PMID- 9542247
TI - [Treatment review in rhinocerebral mucormycosis].
AB - The rhinocerebral mucormycosis is the more common form produced by Rhizopus, a
genus of fungi. It's a serious infective disease with high mortality, that needs
a precocious medical treatment. Amphotericin B is the choice medical treatment,
but liposomal amphotericine B in recent years is a better drug, due to minor
renal toxicity and greater tisular diffusion. Even can not to treat all affected
areas it's necessary an extensive surgical treatment according to individual
characteristics and disease evolution. A 56-year-old man with rhinocerebral
mucormycosis, caused by Rhizopus, who was treated with liposomal-amphotericin B
and extensive rhino-orbital surgery is presented.
PMID- 9542248
TI - Encephalocele with spontaneous CSF otorrhea.
AB - Spontaneous encephalocele of the temporal bone is an uncommon condition (37 cases
to date) associated with cerebrospinal fluid otorrhea. It results from a
congenital dehiscence of the tegmen tympani and tegmen mastoideum. The AA. report
3 additional cases and review methods for diagnosing and surgical treatment.
PMID- 9542249
TI - [Cartilaginous tumors of the larynx. A report of 3 cases].
AB - Cartilaginous tumours of the larynx are very seldom encountered. Worldwide
literature report until now no more than 250 cases. The greatest number of cases
(72%) are benign and localized on cricoid cartilage. They are characterized by
its slow pace spread and chondrosarcomata shows scant tendency to metastasize,
prevailing, instead, local increase. Best treatment resulted the conservative
surgery. We report 3 cases (1 chondroma and 2 low ranked chondrosarcomata)
diagnosed and treated in our Hospital in the last 15 years. Clinical and
anatomopathologic features are exposed and the management as well, and also the
postoperative course of each patient.
PMID- 9542250
TI - [Tympanic chemodectoma. A report of 2 cases].
AB - Report of 2 chemodectoma cases diagnosed in the ENT-Department (Prof. Labella) at
C.H.U.S. The condition could be suspected because a tinnitus aurium and the
transtympanic reddish image by otoscopy. And diagnosis settled through imaging
techniques (computed tomography, magnetic resonance and selective angiography).
Surgical treatment.
PMID- 9542251
TI - [Lectin-mediated histochemical study of submucous glands of the normal nasal
mucosa].
AB - We have performed an histochemical study with lectins of the normal nasal mucosa
of 6 patients. These patients were admitted at the Hospital for abdominal
surgery. A wide biopsy was taken of the inferior nasal turbinate mucosa. The
results show a different reactivity between the serous and mucous cells of the
submucosal glands and with the goblet cells. We have not found reactivity to DBA,
SBA and LTA lectins.
PMID- 9542252
TI - Diabetes in pregnancy: state of the art in the Mediterranean countries, Portugal.
AB - In Portugal since 1980 the health care for diabetes in pregnancy has begun to be
specialised and centralised, and the care is provided by multidisciplinary teams.
At present there are eight diabetic teams in the main cities in the North, Centre
and South of the country: three in Oporto, two in Coimbra, two in Lisbon and one
in Almada. In our Center of the University Hospital, Coimbra, from 1980 to 1992
neonatal mortality dropped from 110/1000 to near 0/1000, macrosomia from 55% to
20%, neonatal hypoglycemia from 28% to 5.6%, RDS from 26% to 2.5%, congenital
malformation from 9% to 2%. A "consensus on diabetes and pregnancy" to implement
and give uniformity to health care was recently done (1996): a) criteria for
pregnancy planning and management for pregestional diabetes (type 1 and 2) have
been given; b) protocol of screening, diagnosis and management for gestational
diabetes have been suggested; c) finally a recent (1995) epidemiologic report of
a multicentric Portuguese survey has been reported.
PMID- 9542253
TI - Congenital malformations in infants of 517 pregestational diabetic mothers.
AB - To determine whether the maternal metabolic control and/or the use of
hypoglycemic drugs during early gestation is associated with a risk of congenital
malformations, beginning on January 1989 to December 1994, clinical data from 16
Italian centers were collected retrospectively and entered in a computerized data
base: 517 pregnant women with pregestational diabetes mellitus, 362 with insulin
dependent diabetes mellitus (IDDM) (mean age 28.13 +/- 4.8 years), 130 with non
insulin-dependent diabetes mellitus (NIDDM) (mean age 33.01 +/- 5.32 years) and
25 with impaired glucose tolerance (IGT) (mean age 32.48 +/- 6.2 years). The
percentage of congenital malformations in NIDDM that took oral hypoglycemic drugs
was 11.6% respect to 1.4% of NIDDM that did not take hypoglycemic drugs (p <
0.01) and 3.7% of IDDM. Fasting blood glucose, glycosylated hemoglobin and urine
keton bodies were more elevated in IDDM respect to NIDDM (p < 0.005). The
percentage of malformations in offspring of NIDDM mothers is higher with respect
to that of IDDM women, in spite of a better metabolic control.
PMID- 9542254
TI - Diabetic pregnancy in over 35 years old women.
AB - 87 pregnancies in diabetic women older than 35 years at time of conception were
studied. 3% were insulin-dependent diabetes mellitus (IDDM), 52% non insulin
dependent diabetes mellitus (NIDDM) and 45% gestational diabetes mellitus (GDM).
Mean age was 38 +/- 3 years; BMI was 33.2 +/- 7.0 kg/m2; gestation rate was 5 +/-
3 and number of alive children was 2 +/- 2. Only 3% of pregnancies were planned.
Mean time of reference to diabetic care unit was 17 +/- 10 weeks. 95% of the
women required human insulin. Mean total daily insulin dose was 0.49 +/- 0.28
UI/kg/d, increasing with gestational age. Mean fasting glycemia was 6.85 +/- 1.93
mmol/l and mean post-prandial glycemia was 8.29 +/- 2.52 mmol/l. Mean time of
delivery was 38 +/- 2.1 weeks (less than 37 weeks in 9%). Cesarean section was
performed in 44% of 34 cases. Death in utero occurred in 11% of 54 cases,
postnatal death in 4%, congenital malformations in 4%, macrosomia in 40%. 9% of
infants received intensive neonatal care. No difference was found between NIDDM
and GDM about outcome of pregnancy. These results underlined importance of early
screening for GDM as most cases seem to be undiagnosed pregravid diabetes
mellitus (DM).
PMID- 9542255
TI - Diabetes in pregnancy.
AB - Despite the dramatic decline in maternal and perinatal morbidity and mortality
over the past few decades, controversy still exists regarding the care of
pregnant women with both pregestational and gestational diabetes mellitus.
Carbohydrate intolerance is the most common metabolic complication of pregnancy.
A review of the literature over the last two decades indicates that the incidence
of gestational diabetes mellitus (GDM) varies from 0.15-12.3%. Between 0.2 and
0.3% of pregnancies occur in women with insulin dependent diabetes mellitus
(IDDM). When not diagnosed and treated properly, diabetes in pregnancy is
associated with adverse maternal and fetal outcome; such as high perinatal
wastage, congenital anomalies, macrosomia, and neonatal, childhood and adult
complications. The main problems regarding maternal-fetal outcome in pregnancy
complicated by diabetes can be divided into three main categories: the
pathophysiology of the metabolic state in pregnancy and its implications on the
mother and the conceptus. This presentation dealing with feto-maternal outcome of
these high risk pregnancies will discuss accelerated fetal growth, congenital
anomalies, future obesity and diabetes in babies born to GDM and pre-GDM mothers
and future maternal diabetes in GDM and vascular complications in pre-GDM. Our
organized team approach combined with intensive monitoring and therapy throughout
pregnancy which has achieved successful results in women with complicated
diabetes will be presented.
PMID- 9542256
TI - Reclassification after delivery of diabetes in pregnancy.
AB - Gestational diabetes mellitus (GDM) constitutes a risk factor for the development
of non insulin-dependent diabetes mellitus (NIDDM). The search for parameters to
provide discrimination between a high risk and a low risk for future development
of NIDDM is today the aim of many investigations. The absence or presence of
several factors such as glycemia during pregnancy and post partum, the need for
insulin treatment, disorders of the pancreatic insulin secretion, the number of
pregnancies, maternal obesity, the early diagnosis of GDM, the family history of
diabetes mellitus, the race and immune disorders give rise to a very high
relative risk (RR) of developing NIDDM. To know the degree of risk will allow a
future appropriate clinical intervention to reduce the incidence of NIDDM and its
economic cost.
PMID- 9542257
TI - Delivery in diabetic pregnancy.
AB - Two hundred and twenty deliveries of diabetic pregnant women, occurring from 1990
1994 were studied: 186 gestational (GDM) and 34 pregestational diabetes (PGDM).
Women who delivered during the year of 1994 were considered as control population
(3615 births). Mode of delivery, planned delivery, delivery's gestational age,
shoulder dystocia, macrosomia and large for gestational age (LGA) were
investigated. Cesarean section and planned delivery were respectively 39% vs
20.5% and 51.6% vs 16% respectively in diabetic vs control women. Deliveries
after 40 weeks were 29% in GDM, 3% in PGDM and 50% in control women. Macrosomia
occurred in 17.7% of diabetic against the 8% of controls. Finally shoulder
dystocia occurred in the 3.6% of diabetic women against the 0.3% of the control
group. These data indicate that in our diabetic population there is a high rate
of cesarean sections and planned deliveries, as well as macrosomia, LGA and
shoulder dystocia. Obstetric decision to allow the delivery to term or near term
was not enough to bring the rate of macrosomia and LGA close to the normal, which
can be consequence of the diabetic control in pregnancy, in spite of intensive
care intervention.
PMID- 9542258
TI - Does preconceptional counselling in diabetic women influence perinatal outcome?
AB - We aimed to assess the impact of a preconceptional clinic (PC) on the perinatal
outcome (PO) of diabetic pregnancies attended in our centre. We studied 185
pregnancies attended in the 1986-1996 period (152 in women with insulin dependent
diabetes mellitus (IDDM) and 33 with non insulin-dependent diabetes mellitus
(NIDDM)) and we analysed the perinatal outcome for both mother and fetus. Sixty
six women (36.1%) had enrolled in the PC, 41.4% for IDDM and 9.1% for NIDDM
pregnancies, p < 0.01. First pregnancy HbA1c (in SD around the mean) was 3.98 +/-
3.00 in non-attenders (NA) vs 2.57 +/- 2.41 in attenders (A), p < 0.01. The final
HbA1c was in the normal range in both groups. D-R class according to White
classification was 33.0% for NA vs 54.5% for A, p < 0.01. There were no
differences in the rates of abortion and major malformations (8.8% NA vs 3.6% A,
ns). Both groups differed in the rate of cesarean sections (54.9% NA vs 71.0% A,
p < 0.05) and in the rate of small for gestational age infants (SGA) (8.7% NA vs
1.8% A, p < 0.05). There were no differences between groups in maternal or
neonatal outcomes. In this group of diabetic women with a moderate although less
than optimal metabolic control at the beginning of pregnancy, the impact of PC on
PO is less evident than described.
PMID- 9542259
TI - Blood pressure monitoring in diabetic pregnancy.
AB - Hypertensive disorders which complicate 5-10% of all pregnancies are more
frequent in diabetic women. We longitudinally monitored blood pressure (BP) for a
24 h period in 54 diabetic out patients, at each trimester of pregnancy, in order
to observe the relationship between the blood pressure behaviour and the main
clinical features of these subjects. A relationship was found between blood
pressure and the diabetes type. In insulin-dependent diabetes mellitus (IDDM)
women, the age of diagnosis and the diabetes duration played the major role
whereas, in non insulin-dependent diabetes mellitus (NIDDM) women only the
patients' age was correlated with the BP levels. Higher BP levels were found in
women belonging to the White class D, and whose diabetes duration was more than
10 years. An interesting correlation was also demonstrated between BP and insulin
requirement, in late pregnancy as well as the time of delivery. Early in
pregnancy, BP levels, even if within normal range, were undoubtedly higher in
those women who developed hypertension compared to those who continued to be
normotensive. Daytime BP values were always found higher than night-time BP
values but, the physiological biorhythm seemed to be altered at the end of
pregnancy.
PMID- 9542260
TI - Diabetes and pregnancy: prophylaxis of genital infections.
AB - Diabetic pregnant women have many potential reasons to have genital infections
such as poor metabolic control and impairement of leucocyte function. Relative
immune deficiency exists in pregnancy. This study was designed to test the
hypotheses that pregnant patients with insulin-dependent diabetes have a higher
rate of ante partum genital infections when compared with a pair-matched control
population. Two groups of pregnant women consisting of 23 patients with and 23
without diabetes mellitus, underwent colposcopy and cytology between 16th and
24th week of gestation to detect the presence of human papilloma virus (HPV),
Gardnerella vaginalis, Candida albicans and aspecific infections. No significant
differences were observed between the two groups.
PMID- 9542261
TI - Telemedicine in the treatment of diabetic pregnancy.
AB - Good diabetic control requires that treatment be continuously adapted to the
patient behavior. We investigated whether the use of telemedicine could present
an advantage to the management of the diabetic woman during pregnancy. A system
completely automatic (DIANET system) was used. Twenty IDDM women participated in
the study: 10 treated by telemedicine and 10 by conventional system, at times
"entry" (9.5 weeks), "basal" (9.5-16.8 weeks), "1st month" of investigation, and
"end" (near delivery). All women used intensified protocols of insulin
administration. The treatment with DIANET vs conventional showed a better
metabolic control as estimated by profile of blood glucose absolute values (at
time "end": values significantly lower before breakfast: 87 +/- 6 vs 104 +/- 4
mg, lunch: 85 +/- 5 vs 104 +/- 4 mg, and after dinner: 102 +/- 5 vs 124 +/- 6
mg). These results were associated with higher insulin doses in the DIANET vs
conventional treatment, and a significant reduction of hypoglycemic reaction in
both group. Our results suggest that telemedicine-DIANET is a practical way of
providing specialist care in the pregnancy area.
PMID- 9542262
TI - Pathophysiology of diabetes in pregnancy.
AB - Pregnancy is attended by extensive hormonal readjustments on the part of the
mother. Almost every endocrine tissue participates in adaptive changes that
maintain the metabolic state of the woman during normal pregnancy. Endocrinologic
and metabolic adaptations characterizing pregnancy in women with normal
carbohydrate metabolism also impinge upon the metabolism of the diabetic during
pregnancy. In the diabetic woman the impairment of metabolism which follows the
modifications of endocrinologic adaptations induces a compromised metabolic
"milieu" in both the foetal blood and amniotic fluid in which swallows the fetus,
promoting several damages according to the gestational age in the conceptus.
Disturbances of intermediary metabolism undoubtedly play a major role in the
etiology of complications of diabetic pregnancy. However an increasing amount of
evidence is accumulating that suggests that abnormalities of immune function may
also be operative in both the mother and fetus as well as in placenta. Finally
there is limited information on the long-term prognosis of infants born to
mothers with pre-gestational and gestational diabetes mellitus. Follow-up studies
have mainly focused on two aspects: the risk of appearance of diabetes later in
life, and psychosomatic development. Genetic aspects and the role of metabolic
disorders during pregnancy must be once again emphasized.
PMID- 9542263
TI - Glucose transporters (GLUT 1, GLUT 3) mRNA in human placenta of diabetic and non
diabetic pregnancies.
AB - Glucose transporters (GLUT) catalyse the transport of glucose in many human
tissues, including the placenta. On the other hand glucose concentrations can
affect both glucose transport activity and level of GLUT mRNA and protein. Up to
now very few studies, concerning GLUT in the placenta appeared and studies in
vivo in human diabetic pregnancy are lacking. Therefore we investigated placental
GLUT 1 and GLUT 3 mRNA in 10 diabetic (5 IDDM, 2 NIDDM, 3 GDM) and 9 non-diabetic
women. GLUT 1 mRNA was found significantly correlated with maternal age (> 30 vs
< 30 years: p < 0.025), with placental weight (> 575 vs < 575 g: p < 0.05), while
GLUT 3 mRNA decreased significantly in late gestation of diabetic women (38-40 vs
< 38 weeks: p < 0.025). In addition GLUT 3 was significantly lower in the
diabetic than in non-diabetic women in late gestation. These preliminary results
deserve to better elucidate feto-maternal carbohydrate metabolism at the
placental level in normal as well as diabetic pregnancy.
PMID- 9542264
TI - Na(+)-H+ exchange activity throughout pregnancy: the proper experimental
approach.
AB - Pregnancy is associated with a 30-50% rise in cardiac output and a close to 50%
increase in blood volume. The Na(+)-H+ exchanger is a key mediator of tubular
NaCl absorption and a stimulus-response coupling mediator. We measured
erythrocyte Na(+)-H+ exchange activity over the course of normal pregnancy in 18
healthy pregnant women (mean age 32 +/- 4 years) at 14, 24 and 33 weeks of
gestation and 15 nonpregnant healthy women (mean age 32 +/- 9 years). No
pregnancy was complicated by hypertension. Serum urea, creatinine and sodium did
not change through gestation, while serum potassium slightly but significantly
decreased. Urinary excretion rates of both sodium and potassium remained
unchanged. Urea and creatinine clearances were constantly elevated in pregnant vs
non-pregnant control women. Erythrocyte Na(+)-H+ exchanger reached the highest
activity at about the 14th week of gestation, when cardiac output also peaked.
Thereafter, it tended to decrease, yet remaining above the normal values until
the 34th week. Conceivably, the observed hyperactivity of the transporter may be
a contributing factor to the hemodynamic adjustments attending to normal
pregnancy.
PMID- 9542265
TI - Levels of advanced glycosylation end-products (AGE) in sera of pregnant diabetic
women: comparison between type 1, type 2 and gestational diabetes mellitus.
AB - The chronic hyperglycemia can lead to an increase of the advanced glycosylation
end-products (AGE) levels on proteins and macromolecules. Abnormal levels of AGE
in several tissues has been associated with the pathogenesis of late diabetic
complications. In diabetic pregnant women, high AGE levels might influence the
delicate maternal-fetal balance and therefore alter the pregnancy outcome. In
this preliminary study, we have measured the AGE in sera of 44 diabetic women in
two trimester. Sixteen sera from non diabetic pregnant women have been used as
controls. The AGE have been analyzed by means of an ELISA method with an
antiserum anti-RNAse-AGE, produced in the Laboratory of Clinical Biochemistry of
the Istituto Superiore di Sanita. Diabetic patients type 1 and type 2, in good
metabolic control, showed normal AGE levels at both trimester. Patients with
gestational diabetes showed significantly high serum AGE levels (p < 0.05). A
more extended study will give better insight on the association between AGE
levels and a physiopathology of diabetic pregnancy.
PMID- 9542266
TI - IGF-1 levels in diabetic pregnant women and their infants.
AB - Plasma IGF-1 was measured in 38 diabetic pregnant women (DPW) and in 12 non
diabetic pregnant women (NDPW) during the 1st, 2nd and 3rd trimester of
pregnancy. IGF-1 was measured in the cord blood of 24 infants of diabetic mothers
(IDDM) and IGF-1 in 11 infants of non diabetic mothers (NIDDM). A progressive and
significant (p < 0.0001) increase of IGF-1 values was found throughout the
pregnancy both in DPW and NDPW IGF-1 (149 +/- 18 ng/ml vs 181 +/- 14 ng/ml, 184
+/- 17 ng/ml vs 232 +/- 25 ng/ml, 279 +/- 20 ng/ml vs 325 +/- 17 ng/ml).
Furthermore IGF-1 decreased significantly soon after delivery in both groups of
women. In type 1 diabetic pregnant women IGF-1 values were significantly lower
than the controlled non diabetic patients. IGF-1 in the cord blood was
significantly higher in IDDM than in NIDDM 86 +/- 7 ng/ml and 62 +/- 7 ng/ml
respectively (p < 0.03). In addition, DPW plasma levels IGF-1 were positively
correlated with the weight of the placenta (r = 0.233, p < 0.03) and negatively
correlated with the diabetes duration (r = 0.412, p < 0.05). No correlations were
found between IGF-1 cord blood concentrations and gestational age, birth weight
and length, but there was a significant correlation with weight percentile (r =
0.846, p < 0.001). No correlation was found between maternal IGF-1 plasma levels
and other parameters like insulin need, weight gain, metabolic control and time
of delivery.
PMID- 9542267
TI - A protocol of screening of gestational diabetes mellitus.
AB - We evaluated GDM frequency in the Padua area. 490 non-diabetic pregnant women
were divided into group A (234), with at least one GDM risk factor, and group B
(256), with no risk factors. Group A underwent this screening program with oral
glucose challenge test (OGCT) and OGTT when OGCT was positive at 10-14th
gestational week (gw), at 24-28th gw and at 30-34th gw. Group B underwent the
same screening starting at 24-28th gw. 46.9% of the pregnant women had positive
OGCT with higher frequency in group A (group A vs group B p < 0.01). GDM
prevalence in all women was 10.8% with higher frequency in group A women (group A
vs group B p < 0.01). The anticipation of the screening at the first trimester of
pregnancy in group A women allowed early diagnosis of 11.6% of GDM. Regarding
maternal and fetal outcome the only significative differences between GDM and non
GDM were prevalence of macrosomia and of cesarean sections.
PMID- 9542268
TI - Screening of gestational diabetes in Tuscany: results in 2000 cases.
AB - According to the guidelines of the "Third international workshop conference on
GDM", we have examined 2000 pregnant women. The glucose challenge test (GCT) was
positive in 408 cases (20.4%) and negative in 1592 (79.6%). The OGTT (Carpenter
and Coustan's criteria) was performed in 647 pregnant women. GDM and IGGT
prevalence was of 6.25% and 5.5% respectively and normal glucose tolerance (NGT)
88.25%. The GCT effectiveness for GDM and IGGT diagnosis is: sensibility 75.1%,
specificity 44%, positive predictive value 46.4% and negative predictive value
74%. GDM and IGGT compared with NGT women were significantly older (p < 0.05) and
prepregnancy BMI was higher (p < 0.01); the prevalence of previous macrosomia (p
< 0.01), previous gestational diabetes (p < 0.01) and family history for diabetes
mellitus (p < 0.05) was greater in GDM and IGCT. The prevalence of preterm
delivery was higher in both GDM and IGCT (GDM 12.5% and IGGT 15.4% vs NGT 6%; p <
0.01), as well as the prevalence of cesarean sections (GDM 31.6% vs IGGT 23.5%
and NGT 20.3%; p < 0.02), and the occurrence of macrosomia (GDM 27.6%, IGGT 16.6%
and NGT 16.2%). In addition a higher prevalence (p < 0.01) of
hyperbilirubinaemia, hypoglycemia and hypertrophy cardiomyopathy was observed in
newborns from GDM women. Our data show that: GCT has a good specificity for GDM
diagnosis, prevalence of GDM in our population is about 6%, GDM is still
correlated to an elevated maternal and neonatal morbility.
PMID- 9542269
TI - Should we treat minor degrees of glucose intolerance in pregnancy?
AB - We examined the pregnancy outcome of 112 women classified as minor degrees of
glucose intolerance (MDGI) in pregnancy in a screening program based on Carpenter
and Coustan's criteria. The MDGI group comprised 49 women with abnormal oral
glucose challenge test (OGCT) followed by normal OGTT (group A), and 63 with
"borderline" OGTT (1 abnormal value, group B). No treatment was offered to 88
MDGI women, while 26 received dietary advice and metabolic monitoring. A control
group was constituted from 112 age- and BMI-matched negative screenees. Similar
rates of cesarean sections and macrosomia, but higher rate of large for
gestational age (LGA) babies (25.9% vs 14.3%) were found in MDGI, without
difference between groups A and B. When comparing treated and untreated MDGI,
lower LGA incidence (11.5% vs 30.2%) and no macrosomia were found in the former.
In conclusion, untreated MDGI may present excessive fetal growth, which can be
normalized by dietary treatment and metabolic monitoring.
PMID- 9542270
TI - Gestational diabetes mellitus (GDM) and macrosomia: a controversial story.
AB - Increased perinatal morbidity-mortality are associated with gestational diabetes
mellitus (GDM). We studied 69 non-diabetic pregnancies (age 30 +/- 5 years) by
repeating oral glucose tolerance test (OGTT, 100 g; area under glycemic, AUGC as
g min/dl, and insulinemic, AUIC as mU min/ml, curves were calculated) and HbA1c
measurement at 14, 24 and 33 weeks. In the 3rd trimester, 7 women had abnormal
OGTT, but none of the 12 mothers of large babies (> 3.9 kg) had GDM. Among 15
pregnants with basal body mass index (BMI) > 25 kg/m2, 2 developed GDM, 5 had
babies > 3.9 kg, 8 had normal birthweight babies. Those pregnants who showed
after-load hyperglycemia despite normal insulin secretory response (insulin
resistance) developed GDM, but delivered normal birthweight babies. Large
neonates were delivered from women with the greatest both gestational weight gain
and insulin sensitivity, but normal glucose tolerance. The heaviest pregnants
with normal both glucose tolerance and insulin sensitivity had normal weight gain
and normal birthweight infants. Neonatal body weight was correlated with maternal
gestational weight gain, placental weight, 3rd trimester AUIC/AUGC ratio and 1st
2nd trimester HbA1c.
PMID- 9542271
TI - Predictive factors for insulin treatment in women with diagnosis of gestational
diabetes.
AB - To evaluate if at diagnosis some factors are predictive of the insulin treatment,
75 pregnant women with gestational diabetes mellitus (GDM) and 75 with normal
glucose tolerance were examined. The GDM group underwent a diet containing 25
kcal/kg/24 h and insulin was started when fasting and 2 h after meals glucose
levels were respectively > 95 and > 125 mg/dl. 52 patients were treated with diet
(GDd) and 23 with diet and insulin (GDi). Diagnosis week, prepregnancy body mass
index (BMI), weight gain, glucose levels during oral glucose tolerance test
(OGTT) (0', 60', 120' and 180'), area under curve (AUC), triglyceride levels and
infant weight at delivery were evaluated. Triglyceride levels were higher in GDi
respect to NGT group (232.2 +/- 110.7 mg/dl vs 147.4 +/- 70 mg/dl; p < 0.001).
Diagnosis was earlier and 180' glucose levels, AUC and BMI were higher in GDi
than GDd group. In conclusion, triglyceride and 180' glucose levels, AUC,
pregestational BMI and diagnosis week are predictive factors for insulin
treatment in gestational diabetes.
PMID- 9542272
TI - Gestational diabetes: clinical characteristics and birth weight.
AB - This retrospective study investigates the clinical characteristics of gestational
diabetes mellitus (GDM) (time of diagnosis, different treatment, metabolic
parameters, etc.) in relation to prepregnancy body mass index (BMI) and the
influence of BMI on neonatal outcome. 93 GDM women and 110 control subjects were
divided into three groups in relation to their prepregnancy BMI: normalweight
(Nw), overweight (Ow) and obese (Ob). GDM was diagnosed significantly (p < 0.01)
earlier in Ow and Ob than in Nw. Preterm deliveries and cesarean sections
resulted significantly (p < 0.01) increased in all BMI categories of GDM respect
to matched controls. Prevalence of neonatal macrosomia was higher in GDM patients
(44.6%) compared with normal controls (15.4%) and correlated (p < 0.01) with
prepregnancy BMI in both groups. Nevertheless in each BMI category the prevalence
of macrosomia was significantly higher in GDM patients. The body weight increase
during pregnancy was not associated with neonatal macrosomia. This study shows
that prepregnancy BMI is an important risk factor for GDM and is predictive for
macrosomia specially in women suffering from GDM.
PMID- 9542273
TI - Lipid metabolism alterations in patients with gestational diabetes mellitus
associated fetal macrosomia.
AB - Fetal macrosomia is commonly associated with gestational diabetes mellitus (GDM)
which may lead to various complications. It has been suggested that some other
metabolites apart from maternal hyperglycemia are responsible for the genesis of
macrosomia. Lipid metabolism changes in GDM patients having macrosomic fetuses
were studied. A lipid tolerance test (10% Lipovenous solution) was performed in
14 GDM. Pre- and post-infusion plasma lipid levels and their elimination rates
were measured and compared to the ones of 8 non diabetic control pregnant women.
HbA1c, basal glucose and triglyceride levels were found to be higher in GDM group
and significantly higher levels of triglycerides persisted throughout the
infusion. FFA, glycerol and phospholipid levels increased following infusion in
both groups without significant differences. Glucose, C-peptide and insulin
levels remained unchanged after the infusion. Increased basal triglycerides with
slowed triglyceride metabolism may be responsible for the fetal macrosomia in
mild GDM patients whose fasting blood glucose are below 105 mg/dl. A better
metabolic control that provides plasma lipid regulation as well as glucose
control may forestall the occurrence of fetal macrosomia.
PMID- 9542274
TI - The "Sardinia-IDDM study": an attempt to unravel the cause of insulin-dependent
diabetes mellitus in one of the countries with the highest incidence of the
disease in the world.
AB - Sardinia and Finland have the highest incidence of IDDM in the world. Thus, both
regions represent ideal observatories for investigating the environmental,
genetic and immunological factors, which have led to this dramatic increase. We
have concentrated our efforts in Sardinia. Among several projects, there is the
mapping of the Island for hot and cold spots for overt IDDM. In order to map the
Island for pre-IDDM, we have collected and bled around 10,000 school children
(age 6-14 years) and we are now in the process to enroll around 30,000 newborn.
We report here our initial results, which show that progression to IDDM is
accompanied in both cohorts by the presence of a combination of ICA with either
GAD and IA-2 antibodies or both. This approach should lead to design reliable
models of IDDM prediction in the general population, which will benefit an early
insulin treatment and, hopefully, an effective prevention of the disease.
PMID- 9542275
TI - Autoimmune markers of diabetes in diabetic pregnancy.
AB - Gestational diabetes mellitus (GDM) has been described in 1-3% of pregnancies and
increases the risk (up to 60-70%) to subsequently developing an overt diabetes
(generally of type 2 non insulin-dependent diabetes mellitus (NIDDM)). Several
humoral autoimmune phenomena have been described in GDM: islet cell antibodies
(ICA) have been found and it was shown that ICA+ patients tend to have a worse
glucose tolerance. Recently, autoantibodies against glutamic acid decarboxylase
(GAD), were detected in type 1 diabetic sera before or at the onset of the
disease; these markers, as well as ICA and insulin antibodies, seem to have a
predictive value for the onset of the disease. Aim of our study was to
investigate the presence of GAD65 in 83 GDM, 79 NIDDM and 64 pregnant normal
women in late gestation. GAD Ab positivity was found (0.035 index as limit) only
in GDM and NIDDM (3.6% in GDM, 3.8% in NIDDM, and nothing in control women).
These results indicate that GAD positivity in GDM overlaps that of NIDDM,
suggesting that the two diabetic populations have the same predisposition to
develop a type 1 diabetes mellitus, and likely they share the same disease.
Further studies need to clarify whether this prevalence of GAD positivity may
unmask type 1 diabetes in both GDM and NIDDM diabetic women.
PMID- 9542276
TI - A study on lymphocyte subpopulations in diabetic pregnant women and their
newborn.
AB - We studied the lymphocyte subpopulations in 14 pregnant women with type 1 insulin
dependent diabetes mellitus (IDDM), mean age (+/- SD) 30 +/- 4 years, mean
disease duration 12 +/- 5 years, in 14 with gestational diabetes mellitus (GDM)
(mean age 33 +/- 6 years) and 21 matched healthy pregnant controls (C), when the
subjects delivered, and in their newborn. The GDM and IDDM mothers show a
significant increase (p < 0.05) of lymphocytes in comparison with C (GDM 1.83 +/-
0.5 x 10(9)/l, IDDM 1.6 +/- 0.68 x 10(9)/l, C 1.06 +/- 0.45 x 10(9)/l
lymphocytes), which has repercussion on lymphocyte subpopulations absolute
values. The newborn of GDM mothers have an increase of lymphocytes T-activated
(0.6 +/- 0.3 vs 0.3 +/- 0.2%; p < 0.05) and a reduction of NK lymphocytes than C
(8.9 +/- 9 vs 15.5 +/- 7.6%; p < 0.05). The newborn of IDDM mothers show a
significant reduction of NK lymphocytes than C (10 +/- 6 vs 15.5 +/- 7.6%; p <
0.05). So in newborn of diabetic mothers there is a deficit of natural immunity
at birth which has to be evaluated by follow-up study.
PMID- 9542277
TI - Target antigens in autoimmune diabetes: pancreatic gangliosides.
AB - Type 1 diabetes mellitus is a disease caused by the autoimmune destruction of
insulin-producing pancreatic beta-cells that takes place in genetically
prodisposed individuals. Autoantibodies and autoreactive T lymphocytes reacting
with islet target molecules or protein of glycolipid nature have been shown in
the circulation of individuals and of animal models of type 1 diabetes (NOD mouse
and BB rat) before and at the onset of the disease. As far as autoantigens of
glycolipid nature is concerned, gangliosides such as GT3, GD3 and especially GM
1, have been shown to be target of autoantibodies associated to autoimmune
diabetes. Of particular interest is the islet-specific monosialo-ganglioside GM2
1, which is target of an autoimmune response highly associated to future
progression to diabetes development in first degree relatives of type 1 diabetic
individuals. This molecule is recognized by IgG autoantibodies which have been
detected before the appearance if clinical diabetes both in man and in the NOD
mouse, representing a novel marker of beta-cell autoimmunity.
PMID- 9542278
TI - Autoimmune thyroid disease and insulin-dependent diabetes mellitus during
pregnancy and post partum.
AB - The aim of this study was to assess thyroid dysfunction and autoimmunity in
pregnant insulin-dependent diabetes mellitus (IDDM) women during pregnancy and
early post partum. Fifteen pregnant IDDM women and 77 healthy pregnant women were
studied. Free T4, TSH, TPO-Ab and Tg-Ab were assayed during the first and third
trimester of pregnancy and 3 months post partum. In IDDM women FT4 levels
significantly decreased (p < 0.05) during third trimester and 3 months post
partum and also TPO-Ab during third trimester (p < .01). 26% of IDDM and 4% of
the controls presented post partum thyroid dysfunction. We recommend that
prepregnant IDDM be screened for TPO-Ab. Those with a positive result would be
followed with serial monitoring of free T4 and TSH levels during each trimester
as well as during the post partum period.
PMID- 9542279
TI - Influences of thyroid diseases in diabetic pregnant women.
AB - Thyroid disorders are particularly frequent in women and, second to diabetes
mellitus, are the most common endocrine diseases during pregnancy. An association
between insulin-dependent diabetes mellitus and thyroid autoimmunity has long
been recognized. Management of thyroid diseases in pregnancy is different than in
non pregnant women, due to physiological changes of thyroid hormone economy in
the childbearing period. Thyroid dysfunction may affect carbohydrate metabolism
and worsen glucose control in diabetic patients. On the other hand, poorly
compensated diabetes mellitus may cause alteration in the production and
metabolism of thyroid hormones. Pregnant women with insulin-dependent diabetes
mellitus have an increased risk of developing post partum thyroiditis. These
observations have lead to the recommendation that thyroid function should be
checked in diabetic women during pregnancy and in the post partum.
PMID- 9542280
TI - Thyroid autoimmunity in pregnant women at risk for GDM.
AB - Presence of antithyroid autoantibodies (ThyAb) during pregnancy is strictly
related to the risk of developing post partum thyroiditis (PPT) and this risk is
increased in IDDM pregnant women. Gestational diabetes mellitus (GDM) is defined
as carbohydrate intolerance of variable severity that begins, or is first
diagnosed, during pregnancy. GDM is considered a risk factor for both type 1 and
type 2 diabetes and various non-organ specific autoantibodies have been found to
be associated with GDM, although there is little information on the association
of GDM with thyroid autoimmunity. In this study oral glucose tolerance and
prevalence of ThyAb were evaluated in a group of 41 pregnant women at increased
risk of developing GDM and in a healthy control group. Our results showed that
22% of GDM risk group had impaired glucose gestational tolerance (IGGT) or GDM at
the time of oral glucose tolerance test (OGTT). Moreover, ThyAb prevalence found
in the women at increased risk of GDM (14.6%) was similar to that observed in
healthy pregnant controls (12.5%). Nevertheless ThyAb frequency was higher in
those GDM risk women with family history of diabetes (30.7%).
PMID- 9542281
TI - The 6 volt battery for implantable cardioverter/defibrillators.
AB - The usage of a 6 V lithium manganese dioxide battery results in a significant
reduction of capacitor loading time within implantable
defibrillators/cardioverters. In order to provide ERI indication a new cathode
formulation has been developed. The battery shows no voltage delays, a low self
discharge and fulfilled all requirements to an energy source for an implantable
device.
PMID- 9542282
TI - [Possibilities and limits of automatic detection of pathologic intracranial
pressure waves with FFT].
AB - Owing to the existence of "reserve spaces" varying individually in extent and
expressed by the term compliance, space-consumption intracranial processes do not
raise the intracranial pressure (ICP) primarily. Only when this compliance has
been exhausted may ICP rise dramatically and may rapidly reach dangerously high
levels. It has been shown in the past that "anticipatory" initiation of ICP
reducing measures--i.e. very early in the development of increasing mean ICP--may
greatly benefit patient outcome. To recognize an imminent ICP crisis, the
available compliance needs to be known. The classical method for determining this
latter is the bolus test, which, however, has the disadvantage of being
discontinuous and associated with the risk of infection. Another, less invasive
and continuous, option is the recognition of pathological intracranial pressure
waves. However, recognition of such patterns requires specialized knowledge, that
is not widely available. Since, however, knowledge of the compliance is of
general importance for intensive care, the idea of developing a PC-based
automated system for the identification of pathological waves was followed up.
During the course of our basic research effort, we investigated the suitability
of the fast Fourier transformation (FFT) algorithm for this purpose. We were able
to show that while the FFT is theoretically useful for the detection of
pathological intracranial waves, its shortcomings in terms of its sensitivity to
extraneous signals (noise) (of considerable importance for biological data
handling) and errors in correctly estimating the amplitudes of pathological waves
(of great importance for clinical evaluation) make FFT appear less than optimally
suitable for this purpose.
PMID- 9542283
TI - [Reduction of bacterial contamination during mechanical autotransfusion by uv
irradiation--initial results].
AB - OBJECTIVE: To investigate the effects of UV-radiation of autologous blood on
bacteria and red blood cells when using intraoperative sampling of autologous
blood using a cell separator--an established method for reducing the need for
donor blood during surgery--which is reported to have a bacterial contamination
rate of 5-75%, due mainly to coagulase-negative staphylococci (CNS). METHODS:
Cell-separator blood was diluted to a haematocrit level permitting transmission
of 1% of the UV-radiation used in this study (lambda 254 nm, coat thickness 1
mm). CNS samples were irradiated for 2, 4, 10, 20 and 30 seconds. Free
haemoglobin and methaemoglobin levels were measured, and erythrocytes examined
microscopically at the end of the procedure. RESULTS: Blood samples had to be
diluted to a haematocrit of 1% to permit transmission of 1% of the UV light. The
optimal irradiation duration was 4 seconds, when bacteria were completely
eliminated. Longer irradiation durations were associated with increasing levels
of free haemoglobin and methaemoglobin, the levels of which at 4 seconds exposure
were 12.5 mg/L and 15.5%, respectively. CONCLUSIONS: It is possible to prevent
CNS contamination of cell-separator blood by irradiation with UV light. Prior to
clinical application, however, the method will need to be modified to minimize
side effects and increase its decontamination efficacy.
PMID- 9542284
TI - [ISO 9001 conformity in research, teaching and rehabilitation].
AB - Quality assurance, in particular in the areas of development and production of
medical devices, is one of the tasks of biomedical engineering. The
interdisciplinary working group "Functional Rehabilitation and Group Education,
Vienna" is committed to the development and implementation of group education
models on three levels: (1) direct education/instruction of patients with chronic
diseases, (2) university research and teaching, and (3) development of technical
aids for rehabilitation and the means for disseminating group education models in
rehabilitation and therapy. Major aims were, by generating conformity with ISO
9001 standards, to achieve greater transparency and process optimization with
very small resources in university (teaching, research, technical aids) and extra
university (rehabilitation) areas. A secondary aim was the establishment of
interdisciplinary (clinical and biomedical) cooperation at university level. In
all main areas (research, teaching and group education/instruction), ISO 9001
conformity was achieved by our activities on three methodological levels: (1)
description and analysis of processes, (2) use of ISO 9001 standards for
evaluating internal processes, and (3) optimization measures. The following
article contains relevant elements of the quality manual and quality assurance
system, and offers a typical example of innovative cooperation between medicine
and medical engineering.
PMID- 9542285
TI - [Effect of prosthesis shaft coating on postoperative load bearing of the femur].
AB - Stems and cups for total hip replacement (THR) must be coated with hydroxyapatite
(HA), which enhances the osseo-integration of the implant. The aim of the present
report was to investigate the basic influence of coating on the biomechanical
situation, for example, the mechanical stress in the femur and at the femur
implant interface. Using the finite element method, three types of stems for THR
were investigated: non-coated, completely HA-coated, and proximally HA-coated.
All three stems were of the same design, and had identical material properties.
In addition, all other conditions were identical. The results show that, in terms
of the nature of the coating, the HA-coated stem is biomechanical superior to the
non-coated stem, and the proximally coated stem is superior to the completely
coated stem.
PMID- 9542286
TI - HIV-associated autoimmune hemolytic anemia complicated by pulmonary embolism
following a red blood cell transfusion: case report and review of the literature.
AB - BACKGROUND: Though positive direct antiglobulin tests are common in AIDS
patients, overt hemolysis is rare. A hypercoagulable state has recently been
recognized in these patients and may contribute to the thromboembotic
complications previously reported in three patients with HIV-associated
autoimmune hemolytic anemia. CASE REPORT: An AIDS patient with severe warm
autoimmune hemolytic anemia developed a pulmonary embolus after a single red
blood cell transfusion. CONCLUSION: There may be an increased risk of
thromboembolism in AIDS patients with autoimmune hemolytic anemia who receive red
blood cell transfusions, a concern we have previously raised. Prophylactic
anticoagulation should be considered in this setting.
PMID- 9542287
TI - Noxious fumes in a medical center: chemical and psychological aspects.
AB - A group of operating room personnel at a medical center in Connecticut reported
severe respiratory irritation manifested by either proxysmal cough or throat
irritation suggestive of a noxious fume exposure, 13 April 1994. However,
persistent complaints on 14 April 1994 were significantly different and more
suggestive of a psychological reaction. By careful interviewing, physical
examination, toxicological assays, and epidemiological investigation, the true
nature of a mixed physiological and psychological episode was delineated.
Enlightened management policy enabled rapid restoration of return to work with
minimal economic loss.
PMID- 9542288
TI - Clinical evaluation of hand-arm-vibration syndrome in shipyard workers:
sensitivity and specificity as compared to Stockholm classification and
vibrometry testing.
AB - The hand-arm-vibration syndrome (HAVS) is a complex entity composed of
circulatory, sensory, and motor disturbances, as well as associated
musculoskeletal components. This study was performed to find a diagnostic testing
modality with sufficient sensitivity, specificity, and predictive value to be
utilized as a screening test for this disorder in a working population. A full
range of testing modalities was utilized in the shipyard medical department. In
addition, a clinical diagnosis of vascular and sensorineural disease was
established in the workers by a combination of plethysmography, vibrometry, two
point discrimination, and monofilament testing in an independent occupational
medicine clinic. No one test modality met the requirements for such a definitive
diagnostic test. Rather, a range of modalities was required to reach any
acceptable level of predictive value, with sufficient degrees of specificity and
sensitivity.
PMID- 9542289
TI - Remifentanil (Ultiva).
PMID- 9542290
TI - A community hospital's ambulatory addiction medicine program.
PMID- 9542291
TI - Why not to invest in a publicly traded managed care company.
PMID- 9542292
TI - "Slow down, you move too fast".
PMID- 9542293
TI - The corporatization of the United States health-care system.
PMID- 9542295
TI - In response to Physician assisted living (PAL)
PMID- 9542294
TI - Should the city medical societies take an active part?
PMID- 9542296
TI - In response to the physicians assisted living: the PAL partner initiative
article.
PMID- 9542297
TI - In response to Dr. Maria Lenaz's letter to the editor, "Ethics in managed care".
PMID- 9542298
TI - In response to Dr. Maria Lenaz's letter to the editor, "Ethics in managed care".
PMID- 9542299
TI - In response to Dr. Maria Lenaz's letter to the editor, "Ethics in managed care".
PMID- 9542300
TI - In response to Dr. Richard Evans's Update on childhood asthma.
PMID- 9542301
TI - [The usefulness of intrinsic risk factors of infection of the surgical site as
predictors of other infections and death].
AB - BACKGROUND: The use of two indices of patient intrinsic risk of surgical site
infection, the SENIC index and the NNIS index, have been recommended to adjust
for the case-mix and improve the comparability of infection rates across
different hospitals. We assess the usefulness of the indices in predicting other
infection sites and in-hospital death. METHODS: A prospective study on 1,483
patients admitted to a service of general surgery was performed. The outcomes
were nosocomial infection and in-hospital death. Relative risk and its 95%
confidence interval were estimated. Unconditional logistic regression analysis
was used to adjust for potential confounders. RESULTS: In the follow-up, 155
surgical site infections (10.5%), 19 postoperative pneumonias (1.3%), 33 urinary
tract infections (2.2%) and 33 in-hospital deaths (2.2%). Both the NNIS index and
the SENIC index showed a clear trend with infection risk and death; the higher
the index, the higher the risk. After controlling for several confounders, the
association was still observed. To assess whether the SENIC index added
predictive power to the NNIS index (and vice versa) a linear regression analysis
of the SENIC index on the NNIS index. A set of residuals (difference between the
observed and expected values according to the regression equation) were
estimated. In the logistic regression models, residuals of the NNIS index (part
of the NNIS index unrelated to the SENIC index, whereas the residuals of the
SENIC index did not increase the predictive power of the NNIS index. CONCLUSIONS:
Both the SENIC index and the NNIS index are independent predictors of several
sites of nosocomial infection and in-hospital death. The NNIS is a better
predictor than the SENIC index.
PMID- 9542302
TI - [Genetic typing by PCR of isolates of C. albicans obtained in a resuscitation
unit].
AB - BACKGROUND: Typing by PCR (random polymorphic amplification or arbitrarily primed
PCR) consists in a random amplification with the use of initiators of unknown
homology with respect to the mold sequence. This study is of interest given the
development of the technology of the amplification of nucleic acids and its
application in the epidemiologic characterization of isolates of C. albicans.
METHODS: Fourteen strains isolates in blood cultures of 8 patients were studied.
All were identified as C. albicans. For amplification the sequence of AP3 and
ERIC2 were selected. RESULTS: With one strain a band pattern very different from
that obtained with the remaining isolates identified as C. albicans was achieved
leading to reidentification and proving that it was C. parapsilopsis. On
combining the results obtained with the use of both initiators 7 different
genotypes were obtained with the remaining strains: A1, 2B, 3C, 4C, 5D, 6B and
7E. CONCLUSIONS: The discriminative power of the two initiators was similar
although the AP3 was greater obtaining one more genotype than ERIC2. The patients
with repeated yeast isolates over time which may be considered as the same
episode of bacteremia, each presented the same band pattern and each was infected
by one single clone. We herewith confirm the usefulness of typing by PCR with one
initiator by reaction. The results may be improved with the combination of the
profiles obtained with the use of several sequences if greater discrimination is
required. Likewise, its use has shown to be satisfactory in both the
identification of clones within one species and the identification of species
within the genus.
PMID- 9542303
TI - [Meningitis by enterovirus in pediatrics. Clinical characteristics and virologic
diagnosis].
AB - BACKGROUND AND METHODS: With the aim of knowing the etiology of aseptic
meningitis (pleocytosis in LCR with negative bacterial culture and positive or
negative virus culture or without pleocytosis with viral culture in positive
LCR), 48 children attending the Emergency Department of our hospital from June to
December, 1995 were prospectively studied. Pharyngeal and rectal swab, LCR for
bacteria and virus and blood cultures were carried out. The samples were
inoculated in fibroblasts MRC-5, RD and BGM. The cytopathic effect was identified
by immunofluorescence. Typing was performed in the National Center of Public
Health Care Microbiology, Virology and Immunology in Majadahonda (Spain).
RESULTS: Isolation of the virus was positive in 40/48 (83.3%) of the children: in
17 (35.5%) of LCR and the remaining 23/40 (47.9%) of pharyngeal and/or rectal
swab. In all the cases the cytopathic effect was detected in MRC-5. The viruses
found were echovirus 30 and 5. A greater incidence of the disease was observed in
November and December. CONCLUSIONS: Meningitis by enterovirus is frequent in our
area. Culture of the virus in LCR, the pharynx and stools is useful on suspicion
of aseptic meningitis since the virus may be isolated from LCR in more than one
third of the patients. Serotyping aids in surveilling the appearance of outbreaks
and to know the predominant viruses. Cell culture is the diagnostic treatment of
choice, but has a low sensitivity and is slow. The application of other
techniques such as PCR which have a greater sensitivity and with high specificity
for the diagnosis of these infections is necessary.
PMID- 9542304
TI - [Abscess of the psoas muscle: analysis of 11 cases and review of the literature].
AB - BACKGROUND: Abscess of the psoas muscle (AP) is an infrequent disease of
difficult diagnosis, developing spontaneously (primary AP) or by extension of a
subjacent infection (secondary AP). In recent years changes have been observed in
its etiology, advances in its diagnosis and modifications in the treatment
schedules. METHODS: The cases of AP diagnosed from 1983-1996 were retrospectively
studied. RESULTS: The cases included 11 AP, 5 (45%) primary and 6 (55%)
secondary, of which the source of origin were: spondylitis in four, sacroiliac
arthritis in one and intestinal in another. The clinical presentation was
characterized by its prolonged course (evolution of symptoms greater than 30 days
in 64% of the cases), with the most frequent symptoms being flank/abdominal pain
(82%) and hip/inguinal pain (45%), with fever being presented in only 36%. The
diagnostic profitability of echography and computerized tomography (CT) were 57%
(4/7) and 91% (10/11), respectively. One case was diagnosed with magnetic
resonance. The causal microorganisms were: Mycobacterium tuberculosis (36% of the
cases), Staphylococcus aureus (18%), polymicrobian flora (18%) and Salmonella
enteritidis, Streptococcus intermedius and Escherichia coli in 9% each. Eight
cases (73%) underwent percutaneous (5 cases) and surgical (3 cases) drainage,
with the evolution being favorable in 10 (91%) and death in one despite adequate
medicosurgical treatment. CONCLUSIONS: The clinical presentation of AP is often
unspecific, thereby delaying its diagnosis, and thus, CT is the procedure of
choice. The tuberculous etiology continues to be frequent in our environment.
Ultrasonographic or CT guided percutaneous drainage is a valid therapeutic
alternative versus surgery.
PMID- 9542305
TI - [Seroprevalence of anti-human parvovirus B19 antibodies in a sample of blood
donors in Galicia].
AB - BACKGROUND: To determine the seroprevalence of antibodies to human parvovirus B19
(PVB19) in a series of 92 blood donors in Galicia. METHODS: Antibodies of the
immunoglobulin G (IgG) class were investigated in serum samples from 44 females
and 48 males aged 18-63 years (mean: 29.40; SD: 10.81) using a commercial ELISA
system consisting of highly specific recombinant antigen. RESULTS: Nine positive
cases (9.78%; CI 95%: 4.76-17.98%) were detected, including six females and three
males with a mean age slightly higher as compared to all blood donors group. The
prevalence of antibodies against PVB19 increased with age. No sex or age
differences in the positive results were observed. CONCLUSIONS: These data
indicate a PVB19 seroprevalence lower that in previous studies in several
countries and in other areas in our country; since published references are
limited in this community, complementary studies to establish the importance of
this virus infection are justified.
PMID- 9542306
TI - [Human fascioliasis with atypical severe presentation. Treatment with
triclabendazole].
AB - BACKGROUND: Fascioliasis is a zoonosis mainly involving sheep but which
occasionally may be found in man as an accidental host. It is acquired by the
consumption of herbs (watercress, wild endive, and dandelion) contaminated with
metacercarias. The adult phase is established in the biliary tree. Most of the
human infections are asymptomatic or with unspecific self limited abdominal
symptoms making diagnosis difficult. METHODS: A case of human fascioliasis is of
note because of two aspects: a) the infrequent, severe life threatening form of
presentation: recurrent subcapsular hepatic hematomas, and b) favorable evolution
of the patient on treatment with triclabendazol (to date its use is not approved
in humans). RESULTS: Resistance to treatment with praziquantel was observed at a
dosis of 75 mg/day for 2 days, being repeated 15 days later with no response. The
patient was posteriorly treated with 10 mg/kg of a single dosis of triclabendazol
following approval as "compassive use" with a favorable clinical response.
CONCLUSIONS: This unusual disease requires a high index of suspicion to achieve
diagnosis. Treatment with triclabendazol should be studied as a possible
treatment of choice given is efficacy, absence of adverse effects and comfortable
dosage.
PMID- 9542307
TI - [Disseminated tuberculosis with cutaneous manifestations in AIDS patients.
Presentation of 4 cases].
AB - BACKGROUND: Acute cutaneous miliary tuberculosis is a rare form of Mycobacterium
tuberculosis infection which has been described in only 25 published cases in the
last 15 years. The appearance of serious disseminated forms of tuberculosis is
enhanced by the severe immunodeficiency which characterizes AIDS. METHODS: Four
cases are described of disseminated tuberculosis with cutaneous localization
clinically described as the acute miliary form. Patients had AIDS and CD4
lymphocyte levels of < 100 cells/mm3. Diagnosis was established in all cases by
scraping of cutaneous lesions and direct examination with Ziehl-Neelsen
coloration. RESULTS: The 4 patients presented signs and symptoms of disseminated
tuberculosis with cutaneous manifestations, without a definite pattern and with
localization predominantly on the thorax. Three had BAAR-positive sputum.
Multiresistant strains of Mycobacterium tuberculosis were confirmed by
antibiogram. One patient infected by a strain sensitive to first-line drugs
responded favorably to conventional treatment for disseminated tuberculosis. In
the remaining three with multiresistant strains, the evolution of the disease was
rapid and unfavorable. CONCLUSIONS: Abrupt appearance of cutaneous lesions in a
patient with disseminated tuberculosis and advanced HIV-disease should raise the
suspicion of its etiology. Scraping and direct examination using Ziehl-Neelsen
coloration is practical, economical and non-invasive diagnostic method.
PMID- 9542308
TI - [Otitis externa in a patient with radical mastoid cavity].
PMID- 9542309
TI - [Ocular sensation of foreign body and generalized pruritus in a young Guinean
woman].
PMID- 9542310
TI - [Ciprofloxacin and acute psychosis].
PMID- 9542311
TI - [Bacteremia by Agrobacterium radiobacter of unknown origin].
PMID- 9542312
TI - [Corynebacterium pseudodiphtheriticum: a new respiratory pathogen? Presentation
of one case of acute suppurative tracheobronchitis].
PMID- 9542313
TI - [Evaluation of the detection of IgM by EIA against the p18 protein of the IgG
capsid against EBNA in the diagnosis of acute Epstein-Barr infection].
PMID- 9542314
TI - [Infection by Chromobacterium violaceum in a patient with acquired
immunodeficiency virus infection].
PMID- 9542315
TI - [Lymph node cryptococcosis as the initial manifestation of AIDS].
PMID- 9542316
TI - [Sparfloxacin].
PMID- 9542317
TI - Primary effusion lymphoma containing human herpesvirus 8 DNA in two AIDS patients
with Kaposi's sarcoma.
AB - BACKGROUND AND OBJECTIVE: Primary effusion lymphomas (PELs) containing Kaposi's
sarcoma-associated herpesvirus (human herpesvirus 8/HHV-8) DNA sequences
represent a distinct but heterogeneous group of rare non-Hodgkin's lymphomas of
null-cell phenotype/B-cell origin. We aimed to describe the clinicopathologic
features of two human immunodeficiency virus (HIV)-related PELs occurring in
homosexual men with Kaposi's sarcoma (KS). DESIGN AND METHODS: Thoracentesis was
followed by morphologic plus immunophenotypic studies and molecular analysis of
tumor cell DNA by means of combination of polymerase chain reaction and Southern
blot analysis. RESULTS: Patients developed recurrent lymphomatous effusions
lacking tissue involvement, in the context of severe immunodepression (CD4 count
< 60/microL) and anti-retroviral therapy. The effusions disclosed an immunoblast
like population CD45/CD30+, but B-cell- and T-cell-associated antigen negative,
showing clonal immunoglobulin heavy chain gene rearrangements and harbouring HHV
8 DNA sequences. One case contained Epstein-Barr virus genome with no evidence of
c-myc, bcl-2 and bcl-6 gene alterations. Both patients had aggressive disease.
INTERPRETATIONS AND CONCLUSIONS: These cases represent additional examples of PEL
associated with HHV-8 and confirm that the group of HIV-positive homosexual men
may be at highest risk for PEL.
PMID- 9542318
TI - Intracellular expression of P-170 glycoprotein in peripheral blood mononuclear
cell subsets from healthy donors and HIV-infected patients.
AB - BACKGROUND AND OBJECTIVE: P-glycoprotein (P-gp) is a transmembrane efflux pump
that actively extrude a variety of unrelated drugs from cancer cells, leading to
the so-called multidrug resistance (MDR) phenomenon. However, P-gp has also been
found in normal bone marrow and peripheral blood mononuclear cells (PBMC).
Recently, the presence of P-glycoprotein in PBMC from human immunodeficiency
virus (HIV)-infected patients has also been investigated and a phenotype
associated P-gp expression has been detected. DESIGN AND METHODS: A total of
thirty-eight HIV-1 positive patients with a mean age of 34 years (range, 24-41
years) were studied after an informed consent. Peripheral blood mononuclear cells
(PBMC) were isolated by centrifugation on a Ficoll/Hypaque and P-glycoprotein
expression was investigated on lymphocyte population by single and double-color
immunofluorescence techniques. We investigated: i) both surface and intracellular
expression of the P-gp molecule in different PBMC subsets, ii) P-gp expression
modifications occurring during HIV infection, and iii) the effect of HIV-gp120 on
the expression of P-gp by T lymphocyte subsets from healthy donors. RESULTS: Our
experimental findings indicate that: a) P-gp glycoprotein can be detected on an
intracellular level in different PBMC subpopulations (mainly CD8+ T lymphocytes,
CD16+ NK cells and CD14+ monocytes); b) this intracellular expression is
decreased in specific PBMC subsets (i.e. T-CD8+ and NK-CD16+) from HIV-infected
patients and c) a rearrangement was obtained when CD4+ and CD8+ lymphocytes from
healthy donors were exposed in vitro to the HIV-binding glycoprotein gp120.
INTERPRETATION AND CONCLUSIONS: Our results indicate that P-gp glycoprotein can
also be expressed intracellularly and can be rearranged in PBMC subsets from HIV
infected patients.
PMID- 9542319
TI - Detection and monitoring of trisomy 8 by fluorescence in situ hybridization in
acute myeloid leukemia: a multicentric study.
AB - BACKGROUND AND OBJECTIVE: The role of fluorescence in situ hybridization (FISH)
in the detection and monitoring of trisomy 8 (+8) in acute myelogenous leukemia
(AML) has not been defined exactly. This multicentric study was performed in
order to: i) analyze the sensitivity of interphase FISH with respect to
conventional chromosome analysis (CCA) in detecting +8; ii) compare the results
of FISH and CCA in the quantitation of the frequency of +8-positive cells; iii)
analyze the possible role of FISH in the cytogenetic follow-up of patients with
+8. DESIGN AND METHODS: One hundred and ninety-eight nonconsecutive patients with
a diagnosis of AML seen at five centers over a 3-year period were studied by CCA
and FISH with a chromosome 8-specific centromeric probe. Two hundred interphase
cells were scored in each test and the cut-off for the recognition of +8 was set
at 3%. An irrelevant pericentromeric probe was used as negative control in those
cases with an apparently normal karyotype and trisomy 8 in interphase cells. FISH
studies were conducted at diagnosis and, in 14 cases with +8, on 1.5 occasions
during follow-up. RESULTS: Karyotype aberrations were seen in 121 cases (61.1%),
with +8 being present in 38 of them (16 as the sole aberration). Interphase FISH
detected +8 in 37/38 cases; in a patient with 1/10 metaphases with +8, 2.3%
interphase cells with 3 signals were seen. Fourteen additional cases with occult
+8 were detected by FISH, which showed 4-22% interphase cells with three signals;
6 patients had an abnormal karyotype without +8, 3 had a normal karyotype, 5 had
no analyzable mitoses. In 24 cases with > 15 analyzable metaphases, percent
variations between CCA and FISH in the estimation of the size of the trisomic
clone ranged between 0.4% and 51%, median value 22%. Underestimation of the
percent of trisomy 8 by FISH occurred in all 10 cases with > 90% +8 metaphases.
In 7/14 cases investigated sequentially, FISH detected 5-35% trisomic cells in
the BM after induction therapy (4 CR, 3 PR); 4 cases relapsed with +8 at 8-15
months. The absence of +8 in remission marrows was documented in the remaining 7
cases, 4 of which relapsed at 20-32 months. INTERPRETATION AND CONCLUSIONS: It is
concluded that FISH was a valuable method in this multicentric study since it
showed greater sensitivity than CCA in detecting minor clones with +8, in
patients with both normal and abnormal karyotypes. The role of FISH in the
cytogenetic follow-up of trisomies in AML patients may be promising.
PMID- 9542320
TI - Short course infusional idarubicin plus intermittent cytarabine and etoposide for
refractory hematologic malignancies: clinical and preliminary pharmacological
results.
AB - BACKGROUND AND OBJECTIVE: Idarubicin (IDA) is relatively immune to the multidrug
resistance P-gp mechanism that is frequently expressed in recurrent and
refractory hematologic malignancies. Owing to rapid metabolism in vivo, a
continuous infusion (CI) of IDA might prolong exposure time to the parent drug
rather than its more P-gp susceptible alcohol metabolite. For this reason we
developed a brief retreatment schedule incorporating CI IDA in order to obtain
clinical as well as preliminary pharmacological data in patients with refractory
leukemias and lymphomas. DESIGN AND METHODS: Eligible patients had either
advanced-stage acute myeloid or lymphoid leukemias (AML, ALL) or high-grade non
Hodgkin's lymphomas (NHL) which failed curative-intent frontline or salvage
regimens in use at our institution during the study period (July-October 1992).
CI IDA 5 mg/m2/d was employed together with intermittent (every 8 hours)
intermediate-dose cytarabine (500 mg/m2) and etoposide (200 mg/m2); all drugs
were given for 2-4 days. A preliminary pharmacokinetic evaluation of CI IDA was
carried out in three patients, including a comparison with bolus delivery in one.
The in vitro effects of CI-type vs bolus-type IDA delivery in terms of
intracellular IDA accumulation and related pro-apoptotic activity were assessed
in P-gp- and P-gp+ human leukemic CEM cells by means of cytofluorimetry (IDA
fluorescence intensity = FI, annexin V expression), with and without the addition
of P-gp inhibitor cyclosporin A (CsA). RESULTS: Complete (2) or partial (4)
responses were achieved in a total of 12 patients (17% and 33%, respectively),
despite prior treatments with anthracyclines (100% of cases) and cytarabine
etoposide (33% of cases). Hematological toxicity caused the duration of treatment
to be reduced from 4 days to 2 days after the first 4 patients. The procedural
death rate was 42% (5/12), which was probably related in part to the sum of
adverse prognostic characteristics: median patient age 55 years, two-thirds of
cases having previously failed second/third-line regimens. The pharmacokinetic
study showed an increased plasma AUC value with CI IDA in one patient (2.9-fold
increase vs bolus delivery) due to the prolonged presence of low IDA plasma
levels (10-20 ng/mL vs 50 ng/mL), as seen in two other cases as well. On the
other hand, the in vitro study did not prove to be in favor of CI IDA because the
FI threshold (> 1500 units) associated with increased apoptosis of P-gp+ cells (>
10%) was achieved only with bolus-type IDA exposure (50 ng/mL for 30') plus CsA.
INTERPRETATION AND CONCLUSIONS: This short regimen demonstrated activity against
end-stage leukemias and lymphomas and might prove to be more effective and less
toxic in younger patients and in those with less advanced disease. In view of the
results from plasma pharmacokinetics and in vitro intracellular IDA accumulation
and apoptosis assays in lymphoblastic CEM cells, CI IDA 5 mg/m2/day may not
represent a better therapeutic option than a rapid bolus injection, particularly
in P-gp+ neoplasms. If obtaining an adequate intracellular drug concentration is
the primary treatment goal, a higher CI IDA dosage, the addition of a P-gp down
regulator such as CsA and others, and in vivo study focusing on tumor samples
from patients could all be helpful.
PMID- 9542321
TI - Treatment of elderly patients with AML: results of an individualized approach.
AB - BACKGROUND AND OBJECTIVE: AML treatment in elderly patients must be
individualized according to their characteristics. We report the results of a
tailored treatment approach in all consecutive AML patients older than 60 years
diagnosed at our institution during the last 2 years. DESIGN AND METHODS: Between
December 1994 and December 1996, 43 AML patients over 60 years of age (median,
72; range 61-89) were managed according to their performance status (PS) and
associated diseases. Twenty patients (46%) were eligible for intensive
chemotherapy and received combination chemotherapy including an anthracycline
(Idarubicin or daunorubicin), ara-C and VP-16. After complete remission (CR),
consolidation chemotherapy with mitoxantrone and intermediate-high-dose ara-C was
given to 13 of the 15 patients in remission (65% of all patients candidates for
intensive treatment). Twenty-three patients who were not eligible for intensive
chemotherapy received palliative measures. RESULTS: Patients treated with one
course of intensive chemotherapy had a CR rate of 70% (95% CI: 48-92%)(n = 14)
with a mortality rate of 20% (n = 4) and a resistance of 10% (n = 2). An
additional patient reached CR after rescue therapy. Median CR duration was 10.5
months. Median survival was 10.5 months. Patients above 70 years had a median
survival of 5 months compared to the median not reached for those aged between 60
and 70 years (p = 0.03). This latter group had a probability of survival of 52 +/
18% at 18 months. None of the patients treated with palliative measures achieved
CR and the median survival in this group was only 1.5 months. INTERPRETATION AND
CONCLUSIONS: Patients with AML aged 70 years or less with good PS and without
severe associated diseases should be intensively treated due to the high
probability of achieving CR and an acceptable median-term survival. By contrast,
results in patients 70 years or older and in those suitable only for palliative
treatment because of a poor PS or severe associated diseases are very poor.
Alternative treatment approaches for these patients should be investigated.
PMID- 9542322
TI - Two dosage interferon-alpha 2b maintenance therapy in patients affected by low
risk multiple myeloma in plateau phase: a randomized trial.
AB - BACKGROUND AND OBJECTIVE: The role of interferon (IFN) in the remission phase of
multiple myeloma (MM) is still an open question, particularly for its scheduling
and the subset of patients who could benefit from this approach. The present
randomized multicenter study was designed to compare two schedules of IFN
maintenance therapy in order to assess the difference in effectiveness and
tolerance. DESIGN AND METHODS: This prospective randomized multicenter study was
attempted to assess the best schedule of IFN administration in the maintenance
treatment of MM in plateau phase with regard to progression free survival (PFS)
and toxicity. The second aim was defining the difference between the two
schedules in overall survival (OS) and identifying the critical dose of IFN
therapy needed to prolong plateau phase and survival. We enrolled 52 patients
affected with low-risk MM (i.e. with serum beta 2-microglobulin < 6.0 mg/L and
serum albumin > 3.0 g/dL); 27 patients (group A) were randomly assigned to
receive IFN alpha-2b 3 megaunits (MU) subcutaneously three times a week and 25
patients (group B) 3 MU/day until disease progression. RESULTS: Median
progression free survival (PFS) was 11.9 months in group A and 38.3 months in
group B (p = 0.0038). Median survival was 63.2 months in group A and 61.9 months
in group B (p = 0.489). However, those patients who were given an IFN dose > or =
30 MU/month experienced a significantly longer PFS and survival than the other
patients. Seventeen patients (32.7%) discontinued therapy and sixteen patients
(30.8%) reduced IFN alpha-2b dose because of severe side effects without having a
significant difference between the two schedules. INTERPRETATION AND CONCLUSIONS:
Our results show that patients treated with IFN alpha 3 MU/day had a
significantly longer remission duration than patients treated with IFN alpha 3 MU
three times weekly. Moreover, an IFN dose is probably critical for obtaining a
longer survival in patients affected with low-risk MM. Since the patients'
discomfort during a IFN maintenance therapy was frequently experienced the
quality of their lives should be carefully taken into account.
PMID- 9542323
TI - Allogeneic peripheral blood stem cell transplantation in patients with early
phase hematologic malignancy: a retrospective comparison of short-term outcome
with bone marrow transplantation.
AB - BACKGROUND AND OBJECTIVE: Transplantation of mobilized allogeneic peripheral
blood stem cells (PBSC) has recently been reported by several groups. However,
few patients receiving an allograft in the early stage of their disease have been
described so far. DESIGN AND METHODS: Fifteen patients with early stage
hematologic malignancies were transplanted with cryopreserved allogeneic PBSC
from HLA-identical siblings. PBSC were collected after priming with 10
micrograms/kg/day of glycosylated granulocyte colony-stimulating factor (G-CSF,
lenograstim). Outcomes were compared to a historical control group of 15 patients
who received conventional bone marrow transplantation (BMT) from HLA-identical
sibling donors. The two groups were matched for diagnosis, stage of disease, age,
preparative regimen, graft-versus host (GVHD) prophylaxis, patients' and donors'
gender and cytomegalovirus (CMV) serology. Diagnoses in both groups were: chronic
myelogenous leukemia (CML) in first chronic phase (= 5), acute leukemia in first
complete remission (CR) (= 5), non-Hodgkin's lymphoma in CR (= 1) and multiple
myeloma (MM) with sensitive disease (= 4). All patients were given cyclosporin-A
(CsA) and methotrexate (MTX) for GVHD prophylaxis. Preparative regimens varied
according to diagnosis and included either busulfan/cyclophosphamide combination
(BU/Cy) or total body irradiation/cyclophosphamide +/- melphalan (TBI/Cy +/-
Mel). RESULTS: The patients in the PBSC group showed a more rapid hematopoietic
reconstitution with a significant difference in the median times to 1 x 10(9)
neutrophils/L (19 days vs. 26 days; p = 0.03) and to platelet transfusion
independence (18 days versus 22 days; p = 0.02). This finding was associated with
a significantly shorter hospitalization (28 days versus 33 days after
transplantation; p = 0.01). In the PBSC series, grade II-IV acute GVHD occurred
in 3 patients (20%) and grade III-IV in 1 patient (7%). In the BMT control group,
grade II-IV aGVHD was reported in 2 cases (13%; p = NS) and 1 case had grade III
IV GVHD. Chronic GVHD developed in 7 patients (47%) (limited = 6; extensive = 1)
undergoing PBSC transplantation and 5 patients (33%) (limited = 4; extensive = 1)
in the BMT series (p = NS). No difference was found in the incidence of grade II
IV (according to the World Health Organization) mucositis, whereas PBSC
recipients did have a significantly lower incidence of additional severe (grade
III-IV) organ toxicity. After a median follow-up of 300 days (range 180-630), all
PBSC patients are still alive with a median Karnofsky score of 100% (range 80%
100%). Thirteen patients are in CR and 2 myeloma patient are in good partial
remission (PR). Also, in the BMT group the peritransplant mortality was absent;
two MM patients died due to progressive disease at day +796 and +1,023,
respectively; one leukemic patient died of chronic GVHD 407 days after
transplantation and one additional leukemic individual relapsed 1,140 days after
BMT. INTERPRETATION AND CONCLUSIONS: This retrospective comparison suggests that
allogeneic PBSC transplantation performed in the early stage of the disease is
safe and may be associated with a more rapid hematopoietic reconstitution than
BMT, as well as lower transplant-related toxicity and earlier hospital discharge
with apparently no increased risk of acute and chronic GVHD.
PMID- 9542324
TI - The molecular biology and pyridoxine responsiveness of X-linked sideroblastic
anaemia.
AB - Pyridoxine-responsive, X-linked sideroblastic anaemia (XLSA) has been shown to be
caused by missense mutations in the erythroid-specific ALA synthase gene, ALAS2.
These are scattered widely across the part of the gene encoding the catalytic
domain and in half the cases affect residues conserved throughout evolution. Only
a loose correlation has been found between the in vitro kinetics and stability of
the catalytic activity of the recombinant variant enzymes and the in vivo
severity and pyridoxine-responsiveness of the anaemia. Enhanced instability in
the absence of pyridoxal phosphate (PLP) or decreased PLP and substrate binding
have been noted. A detailed explanation of the anaemia and its response to
pyridoxine, however, requires greater insight into the structure-function
relationships of this protein than we have at present. Knowledge of its tertiary
structure and further knowledge of intracellular factors which impinge on the
ability of normal and variant ALAS2 to contribute to haemoglobin production are
also required. Mutations in the same gene which affect mitochondrial processing,
terminate translation prematurely, or are thought to abolish function altogether
cause an XLSA that is refractory to treatment with pyridoxine. A major
complication of this disorder is its accompanying increased iron absorption and
iron overload which occurs in patients and female heterozygotes. Mutation
detection enables the early diagnosis of those affected, targeted education of
families, early treatment with pyridoxine and prevention of iron overload. It
also allows for a distinction to be made between late-onset variants of this
condition and the more insidious refractory anaemia with ring sideroblasts. The
next few years of investigation should be illuminating as tools now exist to
study all aspects of this protein from the gene to the mitochondrial matrix.
PMID- 9542325
TI - Pathogenesis, etiology and epidemiology of myelodysplastic syndromes.
AB - BACKGROUND AND OBJECTIVE: The myelodysplastic syndromes are common hematological
malignancies affecting predominantly elderly people. Patients usually present
with chronic cytopenias which gradually worsen due to progressive bone marrow
failure or transformation into acute myeloid leukemia. Disease prevention is more
cost-effective than therapeutic intervention and the establishment of the
etiology and pathogenesis of MDS therefore assumes considerable importance. This
review will outline current concepts of the pathobiology of MDS, putative
etiological insults and the mechanisms of disease initiation as well as recent
contributions to the descriptive epidemiology of these disorders. EVIDENCE AND
INFORMATION SOURCES: The authors of the present review have a long-standing
interest in the pathogenesis, etiology and epidemiology of MDS. Journal articles
covered by the Science Citation Index and Medline have been reviewed and personal
experience and discussion with international experts collated. STATE OF THE ART
AND PERSPECTIVES: The initiation processes for the development of MDS remain
unknown. A poorly defined transforming event affects a pluripotent or multipotent
progenitor cell in the bone marrow, conferring a growth advantage upon it and
eventually establishing clonal hematopoiesis. An important pathogenetic mechanism
in MDS is premature intramedullary cell death via excessive apoptosis, explaining
the apparent paradox of a cellular marrow in combination with peripheral
cytopenias (ineffective hematopoiesis). Therapy-related MDS/AML following
exposure to alkylating agents is the only clear etiological factor thus
identified. Increasing evidence for exposure to benzene and radiation and the
development of MDS is emerging. Benzene hematotoxicity is mediated via both
genotoxic and non-genotoxic mechanisms, leading to aplasia, apoptosis and
initiation (via genetic mutation) of clonal disorders such as MDS. Further
studies of benzene hematotoxicity and therapy-related MDS should provide models
for the elucidation of initiation events in MDS pathogenesis. The importance of
such studies is emphasized by the rising frequency of MDS which largely reflects
improved diagnostic criteria, increased physician awareness and extended use of
diagnostic procedures in the elderly. Demographic changes will lead to a marked
increase in MDS over the next few decades.
PMID- 9542326
TI - Plasmablastic lymphoma of the stomach. A case report.
AB - We report the case of a 53 year-old woman with a gastric tumor showing
morphological, phenotypical and molecular features of a plasmablastic lymphoma, a
recently recognized subtype of diffuse large B-cell lymphoma. The tumor was
composed of plasmablast-like cells, lacked CD45 and B-cell associated antigens,
expressed the plasma cell-associated antigen CD38, and showed clonally rearranged
IgH genes in the absence of bcl-2 and bcl-6 genes rearrangement.
PMID- 9542327
TI - A case of microcytic anemia.
PMID- 9542328
TI - Waldenstrom's macroglobulinemia complicated with acute myeloid leukemia. Report
of a case and review of the literature.
AB - The evolution of Waldenstrom's macroglobulinemia (WM) into chronic or acute
myeloid leukemia (AML) is a rare event. Most of these cases have occurred after
treatment with alkylating agents. We herein report a case of WM terminating in an
acute myelomonocytic leukemia after treatment with prednimustine and chlorambucil
and present a review of the literature.
PMID- 9542329
TI - Idiopathic thrombocytopenic purpura associated with Crohn's disease.
AB - Besides cytopenia related to treatment, several hematological disorders such as
anemia, abnormal platelet activity, thrombosis, presence of anticardiolipin or
anti-neutrophil antibodies, cyclic neutropenia, and myelodysplasia, have been
reported in patients with Crohn's disease (CD). The case we report here is the
first one documenting the association of idiopathic thrombocytopenic purpura
(ITP) with CD.
PMID- 9542330
TI - More on the appropriate fluorochrome-conjugated CD34 antibody choice for the flow
cytometric detection of circulating progenitor cells.
PMID- 9542331
TI - [Kinetics of development of human melanoma xenografts in immunosuppressed
animals].
AB - An experimental model of development of the human tumor xenografts (melanomas
HCMB and Bro) in immunosuppressed phenotypically normal animals (CBA/Ca mice) was
developed. Optimal conditions were established for immunodeficiency induction in
the animals. Kinetics of development of the xenografts in the immunosuppressed
animals was studied. The level of 0(6)-alkyl-guanine-DNA-alkyltransferase, an
enzyme responsible for repair of DNA damage in the tumor cells induced by
chemotherapeutic agents (nitroalkylurea), was determined.
PMID- 9542332
TI - [Cytochrome p-450-dependent monooxygenase in fish tissues].
AB - Data about enzymes involved in metabolism and detoxification of xenobiotics in
fish are summarized. Special attention is given to the comparison of
monooxygenase systems of fish and mammals. 3-Methylcholanthrone, benzo-pyrene,
benzo-naphthoflavone, and various technogenic pollutants present in water are
examined as inducers of fish monooxygenase systems. The induction of cytochrome P
450 isozymes is specially reviewed, and we discuss their difference from similar
isozymes of other vertebrates classes. We also discuss the relationship between
the activity of the monooxygenase system in fish and temperature conditions of
water bodies, as well as sex-related differences in the activity of this system.
Perspective in the use of the monooxygenase system for biological monitoring are
reviewed.
PMID- 9542333
TI - [Taxonomy of the musk deer (Artiodactyla, Mammalia)].
AB - We studied the chromosome sets and specific morphological features and phenetic
traits of hair cover coloration, as well the pattern of its inheritance upon
experimental hybridization. The diploid set of chromosomes in the animals from
the northern part of the range contains 2n = 58 (there are two additional B
chromosomes in the Far Eastern musk deer) and is identical to that from the
southern musk deer forms. Discrete polymorphic features of neck and hair cover
coloration have been identified in the northern and southern musk deer, and these
are used as taxonomic features. A map illustrates distribution of the established
subspecies.
PMID- 9542334
TI - [Comparative analysis of the acoustic characteristics of speech models of human
prototypes and budgerigar (Melopsittacus undulatus) imitations].
AB - Phonemic comparative analysis of vowel (i) of the Russian language was carried
out in pronunciation of nine budgerigars and humans (three men, five women, and
three children under eleven years old). A complex device "KAPROS-01" was used as
an analyzer. The contact signals of the same individuals was also analyzed.
Transposition of the main tone and formants in the frequency range by 2 kHz
upwards and adjacency of the main tone harmonics to the first formant area are
the main distinctions of the three-dimensional (3D) graph between bird and human.
The bird's signal does not differ practically from the human signal according to
the number of formants (two to three). The length of vowel (i) in budgerigars
averages 19% of the total word length, versus 29% in humans. The main voice
frequency in budgerigars in their contact signals varies from 2.2 to 3.4 kHz and,
in imitations, from 2.3 to 3.0 kHz.
PMID- 9542335
TI - [Changes in the serum albumin system during toxic syndrome and their
pharmacologic correction].
AB - In connection with the important role of serum albumins in pathogenesis and
sanogenesis of numerous toxic states, we examined binding capacity of these
proteins and conditions of their binding sites after acute poisoning with
tetrachloromethane (TCM) and administration of antihypoxic agents (sodium gamma
hydroxybutirate), antioxidants (Dibunol), and actoprotector (Tomersol) to rats.
We demonstrated that tetrachloromethane intoxication (3.2 g/kg over 24 h) was
accompanied by a certain decrease (by 13.8%) in the total blood serum level of
albumins and a tendency to a decrease in the value of the binding constant of
negatively charged fluorescent probe 1-(phenylamino)-8-sulfonaphthalene. Under
these conditions, the mean number of probe binding sites per albumin molecule
increases, and as a result, the total concentration of albumin binding sites in
the serum remains virtually unchanged. We found that accessibility of the probe
to a quenching agent (potassium nitrate) increases in the protein--probe complex
under intoxication conditions, suggesting that the type of interaction between
the protein and the fluorescent probe changes as well. Therapeutic/prophylactic
administration of an antioxidant, antihypoxic agent, or actoprotector leads to an
increase in the level of albumin in the serum (Tomersol), partial normalization
of its binding properties (binding constant in the case of sodium gamma
oxybutirate, mean number of binding sites per molecule for Dibunol and Tomersol),
and the state of binding sites (sodium gamma-oxybutirate, Dibunol).
PMID- 9542336
TI - [Various aspects of the effect of heparin-serotonin complex on blood and blood
flow].
AB - High-molecular heparin-serotonin complex (3:1 weight ratio) was obtained in
vitro. The complex, its components, and heparin-serotonin mixture were introduced
intraperitoneally in rats, and the resulting effects were registered 10, 30, and
60 min later. The complex had anticoagulant and lytic activities distinct from
those of plasmin. According to decrease activity of factor XIII and decreased
concentration of fibrinogen, the complex stimulated the anticoagulant system. In
addition, the heparin-serotonin complex penetrated the hematoencephalic barrier
and decreased the rate of brain bloodstream. The observed physiological
properties of the heparin-serotonin complex were distinct from those of
serotonin, heparin, and their mixture.
PMID- 9542338
TI - Trends in funding for medical entomological research.
PMID- 9542337
TI - [Receptor binding of aldosterone in the brain of rats with different types of
behavior under normal conditions and after stress].
AB - Results are given from experiments on binding of [3H]aldosterone to the
cytoplasmic corticosteroid receptors, in the brain structures of the rat with
different types of behavior under normal conditions 10 min and two weeks after
its peritoneal injection. Binding of [3H]aldosterone to cytoplasmic
corticosteroid receptors of the hippocampus, rather than the brain (without
hippocampus and cerebellum), was shown to depend on the type of animal behavior.
Stress was also shown to affect binding of this hormone to cytoplasmic
corticosteroid receptors of the brain (without hippocampus and cerebellum),
rather than hippocampus.
PMID- 9542339
TI - Fleas in French Guiana (Insecta: Siphonaptera).
AB - Based on a collection of approximately 760 fleas, of which 520 were collected in
1994-1995 during scientific studies at the Petit Saut dam site in French Guiana,
12 species and subspecies are discussed. Two taxa, Rhopalopsyllus garbei
Guimaraes, 1940 and Adoratopsylla intermedia copha (Jordan, 1926), are new
records for French Guiana. The fleas collected during the 1994-1995 study were
obtained from 35 species of mammals (3,484 specimens); of which, 21 (60%) species
were negative for fleas. The mammals were captured primarily by live-trapping
during a capture-release study along a portion of the Sinnamary River and its
tributaries up to a distance of 70 km upstream from the Petit Saut dam site.
PMID- 9542340
TI - Patterns of activity in host-seeking adult Ixodes scapularis (Acari: Ixodidae)
and host-produced kairomones.
AB - Adult blacklegged ticks, Ixodes scapularis Say, were confined to clay islands
each surmounted with a vertical glass rod, and tick activities were videotaped
continuously for 48 h. Some rods were treated basally or apically with substances
rubbed from pelage associated with the tarsal or interdigital glands of white
tailed deer, Odocoileus virginianus (Zimmermann). Except for the activity
immediately following their release, tick activity on both days was greatest
during the period from 1700 to 2300 hours, which coincided with the onset of
scotophase. Ticks were most active when rods had interdigital gland substances
applied to their basal 2 cm, whereas they were least active when confined with
rods treated with tarsal gland substances on their apical 2 cm. Overall, ticks
spent more time on the apical 2 cm of the glass rods during the scotophase than
during the photophase. The highest level of apical arrestment among treated and
untreated rods occurred when the rod tips were treated with tarsal gland
substances, with female ticks on the apical 2 cm of the rods 70-100% of every 3-h
period beginning with the period from 2000 to 2300 hours on day 1. In contrast,
when tarsal gland substances were applied to the basal 2 cm of the rods, the
ticks spent < 40% of every period on day 2 on the rod tips.
PMID- 9542341
TI - Morphometric multivariate analysis of field samples of adult Anopheles arabiensis
and An. gambiae s.s. (Diptera: Culicidae).
AB - The Afrotropical complex of sibling species Anopheles gambiae Giles includes the
most efficient vectors of human malaria south of the Sahara. Anopheles arabiensis
Patton and An. gambiae s.s. Giles are the members of the complex more adapted to
the human environment. They are sympatric and synchronic over most of their
distribution range; however, they show a different involvement in malaria
transmission, with An. gambiae being more anthropophilic and endophilic than An.
arabiensis. Discriminating between them is essential for a correct assessment of
epidemiological parameters. The identification is currently achieved through
recognition of species-specific chromosomal inversions or by molecular biology
techniques. Both methods require considerable technical resources, not always
available in the field. We carried out a morphometric analysis of field and
laboratory samples of An. arabiensis and An. gambiae s.s. from sites in
Madagascar, Burkina Faso, Mali, and Liberia to evaluate the degree of
morphological differentiation. We examined 17 morphometric characters in samples
representing each of the geographic sites. All of the measures were significantly
larger for An. arabiensis (regardless of the collection site), demonstrating an
intrinsic greater body size of this species. To assess the reliability associated
with the multivariate statistic, we applied the discriminant function analysis,
which provided a method for predicting to which group a new case will most likely
be assigned. In a blind experiment, the morphometric method correctly identified
approximately 85% of field-collected An. arabiensis and An. gambiae s.s., which
provided a relatively simple method to approximate the relative frequencies of
the 2 species in areas in which their concurrent presence was already known. The
influence of laboratory conditions on the morphometrics of the 2 species was also
analyzed.
PMID- 9542342
TI - Seasonal oviposition and temperature requirements of eggs may limit northern
distribution of European Argas reflexus (Acari: Argasidae).
AB - Seasonal reproduction and embryonic development was investigated in Argas
reflexus (F.) throughout a 5-yr period. Ticks were kept in desiccators at
approximately 76% RH at 2 experimental sites--an attic and an outdoor aviary-
that provided a natural photoperiod and temperature. Tick oviposition was limited
to the summer months (June through August) regardless of the year of
investigation and of the seasonal time of tick feeding. Engorged female ticks
entered diapause between late July and late August. Ticks that had already
started oviposition, stopped at that time and continued in the following year
without requiring another blood meal. In the laboratory, A. reflexus eggs
exhibited an upper lethal temperature (ULT50: 1-h exposure) of 44.1 degrees C
(95% CL: 43.7-45.5 degrees C), which is in accordance with the increased egg
mortality observed in the attic, where temperatures reached > or = 45 degrees C.
A. reflexus eggs showed a low level of cold tolerance. Despite a supercooling
point of approximately -25 degrees C, their lower lethal temperature (LLT50: 24-h
exposure) was only -12.3 degrees C. Even at a typical winter temperature of 3
degrees C and 76% RH, 50% egg mortality occurred after only approximately 34 d.
In the attic and the aviary, none of the A. reflexus eggs were able to overwinter
successfully during any of the investigated winters, including comparatively mild
ones. The results strongly suggest that the temperature sum available for
embryonic development in summer/autumn limits the northern distribution of A.
reflexus.
PMID- 9542343
TI - Random amplification of polymorphic DNA as a tool for taxonomic studies of
triatomine bugs (Hemiptera: Reduviidae).
AB - Eleven of 27 decameric primers were found to be suitable for random amplification
of polymorphic DNA (RAPD) from triatomine bugs on the basis that they produced
discrete profiles and distinguished among Panstrongylus megistus (Burmeister),
Rhodnius prolixus Stal, and Triatoma infestans (Klug). The legs, or single leg
segments, of individual bugs were used as the source of DNA so that the taxonomic
value of the bug was conserved. Within the scope of the specimens studied, RAPD
profiles allowed assignment to species even when bugs were kept dry for up to 12
mo. Profiles for individuals within a species were not identical. RAPD profiles,
with the specimens tested, distinguished among species of 3 pairs considered to
be morphologically similar and closely related, namely, Rhodnius ecuadorensis
Lent & Leon and Rhodnius pictipes Stal; Rhodnius nasutus Stal, and Rhodnius
neglectus Lent; Rhodnius prolixus Stal and Rhodnius robustus Larrousse. RAPD data
conformed with the perceived affinities among these species. RAPD polymorphisms
were seen with T. infestans from 3 different localities, but none of the
polymorphisms was confined to 1 source. RAPD provided a molecular basis to
reassess taxonomic relationships within the Triatomine subfamily. The accurate
distinction of triatomine species and of intraspecific bug populations may
contribute to elimination of vector-borne Chagas disease from the Americas.
PMID- 9542344
TI - Population dynamics of the house dust mites Dermatophagoides farinae, D.
pteronyssinus, and Euroglyphus maynei (Acari: Pyroglyphidae) at specific relative
humidities.
AB - Experiments were conducted to determine the effects of relative humidity on the
population dynamics of single and mixed species of Dermatophagoides farinae
Hughes, D. pteronyssinus (Trouessart), and Euroglyphus maynei (Cooreman) at
specific relative humidities maintained at 20 degrees C, with unlimited food. The
population density of single and mixed species (D. farinae and D. pteronyssinus)
increased exponentially when cultured at 65, 70, and 75% RH. The mean population
growth rates were 17.3 +/- 4.4 SD and 32.5% +/- 4.7/wk for D. farinae and D.
pteronyssinus, respectively. Mean population doubling times were 2.2 +/- 0.3 and
4.2 +/- 1.3 wk for D. pteronyssinus and D. farinae, respectively. Mixed species
cultures, started with equal numbers of D. farinae and D. pteronyssinus, resulted
in higher percentages of D. farinae than D. pteronyssinus. In cultures started
with 75% of one species and 25% of the other, the more numerous species remained
dominant and in similar ratios throughout the experiment. Both D. farinae and D.
pteronyssinus population densities maintained at 85% RH declined over a 12-wk
culture period because of mold growth. E. maynei were unable to survive at 65,
70, 75, and 85% RH, which indicated that their climatic requirements were
different from those of D. farinae and D. pteronyssinus. Population densities of
D. farinae and D. pteronyssinus cultures declined when held at 21-22 degrees C
and relative humidities of < or = 50%; however, at 50% RH, significant
proportions of the populations survived for 10 wk. Half-life for desiccation of
D. farinae and D. pteronyssinus at 45% RH was 11.5 and 1.2 wk, respectively, but
at 50% RH was 86.3 and 4.0 wk, respectively. The data indicated that a < or = 50%
RH would have to be maintained for long periods to reduce both D. farinae and D.
pteronyssinus by desiccation procedures. The results of this study show that D.
farinae and D. pteronyssinus have high reproductive potentials and population
growth rates, which indicate that mite reduction procedures must be thorough or
mite densities will return to high levels quickly following remediation if
adequate food and suitable microclimatic conditions exist.
PMID- 9542345
TI - Occurrence of Ixodes scapularis (Acari: Ixodidae) on a selected segment of the
Appalachian Trail.
AB - A 918-km section of the Appalachian National Scenic Trail from the West Virginia
Maryland border to the Massachusetts-Vermont border was surveyed for the presence
of Ixodes scapularis Say. The trail and its edges were drag-sampled during 4
hikes between May and October 1991. Trips were designed to survey areas of the
Appalachian Trail when I. scapularis might be questing and to revisit states
endemic for Lyme disease during differing times. After sampling for ticks,
meteorological and ecological characteristics were measured at each site. In
total, 1,776 km of the Appalachian Trail were hiked during 88 d and resulted in
sampling 489 sites. All life stages of Ixodes scapularis (n = 46) were collected
from 21 sites within a 331-km range of the Appalachian Trail between Salisbury,
CT, to Delaware Water Gap, PA. This segment of Appalachian Trial is easily
accessible to a large urban population and should be posted with tick warning
signs to alert the public to the presence of I. scapularis.
PMID- 9542346
TI - Attachment-site patterns of adult blacklegged ticks (Acari: Ixodidae) on white
tailed deer and horses.
AB - The attachment site pattern of adult Ixodes scapularis Say on white-tailed deer
and horses in Maryland was determined by whole-body examinations during fall and
spring periods of tick host-seeking activity. On deer in the fall, both female
and male I. scapularis attached largely to anterior dorsal body regions, with
attachment to the ears (outside), head, neck, and brisket accounting for 87.9% of
females and 86.6% of males. The attachment pattern of females differed between
bucks and does during fall, but not in spring, and both females and males were
more abundant on bucks than does during fall, but not in spring. Neither female
nor male attachment patterns on deer differed between fall and spring seasons. In
contrast to deer, the ears and neck of horses were largely devoid of blacklegged
ticks, and 84% of the females were attached either on the chest, in the axillae
of the fore and rear legs, or under the jawbone. The restricted attachment of
female blacklegged ticks to ventral body regions of horses may reflect avoidance
of light. An understanding of the attachment patterns of adult I. scapularis, an
increasingly abundant and economically important species, enhances sampling of
feeding ticks, deticking to limit host irritation or exposure to tick-borne
pathogens, and identifies body areas that should be targeted for delivery of
repellents or acaricides.
PMID- 9542347
TI - Comparison of Ixodes scapularis (Acari: Ixodidae) populations and their habitats
in established and emerging Lyme disease areas in New Jersey.
AB - Hunterdon Country, New Jersey, experienced a significant increase in the number
of Lyme disease cases during 1990-1995, accounting for 21.2% of all New Jersey
cases. This study compares the relative abundance of Ixodes scapularis Say in
similar habitats in Hunterdon County, an emerging Lyme disease area, and Monmouth
County, where Lyme disease has been established for well over a decade. The
extent to which differences in habitat physiognomy could explain differences in
tick populations, and consequently Lyme disease case rates, is addressed. Ticks
were surveyed and vegetation measurements made in 4 habitat types at 1 site in
each county. I. scapularis was 7 times more abundant in Monmouth County than in
the Hunterdon County site, and the distribution of all life stages among habitats
differed significantly between sites. The greater numbers of subadult ticks at
the Monmouth County site was attributed to greater shrub cover and litter depth
which created more favorable microclimatic conditions for tick survival. However,
the overall physiognomy of the different vegetation types at the sites studied in
Monmouth and Hunterdon counties was remarkably similar and did not appear to
explain differences in tick abundance. Until further research clarifies
microscale differences between habitats, the differences in the case rates
between the counties appear to be more likely the result of reporting artifact.
PMID- 9542348
TI - Ultrastructural studies on the reproductive system of male Aedes aegypti
(Diptera: Culicidae) infected with dengue 2 virus.
AB - Dengue 2 virus was found by transmission electron microscopy to be present in the
reproductive tissues of male Aedes aegypti (L) 14 d after intrathoracic
inoculation. Dengue 2 particles were detected in the matrix, epithelial cells,
and the peripheral fat body of the testes; secretory droplets of columnar cells
of the accessory glands; and the epithelial and muscle cells of the seminal
vesicles. However, none was found in the germ cells (i.e., spermatogonia,
spermatocytes, spermatid, or spermatozoa). These observations indicate that fluid
transfer may be the mechanism of venereal transmission of dengue 2 virus by Ae.
aegypti.
PMID- 9542349
TI - Competence of pheasants as reservoirs for Lyme disease spirochetes.
AB - Pheasants, Phasianus colchicus L., constitute a major part of the ground-feeding
avifauna of England and Wales and are important hosts to immature stages of
Ixodes ricinus L., the principal tick vector of Lyme borreliosis spirochetes in
Europe. Therefore, their competence as hosts for Borrelia burgdorferi Johnson,
Schmid, Steigerwalt & Brenner sensu lato was investigated. One group of pheasants
was inoculated by needle with 1 x 10(6) cultured B. burgdorferi s.s. organisms,
and a 2nd group of birds was infested with I. ricinus nymphs collected from a
focus of Lyme borreliosis in southern England. Both bird groups were subjected to
xenodiagnoses using uninfected I. ricinus nymphs. All recovered engorged ticks,
as well as pheasant skin biopsies, were analyzed by a nested polymerase chain
reaction targeting the 5S-23S rRNA genes of B. burgdorferi s.l. Both groups
proved to be infective for ticks. The birds that were infected by tick bites
proved to be significantly more infective for ticks (23% of the xenodiagnostic
ticks positive) than those infected by needle (5%). The results show that
pheasants can be infected experimentally with B. burgdorferi s.l., that they can
pass the spirochetes to ticks and that their infectivity for ticks may persist as
long as 3 mo. We conclude that pheasants are reservoir competent for Lyme
borreliosis spirochetes and potentially play an important role in the maintenance
of B. burgdorferi s.l. in England and Wales.
PMID- 9542350
TI - Genetic structure of local populations of Lutzomyia longipalpis (Diptera:
Psychodidae) in central Colombia.
AB - Lutzomyia longipalpis (Lutz & Neiva), the sand fly vector of American visceral
leishmaniasis in the New World tropics, has a broad but discontinuous
geographical distribution from southern Mexico to Argentina. A baseline for
population genetic structure and genetic variability for this species was
obtained by analyzing 5 local, peridomestic populations at the approximate center
of its distribution, the Magdalena River Valley of central Colombia. Three
populations of L. longipalpis from El Callejon, a small rural community, were
compared with 2 populations from neighboring areas 12 and 25 km distant for
genetic variation at 15 isoenzyme loci. The mean heterozygosity ranged from 11 to
16%, with 1.2 to 2.3 alleles detected per locus. Nei's genetic distances among
the populations were very low, ranging from 0.001 to 0.007. Gene flow estimates
based on FST indicated high levels of gene flow among local L. longipalpis
populations, with minimal population substructuring.
PMID- 9542351
TI - Kairomonal activity of white-tailed deer metatarsal gland substances: a more
sensitive behavioral bioassay using Ixodes scapularis (Acari: Ixodidae).
AB - A behavioral bioassay is described that detected kairomonal activity in
substances associated with the metatarsal glands of white-tailed deer, Odocoileus
virginianus (Zimmermann). Dry and aqueous wipes or rubs of glandular areas
elicited an arrestant response in adult blacklegged ticks, Ixodes scapularis Say.
PMID- 9542352
TI - Bone grafting in foot and ankle surgery. A review of 300 cases.
AB - Three hundred foot and ankle bone grafts were reviewed in three separate series
of 100 consecutive grafts from two institutions. The series represent a period
from 1977 to 1990 and demonstrate treatment patterns that varied over time and
between institutions in indications, graft material, and perioperative
management. Over 42% of the 300 grafts were for calcaneal osteotomies; most were
Evans calcaneal osteotomies. Over 72% of the grafts were allogeneic bone-bank
bone, which performed well in calcaneal osteotomies and for packing of defects.
Upon review of the incidence of bone complications, no significant differences
were observed between surgical procedures that used autogenous versus allogeneic
grafts. However, four out of six failures of first metatarsal repair were with
allogeneic bone. There was a significant difference in complication rates for the
major indications for bone-graft surgery. Nonunions and arthrodeses resulted in
higher complication rates than expected, whereas calcaneal osteotomies resulted
in a lower complication rate than expected.
PMID- 9542353
TI - Alternative techniques for the clinical assessment of foot pronation.
AB - Clinical measurement is a fundamental component of podiatric biomechanics.
However, recent research has seriously questioned the reliability and validity of
the commonly used approaches to clinical measurement of foot posture. A
reevaluation of foot-morphology measurement is therefore warranted. This article
discusses alternative clinical techniques of measuring foot type reported in the
literature (arch height, footprint indices, the valgus index, and navicular drop)
that may prove to be superior to the commonly used podiatric measurement system.
On the basis of a critical evaluation of the literature, it would appear that
arch height and footprint indices are invalid as means of categorizing foot
morphology, while the valgus index and navicular drop offer a number of benefits
over traditional frontal-plane measurements. An additional clinical measurement
suggested by the author, navicular "drift," is also introduced. The advantages,
disadvantages, and clinical application of each of these approaches are discussed
in detail.
PMID- 9542354
TI - Post-traumatic first metatarsal reconstruction using coralline hydroxyapatite.
AB - Autogenous bone grafting has been the standard approach to reconstruction of
trauma-induced metatarsal defects. However, this treatment has well-known
disadvantages related to the harvesting, size, shape, and availability of
autografts. The authors used a synthetic hydroxyapatite bone-graft substitute
manufactured from a marine coral with a morphology similar to that of cancellous
bone in the reconstruction of a large, post-traumatic first metatarsal defect.
The authors found grafting with coralline hydroxyapatite to be a safe and
effective substitute for autogenous bone grafting in the post-traumatic setting.
PMID- 9542355
TI - Rare presentation of hereditary multiple exostoses. A case report.
AB - Hereditary multiple exostoses is a relatively uncommon disorder of endochondral
bone characterized by the presence of multiple, cartilaginous-capped exostoses
arising from the metaphyses. A rare presentation of hereditary multiple exostoses
in the calcaneus of a 35-year-old man is reviewed and discussed. A brief review
of the literature is provided, as well as a discussion of the patient's family
history.
PMID- 9542356
TI - Charcot's joint following Keller arthroplasty. A case report.
AB - Neuropathic osteoarthropathy, i.e., Charcot's joint, has not previously been
reported as a sequela of elective foot surgery. The authors present a challenging
case of a patient with long-standing diabetes mellitus and peripheral neuropathy
who developed neuropathic osteoarthropathy after a Keller arthroplasty for a
recalcitrant hallux ulcer. The radiographic findings, diagnostic tests, and
histopathology are discussed. Finally, the authors offer suggestions for surgeons
contemplating a Keller arthroplasty for patients with peripheral neuropathy.
PMID- 9542357
TI - Recurrent ringed lesion of the sole: erythema annulare centrifugum.
PMID- 9542358
TI - Secondary hypertrophic osteoarthropathy.
AB - Whenever hypertrophic osteoarthropathy is diagnosed, it is imperative to search
for the underlying pathology. The disorder is usually associated with a primary
pulmonary lesion and periostitis and paresthesias of the lower extremities.
Recognizing and understanding the primary pathology is essential to the effective
treatment of secondary hypertrophic osteoarthropathy.
PMID- 9542359
TI - Abscess-like gouty tophus of the foot.
PMID- 9542360
TI - Synovial sarcoma: an unusual case presentation.
PMID- 9542361
TI - Characterization of pulsatile secretion of gonadotropin and prolactin in women
with normal menstrual cycle, secondary amenorrhea and polycystic ovary syndrome
(PCOS).
AB - To characterize the episodic fluctuations of serum LH, FSH and PRL in women with
normally cycling, secondary amenorrhea and polycystic ovary syndrome (PCOS), four
groups of women were studied: group I (N = 8) consisted of normal women in the
follicular phase of the cycle; group II (N = 10) of women with secondary
amenorrhea and positive progesterone withdrawal bleeding; group III (N = 8) of
women with secondary amenorrhea and negative progesterone withdrawal bleeding;
group IV (N = 9), women with polycystic ovary syndrome (PCOS). Blood samples were
obtained at 15 minute intervals for 4 hours during one admission day. Ovarian
steroids were measured to evaluate the baseline endocrine environment in each
group. Distinct pulsatile fluctuations of serum LH, FSH and PRL were observed in
all subjects. These pulses showed a high degree of coincidence in LH with FSH and
LH with PRL in each group. However, the mean (+/- SD) frequencies of LH in group
III and group IV were significantly lower (P < 0.01) and higher (P < 0.01) than
in group I, respectively. The mean frequencies of FSH in groups III and IV were
lower (P < 0.05), as compared with those of group I. The mean amplitude of LH in
group IV was significantly higher (P < 0.001) than in group I. These results
suggest that loss of the regulatory pulsatility of gonadotropin releases may be a
contributory cause to anovulation and secondary amenorrhea. The concomitant
pulsatile releases of gonadotropin and PRL are essential to reproductive function
and their regulatory controls in the follicular phase may be mediated through a
common neuroendocrine mechanism in normal and hypogonadal women.
PMID- 9542362
TI - Anti-GT1b and anti-GM1 antibodies can increase after stroke but neither is
associated with late post-apoplectic epilepsy.
AB - The role of antiganglioside antibodies (AGAs) in late post-apoplectic epilepsy
(LPAE) was studied. Serum AGAs from 8 patients with large lobar infarctions were
serially checked for 2.5 months. Sera from another 30 patients with fronto
temporoparietal (FTP) or frontal (F) infarction were obtained 3 months to 3 years
after a stroke for AGA analysis. These 30 patients were followed up for 3 years
following their strokes to determine if LPAE developed. Results showed that 7/8
patients with large lobar infarction showed increase in either anti-GT1b or anti
GM1 (IgM or IgG) within a few weeks, but levels returned to the baseline 2-3
months after stroke. LPAE occurred in 9/21 patients with FTP infarction and 5/9
with F infarction. There was no difference in AGAs among patients with FTP and F
infarctions. Pooled data from these 2 groups showed no correlation between AGAs
and LPAE. These data document for the first time that anti-GT1b and anti-GM1
antibodies can transiently increase after stroke, but their late titers are not
associated with LPAE.
PMID- 9542363
TI - Simultaneous determination of paraquat and diquat in urine by capillary
electrophoresis.
AB - Qualitative and quantitative detection of paraquat and diquat in urine was
performed by capillary zone electrophoresis (CZE). In non-extracted urine, these
two closely related herbicides were hydrodynamically or electrokinetically
injected into the capillary and well separated in a acidic (pH 3.0) buffer (10 mM
glycin, 50 mM NaCl and 20% methanol) within 8 min. The analytes can be identified
by their respective migration time with no interfering endogeous compounds
around. The peaks were further confirmed by their respective multi-wavelength
scanning spectra. Limits of detection (LOD) were 0.2 and 0.1 mg/ml for PQ and DQ,
respectively, in nonextracted urine using hydrodynamic injection. Detection
sensitivity was greatly improved by solid phase extraction of the compounds
followed by CZE using electro-injection under which LODs were 15 and 8 ng/ml for
paraquat and diquat respectively. We conclude CZE is a useful method for
laboratory diagnosis of herbicide intoxication.
PMID- 9542364
TI - Ankle arthrography and chronic lateral ankle instability.
AB - Sixty-five ankle arthrograms of the patients who underwent surgical
reconstruction for their chronic ankle instability from 1987 to 1995 were studied
retrospectively by comparing their operative findings. There were 15 cases
(23.1%) with definite positive arthrographic findings. In the remaining 50 cases
(76.9%), the arthrograms showed a "tear-drop" extravasation of dye beneath the
fibular tip which we called "suspectable positive". Of these all but one, which
had normal ligament, proved to correspond to the operative finding. As there was
only one false positive finding among our surgical cases with both the "definite"
and "suspectable" positive arthrograms, we concluded that ankle arthrography is
relatively reliable and may be worth doing even in chronic cases if only for
reference. Even when other diagnostic methods are negative, arthrography might
help surgeons make surgical decisions in clinical symptomatic cases.
PMID- 9542365
TI - Tear of the anterior cruciate ligament: evaluation with MR imaging.
AB - Sixteen patients with traumatic injury to the knees were surveyed with magnetic
resonance (MR) machines with field strength of either 0.5 Tesla (T) using head
coil (10 cases) or 1.5 T using dedicated knee coil (6 cases). Tears of the
anterior cruciate ligament (ACL) were found in eight cases. The other eight cases
had injuries of the other ligaments, meniscus or bone with intact ACL. All cases
were proved by arthroscopy. Primary and secondary signs of the ACL tears were
evaluated by MR imaging. Primary signs included the status of ACL. Secondary
signs consisted of bone bruise in the posterolateral tibial plateau, in the
lateral femoral condyle, or both (so-called kissing bone bruise), fracture at the
posterolateral tibial plateau, Segond fracture, anterior dislocation of the tibia
(> 5 mm), buckled posterior cruciate ligament (PCL), positive PCL line and the
deep lateral femoral notch (> 1.5 mm). Of the eight cases of the ACL tears, 5
cases (62.5%) revealed thickening and edema of the ACL, 3 cases (37.5%) kissing
bone bruise, 1 case (12.5%) Segond fracture, 2 cases (25%) buckled PCL, 2 cases
(25%) deep lateral femoral notch, 2 cases (25%) anterior dislocation of the tibia
and 0 case (0%) positive PCL line. The ACL had normal thickness of low signal
intensity in 3 cases of chronic ACL tears (50%). Lateral meniscal tears were
found in seven of the eight cases of ACL tears (87.5%). For the eight cases with
intact ACL, the ACL was normal in thickness and of low signal intensity. Other
findings were bone bruise in the lateral femoral condyle (1 case, 12.5%),
fracture at the posterolateral tibial plateau (1 case, 12.5%), buckled PCL (1
case, 12.5%) and positive PCL line (1 case, 12.5%). It is concluded that primary
sign is important in the MR diagnosis of the ACL tears. Secondary signs are
helpful but may be present in lesions with intact ACL.
PMID- 9542366
TI - The effects of Western music on postoperative pain in Taiwan.
AB - Music is a method nurses can use to help relieve pain, however little is known
about its effectiveness across cultures. In this study, Western music was tested
for its effectiveness in reducing postoperative pain in 38 Taiwanese patients,
and its acceptability was explored. A pretest and post-test experimental design
was used with visual analogue scales to measure sensation and distress of pain.
Before surgery, subjects were randomly assigned to receive tape recorded music or
the usual care. Those who were assigned to the music group chose among 5 types of
sedative music. On postoperative Day 1 and Day 2, the effectiveness of the tape
recorded music was investigated during 15 minutes of rest in bed. Patients were
interviewed on Day 3 to determine their liking for the music, its calming
effects, and the helpfulness of the music. Repeated measures analysis of variance
showed a significant interaction between time and group in the distress of pain
on Day 1, but not on Day 2, and in pain sensation on Day 2, but not Day 1.
Subjects from Taiwan were similar to subjects in a previous study in the United
States in their liking for the music, and in reports of the helpfulness of the
music for pain sensation and distress, but fewer Taiwanese found the music
calming, and they had different choices: more chose harp music and fewer chose
jazz than subjects in the U.S. study, and some would prefer Buddhist hymns or
popular songs heard in Taiwan. Findings support the use of culturally acceptable
music in addition to analgesic medication for the sensation and distress of
postoperative pain.
PMID- 9542367
TI - Factors related to adolescents' perceptions of treatment outcomes in an
adolescent health clinic.
AB - To determine factors related to adolescents' perceived treatment outcomes of
their health problems in an adolescent health clinic located at a college
hospital, 246 adolescent patients between the ages of 11 and 21 who visited the
clinic twice or more during the period January 1994 to December 1995 were
included in this study. Information concerning adolescents' sociodemographic
characteristics, family function, office visits and health problems of first
visits was collected by reviewing subjects' medical and other clinic-related
records. In addition, a structured questionnaire was mailed to assess subjects'
satisfaction with physicians and the environment and services provided by the
clinic as well as their perceived treatment outcomes. 148 patients completed the
questionnaire, a response rate of 60.2%. Most of the respondents were in late
stage adolescence (71.0%) and were in school (71.0%). About half of respondents
had normal family function, while the other half had moderate or severe family
dysfunction. Most of the health problems of respondents were acute (64.2%) and
were biological (76.4%) conditions. Most of the respondents were satisfied with
the various characteristics of physicians except confidentiality emphasized by
the physicians, while many fewer respondents were satisfied with the environment
and services provided by the clinic. Family function, physicians' respect toward
the adolescents, and the adolescents' satisfaction with the services provided in
general were the factors significantly related to adolescents' perceived
treatment outcomes based on a stepwise, multiple logistic regression analysis. We
conclude that efforts to provided could result in better adolescent perceived
treatment outcomes.
PMID- 9542368
TI - Shaken baby syndrome.
AB - Fourteen cases of shaken baby syndrome seen between 1993 to 1997 at the Kaohsiung
Medical College Hospital were reviewed. The common clinical presentations were
seizure, respiratory problem and disturbed consciousness. The signs and symptoms
of this form of head trauma were nonspecific. The findings may mimic infection,
intoxication, seizure disorder or metabolic abnormalities. The CT scan is the
most common diagnostic tool in cases of suspected shaken baby syndrome. The
common CT findings were acute subdural hematoma followed by chronic subdural
hematoma and subarachnoid hemorrhage. One infant died due to delay in seeking
medical help. Five patients sustained significant morbidity which included
developmental delay, seizure, motor deficit and visual impairment. Early
recognition and prompt treatment were key to the overall success of case
management. The incidence of shaken baby syndrome can be reduced through public
awareness and education of the parents not to shake the baby.
PMID- 9542369
TI - Cavernous sinus syndrome and hepatoma metastasis.
AB - A 46-year-old man presented with left cavernous sinus syndrome and subsequent
right leg pain proved clear cell type hepatocellular carcinoma metastasis. An
initial liver function test was normal and alpha-fetoprotein was only 15 ng/ml
but they increased rapidly and he progressed to hepatic failure 2 weeks later.
Therefore, a subclinical hepatoma with metastasis should be differentiated in
cavernous sinus syndrome, even in cases of normal hepatic enzymes, because
hepatoma is prevalent in Taiwan.
PMID- 9542370
TI - Gastric duplication cyst: report of a case.
AB - Gastric duplication cyst is a rare disease entity, especially in the adult
population. We report a case of 33-year-old female patient who presented with
epigastric pain, postprandial fullness and nausea for the past several months.
Gastroendoscopy showed a submucosal mass with normal overlying gastric mucosa.
Upper gastrointestinal series confirmed a extrinsic compression of mass in the
fundus of the stomach. Endoscopic ultrasonography and computerized tomography
demonstrated the lesion to be a cyst in nature. The surgical procedure consisted
of total excision without violation of the gastric lumen. Gastric mucosa was
found by the histologic study of the excised cyst.
PMID- 9542371
TI - [The contributions of occupational medicine to ergonomics].
AB - Major contributions to the development of ergonomics, originating from
observations, studies, research and applications in numerous working situations
in the occupational health area, are presented and discussed in an analytical and
concise manner. Ergonomics can provide an extremely useful conceptual and
methodological approach provided it complies with the trends developed by the
European Coal and Steel Commission in the past ten years for the coal and steel
industry and now adopted by the International Ergonomics Association. Otherwise
prevention of occupational hazards would be reduced to early diagnosis only,
relinquishing all prospects of primary prevention which, if correctly applied,
can only be achieved via an anthropocentric design concept. Therefore new
epistemological choices, new theories, methods and design procedures need to be
widely implemented so that they can be correctly synthetized, in accordance with
the centrality, the values and the aspirations of the human operator in complex
systems.
PMID- 9542372
TI - [Biomechanical pathology of the upper limb: a new epidemic?].
AB - Work-related upper limb disorders are one leading occupational diseases in many
industrialized countries. The paper reviews the evidence of work-relatedness of
the most common upper limb disorders (namely carpal tunnel syndrome, hand-wrist
and shoulder tendinitis, trapezius myalgia, hand hammer syndrome). Attention is
drawn to the difference in the number of reported cases in Italy and other
countries, assuming, as an underlying cause, underreporting of such conditions in
Italy.
PMID- 9542373
TI - [The health risks of exposure to electromagnetic fields in work environments].
AB - In the last few years the debate on possible health risks of electromagnetic
fields has focused on specific sources, namely power lines and, more recently,
base stations for cellular telephones. This has drastically diverted the
attention of the research and prevention community towards residential exposures.
On the other hand, the increasing number of technological process exploiting or
generating electromagnetic fields requires greater attention to exposures at the
workplace. The scope of research in this area is vast because of different
emission characteristics of the sources, different interaction mechanisms at
various frequencies, and different effects that have been identified or
hypothesized. The paper presents an overview of health problems involved in
exposure to electromagnetic fields at the workplace. Different frequency ranges
and related sources are considered separately. In particular, the different
levels of knowledge are noted and areas requiring further research are
identified.
PMID- 9542374
TI - [The concentration levels of airborne quartz at an urban site].
AB - The IARC has recently included crystalline silica among substances considered
carcinogenic for man. This new evaluation immediately posed the need to measure
the exposure levels of the general population. The paper reports the results of
measurements of the concentrations of quartz (i.e., the most common form of
crystalline silica) in a location in the urban area of Rome. First we studied the
respirable fractions of the airborne particles (PM10) sampled in the Spring of
1996 with a cascade impactor, which were characterized using a scanning electron
microscope equipped with an X-ray microprobe. Ten components were identified
including total silica (crystalline and amorphous), which was present in a
percentage of 3.7% on average. On the basis of these data a methodological study
was undertaken of the concentration of quartz in the historic series of PM10
sampled daily at the same site by means of an AMP instrument (Airborne Particles
Monitor). The filters of mixed cellulose esters on which the PM10 was collected
were incinerated at low temperature in oxygen plasma to eliminate the organic
component. The residue was deposited on silver filters which were read with a
conventional X-ray diffractometer in order to determine the quantity of quartz.
We analyzed 28 filters from four representative weeks of the four seasons of
1994, the year in which systematic sampling was initiated. The results showed a
mean weekly concentration of airborne quartz of between 0.6 and 1.5
micrograms/Nmc, which gives a percentage over PM10 of 1.7 and 3.4 respectively.
These data substantially agree with previous results obtained with electron
microscopy and show that the levels of quartz in the urban atmosphere under study
were about one hundred times lower than the TLV currently recommended by the
ACGIH for working environments (100 micrograms/Nmc) and which are also in force
in Italy.
PMID- 9542375
TI - [Allergic pathology due to enzymes: a case report of asthma due to pectinase
(polygalacturonase)].
AB - The paper described the case of a worker handling pectinase, an enzyme used in
the manufacture of food additives. This enzyme is a carbohydrase
(polygalacturonase) obtained by extraction, and consists of three active phases.
After little more than a year at the job, the subject complained of bouts of
asthma, especially when she had to weigh the enzyme in dust form. Symptoms
appeared even when this operation was performed by others near her work station.
An allergological examination revealed skin hypersensitivity to the enzyme,
without atopy. The methods of preparing the tests performed are described. The
authors stress the need to perform similar investigations on other exposed
workers in order to assess the allergogenic potential of the substance and adjust
environmental preventive measures accordingly.
PMID- 9542376
TI - Epidemiological study on knowledge, attitudes and behaviour of health care
workers with respect to HIV infection.
AB - To analyse knowledge, perception of risk, attitudes and behaviour towards HIV
infection among health workers in two hospitals in the North-East of Italy, we
sent all health care workers who were working in direct contact with patients an
anonymous self-administered questionnaire covering personal and occupational
data, perception and knowledge of risk, behaviour in routine activities,
attitudes towards and care of HIV patients. The response rate was 70.06%. The
perception of the risk of acquiring HIV infection was influenced by occupational
qualification, by work unit and by having cared for a HIV-positive patient.
Scientific knowledge about transmissibility of HIV infection was poor and 11.3%
of the staff did not know the Universal Precautions. 28.3% behaved correctly in
recapping needles, but with patients considered not at risk 29.9% did not use any
protection in drawing venous blood. A significant portion of staff showed low
willingness to care for HIV-positive patients. We found a high mean perception of
the risk of contracting HIV infection through occupational exposure; health
workers overestimated the specific risk and wrong behavioural attitudes
persisted. To conclude, more attention should be paid to educational programs for
health workers.
PMID- 9542377
TI - [The presence of asbestos on board ships: optical microscopy as a research
instrument].
AB - Identification of asbestos in many different kinds of bulk materials was
performed by means of optical microscopy and the results are reported in the
present paper. Some hundreds of various samples taken aboard ships were analysed:
panels, laggings, spray insulations, etc. These analyses were required to be not
only reliable but also rapid. The results demonstrated the high reliability as
well as the rapidity of the technique. Using both the well-known dispersion
staining technique (with central stop objectives or with dark field condensers)
and phase-contrast analyses on the same polarizing microscope, we carried out
numerous checks on the optical properties of the fibres. Not only were dispersion
staining colours detected but also refractive index, elongation and extinction
signs, in order to obtain an absolutely certain identification. The Italian laws
which deal with the asbestos detection discourage the use of the optical
microscope because of its presumed unreliability. This paper tends to demonstrate
that Italian laws underestimate the potential of the optical microscope. Optical
microscopy is probably the only technique that is reliable, inexpensive and rapid
at the same time.
PMID- 9542378
TI - Practice management contracts/illegal fee-splitting.
PMID- 9542379
TI - A physician's primer for managed care contracting.
PMID- 9542380
TI - MSMSNET a "hit".
PMID- 9542381
TI - "Back to sleep" campaign a success. SIDS rates drop due to information,
education.
PMID- 9542382
TI - Staying ahead financially. Reimbursement tips for a changing environment.
AB - Physicians' primary goal is to give good care to their patients. But like other
managers in changing times, they face big challenges to achieving their goals.
Major national stressors for all professionals today, experts report, are time
and money. MSMS leaders, participating in strategic planning sessions this past
summer and fall, agreed, ranking reimbursement/revenue problems as second on
their list of concerns, right behind autonomy as physicians.
PMID- 9542383
TI - Area hospital receives a "breath of fresh air".
PMID- 9542384
TI - [Control of apparatus in anesthesia. Gruppo di Studio SAARTI per la Sicurezza in
Anestesia e Terapia Intensiva].
PMID- 9542385
TI - [Recommendations for basic monitoring of patients during anesthesia. Gruppo di
Studio SAARTI per la Sicurezza in Anestesia e Terapia Intensiva].
PMID- 9542386
TI - [Informed consent in anesthesia. In accordance with the general guidelines
proposed by the European Board of Anesthesiologists (EBA)].
PMID- 9542387
TI - [Recommendations for post-anesthetic care. Gruppo di Studio SAARTI per la
Sicurezza in Anestesia e Terapia Intensiva].
PMID- 9542389
TI - [Recommendations for anesthesia in the day hospital. Gruppo di Studio SAARTI per
la Sicurezza in Anestesia e Terapia Intensiva].
PMID- 9542388
TI - [Recommendations on malignant hyperthermia. Gruppo di Studio SAARTI per la
Sicurezza in Anestesia e Terapia Intensiva].
PMID- 9542390
TI - [The HIV positive patient in anesthesia and intensive care. Organizational,
medico-legal aspects. Gruppo di Studio SAARTI per la Sicurezza in Anestesia e
Terapia Intensiva].
PMID- 9542391
TI - Treatment of the epileptic patient in the dental office.
AB - Epilepsy is a relatively common problem in children, adults and the elderly.
Dentists need to be familiar with the various manifestations of the disease, the
anticonvulsant medications (AEDs) the patients are taking, and the complications
and side effects of these drugs. In this article the types of seizures and AEDs
in common use are described. Guidelines for treatment planning are given.
Recommendations are made for managing the patient who has a seizure in the dental
office.
PMID- 9542392
TI - Dental caries in developing countries. Preventive and restorative approaches to
treatment.
AB - The rate of dental caries in developing countries is rising. Because more than 80
percent of the world's children live in these countries, this alarming trend is
of great concern from a public health standpoint. Currently, most dental care in
developing nations consists of dental surgery in urban areas. Decay is usually
left untreated until it becomes so extensive and/or painful that extraction is
the only option. Traditional approaches to treating carious lesions have met with
marginal success. There is a need for widespread implementation of preventive
strategies, which have proven extremely effective in industrialized nations.
Also, promising new techniques and materials are being developed that are
enabling dentists and dental personnel to make less costly treatment of dental
caries more readily available to underserved populations.
PMID- 9542393
TI - Recommendations for fluoride use in children. A review.
AB - Fluoride has played a significant role in the improvement of the oral health of
all Americans. Because of its effectiveness, cost and frequency of exposure,
water fluoridation is the preferred method of delivery. Today, many products
containing fluoride are available over the counter and as prescription items. The
potential for exposure to multiple sources of fluoride has increased. Therefore,
practitioners should prescribe fluoride therapy based on an understanding of
patients' total exposure to fluoride and the need for additional amounts.
PMID- 9542394
TI - When children put their fingers in their mouths. Should parents and dentists
care?
AB - We have heard mothers tell their children not to stick their fingers in their
mouths because they will get sick. Medical and dental professionals know this is
true. Oral habits like thumb sucking and nail biting can damage the structure of
the mouth and can lead to the spread of infectious diseases.
PMID- 9542395
TI - [One general pattern in the development of pathologic processes in the heart in
various types of myocardial involvement].
AB - Experiments on 50 rabbits were made to study left and right ventricular function
and ultrastructure of the heart in its diffuse and focal disease, overload of the
intact heart. In the middle stage of the above conditions there was a distinct
dyscoordination of the heart function and the growth of differences in the heart
ventricles ultrastructures. This phenomenon may underlie the rise of intracardiac
and general hemodynamic disturbances.
PMID- 9542396
TI - [Pathogenesis, diagnosis and therapy of heart disease caused by enteroviruses
(molecular biological study)].
AB - Molecular hybridization studies have demonstrated that human enteroviruses,
including group B coxsackieviruses (CVB), are detectable in myocardial tissue of
patients with acute and chronic myocarditis. As well, such infections are
observed in some patients with end-stage dilated cardiomyopathy indicating the
possibility of persistent heart muscle infection. Enterovirus persistence in the
human heart is supported by the discovery in various murine models of chronic
myocarditis, demonstrating that coxsackievirus B3 (CVB3), typically a cytolytic
virus, is capable of evading immunological surveillance in a host-dependent
manner. Currently attention is focused on the analysis of molecular mechanisms of
virus persistence, the characterization of viral and host factors and their
impact in determining the natural course of myocardial enterovirus infections.
The evidence for a causal linkage of enterovirus infection with heart muscle
diseases has emerged therapeutic implications. From the view of a virologist,
immunosuppressive treatment of patients revealing enterovirus infection in the
myocardium with steroids is clearly contraindicated. The evaluation of potent
antiviral agents, such as interferons, in established in vitro and in vivo model
systems of enterovirus infection is expected to contribute significantly to new
therapeutic strategies in human enteroviral heart disease.
PMID- 9542397
TI - [Visceral afferentation and nociception].
AB - The authors present the results of acute cat experiments in which characteristics
of the heart afferent reactions were studied by registration of evoked
potentials. It was shown that in occlusion of the coronary arteries afferent and
vegetative reactions did not correlate with development of cardial nociception.
This was related to opiate mechanisms of the intraorgan regulation. In myocardial
histotoxic hypoxia intraorgan mechanisms of the heart afferent reactions were
destroyed.
PMID- 9542398
TI - [Functional disturbances of the immune system in rheumatic diseases and their
dynamics in the context of pathogenetic therapy].
AB - Immunological investigations in patients with rheumatic diseases (rheumatoid
arthritis, Reiter's disease, infectious endocarditis, rheumatic heart disease)
evidence that the time of onset of different immunologic pathogenetic mechanisms
was the same. Immunological rehabilitation was achieved by different therapeutic
methods: drugs, plasmapheresis, hemosorption, electrophoresis, ultrasound. In
experiments it was beta-1-trophoblastic glycoprotein.
PMID- 9542399
TI - [Use of thymogen in the treatment of various forms of acute abdominal disorders
in an experiment].
AB - The authors have carried out experimental studies of thymogen action on the
course of acute pancreatitis and acute peritonitis in white albino rat males. The
preparation was introduced into the abdominal cavity early after the modeling and
every 24 hours for 5 days. The results of the trial demonstrate that the degree
of autoenzyme aggression (the data of blood serum alpha-amylolytic activity
control) and the content of lipid peroxidation products (assessment of malonic
dialdehyde quantity in tissue homogenate) were low in the experimental group as
compared to the untreated animals. In the experimental group less pronounced
depression of antiradical activity (superoxide dismutase and catalase activity
control) was found, leukocytosis and leukocyte intoxication index were
diminished. Thus, the efficiency of thymogen in acute inflammatory and
destructive abdominal diseases has been proved.
PMID- 9542400
TI - [Ultrastructure of human peripheral blood lymphocytes as affected by extreme
factors].
AB - Characteristic features of ultrastructure of peripheral blood lymphocytes were
studied in males aged 20-24 years performing hard muscular labour under emotional
stress in unfavourable climate conditions. It was found that a prolonged exposure
(> 3 mo) to the extreme factors brings about characteristic changes in
ultrastructure of peripheral blood lymphocytes: a complicated shape of the
lymphocytic nuclei, plasma membrane labilization, partial or total destruction of
the mitochondrial cristae in most of the cells. It was suggested that all these
changes were morphological criteria of reduced resistance of the body in response
to extreme conditions. It was also established that autumn is less favourable for
adaptation to extreme physical and climate conditions than summer.
PMID- 9542401
TI - [Ultrastructural characteristics of nonphlogogenic and phlogogenic reaction of
mono- and polynuclear phagocytes in their interaction with Staphylococcus
aureus].
AB - Antibacterial function of neutrophil leukocytes and peritoneal macrophages in
their interaction with massive doses of Staphylococcus aureus (25 x 10(6) and 25
x 10(8) microorganisms) has been studied in the experiment in vivo. Two types of
antibacterial reaction of phagocytes has been found, i.e. nonphlogogenic
(physiological) and phlogogenic (inflammatory). nonphlogogenic type was
characterized by marked antibacterial influence of phagocytes. phlogogenic
reaction was accompanied by an increase of failure of phagocyte function, by
their self-damage and break-up that leads to a decrease of their antibacterial
activity followed by the inflammation.
PMID- 9542402
TI - [Change in the content of alpha-fetoprotein and sex steroid hormones in the blood
of rabbits in fever or subnormal temperature].
AB - In experiments on rabbits, changes in the content of alpha-fetoprotein, estradiol
and progesterone in blood serum in fever and subnormal temperature simulated with
the use of pyrogenal and Freund's complete adjuvant were studied. The
concentration of alpha-fetoprotein decreased and that of estradiol and
progesterone increased. The results were analyzed in terms of the return of
certain signs and properties in disease to the period of antenatal ontogenesis. A
possible relation between the changes in alpha-fetoprotein in fever, subnormal
temperature and immune, hormonal mechanisms of the thermoregulatory disorder was
hypothesized.
PMID- 9542403
TI - [Role of vascular and cellular complexes of nerve tissue in the mechanism of anti
edema action of phenothiazine derivatives].
AB - The stochastic model has been designed enabling elucidation of structural
components of the nervous tissue involved in antiedema mechanism of phenotiazine
derivatives in conditions of negative effects of edematous factors. The
stochastic model helped detection of basic control structures in the tested
morphofunctional complexes, provided quantitative assessment of the effects of
interrelations of the morphofunctional structures in response to the interfering
factors.
PMID- 9542404
TI - [Vasotropic action of met-enkephalin in sympathetic nervous system block].
AB - Administration of met-enkephalin to anesthetized cats promoted inhibition of the
heart rate, weakening of the vagus chronotropic effect with changes of its
functional structure consisting of suppression of the inhibitory tonic effect and
potentiating synchronizing component. The comparison of the peptide's vagotropic
action in the initial conditions versus in the block of the sympathetic nervous
system induced by obsidan, guanethidine or reserpine allows the conclusion that
the effect of met-enkephalin on the baseline heart rate, strength of the vagus
chronotropic effect and its tonic component stems from weakened sympathetic
effects on the heart, whereas potentiation of the synchronizing vagus component
is achieved through the peptides effects in the limits of vagus regulation
system.
PMID- 9542405
TI - [The immune system and pathology (continuation). Chapter 4. Pathologic processes
with involvement of the immune system. Pathogenetic methods of immunocorrective
therapy].
PMID- 9542406
TI - [Glucocorticoids and myocardial infarction].
PMID- 9542407
TI - Keynote address: PDA/FDA joint conference.
PMID- 9542408
TI - Evaluation of high-temperature and short-time sterilization of injection ampules
by microwave heating.
AB - The high-temperature and short-time sterilization by microwave heating with a
continuous microwave sterilizer (MWS) was evaluated. The evaluation were
performed with respect to: [1] lethal effect against microorganisms corresponding
to F-value, and [2] reliability of MWS sterilization process. Bacillus
stearothermophilus ATCC 7953 spores were used as the biological indicator and the
heat-resistance of spores was evaluated with conventional heating method (121-129
degrees C). In MWS sterilization (125-135 degrees C), the actual lethal effect
against B. stearothermophilus spores was almost in agreement with the F-value and
the survival curve against the F-value was quite consistent with that for the
autoclave. These results suggest that the actual lethal effect could be estimated
by the F-value with heat-resistance parameters of spores from lower than actual
temperatures and that there was no nonthermal effect of the microwave on B.
stearothermophilus spores. The reliability of sterilization with the MWS was
confirmed using more than 25,000 test ampules containing biological indicators.
All biological indicators were killed, thus the present study shows that the MWS
was completely reliable for all ampules.
PMID- 9542409
TI - Application of a newly developed hydrogen peroxide vapor phase sensor to HPV
sterilizer.
AB - A new type of concentration sensor for hydrogen peroxide vapor has been developed
by making use of a semiconductor. Output from the vapor sensor has been shown to
have a good linear relationship with the logarithm of the concentration of
hydrogen peroxide vapor. Concentration of hydrogen peroxide vapor introduced into
the sterilization chamber could be kept constant by monitoring the concentration
of the hydrogen peroxide vapor continuously and controlling the vapor supply.
Temperature and humidity have also been kept constant. D-values for B.
stearothermophilus ATCC 12980 at various concentrations of hydrogen peroxide
vapor have been determined by using the combination system of the hydrogen
peroxide vapor sensor, the hydrogen peroxide vapor supplier, thermosensor and
humidity sensor. D-values at the temperature of 30 degrees C and the absolute
humidity of 0.7 mg H2O/L thus obtained, were 0.2 minutes at hydrogen peroxide
concentration of 600 ppm and 1.2 minutes at 200 ppm at the temperature of 30
degrees C and 0.7 mg/L absolute humidity. D-values for B. stearothermophilus ATCC
12980 at various temperatures, humidity and levels of hydrogen peroxide
concentration have also been determined. These fundamental data indicate that the
sterilization by hydrogen peroxide vapor can be validated as precisely as steam
sterilization by measuring and controlling the concentration of hydrogen peroxide
vapor using a combination of the hydrogen peroxide concentration sensor and the
vapor generator. Influence of temperature and humidity have also been studied.
The hydrogen peroxide sensor has been calibrated and standardized by using the
standard hydrogen peroxide vapor whose concentration has been determined by
calculating partial pressure of hydrogen peroxide over the water-hydrogen
peroxide solution.
PMID- 9542410
TI - Silicone absorption of elastomeric closures--an accelerated study.
AB - There is a trend in the parenteral industry to move from the use of elastomeric
closures which are washed, siliconized, dried and sterilized in-house at the
pharmaceutical manufacturers' site to pre-prepared closures purchased from the
closure supplier. This preparation can consist of washing to reduce particle-load
and bioburden, siliconization, placement in ready-to-sterilize bags and may
eventually extend to sterilization by steam autoclave or gamma irradiation. Since
silicone oil lubrication is critical to the processability/machinability of
closures, research was designed to investigate this phenomenon in closures
prepared using the Westar RS (Ready-to-Sterilize) process. This paper presents
the data gathered in a study of the characteristic of silicone absorption into
elastomeric closures under accelerated conditions. Variables such as silicone
viscosity, rubber formulation, effect of sterilization and others are considered.
PMID- 9542411
TI - Storage stability of stabilized MLV and REV liposomes containing sodium
methotrexate (aqueous & lyophilized).
AB - Multilamellar and unilamellar liposomes containing sodium methotrexate (MTX) were
prepared by thin film hydration and reverse-phase evaporation methods.
Encapsulation efficiency and release of MTX from liposomes at 4 degrees C, 25
degrees C and 37 degrees C were determined. When stored at 25 degrees C the
liposomes lost 33% MTX after one month. To stabilize liposomes, they were freeze
dried in presence of different amounts of cryoprotectants (trehalose, PEG 10,000,
PEG 20,000, and a mixture of trehalose-PEG 20,000). Measurements showed that the
mixture of trehalose-PEG 20,000 imparted an MTX retention of about 70% after
lyophilization. Stability tests of the lyophilized product at 4 degrees C, 25
degrees C and 37 degrees C demonstrated they were fairly stable even at 37
degrees C, indicating their potential use in commercial applications.
PMID- 9542412
TI - Determining whether a product is steam sterilizable.
AB - The FDA has issued proposed regulations to require that manufacturer's evaluate
the "steam sterilizability" of parenteral products. There are many different ways
to assess sterilizability. Within a company, it is helpful to standardize the
methodology used to determine whether the product should be terminally
sterilized. The following is one approach to determining product sterilizability.
This approach is also depicted in a flow chart (Figure 4).
PMID- 9542413
TI - Bacterial cell size and surface charge characteristics relevant to filter
validation studies.
AB - There are two recognized mechanisms whereby organisms are retained by liquid
filters; namely, sieve-retention and adsorption. The efficiency of each may be
influenced by the organism, suspending milieu, and by the filtration conditions.
Validations of sterilizing filtrations require the use of organism suspensions in
product-specific media. However, where the product is bactericidal to the
challenge organism(s), surrogate solutions may be required. The ideal surrogate
solution would minimize adsorptive retention, ensuring that the sterilizing
action of the filter under consideration is the consequence of sieve-retention.
This review explores the impact that various physicochemical factors may have on
bacterial cell size and cell surface characteristics. An understanding of
interactions among challenge bacteria, suspending fluid, and filter medium is
essential for the development of surrogate solutions that provide a "worst case"
mileu for filter validation studies or a "placebo," non-inhibitory challenge
solution.
PMID- 9542414
TI - Pharmaceutical laboratory compliance--manufacturer's view.
PMID- 9542415
TI - Experimental evaluations of diffusive airflow integrity testing.
PMID- 9542416
TI - [New trends in the management of asthma. Satellite Symposium of the 24th Congress
of the German Society of Allergology. Hamburg, 6 September 1997].
PMID- 9542417
TI - Pediatric nuclear medicine: a practical approach.
AB - This paper is devoted to the practical aspects of pediatric nuclear medicine,
particularly the controversy about drug sedation. The authors conclude that drug
sedation should be exceptionally used. There is an alternative way, consisting in
an adequate approach of the patient: good information to the parents and the
child; taking care of the child's environment, starting from the first contacts
in the waiting room; specific education of technologists: this includes
injections and blood sampling, but also proper handling of the child during the
procedure and adequate psychological attitudes toward child and parents. Taking
these factors into account, it is exceptional that a test has to be postponed
because of the lack of collaboration of the patient; good quality images, using
the recommended paediatric amounts of radioactivity can be achieved even for
procedures of prolonged duration.
PMID- 9542418
TI - Assessment of gastro-esophageal dysfunction in children.
AB - Scintigraphic methods to assess esophageal transit, gastro-esophageal reflux and
gastric emptying are widely used in pediatric patients. This review describes the
methodology and considers the clinical application of these techniques as well as
the utility of alternative diagnostic studies.
PMID- 9542419
TI - PET applications in pediatrics.
AB - This article summarizes the major PET studies which have been performed in
pediatric patients to elucidate and characterize diseases and normal development.
Issues special for the application of the technique in children, such as
dosimetry, patient preparation, and image acquisition are discussed. Studies of
central nervous system (CNS) development and pathology, including epilepsy,
intraventricular hemorrhage, neonatal asphyxia, tumors, and effects on the CNS
from treatment of other tumors are reviewed. These have contributed information
fundamental to our understanding of CNS development and pathology. PET
investigations into the pathophysiology of congenital heart disease have begun
and hold great promise to aid our understanding of these conditions. The second
major area in which PET has been applied is the study of non CNS neoplasms.
Neuroblastoma has been investigated with tracers which explore basic biochemical
features which characterize this tumor, as well as with tracers which explore
biochemical events relatively specific for this malignancy. Other common and
uncommon tumors of childhood are discussed. The PET technique has been shown
useful for answering questions of clinical relevance for the management of these
uncommon neoplasms. PET, using tracers that reflect basic metabolic processes, is
likely to continue to aid our understanding of many pediatric diseases and may
gain more widespread clinical acceptance as the technology continues to
disseminate rapidly.
PMID- 9542420
TI - Lung scintigraphy in the assessment of recurrent bronchitis and pneumonia in
children.
AB - Recurrent bronchitis and pneumonia in childhood are a significant factor in
predisposing adults to chronic respiratory disease. Lung scintigraphy in children
with recurrent respiratory problems very frequently shows regional abnormalities,
even in the absence of radiological signs: the main problem being the correct
clinical use of such a high sensitivity. Structural changes, also at the
histological level, are accompanied by functional disturbances that cause lung
scan abnormalities to become stable with time and are very likely responsible for
persisting disease in adulthood: the above condition needs to be identified by
means of follow-up scintigraphies. Moreover, any chronic respiratory condition
that has already been diagnosed, like cystic-fibrosis, bronchiectasis,
bronchopulmonary malformations, lung fibrosis, should be assessed and followed-up
by means of lung scintigraphy. Suspected radiotransparent foreign-body
inhalation, radiographical hyperlucencies (compensatory or pathological
emphysema?), functional assessment before lung surgery, suspected mucociliary
function impairment, suspected interstitial pneumonia, pre-bronchographic or
angiographic assessment, all of the above conditions represent important
indications to lung scintigraphy in children. Finally, it is wise pointing out
that, in order to avoid false positive results towards the diagnosis of
structural disease, any easily reversible functional impairment should be removed
before the scan, by proper patient preparation: in children this is done by at
least aerosol therapy with beta-agonists, local steroids and mucolytics for 1
week-10 days.
PMID- 9542421
TI - Economic issue in pediatric nuclear medicine: cortical scanning of acute
pyelonephritis.
AB - Pediatric nuclear medicine, in order to survive, must be innovative in finding
ways of competing with other pediatric imaging subspecialties for the health care
dollars. Newer radiopharmaceuticals and imaging methods that are time-effective
in answering clinical problems and cost-effective in attracting the health care
providers are ways of accomplishing this difficult task. Renal cortical scanning
for the diagnosis of acute pyelonephritis is presented as an example of an
existing nuclear medicine study that is accurate and cost-effective, but has not
yet taken a major place in the imaging armamentarium. In this discussion, the
cortical scan is endorsed as the primary imaging tool for children presenting
with acute urinary infection.
PMID- 9542422
TI - Inflammatory bowel disease in pediatric patients.
AB - Optimal management of chronic idiopathic inflammatory bowel disease requires
determination of disease localization and intensity. Scintigraphy with the use of
99mTc-HMPAO-White Blood Cells (99mTc-HMPAO-WBC) is a relatively new noninvasive
nuclear medicine procedure. We have evaluated more than 230 children and have
found a high correspondence between the disease distribution shown by the 99mTc
HMPAO-WBC scan and that shown by endoscopic, radiologic, or surgical methods.
Additionally the 99mTc-HMPAO-WBC scan has the ability of identifying extra
intestinal site of inflammation, such as appendicitis and others. The erythrocyte
sedimentation rate, the most frequently used indicator of disease activity in the
clinical setting, has better correlation with the scan scores than the clinical
activity index. The 99mTc-HMPAO-WBC scan is reliable in differentiating Crohn's
disease from ulcerative colitis. Some patients because of unequivocal
demonstrable small bowel uptake are reclassified from ulcerative colitis to
Crohn's disease. The medication regimen is frequently altered because of the
intensity of uptake displayed by the 99mTc-HMPAO-WBC scan. It is a practical and
safe study even in an acutely ill patient who may not tolerate endoscopic or
radiological study. At our institution, the 99mTc-HMPAO-WBC scan is now part of
the initial evaluation, and follow-up of patients with inflammatory bowel
disease. In conclusion the 99mTc-HMPAO-WBC is excellent for the detection,
localization and characterization of inflammatory bowel disease in children.
Compared with the other methods of investigation this study requires no bowel
preparation, is noninvasive and has excellent diagnostic accuracy.
PMID- 9542423
TI - Pediatric nuclear oncology.
AB - Nuclear medicine plays an important and increasing role in the management of
childhood malignancy. This is particularly true in the solid tumours of
childhood. It is also helpful in the management of the complications of cancer
treatment such as the infections which often accompany immune suppression in
oncology patients. Scintigraphy is a complementary investigation to other
radiological techniques and adds the functional dimension to anatomical
investigations such as CT, MRI and ultrasound. Scintigraphy is used in the
initial diagnosis, staging, assessment of tumour response to treatment, detection
of recurrence and the diagnosis of complications. In selected malignancies
radionuclides are also used in treatment. This review discusses the technical
considerations relating to children and the specific techniques relating to
pediatric oncology. Specific tumours and the various applications of
radionuclides are discussed in particular lymphoma, primary bone tumours, soft
tissue sarcomas, neuroblastoma, Iangerhan's cell histiocytosis, Wilms' tumour,
brain tumours and leukemia. Uncommon tumours are also discussed and how
radionuclides are useful in the investigation of various complications which
occur in oncology patients.
PMID- 9542424
TI - [Hemodynamic monitoring: Swan-Ganz catheter].
PMID- 9542425
TI - [Mechanical ventilation].
PMID- 9542426
TI - [Acute myocardial infarct].
PMID- 9542427
TI - [General assessment of the trauma patient].
PMID- 9542428
TI - [Poisoning].
PMID- 9542429
TI - [Changes of the level of consciousness: coma and related conditions].
PMID- 9542430
TI - [Immediate postoperative management].
PMID- 9542431
TI - [Multiple organ dysfunction syndrome].
PMID- 9542432
TI - [Continuous education in cardiology. Education Commission, Spanish Society of
Cardiology].
PMID- 9542433
TI - [Structure and function of the heart].
PMID- 9542434
TI - [Cardiac tumors (II). Malignant primary tumors. Metastatic tumors. Carcinoid
tumor].
AB - Heart neoplasms are of increasing interest among clinicians and surgeons. A
review of primary malignant cardiac tumors, secondary cardiac tumors and
carcinoid heart tumors is presented, with special reference to their pathological
and surgical aspects. Primary malignant heart tumors represent about 25% of all
cardiac tumors, the great majority are sarcomas and the whole family of this
group is described including angiosarcoma, rhabdomyosarcoma, fibrosarcoma,
leiomyosarcoma, liposarcoma, neurogenic sarcoma, synovial sarcoma and
osteosarcoma; mesothelioma, lymphoma, malignant teratoma and thymoma are also
included. Metastatic heart tumors are 20-40 times more common than primary
malignancies, their behavior and more relevant aspects in diagnostic and surgical
therapy are mentioned. Carcinoid heart tumors represent a distinctive entity and
are discussed individually.
PMID- 9542435
TI - [The value of cardiac troponin I as diagnostic test in the study of chest pain].
AB - BACKGROUND AND OBJECTIVES: Cardiac troponin I is a highly sensitive and specific
myocardial injury marker. We have analyzed the use of cardiac troponin I values
in the diagnosis of coronary artery disease, in previously healthy patients who
developed chest pain with inconclusive analytical and ECG diagnostic findings.
PATIENTS, MATERIAL AND METHODS: A one year cross-sectional consecutive study was
conducted, in a total of 37 patients with no previously known heart disease who
were admitted to the coronary unit for suspected anginal chest pain with normal
cardiac enzymes and ECG. Abnormal cardiac troponin I levels at admission were
defined as > or = 0.4 ng/ml, and were compared with coronary angiography or
exercise test results and related to the duration of pain and the time from the
appearance of symptoms to blood extraction. RESULTS: Thirty-three of the 37
initially included patients were studied. Coronary artery disease was diagnosed
in 22, 15 of whom had increased troponin I values, yielding a sensitivity of 68%
(48%-84%) and a specificity of 82% (53%-97%). In the subgroup of patients with
pain lasting > 30 min, sensitivity reached 85% (59%-97%) and specificity 83% (42%
99%). There were no significant differences between subgroups with different time
delays from appearance of symptoms to blood extraction. CONCLUSIONS: Cardiac
troponin I is very useful for the studying ischemic chest pain without a
definitive diagnostic ECG nor biochemical data, resulting in a high sensitivity
and specificity for myocardial ischemic injury detection. Its diagnostic value
increases in cases of prolonged pain episodes.
PMID- 9542436
TI - [Coronary surgery without extracorporeal circulation: 5-year experience].
AB - INTRODUCTION: Coronary surgery without extracorporeal circulation is now an
accepted technique of myocardial revascularization. A progressive increase in
operations has recently been observed. OBJECTIVE: We report our total experience
with this technique in a consecutive series of patients operated on since 1991.
This series is compared with other series of patients who underwent coronary
surgery using cardiopulmonary bypass. PATIENTS AND METHODS: From December 1991 to
July 1996, thirty patients underwent myocardial revascularization without
cardiopulmonary bypass through median sternotomy at our institution. This group
was retrospectively compared with 22 patients who received isolated coronary
artery bypass grafting with cardiopulmonary bypass (excluding reoperations)
during the same period of time. RESULTS: There were two hospital deaths and one
case of myocardial infarction during the early postoperative period which
required urgent reintervention. There were two variables showing a statistically
significant difference between the groups with and without cardiopulmonary
bypass. Incidence of non-fatal preoperative myocardial infarction increased (53%
vs 23%), whereas minor mechanical ventilation time was reported (7 +/- 5 vs 14 +/
9 h) in the group without cardiopulmonary bypass. Follow-up (1 to 55 months
after operation, mean 29 months) was completed. There were no cardiac-related
deaths. No return of angina nor any new myocardial infarctions were recorded. New
myocardial revascularizations were not necessary. CONCLUSIONS: Myocardial
revascularization without extracorporeal circulation obtained good results that
were similar to conventional procedures and were cost-effective.
PMID- 9542437
TI - [Clinical and echocardiographic impact of neonatal aortic valvuloplasty].
AB - OBJECTIVES: The selection of patients for balloon aortic valvuloplasty is a vital
clinical challenge in neonatal aortic stenosis. The present study was designed to
establish possible predicting factors for poor results after balloon therapy.
PATIENTS AND METHODS: 2D echocardiographic, Doppler color and clinical variables
(grade of cardiac failure, aortic "anulus", mitral anulus, left ventricular
diameter, ascending aorta, instantaneous Doppler gradient, and grade of aortic
regurgitation) were analyzed in 32 neonates submitted to balloon dilation at 22
+/- 18 days of life. The evaluations were conducted during three periods in
respect to balloon therapy (A: before; B: immediately after, and C: mid-term
follow-up). The outcome in both, B and C periods was defined as favorable (all
survivors with Doppler gradient < or = 70 mmHg and no other intervention on the
valve) and unfavorable (death, first stage of univentricularization, valvular
replacement or survivors with Doppler gradient > 70 mmHg). Mean values between
subgroups were compared by Wilcoxon test; unconditional logistic regression was
used to analyze the impact of cardiac failure and anatomic variables (continuous,
categorized or Z) on the outcome. RESULTS: The Doppler gradient decreased from 70
+/- 28 to 34 +/- 14 mmHg after the valvuloplasty, and no changes were detected in
the follow-up period (36 +/- 8 mmHg). An immediate favorable result was obtained
in 72% of the patients; its consisted of 50% in period C. Nine neonates had an
immediate unfavorable outcome (6 deaths and 3 with Norwood operation). In the
follow-up, three patients had valvular replacement, one patient Doppler gradient
> 70 mmHg and one patient with left ventricular endomyocardial abnormalities
died. The severe cardiac failure (odds ratio: 33; CL 2.4-443; p = 0.008) and all
categorized anatomic variables (aortic "anulus" < or = 6 mm; mitral anulus < or =
9 mm; ascending aorta < or = 8 mm; left ventricular diameter < or = 13 mm) were
related with the immediate poor outcome. At 7.6 years, survival and freedom with
no valvular replacement nor reintervention probability rates were 83% and 67%,
respectively. CONCLUSIONS: 2D echo Doppler provides essential information about
the anatomic and functional lesions coexisting with severe or critical aortic
stenosis in neonates. Patients with left heart hypoplasia and severe heart
failure should not be candidates for balloon valvuloplasty. The degree of
residual aortic regurgitation and endomyocardial abnormalities of the left
ventricle play an important role in the mid-term follow-up.
PMID- 9542438
TI - [Heart pathology of extracardiac origin (V). Recent advances in chagasic
cardiomyopathy].
AB - INTRODUCTION AND OBJECTIVES: Chronic Chagas' heart disease is an important public
health problem in Latin America. Rural migration from endemic to nonendemic
countries has aroused widespread interest (United States, Spain) because of the
possibility of observing affected patients. METHODS: Review of recent literature.
RESULTS: The diagnosis of Chagas' cardiomyopathy is based on the triad of
epidemiological history, positive serology and the clinical Chagas' syndrome.
About 75% of asymptomatic seropositive subjects had no or almost no heart damage
but the disease could be transmitted by blood donation. The other 25% may develop
arrhythmias, heart failure and/or embolisms. Specific parasiticidal drugs are
mainly used in the acute phase. CONCLUSIONS: In countries where Chagas' disease
is infrequent, patients may be inadvertently diagnosed as having primary dilated
or ischemic cardiomyopathy. Disease reactivation in immunodepressed patients due
to AIDS, chemotherapy for cancer or for organ transplantation constitutes a
formidable clinical challenge. Sanitary prophylactic measures are the strategies
of choice.
PMID- 9542439
TI - [Staphylococcus aureus bacteremia and a mass in the right atrium in a patient
carrying a central port].
AB - A male heroin abuser was admitted because of Candida endophthalmitis. A permanent
central venous line was inserted. Three months later, he had positive catheter
and blood cultures with Staphylococcus aureus. Transthoracic and transesophageal
echocardiography and magnetic resonance revealed a right atrial mass. Treatment
with antibiotics in addition to clinical and echocardiographic follow up was
decided upon. Six weeks later, a transesophageal echocardiography showed a
decrease in right atrial mass size and the patient was discharged asymptomatic
without treatment. Three months later, he was well and a new transesophageal
echocardiography showed a further decrease in atrial mass size with signs of
fibrosis. This follow up supports the clinical suspicion of thrombus in the right
atrium attributable to a central venous line and Staphylococcus aureus
bacteremia.
PMID- 9542440
TI - [Minimally invasive surgery of the mitral valve].
AB - The technique of minimal access for mitral valve operations is commented on. A
small right mediastinotomy is performed, which is a small right parasternal
incision with resection of two costal cartilages. A correct exposure of the
mitral valve is achieved through the right atrium and interatrial septum,
allowing for adequate surgical correction.
PMID- 9542441
TI - [Pericardial tamponade and a mass in the pericardial cavity as the first clinical
manifestation of a pulmonary neoplasms].
AB - Cardiac tamponade and the finding of a simple pericardial mass as the first
manifestations of a malignant neoplasia from another location are exceedingly
rare events. Here we present a patient affected with a lung carcinoma whose first
clinical manifestation was the development of a cardiac tamponade that
established itself quickly within the context of a mass inside the pericardial
cavity and adhered to the left atrium.
PMID- 9542442
TI - Anticipating rotavirus vaccines: review of epidemiologic studies of rotavirus
diarrhea in Argentina.
AB - Rotavirus is the most common cause of severe diarrhea in children worldwide, and
vaccines currently being field-tested could be available for childhood
immunization in several years. To assess the rotavirus disease burden in
Argentina and the value of future national surveillance for the disease, we
reviewed available data on rotavirus detections reported by published and
unpublished studies conducted in nine Argentine cities and by a multicenter
study. Data from these studies indicated that rotavirus was detected in 20% of
5,226 specimens (within a range of 6% to 54% for different studies) from children
hospitalized for diarrhea and in 9% of 6,587 specimens (within a range of 5% to
22% for different studies) from children who were outpatients, members of mixed
populations (hospitalized patients and outpatients), or survey subjects in
community-based studies. The hospital data showed that while rotavirus was
detected throughout the year, a peak occurred during the winter months (May-July)
when up to half of the children with diarrhea were found positive for rotavirus.
Attempted serotyping of 294 rotavirus-positive specimens for G-protein by three
laboratories was successful in 230 cases (78%); the resulting data indicated that
serotype G1 was the most common (being present in 60% of the successfully
serotyped specimens), followed by G2 (in 20%), G4 (in 14%), and G3 (in 5%). Based
on national data for Argentina, we estimate that in 1991 there were roughly
84,500 rotavirus-associated outpatient visits (1 for every 8 births) and 21,000
hospitalizations averaging 4 days in length (1 for every 31 births), all of which
entailed direct medical costs estimated at US$ 27.7 million. These preliminary
data show that the rotavirus disease burden in Argentine children is extensive
and could be decreased by a safe and effective vaccine. Further surveillance is
needed to improve our understanding of the epidemiology and distribution of
rotavirus strains in Argentina, to more accurately assess the cost-effectiveness
of a rotavirus vaccine program, and to indicate what methods might best be used
to monitor such a program's impact.
PMID- 9542443
TI - [Program for the prevention and control of acute respiratory diseases in infancy
in Santiago, Chile].
AB - This paper describes and examines the activities for the prevention and control
of acute respiratory infections (ARI) carried out by a pediatric program in a
government health service that provides care to a low-income population in
Santiago, Chile. The study area has a population of just over one million people
and is served by one general hospital, 16 primary care clinics, and eight rural
health posts. Specific activities carried out by the ARI program include
personnel training as well as control measures at the primary care level and
hospitalization of children with severe ARI. In the first 5 years of the program
(1990-1994), a reduction in annual mortality from pneumonia from 3.0 to 1.7 per
1,000 was observed among children under the age of one year, which contributed to
a decline in infant mortality from 13.5 to 8.9 deaths per 1,000 live births. In
1994, program costs amounted to US$ 224,000. Judging from the results obtained,
the ARI prevention and control program has made a valuable contribution in the
area of child health.
PMID- 9542444
TI - [Determination of the dispersion of microorganisms in the course of dental
surgical activity].
AB - The professionals and patients involved in dental examinations are at risk for
infection by various disease-causing bacteria, viruses, and fungi, such as those
responsible for hepatitis, tuberculosis, herpes, and AIDS. It is known that
aerosols and spatter containing pathogenic microorganisms can spread during an
examination. Nevertheless, some dental clinics are designed to have multiple
examination areas in the same room, with no physical barriers between them. The
objective of this study was to verify the reach of spatter resulting from the use
of a triple syringe and high-rotation turbine during five simulated exams in a
collective clinic, bearing in mind that spatter can contain the patient's saliva
and blood. To facilitate tracking of the spatter, aniline dye (pink, blue,
yellow, green, and brown) was added to the water in the appropriate receptacle in
each of the five units. The room, the equipment, and the patient's and operator's
clothing were covered with white paper. A high concentration of spatter was
observed on the chair, the operator, and the floor of each unit, and it also
appeared on the chairs and trays of the surrounding units. The maximum distance
reached by spatter was 1.82 m from a point on the chair corresponding to the
position of the patient's mouth. During real simultaneous examinations, the
surrounding chairs and their patients and operators, as well as the trays
containing sterilized instruments, are within spatter range. Therefore, there is
a real possibility of cross-infection, and physical barriers should be placed
between the units. This study also confirmed the need for protection of the
operator's face, body, hair, and arms, since these regions were heavily affected
by spatter.
PMID- 9542445
TI - [Data on birthweight in developing countries: are surveys useful?].
AB - The main source of data on birth weight in developing countries is statistics
from health facilities, although most developing countries do not produce annual
estimates of the incidence of low birth weight from these data. Such estimates
would be subject to selection bias as the data are usually limited to babies born
within health facilities, and therefore are representative of a subgroup that is
markedly different from the overall population of neonates. Since 1990 the
Demographic and Health Surveys programme has included questions on recalled birth
weight and relative size at birth in 15 national surveys. In this article, we
show that these cross-sectional surveys can provide a useful data source for
making national estimates of mean birth weight and the incidence of low birth
weight. The extent of misclassification of birth weight is, however, too large to
use the data on relative size as birth as an indicator of low birth weight at the
individual level.
PMID- 9542446
TI - [Epidemic outbreak of Salmonella richmond infection in Castellon, Spain].
AB - A case-control study was carried out to investigate an outbreak of acute
gastroenteritis among a military detachment stationed in a rural area of
Castellon, Espana. The purpose of the study was to determine the causes of the
outbreak and develop control measures. Of the 153 men in the detachment, 135 were
included in the study. Between 9 and 11 August 1993, 45 cases were reported; the
patients' average age was 19.2 +/- 1.5 years. The attack rate was 33.3%. The
clinical picture was dominated by the following symptoms: diarrhea (76%),
vomiting (67%), nausea (67%), and abdominal pain (28%). The median duration of
symptoms was one day, and that of the incubation period was 33 hours. Only one
patient required hospitalization and all of them recovered. Salmonella richmond
(6.7: and :1.2) was isolated in 5 of the 14 stool cultures performed. An
association was also discovered between the illness and consumption of water from
an aqueduct that flowed near the camp. A logistic regression model showed that
consumption of water from this source remained associated with cases after
adjusting for age and the consumption of various foods (odds ratio = 96.5; 95%
confidence interval, 11.4-814.4). The risk of suffering from the illness rose
with the amount of water consumed (chi 2 trend test = 65.4, P < 0.0001). Chemical
and bacteriological analyses of the aqueduct water indicated the presence of
fecal contamination. The aqueduct had not been subject to sanitary monitoring,
even though the water was used to irrigate agricultural crops. The widespread
presence in the environment of species of Salmonella was demonstrated. Health
education and microbiological studies of water courses can be of great value in
preventing such epidemics.
PMID- 9542447
TI - Technologic organization of malaria control in Sao Paulo, Brazil, 1930-1990.
AB - Since the 1970s, when the world seemed on the threshold of malaria eradication,
the incidence of the disease has increased in several countries. The upturn in
cases raised a series of questions, and for some time malariologists and public
health authorities scarcely understood what was happening. In an attempt to
better comprehend the process, this article reviews the frequency of malaria
cases in Sao Paulo, Brazil, between 1930 and 1990, examining the following
factors in each of three 20-year time periods: the importance of malaria in the
society, the conditions under which the disease occurred, the epidemiologic
knowledge of the time, the technical instruments available to fight it, and the
control strategies that were used. Through the construction of technological
models based on these factors, it became clear that the occurrence of the
disease, knowledge about it, and, consequently, the ways it was dealt with
changed over time. In light of this research, the article discusses current
options for the control of malaria.
PMID- 9542448
TI - [Efficiency of oxidant gas generator cells powered by electric or solar energy].
AB - Diseases caused by microbial contaminants in drinking water continue to be a
serious problem in countries like Mexico. Chlorination, using chlorine gas or
chlorine compounds, is one of the best ways to treat drinking water. However,
difficulties in handling chlorine gas and the inefficiency of hypochlorite
solution dosing systems--due to sociopolitical, economic, and cultural factors-
have reduced the utility of these chlorination procedures, especially in far
flung and inaccessible rural communities. These problems led to the development
of appropriate technologies for the disinfection of water by means of the on-site
generation of mixed oxidant gases (chlorine and ozone). This system, called
MOGGOD, operates through the electrolysis of a common salt solution. Simulated
system evaluation using a hydraulic model allowed partial and total costs to be
calculated. When powered by electrical energy from the community power grid, the
system had an efficiency of 90%, and in 10 hours it was able to generate enough
gases to disinfect about 200 m3 of water at a cost of approximately N$8 (US
$1.30). When the electrolytic cell was run on energy supplied through a
photoelectric cell, the investment costs were higher. A system fed by
photovoltaic cells could be justified in isolated communities that lack
electricity but have a gravity-fed water distribution system.
PMID- 9542449
TI - Tobacco use among Cuban migrants at Guantanamo Bay, Cuba.
PMID- 9542450
TI - [Public health services: response to demands or needs?].
PMID- 9542451
TI - Evaluation of a novel drinking water treatment and storage intervention in
Nicaragua.
PMID- 9542452
TI - [The cataract, an unavoidable sign manifestation of aging?].
PMID- 9542453
TI - [Inline skating, an old sport, newly discovered: harmless or a potential danger
with socioeconomic effects?].
AB - Over a period of one year, all accidents associated with in-line skating (ILS)
were surveyed. Sport-specific data was recorded with a standardized
questionnaire. The study comprised 66 patients with 75 injuries (48 upper limb,
16 skull, eight lower limb, three trunk). We were looking after 42 male and 24
female patients with an average age of 20 years (5-53 years). Twenty-seven
patients (40%) had to be treated as inpatients. Overall, the most frequent injury
(one third of all injuries) was forearm fracture close to the wrist (21 radius
fractures, four radioulnar fractures). It had to be reset in 20 cases. Additional
internal fixation was required in 10 cases (Kirschner wire osteosynthesis,
intramedullary nailing or plate osteosynthesis). Only five patients could be
treated with plaster cast fixation alone. Most patients with injuries in the
vicinity of the wrist were not wearing a wrist protector at the time of the
accident. The most frequent reasons given for not wearing protectors was
forgetfulness or the high price of protectors. However, there were also two
distal radius fractures and a disc injury in the wrist in patients who had been
wearing wrist protectors. In most cases, ILS accidents lead to appreciable damage
requiring a healing period of several weeks to months (average period of loss of
work 41 days). The bfu (advisory center for accident prevention) reckons with
60,000 ILS cases annually in Switzerland. These injuries are thus of great
socioeconomic importance. In the future, better risk behavior must be achieved by
informing the population (wearing protectors, especially for the wrist and head,
attendance of training courses).
PMID- 9542454
TI - [Depression as a psychophysical illness phenomenon].
AB - The old Greeks understood depression as a somatic process as well as an
oppressing experience. Disturbances of the transmitters, ligands and receptors
and the decoupling of the feedback-systems of the hypothalamic-pituitary
adrenocortical systems with an impairment of the immune-system are experienced as
depression with its narcissistic depletion and orientation towards conscience and
order. Thereby the conscious experience is less differentiated than the complex
somatic processes which are proving it. Under a holistic aspect it is, however,
doubtful whether psychotherapy can be differentiated from somatotherapy. Each
psychotherapy acts through the sensory organs on the body like somatotherapy.
Until now, however, only a few results of research are known concerning somatic
parameters, for example of the transmitter- and immune-processes of the body,
during a simple, with preference cognitive-behavioral psychotherapy. For that the
researchers would have to be trained to reach a reliable evaluation of its
somatic parameters. As it was proved scientifically, the influence onto somatic
functions is even possible with complex psychotherapeutic methods such as
hypnosis. Such research is until now still relatively seldom done. This may be
due, on one hand, to the fact that many psychiatrists and other physicians still
maintain the fatal psychophysical dualism and on the other hand, that the
pharmaceutical industry has until now not had an interest in comparative
investigations concerning the effects of psychotherapy and pharmacotherapy.
PMID- 9542455
TI - [New developments in asthma therapy: how do individual leukotriene antagonists
work?].
AB - Today it is generally acknowledged that bronchial asthma is a chronic
inflammatory airway disease which is marked by recurrent bronchial obstructions
and hyperreactivity of the airways. The best anti-inflammatory characteristics
are shown by corticosteroids. However these can have considerable side-effects in
long-term, systemic use. The search for alternative forms of therapy has for some
time concentrated on the development and testing of leukotriene antagonists.
These can limit the effect of leukotrienes via receptor antagonism or synthesis
inhibition. The leukotrienes B4, C4, and D4 count as important key mediators in
bronchial asthma. They are released by numerous inflammatory cells, have a
bronchoconstricting effect and chemotactic characteristics, promote vessel
permeability and increase mucous secretion. In addition, they probably increase
bronchial hyperreactivity. Among biosynthesis restrictors, the 5-lipoxygenase
restrictors have shown an anti-inflammatory effect in both experimental asthma
models and in clinical use. In mild to moderate asthma, lung function improved
and the use of a concomitant beta-agonist medication was reduced. While the older
leukotriene receptor antagonists were rather disappointing, the newer substances
display a significantly improved effect, are generally well tolerated and can
also be given orally. In experimental asthma models, receptor antagonists, after
antigen provocation, led to a marked reduction in bronchoconstriction and a
decrease in the number of inflammatory cells (lymphocytes and eosinophils) in
bronchial alveolar fluid. In clinical studies, this new class of drugs showed a
reduction in clinical symptoms and an improvement in lung function in mild to
moderate asthma. In addition, a bronchodilatatory effect was shown. The option of
oral administration and good tolerance should improve compliance. The potential
and long-term efficacy in severe asthma remains unclear. Further studies are
required to elucidate the scope of their role and define their place in the
treatment of asthma.
PMID- 9542456
TI - [Dealing with the scientific literature--a report of experiences].
AB - There are several problems in collecting, analysing and receiving medical
articles or literature. The increasing number of medical articles calls for a
computer-aided system for literature data base programs. Therefore we want to
present our own experiences. The computer-aided data bases such as MEDLINE and
EMBASE are very useful but many other difficulties regarding citation and
procurement of articles remain.
PMID- 9542457
TI - [Obstructive sleep apnea, treatment with CPAP and health risks].
PMID- 9542458
TI - [Fever, headache and weakness. Primary cytomegalovirus infection].
AB - We report on an acute primary infection with cytomegalo virus in a 26 year old
immunocompetent and hitherto healthy man. The course of the disease was
characterized by prolonged febrile state, headaches, myalgias and markedly
reduced general condition. Indicators leading to diagnosis were in view of
otherwise unremarkable clinical findings, reactive lymphocytosis, mild
splenomegaly as well as elevated transaminases interpreted as concomitant
hepatitis. The evolution was benign under symptomatic treatment. The patient
recovered rapidly and completely. The clinical picture of primary CMV infection
in nonimmunosuppressed adults is discussed.
PMID- 9542459
TI - [Sarcoidosis and subclinical hyperthyroidism].
PMID- 9542460
TI - Surveillance of tuberculosis in the WHO European Region in 1995. Results of a
feasibility study.
PMID- 9542461
TI - Global Programme for Vaccines and Immunization (GPV). The WHO position paper on
Haemophilus influenzae type b conjugate vaccines.
PMID- 9542462
TI - Dracunculiasis. Certification of transmission-free status.
PMID- 9542463
TI - National Leadership Conference on Physical Activity and Women's Health.
PMID- 9542464
TI - The role of physical activity in minority populations.
PMID- 9542465
TI - Tailoring interventions to promote physically active lifestyles in women.
PMID- 9542467
TI - Principles and practice of women's health care.
PMID- 9542466
TI - Correlates of intention to use the female condom among women taking methadone.
PMID- 9542468
TI - Society of Cardiovascular Anesthesiologists 20th annual meeting. Seattle,
Washington, USA. April 25-29, 1998. Abstracts.
PMID- 9542469
TI - Experiences with recombinant factor VIII products: development of inhibitors and
immune tolerance therapy.
PMID- 9542470
TI - 42nd Annual meeting of the GTH (Gesellschaft fur Thrombose- und
Hamostaseforschung). Frankfurt am Main, Germany, February 25-28, 1998. Abstracts.
PMID- 9542471
TI - Clinical pharmacology in an aging population.
PMID- 9542472
TI - Protein binding of aspirin and salicylate measured by in vivo ultrafiltration.
AB - OBJECTIVE: Methods for measuring protein binding of drugs generally require
direct measurement of the concentration of unbound drug and thus may require a
highly sensitive assay. In vivo ultrafiltration has been used to determine
protein binding of endogenous substances. We have examined its value for
measuring protein binding of drugs because it requires measurement of only the
concentration of total drug, not unbound drug, in plasma. METHODS: The protein
binding of aspirin and its metabolite salicylate was measured in 29 healthy
subjects 20 minutes after a single oral dose of 600 mg soluble aspirin, by the
new method, in vivo ultrafiltration, as well as by a standard method, in vitro
ultracentrifugation. RESULTS: The data for salicylate were examined
systematically to determine the optimal method of determining estimates of
protein binding by in vivo ultrafiltration. Estimates of protein binding of
salicylate were 81.7% +/- 10.1% (mean +/- SD) by the in vivo method and 81.6% +/-
11.3% by in vitro ultracentrifugation. Bland-Altman analysis of agreement showed
that within-individual differences in percentage of protein binding determined by
the two methods did not differ significantly from zero (mean difference, 0.07%;
95% confidence interval, -2.33 to +2.46). There was a highly significant
correlation between estimates of protein binding by the two methods (r = 0.82; p
= 0.001). Protein binding of aspirin was estimated of protein binding by the two
methods (r = 0.82; p = 0.001). Protein binding of aspirin was estimated at 58.3%
+/- 9.6% by in vivo ultrafiltration and could not be estimated by in vitro
ultracentrifugation because the concentration of unbound aspirin in plasma was
below the limit of detection for the assay. CONCLUSION: In vivo ultrafiltration
can be used to measure protein binding of drugs and has potential advantages over
conventional methods. A sensitive assay may not be required because the unbound
drug need not be measured, measurement in vivo may maintain more physiologic
conditions, and it may be useful in measuring protein binding of drugs that are
degraded rapidly in vitro.
PMID- 9542473
TI - Induction of CYP2E1 activity in liver transplant patients as measured by
chlorzoxazone 6-hydroxylation.
AB - OBJECTIVE: To examine the phenotypic expression of CYP2E1 in liver transplant
patients, as measured by the in vivo probe chlorzoxazone, and to evaluate CYP2E1
activity over time after transplantation. METHODS: Thirty-three stable liver
transplant patients were given 250 mg chlorzoxazone within 1 year after
transplantation as part of a multiprobe CYP cocktail; urine and blood were
collected for 8 hours. Chlorzoxazone and 6-hydroxychlorzoxazone concentrations
were determined by HPLC. Twenty-eight healthy control subjects, eight patients
with moderate to severe liver disease, and four patients who had not received
liver transplants were also studied for comparison. The chlorzoxazone metabolic
ratio, calculated as the plasma concentration of 6
hydroxychlorzoxazone/chlorzoxazone at 4 hours after chlorzoxazone administration,
was used as the phenotypic index. In a subgroup of patients and control subjects,
additional blood samples were obtained to allow for the calculation of
chlorzoxazone pharmacokinetic parameters by noncompartmental methods. RESULTS:
The chlorzoxazone metabolic ratio for the liver transplant patients in the first
month after transplantation (mean +/- SD, 6.4 +/- 5.1) was significantly higher
than that after 1 month after surgery (2.1 +/- 2.0), when the chlorzoxazone
metabolic ratio was not different from control subjects (0.8 +/- 0.5). The
chlorzoxazone metabolic ratios in the patients who had not received liver
transplants (1.1 +/- 0.7) were equivalent to those of healthy control subjects.
The maximum observed 6-hydroxychlorzoxazone plasma concentration was 3046 +/-
1848 ng/ml in seven liver transplant patients in the first month after surgery
compared with 1618 +/- 320 ng/ml in 16 healthy control subjects (p < 0.05). The
maximum observed concentration of chlorzoxazone, the chlorzoxazone apparent oral
clearance, and the formation clearance of 6-hydroxychlorzoxazone were also
significantly different between the groups. CONCLUSIONS: We conclude that
significant induction of CYP2E1, as indicated by the chlorzoxazone metabolic
ratio, occurs in the first month after surgery in liver transplant patients and
that drugs that are substrates for CYP2E1 may require dosage alteration during
that period. Contrary to expectations, drug metabolism is not uniformly depressed
after liver transplantation.
PMID- 9542474
TI - Passive versus electrotransport-facilitated transdermal absorption of ketorolac.
AB - OBJECTIVE: To investigate the bioavailability (extent and rate of absorption) of
ketorolac from two cutaneous absorption sources, active electrotransport and
passive transdermal, and to examine the enantiomeric selectivity of
bioavailability for each source. METHODS: Based on a crossover study in 12
healthy volunteers, the extent and rate of absorption of ketorolac, delivered by
a patch, were found by estimating the input rate function of the drug. For that
purpose, deconvolution was used in two steps. First, intravenous data were
analyzed to estimate the ketorolac disposition function, and second, postpatch
data were deconvolved to estimate the unknown patch input profile given the
disposition function estimated in the first step. Because the input rate function
curves to be estimated for the patches may be of arbitrary shape, a spline was
used to model the patch input function, whereas intravenous data were modeled
with use of a sum of exponentials. Differences in the extent of absorption (F)
for the four treatment-enantiomer combinations were further examined with a mixed
effect regression model, based on the sets of four individual estimates of
bioavailability. RESULTS: On average, the F value for the active electrotransport
treatment, which exhibited the faster absorption rate, was four times greater
than the F for the passive transdermal treatment. Further, during the passive
treatment, R-ketorolac yielded an average F that is 42% greater than that for S
ketorolac and also exhibited a smaller absorption lag-time. During the active
treatment, there was no important enantiomeric difference in either extent or
rate of absorption.
PMID- 9542475
TI - Effects of erythromycin or rifampin on losartan pharmacokinetics in healthy
volunteers.
AB - BACKGROUND: Losartan is metabolized by CYP2C9 and CYP3A4 to an active metabolite,
E3174, which has greater antihypertensive activity than the parent compound.
Coadministered drugs that inhibit or induce metabolic processes may therefore
alter the pharmacokinetics and pharmacologic response of losartan and E3174.
OBJECTIVE AND METHODS: Ten healthy volunteers were studied to assess the effects
of CYP3A4 inhibition and nonspecific P450 enzyme induction on the
pharmacokinetics of losartan and E3174. Subjects completed three 1-week phases
separated by 6 days: 50 mg losartan every morning, losartan plus 500 mg
erythromycin four times a day, and losartan plus 300 mg rifampin (INN,
rifampicin) twice a day. On the eighth day of each phase, serial plasma
concentrations of losartan and E3174 were obtained over 32 hours and steady-state
pharmacokinetics were determined. RESULTS: Rifampin decreased the area under the
concentration-time curve from time zero to 24 hours after the dose (AUC[0-24]) of
losartan by 35% (349 +/- 246 versus 225 +/- 130; p = 0.0001) and decreased the
AUC(0-24) of E3174 by 40% (1336 +/- 445 versus 792 +/- 302; p < 0.005). Losartan
oral clearance was increased by 44% (p = 0.0001). The half-life values of both
compounds were decreased by 50% (p < 0.005). In contrast, erythromycin did not
significantly affect the AUC(0-24) or half-life of either losartan or E3174.
CONCLUSIONS: Rifampin is a potent inducer of losartan and E3174 elimination.
Given the magnitude of the effect, this interaction is likely to be clinically
significant. On the basis of the minimal inhibitory effects observed with
erythromycin, CYP3A4 appears to play a minor role in the in vivo metabolism of
losartan to E3174. Further studies are needed to define the contribution of other
isozymes, particularly CYP2C9, to the pharmacokinetics of losartan and E3174.
PMID- 9542476
TI - Pharmacokinetics and pharmacodynamics of single and multiple oral doses of a
novel 5-lipoxygenase inhibitor (ABT-761) in healthy volunteers.
AB - OBJECTIVE: This study evaluated the safety, pharmacokinetics and pharmacodynamics
of ABT-761 [R(+)-N-[3-[5-(4-fluorophenylmethyl)-2-thienyl]-1- methyl-2-propynyl]
N-hydroxyurea], a new N-hydroxyurea analog. METHODS: This was a randomized,
double-blind, placebo-controlled, single- and multiple-dose (15-day) study of ABT
761 (50 to 200 mg/day) in healthy, nonsmoking adult male volunteers. The
pharmacokinetics were evaluated by investigation of the time- and dose-dependent
effects of ABT-761, and the pharmacologic selectivity of ABT-761 was evaluated
based on calcium ionophore-stimulated leukotriene B4 (LTB4) and thromboxane B2
(TXB2) biosynthesis ex vivo in whole blood. RESULTS: After single and multiple
doses, mean observed time to reach maximum concentration values of ABT-761 ranged
from 4.0 to 7.5 hours. Mean values for maximum concentration and area under the
plasma concentration-time curve from 0 to 24 hours increased approximately
linearly with dose. Mean terminal half-life and apparent volume of distribution
during the terminal elimination phase of ABT-761 ranged from 15.4 to 17.8 hours
and 69.5 to 78.9 L, respectively, and was dose independent. Steady state was
reached on day 11 after multiple dosing. Less than 0.05% of unchanged ABT-761 was
recovered in urine within the 24-hour period after day 15 dosing. Population ABT
761 plasma concentration at which 50% of the maximum possible inhibition was
observed for LTB4 inhibition was 0.24 microgram/ml. No differences in mean TXB2
inhibition were observed between the subjects receiving ABT-761 and placebo.
CONCLUSIONS: These results indicate that ABT-761 is a potent and selective
inhibitor of 5-lipoxygenase and the pharmacokinetics of ABT-761 are time and dose
independent between 50 and 200 mg/day after single and multiple dosing.
PMID- 9542477
TI - Simvastatin but not pravastatin is very susceptible to interaction with the
CYP3A4 inhibitor itraconazole.
AB - BACKGROUND: Itraconazole increases the risk of skeletal muscle toxicity of some 3
hydroxy-3-methylglutaryl coenzyme A' (HMG-CoA) reductase inhibitors by increasing
their serum concentrations. We studied possible interactions of itraconazole with
simvastatin and pravastatin. METHODS: Two randomized, double-blind, two-phase
crossover studies were performed with use of an identical design, one with
simvastatin (study I) and one with pravastatin (study II). In both studies, 10
healthy volunteers received either 200 mg itraconazole or placebo orally once a
day for 4 days. On day 4, each subject ingested a single 40 mg dose of
simvastatin (study I) or pravastatin (study II). Serum concentrations of
simvastatin, simvastatin acid, pravastatin, HMG-CoA reductase inhibitors,
itraconazole, and hydroxyitraconazole were determined. RESULTS: In study I,
itraconazole increased the peak serum concentrations (Cmax) and the areas under
the serum concentration-time curve [AUC(0-infinity)] of simvastatin and
simvastatin acid at least tenfold (p < 0.001). The Cmax and AUC(0-infinity) of
total simvastatin acid (naive simvastatin acid plus that derived by hydrolysis of
the lactone) were increased 17-fold and 19-fold (p < 0.001), respectively, and
the half-life (t1/2) was increased by 25% (p < 0.05). The AUC(0-infinity) of HMG
CoA reductase inhibitors was increased fivefold (p < 0.001) and the Cmax and t1/2
were increased threefold (p < 0.001). In study II, itraconazole slightly
increased the AUC(0-infinity) and Cmax of pravastatin, but the changes were
statistically nonsignificant (p = 0.052 and 0.172, respectively). The t1/2 was
not altered. The AUC(0-infinity) and Cmax of HMG-CoA reductase inhibitors were
increased less than twofold (p < 0.05 and p = 0.063, respectively) by
itraconazole. There were no differences in the serum concentrations of
itraconazole and hydroxyitraconazole between studies I and II. CONCLUSIONS:
Itraconazole greatly increased serum concentrations of simvastatin, simvastatin
acid, and HMG CoA reductase inhibitors, probably by inhibiting CYP3A-mediated
metabolism, but it had only a minor effect on pravastatin. Concomitant use of
potent inhibitors of CYP3A with simvastatin should be avoided or its dosage
should be greatly reduced.
PMID- 9542478
TI - The pharmacodynamics and pharmacokinetics of the 5HT1B/1D-agonist zolmitriptan in
healthy young and elderly men and women.
AB - OBJECTIVE: Zolmitriptan is a selective 5HT1B/1D-agonist for the treatment of
migraine. In this study we investigated the cardiovascular and central nervous
system effects and the pharmacokinetics of zolmitriptan in young and elderly
adults. METHODS: Twelve young adult and 12 elderly volunteers received single
doses of 5, 10, and 15 mg zolmitriptan during a randomized, double-blind, placebo
controlled study. Blood pressure, heart rate, ECG, and central nervous system
effects were monitored, and pharmacokinetic parameters of zolmitriptan and its
metabolites calculated. RESULTS: Zolmitriptan did not affect heart rate and had
little effect on systolic blood pressure in the young adults. In the elderly,
mean peak supine systolic blood pressure values were 9 to 16 mm Hg higher after
zolmitriptan than after placebo. Mean peak diastolic pressure was 6 to 10 mm Hg
higher in both age groups. These changes were transient. Postural changes in
blood pressure were unaffected. There was a dose-related increase in sedation,
but the magnitude of the effects was small. Mean observed peak plasma
concentration (Cmax) and area under the plasma concentration-time profile [AUC(0
infinity)] for zolmitriptan and its active N-desmethyl metabolite were similar in
both age groups but higher in young women than in young men. Metabolite/parent
ratios probably the result of greater first-pass metabolism in young men.
Zolmitriptan half-life was 2.8 to 3.6 hours in the elderly compared with 2.7 to
2.9 hours in young adults. Mean Cmax and AUC(0-infinity) for the inactive, N
oxide, and the indole acetic acid metabolites were higher in the elderly,
associated with lower renal clearance. CONCLUSIONS: Zolmitriptan was well
tolerated, with an effect of age on its effects on blood pressure and the
pharmacokinetics of its metabolites. The data suggest no need for dose adjustment
for age. In young subjects, concentrations were higher in women than in men, but
the differences were insufficient to justify dosage adjustment.
PMID- 9542479
TI - Pharmacokinetics and pharmacodynamics of FK143, a nonsteroidal inhibitor of
steroid 5 alpha-reductase, in healthy volunteers.
AB - The pharmacokinetics and pharmacodynamics of FK143, a new nonsteroidal inhibitor
of steroid 5 alpha-reductase, were investigated in healthy volunteers, with use
of plasma FK143 concentrations and serum dihydrotestosterone levels as an index
for pharmacologic effects. The area under the plasma concentration-time curve
from zero to infinity [AUC(0-infinity)] and maximum plasma concentration [Cmax]
were increased dose proportionally after oral administration (100 to 500 mg)
while subjects were in the fed state. The AUC(0-infinity) and Cmax after 500 mg
oral administration during fed conditions were significantly larger than those
during the fasted state, suggesting an increase of the absorption of FK143.
Dihydrotestosterone concentrations after a single administration of FK143 (100 to
500 mg) during fed conditions decreased to about 65% of predose values and
thereafter slowly recovered to the same levels as predose values at 168 hours. A
combined pharmacokinetic-pharmacodynamic model was constructed with use of
changes in dihydrotestosterone concentrations. The pharmacokinetic
pharmacodynamic profiles of FK143 after repeated administration were predictable
with use of the pharmacokinetic-pharmacodynamic parameters obtained after a
single administration of FK143.
PMID- 9542480
TI - A pharmacokinetic interaction study of avitriptan and propranolol.
AB - OBJECTIVE: To assess whether a clinically significant change in the
pharmacokinetics of avitriptan and propranolol is observed in healthy subjects
after coadministration of the two drugs. METHODS: The pharmacokinetics of
avitriptan and propranolol were investigated when the two drugs administered
separately and when two 150 mg doses of avitriptan 2 hours apart were added to a
steady-state regimen (80 mg twice a day) of propranolol. The pharmacokinetics of
metabolites of avitriptan (N-desmethylavitriptan, methoxypyrimidinyl piperazine,
and O-desmethylavitriptan) and the pharmacokinetics of 4-hydroxypropranolol were
also assessed. RESULTS: Administration of avitriptan alone and together with
propranolol resulted in small increases in mean blood pressure and small
decreases in heart rate. Administration of propranolol resulted in lowering of
blood pressure and heart rate consistent with the beta-blocking actions of
propranolol. There were no changes in the pharmacokinetics of avitriptan after
coadministration with propranolol. However, area under the plasma concentration
time curve (AUC) of propranolol showed a 20% increase after coadministration with
avitriptan, whereas the AUC of 4-hydroxypropranolol significantly decreased.
Avitriptan therefore appeared to affect the metabolism of propranolol to 4
hydroxypropranolol. The peak plasma concentration and AUC for N
desmethylavitriptan and the AUC for methoxypyrimidinyl piperazine also showed
statistically significant increases (about 25%) when avitriptan was
coadministered with propranolol. CONCLUSIONS: Considering the wide safety margin
of propranolol, the increase in the exposure is not clinically significant. The
increase in the exposure to the metabolites of avitriptan is also not considered
to be clinically significant because the metabolite contribution to the
pharmacologic activity or side effects is expected to be minimal. Based on these
findings, avitriptan may be added to a steady-state regimen of propranolol as an
abortive antimigraine therapy.
PMID- 9542481
TI - Dose-related effects of oral acetaminophen on cold-induced pain: a double-blind,
randomized, placebo-controlled trial.
AB - The cold-pressor test is a widely used pain-induction model in humans. This
method has been shown to be a sensitive measure for detecting opioid analgesia.
However, nonsteroidal anti-inflammatory drugs have not produced consistent
analgesic effects with use of this model. The analgesic effect of acetaminophen
(INN, paracetamol) on cold pressor-induced pain has not been reported by other
investigators. In this study, a double-blind, randomized, placebo-controlled
design was used to evaluate the dose-related effects of oral acetaminophen on
cold pressor-induced pain in 18 normal healthy human subjects. We observed dose
related analgesic activity of oral acetaminophen using the cold pressor-induced
pain model in these subjects. There were statistically significant main effects
of both dose and time (pain and bothersomeness ratings decreased with increasing
drug dose and increased over time). In pairwise comparisons only the contrast
between the highest dose of acetaminophen (1000 mg) and placebo reached
statistical significance. Results from our study suggest that the cold-pressor
method may have clinical value in evaluating nonopioid analgesic agents.
PMID- 9542482
TI - Pharmacodynamics and pharmacokinetics of DMP 728, a platelet GPIIb/IIIa
antagonist, in healthy subjects.
AB - DMP 728 showed a dose-dependent inhibition of platelet aggregation at doses of
0.05 to 0.9 mg per subject, with a maximal inhibition (> 90%) of platelet
aggregation at doses of 0.9 mg per subject and higher. Minimal changes in
bleeding time from baseline were observed at doses up to 0.6 mg per subject. At
the 0.9 mg/subject dose level, bleeding time was prolonged by approximately
twofold to threefold above the baseline. At higher doses (1.5 mg/subject to 3.9
mg/subject), bleeding time prolongation was > 30 minutes during the infusion. In
all dose groups, bleeding times returned to the control value within 8 hours
after cessation of the infusion. Maximum plasma concentration and area under the
curve of DMP 728 increased linearly and proportionally to the dose. No clinical
changes in vital signs, 12-lead electrocardiograms, physical examinations,
coagulation tests, or stool hemoccult tests were observed at any of the doses. In
conclusion, DMP 728 is a potent antiplatelet agent and well tolerated at doses
ranging from 0.05 to 3.0 mg/subject.
PMID- 9542483
TI - Gestational diabetes mellitus--are African diagnostic criteria warranted?
PMID- 9542484
TI - Does successful completion of the Perinatal Education Programme result in
improved obstetric practice?
AB - OBJECTIVE: To determine whether successful completion of the Perinatal Education
Programme (PEP) improves obstetric practice. METHOD: The three midwife obstetric
units (MOUs) in a health district of Mpumalanga were included in the study. Two
MOUs enrolled in the PEP and the third did not. A 'before-and-after' study design
was used to assess any changes in practice, and to monitor whether any changes
occurred in the district during the time of the study; data were also collected
at the third MOU. Data were collected by scoring of the obstetric files after the
patient had delivered. OUTCOME MEASURES: We ascertained whether the obstetric
history, syphilis testing, blood group testing, haemoglobin measurement and
uterine growth assessment were performed during antenatal care along with whether
appropriate action was taken. For intrapartum care, estimation of fetal weight,
the performance of pelvimetry, blood pressure monitoring, urine testing,
evaluation of head above pelvis, fetal heart rate monitoring, monitoring of
contractions and plotting of cervical dilatation, and whether the appropriate
actions were taken, were assessed. RESULTS: Eight of the 13 midwives at the two
MOUs completed the PEP and all demonstrated an improvement in knowledge. Case
notes of 303 patients from the various clinics were studied. There was no change
in the referral patterns of any of the clinics during the study period. The
obstetric history was well documented, but in no group was there a satisfactory
response to a detected problem; appropriate action was taken in between 0% and
12% of cases. Syphilis testing was performed in 56-82% of cases, with no
difference between the groups. The haemoglobin level was measured in only 4-15%
of patients, with no difference before or after completion of the PEP. Where a
problem in uterine growth was detected, an appropriate response occurred in 0-8%
of patients and no difference before or after completion of the PEP was
ascertained. In all groups, estimation of fetal weight and pelvimetry were seldom
performed, the urine and fetal heart rate documentation were moderately well done
and the blood pressure monitoring, assessment of head above pelvis, monitoring of
contractions and plotting of cervical dilatation were usually performed. No
differences before or after the PEP were detected. Where problems were detected,
appropriate actions taken during labour improved, but not significantly.
CONCLUSION: Completion of the obstetric manual of the PEP improved the knowledge
of the midwives but no alteration in practice was detected.
PMID- 9542485
TI - Comparison of the footpump suction evacuator with the manual vacuum aspirator for
uterine evacuation.
AB - OBJECTIVE: To compare the efficacy of a novel footpump suction evacuator with the
manual vacuum aspirator in the management of women with incomplete abortions
requiring uterine evacuation. DESIGN: A prospective comparative analysis of women
allocated to either manual vacuum aspiration of the uterus or footpump suction
evacuation, following first- or second-trimester incomplete abortion. SETTING:
The gynaecology casualty theatre, Groote Schuur Hospital, Cape Town. PATIENTS:
121 women with first- or second-trimester abortions. Patients with signs of
septic abortion were excluded from the study. INTERVENTIONS: Uterine evacuation
under general anaesthesia by means of a manual vacuum aspirator or a novel
footpump suction evacuator. OUTCOME MEASURES: Endpoints assessed included
duration of the procedures, ease of evacuation, estimated blood loss, volume of
products of conception obtained, postoperative complications of the procedures
and amount of analgesia required postoperatively. RESULTS: The manual vacuum
aspirator and footpump suction evacuator appeared equally effective for uterine
evacuation. There were no significant differences in the endpoints assessed.
CONCLUSIONS: Both methods appear equally effective for uterine evacuation.
PMID- 9542486
TI - Unbooked mothers and their babies--what causes the poor outcomes?
AB - OBJECTIVES: To compare perinatal outcome between booked and unbooked mothers of
similar gestational age using birth weight as a proxy for gestational age.
DESIGN: 91 unbooked mothers were obtained from a pool of 2,054 mothers from the
Chiawelo district in Soweto delivered consecutively at the local community clinic
or at Baragwanath, the referral hospital. For each of these, a single booked
control from the same pool was found, matched to within 50 g birth weight.
Detailed information from case notes was used to compare the two groups and their
perinatal outcomes. RESULTS: Unbooked mothers tended to be at lower obstetric
risk. None of the unbooked versus 10 of the booked mothers had a poor obstetric
history (2 previous abortions or a previous perinatal death). There was a trend
to more twin pregnancies (5 v. 1) and more previous caesarean sections (12 v. 8)
in the booked mothers. Perinatal mortality rates were not significantly different
(unbooked 258/1,000; booked 268/1,000). Perinatal morbidity, as assessed on the
basis of need for neonatal admission and ventilation, was similar in the two
groups. CONCLUSION: Booked mothers were at higher risk, with worse obstetric
histories, which probably influenced their decisions to book for antenatal care.
Unbooked mothers seemed to be at lower risk, often presenting 'unbooked' because
of preterm complications. Many of the latter would probably have booked had their
pregnancies advanced uneventfully. As such, unbooked status should not be
regarded as a high-risk, poor prognostic category. These mothers and their babies
should therefore receive the same perinatal care as booked patients.
PMID- 9542487
TI - Fetal vibro-acoustic stimulation with a can--a clinical study.
AB - OBJECTIVE: To assess the usefulness of the can as a fetal vibro-acoustic
stimulator in the clinical environment. PATIENTS AND SETTING: 112 high-risk
obstetric patients at Coronation Hospital, Johannesburg. METHOD: 161 vibro
acoustic stimulation tests with a can and 159 non-stress tests (NSTs) were
performed. The results of the can test were compared with those of the NSTs and
with fetal outcome at delivery. RESULTS: The can test showed poor sensitivity
(5/9). Three of the 4 false-negative results were due to placental abruption that
occurred subsequent to the can test. The ability of the can test to predict a
reactive NST and good fetal outcome was 94% (negative predictive value).
CONCLUSIONS: In view of the reasonable negative predictive value, the test should
be evaluated further as a screening test at primary care level, where there are
few or no cardiotocographic facilities.
PMID- 9542488
TI - The fascination and challenges of epidemiological research.
PMID- 9542489
TI - HLA-A, -B, -DR and -DQ antigens in black patients with infective endocarditis.
AB - In order to determine if genetically determined immune response factors could
play a role in the pathogenesis of infective endocarditis in black patients, we
performed HLA-A and HLA-B typing in 38 patients with this disease and HLA-DR and
HLA-DQ typing in 33 and 27 of these individuals, respectively. HLA typing was
also carried out in a control group of normal black adults. The HLA typing was
done by means of a standard microlymphocytotoxicity test. No difference in HLA-A,
HLA-B, HLA-DR and HLA-DQ antigen frequencies between patients and controls were
noted. This study did not provide any evidence that genetic factors could
contribute to a disposition to infective endocarditis.
PMID- 9542490
TI - Two roles for caveolae in the cardiac myocyte?
AB - The presence of caveolae in many cell types including heart myocytes is well
established. It is hypothesized that caveolae may play a role in the storing of
excess Ca2+ and may be instrumental in Ca2+ transients during contraction and
relaxation in pathological conditions. Furthermore, the presence of substances in
caveolae and in their membranes may imply a role in the importing and exporting
of key molecules under physiological and pathological conditions. Secretory
activity is also suggested by an electron micrograph of rat heart muscle.
PMID- 9542491
TI - Respiratory muscle endurance in heart failure--the effect of clinical severity.
AB - In chronic heart failure there is no single explanation for reduced effort
tolerance. Recently, abnormalities of skeletal muscles, which include respiratory
muscles, have been described in cases of chronic heart failure. The aim of this
study was to investigate the effect of clinical severity of heart failure,
measured by means of the Boston score, on respiratory muscle performance
(strength and endurance). METHODS: Using the Boston score, we compared 20
patients with chronic heart failure and low ejection fraction to 20 normal
people, measuring maximal inspiratory mouth pressures (MIPs), maximal expiratory
mouth pressures (MEPs) and endurance. Endurance was measured by repeated maximal
static contractions of MIP and MEP as well as maximal voluntary ventilation
(MVV). RESULTS: Inspiratory strength (MIP 75 +/- 34 cmH2O) but not expiratory
strength (MEP 116.9 +/- 43.7 cmH2O) were reduced in heart failure patients,
compared with controls (MIP 96.2 +/- 29.2, MEP 120.4 +/- 31 cmH2O). Endurance of
inspiratory muscles was significantly reduced (P < 0.007) but not of expiratory
muscles (P > 0.25). Clinical severity did not correlate with reduced endurance.
CONCLUSION: Endurance of the inspiratory muscles was reduced in chronic heart
failure unrelated to clinical severity.
PMID- 9542493
TI - Effects of adrenaline, administered early or later after ischaemia, and
reperfusion on the isolated rat heart.
AB - OBJECTIVE: To evaluate the effect of adrenaline on cardiac function when given
early or later in the reperfusion period. DESIGN: Prospective study. SETTING:
University laboratory. PARTICIPANTS: Wistar rats. INTERVENTIONS: Isolated rat
hearts were subjected to 45 minutes of normothermic ischaemic arrest. During
reperfusion, adrenaline was administered early (2 minutes) or later (12 minutes)
after termination of ischaemic arrest in addition to a short (5 minutes) or
longer (10 minutes) recovery period before function was resumed. MEASUREMENTS AND
RESULTS: Aortic and coronary flow, peak systolic pressure and heart rate were
determined before arrest, 10 and 15 minutes after termination of ischaemic
arrest. Adenosine triphosphate and creatine phosphate levels were also determined
after cardioplegic arrest and reperfusion. Results indicate that early
administration of adrenaline was not detrimental but that a longer recovery
period after arrest resulted in significantly better cardiac function.
CONCLUSION: After ischaemic arrest of the isolated rat heart a longer recovery
period resulted in better cardiac function than a shorter period of recovery.
PMID- 9542492
TI - Evaluation of ibopamine plus prazosin in congestive heart failure.
AB - STUDY OBJECTIVE: To determine the acute haemodynamic response of a single dose co
administration of ibopamine plus prazosin in patients with congestive heart
failure. DESIGN: A double-blind, placebo-controlled randomised crossover study
followed by a 2-week, open safety evaluation. SETTING: Wentworth Hospital,
Durban. PATIENTS: 12 patients with congestive heart failure who were in
functional class (NYHA) II-III. INTERVENTIONS: All patients underwent right heart
catheterisation. On days 1 and 2 they received study drug or placebo plus
prazosin and underwent haemodynamic recordings for 4 hours. RESULTS: Single-dose
(200 mg) ibopamine plus prazosin augmented cardiac output (and index) and an
early (0-60 minute) phasic response in the pulmonary capillary wedge pressure
(PCWP) that did not appear to be influenced by the presence of prazosin. The
increase in cardiac output was accompanied by a moderate decline in systemic
vascular resistance (P = NS) without a change in heart rate. In the open
evaluation, 8/14 patients reported adverse events. Six events were considered to
be related to study medication of which one (dizziness) occurred in the
haemodynamic phase. CONCLUSION: This study shows that ibopamine has beneficial
haemodynamic effects in patients with moderate to severe heart failure. The
increase in cardiac output was mild and sustained but with little change in
systemic vascular resistance. The early rise in PCWP is not mediated by the alpha
agonistic vasoconstrictor effects of ibopamine.
PMID- 9542494
TI - Numerical simulation of pulsating flow in the aortic arch.
AB - In order to investigate the flow profiles in the aorta a numerical three
dimensional model of the aortic arch was created. The velocity fields were
simulated by applying an inlet velocity corresponding to the physiological
velocity of the pressure wave at the aortic valve. The velocity field
distribution was found to be uniform throughout the model during the time of
increasing inlet velocities. With decreasing inlet velocities a region of low
flow developed in the descending portion of the model leading to recirculating
flow at the inner wall. At this region of low flow the variation in velocity with
time at the inner wall was approximately twice the variation at the outer wall.
As a result of the recirculating flow, the wall shear stresses at the inner wall
are low and oscillating, predisposing to the development of atherosclerosis. This
model shows that transient fluid flow in the aortic arch can be simulated.
Biological studies are needed to prove that this model can be used to predict
sites of pathology.
PMID- 9542495
TI - Cardiology in China and Mongolia.
PMID- 9542504
TI - Editorial report.
PMID- 9542500
TI - Lipids, the cardiovascular system and HRT.
PMID- 9542505
TI - The European Journal of Surgical Oncology and the Internet II--World Wide Web
standard networks and clinical applications.
PMID- 9542506
TI - Laparoscopic resection of colorectal cancer--high art or access artistry?
PMID- 9542507
TI - Self-perceptions of women after early breast cancer surgery.
AB - AIMS: To discover satisfaction with treatment decision and the late influences of
surgery for early breast cancer on the lives and self-perceptions of women.
METHODS: A two-part mail survey was returned by 90 women aged 2.8-7.6 years after
breast-conserving treatment (BCT) and by 56 women aged 3.0-8.0 years after
modified radical mastectomy (MRM). RESULTS: Approximately one-third of all
patients felt the information and time before the treatment decision was
inadequate. Most women in both treatment groups had participated in treatment
decision-making. When the surgeon alone had made the choice it did not affect
satisfaction with the treatment result. Few patients regretted the treatment
modality chosen. The majority of patients felt no discomfort in their treated
breast, but a quarter of all the women suffered from rib pain. Fifteen of 52
sexually active women reported of reduced breast pleasure sensation in their
resected breast. The women in both treatment groups were asked to score a summary
satisfaction index (SSI) on a scale of 0-10 for seven different areas of life:
cosmesis, function, work, home, recreation/sports, social life and sexuality. SSI
was used as a measure of quality of life. There was a difference in all these
categories between BCT and MRM groups, the former giving significantly higher
values. Post-menopausal women tended to be more-satisfied than younger women and
women over 70 years showed no difference in satisfaction between the two
treatment modalities. Treatment of early breast cancer caused little morbidity in
the long run. After MRM slightly more local symptoms were reported. CONCLUSIONS:
Most women treated with breast-conserving surgery esteemed their life normal or
close to normal, giving us a reason to favour BCT when suitable. For women over
70 years old mastectomy remains a viable alternative.
PMID- 9542508
TI - Prediction of nipple and areola involvement in breast cancer.
AB - AIMS: To find a pre-operative test for nipple and areola involvement in breast
cancer. METHODS: Areola-tumour distance was measured in 140 consecutive patients
(median age 45, range: 23-83) undergoing a mastectomy. We analysed whether nipple
and areola correlated with areola-tumour distance, tumour size, nodal status,
perinodal involvement and lymphatic embolization. RESULTS: The nipple was
involved in 22 (16%) cases and this correlated with tumour size, number of lymph
nodes, perinodal extension and presence of lymphatic emboli. In all these 22
cases, the tumour was within 2.5 cm of the areola. Tumour size, however, could
not predict nipple involvement in tumours within 2.5 cm of the areolar edge.
CONCLUSIONS: In the one-fifth of cases where the tumour is over 2.5 cm from the
areola, preserving the nipple and areola for reconstruction may be worthwhile. In
remaining cases, some other predictive test for nipple involvement would be
necessary.
PMID- 9542509
TI - Axillary lymphadenectomy prepared by fat and lymph node suction in breast cancer.
AB - AIMS: To describe a new technique of axillary dissection and evaluate the
results. METHODS: Axillary lymphadenectomy prepared by fat and lymph node suction
was performed on 43 patients with breast cancer and uninvolved axilla on physical
examination. The mean follow-up was 18 months (range 12-27). After lipolysis and
liposuction of the axilla, lymph node dissection was performed by axilloscopy in
patients treated with conservative surgery. For patients undergoing modified
radical mastectomy, a mastectomy with open axillary dissection was carried out.
The axillary space was drained until less than 20 ml of lymphorrhea was being
produced per day. Seventeen modified radical mastectomies (group M) and 26
lumpectomies (group L) were performed. RESULTS: No injury of muscles, vessels or
nerves was observed. An average of 13.6 lymph nodes (8-31) were removed. In group
L, the mean number of lymph nodes removed by liposuction, axilloscopy and control
incision was 2.5, 5.4 and 4.2, respectively. In group M, the mean number of lymph
nodes removed was 14. None of the 589 lymph nodes examined showed any
pathological trauma. Fourteen patients (32%) had more than one histologically
positive node. The mean quantity of lymphorrhea was 390 ml in group M and 275 ml
in group L. The mean duration of drainage was 6 days in group M and 5 days in
group L. Four patients had seromas which required punctures. Two patients had
shoulder restriction (movements < 90 degrees) at 12 months. No arm oedema was
seen. CONCLUSIONS: Axillary lymphadenectomy prepared by fat and lymph node
suction is a reliable and effective procedure. However, it does not appear to be
better than standard dissection as regards post-operative complications, except
for arm oedema, but this must be confirmed by further studies.
PMID- 9542510
TI - Modern trends in breast cancer therapy: towards less lymphoedema?
AB - AIMS: To review from the evidence, with special reference to axillary node
management, whether the incidence of lymphoedema following breast cancer
treatment is falling in modern breast practice. CONCLUSIONS: The incidence of
lymphoedema does seem to be reducing with modern approaches to breast cancer
management. Axillary treatment seems to determine its development but more
studies looking specifically at this problem are needed.
PMID- 9542511
TI - The lack of age as a significant prognostic factor in non-metastatic breast
cancer.
AB - AIMS: To determine the prognostic significance of age at diagnosis in women with
non-metastatic breast cancer. METHODS: A retrospective review of all newly
diagnosed breast cancer in women between 1975 and 1991 was carried out at a
tertiary Oncology Referral Centre. Patients were divided into three age groups: <
40 years, 40-50 years and > 50 years. Demographic and management/outcome details
were collected from patients with UICC stages I-III. The effect of age on overall
and relapse free survival was analysed by standard statistical methods. RESULTS:
Of 1289 new cases registered during the study period, 710 (55%) were UICC stages
I-III. Of the latter group 250 (35%) women were in the age group of less than 40
years, 237 (33%) were between 40 and 50 years and 223 (32%) were older than 50
years. Women from the younger age group had a higher proportion of breast
conserving surgery, and adjuvant chemo- and radiation therapy, while the
proportion of hormone therapy usage was higher in older women. There was no
difference in overall survival (P = 0.64) and relapse-free survival (P = 0.53)
between the three age groups. CONCLUSION: In this study, age was not a prognostic
factor in predicting overall or relapse-free survival in women with breast
cancer.
PMID- 9542512
TI - Assessment of c-erbB2 and vascular endothelial growth factor mRNA expression in
fine-needle aspirates from early breast carcinomas: pre-operative determination
of malignant potential.
AB - AIMS: Although axillary lymph nodes status, tumour size, hormonal-receptor status
and histological grade at diagnosis are frequently used to orient the treatment
of breast cancer patients, some tumours recur in patients with early stage
disease. Pre-operative assessment of individual tumour characteristics, based on
oncogenes and growth factors related to tumour growth, invasion or metastasis,
may guide the treatment for patients with breast carcinomas. METHODS: We examine
here the prognostic significance of cyclin D1, urokinase type plasminogen
activator, vascular endothelial growth factor (VEGF), platelet-derived growth
factor, and c-erbB2 expression in pre-operatively obtained fine-needle aspirates
from breast carcinomas less than or equal to 3 cm in size. Correlation between
mRNA expression of these factors and clinicopathological characteristics was
analysed. RESULTS: The level of c-erbB2 mRNA expression was significantly higher
in tumours with lymph node metastases than in those without lymph node
metastases. VEGF mRNA expression positively correlated with the degree of
angiogenesis as quantitated by immunohistological staining with a CD31 monoclonal
antibody. CONCLUSIONS: Analysis of c-erbB2 and VEGF mRNA expression in fine
needle aspirates may be useful in assessing the malignant potential of individual
breast carcinomas, leading to a pre-operative discrimination of a high-risk
group.
PMID- 9542513
TI - Loss of heterozygosity at microsatellite marker sites for tumour suppressor genes
in oesophageal adenocarcinoma.
AB - AIMS: Loss of cell cycle control is an important step in the development of human
tumours. A number of tumour suppressor genes are involved in cell cycle control,
including p16, p53 and Rb. The aim of this study was to seek evidence of
deletions of these genes in oesophageal adenocarcinoma. METHODS: Paired (tumour
and normal squamous epithelium) frozen tissue samples from 12 patients were
analysed by polymerase chain reaction (PCR) for loss of heterozygosity (LoH) at
five microsatellite marker sites (two each for p16 and Rb, one for p53).
Aneuploid tumour cell populations were sorted by flow cytometry prior to PCR, to
eliminate stromal cell contamination. RESULTS: Of the 12 tumours, 11 (92%) had
LoH at one or more loci. LoH at the p53 locus occurred in nine of 12 tumours, at
one or both p16 loci in seven of 11 tumours, and at one or both Rb loci in eight
of 12 tumours. Five tumours had LoH at two tumour suppressor gene loci, and a
further four tumours had LoH at loci for all three genes. CONCLUSIONS: Allelic
deletions of p53, p16 and Rb are common in oesophageal adenocarcinoma, and may be
important in the development of this disease.
PMID- 9542514
TI - Transforming growth factor alpha immunoreactivity in human gallbladder and
extrahepatic biliary tract tumours.
AB - AIMS: Transforming growth factor alpha (TGF-alpha), a protein structurally
similar to epidermal growth factor (EGF), is implicated in the development of
many human tumours. This study examines the expression of TGF-alpha in
gallbladder and extrahepatic biliary tract tumours in which EGFR expression has
been previously shown to be important. METHODS: A monoclonal antibody to the TGF
alpha protein was used to investigate the immunohistochemical expression of TGF
alpha in carcinoma of the gallbladder (n = 13), common bile duct (CBD) (n = 6)
and ampulla of Vater (n = 8). Tissues from cases of chronic cholecystitis (n =
11), gallbladder dysplasia (n = 3) and adenoma (n = 1), and ampullary carcinoma
in situ (CIS) (n = 3) were used as non-malignant controls. These cases were
previously studied for EGFR expression. RESULTS: TGF-alpha overexpression,
defined as intense immunoreactivity in more than two-thirds of cells
immunostained for TGF-alpha, was present in most gallbladder carcinomas (n = 10;
77%) but with no significant differences in expression between different tumour
grades. None of the cases of gallbladder dysplasia or chronic cholecystitis had
strong TGF-alpha expression and this was significantly different from the
carcinomas (P = 0.013 and P = 0.0001, respectively; chi 2 test), although a few
cases of chronic cholecystitis showed weak (n = 4), moderate (n = 6) or no (n =
1) immunoreactivity. A few ampullary carcinomas (n = 2; 25%) and CIS (n = 1;
33%), and half of the CBD carcinomas (50%) had strong TGF-alpha immunoreactivity.
There was correlation between TGF-alpha and EGFR immunoreactivity in the tumour
cases (r = 0.70, r2 = 0.49, P = 0.0001; simple regression analysis), although the
rate of EGFR immunoreactivity in CBD and ampullary carcinomas was somewhat higher
than that of TGF-alpha. However, no statistically significant correlation between
TGF-alpha expression with patient survival or tumour recurrence (r = 0.11, r2 =
0.012, P = 0.65; simple regression analysis) was found. CONCLUSIONS: Increased
TGF-alpha expression occurs more frequently in gallbladder carcinoma than in
gallbladder dysplasia, chronic cholecystitis, CBD or ampullary tumour, with no
specific relationship to tumour grade, suggesting that TGF-alpha overexpression
occurs early in the development of gallbladder cancers, and that biliary tract
cancers have a different molecular origin. Correlation was found between TGF
alpha and EFGR expression in gallbladder and biliary tract tumours.
PMID- 9542515
TI - Erythrocyte membrane stearic to oleic acid ratio in carcinoma of the gallbladder:
a preliminary study.
AB - AIMS: The role of erythrocyte membrane stearic to oleic acid ratio (saturation
index) as a marker of malignancy is still unclear, though an association has been
found in colorectal carcinoma, bronchogenic carcinoma, leukaemia, lymphoma and in
hepatic malignancies. This study aims to investigate the role of the saturation
index in primary carcinoma of the gallbladder. METHODS: This paper describes the
results of the stearic to oleic acid ratio determination in 26 subjects with
either cholelithiasis or carcinoma of the gallbladder, also including a group of
age- and sex-matched controls, using gas chromatography. This is the first report
of the saturation index in carcinoma of the gallbladder. RESULTS: A significantly
lower saturation index was observed in patients with carcinoma of the gallbladder
than with cholelithiasis (t = 2.19, P = 0.043, T = 47, P < 0.05, Wilcoxon P <
0.001, F = 2192.23, P < 0.001; 95% CI 18.45-30.44) and controls (t = 2.5, P =
0.024, T = 36, P < 0.05, F = 10904.11, P < 0.001, Wilcoxon P < 0.001; 95% CI
52.42-63.39). Among the carcinoma patients a further lowering was noted in stage
IV disease compared with stage III (T = 6, P < 0.05). CONCLUSIONS: These changes
are probably due to a marked increase in oleic acid content at the expense of
stearic acid. This lowering of the saturation index in carcinoma of the
gallbladder is similar to that observed previously in the other malignancies.
PMID- 9542516
TI - Screening for colorectal cancer reduces emergency admissions.
AB - AIMS: Colorectal cancer is common and accounts for over 15,000 deaths annually in
England and Wales. Up to 30% of these patients require emergency surgery.
Screening for colorectal cancer can reduce the mortality of colorectal cancer.
This study addresses the impact of a population-based screening study on
emergency admissions with colorectal cancer. METHOD: From 1981 a randomized trial
of Faecal Occult Blood (FOB) screening has been undertaken in the Nottingham
area, recruiting over 150,000 patients. The present study examined the records of
patients enrolled in this study who presented as an emergency with colorectal
cancer. RESULTS: Colorectal cancer was identified in 1962 cases, of which 468
(23.9%) presented as emergencies. The overall compliance was 60% (proportion of
individuals completing at least one test). There were significantly fewer
emergencies in the Screen-detected group compared with the Control group (P = <
0.0001). This group also had a significantly reduced 30-day mortality and a lower
stoma rate than the Control group. Conversely the Non-responders had a
significantly greater proportion of emergency admissions and a significantly
increased stoma rate compared with the Control group. CONCLUSIONS: Screening for
colorectal cancer using a faecal occult blood test can significantly reduce the
number of emergency presentations with colorectal cancer. It is likely that the
introduction of a national programme of screening for colorectal cancer would
lead to increased compliance and that this would lead to a significant reduction
in the emergency workload on the National Health Service from colorectal cancer.
PMID- 9542517
TI - Computed tomography for the detection of neck node metastases in melanoma
patients.
AB - AIMS: To assess the value of CT scanning for detection of lymph node metastases
in the neck. METHODS: The appearance and site of the metastases was studied, as
well as the sensitivity and specificity of CT. RESULTS: Nodal metastases did not
always show a high contrast uptake and nodal density therefore cannot be used as
a criterion for metastasis. Irregular contrast enhancement was seen in seven of
the 21 tumour-positive necks. Frequently, metastases in the parotids, superficial
nodes in the neck and in the posterior triangle were seen. The sensitivity and
specificity of palpation and CT scanning were 87 and 100%, respectively.
CONCLUSIONS: However, because small, clinically occult, melanoma metastases were
frequently overlooked on CT, the role of this imaging modality in assessing
occult metastases remains limited. Based on recent data from literature it is
reasonable to speculate that ultrasound guided fine needle aspiration cytology
(FNAC) will prove to be more effective than a non-invasive staging procedure of
the neck in melanoma patients.
PMID- 9542518
TI - Breast cancer--mysteries of the axillary pyramid.
PMID- 9542519
TI - Endothelin-1 and tumour development.
AB - There has been a growing conviction amongst oncologists that cancer is a disease
characterized by changes in specific molecules. These changes include alteration
in the structure, regulation or quantity of growth factors and their receptors,
signal transducers and the proteins encoded by dominant or suppressor/recessive
oncogenes. The role of endothelin (vasoactive peptide) in tumour cell signal
transduction and mitogenesis and induction of endothelial cell growth and
angiogenesis in tumour growth is discussed in this article.
PMID- 9542521
TI - The (continued) importance of the hypothesis in surgical oncology research.
PMID- 9542520
TI - Appraisal of transplantation for malignant tumours of the liver with special
reference to early stage hepatocellular carcinoma.
AB - The enthusiasm to treat or even cure patients with unresectable hepatobiliary
malignancy by total hepatectomy and liver transplantation has considerably
diminished. Nowadays, due to organ-donor shortage, patients have to be selected
with predictable likelihood for long-term survival. According to own experience
and a review of the literature, liver transplantation may be considered in
unresectable early stage hepatocellular and proximal bile duct carcinoma, the
uncommon entities fibrolamellar carcinoma, epithelioid haemangioendothelioma and
hepatoblastoma as well as in liver metastases from neuroendocrine tumours. At
present, advanced stages of hepatocellular and proximal bile duct carcinoma, as
well as intrahepatic bile duct carcinoma, haemangiosarcoma and metastases from
nonendocrine tumours, should be excluded from transplantation. In order to cure
the cancer-bearing disease, liver transplantation might be the ideal treatment
for small but still resectable hepatocellular carcinoma with underlying
cirrhosis. Our retrospective comparison of survival after resection and
transplantation for early stage hepatocellular carcinoma does not reveal a
significant difference. Although a tendency has been observed in favour of
transplantation, resection of these tumours is still justifiable, not least
because of donor organ shortage.
PMID- 9542522
TI - Huge non-functioning pancreatic cystic neuroendocrine tumour: a case report.
AB - A case of an 18-cm large cystic, non-functioning endocrine (islet cell) tumour
located at the tail of the pancreas in a 29-year-old Caucasian female is reported
here. Pre-operative radioimmunoassays for pancreatic peptides were negative,
while immunohistochemistry confirmed the neuroendocrine nature of the tumour.
This is the largest cystic non-functioning islet-cell tumour so far described.
PMID- 9542523
TI - Primary angiosarcoma of the breast.
AB - We report a case of a 44-year-old woman with primary angiosarcoma of the left
breast. An excisional biopsy was performed initially and the mass was interpreted
as angiosarcoma. The pre-operative staging provided no evidence of metastasis.
The patient then underwent a left mastectomy with the placement of an expandable
prosthesis. For 3 months the prosthesis was progressively expanded to the desired
size and it was then replaced with a permanent one. Primary angiosarcoma of the
breast is a rare and often misdiagnosed disease. Treatment options are numerous
and conflicting. The diagnostic approach and treatment options from the
literature are presented and discussed.
PMID- 9542524
TI - Mucoepidermoid carcinoma of the breast: a case report and review of the
literature.
AB - Muco-epidermoid carcinoma is a rare primary of the breast with previous reports
of only 15 cases. As the following case report demonstrates, it can be very
difficult to diagnose on aspiration cytology and a negative result should be
interpreted with caution.
PMID- 9542525
TI - Nodular fasciitis-type papillary thyroid carcinoma. Presentation of a new case.
PMID- 9542526
TI - Rare microsatellite polymorphisms in the DNA repair genes XRCC1, XRCC3 and XRCC5
associated with cancer in patients of varying radiosensitivity.
AB - DNA repair defects might contribute both to cancer progression and to the extreme
reactions to radiotherapy observed in approximately 5% of patients. Polymorphic
microsatellites in three DNA repair genes, XRCC1, XRCC3 and XRCC5, were analyzed
for possible linkage to cancer status or clinical radiosensitivity. XRCC1, 3 and
5 proteins are involved in single-strand DNA break rejoining, recombinational
repair, and double-strand DNA break rejoining respectively. Mendelianly inherited
microsatellite polymorphisms in these genes were analyzed in three groups:
volunteers with no cancer history; radiosensitive cancer patients; cancer
patients with acceptable reactions to radiotherapy. Rare heterozygous alterations
in all three gene regions were found solely in the cancer subpopulation.
Association testing between these rare polymorphisms and cancer status revealed a
significant association for XRCC1 (P = 0.005), and XRCC3 (P = 0.004). There was
also an association between these polymorphisms and clinical radiosensitivity for
XRCC1 (P = 0.03), and XRCC3 (P = 0.005).
PMID- 9542527
TI - Death of solid tumor cells induced by Fas ligand expressing primary myoblasts.
AB - Anticancer therapy for solid tumors suffers from inadequate methods for the
localized administration of cytotoxic agents. Fas ligand (FasL) has been reported
to be cytotoxic to a variety of cells, including certain tumor cell lines. We
therefore postulated that myoblasts could serve as non-transformed gene therapy
vehicles for the continuous localized delivery of cytotoxic anticancer agents
such as FasL. However, contrary to previous reports, fluorescence activated cell
sorting (FACS) analyses revealed that both primary mouse and human myoblasts
express Fas, the receptor for FasL. To avoid self-destruction and test the
cytotoxic potential of myoblasts, the cells were isolated from mice deficient in
Fas (lpr/lpr), the mouse counterpart of human autoimmune lymphoproliferative
syndrome (ALPS). These primary mouse myoblasts were transduced with a retroviral
vector encoding mouse FasL and expression of a biologically active and soluble
form of the molecule was confirmed by the apoptotic demise of cocultured Fas
expressing Jurkat cells, the standard in the field. To test whether the lpr
myoblasts expressing FasL could be used in anticancer therapy, human
rhabdomyosarcoma derived cell lines were assayed for Fas and then tested in the
apoptosis coculture assay. The majority of Fas-expressing muscle tumor cells were
rapidly killed. Moreover, FasL expressing myoblasts were remarkably potent;
indeed well characterized cytotoxic antibodies to Fas were only 20% as efficient
at killing rhabdomyosarcoma cells as FasL expressing myoblasts. These findings
together with previous findings suggest that primary myoblasts, defective in Fas
but genetically engineered to express FasL, could function as potent anticancer
agents for use in the localized destruction of solid tumors in vivo by three
synergistic mechanisms: (1) directly via Fas/FasL mediated apoptosis, (2)
indirectly via neutrophil infiltration and immunodestruction, and (3) as
allogeneic inducers of a bystander effect via B and T cells.
PMID- 9542528
TI - Maintenance of hypomethylation status and preferential expression of exogenous
human MDR1/PGY1 gene in mouse L cells by YAC mediated transfer.
AB - Selection of cells for resistance to vincristine or doxorubicin often induces
overexpression of the multidrug resistance (MDR) genes, which encode the cell
surface P-glycoproteins, as a result of gene amplification, transcriptional
activation, or mRNA stabilization. The LMD1 and LMD4 cell lines were established
after the transfer into mouse L cells of two independent yeast artificial
chromosome clones containing 300 and 850 kb, respectively, of the human MDR
locus. The human MDR1/PGY1 gene, but not the endogenous mouse mdr1a and mdr1b
genes, was overexpressed as a result of gene amplification and transcriptional
activation in various sublines of LMD1 and LMD4 cells selected for resistance to
vincristine. Then we asked why human MDR1/PGY1 gene, but not mouse relevant gene,
was expressed. Determination of the methylation status of cytosine residues at
Msp I/Hap II cleavage sites (CCGG) in the promoter regions of human MDR1/PGY1 and
mouse mdr1a revealed hypomethylation and hypermethylation of the human and mouse
genes, respectively in LMD1, LMD4, and their vincristine-resistant derivatives.
Various vincristine-resistant sublines were also established after exposure of
LMD1 cells for 48 h to 5-aza-2'-deoxycytidine, an inhibitor of DNA
methyltransferase. These sublines exhibited overexpression of mouse mdr1a and
mdr1b, but not of human MDR1/PGY1, as well as hypomethylation of the mouse mdr1a
promoter region. Thus, the selective expression of human or mouse MDR genes in
this cell system appears to be related to the methylation status of the
respective gene promoter regions.
PMID- 9542529
TI - Organization and expression of human telomere repeat binding factor genes.
AB - The ends of mammalian chromosomes terminate in structures called telomeres.
Recently a human telomere repeat binding factor (TRF1) that binds the vertebrate
TTAGGG telomeric repeat in situ was isolated by Chong et al. (1). TRF1 regulates
telomere length (2), which is often altered in cancer cells. To understand their
genetic organization, TRF1 genes were localized to human chromosomes 13cen,
21cen, and Xq13 by analysis of human monochromosomal hybrids, and by fluorescent
in situ hybridization. We also confirmed the recent localization of a human TRF1
gene to chromosome 8, and provide evidence that this locus is alternatively
spliced. In contrast to the TRF1 genes on chromosomes 8 and X, the chromosomes 13
and 21 TRF1 genes contained a 60 bp deletion in the coding region. The results
suggest that two distinct forms of TRF1 are expressed and that the TRF1 gene
family includes at least three pseudogenes whose dispersal in the human genome
may have occurred via cDNA intermediates.
PMID- 9542530
TI - Depletion of mitochondrial DNA by ddC in untransformed human cell lines.
AB - In order to study the interaction between the nuclear and mitochondrial genomes
we have developed a non-transformed cell system. It is based upon the complete
removal of mtDNA from fibroblasts by treatment with a nucleoside analogue, 2',3'
dideoxycytidine (ddC). After exposure to ddC we were able to generate viable
fibroblasts devoid of mtDNA and to successfully repopulate them with exogenous
mitochondria. This model system will be useful in characterizing nuclear
mitochondrial interactions and in studying the effects of different nuclear
backgrounds on the expression of different primary defects of mtDNA associated
with human disease.
PMID- 9542531
TI - Colocalization of P2Y2 and P2Y6 receptor genes at human chromosome 11q13.3-14.1.
AB - Extracellular nucleotides mediate a number of physiological responses through
either ligand gated P2X or G protein-coupled P2Y receptors. To date, six P2Y
receptor subtypes, P2Y1-P2Y6, have been cloned. We mapped the human P2Y6 receptor
gene to chromosome 11q13.3-13.5. Oligonucleotide primers complementary to a part
of the human P2Y6 receptor cDNA were used to amplify a region from genomic DNA
from a panel of mouse/human somatic cell hybrid cell lines, each containing a
single human chromosome. A PCR product of the expected size (714 bp) resulted
from a single hybrid cell line containing human chromosome 11. The gene was
further localized to a region of chromosome 11 using a subchromosomal hybrid
panel containing different segments of chromosome 11. Based on the specific PCR
product obtained and its Southern hybridization to the P2Y6 receptor cDNA, the
human P2Y6 receptor gene was localized to chromosome 11q13.3-13.5. Previously, we
have localized the P2Y2 receptor gene to human chromosome 11q13.5-14.1. This is
the first report of the clustering of the P2 receptor genes. The clustering of
these two P2Y receptor subtypes suggests a relatively recent expansion of the
gene family by gene duplication.
PMID- 9542532
TI - Mapping of the human P84 gene to the subtelomeric region of chromosome 20p.
AB - P84 is a novel neural adhesion molecule that may play an important role in
synaptogenesis. We have recently cloned a murine cDNA encoding the P84 adhesion
molecule. The human homologue of P84 has previously been isolated (by others) as
a brain specific cDNA containing CCA repeats. We have mapped the human P84 gene
to the subtelomeric region of chromosome 20p (20p13) by FISH. In addition, we
have been able to place P84 onto the high resolution physical map of the human
genome by utilizing the Unigene database. P84 maps to several YAC clones, between
STS markers IB255 and WI-9632, and very close to the polymorphic marker D20S199,
in an interval of less than 1 Mb on 20p13. P84 is a strong candidate gene for
neurological disorders which map into this region.
PMID- 9542533
TI - [XXVIII Argentine Congress on Gastroenterology, XV Argentine Congress on
Digestive Endoscopy, V meeting of Pediatric Gastroenterology and Nutrition.
Rosario, 21-24 September 1997. Abstracts].
PMID- 9542535
TI - Canadian Digestive Diseases Week. 37th Annual meeting of the Canadian Association
of Gastroenterology in conjunction with the Canadian Association for the Study of
the Liver. Banff, Alberta, Canada. March 1-8, 1998. Abstracts.
PMID- 9542536
TI - Cytokine and chemokine signaling in leukocyte development and function. 32nd
National meeting of the Society for Leukocyte Biology. Baltimore, Maryland, USA.
December 4-7, 1997. Abstracts.
PMID- 9542537
TI - Membership directory, Society for Leukocyte Biology.
PMID- 9542538
TI - XII Meeting of Brazilian Society of Protozoology and XXIII Annual meeting on
Basic Research in Chagas' Disease. Caxambu, MG, Brasil, 5-8 November 1996.
Abstracts.
PMID- 9542539
TI - Reconsidering the effects of seat belt laws and their enforcement status.
AB - The debate over the benefits of mandatory seat belt laws and their enforcement
status has focused on a controversial empirical enigma: why have these policies,
which appear to have increased belt use sharply, had a relatively small impact on
traffic fatalities? In this paper, I offer new insights into this question by
examining panel data on observed belt use from the National Highway Traffic
Safety Administration and self-reported data on belt use from pooled cross
sections of the Centers for Disease Control and Prevention's 1985-1993 Behavioral
Risk Factor Surveillance System. By exploiting the panel nature of these data, I
demonstrate that prior estimates, which have not conditioned on the unobserved
time-varying determinants of belt use, have dramatically overestimated the impact
of seat belt laws and their enforcement status on belt use. The true effects are
more consistent with the modest impact these policies have had on traffic
fatalities without having to appeal to the possibility of risk compensation by
drivers. However, I find strong evidence in support of the selective recruitment
hypothesis. Belt use among those most likely to be involved in traffic accidents
(e.g. males, drinkers of alcohol, the young) has been significantly less
responsive to seat belt laws and their enforcement status.
PMID- 9542540
TI - Analysis of circumstances and injuries in 217 pedestrian traffic fatalities.
AB - We performed a retrospective analysis of 217 pedestrian traffic fatalities in
Seattle, WA, U.S.A. that occurred over a six-year period using medical examiner
records with essentially all of the deaths examined by autopsy. The annual
pedestrian fatality rate for the county averaged 2.0/100,000 for all ages and
both sexes, and the age-specific rate varied from 1.0/100,000 for the 22-34 year
age group to 1.5/100,000 for children under seven years and 7.0/100,000 for ages
70 years and older. Males had a 50% higher rate than females. Fatal accidents
were most common during December and January and during the evening hours.
Wednesday had the greatest number of accidents leading to death, 79% higher than
the Saturday weekend rate. Of those tested, 24% had ethanol in their blood. 66%
of the fatal injuries occurred on city or residential streets, and 29% occurred
on major thoroughfares. A single urban highway accounted for 12% of pedestrian
fatalities and represented a particularly hazardous traffic environment. Fatal
head injuries and severe chest injuries were present in 73% of cases; injuries
involving multiple sites were present in 60%. There were few significant
differences in the extent of injuries with respect to vehicle speed or type of
vehicle. Head injuries were much less common in the oldest age group, probably
because elderly pedestrians were more vulnerable to death from less severe trunk
and extremity injuries. Severe chest injury was the most important predictor of
death occurring at the scene.
PMID- 9542541
TI - Comparison of lifestyle and substance use factors related to accidental injuries
at work, home and recreational events.
AB - The purpose of this study was to examine whether risk factors vary for injuries
that occur at work, at home, at recreational events and at multiple settings.
Three major types of factors were investigated: lifestyle factors such as sleep,
stress and exercise; substance use; and demographic characteristics. Data were
obtained from a household survey of 882 Ontario adults. In order to determine
whether different factors were related to different kinds of accidental injuries,
chi 2 tests were conducted among five injury groups: no injuries; work; home;
recreational; and multiple injury episodes (i.e. at least two separate injury
episodes in two different settings). The first set of comparisons were conducted
between those with zero injuries and each of the aforementioned four injury
groups. Those with multiple injury episodes were significantly more likely than
those with no injuries to be single, under the age of 30, and have lifestyle
problems (i.e. sleep problems, financial problems and a desire for counselling)
and substance use/problems (i.e. cigarettes, alcohol, licit and illicit drugs).
For comparisons between each of the work, home and recreational injury groups and
no injury group, eight factors were significant altogether, but no single factor
was significantly related to more than one injury group. Contrasts between all
combinations of injury group pairs (i.e. excluding the no injury group) indicated
that risk factors for those with multiple injury episodes differed significantly
from those with home and recreational injuries for several characteristics. This
exploratory study provides some support that risk factors may vary, depending on
the injury group.
PMID- 9542542
TI - Ottawa-Carleton commuter cyclist on- and off-road incident rates.
AB - This analysis overcomes the known limitations of police and emergency room
bicycle accident databases through use of a survey that asked cyclists to
indicate their accident history as well as their regular commute route to work or
school. By relating the route information of the 1604 respondents (52.5% of the
distributed questionnaires) to facility attributes in a Geographic Information
System, defensible estimates of travel exposure on roads, off-road paths and
sidewalks were developed. The relative rates of collisions on the three different
facility types were not statistically different from 1.0. The relative rates for
falls and injuries suggest it is safest to cycle on-road followed by off-road
paths and trails, and finally least safe on sidewalks. While there were no major
injuries reported on sidewalks, the relative rate for these events on paths was
greater than the rate for roads. The absolute event rates per bicycle kilometre
were found to be between 10 and 41 times higher than similar rates for automobile
travel. Results suggest a need to discourage sidewalk cycling, and to further
investigate the safety of off-road paths/trails. The analysis also demonstrates
the need for bicycle travel exposure information and the use of more than just
collision databases for bicycle safety analysis.
PMID- 9542543
TI - The situational risks of young drivers: the influence of passengers, time of day
and day of week on accident rates.
AB - This paper provides new insight into the situational risks of young drivers,
especially in terms of the passenger effect. Two 1988 data bases from the Ontario
Ministry of Transportation were used to estimate accident involvement rates by
number of passengers, time of day and day of the week--first individually and
then for all two-way combinations with the passenger variable. Accident data were
derived from police reports for all accidents involving a fatality, personal
injury or property damage exceeding $700. Estimates of exposure were based on the
most up-to-date provincial travel survey available at the time of the study.
Results indicate that the accident involvement rates of 16-19 year old drivers
are higher than those of 20-24 and 25-59 year olds in all situations that were
examined, but that they were disproportionately high on weekends, at nighttime
and with passengers. The results of the passenger variable are particularly
interesting because, unlike weekends and nighttime, the negative effect of
passengers on overall accident rates was evident only for 16-19 year old drivers.
This effect was quite pronounced for both sexes, with accident involvement rates
being approximately twice as high with passengers as without. For 16-19 year
olds, accident rates were also significantly higher for two or more passengers
versus one passenger. The highest rates for this age group occurred with
passengers at nighttime. Possible explanations for these patterns and policy
implications are discussed.
PMID- 9542544
TI - Studies on tractor related injuries in northern India.
AB - Epidemiological studies were conducted in two phases each of 1 year duration in
nine and 30 villages, respectively, in two northern states of India.
Investigations were carried out to determine the causal factors, the activities
involved and severity of injuries for farming and non-farming activities in
tractor related accidents. A total of 76 cases involving five fatalities and 71
non-fatal injuries were recorded. The pattern of tractor related injuries in
India have been found to be very different compared to those reported from highly
industrialized countries. Fifty-four percent of tractor related injuries in the
first phase and 49% in the second phase were because of non-farming activities.
Of the total injuries recorded in both the phases only 1 and 6% were tractor
related. A major cause of tractor related injuries were collisions. In the two
phases 28 and 40% injured were passengers on tractor or trailer.
PMID- 9542545
TI - A study of commercial vehicle safety alliance's out-of-service criteria.
AB - This paper summarizes a two-phase project that reviewed the Commercial Vehicle
Safety Alliance's out-of-service criteria for vehicles. The first phase examined
relevant background information and conducted a questionnaire survey of CVSA
inspectors and industry representatives. The second phase of the project involved
extensive collection and evaluation of accident data. The results of both phases
show a high level of support, in terms of contribution to vehicle accidents, for
four of the vehicle criteria (regarding brakes, load securement, tires, and
wheels and rims). There was some support for coupling devices, fuel systems,
lighting devices, steering and suspension. The support for the remaining vehicle
criteria (exhaust systems, frames, van and open top trailer bodies, and
windshield wipers) was little to none. Further research continuing the study of
accident data is recommended to confirm these findings. However, the data must be
collected in a consistent and detailed manner if accurate information on the
relationship of accidents and vehicle criteria is to be established.
PMID- 9542546
TI - Impact from changes in Illinois drivers license renewal requirements for older
drivers.
AB - In late 1989, Illinois revised the length of license term and renewal
requirements for older drivers. The term was shortened from 4 to 2 years for
those ages 81-86 and 1 year for those ages 87 and up. A mandatory road test which
had been required at renewal for all drivers ages 69 and over, was eliminated for
those ages 69 to 74. Data are available to explore the impact of these changes on
crashes, fatal crashes, crash rates, and licensure rates of senior drivers.
Comparisons are made between 1987-1989 averages and 1995 for three age groups: 70
74, 75-80 (the control group that had no changes in requirements), and 81 and up.
It does not appear that eliminating the road test for those ages 69 to 74 had any
negative impact. On the contrary, it does not appear that the more frequent
renewal period for those ages 81 and up produced any benefit compared to the
control group. As the number of older drivers continue to increase into the
future, the analysis of licensing requirements and their impact is important.
PMID- 9542547
TI - The effect of resurfacing on friction, speeds and safety on main roads in
Finland.
AB - This study aimed at examining how resurfacing and the first winter period after
resurfacing affect the safety of main roads in Finland. The study consisted of
three substudies. In the first substudy the changes of side friction and lock
braking friction were measured on newly paved roads after resurfacing and after
the first winter period. The effect of different resurfacing methods was also
compared in the course of the study. All the 50 road sections in the study were
resurfaced in summer 1991 and measured with the friction truck of the Technical
Research Centre of Finland (VTT). Friction was found to be highly dependent on
the type of resurfacing treatment. In general, the friction of surfaces with high
coefficients after resurfacing decrease and the lowest frictions increase with
time, locked braking friction values immediately after resurfacing can be
undesirably low. The second substudy dealt with the effect of resurfacing on the
vehicle speeds. The analysis was based on automatic speed and weather measurement
in 1991 and 1992 on resurfaced roads, which were resurfaced in the summer 1991
and on a sample of comparison roads which had not been resurfaced. There is
little change in speeds on the non-resurfaced roads during the study period, but
there is some indication that resurfacing increases the average speeds, at least
when the road is dry. Complete data were available for only one site, where the
result was that average speeds on dry roads increased after resurfacing by 0.6
km/h and increased still more (by 0.5 km/h) after the first winter period. The
third substudy analysed fatal and injury accidents reported to the police on the
resurfaced and comparison roads one and two years before, the same year
resurfacing was performed and one and two years after the resurfacing. The
accident results were similar to the speed findings. The most likely effect is a
risk increase immediately after resurfacing by somewhat less than 7% and of 3 to
7% of the first winter period. These results are, however, subject to large
uncertainty because of the small number of accidents on the treatment roads.
PMID- 9542548
TI - Fatalities from non-use of seat belts and helmets in Greece: a nationwide
appraisal. Hellenic Road Traffic Police.
AB - It has been established that seat belt use by car occupants and helmet use by
motorcycle riders substantially reduces the risk of serious and fatal injuries
following accidents. No study, however, has evaluated the motor vehicle deaths
that could be prevented in Greece by general use of these devices, even though
this country has the highest mortality from motor vehicle accidents in the
European Union. We have estimated the odds ratios (OR) for death rather than
injury in a motor vehicle accident by seat belt use among occupants of passenger
cars or helmet use among motorcycle riders, using a nationwide database in which
persons killed or injured in road traffic accidents in 1985 and 1994 were
recorded. The study base included 910 dead and 19,511 injured persons for 1985
and 1203 dead and 22,186 injured persons for 1994. The OR and 95% confidence
intervals (CI) for death rather than injury was 0.69 (CI: 0.58 to 0.81, p < 10(
5)) for seat belt users versus non-users and 0.64 (CI: 0.51 to 0.81; p < 10(-3))
for helmet users versus non-users. There was evidence that the protective effect
of these passive safety devices increased from 1985 to 1994 probably reflecting
technological improvements. The proportion of all deaths that could have been
avoided if all car occupants used seat belts was estimated to 27%, whereas 38% of
motorcycle deaths could have been avoided if all motorcycle riders used helmets.
These proportions translate to about 500 deaths per year, mostly deaths among
young men.
PMID- 9542549
TI - The assured clear distance ahead rule: implications for nighttime traffic safety
and the law.
AB - The assured clear distance ahead (ACDA) rule holds the operator of a motor
vehicle responsible to avoid collision with any obstacle that might appear in the
vehicle's path. Although widely considered a fundamental responsibility of safe
driving, the ACDA rule is routinely violated by most drivers under nighttime
conditions. This fact does not necessarily imply reckless disregard for public
safety, however. Rather the troublesome discrepancy between drivers' behavior and
the principles of safe driving may be understood in terms of vehicle operators'
lack of awareness of selective losses of visual function that occur in low light.
This theoretical perspective holds basic implications both for traffic
regulations and for assessment of liability in nighttime road accidents.
PMID- 9542550
TI - Are road safety evaluation studies published in peer reviewed journals more valid
than similar studies not published in peer reviewed journals?
AB - The peer review system of scientific journals is commonly assumed to prevent
seriously flawed research from getting published. This paper compares the quality
of 44 road safety evaluation studies published in peer reviewed journals to the
quality of 79 evaluation studies dealing with the same safety measures, but not
published in peer reviewed journals, in terms of seven criteria of study
validity. Studies were scored for validity in terms of (1) sampling technique,
(2) total sample size, (3) mean sample size for each result, (4) specification of
accident or injury severity, (5) study design, (6) number of confounding factors
controlled and (7) number of moderator variables specified. Confounding factors
are all factors that disturb the attribution of a causal relationship between the
safety measure being evaluated and the observed changes in safety, moderator
variables are all variables that influence the size of the effect of the safety
measure. Very few statistically reliable differences in study validity were found
between studies published in peer reviewed journals and studies not published in
such journals. There was, at best, a weak tendency for studies published in peer
reviewed journals to score higher for validity. An interaction was found between
author affiliation and type of publication with respect to study validity.
Studies published in peer reviewed journals by authors who were at a university
scored highest for validity. For a number of reasons, this study must be regarded
as exploratory and its results as indicative only. The study does, however, point
to a line of research that might be worth pursuing in larger and more rigorous
studies.
PMID- 9542551
TI - The occupations of drink drivers: using occupational information to identify
targetable characteristics of offenders.
AB - Data collected by the Victoria Police at the time an alleged drink-driving
offender undergoes an evidential breath test for the presence of alcohol were
analyzed to investigate the possibility that occupational information could be
used to define groups of drink-drivers with similar characteristics. Such groups
could then be utilized in the development of targeted public education campaigns
in the Victorian (Australia) context where there are already high levels of
enforcement and mass-media publicity. It is argued that drink-drivers in this
context are likely to share some characteristics which might reduce the impact of
current programs. Analysis of the data relied on the application of a theory of
the relationship between career choice and other behavioral characteristics
(Holland, 1973, Making Vocational Choices, Prentice Hall, Englewood Cliffs, N.J.;
Holland, 1975, Manual for the Vocational Preference Inventory, Consulting
Psychologists Press, Palo Alto, CA). The analysis identified two potential groups
which accounted for 58% of the male drink-drivers. These groups differed from
other male drink drivers in a number of ways, underlining the potential for their
use as targets in future campaigns. One occupational category accounted for 42%
of the male drink drivers, including occupations such as carpenter, electrician,
chef, mechanic, gardener, and laborer. The behavioral characteristics associated
with these occupational codes in the Holland model included asocial, conforming,
reserved, introspective, unpopular, orderly, careful, unimaginative, and
defensive. The other occupational category accounted for 16% of the male drink
drivers and included occupations such as business manager, company director,
public servant, and sales representative. Behavioral characteristics associated
with this combination included acquisitive, adventurous, ambitious, energetic,
extroverted, friendly, and generous.
PMID- 9542552
TI - Lowering the legal blood alcohol level for motorcyclists.
AB - The blood alcohol concentrations (BAC) of all operators involved in motorcycle
accidents (MCA) and drivers of motor vehicle accidents (MVA) admitted to a New
Jersey Level I Trauma Center during 1992 (the first year such data were
computerized) were evaluated. Comparable to other institutional statistics (one
third of vehicular accidents are related to alcohol consumption) our data showed
13 (33%) of 40 MCA operators and 117 (35%) of 340 MVA drivers had measurable BAC.
These values, as well as their respective Injury Severity Scores (ISS), were
recorded and compared for significance of apparent differences using the 't' test
for unpaired observations. Mean BAC was 124 +/- 24 (SE) mg dl-1 for MCA and 180
+/- 9 mg dl-1 for MVA (p < 0.05). The respective mean ISS for MCA was 13.1 +/-
5.4 and MVA was 7.9 +/- 0.9 (p = 0.12). These data indicate that drivers involved
in MVA and MCA are frequently under the influence of alcohol. The mean BAC for
motorcyclists is significantly less than that for drivers of four-wheeled
passenger vehicles and is likely to reflect the need for greater coordination and
balance when operating a two-wheeled vehicle.
PMID- 9542553
TI - Does epidural analgesic technique influence mode of delivery?
PMID- 9542554
TI - Obstetric outcome following epidural analgesia with bupivacaine-adrenaline 0.25%
or bupivacaine 0.125% with sufentanil--a prospective randomized controlled study
in 1000 parturients.
AB - BACKGROUND: Epidural analgesia (EDA) is the most efficient method for pain relief
during labour, but there is still a debate as to whether it interferes with the
normal process of delivery. Some authors argue that the incidence of instrumental
deliveries, Caesarean section, malrotation and protracted labour is increased in
parturients receiving EDA. METHODS: 1000 parturients were prospectively
randomized to receive EDA either with a high dose of local anaesthetic (0.25%
bupivacaine with adrenaline = HD) or with a low dose (0.125% bupivacaine with
sufentanil 10 micrograms = LD). RESULTS: The incidence of instrumental delivery
and Caesarean section and the need for oxytocin was reduced in the LD compared to
HD group. The delivery time was similar with HD and LD among primiparous, but
decreased significantly among multiparous in the LD group. The incidence of
malrotation was low in both groups. The quality of analgesia was equal during the
first stage in the 2 groups, but was lower in the LD group during the second
stage. More parturients in the LD group ambulated, but this did not affect the
incidence of instrumental delivery. CONCLUSION: It is concluded that a lower
dosage of bupivacaine combined with sufentanil in epidural analgesia
significantly improves the obstetric outcome as compared to a higher dosage of
bupivacaine with adrenaline using intermittent bolus technique.
PMID- 9542555
TI - Efficacy of propacetamol in the treatment of postoperative pain. Morphine-sparing
effect in orthopedic surgery. Italian Collaborative Group on Propacetamol.
AB - BACKGROUND: Combined analgesic regimens have been suggested to improve the
treatment of postoperative pain. The aim of our study was to evaluate the
analgesic efficacy and tolerability of propacetamol, in combination with
morphine. METHODS: Four i.v. infusions of propacetamol 2 g or placebo were
administered, in a double-blind fashion, after orthopedic surgery (n = 97).
Morphine was administered by a patient-controlled analgesia (PCA) device. The
total dose of morphine, pain intensity and global efficacy of treatment were
evaluated. Tolerability was assessed by monitoring blood pressure, heart and
respiratory rate, sedation scores, adverse events, and renal and hepatic
parameters. RESULTS: The total dose of morphine was significantly decreased in
the propacetamol group compared to placebo (9.4 +/- 8.5 mg vs 17.6 +/- 12 mg; P <
0.001), arriving at a sparing effect of 46%. The evolution of pain intensity
showed a similar pattern in the two groups. Global efficacy of treatment was
rated significantly better by patients receiving the combination propacetamol +
PCA morphine (87% of "good"/"excellent" ratings vs 65%; P = 0.01). Tolerability
was comparable in the two groups. Eight patients in the propacetamol and 4
patients in the placebo group reported adverse events, of mild/moderate
intensity, most commonly nausea/vomiting. Renal and hepatic parameters were also
seen to be comparable. CONCLUSION: These results confirm a significant morphine
sparing effect, significantly better scores in the final assessment by patients,
and a good tolerability of propacetamol after orthopedic surgery. The drug may,
therefore, represent a useful alternative to NSAIDs, as complementary drug to
opioids, in the management of moderate/severe postoperative pain.
PMID- 9542556
TI - Preoperative adjuvant epidural tramadol: the effect of different doses on
postoperative analgesia and pain processing.
AB - BACKGROUND: Tramadol is an analgesic with combined opioid agonist and monoamine
reuptake blocker properties, which may be useful as a perioperative analgesic and
antinociceptive adjuvant. METHODS: The dose-dependent effects of adjuvant
preoperative epidural tramadol on postoperative analgesia (pain scores and
patient-controlled analgesia (PCA) use) and pain processing (heat pain
thresholds) were prospectively studied in a double-blind, randomised, placebo
controlled 5-day trial. Forty patients undergoing knee or hip surgery received
anaesthesia with epidural lidocaine and epidural tramadol 20, 50 or 100 mg or
placebo as a preoperative adjuvant. Postoperative analgesia was by intravenous
PCA tramadol in all patients. RESULTS: Postoperative pain scores were similar in
all groups. The time to first PCA use was shorter, the total dose and duration of
PCA use greater, and side-effects more common with 20 mg tramadol than with 100
mg or placebo (P < 0.05). There were no differences in PCA doses required or side
effects between the tramadol 100 mg and placebo treatment groups. Heat pain
tolerance thresholds were increased with 100 mg tramadol at 48 h postoperatively
compared to baseline and placebo (P = 0.01). CONCLUSIONS: Preoperative adjuvant
epidural tramadol does not improve postoperative analgesia after lidocaine
epidural anaesthesia compared to placebo. Tramadol 20 mg results in anti
analgesia and increased side-effects. While tramadol 100 mg depresses
postoperative pain-processing, as measured by heat pain tolerance thresholds,
this is not reflected in improved clinical pain measures.
PMID- 9542557
TI - Plasma levels of clonidine following epidural bolus injection in children.
AB - BACKGROUND: The use of clonidine as an adjunct to epidural administration of
local anesthetics in children has been reported to substantially improve the
duration and quality of postoperative analgesia. The aims of the present study
were to determine the pharmacokinetic profile and to investigate the interaction
between postoperative sedation and analgesia after epidurally administered
clonidine in children. METHODS: Plasma levels of clonidine (0-10 h postop) and
assessment of postoperative analgesia and sedation (0-24 h postop) were performed
at predetermined intervals following lumbar epidural administration of
bupivacaine 2.0 mg/kg and clonidine 2 mg/kg in 8 children undergoing ureteral re
implantation surgery using general anesthesia (age range: 1-9 yr, weight range: 9
41 kg). Plasma levels of clonidine were analyzed by radioimmunoassay, and
sedation and analgesia were assessed by previously described scoring systems.
RESULTS: The venous plasma pharmacokinetics of clonidine following epidural
administration showed a considerable interindividual variation. Cmax and Tmax
values of clonidine were found to be within the 0.45-0.77 ng/mL and 48-193 min
range, respectively. The time to absorb 95% of the clonidine dose from the
epidural space into plasma varied between 36 min and 7.6 h. In 6 of the 8
patients postoperative analgesia substantially outlasted the duration of sedation
(> or = 2 h). Sedation could not be detected in any patients at plasma
concentrations below 0.3 ng/mL. CONCLUSIONS: The pharmacokinetic profile
associated with epidural clonidine administration in children (1-9 y) was similar
to that previously reported in adults. The postoperative analgesia seen after
administration of epidural bupivacaine-clonidine during general anesthesia in
children cannot only be explained by residual postoperative sedation.
PMID- 9542558
TI - Granisetron prevents nausea and vomiting during spinal anaesthesia for caesarean
section.
AB - BACKGROUND: Nausea and vomiting during spinal anaesthesia for caesarean section
are common and unpleasant complications. This study was undertaken to evaluate
the efficacy of granisetron, a selective 5-hydroxytryptamine type 3 receptor
antagonist, for prophylactic treatment of nausea and vomiting in parturients
undergoing nonemergent caesarean section under spinal anaesthesia. METHODS: In a
randomized, double-blind, placebo-controlled trial, 100 patients, 21-38 years,
received either placebo (saline) or granisetron at 3 different doses (20
micrograms.kg-1, 40 micrograms.kg-1 or 80 micrograms.kg-1) (n = 25 for each)
intravenously immediately after clamping of the foetal umbilical cord. Nausea,
vomiting and safety assessments were performed during spinal anaesthesia for
caesarean section. RESULTS: The treatment groups were similar with regard to
maternal characteristics and operative management. The incidence of nausea and
vomiting was 64%, 52%, 14% and 12% after administration of placebo and
granisetron in a dose of 20 micrograms.kg-1, 40 micrograms.kg-1 and 80
micrograms.kg-1, respectively (P < 0.05; overall Fisher's exact probability
test). No clinically important adverse effects were observed in any group.
CONCLUSION: Prophylactic use of granisetron in a minimum dose of 40 micrograms.kg
1 is effective for preventing nausea and vomiting during spinal anaesthesia for
caesarean section.
PMID- 9542559
TI - Operations on patients deemed "unfit for operation and anaesthesia": what are the
consequences?
AB - BACKGROUND: The decision "patient unfit for anaesthesia and operation" is likely
to cause a delay of the scheduled operation. This retrospective evaluation was
done: 1) to determine the correctness of preoperative tentative diagnoses of
coexisting diseases making anaesthesia and operation excessively risky in
relation to the physician's training status; 2) to examine the question of
whether preoperative medical management modified according to the
anaesthesiologist's suggestions had a positive impact on the perioperative
course. METHODS: The medical records of patients scheduled for elective non
cardiac surgery who were rated "unfit for operation and anaesthesia" were
evaluated. The accuracy of the tentative diagnoses was examined for relation to
the training status of the anaesthesiologists. The preoperative management was
tested for its impact on postoperative outcome. RESULTS: During the observation
period 16,122 patients underwent preoperative anaesthesiological assessment; 1021
(6.3%) were initially considered to be unfit for operation and anaesthesia. The
records of 807 patients were available for review. The accuracy of the tentative
diagnoses was 70%, and was not significantly affected by the training status of
the physicians (P = 0.022). Four hundred and seventeen patients were excluded
from the second part of the investigation (discharged without operation,
underwent operation using local anaesthesia or tentative diagnosis not
confirmed). Three hundred and ninety patients were operated under general
anaesthesia. Group I (n = 216) was managed according to the anaesthesiologist's
suggestions and was found to have a significantly lower complication rate (18.1%)
than group II (n = 174) in which the suggestions from the preoperative assessment
were ignored (32.2%; P < 0.05). The perioperative mortality rate in group I was
2.3% compared with 5.2% in group II (n.s.; P > 0.05). CONCLUSIONS: We conclude
that the anaesthesiology decision "patient unfit for operation and anaesthesia"
has a high accuracy, independent of the anaesthesiologist's training status, and
that preoperative medical management significantly reduces complications.
PMID- 9542560
TI - Pharmacokinetics and clinical effects of intramuscular scopolamine plus morphine.
A comparison of two injection sites.
AB - BACKGROUND: Intramuscular scopolamine plus morphine premedication is
traditionally used when prominent sedative or antisialogogue effect is needed.
Knowledge of the pharmacokinetics of scopolamine is limited due to low plasma
concentrations found after therapeutic doses. This investigation compares the
pharmacokinetics and the clinical responses of this drug combination injected
into two commonly used injection sites. METHODS: Twelve ASA class 1 patients
scheduled for minor surgery under spinal anaesthesia received scopolamine 6
micrograms/kg plus morphine 200 micrograms/kg injected in either deltoid (group
D, n = 6) or gluteal (group G, n = 6) muscle. RESULTS: The peak plasma
concentrations of scopolamine after deltoid or gluteal injection (2.2 vs 1.6
micrograms/l) and the time they were reached (17 vs 19 min) were comparable. The
absorption of morphine was similar in both groups (Tmax 16 min), but the peak
plasma concentrations were higher after deltoid injection (71 vs 49
micrograms/l). The individual variation in the elimination half-lives of both
scopolamine and morphine was smaller after deltoid injection (T1/2 scopolamine
1.9 +/- 0.7 vs 2.1 +/- 1.1 h, morphine 1.3 +/- 0.7 vs 2.3 +/- 1.5 h). Moderate
slowing (25%) of heart rate was found in both groups. A heavy sedation and
antisialogogue effect (VAS) was found in both groups with faster occurrence of
maximal effect in group D (60 vs 120-180 min). CONCLUSION: More predictable
pharmacokinetics and clinical effects of intramuscular scopolamine plus morphine
premedication can be achieved after an injection into deltoid muscle.
PMID- 9542561
TI - Improved oxygenation using the prone position in patients with ARDS.
AB - BACKGROUND: The prone position is known to increase oxygen uptake in patients
with Adult Respiratory Distress Syndrome (ARDS). METHODS: In this clinical study
from 1995-96, 14 ARDS patients with severe respiratory failure were treated for
at least 1 h in the prone position. Responders, defined as having more than 10%
increase in PaO2/FiO2 ratio from baseline after 1 h, were treated at least 6 h in
the prone position. RESULTS: 11 patients responded during the first period of the
prone position (primary responders). Two of the 3 non-responders were turned
prone a second time with increase in the PaO2/FiO2 ratio (secondary responders).
Mean PaO2/FiO2 ratio (mean +/- SEM) in the supine position was 11.7 +/- 0.8 kPa,
increasing to 16.6 +/- 1.8 kPa and 18.0 +/- 1.4 kPa after 1 and 6 h respectively
(P = 0.009). Mean time spent in the prone position was 69 h (range 3-256 h), and
mean ventilatory time was 17 d (3-52 d). The mortality in this subgroup of our
patients with ARDS was 42%, compared to 58% in 19 patients not turned prone in
the same period. CONCLUSION: The prone position together with PEEP appears to
improve ventilation-perfusion matching. The prone position is simple, effective
and readily available and could be used early in most patients with ARDS.
PMID- 9542562
TI - Reduced CO2-elimination during combined high-frequency ventilation compared to
conventional pressure-controlled ventilation in surfactant-deficient piglets.
AB - BACKGROUND: Combined high-frequency ventilation (CHFV) combines a conventional
low-frequency component with super-imposed high-frequency jet pulses. The
intention is to overcome the limited CO2-elimination of high-frequency
ventilation, and to decrease airway pressures and enhance hemodynamic performance
by reducing the conventional component. The present study was performed to
compare the effects of conventional continuous positive-pressure ventilation
(CPPV) on gas exchange, airway pressures and cardiac output to those of CHFV at
matched minute volume (MV) and mean airway pressure (MPAW). METHODS: Sixteen
anaesthetised piglets with lavage-induced surfactant deficiency were ventilated
with CPPV, with positive end-expiratory pressure (PEEP) set to obliterate the
lower inflection point of the inspiratory pressure-volume loop. This setting was
compared to CHFV during which 50% of the total MV was applied as superimposed jet
pulses of 20 Hz at otherwise unchanged settings, and to CPPV at a PEEP level
which was reduced (CPPVred) until MPAW matched MPAW during CHFV. Gas exchange,
airway pressures and hemodynamics were measured after the ventilatory setting had
been applied for 20 min. RESULTS: MPAW decreased from (median) 2.7 kPa with CPPV
to 2.4 kPa with CHFV (P < or = 0.05). Peak inspiratory pressure was 3.6 kPa with
CPPV, 3.2 kPa with CHFV, and 3.2 kPa with CPPVred (P < or = 0.05 for differences
to CPPV), respectively. PaCO2 was comparable during CPPV (5.9 kPa), CPPVred and
CHFVCO2, while it increased during CHFV (6.8 kPa, (P < or = 0.05)). Cardiac
output did not differ significantly between the settings. CONCLUSION: In the
porcine lavage model, CO2-elimination is reduced during CHFV compared to CPPV at
matched minute volume. At matched mean airway pressure, CHFV fails to reduce peak
inspiratory airway pressure and to improve hemodynamic performance compared to
CPPV.
PMID- 9542563
TI - Plasma catecholamines and haemodynamic changes during pneumoperitoneum.
AB - BACKGROUND: Insufflation of CO2 into the abdomen is used during all kinds of
laparoscopic operations. The procedure elicits haemodynamic and hormonal
responses. The reports on sympathetic responses to laparoscopic surgery have been
conflicting. However, few studies have assessed sympathetic and haemodynamic
responses to CO2 insufflation per se, eliminating possible effects of intubation,
skin incision, surgical manipulation and positioning of the body. No studies have
measured both venous and arterial plasma catecholamines, the latter being a more
sensitive indicator of sympathetic activity. In the present study, we
hypothesised an increased sympathetic activity during pneumoperitoneum and an
association between haemodynamic and sympathetic responses. METHODS: Plasma
adrenaline and noradrenaline from the radial artery and superior vena cava were
measured immediately before and 10 min after abdominal insufflation of CO2 in 11
subjects. Haemodynamics were monitored invasively. RESULTS: During
pneumoperitoneum arterial plasma noradrenaline increased from 155 (106, 209)
pg/ml (median, lowest and highest quartile) to 283 (188, 378) pg/ml (P = 0.003),
while there were no changes in arterial plasma adrenaline. The calculated
arterial-superior vena cava difference in plasma noradrenaline did not change,
indicating no increased sympathetic activity in the drainage area of the superior
vena cava. Heart rate and cardiac index were unchanged, while total peripheral
resistance and mean arterial blood pressure increased (P = 0.002). The changes in
arterial plasma noradrenaline were closely related to the changes in total
peripheral resistance (r = 0.69, P = 0.01). CONCLUSIONS: Plasma noradrenaline
increases during pneumoperitoneum and is associated with changes in total
peripheral resistance. Plasma adrenaline is unchanged and there is no evidence of
increased sympathetic outflow to the drainage area of the superior vena cava.
Thus, the increase in plasma noradrenaline may be due to more local activation of
the sympathetic nervous system, probably somewhere from the drainage area of the
inferior vena cava.
PMID- 9542564
TI - Forced-air surface warming versus oesophageal heat exchanger in the prevention of
peroperative hypothermia.
AB - BACKGROUND: In a prospective, randomized, placebo-controlled study we
investigated the efficacy of 2 different heating methods in 24 patients
undergoing abdominal surgery of at least 2 h expected duration. METHODS: Group I:
control, no active warming. Group II: forced-air surface warming on upper
extremities and upper thorax. Group III: warming with oesophageal heat exchanger.
All patients had a standardized, combined general and epidural anaesthesia. Core
and skin temperatures were measured at induction of general anaesthesia, and
subsequently every 30 min, and changes in total body temperature were calculated.
RESULTS: There were no statistically significant differences between the 3 groups
regarding demographic data. Patients in groups I and III developed hypothermia,
while this was not the case with patients in group II. When using analysis of
variance with repeated measurements, there was no significant difference in core
temperature, comparing group I and group III (P = 0.299) or the interaction
between time and treatment of these groups (P = 0.373). As a consequence, data
from groups I and III were pooled and regarded as an internal group on the one
hand, and group II as an external group on the other hand. Core temperature, the
mean skin temperature and total body temperature were significantly different
comparing the internal group and the external group. The interaction between time
and treatment was likewise found to be significantly different. CONCLUSION: We
conclude that in major abdominal procedures lasting 2 h or more, serious
hypothermia develops unless effective measures to prevent hypothermia are used.
Forced-air warming of the upper part of the body is effective in maintaining
normothermia in these patients, while central heating with an oesophageal heat
exchanger, at least in its present form, does not suffice to prevent hypothermia.
PMID- 9542565
TI - Effects of desflurane, sevoflurane and halothane on postinfarction spontaneous
dysrhythmias in dogs.
AB - BACKGROUND: Although desflurane (DES) and sevoflurane (SEV) have desirable
features for use in patients with coronary artery disease, their effects on
ventricular dysrhythmias following infarction are less known. We therefore
examined the effects of DES and SEV upon spontaneous postinfarction ventricular
dysrhythmias in dogs, and compared those effects to the well-established
antidysrhythmic effects of halothane (HAL) in this model. METHODS: After
institutional approval, the left anterior descending coronary artery was ligated
in 16 adult mongrel dogs during isoflurane anesthesia. All dogs developed acute
myocardial infarction and severe ventricular tachydysrhythmias. Twenty-two hours
after infarction, dogs were anesthetized at 1.5 MAC with desflurane (10.8%)
followed by sevoflurane (3.5%) in the treatment group (n = 10), or halothane
(1.3%) in the other group (n = 6). Anesthetic gases were allowed to equilibrate
for at least 20 min at each end-tidal concentration. At this time, the ECG was
recorded for 9 min and evaluated for the number of ventricular ectopic and
sinoatrial beats and summed duration of ventricular tachycardia. RESULTS: DES and
SEV reduced the average rate of total ventricular ectopic beats by 40 +/- 4% and
42 +/- 4%, respectively. HAL decreased total ventricular ectopic rate by 59 +/-
6% and 62 +/- 5% after durations of anesthesia comparable to DES and SEV,
respectively. Decreases in dysrhythmia in the presence of DES and SEV were
significantly smaller than those produced by HAL after a comparable total
duration of anesthesia. CONCLUSION: DES and SEV inhibit spontaneous
postinfarction ventricular dysrhythmias, although attenuation of dysrhythmias was
smaller than the inhibition during comparable doses of HAL.
PMID- 9542566
TI - Effects of inhaled nitric oxide on platelet-activating factor-induced pulmonary
hypertension in dogs.
AB - BACKGROUND: Platelet-activating factor (PAF), a lipid mediator released during
endotoxin shock, induces pulmonary hypertension, systemic hypotension and cardiac
dysfunction. In this study, we compared the effect of inhaled nitric oxide (NO)
on PAF-induced pulmonary hypertension and NO metabolism with that on pulmonary
hypertension induced by a stable thromboxane A2 mimetic, U46619. Since PAF
induced hypotension might be mediated by NO, the effect of inhaled NO combined
with an intravenously administered NO synthase inhibitor, NG-nitro-L-arginine (L
NNA), on PAF-induced hemodynamic change was also investigated. METHODS: In a
total of 28 beagles anesthetized with pentobarbital the following substances were
intravenously administered: PAF 0.56 +/- 0.30 microgram.kg-1.min-1 (group PAF), L
NNA 10 mg.kg-1 + PAF 0.04 +/- 0.03 microgram.kg-1.min-1 (group L-NNA + PAF),
U46619 0.60 +/- 0.11 microgram.kg-1.min-1 (group U46619) or L-NNA 10 mg.kg-1 +
U46619 0.61 +/- 0.23 microgram.kg-1.min-1 (group L-NNA + U46619) to obtain a mean
pulmonary arterial pressure (MPAP) of 25 mmHg. Nitric oxide was then inhaled at
5, 10, 20 and 40 ppm for 15 min at 15-min intervals in the order of increasing
concentration. An additional 7 dogs (control group) inhaled NO at normal MPAP (17
mmHg). Hemodynamic and respiratory parameters, NOHb, NO2- + NO3-, and MetHb
levels in blood were measured before and during NO administration. RESULTS: In
the control group, hemodynamic and respiratory values did not change
significantly during NO administration. In group PAF, NO significantly reversed
the PAF-induced pulmonary hypertension. PAF induced a marked systemic hypotension
and cardiac output reduction, but these changes were not affected by inhalation
of NO. L-NNA pretreatment markedly decreased the dose of PAF required to maintain
a MPAP of 25 mmHg, and abolished the PAF-induced hypotension. In group L-NNA +
PAF, the diminishing effect of inhaled NO on pulmonary vascular resistance (PVR)
was significantly greater than that in group PAF. U46619 induced pulmonary
hypertension and increases in blood pressure, intrapulmonary shunt and peak
airway pressure. L-NNA pretreatment did not change the dose of U46619 required to
maintain a MPAP of 25 mmHg. The effects of inhaled NO on PVR decrease were
similar in groups U46619 and L-NNA + U46619. No NOHb was detected in any group.
NO2- + NO3- concentration increased during NO administrations. There were no
significant differences in NO2- + NO3- concentration among groups. CONCLUSIONS:
Inhaled NO at the dose of 5-40 ppm effectively reversed PAF-induced pulmonary
hypertension, especially following pretreatment with L-NNA. Inhaled NO did not
affect PAF-induced hypotension or cardiac dysfunction. These findings indicate
that low concentrations of inhaled NO may be useful in reversing pulmonary
hypertension in the endotoxemia where PAF may be one mediator.
PMID- 9542567
TI - The end-systolic pressure-volume relationship and ventriculoarterial coupling in
patients undergoing coronary artery bypass graft surgery.
AB - BACKGROUND: The end-systolic pressure-volume relationship and analysis of
ventriculoarterial coupling have been established as a useful tool to determine
the left ventricular performance and arterial loading conditions. The purpose of
this study was to evaluate the end-systolic pressure-volume relationship and
ventriculoarterial coupling in anesthetized patients with either a normal heart
or coronary artery disease (CAD) using a transesophageal echocardiography (TEE)
monitor. METHODS: Sixteen patients with CAD and 4 patients without ischemic
disease were studied. The end-systolic volume of the left ventricle was obtained
by TEE, and the end-systolic pressure was obtained from the brachial arterial
dicrotic pressure. In order to obtain the end-systolic pressure-volume
relationship, we plotted 7 different left ventricular end-systolic pressures
against the corresponding left ventricular end-systolic volumes during the
pressure manipulation. The linear regression obtained by this method was
designated as the end-systolic elastance (Ees). Furthermore, we calculated the
effective arterial elastance (Ea) using the pressure-volume framework. RESULTS:
We divided the patients with CAD into 3 groups: Group A: left ventricular
ejection fraction (LVEF) > 50%, Group B: LVEF 35-50%, Group C: LVEF < 35%. We
also studied a control group (Group D) who did not suffer from an ischemic heart
condition. Ees in group C (1.4 +/- 0.2) was lower than in the other 3 groups (P <
0.05). Ea/Ees in group C (1.9 +/- 0.1) was greater than in group A (0.7 +/- 0.1),
group B (1.0 +/- 0.06) and group D (0.6 +/- 0.1)(P < 0.05). There were no
significant differences in Ees and Ea/Ees between group A and group D.
CONCLUSIONS: We found that patients with CAD and a normal LVEF had a
physiological Ea/Ees identical to the control subjects. We also demonstrated that
patients with CAD and a reduced LVEF showed a deterioration in Ea/Ees.
PMID- 9542568
TI - Transient radicular irritation with intrathecal plain lignocaine.
AB - BACKGROUND: The aetiology of the syndrome known as transient radicular irritation
(TRI) has generated much interest. METHOD: A 50-year-old woman had right knee
arthroscopy performed under spinal anaesthesia with 1% plain lignocaine. RESULT:
At home, on the night of the procedure, she was woken by severe, bilateral cramp
like pain in both buttocks radiating to her thighs. Neurological examination of
her lower limbs, the next morning, was entirely normal. The pain lasted for 36 h
and a full recovery was made. CONCLUSION: This case of transient radicular
irritation occurred in a patient given 40 mg of subarachnoid lignocaine (the
lowest dose of isobaric preservative-free lignocaine reported thus far that has
been associated with these symptoms). Her operation was performed in the supine
position. The lack of confounding factors (hyperbaricity, high concentration
solution, preservatives, lithotomy position) suggests lignocaine as a possible
cause, yet current theories do not fully explain the aetiology of transient
radicular irritation. Results from large-scale epidemiological studies will
hopefully provide insight into the cause of this problem.
PMID- 9542569
TI - Combined overdose with verapamil and atenolol: treatment with high doses of
adrenergic agonists.
AB - A 55-year-old man was admitted following an overdose of sustained-release
verapamil (calcium channel blocker) and ordinary-release atenolol (beta-1
blocker). At admission, there was extreme bradycardia (20-25 beats min-1) and
hypotension (systolic arterial pressure 40-50 mm Hg). To counteract the
cardiovascular depression, prenalterol, dopamine, dobutamine, isoprenaline,
adrenaline and noradrenaline were used. A satisfactory state was obtained with
adrenaline, noradrenaline and dopamine infused at high rates. Cardiac output was
then more than 101 min-1, with a very low total peripheral resistance. The
infusion of the adrenergic agonists could be interrupted on day 3. Prolonged
ventilator treatment was necessary but the patient recovered without sequelae.
Treatment options for similar cases are outlined.
PMID- 9542570
TI - When fiberoptic bronchoscopy is indicated in the management of postoperative
atelectasis.
PMID- 9542571
TI - Calculated versus measured oxygen consumption during and after cardiac surgery.
Is it possible to estimate lung oxygen consumption?
PMID- 9542572
TI - Tracheal adrenaline in infants.
PMID- 9542573
TI - Some electrocardiographic patterns predicting sudden cardiac death that every
doctor should recognize.
AB - In recent years major advances have been made in the recognition and treatment of
candidates to sudden cardiac death. These advances include very sophisticated
diagnostic and therapeutic techniques, such as genetic testing and the
implantable cardioverter-defibrillator, new knowledge coming from large
multicenter trials, particularly about the poor efficacy of so-called
"antiarrhythmic" drugs, but also very important advances have been made in
improving the diagnostic value of simple techniques such as the twelve-lead
electrocardiogram. In this article six different electrocardiographic patterns
associated to sudden cardiac death are described. Some patterns, like left
ventricular hypertrophy or low voltage in the limb electrocardiographic leads,
are frequent and the incidence of sudden death in these patients is relatively
low, although clearly higher as compared to individuals with a normal
electrocardiogram. On the other hand, other patterns which are rarer (like the
long QT syndrome or the syndrome of right bundle branch block and ST segment
elevation in V1-V3) are associated to a very high rate of sudden death. Because
sudden death can be prevented in many cases, every doctor should be able to
recognize these types of electrocardiograms.
PMID- 9542574
TI - Ambulatory blood pressure, nocturnal blood pressure reduction and plasma
catecholamines.
AB - OBJECTIVE AND DESIGN: Controversial data have been reported on plasma
catecholamines in hypertensives. Aims of this study were to find whether 24-hour
ambulatory blood pressure was correlated with circulating catecholamines and to
investigate whether nocturnal blood pressure reduction was associated with
baseline plasma catecholamines. Samples for catecholamine determination were
obtained in 34 consecutive male subjects after a 30-minute rest and before
ambulatory blood pressure monitoring. RESULTS: Hypertensive patients (n = 22; 24
hour blood pressure: 145 +/- 14/94 +/- 6 mm Hg) showed similar norepinephrine and
epinephrine levels when compared with normotensives (n = 12; 24-hour blood
pressure: 124 +/- 6/81 +/- 6 mm Hg), and higher dopamine values (hypertensives:
64.6 +/- 58; normotensives: 26.2 +/- 31 pg/ml; p < 0.05). A positive correlation
was observed between dopamine and diastolic nocturnal blood pressure (p < 0.05)
while a negative correlation was found between dopamine and nocturnal diastolic
blood pressure reduction (p < 0.025). No significant relationship was observed
between both norepinephrine and epinephrine, and 24-hour blood pressures.
CONCLUSIONS: Since previous reports have documented malfunctioning of
dopaminergic system in hypertension, the higher levels of circulating plasma
dopamine found in hypertensive patients in the present study may account for a
peripheral compensatory increase. The correlation between dopamine and nocturnal
blood pressure fall seems to indicate that the impairment of dopaminergic system
may influence the 24-hour blood pressure profile, affecting the nocturnal blood
pressure reduction.
PMID- 9542575
TI - A randomized, double-blind comparison of the antihypertensive efficacy and safety
of once-daily losartan compared to twice-daily captopril in mild to moderate
essential hypertension.
AB - INTRODUCTION: The antihypertensive efficacy and safety of losartan, a specific
and selective angiotensin II (AII) receptor antagonist, was compared to captopril
in patients with mild or moderate essential hypertension. DESIGN: This
multinational, randomized trial consisted of a 4-week single-blind, placebo
baseline period followed by a 12-week double-blind, parallel comparison of once
daily administration of losartan 50 mg or twice-daily administration of captopril
25 mg. After 6 weeks of treatment, the daily dosage was doubled in patients whose
sitting diastolic blood pressure (SiDBP) remained > or = 90 mm Hg. PATIENTS:
Patients with essential hypertension having a mean trough SiDBP of 95-115 mm Hg
after the placebo baseline period were randomized to losartan (N = 192) or
captopril (N = 204) treatment. MAIN OUTCOME MEASURES: The primary efficacy
variable was the mean change from baseline to Week 12 in trough SiDBP. Safety was
assessed by recording spontaneously reported or observed adverse experiences and
clinical laboratory measurements. RESULTS: After 12 weeks, both treatments
produced clinically important reductions in trough SiDBP and sitting systolic
blood pressure (SiSBP). These mean reductions (SiDBP, SiSBP) were significantly
greater in the losartan group (-11.5 and -15.4 mm Hg, respectively) than in the
captopril group (-9.3 and -12.2 mm Hg, respectively) (p = 0.010 for diastolic and
p = 0.023 for systolic). The percentage of patients exhibiting an excellent
(trough SiDBP < 90 mm Hg) or good (trough SiDBP > 90 mm Hg, with decrease of > or
= 10 mm Hg) antihypertensive response to losartan and captopril therapy at Week
12 was comparable (60.0% and 54.7%, respectively). The percentage of patients
reporting a clinical adverse experience considered drug-related by the
investigator was 13% in the captopril group and 10% in the losartan group. The
incidence of drug-related cough was 2.6% in the losartan group and 4.4% in the
captopril group. CONCLUSION: Once daily administration of losartan 50 to 100 mg
is an effective treatment for patients with essential mild to moderate
hypertension. The antihypertensive efficacy of losartan 50/100 mg is
significantly greater than that of twice daily captopril 25/50 mg. Both
treatments were generally well-tolerated. The number of patients with the side
effect of cough was higher following captopril.
PMID- 9542576
TI - BWGIC guidelines for training and quality control in adult interventional
cardiology. Belgian Working Group of Invasive Cardiology.
PMID- 9542577
TI - Lectin histochemistry of human leukaemic mast cells (HMC-1) transplanted into
severe combined immunodeficient (scid) mice.
AB - It is difficult to isolate and impossible to propagate human mast cells in tissue
culture. As an alternative to the use of human differentiated mast cells, a human
leukaemic mast cell line (HMC-1), which can be propagated in vitro, has been
employed in a number of studies. Carbohydrate binding proteins, lectins, have
been used to characterise the terminal sugar residues of human mast cells in
situ. The aim of the present study is to characterise the lectin binding sites of
HMC-1 cells transplanted into severe combined immunodeficient (scid) mice.
Lectins specific for the complex carbohydrates, neuraminic acid and N
acetylglucosamine residues showed generally a strong uniform binding pattern,
whereas mannose and glucose specific yielded lectins a greater heterogeneity.
This glycotope expression pattern has some similarities with those of human mast
cells in situ, and therefore HMC-1 cells grown in scid mice constitute a valuable
model system for the study of carbohydrate expression in human mast cells.
PMID- 9542578
TI - Long-term action of potassium bromide on the rat thyroid gland.
AB - Male rats fed by a standard diet with determined of bromine and iodine content
were exposed to a 133-day oral administration of KBr (100, 200, 400 mg Br-/l
drinking water). Their thyroid glands showed increased growth of the epithelial
cells reflected by a microfollicular rearrangement of the parenchyma due to
proliferation of very small follicles with a low or zero content of colloid.
Morphometric analysis of thyroids of Br(-)-exposed animals revealed a significant
decrease in the volume of intrafollicular colloid and marked increase in the
number of the smallest follicles (areas up to 100 and 100-300 micron 2). In
addition, the nuclei of thyrocytes showed an increased number of mitoses. The
vascularization was increased as well. In the blood plasma of the Br(-)-exposed
animals the T4 concentration was significantly decreased in dependence on the
bromine concentrations. Thyroglobulin immunoreactivity in the colloid of Br(-)
exposed animals decreased after administration of 400 mg Br-/l drinking water.
Increasing concentrations of Br- in the drinking water caused an increased
bromine concentration in the thyroid, a decreased iodine content and a decreased
I/Br molar ratio. The changes in the rat thyroid caused by long-term
administration of 100 mg Br-/l were similar to hyperplastic parenchymal goitre
and were comparable to those induced in previous experiments by the same bromine
concentration administered over a 16- and 66-day period respectively.
PMID- 9542579
TI - Succinate dehydrogenase (SDH) activity in single Paramecium caudatum cells.
AB - We measured in situ the activity of succinate dehydrogenase (SDH), one of the
mitochondrial marker enzymes, in single Paramecium cells. SDH activity was
detected with nitroblue tetrazolium (Nitro BT). Images of cells were captured
every 30 sec at 590 nm, nearly the isosbestic wavelength of two reduction
products of Nitro BT, by using a microphotometric system for image analysis.
Activity was estimated by the slope of linear regression lines representing the
relationship between total absorbance of the processed image and delta reaction
time (real reaction time minus 30 sec). To investigate individual differences in
Paramecium cell populations, SDH activity was measured in cells at various
succinate concentrations. Paramecium SDH showed bimodal activity distribution
patterns at three of four succinate concentrations tested. This result suggests
that there are two groups of Paramecium populations with different SDH activity
under control culture conditions. On the basis of the relationship between SDH
activity and succinate concentration, mean Vmax and apparent Km values were
estimated. A Km of 3.2 mM was found for Paramecium.
PMID- 9542580
TI - Region- and age-dependent variations of muscle fibre properties.
AB - The cytophotometric-morphometrical analysis of extensor digitorum longus and
soleus muscles of 2.5 and 18 months old rats revealed regional and age-dependent
differences in fibre type distribution, fibre area and fibre type related-enzyme
activities which characterize contractility and metabolic profile. Variations
along the longitudinal axis from the origin to the insertion and along three
transversal axes from superficial to deep were found dependent on the muscle
investigated. For example, the fibres of extensor digitorum longus muscle showed
increased contractile and glycolytic capacities near insertion and the fibres of
soleus muscle increased oxidative capacity in its middle part. Furthermore, the
contribution of the fibre type that is dominant in a muscle (fast-glycolytic
fibre type in extensor digitorum longus and slow-oxidative fibre type in soleus
muscle) to the total number of fibres increased from origin to insertion by 15
and 30%, respectively. Along the superficial-deep axes the oxidative capacity of
all fibres increased, the most in fast fibres of the soleus muscle by
approximately 50%. In soleus muscle, a decrease of cross areas of all fibre types
from superficial to deep was found, correlating negatively with the succinate
dehydrogenase activity of the fibres. In extensor digitorum longus muscle the
change in cross areas of slow-oxidative and fast-oxidative glycolytic fibres was
dependent on the position of the transversal axis in the muscle. The results
suggest that distribution patterns of fibre types and the metabolic make up of
individual muscle fibres are adapted on the basis of local functional demands. In
both muscles, higher numbers and increased oxidative capacity of fast-glycolytic
fibres were found during ageing, but variations from superficial to deeper
regions were irrespective of age.
PMID- 9542581
TI - Intercellular adhesion molecule-1 (ICAM-1) expression in the liver of patients
with extrahepatic cholestasis.
AB - ICAM-1 mediates the recruitment of neutrophils through the endothelium to the
site of inflammation by the ICAM-1/Mac-1 and ICAM-1/LFA-1 adhesion pathways. In
extrahepatic cholestasis, recruitment of neutrophils is a main feature of the
inflammatory infiltrate in areas of parenchymal damage. The aim of the present
study was to describe the light and electron microscopical localization of ICAM-1
expression in the liver of cholestatic patients. The peroxidase-antiperoxidase
technique was used. Increased ICAM-1 expression was detected on sinusoidal
endothelial and Kupffer cells. A de novo ICAM-1 expression was described on some
Ito cells and the sinusoidal hepatocyte membrane in areas of parenchymal injury.
In the portal areas of livers of cholestatic patients, ICAM-1 was observed on the
endothelial surface of portal veins and on hepatic arteries. Occasionally, ICAM-1
was found on the surface of bile duct epithelia. It is suggested that ICAM-1
expression is up-regulated by cytokines like TNF-alpha, IL-1 and interferons
released from activated Kupffer cells. The mechanisms of ICAM-1 upregulation and
neutrophil recruitment in the liver during extrahepatic cholestasis are
discussed.
PMID- 9542582
TI - Pan-cadherin concentrates apically in uterine epithelial cells during uterine
closure in the rat.
AB - The ubiquitous cadherin probe, pan-cadherin was used to study changes in the
distribution of cadherins in the plasma membrane of rat uterine epithelial cells
during early pregnancy when the uterine lumen closes down. A major reorganisation
of cadherin expression was observed to occur in uterine epithelial cells between
days 1 and 6 of pregnancy with a clear shift in molecular distribution from a
basal location on day 1 to a distinctly and almost exclusively apical
distribution by day 6 of pregnancy when the blastocyst is attached. We suggest
these results indicate participation of this molecule in closure of the uterine
lumen, a phenomenon well-known to occur in the rat uterus during early pregnancy
and in which apical surfaces of opposing uterine epithelial cells cohere.
PMID- 9542583
TI - Distribution of N-cadherin and NCAM in neurons and endocrine cells of the human
embryonic and fetal gastroenteropancreatic system.
AB - For the first time, the distribution of N-cadherin and neural cell adhesion
molecule (NCAM) as well as some neuropeptides in nerve cells and endocrine cells
of the human embryonic and fetal gastroenteropancreatic system has been detected
in early stages (from the 6th postovulatory week onwards). Epithelial cells of
the stomach and small intestine contained gastrin and somatostatin and the
epithelium of the small intestine also bombesin-positive cells. Myenteric
ganglionic cells showed both bombesin and VIP and were NCAM- and N-cadherin
positive at all ages studied. Some basally granulated epithelial cells of
stomach, duodenum and the upper part of jejunum contained N-cadherin. The number
of these cells increased from 6th to 10th postovulatory weeks. Nerve cells and
the cytoplasm of individual epithelial cells of pancreatic ducts were
immunoreactive for NCAM and N-cadherin. NCAM- and N-cadherin-positive cells also
appeared in Langerhans islets (> 10 weeks), mainly in their peripheral part. NCAM
and N-cadherin-positive endocrine cells were less numerous than endocrine cells
producing somatostatin, bombesin, and VIP, probably reflecting the features of
embryonic/fetal histogenesis of Langerhans islets from epithelial endocrine cells
of pancreatic ducts. NCAM and N-cadherin were localized on the surface of
endocrine islets cells as well as in the cytoplasm of single islet cells. This
suggests the involvement of both membrane and soluble forms of adhesion proteins
in embryonic/fetal histogenesis of human pancreatic islets. The early occurrence
of N-cadherin (6th postovulatory week) in enteroendocrine cells supports the
existence of a common precursor. The expression of NCAM and N-cadherin in nerve
cells and endocrine cells of the human fetal gastroenteropancreatic system may
indicate the involvement of neuronal adhesion mechanisms in the development of
neuro-endocrine complexes of fetal stomach, small intestine and pancreas.
PMID- 9542584
TI - Caveolin-3 and nitric oxide synthase I in healthy and diseased skeletal muscle.
AB - Recently, it has been shown for mouse skeletal muscle that caveolin-3 is
localized in the sarcolemma and cofractionates with the original dystrophin
complex (DC). In order to find out whether caveolin-3 is a further component of
the recently established and enlarged nitric oxide synthase (NOS) I-DC and
whether members of this complex interact with and are potentially regulated by
caveolin-3, mammalian and non-mammalian healthy and diseased (dystrophic)
skeletal muscles were investigated using caveolin-3, NOS I, DC components and
myosin immunohistochemistry as well as NOS I-associated diaphorase
histochemistry. In healthy mammalian skeletal muscle, caveolin-3 was colocalized
with the DC components in all extra- and intrafusal fibers. By contrast, NOS I
was absent in type I extrafusal fibers of certain species. In patients with
Duchenne muscular dystrophy and mdx mice the components of the NOS I-DC were not
detected in all extra- and intrafusal fiber types, while caveolin-3 was found
unchanged. In healthy non-mammalian skeletal muscle, i.e. of birds, reptiles and
fishes, caveolin-3 immunoreactivity was lacking in the sarcolemma as was alpha
sarcoglycan; the other NOS I-DC components were either present or absent. In
conclusion, although caveolin-3 is localized in the sarcolemma of mammalian
myofibers, there are differences in the microarchitecture of the components of
the DC complex and of caveolin-3 which does not appear to be linked with the NOS
I-DC. Potential regulatory interactions between caveolin-3 and NOS I may
nevertheless exist in those fibers where both molecules are colocalized. The
absence of caveolin-3 and alpha-sarcoglycan immunoreactivities in non-mammalian
myofibers may suggest that the functions of these proteins are subserved by other
components of NOS I-DC complex.
PMID- 9542585
TI - Diffuse plaques associated with astroglial amyloid beta protein, possibly showing
a disappearing stage of senile plaques.
AB - To clarify whether senile plaques disappear, we examined amyloid beta protein (A
beta) deposits in non-demented subjects, and found novel diffuse plaques
associated with astroglial A beta. Formalin-fixed paraffin-embedded sections from
cortical areas were immunolabeled with a panel of A beta antibodies, and
astroglial and microglial markers. Cerebral A beta deposition was primarily found
as diffuse plaques (DP) in these subjects. A subset of DP was associated with
clusters of intensely A beta-positive small granules. The clusters, which were
located just adjacent to astroglial nucleus, had the characteristics of
lipofuscin granules and, therefore, were quite different from "small stellate
deposits". Substantial amounts of A beta-positive granules were found inside
astrocytes by dual labeling of A beta and glial fibrillary acid protein, and the
majority of astroglial A beta immunoreactivity was located on lipofuscin
granules. A beta-positive granules lacked immunoreactivity with antisera for the
N-terminal region of A beta. These peculiar DP showed a much weaker staining than
ordinary DP. The DP associated with astroglial A beta were found in about one
third of the subjects, although the density varied widely among individuals. From
these findings, we propose that DP, which are associated with the N-terminal
truncated A beta in astrocytes, represent the disappearing stage of senile
plaques.
PMID- 9542586
TI - Immunolabelling of the cytoplasm and processes of apoptotic facial motoneurons
following axotomy in the neonatal rat.
AB - A polyclonal antibody intended to recognize c-Jun (Oncogene Science, c-jun/AP-1,
Ab-2) has previously been shown to recognize an apparently novel "apoptosis
specific protein" (ASP) in the cytoplasm of cells undergoing apoptotic cell death
in vitro. We have investigated whether this antibody would also serve as a
reliable marker for apoptotic motoneurons in vivo. Following transection of the
left facial nerve in anesthetized neonatal rat pups, which results in over 90%
death of the facial motoneurons, we performed immunohistochemistry on frozen
brain stem sections with Oncogene Science Ab-1 and Ab-2 antibodies which are
raised against different peptide fragments of c-Jun. While Ab-1/c-Jun labelling
was seen in the nuclei of the majority of axotomized motoneurons, Ab-2/ASP
immunoreactivity was present only in scattered cells, all of which had
characteristic apoptotic morphology. Furthermore, Ab-2/ASP immunoreactivity was
cytoplasmic and frequently included the dendrites and axons of dying neurons.
Some cerebellar granule cells undergoing postnatal developmental cell death were
also Ab-2/ASP positive. The time course of the number of Ab-2/ASP-labelled
motoneurons corresponded relatively closely with our previous data on DNA
fragmentation in these cells, as assessed by an in situ end labelling (ISEL)
technique. When facial nerve axotomy was performed at 7 and 14 days postnatum,
resulting in reduced cell death, the number of Ab-2/ASP immunoreactive cells
decreased correspondingly. Although the exact identity of the epitope recognized
by Ab-2 is unclear, we conclude that, by labelling the cytoplasmic and neuritic
components of apoptotic motoneurons, Ab-2/ASP immunohistochemistry is a valuable
complementary technique to existing in situ methods based on the detection of
fragmented DNA in the cell nucleus.
PMID- 9542587
TI - Enlarged and phagocytic, but not primed, interleukin-1 alpha-immunoreactive
microglia increase with age in normal human brain.
AB - Microglia-mediated inflammatory responses have been implicated in the
pathogenesis of neuritic plaques in Alzheimer's disease. The strong age
association of Alzheimer's disease incidence suggests that events in normal aging
may promote such responses. We used immunohistochemistry and computerized image
analysis to determine the numbers, size, activation state, and immunoreactive
intensity of interleukin-1 alpha-immunoreactive (IL-1 alpha +) microglia in
mesial temporal lobe of 20 neurologically normal individuals, 2-80 years of age.
We also used Northern analysis to determine tissue levels of IL-1 alpha mRNA in
an additional 11 neurologically normal individuals aged 1 day to 78 years. IL-1
alpha + microglia were characterized as primed, enlarged, or phagocytic (enlarged
with heterogeneous cytoplasmic contents) based on morphology. These three
microglial subtypes showed significant differences in size [27 +/- 1 58 +/- 2 114
+/- 6 (mean +/- SEM) micron 2/cell, respectively, P < 0.001 for each comparison]
and in immunoreactive intensity [60 +/- 1 68 +/- 2 79 +/- 2 (arbitrary units),
respectively, P < 0.001 or better for each comparison]. There were significant
age-associated increases in the total numbers of activated IL-1 alpha +
microglia. Among microglial subtypes, there were significant increases in the
numbers of enlarged (threefold) and especially phagocytic (elevenfold), but not
primed, microglia. Tissue IL-1 alpha mRNA levels were higher in individuals over
60 than in those less than 60 (P < 0.05). The age-associated increases in
microglial activation were independent of postmortem interval, patient sex, and
the presence of Alzheimer-type 'senile' changes. Age-associated increases in
microglial activation and IL-1 expression may contribute to the age-associated
increased risk of Alzheimer's disease.
PMID- 9542588
TI - Secondary microvascular degeneration in amyloid angiopathy of patients with
hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D).
AB - Various secondary microvascular degenerative and inflammatory alterations may
complicate cerebral amyloid angiopathy (CAA) and contribute to the morbidity of
CAA-associated stroke. We have investigated the severity of CAA-associated
microangiopathy in a genetically determined Dutch form of CAA (HCHWA-D) that has
major similarities to the type of CAA that more commonly occurs with aging or
Alzheimer's disease (AD). The presence and extent of the following vascular
abnormalities was assessed: (1) hyalinization/fibrosis, (2) microaneurysm
formation, (3) chronic (especially lymphocytic) inflammation, (4) perivascular
multinucleated giant cells/granulomatous angiitis, (5) macrophages/histiocytes
within the vessel wall, (6) vessel wall calcification, (7) fibrinoid necrosis,
and (8) mural or occlusive thrombi. (Of these, calcification of CAA-affected
vessel walls has, to our knowledge, been described in only a single patient with
CAA-associated cerebral hemorrhage.) Some of the changes, such as histiocytes in
blood vessel walls and the relationship of vascular hyalinosis to amyloid beta/A4
protein deposition, were highlighted by immunohistochemistry. By assessing the
numbers of sections in which the changes were present for each case, a 'score'
reflective of CAA-associated angiopathy could be obtained. This 'score' was
reproducible among several observers. We suggest that it might also be applicable
to quantifying severe CAA and related microvascular degenerative changes in
patients with AD. beta/A4 immunoreactivity was often sparse and adventitial (or
almost absent) in severely hyalinized arterioles and microaneurysms. However,
macrophages were prominent in the walls of such vessels and may play a role in
the pathogenesis and progression of CAA-related microvasculopathy.
PMID- 9542590
TI - Increase in SNAP-25 immunoreactivity in the mossy fibers following transient
forebrain ischemia in the gerbil.
AB - SNAP-25 (a synaptosomal-associated protein of 25 kDa) has been shown to be
involved both in synaptic vesicle exocytosis and in axonal outgrowth. In the
present study, we investigated the changes in SNAP-25 immunoreactivity in the
hippocampus of the Mongolian gerbil (Meriones unguiculatus) at different time
points after transient forebrain ischemia insult. In parallel, immunostaining for
GAP-43, a protein involved in axonal outgrowth, and for syntaxin-1 (stx1A and
stx1B), another protein implicated in neurotransmitter release, was also
analyzed. The animals were subjected to 2.5 or 5 min of transient forebrain
ischemia through bilateral common carotid occlusion, and examined at different
intervals after ischemia. SNAP-25 immunoreactivity was increased in the mossy
fiber layer as early as 2 days after 5 min of ischemia. Increased SNAP-25
immunoreactivity in mossy fibers was also detected at days 4 and 7 after
ischemia. On day 15, SNAP-25 staining was similar to that observed in control non
ischemic animals. In contrast, no changes in GAP-43 and syntaxin-1
immunoreactivity were observed in the mossy fiber layer following 5 min of
ischemia. No modifications in SNAP-25, syntaxin-1 or GAP-43 immunoreactivity were
observed following 2.5 min of ischemia, the longest period for which no neuronal
damage is observed. These results provide evidence of a specific involvement of
SNAP-25 in the reactive changes associated with transient forebrain ischemia.
PMID- 9542589
TI - The fragmented neuronal Golgi apparatus in amyotrophic lateral sclerosis includes
the trans-Golgi-network: functional implications.
AB - The Golgi apparatus (GA) of spinal cord motor neurons is fragmented in sporadic
amyotrophic lateral sclerosis (ALS), and in asymptomatic and symptomatic
transgenic mice expressing the G93A mutation of the gene of the human Cu,Zn
superoxide dismutase, found in certain cases of familial ALS (FALS) [Gonatas NK
(1994) Am J Pathol 145:751-761; Mourelatos Z, et al. (1996) Proc Natl Acad Sci
USA 93:5472-5477]. A similar fragmentation of the GA has been described in cells
treated with microtubule-depolymerizing drugs, where the organelle is functional
and contains both Golgi stacks and trans-Golgi network (TGN), the compartment of
exit and targeting of proteins processed by the GA. To gain a better definition
of the structure of the fragmented neuronal GA in ALS, four cases of sporadic ALS
with numerous Bunina bodies in spinal cord motor neurons were stained with
antibodies against human TGN and against the lumenal and cytoplasmic domains of
MG160, a protein of the medial cisternae of the GA. The fragmented GA was stained
with the three antibodies, indicating the presence of both Golgi stacks and TGN.
Furthermore, the staining of the fragmented GA by the antiserum against the
cytoplasmic domain of MG160 indicates that the fragmentation of the GA is not the
result of a terminal and global cytoplasmic lytic event. The Bunina bodies were
not stained by the anti-MG160 antibodies, suggesting that they are not derived
from the GA. The perikarya of neurons with fragmented GA showed normal
immunoreactivity with antibodies against the heavy neurofilament subunit and
alpha-tubulin. However, because of the lack of appropriate antibodies the
localization of proteins such as spectrin, ankyrin, centractin and others which
link the microtubules with the GA were not done. The findings support the
hypothesis that, in ALS, the fragmented neuronal GA is functional. Additional
work with animal models of ALS may establish whether the fragmentation of the GA
is a sign of early degeneration or a compensatory reaction of the injured motor
neuron.
PMID- 9542591
TI - Lectin histochemistry in the aged dog brain.
AB - Formalin-fixed and paraffin-embedded canine brains were examined histochemically
using 15 selected lectins. Concanavalin A (Con A), Lens culinaris agglutinin,
Lycopersicon esculentum agglutinin (LEL) and Limulus polyphemus agglutinin (LPA)
labeled neurons in an age-dependent manner. These and some other lectins
[Dolichos biflorus agglutinin (DBA), Vicia villosa agglutinin (VVA), Ricinus
communis agglutinin 120 (RCA-I), Bandeiraea simplicifolia agglutinin (BSL-I), and
Phaseolus vulagaris agglutinin-L (PHA-L)] also age-dependently labeled glial
cells. These results indicate that monosaccharide composition and biochemical
metabolism in brain cells change with age and that these lectins may be useful as
histochemical markers for investigating senile changes in the canine brain.
However, no significant correlation was found between ApopTag-positive and lectin
positive cells. Amyloid plaques were positive for Con A, DBA, Glycine maximus
agglutinin (SBA), LEL, PHA-L, Limax flavus agglutinin (LFA) and VVA. Among these
lectins, VVA, SBA and LFA intensely stained amyloid both in blood vessel walls
and senile plaque cores. Therefore, the sugar residues recognized by these
lectins likely play specific roles in beta-amyloid deposition in the aged dog
brain.
PMID- 9542592
TI - Regulation of Schwann cell numbers in tellurium-induced neuropathy: apoptosis,
supernumerary cells and internodal shortening.
AB - We have used an experimental model of tellurium(Te)-induced demyelinating
neuropathy in the rat to study cellular mechanisms involved in regulating Schwann
cell (SC) numbers during remyelination. Starting at postnatal day 21, weaned rats
were fed a diet containing 1.1% elemental Te. Following 7 days of Te treatment
and at several time points of post-tellurium treatment (PTe), the animals were
processed for ultrastructural analysis, SC nuclei quantification and teased fibre
preparations. It is well-established that Te induces a transient
demyelinating/remyelinating sequence in sciatic nerves. The loss of the myelin
sheath in this neuropathy produces active proliferation and overproduction of
immature SCs. By electron microscopy analysis most mitotic SCs were located along
demyelinated segments. Quantitative determination of SC nuclei per transverse
section of sciatic nerve revealed a dramatic increase of SCs at 2 days PTe
relative to control nerves. The number of SC nuclei then decreased progressively
during the long-term period of recovery studied (330 days PTe). In Te-treated
rats, SCs undergoing cell death were regularly found within the nerve fibre
compartment, especially on demyelinated segments. Dying cells exhibited
morphological features of apoptosis and appeared enclosed by lamellar processes
of adjacent healthy SCs in extracellular compartments. Both healthy immature SCs
and endoneurial macrophages were involved in the phagocytosis of apoptotic SCs.
Particularly during remyelination, supernumerary endoneurial SCs were observed
surrounding myelinated fibres. These cells progressively became atrophic with a
morphological phenotype similar so that of "onion bulb" cells. On the other hand,
teased fibre measurements revealed a remarkable permanent internodal shortening
in remyelinated fibres from Te-treated sciatic nerves. These results indicate
that a portion of redundant immature SCs are susceptible to elimination by
apoptosis. However, other distinct biological mechanisms such as the persistence
of supernumerary SCs in the endoneurium and the shortening of internodal lengths
are also involved in regulating SC numbers during the remyelination stage.
PMID- 9542593
TI - Enhanced reactivity of Alz-50 antibody in brains of sudden infant death syndrome
victims versus brains with lethal hypoxic/ischemic injury. Diagnostic
significance after application of the ImmunoMax technique on routine paraffin
material.
AB - Alz-50 antibody is immunoreactive with brain tissue of subjects with Alzheimer's
disease and can also be demonstrated by immunocytochemistry in neurons of
vibratome-prepared brain tissue of victims of sudden infant death syndrome
(SIDS). The application of a slightly modified ImmunoMax method enabled us to
demonstrate Alz-50 immunoreactivity in paraffin-embedded material. The Alz-50
epitope was detected in the hippocampus region and in nuclei of the medulla
oblongata at the level of the inferior olivary protuberance in three diagnostic
groups: victims of SIDS (n = 10), infants dying of subacute hypoxia/ischemia with
subsequent (re-)perfusion (n = 9), and infants dying of acute ischemia without
(re-) perfusion (n = 7). Quantitative evaluation of the hippocampal cortex and
the nucleus olivaris inferior disclosed a significantly (P < 0.05) higher
percentage of Alz-50-reactive neurons in SIDS cases than in the control groups
(hippocampal cortex and the nucleus olivaris; SIDS victims: median = 100%;
subacute hypoxia/ischemia: median = 33.6-81%; acute ischemia: median = 89.2-99%).
Semiquantitative analysis revealed an equally pronounced preponderance of Alz-50
reactive neurons in SIDS victims versus the control groups. This greater
expression in SIDS victims may be due to an ongoing hypoxia/ischemia during
agony, but the present paucity of knowledge prohibits definitive elucidation.
Nevertheless, the method described here appears to offer the realistic
possibility of distinguishing SIDS cases from cases of sudden death in infants
due to other causes, i.e., it offers for the first time a positive criterion for
the diagnosis of SIDS.
PMID- 9542594
TI - Co-expression of Fas and Fas ligand in malignant glial tumors and cell lines.
AB - Fas ligand (FasL) is involved in tumor evasion from the immune system. We
analyzed 22 human gliomas for expression of FasL and its receptor, Fas. Positive
FasL and Fas immunoreactivity was detected in 13 out of 22 tumors by Western
blotting and in 15 out of 22 tumors by immunohistochemistry. Immunohistochemistry
also showed that Fas and FasL expression was confined to tumor cells. Co
expression of these molecules was confirmed by Western blotting and
immunohistochemistry in 4 of 7 glioma cell lines. Co-expression of FasL and Fas
within tumor cells suggests that their contribution in vivo to the process of
immune system evasion and tumor cell apoptosis is complex and probably involves
additional factors.
PMID- 9542595
TI - Rare occurrence of inactivating p53 gene mutations in primary non-astrocytic
tumors of the central nervous system: reappraisal by yeast functional assay.
AB - While it is established that p53 mutation plays a critical role in the
carcinogenesis of astrocytic brain tumors, its role remains to be clarified for
other types of tumors in the central nervous system (CNS). Using a yeast-based
assay which tests the ability of human p53 to activate transcription, we analyzed
p53 mutations in 85 non-astrocytic CNS tumors, including 4 benign neuronal tumors
(3 central neurocytomas and 1 pineocytoma), 12 primitive neuroectodermal tumors,
14 germ cell tumors (7 germinomas, 7 non-germinomatous tumors), 4
craniopharyngiomas, 14 ependymomas, 22 schwannomas, 10 primary brain lymphomas in
immunocompetent patients, and 5 bone tumors of the skull. The only tumors found
to contain p53 mutations were 3 malignant lymphomas. The presence of mutations in
these cases was confirmed by DNA sequencing. Given the high accuracy and
sensitivity of the yeast assay and previous negative results using conventional
techniques, this indicates that p53 mutation is a rare event in non-astrocytic
CNS tumor types examined here.
PMID- 9542596
TI - Systemic complement depletion reduces inflammation and demyelination in adoptive
transfer experimental allergic neuritis.
AB - The effect of systemic complement depletion by cobra venom factor (CVF) was
evaluated in adoptive transfer experimental allergic neuritis (AT-EAN). Spleen
cells of rats immunized with a neuritogenic peptide SP26 were injected into naive
rats. On days 3 and 6 after cell transfer AT-EAN rats were treated with CVF or
saline intraperitoneally. AT-EAN rats treated with CVF had significantly lower
scores for histological inflammation (0.25 +/- 0.25 vs 1.9 +/- 0.4, mean +/- SEM,
P < 0.03) and demyelination (0.13 +/- 0.13 vs 1.6 +/- 1.4, P < 0.02) than saline
treated AT-EAN rats. Immunocytochemistry of lumbosacral nerve roots showed
significantly less ED1-positive macrophages (0.5 +/- 0.3 vs 1.6 +/- 0.6, P <
0.04) and CD11bc-positive (expressing complement receptor 3 or CR3) inflammatory
cells (0.6 +/- 0.4 vs 1.7 +/- 0.5, P < 0.03). Our data suggest that complement
plays a crucial role in inflammatory demyelination since systemic complement
depletion significantly reduces recruitment of macrophages into the nerve and
subsequent macrophage-mediated demyelination.
PMID- 9542597
TI - Anti-tubulin antibodies in a sensorimotor neuropathy patient alter tubulin
polymerization.
AB - The effect of anti-tubulin antibodies present in the serum of a patient with a
progressive sensorimotor neuropathy on microtubule assembly was examined. The
patient's serum was reactive on immunoblots with a single band of proteins of 55
kDa from homogenates of neural tissues. Tubulin was identified as the
quantitatively major component of these 55-kDa proteins. Polymerization of
tubulin in vitro was significantly enhanced by the patient's serum. A monoclonal
antibody to nerve-specific class III beta-tubulin precisely duplicated the
immunoreactive profile of the patient's serum, while an antibody to class (I +
II) beta-tubulins also reacted with tubulins in non-neural tissues. The results
indicate for the first time that human antisera reactive with nerve specific beta
tubulin can alter tubulin polymerization-depolymerization dynamics.
PMID- 9542598
TI - Atypical juvenile neuronal ceroid lipofuscinosis with granular osmiophilic
deposit-like inclusions in the autonomic nerve cells of the gut wall.
AB - In this 8-year-old boy, who had been exposed to alcohol and oxazepam during
pregnancy, visual failure was the first symptom of a neuronal ceroid
lipofuscinosis (NCL) disorder, noticed at the age of 5 years. Ophthalmological
examinations revealed a cystic type of macular degeneration, which would be more
likely to be found in variant late infantile NCL. However, vacuolated lymphocytes
were found in peripheral blood films and a diagnosis of the juvenile form of NCL
(JNCL) was made. Molecular genetic studies showed the patient to be homozygous
for the major mutation of JNCL, a 1.02-kb deletion. In whole-night
polysomnography, there was significantly more epileptiform activity than in other
JNCL patients under 10 years of age. Using magnetic resonance imaging, the signal
intensity of the white matter was increased, especially in the periventricular
area. In addition, there were enlarged perivascular spaces in the watershead
areas. The corpus callosum was thin. Finally, in the autonomic ganglion cells of
the submucosal nerve plexus there were membrane-enclosed homogeneous and granular
cytosomes resembling the granular osmiophilic deposits of infantile NCL. However,
extraneural cells, including blood capillaries and smooth muscle, showed
inclusions with fingerprint and curvilinear profiles. The features of the present
case indicated a phenotypic variant of JNCL.
PMID- 9542599
TI - Disseminated perivenous necrotizing encephalomyelitis in systemic lupus
erythematosus: report of an autopsy case.
AB - The patient, a 22-year-old woman who had been treated for systemic lupus
erythematosus (SLE) for 10 years, was hospitalized for arthralgia, melena, and
difficulty in walking. CT examination of the brain showed grain-like high-density
lesions scattered throughout the cerebral white matter and basal ganglia. At
autopsy, multiple perivenous, well-demarcated foci of brownish discoloration were
seen scattered throughout the cerebral white matter and basal ganglia.
Histopathologically these lesions consisted of foci of coagulation necrosis
surrounding the veins. The veins in the foci showed fibrous thickening of the
walls, but there were no indications of vasculitis. At the periphery of the
lesions, the axons were better preserved than their myelin sheaths. The
neuropathological findings in the present case closely resemble those of acute
disseminated (perivenous) encephalomyelitis, although an inflammatory cell
infiltration had apparently already subsided. Although its pathogenesis remains
unclear, this finding should not be regarded as an incidental complication but
rather as a rare subtype of central nervous system lesion occurring with SLE.
PMID- 9542600
TI - Neurocytoma/rhabdomyoma (myoneurocytoma) of the cerebellum.
AB - An unusual case of cerebellar neurocytoma with rhabdomyomatous differentiation in
a 6-year-old boy is reported. Immunocytochemical and ultrastructural features of
the tumour were studied. Abortive synapse formation, the presence of clear
vesicles and synaptophysin immunoreactivity of the tumour cells indicated its
intermediate neuronal differentiation, while the presence of myoblasts and
myotubes and immunolabelling by desmin confirmed the rhabdomyomatous
differentiation. In addition, the mesenchymal cells variably expressed
neurofilament protein and glial fibrillary acidic protein, suggesting inductive
interaction between the neuroectodermal and ectomesenchymal elements and
persistence of the pleuripotential nature of the cells along the rhombic area of
the brain stem.
PMID- 9542601
TI - Role of T cells in drug allergies.
PMID- 9542602
TI - Systemic T-cell unresponsiveness during rush bee-venom immunotherapy.
AB - By rush bee-venom immunotherapy, subjects reacting allergically to the venom can
be effectively anergized, although the mechanism of action is not known. Here we
analyzed the systemic effects of rush desensitization on the T cells of allergic
patients. In most patients, we found reduced frequencies of T cells recalled to
express CD69 and the cytokines interleukin (IL)-4 and interferon-gamma (IFN
gamma) after stimulation of peripheral blood mononuclear cells with phorbol 12
myristate 13-acetate (PMA) and ionomycin, as compared with normal donors. These
frequencies are progressively reduced during immunotherapy. The frequency of
cells expressing IL-2 does not change. A few patients show a different response
to immunotherapy: frequencies of cells expressing CD69, IL-4, or IFN-gamma do not
change, and remain similar to those of normal donors. However, the frequency of
cells able to express IL-2 is increased. The analysis of cytokine expression in
CD45RO+ vs CD45RO- T-cell populations revealed differences between normal and
allergic donors. In allergic patients, higher frequencies of IL-4- and IFN-gamma
expressing cells among the CD45RO- subpopulation were found than in normal
donors. This situation is not modified by immunotherapy. The results reveal a
certain degree of heterogeneity in the response of allergic patients to bee-venom
rush immunotherapy; however, all are clearly differentiated from normal controls
as judged by cytokine expression of CD45RO- T cells. In most allergic patients, a
considerable percentage of Th cells become unresponsive to mitogenic stimulation,
and may be responsible for the desensitization itself.
PMID- 9542603
TI - Sensitization to Zygophyllum fabago pollen. A clinical and immunologic study.
AB - Zygophyllum fabago is a herbaceous plant found widely in the Mediterranean area.
There are no previous reports of its allergenicity. An aerobiologic and clinical
survey was conducted in Murcia, southern Spain, to determine the quantity of
airborne pollen and establish the possible role of this pollen as a cause of
allergic symptoms. With a Hirst volumetric trap, we determined the atmospheric
concentrations of this pollen in 1993, 1994, 1995, and 1996. Of 1180 patients
tested, 181 (15.34%) had a positive skin test. To determine its allergenicity, we
divided 47 patients into three groups: in group 1, all the patients had symptoms
of rhinoconjunctivitis plus asthma; in groups 2 and 3, rhinoconjunctivitis. In
group 1, we performed a bronchial provocation test (BPT); in groups 2 and 3, we
performed nasal provocation (NPT) and conjunctival provocation (CPT) tests,
respectively. SDS-PAGE was used to characterize the antigenic fractions and RAST
inhibition to determine cross-reactivity with other pollens. The pollen
dispersion period is from May to September (445 grains/m3). BPT was positive in
13 of 15 patients, NPT in 14 of 16 patients, and CPT in 13 of 16 patients. RAST
inhibition revealed cross-reactivity with Mercurialis, Ricinus, Olea, and Betula.
SDS-PAGE identified 25 IgE antibody-binding components, five of which (60, 65,
41, 38, and 15.5/14.7 kDa) were recognized by 40% of the sera. By SDS-PAGE
immunoblotting with sunflower antiprofilin rabbit serum and affinity
chromatography we established that the Z. fabago extract has profilin. This study
shows that this pollen becomes airborne and elicits an IgE response which
triggers respiratory symptoms in allergic subjects.
PMID- 9542604
TI - Prevalence of allergy in children in relation to prior BCG vaccination and
infection with atypical mycobacteria.
AB - By influence on the Th1/Th2 cell balance, infectious agents may affect the
development of atopic allergy. In this study, we investigated whether previous
BCG vaccination or infection with atypical mycobacteria might be related to the
development of atopic disease. The study, which involved skin testing with
mycobacteria and answers to a questionnaire for more than 6000 children in
Sweden, revealed a low prevalence of allergy among BCG-vaccinated children who
were immigrants or adopted from other countries. Vaccinated children born in
Sweden, however, did not have significantly lower allergy prevalence than age
matched, unvaccinated children. Furthermore, the overall frequencies of skin-test
reactivity to the atypical mycobacteria M. avium and M. scrofulaceum were higher
rather than lower in allergic than in nonallergic children. By contrast, there
was a tendency toward a lower frequency of more strongly positive skin reactions
(> or = 10 mm) to mycobacteria in allergic than in nonallergic children. These
findings do not support the hypothesis that early mycobacterial infections have a
suppressive effect on the development of atopic disease. Earlier findings of an
apparent association between atopy and lack of previous mycobacterial infection
may possibly be explained by a relatively decreased ability of atopic patients to
mount strong Th1 cell-mediated immune responses.
PMID- 9542605
TI - Aeroallergens and viable microbes in sandstorm dust. Potential triggers of
allergic and nonallergic respiratory ailments.
AB - Aeroallergens and antigens in sandstorm dust, extracts of which were skin prick
test (SPT) positive in allergic patients, were detected by rocket
immunoelectrophoresis and ELISA. Fungi and bacteria isolated by agar settle
plates and soil dilution and soil washing methods were enumerated and identified.
Cat dander, Acacia, Alternaria, Aspergillus, Chenopodium, Cladosporium, Bermuda
grass, Pithecellobium, Prosopis, Rumex, cultivated rye, and Washingtonia palm
allergens were detected by both methods. Viable microbes including 1892 +/- 325
colony-forming units (cfu) of bacteria, and 869 +/- 75 cfu of fungi were isolated
per gram of dust by the soil dilution method. Randomly selected microbial
colonies on streaking and subculture were found to consist of between two and
seven mixed colonies. Fungi including Alternaria, Aspergillus, Botrytis,
Cladosporium, Mortierella, Mucor, Mycelia sterilia, Penicillium, Pythium,
Ulocladium, Verticillium, and some yeasts were isolated. Actinomyces, Bacillus,
Pseudomonas, and mostly coagulase-negative Staphylococcus species were
identified, but the bulk of unidentified bacterial isolates were mainly mixed
colonies of rods, cocci, coccobacilli, and some filamentous types. Six-hour agar
settle-plate counts during sandstorms were 100 and 40% higher for bacteria and
fungi, respectively, than without sandstorms. The most abundant aeroallergens
were those of Acacia, Alternaria, Aspergillus, Bermuda grass, Cladosporium,
cultivated rye, Prosopis, and cat dander. Pithecellobium dulce, Rumex crispus,
and Washingtonia palm allergens were detectable for the first time in Riyadh. IgE
reactivities of the dust in man were demonstrated by ELISA using sera from
atopic, exposed, and normal subjects. These results indicate that sandstorm dust
is a prolific source of potential triggers of allergic and nonallergic
respiratory ailments, and the methods mentioned here should be routinely used for
quick sampling of the environment.
PMID- 9542606
TI - Airborne grass (Poaceae) pollen in southern Spain. Results of a 10-year study
(1987-96).
AB - This work reports an exhaustive study of the aerobiology of the Gramineae in
Seville, Spain, which is typical of coastal Mediterranean areas. Sampling was
done with a Cour trap installed on the roof terrace of the School of Pharmacy,
Seville, from 1987 to 1996, both inclusive. The climatic pattern of that period
was characterized by two exceptionally wet years (1989 and 1996), between which
were 5 consecutive years of drought (1990-5). This typically Mediterranean
climate affects grass aerobiology. The annual amounts of total grass pollen are
low, never exceeding 2500 grains/m3. The start, length, and intensity of the
pollen season are significantly correlated with preseasonal meteorologic factors
(precipitation and temperature), but intraseasonal meteorologic conditions have
no effect on the three variables. The relationships are stated by three equations
that, while further years of observations are anticipated, can be considered
models to forecast the characteristics of the pollen season: the starting date
depends on the mean temperatures of January and February, and the length and
intensity of the season depend on the rainfall between the beginning of January
and the starting date of the season. For the study period, the weekly
concentrations (pollen curves) throughout the year showed no typical pattern of
variation over the years, so that it was impossible to make mid- and long-term
forecasts of the variation in weekly concentration. The most noteworthy aspects
of grass pollen curves are a long pollen season, which starts in February or
March and lasts until September or October; peaks of higher concentration (> 100
grains/m3) in May and June, associated with increases in temperature and absence
of precipitation; and other peaks in the summer months that may be as high as the
spring peaks.
PMID- 9542607
TI - Allergen-specific increase in interleukin (IL)-4 and IL-5 secretion from
peripheral blood mononuclear cells during birch-pollen immunotherapy.
AB - The mechanisms behind the effects of immunotherapy (IT) with birch-pollen extract
are largely unknown. In this pilot study, we measured the cytokine secretion in
vitro from peripheral blood mononuclear cells (PBMC) obtained from birch-pollen
allergic patients undergoing IT treatment (n = 4) or placebo administration (n =
4), collected before treatment, 1 and 4 weeks after start of treatment, and
during and just after the pollen season (12-14 weeks after start of treatment).
The PBMC were stimulated with birch-pollen extract in vitro for 7 days, followed
by restimulation with the mitogens phytohemagglutinin (PHA) and phorbol 12
myristate 13-acetate (PMA) for 24 h, to enhance the production of cytokines. The
supernatants were analyzed with ELISA and radioimmunoassay for interferon-gamma
(IFN-gamma), interleukin (IL)-4, and IL-5. In the therapy group, we noted an
increased secretion of IL-4 and IL-5 from PBMC collected at 4 weeks after the
start of treatment (IL-4: 29 +/- 21 pg/ml [day 0] to 374 +/- 448 pg/ml [week 4],
mean +/- SD; IL-5: 95 +/- 48 pg/ml to 1147 +/- 697 pg/ml). No increase was seen
in the placebo group. During the pollen season, we noted a trend toward increased
IL-4 and IL-5 secretion in both groups. We conclude that the temporary increase
in serum IgE observed in many IT studies may be a consequence of increased IL-4
production due to the allergen exposure.
PMID- 9542608
TI - Late skin-prick-test reactions to malted wheat. Clinical observations and
immunohistochemical characterization.
AB - This study reports late skin-prick-test (SPT) reactions in seven bakers and seven
control subjects to malted wheat appearing after 6-10 h, and not preceded by an
immediate-phase reaction. Two subjects in each group had a history of atopic
symptoms and were Phadiatope positive. Serologic IgE analysis (RAST) of normal
wheat flour and of malted wheat grain was negative in all subjects. Skin biopsy
specimens were obtained 16-18 h after SPT to malted wheat grain and to histamine
and from untested skin. The late SPT reactions in all participants had an
urticarial appearance, clinically and in routine histology. Immunohistologically
mild to moderate perivascular dermal cell infiltrates were observed in both
groups, consisting mainly of CD4+ and HLA-DR+ cells. The number of CD1a+
epidermal cells was statistically significantly higher (P < 0.01) in the bakers'
prick-tested skin compared to that of the controls, a fact which might reflect
preparedness to react upon challenge. There were no statistical differences
between the two groups in IgE+ epidermal cells or epidermal cells expressing the
high-affinity IgE receptor (Fc epsilon RI). However, there was a correlation
between serum-IgE levels and the number of IgE+ epidermal cells. The late skin
reactions observed in both bakers and controls were probably more of an irritant
or toxic than immune-mediated nature, but they raise the question of whether skin
contact with malted flour contributes to an unfavorable prognosis of hand eczema
in bakers.
PMID- 9542609
TI - Determination and characterization of cross-reacting allergens in latex, avocado,
banana, and kiwi fruit.
AB - Sera of 11 patients were used to characterize allergens in kiwi fruit, latex,
avocado, and banana by SDS-PAGE/immunoblotting and to determine cross-reactions
between these allergen extracts in EAST inhibition and immunoblot inhibition. By
SDS-PAGE/immunoblotting, allergens with apparent molecular weights of 21, 38, 40,
and 42 kDa were visualized in latex extract. In avocado extract, IgE-binding
components of 27, 43, 52, 58, 65, 75, and 88 kDa were to be seen, whereas, in
banana extract, a 40-kDa protein showed strong IgE binding. Furthermore,
allergens of 52, 58, 88, and 94 kDa were detected in the extract of banana. Cross
reactions between these allergen extracts were determined by EAST inhibition.
Immunoblot inhibition demonstrated that almost all IgE-reactive bands in
nitrocellulose-blotted latex, avocado, and banana extracts and two components of
43 and 67 kDa in kiwi fruit shared common IgE epitopes.
PMID- 9542610
TI - Comparison of olfactory function in patients with seasonal and perennial allergic
rhinitis.
AB - Hyposmia is a common symptom in allergic rhinitis. However, little is known about
differences in the olfactory function of patients with seasonal or perennial
allergy. A prospective controlled study was performed on 28 patients with
allergic rhinitis to grass pollen and on 47 patients with allergic rhinitis to
mites. Sixty-six healthy volunteers served as a control. Olfactory function was
evaluated by a modified Connecticut Chemosensory Clinical Research Center testing
procedure for threshold, identification, and discrimination. The grass pollen
allergic patients were tested preseasonally and after 3 weeks of intraseasonal
grass pollen exposure; the mite-allergic patients and the volunteers were tested
once. In the mite allergics, olfactory threshold, identification, and
discrimination tests were significantly worse than in the volunteers (all P <
0.0001). In the grass pollen allergics, the results in olfactory identification
and discrimination tests were not different from the controls if tested out of
the season (both P > 0.05). However, in threshold testing (P = 0.0139), the
results were worse. Intraseasonally, the grass pollen allergics showed a
significant decrease in threshold, identification (both P < 0.0001), and
discrimination testing (P = 0.0029). If the intraseasonal pollen allergics were
compared to the mite allergics, they showed better results in identification (P =
0.0087) and threshold (P < 0.0001) tests, but worse results in discrimination
testing (P = 0.0002). Therefore, the different kind of allergen exposure seems to
result in a different pattern of allergic olfactory dysfunction.
PMID- 9542611
TI - Factors determining spontaneous histamine release from human basophils purified
with Percoll gradients and Dynabeads.
AB - Identification of factors influencing histamine release from purified and
cultured basophil leukocytes is important for proper interpretation of results
obtained on histamine release. This paper describes factors that influence
spontaneous histamine secretion from human basophil leukocytes purified on
Percoll gradients, followed by negative selection with Dynabeads. Anti-IgE and
recombinant human interleukin-3 were used as model stimulants, and the purified
basophil leukocytes were stimulated for 10 min and 6 h. The effect of the
following conditions was examined: Percoll temperature, cell-suspension density,
and serum in the media. The results showed that low Percoll temperature, high
cell-suspension density, and the presence of serum in the media decreased
spontaneous histamine release and increased maximal net histamine release upon
stimulation.
PMID- 9542612
TI - Milk hypersensitivity--key to poorly defined gastrointestinal symptoms in adults.
AB - Lactose intolerance is a common adverse reaction to milk in adults, while milk
hypersensitivity is a disorder of infancy. We hypothesized that milk
hypersensitivity may cause many unspecific gastrointestinal disorders in adults.
Twenty adults were subjected to double-blind, placebo-controlled milk challenge.
Phagocyte activity, and Fc gamma and complement receptor expression of phagocytes
were assayed, and serum total IgE, milk-specific IgE, and serum reactivity to
milk protein were determined. The challenge increased phagocyte activity and
complement receptor expression of phagocytes in subjects designated milk
hypersensitive, who had gastrointestinal symptoms from milk ingestion but normal
lactose tolerance. The increase was not detected in lactose-intolerant or control
subjects. The milk-hypersensitive group was also distinguished from the lactose
intolerant group by enhanced serum reactivity to milk protein. Only two out of
nine milk-hypersensitive subjects had detectable milk-specific serum IgE. It is
concluded that milk hypersensitivity in adults, occurring as gastrointestinal
reactions, may be more common than previously thought.
PMID- 9542613
TI - Isolation and immunobiochemical characterization of a major allergen (65 kDa)
from Fusarium equiseti.
AB - Fusarium equiseti is one of the most important species in the class
Deuteromycetes (Fungi Imperfecti). For proper diagnosis and immunotherapy,
isolation and characterization of allergens of F. equiseti are necessary. In the
present study, culture filtrate (CF) extract of F. equiseti was resolved into 35
37 bands on isoelectric focusing pI (3-9) and SDS-PAGE (mol. wt. 10-100 kDa).
Most of them were glycoproteins, as identified by PAS staining. F. equiseti CF
revealed 15 allergenic proteins on immunoblot with an allergic serum pool. It was
fractionated into nine fractions (I-IX) on a Superose-12 column by FPLC. Fraction
IV (65 kDa) and fraction VI (25 kDa) were found to be highly allergenic by IgE
ELISA. A 65-kDa protein was observed as a major allergen because it was
recognized by most of the patient sera on immunoblot. After elution from SDS-PAGE
gel, it gave two bands of pI 7.4 and 6.0. Inhibition in IgE-binding components of
F. equiseti CF with CF extracts of F. solani and F. moniliforme by immunoprint
inhibition assay indicated the allergenicity shared between the extracts of
Fusarium species. Data suggested that the 65-kDa is the major allergen in the
Fusarium species and can be used for the treatment of allergic patients.
PMID- 9542614
TI - Comparison of the oral health status and salivary flow rate of asthmatic patients
with those of nonasthmatic adults--results of a pilot study.
AB - The oral health status and stimulated salivary flow rate of 33 adult asthmatic
outpatients were compared with those of 33 nonasthmatic controls. The groups were
matched by age and sex, and an adjustment for education was made in the
statistical analysis. In the oral examination, a small difference in the
prevalence of caries was observed when the sums of decayed, missing, and filled
teeth (DMFT) were compared. The mean (SD) crude DMFT score was 20.1 (5.8) in the
asthma group and 18.4 (7.6) in the control group. A statistically significant
difference was seen in the amount of periodontal inflammation and in the
stimulated salivary flow rate between the groups. The mean (SD) crude periodontal
status index (PSI) was 52.7% (23.8%) in the asthmatics and 37.1% (20.4%) in the
controls. The 95% confidence interval (95% CI) for the difference in adjusted
means of PSI ranged from 0.1% to 21.9% (P = 0.05). In the stimulated salivary
flow rate, crude mean values were 1.0 (0.5) ml/min and 1.3 (0.5) ml/min,
respectively, and the 95% CI for the difference was from 0.05 ml/min to 0.57
ml/min (P = 0.01). Mucosal lesions in the oral cavity were found in 15 asthmatics
(45%) and in eight controls (24%). In conclusion, the results of this study
support the hypothesis that adult asthmatics have a higher risk of oral diseases
than nonasthmatic subjects.
PMID- 9542615
TI - A case of episodic angioedema associated with blood eosinophilia: upregulated C5a
receptor expression on eosinophils.
AB - A 47-year-old woman was admitted to hospital complaining of swelling and pain of
the extremities, accompanied by high fever and generalized erythema. Laboratory
examination showed marked blood eosinophilia with elevation of IgM, IgE, and C
reactive protein. All autoantibodies examined were negative. The heart and lungs
showed no untoward findings. Biopsies of the skin and muscle revealed cellular
infiltration of eosinophils around small blood vessels. Quantitation of C5a
receptor (C5aR) expression by flow cytometry using anti-C5aR antibody showed
upregulated expression of C5aR on blood eosinophils but downregulated expression
on neutrophils. The abnormal C5aR expression on eosinophils and neutrophils
became normal after spontaneous resolution of symptoms and blood eosinophilia.
The possibility that C5aR expression on granulocytes is related to the
pathogenesis of this syndrome may be considered.
PMID- 9542616
TI - Allergy to adhesive plaster.
PMID- 9542617
TI - Non-IgE-mediated anaphylaxis to sesame.
PMID- 9542618
TI - Evaluation of nasal cytology: a comparison between methods.
PMID- 9542619
TI - Occupational asthma to hyacinth.
PMID- 9542620
TI - Anaphylaxis after prednisone.
PMID- 9542621
TI - Syndromes associated with eosinopenia.
PMID- 9542622
TI - Conjunctivitis to thimerosal mistaken as hay fever.
PMID- 9542623
TI - Cell cross-contamination in cell cultures: the silent and neglected danger.
AB - Cell cross-contamination in cell cultures is a common problem during cell
culturing and use. Contamination invalidates research results, compromises the
comparison of results between laboratories, reduces reproducibility required in
industrial production of cell lines, and may lead to unusable therapeutic
products. The problem can be solved by increasing the awareness of its
seriousness and by introducing regular quality control of cell cross
contamination in every laboratory where cells are grown and used.
PMID- 9542624
TI - Preparation of a pressurization system to study the effect of hydrostatic
pressure on chondrocyte cultures.
PMID- 9542625
TI - Aneuploidy induced by cyclophosphamide in developing rat testes.
PMID- 9542626
TI - Construction of Xenopus (B3.2) and human (HeLa) cell lines expressing the
tetracycline-controlled transactivator (tTA)
PMID- 9542627
TI - Cultured human nasal gland cells in a three-dimensional collagen gel.
PMID- 9542628
TI - Ca2+ mobilization in fetal-human cardiac myocytes is stimulated by isoproterenol
and inhibited by ryanodine.
PMID- 9542629
TI - Promoting matrix invasion by human lung epithelial cells.
PMID- 9542630
TI - Integrins: utility as cell type- and stage-specific markers for hepatocellular
carcinoma and cholangiocarcinoma.
PMID- 9542631
TI - A simple method for freezing and storing viable tissue fragments.
PMID- 9542632
TI - The effect of impermeable oxidants on the growth of neoplastic cells.
PMID- 9542633
TI - Sensitivity of isoenzyme analysis for the detection of interspecies cell line
cross-contamination.
AB - The analysis of the gel electrophoresis banding patterns and relative migration
distances for the individual isoforms of intracellular enzymes, such as lactate
dehydrogenase, purine nucleoside phosphorylase, glucose-6-phosphate
dehydrogenase, and malate dehydrogenase, is used routinely in the
biopharmaceutical industry for confirmation of cell line species of origin. In
the present study, the sensitivity of the technique (AuthentiKit, Innovative
Chemistry, Marshfield, MA) for determining interspecies cell line cross
contamination was examined. Extracts were prepared from a CHO-K1 line (AA8,
Chinese hamster), MRC-5 (human) cells, and L929 (mouse) cells and from several
proportional mixtures of the various binary combinations of cells. The isoenzymes
were analyzed according to standard procedures for the technique. Contamination
of MRC-5 cells with CHO-K1 or with L929 cells was clearly detectable with each
enzyme analyzed. Similarly, the contamination of L929 or CHO-K1 cells with MRC-5
cells was readily apparent with each enzyme. On the other hand, contamination of
CHO-K1 cells with L929 cells was only detected with lactate dehydrogenase
analysis, and contamination of L929 cells with CHO-K1 cells was not detected with
any of the four enzymes examined. For the latter case, the analysis of an
additional enzyme (peptidase B) was required. The results indicate that
interspecies cross-contamination should be detectable with isoenzyme analysis if
the contaminating cells represent at least 10% of the total cell population.
PMID- 9542634
TI - Primary culture of choroidal epithelial cells: characterization of an in vitro
model of blood-CSF barrier.
AB - A primary rat choroidal epithelial cell culture system was developed to
investigate mechanisms of heavy metal toxicity on the blood-cerebrospinal fluid
(CSF) barrier. Epithelial cells were dissociated from choroidal tissue by pronase
digestion and cultured in standard DMEM culture media supplemented with 10% fetal
bovine serum and 10 ng epithelial growth factor per ml. The procedure yielded 2-5
x 10(4) cells from pooled plexuses of three to four rats, and a viability of 77
85%. The cultures displayed a dominant polygonal type of epithelial cells, with a
population doubling time of 2-3 d. The cultures were of distinct choroidal
epithelial origins. For example, immunocytochemical studies using monospecific
rabbit anti-rat TTR polyclonal antibody revealed a strong positive stain of
transthyretin (TTR), a thyroxine transport protein exclusively produced by the
choroidal epithelia. Also, reverse-transcriptase polymerase chain reaction (PCR)
confirmed the presence of specific TTR mRNA in the cultures. The cultures were
further adapted to grow on a freely permeable membrane sandwiched between two
culture chambers. The formation of an impermeable confluent monolayer occurred
within 5 d after seeding and was verified by the presence of a steady electrical
resistance across the membrane (80 +/- 10 ohm per cm2). The epithelial barriers
appeared to actively transport [125I]-thyroxine from the basal to apical chamber.
These results suggest that this primary cell culture system possesses typical
choroidal epithelial characteristics and appears to be a suitable model for in
vitro mechanistic investigations of blood-CSF barrier.
PMID- 9542635
TI - Reconstituted human oral and esophageal mucosa in culture.
AB - We have successfully established monolayer and organotypic culture techniques for
growing human oral and esophageal epithelial cells. Cells in monolayer culture
were grown in serum-free medium, modified from techniques previously reported by
our group. The organotypic cultures were grown in a defined medium supplemented
with 10% fetal calf serum. Oral and esophageal cells were maintained in
keratinocyte basal medium with pituitary extract and other supplements, and 0.05
mM calcium for 7-9 and 9-11 passages, respectively. Both cell types had similar
morphology by phase contrast microscopy. When confluent, the cells were
predominantly small, basaloid, and uniform and interspersed with larger,
differentiated cells. By immunohistochemistry, both cell types in monolayer were
positive to AE1, AE3, and 34BE12 antibodies to keratins of stratified epithelia.
Oral epithelial cells in monolayer also were positive to 35BH11, representative
of simple epithelial keratins, while esophageal cells were not. The esophageal
cells were focally positive to K13, while the oral cells were negative. Both were
negative for K19. When comparing monolayer to organotypic cultures and to in vivo
specimens, there was a significant difference in the expression of keratins.
Using organotypic cultures, AE1, AE3, and 34BE12 were strongly positive in both
oral and esophageal cells, similar to in vivo tissues. In contrast to monolayers,
both were also focally positive for K19. Esophageal cells were strongly positive
for K13, while the oral cells were mildly but uniformly positive. Both were
negative for keratins of simple epithelia. These two cell culture techniques
offer unique opportunities to study the pathobiology, including carcinogenesis,
of stable cell systems from the oral and esophageal epithelia.
PMID- 9542636
TI - Establishment and characterization of a porcine kidney cell line, FS-L3, which
forms unique multicellular domes in serum-free culture.
AB - A stable porcine kidney epithelial cell line, FS-L3, was established and
maintained in Eagle's minimum essential medium containing 0.295% tryptose
phosphate broth, 0.5% Bacto Peptone, and 10 mM N, N-Bis (2-hydroxyethyl)-2
aminoethanesulfonic acid without any serum. The mode of chromosomes is 37 to 38.
The FS-L3 cells formed fluid-filled, multicellular, three-dimensional domes on a
single monolayer. The number of domes increased markedly after further
cultivation. The origin of this cell line was confirmed as porcine by
hybridization using PRE-1, which can be detected as a specific sequence in the
porcine genome. It was also found that FS-L3 cells were free from possible
adventitious viruses and mycoplasmas.
PMID- 9542637
TI - Development and characterization of SV40 immortalized rat parotid acinar cell
lines.
AB - Rat parotid salivary gland acinar cells were transfected by CaPO4 precipitation
using a plasmid containing a replication-defective simian virus (SV40) genome.
Out of 30 clonal cell lines, 2 were shown to have moderate to high levels of
cytodifferentiation and salivary gland acinar cell function. Functional studies
with the two cell lines indicated that the beta-adrenergic agonist
(isoproterenol), vasoactive intestinal peptide prostaglandin E1, and forskolin
were effective activators of intracellular cyclic adenosine 3':5'-cyclic
monophosphate production. Phenylephrine, carbamylcholine, and UTP were effective
in increasing inositol phosphate production and intracellular free calcium
levels, whereas substance P was without affect. Utilizing indirect
immunofluorescence analysis, both cell lines were shown to express the SV40 large
T antigen. Electron microscopic evaluation documented moderate to high levels of
cytodifferentiation with the maintenance of tripartite junctional complexes,
cellular polarization, and presence of moderate amounts of secretory granules and
rough endoplasmic reticulum. The two cell lines had doubling times of 22 and 36
h, respectively.
PMID- 9542638
TI - Stimulation of rat hepatocyte proliferation in vitro and in vivo by factors
derived from the bovine small intestinal mucosa.
AB - A factor with a molecular weight of less than 1 kDa in the mucosa of the bovine
small intestine (low molecular weight factor or LMW factor) stimulated DNA
synthesis in rat hepatocytes in primary culture. This factor only showed its
activity when it was added with a larger factor with a molecular weight of 30 kDa
that was also found in the same tissue (high molecular weight factor or HMW
factor). The LMW factor probably acts to enhance the action of a hepatotrophic
growth factor, since EGF and HGF can substitute for the HMW factor. The action of
the LMW factor was not due to the actions of low molecular weight substances such
as norepinephrine, estradiol, triiodothyronine, and putrescine, which enhance the
action of EGF or HGF, since substantial amounts of these substances were not
found in the extract. When intraperitoneally administered into rats, after two
thirds hepatectomy, the LMW factor enhanced hepatocyte proliferation without the
administration of the HMW factor. In the regenerating liver, a hepatotrophic
growth factor(s), which acts synergistically with the LMW factor, might be
properly provided, but the supply of the LMW factor might be below the level that
maximally stimulates hepatocyte proliferation.
PMID- 9542639
TI - Cross-talk between signaling pathways in murine embryonic palate cells: effect of
TGF beta and cAMP on EGF-induced DNA synthesis.
AB - Signaling pathways utilized by EGF, cAMP, and TGF beta have been demonstrated to
play critical roles in normal palate development. Stimulation of these pathways
has been shown in palate cells and numerous other systems to affect cell growth.
Because proper regulation of cell growth is critical to palate development, we
speculate that fine regulation of palatal cell growth may be accomplished through
crosstalk between these signaling pathways. We therefore set out to determine the
effects of cAMP and TGF beta on EGF-induced cell proliferation in murine
embryonic palate cells. We found that both TGF beta and cAMP inhibited the
proliferative response of cells to treatment with EGF, whereas H89, a serine/
threonine protein kinase inhibitor with selectivity towards cAMP-dependent
protein kinase, increased the cells' proliferative response to EGF. Genestein, a
selective inhibitor of tyrosine kinases, at high doses abrogated the cells'
proliferative response to EGF, confirming that EGF's ability to induce cell
proliferation is critically dependent upon tyrosine kinase activity. Lower doses
of genestein, however, actually enhanced cellular response to EGF. The data
suggest that both the TGF beta- and cAMP-mediated signaling pathways may be
involved in modulation of the effects of EGF on palate cell growth in vivo.
PMID- 9542640
TI - In vitro and in vivo host range of Anticarsia gemmatalis multiple nuclear
polyhedrosis virus.
AB - A clone of the wild type (wt) Anticarsia gemmatalis multiple nuclear polyhedrosis
virus AgMNPV, derived from a geographical isolate (Hondrina, Brazil) and
designated AgMNPV-CL4-3A1, was used to determine the host range of this virus in
six established lepidopteran cell lines: Anticarsia gemmatalis (BCIRL-AG-AM1),
Helicoverpa zea (BCIRL-HZ-AM1), Heliothis virescens (BCIRL-HV-AM1), Helicoverpa
armigera (BCIRL-HA-AM1), Trichoplusia ni (TN-CL1), Bombyx mori (BMN), and a
coleopteran cell line Anthonomus grandis (BRL-AG-1). In addition, the in vivo
host range of this clone was also assayed in larvae of Helicoverpa zea, Heliothis
virescens, Trichoplusia ni, and the homologous species Anticarsia gemmatalis by
probit analysis. On the basis of temporal studies of TCID50 values, BCIRL-HV-AM1
cells gave the highest extracellular virus (ECV) titer (9.7 x 10(6) TCID50/ml)
followed by BCIRL-HA-AM1 cells (8.3 x 10(5) TCID50/ml) and BCIRL-AG-AM1 cells
(3.2 x 10(5) TCID50/ml). In addition, a low ECV titer of 1.37 x 10(3) TCID50/ml
was detected from TN-CL1 cells 96 h postinoculation, while BRL-AG-1, BMN, and
BCIRL-HZ-AM1 cells were nonpermissive to AgMNPV-CL4-3A1 on the basis of TCID50
results. AgMNPV-CL4-3A1 and the wild type AgMNPV had similar restriction profiles
that were different from wild type AcMNPV. The LC50 values were 96.9, 564.6,
733.3, and 1.1 x 10(4) occlusion bodies/cm2 of diet for A. gemmatalis,
Helicoverpa zea, Heliothis virescens, and T. ni, respectively.
PMID- 9542641
TI - A novel synoviocyte line (RAMAK-1), derived from a patient with rheumatoid
arthritis.
PMID- 9542642
TI - M-CMRL, a new axenic medium to replace indicator cell cultures for the isolation
of all strains of Mycoplasma hyorhinis.
PMID- 9542643
TI - Cell-material systems for anterior cruciate ligament regeneration.
PMID- 9542644
TI - Establishment of a human leukemia HL-60 cell line that expresses high levels of M
CSF receptors.
PMID- 9542645
TI - B-lymphoblastoid cell lines from cancer patients.
PMID- 9542646
TI - N-glycosylation of a baculovirus-expressed recombinant glycoprotein in three
insect cell lines.
AB - The capacity of two Trichoplusia ni (TN-368 and BTI-Tn-5b 1-4) and a Spodoptera
frugiperda (IPLB-SF-21A) cell lines to glycosylate recombinant, baculovirus
encoded, secreted, placental alkaline phosphatase was compared. The alkaline
phosphatase from serum-containing, cell culture medium was purified by phosphate
affinity column chromatography. The N-linked oligosaccharides were released from
the purified protein with PNGase F and analyzed by fluorophore-assisted
carbohydrate electrophoresis. The majority of oligosaccharide structures produced
by the three cell lines contained two or three mannose residues, with and without
core fucosylation, but there were structures containing up to seven mannose
residues. The oligosaccharides that were qualitatively or quantitatively
different between the cell lines were sequenced with glycosidase digestions. The
S. frugiperda cells produced more fucosylated oligosaccharides than either of the
T. ni cell lines. The smallest oligosaccharide produced by S. frugiperda cells
was branched trimannose. In contrast, both T. ni cell lines produced
predominantly dimannose and linear trimannose structures devoid of alpha 1-3
linked mannose.
PMID- 9542647
TI - Massive culture of human liver cancer cells in a newly developed radial flow
bioreactor system: ultrafine structure of functionally enhanced hepatocarcinoma
cell lines.
AB - With a view to initiating clinical trials, cell morphology and function for a
newly developed artificial liver support system employing highly functional human
liver cell line, FLC-7, cultured in a radial flow bioreactor were compared to
cells grown in a conventional monolayer culture. The radial flow bioreactor
consists of a vertically extended cylindrical matrix comprised of porous glass
bead microcarriers through which liquid medium flows from the periphery in toward
the central axis generating a beneficial concentration gradient of oxygen and
nutrients, while preventing excessive shear stresses or buildup of waste
products. The three-dimensional culture system supports high-density (1.1 x 10(8)
cells/ml-matrix), large scale cultures (4.4 x 10(10) cells/400 ml-bioreactor)
with long-term viability. Scanning and transmission electron microscopy (SEM and
TEM) revealed that cells cultured in a monolayer system were flattened and
extended with numerous cytoplasmic projections. Cells in the three-dimensional
culture were spherical and covered with microvillilike processes resembling liver
cells in vivo. The cells were solidly attached on the surfaces and within the
pores of the microcarriers in highly dense colonies. The spherical cells remained
in close contact with adjacent cells, while circulation of liquid medium flowed
freely through spaces between cells. FLC-7 cells produced albumin at a rate of
6.41 micrograms/24 h/10(6) cells. Alpha-fetoprotein (AFP) production dropped
nearly threefold in comparison to monolayer cultures. Results demonstrated that
the new artificial liver support systems (ALSS) provides a superior three
dimensional culture environment that allows cells to perform at naturally
functioning levels.
PMID- 9542648
TI - Ecdysteroid resistant subclones of the epithelial cell line from Chironomus
tentans (Insecta, Diptera). I. Selection and characterization of resistant
clones.
AB - Chironomus tentans cells were cultured in the presence of gradually increasing
concentrations of 20-OH-ecdysone or a nonsteroidal molting hormone agonist, the
benzoylhydrazine RH 5992, for a period of about 2 yr. From these cultures,
subclones were selected, which are resistant to up to 25 microM 20-OH-ecdysone
according to morphological (changes in cell shape and cell arrangement) and
physiological criteria (acetylcholinesterase induction, secretion of chitinolytic
enzymes, thymidine incorporation). Some subclones, selected in the presence of 20
OH-ecdysone, are resistant only to molting hormone, but still respond to RH 5992
morphologically and biochemically, whereas subclones selected in the presence of
the benzoylhydrazine showed no reaction neither to 20-OH-ecdysone nor to the
hormone agonist. Hormone resistance is stable; 3 mo. after hormone withdrawal,
resistant clones still do not respond to renewed exposure to 20-OH-ecdysone or RH
5992, respectively. Because in all resistant subclones tested so far all
hormonally regulated responses known from sensitive cells were no longer
detectable, it is assumed that the hormone signaling pathway itself is
interrupted. Possible mechanisms of hormone resistance were discussed.
PMID- 9542649
TI - Culture of chondrocytes in alginate gel: variations in conditions of gelation
influence the structure of the alginate gel, and the arrangement and morphology
of proliferating chondrocytes.
AB - Sodium alginate, which gels in the presence of calcium ions, is commonly used for
culture of anchorage-independent cells, such as chondrocytes. Normally, the gel
appears microscopically homogeneous but, depending on the conditions of gelation,
it may contain a varying number of small channels that extend inward from the
surface. We have examined the influence of these channels on the morphology of
cultured chondrocytes entrapped in alginate beads. Growth-plate or articular
chondrocytes cultured in alginate normally proliferate and form rounded cell
clusters but, in alginate beads containing numerous channels, many chondrocytes
become aligned and form columns similar to those in the growth plate in vivo. As
the pattern of cellular growth and morphology in alginate is profoundly
influenced by the presence of channels in the gel, further studies were conducted
to determine what specific conditions of gelation affect their formation. The
channels are especially numerous when both the alginate and the gelling solutions
lack sodium ions or other monovalent cations. The channels are cavities in the
gel formed by particulate blocking of the rapid diffusion of calcium ions from
the gelling solution into the boundary of the calcium alginate solution, and
hence they extend inward from cells at the surface of the alginate gel. An
understanding of the conditions under which these channels develop makes it
possible either to avoid their formation or, alternatively, to enhance the number
of channels in order to encourage proliferating cells to grow in radial columns,
rather than in a less organized pattern characteristic of most culture systems.
PMID- 9542650
TI - A simplified model of hypoxic injury in primary cultured rat hepatocytes.
AB - The Anaeropack system for cell culture, which was originally designed for the
growth of anaerobic bacteria, was used to produce a hypoxic atmosphere for
cultured hepatocytes. We measured changes in the oxygen and carbon dioxide
concentrations and the atmospheric temperature in an airtight jar. We also
measured changes in the pH of the medium during hypoxia to assess the accuracy of
this system. Moreover, we used three durations (2, 3, and 4 h) of hypoxia and 8 h
of reoxygenation in cultured rat hepatocytes, and then measured the lactate
dehydrogenase (LDH), ketone body concentration (acetoacetate + beta
hydroxybutyrate), and the ketone body ratio (KBR: acetoacetate/beta
hydroxybutyrate) in the medium in order to assess the suitability of this system
as a model for reperfusion following liver ischemia. The oxygen concentration
dropped to 1% or less within 1 h. The concentration of carbon dioxide rose to
about 5% at 30 min after the induction of the hypoxic conditions, and was
maintained at this level for 5 h. No effect of the reaction heat produced by the
oxygen absorbent in the jar was recognized. The extent of cell injury produced by
changing the hypoxic parameters was satisfactorily reflected by the KBR, the
ketone body concentration, and the LDH activity released into the medium. Because
this model can duplicate the conditions of the hepatocytes during
revascularization following ischemic liver, and the Anaeropack system for cell
culture is easy to manipulate, it seems suitable for the experimental study of
hypoxic injury and revascularization in vitro.
PMID- 9542651
TI - Evaluation of metanephric maturation in a human fetal kidney explant model.
AB - We have developed a unique human fetal kidney explant model to study the role of
the insulin-like growth factor (IGF) system in metanephric development. Kidneys
from 10-18 wk gestation human abortuses were maintained in serum-free conditions
and defined medium, which was shown to support the induction and differentiation
of the viable metanephric blastema. Histologically the tissue remained viable to
192 h of serum-free culture, while metanephric differentiation, reflected by a
shrinking nephrogenic zone and the formation of maturing S-shape and glomerular
forms, was accelerated and occurred between 48 and 96 h. In the nephrogenic zone,
a significant decrease in IGF-II gene expression occurred, which reflected the
differentiation of the metanephric blastema cell mass, IGF-II expression
persisted, however, in the expanded interstitial mesenchyme. With differentiation
over 48 h an increase in IGFBP-2 and WT1 gene expression by Northern blot
analysis occurred, and was localized by in situ hybridization to the
differentiating glomerular epithelial cell mass. Analysis of the explant
conditioned media by Western ligand blot demonstrated an increase in the rate of
IGF binding protein (IGFBP)-2 peptide production by the differentiating explant,
consistent with an increase in IGFBP-2 gene expression and with metanephric
differentiation. This pattern of temporal and spatial gene expression closely
approximates that of normal in vivo fetal renal development and of glomerular
epithelial cell differentiation.
PMID- 9542652
TI - Different characteristics of endothelial cells from central and peripheral human
cornea in primary culture and after subculture.
AB - Several methods for isolation and cultivation of human corneal endothelial cells
have been described during the last few decades. In contrast to the situation in
vivo, the cultured cells show mitogenic activity but often lose their typical
morphological appearance. In this paper, we describe a technique to isolate and
cultivate morphologically unchanged endothelium from the human cornea. This
method revealed different characteristics of endothelial cells according to their
position within the human cornea. Endothelial cells isolated from the central
part have a morphology similar to that of cells in vivo (i.e., they are densely
packed and show no mitogenic activity). In contrast, endothelial cells derived
from the peripheral part of the cornea are characterized by mitogenic activity
but their cell-to-cell attachment seems to be less tight than in vivo. The
significance of these two different endothelial cell types for wound healing in
the human cornea is discussed.
PMID- 9542653
TI - Transient inhibition of L929 cell mitosis and locomotion by argon ion laser
irradiation.
AB - Argon ion laser irradiation of L929 cells transiently inhibits both entry into
and passage through mitosis without affecting clonogenic survival. Anaphase
mitotic figures virtually disappear from irradiated cell monolayers although
prophase + metaphase mitotic figures can still be identified. The total number of
mitotic figures does not change significantly and time-lapse video recording
shows that cells do not enter mitosis following irradiation. This effect is
dependent on light dose within the 900-2700 J/cm2 range and persists for 10-48 h
depending on the initial light exposure. Inhibition of cell locomotion and
subsequent recovery were observed to occur over a similar time course. The
possible contribution of these phenomena must be considered whenever biological
systems are exposed to argon ion laser irradiation.
PMID- 9542654
TI - Rapid, fluorometric DNA determination for chick limb-bud mesenchymal-cell
microcultures.
AB - Micromass cultures of chick and mouse limb-bud mesenchymal cells are commonly
used for in vitro studies of cellular differentiation. Previously, adaptation of
these cultures to 96-well plates facilitated analyses of various aspects of
cellular behavior and the effects of different media components in these
cultures. These adjustments allowed development of a serum-free medium for chick
limb-bud mesenchymal cells and substantially decreased costs associated with
media and reagents. Here we report a further development for this model system; a
Hoechst 33342-based in situ DNA assay that provides reliable data much more
quickly and with considerably less effort than had been feasible in the past.
Because it allows quantitation of products of cellular differentiation and DNA in
the same cultures, the number of cultures needed to provide the same data is
essentially halved and the accuracy of normalized values for quantitative
estimates of markers of differentiation is improved. Studies of the effects of
retinoic acid on chick limb-bud mesenchymal cells were performed to document the
usefulness of this method.
PMID- 9542655
TI - The time-pattern of rises and falls in proliferation fades with senescence of
mortal lines and is perpetuated in immortal rat hepatoma Fao cell line.
AB - Immortal cells perpetuate the rises and falls of proliferation that are
progressively damped in mortal long-term cultured cells. For immortal rat
hepatoma Fao cells, similar waves of proliferation occurred about every 3-4 wk.
Under the same conditions, embryonic human fibroblasts and transformed but not
immortalized embryonic fibroblasts display similarly recurring proliferation
waves that progressively decrease in amplitude until senescence of the lines. In
addition, strains of diploid normal human skin fibroblasts cultured under
different culture conditions display a similar time-pattern of proliferation.
Although the amplitude and baseline of these fluctuations are characteristic for
each cell line, a common point was marked slow down in proliferation after every
sequence of about 25 population doublings for all cells. Renewed proliferation
waves of Fao cells allow about 22-23 additional population doublings each. Normal
embryonic fibroblast culture and its transformed counterpart accumulate about 30
and 60 population doublings, respectively, before senescence. Normal fibroblast
strains accumulate about 25 population doublings over their entire life spans.
This halt in proliferation after every stretch of about 25 population doublings
may correspond to a structural or functional stop following attrition of
telomeric DNA. This putative stop may be bypassed once in transformed embryonic
cells and repetitively in immortal cells. In support of this hypothesis, we
observed rapid telomere shortening, in two steps, during divisions of mortal
embryonic cells, and maintenance of long telomeres in immortal Fao cells, which
may indicate episodic repair of telomeres. Alternatively, such maintenance of
long telomeres may reflect survival and successive clonal growth of rare cells
with long telomeres. We suggest that the balance between telomere attrition and
repair processes regulates the waves of proliferation.
PMID- 9542656
TI - The presence of transcription factors in fetal bovine sera.
AB - Three sources of fetal bovine serum (FBS) were fractionated by ammonium sulfate
precipitation and by sodium dodecyl sulfate-polyacrylamide gel electrophoresis
(SDS-PAGE), transferred to Immobilon-P membranes, immunoblotted with a panel of
transcription factor antibodies, and detected by enhanced chemiluminescence. Nine
transcription factors were detected--ATF-2, SRE-ZBP, GATA-2, TFIID, Ets-1/Ets-2,
E2F-1, Oct-2, p53, and AP-2; four transcription factors were not detected--Myo D,
CREB, Sp2, and Wilms' tumor. The results indicated the presence of varying
amounts of several transcription factors in three commercial sources and may
represent heretofore unrecognized factors influencing cell culture.
PMID- 9542657
TI - Apoptosis in the chick wing bud and the permanence of FGF-2 rescue.
AB - Two regions of programmed cell death that occur in the mesoderm of developing
chick wing buds were studied in vitro. The opaque patch (OP) and posterior
necrotic zone (PNZ) were examined for the presence of internucleosomal DNA
degradation and for rescue by protein synthesis inhibition, two defining
characteristics of apoptosis. Agarose gel electrophoresis showed that DNA from OP
and PNZ tissue was cleaved into nucleosome size pieces and this cleavage was
prevented by inhibition of protein synthesis with cycloheximide. Both regions
showed rescue with cycloheximide as determined by the chromium release assay and
examination of electron micrographs. Also, the permanence of basic fibroblast
growth factor (EGF-2) rescue in the OP and NPZ was examined using the chromium
release assay. While rescue in the OP was found to be permanent, rescue in the
PNZ only delayed death while FGF-2 was present in the culture medium. This
research shows that death in the OP and PNZ exhibits internucleosomal DNA
fragmentation and is prevented by inhibition of protein synthesis with
cycloheximide, biochemically characterizing this death as apoptosis. It also
suggests that in vitro FGF-2 rescue is permanent in the OP but is merely a delay
of cell death in the PNZ.
PMID- 9542658
TI - Topography of amphiregulin expression in cultured human keratinocytes:
colocalization with the epidermal growth factor receptor and CD44.
AB - Much of the autonomous growth of cultured keratinocytes is attributable to the
signaling of amphiregulin, a heparin-binding autocrine growth factor, through the
epidermal growth factor receptor. Emerging evidence suggests, moreover, that the
membrane proteoglycan, CD44, is a cofactor for the interaction of heparin-binding
ligands with their receptors. This model was evaluated by characterizing the
patterns of the immunolabeled molecules in cultured human neonatal keratinocytes,
to test the hypothesis that involvement in a common function results in
coordinate segregation within or on the cell. The molecules were localized by
double immunofluorescence labeling to detect amphiregulin and either the
epidermal growth factor receptor or CD44, and the immunostained products were
imaged by scanning laser confocal microscopy. Both amphiregulin and the epidermal
growth factor receptor segregated to a perinuclear distribution and to
intercellular contacts. In addition, amphiregulin localized to the outer leading
edge of colonies and focally to intranuclear sites. Metabolic blockade of
proteoglycan sulfation with sodium chlorate inhibited growth of the cells and
concurrently enhanced the nuclear, but decreased the outer leading edge, labeling
for amphiregulin. There was no nuclear or perimeter labeling for the epidermal
growth factor receptor. Cultures co-immunolabeled for CD44 and amphiregulin
exhibited variable perinuclear staining for both, but otherwise CD44 was
distributed to intercellular contacts. The intercellular localizations of CD44
with amphiregulin and of amphiregulin with the epidermal growth factor receptor
were strongly concordant. These data are consistent with a concerted function at
intercellular contacts, where cytokine signaling is mediated via receptor binding
and possibly regulated by the CD44 proteoglycan as cofactor. The intranuclear and
perimeter labeling of amphiregulin, however, suggests that this cytokine has
additional functions, both in the nucleus and as a matrix receptor.
PMID- 9542659
TI - The role of hepatocyte growth factor (HGF) at progressive stages of metanephric
development.
AB - Several lines of evidence suggest that hepatocyte growth factor (HGF), a soluble
protein secreted by mesenchymal cells, may elicit a morphogenic response in the
developing metanephros. We investigated the role of HGF at three different stages
of murine metanephric development utilizing serum-free organ culture. Cultures
were initiated at E-13, E-15, and E-17; treated with exogenous HGF or antibodies
to HGF (to block endogenous HGF) for 120 h in vitro; and evaluated for growth and
differentiation in comparison to control explants cultured for 120 h in basal
medium. HGF treatment of E-13 explants resulted in a reduction of growth and
differentiation compared to control explants. Treatment of E-13 explants with
antibodies to HGF produced explant growth and differentiation indistinguishable
from control explants. In contrast to the results of E-13 cultures, explants
initiated at E-15 and E-17 demonstrated an increased growth and differentiation
profile when treated with HGF compared to controls. Treatment of E-15 and E-17
explants with antibodies to HGF resulted in a decrease growth and differentiation
profile compared to control or HGF-treated explants. These data demonstrate that
HGF has differential effects on renal morphogenesis at progressive developmental
stages of metanephric development.
PMID- 9542660
TI - Immunology of HPV infection and HPV-associated tumors.
PMID- 9542661
TI - Acne inversa.
PMID- 9542662
TI - Spontaneous course of hemangiomas: facts and speculations.
PMID- 9542663
TI - Erythroderma: a clinico-etiologic study of 90 cases.
AB - BACKGROUND: The difficulty with erythroderma lies in finding the underlying
cause. Almost all the published original clinical series of erythroderma
originate from western countries. Our aim was to evaluate various causes of
exfoliative dermatitis in our community and compare the findings with previous
studies. METHODS: Ninety patients with erythroderma of either sex and any age,
were studied at the Dermatology Department, Mayo Hospital, Lahore, Pakistan,
between April 1992 and May 1995. A through clinical examination and relevant
laboratory investigations, including skin biopsies, were performed. RESULTS: The
mean age of onset was 41.6 years with a male:female ratio of 2.8:1. The onset was
acute in 69% of patients. The salient features included nail changes (80%),
mucosal involvement (36.6%), alopecia (30%), islands of normal skin (14.4%), and
the "deck chair sign" (5.5%). The most frequent cause of erythroderma was pre
existing dermatoses (74.4%), including psoriasis (37.8%), dermatitis (12.2%),
ichthyoses (7.8%), and pemphigus foliaceus (5.6%). Drugs and malignancy each
induced erythroderma in 5.5% of cases. No cause could be found in 14.6% of cases.
CONCLUSIONS: Etiologically, pre-existing dermatoses showed the highest incidence
and drugs the lowest compared with previous studies. Dermatitis was less common.
There was a greater variety of causes of erythroderma in our series. Hair and
nails were more frequently involved. Mucosal involvement, not mentioned in other
studies, was present in 36.6% of our cases. The "deck chair sign" and islands of
normal skin were seen in dermatoses not reported previously.
PMID- 9542664
TI - Sweet's syndrome without granulocytosis.
AB - BACKGROUND: Sweet's syndrome (SS), acute febrile neutrophilic dermatosis, has
been linked to hematologic malignancies and presents with characteristic
edematous dermal plaques. Peripheral blood neutrophilia is frequently seen in
association with SS and is one of the diagnostic criteria. OBJECTIVE: To report
the clinical, laboratory, and hematologic data of four patients with myeloid
leukemia who developed SS after chemotherapy. Three of these patients were
neutropenic. METHODS: A retrospective study of four patients with SS and
hematologic malignancies was undertaken. Three patients had de novo acute
myelogenous leukemia and one was in the acute blast crisis of chronic myelogenous
leukemia. RESULTS: Sweet's syndrome was not originally suspected in these
patients because of the low peripheral white blood cell counts caused by
chemotherapy. All of the patients presented with fevers, arthralgias, and an
eruption. They had been treated with antibiotics because of a presumed infection.
Once the correct diagnosis was made and oral prednisolone was started, a rapid
response followed. CONCLUSIONS: Sweet's syndrome should be considered in the
differential diagnosis when acute myeloid leukemic patients develop skin lesions
and unexplained fevers regardless of the peripheral blood counts.
PMID- 9542665
TI - Diabetic dermopathy and internal complications in diabetes mellitus.
AB - BACKGROUND: Diabetic dermopathy is the most common cutaneous marker of diabetes
mellitus. The relationship of diabetic dermopathy to internal complications of
diabetes mellitus, such as nephropathy, retinopathy, and neuropathy, is still
unknown. METHODS: The possible role of diabetic dermopathy as a clinical sign of
internal complications in diabetes mellitus was investigated. One hundred and
seventy-three patients with diabetes mellitus, of whom 125 (72%) had insulin
dependent diabetes mellitus and 48 (28%) had non-insulin-dependent diabetes
mellitus, were studied. RESULTS: Diabetic dermopathy was present in 69 (40%) of
patients, statistically more significant in patients 50 years of age and older.
The mean diabetic duration was significantly higher in patients with diabetic
dermopathy than in those without. The associations of diabetic dermopathy with
retinopathy, nephropathy, and neuropathy were each statistically significant, and
the increased frequency of diabetic dermopathy correlated with an increased
number of these three complications in each patient. CONCLUSIONS: Some of the
factors that affect the development of internal complications in diabetes
mellitus may play a role in the development of diabetic dermopathy, and diabetic
dermopathy may serve as a clinical sign of an increased likelihood of these
internal complications in diabetic patients.
PMID- 9542666
TI - Immunophenotypic analysis of normal human dendritic cells isolated from epidermis
and dermis.
AB - BACKGROUND: The skin immune system comprises two types of dendritic cells, i.e.
CD1a-positive Langerhans cells in the epidermis and CD36-positive dendritic
macrophages in the dermis. Dendritic cells can migrate from skin explants into a
culture medium. METHODS: We have examined the morphology and immunophenotype of
the dendritic cells migrating from epidermal and dermal sheets in vitro. The
epidermis and dermis of keratomes of normal human skin were separated with
dispase and cultured for 72 h. At this time, the non-adherent cells in the medium
were removed, enriched on a metrizamide or Lymphoprep gradient, counted, prepared
by cytospin, and labeled for CD1a, CD36, and HLADr. RESULTS: Cells migrating from
the epidermis and dermis show many thin projections or a few veils from the cell
surface. Approximately four times more cells migrate from epidermal than dermal
sheets from the same keratome. CONCLUSIONS: Using methods to separate the
epidermis from the dermis, both CD1a-positive Langerhans cells and CD36-positive
dendritic macrophages can be obtained from both tissues, although in different
numbers.
PMID- 9542667
TI - Wound healing in Behcet's syndrome.
AB - BACKGROUND: Because there is an increased inflammatory response to trauma,
particularly of the skin, in patients with Behcet's syndrome (BS), an alteration
in wound healing in BS is expected. The aim of this study was to investigate the
healing features of punch biopsy wounds in BS and acne vulgaris (AV) patients
used as controls. METHOD: Full-thickness skin punch biopsies (4 mm) were taken
from the hairless sites of the non-dominant forearms in 20 BS and 20 AV patients.
Each patient was examined on days 1, 2, 3, 4, 5, 8, and 10, and the biopsy wound
area and induration were marked on sterile glass slides. Other inflammatory
changes, such as suppuration and pain, were also recorded. No antiseptic
solutions or ointment, except saline, were used. RESULTS: The wound area healed
similarly in both groups (p > 0.05). Thirteen (65%) BS patients had erythematous
haloes around the wound on the first day. The number of patients presenting
inflammatory changes reached 18 (90%) on the second day in the BS group. The area
of erythema around the wound in BS patients was significantly greater than that
in AV patients (5; 25%). It gradually decreased day by day. Purulent changes were
observed in four BS patients on day 1, and induration around the biopsy wound in
six patients on day 2. Only one patient with AV had suppuration, which appeared
on the second day, while no AV patient displayed induration. CONCLUSION: Biopsy
induced trauma may cause increased inflammation in BS, but wound healing is not
altered.
PMID- 9542668
TI - Protein C and protein S activities in Behcet's disease as risk factors of
thrombosis.
AB - BACKGROUND: In Behcet's disease (BD), there is a marked increase in vascular
complications. Approximately 30% of patients with BD suffer from thrombosis of
the arteries and veins, varices, aneurysms, and thrombophlebitis of superficial
or deep veins. Protein C and Protein S are major inhibitors of coagulation, and
it is well known that the deficiency of Protein C and Protein S causes thrombotic
disorders. METHODS: Protein C and Protein S activities were measured in 23
patients with BD and in a control group consisting of 23 age- and sex-matched
healthy volunteers. Patients who had received anticoagulant or oral contraceptive
drugs, or who had liver disease or active thrombosis, were not included in the
study. RESULTS: Of the 23 patients with BD (age, 13-55 years), the mean Protein S
activities (94.2 +/- 11.3%) were slightly lower than the means of the control
group (109.1 +/- 8.4%), but not statistically significant differences could be
demonstrated (p > 0.05). Compared with the means of the control group (103.5 +/-
6.9%), the Protein C activities were not lower in BD (106.3 +/- 8.4%). No
statistical difference was determined. CONCLUSIONS: Protein C and Protein S
deficiencies are not a probable cause of thrombotic manifestations in BD. We do
not recommend the measurement of these activities routinely in BD unless
thrombosis is the major and primary manifestation of BD.
PMID- 9542669
TI - Malignant blue nevus of the scalp.
AB - A 70-year-old woman had noticed, at the age of 30, a single blue nodule of about
1 cm in size on her scalp. The lesion remained stable until 1991, when it became
larger and ulcerated and, because of the sudden onset of additional macules and
nodules around it, the patient presented at our Dermatological Division in August
1992. Physical examination showed a blue-black plaque, 2 x 2 cm in size, on the
left parietal area of the scalp, surrounded by several blue-grey pigmented
nodules and macules (Fig. 1). Chest X-ray, abdomen scan, and a total body
computed tomography (CT) scan were negative for metastatic disease. A wide
resection of the scalp lesion was performed. The histologic evaluation revealed a
dense collection of spindled melanocytes in the dermis and in the subcutaneous
fat. Nuclear and cytoplasmic pleomorphism, some mitotic figures, and necrosis
foci were present (Figs 2 and 3). Pictures of cellular blue nevus were found in
the surrounding lesions. Ten months later, new blue macular and papular lesions
appeared in proximity to the surgical scar. The patient refused any additional
surgery, and so was treated with dacarbazine (DTIC) 800 mg intravenously (every
20 days) and 2 alpha interferon (3 million units subcutaneously, three times
weekly). The growth of the lesions slowed down for a few weeks, and then
increased again to become a wide, blue-black vegetating mass (Fig. 4). In June
1995, a total body CT scan revealed multiple focal nodules on the lungs and two
metastatic masses on the eighth segment of the liver. A palliative
polychemotherapy, with vindesin 3 mg/m2 and DTIC 400 mg/m2, was started, but did
not stop the progression of the disease, and the patient died in December 1996.
PMID- 9542670
TI - Well-differentiated squamous cell carcinoma of the penis associated with HPV type
33.
PMID- 9542671
TI - Flexural purpura and Epstein-Barr virus infection.
PMID- 9542672
TI - Anhidrotic ectodermal dysplasia (Christ-Siemens-Touraine syndrome) presenting as
a fever of unknown origin in an infant.
PMID- 9542673
TI - Kwashiorkor/zinc deficiency overlap following partial gastrectomy.
PMID- 9542674
TI - Cutaneous bronchogenic cysts.
PMID- 9542675
TI - Short-term itraconazole versus terbinafine in the treatment of tinea pedis or
manus.
AB - A total of 304 patients with a clinical diagnosis of palmar-type tinea pedis or
manus and a positive mycologic examination were recruited into this double-blind,
randomized, multicenter, phase III study. Patients were randomized to receive
either oral itraconazole 200 mg twice daily (in the morning and evening) for 7
days, followed by placebo for 7 days (n = 153), or placebo in the morning and
oral terbinafine 250 mg in the evening for 14 days (n = 151). At the first visit
and 1, 2, and 6 weeks after the start of the study, signs and symptoms were
assessed clinically, and scales were taken for mycologic assessments (microscopy
and culture). At weeks 1, 2, and 6, the effectiveness of therapy was evaluated
globally and given a rating of healed (absence of signs and symptoms), marked
improvement (> or = 50% clinical improvement), considerable residual lesions (<
50% clinical improvement), no change, or worsened. The primary efficacy parameter
was the mycologic cure rate at the follow-up end-point (week 6). The tolerability
of the study medications was assessed at weeks 1 and 2. Adverse events were
recorded at weeks 1, 2, and 6. Routine hematologic and biochemical tests were
performed at the start of the study and after 1 week of treatment. No significant
differences were seen in the baseline patient characteristics between the two
groups. The rate of mycologic cure (negative microscopy and culture test result)
was 79% in the itraconazole group and 80% in the terbinafine group at the follow
up end-point. The analysis of the 90% confidence interval for the difference
between the treatment groups (-7.1, 5.4) and the outcome of the Blackwelder test
(for two one-sided tests, P = 0.013 and P = 0.029) showed the two treatments to
be equivalent. The results of the global evaluations of the efficacy in the two
treatment groups are shown in Table 1. The rate of clinical response (healed or
markedly improved) was 93% in the itraconazole group and 91% in the terbinafine
group at the follow-up end-point. The analysis of the 90% confidence interval for
the difference between the two groups (-2.5, 5.7) and the outcome of the
Blackwelder test (for two one-sided tests, P = 0.004 and P < 0.001) showed the
two treatments to be equivalent. The severity of the clinical signs and symptoms
decreased from the baseline to the treatment end-point and from the treatment end
point to the follow-up end-point in both groups. At the double-blind treatment
period end-point (week 2), the tolerability of the study medication was rated as
very good or good in more than 97% of patients. During treatment, 21 of 153
patients (14%) in the itraconazole group and 28 of 151 patients (19%) in the
terbinafine group reported adverse events. During follow-up, one patient in the
itraconazole group and two in the terbinafine group reported adverse events. The
most frequent events were headache, abdominal pain, nausea, vomiting, and
hypertriglyceridemia. Two patients in the itraconazole group and four in the
terbinafine group withdrew because of adverse events. Severe adverse events were
reported by one patient in the itraconazole group and five in the terbinafine
group. Serious adverse events were reported by two patients in the terbinafine
group, although these were probably not drug related. No clinically relevant
changes in laboratory variables were observed.
PMID- 9542676
TI - Clobetasol propionate emollient 0.05% in the treatment of atopic dermatitis.
AB - A 4-week, double-blind, randomized clinical trial, comparing the efficacy and
safety of clobetasol propionate emollient cream 0.05% and its vehicle, was
conducted at four private dermatology clinics in 81 non-hospitalized patients (>
or = 12 years old) with moderate-to-severe atopic dermatitis covering 2% or more
of their body surface. All patients had at least one lesion 2 cm or more in
diameter. Three signs/symptoms of target lesions (erythema, pruritus, and
induration/papulation) were scored by investigators on a scale of 0-3 (in 0.5
point increments; 0 = absent, 1 = mild, 2 = moderate, and 3 = severe); the total
of the three scores had to be > or = 6 for patients to qualify for study entry.
Patients were excluded if they were immunocompromised, pregnant, or nursing; had
skin atrophy, telangiectasia or striae in skin areas to be treated; or had
received topical treatments for atopic dermatitis within 1 week prestudy,
intramuscular triamcinolone within 6 weeks prestudy, or long-term systemic
corticosteroid usage within 6 months prestudy. Patients were randomized in a 1:1
ratio to receive either clobetasol propionate emollient 0.05% twice daily (n =
41), or the emollient vehicle twice daily (n = 40), for 4 weeks. A fingertip
unit, equaling approximately 0.5 g in males and 0.43 g in females (enough to
cover approximately 2% of the body), was used to measure and apply a thin film of
study drug to the affected areas. The efficacy was evaluated by investigators and
patients on days 4, 8, 15, and 29 after initiation of therapy, and 2 weeks after
the end of treatment (day 43). Investigators performed a physician's gross
assessment based on the percentage improvement of the target lesion. They also
rated changes from baseline in mean severity scores for six individual
signs/symptoms (erythema, pruritus, induration/papulation, lichenification,
erosion/oozing/crusting, and scaling/dryness) and for total signs/symptoms
according to the severity scoring system described above. Patients rated their
response to treatment as excellent, good, fair, poor, or worse. Laboratory
assessments were made on days 15, 29, and (if necessary) day 43.
PMID- 9542678
TI - The first 'rules' of an ancient dermatologic hospital, the S. Gallicano Institute
in Rome (1725).
PMID- 9542677
TI - Epidemiology and in vitro activity of antimycotics against candidal
vaginal/skin/nail infections in Singapore.
AB - BACKGROUND: Candidal infections of the skin/nails and vagina are very common
worldwide. Various in vitro test systems are available to help to determine the
antifungal activity of drugs. The minimum inhibitory concentration (MIC) is a
standard measure of the in vitro potency of drugs against yeasts. METHODS:
Vaginal smears and skin/nail scrapings of 50 consecutive patients with candidal
vaginitis and 46 consecutive patients (28 women, 18 men) with cutaneous/nail
candidosis were used in the study. Direct microscopy and culture from vaginal
smears and skin scrapings were performed on all patients. The MICs were
determined using the broth dilution method. RESULTS: For vaginal candidosis, the
mean age of the patients was 28.2 years (range, 9-49 years). Candida albicans
accounted for 58% of the isolates, C. glabrata for 32%, C. tropicalis for 6%, and
C. parasilosis for 4%. At the MIC of < or = 4 mg/L, 65-95% of C. albicans, 66-94%
of C. glabrata, 33-100% of C. tropicalis, and 0-50% of C. parasilosis were
susceptible to the drugs tested (ketoconazole, itraconazole, nystatin,
amorolfine, clotrimazole, and miconazole). For cutaneous/nail candidosis, the
mean age of the patients was 45 years (range, 19-82 years). C. albicans made up
59% of the isolates, C. parasilosis 20%, C. krusei 13%, C. glabrata 4%, and C.
tropicalis 4%. At the MIC of < or = 4 mg/L, 59-96% of C. albicans, 100% of C.
glabrata, 83-100% of C. krusei, 89-100% of C. parasilosis, and 100% of C.
tropicalis were susceptible to the drugs tested (ketoconazole, itraconazole,
nystatin, amorolfine, clotrimazole, and miconazole). CONCLUSIONS: C. albicans is
the most common Candida species causing cutaneous/nail and vaginal candidosis in
Singapore. The in vitro antifungal activities of ketoconazole, itraconazole,
nystatin, amorolfine, clotrimazole, and miconazole are similar against the
various Candida species. C. parasilosis in vaginal candidosis appears to be less
susceptible. Here, itraconazole and amorolfine may be more effective.
PMID- 9542679
TI - Peculiar dyschromic changes of finger nails in a patient with multiple system
atrophy.
PMID- 9542680
TI - Bowen's disease of the palm.
PMID- 9542681
TI - Pemphigus Area and Activity Score (PAAS)--a novel clinical scoring method for
monitoring of pemphigus vulgaris patients.
PMID- 9542682
TI - Lichen planus developing on the border of tinea corporis.
PMID- 9542683
TI - Evaluation of the alleviative action of neurotropin for penile pain associated
with intracavernous injection of prostaglandin E1 assessed using the visual
analogue scale.
AB - We examined whether penile pain associated with intracavernous injection of PGE1
could be alleviated with a intracavernous injection of neurotropin, a non
protein, bioactive agent extracted from skin tissue with inflammation elicited by
the Vaccinia virus. Twenty-three patients with erectile dysfunction were enrolled
in this study. They were divided into two groups. The first group was allocated
20 micrograms of PGE1 alone first, followed by PGE1 plus 1.5 ml of neurotropin
after two weeks. The second group was allocated PGE1 plus 1.5 ml of neurotropin
first, followed by PGE1 alone after two weeks. Pain was evaluated by the visual
analogue scale (VAS). In the 17 patients reporting discomfort, pain scores for
PGE1 injection with neurotropin were significantly lower than those without
neurotropin. No patients showed local or systemic complications that might be
related to neurotropin. From these data we conclude that neurotropin may be an
effective and safe drug for penile pain associated with PGE1 intracavernous
injection.
PMID- 9542684
TI - Drop-out reasons and complications in self-injection therapy with a triple
vasoactive drug mixture in sexual erectile dysfunction.
AB - The usefulness, complications and reasons for discontinuing the self-injection
program with a combination of papaverine, phentolamine and prostaglandin E1 were
evaluated in 189 patients (mean age 57.2 y), who were included from April 1993 to
September 1995 (mean follow-up 10.25 months). Patients were split into two
groups: Active, those who continued with the program (48%); and Inactive, those
who discontinued treatment or failed to attend consultation after five months
from the last visit (52%). Only 30% of the inactive group reported failure to
achieve response with the self-injected doses. Fibrosis in 5.3% and prolonged
erection in 3.7% were the most severe complications. Patients lacking organic
pathology showed a clear tendency to reduce the drug dose during treatment,
recover spontaneous erections and discontinue the program for reasons unrelated
to drug efficacy. The triple drug mixture provides an effective alternative in
the treatment of impotence, with a low rate of complications.
PMID- 9542685
TI - Alternative approaches to the management of priapism.
AB - Herein we describe the use of intracavernous methylene blue (MB), a guanylate
cyclase inhibitor, or internal pudendal artery embolization for the treatment of
priapism. Eleven patients with priapism were treated from 1993-1996. Etiologies
of priapism included PGE1/papaverine (3), trazodone (2), and sickle cell disease
(1), in the other five cases the causes the cause was unknown. The average
duration of priapism was 27 h for all patients (6-72 h). Five patients who failed
intracavernous MB or an alpha-adrenergic agonist, underwent unilateral or
bilateral pudendal artery embolization. The average duration of priapism for
patients undergoing embolization was 43 h. Sixty-seven percent of the patients
treated with MB responded with immediate detumescence. One-hundred percent of
patients with priapism secondary to intracavernous injection therapy or trazodone
responded. Of the five patients who underwent embolization, 40% achieved
immediate pain relief and subsequent detumescence. The three non-responders
exhibited a partial detumescence over 47-72 h. After follow-up of one year
embolization available for only two patients revealed that one regained potency
while the other remained impotent. These results confirmed that MB is effective
for pharmacologically-induced priapism. Embolization is a less invasive option
for refractory priapism, although results are less than satisfactory in men with
priapism of several days duration.
PMID- 9542686
TI - Engineering analysis of penile hemodynamic and structural-dynamic relationships:
Part I--Clinical implications of penile tissue mechanical properties.
AB - PURPOSE: The least investigated physical determinant of penile rigidity has been
penile tissue material properties. The goals in this study (Part I) were to
define two penile mechanical parameters, cavernosal expandability X and tunical
distensibility VE/VF, determine their magnitudes in humans and develop an
analytical expression for penile volume as a function of these two tissue
characteristics and intracavernosal pressure. METHODS: Dynamic infusion
pharmacocavernosometry was performed in 21 impotent patients (age 43 +/- 19 y) to
provide human geometric, hemodynamic and structural data. A mathematically
derived model of hemodynamic and structural-dynamic characteristics of penile
erection was developed (Parts I, II, III) incorporating penile tissue mechanical
qualities. RESULTS: Cavernosal expandability X provided a measure of the ability
to approach maximum volume at relatively low intracavernosal pressures. Tunical
distensibility VE/VF denoted the maximal erect to flaccid penile volume ratio.
The magnitudes of X and VE/VF in the study population were 0.04-0.17 mmHg-1 and
1.7-5.0 respectively. CONCLUSIONS: Enabling penile volume to be derived as a
function of tissue mechanical characteristics and pressure, allows for penile
rigidity to be expressed (in Part II) as a function of pressure, geometry and
tissue qualities.
PMID- 9542687
TI - Engineering analysis of penile hemodynamic and structural-dynamic relationships:
Part II--Clinical implications of penile buckling.
AB - PURPOSE: Penile buckling force was analytically described in terms of its
constituents. In addition, theoretically-derived buckling force data were
compared to clinically measured data and the influence of each constituent on
penile buckling force data was assessed. METHODS: Using engineering buckling
theory for a column, a mathematically-derived penile buckling model was developed
which incorporated geometric and hemodynamic data obtained by dynamic infusion
pharmacocavernosometry studies in 21 impotent patients (age 43, range 24-62 y) as
well as penile tissue mechanical characteristics previously developed (Part I).
RESULTS: In 17 of 21 patients the mean difference between theoretically derived
and clinically measured buckling force data was 0.33 +/- 0.25 kg (r = 0.96).
Factors which increased penile buckling forces were: (1) high intracavernosal
pressure values (rigidity was related to pressure in an exponential-like
fashion); (2) high penile aspect ratio (D/L) values (relatively large
diameter/short length penile geometry) and high flaccid diameter; and (3) high
cavernosal expandability values (a measure of the ability of the corpora to
approach its erect volume with relatively low intracavernosal pressures).
CONCLUSIONS: Pressure-volume data (pressure, geometry and tissue characteristics)
obtained during erectile function testing have been shown, for the first time, to
theoretically predict the magnitude of clinically-measured penile buckling
forces.
PMID- 9542688
TI - Effect of Korean red ginseng on the rabbit corpus cavernosal smooth muscle.
AB - The extracts of Korean red ginseng (EKG) is a complex mixture containing
ginsenosides, polysaccharides, and several other products. Animal experiments
have shown that the intravenous administration of extract of ginseng reduces
blood pressure. Recently, it has been reported that ginseng has a relaxing effect
on vascular smooth muscle and that the relaxation is associated with nitric oxide
(NO) released from the vascular endothelium. The present study was undertaken to
investigate the effects of EKG on isolated rabbit corpus cavernosal smooth muscle
for evaluation of the possibility of developing EKG as an pharmacoerecting agent.
Strips of rabbit corpus cavernosum were mounted in organ chambers to measure
isometric tension. On the precontracted muscle strip with phenylephrine (PHE; 5 x
10(-6) M), EKG began to exert a relaxing effect at the concentration of 1 mg/ml
and the maximal relaxation effect was reached at 40 mg/ml in a dose-dependent
manner. EKG was inhibited significantly by endothelial disruption and by
pretreatment with methylene blue, pyrogallol, L-NNA or atropine. EKG partially
inhibited the PHE (5 x 10(-6) M) induced contraction up to 45.67% of the control
in a dose-dependent fashion. EKG decreased basal tension as well as inhibited the
contraction induced by addition of CaCl2 (10(-3) M) dose-dependently in muscle
strips at basal equilibrated state in Ca2+ free, high K+ depolarizing solution.
EKG also inhibited the contraction induced by depolarization with 20, 40 and 60
mM of KCl. However, this inhibitory effect did not occur with high concentrations
of KCl (80 and 120 mM). EKG has a relaxing effect on the rabbit corpus cavernosal
tissue in a dose dependent manner. The relaxation action of EKG is mediated by
multiple action mechanisms that include increasing the release of NO from the
corporal sinusoids, increasing intracellular calcium sequestration, and a
hyperpolarizing action.
PMID- 9542689
TI - Erectile dysfunction following Nd-YAG visual laser-assisted prostatectomy (VLAP).
AB - We investigated if side fire Nd-YAG visual laser prostatectomy (VLAP) causes
erectile dysfunction (ED) in patients who were sexually active prior to the
procedure. The 36 study patients gave a detailed medical/sexual history: physical
examination included bulbo-cavernous reflex (BCR) on rectal examination and
routine blood tests. Lasing time, power of the applied laser beam (in watts),
coagulation site and energy intensity were recorded. Patients with new onset ED
during the one year study period underwent pudendal nerve conduction (PNC), color
duplex Doppler ultrasonography, and NPT/RigiScan testing. In 6 out of 36 (16.7%)
patients reporting significant post-operative ED, there was a tendency towards
higher energy applied and longer lasing time but no correlation between prostate
size or the site of energy application. Patients reported loss of night and/or
morning erections (n = 5), retrograde ejaculations (n = 2), loss of ejaculate (n
= 2), and decreased sensation of orgasm (n = 3). Three had abnormal PNC, duplex
Doppler showed abnormal blood supply in four, and all six had abnormal
NPT/RigiScan. We believe this is the first demonstration that VLAP may be
associated with a high rate of ED and that the lasing time and intensity of
applied laser energy may play a role in this outcome.
PMID- 9542690
TI - Repetition of color Doppler ultrasonography: is it necessary?
AB - The aim of the study was to determine whether any difference would occur in peak
systolic velocity (PSV) and end diastolic velocity (EDV) measurements of color
Doppler ultrasonography (CDU) between proximal and distal segments of the
cavernous arteries obtained at different times. Twenty-six cases have undergone
CDU three times in weekly intervals. PSV and EDV measurements of cavernous
arteries were obtained both proximally and distally. The results have shown that
statistically there was no difference between each measurement obtained on either
sides at three different tests. (ANOVA PSV F(2-50) = 0.63, EDV F(2-50) = 0.81).
Four of the 26 cases had different PSV results and six cases had different EDV
results in three CDU tests. There was a statistical difference in measurements
between proximal and distal segments of the cavernous arteries. (t-test t = 2.53,
P = 0.015) In conclusion, repetition of CDU would not be necessary in majority of
the cases. However investigators should always be aware and cautious about
falsely abnormal results of CDU. Proximal segments of the cavernous arteries
should be the site to obtain true CDU measurements.
PMID- 9542691
TI - Percutaneous core biopsy of the penis.
AB - To describe the efficacy of percutaneous core biopsy of penile corporal tissue,
on ten impotent men, the biopsy was performed with a 19 and a 20 gauge core
biopsy co-axial system using an automatic biopsy device. All biopsies were
performed on an outpatient basis under local anesthesia. Adequate biopsy
specimens were obtained in all. Percutaneous core biopsy of the penis is a safe
procedure that is technically easy to perform.
PMID- 9542692
TI - Transurethral alprostadil with MUSE (medicated urethral system for erection) vs
intracavernous alprostadil--a comparative study in 103 patients with erectile
dysfunction.
PMID- 9542693
TI - Pediatric psychopharmacoepidemiology: an introduction.
AB - The increased use of psychopharmacological agents in children and adolescents,
the increased public debate about the possible adverse effects of these agents,
and the growth of managed care have led to a burgeoning of interest in the
pharmacoepidemiology of child psychiatric medications. This special issue of the
Journal of Child and Adolescent Psychopharmacology reviews pharmacoepidemiology
in child psychiatry. This introduction gives an overview of the articles that
follow.
PMID- 9542694
TI - An overview of three decades of research in pediatric psychopharmacoepidemiology.
AB - Although psychotropic drugs are prescribed relatively often for childhood
psychiatric and seizure disorders, relatively little is known about their use in
everyday clinical settings--with the exception of children with ADHD and
individuals with mental retardation. A legion of methodological and logistical
obstacles are encountered when trying to gather information about pharmacotherapy
for children, and this has often limited data collection to institutional
settings or highly restricted geographic areas. Although initial efforts to study
the extent of drug therapy focused primarily on the number of individuals
receiving treatment and secondarily on drug dose, the breadth of topics quickly
expanded to include numerous issues pertaining to the way psychotherapeutic
agents are prescribed, evaluated, and monitored in typical clinical situations.
This article presents an overview of treatment prevalence studies conducted
during the past three decades and reviews a variety of clinical concerns raised
by researchers in pediatric psychopharmacoepidemiology. The most salient findings
from these studies are: (a) medication use continues to increase, (b) treatment
prevalence rates in residential programs continue to be very high (40%-60%), and
(c) many researchers continue to be concerned about the quality of treatment
practices. The methodologies of this field show considerable promise for
addressing pressing issues in health care for children and adolescents with
emotional or behavioral disorders.
PMID- 9542695
TI - Sources of data for pharmacoepidemiological studies of child and adolescent
psychiatric disorders.
AB - In view of the dramatic shift to managed care models for United States health
care delivery, reliable information on the prevalence and variations in
psychopharmacological drug therapies for youth in community practice settings is
essential. Pharmacoepidemiology, the study of medication use in large
populations, aims to accomplish that challenging task. This article offers child
psychopharmacologists a brief introduction to data sources for
pharmacoepidemiology. Knowledge of these data sources combined with
epidemiological methods for data analysis is a beginning step to assess the
psychotropic medication prescribing patterns of community physicians. This review
is organized in the following sequence: (1) characteristics of the "usual
practice environment" according to setting, patient population, and physician
characteristics; (2) validity issues related to data sources and their potential
for outcomes research; (3) data sources divided into primary and secondary types
that are described in terms of their features, advantages, and limitations,
followed by examples of selected applied studies using such information; (4)
procedures for analyzing secondary data; (5) data analytic and longitudinal
approaches; and (6) access, confidentiality, and funding. A goal for future
investigators in this emerging field is to develop applied research that is
clinically sophisticated, methodologically sound, and public health-minded.
PMID- 9542696
TI - Psychopharmacoepidemiology of mental retardation: 1966 to 1995.
AB - We present a brief historical overview of the prevalence studies of psychotropic
drugs in individuals with mental retardation that were published between 1966 and
1985, and a more comprehensive review of the prevalence studies from 1986 to
1995. During the 1966 to 1985 period, typical prevalence rates of drug treatments
in institutions (children and adults analyzed together) were found to range from
30% to 40% for psychotropic drugs, 25% to 45% for anticonvulsants, and 50% to 70%
for psychotropic and/or anticonvulsant drugs (i.e., psychotropics,
anticonvulsants, or their combinations). In the community during the same period,
prevalence rates in children were typically 2% to 7% for psychotropics, 12% to
31% for anticonvulsants, and 18% to 33% for psychotropic and/or anticonvulsant
drugs. For adults in the community, prevalence rates ranged from 26% to 36% for
psychotropics, 18% to 24% for anticonvulsants, and 36% to 48% for psychotropic
and/or anticonvulsant drugs. In contrast, during the 1986 to 1995 period, typical
prevalence rates in institutions ranged from 12% to 40% for psychotropics, 24% to
41% for anticonvulsants, and 44% to 60% for psychotropic and/or anticonvulsant
drugs. In the same period, the prevalence rates in the community (for adults and
children analyzed together) ranged from 19% to 29% for psychotropics, 18% to 23%
for anticonvulsants, and 35% to 45% for psychotropic and/or anticonvulsant drugs.
An analysis of the patterns of medication use showed that patient demographic,
physical, social, behavioral, and psychiatric variables, as well as a number of
staff variables, were correlated with use of pharmacotherapy in the entire
population of individuals with mental retardation. A substantial number of
individuals with mental retardation appeared to be prescribed psychotropic
medications that may have been inappropriate for their diagnosis.
PMID- 9542697
TI - Changing patterns of psychotropic medications prescribed by child psychiatrists
in the 1990s.
AB - The active (1994) and closed (1988 to 1992) outpatient records of youths seen in
four separate community mental health centers (CMHC) in Baltimore County,
Maryland were reviewed in mid-1994 to document recent changes in the medication
prescribing practices of local child psychiatrists. Inpatient summaries of
previously hospitalized CMHC youths were also reviewed to supplement the
outpatient medication assessment with hospital data. This regional survey of
medication treatments in child psychiatry revealed that, during the half decade
before 1994, there was an increase in overall psychotropic medication treatment,
multiple concurrent medication treatments (polypharmacy), and antidepressant
treatment with serotonin reuptake inhibitors (SRIs). Inpatient youths were
consistently prescribed more psychotropic medications and diagnosed more
frequently with major depressive disorder than outpatients. Medications typically
used to first treat mood disorders became the predominant medication prescribed
for both outpatients and inpatients by child psychiatrists in 1994, leading to a
proportional decline in prescribed stimulant treatment. The shift from tricyclic
antidepressants to SRI antidepressants in the 1990s by child psychiatrists
matches the same recent practice shift by adult psychiatrists. Likewise, the
increased prescription of drugs to treat mood disorders and the increased rate of
polypharmacy notable of late among child psychiatrists now also mirrors adult
psychiatry practice. Wide geographic variations in neuroleptic and antidepressant
medication patterns were noted, even among facilities in the same metropolitan
region. After psychiatric hospitalization, most youths who continued treatment at
a CMHC outpatient clinic discontinued their inpatient medications within 3
months; the sole exception were children who had been placed on psychostimulants.
PMID- 9542699
TI - Pediatric pharmacoepidemiology: clinical applications and research priorities in
children's mental health.
PMID- 9542698
TI - Prescribing practices of inpatient child psychiatrists under three auspices of
care.
AB - To study prescribing practices of inpatient child psychiatrists under 3 auspices
of care, 137 medicated patients were compared to 122 nonmedicated patients at a
state hospital, a private hospital and a county-university hospital in New York
during 1991. Overall, 79% of state, 76% of private, and 68% of county-university
hospital patients received at least one dose of psychotropic medication, with the
state versus county-university comparison significant (p < 0.05). Significantly
more medicated patients at the private hospital (80%) than at the state or county
university hospitals (each 26%) received antidepressants (p's < 0.001).
Significantly more county-university (74%) than private (35%) patients received
antipsychotic medications, but the proportion of nonpsychotic patients receiving
antipsychotic medication was statistically similar across the three hospitals. In
nonpsychotic patients, antipsychotic agents were used to treat aggressive
behavior. Patients 12 years of age or younger received more stimulants, and
patients 13 years of age or older received more lithium (p's < 0.01). In a
clinical review of medical charts of medicated patients from the 3 auspices of
care, approximately 90% of the medication-treated patients were treated at an
acceptable dose level and with an acceptable rationale based on symptom or
diagnosis. These and other findings and other suggest that children in state
hospitals are not over-medicated in comparison to children in private hospitals
or university-county hospitals, and that prescribing practices among the three
hospitals, despite their different funding sources, are comparable.
PMID- 9542700
TI - Determinants of cancer screening frequency: the example of screening for cervical
cancer.
AB - BACKGROUND: Cancer screening frequency should be based on the rate of progression
of the disease and the sensitivity of the screening test. A common misconception
is that a person's risk of getting the disease determines how often they should
be screened. METHODS: We describe algebraically the theoretical interaction of
disease progression rate and screening test sensitivity determining the portion
of invasive cancers prevented by screening. After discussing the assumptions and
limitations of the model, we apply this model to the example of screening for
cervical cancer. Actual data from large screening programs assembled by the
International Agency for Research on Cancer (IARC) are used to test the
assumptions of the model. RESULTS: A simple formula can express the relation
between disease progression rate, sensitivity of the screening test, screening
frequency, and screening error. Disease prevalence does not figure in this
equation. The IARC data suggest that, at least for cervical cancer, as screening
frequency increases, incremental sensitivity of the test decreases or remaining
undetected cases progress more rapidly so that anticipated benefits from more
frequent screening are not realized. CONCLUSIONS: Rate of disease progression and
sensitivity of the screening test are the proper determinants of cancer screening
frequency. Because these factors can vary depending on screening frequency,
however, the optimal screening interval for a particular cancer must be
determined by clinical trials.
PMID- 9542702
TI - Frequent users of rural primary care: comparisons with randomly selected users.
AB - BACKGROUND: Frequent users of primary care have not been adequately
characterized. The unique characteristics of this population was sought--why they
come so often, what their care costs, and whether psychosocial factors play a
role in their high utilization of health care. METHODS: The billing system of a
rural primary care clinic was used to find the frequency of visits for all
patients attending the clinic for the previous 12 months. The 211 most frequent
visitors were selected. A comparison group of 250 patients was drawn from the
billing records using a random number generator. Charts were reviewed to compare
diagnoses (by frequency), number of procedures, amount billed for care, amount
received from those billings, number of psychotropic medications prescribed, and
response to medication. A subgroup of each group was interviewed to confirm chart
review findings and to inquire about personal reasons for coming to the clinic.
RESULTS: Compared with patients who were random users, patients who were frequent
users were more likely to come from the younger and older age groups, they
averaged significantly more emergency department visits and visits to other
specialists (P < 0.0001), and they had more mental health problems diagnosed (P <
0.01). Significantly more frequent users were insured by Medicaid and fewer were
insured by Medicare. They had more detailed office visits and more laboratory
tests. They received twice as much psychotherapy and had a higher percentage of
problem-focused office visits. Chart audits and interviews of selected patients
revealed that many nonmedical reasons were related to visits in addition to
psychosocial stressors. CONCLUSIONS: Nonmedical factors are important among the
most frequent users of a primary care clinic. Proposals to improve care for
frequent users should consider the psychosocial needs of this population.
PMID- 9542701
TI - Computerized prompts for cancer screening in a community health center.
AB - BACKGROUND: We describe the implementation and subsequent use of a computerized
health maintenance tracking system in a large, urban, North Carolina community
health center (Lincoln Community Health Center) as part of a larger study
designed to increase rates of mammography, Papanicolaou tests, and smoking
cessation in low-income African-Americans. METHODS: Clinicians from the Lincoln
Community Health Center were involved in the design and implementation of the
computer system. At each office visit, clinicians received a computerized
encounter form indicating needed screening tests, counseling, and immunizations
for each randomly selected study patient (n = 1318). RESULTS: Initial clinician
compliance rates with filling out the form were 95 percent (mammography), 82
percent (Papanicolaou test), 77 percent (clinician breast examination), and 55
percent (smoking cessation). Cumulative compliance leveled off at 21 months to 65
percent, 57 percent, 53 percent, and 38 percent, respectively, despite multiple
reminder strategies. When surveyed, most clinicians thought it was a good
reminder system but said they did not always complete the form because of time
demands. Costs of adapting and implementing the system were $23,332.08 ($17.70
per study). Per-patient costs would have been reduced further if more patients
had been included in the project. CONCLUSIONS: State-of-the-art computer
prompting systems can be useful in a community health center; however, even with
prompting, clinicians still only addressed health maintenance with their patients
about 50 percent of the time. Additional interventions will be needed,
particularly in low-income populations, to meet the Healthy People 2000 goals in
health promotion.
PMID- 9542703
TI - Putting population-based care into practice: real option or rhetoric?
AB - BACKGROUND: Efforts to improve care have focused on population-based approaches,
though little practical information exists about implementation. METHODS: This
report reviews relevant literature on teamwork in the context of a time-series
evaluation of a demonstration project to reorganize care of a single panel of
patients in a managed care setting. The proportion of the study panel achieving
recommended levels for breast and colon cancer screening, warfarin control, and
diabetic eye care was compared with the surrounding practice panels and the
managed care population as a whole. Using unconditional logistic regression, we
compared changes within populations between March 1993 and March 1995, and the
rate of change between populations during the same period. RESULTS: A model of
team care was successfully implemented. Colon (occult blood in the stool) and
breast (mammography) screening increased more rapidly in the study population
than in the surrounding practices or plan as a whole (P < 0.05 for all
comparisons). There was no significant improvement in warfarin control or
diabetic eye examinations, though absolute increases occurred. CONCLUSION: This
work shows that a team approach to population-based care is a real option. Such
an approach, however, will not generalize to other settings or all conditions,
and its implementation involves some major challenges.
PMID- 9542704
TI - The pharmacologic treatment of depression.
AB - BACKGROUND: Family physicians often provide the first line of treatment for
patients with depression. Many effective drugs are now available for the
pharmacologic treatment of depression. METHODS: We searched Medline from 1991-96
under the topics of depressive disorders/treatment and antidepressant
medications. Other sources were found by back-referencing from these references
and from pharmacology texts. RESULTS: Although antidepressants appear to be
equally effective, selective serotonin reuptake inhibitors are frequently the
drugs of choice because of their safety profile the less troublesome side
effects. CONCLUSIONS: When prescribing antidepressant medications, the clinician
must educate patients about potential side effects and about the amount of time
that must be allowed for therapeutic efficacy. Drug interactions and concurrent
medical conditions are important factors in the choice of an antidepressant.
PMID- 9542705
TI - Polypharmacy: a case report and new protocol for management.
AB - BACKGROUND: Polypharmacy is an important issue in primary care, yet few data are
available concerning its prevalence, complications, and management in clinical
medicine. The following case illustrates the clinical perils of polypharmacy and
serves as a point for critical discussion. METHODS: MEDLINE was searched, using
the key word "polypharmacy," from 1994 to the present. A case report of
polypharmacy is described, and a novel protocol for the management of
polypharmacy is proposed. RESULTS: Polypharmacy can lead to unnecessary expense,
wasted time, and embarrassment on the part of the patient and confusion and
mismanagement on the part of the physician. The literature reveals controversy
surrounding the definition of polypharmacy and reflects the considerable
morbidity and expense associated with polypharmacy. Finally, the SAIL protocol
shows that physicians need to keep in mind simplicity, adverse effects,
indications, and a precise list of all medications to manage appropriately a
patient's drug regimen. CONCLUSIONS: Polypharmacy is associated with morbidity
and iatrogenic complications. The SAIL protocol can be a useful tool in the
management of this entity. More research needs to be done on the prevalence,
complications, and management of polypharmacy.
PMID- 9542706
TI - Thrombolysis in acute ischemic stroke.
AB - The administration of rt-PA to patients with acute ischemic stroke can result in
improved functional outcomes. The safe and effective use of rt-PA in routine
medical practice requires that patients seek help early, have a well-defined
onset of their symptoms, be carefully examined for contraindications to rt-PA,
receive a CT scan and interpretation to exclude hemorrhage, and receive the drug
within a 3-hour period (Table 5). Intravenous rt-PA is given in a dosage of 0.9
mg/kg (up to a maximum of 90 mg) with 10 percent of the dose administered as a
bolus followed by a 60-minute infusion within 3 hours of the onset of symptoms.
If these conditions cannot be achieved, the drug should not be administered.
Although most patients will not meet the criteria of the NINDS trial, rt-PA is an
important advance in the treatment of acute ischemic stroke.
PMID- 9542707
TI - Dog bites: hidden danger of fulminant sepsis.
PMID- 9542708
TI - Acute toxicity from home-brewed gamma hydroxybutyrate.
PMID- 9542709
TI - Individualized strategies in the era of combination antiretroviral therapy.
PMID- 9542710
TI - Put to sleep.
PMID- 9542711
TI - Polypharmacy: old bad habits.
PMID- 9542712
TI - Man's best friend?
PMID- 9542713
TI - Breath test and serologic testing for Helicobacter pylori.
PMID- 9542714
TI - Management of Parkinson disease.
PMID- 9542715
TI - Health problems of refugees.
PMID- 9542716
TI - Training residents to care for handicapped patients.
PMID- 9542717
TI - Localization of dopamine1A receptor mRNA in different vascular beds in rat: a
nonradioactive in situ hybridization study.
AB - In situ hybridization of a biotin-labeled specific dopamine1A (D1A) receptor gene
oligonucleotide probe combined with computer-assisted image analyzer was used to
directly visualize D1A receptor mRNA and quantify the relative mRNA levels in
sections of rat aorta and pulmonary and caudal arteries. Positive D1A receptor
mRNA signals were found in rat aorta and pulmonary arteries, while no specific
signals could be detected in the caudal artery. D1A receptor mRNA was located
mainly within the medial layer of aorta, with intimal distribution in the
pulmonary artery. The density of D1A receptor mRNA in different vascular beds
demonstrated heterogeneity. D1A receptor mRNA levels in the aorta were much
higher than those in the pulmonary artery (p < 0.01). These results demonstrate
the existence of D1A receptor mRNA in both aorta and pulmonary beds, although
with different distribution and density. The results further support the
heterogeneity of the D1A receptor in different vascular beds.
PMID- 9542718
TI - Reversal of benzodiazepine inverse agonist FG 7142-induced anxiety syndrome by
neurosteroids in mice.
AB - We have previously shown that neurosteroids produce GABA-A receptor mediated
antistress, anxiolytic and other behavioral effects in rodents. In the present
study, the effects of neuroactive steroids on benzodiazepine receptor inverse
agonist FG 7142-induced anxiogenesis were investigated using mirrored chamber and
elevated plus-maze paradigms in mice. FG 7142 (5-20 mg/kg) not only produced a
dose-dependent reduction in the duration of open arm exploration and the total
number of open arm entries, but also increased the latency to enter the mirrored
chamber, decreased the number of entries and total time spent in the chamber,
indicative of anxiogenic-like effects. Neurosteroids allopregnanolone (0.5 and
1.5 mg/kg) and pregnenolone sulfate (2 mg/kg) significantly reversed the FG 7142
(10 mg/kg)-induced anxiogenic response in both the paradigms, without producing
any neurotoxicity. While dehydroepiandrosterone sulfate (1 and 2 mg/kg) failed to
influence the anxiogenic effects of FG 7142. The neuroactive steroid progesterone
(1-10 mg/kg), and the mitochondrial diazepam binding inhibitor (DBI) receptor
agonist 4'-chlordiazepam (0.5 and 1 mg/kg) dose-dependently blocked the FG 7142
induced anxiogenesis in a flumazenil (2 mg/kg)-insensitive manner. The 4'
chlordiazepam-induced reversal response was, however, prevented by pretreatment
with PK11195 (2 mg/kg), a selective mitochondrial DBI receptor antagonist.
Further, at the anxiolytic doses, these neurosteroids did not produce locomotor
inhibition and ataxia. These data suggest that neurosteroids allopregnanolone,
pregnenolone sulfate, progesterone and the mitochondrial DBI receptor agonist 4'
chlordiazepam reverses the anxiogenic-like effects of benzodiazepine receptor
inverse agonist FG 7142 in the mouse models of anxiety.
PMID- 9542719
TI - Effect of nimodipine on the cognitive dysfunction induced by phenytoin and
valproate in rats.
AB - Anticonvulsant effects of phenytoin (PHT) and valproate (VPA) were studied alone
and in combination with nimodipine (NMD) against maximal electroshock (MES)
induced seizures in rats. PHT and VPA induce cognitive deficit in terms of long
term memory loss. The effect of NMD on the cognitive deficit induced by PHT and
VPA was studied through the step-through passive avoidance test (PAT). It was
seen that there was a potentiation of antielectroshock effect of PHT and VPA when
NMD at a dose of 4 mg/kg was combined with PHT or VPA. NMD reversed the long-term
memory loss induced by PHT and VPA in the PAT.
PMID- 9542720
TI - Alacepril, an angiotensin-converting enzyme inhibitor, prevents cerebral
vasospasm in subarachnoid hemorrhage model in rats.
AB - The effects of angiotensin-converting enzyme (ACE) inhibitors was investigated on
the development of cerebral vasospasm and on the endothelium-dependent relaxation
in the rat subarachnoid hemorrhage (SAH) model. Alacepril or enalapril was used
as an ACE inhibitor with or without a thiol moiety in the structure. SAH rats or
sham-operated rats were produced by the injection of homologous blood or
artificial cerebrospinal fluid into the cisternal magna, respectively. In the SAH
rat, cerebral vasospasm was observed at 24 h after blood injection. Acetylcholine
(Ach)-induced relaxation in basilar arteries from SAH rats significantly
decreased compared to that from sham-operated rats, although the relaxation
induced by 3-morpholinosydnonimine, sodium nitroprusside or papaverine did not
decrease. These results suggest that the endothelium cell function of basilar
arteries in SAH rats is damaged. Alacepril prevented both the development of
cerebral vasospasm and the suppression in the Ach-induced relaxation of basilar
artery in SAH rats. However, enalapril did not prevent the suppression of Ach
induced relaxation in SAH rats, despite the tendency to prevent cerebral
vasospasm. Therefore, it is suggested that the preventive effect of alacepril on
cerebral vasospasm could be based on its protective effect on endothelium
dependent relaxation system.
PMID- 9542721
TI - Further pharmacological study on Sho-seiryu-to as an antiallergic.
AB - Examination was made of the pharmacological characteristics of Sho-seiryu-to, an
antiallergic kampo medicine. Sho-seiryu-to suppressed histamine release from rat
peritoneal mast cells, but failed to inhibit the binding of [3H]-mepyramine to
histamine H1 receptors in guinea pig cerebral cortex and lung. Sho-seiryu-to had
no effect on cutaneous reactions induced by serotonin, platelet-activating factor
(PAF), leukotriene (LT) C4 or LTD4. Ketotifen prolonged electrically induced
convulsions, while Sho-seiryu-to did not. Sho-seiryu-to did not affect salivation
induced by pilocarpine. Sho-seiryu-to thus does not appear to inhibit histamine
H1 receptors or inflammation induced by serotonin, PAF, LTC4 and LTD4, but
suppresses mast cell activity. Sho-seiryu-to would thus have only a few side
effects such as dry mouth and convulsions due mainly to the blockage of the
action of muscarinic in salivary glands and histamine in the brain.
PMID- 9542722
TI - Influence of food on glycemia, insulin, C-peptide and glucagon levels in diabetic
patients treated with antidiabetic metformin at steady-state.
AB - Seventeen diabetic patients (5 males and 12 females) treated with long-term
metformin therapy received their morning dose after an overnight fast or after
one of four types of breakfast: low protein, low fat, low carbohydrate or
standard. Mean (+/- SD) and median areas under the serum concentration curves
(AUC), maximum concentrations (Cmax) and time to reach the maximum concentrations
(tmax) were calculated for the major biological parameters (glycemia, C-peptide,
insulin and glucagon levels). None of the diets were bioequivalent to the fasting
condition and only the low carbohydrate diet gave comparable results. A strong
relationship was found between the carbohydrate intake (in g) and the AUC of the
various markers except glucagon.
PMID- 9542723
TI - Indirect pharmacodynamic response models do not require any parametric
pharmacokinetic model to be fitted to effect-time data.
AB - Indirect response models (IRM) represent one of the possible ways to explain and
quantitatively describe a delayed pharmacodynamic effect at non-steady-state
conditions. The standard way to get estimates of pharmacodynamic (PD) parameters
of IRM consists of two steps. First, an appropriate parametric pharmacokinetic
(PK) model (compartmental, polyexponential, etc.) is to be fitted to plasma
concentration-time data, and then IRM is fitted to PD data having PD model as an
input. In the present work it is demonstrated that a simple piecewise function
which consists in interpolation lines connecting concentration-time points can be
used as a universal nonparametric PK model thereby allowing to skip the first
step. MS Excel spreadsheets implementing this PK model and four known versions of
IRM are presented. The usefulness of the approach is demonstrated by fitting IRMs
to simulated data as well as to real PK/PD data of warfarin and terbutaline.
Estimates of IRM parameters obtained with the nonparametric PK model were close
to that published in the literature.
PMID- 9542724
TI - Free radicals and the pathobiology of brain dopamine systems.
AB - Oxygen is an essential element for normal life. However, reactive oxygen species
(ROS) can also participate in deleterious reactions that can affect lipid,
protein, and nucleic acid. Normal physiological function thus depends on a
balance between these ROS and the scavenging systems that aerobic organisms have
developed over millennia. Tilting of that balance towards a pro-oxidant state
might result from both endogenous and exogenous causes. In the present paper, we
elaborate on the thesis that the neurodegenerative effects of two drugs, namely
methamphetamine (METH, ICE) and methylenedioxymethamphetamine (MDMA, Ecstasy) are
due to ROS overproduction in monoaminergic systems in the brain. We also discuss
the role of oxygen-based species in 6-hydroxydopamine (6-OHDA)-induced
nigrostriatal dopaminergic degeneration and in Parkinson's disease. Studies are
underway to identify specific cellular and molecular mechanisms that are
regulated by oxygen species. These studies promise to further clarify the role of
oxidative stress in neurodegeneration and in plastic changes that occur during
the administration of addictive agents that affect the brain.
PMID- 9542725
TI - Serotonergic projections to the retina of rat and goldfish.
AB - Serotonin amacrine cells have been described in the retina of vertebrates, except
mouse and rat. Moreover, serotonin immunoreactive fibers have been reported in
the optic nerve of rodents, frog and stingray. The purpose of this work was to
study serotonin dorsal raphe nucleus projections to the retina, and to determine
whether this pathway occurs in teleosts. The existence of specific connections
was investigated in the rat and in the goldfish by the use of the neurotoxic
substance 5,7-dihydroxytryptamine followed by monoamines determination in the
retina by HPLC. The administration of 5,7-dihydroxytryptamine into the central or
the lateral area of the rat dorsal raphe nucleus decreased serotonin levels in
the raphe area and in the hippocampus, but only the bilateral injection into the
dorsal raphe nucleus decreased it in the retina. In the goldfish, the injection
of 5,7-dihydroxytryptamine into the optic tectum decreased serotonin
concentration in situ and in the retina. The binding of [3H]paroxetine, a marker
of serotonin transporter, was reduced in the retina of both species after the
central treatment with the neurotoxic substance. In addition, the administration
of the serotonin precursor 5-hydroxytryptophan into the optic tectum increased
serotonin levels in the site of the injection and in the retina. The intraocular
administration of 5,7-dihydroxytryptamine produced a big decrease in the content
of retinal serotonin. This indoleamine and 5-hydroxyindoleacetic acid were
detected in the optic nerves of rat and goldfish. The results indicate the
existence of serotonergic retinopetal fibers in the rat and in the goldfish, a
pathway that was not specifically demonstrated for the rat and was not previously
proposed for the fish. The study of these serotonergic projections from the brain
to the retina could be of interest in the understanding of the functional role of
serotonin in the retina.
PMID- 9542726
TI - Distribution of GABAA receptors in the limbic system of alcohol-preferring and
non-preferring rats: in situ hybridisation histochemistry and receptor
autoradiography.
AB - The present study has employed quantitative receptor autoradiography and in situ
hybridisation histochemistry to compare the expression of the mRNA encoding the
alpha 1 and alpha 2 subunits of the GABAA receptor and the binding density of
mature GABAA receptors in the limbic system of alcohol-preferring Fawn-Hooded
rats (FH) with Wistar-Kyoto rats (WKY). Quantifiable levels of mRNA encoding the
alpha 1 subunit were found in cortical regions, ventral pallidum, substantia
nigra, horizontal limb of the diagonal band and the hippocampus of both rat
strains. Interestingly, expression of the alpha 1 subunit mRNA was decreased by
approximately 30% in the hippocampus of FH compared to WKY rats. Following a 28
day period with free access to 10% ethanol, expression of the alpha 1 subunit
transcript, was significantly increased in the piriform cortex and horizontal
limb of the diagonal band, unaltered in the hippocampus but decreased in the
substantia nigra of FH rats. Quantifiable levels of mRNA encoding the alpha 2
subunit were found in nucleus accumbens, amygdala, cortical regions, lateral
septal nucleus, hippocampus, medial habenula and ventral pallidum of both
strains. Expression of the alpha 2 subunit mRNA was decreased by approximately
35% in both the hippocampus and occipital cortex of FH compared to WKY rats.
However, consumption of 10% ethanol in FH rats had no impact upon expression of
the mRNA encoding the alpha 2 subunit in any region examined. Mature GABAA
receptors were studied by autoradiography utilising the antagonist radioligand
[3H]SR95531 and the agonist radioligand [3H]muscimol. Topographic binding
throughout the limbic system of both strains was observed for both radioligands.
Specifically, [3H]SR95531 binding was higher in the occipital cortex,
hippocampus, lateral septal nucleus, superior colliculus and ventral pallidum of
the FH rats compared to WKY rats; however, in the nucleus accumbens [3H]SR95531
binding was lower in FH compared to WKY. Ethanol consumption had no measurable
effect on the binding of [3H]SR95531 in FH rats. In the case of [3H]muscimol,
binding was higher in the cortex, lateral septum and ventral pallidum of FH
compared to WKY. Furthermore, ethanol consumption resulted in a 25-30% increase
in [3H]muscimol binding in the lateral septum and striatum of FH rats. These data
provide evidence for differential expression of GABAA receptor subunits in FH and
WKY rats, and additionally indicate anatomically defined variations in GABAA
receptor binding between the two rat strains.
PMID- 9542727
TI - Stimulation of 5-HT2A receptors on astrocytes in primary culture opens voltage
independent Ca2+ channels.
AB - Mechanisms underlying the 5-HT2A receptor induction of intracellular Ca2+
mobilization and Ca2+ influx in type I astroglial cells in primary culture from
newborn rat cerebral cortex were evaluated. The 5-HT-evoked Ca(2+)-transients,
inhibited by the 5-HT2A antagonists ketanserin or 4-(4-fluorobenzoyl)-1-(4
phenylbutyl) piperidine oxalate, consisted of an initial peak caused by inositol
1,4,5-trisphosphate (IP3)-mediated Ca2+ release from internal stores, and a
second sustained part which was due to Ca2+ transport over the plasma membrane.
The responses were pertussis toxin-insensitive, suppressed by the phospholipase C
inhibitor neomycin and were inhibited by the Ca(2+)-ATPase inhibitor
thapsigargin. Furthermore, the responses were inhibited by the IP3 receptor
antagonist heparin. When the second sustained part of the 5-HT-evoked response
was studied, it was concluded that Ca2+ influx was not a result of opening of
voltage operated calcium channels of either L, N or T-type. Instead it appeared
that Ca2+ entered the cells through specialized voltage independent Ca2+ channels
which were dependent of the IP3 production and subsequent Ca2+ release from
internal stores. From this, we conclude that 5-HT opens Ca2+ channels in
astrocytes which closely resemble depletion-operated Ca2+ channels (DOCCs).
PMID- 9542729
TI - Effect of dantrolene on K(+)- and caffeine-induced dopamine release in rat
striatum assessed by in vivo microdialysis.
AB - Recently, dantrolene has been reported to affect the central nervous system in
addition to peripheral targets such as skeletal muscle. We examined effects of
dantrolene on K(+)- and caffeine-induced dopamine release in rat striatum using
in vivo microdialysis. Perfusion with KCl via the dialysis probe for 20 min
induced immediate increase in DA release. Either chelation of extracellular
calcium or addition of dantrolene for 120 min preceded reapplication of 100 mM
KCl for 20 min. Calcium chelation attenuated the increase in DA release induced
by KCl. Application of dantrolene enhanced the KCl-induced increase in DA
release, but this effect disappeared at 100 microM. Caffeine caused a dose
dependent increase in dopamine release, independently of extracellular calcium.
Treatment with 100 microM dantrolene for 120 min reduced the increase in DA
release induced by caffeine. These findings that dantrolene modulates dopamine
release in rat striatum indicate that conventionally administered dantrolene is
likely to act on the central nervous system.
PMID- 9542728
TI - Axonal transports of Boc-Gly-Arg-Arg-MCA hydrolysing enzyme in rat sciatic
nerves.
AB - Study on neural axon transport is a very useful method to find a neuron-specific
protease. In the present study, the enzyme activity (release of 7-amino-4-methyl
coumarin from t-butyloxycarbonyl-glycyl-L-arginyl-L-arginine-4-methylcoumaryl-7
amide) was measured in the proximal, middle, and distal segments between 12 and
120 h after double ligations of rat sciatic nerves to find precursor processing
enzyme specific for pair of basic amino acid residue. The enzyme activity was
significantly increased not only in the proximal but also in the distal segments
12-120 h after the ligation, and the maximal enzyme activity was found in both
segments at 72 h. The enzyme activity eluted by anion exchange chromatography of
the proximal segment showed at least three peaks, and was slightly higher than
the activity of the distal one. The activity in the middle segment was very low
in comparison with the activity in the proximal and distal segments. These data
indicate that some of the enzymes specific for pair of basic amino acid residue
are transported by both anterograde and retrograde axonal flow, and may undergo a
neuron-specific processing.
PMID- 9542730
TI - Hypothalamic GABA-ergic activity and T-cell proliferation in aged mammal: effect
of dietary protein.
AB - Short-term supplementation of low protein diet (LPD) or high protein diet (HPD)
to the aged (18 months old) rats did not change the hypothalamic GABAergic
activity and immune response. Long-term supplementation of LPD on the other hand,
enhanced hypothalamic GABAergic activity with an immunopotentiation by increasing
the T-cell proliferating activity and peripheral blood lymphocyte count in the
same age group of rats. Unlike LPD, HPD under long-term supplementation to the
aged rats reduced the hypothalamic GABAergic activity with immunosuppression.
These results thus suggest that (i) hypothalamic GABAergic activity is a
regulatory index of immune response in aged mammals and (ii) long-term
consumption of protein-poor or protein-rich diet may be an exogenous modulator of
neuroimmune regulation in relation to central GABAergic activity and immune
response.
PMID- 9542732
TI - Differential regulation by pregnenolone sulfate of intracellular Ca2+ increase by
amino acids in primary cultured rat cortical neurons.
AB - We investigated the effects of pregnenolone sulfate (PS) on the [Ca2+]i increase
induced by gamma-aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) using
fluorescence imaging. PS inhibited the 50 microM GABA-induced increase in [Ca2+]i
in a dose-dependent manner with an IC50 of 30 microM. The inhibitory effect of PS
was apparent within 5 min and was in a non-competitive manner, suggesting that PS
may act directly to the membrane level but indirectly to the GABA binding sites.
Our previous study has already shown that the GABA-induced Ca2+ increase involves
GABAA receptors and the similar pathway to a high K(+)-induced Ca2+ response
(Takebayashi et al., 1996). Because 50 microM of PS could not inhibit a 25 mM
K(+)-induced Ca2+ increase, it seems likely that the site of the inhibitory
action of PS on the GABA-induced Ca2+ increase may be independent of the pathway
of the high K(+)-induced Ca2+ response, but rather at GABAA receptor complex. In
contrast, PS potentiated the 50 microM NMDA-induced increase in [Ca2+]i in a dose
dependent manner. The magnitude of the NMDA response was approximately doubled in
the presence of 100 microM of PS. However, PS did not affect the
acetylcholine(Ach)-induced increase in [Ca2+]i. Furthermore, corticosterone had
little effect on the GABA- and NMDA-induced Ca2+ increases, indicating that the
alteration of the Ca2+ response is specific for PS. In conclusion, it is
suggested that PS modulates differentially [Ca2+]i increase induced by GABA and
NMDA.
PMID- 9542731
TI - The neurochemical markers in cerebrospinal fluid to differentiate between aseptic
and tuberculous meningitis.
AB - In this study, the use of neurochemical markers in patients with aseptic and
tuberculous meningitis has been investigated. The cerebrospinal fluid levels of
amino acids, nitrite (a metabolite of nitric oxide), vitamin B12 and homocysteine
were quantitated in both groups of patients. Among the amino acids, aspartic acid
and glutamic acid both excitatory amino acid, GABA, glycine and tryptophan were
all significantly increased in both patient groups whereas decreased level of
taurine and increased level of phenylalanine were only found in patients with
tuberculous meningitis. The levels of nitrite and its precursor arginine were
significantly higher in patients with tuberculous meningitis whereas unchanged
levels were found in patients with aseptic meningitis. A significantly increased
homocysteine level and a decreased level of vitamin B12 were found only in
patients with tuberculous meningitis whereas unchanged levels were found in
patients with aseptic meningitis. This indicates that patients with tuberculous
meningitis are particularly prone to vitamin B12 deficiency resulting into
increased level of HC, and involvement of free radical showing the importance of
these biological markers for promoting the possibility for the design of
therapeutic approach.
PMID- 9542733
TI - Brain benzodiazepine binding in aged rats.
AB - Membrane [3H]flunitrazepam binding to central and peripheral benzodiazepine
binding sites was studied in four brain areas (cerebellum, cortex, striatum and
midbrain) of young (age 2-4 months) and aged (> 24 months) rats. A generalized
reduction in the density of central binding sites (Bmax) was observed in all
brain areas examined in aged rats. This reduction is irrelevant of the brain area
and, according to literature, may correspond to cell loss and/or differential
expression of mRNAs coding for the subunits of the GABA/benzodiazepine receptor
complex during ageing. In the case of the peripheral binding sites, there was a
decrease of Bmax in all brain areas with the exception of the cerebellum.
However, the percent reduction of peripheral binding sites varied significantly
among the different brain areas. These data suggest a differential effect of
ageing on brain benzodiazepine binding which may reflect the special role for
each brain area during ageing.
PMID- 9542734
TI - Biological and clinical MRS at ultra-high field.
AB - The advantages of performing spectroscopic studies at higher field strengths
include increased SNR, improved spectral resolution for J-coupled resonances, and
improvements in the selectivity of spectral editing schemes. By using pulse
sequences that minimize the required echo time, refocus J-evolution, employ low
peak B1 requiring pulses and take advantage of spectroscopic imaging methods,
these advantages can also be utilized in clinical applications of spectroscopy at
high field. In addition to the static measurements measurements of N-acetyl
aspartate (NAA), creatine (CR) and choline (CH) which can be performed at 1.5 T,
high resolution measurements of glutamate, glutamine, GABA and the incorporation
of 13C labeled glucose into glutamate are possible with improved spatial and
spectral resolution. These methods have been utilized in patients with seizure
disorders and multiple sclerosis to identify, characterize and map the metabolic
changes associated with these diseases and their treatment.
PMID- 9542735
TI - Decoupling: theory and practice. I. Current methods and recent concepts.
AB - Current methods for broadband heteronuclear decoupling are reviewed from a
historical perspective. The principal concern is that decoupling should be
effective over a wide range of chemical shifts without undue radiofrequency
heating of the sample, particularly when human patients are involved. Continuous
wave methods are the least efficient in this respect, followed by noise
decoupling. Composite pulse schemes offer a more effective use of radiofrequency
power, while adiabatic passage methods are the most efficient of all. Bi-level
decoupling employs a low level of radiofrequency irradiation during the
relaxation delay to maintain the nuclear Overhauser effect, with a higher level
during signal acquisition in order to decouple over a wide frequency band. All
decoupling sequences introduce cycling sidebands into the observed spectrum, and
schemes are described to minimize the intensity of these artifacts. In part II,
practical applications of decoupling methods are examined in the context of in
vivo spectroscopy, where the improvements in sensitivity and resolution through
broadband decoupling can be critical for solving clinical problems. Attention is
focused on the regulatory limits on power deposition in these experiments. A
tabulation of the existing work on decoupling in biological tissue is presented,
mainly involving 31P and 13C spectroscopy in vivo or in vitro.
PMID- 9542736
TI - Decoupling: theory and practice. II. State of the art: in vivo applications of
decoupling.
AB - Current methods for broadband heteronuclear decoupling are reviewed from a
historical perspective. The principal concern is that decoupling should be
effective over a wide range of chemical shifts without undue radiofrequency
heating of the sample, particularly when human patients are involved. Continuous
wave methods are the least efficient in this respect, followed by noise
decoupling. Composite pulse schemes offer a more effective use of radiofrequency
power, while adiabatic passage methods are the most efficient of all. Bi-level
decoupling employs a low level of radiofrequency irradiation during the
relaxation delay to maintain the nuclear Overhauser effect, with a higher level
during signal acquisition in order to decouple over a wide frequency band. All
decoupling sequences introduce cycling sidebands into the observed spectrum, and
schemes are described to minimize the intensity of these artifacts. In part II,
practical applications of decoupling methods are examined in the context of in
vivo spectroscopy, where the improvements in sensitivity and resolution through
broadband decoupling can be critical for solving clinical problems. Attention is
focused on the regulatory limits on power deposition in these experiments. A
tabulation of the existing work on decoupling in biological tissue is presented,
mainly involving 31P and 13C spectroscopy in vivo or in vitro.
PMID- 9542737
TI - Theory and application of array coils in MR spectroscopy.
AB - The theory and application of array coils are reviewed in the context of phased
array spectroscopy. The optimization of the signal-to-noise ratio from an array
of coils is developed by considering the efficiency of a phased array transmit
coil. This approach avoids the need to consider noise correlation, and should be
useful in future considerations of transmit phased array coils for MR
spectroscopy. Methods to characterize array coil performance, including fields
and coupling are briefly summarized, along with methods to minimize the effects
of mutual inductance. The signal-to-noise advantages of array coils over single
coils are examined for both planar and cylindrical arrays. Numerical simulations
of planar arrays of 2 x 2, 4 x 4 and 8 x 8 elements and constant overall
dimension are compared to a single coil of the same size. The results demonstrate
a significant improvement in sensitivity near the array coil. Although the
benefits of the array decrease as a function of distance from the array, the
array sensitivity never drops below that of a single coil with the same overall
dimensions, or that of a single element of the array. Similar results are
obtained for a sixteen element cylindrical array, which is compared to a standard
quadrature birdcage coil using both computational methods and phantom
measurements. The phased array techniques reviewed are demonstrated with proton
spectroscopic images of the brain.
PMID- 9542739
TI - Adiabatic pulses.
AB - Adiabatic pulses are sometimes considered to be mysterious and exotic entities
which are difficult to understand, complex to generate and impractical to
implement. This work is an attempt to bring familiarity and to fulfill the
preliminary needs of anyone interested in learning more about this subject. The
response of magnetization to stimuli produced by adiabatic pulses is analyzed
using vector representations in a frequency modulated rotating frame. The first
section deals with basic principles of amplitude and frequency modulated pulses
and a vector representation in a second rotating frame is used to explain how the
adiabatic condition can be satisfied. The subsequent section explains the
principles of offset independent adiabaticity. These principles are then used to
design optimal functions for the amplitude, frequency, and magnetic field
gradient modulations for adiabatic inversion pulses. The last section considers
some practical aspects for those who want to develop methodologies involving
adiabatic pulses.
PMID- 9542738
TI - High spatial resolution and speed in MRSI.
AB - The in vivo applications of magnetic resonance spectroscopic imaging (MRSI) have
expanded significantly over the past 10 years and have reached the point where
clinical trials are underway for a number of different diseases. One of the
limiting factors in the widespread use of this technology has been the lack of
widely available tools for obtaining data which are localized to sufficiently
small tissue volumes to make an impact upon diagnosis and treatment planning.
This is especially difficult within the timeframe of a clinical MR examination,
which requires that both anatomic and metabolic data are acquired and processed.
Recent advances in the hardware and software associated with clinical scanners
have provided the potential for improvements in the spatial and time resolution
of imaging and spectral data. The two areas which hold the most promise in terms
of MRSI data are the use of phased array coils and the implementation of echo
planar k-space sampling techniques. These could have immediate impact for 1H MRSI
and may prove valuable for future applications of 31P MRSI.
PMID- 9542740
TI - Metabolite-specific NMR spectroscopy in vivo.
AB - An outline is presented of metabolite-specific in vivo NMR spectroscopy
(particularly in brain). It reviews from a physical spectroscopist's perspective,
the need for and the methods of observation of, individual metabolite resonances.
PMID- 9542741
TI - Current awareness in NMR in biomedicine.
PMID- 9542742
TI - Expression of hMSH2 and hMLH1 in colorectal carcinomas with microsatellite
instability.
AB - Microsatellite instability (MIN) due to defective mismatch repair (MMR) genes has
been reported in a subset of sporadic colorectal carcinomas and in the majority
of tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC)
syndrome. Among the known MMR genes, hMSH2 and hMLH1 genes are known to be
predominantly altered in HNPCC patients and MIN-positive tumors. In this study,
we examined MIN and the protein expression pattern of the hMSH2 and hMLH1 by
Western blot and immunohistochemistry from 32 sporadic colorectal carcinomas. MIN
was observed in 6 (18%) colorectal carcinomas. Of the 6 MIN-positive tumors, one
case showed no expression of either protein, 3 cases showed an absence of hMSH2
protein expression, one case showed an absence of hMLH1 protein expression and
one case showed no altered expression of either protein by immunohistochemistry.
The decreased expression of the hMSH2 protein in a tumor compared to the normal
mucosa was also observed in 5 of the 6 MIN-positive cases by Western blot
analysis. All of the MIN-negative tumors showed expression of both proteins by
immunohistochemistry. Thus most of the MIN-positive tumors appear to be directly
related to the altered expression of these two genes and can be diagnosed by the
examination of protein expression.
PMID- 9542743
TI - Prognosticating tools in primary neuroendocrine (Merkel-cell) carcinomas of the
skin: histopathological subdivision, DNA cytometry, cell proliferation analyses
(Ki-67-immunoreactivity) and NCAM immunohistochemistry. A clinicopathological
study in 25 patients.
AB - Histopathologically, 18 of our patients had classical Merkel-cell carcinomas
(MCC); seven had neuroendocrine (NE) carcinomas with features different from MCC,
here called "aberrant MCC". These patients showed a progressive neoplastic
disease with a fatal outcome in four of them. The cytometric DNA distribution
pattern of the tumor cell nuclei of all the aberrant MCCs was found to be of the
aneuploid type. By contrast, the neoplastic disease of the majority of patients
with classical MCC ran a milder course; a fatal outcome occurred in only one of
them. Here, the DNA ploidy pattern was of the euploid (diploid or tetraploid)
type in eight cases and of the aneuploid type in another eight. Our recently
described "proliferation cell index" (PCI), based on nuclear immunoreactivity
(IR) with the proliferation "marker" antigen Ki-67, was significantly lower in
those five MCCs of the classical "DNA-diploid" type than in the seven "DNA
aneuploid" ones. These five patients presented a mild neoplastic disease; only
one had a local recurrence and none had metastases. Otherwise, neither the PCI
values nor the NCAM IR of the MCC cells were found to be of any prognostic
significance.
PMID- 9542744
TI - Oncogene expression in tumour cells of pediatric Hodgkin's disease in Argentina-
correlation with Epstein Barr virus presence.
AB - A new category of oncogenes regulating apoptosis, p53 and bcl-2, and the Epstein
Barr virus (EBV) latent membrane protein-1 (LMP-1) have been related to Hodgkin's
disease (HD) pathogenesis. We attempt to determine p53, mdm2, p21waf-1, bcl-2 and
LMP-1 immunohistochemical expression in tissue sections from formalin-fixed,
paraffin-embedded lymph node biopsies of pediatric HD. P53 was detected in the
nucleus of Reed Sternberg cells and their variants (H-RS) in 68% of the HD cases.
However, there was no statistically significant association with either clinical
stages or with histological subtypes. P21waf-1, an indirect marker of p53
functional status, showed nuclear labelling of H-RS in all the studied cases.
MDM2 co-expressed with p53 in 62% of the cases, suggesting that both proteins
regulate one another, in HD by a self regulatory loop. Bcl-2 cytoplasmatic
expression in H-RS was demonstrated in 65% of the cases. There was co-expression
of bcl-2 and p53 in 51%, but it failed to correlate with a poor prognosis. LMP-1
labelling was shown in 51% of the cases, disclosing a statistically significant
association with the under 6-year group (p = 0.005, Fisher's exact test). Since
LMP-1 induces the expression of bcl-2 in vitro, the relation of both proteins was
analysed and found to co-express in 15/37 cases, with a statistically significant
association only in the under 6-year group (p = 0.001, Fisher's exact test).
Abnormal accumulation of these oncoproteins in tumour cells could play a role in
the pathogenesis of a subset of pediatric HD.
PMID- 9542745
TI - The value of PCNA and AgNOR staining in endoscopic biopsies of gastric mucosa.
AB - The aim of the present study was to examine the usefulness of the quantification
of PC10-positive-cells and of Argyrophilic Nucleolar Organizer Regions (AgNORs)
in gastric biopsies for the identification of gastric mucosal proliferative
lesions. Fifty seven paraffin-embedded endoscopic biopsies were classified into
four histologic groups: normal, inflammatory, dysplastic and neoplastic mucosa.
The percentage of PC10-positive cells was determined by immunohistochemistry. The
AgNOR parameters determined included the total number of all identifiable silver
precipitations in the nucleus, the mean number of silver precipitations per
cluster, and the presence of morphologically heterogenous silver precipitations.
Group comparisons were performed using the Kruskall Wallis and Dunn non
parametric tests with a significance level of 5%. A discriminant analysis
(followed by the jack-knife procedure) was performed using the three AgNOR
parameters plus the percentage of PCNA-positive cells as the independent
variables and histological groups as the dependent variable. All three AgNOR
parameters, as well as the percentage of PCNA-stained nuclei, showed their
highest values in the carcinoma group. However, no good differentiation among the
four histologic groups was obtained using only one of these parameters, since
there was always considerable overlap among them. By combining all the parameters
in a linear discriminant analysis, we obtained a correct classification in 48 out
of 57 cases. Within the classification errors there was only one false positive
carcinoma, which was in fact a dysplasia and only one false negative carcinoma
erroneously classified as dysplasia. The number of cells with heterogenous AgNORs
was the most important parameter for the discriminant analysis. No correlation
between PCNA values and the AgNOR parameters could be found, thus indicating that
they do not represent the same phenomenon in the cell cycle. We concluded that
the use of a combination of various proliferation parameters in a linear
discriminant analysis may be helpful for differentiating gastric mucosal lesions.
The peculiar AgNOR morphology is an important variable which should be taken in
consideration in quantitative studies. PCNA and AgNORs seem to represent
different physiological phenomena in the cell cycle.
PMID- 9542746
TI - Development of osteoarthritis in the knee joints of Wistar rats after strenuous
running exercise in a running wheel by intracranial self-stimulation.
AB - The influence of excessive running load on the development of knee osteoarthritis
(OA) was investigated in male Wistar rats. Running exercises were performed in a
running wheel using intracranial self-stimulation to motivate Wistar rats to run
daily distances of 500 m at 5 days/week. Hereby, ten rats ran a distance of 15 km
within three weeks while a further ten rats run a total of 30 km within six
weeks. Thirteen Wistar rats without running exercises served as controls.
Complete knee joint sections of all rats were evaluated histologically using
MANKINs grading system with categorization of the findings into non, mild
moderate, and severe osteoarthritis. In addition, immunoreactivity of the
chondrocytes to MMP-3 as an important cartilage degrading enzyme in OA was
assessed by immunostaining with monoclonal MMP-3 IgG antibodies. Histological
assessment of the knee joint sections revealed a significant increase in
osteoarthritic changes with higher running load. While in rats with 15 km running
all but two knee joints showed mild OA, moderate OA was the predominant finding
in rats with 30 km running. In contrast, no OA was found in the controls.
Immunostaining for MMP-3 revealed a significant increase in immunoreactivity of
the chondrocytes to MMP-3 with higher running load, indicating a running load
depending production of this cartilage-degrading enzyme in the course of
increasing OA. Compared to 47.4% immunoreactive chondrocytes to MMP-3 in the
controls, this ratio rose to 70.4% in rats with 15 km running and even up to
89.9% in rats with 30 km running. In conclusion, in Wistar rats, excessive
running load leads to marked, running distance-depending osteoarthritic changes
which are caused, at least in part, by an increase in MMP-3 production rising
with greater running distance. Within this exercise model of OA, intracranial
self-stimulation is an effective method to motivate Wistar rats to extremely
excessive running in a running wheel. This model offers a wide range of further
approaches to studying different processes of the development of OA.
PMID- 9542747
TI - Multilocular cystic epithelioid leiomyoma of the uterus with focal lymphangioma
like pattern: report of a case with immunohistochemical study.
AB - We report a rare case of epithelioid leiomyoma of the uterus presenting as a
multilocular cystic mass containing clear fluid. The histologic basis of cysts
was the diffuse intratumoral cystic degeneration. Histologically, the presence of
numerous cystic cavities of variable size raised the possibility that vascular
abnormalities, such as hemangioma, lymphangioma, and diffuse cavernous
angiomatosis, could be associated with epithelioid leiomyoma. An
immunohistochemical study using endothelial cell and basement membrane markers,
was helpful in excluding the vascular nature of the cystic cavities and revealed
an unexpected focal lymphangioma-like pattern as a peculiar component of tumor.
PMID- 9542748
TI - Angiomyxoma of the umbilical cord in one twin with cystic degeneration of
Wharton's jelly. A case report.
AB - We report the prenatal diagnosis of an angiomyxoma of the umbilical cord in a
female fetus of a dizygotic twin pregnancy. The pregnant woman was hospitalized
at 18 weeks for exclusion of a suspected exomphalos. Using high-resolution
ultrasound and color doppler, the umbilical tumor (8 x 5 x 4 cm) was suspected to
be an angiomyxoma without malformations in the fetus. Neither chromosomal
aberrations nor elevated alphafetoprotein were found after amniocentesis. Serial
examinations showed an increase in the size of the cystic mass without
deterioration of the fetal condition. Macroscopical and microscopical
examinations of the tumor performed after delivery revealed an angiomyxoma with
cystic degeneration of Wharton's jelly. Tumors of the umbilical cord are rare
anomalies and should be considered when using prenatal ultrasound for detection
of cystic lesions.
PMID- 9542749
TI - Alveolar soft part sarcoma of the uterine corpus. Report of two cases and review
of the literature.
AB - Alveolar soft-part sarcoma (ASPS) is a rare tumor of uncertain histogenesis,
mainly localized in the extremities and less frequently found in the head, neck
and trunk. The present report describes two cases of ASPS localized in the
uterus. In general, this entity is very rarely encountered in the female genital
tract. Including the two cases presented here, 27 patients have been described in
the literature. Whereas the prognosis for ASPS in soft tissues is usually poor
(most of the patients died of lung metastases), those localized in the female
genital tract are associated with a much better survival. This could be explained
by the fact that their diameter seldom exceeds 5 cm, the size which is regarded
as being the critical prognostic limit. Histologically, both tumors showed the
same characteristics as known for ASPS in other localizations: organoid or nest
like arrangement of tumor cells; rounded or polygonal cells with cytoplasm of
varying density; thin-walled, sinusoidal vascular spaces between tumor cell
nests. Immunohistochemically, we found positivity for desmin and, to a lesser
extent, for vimentin. Cytokeratin was negative, which is important in
differential diagnosis to other rare uterine neoplasias like clear cell
(mesonephroid) adenocarcinomas or metastases.
PMID- 9542750
TI - Physiologic doses of urocanic acid do not alter the allostimulatory function or
the development of murine dendritic cells in vitro.
AB - Exposure to UVB results in the isomerization of trans-urocanic acid (UCA),
localized in the stratum corneum, to cis-UCA. Cis-UCA can mediate at least some
of the immunosuppressive effects of UVB, though the mechanism of cis-UCA action
remains incompletely defined. Alterations in Langerhans cells, and other
dendritic antigen presenting cell populations in the skin, may contribute to the
loss of skin immune function following UVB exposure. Hence, this study was
designed to investigate whether cis-UCA directly can induce changes in the
immunostimulatory capacity of dendritic cells (DC) and the development of DC from
precursor cells. Murine DC were generated from C57BL/6 bone marrow (BM) using
granulocyte-macrophage colony-stimulating factor (GM-CSF), and were used as
stimulator cells in mixed lymphocyte reactions (MLR) using BALB/c lymph node
cells (LNC) as responders. The addition of cis- and trans-UCA at concentrations
ranging from 0.1-500 micrograms/ml to the MLR did not affect proliferative
responses. Cis- or trans-UCA (100 micrograms/ml) was added to GM-CSF stimulated
mouse BM cells on day 0, day 3 or day 5 of culture, and the phenotype and allo
stimulatory function of the DC were analysed on day 7. Treatment with cis- or
trans-UCA did not affect the numbers or the viability of cells in the BM
cultures. In addition, the expression on DC of Iab, CD11c or the costimulatory
molecules ICAM-1, B7-1, B7-2 and CD40 was not altered by the addition of cis-UCA
to BM cultures. The inability of cis-UCA to alter the development of DC in vitro
was confirmed by analysing the functional capacity of DC in MLR. DC generated in
the presence of cis-UCA were equally efficient in the induction of allo
stimulation, when compared with control DC. These results suggest that cis-UCA
does not exert its immunosuppressive activity through direct effects on DC. Such
activity may be independent of DC, or alternatively, cis-UCA may influence DC
function indirectly, through the induction of secondary mediators.
PMID- 9542751
TI - Assessment of skin types, skin colours and cutaneous responses to ultraviolet
radiation in an Asian population.
AB - Ninety normal individuals were included in this study on skin types, skin colours
and cutaneous responses to ultraviolet radiation. Skin types were recorded using
Fitzpatrick's classification, skin colours were measured using the Minolta
Chromameter CR-300, and cutaneous responses to UV radiation were measured in
terms of minimal erythema dose (MED) to UVA, UVB and the immediate pigment
darkening dose to UVA (IPDDA). Skin colour measurements were taken from the right
cheek to represent facultative skin colours, and from the buttock to represent
constitutive skin colours. The colours measured were expressed by the L x a x b
colour space. Skin types and some colour parameters (L and b from covered parts
of body) correlated fairly well with the minimal erythema doses (MED) to UVA and
UVB. Skin colour measurements are more objective than skin type assessment and
could be better markers of photosensitivity. However, there is still considerable
overlap in MEDs for persons with different skin colours, and further studies of
these parameters are warranted. Our MEDs are higher than other reports on similar
skin types and skin colours. This could be due to differences in methodology,
genetic make-up or acclimatization from chronic sun exposure. This illustrates
the importance of local controls for each institution dealing with photosensitive
disorders.
PMID- 9542753
TI - Total body heliotherapy.
AB - Sunlight has long been known to be beneficial for a variety of skin diseases.
Patients with psoriasis and eczema frequently employ ambient heliotherapy to
control their conditions. However, social norms do not permit a person to expose
the entire body in public, thus placing severe restrictions on the utility of
this modality for the treatment of generalized psoriasis, for example. Tan-Thru
bathing suits, designed to attract those who wish to tan without an accentuated
"tan line", are reported to absorb ultraviolet (UV) rays up to a maximum
equivalent of a sun protection factor (SPF) 10 sunblock, thus offering
approximately 89% protection while in use, according to their manufacturer. If
so, this bathing suit may allow patients with UV-responsive skin dermatoses to
achieve full body exposure in a socially acceptable manner. The objective of this
study was to verify the SPF and to determine the actual transmittance to skin
covered by a Tan-Thru bathing suit. Ten healthy adult subjects were recruited for
this investigation. UVB minimal erythema dose (MED) was determined on unaffected
gluteal or lower back skin, once with and once without the swimsuit on. Our
results showed that the mean SPF afforded by the bathing suit was in fact 4.9
(range 4.5-5.6). In conclusion, theoretically, the Tan-Thru bathing suits could
allow enough UVB penetration under ambient conditions to be beneficial for
patients with UVB responsive conditions.
PMID- 9542752
TI - Phototoxic lysis of erythrocytes from humans is reduced after oral intake of
ascorbic acid and d-alpha-tocopherol.
AB - Ultraviolet (UV) radiation causes hemolysis of human erythrocytes in the presence
of photosensitizers. This can be used as an in vitro model for evaluating
photosensitizing properties of substances. Antioxidants such as ascorbic acid
(vitamin C) and d-alpha-tocopherol (vitamin E) have been found to be
photoprotective in such test systems. We assessed the effect of combined systemic
intake of both ascorbic acid and d-alpha-tocopherol by human volunteers on
phototoxic in vitro lysis of their erythrocytes. In a double-blind placebo
controlled study, 10 subjects took daily 2 g ascorbic acid combined with 1000 IU
d-alpha-tocopherol, and 10 took a placebo. Blood was taken before and after 7
days of treatment, erythrocytes were prepared and then incubated with 10(-3)
mol/l fenofibrate, a photosensitizer acting in the UVA and UVB region. The
suspensions were exposed to radiation rich in UVA (up to 40 J/cm2 UVA) or to
radiation rich in UVB (up to 1.6 J/cm2). Photohemolysis of the samples was
calculated as a percentage of complete hemolysis. At the end of the treatment
phase, in the placebo group photohemolysis was not significantly reduced compared
with the initial values at all irradiation doses except for 1.6 J/cm2 UVB (96% vs
79%; P < 0.01). In the group taking vitamins, photohemolysis was significantly
reduced at nearly all UV doses, most impressively after moderate UVA irradiation
(20 J/cm2 UVA: 86.5% vs 14.5%; P < 0.01). It is concluded that the results of the
photohemolysis test are influenced by the antioxidative status of the cell donor
and that ascorbic acid and d-alpha-tocopherol also may protect against phototoxic
damage in vivo.
PMID- 9542754
TI - Green light is effective and less painful than red light in photodynamic therapy
of facial solar keratoses.
AB - Photodynamic therapy (PDT) with topically applied delta-aminolevulinic acid (ALA)
is increasingly employed to treat patients with multiple solar keratoses and
superficial skin tumors. For these indications, ALA-PDT has been shown to be
highly efficient. Treatment of multiple or extended lesions, however, is
substantially hampered by the fact that ALA-PDT is associated with burning pain
during the irradiation procedure. The standard irradiation devices commonly used
for ALA-PDT emit red light around 630 nm. In the present half-side comparison
study we have observed that ALA-PDT employing a green light irradiation device
(543-548 nm) is equally effective, as compared with standard red light ALA-PDT.
In contrast to red light ALA-PDT, however, green light ALA-PDT caused only little
tingling and burning but no pain. These observations indicate that green light
ALA-PDT is superior to standard ALA-PDT, because it is associated with less
unwanted side effects.
PMID- 9542755
TI - How well are sunscreen users protected?
AB - Previous studies have shown that people often apply less sunscreen than the
recommended amount of 2 mg/cm2. Our purpose in this study was to determine
objectively how photoprotection varies with application thickness. The protection
provided by differing quantities of sunscreens containing varying amounts of
titanium dioxide was measured in vitro using excised human epidermis as the
substrate. It was found that application thickness had a significant effect on
the sun protection factor (SPF), with most users probably achieving a mean SPF of
between 20-50% of that expected from the product label. Underprotection due to
inadequate application, coupled with overexposure to the sun, might partially
explain why sunscreen use has been reported to be a risk factor in melanoma.
PMID- 9542756
TI - Clearance of UVB-induced erythema in patients with non-melanoma skin cancer.
AB - We have examined the clearance of UVB-induced erythema in 10 non-melanoma skin
cancer (NMSC) patients, comparing their responses to a control group. All
participants were followed to resolution of erythema, as measured by a
chromameter. The resultant response pattern was modelled in three phases, with
comparison of the rates of decay in erythema carried out. Analysis of the rapid
decay phase demonstrated a significantly slower rate of resolution of erythema in
the NMSC group, compared with the controls. Further elucidation of the molecular
and genetic mechanisms controlling this response may improve our understanding of
UV-induced carcinogenesis.
PMID- 9542757
TI - Time course of 8-methoxypsoralen-induced skin photosensitization in PUVA-bath
photochemotherapy.
AB - In recent years PUVA-bath photochemotherapy has been shown to be an effective
treatment modality for several dermatoses. A limitation of PUVA-bath
photochemotherapy has been the lack of guidelines for optimal performance,
including the time course of photosensitization of the skin exposed to the 8
methoxypsoralen (8-MOP) bath water solution. In the present study 12 healthy
volunteers were exposed to a 20 min bath in 150 l of an 8-MOP water solution (0.5
mg/l, 37 degrees C). Immediately, as well as 1, 2, 3 and 5 h after the 8-MOP
bath, irradiation was performed with increasing doses of UVA (0.5, 1, 2, 3, 5
J/cm2) on 2 cm2 test areas. The minimal phototoxic dose (MPD) was determined 72 h
after the UVA exposure. In all volunteers, photosensitization was highest
immediately after the bath, with a MPD significantly below 5 J/cm2 (0.5-2 J/cm2).
One hour after the bath, erythema could be induced by 2 to 5 J/cm2 UVA. Two hours
after the bath, erythema could be induced using irradiation of 5 J/cm2 only in
two volunteers. Three and five hours after the 8-MOP bath, no erythema could be
induced in any volunteer by UVA doses up to 5 J/cm2. Our results indicate that
optimal bath-PUVA requires UVA irradiation immediately after the 8-MOP bath.
Further, these results imply that no restrictions on further sun exposure are
mandatory 3 h after the 8-MOP bath, thus allowing the patient to pursue normal
life activities.
PMID- 9542758
TI - The antimicrobial effect of narrow-band UVB (313 nm) and UVA1 (345-440 nm)
radiation in vitro.
AB - Two new UV lamps were investigated with respect to their antibacterial
effectiveness in vitro. Propioni (n = 20 strains) and Micrococcaceae (n = 16
strains) bacteria extracted from acne patients were applied to RCM and sheep
blood agar plates and irradiated with a narrow-band UVB lamp (TL 100W/10R) at a
wavelength of 313 nm and a UVA1 lamp (TL 01) at a wavelength of 345-440 nm. The
precisely defined energy levels were, in the case of narrow-band UVB, 0.00, 0.30,
0.50, 1.00, 2.00 and 3.00 J/cm2 and, in the case of UVA1, 0.00, 2.50, 5.00, 7.50,
10.00 and 20.00 J/cm2. UVA1 inhibited neither the growth of Propioni nor
Micrococcaceae bacteria. In contrast, the growth of Micrococcaceae was inhibited
already at a dosage of 0.30 J/cm2 of narrow-band UVB (P < 0.05), highly
significant from 0.50 J/cm2 (P < 0.01) and to a maximum of 2.2 powers of 10 at
3.00 J/cm2 compared with non-radiated control plates. Propioni bacteria were
significantly inhibited at the minimum dosage of 0.30 J/cm2 of narrow-band UVB (P
< 0.01) and to a maximum of 2.8 powers of 10 at 3.00 J/cm2.
PMID- 9542759
TI - Laboratory testing of UV transmission through fabrics may underestimate
protection.
AB - Laboratory testing of the ultraviolet protection factor (UPF) provided by fabrics
normally utilizes a collimated source of UV radiation and either a broadband
sensor or spectroradiometer to detect the radiation, both unattenuated and after
passing through the fabric sample held in a flat tensionless state. We report the
results of an in vivo study of UV transmission through various T-shirts at
several sites on the trunk and arms of a life-size mannequin irradiated with
diffuse radiation and using UV sensitive polymer films as the sensor. We found a
variation in UPF by a factor of two or more at different anatomical sites for a
given T-shirt, with lower UPFs seen at sites where the fabric is stretched; and
found that at every site and for each T-shirt this in vivo UPF was higher than
the conventional in vitro UPF determined using collimated radiation.
PMID- 9542760
TI - In vitro spontaneous and UVB-induced lymphocyte apoptosis are not specific to
SLE.
AB - We studied in vitro spontaneous and ultraviolet light (UV)-induced lymphocyte
apoptosis in patients with systemic lupus erythematosus (SLE, n = 11), cutaneous
lupus erythematosus (CLE, n = 8), and other collagen diseases (n = 6), as well as
normal individuals (n = 6). Apoptosis was confirmed by the presence of a 180 bp
DNA ladder on gel electrophoresis. UVB-induced apoptosis was observed in 4 of 11
patients with SLE (36.3%), 3 of 8 patients with CLE (37.5%) and 2 of 6 patients
(33.3%) with other collagen diseases. There was no clinical correlation between
clinical photosensitivity and UV-induced apoptosis. Similarly, spontaneous
apoptosis was also found in lymphocytes from patients with diseases other than
SLE. No apoptosis was found in normal subjects with or without UVB irradiation
(25 mJ/cm2). These data suggest that UV-induced lymphocyte apoptosis may not be
specific to SLE but may be common in collagen diseases.
PMID- 9542762
TI - A Ph.D. in clinical science for physicians: one solution to the vanishing breed
of the physician-scientist.
PMID- 9542761
TI - Relationship between skin phototype and MED in Korean, brown skin.
AB - The Fitzpatrick skin classification has been a useful method to categorize
cutaneous sensitivity to ultraviolet radiation (UVR), although it was based
originally on responses in white skin. Because the relevance of this phototype in
brown skin is in question, we investigated skin phototypes of university students
by a self-reporting questionnaire and measured their MEDs in Korean, brown skin.
After studying our explanation of the definition of Fitzpatrick skin types, 707
Korean university students answered the questionnaire. We then measured UVB MEDs
in 156 randomly selected male students. The order of frequency of skin type was
type III (55.0%), IV (29.0%), and V (12.3%) by the questionnaire, with the sun
sensitive categories (types I and II) reported only for 3.7%. There was no
significant difference in MEDs between types IV and V, and the mean MED of each
skin type did not show a monotonic increase with increasing skin type. Subjects
with MEDs of 70-90 mJ/cm2 (corresponding to the MED of skin type V, as proposed
by Pathak & Fitzpatrick) represented about half or more of the subjects in all
categories, even types II and III. Subjects with MEDs lower than 60 mJ/cm2 were
more prevalent in types II and III compared with types IV and V. We suggest that
there is at best a weak relationship between the skin types, by the Fitzpatrick
method, and MEDs in Korean, brown skin.
PMID- 9542763
TI - The need for basic science research education in the medical school curriculum.
PMID- 9542764
TI - The need for clinical research education in the medical school curriculum.
PMID- 9542765
TI - Hepatitis B and C viruses: molecular identification and targeted antiviral
therapies.
AB - Four agents are in clinical development for the treatment of chronic hepatitis B
infection. These nucleoside analogs are incorporated into the growing DNA chain
and terminate replication. Lamivudine, a cytadine analog that inhibits the
synthesis of negative strand DNA from pre-genomic RNA, predictably inhibits
replication and improves liver enzymes and histology in infected individuals.
Following cessation of treatment, relapse is common, and genetic causes of viral
resistance have been described. Other drugs for HBV infection include
famciclovir, a guanosine analog that has also shown to suppress replication in
immunocompetent as well as in immunocompromised patients; lobucavir, a guanosine
analog; and adevfovir, an adenine nucleotide analog. The future of drug therapy
against HBV likely includes combination agents with one or more
nucleoside/nucleotide analogs and immune stimulants, such as interferon, or
therapeutic vaccines. Recent advances in the treatment of HCV have been less
impressive. An effective vaccine is greatly needed yet development in the near
future is unlikely. Recommendations for therapy of chronic HCV have been proposed
following the National Institutes of Health Consensus Conference. Interferon
alpha is advised in patients with elevated serum alanine aminotransferases and
liver histology demonstrating active hepatitis, regardless of level of
pretreatment viremia or infecting genotype. Therapy should be continued for three
months, at which time response should be assessed. If a biochemical and/or
virological response has been achieved, treatment should be continued for a year.
Trials are underway to evaluate interferon in combination with ribavirin. Recent
identification of the crystalline structure of the HCV NS3 protease promises
development of effective inhibitors of this critical viral enzyme.
PMID- 9542766
TI - The genetic basis of systemic lupus erythematosus.
AB - Although cumulative evidence suggests that a genetic predisposition plays a major
role in the development of systemic lupus erythematosus (SLE), the susceptibility
genes are mostly unknown. The difficulty in identifying susceptibility genes is
due in part to the inherent nature of this polygenic complex disease and the
diverse genetic backgrounds of human populations. Murine SLE models that have
homogenous genetic backgrounds are less complex for genetic dissection. Genome
wide linkage studies of murine SLE have mapped the position of a number of
susceptibility loci. Recently, several of these major murine loci have been shown
to link to different clinical and laboratory features of lupus-like phenotypes.
In addition, evidence for additional genetic contributions via interaction
between murine loci has been reported. In human SLE, many polymorphic genes
(which have potential roles in SLE, as suggested by their known functions) have
been associated with SLE or SLE subsets by population-based case-control or
within-case studies. Because more compelling genetic evidence includes linkage
analysis, our group has used the identified murine susceptibility loci as a guide
and conducted linkage analysis of genetic markers located within a specific,
possibly syntenic human chromosomal region. Evidence for linkage of a chromosome
1q41-42 region was observed in SLE-affected sibling pairs from multiple ethnic
groups. This article summarizes recent developments and outlines possible future
directions in delineating the genetic basis of SLE.
PMID- 9542767
TI - Modulation of cytokine function by heparan sulfate proteoglycans: sophisticated
models for the regulation of cellular responses to cytokines.
AB - Cytokines are diffusible, soluble factors with pleiotropic actions. The ability
of some cytokines to blind to and be immobilized by heparan sulfate proteoglycan
(HS-PG) on either the surface of cells or within the extracellular matrix
accentuates their action by 1) promoting the accumulation of cytokines at high
concentrations in the appropriate location to encounter their target cells; 2)
activating cytokines by inducing conformational changes in the bound cytokine; 3)
promoting conformation-dependent association or polymerization of cytokines and
their cell-surface receptors and facilitating the assembly of the appropriate
molecular complex to initiate signal transduction; and 4) protecting cytokines
from both chemical and physiological degradation. Furthermore, many interactions
between HS-PG and cytokines are highly specific. Thus, variations in the HS-PG,
core protein, or carbohydrate sequences that are seen at different sites or that
occur with inflammation will determine which cytokines bind to a particular HS
PG, providing multiple options for cytokine binding and regulation. HS-PG
therefore plays a pivotal role in regulating the function of the large number of
heparin-binding cytokines. The involvement of HS-PG in promoting paracrine,
autocrine, juxtacrine, and matricrine functions provides a powerful and
sophisticated model for regulating cytokine-mediated cellular interactions. These
functions of HS-PG have direct relevance for the control of cell growth as well
as for the pathogenesis of leukocyte trafficking and inflammation, cell
infiltration, and tumor metastasis. Therapies aimed at modulating HS-PG/cytokine
binding may provide powerful tools for inhibiting unwanted cytokine effects in
several disease processes.
PMID- 9542768
TI - Dual-parameter model for prediction of type I diabetes mellitus.
AB - The recent cloning and recombinant expression of novel islet autoantigens
[glutamic acid decarboxylase (GAD) 65 and islet-cell autoantibody 512 (ICA512)]
has made possible the determination of whether the quantitative expression of
autoantibodies to these molecules is correlated with age of diabetes onset and
rate of progression to diabetes, similar to insulin autoantibodies (IAAs). We
measured autoantibodies reacting with GAD65 (GAD65AA), ICA512 (ICA512AA), and
insulin in patients who recently had received a diagnosis of diabetes and in
first-degree relatives prospectively identified and then followed because of the
expression of high titers of ICA. Levels of IAAs (but not GAD65AA or ICA512AA)
correlated inversely with age at diagnosis of diabetes and directly with time to
diabetes onset among the ICA-positive relatives. In multiple linear regression
models, the level of IAAs remained a significant predictor of the time to
diabetes after allowing for first-phase insulin secretion. The unique and
dramatic association of IAAs with progression to diabetes suggests that IAAs
contribute directly to disease pathogenesis or that levels of IAAs are influenced
uniquely by the process, leading--at different rates in different prediabetic
individuals--to type I diabetes. In addition, the linear regression model
described (involving two variables, first-phase insulin secretion and levels of
IAAs) aids in the prediction of time to diabetes among ICA-positive relatives.
PMID- 9542769
TI - Cell-specific induction of hsp72-mediated protection by glutamine against oxidant
injury in IEC18 cells.
AB - Glutamine is a major metabolic fuel and trophic agent for intestinal epithelial
cells that can enhance intestinal epithelial cell survival against oxidant and
thermal stress, possibly through the induction of heat shock protein 72 (hsp72).
In this study, we examined the possibility of a direct causal relationship and
tissue specificity of glutamine-induced hsp72. Glutamine treatment of intestinal
(epithelial) IEC18 cells, but not HeLa (epidermoid) cells, induces the production
of hsp72 in a concentration-dependent fashion, without affecting the expression
of the constitutively expressed heat shock protein, hsc73. To determine the
specific role that hsp72 induction by glutamine plays in resistance of IEC18
cells to oxidant injury, stable transfected cells expressing an hsp72 antisense
construct were established. Although thermal induction of hsp72 was blocked only
partially by the antisense construct, glutamine induction of hsp72 was completely
inhibited. This was associated with a loss of the protective effects of glutamine
against oxidant-induced stress. Thus, glutamine specifically induces hsp72 in
intestinal epithelial cells, which mediates cell protection against inflammation
induced stress such as oxidants.
PMID- 9542771
TI - Creatine supplementation does not improve physical performance in a 150 m race.
AB - Creatine supplementation has been shown by several authors to improve physical
performance in very high intensity, intermittent, exercises. The effect on
performance, as well as in plasma creatine and lactate concentrations has been
studied in a group of twelve sprinters of national class when running a distance
of 150 m on two occasions, before and after creatine (or placebo) supplementation
for the previous three days. The most important differences in the biochemical
parameters analyzed have been in plasma creatinine concentration, which increased
substantially both before and after the race in the group that had received a
daily supplement of 25 grams of creatine monohydrate for the previous three days.
Creatine supplementation, therefore, did not improve physical performance, in the
conditions, when running a 150 m distance.
PMID- 9542770
TI - An HMG-I protein from human endothelial cells apparently is secreted and impairs
activation of Hageman factor (factor XII).
AB - A highly purified protein from lysates of human umbilical vein endothelial cells
(HUVECs) inhibited the activation of factor XII [Hageman factor (HF)] and removed
factor XIIa from an activating surface, thus impairing HF-dependent coagulation
and kinin-releasing activities. Two tryptic peptides from this protein had 100%
identity with amino acids 31-44 and 89-101 of a nonhistone DNA-binding protein
known as high-mobility group protein (HMG-I). In specific antibody experiments,
the clot-inhibiting property in purified lysate protein from HUVECs was
associated with HMG-I. The molecular weight of the protein that inhibited
clotting was consistent with that predicted for HMG-I. Protein that inhibited
contact activation and had antigenic properties of HMG-I and HUVEC lysate protein
also was found in conditioned media from unchallenged cultured HUVECs. After
HUVECs were incubated with 14C lysine, conditioned media contained
immunoprecipitable radiolabeled protein with the same molecular weight as that
recovered from cell lysates, suggesting that this high-mobility group protein
(HMG-I) may be secreted. Purified factor XII antigens were displaced from a glass
surface by HMG-I from lysates in proportion to the amount of HMG-I protein that
was added. This HMG-I probably inhibits factor XII functions because its high
positive charge favors competitive binding to an activating substance.
PMID- 9542772
TI - Heterogeneous responsiveness of normolipemic women to n-3 long chain fatty acid
supplementation. Changes in serum lipids and apoproteins.
AB - The effect of 10 day-low dosage of n-3 long chain fatty acids (390 mg/day of EPA
and 252 mg/day of DHA) on lipid and apolipoprotein (Apo) concentrations has been
studied in nine normolipidaemic women aged 28.9 +/- 4.2 years. n-3 fatty acid
supplementation did not significantly decrease total cholesterol and triglyceride
levels but markedly decreased the Apo A1 and Apo B concentrations (12.7%, p <
0.01 and 23.1%, p < 0.001, respectively), while the Apo A1/Apo B ratio
significantly increased (14.8%, p < 0.02). In contrast to the individual
variations found for triglycerides and cholesterol, Apo changes indicate a fairly
homogeneous response to the fish oil supplement. In seven women Apo A1 decreased
(> 10%), whereas Apo B decreased (> 10%) in all of them. The Apo A1/Apo B ratio
increased (> 10%) in five of these nine women. Changes in Apo A-1 and Apo B did
not significantly correlate with changes in serum lipids. These findings suggest
that short-term supplementation with low amount of n-3 long chain fatty acids,
EPA and DHA, influences the serum Apo content more than the lipid levels in
normolipidaemic women.
PMID- 9542773
TI - Downmodulation of HLA class I expression by dexamethasone in MCF-7 cell line.
AB - Several reports have shown the importance of MHC class I antigens in enabling the
host to regulate tumour growth in vivo. Glucocorticoid hormones have strong
immunosuppressive effects and are known to be regulators of gene transcription.
In this report the expression of Major Histocompatibility Complex (MHC) class I
antigens in six breast carcinoma cell lines have been studied before and after
treatment with the synthetic glucocorticoid dexamethasone. Hence, HLA class I
expression in the MCF-7 cell line was down-regulated in the presence of
dexamethasone. This down-modulation of expression appeared to be mediated by
transcriptional mechanisms, as revealed by HLA-class I mRNA levels.
PMID- 9542774
TI - c-fos expression in the rat hypothalamic paraventricular nucleus induced by LiCl:
descending projections to the dorsal vagal motor nucleus.
AB - Anorexia inducing lithium chloride is believed to involve descending projections
from hypothalamus to preganglionic autonomic output neurons. A multiple-labelling
technique has presently been used to analyze the anatomical projections of
lithium chloride sensitive neurons in the hypothalamus. Immunolabelling of c-fos
was performed to stain neurons activated after LiCl administration, while neurons
projecting toward vagal parasympathetic preganglionic levels were identified by
injection of diamidino yellow in the dorsal motor nucleus of the vagus. Perikarya
of descending neurons were mainly observed in the ventral and lateral areas of
the paraventricular hypothalamic nucleus. In contrast, lithium chloride activated
neurons were observed mainly in the magnocellular division of the paraventricular
nucleus and supraoptic nucleus. Double-labelled neurons were not observed. These
data provide evidence that lithium chloride sensitive neurons in the
paraventricular nucleus are clearly different from those descending toward
preganglionic vagal outflow neurons.
PMID- 9542775
TI - Effects of 3-hydroxybutyrate on the hypoxic and reoxygenated atria from fed and
fasted rats.
AB - When exposed to hypoxia, the isolated atria from fed rats released lactate into
the medium and underwent a decline of the peak developed tension and pacemaker
frequency. The atria from 24-h fasted rats showed a rise in the resting tension
together with a greater decline of the pacemaker rate and a lower lactate output
than those from fed rats. The exposure to 5 mM 3-hydroxybutyrate caused only a
small and brief decline in the pacemaker rate in the fed rats atria indicating
that ketone bodies are able to exert only a minor detrimental effect on the
hypoxic atria. Since the lactate output remained unaffected, this effect cannot
be ascribed to a lowering in the energy supply from anaerobic glycolysis. On the
contrary, 3-hydroxybutyrate improved the post-hypoxic recovery of the peak
tension in the atria from fasted rats. This finding may be reflecting an
anaplerotic role of 3-hydroxybutyrate, thus suggesting that in addition to
glucose a second substrate is needed to meet the energy demand in the
reoxygenated atria from fasted rats.
PMID- 9542776
TI - Rate of muscle protein synthesis in rats fed raw and extruded pea diets.
PMID- 9542777
TI - Anti-collagenolytic mechanism of action of doxycycline treatment in rheumatoid
arthritis.
AB - Tetracyclines exert, independently of their antimicrobial activity, anti
collagenolytic effects by inhibiting activities of human interstitial
collagenases and by preventing the oxidative activation of latent pro
collagenases. We tested the clinical response to a 3-month doxycycline in concert
with collagenase activity in 12 rheumatoid arthritis (RA) patients. Patients
received 150 mg/day of doxycycline for 3 months. Clinical assessments at zero,
six and 12 weeks comprised classification of the functional class, joint score
index, Hb, CRP, ESR, health assessment questionnaire, visual analogue scale (VAS)
of pain, pain disability index, comprehensible psychopathological rating scale
(CPRS), SDS-PAGE laser densitometric collagenase activity measurements and
Western blots. Significant reductions were seen in joint score index (P < 0.01),
pain VAS (P < 0.05) and some CPRS parameters. Furthermore, collagenase activities
measured from saliva by quantitative SDS-PAGE electrophoresis were significantly
reduced during the 12-week intervention (P < 0.01). Western blots demonstrated
intact 75-80 kDa enzyme protein (classic neutrophil collagenase), but also a
newly discovered mesenchymal, less glycosylated 40-55 kDa MMP-8 subtype of
fibroblast/chondrocytic origin. These results indicate that the documented
favourable clinical response may in part be due to in vivo inhibition of classic
neutrophil and mesenchymal collagenase/MMP-8 activities produced by doxycycline.
This anti-collagenolytic doxycycline effects is mediated through inhibition of
the enzyme activity and not through degradation of the enzyme, which may have
contributed to the reportedly reduced tissue destruction, as has been seen in
clinical studies concerning RA as well as reactive arthritis.
PMID- 9542778
TI - Ankylosing spondylitis and infections of the female urogenital tract.
AB - Thirty-two female patients with confirmed ankylosing spondylitis (AS) and 33
women of similar age with pure ileitis terminalis Crohn were examined for
genitourinary infection. Urethral syndrome was found in 15 out of 32 patients
with AS: 11 of them had urethritis and 4 urethritis associated with vaginitis.
Five women of the control group suffered from urethritis. In all cases with
genitourinary infection, Chlamydia trachomatis was isolated. By comparing the AS
patients (urogenital infection group and the non-infected group) with regard to
other present clinical parameters, it was found, as expected, that the
erythrocyte sedimentation rate in the 1st hour was significantly higher in the
infected group. In addition, the infected patients had a significantly higher
incidence of enthesopathy, involvement of the spinal column, and higher C
reactive protein values (CRP > or = 5 mg/l). A family history of AS was equally
present. Other clinical parameters, such as inflammatory involvement of the
joints and HLA-B27 correlation, did not differ significantly between infected and
non-infected patients.
PMID- 9542779
TI - TNF-alpha induces the transcription factor Egr-1, pro-inflammatory cytokines and
cell proliferation in human skin fibroblasts and synovial lining cells.
AB - In rheumatoid arthritis (RA) cell proliferation and altered metalloproteinase
expression of synovial lining cells are associated with increased levels of TNF
alpha in the rheumatoid joint. We previously showed that synoviocytes of RA
patients express high levels of the transcription factor Egr-1. Here we report
that TNF-alpha is capable of inducing high Egr-1 mRNA levels in human skin
fibroblasts and in synoviocytes from both, RA and reactive arthritis patients.
Moreover, we observed in vitro a marked increase in fibroblast proliferation, a
loss of growth inhibition by cell-to-cell contact with pannus-like cell growth
and an altered cytokine expression pattern when synoviocytes were cultured in
presence of TNF-alpha.
PMID- 9542780
TI - The demographic and clinical spectrum of Arab versus Asian patients with
ankylosing spondylitis in the UAE.
AB - Ankylosing spondylitis is a rather uncommon condition in the UAE. Over a period
of 10 years. 28 hospital-based patients diagnosed as having AS were
retrospectively studied. They included 17 Arabs and 11 Asians. The onset of AS in
most patients in this study was in adulthood (mean age at onset was 27.7 years in
Arabs and 28.75 years in Asians). HLA B27 was positive in 56 and 81% in these two
populations, respectively (P > 0.05). Analysis of these figures, however, along
with previous relevant published data, could indicate that Arabs with AS are less
likely to be B27-positive than Asians. Among the Arab patients there was not a
single case from the local community, which could be attributed to the extremely
low rate of B27 phenotype in their normal population. The interracial variations
in the frequency of clinical features were statistically insignificant, therefore
indicating some degree of similarity in the form and disease expression in both
groups. AS is characterized as being predominantly axial in the majority of our
patients. Extraspinal (oligo-poly) arthropathy involved mainly hips and knees,
and there have been fewer extra-articular manifestations compared with other
series published.
PMID- 9542781
TI - Pharmacokinetic effects of conversion to a new formulation of cyclosporin A in
rheumatoid arthritis patients.
AB - In this study we aimed at evaluating the modifications in the pharmacokinetic
profile of cyclosporin A (CyA) after conversion from standard formulation (CyA
ST) to a new formulation (CyA-NF, Sandimmun Neoral) in patients with rheumatoid
arthritis (RA). It was an open, crossover study that involved 15 RA patients who
were on stabilized treatment with CyA-ST. The patient continued receiving CyA-ST
(mean dose of 3.0 +/- 0.7 mg/kg per day) for 3 weeks and then converted 1:1 to
CyA-NF for a further 3 weeks. CyA pharmacokinetics were established on day 1 (CyA
ST evaluation) and +21 (CyA-NF evaluation). The results showed that the
bioavailability of CyA-NF was greater than that of CyA-ST (AUC tau, bss: 3335 +/-
1300 vs 2667 +/- 1155 ng.h/ml, P = 0.0073; AUC tau, bss ratio 1.26 +/- 0.40 vs
1.0 as reference, P < 0.05), with higher and earlier peak blood concentrations
(Cmax: 677 +/- 256 vs 475 +/- 213 ng/ml, P = 0.0329; tmax: 1.5 +/- 0.7 vs 2.6 +/-
1.6 h, P = 0.0720). The pharmacokinetic profile of CyA-NF showed greater between
patient reproducibility (lower CV% for all of the considered parameters). In
conclusion, when using CyA-NF instead of CyA-ST, greater and more constant
exposure to CyA should be expected.
PMID- 9542782
TI - Antibiotic sensitivity and proticine typing of Proteus mirabilis strains
associated with rheumatoid arthritis.
AB - Urinary isolates of Proteus mirabilis, obtained from 49 RA patients and 44
healthy controls, were tested for susceptibility to antibiotics by the disc
diffusion method. In addition, P. mirabilis isolates were also tested for
proticine production and sensitivity (p/s) typing by the inhibition of growth of
each test isolate against 13 reference strains of P. mirabilis. The P. mirabilis
isolates from both RA patients and healthy controls were highly susceptible to
norfloxacin, ciprofloxacin and trimethoprim, but less to minocycline. The urine
of RA patients contained fewer different types of P. mirabilis strains than those
isolated from healthy controls. All of the strains found in the RA patients were
proticine producers (P < 0.001), mostly of proticine 3 (P < 0.005). The presence
of such strains provides evidence of a sub-clinical upper urinary tract infection
with P. mirabilis in some RA patients. Therapeutic intervention in RA with
relevant antibiotics requires evaluation.
PMID- 9542783
TI - Diagnosis of idiopathic myositis: value of 99mtechnetium pyrophosphate muscle
scintigraphy and magnetic resonance imaging in targeted muscle biopsy.
AB - Our objective was to study the value of 99mtechnetium-pyrophosphate (99mTc-PYP)
muscle scintigraphy and magnetic resonance imaging (MRI) in detecting areas of
likely muscle inflammation and in increasing the rate of positive muscle biopsies
in patients with suspected myositis. The results showed that in 13 out of 13
patients with clinical and/or signs of inflammatory muscle disease, increased
99mTc-PYP uptake was demonstrated at different muscle sites 3 h after isotope
injection. Subsequent MRI of symmetric muscle areas with enhanced 99mTc-PYP
uptake revealed signal patterns suggesting inflammation in all cases. Biopsy of
these targeted muscles demonstrated characteristic histopathologic signs of
muscle inflammation in 9 out of 13 patients. Four of these 9 patients had
clinically atypical disease or did not show elevated creatine phosphokinase
levels. Seven of these 9 patients had not been pretreated with corticosteroids.
In 4 patients only muscle fiber atrophy and/or necrosis without cellular
infiltrations was seen. These 4 patients had received either high doses of
corticosteroids or low doses over longer periods of time before muscle biopsy. In
conclusion, the combination of 99mTc-PYP muscle scintigraphy and MRI demonstrated
muscle areas with maximum inflammatory signal patterns. Targeting of muscles by
MRI only will probably yield reliable results of muscle biopsy in cases of
clinically and serologically characteristic myositis. 99mTc-PYP muscle
scintigraphy may provide useful initial information about localization of
inflamed muscle tissue, especially in atypical disease. Treatment with
corticosteroids prior to histologic diagnosis may abolish inflammatory
infiltrations in affected muscle tissue.
PMID- 9542784
TI - The New York High-Risk Project: attention, anhedonia and social outcome.
AB - In the New York High-Risk Project we have followed two samples of subjects
(Sample A and Sample B) at risk for schizophrenic or affective disorders and low
risk controls from childhood to adulthood, in an attempt to identify early
predictors of later psychopathology. We administered a large number of cognitive,
psychometric and other types of measures to both samples as possible
psychopathology predictors, including an index of attentional deviance assessed
in childhood, the Physical Anhedonia Scale in adolescence, and three measures of
social outcome in adulthood ('Suspicious Solitude', 'Social Insecurity', and
'Lack of Empathy'), derived from the Personality Disorders Examination. In the
analysis of the combined samples, parental diagnostic group, gender, attentional
deviance in childhood, and physical anhedonia in adolescence were used to predict
three measures of social outcome in adulthood. While only physical anhedonia was
directly related to all three social outcome measures, with the strongest
relationship to Suspicious Solitude, attention deviance successfully predicted
two of the three outcomes. Subjects at risk for affective disorder did not show
increased levels of attention deviance, physical anhedonia, or social
dysfunction, relative to the normal control subjects. Attention deviance appears
to be a key neurobiological indicator and physical anhedonia appears to be a
potentiating factor mediating the relationship between risk for schizophrenia and
later social dysfunction.
PMID- 9542785
TI - The state of functioning of working memory in schizophrenia.
AB - The functioning of working memory in schizophrenic patients according to
Baddeley's model was examined in two complementary experiments. Experiment 1
comprised 27 patients and their controls, matched in age and level of education.
Of this pool, 20 pairs participated also in Experiment 2. Digit span, reading
rate, and immediate serial recall assessed the functioning of the phonological
loop. Corsi and pattern span tasks assessed the capacity of visuo-spatial memory.
The central executive's ability to monitor two concurrent tasks was evaluated in
a dual task paradigm, and its capacity to control action in a random generation
task. A preliminary set of analyses showed that the patients' performances were
reduced in all tasks explored, except in digit span. This initial pattern changed
consistently after controlling for reading rate. While slow and fast reading
patients were comparable in demographic and clinical criteria, slow reading
patients showed impaired performance in all tasks, whereas fast reading patients
exhibited reduced performance in visuo-spatial tasks and in the random generation
task only. The state of functioning of working memory in schizophrenia appears,
therefore, to vary consistently among the components of the model and is markedly
impaired in slow reading patients. The implications of slowness are discussed.
PMID- 9542786
TI - Memory impairment and schizophrenia: the role of processing speed.
AB - A link between slowing of processing speed and cognitive disorders, including
memory, has repeatedly been found in research on aging, and suggested in other
cognitively impaired populations. We tested the hypothesis that a link between
memory impairment and slowing of processing speed would also be observed in
schizophrenia. Forty-four schizophrenic patients and 40 normal controls were
administered a memory task involving free recall and recognition. Processing
speed was assessed by the Digit Symbol Substitution Test. Working memory span was
assessed as well. The measure of processing speed was consistently correlated
with the various memory measures in patients, including efficiency of encoding.
These correlations remained significant, or tended to be significant, when
working memory span was partialled out. Memory deficits observed in schizophrenia
may thus be partly accounted for by a slowing of processing speed. It is
suggested that research on cognitive deficits in this and other mental diseases
focus more on processing speed.
PMID- 9542787
TI - Cognitive processing efficiency in schizophrenia: generalized vs domain specific
deficits.
AB - The issue of generalized vs specific cognitive deficits in schizophrenia was
explored by examining reaction time data from 40 published studies with 196
reaction time conditions. Using a regression-based approach, the proportional
relationship between the response times of groups with schizophrenia was compared
with those of age-matched, healthy comparison groups. Through this method, the
extent to which deficits in processing efficiency are explained by a single
factor, general processing speed, was compared with possible domain specific or
task specific deficits. The results suggest that, overall, the data conforms well
to a general linear slowing model which accounts for 87% of the variance in
reaction time performance. Some additional variance, however, is accounted for by
different degrees of linear slowing for three types of tasks: tasks involving
selective attention/inhibition showed the most slowing (2.3-times slower for
schizophrenia), followed by lexical tasks (1.8-times slower for schizophrenia),
and finally, non-lexical tasks showed the least slowing (1.4-times slower for
schizophrenia). This pattern is distinct from other groups showing generalized
slowing, such as older adults, and suggests a unique pattern of information
processing deficits in schizophrenia.
PMID- 9542788
TI - Delusional disorder and eye tracking dysfunction: preliminary evidence of
biological and clinical heterogeneity.
AB - This study used eye tracking movement tests to examine the relationships between
frontal field functions and clinical features. Smooth pursuit and voluntary
saccadic eye movements were recorded and analyzed in 34 delusional disorder (DD)
patients and in 40 normal subjects. The DD group differed significantly from the
group of normal subjects in some eye tracking performances. As reported in our
previous study (Gambini et al., 1993), DD patients showed abnormalities of
voluntary saccadic eye movements. In this study, we also found abnormal smooth
pursuit eye movements, indicating a cerebral dysfunction similar to those
detected in schizophrenic patients. Moreover, normal smooth pursuit eye movement
performance in DD patients was related to remitted depressive mood and probably
to benefit from antipsychotic medications, thus supporting the idea of the
biological and clinical heterogeneity of DD.
PMID- 9542789
TI - Familial transmission of two independent saccadic abnormalities in schizophrenia.
AB - Difficulties with inhibiting inappropriate responses, i.e. disinhibition, and
problems with spatial memory are both presumed to be a part of the phenotypic
expression of the genetic risk for schizophrenia. Schizophrenic probands are
impaired on saccadic eye movement tasks which require (a) response inhibition to
prepotent stimuli and (b) generation of an accurate response to a remembered or
calculated spatial location, but it is unknown how these deficits are inherited.
Sixteen schizophrenic probands, their 32 parents, and two normal control groups
completed a delayed oculomotor response and an antisaccade task. The parents with
a positive ancestral family history for chronic psychosis (n = 8) were presumed
to be more likely than their family history-negative spouses to be genetic
carriers for schizophrenia. Probands and their positive family history parents
had more failures of response inhibition than did normal control groups. However,
it was the probands and their negative family history spouses who demonstrated
impaired accuracy of the remembered- or antisaccades. Disinhibition may be
closely tied to a specific genetic risk for schizophrenia. However, a second
familial factor related to the maintenance or manipulation of spatial information
may also contribute to the genetic risk of the full clinical disorder.
PMID- 9542790
TI - Multiple site evaluation of P50 suppression among schizophrenia and normal
comparison subjects.
AB - Normally, when two brief, non-startling auditory stimuli are presented 500 ms
apart, with long (e.g., 10 s) interpair intervals, the positive potential
occurring approx. 50 ms after the first stimulus (P50) is relatively large, and
the P50 to the second stimulus is smaller. In schizophrenia patients, however,
the P50 to the second stimulus is larger than normal. In this study, 36
schizophrenia and 36 normal comparison subjects were tested in a two-click
paradigm. Data were recorded from six electrode locations (F3, Fz, F4, C3, Cz,
C4). The results support the hypothesis that schizophrenia patients have poor P50
suppression that is not an artifact of differential P50 wave morphology or
differences in the number of usable trials between groups. In addition, the
vertex location alone (Cz) was equal to, if not better than, any combination of
sites for differentiating between groups. These results support the use of the Cz
site alone in most investigations of P50 suppression deficits among schizophrenia
spectrum patients. Further work investigating the neuropathological correlates of
poor P50 suppression among schizophrenia patients by recording from multiple
electrode locations, however, could be helpful.
PMID- 9542791
TI - MRI correlates of treatment response in first episode psychosis.
AB - It is not known whether the magnitude of the structural brain abnormalities that
underlie schizophrenia is a determinant of the extent to which patients respond
to antipsychotic medication. This study was undertaken in order to explore this
relationship. Twenty-six patients receiving treatment for a first episode of
psychosis were involved in both a study measuring treatment response and a
magnetic resonance imaging (MRI) study. In the treatment study, haloperidol dose
was increased weekly beginning at 2 mg/day until patients showed evidence of a
response or extrapyramidal symptoms. MRI scans were analyzed using a computerized
volumetric approach to yield estimates of cerebrospinal fluid (CSF), gray-matter
and white-matter volumes. Improvement in positive and negative symptoms after 1
week of treatment was significantly correlated with cortical gray-matter volumes.
Those patients who were maintained on 2 mg/day of haloperidol had greater
cortical gray-matter volume than those who were treated with higher doses. The
severity of structural brain abnormalities at the onset of psychosis may
contribute to individual variation in response to antipsychotic medication. It
remains to be determined whether the degree to which particular domains of
symptomatology can improve is related to the severity of structural brain
pathology in specific brain regions.
PMID- 9542792
TI - Prolactin response to D-fenfluramine challenge test as a predictor of treatment
response to haloperidol in acute schizophrenia.
AB - D-fenfluramine has been identified as a highly selective serotonin (5-HT)
releaser and re-uptake inhibitor. The objective of our study was to investigate
prolactin response to D-fenfluramine challenge in non-medicated, first episode
schizophrenics. We hypothesized that 5-HT reactivity can predict a response to
the neuroleptic treatment. Twenty-three inpatients, 11 males and 12 females, at
the Prague Psychiatric Center participated in the study. Inclusion criteria were:
ICD-10 diagnosis of schizophrenia, first episode or duration of illness shorter
than 36 months. D-fenfluramine challenge test was performed before 4 weeks of the
haloperidol treatment. During the test, prolactin plasma levels were measured.
The Brief Psychiatric Rating Scale (BPRS) was administered before and after the
treatment. A statistically significant negative correlation was found between
prolactin response to the D-fenfluramine challenge and improvement of
psychopathology measured by the change in total BPRS score (p = 0.0004), in
positive (p = 0.0403), negative (p = 0.0267), and anxiety-depression symptoms of
BPRS (p = 0.0014). Our data support the original hypothesis that there is a
relationship between 5-HT system activity and treatment response. The higher
responsiveness of the 5-HT system in first episode, non-medicated schizophrenics,
was associated with a poorer treatment response to haloperidol, an
antidopaminergic neuroleptic.
PMID- 9542793
TI - Prenatal exposure to influenza and schizophrenia in Surinamese and Dutch
Antillean immigrants to The Netherlands.
AB - There is evidence of an increased incidence of schizophrenia in Afro-Caribbean
immigrants to the UK and in Surinamese- and Dutch Antillean immigrants to The
Netherlands. We tested the hypothesis that second-trimester exposure to the 1957
A2 influenza pandemic, which swept through the Caribbean in the same period as it
affected Western Europe, contributes to this phenomenon. The dates of birth of
immigrants, discharged from a Dutch psychiatric institute with a diagnosis of
schizophrenia, were examined for any effect of the pandemic. Individuals who were
in their second-trimester of fetal life at the peak of the pandemic were at no
greater risk of developing schizophrenia than controls.
PMID- 9542794
TI - A case of treatment-refractory psychosis responsive to sertindole.
AB - Sertindole is an antipsychotic with atypical in vitro and ex vivo binding
profiles and little propensity to cause extrapyramidal symptoms. However, its
potential usefulness in the treatment of psychosis resistant to the 'classical'
neuroleptics has not been determined. In the present study we used a double
blind, placebo-controlled trial of sertindole and observed dramatic, sustained
resolution of formerly-chronic positive and negative psychotic symptoms in a
schizophrenic patient. This patient had averaged 2.5 inpatient admissions per
year for the 8 years preceding initiation of sertindole therapy, but has had no
hospitalizations or psychosis in the 3.5 years since. Improved cognitive function
has also been documented. This preliminary, but controlled, experience suggests
that sertindole may possess a spectrum of clinical activity distinct from that of
the typical antipsychotic agent.
PMID- 9542795
TI - Literary descriptions of the restless legs syndrome.
PMID- 9542796
TI - Serotonin 5-HT3-receptor antagonist GR 38032F suppresses sleep apneas in rats.
AB - The effects of administration of GR38032F, a 5-HT3 receptor antagonist, on
spontaneous sleep apneas were studied in adult Sprague-Dawley rats by monitoring
sleep, respiration and blood pressure for 6 hours. Intraperitoneal injection of
GR38032F (1 mg/kg) suppressed spontaneous central apneas during non-rapid-eye
movement (NREM) and especially during rapid-eye-movement (REM) sleep. This effect
was associated with increased respiratory drive but did not cause cardiovascular
changes at the dose tested. The suppressive action of GR38032F on spontaneous
sleep apneas is analogous to findings in anesthetized rats in which 5-HT and 2
methyl-5-HT provoked central apneas that were antagonized by GR38032 (Yoshioka et
al, JPET 1992; 260:917-924). Our data implicate 5-HT3 receptor systems in
determining sleep-related respiratory drive and apnea expression in rats, effects
which are most probably mediated by vagal afferents.
PMID- 9542797
TI - The effects of sensory stimulation on REM sleep duration.
AB - Previous experiments have demonstrated that auditory (AS) and/or somatosensory
(SS) stimulation can increase the duration of REM sleep periods in rats, cats and
humans. The objectives of this study were to determine whether repeated AS
stimulation causes habituation to the stimulus and whether any additive effects
could be obtained with the simultaneous application of AS and SS. Three
experimental procedures were used in this study. In experiment 1, animals were
recorded for 4 consecutive days with AS, followed by a post-stimulus session. In
experiment 2, they were recorded for 24 hours with AS applied at each REM period,
followed by a subsequent 24-hours-post-stimulus recording. In experiment 3,
animals underwent AS, SS stimulation, or simultaneous application of both in a
random fashion at each REM period. The results of all experiments confirm
previous findings showing that auditory or somatosensory stimuli significantly
increase REM sleep period duration. In addition, AS--applied with different
presentations during REM and throughout the sleep-wake cycle--are capable of
increasing REM duration regardless of the manner in which they were presented.
However, the effects of the stimuli were not additive. It is worth noting that
although REM duration increased, REM period frequency decreased, resulting in no
net change of total REM sleep through time. Furthermore, no changes were observed
in other sleep-wake variables. These experiments clearly demonstrate that
repeated auditory stimulation does not cause habituation, and there are no
evident side effects on the sleep-wake cycle. These results confirm that the
mechanisms involved in REM generation and maintenance can be modulated by sensory
modalities.
PMID- 9542798
TI - Developmental alterations in auditory arousal from sleep in healthy and virus
infected cats.
AB - To investigate the impact of respiratory-tract infections on arousability from
sleep, we evaluated the auditory arousal responses of healthy and virus-infected
cats in two age groups. Arousability was positively associated with stimulus
intensity but negatively associated with experimental day. Infected animals were
more responsive to auditory stimuli than were uninfected ones, and younger cats
were less responsive than older animals. Within the younger groups, infected cats
demonstrated increased arousability across the entire range of stimulus volumes
during quiet sleep but not during active sleep. Young infected cats also
demonstrated lower EEG delta-wave amplitudes than did uninfected animals. These
effects on arousability and EEG amplitudes were not observed in older cats. Thus,
under the conditions studied, cats with mild viral infections show an age-related
enhancement of auditory arousability from sleep, suggesting that they sleep less
deeply than do healthy, age-matched animals. The generalization of these
observations to other arousing stimuli, such as hypoxia or hypercapnia, and
possible implications for the pathogenesis of sudden infant death syndrome remain
to be determined.
PMID- 9542799
TI - Medium-intensity light produces circadian rhythm adaptation to simulated night
shift work.
AB - STUDY OBJECTIVES: To assess the effect of nocturnal light intensity on circadian
adaptation to simulated night work. SETTING AND PARTICIPANTS: Normal young men
and women, simulated night work, home sleep. DESIGN AND MEASUREMENTS: We compared
temperature rhythm phase shifts following timed exposure to high (approximately
5700 lux 3 hours/day), medium (approximately 1230 lux 3 hours/day) or constant
low-intensity (< 250 lux) light during consecutive night shifts. Subjects (n =
35) followed a schedule of 7 days baseline, 6 days of 8-hour night shifts (with
day sleep delayed 10 hours from baseline sleep), and 4 days of recovery. Subjects
wore dark sunglasses while outdoors during daylight. Sleep logs were completed
after each 8-hour sleep/dark period. Night work fatigue was rated by
questionnaire. RESULTS: During the 3rd through 5th days of night work, most
subjects in the high and medium groups (100% and 85%) exhibited phase delays
large enough that their body temperature minima occurred within the daytime
sleep/dark period. Only 42% of subjects in the low group exhibited phase delays
large enough to meet this criterion of circadian adaptation. The phase shifts of
the high and medium groups were not significantly different, and were
significantly different from the low group. Larger phase shifts were correlated
with more sleep and less fatigue. CONCLUSIONS: Extremely "bright" light may not
be necessary for circadian adaptation in shift work situations similar to our
study protocol (e.g., regular daytime sleep/dark periods, sunglasses).
PMID- 9542800
TI - Diurnal rhythm of fetal behavioral state.
AB - To test for the presence in utero of diurnal periodicity in the amount of time
spent in organized behavioral states, seven records of 24-hour duration were
obtained from each of five chronically instrumented fetal baboons between 144 and
158 days gestation (term = 175 days). Concordance of fetal breathing activity,
heart-period variability, and electroencephalographic parameters were used to
define two distinctive patterns of fetal physiological activities. One pattern
was characterized as EEG activity dominated by trace alternant, reduced heart
period variability, and fewer breaths in epochs of fetal breathing. This fetal
behavioral state (1FB) is analogous to quiet sleep in infants. A second pattern
was characterized by the relative absence of trace alternant, increased heart
period variability, and fetal breathing activity. This fetal behavioral state
(2FB) is analogous to active sleep. Cycles of these states were present 29% of
time, with a duration of approximately 26 minutes and a 1.7:1 predominance of
2FB/1FB. Cosinor analysis across fetuses revealed a significant (p < .01) 24-hour
periodicity of the time spent by the fetus in organized behavioral states, with a
peak around 1400 (lights-on 0700 to 1900) and a peak-nadir fluctuation of 15%.
These periodicities in the incidence of organized state were significant (p <
.01) in three fetuses, and approached significance (< .09) in the two others.
Data demonstrate a diurnal rhythmicity in fetal behavioral states, with less time
spent in organized state at night than during the day.
PMID- 9542801
TI - Epidemiology of alcohol and medication as aids to sleep in early adulthood.
AB - STUDY OBJECTIVES: In a representative sample of adults 18-45 years of age, this
study addressed three questions about the use of sleep aids in the general
population: (1) what are the past-year prevalences of the use of alcohol, over
the-counter medication and prescription medication to facilitate sleep? (2) among
those who use these substances for sleep problems, what are the patterns of use?
and (3) are there social factors, independent of sleep characteristics, that
increase the likelihood of alcohol and medication use to aid sleep? DESIGN: The
1996 Detroit Area Survey was a random-digit-dial, computer-assisted survey of a
representative sample of 2,181 adults ages 18-45 in the Detroit primary
metropolitan statistical area. Eligible household response rate was 86.8%.
RESULTS: In the general population, use of alcohol and medication as sleep aids
in the past year was found to be fairly common: 13% used alcohol, 18% used
medications and 5% used both. The prevalence of any substance use to aid sleep
was 26%. The duration of use was short for the majority of users, less than 1
week. However, duration of use was greater for the majority of those using
prescription sleep aids. A substantial minority of users report regular use
lasting longer than 1 month: 15%, 9%, and 36% for alcohol, OTC medications, and
prescription medications, respectively. Both sociodemographic and sleep
characteristics were associated with alcohol and medication use to aid sleep.
Difficulty falling asleep was the factor most strongly associated with use of
substances to improve sleep. Sex, race/ethnicity, work shift, marital status and
education were also significantly associated with one or more types of sleep aid
use adjusting for difficulty falling asleep.
PMID- 9542802
TI - Evaluation of a computerized polysomnographic system.
AB - Computerized polysomnographic systems have came into common use in sleep
laboratories around the world. Despite potential advantages over standard paper
polysomnography, these computerized systems have been minimally evaluated as to
accuracy, analysis time, or cost effectiveness when compared to paper. We
evaluated the Healthdyne ALICE 3 system for comparability to paper
polysomnography in sleep quantification and technician analysis time. Fifty
patients were recorded simultaneously both on paper and on the ALICE 3 system and
analyzed blindly with summary data from these records being quantified and
compared. Five additional patients were studied for epoch-by-epoch analysis.
Score-rescore assessments were accomplished for both groups. The results indicate
that when allowed to autoscore, this computerized system produced substantial
errors in sleep staging (REM sleep time 56.4 + 4.9 minutes vs 73.2 + 8.4 minutes
for paper versus computer). This was the case for respiratory (AHI of 26.5 + 4.3
vs 15.3 + 2.6 for paper vs computer) and arousal assessment as well. However,
with editing, similar results to those obtained with paper were achieved (REM
sleep time -56.4 + 4.9 vs 59.0 + 4.6; AHI -26.5 + 4.3 vs 26.1 + 4.7 for paper and
computer respectively), with differences rarely exceeding score-rescore
discrepancies. Analysis time was substantially reduced by use of the computer
(172.6 + 9.9 vs 79.7 + 4.8 minutes for paper vs computer). Epoch-by-epoch
analysis revealed a trend to score toward wakefulness or lighter sleep on
computer compared to paper although the differences were small. Respiratory,
arousal and PLM scoring were quite similar. In conclusion, this study suggests
that the ALICE 3 system with editing can produce results similar to those
obtained with paper.
PMID- 9542803
TI - Evaluation of the Healthdyne NightWatch system to titrate CPAP in the home.
AB - Although a number of devices have been developed to monitor sleep and breathing
in the home, there are few publications on methodologies by which CPAP can be
titrated in the home setting. This study was conducted to determine the outcome
of CPAP titration in the home using the Healthdyne NightWatch (NW) system. This
home sleep-evaluation system was used to diagnose sleep apnea in 30 patients
using a previously described methodology. These patients subsequently underwent
CPAP titration in the home using the NW system, with modem technology allowing
the transfer of data from the home to the laboratory. This group was compared
with 30 patients who were diagnosed with sleep apnea using standard in-lab
polysomnography and had CPAP titrated on a full night in the laboratory. Both
groups were subsequently placed on CPAP at the appropriate pressure for 6-8
weeks, after which a full in-lab study was completed to assess CPAP efficacy at
the prescribed pressure. Compliance was also determined using a pressure
activated monitor. No differences in any variable assessed could be found between
the two groups. Mean compliance was 4.6 + 0.5 (SEM) and 4.3 + 0.5 hours of CPAP
use per night for the home and in-lab groups respectively. Mean AHIs on the
follow-up study were 7.4 + 1.2 and 7.6 + 1.6 events per hour for the home versus
in-lab groups. Sleep stage distribution was also quite comparable between groups.
As a result, this study suggests that sleep apnea can be diagnosed and CPAP
titrated in the home with a similar outcome, at least at 6 to 8 weeks, to
standard in-laboratory testing.
PMID- 9542804
TI - Direct comparison of two widely used activity recorders.
AB - Wrist actigraphy is increasingly used to track circadian rest-activity cycles and
to identify states of wakefulness and sleep, yet the measurement characteristics
of activity recorders have never been compared. Two widely used recorders are
compared here: the MotionLogger from Ambulatory Monitoring, Inc (AM) and the
Gaehwiler (G). They were worn together on the same wrist for periods averaging
41.5 hours by five members of a research team. Activity counts were stored every
half-minute. Pairwise comparisons between recorders of each type showed both
types to be reliable. Each also validly detected circadian rest/activity cycles.
Both types suffered, however, from insensitivity. For the lower 75% of activity
levels, the variance of data from the G was indeed so small as to be essentially
uninformative. Since these levels include over 95% of all nocturnal data, the G
must be less sensitive than the AM to small nocturnal movements, including those
signifying arousal. An additional difference is that data from the AM but not the
G were distributed in biphasic fashion. Biphasic activity levels are consistent
with the common assumption that activity/wakefulness and rest/sleep are distinct
neurobehavioral states. As the use of actigraphy increases, the important
differences found here between two leading instruments point to an urgent need
for standards by which activity recorders can be compared. Aspects of instrument
design that could be quantitatively rated are reliability, validity, ruggedness
and artifact rejection.
PMID- 9542805
TI - Bibliography of recent literature in sleep research.
PMID- 9542806
TI - [Activities of the enzymes LDH, gamma-GT, GOT, GPT and lactoperoxidase in the
milk of breeding mares during the course of lactation].
AB - Milk samples were collected from 44 mares (trotters, warm blood horses, quarter
horses) during lactation between the 1st and 90th day p.p. at 20 defined days.
The activity of the enzymes LDH, gamma-GT, GOT, GPT and lactoperoxidase was
investigated. The aim of this study was to find out the changes of these
parameters during lactation and whether an influence of race, conception, date of
foaling, age and number of lactations existed on the enzyme activities in mare's
milk. The following results were obtained: In mare's milk the LDH-activity was
highest (xg = 629 x 1.5 +/- 1 U/l) on the 1st day p.p. and showed a marked
decrease on the 3rd day p.p. followed by a slight decrease until the 20th day
p.p. It remained then at a constant level of about 80 U/l. The lowest activity
(xg = 65.2 x 1.51 +/- 1 U/l) was measured on the 76th day p.p. The influence of
conception and date of foaling time were statistically significant. The gamma-GT
activity was highest on the 3rd day p.p. (xg = 143.4 x 1.45 +/- 1 U/L) and
decreased during lactation. The lowest activity was measured on the 90th day p.p.
(xg = 23.2 x 1.51 +/- 1 U/L). The influence of race and conception--time were
statistically significant. The GOT-activity of the 1st day p.p. (xg = 38.3 x 1.77
+/- 1 U/L) was higher than in mature milk. After the 3rd day p.p. activities
between 15.5 x 1.38 +/- 1 U/l and 11.9 x 1.38 +/- 1 U/L were measured. The GPT
activity was highest on the 1st day p.p. (xg = 37.5 x 1.81 +/- 1 U/L) and
decreased on the following days. After the 9th day p.p. activities between 9.1 x
1.37 +/- 1 U/l and 8.5 x 1.32 +/- 1 U/l were found. The influence of age, race,
race (time, date of foaling (time and conception (time were significant. No
Lactoperoxidase activity could be found in mare's milk. The origin and importance
of the mare's milk enzymes are discussed.
PMID- 9542807
TI - [Protein patterns of Pasteurella multocida strains in relation to the animal host
and the geographic site of isolation].
AB - Protein patterns from 681 Pasteurella multocida strains of different animal
species and distinct geographical regions were analyzed by PAGE. We found 9
protein types taking the most intense band as reference. This band represents a
protein of the outer membrane (OMP). In assigning the strains to protein types a
relation to animal hosts of the strains was established. The majority of isolates
from rabbits (88%) belongs to type P6, which is not found in strains isolated
from cattle or pigs. Strains from pigs did not include the protein types P2, P4
and P8, in cattle strains type P9 was absent. The distribution of protein types
in bovine isolates was shown to be related to the geographical location. The
results are discussed with particular emphasis on immuno-prophylaxis. It appears
promising to develop P. m. vaccines specific for certain animal species.
PMID- 9542808
TI - [Characterization of viral hemorrhagic septicemia (VHS) virus isolates in trout].
AB - Virus diseases of fish can seriously impair the economy of aquacultur. Control
and prevention of fish diseases in the European Union (EU) are focussed on the
viral haemorrhagic septicaemia (VHS) and the infectious haematopoeitic necrosis
(IHN). The diagnosis of VHS and IHN is performed in the Federal Republic of
Germany (FRG) on the basis of the legislation of the EU. Since 1994 we received
an increasing number of VHS virus (VHSV) isolates which did not react with a
commercially available anti-VHSV monoclonal antibody (MAb) in the indirect immuno
fluorescence test. With our own MAb ID8, however, as well as with additional
diagnostic methods these virus isolates could be identified. These isolates of
rainbow trouts were designated as VHSV type "Wi". Electron microscopically all
stages of rhabdovirus maturation could be detected. Morphologically the isolates
were undistinguishable from other rhabdoviruses. By immuno electron microscopy
using the MAb ID8 rhabdovirus nucleocapsid structures were demonstrated. The
virulence of the new VHSV type Wi was not different from that of a VHSV isolate
with conventional reaction patterns as well as of a VHSV laboratory strain.
PMID- 9542809
TI - [A case of Echinococcus granulosus hydatid cyst in a zoo born dromedary in the
Berlin-Fridrichsfelde zoo].
AB - In Germany, the threat to human health by the small fox tapeworm (Echinococcus
multilocularis) has been increasingly discussed in the last few years. On the
other hand, the hydatid worm of the dog (Echinococcus granulosus) became more and
more rare in Germany and was often declared to be eradicated. This paper presents
a case of hydatid infection of the lung in an adult dromedary (Camelus
dromedarius), which was born and kept all its life at Tierpark Berlin
Friedrichsfelde. Questions connected with E. granulosus infection are discussed
from an ecological point of view: history, urbanisation, biology, clinical signs,
potential threat to man, prophylaxis and treatment. In view of the extensive and
sometimes uncontrolled dog keeping in urban households it must be stressed that
careful documentation and surveillance of this life-threatening zoonosis, which
was the main reason for its decline in the past, has not yet lost its importance.
PMID- 9542810
TI - [Digital and analog radiographic techniques in the case of thoracic diagnosis].
AB - Up to now digital luminescens radiography has not been used widely in veterinary
medicine. This paper gives an overview of the first experiences with the
application of the digital ADC-System (Agfa Diagnostic Center) for imaging
pulmonary nodules and other lung diseases in dogs in comparison to the
conventional method. For this, we used radiographs of dogs of several weight
groups with lung diseases. To compare both systems (conventional and digital) we
took pictures with either method in the same positioning. Compared to the analog
film screen system, the phosphor storage radiographs enhance the detection of
fine details. Additionally, the digital technology gives an opportunity for post
processing of image data in order to optimize the discrimination of various image
details and offers a wide latitude for exposure, which means less retakes and a
wider range for dose selection. The advantage of digital filing stations is on
the one hand the possibility of space saving and storage unlimited by time, on
the other hand it offers the possibility to recover X ray pictures in very short
time.
PMID- 9542811
TI - [Treatment of hypertensive insulin-resistant patients is a difficult decision to
make. Metabolically neutral drugs should be the choice of treatment].
PMID- 9542812
TI - [Risk of depression may be discovered by sleep. The sleep pattern is predictable
and possible to manipulate].
PMID- 9542813
TI - [Heart rehabilitation in Nynashamn. Life-saving activities may be closed down].
PMID- 9542814
TI - [Maintain medical ethics!].
PMID- 9542816
TI - [Quality and/or safety of health care].
PMID- 9542815
TI - [The art of reading a debate on the treatment of schizophrenia].
PMID- 9542817
TI - [The rattlesnake is not more dangerous than the viper].
AB - The article consists of a comparison of the effects of snakebites inflicted by
North American rattlesnakes and those of European vipers, based on a review of
series of snake bite victims reported in the literature since 1980. The two
groups of snakebites were found to manifest close similarity, even regarding the
currently low fatality rates. Whereas local reactions seem to be more extensive
after rattlesnake bites, circulatory symptoms including severe hypotension appear
to be more common after viper bites. It is concluded that the two groups of
snakes may be regarded as equally dangerous.
PMID- 9542818
TI - [For a long time it was believed that "giants on Earth" were ancestors of
humans].
PMID- 9542819
TI - [Cultural aspects of pain: pain behavior--symptom or communication?].
PMID- 9542820
TI - [Is antihypertensive treatment a risk factor of coronary disease? Therapy-related
triglyceride increase nor diabetes increase the risk].
AB - In an observational study designed to determine whether metabolic changes during
long-term antihypertensive drug treatment are associated with an increased risk
of coronary heart disease (CHD), 686 middle-aged hypertensive men recruited from
a random population screening sample were followed up for 15 years.
Antihypertensive treatment predominantly consisted of beta-adrenoceptor blockers
and/or thiazide diuretics. CHD and diabetes mellitus were checked for at annual
examinations. Time-dependent Cox regression analysis was used to determine
correlation between the incidence of CHD and entry characteristics, the monitored
serum levels of cholesterol and triglyceride concentrations and the development
of diabetes mellitus. Univariate analysis showed the presence of diabetes
mellitus a entry to the study and increased baseline serum concentrations of
cholesterol and of triglycerides each to be a significant predictor of CHD, the
respective relative risks (RR) being 2.12, 1.21 and 1.21. However, analysis of
monitored levels of metabolic variables during follow-up showed only an increased
serum cholesterol concentration to be significantly and independently associated
with CHD (RR 1.07). Although serum triglyceride concentrations increased slightly
during follow-up, they were unrelated to the incidence of CHD; nor was onset of
diabetes mellitus during follow-up significantly associated with an increased
risk of CHD (RR 1.48. Thus, the study showed the presence of metabolic
disturbances such as diabetes mellitus and hyperlipidaemia before the start of
antihypertensive treatment to be of positive predictive value in middle-aged
hypertensive men, and an increase in the monitored serum cholesterol level to be
an independent predictor of CHD, whereas neither drug-related diabetes nor an
increase in the monitored serum triglyceride concentration seemed to be
associated with the occurrence of CHD.
PMID- 9542821
TI - [Gynecologic examination, a role-playing for two].
AB - Although pelvic examination (PE) is a common procedure in gynaecological
practice, there is little discussion among gynaecologists about the decision
making process and the possible indications and contraindications. Moreover,
examiners need to be aware that their approach and body language during PE will
inevitably reflect their attitude toward women. At PE, there is tacit agreement
between the examiner and the patient involving a cognitive restructuring of the
situation. However, if memories of earlier experiences bearing some resemblance
to the PE situation are aroused in the patient, and the emotions connected with
them reactivated, she may become overwhelmed by the intensive reactions
triggered. In such cases, the examiner needs to be able to recognise what is
happening and provide the support the patient needs. Other responsibilities of
the examiner at PE include recognising symptoms of post-traumatic stress
reactions and vaginismus. In performing a young woman's first PE, the examiner's
primary aim should be provide the experience; that PE is a benign procedure,
unconnected with pain or distress; as the patient's experience at her first PE
will inevitably influence all future examinations. Learning to perform a PE in
such a way that it is beneficial to the patient in all these respects is an
intricate and challenging task. However, experience with students and
gynaecological teaching associates suggests that such skills can be taught and
learned. The PE situation is charged with latent salubrious potential, which is
usually insufficiently exploited.
PMID- 9542822
TI - [Pain analysis is vital in rheumatic diseases. The pain is often the patient's
worst problem].
AB - The article consists of a synthesis of a rheumatic pain symposium held at the
annual meeting of the Swedish Medical Association in 1996. Various aspects of
pain in rheumatic diseases were discussed, such as physiological, neurohumoral
and neurogenic mechanisms, sensory stimulation treatment, differentiation of
mechanical and inflammatory pain, quality enhancement by improved cooperation
between primary and tertiary care facilities, pharmacological treatment with
(centrally and peripherally acting) opioids, selective cyclo-oxygenase
inhibitors, and NMDA (N-methyl-D-aspartate) receptor antagonists. The aim of the
symposium, with its focus on the manifest pain problem, was to improve our
knowledge and skill in the understanding and treatment of this large patient
category. For patients with rheumatic disorders exacerbated by pain problems, as
for other patients, a pain diagnosis is of fundamental importance. This can be
achieved by analysis of the social, psychological, physiological and medical
factors contributing to the cause and degree of pain and to pain behaviour, and
of the extent to which the pain may be nociceptive (i.e., inflammatory,
mechanical, or ischaemic in origin), neurogenic or idiopathic. Pain analysis
should be followed by individualised treatment focused on the patient's most
crucial problems, thus enhancing the prospect of optimal treatment outcome.
PMID- 9542823
TI - [Radiation-induced hemorrhagic proctitis treated with formalin. A simple and
efficient help against adverse effects of radiation].
PMID- 9542825
TI - [How much more care do the elderly need when compared to the younger? The age
weighting differences are difficult to understand].
PMID- 9542824
TI - [Hemicraniectomy in malignant mid-cerebral infarction. Further trials needed
before its acceptance in clinical practice].
AB - In cases of completed middle cerebral artery territory stroke, prognosis is very
poor and the clinical course is characterised by a rapid decline in consciousness
and signs of herniation 2-4 days after the onset of symptoms due to a space
occupying mass. Failure of conservative therapy is the rule, and herniation is
the usual cause of death, occurring in almost 80 per cent of cases. Recently
published results have suggested that hemicraniectomy may improve survival in
patients with massive hemisphericstroke, decreasing mortality to less than 35 per
cent. The article presents what is probably the first case to be reported in
Sweden, where hemicraniectomy was performed on a 45-year-old woman with right
hemispheric completed middle cerebral artery infarction.
PMID- 9542826
TI - [Child welfare. Concentration on education, research and service].
PMID- 9542827
TI - [Stem cell transplanted to fetus].
PMID- 9542828
TI - [DNA contaminated drugs may be the cause of antibiotic resistance. Insufficiently
purified preparations are carriers of danger].
PMID- 9542829
TI - [Surgery for cleft lip and palate should benefit from centralization. Experts of
social medicine should also be included in the team].
PMID- 9542830
TI - [The new occupational health services and ethics. Are physicians in occupational
health services reliable?].
PMID- 9542831
TI - [Physicians should respect work of their colleagues].
PMID- 9542832
TI - [Persons with self-destructive behavior may have been sexually abused as
children].
PMID- 9542833
TI - [First generation cephalosporins are not suitable in bacterial respiratory tract
infections].
PMID- 9542834
TI - [Important questions in connection with "How dangerous is health care service"?].
PMID- 9542835
TI - [Surgery or training in urinary incontinence?].
PMID- 9542836
TI - [Improved treatment of cleft lip and palate is now available].
AB - When cleft lip and palate treatment was introduced at Gothenburg in 1957, the
procedure used was early bone grafting (EBG). By 1965, EBG had been omitted from
the regimen, bone grafting being postponed until the appearance of mixed
dentition. Analysis of the results of both techniques showed maxillary retrusion
of different degrees. Accordingly, this routine was abandoned in 1975, being
replaced by a procedure which is characterised by delayed closure of the hard
palate (DCHP). Thus, the surgical procedure comprised the following steps: 1, lip
closure at 1-2 months of age; 2, soft palate repair at 6-8 months; 3, final lip
nose surgery at 12 months; and 4, closure of the left in the hard palate, and
bone grafting to the alveolar process during mixed dentition at about 8-10 years
of age. Follow-up has shown the majority of patients to manifest acceptable
speech development during childhood, though problems may occur in some cases.
Maxillary growth has been found to be improved after DCHP, and at present the
need of maxillary advancement surgery has been reduced to approximately 5% of
cases, as compared with the former rates of 50% of cases among those treated with
EBG, and of 25% among those treated with the vomer flap procedure.
PMID- 9542837
TI - [Parturients are under-treated. Only 21 out of 55 clinics administer oxytocics
routinely during the third stage of labor].
AB - A questionnaire answered by all 55 Swedish labour wards in 1995 showed oxytocic
treatment to be given routinely to all parturients during the third stage of
labour at only 38% (21/55) of the units, and that five of these 21 units were
considering cessation of the practice. At a further 25 units the treatment was
given routinely only in selected risk cases, the most common risk factors being a
history of postpartum haemorrhage (a criterion at 20 units), multiple pregnancy
(14 units), prolonged labour (12 units), and a large baby (8 units). Of the
remaining nine units, where oxytocic treatment was given only on clinical
indications (i.e., postpartum haemorrhage), two were considering the introduction
of routine treatment. In view of results obtained in a recent randomised, placebo
controlled Swedish study, the authors of the article conclude that, if clinical
practice in this respect has remained unchanged since the questionnaire study was
performed, Swedish parturients are undertreated with oxytocics during the third
stage of labour.
PMID- 9542838
TI - [A study of young offenders undergoing forensic psychiatric evaluation. There is
a need of correctional care alternatives].
AB - With effect from January 1, 1992, legislation regulating the practice of forensic
psychiatry in Sweden, the Forensic Mental Care Act, was changed to meet more
restrictive demands. A retrospective study of 15-20-year-old male offenders,
investigated at the Dept. of Forensic Psychiatry in Stockholm during the period
1990-93, showed the proportion sentenced to forensic psychiatric care to have
decreased by 21 per cent since the introduction of the new legislation. The
majority of young offenders otherwise sentenced, mainly to correctional
treatment, were suffering from personality disorders. Most of them had previously
been in contact with the correctional and social service sectors. Several of them
received prison sentences despite the fact that young offenders are not to be
sent to prison without exceptional reasons. One such exceptional reason might be
the lack of an appropriate alternative. A third treatment alternative is called
for.
PMID- 9542839
TI - [Association of parents of children with diaphragmatic hernia: prenatal diagnosis
-a right for all who want it].
PMID- 9542840
TI - [Simpler prenatal diagnosis results in new ethical problems. Blood tests of
pregnant women may detect Down syndrome].
PMID- 9542841
TI - [An analysis of mortality in Sweden during 1987-1994: no overmortality among
persons born outside the Nordic countries].
PMID- 9542842
TI - [Careful optimism when it comes to xenotransplantations].
PMID- 9542843
TI - [The picture of the psychiatrist should be more nuanced. General practitioners
react to articles on depression in primary health care].
PMID- 9542844
TI - [More than 20,000 adolescents start smoking every year. Is school-based
prevention a possible way?].
PMID- 9542845
TI - [Hippocrates' ethics are still of current interest].
PMID- 9542846
TI - [Hippocrates' ethics still up to date? No, it should be re-evaluated!].
PMID- 9542847
TI - [Death in literature].
PMID- 9542848
TI - 1st Croatian Congress on Atherosclerosis. Brijuni Islands, Croatia, September 30
October 3, 1997. Abstracts.
PMID- 9542849
TI - Treatment of the wounded at Chipyong-ni.
AB - The battle fought by a U.S.-French force at Chipyong-ni in mid-February 1951 has
been called the turning point of the Korean War, and may have been the first time
that transfusions of whole blood were given as far forward as the regimental area
during combat. The surgeon, or chief medical officer, of the United Nations force
at Chipyong-ni describes this and other measures required by the tactical and
medical situations there, and illustrates how they were made possible, in large
part, because an important lesson learned during World War II had been applied:
the surgeon had direct access to the commander as a member of his staff, and
controlled the task force medical facilities.
PMID- 9542850
TI - Co-occurrent use of cigarettes, alcohol, and caffeine in a retired military
population.
AB - Previous studies have linked the use of caffeine, nicotine, and alcohol to health
complications and have also found that the use of these substances significantly
covary. Given the prevalence of health problems of older adults, it is surprising
that no studies to date have examined the co-occurrent use of alcohol, caffeine,
and nicotine in a senior population. This investigation evaluated the co
occurrent use of cigarettes, caffeine, and alcohol in a community sample of older
Americans. Respondents (1,095 women and 1,371 men) completed a questionnaire
examining their use of caffeine, nicotine, and alcohol. This study replicated
earlier findings that tobacco, caffeine, and alcohol use co-occur and that there
are consistent use patterns for these substances. The results suggest that health
organizations could better target services by prescreening for smoking, alcohol,
and caffeine use and possibly targeting smokers and ex-smokers for potentially
problematic use patterns of caffeine and alcohol.
PMID- 9542851
TI - The impact on a health care system of a program to facilitate self-care.
AB - BACKGROUND: High utilization for self-limiting conditions has challenged health
care systems to be innovative. The facilitation of self-care has been identified
as a viable concept to control demand and encourage efficient use of resources. A
Self-Care Intervention Program (SCIP) coupled with a Health Promotion Pharmacy
(HPP) was implemented in an Army health care system to determine the impact on
the use of self-care. METHODS: A questionnaire was mailed to 283 SCIP
participants at the 6-month interval to assess achievement of program objectives.
Use of the HPP was documented during the same interval. The response rate was
67.5% (n = 191). RESULTS: A positive response was obtained for all six program
OBJECTIVES: Increased knowledge of personal health issues (84.3%); increased
confidence to treat minor illnesses (77%); improved opinion of the health care
system (74.9%); increased practice of healthy behaviors (64.9%); and an increased
commitment to seek preventive medicine (62.8%). Seventy-two percent of the
respondents reported avoiding at least one clinic visit, and 39.8% reported
avoiding at least one visit to the emergency room. The calculated return on
investment was 11:1. CONCLUSION: A formal self-care program supported by a
pharmacy can have a positive effect on participants' health and health care,
resulting in cost-effective demand management.
PMID- 9542852
TI - A comparison of 5-minute povidone-iodine scrub and 1-minute povidone-iodine scrub
followed by alcohol foam.
AB - The purpose of this study was to determine if a 1-minute scrub with povidone
iodine followed by alcohol foam is as effective as a 5-minute scrub with povidone
iodine in reducing skin bacterial counts. A 1-minute scrub with povidone-iodine
followed by alcohol foam and a 5-minute scrub with povidone-iodine was done. In
the first study, cultures were obtained after 1 hour, and in the second study,
cultures were obtained after 2 hours. Cultures were obtained by imprinting the
first, second, and third fingers on nutrient agar plates. Bacterial counts were
then obtained at 24 and 48 hours. The study involved two groups of 12
participants and a total of 37 patients over a period of 5 months. The results
show that there was no significant difference between the number of colonies
cultured for the 1-minute scrub compared with the 5-minute scrub for either the 1
hour or the 2-hour study. In fact, the total number of bacterial colonies was
less after the 1-minute scrub with alcohol foam than after the standard 5-minute
scrub in both the 1-hour group (10 vs. 18) and the 2-hour group (18 vs. 44).
PMID- 9542854
TI - Dental utilization by spouses of active duty U.S. military personnel.
AB - This study explores dental utilization and access barriers to dental care for
spouses of active duty U.S. military personnel as reported by their military
sponsor. It also compares dental utilization of spouses and civilians. The data,
collected using self-administered questionnaires between April 1994 and January
1995, are from 5,732 Army, Air Force, Navy, and Marine personnel with nonmilitary
spouses. Comparative civilian data are from the most recent (1985-1986) U.S. oral
health survey of working adults. Results show that dental utilization of military
spouses parallels that of civilians. Cost was the most commonly cited barrier to
dental care for spouses. Logistic regression results show that the likelihood of
a spouse having seen a dentist within the past year is influenced by insurance
status, sex, branch of service of sponsor, and rank of sponsor. Insurance status
is the strongest predictor of dental utilization for spouses.
PMID- 9542853
TI - Comparing annual dental utilization rates of active duty U.S. military personnel
and their employed civilian cohorts.
AB - This study compares annual dental utilization rates between a representative
sample of active duty U.S. military personnel (N = 11,765) and a national sample
of employed U.S. civilians (N = 10,798). Military data were collected between
April 1994 and January 1995 at 26 sites using self-administered questionnaires on
a prestratified, random sample of Army, Air Force, Navy, and Marine personnel.
Women and blacks were oversampled. Civilian data are from the most recent U.S.
oral health survey of working adults. Results show that annual dental utilization
rates of service members exceed those of their employed civilian cohorts.
Overall, 86% of active duty military personnel have seen a dentist in the past
year versus barely half of employed civilians. For service members, annual dental
utilization is invariant across age, sex, race, education, branch of service, and
rank. Dental health class and perceived need for dental care are inversely
related to annual dental utilization.
PMID- 9542855
TI - The need for and prevalence of dental sealants in active duty U.S. military
personnel.
AB - This paper explores the need for and the prevalence of dental sealants in active
duty U.S. military personnel. The data come from the 1994 Tri-Service
Comprehensive Oral health Survey. Data were collected on 13,050 Army, Air Force,
Marine Corps, and Navy active duty personnel at 26 sites. Women and minorities
were oversampled. Both bivariate and logistic regression analyses were done on
the need for at least one dental sealant and the prevalence of at least one
dental sealant in service members. Weighted data (1,669,662) were used for the
bivariate analyses; unweighted data were used for the regressions. Results show
that 3.6% of service members need dental sealants and that 6.8% have dental
sealants. The need for dental sealants varies across age, rank, and branch of
service. The prevalence of dental sealants varies across age, race, rank, and
branch of service. The cost-effectiveness of dental sealants in this population
should be established.
PMID- 9542856
TI - Performance of the universal portable anesthesia complete vaporizer with
mechanical ventilation in both drawover and pushover configurations.
AB - Currently, a mechanical ventilator that can be adapted to the Universal Portable
Anesthesia Complete (UPAC) vaporizer and anesthetic delivery system does not
exist. The need for the anesthetist to concentrate on drug delivery and fluid
resuscitation for the combat casualty in the field setting provides an expedient
for the adaptation of a ventilator to the UPAC system. The purpose of this study
was to determine whether the performance of the UPAC vaporizer was significantly
altered when mechanical ventilation was provided in a drawover versus a pushover
configuration, and to provide vaporizer performance curves for ventilatory
parameters common for mechanical ventilation. The Ohio V5A and Lifecare PLV-100
ventilators were used in controlled benchwork analysis. The results of the
comparison between the two ventilators indicated that there was no significant
difference in vaporizer output between drawover and pushover configurations. The
data indicated that vaporizer output could be reliably predicted in either mode
and was correlated with tidal volume and respiratory rate.
PMID- 9542857
TI - Clinical evaluation of pushover mechanical ventilation with the Ohmeda Universal
Portable Anesthesia Complete vaporizer.
AB - Previous studies have not demonstrated the usefulness of a mechanical ventilator
with the Universal Portable Anesthesia Complete (UPAC) field anesthesia delivery
system in a pushover mode. This study demonstrated that the Lifecare PLV-100
ventilator can function effectively in a practical pushover configuration with
the UPAC vaporizer. By comparison, vaporizer output followed the patterns of
documented concentration curves for isoflurane at a given dial setting and minute
ventilation. Measured airway pressures in the breathing circuit were within
physiological parameters.
PMID- 9542858
TI - Recognition and treatment of osteosarcoma in the military health care system.
AB - Forty-two patients with high-grade intramedullary osteosarcoma treated at Walter
Reed Army Medical Center between 1985 and 1995 were reviewed to determine what
effects military "managed health care" had on diagnosis, treatment, and outcome.
Five-year survival was 61% overall (SE +/- 9.9%), despite local disease control
obtained in 95% of patients. There was a statistically significant difference
between active duty members and dependents in time to diagnosis (p = 0.008), yet
there was no significant difference in survival between the two groups. Five-year
survival in our patient population was slightly lower than 5-year survival
reported in some large civilian medical centers despite good local disease
control and intensive multiagent chemotherapy. Delays in diagnosis and military
status had no apparent effect on survival, although limb salvage was not possible
in nearly 40% of patients because of tumor size, disease extent, and involvement
of neurovascular structures.
PMID- 9542859
TI - Radiographic characteristics of the vesicourethral anastomosis after radical
retropubic and perineal prostatectomy.
AB - A fundamental difference between the surgical techniques of radical retropubic
and radical perineal prostatectomy is the method by which the vesicourethral
anastomosis is accomplished. In the latter procedure, because the anastomosis is
performed under direct vision, some authors have suggested that continence may be
improved while reducing the risk of obstruction. The merit of this observation
has not been established. To evaluate the characteristics of the vesicourethral
anastomosis in retropubic and perineal prostatectomy, postoperative cystograms of
59 patients who underwent these procedures were reviewed in a blinded fashion. A
normal, tapering bladder neck to the proximal urethra was noted in 80% of
patients undergoing perineal prostatectomy compared with 2% of patients
undergoing the retropubic approach. Various grades of diamond-shaped or bulbous
irregularity of the vesicourethral anastomosis were seen in 98% of patients
undergoing retropubic prostatectomy, and a system of grading of these
abnormalities was established. These data suggest that a more physiologic
appearing bladder neck and proximal urethra is achieved with radical perineal
prostatectomy. Further study is required to determine the impact of this
radiologic finding on urinary function and continence.
PMID- 9542860
TI - Nomograms to follow recovery rate in status asthmaticus in a veteran population.
AB - Data from 12 Department of Veterans Affairs patients hospitalized for status
asthmaticus were analyzed to determine the rate and degree of response to
therapy. The time to achieve recovery was directly related to the level of
baseline obstruction at the time of hospital admission. The recovery rate was
constant and could be described by a single second-degree polynomial regression
equation. Nomograms were constructed showing this rate of improvement of
pulmonary function over time at four levels of baseline pulmonary obstruction.
PMID- 9542861
TI - Prevalence of sinusitis in young asthmatics and its relation to bronchial asthma.
AB - In this paper, we present data on the prevalence of sinusitis and its
relationship to bronchial asthma in 120 young male asthmatics evaluated without
exacerbations of their disease. All patients reported respiratory symptoms during
the preceding year, and in the most of them (74%), the severity of asthma was
mild. Sinusitis was observed in 52 patients (43.3%), and the maxillary sinus was
involved in 36 asthmatics. Sixteen of 52 patients with sinusitis had never had
nasal symptoms of rhinitis. In all patients, physical examination of the lung was
negative for wheezing. All patients had FEV1 (forced expiratory volume/forced
vital capacity x 100 in 1 second of expiration) values in the normal range, and
bronchial hyperresponsiveness was detected in 101 asthmatics (84.2%). One hundred
sixteen patients (96.6%) were found to be skin reactors. We did not find
statistical differences between asthmatics with or without sinusitis with regard
to severity of asthma, basal lung function, and bronchial hyperresponsiveness. We
suggest that antibiotic therapy for sinusitis should be given only to asthmatics
with worsening respiratory symptoms and obvious signs of chronic sinusitis.
PMID- 9542862
TI - Multiple giant cell tumors in a patient with Gulf War syndrome.
AB - "Persian Gulf syndrome" refers to a group of clinical findings found in military
personnel who served in the Persian Gulf War. The most commonly reported symptoms
include chronic fatigue, headache, and neurologic disorders. Recently, new
information has linked Whipple's disease and Ki-1 anaplastic large cell lymphoma
to this syndrome. Presented here is an unusual case of multiple giant cell tumors
of the hand in a patient with documented Persian Gulf syndrome. The epidemiologic
significance between these two entities is unclear, because this is a single
reported case. However, the practical message is clear. Physicians must
meticulously evaluate patients who are veterans of the Persian Gulf conflict to
further our understanding and confirm the existence of this syndrome.
PMID- 9542863
TI - Fibrous dysplasia of the clivus and sphenoid sinus.
AB - Fibrous dysplasia is a primary disease of bone that may lead to bony distortion,
expansion, and weakness. Craniofacial involvement is an important entity for
physicians to be aware of because of the potential for impingement on
neurovascular structures, intracranial extension, and cosmetic deformity. We
report two cases of craniofacial fibrous dysplasia and discuss the clinical
presentation, radiographic and histologic findings, and the management of
affected patients.
PMID- 9542864
TI - [Glomerulonephritis caused by acute serum sickness].
AB - A 51-year-old male patient was treated for a rejection episode after kidney
transplantation with horse antithymocyte globulin (ATG). Twelve days after the
start of the ATG treatment he developed fever, arthralgia, purpura and acute
renal failure. This clinical picture is characteristic of serum sickness,
resulting from formation of antibodies to a foreign protein and development of
immune complexes. Kidney biopsy revealed an endocapillary glomerulonephritis.
Immune complexes probably develop in the mesangium and along the glomerular basal
membrane through local formation and precipitation from the circulation.
Spontaneous recovery is the rule.
PMID- 9542865
TI - ['Open season in the hunt for poliovirus' (continued)].
AB - Global eradication of poliomyelitis was started in 1988. Polio eradication is
considered feasible on theoretical and practical grounds, is cost-effective and
is endorsed at the highest political levels. The strategy is based on (a)
increasing vaccination coverage through routine immunization, national
immunization days and so-called mopping-up campaigns, (b) improving surveillance,
and (c) polio-free certification. Since the start of the programme global
vaccination coverage increased from 67% in 1988 to 83% in 1995; the number of
reported cases--an estimated 10% of the total number--decreased by 90% from
35,251 (1988) to 3,755 (1996). A rapid further decrease is expected with the
start of national immunization days on the Indian subcontinent. In the next years
the emphasis will be strongly on surveillance i.e. detection of possible polio
patients and (wild) poliovirus circulation. All countries will need to implement
reliable surveillance to show their polio-free status. Only then can the world be
declared polio-free.
PMID- 9542866
TI - [Side effects of minocycline in the treatment of acne vulgaris].
AB - Minocycline is the most commonly used systemic antibiotic in the long-term
treatment (weeks to months) of severe acne vulgaris. Currently much attention is
being paid in the Dutch and international literature to the safety of
minocycline, after several reports on serious adverse events. The clinical
efficacy of minocycline in the treatment of acne vulgaris is better than that of
tetracycline and equal to that of doxycycline. The serious adverse events of
minocycline therapy described consist of hyperpigmentation of various tissues,
autoimmune disorders (systemic lupus erythematosus, autoimmune hepatitis) and
serious hypersensitivity reactions (hypersensitivity syndrome reaction,
pneumonitis and eosinophilia, and serum sickness-like syndrome). In relation to
the number of prescriptions, the number of serious adverse events of minocycline
described is small. However, it is very important that prescribing doctors should
be aware of the possibility of these adverse events occurring during long-term
minocycline therapy and able to recognize the characteristic symptoms at an early
stage.
PMID- 9542867
TI - [A painful encounter with the weever (Echiichtis vipera)].
AB - The National Poisons Information Centre of the National Institute of Public
Health and the Environment in the Netherlands in the past 2 years received dozens
of requests for information about intoxication due to stings of the weever,
Echiichtis vipera. The venomous apparatus of the weever consists of gill cover
spines and 5 to 8 dorsal fin spines. The fish buries itself in the sandy or muddy
bottom of the sea to wait for prey. The mixture of toxins that enters the skin
upon contact with the spines causes a heavy local reaction, characterized mostly
by pain, which untreated persists for 24 hours. An erythematous oedema may
develop locally, spread over the entire extremity and persist for days. Systemic
reactions are rare. Since the toxin mixture is heat labile, treatment is
essentially simple: clean the wound and immerse the affected limb as soon as
possible in warm water (45 degrees C) for 30 to 90 minutes. This makes the pain
disappear.
PMID- 9542869
TI - [An amebic liver abscess; early suspicion, late detection].
AB - Two men aged 38 and 26 years developed symptoms including pain in the (upper)
abdomen, malaise and fever 1.5-5 months after visiting the Caribbean. It was only
after repeated ultrasonography that liver abscesses were observed. Adequate
treatment was instituted and the patients recovered. The diagnosis of 'amoebic
abscess of the liver' is usually based on the clinical presentation, the
serological findings and characteristic observations at ultrasonography. However,
if patients are seen at an early stage of development of the abscess, the
serological findings may be negative and the ultrasonographic findings normal;
consequently these findings do not justify exclusion of the diagnosis.
PMID- 9542870
TI - [Is the term 'registration' applicable for homeopathic drugs?].
PMID- 9542871
TI - [Is the term 'registration' applicable for homeopathic drugs?].
PMID- 9542872
TI - [Is the term 'registration' applicable for homeopathic drugs?].
PMID- 9542873
TI - [Blue toes and kidney insufficiency].
PMID- 9542874
TI - [European registration of drugs; consequences for prescriber and patient].
PMID- 9542875
TI - [Thorn apple poisoning].
PMID- 9542876
TI - [Barrett esophagus and Barrett carcinoma].
PMID- 9542877
TI - [A sleeping disorder seldom comes alone].
PMID- 9542878
TI - [Failing diuretics in severe chronic heart failure].
AB - Three patients with chronic heart failure, men aged 29, 78 and 69 years,
developed severe dyspnoea and oedema in spite of reduced sodium and fluid intake
and medication including furosemide. Heart failure may become 'resistant to
diuretics' due to pharmacokinetic and pharmacodynamic causes. High-dose
continuous intravenous administration of a loop diuretic may afford relief in
such cases, if necessary in combination with a thiazide derivative, an ACE
inhibitor, an inotropic agent or an extracorporal technique. Monitoring and
correction of the state of hydration of a patient with chronic heart failure may
improve the prognosis and the quality of life.
PMID- 9542879
TI - [Kidney transplantation without previous dialysis: limitations, but also
possibilities].
AB - Kidney transplantation guarantees a better quality of life than dialysis and is
less costly. Transplantation without preceding dialysis is an attractive option.
However, transplantation long before end-stage renal failure prolongs the period
of exposure to immunosuppressive therapy, thereby increasing the risk of
malignancy. Transplantation at one year before dialysis-dependency is expected
would seem an acceptable compromise. Unfortunately, this option is purely
theoretical because there is a long waiting-list due to the existing donor
shortage. Patients are usually put on the waiting-list after dialysis has already
been started. Extension of the list with pre-dialysis patients is currently only
justifiable in exceptional cases. These limitations do not apply to patients who
have received an offer of kidney donation from a living (related or unrelated)
donor. In these patients transplantation can be done as soon as the creatinine
clearance has reached a level of 10-12 ml per minute. More attention should be
paid to this form of transplantation, because it can help to decrease the donor
shortage.
PMID- 9542880
TI - [Acute dystonia].
AB - Acute dystonia is a side effect of antipsychotic medication; it nearly always
develops a few weeks after the start of a dopamine-blocking agent or substantial
increase of the dosage. Acute dystonia is characterized as a syndrome of
sustained muscle contractions, frequently causing twisting and repetitive
movements or abnormal postures. The risk of acute dystonia depends greatly on the
presence of risk factors: early age, male sex, use of cocaine, a history of acute
dystonia, and use of a highly potent antipsychotic agent in a normal dosage. The
mechanism underlying acute dystonia is unknown: both increase and decrease of the
striatal dopamine transmission have been put forward as possible causes. Acute
dystonia may also be caused by dopamine-blocking agents that are used not as
antipsychotic medication but, for instance, as anti-emetics. Anticholinergic
agents are extremely efficacious in treatment as well as prevention of acute
dystonia. Prophylaxis of acute dystonia is indicated for patients belonging to
the risk groups.
PMID- 9542881
TI - [Good experiences with an implantable automatic defibrillator with transvenous
electrodes for patients with life-threatening arrhythmias].
AB - OBJECTIVE: To describe the results of treatment of patients with a life
threatening arrhythmia by implantation of an second generation implantable
cardioverter defibrillator with transvenous electrodes. DESIGN: Descriptive.
SETTING: St.-Antonius Hospital, Nieuwegein, the Netherlands. METHOD: In the
period October 1991-February 1996 the ICD with transvenous electrodes was
implanted in 44 patients. After a year the quality of life was assessed by
written questionnaire. RESULTS: The in-hospital mortality was 1/44 (2%), without
peroperative death. During follow-up 4 patients died: 3 due to congestive heart
failure and 1 due to sudden cardiac death. Within one year 50% of the patients
had a therapeutical ICD discharge. In 30/44 (68%) patients antiarrhythmic drugs
were prescribed to reduce the number of ICD discharges or because they were
suffering from paroxysmal atrial fibrillation with high heart rates, which could
result in an inappropriate ICD discharge. Quality of life analysis showed a good
acceptance of the ICD, although 86% of the patients considered it a very serious
limitation that they were not allowed to drive a motor vehicle anymore.
CONCLUSION: The ICD constitutes a major step forward in the treatment of life
threatening ventricular arrhythmias because the implantation is easier and follow
up shows adequate antiarrhythmic effects and survival.
PMID- 9542882
TI - [Initial Groningen experiences with dynamic cardiomyoplasty].
AB - Four patients, one woman and three men aged 48, 62, 49, en 54 years respectively,
were subjected to cardiomyoplasty because of medically refractory heart failure
secondary to ischaemic or idiopathic dilating cardiomyopathy. The operation and
the training period were uncomplicated. In one patient symptoms of heart failure
did not improve; the other patients experienced substantial relief of symptoms.
However, all three died suddenly within one year after the operation, probably
due to ventricular arrhythmias. Cardiomyoplasty may deserve a place in the
treatment of heart failure, provided sudden death can be better prevented.
Possibly, treatment with an implantable cardioverter-defibrillator might be
useful.
PMID- 9542883
TI - [Suppurative hidradenitis].
AB - An obese woman aged 18 years had been suffering for several years from axillary
hidradenitis suppurativa. Repeated incision and drainage never gave lasting
results and the patient became socially isolated. Hidradenitis suppurativa is a
chronic suppurative inflammation of skin areas containing apocrine glands: the
skin of the axillae, of the breasts and of the anogenital region. Treatment in
the first instance consists of general hygienic measures. Pharmaceuticals used
include antibiotics, antiandrogens and oestrogens. Surgery is performed when the
condition is at an advanced stage, with cellulitis and scarring; ample excision
is necessary to reduce the risk of recurrence. CO2 laser therapy is a new method
of treatment that shows good results in incipient and advanced lesions.
PMID- 9542884
TI - [History of healing; bath treatment as psychiatric therapy (1900-1950)].
AB - During the first decade of the twentieth century the prolonged bath treatment was
introduced as a therapy for restless patients in Dutch psychiatric institutions.
They were kept for hours or days at a stretch in lukewarm water, in order to calm
them down. It became a common treatment, which nevertheless was gradually
replaced by occupational therapy. The rise of psychopharmacology during the
fifties of this century marked the end of the prolonged bath treatment.
PMID- 9542885
TI - [The changed role of chemotherapy in the treatment of stage III non-small-cell
lung carcinoma].
PMID- 9542886
TI - [The changed role of chemotherapy in the treatment of stage III non-small-cell
lung carcinoma].
PMID- 9542887
TI - [The changed role of chemotherapy in the treatment of stage III non-small-cell
lung carcinoma].
PMID- 9542888
TI - [A uniform protocol for liver transplantation in adults in The Netherlands].
PMID- 9542889
TI - Consciousness and neuroscience.
PMID- 9542890
TI - EAAC1, a high-affinity glutamate tranporter, is localized to astrocytes and
gabaergic neurons besides pyramidal cells in the rat cerebral cortex.
AB - High-affinity uptake of glutamate from the synaptic cleft plays a crucial role in
regulating neuronal activity in physiological and pathological conditions. We
have used affinity-purified specific polyclonal antibodies raised against a
synthetic peptide corresponding to the C-terminal region of rabbit and rat EAAC1,
a glutamate (Glu) transporter believed to be exclusively neuronal, to investigate
its cellular and subcellular localization and whether it is expressed exclusively
in glutamatergic cells of infragranular layers, as suggested by previous studies.
Light microscopic studies revealed that EAAC1 immunoreactivity (ir) is localized
to neurons and punctate elements in the neuropil. EAAC1-positive neurons were
more numerous in layers II-III and V-VI, i.e. throughout all projection layers.
Most EAAC1-positive neurons were pyramidal, although nonpyramidal cells were also
observed. Some EAAC1-positive non-pyramidal neurons stained positively with an
antiserum to GAD, thus demonstrating that EAAC1 is not confined to glutamatergic
neurons. Non-neuronal EAAC1-positive cells were also observed in the white
matter, and some of them stained positively with an antiserum to GFAP.
Ultrastructural studies showed that EAAC1-ir was in neuronal cell bodies,
dendrites and dendritic spines, but not in axon terminals, i.e. exclusively
postsynaptic. Analysis of the type of axon terminals synapsing on EAAC1-ir
profiles showed that 97% of them formed asymmetric contacts, thus indicating that
EAAC1 is located at the very sites of excitatory amino acid release.
Unexpectedly, EAAC1-ir was also found in a few astrocytic processes located in
both the gray and the white matter. The localization of EAAC1 may explain the
pathological symptoms that follow EAAC knockout (seizures and mild toxicity), as
seizures could be due to the loss of EAAC1-mediated fine regulation of neuronal
excitability at axodendritic and axospinous synapses, whereas the mild toxicity
may be related to the functional inactivation of astrocytic EAAC1.
PMID- 9542891
TI - A profile of cortical gray matter volume deficits characteristic of
schizophrenia.
AB - Quantitative magnetic resonance imaging (MRI) studies from our laboratory have
reported that patients with schizophrenia show a widespread cortical gray matter
volume deficit, which is especially pronounced in the prefrontal and anterior
superior temporal cortices. The present study compared two separate samples of
schizophrenic patients -- 71 men from a Veterans Administration (VA) hospital and
a sample of 57 severely ill men from a state hospital (SH) -- in an effort to
test whether the pattern of brain volume abnormalities previously observed in VA
schizophrenic patients can be generalized to other groups of schizophrenic
patients. MRI-derived brain volumes of gray matter, white matter and sulcal
cerebrospinal fluid (CSF) in six cortical regions, and CSF in the lateral and
third ventricles were computed. All MRI volumes were adjusted for normal
variation in head size and age and were expressed as standardized Z-scores, which
also permitted structures of different sizes to be compared directly. The two
schizophrenic groups displayed similar patterns of volume abnormalities: cortical
gray matter but not white matter volume deficits that were widespread but
especially notable in the prefrontal and temporal regions. The regional gray
matter deficits in the SH group were generally greater than those in the VA
group, particularly in the prefrontal and posterior superior temporal regions.
Both schizophrenic groups had abnormally large volumes of the cortical sulci and
lateral and third ventricles; however, the SH group showed greater enlargements,
the most prominent occurring in the ventricles and temporal sulci. The
overlapping patterns of cortical gray matter deficits in the two groups provide
evidence for generality of this pattern of regional brain volume abnormalities in
schizophrenia.
PMID- 9542892
TI - The posterior field P of cat auditory cortex: coding of envelope transients.
AB - The posterior field (P) of the cat auditory cortex contains a very high
proportion of neurons whose responses change non-monotonically with the sound
pressure level (SPL) of tonal stimuli, leading to circumscribed frequency-SPL
response areas, and it has therefore been suggested that field P may be
specialized for processing of sound intensity. We demonstrate here a great
diversity of response areas in field P. Furthermore, by varying tone SPL and rise
time, we show that, as in primary auditory cortex (AI), the onset response of a
field P neuron is better described as a function of the instantaneous peak
pressure (envelope) at the time of response generation than of the steady-state
SPL of the stimulus. Such responses could be used to track transients or
represent envelopes in more general terms, rather than to code SPL. Compared with
AI, field P neurons have relatively long minimum latencies along with a large
jitter in spike timing. Tracking would therefore be most effective for slowly
varying envelopes, and one function of the inhibition that generates non
monotonicity in field P may be to suppress temporally sluggish responses to rapid
transients, such as the onsets of high-SPL, short rise time tones. Field P may
thus be specialized for coding slowly varying signals.
PMID- 9542893
TI - Neonatal treatment with 192 IgG-saporin produces long-term forebrain cholinergic
deficits and reduces dendritic branching and spine density of neocortical
pyramidal neurons.
AB - The role of basal forebrain-derived cholinergic afferents in the development of
neocortex was studied in postnatal rats. Newborn rat pups received
intraventricular injections of 192 IgG-saporin. Following survival periods
ranging from 2 days to 6 months, the brains were processed to document the
cholinergic lesion and to examine morphological consequences. Immunocytochemistry
for choline acetyltransferase (ChAT) and in situ hybridization for ChAT mRNA
demonstrate a loss of approximately 75% of the cholinergic neurons in the medial
septum and nucleus of the diagonal band of Broca in the basal forebrain. In situ
hybridization for glutamic acid decarboxylase mRNA reveals no loss of basal
forebrain GABAergic neurons. Acetylcholinesterase histochemistry demonstrates a
marked reduction of the cholinergic axons in neocortex. Cholinergic axons are
reduced throughout the cortical layers; this reduction is more marked in medial
than in lateral cortical areas. The thickness of neocortex is reduced by
approximately 10%. Retrograde labeling of layer V cortico-collicular pyramidal
cells reveals a reduction in cell body size and also a reduction in numbers of
branches of apical dendrites. Spine densities on apical dendrites are reduced by
approximately 20-25% in 192 IgG-saporin-treated cases; no change was detected in
number of spines on basal dendrites. These results indicate a developmental or
maintenance role for cholinergic afferents to cerebral cortical neurons.
PMID- 9542894
TI - Auditory cortical responses in hearing subjects and unilateral deaf patients as
detected by functional magnetic resonance imaging.
AB - Functional magnetic resonance imaging is a non-invasive method for the detection
of focal brain activity at high spatial resolution. Acoustic stimulation leads to
a blood oxygenation level dependent signal change in the plane of the superior
temporal gyrus. The dependence of this response in the auditory cortex on
binaural, monaural left and monaural right acoustic stimulation for 10 healthy
subjects and five monaural deaf patients is described. Acoustic stimulation
consists of 1000 Hz pulsed sine tones at a pulse rate of 6 Hz and a sound
pressure level of 95 dB. For monaural stimulation, normal-hearing subjects
revealed a strong lateralization of cortical response towards the contralateral
hemisphere. The lateralization ratios between left and right hemispheric response
areas were 3.4-5.2 for monaural stimulation and nearly balanced for binaural
stimulation. Additionally, the sum of cortical activation volumes induced by
monaural left and right stimulation was approximately 30% smaller than for
binaural stimulation, indicating either inhibitory mechanisms or neuronal
facilitation within the auditory pathways. For monaural deaf subjects the
lateralization ratio between left to right response was just 1.3 towards the
contralateral hemisphere of the healthy ear, which is comparable to binaural
responses of normal-hearing subjects. This observation seems to indicate a
plasticity or a reorganization of auditory pathways of monaural deaf patients.
PMID- 9542895
TI - Age-related differences in distractibility and response to methylphenidate in
monkeys.
AB - Increased susceptibility to distraction is a symptom of normal aging and several
clinical syndromes, including Alzheimer's disease and attention deficit
disorders. In the present study, aged and young adult macaques were well-trained
to perform an automated delayed matching-to-sample (DMTS) task which assesses
both attention and short-term memory. On 19% of all trials, a task-relevant
distracting stimulus was presented during either the initial 1 or 3 s of delay
intervals (early onset) or the final 1 or 3 s of delay intervals (late onset). In
aged monkeys, both early and late onset distractors lasting 1 or 3 s impaired
delayed recall on trials with the shortest delay intervals, but did not affect
accuracy on trials with long delay intervals. In contrast, young adult monkeys
were impaired only by the presence of an early onset distractor lasting 3 s.
Impairment was selective for only those trials with the shortest delay intervals.
Late onset distractors were relatively ineffective in producing distractibility
in young adult animals. Methylphenidate (MPH; 0.005-1.0 mg/kg) failed to reduce
distractibility in aged monkeys, producing locomotor abnormalities and hypophagia
at doses ranging from 0.25 to 1.0 mg/kg. In young adult monkeys, however,
distractibility was significantly attenuated by administration of the 0.125 mg/kg
dose. Habituation to the distracting stimulus (under saline conditions) was
assessed throughout the study and was not evident at any time point of testing.
These data indicate that attention and recall after brief delays are impaired
following exposure to a task-relevant distracting stimulus in both aged and young
adult monkeys, but that aged monkeys are more susceptible to distraction and do
not receive significant benefit from MPH administration.
PMID- 9542896
TI - Optical imaging and electrophysiology of rat barrel cortex. I. Responses to small
single-vibrissa deflections.
AB - A study was undertaken to investigate the response of the rodent somatosensory
barrel cortex to single-whisker, near-threshold vibrissal stimuli. Cortical
responses to controlled whisker deflections were recorded by (i) conventional
multi-unit extracellular recording within the cytochrome oxidase rich barrels
centers and the interbarrel septa, and (ii) intrinsic signal optical imaging, a
technique that provides a spatial view of cortical activation thought to be
related to the deoxygenation of hemoglobin in activated areas. Barrel cortex
neurons responded weakly to whisker deflections of 0.04 degrees. Their response
to a series of small stimuli of increasing amplitude was well-fitted by a
logarithmic function. Responses to larger stimuli declined monotonically with
distance from the center of the barrel column, and were characterized by greater
onset and offset firing rates, by greater post-excitatory reduction of firing to
below spontaneous levels, and by shorter response latency. In comparison to
measurements taken previously from primary vibrissal afferent fibers, we conclude
that cortical cells can respond to activity in a very small fraction of first
order sensory neurons.
PMID- 9542897
TI - Optical imaging and electrophysiology of rat barrel cortex. II. Responses to
paired-vibrissa deflections.
AB - A study was undertaken to investigate the response of the rodent somatosensory
barrel cortex to paired-whisker stimuli. Cortical responses to controlled whisker
deflections were recorded by (i) conventional multi-unit extracellular recording
within the cytochrome oxidase rich barrels centers, and (ii) intrinsic signal
optical imaging, a technique that measures an optical correlate of neuronal
activity thought to be related to the deoxygenation of hemoglobin in activated
regions. Stimuli were applied to two whiskers in sequence, at temporal
separations ranging from 0 to 60 ms. Over intervals of 10-40 ms, the primary
effect of paired-whisker stimulation was suppressive. We suggest that paired
whisker inhibition results from the activation of layer IV fast-spike units
within the principle whisker's barrel, by excitatory input arriving from a
surround-whisker. Paired-whisker stimulation produces inhibition in intrinsic
images, because it results in a net reduction in layer II/III and/or layer IV
metabolism. Intra-cortical inhibition may serve to convert the sequence of inputs
from the whisker array into a barrel cortex magnitude code that can be read by
higher cortical areas.
PMID- 9542898
TI - Enzyme-linked immunosorbent assay using recombinant OspC and the internal 14-kDa
flagellin fragment for serodiagnosis of early Lyme disease.
AB - The outer surface protein C (OspC) and the internal 14-kDa flagellin fragment of
strain GeHo of Borrelia burgdorferi sensu stricto were expressed as recombinant
proteins in Escherichia coli and were purified for use in an immunoglobulin M
(IgM) enzyme-linked immunosorbent assay (OspC-14-kDa antigen ELISA). No hint at
disturbing protein-protein interferences, which might influence the availability
of immunoreactive epitopes, was found when the recombinant antigens were combined
in the ELISA. The recombinant OspC-14-kDa antigen ELISA was compared to a
commercial IgM ELISA that used a detergent cell extract from Borrelia afzelii PKo
as the antigen. According to the manufacturer's information, the cell extract
contains, in addition to other antigens, the following diagnostically relevant
antigens: the 100-kDa (synonyms, 93- and 83-kDa antigens), 41-kDa, OspA, OspC,
and 17-kDa antigens. The specificity was adjusted to 95% on the basis of data for
154 healthy controls. On testing of 104 serum samples from patients with erythema
migrans (EM), the sensitivity of the recombinant ELISA (46%) for IgM antibodies
was similar to that of the commercial ELISA (45%). However, when 42 serum samples
from patients with polyclonal B-cell stimulation due to an Epstein-Barr virus
infection were tested, false-positive reactions were significantly less frequent
in the recombinant ELISA (10%) than in the whole-cell-extract ELISA (23%). OspC
displays sequence heterogeneity of up to 40% according to the genomospecies.
However, when the reactions of serum specimens from controls and EM patients with
OspC from representative strains of B. burgdorferi sensu stricto (strain GeHo)
and B. afzelii (strain PKo) were compared in an ELISA, almost no differences in
specificity and sensitivity were seen. This demonstrates that the sera
predominantly recognize the common epitopes of OspC tested in this study. In
conclusion, we suggest that the OspC-14-kDa antigens ELISA is a suitable test for
the detection of an IgM response in early Lyme disease.
PMID- 9542899
TI - Multicenter evaluation of the COBAS AMPLICOR HCV assay, an integrated PCR system
for rapid detection of hepatitis C virus RNA in the diagnostic laboratory.
AB - The benefits shown by the recent introduction of PCR for the in vitro diagnosis
of hepatitis C virus (HCV) infection has prompted the development of
standardized, ready-to-use assays that can be implemented in routine clinical
laboratories. We have evaluated the clinical performance of COBAS AMPLICOR HCV
(COBAS), the first instrument system that allows the automation of HCV RNA
amplification and detection, to determine its performance in the routine
laboratory setting. More than 2,000 specimens collected at five centers were
analyzed in parallel by the COBAS and the manual AMPLICOR HCV (AMPLICOR) tests,
and the results were compared with the results for biochemical and serological
markers of HCV. In this study the two PCR systems showed the same accuracy, with
a concordance rate of 99.8%. As expected, the correlation between serology and
PCR was not absolute because the presence of anti-HCV antibodies may be
associated with a latent or past infection. On the other hand, if the presence of
confirmed anti-HCV antibodies and elevated alanine aminotransferase levels are
taken as the "gold standard," indicating an active, ongoing infection, the COBAS
and AMPLICOR tests show high and comparable sensitivities (100%) and
specificities (98%), with positive and negative predictive values of 100 and 97%,
respectively. During the study no false-positive reactions were detected. The use
of an internal control allowed the identification of inhibitory substances that
prevented amplification for 0.3 and 0.4% of samples tested by the COBAS and
AMPLICOR tests, respectively. Compared to the manual system, the COBAS system
allowed a significant reduction of hands-on time and could improve the overall
laboratory work flow. In conclusion, these results support the use of the COBAS
and AMPLICOR tests for the molecular diagnosis of active HCV infections.
PMID- 9542901
TI - Different hepatitis C virus (HCV) RNA load profiles following seroconversion
among injecting drug users without correlation with HCV genotype and serum
alanine aminotransferase levels.
AB - Hepatitis C virus (HCV) infection often persists in association with chronic
hepatitis. Different factors have been proposed to determine the clinical outcome
of HCV infection. The aim of this study was to examine three different factors of
HCV infection among injecting drug users. Nineteen untreated HCV seroconverters
were tested longitudinally for the presence of HCV RNA by reverse transcriptase
(RT) PCR, and results were quantified by the branched-DNA (bDNA) assay. HCV
genotypes were determined with the first sample taken after HCV seroconversion.
To assess the natural course of infection, serum alanine aminotransferase (ALT)
levels were measured at three stages in every individual. The concordance between
bDNA and RT-PCR was 98.9%. Three distinct patterns were found, according to the
HCV RNA load after seroconversion during a mean follow-up period of 5 years
(range, 1 to 8 years). HCV genotype 1a was predominant (52.6%). There was a
significant increase in serum ALT levels (mean 55.5 U/liter) in the early phase
of HCV infection, compared with basal serum ALT levels before HCV seroconversion
and at the end of the follow-up period. Three distinct HCV RNA load profiles were
found, without apparent relationship to genotype and serum ALT levels in the
first 5 years of HCV infection.
PMID- 9542900
TI - Molecular identification of Gemella species from three patients with
endocarditis.
AB - Gemella morbillorum and Gemella haemolysans are opportunistic pathogens which
cause endocarditis and other severe infections. We report on three patients with
endocarditis, one with endocarditis caused by G. haemolysans and two with
endocarditis caused by G. morbillorum. The paucity of reports concerning these
bacteria is probably related to the difficulties associated with their
identification. For example, one of the strains reported in this study was
originally sent to our laboratory with a preliminary characterization as a short
"gram-negative" coccobacillus, highlighting the specific problem associated with
Gram staining of these bacteria. The usefulness of 16S rRNA gene amplification,
partial sequencing, and comparison of the nucleotide sequence to those in
databases when standard phenotypic identification schemes are not helpful is
emphasized. We also suggest that the use of simple tests, such as testing
susceptibility to vancomycin for gram-negative bacteria and colistin for gram
positive bacteria, could prevent misinterpretation of Gram staining in gram
variable bacteria such as Gemella spp.
PMID- 9542902
TI - Isolation and characterization of verocytotoxin-producing Escherichia coli O157
strains from Dutch cattle and sheep.
AB - In the periods from July to November 1995 and 1996, fecal samples from Dutch
cattle and sheep were collected at the main slaughterhouses of The Netherlands,
located at different geographic sites. The samples were examined for the presence
of verocytotoxin (VT)-producing Escherichia coli (VTEC) of serogroup 0157. E.
coli O157 strains could be isolated from 57 (10.6%) of 540 adult cattle, 2 (0.5%)
of 397 veal calves, 2 (3.8%) of 52 ewes, and 2 (4.1%) of 49 lambs. Immunomagnetic
separation with O157-specific-antibody-coated beads appeared to be significantly
more sensitive than conventional plating for detection of the organism in feces.
With the exception of two isolates from adult cattle which appeared to be
negative for VT genes, all animal isolates were positive for both VT (VT1 and/or
VT2) and E. coli attaching-and-effacing gene sequences, and therefore, they were
regarded as potential human pathogens. Although genomic typing by pulsed-field
gel electrophoresis revealed a wide variety of distinct restriction patterns,
comparison of the 63 animal isolates with 33 fecal O157 VTEC strains previously
isolated from humans with the diarrhea-associated form of the hemolytic-uremic
syndrome by their phage types and VT genotypes showed a marked similarity between
animal and human isolates: 30 (90.9%) of the 33 human isolates appeared to be of
E. coli O157 strain types also isolated from cattle and sheep. It was concluded
that Dutch cattle and sheep are an important reservoir of E. coli O157 strains
that are potentially pathogenic for humans.
PMID- 9542903
TI - Comparison of RapID yeast plus system with API 20C system for identification of
common, new, and emerging yeast pathogens.
AB - The ability to identify yeast isolates by the new enzymatic RapID Yeast Plus
System was compared to the ability to identify yeast isolates by the API 20C
system. A total of 447 yeast isolates representing Blastoschizomyces capitatus,
17 Candida spp., 5 Cryptococcus spp., Geotrichum spp., 2 Hanseniaspora spp.,
Hansenula anomala, Hansenula wingei, 3 Rhodotorula spp., Saccharomyces
cerevisiae, Sporobolomyces salmonicolor, Trichosporon beigelii, and 2 Prototheca
spp. were evaluated. Also, five quality control strains (Candida spp. and
Cryptococcus laurentii) with well-documented reactivities by the RapID Yeast Plus
System were used. Each isolate was evaluated by both methods with a 48-h culture
grown at 30 degrees C on Sabouraud dextrose agar (Emmons modification) by
following the recommendations of the manufacturers. The RapID Yeast Plus System
enzymatic reactions were read after 4 h of incubation, and the API 20C
carbohydrate assimilation identification profiles were obtained after 72 h of
incubation. There was good (95.7%) agreement between the identifications obtained
by the two methods with the eight common Candida spp. and with Cryptococcus
neoformans. The agreement was lower when the emerging Candida spp. and other
yeast-like pathogens were tested (79.1 and 75.2%, respectively). These
preliminary data suggest the potential utility of the RapID Yeast Plus System for
use in the clinical laboratory for the rapid identification of common yeast
pathogens as well as certain new and emerging species.
PMID- 9542904
TI - Taxonomic relationships among spotted fever group rickettsiae as revealed by
antigenic analysis with monoclonal antibodies.
AB - The spotted fever group (SFG) is made up of more than 20 different rickettsial
species and strains. Study of the taxonomic relationships among the group has
been attempted by phenotypic, genotypic, and phylogenetic analyses. In this
study, we determined taxonomic relationships among the SFG rickettsiae by
comparative analysis of immunogenic epitopes reactive against a panel of
monoclonal antibodies. A total of 98 monoclonal antibodies, which were directed
against epitopes on the major immunodominant proteins or on the
lipopolysaccharide-like antigens of strains of Rickettsia africae, Rickettsia
conorii, Rickettsia massiliae, Rickettsia akari, Rickettsia sibirica, and
Rickettsia slovaca, were used in the study. The distribution and expression of
the epitopes among 29 SFG rickettsiae and Rickettsia bellii were assessed by
determination of reaction titers in a microimmunofluorescence assay. The results
were scored as numerical taxonomic data, and cluster analysis was used to
construct a dendrogram. The architecture of this dendrogram was consistent with
previous taxonomic studies, and the implications of this and other findings are
discussed.
PMID- 9542905
TI - Emergence of multidrug resistance in ubiquitous and dominant Pseudomonas
aeruginosa serogroup O:11. The Greek Pseudomonas Aeruginosa Study Group.
AB - The serotypes of 88 nonreplicate nosocomial Pseudomonas aeruginosa isolates from
11 Greek hospitals were studied in relation to their antibiotic susceptibilities.
Rates of resistance to beta-lactams, aminoglycosides, and quinolones ranged from
31 to 65%, except for those to ceftazidime (15%) and imipenem (21%). Four
serotypes were dominant: O:12 (25% of isolates), O:1 (17%), O:11 (16%), and O:6
(10%). Multidrug resistance rates in the major serogroups O:12 (91%) and O:11
(79%) were higher than those in serogroups O:1 (40%) and O:6 (43%). Further
typing with respect to pulsed-field gel electrophoresis patterns following XbaI
digestion of genomic DNA discriminated the isolates into 74 types. Pulsed-field
gel electrophoresis revealed that the ubiquitous O:12 group was genetically
homogeneous, since 95% of strains belonged to two clusters of genotypic
similarity, while the O:11 strains, present in 8 of the 11 hospitals, were
distributed among five such clusters. Therefore, apart from the already reported
O:12 multidrug-resistant European clone, an O:11 population, characterized by a
serotype known to be dominant in the environment and the hospital in several
parts of the world, but previously not associated with multidrug resistance to
antibiotics, has progressed to a multidrug-resistant state.
PMID- 9542906
TI - Group A streptococcal Vir types are M-protein gene (emm) sequence type specific.
AB - The M-protein genes (emm genes) of 103 separate impetiginous Streptococcus
pyogenes isolates were sequenced and the sequence types were compared to the
types obtained by Vir typing. Vir typing is based on restriction fragment length
polymorphism (RFLP) analysis of a 4- to 7-kb pathogenicity island encoding emm
and other virulence genes. By using both HaeIII and HinfI to generate RFLP
profiles, complete concordance between Vir type and emm sequence type was found.
Comparison of the emm sequences with those in GenBank revealed new sequence types
sharing less than 90% identity with known types. Diversity in the emm sequence
was generated by corrected frameshift mutations, point mutations, and small in
frame mutations.
PMID- 9542907
TI - Identification of a novel enteric Helicobacter species in a kitten with severe
diarrhea.
AB - A previously undescribed Helicobacter sp. was recovered from a cat with severe
diarrhea. Based upon the absence of any other identifiable cause of diarrhea,
this helicobacter may be involved in the development of the disease signs. The
organism could not be cultured but was described on the basis of 16S rRNA gene
sequence analysis and morphology and appeared to be a new species, with
Helicobacter canis being the most genetically similar species. The presence of a
diarrhea-inducing helicobacter in a companion animal may pose a risk of zoonosis.
PMID- 9542908
TI - Novel recombinant-antigen enzyme immunoassay for serological diagnosis of
syphilis.
AB - Enzyme immunoassay (EIA) is an ideal method for screening large numbers of
patients for syphilis. We evaluated a novel immune-capture EIA (ICE Syphilis;
Murex Diagnostics) that uses three recombinant Treponema pallidum antigens
(TpN15, TpN17, and TpN47) and compared the results with those obtained by the
native T. pallidum antigen EIA (Captia SelectSyph-G; Centocor) that we currently
use for the serodiagnosis of syphilis. Specificity was evaluated by screening
1,184 unselected serum specimens in parallel by the ICE Syphilis and SelectSyph-G
assays, while sensitivity was tested with a panel of 101 serum specimens
containing antitreponemal antibodies (treated and untreated) from patients with
various stages of infection. The specificity of the ICE Syphilis EIA (99.8%) on
screening was significantly higher (P < 0.02) than that of the SelectSyph-G EIA
(99.2%). The sensitivity of the ICE Syphilis EIA was significantly higher (P <
0.01) than that of the SelectSyph-G EIA on both initial (99 versus 91.4%) and
repeat (100 versus 92.4%) testing. The ICE Syphilis EIA was also significantly
more sensitive (P < 0.01) than the fluorescent treponemal antibody-abs (92.4%)
but not the T. pallidum hemagglutination assay (97.1%). Sera containing
antitreponemal antibodies gave a much higher antibody index (absorbance of test
serum/kit cutoff) by the ICE Syphilis EIA than by the SelectSyph-G EIA. This
combined with the overall high sensitivity makes the ICE Syphilis EIA an ideal
test for excluding or detecting treponemal infection in human immunodeficiency
virus (HIV)-infected patients. The ICE Syphilis EIA was positive with sera from
all 15 HIV-infected patients in the study, whereas sera from 3 HIV-infected
patients were negative by the SelectSyph-G EIA. We conclude that the high
sensitivity and specificity of the ICE Syphilis EIA and its suitability for
automation make it an ideal screening test.
PMID- 9542909
TI - Differentiation of Mycobacterium ulcerans, M. marinum, and M. haemophilum:
mapping of their relationships to M. tuberculosis by fatty acid profile analysis,
DNA-DNA hybridization, and 16S rRNA gene sequence analysis.
AB - Although Mycobacterium ulcerans, M. marinum, and M. haemophilum are closely
related, their exact taxonomic placements have not been determined. We performed
gas chromatography of fatty acids and alcohols, as well as DNA-DNA hybridization
and 16S rRNA gene sequence analysis, to clarify their relationships to each other
and to M. tuberculosis. M. ulcerans and M. marinum were most closely related to
one another, and each displayed very strong genetic affinities to M.
tuberculosis; they are actually the two mycobacterial species outside the M.
tuberculosis complex most closely related to M. tuberculosis. M. haemophilum was
more distinct from M. ulcerans and M. marinum, and it appeared to be as related
to these two species as to M. tuberculosis. These results are important with
regard to the development of diagnostic and epidemiological tools such as species
specific DNA probes and PCR assays for M. ulcerans, M. marinum, and M.
haemophilum. In addition, the finding that M. ulcerans and M. marinum are more
closely related to M. tuberculosis than are other pathogenic mycobacterial
species suggests that they may be evaluated as useful models for studying the
pathogenesis of M. tuberculosis. M. marinum may be particularly useful in this
regard since strains of this species grow much more rapidly than M. tuberculosis
and yet can cause systemic disease in immunocompromised hosts.
PMID- 9542910
TI - Comparative evaluation of FUNGITEST and broth microdilution methods for
antifungal drug susceptibility testing of Candida species and Cryptococcus
neoformans.
AB - The FUNGITEST method (Sanofi Diagnostics Pasteur, Paris, France) is a microplate
based procedure for the breakpoint testing of six antifungal agents (amphotericin
B, flucytosine, fluconazole, itraconazole, ketoconazole, and miconazole). We
compared the FUNGITEST method with a broth microdilution test, performed
according to National Committee for Clinical Laboratory Standards document M27-A
guidelines, for determining the in vitro susceptibilities of 180 isolates of
Candida spp. (50 C. albicans, 50 C. glabrata, 10 C. kefyr, 20 C. krusei, 10 C.
lusitaniae, 20 C. parapsilosis, and 20 C. tropicalis isolates) and 20 isolates of
Cryptococcus neoformans. Overall, there was 100% agreement between the methods
for amphotericin B, 95% agreement for flucytosine, 84% agreement for miconazole,
83% agreement for itraconazole, 77% agreement for ketoconazole, and 76% agreement
for fluconazole. The overall agreement between the methods exceeded 80% for all
species tested with the exception of C. glabrata (71% agreement). The poorest
agreement between the results for individual agents was seen with C. glabrata
(38% for fluconazole, 44% for ketoconazole, and 56% for itraconazole) and C.
tropicalis (50% for miconazole). The FUNGITEST method misclassified as
susceptible 2 of 12 (16.6%) fluconazole-resistant isolates, 2 of 10 (20%)
itraconazole-resistant isolates, and 4 of 8 (50%) ketoconazole-resistant isolates
of several Candida spp. Further development of the FUNGITEST procedure will be
required before it can be recommended as an alternative method for the
susceptibility testing of Candida spp. or C. neoformans.
PMID- 9542911
TI - Use of immunoblot assay to define serum antibody patterns associated with
Helicobacter pylori infection and with H. pylori-related ulcers.
AB - Serology has been used worldwide to detect Helicobacter pylori infection. Using
an immunoblot assay with an antigen from strain ATCC 43579, we sought to
determine the antibodies which were good markers of colonization and the antibody
patterns associated with ulcers or atrophy. Out of 98 dyspeptic patients, 41 were
colonized by H. pylori, based on a positive culture or on positive results of
both a urease test and direct examination. These 41 patients were seropositive by
an enzyme immunoassay, and 12 of them had ulcers and 29 had evidence of atrophy.
Fifty-seven of the 98 patients were noncolonized. Twenty-five of the 57 had
evidence of gastric atrophy, and 10 were seropositive; 5 of these 10 had ulcers.
By Western blot analysis, 12 antibodies were significantly more frequent in sera
from colonized patients, and they produced immunoreactive bands at 125, 87, 74,
66, 54, 48, 46, 42, 35, 30, 16 and 14 kDa. The presence of at least one band at
54, 35, or 42 kDa was the best marker of infection (sensitivity, 95%;
specificity, 82%). In the group of colonized patients, none of the antibody
patterns were correlated to gastric atrophy. Conversely, the presence of a band
at 125, 87, or 35 kDa was statistically associated with the presence of an ulcer.
The simultaneous presence of bands at 87 and 35 kDa predicted the risk of ulcers
with 83% sensitivity and 69% specificity. By using CagA-positive and VacA
positive strains and CagA-negative and VacA-negative isogenic mutants, the
antigens corresponding to the bands at 125 and 87 kDa were shown to be CagA and
VacA, respectively. On the other hand, the 35-kDa antigen is a novel
uncharacterized component of H. pylori. These results may help to optimize the
composition of antigenic preparations for serologic detection of H. pylori
colonization. Immunoblot assay would be useful for screening patients at high
risk of ulcers.
PMID- 9542912
TI - Identification of a new DNA region specific for members of Mycobacterium
tuberculosis complex.
AB - The successful use of DNA amplification for the detection of tuberculous
mycobacteria crucially depends on the choice of the target sequence, which
ideally should be present in all tuberculous mycobacteria and absent from all
other bacteria. In the present study we developed a PCR procedure based on the
intergenic region (IR) separating two genes encoding a recently identified
mycobacterial two-component system named SenX3-RegX3. The senX3-regX3 IR is
composed of a novel type of repetitive sequence, called mycobacterial
interspersed repetitive units (MIRUs). In a survey of 116 Mycobacterium
tuberculosis strains characterized by different IS6110 restriction fragment
length polymorphisms, 2 Mycobacterium africanum strains, 3 Mycobacterium bovis
strains (including 2 BCG strains), and 1 Mycobacterium microti strain, a specific
PCR fragment was amplified in all cases. This collection included M. tuberculosis
strains that lack IS6110 or mtp40, two target sequences that have previously been
used for the detection of M. tuberculosis. No PCR fragment was amplified when DNA
from other organisms was used, giving a sensitivity of 100% and a specificity of
100% in the confidence limit of this study. The numbers of MIRUs were found to
vary among strains, resulting in six different groups of strains on the basis of
the size of the amplified PCR fragment. However, the vast majority of the strains
(approximately 90%) fell within the same group, containing two 77-bp MIRUs
followed by one 53-bp MIRU.
PMID- 9542914
TI - Identification and purification of specific Penicillium marneffei antigens and
their recognition by human immune sera.
AB - Disseminated infection with the dimorphic pathogenic fungus Penicillium marneffei
is increasingly seen among patients with AIDS in southeast Asian countries.
Previous studies have demonstrated the presence of humoral immune responses to
this fungus in patient sera; we have confirmed this work using sera from P.
marneffei-infected patients (n = 21) to develop Western blots of P. marneffei
cytoplasmic yeast antigen (CYA). P. marneffei CYA was then partially purified by
liquid isoelectric focusing, and fractions were subjected to sodium dodecyl
sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting.
Immunoenzyme development of the Western blots with pooled sera from patients with
P. marneffei infection and with pooled sera from patients with aspergillosis (n =
20), candidiasis (n = 10), cryptococcosis (n = 9), and histoplasmosis (n = 11)
revealed three antigens with relative molecular masses of 61, 54, and 50 kDa.
These antigens were specifically recognized by the pooled sera from the P.
marneffei-infected patients. The 61- and 54-kDa antigens were subsequently
purified to homogeneity by preparative gel electrophoresis, and the 50-kDa
antigen was partially purified by the same technique. N-terminal amino acid
sequencing revealed that the 61-kDa antigen had a strong homology (87% identity)
with the antioxidant enzyme catalase. The three antigens were then subjected to
SDS-PAGE and Western blotting and to immunoenzyme development with individual
patient sera; sera from 86% of P. marneffei-infected patients recognized the 61
kDa antigen, sera from 71% recognized the 54-kDa antigen, and sera from 48%
recognized the 50-kDa antigen. These specifically recognized antigens are the
first to be purified from P. marneffei and can be used either singly or in
combination to detect antibody responses in a large percentage of individuals
infected with P. marneffei.
PMID- 9542913
TI - Diversity of Helicobacter pylori vacA and cagA genes and relationship to VacA and
CagA protein expression, cytotoxin production, and associated diseases.
AB - The vacuolating cytotoxin and the cytotoxin-associated protein, encoded by vacA
and cagA, respectively, are important virulence determinants of Helicobacter
pylori. Sixty-five H. pylori strains were isolated from dyspeptic patients (19
with peptic ulcer disease, 43 with chronic gastritis, and 3 with gastric cancer)
and studied for differences in the vacA and cagA genes and their relationship to
VacA and CagA expression, cytotoxin activity, and the clinical outcome of
infection. By PCR, fifty-four (83.1%) of 65 strains had the vacA signal sequence
genotype s1 and only 10 (15.4%) had the type s2. After primer modification, the
vacA middle-region types m1 and m2 were detected in 24 (36.9%) and 41 (63.1%)
strains, respectively. The combinations s1-m2 (31 [47.7%]) and s1-m1 (23 [35.4%])
occurred more frequently than s2-m2 (10 [15.4%]) (P = 0.01). No strain with the
combination s2-m1 was found. All 19 patients with peptic ulcers harbored type s1
strains, in contrast to 32 (74.4%) of 43 patients with gastritis (P = 0.02). The
vacA genotype s1 was associated with the presence of cagA (P < 0.0001), VacA
expression (P < 0.0001), and cytotoxin activity (P = 0.003). The cagA gene was
detectable in 48 (73.8%) of 65 isolates and present in 16 (84.2%) of 19 ulcer
patients and 29 (67.4%) of 43 patients with gastritis (P = 0.17). The vacA
genotypes of German H. pylori isolates are identical to those previously
reported. H. pylori strains of vacA type s1 are associated with the occurrence of
peptic ulceration and the presence of cagA, cytotoxin activity, and VacA
expression.
PMID- 9542915
TI - Evaluation of Pyloriset Screen, a rapid whole-blood diagnostic test for
Helicobacter pylori infection.
AB - Helicobacter pylori infection can be detected by several invasive tests based on
gastroscopy and by noninvasive methods such as serologic assays. Noninvasive
tests can be used not only in addition to invasive tests but also by themselves
to screen for H. pylori infection in patients who are not in urgent need of
endoscopy. Lately, rapid qualitative serologic tests have been developed. In the
present study, the accuracy of a novel rapid whole-blood test, Pyloriset Screen,
detecting immunoglobulin G (IgG) and IgA antibodies against H. pylori was
evaluated. A total of 207 consecutive adult outpatients referred for upper
endoscopy were enrolled. Gastric biopsy specimens were taken from the antrum and
corpus for histologic examination and rapid urease testing. Cultures were
available for 113 patients. Serum samples collected from all patients were tested
for H. pylori antibodies by two enzyme immunoassays (EIAs) (Pyloriset EIA and an
in-house EIA), a rapid latex agglutination test (Pyloriset Dry), and Pyloriset
Screen. Patients were considered H. pylori positive if helicobacters were seen on
histologic examination (77 patients) or, if in combination with histologically
verified (although helicobacter-negative) gastritis, their IgG antibody titers
were elevated in the two EIAs (five patients). The Pyloriset Screen test had a
sensitivity of 95%, a specificity of 94%, a positive predictive value of 91%, and
a negative predictive value of 97%. Among 63 patients under the age of 45 years,
the Pyloriset Screen test did not miss a single H. pylori diagnosis, and only 1
patient had a false-positive result. Pyloriset Screen could be used reliably to
screen for H. pylori infection.
PMID- 9542916
TI - Flow cytometric determination of ganciclovir susceptibilities of human
cytomegalovirus clinical isolates.
AB - A flow cytometric assay has been developed for the measurement of
susceptibilities to ganciclovir of laboratory strains and clinical isolates of
human cytomegalovirus (HCMV). The assay uses fluorochrome-labeled monoclonal
antibodies to HCMV immediate-early and late antigens to identify HCMV-infected
cells and flow cytometry to detect and quantitate the number of antigen-positive
cells. By this assay, the 50 and 90% inhibitory concentrations (IC50 and IC90,
respectively) of ganciclovir for the AD169 strain of HCMV were 1.7 and 9.2
microM, respectively, and the IC50 for the ganciclovir-resistant D6/3/1
derivative of the AD169 strain was greater than 12 microM. The ganciclovir
susceptibilities of 17 HCMV clinical isolates were also determined by flow
cytometric analysis of the effect of ganciclovir on late-antigen synthesis in
HCMV-infected cells. The average IC50 of ganciclovir for drug-sensitive HCMV
clinical isolates was 3.79 microM (+/-2.60). The plaque-reduction assay for these
clinical isolates yielded an average IC50 of 2.80 microM (+/-1.46). Comparison of
the results of the flow cytometry assays with those obtained from the plaque
reduction assays demonstrated acceptable bias and precision. Flow cytometric and
plaque-reduction analysis of cells infected with ganciclovir-resistant clinical
isolates failed to show a reduction in the percentage of late-antigen-positive
cells or PFU, even at 96 microM ganciclovir. The flow cytometric assay for
determining ganciclovir susceptibility of HCMV is quantitative, and objective,
and potentially automatable, and its results are reproducible among laboratories.
PMID- 9542917
TI - Epidemiology of a dominant clonal strain of vancomycin-resistant Enterococcus
faecium at separate hospitals in Boston, Massachusetts.
AB - In 1996, the dominant (43%) strain of vancomycin-resistant enterococci (VRE; type
A) at Massachusetts General Hospital was identified at Brigham and Women's
Hospital (BWH). To characterize the epidemiology of infection with type A
isolates of VRE at BWH, we collected demographic and clinical data for all
patients from whom VRE were isolated from a clinical specimen through September
1996. The first clinical isolates from all BWH patients from whom VRE were
isolated were typed by pulsed-field gel electrophoresis of SmaI digests of
chromosomal DNA. Among patients hospitalized after the first patient at BWH
infected with a type A isolate of VRE was identified, exposures were compared
between patients who acquired type A isolates of VRE and those who acquired other
types of VRE. Isolates from 99 patients identified to have acquired VRE were most
commonly from blood (n = 27), urine (n = 19), or wounds (n = 19). Three months
after the index patient arrived at BWH and at a time when > or =12 types of
strains of VRE were present, type A isolates of VRE became dominant; 39 of 75
(52%) of the study cohort had acquired type A isolates of VRE. We found no
association between the acquisition of type A isolates of VRE and transfer from
another institution or temporal overlap by service, ward, or floor with patients
known to have acquired type A isolates of VRE. By multivariate analysis, only
residence in the medical intensive care unit (adjusted odds ratio [OR], 3.2; 95%
confidence interval [CI], 1.4 to 107) and the receipt of two or more antibiotics
per patient-day (adjusted OR, 12.2; 95% CI, 1.2 to 9.0) were associated with the
acquisition of strain A. This strain of VRE, dominant at two Boston hospitals,
was associated with intensity of antibiotic exposures (i.e., two or more
antibiotics per patient-day). We hypothesize that this strain may have
unidentified properties providing a mechanism favoring its spread and dominance
over other extant isolates, and further studies are needed to define these
properties.
PMID- 9542918
TI - Epidemiological analysis of Salmonella enteritidis isolates from humans and
broiler chickens in Thailand by phage typing and pulsed-field gel
electrophoresis.
AB - To determine the phage types (PT) of Salmonella enteritidis found in Thailand and
to clarify the potential for human infection by S. enteritidis in broiler chicken
meat, human and poultry isolates taken from Thailand between 1990 and 1997 were
phage typed and analyzed by pulsed-field gel electrophoresis (PFGE). Ten
different PT were found among the 302 isolates phage typed, with PT 4 being the
most frequent in human (73.9%) and poultry (76.2%) isolates, followed by PT 1
(8.0%), 8 (3.6%), and 7a (2.2%) in human isolates and by PT 7a (4.9%), 1 (3.7%),
and 12 (2.4%) in poultry isolates. Of the 53 isolates analyzed by PFGE, 45 showed
an indistinguishable pattern (pattern A) by BlnI-digested PFGE and the other 8
isolates showed a very similar pattern that differed by only a few bands. These
results indicate the spread of a genetically identical clone of S. enteritidis in
humans and poultry in Thailand.
PMID- 9542919
TI - Detection of Mycobacterium tuberculosis complex in sputum specimens by the
automated Roche Cobas Amplicor Mycobacterium Tuberculosis Test.
AB - Three hundred twenty-four sputum specimens from 151 patients with suspected
active pulmonary tuberculosis were tested for the presence of the Mycobacterium
tuberculosis complex with auramine fluorochrome stain and automated PCR assay
(Roche Cobas Amplicor Mycobacterium Tuberculosis Test [MTB]). The results were
compared with those of the conventional Lowenstein-Jensen tube culture and the
BACTEC radiometer liquid culture. A total of 76 specimens from 32 patients were
culture positive for M. tuberculosis. In addition, 37 specimens from 15 patients
were smear and culture positive for other Mycobacterium species but negative by
the present nucleic acid amplification method and thus were not included in the
comparison. Compared with culture, the sensitivities, specificities, and positive
and negative predictive values for acid-fast smear were 67, 98, 93, and 91% and
those for the Cobas Amplicor MTB were 83, 99, 97, and 95%, respectively. When
three consecutive sputum specimens per patient could be obtained, the sensitivity
of the Cobas Amplicor MTB improved to 91%, whereas the sensitivity of the acid
fast smear remained unchanged.
PMID- 9542920
TI - Performance of a PCR assay for detection of Pneumocystis carinii from respiratory
specimens.
AB - This study evaluates the performance of a PCR assay for the detection of
Pneumocystis carinii from respiratory specimens that has been designed for use in
the clinical microbiology laboratory. The test includes a simple method for
nucleic acid extraction and amplification, a colorimetric probe hybridization
technique for detection of amplicons, and an internal control to evaluate for the
presence of inhibitors of amplification. Two hundred thirty-two clinical
specimens (120 induced-sputum [IS] and 112 bronchoalveolar lavage [BAL]
specimens) from 168 patients were tested by both immunofluorescent (direct
fluorescent-antibody [DFA]) staining and PCR. Of the 112 BAL specimens, 17 were
positive for P. carinii by DFA staining and PCR. An additional two specimens were
DFA negative and PCR positive. For BAL specimens, the sensitivity and specificity
of PCR compared to DFA were 100 and 98%, respectively. Eighteen IS specimens were
positive for P. carinii by DFA, and 27 were positive by PCR. One of the 18 DFA
positive IS specimens was negative by PCR; this patient had just completed
therapy for P. carinii pneumonia. Of the 10 specimens that were PCR positive and
DFA negative, 4 were from patients who had a subsequent BAL specimen that was
positive by DFA and PCR. For IS specimens, the sensitivity of DFA and PCR was 82
and 95%, respectively. The specificity of PCR for IS specimens was 94%. Due to
the high sensitivity of PCR for the detection of P. carinii from IS specimens, a
PCR-based diagnostic test may be a useful screening test and may alleviate the
need for bronchoscopy in some patients.
PMID- 9542921
TI - Identification of Lactococcus garvieae by PCR.
AB - Lactococcus garvieae junior synonym Enterococcus seriolicida) is an emerging
zoonotic agent isolated from economically important fish (rainbow trout and
yellowtail), from cattle, and from humans. Clindamycin susceptibility is the only
phenotypic test which can differentiate L. garvieae from Lactococcus lactis,
another emerging agent in humans. A PCR assay for the identification of L.
garvieae was developed and resulted in an amplified fragment of 1,100 bp in size.
The PCR assay was shown to be specific to L. garvieae. The PCR assay was positive
for all the L. garvieae strains tested, which originated from three different
continents (Asia, Australia, and Europe). The PCR assay was negative for the
phenotypically similar L. lactis and for all the other fish pathogens tested,
including Streptococcus iniae and Aeromonas salmonicida. The PCR assay was
applied to plasma obtained from diseased animals and was found sensitive enough
to detect bacteria from 1 microl of plasma. The PCR assay that was developed is
the only practical test besides the clindamycin test which can specifically
identify the zoonotic agent L. garvieae and which can differentiate it from L.
lactis.
PMID- 9542922
TI - Soft salt-mannitol agar-cloxacillin test: a highly specific bedside screening
test for detection of colonization with methicillin-resistant Staphylococcus
aureus.
AB - The early detection of colonization with methicillin-resistant Staphylococcus
aureus (MRSA) of patients in intensive-care units is an essential step in the
strategy for preventing MRSA epidemics. In this study, tubes containing soft salt
mannitol agar with cloxacillin (6 microg/ml) (SSMAC) were prepared for
inoculation of clinical samples at patients' bedsides by personnel of an
intensive-care unit. A total of 1,914 swabs from different sample sites of 81
patients were dipped into SSMAC tubes, and after 24 h of incubation (in an
incubator located near the intensive-care unit), an evident color change was
considered by the intensive-care-unit personnel to be an MRSA alarm. Sixty-three
(3.3%) SSMAC tubes were considered positive for MRSA, 1,827 (95.4%) were
considered negative, and 24 (1.2%) were considered intermediate. Compared with
values for parallel conventional surveillance cultures for MRSA, excluding tubes
with intermediate results, the SSMAC test had a sensitivity of 72.7%, a
specificity of 99.2%, a positive predictive value of 76.2%, and a negative
predictive value of 99.0%. When intermediate tubes were considered positive, the
corresponding values were 75.3, 98.2, 63.2, and 99.0%, respectively. The
sensitivity and specificity values of the test to identify MRSA-colonized
patients were 89.4 and 100%, respectively. Oropharyngeal and naris specimens were
the most reliable samples for MRSA detection. False-negative results were
frequent in bronchial aspirates with low (< 10(3) to 10(6) CFU/ml) MRSA counts.
False-positive results were mainly due to methicillin-resistant Staphylococcus
haemolyticus. The SSMAC tube is a useful, rapid, and inexpensive tool for the
early identification of MRSA-colonized patients and, consequently, for the
implementation of measures to prevent the spread of MRSA.
PMID- 9542923
TI - Evaluation of use of a new chromogenic agar in detection of urinary tract
pathogens.
AB - CHROMagar Orientation, a new chromogenic medium, was evaluated for the detection
and differentiation of gram-positive and gram-negative pathogenic microorganisms
in 900 urine samples from hospitalized patients. Performance characteristics of
the medium were evaluated in comparison to those of 5% sheep blood and MacConkey
agars by direct inoculation of the urine samples on the three media. Four gram
negative and two gram-positive strains as well as one yeast control strain from
the American Type Culture Collection were used to ensure quality control.
CHROMagar Orientation succeeded in detecting all the urine pathogens that were
detected by the reference media, including gram-negative bacilli, staphylococci,
streptococci, and yeasts. Colony color and morphology on CHROMagar Orientation
accurately differentiated Escherichia coli, Proteus mirabilis, Proteus vulgaris,
Pseudomonas aeruginosa, and Acinetobacter spp. Owing to the similarity in the
pigmentation produced by Klebsiella, Enterobacter, and Citrobacter isolates, the
medium failed to distinguish among them; however, these isolates were easily
recognized as coliforms because of their metallic blue coloration. Staphylococci
were clearly perceptible: S. aureus and S. epidermidis grow in regular-size
colonies that range from opaque white to yellowish, and S. saprophyticus produces
opaque pink colonies. All streptococcus strains, including those from groups B
and C, were detected. They grow as undifferentiated flat dry diffused colonies,
and additional tests were required for identification. Enterococci were easily
discriminated by their strong turquoise pigmentation and their typical growth on
the agar's surface. Yeast grow in typical creamy wet convex colonies. The
accuracy of antibiotic susceptibility determinations according to standard
methods was also tested by picking isolates directly from CHROMagar Orientation.
The results showed excellent correlation with those obtained with microorganisms
picked from reference media. Owing to the ease in differentiating mixed flora on
CHROMagar Orientation, antimicrobic susceptibility tests were performed directly
from primary isolates in all cases without the need for subcultures.
PMID- 9542924
TI - Comparison of PCR and microscopy for detection of Cryptosporidium parvum in human
fecal specimens: clinical trial.
AB - PCR technology offers alternatives to conventional diagnosis of Cryptosporidium
for both clinical and environmental samples. We compared microscopic examination
by a conventional acid-fast staining procedure with a recently developed PCR test
that can not only detect Cryptosporidium but is also able to differentiate
between what appear to be host-adapted genotypes of the parasite. Examinations
were performed on 511 stool specimens referred for screening on the basis of
diarrhea. PCR detected a total of 36 positives out of the 511 samples, while
routine microscopy detected 29 positives. Additional positives detected by PCR
were eventually confirmed to be positive by microscopy. A total of five samples
that were positive by routine microscopy at Western Diagnostic Pathology but
negative by PCR and by microscopy in our laboratory were treated as false
positives. Microscopy therefore exhibited 83.7% sensitivity and 98.9% specificity
compared to PCR. PCR was more sensitive and easier to interpret but required more
hands-on time to perform and was more expensive than microscopy. PCR, however,
was very adaptable to batch analysis, reducing the costs considerably. Bulk
buying of reagents and modifications to the procedure would decrease the cost of
the PCR test even more. An important advantage of the PCR test, its ability to
directly differentiate between different Cryptosporidium genotypes, will assist
in determining the source of cryptosporidial outbreaks. Sensitivity, specificity,
ability to genotype, ease of use, and adaptability to batch testing make PCR a
useful tool for future diagnosis and studies on the molecular epidemiology of
Cryptosporidium infections.
PMID- 9542925
TI - Bordetella parapertussis infection in children: epidemiology, clinical symptoms,
and molecular characteristics of isolates.
AB - The clinical trial conducted in Italy to evaluate the efficacy of acellular
pertussis vaccines provided an opportunity to estimate the frequency of clinical
infections with Bordetella parapertussis and to compare the clinical
characteristics of children suffering from Bordetella pertussis illness with
those of children with B. parapertussis illness. This study dealt with 76 B.
parapertussis infections diagnosed from a population of 15,601 children
participating in the follow-up of suspected cases of pertussis. An overall
incidence of 2.1 cases of laboratory-confirmed parapertussis per 1,000 person
years was observed. Children affected by B. parapertussis infections showed a
less severe clinical picture both in the duration of symptoms and in the
percentage of patients affected, even when compared with vaccinated children with
pertussis. To characterize the isolated strains, we performed assays for
susceptibility to erythromycin and sulfamethoxazole-trimethoprim, and we examined
the genomic DNAs by pulsed-field gel electrophoresis. The results showed a high
degree of genetic stability among B. parapertussis strains regardless of time of
collection and geographical distribution.
PMID- 9542926
TI - Diversity of DNA fingerprints of Mycobacterium tuberculosis isolates in the
United States.
AB - To investigate the diversity of IS6110 fingerprints of Mycobacterium tuberculosis
isolates in the United States and to determine if matching IS6110 fingerprints
represent recent interstate tuberculosis transmission, we performed restriction
fragment length polymorphism analysis of M. tuberculosis isolates from 1,326
patients in three geographically separated states. Seven hundred ninety-five
different IS6110 fingerprint patterns were generated, and pattern diversity was
similar in each state. Ninety-six percent of the fingerprint patterns were
observed in only one state, demonstrating that most IS6110 fingerprint patterns
are confined to a single geographic location. Of the IS6110 fingerprint patterns
that were shared by isolates from more than one state, most isolates with 1 to 5
IS6110 copies were separable by pTBN12 fingerprinting whereas those with > 15
copies were not. One high-copy-number M. tuberculosis strain had identical IS6110
and pTBN12 fingerprints and included 57 isolates from three states.
Epidemiological data demonstrated significant recent transmission of tuberculosis
within each city but not among the states. This suggests that identical
fingerprints of isolates from geographically separate locations most likely
reflect interstate tuberculosis transmission in the past, with subsequent
intrastate spread of disease. Further evaluation of M. tuberculosis strains that
cause outbreaks in different geographic locations will provide insight into the
epidemiological and bacteriological factors that facilitate the spread of
tuberculosis.
PMID- 9542927
TI - Utility of major leukocyte subpopulations for monitoring secondary
cytomegalovirus infections in renal-allograft recipients by PCR.
AB - The feasibility of the major peripheral blood leukocyte (PBL) subsets for use in
qualitative and quantitative PCR to monitor secondary cytomegalovirus (CMV)
infection and ganciclovir therapy was assessed with 188 blood samples derived
from 40 CMV immunoglobulin G-positive renal-allograft recipients. In pp65 antigen
positive patients all leukocyte fractions, but only 79.5% of plasma preparations,
were PCR positive. In pp65 antigen-negative samples from patients after antiviral
treatment only 7.3% of polymorphonuclear cell (PMNL) samples, but 81.8% of
peripheral blood mononuclear cells (PBMC), and 10.9% of plasma samples remained
PCR positive. Similarly, in patients with latent infections only 5.0% of PMNL,
but 51.7% of PBMC preparations, and 8.0% of plasma samples were PCR positive.
Regarding patients with active CMV infection, CMV DNA copy numbers in PMNL
correlated significantly with pp65 antigen-positive cell counts before and after
onset of ganciclovir therapy. Significant differences in CMV DNA copy numbers in
PMNL and plasma were observed (i) between patients with symptomatic infection and
those with asymptomatic infection and (ii) between patients with active infection
and those with latent infection. In contrast, PBMC harbored equally low CMV DNA
levels both in patients with active infection and those with latent infections,
and no decline of CMV DNA load in PBMC was observed during antiviral treatment.
We conclude that detection of CMV DNA in PMNL, not in PBMC, is associated with
active infections and is more sensitive than detection of CMV DNA in plasma.
Negative PCR results for PMNL after antiviral therapy indicate recovery, and
fewer unwanted positive results occur compared to PBMC and plasma. Therefore,
purified PMNL should be preferred for analysis by qualitative CMV PCR to avoid
unwanted positive results. The CMV DNA load in PBMC compared with that in PMNL is
negligible during active infection, so mixed PBL are sufficient for use in
quantitative PCR.
PMID- 9542928
TI - Culture-confirmed reinfection of a person with different strains of Borrelia
burgdorferi sensu stricto.
AB - In recent years, the utility of serum-based diagnostic testing for Lyme disease
has improved substantially; however, recovery by culture of the bacterium from
skin biopsies of suspected patients is still the only definitive laboratory test.
Reinfection of patients has been assumed to occur but as yet has not been
documented by serial isolates from the same person. We present a case of culture
confirmed reinfection of a patient in Menominee County, Michigan. Borrelia
burgdorferi was isolated from the skin punch biopsy specimens during each episode
of erythema migrans (EM) and was subjected to molecular strain typing, genetic
analysis of two outer surface protein genes, protein profile analysis, and serum
antibody response testing. Results show that these isolates are distinct strains
of the bacterium and that the two episodes of EM were caused by independent
infections. This report describes the documented, culture-confirmed reinfection
of a human by two different strains of B. burgdorferi.
PMID- 9542929
TI - Characterization of staphylococci with reduced susceptibilities to vancomycin and
other glycopeptides.
AB - During the last several years a series of staphylococcal isolates that
demonstrated reduced susceptibility to vancomycin or other glycopeptides have
been reported. We selected 12 isolates of staphylococci for which the vancomycin
MICs were > or =4 microg/ml or for which the teicoplanin MICs were > or =8
microg/ml and 24 control strains for which the vancomycin MICs were < or =2
microg/ml or for which the teicoplanin MICs were < or =4 microg/ml to determine
the ability of commercial susceptibility testing procedures and vancomycin agar
screening methods to detect isolates with reduced glycopeptide susceptibility. By
PCR analysis, none of the isolates with decreased glycopeptide susceptibility
contained known vancomycin resistance genes. Broth microdilution tests held a
full 24 h were best at detecting strains with reduced glycopeptide
susceptibility. Disk diffusion did not differentiate the strains inhibited by 8
microg of vancomycin per ml from more susceptible isolates. Most of the isolates
with reduced glycopeptide susceptibility were recognized by MicroScan
conventional panels and Etest vancomycin strips. Sensititre panels read visually
were more variable, although with some of the panels MICs of 8 microg/ml were
noted for these isolates. Vitek results were 4 microg/ml for all strains for
which the vancomycin MICs were > or =4 microg/ml. Vancomycin MICs on Rapid
MicroScan panels were not predictive, giving MICs of either < or =2 or > or =16
microg/ml for these isolates. Commercial brain heart infusion vancomycin agar
screening plates containing 6 microg of vancomycin per ml consistently
differentiated those strains inhibited by 8 microg/ml from more susceptible
strains. Vancomycin-containing media prepared in-house showed occasional growth
of susceptible strains, Staphylococcus aureus ATCC 29213, and on occasion,
Enterococcus faecalis ATCC 29212. Thus, strains of staphylococci with reduced
susceptibility to glycopeptides, such as vancomycin, are best detected in the
laboratory by nonautomated quantitative tests incubated for a full 24 h.
Furthermore, it appears that commercial vancomycin agar screening plates can be
used to detect these isolates.
PMID- 9542931
TI - Evaluation of four methods for rapid identification of Staphylococcus aureus from
blood cultures.
AB - The identification of Staphylococcus aureus directly from blood cultures is
clinically relevant, but it requires a test that is both rapid and reliable.
Previously, biochemical, immunological, tube coagulase, and thermostable
endonuclease methods have shown variable sensitivity and specificity. Testing
directly from blood culture broth has not been described for the latex kit
Staphaurex Plus (Murex Diagnostics Ltd.), and the modified conventional tests
have not been used with the newer, continuously monitored blood culture systems.
In addition, the commercial RAPIDEC staph kit (bioMerieux Vitek, Inc.) has been
used to detect S. aureus directly from the Vital blood culture system
(bioMerieux, Marcy l'Etoile, France), but its performance has not been evaluated
with other continuously monitored systems. A total of 201 clinical blood cultures
(BACTEC 9240 culture system; Johnston Laboratories, Inc.) in which a Gram stain
showed gram-positive cocci resembling staphylococci were evaluated prospectively.
The Staphaurex Plus kit, the tube coagulase test, the thermostable-endonuclease
test, and the RAPIDEC staph kit were compared. The sensitivities were 23, 92, 85,
and 98% and the specificities were 99, 100, 93, and 100%, respectively. The
RAPIDEC staph kit was the most reliable test, with a diagnostic accuracy
comparable to that of the best published results for any of the rapid tests.
However, it was the most expensive of the tests and relatively labor-intensive.
The tube coagulase test was also sensitive, the simplest to perform, and
inexpensive.
PMID- 9542930
TI - Detection and identification of Mycobacterium tuberculosis directly from sputum
sediments by ligase chain reaction.
AB - Sputum specimens received for the diagnosis of tuberculosis or other
mycobacterial infections were tested by a ligase chain reaction (LCR)-based assay
and acid-fast stain and culture techniques. Results from the LCR assay (Abbott
LCx Mycobacterium tuberculosis [MTB] Assay) were compared to results from
standard culture techniques held for 6 weeks. Four hundred ninety-three specimens
from 205 patients suspected of pulmonary tuberculosis were included in the
prospective study. Thirty-four (6.9%) of the specimens were culture positive for
M. tuberculosis, and 13 (38%) of these were also fluorochrome stain positive. LCR
sensitivities and specificities compared to culture were 74 and 98%,
respectively. LCR sensitivity was 100% for fluorochrome stain-positive specimens
and 57% for fluorochrome stain-negative specimens. Nine LCR-negative, culture
positive specimens were the result of low concentrations of M. tuberculosis. No
inhibitors were detected in any of these specimens. Of the eight LCR-positive,
culture-negative specimens, five were from patients with active tuberculosis.
With these considered culture misses, final LCR sensitivity, specificity,
positive predictive value, and negative predictive value were 77, 99, 91, and
98%, respectively. The same performance values for the fluorochrome acid-fast
bacillus smear were 33, 98, 62, and 94%, respectively. After normal laboratory
sputum processing, the Abbott LCx MTB Assay can be completed in 6 h. Thus, it is
possible to have results available within 8 h of specimen submission.
PMID- 9542932
TI - Intergenic transcribed spacer PCR ribotyping for differentiation of Saccharomyces
species and interspecific hybrids.
AB - The taxonomy of the genus Saccharomyces has undergone significant changes
recently with the use of genotypic rather than phenotypic methods for the
identification of strains to the species level. The sequence of rRNA genes has
been utilized for the identification of a variety of fungi to the species level.
This methodology, applied to species of Saccharomyces, allows unknown
Saccharomyces isolates to be assigned to the type strains. It was the aim of the
present study to assess whether typing of the intergenic spacer region by using
restriction fragment length polymorphisms of PCR products (intergenic transcribed
spacer PCR [ITS-PCR] ribotyping) could distinguish among type strains of the 10
accepted species of Saccharomyces and further to assess if this method could
distinguish strains that were interspecific hybrids. Cellular DNA, isolated after
the lysis of protoplasts, was amplified by PCR using ITS1 and ITS4 primers,
purified by liquid chromatography, and digested with restriction endonucleases.
Ribotyping patterns using the restriction enzymes MaeI and HaeIII could
distinguish all species of Saccharomyces from each other, as well as from Candida
glabrata, Candida albicans, and Blastomyces dermatitidis. The only exception to
this was the inability to distinguish between Saccharomyces bayanus and S.
pastorianus (S. carlsbergensis). Furthermore, interspecific hybrids resulting
from the mating of sibling species of Saccharomyces were shown to share the ITS
PCR ribotyping patterns of both parental species. It should now be possible, by
this simple PCR-based technique, to accurately identify these strains to the
species level, thereby allowing an increase in our understanding of the
characteristics required by these interspecific hybrids for their particular
ecological niches.
PMID- 9542933
TI - Evaluation of PCR for diagnosis of melioidosis.
AB - Previously published PCR-based diagnostic tests for melioidosis were evaluated
for clinical usefulness. A Burkholderia pseudomallei 16S rRNA-derived primer set
had a sensitivity approaching 100% for clinical samples from 22 culture-confirmed
cases of melioidosis and enabled diagnosis of 3 culture-negative cases. However,
samples from 10 of 30 inpatients from Royal Darwin Hospital with other diagnoses
were positive by PCR, giving a specificity of 67% and a positive predictive value
of only 70%. Although there are a number of intriguing possible explanations for
our results, concerns of inappropriate therapy resulting from a positive result
by PCR have led us to forgo the advantage of rapid PCR diagnosis for melioidosis
until a better system is validated.
PMID- 9542934
TI - Detection of staphylococcal superantigenic toxins by a CD69-specific
cytofluorimetric assay measuring T-cell activation.
AB - The presence of staphylococcal superantigenic toxins in the supernatants of
liquid cultures was detected by an easy and rapid method assessing the activation
of T lymphocytes by cytofluorimetric measurement of CD69 expression.
Staphylococcus aureus cells were grown in Eagle's minimum essential medium
supplemented with 5% heat-inactivated fetal calf serum. Supernatant fluids from
all S. aureus strains producing superantigen-related toxins, including
enterotoxins A to E, toxic shock syndrome toxin, and exfoliative toxins A and B,
induced CD69 expression in a significantly higher number of T cells than a cutoff
of 2%. This CD69 assay might be used for initial detection of superantigens from
S. aureus strains isolated in the context of staphylococcal toxemia or related
chronic human diseases such as atopic dermatitis or Kawasaki syndrome.
PMID- 9542936
TI - Detection of Mycobacterium tuberculosis complex in cattle by PCR using milk,
lymph node aspirates, and nasal swabs.
AB - The PCR technique was applied to the diagnosis of tuberculosis in live cattle,
and both skin-test-negative and skin-test-positive animals were studied. DNA was
taken from various sources including specimens of lymph node aspirates, milk, and
nasal swabs. After slaughter and visual inspection, tissues such as lymph nodes,
lungs, and udders from tuberculin reactors were tested by the same technique.
Specific oligonucleotide primers internal to the IS6110 insertion element were
used to amplify a 580-bp fragment. A 182-bp fragment was obtained by designating
a nested PCR from the first amplification product. This fragment was cloned and
sequenced, and after being labeled it was employed in dot blot hybridization. A
total of 100 cattle were tested, and PCR analysis was performed using nasal swab,
milk, and lymph node aspirate. Sixty skin-test-positive cows were also tested to
detect mycobacterial DNA in tissue samples from lymph nodes, lungs, and udders,
and the infection was confirmed in all of the animals. Using PCR analysis of
tissue samples from slaughtered animals as a "gold standard" we calculated 100%
values for sensitivity, specificity, and positive and negative predictive values
for milk and lymph node aspirate samples. The respective values for nasal swab
samples were 58, 100, 100, and 28%. The respective values for all of the samples
were 74, 100, 100, and 35%, while for visual inspection the values were 81, 100,
100, and 58%, respectively. PCR analysis of specimens of lymph node aspirates,
milk, and nasal swabs from skin-test-negative animals showed that 52% of these
skin test results were false negatives. These animals, not being removed from the
farms, represent a potential source of further infection.
PMID- 9542935
TI - Sensitivity of fluorochrome microscopy for detection of Mycobacterium
tuberculosis versus nontuberculous mycobacteria.
AB - The results for 6,532 consecutive mycobacterial respiratory specimens collected
from 1,040 patients from 1993 to 1995 in a Texas hospital were studied to
determine the sensitivity of fluorescence microscopy for detection of
Mycobacterium tuberculosis and nontuberculous mycobacteria (NTM). Smears were
positive for acid-fast bacilli (AFB) in 63% (677 of 1,082) of specimens growing
M. tuberculosis and 56% (638 of 1,148) of specimens growing the four most common
species of NTM. Smear positivity by species was 58% (446 of 776) for M. avium
complex, 51% (154 of 300) for rapidly growing mycobacteria (98% were M.
abscessus), 78% (29 of 37) for M. kansasii, and 26% (9 of 35) for M. gordonae.
Definite or probable disease by clinical criteria was present in 79% of patients
with M. avium complex, 93% of patients with rapidly growing mycobacteria, 100% of
patients with M. kansasii, and 0% of patients with M. gordonae. Patients with M.
avium complex had a low incidence of AIDS (7%), and approximately 50% of non-AIDS
patients had upper-lobe cavitary disease and 50% had nodular bronchiectasis. Only
23 of 6,532 (0.35%) of AFB smears were positive with a negative culture excluding
patients on therapy for established mycobacterial disease. These studies suggest
that NTM are as likely as M. tuberculosis to be detected by fluorescent
microscopy in specimens from patients from areas endemic for NTM lung disease and
at low risk for AIDS.
PMID- 9542937
TI - Comparison of culture- and non-culture-based methods for quantification of viral
load and resistance to antiretroviral drugs in patients given zidovudine
monotherapy.
AB - Virological assays for human immunodeficiency virus type 1 load and drug
resistance can broadly be divided into culture-based and molecular biology-based
methods. Culture-based methods give a direct measure of infectious virus load and
phenotypic drug resistance, whereas molecular biology-based methods are indirect,
assaying nucleic acid levels to determine virus load and point mutations
associated with drug resistance. We have compared culture-based and non-culture
based methods for patients enrolled in a placebo-controlled trial of zidovudine
(the Concorde Trial). Virus loads were assayed by culture of peripheral blood
mononuclear cells (PBMCs) or quantitative PCR, and drug resistance was assayed in
culture or in a quantitative, PCR-based point mutation assay. The rates of
detection of viremia and drug resistance were higher by PCR than by culture for
this population of subjects. Comparison of the virus loads by the two measures
showed a good correlation for virus loads in PBMCs but a poor correlation for
virus loads in plasma. The latter result probably reflected the inaccuracies of
culture in assaying plasma with the low infectious virus titers seen in the study
population. The concordance of phenotypic and genotypic drug resistance methods
was high, with all phenotypically resistant isolates having at least one
resistance-associated mutation and with no mutations being found in a drug
sensitive isolate. Genomic resistance scores (weighted sums of levels of
resistance mutations) showed good correlations with the levels of phenotypic
resistance, and both resistance measures were observed to increase as the
duration of exposure to drug increased. Overall, non-culture-based methods were
shown to correlate well with culture-based methods and offer a low-cost, high
throughput alternative. However, culture-based methods remain the final arbiters
of infectious virus load and phenotypic drug resistance and are unlikely to be
superseded entirely.
PMID- 9542938
TI - Detection of Norwalk virus and other genogroup 1 human caliciviruses by a
monoclonal antibody, recombinant-antigen-based immunoglobulin M capture enzyme
immunoassay.
AB - Sera obtained from two groups of adult volunteers infected with Norwalk virus
(NV) and two groups of patients involved in two natural outbreaks were tested for
NV-reactive immunoglobulin M (IgM) by use of a monoclonal antibody, recombinant
antigen-based IgM capture enzyme immunoassay (EIA). No NV-reactive IgM was
detected in the preinoculation sera of 15 volunteers, and 14 of 15 showed NV
reactive antibodies postinfection with NV. All of the volunteers showed IgG
seroconversion to NV. In the outbreak studies, all 9 persons in one outbreak and
19 of 24 in another outbreak had NV-reactive IgM. In the first outbreak, only
three of nine seroconverted to NV, which was likely due to late collection of
acute-phase sera. In the second outbreak, 21 of 24 showed IgG seroconversion to
NV. Sequencing of viruses isolated from five stool samples selected from those in
the second outbreak showed that they were human calicivirus (HuCV) genogroup 1
viruses related, but not identical, to NV. In the volunteer studies, NV-reactive
IgM was first detected 8 days postinoculation. The time of development of NV
reactive IgM antibodies in natural outbreaks was estimated to be similar to that
found in the volunteer studies. Sera from three Hawaii virus-infected volunteers,
four Snow Mountain virus patients, and 80 healthy individuals were negative for
NV-reactive IgM, indicating test specificity for HuCV genogroup I infections.
This capture IgM EIA is suitable for diagnosis of NV and other HuCV genogroup I
infections and is especially useful when sera and fecal samples have not been
collected early in the course of an outbreak.
PMID- 9542939
TI - Optimization of specimen-handling procedures for accurate quantitation of levels
of human immunodeficiency virus RNA in plasma by reverse transcriptase PCR.
AB - Human immunodeficiency virus type 1 (HIV-1) RNA levels in plasma are currently
widely used clinically for prognostication and in monitoring antiretroviral
therapy. Accurate and reproducible results are critical for patient management.
To determine the effects of specimen collection and handling procedures on
quantitative measurement of HIV-1 RNA, we compared anticoagulants and sample
processing times. Whole blood was collected from 20 HIV-1-infected patients in
EDTA, acid citrate dextrose (ACD), and heparin tubes, aliquoted, and stored at
room temperature. Plasma was separated from whole-blood aliquots prepared at < or
=1, 3, 6, 24, and 48 h postcollection and then stored at -70 degrees C until use.
HIV-1 RNA levels were determined by the AMPLICOR HIV-1 MONITOR assay. Heparinized
plasma samples, which were pretreated with heparinase prior to analysis, had the
lowest baseline HIV-1 RNA levels. In the first 6 h, HIV-1 RNA levels decreased by
10, 20, and 31% in EDTA, ACD, and heparin tubes, respectively. From 6 to 48 h
postcollection, HIV-1 RNA levels decreased in all anticoagulants, albeit at a
slower, more consistent rate. Our results indicate that EDTA should be the
anticoagulant of choice for plasma HIV-1 RNA measurement by reverse transcriptase
PCR, but ACD tubes are acceptable if the plasma is separated within 6 h of blood
collection. Caution must be applied in the interpretation of absolute HIV-1 RNA
copy number values obtained with suboptimal specimen collection and processing
procedures.
PMID- 9542940
TI - Immunoglobulin M capture assay for serologic confirmation of early Lyme disease:
analysis of immune complexes with biotinylated Borrelia burgdorferi sonicate
enhanced with flagellin peptide epitope.
AB - We previously reported on the efficacy of the enzyme-linked immunoglobulin M
capture immune complex (IC) biotinylated antigen assay (EMIBA) for the
seroconfirmation of early Lyme disease and active infection with Borrelia
burgdorferi. In earlier work we identified non-cross-reacting epitopes of a
number of B. burgdorferi proteins, including flagellin. We now report on an
improvement in the performance of EMIBA with the addition of a biotinylated form
of a synthetic non-cross-reacting immunodominant flagellin peptide to the
biotinylated B. burgdorferi B31 sonicate antigen source with the avidin
biotinylated peroxidase complex detection system used in our recently developed
indirect IgM-capture immune complex-based assay (EMIBA). As in our previous
studies, the enzyme-linked immunosorbent assay (ELISA) reactivities of antibodies
liberated from circulating ICs (by EMIBA) were compared with those of antibodies
in unprocessed serum (antibodies found free in the serum, thus as an IgM-capture
ELISA, but not EMIBA, because the antibodies were not liberated from ICs), the
sample usually used in standard ELISAs and Western blot assays. The addition of
the flagellin epitope enhanced the ELISA signal obtained with untreated sera from
many Lyme disease patients but not from healthy controls. In tests with both free
antibodies and ICs, with or without the addition of the flagellin epitope to the
sonicate, we found the most advantageous combination was IC as the source of
antibodies and sonicate plus the flagellin epitope as the antigen. In a blinded
study of sera obtained from patients with early and later-phase Lyme disease,
EMIBA with the enhanced antigenic preparation compared favorably with other
serologic assays, especially for the confirmation of early disease.
PMID- 9542941
TI - Glycogen assay for diagnosis of female genital Chlamydia trachomatis infection.
AB - Chlamydia trachomatis can synthesize glycogen at various stages in its
developmental cycle. The glycogen content of female genital epithelial cells was
detected by anthrone, and the results were compared with those from PCR. A total
of 320 cervical samples were examined. Of 92 specimens that were positive by PCR,
78 were positive and 14 were negative by the glycogen assay. Of 228 specimens
that were negative by PCR, 220 were negative and 8 were positive by the glycogen
assay. The sensitivity and specificity of the glycogen assay obtained from these
data were 84.8% (78 of 92) and 96.5% (220 of 228), respectively. Use of the
glycogen assay to detect the glycogen content in genital epithelial cells may be
helpful in the diagnosis of C. trachomatis infection. This is an easy, fast, and
inexpensive assay and can be done in less-sophisticated labs.
PMID- 9542942
TI - Molecular typing of Staphylococcus aureus based on PCR restriction fragment
length polymorphism and DNA sequence analysis of the coagulase gene.
AB - A typing procedure for Staphylococcus aureus was developed based on improved PCR
amplification of the coagulase gene and restriction fragment length polymorphism
(RFLP) analysis of the product. All coagulase-positive staphylococci produced a
single PCR amplification product of either 875, 660, 603, or 547 bp. Those
strains of epidemic methicillin-resistant S. aureus 16 (EMRSA-16) studied all
gave a product of 547 bp. PCR products were digested with AluI and CfoI, and the
fragments were separated by gel electrophoresis. Ten distinct RFLP patterns were
found among 85 isolates of methicillin-resistant S. aureus (MRSA) and 10
propagating strains (PS) of methicillin-sensitive S. aureus (MSSA) examined. RFLP
patterns 1, 2, and 3 were specific to strains of EMRSA-3, -15, and -16,
respectively. By contrast, RFLP patterns 4 and 5 were seen with a heterogeneous
collection of strains, together with drug-resistant forms of S. aureus isolated
in Europe and four propagating strains used for the international phage set. RFLP
pattern 6 was given by the Airedale isolate and PS 95. RFLP pattern 7 encompassed
EMRSA-2 (isolate 331), PS 94, and PS 96. An isolate from Germany gave RFLP
pattern 8. Eight strains of MSSA gave patterns similar to those of methicillin
resistant strains (RFLP patterns 3, 4, 5, 6, and 7), but two, PS 42E and PS 71,
gave unique RFLP patterns 9 and 10, respectively. The coagulase gene PCR products
for 24 isolates of MRSA and two isolates of MSSA were sequenced for both strands.
The sequences were aligned, and evolutionary lineages were inferred based on
pairwise distances between isolates.
PMID- 9542943
TI - Nested PCR assay for detection of granulocytic ehrlichiae.
AB - A sensitive and specific nested PCR assay was developed for the detection of
granulocytic ehrlichiae. The assay amplifies the 16S rRNA gene and was used to
examine acute-phase EDTA-blood and serum samples obtained from seven humans with
clinical presentations compatible with human granulocytic ehrlichiosis. Five of
the seven suspected cases were positive by the PCR assay using DNA extracted from
whole blood as the template, compared with a serologic assay that identified only
one positive sample. The PCR assay using DNA extracted from the corresponding
serum samples as the template identified three positive samples. The sensitivity
of the assay on human samples was examined, and the limit of detection was shown
to be fewer than 2 copies of the 16S rRNA gene. The application of the assay to
nonhuman samples demonstrated products amplified from template DNA extracted from
Ixodes scapularis ticks collected in Rhode Island and from EDTA-blood specimens
obtained from white-tailed deer in Maryland. All PCR products were sequenced and
identified as specific to granulocytic ehrlichiae. A putative variant
granulocytic ehrlichia 16S rRNA gene sequence was detected among products
amplified from both the ticks and the deer blood specimens.
PMID- 9542944
TI - Development of PCR assays for species- and type-specific identification of
Pasteurella multocida isolates.
AB - Genomic subtractive hybridization of closely related Pasteurella multocida
isolates has generated clones useful in distinguishing hemorrhagic septicemia
causing type B strains from other P. multocida serotypes. Oligonucleotide primers
designed during the sequencing of these clones have proved valuable in the
development of PCR assays for rapid species- and type-specific detection of P.
multocida and of type B:2 in particular. This study demonstrated that the primer
pair designed from the sequence of the clone 6b (KTT72 and KTSP61) specifically
amplified a DNA fragment from types B:2, B:5, and B:2,5 P. multocida and that the
primers KMT1T7 and KMT1SP6 produced an amplification product unique to all P.
multocida isolates analyzed. It was also shown that PCR amplification performed
directly on bacterial colonies or cultures represents an extremely rapid,
sensitive method of P. multocida identification.
PMID- 9542945
TI - Mycobacterium tuberculosis infection in a green-winged macaw (Ara chloroptera):
report with public health implications.
AB - Mycobacterium tuberculosis was isolated from the eyelid, skin, tongue, and lungs
of a green-winged macaw (Ara chloroptera). Two persons living in the same
household were culture positive for pulmonary tuberculosis 3 to 4 years before
tuberculosis was diagnosed in the bird. Although humans have not been shown to
acquire tuberculosis from birds, an infected bird may be a sentinel for human
infection.
PMID- 9542946
TI - Misidentification of unusual Aeromonas species as members of the genus Vibrio: a
continuing problem.
AB - Two unusual cases of Aeromonas infection are described, one associated with
bacteremia (Aeromonas schubertii) and another in which the organism was recovered
from an infected gall bladder (Aeromonas veronii biotype veronii). These strains
were initially identified as Vibrio damsela and Vibrio cholerae by the Vitek and
API 20E systems, respectively. Use of appropriate screening tests and familiarity
with the newer Aeromonas species could prevent initial misidentifications and
potential public health consequences.
PMID- 9542947
TI - Baculovirus expression of the fusion protein gene of bovine respiratory syncytial
virus and utility of the recombinant protein in a diagnostic enzyme immunoassay.
AB - The fusion (F) protein of bovine respiratory syncytial virus (BRSV) was expressed
by using a baculovirus vector. Antigenicity was tested by immunofluorescence
analysis with F-specific monoclonal and polyclonal antibodies. Antibodies to
recombinant F protein raised in a rabbit neutralized BRSV and human respiratory
syncytial virus infectivity when tested in a plaque reduction assay. The
recombinant F protein was evaluated as a source of antigen in an enzyme-linked
immunosorbent assay (ELISA), and this ELISA was compared with the virus
neutralization (VN) test for detecting BRSV antibodies in 10 consecutive serum
samples from four calves vaccinated with a live modified BRSV vaccine and from
two nonvaccinated control calves. The ELISA with the baculovirus-expressed F
protein as an antigen compared favorably with the VN test and is a rapid,
sensitive, and specific method for detecting serum antibodies to BRSV.
PMID- 9542948
TI - Sensitivity and specificity of an improved rapid latex agglutination test for
identification of methicillin-sensitive and -resistant Staphylococcus aureus
isolates.
AB - The performance of a second-generation rapid agglutination kit, Slidex Staph Plus
(SSP; bioMerieux), was compared to those of the Slidex Staph (SS; bioMerieux),
Staphaurex (SRX; Murex Diagnostics), and BBL Staphyloslide (BBL; Becton
Dickinson) kits by using 508 clinical isolates composed of 150 methicillin
sensitive Staphylococcus aureus (MSSA) organisms, 154 methicillin-resistant S.
aureus (MRSA) organisms, and 204 non-S. aureus Staphylococcus spp. Of the 508
isolates tested, 75% were fresh clinical isolates, with the remainder taken from
five different freezer collections. All four agglutination tests had comparable
sensitivities for MSSA and MRSA. However, the SS kit was significantly less
specific (93.1%) than the three other tests (P > 0.05, McNemar test). These
results demonstrate that the new rapid latex agglutination kit, SSP, was more
specific for the identification of S. aureus than the previous version and
performed comparably to the SRX and BBL kits.
PMID- 9542949
TI - Rising levels of human cytomegalovirus (HCMV) antigenemia during initial
antiviral treatment of solid-organ transplant recipients with primary HCMV
infection.
AB - In 7 of 18 solid-organ transplant recipients with primary human cytomegalovirus
(HCMV) infection, HCMV antigenemia levels were unexpectedly found to rise
significantly (P = 0.018) during a mean time of 7.3 +/- 3.2 days after initiation
of specific antiviral treatment, whereas corresponding levels of viremia dropped
significantly (P = 0.043). Thus, shifting to an alternative antiviral drug based
solely on increasing antigenemia levels is not justified in this group of
patients.
PMID- 9542951
TI - Spoligotyping followed by double-repetitive-element PCR as rapid alternative to
IS6110 fingerprinting for epidemiological studies of tuberculosis.
AB - A total of 129 clinical isolates of Mycobacterium tuberculosis representing 91
patients were typed by a combination of direct-repeat (DR)-based spoligotyping
and an inter-IS6110-PGRS (polymorphic GC-rich region)-PCR, also designated double
repetitive-element PCR (DRE-PCR). During the first phase of this investigation,
72 clinical strains representing 52 patients were initially typed by IS6110
restriction fragment length polymorphism (RFLP) and DR-RFLP, followed by
spoligotyping and DRE-PCR. In the second phase of this investigation, the
discriminating ability of spoligotyping plus DRE-PCR was studied for 57 isolates
from 39 patients who were suspected to be epidemiologically linked, and the
typing results were later confirmed by IS6110-RFLP and DR-RFLP analyses. The
molecular clustering of the isolates remained identical irrespective of the
methods used. These results show that the association of two PCR-based
fingerprinting techniques for molecular epidemiology of tuberculosis has a
discriminating ability similar to the IS6110-RFLP reference method.
PMID- 9542950
TI - Intravitam diagnosis of human rabies by PCR using saliva and cerebrospinal fluid.
AB - An optimized reverse transcription (RT)-PCR protocol for the intravitam detection
of rabies virus genomic RNA was tested with clinical samples obtained from 28
patients suspected of having rabies, 9 of whom were confirmed to have had rabies
by postmortem examination. RT-PCR using saliva combined with an
immunofluorescence assay performed with skin biopsy samples allowed detection of
rabies in the nine patients.
PMID- 9542952
TI - Development of a monoclonal antibody to a Ureaplasma urealyticum serotype 9
antigen.
AB - We produced a monoclonal antibody (MAb) to Ureaplasma urealyticum Vancouver, the
serotype 9 standard strain. By immunoblotting, this MAb showed a single, 85-kDa
band with the homologous serotype and a minor, 100-kDa band with serotype 2 but
did not react with any other serotype standard strain. Clinical isolates of U.
urealyticum were tested with this MAb and with two sets of polyclonal antisera
against the 14 serotype standard strains. The use of MAb 9-2H9 correctly
identified certain serotype 9 strains but did not react with wild-type strains
lacking the serotype 9 determinant.
PMID- 9542953
TI - Application of an optimized and highly discriminatory method based on arbitrarily
primed PCR for epidemiologic analysis of methicillin-resistant Staphylococcus
aureus nosocomial infections.
AB - The optimization of an arbitrarily primed PCR method for typing 96 methicillin
resistant Staphylococcus aureus (MRSA) isolates was compared with pulsed-field
gel electrophoresis. Identical results in the differentiation of MRSA clones and
identification of the main cluster that included 82 strains (88% of patients)
were obtained by both techniques.
PMID- 9542954
TI - Bile-esculin test for presumptive identification of enterococci and streptococci:
effects of bile concentration, inoculation technique, and incubation time.
AB - The bile-esculin test is used to differentiate enterococci and group D
streptococci from non-group D viridans group streptococci. The effects on test
performance of the concentration of bile salts, inoculum, and duration of
incubation were examined with 110 strains of enterococci, 30 strains of
Streptococcus bovis, and 110 strains of non-group D viridans group streptococci.
Optimal sensitivity (> 99%) and specificity (97%) of the bile-esculin test can be
obtained with a bile concentration of 40%, a standardized inoculum of 10(6) CFU,
and incubation for 24 h.
PMID- 9542955
TI - Detection of JC virus in cerebrospinal fluid (CSF) samples from patients with
progressive multifocal leukoencephalopathy but not in CSF samples from patients
with herpes simplex encephalitis, enteroviral meningitis, or multiple sclerosis.
AB - JC virus (JCV) DNA was detected in cerebrospinal fluid (CSF) samples from
patients with progressive multifocal leukoencephalopathy (PML) but not in CSF
samples from patients with herpes simplex encephalitis, enteroviral meningitis,
or multiple sclerosis. This suggests that inflammatory processes in the brain do
not necessarily reactivate JCV, which further supports the proposal that the
presence of JCV DNA in the CSF is diagnostic for PML.
PMID- 9542956
TI - Long-term survival of Streptococcus pneumoniae at room temperature on Dorset egg
medium.
AB - Forty-five isolates of Streptococcus pneumoniae were inoculated on Dorset egg and
supplemented Columbia agar base media, incubated overnight at 37 degrees C, and
then kept at room temperature (RT; 21 degrees C) or 4 degrees C. Long-term
viability was best at RT for both media, with all isolates remaining viable on
Dorset egg medium for 44 days; viability was 90 and 57% on Columbia agar base
medium after 7 and 30 days. We recommend the use of Dorset egg medium for the
maintenance of pneumococci at RT.
PMID- 9542957
TI - Phylogenetic relationships among highly virulent Newcastle disease virus isolates
obtained from exotic birds and poultry from 1989 to 1996.
AB - Newcastle disease virus [NDV (avian paramyxovirus type 1 [APMV1])] isolates were
recovered from imported exotic birds confiscated following importation into the
United States, from waterbirds in the United States, and from poultry. The exotic
birds probably originated from Central and South America, Asia, and Africa. The
NDV isolates were initially characterized as highly virulent because of a short
mean death time in embryonated chicken eggs. The isolates were typed as
neurotropic or viscerotropic velogenic by intracloacal inoculation of adult
chickens. Intracerebral pathogenicity index values for the virulent NDV isolates
ranged from 1.54 to 1.90, compared to a possible maximum value of 2.0. These
isolates had a dibasic amino acid motif in the fusion protein cleavage site
sequence required for host systemic replication. Sequence differences were
detected surrounding the fusion protein cleavage site and the matrix protein
nuclear localization signal, indicating evolution of highly virulent NDV.
Phylogenetically, these isolates were categorized with other highly virulent NDV
strains that caused outbreaks in southern California poultry during 1972 and in
cormorants in the north central United States and southern Canada during 1990 and
1992. These isolates are related to NDV that may have the APMV1 strain
chicken/Australia/AV/32 or a related virus as a possible progenitor. Recent
virulent NDV isolates and those recovered during disease outbreaks since the
1970s are phylogenetically distinct from current vaccine viruses and standard
challenge strains.
PMID- 9542958
TI - Disseminated invasive infection due to Metarrhizium anisopliae in an
immunocompromised child.
AB - The first reported human case of possible disseminated infection with the insect
pathogen Metarrhizium anisopliae var. anisopliae, a fungus which has been used
commercially for biocontrol of insects, is described. The patient, a 9-year-old
boy, had a 5-year history of pre-B-cell acute lymphoblastic leukemia and had been
on chemotherapy throughout this period. After 10 days of profound neutropenia,
lesions consistent with ecthyma gangrenosum appeared on his arms and legs. M.
anisopliae was grown from specimens from three separate sites, collected at
different times over a period of 1 month: a skin biopsy, a swab from the base of
a lesion, and the core of another skin lesion which spontaneously discharged. The
initial skin biopsy also showed histological evidence of epidermal necrosis and
dermal invasion with fungal hyphae. A computed-tomography (CT) scan of the chest
demonstrated a lesion in the superior segment of the lower lobe of the left lung.
A CT scan of the brain revealed a lesion in the left temporoparietal region of
the brain, consistent with an abscess. Despite antifungal treatment including
liposomal amphotericin and 5-flucytosine, the patient eventually died. The
initial portal of entry is unknown, but hematogenous dissemination to the skin
appears likely because of the multiple ecthymic lesions, and the appearances of
the brain lesion on the CT scan are consistent with a hematogenous fungal
abscess.
PMID- 9542959
TI - Diagnosis of Mycoplasma pneumoniae infection in autopsy and open-lung biopsy
tissues by nested PCR.
AB - A nested PCR specific for the Mycoplasma pneumoniae P1 gene was used to diagnose
mycoplasma infection in two cohort patients with severe pneumonia within 24 h of
tissue receipt. A postmortem diagnosis of M. pneumoniae infection was obtained
for the first patient, who died without the collection of appropriate paired
samples for serodiagnosis. An open-lung biopsy obtained from the second patient
allowed a quick, definitive diagnosis and proper selection of therapy.
PMID- 9542960
TI - Corneal ulcer caused by Nocardia asteroides in a patient with leprosy.
AB - Nocardia asteroides is a rare cause of keratitis usually associated with trauma.
We report a case of corneal ulceration caused by N. asteroides in a patient with
leprosy. This is the first case report of nocardial keratitis from Southeast
Asia. The diminished corneal sensation in a patient with leprosy could be a
predisposing factor for development or exacerbation of corneal ulceration.
PMID- 9542961
TI - Chromogenic tube test for presumptive identification or confirmation of isolates
as Candida albicans.
AB - This report describes a new, modified, simple, and cost-effective method for the
use of CHROMagar Candida (CHROMagar Company, Paris, France) for the presumptive
identification of isolates as Candida albicans after preliminary growth. Sixty
randomly selected clinical isolates were evaluated, including 38 of C. albicans.
With incubation at 37 degrees C for 24 h, the sensitivity and specificity
appeared to be excellent and the test performed better than the traditional germ
tube test. However, at earlier times, C. tropicalis isolates gave false-positive
results.
PMID- 9542962
TI - Nosocomial pneumonia caused by three genetically different strains of Legionella
pneumophila and detection of these strains in the hospital water supply.
AB - A 44-year-old woman developed Legionella pneumophila pneumonia after cerebral
surgery. Initially, one colony from a clinical specimen and two colonies from
water samples, all belonging to serogroup 12, did not match when their DNA
restriction patterns were compared. When additional colonies from the water
specimens were analyzed, a serogroup 12 strain complementary to that found in the
clinical specimen was identified. Other colonies from the clinical specimen were
identified as serogroup 12 strains complementary to those identified from the
water. In addition, the same serogroup 1 strain was isolated from the patient and
the water system.
PMID- 9542963
TI - Effect of nonionic detergents on amplification of human papillomavirus DNA with
consensus primers MY09 and MY11.
PMID- 9542964
TI - Discrepancies between E-test and agar dilution methods for testing metronidazole
susceptibility of Helicobacter pylori.
PMID- 9542966
TI - CFTR gene and male fertility.
AB - Secretion of electrolytes and water by the epididymal epithelium is important in
the formation an optimal fluid environment for sperm maturation and transport.
This process is disrupted in the genetic disease cystic fibrosis caused by
mutation of the cystic fibrosis transmemebrane conductance regulator (CFTR) gene.
Recent findings of CFTR gene mutations in healthy men with congenital bilateral
absence of the vas deferens or poor sperm quality may indicate that CFTR gene
mutations have a far-reaching effect on human reproduction.
PMID- 9542965
TI - Clostridium difficile bacteremia in an immunocompetent child.
PMID- 9542967
TI - The fatty acid composition of phospholipids of spermatozoa from infertile
patients.
AB - The lipid composition of the sperm membrane has a significant effect upon the
functional characteristics of spermatozoa. In the present study we investigated
the fatty acid (FA) composition of subpopulations of spermatozoa separated on a
discontinuous Percoll gradient (47:90%) and the FA composition of phospholipids
(PL) of sperm heads and tails in both normal and abnormal semen samples. In
normozoospermic samples, polyunsaturated fatty acids (PUFA) represented 34.0 +/-
1.3 (mean +/- SE, mole %) and 25.6 +/- 1.2% of total FA of PL of the 47 and 90%
Percoll fractions respectively. Docosahexaenoic acid (22:6omega3, DHA)
contributed to more than 60% of total PUFA. DHA was significantly lower in both
the 47% (P < 0.05) and the 90% (P < 0.01) Percoll fractions of oligozoospermic
samples and in the 90% Percoll layer of asthenozoospermic samples (P < 0.01),
compared with normozoospermic samples. The omega6/omega3 ratio was significantly
increased in both Percoll fractions of samples with oligozoospermia (47%, P <
0.001 and 90%, P < 0.001) or with asthenozoospermia (47%, P < 0.05 and 90%, P <
0.001) compared with normozoospermic samples. The oxidative potential index (OPI)
of spermatozoa recovered from the 47% Percoll layer was significantly higher (P <
0.0001) than of those recovered from the 90% Percoll. Mean melting point (MMP),
an index of membrane fluidity, was significantly lower in head than in tails (P <
0.01) of spermatozoa, and also in both the 47% (P < 0.01) and 90% (P < 0.001)
Percoll fractions of normozoospermic samples in comparison with oligozoospermic
samples. The MMP was significantly higher (P < 0.05) in samples of patients with
idiopathic oligo/asthenozoospermia, varicocele, and male accessory gland
infection (MAGI). These differences in FA composition of PL in subpopulations of
human spermatozoa, and in their heads and tails may be related to sperm maturity
and to differences in physiological function.
PMID- 9542968
TI - Specific localization in the equatorial region of gp20, a 20 kDa
sialylglycoprotein of the capacitated human spermatozoon acquired during
epididymal transit which is necessary to penetrate zona-free hamster eggs.
AB - In this study we set out to characterize gp20, a 20 kDa glycoprotein of the human
sperm surface, first identified by us by radiolabelling the sialic acid residues
of the sperm surface [R. Focarelli et al. (1995), Mol. Hum. Reprod., 2, 2755
2759]. The protein was partially purified from pooled sperm samples of several
healthy donors and used to raise a specific antiserum to study its localization
in the reproductive system. When tested with freshly ejaculated spermatozoa, the
anti-gp20 antibody intensely stained the head and midpiece. However, on
capacitated spermatozoa the antigen was restricted to a sharp zone in the
equatorial region. The antibody did not bind to differentiating germ cells but
the antigen was present in epididymal epithelial cells and also in seminal
plasma. Anti-gp20 exerted a blocking effect in a test for sperm penetration of
zona-free hamster eggs, thus suggesting that gp20 is involved in the early stages
of fertilization.
PMID- 9542969
TI - In-situ competition between protamine and fluorochromes for sperm DNA.
AB - In this study we investigated the relationship between the presence of bound
protamine on mouse and human sperm DNA and the level of chromomycin A3 (CMA3) and
4'6-diamidino-2-phenylindole (DAPI) fluorescence. This was accomplished by
performing a competition assay between salmon protamine and fluorochromes on
decondensed spermatozoa that had their nuclear proteins extracted and were fixed
on slides. Various concentrations (0, 0.005, 0.0225, 0.05, 0.225, 0.5 and 5
mg/ml) of salmon protamine were added to either the CMA3 or DAPI staining
solutions. Fluorescence emission measurements of stained sperm nuclei were then
performed using a microfluorometer. When the treated decondensed sperm heads were
stained with either CMA3 or DAPI all spermatozoa were found to fluoresce
intensely. The addition of protamines to the spermatozoa led to an elimination of
CMA3 fluorescence, while the intensity of DAPI staining was decreased to
approximately 50% at the highest concentrations of protamine. The addition of
increasing amounts of salmon protamine also induced the sperm nuclei to regain
their initial condensed appearance. This study shows that protamine retains a
strong affinity for sperm DNA in situ and that CMA3 fluorescence is a strong
indicator of the protamination state of spermatozoa.
PMID- 9542970
TI - In-vitro human spermatozoa nuclear decondensation assessed by flow cytometry.
AB - The process of sperm chromatin decondensation occurs when a spermatozoon enters
an ovum. Protamine disulphide bonds are reduced to SH and the polycationic
protamines combine with the polyanionic egg protein, nucleoplasmin, thus being
stripped from DNA which then combines with histones. Defective chromatin
decondensation will thus prevent further development of the male pronucleus. In
this study human sperm samples were incubated in vitro at 28 degrees C (using a
medium in which the polyanion, heparin, substitutes for nucleoplasmin and beta
mercaptoethanol for egg glutathione) for 10, 20 and 30 min before stopping the
reaction with formalin (to 3.6%). The DNA of the fixed cells was stained with
Acridine Orange by a one-step method and subjected to flow cytometry and data
analysis, in which a zone characteristic of condensed chromatin is outlined on
red-green fluorescence contour plots. After 20 min of incubation 97% of the
control spermatozoa that were in the mature window (WIN M) had decondensed and
moved out of this region. Defects in sperm decondensation were seen in four semen
samples of the 20 that were tested. In cases where spermatozoa fail to produce a
fertilized egg the cause may lie with defective chromatin quality, including
failure of the sperm chromatin to decondense. The method described here is a
simple procedure for detecting sperm samples containing such defective cells.
PMID- 9542971
TI - Effect of maternal age and conditions of fertilization on programmed cell death
during murine preimplantation embryo development.
AB - One of the major morphological anomalies observed in many human pre-embryos is
extensive cellular fragmentation. Previously we confirmed that embryo
fragmentation seemed to be associated with the activation of programmed cell
death (PCD). The purpose of our experiments was to establish a rate for murine
embryo fragmentation in vivo after hormonal stimulation in young versus older
females and to compare it with the rate of embryo fragmentation during in-vitro
fertilization (IVF). While murine maternal age beyond 40 weeks increased the rate
of embryo fragmentation following in-vivo fertilization (P = 0.001), oocytes from
females of all ages had a uniformly high rate of fragmentation when fertilized in
vitro (33%). None of the fragmented murine embryos proceeded further in
development. In the mouse, fragmentation occurs exclusively during the first cell
cycle. Furthermore, IVF significantly reduced the rate of blastocyst formation (P
= 0.0001) and decreased the mean cell number at the blastocyst stage in
comparison with embryos produced in vivo (P < 0.0001). The cell death index was
significantly affected by both maternal age (P = 0.005) and IVF (P = 0.0001).
Identification of specific factors which trigger PCD, especially those associated
with IVF, may enable us to lower the rates of fragmentation in preimplantation
embryos and thereby increase pregnancy rates after human IVF.
PMID- 9542972
TI - A rapid method for the measurement of the oxoreductase activity of 11beta
hydroxysteroid dehydrogenase in granulosa-lutein cells from patients undergoing
in-vitro fertilization.
AB - The presence of 11beta-hydroxysteroid dehydrogenase (11beta-HSD; EC1.1.1.146),
the enzyme responsible for the interconversion of cortisol and cortisone, in
granulosa-lutein (GL) cells is associated with a poor outcome in in-vitro
fertilization (IVF). We have developed a simple method of assessing the reductase
component of 11beta-HSD in these cells which is sufficiently rapid to provide
data on the enzyme's activity prior to embryo replacement. Cells were pooled from
follicular aspirates and challenged with cortisone within 2 h of aspiration.
Cortisol secretion was then measured by radioimmunoassay. Conversion of cortisone
to cortisol was linear for up to 3 h and was completely inhibited by
glycyrrhetinic acid, a specific 11beta-HSD inhibitor. Initial velocity rates were
determined for eight cortisone concentrations (range 0.1-8 micromol/l), and the
apparent Km calculated (1.6 +/- 0.4 micromol/l). There was no evidence of
substrate/product inhibition and conversion of cortisone to cortisol was <2% in
all experiments. In subsequent work, cells were challenged with cortisone (6
micromol/l) for 2 h. Cells challenged for 2 h immediately following purification
from follicular aspirates produced varying amounts of cortisol (range 25-150
nmol/pooled follicles from each patient, n = 10 patients), while basal outputs
were <6 nmol/l. Enzyme activity was also examined in cells on a per follicle
basis from individual patients and found to vary considerably (e.g. 19, 53 and 36
nmol/l cortisol/1000 cells, three follicles). Having established the method for
assessing 11beta-reductase activity within GL cells, we performed a small
prospective study on a series of 20 patients examining the enzyme activity within
110 individual follicles. 11Beta-reductase activity varied greatly from patient
to patient and from follicle to follicle ranging from <0.024-0.57 nmol
cortisol/microg DNA but at present low patient numbers preclude a meaningful
correlation between enzyme activity and pregnancy rate. In summary, we have
developed a simple, rapid (<8 h) assay for detecting the reductase activity of
11beta-HSD in GL cells isolated from pooled or individual follicles. This
procedure is sufficiently quick to aid in the choice of embryo for replacement.
PMID- 9542973
TI - Expression of insulin-like growth factor-binding protein-1 (IGFBP-1) mRNA in
embryos and endometrial stromal cells.
AB - The objective of the present study was to investigate the effects of insulin-like
growth factor-binding protein-1 (IGFBP-1) on the interaction between mouse
embryos and endometrial stromal cells in co-culture systems. To explore
quantitatively the changes in expression of IGFBP-1 mRNA from endometrial stromal
cells cultured alone or co-cultured with embryos, a combination of reverse
transcription-polymerase chain reaction (RT-PCR) and Southern blotting followed
by a densitometric analysis was used. In co-culture systems, development of
embryos was significantly improved and the production of IGFBP-1 from endometrial
stromal cells was stimulated by the embryos. Quantitative analysis showed that
expression of IGFBP-1 mRNA in endometrial stromal cells co-cultured with embryos
was higher on days 3,5 and 8 (1.6-, 4.5- and 2.3-fold respectively) than in
endometrial stromal cells cultured alone. In addition, intensity of PCR products
for IGFBP-1 mRNA in endometrial stromal cells co-cultured with embryos was higher
on day 5 than on days 3 and 8. However, the expression of IGFBP-1 mRNA in embryos
cultured alone was very low. In conclusion, co-culture of embryos with
endometrial stromal cells improved the development of embryos and may be
associated with the production of IGFBP-1 by the co-cultured endometrial stromal
cells. A combination of RT-PCR and Southern blotting followed by a densitometric
analysis appeared to be a sufficiently quantitative method to determine changes
in IGFBP-1 mRNA values.
PMID- 9542974
TI - Immunodetection of benzo[a]pyrene adducts in ovarian cells of women exposed to
cigarette smoke.
AB - Benzo[a]-pyrene (B[a]P) is a potent mutagen and carcinogen present in cigarettes.
We report here on immunodetection and quantification of B[a]P-DNA adducts in
granulosa-lutein cells of patients undergoing in-vitro fertilization (IVF) and
embryo transfer, who were exposed to cigarette smoke. Follicular fluids (FF) and
granulosa-lutein cells were obtained from the same follicular aspirate from 32
women self-reported as active smokers, passive smokers, or non-smokers. Cells
were immunostained with 5D11, an anti-B[a]P diolepoxide monoclonal antibody that
recognizes DNA adducts. Cotinine, a reliable marker for recent smoke exposure and
dose, was assessed by radioimmunoassay in 32 FF samples. Individual scores of
cell immunoreactivity were highly correlated with FF cotinine concentrations.
Evaluations of immunostaining intensity in 9770 granulosa-lutein cells from the
32 women revealed higher average scores in active and passive smokers, relative
to non-smokers. In passive smokers the average level of cell immunostaining was
63% of that of active smokers. These relationships provide quantitative evidence
that B[a]P-DNA adduct levels are related to smoke exposure and dose, both recent
and long term. Immunostaining was confined to the nucleus, suggesting adduct
formation by covalent binding to DNA. Presence of adducts in granulosa-lutein
cells from women exposed to cigarette smoke may increase the risk for DNA damage.
PMID- 9542975
TI - Preimplantation genetic diagnosis of chromosome balance in embryos from a patient
with a balanced reciprocal translocation.
AB - Duplications or deletions are present in a high percentage of the gametes
produced by individuals carrying balanced translocations. Preimplantation genetic
diagnosis was used to examine chromosome balance in embryos from a patient having
a reciprocal translocation within the short arms of chromosomes 5 and 8
(46,XX,t(5;8)(p13;p23)). This woman has two sisters with the translocation
unbalanced, resulting in a partial trisomy for chromosome 5 and partial monosomy
for chromosome 8 (46,XX,-8, +der(8)t(5;8)(p13;p23)) with associated mental
retardation and physical abnormalities. The patient and her husband desired to
have children without the abnormal chromosome balance and wished to reduce the
likelihood of spontaneous abortion or need for therapeutic abortion. Fluorescence
in-situ hybridization (FISH) probes for the alpha-satellite region of chromosome
8 and for a region on the short arm of chromosome 5 (5p15.2) were tested
initially on lymphocytes from the patient and her sisters. The hybridization
signal for chromosome 5 was detected in the expected two copies for the patient
and three copies for the sisters in 87% of the cells. Two hybridization signals
for chromosome 8 were detected in 96% of the cells from all individuals.
Additional probe testing was done using blastomeres from polyspermic embryos. The
couple then proceeded with a stimulated in-vitro fertilization (IVF) cycle and
biopsies were done on 13 embryos at the 7-10-cell stage using a method of zona
drilling and fluid displacement. Diagnosis was possible on at least one
blastomere for nine embryos. Three embryos had nuclei with three hybridization
signals for chromosome 5, three had fewer than two signals for one or both
chromosomes, one was mosaic, and two had two signals for each chromosome. The
latter were transferred to the patient, but pregnancy was not achieved. The
results demonstrate that preimplantation genetic diagnosis for patients with
reciprocal translocations can be used to identify embryos having normal
chromosome balance. The potential advantages and limitations of this approach are
discussed.
PMID- 9542976
TI - Telomerase activity in the human endometrium throughout the menstrual cycle.
AB - In a total of 41 endometrial tissue samples, the relationship between telomerase
activity and proliferating cell nuclear antigen (PCNA) labelling index was
studied. In samples of endometrium from the proliferative phase of the menstrual
cycle, telomerase activity was found in 15 out of 17 cases (88%). Two samples
from the early proliferative phase showed negative telomerase activity and a low
PCNA labelling index. However, three out of 16 samples of early secretory phase
endometrium showed telomerase activity and a PCNA labelling index. In mid- to
late secretory phase endometrium, in menopausal endometrium and in decidualized
endometrium induced by progesterone neither telomerase activity nor PCNA
labelling was found. These results suggest that telomerase activity of the
endometrium may be correlated with the proliferative potential of the epithelial
cells and that its activity may be regulated by oestrogen.
PMID- 9542977
TI - The presence of chorionic gonadotrophin beta subunit in normal cyclic human
endometrium.
AB - The aim of the present study was to determine whether human endometrial cells are
able to secrete beta-chorionic gonadotrophin (betaCG). Immunohistochemical
studies and in-situ hybridization were performed in order to provide evidence for
the occurrence of betaCG in the normal endometrium in 15 patients in the
proliferative phase, two patients in the periovulatory phase and 13 patients in
the secretory phase. Neither immunohistochemical nor hybridization reactions
could be recognized during the proliferative phase. In contrast, both protein and
betaCG mRNA were observed in the glandular cells of the endometrium during the
secretory phase. The results were supported by Western blotting of secretory
phase endometrium extracts and the assessment of the functional secretory
capacity of primary endometrium cultures. In comparison with cultured and
separated cell fractions, tissue extracts showed a higher betaCG, indicating a
regulatory interaction. In conclusion, betaCG can be demonstrated in normal human
cyclic endometrium, suggesting a paracrine role in endometrial physiology.
PMID- 9542978
TI - Endothelin receptor expression in human decidua.
AB - The endothelins are signalling peptides that act via two receptors, ET(A) and
ET(B). In the human endometrium, endothelin receptors have been demonstrated in
glands and stroma and have been shown to vary during the course of the menstrual
cycle. The present study was undertaken to determine whether or not expression of
endothelin receptors changes during pregnancy or after administration of
exogenous progestagens. The expression of the receptors was correlated with the
appearance of basement membrane components during decidualization of the
endometrial stroma. Decidual specimens (n = 15) were obtained during the first
trimester of pregnancy and 10 at term. Sixteen pairs of endometrial biopsies were
obtained from women with menorrhagia before and after exposure to exogenous
progestagens. A total of 15 hysterectomy specimens were used as controls for the
expression of stromal basement membrane proteins in the absence of
decidualization. Autoradiography was carried out with selective ligands for ET(A)
([125I]-PD 151242) and ET(B) ([125I]-BQ3020). The distribution of ligand binding
was then compared with the distribution of laminin alpha2 light chain and
collagen IV. ET(A), ET(B), laminin alpha2 light chain, and collagen IV were
expressed in stromal decidual cells in the first trimester of pregnancy. ET(B)
was also found on endometrial glandular epithelium. Quantitative macro
autoradiography and multiple regression analysis demonstrated a highly
significant positive correlation (P < 0.001) between expression of ET(B) and
laminin alpha2 light chain. In the third trimester qualitative examination
suggested a reduction of ET(A) in the stroma. Progestagen-induced decidua
exhibited a similar pattern to that found in first trimester decidua. This study
has demonstrated up-regulation of ET(B) during the progesterone-dependent process
of decidualization and suggests a paracrine or autocrine role for endothelins in
the decidua.
PMID- 9542979
TI - Expression of the Kir2.1 (inwardly rectifying potassium channel) gene in the
human placenta and in cultured cytotrophoblast cells at different stages of
differentiation.
AB - The aim of this study was to investigate whether the Kir2.1 gene is expressed by
the human placenta throughout pregnancy and in cytotrophoblast cells at different
stages of differentiation in culture. RNA was extracted from cytotrophoblast
cells isolated from term placentas and maintained in culture for 18, 66 and 114 h
and from first, second and third trimester placentas. Using the reverse
transcriptase-polymerase chain reaction (RT-PCR) with gene-specific primers, a
cDNA product of 1.2 kb, as expected for Kir2.1 gene expression, was detected in
all the RNA samples from cytotrophoblast cells and from placentas. The RT-PCR
products were verified by sequencing and by detection of the expected transcript
size for the Kir2.1 mRNA at 5.6-5.7 kb on Northern blots, using the 1.2 kb cDNA
generated by RT-PCR. Northern blot quantification, using a control 28S rRNA
probe, showed no significant difference in Kir2.1 mRNA expression between any of
the three stages of cytotrophoblast cell differentiation studied (ANOVA; n = 3
RNA samples from each stage). These data demonstrate that the Kir2.1 gene is
expressed by the human placenta and, specifically, by cytotrophoblast cells, at
all stages of development and differentiation.
PMID- 9542981
TI - Salvage treatment of failed hallux valgus operations with proximal first
metatarsal osteotomy and distal soft-tissue reconstruction.
AB - We reviewed the results of 15 patients (16 feet) in whom a hallux valgus
procedure had failed. Salvage was by proximal crescentic first metatarsal
osteotomy with distal soft-tissue reconstruction. Results based on a clinical
scale considering the level of pain, activity limitations, support requirement,
footwear limitations, and alignment were good in 11, fair in two, and poor in
three. Patients were satisfied with the results in 10 feet, satisfied with
reservations in four feet, and dissatisfied in two feet. Complications were:
transfer metatarsalgia in three, hallux varus in one, and osteotomy nonunion in
one. One of the patients required reoperation to bone graft a proximal osteotomy.
Metatarsal osteotomy was helpful in the salvage treatment of recurrent,
symptomatic hallux valgus when the first metatarsophalangeal joint was functional
and painless.
PMID- 9542982
TI - Effect of medial displacement calcaneal osteotomy on ankle kinematics in a
cadaver model.
AB - Although medial displacement calcaneal osteotomy has been advocated for treatment
of acquired pes planus, no studies have determined the biomechanical consequences
at the ankle of such a procedure. The present investigation examined the
alteration in ankle motion that resulted from a medial sliding calcaneal
osteotomy. In dorsiflexion, the ankle specimens were found to have altered
internal rotation and varus alignment. At maximal dorsiflexion, there was a 76%
increase in internal rotation (4.4 degrees +/- 2.5 degrees versus 2.5 degrees +/-
1.7 degrees for intact ankles, P < 0.0004) and an increase of 425% in varus (0.42
degrees +/- 0.56 degrees versus 0.08 degrees +/- 0.34 degrees for intact ankles,
P < 0.003). There were no significant differences seen in plantar flexion. Based
on these results, caution is advised in the indiscriminate use of medial sliding
osteotomies, because this procedure may predispose the patient to premature ankle
arthritis as a consequence of the altered ankle motions.
PMID- 9542983
TI - Surgical treatment of patients with painful instability of the second
metatarsophalangeal joint.
AB - An unstable second metatarsophalangeal joint may produce pain in the forefoot.
Eighteen patients (20 feet) had a transfer of the flexor digitorum longus to the
extensor side of the base of the proximal phalanx performed as the primary
procedure to stabilize this painful joint. Most patients had a hallux valgus
deformity that also required correction, because it either was also symptomatic
or was preventing adequate reduction of the second toe. A ruptured plantar plate
of the second metatarsophalangeal joint was demonstrated in 13 feet and in these
joints appeared to be the cause of the vertical instability. However, all feet
showed an unstable joint upon clinical examination. A vertical-stress test almost
always reproduced the patient's pain while demonstrating instability in the
joint; this was the most prominent physical finding in these patients. Eleven
patients (13 feet) had an excellent result. Seven patients (seven feet) had a
fair result, but they complained only of mild and occasional pain at the joint on
exertion. Although difficult to quantify, it appears that postoperative stiffness
in the joint provided some of the joint stability seen in our patients. The
flexor tendon transfer appears to be a satisfactory method to treating the
unstable metatarsophalangeal joint and of relieving patients' pain, but may not,
however, restore a normal alignment of the second toe. Correction of other
forefoot deformities as hallux valgus and hammertoes may also be important in
restoring metatarsophalangeal stability.
PMID- 9542984
TI - An evaluation of the use of gait plate inlays in the short-term management of the
intoeing child.
AB - A method of short-term intervention in cases of symptomatic intoeing in young
children was evaluated. Foot placement angle (FPA) in subjects (N = 18) suffering
from symptomatic intoeing was compared before and during the wearing of "gait
plate" inlays in the footgear. The median preintervention FPA in the study group
was -9.5 degrees (i.e., 9.5 degrees of intoeing). After the addition of gait
plate inlays, this angle fell to -3.5 degrees (Wilcoxon's matched pairs test P <
0.0001). There was no correlation found between the site of the underlying
pathology, gender, or age in relation to either the degree of original intoeing
or resulting improvement. There was a significant negative correlation
(Spearman's correlation coefficient -0.512, P < 0.001) between the FPA at
diagnosis and the subsequent improvement.
PMID- 9542985
TI - Biomechanical consequences of sequential plantar fascia release.
AB - Plantar fascia release has long been a mainstay in the surgical treatment of
persistent heel pain, although its effects on the biomechanics of the foot are
not well understood. With the use of cadaver specimens and digitized computer
programs, the changes in the medial and lateral columns of the foot and in the
transverse arch were evaluated after sequential sectioning of the plantar fascia.
Complete release of the plantar fascia caused a severe drop in the medial and
lateral columns of the foot, compared with release of only the medial third.
Equinus rotation of the calcaneus and a drop in the cuboid indicate that strain
of the plantar calcaneocuboid joint capsule and ligament is a likely cause of
lateral midfoot pain after complete plantar fascia release.
PMID- 9542986
TI - Differences in impulse distribution in patients with plantar fasciitis.
AB - The impulse distribution based upon vertical foot-floor reaction forces and time
under the fore-, mid-, and hindfoot was determined using Tekscan's F-Scan system.
This was compared in 40 barefoot patients with long-standing plantar fasciitis
with an equal number of normal subjects. The patient group tended to load the
hind- and midfoot to a lesser extent than the control group. Consequently, a
greater proportionate load was borne by the forefoot. This result was highly
significant for both the midfoot (P < 0.001) and forefoot (P = 0.002)
comparisons. An objective biomechanical method such as this may be useful as a
diagnostic aid, to identify individuals predisposed to this condition, and for
evaluating the efficacy of various treatment modalities.
PMID- 9542987
TI - Stress fracture of the base of the third metatarsal after an endoscopic plantar
fasciotomy: a case report.
PMID- 9542988
TI - Treatment of diabetic (neuropathic) foot ulcers with two-stage debridement and
closure.
AB - We reviewed 33 patients with 37 wounds treated between November of 1991 and
December of 1995 in the Wound Care Center. A two-stage debridement and closure
technique for neuropathic foot ulcers was performed. Patients selected included
those with obvious osteomyelitis and those who had failed nonsurgical treatment.
The approach included initial surgical excision of the ulcer with biopsy, bone
resection with biopsy, and deep culture. The second-stage procedure 4 to 8 days
later included debridement of the wound and delayed closure. Intravenous
antibiotic treatment using a central line was given postoperatively in patients
with documented osteomyelitis for at least 6 weeks and in patients with infected
soft tissues only for about 4 weeks. All patients remained nonweightbearing for 4
weeks; this was felt necessary to prevent separation of the wound edges. Four
wounds in four patients failed to heal, and two of these went on to amputation.
Satisfactory healing occurred in 29 of 33 patients and in 33 of 37 wounds. The
authors conclude that two-stage surgical debridement and closure is an acceptable
treatment in selected nonhealing diabetic (neuropathic) foot ulcers.
PMID- 9542989
TI - Results of preprocedure and postprocedure toe cultures in orthopaedic surgery.
AB - This study was to determine whether there is any benefit to wrapping the toes
sterilely during orthopaedic procedures not involving the foot but performed on
the lower extremity. The group studied consisted of 12 patients who had an
orthopaedic procedure performed in which the foot and toes were included in the
surgical prep, but not involved in the surgical procedure. Nine of the 12
patients (75%) had positive results from preprocedural aerobic cultures and two
of the 12 (16.6%) had positive results from preprocedural fungal cultures.
Recolonization of the bacteria between the toes was also demonstrated. Sterile
draping of the toes would minimize the risk of infection and also protect against
bacteria that recolonize during the procedure.
PMID- 9542990
TI - Piperacillin/tazobactam therapy for diabetic foot infection.
AB - In this study, 29 patients were hospitalized with a diabetic foot infection and
were treated with piperacillin/tazobactam. Of these 23 patients who were
evaluated for efficacy of treatment, 22 patients improved or were clinically
cured. In seven patients (30%), there was persistence of one of the baseline
pathogens. Adverse events were reported in 15 patients (58%), three of which were
serious. Piperacillin/tazobactam may be useful as monotherapy in diabetic foot
infection giving an adequate clinical response and the level of side effects
equivalent to those of other broad-spectrum antibiotics.
PMID- 9542991
TI - Risk of contamination of the wound in a hydrotherapeutic tank.
AB - Over a 4-week period, samples for culture were taken from active hydrotherapeutic
tanks (whirlpools) from two institutions in a university medical center. Samples
were obtained in the morning before treatments began, and in the evening after,
the final patient had been treated. Specific attention was directed toward
recovery of S. aureus, P. aeruginosa, and E. coli, organisms felt to be
especially dangerous for the diabetic dysvascular patients utilizing the
hydrotherapeutic tanks involved in this study. Only eleven of 96 cultures (11.5%)
were positive for these prospective pathogens. Of the positive cultures, nine
(9.4%) were taken from near the agitator-jet, and only two (2.1%) from the floor
of the hydrotherapeutic tanks, where the extremity is likely to be placed. Our
results reveal that hydrotherapeutic immersion is not likely to expose patients
with open wounds to potential iatrogenic contamination of the wound.
PMID- 9542992
TI - An unusual cause of posterior tibial tendon degeneration.
AB - A case demonstrating a mechanical cause of posterior tibial tendon degeneration
is reported. The possible etiologies for degeneration of the posterior tibial
tendon are discussed.
PMID- 9542993
TI - Posttraumatic posterior tibialis tendon insertional elongation with functional
incompetency: a case report.
AB - We present a case report and literature review of distal intrasubstance rupture
of the posterior tibial tendon with progressive pes planovalgus secondary to
tendon incompetence. Three months after a severe ankle sprain, a 25-year-old
basketball player presented with ankle weakness and pain. Treatment by
advancement of the posterior tibial tendon to the navicular and medial
displacement osteotomy of the calcaneal tuberosity restored alignment, strength,
and full function.
PMID- 9542994
TI - Arthroscopy of the foot and ankle: current concepts review.
PMID- 9542995
TI - Fold recognition and molecular modeling of a lectin-like domain in UDP
GalNac:polypeptide N-acetylgalactosaminyltransferases.
AB - By use of threading methods, the C-terminal region of uridine diphospho-N-acetyl
D-galactosamine:polypeptide N-acetylgalactosaminyltransferases (ppGalNAc
transferases) was predicted to have the same fold as the lectin-domain of the
plant cytotoxins ricin and abrin-a, for which crystal structure are available.
The sequence identities are very low. Nevertheless, the amino acids involved in
the hydrophobic core essential for the structure stability and the cysteine
residues are conserved. In addition, the amino-acids involved in carbohydrate
binding are conserved in ppGalNAc-transferases. The extra C-terminal domain of
these enzymes is therefore a putative glycan-binding domain. A model of the
lectin-like domain of human ppGalNAc-transferase T1 was built using knowledge
based methods. Geometry optimization of the complex with galactose allowed
prediction that this domain could bind this monosaccharide. However, the
interaction seems to be rather weak, and at the moment there is no evidence that
ppGalNAc-transferases displays a lectin activity in vivo.
PMID- 9542996
TI - The dimerization of Pseudomonas putida cytochrome P450cam: practical consequences
and engineering of a monomeric enzyme.
AB - Cytochrome P450cam dimerizes via the formation of an intermolecular disulfide
bond, complicating the storage and handling of the enzyme, particularly at higher
concentrations. The dimeric enzyme is 14% less active than the monomer and forms
at a slow but significant rate even at 4 degrees C [k = 1.09 x 10(-3) mM(-1) h(
1)]. To eliminate any ambiguity introduced by dimer formation and to simplify
handling and storage of the enzyme, site-directed mutagenesis was used to
identify C334 as the single cysteine residue responsible for the formation of the
disulfide linkage and to engineer a monomeric enzyme by substituting an alanine
in its place. The C334A mutant is identical with the wild-type P450cam monomer in
terms of optical spectra, camphor binding and turnover activity, but shows no
evidence of dimerization and aggregation even at millimolar concentrations.
Preliminary 1H NMR investigations also indicate a significant improvement in the
quality of spectra obtained with this mutant. (C334A)P450cam is therefore
proposed as an alternative to the wild-type enzyme-a base mutant otherwise
identical with the wild-type but with improved handling characteristics.
PMID- 9542997
TI - A fast estimate of electrostatic group contributions to the free energy of
protein-inhibitor binding.
AB - Dissecting ligand-protein binding free energies in individual contributions of
protein residues (which are referred to here as 'group contributions') is of
significant importance. For example, such contributions could help in estimating
the corresponding mutational effects and in studies of drug resistance problems.
However, the meaning of group contributions is not always uniquely defined and
the approximations for rapid estimates of such contributions are not well
developed. In this paper, the nature of group contributions to binding free
energy is examined, focusing particularly on electrostatic contributions which
are expected to be well behaved. This analysis examines different definitions of
group contributions; the 'relaxed' group contributions that represent the change
in binding energy upon mutation of the given residue to glycine, and the 'non
relaxed' group contributions that represent the scaled Coulomb interaction
between the given residue and the ligand. Both contributions are defined and
evaluated by the linear response approximation (LRA) of the PDLD/ S method. The
present analysis considers the binding of pepstatin to endothiapepsin and 23 of
its mutants as a test case for a neutral ligand. The 'non-relaxed' group
contributions of 15 endothiapepsin residues show significant peaks in the
'electrostatic fingerprint'. The residues that contribute to the electrostatic
fingerprint are located in the binding site of endothiapepsin. They include the
aspartic dyad (Asp32, Asp215) with adjacent residues and the flap region. Twelve
of these 15 residues have a heavy atom distance of <3.75 A to pepstatin. The
contributions of 8 (10) of these 12 residues can be reconciled with the
calculated 'relaxed' group contributions where one allows the protein and solvent
(solvent only) to relax upon mutation of the given residue to glycine. On the
other hand, it was found that residues at the second 'solvation shell' can have
relaxed contributions that are not captured by the non-relaxed approach. Hence,
whereas residues with significant non-relaxed electrostatic contributions are
likely to contribute to binding, residues with small non-relaxed contributions
may still affect the binding energy. At any rate, it is established here that
even in the case of uncharged inhibitors it is possible to use the non-relaxed
electrostatic fingerprint to detect 'hot' residues that are responsible for
binding. This is significant since some versions of the non-relaxed approximation
are faster by several orders of magnitude than more rigorous approaches. The
general applicability of this approach is outlined, emphasizing its potential in
studies of drug resistance where it is crucial to have a rapid way of
anticipating the effect of mutation on both drug binding and catalysis.
PMID- 9542998
TI - Is there a Mobius band in closed protein beta-sheets?
AB - Protein beta-strands can form beta-barrels and other complicated structures. This
paper defines bifurcations and pseudobifurcations of beta-sheets. They are
important structural elements for protein folding. This paper also presents a
characteristic number that can be used to test whether the surface of a closed
beta-sheet is one- or two-sided. Searching the whole Protein Data Bank released
in April 1997 with the definition of beta-structures given by the DSSP program,
we do not find any one-sided beta-Mobius band. However, there are interesting
structures such as beta-bands with odd number of antiparallel ladders and odd
number of bifurcations. There are also beta-structures that are closed only at a
singular point. Adding a small patch near the singular point in different ways
can make it a one- or two-sided surface. The catalytic triad of a GMP synthetase
(1GPM) is near the singular point of such a beta-sheet.
PMID- 9543000
TI - Structural studies of EcoRII methylase: exploring similarities among methylases.
AB - EcoRII methyltransferase (M.EcoRII) is a cytosine-C5 DNA methylating enzyme. A
model of its three-dimensional structure is proposed on the basis of homology
modeling. Crystal structures of two members of the same family of enzymes, HaeIII
and HhaI methyltransferases (M.HaeIII and M.HhaI respectively), were used as
template molecules. Molecular dynamics was used to ensure sampling of
conformationally stable structures. The final model has good geometry. The DNA
and cofactor binding residues are in expected positions and form proper
interactions. M.EcoRII is 147 amino acids longer than the template molecules, and
hence the model contains several loops that are significantly longer than those
in M.HaeIII and M.HhaI. The model provides a framework for interpretation and
designing site-directed mutants that have a potential to improve crystallization
experiments of this enzyme, and possibly other similar enzymes.
PMID- 9542999
TI - Molecular modeling of HIV-1 reverse transcriptase drug-resistant mutant strains:
implications for the mechanism of polymerase action.
AB - A computer model of human immunodeficiency virus type 1 (HIV-1) reverse
transcriptase (RT) either alone, or complexed with a non-nucleoside inhibitor
(NNI), was constructed using crystal coordinate data from a subset of the protein
surrounding the binding pocket region. Molecular mechanics calculations were
carried out on solvated wild-type RT and RT that contained modifications
corresponding to resistance-engendering mutations. Results from the calculations
revealed that the r.m.s. difference between 12 modified proteins and that of wild
type RT could be qualitatively correlated with the measured polymerase activity
of the enzyme in the presence of these mutations. In addition, the level of
activity was related to the measured distance between the primer grip and dNTP
binding regions of the protein. These data suggest a direct correlation between
RT structure and function. Complexes of RT-8-C1 TIBO and RT-alpha-APA were also
minimized in models containing modifications corresponding to key drug-resistant
mutants. The variant complexes all showed weaker binding than wild-type RT, while
giving rise to similar, but critical changes in the protein. Therefore, the
design of new inhibitors should center on obtaining stronger binding drugs to key
drug-resistant RT variants.
PMID- 9543001
TI - Development of a structural model for the cytoplasmic domain of an integrin.
AB - The cytoplasmic tails of integrin heterodimers play central roles in controlling
the activation states of integrins and in transmitting intracellular signals.
Despite their short length, no structure of any integrin cytoplasmic domain has
been determined. Therefore, molecular models for the cytoplasmic domain of
alpha(IIb)beta3, the major platelet integrin, were generated, including models
for the individual cytoplasmic tails, the binary alphaIIb-calcium complex, and
the ternary alphaIIb-beta3-calcium complex. Structural analysis of circular
dichroism spectra were compiled with data obtained from short homologous
sequences within crystallized proteins, and with secondary structural predictions
to develop starting models for each subunit. These models were subjected to a
series of energy minimization and molecular dynamic simulations to generate final
models. AlphaIIb was predicted to be ordered at its N-terminus and its C-terminus
could accommodate a cation in a multicoordinated complex. The structure of beta3
was dominated by a beta-turn at its NPXY motif (beta3 744-747). In docking of
alphaIIb to different sites within beta3, the conformation of the beta3 juxta
transmembrane (beta3 716-721) was greatly altered. This region was confirmed to
be a conformational 'hot-spot' by circular dichroism. The conformational
flexibility of this juxta-transmembrane region, which is highly conserved amongst
integrins, is ideally located to regulate signaling.
PMID- 9543002
TI - Identification of indispensable residues for specific DNA-binding in the
imperfect tandem repeats of c-Myb R2R3.
AB - The individual repeats, R2 and R3, of the minimum specific DNA-binding domain
(R2R3) of c-Myb have very similar structures, with a helix-turn-helix variation
motif, although their sequence identity in the tandem repeats is only 31%. From
previous mutational and structural studies, the third helices in both repeats
were shown to directly recognize the specific base sequence, PyAACG/TG. In order
to elucidate the reason for the imperfection of the tandem repeats at amino acid
positions other than the recognition helices, a series of R2R3 mutants was
generated by swapping the helices and the N-terminus in R2 to those in R3.
Consequently, the sequence composing the first helix of R2 was found to be
essential for specific DNA-binding, in addition to the third recognition helix of
R2. Further mutational studies revealed that the only indispensable residues in
the first helix are Val103 and Val1O7, which are involved in the hydrophobic core
of R2. These residues do not directly interact with the DNA, but they contribute
to the correct formation of helix 1 and the characteristic packing of R2, which
is slightly different from that of R3, and are required for specific base
recognition through strong cooperativity with R3.
PMID- 9543003
TI - A glutamine 67--> histidine mutation in homotetrameric R67 dihydrofolate
reductase results in four mutations per single active site pore and causes
substantial substrate and cofactor inhibition.
AB - R67 dihydrofolate reductase (DHFR) is a type II DHFR produced by bacteria as a
resistance mechanism to increasing clinical use of the antibacterial drug
trimethoprim. Type II DHFRs are not homologous in either sequence or structure
with chromosomal DHFRs. The crystal structure of R67 DHFR shows a single active
site pore that spans the length of the homotetramer. Related sites (due to a 222
symmetry element at the center of the pore) are used to bind ligands, i.e. each
half of the pore can accommodate either the substrate, dihydrofolate (DHF), or
the cofactor, NADPH, although DHF and NADPH are bound differently. To evaluate
the role of glutamine 67 (and its symmetry-related Q167, Q267 and Q367 residues
which occur at the center of the active site pore), a Q67H mutation was
constructed. Binary binding of dihydrofolate (DHF; monitored by isothermal
titration calorimetry) displays two identical sites with a Kd value of 0.04
microM, while binding of NADPH shows two sites possessing negative cooperativity
with Kd values of 0.027 and 0.62 microM. A comparison of ligand binding in Q67H
versus wild-type (wt) R67 DHFR indicates both ligands bind more tightly (80-6000
fold) and DHF binding in Q67H R67 DHFR no longer displays positive cooperativity
as seen in wt R67 DHFR. Ternary complex binding in the Q67H mutant indicates a
total of two ligands can bind per pore. Substantial substrate and cofactor
inhibition are observed during catalysis, consistent with non-productive binding
of either two DHF or two NADPH molecules in Q67H R67 DHFR. Because of the
symmetry-related binding sites in the active site pore, the accumulation of
potentially positive mutations in R67 DHFR is limited by the balance between
tighter binding of ligands (and thus potentially increased catalytic efficiency)
and inhibition that arises upon tighter binding of two identical ligands at
symmetry-related sites.
PMID- 9543004
TI - Structural and functional roles of a conserved proline residue in the alpha2
helix of Escherichia coli thioredoxin.
AB - Proline 40 in Escherichia coli thioredoxin is located close to the redox active
site (Cys32-Cys35) within the alpha2 helix. The conservation of this residue
among most of the thioredoxins suggests that it could play an important role in
the structure and/or function of this protein. We have substituted Pro40 for Ala
by using site-directed mutagenesis and expressed the mutant P40A in E.coli. The
effects of the mutation on the biophysical and biological properties of
thioredoxin have been analyzed and compared with molecular dynamics simulations.
Modeling predicted that the replacement of Pro40 by Ala induced a displacement of
the active site which exposes Trp31 to the solvent and opens a cleft located
between helices alpha2 and alpha3. The solvation free energy (SFE) calculation
also indicated that P40A became more hydrophobic as W31 became more accessible.
These predictions were totally in agreement with the experimental results. The
mutant P40A exhibited chromatographic behavior and fluorescence properties very
different from those of the wild-type (WT) protein, in relationship with the
displacement of W31. The determination of the free energy of unfolding of P40A
showed that the mutant was globally destabilized by 2.9 kcal/mol. However, the
effect of the mutation on the transition curve was highly unusual as the midpoint
of the unfolding transition increased, indicating that some local structures were
actually stabilized by the mutation. Despite these structural modifications,
neither the ability of the protein to reduce a chloroplastic enzyme nor its
reactivity with the bacterial reductase decreased. The only functional difference
was the higher stability of P40A in light activation of NADP-malate dehydrogenase
under air, which suggests that the mutant was less rapidly re-oxidized than WT.
Therefore, it can be concluded that Pro40 is not essential for maintaining the
redox function of thioredoxin but rather is required for the stability of the
protein.
PMID- 9543005
TI - Spontaneous oligomerization of a staphylococcal alpha-hemolysin conformationally
constrained by removal of residues that form the transmembrane beta-barrel.
AB - Staphylococcal alpha-hemolysin is a water soluble, monomeric, bacterial exotoxin,
which forms heptameric pores in membranes. The rate determining step in assembly
is the conversion of a heptameric prepore to the fully assembled pore in which
the central glycine-rich domain of each subunit inserts into the membrane to form
a 14 strand beta barrel. Barrel formation is accompanied by a conformational
change in which each N terminus latches onto an adjacent subunit. In the monomer
in solution, the central domain is loosely organized and exposed to solvent. In
this study, 25 amino acids of the central domain were removed and replaced with
the sequence Asp-Gly, which favors the formation of a type I' beta-turn, to yield
a mutant devoid of hemolytic activity. Within minutes after synthesis in the
absence of membranes, the mutant polypeptide spontaneously assembled into
heptamers, as demonstrated by atomic force microscopy. Limited proteolysis
suggested that the N termini of the subunits in the heptamers were in the fully
assembled pore conformation rather than the prepore conformation. Based on these
findings, the deletion is proposed to constrain the central domain and thereby
force the creation of a shortened beta barrel, which in turn induces the
additional structural changes that normally accompany pore formation. The
truncated pore might make a useful framework for the construction of designed
membrane active macromolecules.
PMID- 9543006
TI - Effects of sulfhydryl regents on the activity of lambda Ser/Thr phosphoprotein
phosphatase and inhibition of the enzyme by zinc ion.
AB - Sulfhydryl reagents, such as dithiothreitol (DTT), affected the activity of
Ser/Thr phosphoprotein phosphatases. Addition of DTT to the assay buffer
increased the affinity of lambda Ser/Thr phosphoprotein phosphatase (lambda
PPase) for its Mn2+ cofactor. On the other hand, the enzyme was found to be
inactivated simply by dilution in Tris buffer. The inactivation could be
completely prevented by the presence of DTT or Mn2+ in the buffer. Further
studies showed that oxidation or reduction of cysteine residues in lambda-PPase
may not be the cause of the change in the enzyme activity. Without exception,
mutation of all cysteine residues in lambda-PPase to serine did not convert the
enzyme into a thiol-insensitive mutant. By careful examination of the effects of
different sulfhydryl reagents, metal ion cofactors and substrates on lambda
PPase, it was found that the role of sulfhydryl reagents was the chelation of
small amounts of inhibitory metal ions, which were present in plastic laboratory
ware, such as disposable cuvets and tubes, with prevention of the enzyme from
inactivation. One of the main contaminants found in plastic cuvets was Zn2+,
which is a potent inhibitor of lambda-PPase. The inhibition of lambda-PPase by
Zn2+ was characterized. Pre-treatment of the enzyme (1-4 nM) with 1 microM of
ZnCl2 almost completely inhibited the enzymatic activity in response to 2 mM
Mn2+. However, no significant inhibition was found when the enzyme was added to
the assay mixture containing 1 microM Zn2+ and 2 mM Mn2+ . This confirms the
sensitivity of the holoenzyme to inhibitory metal ions in vitro. The kinetic
analysis indicated that the inhibitory metal ion might compete with Mn2+ to bind
to the active site of lambda-PPase. This was further supported by the mutation of
metal cofactor binding amino acid residues of the enzyme. Mutants which have less
affinity for Mn2+ are also less sensitive to Zn2+. Our results suggest that
inhibitory metal ions may induce a different structural conformation for lambda
PPase.
PMID- 9543007
TI - A form of anti-Tac(Fv) which is both single-chain and disulfide stabilized:
comparison with its single-chain and disulfide-stabilized homologs.
AB - Disulfide-stabilized Fvs (dsFvs) are recombinant proteins composed of a heavy
chain variable domain (VH) of an antibody connected via a disulfide bond to the
light-chain variable domain (VL). In single-chain Fvs (scFvs), a peptide
connector links VH and VL. The dsFv form of the anti-Tac monoclonal antibody
which reacts with the alpha subunit of the IL2 receptor was recently reported to
be more stable and to aggregate less during renaturation than anti-Tac(scFv). In
addition, it could be produced in a better yield owing to less aggregation.
However, the yields are still too low to permit the production of material for
clinical trials in which the dsFv will be used to image or treat IL2 receptor
(CD25)-containing tumors. To increase the efficiency by which VH and VL associate
and form a disulfide bond during renaturation, we have prepared an Fv form of
anti-Tac which is both single chain and disulfide stabilized (scdsFv). The
recombinant protein is expressed in Escherichia coli, where it accumulates in
inclusion bodies. Using inclusion body protein as the reference point, the yield
of purified anti-Tac(scdsFv) was 13% compared with 2% for anti-Tac(dsFv). Anti
Tac(scdsFv) has equivalent binding affinity, immunoreactivity after radiolabeling
and stability. The results show that a linker between VH and VL facilitates
heterodimer formation and leads to disulfide bond formation in a higher
percentage of the molecules renatured. Thus anti-Tac(scdsFv) is the preferred
form of anti-Tac(Fv) to be used for clinical studies. We anticipate that scdsFvs
will be the optimum recombinant form of Fv to produce from bacteria.
PMID- 9543008
TI - Purification and crystallization of complexes modeling the active state of the
fragile histidine triad protein.
AB - Fragile histidine triad protein (Fhit) is a diadenosine triphosphate (ApppA)
hydrolase encoded at the human chromosome 3 fragile site which is frequently
disrupted in tumors. Reintroduction of FHIT coding sequences to cancer cell lines
with FHIT deletions suppressed the ability of these cell lines to form tumors in
nude mice even when the reintroduced FHIT gene had been mutated to allow ApppA
binding but not hydrolysis. Because this suggested that the tumor suppressor
activity of Fhit protein depends on substrate-dependent signaling rather than
ApppA catabolism, we prepared two crystalline forms of Fhit protein that are
expected to model its biologically active, substrate-bound state. Wild-type and
the His96Asn forms of Fhit were overexpressed in Escherichia coli, purified to
homogeneity and crystallized in the presence and absence of ApppA and an ApppA
analog. Single crystals obtained by vapor diffusion against ammonium sulfate
diffracted X-rays to beyond 2.75 A resolution. High quality native synchrotron X
ray data were collected for an orthorhombic and a hexagonal crystal form.
PMID- 9543009
TI - Prion protein expression in Chinese hamster ovary cells using a glutamine
synthetase selection and amplification system.
AB - Syrian hamster prion protein (PrPC) and a truncated Syrian hamster prion protein
lacking the glycosylphosphatidylinositol (GPI) anchor C-terminal signal sequence
(GPI-) were expressed in Chinese hamster ovary cells using a glutamine synthetase
selection and amplification system. The CHO cell clones expressing the GPI- PrP
secreted the majority of the protein into the media, whereas most of the PrP
produced by clones expressing the full-length protein with the GPI anchor was
located on the cell surface, as demonstrated by its release upon treatment with
phosphatidylinositol-specific phospholipase C (PIPLC). A cell clone that
expressed the highest levels of full length PrP was subcloned to obtain clone
30C3-1. PrP from clone 30C3-1 was shown to be sensitive to proteolysis by
proteinase K and to react with monoclonal and polyclonal antibodies that
recognize native PrPC. The recombinant PrP migrated as a diffuse band of 19-40
kDa but removal of the N-linked oligosaccharides with peptide N-glycosidase F
(PNGase F) revealed three protein species of 19, 17 and 15 kDa. The 19 kDa band
corresponding to deglycosylated full-length PrP was quantified and found to be
expressed at a level approximately 14-fold higher than that of PrPC found in
Syrian hamster brain.
PMID- 9543010
TI - Analysis of constitutive heterochromatin of Aotus (Cebidae, Primates) by
restriction enzyme and fluorochrome bands.
AB - The current classification of genus Aotus includes nine species, four of which
occur above the Amazon River and five below it. The position of several of these
taxa as a valid species has been questioned. Recently, we described the
chromosomal constitution of a population in the state of Rondonia, Brazil, whose
karyotype typically presented a considerable accumulation of constitutive
heterochromatin. To best characterize these heterochromatins, in this work we
subjected the metaphases of these animals to banding using AluI, HaeIII, HinfI,
RsaI, DdeI, MboI and MspI restriction enzymes and CMA3 and DAPI fluorochromes.
The banded metaphases were also submitted to sequential C-banding. RsaI, DdeI and
MboI enzymes showed, in all chromosomes, a banding pattern of C type, similar to
that obtained using barium hydroxide. This banding was also seen with AluI, HinfI
and MspI, but with reduction or elimination of the C-bands in the chromosome
pairs 1, 3-7 and 9. MspI also reduced the C-band of pairs 11, 16-21 and 23.
HaeIII induced intermediate bands between G and C. Considering the data of the
different bands produced, it was possible to characterize at least three distinct
types of constitutive heterochromatin in Aotus from Rondonia: (a) centromeric
bands, (b) bands of the heterochromatic short arms and (c) interstitial bands.
PMID- 9543011
TI - Molecular cloning of metaphase chromosome protein 1 (MCP1), a novel human
autoantigen that associates with condensed chromosomes during mitosis.
AB - Systemic lupus erythematosus autoantibodies were used to identify and to
characterize new human chromosome-associated proteins. Previous
immunolocalization studies in human and murine tissue culture cells showed that
some of these monoclonal antibodies recognize nuclear antigens that associate
with condensed chromosomes during mitosis. One antibody was selected for
screening a human HeLa S3 cDNA expression library, and cDNAs that code for an
antigen of 31-33 kDa were isolated. Immunological, biochemical and cell
fractionation data indicate that the 31- to 33-kDa antigen corresponds to the
chromosome-associated protein recognized by the original monoclonal antibody.
Sequence analysis shows that we isolated a novel human gene. Immunolocalization
to human tissue culture cells shows that during interphase the antigen is
dispersed in the nucleus and that during mitosis it associates exclusively with
condensed chromosomes. A similar pattern of localization was also observed in
mouse fibroblasts, suggesting that the antigen is conserved among different
species. Finally, we show that part of the antigen remains bound to the
scaffold/matrix component, even after high salt extraction.
PMID- 9543012
TI - Chromosomal localization and distribution of simple sequence repeats and the
Arabidopsis-type telomere sequence in the genome of Cicer arietinum L.
AB - We used fluorescence in situ hybridization to probe the physical organization of
five simple sequence repeat motifs and the Arabidopsis-type telomeric repeat in
metaphase chromosomes and interphase nuclei of chickpea (Cicer arietinum L.).
Hybridization signals were observed with the whole set of probes and on all
chromosomes, but the distribution and intensity of signals varied depending on
the motif. On root-tip metaphase chromosomes, CA and GATA repeats were mainly
restricted to centromeric areas, with additional GATA signals along some
chromosomes. TA, A and AAC repeats were organized in a more dispersed manner,
with centromeric regions being largely excluded. In interphase nuclei of the
inner integument, CA and GATA signals predominantly occurred in the
heterochromatic endochromocentres, whereas the other motifs were found both in eu
and heterochromatin. The distribution of the Arabidopsis-type telomeric repeat
(TTTAGGG)n on metaphase chromosomes was found to be quite exceptional. One major
cluster of repeats was spread along the short arm of chromosome B, whereas a
second, weaker signal occurred interstitially on chromosome A. Only faint and
inconsistent hybridization signals were visualized with the same probe at the
chromosomal termini.
PMID- 9543013
TI - Germ cell restriction and regular transmission of an accessory chromosome that
mimics a sex body in the zebra finch, Taeniopygia guttata.
AB - Mitotic and meiotic analysis with light and electron microscopy was performed in
male and female zebra finches (Taeniopygia guttata). Somatic cells from bone
marrow have a 2n = 80 and show the usual sex chromosome mechanism of birds ZZ
(male)/ZW (female). In the germ lines of both sexes, a single accessory
chromosome was regularly present in all the cells examined from all the
individual birds. In synaptonemal complex (SC) spreads of pachytene oocytes and
spermatocytes, this accessory chromosome forms a single axis, but it behaves
differentially in male and female meiosis. While this accessory chromosome is
euchromatic in oocytes, it is strongly heterochromatic in spermatocytes. In
pachytene spermatocytes, the accessory chromosome adopts a morphology strikingly
similar to that of the XY body ('sex vesicle') of mammalian spermatocytes. This
accessory chromosome is eliminated during male meiosis and forms a cytoplasmic
dense body in young spermatids that shows strong fluorescence with DAPI. The
presence of this germ line-restricted chromosome does not affect the behaviour of
the ZW pair in oocytes, as the sex chromosomes pair regularly and show a
localized recombination nodule. It is suggested that this accessory chromosome
has transcriptional activity during oogenesis, and thus it is regularly
transmitted through preferential segregation during female meiosis.
PMID- 9543014
TI - Chromosome stability is maintained by short intercentromeric distance in
functionally dicentric human Robertsonian translocations.
AB - While the formation of a dicentric chromosome often leads to chromosome
instability, human dicentric Robertsonian translocations usually remain stable.
To investigate the basis for this stability, we have examined the centromeres of
15 structurally dicentric rob(13q14q) Robertsonian translocations using
immunofluorescence and fluorescence in situ hybridization (FISH). The
immunofluorescence detection of centromere protein C (CENP-C) was used as a
marker for centromere function as CENP-C seems to play an essential role in
kinetochore structure and stability and was previously shown to be absent from
inactive centromeres. In all 15 translocation-containing cell lines, CENP-C was
confined to only one of the centromeres of the translocation in a fraction of the
cells analyzed. This suggests that centromere inactivation commonly occurs on
dicentric Robertsonian translocations and may serve as one mechanism allowing for
their stability. However, in the majority of the translocations (12 out of 15), a
portion of the cells analyzed displayed CENP-C immunofluorescence at both
centromeres, suggesting that both centromeres were active and that the
translocation was functionally dicentric. The percentage of cells with CENP-C at
both centromeres ranged from 2% to 82%. These results support the hypothesis that
the close proximity of two functional centromeres on Robertsonian translocations
allows them to remain stable.
PMID- 9543015
TI - Relevance of kinetochore size and microtubule-binding capacity for stable
chromosome attachment during mitosis in PtK1 cells.
AB - Chromosomes attach to the mitotic spindle via their kinetochores. The average
number of spindle microtubules binding to each kinetochore varies with species,
the stage of mitosis, and the length of time that the kinetochore has been
attached to the spindle. In this report, we investigate how kinetochore
microtubule number varies with kinetochore size and chromosome size in PtK1
cells. From an analysis of serial-section electron micrographs, we determined
that the average surface area of metaphase, taxol-treated metaphase, and anaphase
kinetochores is 0.16 +/- 0.05 microm2 (N = 181). Surprisingly, kinetochore
microtubules are packed more densely on the smaller kinetochores, as seen by a
reduction in the average spacing between kinetochore microtubules from 89 nm to
59 nm. Our interpretation of this result is that PtK1 cells require a minimum
kinetochore microtubule-binding capacity for survival during repeated rounds of
mitotic division. We estimate the lower limit to be 23 kinetochore microtubules
and suggest that this capacity is required to ensure stable attachment during the
dynamic and highly stochastic process of kinetochore fiber formation. There is a
modest but statistically significant increase in kinetochore microtubule number
with chromosome size, indicating that chromosome size is a minor determinant of
kinetochore microtubule number.
PMID- 9543017
TI - The X1X2Y sex chromosome system in the fish Hoplias malabaricus. II. Meiotic
analyses.
AB - The neotropical fish Hoplias malabaricus shows diversified cytotypes and may
represent a group of distinct species. One of these cytotypes is characterized by
2n = 40 and 2n = 39 chromosomes in females and males, respectively, with a
multiple sex chromosome system of the X1X1X2X2/X1X2Y type. The Y, representing a
large chromosome in male karyotype, is derived from a translocation event between
two biarmed chromosomes: one of them similar to X1 chromosome (no. 6) and another
one similar to X2 chromosome (probably no. 20). Meiotic data (standard and
synaptonemal complexes analyses) show 18 bivalents and one characteristic
trivalent in pachytene and metaphase I spermatocytes, as well as two kinds of
metaphase II cells with 19 and 20 chromosomes. The trivalent is formed by the Y,
X1 and X2 chromosomes and usually presents a complete pairing in pachytene.
However, trivalents with partially or fully asynapsed segments are also observed.
These segments are assumed to be non-homologous regions of the X1 and X2
chromosomes without correspondence with the Y chromosome, which can
heterosynapse. This behaviour of the sex trivalent leading to a fully paired
structure, taken together with the close frequencies of the two spermatocyte
types at metaphase II, suggests a normal pattern for male H. malabaricus meiosis,
representing a stabilized multiple sex chromosome system in this species.
PMID- 9543016
TI - Nucleotide specificity at the boundary and size requirement of the target sites
recognized by human centromere protein B (CENP-B) in vitro.
AB - Human centromere protein B (CENP-B) has a sequence-specific DNA binding activity.
We previously reported several CENP-B binding motifs by analysing synthetic
oligonucleotides as well as alphoid DNA isolated from the human genomic library.
Here, we examined the size requirement and nucleotide specificity of human CENP-B
binding sequences in vitro. We synthesized three sets of mixed oligonucleotides
containing diverged authentic binding sites (CTTCGTTGGAAACGGGA) in which certain
pairs of nucleotides (underlined) were degenerated. Each oligonucleotide with a
defined sequence was separately introduced into a plasmid and mixed with GST
fused recombinant CENP-B. The DNA-protein complex formed was affinity purified
with glutathione Sepharose. Any nucleotide substitutions at the positions 1, 2
and 17 did not significantly influence the recovery, while the substitutions at
positions 3, 4 and 16 did, suggesting that the internal 14-bp motif
(TCGTTGGAAACGGG) constituted the minimum requirement. However, it showed a lower
affinity to CENP-B, compared with the authentic motif. The inclusion of T at the
5' end greatly increased the affinity, and the further addition of A or T at the
3' end (TTCGTTGGAAACGGGA/T) offered affinity similar to the authentic motif. The
first nucleotide of the 17-bp authentic binding motif may not be essential for
CENP-B binding.
PMID- 9543018
TI - Rights and welfare of incapable adults: advocacy, ethics and the law.
PMID- 9543019
TI - Eradication of poliomyelitis is on track in the WHO European and Eastern
Mediterranean regions.
PMID- 9543020
TI - Stop exporting tobacco madness.
PMID- 9543021
TI - Aspirin treatment.
PMID- 9543023
TI - The hidden waiting lists--older people denied care.
PMID- 9543022
TI - Midwives and woman-centred care.
PMID- 9543024
TI - Clinical effectiveness can be routine, says King's Fund.
PMID- 9543025
TI - Primary and secondary interface for mental healthcare.
PMID- 9543026
TI - HAS 2000.
PMID- 9543027
TI - Healthcare inadequate according to MS society.
PMID- 9543028
TI - Recommendations for psychiatrists working with recovered memories of child sexual
abuse.
PMID- 9543029
TI - Cultural safety: a new concept in nursing people of different ethnicities.
AB - Cultural safety is a concept which has been developed by Maori nurses in New
Zealand in order to reflect on nursing practice from their point of view as the
indigenous minority in our country. The paper contrasts this new concept
critically with Leininger's well-known model of transcultural nursing in order to
suggest its potential significance. To date work on cultural safety in New
Zealand has focused on the attitudes which individual nurses bring to their
practice, attempting to change the effects of their social conditioning on their
approach to nursing. The paper supports the view that all nursing care is
provided in a social context which influences its efficacy, and specifies that
the structural elements, such as the institutional context within which nursing
care is provided and policies which influence how care is the provided, need to
be explicitly recognized. The paper concludes that until the effects on the
health care system of inequalities in power between groups in society are
addressed we cannot ensure that the needs of persons from minority cultures will
be met. Because it illuminates this dimension of nursing care, cultural safety is
a concept of general significance for all nurses.
PMID- 9543030
TI - Relationships between infant temperament, demographic variables, and family
dynamics of childrearing families.
AB - Relationships between infant temperament, demographic variables, and family
dynamics of child-rearing families were investigated in this study. The revised
Infant Temperament Questionnaire (RITQ), the Family Dynamics Questionnaire (FDQ)
and the Family Dynamics Measure (FDM) were sent to 118 families who had
participated in the first stage of the study as child-bearing families. About 8
months after childbirth 96 mothers and 95 fathers completed the questionnaires.
The characteristics of infant temperament and demographic variables related to
the variance of dimensions of family dynamics. Characteristics of the
temperamentally easy baby related to more positive family dynamics perceived by
child-rearing parents. Fathers rearing their first child reported that their
families functioned better than fathers with their second infant. In child health
clinics families rearing their second child should also be supported, especially
families with arrhythmic and negative mood infants.
PMID- 9543031
TI - Relaxation techniques for acute pain management: a systematic review.
AB - This review aims to document the effectiveness of relaxation techniques, when
used alone for the management of acute pain, after surgery and during procedures.
A systematic review of randomized controlled trials (RCTs) was undertaken. Seven
studies involving 362 patients were eligible for this review. One hundred and
fifty patients received active relaxation as the sole intervention. Reports were
sought by searching MEDLINE, psycLIT, CINAHL, and the Oxford Pain Relief
Database. The outcome measures used were pain and psychological factors. A meta
analysis was not possible, due to lack of primary data. Three of the seven
studies demonstrated significantly less pain sensation and or pain distress in
those who had relaxation. Four studies did not detect any difference. There was
some weak evidence to support the use of relaxation in acute pain. However, this
was not conclusive and many of both the positive and the negative studies
suffered from methodological inadequacies. Well designed and executed randomized
controlled trials are needed before the clinical use of relaxation in acute pain
management can be firmly underpinned by good quality research evidence. Until
this evidence is available we recommend that the clinical use of relaxation in
acute pain settings is carefully evaluated and not used as the main treatment for
the management of acute pain.
PMID- 9543032
TI - Relaxation for the relief of chronic pain: a systematic review.
AB - The effectiveness of relaxation techniques in the management of chronic pain was
determined in this systematic review of published randomized controlled trials.
Reports were sought by searching MEDLINE, psycLIT, CINAHL, EMBASE and the Oxford
Pain Relief Database. Studies were included in this review if they were
randomized controlled trials of relaxation techniques in chronic pain. Studies
which investigated the effects of relaxation in combination with other
interventions were not considered. Nine studies involving 414 patients met the
predefined inclusion criteria and are critically appraised in this review. Meta
analysis was not possible, due to lack of quantitative data in the primary
studies. Studies involved patients with a range of chronic pain conditions. The
McGill Pain Questionnaire was the most common pain outcome used. Whilst four
studies were able to show a significant difference for the pain outcomes in
favour of relaxation for the pre- and post-treatment assessments, few
statistically significant differences were reported in favour of relaxation when
between treatment comparisons were used. Only three studies reported
statistically significant differences in favour of relaxation (judged as a
significant difference for at least 1 of the pain outcomes) compared to the other
treatment groups. In rheumatoid arthritis the McGill Pain Questionnaire scores
were significantly lower for patients receiving relaxation compared to those who
were in the routine treatment control group. In ulcerative colitis significant
differences were reported for six of seven different pain outcome measures in
favour of progressive muscle relaxation compared to patients in the waiting list
control group. In one of the two cancer pain studies, relaxation taught by nurses
produced significantly lower pain sensation scores compared to the control group.
Two studies reported significant differences in favour of the experimental
control groups rather than for relaxation. There is insufficient evidence to
confirm that relaxation can reduce chronic pain. Many of the studies both
positive and negative suffer methodological inadequacies. Recommendations for
future research into the effectiveness of relaxation techniques for chronic pain
are made.
PMID- 9543033
TI - Investigating psychosocial aspects of participation in early anti-cancer drug
trials: towards a choice of methodology.
AB - This paper presents the methodological approach and research methods chosen to
explore psychosocial aspects of participation in early anti-cancer drug trials
from the perspective of those actually involved. The paper describes how an
appropriate methodology, or principles of reasoning behind the choice of research
methods, emerged. The choice of methodology was based on three elements: first,
an understanding of the competing philosophies about how research can be
approached and conducted; second, the author's view of the subject area; and
third, a consideration of previous research approaches which have investigated
psychosocial aspects of cancer clinical trials. A qualitative methodology
situated within an interpretative paradigm was eventually chosen as the most
appropriate means of exploring trial participants' experiences and the aim and
objectives of the research were developed within this methodological framework.
PMID- 9543034
TI - The co-existence of psychiatric disorders and substance misuse: working with dual
diagnosis patients.
AB - The co-existence of substance misuse and psychiatric disorders is often referred
to by the term 'dual diagnosis'. The health-related problems associated with dual
diagnosis has received growing attention by clinicians and researchers alike.
Severely mentally ill patients who misuse drugs (prescribed and illicit) or
alcohol have complex health and social needs. Mental health nurses have a key
role to play in the early recognition and management of this group of patients.
This paper examines the nature and extent of dual diagnosis and its implications
for mental health nurses. It also addresses treatment strategies that are
required to meet the needs of this cohort of patients.
PMID- 9543035
TI - Developing a non-aversive intervention strategy in the management of aggression
and violence for people with learning disabilities using natural therapeutic
holding.
AB - This paper builds upon a previous piece of research regarding the development of
'natural therapeutic holding' as a non-aversive alternative to control and
restraint (C and R) in managing aggression and violence in people with learning
disabilities. This paper represents aspects of an ongoing programme of research
and explains the aims and values which underpin natural therapeutic holding by
describing the theory, aims, values and practical application. The concepts of
individual risk management and pro-active intervention strategies are discussed
with illustrations of practical application given by means of a case study. The
case study shows that over a relatively short period of time, an individual with
severe learning disabilities who is aggressive and violent, learns alternative
coping strategies to aggression and violence through the application of natural
therapeutic holding. The article concludes that natural therapeutic holding is a
very effective intervention strategy in the management of violence in people with
learning disabilities from two perspectives: (a) it provides staff with safe,
professional and ethical skills with which they can manage aggressive and violent
clients and (b) as a therapy, natural therapeutic holding gives clients the
opportunity to learn coping strategies which are more effective than violence.
PMID- 9543036
TI - The contexts for managing depression and its stigma among black West Indian
Canadian women.
AB - There is a paucity of literature available to assist nurses and other care
providers in knowing how to meet the needs of depressed women from non-dominant
cultural backgrounds. To begin to address this need, we conducted a grounded
theory study on black West Indian Canadian Women's strategies for managing
depression. We discovered a basic social process, Being Strong, that the women
used to manage or ameliorate depression. Being strong occurs within the
overlapping areas of three social contexts: the cultural stigma of depression,
male-female roles and relationships, and belief in Christian doctrine. These
contexts are located against a backdrop of visible minority status within a
eurocentric society. This socio-cultural contextual material provides the setting
within which black West Indian Canadian women live and make decisions. In this
article, we present findings related to the social and cultural aspects of the
women's situation.
PMID- 9543037
TI - Stress and the intensive care patient: perceptions of patients and nurses.
AB - This study was a replication of an earlier Cochran & Ganong study that
investigated the perception of nurses and patients regarding the stressors faced
by patients in the intensive care unit environment. As the original study was
American in origin, one of the aims of the present study was to discover if the
results would be replicated in a United Kingdom (UK) intensive care unit. Data
collection was by the use of an environmental stress questionnaire that was an
adaptation of the original data collection tool modified for use in a UK
intensive care unit. The study was undertaken in two intensive care units
producing a sample size of 71 patients and 71 nurses. There appears to be a wide
variation in the perception of nurses and patients regarding the stress faced by
patients in the intensive care unit. Similarities were noted between subject
groups as to the nature of the stressors, although nurses tended to rate items
over which they believed they had control as being more stressful than did the
patients. Patients tended to rate items related to their illness and physical
comfort as being most stressful. The results are in keeping with those from the
Cochran & Ganong study.
PMID- 9543038
TI - The influence of psychological factors on the self-management of insulin
dependent diabetes mellitus.
AB - This study investigated the influence of a number of psychological factors upon
the practice and outcome of diabetic self-management among young adults with
insulin-dependent diabetes mellitus. Health beliefs, perception of control and
knowledge were assessed by scales and questionnaires and glycosylated haemoglobin
results and clinic attendance records obtained for 263 patients. The results
demonstrated that the sample members perceived that they were responsible for the
control of their diabetes, that the benefits of following treatment were greater
than any barriers and that they were knowledgeable about their diabetes. However,
these factors were not predictive of the outcome variables of metabolic control
or clinic attendance according to multiple regression analysis. Implications of
these results for nursing practice and for future research are discussed.
PMID- 9543039
TI - Successive surveys of an expert panel: research in decision-making with health
visitors.
AB - A United Kingdom expert panel was consulted to develop a self-completion
instrument for research on decision making in health visiting practice. The use
of a Delphi-type technique demonstrated how a stand-alone postal survey was an
insufficient measure for health visitors, requiring a supplementary follow-up
method to study types of casework. A review of literature raised questions about
the significance of intuitive thinking and reasoning in health visitor practice,
in relation to measuring professional service and individual performance.
PMID- 9543040
TI - Working with team midwifery: health visitors' views of one team midwifery scheme.
AB - The fragmented nature of maternity services in the UK has led to the introduction
of various forms of team midwifery scheme. The aim of such schemes is usually to
increase continuity through the provision of antenatal, intrapartum and postnatal
care to women by a small team of midwives. Few published studies of this
organization of midwifery care exist, and even fewer consider the impact of such
schemes on related health professionals. This paper presents the results of an
independent survey of health visitors working alongside one team midwifery scheme
in the south-east of England. Eighty per cent of the health visitors thought that
team midwifery was a good idea in theory; however, just 27% thought it was
working well locally and 70% reported that they would like to go back to working
in the way they did before the introduction of team midwifery. The survey
highlighted the health visitors' concerns in relation to team midwifery locally.
Two issues were paramount: firstly a reported deterioration in interdisciplinary
communications, and secondly a perceived loss of continuity for the women. Thus
team midwifery, as implemented in this locality, may not attain the goals aimed
at by the organization of care in this way.
PMID- 9543041
TI - Nursing assessments in New Zealand mental health.
AB - During 1992 a new Mental Health Act was implemented in New Zealand. The Act
created a new role, that of the duly authorised officer (DAO) which has been
mainly carried out by community mental health nurses. During 1994 a multisite
qualitative research study was undertaken to describe the newly structured mental
health nursing role and examine the issues related to it. A key issue which
emerged was the concern that the nursing role had been defined and resourced by
other groups (legal, medical and management) on the basis of its visible tasks
rather than the invisible components of professional nursing knowledge and
expertise. The legal descriptions of the DAO role negated the highly developed
assessment skills of mental health nurses, suggesting that nurses are there for
advice and assistance. Yet expert clinical judgement was pivotal to the effective
functioning of the new role. This paper argues that the initial nursing mental
health crisis assessment which is carried out in the community is a highly
skilled nursing activity which must be recognized and resourced accordingly.
PMID- 9543042
TI - Getting going with clinical supervision: an introductory seminar.
AB - Clinical supervision is an emerging force in nursing practice in the United
Kingdom. However, much of the nursing literature suggests uncertainty with
regards to what clinical supervision is and the resources needed for safe
professional practice. This paper explores a method of introducing clinical
supervision to nurses in such a way as to model the skills and competencies
required for developing productive working relationships. The main recommendation
of this paper is that procedures for introducing clinical supervision mirror
qualities required for developing effective nursing relationships.
PMID- 9543043
TI - Living with high blood pressure.
AB - This study was undertaken to explore the experience of people taking long-term
antihypertensive medication. The study contributes to the understanding health
professionals have of people with high blood pressure and the antihypertensive
treatments they receive. Consideration was given to the full life context of
people taking long-term antihypertensive medication and the health/medical
culture in which people find themselves. A qualitative method of inquiry
generated the descriptive data. Nineteen participants (four men and 15 women)
were interviewed once, of which 16 were interviewed a second time. Data analysis
involved extraction of concepts which in turn were clustered into themes. An
organizing framework was constructed to integrate the six themes and 18 sub
themes. The framework represents the individual's experience as a sequence,
starting broadly in the social context of her/his life, and narrowing down to the
particulars of personal routine and patterns referring to living with
hypertension and it's medication regimens. The final theme refers to the broader
context of the health culture. A vast range of experiences were described by
participants taking long-term antihypertensive medication. This accentuates the
necessity for health professionals to address the uniqueness of the individual,
and consider the context of a person's life when prescribing and monitoring
medications for people with high blood pressure.
PMID- 9543044
TI - Interviewing older people by telephone following initial contact by postal
survey.
AB - Although the use of the telephone for interviewing has become a commonly used and
largely accepted research method, the literature on this subject makes it clear
that certain reservations remain. Some of these relate to problems encountered
when interviewing older adults by telephone and others concern the use of the
telephone in interviews where there has been no prior face-to-face contact. The
conclusions of others who have studied these two sets of problems in combination
are that special difficulties exist. These conclusions are examined with
reference to researchers' experiences of conducting a study on continence care,
in which a postal survey (as opposed to face-to-face contact) preceded telephone
interviews. Interviews were conducted with adults of all ages, including a high
proportion of older people. Researchers encountered few major difficulties and
were satisfied with both response rate and response quality. Research to compare
the effects of a variety of initial contact modes on telephone interviews with
both younger and older adults is recommended.
PMID- 9543045
TI - A model of professional nurse caring: nursing students' experience.
AB - Research into caring from the perspective of nursing students is poorly
documented. This paper presents a study which described the construct of caring
as experienced by students in pre-registration programmes at two universities in
New South Wales, Australia. Qualitative data were collected using a questionnaire
and semi-structured interviews. From the analysis of the data a model of
professional nurse caring from the student's perspective was created. In this
model, compassion, as the core of caring is actualized in the students' nursing
of patients by communicating, providing comfort, being competent, being
committed, having conscience, being confident and being courageous. Communication
is not only an actualization of this caring but constitutes an important medium
for the expression of caring actions.
PMID- 9543046
TI - Empirically generated attributes of experience in nursing.
AB - Researchers examining clinical decision-making often explored the role of the
nurse's experience. In these studies, experience was conceptualized as either the
time spent in nursing or the knowledge which came from practice. This paper
reports on the conceptualization of the nurse's experience emerging from a
grounded theory study describing one decision-making process: 'knowing the
patient'. Data included in-depth interview text, participant observation
fieldnotes, and documents. Data were analysed using the constant comparative
method and open, axial and selective coding techniques. In the analysis, the
nurse's experience was conceptually defined as 'the application of that learned
from previous practice situations'. Three attributes of the nurse's experience
emerged. These included a focus on the patient, confidence in practice, and
knowledge of antecedents and consequences of similar patient situations. Each
aspect enhanced the individualization of nursing interventions. The findings are
related to other investigations in nursing and insights for practice are offered.
PMID- 9543047
TI - Self-efficacy as a predictor of academic performance in science.
AB - Nursing students have traditionally experienced difficulties with the science
subjects in nursing curricula, and irrespective of the institution conducting a
nursing programme, this trend appears to be continuing. A satisfactory means of
predicting academic performance in these subjects will facilitate the development
of educational strategies designed to assist students overcome their
difficulties. In this study, an instrument called the Self-Efficacy for Science
(SEFS) was developed and tested. The SEFS was designed to predict academic
performance in the science areas of a first-year undergraduate nursing course. A
cohort of first-year students enrolled in a bachelor of nursing course were
surveyed by questionnaire. Students' academic scores for two first-year science
subjects were obtained and used as the criterion measure for the study. Principal
component factor analysis revealed the SEFS contained six instead of the
hypothesized four factors. These six factors could explain 70% of students' self
efficacy for science. Cronbach alpha of the SEFS was 0.9. The SEFS could predict
24% of the cohort's academic performance in a physical science subject and 18.5%
for a bioscience subject. Studying science in the final year at high school was
not statistically significantly related to the SEFS. Implications for students
and future research are discussed.
PMID- 9543048
TI - Non-English speaking background high school students' attitudes towards the
nursing profession.
AB - Australia is a multicultural nation with its population coming from over 120
different cultural backgrounds. With the arrival of new immigrants from Southeast
Asia, China, Korea and Lebanon over the last 20 years, issues such as the
recruitment of bilingual and cross-cultural knowledgeable nurses have become a
high priority within the health care system. However, recruiting these skilled
professionals has been difficult. This study aimed to examine (1) non-English
speaking background (NESB) high school students' career preferences in relation
to nursing; and (2) whether nursing is perceived differently by the Korean,
Lebanese, Vietnamese and mainland Chinese high school students. A convenience
sample of 162 NESB high school students with parents from Korea, Lebanon, Vietnam
and China was recruited from Sydney, New South Wales, Australia. Data were
collected by a questionnaire to measure students' knowledge about, attitudes
towards and intention to study nursing and their demographic details. Descriptive
and inferential statistics were used to describe students' demographic
background, their career preference and to compare knowledge, attitudes and
intention scales among the NESB groups. Results indicated that less than 10% of
students included nursing among their preferred career options. Korean students
scored lower than the other NESB groups on attitude and intention towards
nursing. The findings provide clues as to how nursing can be better promoted to
NESB school leavers. Limitations of the study were discussed and recommendations
were suggested for future research.
PMID- 9543049
TI - The role of personal tutor in nurse education: towards an understanding of
practice in a college of nursing and midwifery at a particular point in time.
AB - This paper describes an inquiry to increase understanding of the role of personal
tutor in a college of nursing and midwifery. Concepts of tutor and role are
discussed in relation to their historical influences and an over view is provided
of the research process which included document analysis and reflective audio
taped interviews with student nurses, teachers and education managers. Five
conceptual categories are identified and critically analysed in relation to
personal, institutional and social contexts and the factors which influence them.
The first two categories identified reflect the concepts discussed in the
literature. The third category reflects the uncertainties and confusion which
surround differing perceptions of the role. The fourth category suggests the
misunderstandings which may occur through taking for granted apparently shared
concepts. The fifth category suggests the significance of personal theory in
practice and the extent to which roles are taken or made. Traditional values
concerning theory and practice are thus challenged. The reflective evidence
provided by the participants suggests a theory, generated by them through the
meanings they give to their views and actions, concerning their roles and the
situation in which they find themselves at a particular point in time.
PMID- 9543050
TI - The use of professional nursing practice standards in nursing labour arbitrations
in British Columbia, 1987-1994.
AB - This study examined the use of nursing practice standards in British Columbia in
labour arbitrations related to patient care for the years 1987-1994.
Retrospective secondary content analysis was the method used to analyse the
cases. Although practice standards were referred to in some of the cases, the
nature and clarity of these standards were not always evident. In addition,
corporate and industrial precedents, rather than health care precedents, formed
the basis for much of the arbitration deliberations. The perspectives of nurses,
patients, and families were not significantly represented. Many of the
arbitration hearings did not get beyond procedural matters, and so did not
address substantive patient care situations. Clearly, the visibility and
importance of nursing standards need to be raised among nurses and non-nurses
alike. Implications and recommendations for nursing practice, administration,
education and research, as well as for nursing professional associations and
unions are discussed. Research questions for the future are suggested.
PMID- 9543051
TI - Backs to the future? Reflections on women, ageing and nursing.
AB - There is now a certain amount of evidence to support the contention that ageism
is not only rife amongst the population at large, but also amongst many of those
who care for older people in a professional capacity. Given that many of these
professionals are women caring for other women -- and nursing is a prime example
- this should at the very least give us serious cause for concern. This paper
explores the relationship between 'ageing women' and 'old women' from the point
of view of personal and professional attitudes and practices. It examines the
proposition that until we, as women, fully explore and understand our own
attitudes towards ageing and old age, we cannot work in ways which are truly
beneficial and empowering for the older women in our care. The purpose of the
paper is threefold. First, it reviews what is a relatively limited body of
literature and research on this topic. Second, it reports on the preliminary
findings from an exploratory study examining the attitudes of female nurses to
their own ageing. Finally, it reflects further on the issues raised and considers
some of the ways in which we can begin to address and confront the challenges
which being 'ageing women' and 'aged women' in late 20th century Britain
presents.
PMID- 9543052
TI - Student nurses' lived experience of the sudden death of their patients.
AB - This phenomenological study looks at the lived experience of third-year student
nurses caring for dying patients in surgical, medical and elderly care units.
Informal interviews were tape recorded and interpretive analysis was applied to
narrative accounts of the nursing students' experiences. Themes which emerged
from the students' narrative accounts included sudden death experience,
vulnerability and support. These are evaluated in terms of their meaning for
students and the possible implications for clinical care. In addition, the use of
students' narratives is also suggested as a valuable learning tool both within
clinical and academic frameworks.
PMID- 9543053
TI - The work of clinical nurse specialists (HIV/AIDS) in areas with a low prevalence
of HIV infection.
AB - The role of the clinical nurse specialists (HIV/AIDS) who work in areas with a
low known prevalence of HIV is considered and their contribution to patient care,
either directly or indirectly through the education and support of other health
care workers, is discussed. Attention is given to the implications for nursing
practice and the role of the clinical nurse specialist associated with the
relative infrequency of contact with patients who have HIV disease; and some of
the issues for people living with HIV/AIDS in rural areas are alluded to.
Finally, some of the limitations of the clinical nurse specialist role are
delineated and some consideration is given to the future role of clinical nurse
specialists for HIV and AIDS.
PMID- 9543054
TI - Decision making: the context of nurse prescribing.
AB - From October 1994 qualified district nurses and health visitors from eight
demonstration sites in England have been able to prescribe from a limited list of
formulary items. Data collected from nurses formed only one part of the
evaluation of nurse prescribing. These data highlighted a number of areas where
prescribing nurses were faced with difficult decisions. A number of authors have
considered how both doctors and nurses make decisions, and the factors which may
influence the decision making process. With reference to the literature this
paper focuses on the findings related to decision making in the context of nurse
prescribing.
PMID- 9543055
TI - Clinical nurse specialisation: the route to future practice? Conference organised
by Professional Nurse, held at the Kensington Town Hall, London, England, 24-25
November 1997.
PMID- 9543056
TI - T cell-depleted autologous hematopoietic stem cell transplantation for multiple
sclerosis: report on the first three patients.
AB - Multiple sclerosis (MS) is a disease of the central nervous system characterized
by immune-mediated destruction of myelin. In patients with progressive
deterioration, we have intensified immunosuppression to the point of
myeloablation. Subsequently, a new hematopoietic and immune system is generated
by infusion of CD34-positive hematopoietic stem cells (HSC). Three patients with
clinical MS and a decline of their Kurtzke extended disability status scale
(EDSS) by 1.5 points over the 12 months preceding enrollment and a Kurtzke EDSS
of 8.0 at the time of enrollment were treated with hematopoietic stem cell (HSC)
transplantation using a myeloablative conditioning regimen of cyclophosphamide
(120 mg/kg), methylprednisolone (4 g) and total body irradiation (1200 cGy).
Reconstitution of hematopoiesis was achieved with CD34-enriched stem cells. The
average time of follow-up is 8 months (range 6-10 months). Despite withdrawal of
all immunosuppressive medications, functional improvements have occurred in all
three patients. We conclude that T cell-depleted hematopoietic stem cell
transplantation can be performed safely in patients with severe and debilitating
multiple sclerosis. Stem cell transplantation has resulted in modest neurologic
improvements for the first time since onset of progressive disease although no
significant changes in EDSS or NRS scales are evident at this time.
PMID- 9543057
TI - T cell-depleted bone marrow transplantation and delayed T cell add-back to
control acute GVHD and conserve a graft-versus-leukemia effect.
AB - Thirty-eight patients with hematological malignancies, received T cell-depleted
marrow transplants (BMT) and cyclosporine to prevent acute graft-versus-host
disease (aGVHD), followed by delayed add-back of donor lymphocytes to prevent
leukemia relapse. In 26 patients scheduled for donor T cell add-back of 2 x 10(6)
cells/kg on day 30 and 5 x 10(7) cells/kg on day 45 (schedule 1), the overall
probability of grade > or = II aGVHD developing was 31.5%, with a 15.5%
probability of aGVHD occurring after T cell add-back. In 12 patients receiving
10(7) donor T cells/kg on day 30 (schedule 2), the probability of grade > or = II
aGVHD was 100%. The incidence of grade III-IV aGVHD was higher in schedule 2 than
in schedule 1 (P=0.02). Of 24 evaluable patients, 10 (46%) developed chronic GVHD
which was limited in eight and extensive in two. Current disease-free survival
for 18 patients at standard risk for relapse (chronic myeloid leukemia (CML) in
chronic or accelerated phase, acute myeloid leukemia in remission) vs 20 patients
with more advanced leukemia or multiple myeloma were respectively 72% vs 12% (P <
0.01) with a 29% vs 69% probability of relapse (P=0.08). In 12 CML patients
surviving more than 3 months, PCR analysis of the BCR/ABL transcript showed that
minimal residual disease after T cell add-back was transient except in two
patients who developed hematological relapse. Results indicate that the risk of
acute GVHD is low following substantial T cell doses, transfused 45 days after
transplant, using cyclosporine prophylaxis. Furthermore a graft-versus-leukemia
effect was conserved.
PMID- 9543058
TI - Generation of leukemia-reactive cytotoxic T lymphocytes from HLA-identical donors
of patients with chronic myeloid leukemia using modifications of a limiting
dilution assay.
AB - Donor leukocyte transfusions (DLT) have an anti-leukemic effect in most patients
with a relapse of chronic myeloid leukemia (CML) after allogeneic stem cell
transplantation. However, DLT are often complicated by graft-versus-host disease.
Selection of donor lymphocytes with a relative specificity for leukemic cells is
desirable. The generation of leukemia-reactive cytotoxic T lymphocyte (CTL)
responses between HLA-identical donors and patients in bulk cultures showed major
variations, and false negative results were observed. In a modification of a
limiting dilution analysis (LDA) two-fold serial dilutions of HLA-identical donor
mononuclear cells (MNC) were cultured in the presence of CML cells. The anti
leukemic CTL precursor frequencies in these donors varied between <1 and 9 per
106 MNC. HLA-restricted CD4+ or CD8+ lymphocytes as well as MHC non-restricted
gammadelta T cells were responsible for the anti-leukemic responses. A positive
correlation between cytotoxicity in the various wells after 3, 4 and 5 weeks of
culture could be found. The LDA may be superior to bulk cultures in selecting
stable immune responses and in separating multiple different anti-leukemic T cell
responses in each donor-patient combination.
PMID- 9543059
TI - CD34+ cells mobilized by cyclophosphamide and granulocyte colony-stimulating
factor (G-CSF) are functionally different from CD34+ cells mobilized by G-CSF.
AB - Mobilized peripheral blood progenitor cells (PBPC) are increasingly used as an
alternative to bone marrow for autografting procedures. Currently,
cyclophosphamide (CY) followed by granulocyte colony-stimulating factor (G-CSF)
or G-CSF alone are the most commonly used PBPC mobilization schedules. In an
attempt to investigate whether the use of these two mobilization regimens could
result in the collection of functionally different CD34+ cells, we analyzed
nucleated cells (NC), CD34+ cells, committed progenitor cells and long-term
culture initiating-cells (LTC-IC) in 52 leukaphereses from 26 patients with
lymphoid malignancies, mobilized either by CY+G-CSF (n=16) or G-CSF alone (n=10).
Thirty-four aphereses from the CY+G-CSF group and 18 aphereses from the G-CSF
group were investigated. According to the study design, leukaphereses were
carried out until an average number of 7 x 10(6) CD34+ cells/kg body weight were
collected. The mean (+/-s.e.m.) numbers of CD34+ cells mobilized per apheresis by
CY+G-CSF and G-CSF were not significantly different (2.76+/-0.6 x 10(8) vs 2.53+/
0.4 x 10(8), P < or = 0.7). This resulted from a mean number of NC that was
significantly lower in the CY+G-CSF products than in the G-CSF products (12.4+/
1.7 x 10(9) vs 32+/-5.4 x 10(9), P < or = 0.0001) and a mean incidence of CD34+
cells that was significantly higher in the CY+G-CSF products than in the G-CSF
products (2.9+/-0.6% vs 0.9+/-0.2%, P < or = 0.0018). The mean (+/-s.e.m.) number
of CFU-GM collected per apheresis was significantly higher in the CY+G-CSF group
than in the G-CSF group (37+/-7 x 10(6) vs 14+/-2 x 10(6), P < or = 0.03).
Interestingly, CY+G-CSF-mobilized CD34+ cells had a significantly higher plating
efficiency than G-CSF-mobilized CD34+ cells (25.5+/-2.9% vs 10.8+/-1.9%, P < or =
0.0006). In addition, the mean number of LTC-IC was significantly higher in the
CY+G-CSF products than in the G-CSF products (6.3+/-1 x 10[6] vs 3.3+/-0.3 x
10[6], P < or = 0.05). In conclusion, our data provide evidence that CY+G-CSF and
G-CSF induce the mobilization of CD34+ cells with different clonogenic potential.
As mobilized PBPC containing large numbers of progenitors lead to safer
transplantation, this issue may have implications for planning mobilization
strategies.
PMID- 9543060
TI - Long-term results of autologous marrow transplantation for relapsed or refractory
male or female germ cell tumors.
AB - Twenty-one patients with relapsed or refractory germ cell tumors were treated
with high-dose chemotherapy and marrow transplantation (HDC/BMT) from 1982-1993.
Primary sites of disease were testis (17), ovary (three), and pineal gland (one).
Pathology included dysgerminoma (one), choriocarcinoma with adenocarcinoma (one),
seminoma (four), and nonseminoma or mixed germ cell tumor (15). Nineteen had at
least two prior chemotherapy regimens and eight had cisplatin-refractory disease
defined as progression within 4 weeks of a cycle of cisplatin-based chemotherapy.
HDC regimens were mostly combinations of cyclophosphamide with etoposide and
cisplatin or carboplatin. There were only two treatment-related deaths
(aspergillosis and interstitial pneumonitis). Times to engraftment of
granulocytes (21+/-8.3 days) and platelets (32+/-20.2 days) were reasonable with
only the last nine patients receiving growth factors. At a minimum of 4 years
follow-up, eight patients have died of disease, six of whom were cisplatin
refractory prior to transplant. Eleven patients (52% overall) are alive and
continuously free of disease after 4-10 years including one of three with
refractory ovarian germ cell tumor. HDC/BMT provides significant long-term
disease-free survival as salvage therapy for both male and female relapsed germ
cell tumor patients who are not refractory to cisplatin.
PMID- 9543061
TI - The role of thalidomide in the treatment of refractory chronic graft-versus-host
disease following bone marrow transplantation in children.
AB - Chronic graft-versus-host disease (cGVHD) is a frequent complication of
allogeneic bone marrow transplantation (BMT). Thalidomide was found to have
immunosuppressive properties and it has been used in a limited number of children
with cGVHD. We report our experience with refractory and/or high-risk cGVHD in 14
children. Six children showed complete clinical response to thalidomide in a
median time of 2 months. Four children had partial responses and four failed.
Side-effects were usually mild (somnolence, constipation) and only two patients
developed sensory peripheral neuropathy. An increased incidence of infectious
complications attributable to thalidomide was not observed. Nine out of 10
responding patients are alive 49-111 months post-BMT. Thalidomide can be
effective particularly in children with prevailing mucocutaneous cGVHD. All
patients should be carefully monitored to detect peripheral neuropathy early.
PMID- 9543062
TI - Relative importance of CD4+ and CD8+ T cell repertoires in the development of
acute graft-versus-host disease in a murine model of bone marrow transplantation.
AB - T cell repertoire alterations occurring after allogeneic BMT and related
emergence of aGVHD has not been directly demonstrated. CD4, CD8 and Vbeta usage
of T cells infiltrating spleen, lymph nodes and liver was compared in lethally
irradiated F1(DBA/2 x B10.D2) recipients which develop (GVHD mice) or not (long
survivor:LS mice) aGVHD across minor histocompatibility antigens (mHAgs) and Mtv
6 and Mtv-7 encoded super-antigens (SAgs) barriers according to experimental
conditions. The early expansion in GVHD mice of CD4Vbeta6+ and of CD4Vbeta3+ T
cell subsets specific for Mtv-7 and Mtv-6 SAgs, respectively, is abolished in LS
protected mice. By contrast, CD8+ T cells infiltrate lymph nodes, the liver but
not the spleen of LS as in GVHD mice. Vbeta subset overexpression is frequent in
all T cell phenotypes in GVHD but only among CD8+ T cells in LS mice. Predominant
Vbeta pattern subpopulation is unique to each mouse. Overexpressed Vbeta
subpopulation sequencing clearly indicates that expansion results from a very
limited number of clones. Association of a given Vbeta segment with different
Jbeta for each mouse suggests that the response is directed towards many
different antigens. The data emphasize that Mtv-SAg and mHAgs CD4+ T cells are of
crucial importance during GVHD and that there is no relationship between CD8+ T
cell repertoires and pathological status.
PMID- 9543063
TI - Streptococcus viridans bacteremia following autologous peripheral blood stem cell
transplantation.
AB - A retrospective evaluation of 200 consecutive recipients of autologous peripheral
blood stem cell transplantation was conducted to ascertain the incidence and
outcome of Streptococcus viridans bacteremia as well as to determine the role of
prophylactic ampicillin therapy in the peri-transplant setting. Viridans
streptococci were isolated from the blood of 35 individuals at a median of 6 days
(range 2-8 days) following stem cell infusion. The most common isolates were S.
sanguis and S. mitis. All patients received ciprofloxacin orally during the peri
transplant period. Additionally, 79 patients received oral ampicillin
prophylactically against gram-positive cocci. Although none of the patients
suffered a fatal outcome, three individuals developed respiratory compromise
requiring mechanical ventilation. Female sex proved to be the only independent
risk factor for viridans streptococcal bacteremia (P=0.04). The shorter duration
of neutropenia observed after stem cell transplantation did not impact on the
incidence of S. viridans infections. Moreover, the prophylactic use of ampicillin
failed to decrease the incidence of viridans sepsis and selected out organisms
that were resistant to beta-lactam antibiotics.
PMID- 9543064
TI - Longitudinal fluctuations in cytomegalovirus load in bone marrow transplant
patients: relationship between peak virus load, donor/recipient serostatus, acute
GVHD and CMV disease.
AB - Quantitative competitive PCR was used to monitor the quantity of cytomegalovirus
(HCMV) in 1647 blood samples from 110 BMT recipients. DNAemia was detected in
49/110 (45%) of the patients, of whom 15/49 experienced HCMV disease. Peak virus
load during surveillance was elevated in symptomatic (median 4.5 log10
genomes/ml) vs asymptomatic patients (median 3.6 log10 genomes/ml, P=0.002) and
was also significantly elevated in HCMV seropositive recipients of seronegative
marrow, (R+D-, median 5.0 log10), compared to those in the R-D- and R+D+ groups
(P < 0.01 and <0.005). Odds ratios for disease per 0.25 log10 increase in viral
load, recipient seropositivity and aGVHD were 1.43 (P=0.004), 6.60 (P=0.05) and
3.17 (P=0.08), respectively. In multivariate logistic regression analysis only
elevated viral load remained a significant risk factor for HCMV disease. The
computed disease probability viral load curve showed a rapid increase in disease
risk at viral loads between 3.8 and 5.5 log10 genomes/ml in blood, and odds
ratios for disease were determined for different threshold viral loads. These
data demonstrate the central role of viral load in the pathogenesis of HCMV in
BMT recipients and provide an additional marker for targeting and monitoring
therapy.
PMID- 9543065
TI - Prospective economic evaluation accompanying a trial of GM-CSF/IL-3 in patients
undergoing autologous bone marrow transplantation for Hodgkin's and non-Hodgkin's
lymphoma. IL-3 BMT Study Team.
AB - Our objective was to assess the economic impact of a new cytokine therapy that
was being compared to standard therapy as supportive care in patients receiving
autologous bone marrow transplantation for treatment of lymphoma. We performed an
economic study accompanying a multicenter, randomized, controlled clinical trial
in academic medical centers. One hundred and fifteen patients consented to
participate in a parallel economic study of a randomized controlled trial of
sequential IL-3 followed by GM-CSF vs GM-CSF alone after autologous bone marrow
transplantation. We measured costs and quality-adjusted survival over a 13-month
follow-up period. For the 13-month study period, the total cost estimates were
$79892 (95% CI $69343 to $90544) for patients receiving GM-CSF alone and $89651
(95% CI $79769 to $102114) for patients receiving IL-3/GM-CSF. The difference was
not statistically significant. During the 13-month study period, the total number
of quality-adjusted life-months in the GM-CSF arm was 6.67 (95% CI 5.75 to 7.56)
months, while the total number of quality-adjusted life-months in the IL-3 arm
was 6.26 (95% CI 5.34 to 7.15) months. The difference in quality-adjusted life
months between the two treatment arms was not statistically significant. We
conclude that economic analysis of a phase III clinical trial of IL-3/GM-CSF
compared with GM-CSF alone showed no significant effect of IL-3 on the costs of
care for patients undergoing bone marrow transplantation for a period of up to 13
months after the procedure. This study demonstrates the feasibility of
prospective economic evaluation within phase III trials of new cancer therapies.
Data from this type of economic protocol could be used to help physicians,
patients and managed care organizations understand the effect of new treatments
from both a clinical and an economic perspective.
PMID- 9543066
TI - Bone marrow infarction due to acute graft-versus-host disease in an acute
lymphoblastic leukemia patient after unrelated bone marrow transplantation.
AB - We report a case of bone marrow infarction in a 20-year-old woman with acute
lymphocytic leukemia (ALL) who underwent unrelated bone marrow transplantation
(BMT). Hematopoietic engraftment occurred on day 9 and, thereafter, the patient
developed acute dermal and hepatic graft-versus-host disease (GVHD). She also
experienced severe arthralgia in her knee joints on day 21. Immunosuppressive
therapy with prednisolone (PSL) for acute GVHD was given, and the arthralgia
improved rapidly, correlating with the improvement in dermal and hepatic GVHD.
Based on the laboratory findings and analysis of magnetic resonance images, she
was diagnosed as having bone marrow infarction. The cause of the bone marrow
infarction was thought to be acute GVHD-related microangiopathy.
PMID- 9543067
TI - Fatal CMV pneumonia associated with steroid therapy after autologous
transplantation in patients previously treated with fludarabine.
AB - Fludarabine has been associated with an increased risk of opportunistic
infections, possibly related to the induction of profound CD4+ lymphopenia. We
observed two cases of cytomegalovirus pneumonia (CMV-IP) in a total of nine
patients over a 5-year period who had previously received fludarabine and who
proceeded to autografting. Both patients also received steroids post-transplant.
CMV-IP was observed in one of 104 other autograft recipients over this time who
had not received prior fludarabine. This observation suggests that the
combination of fludarabine pre-transplant and steroids post-transplant may
increase the risk of invasive CMV disease in autograft recipients.
PMID- 9543068
TI - B cell lymphoma-associated hemophagocytic syndrome after PBSCT.
AB - Hemophagocytic syndrome (HPS) associated with T cell lymphoma is well known, but
an association with B cell lymphoma is rare. We report a patient who developed
subcutaneous non-Hodgkin's lymphoma (NHL) of B cell origin. Autologous peripheral
blood stem cell transplantation (PBSCT) was undertaken in her second complete
remission (CR), but HPS appeared 5 months after transplantation. The patient
deteriorated rapidly and died of metabolic acidosis. Necropsy revealed that she
had relapsed B cell NHL involving liver, spleen and bone marrow. B cell NHL after
PBSCT, associated with HPS as an initial sign, is rare. We report this case and
review the literature.
PMID- 9543069
TI - Treatment of MPS VII (Sly disease) by allogeneic BMT in a female with homozygous
A619V mutation.
AB - A 12-year-old girl with Sly disease (mucopolysaccharidosis VII; beta
glucuronidase deficiency), who is homozygous for the A619V mutation, had a
successful allogeneic BMT, donored by an HLA-identical unrelated female to
replace the deficient enzyme. Within 5 months after BMT, the enzyme activity of
the recipient's lymphocytes increased to normal range. No signs of acute or
chronic GVHD were observed. For the successive 31 months post-BMT, beta
glucuronidase activity in her lymphocytes was maintained at almost normal levels
and excretion of glycosaminoglycans in the urine was greatly diminished.
Ultrastructural findings demonstrated no abnormal vacuoles and inclusion bodies
in the cytoplasm of her rectal mucosal cells. Coincident with the restoration of
the enzyme activity, clinical improvement was dramatic. Especially notable were
improvements in motor function. The patient was able to walk alone for a long
time without aid, and she even became able to ride a bicycle and take a bath. In
addition, recurrent infections of the upper respiratory tract and the middle ears
decreased in frequency and severity, and dyspnea on exertion, severe snoring and
vertigo have substantially improved. Thus, allogeneic BMT in this patient
produced a better quality of life and provided a more promising outlook.
PMID- 9543070
TI - Toxoplasma retinitis/encephalitis 9 months after allogeneic bone marrow
transplantation.
AB - In a 34-year-old patient toxoplasma retinitis/encephalitis developed 9 months
after bone marrow transplantation. The BMT was complicated with a serious GVHD.
Although she initially responded well to antibiotic therapy she died 2 years
after BMT due to progressive infection.
PMID- 9543071
TI - Successful treatment of severe Shulman's syndrome by allogeneic bone marrow
transplantation.
AB - We describe a patient with severe Shulman's syndrome (ShS) (eosinophilic
fasciitis). This auto-immune disease involved not only the skin and muscles, but
the bone marrow as well - thereby fulfilling the criteria of severe aplastic
anemia. As the disease was steroid-resistant, the patient underwent allogeneic
bone marrow transplantation (BMT). Remission of ShS was achieved. Eight months
later chronic GVHD developed and relapse of ShS (probably induced by GVHD)
occurred. He was successfully treated with corticosteroids and the disappearance
of GVHD was followed by cessation of the symptoms of ShS. At present (34 months
following BMT) he is doing well and displays no signs of ShS or GVHD. This case
suggests that an aggressive immunoablative preparative regimen with subsequent
allogeneic BMT can result in long-lasting clinical remission of a severe auto
immune disease.
PMID- 9543072
TI - Beta2-adrenoceptor responsiveness and asthma activity.
PMID- 9543073
TI - Can asthma be prevented? Evidence from epidemiological studies of children in
Australia and New Zealand in the last decade.
PMID- 9543074
TI - Symptom control in patients with hay fever in UK general practice: how well are
we doing and is there a need for allergen immunotherapy?
AB - BACKGROUND: Seasonal allergic rhinitis is often regarded as a trivial condition
which patients should treat themselves. However, a significant proportion of
sufferers are not fully controlled on standard hay fever medication, either
because they do not use it properly or because their symptoms are resistant to
standard therapy. The latter group may be suitable for allergen immunotherapy,
which was once widely available in UK general practice but is now only available
through specialist centres. AIMS: To describe the symptom control of patients
with hay fever, to assess concordance with prescribed medication, and to estimate
the number of patients who may benefit from referral for allergen immunotherapy.
SETTING: General practices in Hampshire and Dorset, UK. METHOD: Survey of adult
hay fever sufferers prescribed a non-sedating antihistamine and nasal steroid
spray by their general practitioner. A postal questionnaire was sent to all
eligible patients aged 16-64 registered with 16 general practices. Self
assessment of symptom control and reported compliance with medication were used
to identify those patients who were suboptimally controlled and might therefore
benefit from immunotherapy. RESULTS: Eight hundred and forty-six out of 62500
registered patients aged 16-64 (1.4%) were receiving both drugs, and responses
were received from 627 (74.1%); 526 of these met the full entry criteria. One
hundred and forty-two patients (27.0%) were using both types of drug regularly.
Of the 142 patients using optimum pharmacotherapy, 54 (38.0%) reported good
control of their hay fever symptoms. The remaining 62.0% experienced troublesome
residual symptoms and described symptom control as partial or poor. Among those
using suboptimal pharmacotherapy, 181/376 (48.1%) reported good control.
CONCLUSION: Many patients are using treatment inappropriately. Current guidelines
need to be applied better but there is also a significant burden of residual
symptoms, even among those receiving current optimal therapy. This indicates a
need for patients with severe summer hay fever to receive specialist assessment.
PMID- 9543075
TI - Seasonal variations in cyclic AMP production by peripheral blood mononuclear
cells in allergic asthmatics.
AB - BACKGROUND: Dysfunction of the beta-adrenoceptor (betaAR)/adenylyl cyclase (AC)
system can impair the response of different cell types, including lymphocytes. In
asthma, impairment of this system as well as changes in cytokine production by
lymphocytes have been described. Because the severity of asthma can change over
the year, a circannual pattern of the betaAR/AC system activity may also exist.
OBJECTIVES: We set out to examine the activity of this betaAR/AC signal
transduction system in peripheral blood mononuclear cells (PBMCs) of allergic
asthmatics to asses whether differences existed between seasons. We investigated
whether changes were associated with asthma severity and circannual changes in
serum cortisol levels. METHODS: During 19 months, 41 allergic asthmatics (mean
age 28 years) with nocturnal airway obstruction were enrolled in the study. AC
activity was measured by cyclic AMP production. Resting, stimulated and
potentiated AC activities and their relationships with clinical parameters,
seasonal influences and serum cortisol levels were assessed. RESULTS: The AC
activity in resting, stimulated and potentiated cells varied during the year. AC
activity was relatively low in the periods June-August and September-November,
and higher in December-February and March-May. Receptor-mediated and potentiated
responses expressed as percentage of the resting response were equivalent
throughout the year. Serum cortisol levels were positively related to AC
activity. No relationships were found between clinical parameters and AC activity
or serum cortisol levels. CONCLUSIONS: These results indicate that AC activity in
PBMCs of allergic asthmatics shows a seasonal variation. However, seasonal
differences in AC activity seems to be unrelated with clinical parameters. Other
factors such as serum cortisol levels may have a modulating influence on AC
activity. Future studies of AC systems in blood cells of asthmatic patients need
to take into account these seasonal influences.
PMID- 9543076
TI - Expression of cyclo-oxygenase 1 and 2 proteins in upper respiratory mucosa.
AB - BACKGROUND: Cyclo-oxygenases 1 (Cox-1) and 2 (Cox-2) catalyse the conversion of
arachidonic acid to prostaglandin endoperoxides, leading to the formation of
prostaglandin and thromboxane mediators of inflammation. The involvement of these
enzymes in inflammatory disorders such as sinusitis and nasal polyps is unknown
although this may be relevant to their pathophysiology. METHODS: We studied Cox-1
and Cox-2 immunoreactivities in nasal polyp, maxillary sinus, and turbinate
biopsies obtained from eight patients with chronic allergic rhinitis and
sinusitis and/or nasal polyps, 15 patients with chronic non-allergic rhinitis and
sinusitis and/or nasal polyps and five control subjects (patients requiring nose
surgery not related to sinusitis or nasal polyps). RESULTS: Both Cox- and Cox-2
were mainly expressed in the epithelium (basal, ciliated) and were found in 16/28
and 25/28 subjects for Cox-1 and Cox-2 respectively. We did not find any
differences between the patient populations. There were no correlations between
any of the clinical parameters studied nor the pathological patterns and the
presence and characteristics of the Cox immunoreactivities. CONCLUSION: Both
cyclo-oxygenase enzymes are expressed in normal human upper respiratory
epithelium and are not upregulated in chronic sinusitis nor in nasal polyposis,
possibly suggesting that Cox products do not have an important role as mediators
of the chronic upper airway inflammation.
PMID- 9543077
TI - Changes in sputum composition during sputum induction in healthy and asthmatic
subjects.
AB - BACKGROUND: Induced sputum is increasingly used to characterize the cellular and
biochemical composition of the airways. OBJECTIVE: We studied whether the
composition of induced sputum is different between samples obtained sequentially
during one sputum induction. METHODS: Subjects with mild asthma (n=7) or healthy
subjects (n=6) produced sputum during and after three consecutive 10 min periods
of hypertonic saline inhalation. Samples were analysed separately for the three
periods. To determine the reproducibility of the cellular composition, sputum
induction was repeated on another two days. RESULTS: The mean percentage of
neutrophils decreased significantly (P<0.01) during sputum induction in asthmatic
(36.9, 29.8, 16.3%) and healthy subjects (43.6, 17.2, 18.0%). Correspondingly,
percentages of macrophages increased and percentages of eosinophils were 4.9,
3.5, and 3.7% in the asthmatic and 0.6, 0.7, and 0.5% in the healthy subjects,
without significant change over the three periods; mean eosinophil numbers were
significantly higher in the subjects with asthma (P< 0.05). Reproducibility of
percentage cell counts did not markedly depend on sampling periods in terms of
coefficients of variation. The concentration of eosinophil cationic protein
decreased in both groups during sputum induction (P<0.01), geometric mean values
being 579, 143, 57.4 microg L(-1) in the asthmatic and 130, 47.3, 28.4 microg L(
1) in the healthy subjects. Similar changes were seen for lactate dehydrogenase.
CONCLUSION: The separate analysis of induced sputum from three consecutive
sampling periods of a single induction procedure demonstrated significant changes
in their cellular and biochemical composition, both in healthy and mild asthmatic
subjects.
PMID- 9543078
TI - Intranasal fluticasone propionate reduces ICAM-1 on nasal epithelial cells both
during early and late phase after allergen challenge.
AB - BACKGROUND: Allergen specific nasal challenge (ASNC) is an optimal method to
study the pathophysiological mechanisms sustaining the allergic inflammation and
in particular the adhesion molecule system, which is involved in cellular
infiltration of nasal mucosa. Topical steroids have been accepted as a highly
effective anti-inflammatory therapy for allergic rhinitis. OBJECTIVE: The aim of
this double-blind placebo- controlled study was the evaluation of clinical and
cytological parameters, including ICAM-1 expression on nasal epithelial cells,
after a 4 week treatment with nasal fluticasone propionate (200 microg/daily) or
placebo, using the model of ASNC. METHODS: Twenty allergic rhinitics underwent
nasal challenge before and after treatment. The following parameters were
evaluated: (i) nasal symptoms (rhinorrhoea, itching, sneezing, obstruction), (ii)
inflammatory cells (eosinophils and neutrophils), (iii) ICAM-1 expression on
nasal epithelial cells at baseline, 30 min (early phase) and 6 h (late phase)
after ASNC. RESULTS: Fluticasone propionate was capable of reducing: (i) clinical
symptoms during both early (P<0.001) and late phase (P<0.04), (ii) eosinophil
(P<0.002) and neutrophil (P<0.001) infiltrate during late phase, and (iii) ICAM-1
expression on nasal epithelial cells during both early (P < 0.01) and late phase
(P < 0.03). CONCLUSIONS: The present results demonstrate that fluticasone
propionate exerts a significant action on early and late phase clinical events
following specific nasal challenge, reducing also the cellular influx during the
late phase. This event is likely due to the modulation of ICAM-1 expression on
epithelial cells.
PMID- 9543079
TI - Determinants of eosinophil cationic protein in nasal lavages in children.
AB - BACKGROUND: Nasal lavages are increasingly used to assess airways inflammation in
children. However, there are no studies assessing how measurement error as well
as biological influences contribute to the concentration of nasal inflammatory
parameters in a population based survey. OBJECTIVE: To investigate determinants
of concentration of eosinophil cationic protein (ECP) in nasal lavages we studied
147 schoolchildren (mean age 8.1 years, SD 0.6 years) by repeated nasal
lavages/year over a 2 year period. METHODS: Standardized questionnaires were
completed by the parents each year. A skin-prick test with seven aeroallergens
(birch, cat, dog, hazel, weeds, Dermatophagoides pteronyssinus and D. farinae)
was performed. One hundred and one children could perform valid lavages at least
five times a year. As a measure of reproducibility the intraclass coefficient of
reliability was calculated. RESULTS: The intraclass coefficient of reliability
was 0.27 over all observations suggesting that about a quarter of total variance
is due to between-subject variance. Taking means over each year increased
reliability to 0.60. Linear regression analyses with ECP being the dependent
variable demonstrated significant higher values for boys (beta=12.26; P < 0.01),
children sensitized to seasonal (beta=34.27; P=0.02) but not to perennial
allergens (beta=-4.44; P=0.57), and for children with a serous (beta=10.01;
P=0.01) or purulent rhinitis (beta=22.45; P < 0.001). CONCLUSION: Assessment of
inflammatory mediators in nasal lavages is a useful tool for epidemiological
paediatric studies. However, due to the relatively high intraindividual
variability of ECP concentrations multiple lavages are necessary to characterize
the individual.
PMID- 9543080
TI - Changes in CD23 expression of blood and skin in atopic eczema after Chinese
herbal therapy.
AB - BACKGROUND: Aberrant expression of CD23 (low affinity IgE receptor) on cells of
the monocyte/macrophage series in peripheral blood and lesional skin of patients
with atopic eczema has been demonstrated. It is not known whether this
abnormality results from a fundamental systemic problem of the monocytes of these
patients or reflects local changes to cell populations within the skin tissues.
OBJECTIVES: This study was designed to determine whether this aberrant expression
was caused by local cutaneous influences on mature cells or fundamental changes
in monocyte differentiation. The possible relationship between these aberrations
and clinical severity was also investigated by repeating these immunopathological
studies after a course of efficacious treatment with Chinese herbal therapy
(CHT). METHODS: Peripheral blood mononuclear cells were obtained from patients
with atopic eczema before, and after 8 weeks of treatment. Efficacy of CHT was
quantified on clinical grounds. Monocytes were isolated by adherence to plastic
and cultured for up to 7 days. Samples were harvested at 2, 5 and 7 days of
culture and cytospins prepared. Immunocytochemical staining to identify
phenotypic subsets was performed on the monocytes at time 0 and on maturing cells
from culture. This immunocytology was quantified using computerized image
analysis equipment to determine the emergence of macrophage subsets and their
level of CD23 expression. Biopsies were taken from lesional skin before and after
treatment and immunohistology was performed on cryostat sections to determine the
number of antigen presenting cells expressing CD23 as well as the level of
expression of these molecules. RESULTS: The results showed that increased numbers
of monocytes from patients with atopic eczema express CD23 at day 0 and that
cultured monocytes from these patients differentiate faster during the 7 day
culture period as compared to normal controls. Efficacious treatment did not
affect the number of peripheral blood monocytes expressing CD23. However,
treatment did lead to a significant decrease in the number of CD23+ mature
macrophages in the skin as well as a reduction in the level of expression of this
moiety. These results demonstrate that changes in clinical severity are more
closely related to the expression of CD23 on mature antigen presenting cells in
lesional skin rather than to differentiating peripheral blood monocyte CD23
expression. CONCLUSIONS: These results suggests that local factors within
lesional skin govern the accumulation and the expression of CD23 on mature
macrophages and that these factors may be more relevant to the pathogenesis of
the disease than aberrations in CD23 expression that may occur systemically.
PMID- 9543081
TI - Post-translational modifications influence IgE reactivity to the major allergen
Phl p 1 of timothy grass pollen.
AB - BACKGROUND: Grass group I consists of very potent allergenic components which are
found in the pollen of all temperate grasses. Several post-translational
modifications are predicted from the cDNA data. OBJECTIVE: The aim of this study
was to identify sequential IgE-binding sites on the allergen Phl p 1 and to
determine their influence on IgE reactivity. METHODS: Based on cDNA data and
microsequencing results we synthesized overlapping decapeptides covering the
complete Phl p 1 molecule and tested them for immunological reactivity by means
of the PEPSCAN technique. In a dot test we determined the frequency of IgE
reactivities to post-translationally modified structures (hydroxylated proline
residues, carbohydrate structure, and disulphide formations). RESULTS: Screening
by overlapping peptides demonstrated an IgE binding site on the 10 N-terminal
amino acids. Comprehensive studies showed that the two hydroxyproline residues of
the native Phl p 1 allergen (at positions 5 and 8) and the N-glycan (at position
9) can result in an increased IgE reactivity; 3.3% of the sera exclusively bound
to the hydroxyproline bearing peptide, while only 0.4% bound to the proline
containing peptide. With regard to glycosylation, we estimated that 20% of sera
recognized protein and carbohydrate epitopes, while one serum exclusively bound
to the glycan. The formation of disulphide bonds has no detectable effect on the
IgE reactivity to Phl p 1. CONCLUSION: Our results indicate that the post
translational modifications, the carbohydrate structure and the hydroxylation of
proline residues, can enhance the IgE reactivity of Phl p 1.
PMID- 9543082
TI - Limited genetic control of specific IgE responses to rye grass pollen allergens
in Australian twins.
AB - BACKGROUND: Both genetic and environmental factors are thought to contribute to
specific IgE responses, however, the relative contribution of each in the
responses to individual ryegrass pollen allergens is largely unknown even though
some responses to allergens have been linked to certain HLA complexes. OBJECTIVE:
Using a large group of monozygotic and dizygotic twins, this study was designed
to investigate the IgE binding profiles of individual ryegrass pollen (Lolium
perenne) components to assess the relative contribution of genetic and
environmental factors in determining IgE responses to specific allergens.
METHODS: Ryegrass pollen proteins were separated by electrophoresis and
immunoblotted with sera from 191 pairs of twins where at least one sibling had a
SPT > 2 mm to perennial ryegrass. Concordance levels for individual ryegrass
pollen components were compared between monozygotic and dizygotic twins in a
subset group where both twins had SPT > 3 mm to perennial ryegrass. RESULTS:
Immunoblotting revealed 23 individual IgE-binding components from ryegrass
pollen. Although there was a significantly greater proportion of monozygotic
twins with SPT wheals greater than 3 mm when compared with the dizygotic twins,
the mean case-wise concordance for the immunoblot components was similar for both
groups of twins. The mean case-wise concordance when at least four pairs of sera
were involved was 44% for the MZ twins (n=11 components) and 45% for the DZ twins
(n=12 components). We found no significant differences in concordance levels for
any of the 23 individual components including allergens previously associated
with HLA. CONCLUSION: Evidence for genetic control of allergen-specific IgE
responses in a large population sample of twins to individual ryegrass allergens
is limited, indicating that the IgE responses to specific ryegrass pollen
allergens are determined largely by environmental factors.
PMID- 9543083
TI - Identification of volatile organic compounds emitted in the field by oilseed rape
(Brassica napus ssp. oleifera) over the growing season.
AB - BACKGROUND: Oilseed rape has been associated by rural dwellers with seasonal
symptoms, such as sneezing, coughing, headache and eye irritation, during its
flowering season, for a number of years. This study was performed to identify the
volatile chemicals emitted from oilseed rape in the field. OBJECTIVE: The
objective of this study was to establish which volatile chemicals may be
causative factors of oilseed rape allergy/toxicity. METHODS: The volatile organic
compounds were sampled over the flowering period using a modified entrainment
technique for headspace analysis under field conditions. These volatiles were
then identified using thermal desorption-gas chromatography-mass spectrometry.
RESULTS: The major constituents identified were the monoterpenes limonene,
sabinene, beta-myrcene, and cis-3-hexen-l-ol acetate, a 'green leaf' volatile.
The minor constituents included monoterpenes, sesquiterpenes, short chain
aldehydes and ketones, other 'green leaf' volatiles and organic sulphides
including the respiratory irritant, dimethyl disulphide. CONCLUSIONS: This report
highlights the diversity of volatile chemicals emitted by oilseed rape and
confirms field emissions to be broadly similar to those found previously in
laboratory studies. A review is carried out on the scientific literature already
published on oilseed rape flower headspace analysis.
PMID- 9543085
TI - IgG subclass responses to pigeon intestinal mucin are related to development of
pigeon fanciers' lung.
AB - BACKGROUND: Pigeon fanciers' lung (PFL) is a form of extrinsic allergic
alveolitis. Affected individuals produce antibodies to various pigeon antigens,
and the resulting immune complexes are thought to initiate the disease. However,
high antibody titres also occur in some asymptomatic individuals. Previously
attention has focused on protein antigens, but we have recently identified pigeon
intestinal mucin as a novel antigen in PFL. OBJECTIVE: To determine the
relationship between IgG subclass antibodies to pigeon intestinal mucin and the
development of pigeon fanciers' lung. METHODS: Sera were collected from 250
pigeon fanciers, who also completed a clinical questionnaire. Sera were screened
for precipitating antibodies to pigeon serum and droppings. Individuals with
symptoms and precipitating antibodies were considered to have classical PFL.
Serum IgG and IgG subclass antibodies to pigeon intestinal mucin and pigeon serum
proteins were investigated by quantitative enzyme-linked immunosorbent assay
(ELISA). RESULTS: Very high titres of IgG antibodies against pigeon mucin were
found in all precipitin-positive individuals. A strong positive correlation was
seen between titres of antibodies to mucin and to serum proteins, but this was
not due to crossreactivity. No significant differences in IgG titres to either
mucin or pigeon serum proteins were found between individuals with PFL and
asymptomatic precipitin positive fanciers. IgG1 and IgG2 were the major
subclasses of anti-mucin, with lower titres of IgG3. Patients with PFL had
significantly higher titres of IgG1 to mucin than asymptomatic, precipitin
positive individuals. In contrast, no significant differences were seen between
PFL and asymptomatic precipitin-positive sera with respect to the subclass titres
against pigeon serum proteins. CONCLUSION: The high titres of anti-mucin IgG in
sera of all individuals with PFL, together with the finding that high IgG1 titres
to mucin are associated with the development of disease confirm pigeon intestinal
mucin as an important antigen in PFL.
PMID- 9543084
TI - Analysis of T-cell reactive regions and HLA-DR4 binding motifs on the latex
allergen Hev b 1 (rubber elongation factor).
AB - BACKGROUND: The rubber elongation factor in Hevea rubber (Hev b 1) is one of the
important latex-allergenic proteins inducing the production of specific IgE
antibodies in latex-exposed subjects. In addition, Hev b 1 induces lymphocyte
proliferation responses. A study about detailed T-cell epitope analysis of major
latex allergens has not been published yet. OBJECTIVE: The aim of this study was
to define the T-cell reactive regions on the latex allergen Hev b 1. METHODS:
Nine overlapping peptides with 19 or 17 amino acid lengths representing the
complete sequence of Hev b 1 were used for T-cell epitope mapping. Peripheral
blood mononuclear cells (PBMCs) of latex-sensitized patients and healthy subjects
were isolated and stimulated with the synthetic peptides to determine the
specific proliferation response. The examined patients were sensitized to latex
by occupational exposure (n=14) and suffered from rhinitis, conjunctivitis,
contact urticaria and/or asthma. Two control groups of non-sensitized subjects
were studied, one occupationally exposed to latex (n=4), the other one not
exposed to latex (n=4). RESULTS: Positive proliferation response induced by one
or more peptides was detected in 10 of the latex-sensitized patients and in two
of the latex-exposed non-sensitized subjects. Each patient exhibited an
individual epitope reactivity pattern. The whole protein was found to be
immunogenic, but the intensity of lymphocyte responses induced by the peptides
was different. The majority of the patients' PBMCs (more than 66%) responded to
the peptides 31-49 and 91-109. Using the peptide selection of Stille's
algorithms, three epitopes were predicted covering region 38-74 and two others
covering region 82-104; the two peptides 31-49 and 91-109 are part of these
regions. A strong HLA-DR4Dw4 (DRB1*0401)-binding motif according to published
DR4w4 binding motifs was predicted in the region of 102-110 including peptide 91
109 to which the majority of tested HLA-DR4-positive patients responded.
CONCLUSIONS: Our data indicate that the whole 14 kDa protein Hev b 1 is
immunogenic having regions that demonstrate individual and varying PBMC
stimulation. Experimental data of T-cell reactive regions based on PBMC
stimulation complement the information on T-cell epitope prediction. In addition,
the Hev b 1 molecule contains a HLA-DR4Dw4 (DRB1*0401)-binding motif.
PMID- 9543086
TI - Diethanolamine-induced occupational asthma, a case report.
AB - BACKGROUND: Amino alcohols are low molecular weight chemicals used widely in
industrial processes, often as minor constituents. They have been found to cause
allergic contact dermatitis. Marked exposure through airways is uncommon in other
than occupational settings where chemicals containing amino alcohols may be
heated or vaporized, liberating free amino alcohols into the ambient air. A few
cases of asthma and allergic rhinitis have been reported, but the amounts
inducing the airway reactions have not been defined. OBJECTIVE: To further
characterize ethanolamine-induced asthma and define the concentration inducing
the asthmatic reaction, a case of diethanolamine-induced occupational asthma in a
patient handling diethanolamine containing cutting fluid is reported. METHODS:
Suspicion of work related asthma was raised by symptoms and peak expiratory flow
monitorings at work and at home. Specific bronchial provocation tests with the
cutting fluid containing DEA and with DEA aerosol at two different concentration
below the American Conference of Governmental Industrial Hygienists threshold
limit value of DEA (2.0 mg/m3) were done. RESULTS: DEA caused asthmatic airway
obstruction at two different concentrations below the ACGIH TLV. A slight dose
response relationship was observed. Specific IgE-antibodies against DEA could not
be found. CONCLUSIONS: DEA is able to induce occupational asthma by a
sensitization mechanism, the exact pathophysiological mechanism of which is not
known.
PMID- 9543087
TI - Occupational asthma in fruit salad processing.
AB - BACKGROUND: Three subjects employed in the preparation of fruit for fruit salads
reported work-related respiratory symptoms. Their work entailed removing the peel
from citrus fruits, primarily oranges, following soaking of the fruits in a bath
of enzymes including fungal derived pectinase and glucanase. Objectives To
investigate the respiratory symptoms reported by these workers and determine
their causes. METHODS: The three workers were investigated by a respiratory
physician, including spirometry and serial peak flow measurements. Blood was
taken for the measurement of IgE and IgG antibody responses against the enzyme
solution. RESULTS: Predominant symptoms in these workers were shortness of
breath, chest tightness and wheezing which were all alleviated at weekends and
holidays only to occur when returning to work. Serial peak flow measurements
showed a clear work-related pattern. All three had strong IgE responses to the
enzyme solution used at the workplace and showed distinct patterns of binding in
immunoblots. All three improved immensely following withdrawal from the workplace
environment. CONCLUSION: Enzymes appear to be widely used in the preparation of
fruit and although they are used in liquid form, exposure can occur to induce
immunological sensitization and asthma.
PMID- 9543088
TI - Oral sensitization to food proteins: a Brown Norway rat model.
AB - BACKGROUND: Although several in vivo antigenicity assays using parenteral
immunization are operational, no adequate enteral sensitization models are
available to study food allergy and allergenicity of food proteins. OBJECTIVE:
This paper describes the development of an enteral model for food allergy
research in the Brown Norway (BN) rat. METHODS: The animals were exposed to
ovalbumin either ad libitum via the drinking water (0.002 to 20 mg/mL)
continuously for 6 weeks or by gavage (1 mg/mL per rat). Gavage dosing was
performed either daily, twice a week, once a week or once every 2 weeks during a
period of 6 weeks. No adjuvants were used during the sensitization studies.
RESULTS: After intra-gastric administration of ovalbumin once or twice a week or
once every two weeks, no or only a very low frequency of ovalbumin-specific
antibody responses were detected. Daily intra-gastric dosing with ovalbumin
resulted in antigen-specific IgG as well as IgE responses in almost all animals
tested. Upon ad libitum exposure, ovalbumin-specific IgG but no ovalbumin
specific IgE was detected. The cellular response was examined by determination of
delayed-type hypersensitivity (DTH) reactions in the animals dosed by daily
gavage and in the ad libitum exposed rats. Both sensitization protocols
sensitized for DTH. The response was most pronounced in ad libitum exposed rats
at day 28 of exposure. CONCLUSIONS: These studies show that the BN rat may
provide a suitable animal model for inducing specific IgG and IgE responses as
well as specific T-cell mediated hypersensitivity (DTH) to ovalbumin upon
exposure via the enteral route without the use of adjuvants.
PMID- 9543089
TI - Leflunomide, a novel immunomodulating agent, prevents the development of allergic
sensitization in an animal model of allergic asthma.
AB - BACKGROUND: Leflunomide is a new anti-inflammatory and immunomodulating agent
which is showing promise in several immune disorders, especially rheumatoid
arthritis. Its activity profile suggests it may be of use in modulating allergic
sensitization. OBJECTIVE: To investigate the effectiveness of leflunomide in
preventing the development of allergic sensitization. METHODS: Fifty-three brown
Norway rats were sensitized by intraperitoneal injection of ovalbumin and
adjuvant (ricin) on day 0. To determine the ability of leflunomide to inhibit
primary allergic sensitization six rats were treated with A77 1726, the active
metabolite of leflunomide, from day 0 through day 5, six were treated from day 5
through day 10, and nine rats acted as controls. On day 14, ovalbumin-specific
serum antibody levels and the magnitude of the early-phase airway response (EAR)
after inhalation allergen challenge were assessed. To determine the ability of
acute topical treatment with leflunomide to inhibit mast cell degranulation,
three groups of five animals received either vehicle, 100 microg A77 1726, or
1000 g A77 1726 60 min prior to aerosol allergen challenge. To determine the
effects of leflunomide treatment in vivo on mast cell function in vitro, mast
cells were obtained by bronchoalveolar lavage from 17 rats (nine treated with
leflunomide and eight controls). Allergen-specific and non-specific degranulation
(48/80 induced) were studied. RESULTS: In the leflunomide treated rats both
ovalbumin-specific IgE and IgG levels were significantly reduced, and the
increases in lung resistance and lung elastance were essentially abolished,
compared to those of the control group. Non significant differences were found in
any of the parameters between the two leflunomide treated groups. Topical pre
treatment with leflunomide did not prevent the allergen-induced EAR. Treatment
with leflunomide in vivo prevented allergen-induced mast cell degranulation in
vitro because the mast cells lacked IgE on their surface. Non allergen-specific
degranulation was normal and allergen-induced degranulation could be restored by
passive sensitization. CONCLUSIONS: These data suggests that leflunomide can
prevent primary allergic sensitization and prevent allergen-induced EAR by
inhibiting production of allergen-specific IgE antibodies. Further studies in
atopic conditions are warranted.
PMID- 9543090
TI - A specific 15-lipoxygenase inhibitor limits the progression and monocyte
macrophage enrichment of hypercholesterolemia-induced atherosclerosis in the
rabbit.
AB - Oxidant signalling and lipoprotein oxidation may play important roles in
atherosclerotic lesion development. Given coincident localization of 15
lipoxygenase (15-LO), stereospecific products of 15-LO and epitopes of modified
LDL in atherosclerotic lesions, we hypothesized that inhibition of 15-LO by
PD146176, an inhibitor of 15-LO with an IC50 in cells or isolated enzyme of 0.5
0.8 microM, may limit atherosclerotic lesion development through regulation of
monocyte-macrophage enrichment. Rabbits exposed to chronic endothelial denudation
of the iliac-femoral artery were meal-fed a 0.25% cholesterol (C), 3% peanut oil
(PNO), 3% coconut oil (CNO) diet twice daily with and without 175 mg/kg PD146176
for 12 weeks. In a second study, atherosclerotic lesions were pre-established in
rabbits through chronic endothelial denudation and meal-fed a 0.5% C, 3% PNO, 3%
CNO diet for 9 weeks and a 0% C/fat diet for 6 weeks prior to an 8 week
administration of PD146176 at 175 mg/kg, q.d. Plasma total and lipoprotein
cholesterol exposure were similar in control and PD146176-treated animals in both
studies but PD146176 increased plasma triglyceride exposure 2- to 4-fold. Plasma
PD146176 concentrations ranged from 99 to 214 ng/ml at 2 h post-dose. In the
progression study, the iliac-femoral monocyte-macrophage area was reduced 71%,
cross-sectional lesion area was unchanged and cholesteryl ester (CE) content was
reduced 63%. In the regression study, size and macrophage content of iliac
femoral, fibrous plaque-like lesions were decreased 34%, CE content was reduced
19% and gross extent of thoracic aortic lesions were reduced 41%. We conclude
that PD146176 can limit monocyte macrophage enrichment of atherosclerotic lesions
and can attenuate development of fibrofoamy and fibrous plaque lesions in the
absence of changes in plasma total or lipoprotein cholesterol concentrations.
PMID- 9543091
TI - The codon 55 polymorphism in the paraoxonase 1 gene is not associated with the
risk of coronary heart disease in Asian Indians and Chinese.
AB - Recently several but not all studies have implicated the codon 192 polymorphism
in the paraoxonase 1 (PON1) gene with the risk of coronary heart disease (CHD).
These findings suggest that this polymorphism is not functional but rather may be
in linkage disequilibrium with a functional mutation in the PON1 or a nearby
gene. In this investigation, we have evaluated the role of another common
polymorphism in the PON1 gene at codon 55 with the risk of CHD in a biracial
sample of Asian Indians and Chinese. We observed a significant inter-racial
variability in the allelic distribution as the frequency of the less common
allele, codon 55/L, was significantly higher in Indians than Chinese (0.202
versus 0.036; P < 0.0001). However, despite this inter-racial difference the
codon 55 polymorphism was neither associated with CHD risk nor with plasma
lipoprotein-lipids variation in both racial groups. We also used two site
haplotype data (codons 55 and 192) to assess the combined contribution of the two
polymorphisms to the risk of CHD. There was a strong linkage disequilibrium
between the two polymorphic sites in both racial groups (P < 0.0001). While the
haplotype data revealed no association with CHD in Chinese, the frequency of the
BL haplotype was significantly higher (0.430 versus 0.311; P = 0.004) and the
frequency of the AL haplotype was significantly lower (0.368 versus 0.483; P =
0.006) in Indian patients than controls. Since the B allele of the codon 192
polymorphism was shown to be an independent risk factor for CHD in Indians in our
previous study, the positive association of the BL haplotype with CHD appears to
be mediated by the B allele with no independent contribution from the codon 55
polymorphism.
PMID- 9543092
TI - Remnant-like particle cholesterol is a major risk factor for myocardial
infarction in vasospastic angina with nearly normal coronary artery.
AB - We investigated the association of remnant-like particle cholesterol (RLP-C),
with vasospastic angina (VSA). We selected 66 subjects with nearly normal
coronary artery as a control group, and 74 VSA with nearly normal coronary
artery, of whom 19 had prior myocardial infarction (MI). Coronary risk factors,
triglyceride, lipoproteins and apolipoproteins were evaluated using stepwise
discriminant analysis, smoking was the only discriminator of the control group
from VSA and RLP-C was the only discriminator of VSA with MI from VSA without MI.
In comparison between VSA with and without MI, using stepwise logistic regression
analysis, the only significant variable was RLP-C, and odds ratio of RLP-C for MI
was 1.59. Thus, RLP-C is a major discriminator of VSA with MI and appears to be a
major risk factor for MI in VSA.
PMID- 9543093
TI - R451Q mutation in the cholesteryl ester transfer protein (CETP) gene is
associated with high plasma CETP activity.
AB - Cholesteryl ester transfer protein (CETP), as a candidate gene for
dyslipoproteinemia and coronary heart disease, was studied in 105 men with low
plasma concentrations of high density lipoprotein cholesterol (HDL-C) and
established coronary heart disease as well as in 515 randomly selected men and
women. A one-nucleotide substitution (G to A) in exon 15, which changes arginine
(451) to glutamine in CETP protein, was detected by PCR-SSCP and direct
sequencing and screened in the population sample by a simple PCR-based
restriction assay. In the random population sample the allele frequency of the
R451Q mutation was 1.9%. Men heterozygous for the R451Q mutation (n = 7) had 27%
higher CETP activity than age-, body mass index-, smoking- and alcohol
consumption-matched controls with normal genotype (n = 21; P = 0.003). Women
heterozygous for the R451Q mutation (n = 7) had 16% lower total cholesterol
compared to matched controls (n = 21; P = 0.07), but no such difference was
detected in men. In the random population sample the correlation between plasma
total cholesterol level and CETP activity was 0.19 (P = 0.044), both in men and
women. When women with total cholesterol over 5.2 mmol/l were excluded from
analysis, heterozygotes (n = 4) had plasma CETP activity of 113 nmol/h/ml plasma,
whereas those of normal genotype (n = 12) had 103 nmol/h/ml plasma, but this
difference was not statistically significant. Women heterozygous for the R451Q
mutation and consuming less than 10 g alcohol a week had 23% lower HDL-C compared
to women with the normal genotype (P = 0.032). In conclusion, we describe a
mutation in the CETP gene associated with high plasma CETP activity in men and
with low total cholesterol in women. Further studies are needed to evaluate the
effect of mutation on the risk of coronary heart disease.
PMID- 9543094
TI - Iron measures in coronary angiography patients.
AB - Excess iron has been postulated as a risk factor for coronary artery disease
(CAD) because of its presence in atherosclerotic lesions, its ability to oxidize
low density lipoprotein cholesterol (LDLc), and its promotion of oxygen
reperfusion damage after an ischemic event. Whether iron, indirectly measured by
its storage protein ferritin and its transport protein transferrin, is related to
CAD was examined in a consecutive series of white male (n = 457) and female (n =
114) cardiac patients. Atherosclerosis measures were analyzed in patients grouped
by tertiles of ferritin. A similar analysis was done with tertiles of
transferrin. Contrary to expectations, men in the third tertile of ferritin had a
smaller mean number of stenoses than men in the two lower tertiles (4.9 versus
5.6 and 5.9; P = 0.027); otherwise, there were no statistically significant
differences in either number of lesions or extent of arterial narrowing based on
tertiles of either measure. Separate multiple logistic regression models with
age, fibrinogen, LDLc and triglycerides as covariates provided no evidence that
ferritin (odds ratio = 0.88 with 95% C.I. = 0.72-1.07 for men and odds ratio =
0.79 with 95% C.I. = 0.54-1.16 for women) or transferrin (odds ratio = 0.60 with
95% C.I. = 0.31-1.16 for men and odds ratio = 1.33 with 95% C.I. 0.52-3.42 for
women) were important correlates of the presence of atherosclerosis in this
study.
PMID- 9543095
TI - Similar response to simvastatin in patients heterozygous for familial
hypercholesterolemia with mRNA negative and mRNA positive mutations.
AB - In patients heterozygous for familial hypercholesterolemia, the low-density
lipoprotein (LDL) cholesterol lowering effect of beta-hydroxy-beta-methylglutaryl
coenzyme A reductase inhibitors may depend on the nature of the mutation in the
LDL receptor gene. To test this hypothesis, we compared the response to
simvastatin, 20 mg daily for 9 weeks, between heterozygous carriers of
functionally different classes of mutations, i.e. mRNA negative or mRNA positive
mutations. Out of 116 consecutive, unrelated patients with familial
hypercholesterolemia, 27 patients were selected for molecular analyses: 14
patients with mRNA negative and 13 with mRNA positive mutations. Before
simvastatin treatment, patients with mRNA negative mutations had higher levels of
LDL cholesterol, lower levels of high-density lipoprotein (HDL) cholesterol and
significantly more often tendon xanthomas, compared to patients with mRNA
positive mutations. Simvastatin reduced the mean fasting LDL cholesterol levels
to a similar percentage in the mRNA negative and mRNA positive patients (37, 36%,
respectively, 95% CI of difference--8 to 5%, P = 0.2). This effect was similar to
the 37% decrease observed in our total series of patients with familial
hypercholesterolemia (n = 116). The increase in mean concentration of HDL
cholesterol was greater in the mRNA negative group than in the mRNA positive
group (16, 0%, respectively, 95%, CI of difference 8-25%, P = 0.002) independent
of the response of total triglycerides to simvastatin. The percentage LDL
cholesterol lowering response varied among multiple carriers of the same
mutation, even in the case of mRNA negative mutations. We conclude that the
percentage LDL lowering response to simvastatin treatment was similar in patients
with mRNA negative and mRNA positive mutations. Moreover, variation of this
response within multiple carriers of the same mutation suggests an influence of
additional factors.
PMID- 9543096
TI - Effect of apolipoprotein E variants on lipolysis of very low density lipoproteins
by heparan sulphate proteoglycan-bound lipoprotein lipase.
AB - Lipoprotein lipase (LPL) is bound to heparan sulphate proteoglycans (HSPG) at the
luminal surface of endothelium. It is the key enzyme involved in the hydrolysis
of very low density lipoproteins (VLDL). Prior to lipolysis by LPL, the
lipoproteins are considered to interact with vessel wall HSPG. Apolipoprotein
(apo) E is thought to mediate this interaction thereby enhancing the stability of
the lipoprotein-LPL complex. We hypothesize that apo E mutations may cause a
diminished interaction of VLDL with HSPG leading to impaired lipolysis of VLDL by
HSPG-bound LPL. In order to test this hypothesis, lipolysis experiments were
performed using HSPG-bound LPL. The mean lipolysis rates of VLDL, isolated from
the apo E2 (Lys146-->Gln) heterozygotes, apo E2 (Arg158-->Cys) homozygotes and
apo E3-Leiden heterozygotes were 92.3 +/- 10.3 (ns), 77.3 +/- 4.2 (P < 0.05) and
76.7 +/- 10.0% (P < 0.05), respectively, of that of control VLDL (100.0 +/-
9.7%). No differences in lipolysis were observed between VLDL from controls and
VLDL from the same patients if LPL in solution was used. Thus, compositional
differences alone can not explain the differences in lipolysis rates observed
with HSPG-bound LPL. In competition experiments, the binding efficiency to HSPG
LPL of VLDL from the apo E2 (Lys146-->Gln) heterozygotes, apo E2 (Arg158-->Cys)
homozygotes and apo E3-Leiden heterozygotes was 63 (ns), 41 (P < 0.05) and 35% (P
< 0.05), respectively of that of control VLDL (100%). We conclude that VLDL
isolated from apo E2 homozygotes and apo E3-Leiden heterozygotes display
decreased lipolysis by HSPG-bound LPL due to a defective binding of these
lipoproteins to the HSPG-LPL complex.
PMID- 9543097
TI - Oxidative damage of vascular smooth muscle cells by the glycated protein-cupric
ion system.
AB - To clarify the mechanism of cellular injury through the nonenzymatic reaction of
glucose with proteins, we studied the cytotoxic effect of glycated bovine serum
albumin on cultured smooth muscle cells in the presence of cupric ion. Glycated
proteins were prepared by incubating bovine serum albumin with 0.5 M D-glucose in
0.3 M sodium phosphate buffer at 37 degrees C for 2, 4 and 16 weeks (g-BSA-2, g
BSA-4 and g-BSA-16, respectively). Early glycation products, such as
fructosamine, were formed more than two weeks after incubation. However, the
immunoreactivity of glycated proteins to anti-AGE antibody was 12-fold higher in
g-BSA-16 than in g-BSA-2. Both g-BSA-2 and g-BSA-16 showed a concentration
dependent cytotoxicity in smooth muscle cells in the presence of 80 microM cupric
ion by an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) dye
reduction assay and dye exclusion test. Flow cytometry and
spectrofluorophotometry using dihydrorhodamine 123 showed that the extracellular
generation of oxidants was dose-dependently enhanced with increasing
concentrations of g-BSA-2 or g-BSA-16 in the presence of cupric ion. However, no
difference was observed in the intracellular generation of oxidants between the
presence and absence of glycated proteins by flow cytometry using 2', 7'
dichlorofluorescein diacetate. Cytotoxicity and oxidant generation were prevented
by catalase and tiron, but not by superoxide dismutase or mannitol, a hydroxyl
radical scavenger. These results indicate that smooth muscle cells may be damaged
by reactive oxygen species which are produced extracellularly by the interaction
with the early glycation products and cupric ion, and suggest that hydrogen
peroxide may be a candidate for reactive oxygen species which contribute to such
oxidative damage of smooth muscle cells.
PMID- 9543098
TI - Troglitazone suppresses intimal formation following balloon injury in insulin
resistant Zucker fatty rats.
AB - Troglitazone, a thiazolidinedione derivative, overcomes insulin resistance
through promoting insulin receptor function. However, the effect of the resultant
enhancement of insulin action on the regulation of cellular proliferation remains
unknown. We investigated the effect of troglitazone on intimal proliferation
after balloon injury in insulin-resistant Zucker fatty rats. Troglitazone
markedly decreased blood glucose and triglyceride levels at the therapeutic
dosage. The area of neointima significantly decreased in treated animals 2 weeks
after operation, as compared with the untreated control animals (0.0526 +/-
0.0292 and 0.115 +/- 0.0354 mm2, respectively). The ratio of neointimal to medial
area in treated rats (0.75 +/- 0.26) decreased by as much as 53% compared with
untreated rats (1.40 +/- 0.05). We next examined DNA synthesis in cultured smooth
muscle cells (SMCs) derived from non-insulin-resistant rats, to assess whether
troglitazone suppresses the proliferation of vascular SMCs independent of
metabolic effects. The result showed that troglitazone decreased [methyl
3H]thymidine incorporation into DNA. In conclusion, treatment with troglitazone
in Zucker fatty rats resulted in a reduction in neointima formation after balloon
injury, and also corrected hypertriglyceridemia and hyperglycemia. In addition,
in vitro studies revealed that the anti-proliferative effect of troglitazone
stems from its direct action on DNA synthesis rather than any accompanying
metabolic changes. Therefore, troglitazone seems to be applicable in preventing
atherosclerosis in patients with insulin resistance.
PMID- 9543099
TI - Advanced glycosylation end products induced tissue factor expression in human
monocyte-like U937 cells and increased tissue factor expression in monocytes from
diabetic patients.
AB - Tissue factor (TF) plays a central role in the initial activation of the
extrinsic coagulation pathway and is thought to be involved in the development of
atherosclerosis and thrombosis. The effect of advanced glycosylation end products
(AGEs) on TF expression and its mechanism were assessed by flow cytometric
analysis. Human macrophage-like U937 cells, which were shown to contain mRNA
encoding the receptors of advanced glycosylation end products (RAGE), expressed
TF in a dose-dependent manner on incubation with AGE-albumin. AGE-albumin-induced
TF expression was completely inhibited by the anti-oxidant agents, catalase and
probucol. TF expression in peripheral monocytes from normal volunteers was also
increased by AGE-albumin. Finally, TF expression in monocytes from individuals
with diabetes mellitus, in whom the concentration of circulating AGEs is reported
to be increased, was higher than that in monocytes from normal controls. These
results suggest that AGE-induced TF expression in macrophages/monocytes is
mediated by oxidant stress. AGEs may promote thrombosis and the development of
atherosclerosis by inducing TF expression in monocytes in patients with diabetes
mellitus.
PMID- 9543100
TI - Diabetes mellitus in a new kindred with familial hypobetalipoproteinemia and an
apolipoprotein B truncation (apoB-55).
AB - Familial hypobetalipoproteinemia is an autosomal co-dominant disorder, which in a
minority of cases is due to a truncation producing mutation in the apoB gene. We
have identified an apoB mutation in a 40-year old hypobetalipoproteinemic man
with Type II diabetes mellitus. Immunoblotting of plasma revealed a major band
for apoB-100 and a minor band with estimated size between apoB-52 and apoB-55.
The proband's 75-year old father with Type II diabetes and a non-diabetic
daughter also possessed the truncated protein. Direct sequencing of the amplified
fragment of genomic DNA revealed a C-->T transition at nt 7692 in exon 26 of the
apoB gene. This substitution yielded a premature stop codon at residue 2495 and
abolished a BsaI restriction endonuclease site. The identical mutation has been
described previously; however, the genotypes and ancestors of the kindred were
different, suggesting that the mutation may have occurred independently. The
majority of apoB-55 was eluted as particles smaller than LDL-sized apoB-100, and
floated mostly between the LDL and HDL density range. It is worth noting that
despite the presence of Type II diabetes, both the proband and his father have
very low plasma lipid levels and neither have any clinically manifest
macrovascular complications.
PMID- 9543101
TI - Monocytic cell adhesion to endothelial cells stimulated by oxidized low density
lipoprotein is mediated by distinct endothelial ligands.
AB - Treatment of human umbilical vein endothelial cells (HUVEC) with oxidized low
density lipoprotein (ox-LDL, 100 microg/ml) for 24 h increased adhesion of human
monocytic Mono Mac 6 cells from 4.8 +/- 0.9% to 17.6 +/- 2.5% (P < 0.001). The
effect was dose dependent and first evident at 10 microg/ml ox-LDL. In contrast,
adhesion of U937 cells was not significantly increased. Mac-1 (CD11b/CD18), a
monocytic counter-receptor for intercellular adhesion molecule-1 (ICAM-1), that
also binds to heparin, is present on Mono Mac 6 but not on U937 cells, and may
thus explain these differences in adhesion. Consistently, ox-LDL induced a 2-fold
upregulation of ICAM-1 surface expression on HUVEC. The presence of maltose-1
phosphate or heparin but not monoclonal antibodies (mAbs) to ICAM-1 reduced
adhesion of Mono Mac 6 cells to untreated HUVEC. Combinations of mAbs to ICAM-1
with either maltose-1-phosphate or heparin inhibited Mono Mac 6 adhesion to ox
LDL-stimulated HUVEC by more than 50%, while either alone had no effect. This
suggests that two distinct endothelial ligands for Mac-1, inducible ICAM-1 and
carbohydrate-decorated heparin-like proteoglycan structures mediate monocytic
cell interaction with ox-LDL-treated HUVEC. The stimulating activity in ox-LDL
could partly be transfered to bovine serum albumin, while lysophosphatidylcholine
or 8-epi prostaglandin F2alpha produced no stimulatory effects. The inhibition of
ox-LDL effects with the antioxidant PDTC indicates radicals as possible
mediators. In conclusion, we show that oxidatively modified LDL induces adhesion
of monocytic cells, which utilize at least two distinct adhesive receptors on
endothelium, one being identified as ICAM-1.
PMID- 9543102
TI - Inhibition of LDL oxidation by a new estradiol receptor modulator compound LY
139478, comparative effect with other steroids.
AB - Oxidation of low-density lipoprotein (LDL) is postulated to be essential for the
development of atherosclerosis. LY-139478 is a new non-steroidal potent estrogen
analog, but its effects on in vitro LDL oxidation have not been completely
elucidated. We investigated the ability of LY-139478 to inhibit in vitro copper
sulfate-mediated LDL oxidation using several methods, including conjugated diene
(CD) accumulation, relative electrophoretic mobility on agarose gel,
thiobarbituric acid-reactive substances (TBARS) assay, and superoxide anions
scavenging activity. The antioxidative potential of LY-139478 was compared to
testosterone (T), 17-alpha-estradiol (17alphaE), 17-beta-estradiol (17betaE),
dehydroepiandrosterone (D), and dehydroepiandrosterone-3-sulfate (DS). LY-139478
was superior to 17alphaE and 17betaE in prolonging the lag phase and decreasing
the slope and peak concentration of the conjugated diene accumulation, decreasing
the rate of migration of LDL on agarose gel electrophoresis, and inhibiting the
production of melonyldialdehyde (MDA) in the TBARS assay. T, D and DS were
ineffective in all three assays. It was previously shown that when native LDL is
oxidized by previously oxidized LDL (secondary oxidation) the lag phase is lost
(Schnitzer et al. Free Rad Res 1995;23:137). LY-139478 was at least 15-fold more
effective than 17alphaE, and 17betaE in slowing the propagation phase and
reducing CD accumulation in this secondary oxidation, with 50% inhibition at 10
microM and 98% inhibition at 100 microM. However, none restored the lag phase. T,
D and DS were ineffective. Superoxide anion generation was inhibited only by DS
at high doses (500 microM). These results demonstrate that LY-139478 is an
effective inhibitor of LDL oxidation and is superior to natural steroidal
hormones, including 17betaE, in protecting against primary and secondary LDL
oxidation.
PMID- 9543103
TI - Hypochlorite-modified low-density lipoprotein stimulates human polymorphonuclear
leukocytes for enhanced production of reactive oxygen metabolites, enzyme
secretion, and adhesion to endothelial cells.
AB - Hypochlorite-oxidized low-density lipoprotein ((-)OCl-LDL) has been shown to
stimulate various functions of human polymorphonuclear leukocytes (PMNLs).
Incubation of PMNLs with (-)OCl-LDL (produced by incubation of 0.4 mM LDL
cholesterol with 1 mM NaOCl for 40 min at 37 degrees C) but not native or copper
oxidized LDL induced a substantial generation of reactive oxygen species (ROS) as
measured by means of chemiluminescence with one peak at 10-12 min. Upon
stimulation with (-)OCl-LDL about 70% of ROS (hydrogen peroxide and superoxide
anion) were released from the cells into the extracellular environment. The (
)OCl-LDL-induced increase of the respiratory burst was dependent upon the dose,
exposure time, and extent of LDL oxidation. Cytochalasin B, an inhibitor of
phagocytosis, markedly diminished the LDL-induced ROS generation to nearly 40% of
control values. (-)OCl-LDL enhanced the adhesion of PMNLs to human umbilical
venous endothelial cells 2.5-fold as compared to native LDL and promoted the
secretion of the active granule enzymes lysozyme and beta-glucuronidase.
Together, the results suggest a potential role of LDL-activated PMNLs in
initiating and/or maintaining the inflammatory process during the early phase of
atherosclerotic lesion development. Alternatively, PMNLs may also play a
protective role by phagocytosing oxidized LDL and, thus, preventing further
detrimental atherogenic effects of oxidized LDL.
PMID- 9543104
TI - Triglyceride metabolism in heterozygote of Watanabe heritable hyperlipidemic
rabbit.
AB - The present study was conducted in order to examine the role of low-density
lipoprotein (LDL)-receptor activity in very-low-density lipoprotein (VLDL)
triglyceride metabolism in vivo. Fructose-feeding (10% in drinking water) for 2
weeks resulted in elevated plasma triglyceride in heterozygote of Watanabe
heritable hyperlipidemic (WHHL) rabbit (WHHLH) associated with suppressed
fractional catabolic rate (FCR) of plasma triglyceride, whereas Japanese white
(JW) rabbit with normal LDL receptor activity showed no remarkable change in
plasma triglyceride turnover after fructose-feeding, suggesting an involvement of
LDL receptor activity on triglyceride metabolism. Thereafter, in order to
stimulate cellular LDL receptor activity, fluvastatin, a new 3-hydroxy-3
methylglutaryl-coenzyme-A (HMG-CoA) reductase inhibitor, was administered orally
(1.52 +/- 0.26 mg/kg) to fructose-fed WHHLH. Significant suppression of
triglyceride secretion rate (TGSR) was observed after treatment. However, since
plasma triglyceride level was markedly suppressed, FCR of plasma triglyceride was
significantly elevated by fluvastatin. Thus, it is speculated from the present
data that LDL receptor activity is significantly involved in VLDL triglyceride
metabolism in rabbits.
PMID- 9543105
TI - Effects of reducing LDL and increasing HDL with gemfibrozil in experimental
coronary lesion development and thrombotic risk.
AB - The use of lipid-lowering drugs has been shown to have beneficial effects in
primary and secondary prevention of cardiovascular disease. Gemfibrozil has shown
beneficial effects as a lipid lowering agent; however, some proactivating effects
on platelet function in vitro have been described. We have studied in a porcine
model of atherosclerosis if gemfibrozil could prevent the early vascular effects
of a cholesterol-rich diet without inducing platelet activation and, hence, mural
thrombosis. Pigs were fed for 50 days with a diet rich in saturated fat and
cholesterol (cho). The longitudinal follow-up study showed that in control
animals LDL-cho increased significantly up to 181.9 +/- 34.2 mg/dl or 79% of
total-cho, while HDL-cho was reduced to 19% of total-cho. Gemfibrozil, at average
therapeutic plasma levels (peak levels of 28 micrograms/ml) [corrected], induced
a significant reduction in the relative amount of LDL (P < 0.05) and increased
HDL (P < 0.05). The increase in fibrinogen plasma levels observed in the control
group due to the dietary intervention (+25%) was prevented in the treated animals
(-5%). In treated animals, vascular lesions were significantly less severe,
platelet deposition upon exposure of damaged vessel wall was unchanged and the
fibrin layer deposited on the damaged vessel wall was significantly reduced over
control animal values. This short term pharmacologic lipid lowering intervention
has been able to slow down lesion development and to reduce fibrin formation onto
lesioned disrupted vascular substrates without increasing platelet mural
thrombosis.
PMID- 9543106
TI - C677T (thermolabile alanine/valine) polymorphism in methylenetetrahydrofolate
reductase (MTHFR): its frequency and impact on plasma homocysteine concentration
in different European populations. EARS group.
AB - A common polymorphism has been described in the methylenetetrahydrofolate
reductase (MTHFR) gene, substituting an alanine (A) for a valine (V), where the V
allele results in a thermolabile enzyme with reduced activity. This polymorphism
is easily detectable by PCR amplification and digestion with HinfI restriction
enzyme. We describe the use of the MADGE high throughput genotyping system for
rapid typing of this polymorphism. Seven hundred and eighty five individuals
participating in the European Atherosclerosis Research Study II (EARS II), aged
22-25 from 14 universities in 12 countries across Europe were genotyped for this
polymorphism. The frequency of the V allele was 0.32 overall (95% CI; 0.30-0.35),
but was significantly lower in the Baltic countries (0.23; 95% CI; 0.19-0.28)
compared with the other regions of Europe (0.37; 95% CI; 0.32-0.38) (P < 0.001).
Individuals homozygous for the V allele had statistically significant (P < 0.001)
higher plasma homocysteine (16.5 micromol/l) compared with those heterozygous for
an A allele (10.4 micromol/l) or homozygous for an A allele (10.0 micromol/l).
This effect was seen in all countries and regions of Europe. Mean plasma
homocysteine levels were significantly higher in the South compared to the
Baltic, UK and Middle regions (P = 0.001), but this difference was not explained
by the difference in the frequency of the V allele in the samples. This
polymorphism explained 12.3% of the total sample variance in plasma homocysteine,
other measured factors (smoking, alcohol consumption, systolic blood pressure,
physical activity) explained 0.7%. This study demonstrates the large and
consistent impact of the thermolabile MTHFR variant on plasma homocysteine levels
in different European populations, and shows a regional difference in the levels
of homocysteine that must be explained by other genetic or environmental factors.
PMID- 9543107
TI - Glycoxidation in aortic collagen from STZ-induced diabetic rats and its relevance
to vascular damage.
AB - Glycoxidation reactions lead to the formation of permanent, irreversible chemical
modifications and cross-links in protein, such as the glycoxidation products
carboxymethyllysine (CML) and pentosidine. It has been implicated that CML as
well as Amadori products play a role in the formation of superoxidative products,
such as H2O2 and advanced glycosylation endproducts in trapping LDL. Therefore, a
possible relationship between glycoxidation and lipoperoxidation might exist
because oxidized lipoprotein, which has been directly linked to atheroma
formation, could be produced by the superoxidative products released from the
pathway of CML formation. Using a CML-specific monoclonal antibody (6D12) and a
specific antiserum against hexitol-lysine (HL), an Amadori product, we studied
the relationship between glycoxidation and lipoperoxidation by determining the
aortic CML contents with ELISA and the fluorescence levels of lipoperoxidation
side products, malondialdehyde (MDA) and hydroxynonenal (HNE) from STZ-induced
diabetic rats and age-matched control rats. The immunohistochemical and
ultrastructural changes relevant to glycoxidation and lipoperoxidation were also
studied. The CML content measured by ELISA in DM rats was significantly higher
than that in the control rats at 28 weeks (n = 11, P < 0.01). The levels of MDA
linked and HNE-linked fluorescence in the DM rats increased in a similar way and
were significantly higher than the levels in control rats at 28 weeks (n = 11,
both P < 0.01 at 28 weeks). The CML contents correlated with the fluorescence
levels of both MDA-linked (n = 19, r = 0.638, P < 0.01) and HNE-linked
fluorescence (n = 19, r = 0.629, P < 0.01) only in the DM rats, but not in the
control rats. Our immunohistochemical study thus demonstrated that CML was
initially formed in the aortic media of diabetic rats in the 16th week of
diabetes, localized primarily in the extracellular matrix surrounding the aortic
smooth muscle cells after HL occurred early in the 2nd week of diabetes.
Consequently, a significant increase in the extracellular matrix and decrease in
the area of the SMCs were observed in the aortic media in the DM rats by a
morphometrical study. The in vivo results of this study provided the first
evidence that CML correlated with fluorescence levels of MDA and HNE, and thus
suggested the existence of a close relationship between glycoxidation and
lipoperoxidation in vivo. This information is thus considered to shed some new
light on the etiology of atherogenesis in diabetes.
PMID- 9543108
TI - Reduction of hypercholesterolemic atherosclerosis by CDC-flaxseed with very low
alpha-linolenic acid.
AB - Flaxseed (Type I flaxseed) with 51-55% alpha-linolenic acid in its oil and
richest source of plant lignans, has been shown to reduce hypercholesterolemic
atherosclerosis by 46% without lowering serum lipids. Antiatherogenic activity
was claimed to be due to its alpha-linolenic acid and/or lignan content. If alpha
linolenic acid component of flaxseed is responsible for antiatherogenic activity,
then, CDC-flaxseed (Type II flaxseed) which has similar oil and lignan content
but has very little (2-3% of the total oil) alpha-linolenic acid would have no
antiatherogenic effect. An investigation, therefore, was made of Type II flaxseed
on high cholesterol diet-induced atherosclerosis and serum lipids [total
cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL
C), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein
cholesterol (VLDL-C)] in rabbits. Rabbits were assigned to four groups: Group I,
Control; Group II, Type II flaxseed diet (7.5 g/kg orally daily); Group III, 1%
cholesterol diet; Group IV, 1% cholesterol diet supplemented with Type II
flaxseed (7.5 g/kg orally daily). Blood samples were collected before (0 time)
and after 4 and 8 weeks of experimental diets for measurement of serum lipids.
Aorta was removed at the end of 8 weeks for assessment of atherosclerotic
plaques. Serum TC, LDL-C, TC/HDL-C, and LDL-C/HDL-C were lower in Group IV as
compared to Group III by 14 and 31%, 17 and 32%, 28 and 34% and 24 and 32%,
respectively, at 4 and 8 weeks. HDL-C was not affected by Type II flaxseed in
hypercholesterolemic rabbit. TG and VLDL-C were markedly increased in Group IV as
compared to Group III. Type II flaxseed reduced the development of
atherosclerosis by 69%. Histological changes in the atherosclerotic regions were
qualitatively similar in Groups III and IV. Results indicate that reduction in
hypercholesterolemic atherosclerosis by Type II flaxseed is due to a decrease in
serum TC and LDL-C. In conclusion, antiatherogenic activity of Type II flaxseed
is not due to alpha-linolenic acid.
PMID- 9543109
TI - Transforming growth factor beta1 induces IL-1 receptor antagonist production and
gene expression in rat vascular smooth muscle cells.
AB - Atherosclerosis is an inflammatory-fibroproliferative process that may represent
a possible milieu in which transforming growth factor-beta (TGF-beta) can be
involved. Vascular smooth muscle cells (VSMC) may represent a source or a target
of a large number of growth factors and proinflammatory cytokines, including
interleukin-1 and its receptor antagonist (IL-1Ra). We tested the effect of TGF
beta1, on IL-1Ra production and gene expression in rat VSMC cultures. We found a
significant dose (3-30 ng/ml) and time-dependent (0-48 h) increase in IL-1Ra
immunoactivity in the supernatant of conditioned medium and cell lysates. The
maximal effect was observed with TGF-beta at 30 ng/ml and after 24 h incubation
time, respect to untreated cells (320 +/- 26 vs. 211 +/- 20 pg/ml; P < 0.01).
Furthermore, TGF-beta1 induced an increased mRNA expression which began at 2 h
and peaked at 18 h incubation time (about a 6-fold increase with respect to
unstimulated cells). The effect of TGF-beta1 on IL-1Ra production was completely
inhibited by an anti-IL-1beta antibody (10 microg/ml) (from 320 +/- 81 to 181 +/-
46 pg/ml). These experiments suggest that TGF-beta1, potentially produced in the
vascular wall during atherogenesis, may play a pathophysiological role in the
autocrine control of IL-1 actions, via VSMC IL-1Ra production.
PMID- 9543110
TI - Association of smoking and low serum bilirubin antioxidant concentrations.
AB - This study sought to examine the association between cigarette smoking and serum
bilirubin antioxidant concentrations in 715 middle-aged men undergoing coronary
angiography. The study involved 153 current smokers, 251 who quit smoking and 311
who never smoked. Serum bilirubin concentrations were divided into the following
quartiles; 0.20-0.57, 0.58-0.73, 0.74-0.95 and 0.96-3.26 mg/dl. The percentage of
individuals within each quartile were as follows; current smokers (42, 22, 24,
12), former smokers (22, 27, 23, 28), nonsmokers (16, 28, 27, 29). A total of 42%
of the current smokers had bilirubin concentrations in the lowest quartile
compared to 16% of the nonsmokers. Also, 12% of the current smokers had bilirubin
concentrations in the highest quartile compared to 29% in the nonsmoking group.
The Mantel-Haenszel chi-square test for association between ordered categorical
variables was 30.6 (P < 0.0001). Subdividing the subjects according to maximum
percent stenosis on angiography (< 10, 10-49, 50-100%) revealed a significant
inverse association between smoking and bilirubin (< 0.01) within each subset.
The data shows that smoking is associated with decreased serum bilirubin
concentrations. In addition, it supports the hypothesis that cigarette smoking
may increase the risk of coronary artery disease by lowering antioxidant
concentrations and raising oxidized lipid and lipoprotein concentrations.
PMID- 9543111
TI - Elevated lipoprotein(a) levels and small apo(a) isoforms are compatible with
longevity: evidence from a large population of French centenarians.
AB - Epidemiological studies have shown lipoprotein(a) (Lp(a)) to be an independent
risk factor for cardiovascular disease. Lp(a) is a cholesterol-rich, low-density
lipoprotein (LDL)-like particle to which a large glycoprotein, apolipoprotein(a)
(apo(a)) is attached. Plasma Lp(a) levels are highly genetically determined and
influenced to a minor degree by environmental factors. In an effort to determine
whether Lp(a) might be associated with longevity, we have evaluated Lp(a) levels
and apo(a) isoform sizes in a population of French centenarians (n = 109)
compared to a control group (n = 227). The mean age of centenarians was 101.5 +/-
2.4 years while the control group was 39.4 +/- 7.2 years. Plasma levels of total
cholesterol and triglyceride were within the normal range in both centenarian and
control subjects. Lp(a) levels were higher in centenarians (both male and female)
than in the normolipidemic control group (mean Lp(a) level = 0.33 +/- 0.42 and
0.22 +/- 0.27 mg/ml, respectively, P < 0.005). The distribution of apo(a)
isoforms was significantly shifted towards small isoform size in the centenarian
population as compared to the controls (54.4 and 41.4% of isoforms < or = 27
kringles (kr), respectively, P = 0.04). Nonetheless, the apo(a) size distribution
in centenarians did not entirely explain the high Lp(a) levels observed in this
population. Factors other than apo(a) size, and which may be either genetic or
environmental in nature, appear to contribute to the elevated plasma Lp(a) levels
of our centenarian population. We conclude therefore that high plasma Lp(a)
levels are compatible with longevity.
PMID- 9543112
TI - Lipid profiles reflecting high and low risk for coronary heart disease:
contribution of apolipoprotein E polymorphism and lifestyle.
AB - To elucidate the role of modifiable factors and the apolipoprotein E polymorphism
in explaining lipid profiles reflecting low, average and high risk for coronary
heart disease, we selected subjects from a large population-based study. Subjects
with low total cholesterol (TC) (< 15th percentile) and high HDL-cholesterol
levels (> 85th percentile) were randomly selected (n = 99) and represent subjects
with a low risk lipid profile. Additionally, 95 subjects with total and HDL
cholesterol levels in the 15% around the population-median (median risk lipid
profile) and 100 subjects with high TC (> 85th percentile) and low HDL
cholesterol levels (< 15th percentile) (high risk lipid profile) were selected.
Compared with E3/3 subjects, the likelihood for a low risk lipid profile was
considerably higher (odds ratio 14.3; 2.6-79) in female, but not in male E2
carriers (1.5; 0.3-6.7). Smoking and alcohol consumption were independently
associated with a low risk lipid profile in both genders, physical inactivity
only in women. The odds ratio for a high risk lipid profile was elevated in male
E4-carriers (4.9; 1.1-23) only. In addition to the E4 isoform, smoking and
physical inactivity, overweight was the main determinant for a high risk lipid
profile (odds ratio 16.8; 3.4-82). Male overweight E4-carriers had a 50 times
higher likelihood of a high risk lipid profile than E3/3 men of normal weight. In
women, only overweight was independently associated with a high risk lipid
profile. Our results suggest that both modifiable factors and the apolipoprotein
E polymorphism contribute to a lipid profile, reflecting low, average and high
risk for coronary heart disease, but effects may be gender-specific.
PMID- 9543113
TI - A little more on lipoprotein profile in peripheral arterial disease.
PMID- 9543114
TI - Susceptibility to oxidation and physicochemical properties of LDL in insulin
dependent diabetics.
PMID- 9543115
TI - Clinical review 93: Autoimmune polyglandular syndrome type 1.
PMID- 9543116
TI - Bone turnover during lactation--can calcium supplementation make a difference?
PMID- 9543117
TI - Biochemical markers of calcium and bone metabolism during 18 months of lactation
in Gambian women accustomed to a low calcium intake and in those consuming a
calcium supplement.
AB - The effect of 18 months of lactation on indexes of calcium and bone metabolism
was studied in 60 Gambian women accustomed to a very low calcium intake. Half the
women consumed a calcium supplement from 10 days postpartum for 52 weeks
(supplement, 714 mg Ca/day; total Ca intake, 992 +/- 114 mg/day), and half
consumed placebo (total Ca intake, 288 +/- 128 mg/day). Fasting blood and 24-h
urine samples were collected at 1.5, 13, 52, and 78 weeks of lactation and
analyzed for calciotropic hormones (intact PTH, 1,25-dihydroxyvitamin D, and
calcitonin), bone turnover markers (osteocalcin, bone alkaline phosphatase, and
urinary deoxypyridinoline), and plasma minerals (calcium and phosphate). The
first months of lactation were associated with increased bone turnover and plasma
phosphate, and decreased PTH and 1,25-dihydroxyvitamin D. These effects
diminished by 52 weeks, although breast milk volumes remained high. The Gambians
had higher PTH, 1,25-dihydroxyvitamin D, and bone formation than British women
with a greater customary calcium intake. None of the biochemical indexes was
affected by calcium supplementation, with the possible exception of bone alkaline
phosphatase (-29% at 52 weeks; P = 0.015). These data demonstrate that lactation
associated changes in calcium and bone metabolism are physiological and are
independent of dietary calcium supply in women with very low calcium intakes.
PMID- 9543118
TI - Does growth hormone have a role in the management of children with nongrowth
hormone deficient short stature and intrauterine growth retardation?
PMID- 9543119
TI - Short stature associated with intrauterine growth retardation: final height of
untreated and growth hormone-treated children.
AB - Short term studies have demonstrated the acceleration of growth velocity after
the administration of GH in short children born with intrauterine growth
retardation (IUGR). We report the final heights of 70 IUGR children whose short
stature was attributed to idiopathic GH deficiency (peak plasma GH <10 ng/mL at 2
provocative tests) and treated with GH at a mean dosage of 0.4 +/- 0.1 U/kg x
week during an average of 4.6 +/- 2.5 yr. They were compared to a control group
of 40 untreated short children born with IUGR, without GH deficiency. At the time
of evaluation, age, auxological data, and pubertal status were similar in the 2
groups (height, -2.9 +/- 0.8 and -2.8 +/- 0.7 SD score). Final heights were
comparable in both groups of children (-2 +/- 0.7 and -2.2 +/- 1.1 SD score). A
multivariate analysis identified 4 independent predictors of final height, namely
target height, age and body mass index at evaluation, and GH treatment. Treatment
was associated with a gain of 0.6 SD score, suggesting a final height gain of
about 3.4 cm. Fifty-three of 70 treated children were reevaluated after
completion of growth, and 43 of 53 had a peak plasma GH level of 10 ng/mL or
more. Auxological characteristics of these 53 patients were not different from
those of nonreevaluated patients. We believe that the transient character of the
GH deficiency in most patients and the nonstringent initial criteria used for the
diagnosis of GH deficiency render the spontaneous growth potentials identical in
the 2 groups of patients. Our data, therefore, suggest that GH treatment at this
dosage has a limited effect on the final height of short children born with IUGR.
PMID- 9543120
TI - Comparison of final heights of growth hormone-treated vs. untreated children with
idiopathic growth failure.
AB - We measured adult heights (Ht) of 94 healthy GH-sufficient children (peak GH > 10
ng/mL, polyclonal RIA) whose Ht at presentation were more than 2 SD below the
mean for chronological age, with normal weight-to-Ht ratios, normal body
proportions, and pathologic growth velocity for chronological age. Group 1 (n 36,
6 females) received standardized doses (0.3 mg/kg x week) of GH (mean duration =
41 months), while group 2 (n = 58, 17 females) received no treatment. Our
conclusion was that the mean final Ht SD score in the GH-treated group (-1.5) was
significantly greater than in the untreated group (-2.1); P < .001. Genetic
predisposition to short stature was evident in both groups: the midparental Ht SD
score was -1.1 in the treated and -1.0 in the untreated group. Midparental Ht was
met or exceeded by 42% of the GH-treated group but only 15% of the untreated
group. Final Ht was not significantly different from predicted Ht, except from GH
treated girls, who exceeded their predicted Ht. Although the mean Ht gains (6.8
cm in girls and 3 cm in boys) were modest and variable, GH treatment provided
significantly better Ht outcomes for the majority of children with idiopathic
growth failure.
PMID- 9543121
TI - Calcimimetics--new drugs with the potential to control hyperparathyroidism.
PMID- 9543122
TI - Treatment of hypercalcemia secondary to parathyroid carcinoma with a novel
calcimimetic agent.
AB - Parathyroid carcinoma is one cause of primary hyperparathyroidism, a condition in
which there is hypercalcemia and dysregulated hypersecretion of PTH. In normal,
and in some neoplastic parathyroid cells, PTH secretion is mediated by the cell
surface calcium-sensing receptor. We describe the first therapeutic use of a
novel molecule, a calcimimetic, that has agonist action at the calcium-sensing
receptor. A 78-yr-old man with parathyroid carcinoma was admitted with
hypercalcemia, markedly elevated PTH, and a change in mental status. He was
treated for 17 days with conventional therapy, which included saline hydration,
furosemide, pamidronate, and calcitonin. This was ineffective, and on hospital
day 18, calcimimetic at a dose of 50 mg, orally, every 6 h was added. On hospital
day 25, the dose was increased to 100 mg, orally, every 6 h, and on hospital day
30, saline and furosemide were discontinued. He was discharged on hospital day
40. With several dose adjustments, he has been treated with monotherapy
calcimimetic for over 600 days and has not required any other interventions for
his parathyroid carcinoma. Mean daily precalcimimetic treatment values of serum
ionized calcium and PTH were 1.83 mmol/L and 872 pg/mL, respectively. During
hospitalization, at the lower dose of calcimimetic, calcium and PTH decreased to
1.67 mmol/L and 538 pg/mL; with the higher dose they further decreased to 1.51
mmol/L and 444 pg/mL. Since discharge, and despite increasing levels of PTH,
serum calcium has remained high, but lower than the admission level and acutely
responsive to changes in calcimimetic doses. This compound, a calcimimetic, the
first of a new class of compounds with activity at the calcium-sensing receptor,
has been used to treat a patient with parathyroid carcinoma. During 2 yr of
treatment, no adverse clinical effects have been observed, and it appears to have
been effective at controlling hypercalcemia.
PMID- 9543123
TI - Leptin and puberty.
PMID- 9543125
TI - Therapeutic controversy: Thyroid surgery--the choice.
PMID- 9543126
TI - Normal postprandial lipemia and chylomicron clearance in offspring of parents
with early coronary artery disease.
AB - To assess the importance of postprandial lipemia and delayed chylomicron
clearance as early atherogenic risk factors, 60 male offspring of parents with
early coronary artery disease (CAD) and 41 controls were administered a fat-rich
meal containing vitamin A. There were no significant differences between CAD
positive (CAD+) offspring and CAD-negative controls for areas under the
postprandial curves for triglyceride and plasma, chylomicron, and chylomicron
remnant retinyl palmitate. Older CAD+ offspring, aged 31-45 yr, had significantly
increased very low density lipoprotein (VLDL) cholesterol, VLDL triglyceride,
VLDL apoprotein B, and areas under postprandial curves for triglyceride and
plasma, chylomicron, and chylomicron remnant retinyl palmitate than younger CAD+
offspring, aged 15-30 yr. Correcting for waist/hip ratio eliminated significant
differences between the two groups for VLDL and areas under the triglyceride and
chylomicron remnant curves, but this was not the case for the insulin sensitivity
index. We conclude that neither increased postprandial lipemia nor abnormalities
of chylomicron clearance are important early atherogenic risk factors in this
population. An increase in age is associated with increased VLDL and postprandial
lipemia and decreased chylomicron remnant clearance. This is due mainly to an
increase in the waist/hip ratio and not to a change in insulin sensitivity.
PMID- 9543124
TI - The impact of reversible gonadal sex steroid suppression on serum leptin
concentrations in children with central precocious puberty.
AB - Serum leptin concentrations increase during childhood in both sexes. During
sexual maturation, levels rise further in girls, but decrease in boys. These data
suggest that testosterone either directly suppresses leptin levels or induces
changes in body composition that result in lower leptin concentrations. To
examine further the relationship between sex steroids and leptin, we performed a
longitudinal study in children with central precocious puberty (28 girls and 12
boys) before, during, and after discontinuation of GnRH agonist-induced pituitary
gonadal suppression. Nighttime and daytime leptin levels were measured to
determine whether the activity of the pituitary-gonadal axis affects their
diurnal variation. In the boys, suppression of testosterone increased leptin
levels, whereas resumption of puberty was associated with decreased leptin levels
[3.5 +/- 0.8 vs. 9.5 +/- 3.1 ng/dL (P = 0.005) and 12.2 +/- 4.5 vs. 7.0 +/- 2.6
ng/dL (P = 0.012), respectively]. Serum leptin levels did not change in the girls
with alteration of the pituitary-ovarian axis and consistently exceeded those in
boys. Nighttime levels were consistently greater than daytime values by an
average of 38.3% in the girls and 29.4% in the boys. These serial observations
during reversible pituitary-gonadal suppression suggest that testosterone
decreases leptin concentrations, but that estrogen, at least in this childhood
model, has no discernible effect. In addition, our data indicate that the
presence of the diurnal rhythm in leptin concentrations is independent of the
state of the reproductive axis.
PMID- 9543127
TI - Suppressibility of plasma adrenocorticotropin by hydrocortisone: potential
usefulness in the diagnosis of Cushing's disease.
AB - Repeatedly normal cortisol suppressibility by dexamethasone in 2 patients with
Cushing's disease led to the present study of the prevalence of this phenomenon
in 58 patients with otherwise incontrovertible evidence of Cushing's disease.
Because as many as 23% of these patients manifested this phenomenon, we
investigated the suppressibility of plasma ACTH: 1) during i.v. infusion of
hydrocortisone, after a priming dose (7 mg), at 3 mg/h in 8 patients and 8 normal
controls; and 2) for 2 h, after oral hydrocortisone, 0.25 mg/kg, in 13 patients
and 16 controls. The data showed invariable suppression of plasma ACTH to < or =
10 pg/mL (< or = 2.2 pmol/L) after 120 min of the infusion or at 90 min after
oral hydrocortisone in 16 fasting normal subjects given oral hydrocortisone
between 0800 and 0830 h. Plasma ACTH exceeded 10 pg/mL (2.2 pmol/L) at the same
times in 14/14 patients with active Cushing's disease, including 3 patients whose
cortisol suppressibility by dexamethasone had been misleadingly normal and in 4/7
patients with intermittent hypercortisolism. Occasional variations in plasma
cortisol elevations after the oral dose require that plasma cortisol
concentration be monitored at 60 min after the oral hydrocortisone dose, because
the present evidence supports the validity of the conclusion that a plasma ACTH
concentration below 10 pg/mL excludes Cushing's disease only when plasma cortisol
concentration at 60 min lies between 16 and 38 microg/dL. Further evaluation of
ACTH suppressibility by cortisol would be worthwhile, to confirm its potential
value in facilitating positive diagnosis of Cushing's disease when dexamethasone
suppressibility seems misleading.
PMID- 9543128
TI - Serum thyroglobulin autoantibodies: prevalence, influence on serum thyroglobulin
measurement, and prognostic significance in patients with differentiated thyroid
carcinoma.
AB - The prevalence of circulating thyroid autoantibodies (TgAb or antithyroid
peroxidase) was increased nearly 3-fold in patients with differentiated thyroid
cancers (DTC) compared with the general population (40% vs. 14%, respectively).
Serum TgAb (with or without antithyroid peroxidase) was present in 25% of DTC
patients and 10% of the general population. Serial postsurgical serum TgAb and
serum Tg patterns correlated with the presence or absence of disease.
Measurements of serum Tg were made in 87 TgAb-positive sera by a RIA and two
immunometric assay (IMA) methods to study TgAb interference. TgAb interference,
defined as a significant intermethod discordance (>41.7% coefficient of
variation) between the Tg RIA and Tg IMA values relative to TgAb-negative sera,
was found in 69% of the TgAb-positive sera. TgAb interference was characterized
by higher Tg RIA vs. IMA values and was, in general, more frequent and severe in
sera containing high TgAb concentrations. However, some sera displayed marked
interference when serum TgAb was low (1-2 IU/mL), whereas other sera with very
high TgAb values (>1000 IU/mL) displayed no interference. An agglutination method
was found to be too insensitive to detect low TgAb concentrations (1-10 IU/mL)
causing interference. Exogenous Tg recovery tests were an unreliable means for
detecting TgAb interference. Specifically, the exogenous Tg recovered varied with
the type and amount of Tg added and the duration of incubation employed. Further,
recoveries of more than 80% were found for some sera displaying gross serum
RIA/IMA discordances. The measurement of serum Tg in DTC patients with
circulating TgAb is currently problematic. It is important to use a Tg method
that provides measurements that are concordant with tumor status. IMA methods are
prone to underestimate serum when TgAb is present, increasing the risk that
persistent or metastatic DTC will be missed. The RIA method used in this study
provided more clinically appropriate serum Tg values in the group of TgAb
positive patients with metastatic DTC. Furthermore, as serial serum TgAb
measurements paralleled serial serum Tg RIA measurements, TgAb concentrations may
be an additional clinically useful tumor marker parameter for following TgAb
positive patients. Disparities between serial serum Tg and TgAb measurements
might alert the physician to the possibility of TgAb interference with the serum
Tg measurement and prompt a more cautious use of such data for clinical decision
making.
PMID- 9543129
TI - Randomized trial of effect of cyclical etidronate in the prevention of
corticosteroid-induced bone loss. Ciblos Study Group.
AB - Osteoporosis is a well-recognized adverse effect of corticosteroid therapy. This
study aimed to investigate the effect of etidronate, intermittent cyclical
therapy, in the prevention of corticosteroid-induced bone loss. Patients with
various medical conditions starting high-dose corticosteroid therapy were
enrolled in the study. The treatment had to be expected to continue for at least
12 months with the initial 90 days at a mean daily dose of at least 7.5 mg of
prednisone, with subsequent treatment of at least 2.5 mg/day. One hundred
seventeen patients were randomly assigned oral etidronate 400 mg/day, or placebo,
for 14 days, followed by 76 days of oral calcium carbonate (500 mg elemental
calcium), cycled over 12 months. The primary outcome measure was the difference
in percent change from baseline in bone mineral density of the lumbar spine
between the groups at the end of year 1. Secondary measures included changes in
femur bone density and in biochemical markers of bone remodeling. The mean (+/-
SEM) lumbar spine bone density changed 0.30 +/- 0.61% and -2.79 +/- 0.63% in the
etidronate and placebo groups, respectively. The mean difference between groups
after 1 yr was 3.0 +/- 0.84% (P = 0.004). The changes in the femoral neck and
great trochanter were not different between the groups. There was a decrease in
pyridinium crosslinks, significant from baseline at both 6 and 12 months, in the
etidronate group. Osteocalcin increased in the placebo group, and difference
between groups was -25.07 +/- 14.89% (P = 0.032) and -34.68 +/- 19.77% (P =
0.051), at 6 and 12 months respectively. There was no significant difference
between the groups in number of adverse experiences, including gastrointestinal
disorders. Etidronate intermittent cyclical therapy prevents lumbar vertebral
bone loss in patients starting high-dose corticosteroid therapy.
PMID- 9543130
TI - Quality of life among formerly treated childhood-onset growth hormone-deficient
adults: a comparison with unaffected siblings.
AB - Several studies have investigated the quality of life (QOL) of GH-deficient (GHD)
adults who, as children, had been treated with GH. Variable findings are probably
related to sample heterogeneity and disparate research methodologies and designs,
particularly the choice of control or comparison groups. In addition to comparing
a relatively large sample to questionnaire norms, the present study is the first
to compare the QOL adjustment of GHD patients to that of same sex siblings. A
total of 140 former patients (76% of those eligible; mean age, 26 yr; n = 95
isolated GHD, n = 45 multiple pituitary hormone deficiencies; 117 males and 23
females) and 53 same sex siblings (84% participation), 18 yr and older,
participated in the telephone questionnaire survey. The majority of interviews
with GHD patients (78%) and siblings (87%) were conducted blind to the subject's
clinical status. Comparisons between GHD patients and norms for standardized
questionnaires indicated both better and worse functioning in several domains. In
contrast, very limited differences were detected between GHD cases and same sex
siblings. Isolated GHD patients were functioning better than those with multiple
pituitary hormone deficiencies, but the effect sizes of these differences in most
areas were relatively small. Adult height and degree of growth over the course of
GH therapy were generally unrelated to QOL outcomes. Findings from the present
study underscore the importance of selecting unbiased control/comparison groups
in evaluating psychological outcomes among GHD adults.
PMID- 9543131
TI - High prevalence of polycystic ovaries and associated clinical, endocrine, and
metabolic features in women with previous gestational diabetes mellitus.
AB - The prevalence of polycystic ovaries, according to ultrasonography, and
associated clinical, endocrine, and metabolic features were investigated in women
with previous gestational diabetes mellitus (GDM). Thirty-four women with GDM 3-5
yr before the investigation and 36 controls with uncomplicated pregnancies,
selected for similar age, parity, and date of delivery, were investigated. The
women with previous GDM showed a higher prevalence of polycystic ovaries [14 of
34 (41%) vs. 1 of 36 (3%); P < 0.0001], hirsutism (P < 0.01), irregular menstrual
cycles (P < 0.01), and a higher body mass index (BMI; P < 0.001) than the
controls. Five women (15%) with previous GDM had developed manifest diabetes
(excluded in comparisons of metabolic variables). After dividing the women with
previous GDM into subgroups according to ovarian appearance, the 2 subgroups
showed similar glucose tolerance and prevalence of diabetes, whereas the women
with polycystic ovaries were younger (mean +/- SD, 33.3 +/- 1.4 vs. 38.2 +/- 1.1;
P < 0.01), had higher truncal-abdominal/femoral fat ratio according to skin folds
(P < 0.05), had higher concentrations of androstenedione (P < 0.01) and
testosterone (P < 0.01), and had a higher LH/FSH ratio (P < 0.01), lower levels
of GH (P < 0.01), higher levels of triglycerides (P < 0.05) and cholesterol (P <
0.05) in very low density lipoprotein, all independent of age and BMI, and had a
higher prevalence of pregnancy-induced hypertension (50% vs. 15%; P < 0.05)
during the index pregnancy compared with the women with normal ovaries. The group
of women with GDM showed a lower early insulin release after glucose (i.v.
glucose tolerance test) for their degree of insulin resistance (euglycemic
hyperinsulinemic clamp) compared with controls (P < 0.05). In the two subgroups,
insulin sensitivity was lower in the polycystic ovaries group, independent of BMI
(P < 0.05), than in the group with normal ovaries. In conclusion,
ultrasonographic, clinical and endocrine signs of polycystic ovary syndrome were
much increased in women with a history of GDM. Compared with the women with
normal ovaries and previous GDM, those with polycystic ovaries formed a distinct
subgroup that may be more prone to develop various features of the insulin
resistance syndrome. Both groups showed a similarly disturbed balance between
beta-cell activity and insulin sensitivity, but in women with polycystic ovaries,
insulin resistance may be the dominant component.
PMID- 9543132
TI - Influence of exogenous atrial natriuretic peptide on the pituitary-adrenal
response to corticotropin-releasing hormone and vasopressin in healthy men.
AB - Atrial natriuretic peptide (ANP) has been considered a potential candidate
participating in the inhibitory control of pituitary-adrenal secretory activity.
Here, we investigated the influence of ANP, infused at two different doses and
over infusion intervals of two different durations, on the release of ACTH and
cortisol after stimulation with CRH and with combined administration of CRH and
vasopressin (VP). In young healthy men, three experiments were conducted. In Exp
I, ACTH/cortisol secretory responses to CRH (50 microg) were examined during and
after a 45-min period of ANP infusion at a rate of 4.4 microg/min (starting 15
min before CRH injection). In Exp II, ACTH/cortisol secretory responses to CRH
(50 microg) were examined during and after a 90-min infusion period of ANP
administered at rates of 4.4 and 8.8 microg/min. In Exp III, ANP was infused at a
rate of 4.4 microg/min over 90 min, but instead of CRH, a combined administration
of CRH (50 microg) and VP (0.5 IU infused within 5 min) was employed to stimulate
ACTH/cortisol release. ANP diminished pituitary-adrenal secretory responses
within the first hour after stimulation with exogenous secretagogues. Thereafter,
the effect of ANP turned in the opposite direction, with distinctly enhanced
concentrations of ACTH and cortisol during the third hour after stimulation. The
inhibitory effect of ANP during the first hour of the pituitary-adrenal response
was more pronounced on concentrations of cortisol than ACTH and was also more
pronounced after combined administration of CRH/VP than after stimulation with
CRH alone. Increasing the dose of ANP enhanced the late stimulatory effect on
ACTH/cortisol release, thereby terminating the early period of inhibited
ACTH/cortisol release more abruptly. The late stimulatory effect was enhanced
with prolonged infusion of ANP. In addition, it was associated with reduced
hematocrit, increased urine volumes collected, increased heart rate, and enhanced
plasma VP concentrations. Together, these changes suggest that the late
stimulatory effect of ANP on ACTH/cortisol release reflects an effect secondary
to its hypovolemic actions. This stimulatory effect originating from peripheral
systemic actions of ANP after exogenous administration appears to override a more
direct inhibitory action of the peptide on pituitary-adrenal secretory activity.
Therefore, we would expect that with localized release into portal hypophyseal
blood the inhibitory component of the action of ANP on pituitary-adrenal
secretory activity prevails.
PMID- 9543133
TI - Comparison of effects of tamoxifen and toremifene on bone biochemistry and bone
mineral density in postmenopausal breast cancer patients.
AB - Antiestrogens are used in the treatment, and sometimes even in the prophylaxis,
of breast cancer. Tamoxifen is the most commonly used antiestrogen, but
toremifene is gaining in popularity. We compared here the effects of tamoxifen
and toremifene on bone metabolism and density in 30 postmenopausal patients with
breast cancer, who were randomized to receive tamoxifen (20 mg/day, n = 16) or
toremifene (40 mg/day, n = 14) for 1 yr. Biochemical markers of bone resorption
[urinary hydroxyproline, serum cross-linked carboxyterminal telopeptide of type I
collagen, urinary cross-linked aminoterminal telopeptide of type I collagen
(NTx)] and bone formation [serum bone-specific alkaline phosphatase, osteocalcin,
and aminoterminal and carboxyterminal propeptide of type I procollagen] were
assessed before treatment and at 6 and 12 months of the antiestrogen regimen.
Bone mineral density (BMD) in the lumbar spine and proximal femur (neck,
trochanter, and Ward's triangle) was measured using dual-energy x-ray
absorptiometry before treatment and at 12 months of treatment. Urinary NTx
decreased after 6 months' use of tamoxifen (mean fall: 33%) and of toremifene
(mean fall: 16%). Use of tamoxifen was associated with a significant decrease in
osteocalcin (mean fall: 25%) and aminoterminal propeptide of type I procollagen
(mean fall: 22%), whereas toremifene failed to influence these markers. Tamoxifen
increased BMD, on average, by 2% in the lumbar spine, 1% in the femoral neck, and
5% in Ward's triangle. Toremifene failed to increase BMD at any site measured,
and in contrast, a slight trend toward a fall (-0.3 to -0.9%) in BMD was seen in
patients treated with toremifene. Falls in urinary NTx, from baseline to 6
months, correlated significantly with changes in the lumbar spine BMD (r = -0.57,
P = 0.0002) in the whole patient series. We conclude that tamoxifen (20 mg/day)
increases BMD in postmenopausal breast cancer patients, whereas toremifene (40
mg/day) merely prevents the increasing age-associated fall in BMD. More prolonged
studies on bone metabolism, comparing these two antiestrogens, are needed; but
even now, clinicians should be aware of these differences between tamoxifen and
toremifene.
PMID- 9543134
TI - A single midnight serum cortisol measurement distinguishes Cushing's syndrome
from pseudo-Cushing states.
AB - Cushing's syndrome (CS) may be difficult to distinguish from pseudo-Cushing
states (PCS) based on physical findings or urinary glucocorticoid excretion. As
the lack of diurnal variation in serum cortisol is characteristic of CS, we
studied whether diurnal cortisol determinations could discriminate CS from PCS.
Two hundred and sixty-three patients were evaluated: 240 had CS, and 23 had PCS.
Urine was collected for 24 h for measurement of cortisol and 17
hydroxycorticosteroids (17OHCS). Blood was drawn at 2300, 2330, 0000, 0030, and
0100 h and at 0600, 0630, 0700, 0730, and 0800 h the next morning for serum
cortisol determination. The main outcome measure was the sensitivity of these
parameters for the diagnosis of CS at 100% specificity. A midnight cortisol value
greater than 7.5 microg/dL correctly identified 225 of 234 patients with CS and
all PCS patients. This sensitivity (96%) was superior to that obtained for any
other measure, including urinary cortisol (45%), 17OHCS (22%), any other
individual cortisol time point (10-92%), the morning (23%) or the evening (93%)
cortisol mean, and the ratio (11%) of morning to evening values. We conclude that
at 100% specificity, a single serum cortisol value above 7.5 microg/dL at
midnight discriminates CS from PCS with higher sensitivity than 24-h urinary
cortisol or 17OHCS, or other individual or combined measures of serum cortisol.
PMID- 9543135
TI - Pharmacokinetics and pharmacodynamics of growth hormone-releasing peptide-2: a
phase I study in children.
AB - Administration of GH-releasing peptide-2 (GHRP-2) represents a potential mode of
therapy for children of short stature with inadequate secretion of GH. Requisite
information to determine the dosing route and frequency for GHRP-2 consists of
the pharmacokinetics (PK) and pharmacodynamics (PD) for this compound, neither of
which have been previously evaluated in children. The purpose of this study was
to characterize the PK and PD of GHRP-2 in children with short stature. Ten
prepubertal children (nine boys and one girl; 7.7 +/- 2.4 yr old) received a
single 1 microg/kg i.v. dose of GHRP-2 over 1 min, followed by repeated (n = 9)
blood sampling over 2 h. GHRP-2 and GH were quantitated by specific RIA methods.
PK parameters were calculated from curve fitting of GHRP-2 and GH vs. time data.
Posttreatment plasma GH concentrations (normalized for pretreatment values) were
used as the effect measurement. PD parameters were generated using the sigmoid
Emax model. Disposition of GHRP-2 best fit a biexponential function. GHRP-2 PK
parameters (mean +/- SD) were: alpha = 13.4 +/- 9.7 h(-1), beta = 1.3 +/- 0.3 h(
1), t(1/2beta) = 0.55 +/- 0.14 h, AUC(0-infinity) = 2.02 +/- 1.37 ng/mL x h, Cmax
= 7.4 +/- 3.8 ng/mL, plasma clearance = 0.66 +/- 0.32 L/h x kg, and apparent
volume of distribution = 0.32 +/- 0.14 L/kg. PK parameters for GH were:
appearance rate constant = 5.9 +/- 3.1 h(-1), elimination t(1/2) = 0.37 +/- 0.15
h, lag time = 0.05 +/- 0.01 h, Cmax = 50.7 +/- 17.2 ng/mL, Tmax = 0.42 +/- 0.16
h, and AUC(0-infinity) = 47.9 +/- 26.1 ng/mL x h. PD parameters for GHRP-2 were:
Ke0 = 1.13 +/- 0.94 h(-1), gamma = 13.15 +/- 9.44, E0 = 6.63 +/- 4.86 ng/mL (GH),
Emax = 67.5 +/- 23.5 ng/mL (GH), and EC50 = 1.09 +/- 0.59 ng/mL. We concluded
that 1) GHRP-2 produced a predictable and significant (i.e. compared to
pretreatment values) increase in plasma GH concentrations; 2) the PK-PD link
model enabled quantitative assessment of GHRP-2 modulation of serum GH levels;
and 3) definition of the EC50 for GHRP-2 will enable PD and PK evaluations of
extravascular dosing regimens for children.
PMID- 9543136
TI - Response to androgen treatment in a patient with partial androgen insensitivity
and a mutation in the deoxyribonucleic acid-binding domain of the androgen
receptor.
AB - Supplemental androgen therapy has enhanced virilization in only a few patients
with partial androgen insensitivity (PAIS). We herein report on virilization in a
patient with PAIS and a point mutation in the DNA-binding domain of the androgen
receptor. At the age of 19 yr, the patient sought medical attention because of
undervirilization. Endocrine findings were typical for androgen insensitivity,
but 5alpha-reductase activity and androgen binding characteristics in fibroblasts
cultured from genital skin were normal. In an attempt to improve virilization,
high dose testosterone enanthate treatment (250 mg by i.m. injection once a week)
was begun. After 3.5 yr of this treatment, marked promotion of virilization was
achieved, i.e. lowering of voice, male pattern secondary hair distribution,
marked growth of beard and coarse body hair, increase in phallic size, increase
in bone mineral density, and decrease in mammary gland size. In addition, serum
lipid levels were not affected. To our knowledge this is the first documentation
of successful treatment in a patient with PAIS and a point mutation in the DNA
binding domain of the androgen receptor.
PMID- 9543137
TI - Elevated connexin-43 expression in term human myometrium correlates with elevated
c-Jun expression and is independent of myometrial estrogen receptors.
AB - Just previous to the onset of parturition, a number of genes such as the one that
codes for connexin-43 (Cx43) gap junction protein are induced in the myometrium.
We have shown previously that activation of protein kinase C in human myometrial
cultured cells leads to an up-regulation of cx43 transcription through an
activating protein-1 element in the 5'-flanking promoter. Analyses were now
performed on extracts of term myometrial tissue to test for an association
between the up-regulation of cx43 expression and the expression of transcription
factors and steroid hormone receptors that might regulate cx43 expression at
term. Immunoblot analyses were performed on extracts of term myometrial tissue
from women receiving elective or indicated cesarean sections to test for an
association between the up-regulation of cx43 expression and the up-regulation of
expression of the transcription factors c-Jun, c-Fos, and Sp1, which have cognate
binding elements in the cx43 5'-flanking promoter. Immunoblot analysis,
immunohistochemistry, and receptor binding assays were also performed to analyze
the levels of progesterone receptors (PR) and estrogen receptors (ER) in the same
term myometrial tissue, and these were compared to the levels in nonpregnancy
myometrial tissue. The levels of PR were consistently 2- to 3-fold higher in term
myometrial tissue than in nonpregnancy values and did not fluctuate during the
menstrual cycle as did ER levels. Surprisingly, in term myometrium, ER was barely
detectable by immunoblot and had whole cell diffuse staining by
immunohistochemistry. In addition, very low levels of estrogen binding were
observed in the term myometrial tissue. Treatment of primary myometrial cultures
containing ER with estrogen for 3 or 48 h did not result in up-regulation of c
Jun or c-Fos proteins or in trans-activation from the proximal cx43 promoter with
the activating protein-1 element. In contrast, an activated form of c-Jun protein
was 10- to 18-fold higher in term myometrial tissue that also had elevated cx43
expression compared to c-Jun levels in term myometrial tissue with low cx43
expression. Likewise, c-Fos and Sp1 levels were 2-4 fold higher in term
myometrial tissue with elevated cx43 expression. Although c-Fos and Sp1 proteins
could be detected by immunoblot in myometrial tissue from nonpregnant women, c
Jun and Cx43 proteins could not. In summary, these results suggest that up
regulation of human myometrial cx43 gene expression at term involves induction of
primarily c-jun expression through a mechanism that does not directly involve
myometrial ER or the loss of PR. Peptide hormones that activate protein kinase
cascades, such as the protein kinase C cascade, may be important to signal the
onset of labor in humans.
PMID- 9543138
TI - Growth hormone (GH)-releasing peptide-6 requires endogenous hypothalamic GH
releasing hormone for maximal GH stimulation.
AB - GH-releasing peptide-6 (GHRP-6) is a potent GH secretagogue that releases GH by
uncertain mechanisms. To assess whether GHRH is required for GH release by GHRP-6
in humans, we used the specific antagonist to GHRH (N-Ac-Tyr1,D-Arg2)GHRH(1
29)NH2 (GHRH Ant). We have previously shown that GHRH-Ant (400 microg/kg) blocked
the GH response to 0.33 and 3.3 microg/kg boluses of GHRH by 95% and 81%,
respectively. Nine healthy men between the ages of 20 and 30 yr were studied on
two occasions. They received either saline or GHRH-Ant (400 microg/kg, i.v.) at
0840 h, followed by GHRP-6 (1 microg/kg, i.v. bolus) at 0900 h. Blood was sampled
every 10 min from 0800-1100 h. GH responses were measured as the maximal increase
over the baseline GH concentration and as the area under the curve. GHRH-Ant
eliminated most of the GH response to GHRP-6 [maximal increase over the baseline
GH concentration, 33.8 +/- 4.8 vs. 6.2 +/- 1.8 microg/L (mean +/- SEM; P <
0.0001); area under the curve, 1701 +/- 278 vs. 376 +/- 113 microg/min x L (P <
0.001)]. These data show that endogenous GHRH is necessary for most of the GH
response to GHRP-6 in humans.
PMID- 9543139
TI - 17Beta-hydroxysteroid dehydrogenase type 1 in normal breast tissue during the
menstrual cycle and hormonal contraception.
AB - Our purpose was to assess 17beta-hydroxysteroid dehydrogenase (17HSD) type 1
protein expression in normal breast tissue during the menstrual cycle and
hormonal contraception. We analyzed 17HSD type 1 protein expression by
immunohistochemistry during the regular menstrual cycle (n = 12) and hormonal
contraception (n = 7) in women undergoing reduction mammoplasty. 17HSD type 1
protein was detected in normal breast epithelial cells throughout the menstrual
cycle and in all women using hormonal contraception. Mean 17HSD type 1 staining
intensity was higher in alveolar epithelial cells in women using hormonal
contraception (2.14) than in untreated women (1.25; P < 0.04). For ducts, this
difference approached significance (2.29 vs. 1.41; P = 0.06). There was a
negative correlation between serum estradiol (E2) levels and 17HSD type 1 protein
expression for both alveolar (r(s) = -0.68; P = 0.004) and ductal (r(s) = -0.75;
P = 0.002) breast epithelial cells. Enhanced 17HSD type 1 protein expression
might increase the conversion to E2 in normal breast tissue during hormonal
contraception. The negative correlation between serum E2 levels and 17HSD type 1
suggests this enzyme to be one of the regulatory mechanisms of intratissue E2
concentration in normal breast tissue.
PMID- 9543140
TI - Expression and secretion of inhibin and activin in normal and neoplastic uterine
tissues. High levels of serum activin A in women with endometrial and cervical
carcinoma.
AB - Inhibins and activins are growth factors belonging to the transforming growth
factor-beta) family and are known to influence cell proliferation and
differentiation. Because transforming growth factor-beta is involved in
physiological and tumoral changes of uterine tissues, the present study aimed to
evaluate whether human normal and neoplastic endometrial and cervical epithelial
cells express and secrete inhibin A, inhibin B, and activin A. To test this
hypothesis, different approaches were used. By RT-PCR, the expression of specific
messenger RNAs (mRNAs) for the inhibin alpha, activin betaA and betaB subunits,
and activin receptor type II and type IIB was investigated: 1) in primary
cultures of endometrial (stroma and epithelium) or cervical (epithelium) cells
from healthy women; and 2) in specimens of endometrial or cervical carcinoma. To
demonstrate a possible secretion of the proteins, dimeric inhibin A, inhibin B,
and activin A were measured in culture medium of normal epithelial or stromal
endometrial cells and in uterine washing fluid of healthy women or patients with
endometrial adenocarcinoma. Levels of the proteins were also measured in serum of
women with endometrial or cervical carcinoma. Cultured endometrial stromal or
epithelial cells and epithelial cervical cells expressed inhibin alpha, activin
betaA and betaB, and activin receptor type II and type IIB mRNAs. The same
finding was obtained in specimens of endometrial or cervical carcinomas. Dimeric
inhibin A, inhibin B, and activin A were measured in culture medium of both
endometrial and cervical cells. In particular, resulting activin A levels were
significantly higher in epithelial than in stromal cultured endometrial cells (P
< 0.01). Dimeric proteins were also detected in the washing fluid of the uterine
cavities of healthy women (controls) and with endometrial adenocarcinoma, in
which higher activin A levels were found (P < 0.01 vs. controls). Women with
endometrial carcinoma showed serum activin A levels significantly higher than
healthy controls (P < 0.01), which significantly decreased after surgical removal
of endometrial or cervical tumors (P < 0.01). The present study, for the first
time, showed that inhibin A, inhibin B, and activin A, as well as activin
receptors, are expressed in normal and neoplastic human uterine tissues. A
secretion of activin A from tumoral cells into systemic circulation is suggested
by the observation that the high levels in serum of patients with endometrial or
cervical carcinoma decreased after the surgical removal of the tumor.
PMID- 9543141
TI - Interleukin-8 induces proliferation of endometrial stromal cells: a potential
autocrine growth factor.
AB - Proliferation of endometrium is dependent on sex steroid hormones, but specific
growth factors are likely to play an important role in regulating this process. A
number of cytokines and growth factors are synthesized in the endometrium in
response to sex steroid hormones and act to regulate endometrial function.
Endometrial cells produce interleukin-8 (IL-8) both in vivo and in vitro. We
hypothesized that IL-8, a neutrophil chemoattractant/activating factor and a
potent angiogenic agent that has been shown to stimulate growth in other cell
types, may directly stimulate proliferation of endometrial cells. We first
investigated the effect of IL-8 and mouse antihuman-IL-8 neutralizing antibody on
endometrial stromal cell proliferation using both a colorimetric assay and
thymidine uptake. We then investigated the modulation of endometrial stromal cell
IL-8 production and proliferation by antisense oligonucleotides specific for IL
8. There was a concentration-dependent increase of cell proliferation with IL-8
(2-fold at 1 ng/mL; P < 0.01 between control and concentrations above 0.01 ng/mL)
and a concentration-dependent inhibition of cell proliferation with anti-IL-8
antibody (to 30% of the control at 1 microg/mL; P < 0.01 between control and
concentrations above 0.1 microg/mL). IL-8 antisense oligonucleotide treatment
decreased IL-8 production by endometrial stromal cells in culture as well as cell
proliferation when it is compared with scrambled (nonsense) oligonucleotide
treatment (P < 0.01). Addition of IL-8 (1 ng/mL) reversed the proliferation
inhibitory effect of IL-8 antisense oligonucleotides. We propose that IL-8 may
act as an autocrine growth factor in the endometrium, and suggest that it may
also play a role in the pathogenesis of endometriosis.
PMID- 9543142
TI - No effect of growth hormone on serum insulin-like growth factor binding protein-3
proteolysis.
AB - Increased proteolysis of insulin-like growth factor binding protein (IGFBP)-3 is
seen in several pathophysiological conditions and may represent an important
mechanism for the regulation of insulin-like growth factor bioavailability. It
has previously been suggested that proteolysis of IGFBP-3 is dependent on the GH
status. To investigate this, IGFBP-3 proteolysis was measured in three groups of
subjects: 1) GH-deficient patients before and after GH replacement (n = 14); 2)
healthy subjects before and after 14 days of GH administration (n = 7); and 3)
acromegalic patients before and after treatment with a long-acting SRIH analogue
(octreotide; n = 14). In vivo IGFBP-3 proteolysis was investigated by Western
immunoblotting. No difference was detected in pretreatment samples, and GH
treatment in GH-deficient subjects or octreotide treatment in acromegalic
subjects had no impact on in vivo proteolysis. In contrast, GH administration to
healthy subjects caused a 21% increase in in vivo proteolysis (P = 0.0008). In
vitro IGFBP-3 proteolysis was investigated by incubation of serum with 125I
rhIGFBP-3, followed by SDS-PAGE. In pretreatment samples, the percentage of
proteolyzed 125I-rhIGFBP-3 was 13 +/- 1% (acromegalic subjects), 11 +/- 1%
(healthy subjects), and 9 +/- 1% (GH-deficient subjects) (P < 0.009, GH-deficient
vs. acromegalic subjects). Treatment had no effect on in vitro proteolysis. We
conclude that GH status has no major impact on IGFBP-3 protease activity in
serum.
PMID- 9543143
TI - How much insulin-like growth factor I (IGF-I) circulates? Impact of
standardization on IGF-I assay accuracy.
AB - There is a significant systematic difference between the normal range obtained
from ethylenediamine tetraacetate plasma samples using the Genentech total
insulin-like growth factor I (IGF-I) RIA and normal ranges for other total IGF-I
RIAs. To determine whether the quality of the assay standard was the cause of
this systematic difference, we analyzed commercially available preparations of
recombinant human IGF-I (rhIGF-I) typical of those used as IGF-I immunoassay
standards along with our own well characterized rhIGF-I assay standard. For the
commercial standards, high performance liquid chromatography-derived purities
were low, and some vendor-assigned protein concentrations were inconsistent with
values from quantitative amino acid analysis. The Genentech rhIGF-I assay
standard was highly pure and quantitatively correct. However, the poor quality of
some commercial rhIGF-I preparations was not the primary reason for the
systematic discrepancy between the Genentech total IGF-I RIA normal range and
most other normal ranges. Most assays for total IGF-I are calibrated against the
WHO International Reference Reagent (IRR) for IGF-I Immunoassays (87/518). The
Genentech total IGF-I RIA is not calibrated against WHO IRR 87/518. The protein
content assigned to WHO IRR 87/518 was a consensus value from a multicenter
collaborative study. Physicochemical analyses showed that WHO IRR 87/518 is Met(
1)-IGF-I of low purity (44%), and that the assigned protein content is higher
than the value determined by quantitative amino acid analysis. Thus, assays that
are calibrated against WHO IRR 87/518 will report total IGF-I concentrations in
excess of actual values. We believe that calibration against WHO IRR 87/518 is
the cause of the systematic discrepancy between the Genentech IGF-I assay normal
range and most other normal ranges, and that much of the plasma IGF-I
concentration data in the literature are of questionable accuracy.
PMID- 9543144
TI - The modulation of the human sodium iodide symporter activity by Graves' disease
sera.
AB - The transport of iodide into the thyroid, catalyzed by the Na+/I- symporter
(NIS), is the initial and rate-limiting step in the formation of thyroid
hormones. To study the basic characteristics of the human (h) NIS, we have
established a Chinese hamster ovary cell line stably expressing the hNIS (CHO
NIS9). In agreement with previous work on the rat NIS, iodide uptake in these
cells was initiated within 2 min of the addition of 131I, reaching a plateau
after 30 min. Both perchlorate and thiocyanate inhibited iodide uptake in a dose
dependent manner, with inhibition evident at concentrations of 0.01 and 0.1
micromol/L, respectively, and reaching complete inhibition at 20 micromol/L and
500 micromol/L, respectively. Ouabain, which blocks the activity of the Na+/K+
adenosine triphosphatase, also inhibited iodide uptake in a dose-dependent
manner, starting at concentrations of 100 micromol/L and reaching maximum
inhibition at 1600 micromol/L, indicating that iodide uptake in these cells is
sodium dependent. CHO-NIS9 cells were further used to study 88 sera from patients
with Graves' disease, for iodide uptake inhibitory activity, which were compared
with sera from 31 controls. Significant iodide uptake inhibition was taken as any
inhibition in excess of the mean + 3 SD of the results with the control sera. On
this basis, 27 (30.7%) of the Graves' sera, but none of the controls, inhibited
iodide uptake in CHO-NIS9. IgGs from these patients also inhibited iodide uptake,
indicating that this inhibitory activity was antibody mediated. In summary, we
have established a CHO cell line stably expressing the hNIS and shown that
antibodies in GD sera can inhibit iodide uptake in these cells. This further
emphasizes the role of NIS as a novel autoantigen in thyroid immunity.
PMID- 9543145
TI - Soluble intercellular adhesion molecule-1 (sICAM-1) concentrations in Graves'
disease patients followed up for development of ophthalmopathy.
AB - It is commonly recognized that a few patients with Graves' disease (GD) develop
an overt ophthalmopathy, although most of them show subclinical extraocular
muscle enlargement by appropriate imaging techniques. At present, it is not
possible to identify the subgroup of GD patients with subclinical retroorbital
connective involvement. Recently, it has been shown that increase of soluble
intercellular adhesion molecule-1 (sICAM-1) serum levels is correlated to
clinical activity score in active Graves' ophthalmopathy (GO) patients with or
without hyperthyroidism, suggesting that sICAM-1 serum values could reflect the
degree of ocular inflammatory activity. The aim of this longitudinal study was to
evaluate sICAM-1 serum levels in GD patients without clinical ophthalmopathy and
to assess their possible relationship with occurrence of GO. We measured sICAM-1
serum levels in 103 initially hyperthyroid GD patients without clinical
ophthalmopathy and in 100 healthy subjects. All patients were treated with
methimazole for 2 yr. Sera were collected from all patients before treatment and
then monthly for the first 6 months of therapy, every 2 months in the following 6
months, and finally at the end of the follow-up study. Patients developing GO
were excluded from the follow-up at the onset of ophthalmopathy. During the
follow-up 17 GD patients (16.5%, group 1) developed overt eye involvement (14 as
active inflammatory ophthalmopathy and 3 as ophthalmopathy without clinical
retroorbital connective inflammation) and 86 (83.5%, group 2) did not. At start
of the study, the mean of sICAM-1 serum concentrations did not differ
significantly between the 2 groups, but it was significantly higher than in
controls in both groups. No significant correlation between serum sICAM-1
concentrations and free thyroid hormone levels was found in the 2 groups of
patients. During the follow-up study, a further increase of sICAM-1 serum levels
was observed in 12 of the 14 patients (85.7%) of group 1 who developed active
inflammatory ophthalmopathy not only at the onset but also before clinical GO
appearance. On the contrary, the 3 patients of group 1 that developed
ophthalmopathy without clinical retroorbital inflammation did not show any
further increase of sICAM-1 levels at every time of follow-up in comparison with
the starting values, even if their sICAM-1 levels were always higher than in
normal controls. Finally, group 2 patients showed significantly decreased sICAM-1
levels throughout the follow-up period when compared with the starting values,
although they were still significantly higher than in controls. These results
indicate that a further increase of sICAM-1 serum levels before the onset of
clinical ophthalmopathy may be a marker of subclinical retroorbital connective
inflammation in GD patients. Therefore, our study suggests that serial
determinations of sICAM-1 serum levels could help to identify and trace at the
right time those GD patients prone to developing active inflammatory
ophthalmopathy.
PMID- 9543146
TI - Regulation of the glycosylated beta-lactoglobulin homolog, glycodelin [placental
protein 14:(PP14)] in the baboon (Papio anubis) uterus.
AB - In vitro studies indicate that glycodelin (PP14) synthesis by the human
endometrium increases dramatically at the time of implantation and early
pregnancy. It has been postulated that this protein may have an immunosuppressive
function. Due to the limitations associated with in vivo studies in the human,
this study was undertaken to study the regulation of the baboon glycodelin
homolog in vivo during the menstrual cycle and early pregnancy. In nonpregnant
baboons, between days 10-12 postovulation (n = 3) the mid and apical regions of
the glandular epithelium showed a distinct punctate staining pattern, which
increased between days 12-18 of pregnancy (n = 3). Between days 25-60 of
pregnancy, staining intensity in the glandular epithelium decreased. The decrease
was more apparent at the implantation site compared with the nonimplantation
site. The immunostaining correlated with the synthesis of radiolabeled baboon
glycodelin in explant culture. Northern blot analysis demonstrated two messenger
RNA (mRNA) transcripts [1.0 and 1.7 kilobases (kb)] in the baboon uterus compared
with a single 1.0-kb transcript in the human, and mRNA expression was consistent
with protein localization and synthesis. The protein and mRNA expression was
consistently higher in the deeper glands of the functionalis and basalis during
early pregnancy. Because the increased expression of glycodelin in the baboon
endometrium coincided with peak levels of CG, a simulated pregnant baboon model
was used to confirm hormonal regulation. Exogenous human CG (hCG) followed by
estrogen and progesterone treatment in intact and ovariectomized baboons up
regulated glycodelin expression between days 18-25 postovulation (n = 10). By day
32 postovulation (n = 3), glycodelin synthesis decreased. Estrogen and
progesterone treatment in the absence of exogenous hCG did not result in an
increase of glycodelin synthesis. Analysis of uterine flushings from hCG-treated
animals revealed that a minimum of 7 days of hCG treatment was required for
glycodelin to be detectable in the uterine lumen. These studies indicate that a
posttranslationally modified glycodelin homolog is synthesized by the baboon
uterus during early pregnancy and appears to be regulated directly by CG. This
pattern of synthesis is comparable with that observed with in vitro studies in
the human. Because glycodelin expression is associated with CG secretion, we
suggest that this protein may have a functional role during implantation in the
primate. Thus, the baboon may serve as a nonhuman primate model to elucidate the
function of this protein in vivo.
PMID- 9543147
TI - Effect of glucose on production and release of proinsulin conversion products by
cultured human islets.
AB - Isolated human islets were examined for the rates of conversion and release of
newly formed (pro)insulin-like peptides. The rate of proinsulin (PI) conversion
was 2-fold slower in human beta-cells (t(1/2) = 50 min) than in rat beta-cells
(t(1/2) = 25 min). During the first hour following labeling of newly synthesized
proteins, PI represented the main newly formed hormonal peptide in the medium;
its release was stimulated 2-fold over the basal level by 20 mmol/L glucose.
During the second hour, newly synthesized hormone was mainly released as insulin,
with 10- to 20-fold higher rates at 20 mmol/L glucose. Prolonged preculture of
the islets at 20 mmol/L glucose did not delay PI conversion, but markedly
increased the release of newly formed PI, des(31,32)-PI, and insulin at both low
and high glucose levels. Our data demonstrate that 1) the release of PI provides
an extracellular index for the hormone biosynthetic activity of human beta-cells;
2) an acute rise in glucose exerts a stronger amplification of the release of
converted hormone than in that of nonconverted hormone; and 3) prolonged exposure
to high glucose levels results in an elevated basal release of converted and
nonconverted PI; this elevation is not associated with a delay in PI conversion,
but is attributed to the hyperactivated state of the human beta-cell population,
which was recently found to be responsible for an elevation in basal rates of
hormone synthesis. These in vitro observations on human beta-cells provide a
possible explanation for the altered circulating (pro)insulin levels measured in
nondiabetic and noninsulin-dependent diabetic subjects.
PMID- 9543148
TI - Expression of c-kit messenger ribonucleic acid in human oocyte and presence of
soluble c-kit in follicular fluid.
AB - The c-kit protooncogene receptor and its ligand stem cell factor (SCF) regulate
the proliferation and survival of germ cells as well as hematopoietic cells and
melanocytes. In adult rodent ovary, c-kit and SCF play important roles in
follicular development. However, little information about c-kit in the human
ovary is available. In this study, we examined the expressions of c-kit messenger
ribonucleic acid (mRNA) and c-kit protein in human oocytes, granulosa cells, and
follicular fluid obtained from the women who underwent in vitro fertilization or
laparoscopic examination. Expression of c-kit mRNA was detected by RT-PCR in the
oocytes and granulosa cells. Western blot analysis showed the presence of soluble
c-kit protein in the follicular fluid, and lower levels of c-kit protein were
detected in the granulosa cells and the supernatant of granulosa cell cultures.
The concentration of soluble c-kit in follicular fluid measured by enzyme-linked
immunosorbent assay showed significant correlation with fluid volume and
follicular fluid concentrations of estradiol, testosterone, and androstenedione.
In summary, we found for the first time the presence of c-kit mRNA and soluble c
kit protein in human oocytes and follicular fluid. The results suggested that in
human ovary, c-kit may play an important role in follicular development.
PMID- 9543149
TI - Ontogeny of leptin in human fetuses and newborns: effect of intrauterine growth
retardation on serum leptin concentrations.
AB - The aim of this study was to investigate the ontogeny of serum leptin
concentrations during the second half of gestation and at birth in small for
gestational age and normal fetuses and newborns. Serum leptin concentrations were
measured in arterial cord blood of fetuses (n = 79) and newborns (n = 132), with
or without intrauterine growth retardation, at 18-42 weeks gestation. Serum
leptin was detectable in fetal cord blood in all subjects as early as 18 weeks
gestation. Leptin levels dramatically increased after 34 weeks gestation. In
newborns, serum leptin concentrations were positively correlated with body weight
(P < 0.001) and body mass index (P < 0.001). Newborns with intrauterine growth
retardation had significantly lower serum leptin values (P < 0.001) than those
with normal growth, and leptin levels were only positively correlated with body
mass index (P < 0.001). These results suggest that the development of adipose
tissue and the accumulation of fat mass are the major determinants of fetal and
neonatal serum leptin levels. In addition, a gender difference, with higher
leptin concentrations in female fetuses, was observed during the last weeks of
gestation and was confirmed at birth regardless of growth status, suggesting that
a sexual dimorphism already exists in utero.
PMID- 9543150
TI - The daily cortisol production reinvestigated in healthy men. The serum and
urinary cortisol production rates are not significantly different.
AB - We have measured the urinary cortisol production rate (uCPR) simultaneously with
the serum cortisol production rate (sCPR) in four healthy men within a period of
3 days. uCPR, determined by isotope dilution of 11-oxoetiocholanolone was
compared with sCPR, which was measured in three different ways (a, b, c). Blood
was sampled at 10-min intervals for 24 h, and deconvolution analysis was applied
to the cortisol concentrations. The daily serum cortisol production per liter,
multiplied by the distribution volume yielded sCPR. The measurement methods are
characterized as follows: a) the secretion and elimination terms were free; b)
like method a, but with the input of the rate constants alpha and beta into the
elimination function; c) the average 24-h cortisol concentration was multiplied
by the metabolic clearance rate. uCPR was 25.4 +/- 4.7 [range: 21.3-31.4]
micromol/(m2 x day), sCPR (method a) was 28.8 +/- 4.5 [range: 23.5-34.3]
micromol/(m2 x day), sCPR (method b) was 27.9 +/- 8.1 [range: 18.5-37.7]
micromol/(m2 x day), and sCPR (method c) was 29.3 +/- 4.8 [range: 22.7-33.2]
micromol/(m2 x day). uCPR did not significantly differ from each of the 3 sCPR
values (P > 0.30; > 0.46; and > 0.06, respectively). The patterns of the cortisol
secretory rates in the present and previous studies do not necessarily represent
the physiological process of the secretory bursts. We conclude that the estimated
CPR, being 25-30 micromol/(m2 x day) [9-11 mg/(m2 x day)], can serve as a
guideline for glucocorticoid replacement dose and that the urinary route to
measure CPR is preferred because of its relative ease.
PMID- 9543151
TI - Suppression of cell proliferation and induction of apoptosis in uterine leiomyoma
by gonadotropin-releasing hormone agonist (leuprolide acetate).
AB - Cell proliferation and apoptosis in uterine leiomyoma were investigated during
therapy with GnRH agonist (GnRHa). Patients with uterine leiomyomas were injected
with 3.75 mg GnRHa (depot leuprolide acetate) at intervals of 4 weeks and
underwent hysterectomy or myomectomy at the 2nd, 4th, 8th, 12th, or 16th week of
GnRHa therapy. Tissue sections of leiomyomas from these patients and from control
patients (control patients received no GnRHa therapy) were stained with the Ki-67
antibody or by an in situ DNA 3'-end labeling method, and numbers of Ki-67
immunostained cells and DNA 3'-end-labeled cells per cm2 were examined as indices
of cell proliferation and apoptosis, respectively. The number of Ki-67
immunostained cells/cm2 in leiomyomas at the 2nd week of the GnRHa therapy was
comparable with that of control patients. However, it decreased to a level less
than one forth that of control patients at the 4th week, and it remained at
similar low levels at the 8th, 12th, and 16th week. The number of DNA 3'-end
labeled cells/cm2 in leiomyomas of control patients and in leiomyomas at the 2nd,
8th, 12th, and 16th weeks of GnRHa therapy were at low levels but, at the 4th
week, was at an extremely high level (about 5 times more than that of control
patients). The present results indicate that GnRHa therapy suppresses cell
proliferation and causes a transient increase in apoptosis in uterine leiomyomas.
PMID- 9543152
TI - Developmentally regulated responses of human granulosa cells to insulin-like
growth factors (IGFs): IGF-I and IGF-II action mediated via the type-I IGF
receptor.
AB - In experimental animal models, insulin-like growth factors (IGFs) have been found
to be more potent stimulators of ovarian function than insulin. In human theca
cells, however, insulin, IGF-I, and IGF-II have similar effects on androgen
production. The relative effects of insulin and IGFs on human granulosa cell
steroidogenesis is unknown. Furthermore, it is unclear whether effects of IGF-II
on steroidogenesis are mediated by the type-I or type-II IGF receptor. The
effects of insulin, IGF-I, and IGF-II on human granulosa cell steroidogenesis
were compared in vitro. As expected, insulin, IGF-I, and IGF-II enhanced
steroidogenesis. Previously, IGF-II has been shown to enhance granulosa cell
steroid production after insulin preincubation. In this study, an effect of IGF
II, independent of insulin priming, also was observed. In granulosa cell cultures
from small antral follicles (< or = 13 mm), insulin and IGF-I stimulated steroid
production to a similar degree, whereas IGF-II was less effective. In contrast,
IGFs were more effective than insulin (IGF-I > IGF-II > insulin) in granulosa
cells isolated from preovulatory follicles. IGF-I and IGF-II actions were
mediated via the type-1 IGF receptor. The increased responsiveness of mature
granulosa cells to IGFs may be an important mechanism by which granulosa cells
increase their steroidogenic output in the preovulatory follicle.
PMID- 9543153
TI - Pima Indian males have lower beta-adrenergic sensitivity than Caucasian males.
AB - The sympathetic nervous system controls cardiovascular homeostasis and regulates
energy metabolism. Pima Indians, a population with a low prevalence of
hypertension and a high prevalence of obesity, have low sympathetic nervous
activity, compared with Caucasians. Preliminary findings suggest that they may
also have a low beta-adrenergic sensitivity. We studied beta-adrenergic
sensitivity in 87 nondiabetic normotensive individuals [52 Pima Indians (35
males/17 females) and 35 Caucasians (24 males/11 females)], matched for age and
body weight. Chronotropic sensitivity to beta-adrenergic stimulation was assessed
by the dose of isoproterenol necessary to increase heart rate by 25 beats per
minute [chronotropic dose-25 (CD25)]. Despite a similar basal heart rate and
arterial blood pressure, Pimas tended to have lower beta-adrenergic sensitivity
than Caucasians (CD25 = 2.37 +/- 2.27 vs. 1.57 +/- 1.38 microg, P = 0.07; mean +/
SD). This difference was significant in males (CD25 = 3.03 +/- 2.39 vs. 1.85 +/-
1.56 microg, P = 0.02) but not in females (CD25 = 1.01 +/- 1.17 vs. 0.96 +/- 0.61
microg, P = 0.99). In males only, CD25 was positively correlated to percent body
fat (r = 0.36, P < 0.01). After adjustment for percent body fat, beta-adrenergic
sensitivity was still significantly lower in Pima than in Caucasian males (CD25 =
3.44 +/- 2.24 vs. 2.57 +/- 1.60 microg, P = 0.05). In conclusion, our data
suggest that increased adiposity is accompanied by decreased beta-adrenergic
sensitivity in males only. However, at each level of adiposity, Pima Indian males
have lower beta-adrenergic sensitivity than Caucasian males. In combination with
a low sympathetic nervous system activity, a reduced beta-adrenergic sensitivity
may contribute to the low prevalence of hypertension and the high prevalence of
obesity observed in Pima Indians.
PMID- 9543154
TI - Proteins in the heat shock-70 family specifically bind 25-hydroxyvitamin D3 and
17beta-estradiol.
AB - Most New World primates evolved to express a form of compensated resistance to
steroid hormones from the gonads and adrenal glands as well as to the
hydroxylated vitamin D3 prohormone, 25-hydroxyvitamin D3 (25OHD3), and the
vitamin D hormone 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] originating from the
liver and kidney, respectively. We recently demonstrated that this form of
resistance is associated with the overexpression of a novel member of the 70-kDa
heat shock protein (hsp-70) molecular chaperone family, which we have termed the
intracellular vitamin D binding protein (IDBP). In the current report we more
closely examine the ligand-binding capability of purified IDBP and two other
mammalian hsp-70 family members, heat-inducible (hsp-70) and constitutively
expressed (hsc-70) hsp-70 proteins. Purified IDBP, hsp-70, and hsc-70 all bound
25OHD3 with relatively high affinity; the mean Kd for 25OHD3 ranged from 0.5-2.2
nmol/L (rank order: IDBP > or = hsp-70 > or = hsc-70). By Scatchard analysis,
high affinity, specific binding of 1,25-(OH)2D3 was not reproducibly observed for
any of the three members of the hsp-70 family. Unlike purified IDBP, hsc-70 and
hsp-70 were also competent binders of the gonadal steroid 17beta-estradiol (mean
Kd for 25OHD3, 2.5 and 6.6 nmol/L by hsc-70 and hsp-70, respectively), but not of
two other gonadal hormones, progesterone and testosterone. These data suggest
that IDBP is relatively specific for 25OHD3 and that additional hsp-70-like
binding proteins are present in unpurified New World primate cell extracts that
are specific for 1-hydroxylated vitamin D metabolites as well as other gonadal
steroid hormones.
PMID- 9543155
TI - Detection of CD40 on human thyroid follicular cells: analysis of expression and
function.
AB - Thyroid follicular cells (TFC) are a common target of autoimmune attack, but the
role they play in inciting and maintaining this attack is unclear. TFC express
cytokines, adhesion molecules, and class I and II major histocompatibility
complex molecules, but without additional signals that costimulate T cells, they
may down-regulate, rather than stimulate, T cell function. In this report, we
have investigated whether TFC can express the CD40 molecule, which plays a
crucial role in the reciprocal two-way communication between T and B cells. We
have shown by immunohistochemistry and flow cytometry that CD40 is expressed by
TFC in vivo and in vitro in both autoimmune and nonautoimmune glands. CD40
expression was up-regulated by interleukin-1alpha and interferon-gamma, but not
by TSH. Although there was no significant effect of CD40 ligation on cAMP
synthesis or [3H]thymidine incorporation, there was a significant increase in
interleukin-6 release by TFC. Thus, although TFC do not express members of the B7
family of T cell costimulators, they do express CD40, indicating the possibility
of mutually stimulatory T cell-TFC interaction. This has important implications,
both for TFC synthesis of immunological mediators and for the biasing of T cell
behavior toward a T helper 2-type phenotype.
PMID- 9543156
TI - Measurement of leukemia inhibitory factor in biological fluids by
radioimmunoassay.
AB - Leukemia inhibitory factor (LIF) exhibits multiple biological activities in
various tissues, and we have shown that LIF activates POMC gene transcription in
response to immune signals. As higher serum levels of LIF have been reported in
septicemia, we measured LIF values in biological fluids by RIA. Immunoreactive
LIF was detected in 303 of 428 human serum samples. Circulating LIF detection
rates were 69% in acute inflammatory diseases, 83% in chronic inflammatory
diseases, 61% in noninflammatory diseases, and 90% in cancer patients. Serum
concentrations of human LIF was higher in patients with inflammatory disease than
in noninflammatory disease (0.80 +/- 0.10 vs. 0.53 +/- 0.02 ng/mL; P < 0.05) or
in cancer patients (0.44 +/- 0.06; P < 0.05). Higher serum human LIF levels were
found in septicemia (0.78 +/- 0.14 ng/mL), pneumonia (0.80 +/- 0.10 ng/mL), acute
bronchitis (0.88 +/- 0.09 ng/mL), other infections (1.01 +/- 0.17 ng/mL), and
systemic lupus erythematosus (SLE; 0.79 +/- 0.06 ng/mL). In 7 septicemia
patients, Gram-negative infection was associated with higher LIF levels (1.06 +/-
0.16 ng/mL) than was Gram-positive infection (0.58 +/- 0.14 ng/mL). In patients
with acute inflammatory disease, serum LIF levels decreased within several days
after hospitalization. To test circulating mouse (m) LIF changes in response to
inflammatory stress, lipopolysaccharide (LPS) was injected ip to mice. LPS
increased serum mLIF values concordantly with ACTH levels. After i.p. injection
of 80 microg LPS, serum mLIF increased by 144% (P < 0.05), 173% (P < 0.05), and
134% at 30, 90, and 120 min respectively. In vitro, however, LPS did not increase
ACTH and mLIF secretion from dispersed mouse primary pituitary cells. These
results suggest that LIF is an important participant in the pathogenesis of the
acute inflammatory response. The elevated serum LIF levels observed in
inflammation do not appear to originate from the pituitary.
PMID- 9543157
TI - Stereological evaluation of human spermatogenesis after suppression by
testosterone treatment: heterogeneous pattern of spermatogenic impairment.
AB - Testosterone (T) treatment suppresses gonadotropin levels in normal men and is a
promising reversible contraceptive that induces azoospermia in approximately 70%
of subjects and oligospermia in the remainder; however, the basis of this
variable response is unclear. This study aimed to investigate this reported
variable response by examining the spermatogenic process and quantitating germ
cell number in men after T-induced gonadotropin withdrawal. Ten normal fertile
men (31-46 yr), already planning to undergo vasectomy, either received T
enanthate (200 mg, i.m., weekly) for 19-24 weeks (n = 5; TE group) or proceeded
directly to surgery (n = 5; controls), at which time a unilateral testicular
biopsy was taken, and germ cell numbers were estimated using the optical disector
stereological method. In response to TE treatment, serum T levels rose 2-fold,
and FSH/LH levels became undetectable. Sperm counts fell to azoospermia in 4 men
and to 21 million/mL in the fifth man. The mean number of type A spermatogonia
per 100 Sertoli cells was unchanged, but type B spermatogonia fell markedly to
10% of the control values, and later germ cell types decreased to 11-18% of the
control values. The pattern of germ cell suppression varied widely and showed no
relationship with sperm count or the time to azoospermia. Despite the presence of
elongated spermatids (1.4-20% of the control), four men remained azoospermic. Two
TE subjects with similar early germ cell complements and elongated spermatid
numbers had sperm counts of zero and 21 million/mL; the latter man demonstrated
marked variability in germ cell numbers between adjacent tubules. We conclude
that 1) the principal spermatogenic lesion in TE-treated men is the marked (90%)
inhibition of type A-->B spermatogonial maturation. Other sites are also
affected, particularly the release and/or survival of elongated spermatids during
transit; and 2) a steady state in germ cell number may not be established even
after 4-5 months of TE treatment. The findings suggest that TE treatment does not
adequately or consistently withdraw hormonal support for spermatogenesis, leading
to variable between- and within-individual patterns of germ cell suppression.
PMID- 9543158
TI - The follicle-stimulating hormone (FSH) threshold/window concept examined by
different interventions with exogenous FSH during the follicular phase of the
normal menstrual cycle: duration, rather than magnitude, of FSH increase affects
follicle development.
AB - According to the threshold concept, FSH concentrations need to surpass a distinct
level to stimulate ovarian follicle growth. The window concept stresses the
significance of a limited duration of elevated FSH levels above the threshold for
single dominant follicle selection. The aim of this study was to investigate
effects on follicle growth of increased FSH levels, differing in duration and
magnitude of elevation, during the follicular phase. Twenty-three normo-ovulatory
(cycle length, 26-31 days), young (age, 20-31 yr) women volunteered for this
study. In all subjects a series of daily transvaginal sonography scans of the
ovaries and blood sampling [for FSH and estradiol (E2) determinations] were
performed during two consecutive cycles. The first study cycle (control cycle)
started 10 days after urinary assessment of the LH surge in the preceding cycle
(DayLH) and was concluded on the day of ovulation assessed by transvaginal
sonography scans. The second series of daily monitoring (intervention cycle)
started 10 days after DayLH in the control cycle. After randomization, subjects
received either 375 IU urinary FSH, s.c., as a single injection on Day(LH+14)
(group A; n = 11) or 75 IU daily from Day(LH+19) until Day(LH+23) (group B; n =
12). In group A, FSH levels increased on the day after injection to a median
concentration of 10.1 IU/L, which was 1.9 times higher (P < 0.01) than levels on
matching days during the control cycle. Concentrations returned to basal levels 3
days after injection. In group B, a moderate elevation of FSH concentrations (15%
increase; P < 0.05) was observed compared to levels during the control cycle. In
group A, E2 concentrations increased (P = 0.03) 1 day after FSH injection and
returned to baseline levels within 2 days. In group B, E2 levels started to
increase after the first injection of FSH and remained significantly higher (P <
0.01) during the following 5 days compared to those on matching days in the
control cycle. Compared to matching days in the control cycle an increased number
of follicles 8-10 mm in size was found in group A (P < 0.01) during the period
from Day(LH+14) until Day(LH+19), without an increase in follicles 10 mm or
larger thereafter. In contrast, in group B, the numbers of both 8- to 10-mm and
10-mm or larger follicles were higher during the period from Day(LH+19) until
Day(LH+24) in group B (P = 0.02 and P < 0.01, respectively). Results from the
present study suggest that a brief, but distinct, elevation of FSH levels above
the threshold in the early follicular phase does not affect dominant follicle
development, although the number of small antral follicles did increase. In
contrast, a moderate, but continued, elevation of FSH levels during the mid to
late follicular phase (effectively preventing decremental FSH concentrations)
does interfere with single dominant follicle selection and induces ongoing growth
of multiple follicles. These findings substantiate the FSH window concept and
support the idea of enhanced sensitivity of more mature follicles for stimulation
by FSH. These results may provide the basis for further investigation regarding
ovulation induction treatment regimens with reduced complication rates due to
overstimulation.
PMID- 9543159
TI - Localization, characterization, and second messenger coupling of pituitary
adenylate cyclase-activating polypeptide receptors in the fetal human adrenal
gland during the second trimester of gestation.
AB - The distribution and pharmacological properties of pituitary adenylate cyclase
activating polypeptide (PACAP) receptors were studied in the fetal human adrenal
gland during the second trimester of gestation. Autoradiographic studies, using
[125I]PACAP27 as a radioligand, revealed that PACAP-binding sites are exclusively
located on chromaffin cells of adrenals from fetuses 14-20 weeks old. Biochemical
characterization of binding revealed the occurrence of a single class of PACAP
binding sites with a dissociation constant value of 0.32-0.74 nmol/L and a
binding capacity of 0.30-0.81 pmol/mg wet tissue. PACAP27 and PACAP38 were
equipotent in competing for [125I]PACAP27 binding (IC50 = 0.28-0.64 nmol/L and
0.15-0.81 nmol/L, respectively), and the Hill coefficients were close to 1. In
contrast, vasoactive intestinal polypeptide was much less efficient in displacing
the tracer (IC50 = 4-362 nmol/L), and the Hill coefficients were less than 0.6.
PACAP38 induced a dose-dependent increase in cAMP production in fetal human
adrenal cell suspension (ED50 = 0.07 +/- 0.02 nmol/L), as well as in cells
maintained in culture for 5 days (5.4 +/- 1.8 nmol/L). In contrast, PACAP38
induced a modest increase in inositol phosphate formation. These data indicate
that type I PACAP receptors are present in the early stages of the human medulla
organization during the process of migration of chromaffin cells from the
periphery to the central part of the gland. The present results suggest that
PACAP could be involved in the regulation of the human adrenochromaffin cells
during ontogenesis.
PMID- 9543160
TI - Evaluation of abdominal fat distribution in noninsulin-dependent diabetes
mellitus: relationship to insulin resistance.
AB - Accumulation of visceral adipose tissue is associated with metabolic
complications such as noninsulin-dependent diabetes mellitus. The aim of this
study was to evaluate the effect of abdominal adipose tissue on insulin
sensitivity in subjects with noninsulin-dependent diabetes mellitus (NIDDM).
Areas of abdominal fat were calculated from axial magnetic resonance images
obtained at the level of the umbilicus in 21 men with NIDDM [age, 45.6 +/- 8.3
(+/-SD) yr; body mass index, 29.3 +/- 4.5 kg/m(-2); total body fat (skinfold
thickness), 26.8 +/- 5.4%; waist to hip ratio, 0.97 +/- 0.07; duration of
diabetes, 59 +/- 47 months; hemoglobin A1c, 8.1 +/- 1.5%]. Insulin sensitivity
was evaluated by an insulin tolerance test. The areas of deep abdominal fat and
sc abdominal fat were, respectively, 135.3 +/- 55.1 and 211.8 +/- 99.1 cm2. The
blood glucose disappearance rate was 2.11 +/- 0.87%/min and was negatively
related to deep abdominal fat (r = 0.72; P = 0.0025). In contrast, areas of sc
abdominal fat, total body fat, body mass index, and waist to hip ratio were not
related to the blood glucose disappearance rate. Plasma triglyceride
concentrations averaged 1.8 +/- 0.8 mmol/L and were positively related to deep
abdominal fat (r = 0.69; P = 0.0018). We conclude that insulin sensitivity is
strongly related to visceral adipose tissue accumulation in NIDDM.
PMID- 9543162
TI - Human 17beta-hydroxysteroid dehydrogenase type 2 messenger ribonucleic acid
expression and localization in term placenta and in endometrium during the
menstrual cycle.
AB - According to the current hypothesis, 17beta-hydroxysteroid dehydrogenases
(17HSDs) regulate the extent of estrogen influence in the endometrium by
converting estradiol (E2) locally into a biologically less active sex steroid,
estrone (E1), and vice versa. Recently, we have shown that both 17HSD type 1 and
type 2 are expressed in the human endometrium, and in the present work, using in
situ hybridization, we show that 17HSD type 2 is localized in the glandular
epithelial cells as previously shown for the type 1 enzyme, but in contrast to
type 1, the expression of type 2 is highest at the end of the cycle. Hence, we
hypothesize that the differential expression of the two 17HSD enzymes, with
opposite activities in same cell types, could modulate intracellular E2
concentrations during the end of the luteal phase of the menstrual cycle. We
further analyzed the expression of 17HSD type 1 and type 2 mRNAs in term human
placenta. Expression of 17HSD type 1 mRNA was detected in the
syncytiotrophoblasts, and signals for type 2 mRNA were found inside the villi,
corresponding to cytotrophoblasts. The expression of 17HSD type 2 in the placenta
may serve to maintain the presence of inactive sex steroids and attenuate the
formation of biologically potent androgens and estrogens.
PMID- 9543161
TI - The use of a sensitive equilibrium dialysis method for the measurement of free
testosterone levels in healthy, cycling women and in human immunodeficiency virus
infected women.
AB - Measurements of total and free testosterone levels in women have lacked precision
and accuracy because of limited assay sensitivity. The paucity of normative data
on total and free testosterone levels in healthy women has confounded
interpretation of androgen levels in women with human immunodeficiency virus
(HIV) infection and other disease states. Therefore, the objectives of this study
were to develop sensitive assays for the measurement of the low total and free
testosterone levels in women to define the range for these hormones during the
normal menstrual cycle and assess the total and free testosterone levels in HIV
infected women. By using a larger volume of serum, increasing the incubation
time, and reducing the antibody concentration, the sensitivity of the total
testosterone assay was increased to 0.008 nmol/L, and that of the free
testosterone assay was increased to 2 pmol/L. The mean percent free testosterone
was 1.0 +/- 0.1% of the total testosterone. Serum total and free testosterone
levels in the follicular and luteal phases were not significantly different, but
both demonstrated a modest preovulatory increase, 3 days before the LH peak.
Serum total [0.50 +/- 0.32 (14.60 +/- 9.22) vs. 1.2 +/- 0.7 nmol/L (34.3 +/- 21.0
ng/dL); P < 0.0001] and free testosterone levels (5.56 +/- 2.70 (1.58 +/- 0.80)
vs. 12.8 +/- 5.5 pmol/L (3.4 +/- 1.7 pg/mL); P < 0.0001) were significantly lower
in HIV-infected women (n = 37) than in healthy women (n = 34). Serum total and
free testosterone levels were also significantly lower in HIV-infected women who
were menstruating normally. There were no significant differences in serum total
and free testosterone levels between those who had lost weight and those who had
not. Testosterone levels correlated inversely with plasma HIV ribonucleic acid
copy number. Serum FSH, but not LH, levels were significantly higher in HIV
infected women than in controls. Using assays with sufficient sensitivity, we
defined the range for total and free testosterone levels during the normal
menstrual cycle. Serum total and free testosterone levels are lower in HIV
infected women and correlate inversely with plasma HIV ribonucleic acid levels.
The hypothesis that androgen deficiency contributes to wasting in HIV-infected
women remains to be tested.
PMID- 9543163
TI - Immunohistochemical localization of type 1 11beta-hydroxysteroid dehydrogenase in
human tissues.
AB - Two isozymes of 11beta-hydroxysteroid dehydrogenase (11betaHSD) catalyze the
interconversion of hormonally active cortisol to inactive cortisone. Activity and
messenger ribonucleic acid studies indicate that type 1 11betaHSD (11betaHSD1) is
expressed in glucocorticoid target tissues such as liver, gonad, and cerebellum,
where it regulates the exposure of cortisol to glucocorticoid receptors. To
further understand the role of 11betaHSD1 in human tissues, we have studied the
localization of this isozyme using an antibody raised in sheep against amino
acids 19-33 of human 11betaHSD1. Western blot analyses indicated that the
immunopurified antibody recognized a band of approximately 34 kDa in human liver
and decidua. Immunoperoxidase studies on liver, adrenal, ovary, decidua, and
adipose tissue indicated positive cytoplasmic staining for 11betaHSD1. 11BetaHSD1
immunoreactivity was observed more intensely around the hepatic central vein,
with no staining around the portal vein, hepatic artery, or bile ducts. No
staining for 11betaHSD1 was observed in the adrenal medulla, but 11betaHSD1
immunoreactive protein was observed in all three zones of the adrenal cortex,
with the most intense staining in the zona reticularis > zona glomerulosa > zona
fasciculata. In the human ovary, immunoreactivity was observed in the developing
oocyte and the luteinized granulosa cells of the corpus luteum. No staining was
observed in granulosa cells, thecal cells, or ovarian stroma, which contrasted
with the marked expression of 11betaHSD2 in the granulosa cell layer. Sections of
human decidua showed high expression of 11betaHSD1 in decidual cells. In omental
adipose tissue, 11betaHSD1 immunoreactivity was observed in both stromal and
adipocyte cells. Immunohistochemical localization of 11betaHSD1 in human liver,
adrenal, ovary, decidua, and adipose tissue using this novel antiserum provides
us with a tool to investigate the role of this isozyme in modulating
glucocorticoid hormone action within these tissues.
PMID- 9543164
TI - Fibroblast growth factors 1 and 2 and fibroblast growth factor receptor 1 are
elevated in thyroid hyperplasia.
AB - We have previously reported increased expression of fibroblast growth factor (FGF
1 and FGF-2) in benign and malignant human thyroid neoplasia. To determine the
role of these factors in thyroid hyperplasia we have examined their expression in
multinodular goiter and compared findings with those in normal thyroid tissue.
Because the effects of FGF-1 and FGF-2 are predominantly mediated through the FGF
receptor-1 (FGFR-1), its expression has also been examined. Immunocytochemistry
was performed on sections from multinodular goiters (n = 18) and normal thyroid
(n = 7). Cytoplasmic staining for FGF-1, FGF-2, and FGFR-1 was scored on a scale
of 0 (no staining) to 3 (heavy staining) and expressed as a percentage of total
cells stained. Confocal microscopy of immunofluorescent staining for FGF-1, FGF
2, and FGFR-1 in sections of multinodular goiter (n = 3) and normal thyroid (n =
3) provided quantitation of immunostaining. FGF-1 expression was significantly
increased in multinodular goiter when compared with normal. A mean of 74% of
follicular cells in multinodular goiter compared with 9% of follicular cells in
normal thyroid expressed FGF-1 (P < 0.0001). When expression of FGF-2 was
examined, 77% of the follicular cells in multinodular goiter compared with 5% in
normal thyroids were immunopositive (P < 0.0001). Confocal microscopy revealed
that the intensity was 160 times greater in follicular cells in sections of
multinodular goiters when compared with normal. When expression of FGFR-1 was
analyzed, 89% of the follicular cells in multinodular goiter stained positively,
compared with 15% of follicular cells in sections of normal thyroid. Confocal
microscopy revealed a 6-fold increase in intensity of FGFR-1 expression in
follicular cells of multinodular goiter (P < 0.05). In addition, there was
significant nuclear expression of FGFR-1 in multinodular goiter contrasting with
negligible expression in normal thyroid. These data show that enhanced expression
of FGF-1, FGF-2, and FGFR-1 accompany thyroid hyperplasia and are not exclusively
associated with the neoplastic state. These factors may be involved in the
pathogenesis of uncontrolled thyroid growth observed in these conditions.
PMID- 9543165
TI - Corticotropin regulates vascular endothelial growth factor expression in human
fetal adrenal cortical cells.
AB - The human adrenal cortex has a complex vasculature that is essential for growth,
organ maintenance, and access of secreted hormones to the circulation. Growth and
function of the adrenal cortex are regulated by corticotropin (ACTH), the actions
of which are in part mediated by locally produced growth factors. As cortical
growth and vascularization must increase in a coordinated manner, we hypothesized
that ACTH also influences adrenal cortical angiogenesis by stimulating the local
expression of specific angiogenic factors. Vascular endothelial growth factor
(VEGF) is a potent endothelial cell-specific angiogenic peptide, the expression
of which has been detected in adrenal cortical cells. Therefore, we examined the
localization of VEGF expression in the midgestation (16-20 weeks) human fetal
adrenal cortex and determined whether VEGF expression and secretion by isolated
human fetal adrenal cortical cells are regulated by ACTH. By immunohistochemical
analysis, strong cytoplasmic staining for VEGF was detected in scattered clusters
of fetal zone (inner cortical compartment) cells. In contrast, cells in the
outer, definitive zone of the cortex stained only weakly for VEGF. The
predominant staining for VEGF in the fetal zone correlated with the extensive
vasculature of this zone as detected by immunohistochemical staining for von
Willebrand factor, which is specific for endothelial cells. In primary cultures
of human fetal adrenal cortical cells, ACTH (1 nmol/L) and forskolin (10
micromol/L) increased the abundance of messenger ribonucleic acid transcripts
encoding VEGF, as assessed by Northern and slot blot analyses. The stimulatory
effect of ACTH and forskolin on VEGF gene expression occurred within 2 h of
agonist exposure and persisted for at least 24 h. ACTH and forskolin also
increased VEGF protein secretion by fetal adrenal cortical cells, as assessed by
enzyme-linked immunosorbent assay for VEGF in fetal adrenal cortical cell
conditioned medium. A significant (P < 0.05) increase in VEGF secretion was
detected as early as 8 h after ACTH or forskolin treatment. By 24 h after the
addition of ACTH or forskolin, VEGF secreted from isolated human fetal adrenal
cells was increased 5- to 6-fold. These data demonstrate that the human fetal
adrenal cortex, particularly the cells of the inner fetal zone, express VEGF and
that VEGF expression and secretion by these cells are directly regulated by ACTH
and the activation of adenylate cyclase. Thus, VEGF may be a local regulator of
adrenal cortical angiogenesis and an important mediator of the tropic action of
ACTH, ensuring the coordination of ACTH-stimulated cortical growth and
vascularization.
PMID- 9543166
TI - The aromatase excess syndrome is associated with feminization of both sexes and
autosomal dominant transmission of aberrant P450 aromatase gene transcription.
AB - Increased extraglandular aromatization has been reported as the cause of familial
gynecomastia. We studied a kindred with aromatase excess inherited in an
autosomal dominant manner, in which affected males had heterosexual precocity
and/or gynecomastia, and affected females had isosexual precocity and/or
macromastia. The propositus was a 9-yr-old boy with gynecomastia. His 7.5-yr-old
sister had precocious puberty, and their father and paternal grandmother had
peripubertal gynecomastia and macromastia, respectively. Serum concentrations of
gonadal and adrenal steroid hormones were determined before and after the
administration of corticotropin and/or hCG. Aromatase activity was determined by
[3H]delta4-androstenedione to [3H]estrone conversion by cultured skin fibroblasts
and/or Epstein-Barr virus-transformed lymphocytes and was detected by
immunohistochemistry and/or Western analysis. Linkage was examined with a
polymorphism of the aromatase (P450arom) gene. The P450arom messenger ribonucleic
acid was analyzed by rapid amplification of complementary DNA (cDNA) ends,
ribonuclease protection assay, and RT-PCR. hCG testing demonstrated a high rate
of conversion of delta4-androstenedione to estrone and of testosterone to
estradiol in the propositus and his father. Treatment of the propositus and his
sister was initiated with an aromatase inhibitor (testolactone) and a GnRH
analog, which successfully delayed skeletal and pubertal development in both
children. Markedly increased aromatase activity was found in the patients'
fibroblasts and Epstein-Barr virus-transformed lymphocytes. The P450arom
polymorphism segregated with the disease in the family. A new 5'-splice variant
was present in the patients' P450arom messenger ribonucleic acid, thus
identifying yet another first exon of this gene, which appears to be aberrantly
expressed in this family. In conclusion, a family with the aromatase excess
syndrome is described, in which the condition was inherited in an autosomal
dominant manner, led to feminizing manifestations in both sexes, and was
associated with the aberrant utilization of a novel transcript of the P450arom
gene.
PMID- 9543167
TI - Prostaglandin endoperoxide H synthase (PGHS) activity and PGHS-1 and -2 messenger
ribonucleic acid abundance in human chorion throughout gestation and with preterm
labor.
AB - Term and preterm parturition is associated with elevated intrauterine PG
production. Although an increase of PG synthesis by the fetal membranes during
term labor is well documented, there is little data available regarding the
prostanoid production of these tissues at term, before the spontaneous onset of
labor. In the present study, we determined the expression of PG H2 synthase
(PGHS), the committing and rate-limiting enzyme of prostanoid biosynthesis, in
the chorion laeve during gestation. Tissues were collected from 18 patients at
term (37-41 weeks of gestation) and from 13 patients between 17 and 35 weeks of
pregnancy. None of the patients were in labor. PGHS-specific activity and the
abundance of messenger RNAs (mRNAs) encoding the two PGHS isoenzymes (the
constitutive PGHS-1 and the inducible PGHS-2) were measured by a cell-free enzyme
assay and specific ribonuclease protection assays, respectively. PGHS-specific
activity as well as PGHS-1 and -2 mRNA levels were significantly (P < 0.01)
higher at term before labor than earlier during gestation. Furthermore, PGHS
activity at term exhibited significant positive correlation with PGHS-2 mRNA
levels, but not with PGHS-1 mRNA levels. In situ hybridization indicated that the
expression of both PGHS mRNAs increased in the epithelial and the mesenchymal
cells of the amnion and the chorion laeve at term. Additionally, PGHS activity
and mRNA levels were determined in the chorion laeve of a group of patients who
gave birth spontaneously before term (30.6 +/- 1 weeks, mean +/- SEM, n = 5), and
the values were compared with a group who delivered by cesarean section before
labor at a similar gestational age (31.9 +/- 1.4 weeks, n = 5, P > 0.05 vs. the
preterm labor group). None of the patients exhibited signs of genital tract
infection. PGHS-specific activity and PGHS-1 and -2 mRNA levels were
significantly higher in the preterm labor group than in the group who delivered
preterm without labor. In situ hybridization suggested that the enhanced PGHS-1
and -2 mRNA expression occurred predominantly in the mesenchymal cells of the
fetal membranes at preterm labor. Thus, PGHS-1 and -2 expression increases in the
chorion laeve at term before labor, with PGHS-2 as the functionally prevalent
isoform. This supports the possibility that PGs originating in the fetal
membranes promote the onset of normal labor. Furthermore, preterm labor is
associated with the elevated expression of the two PGHS isoenzymes in the chorion
laeve. The maturation of the fetal membranes in preparation for term labor
involves both the epithelial and the mesenchymal cells, whereas preterm labor is
accompanied by the maturation of the mesenchymal tissue components, as reflected
by PGHS expression. This difference may have implications in the early
recognition of preterm labor.
PMID- 9543168
TI - Heterogeneous dopamine D2 receptor subtype messenger ribonucleic acid expression
in clinically nonfunctioning pituitary adenomas.
AB - Little is known about differences in the expression, localization, and function
of the two dopamine D2 receptor subtypes, D2short and D2long (D2s and D2l), in
either normal or adenomatous pituitary. We investigated the messenger RNA (mRNA)
expression of the D2 receptor (D2R) subtypes in clinically nonfunctioning
pituitary adenomas by in situ hybridization using subtype-specific
oligonucleotides. The five normal pituitaries studied expressed similar ratios of
D2R subtypes mRNA with a predominant expression of the D2l isoform. In 2 of 18
clinically inactive adenomas no D2R mRNA was found, whereas in 16 a heterogeneous
expression of D2R isoforms was observed. Six adenomas expressed only the D2l and
2 adenomas only the D2s subtype mRNA; the remaining 8 expressed extremely varying
proportions of the two subtypes. The D2R was found only in a subset of the
nonfunctioning adenoma cells. In gonadotropin-immunopositive adenomas, the D2R
was mainly localized in LH- and FSH-immunopositive cells. Probably because of the
heterogeneous D2R subtype expression, suppression of cell proliferation was
observed in only 3 of 9 adenoma cell cultures in which the growth inhibitory
effect of bromocriptine was studied. Although there is some evidence that the
presence of the D2s receptor subtype favors the growth inhibitory response to
bromocriptine, further studies with a larger number of inactive adenomas are
needed to confirm this speculation.
PMID- 9543169
TI - The human placenta and fetal membranes express the corticotropin-releasing
hormone receptor 1alpha (CRH-1alpha) and the CRH-C variant receptor.
AB - Placentally derived CRH plays a major role in the mechanisms controlling human
pregnancy and parturition. It has been suggested that there is a CRH placental
clock that is active from the early stages of pregnancy and determines the length
of gestation and the timing of parturition. CRH can influence human reproductive
tissue function via specific CRH receptors. Two distinct CRH receptors have been
cloned (R1 and R2) that share 70% homology at the amino acid level and exist as
two alternatively spliced forms (alpha and beta). In this study we investigated
the presence of CRH receptor subtypes in human fetal membranes derived from
spontaneous rupture and placental biopsies at term. Using RT-PCR, we identified
the full length of the CRH-R1alpha subtype in placental and fetal membranes. In
both tissues we also identified a spliced variant of the CRH receptor (CRH-Rc).
We were unable to detect any CRH-R2 messenger ribonucleic acid in any of the
biopsies. Fluorescent in situ hybridization and immunofluorescence in both
tissues demonstrated that syncytiotrophoblast cells and amniotic epithelium are
the major cell types expressing CRH-1alpha and CRH-Rc receptor messenger
ribonucleic acid. Further studies are necessary to give a better insight into the
role of CRH and its receptors in these tissues.
PMID- 9543170
TI - Age-related changes in glucocorticoid fast feedback inhibition of
adrenocorticotropin in man.
AB - A decrease in hypothalamic-pituitary-adrenal axis sensitivity to glucocorticoid
feedback suppression seems to occur with aging. To investigate possible
abnormalities in the inhibitory effect of glucocorticoids on ACTH secretion in
the elderly, we evaluated the endogenous ACTH response to hydrocortisone (25 mg
as an i.v. bolus) in 15 healthy aged (65-88 yr) and 15 healthy young (18-26 yr)
men. Blood samples for ACTH and cortisol determinations were collected at -15, 0,
2, 5, 10, 15, 30, 45, 60, 90, 120, and 180 min. Hydrocortisone injection produced
a rapid increase in plasma cortisol levels within the first 2 min in both groups.
In old men, in concomitance with the cortisol increase, ACTH levels showed only a
slight and nonsignificant decrease within the first 15 min, followed by a
pronounced and significant decline thereafter. In young subjects, in concomitance
with the plasma cortisol increase, a marked decrease in ACTH levels was observed
within the first 15 min, followed by a less pronounced decline thereafter. The
response curve of ACTH inhibition could be arbitrarily divided in two parts. The
first part (from 0-60 min) showed a significant difference between old and young
men, whereas the remaining part of the curve (from 60-180 min) showed no
differences between the two groups. The slower response in glucocorticoid
feedback inhibition of ACTH in old men supports the concept of some alteration in
the central regulation by steroids in aging. Age-related vascular factors
affecting cortisol penetration through the blood-brain barrier more than
hippocampus-hypothalamus receptor abnormalities could be involved in the fast
component of hypothalamic-pituitary-adrenal axis feedback regulation.
PMID- 9543171
TI - Retinoid receptors expression in human term placenta: involvement of RXR alpha in
retinoid induced-hCG secretion.
AB - To investigate the role of retinoids on human placental development and
functions, we characterized the spatial distribution of retinoid receptors in
human term chorionic villi. In situ hybridization with 35S labeled sense and
antisense probes for the RARs, alpha, beta, gamma and RXRs, alpha, beta, gamma,
specifically detected only RAR alpha and RXR alpha. Both RAR alpha and RXR alpha
mRNA were preferentially expressed in the trophoblast cell layer. This
syncytiotrophoblast expression was confirmed by immunohistochemical analyses
using anti-RAR alpha and RXR alpha antibodies. Using trophoblast cells in
culture, we then studied the effect on hCG secretion of 0.1 microM RA
physiological forms and of selective RAR alpha and RXR alpha synthetic agonists.
Only RXR alpha specific ligands such as physiological 9-cis RA and synthetic Ro
25-7386 stimulated hCG secretion (doubled). These results suggest an important
role for RXR alpha in human placental development and function.
PMID- 9543172
TI - Molecular characterization of the men1 tumor suppressor gene in sporadic
pituitary tumors.
AB - Anterior pituitary tumors arise sporadically, and also as part of the inherited
multiple endocrine neoplasia type 1 (MEN 1) syndrome. To investigate the role of
the recently isolated men1 gene in sporadic pituitary tumorigenesis, the complete
coding sequence was screened for mutations in 45 sporadic anterior pituitary
tumors, including 14 hormone-secreting tumors and 31 nonsecreting tumors, by
dideoxy fingerprinting and sequence analysis. No pathogenic sequence changes were
found in the men1 coding region. The men1 gene was expressed in 43 of these
tumors with sufficient RNA, including one tumor with loss of heterozygosity (LOH)
for several polymorphic markers on chromosomal region 11q13. Furthermore, both
alleles were expressed in 19 tumors in which the constitutional DNA was
heterozygous for intragenic polymorphisms. Thus, inactivation of the men1 tumor
suppressor gene, by mutation or by imprinting, does not appear to play a
prominent role in sporadic pituitary adenoma pathogenesis.
PMID- 9543173
TI - Insulin and IGF binding by IGFBP-3 fragments derived from proteolysis,
baculovirus expression and normal human urine.
AB - Recombinant human IGFBP-3 was proteolysed with different concentrations of
plasmin for various periods of time. The major IGFBP-3 fragment resulting from
this digestion migrated at ca. 15 kDa in nonreducing SDS-PAGE. Following the
identification of this fragment as an N-terminal IGFBP-3 fragment, by use of N
terminus-specific monoclonal antibody and amino acid sequence analysis, we
constructed and expressed a similar fragment in a baculovirus expression system.
The fragments resulting from plasmin digestion, as well as the baculovirus
expressed recombinant human IGFBP-3(1-97), retain weak IGF binding and show
specific insulin binding on cross-linking and western ligand blot. RhIGFBP-3(1
97) can inhibit insulin receptor autophosphorylation in insulin receptor
overexpressing NIH 3T3 cells. Insulin and IGF binding to IGFBP-3 fragments could
be further demonstrated in normal urine. These data indicate the physiological
significance of IGFBP-3 fragments derived from proteolysis in vivo.
PMID- 9543174
TI - Different effects of GH treatment on cognitive function in girls with Turner's
syndrome and in adults with GH deficiency.
PMID- 9543175
TI - Psychological stress and skydiving.
PMID- 9543176
TI - Childhood Graves' disease--remission rate and risk factors.
PMID- 9543177
TI - Why nobody has P450scc (20,22 desmoslase) deficiency.
PMID- 9543178
TI - Serum leptin levels in a patient with pheochromocytoma.
PMID- 9543179
TI - Differential expression of HGF and Met in human placenta.
PMID- 9543180
TI - Low BMD in calcium stone formers with hypercalciuria.
PMID- 9543181
TI - The influence of mouse housing density on autoimmune reactivity.
AB - Splenic cells from C57BL/6 mice housed in groups (six per cage) or individually
(one per cage) were analyzed for their ability to synthesize autoantibodies
against autologous bromelain-treated erythrocytes. Group-housed male mice had a
significantly lower number of autoimmune plaque forming cells (APFC) in their
spleens than age matched female mice housed under similar conditions. However,
when male mice were housed individually for 4 to 44 weeks, a marked increase in
numbers of APFC were found in their spleens, approaching those of female control
mice. Our results demonstrate that a simple environmental manipulation such as
housing conditions can profoundly modulate autoimmune reactivity. Thus,
alteration of the psychophysiological state determined by the quality of housing
may significantly affect the development of autoimmune disease.
PMID- 9543182
TI - Pancreatic IL-10 induces diabetes in NOD.B6 Idd3 Idd10 mice.
AB - Transgenic NOD backcross mice expressing pancreatic interleukin 10 (IL-10) were
crossed and backcrossed to NOD.B6 Idd3 Idd10 mice, which have diabetes-resistance
alleles at Idd3 and Idd10 on chromosome 3 and have a very low frequency diabetes
and insulitis. Insulitis and diabetes developed in almost all IL-10 transgenic
backcross 1 (BC1) mice of the H2g(7/g7) haplotype regardless of the allelic
status at Idd3 and Idd10. Furthermore, diabetes occurred in 23% of IL-10
transgenic H2g(7/d) BC1 mice. These results indicate that pancreatic IL-10 is
able to overcome the diabetes protection afforded by C57BL/6 (B6)-derived alleles
at Idd3 and Idd10 as well as the absence of NOD MHC homozygosity, if other non
MHC NOD-derived Idd alleles are provided.
PMID- 9543183
TI - Serum levels of interleukins 8 and 10, interferon gamma, granulocyte-macrophage
colony stimulating factor and soluble CD23 in patients with primary sclerosing
cholangitis.
AB - The presence of auto-antibodies and hypergammaglobulinaemia in patients with
primary sclerosing cholangitis (PSC) suggest an overactive humoral immune system.
Serum cytokines, measured using in-house double monoclonal sandwich ELISA, were
used to assess the state of cellular and humoral immunity in this condition by
comparison with sex and age matched normal controls and patients with alcoholic
cirrhosis (AC). Soluble CD23 (sCD23) as a marker of humoral immunity was
significantly elevated in PSC (N = 31) relative to patients with AC (N = 12) and
the control group (N = 20) (P < 0.0001 and P < 0.001 respectively). Serum
interleukin (IL) 10, as an anti-inflammatory cytokine and IL8, as a marker of
neutrophil activation were significantly elevated in patients with PSC relative
to those with AC and the controls (P < 0.001 and P < 0.05 respectively).
Interferon gamma, as a marker of cellular immunity, and granulocyte-macrophage
colony stimulating factor, a marker of monocyte/macrophage function were similar
in all the groups. Cytokines and sCD23 were no different between patients with AC
and the control group. While more than two thirds of the patients with PSC were
positive for ANCA, there was no correlation between the presence of ANCA or ANCA
titre and serum levels of either IL8, IL10 and sCD23. These results suggest
exaggerated humoral immunity in PSC. The raised levels of IL10 and IL8 in PSC are
discussed in the context of inflammatory bowel disease and liver dysfunction.
PMID- 9543185
TI - Cytokines and autoimmune beta cell destruction in NOD mouse fetal pancreas
isografts in cyclophosphamide-induced diabetes.
AB - The role of cytokines in a model of cyclophosphamide (CP)-accelerated beta cell
destruction in fetal pancreas isografts transplanted into NOD mice was studied.
One group of prediabetic NOD mice was injected with CP at a dose of 300 mg/kg
i.p. and 7 days later isografts of organ cultured fetal pancreas (FP) were
transplanted under the kidney capsule of these and untreated control mice. The
mice were killed at several time points post-transplantation and the histological
appearance of the host pancreas used to evaluate the disease progress in the
grafts since previous studies had shown good correlation between isograft and
native pancreas pathology. Intragraft cytokine gene expression was monitored by
reverse-transcriptase polymerase chain reaction (RT-PCR) at the same time points
and the expression levels between the experimental groups compared to normal
kidney tissue. In comparison to isografts from non-CP injected mice, isografts
from CP-treated mice showed increased expression of IFN-gamma, TNF-alpha, TNF
beta, IL-5, and eotaxin but no increase in IL-10 expression. The enhanced
transcription of these cytokines correlated with massive infiltration of immune
cells and ongoing beta cell destruction in the host pancreas of the CP-treated
recipients.
PMID- 9543184
TI - Anti-laminin reactivity and glomerular immune deposition by in vitro recombinant
antibodies.
AB - Growing evidence suggests that recombinatorial events prior to antigen contact
can generate pathogenic autoantibodies in the nonautoimmune individual, thus
providing potential disease mediators if conditions arise that permit bypass of
tolerance and activation of autoreactive lymphocytes. To examine the disease
potential of selected germline antibody genes, Ig were created de novo by in
vitro recombination of Ig H and L chains. H chain loss variant (i.e., L-chain
only) cell lines were transfected with a DNA construct encoding the variable
region and regulatory sequences (LamH) of a nephrotropic murine lupus anti
laminin Ig, and the resultant Ig were examined for in vitro antigen reactivity
and in vivo glomerular immune deposition. The results indicate that two light
chains, LamL (Vk8, Jk5) and 238L (Vk4, Jk5), expressing unrelated germline V1
genes, combine with LamH to generate Ig that bind basement membrane laminin in
vitro, diverge in their capacity to bind ssDNA, and produce two distinct patterns
of glomerular immune deposits in vivo: dense mesangial matrix (LamH/LamL) and
dramatic linear glomerular basement membrane (LamH/238L) deposits. The Ig genes
used by both LamH and 238L are present in nonautoimmune mice as well as in lupus
prone strains. We conclude that certain unmutated Ig genes can contribute to
multiple distinct disease associated specificities, including binding to
intrinsic kidney antigens, and that mutation is not essential to generate these
Ig. Collectively, these observations suggest that pathogenic autoantibodies can
be generated in the normal preimmune repertoire by random recombinatorial and
somatic events in the absence of mutation.
PMID- 9543186
TI - Autoantibody binding to steroid 21-hydroxylase--effect of five mutations.
AB - Steroid 21-hydroxylase (21-OH) is a key haem containing steroidogenic enzyme and
a major adrenal specific autoantigen. Cys 428 in 21-OH is thought to have an
important role in haem binding and we now describe the effects of mutations at
Cys 428 (to Ser, Arg and Phe) on 21-OH autoantibody binding. Expression of wild
type and mutated 21-OH was carried out using an in vitro
transcription/translation (TnT) system and reactivity of 21-OH autoantibodies
with mutated 21-OH analysed by western blotting (in the case of unlabelled
proteins) or immunoprecipitation assay (IPA) (in the case of 35S-labelled
proteins). All 3 substitutions at Cys 428 had similar effects on 21-OH
autoantibody binding and each one caused a reduction in autoantibody binding to
about 50% of wild type in the case of IPA and to about 70% of wild type in the
case of western blotting analysis. In addition to mutations at Cys 428, we
studied 2 naturally occurring mutations at Pro 30 to Leu and Ile 172 to Asn which
are associated with diminished 21-OH enzyme activity. The Pro 30 mutation had no
effect, but the Ile 172 mutation caused a reduction in 21-OH autoantibody binding
in the IPA to about 80% of wild type. Overall, our studies emphasise the close
relationship between the 21-OH aminoacid sequences important for 21-OH enzyme
activity and 21-OH autoantibody binding.
PMID- 9543187
TI - Glutamate decarboxylase antibodies in non-diabetic pregnancy precedes insulin
dependent diabetes in the mother but not necessarily in the offspring.
AB - We studied the risk for diabetes of glutamate decarboxylase (GAD65Ab) and islet
cell (ICA) autoantibodies in non-diabetic pregnant mothers and their children.
Pregnancy and cord blood sera were collected in 1970-87 from about 35,000 mothers
who delivered a child in the city of Malmo, Sweden. A total of 42 mothers were
identified in 1988 who, 1-18 years after their pregnancies, had developed either
insulin-dependent (n = 22) or non-insulin dependent (n = 20) diabetes mellitus.
First, in 123 pregnant mothers selected as controls, 0.8% had GAD65Ab and 0.8%
ICA. Second, among the mothers with non-insulin dependent diabetes, 7/20 (35%)
had GAD65Ab eight months to 13 years, 10 months before clinical diagnosis. Third,
in mothers who later developed insulin-dependent diabetes, 12/22 (55%) had
GAD65Ab and 10/22 (45%) had ICA in pregnancies preceding the clinical diagnosis
by 13 months to 9 years, 4 months. In 1996, none of the children born to the 42
mothers have developed diabetes. GAD65Ab and ICA in non-diabetic pregnancies may
predict insulin-dependent diabetes in the mother but not necessarily in the
offspring.
PMID- 9543188
TI - The relationship of health beliefs and psychological mood to patient adherence to
oral hygiene behaviour.
AB - Patient adherence to oral hygiene instructions (compliance) is important for the
success of periodontal treatment. However, there are many different definitions
and measures of what constitute patient adherence. Also, many different models of
patient behaviour have been studied, with inconsistent or conflicting findings.
The purpose of this study was to explore the relationships between health beliefs
(three aspects of dental health locus of control, health values and adherence
intent), psychological mood and periodontal outcomes. Complete periodontal data
were obtained for 47 untreated patients prior to instruction in oral hygiene, and
again 4-6 weeks later. Psychological variables were measured by questionnaire and
adherence was measured by reductions in clinical variables (plaque and
inflammation). Data were analysed using an item analysis of the questionnaire to
assess the internal consistency of the subscales. The results showed overall
stability in the psychological variables and reductions in the clinical
variables. The main result was a series of negative associations between plaque
scores and adherence intent. Inflammatory variables showed some association with
psychological constructs related to dependence on external factors.
PMID- 9543189
TI - Influence of smoking on the outcome of periodontal surgery. A 5-year follow-up.
AB - The 5-year outcome following periodontal surgery was evaluated in 57 patients
that had received regular maintenance care throughout the follow-up period. The
study population included 20 smokers, 20 former smokers and 17 non-smokers in the
age range 37-77 years. The clinical characteristics evaluated were supragingival
plaque, gingival bleeding and pocket probing depth. The region assigned for
surgery was, in addition, radiographically evaluated in terms of periodontal bone
height. Furthermore, the occurrence of the periopathogens Actinobacillus
actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg) and Prevotella
intermedia (Pi) and the gingival crevicular fluid (GCF) levels of tumor necrosis
factor alpha (TNF-alpha) were assessed at follow-up. Plaque index was 28.5% at
baseline and 32.9% at follow-up, indicating a good standard of oral hygiene, and
gingival bleeding 31.7% and 24.9%, respectively, suggesting a low to moderate
level of gingival inflammation. In regions assigned for surgery, pocket probing
depth decreased significantly from on average 5.6 mm to 4.3 mm (p<0.0001) and
periodontal bone height increased significantly from on average 62.5% to 67.5%
(p<0.0001). In terms of bone height, the outcome was less favorable among smokers
compared with non-smokers. There was a predominance of smokers among patients
exhibiting loss of bone height after the 5 years of maintenance. No significant
associations were found between the therapeutical outcome and supragingival
plaque or subgingival occurrence of periopathogens. The associations between GCF
levels of TNF-alpha and probing depth and bone height were unclear, whereas the
level of TNF-alpha was significantly elevated in smokers.
PMID- 9543190
TI - The effectiveness of different root debridement modalities in open flap surgery.
AB - It is unclear what degree of roughness or smoothness result from use of hand
instruments alone in comparison to the use of hand instruments in combination
with other aids and how it may effect the grade of cleanliness. The aim of this
study was to determine in vivo whether the combination of hand instruments with
other aids can increase the effectiveness of root debridement. 11 patients with
holpless 4 mandibular incisors were involved in this study. After elevating a
lingual and buccal mucoperiosteal flap, the 4 incisors were randomly treated with
either: (1) no treatment (control); (2) 5-min scaling (method 1); (3) 4-min
scaling and 1 min instrumentation with a perio-diamond bur (15 microm) (method
2); (4) 3-min scaling, 1-min instrumentation with a perio-diamond bur (15 microm)
and 1 min with an air abrasive system (method 3). The cleanliness of the surface
was determined using the method of Eschler and -Rapley. The degree of roughness
(Ra and Rt) were measured with a laser beam (computer supported optical surface
sensor system). In addition, an SEM analysis was performed. With regard to the
remaining calculus (surface cleanliness), method 3 yielded significantly better
results than the other 2 methods. The roughness analyses also exhibited that
method 3 is superior to methods 1 and 2. The qualitative results of the SEM
investigations demonstrated the most homogeneous and smooth surfaces with method
3. Root debridement in vivo was most significant using a combination of different
treatment modalities (i. e., curettes, perio-diamond bur and air abrasive
system).
PMID- 9543191
TI - Long-term effects of root-resective therapy in furcation-involved molars. A 10
year longitudinal study.
AB - The present investigation was designed to evaluate the long-term effect of root
resective therapy in the treatment of furcation-involved molars. The patient
sample included 72 patients, 21-62 years of age, who presented periodontal
lesions in the posteriors segments of the mouth including furcation involvement
of various degrees. After an initial examination, each patient was subjected to a
series of full-mouth scaling and root planing. They were recalled 1-3 months
later for a presurgical examination and subsequently underwent the corrective
phase of therapy. During the surgical procedure, the furcation-involved teeth
were subjected to root-resective therapy in conjunction with osseous recontouring
and apically positioned flaps (test sites). A surgical procedure identical to the
test procedure was performed in the non-furcation-involved teeth (control sites)
with the exception of the root resection. At the completion of the active phase
of treatment, 175 test and 175 control sites were available for the study. After
a period of 6 months of healing and plaque control supervision following surgical
procedures, the patients were recalled for a baseline examination. They were then
enrolled in a maintenance program including professional tooth cleaning every 26
months. The patients were re-examined 3, 5 and 10 years post-operatively. The
results of the assessments demonstrated that the survival rate, during the 10
year period of observation, reached 93% at test and 99% at control sites. The
positive treatment outcome at the root-resected, furcation-involved teeth as well
as at non-furcation-involved teeth was probably the consequence of the
reestablishment of a tissue morphology favorable for oral hygiene and careful
plaque control by the patients.
PMID- 9543192
TI - Untreated periodontal disease in Indonesian adolescents. Clinical and
microbiological baseline data.
AB - At present, several risk factors for the initiation and progression of
periodontitis have been identified. In order to investigate the role of various
potential clinical and microbiological risk factors and indicators, a
longitudinal study was initiated in a young population deprived from regular
dental care. The present communication describes the baseline cross-sectional
data obtained in 1987 in terms of the clinical periodontal condition and
prevalence of periodontal bacteria in the oral cavity. All inhabitants in the age
range 15-25 years of a village with approximately 2000 inhabitants at a tea
estate on Western Java, Indonesia, were examined clinically and
microbiologically. In total, 255 adolescents, comprising 130 males and 125
females participated in the study. Samples for bacteriological examination were
taken from the gingiva, the dorsum of the tongue, and the saliva. Plaque index,
bleeding upon probing, pocket depth, and attachment loss (AL) were scored on the
approximal surfaces from the vestibular aspect of all teeth as well as the mid
vestibular and mid-lingual aspects of the Ramfjord teeth. Calculus was scored
only on the 4 surfaces of the Ramfjord teeth. Following the clinical
measurements, the deepest bleeding pocket with no clinical loss of attachment was
sampled for microbiological examination. In addition, in 37 subjects a deep
bleeding (> or = 4 mm) with at least 4 mm of attachment loss was sampled.
Moderate periodontitis (max. AL 3-4 mm) was found in 26% of the population,
advanced periodontitis (max. AL > or = 5 mm) in 8%, whereas 66% of the population
showed no or minor periodontitis (max. AL 0-2 mm). Actinobacillus
actinomycetemcomitans was found in 57% of the population, Porphyromonas
gingivalis in 87%, Prevotella intermedia and motile rods in all cases and
spirochetes in 89%. P. gingivalis (66%), A. actinomycetemcomitans (37%) and
spirochetes (63%) were, of all the sampled sites of the oral cavity, most
frequently detected in pockets without attachment loss. Motile rods were most
prevalent on the tongue and in the saliva (92% and 89%, respectively). A high
prevalence of the investigated periodontal bacteria was detected both in the
pockets without and with attachment loss. No significant association between the
clinical periodontal parameters and the prevalence of the microorganisms was
observed at a patient level. At a site level, both P. gingivalis and spirochetes
were more prevalent in sites with attachment loss. The actual role of these
putative periodontal pathogens may be elucidated more extensively, when
longitudinal data on the present population become available.
PMID- 9543193
TI - Pre-transplant gingival hyperplasia predicts severe cyclosporin-induced gingival
overgrowth in renal transplant patients.
AB - The relationship between the pre-transplant periodontal status and the
development of post-transplant gingival overgrowth was investigated in a
longitudinal study. The periodontal condition of 35 patients was examined on 2
occasions while they were on the transplant waiting list and then at 4-6, 10-12,
16 and 20 weeks post-transplant. At each visit the plaque index, the bleeding
index and a pocket index (CPITN) were measured. Dental impressions were taken of
the pre- and post-transplant gingival condition and used to make stone models
which were used to score the gingival overgrowth index (GOI). The patients
divided into 3 distinct groups having severe (n=13), mild (n=16) or no post
transplant gingival overgrowth (n=6). Only 1 of the patients had taken
cyclosporin prior to inclusion into the study. All the patients who developed
severe overgrowth had evidence of gingival hyperplasia before the transplant.
There was no difference in the serum cyclosporin levels between the three groups
(chi2<2.28, p>0.319). Furthermore, there was no statistical difference for any of
the periodontal indices. This study indicates that the hyperplastic gingival
inflammatory response of some individuals appears to be potentiated by
cyclosporin resulting in severe post-transplant overgrowth. In other patients the
same reaction may allow the fibroblastic activity to occur to an extent where it
produces a mild clinically apparent overgrowth.
PMID- 9543194
TI - Gingival inflammation and subgingival calculus as determinants of disease
progression in early-onset periodontitis.
AB - This study was undertaken to test the hypothesis that gingival inflammation and
dental calculus are important determinants of the development and progression of
early-onset periodontitis. The study sample included 156 individuals who were 13
20 years old at baseline and who were examined 2x during 6 years to assess the
attachment loss, gingival state and the presence of dental calculus. 33 (21%), 62
(40%), and 61 (39%) individuals were classified as having localized, generalized,
or incidental EOP, respectively. The results showed an increase in the % of teeth
with overt gingivitis and subgingival calculus, and also an increase in the % of
teeth showing attachment loss during the 6-year period in all classification
groups. Of teeth with 0-2 mm attachment loss at the beginning of the study and
which developed > or = 3 mm attachment loss during the following 6 years, there
were 2x as many teeth with overt gingival inflammation, and 4x more teeth with
subgingival calculus at baseline than teeth without. Gingivitis and subgingival
calculus when present at both examinations resulted in a stronger association
with the development of new lesions than presence of these variables at baseline.
Teeth with gingivitis at baseline had a significantly higher mean attachment loss
during 6 years than teeth without gingivitis (p<0.0001), and teeth with
subgingival calculus at baseline had a significantly higher mean attachment loss
than teeth without subgingival calculus (p<0.0001). The presence of gingivitis
and subgingival calculus at baseline and 6 years later was associated with the
occurrence of even higher disease progression during this period. The association
between gingival inflammation and subgingival calculus and the development and
progression of attachment loss during the study period in the generalized and the
localized EOP groups was significantly higher than the association in the
incidental EOP group. In an appreciable % of the sites in all 3 groups, however,
the presence of the 2 factors was not associated with attachment loss during 6
years. The results suggest a significant association between gingival
inflammation and subgingival calculus and the development and progression of
early-onset periodontitis.
PMID- 9543195
TI - Nicotine and smokeless tobacco effects on gingival and peripheral blood
mononuclear cells.
AB - The pathogenesis of tobacco-related periodontal diseases is not well understood.
The purpose of this study was therefore to investigate smokeless tobacco extract
(ST) and nicotine effects on prostaglandin E2 (PGE2) and interleukin-1beta (IL
1beta) secretion by peripheral blood mononuclear cells (PBMC, consisting of
monocytes and lymphocytes) and gingival mononuclear cells (GMC). Both peripheral
blood and gingival tissue adjacent to the alveolar crest were taken from non
smoking adult periodontitis patients. Gingival tissue was treated with
collagenase and deoxyribonuclease and GMC and PBMC were isolated by Ficoll
Hypaque centrifugation. GMC and PBMC (100,000 cells/200 microl) were cultured for
24 hours in supplemented RPMI 1640 alone (control), or in supplemented RPMI 1640
containing 1% ST, 100 microg/ml nicotine, 1 microg/ml Porphyromonas gingivalis
LPS, or 1 microg/ml P. gingivalis LPS and either 100 microg/ml nicotine or 1% ST.
Enzyme immunoassays were used to quantify PGE2 and IL-1beta. Treatments were
compared by repeated measures ANOVA. 100 microg/ml nicotine (7-fold, p<0.02) and
1% ST (3.5-fold, p<0.004) significantly increased secretion of PGE2 by PBMC
relative to control cultures. 100 microg/ml nicotine and 1% ST, however, had no
effect on IL-1beta secretion by PBMC. Enhanced PGE2 secretion also was seen when
PBMC were treated with P. gingivalis LPS+ 100 microg/ml nicotine relative to P.
gingivalis LPS alone (p<0.007). In contrast, 100 microg/ml nicotine significantly
downregulated IL-1beta secretion by GMC relative to medium alone (p<0.008) and
had no effect on PGE2 secretion by GMC. These data indicate that while nicotine
and ST can stimulate PBMC to secrete PGE2, they cannot activate further
mononuclear cells extracted from gingiva, possibly due to maximal previous
stimulation in the periodontitis lesion.
PMID- 9543196
TI - GTR treatment of degree III furcation defects with 2 different resorbable
barriers. An experimental study in dogs.
AB - The aim of the present study was to describe the periodontal tissue that formed
after GTR when different resorbable barriers were applied to degree III furcation
defects. The study was performed in 5 foxhound dogs. The 2nd and 4th premolars in
both sides of the mandible were extracted. Degree III furcation defects were
produced in the 3rd mandibular premolars. 5 weeks later, GTR therapy using a
barrier composed by a polylactide-glycolide copolymer was performed on one
quadrant (group A). In the contralateral quadrant, a barrier made of polylactide
and citric acid ester (group B) was used. The dogs were sacrificed 6 months after
reconstructive therapy. Tissue blocks containing the experimental teeth were
excised, demineralised in EDTA and embedded in paraffin. Serial sections were cut
in the mesio-distal plane and parallel with the long axis of the roots. The
microtome was set at 7 microm. The sections were stained in hematoxyline and
eosin. From each biopsy, 3 sections representing the central part of the
furcation were selected for light microscopic examination. In the healed
furcation sites, descriptive histological analysis and histomorphometric
measurements of the newly formed tissues were performed. In both groups the root
surface of the healed furcation defects was covered by a cellular, extrinsic
intrinsic fibers type cementum. The composition of the newly formed periodontal
ligament was similar in both groups. The proportions of bone, bone marrow and
periodontal ligament, however, were substantially larger in group A than in group
B. In Group B, an area in the previous furcation defect was consistently occupied
by a granuloma. It is suggested that the presence of the granuloma in the healed
furcation defect prevented bone regrowth.
PMID- 9543197
TI - Gingival ulceration in HIV infection. A case series and case control study.
AB - All cases of HIV-associated gingival ulceration seen at a dedicated dental clinic
in a 5-year period were reviewed and compared against other patients attending
the clinic. 94 (7.1%) of 1308 patients had 146 episodes of gingival ulceration.
89 patients had 140 episodes similar to acute necrotising ulcerative gingivitis
(ANUG) and responded well to conventional treatment for ANUG. The cases were
compared with 269 controls in logistic regression. Gingival ulceration was
associated with oral candidiasis, lower age and lack of AIDS diagnosis possibly
due to a protective effect of co-trimoxazole medication. 5 patients with
neutropenia had extensive ulceration without the microflora of ANUG.
Histopathology, viral and bacterial culture revealed non-specific changes. The
ulcers did not respond to the treatment regimen for ANUG but responded to
treatment of their neutropenia. Gingival ulceration is not common in HIV
infection. Most cases resemble severe ANUG. It is more frequent in younger
people, those with oral candidiasis and without AIDS. Co-trimoxazole may be
protective. A minority of cases with ulceration and associated neutropenia
resembled the non-specific oral ulceration associated with HIV.
PMID- 9543198
TI - Clozapine in bipolar disorder: treatment implications for other atypical
antipsychotics.
AB - Traditional neuroleptics are often utilized clinically for the management of
bipolar disorder. Although effective as antimanic agents, their mood stabilizing
properties are less clear. Additionally, their acute clinical side effect profile
and long term risk of tardive dyskinesia, particularly in mood disorder patients,
portend significant liability. This review focuses on the use of atypical
antipsychotics in the treatment of bipolar disorder focusing on clozapine as the
prototypical agent. Although, preclinical research and clinical experience
suggest that the atypical antipsychotics are distinctly different from typical
antipsychotics, they themselves are heterogeneous in profiles of
neuropharmacology, clinical efficacy, and tolerability. The early clinical
experience of clozapine as a potential mood stabilizer suggests greater antimanic
than antidepressant properties. Conversely, very preliminary clinical experience
with risperidone suggests greater antidepressant than antimanic properties and
some liability for triggering or exacerbating mania. Olanzapine and sertindole
are under investigation in psychotic mood disorders. The foregoing agents and
future drugs with atypical neuroleptic properties should come to play an
increasingly important role, compared to the older classical neuroleptics, in the
acute and long term management of bipolar disorder.
PMID- 9543199
TI - Auditory event related potentials in major depression: prolonged P300 latency and
increased P200 amplitude.
AB - BACKGROUND: Some studies have shown disturbances in auditory event related
potentials (AERPs) in patients with major depression. METHODS: In this
exploratory study, the late AERP components, N100 (latency), P200 (amplitude and
latency) and P300 (amplitude and latency) were recorded in 68 subjects, i.e. 39
major depressed subjects, with (n=4) or without (n=35) cognitive deterioration,
18 patients with Alzheimer's dementia (SDAT) and 11 normal volunteers. Twenty
five major depressed patients had repeated measurements of AERPs both before and
after treatment with antidepressants. RESULTS: Major depressed subjects without
cognitive deterioration had significantly higher P300 latency and P200 amplitude
than normal volunteers. SDAT patients and major depressed patients with cognitive
impairment had a significantly higher P300 latency than depressed patients
without cognitive impairment. In the latter, no significant alterations in any of
the AERP components upon subchronic treatment with antidepressants were recorded.
Nonresponders to antidepressant therapy had significantly higher pretreatment
P300 latency and P200 amplitude than responders to treatment (P=0.006) and normal
volunteers (P=0.0004). CONCLUSIONS: The findings may suggest that delayed P300
latency as well as increased P200 amplitude accompany major depression and may
predict a nonresponse to subsequent antidepressive therapy.
PMID- 9543200
TI - Increased heart rate in depressed subjects in spite of unchanged autonomic
balance?
AB - A clinical study was conducted to examine the effects of depression on cardiac
autonomic control. Cardiac autonomic control was measured in 26 nonmedicated
patients (19 females) suffering from Major Depression, melancholic type, and in
26 age- and sex-matched normal controls. We measured heart rate and high
frequency heart rate variability (respiratory sinus arrhythmia), pulsewave
velocity and blood pressure, during 10 min of supine rest under controlled
conditions. Using a log transformed time domain measure of respiratory sinus
arrhythmia (logRSA), we found an inverse linear dependence between cardiac vagal
tone and age in the healthy subjects as well as the depressed patients. logRSA
was 0.22+/-0.25 in the patients and 0.25+/-0.16 in the control group. While this
difference was not significant (P > 0.1), the deviations from the regression line
were significantly (P < 0.0005) greater in the patients (0.21+/-0.12) than in the
control group (0.09+/-0.07), indicating a more heterogeneous vagal tone in the
depressed patients. Heart rate was also significantly (P < 0.03) greater in the
depressed patients (76.6+/-12.4) than in the control group (69.5+/-6.9). No
between-group differences were found in pulsewave velocity or systolic blood
pressure, but diastolic blood pressure was lower in depressed patients (73.5+/
8.7 vs. 80.8+/-9.1). We discuss the possibility that the increased heart rate
seen in the absence of vagal tone changes may not be due to altered vagal or
sympathetic tone, as measured in this study. Other factors, including altered
autonomous heart rate, may be responsible for the higher heart rate in the
depressed group.
PMID- 9543201
TI - Choosing an antidepressant: effectiveness based pharmacoeconomics.
AB - BACKGROUND: SSRIs have been one of the major innovations in psychopharmacology in
recent years. The debate over the competing claims of SSRIs and the older,
cheaper TCAs has implications for clinical practice and prescribing expenditure.
Several reviewers have focused on acquisition costs and stressed the higher costs
associated with using SSRIs. METHODS: Recently there have been several
applications of economics to the issue of whether to use SSRIs or TCAs as first
line antidepressants. Most have argued that there is an economic case for using
SSRIs. Several previous papers have used modelling techniques and decision
analysis to generate economic evaluations from clinical trials. This paper
examines some recent studies based on retrospective evaluations of real patients
and real practices. Their methods and results are summarised and discussed.
RESULTS: They all suggest that in practice, where concerns are with effectiveness
rather than efficacy, there are advantages to be gained from using SSRIs.
CONCLUSIONS: There are important questions about how to perform such economic
evaluations. Clinical practice has long viewed the RCT as a 'gold standard' for
evaluation. Some SSRI/TCA comparisons, incorporating economic studies, are under
way and will be reported on eventually. When they appear, these studies should be
examined carefully for their implications for antidepressant prescribing.
PMID- 9543202
TI - A functional variant of the serotonin transporter gene in families with bipolar
affective disorder.
AB - BACKGROUND: The serotonin transporter protein (SERT) reuptakes serotonin from
synapses and has been implied as the site of therapeutic action of many
antidepressant drugs. SERT is one of the most relevant candidate genes for
bipolar affective disorder. Recently a functionally important 44 basepair
deletion in the regulatory region of the SERT gene was described. Association
between this variant and affective disorder has been suggested. METHODS: The
present study analysed this variation and another variation in the SERT gene and
nearby DNA markers in order to test for linkage between SERT and bipolar
affective disorder in two Danish families. RESULTS AND CONCLUSION: There was no
evidence that variants in the SERT gene were a stronger dominant disease gene for
the development of affective disorder in the families. The possibility of a
recessive disease gene at or near SERT could not be excluded. LIMITATIONS: The
present study cannot exclude if variations at or near the SERT gene were weak
susceptibility genes or determine if they are important for other characteristics
than presence or absence of disease. CLINICAL RELEVANCE: Further studies of the
SERT gene in affective and other disorders, as well as in relation to treatment
response to antidepressants are needed.
PMID- 9543203
TI - Seasonal Affective Disorder and response to light in two patients with learning
disability.
AB - BACKGROUND: Seasonal Affective Disorder is now a well recognised variant of
recurrent depressive disorder. No previous description of its occurrence in
people with a learning disability has appeared. METHODS: Two patients are
described who manifested seasonal cycles in mood related behaviour. RESULTS: Both
patients were treated with bright artificial light and showed adequate clinical
responses. CONCLUSION: Patients with a learning disability and recurrent
behavioural changes indicative of a mood disorder should be assessed for the
seasonal pattern of the illness and, if appropriate, given a trial of treatment
with bright artificial light. LIMITATION: The data relates to two case reports
without structured assessments. Further studies in this population should use
standardised diagnostic criteria and systematic severity of depression scores.
CLINICAL RELEVANCE: Patients with poor verbal skills may not be able to express
their seasonal changes adequately but careful observation of the timing of
behavioural abnormalities may aid the diagnosis of SAD leading to new therapeutic
possibilities in phototherapy.
PMID- 9543204
TI - Omega-3 polyunsaturated fatty acid levels in the diet and in red blood cell
membranes of depressed patients.
AB - BACKGROUND: There is a hypothesis that lack of n-3 polyunsaturated fatty acids
(PUFAs) is of aetiological importance in depression. Docosahexaenoic acid, a
member of the n-3 PUFA family, is a crucial component of synaptic cell membranes.
The aim of this study was to measure RBC membrane fatty acids in a group of
depressed patients relative to a well matched healthy control group. METHOD: Red
blood cell (RBC) membrane levels, and dietary PUFA intake were measured in 10
depressed patients and 14 matched healthy control subjects. RESULTS: There was a
significant depletion of RBC membrane n-3 PUFAs in the depressed subjects which
was not due to reduced calorie intake. Severity of depression correlated
negatively with RBC membrane levels and with dietary intake of n-3 PUFAs.
CONCLUSION: Lower RBC membrane n-3 PUFAs are associated with the severity of
depression. LIMITATIONS: Although patient numbers were small, confounding factors
were well controlled for and the results were highly significant. Results of the
dietary data would tend to be weakened due to the limitations associated with
dietary assessment. CLINICAL RELEVANCE: The findings raise the possibility that
depressive symptoms may be alleviated by n-3 PUFA supplementation.
PMID- 9543205
TI - Testosterone replacement therapy for hypogonadal men with SSRI-refractory
depression.
AB - BACKGROUND: Testosterone replacement therapy is an effective treatment of some
depressive symptoms in hypogonadal men, and may be an effective augmentation
treatment for SSRI-refractory major depression in such men. METHODS: We treated
five depressed men who had low testosterone levels and had not responded to an
adequate SSRI trial with 400 mg testosterone replacement biweekly for 8 weeks.
Four patients underwent single-blind placebo discontinuation. Patients were
assessed at baseline and biweekly thereafter using the Hamilton Depression Rating
Scale (HAM-D) and the Endicott Quality of Life Enjoyment and Satisfaction Scale
(Q-LES-Q). RESULTS: Patients' mean age was 40 years, and mean testosterone level
277 ng/dl. All had a rapid and dramatic recovery from major depression following
testosterone augmentation: mean 21-item HAM-D decreased from 19.2 to 7.2 by week
2, and to 4.0 by week 8; mean Q-LES-Q increased from 45% to 68%. Three of four
subjects who underwent discontinuation of testosterone under single-blind placebo
treatment began to relapse. CONCLUSION: Testosterone replacement therapy may be
an effective treatment of depressive symptoms in some men, and warrants further
research.
PMID- 9543206
TI - Negative symptoms, depression, and parkinsonian symptoms in chronic, hospitalised
schizophrenic patients.
AB - BACKGROUND: Negative symptoms of schizophrenia are often confounded by
overlapping depressive and parkinsonian symptoms. The role of medication as an
aetiological factor in the development of these symptoms is an important issue
for prevention and treatment. METHODS: A total of 45 inpatients in chronic wards
who met RDC criteria for schizophrenia were assessed with the Hamilton depression
rating scale (HDRS) and negative symptom rating scale (NSRS) and the targeting
abnormal kinetic effect scale (TAKE). RESULTS: No significant correlation was
found between the total scores on the vegetative superfactor of the HDRS and the
NSRS. Duration of neuroleptic treatment was positively correlated with depressive
symptoms (r=0.299, P < 0.05) and negative symptoms (r=0.443, P < 0.001). Dose of
antipsychotic was also correlated positively with negative symptoms (r=0.260, P <
0.05). Age was negatively correlated with depressive symptoms as assessed by the
HDRS (r=0.306, P <0.05). CONCLUSION: The data suggest that depressive and
negative symptoms can be separated in chronic schizophrenia, while pointing to a
possible role of antipsychotic medication in the aetiology. LIMITATIONS: The
study was conducted in a small chronically hospitalised population treated with
relatively high doses of antipsychotics. It is not clear that the results
obtained here would be applicable to an acute patient population.
PMID- 9543207
TI - Risk factors for depression in primary care. Findings of the TADEP project.
AB - BACKGROUND: Depression is a common but poorly recognized disorder in primary
care. Knowing risk factors related to depression can help doctors in diagnosing
and treating depressive patients. METHODS: A random sample of 1643 individuals,
aged 18 to 64, attending community health centres in Central Finland, took part
in an inquiry with an instrument (the DEPS) measuring their depressiveness.
RESULTS: Negative life events, poor physical health, poor marital or other
interpersonal relationships, spouse's poor health, poor socio-economic and work
situation and problems with alcohol were the major variables explaining the
variance of depressive symptoms both in regression and discriminant analyses.
CONCLUSION: In the primary care patients, negative life events, poor physical
health, poor marital or other interpersonal relationships, spouse's poor health,
poor socio-economic and work situation and problems with alcohol indicate high
risk for depression; they also often accumulate in the same patients. The
connection between risk factors and depression is stronger in males than in
females. LIMITATION: The assessment of depression is based on the self-fulfilled
scale and cannot, therefore, be directly generalized to clinical depression.
Because of the cross-sectional study design, it is not possible to make any
causal conclusion between risk factors and depression. CLINICAL RELEVANCE: By
paying attention to the most general risk factors of depression, general
practitioners can become more sensitive in their recognition of depression.
PMID- 9543208
TI - Subpopulations of early separation anxiety: relevance to risk of adult anxiety
disorders.
AB - BACKGROUND: The present study aims to examine whether discrete subpopulations can
be identified according to their levels of early separation anxiety (SA), and if
so, whether such a typology of SA influences risk to particular adult anxiety
disorders. METHODS: Mixture analysis was applied to early SA scores provided
retrospectively by a composite group (n=1800) of adult community and patient
samples. The distribution of adult anxiety diagnoses across the SA categories was
assessed in a community (n=136) and a clinic (n=74) sample. RESULTS: The mixture
analysis yielded two subpopulations according to SA scores. Odds ratios for
assignment to the high SA category for the various anxiety disorders ranged from
3.6 to 6.7. A logistic regression analysis revealed that when comorbidity was
taken into account, the panic disorder-agoraphobia (PD-Ag) group was the only
anxiety disorder to be associated with the high SA category. CONCLUSION:
Assignment to a high early SA category appears to increase risk to adult anxiety
disorders, particularly PD-Ag. Several possible pathways may account for such a
risk including the persistence of separation anxiety disorder into adulthood.
LIMITATIONS: Assessment of early SA was made using a retrospective measure and
the samples included groups which were known to have high SA scores. CLINICAL
RELEVANCE: Only a subpopulation of anxiety sufferers may have elevated levels of
SA. Identification of this group may be important for early detection and
intervention.
PMID- 9543209
TI - Self-concept and mood: a comparative study between depressed patients with and
without borderline personality disorder.
AB - Within the framework of Self-Structure Theory, this study investigated the
relationship between depressed mood and Borderline Personality Disorder (BPD) on
self and others descriptions, with a special emphasis on the self-structure's
valence, that is, its affective, negative and/or positive content. Seventeen DSM
III-R unipolar depressed patients with associated BPD (DSM-III-R axis II) and
twelve unipolar depressed patients without BPD were compared to eighteen non
psychiatric controls on four measures of evaluation and of affective discrepancy
of descriptions of self and others. Subjects were administered the grid repertory
technique. The analysis of the resulting two-way valence matrix, with
attributions as columns, and self and others as rows, showed that depressed
patients with and without BPD differed from the non-psychiatric controls with
regard to negativity of the descriptions. As compared with the two other groups,
depressed patients with BPD showed a distinctive pattern characterised by the
joint presence of a negative view of self and a larger affective discrepancy for
others, with others being conjunctively assigned positive and negative
attributes. Despite some limitations, the distinctive pattern evidenced
corroborates the conflicted interpersonal relationship and is in keeping with
clinical theorising on BPD.
PMID- 9543210
TI - Conduct disorder and mania: what does it mean in adults.
AB - OBJECTIVE: Because of the relationship between childhood behavior disorders and
adult substance abuse, we hypothesized that substance abusing adult bipolars were
more likely to have had behavior disorders as children than nonabusing bipolar
adults. METHODS: Conduct disorder (CD) symptoms in 132 bipolar adults were
compared by age and presence of comorbid substance use problems using data from
the Epidemiologic Catchment Area study. RESULTS: Rates of CD were higher in
bipolar subjects under age 30 (32.6%) versus those over (16.3% P<0.05). Young BPs
with substance use problems (SUBST) had CD rates three times those without SUBST
(52% vs. 14.8%) (P < 0.01). Young subjects without mania or SUBST had CD rates of
7.75%. CONCLUSION: Substance abuse in bipolar adults may be more related to
childhood conduct disorder than uncomplicated bipolar disorder.
PMID- 9543211
TI - Health-related quality of life assessment in euthymic and depressed patients with
bipolar disorder. Psychometric performance of four self-report measures.
AB - The purpose of this study was to evaluate the psychometric properties of selected
health-related quality of life (HRQL) self-report measures in 62 euthymic and
depressed patients diagnosed with bipolar disorder. Patients completed the
Quality of Life in Depression Scale (QLDS), Mental Health Index-17 (MHI-17),
Cognitive Function Scale, and Medical Outcomes Study Short Form-36 (SF-36) at
baseline and 8 weeks following treatment. Hamilton and Young Rating Scales were
used to assess clinical status and validate the HRQL measures. The MHI-17,
Cognitive Function Scale, QLDS, and SF-36 social function, vitality, role
limitations-emotional, and mental health scales have good reliability and
validity, and are responsive to changes in clinical status in patients with
bipolar disorder. Although the small sample size limits generalizablity, euthymic
and depressed outpatients with bipolar disorder appear to contribute reliable
self reports on selected aspects of their quality of life.
PMID- 9543212
TI - To what extent do premenstrual and interictal dysphoric disorder overlap?
Significance for therapy.
AB - BACKGROUND: Premenstrual dysphoria has shown a significant relationship to
epilepsy, and its symptoms correspond to those of the interictal dysphoric
disorder. The established treatment for interictal dysphoric disorder is explored
as an effective treatment for premenstrual dysphoria. METHODS: Women with
premenstrual dysphoria (the majority with epilepsy) were evaluated and treated
systematically. RESULTS: Premenstrual disorder responded well to the combination
of antidepressant and antiepileptic medication. CONCLUSION: Concordance of
symptomatology between interictal and premenstrual dysphoric disorder may extend
to treatment. LIMITATIONS: The treatment needs to be evaluated in a large series
of women without epilepsy. CLINICAL RELEVANCE: A novel understanding and
treatment of premenstrual dysphoria is suggested.
PMID- 9543213
TI - Minor depressive disorder and subsyndromal depressive symptoms: functional
impairment and response to treatment.
AB - BACKGROUND: This study quantifies functional impairment and depressive
symptomatology in patients with minor depressive disorder (MinD) and subsyndromal
depressive symptomatology (SSD) before and after 8 weeks of treatment with
fluvoxamine. Study patients were compared and contrasted with archival data from
a sample of the general population measured by the Medical Outcome Survey Short
Form 36. METHOD: Fifteen patients with MinD and 15 patients with SSD were
identified from primary care clinics, referrals and newspaper advertisements.
Patients signed informed consent and were offered open label treatment with
fluvoxamine 25-100 mg/day. Patients were seen biweekly and measures of functional
impairment and depressive symptomatology were gathered systematically. RESULTS:
MinD and SSD were associated with dysfunction and disability when compared to
archival normative data from the general population. Eight week treatment with
fluvoxamine was associated with a substantial decrease in depressive
symptomatology and a normalization of psychosocial functioning. CONCLUSION: This
is the first study to quantify functional impairment and the severity of
depressive symptomatology in a clinical sample of patients with MinD and SSD, and
to demonstrate that treatment with a selective serotonin reuptake inhibitor
decreases depressive symptomatology and improves psychosocial functioning.
Placebo-controlled double-blind confirmation of these preliminary observations
seems warranted.
PMID- 9543214
TI - An epidemiological and clinical investigation of postpartum psychiatric illness
in Japanese mothers.
AB - A case note study of postpartum psychiatric illness as defined by Research
Diagnostic Criteria (RDC) was conducted in an epidemiologically defined large
area of Japan. The admission rate was 0.34/1000 live births. The most frequent
diagnostic category was affective disorder (53%). "Atypical" symptoms were
observed in 31% of all cases and were more frequent (67%) in patients with
schizoaffective disorder. Fifty six percent of mothers developed a psychiatric
illness within two weeks of delivery. The patients with "atypical" symptoms were
admitted much more quickly and their length of stay in hospital was shorter.
PMID- 9543215
TI - The clinical value of duplex surveillance following internal carotid artery
reconstruction.
AB - BACKGROUND: The purpose of this retrospective analysis was to evaluate the
benefit of a yearly duplex ultrasonography of both the reconstructed and the
contralateral internal carotid artery (ICA). METHODS: From 1985 to 1994, 1210
unilateral, primary ICA reconstructions were performed. Although these patients
received yearly invitations, duplex follow-up was not available in 114 patients
(9%). RESULTS: At 5 years a stenosis of 50% or more was found in 9% and at 10
years in 14% of patients. During the follow-up period 20 patients developed a
stenosis of 80-99%. Ten patients had a redo-procedure. The others remained
asymptomatic, even though one patient developed an occlusion. A stroke occurred
in 96 patients. 58 of these had no significant stenoses. 57% of all patients had
no significant contralateral lesion at the time of the first procedure. In only
4% of these a contralateral CAE was performed during the follow-up. CONCLUSIONS:
In view of the above data, we would conclude that the clinical benefit of duplex
surveillance is doubtful.
PMID- 9543216
TI - Transcranial duplex ultrasound: experience with contrast enhancing agents.
AB - Transcranial duplex real time sonography (TCCS) is a non-invasive imaging
modality that allows repetitive examinations of central nervous system vascular
and parenchymal anatomy; a broad spectrum of cerebral pathology may be disclosed:
vascular changes include ischemic and hemorrhagic stroke, arteriosclerotic
vascular degeneration, arteno-venous malformations and aneurysms, as well as
neoplastic and degenerative parenchymal disorders. Imaging was performed with a
duplex ultrasound system, employing a 2.25 resp. 2.0 MHz phased-array transducer.
Imaging was achieved through the acoustic bone window of the temporal bone and
through the foramen magnum. For three-dimensional image reconstruction a
mechanical position sensor and online video grabbing was applied. To evaluate the
potential of a transpulmonary stable ultrasound contrast enhancing agent we used
galactose-based SH U 508 A (Levovist, Schering, Berlin) with 1 to 6 i.v.
injections per patient in a phase 2/3 clinical protocol. The signal to noise
ratio is significantly improved; the Doppler signal intensity is increased by
approx. 25 dB. Levovist was well tolerated and no adverse events occurred,
approx. 30% of patients had a sensation of heat and slight pain at the injection
site during and shortly after the injection. With the increase in signal
intensity, the complete circle of Willis, the peripheral arterial branches, the
vertebro-basilar system and the basal venous system may be depicted. In addition,
tumour parenchyma vascularisation may be detected, as well as improved
delineation of arteriovenous malformations and aneurysms. Three dimensional image
reconstruction may represent a novel option in contrast enhanced transcranial
duplex imaging including additional information about 3D structure and
continuity.
PMID- 9543217
TI - The importance of the Doppler angle.
AB - We examined 118 infrainguinal grafts (103 patients) to determine the effect
changes in the angle of theta or Doppler angle had on the accuracy of velocity
measurements made with a duplex scanner. Four separate measurements of peak
velocity were made on each graft. Three measurements were made with the flow
toward the probe at 60 degrees, 50 degrees, 120 degrees (60 degrees the other
way). The probe was then turned 180 degrees so the flow was away from the probe
and measurements were made at 60 degrees. When the primary cursor was aligned
with the vessel wall (Technologist A), the mean velocity at 60 degrees was 69.4
cm/sec and 57.3 cm/sec at 50 degrees, a difference of 12 cm/sec. The same
measurements done by Technologist B (primary cursor non aligned with the wall),
showed a 10 cm/sec difference (60.7 and 50.5). We saw a consistent difference
with even this small difference in the angle of theta throughout the study. The
mean velocity obtained by Technologist A when the flow was toward the probe was
61.7. When the probe was turned 180 degrees (flow away from the probe), the mean
velocity was 60.5. The same measurements by Technologist B were 51.8 and 50.5.
This indicates that the direction of the flow of blood towards or away from the
probe does not effect the velocity measurements. Using the vessel wall to line up
the primary cursor provides a consistent and easily reproducible reference point
to compare measurements made on different days but is less important for single
measurements.
PMID- 9543218
TI - Characteristics of chronic venous insufficiency in 895 patients followed in
general practice.
AB - BACKGROUND: This study was designed to describe the main semiological and
etiological characteristics of chronic venous insufficiency (CVI) and to
determine if there was a relationship between the extent of objective signs,
severity of symptoms and aetiology. MATERIALS AND METHODS: 895 outpatients
presenting CVI of the lower limbs over a period of at least one year,
irrespective of grade of severity or aetiology, were included in this
retrospective study. They were treated with 2 different pharmaceutical forms of
the same venoactive medication (1000 mg of micronised flavonoid fraction) for 2
months. Organic CVI (OCVI) was classified, in stages of increasing severity,
according to the Widmer and Porter classification. In the absence of anatomical
lesions of the main veins or their valvular system, CVI was termed functional
(FCVI). RESULTS: Analysis indicated that CVI was more frequent in women than in
men (sex ratio 10:1). 26% were FCVI and 91% of OCVI were of varicose origin. The
mean progression time of the disease was 13+/-11 years. Disease began earlier in
women than in men (34+/-14 vs 41+/-14 years). Oedema was the first objective sign
in 68% of patients and the only one in 20% of FCVI. Heaviness was more frequent
in FCVI and its intensity was not related to the severity of CVI. Trophic
complications were more frequent in the advanced stages. CONCLUSIONS: In order to
avoid progression to more severe forms which are disabling or expensive to treat,
a rational approach to the management of early CVI is essential.
PMID- 9543219
TI - Conservative management of superior mesenteric and portal vein thrombosis
associated with protein C and S deficiency. Case report.
AB - Protein C and S, vitamin K-dependent proteins, are blood coagulation inhibitors.
Their deficiency causes systemic thrombosis. A 35-year-old man who developed
superior mesenteric venous thrombosis and portal vein thrombosis showed markedly
decreased protein C and S levels. The therapeutic modality of this thrombosis
associated with protein C and S deficiency is still debated. We treated this
patient with systemic anticoagulation and long term total parenteral nutrition
without surgical intervention.
PMID- 9543220
TI - Clinical and morphological aspects of Buerger's disease.
AB - BACKGROUND: Thirty-five patients with TAO and 35 with ASO have been studied. To
determine differences between these two arterial diseases, we used clinical
criteria, arteriographic and morphological methods. The peripheral (below the
bifurcation of the popliteal artery) angiographic changes were found in TAO with
94% sensitivity, 94% specificity and with 96% of positive predictive value. Other
clinical diagnostic criteria for differential diagnosis had a lower value (they
had high sensitivity and low specificity or low sensitivity and high
specificity). RESULTS: The histologic studies confirmed the clinical diagnoses of
Buerger's disease in 92,9% cases. The pathologic findings in TAO and ASO were
different. CONCLUSIONS: Our investigations proved that the characteristics of
Buerger's disease include the development of changes not only in small and medium
size arteries or veins, but also in microcirculation.
PMID- 9543221
TI - New method and device for assessment of functional capacity of upper extremity
with chronic ischemia.
AB - BACKGROUND: The aim of this study is to establish an objective diagnostic method,
through which the functional capacity of the upper extremity with chronic
ischemia could be best assessed. METHODS: For a 9-year period (1986-1994) 74
patients suffering Arterial Occlusive Disease (AOD) of the upper extremity with
chronic ischemia were treated. Fifty five of them (74.3%) were males (an average
age of 52.4 years) and 19 females (25.6%), (an average age of 42.5 years). Forty
nine of them (66.2%) were in second stage according to the adapted Fontain's
classification. An original method and device have been established for the
investigation of the abilities of the upper extremity to make repeated movements
till they get an intermittent claudication. The apparatus consists of tree
modules: a mechanical device, an interface adapter and a microcomputer. RESULTS:
During the flexion of the fingers the patient overcomes the resistance of springs
which is 1.82 Nm. An Ischemic Fatigue Index (IFI) is calculated--it gives the
quantitative value of the functional capacity of the limb. IFI in patients in
second stage of Chronic Arterial Ischemia (CAI) is from 0.14 to 0.76 during the
diagnostic test and from 0.18 to 1.0 after the operative or drug treatment or
Percutaneous Transluminal Angioplasty (PTA). A retrospective analysis shows that
in patients who were operated on, the preoperative IFI was less than 0.50. The
measurement of Arm-Arm Blood Pressure Index (AABPI) before treatment and after it
in some cases shows normal values in spite of the presence of subclavian artery
stenoses. The angiographies that were done could not help for the evaluation of
the functional capacity of the upper extremities. The presence of pulse in 9
patients (18.4%) does not exclude a presence of occlusion. CONCLUSIONS: IFI is a
quantitative indicator for the upper extremity capacity. It shows whether the
symptoms are severe enough to justify the surgery. The periodical measurement of
IFI is a monitoring of the development of AOD.
PMID- 9543223
TI - Cure of renovascular hypertension by percutaneous occlusion of a large idiopathic
renal arteriovenous fistula. Case report.
AB - Percutaneous balloon occlusion of a large hypertensive idiopathic renal
arteriovenous fistula is reported. A lumbar thrill was noted in a 52-year-old
hypertensive woman. Intravenous digital substraction angiography identified the
lesion. After arteriographic assessment a percutaneous embolisation was performed
with a releasable balloon positioned on a coaxial micro-catheter. Immediate post
procedural angiographic control demonstrated complete occlusion with a small
segmental area of renal hypoperfusion. The lumbar thrill disappeared.
Normalisation of the blood pressure was noted two days later and confirmed eight
months later. Persistent occlusion of the fistula was angiographically confirmed,
whereas the area of renal hypoperfusion had partially decreased. Releasable
balloon percutaneous embolisation appears to be a safe alternative to surgery in
the treatment of large renal arteriovenous fistulas.
PMID- 9543222
TI - Treatment of severe Raynaud's syndrome by injection of autologous blood
pretreated by heating, ozonation and exposure to ultraviolet light (H-O-U)
therapy.
AB - OBJECTIVE: To determine the effect of re-injection of small samples of autologous
blood, pretreated with heat, ozone and ultraviolet light (H-O-U therapy) in
patients with severe Raynaud's syndrome. EXPERIMENTAL DESIGN: Open trial in 4
patients. SETTING: Temperature/humidity controlled vascular laboratory. PATIENTS:
Severe Raynaud's syndrome of more than 5 years duration and defined as more than
5 attacks daily or 10 attacks in one week, at least half of which were painful
and lasting for more than 30 minutes. Three patients were refractory to infusions
of Iloprost. INTERVENTIONS: Patients were treated daily or on alternate days for
a two to three weeks period by re-injection of citrated autologous blood pre
treated with heat, ozone and ultraviolet light (H-O-U therapy). MEASURES:
Clinical observations; mean equilibrated hand temperature (infrared
thermography); distributive and microcirculatory blood-flow (venous occlusion
strain-gauge plethysmography, infrared photoplethysmography, laser Doppler
flowmetry) iontophoresis of acetylcholine and sodium nitroprusside; estimations:
serum levels of 6-keto-PGF1alpha and serum levels of anti-hsp65 antibody.
RESULTS: Reduction or abolition of Raynaud's attacks for at least three months
after treatment. Mean equilibrated hand temperature increased but did not
normalise. Blood flow parameters improved but did not reach statistical
significance. Iontophoresis of acetylcholine showed an increase in laser Doppler
flowmetry which was statistically significant. Serum levels of 6-keto-PGF1alpha,
fell significantly in three patients. Serum levels of anti-hsp65 antibody fell in
the one patient which was followed sequentially. CONCLUSIONS: H-O-U therapy may
prove useful in patients with severe Raynaud's syndrome.
PMID- 9543224
TI - Effect of gemfibrozil on early carotid atherosclerosis in diabetic patients with
hyperlipidaemia.
AB - BACKGROUND: An increased thickness of the carotid artery wall is thought to be a
sign of early atherosclerosis. We have investigated the effects of gemfibrozil in
asymptomatic diabetic hyperlipidaemic subjects on the 12-month progression of
arterial wall thickness. METHODS: Forty non-insulin-dependent diabetics with
hyperlipidaemia and without hypertension were studied. After a 4-week run-in-diet
phase, oral gemfibrozil was administered (900 mg once daily) in 20 patients
randomly selected, while 20 subjects were treated only with diet. The two groups
were matched for age, sex, body mass index (BMI), duration of diabetes and
glycaemic control. Arterial wall thickness was measured as the mean of the
maximum intima of media thickness (IMT) in 16 carotid segments by B-mode
ultrasound. RESULTS: Baseline size of IMT and lipid values were similar in both
groups. The IMT increase over 12 months was 5% in the gemfibrozil group vs 15.2%
in subjects treated by diet alone. CONCLUSIONS: We conclude that gemfibrozil
treatment may be useful in decreasing the progression rate of arterial wall
thickness.
PMID- 9543225
TI - Effect of cooling on vascular smooth muscle response to endothelin-1 in human and
rat veins.
AB - BACKGROUND: The plasma level of endothelin-1 is locally increased during cooling
but the net vasoconstrictor effect will be dependent on temperature effects on
the vascular smooth muscle reactivity in response to the polypeptide. The aim of
this study was to investigate the effect of cooling on the vascular smooth muscle
response to endothelin-1 in human and rat veins. METHODS: Registration of
vascular smooth muscle activity in vitro in vessel preparations from normal
subjects. SETTING: Laboratory. PATIENTS AND ANIMALS: Superficial hand veins from
14 patients undergoing hand surgery and external jugular veins from 14 rats.
INTERVENTIONS: Effects of endothelin-1, after denudation of the endothelium and
during cooling, were compared with controls without these interventions. RESULTS:
At 37 degrees C, endothelin-1 induced a concentration-dependent contraction in
the human hand and rat jugular veins. The sensitivity to endothelin-1 was
enhanced in segments without endothelium. At 37 degrees C, no relaxation in
response to endothelin-1 was observed. Cooling to 10 degrees C did not alter
precontraction achieved by endothelin-1 at 37 degrees C in the human hand veins,
while it depressed the precontraction in the rat jugular vein. The effect of cold
was reversible. Removal of the endothelium did not alter the response to cooling.
CONCLUSIONS: The maintained reactivity in response to endothelin-1 during cooling
of the human vessels suggests that the reported increase in endothelin-1 levels
due to local cooling could contribute in the pathophysiology of peripheral
vasospasm in humans.
PMID- 9543226
TI - Endothelin-1 in arterial hypertension after cold pressor test.
AB - BACKGROUND: We assessed plasma endothelin-1 (ET-1) concentrations in a group of
hypertensive subjects in order to determine the possible presence of a disorder
of ET-1 production and release. METHODS: A selected cohort of hypertensive
subjects was compared with a control group. Plasma levels of ET-1 in baseline
conditions and after cold the pressor test (CPT) were measured. All subjects were
studied as outpatients. Twenty-one male hypertensive patients were compared with
15 male controls. The hypertensive patients had undergone clinical examinations
to rule out the presence of vascular damage. Clinical examination of the controls
was performed to rule out hypertension. Patients with essential hypertension were
21 males, age: 57+/-7 years, body mass index 22.3+/-11.2 kg/m2. We assessed
plasma ET-1 in baseline conditions and after a cold pressor test. RESULTS: Means
+/-SD baseline concentrations of ET-1 were 12.47+/-2.41 pg/ml in hypertensives
and 8.2+/-3.8 pg/ml in controls (p<0.01). Mean +/-SD post CPT plasma ET-1 was
12.55+/-2.83 pg/ml in hypertensive subjects and 8.6+/-1.9 pg/ml in controls
(p<0.01). CPT did not modify plasma ET-1 concentrations in either group. CPT
significantly raised arterial pressure only in hypertensive subjects.
CONCLUSIONS: These results lead us to postulate the presence of a disorder of ET
1 production and release in hypertensive subjects.
PMID- 9543227
TI - Plasma adrenomedullin in cerebrovascular disease: a possible indicator of
endothelial injury.
AB - BACKGROUND: Cultured vascular endothelial and smooth muscle cells actively
produce adrenomedullin, a novel vasodilator peptide discovered in human
pheochromocytoma tissue. This present study was designed to determine whether the
plasma level of adrenomedullin is a useful indicator for estimating the degree of
endothelial injury in patients with atherosclerotic disease. METHODS: We used a
radioimmunoassay to measure plasma adrenomedullin concentrations in 51 patients
with chronic cerebrovascular disease (34 infarctions and 17 haemorrhages) and in
10 subjects without symptomatic cerebrovascular disease. We also measured the
plasma concentrations of thrombomodulin and endothelin as markers of endothelial
injury. The patients were divided into three groups (A, B, and C) on the basis of
the number of risk factors for atherosclerosis: hypertension, hyperlipidemia,
smoking, low HDL-cholesterol, diabetes mellitus, and hyperuricaemia. Group A
(68.7+/-2.7 years) consisted of patients with 0 or 1 risk factors; B (68.3+/-4.2
years) those with 2 risk factors; and C (69.2+/-3.6 years) those with 3 or more
risk factors. RESULTS: The plasma concentration of adrenomedullin in these
patients showed a significant positive correlation with age (r=0.33, p<0.05), as
well as with the plasma concentrations of thrombomodulin (r=0.54, p<0.001) and
endothelin (r=0.53, p<0.001). Moreover, the plasma concentrations of
adrenomedullin and thrombomodulin (p<0.005 and p<0.02, respectively) tended to be
higher in Group B and to be significantly higher in Group C as compared to Group
A. Plasma adrenomedullin concentrations did not, however, significantly differ
between the infarction and haemorrhage patients. CONCLUSIONS: These findings
suggest that the plasma adrenomedullin concentrations reflect the degree of
endothelial injury in patients with atherosclerotic disease.
PMID- 9543228
TI - Conditioned fear stress induces ethanol-associated place preference in rats.
AB - The purpose of the present study was to establish ethanol-induced place
preference under conditioned fear stress (exposure to an environment paired
previously with electric foot shock) in rats by using the conditioned place
preference paradigm. The administration of ethanol (300 mg/kg, i.p.) with
conditioned fear stress, but not without conditioned fear stress, induced a
marked and significant place preference. Furthermore, additional exposure to
conditioned fear stress immediately before the post-conditioning test further
enhanced the development of ethanol-induced place preference. These results
suggest that psychological stress may play an important role in the development
of ethanol-induced place preference, and the present method may be useful for
studying the mechanism of the rewarding effect of ethanol.
PMID- 9543229
TI - 'Candyflipping': synergistic discriminative effect of LSD and MDMA.
AB - The co-administration of D-lysergic acid diethylamide (LSD; 'Acid') and 3,4
methylenedioxymethamphetamine (MDMA; 'Ecstasy'; 'XTC'), has reached a prevalence
that has allowed for the street terminology 'candyflipping' to describe the
combination. Internet sites indicate a significant enhancement of central effects
with their simultaneous use. In this preliminary observation, male Fawn-Hooded
rats were trained to discriminate 1.5 mg/kg MDMA and were, subsequently, tested
with doses of MDMA (0.15 mg/kg) or LSD (0.04 mg/kg) that each produced a saline
like response. Co-administration of these doses of MDMA and LSD synergized to
produce a maximal MDMA-like response. The possible mechanism for synergistic
action upon central serotonergic neurons is discussed to explain the observed
effect.
PMID- 9543230
TI - Meta-chlorophenylpiperazine induced changes in locomotor activity are mediated by
5-HT1 as well as 5-HT2C receptors in mice.
AB - 1-(Meta-chloro)phenylpiperazine (m-CPP) is a 5-HT receptor agonist which has been
purported to be relatively selective for the 5-HT2C receptor. In particular, the
hypolocomotion produced by m-CPP has been suggested to be mediated by 5-HT2C
receptors. m-CPP binds with high affinity to 5-HT1 as well as 5-HT2 receptors,
thus effects of m-CPP on locomotor activity may be due to the physiologic
summation of the actions of m-CPP at 5-HT1 as well as 5-HT2 receptors. The
present study investigated the effects of m-CPP alone and in the presence of the
5-HT2 receptor antagonist 6-methyl-1-(-methyethyl)-ergoline-8beta-carboxylic acid
2-hydroxy-1-methylpropyl ester maleate (LY53857), the 5-HT1A receptor antagonist
N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2pyridinyl)c
yclohexanecarboxamide trihydrochloride (WAY 100,635), and the 5-HT(1B/1D)
receptor antagonist 2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4
corbox ylic acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]amide (GR 127935)
on locomotor activity. Administration of m-CPP alone (0.3-10 mg/kg) produced a
dose-related decrease in locomotor activity. The 5-HT(1B/1D) receptor antagonist
GR 127935 (3.0 mg/kg) in combination with m-CPP produced a slight leftward shift
of the dose-response curve of m-CPP. The 5-HT1A receptor antagonist WAY 100,635
(1.0 mg/kg) in combination with m-CPP did not alter the m-CPP dose-response
curve. The non-selective 5-HT2 receptor antagonist LY53857 (1.0 mg/kg) in
combination with m-CPP unmasked a hyperlocomotion produced by m-CPP. Furthermore,
the hyperlocomotion produced by m-CPP in the presence of LY53857 (1.0 mg/kg) was
blocked by both the 5-HT(1B/1D) receptor antagonist GR 127935 (3.0 mg/kg) and the
5-HT1A receptor antagonist WAY 100,635 (1.0 mg/kg). The present results
demonstrate that the hyperlocomotion seen with the combination of m-CPP and
LY53857 is mediated by 5-HT1 receptors. Taken together the data indicate that m
CPP affects locomotor activity by the physiologic summation of agonist activity
at the 5-HT2C receptor as well as the 5-HT1 receptor family.
PMID- 9543231
TI - Properties of ginseng saponin inhibition of catecholamine secretion in bovine
adrenal chromaffin cells.
AB - To investigate the relationship between the inhibitory effects of ginseng
saponins (ginsenosides) on acetylcholine-evoked secretion of catecholamines and
the structures of ginsenosides, we examined the effects of ginsenoside-Rg3 and
Rh2, which are panaxadiol saponins, 20(R)- and 20(S)-ginsenoside-Rg2, which are
epimers involving the hydroxyl group at C-20 of sapogenin, and other plant
saponins on the acetylcholine-evoked secretion of catecholamines from cultured
bovine adrenal chromaffin cells. The ginsenoside-Rg3 (1-100 microM) and -Rh2 (10
100 microM) greatly reduced the acetylcholine-evoked secretion in a concentration
dependent manner comparable to that of ginsenoside-Rg2, a panaxatriol saponin,
which was the most potent inhibitor in our previous study. 20(R)- and 20(S)
ginsenoside-Rg2 (1-100 microM) similarly reduced the acetylcholine-evoked
secretion. In contrast, saikosaponin-a, glycyrrhizin and the cardiac glycosides
(100 nM-100 microM), digitoxin and digoxin, had no significant inhibitory effect
on catecholamine secretion. Saikosaponin-c (10-100 microM), however, had an
inhibitory effect, which was less than that of ginsenoside-Rg2 and -Rg3. These
results strongly suggest that the inhibitory effects of ginsenosides on the
acetylcholine-evoked secretion of catecholamines from bovine adrenal chromaffin
cells are a unique property of ginseng. Further, the relationship between the
inhibitory effects and the structures of ginsenosides is discussed.
PMID- 9543233
TI - Time course of chronic diazepam effects on the auditory evoked potential of the
rat.
AB - The time course of chronic diazepam effects on auditory evoked potentials was
studied in rats. Auditory evoked potentials were elicited by background and
target tones in a passive oddball paradigm. Diazepam was administered by slow
release implants to establish constant blood concentrations. Recordings were made
during 21 days of treatment and 9 days after treatment ceased. Diazepam increased
the amplitude of the P40 component and decreased the amplitude of the P72-P102
components elicited by background tones. Diazepam increased the amplitude of the
P40-P48 component and decreased that of the N58 component elicited by target
tones. These effects remained constant during treatment. Diazepam further
decreased the amplitude of the P102 component elicited by target tones. This
effect became more distinct over time. No group differences were found 9 days
after treatment. The constant drug effects on middle-latency components (P40-P48)
might reflect diazepam-induced changes in sensory information processing. The
decreased long-latency component (P102) might reflect a diminished attention to,
or discrimination of, target tones. The time course of this effect might reflect
diazepam-enhanced habituation.
PMID- 9543232
TI - Anticonvulsant effect of polyunsaturated fatty acids in rats, using the cortical
stimulation model.
AB - Recent studies have shown that long-chain polyunsaturated fatty acids can prevent
cardiac arrhythmias, attributed to the reduction in excitability of
cardiomyocytes, owing mainly to a shift in hyperpolarizing direction of the
inactivation curves of both Na+ and Ca2+ currents and to a slowed recovery from
inactivation. Qualitatively similar effects of polyunsaturated fatty acids on
inactivation parameters have been observed in freshly isolated hippocampal
neurons. Since the same effects are presumed to underlie the action of some
established anticonvulsant drugs, polyunsaturated fatty acids might have an
anticonvulsant action as well. We have investigated this for eicosapentaenoic
acid, docosahexaenoic acid, linoleic acid and oleic acid, employing cortical
stimulation in rats, a seizure model allowing the determination of the full
anticonvulsant effect-time profile in freely moving, individual animals. I.v.
infusion of 40 micromol of eicosapentaenoic acid or docosahexaenoic acid over a
period of 30 min, modestly increased the threshold for localized seizure activity
after 6 h by 73 +/- 13 microA (mean +/- S.E.M.; n = 7) and 77 +/- 17 microA (n =
7), respectively, and the threshold for generalized seizure activity by 125 +/-
20 and 130 +/- 19 microA, respectively (P < 0.001). The thresholds remained
elevated for 6 h after infusion, but returned to baseline the next day. Free
plasma concentrations in rats treated with eicosapentaenoic acid or
docosahexaenoic acid, averaged 5.7 +/- 1.6 microM (n = 4) for eicosapentaenoic
acid and 12.9 +/- 1.8 microM (n = 5) for docosahexaenoic acid at the end of
infusion, but declined to undetectable levels within 3 h. Linoleic acid and oleic
acid were less effective. Possible mechanisms for the modest anticonvulsant
effect but of long duration with the polyunsaturated fatty acids are discussed.
PMID- 9543234
TI - Acute effects of morphine on the expression of mRNAs for NMDA receptor subunits
in the rat hippocampus, hypothalamus and spinal cord.
AB - The acute effects of subcutaneously injected morphine on transcripts of the NMDA
receptor subunits NR1, NR2A and NR2B in certain areas of the central nervous
system of male rats were examined by Northern blot analysis. The result clearly
indicated that a single dose (10 mg/kg) of the opioid alters the expression of
the mRNA for receptor subunits in the hippocampus and hypothalamus 4 h after drug
injection. No change in the mRNA levels was observed 30 min following injection,
and after 24 h most of the levels were restored to control values. The
observation suggests that morphine affects this type of glutamate receptor
already in the acute phase of its administration.
PMID- 9543235
TI - WAY 100,635 enhances both the 'antidepressant' actions of duloxetine and its
influence on dialysate levels of serotonin in frontal cortex.
AB - The mixed serotonin and noradrenaline reuptake inhibitor, duloxetine, (5.0 mg/kg,
s.c.), increased levels of serotonin (220%), dopamine (180%) and noradrenaline
(470%) in individual dialysates of frontal cortex of freely moving rats. Its
influence on serotonin, but not dopamine or noradrenaline, levels was enhanced by
the 5-HT1A receptor antagonist, WAY 100,635 (N-[2-[4-(2-methoxyphenyl)-1
piperazinyl]ethyl]-N-(2-pyridinyl) cyclo-hexanecarboxamide 3HCl) (0.16 mg kg(-1),
s.c). In the forced swimming test, although duloxetine was inactive alone, it
dose dependently reduced immobility in the presence of WAY 100,635. Thus,
blockade of 5-HT1A (auto)receptors selectively facilitates the influence of
duloxetine on serotonin levels in the frontal cortex in rats and, in the forced
swimming model, enhances its 'antidepressant' properties in parallel.
PMID- 9543236
TI - Activation of neurotensin receptors in the prefrontal cortex stimulates midbrain
dopamine cell firing.
AB - The effects of medial prefrontal cortex microinjections of 3 nmol/0.5 microl of
neurotensin-(1-13), the inactive fragment neurotensin-(1-8), or vehicle on the
firing rate of midbrain dopamine neurons were studied in anesthetized rats.
Twelve of 19 cells tested with neurotensin-(1-13) showed an average 20-25%
increase in firing rate between 10 and 20 min after the injection. This effect
was not mimicked by neurotensin-(1-8) (9 cells), nor by a control injection (10
cells) suggesting that it is mediated by high-affinity neurotensin receptors.
These results suggest that activation of neurotensin receptors in the medial
prefrontal cortex can modulate neural activity of a subpopulation of midbrain
dopamine neurons.
PMID- 9543237
TI - Inhibition of protein phosphatases alters the expression of morphine tolerance in
mice.
AB - Recently our laboratory found that tolerance to morphine-induced antinociception
could be completely reversed with intracerebroventricular (i.c.v.) administration
of a protein kinase A inhibitor, whereas intrathecal (i.t.) administration of the
inhibitor produced hyperalgesia in morphine-tolerant mice. In the experiments
described here, we sought to characterize further the role of phosphorylation
events in supraspinal versus spinal opioid-mediated pain pathways and how such
events might be involved in the development of antinociceptive tolerance. Two
phosphatase inhibitors were administered centrally to determine whether they
affected morphine-induced antinociception in naive or chronically morphine
treated mice. By the i.c.v. route, okadaic acid enhanced morphine-induced
antinociception in tolerant mice and produced toxicity by the i.t. route. The
calcineurin inhibitor ascomycin had no effect on antinociception following acute
or chronic morphine treatment. These results suggest that increased activity of
protein phosphatase types 1 and/or 2A in the brain may contribute to the
development of morphine tolerance.
PMID- 9543238
TI - Antagonism of alpha1-adrenoceptor agonist-induced responses by rilmenidine in
vascular smooth muscle.
AB - The effect of the centrally acting antihypertensive agent, rilmenidine, was
examined on the contractile properties of isolated rat portal vein strips and on
the free cytosolic [Ca2+] ([Ca2+]i) in isolated myocytes. Rilmenidine (1-30
microM) relaxed strips precontracted with noradrenaline. This effect was not
inhibited by the alpha2-adrenoceptor antagonist, yohimbine, and was not mimicked
by the alpha2-adrenoceptor agonist, 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6
quinoxalinamine (UK 14,304). Rilmenidine dose dependently shifted to the right
the concentration-response curves to noradrenaline and to phenylephrine but not
that to carbachol. Rilmenidine alone (0.1-30 microM) caused a contraction which
maximally corresponded to 18% of the maximal noradrenaline-induced contraction.
This effect was not produced by UK 14,304, was not affected by yohimbine, but was
inhibited by the alpha1-adrenoceptor antagonist, prazosin. In isolated myocytes,
rilmenidine reduced the noradrenaline-induced [Ca2+]i increase but alone, it
produced a rise in [Ca2+]i, the peak amplitude of which averaged 15% of the
noradrenaline-induced transient [Ca2+]i rise. It is concluded that rilmenidine
acts as a partial agonist of alpha1-adrenoceptors of vascular smooth muscle,
causing relaxation of vessels precontracted by full agonists of alpha1
adrenoceptors.
PMID- 9543239
TI - Endothelin-1 and unstable angina: effect of either endothelin ET(A) or ET(B)
receptor antagonism in a locally injured canine coronary artery.
AB - The role of endogenous endothelin-1 in variant angina was investigated using two
endothelin receptor antagonists: LU 135252 (ET(A)) and BQ 788 (ET(B)). Cyclic
flow reductions were induced in a coronary artery of mongrel dogs by combining
critical stenosis with endothelial injury. One hour after induction of cyclic
coronary flow reductions the dogs were randomized to intravenous treatment with
either saline, or LU 135252 (10 mg kg(-1)), or BQ 788 (0.1 mg kg(-1)). Cyclic
coronary flow reductions were monitored for two hours after drug and remained
constant in controls as well as after BQ 788. LU 135252 reduced the number of
cyclic coronary flow reductions significantly (about 50%) without effects on
hemodynamics or hemostasis.
PMID- 9543240
TI - Effects of FK409, a nitric oxide donor, on renal responses to renal nerve
stimulation in anesthetized dogs.
AB - We examined the effects of (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3
hexenamide (FK409), a nitric oxide (NO) donor, on renal actions and
norepinephrine overflow induced by renal nerve stimulation in anesthetized dogs,
with or without N(G)-nitro-L-arginine (NOARG), a NO synthase inhibitor. Renal
nerve stimulation at a low frequency (0.5-2.0 Hz) produced significant decreases
in urine flow and urinary excretion of Na+ and increases in norepinephrine
secretion rate. Renal nerve stimulation at a high frequency (2.5-5.0 Hz) which
diminishes renal hemodynamics, elicited more marked decreases in urine formation
and increases in norepinephrine secretion rate. Intrarenal arterial infusion of
FK409 (0.25 microg/kg/min) failed to alter renal actions and increases in
norepinephrine secretion rate in response to both low- and high frequency renal
nerve stimulation. When NOARG (40 microg/kg/min) was administrated intrarenally,
low-frequency renal nerve stimulation caused a potent antidiuresis and renal
vasoconstriction. The renal nerve stimulation-induced increase in norepinephrine
secretion rate was markedly enhanced by NOARG infusion. Simultaneous infusion of
FK409 markedly attenuated the NOARG-induced enhancement of renal actions and
increases in norepinephrine secretion rate, in response to low-frequency renal
nerve stimulation. These results suggest that exogenous NO suppresses the renal
nerve stimulation-induced norepinephrine overflow and renal actions in NO
depleted conditions. We also propose that endogenous NO functions tonically as an
inhibitory modulator of renal noradrenergic neurotransmission.
PMID- 9543241
TI - Pharmacology of the peptidomimetic, MEN 11149, a new potent, selective and orally
effective tachykinin NK1 receptor antagonist.
AB - In this study we investigated the pharmacological properties of MEN 11149, 2-(2
naphthyl)-1-N-[(1R,2S)-2-N-[1(H)indol-3-ylcarbonyl]aminocy clohexanecarbonyl]-1
[N'-methyl-N'-(4-methylphenylacetyl)]di aminoethane, a novel partially retro
inverse pseudo peptide antagonist of tachykinin NK1 receptors. MEN 11149 potently
inhibits the binding of [3H]substance P to tachykinin NK1 sites in IM9 cells (pKi
= 8.5 +/- 0.1). The compound is highly specific for the human tachykinin NK1
receptors, since it has negligible effects (pKi < 6) on the binding of specific
ligands to tachykinin NK2, NK3 receptors and a battery of central and peripheral
receptors or ion channels. The tachykinin NK1 receptor antagonism of MEN 11149
appears to be insurmountable since, in saturation binding experiments, both K(D)
and Bmax are significantly affected by incubation with the compound (1-30 nM). In
isolated guinea-pig ileum, MEN 11149 (0.1-100 nM) shifts to the right in a non
parallel way the substance P methyl ester-induced cumulative concentration
response curve with progressive inhibition of the maximal response (pK(B) = 9.6
+/- 0.1). When tested for reversibility at 5 nM in the same preparation, the
compound displays a slow dissociation rate compared to the fast dissociation rate
with FK888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-prolyl]-N
methy l-N-phenylmethyl-L-3-(2-naphthyl)alaninamide) at 5 nM. In the same
preparation, MEN 11149 (10 microM) did not affect the cumulative concentration
response curve to acetylcholine. In vivo, MEN 11149 dose dependently antagonizes
[Sar9,Met(O2)11]substance P-induced bronchoconstriction in anaesthetized guinea
pigs (ID50 = 83 +/- 31 nmol/kg i.v.). The duration of the effect exceeds 3 h. MEN
11149 does not affect the bronchoconstriction induced by neurokinin A. The
compound dose dependently inhibits [Sar9,Met(O2)11]substance P-induced plasma
protein extravasation in guinea-pig bronchi whether administered intravenously
(ID50 = 0.22 +/- 0.02 micromol/kg) or orally (ID50 = 0.97 +/- 0.21 micromol/kg).
These results demonstrate that MEN 11149 is a potent, highly selective and orally
effective insurmountable antagonist of tachykinin NK1 receptors with a long
duration of action.
PMID- 9543242
TI - Tachykinin NK2 receptors predominantly mediate tachykinin-induced contractions in
ovine trachea.
AB - In vitro studies were conducted to characterize the contractile effects of
tachykinins in normal ovine trachea with a view in the future to compare
tachykinin contractile responses in allergic tissue. Tracheal smooth muscle
strips were prepared for in vitro studies of isometric contraction in response to
cumulative addition of carbachol, acetylcholine, histamine, neuropeptide gamma,
substance P, neurokinin A, neurokinin B, [Sar9, Met(O2)11]substance P,
[Nle10]neurokinin A-(4-10), and [Succinyl-Asp6, Me-Phe8]substance P-(6-11)
(senktide). The rank order of potency was neuropeptide gamma > carbachol >
neurokinin A > or = [Nle10]neurokinin A-(4-10) > acetylcholine > or = histamine.
Phosphoramidon enhanced the contractile response to neurokinin A and substance P,
but not to neuropeptide gamma, [Sar9, Met(O2)11]substance P or senktide. Repeated
cumulative concentration responses for acetylcholine, substance P, neurokinin A,
[Sar9, Met(O2)11]substance P and histamine were also conducted to test for
tachyphylaxis. No tachyphylaxis to acetylcholine, substance P, or neurokinin A
was observed, however, [Sar9, Met(O2)11]substance P and histamine did exhibit
tachyphylaxis. Atropine had no effect on tracheal contractions to neurokinin A
and substance P, while [Sar9, Met(O2)11]substance P contractions were atropine
sensitive. Pyrilamine did not affect substance P-induced tracheal smooth muscle
contractions, indicating that the response to substance P was not mediated by
histamine release. These results show that, in vitro, natural tachykinins induce
tracheal smooth muscle contraction predominantly by a direct effect mediated by
tachykinin NK2 receptors, and a small tachykinin NK1 receptor mediated
cholinergic mechanism.
PMID- 9543243
TI - The role of cGMP in the relaxation to nitric oxide donors in airway smooth
muscle.
AB - The aim of this study was to determine the effect of the soluble guanylyl cyclase
inhibitors methylene blue and LY83583 (6-anilino-5,8-quinolinedione) on
relaxation and increases in intracellular guanosine 3',5'-cyclic monophosphate
(cGMP) concentration ([cGMP]i) induced by sodium nitroprusside, 3
morpholinosydnonimine (SIN-1) and diethylamine-nitric oxide (NO) in porcine
tracheal smooth muscle in vitro. We measured (1) the effect of NO donors on
isometric force and [cGMP]i and (2) the ability of methylene blue and LY83583 to
antagonize these effects. In muscle strips contracted with carbachol (0.1-0.3
microM), both sodium nitroprusside and diethylamine-NO caused relaxation and an
increase in [cGMP]i. By contrast, SIN-1 caused a relaxation which was not
associated with a concomitant increase in [cGMP]i. Methylene blue (10 microM) and
LY83583 (10 microM) completely blocked the increase in [cGMP]i induced by sodium
nitroprusside and diethylamine-NO; however substantial relaxation remained. It is
concluded that in porcine airway smooth muscle, (1) relaxation induced by some NO
donors may occur without a concomitant increase in [cGMP]i; and (2) whereas
relaxation induced by some NO donors may be associated with increases in [cGMP]i,
the relaxation is not completely dependent upon it.
PMID- 9543244
TI - Pharmacological profiles of new orally active nonpeptide tachykinin NK1 receptor
antagonists.
AB - Pharmacological profiles of new orally active amide-based tachykinin NK1 receptor
antagonists, N-[3,5-bis(trifluoromethyl)benzyl]-5-(4-fluorophenyl)-7,8-dihydro
N,7-di methyl-8-oxo-1,7-naphthyridine-6-carboxamide (referred to as compound I)
and two related compounds (compounds II and III), were compared with that of (+)
(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994), another
nonpeptide tachykinin NK1 receptor antagonist. Compounds I, II, III and CP-99,994
caused parallel rightward shifts of the concentration-response curve of substance
P in the guinea-pig ileum pretreated with atropine, mepyramine and indomethacin,
with the pA2 values of 8.70, 7.56, 8.41 and 8.27, respectively. These antagonists
did not alter the concentration-response curve of acetylcholine in the guinea-pig
ileum nor that of neurokinin A in the rat vas deferens. Furthermore, contractile
responses to senktide of the rat portal vein were not affected by these
antagonists. In the isolated neonatal gerbil spinal cord pretreated with
tetrodotoxin, substance P produced a dose-dependent depolarization of ventral
roots. Compounds I, II, III and CP-99,994 caused parallel rightward shifts of the
concentration-response curve of substance P in the spinal cord with the pA2
values of 7.07, 5.93, 6.40 and 7.26, respectively. In contrast, these antagonists
did not affect the concentration-response curve of L-glutamate. These results
suggest that compounds I, II and III are selective antagonists for tachykinin NK1
receptor both in peripheral tissues and the central nervous system.
PMID- 9543245
TI - Effect of a cardiotonic agent, MCI-154, on the contractile properties of skinned
skeletal muscle fibers.
AB - We have studied the effect of a cardiotonic agent, MCI-154 (6-[4-(4
pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride trihydrate), on
the contractile properties and adenosine triphosphatase (ATPase) activity of
chemically skinned rabbit skeletal muscle fibers. As in cardiac muscle, MCI-154
potentiated isometric tension and improved isometric tension cost at full Ca2+
activation. It showed little Ca2+-sensitizing effect. In contrast to its effect
on cardiac muscle, however, MCI-154 decreased all the kinetic parameters tested
(shortening velocity, the rate of rise of tension, and actomyosin ATPase
activity). All the results are explainable if MCI-154 acts directly on skeletal
actomyosin and inhibits a reaction step(s) of the ATPase cycle later than the
force-generating event. The qualitative difference between cardiac and skeletal
muscles in the responsiveness to this class of cardiotonic agents (MCI-154 and
EMD 53998, a thiadiazinone derivative) is most readily understood if the agents
have two independent actions, one on troponin and the other on actomyosin itself,
the latter being dominant in skeletal muscle.
PMID- 9543246
TI - Histamine H3 receptor desensitization in the guinea-pig ileum.
AB - Histamine H3 receptor ligands are usually tested in guinea-pig intestine
preparations. A possible desensitization of agonist-induced twitch inhibition was
studied in longitudinal muscle-myenteric plexus from ileal segments. A cumulative
concentration-response curve for R-alpha-methylhistamine was made; when a second
curve was made 30 min afterwards, a marked decrease of pD2 and a more modest
decrease of Emax were observed without changes in tissue sensitivity to
electrical stimulation or morphine inhibition. At 120 min, pD2 and Emax were not
different from those for the first curve. Receptor desensitization seems
homologous and reversible and could interfere with repetitive testing of
histamine H3 receptor ligands.
PMID- 9543247
TI - Acute glucosuria after continuous glucocorticoid loading in the rat in vivo.
AB - We investigated the effects of the continuous infusion of various steroids in
rats on renal tubular reabsorption of glucose in vivo to elucidate the
pathogenesis of steroid-induced glucosuria. Urinary glucose excretion increased
60 min after administration of dexamethasone (2.38 mM). By 120 min, urinary
excretion of glucose was three times higher in the dexamethasone group than in
the control group (24.1 +/- 4.6 versus 72.4 +/- 16.7 micromol); the plasma level
of glucose did not increase. Dexamethasone had no effect on the resorption of 1,5
anhydro-D-glucitol, which is a glucose-resembling polyol that is actively
absorbed by the renal tubules as glucose. Neither estradiol nor progesterone
increased urinary excretion of glucose. These findings suggest that continuous
administration of a high-dose glucocorticoid selectively influences the glucose
reabsorption system in the kidney.
PMID- 9543248
TI - Zn2+ inhibits nitric oxide formation in response to lipopolysaccharides:
implication in its anti-inflammatory activity.
AB - There is compelling evidence to indicate an anti-inflammatory action of Zn2+.
Most inflammatory diseases are associated with an increase of the inducible form
of nitric oxide (NO) synthase. Additionally, inflammatory mediators such as
histamine or bradykinin stimulate the constitutive NO synthase. Thus, the present
study was undertaken to investigate whether Zn2+ inhibits production of inducible
NO synthase and/or constitutive NO synthase activity to produce NO.
Lipopolysaccharide, 5 mg/kg i.v., administered to Zn2+-deficient (ZD) rats, rats
supplemented with Zn2+ sulfate (ZG), 10 mg/kg s.c., or controls resulted in a
significant reduction of their serum Zn2+. The levels of N(G)-nitro-L-arginine
methylester (L-NAME)-sensitive cyclic GMP (cGMP) in aortas isolated from ZD or ZG
were significantly lower than those obtained from control animals. Zinc (100-150
microM) produced a dose-dependent inhibition of lipopolysaccharide or interleukin
1beta-induced NO formation in isolated rat aortic smooth muscle cells. Compared
to cyclohexamide or actinomycin-D, the time course of inhibition of NO formation
by 150 microM Zn2+ did not suggest an effect of Zn2+ on inducible NO synthase
protein synthesis. Moreover, Zn2+ (150 microM) significantly reduced the rate of
conversion of [3H]arginine to [3H]citrulline in lung homogenates from
lipopolysaccharide-treated rats. Incubation of rat aortic smooth muscle cells and
bovine pulmonary artery endothelial cell co-cultures with Zn2+ (150 microM)
caused a significant reduction in basal and bradykinin- or A-23187-induced
formation of cGMP. Thus, our results indicate that Zn2+ is capable of inhibiting
lipopolysaccharide- or interleukin-1beta-induced NO formation as well as NO
formation by constitutive NO synthase basally or in response to bradykinin or A
23187, and may explain the reported anti-inflammatory activity of Zn2+.
PMID- 9543249
TI - Amino acid release during volume regulation by cardiac cells: cellular
mechanisms.
AB - Mechanisms of amino acid efflux during volume regulation in hypoosmotically
treated isolated rat hearts were studied by collecting the coronary artery
perfusate and analysis by high pressure liquid chromatography. Hypoosmotic stress
resulted in marked percentage increases in perfusate taurine, aspartate and
glutamate levels, smaller increases in phosphoethanolamine, glycine and alanine
and non-significant increases in serine and glutamine. Amino acid levels declined
during reperfusion with isosmotic perfusate. The anion channel blocker 4
acetamido-4-isothiocyanostilbene-2:2'-disulfonic acid (SITS, 500 microM)
significantly reduced hypoosmotic release of taurine, aspartate, glutamate and
glycine. Furosemide reduced hypoosmotically-evoked releases of taurine, glycine,
alanine and phosphoethanolamine. The polyunsaturated amino acids, arachidonic and
linoleic also reduced amino acid efflux. Phospholipase A2 inhibition with 7,7
dimethyleicosadienoic acid (DEDA, 2 microM) reduced osmotically-evoked releases
of taurine, aspartate and glutamate. 4-Bromophenacyl bromide (1 microM) inhibited
osmotically-evoked release of glutamate and glycine. Combined applications of
SITS + DEDA markedly reduced osmotically evoked release of all eight amino acids.
Glutamate and aspartate effluxes were not inhibited by the glutamate transport
inhibitor dihydrokainic acid (1 mM). These results indicate that the hypoosmotic
stress, by inducing cell swelling, can initiate an amino acid efflux as part of a
regulatory volume decrease. An opening of anion-permeant channels and
phospholipase activation appear to be involved in the regulatory volume decrease
phenomenon.
PMID- 9543250
TI - The effect of arachidonic acid and free fatty acids on vesicular uptake of
glutamate and gamma-aminobutyric acid.
AB - The manner in which arachidonic acid and other free fatty acids influence the
vesicular uptake of glutamate and gamma-aminobutyric acid (GABA) has been
investigated. The cis-polyunsaturated fatty acid arachidonic acid (20:4),
eicosapentanoic acid (20:5) and linolenic acid (18:3) at 150 nmol/mg protein (50
microM) inhibited the vesicular uptake of glutamate and GABA more than 70%.
Reduced inhibition of vesicular uptake was seen with the cis-monounsaturated
fatty acid oleic acid (18:1) and the trans-mono-unsaturated fatty acid elaidic
acid (18:1). The saturated fatty acids stearic acid (16:0) and arachidic acid
(20:0) had no significant effect on the uptake. The inhibition of vesicular
uptake by arachidonic acid was prevented by the addition of fatty acid free
bovine serum albumin. Arachidonic acid inhibited in a dose-dependent manner the
generation of the transmembrane pH gradient of the synaptic vesicles. This
inhibition was proportional to the inhibition of the vesicular uptake of
glutamate and GABA. The saturated fatty acid arachidic acid showed no inhibition
of delta pH generation. Arachidonic acid at 200 nmol/mg of protein did not
increase the uptake-independent leakage of glutamate and GABA from the vesicles,
showing that the effect of arachidonic acid is not caused by an unspecific
detergent effect. These results suggest that arachidonic acid and other
polyunsaturated fatty acids are acting like proton-ionophores on the vesicular
uptake of these neurotransmitters. This finding may have implications for the
increased fatty acid concentration during pathological conditions like ischemia
and in long term potentiation.
PMID- 9543251
TI - Adenosine modulates cell proliferation in human colonic adenocarcinoma. I.
Possible involvement of adenosine A1 receptor subtypes in HT29 cells.
AB - Several lines of evidence suggest that extracellular adenosine interacting with
specific cell surface receptors may influence cell growth and differentiation of
cancer cells in culture. The data presented here demonstrate that various
treatments of human colonic adenocarcinoma HT29 cells in the presence of
exogenously added adenosine deaminase, which converts extracellular adenosine
into inosine, resulted in a significant decrease of the proliferation. Cell
growth inhibition was also observed in the presence of adenosine A1 receptor
antagonists. These various treatments also induced a significant elevation of
basal intracellular cAMP levels. This strongly indicated that extracellular
adenosine was maintaining low intracellular cAMP levels in HT29 cells. A partial
pharmacological characterization of the binding of the adenosine A1 receptor
agonist [3H]CCPA (2-chloro-N6-cyclopentyl[2,3,4,5-(3)H]adenosine), and the
adenosine A1 receptor antagonist [3H]DPCPX (cyclopentyl-1,3-dipropyl[2,3
(3)H]xanthine), to HT29 cells is also provided. Together the data support the
idea that A1-adenosine receptors are expressed in HT29 cells and might mediate
part of the above described effects of adenosine on cell proliferation.
PMID- 9543252
TI - Adenosine modulates cell proliferation in human colonic carcinoma. II.
Differential behavior of HT29, DLD-1, Caco-2 and SW403 cell lines.
AB - In a previous study, we provided evidence that extracellular adenosine modulates
growth of the poorly differentiated colonic adenocarcinoma cells HT29 and
proposed that adenosine A1 receptors might mediate proliferative effects. We now
extend our investigations to a group of colonic adenocarcinoma cells at different
stages of enterocytic differentiation. In HT29, DLD-1, Caco-2 and SW403,
proliferation was decreased in the presence of adenosine deaminase (5 or 10
U/ml), 5'-N-ethylcarboxamido-adenosine (NECA; 1 microM), xanthine amine congener
and 8-phenyltheophylline (both at 1 nM or 1 microM). NECA stimulated cAMP
accumulation in all cell lines except for HT29. In the presence of forskolin
(adenyl cyclase activator) cAMP accumulation was inhibited at sub-nanomolar
concentrations of NECA and stimulated at micromolar concentrations in all four
cell lines. The inhibitory response disappeared in the presence of 50 nM
cyclopentyladenosine (CPA). The binding of [3H]cyclopentyl-1,3-dipropylxanthine
and [3H]NECA was also investigated in the four cell lines. Results of
displacement experiments were consistent with the idea that poorly differentiated
cells with high proliferation rates (e.g. HT29) express mainly adenosine A
receptors. In contrast, displacement curves with more differentiated cells
exhibiting low proliferation rates (e.g. Caco-2, DLD-1, SW403) displayed two
components. The high-affinity component was no longer seen in competition
experiments performed in the presence of [3H]NECA and 50 nM CPA. Together, our
results further support the idea that extracellular adenosine stimulates cell
proliferation in colonic adenocarcinoma cells. The effects might involve cAMP
coupled adenosine receptors.
PMID- 9543253
TI - Corticosteroids inhibit the expression of the vascular endothelial growth factor
gene in human vascular smooth muscle cells.
AB - The vascular endothelial growth factor (VEGF) is a specific mitogen for vascular
endothelial cells and enhances vascular permeability and edemagenesis. VEGF is
also a major regulator of angiogenesis and may be a key target for inhibiting
angiogenesis in angiogenesis-associated diseases. Among the extensively studied
angiostatic compounds are several corticosteroids when used alone or in
combination with heparin. In this study we present evidence for an additional
mechanism of action of hydrocortisone, cortisone and dexamethasone in inhibiting
edemagenesis or angiogenesis. In cultures of aortic human vascular smooth muscle
cells these corticosteroids (1 x 10(-8) to 1 x 10(-12) M) abolished the platelet
derived growth factor-induced (PDGF) expression of the VEGF gene in a dose
dependent manner. In contrast, two precursors of corticosteroids,
desoxycorticosterone or pregnenolone, did not affect PDGF-induced VEGF
expression. Our findings indicate that the capacity of corticosteroids to reduce
edema or to prevent new blood vessel formation may be attributed, at least in
part to the ability of these agents to abolish the expression of VEGF.
PMID- 9543254
TI - Suppression of phospholipase C blocks Gi-mediated inhibition of adenylyl cyclase
activity.
AB - The potential effect of inhibition of phospholipase C on the response of Gi
coupled receptors was investigated in neuroblastoma x glioma hybrid (NG108-15)
cells. The phospholipase C specific inhibitor 1-[6-((17beta-3-methoxyestra
1,3,5(10)-trien-17-yl)amino)hexyl]-1H -pyrrole-2,5-dione (U73122), which did not
affect basal and forskolin-stimulated adenylyl cyclase activities, time- and dose
dependently blocked delta-opioid receptor-mediated inhibition of adenylyl cyclase
activity, the EC50 (0.5 microM) of which was consistent with that for inhibition
of bradykinin-dependent phospholipase C activation (EC50 = 1 microM). U73122
treatment also blocked functional responses of m4 muscarinic receptor and alpha2
adrenoceptor in NG108-15 cells and three opioid receptors (mu, delta and opioid
receptor-like receptor (ORL1)) in human neuroblastoma SK-N-SH cells. 1-[6
((17Beta-3-Methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-2, 5-pyrrolidinedione
(U73343), an inactive analog of U73122, did not show any effect, which suggests
that the blockade by U73122 of Gi-coupled receptor-mediated signaling is probably
mediated through inhibition of phospholipase C, although a possible direct
modification of G proteins can not be excluded. Furthermore, treatment with
U73122 but not U73343 blocked the GTP-induced inhibition of adenylyl cyclase,
indicating blockade at the level of Gi proteins.
PMID- 9543255
TI - Synergy of CD95 ligand and teniposide: no role of cleavable complex formation and
enhanced CD95 expression.
AB - Teniposide (VM26) enhanced the anti-glioma activity of the cytotoxic cytokine,
CD95 ligand. Synergy was observed at concentrations of teniposide that were
insufficient for cleavable DNA topoisomerase II complex formation. CD95 ligand
did not modulate the formation or removal of such complexes after teniposide
treatment. These processes were also unaffected by ectopic expression of bcl-2.
Teniposide enhanced CD95 expression in a glioma cell line with wild-type p53 (LN
229) but not in two p53 mutant cell lines (T98G, LN-308). Forced expression of a
transdominant negative p53 mutant prevented the teniposide induced augmentation
of CD95 expression in LN-229 cells but did not prevent the synergy of CD95 ligand
and teniposide. Teniposide did not alter CD95 ligand expression, and forced
expression of CD95 did not modulate sensitivity to VM26. Thus, teniposide-induced
DNA lesions and alterations in CD95 or CD95 ligand are not necessary for
teniposide-induced sensitization of human malignant glioma cells to CD95-mediated
apoptosis.
PMID- 9543256
TI - Substance P-related inhibitors of mast cell exocytosis act on G-proteins or on
the cell surface.
AB - [p-Glu5,D-Trp(7,9,10)]substance P-(5-11) inhibited mastoparan-stimulated GTPase
activity in homogenized rat peritoneal mast cells and decreased histamine
secretion induced by mastoparan from streptolysin O-permeabilized mast cells
(IC50 of about 30 microM), but not from intact cells. In contrast, [D-Pro4,D
Trp(7,9,10)]substance P-(4-11) inhibited the secretion from intact cells (IC50 of
about 10 microM) but had no effect on histamine secretion from permeabilized
cells, suggesting that this peptide exerts its inhibitory effect on the plasma
membrane, whereas [p-Glu5,D-Trp(7,9,10)]substance P-(5-11) interacts with G
proteins. Pretreatment of mast cells with neuraminidase led to an inhibition of
the secretory response to mastoparan and related triggers. This response was
restored following cell permeabilization, demonstrating the role of the cell
surface on the entry of mastoparan and related triggers and on their ability to
reach G proteins sensitive to pertussis toxin and [p-Glu5,D-Trp(7,9,10)]substance
P-(5-11).
PMID- 9543257
TI - Signal transduction in cardiac and vascular tissue from normotensive and
transgenic hypertensive TGR(mREN2)27 rats.
AB - Adenylyl cyclase and soluble guanylyl cyclase activities were measured in cardiac
and aortic tissue from transgenic hypertensive TGR(mREN2)27 and normotensive
Sprague-Dawley rats. Cardiac basal and stimulated adenylyl cyclase activity was
significantly lower in TGR(mREN2)27 than in Sprague-Dawley rats except after
uncoupling of G-proteins by Mn2+-ions. Aortic cAMP formation did not differ
between both strains, indicating that the disturbance of cardiac adenylyl cyclase
activity was due to local rather than systemic factors. Vascular cGMP formation
was significantly reduced in TGR(mREN2)27 aortae under basal conditions and after
stimulation with sodium nitroprusside, indicating that there is a subsensitive
vasodilating second messenger pathway in the transgenic strain.
PMID- 9543258
TI - Cyclopiazonic acid and thapsigargin induce platelet aggregation resulting from
Ca2+ influx through Ca2+ store-activated Ca2+-channels.
AB - The effects of cyclopiazonic acid and thapsigargin, selective inhibitors of the
endoplasmic reticulum Ca2+-ATPase pump, on the platelet aggregation were
investigated using washed rat platelets prepared by chromatography on Sepharose
2B columns. In Ca2+-free medium, cyclopiazonic acid and thapsigargin did not
induce aggregation, but in the presence of 1 mM Ca2+, platelet aggregation was
induced in a concentration-dependent manner. Cyclopiazonic acid- and thapsigargin
induced platelet aggregation was blocked by 1 mM Ni2+ but not by 100 microM
indomethacin or 1 microM nifedipine. In aequorin-loaded platelets, cyclopiazonic
acid and thapsigargin caused sustained elevation of the cytosolic Ca2+
concentration, an effect which was blocked by Ni2+, a non-selective Ca2+ channel
blocker and SK&F 96365 (1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenyl]-1H
imidazole hydrochloride), a putative receptor-operated Ca2+ channel antagonist.
The above results indicated that both cyclopiazonic acid and thapsigargin induced
platelet aggregation and elevation of cytosolic Ca2+ concentration, that
extracellular Ca2+ was essential for cyclopiazonic acid- and thapsigargin-induced
platelet aggregation, and that platelet aggregation may be associated with Ca2+
influx through Ca2+ store-activated Ca2+ channels.
PMID- 9543259
TI - Stereoselective actions of halothane at GABA(A) receptors.
AB - Isoflurane anesthesia exhibits stereoselectivity, and a corresponding
stereoselectivity ((+)->(-)-isomer) has been reported at GABA(A) receptors in
vitro. The objective of the present study was to determine if the positive
modulatory actions of halothane at GABA(A) receptors exhibited a similar
stereoselectivity. Both (R)- and (S)-halothane ((+)- and (-)- isomers,
respectively) enhanced [3H]flunitrazepam binding to brain membranes in a
concentration dependent manner without a significant difference in either potency
(EC50) or efficacy (Emax). While both (R)- and (S)-halothane enhanced
[3H]muscimol binding, the potency of the (+)-isomer was slightly greater than the
corresponding (-)-isomer (0.91 +/- 0.17 versus 1.45 +/- 0.04% atmospheres,
respectively (P < 0.02)). Thus, subtle structural differences between
inhalational anesthetics can have a significant impact on the degree of
stereoselectivity at the receptor level and may provide insights for the
development of more specific drugs.
PMID- 9543260
TI - Upregulation of NMDA receptor subunit proteins in the cerebral cortex during
diazepam withdrawal.
AB - The present study investigated the changes in NMDA receptor subunit proteins in
diazepam-withdrawn rat cerebral cortex, using Western blotting analysis. The
protein levels of the NR1 and NR2B, but not NR2A, subunits were significantly
increased in diazepam-withdrawn rats compared to those in control rats.
Therefore, an increase in the NR1 and NR2B subunit proteins may be responsible
for both the previously observed upregulation of [3H]dizocilpine binding in the
cerebral cortex and the appearance of diazepam withdrawal signs.
PMID- 9543261
TI - Augmented chemosensitivity to hypercapnia: another link in our understanding of
the pathogenesis of Cheyne-Stokes respiration.
PMID- 9543262
TI - Testing health status ("quality of life") questionnaires for asthma and COPD.
PMID- 9543263
TI - Ventilatory control in patients with sleep apnoea and left ventricular
dysfunction: comparison of obstructive and central sleep apnoea.
AB - Sleep apnoea is common in patients with heart failure. While most patients have
central sleep apnoea (CSA), a minority have obstructive sleep apnoea (OSA). The
pathophysiology of CSA is not well understood. We hypothesized that central
chemosensitivity would be an important pathophysiological factor in patients with
CSA, and not in OSA. The aim of this study was to compare ventilatory responses
between patients with CSA and those with OSA. Acute ventilatory responses to
eucapnic hypoxia and hyperoxic hypercapnia were measured during wakefulness in 34
patients (33 males and one female, aged 59+/-8 yrs (mean+/-SD)), with stable
medically-treated left ventricular dysfunction (LVD) and sleep apnoea (18 OSA and
16 CSA). Patients with CSA had a decreased awake end-tidal carbon dioxide tension
(4.1+/-0.5 kPa), increased ventilatory response to carbon dioxide (0.65+/-0.43
L.min.(-1).kPa PCO2(-1)), and eucapnic hypoxic responses in the normal range
(0.6+/-0.4 L.min(-1)/% fall in arterial oxygen saturation (Sa,O2)). In contrast,
patients with OSA had normal end-tidal carbon dioxide tension (4.9+/-0.5 kPa),
and normal ventilatory responses to hypercapnia (0.29+/-0.16 L.min(-1).kPa PCO2(
1)) and hypoxia (0.5+/-0.5 L-min(-1)/% fall in Sa,O2). These findings suggest
that augmented chemosensitivity to hypercapnia may be an important factor in the
pathophysiology of central sleep apnoea in patients with heart failure.
PMID- 9543264
TI - Obstructive sleep apnoea and diabetes mellitus: the role of cardiovascular
autonomic neuropathy.
AB - Knowledge of conditions associated with an increased prevalence of obstructive
sleep apnoea (OSA) may help to identify patients with OSA and might give some
insight into the pathogenesis of OSA and its sequelae. A number of earlier,
smaller studies hinted at an association between diabetic cardiovascular
autonomic neuropathy (AN) and OSA. The present study was, therefore, conducted
with the aim of establishing the prevalence of OSA in diabetics with AN and of
determining whether OSA is more prevalent in diabetics with AN, than in those
without. We studied two groups of diabetic patients: 23 with and 25 without AN.
All patients were evaluated for possible OSA (apnoea/hypopnoea index > or = 10)
using initial ambulatory screening followed by polysomnography. Six patients with
AN (26%) were found to have OSA, but none of the patients without AN met the
diagnostic criteria (p<0.01). When the patients with OSA were compared to those
without, no differences were found in terms of age, sex, body mass index or
diabetes type or duration. In conclusion, about one in four diabetic patients
with autonomic neuropathy suffers from OSA. Thus, obstructive sleep apnoea is
more prevalent in diabetic patients with autonomic neuropathy, than in those
without.
PMID- 9543265
TI - Cardiorespiratory consequences of sleep apnoea syndrome in patients with massive
obesity.
AB - Assessment of cardiorespiratory consequences of sleep apnoea syndrome (SAS) is
difficult owing to confounding factors, especially obesity, that are strongly
associated with SAS. This study was designed to assess the cardiorespiratory
consequences of SAS by comparing the results of a comprehensive cardiorespiratory
evaluation in apnoeic and nonapnoeic patients with massive obesity. In a
retrospective chart-review study, we studied 60 patients with massive obesity
defined by a body mass index (BMI) >40 kg.m(-2), presenting no chronic
respiratory disease, who underwent an extensive assessment of cardiorespiratory
consequences of obesity, including overnight polysomnography, lung function
tests, arterial blood gas analysis, evaluation of vascular risk factors,
myocardial scintigraphy with dipyridamole stress-test, isotopic ventriculography,
Doppler echocardiography and Holter electrocardiogram recording. SAS defined by
an apnoea + hypopnoea index (AHI) > or = 10 was diagnosed in 42% of patients (25
out of 60). Mean+/-SD AHI of SAS-positive (SAS+) patients was 38+/-24. Age, BMI,
ventilatory function parameters, prevalence of smoking history and diabetes
mellitus did not differ significantly in SAS+ versus SAS-negative (SAS-) groups.
The following complications were observed more frequently in SAS+ than in SAS-
patients: daytime hypoxaemia (35 vs 9%, p<0.02), pulmonary arterial hypertension
(36 vs 7%, p<0.05) and increased interventricular septal thickness (50 vs 15%,
p<0.03). No association was found between SAS on the one hand and systemic
arterial hypertension, coronary artery disease, left ventricular dysfunction and
nocturnal cardiac arrhythmias on the other. Nocturnal apnoeas in massive obesity
may thus be associated with moderate daytime hypoxaemia, mild pulmonary arterial
hypertension and moderate left ventricular hypertrophy, but not with severe
cardiorespiratory complications.
PMID- 9543266
TI - Effect of inspiratory muscle training with an intermediate load on inspiratory
power output in COPD.
AB - There is very little information about the effect of inspiratory muscle training
on inspiratory flow (V'I) and thus on power output (PO) in patients with chronic
obstructive pulmonary disease (COPD). In this study we aimed to evaluate the
changes induced by training on the determinants of PO. Thirty one patients with
severe COPD were randomly divided into: Group 1, trained with 30% maximal
inspiratory pressure (PI,max); Group 2, with 10% PI,max; and Group 3 also trained
with 30% PI,max, but the breathing pattern was evaluated while performing the
training manoeuvres along inspiratory muscle training (IMT). All groups used a
threshold device for 10 weeks. The PO for each of the loads during an incremental
threshold test was evaluated prior to and after training. Maximal PO (POmax)
increased in all groups, but the increment was higher in groups trained with 30%
PI,max (p<0.005), mainly due to an increase in V'I. Group 3 showed a progressive
increase in V'I (p<0.001) during the training manoeuvres in spite of an increase
in load along IMT. In addition, the load after IMT was overcome with a shorter
inspiratory time (tI) (p<0.02), a smaller tI/total duration of the respiratory
cycle (t(tot)), (p<0.001) with no change in tidal volume or t(tot). The increment
in POmax in this group correlated with the V'I generated while training (r=0.85;
p<0.0001). We conclude that in patients with chronic obstructive pulmonary
disease, the use of an intermediate threshold load for training improves power
output mainly by increasing inspiratory flow, an effect consistent with an
increase in shortening velocity of inspiratory muscles.
PMID- 9543267
TI - Mask intermittent positive pressure ventilation in chronic hypercapnic
respiratory failure due to chronic obstructive pulmonary disease.
AB - Noninvasive ventilation in chronic obstructive pulmonary disease (COPD) has been
shown to improve arterial blood gases but its long-term role has not been
established. We retrospectively studied 26 consecutive patients with hypercapnic
ventilatory failure due to COPD in whom oxygen therapy caused worsening
hypercapnia (defined as a rise in the daytime arterial carbon dioxide tension
(Pa,CO2) to >8.0 kPa or nocturnal transcutaneous carbon dioxide tension (Ptc,CO2)
to >9 kPa). All were treated with mask ventilation (15 with nasal and 11 face
masks) at night and during daytime naps. Additional oxygen therapy was required
in 15 patients. The mean annualized death rate was 10.8% with a 1 and 3 yr
survival of 92 and 68%, respectively. After 1 yr the median daytime Pa,CO2 had
fallen by 1.35 kPa and the arterial oxygen tension (Pa,O2) had risen by 2.4 kPa.
In subjects not using additional oxygen the median overnight Sa,O2 rose by 12%
and the Ptc,CO2 fell by 2.8 kPa after 1 yr. The haematocrit was significantly
less than pretreatment at 6 months and 1 yr. Quality of life in the domain of
role limitation by physical health (measured using the SF-36 questionnaire)
improved significantly at 6 months. Survival in this selected group with
clinically stable airflow obstruction unable to tolerate oxygen therapy and
treated with noninvasive mask ventilation is better than historical controls and
is comparable to those able to tolerate oxygen therapy. Poor survival was
associated with a low forced expiratory volume in one second, a low body mass
index and a high nocturnal transcutaneous carbon dioxide tension. No difference
in survival was found between those treated with mask intermittent positive
pressure ventilation alone or with mask intermittent positive pressure and
supplementary oxygen therapy.
PMID- 9543268
TI - Testosterone levels in men with chronic obstructive pulmonary disease with or
without glucocorticoid therapy.
AB - Under the clinical impression that patients with chronic obstructive pulmonary
disease (COPD) may demonstrate signs compatible with hypogonadism, we
investigated whether oral glucocorticoid therapy is associated with testosterone
deficiency. Thirty six men with COPD of whom 16 were receiving oral
glucocorticoid medication (mean+/-SEM dose 9.4+/-1.1 mg prednisolone) were
investigated in a cross-sectional cohort study. Patients with or without oral
glucocorticoid therapy were not different in terms of age, smoking history and
additional therapy. Vital capacity, forced expiratory volume in one second,
airway resistance, intrathoracic gas volume and blood gases at rest were not
different between the groups. However, patients receiving glucocorticoids had a
shorter 6 min walking distance (mean+/-SEM 205+/-27 versus 288+/-26 m; p=0.02)
compared to patients without oral steroid therapy. Serum levels of testosterone
(mean+/-SEM 13.7+/-0.9) were below normal (<12 nM) in 15 of 36 patients. Serum
testosterone did not correlate with any other evaluated parameter. Serum levels
of free testosterone (free T) (mean+/-SEM 172.3+/-7.8 pM) were decreased in 25 of
the 36 patients, including all patients receiving glucocorticoid treatment. In
the 16 patients taking glucocorticoids free T was correlated (p=0.016) with the
current glucocorticoid dosage (r=-0.504; p=0.007) and the body mass index
(r=0.241; p=0.037). All other parameters examined revealed no significant
correlations in multiple regression analysis. Glucocorticoid treatment appears to
aggravate hypogonadism and a therapeutic study using testosterone in patients
with chronic obstructive pulmonary disease receiving glucocorticoid medication
appears warranted.
PMID- 9543269
TI - Immunological findings in blood and bronchoalveolar lavage fluid in chronic
bronchitis patients with recurrent infectious exacerbations.
AB - Bronchial infections are common in smokers and seem to be related to the presence
of chronic bronchitis (CB). Why only some smokers develop repeated bronchial
infections is not known. The aim of this study was to screen for immunological
changes associated with disease in patients with CB and recurrent infectious
exacerbations compared to asymptomatic smokers. Sixteen smokers with stable CB
and recurrent infectious exacerbations, and 18 asymptomatic smokers, all without
any immunomodulating treatment, underwent bronchoscopy and bronchoalveolar lavage
(BAL). Smoking history and current smoking status were comparable. Serum levels
of immunoglobulin (Ig)A, IgM, IgG and IgG subclasses were measured. Blood and BAL
lymphocyte phenotypes and proliferative responses of peripheral blood mononuclear
cells (PBMCs) to various stimulators were analysed. Unstimulated and tetanus
toxoid-stimulated production of cytokines in PBMC cultures was measured. Natural
killer (NK-) cell activity was analysed. A significantly (p<0.05) lower level of
IgG3 was found in the CB group, and a significantly (p<0.01) higher proliferative
response of PBMCs was found in the CB group after stimulation with diphtheria
toxoid. Detectable levels of interleukin (IL)-6, tumour necrosis factor-alpha
(TNF-alpha) and interferon-gamma, but not of IL-2, IL-4 or transforming growth
factor-beta2, were found in supernatants from cultured cells in both study
groups. Stimulated TNF-alpha production was significantly (p<0.05) higher in the
CB group. NK-cell activity did not differ significantly between the study groups.
There were no major differences between the groups in lymphocyte subpopulations
in blood or BAL. In conclusion, no major alterations in the analysed indices of
cell-mediated and humoral immunity were found in patients with chronic bronchitis
prone to recurrent infectious exacerbations when compared with asymptomatic
smoking controls.
PMID- 9543270
TI - Quality of life in patients with chronic respiratory disease: the Spanish version
of the Chronic Respiratory Questionnaire (CRQ)
AB - The aim of this study was to translate the Chronic Respiratory Questionnaire
(CRQ) into Spanish and to test its measurement properties. The study was
performed in 60 patients with chronic obstructive pulmonary disease (forced
expiratory volume in one second (FEV1) mean+/-SD 35+/-14% of reference value). A
rigorous process of forward and back translation and review produced an easily
comprehensible questionnaire, which was administered together with measures of
pulmonary function and exercise capacity. The patients were randomly allocated to
one of two groups: 30 received respiratory rehabilitation and the other 30
received standard community care only. Weak to moderate statistically significant
correlations (0.2-0.38) were found between the domains of the CRQ and pulmonary
function and exercise measures. For the three CRQ domains that measure
differences between patients at a point in time, Crohnbach's alpha and intraclass
correlation coefficients were: fatigue 0.80 and 0.80; emotional function 0.86 and
0.68; and mastery domains 0.84 and 0.67, respectively. Scores remained stable in
patients who were deemed clinically stable, and showed large statistically
significant improvement (p<0.0001) in patients in the rehabilitation programme.
Only low correlations were found between the changes in CRQ and the changes in
pulmonary function and exercise capacity. The index of responsiveness was 0.92
for fatigue, and 0.91 for dyspnoea, emotional function and mastery. In
conclusion, the Spanish translation of the Chronic Respiratory Questionnaire is
likely to be useful for measuring differences between patients, and particularly
for measuring the effects of intervention on quality of life in chronic
respiratory disease.
PMID- 9543271
TI - Reliability and validity of a Swedish version of the St George's Respiratory
Questionnaire.
AB - The St George's Respiratory Questionnaire (SGRQ) was designed to measure quality
of life (QoL) in obstructive pulmonary disease. Its reliability, validity and
sensitivity have been demonstrated. The aim was to develop a Swedish version of
the SGRQ and to confirm its scaling and clinical properties. The SGRQ was adapted
for Swedish conditions following a translation-backtranslation procedure. The
psychometric and clinical evaluation included 68 patients with chronic
obstructive pulmonary disease (COPD). Supplementary QoL, clinical and
physiological data were collected. A follow-up study was performed 1 yr later.
Correlation analysis used a multitrait-multimethod model. Internal consistency
reliability and discriminant validity were documented by performing a multitrait
analysis. The results confirmed expected levels of associations. Correlation
coefficients between the SGRQ total score and the Sickness Impact Profile Total
score (a generic health measure), forced expiratory volume in one second (FEV1)
and 6 min walking distance were 0.69, -0.42 and -0.61 respectively. The pattern
of correlations in the Swedish data set was very similar to that of the original.
The stability of the SGRQ scores was confirmed at follow-up after 1 yr. The
reliability was satisfactory, with Cronbach's alpha coefficients >0.80 for the
SGRQ and its subdimensions. In conclusion, the Swedish version of the St George's
Respiratory Questionnaire is reliable, valid and compares well with the
corresponding tests of the original version.
PMID- 9543272
TI - Association between health-related quality of life and consultation for
respiratory symptoms: results from the DIMCA programme.
AB - In general practice, diagnosis of chronic obstructive pulmonary disease (COPD) is
hampered by underpresentation. A substantial proportion of subjects experiencing
respiratory complaints do not consult their general practitioner (GP). In this
study, the relationship between disease-specific quality of life and presentation
of respiratory symptoms to a GP is investigated. A random sample from the general
population (undiagnosed subjects) was screened for symptoms and objective signs
of COPD (n=1,155). The lung function of subjects with symptoms of COPD was
monitored for 6 months. During this period, 48 new COPD patients with a
persistently reduced lung function (forced expiratory volume in one second (FEV1)
less than or equal to the predicted value minus 2 SD) were detected. A disease
specific quality-of-life questionnaire (chronic respiratory questionnaire (CRQ))
was administered and clinical and GP consultation data were collected.
Multivariate analysis showed that quality-of-life impairments due to dyspnoea and
fatigue and variability in lung function (bronchial hyperresponsiveness,
reversibility and peak expiratory flow rate variability) were related to medical
consultation. Only 31% of the newly detected patients reported that they had ever
visited their GP for respiratory complaints. A similarly low percentage was found
in the rest of the sample (26%). It is concluded that the mere presence of
respiratory symptoms or a (gradually) reduced lung function is insufficient
reason for patients to seek medical help. Subjects are more likely to consult
their general practitioner once their quality of everyday life is affected or
they experience variability in lung function.
PMID- 9543273
TI - Empirical therapy for nonhospitalized patients with community-acquired pneumonia.
Study Group of General Practitioners.
AB - A prospective survey involving a group of 95 general practitioners (GPs) in
France was conducted to describe antibiotic therapy prescribed for out-patients
with community-acquired pneumonia (CAP). A total of 173 cases of CAP, defined by
the association of fever and pulmonary focal crackles and/or radiological changes
consistent with a pulmonary infection, were reported between February 1993 and
March 1994: 84 males and 89 females (mean age: 48 yrs) of whom 45% had no
underlying disease. Nineteen (11%) were immediately hospitalized and the
remaining 154 out-patients were treated without microbiological investigation.
First-line antibiotic therapy was amoxicillin or amoxicillin-clavulanic acid
combination (57%), a first or second generation cephalosporin (12%), ceftriaxone
(8%), oral broad-spectrum cephalosporin (3%), a macrolide (16%), a tetracycline
(1%) and a fluoroquinolone (2%). A total of 120 (78%) patients recovered with no
change in treatment and 34 (22%) patients failed to improve: 18 were hospitalized
and 16 had a second-line therapy, mainly a macrolide or a quinolone. Five
patients died at hospital. The overall mortality was 3%, and 14% in hospitalized
patients. Empirical therapy using a betalactam to target a presumed pneumococcal
infection, in agreement with European guidelines, is appropriate for out-patients
with mild lobar community-acquired pneumonia.
PMID- 9543274
TI - Distribution of immunoreactive endothelin in the lungs of mice during respiratory
viral infection.
AB - Respiratory tract viral infections are associated with the generation of a wide
array of pro-inflammatory cytokines, some of which enhance the release of the
potent airway smooth muscle spasmogen, endothelin, from respiratory epithelial
cells in tissue culture. The aim of this study was to determine whether the
content and distribution of immunoreactive endothelin in the intact murine lung
is increased during the course of a respiratory tract viral infection. Mice were
inoculated intranasally with Influenza A/PR-8/34 virus or sterile vehicle and at
various days postinoculation were sacrificed, and their lungs processed for
either fluorescence immunohistochemistry with rabbit anti-endothelin sera or
measurement of immunoreactive endothelin with an enzyme-linked immunosorbent
assay (ELISA). At 2 and 4 days postinoculation, the content of immunoreactive
endothelin in lung extracts of virus-infected mice was approximately twice that
present in lung extracts from control mice (n=3-4, p<0.05). Consistent with this,
an increased intensity and broader distribution of fluorescent
immunohistochemical staining for endothelin was observed in the airway epithelium
of the trachea and intrapulmonary airways of virus-infected mice. This study has
clearly demonstrated that respiratory tract viral infection is associated with an
increased content and broader distribution of immunoreactive endothelin within
the lungs of mice. Whether the elevated content of endothelin contributes to the
symptoms of virus-induced hyperresponsiveness or to virus-induced exacerbations
of asthma remains to be established.
PMID- 9543275
TI - Effect of salmeterol on Haemophilus influenzae infection of respiratory mucosa in
vitro.
AB - Haemophilus influenzae is a common bacterial pathogen causing human respiratory
tract infections. We have previously shown that the beta2-agonist salmeterol
reduces damage to the respiratory mucosa caused by Pseudomonas aeruginosa in
vitro. We have now investigated the effect of salmeterol on H. influenzae
infection of adenoid tissue in an organ culture by scanning electron microscopy.
Tissue was preincubated with or without salmeterol (4x10(-7)M), prior to
infection with H. influenzae and incubated for 12 or 24 h. Infected organ
cultures had increased epithelial damage and decreased numbers of both ciliated
and unciliated cells at 12h, which were significantly different (p < or = 0.01)
from the controls at 24 h. Salmeterol (4x10(-7)M) significantly (p < or = 0.03)
reduced damage and loss of ciliated cells in infected organ cultures at both 12
and 24, and significantly (p < or = 0.03) reduced loss of unciliated cells at 24
h. Salmeterol had no effect on the density of bacteria adhering to each
individual mucosal feature or the total number of bacteria adhering to the organ
culture. These results suggest that salmeterol protects the respiratory
epithelium against Haemophilus influenzae-induced damage. The mechanism of
salmeterol cytoprotection and its potential clinical relevance remain to be
investigated.
PMID- 9543276
TI - Adhesion molecule expression in the lung: a comparison between normal and diffuse
interstitial lung disease.
AB - Cellular adhesion molecules are crucial determinants of the migration of immune
effector cells to the tissues. In chronic inflammatory diseases, upregulation of
the expression of these molecules may contribute to the persistent inflammatory
process. The aim of this study was to determine whether there is evidence of
adhesion molecule expression in chronically inflamed lung. Soluble adhesion
molecules in bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked
immunoassay in 54 patients with chronic interstitial lung diseases and 16 normal
controls. Adhesion molecule expression in fibrosing alveolitis (FA) lung and in
control lung was assessed using immunohistology and reverse transcription
polymerase chain reaction (RT-PCR) amplification. Soluble intercellular adhesion
molecule-1 (ICAM-1) was detected in all but two subjects. There was no difference
in ICAM-1 concentration between disease groups and normal subjects. In contrast,
soluble E-selectin was detected in 17 of the 70 subjects and was significantly
associated with the presence of lung disease (p=0.0173). Furthermore, the
presence of soluble E-selectin was associated with a raised lymphocyte percentage
in BALF (p=0.0069). Soluble VCAM was only detected in five of the 70 subjects
(two normals, three patients). There was no difference in adhesion molecule
expression in lung parenchyma between FA and controls assessed by immunohistology
and RT-PCR. The most striking finding of our study was the universal expression
of intercellular adhesion molecule-1 in both normal and diseased lung,
emphasizing the important role of the lung in immune function. Upregulation of E
selectin may contribute to inflammatory cell accumulation in chronic interstitial
lung diseases.
PMID- 9543277
TI - Changing strategies of lung biopsies in diffuse lung diseases: the impact of
video-assisted thoracoscopy.
AB - The aims of this report were: 1) to compare the strategy of bioptic approach in
Italy during the last 4 yrs with a previous period; and 2) to compare efficacy
and safety of video-assisted thorascopic lung biopsy (VTLB) versus OLB. We
retrospectively evaluated: 1) the strategy of the bioptic approach in the Milan
Sarcoid Clinic in the years 1992-1995 (201 patients) versus 1988-1991 (197
patients); and 2) data from 65 VTLB procedures in the years 1992-1995 versus 68
OLB procedures in the years 1988-1991 performed in patients with diffuse lung
disease. It was found that the use of OLB (17-9%), mediastinoscopy (15-5%), and
scalene node biopsy (20-7%) decreased, whereas transbronchial biopsy (TBB)
increased (11-17%). VTLB biopsy is now performed in 17% of patients. VTLB
compares favourably with OLB as there is less need for analgesia (7.5+/-7.5
versus 17.5+/-8.0 methadone mg i.m.: p<0.001), lower blood loss (61+/-58 versus
156+/-84 mL in the first postoperative day: p<0.001), and shorter postoperative
stay (4.7+/-1.6 versus 5.7+/-1.4 days: p<0.001). Specimen adequacy (98.6 versus
985%) and diagnostic accuracy (86.1% VTLB, versus 92.6% OLB: p>0.05) were the
same in the two groups. In conclusion, video-assisted thoracoscopic lung biopsy
is replacing both mediastinoscopy and open lung biopsy. It is at present the best
option when a surgical procedure is required for histological confirmation of
diffuse lung disease.
PMID- 9543278
TI - Elevated concentrations of defensins in bronchoalveolar lavage fluid in diffuse
panbronchiolitis.
AB - Human neutrophils contain three isoforms of antimicrobial and cytotoxic peptides
in the azurophil granules, which belong to a family of mammalian neutrophil
peptides named defensins. Here we investigate the role of these peptides in
diffuse panbronchiolitis (DPB). Defensins (human neutrophil peptide-1, -2 and -3)
were measured by radioimmunoassay in bronchoalveolar lavage fluid (BALF) of 30
patients with DPB, 16 patients with idiopathic pulmonary fibrosis (IPF) and 15
healthy adults. The concentration of defensins was higher in BALF of patients
with DPB than in patients with IPF and healthy subjects. DPB and IPF patients
also had significantly higher plasma concentrations of defensins than controls.
In patients with DPB, BALF concentration of defensins correlated significantly
with neutrophil count or BALF concentration of interleukin (IL)-8.
Immunohistochemistry of open-lung biopsy specimens from four DPB patients showed
localization of defensins in neutrophils and mucinous exudate in the airways, and
on the surface of bronchiolar epithelial cells. In vitro studies showed an
enhanced extracellular release of defensins following stimulation of neutrophils
with phorbol myristate acetate, N-formyl-methionyl-leucyl-phenyalamine, and human
recombinant IL-8. Treatment of DPB with macrolides for 6 months significantly
reduced neutrophil count and concentrations of defensins and IL-8 in BALF. Our
results indicate accumulation of neutrophil-derived defensins in the airway in
diffuse panbronchiolitis, and suggest that defensins may be a marker of
neutrophil activity in this disease.
PMID- 9543279
TI - Soluble complement receptor type 1 (CD35) in bronchoalveolar lavage of
inflammatory lung diseases.
AB - Complement receptor type 1 (CR1) (CD35; C3b/C4b receptor) is a transmembrane
protein of many haematopoietic cells. Once cleaved, soluble complement receptor
type 1 (sCR1) exerts opposite effects as a powerful inhibitor of complement. This
study addressed both the question of whether sCR1 was found in bronchoalveolar
lavage (BAL) of normals and patients with various inflammatory disease, and its
possible origin. In this retrospective study covering specimen and clinical data
of 124 patients with acute and chronic inflammatory lung pathologies, BAL
supernatants were analysed by enzyme-linked immunosorbent assay technique for
sCR1. Correlations were made between the sCR1 levels obtained and the
constituents of BAL. Human alveolar macrophages were cultivated in order to
determine their secretory capacity of sCR1. Alveolar macrophages from normal
subjects were shown to release sCR1 in vitro. In addition, sCR1 was present in
BAL of normal controls and was significantly increased in acute inflammatory lung
diseases such as acute respiratory distress syndrome (ARDS), bacterial and
Pneumocystis carinii pneumonia, as well as in chronic inflammatory diseases such
as interstitial lung fibrosis and sarcoidosis. In BAL of ARDS, bacterial, and P.
carinii pneumonia, there was a good correlation between sCR1 and the absolute
neutrophil counts. In sarcoidosis, a correlation was found with BAL lymphocyte
counts. Serum sCR1 was not increased in patients compared to controls. Soluble
complement receptor type 1 (sCR1) is found in the bronchoalveolar lavage in
health as well as in acute and chronic inflammatory disease. Alveolar macrophages
are capable of releasing sCR1 in vitro and may be the main physiological source
of sCR1 in the alveoli. The good correlation between sCR1 and the absolute
neutrophil or lymphocyte numbers in bronchoalveolar lavage of inflammatory
diseases suggests a predominant role of leucocytes for the release of sCR1 in
such conditions. The release of this inhibitor of complement may be crucial to
control and reduce complement activation and thus prevent lung injury.
PMID- 9543280
TI - Neutrophil elastase: alpha-1-proteinase inhibitor complex in serum and
bronchoalveolar lavage fluid in patients with pulmonary fibrosis.
AB - It was hypothesized that neutrophil elastase released from activated neutrophils
may play an important role in the pathogenesis of pulmonary fibrosis. In the
present study, we measured the neutrophil elastase:alpha-1-proteinase inhibitor
complex (E-PI) in serum and bronchoalveolar lavage fluid (BALF) in 26 patients
with pulmonary fibrosis and evaluated the correlation between E-PI levels and
several parameters. E-PI levels in serum of patients with pulmonary fibrosis
(635.8+/-112.0 ng.mL(-1)) were significantly elevated compared to normal
nonsmokers (122.0+/-4.0 ng.mL(-1)) as well as normal smokers (132.8+/-8.4 ng.mL(
1)) (p<0.01). E-PI levels in serum significantly correlated with hepatocyte
growth factor (HGF) levels in serum, C-reactive protein (CRP), and negatively
correlated with arterial oxygen tension (Pa,O2), and arterial carbon dioxide
tension (Pa,CO2). E-PI/albumin levels in BALF significantly correlated with
HGF/albumin levels in BALF, lactate dehydrogenase (LDH)/albumin in BALF, total
number of inflammatory cells (alveolar macrophages and neutrophils) in BALF, and
several markers derived from epithelial cells in BALF. Our data demonstrated: 1)
neutrophil elastase:alpha-1-proteinase inhibitor complex in serum increased in
patients with pulmonary fibrosis; and 2) neutrophil elastase:alpha-1-proteinase
inhibitor complex in serum and bronchoalveolar lavage fluid correlated with
clinical parameters in pulmonary fibrosis. These results suggest that neutrophil
elastase may play a significant role in the process of lung injury in pulmonary
fibrosis.
PMID- 9543281
TI - Relationship between exhaled nitric oxide and airway hyperresponsiveness
following experimental rhinovirus infection in asthmatic subjects.
AB - Exhaled nitric oxide (NO) is elevated in asthmatics, and varies with disease
severity. We postulated that a respiratory virus infection increases exhaled NO
levels in asthma, and examined the relationship between the virus-induced changes
in exhaled NO and in airway hyperresponsiveness to histamine. In a parallel
study, seven patients underwent experimental rhinovirus 16 (RV16) inoculation at
days 0 and 1, whilst seven patients received placebo. Exhaled NO was measured at
baseline (day 0) and at days 1, 2 and 3 after inoculation. Histamine challenges
were performed prior to (day -7) and after inoculation (day 3), and were
expressed as provocative concentration causing a 20% fall in forced expiratory
volume in one second (FEV1) (PC20). Following RV16 infection there was a
significant increase in NO at days 2 and 3 as compared to baseline (median change
(range): 4.2 (7.5) parts per billion (ppb), p=0.03, and 3.0 (10.1) ppb, p=0.02,
respectively). Furthermore, PC20 decreased significantly following RV16 infection
(mean+/-SD change in doubling dose: -0.65+/-0.54, p=0.02), whereas PC20 did not
change in the placebo group (p=0.1). There was a significant correlation between
the RV16-induced changes in exhaled NO levels at day 2 and the accompanying
changes in PC20 at day 3 (rank correlation coefficient (rs): 0.86, p=0.01).
Hence, the greater the increase in exhaled NO, the smaller the decrease in PC20.
We conclude that rhinovirus infection increases exhaled nitric oxide levels in
asthmatics, and that this increase is inversely associated with worsening of
airway hyperresponsiveness to histamine. These results suggest that viral
induction of nitric oxide synthase within the airways may play a protective role
in exacerbations of asthma.
PMID- 9543282
TI - Superoxide anion production by monocytes of corticosteroid-treated asthmatic
patients.
AB - Reactive oxygen species play an important role in promoting inflammation. Blood
monocytes have been described to release higher amounts of superoxide anion in
uncontrolled and untreated asthmatics. Corticosteroids are widely used in asthma,
but little is known about their molecular mechanism of action. The aim of our
study was to analyse the ex vivo effect of corticosteroid treatments on
superoxide anion release by blood monocytes. Superoxide anion release was
measured by a spectrophotometric method based on the superoxide dismutase (SOD)
inhibitable reduction of ferricytochrome C by blood monocytes from untreated
patients and asthmatics treated with i.v., inhaled and oral corticosteroids.
Monocytes from uncontrolled and untreated asthmatics, released high amounts of
superoxide anions. After short-term treatment with i.v., corticosteroids, this
release was found to decrease significantly (1.410 versus 0.340 nM, p<0.05).
Cells from asthmatics who had undergone long-term treatment with inhaled or oral
steroids presented low amounts of superoxide anion production, with a significant
difference as compared to untreated asthmatics (0.375 nM p<0.01 and 0.620 nM
p<0.02 respectively). In general, patients with controlled asthma (treated with
short-term oral steroids, or with long-term inhaled steroids) released lesser
amounts of superoxide anion than uncontrolled and untreated asthmatics. In the
case of steroid-dependent asthmatics there was no difference between patients
with a controlled or uncontrolled disease.
PMID- 9543283
TI - Effects of long-term inhaled corticosteroids on skin collagen synthesis and
thickness in asthmatic patients.
AB - There are only a few studies on the adverse effects of inhaled corticosteroids on
the skin in asthmatic patients. Therefore, we evaluated the effect of inhaled
corticosteroids on de novo collagen synthesis of skin and bone, skin thickness
and the total amount of skin collagen. Twenty seven consecutive new asthmatic
patients, on a moderate dose of budesonide or beclomethasone dipropionate, were
invited to take part in this prospective study. Radioimmunological analyses of
aminoterminal propeptides of type I and III procollagens (PINP, PIIINP,
respectively) in suction blister fluid (SBF) of skin and in serum and
carboxyterminal propeptide of type I procollagen (PICP) and cross-linked carbox
terminal telopeptide of type I collagen (ICTP) in serum were performed at entry
and after 3 and 6 months of inhaled corticosteroid treatment. Ultrasound
measurements of skin thickness at two sites were performed at entry, at 3 and 6
months and after 1-2 yrs of inhaled corticosteroid treatment in 20 patients, six
of whom had been prescribed one or more courses of oral corticosteroids. Skin
hydroxyproline of punch biopsies was determined to measure the total amount of
skin collagen (males, at entry and at 6 months). Skin thickness and the total
amount of skin collagen on the abdomen were unchanged after 1-2 yrs of inhaled
corticosteroid use. A slight decrease was observed in the upper arm skin
thickness, especially in those subjects who had received inhaled plus oral
corticosteroids. The procollagen propeptide concentrations (PINP, PIIINP) were
markedly decreased in SBF at 3 months and remained at this level at 6 months. In
serum, a slight decrease was seen in the PINP, PIIINP and ICTP concentrations at
3 and 6 months. In conclusion, inhaled corticosteroids decrease the collagen
synthesis of skin and bone, but skin thickness and the total amount of collagen
in skin are not changed markedly after 1-2 yrs of treatment.
PMID- 9543284
TI - Effects of oral hyposensitization with recombinant Der f2 on immediate airway
constriction in a murine allergic model.
AB - Recombinant Der f2 (rDer f2) has recently been developed as a promising allergen
for the diagnosis and immunotherapy of house-dust mite allergy, and studies in
immunology. The aim of the present study was to evaluate whether oral
administration of rDer f2 could suppress an immediate allergic reaction in mice
sensitized with mite allergen. We developed a murine allergic model that showed
bronchoconstriction after inhalation of rDer f2, and studied the effect of oral
administration of rDer f2 on the reaction. Seven week old male A/J mice were
intranasally immunized with rDer f2 12 times. Sensitized mice showed anti-rDer f2
immunoglobulin (Ig)E production and immediate airway constriction after
inhalation of 10 mg.mL(-1) of rDer f2, as determined by the Konzett-Rossler
method. Immunized animals were divided into three groups, and fed phosphate
buffered saline (PBS), 0.1 mg.day(-1), or 1 mg.day(-1) of rDer f2 for 4 weeks,
respectively. Seven days after the last feeding, the mice were examined for their
immediate response. Animals fed with 1 mg.day(-1) rDer f2 showed significantly
reduced bronchoconstriction after inhalation of both 2 mg.mL(-1) and 10 mg.mL(-1)
of rDer f2 compared with PBS-fed mice. Similar results were obtained when we
examined mice 10 weeks after the last feeding. Reactions in the 0.1 mg.day(-1)
rDer f2-fed group also tended to decrease in comparison with PBS-fed animals.
Plasma anti-rDer f2 IgE, IgG1, IgG2a, and IgG2b levels were not changed by
feeding with rDer f2. We conclude that recombinant Der f2 exhibits both
sensitizing and hyposensitizing activities in mice. rDer f2 may be useful in
immunotherapy and diagnosis of house-dust mite allergy.
PMID- 9543285
TI - Reported food intolerance and respiratory symptoms in young adults.
AB - The aim of the study was to assess the ability of the European Community
Respiratory Health Survey (ECRHS) questionnaire to provide data on the
prevalence, type and reported symptoms associated with food intolerance from a
group of young adults in Melbourne. Six hundred and sixty nine randomly selected
subjects completed the questionnaire with 553 attending the laboratory for skin
prick tests, anthropometry, and ventilatory function tests. A further 207
symptomatic participants completed the questionnaire, with 204 of them attending
the laboratory. Seventeen per cent of all respondents reported food intolerance
or food allergy. A wide variety of food items was cited as being responsible for
food-related illnesses. Those with current asthma did not report food-related
illness more frequently than those without asthma. Respondents who reported
respiratory symptoms following food ingestion were more likely to be atopic, to
have used inhaled respiratory medications in the previous 12 months, reported
less exposure to regular passive smoking over the past 12 months and weighed
more. These associations between respiratory symptoms and food intolerance
require further prospective investigation and verification. The importance of
using appropriate dietary methodology in future studies for determining diet
disease relationships was highlighted by this study.
PMID- 9543286
TI - Airway dynamics, oesophageal pressure and cough.
AB - This study hypothesizes that: peak supramaximal airflow during cough reflects
expiratory muscle effort, and that expiratory muscle function during cough might
be assessed from the airflow signal alone. We monitored airflow and oesophageal
pressure (Poes) in normal subjects during cough generated under two conditions:
1) voluntarily from functional residual capacity (FRC); and 2) involuntarily
after inhalation of citric acid (CA). Maximal expiratory cough flow was
quantified as the quotient of maximal flow during a given cough divided by
maximal flow at the matched volume of thoracic gas (Vtg) as identified on the
maximal expiratory flow-volume curve. We found: flow ratios correlated poorly
with Poes; the variance of flow ratios associated with a series of voluntary
coughs was poorly explained by Poes. During CA inhalation, when the Vtg
compressed during cough could not be controlled, correlation of Poes with flow
ratio remained poor. We conclude that to study the motor limb of the cough
reflex, measurements of both airflow and oesophageal pressure are required.
PMID- 9543287
TI - High dose rate endobronchial brachytherapy: results and complications in 189
patients.
AB - The purpose of this study was to determine the benefit of high dose rate
endobronchial brachytherapy in the treatment of obstructive lung cancer. Between
September 1990 and March 1995, 189 patients with bronchogenic carcinoma were
treated with high dose rate endobronchial brachytherapy. Most patients (69.3%)
had received prior treatment and presented with symptomatic bronchial obstruction
due to either recurrent or residual endobronchial disease. A small group (12%)
was medically unfit for either surgical resection or thoracic radiotherapy and
benefited from endobronchial brachytherapy alone for small endobronchial tumours.
The remainder of the patients had not been treated previously and endobronchial
brachytherapy was performed for life-threatening symptoms requiring emergency
obstruction relief before other therapy. Treatment was performed weekly and
consisted of three to four 8 to 10 Gy fractions at a radius of 10 mm from the
centre of the source. Major symptomatic relief was obtained for haemoptysis
(74%), dyspnoea (54%), and cough (54%). Complete endoscopic response was observed
in 54% of cases. Median survival was 7 months for the entire group. For small,
strictly endobronchial tumours, complete response rate was 96%, median survival
17 months, and 30 month survival 46%, with a plateau starting at 18 months. Grade
3 to 4 toxicities occurred at a rate of 17% and included massive haemoptysis
(n=13), bronchial stenosis (n=12), soft tissue necrosis (n=8), and bronchial
fistula (n=3). By univariate analysis, no factor was found to be predictive of
late pulmonary toxicity. The present study confirms the usefulness of
endobronchial brachytherapy in alleviating symptoms caused by endobronchial
recurrence of bronchogenic carcinoma. In addition, this therapy can be tried with
curative intent in patients who present with small endobronchial tumours and are
not candidates for other forms of therapy.
PMID- 9543288
TI - Radiographically occult lung cancer treated with fibreoptic bronchoscopic
electrocautery: a pilot study of a simple and inexpensive technique.
AB - The curative potential of bronchoscopic intervention, e.g. photodynamic therapy
(PDT) and brachytherapy, for resectable radiographically occult lung cancer has
been reported previously. Bronchoscopic electrocautery is currently feasible
using an insulated flexible bronchoscope to coagulate and vaporize tumour tissue.
Since the lesions are usually small, noninvasive bronchoscopic electrocautery may
be able to eradicate radiographically occult lung cancer completely. In a
prospective study, 13 patients with 15 radiographically occult lung cancer
lesions were treated with bronchoscopic electrocautery. The duration of follow-up
was > or = 16 months. The median age of the patients was 69 yrs (range 48-79
yrs). Fibreoptic bronchoscopy under local anaesthesia was used to coagulate the
occult lung cancer. Approximately 30 W of energy was applied until visible
necrosis of the tumour area became apparent. There were no immediate
complications. In 10 patients with 12 lesions, a complete response (CR) was
obtained (CR rate 80%; 95% confidence interval (95% CI) 52-96%). Median duration
of follow-up was 21 months (range 16-43 months). Bronchoscopic electrocautery did
not obtain a CR in the remaining three patients, but PDT also failed to achieve
CR. Two patients underwent radical resection, and the tumours were histologically
confirmed to be more invasive. One patient received external radiotherapy. Three
patients with a CR died during follow-up, two as a result of myocardial
infarction and apoplexy, and one because of metastasis from his previously
resected T3N1 primary large cell cancer. Current data show bronchoscopic
electrocautery to be equally effective and potentially as curative as
photodynamic therapy for treating patients with radiographically occult lung
cancer. Obvious advantages are that it is an inexpensive and simple procedure,
which does not cause photosensitivity.
PMID- 9543289
TI - Depressive reactions to lung cancer are common and often followed by a poor
outcome.
AB - In diverse human malignancies, including lung cancer, quality of life (QOL)
affects the clinical outcome of patients. Many QOL dimensions, however, are
influenced by physical status. The current study was undertaken to delineate the
role of depression, a state of mind not necessarily influenced by somatic
factors. All patients, seen for a newly diagnosed carcinoma of the lung, received
a copy of the Self-rating Depression Scale (SDS) proposed by W.W.K. Zung. One
hundred and thirty three patients were able and willing to complete the
questionnaire. A depression index was calculated, as originally described.
Nineteen other prognostically important variables were recorded and available for
evaluation. Among the 95 patients who completed all 20 items included in the
questionnaire, 53 had an SDS index < or = 50 (no depression), while 42 were
moderately or severely depressed (SDS index >50). The survival of depressed
patients was significantly lower (p=0.048). Diverse SDS subscales were associated
with survival, in either univariate or multivariate analysis. SDS item 19, "I
feel that others would be better off if I were dead", emerged as the most
significant one. A multivariate model of survival, constructed using only SDS
data, had a global Chi-squared value of 29.78, and a p-value of 0.00023. Based on
this evidence, it appears that a relationship does exist between patients'
depression and prognosis, at least in lung cancer. Further studies are needed to
clarify the prognostic effect of depression in more specific (and homogeneous)
subgroups of patients.
PMID- 9543290
TI - Accuracy of thermistors and thermocouples as flow-measuring devices for detecting
hypopnoeas.
AB - The aim of this work was to assess the accuracy of thermistors/thermocouples as
devices for detecting hypopnoeas in sleep studies. Conventional
thermistor/thermocouples were studied with a respiratory model allowing the
simulation of inspiratory (22 degrees C) and expiratory (37 degrees C) flows. The
thermistor signal (V'th) was compared with a pneumotachograph (V'th): 1) for
sinusoidal and square-wave airflows (+/-0.05 to +/-0.8 L.s(-1), 10-20
breaths.min(-1) (bpm)); 2) when changing the distance from the thermistor to the
nose (0-20 mm); and 3) when doubling the section of the nostrils. The thermistor
was strongly nonlinear and flow reductions (hypopnoeas) were underestimated: a
50% reduction in V' (+/-0.5 L.s(-1), 15 bpm, sinusoidal) resulted in only an 18%
reduction in V'th. V'th depended considerably on the airflow pattern: for V'=+/
0.5 L.s(-1), V'th increased by 100% from sinusoidal (20 bpm) to square-wave (10
bpm). For V'=+/-0.5 L.s(-1), 15 bpm, sinusoidal flow, V'th increased by 79% when
the distance thermistor-nose varied from 20-0 mm, and V'th decreased by 37% when
doubling the nose section. We concluded that thermistor/thermocouples are
inaccurate flow-measuring devices when used at the airflow conditions typical of
sleep studies. Their use for quantifying hypopnoeas may lead to considerable
underdetection of these respiratory events.
PMID- 9543291
TI - Assessment of the lactate biosensor methodology.
AB - The rapid determination of lactate level is useful for clinical emergencies, as
in the case of shock conditions or during surgical operations, as well as in
numerous cases of respiratory failure, in cardiac or paediatric pathology and
during exercise tests. Moreover, it is of prognostic significance in critically
ill patients. Photometric methods are slow and, even when performed in good
conditions, will give results only 30 min after blood collection, during which
time the clinical condition of the patient may change. In this study, we have
assessed the lactate biosensor, a method that yields lactate measurements in less
than 1 min with only 100 microL of biological fluid. In order to test the
validity of this method, we performed comparisons between the Sigma classical
enzymatic reference method and two commercially available biosensors: the Ciba
Corning biosensor 865 and the Yellow Springs lactate biosensor. Lactate
measurements were performed in heparinized arterial blood samples without
antiglycolitic agent (n=71). In order to cover a wide range of lactate levels,
samples came from patients admitted to the intensive care unit for severe
conditions and patients addressed for bicycle exercise testing. Each whole blood
sample was processed in duplicate by both biosensors. For plasma measurement,
subsamples of whole blood were centrifuged and the resulting plasma were
processed by the biosensors and the Sigma method. Two parameters that can
potentially influence lactate measurement were also investigated: haematocrit and
total protein levels. The data showed that measurements performed on plasma are
satisfactory for both biosensors. For whole blood, the Ciba-Corning device gives
accurate results but the Yellow Springs apparatus seriously underestimates
lactate levels. This underestimation is strongly influenced by the haematocrit
level, so that a correction factor can be calculated (based on the haemoglobin
level), which allows accurate "corrected" results to be obtained for whole blood
with the Yellow Springs analyser.
PMID- 9543292
TI - Eleven peak flow meters: a clinical evaluation.
AB - Peak flow meters are essential tools in the management of asthma. Many types are
on the market. A computer-driven piston pump is normally not available for
evaluation of the various meters. Comparison with values from a pneumotachograph
is an accepted way of testing peak flow meters. This study aims at comparing 11
peak flow meters, for accuracy and linearity. Seven adult peak flow meters were
tested: Miniwright with an equidistant scale (Clement Clarke); Personal Best
(Healthscan); Wright Pocket fdE (Ferraris); Vitalograph (Vitalograph); Assess
(Healthscan); Pocket Peak flow meter (Micro Medical); and Truzone (Monaghan).
Furthermore, four low-range (LR) peak flow meters were tested: LR Miniwright with
equidistant scale (Clement Clarke); LR Personal Best (Healthscan); LR Wright
Pocket (LR Ferraris); and LR Pocket peak flow meter (LR Micro Medical). Two test
series were performed: in the first one, a peak flow meter was connected
downstream in series with a Fleisch #4 pneumotachograph. One subject performed 50
partial forced expiratory manoeuvres through this ensemble. In the second series,
50 adult patients and 25 healthy children performed sequential maximal forced
expiratory manoeuvres on each peak flow meter, and on the pneumotachograph. A
ranking system was devised for the various parameters of agreement of the meters
with the pneumotachograph. Substantial differences in the quality of the adult
meters were found. The adult peak flow meters with the closest agreement to the
pneumotachograph were Personal Best and Micro Medical. In the low-range peak flow
meters, the lowest differences were seen in the LR Personal Best and LR Micro
Medical.
PMID- 9543293
TI - Magnetic resonance imaging of the thorax in the evaluation of asbestosis.
AB - The purpose of the study was to evaluate the accuracy of magnetic resonance
imaging (MRI) in detecting subclinical morphological changes caused by asbestos
exposure. Conventional chest radiographs according to the International Labour
Organisation (ILO) categories 0-11 and spirometric data were compared with MRI in
17 men with mean (+/-2SD) asbestos exposure time of 24.6+/-13.0 yrs. Mean age was
62.0+/-9.4 yrs. The inclusion criterion was an ILO score of 2 or more.
Electrocardiographic registrations and antirespiratory movement artefact
techniques were used in all MRI examinations to avoid movement artefacts. Mean
ILO grading was found to be 7.7+/-3.8 on chest radiography and 9.8+/-2.0 with MRI
(p=0.01). Five patients had a higher ILO stage as evaluated by MRI, but in nine
patients the staging remained unchanged. MRI revealed mediastinal adenopathy in
four patients. Forced expiratory volume in one second (expressed as a percentage
of the predicted value) was negatively correlated with ILO score as assessed by
MRI (r=-0.4, p=0.032). Magnetic resonance imaging seems to be more sensitive than
conventional radiographs in detecting subclinical fibrosis as well as the extent
of pleural asbestosis.
PMID- 9543294
TI - Functional evaluation of the lung resection candidate.
AB - Advances in operative technique and perioperative care have considerably reduced
surgical morbidity and mortality after pulmonary resections. Various single and
combined parameters of functional operability have been proposed to assess the
surgical risk. Pulmonary function tests adequately assess the pulmonary risk, and
baseline or stress electrocardiography, echocardiography and nuclear cardiac
studies assess the cardiac risk. Patients with normal or only slightly impaired
pulmonary function (forced expiratory volume in one second (FEV1) and transfer
factor of the lung for carbon monoxide (TL,CO) > or = 80% of predicted) and no
cardiovascular risk factors can undergo pulmonary resections up to a
pneumonectomy without further investigation. For others, exercise testing,
pulmonary split-function studies, or a combination of these two methods are
recommended. Exercise testing, most frequently performed as a symptom-limited
test with the measurement of maximal oxygen uptake (V'O2,max), assesses both the
pulmonary and cardiovascular reserves. A V'O2,max of <10 mL.kg(-1).min(-1) is
generally considered prohibitive for any resection, a value of >20 mL.kg(-1).min(
1) or >75% of predicted normal, safe for major resections. Split-function studies
are radionuclide-based estimations of the predicted postoperative (ppo) values of
various parameters. The currently used ppo-parameters are FEV1-ppo, TL,CO-ppo
and, most recently, V'O2,max-ppo. Suggested cut-off values for safe resection
are: for FEV1-ppo and TL,CO-ppo > or = 40% pred; and for V'O2,max > or = 35%
pred, combined with an absolute value of > or = 10 mL.kg(-1).min(-1). The lowest
acceptable ppo-values will still have to be established by additional prospective
studies. In the long-term, resections involving not more than one lobe usually
lead to an early functional deficit followed by later recovery. The permanent
functional loss in pulmonary function is small (< or = 10%) and exercise capacity
is only slightly reduced or not at all. Pneumonectomy, on the other hand, leads
to an early permanent loss of about 33% in pulmonary function and 20% in exercise
capacity. Thus, pulmonary function tests alone overestimate the functional loss
after lung resection.
PMID- 9543295
TI - Thoracoscopy--state of the art.
AB - "Medical" thoracoscopy as compared with "surgical" thoracoscopy (which is more
precisely known as video-assisted thoracic surgery (VATS)) has the advantage that
it can be performed under local anaesthesia or conscious sedation, in an
endoscopy suite, using nondisposible rigid instruments. Thus, it is considerably
less invasive and less expensive. The main diagnostic and therapeutic indications
for medical thoracoscopy are pleural effusions and pneumothorax. Due to its high
diagnostic accuracy, approaching almost 100% in malignant and tuberculous pleural
effusions, it should be used when pleural fluid analysis and needle biopsy are
nondiagnostic. In addition, medical thoracoscopy provides staging for lung cancer
and diffuse malignant mesothelioma. Talc poudrage, as the best conservative
method for pleurodesis in 1998, can also be performed with medical thoracoscopy.
It can also be effectively used in the early management of empyema. In
spontaneous pneumothorax it allows staging, thereby facilitating treatment
decisions, and in addition coagulation of eventual blebs and talc poudrage for
efficient pleurodesis. Medical thoracoscopy is a safe procedure which is even
easier to learn than flexible bronchoscopy. Due to its high diagnostic and
therapeutic efficiency, it should be applied increasingly in the management of
the above-mentioned pleuropulmonary diseases.
PMID- 9543296
TI - Experimental models for studying mucociliary clearance.
AB - Respiratory tract mucus is a viscoelastic gel, the rheological properties of
which are determined mainly by its content of mucous glycoproteins and water. The
rheology and quantity of mucus, in concert with ciliary factors, are the major
determinants of mucociliary clearance. A wide range of animal models for studying
the secretion and clearance of mucus are available. Ex vivo models, such as the
frog palate or excised bovine trachea, provide direct, meaningful data regarding
the clearability of mucus. Rodent models of chronic bronchitis, based on irritant
gas or cigarette smoke exposure, show important features of the human condition
in a relatively short time. The rheological characterization of mucus is made
difficult by the small quantities obtainable, particularly from normal animals.
Large animal models, such as the dog or sheep, although more expensive, offer
many advantages, such as the ability to carry out long-term serial measurements,
and to make integrated measurements of the clearance of mucus, ciliary function,
epithelial ion transport, and the rheology of mucus in the same preparation.
PMID- 9543297
TI - A childhood asthma death in a clinical trial: potential indicators of risk.
AB - A 9 yr old girl with a history of eczema and asthma was admitted to our
specialist asthma service and recruited into a trial designed to investigate
systemic as well as therapeutic benefits of inhaled corticosteroids. Eight months
after referral the patient died from an acute asthma attack. This childhood
asthma death during an inhaled steroid trial has facilitated identification of
risk factors. Despite good clinical response to inhaled corticosteroids, the
patient was distinguishable from the other patients by: increased variability of
the morning and evening peak flow rates; increased reactivity, though not
sensitivity, to histamine; and an unprecedented rise in serum soluble interleukin
2 receptor levels immediately after commencing inhaled steroids. The
immunological basis for corticosteroid resistance and immunohistochemical studies
on postmortem specimens from asthma deaths suggest that T-cell activation markers
may be indicators of the fatality prone asthmatic.
PMID- 9543298
TI - High-frequency ventilation augments the effect of inhaled nitric oxide in
persistent pulmonary hypertension of the newborn.
AB - Does inhaled nitric oxide (iNO) during high-frequency ventilation (HFV) lead to a
more pronounced improvement in oxygenation than iNO during conventional
ventilation? We report two cases of newborn infants with profound hypoxaemia, who
did not respond with an increase in arterial oxygenation following iNO therapy
during conventional mechanical ventilation. The first infant was a term neonate
with persistent pulmonary hypertension of the newborn (PPHN) following postnatal
hypoxia, the second patient a premature infant of 29 weeks of gestation with PPHN
secondary to lung hypoplasia and perinatal asphyxia. After the initial failure of
iNO we switched both neonates to HFV without NO, which did not lead to a
significant improvement of oxygenation in either case. Shortly after the
initiation of HFV a second trial of iNO was started. Both infants responded
favourably to iNO with a marked and sustained increase in arterial oxygenation
and absent right-to-left shunting via the ductus arteriosus and the foramen
ovale. We conclude that the favourable response to inhaled nitric oxide is
dependent on the degree of lung expansion and is more readily achieved by the use
of high-frequency ventilation than conventional ventilation.
PMID- 9543299
TI - Bronchoalveolar lavage cell analysis in a child with chronic lipid pneumonia.
AB - In an asymptomatic 4 yr old child with radiographic evidence of parenchymal lung
disease, bronchoalveolar lavage (BAL) yielded the diagnosis of chronic lipid
pneumonia caused by chronic aspiration of mineral oil given as a laxative. BAL
analysis showed a marked reduction in the total number of alveolar macrophages;
almost 70% of these cells contained intracytoplasmic lipid vacuoles. It also
disclosed lymphocytic (cytotoxic/suppressor) alveolitis. A high percentage of
lymphocytes expressed antigen markers of activation (human leucocyte antigen
(HLA)-DR), CD54 and CD25). BAL analysis 18 months after mineral oil intake
revealed that lymphocytes bearing antigen markers of activation had markedly
decreased whereas alveolar macrophages (normal and lipid-laden) had increased. A
subsequent whole lung BAL was considered unnecessarily invasive in this otherwise
healthy child.
PMID- 9543300
TI - An unusual presentation of secondary pleural hydatidosis.
AB - Although pleural involvement is relatively common in cystic hydatid disease, one
of the rarest and least known complications is secondary pleural hydatidosis. We
report the case of a patient who presented with polycystic secondary pleural
hydatidosis 4 yrs after treatment for a pyopneumothorax caused by rupture of a
pulmonary cyst near the pleural space. Due to the coexistence of severe chronic
obstructive pulmonary disease, surgery was ruled out. The patient was treated
with albendazole, with a favourable outcome.
PMID- 9543301
TI - Multiple breath helium dilution measurement of lung volumes in adults.
PMID- 9543302
TI - Corticosteroid-resistant asthma: pathogenesis and clinical implications for
management.
PMID- 9543303
TI - Prevalence of mood disorders in the rural population of Udmurtia.
AB - A sample of 855 rural adult inhabitants of Udmurtia was interviewed by means of
the Composite International Diagnostic Interview (CIDI) in order to investigate
the incidence and prevalence of mood disorders. Depression affected 30.5% of the
population according to ICD-10, and 22% according to DSM-III-R over a 12-month
period. Depressive disorders were more common in women (40.5%) than in men
(17.4%), and in subjects who were widowed (68.8%), divorced (55.6%) or had poor
family relationships. Depression was not related to ethnicity, educational level,
income or living conditions. Depression showed a high level of comorbidity with
social phobia in Udmurts and with persistent somatoform pain disorder in Russian
women. The annual incidence of depressive episode was 7.5%, and the highest risk
of depression was among younger women and older men.
PMID- 9543304
TI - Trauma exposure, postmigration stressors, and symptoms of anxiety, depression and
post-traumatic stress in Tamil asylum-seekers: comparison with refugees and
immigrants.
AB - Compared to research on displaced persons whose refugee status has been endorsed
prior to arriving in Western countries, there is little systematic information
available about levels of past trauma, postmigration living difficulties and
psychiatric symptoms amongst asylum-seekers who claim refugee status only after
arrival. Asylum-seekers, authorized refugees and immigrants of Tamil background
were recruited by personal contact and mail-out in Sydney, Australia. A total of
62 subjects, constituting approximately 60% of the estimated pool of Tamil asylum
seekers, agreed to participate in the study. They returned statistically
significantly higher scores than immigrants (n = 104) on measures of past trauma,
symptoms of anxiety, depression and post-traumatic stress, and on all dimensions
of postmigration difficulties. Asylum-seekers did not differ from refugees (n =
30) on measures of past trauma or psychiatric symptoms, but they scored higher on
selective components of postmigration stress relating to difficulties associated
with their insecure residency status. Although limited by sampling and diagnostic
constraints, the present study suggests that asylum-seekers may be a high-risk
group in relation to ongoing stress in the postmigration period.
PMID- 9543305
TI - Executive deficits in major depression.
AB - Clinically depressed patients and control subjects were examined by means of
different tests to assess executive functions (the Wisconsin Card Sorting Test,
the Stroop Color Word Test and a test of verbal fluency). The results indicate
that the depressed patients were generally slower than the controls, as reflected
by longer retrieval times for both words and colours. Furthermore, the depressed
patients showed impairment with regard to altering behaviour appropriately in
response to feedback. However, there were no depression-related increases in
perseverative responses, and the ability to inhibit irrelevant information was
unaffected by depression. No relationship was found between specific depressive
symptoms or the severity of depression and cognitive performance. The overall
pattern of results suggests that depression may affect various executive
functions in a differentiated manner.
PMID- 9543306
TI - Clinical characteristics of a total cohort of female and male applicants for sex
reassignment: a descriptive study.
AB - The objective of this study was to compare the features of female-to-male
transsexuals (F-M) with those of male-to-female transsexuals (M-F) in the cohort
of all applicants for sex reassignment over a 20-year period. In an
observational, cross-sectional design the cohort was retrospectively identified,
consisting of all 233 subjects who applied for sex reassignment in Sweden during
the period 1972-1992. The cohort was subdivided into the groups M-F (n=134) and F
M (n=99), and the two groups were compared. M-F were older when applying for sex
reassignment surgery than F-M, and more often had a history of marriage and
children than their F-M counterparts. M-F also had more heterosexual experience.
F-M, on the other hand, more frequently exhibited cross-gender behaviour in
childhood than did M-F transsexuals. The present and previous studies strongly
support the view that transsexualism manifests itself differently in males and
females. Various models for understanding these differences are discussed.
PMID- 9543307
TI - The association between attitudes toward suicide and suicidal ideation in
adolescents.
AB - The aims of this study were to determine whether adolescent attitudes to suicide
could be grouped into distinct factors, and then to examine the relationship
between these factors and the psychosocial parameters known to be associated with
suicide, and between attitudes towards suicide and suicidal ideation. A
questionnaire designed to assess attitudes to suicide was distributed to a total
of 525 Israeli adolescents. Statistical analysis indicated that the attitude
items could be grouped into four distinct factors: the right of society to
prevent suicide; suicide as a symptom of mental illness; the right of the
individual to talk about suicide; and taking suicidal behaviour seriously. Each
factor was differentially associated with the various psychosocial parameters
examined. The association between the attitude factors and subjects' suicidal
ideation was significant and at least as strong as that of the psychosocial
parameters normally associated with adolescent suicide, namely gender and
exposure to suicide. A generally approving attitude towards suicide was
correlated with a high level of suicidal ideation.
PMID- 9543308
TI - Fatigue mood as an indicator discriminating between anorexia nervosa and bulimia
nervosa.
AB - In order to clarify the differences in mood states between anorexia and bulimia
nervosa, the Profile of Mood States (POMS) with tension-anxiety, depression,
anger-hostility, vigour, fatigue and confusion scales was administered to 32
female patients with anorexia nervosa (age range 14 to 32 years, mean age 20
years), 49 female patients with bulimia nervosa (age range 15 to 33 years, mean
age 23 years) and 410 'normal' female subjects (age range 14 to 35 years, mean
age 23 years). The scores on the depression, fatigue and confusion scales for
both anorexia and bulimia nervosa and those on the tension-anxiety and anger
hostility scales for bulimia nervosa were significantly higher than those for the
control subjects. The score on the fatigue scale for bulimia nervosa was
significantly higher than that for anorexia nervosa. Moreover, the result of the
multiple logistic regression analysis including all of the POMS scales indicated
that the fatigue scale significantly discriminated between the two disorders.
Fatigue mood appears to be a principal indicator for differentiating between the
two disorders.
PMID- 9543309
TI - Eating disorders and insulin-dependent diabetes mellitus (IDDM): relationships
with glycaemic control and somatic complications.
AB - This study was designed to assess (by means of a diagnostic interview based on
DSM-III-R criteria) the prevalence of eating disorders in 69 insulin-dependent
diabetic (IDDM) out-patients, and the relationship with somatic risks. We found
no cases of anorexia nervosa or bulimia nervosa, current or lifetime, in male
patients with IDDM. No female patients with IDDM had anorexia, and 4.8% had
current and lifetime bulimia. Eating disorders not otherwise specified (bulimic
type) were significantly more frequent in women than in men (lifetime incidence
43% vs. 21%; current incidence 33% vs. 5%), and generally occurred after the
onset of IDDM. Self-reports of bulimic behaviours according to the Bulimic
Investigatory Test of Edinburgh (BITE) were associated with high levels of
glycosylated haemoglobin. There was no association between eating disorders
(current or lifetime), with somatic complications being more likely to be
explained by a long duration of illness and impaired glycaemic control.
PMID- 9543311
TI - Factors affecting the development of spontaneous recurrence of methamphetamine
psychosis.
AB - The process triggering spontaneous recurrences of methamphetamine (MAP) psychosis
(i.e. flashbacks) was studied in 41 flashbackers, along with 84 non-flashbackers
with a history of MAP psychosis. Plasma monoamine metabolite levels were assayed
in 25 of the 41 flashbackers, 16 of the 84 non-flashbackers, 9 subjects with
persistent MAP psychosis and 28 control subjects. All flashbackers had
experienced threatening events or frightening paranoid-hallucinatory states
during previous MAP use. The dominant factor triggering flashbacks was a mild
fear of other people. Plasma norepinephrine levels were elevated during
flashbacks. The results suggest that a mild fear of other people may have
elicited memories of MAP psychosis associated with threatening experiences
through increased sensitivity to psychosocial stressors. As a result the
flashbacks occurred, including an increase in peripheral noradrenergic activity.
PMID- 9543310
TI - Collaboration with drug treatment by schizophrenic patients with and without
psychoeducational training: results of a 1-year follow-up.
AB - Within a controlled prospective intervention study, schizophrenic outpatients
randomly assigned to four treatment groups and one control group were assessed
with regard to collaboration with drug treatment. In total, 39.3% of 84 regular
attenders of the psychoeducational training programme and 26.6% of 64 control
patients reported having persuaded their psychiatrists to modify their medication
prescriptions. A total of 8.3% and 7.8%, respectively, modified their medication
on their own initiative, although with subsequent approval by the psychiatrist,
and 20.2% and 15.6%, respectively, modified their medication after consulting
their psychiatrist. With regard to medication management, the groups did not
differ either at post-treatment or at follow-up. At follow-up, regular attenders
showed a reduced fear of side-effects, increased confidence in their medication
and stable confidence in their physician. Among the control subjects, confidence
in the medication and in their physician declined, and fear of side-effects
increased. Psychoeducational training therefore led to an optimization of
patients' attitudes toward treatment, but not to changes in medication
management.
PMID- 9543312
TI - A prevalence study of folate deficiency in a psychiatric in-patient population.
AB - Controlled clinical trials in the UK have shown folate deficiency in psychiatric
patients, and it has been suggested that such deficiency is most likely to occur
among patients with affective disorders. Studies have led to the use of folate as
an adjunct to therapy in such patients. The present paper describes a preliminary
investigation into the red cell folate status of psychiatric patients in a
general hospital unit compared with age- and sex-matched healthy controls, using
up-to-date assays and strict entry criteria and overall improved methods on
previous studies. The study showed that, although there is a trend for
psychiatric patients to have lower serum folate levels than controls, there is no
statistically significant difference in folate levels as measured by red cell
folate, a more reliable measure of folate status, between healthy controls and
psychiatric patients, and all but one of the patients had normal haematological
indices.
PMID- 9543313
TI - Amitriptyline vs. lorazepam in the treatment of opiate-withdrawal insomnia: a
randomized double-blind study.
AB - Benzodiazepine use in the treatment of insomnia may cause benzodiazepine
dependence, especially in opiate users. The aim of this study was to investigate
the sedative-hypnotic effects of amitriptyline in treating opiate-withdrawal
insomnia. A total of 27 patients with opiate withdrawal were given either
amitriptyline or lorazepam in a randomized double-blind trial. Sleep was assessed
by means of the Sleep Evaluation Questionnaire and three insomnia items of the
Hamilton Depression Rating Scale. The scores of two sleep measures showed that
all aspects of sleep, except for ease of awakening from sleep, in the two
treatment groups were not significantly different. In conclusion, apart from the
hangover effect, amitriptyline is as effective as lorazepam in the treatment of
opiate-withdrawal insomnia.
PMID- 9543314
TI - Naturalistic experience with the use of divalproex sodium on an in-patient unit
for adolescent psychiatric patients.
AB - This paper focuses on the importance of data collected not only from controlled
clinical trials, but also from naturalistic treatment experience. In particular
we examine the use of divalproex sodium either as monotherapy or as part of
combined therapy on an in-patient ward for adolescents aged 13-18 years. All
admissions in which divalproex sodium use was attempted (n=36) were analysed over
a 1-year period. The most common use was in patients with a mixed-presentation
bipolar disorder (n=16), followed by patients with major depression (n=7), mania
(n=4) or psychoses not otherwise specified (n=4). Divalproex sodium use was
evaluated in the control of mania, psychosis, agitation, mood swings, aggression
and/or anxiety. Overall, the use of divalproex sodium was associated with a
marked improvement along all psychopathological variables in the vast majority of
patients. Few side-effects or medical complications were noted. We believe that
divalproex sodium is a potentially useful drug in adolescent patients with
varying forms of psychopathology.
PMID- 9543315
TI - Severe motor-dominant neuropathy with IgM M-protein binding to the NeuAcalpha2
3Galbeta- moiety.
AB - We report the occurrence of a relapsing, severe predominantly motor neuropathy in
a 75-year-old man with an IGM-K M-protein binding to gangliosides GM2, GM3, GM4,
GD1a, GT1b and LM1. Motor nerve conduction velocities were slowed with conduction
block. A superficial peroneal nerve biopsy specimen revealed segmental
demyelination and remyelination. The patient improved after repeated plasma
exchanges, and the antibody titer decreased in association with clinical
recovery. This IgM M-protein has a unique, previously unreported binding
specificity for terminal NeuAcalpha2-3Galbeta- moiety in common to all
gangliosides bound by the antibody except GM2. M-proteins with this affinity may
be involved in the pathogenesis of this and other cases of motor-dominant
demyelinating neuropathy.
PMID- 9543316
TI - Bulbocavernosus reflex studies and autonomic testing in the diagnosis of erectile
dysfunction.
AB - The electrophysiologic evaluation of patients with erectile dysfunction presents
an important diagnostic challenge. The bulbocavernosus reflex (BCR) latency has
been commonly used to evaluate these disorders. However, it is a measure of
somatic penile innervation, whereas erection is primarily dependent on autonomic
function. We evaluated 195 men with erectile dysfunction over a 3 year period.
Each had electrophysiologic studies, nerve conduction studies and a BCR. BCR
studies were abnormal in only 7%, of which most had diabetes or pelvic trauma.
The BCR was the sole electrophysiologic abnormality in only 2%. Autonomic testing
(AT) was additionally performed in 19 diabetic and 23 non-diabetic patients. This
included sympathetic skin responses and measurement of the Valsalva ratio and
heart rate variability with 6/min breathing. In the diabetic group, AT was
positive in 63%, and most often was the sole abnormality. The bulbocavernosus
reflex is relatively insensitive in the diagnosis of erectile dysfunction. Brief
autonomic testing may provide valuable additional data, particularly in
diabetics.
PMID- 9543317
TI - Acute cytomegalovirus infection and IgM anti-GM2 antibody.
AB - Guillain-Barre syndrome (GBS) sometimes is preceded by cytomegalovirus (CMV)
infection. Irie et al. (J. Neuroimmunol. 1996;68:19-26) reported that three
patients with GBS subsequent to CMV infection had IgM and IgG anti-GM2
antibodies. In our larger study, the IgMs from the CMV-associated GBS patients
showed significantly higher anti-GM2 antibody titers than anti-GM3, anti-GD1a,
anti-GD1b, anti-GD2, anti-GD3, anti-GT1b, anti-GQ1b, and anti-SGPG antibody
titers. None of the anti-glycosphingolipid antibody titers differed significantly
from the others in the IgGs from the CMV-associated GBS patients. However, IgM
anti-GM2 antibody frequently was present in GBS patients who were not preceded by
CMV infection and non-GBS patients with acute CMV infection. Our results did not
support the conclusion of Irie et al. that anti-GM2 antibodies were closely
associated with acute CMV infection in GBS, but acute CMV infection, with and
without GBS, was associated with IgM anti-GM2 antibody.
PMID- 9543318
TI - Alteration of spatial-temporal parameters of gait in Chronic Fatigue Syndrome
patients.
AB - Chronic Fatigue Syndrome (CFS) has been widely studied and a lot of information
is available in the literature regarding the immunological, virological,
neuroendocrinal and psychiatric aspects of the disease, but its aetiology is
still poorly understood. Great attention has also been paid to the alteration of
the muscular function caused by CFS. The aim of the present work was to study CFS
patients' gait in order to find out objective measures which can better
characterize the pathology. Spatial and temporal parameters of gait were
collected from a group of 12 CFS informed volunteers by using the typical
instrumentation of movement analysis, and raw data were statistically elaborated.
Comparisons with reference data from a population of healthy subjects revealed
significant abnormalities in the symmetry indices of the bilateral parameters and
in the linear relationships among parameters, and between these parameters and
the physical characteristics of the patients. Interestingly, the abnormalities
were present as from the beginning of the gait, which indicates that they are
unlikely to be caused by the rapid increasing fatigue. This strengthens the
hypothesis of a direct involvement of the central nervous system (CNS) in the
onset of the disease.
PMID- 9543319
TI - Microvascular endothelial activation in the skeletal muscles of patients with
multiple organ failure.
AB - The relationship between microvascular damage and the presence of muscle fibre
atrophy and necrosis has been investigated in skeletal muscle biopsies taken from
57 patients with multiple organ failure. Immunohistochemical studies showed no
loss of capillaries and no luminal thrombosis, while neutrophil leucocytes were
more prevalent in the patients' biopsies than in controls. Deposition of the
complement membrane attack complex (C5-9MAC) in capillaries was observed in 41%
of cases. Endothelial activation was suggested by an increased intensity of
expression of ICAM-1, and by an increased proportion of capillaries expressing P
selectin and E selectin, although this was not directly associated with
neutrophil accumulation. Endothelial swelling was present in many biopsies with
38% of the biopsies having larger capillary profiles on immunohistochemical
labelling for von Willebrand factor (vWF), thrombomodulin and CD34, and on Ulex
europaeus agglutinin 1 binding. Endothelial swelling was confirmed by image
analysis and morphometric evaluation of capillary ultrastructure, however, the
capillary luminal area was not reduced as the capillaries were dilated. Increased
vWF labelling was associated with C5-9MAC deposition and with fibre necrosis, but
the vascular changes were not related to fibre atrophy nor to clinical indices of
the severity of the patients' illness. The results suggest that microvascular
damage and ischaemia may not be major factors in the pathogenesis of muscle fibre
damage in multiple organ failure, but that endothelial activation is a common
occurrence. The variability in the patterns of markers of endothelial activation,
and the small proportion of capillaries affected, may reflect the complexity of
the endothelial response to circulating or locally produced cytokines.
PMID- 9543320
TI - Adverse changes in fibre type composition of the human masseter versus biceps
brachii muscle during aging.
AB - The fibre composition of functionally different regions, the superficial and the
deep portions, of the human masseter and the biceps brachii muscles of six
elderly subjects (mean age 74 years) was studied by morphological and enzyme
histochemical methods. When compared to previous data for young adults, the
masseter muscle from elderly subjects showed a significant decrease in the
proportion of type I fibres and an increase of type IM and II fibre types,
concomitant with muscle fibre atrophy. In the old biceps, there were no changes
in the type I fibre proportion and fibre diameter, but a significant decrease in
the type IIB fibre content. The present results of changes in fibre composition,
in addition to previous findings of functional deterioration of the old masseter,
probably reflect a combination of age related degenerative and adaptive processes
within the trigeminal neuromuscular system. When compared with previous findings
in young adult masseter, it can be concluded that the human masseter muscle
differs from limb muscles both in fibre composition and in structural response of
the muscle during aging. These differences between the masseter and the biceps
brachii muscle suggest muscle specific alterations during aging probably due to
differences in genetical control, functional performance and nerve and hormonal
influences.
PMID- 9543321
TI - Clinical diagnosis in Karwinskia humboldtiana polyneuropathy.
AB - Intoxication by Karwinskia humboldtiana presents a neurological picture similar
to that for Guillain-Barre syndrome or other polyradiculoneuropathies. Clinical
diagnosis in poisoned humans may be difficult if no evidence of previous fruit
ingestion is available. We present our experience in the clinical diagnosis of
Karwinskia humboldtiana polyneuropathy, as confirmed by toxin detection in blood.
We designed an open trial at the Pediatric Neurology service and included all
cases with acute ascending paralysis that were admitted to our hospital in the
last two years. In all cases, we performed hematological, immunological and
biochemical profiles, CSF analysis including immunological studies, oligoclonal
bands and myelin basic protein determinations. Electrodiagnostic studies were
performed, including motor conduction velocities, distal latencies, F-wave
latency and compound muscle action potential (CAMP) amplitude. The presence of
Karwinskia humboldtiana toxins in blood were determined by thin layer
chromatography. In six cases, T-514 Karwinskia humboldtiana toxin was detected.
These cases had a symmetric motor polyneuropathy with the absence of tendon
reflexes and no sensory signs or cranial nerve involvement. Only one patient
required assisted ventilation due to bulbar paralysis. In two of these cases, a
sural nerve biopsy revealed a segmental demyelination with swelling and
phagocytic chambers in Schwann cells and without lymphocytic infiltration. All
six cases survived, with complete recovery in five. We conclude that this
intoxication is common in Mexico. The availability of toxin detection in blood
samples allows the clinician to establish an accurate diagnosis and should be
included in the study of children with polyradiculoneuropathy, especially in
countries where this poisonous plant grows.
PMID- 9543322
TI - Positron emission tomography in vascular dementia.
AB - BACKGROUND: Vascular dementia (VaD) is an ill-defined entity. It is not known how
acute brain failure related to stroke becomes chronic leading to dementia.
PURPOSE: The present study investigates whether positron emission tomography
(PET) can detect different metabolic patterns in VaD. PATIENTS AND METHODS: Four
groups of stroke patients were selected. The PET findings of 14 stroke patients
with multiple large infarcts and dementia (MID) and 14 without dementia (MS) were
compared. Sixteen stroke patients with lacunes, leukoaraiosis and dementia (LD)
were assessed against nine without dementia (LS). The PET examination utilised
the 15-O-steady-state technique in order to determine regional cerebral blood
flow (rCBF), regional oxygen extraction rate (rOER) and regional cerebral
metabolic rate for oxygen (rCMRO2) in different pre-established cortical,
subcortical and cerebellar regions. RESULTS: Decreased coupled mean rCBF and
rCMRO2 with comparable rOER values were observed in all cerebral regions except
in the cerebellum of the MID compared to the MS group. In the LD group mean rCBF
and rCMRO2 were decreased with increased rOER in all cerebral regions except in
the cerebellum compared to the LS group. CONCLUSIONS: The PET findings in
demented patients with multiple large infarcts are in agreement with the concept
of multi-infarct dementia. In demented patients with lacunes and leukoaraiosis,
the PET pattern suggests a state of misery perfusion not only in the deep
structures but also in the whole cerebral cortex. The present PET study argues
that there are at least two possible mechanisms that can explain the occurrence
of VaD in stroke patients.
PMID- 9543323
TI - Gly341Arg mutation indicating malignant hyperthermia susceptibility: specific
cause of chronically elevated serum creatine kinase activity.
AB - We report on three families with the Gly341Arg ryanodine receptor gene (RYR1)
mutation. Thirteen individuals were heterozygote carriers of the Gly341Arg
mutation and had clearly positive in vitro contracture tests, indicating
malignant hyperthermia susceptibility. Nine Gly341Arg mutation positive
individuals from two families had elevated serum creatine kinase (CK) activity at
rest (up to six times the normal upper limit). Their clinical and neurological
examinations as well as detailed muscle histology were normal. The third family
did not show increased CK activity. These findings indicate that the Gly341Arg
mutation can be a specific cause of chronically elevated serum CK activity in
asymptomatic individuals.
PMID- 9543324
TI - Clinicopathological features of chronic inflammatory demyelinating
polyradiculoneuropathy in childhood.
AB - The clinical, electrophysiological, and pathological findings, and the
therapeutic characteristics in ten children with chronic inflammatory
demyelinating polyradiculoneuropathy (CIDP), whose onset age was less than 16
years, were evaluated. The clinical progression pattern of the initial phase
divided the patients into two groups. One group (six patients) showed a subacute
progression for up to 2 months after onset and a subsided progression over 3
months. Three patients in this group had a preceding febrile episode. The other
group (four patients) showed a chronic insidious progression for more than 3
months. The former group of patients revealed a favourable response to
corticosteroid therapy as compared with the latter group. However, other clinical
and laboratory features at the peak impairment were not distinguishable between
these two groups. Motor dominant neuropathy was common to all patients, and only
three cases showed sensory disturbance on the distal limbs. No cases revealed
cranial nerve involvement. Motor and sensory nerve conduction and sural nerve
biopsy studies revealed the demyelinating nature of the neuropathy. These
clinicopathological features suggest that the subacute progression form
frequently associated with prodromal episode and rather favourable corticosteroid
response is characteristic in childhood CIDP, while the chronic insidious
progression form is indistinguishable from the common adult CIDP.
PMID- 9543325
TI - Roussy-Levy syndrome is a phenotypic variant of Charcot-Marie-Tooth syndrome IA
associated with a duplication on chromosome 17p11.2.
AB - The Roussy-Levy syndrome (MIM #180800) was described in 1926 as a disorder
presenting with pes cavus and tendon areflexia, distal limb weakness, tremor in
the upper limbs, gait ataxia and distal sensory loss. We report a family with
affected members in four generations, showing these clinical signs of Roussy-Levy
syndrome and a partial duplication at chromosome 17p11.2. This genetic defect is
commonly found in patients with the hypertrophic form of the Charcot-Marie-Tooth
syndrome. Our finding provides evidence against the Roussy-Levy syndrome as a
distinct entity but suggests a close relation with the Charcot-Marie-Tooth
syndrome. What causes the additional features of gait ataxia and essential tremor
needs further clarification.
PMID- 9543326
TI - Propentofylline enhances cerebral metabolic response to auditory memory
stimulation in Alzheimer's disease.
AB - To evaluate efficacy, safety, metabolic and clinical effects of propentofylline
in Alzheimer's disease (AD), a prospective, randomized, double-blind, placebo
controlled trial was performed in 30 patients with mild to moderate AD who
underwent pretreatment and posttreatment 18F-2-fluoro-2-deoxy-D-glucose positron
emission tomography under resting conditions and during stimulation with an
auditory memory paradigm. Twenty-eight subjects completed the 3-month study. The
drug was well tolerated. In the active treatment group, a significant increase of
cerebral metabolic response to the memory task was observed (multiple measurement
ANOVA P = 0.02). The placebo group showed a significantly decline in the MMSE
score (P = 0.02) while there was no change in the treatment group. This suggests
a protective role for propentofylline in slowing the progression of AD.
PMID- 9543327
TI - Substantial spontaneous long-term remission in subacute sclerosing
panencephalitis (SSPE).
AB - We report a 25-year-old female who developed clinical and electroencephalographic
(EEG) features of subacute sclerosing panencephalitis (SSPE) at the age of 17
years. After almost 17 months of progressive neurological deterioration to a
level where she was bedridden and incapable of self-care (Risk and Haddad stage
3a), she experienced a substantial spontaneous clinical and EEG remission (stage
4c) which she has maintained for the last 8 years. The measles antibody titer in
the cerebrospinal fluid (CSF), however, progressively increased during follow-up.
There are only very few patients with well documented diagnosis of SSPE who have
maintained such a prolonged remission. The age at onset of SSPE of > or = 12
years, disappearance of periodic complexes and a tendency for normalization of
the background activity in the EEG, and a progressive increase in the measles
antibody titer in the CSF appears to predict a favourable outcome of SSPE.
PMID- 9543328
TI - Case report: a veterinarian who collapsed after the delivery of a calf by
cesarean section.
AB - We report a patient who experienced internal carotid artery dissection with
cerebral ischemia and cranial nerve involvement. The clinical features, the
diagnostic approach and the therapeutic options are discussed in view of the
recent literature.
PMID- 9543329
TI - Horner's syndrome associated with mononeuritis multiplex due to cytomegalovirus
as the initial manifestation in a patient with AIDS.
AB - We report on a 60-year-old male with AIDS who presented Horner's syndrome that
was associated with mononeuritis multiplex due to cytomegalovirus (CMV)
infection. This is the first case who presented Homer's syndrome in the course of
AIDS. Horner's syndrome associated with mononeuritis multiplex in this patient
was the initial manifestation without any opportunistic infections. Since
Horner's syndrome and mononeuritis multiplex in the present case were both
improved by ganciclovir, it is important to consider CMV infection when Horner's
syndrome or mononeuritis multiplex is observed in immunocompromised patients,
such as those with HIV-1 infection or AIDS, even if they do not show any other
opportunistic infections.
PMID- 9543330
TI - Uncommon presentations of neurocysticercosis.
AB - Neurocysticercosis commonly presents with seizures, raised intracranial tension
and dementia. The unusual location of the cysts may result in uncommon
manifestations mimicking a host of neurological disorders. Ten patients with
neurocysticercosis with rare clinical presentations have been described in this
series. These include dorsal midbrain syndrome, isolated bilateral ptosis,
papillitis, cerebral hemorrhage, painful cervical radiculopathy, progressive
swelling of arm, paraplegia due to intramedullary cyst, third ventricular cyst,
dystonia and nominal aphasia masquerading as transient ischaemic attacks. The
clinical details and possible mechanisms for these rare presentations are
discussed.
PMID- 9543331
TI - Recurrent cranial neuropathy as a clinical presentation of idiopathic
inflammation of the dura mater: a possible relationship to Tolosa-Hunt syndrome
and cranial pachymeningitis.
AB - We report 14 patients with idiopathic recurrent cranial neuropathy, in whom
multiple cranial nerves were involved recurrently, either at the same or
different times, and appeared bilaterally. Oculomotor nerve involvement was most
frequent, while the abducens and facial nerves were the next most frequent.
Clinical courses were benign and not progressive, and the symptoms responded well
to corticosteroids. Ten patients developed Tolosa-Hunt syndrome during the course
of their illness. Laboratory findings and CSF were normal. MRI and CT studies
were unremarkable, except for an asymmetric appearance of the cavernous sinus in
some patients. One patient showed focal hypertrophic pachymeningitis in the
posterior fossa in MRI. We discuss the relationship of the idiopathic recurrent
cranial neuropathy with disorders characterized by inflammation of the dura
mater, such as Tolosa-Hunt syndrome and cranial pachymeningitis.
PMID- 9543332
TI - Non-familial olivopontocerebellar atrophy combined with late onset Alzheimer's
disease: a clinico-pathological case report.
AB - A 76-year-old woman with olivopontocerebellar atrophy (OPCA) presented with
progressive intellectual deterioration. She showed cerebellar ataxia and muscle
atrophy and weakness, and gradually developed generalized dementia with
visuospatial disturbance. An autopsy revealed numerous senile plaques (SPs),
neurofibrillary tangles (NFTs) and neuropil threads particularly in the CA1,
subiculum and entorhinal cortex and to a lesser degree in the cerebral neocortex
shown by immunostaining and specific silver impregnation techniques. The nucleus
basalis of Meynert had numerous NFTs with fibrillary gliosis and neuronal cell
loss. The basis pontis was markedly atrophied and the pontine nucleus had severe
neuronal depopulation and gliosis. The pontine transverse fibers were
demyelinated with their axons being fragmented. The cerebellar white matter was
also severely degenerated. The striatum, Onuf's and intermediolateral nuclei of
the spinal cord remained unchanged. Ubiquitin immunohistochemistry and Gallyas
silver impregnation technique revealed oligodendroglial inclusions in the pontine
nucleus, corticopontine tract, cerebral and cerebellar white matter. On double
immunostaining of KP1 and ubiquitin, globular neurite SPs encircled by KP1
positive fibrous structures were found in the hippocampus and cerebral neocortex.
The curly neurite SPs contained KP1-positive granules. The KP1-positive
microglial cells were distributed widely in the cerebral white matter and HLA-DR
positive ones were found around the SPs. The present case showed generalized
dementia compatible with Alzheimer's disease (AD) and had a pathologically limbic
type of late onset AD. This is the first case where AD affected non-familial
OPCA.
PMID- 9543333
TI - Localized muscle wasting as an initial symptom of skeletal muscle lymphoma.
AB - A 25-year-old man who developed painless muscle wasting and weakness of only the
right thigh, was eventually shown to have systemic lymphoma with muscle
infiltration. The patient was initially misdiagnosed as focal inflammatory
myopathy, and he had a partial response to steroid therapy. Immunohistochemical
analysis of the biopsied muscle and the subcutaneous tumor revealed the
infiltrating cells with a positive macrophage-associated marker (CD68) and
negative T- or B-cell-associated antigens, leading to the final diagnosis of true
histiocytic lymphoma. Although skeletal muscle lymphoma is extremely rare, it
should be considered in the differential diagnosis of localized muscle wasting.
PMID- 9543334
TI - Suprachiasmatic nucleus in a patient with multiple system atrophy with abnormal
circadian rhythm of arginine-vasopressin secretion into plasma.
AB - We performed a quantitative investigation of arginine-vasopressin (AVP)
immunopositive neurons in the suprachiasmatic nucleus (SCN), which is the
endogenous clock of the brain of a patient with multiple system atrophy (MSA) who
exhibited nocturnal polyuria associated with decreased urinary specific gravity
and depression of nocturnal AVP secretion. Eleven age- and sex-matched subjects
were used as controls. Although, the number of AVP-positive neurons was decreased
in neither the supraoptic nucleus nor the paraventricular nucleus, the number of
AVP-positive neurons in the SCN was decreased and gliosis was present in the SCN.
The cytoplasmic area of AVP-immunopositive neurons in the SCN was smaller in the
patient than in the control subjects. These findings raise the possibility that
SCN is involved in MSA and the neurodegeneration in the SCN results in altered
circadian rhythm of AVP secretion and nocturnal polyuria.
PMID- 9543335
TI - Neurulation in the rabbit embryo.
AB - Among a broad range of factors and mechanisms involved in the complex process of
neurulation a relationship between the curvature of the craniocaudal body axis
and rate of neural tube closure has been proposed, but more examples and models
are needed to further substantiate the existence of this relationship. This is
particularly true for mammals, where marked differences in embryonic body
curvature between species exist. The rabbit embryo has virtually no curvature
during the main phase of neurulation and is therefore a suitable model, but
neurulation is hardly documented in this species. In the present study,
therefore, neural tube closure in the rabbit embryo is presented in detail by
morphological and morphometrical parameters, as well as from scanning electron
microscopic investigations. At the stages of 6-8 somites, the flat neural plate
transforms into a V-shaped neural groove, beginning at the rhombo-cervical level.
Between the stages of 8 and 9 somites, multiple closure sites occur
simultaneously at three levels: at the incipient pros-mesencephalic transition,
at the incipient mes-rhombencephalic transition, and at the level of the first
pairs of somites. This results in four transient neuropores. The anterior and
rhombencephalic neuropores close between the stages of 9-11 somites. The
mesencephalic neuropore is very briefly present. The posterior neuropore is the
largest and remains longest. Its tapered (cranial) portion closes fast within
somite stages 9-10. Subsequently its wide (caudal) portion closes up to a narrow
slit, but further closure slows down till full closure is achieved at the 22
somite stage. In comparing rabbit neurulation with that of chick and mouse, the
sequence of multiple site closure resembles that of the mouse embryo, but other
important aspects of neurulation resemble those of the chick embryo. In contrast
to mouse and chick, no time lag between closure at the three closure sites in the
rabbit was seen.
PMID- 9543336
TI - Expression of the axon growth-related neural adhesion molecule TAG-1/axonin-1 in
the adult mouse brain.
AB - TAG-1/axonin-1 is a neuronal cell adhesion molecule of the immunoglobulin
superfamily. It is predominantly expressed during neural development and has been
reported to be involved in axonal growth and pathfinding. Here, the expression of
TAG-1/axonin-1 was investigated anatomically in the adult mouse brain by in situ
hybridization using digoxigenin-labeled cRNA probes. Low levels of TAG-1/axonin-1
could be detected in cerebellar granule cells, in tufted and mitral cells of the
olfactory bulb, and in pyramidal cells of area CA1 and CA3 of the hippocampus. We
suspect that the expression of TAG-1/axonin-1 in these structures of the adult
brain may serve neural plasticity.
PMID- 9543337
TI - Normal ontogenic observations on the expression of Eph receptor tyrosine kinase,
Cek8, in chick embryos.
AB - The spatio-temporal pattern of expression for the Eph receptor tyrosine kinase,
Cek8, was observed in normal chick embryos from H-H stage 6 to 23 by
immunohistochemical techniques. Expression of Cek8 was already present in embryos
at H-H stage 6, where it was located in the neural plate of the brain region,
paraxial mesoderm, and the primitive streak. Regions expressing Cek8 subsequently
increased during development to include the neural folds of the brain,
rhombomeres 3 and 5, the caudal part of the neural plate, neural crest cells
related to the formation of glossopharyngeal nerve ganglia, invaginated cells
throughout the primitive groove and the epithelium of the rudiment of the gall
bladder. Cek8 was also expressed in the mesenchymal cells of the pharyngeal
arches, allantoic stalk and limb buds as well as in the areas surrounding the eye
vesicles and nasal pits. Furthermore, cells in the tail bud progressing to the
secondary neurulation expressed Cek8. Thus, the spatiotemporal patterns of Cek8
expression appears to have intimate relationships with tissue rebuilding, the
maturation of differentiated cells, and the spatial organization of tissues.
Consequently, it appears that Cek8 plays an integral role in the developmental
events leading to the formation of a wide--though not inclusive--variety of
tissues and organ systems.
PMID- 9543338
TI - Immunohistochemistry and in situ hybridization of the androgen receptor in the
developing human prostate.
AB - As it is suggested that the androgen receptor mechanism is required for prostatic
development, we attempted to determine the appearance, expression and
distribution of the androgen receptor in embryonic, infantile and pubertal human
prostate. Using mono- and polyclonal antibodies and a digoxigenin-labeled 713 bp
riboprobe, the androgen receptor expression in paraffin sections of fetal,
infantile, and pubertal prostates was studied at the protein and RNA level. Under
highly standardized conditions, application of the polyclonal antibodies resulted
in a weak cytoplasmic and nuclear labeling of the epithelium of fetal glands. No
immunoreaction was obtained with monoclonal antibodies. Applying the polyclonal
antibody to pubertal and adult specimens, immunoreactivity of the androgen
receptor was positive in nuclei of adluminal and basal epithelial cells, in
interstitial and vascular smooth muscle cells and vascular endothelium, whereas
ganglionic cells and enteroendocrine cells were negative. In situ hybridization
with the digoxigenin-labeled riboprobe gave clear positive results already in
epithelium of very young fetal specimens. A semiquantitative visual evaluation of
in situ hybridizations showed that intermediate intensity of expression was
increased in pubertal and adult specimens, whereas strong expression was reduced
in prostatic epithelium. CONCLUSIONS: The essential findings are: (1) an early
expression of androgen receptor mRNA in the fetal prostate; (2) no immunoreaction
of monoclonal antibodies against the androgen receptor in the same specimens, (3)
a decrease of androgen receptor mRNA expression, but increase in immunoreactivity
of the androgen receptor protein with the onset of glandular maturation during
puberty.
PMID- 9543340
TI - Development of the male urogenital system of the koala phascolarctos cinereus.
AB - This paper described several developmental stages of the male urogenital system
in the koala Phascolarctos cinereus, employing both light and scanning electron
microscopy. There are few studies of the development of the urogenital system in
male marsupials. Findings by White and Timms (1994) that male koalas can be
infected with Chlamydia psittaci emphasise the importance of studies on male
animals and in particular their reproductive system. Specimens in our study
ranged in age from 15 days postnatal to adults. Due to the rarity of such
specimens, details of each specimen are linked to the changes of the structures
at each available stage. Light microscopy revealed that differentiation of the
gonads had commenced by 15 days postnatal and that the cytological arrangements
of the urogenital system are essentially the same as those of other mammals.
Scanning electron microscopy revealed stereocilia and microvilli along the lumen
of each ductus epididymis and cilia and microvilli along the lumina of the vasa
deferentia and urethra. The development of these structures coincided with the
onset of sexual maturation, sperm production and differentiation at about three
years of age.
PMID- 9543339
TI - Differential expression of lactoseries carbohydrate epitopes HNK-1, CD15, and
NALA by olfactory receptor neurons in the developing chick.
AB - The formation of the nasal lining with its sensory and its nonsensitive
respiratory epithelium requires a spatially ordered pattern of cellular
differentiation. Aiming at identifying cell recognition molecules that may be
involved in cellular differentiation steps, we applied a panel of antibodies to
terminal carbohydrate sequences of the lactoseries on the developing chick
olfactory epithelium. This approach is based on the idea that these terminal
sugar residues may be involved in certain steps of maturation. Restricted
expression of three epitopes NALA, HNK-1, and CD15 was observed in olfactory
receptor neurons. The first immature olfactory receptor neurons were observed by
day 3 of incubation, expressing the HNK-1 epitope, whereas a total epithelial
staining was observed for NALA. By day 9 of incubation high numbers of HNK-1
positive immature olfactory receptor neurons were observed. At the same time
mature olfactory receptor neurons showed immunoreactivity for CD15, whereas NALA
was still expressed throughout the whole epithelial cell population. However,
there was a pronounced staining in the population of mature olfactory receptor
neurons. Around hatching only CD15 was detectable in (mature) olfactory receptor
neurons, whereas HNK-1 and NALA immunoreactivity have switched to glandular and
sustentacular cells respectively. The differentiation-dependent expression
patterns of these three cell surface molecules suggest them as suitable markers
to explore mechanisms that determine embryonic olfactory receptor neurogenesis.
PMID- 9543341
TI - Ontogeny of NADPH-diaphorase in rat forebrain and midbrain.
AB - This study characterizes the developmental expression of NADPH-diaphorase from
embryo to adulthood in the forebrain, midbrain and cerebellum of rat brain via
histochemical staining. On embryonic day 12 no neurons stained. Labeling was
observed in certain nuclei from E15 through the postnatal period to adulthood.
Labeling in neurons increased or maintained a constant level with increased age.
The embryo demonstrated substantial labeling in neurons of the caudate putamen,
bed nucleus of the stria terminalis, preoptic area, lateral hypothalamic area,
paraventricular thalamic nucleus, ventromedial hypothalamic nucleus,
magnocellular nucleus posterior commissure, and periaqueductal central gray.
Additional neuronal labeling was observed postnatally in the olfactory bulb,
cerebral cortex, amygdala, various nuclei of the thalamus, interpeduncular
nucleus, linear nucleus of the raphe, pretectal area and superior colliculus. In
the cerebellum, labeling appeared only after P14 in cells of the molecular cell
layer and granular cell layer. The sizes of labeled neurons developed
significantly from P4 to P14 in several nuclei. The distinctive temporal and
spatial expression pattern of NADPH-diaphorase implies that the NO/cGMP system
may play an important role in physiological and developmental functions.
PMID- 9543342
TI - Induction of monocyte chemotactic protein-1 (MCP-1) and TNF alpha by Trichinella
spiralis in serum of mice in vivo.
AB - MCP-1 is a small (8-10 KDa) protein and a prototype member of the CC chemokine
beta subfamily, which plays a critical role in acute and chronic inflammation.
Recent evidence suggests an important role for MCP- 1, MCP-2 and MCP-3 in a
number of pathological states, including delayed type hypersensitivity
conditions, parasitic infections and rheumatoid arthritis. Forty BALB-c mice were
treated with the parasite Trichinella spiralis. After the infection the animals
were sacrificed at different periods from the initial infection and MCP-1 and
TNFalpha were quantified in the mouse serum. The level of MCP-1 in the serum of
mice infected with 100 larvae increases from 27.5+/-7.0 pg/ml at day 23, to a
maximum level of 31.5+/-5.0 pg/ml at day 33, then decreased to 14.6+/-2.0 pg/ml
at day 47. When the mice were infected with 200 larvae of T. spiralis the maximum
increase was 34.4+/-2.5 pg/ml found on day 23. From day 33 to day 47 MCP-1 levels
were decreased. In addition, in infected mice levels of TNFalpha were detectable
in the serum as early as day 1. The level of TNFalpha was maximum at day 35
(3812+/-224 pg/ml). Serum from non-infected mice contained no detectable levels
of either MCP-1 or TNFalpha. However, even if MCP-1 seems to be implicated in
Trichinellosis, its exact role and function in inflammatory parasitic diseases
remains to be determined.
PMID- 9543343
TI - Possible role of GH/IGF-1 in the ovarian function of adult hypothyroid rats.
AB - We have monitored estrous cycle and measured serum estradiol, GH, IGF-1, T4 and
T3 levels in adult hypothyroid female rats which were divided into four groups: H
group, hypothyroid rats without treatment; H-T4 group, hypothyroid rats injected
daily with T4; HT4-PTU group, hypothyroid rats injected daily with T4 plus PTU
(propylthiouracil), and H-T4-IOP group, hypothyroid rats injected daily with T4
plus IOP (iopanoic acid); Euthyroid rats (E group) were used as control. Our
results indicate that the lack of sexual cycle in H animals was associated with
lower values of estradiol, GH and IGF-1 in comparison to E group; the restoration
of sexual cycle in H-T4 group was associated with values of estradiol, GH and IGF
1 higher than those of H group, whereas in H-T4-PTU and H-T-IOP groups the
restoration was associated with higher values of GH and IGF-1 and values of
estradiol similar to those of H group. These data could suggest a potential role
of GH/IGF-1 axis, at least in part, in the lack of sexual cycle in H group and in
the ovulation induction in H-T4, H-T4-PTU and H-T4-IOP groups.
PMID- 9543344
TI - Purification of guinea pig small intestinal peroxisomes and the subcellular
localization of glucose-6-phosphate dehydrogenase.
AB - A method for the isolation of highly purified peroxisomes from guinea pig small
intestine was developed. This two-stage process involved a rate-dependent banding
of a light-mitochondria lambda-fraction followed by a density-dependent banding
of the catalase enriched fractions obtained from the first step, using a
horizontal rotor. Furthermore, the subcellular localization of glucose-6
phosphate dehydrogenase (NADP+-dependent) activity in guinea pig small intestine
was examined. Analysis of density-gradient fractions indicated that approximately
3-4% of the cellular NADP+-dependent glucose-6-phosphate dehydrogenase activity
is associated with peroxisomal fractions and that it is localized to the matrix
of peroxisomes. It is therefore suggested that a peroxisomal source of NADPH may
be utilized by enzyme systems that use NADPH specifically as a reductant.
PMID- 9543345
TI - Human mitochondrial function during cardiac growth and development.
AB - Little information is presently available concerning mitochondrial respiratory
and oxidative phosphorylation function in the normal human heart during growth
and development. We investigated the levels of specific mitochondrial enzyme
activities and content during cardiac growth and development from the early
neonatal period (10-20 days) to adulthood (67 years). Biochemical analysis of
enzyme specific activities and content and mitochondrial DNA (mtDNA) copy number
was performed with left ventricular tissues derived from 30 control individuals.
The levels of cytochrome c oxidase (COX) and complex V specific activity, mtDNA
copy number and COX subunit II content remained unchanged in contrast to
increased citrate synthase (CS) activity and content. The developmental increase
in CS activity paralleled increasing CS polypeptide content, but was neither
related to overall increases in mitochondrial number nor coordinately regulated
with mitochondrial respiratory enzyme activities. Our findings of unchanged
levels of cardiac mitochondrial respiratory enzyme activity during the
progression from early childhood to older adult contrasts with the age-specific
regulation found with CS, a Krebs cycle mitochondrial enzyme.
PMID- 9543346
TI - Sodium selenate corrects glucose tolerance and heart function in STZ diabetic
rats.
AB - Sodium selenate, administered intraperitoneally (i.p.), resulted in an
improvement in glucose tolerance in treated diabetic rats. Fed rat plasma glucose
levels were reduced by selenate treatment in streptozotocin diabetic rats. The
lowest values of blood glucose were reached within 3 weeks of beginning the
treatment. Food and fluid consumption was reduced in treated compared to
untreated diabetic rats. Diabetic treated rats did not release insulin in
response to a glucose challenge and insulin release in response to a challenge
was markedly reduced in control treated rats. Assessment of heart function using
a working heart apparatus showed that treated diabetic rats with improved blood
glucose levels had normal heart function at 8 weeks of diabetes in contrast to
hearts from non-treated diabetics. This study extends previous observations on
the in vivo insulin-like effects of sodium selenate.
PMID- 9543347
TI - Hepatic heterogeneity in the response to ATP studied in the bivascularly perfused
rat liver.
AB - The zonation of the purinergic action of ATP in the hepatic parenchyma was
investigated in the bivascularly perfused rat liver by means of anterograde and
retrograde perfusion. Livers from fed rats were used, and ATP was infused
according to four different experimental protocols: (A) anterograde perfusion and
ATP infusion via the portal vein; (B) anterograde perfusion and ATP via the
hepatic artery; (C) retrograde perfusion and ATP via the hepatic vein; (D)
retrograde perfusion and ATP via the hepatic artery. The following metabolic
parameters were measured: glucose release, lactate production and oxygen
consumption. The hemodynamic effects were evaluated by measuring the sinusoidal
mean transit times by means of the indicator-dilution technique. ATP was infused
during 20 min at four different rates (between 0.06-0.77 micromol min[-1] g
liver[-1]; 20-200 microM) in each of the four experimental protocols. The results
that were obtained allow several conclusions with respect to the localization of
the effects of ATP along the hepatic acini: (1) In retrograde perfusion the
sinusoidal mean transit times were approximately twice those observed in
anterograde perfusion. ATP increased the sinusoidal mean transit times only in
retrograde perfusion (protocols C and D). The effect was more pronounced with
protocol D. These results allow the conclusion that the responsive
vasoconstrictive elements are localized in a pre-sinusoidal region; (2) All
hepatic cells, periportal as well as perivenous, were able to metabolize ATP, so
that concentration gradients were generated with all experimental protocols.
Extraction of ATP was more pronounced in retrograde perfusion, an observation
that can be attributed, partly at least, to the longer sinusoidal transit times.
In anterograde perfusion, the extraction of ATP was time-dependent, a phenomenon
that cannot be satisfactorily explained with the available data; (3) ATP produced
a transient initial inhibition of oxygen uptake when protocols A and B were
employed. These protocols are the only ones in which the cells situated shortly
after the intrasinusoidal confluence of the portal vein and the hepatic artery
were effectively supplied with ATP. The decrease in oxygen consumption was more
pronounced at low ATP infusions when protocol B was employed. These observations
allow the conclusion that the former phenomenon is localized mainly in cells
situated shortly after the intrasinusoidal confluence of the portal vein and
hepatic artery. Oxygen consumption in all other cells, especially the proximal
periportal ones, is increased by ATP; (4) In agreement with previous data found
in the literature, glycogenolysis stimulation by ATP was more pronounced in the
periportal region. The cells that respond more intensively are not the proximal
periportal ones, but those situated in the region of the intrasinusoidal
confluence of the portal vein and the hepatic artery.
PMID- 9543348
TI - Immunodetection of ralA and ralB GTP-binding proteins in various rat tissues and
platelets.
AB - Polyclonal antibodies were generated against a synthetic peptide corresponding to
the C-terminal (amino acids 192-204) region of ralA and ralB GTP-binding
proteins. The ralA and ralB antibodies recognized a 27 kDa protein in the human
platelet particulate fraction. Incubation of ralA antibodies with ralB immunizing
peptide and ralB antibodies with ralA immunizing peptide prior to Western
blotting did not abolish the ability of antibodies to recognize the 27 kDa
protein in human platelet particulate fraction. However, when antibodies were
incubated with the respective immunizing peptide prior to Western blotting, the
27 kDa human platelet protein was no longer recognized by the antibodies.
Incubation of nitrocellulose blots containing polypeptides separated using SDS
PAGE with [alpha-32P]GTP demonstrated the presence of GTP-binding proteins of
molecular mass between 23-27 kDa in rat platelets and the various tissues tested.
Analysis using subtype specific antibodies demonstrated that both ralA and ralB
GTP-binding proteins were expressed in rat platelets and the various tissues
tested. The protein recognized by the ralA and ralB antibodies in rat tissues and
platelets had mobility on SDS-PAGE identical to that of the human platelet ral
protein. Varying amounts of these proteins were detected in all the tissues
tested except white muscle which contained very low level of ralB protein. The
widespread distribution of ralA and ralB GTP-binding proteins suggests that they
may participate in a common pathway in mammalian cells and tissues.
PMID- 9543349
TI - Respiratory muscle injury: is it important?
PMID- 9543350
TI - Respiratory muscle injury in animal models and humans.
AB - Respiratory muscle injury may result from excessive loading due to a decrease in
respiratory muscle strength, an increase in the work of breathing, or an increase
in the rate of ventilation. Other conditions such as hypoxemia, hypercapnia,
aging, decreased nutrition, and immobilization may potentiate respiratory muscle
injury. Respiratory muscle injury has been shown in animal models using direct
muscle or phrenic nerve stimulation, acute inspiratory resistive loading,
tracheal banding, corticosteroids, phrenic nerve section, and the mdx mouse.
Although numerous examples of diaphragm injury have been shown in animal models,
evidence in humans is sparse. Potential mechanisms which may contribute to
respiratory muscle injury include high levels of intracellular calcium-activated
degradative enzymes, non-uniformity of stresses and strains, plasma membrane
disruptions, and activation of the inflammatory process.
PMID- 9543351
TI - Determinants of diaphragmatic injury.
AB - Limb muscles can be injured during and after vigourous contractions. However,
this injury is most evident under specific conditions. The strength and type of
muscle contraction as well as the contractile status of the muscle are important
determinants of injury. The initiating event leading to muscle injury is not
clearly understood but there are several leading theories. The respiratory
muscles are of obvious importance to survival, and fatigue or injury to them has
been hypothesized to be prevented by various mechanisms. One such mechanism is
reduced activation by the central nervous system. In this review information on
the neural activation of the breathing muscles during inspiratory loading is
discussed and reveals that neural activation to the diaphragm, the main
inspiratory muscle, is high. Previous studies investigating the presence of
muscle fatigue immediately after such inspiratory loading have shown little
evidence of it. However, based on information from limb muscles, delayed or
secondary muscle injury might occur and could produce deleterious effects on
respiratory muscle function. Recent evidence shows that chronic low intensity
inspiratory loading can produce diaphragmatic injury (Reid et al.) and secondary
or delayed muscle injury can occur three days after an acute period of high
intensity inspiratory loading. The results reviewed in this article suggest that
the respiratory muscles, specifically the diaphragm, are not spared from injury
or the results of muscle injury. Diaphragmatic function during the period of
secondary muscle injury is markedly impaired and thus respiratory muscle injury
is a phenomenon that warrants further investigation.
PMID- 9543352
TI - Respiratory muscle dysfunction in mechanically-ventilated patients.
AB - The interaction between a patient and a ventilator is the major determinant of
the amount of respiratory muscle rest achieved by the machine. We are beginning
to acquire a better understanding of the mechanisms that underlie this complex
interaction, but this information has yet to be integrated into the routine
clinical management of ventilator-supported patients. To achieve that goal, we
need better techniques of detecting and monitoring patient-ventilation
asynchrony, and the development of simple algorithms that can minimize its
occurrence. Finally, research is needed to determine the occurrence and
importance of respiratory muscle fatigue during failed weaning attempts so as to
better guide the timing and pace of the weaning process in problematic patients.
PMID- 9543353
TI - Free radical induced respiratory muscle dysfunction.
AB - It is now recognized that respiratory muscle fatigue contributes to the
development of respiratory failure in some patients with lung disease. This
observation has prompted an examination into the mechanisms of development of
muscle fatigue, with the understanding that an elucidation of these processes may
lead to new therapeutic approaches to the treatment of these patients. A series
of recent studies examining this issue have, moreover, discovered that oxygen
derived free radicals generated during strenuous contraction may modulate
respiratory muscle contractile function and contribute to the development of
muscle fatigue. The data supporting this concept include: (a) direct (e.g. EPR,
ESR studies) and indirect (evidence of lipid peroxidation, protein carbonyl
formation, glutathione oxidation) evidence that there is heightened free radical
production in contracting muscle, (b) evidence that pharmacologic depletion of
muscle antioxidant stores increases degree of muscle fatigue present after a
period of exercise, and (c) evidence that administration of agents that act as
free radical scavengers retard the development muscle fatigue. Free radicals may
produce these changes in muscle force generating capacity by interacting with and
altering the function of a number of intracellular-biophysical processes (i.e.
sarcolemmal action potential propagation, sarcoplasmic reticulum calcium
handling, mitochondrial function, contractile protein interactions).
PMID- 9543354
TI - The molecular basis of activity-induced muscle injury in Duchenne muscular
dystrophy.
AB - Duchenne muscular dystrophy (DMD) is the most common of the human muscular
dystrophies, affecting approximately 1 in 3500 boys. Most DMD patients die in
their late teens or early twenties due to involvement of the diaphragm and other
respiratory muscles by the disease. The primary abnormality in DMD is an absence
of dystrophin, a 427 kd protein normally found at the cytoplasmic face of the
muscle cell surface membrane. Based upon the predicted structure and location of
the protein, it has been proposed that dystrophin plays an important role in
providing mechanical reinforcement to the sarcolemmal membrane of muscle fibers.
Therefore, dystrophin could help to protect muscle fibers from potentially
damaging tissue stresses developed during muscle contraction. In the present
paper, the nature of mechanical stresses placed upon myofibers during various
forms of muscle contraction are reviewed, along with current lines of evidence
supporting a critical role for dystrophin as a subsarcolemmal membrane
stabilizing protein in this setting. In addition, the implications of these
findings for exercise programs and other potential forms of therapy in DMD are
discussed.
PMID- 9543355
TI - Respiratory muscle dysfunction in sepsis.
AB - It became evident in the past 12 years that venitlatory muscle contractile
performance is significantly impaired during the course of septic shock. In
animal models of septic shock, depression of ventilatory muscle contractile
performance has been shown to cause hypercapneic ventilatory failure and
respiratory arrest. Failure of ventilatory muscle contractility in septic shock
has never been attributed to a single factor, but two groups of factors are
likely to be involved: (a) increased ventilatory muscle metabolic demands due to
augmentation of ventilation, hypoxemia and increased pulmonary impedance; and (b)
specific cellular, metabolic, immune and hemodynamic defects which interfere with
several processes necessary for normal force generation. These defects are
mediated by complex interactions between several local and systematic mediator
such a bacterial endotoxin, proinflammatory cytokines, prostaglandins, platelet
activating factor, reactive oxygen species and nitric oxide. This is a summary of
how these interactions are likely to interfere with ventilatory muscle
contractile performance in septic shock with particular emphasis on the newly
described role of nitric oxide.
PMID- 9543356
TI - Exercise-induced muscle injury: a calpain hypothesis.
AB - It is well established that periods of increased contractile activity result in
significant changes in muscle structure and function. Such morphological changes
as sarcomeric Z-line disruption and sarcoplasmic reticulum vacuolization are
characteristic of exercise-induced muscle injury. While the precise mechanism(s)
underlying the perturbations to muscle following exercise remains to be
elucidated, it is clear that disturbances in Ca2+ homeostasis and changes in the
rate of protein degradation occur. The resulting elevation in intracellular
[Ca2+] activates the non-lysosomal cysteine protease, calpain. Because calpain
cleaves a variety of protein substrates including cytoskeletal and myofibrillar
proteins, calpain-mediated degradation is thought to contribute to the changes in
muscle structure and function that occur immediately following exercise. In
addition, calpain activation may trigger the adaptation response to muscle
injury. The purpose of this paper is to: (i) review the chemistry of the calpain
calpastatin system; (ii) provide evidence for the involvement of the non
lysosomal, calcium-activated neutral protease (calpain) in the response of
skeletal muscle protein breakdown to exercise (calpain hypothesis); and (iii)
describe the possible involvement of calpain in the inflammatory and regeneration
response to exercise.
PMID- 9543357
TI - Simultaneous stiffness and force measurements reveal subtle injury to rabbit
soleus muscles.
AB - The time course of force generation and the time course of muscle stiffness were
measured in rabbit soleus muscles during eccentric contraction to understand the
underlying basis for the force loss in these muscles. Muscles were activated for
600 msec every 10 sec for 30 min. Soleus muscles contracting isometrically
maintained constant tension throughout the treatment period, while muscles
subjected to eccentric contraction rapidly dropped tension generation by 75%
within the first few minutes and then an additional 10% by the end of 30 min.
This indicated a dramatic loss in force-generating ability throughout the 30 min
treatment period. To estimate the relative number of cross-bridges attached
during the isometric force generation phase immediately preceding each eccentric
contraction, stiffness was measured during a small stretch of a magnitude equal
to 1.5% of the fiber length. Initially, muscle stiffness exceeded 1300 g/mm and,
as eccentric treatment progressed, stiffness decreased to about 900 g/mm. Thus,
while muscle stiffness decreased by only 30% over the 30 min treatment period,
isometric force decreased by 85%. In isometrically activated muscles, stiffness
remained constant throughout the treatment period. These data indicate that,
while soleus muscles decreased their force generating capability significantly,
there were a number of cross-bridges still attached that were not generating
force. In summary, the loss of force generating capacity in the rabbit soleus
muscle appears to be related to a fundamental change in myosin cross-bridge
properties without the more dramatic morphological changes observed in other
eccentric contraction models. These results are compared and contrasted with the
observations made on muscles composed primarily of fast fibers.
PMID- 9543358
TI - Cytokines in exertion-induced skeletal muscle injury.
AB - Cytokines are a diverse family of intercellular signaling proteins that influence
the movement, proliferation, differentiation, metabolism and membrane processes
of target cells. Synthesis and release of cytokines from leukocytes in response
to microbial stimuli are well known. This review, however, will present evidence
that non-infectious stimuli can induce cytokine secretion from leukocytes and
other cells (including muscle cells) following myocellular injury. The biological
actions and potential adaptive values of these cytokines through the course of
muscle necrosis and regeneration will be described.
PMID- 9543361
TI - Pediatric renal transplantation without steroids.
AB - Pediatric renal transplant patients present a number of challenges and problems,
especially the inhibited post-transplant growth seen in children receiving
standard immunosuppressive triple therapy that includes steroids. We report the
successful use of steroid-free immunosuppression since 1990 in 14 pediatric renal
allograft recipients who received a 10-day initial course of anti-lymphocyte
globulin and surface area-adjusted doses of cyclosporine, 7 of whom also received
mycophenolate mofetil (MMF) as maintenance immunosuppression. Only 1 patient died
(3 months after transplantation as a result of a primary Epstein-Barr virus
infection-induced lymphoproliferative disorder), 1 patient's graft never
functioned, and another patient lost his graft after 3 years because of chronic
rejection. Three patients experienced early acute cellular rejection, which
resolved in 2 cases with OKT3, and in the 3rd with MMF. There were no late acute
rejections. All patients evidenced growth and a growth spurt under this regimen.
We conclude that all the pediatric patients benefited from our steroid-free
protocol and that this protocol is superior to conventional triple therapies,
which entail the eventual reduction and discontinuation of steroids, a procedure
that not only inhibits growth but also carries an additional risk of acute
rejection due to a steroid-adapted immune response.
PMID- 9543360
TI - Cellular responses in exertion-induced skeletal muscle injury.
AB - Muscle injury is a common result of muscle exertion caused by overload and over
activity. In this presentation, an attempt was made to discuss models of muscle
injury which involve exertion but not excessive strain, although most functional
activities of the extremities require some eccentric muscle actions. Muscle
injury is characterized by cellular and extracellular matrix responses which
appear to be common to all types of muscle trauma -- even in the absence of
bleeding. Using tenotomy and functional over-load of the rat hindlimb muscles as
examples, illustrations of several of these responses are presented and
discussed.
PMID- 9543363
TI - Pediatric renal biopsy: should this procedure be performed in an outpatient
setting?
AB - Although several retrospective reports suggest that pediatric outpatient renal
biopsies may be done in a safe and cost-effective manner, risk factors and the
natural history of major complications following this procedure have not been
clearly delineated. In an effort to determine the minimal observation period
required to detect major post-renal biopsy complications in children and to
establish clinical parameters predictive of these complications, a retrospective
review of 177 percutaneous renal biopsies was performed. The overall major
complication rate was 3.4%, while the minor complication rate was 14.1%. The mean
percentage change in hemoglobin 4-10 h postbiopsy in patients with major bleeding
complications was significantly greater than patients with minor bleeding
complications. Using a 16% drop in hemoglobin 4-10 h postbiopsy, the sensitivity
and specificity of identifying a major bleeding complication was 100% and 98%,
respectively, while the positive and negative predictive value was 68% and 100%,
respectively. All patients with major complications due to excess sedation or
immediate bleeding were diagnosed within 11 h of the biopsy. Automated renal
biopsies offered several safety and efficiency advantages compared with non
automated methods. Our results suggest that outpatient pediatric renal biopsies
should be encouraged provided certain precautions are taken to reduce the risk of
developing major complications.
PMID- 9543362
TI - Hepatitis G virus infection in children on dialysis and after renal
transplantation.
AB - The aim of the present study was to use a combination of the reverse
transcription-polymerase chain reaction and a new diagnostic test for antibodies
against the viral envelope protein E2 to assess the prevalence of hepatitis G
virus (GBV-C/HGV) infection in sera of Hungarian children on hemodialysis (HD) or
peritoneal dialysis (CAPD), as well as in sera of renal transplant patients
(RTx). The GBV-C/HGV RNA prevalence was significantly higher in the whole group
of children with renal failure (18.5%) than in the control group (children with
urinary tract infection, 2.5%). The difference between the GBV-C/HGV RNA
prevalence in the RTx group (33.3%) and in the control group (2.5%) was
significant (P = 0.007). Anti-E2, which is considered an indicator of a past GBV
C/ HGV infection, was detected in 10% (1/10) of HD patients, in 33.3% (4/12) of
RTx patients, but in none of the children on CAPD. These differences were not
significant. Children receiving a renal graft are at an increased risk of
developing GBV-C/HGV infection, which may be attributed to the immunosuppressive
drugs necessary to maintain the grafts.
PMID- 9543364
TI - Steroids in the hemolytic uremic syndrome.
AB - To determine whether steroids could be of clinical benefit in the treatment of
the hemolytic uremic syndrome (HUS), we conducted a randomized, double-blinded,
placebo-controlled trial of methylprednisone (5 mg/kg per day in four oral doses
over 7 days), in children with HUS during the acute phase. Ninety-two patients
with typical HUS (47 receiving placebo and 45 receiving steroids) were
investigated for neurological, hematological, and nephrological variables. There
were no differences between groups in the number of convulsive episodes or
transfusion requirements during the hospital stay. Serum creatinine levels were
slightly increased on day 10 in the placebo group compared with the steroid group
(P = 0.06) and declined significantly between days 1 and 10 only in the steroid
group (P = 0.001). In the 51 patients with anuria (24 placebo, 27 steroids),
median serum creatinine levels were reduced in the steroid group compared with
the placebo group on the 10th day (P = 0.01). Differences in median days of
oliguria [11.5 versus 8 (P = 0.28)], anuria [5 versus 7 (P = 0.20)], and dialysis
[12 versus 10 (P = 0.26)] for the placebo and the steroid group respectively were
not significant. Our data suggest that oral steroids are not able to modify
hematological, neurological, or nephrological clinical parameters during the
acute phase of childhood HUS, even though they do seem to be associated with a
more rapid decline in serum creatinine levels.
PMID- 9543365
TI - The paucity of minimal change disease in adolescents with primary nephrotic
syndrome.
AB - Data are sparse regarding the histological lesions associated with the primary
nephrotic syndrome in adolescents. To our knowledge there are only two published
articles that have specifically addressed the histopathological lesions that
typify idiopathic nephrotic syndrome in the adolescent population. We reviewed
our experience from the last 14 years of children between the ages of 12 and 18
years who were referred to our center for the evaluation of the nephrotic
syndrome. A total of 29 adolescents met the inclusion criteria for this review.
All patients were biopsied prior to the initiation of treatment. The sex ratio
consisted of 52% males and 48% females and the racial breakdown was largely
African-American, with 83% black adolescents, 7% Hispanic, and 10% Caucasian
patients. Minimal change nephrotic syndrome (MCNS), the predominant lesion of
children at an early age, was noted in only 20% of patients. The majority of
patients (55.2%) had focal segmental glomerulosclerosis (FSGS); 7% had IgM
nephropathy and 3.5% had diffuse mesangial hypercellularity. Only 7% of biopsied
adolescents had membranoproliferative glomerulonephritis. Our results indicate
that the most common lesion in this predominantly African-American patient
population is FSGS, with only a small number showing MCNS. Thus, in our
experience derived from a racially mixed population, adolescents with the
nephrotic syndrome are less likely to have MCNS than younger children.
PMID- 9543359
TI - Inflammatory responses to ischemia and reperfusion in skeletal muscle.
AB - Skeletal muscle ischemia and reperfusion is now recognized as one form of acute
inflammation in which activated leukocytes play a key role. Although restoration
of flow is essential in alleviating ischemic injury, reperfusion initiates a
complex series of reactions which lead to neutrophil accumulation, microvascular
barrier disruption, and edema formation. A large body of evidence exists which
suggests that leukocyte adhesion to and emigration across postcapillary venules
plays a crucial role in the genesis of reperfusion injury in skeletal muscle.
Reactive oxygen species generated by xanthine oxidase and other enzymes promote
the formation of proinflammatory stimuli, modify the expression of adhesion
molecules on the surface of leukocytes and endothelial cells, and reduce the
bioavailability of the potent antiadhesive agent nitric oxide. As a consequence
of these events, leukocytes begin to form loose adhesive interactions with
postcapillary venular endothelium (leukocyte rolling). If the proinflammatory
stimulus is sufficient, leukocytes may become firmly adherent (stationary
adhesion) to the venular endothelium. Those leukocytes which become firmly
adherent may then diapedese into the perivascular space. The emigrated leukocytes
induce parenchymal cell injury via a directed release of oxidants and hydrolytic
enzymes. In addition, the emigrating leukocytes also exacerbate ischemic injury
by disrupting the microvascular barrier during their egress across the
vasculature. As a consequence of this increase in microvascular permeability,
transcapillary fluid filtration is enhanced and edema results. The resultant
increase in interstitial tissue pressure physically compresses the capillaries,
thereby preventing microvascular perfusion and thus promoting the development of
the no-reflow phenomenon. The purpose of this review is to summarize the
available information regarding these mechanisms of skeletal muscle
ischemia/reperfusion injury.
PMID- 9543366
TI - Glomerular growth in childhood focal segmental glomerulosclerosis.
AB - Studies have suggested that glomerular size increases in childhood minimal lesion
with age or growth. To examine whether mean glomerular volume (MGV) of pediatric
patients with focal segmental glomerulosclerosis (FSGS) also increases with age
and whether FSGS by itself can contribute to glomerular hypertrophy, we studied
67 children (40 boys, 27 girls) with primary FSGS and 95 children (68 boys, 27
girls) with minimal lesion by morphometry. FSGS patients had segmental sclerosis
affecting 17.1% +/- 14.8% of the glomeruli. The percentage of segmental
glomerulosclerosis was not related to age. MGV increased with age in the FSGS
patients (r2 = 0.36, P < 0.001) and in the minimal lesion patients (r2 = 0.37, P
< 0.001). MGV of children with FSGS is significantly larger than that of the
minimal lesion group [(14.8 +/- 5.7) x 10(5) microm3 vs. (12.1 +/- 3.7) x 10(5)
microm3, P < 0.001]. Multiple regression estimates suggest that the FSGS lesion
affects MGV independently (P < 0.001). The volume density of mesangium and the
volume density of cortical interstitium were significantly greater in the FSGS
patients than in the minimal lesion patients (P < 0.001). These results indicate
that MGV of pediatric FSGS patients increases with age and that the FSGS lesion
itself may cause glomerular hypertrophy, possibly via mesangial expansion. Thus,
glomerular hypertrophy in childhood minimal lesion may be an indicator of FSGS
that is undetected because of the problem of sampling.
PMID- 9543367
TI - Systemic juvenile rheumatoid arthritis complicated by two different renal
lesions.
AB - Systemic-onset juvenile rheumatoid arthritis (JRA) is a complex disease which
affects many organ systems. Associated renal lesions are unusual, with the
possible exception of amyloidosis. We describe a girl with systemic-onset JRA who
developed first membranous nephropathy and then, 3.5 years later, a severe
crescentic glomerulonephritis. The membranous lesion followed therapy with
intravenous immune globulin, and the possibility that this intervention caused
the renal disease must be considered. It appears that both of these lesions
should be added to the list of possible complications of systemic-onset JRA.
PMID- 9543368
TI - In situ hybridization of hepatitis B DNA in hepatitis B-associated
glomerulonephritis.
AB - Renal tissues from 43 of 49 children with hepatitis B virus-associated
glomerulonephritis (HBV-GN) were examined for HBV DNA by in situ hybridization
(ISH) assay within the last 10 years. HBV DNA was identified in 41 of the 43
cases (95.3%). HBV DNA was distributed generally in the nucleus and cytoplasm of
epithelial cells and mesangial cells of glomeruli, and epithelial cells of renal
tubules. HBV DNA also existed simultaneously in renal interstitial tissues in
some of these cases. The positive results from HBV DNA ISH correlated well with
HBV antigen assays. The analyses implied that the more extensive the existence of
HBV DNA in the nephron unit and interstitial tissue, the more severe the clinical
manifestation. The duration of proteinuria in cases with HBV DNA in renal tubules
was much longer than in those with no HBV DNA in renal tubules. The persistence
of the HBV genome or genes in the kidney could lead to the expression of viral
antigens in renal tissues and might cause cellular pathological alteration. This
would support utilization of antiviral therapy, such as cytokines, in the
treatment of HBV-GN.
PMID- 9543369
TI - Renovascular hypertension and vascular anomalies in Alagille syndrome.
AB - Alagille syndrome (AS) is characterized by the association of at least three of
the following five abnormalities: chronic cholestasis, peripheral pulmonary
artery stenosis, vertebral arch defects, embryotoxon, and typical facies. In
addition to urological abnormalities, tubulointerstitial nephritis, renal tubular
acidosis, and mesangiolipidosis have been noted in AS. The usual manifestations
of such renal pathologies rarely include hypertension. We report five patients
with at least four of the five major features of AS who developed secondary
hypertension of renovascular origin 3.5-28 years after the initial diagnosis of
AS. Angiography demonstrated uni- or bilateral renal artery stenosis and various
other abnormalities of the main arteries in all five patients: aorta (3 cases),
celiac artery (4 cases), superior mesenteric artery (1 case), subclavian artery
(1 case). Our findings underscore the value of arterial blood pressure monitoring
in patients with AS. If hypertension occurs, a renovascular origin should be
sought. The diffuse vascular abnormalities which appeared to be a feature of AS
in these patients should prompt larger studies of vascular abnormalities in AS.
PMID- 9543370
TI - Reference values for cystatin C serum concentrations in children.
AB - Cystatin C, a low molecular weight protein, is a new endogenous marker of renal
function whose serum concentration correlates better with glomerular filtration
rate than creatinine. The aim of the present study was to define a reference
interval for cystatin C concentrations in children. Cystatin C was measured by an
immunoturbidimetric assay in sera obtained from 258 children (93 girls, 165 boys,
median age 6.29 years, range 1 day to 18 years) without evidence of kidney
disease. The reference interval was calculated non-parametrically using the 2.5th
and 97.5th percentiles. For comparison, creatinine was measured in the same
samples. The cystatin C concentration was highest on the first days of life
(range 1.64-2.59 mg/l) with a rapid decrease during the first 4 months. Beyond
the 1st year, the cystatin C concentration was constant, with a reference
interval of 0.7-1.38 mg/l. In contrast, serum creatinine concentrations steadily
increased with age until adulthood. Compared with creatinine, cystatin C
facilitates the recognition of abnormal renal function in children as its
reference range is constant beyond the 1st year of life. The higher levels of
cystatin C in the 1st year of life probably reflect the low glomerular filtration
rate of neonates and infants.
PMID- 9543371
TI - Adequate clinical control of congenital nephrotic syndrome by enalapril.
AB - The combination of captopril and indomethacin has been shown to control nephrotic
proteinuria in an infant with congenital nephrotic syndrome of the Finnish type.
We report the satisfactory control of congenital nephrotic syndrome by enalapril,
maintaining normal serum albumin levels without albumin infusions. The haplotype
data of our patient were consistent with the diagnosis of a Finnish-type
nephrotic syndrome. After 21 months, during which daily infusions of albumin
allowed partial control of the symptoms, captopril treatment was started. No
adverse effects were noted. Serum creatinine levels remained normal. Within 8
weeks, albumin infusions were completely stopped. After 1 month the treatment was
changed to a single dose of enalapril (0.8 mg/kg per day). During the next 15
months, the serum protein concentration was maintained around 6.5-7 g/dl,
although proteinuria persisted (0.3-0.5 g/day). Weight and length gain are now
satisfactory. We conclude that enalapril may be safely used in infants with
severe forms of congenital nephrotic syndrome and might allow the avoidance of
aggressive treatments for prolonged periods.
PMID- 9543372
TI - Subclinical activation of lupus nephritis by recombinant human growth hormone.
AB - The effect of growth hormone (GH) on subclinical disease activity in a 15-year
old boy with previously quiescent lupus nephritis and chronic renal failure is
described. Institution of supraphysiological doses of GH resulted in a rise in
erythrocyte sedimentation rate, decrease in serum complement, rise in anti-DNA
antibody titers, and increase in T-cell activation markers, all of which improved
following cessation of GH treatment.
PMID- 9543373
TI - Remission of infantile systemic lupus erythematosus with intravenous
cyclophosphamide.
AB - We report an 8-month-old boy with systemic lupus erythematosus and World Health
Organization class IV lupus nephritis who has gone into complete clinical and
serological remission with pulse i.v. cyclophosphamide therapy. To our knowledge
this is the first case of pulse i.v. cyclophosphamide therapy in infantile
systemic lupus erythematosus resulting in long-term remission.
PMID- 9543374
TI - Chronic interstitial cystitis and systemic lupus erythematosus in an 8-year-old
girl.
AB - An 8-year-old girl with systemic lupus erythematosus (SLE) and diffuse
proliferative glomerulonephritis had chronic interstitial cystitis (CIC) early in
the course of SLE. The early occurrence of CIC, the lack of intestinal symptoms,
the association with vesicoureteric reflux, and the improvement of CIC during
therapy with cyclosporin A were the prominent features of the patient reported
here.
PMID- 9543375
TI - Coexistence of VATER association and recurrent urolithiasis: a case report.
AB - VATER association is diagnosed by the combined presence of at least three of the
following features: vertebral anomalies, anal atresia, tracheo-esophageal fistula
and/or esophageal atresia, radial ray anomalies, and renal anomalies (53%).
Urolithiasis has not been reported in this syndrome. A 4-month old girl presented
because of irritability, and the presence of stones in the diapers. Physical
examination revealed anal atresia for which colostomy was performed in the
newborn period. The diagnosis of VATER association was established by the
additional findings of hemivertebrae, sacral dysgenesis, and horseshoe kidney
which was partly non-functional. Urinary pH was repeatedly below 6. An excreted
stone consisted of pure uric acid. Metabolic investigations detected no specific
pathology in purine metabolism. Urolithiasis did not recur after reconstructive
anal and anorecto-vaginoplasty, implying that it was a consequence of colostomy
and/or of the underlying renal anomaly. We suggest that after colostomy patients
with VATER association should be followed for possible urate stones, e.g. by
regular screening of urinary pH.
PMID- 9543376
TI - Nephrocalcinosis in three siblings with idiopathic hypercalciuria.
AB - Idiopathic hypercalciuria (IH) associated with nephrocalcinosis was found in
three of six siblings. After the three affected children were maintained on a low
calcium diet, they demonstrated increasing hypercalciuria, parathyroid hormone,
and vitamin D3 levels. An oral calcium loading test was not necessary to diagnose
renal IH. During treatment with hydrochlorothiazide, the calcium excretion was
normalized. These patients are remarkable because nephrocalcinosis is generally
regarded as a rare complication of renal IH. Moreover, the fact that three of six
siblings are affected raises the question of whether the renal form of IH is
genetically distinct from other forms of IH.
PMID- 9543377
TI - Sedation with intravenous benzodiazepine and ketamine for renal biopsies.
AB - "Lytic cocktail" is the customary sedation before percutaneous renal biopsy.
Owing to deficient sedation and respiratory depression, this approach is no
longer advised. The intravenous combination of a benzodiazepine plus ketamine,
which has been found to be effective and safe in several conditions, was
therefore used for 60 pediatric biopsies. In addition to pulse oximetry, a
physician trained in airway management monitored the patient. The quality of
sedation was acceptable (n = 7) or optimal (n = 53) in all cases. None of the
patients required ventilation or intubation. A mild oxygen desaturation lasting 4
min or less was detected in 6 patients. None of the patients experienced major
change in respiratory rate or blood pressure. The administration of ketamine and,
in some cases, the biopsy puncture were associated with a mildly increased heart
rate. In conclusion, a benzodiazepine plus ketamine provides effective deep
sedation for renal biopsy in childhood.
PMID- 9543378
TI - Evaluation of perioperative antibiotics at the time of dialysis catheter
placement.
AB - The effect of prophylactic antibiotics on the occurrence of peritonitis in the 14
days following surgical peritoneal dialysis catheter placement was evaluated.
Medical records from 73 pediatric patients who had 89 Tenckhoff catheters
inserted over 6 years were reviewed. Twelve catheter procedures were excluded for
rapid catheter loss, unavailable charts, eosinophilic peritonitis, and antibiotic
administration > 3 h postoperatively. Chi-squared analysis for non-continuous
variables compared factors at the time of catheter placement with outcome
(peritonitis). Thirteen patients developed postoperative peritonitis when 77
catheter insertions were analyzed (17%). Peritonitis was significantly more
common in patients who did not receive perioperative antibiotics (7 of 16
catheter placements) (chi(2) = 12.48, P < or = 0.001). The reduced incidence of
peritonitis was not specific to any one antibiotic class. Using step-wise
logistic regression analysis, no association was found between peritonitis
incidence and nephrotic syndrome, immunosuppression, recent surgery (< 14 days),
acute versus chronic use, year of catheter placement, surgeon, or patient age.
Catheter type, implantation technique, exit site care, and operative wound care
did not vary. These results indicate that perioperative peritonitis episodes can
be significantly reduced by the use of prophylactic antibiotics prior to or at
the time of surgery.
PMID- 9543379
TI - Acute changes in endothelin after hemodialysis in children.
AB - The purpose of this study was to investigate the acute changes in endothelin (ET)
levels immediately after hemodialysis and to determine whether these changes vary
with the use of different membranes and hemodialysis solutions. Ten children were
included in the study. Three different hemodialysis sessions were performed on
all patients: session 1, acetate-based dialysate and polycarbonate membrane;
session 2, bicarbonate-based dialysate and polycarbonate membrane; session 3,
acetate-based dialysate and polysulfone membrane. In all cases blood samples were
obtained before and after dialysis. Pre- and post-hemodialysis ET levels of the
patients with acetate-based dialysate and polycarbonate membrane were 33.68 +/-
11.51 pg/ml and 28.27 +/- 12.85 pg/ml, respectively. The fall in ET levels after
this session was statistically significant (P = 0.015). We did not observe a
statistically significant change in ET levels in the other sessions. Post
dialysis mean arterial pressure values were significantly lower than the pre
dialysis values in all three dialysis sessions (P < 0.01). A positive correlation
was observed between plasma ET levels and blood urea nitrogen and serum
potassium; a negative correlation was observed between plasma ET levels and
hematocrit.
PMID- 9543380
TI - Growth hormone and renal osteodystrophy: a case report.
AB - A 14-year-old male with end-stage renal disease on hemodialysis was treated with
recombinant growth hormone for growth retardation. He developed severe renal
osteodystrophy, which responded only to the discontinuation of growth hormone.
PMID- 9543381
TI - A bridge over troubled water...mixed water and electrolyte disorders.
AB - Plasma volume, nitrogenous wastes in the plasma, and plasma osmolality profoundly
affect the function of various organs in the body, particularly the central
nervous system and the heart. Some parameters are more critical for these organs
than others, so that, when homeostatic mechanisms come into play, the body often
defends the parameter of greatest importance at the expense of others. The
hyponatremia and azotemia that develop in dehydrated infants exemplify this
prioritization of the body. The primary goal of therapeutic intervention in such
circumstances is, therefore, geared toward a correction of dehydration. While
alterations in plasma and urinary electrolyte patterns commonly reflect
adjustments made by the body's machinery, it is essential at the bedside to
identify factitiously abnormal laboratory results produced by laboratory
analytical machines. They measure not only biologically active but also
insignificant components of plasma electrolytes and osmolality.
PMID- 9543382
TI - Hyposensitization is contraindicated in Hymenoptera venom-allergic children
treated with cyclosporin.
PMID- 9543383
TI - Additional cases of ureteral obstruction associated with Henoch-Schonlein
purpura.
PMID- 9543384
TI - More on ureteral obstruction associated with Henoch-Schonlein purpura.
PMID- 9543385
TI - Which antibiotics must I use to treat acute pyelonephritis in an oligoanuric
child?
PMID- 9543386
TI - C-TAK1 protein kinase phosphorylates human Cdc25C on serine 216 and promotes 14-3
3 protein binding.
AB - Cdc25C is a dual-specificity protein kinase that controls entry into mitosis by
dephosphorylating Cdc2 on both threonine 14 and tyrosine 15. Cdc25C is
phosphorylated on serine 216 throughout interphase but not during mitosis. Serine
216 phosphorylation mediates the binding of 14-3-3 protein to Cdc25C, and
Cdc25C/14-3-3 complexes are present throughout interphase but not during mitosis.
Here we report the cloning of a human kinase denoted C-TAK1 (for Cdc twenty-five
C associated protein kinase) that phosphorylates Cdc25C on serine 216 in vitro. C
TAK1 is ubiquitously expressed in human tissues and cell lines and is distinct
from the DNA damage checkpoint kinase Chk1, shown previously to phosphorylate
Cdc25C on serine 216. Cotransfection of Cdc25C with C-TAK1 resulted in enhanced
phosphorylation of Cdc25C on serine 216. In addition, a physical interaction
between C-TAK1 and Cdc25C was observed upon transient overexpression in COS-7
cells. Finally, coproduction of Cdc25C and C-TAK1 in bacteria resulted in the
stoichiometric phosphorylation of Cdc25C on serine 216 and facilitated 14-3-3
protein binding in vitro. Taken together, these results suggest that one function
of C-TAK1 may be to regulate the interactions between Cdc25C and 14-3-3 in vivo
by phosphorylating Cdc25C on serine 216.
PMID- 9543387
TI - Rac1 and extracellularly regulated kinase activation are sufficient for E1A
dependent cooperative transformation of primary epithelial cells, but progression
can only be modulated by E1A or Rac1.
AB - Ras transformation of fibroblast cell lines requires activation of multiple
distinct signal pathways that act synergistically. E1A-ras cotransformation of
primary epithelial cells is enhanced by distinct mutations in the second exon of
E1A, resulting in "hypertransformation" and metastasis. The molecular and
cellular differences in the in vitro properties of such transformed cells are
characterized here. Hypertransformed cells grew faster and to higher saturation
densities; had smaller, more refractile cell morphologies with pronounced actin
microspikes; and were less adhesive when compared with wild-type (WT) E1A+ras
expressing cells. No significant differences were observed in extracellularly
regulated kinase activity levels between the hypertransformed and WT transformed
cells. Activated raf and Rac1 together were sufficient for transformation of
primary epithelial cells with E1A, whereas neither alone was competent to
cooperate with E1A. In the presence of activated ras and WT E1A, activated Rac1
expression effected all of the hypertransformation properties. Dominant-negative
Rac1 expression was suppressive of the hypertransformation phenotype, including
cell morphology, actin cytoskeletal structures, decreased growth rates, and
increased adhesion. Thus, hypertransformation is not the result of
extracellularly regulated kinase differences but can be effected by perturbations
in Rac1 signals, as well as E1A 12S COOH-terminal mutants.
PMID- 9543388
TI - FKBP12 is not required for the modulation of transforming growth factor beta
receptor I signaling activity in embryonic fibroblasts and thymocytes.
AB - Transforming growth factor beta (TGF-beta) signals through a heteromeric complex
of type I and type II transmembrane serine-threonine kinases. Recent evidence
suggests that the immunophilin FKBP12 modulates the activity of the type I
receptor, based on data that immunosuppressive drugs that disrupt FKBP12 binding
to the type I receptor enhance TGF-beta signaling in mink lung epithelial cells,
and overexpression of FKBP12 inhibits type I receptor phosphorylation by the type
II receptor. To determine the physiological relevance of the FKBP12-TGF-beta
receptor I interaction, we investigated whether disruption of this interaction
affects TGF-beta-signaling in primary mouse embryo fibroblasts and thymocytes. We
found that the addition of excess drugs had no effect on either TGF-beta-mediated
transcriptional responses or growth inhibition. Dose-response curves for TGF-beta
mediated signaling in primary fibroblasts and thymocytes isolated from either
wild-type or FKBP12-deficient mice were identical. Taken together, our results
indicate that FKBP12 does not play a unique physiological role in TGF-beta
signaling in primary fibroblasts and thymocytes.
PMID- 9543389
TI - Dominant-negative interference of the transforming growth factor beta type II
receptor in mammary gland epithelium results in alveolar hyperplasia and
differentiation in virgin mice.
AB - Transforming growth factor (TGF)-beta1 and TGF-beta3 are normally expressed at
high levels in the mammary gland during quiescence and at all stages of
development, except lactation. Exogenously added TGF-beta1, -beta2, and -beta3
have been shown to regulate growth and differentiation of mammary epithelial
cells in vitro and in vivo. TGF-betas signal through a heteromeric complex of
type I and type II serine/threonine kinases. The type II receptor is necessary
for ligand binding and growth suppression by TGF-betas. Deletions of the
cytoplasmic domains of several kinase receptors known to function in multimeric
complexes have been shown to act as dominant-negative mutations. To evaluate the
role of endogenous TGF-betas in the growth and differentiation of the mammary
gland in vivo, we have targeted expression of a truncated, kinase-defective TGF
beta type II receptor to mammary epithelial cells in transgenic mice using the
mouse mammary tumor virus promoter/enhancer. Transgene expression was localized
to the epithelial cells of terminal ducts and alveolar buds. At approximately 20
weeks of age, virgin female transgenic mice demonstrated varying degrees of
mammary epithelial hyperplasia. Mammary glands from transgenic, virgin animals
exhibited alveolar development and expression of the milk protein, beta-casein.
The data suggest that impaired responsiveness in the epithelium to endogenous TGF
betas results in inappropriate alveolar development and differentiation in the
mammary gland. We conclude that endogenous TGF-betas signal to the epithelium to
maintain quiescence in the mammary glands of virgin animals.
PMID- 9543390
TI - Effects of endothelial nitric oxide synthase gene expression on the tumor biology
of human oral carcinoma SCC-25 cells.
AB - Stable transfection of endothelial nitric oxide synthase (eNOS) cDNA in human
oral carcinoma SCC-25 cells was performed. Two eNOS-expressing clones were
isolated, and both were shown to have increased eNOS expression as assayed by
Northern and Western analyses. Furthermore, a nitrite assay indicated that nitric
oxide production in eNOS-transfected cells was increased. The growth rate and
plating efficiency of eNOS-transfected cells in vitro were lower than that of the
wild-type parental or vector control-transfected cells as assayed by growth
curves, [3H]thymidine incorporation, and standard plating efficiency assays in L
arginine-rich medium. However, when these cancer cells were inoculated into nude
mice, tumor size of eNOS-transfected cells was smaller during the first 25 days
but increased later as compared to tumor size of parental and vector control
transfected cells. It is not clear whether the later increase in tumor size was
due to an increase in SCC-25 cancer cell proliferation, normal stromal cell
proliferation, or both. These results show significant effects of overexpression
of eNOS on tumor growth in vitro and in vivo.
PMID- 9543391
TI - Activation of phosphatidylinositol 3-kinase is necessary for differentiation of
FDC-P1 cells following stimulation of type III receptor tyrosine kinases.
AB - Signaling molecules that are responsible for proliferation and differentiation of
hematopoietic cells following ectopic expression of receptor tyrosine kinases
(RTKs) were investigated in the interleukin 3 (IL-3)-dependent hematopoietic cell
line, FDC-P1. Cells were transfected with human platelet-derived growth factor
receptor (PDGF-R), macrophage colony stimulating factor-1 receptor (CSF-1R),
epidermal growth factor receptor (EGF-R), and chimeras consisting of the
extracellular domain of EGF-R and the transmembrane and cytoplasmic domains of
either HER2 (HER1-2) or c-kit (EK-R). All FDC-P1 transfectants proliferated in
response to the corresponding growth factor in the absence of IL-3. However, only
cells expressing PDGF-R, CSF-1R, and EK-R (type III RTKs) differentiated along
the monocyte-macrophage lineage after treatment with their activating ligands.
Analysis of proteins from these RTK-expressing cells revealed that a Mr 85,000
protein showed in vitro phosphorylation, and V8 protease peptide mapping showed
that this protein was p85, the regulatory subunit of phosphatidylinositol 3
kinase (PI3-kinase). Accordingly, activation of PDGF-R-, CSF-1R-, and EK-R
expressing cells led to an increase in PI3-kinase activity. Expression of EK-R
mutant Y721F, which lacked the known p85 binding site, blocked differentiation
and activation of PI3-kinase, without affecting proliferation. Last, addition of
wortmannin to cells expressing PDGF-R, CSF-1R, and EK-R blocked ligand-induced
differentiation in a concentration-dependent manner, and this effect correlated
with wortmannin's ability to inhibit PI3-kinase. Thus, ectopic expression of both
type I and III RTKs could stimulate FDC-P1 proliferation in the absence of IL-3;
however, only activation of type III RTKs led to differentiation via selective
coupling to p85 and PI3-kinase activation.
PMID- 9543392
TI - Negative regulation of the rat cdc2 promoter in G1 by the silencer element.
AB - Expression of the cdc2 gene is induced steeply at the G1-S-phase boundary. The
previous analysis of promoter elements that confer inducibility revealed the
enhancer at positions -276 to -265. Enhancer activity is suppressed by the
upstream sequence that seems to contain the silencer. The silencer element was
analyzed by fusing several oligonucleotides covering the silencer region upstream
of the enhancer in the cdc2 promoter-luciferase construct. Oligonucleotide IV,
which suppressed enhancer activity, was further dissected by the introduction of
base substitutions and by forming the DNA-protein complexes with quiescent rat
cell extract. The silencer element, AAGTAGTAAAAATA, was finally identified at
positions -374 to -360, which resembles the enhancer sequencer but contains extra
internal AG residues. Silencer complexes were formed with the quiescent cell
extract, whereas the amounts of the complexes decreased with the progression of
the cell cycle, and nearly no complexes were formed with the late G1 cell
extracts. Conversely, the enhancer complex begins to be formed after late G1.
Among the three silencer complexes, the formation of the slowest-migrating
complex (complex III) was inhibited by the enhancer sequence, suggesting that a
common factor interacts with both the silencer and enhancer. These results
suggest that the conversion of complex formation from the silencer to the
enhancer site regulates the induction of cdc2 promoter activity at the G1-S-phase
boundary.
PMID- 9543393
TI - Induction of the nuclear orphan receptor RORgamma during adipocyte
differentiation of D1 and 3T3-L1 cells.
AB - Here, we analyzed the expression of the three members of the retinoid-like orphan
receptor (ROR) nuclear receptor subfamily during adipocyte differentiation.
RORalpha and RORgamma mRNA were upregulated during adipocyte differentiation in
preadipocyte D1 and 3T3-L1 cells, whereas RORbeta mRNA could not be detected. The
induction of RORalpha and RORgamma mRNA succeeded the induction of peroxisome
proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer binding
protein alpha and occurred at a similar time interval as did the increase in aP2
and lipoprotein lipase mRNA. Like the expression of PPARgamma and aP2, the
induction of RORgamma mRNA was repressed by tumor necrosis factor alpha and
transforming growth factor beta. The induction of adipogenesis by prostaglandin
D2 and two thiazolidinediones in the multipotent stem cells C3H10T1/2 was also
accompanied by an induction in RORgamma mRNA. In contrast to parental cells,
clofibrate induces adipogenesis and RORalpha and RORgamma mRNA in BALB/c3T3 cells
that ectopically express PPARgamma. RORgamma mediates its effect on transcription
through specific response elements. Cotransfection of RORalpha or RORgamma and
(RORgamma response element)4-chloramphenicol acetyltransferase into preadipocyte
D1 cells induced transactivation of chloramphenicol acetyltransferase about 100
fold, suggesting that ROR plays a role in the regulation of gene expression in
adipocytes. The nuclear orphan receptor Rev-ErbAalpha, which did not exhibit
transactivation function, was able to inhibit transactivation by RORgamma at two
different levels. Our results show that RORgamma is induced during adipocyte
differentiation in D1 and 3T3-L1 cells and functions as an active transcription
factor, suggesting a role for RORgamma in the regulation of gene expression
during this differentiation process.
PMID- 9543394
TI - Problems associated with the Z-fold region of defibrillation electrodes.
AB - To examine performance failures of automatic external defibrillator (AED) self
adhesive electrodes, a retrospective analysis of patient reports and electrodes
was conducted in a suburban emergency medical service (EMS) system. In all cases,
only records from out-of-hospital cardiac arrests (OHCA) were used if the EMS was
activated and an AED was used. Electrode failures were assessed as follows: 1)
EMS staff returned defibrillation electrodes when they were unable to resolve
repeated "Check Electrode" messages, and 2) an audit of selected records was used
to determine the frequency of electrode problems during calls. Of 302 OHCA calls
during the study period, 22 (7%) resulted in returned electrodes. Defects (cracks
or faults) in the internal conductor were present in 37 (86%) of the 43 returned
electrodes; 2 (5%) possessed dehydrated conductive gel, and in 4 (9%) electrodes
no faults could be identified. Of the 21 complete sets of defective electrodes,
16 (76%) had faults in both electrodes. Chart review revealed at least one "check
electrode" message occurring in 21 (60%) of 35 OHCA reports. The electrode checks
were present for a total of over 83 min, representing 11% of the call times.
Paramedics were required to change electrodes in 9 (26%) of the 35 cases,
resolving the malfunction in all instances. Electrode malfunction appears to be a
common prehospital problem; the conductor is responsible for the majority of
electrode problems and is probably subjected to the most stress during storage
and handling. More reliable, durable defibrillation electrodes are required for
OHCA treatment. Other strategies for electrode storage and quality control are
also discussed.
PMID- 9543395
TI - Case report of an unusual source of tetanus.
AB - We report a case of generalized tetanus in a 31-year-old male originating from a
surgical wound after repair of an achilles tendon rupture. Our case illustrates
an unusual source of tetanus, the need for tetanus prophylaxis before surgery,
and the importance of asking about primary tetanus immunization, particularly in
immigrants.
PMID- 9543396
TI - Facial injury and airway threat from inhalant abuse: a case report.
AB - Fluorinated hydrocarbons cause toxicity in humans via their dysrhythmogenic
potential and their local physical effects on the skin and mucous membranes. The
former is generally the more life-threatening toxic consequence. We present a
case of fluorinated hydrocarbon injury resulting from an intentional inhalation
exposure that created facial frostbite, which threatened the patient's airway.
The clinical range and management of these tissue-toxic effects are reviewed.
PMID- 9543397
TI - Heavy metal toxicity, part II: lead and metal fume fever.
AB - This review is the second of a two-part review of heavy metal toxicity. This part
will identify the salient features of the toxicopathophysiology, clinical
presentation, and emergency department management of lead toxicity and metal fume
fever.
PMID- 9543398
TI - Missed cervical dissociation--recognizing and avoiding potential disaster.
AB - Complete cervical disruptions are high-energy injuries often associated with
polytrauma and spinal cord injury. Because these injuries disrupt all anterior
and posterior stabilizers, they result in a highly unstable spine, and the
injuries are usually apparent on screening radiographs. Patients with these
injuries must be identified and protected during the multiple diagnostic and
surgical procedures they may require during their initial evaluation and
treatment. Emergency procedures must be carefully prioritized relative to other
life-threatening injuries; formal evaluation of the cervical spine may be carried
out before, after, or in stages around other urgently indicated procedures. Until
the cervical spine is cleared, careful observation of precautions can avoid
disasterous complications in even the most unstable situation. A case of complete
cervical disruption in a neurologically intact, hemodynamically unstable patient
is presented for discussion. For polytraumatized patients with cervical
dissociation, combined anterior and posterior stabilization is the treatment of
choice.
PMID- 9543399
TI - Lacerations against Langer's lines: to glue or suture?
AB - This study evaluated the effects of initial wound orientation on the cosmetic
outcome of facial lacerations repaired with histoacryl blue (HAB), a tissue
adhesive, vs. conventional suturing. This was a retrospective analysis of
patients from a prospective randomized clinical trial on the use of HAB. Children
in the initial cohort who had facial lacerations and were also evaluated for
cosmetic appearance at a 2-month follow-up appointment were eligible. Orientation
along Langer's Lines, which define the functional anatomy of the underlying
structures to the skin, was determined by two investigators blinded to the
initial method of repair. Photographs of the wounds were reviewed and the wounds
were categorized as being: Langer (+) (<20 degrees deviated from Langer's Lines)
or Langer (-) (> or =20 degrees deviated from Langer's Lines). Photographic
appearance at follow-up was evaluated using a 100-mm visual analog scale (0=best,
100=worst) by two plastic surgeons blinded to the method of repair. Sixty-one
patients were enrolled in the initial cohort, with 55 (90%) evaluated at the 2
month follow-up. Forty-eight of the 55 (87%) had facial lacerations, therefore
meeting present study criteria: [HAB (n=26), Suturing (n=22), Langer (+) (n=27),
Langer (-) (n=21)]. Langer (+) patients were comparable to Langer (-) for
demographics, wound characteristics, and method of repair. There was no
difference in overall cosmetic appearance of facial wounds closed with HAB vs.
conventional suturing. Follow-up appearance was significantly worse for sutured
Langer (-) vs. Langer (+) wounds. In contrast, cosmetic appearance of lacerations
closed by HAB were comparable between Langer (-) and Langer (+) wounds. In
conclusion, initial wound orientation had a greater impact on the cosmetic
appearance for lacerations closed by suturing compared to HAB. HAB may be the
preferred method of cutaneous closure for facial lacerations oriented against
Langer's Lines.
PMID- 9543400
TI - Parenteral hydralazine revisited.
AB - Historical aspects of the development and application of the vasodilator
hydralazine are reviewed. The pharmacology, pharmacokinetics, metabolism, and
mechanism of action are discussed, with emphasis on the parenteral use of this
drug. It is reiterated that parenteral hydralazine is the preferred drug for the
treatment of severe preeclampsia, but its usefulness in other forms of
accelerated hypertension is also addressed. Through comparisons with other
established antihypertensive agents, the efficacy and pharmacoeconomic potential
of hydralazine are stressed.
PMID- 9543401
TI - A close look at fenfluramine and dexfenfluramine.
AB - In an effort to combat obesity, several medications have been developed. The
nonamphetamine anorectics, such as phentermine, fenfluramine, and
dexfenfluramine, have been recommended as first-line drug therapy for the
treatment of obesity once diet and exercise alone have failed. Numerous studies
have shown that these agents can promote weight loss when combined with diet
restriction and exercise. Although fenfluramine and dexfenfluramine lack the
abuse potential of amphetamine and its congeners, these agents are associated
with drug interactions and adverse effects. Concomitant administration of
fenfluramine or dexfenfluramine with medications that enhance serotonin levels
(e.g., antidepressants, monoamine oxidase inhibitors, and migraine medications)
can precipitate serotonin syndrome. Sudden discontinuation of fenfluramine or
dexfenfluramine after prolonged administration can precipitate withdrawal
depressive symptoms. Primary pulmonary hypertension, a potentially fatal
disorder, has been reported to occur approximately 30 times more frequently in
patients receiving anorectic agents for more than 3 months compared to the
general population. More recently, the association of these popular anorectics
with valvular heart disease has caused increased concerns about their use. The
risks of primary pulmonary hypertension, valvular heart disease, and the
occurrence of convulsions, coma, and death in overdose appear to be equally
likely with dexfenfluramine and fenfluramine. In addition, many patients who lose
weight while taking these anorectics rapidly regain it after the medication has
been discontinued.
PMID- 9543402
TI - High-speed motor vehicle crash.
PMID- 9543403
TI - Erythema multiforme major.
PMID- 9543404
TI - Cost-effective medicine: the financial impact that practice guidelines have on
outpatient hospital charges in the emergency department.
AB - The objective of this study was to determine whether specific cost-effective
guidelines based on a patient's chief complaint can significantly reduce
outpatient hospital charges in the ED. A prospective randomized single-blinded
clinical trial was conducted in an urban community hospital ED with a 14,000
annual census. The first phase of the study involved preintervention data
collection. The second phase focused on development, physician approval, and
implementation of 23 specific cost-effective guidelines, as well as general
recommendations for diagnostic tests. The third phase involved postintervention
data collection. Results showed that the total outpatient hospital charge
decreased by 28% per patient. The laboratory hospital charge decreased by 46% per
patient. The radiology hospital charge decreased by 20% per patient. The hospital
supply charge and pharmacy charge decreased by 31% per patient and 11% per
patient, respectively. In conclusion, cost-effective medicine practiced with
specific guidelines, based on a patient's chief complaint, significantly reduces
unnecessary diagnostic tests and medical treatments ordered by emergency
physicians.
PMID- 9543405
TI - The duality of medicine: reaching a balance.
PMID- 9543406
TI - "Black plaque" on the Internet.
PMID- 9543407
TI - Pneumothorax following acupuncture is a generally recognized complication seen by
many emergency physicians.
PMID- 9543408
TI - Against customer service.
AB - This essay examines the nature of service in medicine and the relationship
between service and profit. "Customer service medicine" is identified with the
interrelated views that 1) profit is or ought to be healthcare's fundamental
concern and 2) the quality of medical service corresponds to the degree to which
it produces a feeling of approval in patients. This position is contrasted with
the more traditional "beneficence model," which holds that 1) service ought to be
healthcare's fundamental concern and 2) the proper criterion of quality medical
service is the alleviation, mitigation, or prevention of the human suffering that
occasions illness. Five shortcomings in the customer service model are
identified: 1) customer service advocates often appeal to an unsound "efficiency
argument"; 2) the prioritization of profit over service will vitiate patients'
legitimate trust in healthcare; 3) the prioritization of profit converts medicine
from a "practice" into an "instrumental activity"; 4) the prioritization of
profit countervails the values of continuity and thoroughness; and 5) the notion
of service as customer satisfaction derives more from the exigencies of turning a
profit than from an analysis of sick persons' needs.
PMID- 9543409
TI - Guidelines for red blood cell and plasma transfusion for adults and children: an
emergency physician's overview of the 1997 Canadian Blood Transfusion Guidelines.
Part 2: Plasma transfusion and infectious risk.
PMID- 9543410
TI - Physician services in small and rural emergency departments: a critique of the
Scott Report.
PMID- 9543411
TI - Imaging asynchronous mechanical activation of the paced heart with tagged MRI.
AB - A method for imaging the rapid temporal-spatial evolution of myocardial
deformations in the paced heart is proposed. High time resolution-tagged MR
images were obtained after stimulation of the myocardium with an MR-compatible
pacing system. The images were analyzed to reconstruct dynamic models of local 3D
strains over the entire left ventricle during systole. Normal canine hearts were
studied in vivo with pacing sites on the right atrium, left ventricular free wall
and right ventricular apex. This method clearly resolved local variations in
myocardial contraction patterns caused by ventricular pacing. Potential
applications are noninvasive determination of electrical conduction abnormalities
and the evaluation of new pacing therapies.
PMID- 9543412
TI - Improved coverage in dynamic contrast-enhanced cardiac MRI using interleaved
gradient-echo EPI.
AB - An interleaved gradient-echo echo-planar imaging (IGEPI) sequence was modified
for and applied to dynamic contrast-enhanced imaging of the heart. Using IGEPI,
images with 3.0 x 3.9 mm nominal in-plane resolution are acquired in 100 ms,
enabling eight slices per heartbeat for a heart rate of 60 beats/min. The
acquisition speed and use of saturation prepulses allows acquisition of short-
and long-axis images during the same contrast bolus. IGEPI maintains the
acquisition characteristics required for performing a quantitative first-pass
perfusion analysis as well as providing improved coverage compared with
conventional fast gradient echo.
PMID- 9543413
TI - Spatial and temporal differentiation of fMRI BOLD response in primary visual
cortex of human brain during sustained visual simulation.
AB - The blood oxygenation level dependent (BOLD) response during sustained visual
stimulation has been studied by several groups using fMRI with controversial
conclusions. This issue was investigated for the human brain at high (4 Tesla)
magnetic field strength using a flashing goggle at 8 Hz. The results demonstrate
that the overall BOLD response in the primary visual cortex has an initial
overshoot after the onset of visual stimulation and an undershoot after the
termination of visual stimulation. A significant and positive BOLD response,
however, remains constant between the initial and terminal transient responses.
The temporal BOLD responses in the primary visual cortex were spatially
dependent. The regions identified as draining veins in images displayed
proportionately larger initial and terminal transient responses, whereas regions
devoid of such vessels and associated mainly with parenchyma exhibited a more
time-independent BOLD response. These results reveal that the BOLD effect and,
presumably, the uncoupling between cerebral blood flow and cerebral metabolic
rate of oxygen consumption, are maintained in the primary visual cortex during
sustained visual stimulation, and the temporal characteristics of the BOLD effect
are spatially dependent.
PMID- 9543415
TI - Sound generation in gradient coil structures for MRI.
AB - When supporting plates of plastic material are subjected to alternating
transverse Lorentz forces while in a strong magnetic field normal to the plate
surface, compressional waves within the solid produce a modulation of the plate
surface that launches an acoustic wave in air along the magnetic field axis. We
have extended our previous theory describing this process to include a detailed
description of the formation of an acoustic interference pattern in air described
by Fraunhofer diffraction at a distance from the plate surface. The extended
theory predicts that the observed acoustic signal midpoint and normal to the
plate surface gives a variation with frequency in approximate agreement with our
previous measurements. The acoustic output off axis shows acoustic blazing that
produces two main diffraction peaks with a splitting inversely proportional to
the velocity of sound in the plate material. The new results could have important
ramifications for the minimization of sound output in gradient coil design for
MRI. A new arrangement of coils is proposed to ameliorate the acoustic output
problem centrally and normal to the plate by extending the frequency response of
the supporting plates to much higher frequencies. Also presented are estimates of
the compressional wave velocities deduced from frequency response data recorded
at the center-point of a number of different plates.
PMID- 9543414
TI - Multiple-echo proton spectroscopic imaging using time domain parametric spectral
analysis.
AB - A multiple-echo MR spectroscopic imaging (MRSI) method is presented that enables
improved metabolite imaging in the presence of local field inhomogeneities and
measurement of transverse relaxation parameters. Short echo spacing is used to
maximize signal energy from inhomogeneously line-broadened resonances, and time
domain parametric spectral analysis of the entire echo train is used to obtain
sufficient spectral resolution from the shortened sampling periods. Optimal
sequence parameters for 1H MRSI are determined by computer simulation, and
performance is compared with conventional single-echo acquisition using phantom
studies at a field strength of 4.7 T. A preliminary example for use at 1.5 T is
also presented using phantom and human brain MRSI studies. This technique is
shown to offer improved performance relative to single-echo MRSI for imaging of
metabolites with shortened T2* values due to the presence of local field
inhomogeneities. Additional advantages are the intrinsic measurement of
metabolite T2 values and determination of metabolite integrals without T2
weighting, thereby facilitating quantitative metabolite imaging.
PMID- 9543416
TI - Simultaneous intracellular and extracellular pH measurement in the heart by 19F
NMR of 6-fluoropyridoxol.
AB - 6-Fluoropyridoxol (6-FPOL) was evaluated as a simultaneous indicator of
intracellular and extracellular pH and, hence, pH gradient in perfused rat
hearts. After infusion, 19F NMR spectra rapidly showed two well-resolved peaks
assigned to the intracellular and extracellular compartments, and pH was
calculated on the basis of chemical shift with respect to a sodium
trifluoroacetate standard. To demonstrate use of this molecule, dynamic changes
in myocardial pH were assessed with a time resolution of 2 min during respiratory
and metabolic alkalosis or acidosis and ischemia. For a typical heart,
intracellular pH (pHi) = 7.14+/-0.01 and extracellular pH (pHe) = 7.52+/-0.02. In
response to metabolic alkalosis, pHi remained relatively constant and the pH
gradient increased. In contrast, respiratory challenge caused a significant
increase in pHi. Independent measurements using pH electrodes and 31P NMR
confirmed validity of the 19F NMR results.
PMID- 9543418
TI - Quantitative measurements of cerebral blood flow in rats using the FAIR
technique: correlation with previous iodoantipyrine autoradiographic studies.
AB - Flow-sensitive alternating inversion recovery (FAIR) is a recently introduced MRI
technique for assessment of perfusion that uses blood water as an endogenous
contrast agent. To characterize the FAIR signal dependency on spin tagging time
(inversion time (TI)) and to validate FAIR for cerebral blood flow (CBF)
quantification, studies were conducted on the rat brain at 9.4 T using a
conventional gradient-recalled echo sequence. The T1 of cerebral cortex and blood
was found to be 1.9 and 2.2 s, respectively, and was used for CBF calculations.
At short TIs (<0.8 s), the FAIR signal originates largely from vascular
components with fast flows, resulting in an overestimation of CBF. For TI > 1.5
s, the CBF calculated from FAIR is independent of the spin tagging time,
suggesting that the observed FAIR signal originates predominantly from
tissue/capillary components. CBF values measured by FAIR with TI of 2.0 s were
found to be in good agreement with those measured by the iodoantipyrine technique
with autoradiography in rats under the same conditions of anesthesia and arterial
pCO2. The measured pCO2 index on the parietal cortex using the FAIR technique was
6.07 ml/100 g/min per mmHg, which compares well with the pCO2 index measured by
other techniques. The FAIR technique was also able to detect the regional
reduction in CBF produced by middle cerebral artery occlusion in rats.
PMID- 9543417
TI - Sodium TQF NMR and intracellular sodium in isolated crystalloid perfused rat
heart.
AB - The feasibility of monitoring intracellular sodium changes using Na triple
quantum filtered NMR without a chemical shift reagent (SR) was investigated in an
isolated rat heart during a variety of interventions for Na(i) loading. Perfusion
with 1 mM ouabain or without K+ present in the perfusate for 30 min produced a
rise of the Na TQF signal with a plateau of approximately 190% and approximately
228% relative to the preintervention level, respectively. Stop-flow ischemia for
30 min resulted in a TQF signal growth of approximately 147%. The maximal Na TQF
signal increase of 460% was achieved by perfusion without K+/Ca2+, corresponding
to an elimination of the Na transmembrane gradient. The observed values of Na NMR
TQF growth in the physiological and pathological ranges are in agreement with
reported data by other methods and have a linear correlation with intracellular
sodium content as determined in this study by Co-EDTA method and by sucrose
histidine washout of the extracellular space. Our data indicate that the increase
in Na TQF NMR signal is determined by the growth of Na(i), and the extracellular
Na contribution to the total TQF signal is unchanged at approximately 64%. In
conclusion, Na TQF NMR without using SR offers a unique and noninvasive
opportunity to monitor alterations of intracellular sodium. It may provide
valuable insights for developing cardioprotective strategies and for observing
the effects of pharmaceutical treatments on sodium homeostasis.
PMID- 9543419
TI - Ultra-fast velocity imaging in stenotically produced turbulent jets using RUFIS.
AB - A method for rapidly producing velocity images is presented. This sequence
combines a modified bipolar gradient pulse to magnitude encode the velocity with
the rotating ultra-fast imaging sequence (RUFIS) to image the encoded spins.
Velocity encoding is done in 3 msec, and RUFIS acquires 32 projections in 8 msec.
The method is applied to turbulent jets associated with a 75% stenosis in a 15-mm
inner diameter glass pipe. Data is acquired upstream and downstream from the
stenosis for Reynolds numbers from 560 to 3750. In addition, a robust method of
reconstructing the unobserved short time region of a free induction decay is
presented and incorporated into the image processing.
PMID- 9543420
TI - Gradient characterization using a Fourier-transform technique.
AB - This paper describes a technique for characterizing the gradient subsystem of a
magnetic resonance (MR) system. The technique uses a Fourier-transform analysis
to directly measure the k-space trajectory produced by an arbitrary gradient
waveform. In addition, the method can be easily extended to multiple dimensions
and can be adapted to measuring residual gradient effects such as eddy currents.
Several examples of gradient waveform and eddy-current measurements are
presented. Also, it is demonstrated how the eddy-current measurements can be
parameterized with an impulse-response formalism for later use in system tuning.
When compared to a peak-fitting analysis, this technique provides a more direct
extraction of the k-space measurements, which reduces the possibility of analysis
error. This approach also has several advantages as compared to the conventional
eddy-current measurement technique, including the ability to measure very short
time constant effects.
PMID- 9543421
TI - Off-resonance proton T1rho dispersion imaging of 17O-enriched tissue phantoms.
AB - Proton T1rho dispersion imaging is a recently described method for indirect
detection of 17O. However, clinical implementation of this technique is hindered
by the requirement for a high-amplitude spin-locking field (gammaB1 > 1 kHz) that
exceeds current limitations in specific absorption rate (SAR). Here, a strategy
is offered for circumventing high SAR in T1rho dispersion imaging of 17O through
the use of low-amplitude off-resonance spin-locking pulses (gammaB1 < 300 Hz).
Proton spin-lattice relaxation times in the off-resonance rotating frame were
measured in H2(17)O-enriched tissue phantoms. On- and off-resonance T1rho
dispersion imaging was implemented at 2 T using a spin-locking preparatory pulse
cluster appended to a standard spin-echo sequence. On- and off-resonance
dispersion images exhibited similar 17O-based image contrast. Magnetization
transfer effects did not depend on 17O concentration and had no effect on image
contrast. In conclusion, off-resonance proton T1rho dispersion imaging shows
promise as a safe, sensitive technique for generating 17O-based T1rho contrast
without exceeding SAR limitations.
PMID- 9543422
TI - Concomitant magnetic-field-induced artifacts in axial echo planar imaging.
AB - When a linear magnetic field gradient is used, spatially higher-order magnetic
fields are produced to satisfy the Maxwell equations. It has been observed that
the higher-order magnetic field produced by the readout gradient causes axial
echo planar images acquired with a horizontal solenoid magnet to shift along the
phase-encoding direction and lose image intensities. Both the shift and intensity
reduction become increasingly severe as the slice offset from the isocenter
increases. These phenomena are quantitatively analyzed, and good correlation
between experiments and theory has been established. The analysis also predicts a
previously unreported Nyquist ghost on images with very large slice offsets. This
ghost has been verified with computer simulations. Based on the analysis, several
methods have been developed to eliminate the image shift, the intensity
reduction, and the ghost. Selected methods have been implemented on a commercial
scanner and proved effective in removing these image artifacts.
PMID- 9543423
TI - Effects of gradient anisotropy in MRI.
AB - A gradient system is anisotropic if the impulse responses of at least two of the
gradient channels, x, y, or z, differ from each other. Such an undesired
condition may arise, for example, from differences between the gradient channels
with respect to eddy currents or from unbalanced time delays in the electronic
components. Depending on the degree of anisotropy, the actual gradient then
deviates from the nominal, desired gradient under certain oblique orientations
during the transient periods of gradient switching. The adverse consequence is
degradation of image quality, such as distortion, ghosting, and blurring. In this
paper, a theoretical analysis is given of the basic effects. Furthermore, the
implications for the MRI process and possible correction methods are described.
The effects of anisotropy are shown experimentally for echo-planar imaging and
two-dimensional selective RF excitation with spiral gradient pulses.
PMID- 9543425
TI - Asymmetric sampling along k(slice-select) in two-dimensional multislice MRI.
AB - Reduction of the slice-select refocusing gradient in two-dimensional multislice
imaging results in asymmetry of the k-space representation of collected data
along the slice-select direction. Standard methods of partial Fourier
reconstruction developed for other methods of asymmetric k-space sampling can be
used to reconstruct these data with final through-plane resolution smaller than
the collected slice thickness. This method can be used for reducing scan time in
the same manner as asymmetric sampling in the phase-encoded direction. In
addition, the reduced refocusing gradient reduces minimum TE and motion artifacts
in the same manner as for asymmetric sampling in the frequency-encoded direction
(fractional echoes). Results using a resolution phantom and a flow phantom
illustrate these concepts.
PMID- 9543424
TI - Dynamic functional imaging of relative cerebral blood volume during rat forepaw
stimulation.
AB - Dynamic measurements of regional changes in cerebral blood volume (CBV) were
performed in rat models of hypercarbia and focal neuronal activation using T2
weighted imaging after injection of an intravascular contrast agent with a very
long blood half-life. Calculated percent CBV change during hypercarbia was
consistent with literature results from other non-invasive modalities. Equivalent
percent CBV increases were found using spin- and gradient-echo images, suggesting
proportional changes in blood volume for capillaries and small veins. During
electrical stimulation of rat forepaw, focal CBV response to stimulation (24+/
4%) was significantly delayed relative to blood oxygen level dependent (BOLD)
signal after both onset and cessation of stimulation. Poststimulus CBV decay was
temporally consistent with the BOLD poststimulus undershoot. The use of exogenous
agent increased the functional contrast-to-noise ratio relative to BOLD imaging
by 5.7+/-1.3 at a magnetic field strength of 2 Tesla and 1.5+/-0.2 at 4.7 Tesla.
PMID- 9543426
TI - On the nature and reduction of plaque-mimicking flow artifacts in black blood MRI
of the carotid bifurcation.
AB - Cardiac-gated black blood MRI of the carotid artery bifurcation in normal human
subjects shows signal within the lumen suggesting wall thickening or
atherosclerotic plaque. This signal was believed to be artifactual, arising from
complex flow patterns present at the carotid bifurcation. Computer simulation of
the hemodynamics and black blood multislice image acquisition in a model of the
carotid bifurcation showed that these artifacts arise from spins recovering their
signal within the slow, recirculating flow of the carotid bulb. The computed
hemodynamics also suggested that these artifacts could be minimized or eliminated
entirely by gating the acquisition of slices in the most artifact-prone region of
the carotid bulb within a 250-ms window after peak systole. Application of these
predictions to studies of normal volunteers showed that, in most cases, these
flow artifacts in black blood MRI can be eliminated simply by altering the phase
of the cardiac cycle to which the image acquisition is gated. The observation
that the size and placement of the saturation slabs had little effect on these
artifacts suggested that, in those cases in which recirculation persists
throughout the cardiac cycle, either inversion-recovery or presaturation within
the bulb itself would be required to suppress them.
PMID- 9543427
TI - Calibration of the 1H decoupling field strength and experimental evaluation of
the specific RF absorption rate in 1H-decoupled human 13C-MRS.
AB - For patient safety in human 1H decoupled 13C-MRS, it is absolutely necessary to
evaluate the specific RF absorption rate (SAR) of the tissue exposed to 1H
frequency irradiation. With the use of surface coils, the local SAR at the body
surface is of most concern due to the inherent RF field inhomogeneity. An
empirical procedure to spatially calibrate the decoupler power level and to
evaluate the local SAR at the body surface is described. For head, liver, muscle
gastrocnemius, and muscle vastus lateralis, the SAR at the body surface was
estimated for an 1H/13C double surface coil setup. Optimized duty cycle values
obtained with this procedure show that broad-band 1H-decoupled 13C-MR
spectroscopy is clinically feasible at 1.5 T for such a coil configuration within
safety guidelines.
PMID- 9543428
TI - Proton T2 relaxation of cerebral metabolites during transient global ischemia in
rat brain.
AB - Putative changes of metabolite T2 relaxation times were investigated before and
after a 20-min period of global ischemia in rat brain in vivo (n = 10) using
localized proton MRS at different echo times (2.35 T). Neither absolute T2
relaxation times (TE = 20-270 ms) nor time courses of T2-weighted metabolite
signals (TE = 135 ms) revealed statistically significant changes during the
occlusion or early reperfusion relative to pre-ischemic baseline. These findings
are in line with reports of relaxation changes at much later stages and further
demonstrate that altered T2 relaxation is not a confounding factor in diffusion
weighted long-TE proton MRS during early ischemic events.
PMID- 9543429
TI - A localized double-quantum filter for the in vivo detection of brain glucose.
AB - A double-quantum filter (DQF) sequence with PRESS localization was developed for
in vivo detection of the glucose resonances in the 3.85-ppm region of the brain
proton spectrum. The efficiency and spectral editing characteristics were studied
in phantom and animal experiments. Approximately 45% detection efficiency was
achieved at 4.7 T with TE = 68 ms. Since the efficiency of the DQF method is
dependent on the relative phases of the RF pulses, a phase calibration procedure
was used to correct for phase shifts induced by the spatial localization. In
addition to detecting the 3.85-ppm glucose resonances with approximately 45%
efficiency, the DQF sequence simultaneously detects 1.3-ppm lactate resonance
with approximately 20% efficiency. The use of the DQF technique for
simultaneously monitoring both the input and output of anaerobic glycolysis in
the brain was demonstrated by detecting brain glucose and lactate in the same
acquisition after iv injection of glucose followed by the induction of global
ischemia.
PMID- 9543430
TI - Improved sampling of myocardial motion with variable separation tagging.
AB - A novel tagging method is introduced that increases the spatial resolution of
estimates of myocardial radial thickening. The separation of adjacent parallel
tag planes is customized to match the expected motion of specific regions of the
heart wall. In regions in which the tags increase their separation over systole
(radial thickening), the tag planes are placed close together at end diastole. In
regions in which the tags decrease their separation over systole (circumferential
shortening), the tags are placed farther apart so they remain detectable at end
systole. With variable separation tagging (VTAG), parallel plane tagging can be
used to obtain higher-resolution estimates of radial thickening and
circumferential shortening simultaneously.
PMID- 9543431
TI - Simultaneous multislice acquisition with arterial-flow tagging (SMART) using echo
planar imaging (EPI).
AB - Arterial spin tagging techniques have been used to image tissue perfusion in MR
without contrast injection or ionizing radiation. Currently, spin tagging studies
are performed primarily using single-slice imaging sequences, which are time
consuming. This note reports a multislice echo-planar arterial spin tagging
technique (Simultaneous Multislice Acquisition with aRterial-flow Tagging, or
"SMART"). Multiband RF encoding (Hadamard) is used to provide simultaneous
multislice acquisition capability for spin tagging techniques (such as echo
planar imaging signal targeting with alternating radio frequency and flow
sensitive alternative inversion recovery). The method is illustrated with a two
slice pulse sequence that was implemented using the FAIR technique to generate
two perfusion weighted images simultaneously. Compared with single-slice
sequences, this two-slice sequence provided similar image quality, signal-to
noise ratio, and twice the spatial coverage compared with the single-slice
technique within the same scan time.
PMID- 9543432
TI - FID-based lung MRI at 0.5 T: theoretical considerations and practical
implications.
AB - Pulse sequences based on FID signals and projection reconstruction (PR) were
investigated for lung MRI at 0.5 T and evaluated for artifacts caused by: (1) k
space mismapping due to either delay or distortion of the readout gradient
waveform, (2) cardiac motion and pulsatile flow, and (3) respiratory motion.
Nonstructured artifacts were described, simulated, and experimentally confirmed
for the first time. Nonstructured artifacts did not impair the demonstration of
structures of high signal-to-noise ratio (SNR) but generated quantitative errors
in the image intensity analysis over the lung parenchyma. The use of FID-based PR
techniques for lung MRI is not justified at 0.5 T.
PMID- 9543433
TI - Time-course imaging of rat embryos in utero with magnetic resonance microscopy.
AB - Magnetic resonance (MR) microscopy was used to noninvasively investigate the
development of live rat embryos in utero. The difficulty in making sequential
observations of a developing mammalian embryo has frustrated developmental
biologists for many years. Most current technologies analyze normal and abnormal
development by observing end point phenotypes (in fixed specimens) rather than
investigating the live embryo. MR microscopy was adapted to allow rat litters to
be scanned three times each (at 1- to 3-day intervals) and has produced images of
live developing embryos. It was demonstrated that repeated anesthesia and imaging
protocols produced no gross malformations in the rat pups that were subsequently
delivered and observed. Three-dimensional projection encoding with phase
rewinders produced isotropic [256(3)] image data sets in about 30 minutes with
excellent tissue contrast arising from steady-state effects in the amniotic
fluid.
PMID- 9543435
TI - A clinically relevant HIV-1 subunit vaccine protects rhesus macaques from in vivo
passaged simian-human immunodeficiency virus infection.
AB - OBJECTIVES: To investigate whether immunization with recombinant HIV-1 envelope
protein derived from a clinical isolate could protect macaques from infection
with an in vivo passaged chimeric simian-human immunodeficiency virus (SHIV).
DESIGN AND METHODS: A total of 16 animals were studied from which three groups of
four animals were immunized with vaccine formulations of the CC-chemokine
receptor-5-binding recombinant gp120 of HIV-1W6.1D. Four weeks after the last
immunization, all 16 animals were intravenously challenged with in vivo passaged
SHIV derived from the same HIV-1 group B clinical isolate (W6.1D) as the
vaccines. RESULTS: Vaccine protection from infection was demonstrated in 10 out
of 12 macaques immunized with recombinant gp120. Complete protection from
infection was achieved with all of the animals that received the SBAS2-W6.1D
formulation, a potent inducer of both T-cell and humoral immune responses.
Partial protection was achieved with SBAS1-W6.1D, a formulation based on
immunomodulators known to induce T-cell responses in humans. In vaccinated
animals that were infected, virus load was reduced and infection was delayed.
CONCLUSIONS: In a relatively large number of primates, vaccine efficacy was
demonstrated with a clinically relevant HIV-1 vaccine. These results reveal that
it is possible to induce sterilizing immunity sufficient to protect from
infection with SHIV which was passaged multiple times in vivo. Our findings have
implications for current HIV-1 clinical vaccine trials and ongoing efforts to
develop safe prophylactic AIDS vaccines.
PMID- 9543434
TI - The duration of viral suppression during protease inhibitor therapy for HIV-1
infection is predicted by plasma HIV-1 RNA at the nadir.
AB - OBJECTIVE: To determine markers that are associated with the durability of
virologic response to therapy with HIV protease inhibitors in HIV-infected
individuals. DESIGN: This study encompassed two retrospective analyses of the
duration of virologic response to protease inhibitor therapy. The first analysis
included 29 patients receiving either monotherapy or combination therapy with the
protease inhibitor ritonavir whose plasma HIV RNA levels rebounded from the point
of greatest decline with mutations associated with resistance to ritonavir. The
second analysis included a cohort of 102 patients who initially responded to
randomized treatment with either monotherapy with ritonavir or combination
therapy with ritonavir and zidovudine. METHODS: Durability of response was
defined as the time from the initiation of therapy to the point at which plasma
HIV RNA displayed a sustained increase of at least 0.6 log10 copies/ml from the
nadir value. In the first analysis, durability of response was analyzed with
respect to baseline HIV RNA, HIV RNA at the nadir, and the drop in HIV RNA from
baseline to the nadir. In the second analysis, time to rebound was examined using
Kaplan-Meier analysis, stratifying by either baseline HIV RNA or HIV RNA at the
nadir. RESULTS: In both analyses, the durability of response was not highly
associated with either baseline RNA or the magnitude of RNA decline from
baseline. Instead, a strong relationship was observed between the durability of
response and the nadir plasma HIV-1 RNA value (P < 0.01). The nadir in viral load
was generally reached after 12 weeks of randomized therapy. CONCLUSIONS: Viral
RNA determinations at intermediate timepoints may be prognostic of impending
virologic failure of protease inhibitor therapy. Therapeutic strategies that
allow intensification of initial antiretroviral regimens in the subset of
patients with incomplete virological response before the emergence of high level
resistance should be investigated.
PMID- 9543436
TI - The effects of lamivudine treatment on HIV-1 disease progression are highly
correlated with plasma HIV-1 RNA and CD4 cell count.
AB - OBJECTIVE: To determine the value of plasma HIV-1 RNA and CD4 cell count as
predictors of the clinical benefit of antiretroviral treatment. DESIGN AND
SETTING: The CAESAR (Canada, Australia, Europe, South Africa) trial randomized
1840 patients [inclusion CD4 cell count, 25-250 x 10(6)/l] to add either placebo,
lamivudine (3TC) or 3TC plus loviride in a double-blinded fashion to baseline
treatments (zidovudine, zidovudine-didanosine or zidovudine-zalcitabine) for 1
year. PATIENTS: This analysis included 487 patients with data on CD4 cell count
and HIV-1 RNA after 12-20 weeks of treatment and subsequent follow-up for
clinical progression. MAIN OUTCOME MEASURES: The correlation between 12-20-week
change in CD4 cell count, HIV-1 RNA and progression to AIDS or death in the
placebo group was used to predict the clinical benefit of the 3TC-containing arms
of the trial, given their effects on CD4 cell count and HIV-1 RNA. RESULTS: After
12-20 weeks of treatment, HIV-1 RNA fell by 0.37 log10 copies/ml in the 3TC arms
versus a rise of 0.05 log10 copies/ml in the placebo arm. The 12-20-week CD4 cell
count rose by 35 x 10(6)/l in the 3TC arm versus a fall of 8 x 10(6)/l in the
placebo arm. After 12-20 weeks of treatment, a reduction in HIV-1 RNA of 1 log10
at 12-20 weeks predicted a 49% reduction in progression [hazard ratio (HR), 0.51;
95% confidence interval (CI), 0.30-0.87] and a rise in CD4 cell count of 50 x
10(6)/l predicted a 51% reduction in progression (HR, 0.49; 95% CI, 0.33-0.73).
Using the model from the placebo arm, the rises in CD4 cell count and reductions
in HIV-1 RNA during 3TC treatment predicted a 59% reduction in progression to
AIDS or death. The observed clinical benefit was a 57% reduction in progression
for the 3TC arms versus placebo (HR, 0.43; 95% CI, 0.26-0.71). CONCLUSIONS: Rises
in CD4 cell count and reductions in HIV-1 RNA were reliable in predicting the
clinical benefit of 3TC in the CAESAR trial.
PMID- 9543437
TI - Decreasing incidence of HIV and sexually transmitted diseases in young Thai men:
evidence for success of the HIV/AIDS control and prevention program.
AB - OBJECTIVE: To determine whether HIV and sexually transmitted disease (STD)
incidence rates among young men in northern Thailand have declined since the
establishment of the '100% Condom Program', and to prospectively document changes
in the association between behavioral risk factors and incident HIV and STD
infections. SETTING: Thirteen military bases in northern Thailand. METHODS:
Serial prospective cohorts of 19-23-year-old male conscripts (n = 4086) inducted
into military service from six northern Thai provinces between 1991 and 1993 were
followed at 6-month intervals for incident HIV and STD through May 1995. HIV
incidence was determined by serology, and incident STD were reported by
conscripts as diagnosed by health-care providers. RESULTS: HIV incidence declined
from a rate of 2.48 per 100 person-years during 1991-1993 to 0.55 per 100 person
years during 1993-1995. STD incidence showed an even greater decline, with a 10
fold decrease from 1991-1993 to 1993-1995. Behavioral risk factors for incident
STD infections included a history of prior STD and sex with girlfriends and sex
workers. Inconsistent condom use remained a strong predictor of incident STD
among brothel visitors. Other previously-reported risk factors in 1991-1993 such
as illicit drug use, frequency and cost of brothel visits, and low socioeconomic
status were not associated with incident STD or HIV in 1993-1995. CONCLUSIONS:
Although several studies have recently reported decreased prevalence of HIV and
STD infections in Thailand, these data demonstrate that a dramatic decrease in
the incidence rates of STD, including HIV infection, has occurred among young men
in military service in northern Thailand. The Thai AIDS prevention and control
program might be implemented by other countries experiencing major epidemics of
heterosexually transmitted HIV infections. Similar prevention programs targeted
at other populations in Thailand and elsewhere in Asia are needed to decrease the
spread of the HIV epidemic.
PMID- 9543442
TI - Resistance and cross-resistance with saquinavir and other HIV protease
inhibitors: theory and practice.
PMID- 9543443
TI - The frequency of resistant mutant virus before antiviral therapy.
AB - OBJECTIVE: To calculate the expected prevalence of resistant HIV mutants before
antiviral therapy. DESIGN: HIV replication generates virus mutants. The
prevalence of these mutants is determined by mutation and selection/fitness. Some
mutations will confer drug resistance and it is crucial for the success of
antiviral drug therapy to determine whether these resistant viruses are present
before the initiation of therapy. METHODS: A quasispecies equation was used to
calculate the expected frequency of drug-resistant virus prior to therapy.
RESULTS AND CONCLUSIONS: We show how the pretreatment frequency of resistant
virus depends on the number of point mutations between wild-type and mutant
virus, the selective disadvantage of the resistant mutant and the intermediate
mutants, and the mutation rate.
PMID- 9543444
TI - Infection of primary dermal microvascular endothelial cells by Kaposi's sarcoma
associated herpesvirus.
AB - OBJECTIVE: To develop an in vitro model for infection of primary human cells with
Kaposi's sarcoma (KS) herpesvirus (KSHV). DESIGN: The recent identification of a
herpesvirus associated with KS, its successful isolation in vitro, and its
complete DNA sequencing facilitates experiments on the pathogenesis of AIDS
related KS. Completed studies demonstrate that the endothelial cells lining the
vascular slits in KS lesions are productively infected with KSHV and may be the
principal site of virus replication. We have designed a model system to study the
infection of primary human cells with KSHV. METHODS: A coculture technique was
used with KS cells (KS-1) and primary dermal microvascular endothelial cells.
RESULTS: We detected increasing viral DNA concentrations as well as viral mRNA
suggesting that a productive virus infection occurs in the target cells.
Infection of these cells is dose- and time-dependent and is inhibited by
lobucavir, foscarnet and 9-(2-phosphomethoxyethyl) adenine. With a modification
of the model, KSHV can be serially passaged in primary cells in excess of 16
passages. CONCLUSIONS: This novel model assay system makes new studies on the
role of KSHV and KSHV-induced cellular products on the pathogenesis of KS
possible. It also provides a high volume screening method to detect agents that
inhibit KSHV infection of primary endothelial cells.
PMID- 9543445
TI - Phase II controlled trial of post-exposure immunization with recombinant gp160
versus antiretroviral therapy in asymptomatic HIV-1-infected adults. VaxSyn
Protocol Team.
AB - OBJECTIVE: To alter the natural course of HIV-1 infection by inducing or
potentiating immune responses to HIV-1 envelope glycoprotein. DESIGN:
Multicentre, double-blind, three-arm, placebo-controlled study. SETTING:
Outpatients attending clinics in two University Hospitals. PATIENTS: Ninety-nine
asymptomatic HIV-1-infected adults with CD4+ T-cell counts > 400 and < 600 x
10(6)/l and no previous antiretroviral therapy were included. INTERVENTIONS:
Patients were randomly assigned to three groups treated with: (i) gp160 in alum
over a 2-year period in combination with placebo for the full study duration (n =
32); (ii) gp160 in alum over a 2-year period in combination with zidovudine for
the full study duration (n = 34); and (iii) alum over a 2-year period in
combination with zidovudine for the full study duration (n = 33). RESULTS:
Immunotherapy was well tolerated and no significant differences in disease
progression were seen in the treatment groups. The majority of patients (85%)
receiving gp160 showed persistent lymphoproliferative responses to the immunogen
and to a different Env antigen preparation. CD4+ cell count changes in patients
receiving zidovudine alone were significantly higher than those seen in patients
receiving immunotherapy alone after 1 year of treatment. Zidovudine
administration was associated with initial transient reduction of plasma
viraemia. CONCLUSIONS: Prolonged immunization with a soluble HIV-1 subunit
provided no benefit to asymptomatic HIV-1-infected patients and was inferior to
zidovudine monotherapy. Furthermore, immunization with gp160 shortened the
duration of the transient viral load reduction induced by zidovudine.
PMID- 9543446
TI - Role of transforming growth factor-beta1 in the suppressed allostimulatory
function of AIDS patients.
AB - BACKGROUND: The T-cell stimulatory function of accessory cells isolated from
peripheral blood lymphocytes of AIDS patients has been reported to be suppressed.
These patients also have elevated levels of the immunosuppressive factor
transforming growth factor (TGF)-beta1 in their serum and plasma. OBJECTIVE: To
explore the role of TGF-beta1 in the loss of accessory cell function of
peripheral blood lymphocytes from AIDS patients. METHODS: Fluorescent labeled
anti-TGF-beta1 and confocal microscopy were used to detect the presence of TGF
beta1 on the cell membrane of dendritic cells. To assess the role of TGF-beta1 in
the inhibition of accessory cell function in AIDS, antibodies against TGF-beta1
or the TGF-beta1 type III receptor, beta-glycan, were added to a mixed lymphocyte
reaction. RESULTS: TGF-beta1 was detected on the cell membrane of dendritic cells
isolated from AIDS patients. The addition of blocking antibodies against either
TGF-beta1 or beta-glycan restored the T-cell stimulatory function to accessory
cells from these patients. CONCLUSIONS: T-cell stimulatory function was not
irreversibly lost in AIDS patients. Our data suggested that beta-glycan-TGF-beta1
immunosuppressive complexes may contribute to the suppression of accessory cell
function in these patients.
PMID- 9543447
TI - Pilot study of zidovudine-lamivudine combination therapy in vertically HIV
infected antiretroviral-naive children.
AB - OBJECTIVE: To examine tolerance and efficacy of a zidovudine plus lamivudine
combination in HIV-infected children without previous exposure to antiretroviral
drugs. METHODS: Thirteen vertically infected children (aged 4 months to 10 years)
were treated with zidovudine (approximately 100 mg/m2 three times daily) and
lamivudine (4 mg/kg twice daily). CD4 T-cell count, plasma HIV RNA concentration,
complete blood count and blood chemistry profile were monitored before treatment
and at months 1, 3 and 6. RESULTS: In general, treatment was well tolerated. One
child developed slight neutropenia in the presence of antineutrophil antibodies.
CD4 cell count increased from 851+/-621 x 10(6)/l at baseline to 1073+/-945 x
10(6)/l at month 3 (P < 0.05) and to 1133+/-728 x 10(6)/l at month 6 (P = 0.01).
CD4+ cell count increased in 10 patients after 3 months and in 11 patients
treated for 6 months. One child showed a continuous decrease of CD4 cells despite
treatment. Before treatment the plasma HIV RNA concentration was elevated in nine
children (> 4.0 log10 copies/ml) and decreased in all of them: by month 1, the
mean reduction was -1.16 log10 copies/ml; by month 3, -1.38 log10 copies/ml; and
by month 6, -1.53 log10 copies/ml compared with baseline. However, one child
showed steadily increasing viral load from 2.7 log10 copies/ml to a maximum of
4.52 log10 copies/ml, surprisingly in association with increasing numbers of CD4
cells. This child was switched to a new combination regimen after 6 months of
treatment. Plasma HIV RNA levels below limit of detection were reached in six
patients: after 1 month of treatment in one patient, after 3 months in five
patients, and after 6 months in six patients. There was a mean reduction of viral
load from 4.56 log10+/-4.63 log10 copies/ml (n = 13) to 3.8 log10+/-3.9 log10
copies/ml (P < 0.05; n = 9) after 1 month, to 3.67 log10+/-3.88 log10 copies/ml
(P < 0.01; n = 13) after 3 months, and to 3.64 log10+/-3.95 log10 copies/ml after
6 months of treatment (P < 0.001; n = 13). CONCLUSIONS: This pilot study
demonstrates the feasibility of zidovudine-lamivudine combination in children not
previously exposed to antiretroviral drugs. This promising combination should
therefore be evaluated in larger trials.
PMID- 9543448
TI - High incidence of anal high-grade squamous intra-epithelial lesions among HIV
positive and HIV-negative homosexual and bisexual men.
AB - OBJECTIVE: The incidence of anal cancer among homosexual men exceeds that of
cervical cancer in women, and HIV-positive homosexual men may be at even higher
risk than HIV-negative men. Cervical cancer is preceded by high-grade squamous
intra-epithelial lesions (HSIL) and anal HSIL may similarly be the precursor to
anal cancer. In this study, we describe the incidence of and risk factors for
HSIL in HIV-positive and HIV-negative homosexual and bisexual men. DESIGN:
Prospective cohort study of HIV-positive and HIV-negative homosexual men.
SETTING: The University of California, San Francisco. PATIENTS: 346 HIV-positive
and 262 HIV-negative men enrolled at baseline, 277 HIV-positive and 221 HIV
negative homosexual men followed after baseline. STUDY DESIGN: A questionnaire
was administered detailing lifestyle habits, medical history and sexual
practices. Anal swabs for cytology and human papillomavirus studies were
obtained, followed by biopsies of visible lesions. Human papillomavirus testing
was performed using polymerase chain reaction (PCR) and 'hybrid capture'. Blood
was obtained for HIV testing and measurement of CD4 levels. MAIN OUTCOME
MEASURES: Incident HSIL. RESULTS: HIV-positive men were more likely to develop
HSIL than HIV-negative men relative risk (RR), 3.7; 95% confidence interval (CI),
2.6-5.7. Life-table estimates of the 4-year incidence of HSIL was 49% (95% CI, 41
56) among HIV-positive men and 17% (95% CI, 12-23) among HIV-negative men. Among
HIV-positive men, those with lower baseline CD4 counts (P = 0.007) and persistent
infection with one or more human papillomavirus types, determined using PCR (P =
0.0001), were more likely to develop HSIL. CONCLUSIONS: HIV infection, lower CD4
levels and human papillomavirus infection were associated with high rates of
incident HSIL among homosexual men. However, high rates were found at all CD4
levels among HIV-positive men and among HIV-negative men.
PMID- 9543450
TI - Breastfeeding, genetic, obstetric and other risk factors associated with mother
to-child transmission of HIV-1 in Sao Paulo State, Brazil. Sao Paulo
Collaborative Study for Vertical Transmission of HIV-1.
AB - OBJECTIVES: To evaluate the effect of maternal, obstetric, neonatal and post
natal factors on the risk of vertical transmission of HIV-1. DESIGN: Multicentre
retrospective cohort study. SETTING: Obstetric and paediatric clinics in four
cities in Sao Paulo State, Brazil. MAIN OUTCOME: Child's HIV-1 infection status.
METHODS: Data were collected by standardized record abstraction and interview on
553 children born to women identified as HIV-1-infected before or at delivery.
Paediatric infection was determined by immunoglobulin G anti-HIV-1 tests at age
18 months or by AIDS diagnosis at any age. Multivariate logistic regression was
used to assess the effect of potential risk factors on vertical transmission of
HIV-1. RESULTS: HIV-1 infection status was determined for 434 children (follow-up
rate of 78%); 69 were classified as HIV-1-infected [transmission risk, 16%; 95%
confidence interval (CI), 13-20%]. In multivariate analysis, advanced maternal
HIV-1 disease [odds ratio (OR), 4.5; 95% CI, 2.1-9.5], ever breastfed (OR, 2.2;
95% CI, 1.2-4.2), child's negative Rhesus blood group (OR, 2.5; 95% CI, 1.2-5.5),
third trimester amniocentesis (OR, 4.1; 95% CI, 1.2-13.5) and black racial group
(OR, 0.3; 95% CI, 0.1-0.9) were independently and significantly associated with
mother-to-child transmission of HIV-1. Transmission was increased marginally with
prematurity, more than 10 lifetime sexual partners and prolonged duration of
membrane rupture. No association was found between child's HIV-1 infection and
mode of delivery or serological evidence of syphilis during pregnancy.
CONCLUSION: These findings support the importance of severity of maternal HIV-1
disease in the risk of vertical transmission of HIV-1, indicate measures to
reduce transmission by avoiding amniocentesis and breastfeeding and suggest that
race and Rhesus blood type may be markers for genetic susceptibility to
infection.
PMID- 9543449
TI - The Cote d'Ivoire national HIV counseling and testing program for tuberculosis
patients: implementation and analysis of epidemiologic data.
AB - OBJECTIVES: To describe the implementation of a free, voluntary and confidential
HIV counseling and testing program for patients with newly diagnosed tuberculosis
at the eight large outpatient tuberculosis centers in Cote d'Ivoire, and to
present epidemiologic findings on participating patients. DESIGN: HIV counseling
and testing program with ongoing HIV serosurveillance. METHODS: HIV counseling
and testing services were established at the two tuberculosis centers in Abidjan
in 1989 and were extended to six centers in the Cote d'Ivoire interior in the
first half of 1994. Characteristics of counseled patients, acceptance rates of
HIV testing, and HIV serologic results were analyzed for all eight centers from
1994 to 1996. Temporal trends in HIV seropositivity rates were examined for the
two centers of Abidjan from 1989 to 1996. RESULTS: From July 1994 through
December 1996, 17 946 (91.8%) out of 19 594 patients who were counseled at the
eight centers in Cote d'Ivoire consented to HIV testing, of whom 7749 (43.2%)
were HIV-seropositive. The highest rates of 47.0 and 45.6% were found in the two
centers in Abidjan, with rates ranging from 32.9 to 42.4% in the six centers in
the interior. HIV-seropositive tuberculosis patients from each of the 50
districts in Cote d'Ivoire were identified. In Abidjan, the HIV seropositivity
rate remained relatively stable among men (46.7% in 1989, 48.5% in 1991, 43.6% in
1996), but rose sharply among women from 32.7% in 1989 to 50.1% in 1996.
CONCLUSIONS: The high HIV seropositivity rates among tuberculosis patients in all
geographic regions of Cote d'Ivoire indicate that the HIV epidemic has now spread
throughout the country. However, the successful implementation of an extensive
HIV counseling and testing program for more than 37000 tuberculosis patients to
date demonstrates the commitment of the Cote d'Ivoire Ministry of Health to
integrating HIV/AIDS prevention activities with tuberculosis control efforts.
When logistically and economically feasible, the extension of HIV-related social
and clinical services to HIV-seropositive tuberculosis patients should be
considered by other national tuberculosis control programs in Africa.
PMID- 9543451
TI - A molecular epidemiologic survey of HIV in Uganda. HIV Variant Working Group.
AB - OBJECTIVE: Previous data, based on a small sampling of convenience, reported
subtypes A, B, C, D, and G in Uganda, but neither the extent nor the proportion
of these subtypes could be evaluated. To establish correctly the prevalence and
distribution of HIV-1 subtypes, we analysed viral clades in 739 HIV-1
seropositive specimens from different areas of Uganda. METHODS: Blood specimens
from 1100 patients were collected in five districts of Uganda. Within this
collection, 929 HIV-1-seroreactive samples underwent analysis of viral DNA, and
739 were selected for further subtyping in env or pol regions. RESULTS: Using a
combination of subtype A- and D-specific probes to C2-V3 region and DNA
sequencing, HIV-1 env subtypes were determined in 594 specimens: 341 were of
subtype A (57.4%), 250 of subtype D (42.1%), and three of subtype C (0.5%). Sixty
two samples showed reactivity with both probes, suggesting potential mixed
infections, cross-reactivity to probes, or possibly other subtypes. Subsequent
sequence analysis of 19 randomly selected specimens revealed subtypes A (n = 4),
D (n = 12), and C (n = 3). Sequence analysis of the 27 samples chosen from the
remaining 83 samples, which could be amplified only with viral gp41 or protease
gene primers, classified them as subtypes A (n = 13) and D (n = 14). No
significant clinical, demographic, or geographic differences were found between
HIV-1 infections with viruses of subtypes A and D, despite considerable genetic
diversity within these clades. CONCLUSIONS: This is the first major population
based study of the prevalent HIV-1 strains in an African country selected for
vaccine trials. The subtyping methods we describe should be of use to
investigators seeking to conduct large-scale screening for HIV variants in other
populations.
PMID- 9543452
TI - The impact of new antiretroviral regimes on HIV-associated hospital admissions
and deaths.
PMID- 9543453
TI - High prevalence of hepatitis G virus RNA and antibody to probable viral envelope
protein but not both in AIDS patients' plasma.
PMID- 9543454
TI - Fatal acute haemolysis in an AIDS patient treated with indinavir.
PMID- 9543455
TI - New treatments for progressive multifocal leukoencephalopathy in HIV-1-infected
patients.
PMID- 9543456
TI - Longitudinal comparison of HIV-1 RNA burden in plasma and cerebrospinal fluid in
two patients starting triple combination antiretroviral therapy.
PMID- 9543457
TI - Therapeutic concentrations of indinavir in cerebrospinal fluid of HIV-1-infected
patients.
PMID- 9543458
TI - Resolution of azole-resistant oropharyngeal candidiasis after initiation of
potent combination antiretroviral therapy.
PMID- 9543459
TI - Seroprevalence of human herpesvirus-8 in healthy subjects and patients with AIDS
associated and classical Kaposi's sarcoma in France.
PMID- 9543460
TI - The first Zambian population-based HIV survey: saliva-based testing is accurate
and acceptable.
PMID- 9543461
TI - High seroprevalence of human herpesvirus-8 in pregnant women and prostitutes from
Cameroon.
PMID- 9543462
TI - New advances in the treatment of Alzheimer's disease. Proceedings of a symposium.
Dallas, Texas, USA. July 12, 1997.
PMID- 9543463
TI - A multidisciplinary team approach to managing Alzheimer's disease.
AB - Patients with Alzheimer's disease experience a range of symptoms that may
overwhelm the patients, their families, and the people responsible for their
care. With today's drive to reduce health care costs, any plan for managing these
patients must produce maximum effectiveness at the lowest possible cost. A
multidisciplinary team potentially offers both effective and efficient dementia
care by eliminating duplicative or ineffective services and maintaining the
optimum health of the patient and family.
PMID- 9543464
TI - Metrifonate: overview of safety and efficacy.
AB - Metrifonate is a cholinesterase inhibitor with a long-lasting inhibition that
raises brain acetylcholine levels. It is well-absorbed and has limited binding to
serum proteins. In preliminary studies of its utility in the treatment of
Alzheimer disease's (AD), it led to improvements of cognition or reduced the rate
of decline of cognition compared with placebo. It also benefited the global
function of these patients. Side effects include nausea, cramping, and diarrhea.
Metrifonate has promise as a well-tolerated treatment of the symptoms of AD.
PMID- 9543465
TI - Pharmacokinetics and drug interactions of cholinesterase inhibitors administered
in Alzheimer's disease.
AB - Cholinesterase inhibitors are the first agents to be successfully developed
specifically for the treatment of cognitive decline associated with Alzheimer's
disease. Basic knowledge of their pharmacokinetics is important to their
appropriate administration. Their pharmacokinetics help determine the magnitude
and duration of their pharmacologic effects, and also the manner in which they
affect the degree of cholinesterase inhibition and recovery. The clinical utility
of measuring these values in daily practice awaits further research. Drug
interactions with cholinesterase inhibitors may occur by pharmacokinetic or
pharmacodynamic mechanisms. For the most part, interactions that are mediated by
the hepatic cytochrome P-450 system have been inadequately evaluated.
PMID- 9543466
TI - Preclinical pharmacology of metrifonate.
AB - Alzheimer's disease is a chronic neurodegenerative disorder that is characterized
by memory impairment, cognitive dysfunction, behavioral disturbances, and
deficits in activities of daily living. A consistent observation in these
patients is that cholinergic neurons are affected and deteriorate over time,
leading to decreased levels of acetylcholine (ACh). Acetylcholinesterase (AChE)
inhibitors, which attempt to prevent the breakdown of ACh, may be classified as
short acting, intermediate acting, and long acting based on AChE regeneration
time. Metrifonate is converted by a nonenzymatic process to the long-acting
cholinesterase inhibitor 2,2-dichlorovinyl dimethyl phosphate (DDVP).
Acetylcholinesterase inhibition produced by metrifonate occurs rapidly, is dose
dependent, can be detected by inhibition measured in red blood cells, and can be
reversed by oxime administration. Metrifonate and DDVP improved performance in
young rats; cognitive improvement in aged rats also was observed. Both agents
were well tolerated and did not have significant effects on various preclinical
pharmacologic safety tests.
PMID- 9543468
TI - Prospects of developing interventions to prevent Alzheimer's disease.
AB - Based largely on recommendations of scientists from around the world, it is
possible to discover treatments designed to maintain independent functioning of
patients with Alzheimer's disease. It is hoped that discussion of critical
targets for intervention, and possible strategies for altering the degenerative
course of the disease will spur interested groups into action.
PMID- 9543467
TI - Economic considerations in Alzheimer's disease.
AB - Alzheimer's disease (AD) is the third most expensive disease in the United
States, costing society approximately $100 billion each year. It is one of the
most prevalent illnesses in the elderly population, and with the aging of
society, will become even more significant. Costs associated with AD include
direct medical costs such as nursing home care, direct nonmedical costs such as
in-home day care, and indirect costs such as lost patient and caregiver
productivity. Medical treatment may have economic benefits by slowing the rate of
cognitive decline, delaying institutionalization, reducing caregiver hours, and
improving quality of life. Pharmacoeconomic evaluations have shown positive
results regarding the effect of drug therapy on nursing home placement,
cognition, and caregiver time.
PMID- 9543470
TI - Epidemiology of mild pneumonia.
AB - Clinicians define mild pneumonia as patients who are "not too sick," have normal
respiratory and mental status, and are able to maintain oral intake. As yet there
is no uniform definition of mild pneumonia. By inference, mild pneumonia occurs
in younger patients with less comorbidity and has a better outcome than pneumonia
that is moderate to severe. "Atypical" pathogens such as Mycoplasma pneumoniae,
Chlamydia pneumoniae and respiratory tract viruses are common causes of mild
pneumonia.
PMID- 9543471
TI - Management of pneumonia in the outpatient setting.
AB - Most patients with pneumonia never reach the hospital but are managed in the
community. Unlike patients admitted to the hospital, in most, no investigations
are performed and the diagnosis is based on clinical features. Less than half of
those with clinical pneumonia have radiographic infiltrates and some of those
with lower respiratory tract infection that is not considered to be pneumonia do.
Few studies have investigated this condition, partly because of these diagnostic
difficulties. The importance of distinction of these conditions is uncertain at
present. The role of microbiological investigations in patients with pneumonia in
the community requires clarification. For most patients it is unlikely that such
tests will alter management, but it is not possible to predict those in whom such
tests may help. What little is known about the microbial cause of pneumonia
managed outside of the hospital is that the causative pathogens are similar to
those found in studies of hospitalized patients, with the exception of pathogens
usually associated with severe illness such as legionella and staphylococci,
which are uncommon. Empirical antibiotic therapy can be predicted from the above
findings, but much further research is required to fill in current gaps in our
knowledge.
PMID- 9543472
TI - Impact of influenza and other community-acquired viruses.
AB - The incidence of community-acquired pneumonia peaks during the winter season each
year. Increases in mortality from these pneumonias and influenza-like illnesses
(P&I) above an "epidemic threshold" for 2 or more weeks generally signify
increased numbers of influenza virus infections in the community, although peaks
in P&I mortality typically lag a few weeks behind peaks in influenza virus
activity. Most of the pneumonias cases found during influenza virus epidemics are
due to secondary bacterial infections, with an increase in the frequency of
Staphylococcus aureus over that seen in nonepidemic periods. One interaction
between bacteria and influenza viruses that may increase disease severity by
increasing growth of the virus is proteolytic cleaving of the hemagglutinin
mediated directly or indirectly by bacterial products. Influenza virus infections
also have many effects on the host that can enhance secondary bacterial
infections; included are impairments of mucus clearance and T cell,
polymorphonuclear cell and macrophage functions, as well as alterations in
respiratory epithelium that can enhance adherence of bacteria. Recent studies
indicate that the role of respiratory syncytial virus infections in causing acute
pulmonary syndromes in elderly individuals, including secondary bacterial
pneumonia, is essentially equivalent to that of influenza A viruses during years
when there is not a severe influenza epidemic. Although other respiratory viruses
can occasionally cause or facilitate the development of community-acquired
pneumonia, currently available epidemiological data do not support significant
roles for them relative to those of influenza and respiratory syncytial viruses.
PMID- 9543473
TI - What new antibiotics to offer in the outpatient setting.
AB - The treatment of community-acquired pneumonia is empiric. Guidelines have been
developed to assist the clinician in selecting antibiotics to cover the likely
pathogens. Given the difficulty of predicting an etiologic agent from patient
characteristics, radiologic findings, and laboratory studies, initial regimens
recommend broad-spectrum coverage. In some circumstances, two antibiotics may be
required. The prevalence of resistant organisms is increasing and must be
considered when prescribing treatment. Patient compliance is essential for
successful therapy but diminishes with inconvenient dosing schedules and with
poorly tolerated medicines. A number of novel antimicrobials have either been
just launched or are in the late stages of development. Most have been developed
in an attempt to address the above concerns. This article focuses on the new oral
cephalosporins, macrolides, and fluoroquinolones, and discusses the place of each
in the therapy of community-acquired pneumonia.
PMID- 9543474
TI - Duration and route of antibiotic therapy in community-acquired pneumonia: switch
and step-down therapy.
AB - The treatment of hospitalized patients with community-acquired pneumonia (CAP)
has traditional been with intravenous antibiotics. More recently, the focus of
this antibiotic therapy has been empiric and based on the most likely pathogens
in a given patient. The concept of when and how to approach the patient for
conversion to oral therapy, known as switch therapy, is now the focus of
controversy. Recently, several studies have emerged from the literature that shed
some light on the subject of switch therapy for CAP. Although the data are
limited at this time, it seems clear that switching to oral antibiotics in
selected low-risk patients may be feasible and safe. In this article, we focus on
the problem and help formulate a practical approach to switching patients from
intravenous antibiotics to oral therapy for CAP.
PMID- 9543475
TI - Emergence of antimicrobial resistance in community-acquired pulmonary pathogens.
AB - Antibiotic resistance to the common respiratory tract pathogens is increasing
worldwide. Penicillin-resistant pneumococci are of particular concern. Most
strains of penicillin-resistant Streptococcus pneumoniae have intermediate
resistance to penicillin, and highly resistant strains are rare at present.
Careful selection of antibiotics with low resistance potential and excellent
activity against highly penicillin-resistant pneumococci (ie, cefotaxime,
ceftriaxone, cefepime, cefprozil, doxycycline, levofloxacin, sparfloxacin, and
meropenem) is the best current strategy to delay or increase the emergence of
highly penicillin-resistant strains of S pneumoniae.
PMID- 9543476
TI - Chronic pneumonias.
AB - Some patients present in the outpatient setting with persistent respiratory and
constitutional symptoms in association with unresolving parenchymal infiltrates
on the chest radiograph. Clinicians must entertain a wide differential diagnosis
as many infectious and noninfectious conditions can lead to this chronic
pneumonia syndrome. The clinical presentation and radiographic abnormalities are
often nonspecific. A significant proportion of patients have no underlying
predisposing illness, and most of the bacterial pathogens are often considered
constituents of the "normal respiratory flora." Accurate diagnosis generally
requires bronchoscopic evaluation. Prolonged therapy is essential. This article
reviews the epidemiology and the predominant bacterial, mycobacterial, and fungal
pathogens associated with this syndrome. A brief discussion of some of the
noninfectious processes is also included.
PMID- 9543478
TI - Radiographic findings in Klebsiella (Friedlander's) pneumonia: the bulging
fissure sign.
PMID- 9543477
TI - Strategies for prevention of community-acquired pneumonia.
AB - Our rapidly expanding knowledge of the cause and pathogenesis of Community
acquired pneumonia (CAP) offers new opportunities to prevent this disease.
Influenza vaccine is effective for the prevention of respiratory illness,
including pneumonia, in the setting of influenza A and B infection. Pneumococcal
vaccine is effective for preventing the most common form of bacterial CAP, but it
is most effective when administered early in the course of chronic illnesses.
Even with the widespread availability and proven efficacy of influenza and
pneumococcal vaccines, their use has remained suboptimal. Rimantadine and
Amantadine have also been used successfully for prevention of influenza A
infection. Further improvement in strategies for the prevention of CAP lies in
the development of new and improved vaccines, enhanced environmental control, and
general education of physicians and the public, so that new approaches such as
hospital-based immunization can be applied.
PMID- 9543479
TI - Neocortical efferent neurons with very slowly conducting axons: strategies for
reliable antidromic identification.
AB - Although simple in concept, reliable antidromic identification of efferent
populations poses numerous technical challenges and is subject to a host of
sampling biases, most of which select against the detection of the neurons with
slowly conducting axons. This problem is particularly acute in studies of the
neocortex. Many neocortical efferent systems have large sub-populations with very
slowly conducting, nonmyelinated axons and these elements have been relatively
neglected in antidromic studies of neocortical neurons. The present review
attempts to redress this problem by analyzing the steps that must necessarily
precede antidromic identification and the sampling biases associated with each of
these steps. These steps include (1) initial recognition that the microelectrode
is near a neuron; (2) activation of the efferent axon via the stimulating
electrode; (3) conduction of the antidromic impulse from stimulation site to
soma; (4) detection of the antidromic spike in the extracellular record and (5)
discriminating antidromic from synaptic activation. Experimental strategies are
suggested for minimizing the sampling biases associated with each of these steps;
most of which can be reduced or eliminated by appropriate experimental
procedures. Careful attention to such procedures will make it possible to better
understand the nature and function of the information flow along the very slowly
conducting axonal systems of the neocortex.
PMID- 9543480
TI - Multiple fragment statistical analysis of post-spike effects in spike-triggered
averages of rectified EMG.
AB - Spike-triggered averaging of EMG is a useful experimental technique for revealing
functional connectivity from central neurons to motoneurons. Because EMG
waveforms constitute time series, statistical analysis of spike-triggered
averages is complicated. Empirical methods generally have been employed to detect
the presence of post-spike effects (PSEs), since, as we argue in this report, it
is not feasible to develop a rigorous yet sensitive statistical test that detects
PSEs in a single grand average of rectified EMG. We have developed a method of
multiple fragment statistical analysis (MFSA) of PSEs, based on dividing an
experimental record into a large numbers of non-overlapping fragments. The
calculations necessary to obtain accurate P-values using the multiple fragment
method are simple and efficient, and therefore preliminary results can be
obtained while recording. In this report, we present the rationale for MFSA, and
give examples of its application. We found MFSA to have considerable utility in
accurately testing the significance of small PSEs, and in detecting PSEs in
shorter recordings. Statistical corrections that should be used when recording
multiple channels simultaneously are discussed. MFSA could be implemented for
statistical analysis of other waveforms averaged, such as evoked potentials,
movement-related cortical potentials, or event-related desychronizations.
PMID- 9543481
TI - [3H]-noradrenaline secretion from rat cortex synaptosomes perforated with
Staphylococcus aureus alpha-toxin.
AB - Rat cortex synaptosomes have been successfully perforated with high
concentrations (> or = 400 U/ml) of Staphylococcus aureus alpha-toxin. The free
Ca2+-concentration dependence of [3H]-noradrenaline release was similar to that
observed for PC 12 and chromaffin cells. Release from the alpha-toxin perforated
synaptosomes was not significantly inhibited by omega-conotoxin GVIA. Initially,
Ca2+-dependent release was independent of MgATP (for 0.5 min), but became
increasingly dependent on MgATP with time. Lactate dehydrogenase efflux from
alpha-toxin-perforated synaptosomes was not different than efflux from control
synaptosomes, and an antibody to N-ethylmaleimide-sensitive fusion protein did
not enter the synaptosomes. [3H]-noradrenaline release was temperature and alpha
toxin-concentration dependent. Ca2-dependent release was more resistant to
rundown from alpha-toxin- than from streptolysin-O-perforated synaptosomes. This
preparation of perforated synaptosomes should be useful for studies of regulated
exocytosis from nerve endings.
PMID- 9543483
TI - Principal component analysis of minimal excitatory postsynaptic potentials.
AB - 'Minimal' excitatory postsynaptic potentials (EPSPs) are often recorded from
central neurones, specifically for quantal analysis. However the EPSPs may emerge
from activation of several fibres or transmission sites so that formal quantal
analysis may give false results. Here we extended application of the principal
component analysis (PCA) to minimal EPSPs. We tested a PCA algorithm and a new
graphical 'alignment' procedure against both simulated data and hippocampal
EPSPs. Minimal EPSPs were recorded before and up to 3.5 h following induction of
long-term potentiation (LTP) in CA1 neurones. In 29 out of 45 EPSPs, two (N=22)
or three (N=7) components were detected which differed in latencies, rise time
(Trise) or both. The detected differences ranged from 0.6 to 7.8 ms for the
latency and from 1.6-9 ms for Trise. Different components behaved differently
following LTP induction. Cases were found when one component was potentiated
immediately after tetanus whereas the other with a delay of 15-60 min. The
immediately potentiated component could decline in 1-2 h so that the two
components contributed differently into early (< 1 h) LTP1 and later (1-4 h) LTP2
phases. The noise deconvolution techniques was applied to both conventional EPSP
amplitudes and scores of separate components. Cases are illustrated when quantal
size (upsilon) estimated from the EPSP amplitudes increased whereas upsilon
estimated from the component scores was stable during LTP1. Analysis of component
scores could show apparent double-fold increases in upsilon which are interpreted
as reflections of synchronized quantal releases. In general, the results
demonstrate PCA applicability to separate EPSPs into different components and its
usefulness for precise analysis of synaptic transmission.
PMID- 9543482
TI - A method for long term culture of murine type 2 astrocytes.
AB - Producing cultures of mouse type 2 astrocytes is difficult as these cells have
low proliferative ability when isolated as pure cultures. Often standard glial
culture techniques yield mixed glial cultures from mouse which contain little or
no type 2 glia. This has made studies of the nature and activity of type 2
astrocytes difficult. A co-culture technique has been established to allow long
term culturing of type 2 astrocytes which can be grown in large number and
isolated at very high purity. This technique uses co-culture of isolated type 2
astrocytes and their progenitor cells with microglia. Using this method, type 2
astrocytes can be grown to high density cultures and maintained in culture for
over a year without noticeable change in basic phenotypic characteristics. Aged
type 2 astrocytes show increased activity of anti-oxidant enzymes suggesting that
these cells have increased resistance to oxidative stress. This method may allow
analysis of the development of type 2 astrocytes from progenitor cells and may
help to identify the in vivo equivalent of these cells.
PMID- 9543484
TI - Review of neural network applications in sleep research.
AB - To find a better automated sleep-wake staging system for human analyses of
numerous polygraphic records is an interesting challenge in sleep research. Over
the last few decades, many automated systems have been developed but none are
universally applicable. Improvements in computer technology coupled with
artificial neural networks based systems (connectionist models) are responsible
for new data processing approaches. Despite extensive use of connectionist models
in biological data processing, in the past, the field of sleep research appeared
to have neglected this approach. Only a few sleep-wake staging systems based on
neural network technology have been developed. This paper reviews the current use
of artificial neural networks in sleep research. Following a brief presentation
of neural network technology, each of the existing system is described and
attention drawn to the heterogeneity of the different processing approaches in
sleep research. The high performances observed with systems based on neural
networks highlight the need to integrate these tools into the field of sleep
research.
PMID- 9543485
TI - A technique for in vivo vascular perfusion fixation of the sheep central nervous
system.
AB - A method for perfusion fixation of the sheep central nervous system is described.
The technique utilises the vascular anatomy of the spinal cord and brain to
provide fixation that is comparable to transcardiac perfusion of the small
animal. It can be applied with relative ease, cost effectiveness and without
risking premature death of the animal due to complications of a major procedure
such as thoracotomy.
PMID- 9543486
TI - Measurements of (Na+,K+)ATPase after in vitro hypoxia and reoxygenation are
affected by methods of membrane preparation.
AB - (Na+,K+ )ATPase activity was evaluated in membranes from rat hippocampal slices
after in vitro hypoxia and reoxygenation. Membranes were prepared with two
different methods, one using an isotonic medium and another using a hypotonic
one. The changes that were found after hypoxia went into opposite directions in
the two cases. Membranes prepared in a hypotonic medium are probably more
suitable for these measurements. Using these membranes, hypoxia results in a
slight decrease of (Na+,K+)ATPase activity and in a further decrease after
reoxygenation. We also found that expressing (Na+,K+)ATPase activity as a percent
of total ATPase activity is appropriate for membranes prepared under hypotonic
conditions and can unveil (by reducing variability between experiments)
significant changes that may be masked in small samples like ours.
PMID- 9543487
TI - Radio-iodination of neurotrophins and their delivery in vivo: advantages of
membrane filtration and the use of disposable syringes.
AB - This paper reports two simple improvements for the radio-iodination of
neurotrophins and their delivery in vivo. (1) Neurotrophins can be effectively
separated from free iodide by using membrane filtration devices. Seven methods
for the separation of free iodide are compared, including dialysis, gel
filtration, and membrane filtration. Membrane filtration of the iodinated protein
has several important advantages over dialysis or gel filtration. These include
the precise control over the final concentration; excellent recovery of the
neurotrophin; easy and inexpensive procedure; performance of the entire procedure
in a fume hood; and reduced volume of radioactive waste. (2) Disposable,
inexpensive syringes are suitable for the delivery of small volumes of radio
iodinated or non-radioactive neurotrophins. Plastic disposable insulin syringes
are compared with Hamilton syringes. The ejection volume of the disposable
syringes is surprisingly reliable in the dose range 2-15 microl. Their in vivo
performance was tested by injections in the eyes of chick embryos in ovo. The
amounts remaining in the eye varied significantly less with the disposable
syringes. Leakage into the surrounding eye-muscles after intraocular injection
was significantly more frequent with Hamilton syringes than with the disposable
syringes. Thus, disposable syringes can be a reliable and cost-effective
alternative for drug delivery of 2-15 microl volumes.
PMID- 9543488
TI - Construction of 1 mm microdialysis probe for amino acids dialysis in rats.
AB - We describe here a microdialysis probe with 1 mm opening for precise and confined
dialysis area in the awake, freely moving rat. This probe is designed to allow
the local diffusion of the perfusion medium to an area approximately 175 microm
high, 266 microm wide (mediolateral direction), and 305 microm in rostrocaudal
direction. In addition, the probe allows the local application of drugs to the
same precise area of interest. The probe was constructed from a piece of 25 gauge
tubing with 1 mm hallowed opening located 0.5 mm from the distal (inserting) end.
The dialysis fiber which was inserted into the stainless steel 25 gauge tubing
and cemented into place has 200 microm diameter and 5000 molecular weight cut
off. We tested the probe diffusion extent by direct infusion of fluorogold
through the dialysis cannula. Changes in the extracellular concentrations of
amino acids were measured in response to infusion of veratridine a sodium channel
activator. All amino acids tested showed a significant 80% times decrease in
their recovery concentration when compared to their respective concentrations
recovered through 2 mm probe constructed earlier in our laboratory (Renno et al.,
1992). Tests in awake rats with probes in the ventrocaudal PAG showed stable
amounts of 12 different amino acids during repeated (6-8 times) 12 min samples at
3-5 microl/min collecting rate. Depolarization with 75 microM veratridine
resulted in significant elevation in extracellular gamma-aminobutyric acid
(GABA), aspartate, glutamate, taurine, glycine and citrulline. This design
enables us to apply drugs of interest and measure the concentrations of amino
acid neurotransmitters to a more precise, delineated and premeasured areas in the
CNS.
PMID- 9543489
TI - Improved method facilitates reliable APOE genotyping of genomic DNA extracted
from formaldehyde-fixed pathology specimens.
AB - Apolipoprotein E (APOE) genotyping of genomic DNA extracted from formaldehyde
fixed specimens is cumbersome: there is not only a low yield or failure of PCR
amplification (presumably due to degradation of DNA in the formaldehyde-fixed and
paraffin-embedded tissue), but the standard method also involves the separation
of DNA fragments as small as 48, 72, 81 and 91 bp requiring high-yield PCR
products. Here we report about a semi-nested PCR method suitable for providing
specific high-yield PCR products from DNA that has been extracted from
formaldehyde-fixed specimens which initially generate low-quality templates. This
method facilitates reliable APOE genotyping of DNA from difficult templates.
PMID- 9543490
TI - Structure and function of plasma membrane amino acid, oligopeptide and sucrose
transporters from higher plants.
PMID- 9543491
TI - Halide and alkyl phenols block volume-sensitive chloride channels in human glial
cells (U-138MG).
AB - Swelling of cells in hypotonic media activates a volume-sensitive Cl channel with
well-known characteristics, but its structure and its regulation are still
largely undetermined. It also has many inhibitors and most of them are also
blocking other types of Cl channels. The numerous inhibitors of Cl channels have
apparently no structural relationship among them. The purpose of this study was
to try to determine the most simple molecules that could block these channels and
identify some common properties among inhibitors. From the 37 new molecules that
were studied, it was found that simple halide phenols like trichloro and
triiodophenols could block these channels in the micromolar range. Also alkyl
phenols, like butylphenols, are very sensitive blockers, comparable to other well
known blockers. But acidic halide phenols or nitrophenols are poor blockers. Also
neutral polyphenols are more sensitive than acidic polyphenols. All these results
indicate that the common basis for blocking these Cl channels is a phenol with
hydrophobic groups, like short alkyl chains or an additional phenyl ring,
attached to some of its sites, preferably sites 3-4-5. These results identify a
new family of Cl channel blockers and hopefully improve our understanding of the
blocking mechanism.
PMID- 9543492
TI - Regulation of renal Na-HCO3 cotransporter: VIII. Mechanism Of stimulatory effect
of respiratory acidosis.
AB - We examined the effect of respiratory acidosis on the Na-HCO3 cotransporter
activity in primary cultures of the proximal tubule of the rabbit exposed to 10%
CO2 for 5 min, 2, 4, 24 and 48 hr. Cells exposed to 10% CO2 showed a significant
increase in Na-HCO3 cotransporter activity (expressed as % of control levels, 5
min: 142 +/- 6, 2 hr: 144 +/- 13, 4 hr: 145 +/- 11, 24 hr: 150 +/- 15, 48 hr: 162
+/- 24). The increase in activity was reversible after 48 hr. The role of protein
kinase C (PKC) on the stimulatory effect of respiratory acidosis on the
cotransporter was examined in presence of PKC inhibitor calphostin C or in
presence of PKC depletion. Both calphostin C and PKC depletion prevented the
effect of 10% CO2 for 5 min or 4 hr to increase the activity of the
cotransporter. 10% CO2 for 5 min or 4 hr increased total and particulate fraction
PKC activity. To examine the role of phosphotyrosine kinase (PTK) on the increase
in cotransporter activity we studied the effect of two different inhibitors, 2
hydroxy-5-(2,5-dihydroxylbenzyl) aminobenzoic acid (HAC) and methyl 2,5
dihydroxycinnamate (DHC) which inhibit phosphotyrosine kinase in basolateral
membranes. Cells were pretreated either with vehicle or HAC or DHC and then
exposed to 10% CO2 for 5 min or 4 hr. In cells treated with vehicle, 10% CO2
significantly increased cotransporter activity as compared to control cells
exposed to 5% CO2. This stimulation by 10% CO2 was completely prevented by HAC or
DHC at 5 min (5% CO2: 1.8 +/- 0.2, 10% CO2: 2.6 +/- 0.2, 10% CO2 + HAC: 1.6 +/-
0.2, 10% CO2: +DHC: 2.0 +/- 0.3 pH unit/min) and also at 4 hr. The protein
synthesis inhibitors actinomycin D and cycloheximide appear to prevent the effect
of 10% CO2 for 4 hr on the cotransporter. Our results show that early respiratory
acidosis stimulates the Na-HCO3 cotransporter through PKC and PTK-dependent
mechanisms and the late effect appears to be mediated through protein synthesis.
PMID- 9543493
TI - The staphylococcal pore-forming leukotoxins open Ca2+ channels in the membrane of
human polymorphonuclear neutrophils.
AB - The ability of leukotoxins secreted by Staphylococcus aureus to modify the
permeability of the membrane of human polymorphonuclear neutrophils has been
studied by spectrofluorometry and appropriate fluorescent probes. This family of
bicomponent leukotoxins is constituted by, at least, three pairs of proteins:
LukS-PV/LukF-PV, HlgA/HlgB, HlgC/HlgB. After binding of both components to the
membrane, each pair induces influxes of divalent cations and ethidium in
polymorphonuclear neutrophils, although with different intensities. The influx of
divalent cations appears sooner than the influx of ethidium. The pathway for
divalent cations is not permeable to monovalent cations (Na+, K+, ethidium+) and
is blocked by Ca2+ channel inhibitors that do not block the fluxes of ethidium
and monovalent cations. It is concluded that the leukotoxins bind to a receptor
linked to a divalent cation-selective channel or to the channel itself which is
activated. Then, the leukotoxins open a second pathway by insertion into the
membrane and subsequent formation of aspecific pores allowing an influx of
ethidium.
PMID- 9543494
TI - Hypothyroidism decreases the ATP sensitivity of KATP channels from rat heart.
AB - The effects of thyroid status on the properties of ATP-sensitive potassium
channels were investigated. Single-channel recordings were made using excised
inside-out membrane patches from enzymatically dissociated ventricular myocytes
from hearts of control and thyroidectomized rats and each group was studied with
and without administration of thyroid hormone. In patches excised from
hypothyroid myocytes the IC50 for ATP inhibition of KATP channels was 110 micro
m. This value was 3-fold higher than the IC50 in control myocytes (43 micro m).
Treatment of hypothyroid rats to restore physiological levels of thyroid hormone
(tri-iodothyronine, T3), resulted in a return to normal ATP-sensitivity (IC50 =
46 micro M). In patches from animals rendered hyperthyroid, the IC50 for ATP was
50 micro M and this value was not significantly different from the control. There
was no difference in the cooperativity of ATP-binding (Hill coefficient, nH)
among control (nH = 2.2), hypothyroid (nH = 2.1), T3-treated (nH = 2.0) and
hyperthyroid groups (nH = 2.4). The unitary conductance was unchanged and there
was no apparent change in intraburst kinetics between examples of single KATP
channels from control and hypothyroid rats. Action potentials recorded in
myocytes from hypothyroid rats were significantly shortened by 50 micro M
levcromakalim, a KATP channel opener (P < 0.001) but unchanged in control
myocytes.We conclude that hypothyroidism significantly decreased the ATP
sensitivity of KATP channels, whereas the induction of hyperthyroid conditions
did not alter the ATP-sensitivity of these channels. Thus, hypothyroidism is
likely to have important physiological consequences under circumstances in which
KATP channels are activated, such as during ischemia.
PMID- 9543495
TI - Activators of epithelial Na+ channels inhibit cytosolic feedback control.
Evidence for the existence of a G protein-coupled receptor for cytosolic Na+.
AB - We have previously shown that epithelial Na+ channels in mouse mandibular gland
duct cells are controlled by cytosolic Na+ and Cl-, acting, respectively, via Go
and Gi proteins. Since we found no evidence for control of epithelial Na+
channels by extracellular Na+ ([Na+]o), our findings conflicted with the long
held belief that Na+ channel activators, such as sulfhydryl reagents, like para
chloromercuriphenylsulfonate (PCMPS), and amiloride analogues, like
benzimidazolylguanidinium (BIG) and 5-N-dimethylamiloride (DMA), induce their
effects by blocking an extracellular channel site which otherwise inhibits
channel activity in response to increasing [Na+]o. Instead, we now show that
PCMPS acts by rendering epithelial Na+ channels refractory to inhibition by
activated G proteins, thereby eliminating the inhibitory effects of cytosolic Na+
and Cl- on Na+ channel activity. We also show that BIG, DMA, and amiloride
itself, when applied from the cytosolic side of the plasma membrane, block
feedback inhibition of Na+ channels by cytosolic Na+, while leaving inhibition by
cytosolic Cl- unaffected. Since the inhibitory effects of BIG and amiloride are
overcome by the inclusion of the activated alpha-subunit of Go in the pipette
solution, we conclude that these agents act by blocking a previously unrecognized
intracellular Na+ receptor.
PMID- 9543496
TI - Effects of hyperosmolality on Na, K-ATPase gene expression in vascular smooth
muscle cells.
AB - Cultured vascular smooth muscle cells (VSMC) from rat thoracic aortas were
exposed to hyperosmotic media to determine the effects on Na, K-ATPase alpha1-
and beta1-mRNA expression. Hyperosmotic media (500 mOsm/kgH2O) supplemented with
glucose or mannitol increased alpha1-mRNA levels threefold at 24 hr and beta1
mRNA levels sevenfold at 12 hr. In sharp contrast, hyperosmotic urea medium had
no effect at any time. Both the protein synthesis inhibitor cycloheximide and the
RNA transcription inhibitor actinomycin D reduced alpha1- and beta1-mRNA
upregulation induced by hyperosmotic glucose or mannitol media. Protein kinase C
(PKC) inhibitors (staurosporine A or calphostin C) or tyrosine kinase (TK)
inhibitors (genistein or herbimycin A) had no effect on the alpha1-mRNA
upregulation induced by hyperosmotic glucose or mannitol media. Hyperosmotic
glucose or mannitol media (500 mOsm/kgH2O) significantly increased alpha1- and
beta1-subunit protein levels and Na, K-ATPase activity, whereas hyperosmotic urea
medium had no effect. Transfection experiments with the 5'-flanking sequences of
the alpha1- or beta1-subunit genes linked to the luciferase reporter gene
revealed that hyperosmolar glucose medium increased luciferase activity 2.9- and
3.7-fold, respectively. Similarly, hyperosmotic mannitol medium increased such
activity 2.7- and 3.4-fold, respectively. These results demonstrate that: (i)
hyperosmolality induced by the poorly permeating solutes (glucose and mannitol)
stimulates alpha1- and beta1-mRNA accumulation, alpha1- and beta1-subunit protein
accumulation, and Na, K-ATPase activity, whereas the rapidly permeating solute
(urea) has no effect; (ii) the upregulation of alpha1- and beta1-mRNA in response
to hyperosmotic glucose or mannitol media requires, at least in part, de novo
synthesis of intermediate regulatory proteins; (iii) the hyperosmolality-induced
alpha1-mRNA upregulation occurs through PKC- and TK-independent mechanisms,
whereas the hyperosmolality-induced beta1-mRNA upregulation occurs through
activation of PKC and TK; and (iv) hyperosmolality induced by glucose or mannitol
increases promoter activities of the alpha1- and beta1-subunit genes.
PMID- 9543497
TI - Phosphorylated carboxy terminal serine residues stabilize the mouse gap junction
protein connexin45 against degradation.
AB - Phosphoamino acid analysis of mouse connexin45 (Cx45) expressed in human HeLa
cells revealed that phosphorylation occurred mainly at serine residues, but also
on tyrosine and threonine residues. To characterize the role of Cx45
phosphorylation, different serine residues of the serine-rich carboxy terminal
region were deleted or exchanged for other amino acids residues. Human HeLa cells
deficient in gap junctional intercellular communication were stably transfected
with appropriate constructs and analyzed for expression, localization,
phosphorylation, formation of functional gap junction channels and degradation of
mutant Cx45. fter exchange or deletion of nine carboxy terminal serine residues,
phosphorylation was decreased by 90%, indicating that these serine residues
represented main phosphorylation sites of mouse Cx45. The various serine residues
of this region contributed differently to the phosphorylation of Cx45 suggesting
a cooperative mechanism for phosphorylation. Substitution of different serine
residues for other amino acids did not interfere with correct intracellular
trafficking and assembly of functional gap junction channels, as shown by
localization of mutant Cx45 at the plasma membrane and by dye transfer to
neighboring cells. Truncated Cx45 was also weakly phosphorylated but was trapped
in perinuclear locations. Dye transfer of these transfectants was similar as in
nontransfected HeLa cells. The half-life of mouse Cx45 protein in HeLa cells was
determined as 4.2 hr. Pulse-chase experiments with the different transfectants
revealed an increased turnover of Cx45, when one or both of the serine residues
at positions 381 and 382 or 384 and 385 were exchanged for other amino acids. The
half-life of these mutants was diminished by 50% compared to wild type Cx45.
PMID- 9543499
TI - The Extent of Benthic Impacts of CCA-Treated Wood Structures in Atlantic Coast
Estuaries
AB - To ascertain the extent of impacts from CCA-treated wood bulkheads, we sampled
sediments along 10-m transects from these bulkheads and from reference sites
(either bulkheads made of other materials or unbulkheaded areas nearby) and
analyzed the fine fraction for metals. We ascertained metal content in resident
biota, and analyzed species richness, Shannon-Wiener diversity index, and biomass
of the benthic community. We found accumulation of metals in the fine-grained
portion of nearby sediments and reduction in the biotic community nearby
(generally at 0 and 1 m); such gradients were generally not seen in reference
transects. At two of the sites there was evidence for secondary reduction of the
community out further to 3 or 10 m, where the metals in the fines were lower but
the percent fines was greatly increased. At all the other sites, impacts were
generally limited to 0 and 1 m. The lack of reduction at further distances at the
other sites is attributed to factors such as the age of the bulkheads, high
energy of the environment, or nature of the sediments at those sites.
PMID- 9543498
TI - Interactions of primary amphipathic vector peptides with membranes.
Conformational consequences and influence on cellular localization.
AB - The conformations of two peptides produced by the combinations of a nuclear
localization sequence and a sequence issued from the fusion protein gp41 of HIV 1
have been analyzed both in solution and in membranes or in membrane mimicking
environments. Both are shown to be nonordered in water, alpha-helical when
incorporated into SDS micelles where the helical domain concerns the hydrophobic
part of the peptides. Interactions with lipids induce the formation of beta-sheet
and the lipid-peptide interactions are governed by the nature of the lipid polar
headgroups. A monolayer study shows that replacement of the sequence separating
the two sequences with an arginine favors the lipid-peptide interactions which
may contribute to the understanding of the different, nuclear and membrane
associated, cellular localizations of the peptides.
PMID- 9543500
TI - The Fate of Elements in Residential Composters
AB - An investigation into the fate of elements during residential composting was
conducted by studying an Envirocycle residential-type aerobic composter unit that
was set up and operated at the University of Toronto's greenhouse facility.
Source materials consisting of various fruits and vegetables were combined with
Metropolitan Toronto Works Department's finished leaf compost (MWFLC), and
composted over a 2-month period. Instrumental neutron activation analysis (INAA)
was used to determine the concentrations of Al, As, Ba, Ca, Co, Cr, Fe, K, Mg,
Mn, Na, Sb, Sr, Ti, V, and Zn in the source materials and the 2-month greenhouse
finished compost (GHFC). Results indicate that the ratio of final element mass to
input element mass was approximately 1, suggesting that elements are conserved
during the composting process. One tailed t tests (0.05 level of significance) on
element concentrations between the MWFLC and GHFC revealed that supplementing
MWFLC with fruits and vegetables does not significantly change concentrations
>25%. One-way analyses of variances conducted on Toronto residential compost
samples revealed good homogeneity within an individual composter, although
significant elemental variances occurred between separate composters.
Incidentally, it was noticed that several of the Toronto residential compost
samples had Cr levels that exceeded Ontario Ministry of Environment and Energy
guideline values for municipal compost.
PMID- 9543501
TI - Lead content in edible wild mushrooms in northwest Spain as indicator of
environmental contamination.
AB - Lead content was determined in wild growing mushrooms collected from two
different areas in the Province of Lugo (NW Spain). It has been analyzed by
graphite furnace atomic absorption spectrometry in 95 samples of 13 species (7
mycorrhizals and 6 saprophites). In an assessment of lead concentrations, the
following factors have been considered: species and ecology, morphological
portion, and traffic pollution. The average lead concentration of the samples was
1 ppm dry weight (dw). Saprophite species presented higher levels than
mycorrhizal ones (< 1 ppm), Coprinus comatus reaching the maximum mean
concentration with 2.06 and 2.79 ppm of dw in the hymenophore and the rest of the
fruit body. Morphological portion, statistically, did not show significant
difference between the two portions; however, Macrolepiota procera always
presented lead high levels in the hymenophore in all samples. The effect due to
traffic pollution has been specially observed in Coprinus comatus, presenting the
highest concentration with values of 6.51 and 10.43 ppm, respectively, in samples
collected in the city center. This species, as other researchers have indicated,
could be considered as an indicator by lead contamination. The contribution of
mushrooms to the weekly intake of lead was calculated and the possible health
risk for the consumer is pointed out. These data are of great importance in view
of toxicology and partly environmental protection.
PMID- 9543502
TI - In Situ Investigation of Trace Metal Availability in Industrial Effluents Using
Transplanted Aquatic Mosses
AB - Three species of aquatic mosses, Rhynchostegium riparioides, Fontinalis
antipyretica, and Cinclidotus danubicus, were collected from the same reference
location and exposed in five industrial effluents. The purpose was to test their
suitability for assessing trace metal contamination under adverse and contrasted
environmental conditions. Two distinct experiments of 16 and 11 days were
conducted. In spite of short residence times in the effluents, the bryophytes
were considerably affected at several sites, showing a light green to yellowish
color, brown-edged leaves, and even dead strands. Cinclidotus danubicus was the
most resistant whereas Fontinalis antipyretica was the most sensitive species.
The observed physiological damage had no obvious incidence on the accumulation
capacity of the mosses. The biomonitors provided time-integrated patterns of
trace metal bioavailability (copper, chromium, nickel, lead, and zinc) in the
effluents with a clear discrimination between poorly, moderately, and heavily
polluted sites. Compared to water analyses, these more reliable indications could
be obtained with a considerably reduced sampling design. When substantial
accumulation occurred in mosses, the highest concentrations were systematically
found in Rhynchostegium riparioides and the lowest in Cinclidotus danubicus. As
only quantitative, not qualitative, differences were observed, all investigated
moss species can be recommended for the assessment of trace metals in effluents
at their discharge into the natural environment.
PMID- 9543503
TI - Inertia and Resilience in the Responses of the Aquatic Bryophyte Fontinalis
antipyretica Hedw. to Thermal Stress
AB - The physiological responses of the aquatic bryophyte Fontinalis antipyretica
Hedw. to high temperatures, ranging from 16 degreesC (control) to 34 degreesC,
were investigated experimentally. Plant samples were maintained at the
temperature under study for up to 25 days with regular determination of
physiological variables (pigment ratio and photosynthetic and respiratory rates).
Physiological responses to temperature did not differ significantly between
mosses collected from a normal river site and from a river site with abnormally
high temperature due to input from a hot spring. Simple curve-fitting procedures
and summary statistics analogous to those used in toxicological research were
employed to compare responses as revealed by the different physiological
variables. In a second series of experiments, the capacity of F. antipyretica to
recover from high-temperature stress was investigated by maintaining samples at
30 degreesC for 2, 4, or 10 days, then transferring the samples to normal
conditions (16 degreesC) for 40 days. Physiological variables were again
monitored at regular intervals throughout both phases of the experiment. In
general, good recovery was observed even after exposure to high temperatures for
10 days. The results of these assays allow quantification of the relationship
between a pigment ratio and net photosynthesis rate.
PMID- 9543504
TI - Ecotoxicity Assessment of Contaminated Dredged Material with the Marine Amphipod
Corophium volutator
AB - The incorporation of toxicological data from bioassays can improve the present
system of sediment quality criteria in the Netherlands. The use of acute
lethality toxicity tests alone does not however provide sufficient discrimination
and sensitivity for predicting ecological effects of slightly and moderately
contaminated dredged material. Sublethal endpoints are needed for the assessment
of environmental hazards of such dredged material. In this study, two approaches
were used to identify toxicity of marine sediments collected from 16 locations
classified as "slightly and moderately contaminated" on the basis of chemical
data: (1) a comparison of growth vs. mortality as different endpoints in the
marine amphipod Corophium volutator (Pallas); (2) an investigation on the use of
sediment dilutions to characterize the degree of toxicity. The influence of
sediment storage time on toxicity was also evaluated. In four out of 16
locations, mortality over 10 days of exposure ranged 80-100%; in two out of 16
locations mortality ranged 40-60%. In the other 10 locations, mortality was below
15%. Results on growth showed that in all locations final dry weight values were
significantly lower (a factor of 1.5 to 3) than in controls. Results of dilution
experiments showed that if sediments were diluted with a reference sediment of
similar physicochemical characteristics, total concentrations of metals, mineral
oil, and PAHs decreased as expected and so did the effects on C. volutator. In
the 100% contaminated sediments growth was reduced by 32-60% compared to
controls. The dilution rate necessary to reduce toxicity to the EC10 value for
growth of C. volutator was considered an appropriate endpoint for the evaluation.
When sediments were stored for a period of 3-5 months at 4 degreesC and retested,
effects on mortality and growth decreased, although some effects on growth were
still measured after 5 months of storage. The experiments illustrate the
usefulness of ecotoxicity assessment to evaluate contaminted dredged material.
PMID- 9543505
TI - Bioassays using the midge Chironomus riparius and the zebra mussel Dreissena
polymorpha for evaluation of river water quality.
AB - To evaluate if the water quality of the river Meuse affects macrofauna species,
the impact of water from this river on two representative species was tested
under controlled conditions. Short-term bioassays with reference populations of
the midge Chironomus riparius and the zebra mussel Dreissena polymorpha were
performed simultaneously, using growth and filtration rate as sublethal
parameters, respectively. Filtration rates of mussels seemed to be slightly
inhibited by Meuse water in 1994 and 1995, although this was only significant in
the first year. Apparently, although this species is inhabiting the river Meuse,
the water quality still causes sublethal effects. In contrast to the mussel,
midges were less sensitive to Meuse water in laboratory experiments; growth
inhibition was never observed, while in some experiments growth was even
enhanced. In the period of testing, it was not possible to relate effects on
macrofauna species in laboratory tests to individual substances in polluted river
systems. Because the response of the test species was marginal, it is recommended
to include more sensitive species as tested in the present study, especially in
view of a general improvement of the water quality in the river Meuse.
PMID- 9543506
TI - Paraquat tolerance and alteration of internal gill structure of Scinax nasica
tadpoles (Anura: Hylidae).
AB - Paraquat acute tolerance, and histological and ultrastructural response analysis
of gills were evaluated in Scinax nasica tadpoles at stages 25-26. The treated
tadpoles were able to survive with a mortality rate similar to the controls in
media containing 6.48 to 10.80 mg PQ/L. At 18.00 mg PQ/L survival rate was about
85%; at 30.00 and 50.00 mg PQ/L an incremented mortality rate was detected. Their
internal gills appear to have a critical role in adaptation to exposure to PQ.
The LC-50 values found helped us conclude that increasing time of exposure to PQ
produces a decrease of tadpole survival rate. With light microscopy, the apical
ramification gill tufts exhibited a dose response increase of the total volume.
At the ultrastructural level, an increase in the intercellular spaces and
alteration in gill epithelium organization were the most notable changes.
Furthermore, the capillaries showed enlarged endothelial cells, irregular nuclei,
and numerous cytoplasmatic projections.
PMID- 9543507
TI - Comparative toxicity of diuron on survival and growth of Pacific treefrog,
bullfrog, red-legged frog, and African clawed frog embryos and tadpoles.
AB - The effects of the herbicide diuron on survival and growth of Pacific treefrog
(Pseudacris regilla), bullfrog (Rana catesbeiana), red-legged frog (Rana aurora),
and African clawed frog (Xenopus laevis) embryos and tadpoles were determined in
static-renewal tests. P. regilla and X. laevis embryos had reduced growth and
developed increased deformities in diuron concentrations over 20 mg/L. Hindlimb
bud and forelimb development were retarded in R. aurora following 14 days
exposure to diuron concentrations of > 7.6 mg/L. Mean 14-day LC50s for P. regilla
and X. laevis tadpoles were 15.2 and 11.3 mg/L diuron, respectively. The 21-day
LC50 for R. catesbeiana tadpoles was 12.7 mg/L diuron. The 14-day LC50 for R.
aurora tadpoles was 22.2 mg/L. The lowest NOAELs calculated in embryo tests were
14.5 mg/L for P. regilla (10 days) and 7.6 mg/L diuron for X. laevis (4 days).
The lowest NOAELs calculated in tadpole tests were: P. regilla, 14.5 mg/L (14
days); R. catesbeiana, 7.6 mg/L (21 days); R. aurora, 7.6 mg/L (14 days); and X.
laevis, > 29.1 mg/L (14 days). Diuron concentrations having an effect on
survival, growth, and malformation in the laboratory were much higher than those
found in normal field spray situations; field studies would be needed to
determine the hazard to amphibians in areas of localized pooling of recently
applied herbicide in the environment.
PMID- 9543508
TI - Effects of subchronic exposure to cadmium chloride on endocrine and metabolic
functions in rainbow trout Oncorhynchus mykiss.
AB - Adult and juvenile rainbow trout, Oncorhynchus mykiss, were exposed for 30 days
to CdCl2 in water (10 and 25 micrograms Cd/L for adults, and 1 and 5 micrograms
Cd/L for juveniles) to investigate effects of subchronic exposures to Cd on the
hypothalamo-pituitary-interrenal and the hypothalamo-pituitary-thyroid axis, and
on metabolic status. liver size and glycogen content and body mass gain were
significantly reduced in the exposed adult fish and similar changes were detected
in the juveniles. Plasma cortisol levels increased after exposure to the lower
dose but decreased at the higher dose. Plasma T3 and T4 tended to decrease in the
exposed adult fish. No significant differences in plasma glucose or cholesterol
levels were detected between the controls and the exposed fish, plasma calcium
levels were lower in the exposed fish. The results indicate that long-term
exposures to Cd at sublethal doses have adverse effects on the physiological
status of the fish and that these effects are mediated partly through alterations
of endocrine function.
PMID- 9543509
TI - Trace elements in egg contents and egg shells of slider turtles (Trachemys
scripta) from the Savannah River Site.
AB - In this paper we examine the levels of trace elements in the egg contents and egg
shells of slider turtles (Trachemys scripta) from the Savannah River Site, near
Aiken, South Carolina. Trace elements have seldom been examined in the tissues or
eggs of reptiles, although some turtles and large snakes occupy a high trophic
level. Lead, mercury, cadmium, selenium, chromium, and manganese levels were
examined in one egg and its egg shell collected from each of 16 females that laid
in late May and June 1996. We were interested in determining background levels,
whether certain metals were sequestered in the egg shells, and whether levels
were higher in contents or shells. Concentrations were higher in egg contents
than in shells for lead, mercury, and selenium, while chromium was higher in the
shell. There were no differences for cadmium and manganese. Compared to eggs from
other reptiles, levels in slider turtles were generally similar for cadmium and
selenium, lower for chromium and lead, and higher for manganese.
PMID- 9543510
TI - Accumulation Features of Polychlorinated Biphenyls and Organochlorine Pesticides
in Resident and Migratory Birds from South India
AB - Persistent organochlorines such as DDT and its metabolites (DDTs),
hexachlorocyclohexane isomers (HCHs), chlordane compounds (CHLs),
hexachlorobenzene (HCB), and polychlorinated biphenyls (PCBs) were determined in
whole-body homogenates of resident and migratory birds collected from South
India. Organochlorine contamination pattern in birds varied depending on their
migratory behaviour. Resident birds contained relatively greater concentrations
of HCHs (14-8,800 ng/g wet wt) than DDTs and PCBs concentrations. In contrast,
migrants exhibited elevated concentrations of PCBs (20-4,400 ng/g wet wt). The
sex differences in concentrations and burdens of organochlorines in birds were
pronounced, with females containing lower levels than males. Inland piscivores
and scavengers accumulated greater concentrations of HCHs and DDTs while coastal
piscivores contained comparable or greater amounts of PCBs. Global comparison of
organochlorine concentrations indicated that resident birds in India had the
highest residues of HCHs and moderate to high residues of DDTs. It is, therefore,
proposed that migratory birds wintering in India acquire considerable amounts of
HCHs and DDTs. Estimates of hazards associated with organochlorine levels in
resident and migratory birds in India suggested that Pond Heron, Little Ringed
Plover, and Terek Sandpiper may be at risk from exposure to DDTs.
PMID- 9543511
TI - Dietary Exposure to Mercury in Nestling Wood Storks (Mycteria americana) in
Georgia
AB - The United States breeding population of the wood stork (Mycteria americana) was
listed as endangered in 1984; the U.S. Fish and Wildlife Service has listed the
determination of potential contaminant hazards as a task important to the
recovery of the species. Storks nest in colonies and adult storks forage over
wide areas and return with prey items to feed to nestlings. The most recently
consumed prey items are usually regurgitated by nestlings when they are handled.
In 1995, over 200 food items from four wood stork colonies were collected while
banding nestlings between 20 and 40 days old, and total mercury determined in
individual food items. Two colonies were located on the Atlantic coast and two in
inland areas. Overall dietary mercury concentration for each colony was
calculated based on the biomass of each type of food item within the diet.
Freshwater prey items had higher mercury concentrations than saltwater items most
frequently chosen by storks. Daily Hg doses were estimated for a range of
nestling sizes and daily food consumption rates. Risk factors were calculated
based on two lowest observable adverse effect concentrations (LOAECs) from
previous avian mercury ingestion studies. Based on one LOAEC, all four colonies
in this study were at risk of sublethal effects due to mercury in the diet of
nestling wood storks. More extensive studies of sublethal effects in avian
species from mercury contamination are necessary for more accurate risk
assessment.
PMID- 9543512
TI - Organochlorine and heavy metal contaminants in wild mink in western Northwest
Territories, Canada.
AB - The mink (Mustela vision) is a top trophic level species that readily
bioaccumulates environmental pollutants and is considered to be a sensitive
indicator of ecosystem health. Spatial trends in levels of organochlorine and
heavy metal contaminant burdens were determined from 1991 to 1995 for wild mink
from western Northwest Territories (NWT), Canada. Tissue samples from 207 mink
from seven communities were analyzed for residues of 63 organochlorines and 10
heavy metals. All groups of organochlorines were detected in mink livers at
relatively low levels; maximum community means were 9.52 ng/g sigma DDT and 73.07
ng/g sigma PCB (sum of 43 congeners). There was a general trend of decreasing
organochlorine burdens along a northerly or westerly gradient for some groups of
compounds, primarily sigma DDT, sigma PCB, sigma chlordane and dieldrin. Toxic
equivalents (TEQs) of mink liver tissue were low, with the maximum community mean
of 0.28 pg/g wet weight (5.5 pg/g lipid weight). Levels of heavy metal burdens in
liver and kidney tissues were found to be relatively low, with the exception of
Hg, which was found at moderate levels. There was no obvious geographic trend to
the pattern of heavy metal burdens. The available evidence suggests that long
range atmospheric transport is the main source of the organochlorine contaminants
observed. Local conditions (geology, water and soil chemistry, diet, etc.) may
determine heavy metal burdens. Levels of contaminants in NWT mink appear to be
one to two orders of magnitude lower than levels observed to cause reproductive
impairment, reduced survival of kits, or lethality in adult mink. In the western
NWT mink may be the best indicator to assess trends in environmental contaminants
and ecosystem health; periodic monitoring is recommended.
PMID- 9543514
TI - Anouncements
PMID- 9543513
TI - Polychlorinated naphthalenes and other organochlorine contaminants in Swedish
human milk, 1972-1992.
AB - The concentrations of polychlorinated naphthalenes (PCNs) were determined
together with polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs),
dibenzofurans (PCDFs), 1,1-bis-(4-chlorophenyl)-2,2,2-trichloroethane (p,p'-DDT),
2,2-bis(4-chlorophenyl)-1,1-dichloroethylene (p,p'-DDE) and hexachlorobenzene
(HCB) in milk, sampled in the course of 1972-92 from mothers living in Stockholm.
A previously developed method for multicomponent analysis of organochlorine
environmental contaminants was adapted for simultaneous analysis of PCNs. The
mean recoveries of seven chlorinated naphthalene (CN) congeners added to milk
prior to extraction were 76-99%. Similar recoveries were obtained for the
commercial PCN product Halowax 1014. The pattern of PCNs in milk differed to a
great extent from that in the commercial PCN products. The dominating congeners
in breast milk were 1,2,3,5,7-pentachloronaphthalene (CN-52), 1,2,3,4,6,7- and/or
1,2,3,5,6,7-hexachloronaphthalene (CN-66/ CN-67) and one unidentified
tetrachloronaphthalene. There was a notable decrease in the concentrations of
PCNs as was of the other organochlorine contaminants in milk from 1972 to 1992.
During this time period the sum of CN congeners decreased from 3,081 to 483 pg/g
milk fat and the sum of toxic equivalents of dioxin and dioxin-like compounds
decreased from 100 to 39 pg/g milk fat.
PMID- 9543515
TI - Complications of laparoscopic cholecystectomy.
PMID- 9543516
TI - Biliary tract complications in laparoscopic cholecystectomy. A multicenter study
of 148 biliary tract injuries in 26,440 operations.
AB - BACKGROUND: The higher risk of biliary tract injury is considered the most
significant disadvantage of laparoscopic cholecystectomy. METHODS: A national
multicenter retrospective study was performed to determine the frequency,
etiology, and treatment of biliary tract injuries between January 1, 1991, and
December 31, 1994. Follow-up was by questionnaire. RESULTS: Some 148 biliary
tract complications were observed during 26,440 laparoscopic cholecystectomies.
There was no significant correlation found between the number of LCs performed in
one institute and the incidence of biliary tract injuries and postoperative bile
leakage, but in the 2nd year of practice, the incidence of both complications
decreased. In institutes with more conversions, more cases of bile leakage were
also observed. A significant positive relationship was found between biliary
tract injuries and postoperative bile leaks. There was no significant
relationship between usage of intravenous and intraoperative cholangiography and
ERCP. In univariant analysis of the type of injury, the primary treatment
modality did not affect the outcome of injury or entail the necessity of
reoperation. Obscure anatomy leads to significantly more main bile duct injuries.
According to multivariant analysis, the outcome is significantly influenced
unfavorably by the necessity of repeated interventions and advanced age.
CONCLUSIONS: The definitely higher risk of bile duct injury mentioned in early
studies was not confirmed.
PMID- 9543517
TI - Laparoscopic endobiliary stenting as an adjunct to common bile duct exploration.
AB - BACKGROUND: The management of common bile duct stones (CBDS) in the era of
operative laparoscopy is evolving. Several minimally invasive techniques to
remove CBDS have been described, including preoperative endoscopic retrograde
cholangiopancreatography (ERCP), postoperative ERCP, lithotripsy, laparoscopic
transcystic common bile duct exploration, and laparoscopic choledochotomy with
common bile duct exploration (CBDE). Because of the risks and limitations of
these procedures, we utilize laparoscopically placed endobiliary stents as an
adjunct to CBDE. METHODS: Sixteen patients underwent laparoscopic common bile
duct exploration (LCBDE) by either choledochotomy or the transcystic technique
with placement of endobiliary stents. These patients were identified during
laparoscopic cholecystectomy as having occult choledocholithiasis, using routine
dynamic intraoperative cholangiography. RESULTS: CBDS were successfully removed
in all patients as demonstrated by completion cholangiography and intraoperative
choledochoscopy. Eighty percent of patients were discharged the following day;
the first three patients in this series were observed for 48 h prior to
discharge. No patient required T-tube placement and closed suction drains were
removed the morning after surgery. Stents were removed endoscopically at 1 month.
Six- to 30-month follow-up demonstrates no complications to date. CONCLUSIONS:
Laparoscopic endobiliary stenting reduces operative morbidity, eliminates the
complications of T-tubes, and allows patients to return to unrestricted activity
quickly. We recommend laparoscopically placed endobiliary stents in patients
undergoing LCBDE.
PMID- 9543518
TI - Spilled gallstones after laparoscopic cholecystectomy. A relevant problem? A
retrospective analysis of 10,174 laparoscopic cholecystectomies.
AB - BACKGROUND: Spilled gallstones after laparoscopic cholecystectomy may cause
abscess formation, but the exact extent of this problem remains unclear. METHOD:
The data (collected by the Swiss Association of Laparoscopic and Thoracoscopic
Surgery) on 10,174 patients undergoing laparoscopic cholecystectomy at 82
surgical institutions in Switzerland between January 1992 and April 1995 were
retrospectively analyzed with special interest in spilled gallstones and their
complications. RESULTS: In 581 cases (5.7%) spillage of gallstones occurred; 34
of these cases were primarily converted to an open procedure for stone retrieval.
Of the remaining 547 cases only eight patients (0.08%) developed postoperatively
abscess formation requiring reoperation. CONCLUSIONS: Spillage of gallstones
after laparoscopic cholecystectomy is fairly common and occurs in about 6% of
patients. However, abscess formation with subsequent surgical therapy remains a
minor problem. Removal of spilled gallstones is therefore not recommended for all
patients, but an attempt at removal should be performed whenever possible.
PMID- 9543519
TI - Common bile duct injuries during laparoscopic cholecystectomy that result in
litigation.
AB - BACKGROUND: Iatrogenic common bile duct injury is the worst complication of
laparoscopic cholecystectomy. The goal of this study is to increase awareness of
the problem and educate surgeons about the consequences of these injuries.
METHODS: A total of 46 bile duct injuries were analyzed by review of medical
records, cholangiograms, videotapes, and surgeon statements. All cases were
involved in malpractice litigation. RESULTS: All types of injuries were
represented. There were 15 transections, 11 excisions, 6 lacerations, 8 clip
impingements, 3 burns, 2 bile leaks, and 1 cystic duct leak. In all, 72% of these
injuries occurred in elective cases in which there was no acute inflammation.
Cholangiograms were performed in 16 cases, but they were misinterpreted in 11 of
them. Injury type and severity was similar in patients with and without
cholangiography. A total of 80% of these injuries were not detected at the
initial surgery. The average delay in diagnosis was 10 days. Complications were
worse in patients with delayed diagnosis. Primary surgeons had less successful
outcomes from repairs than referral surgeons (27% versus 79%). In 86% of cases,
litigation was resolved in favor of plaintiffs by settlement or verdicts. The
average award was $214,000. CONCLUSIONS: Factors that predispose to lawsuits
include treatment failures in immediately recognized injuries, complications that
result from delays in diagnosis, and misinterpretation of abnormal
cholangiograms. Injury prevention can be improved by increased awareness of
common mistakes,. Improved cholangiographic technique and interpretation should
decrease injury severity, delays in diagnosis, and subsequent morbidity.
PMID- 9543520
TI - Bile duct injury after laparoscopic cholecystectomy. The United States
experience.
AB - BACKGROUND: Forty series reporting experience with laparoscopic cholecystectomy
in the United States from 1989 to 1995 were reviewed. A total of 114,005 cases
were analyzed and 561 major bile duct injuries (0.50%) and 401 bile leaks from
the cystic duct or liver bed (0.38%) were recorded. Intraoperative
cholangiography (IOC) was attempted in 41.5% of the laparoscopic
cholecystectomies and was successful in 82.7%. In major bile duct injuries, the
common bile duct/common hepatic duct were the most frequently injured (61.1%) and
only 1.4% of the patients had complete transection. METHODS: When reported, most
of the bile duct injuries were managed surgically with a biliary-enteric
anastomosis (41.8%) or via laparotomy and t-tube or stent placement (27.5%). The
long-term success rate could not be determined because of the small number of
series reporting this information. The management for bile leaks usually
consisted of a drainage procedure (55.3%) performed endoscopically
percutaneously, or operatively. RESULTS: The morbidity for laparoscopic
cholecystectomy, excluding bile duct injuries or leaks, was 5.4% and the overall
mortality was 0.06%. It was also noted that the conversion rate to an open
procedure was 2.16%. CONCLUSIONS: It is concluded based on this review of
laparoscopic cholecystectomies that the morbidity and mortality rates are similar
to open surgery. In addition, the rate of bile duct injuries and leaks is higher
than in open cholecystectomy. Furthermore, bile duct injuries can be minimized by
lateral retraction of the gallbladder neck and careful dissection of Calot's
triangle, the cystic duct-gallbladder junction, and the cystic duct-common bile
duct junction.
PMID- 9543521
TI - How, when, and why bile duct injury occurs. A comparison between open and
laparoscopic cholecystectomy.
AB - BACKGROUND: Bile duct injury (BDI) is a severe complication of laparoscopic
cholecystectomy (LC). There is general agreement about the increase of this
complication after LC vs open cholecystectomy (OC), but comparative studies are
scarce. The aim of this paper has been to compare the incidence and clinical
features of BDI after LC vs open procedures. MATERIALS AND METHODS: 3,051 OC,
performed from June 1977 to December 1988 were retrospectively analyzed and
compared with 1,630 LCs performed from June 91 to August 96, for which data were
prospectively recorded. Age, sex, type of BDI, performance of intraoperative
cholangiography (IOC), underlying biliary pathology, morbidity, mortality, and
late morbidity were all analyzed. RESULTS: BDI incidence was higher in group II
(LC) (N: 16, 0.95%) than in group I, (OC, N: 19. 0.6%). BDI incidence was also
higher in the group of patients in which it was necessary to convert to an open
procedure (3/109, 2.7%, p < 0.05). BDIs were more frequently diagnosed
intraoperatively in group I (OC, 18/19) than in group II (LC, 12/16). In both
groups, BDI was more prevalent in cases operated by staff surgeons than
residents, mainly in complicated gallbladder patients, with a bile duct of less
than 7-mm diameter. Morbidity, postoperative stay, mortality, and late morbidity
were similar after a BDI in both types of approach. CONCLUSIONS: (1) BDI
increases with LC. (2) BDI after LC carries a similar postoperative morbidity and
mortality to those after OC. (3) Incidence of BDI in converted cases increases
significantly and this constitutes a high-risk group.
PMID- 9543522
TI - Biliary stenting is more effective than sphincterotomy in the resolution of
biliary leaks.
AB - BACKGROUND: Biliary fistulae may occur following surgical injury, abdominal
trauma, or inadequate closure of a cystic duct stump. These leaks are most often
managed by drainage of the associate biloma and either endoscopic sphincterotomy
or placement of a biliary endoprosthesis to decrease the pressure gradient
between the bile duct and the duodenum created by the muscular contraction of the
ampullary sphincter. In a previous study, we demonstrated a statistically
significant reduction in ductal pressures following stent placement as compared
to sphincterotomy. The goal of this present study was to determine if reduction
in ductal pressures correlates clinically with the resolution of biliary leaks in
an animal model. METHODS: Fourteen mongrel dogs underwent laparotomy,
cholecystectomy without closure of the cystic stump, and a lateral duodenotomy to
identify the major papilla. The dogs were then randomized into three groups.
Group I (n = 5) was a control group undergoing closure of the duodenotomy only.
Group II (n = 4) underwent sphincterotomy. Group III (n = 5) underwent placement
of a 7 Fr x 5 cm biliary endoprosthesis prior to duodenotomy closure. A drain was
placed adjacent to the cystic duct stump in all groups. Drain output was recorded
daily. The biliary leak was considered resolved when the output was < 10 cc/day.
Regardless of suspected fistula closure, the drains were not removed until 2
weeks postprocedure. Necropsy was performed to identify undrained intraperitoneal
bile. Statistical analysis was performed using Student's paired t test. RESULTS:
All dogs had bile leaks identified on postoperative day 1. The number of days
required for resolution of bile leak in group I (mean +/- SEM) was 7.60 +/- 0.87
days, as compared to 6.75 +/- 0.80 days for group II and 2.60 +/- 0.24 days for
group III. There was no significant difference in the duration of bile leak
between groups I and II (p = 0.445). Group III, however, had a significant
reduction in the duration of biliary fistulae as compared to both groups I and II
(p < 0.005). At autopsy, persistent bilomas were identified in 80% of group I,
25% of group II, and 0% of group III. None of the dogs showed evidence of
dehisence of the duodenotomy closure site as a source of bile leak. CONCLUSION:
Biliary stenting significantly reduces the time to resolution of cystic duct
leaks as compared to sphincterotomy in a canine model. The results obtained in
this study support the use of biliary endoprostheses in the management of biliary
leaks and fistulae.
PMID- 9543523
TI - Laparoscopic liver surgery. A report on 28 patients.
AB - BACKGROUND: An effort was made to evaluate the indications, safety, and
therapeutic efficacy of laparoscopic liver surgery. METHODS: Between 1989 and
1996, 28 patients, 23 to 88 years old were operated upon laparoscopically.
Pathology consisted of simple cyst (ten), polycystic liver disease (seven),
hydatid cyst (three, two of them calcified), abscess (one), focal nodular
hyperplasia (six), and metastatic breast cancer (one). RESULTS: Operations
included 17 fenestrations, three pericystectomies, and eight resections (two
lateral lobes). Operative time was 45 to 525 min with only four cases longer than
4 h. There was a 21% morbidity rate. There were no mortalities. Follow-up was 1
67 months with one asymptomatic recurrence. CONCLUSIONS: Laparoscopic hepatic
surgery can be performed safely with good results by surgeons with hepatic and
laparoscopic experience when careful selection criteria are followed. We advocate
the "four-hands technique" for simultaneous dissection and control of bleeding
and bile ducts during resections.
PMID- 9543524
TI - Total radiated power, infrared output, and heat generation by cold light sources
at the distal end of endoscopes and fiber optic bundle of light cables.
AB - BACKGROUND: Skin burns and ignition of drapes have been reported with the use of
cold light sources. The aim of the study was to document the temperature
generated by cold light sources and to correlate this with the total radiated
power and infrared output. METHODS: The temperature, total radiated power, and
infrared output were measured as a function of time at the end of the endoscope
(which is inserted into the operative field) and the end of the fiber optic
bundle of the light cable (which connects the cable to the light port of the
endoscope) using halogen and xenon light sources. RESULTS: The highest
temperature recorded at the end of the endoscope was 95 degrees C. The
temperature measured at the optical fiber location of the endoscope was higher
than at its lens surface (p < 0.0001). At the end of the fiber optic bundle of
light cables, the temperature reached 225 degrees C within 15 s. The temperature
recorded at the optical fiber location of all endoscopes and light cables studied
rose significantly over a period of 10 min to reach its maximum (p <0.0001) and
then leveled off for the duration of the study (30 min). The infrared output
accounted only for 10% of the total radiated power. CONCLUSIONS: High
temperatures are reached by 10 min at the end of fiber optic bundle of light
cables and endoscopes with both halogen and xenon light sources. This heat
generation is largely due to the radiated power in the visible light spectrum.
PMID- 9543525
TI - Bilateral thoracoscopic stapled volume reduction for bullous vs diffuse
emphysema.
AB - BACKGROUND: We compared our results with bullous vs diffuse emphysema by
performing a bilateral thoracoscopic stapled volume reduction technique in 15
patients (age 45-80, 10 males, five females). METHODS: Eight patients
demonstrated bullous emphysema and seven patients diffuse emphysema. Lung
reduction was performed with a bilateral thoracoscopic stapled technique
utilizing bovine pericardium in the supine position. RESULTS: Comparison of the
bullous versus diffuse groups revealed no significant differences in means for
the following variables: length of air leak (7.5 vs 3.3 days); length of stay
(8.1 vs 6.5 days); pre-op FEV1, (23% vs 22%); pre-op dyspnea index (3.4 vs 3.6).
At 3 months the bullous subset had a highly significant improvement (p < 0.007)
in FEV1 (88%) compared with the diffuse subset FEV1 (59%). CONCLUSIONS: These
early results suggest that patients with bullous emphysema are at no greater risk
and demonstrate a significantly greater improvement in FEV1 than patients with
diffuse emphysema.
PMID- 9543526
TI - Ultrasonic epithelial ablation of the lower esophagus without stricture
formation. A new technique for Barrett's ablation.
AB - BACKGROUND: The premalignant potential of Barrett's esophagus has stimulated
efforts to find a way to ablate the columnar epithelium in order to reheal the
area with squamous epithelium, thus obviating the cancer risk. This study
describes and evaluates a new technique using ultrasonic energy to ablate the
epithelium of the lower esophagus in a porcine model. METHODS: Eight young farm
pigs were used to develop the technique of applying a laparoscopic Cavitron
Ultrasonic Surgical Aspirator (CUSA) to the lower esophageal mucosa through an
operating gastrostomy. A further 11 Yakutan minipigs then underwent CUSA
epithelial ablation, followed by a laparoscopic Nissen fundoplication or
postoperative acid suppression therapy. We then assessed the healing response in
these subjects. RESULTS: Optimal CUSA energy settings enabled complete ablation
of the squamous epithelium with preservation of the muscularis mucosa and
submucosa. The integrity of the aspirated cells was sufficient for cytological
analysis. Healing occurred by squamous regeneration without stricture formation.
CONCLUSION: The CUSA technique holds promise for complete ablation of the
Barrett's epithelium in a single setting. The unique tissue-selective nature of
the ablative process allows complete mucosal reepithelialization without
stricture formation.
PMID- 9543527
TI - The effect of peritoneal air exposure on postoperative tumor growth.
AB - BACKGROUND: Previous work has demonstrated that cell-mediated immune function is
better preserved in rodents after laparoscopic than open surgery. The cause of
this laparotomy-related immunosuppression is unclear. Some investigators have
attributed it to the length of the incision; others, to peritoneal air exposure.
It has also been shown that tumors in mice are more easily established and grow
larger after sham laparotomy than after pneumoperitoneum. Lastly, the differences
in tumor growth have been shown to be, at least in part, attributable to the
immunosuppression that occurs after laparotomy. The purpose of this study was to
determine if air pneumoperitoneum, presumably via immunosuppression related to
peritoneal air exposure, is associated with increased tumor growth in the
postoperative period. METHOD: A total of 150 immunocompetent syngeneic mice
received high-dose intradermal injections of mouse mammary carcinoma tumor cells.
They were then randomized to undergo one of the following procedures: (a)
anesthesia alone, (b) air insufflation (44 mm Hg), (c) CO2 insufflation, or (d)
full laparotomy. No intraabdominal procedure was carried out. All procedures were
20 min long. After 12 days, the animals were killed and the mean tumor mass
determined for each group. RESULTS: All animals grew tumors. There was no
significant difference in the mean tumor size of the anesthesia control, CO2
insufflation, and air insufflation groups (p > 0.85 by ANOVA). However, the
laparotomy group tumors were 1.5 times as large as those of the other three
groups (p < 0.05 by ANOVA). CONCLUSIONS: In this model, air insufflation did not
significantly affect postoperative tumor growth, nor did CO2 pneumoperitoneum.
However, full laparotomy was associated with increased tumor growth.
PMID- 9543528
TI - Operative technique for thoracoscopic transmyocardial laser revascularization.
AB - We describe herein the operative steps used to perform a transmyocardial laser
revascularization by thoracoscopy. A special technique and specific equipment are
required for the efficacy and safety of the procedure. Our preliminary results
with this novel approach suggest that it could be a valid alternative to the
thoracotomic procedure.
PMID- 9543529
TI - Endoluminal stenting for benign colonic obstruction.
AB - We report a case of complete descending colon obstruction due to diverticular
disease that was initially managed by endoscopic stent placement followed by
single-stage left colectomy with primary anastomosis. Traditional management of
complete large bowel obstruction, whether due to benign or malignant disease,
most often requires a temporary colostomy because of unprepared colon. In this
case, preparation of the colon was accomplished by successful stenting of the
benign colonic obstruction. We believe that endoscopic colonic stenting is an
effective way of avoiding a temporary colostomy in patients with complete large
bowel obstruction.
PMID- 9543530
TI - EndoScope: world literature reviews
PMID- 9543531
TI - J. B. Murphy, M.D. Of buttons and blows.
PMID- 9543533
TI - Intraoperative screening for common bile duct stonesUltrasound or
cholangiography?
PMID- 9543532
TI - SSAT/SAGES minimally invasive surgeryAdvanced laparoscopic hepatobiliary surgery
PMID- 9543535
TI - Laparoscopic transcystic duct common bile duct exploration
PMID- 9543534
TI - ERCP interaction with laparoscopic cholecystectomy
PMID- 9543537
TI - Laparoscopic treatment for right upper quadrant tumors and hepatic metastases
PMID- 9543536
TI - Laparoscopic choledochotomy for treatment of common bile duct stones
PMID- 9543538
TI - Endoscopic surgery for pancreaticobiliary cancer
PMID- 9543540
TI - Integrating advanced laparoscopy into surgical residency training
PMID- 9543539
TI - Laparoscopic surgery for solid lesions
PMID- 9543541
TI - SAGES position statement on advanced laparoscopic training
PMID- 9543542
TI - SAGES statement on concentration in general surgery residency
PMID- 9543543
TI - Guidelines for granting of privileges for laparoscopic and/or thoracoscopic
general surgery
PMID- 9543544
TI - Granting of privileges for gastrointestinal endoscopy by surgeons
PMID- 9543545
TI - News and notices
PMID- 9543546
TI - The impact of allergic rhinitis on quality of life and other airway diseases.
Summary of a European conference.
PMID- 9543547
TI - Turner syndrome: a cytogenetic and molecular study.
AB - Two hundred and eleven patients with a clinical diagnosis of Turner syndrome were
studied. We report (i) the cytogenetic results, (ii) the frequency of cryptic
mosaicism and (iii) the parental age and the parental origin of the abnormality.
We scored 100 cells from blood cultures and found 97 patients to have a 45,X
constitution, 15 to be 45,X/46,XX or 45,X/47,XXX mosaics, 86 to have a
structurally abnormal X and 13 to have a structurally abnormal Y chromosome.
Molecular methods were used to look for cryptic X and Y chromosome mosaicism in
patients with a 45,X constitution. Two cryptic X but no cryptic Y mosaics were
detected. In 74% of the 45,X patients the X was maternal in origin. The i(Xq)s
were approximately equally likely to involve the paternal or maternal chromosome,
while the majority of deletions and rings and virtually all the abnormal Y
chromosomes were paternal in origin. We suggest that the preponderance of
paternal errors in Turner syndrome may result from the absence of pairing along
the greater part of the XY bivalent during paternal mei I, which may make the sex
chromosomes particularly susceptible to both structural and non-disjunctional
errors during male gametogenesis.
PMID- 9543548
TI - Molecular characterization of isochromosomes of Xq.
AB - We have undertaken a study of 35 patients with i(Xq) to determine whether those
that are maternally derived originate by similar mechanisms to those that are
paternally derived. Isochromosome formation is not associated with increased
parental age and > 90% of i(Xq) contain proximal Xp sequences suggesting that
centromere misdivision is not a common mechanism of formation. Our results
indicate that the majority of i(Xq) originate from a single X chromosome and the
usual mechanisms of formation do not appear to differ according to the parent of
origin.
PMID- 9543549
TI - Genetic analysis of a Japanese patient with butyrylcholinesterase deficiency.
AB - A patient (64-year-old, male) with familial cholinesterasemia caused by BChE
deficiency was studied. DNA sequence analysis of all exons identified a point
mutation, an A-->G transition at codon 128, resulting in a Tyr-->Cys
substitution. The propositus showed extremely low BChE activity, but his other
family members (three individuals) showed from intermediate to normal BChE
activity. An immunological method revealed the absence of BChE protein in serum
of the propositus. Both PCR primer introduced restriction analysis (PCR-PIRA) and
sequence analysis revealed all three family members to be heterozygotes for this
mutation.
PMID- 9543550
TI - Development of a microsatellite-based approach to co-segregation analysis of
familial hypercholesterolaemic kindreds.
AB - Co-segregation studies based on a selection of intragenic restriction fragment
length polymorphisms of the low density lipoprotein receptor (LDLR) gene have
been used extensively both for research and diagnostic studies of familial
hypercholesterolaemia (FH) families, because direct mutation screening remains
complex. Here we describe the development and application of a more efficient
approach to co-segregation studies based on highly informative dinucleotide and
tetranucleotide repeats flanking the LDLR gene. A series of microsatellites
(D19S391, D19S394, D19S221 and D19S179) were selected for study on the basis of
linkage analysis in the CEPH families using intragenic polymorphisms for a TA
repeat (exon 18) in the LDLR gene, and earlier data for a Pvu II polymorphism
(intron 15). A physical map of the region of chromosome 19 also contributed to
this selection. One marker in particular, D19S394, sited 150 kilobases telomeric
to the gene, was extremely useful, displaying 90% heterozygosity, robust PCR of
tetranucleotide repeats without stutter bands, and no recombination with the LDLR
gene (theta = 0, LOD 68). Use of this marker in the families of twenty-three FH
probands from Hampshire demonstrated co-segregation of the hyperlipidaemia
phenotype with the LDLR gene region, except in one family with defective
apolipoprotein B-100, and a family turning out to display familial combined
hyperlipidaemia. This approach should facilitate the search for any families
where FH does not co-segregate with the LDLR gene, and will enhance the
repertoire of molecular diagnostic tools available for FH.
PMID- 9543551
TI - A tale of two islands: population history and mitochondrial DNA sequence
variation of Bioko and Sao Tome, Gulf of Guinea.
AB - The hypervariable segment I of the control region of the mtDNA was sequenced in
45 unrelated individuals from Bioko and 50 from Sao Tome, two islands in the Gulf
of Guinea that have had very different settlement patterns: Bioko was colonized
around 10000 BP, while Sao Tome was first settled by the Portuguese, who brought
African slaves to the island. Two different patterns of sequence variation are
evident and are also clearly a consequence of their very different demographic
histories. The Bubi present a low genetic diversity and it is likely that the
island was colonized by a small number of individuals with small later migration.
Sao Tomeans might be considered a subset of a mainland African population
relocated to the island. They present high genetic diversity with a high number
of sequences being shared with many continental populations. This study, with
knowledge of the population history in island populations, strengthens the
genetic approach to unravel past demographic events.
PMID- 9543552
TI - Localization of the fast skeletal muscle troponin I gene (TNNI2) to 11p15.5:
genes for troponin I and T are organized in pairs.
AB - We have localized the gene encoding the fast skeletal muscle isoform of troponin
I (TNNI2) to 11p15.5 by PCR-based analysis of somatic cell hybrid panels: based
on the Genebridge4 radiation hybrid panel, TNNI2 is coincident with the marker
D11S922. The gene encoding the fast skeletal muscle troponin T gene (TNNT3) has
been previously assigned to 11p15.5 suggesting that TNNI2 and TNNT3 may be
closely linked. The overall location of genes encoding troponin I and T isoforms
now reveals that they are organized at three loci each containing a troponin
I/troponin T gene pair. This organization contrasts with all other sarcomeric
protein genes and has implications for the evolution of these two gene families,
for their regulation and for the analysis of mutations suspected to result in
cardiomyopathy.
PMID- 9543553
TI - DNA polymorphisms of apolipoprotein B in the population of Senegal.
AB - Three apolipoprotein B (apoB) genetic polymorphisms, the XbaI, MspI and EcoRI
restriction fragment length polymorphisms (RFLPs), were analysed for 221
individuals in Senegal by polymerase chain reaction. Allelic frequency
determination revealed that this population has 0.79 XbaI- (X-), 0.96 MspI+ (M+),
and 0.89 EcoRI+ (E+). Major genotypes were X-/X- (0.62), M+/M+ (0.92) and E+/E+
(0.80). The XbaI allele frequency is different (p < 10(-9)) from that in
Caucasians (0.47) and from that in Mongoloids (0.98). Significant differences
between Senegalese and Caucasians, and between Senegalese and Mongoloids were
also observed for the EcoRI and MspI alleles of the apoB genes.
PMID- 9543554
TI - The role of the hypothalamus-pituitary-adrenocortical and -gonadal axis in
rheumatoid arthritis.
PMID- 9543555
TI - Mycobacterium tuberculosis infection in a corticosteroid-treated rheumatic
disease patient population.
AB - OBJECTIVE: To investigate the incidence and risk factors of Mycobacterium
tuberculosis infection in longterm corticosteroid treated rheumatic disease
patients. METHODS: We assessed retrospectively the incidence of active
tuberculosis and its risk factors in 269 rheumatic disease patients treated with
moderate to high doses of corticosteroid for an evaluation period representing
1,035 corticosteroid years of therapy. RESULTS: The mean daily dose of steroid
was 18.7 mg prednisolone and the mean daily dose during the first year of
treatment was 20.4 mg prednisolone. 21 of these patients developed active
tuberculosis resulting in an incidence rate of 20/1,000 patient-years. Cumulative
and mean daily steroid doses during the follow-up period and during the first
year of treatment, and a history of steroid pulse therapy were significantly
correlated with the development of tuberculosis. A past history of tuberculosis,
initial chest P-A abnormality, the starting dose of steroid, a history of more
than 30 mg/day of prednisolone for more than one month, and a history of
cytotoxic therapy were not related to the development of tuberculosis.
CONCLUSION: The incidence of active tuberculosis is increased in rheumatic
patients on moderate-to-high dose steroid treatment. Its risk factors are the
cumulative and mean daily steroid doses during the follow-up period and during
the first year of steroid treatment, and a history of steroid pulse therapy.
PMID- 9543556
TI - Relationship between radiographic classification and arthroscopic findings of
articular cartilage lesions in osteoarthritis of the knee.
AB - OBJECTIVE: To examine the relationship between radiographic abnormalities and
arthroscopic findings of the cartilage lesions in patients with osteoarthritis
(OA) of the knee. METHODS: Arthroscopy was performed in 190 patients with primary
medial compartment (MC) OA of the knee to assess the severity of the cartilage
lesion. Standing radiographs of all patients were graded according to the joint
space narrowing (JSN) and Kellgren-Lawrence (K/L) scales. In addition to
evaluating the correlation between arthroscopic articular cartilage lesions and
the radiographic scale, multiple regression analysis was used to identify the
arthroscopic findings and clinical factors that influenced the cartilage lesions.
RESULTS: The positive predictive values of the JSN and K/L scales of the MC for
the presence of essentially abnormal articular cartilage in the MC by arthroscopy
were high (0.98, 0.96, respectively). The sensitivity and specificity of the JSN
scale and the sensitivity and negative predictive value of the K/L scale were
also high in the MC. In contrast, the positive predictive values of these
radiographic scales for the presence of arthroscopic lesions in the lateral
compartment (LC) were poor (0.20 and 0.19). In this study population with severe
OA, there were more patients with a high K/L score than with a high JSN score in
the MC. CONCLUSION: In MC-OA of the knee, the JSN and K/L scores for the MC
correlated highly with cartilage lesions of the MC by arthroscopy. However, the
cartilage lesion of the LC correlated poorly with both of these radiographic
scales.
PMID- 9543557
TI - Prevalence of digital clubbing in bronchogenic carcinoma by a new digital index.
AB - OBJECTIVE: Clubbing can be a paraneoplastic manifestation of bronchogenic
carcinoma. We assessed a new digital index of clubbing and used it to determine
the prevalence of clubbing for different cell types of lung cancer. METHODS:
Clubbing was assessed by measurement of the thickness of both the base of the
nailbed (distal phalangeal depth--DPD) and the distal interphalangeal depth (IPD)
of the index finger in a control group compared to patient groups with either
chronic obstructive lung disease, or lung cancer. RESULTS: Of the 55 normal
subjects, no patient had a DPD/IPD ratio of more than 1.05 on either hand, while
11% of the patients with COPD had a ratio of more than one. For the cancer
patients, 33% had a ratio greater than one, with 30 of 109 (37%) having a ratio >
1.05 (chi(2) = 17.6, p < 0.0001). There was no difference in the prevalence of
clubbing between the 33 squamous cell patients, the 43 adenocarcinoma patients,
and the 33 small cell lung carcinoma patients included. CONCLUSIONS: Measurement
of the interphalangeal and distal phalangeal distance demonstrated that one-third
of patients with lung cancer had evidence of clubbing. The type of bronchogenic
carcinoma did not appear to affect the proportion of patients with clubbing.
PMID- 9543558
TI - Soft tissue composition, quadriceps strength, bone quality and bone mass in
rheumatoid arthritis.
AB - OBJECTIVES: To examine differences in soft tissue composition, bone quality, bone
mass and quadriceps strength between women with rheumatoid arthritis (RA) and
healthy controls. METHODS: 79 women with RA (median disease duration 10 yrs) were
studied. Most were or had been on steroids. 67 healthy age-matched women served
as controls. The lean tissue mass (LTM) and fat mass (FM) of the total body and
of the major body subregions, as well as the bone mineral density (BMD, g/cm2) of
the femoral neck, spine (L2-L4) and distal forearm were measured by dual energy x
ray absorptiometry (DXA). Bone quality expressed as the speed of sound (SOS
m/sec), broadband ultrasound attenuation (BUA, dB/MHz) and stiffness was assessed
by an Achilles ultrasound device, and isometric quadriceps strength by an
isokinetic dynamometer. RESULTS: No between-group differences were found for the
body mass index (BMI, weight/height2), total or regional percentage fat, LTM and
FM. However, women with RA had 20% lower quadriceps strength than controls. BMD
at the femoral neck and distal forearm, and SOS, BUA and stiffness were
significantly lower in patients than in controls. No difference was found for
spine BMD. In the RA group, z-scores for SOS and stiffness were significantly
more reduced than those for BMD. Multiple regression analyses indicated negative
associations between ultrasound parameters and the cumulative steroid dose.
CONCLUSIONS: Reductions in BMD and muscle strength in RA were not accompanied by
changes in soft tissue composition, Bone quality assessed by ultrasonography was
compromised in RA and may be modified by steroids.
PMID- 9543559
TI - Reconstitution of severe combined immunodeficient mice with spleen cells from
autoimmune NZBxNZW F1 mice.
AB - OBJECTIVE: The aim of this study is to establish an animal model to investigate
the role of individual subsets of immune cells in the pathogenesis of systemic
lupes erythematosus. METHODS: Spleen cells isolated with from both young and old
autoimmune NZB/W F1 mice were injected into the peritoneal cavity of severe
combined immunodeficient (SCID) mice. Sera anti-DNA antibody levels and
proteinuria of these SCID mice were followed regularly. In addition, histological
changes of the kidneys were also examined. RESULTS: The data suggest that anti
ss, dsDNA antibody can be detected in the sera of SCID mice 21 days after
reconstitution with the spleen cells of either young or old NZB/W F1 mice, with
titers of antibody increasing over time. In addition, proteinuria was also noted
in most of these mice 3 months after reconstitution. Histopathological
examination of the kidney also revealed the typical changes of
glomerulonephritis. Immunofluorescence staining of kidney sections also
demonstrated immune complex deposition. CONCLUSION: Once validated, this animal
model could be used in future studies to investigate the role of individual
subsets of cells in the pathogenic mechanisms of SLE.
PMID- 9543560
TI - Actinically degenerate elastic tissue: the prime antigen in the giant cell
(temporal) arteritis syndrome? New data from the posterior ciliary arteries.
AB - OBJECTIVE: To search for evidence of actinic elastotic degeneration (actinic
arteriopathy) and giant cell arteritis (GCA) in the posterior ciliary arteries of
eyes from aged white Australians. METHODS: Three hundred donor eyes were given to
us by the Lions Eye Bank of New South Wales at Sydney Hospital. Of these, 146
formed the basis of this study. Portions of the posterior ciliary arteries
located in relation to the optic nerve heads were processed in paraffin and were
then stained by a sensitive haematoxylin and eosin stain that had been especially
developed to display actinic elastotic degeneration of elastic tissue. RESULTS:
Among 60 "aged" subjects (70-90 yrs.), a total of 41 (approximately 68%) showed
definite changes of actinic elastotic degeneration in their laminae, a condition
called actinic arteriopathy. One of these subjects revealed giant cells on
degenerate lamina, giving a picture regarded as early (pre-clinical) GCA. A young
"control" group of 60 subjects 17-59 years of age revealed only one subject with
a similar degree of actinic arteriopathy. CONCLUSIONS: Actinic arteriopathy of
the posterior ciliary arteries was more frequent and advanced in the "aged", over
70 group as compared with changes in the "young" group < 60 years of age. One
aged subject without a history of eye disease showed giant cells associated with
elastotically degenerate internal elastic lamina. Her fortuitous lesions are
regarded as indicative of how GCA is likely to begin in the damaged arteries.
PMID- 9543561
TI - Quality of life assessment during six months of NSAID treatment [Gonarthrosis and
Quality of Life (GOAL) Study].
AB - OBJECTIVE: To identify the time point of the greatest degree of improvement in
daily living activities, pain and depression in patients with osteoarthritis (OA)
of the knee during 6 months of treatment with NSAIDs, in order to define
compliance and drop-out rate. METHODS: 107 patients were recruited into a
multicentre, prospective, randomized, controlled trial comparing two treatments,
piroxicam-beta-cyclodextrin (PBCD) and slow release diclofenac (DCL). RESULTS:
The greatest improvement in quality of life occurred in both groups after 3
months, with a slight further gain observed by the end of treatment. The Stanford
Health Assessment Questionnaire score improved (p < 0.05 vs baseline) at 3 and 6
months with PBCD and at 6 months with DCL. The Arthritis Impact Measurement Scale
score improved (p < 0.05 vs baseline) after 6 months in both groups. Significant
(p < 0.05 vs baseline) improvement in other psychological and pain scores were
recorded in both groups after 3 and 6 months. Compliance with treatment at 3
months was 73% for PBCD and 72% for DCL, and was 60% in both groups at 6 months.
CONCLUSIONS: The results of this study indicate that the optimal length of time
for an NSAID trial in OA patients is 3 months, when assessment of daily living
activities is considered as the main outcome criterion.
PMID- 9543562
TI - C4A and C4B null alleles are genetic markers of different types of systemic
sclerosis in Japanese patients.
AB - OBJECTIVE: The contribution of the polymorphism of complement C4A and C4B alleles
to the pathogenesis of systemic sclerosis (SSc) was studied in Japanese patients.
METHODS: C4A and C4B typing was carried out in 44 SSc patients and in 83 normal
subjects using electrophoresis followed by immunofixation and immunoblotting. HLA
DR typing and HLA DRB1*15 and *08 genotyping were carried out by the PCR method
and the PCR-SSCP method, respectively. RESULTS: In SSc with diffuse scleroderma,
the frequency of C4BQ0 was significantly increased (44.4%, p < 0.001, pc < 0.01).
In SSc with antitopoisomerase I antibody (a-Scl-70) C4BQ0 was also increased
(50.0%, p < 0.001, pc < 0.01). Association analysis indicated that the increase
in C4BQ0 was not primary but reflected an increase in HLA-DRB1*1502. In contrast,
C4A/Q0 was significantly increased in limited scleroderma (53.8%, p < 0.005, pc <
0.05) and SSc without a-SCL-70 (53.8%, p < 0.005, pc < 0.05). CONCLUSION: Diffuse
scleroderma with SSC with a-Scl-70 have different genetical backgrounds from
limited scleroderma and SSc without a-Scl-70, respectively, in Japanese patients.
C4AQ0 were independent genetic markers for each clinical subgroup and for a a-Scl
70 positivity.
PMID- 9543563
TI - The management of osteoporosis-related fractures: a survey of orthopaedic
surgeons' practice.
AB - A questionnaire survey of 70 orthopaedic surgeons regarding their policy for the
management of osteoporosis-related fractures revealed that, in the main, UK
Department of Health guidelines on osteoporosis are not followed uniformly,
although Royal College of Physicians guidelines regarding rehabilitation are met
more frequently. A written policy or agreed protocol with an osteoporosis service
may potentially benefit a large number of patients and reduce future fracture
risks.
PMID- 9543564
TI - Association of mast cells with fibrosis and fatty infiltration in the minor
salivary glands of patients with Sjogren's syndrome.
AB - OBJECTIVE: To determine the distribution and density of mast cells in the minor
salivary glands of patients with primary Sjogren's syndrome (pSS) and of normal
controls. METHODS: Minor salivary gland biopsies were obtained from 19 patients
with pSS, 9 with systemic lupus erythematosus, one each with rheumatoid
arthritis, sarcoidosis, and Hodgkin's disease, and from 10 individuals who had
subjective xerostomia with normal salivary gland biopsies. Biopsy specimens were
evaluated for the degree of inflammation according to Tarpley's classification.
Sections were analysed for staining with Toluidine blue and with the mast cell
specific marker c-kit. The data obtained were correlated with the histological
findings of fatty infiltration, fibrosis and lymphocytic infiltration. RESULTS:
There was a significant correlation between the number of mast cells identified
and the degrees of fibrosis and fatty infiltrates. There was no correlation
between the intensity of lymphoid infiltration and the number of mast cells. c
kit staining showed a high correlation when compared to Toluidine blue staining.
CONCLUSION: Mast cells in the minor salivary glands of patients with pSS are
strongly associated with fibrosis and cell acid infiltration. However, there is
no correlation with parameters of disease activity such as lymphoid infiltration.
PMID- 9543565
TI - HLA-TNF haplotype heterogeneity in Greek SLE patients.
AB - OBJECTIVE: To examine TNF microsatellite allele frequencies in SLE patients in
the Greek population, where disease susceptibility is less associated with HLA
DR3 haplotypes. METHODS: A cohort of 46 Greek SLE patients were investigated.
Allele frequencies for the TNF microsatellite markers a, b, c and d were
determined using a fluorescence based DNA fragment sizing technique. HLA class II
typing was performed using a molecular based technique. RESULTS: Associations
between SLE and DRB1*1501, *1601 and *0701 were observed and DRB1*0301 was only
marginally increased in patients. Linkage disequilibrium was found between
DRB1*1501 and TNF a11 and also for DR3 and TNF a2, b3, d2. Stratification of
patients suggested that DRB*1501 and TNF a11 frequencies were higher in SLE
patients with renal disease and TNF a2 and b 3 frequencies in those without,
although these differences did not reach statistical significance. CONCLUSIONS:
SLE in this Greek population appears to be associated with a number of HLA-DRB1
alleles. The development of renal complications in these patients may be related
to the TNF polymorphism encoded on these HLA haplotypes.
PMID- 9543566
TI - Sucrose permeability as a marker for NSAID-induced gastroduodenal injury.
AB - OBJECTIVE: To evaluate sucrose permeability as a non-invasive test for the
monitoring of upper gastrointestinal mucosal damage (uGMD) in patients treated
with NSAIDs. METHODS: 40 patients with non-inflammatory joint pain were enrolled
in a prospective study. Before and after 14 days of ibuprofen treatment (3 x 400
mg/day), the rates of urinary sucrose excretion after an oral sucrose load were
assessed. Individuals with increased sucrose permeability underwent endoscopy.
RESULTS: 8 patients (20%) showed abnormal sucrose permeability before taking any
NSAID. In 5/20 patients (25%) who completed 2 weeks of ibuprofen medication,
sucrose excretion increased above the normal level. Endoscopic examination and
biopsy revealed mild uGMD, but no ulceration in 8/11 (72%) patients with
increased permeability to this marker. CONCLUSION: Sucrose permeability testing
is a sensitive procedure for research protocols on NSAID-induced gastropathy.
Since this test also seems to detect slight and clinically insignificant mucosal
damage, however, its use in clinical decision-making regarding gastroprotective
medication is limited.
PMID- 9543567
TI - Fever and abdominal pain in a 45-year-old woman with cutaneous necrotising
vasculitis.
PMID- 9543568
TI - Selective IgA deficiency with recurrent vasculitis of the central nervous system.
AB - We describe an unusual case of selective IgA deficiency complicated by recurrent
vasculitis of the central nervous system (CNS). The patient suffered from two
episodes of CNS vasculitis, one of which was located in the cerebrum and the
other in the cerebellum. The vasculitic process resulted in brain tumor-like
lesions shown by computed tomography. There was no evidence of associated
connective tissue diseases. Vasculitis in other organs or tissues was not noted.
This is the first detailed description in the English literature of
pathologically proven CNS vasculitis in a patient with selective IgA deficiency.
Our report demonstrates that isolated CNS angiitis can be a rare clinical feature
of selective IgA deficiency.
PMID- 9543569
TI - Hepatic hypertrophic osteoarthropathy: the value of liver transplantation.
AB - We describe 4 cases of hepatic hypertrophic osteoarthropathy treated successfully
by liver transplantation. Hepatic hypertrophic osteoarthropathy is a rare and
disabling condition associated with severe liver diseases. It responds poorly to
conservative management, and liver transplantation is the only radical treatment
option.
PMID- 9543570
TI - Acquired winged scapula in a patient with systemic lupus erythematosus.
AB - A 34-year-old woman presented with a right winged scapula 8 months after
developing systemic lupus erythematosus (SLE) with subacute cutaneous
manifestations. The patient experienced severe shoulder pain followed by weakness
of the right arm in the typically winged scapula fashion. Electromyography of the
serratus anterior showed long thoracic nerve palsy. Clinical and laboratory signs
did not reveal any associated disease. Paralysis of the long thoracic nerve has
never been described before in SLE.
PMID- 9543572
TI - Reclassifying the pathogenesis of rheumatoid arthritis: from the susceptibility
to the degenerative stages.
AB - Rheumatoid arthritis is a heterogeneous disease in which different pathogenic
mechanisms have been suggested. Recent advances in immunology and immunogenetics
have contributed to a better understanding of this complex illness. Several
stages have been previously described, based on clinical and radiological
findings, and proposing different therapeutic options. We have analysed previous
classification schema, making some changes and incorporating new knowledge. Our
classification system includes a susceptibility stage and a degenerative stage.
Therapeutic options are described for each stage. We hope that this will provide
useful guidelines in the future for clinicians and researchers.
PMID- 9543571
TI - Non-X-linked hyper-IgM syndrome with systemic lupus erythematosus.
AB - A 24-year-old woman had suffered from recurrent bacterial infections and clinical
manifestations of systemic lupus erythematosus (SLE). Laboratory findings
disclosed an elevated level of serum IgM, markedly decreased IgG, IgA, IgD and
IgE levels, and low levels of serum complement. Both the CD40 and CD40 ligands
appeared to be normally expressed. Assays of in vitro immunoglobulin production
by lymphocytes showed that IgM was produced normally and that IgE but not IgG or
IgA production was rescued by signaling through CD40 on B cells. The
proliferative response of lymphocytes to phobol ester was markedly decreased,
suggesting some impairment of signal transduction in the patient's lymphocytes.
PMID- 9543573
TI - Association of ankylosing spondylitis, Crohn's disease and Takayasu's arteritis
in a child.
AB - The authors report the case of a 15-year-old, HLA-B27-positive male patient who
presented a rare association of ankylosing spondylitis, Crohn's disease and
Takayasu's arteritis, which resulted in death. A brief review of the literature
is provided.
PMID- 9543574
TI - Thrombomodulin, tissue plasminogen activator and plasminogen activator inhibitor
1 in Henoch-Schonlein purpura.
AB - OBJECTIVE: To evaluate the changes in the plasma levels of thrombomodulin (TM),
tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1
(PA1-1) as indices of endothelial injury/activation and fibrinolysis in childhood
Henoch-Schonlein purpura (HSP). METHODS: Twenty-six children with HSP aged
between 4-15 years and 10 healthy controls were included in the study. Blood
samples were taken from these patients at admission and 6-12 weeks after healing
of skin rash and arthritis. Plasma levels of TM, t-PA and PAI-1 activities and t
PA and PAI-1 antigen (Ag) levels were measured. RESULTS: The plasma levels of TM,
t-PA Ag and PAI-1 Ag in patients during the acute phase were significantly
different from the controls. The difference in TM between the acute phase and
recovery in patients was also significant. The decrease in plasma levels of t-PA
Ag and PAI-1 Ag in patients between the acute and recovery phases was not
significant. t-PA activity was significantly higher in the acute phase than in
the recovery phase. CONCLUSION: We suggest that increased levels of TM, t-PA, and
PAI-1 activity may reflect the presence of endothelial injury and/or activation
and fibrinolytic activation in patients with HSP.
PMID- 9543575
TI - Epidemiology of juvenile chronic arthritis in northern Norway: a ten-year
retrospective study.
AB - OBJECTIVE: To study the incidence and prevalence of juvenile chronic arthritis
(JCA) in northern Norway. METHODS: Cases from the period 1985-1994 were
retrospectively identified from the hospital files of the only pediatric
department treating JCA in the study area. The European League Against Rheumatism
(EULAR) criteria for JCA were used. RESULTS: The annual incidence of JCA was
22.6/100,000 children under 16 years of age. The incidence of oligoarticular JCA
was 11.8, and the incidence of systemic JCA was 0.8/100,000. In the incidence
group 25% were ANA positive, 14% developed uveitis and 42% of the tested patients
were HLA-B27 positive. The point prevalence was 148.1/100,000. CONCLUSION: These
incidence and prevalence data are higher than those reported in most other
studies. The impact of genetic differences, cyclic variations and other factors
in relation to the onset and course of JCA merit further investigation.
PMID- 9543576
TI - Atypical renal onset and involvement in primary antiphospholipid syndrome in a
child.
AB - A case of primary antiphospholipid syndrome (APS) with renal involvement in a 10
year-old child is reported. The peculiarity of the case resided not only in the
apparent "primary" occurrence of APS in the pediatric age, but also in the
involvement of the kidney. The renal picture in the case described consisted of a
focal proliferative glomerulonephritis, without any sign of glomerular
thrombosis. We conclude that this should lead to a consideration of primary APS
in the differential diagnosis of nephropathies, also in childhood.
PMID- 9543577
TI - Severe anemia due to hemorrhagic gastritis associated with Sjogren's syndrome.
PMID- 9543578
TI - Evaluation of S-adenosylmethionine in secondary fibromyalgia: a double-blind
study.
PMID- 9543579
TI - Simultaneous development of SLE-like syndrome and autoimmune thyroiditis
following alpha-interferon treatment.
PMID- 9543580
TI - CD11b positive blood lymphocytes correlate with disease activity in patients with
RA.
PMID- 9543581
TI - Beneficial effect of a thiazide diuretic on bone mineral density in male
osteoporosis with hypercalciuria.
PMID- 9543582
TI - Magnetic resonance imaging findings in acute cerebellitis.
AB - Cerebellitis, also known as acute cerebellar ataxia, is an inflammatory syndrome
of cerebellar dysfunction that may reflect an infectious, post-infectious, or
post-vaccination disorder. We present serial magnetic resonance imaging (MRI)
findings in a partially reversible, idiopathic cerebellitis. Bilateral cerebellar
parenchymal abnormalities were noted, including hyperintensities on T2-weighted
images and cerebellar swelling. After contrast administration, the cerebellum
showed abnormal bilateral enhancement. The authors state this represents the
first report of abnormal contrast enhancement in this condition. The MRI lesions
most likely reflect the reversible, inflammatory nature of the syndrome.
PMID- 9543583
TI - Power Doppler findings in nasopharingeal angiofibroma.
AB - Juvenile nasopharingeal angiofibroma (JNA) is a rare, histologically benign but
clinically malign hypervascular tumor localized in the nasopharynx which occurs
exclusively in adolescent boys. There is no definite attitude towards etiology of
angiofibroma. In diagnostics, besides epypharyngoscopy, computed tomography and
magnetic resonance imaging are the primary diagnostic tests. Angiography is used
for preoperative embolization. In this case report, we aim to demonstrate the
vascularity of JNA with power Doppler sonography (PDS) and advanced vasculature
was observed into tumoral lesion with PDS.
PMID- 9543584
TI - Evaluation of galactography for nipple discharge.
AB - Galactography is useful in the evaluation of spontaneous discharge from the
nipple of a nonlactating breast. Without galactography, surgeons have relied on
either masectomy or excision of the major duct system responsible for the
discharge. From January 1989 to May 1996, 106 galactograms were performed with
monofilament polypropylene suture guiding for duct cannulation in 105 cases. The
discharge duct was identified by pre-operative galactography, followed by a
selective excision of ductal-lobular unit. In all tissue specimens, the cause of
the pathologic secretion was found histologically; most often, it was intraductal
papilloma (42.6%). In 35.6% of the specimens, findings with a prospective
significance (papillomatosis, hyperplasia, carcinoma) were discovered and further
operative treatment was initiated. The color of the discharge allowed no
prediction of the histological findings. The accuracy of galactography was 88.4%,
84.6%, and 77.4% in papilloma, cancer, and other benign lesions, respectively. It
is better than physical examination and other tests. Galactography represents a
useful test in the diagnostic workup of secretory breasts.
PMID- 9543585
TI - Tamoxifen-induced regression of breast cysts.
AB - The use of Tamoxifen as treatment for breast cancer is well established and its
use experimentally as prophylaxis is promising, but little has been written about
mammographically detected changes in breast parenchyma as a result of Tamoxifen
therapy. We report two cases of spontaneous regression of breast cysts after
Tamoxifen therapy for premenopausal breast cancer in the contralateral breast.
PMID- 9543586
TI - Wegener's granulomatosis upper respiratory tract and pulmonary radiographic
manifestations in 30 cases with pathogenetic consideration.
AB - Although the radiographic manifestations and pathologic features of Wegener's
granulomatosis have been well described, their relationship to two variants of
anti-neutrophil cytoplasmic antibodies (c- and p-ANCA) remains unclear. The
purposes of this study are to analyze the radiographic and pathologic findings in
30 patients with Wegener's granulomatosis and to correlate c- and p-ANCA with
such findings. Major histologic findings included parenchymal necrosis,
necrotizing vasculitis, and granulomatous inflammations. Nodular lesions were
more often associated with arteritis whereas patchy fluffy lesions associated
with hemorrhagic capillaritis. ANCAs, particularly c-ANCA, instead of p-ANCA,
were present in a high percentage of patients tested. These findings suggest that
c-ANCA could play an important pathogenetic role in Wegener's granulomatosis
which showed dual pathologic processes: vasculitis and granulomatous inflammation
manifested radiographically as either nodular or pneumonia-like lesions, whereas
p-ANCA was more often associated with patchy fluffy lung lesions as the
consequence of hemorrhagic capillaritis.
PMID- 9543587
TI - Pancreaticopleural fistula. An unusual cause of persistent unilateral pleural
effusion.
AB - There are a myriad of causes of a large persistent pleural effusion.
Pancreaticopleural fistula is a rare entity seldomly included in the above
differential. As it usually presents with thoracic rather than abdominal
symptoms, a combination of imaging modalities, including chest radiography (CXR),
computerized tomography (CT) and endoscopic retrograde cholangiopancreatography
(ERCP) is essential in obtaining the diagnosis.
PMID- 9543588
TI - Spiral CT with 3D reconstruction in children requiring reoperation for failure of
chest wall growth after pectus excavatum surgery. Preliminary observations.
AB - Pectus excavatum is the most common congenital chest wall deformity. Extensive
corrective surgery prior to age 3 may disturb chest wall growth and result in a
constricted thorax. We describe our surgical and radiologic experience with eight
such cases, paying particular attention to the role of spiral computed tomography
(CT) with 3D reconstruction in patient management. Spiral CT was performed on
children who had developed restrictive chest walls following pectus excavatum
surgery. These children then underwent a unique operation to elevate the sternum
and attempt to correct their restrictive chest wall defects. In several cases,
postoperative spiral CT was performed. Spiral CT with 3D reconstruction defined
the orientation of the ribs and costal cartilages and their relationship to the
sternum, allowing exact preoperative measurement of the bony rib cage and guiding
individualized operative correction. Computed thoracic volumes in select cases
correlated well with subjective patient reports of increased exercise capacity.
Repair of pectus excavatum defects prior to age 3 may result in constrictive
thoracic abnormalities. Surgical correction can increase thoracic volume and
improve prospects for normal thoracic function. Three-dimensional reconstruction
of spiral CT data is useful in both preoperative and postoperative evaluation.
PMID- 9543589
TI - Arterio-esophageal communication from a ruptured aberrant right subclavian artery
aneurysm. CT diagnosis.
AB - We report the computed tomography (CT) findings of an arterio-esophageal
communication from an aberrant right subclavian artery aneurysm which had eroded
into the esophagus. Pathologic correlation is provided. To our knowledge, this is
the first CT demonstration of an aberrant right subclavian aneurysm causing a
communication to the esophagus reported in the literature. Previously, one CT
case of a left aberrant subclavian artery aneurysm that had ruptured into the
esophagus, had been described. The characteristic location of the aberrant vessel
with aneurysmal dilation and the presence of abnormal air identified within the
wall of the aneurysm on CT, helped establish the diagnosis antemortem.
PMID- 9543590
TI - CT demonstration of infected SVC thrombus.
AB - We report a case in which computed tomography (CT) demonstrated gas within a
thrombus in the superior vena cava in a patient with fever of unknown origin
(FUO), indicating that the thrombus was infected. This CT finding is important to
recognize, as it affects subsequent therapy.
PMID- 9543591
TI - Castleman disease mimicking a hepatic neoplasm.
AB - Castleman disease, or angiofollicullar hyperplasia, is a rare cause of lymph node
enlargement. This most commonly occurs within the thorax, although rare
extrathoracic presentations have been described. Only two cases with hepatic
localization have been reported. We present a case of Castleman disease within
the porta hepatis masquerading as a hepatic neoplasm.
PMID- 9543592
TI - MRI findings in adenosquamous carcinoma of the gallbladder.
AB - In this report, we present the MRI findings of adenosquamous carcinoma of the
gallbladder, a rare type of gallbladder malignancy. MRI examination not only
helped established the diagnosis but also accurately depicted the extent of
involvement of the adjacent liver. The ability to image in multiple planes was
also useful in assessing the anatomic location of the tumor and in determining
that the patient could be treated with surgical resection.
PMID- 9543593
TI - Cardiac-triggered and segmented two-dimensional MR angiography of peripheral
arterial occlusive disease. A pictorial essay.
AB - Magnetic resonance (MR) angiography has been shown to be an important technique
to image the vasculature of the lower extremities. The two-dimensional (2D) time
of-flight technique has evolved as the standard method of MR angiography used to
examine patients with peripheral arterial occlusive disease (PAOD). There is
evidence that cardiac triggering substantially improves the quality of 2D time-of
flight angiography. In this pictorial essay, we describe PAOD, show the results
of this nonintrusive angiographic technique, and provide a current overview of
the interventional and surgical management of PAOD.
PMID- 9543594
TI - Membranoproliferative glomerulonephritis in the aged and its possible causal
relationship with CD8+CD57+ lymphocytes.
AB - Membranoproliferative glomerulonephritis (MPGN) is a chronic progressive
glomerulonephritis that occurs primarily in patients under the age of 30, and is
rare in the elderly. We report eight aged patients with MPGN associated with
CD8+CD57+ lymphocytosis. All eight patients showed a significant increase in
CD8+CD57+ lymphocytes with a significant decrease in the ratio of CD4+ cells to
CD8+ cells. Infiltration of CD8+CD57+ lymphocytes was observed within capillary
lumens to various degrees according to the severity of endocapillary
proliferation in each case. Expression of endothelial-leukocyte adhesion molecule
1 was observed in a focal and segmental manner on glomerular endothelial cells
and on the endothelium of arterioles and arteries in kidney tissue in four cases
in which a pronounced endocapillary proliferation was simultaneously seen. These
findings suggest that cell-mediated cytotoxic mechanisms against glomerular
endothelial cells may be involved in the pathogenesis of MPGN in the aged.
PMID- 9543595
TI - Glomerular enlargement in the progression of mesangial proliferative
glomerulonephritis.
AB - A close association between glomerular hypertrophy and subsequent sclerosis had
been demonstrated in diverse animal and human studies. We investigated the
relationship between the glomerular volume and glomerular constituents (mesangial
matrix, mesangial cells and capillary lumens) in human mesangial proliferative
glomerulonephritis (GN). The data were obtained from glomeruli in the specimens
of 23 patients undergoing repeat renal biopsies. Glomerular volume and glomerular
constituents of each patient were obtained by averaging those of all glomeruli in
each specimen. The interval from the first biopsy to the second was 51.2 +/- 6.8
months and the number of glomeruli included in each specimen was 16 +/- 1.
Between glomerular volume and fractional mesangial volume, three patterns were
recognized. In 8 of 23 patients glomerular volume and fractional mesangial volume
were increased in the second biopsy (Group A). In 12 of 23 patients glomerular
volume was decreased and fractional mesangial volume increased in the second
biopsy (Group B), and in 3 of 23 patients glomerular volume was increased and
fractional mesangial volume decreased in the second biopsy (Group C). One patient
who underwent renal biopsy three times shifted from Group A to Group B in the
course of mesangial proliferative GN. At the final follow-up, 4 of 12 patients in
Group B required hemodialysis in contrast to none of 8 patients in Group A.
Between glomerular volume and fractional mesangial volume, a positive and inverse
relation existed, and we considered that in the course of mesangial proliferative
GN, initially, glomerular size increases and thereafter decreases progressively.
With glomerular enlargement, mesangial matrix expansion, glomerular capillary
enlargement and relative decrease of the number of capillary lumen profiles and
mesangial cells per glomerulus to increased glomerular volume were recognized. We
concluded that these histological changes play a role in the progression of
mesangial proliferative GN in humans as has been speculated in animal models of
renal ablation.
PMID- 9543596
TI - Inadequate suppression of angiotensin II modulates left ventricular structure in
humans.
AB - BACKGROUND: In a previous study we found that high angiotensin II levels in
relation to the corresponding urinary sodium excretion aggravate left ventricular
hypertrophy in hypertensive patients. To analyze whether a dysregulation of the
renin angiotensin aldosterone system determines left ventricular structure in
young individuals, we examined whether the response of angiotensin II after
increasing salt intake is related to left ventricular structure. METHODS: In 51
young, male Caucasians with normal or mildly elevated blood pressure, left
ventricular structure, 24-hour ambulatory blood pressure and dietary sodium
intake (as estimated by 24-hour sodium excretion) were determined in parallel
with plasma renin activity, angiotensin II, and aldosterone concentrations.
Angiotensin II concentration and 24-hour sodium excretion were measured twice:
firstly on a normal Bavarian diet and secondly at high salt intake to determine
the resulting suppression of the renin-angiotensin-aldosterone system. RESULTS:
Body mass index (r = 0.42, p < 0.001) and both systolic (r = 0.28, p < 0.05) and
diastolic (r = 0.25, p < 0.05) 24-hour ambulatory blood pressure correlated with
left ventricular mass. No direct relationship was found between left ventricular
structure and baseline angiotensin II concentration. The lower the physiological
decrease of angiotensin II after high oral salt intake, i.e. the higher the
angiotensin II level after salt intake remained, the greater was left ventricular
mass (r = 0.38; p < 0.006) even after taking 24-hour ambulatory blood pressure
into account (partial correlation; r = 0.43, p < 0.005). Consistently,
angiotensin II concentration at high salt intake correlated with left ventricular
mass independently of ambulatory blood pressure (partial correlation: r = 0.29, p
< 0.05). Subgroup analysis revealed that the increase in sodium excretion at high
salt intake was related to the decrease in angiotensin II levels in normotensive
(r = -0.43, p < 0.05), but not in hypertensive subjects (r = 0.16, n.s.). The
changes in angiotensin II concentration at high salt intake were related to left
ventricular mass in hypertensive (r = 0.43, p < 0.02), but not in normotensive
individuals (r = 0.21, n.s.). CONCLUSION: Our finding that angiotensin II
concentration at high salt intake correlated with left ventricular mass
independently of ambulatory blood pressure suggests that inadequate suppression
of angiotensin II after high salt intake contributes to left ventricular
hypertrophy already in young hypertensive individuals independently of blood
pressure.
PMID- 9543597
TI - A comparison of the safety and efficacy of mibefradil and nifedipine SR in
patients with renal disease and hypertension.
AB - The antihypertensive efficacy and safety of mibefradil and nifedipine SR were
compared in 143 patients with chronic renal failure and mild-to-moderate
hypertension in a multicenter, double-blind, randomized, parallel-design study.
At treatment week 12, a significantly greater decrease in sitting diastolic blood
pressure (SDBP) was seen with mibefradil than with nifedipine SR (12.8 mmHg vs
8.1 mmHg, respectively; p = 0.014). A significantly greater number of mibefradil
treated patients achieved normalization of SDBP by week 12 (62% vs 37%; p <
0.01). The changes in renal function parameters and the incidence of adverse
events were similar in both groups. In this population, 12 weeks of treatment
with mibefradil were more effective than nifedipine SR for lowering blood
pressure and had similar effects on renal function parameters.
PMID- 9543598
TI - Contribution of tubular anion and cation secretion to residual renal function in
chronic dialysis patients.
AB - The clearance of organic ions by the tubules may contribute to the removal of
uremic waste products in dialysis patients. The renal excretion of an exogenous
anion p-aminohippurate (PAH) was investigated in 10 peritoneal dialysis patients
and 10 hemodialysis patients during one clearance period and compared with the
clearance of creatinine (Ccr) and inulin (CIn). The clearance period was 24 hours
in the peritoneal dialysis patients and one interdialytic interval of 3 days
divided in 4 parts [CPA-D] in hemodialysis patients. In peritoneal dialysis
patients the renal clearance of total PAH (median 14.3 ml/min, range 3.8-33.0)
exceeded the CIN (median 3.2 ml/min, range 1.6-11.2, p < 0.005) and Ccr (median
4.0 ml/min, range 1.7-15.0, p < 0.005). A positive correlation was found between
the tubular clearances of creatinine (cationic pathway) and of total PAH (anionic
pathway, r: 0.72, p <0.02). In hemodialysis patients the clearance of total PAH
(CPA: median 2.0, range 0.8-9.6; CPD: median 3.8, range 1.7-15.4) also exceeded
the clearance of inulin (CPA: median 1.5, range 0.2-3.4; CPD: median 2.7, range
0.9-4.4) in the beginning and the end of the interdialytic interval (p < 0.005).
The CIN and the clearance of total PAH increased during the interdialytic
interval, but the Ccr (CPA: median 2.2, range 0.4-8.9, CPD: median 2.9, range 1.2
4.6) remained stable. Thus, the change in tubular clearance of creatinine and PAH
was opposite during the interdialytic interval: it increased for total PAH and
decreased for creatinine. The CTPAH/CIN ratio in hemodialysis patients was lower
than in peritoneal dialysis patients. In CPA it was median 1.6 (range 1.1-5.6, p
< 0.05) and in CPD it was median 1.7 (range 1.1-5.0, p < 0.02) and in the
peritoneal dialysis patients it was median 3.6 (range 1.5-9.1). We conclude that
tubular clearances contribute to the residual renal function in dialysis
patients, but the tubular handling of anions and cations in relation to the
residual GFR is different between peritoneal and hemodialysis patients. A
difference in clearance of organic acids caused by the dialysis techniques may be
an explanation for the differences in clinical outcome between the two dialysis
modalities.
PMID- 9543599
TI - Assessment of PD treatment delivered by 125I-Iothalamate plasma disappearance.
AB - The calculation of treatment delivered to PD patients requires the collection of
PD effluent, plasma and urine samples. 125I-Iothalamate plasma disappearance,
which eliminates the need for PD effluent collections, was tested as an alternate
method to measure the weekly PD treatment delivered. Two protocols were designed.
In protocol A, a 35 microCi dose of 125I-Iothalamate was injected in three
subjects and allowed to equilibrate. A plasma sample was taken and patients
returned on both of the following two days with timed labeled effluent bags and a
24-hour urine collection for each day. The timed PD effluent and 24-hour urine
collections were measured for 125I-Iothalamate, urea and creatinine
concentrations. 125I-Iothalamate and urea clearances were strongly correlated for
both PD (R2 = 0.76, n = 24) and renal (R2 = 0.92, n = 6) clearances. In protocol
B, thirteen subjects were given a 35 microCi injection of 125I-Iothalamate. A
blood sample was taken one hour post injection and a second blood sample taken on
day five. Kt/V were calculated from the 125I-Iothalamate plasma disappearance
curve and compared to weekly Kt/V values extrapolated from one day's collections
(Traditional Method). The comparison of Kt/V values found by 125I-Iothalamate
Method vs. the "Traditional Method" yielded R2 = 0.79, n = 13. In conclusion, the
plasma disappearance of 125I-Iothalamate is an alternate method of determining
weekly Kt/V, over an extended period of time, which eliminates the need for PD
effluent collections.
PMID- 9543600
TI - Four-site skinfold anthropometry (FSA) versus body impedance analysis (BIA) in
assessing nutritional status of patients on maintenance hemodialysis: which
method is to be preferred in routine patient care?
AB - BACKGROUND: Both four-site skinfold anthropometry (FSA) and bioelectrical
impedance analysis (BIA) claim to be useful in routine clinical practice of
maintenance dialysis as easy methods to assess nutritional status. The purpose of
this study was to investigate which of these two methods is to be preferred.
METHODS: Both before and after dialysis nutritional and hydration status were
evaluated by BIA in 20 stable hemodialysis patients. Variables of nutritional
status as lean body mass (LBM) and body fat (BF) were assessed by four-site
skinfold anthropometry (LBM-FSA and BF-FSA) and BIA (LBM-BIA and BF-BIA).
Variables of hydration status were total body water (TBW), its distribution into
intracellular and extracellular compartments (ICW and ECW, respectively) and
ICW/ECW. RESULTS: Weight loss during dialysis correlated with a change of LBM-FSA
(r = 0.75, p <0.005) and also with that of LBM-BIA (r = 0.69, p < 0.005). To
promote reliability of follow-up measurements in intervention studies it is
warranted to evaluate nutritional status in an unchanged hydration status. The
highly significant correlation (r = 0.93, p < 0.005) between the two techniques
and the comparability between means and SD indicate that both techniques were
almost equivalent to each other, although, compared to LBM-BIA, LBM-FSA was less
affected by changes in fluid status. The sam held true for BF-BIA and BF-FSA. BF
FSA correlated significantly with BF-BIA (r = 0.65, p <0.005), whereas no
difference of mean +/- SD was found between BF-FSA and BF-BIA. CONCLUSION: FSA
and BIA are almost comparable techniques to assess both LBM and BF, although FSA
is less affected by changes in fluid status. However, assessing LBM in
normohydration is mandatory. Compared with FSA, BIA is able to establish
hydration status and lacks depency on operator interpretation. Therefore, in
routine patient care the BIA technique is the one to be preferred.
PMID- 9543601
TI - Transferrin receptor assay and zinc protoporphyrin as markers of iron-deficient
erythropoiesis in end-stage renal disease patients.
AB - To evaluate storage iron deficiency and iron-deficient erythropoiesis we
determined, in a cross-sectional study of 95 patients mainly including end-stage
renal disease patients (ESRD) with (32) and without rh-EPO therapy (55), the
following parameters: hemoglobin, mean corpuscular red cell volume, ferritin,
transferrin saturation (TS), zinc protoporphyrin (ZPP) and soluble transferrin
receptor (TfR). In the dialysis group the percentage of positive samples with
each marker of tissue iron supply defined as TS < 20%, ZPP > 40 mumol/mol Heme
and TfR > 3.05 microgram/ml was as follows: TS 43.7% and 32.2% at a diagnostic
threshold level of < 16%, ZPP 33.3% and TfR 17.2%. Manifest storage iron
deficiency defined as ferritin < 30 ng/ml was observed in 5.7% of the samples
while the mean ferritin concentration of the rh-Epo treated dialysis patients was
509.3 ng/ml compared to 262.5 ng/ml in the group without rh-EPO therapy. These
data reflect a generous iron substitution in our series taking a TS < 20% as an
intervention criterion. Looking at the different results of the three markers the
best correspondence was found between ZPP and TfR resulting in a weak positive
correlation (+0.64). In conclusion, we found quite different results with
different assays when evaluating endogenous iron availability in our series of
mainly ESRD patients in a cross-sectional study. Because a gold-standard is not
defined further firm conclusions cannot be drawn from this type of study. The
adequacy of the different parameters of iron metabolism including threshold
levels and, consequently, the decision and route of iron substitution deserve an
evaluation in a longitudinal study to characterize the best marker or marker
combination in this setting.
PMID- 9543602
TI - Thrombotic thrombocytopenic purpura accompanied by transient pure red cell
aplasia and thymoma.
AB - We describe a 64-year-old man with thrombotic thrombocytopenic purpura (TTP),
transient pure red cell aplasia (PRCA) and thymoma. TTP in this case was thought
to be idiopathic and was accompanied by microangiopathic hemolytic anemia. The
patient, therefore, had an aplastic crisis due to PRCA. He was treated with
peritoneal dialysis, plasma exchange with plasma infusion, red blood cell
transfusion, methylprednisolone pulse therapy followed by maintenance dosing with
intravenous prednisolone, gamma-globulin, vincristine, and dipyridamol. As a
result, the patient's mental disorder, acute renal failure, anemia and
thrombocytopenia improved; however, the haptoglobin level remained low. The
pathogenesis of PRCA and thymoma indicates that these are immunological disorders
often associated with each other. To our knowledge, there are no reports of TTP
with transient PRCA and thymoma. Although such a combination is considered
relatively rare, this case suggests that there is an immunological contribution
to the pathogenesis of the association of these disorders.
PMID- 9543603
TI - Fungal bezoars as a cause of renal insufficiency in neonates and infants-
recommended treatment strategy.
AB - Fungal bezoars may be a cause of urinary tract obstruction and acute renal
failure in neonates and young infants. We describe a female very low birth weight
infant (25+3 weeks, 795 gram) who developed renal insufficiency on the basis of
systemic fungal infection with fungal bezoars in both kidneys. The girl was
treated by local irrigation of the kidneys and bladder with amphotericin B via
percutaneously inserted bilateral nephrostomy catheters, in combination with
intravenous fluconazol. Renal function subsequently improved and after 11 weeks
of treatment the bezoars had disappeared sonographically. Follow-up of this child
and the one we similarly treated for fungal bezoars before, however, shows
suboptimal renal function as assessed by the clearance of creatinine and the
mercapto acetyl triglycine scan (MAG III). Until now, insufficient data are
available yet to assess with certainly the long-term effects of fungal bezoars on
renal function. Based on our experience and a review of the recent literature
(1980-1996) on systemic candidal infections in premature infants, we recommend to
perform regular renal ultrasound in any case of systemic candidal infection in a
prematurely born infant. If candidal bezoars are found with pelvic obstruction,
we suggest to start treatment by the insertion of bilateral nephrostomy catheters
and local irrigation with amphotericin B in combination with systemic antifungal
agents, aiming at both the restoration of renal function and the eradication of
the fungal infection.
PMID- 9543604
TI - Co-trimoxazole-induced hypouricemia.
PMID- 9543605
TI - The use of brachial arteriovenous fistulas for hemodialysis.
PMID- 9543606
TI - Sjogren's syndrome, renal tubular acidosis and nephrocalcinosis.
PMID- 9543607
TI - Three-dimensional treatment planning for radiotherapy.
PMID- 9543608
TI - Radiation-induced apoptosis.
PMID- 9543609
TI - Prognostic factors in invasive carcinoma of the breast.
PMID- 9543610
TI - An audit of 3D treatment planning facilities and practice in the UK.
AB - The availability and use of 3D treatment planning facilities in the UK was
investigated by questionnaire. Fifty-eight of the 62 UK radiotherapy centres
responded (94%). There was considerable variation in the facilities available and
in the manner in which they were used. Although 36 centres (62%) have the
facilities to undertake complex, non-coplanar treatment planning, only 12 did so
on a regular basis. More surprising was the inconsistent implementation of
coplanar CT planning. It is suggested that we need to work towards reaching a
consensus on best practice in radiotherapy planning. This will require the
creation of systems for guidance and further training of the various staff
involved.
PMID- 9543611
TI - Variations in referral pattern for postoperative radiotherapy of patients with
screen-detected breast cancer in the south Thames (east) region.
AB - This paper describes the findings of a region-wide audit undertaken in 1995-1996
of post-operative radiotherapy treatment for patients with screen-detected breast
cancer. The study covers the first 3 years from the start of the South Thames
(East) Breast Screening Programme in June 1988 up to March 1992. The audit shows
that only 60% of the patients with invasive carcinoma who were treated by
conservation surgery are known to have received radiotherapy. A considerable
variation in referral patterns was observed across the region. Analysis suggests
that whilst geographical, patient choice and tumour factors may play an important
role in the selection of patients for radiotherapy treatment after conservative
surgery for early breast cancer, management protocols of surgical units were the
most critical factor, and that these appear to vary, depending on the level of
involvement of the clinician with the screening programme (as measured by case
load).
PMID- 9543612
TI - Variation in postoperative radiotherapy delivery for patients with screen
detected breast cancer in the south Thames (east) Region.
AB - This paper stems from a region-wide audit of postoperative radiotherapy treatment
for patients with screen-detected breast cancer, commencing from the start of the
South Thames (East) screening programme in June 1988 and ending in March 1992. It
reports on the variation in treatment practices amongst clinical oncologists in
the region. There was diversity in treatment schedules, dose specification
points, and the use of lymph node radiotherapy, breast boost and interstitial
implants. While local protocols vary by centre and individual oncologist, many
treatment decisions appear to have been dictated by the availability of machines
and other resources. However, further analysis suggests that the variation is
within the same range as that described in the nationwide survey of breast
radiotherapy by the Audit Office of the Royal College of Radiologists in 1995 [1
3].
PMID- 9543614
TI - Magnetic resonance imaging of the whole spine in suspected malignant spinal cord
compression: impact on management.
AB - Patients with suspected malignant spinal cord compression may present with a
misleading sensory level or have multiple levels of compression that are not
apparent clinically or on imaging of a limited area of the spine. To estimate how
often this occurs and to evaluate a policy of magnetic resonance imaging (MRI) of
the whole spine for any patient with suspected cord compression, data from 127
patients who had undergone MRI scans of the whole spine were reviewed. In 85 of
127 scans, there was evidence of compression of or impingement upon the spinal
cord. A sensory level was present in 47 of these 85 patients, but in 12/47 (26%)
the sensory level was four or more segments below or three or more segments above
the actual lesion. Multiple levels of compression or impingement were found in 33
of 85 (39%) patients; in 24 of these, more than one region
(cervical/thoracic/lumbar) of the cord was involved. For 32 patients who
commenced radiotherapy to a treatment volume based on clinical criteria before
the MRI scan was available, the radiotherapy fields needed modification in 16
(50%) as a result of the MRI findings. The results support a policy of MRI of the
whole spine in any patient with suspected malignant spinal cord compression.
PMID- 9543613
TI - The effect of cimetidine on the pharmacokinetics of epirubicin in patients with
advanced breast cancer: preliminary evidence of a potentially common drug
interaction.
AB - Epirubicin is known to be metabolized in the liver. Therefore, drugs such as
cimetidine, which inhibit the cytochrome P-450 enzyme system or reduce liver
blood flow, may reduce the plasma clearance of epirubicin. In a small study,
epirubicin 100 mg/m2 every 3 weeks was administered intravenously to eight
patients, who also received oral cimetidine (400 mg b.d. for 7 days starting 5
days before chemotherapy) with either the first or second cycles. Epirubicin
pharmacokinetics and liver blood flow (idocyanine green clearance) were assessed
at each course. The areas under the plasma concentration time curves (AUCs) were
used to compare the systemic exposure to epirubicin and its metabolites with each
course. The estimated median percentage increase (95% confidence interval CI) in
the AUC with cimetidine were: epirubicin 50% (95% CI -18 to 193, epirubicinol 41%
(95% CI 1 to 92). Despite the small numbers studied, the increase in the active
metabolite epirubicinol was significant (P < 0.05). These changes in exposure
were not explained by reduced cytochrome P-450 activity as the 7-deoxy
doxorubicinol aglycone AUC was not reduced (357% increase: 95% CI 17 to 719) or
by a decrease in liver blood flow (17% increase: 95% CI -39 to 104). Cimetidine
is likely to be coprescribed or self-administered with epirubicin and therefore
clinicians should be aware of this potential interaction.
PMID- 9543615
TI - Bone density: is it affected by orchidectomy and radiotherapy given for stage I
seminoma of the testis?
AB - A cross-sectional study of bone density involving 30 patients who had undergone
orchidectomy and para-aortic radiotherapy for Stage I seminoma of the testis, has
been performed. Bone density measurements were made of the whole body, lumbar
spine and hips, including all irradiated areas. Comparison was made with
previously obtained standard sex and age matched control data. The 30 patients
treated for seminoma had a significantly increased mean bone density compared
with age matched normal values. No significant differences were demonstrated
between the mean bone densities of the irradiated and non-irradiated hips. There
was no significant relationship between bone density measurement and time since
orchidectomy or radiotherapy. These results suggest that nodal irradiation for
seminoma has little long term effect on bone density.
PMID- 9543616
TI - Evolution and development of hospice and specialist palliative care services.
PMID- 9543617
TI - Germ cell cancer and dermatomyositis.
AB - Although the association of dermatomyositis and malignancy is well recognized,
there have been few previous reports of germ cell tumours occurring in this
context. Two cases of teratoma with dermatomyositis have presented at the Wessex
Medical Oncology Unit in Southampton, which prompted a review of the literature.
PMID- 9543618
TI - Tuberculosis of the nasopharynx following radiotherapy.
AB - We report the case history of a patient who was treated with radiotherapy for
nasopharyngeal carcinoma. During follow-up, she showed signs, symptoms and
radiological evidence of disease recurrence and progression. However, repeated
biopsies of the posterior nasal space (PNS) failed to demonstrate malignancy. A
diagnosis of nasopharyngeal tuberculosis was finally made when tissue from a PNS
biopsy stained positive for acid-fast bacillus. The patient responded to
antituberculous chemotherapy.
PMID- 9543619
TI - An unusual case of carotid body tumour.
AB - Carotid body tumours are uncommon but fascinating lesions, which arise from
paraganglionic tissue at the bifurcation of the common carotid artery. We report
the case history of a 40-year-old female patient who presented initially with a
malignant left-sided tumour, followed by a right-sided tumour 17 years later.
Although there is no known family history, it is likely, because of the bilateral
tumours and the young age at presentation, that the tumour was inherited in this
patient. The literature on carotid body tumours is reviewed, with particular
emphasis on malignant and multiple tumours and their treatment. We discuss the
recently elucidated mechanism of inheritance and its implications for affected
patients and their families.
PMID- 9543620
TI - Interstitial pneumonitis as a late complication of high dose therapy with
cyclophosphamide/thiotepa and peripheral blood progenitor cell rescue for
carcinoma of the breast.
PMID- 9543621
TI - Where next in the treatment of rectal cancer.
PMID- 9543622
TI - Prenatal care.
AB - This paper describes the psychological and psychosocial aspects of prenatal care,
which are believed to be of particular importance for medical/psychological
practice. The emotional changes that "normally" take place during pregnancy are
surveyed and evidence is provided linking these changes with potential adverse
effect on pregnancy and labour. The salience of anxiety and life stresses in
pregnancy research is highlighted as well as their intricate inverse relationship
with social support. Antenatal classes are offered as an example of social
support provision. The different kinds of such classes and evaluation of their
effectiveness are briefly presented, as well as a number of controlled trials of
enhanced support during pregnancy. Finally, the effect provision of prenatal care
has on women as well as their role in their own care are raised. The need is
stressed for further sophisticated longitudinal and multivariate research
exploring further the causative links between quality of prenatal care, pregnancy
outcome, and subsequent child development.
PMID- 9543623
TI - Meta-analytic investigation of the effectiveness of self-regulatory components in
the treatment of adult problem behaviors.
AB - The present paper utilized meta-analysis to examine the effectiveness of
interventions in which components of self-regulation theories (e.g., self
monitoring, self-reinforcement) were the primary treatment intervention utilized
in treating habit disturbances, depression, anxiety and health-related problems
with adults. The effect size (ES)1 comparing interventions utilizing all
combinations of self-regulatory components to no intervention at all was d = .25
(p < .005). The ES comparing interventions utilizing self-monitoring (SM) plus
any other self-regulatory component(s) to interventions utilizing SM alone was d
= .42 (p < .001). Differential effectiveness was demonstrated for various
combinations of self-regulatory components.
PMID- 9543624
TI - A review of instruments for assessing family history.
AB - The influence of family history on one's development has long been a focus of
psychological theory, research, and practice. In recent years, however,
conceptualizations of family influences on development have evolved considerably,
and there has also been increased concern about the reliability of individuals'
memory for their childhoods in general. Current knowledge regarding these and
other issues are applied to reviewing the instruments that have been developed to
assess aspects of family history. The complexity of this type of assessment is
emphasized, and a variety of problems with the reliability and validity of the
currently available instruments are discussed. Suggestions for future research
are also offered.
PMID- 9543625
TI - Psychiatric rehabilitation: efficacy of four models.
AB - This paper is a critical review of four major rehabilitation programs: assertive
community treatment, case management, vocational rehabilitation, and educational
rehabilitation. Reported outcomes are reviewed in the context of study design,
service characteristics, client characteristics, and operationalization of
outcomes. Findings from the four programs are compared with one another. The
authors concluded that clients are able to learn most of the skills taught,
independently of the rehabilitation model. Furthermore, skills learned in one
life domain generalized to a moderate extent to other areas. The four
rehabilitation programs had varied effects on the outcome variables, and part of
the variability in the findings appears to be related to client characteristics.
Limitations of the studies reviewed are identified and a set of recommendations
was suggested for the future practice of research into psychiatric
rehabilitation.
PMID- 9543626
TI - The Behavior Management Flow Chart: a component analysis of behavior management
strategies.
AB - Representative published child behavior management research was reviewed. Based
upon the review, a task analysis of child behavior management strategies was
conducted. The Behavior Management Flow Chart is a flow chart of the task
analysis that synthesizes the research into a cohesive unit and visually depicts
actions that adults may be trained to use to manage misbehavior displayed by
disruptive children. A discussion compares and contrasts the Behavior Management
Flow Chart with Hanf-model behavior management programs, the appropriate unit of
analysis is examined, and concerns regarding integrating a wide range of research
variables into a unitary model are addressed.
PMID- 9543627
TI - Protein-tyrosine phosphatases: biological function, structural characteristics,
and mechanism of catalysis.
AB - The protein-tyrosine phosphatases (PTPases) superfamily consists of tyrosine
specific phosphatases, dual specificity phosphatases, and the low-molecular
weight phosphatases. They are modulators of signal transduction pathways that
regulate numerous cell functions. Malfunction of PTPases have been linked to a
number of oncogenic and metabolic disease states, and PTPases are also employed
by microbes and viruses for pathogenicity. There is little sequence similarity
among the three subfamilies of phosphatases. Yet, three-dimensional structural
data show that they share similar conserved structural elements, namely, the
phosphate-binding loop encompassing the PTPase signature motif (H/V)C(X)5R(S/T)
and an essential general acid/base Asp residue on a surface loop. Biochemical
experiments demonstrate that phosphatases in the PTPase superfamily utilize a
common mechanism for catalysis going through a covalent thiophosphate
intermediate that involves the nucleophilic Cys residue in the PTPase signature
motif. The transition states for phosphoenzyme intermediate formation and
hydrolysis are dissociative in nature and are similar to those of the solution
phosphate monoester reactions. One strategy used by these phosphatases for
transition state stabilization is to neutralize the developing negative charge in
the leaving group. A conformational change that is restricted to the movement of
a flexible loop occurs during the catalytic cycle of the PTPases. However, the
relationship between loop dynamics and enzyme catalysis remains to be
established. The nature and identity of the rate-limiting step in the PTPase
catalyzed reaction requires further investigation and may be dependent on the
specific experimental conditions such as temperature, pH, buffer, and substrate
used. In-depth kinetic and structural analysis of a representative number of
phosphatases from each group of the PTPase superfamily will most likely continue
to yield insightful mechanistic information that may be applicable to the rest of
the family members.
PMID- 9543628
TI - Enzymes in low water systems.
AB - Water is fundamental for enzyme action and for formation of the three-dimensional
structure of proteins. Hence, it may be assumed that studies on the interplay
between water and enzymes can yield insight into enzyme function and formation.
This has proven correct, because the numerous studies that have been made on the
behavior of water-soluble and membrane enzymes in systems with a low water
content (reverse micelles or enzymes suspended in nonpolar organic solvents) have
revealed properties of enzymes that are not easily appreciated in aqueous
solutions. In the low water systems, it has been possible to probe the relation
between solvent and enzyme kinetics, as well as some of the factors that affect
enzyme thermostability and catalysis. Furthermore, the studies show that low
water environments can be used to stabilize conformers that exhibit unsuspected
catalytic properties, as well as intermediates of enzyme function and formation
that in aqueous media have relatively short life-times. The structure of enzymes
in these unnatural conditions is actively being explored.
PMID- 9543629
TI - An immortalized hamster corneal epithelial cell line for studies of the
pathogenesis of Acanthamoeba keratitis.
AB - PURPOSE: The protozoan Acanthamoeba produces a severe keratitis in a small
percentage of people, especially contact lens-wearers. The purpose of this work
was to develop and characterize an immortalized line of hamster corneal
epithelial cells to be used in studies of the pathogenesis of Acanthamoeba
keratitis. METHODS: Hamster corneal epithelial cells were maintained in primary
culture and immortalized using simian virus 40 (SV40). Foci of transformed cells
were cloned and subsequently characterized by phase-contrast microscopy and
immunocytochemistry. Growth characteristics of the clone that were analyzed
included loss of dependence on conditioned medium and ability to grow in soft
agar. Cytotoxicity experiments were performed, to determine whether the selected
clone was susceptible to Acanthamoeba infection in vitro. RESULTS: A cell line
which exhibited epithelial morphology, as determined by phase contrast
microscopy, was selected and cloned. Immunocytochemistry demonstrated the
presence of keratin in the cloned cells, confirming the epithelial nature of the
cell line. Immortalization was shown by loss of dependence on fibroblast
conditioned medium, ability to form colonies in soft agar and no apparent
senescence following numerous passages in culture. This cell line was found to be
sensitive to the cytotoxic effects of a pathogenic strain of Acanthamoeba.
CONCLUSIONS: An immortalized line of hamster corneal epithelial cells was
developed. This clone is susceptible to infection with Acanthamoeba and will be a
useful tool with which to investigate the pathogenesis of Acanthamoeba keratitis.
PMID- 9543630
TI - Environmental factors influence P. aeruginosa binding to the wounded mouse
cornea.
AB - PURPOSE: To determine whether environmental factors or bacterial viability affect
the binding of two strains of P. aeruginosa to mouse cornea. METHODS: Scarified
corneas were placed in organ culture and inoculated with P. aeruginosa cell
suspensions containing either ATCC 19660 or PAO1 bacterial strains classed as
cytotoxic or invasive, respectively. Eyes were incubated in vitro for 1 h after
bacterial application at different pH or temperature conditions or in PBS
containing various divalent cations. The adhesion of heat-killed or formalin
fixed bacteria was tested similarly. Scanning electron microscopy (scanning EM)
was used to quantitate adherent bacteria. RESULTS: P. aeruginosa ATCC 19660
showed an increase in binding at pH 8.0, favored higher temperatures and required
both calcium and magnesium for optimum binding. Adherence of PAO1 was enhanced at
pH 6.5 and decreased at pH 8.0. This strain favored binding at lower temperatures
and did not require either divalent cation for optimum binding. In addition, the
presence of magnesium ions resulted in reduced binding for this strain. Both
strains exhibited less binding ability after formalin fixation or heat killing.
CONCLUSION: Environmental factors and bacterial viability are important factors
which influence the ability of both cytotoxic and invasive strains of P.
aeruginosa to bind to the scarified cornea.
PMID- 9543631
TI - Localization of TIMP-1, TIMP-2, TIMP-3, gelatinase A and gelatinase B in
pathological human corneas.
AB - PURPOSE: Determine the tissue distribution patterns for tissue inhibitors of
metalloproteinases (TIMP-1, TIMP-2, TIMP-3), gelatinase A and gelatinase B in
normal and pathologic corneas. METHODS: Corneas were examined by
immunohistochemistry, using antibodies to TIMP-1, TIMP-2, TIMP-3, gelatinase A or
gelatinase B. RESULTS: In normal corneas, TIMP-1 antibody stained the epithelium
and endothelium. TIMP-2 and TIMP-3 stained the epithelium, keratocytes and
endothelium. Gelatinase A staining was weak and restricted to the epithelial
cells. Radial keratotomy scars showed increased staining for TIMP-1 and TIMP-2
around the epithelial cell plug and along the incision. Bullous keratopathy
corneas showed TIMP staining patterns similar to normal corneas and increased
gelatinase A staining in regions of subepithelial fibrosis. Stromal scars of
keratoconus corneas also had increased staining with TIMP-1 and TIMP-2
antibodies. In many keratoconus corneas, the TIMP-3 staining pattern was similar
to normal corneas. However, in some keratoconus corneas, when Bowman's layer was
missing, the stroma beneath was completely devoid of TIMP-3 antibody staining. No
gelatinase B was seen in either the normal or diseased corneas. CONCLUSION: These
data suggest that TIMP-1 and TIMP-2 are important for scar formation and corneal
remodeling, since they were found in increased amounts at radial keratotomy
incision sites and keratoconus scars. The significance of the focal stromal
defects in TIMP-3 staining, associated with absence of Bowman's layer on
keratoconus corneas, needs to be elucidated. At the stages of disease examined in
this study, gelatinase B may not play a significant role in these pathological
processes, since it was not seen in any of the corneas examined.
PMID- 9543632
TI - Quantitation of asparagine-101 deamidation from alpha-A crystallin during aging
of the human lens.
AB - PURPOSE: To quantitate deamidation of asparagine-101 from the alpha-A crystallin
protein of human lenses of different ages. METHODS: Alpha-A crystallin was
purified from total proteins of human lenses of different ages, followed by
tryptic digestion and resolution of the peptides, using reverse phase
chromatography. Known amounts of synthetic peptide standards, corresponding to
the amidated and deamidated forms of the expected tryptic peptide containing
asparagine-101, were used to identify and quantitate the amount of deamidation.
RESULTS: From 0-30 yrs of age, approximately 45% of asparagine-101 was
deamidated, while only approximately 5% additional deamidation occurred during 30
68 yrs of age. CONCLUSIONS: In the normal human lens, most deamidation of
asparagine-101 occurs during the first approximately 30 years of age, followed by
a small additional amount of deamidation (approximately 5%) during the next
approximately 38 years, resulting in a maximum of approximately 50% deamidation
during the lifetime of the individual.
PMID- 9543633
TI - The glutathione levels are reduced in Goto-Kakizaki rat retina, but are not
influenced by aminoguanidine treatment.
AB - PURPOSE: To examine the levels of the free radical protecting enzyme glutathione
and the endothelial/pericyte ratio in retinal capillaries in the Goto-Kakizaki
(GK) Wistar rat, with and without aminoguanidine treatment. METHODS: Eight-month
old GK rats, with non-obese, spontaneous non-insulin-dependent diabetes mellitus
(NIDDM), were examined after a six month period of aminoguanidine treatment.
Glutathione levels were measured with high performance liquid chromatography and
the endothelial/pericyte ratio was calculated in trypsin digested vessel
preparations. RESULTS: The levels of glutathione in GK rat retina were
significantly lower compared to controls (p = 0.0108). There was no difference in
the endothelial/pericyte ratio compared to matched control rats (1.8 +/- 0.2 vs.
1.8 +/- 0.1, respectively). Aminoguanidine treatment did not influence either the
degree of hyperglycemia, the levels of glutathione or the endothelial/pericyte
ratio in GK or control rat retina. CONCLUSIONS: The results indicate that
impaired glucose metabolism may influence one of the defense mechanisms for
oxidative stress, but also suggest that decreased glutathione levels occur prior
to morphological signs of pericyte loss and/or endothelial cell proliferation in
this animal model of hereditary NIDDM.
PMID- 9543634
TI - Tear fluid content of electrochemically active components including water soluble
antioxidants.
AB - PURPOSE: To describe the content of water-soluble antioxidants in tear fluid.
METHODS: We collected tear fluid from healthy subjects, either into borosilicate
glass tubing or by absorption onto Schirmer strips. High pressure liquid
chromatography with electrochemical detection provided data on several components
in a single assay. The system was sufficiently sensitive to provide reliable
values for components present in tear fluid collected at normal (basal) or
stimulated rates of secretion. RESULTS: Tear fluid at basal secretion was found
to contain four compounds often considered to function in biology as
antioxidants. Ascorbic acid (AA) is found at 665 microM, tyrosine at 45 microM
and glutathione (GSH) at 107 microM. Cysteine (48 microM) and uric acid (328
microM) are reported for the first time; the latter is somewhat controversial as
a physiologically active antioxidant. One peak on the chromatogram was
consistently present but has not been identified. During stimulation of flow by
brief inhalation of ammonium hydroxide fumes, the concentration of each compound
was lower. CONCLUSION: This work demonstrates the presence of electro-chemically
active components that might function as antioxidants at the anterior surface of
the cornea against potential damage from radiation, oxygen toxicity, abrasion and
environmental chemicals.
PMID- 9543635
TI - Molecular biology and electrophysiology of calcium-activated potassium channels
from lens epithelium.
AB - PURPOSE: We structurally and functionally characterized the alpha and beta
subunits of the human lens epithelium Ca(++)-activated potassium channel (BK).
METHODS: The two subunits were sequenced following RT-PCR with multiple primer
pairs. The subunits were cloned using a PCR approach and were expressed in tsA
201 cells for patch clamp recording. Green fluorescence protein-channel subunit
fusion proteins were characterized by patch clamping and were imaged by
fluorescence microscopy. RESULTS: Alpha subunits alone make a large single
channel conductance, potassium-selective channel with modest Ca++ sensitivity.
Beta subunits alone make no channel but, when coexpressed with the alpha subunit,
make a channel with increased Ca++ sensitivity, although still less than for
natural channels of this type. GFP-BK subunit fusion proteins continue to
function and result in a fluorescing channel, which can be localized by
fluorescence microscopy. The alpha subunit codes for a "minimal" BK channel in
that none of its potential alternative splicing sites contains an "extra" exon.
CONCLUSIONS: The Ca(++)-activated potassium channel known as BK has the
nucleotide sequences of its alpha and beta subunits represented in messenger RNA
of cultured human lens epithelium. It is the first identified channel, to date,
which imparts internal Ca++ dependence to lens epithelial potassium conductance.
PMID- 9543636
TI - Growth factor and cytokine modulation of trabecular meshwork matrix
metalloproteinase and TIMP expression.
AB - PURPOSE: We hypothesize that regulated trabecular extracellular matrix (ECM)
turnover, initiated by the matrix metalloproteinases, is critical for the
maintenance of normal aqueous humor outflow rates. However, very little is known
about the regulation of trabecular ECM turnover. To identify candidate trabecular
regulators, we evaluated the effects of several growth factors and cytokines on
trabecular matrix metalloproteinase and TIMP expression. METHODS: Porcine
trabecular meshwork cells were treated with several doses of a variety of growth
factors and cytokines and culture media was analyzed after 24, 48, and 72 h.
Zymograms were used to evaluate stromelysin, gelatinase A and B activity levels,
while immunoblots of Western transfers were used to evaluate stromelysin,
collagenase, TIMP-1 and TIMP-2 protein levels. RESULTS: A phorbol mitogen (TPA),
and TNF alpha and beta, interleukin-1 alpha and PDGF BB stimulate gelatinase B,
stromelysin, interstitial collagenase and TIMP-1 expression, while having
negligible effects on gelatinase A expression; TIMP-2 levels are reduced by TNF
but not affected by the other treatments. Acidic and basic FGF, IL-1 beta, TGF
beta and PDGF AB produce similar but smaller effects, while HGF, VEGF, EGF, KGF,
and LIF produce small to moderate elevations in stromelysin with minimal other
responses. PDGF AA, gamma INF, oncostatin-M and endothelin-1 produce negligible
changes in these proteinases and inhibitors. CONCLUSIONS: In addition to
providing potential ways to modulate trabecular metalloproteinase and TIMP
levels, the responsiveness of these cells to some of these growth factors and
cytokines suggests possible roles in normal or pathogenic trabecular cell
regulation and some may affect aqueous humor outflow.
PMID- 9543638
TI - Epidermal growth factor stimulates phospholipase D independent of phospholipase
C, protein kinase C or phosphatidylinositol-3 kinase activation in immortalized
rabbit corneal epithelial cells.
AB - PURPOSE: Activation of phospholipase D (PLD) is believed to be an important
signaling pathway involved in cell growth and differentiation in several tissues,
in response to a variety of mitogens. The aim of the present study was to
investigate the effect of epidermal growth factor (EGF) on PLD activity in rabbit
corneal epithelial cells (RCEC). We have also examined whether the EGF effect is
dependent on concurrent activation of phospholipase C (PLC), protein kinase C
(PKC) or phosphatidylinositol 3-kinase (PI-3-kinase) in these cells. METHODS:
RCEC, immortalized with adenovirus SV-40, were cultured until they became
confluent. The cells were labeled with [3H]myristic acid and incubated with or
without EGF or other agents for specified time intervals. PLD activity was
measured by quantifying [3H]phosphatidylethanol in cells incubated in the
presence of ethanol. PLC activity was determined by measuring the radioactivity
in inositol trisphosphate in myo[3H]inositol-labeled RCEC. PI 3-kinase activity
was assessed by measuring the production of PIP3 in 32P-labeled cells. RESULTS:
Addition of EGF to RCEC stimulated PLD activity in a time- and dose-dependent
manner. The maximal effect was observed with 150 ng/ml EGF and at 10 min of
incubation. The PLD activity was also stimulated when phorbol myristate acetate
(PMA) was added to the cells. Treatment of the cells with EGF stimulated PLC
activity which was inhibited by U73122, a PLC inhibitor. Under the same
experimental conditions, the inhibitor had no effect on EGF-stimulated PLD
activity. Down-regulation of PKC or treatment of the cells with RO31-8220, a PKC
inhibitor, inhibited the PMA- but not EGF-stimulated PLD activity. Incubation of
the cells with wortmannin, a PI 3-kinase inhibitor, abolished the EGF-stimulated
PI 3-kinase activity, but potentiated the EGF-stimulated PLD activity. The EGF
effect was inhibited by treatment of the cells with tyrphostin B42, a receptor
tyrosine kinase inhibitor. CONCLUSIONS: These results indicate that EGF
stimulates PLD activity in RCEC by a mechanism that involves tyrosine
phosphorylation of a protein(s) in the cascade of biochemical reactions initiated
by EGF-receptor interaction, and it is not dependent on concurrent activation of
PKC, PLC, or PI 3-kinase in these cells.
PMID- 9543637
TI - TGF-beta s stimulate cell proliferation via an autocrine production of FGF-2 in
corneal stromal fibroblasts.
AB - PURPOSE: Although transforming growth factor-betas (TGF-beta s) inhibit
epithelial cell proliferation, these same substances stimulate cell proliferation
of fibroblasts. In order to elucidate the mechanism of stimulatory activity of
TGF-beta on fibroblast, the present study was performed to determine whether TGF
beta might be an indirect mitogen acting through induction of an endogenous
growth factor(s) that then acts as the direct mitogen in an autocrine manner in
corneal stromal fibroblasts (CSFs). METHODS: Cell proliferation was determined
either by counting cell numbers or by analyzing the incorporation of [3H]
thymidine into DNA. The synthesis of TGF-beta, TGF-beta receptors, FGF-2 and p27
was analyzed by immunoprecipitation and immunoblotting. RESULTS: TGF-beta 1, TGF
beta 2, and TGF-beta 3 significantly stimulated cell proliferation of CSFs in a
dose-dependent manner. The medium conditioned by CSFs and subsequently activated
by acid-inhibited cell proliferation of corneal endothelial cells by 40%. When
the acid-activated media conditioned by CSFs were immunoprecipitated with either
combined anti-TGF-beta 1 and TGF-beta 2 antibodies or anti-TGF-beta 3 antibody,
all three TGF-beta s, with an apparent molecular size of 25 kDa, were detected,
whereas CSFs produced an 80-kDa latent form of TGF-beta 1. These cells can also
express TGF-beta type II receptor and betaglycan. Interestingly, CSFs produced
and secreted 18-kDa FGF-2, the synthesis of which is further stimulated by either
TGF-beta 1 or TGF-beta 3, while both the neutralizing antibody to FGF-2 and the
FGF-2 specific antisense oligonucleotide primers significantly inhibited the
stimulatory activities of TGF-beta 1 in CSFs. The expression of p27, a negative
regulator in cell cycle, was not altered by TGF-beta. CONCLUSIONS: These findings
indicate that CSFs produce both TGF-beta s and FGF-2 and that FGF-2 appears to be
a direct stimulator for TGF-beta-mediated cell proliferation in CSFs.
PMID- 9543639
TI - Augmented retinal endothelin-1, endothelin-3, endothelinA and endothelinB gene
expression in chronic diabetes.
AB - PURPOSE: Endothelins (ETs) belong to a family of vasoactive peptides implicated
in several disorders of the microvasculature. In the present study, we
investigated ET-1 and ET-3 peptide mRNAs and ETA, ETB receptor mRNAs in the
retina of diabetic BB/W rats and age-matched, non-diabetic control animals,
following six months of diabetes. METHODS: Total mRNA was extracted from each
retina and was subjected to reverse transcriptase polymerase chain reaction for
ET-1, ET-3, ETA and ETB. Simultaneously, beta-globin was amplified and used as a
housekeeping gene. The products were analyzed on agarose gels and the specificity
of the amplification was established by hybridization with amplification-specific
biotinylated oligoprobes. For quantification, the products from the linear phase
of amplification were subjected to serial dilution slot-blot hybridization and
densitometry. RESULTS: ETs and their receptor mRNA expressions were present in
the retina. Retinas from the diabetic animals showed significant increases in ET
1, ET-3 ET(A), ET(B) mRNA expressions compared to those from control rats.
CONCLUSIONS: These findings indicate that retinal ET-1, ET-3, ET(A) and ET(B)
mRNA expression in increased in the chronically diabetic BB/W rat. Augmented gene
expression of ETs and their receptors potentially may be of importance in the
pathogenesis of retinal microangiopathy in diabetes.
PMID- 9543640
TI - Effects of nitric oxide synthase inhibitor on intraocular pressure and ocular
inflammation following laser irradiation in rabbits.
AB - PURPOSE: To examine the effects of nitric oxide synthase (NOS) inhibitors on
intraocular pressure (IOP) and ocular inflammation following laser irradiation of
the rabbit iris, and to investigate the involvement of nitric oxide (NO).
METHODS: Thirty min after the intravenous administration of a nonselective
inhibitor of NOS, N omega-nitro-L-arginine methyl ester (L-NAME, 1-100 mg/kg), or
a selective inhibitor of iNOS, aminoguanidine (AG, 100 mg/kg), Q-switched Nd:YAG
laser irradiation was applied to the iris of albino rabbits at an energy level of
48 mJ. IOP was measured prior to and for 24 h after irradiation. In separate
groups of rabbits, aqueous humor was withdrawn 30 min after irradiation to
determine protein and prostaglandin (PG) E2 concentrations. RESULTS:
Intravenously administered L-NAME dose-dependently inhibited the acute increase
in IOP, the peak of which was observed at 30 min, following laser irradiation.
The IOP increase was completely abolished by 100 mg/kg of L-NAME. This dose of L
NAME significantly reduced the elevation of protein concentration in aqueous
humor following irradiation; however, this dose failed to affect the increase in
PGE2 concentration On the other hand, the inhibitory effects of AG (100 mg/kg) on
the increase in IOP and aqueous protein following laser irradiation were not
significant. CONCLUSIONS: Intravenous administration of L-NAME significantly
inhibits the IOP rise and the increase in protein concentration in aqueous humor
following laser irradiation, but AG does not, suggest the involvement of cNOS in
these ocular responses to laser irradiation.
PMID- 9543641
TI - Recombinant adenovirus-mediated gene transfer into the adult rat retina.
AB - PURPOSE: The present study was designed to evaluate the feasibility of gene
transfer into the retina of adult rats, using a recombinant replication-defective
adenovirus vector expressing a reporter gene. METHODS: Purified recombinant
adenovirus expressing beta-galactosidase (lacZ) (Ad5.hCMV.lacZ) at doses ranging
from 1.4 x 10(2) to 1.4 x 10(6) plaque-forming units (pfu) were injected into the
subretinal space of adult Lewis rats. The presence of lacZ was determined by
histochemical assay and reverse transcription and polymerase chain reaction
analysis (RT PCR) of total RNA extracted from eyes injected with recombinant
adenovirus expressing lacZ. RESULTS: As assessed by biomicroscopy, the expression
of lacZ was highest in the retinal pigment epithelium in a localized area
corresponding to the site of injection. The level of lacZ expression was
correlated with the amount of virus delivered to the subretinal space. Persistent
but decreasing expression of lacZ was noted over time. RT PCR revealed the
expression of messenger RNA for at least sixty days. CONCLUSIONS: The results of
this study demonstrate that efficient and stable transfer of genetic material
into the subretinal space of adult rats may be achieved using a recombinant
adenoviral vector. The use of such vectors should prove useful in developing
novel applications and approaches to the study of recombinant protein expression
in vivo.
PMID- 9543642
TI - Sharp vision: a prerequisite for compensation to myopic defocus in the chick?
AB - PURPOSE: Compensatory responses to focusing errors imposed by spectacle lenses in
chicks, tree shrews and primates leave little doubt that active emmetropization
can occur, and debate is now centered on whether this process is uni-directional
or bi-directional in nature. To provide further insight into this emmetropization
process, the studies reported in this paper addressed the question of whether
access to sharp vision is necessary for compensation to myopic defocus in the
chick. METHODS: Two different experimental paradigms were used to address the
above question: (A) Myopic defocus was imposed, either with +15 or +40 d lenses
alone or with +15 D lenses on eyes made myopic by 7 days of form deprivation;
these treatments result in a shift in the plane of focus of the eye (far point)
to 6.67, 2.5 cm and approximately 3.5 cm resp., with only objects at or closer
than these planes being in focus. The addition to the lenses of stand-off cones,
either 2.5 or 5 cm in length, further limited access to (or precluded) sharp
vision by controlling how closely the chicks could approach objects. One group
that had sharp vision precluded also underwent optic nerve section. (B) A range
of positive lenses (+15 to +65 D) were used on their own to impose myopic
defocus; for the high power lenses, access to sharp vision was very restricted
because of the close proximity of the new far point (1.54 cm for +65 D lens).
Refractive errors and axial ocular dimensions were measured in all experiments.
RESULTS: In the first study (A), preclusion of sharp vision not only prevented
compensation but resulted in increased eye growth and myopia. This myopia, like
form-deprivation myopia, was unaltered by optic nerve section surgery. Limiting
but not precluding sharp vision resulted in partial compensation. In the second
study (B), good compensation was observed with the +15 D lens but compensation
progressively declined for higher powers, with the +50 D lens having no apparent
effect on eye growth and refraction and the +65 D lens inducing myopia instead of
hyperopia. CONCLUSIONS: Together these results argue that some sharp vision is
fundamental to compensation to impose myopia. The significance of this new
finding in relation to the processes underlying active emmetropization is
discussed.
PMID- 9543643
TI - A novel homozygous Ile535Asn mutation in the rod cGMP phosphodiesterase beta
subunit gene in two brothers of a Japanese family with autosomal recessive
retinitis pigmentosa.
AB - PURPOSE: Recently, mutations in several genes have been identified as being
responsible for the pathogenesis of autosomal recessive retinitis pigmentosa
(arRP). These genes include rhodopsin, beta-subunit of rod cGMP phosphodiesterase
(PDEB), alpha-subunit of rod cGMP phosphodiesterase (PDEA), and alpha-subunit of
rod cGMP-gated channel. We here attempted to identify a novel mutation in the
PDEB gene in Japanese arRP patients. METHODS: Using the PCR-SSCP method,
sequencing analysis, and restriction endonuclease digestion assay, we analyzed
the PDEB gene in 17 Japanese families with non-dominant retinitis pigmentosa.
RESULTS: A novel Ile535Asn mutation was identified in two patients in a single
family and the mutation cosegregated with RP in this family. Among 90 unrelated
healthy individuals, no one was identified as homozygous for this mutation,
except for one individual who was found to be heterozygous. CONCLUSIONS:
Isoleucine at codon 535 in the PDEB gene is conserved among various mammals.
Missense mutations of the PDEB gene causing arRP have been reported in a limited
region (codon 527-codon 699) in which codon 535 is located. Thus, the Ile535Asn
mutation is an additional missense mutation which is responsible for the
pathogenesis of arRP.
PMID- 9543644
TI - Effect of religion and religiosity on alcohol use in a college student sample.
AB - Two hundred and sixty-three alcohol using college students completed a
questionnaire on their levels of alcohol use, problems with alcohol use, reasons
for drinking, perceptions of control over drinking, impulsivity, venturesomeness,
irrational beliefs, neuroticism, expectations of alcohol effects, depression,
social norms, religious affiliation and intrinsic and extrinsic religiosity.
Analyses of variance revealed that students with no religious affiliation
reported significantly higher levels of drinking frequency and quantity, getting
drunk, celebratory reasons for drinking and perceived drinking norms than those
of either Catholic or Protestant religious affiliation, while no significant
differences across groups were found for alcohol use problems. Protestants
reported significantly higher levels of perceived drinking control than
Catholics. Intrinsic religiosity, reflecting one's ego involvement with the
tenets of one's religion, appeared to play a more important positive role over
drinking behavior for Protestants than for Catholics.
PMID- 9543645
TI - Sociodemographic representation in published studies of cocaine abuse
pharmacotherapy.
AB - This study evaluated: (1) the reporting of sociodemographic characteristics of
research subjects in published outpatient studies of cocaine abuse
pharmacotherapy; (2) the association of study characteristics with such reporting
and with the distribution of characteristics; and (3) the comparison of
sociodemographic characteristics in the research subjects with those of a
community-based sample of cocaine abusers who had sought treatment. Medline
search identified 68 articles on cocaine abuse outpatient pharmacotherapy
published from 1983 to 1993 in an English language, peer-reviewed journal.
Sociodemographic characteristics of research subjects (n = 1802) were compared
with those of respondents (weighted n = 135) to the National Comorbidity Survey
(1990-1992), who reported at least one cocaine-related problem and had sought
substance abuse treatment. Only three (4.4%) articles reported all six of the
following sociodemographic characteristics of their subjects: 82.4%, reported
mean age; 58.8%, race/ethnicity; 85.3%, sex; 22.1%, employment status; 13.2%,
educational status; and 5.9%, socioeconomic status/income. Compared to survey
respondents, research subjects were significantly more likely to be African
American and live in the Northeast region of the US and marginally more likely to
be male and currently unemployed. These findings indicate that many published
articles do not follow currently recommended guidelines for describing
sociodemographic characteristics of research subjects and that, aside from
race/ethnicity and geographic location, research subjects are fairly comparable
in basic sociodemographic characteristics to the larger population of treatment
seeking individuals with cocaine-related problems.
PMID- 9543646
TI - An acute dose of nicotine enhances cue-induced cocaine craving.
AB - The present study examined whether the active component in tobacco, nicotine, can
modulate cocaine craving in patients with a history of smoking crack cocaine when
exposed to crack cocaine related environmental cues. Twenty patients, all
cigarette smokers, were randomly assigned to nicotine (two 22 mg transdermal
patches) or placebo in a single-dose, placebo-controlled, crossover, double-blind
study. Craving and anxiety were measured before and after cocaine cues with
visual analog scales for desire to use cocaine and mood. Skin conductance and
skin temperature were recorded before and during cocaine cues. Following exposure
to cocaine cues, all patients reported an increase in cocaine craving and anxiety
relative to the pre-cue measures. Cue exposure also produced an increase in skin
conductance and decrease in skin temperature. The cue-induced increase in cocaine
craving was strongly enhanced by nicotine, while the increase in anxiety was
slightly augmented. Cue-induced skin conductance and temperature responses were
unaffected by nicotine. These findings show that cue-induced cocaine craving is
enhanced by nicotine. This occurred in the absence of any tobacco smoking-related
cues, suggesting that nicotine may have direct psychopharmacological effects on
conditioned cocaine craving.
PMID- 9543647
TI - A family history and direct interview study of the familial aggregation of
substance abuse: the adolescent substance abuse study.
AB - The adolescent substance abuse (ASA) study collected information concerning drug
use and psychopathology on male adolescent probands in treatment for substance
abuse and also on matched control adolescents, as well as all available family
members of both groups. Information was obtained through direct interview and the
family history method of assessment. Both methods revealed greater alcohol and
drug use, conduct disorder (CD) and antisocial personality disorder (ASP) in the
relatives of treatment probands as compared with control relatives. These results
suggest familial transmission, not only for alcohol abuse, but also for non
alcohol substance abuse. Familial transmission for CD and ASP is also evident for
both male and female relatives, although the prevalence of these disorders is
significantly greater in males than females.
PMID- 9543648
TI - Adolescent versus adult onset and the development of substance use disorders in
males.
AB - This study examines the influence of adolescent age of onset on the development
of substance use disorders (SUD) by comparing adult males (n = 181) with SUD
categorized into adolescent-onset, early-adult onset and late-adult onset groups
on patterns of substance use and related disorders, time course of the
development of substance dependence and rates of comorbid mental disorders. A
sample of male adolescents (n = 81) with SUD was also included as a comparison
group. The subjects were recruited from intervention programs in the community
and participated in semistructured interviews with diagnoses determined by the
best estimate method. Adolescent-onset adults, compared with other adult-onset
groups, had higher lifetime rates of cannabis and hallucinogen use disorders,
shorter times from first exposure to dependence, shorter times between the
development of their first and second dependence diagnoses and higher rates of
disruptive behavior disorders and major depression. Adolescents were similar to
adolescent-onset adults. While the findings must be interpreted in light of
methodological limitations, these results suggest that adolescent-onset SUD is a
distinct subtype involving different substances and more rapid development than
adult-onset SUD.
PMID- 9543649
TI - The relationship of pre-treatment Alcoholics Anonymous affiliation with problem
severity, social resources and treatment history.
AB - Little research has examined the relationship of substance abuse patients' prior
Alcoholics Anonymous (AA) affiliation to important treatment-related variables.
This study of 927 individuals seeking treatment in public, health maintenance
organization (HMO) and private-for-profit medical programs, found that 82.8% of
patients presented at treatment with a history of AA affiliation. Degree of prior
AA affiliation was significantly associated with more extensive prior utilization
of formal and informal helping resources, current seeking of treatment in the
public sector, having low income, being divorced/separated and having more severe
alcohol, employment/support and psychiatric problems. Implications for service
delivery and future research are discussed.
PMID- 9543650
TI - Pharmacotherapy of cerebral ischemia in cocaine dependence.
AB - This paper will examine how cerebral perfusion deficits in cocaine abusers may be
a target for pharmacotherapy. The review covers five areas: (1) cerebral ischemia
and neuropsychological impairment in cocaine abusers, (2) neuroimaging evidence
for cerebral perfusion defects in cocaine abusers, (3) mechanisms for cocaine
induced cerebral thrombosis, (4) neurotoxicity from cerebral ischemia and
excitatory amino acids, (5) glutamate antagonists as potential treatment agents
for cocaine induced neurotoxicity. Several pharmacotherapies are suggested
including antiplatelet agents and excitatory amino acid (EAA) antagonists such as
lamotrigine. Clinical trials in cocaine abusers with cerebral perfusion defects
are indicated and EAA antagonists hold promise as they are developed for stroke
treatment.
PMID- 9543651
TI - International traffic in coca through the early 20th century.
AB - This paper compiles records of coca exported by the major producing sites, Peru,
Bolivia, Java and Formosa, from the late 19th century through the first third of
the 20th century. During most of this era coca was legally produced and
responsive to market demands. World coca exports did not peak [corrected] until
around 1920, followed by a steady decline over the next decade. This export
pattern (if not the exact figures) suggests a period of rising cocaine
consumption, peaking regionally first in North America, then in Europe and other
parts of the world, followed [corrected] by a marked decrease in the drug's
popularity and acceptance.
PMID- 9543652
TI - Self detoxication by amphetamine dependent patients: a pilot study.
AB - Fifty current or past amphetamine dependent clients attending a Community Drug
and Alcohol Team service took part in structured interviews about their previous
attempts to stop using amphetamine. Thirty three had made a total of 47 attempts
at self detoxication; 15 had undergone enforced withdrawal and ten had previously
sought medical treatment. A total of 86% of subjects described significant
withdrawal symptoms on stopping use of amphetamines. Increased use of other drugs
was commonly reported as a means of coping with withdrawal, psycho-social
techniques being used less systematically. The implications for the provision of
attractive, effective treatments are discussed.
PMID- 9543653
TI - Reliability of drug dependents' self-reports.
PMID- 9543654
TI - Extending family therapy's horizons.
PMID- 9543655
TI - Toward a developmentally informed narrative therapy.
AB - Narrative approaches to psychotherapy emphasize the impact of the stories or
narratives we construct on our reality and behavior. However, little effort has
been made to elucidate how individuals' differential capacities for meaning
making influence the process of re-storying lives. The present article introduces
to family therapy a model of the changing nature of individuals' ability to
create meaning. The model, referred to as developmental-constructivism (Kegan,
1994), suggests that, in addition to contextual factors, individual differences
in the capacity for organizing experience will influence therapeutic efforts to
generate new and more adaptive narratives. The model is also presented as a
heuristic for comparing and integrating two influential approaches to narrative
therapy: the externalizing approach of Michael White and the solution-focused
approach of Steve de Shazer.
PMID- 9543656
TI - Hearing metaphor: an approach to working with family-generated metaphor.
AB - This article presents a step-by-step approach to working with family-generated
metaphor in family therapy. Although the use of therapist-generated "therapeutic
metaphors" has been widely advocated and practiced for many years now, less
attention has been paid to the metaphors used by family members. We argue that
the family's metaphors are a neglected linguistic resource in family therapy.
Highlighting and validating these metaphors produces a therapeutic conversation
in which the voices of family members are heard more clearly by the therapist,
and the families' own imaginative energies are engaged in defining and pursuing
the goals of therapy. Several case examples illustrate the use of this approach
with children of various ages.
PMID- 9543657
TI - Family functioning and mental illness: a comparison of psychiatric and
nonclinical families.
AB - The primary objective of the present investigation was to examine adaptive
functioning in the families of patients with a wide range of psychiatric
disorders. Seven dimensions of family functioning, as measured by the Family
Assessment Device (FAD), were compared across families of patients with a
schizophrenia spectrum disorder (n = 61), bipolar disorder (n = 60), major
depression (n = 111), anxiety disorder (n = 15), eating disorder (n = 26),
substance abuse disorder (n = 48), and adjustment disorder (n = 46). Families in
each psychiatric group were also compared to a control group of nonclinical
families (N = 353). Results indicated that regardless of specific diagnosis,
having a family member in an acute phase of a psychiatric illness was a risk
factor for poor family functioning compared to the functioning of control
families. However, with few exceptions, the type of the patient's psychiatric
illness did not predict significant differences in family functioning. Thus,
having a family member with a psychiatric illness is a general stressor for
families, and family interventions should be considered for most patients who
require a psychiatric hospitalization for either the onset of, or an acute
exacerbation of, any psychiatric disorder.
PMID- 9543658
TI - The Family Environment Scale: reliability and normative data for an adolescent
sample.
AB - The Family Environment Scale has been used extensively in family research since
first being published. However, despite its appeal both conceptually and
empirically, doubts have been raised over the scale's reliability. This article
presents normative and reliability data for the Family Environment Scale from a
large, combined sample of adolescents. Means and standard deviations were
generally found to be in line with those reported in the scale's manual; however,
estimates of internal consistency for most subscales could be considered
inadequate for research purposes.
PMID- 9543659
TI - Toward an African American genogram.
AB - This article addresses the inadequacy of the standard genogram for African
American families because of its underlying assumption that "family" is strictly
a biological entity. The author suggests that this assumption is not culturally
valid for African American families who have a long history of defining "family"
as a kinship based on biological and functional ties. Using this
conceptualization, an African American genogram is proposed.
PMID- 9543660
TI - Marital interactions of male versus female alcoholics.
AB - This study assessed the interactions of 131 alcoholic and nonalcoholic couples as
they engaged in discussions of personally relevant problems. For 50 couples, the
husband was alcoholic; for 15 couples, the wife was alcoholic; for 16 couples,
both spouses were alcoholics; and for 50 couples, neither spouse was alcoholic.
Observations were conducted during sessions when alcohol was consumed and in
nondrinking sessions. Female alcoholic couples (with nonalcoholic spouses)
demonstrated high negativity in the "no-drink" session, which was normalized in
the drink session, suggesting an adaptive function to alcohol use. Concordant
couples (both members were alcoholic) also demonstrated high negativity in the no
drink session, but exhibited increased negativity in the drink session,
suggesting that concordance has a maladaptive impact on marital interaction. All
alcoholic groups demonstrated greater negativity and lower positivity and
congeniality in their marital interactions compared to nonalcoholic couples.
Couples with male alcoholics were the least divergent from normal control
couples. Unique female patterns in alcoholism are discussed in terms of adaptive
and reinforcing patterns and spousal influences.
PMID- 9543661
TI - A prospective validation study of inclination, belief, and context predictors of
family-focused prevention involvement.
AB - Prior research by the authors tested a model of factors influencing parent
inclination to participate in parenting interventions. Family context, belief,
attitude, and inclination to participate variables from this model were used to
predict the actual participation of 1,121 families in assessment and intervention
activities of a family-focused preventive intervention research project.
Invitations to the project assessment and intervention components were,
respectively, about 6 months and 10 months following the initiation of a
telephone survey collecting predictor variable data. Logistic regression analyses
examining each predictor individually showed that a number of family context,
belief, attitude, and inclination variables were predictive of project
participation. Subsequently, multiple logistic regressions were conducted,
entering variables by blocks corresponding to theoretical model components. These
analyses showed that prospectively stated inclination to participate in a
parenting intervention and level of education were consistently significant
predictors of both assessment participation and intervention enrollment.
Implications for both research and practice are discussed.
PMID- 9543662
TI - Forbidden suffering: the Pollyanna syndrome of the disabled and their families.
AB - Has suffering become an ugly word in the normalization debate? Are the disabled
and their families forced into a Pollyanna culture in order to be acknowledged
and accepted in good company as the worthy disabled? This essay poses a
controversial question: I would like to start a debate and ask whether
normalization also has an unseen, ideological downside.
PMID- 9543663
TI - The meaning of disability and suffering: sociopolitical and ethical concerns.
PMID- 9543664
TI - Optimizing immunohistochemistry: antigen retrieval and signal amplification.
PMID- 9543665
TI - Intrathyroidal epithelial thymoma (ITET)/carcinoma showing thymus-like
differentiation (CASTLE) exhibits CD5 immunoreactivity: new evidence for thymic
differentiation.
AB - AIMS: Cases of intrathyroidal epithelial thymoma (ITET)/carcinoma showing thymus
like differentiation (CASTLE) were examined for CD5 immunoreactivity, a feature
of true thymic carcinoma, but not other thymic epithelial neoplasms or carcinomas
of other sites. ITET/CASTLE, a rare, low-grade malignant neoplasm arising within
the thyroid gland which resembles lymphoepithelioma-like and squamous cell
carcinoma of the thymus, is postulated to arise from remnants of branchial pouch
capable of thymic differentiation, but thymic differentiation in this neoplasm
remains unproven. METHODS AND RESULTS: The largest published series of cases of
ITET/CASTLE was examined for CD5 immunoreactivity using an anti-CD5 antibody
reactive in fixed, paraffin-embedded tissue with microwave antigen retrieval.
Neoplastic cells in all five cases of ITET/CASTLE studied were immunoreactive for
CD5, including foci of tumour metastatic to lymph node and lung. In contrast,
none of five cases of thyroid carcinoma with squamous differentiation was
immunoreactive for CD5. A minority of cases of typical thyroid carcinomas showed
some weak immunoreactivity for CD5. Other carcinomas of the head and neck were
nonimmunoreactive for CD5. CONCLUSIONS: CD5 immunoreactivity in ITET/CASTLE is
new evidence in support of thymic differentiation in this neoplasm.
PMID- 9543666
TI - Anaplastic large cell malignant lymphoma with extensive eosinophilic or
neutrophilic infiltration.
AB - AIMS: We describe the clinicopathological features of eight cases of Ki-1
positive anaplastic large cell malignant lymphoma (Ki-1 ALCL) in which there was
extensive infiltration by eosinophils and/or neutrophils in the absence of
necrosis. METHODS AND RESULTS: The patients comprised four males and four females
with an age range of 24-74 years. Five cases had originally been diagnosed as
Hodgkin's disease and one as true histiocytic lymphoma. In all cases, there was
massive infiltration by eosinophils and/or neutrophils sometimes to such an
extent that malignant cells were obscured. Immunohistochemical staining was
performed using the monoclonal antibodies CD30, CD15, CD45, CD20, CD3, CD45RO,
epithelial membrane antigen (EMA), CAM5.2, vimentin and CD68. In all cases,
tumour cells were strongly positive for CD30 but negative for CD15. One case was
positive for CD45 but none expressed B or T-cell markers. Five cases were
positive for vimentin and two for EMA. Three of seven patients in whom adequate
clinical details were available had stage III or IV disease at presentation and
four exhibited B symptoms. Four patients had a peripheral neutrophilia and one a
peripheral eosinophilia. CONCLUSIONS: The study shows that an eosinophil and/or
neutrophil-rich variant of Ki-1 ALCD exists, expanding the morphological spectrum
of this tumour.
PMID- 9543667
TI - Multiple polypoid lesions of primary mucosa-associated lymphoid-tissue lymphoma
of colon.
AB - AIMS: This study was focused on unusual cases of mucosa-associated lymphoid
tissue (MALT) lymphoma presenting with multiple polypoid lesions of the colon and
rectum with a special reference to the differential diagnosis of mantle cell
lymphoma. METHODS AND RESULTS: The lesions of these five cases grossly showed a
segmental distribution of nodular protrusions in three patients and of
innumerable small polyps in two. These patterns of involvement simulated those of
multiple lymphomatous polyposis, known as the gastrointestinal presentation of
mantle cell lymphoma (MCL), and caused a differential diagnostic problem between
MALT lymphoma and MCL, which have different prognostic and therapeutic
implications. Their histological features are almost indistinguishable from each
other, especially in the small biopsy specimens via endoscope. The most important
procedure for their differentiation is cyclin D1 immunohistochemistry and its
negative reaction provides strong indication of MALT lymphoma. Of interest, one
case showed a rare karyotypic abnormality of t(11;18)(q21;q21), which has been
reported specifically in MALT lymphoma. CONCLUSIONS: This study has indicated
that the multiple polypoid lesions of the colon occur not only in MCL, but also
in MALT lymphoma, making differential diagnosis between the two entities
necessary, and cyclin D1 immunohistochemistry is indispensable for distinguishing
between them.
PMID- 9543668
TI - Up-regulation of lysozyme production in colonic adenomas and adenocarcinomas.
AB - AIMS: The presence of lysozyme protein in some gastric adenomas and
adenocarcinomas has been well documented. There have been relatively few studies
investigating the presence of lysozyme in tumours of the large intestine and they
show contrasting results. We aim to investigate the cellular source and
expression of lysozyme in colonic adenomas and adenocarcinomas. METHODS AND
RESULTS: We randomly selected 29 and 27 colonic adenomas and adenocarcinomas,
respectively. Using in-situ hybridization (ISH) and immunohistochemistry (IHC),
we found an up-regulation of lysozyme in the dysplastic epithelium of all the
adenomas studied, with more than 80% of cases expressing moderate to strong
signals. Although the up-regulation of lysozyme was also observed in
adenocarcinomas, only 30% of the cases showed moderate to strong signals, mostly
with an uneven distribution. Down-regulation of lysozyme in the severely
dysplastic and invasive foci were noted in some cases of adenoma with malignant
transformation. Normal colonic glands were consistently negative for lysozyme at
both the mRNA and the protein level, but inflamed and immature regenerative
colonic epithelium at the crypt base showed positive signals in a similar pattern
to those observed in the dysplastic epithelium of the adenomas. CONCLUSIONS: Our
results confirm that colonic epithelium can produce lysozyme and its expression
is up-regulated in the dysplastic epithelium in adenomas and in invasive cancer
cells. It is interesting that regenerative colonic epithelium showed a similar
pattern of lysozyme expression as in adenomas. The loss of lysozyme secreting
phenotype in most of the invasive tumours suggests that lysozyme may not confer
an advantage to tumour progression.
PMID- 9543670
TI - Comparison of immunohistochemical staining of the novel antibody melan-A with
S100 protein and HMB-45 in malignant melanoma and melanoma variants.
AB - AIMS: The staining pattern of the recently described antibody melan-A was
compared with those of S100 protein and HMB-45 in a variety of melanocytic
lesions to assess the specificity and sensitivity of these antibodies. METHODS
AND RESULTS: Immunohistochemical staining of paraffin sections of a range of
melanocytic lesions was carried out following a high temperature antigen
retrieval technique. The pattern and intensity of staining was semiquantitatively
scored. S100 remains the most sensitive marker of melanocytic differentiation
being diffusely positive in all benign and all primary and secondary malignant
lesions including naevoid melanomas, and in most desmoplastic/spindle cell
melanomas. Of the two more specific melanocytic markers melan-A stains the
majority of benign and malignant lesions diffusely but with occasional patchy
positivity only in some secondary melanoma deposits and with little staining of
desmoplastic/spindle cell melanomas. HMB-45 is the least sensitive of the three
showing little positivity of benign mature naevus cells, only variable patchy
positivity of primary and secondary melanoma cells and limited positivity in
naevoid, desmoplastic and metastatic melanomas. CONCLUSIONS: Melan-A is a useful
addition to antibody panels as it is apparently specific for melanocytic lesions
and is more sensitive than HMB-45; however, it has less value than S100 in the
detection of spindle cell and desmoplastic melanomas.
PMID- 9543669
TI - Expression of vascular endothelial growth factor in digestive neuroendocrine
tumours.
AB - AIMS: Angiogenesis is a complex multistep process essential for tumour growth.
Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen
and vascular permeability-inducing agent. Recent studies have shown that VEGF
expression is correlated to microvessel density and tumour progression. The aim
of this study was to analyse VEGF expression in a series of gastrointestinal
neuroendocrine tumours. METHODS AND RESULTS: Surgical specimens from 28
gastrointestinal carcinoids and 20 pancreatic endocrine tumours were examined for
VEGF expression by immunohistochemistry. Intense cytoplasmic staining for VEGF
was observed in several cells of the islets of Langerhans and in neuroendocrine
cells of normal digestive mucosa. All midgut carcinoids showed strong VEGF
expression in tumoral cells. Positive VEGF immunostaining was observed in 16 of
20 neuroendocrine pancreatic tumours but it was usually much lower than in midgut
carcinoids. Western blotting analysis in eight cases identified a major band at
30-32 kDa. No correlation between VEGF expression and tumour stage was found.
CONCLUSIONS: This study demonstrates that neuroendocrine cells are a major source
of VEGF, particularly in midgut carcinoids. This finding suggests that the
presence of VEGF may be required to maintain the differentiated state of
capillary vessels in these hypervascular tumours. Such secretion, in conjunction
with the other growth factors synthesized by these neuroendocrine tumours, may
have an important role in tumour growth.
PMID- 9543671
TI - Spontaneous regression of hepatocellular carcinoma.
AB - AIMS: To determine the clinical and histopathological features of a case of a
spontaneous regression of hepatocellular carcinoma (HCC). CASE DETAILS: HCC was
found incidentally in a 73-year-old man during a laparotomy for evaluation of
gastric retention. Despite no treatment being given, he improved gradually with
no sign of tumour as evidenced by coeliac angiography 15 months later, as well as
by explorative laparotomy after another 2 years. The patient died 15 years after
the primary diagnosis of HCC, without known evidence of tumour recurrence. The
patient's clinical records were reviewed, and paraffin-embedded liver tissue was
re-evaluated. Both histological and immunohistochemical features were compatible
with the diagnosis of a well differentiated HCC. Conceivable causes of the
spontaneous regression of this and other reported cases are discussed, but the
phenomenon remains enigmatic. CONCLUSIONS: This case with a histologically proven
HCC and a very long follow-up time confirms that spontaneous regression does
occur. Since the case was found incidentally our report also implies that this
may not be as rare as reported.
PMID- 9543672
TI - Analysis of CD44 expression in serous and mucinous borderline tumours of the
ovary: comparison with cystadenomas and overt carcinomas.
AB - AIMS: To determine the diagnostic and prognostic value of the immunohistochemical
analysis of CD44 variants in benign borderline and malignant tumours of the
ovary. METHODS AND RESULTS: The reactivity of tumour cells with three monoclonal
antibodies, respectively, directed to all CD44 variants, CD44-v3 isoform and CD44
v6 isoform, was assessed by using an indirect immunoperoxidase technique applied
to formalin-fixed, paraffin-embedded samples of 36 cases of borderline, as
compared to 20 cases of benign tumours and 20 cases of carcinomas. CD44 variants
were detected in 97% of borderline tumours, as compared to 60% of benign tumours
and 100% of carcinomas. CD44-v3 was detected in 25% of borderline tumours, as
compared to 0% of benign tumours (P = 0.003) and 55% of carcinomas (P = 0.065).
The expression of CD44-v6 was detected in 28% of borderline tumours, as compared
to 20% of benign tumours and 30% of carcinomas. In borderline tumours, as in
carcinomas, CD44-v6, but not CD44-v3, expression was correlated with an increased
proliferative index and with a higher incidence of p53 expression. CONCLUSION:
Borderline tumours of the ovary present frequent quantitative and qualitative
alterations in the pattern of expression of CD44 proteins. However, these
alterations are unlikely to represent useful diagnostic or prognostic markers.
PMID- 9543673
TI - Dissecting leiomyoma of the uterus with extrauterine extension.
AB - AIMS: Familiarity with benign uterine smooth muscle tumours with unusual growth
patterns by gynaecologists and pathologists is essential in avoiding misdiagnosis
and overtreatment. CASE DETAILS: An enlarged uterus in a 35-year-old woman
contained numerous, ill-defined nodules with marked hydropic changes which showed
an extrauterine extension. Histologically, although some nodules had an
appearance of conventional leiomyoma, the predominant part of the lesion was
characterized by ill-defined spindle cell nodules with marked hydropic changes
and irregular dissection of the myometrium. The cellularity was variable from
area to area and there were neither nuclear atypia nor mitotic figures. No
coagulative tumour necrosis was observed. The extrauterine components, which were
in continuity with the intrauterine nodule, were histologically identical to the
intrauterine nodules except for the complication of endometriosis.
Immunohistochemically, the tumour cells were positive for vimentin, desmin, alpha
smooth muscle actin and muscle actin (HHF35). The tumour was DNA diploid by flow
cytometry. The patient was well and without disease 6 months after hysterectomy.
CONCLUSIONS: This tumour illustrates that rare benign smooth muscle tumours can
proliferate in dissecting and extrauterine growth patterns, findings that should
not be confused with malignant mesenchymal tumours.
PMID- 9543674
TI - Solid alveolar rhabdomyosarcoma of the thorax in a child.
AB - AIMS: This case illustrates the difficulties and pitfalls of diagnosis of
alveolar rhabdomyosarcoma in its solid variant and in an unusual primary
location, the mediastinum. CASE DETAILS: A 9-year-old boy presented with a
primary thoracic tumour associated with metastasis in the left sacroiliac joint.
Bronchial and mediastinal biopsies showed a malignant neoplasm with a solid sheet
like pattern of small round cells with a high nuclear to cytoplasmic ratio
associated with little or no fibrosis usually evocative of a peripheral
neuroectodermal tumour (PNET) at this age. Immunohistochemical positive staining
with vimentin (80% of tumour cells), desmin (20%) and titin (30%) antibodies was
suggestive of a rhabdomyosarcoma. In addition, all neural cell adhesion molecule
(NCAM) markers tested were positive as well as MIC2, a marker for the Ewing
family of sarcomas. There was no rhabdomyoid differentiation at ultrastructural
examination. Molecular analysis with RT-PCR amplification of RNA isolated from
the tumour demonstrated the presence of a PAX3/FKHR fusion transcript, product of
a t(2;13) reciprocal translocation, a genetic marker specific for alveolar
rhabdomyosarcoma. CONCLUSIONS: The diagnostic methodology of a small round cell
tumour of the child must now include immunohistochemical study and molecular
biology to confirm the diagnosis of alveolar rhabdomyosarcoma, in a solid and
undifferentiated variant.
PMID- 9543675
TI - Pathology of the spleen: report on the workshop of the VIIIth meeting of the
European Association for Haematopathology, Paris 1996.
PMID- 9543676
TI - Langerhans cell histiocytosis associated with papillary carcinoma of the thyroid.
PMID- 9543677
TI - Multinodular pleural involvement in aggressive systemic mast cell disease.
PMID- 9543678
TI - Ovarian atypical endometriosis.
PMID- 9543679
TI - Pilomatrixoma of the ovary: a rare variant of mature teratoma.
PMID- 9543680
TI - Prostate specific antigen and the salivary gland.
PMID- 9543682
TI - Pituitary corticotroph adenoma in a primary enlarged empty sella turcica.
PMID- 9543681
TI - Monophasic sarcomatoid carcinoma of the breast.
PMID- 9543685
TI - Metabolic and membrane-altering toxins, molecular differentiation factors, and
pheromones in the evolution and operation of endocrine-signalling systems.
AB - The endocrine systems of vertebrates and higher invertebrates may have evolved
functionally from as far back on the evolutionary scale as bacteria and early
multicellular organisms and their biological communities, which have been shown
to produce a variety of cyclic nucleotides, peptides, fatty acids, prostaglandins
and sterols with endocrine-altering effects in primative as well as more highly
evolved species.
PMID- 9543683
TI - Giant cell angiofibroma of the mediastinum.
PMID- 9543684
TI - Enhancement of apoptotic susceptibility in human endometrial epithelial cell line
HHUA by transforming growth factor-beta 1.
AB - Although reports have been published on the generation of transforming growth
factor-beta 1 (TGF-beta 1) and expression of TGF-beta receptors in human
endometrial tissues, the biological functions of endometrial TGF-beta 1 have
remained unclear. In this study, the effects of TGF-beta 1 on endometrial
apoptosis were examined by using an endometrial epithelial cell line HHUA which
is susceptible to Fas-mediated apoptosis. TGF-beta 1 alone did not affect the
cell growth of HHUA, but pretreatment of HHUA with TGF-beta 1 enhanced Fas
mediated growth suppression and DNA fragmentation of the cells. Flow cytometric
analyses showed that TGF-beta 1 did not affect Fas expression on the cell
surface. These findings lead to the conclusion that TGF-beta 1 enhances
susceptibility to Fas-mediated apoptosis in the endometrial epithelial cell.
Modulation of Fas-mediated endometrial apoptosis by TGF-beta 1 may thus be a
tissue-specific effect which is distinct from other TGF-beta 1 effects on Fas
mediated apoptosis in activated T-cells and rheumatoid synovial cells. The
biological functions of endometrial TGF-beta 1 and endometrial apoptosis are also
discussed.
PMID- 9543686
TI - Effect of insulin on intramuscular 3-hydroxybutyrate levels in diabetic rats.
AB - It has been shown that inhibition of lipolysis and ketogenesis by insulin is more
sensitive than suppression of hepatic glucose production and stimulation of
tissue glucose uptake. Clinically, on the other hand, blood glucose
concentrations fall much more quickly than blood ketone concentrations.
Therefore, during continuous insulin infusion at a rate of 3.0 mU/kg B.W./min
over a period of 150 min we monitored blood glucose and 3-hydroxybutyrate (3
OHBA) concentrations and muscle 3-OHBA levels using the microdialysis technique
in streptozotocin-induced diabetic rats. Blood glucose concentrations decreased
rapidly after insulin infusion. However, significant reduction in blood-3-OHBA
concentration was found for the last 30 min. In muscle dialysate 3-OHBA
concentrations and muscle local blood flow there was no significant change
throughout the study. These results suggest that one possible mechanism of
delayed improvement in ketonemia is a reduction in muscle removal capacity.
PMID- 9543687
TI - Type II diabetics with macrovascular complications: polymorphonuclear leukocyte
(PMN) filtration, PMN membrane fluidity and cytosolic Ca2+ content after
activation.
AB - We evaluated polymorphonuclear (PMN) filtration parameters, membrane fluidity and
cytosolic Ca2+ content in 21 normal subjects and in 18 type II diabetics with
macrovascular complications (MVC). Evaluations were carried out at baseline and
after in vitro activation prolonged for 5 and 15 min. PMA (4-phorbol 12-myristate
13-acetate) and fMLP (N-formyl-methionyl-leucyl-phenylalanine) were used as
stimulating agents. TMA-DPH (1-[4-(trimethylamino)phenyl]-6-phenyl-1,3,5
hexatriene) was used as fluorescent probe for the membrane fluidity tests and
Fura 2-AM for the cytosolic Ca2+ content. A significant variation was evident in
PMN filtration parameters at 5 and 15 min. No variation was present in PMN
membrane fluidity and cytosolic Ca2+ content in normals. In type II diabetics
with MVC, we found an increase solely in PMN cytosolic Ca2+ content after PMA
activation and an early decrease in PMN membrane fluidity and a late increase in
PMN cytosolic Ca2+ content after fMLP activation. After PMA activation alone (at
15 min), PMN filtration distinguishes normals from type II diabetics with MVC.
The PMN filtration parameters behave similarly in the two groups, but PMN
membrane fluidity and cytosolic Ca2+ content behave differently.
PMID- 9543688
TI - Ay-4166 increases the sensitivity of insulin secretion to glucose in isolated
perfused rat pancreas.
AB - To study the effect of a therapeutic dose (3 microM) of AY-4166 on the glucose
stimulated insulin secretion, the rat pancreas was perfused with 5 to 15 mM
glucose. AY-4166 did not affect the basal insulin secretion at 5 mM glucose, and
increased the first and second phases of insulin secretion stimulated by 7.5 to
15 mM glucose. The dose-response curve of the insulin secretion to glucose was
shifted to the left side by AY-4166. These results suggest that AY-4166 ist not a
stimulator releasing insulin independently of glucose concentrations, but a
potentiator of insulin secretion.
PMID- 9543689
TI - Fatty acids inhibit adrenocorticotropin-induced adrenal steroidogenesis.
AB - Unsaturated long chain fatty acids modulate hormone secretion from a variety of
endocrine glands, including the adrenal cortex. Oleic acid and linoleic acid have
been shown to stimulate production of glucocorticoids in the absence of
adrenocorticotropic hormone, but at a high concentration appeared to inhibit the
action of this hormone. In the present study, the concentration dependence of the
inhibitory actions of these two fatty acids was tested in collagenase-dispersed
rat adrenal fasciculata cells, and the effects of both lipids on cAMP production
were also determined. Adrenocorticotropic hormone stimulated steroid production
from isolated cells approximately ten-fold above unstimulated cells. Oleic and
linoleic acid significantly inhibited the response to this hormone by 44% and
54%, respectively. The half-maximally effective inhibitory concentration of both
lipids was between 75-100 microM. A maximal concentration of adrenocorticotropic
hormone increased cAMP secretion 138-fold above unstimulated cells. Oleic and
linoleic acids inhibited the increase in cAMP secretion by 47% and 33%,
respectively. It is concluded that pathophysiological concentrations of
unsaturated fatty acids inhibit the action of adrenocorticotropic hormone on the
adrenal gland, and that the mechanism of action of the lipids may be partly via
inhibition of cAMP production.
PMID- 9543690
TI - Ovariectomy fails to modify the cardiac myosin isoenzyme profile of adult rats.
AB - Estrogen has been shown to help maintain the elevated expression of the high
ATPase myosin isoform, V1, present in the hearts of young rats (< 70 days of
age). Because hearts of this age are still undergoing significant maturation, the
current study sought to determine if estrogen similarly regulates myosin
isoenzyme expression in the mature adult heart. To make this determination, ten
month old retired female Sprague-Dawley rats were made estrogen-deficient by
ovariectomy (OVAR, n = 8). Sham-operated (CONTR, n = 8) animals served as
controls. Nine weeks later, the animals were sacrificed and left ventricular
tissue collected. Crude myofibrills were isolated from these samples and
electrophoretically separated into the three isoenzymatic forms of cardiac myosin
(V1, V2, and V3). OVAR animals were larger than the CONTR group (p < 0.05), but
heart weight/body weight ratios were not different between groups. Distribution
of myosin among its three isoenzymes was similar between groups (CONTR: V1, 80%,
V2, 14%; V3, 6%; OVAR: V1, 77%, V2, 16%, V3, 7%). These data demonstrate that
myosin isoenzyme distribution in the adult heart is unaltered by ovariectomy,
suggesting that estrogen loses its ability to regulate expression of this protein
in the mature heart.
PMID- 9543691
TI - Parathyroid hormone activity increases during endotoxemia in conscious rats.
AB - Our previous studies showed that the phosphaturic effect of parathyroid hormone
(PTH) is blunted during acute-phase endotoxemia in anesthetized rats. However,
the possibility that the antiphosphaturia was secondary to hyponatriuresis due to
endotoxin (Et)-induced acute renal failure could not be ruled out. The objective
of this study was to evaluate phosphate (Pi) excretion during early- and late
phase endotoxemia in conscious rats fed by total parenteral nutrition. Male
Wistar rats weighing 270 g were used. Urine samples were taken to determine the
Pi excretion rate for 12 h just after Et (E. coli B055) challenge (early-phase
endotoxemia), and for 12 h after a 36-h recovery period following Et challenge
(late-phase endotoxemia). Rats given isovolumetric saline instead of Et served as
controls. Et injection reduced endogenous creatinine clearance markedly (0.88 +/-
0.12 ml/min, P < 0.0001, n = 7) and caused hyponatriuresis (0.80 +/- 0.19
microliters/min, P < 0.001) compared with saline injection (1.78 +/- 0.10 ml/min
and 3.12 +/- 0.39 microliters/min, respectively, n = 8) during the early phase.
Greater phosphaturia and hypocalciuria were observed simultaneously during early-
(Pi excretion = 4.18 +/- 1.38 micrograms/min, P < 0.05; calcium excretion = 0.70
+/- 0.14 micrograms/min, P < 0.05) and late-phase (4.76 +/- 1.72 micrograms/min,
P < 0.05; 0.60 +/- 0.18 micrograms/min, P < 0.05, respectively) endotoxemia (n =
8) in comparison with the respective control values (1.61 +/- 0.39 and 1.40 +/-
0.21 micrograms/min, early; 0.34 +/- 0.14 and 1.97 +/- 0.55 micrograms/min, late,
n = 6). Et adminidstration resulted in a significantly increased plasma PTH
concentration during the late phase (34.7 +/- 7.0 pg/ml, P < 0.05) compared with
saline administration (15.4 +/- 2.4 pg/ml). In conclusion, these data suggest
that the hyperphosphaturia during endotoxemia lasting longer than 12 h is
attributable to elevated PTH secretion.
PMID- 9543692
TI - Intravenous methylprednisolone pulse therapy in the treatment of Graves'
ophthalmopathy.
AB - Graves' ophthalmopathy (GO) is a specific immune-mediated disorder, whose
treatment is sometimes difficult. In order to investigate the efficacy of
intravenous methylprednisolone (MP) pulse therapy in GO, we studied eight
patients with GO, followed up for at least 6 months by clinical patient self
assessment, ophthalmological examination and orbital computed tomography (OCT). A
12.5 mg/kg dose of MP was administered intravenously over a 10 hour period, once
every month. Three to six MP pulse administrations were performed in each
patient. All patients were outpatients. A 0.5 mg/kg/day oral prednisone dose was
given to each patient as interpulse therapy. Clinical assessment of MP pulse
therapy showed a good response in 87.5% and no response in 12.5% of patients. The
treatment was rapidly efficient, mostly on patient self-assessment, soft tissue
inflammation, ophthalmoplegia, corneal involvement, visual acuity and extraocular
muscle enlargement on OCT. Post-treatment ophthalmic index was significantly
improved (6.75 +/- 3.06 vs. 2.5 +/- 1.41: p < 0.05). MP pulse therapy had less
effect on proptosis (22.94 +/- 2.32 mm vs. 21.56 +/- 2.22 mm: p < 0.05). No
adverse effects were noted with MP pulse therapy. Patients showed no relapse of
eye involvement during a mean follow up of 31.8 months (2-77 months). In
conclusion, our results suggest that intravenous MP pulse therapy is a good
immunosuppressive therapy for GO. Moreover, in comparison with the previous
studies, the MP dose used in our present study appears to be optimal with high
efficacy. MP pulse therapy represents a safe and efficient treatment in GO, which
can easily be performed in outpatients.
PMID- 9543693
TI - Intracellular magnesium depletion relates to increased urinary magnesium loss in
type I diabetes.
AB - We investigated whether erythrocyte magnesium (Mg) depletion exists in subjects
with Type I diabetes. To this end, Mg levels in plasma, erythrocytes and urine
were determined in 12 patients with Type I diabetes and compared with 12 healthy
control subjects. Mean plasma Mg concentrations were comparable between diabetic
patients and control subjects (0.90 +/- 0.29 mmol/l vs 1.04 +/- 0.14 mmol/l,
respectively; p = 0.16). Mean erythrocyte Mg concentration was significantly
lower in the diabetic group compared with the control group (1.41 +/- 0.56 mmol/l
vs. 2.94 +/- 1.13 mmol/l, respectively; p < 0.0001). Mean urine Mg excretion was
significantly elevated in the diabetic group with respect to the controls (6.86
+/- 3.5 mmol/g creatinine/24 h vs. 4.03 +/- 1.65 mmol/g creatinine/24 h,
respectively; p = 0.02). As to the diabetic group, erythrocyte Mg concentration
showed a significant inverse correlation with urine Mg excretion (r = -0.58, p =
0.049). There was no correlation between urine Mg concentration and glycosylated
hemoglobin or fasting plasma glucose level. The data suggest that intracellular
Mg depletion without significant hypomagnesemia is related to increased urinary
Mg loss in patients with Type I diabetes. The urinary Mg loss is not correlated
with the degree of metabolic control.
PMID- 9543694
TI - Circulating levels of 7 S domain of type IV collagen and atrial natriuretic
peptide in normotensive type 2 diabetic patients with or without retinopathy.
AB - Thickening of the basement membrane and other structural alterations of the
vascular walls occur frequently in patients with diabetes. The vascular response
to atrial natriuretic peptide (ANP) is also altered in these patients. Abnormal
vascular response in diabetes may be due to alteration of vascular
physicochemical properties induced by accumulation of components of vascular
basement membrane. The aim of this study was to evaluate the relationship between
circulating levels of the 7 S domain of type IV collagen (7 S-collagen), and ANP
in normotensive type 2 diabetic patients with or without retinopathy. Forty-one
normotensive type 2 diabetic patients (n = 19 with and n = 22 without
retinopathy) and 18 age-matched control subjects participated in the study. Serum
7 S-collagen and plasma ANP levels were measured by radioimmunoassays. Serum 7 S
collagen (4.4 +/- 0.1 vs 3.5 +/- 0.1 ng/ml; p < 0.01) levels and plasma ANP (20.8
+/- 1.0 vs 15.5 +/- 1.0 pg/ml; p < 0.01) were significantly higher in diabetic
patients than in normal subjects. Serum 7 S-collagen increased significantly in
diabetic patients without retinopathy compared with normal subjects (4.1 +/- 0.1
vs 3.5 +/- 0.1 ng/ml; p < 0.01). Diabetic patients with retinopathy showed
significantly higher circulating concentrations of 7 S-collagen (4.6 +/- 0.1 vs
4.1 +/- 0.1 ng/ml; p < 0.01) and ANP (22.9 +/- 1.4 vs 18.9 +/- 1.3 pg/ml; p <
0.05) than those without retinopathy. There was a significant and positive
correlation (r = 0.51, p < 0.01) between the circulating levels of 7 S-collagen
and ANP in all patients. The results of this investigation showed that increased
circulating levels of ANP correlate with the abnormal metabolism of the vascular
basement membrane observed in diabetic patients with microangiopathy.
PMID- 9543695
TI - In most poorly controlled glyburide-treated type 2 diabetic patients drug
withdrawal causes further increase in glycemia not accompanied by changes in
insulin secretion.
AB - To find out whether the secondary failure of glyburide in type 2 diabetes is
complete or partial, we studied 38 patients, age (M +/- SD) 69 +/- 9 years,
suffering from diabetes from 13.5 +/- 8.4 years and treated with glyburide for 5
13 years, with poor glycemic control (glycohemoglobin 10.6 +/- 2.6%). Serum
glucose, insulin and C-peptide were assayed before and 1 h and 2 h after a
simulated meal load (355 Cal), after which the drug was replaced with placebo for
4 weeks, and the test repeated. After glyburide withdrawal, fasting glycemia
increased from 10.3 +/- 3.3 to 15.1 +/- 4.4 mmol/L (p < 0.001), but in 3/38
patients, it even decreased and in five others the changes were less than +/- 2
mmol/L. These changes negatively but only weakly correlated with initial
glycemia: r = 0.4123, p < 0.010. The mean post-meal glycemia at 1 h and 2 h
increased respectively by 3.3 and 5.9 mmol/L (both p < 0.001). Neither the levels
of glycemia nor its changes after the glyburide withdrawal correlated with the
levels of, or changes in, insulin or C-peptide. We conclude that in most but not
all type-2 diabetic patients, poorly controlled with glyburide, the drug still
retains some limited therapeutic effectiveness, and therefore its withdrawal
causes further deterioration of control with the almost equal increases in
fasting and post-meal levels of glycemia. These changes are not accompanied by
decrease in insulin secretion.
PMID- 9543696
TI - Soluble (s) CD14 and plasmatic lipopolysaccharides (LPS) in patients with chronic
hepatitis C before and after treatment with interferon (IFN)-alpha.
AB - CDI4 is a monocyte/polymorphonuclear cell receptor for lipopolysaccharide (LPS)
LPS Binding Protein (LBP), which mediates most of the toxic effects exerted by
such a bacterial component in the host. Here, we provide evidence that sCD14 and
interferon (IFN)-gamma serum levels are significantly higher in chronic hepatitis
C (CH-C) patients than those detected in normal donors. On the other hand,
CD4+/CD8+ antibacterial activity is depressed, thus facilitating entry of
bacteria into the host. Of note, all these immune parameters are not modified by
in vivo IFN-alpha administration over a period of one year. Finally, after 12
months of IFN-alpha treatment number of CH-C patients with detectable levels of
plasmatic LPS increased, thus indicating a continuous release of LPS into the
host and also suggesting a putative pathogenetic role for sCD14 LPS-LBP complex
in subjects affected by CH-C virus infection.
PMID- 9543698
TI - Enhancing and priming of macrophages for superoxide anion production by taxol.
AB - Taxol, an anticancer drug, has been known not only to block cell division by
stabilizing microtubules but also to activate murine macrophages to express TNF
alpha, interleukin-1, and to produce nitric oxide (NO). We therefore reasoned
that taxol could activate murine macrophages to generate reactive oxygen
intermediates, such as superoxide anion (O2-), which are responsible for
intracellular killing of pathogenic microbes. Treatment of RAW264.7 cells, murine
macrophage cell line, with taxol increased phorbol ester-induced O2- production
in a dose dependent manner (approximately 2 fold). In addition, taxol rapidly (<
1 hr) primed RAW264.7 cells to enhance O2- release stimulated with PMA. Taxol
also enhanced stimulation of O2- production by FMLP, but not by Con A. This
effect was abolished by prior treatment with both superoxide dismutase (SOD) and
N-acetyl-L-cystein, a free radical scavenger. To investigate the mechanism of
taxol-induced macrophage stimulation, we evaluated the ability of colchicine, a
drug that inhibit tubulin polymerization, and cAMP analogues, which is known to
depolymerize microtubule. Taxol-induced O2- production was inhibited by the
treatment with both colchicine and DB-cAMP. Taken together, these results
demonstrated that taxol provides two signals, "priming" and "enhancing", to
generate superoxide anion via the stabilization of microtubules in murine
RAW264.7 cells
PMID- 9543697
TI - Tumor regression of advanced carcinomas following intra- and/or peri-tumoral
inoculation with VRCTC-310 in humans: preliminary report of two cases.
AB - The authors report their clinical experience with VRCTC-310 in two patients
suffering with advanced cancer in which the skin was severely compromised. VRCTC
310 is a combination of the snake venoms crotoxin (CT) and cardiotoxin (CD). The
local (peritumoral) treatment with the drug (0.O14 mg/kg/week during 6 weeks)
provoked the complete disappearance of a relapsed skin squamous cell cancer in
one patient. The other patient was an aged woman with local-advanced breast
cancer (carcinoma en cuirasse) who was inoculated intra-and-peritumoral with
VRCTC-310. After 6 weekly courses (0.014 mg/kg/week) with the drug a > 80% tumor
reduction was seen. A 133 days follow-up demonstrated not only an objective
complete response of the primary tumor mass, but the disappearance of
supraclavicular tumor mass as well a significant reduction in lymphangitis. To
our knowledge, this is the first communication about the in vivo antitumoral
activity of VRCTC-310 when injected locally to humans. Further studies are now in
progress.
PMID- 9543699
TI - Effect of propranolol and IFN-beta on the induction of MHC class II expression
and cytokine production by IFN-gamma IN THP-1 human monocytic cells.
AB - This study was undertaken to investigate the effects of propranolol, IFN-beta,
and the protein kinase modulators on IFN-gamma induction of MHC class II antigen
expression and cytokine production in THP-1 human monocytic cells. IFN-gamma
induced expression of HLA-DR and DQ molecules and secretion of the monokines IL-1
beta and TNF-alpha in THP-1 cells in a time and dose-dependent manner. The effect
of INF-gamma on class II HLA antigens was dose-dependently inhibited by IFN-beta.
H-7, phloretin, staurosporine as well as GF 109203X are selective enzyme
inhibitors of protein kinase C (PKC), down-regulating IFN-gamma induced MHC class
II expression and cytokine production. Stimulators of PKC, like PMA, replaced IFN
gamma in the induction of monokines in THP-1 cells, whereas the addition of HA
1004 or arachidonic acid to the culture had no effect on IFN-gamma mediated
changes. Blocking of phospholipase D (PLD)-derived diacylglycerol (DAG) formation
by propranolol abrogated IFN-gamma increased HLA class II expression and IL-1
beta secretion, but had little effect on IFN-gamma induced TNF-alpha production.
These findings appear to suggest that PLD-derived phosphatidate is not the
primary source of DAG production in IFN-gamma-induced TNF-alpha secretion, but
may be necessary for IFN-gamma-mediated MHC class II induction and IL-1 beta
production in human monocytes, whereas phospholipase A2 may not be required for
IFN-gamma activation of PKC in the process.
PMID- 9543700
TI - Effects of 2-chlorodeoxyadenosine and gold sodium thiomalate on human bcl-2 gene
expression.
AB - Aberrant expression of apoptosis-related genes, including the "cell death
suppressor gene" bcl-2, may play an important pathogenetic role in cancer and
autoimmune diseases, In vivo upregulation of bcl-2 mRNA in synovial lining cells
of patients with rheumatoid arthritis but not in patients with osteoarthritis has
been recently found. In the present study we investigated whether agents exerting
beneficial effects in patients with rheumatoid arthritis, namely the long used
Gold Sodium Thiomalate (GST) and the novel immunosuppressive, purine analogue 2
chlorodeoxyadenosine (2-CdA), a lymphocyte apoptosis-inducing agent interfere
directly with induction of bcl-2 mRNA expression. The phytohemagglutinin (PHA)
induced in vitro proliferation of normal human peripheral blood lymphocytes was
significantly inhibited by non-toxic concentrations of 2-CdA and GST which are
within the range of in vivo plasma concentrations in patients receiving the
respective treatment. Using mRNA dot-blot analysis and hybridization with an IL-2
specific probe we found that GST, similarly to dexamethasone that served as
control, suppressed the PHA-induced IL-2 mRNA accumulation dose-dependently. In
contrast, 2-CdA (0.1 microgram/ml) at concentrations that inhibit by 80-90% the
PHA-induced proliferative responses of lymphocytes did not affect IL-2 mRNA
accumulation. Hybridization with a bcl-2-specific probe showed that the
activation-induced accumulation and kinetics of bcl-2 mRNA were not changed in
the presence of a wide range of concentrations of either GST or 2-CdA. Similarly,
the mRNA accumulation of the "house-keeping" control gene beta-action remained
unchanged by both agents. These findings indicate that biosynthesis of bcl-2 is
not specifically affected by GST and CdA, suggesting that the immunomodulating
effects of these agents, including their efficacy in suppressing chronic
arthritis, are not related with a bcl-2-dependent mechanism.
PMID- 9543701
TI - Effect of macrophage colony-stimulating factor (M-CSF) on mouse immune responses
in vivo.
AB - We examined the effects of recombinant human M-CSF (rhM-CSF) on mouse macrophages
and immune responses in vivo. Intraperitoneal administration of rhM-CSF (20-500
microgram/ml) increased Mac-1+ cell numbers in the peritoneal cavity. The
tumoricidal activities of the macrophages from vehicle-administered (V-M phi) and
from rhM-CSF-administered (M-M phi) mice were the same as those observed in
vitro. However, when activated by lipopolysaccharide (LPS), the tumoricidal
activity of M-M phi was stronger than that of V-M phi. Intravenous administration
of rhM-CSF (500 micrograms/gk) increased the number of spleen cells. Flow
cytometric analysis showed that administration of rhM-CSF increased Mac-1+, B220+
and NK 1.1+ cell counts in the spleen. However, CD4+ and CD8+ cell numbers did
not change. Concomitant increases were observed in levels of IL-4 and IL-10 in
mouse serum following rhM-CSF administration, but no significant changes were
observed in the serum level of IFN-gamma. In experiments involving mouse immune
responses, the administration of rhM-CSF reduced the contact sensitivity (CS)
reaction against picryl chloride (PC) and augmented IgE production in response to
2,4-dinitrophenyl (DNP), but did not affect the production of either IgM or IgC1.
These results suggest that administration of rhM-CSF not only activates murine
macrophages, but modulates antigen-specific immune responses in vivo.
PMID- 9543702
TI - Hydrogen peroxide modulation of the superoxide anion production by stimulated
neutrophils.
AB - Hydrogen peroxide (H2O2) pretreatment of human neutrophils results in a
suppression of the superoxide anion (O2) production in response to surface-acting
stimulants such as lipopolysaccharide (LPS) and opsonized zymosan. This effect
was not observed when phorbol myristate acetate (PMA), formyl-methionyl-leucyl
phenylalanine (fMLP) or tumor necrosis factor alpha (TNF alpha) were used as a
stimuli. Since the response to PMA and other stimuli was unimpaired by
preincubation with H2O2, we assume that the H2O2 modulated O2 production is
probably due to alteration of the LPS receptor conformation rather than effecting
directly NADPH-oxidase. The balance of reactive oxygen species (ROS) produced by
neutrophils in the state of sepsis may thus be autoregulated by negative feedback
phenomena of locally produced H202.
PMID- 9543703
TI - Immunostimulatory activity of Milife, a novel immunomodulator of fungus origin.
AB - Milife is a novel immunomodulator derived from the fungus Fusarium Sambucium. In
this study we examined immunomodulatory properties of Milife in 10 months-old
BLRB mice. Milife was given to mice orally in a daily dose of 1 mg per mouse, for
2 to 6 days. Groups of mice were sacrificed on days 2, 4, and 6 of treatment, and
3 weeks after completion of a 6 days treatment with Milife, and lymphoid organs
were obtained for analysis. Milife administration led to rapid and significant
increase in total leukocyte and lymphocyte numbers in peripheral blood that
persisted for at least 3 weeks after a 6 days treatment. Cellularity of lymph
nodes, bone marrow and thymus increased significantly at days 4 and 6 of
treatment, but returned to pretreatment levels after Milife discontinuation.
Though total splenocyte numbers did not change dramatically, there occurred
delayed increase in CD4+ cells in the spleen 3 weeks following treatment.
Preferential accumulation of CD4+ cells was also consistently found in peripheral
blood, with the peak being observed at day 6 of treatment. As a result, CD4/CD8
ratio in blood and spleen was significantly higher in treated than in untreated
mice. Splenocytes from treated mice proliferated more vigorously in response to
Con A. When added in vitro, Milife also mildly costimulated Con A-induced
proliferation of splenocytes from intact animals. In conclusion, we have found
that Milife can stimulate leuko- and lymphopoesis in BLRB mice, in particular,
accumulation of CD4+ T cells in peripheral lymphoid organs. We conclude that
Milife may represent an immunomodulator with the potential to correct T cell
dysfunction in patients with immunodeficiency.
PMID- 9543704
TI - Solanum lyratum inhibits anaphylactic reaction and suppresses the expression of L
histidine decarboxylase mRNA.
AB - We investigated the effect of aqueous extract of Soloanum lyratum THUNB.
(Solanaceae) (SLAE) on anaphylactic reaction. The mast cell is widely thought to
contribute to the acute changes associated with anaphylaxis. SLAE inhibited skin
mast cells-mediated anaphylactic reaction activated by anti-dinitrophenyl (DNP)
IgE. SLAE dose-dependently inhibited histamine release in mouse peritoneal mast
cells activated by anti-DNP IgE or substance P. Substance P increased steady
state levels of L-histidine decarboxylase (HDC) mRNA in mouse mastocytoma P-815
cells. Northern-blot analysis demonstrated that significantly reduced level of
the mRNA of HDC was expressed in mast cells treated with SLAE, compared to that
without SLAE. We conclude that SLAE directly affect IgE-mediated anaphylactic
reaction and substance P-induced HDC mRNA over-expression.
PMID- 9543705
TI - Evaluation of nitric oxide production by Leishmania infantum-infected dog
macrophages.
AB - Protozoa of the genus Leishmania (L.) infect reticuloendothelial cells of several
mammalian species, including dogs, in which they often give rise to a chronic,
not self-healing visceral disease. Since the parasitocidal mechanism of
macrophages towards Leishmania in dog has not yet been well investigated, in this
work we have evaluated in Leishmania infantum-infected macrophage cultures from
10 healthy dogs, killing capacity and nitric oxide (NO) production, in terms of
nitrite (NO2) levels. Parallel experiments were performed on macrophages
stimulated with both Concanavalin A (ConA)-activated PBMC supernatants and
Salmonella typhimurium lipopolysaccharide (LPS), and in the same conditions, but
in the presence of the NO synthase inhibitor L-N monomethylarginine (L-NMMA). In
L. infantum-infected macrophages, nitric oxide production was observed at a
concentration significantly higher after stimulation with both Con A-activated
PBMC supernatants and LPS than that observed in uninfected cells cultured in
medium alone, or infected cells unstimulated or stimulated by PBMC supernatants
or LPS alone, respectively. Moreover, NO production was abolished in the presence
of the NO synthase inhibitor L-NMMA. Finally, killing of Leishmania by
macrophages was significantly reduced in the presence of L-NMMA.
PMID- 9543706
TI - Effect of streptolysin-O-on rat hepatic acetyl coenzyme-A: arylamine N
acetyltransferase and cytochrome P-450 2B 1/2 activities ex vivo.
AB - Numerous immunostimulants have been found to increase N-acetylation in vivo but
are not associated with a similar increase in vitro. Streptolysin-O (SLO), a
thiol-activated (oxygen-labile) hemolytic and immune-stimulating exotoxin
produced by group A streptococci, has been reported to increase the metabolic
rate constant for sulfamethazine in vivo and arylamine N-acetyltransferase (NAT)
activity toward procainamide (PA) ex vivo. The effect of SLO pretreatment of rats
on cytochrome P-450-catalyzed tolbutamide hydroxylation and NAT activities toward
PA (a substrate for NAT1), and p-aminobenzoic acid (a substrate for NAT2) was
examined ex vivo. Subacute SLO (SIGMA Chemical Company, St. Louis, MO)
pretreatment (100 Hemolytic Units/kg/day, intraperitoneal, for 4 days) did not
alter body weight, liver weight or cytosolic protein content as compared with
controls. SLO-pretreatment did not alter NAT activities measured ex vivo, nor was
an alteration in tolbutamide hydroxylation observed. Pretreatment with an
alternative SLO preparation (DIFCO Laboratories, Detroit, MI) also failed to
alter the parameters of body weight, liver weight or cytosolic protein content as
compared with controls. While treated animals had significantly reduced
microsomal protein content, SLO pretreatment failed to alter the enzyme
activities measured. We conclude that SLO does not serve as a useful model
immunostimulant for mechanistic studies as it produces no consistent effect on
drug metabolizing enzymes.
PMID- 9543707
TI - Dietary quercetin, immune functions and colonic carcinogenesis in rats.
AB - Rats fed 100 mg/kg quercetin (QUE) daily for 7 weeks had significantly enhanced
natural killer cell activity compared to their vehicle (VEH)-fed control. In
contrast, rats fed 100 mg/kg QUE and treated with the colon carcinogen,
azoxymethane had significantly reduced natural killer cell activity compared to
their VEH-fed azoxymethane-treated control. There was no significant difference
in natural killer cell activity between the two control groups. Antibody
production and delayed-type hypersensitivity were not altered by QUE feeding in
any treatment group. In vitro exposure of splenic natural killer cells to 1mM QUE
significantly decreased natural killer cell cytotoxicity. Lower QUE
concentrations produced a non-significant reduction in natural killer cell
activity that was restored to control values at 1 x 10(-13)M QUE. The
distribution, multiplicity and total number of colonic preneoplastic lesions,
aberrant crypt foci, was not significantly different in the QUE-fed azoxymethane
treated rats when compared to azoxymethane-treated vehicle-fed rats at the
conclusion of 7 week feeding period. We found no correlation between immune
function and development of preneoplastic colon lesions in this study.
PMID- 9543708
TI - Therapeutic efficacy of Ashwagandha against experimental aspergillosis in mice.
AB - Therapeutic efficacy of an Indian Ayurvedic medicinal preparation, Ashwagandha
[Withania somnifera L. Dunal (Solanceae; root)] was evaluated against
experimental aspergillosis in Balb/c mice. Ashwagandha given orally once daily
for 7 consecutive days in a dose of 100 mg/kg after intravenous infection of
Aspergillus fumigatus prolonged the survival period of infected mice. This
protective activity was probably related to the observed increases in
phagocytosis and intracellular killing of peritoneal macrophages induced by
Ashwaganda treatment. The number of peripheral leukocytes was not modified,
excluding a possibility of mobilization of cells from other compartments. On the
basis of these findings, the probable mechanism underlying the protective action
of Ashwagandha against systemic Aspergillus infection was discussed in relation
with its possible activity to activate the macrophage function.
PMID- 9543709
TI - Purification and characterization of a male-specific protein in the hemolymph of
the wax moth, Galleria mellonella L.
AB - A male-specific protein (MSP) present only in males was identified from the
hemolymph of the wax moth, Galleria mellonella L., by polyacrylamide gel
electrophoresis (PAGE) and purified by anion-exchange chromatography. MSP has a
native molecular mass of 55 kDa and consists of two 27-kDa subunits. An
isoelectric point of MSP was measured to be approximately 5.8. MSP is a
glycoprotein that contains 1.7% carbohydrate. The compositional analysis of
carbohydrate component indicated a predominance of fructose and glucose. MSP also
contains large amounts of asparagine, aspartic acid, glutamine, glutamic acid,
and lysine but small amounts of tyrosine, methionine, and tryptophan. Western
blot analysis of the hemolymph of each developmental stage indicated that MSP is
present in the hemolymph of 8-day-old pupa and adult. Also, results from Western
blotting indicated that MSP is not present in the tissues of larvae and of female
adults but appears in the fat body of male pupae and adult and testis of adult.
The fat body and testis of male pupae and adult were cultured in vitro to trace
the place and time of MSP synthesis. The fat body began to synthesize MSP in late
pupae and showed active synthesis during the adult stage. The distribution of MSP
in the testis was observed by electron microscopic immunogold labeling, using the
antibody against MSP. MSP is present between the germinal cysts and is taken up
through the basal surface of the seminiferous tubular epithelium.
PMID- 9543710
TI - Localization of allatostatin-immunoreactive material in the central nervous
system, stomatogastric nervous system, and gut of the cockroach Blattella
germanica.
AB - Immunoreactivity against peptides of the allatostatin family having a typical
YXFGL-NH2 C-terminus has been localized in different areas of the central nervous
system, stomatogastric nervous system and gut of the cockroach Blattella
germanica. In the protocerebrum, the most characteristic immunoreactive perikarya
are situated in the lateral and median neurosecretory cell groups. Immunoreactive
median neurosecretory cells send their axons around the circumesophageal
connectives to form arborizations in the anterior neuropil of the tritocerebrum.
A group of cells in the lateral aspect of the tritocerebrum project to the
antennal lobes in the deutocerebrum, where immunoreactive arborizations can be
seen in the periphery of individual glomeruli. Nerve terminals were shown in the
corpora allata. These terminals come from perikarya situated in the lateral
neurosecretory cells in the pars lateralis and in the subesophageal ganglion.
Immunoreactive axons from median neurosecretory cells and from cells positioned
in the anteriormost part of the tritocerebrum enter together in the
stomatogastric nervous system and innervate foregut and midgut, especially the
crop and the valve between the crop and the midgut. The hindgut is innervated by
neurons whose perikarya are located in the last abdominal ganglion. Besides
immunoreactivity in neurons, allatostatin-immunoreactive material is present in
endocrine cells distributed within the whole midgut epithelium. Possible
functions for these peptides according to their localization are discussed.
PMID- 9543712
TI - Binding of heterocyclic amines by lactic acid bacteria from miso, a fermented
Japanese food.
AB - Miso, a widely used Japanese fermented food was analysed for its lactic acid
bacterial count on bromocresol purple agar. The binding of eight different
foodborne carcinogenic heterocyclic amines to 25 bacterial isolates from miso
were investigated. The heterocyclic amines used were 3-amino-1,4
dimethyl[5H]pyrido(4,3-b)indole (Trp-P-1), 3-amino-1-methyl[5H]pyrido(4,3
b)indole (Trp-P-2), 2-amino-6-methyldipyrido(1,2-a:3'2'-d)imidazole (Glu-P-1), 2
amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP), 2-amino
dimethylimidazo(4,5f)quinoline (IQ), 2-amino-3,4-dimethylimidazo(4,5-f) quinoline
(MeIQ), 2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline (MeIQx), and 2-amino-3
methyl-9H-pyrido(2,3)indole (MeA alpha C). The lyophilized cells of all of the
isolates exhibited high binding activity towards Trp-P-1, Trp-P-2, MeA alpha C,
and PhIP, while Glu-P-1 and IQ were not effectively bound. Of the isolates
tested, the strongest and weakest binders were identified as Pediococcus
acidilactici 1 and 2, respectively. Lyophilized cell wall fractions, heat-treated
cells, and the cytoplasmic contents of P. acidilactici 1 and 2 were analysed for
their ability to bind to different mutagens. Pure cell wall and peptidoglycan
showed greater binding activity than the bacterial cells. Cytoplasmic content
also showed some binding, but it was much less effective. The impact of enzymes
(amylase, protease, cellulase, chitinase, muraminase, and peptidase) and
acetylation of Trp-P-1 and IQ on the binding action of bacteria and cell wall
material were also analysed to understand the possible processes involved in the
binding of lactic acid bacteria to carcinogenic heterocyclic amines.
PMID- 9543716
TI - Molecular characterization of Gluconobacter oxydans recA gene and its inhibitory
effect on the function of the host wild-type recA gene.
AB - A DNA fragment containing the recA gene of Gluconobacter oxydans was isolated and
further characterized for its nucleotide sequence and ability to functionally
complement various recA mutations. When expressed in an Escherichia coli recA
host, the G. oxydans recA protein could efficiently function in homologous
recombination and DNA damage repair. The recA gene's nucleotide sequence analysis
revealed a protein of 344 amino acids with a molecular mass of 38 kDa. We
observed an E. coli-like LexA repressor-binding site in the G. oxydans recA gene
promoter region, suggesting that a LexA-like mediated response system may exist
in G. oxydans. The expression of G. oxydans recA in E. coli RR1, a recA+ strain,
surprisingly caused a remarkable reduction of the host wild-type recA gene
function, whereas the expression of both Serratia marcescens recA and Pseudomonas
aeruginosa recA gene caused only a slight inhibitory effect on function of the
host wild-type recA gene product. Compared with the E. coli RecA protein, the
identity of the amino acid sequence of G. oxydans RecA protein is much lower than
those RecA proteins of both S. marcescens and Pseudomonas aeruginosa. This result
suggests that the expression of another wild-type RecA could interfere with host
wild-type recA gene's function, and the extent of such an interference is
possibly correlated to the identity of the amino acid sequence between the two
classes of RecA protein.
PMID- 9543717
TI - Protease activity of Clostridium difficile strains.
AB - The production of proteolytic enzymes by 10 Clostridium difficile isolates of
varying toxigenicity and clinical origin was studied to determine if all isolates
secreted proteases. Different protease substrates were studied: gelatin,
collagen, phenylazobenzyloxycarbonyl-leucyl-glycyl-L-prolyl-D-arginine (Pz
peptide), casein, azocasein, and azocoll. All isolates degraded gelatin,
collagen, and azocoll. The supernatants of all isolates contained an enzyme
capable of attacking gelatin incorporated in a polyacrylamide gel (zymograms) and
forming two closely spaced lytic bands with an estimated molecular mass of 35-40
kDa. Polyclonal antibodies, produced against the C. difficile gelatinase,
revealed in Western blots a 35-kDa protein in the culture supernatants of all C.
difficile isolates. In the same manner, Clostridium perfringens collagenase
polyclonal antibodies detected a 120-kDa protein in the culture supernatants of
all isolates; this suggests that at least two proteases may exist in C.
difficile. The protease activities of the 10 strains examined did not seem
strikingly different quantitatively but were in general weak and their role in
pathogenicity is suspect.
PMID- 9543711
TI - Juvenile hormone acid: evidence for a hormonal function in induction of
vitellogenin in larvae of Manduca sexta.
AB - In the tobacco hornworm (Manduca sexta), vitellogenin (Vg), the major yolk
protein precursor, and its mRNA are first detectable in the prepupal stage; and
production of both can be enhanced by methoprene, a juvenile hormone (JH) analog.
Competence to respond to methoprene is acquired after ecdysteroid-initiated
commitment for metamorphosis. Here we show that acquisition of competence
requires prior exposure to JH-II acid in addition to ecdysteroid. Application of
20-hydroxyecdysone or RH5992, an ecdysteroid analog, to isolated abdomens from
feeding larvae (precommitment) results in exposure of the dorsal vessel (EDV), a
sign of metamorphic commitment--but such abdomens do not make Vg in response to
methoprene. However, injection of JH-II acid along with 20-hydroxyecdysone into
isolated abdomens causes Vg production in response to methoprene. Methoprene acid
similarly induces competence to respond to methoprene. Northern blot analysis
confirmed that Vg transcripts are present in fat body only if isolated abdomens
were pretreated with both ecdysteroid, and JH-II acid or methoprene acid. The
latter two can induce competence even in precocious prepupae resulting from
removal of the corpora allata (the glands that produce JH) from early penultimate
larvae. JH-III acid and related metabolites such as farnesol, farnesoic acid, and
methyl farnesoate do not induce competence. Hitherto, JH acids have been regarded
as precursors or catabolites of JHs. Here we show for the first time that JH acid
has a hormonal function that cannot be performed by JH itself.
PMID- 9543719
TI - Comparative genome analysis of Bacillus sphaericus by ribotyping, M13
hybridization, and M13 polymerase chain reaction fingerprinting.
AB - A comparative genome analysis of 15 strains representing the five homology groups
of the highly heterogeneous species Bacillus sphaericus was performed by M13
hybridization fingerprinting, M13 polymerase chain reaction fingerprinting, and
ribotyping with the whole rrn operon. The computer cluster analyses of the
polymorphic patterns, presented in dendrograms, showed that these methods allow
the differentiation of the individual strains and some homology groups. Our
results confirm the close genetic relatedness of the mosquito pathogenic strains
of group IIA and support the idea for differentiation of a separate species. At
the same time, we present additional proof of the significant genetic
heterogeneity of B. sphaericus and the necessity of reconsideration of its
present classification.
PMID- 9543720
TI - Multidrug- and metal-resistant strains of Klebsiella pneumoniae isolated from
Penaeus monodon of the coastal waters of deltaic Sundarban.
AB - Marine shrimp of the species Penaeus monodon were collected from the coastal
region (Haroa) of the deltaic Sundarbans of West Bengal, India during the
premonsoon period in 1996. Klebsiella pneumoniae was isolated from the alimentary
canal and gills of the shrimp as the sole isolate. All 10 isolated strains were
resistant to erythromycin (30 micrograms/mL), ampicillin (100 micrograms/mL),
furazolidone (100 micrograms/mL), and penicillin (100 IU). These strains were
able to grow in the presence of silver (Ag+), cobalt (Co2+), cadmium (Cd2+),
nickel (Ni2+), lead (Pb2+), copper (Cu2+), and zinc (Zn2+) at concentrations up
to 10 mM. All the strains showed similar plasmid profiles, ranging in sizes from
1.8 to 120 kb. Resistance to lead, cobalt, nickel, and copper was encoded by a
3.5-kb plasmid of K. pneumoniae. Synthesis of a 14-kDa periplasmic protein was
increased when they were grown in presence of 10 mM Cu2+.
PMID- 9543721
TI - Potentiation of the virucidal activity of sterilized natural waters.
AB - After heat, conductivity has been described as the second most inactivating
factor of viruses in surface waters. Using poliovirus-1, we showed that a highly
significant linear relationship between virus inactivation rate and water
conductivity can be obtained for most of the tested sterilized water samples.
Using sterile saline solutions, we demonstrated that this apparent relationship
is false, i.e., virus inactivation rate is not affected by water conductivity
alone. With the hypothesis that salts may serve to potentiate the antiviral
activities of certain microbiological substances that are supposed to be found in
the tested samples, we can explain the apparent relationship observed in this
study and in similar ones. As a consequence, an effective water treatment could
be responsible for the removal of both viruses and some virus-inactivating
factors. Alternatively, virus-inactivating capability of a given water resource
could be enhanced along with its hardness or its degree of mineralization.
PMID- 9543722
TI - Pentatomic cyclic antagonists and muscarinic receptors: a 30-year review.
AB - This work is a sequel to and completes the review, that recently appeared in this
journal, of pentatomic cyclic muscarinic agonists. It reports the results of
structure-activity relationship (SAR) studies of pentatomic cyclic antagonists on
muscarinic receptors and compares these results with some recent advances in
molecular biology and quantitative structure-activity relationship (QSAR)
studies.
PMID- 9543723
TI - Synthesis and anti-ulcer activity of new derivatives of glycyrrhetic, oleanolic
and ursolic acids.
AB - A review is made of the literature describing the structural changes to
glycyrrhetic, oleanolic and ursolic acids and their influence on anti-ulcer
activity. For the glycyrrhetic acid derivatives some analogues were prepared in
which the ketonic group in position 11 was removed and the carboxylic function at
position 30 was either intact, reduced to alcohol or transformed into ketone.
This first series of compounds suggests the possibility of obtaining compounds
devoid of the conjugated ketonic group, maintaining anti-ulcer activity but with
reduced or lacking mineralocorticoid activity. Based on these findings, a series
of carbenoxolone analogues in the beta-amyrin series of glycyrrhetic and
oleanolic acid was prepared. In particular, the delta 9,11 unsaturated compounds
14b and 23b and the 11-methylene derivative 18 present advantages in terms of
acute toxicity and mineralocorticoid activity as compared to the reference
compound. The derivative 14b in the volunteer showed an increase of gastric PGE2
levels with minor pseudoaldosteronic effect. Among the ursolic acid derivatives,
the dihemisuccinate sodium salt 35b demonstrated a good separation between anti
ulcer and mineralocorticoid activities. Nevertheless, kidney and liver toxicity
was observed in the monkey thus jeopardizing its further development. Better
results were obtained with the uvaol dihemiphthalate sodium salt and the diene
analogue 39b. In particular, 38b and 39b showed a potent anti-ulcer activity, 3-
to 25-fold higher than carbenoxolone. Furthermore, compound 38b does not show
signs of liver toxicity in the monkey.
PMID- 9543724
TI - Glycosidopyrroles. Part 1. Acyclic derivatives: 1-(2-hydroxyethoxy)methylpyrroles
as potential anti-viral agents.
AB - Acyclic glycosidopyrroles of type 1, synthesized in good overall yields, were
evaluated for anti-viral activity. Compound 10i was found to inhibit the HIV-1
replication at concentrations that were very close to those cytotoxic for MT-4
cells. Compounds 10a,f,i inhibited both strains HSV-1 and HSV-2 at concentrations
slightly below those cytotoxic for Vero cells. However for this series of
glycosidopyrroles some relationship between calculated log P values and the
observed cytotoxicity was found.
PMID- 9543725
TI - Stereoisomeric effect on antimicrobial activity of a series of quaternary
ammonium salts.
AB - Two homologous series of diastereoisomeric racemic +/- cis and +/- trans-N,N
dimethyl-N-alkyl-2-benzoyloxycyclohexylmethylammonium bromides with the number of
carbon atoms in the alkyl chain from six to twenty (m = 6,8 ... 20) were
synthesised. Their structures have been elucidated by IR, UV and in some cases
also with 1H and 13C NMR spectrometry. The title compounds were assayed for their
antimicrobial activity on microorganisms S. aureus, E. coli and C. albicans. The
highest antimicrobial activity was observed against S. aureus (log 1/MIC = 5.5
mol-1 dm3) and the lowest against E. coli (log 1/MIC = 4.5 mol-1 dm3). The +/-
cis and +/- trans stereoisomers of all eight couples of diastereoisomeric
compounds show differences in their physico-chemical characteristics (including
partition coefficient and lipophilicity) which is also reflected in the different
antimicrobial activity of these diastereoisomers.
PMID- 9543726
TI - Diastereomeric separation of 1,5-benzodiazepines due to the presence of a chiral
centre on the N-5 alkylic chain.
AB - The presence of a chain bearing a stereogenic centre at the N-5 position of 1-(1
adamantylmethyl)-3-arylureido-2,4-dioxo-1,5-benzodiazep ines induces optical
resolution. The synthesis of these compounds and their potency as potential CCK-B
receptor antagonists is discussed briefly here.
PMID- 9543727
TI - Further studies on analgesic activity of cyclic imides.
AB - As part of our research programme to obtain pharmacologically active compounds
structurally related to cyclic imides, we have synthesized different compounds
and examined their analgesic activities using the abdominal constriction test in
mice. The results showed that some of the compounds studied, given
intraperitoneally, exhibited graded and significant analgesia against acetic acid
induced abdominal constriction, being several times more potent than aspirin and
paracetamol, two standard drugs used for comparison.
PMID- 9543728
TI - Synthesis and in vitro and in vivo evaluation of dopaminergic ergoline
derivatives.
AB - A series of ergoline-amides was synthesised in the discovery of new
dopaminomimetic agents. Several compounds exhibited in vivo high prolactin
lowering activity (indirectly measured by the nidation test) in rats. For the
most active, the potential anti-Parkinson activity was evaluated by observation
of the contralateral turning behaviour in 6-OH-DA lesioned rats. The acute
toxicity by oral route in mice was also studied.
PMID- 9543729
TI - Anti-nociceptive and anti-inflammatory activity of some (2-benzoxazolone-3-yl and
2-benzothiazolone-3-yl)acetic acid derivatives.
AB - Sixteen (2-benzothiazolone-3-yl and 2-benzoxazolone-3-yl) acetic acid derivatives
5 have been tested for anti-nociceptive and anti-inflammatory activity in this
study, 4-[2-(6-Benzoyl-2-benzoxazolone-3-yl)acetyl]morpholine (5c), 4-?2-[6-(2
chloro-benzoyl)-2-benzoxazolone-3-yl]acetyl?morpholine (5d), 1-[2-(5-chloro-2
benzoxazolone-3-yl)acetyl]pyrrolidine (5f), methyl (6-methyl-2-benzoxazolone-3
yl)acetate (5k) and N,N-diethyl-2-(2-benzothiazolone-3-yl)acetamide (5m) have
shown more potent anti-nociceptive activity than others. Among these compounds,
5c, 5d and 5m have exhibited good anti-inflammatory activity, with 5f, and to a
lesser extent, the other molecules displaying some toxic potential.
PMID- 9543730
TI - Antioxidant activity of some ascorbic and cinnamic acids derivatives.
AB - Some 4-benzoyl 3-hydroxy furan-2 (5H) ones (3a-d) and 2-amino 3-hydroxymethyl 4
aryl 4-oxo 2-butenoic acids (4a-h) have been synthesized. Compound 3c with an
isobutyl substituent in the 5-position of the furan ring was the most effective
(IC50 = 8.69 x 10(-4) M) in scavenging the superoxide anion. In vivo, 3c was also
protective against reperfusion injury.
PMID- 9543731
TI - Fatal attack among wedge-capped capuchins.
PMID- 9543732
TI - Indiscriminate response to infant calls in wild patas monkeys (Erythrocebus
patas).
PMID- 9543733
TI - Adoption and social interactions between a mother and 'twin' offspring in Macaca
fuscata.
PMID- 9543734
TI - [Chronic fatigue--'tired with 23 i's'].
AB - Two patients, a woman aged 32 years and a man aged 49, presented with severe
chronic fatigue. The woman had chronic fatigue syndrome; she recovered slowly.
The man suffered from a pituitary adenoma producing follicle stimulating hormone;
he recovered after transsphenoidal hypophysectomy. In patients with chronic
fatigue, the history and a thorough physical examination to exclude underlying
illness are very important; secondary symptom criteria must not be overemphasized
(as is the case with the Holmes and Fukuda criteria), chronic fatigue syndrome
should not be diagnosed if the condition has a shorter duration than 6 months,
but it should be diagnosed if the clinical picture is compatible. The prognosis
is not poor: in patients with a median disease duration of 4.5 years, 20% show
significant improvement over an 18-month period.
PMID- 9543735
TI - [Chronic fatigue syndrome].
AB - Chronic fatigue syndrome is a controversial disease entity. Opinions range from
non-disease via psychiatric disorder to a somatic disturbance. Somatic
pathogenetic hypotheses include persisting infections, intoxications, metabolic
or immunologic disturbances, nervous system diseases and endocrine pathology.
None of these hypotheses has been substantiated as yet. Psychological factors are
important in the course of the disorder and can be used in the therapeutic
approach of patients with chronic fatigue syndrome.
PMID- 9543736
TI - [Attributions and chronic fatigue].
AB - It was recently suggested that chronic fatigue is merely a question of
attribution. Attribution clearly contributes to the course of chronic fatigue
syndrome (CFS) but is not its sole determinant. The presence of strong somatic
attributions appears to be one of the perpetuating factors in CFS but not the
only one. Many CFS patients present a self-diagnosis, e.g. myalgic
encephalomyelitis. Communication problems between patient and doctor easily arise
because of different attributions of the complaints. At the start of fatigue
somatic attributions are of less importance than later on in the course of the
complaints. In this process an iatrogenic factor might be involved. On the other
hand doctors are able to influence these attributions actively in a favourable
direction.
PMID- 9543737
TI - [Chronic fatigue syndrome in young persons].
AB - The prevalence of chronic fatigue syndrome (CFS) in teenagers is 10-20 per
100,000 inhabitants in the Netherlands. The natural course of the disorder is not
favourable according to the literature. Proposed criteria for the diagnosis 'CFS'
in adolescence are: absence of a physical explanation for the complaints, a
disabling fatigue for at least six months and prolonged school absenteeism or
severe motor and social disabilities. Exclusion criterion should be a psychiatric
disorder. Factors that attribute to the persistence of fatigue are somatic
attributions, illness enhancing cognitions and behaviour of parents as well as
physical inactivity. The role of the physician and the role of parents can
enhance the problems. The treatment should focus on decreasing the somatic
attributions, on reinforcement by the parents of healthy adolescent behaviour, on
the gradual increase of physical activity and on decreasing attention (including
medical attention) for the somatic complaints.
PMID- 9543738
TI - [Indications for management in long-term, physically unexplained fatigue
symptoms].
AB - In meetings arranged by the minister of Public Health, Welfare and Sports between
general practitioners and specialists concerning chronic fatigue syndrome (CFS),
suggestions for the diagnosis, treatment and assistance and support of patients
with protracted physically unexplained fatigue symptoms, were established in the
light of current scientific insight. The term 'CFS' is applicable in cases of
fatigue complaints, of at least 6 months' standing, reported by the patient
himself and evaluated medically, for which no physical explanation has been found
and which cause considerable disabilities in professional social and/or personal
functioning. The management depends on the duration of the illness. A distinction
is made between an acute phase (up to one month after the first consultation; the
policy is mostly expectative), a subacute phase (until 6 months after the onset
of the complaints and disabilities; the management is aimed at making the patient
accept the condition and persuading him or her to make an effort to promote
health) and a chronic phase (from 6 months after the onset of the complaints and
disabilities; the management is aimed at health-promoting behaviour and
cognitions). Further (laboratory) examinations are useful only if the symptoms
have not disappeared after one month (this is the case in approximately 20% of
the patients); such examinations may be useful in older patients earlier. It is
important that the CFS patient learns to realize that it is useless to continue
to spend energy on searching for causes and possible therapies, but that he
should try to promote his own health, for instance by means of a quantified
programme of activities linked to a time schedule (instead of to a level of
fatigue).
PMID- 9543739
TI - [Prevalence of chronic fatigue syndrome and primary fibromyalgia syndrome in The
Netherlands].
AB - OBJECTIVE: To determine the prevalence of chronic fatigue syndrome (CFS) and of
primary fibromyalgia syndrome (PFS) in the Netherlands. DESIGN: Questionnaire.
SETTING: Department of Medical Psychology, University Hospital Nijmegen, the
Netherlands. METHOD: A questionnaire was mailed to all the 6657 general
practitioners in the Netherlands in order to inform them of the existence of CFS
and to ask them if they had any CFS or PFS patients in their practices. RESULTS:
Sixty percent (n = 4027) of the general practitioners returned the questionnaire.
Of all the general practitioners, 27% said they had no CFS patients, 23% said
they had 1 CFS patient, while 21% had 2 CFS patients, and 29% said they had 3 or
more CFS patients in their practice. Concerning PFS the results were 17% (no PFS
patients), 18%, 18% and 47%, respectively. With a mean practice of 2486 patients
per general practice, the estimated prevalence of CFS was 112 per 100,000 and
that of PFS 157 per 100,000 persons. Of the CFS patients 81% were women and 55%
were 25-44 years old; for PFS these figures were 87% and 48% respectively.
CONCLUSION: Extrapolation of the study results indicates that there are at least
17,000 CFS patients and 24,000 PFS patients in the Netherlands. The found
prevalence is probably an under-estimation.
PMID- 9543740
TI - [Prevalence of chronic fatigue syndrome in 4 family practices in Leiden].
AB - OBJECTIVE: To determine the prevalence of chronic fatigue syndrome (CFS) in
general practice. DESIGN: Descriptive. SETTING: General practice and primary
health care centres in Leyden region, the Netherlands. METHOD: RNUH-LEO is a
computerized database which contains the anonymous patient information of one
general practice (with two practitioners) and four primary health care centres.
The fourteen participating general practitioners were asked what International
Classification of Primary Care (ICPC) code they used to indicate a patient with
chronic fatigue or with CFS. With these codes and with the code for depression
patients were selected from the database. It then was determined whether these
patients met the criteria of CFS by Holmes et al. RESULTS: The general
practitioners used 10 codes. Including the code for depression a total of 601
patients were preselected from a total of 23,000 patients in the database. Based
on the information from the patients' records in the database, 42 of the
preselected patients were selected who might fulfill the Holmes' criteria of CFS.
According to the patients' own general practitioner, 25 of the 42 patients would
fulfil the Holmes' criteria. The men:women ratio was 1:5. The prevalence of CFS
in the population surveyed was estimated to be at least 1.1 per 1,000 patients.
PMID- 9543741
TI - ['Abbreviated fatigue questionnaire': a practical tool in the classification of
fatigue].
AB - The 'Shortened fatigue questionnaire' (SFQ) is a short, reliable and easily used
instrument to determine the intensity of the patient's bodily fatigue. It
consists of four questions which the patient answers by checking an item at a 7
point scale ('I feel tired', 'I tire easily', 'I feel fit' and 'I feel physically
exhausted'). The physician can then calculate a total score and compare it with
the score in standard groups (standardized by load-bearing). The questionnaire
can be completed simply and quickly. It constitutes a valuable addition in daily
medical practice and in clinical scientific studies for the assessment of fatigue
complaints.
PMID- 9543743
TI - [Synopsis of the revised standard 'stomach symptoms' of the Nederlands Huisartsen
Genootschap].
PMID- 9543744
TI - [Temperature measurement in adults: equally good results using the tympanic
membrane thermometer and the rectal digital thermometer in the Internal Medicine
department].
PMID- 9543745
TI - [Acetylcysteine in children with lung disorders prescribed by one third of family
physicians; no support in the literature].
PMID- 9543746
TI - [Peritoneal pseudomyxoma].
PMID- 9543747
TI - [Medical and administrative disregard of a high blood sugar value; notes on a
decision by the medical disciplinary tribunal].
PMID- 9543748
TI - [Allogeneic bone marrow transplantation of unrelated donors; fewer complication,
more donors].
AB - A female patient aged 37 years who suffered from chronic myeloid leukemia
received an allogeneic bone marrow transplantation (BMT) from an HLA-matched
unrelated donor. No life-threatening complications ensued; 2.5 years after BMT
she is still in complete remission. Survival after BMT from an unrelated donor
for the time being is still lower than that after BMT from a related donor, but
is improving due to better prevention and treatment of opportunistic infections
and better selection of registered donors by meticulous HLA matching.
PMID- 9543749
TI - [Hospital Infection Epidemiology Nederland (ZIEN): from club to study group].
AB - Medical care is increasingly a technical business, and hospitalised patients are
more and more susceptible to infections, notably due to the application of
aggressive therapies for all kinds of disorders. As a consequence the
epidemiology of hospital infections requires serious attention. Following the
initiative of some medical microbiologists in the Netherlands, a study group was
established to tackle this epidemiology and to initiate relevant research
(Working party on Hospital Infections and Epidemiology of the Netherlands; WHEN).
Recent subjects include fungemia in hospitalised patients, risk factors for
acquiring methicillin-resistant Staphylococcus aureus during a stay abroad, and
prevalence of vancomycin-resistant enterococci.
PMID- 9543750
TI - [Contact allergy for corticosteroids].
AB - Contact allergy to corticosteroids is not rare. In some studies prevalence rates
up to 6% have been observed among patients suspected of allergic contact
dermatitis. Hypersensitivity occurs especially in individuals who have been
suffering for years from atopic dermatitis, contact dermatitis of the hands and
feet, or stasis dermatitis caused by chronic venous insufficiency. The clinical
picture is rarely that of acute allergic contact dermatitis, because the reaction
is mitigated by the anti-inflammatory properties of the corticosteroid itself;
the diagnosis must be suspected when eczema does not improve or spreads during
topical corticosteroid therapy. Application to the mucous membranes less
frequently leads to sensitisation. Most such cases are caused by nasal sprays
containing tixocortol pivalate or budesonide. Oral or parenteral administration
of corticosteroids to sensitive individuals causes exacerbation of pre-existing
contact dermatitis or widespread allergic cutaneous drug reactions.
Allergological investigation with corticosteroids presents some specific
problems, the most important being occurrence of false-negative reactions.
Nevertheless, most sensitive patients can be identified by testing the
'indicator' allergens, budesonide and tixocortol pivalate, which should be added
to the routine series of contact allergens. Cross-reactions to other
corticosteroids occur frequently. This should be taken into account when
prescribing alternative corticosteroid preparations.
PMID- 9543751
TI - [More than 10 years of revision-cleaning and revision-reconstructive ear surgery
in chronic otitis media; good long-term results].
AB - OBJECTIVE: To describe the long-term results of revision surgery in patients with
chronic otitis media. SETTING: University Hospital, Utrecht, the Netherlands.
METHODS: A personal series of 323 revision mastoidectomies and (or) revision
tympanoplasties was evaluated. Surgery was performed between 1981-1995 with a
follow-up of one (minimal) to 14 years (maximal). Anatomical and functional
results of various subgroups were compared. RESULTS: A preoperative incidence of
cholesteatoma of 34% (n = 99) dropped after revision surgery to 11%
residual/recurrent cholesteatomas (n = 9). A dry, safe and disease-free ear with
a closed tympanic membrane was obtained in nearly 90% of the cases. However, in
5% (n = 10) without pre-existent cholesteatoma (n = 199), a cholesteatoma
developed de novo after revision surgery. A residual air-bone hearing gap < or =
30 dB resulted in 79% of the patients after revision tympanoplasty only (n = 27).
Revision mastoidectomy with revision tympanoplasty in open (n = 91) and closed (n
= 92) procedures lead to a residual air-bone gap < or = 30 dB in 56% of the open
cases (n = 91) and in 73% of the closed cases (before the operation the figures
were 37% and 55% respectively). CONCLUSION: Revision mastoid surgery and (or)
revision tympanoplasty can be quite rewarding and successful.
PMID- 9543752
TI - [Sore throat in rheumatoid arthritis: 2 patients with cricoarytenoid arthritis].
AB - In two patients with chronic rheumatoid arthritis, a woman aged 65 and a man aged
56 years, cricoarytenoid arthritis was diagnosed. The symptoms were hoarseness,
sore throat and stridor. In both patients a narrowed glottic fissure was found.
In one patient tracheostomy was necessary to guarantee a free airway; in the
other, therapy with local corticosteroid injections (triamcinolone), combined
with immunosuppressive therapy (prednisone), was effective. Early detection
through anamnesis and laryngoscopy allows early therapy with a good prognosis.
PMID- 9543753
TI - [Infection with T-lymphotropic virus in Dutch blood donors, 1993-1996].
AB - Infection with human T-lymphotrophic virus (HTLV) type 1 causes a neurological
disorder or leukaemia in a minority of infected persons. Since January 1993 the
Dutch blood banks screen each donation for presence of HTLV-1 infection.
Approximately 4,000,000 donations from 700,000 donors have been tested. The
numbers of confirmed HTLV-1 positive donors were: 1993: 15; 1994: 6; 1995: 8;
1996: 3. In 1995 one case of HTLV-2 infection was detected as well. In 26/32
(81%) of the HTLV-1 positive cases either the donor or his/her partner originated
from HTLV-1 endemic areas. The introduction of HTLV screening prevents the silent
spread of HTLV via blood transfusion.
PMID- 9543754
TI - [Communication between treating physician and occupational physician in the
management of absenteeism].
AB - In case of an employee's absenteeism, both the treating physician and the company
doctor possess relevant medical information. With a view to reducing absenteeism,
exchange of data is considered important. Provision of data requires the consent
of the patient/employee. If the latter is informed of the purpose for which the
data are requested and of how they will be used, medical professional secrecy is
not violated. In order to enhance the exchange of data between treating physician
and company doctor, without bypassing the requirement of consent or cancelling
the division between treatment and checking, the treating physician should be
permitted to provide more information than just the data asked for in specific
questions. This however requires the development of guidelines for careful
consultation.
PMID- 9543755
TI - [In which childbirth should endocarditis prophylaxis be given?].
PMID- 9543756
TI - [Peer review in request for subsidy].
PMID- 9543757
TI - [Pleural mesothelioma in family practice; complicated pain problems].
PMID- 9543758
TI - [Pleural mesothelioma in family practice; complicated pain problems].
PMID- 9543759
TI - [Plastic surgery as a last resort in lichen sclerosus].
PMID- 9543760
TI - [Hypertension in the acute phase of brain infarct; generally do not treat].
PMID- 9543761
TI - [Low birth weight and risk of heart and vascular diseases].
PMID- 9543762
TI - [Increasing incidence of mesothelioma in the future due to occupational exposure
to asbestos in the past].
PMID- 9543763
TI - [Neurological presentation of non-Hodgkin lymphoma: a diagnostic problem].
AB - In two patients, men aged 69 and 38 years, neurological signs were the first
presenting symptoms of systemic non-Hodgkin's lymphoma (NHL). This presentation
is uncommon. The patients had focal neurological deficit and elevated serum
lactate dehydrogenase (LDH) activity. Neurological manifestations of NHL may be
caused by extradural lymphoma or by diffuse leptomeningeal metastasis (meningitis
lymphomatosa). A third patient, a woman of 48, had a third form of nervous system
involvement, primary cerebral NHL, which is not a metastatic sequel to systemic
NHL. Primary neurological presentation of NHL may be difficult to diagnose,
particularly in case of prior treatment with corticosteroids.
PMID- 9543764
TI - [Anglo-Saxon guidelines for the treatment of community-acquired pneumonia
applicable in The Netherlands as well].
AB - There are three Anglo-Saxon guidelines for the management of patients with a
community-acquired pneumonia: an American, a British and a Canadian one. The
guidelines correspond fairly well. There is a subdivision into categories
according to whether the patients are treated at home (formerly healthy patients
younger than 60 years versus patients with pre-existent disease or aged 60 years
and more) or in the hospital (patients not needing intensive care versus those
who do need it). For each category the most common causative micro-organisms are
listed together with recommended antibiotic treatment. The Canadian guidelines
have nursing home patients as a separate category because of slightly different
causative organisms due to frequent microaspiration. The guidelines are
applicable to the situation in the Netherlands, with a few exceptions: antibiotic
resistance is not a major problem in the Netherlands (as yet), and contrary to
what the guidelines state an agent with activity against Pseudomonas aeruginosa
is not necessary; the same agents as in category III can be prescribed in these
patients. A macrolide or azalide antibiotic is advisable for intensive care
patients in view of the possibility of infection with Legionella pneumophila or
Mycoplasma pneumoniae.
PMID- 9543765
TI - [Current lymphoma classification: a step forward for pathologists and
clinicians].
AB - Non-Hodgkin lymphomas encompass a heterogeneous group of lymphoid malignancies
from the clinical as well as from the pathological point of view. Consequently,
one condition of optimal communication among pathologists, clinicians and
scientific researchers is an adequate classification system. A new classification
of lymphomas was proposed in September 1994, the Revised European-American
Lymphoma Classification (REAL classification). The REAL classification is aiming
at integration of pathological and clinical data, making it possible to
distinguish clinical-pathological entities each of which has its characteristic
pathological spectrum, clinical evolution and clinical presentation. The REAL
classification is based not only on morphological and immunohistochemical but
also on molecular and cytogenetic data. Such a system may make it possible to
develop specific therapies for specific pathological entities. The REAL
classification constitutes an important step forward in haemato-oncology.
PMID- 9543767
TI - [Acute tumor lysis syndrome due to mono-therapy with a corticosteroid in a
patient with non-Hodgkin lymphoma].
AB - A 20-year-old man was hospitalised because he nearly suffocated when lying on his
back. After bronchoscopy which revealed severe external compression of the
airways, suddenly respiratory insufficiency developed. Because a malignant
lymphoma was suspected chemotherapy was started, using monotherapy with
prednisolone as the risk of acute tumour lysis syndrome (ATLS) is high with
polychemotherapy of bulky tumours. Nevertheless ATLS developed, for which
haemodialysis had to be applied. The tumour, a T-cell lymphoblastic non-Hodgkin
lymphoma with high grade malignancy, was treated successfully with
cyclophosphamide, doxorubicin, vincristine en prednisone. ATLS is characterized
by hyperkalaemia, hyperuricaemia, hyperphosphataemia, hypocalcaemia, lactate
acidosis and acute renal failure. It can occur in the course of aggressive
cytoreductive therapy in rapidly growing lymphoproliferative malignancies with
large tumour size, due to massive tumour cel lysis. Corticosteroid monotherapy is
a very rare cause of ATLS.
PMID- 9543768
TI - [A special case of 'deafness'; Landau-Kleffner syndrome].
AB - A boy aged 5 had displayed from the age of 3 a fluctuating deficit in
understanding spoken language. Audiometric testing proved his hearing to be
normal. After 18 months, the parents noticed minor attacks of 'absence'. An EEG
showed a normal background pattern and frequent spikes and spike waves complexes;
CT-scanning of the brain revealed no abnormalities. On the basis of the acquired
language disorder, the seizures and the features of the nocturnal EEG, the
diagnosis the syndrome of Landau-Kleffner was made. After treatment with
ethosuximide a temporary improvement of the aphasia occurred. A permanent
improvement however was realized by treatment with prednisone. The boy could
attend a primary school. The syndrome runs a fluctuating course; the patient may
recover, but he may also undergo general mental deterioration. Antiepileptic
agents only may have a brief favorable effect on the aphasia. In case of failure
corticosteroids or even subpial cortical transsection are indicated.
PMID- 9543769
TI - [Dexamethasone in a non-registered ointment from the Far East].
AB - The Oriental cream Piyan Ping 999 has been used in the Netherlands as an
unlicensed product. Chemical analysis revealed the presence of dexamethasone and
dexamethasone-21-acetate in pharmacologically relevant concentrations. It was
prescribed for 2 children; the 3-year-old girl had meanwhile developed bruises
and small, poorly healing wounds.
PMID- 9543770
TI - [Comparison of regional formularies for family physicians].
PMID- 9543771
TI - [Comparison of regional formularies for family physicians. Formulariumcommissie
Formularium Midden-Nederland].
PMID- 9543772
TI - [Diabetes mellitus in connection with a hereditary disorder].
PMID- 9543773
TI - [Pregnancy following oocyte donation].
AB - Five women, aged 31, 26, 31, 34, and 28 years, became pregnant after oocyte
donation and in-vitro fertilization. One was a carrier of Leber's optical
atrophy, three had had an early menopause (in two because of chromosomal
abnormalities), and one had had bilateral ovarian extirpation because of a
cystadenoma and endometriosis. Three developed (pre-)eclampsia during pregnancy
and one had a serious fluxus post partum. One twin died in utero, the other
children were healthy. In the Netherlands in-vitro fertilization (with or without
egg-donation) takes place up to the age of about 40. Regarding the high incidence
of obstetrical complications in women under 40, raising the age limit could lead
to even more pregnancy problems. Candidates for oocyte donation should be
informed about these risks, furthermore they should not deliver at home.
PMID- 9543774
TI - [Mood disorders in daily practice; the North American consensus statement on the
undertreatment of depression].
AB - The American National Depressive and Manic-Depressive Association consensus
statement on the undertreatment of depression may have consequences for the
treatment of patients in the Netherlands. It is concluded that Dutch clinicians,
also, can be expected to play a more active role in cases of mood disorders than
formerly. A comparison of the definitions of depressive disorder in the available
classification system results in the recommendation to be strict about the
distinction between severe and moderate depressive disorders on the one hand and
subthreshold or mild conditions on the other. It is expected that this will limit
the anticipated shift towards a more general willingness to use pharmacotherapy
for mood disorders in patients in whom this can be expected to be efficacious.
PMID- 9543775
TI - [The 'medical work disability criterium'].
AB - Legal texts regarding incapacity to work use normal language and not medical
jargon. Physicians tend to ignore that, with serious consequences. For instance,
'disease' (Dutch 'ziekte') in the law text is not identical to 'diagnosis', but
refers to 'illness' (in Dutch also 'ziekte') as well. Likewise, the term
'objective criteria' for determining disease/illness not only refers to the
results of physical examination and of additional laboratory tests and imaging,
but should also include anamnestic findings provided these are verifiable,
reproducible and consistent. The law is not about diseases, but about ill people.
PMID- 9543776
TI - [Microalbuminuria in essential hypertension: of limited value as an indicator of
patients with a high risk for complications].
AB - Microalbuminuria is usually defined as a urinary albumin excretion of 30-300
mg/24 h (i.e. 20-200 micrograms/min) measured, in view of the short-term
variation of 15-30%, in at least 2 out of 3 urine samples. An alternative
definition is: an albumin-creatinine ratio of 2-20 mg/mmol creatinine.
Microalbuminuria is an indicator of an enhanced risk of chronic kidney failure
and cardiovascular disease in diabetic patients and of cardiovascular disease in
the elderly general population. It is not known whether these relationships exist
in essential hypertension as well. In essential hypertension there is, however, a
relationship between microalbuminuria and endothelial dysfunction, impaired
regulation of renal haemodynamics and an increased risk of left ventricular
hypertrophy and hypertensive retinopathy. By screening for microalbuminuria a
group of patients can be distinguished who have a relatively high risk for the
presence of complications of hypertension. It is not certain, however, that more
intensive treatment of such patients (e.g. with ACE inhibitors) is useful.
Consequently, for the time being, screening of patients with essential
hypertension for microalbuminuria is of little practical importance.
PMID- 9543777
TI - [Folic acid use for women desiring offspring: the family physician's response].
AB - OBJECTIVE: To establish to what extent general practitioners (GP's) are familiar
with the folic acid campaign of the Netherlands Bureau for Food and Nutrition
Education, display a positive attitude regarding use of folic acid tablets by
women who would like to become pregnant and factually provide information on
folic acid. DESIGN: Cross-sectional, descriptive. SETTING: Regions: Central
Brabant, Achterhoek, Randstad and Northern Netherlands. METHOD: In 1996 a printed
questionnaire was sent to 300 GP's selected at random. It contained questions
about knowledge, attitude and management regarding the use of folic acid by women
who would like to become pregnant and with a normal risk to have a child with a
neural tube defect. RESULTS: The response was high (81%). Most GP's were familiar
with the national campaign on folic acid (87%), but 18% considered themselves
insufficiently informed about the education campaign and/or the folic acid
recommendations. Half the GP's considered use of folic acid tablets by women who
would like to become pregnant as important, while two-thirds were of the opinion
that it contributed to medicalization of the pregnancy. Most GP's (82%) thought
that pregnant women who had not used folic acid tablets might develop feelings of
guilt. Nevertheless, 64% recommended use of folic acid tablets and 63% were
willing to write a prescription if the woman asked for it. Seventy-five per cent
of the GP's reported that they themselves suggested use of folic acid tablets to
women who they assumed would like to become pregnant, although most stated they
sometimes forgot (58%). The percentages of GP's who sometimes or always suggested
folic acid tablets during a contraception advice after delivery or who advised
women who would like to become pregnant to switch to a diet rich in folic acid,
were much smaller (29 and 37%, respectively). CONCLUSION: Although a large number
of the GP's mentioned potential problems, the majority actively cooperated in
promoting use of folic acid by women who would like to become pregnant.
PMID- 9543778
TI - [A patient with a cytomegalovirus infection and multiple stomach ulcers].
AB - In a 64-year-old, previously healthy woman an upper gastrointestinal endoscopy
was performed because of serious dyspeptic complaints during fourteen days.
Multiple fundic gastric ulcers were found without Helicobacter pylori and the
patient did not take non-steroidal anti-inflammatory drugs (NSAIDs). The
diagnosis was primary cytomegalovirus infection, based on the demonstration of
infected cells in the biopsy specimens, using specific monoclonal anti
cytomegalovirus antibodies.
PMID- 9543779
TI - [Immune thrombocytopenia attributed to norfloxacin].
AB - A 65-year-old woman developed haemorrhagic diathesis due to a profound
thrombocytopenia (thrombocyte count: 1 x 10(9)/l) within one week after a 10-day
course of norfloxacin (2 x 400 mg/day), prescribed for cystitis. On account of
increased megakaryopoiesis in the bone marrow and absence of other causes of
thrombocytopenia norfloxacin-induced immune thrombocytopenia was diagnosed. No
norfloxacin-dependent antibodies against platelets were detected. Treatment with
prednisone (1.5 mg/kg/day) resulted in the normalization of the platelet count
within 5 days.
PMID- 9543780
TI - [The Stimulation Program Health Research. X. Evaluation of the program section
'Psychogeriatrics'].
AB - In the programme section 'Psychogeriatrics' of the SGO Health Research Promotion
Programme a longitudinal study was carried out in Amsterdam from 1989 until 1994,
concerning the course of mild cognitive decline in elderly people (the AMSTEL
project). The scientific aims were the development of diagnostical instruments
for the early diagnosis of dementia, the development of criteria which predict
the course of mild cognitive impairment and the expansion of knowledge on the
relationship between somatic and psychiatric pathology and dementia. The
programme also had aims regarding medical education and patient care. The results
include the following: in order to diagnose dementia in general practice
questions regarding orientation and short-term memory are helpful. Risk factors
for cognitive deterioration in elderly people include hippocampal atrophy on the
MRI scan, a low level of education and subjective complaints regarding memory.
Subjective complaints regarding memory are not primarily caused by a depressive
mood, as is often thought, but are important as correct self-observations of
cognitive deterioration, and go with an increased risk of developing dementia.
Besides the AMSTEL project a feasibility study was carried out concerning a
psychogeriatric case register in Amsterdam.
PMID- 9543781
TI - [The Diagnostisch Kompas; a recent contribution to diagnosis].
PMID- 9543782
TI - [Automatization of the medical literature and information provisions].
PMID- 9543783
TI - [Misunderstood symptoms in patients with infectious endocarditis].
AB - Infectious endocarditis was diagnosed in four patients, men aged 18, 44, 35 and
22; the bacteria involved were Streptococcus viridans, Eikenella corrodens,
Staphylococcus aureus and Streptococcus mutans, respectively. In all patients
mycotic aneurysms were observed which had led to seemingly unrelated neurological
or abdominal complaints. In one patient an aneurysm of the A. cerebri media
resolved in two years, another patient died following fatal bleeding of a
ruptured aneurysm in the A. hepatica propria. Mycotic aneurysms may be found in
all parts of the body. This complication is often diagnosed too late because it
is not considered.
PMID- 9543784
TI - [Application of the Act Special Admissions in Psychiatric Hospitals; balance
between respect for autonomy and acting in the patient's best interest].
AB - Three years after the implementation of the Dutch Act on Compulsory Admission to
Psychiatric Hospitals an evaluation was made. It shows that the law has
reinforced the patients' rights to self-determination, but that actual practice
is not yet fully according to the law. For the latter the reporters blame the
complexity of the law and the inadequate manner in which the law was introduced.
An evaluation of the effects of a similar law in the USA puts this issue in a
different light. It shows that caregivers and judges do not let the patient's
rights to autonomy prevail if this is not in the patient's best interests. The
right to self-determination, expected in the sixties and seventies to become a
revolution in psychiatry appears to be merely 'a near-revolution'. The moral
importance of caring for a psychiatric patient outweighs the respect for his or
her right to self-determination.
PMID- 9543785
TI - [Therapeutic applications and biomedical effects of cannabinoids; pharmacological
starting points].
AB - A broad range of therapeutic applications has been suggested for cannabis or its
pharmacologically active compound (tetrahydrocannabinol; THC) in many
publications. Psychotropic side effects and the anecdotal character of the
research have limited the pharmacotherapeutic use of THC until now. Therefore,
the Netherlands Health Council recently decided negatively on this matter.
Besides several cannabinoid receptor subtypes present in the central nervous
system and peripheral tissues endogenous cannabinoids have been detected. These
endogenous cannabinoids appear to play an important role in signal transduction,
which may be starting points for therapy regarding: cardiovascular diseases,
multiple sclerosis and spinal cord disorders. cerebrovascular accident and brain
trauma, neurodegenerative diseases, epilepsy, pain management, glaucoma,
oncologic and aids-related disorders such as nausea, vomiting and appetite
problems.
PMID- 9543786
TI - [Vaccination against hepatitis B possibly indicated for elderly institutionalized
mentally handicapped persons with isolated anti-HBc positivity of the
prevaccination serum].
AB - OBJECTIVE: To determine whether vaccination against hepatitis B may be omitted in
persons with isolated positive anti-HBc. DESIGN: Prospective study using control
groups. SETTING'S: Heeren Loo-Lozenoord, Ermelo, the Netherlands. METHOD: Twenty
six older residents (group P) with isolated anti-HBc positivity (HBsAg negative
and anti-HBs < 10 IU/l) were given hepatitis B vaccine (3 doses); 16 matched
controls (group C1) lacking hepatitis B markers, received a primary vaccination
(3 doses), 8 controls (group C2) with a immune status based on infection in the
past received vaccination (3 doses) and 27 controls (group C3) were given a
booster vaccination (1 dose) after vaccination 7 years earlier. The anti-HBs
response was measured 0, 1 and 7 months after the first vaccine dose. An
anamnestic response was defined as a fourfold rise of anti-HBs after one dose of
vaccine or--in the absence of an anti-HBs titer in the prevaccination serum--a
response > or = 10 IU/l after one dose of vaccine. A primary response was defined
as an anti-HBs response > or = 10 IU/l after giving 3 vaccines, while the
criteria for an anamnestic response were not met. RESULTS: In the isolated anti
HBc group (P) and in the corresponding control group (C2) 15 and 12.5%,
respectively, showed an anamnestic response; the majority reacted with a primary
response or did not respond at all. The subjects given a primary vaccination (C1)
responded in 62.5% with a primary response while those vaccinated earlier (C3)
responded in 92.6% with a fourfold rise of anti-HBs. CONCLUSIONS: The anti-HBs
response to vaccination in older mentally handicapped persons is delayed and
there is a reduced chance of development of a protective anti-HBs titer. The
majority of individuals with isolated anti-HBc showed a primary response. In
these persons vaccination should not be omitted, especially if there is a risk of
hepatitis B.
PMID- 9543787
TI - [5 children with hypokalemia, hypomagnesemia and hypocalciuria (Gitelman
syndrome) in one family].
AB - Gitelman's syndrome was diagnosed in five siblings. The parents were relatives in
the third remove. Gitelman's syndrome is a rare autosomal recessive hereditary
magnesium reabsorption defect in the distal tubule. It is characterized by
episodes of muscle weakness, usually accompanied by abdominal pain and vomiting.
Tetany may occur during a febrile illness. Patients are of normal height and
weight and have normal blood pressures. Sometimes eczematous skin lesions are
found. Biochemically there is hypokalaemia, hypomagnesaemia and alkalosis.
Urinary excretion rates of potassium and magnesium are elevated, the excretion of
calcium is diminished. Treatment consists of oral suppletion of magnesium,
sometimes also with oral potassium. A potassium-sparing diuretic may be used. The
prognosis appears to be good.
PMID- 9543788
TI - [Changes in health care in the Middle East and North African regions].
AB - A three-day conference, Regional Seminar on Health Sector Development, was held
in Cairo in June 1997. Top policy makers from countries in the region Middle East
and North Africa were invited. At this conference, the World Bank presented a
model aimed at solving the health care problems in this region. Egypt was used to
illustrate the current problems. In this country, birth rate and infant mortality
are decreasing while the population is increasing. Owing to infectious diseases
in children and chronic diseases in the elderly, the demand for health care is
great. However, physicians, pharmacists and nurses frequently are poorly trained
and more interested in money than in quality of care. Outpatient clinics and
hospitals are funded by the government and by major companies. In addition there
are private practices. No reliable statistical data are available. What
regulation there is, is mostly aimed at users of the health care facilities (to
limit the demand for care). The World Bank proposal implied that governments
should be less concerned with the provision of care and more with the regulation
of care provisions. Care givers' pay should be made dependent on observation of
rules still to be defined, for instance with regard to rational treatment
protocols. The Netherlands was presented as an example with regard to the
(financial) organization of health care. The two countries have been co-operating
for years in a number of projects. Hopefully, the expertise of the World Bank and
good co-operation between all countries involved will lead to improvement of the
health care in the region Middle East and North Africa.
PMID- 9543789
TI - [Changes in therapy-resistant primary depression].
PMID- 9543790
TI - [Hypothermia in patients with a high spinal cord lesion].
PMID- 9543791
TI - [Side effects of minocycline in the treatment of acne vulgaris. Dutch Society of
Family Physicians].
PMID- 9543792
TI - [New proven materials, systems and technologies].
PMID- 9543793
TI - [An introduction to forensic dentistry. Forensic dentistry can be defined as the
dental discipline applied to the needs of justice].
PMID- 9543794
TI - [The adventure that became reality].
PMID- 9543795
TI - [Risk assessment--a tool to find the maximum safety?].
PMID- 9543796
TI - [Sterilization--a re-evaluation?].
PMID- 9543797
TI - [Current reproductive treatment].
PMID- 9543798
TI - [Intracytoplasmic sperm injection].
AB - The first results of intracytoplasmic sperm injection (ICSI) in Norway are
presented. Acceptable fertilization rates were obtained for all indications;
severe male infertility, as well as moderately reduced sperm quality where in
vitro fertilization (IVF) and embryo transfer had previously failed. Furthermore,
in cases where IVF had failed despite normal sperm quality, fertilization rates
of 50-60% were achieved. The overall pregnancy rate was 24.9% per embryo
transfer, and the live pregnancy rate per started cycle was 13.4%. As expected,
the results improved with experience. The results were greatly influenced by the
age of the female. In the age group 34 years or less, the total pregnancy rate
per cycle was 32.4%, with a miscarriage rate of 24.2%. In the age group 35 years
or more, (42% of the study group), the total pregnancy rate per embryo transfer
was 15.2%, with a miscarriage rate of 75%. The corresponding implantation rates
were 17.4% and 7.9% respectively. 23 children have been born so far, none with
major malformations or chromosome abnormality symptoms.
PMID- 9543799
TI - [Gabapentin--a new antiepileptic agent].
AB - Gabapentin is a new antiepileptic drug. Its mechanism of action is not clearly
understood, but it seems to differ from that of other antiepileptic drugs. The
favourable pharmacokinetic properties of gabapentin make it simple to use. Our
preliminary clinical observations with gabapentin at the National Center for
Epilepsy are presented. 58 adult patients (mean age 28.9 years), mainly with
refractory partial seizures, had gabapentin added to their existing medication.
The follow-up period was 6.9 months on average. Only one patient experienced a
reduction in seizures of more than 50%, while 25 patients experienced a moderate
reduction in seizures (10-50%). The clinical effect was most favourable in
patients with secondary generalized tonic-clonic seizures. Gabapentin was well
tolerated, and no clinically significant interactions were encountered. Recent
observations show that the doses of gabapentin used in our study may have been
too low.
PMID- 9543800
TI - [Cholecystectomy in the laparoscopic era].
AB - Since 1991 laparoscopic cholecystectomy has been performed on 323 patients; 47
patients underwent conversion to open surgery. In the same period, 46 patients
were primarily selected for open cholecystectomy. Half the patients were operated
on because of gallbladder colic (the sole symptom). Conversion to open operation
(14%) occurred not so much because of peroperative complications, but rather
because of anatomical problems. On the fourth postoperative day, one patient died
of septicaemia caused by iatrogenic diathermy damage to the duodenum. One patient
developed a stricture of the choledochus as a result of ischemia. This was caused
by dissecting the choledochus, having mistaken it for the ductus cysticus which
was missing in this anatomic variant.
PMID- 9543801
TI - [Neonatal hemochromatosis].
AB - Neonatal haemochromatosis is a disorder which affects foetuses and newborns. It
is characterized by hepatocellular insufficiency, often appearing on the first
day of life in the form of coagulopathy, hypoalbuminemia, hypoglycemia and
jaundice. While spontaneous recovery has been reported, most of these infants
die, and the diagnosis was previously often made during autopsy. With the help of
MRI and salivary gland biopsies, plus increasing awareness of this disorder, the
diagnosis is now often made quite early, and successful liver transplantations
have been reported. Recently, there have also been encouraging preliminary
reports of successful intervention with antioxidant and chelation
pharmacotherapy, using a combination of selenium, vitamin E, N-acetylcysteine,
deferoxamine, and prostaglandin E. We describe two patients with neonatal
haemochromatosis who were both treated with this new "cocktail", one of whom died
at five days of age, while the other survived, but needed a liver transplant at 2
1/2 months of age. The pathology of this condition is characterized by hepatic
cirrhosis with giant cell transformation, and by siderosis of extrahepatic
tissues. The prognosis is poor, and our experience with antioxidant treatment has
been disappointing. Liver transplantation is a therapeutic option, but its use is
limited by the scarcity of donor organs and the small size of many of the
patients.
PMID- 9543802
TI - [Pregnancy, essential hypertension and chronic renal disease].
AB - Women with chronic hypertension or renal disease are at a particular high risk of
developing pre-eclampsia or eclampsia. Pre-eclampsia is associated with an
increased risk of fetomaternal complications. In women with uncomplicated mild
and moderate hypertension, pregnancy is usually normal. Treatment of high blood
pressure aims at reducing maternal cardio- and cerebrovascular catastrophies, and
the benefit of the treatment must be weighed against possible harmful effects on
the foetus. In some cases, antihypertensive treatment can be discontinued, or
medication changed. Preconceptional counselling is important both for women with
chronic hypertension and, even more so, for women with renal disease, since the
outcome of the pregnancy may be affected by the underlying disease.
PMID- 9543803
TI - [Risk assessment in preventive medicine].
AB - The aim of this article is to present and discuss the value of risk analysis in
preventive medicine. Risk analysis consists of three major areas; risk
assessment, risk management and risk communication. Risk analysis is illustrated
here by two examples: exposure to radon and the risk of lung cancer, and
infection with toxoplasma gondii in pregnancy and adverse pregnancy outcome. The
analyses highlight the complementary elements of scientific judgement and
political valuation. The barriers against implementation of preventive measures
are many. Adequate risk assessment and consequence analysis based on empirical
studies, together with risk communication are important for implementing the
correct measures. We suggest that risk analysis should be used more often in
medicine as a tool for systematic evaluation of the need and usefulness of
preventive measures.
PMID- 9543804
TI - [Compulsory collegial guidance. What do candidates in general practice think
about training of practical procedures?].
AB - In 1994 a new module addressing the quality of practical procedures was added to
the Norwegian general practice specialisation programme. Over a five-year period
31 practical procedures must be performed under the supervision of fellow GPs. In
1995 a survey was carried out by questionnaire among all specialist candidates
registered in the new programme (n = 165, response rate 83%) and a control group
consisting of all candidates registered in 1993 (n = 162, response rate 62%). The
aims of the survey were to evaluate the candidates' motivation, self-rated level
of competence, and the presence of barriers to programme implementation. The main
group and control group were almost identical; mean age has 36.5 years, 37% were
females. There were no differences in the self-rated levels of competence between
the groups. The majority (80%) reported a need to improve their performance of
practical procedures, and 93% stated that mutual guidance with colleagues would
be of considerable benefit by improving technical performance, professional
confidence and the quality of relationships with colleagues. The main barriers to
mutual guidance were shortage of time, lack of structured opportunities for
performing procedures in the presence of colleagues, and lack of instruction
manuals or videos detailing the correct performance of procedures.
PMID- 9543805
TI - [Virtual reality in medical education].
AB - Virtual reality technology has found new applications in industry over the last
few years. Medical literature has for several years predicted a break-through in
this technology for medical education. Although there is a great potential for
this technology in medical education, there seems to be a wide gap between
expectations and actual possibilities at present. State of the technology was
explored by participation at the conference "Medicine meets virtual reality V"
(San Diego Jan. 22-25 1997) and a visit to one of the leading laboratories on
virtual reality in medical education. In this paper we introduce some of the
basic terminology and technology, review some of the topics covered by the
conference, and describe projects running in one of the leading laboratories on
virtual reality technology for medical education. With this information in mind,
we discuss potential applications of the current technology in medical education.
Current virtual reality systems are judged to be too costly and their usefulness
in education too limited for routine use in medical education.
PMID- 9543806
TI - [Oslo '96--how is it?].
AB - A new, problem-based integrated medical curriculum was introduced in Oslo in
August 1996. We asked both students and teachers how satisfied they were with the
first semester; teachers were also asked what their expectations were of the new
curriculum. We investigated the relationship between the students' evaluation of
individual elements of the curriculum and their satisfaction with the group
tutors and the semester as a whole. During the course of the first semester
students (n = 127), tutors (n = 26), and lecturers (n = 28) responded to
questionnaires (response rates 92-100%) by rating various elements of the
curriculum on a five point scale. Overall, the semester was rated either "good"
or "very good" by 79% of the students and 91% of the teachers. The students'
degree of satisfaction with the semester correlated with their evaluation of
subject content, subject integration, and the case histories used in problem
solving. The students' degree of satisfaction with the group tutors correlated
with their evaluation of the tutors' contributions to subject content and group
interaction and the tutors' personal attitudes. The tutors themselves expected
the new curriculum to produce better results than the old one in all respects
except the students' knowledge of basic science.
PMID- 9543807
TI - [Group learning in medical education].
AB - The implementation of group learning in medical education puts special demands on
the participants, but also offers pedagogical benefits, which may be conductive
to the efficient learning of facts, skills and attitudes. The group makes it
possible to verify or modify the learned material, which is an important part of
preparing for a career as a doctor. Students develop a dependence on others when
solving problems in groups, whereas as clinicians they are often alone when
confronted with problems demanding quick decisions. In this article we discuss
some of the pedagogical principles involved in group learning and make
suggestions on how to apply them to learning based on problem solving and other
forms of group learning in the medical curriculum.
PMID- 9543808
TI - [Teaching clinical decision making in Trondheim].
AB - In the new medical curriculum at the University of Trondheim the preliminary
teaching in clinical epidemiology is organized as a series of courses held in the
third and fourth year. The objective is to develop skills in clinical appraisal
based on scientific knowledge. A workbook and answers to exercises are provided
for each course. The workbooks contain short introductions to important clinical
epidemiological principles, as well as clinical problems which the students try
to solve. The students' activities vary from reading to working with exercises
and discussing the various topics. The courses give the students the opportunity
to practice their newly acquired knowledge and to apply it to their clinical
thinking.
PMID- 9543809
TI - [Outplacement of medical students in local hospitals].
AB - The organisation and content of the training of medical students in practical and
clinical skills at Norwegian universities is presented and discussed. Based on
experience from Tromso University, an increased use of local hospitals for
training medical students in practical and clinical skills is planned for all
universities in Norway.
PMID- 9543810
TI - [Use of non-approved drugs].
PMID- 9543811
TI - [Sick-listing practice of physicians--should the routines be changed?].
PMID- 9543812
TI - [Massachusetts. Psychiatric rehabilitation and women's health].
PMID- 9543813
TI - [Hemochromatosis--should genetic testing be a routine?].
PMID- 9543814
TI - [Health and health services to the mentally disabled].
PMID- 9543815
TI - [Standardization work in Norwegian medicine].
PMID- 9543816
TI - [Means to measure patient satisfaction].
PMID- 9543817
TI - [Feet--a diagnostic tool?].
PMID- 9543818
TI - [Etidronate versus alendronate].
PMID- 9543819
TI - [Controlled release of pseudoephedrine HCl from pellets].
AB - This study describes the development work on a dosage form, which should release
the drug pseudoephedrine HCl over twelve hours. Pellets were chosen as the dosage
form. The pellets contained 20, respectively, 45 percent pseudoephedrine HCL and
were produced using a high shear mixer-granulator. These pellets were coated in a
fluidized bed and in a high shear mixer-granulator equipped with a microwave
drying installation. The results of the experiments indicate that it is possible
to produce pellets in a high shear mixer-granulator. Strong pellets with a narrow
size distribution were obtained. A high shear mixer-granulator appears,
therefore, to be a valuable alternative to the more commonly used pellet-forming
technique of extrusion-sphere formation. The pellets could be coated as well in a
fluidized bed as in a high shear mixer-granulator equipped with a microwave
drying installation. A major advantage of the high shear mixer-granulator
equipped with a microwave drying installation is the possibility to perform
several unit operations such as mixing, pellet formation drying, and coating in
one piece of equipment. With respect to the requirement of getting a release of
pseudoephedrine HCl over twelve hours, the pellets containing 20 percent
pseudoephedrine HCl fulfilled this requirement. For pellets containing 45 percent
pseudoephedrine HCl it appears to be hard to obtain a sufficient delay in release
using the commonly used coating formulations. This can be attributed to the very
good solubility of pseudoephedrine HCl in water. Optimization of the coating
formulation by changing the nature and concentration of the plasticizer may solve
the problem.
PMID- 9543820
TI - On the roles of extracellular matrix remodeling by gelatinase B.
AB - Human extracellular matrix is constantly remodelled by de novo synthesis of
structural components and by degradation of the matrix proteins by various
proteinases. The secreted proteolytic enzymes are regulated at several levels: by
control of gene transcription, by glycosylation, by specific inhibitors and by
enzyme activation processes. The latter level most often involves clipping of a
proenzyme or zymogen into an active proteinase. A series of such activation
reactions leads to enzyme cascades. Whereas proteolytic activation is an all-or
none phenomenon, glycosylation usually has a restricted or fine-tuning effect on
the catalytic activity of enzymes. Commonly, a two- to threefold reduction in
specific activity is imposed by N-glycosylation on each member of the multi
enzyme chain. In a series comprising e.g. four enzymes, this can lead to
significant influences (2(4)-3(4)-fold increase) on the substrate converting
activity of the terminal member of a cascade. Gelatinase B is a terminal member
of the protease cascade which leads to matrix degradation. It cleaves gelatins
(denatured collagens or collagen fragments after digestion by collagenase) and
other substrates and is thought to be involved in matrix remodeling during the
normal processes of embryogenesis, tissue remodeling and development. Gelatinase
B expression is upregulated in pathological states such as invasion of cancer
cells and when leukocytes are released from the bone marrow and migrate towards
an inflammatory focus. Proteases, including gelatinase B, are transcriptionally
regulated by cytokines and directly by the activation processes. The gene
regulation of enzyme inhibitors as well as other humoral factors, which
contribute to protease activation, influence protease activities in an indirect
way. Proteases might also play a role in the pathophysiology of chronic
inflammation and autoimmunity by cleaving extracellular structural proteins and
by generating proteolytic fragments. Indeed, these remnant fragments
antigenically resemble the original precursor proteins, but are structurally and
quantitatively different and may provoke an autoimmune response. Application of
the knowledge of the structure, function and regulation of gelatinase B has
contributed to the understanding of the mechanism of action of some gelatinase
inhibiting antirheumatic drugs and promises to contribute further to the
development of novel treatment strategies for autoimmune diseases such as
multiple sclerosis and for invasive cancers.
PMID- 9543821
TI - Acute phase proteins as protective factors against the toxicity of tumor necrosis
factor.
AB - Tumor Necrosis Factor is an endogenous messenger molecule (cytokine) exhibiting a
broad range of biological activities. Of special interest is its cytotoxic
activity, specific for transformed tumor cells and which results in outspoken
tumor regression in experimental animals. Administration of high dose of TNF,
necessary to treat internal tumors, however is currently impossible because of
the pro-inflammatory properties of TNF. Injection of TNF causes significant
decrease in blood pressure and serious liver-toxicity. However, the liver is not
only a target organ for TNF, it also produces protecting factors. Based on our
studies of the role of Interleukin-1 and Interleukin-6, two other cytokines, we
investigated the protective role of a set of liver-derived proteins, the acute
phase proteins. We identified two such proteins as protective factors in our
mouse models: alpha-1-Acid Glycoprotein (AGP) and alpha-1-Antitrypsin (AT). Both
proteins confer complete protection against TNF-induced lethality in mouse
models, and are currently evaluated as adjuvans in TNF-based antitumor therapy.
The protection by both proteins also brought us new insights in the mechanism of
TNF-induced liver-toxicity. In this sense, molecules like elastase and Platelet
Activating Factor were recognized as mediating factors.
PMID- 9543822
TI - [Hypersensitivity following low one-time irradiation dosage and induced radio
resistance].
AB - There is now little doubt of the existence of radioprotective mechanisms, or
stress responses, that are upregulated in response to exposure with small doses
of ionizing radiation and other DNA-damaging agents. Phenomenologically, there
are two ways in which these induced mechanisms operate. First, a small
conditioning dose (generally below 30 cGy) may protect against a subsequent,
separate irradiation. This has been termed the adaptive response. Second, the
response to single doses may itself be dose-dependent so that small acute
radiation exposures are more effective per unit dose than larger exposures above
the threshold where the induced radioprotection is triggered. This combination
has been termed low dose hypersensitivity (HRS) and induced radioresistance (IRR)
as the dose increases. Both the adaptive response and HRS/IRR have been well
documented in studies with yeast, bacteria, protozoa, algae, higher plant cells,
insect cells, mammalian and human cells in vitro, and in studies on animal models
in vivo. There is indirect evidence that the adaptive response and the IRR
phenomenon in response to single doses is a manifestation of the same underlying
mechanisms, namely an increase of the amount and rate of DNA repair induced by
low radiation doses.
PMID- 9543823
TI - Some facts about the supply of dental hygienists.
PMID- 9543825
TI - Modern management of dental caries: the cutting edge is not the dental bur.
PMID- 9543824
TI - A brief review of the newer nonsteroidal anti-inflammatory analgesics.
AB - The intent of this article is to present information about selected analgesic
products marketed within the past five years and their potential for use in
dental practice. As a rule, most new drugs are not specifically produced for
dental therapy as economics and medical needs drive research and development.
However, for this group of drugs, the dental pain model involving third molar
extractions has provided some of the clinical data. Because the information
presented is brief, the practitioner is cautioned to consult complete prescribing
information, such as the drug package insert, prior to using of any medication
which might be appropriate to employ in the usual course of dental therapeutics.
PMID- 9543826
TI - DOS, Windows, networks and more!
PMID- 9543827
TI - The amalgam issue ... or is it?
PMID- 9543828
TI - Practicing the principles of gingival non-violence in restorative dentistry.
PMID- 9543829
TI - Ten year results of sealants placed in the New Mexico sealant program.
PMID- 9543830
TI - The handpiece issue.
PMID- 9543831
TI - Subepithelial connective tissue grafts.
PMID- 9543832
TI - The black hole--what happens to your insurance preestimates.
PMID- 9543833
TI - The functional smile: a goal for orthodontics.
PMID- 9543834
TI - Elements of a beautiful smile.
PMID- 9543835
TI - Prevention of post-operative sensitivity in bonded restorations.
PMID- 9543836
TI - Supportive periodontal care. A review of the literature.
PMID- 9543837
TI - Stress and dentistry. Better practice through control.
PMID- 9543838
TI - Health providers in rural New Mexico.
PMID- 9543839
TI - So you thought you knew how to take an alginate impression OR can it really be
done without gagging?
PMID- 9543840
TI - Current trends in periodontal regeneration: a review and case report.
PMID- 9543841
TI - Selection of dental hygiene as a career: associate degree students compared with
baccalaureate students.
AB - One of the most significant issues in the dental hygiene profession is the
recruitment of qualified applicants. Throughout the decade of the 80s, a dramatic
decline in enrollment has occurred in dental hygiene programs across the nation.
According to recent demographic reports, there are fewer individuals in the age
group where dental hygiene students are traditionally recruited and no
significant change is expected. Therefore, in order to maintain and improve the
pool of students preparing for a career in dental hygiene, it is critical that an
attempt be made to understand the forces which lead students to choose the health
care profession. A study was conducted using baccalaureate alumni and three
classes in the baccalaureate degree dental hygiene program at The Ohio State
University in order to determine why they had chosen the career of dental
hygiene. This study was subsequently expanded to include students enrolled in
eight associate degree dental hygiene programs in Ohio. The results from the
survey indicate that career decisions are made at varying points in the
educational process. Dentists and dental hygienists account for half of the
influence in the decision process with high school guidance counselors having
negligible influence. Nearly all respondents chose working with people as the top
career benefit. Those findings point to the importance of involving dental and
dental hygiene professionals in the recruitment process and the necessity to
provide appropriate information to others who may provide career counseling.
PMID- 9543842
TI - Treatment of an unusual case of external resorption and a six-year follow-up of
that treatment.
AB - It seems that few cases of idiopathic external resorption appear in the
literature and fewer that are followed for a number of years. Such a case is
presented with a six-year follow-up. Results showed that there was no remaining
pathology and that the tooth was completely asymptomatic following its initial
treatment.
PMID- 9543843
TI - Relationships between dental hygienists' career attitudes and their retention of
practice. Part II. From the results of the Ohio Dentist and Dental Hygiene
Surveys.
AB - This article utilizes findings from the Ohio Dental Hygiene Survey and Ohio
Dentist Survey to uncover what specific dental hygiene attitudes exist relative
to employment and what factors have led to job termination and to re-entry. Ohio
dental hygiene employees are most satisfied with patient relationships, co-worker
relationships, and flexible working hours. The dental hygienists are least
satisfied with fringe benefits, financial growth, and career creativity. Salary,
benefits, nor career longevity were significant factors in determining
satisfaction. Dental hygienists who were not working when surveyed, said they
would consider returning to practice if a better salary were available, if they
could find part-time work, if there were a good wage scale with benefits, or if
their own financial need changed. Thirty-six percent of the non-practitioners
said they would not ever consider returning to practice due to working
conditions, establishment of a new career, or inadequate compensation. Dentist
employers stated that they were satisfied or very satisfied with their dental
hygienists' patient care and contribution to the practice.
PMID- 9543844
TI - Poverty, health insurance, and use of health services.
PMID- 9543845
TI - An analysis of dental hygienist remuneration. Part III. From the results of the
Ohio Dentist and Dental Hygiene Surveys.
AB - The Division of Dental Hygiene of Ohio State University, working under a grant
from the Ohio Dental Association, completed research defining the practice of
dental hygiene in Ohio utilizing data gathered in the summer of 1991. This
portion of the research focuses on the salaries and benefits earned by practicing
Ohio dental hygienists. It also presents the salary and benefit levels which Ohio
dentists believe to be reasonable for dental hygienist employees. The largest
number of dental hygienists work 27 hours per week and are paid a straight salary
averaging $15.86 per hour. The largest number of dentists believe that
experienced, full-time dental hygienists should receive higher salaries and more
benefits than part-time hygienists. They feel that $16-$21 per hour is a
reasonable salary, and they most often provide reduced dental fees as a benefit.
PMID- 9543846
TI - Comparison of handpiece asepsis among Ohio dentists: 1991 & 1992.
AB - In 1991, we found that 23 percent of Ohio dentists sterilized handpieces between
patients and 67 percent flushed handpieces between patients. In this study, we
chose to investigate the changes in handpiece asepsis within Ohio dental offices
for the twelve-month period ending August, 1992. Sixty-two percent of the 730
offices polled responded to the questionnaire. Offices reporting sterilization of
handpieces between patients in 1992 is 80 percent compared to 23 percent in 1991.
Sixty-nine percent of offices in the 1992 survey reported that they have changed
infection control protocol to include heat sterilization of handpieces between
patients while 24 percent report disinfection between patients. Back order of
equipment, inadequate number of handpieces and fear of damage is cited by the
offices using disinfection as the reasons for not sterilizing handpieces.
Flushing handpieces between patients is reported by 83 percent of the offices.
Previously, only 67 percent flushed between patients. Anti-retraction valves are
present in 69 percent of the water lines. Breakdown of handpieces attributed to
sterilization was reported by 45 percent of the offices. Two-hundred and three
offices (45 percent) report questions from patients regarding office infection
control policies. Infection control awareness of the general population and
implementation of these procedures by dental professionals is increasing in Ohio.
PMID- 9543847
TI - Dentally induced bacteremia and infection of total joint replacement
arthroplasty.
PMID- 9543848
TI - Straight talk on Dental Corps career planning.
PMID- 9543849
TI - AIDS-related knowledge, attitudes, and behavior among Navy personnel.
PMID- 9543850
TI - A denture for Tojo.
PMID- 9543851
TI - U.S. Navy Dental Corps Survey of 1994: analysis of narrative responses.
PMID- 9543853
TI - Aesthetic dentistry systems: positioning advanced materials in a modern dental
practice.
PMID- 9543852
TI - Fiber-reinforced framework and Ceromer restorations: a technical review.
AB - The utilization of synthetic resins and ceramics in combination with metal
frameworks continues to be the mainstay of crown and bridge prosthetics. Although
most of these systems have resulted in years of clinical success, each material
when used in combination has inherent properties that induce stresses to the
system. The combination of ceramic technology and polymer research, in addition
to fiber integration, has resulted in the development and introduction of a new
category of crown and bridge materials--a ceromer and fiber-reinforced
restorative system. This article examines the history of polymer and ceramic
technology, and reports the clinical and research data currently available on one
indirect ceromer system (Targis System, Ivoclar Williams, Amherst, NY).
PMID- 9543854
TI - Anatomical applications of a new direct Ceromer.
AB - Composite resin materials have become the basic restorative materials of the
modern aesthetics-oriented practice. However, the application of composite resin
in posterior teeth remains a challenge as a result of its handling
characteristics and chairside stratification. New ceramic optimized polymers
(ceromers), such as Tetric Ceram (Ivoclar Vivadent, Amherst, NY), now offer
versatility and improved handling properties in response to increasing clinical
demand for producing high-quality natural restorations. With a well-designed
instrumentation, the work of the clinician may be greatly facilitated. This
article evaluates the selection and utilization of a direct ceromer material for
posterior restorations and presents a predictable method to achieve aesthetic
restorations.
PMID- 9543856
TI - Postorthodontic restoration of enamel surface characteristics.
AB - Following orthodontic treatment, the mechanical debonding of brackets often
results in damage to the enamel surface of teeth. Loss of natural luster, a
roughened surface, and scarring may occur. When scarring occurs, a method for re
establishing the enamel luster and surface characteristics can be instituted by
either the restorative dentist or the orthodontist. One method of restoring
enamel luster and natural surface characteristics following removal of
orthodontic fixtures is through a sequence of enamel polishing. This article
discusses logical steps for the restoration of enamel through the utilization of
polishing burs and progressive pastes (Proxyt), Ivoclar Vivadent, Amherst, NY)
for the final aesthetic orthodontic result.
PMID- 9543855
TI - Achieving functional restorations utilizing a new Ceromer system.
AB - The advent of pressed ceramic restorations (IPS Empress, Ivoclar Williams,
Amherst, NY) has driven dental therapy to continuously strive for more aesthetic
and functional materials. The dental profession requires restorations to exhibit
strength, natural color, wear resistance, marginal integrity, and ease of
fabrication in the restorative therapies selected. With the introduction of a new
ceromer and fiber-reinforced composite (FRC) system (Targis System, Ivoclar
Williams, Amherst, NY), the replacement of a single tooth or multiple teeth with
a FRC, metal-free bridge is now a suitable alternative to conventional dental
therapy. This presentation will review the clinical protocol, material
properties, and aesthetic characteristics of this new generation of restorative
material.
PMID- 9543857
TI - Introducing a new brick onto a solid foundation.
PMID- 9543858
TI - Increasing patient satisfaction with natural denture teeth.
AB - Successful laboratory communication in removable prosthodontics will always be
more complex than in fixed prosthodontics. However, the unique characteristics of
natural denture teeth (SR-Antaris/SR-Postaris), Ivoclar Williams, Amherst, NY)
are enabling clinicians to overcome functional and aesthetic challenges.
Specifically, the characterized anatomy of these anterior and posterior teeth,
and their translucency and natural layering, facilitate the reestablishment of a
natural smile. This article describes the benefits of SR-Antaris/SR-Postaris
denture teeth and provides guidelines for communication with the laboratory to
ensure predictable results.
PMID- 9543859
TI - Classification and application of cementation alternatives.
AB - More important than any resin cement is the marginal fit and retentive nature of
the ceramic restoration to be bonded. Cementation should not be intended to
compensate for poor dentistry, but to assist in producing superior aesthetic
results. Responding to the demand for all-ceramic restorations, dental
manufacturers continue to refine the resin cements used in luting for this
modality. The ideal resin cement for ceramic restorations must demonstrate low
viscosity; easy loading; a film thickness which facilitates complete seating high
strength; and excellent wear resistance. This article reviews the available resin
cements, with particular focus on a new type of initiator and stabilizer for
light- and dual-cured resin cements.
PMID- 9543860
TI - Technique for realistic anterior crowns using the IPS Empress porcelain system.
AB - In dentistry, the concept of realism can be applied to the creation of an
artificial prosthesis that is not perfect, but real. If prosthesis are made to a
flawless perfection, they will appear artificial. Ultimately, the clinician and
ceramist should strive for realism. The IPS Empress System (Ivoclar Williams,
Amherst, NY) is an all-ceramic restorative alternative utilizing a pressable
leucite-reinforced glass ceramic for a variety of indications (e.g., crowns,
inlays/onlays, veneers). The resulting tooth-colored and metal-free restorations
combine strength and aesthetics approaching those of natural teeth. This article
describes the technique and procedures required to achieve realistic anterior
crowns with this all-ceramic system.
PMID- 9543861
TI - The changing face of aesthetic dentistry.
PMID- 9543863
TI - Anecdotal, clinical evaluation: a catalyst for the evolution of dentistry.
PMID- 9543862
TI - Securing the position of ceramic veneers in dentistry.
AB - Porcelain laminate veneers have exhibited predictability and, as a result,
experienced an incredibly rapid public acceptance with widespread utilization.
The introduction of a stronger, leucite-reinforced ceramic system which could be
accurately pressed (IPS Empress, Ivoclar Williams, Amherst, NY), presented new
avenues for this remarkable treatment modality beyond aesthetic enhancement.
Porcelain veneer restorations could be utilized to accurately alter and correct
occlusal relationships, and the less abrasive surface of the material offered a
distinct advantage in occlusal modifications, such as altering cuspal guidance or
vertical dimension. This presentation reviews the history of porcelain veneer
restoration and outlines the use of a luting cement (Variolink II, Ivoclar
Vivadent, Amherst, NY) for its application.
PMID- 9543864
TI - Ceromer/FRC technology: the future of biofunctional adhesive aesthetic dentistry.
AB - With recent advancements in adhesive technology, restorative materials have
evolved to an enhanced level of aesthetics while enabling more conservative
cavity preparations and promoting reinforcement of the remaining tooth structure.
These restorations have included both anterior and posterior treatment modalities
applied directly and indirectly. With a growing awareness on the part of many
patients of the possible cosmetic treatment alternatives came the desire for
aesthetic, metal-free, durable restorations. This presentation discusses the
material properties and clinical protocol of a new material which combines a
ceramic optimized polymer with a fiber-reinforced framework for durable,
aesthetic anterior and posterior restorations.
PMID- 9543865
TI - Direct Ceromers: assuring restorative integrity with selective application of two
viscosities.
AB - The objectives of an ideal direct restoration include pulpal health,
biocompatibility, occlusal stability, anatomical restitution, marginal
perfection, and interproximal integrity. While tooth-colored composites have
replaced amalgam as the restorative material of choice for many dental
professionals, the utilization of composite materials of two different
viscosities has proven effective in increasing strength and adaptation, and
facilitating placement of anterior and posterior restorations. Several newly
enhanced composite combinations have begun to allay reservations about directly
placed tooth-colored restorations. This article classifies the ideal handling
characteristics and benefits of a recently introduced, direct Ceromer system
(Tetric Flow and Tetric Ceram, Ivoclar Vivadent, Amherst, NY.)
PMID- 9543866
TI - Conventional cementation technique for Targis restorations.
AB - Ivoclar can now recommend a clinical and laboratory procedure for the
conventional cementation of Targis single- and multiple-unit full-coverage
restorations. The ability to bond restorations utilizing enamel/dentin bonding
systems and dual-cure resin cements (Variolink II, Ivoclar Vivadent, Amherst, NY)
has minimized microleakage and postoperative sensitivity, provided stronger
restorations, and reinforced remaining tooth structure. Unfortunately, the
benefits of the adhesive technique can often be compromised by existing or pre
existing clinical conditions. This challenge has limited the broad use of
adhesive, metal-free restorations in many clinical situations. Targis
restorations can now be successfully cemented utilizing zinc phosphate or
conventional glass ionomer cements. This article describes the technique through
a case presentation.
PMID- 9543867
TI - IPS Empress: a standard of excellence.
AB - For 10 years, clinicians have been able to provide patients with a proven
aesthetic and functional restoration that exhibits wear-compatibility,
durability, and marginal integrity. This leucite-reinforced, pressed ceramic (IPS
Empress, Ivoclar Williams, Amherst, NY) presents to patients and dentists the
option of a metal-free alternative which retains the functional advantages of a
porcelain-fused-to-metal restoration. This article illustrates the importance of
sound laboratory communication in the utilization of this restorative material,
focusing upon three aspects: midline and incisal edge inclination, elimination of
open gingival embrasures, and incisal edge translucency. Techniques are also
presented in order to efficiently communicate details of each case presented to
the laboratory.
PMID- 9543868
TI - Life on the arc: principle-centered comprehensive care.
AB - Today's dental practice is experiencing an evolution in the manner through which
new materials and techniques are marketed and introduced. An increasing concern
among the patient population regarding aesthetics contributes to the acceptance
of a commodity dental philosophy, without questioning the reliability of the
technique or new material. A principle-centered practice differentiates the
product marketing from the viability of a restorative material in vivo. This
article discusses the concept of a principle-centered practice and describes how
to place quality products in a balanced system in which harmony exits between all
components of the masticatory system: the teeth, the muscles, and the
temporomandibular joints.
PMID- 9543869
TI - An innovative approach to Class II preparation and restoration.
AB - When patients exhibit Class II defects requiring restoration, the treatment
modality and respective preparation requirements may present challenges to the
clinician. Aesthetics, chairside time, and expense become factors for the
consideration of both dentist and patient. However, a new sonically driven system
for the preparation and restoration of proximal defects was recently introduced
(SONICSYS, Ivoclar Vivadent, Amherst, NY). This system, composed of diamond
coated tips and prefabricated ceramic inserts, promises to enable clinicians to
efficiently, confidently, and expertly prepare and restore Class II defects in a
timely, consistent, and cost-efficient manner. This article describes the
components of the system and demonstrates its utilization in a case report.
PMID- 9543870
TI - An aesthetically and physically advanced system for post and core restorations.
PMID- 9543871
TI - All-ceramic crown systems: clinical research versus observation in supporting
claims.
PMID- 9543872
TI - Restoration of a single anterior crown.
AB - All-ceramic restorations have gained patient acceptance and are increasingly
being used in aesthetic appearance-related restorations. This case report of a
single anterior crown matching natural dentition utilizes some of the new special
effect ceramic powders designed for use with the layering technique. These
powders help to properly replicate incisal, mamelon, and gingival areas. The
clinical procedure is described, using photographs of the case to illustrate the
steps involved.
PMID- 9543873
TI - Six years of clinical experience with an all-ceramic system.
AB - The search for tooth-colored and metal-free restorations is one of the major
challenges in dental research. For several decades, ceramic has been used as a
restorative material because of its aesthetics and stability. Unfortunately, the
survival rate of most all-ceramic systems seems unsatisfactory; due to the
natural brittleness of ceramic, fractures have been the primary reason for the
high failure rate. Since 1988, the University of Zurich Dental School,
Switzerland, has been working with the IPS Empress all-ceramic system
(Ivoclar/Williams, Amherst, NY). This article reports the clinical and research
data from approximately 3,000 all-ceramic restorations.
PMID- 9543874
TI - A clinical trial of all-ceramic crown restorations: status, fall 1995.
AB - Although porcelain-fused-to-metal (PFM) restorations are the most widely used
full-coverage crown restoration systems, their inherent properties make the
achievement of natural aesthetic restorations an elusive task. In contrast, the
all-ceramic system (IPS Empress, Ivoclar North America, Amherst, NY) offers
excellent translucency and vitality, without the opacity associated with PFM
restorations. Its vitality is further enhanced by an adhesive resin cementation
method that conducts the color of the underlying tooth structure. This article
reports the status of a 5-year investigation, initiated in 1992, of the clinical
performance of the IPS Empress all-ceramic system and the resin cementation
system used with it.
PMID- 9543876
TI - Personal and career management.
PMID- 9543875
TI - IPS Empress veneers. Color communication, laboratory fabrication, and
cementation.
AB - Once considered to be revolutionary, porcelain veneers are now the foundation of
most aesthetic dental practices. Requiring only conservative preparations,
porcelain veneers can dramatically change a smile. This article discusses the
technique necessary to prepare and place porcelain veneers, using a new pressed
ceramic system. Close and thorough cooperation and communication between the
clinician and the laboratory are essential throughout the procedure, and this
article is coauthored by a dentist and a ceramist.
PMID- 9543877
TI - Career development: the key questions.
PMID- 9543879
TI - Presentation of self: being heard.
AB - "Be yourself and you'll be fine." Sound advice but not so easy to achieve in
pressure situations. How does one project oneself effectively? This article
discusses ways to stop selling oneself short and to be heard.
PMID- 9543878
TI - Personal development: a lifelong journey.
AB - This article explores critical aspects of career and personal development, in
particular the importance of a lifelong commitment to reflective practice. It
focuses on the key questions: Where have I been? Where am I now? and Where do I
want to be? Specific approaches discussed include journal writing and collegial
small group work.
PMID- 9543880
TI - Is your financial house in order?
AB - In today's rapidly changing world individuals are being faced by many new issues
that are challenging their ability to survive financially. It is therefore
important that we recognize the need to manage our financial lives. To do that
requires a commitment of time to identify assets held and determine how best to
protect them, set future financial goals, and then determine how assets can be
used to reach those goals.
PMID- 9543881
TI - Strength of character through the ethics of nursing.
AB - "A Practice-Based Bioethic" is a regular column in Advanced Practice Nursing
Quarterly. A practice-based approach is derived from, and therefore is intended
to be appropriate to, the situation of a patient, the purpose of the health care
setting, and the role of the nurse. It is based on a shared state of awareness,
the foundation on which ethical interactions between nurse and patient occur.
PMID- 9543882
TI - Career journeys.
AB - Capturing stories of a culture is important to its life blood. The following
career stories of a sample of our colleagues describe the many and interesting
journeys to advanced practice roles they have explored through their careers.
PMID- 9543883
TI - A reflective approach to career trajectory in advanced practice nursing.
AB - Opportunities in nursing continue to expand. Advanced practice nurses today have
greater control over the scope of their practice and can look forward to mapping
a career pathway using personal and professional talents and interests. This
article offers a reflective process approach to evaluating and relating career
satisfaction and satisfactoriness to personal development needs. Through
implementation of the suggested reflective exercise, a 3- to 5-year career plan
can be constructed that will guide change and affect growth for the advanced
practice nurse.
PMID- 9543884
TI - Clinical leadership.
AB - Leadership skills are necessary no matter what work you are doing. This article
explores some controversial aspects of leadership for clinical professionals.
PMID- 9543885
TI - Crystal ball gazing: back to the future.
AB - This article presents some of the challenges, competencies, and opportunities
that advanced practice nurses will face in the near future as the emerging health
care system unfolds. Nurses must be knowledgeable about, prepared for, and
participate in the creation of a preferred future in health care policy and
practice. Advancing educational programs and orienting research and activism in
the direction of personal and community health will allow advanced practice
nurses to continue to have a significant influence on the transformation of
health care and delivery systems.
PMID- 9543886
TI - An interview with Judith Igoe. Interview by Cheryl Slagle King.
PMID- 9543887
TI - Autonomy in practice: are nurse practitioner students being prepared for reality?
AB - This article reports on a study examining the relationship between nurse
practitioner students' expectations of future professional autonomy and the level
of autonomy experienced by certified nurse practitioners. The findings indicate
that practicing nurse practitioners experience a greater sense of autonomy than
student nurse practitioners perceive. As autonomy is an issue of continuing
importance in nursing, and for advanced practice, further research is needed to
assist schools of nursing in devising reality-based curricula for nurse
practitioner programs.
PMID- 9543888
TI - Cross-jurisdictional advocacy in family violence: the role of the advanced
practice nurse in the judicial system.
AB - Advanced practice nurses have many career alternatives. The role of the advanced
practice nurse in the judicial system is as a cross-jurisdictional advocate--a
case manager, a court advocate, and a legal nurse consultant. This article
explores these roles with specific emphasis to the problem of family violence.
PMID- 9543889
TI - Nurses can influence public health policy.
AB - Nurses can and should take part in making the policy decisions that affect their
practice and the health of their clients. This article provides some common-sense
tips for organizing collaboratively in order to make changes that count.
PMID- 9543890
TI - Giving something back.
AB - The Taoist teachings of self-reflection, openness, and sharing of self illustrate
the need for the seasoned professional to examine one's own practice and share
with the greater professional community. Taoism incorporates interdependency and
harmony for all systems and suggests that as individuals we rely on the well
being of the whole. Four specific methods provide meaningful ways to give back to
the profession; networking, presenting, publishing, and professional association
work. Implementing one or more of these methods promotes the profession's
collegial spirit and facilitates one's own growth while giving to others.
PMID- 9543891
TI - Your career and job success.
PMID- 9543892
TI - From job to career: are you ready?
AB - The times call for a focus on career not on job. Nurses will advance to the
extent they can match their skill sets with the demands of the new age of health
care.
PMID- 9543893
TI - Surprising findings? ... I don't think so.
PMID- 9543894
TI - Despite the continuum of care, is hospice terminal?
PMID- 9543895
TI - Comfort and incidence of abnormal serum sodium, BUN, creatinine and osmolality in
dehydration of terminal illness.
AB - This prospective clinical study was undertaken to evaluate the effect of
spontaneous food/fluid intake on serum sodium and comfort levels in a population
of terminal patients (n = 31) receiving clysis or intravenous hydration. The
median and mode of serum sodium were within normal limits and 56 percent of the
patients were eunatremic. There was no statistically significant difference in
comfort scores between predehydration and dehydration phases, and 85 percent had
an optimal comfort score. A statistically significant difference was found (p <
0.5) between mean daily comfort scores of those with normal sodium versus those
with abnormal sodium; those with hypernatremia were lower but still in the top
third comfort levels. Because the sodium was tested using a Chem7, we also were
able to calculate the BUN, creatinine, and osmolality. These are presented and
compared to other study results. The findings of this study reinforce the belief
that fluid depletion in dying patients results in relatively benign symptoms,
that serum sodium levels are not always altered with limited intake and that
comfort levels can be maintained when the serum sodium is abnormal.
PMID- 9543896
TI - First know thyself ... the value of a hospice environmental analysis.
PMID- 9543897
TI - Palliative chemotherapy.
PMID- 9543898
TI - Barriers to effective pain/symptom control.
AB - We have a challenging call to provide compassionate care and comfort in a
changing and varied clinical, social and financial setting. Multiple variables
including race, creed, age, and sex of the patient can impact the decision-making
process. It is hoped that consideration by professional caregivers of the above
barriers will improve and provide consistent care to those put in our charge.
PMID- 9543899
TI - Palliation of painful bone metastases: Strontium-89.
AB - Most patients with bony metastases experience painful symptoms. Strontium-89
isotope therapy is an alternative to traditional hemibody radiation in cases of
multiple, diffuse metastases. Generally given as a single i.v. slow-push
infusion, relief begins in one to three weeks, peaks at six weeks, and has a mean
duration of 12 months. Up to 22 percent of patients are pain-free at three
months.
PMID- 9543900
TI - Onchologic stress: its causality in myofascial pain disorder or in
temporomandibular disorder.
PMID- 9543901
TI - Hospice or palliative care?
PMID- 9543902
TI - What is your role? You can make a difference!
PMID- 9543903
TI - Preventing amputations in patients with end stage renal disease: whatever
happened to foot care?
AB - Lower extremity amputations in patients with diabetes are largely preventable
through proper foot hygiene, routine foot surveillance, and patient education
about proper foot care. Diabetics with end stage renal disease are at especially
high risk for foot complications, but nephrology nursing has been largely silent
about the importance of diabetic foot care. This article discusses the diabetic
pathophysiology underlying the development of most foot complications and
outlines the basic principles of safe and effective foot care.
PMID- 9543904
TI - Osteitis fibrosa: treatment trends.
AB - Renal osteodystrophy is frequently seen in patients with end stage renal disease.
Osteitis fibrosa associated with secondary hyperparathyroidism is often
diagnosed. Treatment options vary based on disease severity. Individual patient
considerations need to be addressed to determine the best therapeutic plan.
Medical management with calcitriol, dietary modifications, and administration of
phosphate binders continues to be the best treatment for most patients.
Parathyroidectomy should be reserved for patients with complications related to
severe irreversible hyperparathyroidism and/or failure of medical management.
Total resection of all parathyroid tissue with or without autotransplant is the
most common surgery for hyperparathyroid bone disease.
PMID- 9543905
TI - Teaching program effects on high phosphorus levels in patients receiving
hemodialysis.
AB - OBJECTIVE: The objective was to determine the effect of a patient education
intervention on decreasing serum phosphorus levels, increasing calcium levels,
and increasing knowledge in hemodialysis patients with abnormally high phosphorus
levels (n = 29). SAMPLE/SETTING: Study subjects were (a) on hemodialysis at least
3 months, (b) English speaking, (c) mentally alert, (d) not under constant
nursing care, and (e) hyperphosphatemic. The study was conducted at two suburban
dialysis units in the Chicago Metropolitan area. DESIGN: This study had a one
group, pretest-posttest design, using subjects as their own controls. METHODS:
The intervention was a one-on-one education session performed by a nephrology
nurse using a teaching booklet, an Osteodystrophy Tool, and a medication diary.
RESULTS: The mean change score for phosphorus did not reach significance (t [28]
= .68, p = .50). The change in mean phosphorus levels was not related to gender,
education, or dialysis unit. There was a weak relationship between a decrease in
phosphorus and an increase in knowledge about phosphorus (r = 0.21). However,
calcium levels improved significantly after the teaching intervention (t [28] =
3.23, p = 0.003). Mean overall scores for knowledge about phosphorus control
increased significantly also (t [28] = 2.60, p = < 0.01). CONCLUSION: The
findings of this study demonstrated that an education session can have an effect
on patients' knowledge and compliance.
PMID- 9543907
TI - Medication compliance and the older hemodialysis patient.
AB - OBJECTIVE: The purpose of this study was to identify relationships between
demographic factors, psychosocial characteristics, and medication compliance
rates in older patients receiving hemodialysis and to determine the effectiveness
of a teaching program on medication-taking behavior. DESIGN: A descriptive
correlational study design was used. SAMPLE/SETTING: A total of 26 patients, age
65 and over, undergoing hemodialysis at an inner city outpatient dialysis clinic
met sample criteria. METHODS: The instrument included a demographic data form,
the Iowa Self-Assessment Inventory (ISAI) to measure psychosocial variables, and
a form to collect data to calculate medication compliance rates. RESULTS: All
participants were African-American. Mean age was 70. Sample attrition was high.
Scores were below the norm for most ISAI psychosocial factors, medication
compliance rates were low, and the teaching intervention did not affect
compliance rates. CONCLUSION: Medication compliance in this older dialysis
patient population was problematic, and further research in this area is
essential.
PMID- 9543909
TI - Where do young adult renal transplant recipients fit in?
AB - Young adult renal transplant recipients often have unique concerns and interests.
To give them an opportunity to share these concerns with peers, a support group
was established at Boston Children's Hospital. Despite a less than enthusiastic
beginning, this group is now well attended, meets four times a year, and has
continued for over 4 years. The group has become a comfortable setting where the
participants discuss their unique perspectives on schooling, family, and
relationships.
PMID- 9543910
TI - Survey of nephrology nurses' interest in graduate education.
AB - OBJECTIVE: The purpose of the survey was to determine interest in a Master's
nephrology nursing program among ANNA members residing in North Carolina, South
Carolina, and Virginia. DESIGN: Needs assessment. SAMPLE/SETTING: 153 ANNA
members residing in South Carolina, North Carolina, and Virginia. METHOD: Mailed
survey. RESULTS: Response rate was 27%; 54 (35%) expressed interest in attending
such a program, with 62 others (41%) interested "depending." Part-time study was
the most commonly desired program option. Almost half (48%) were not currently
baccalaureate prepared, a requirement for admission. CONCLUSIONS: Enrollment was
inadequate to support the program despite numerous marketing efforts, bringing
into question the adequacy of needs surveys for program planning.
PMID- 9543911
TI - Maintaining iron balance with total-dose infusion of intravenous iron dextran.
AB - Recombinant human erythropoietin (rHuEPO) is an important component of anemia
management in patients with chronic renal failure, however, it can lead to
functional iron deficiency (FID). Patients with FID are less likely to have an
optimal response to rHuEPO (Cavill et al., 1997). Intravenous (i.v.) iron dextran
is often required to replace iron losses, maintain adequate iron stores, and
correct iron deficiency. The following article provides a rationale for the use
of IV iron dextran and details one unit's protocol and experience with its use.
PMID- 9543912
TI - Teaching an illiterate transplant patient.
AB - RSR is now several years posttransplant. He has a serum creatinine of 2.1 mg/dl
and his hypertension remains borderline with additional medication. He is seen
regularly by his local nephrologist and once a year at the transplant center. In
RSR's case, collaboration with physicians, nurses, and home health helped this
patient achieve the goal of self-care. Illiteracy was no barrier to achieving
this goal when assessing the patient's skills, developing a plan that uses those
skills, and working together as a team to implement the plan.
PMID- 9543913
TI - Neoral: the new cyclosporine.
AB - Neoral is an improved formulation of cyclosporine which, through microemulsion
technology, provides a more consistent rate of absorption and exposure. If
patients are able to take less Neoral and still maintain the same cyclosporine
level, there will also be a cost savings involved. A dose reduction of 30% yields
pharmacoeconomic savings. With a more consistent rate of absorption, the risks of
nephrotoxicity may be reduced.
PMID- 9543914
TI - Determining the direction of blood flow.
PMID- 9543915
TI - Dialysis in the newborn with chronic renal insufficiency: ethical considerations.
PMID- 9543916
TI - Hemoglobin and hematocrit: an analysis of clinical accuracy. Case study of the
anemic patient.
AB - Hemoglobin (Hgb) and hematocrit (Hct) are often used interchangeably to evaluate
anemia in dialysis patients. Hgb is the preferred method in most European
countries, while Hct is generally used by clinicians in the United States. This
article examines the comparative accuracy of these two values, including a same
patient assessment of laboratory samples. These data illustrate that Hgb is a
more accurate method of assessing anemia. Using Hgb may help nurses and patients
by: (a) decreasing variability in laboratory assessment, (b) avoiding ongoing
errors in anemia measurement, (c) decreasing the nursing time spent on anemia
management, and (d) increasing the potential for patients remaining in the
recommended DOQI target Hgb range of 11 g/dL to 12 g/dL.
PMID- 9543917
TI - Nursing's past, present, and future: looking back in order to move forward.
PMID- 9543918
TI - Clinical risk modification, quality, and patient safety: interrelationships,
problems, and future potential.
AB - Iatrogenic injury, in which patients are unintentionally injured by medical
treatment, occurs in 4% of hospital admissions and causes considerable human
suffering, financial losses, and waste of healthcare resources. This article
discusses why existing quality initiatives have had little impact on iatrogenic
injury and suggests an approach to clinical risk modification that may enhance
the safety of medical treatment.
PMID- 9543919
TI - Measuring patient satisfaction in healthcare organizations: qualitative and
quantitative approaches.
AB - Patient perceptions of the quality of services provided are a key factor in
determining a healthcare organization's competitive advantage and survival. This
article examines the advantages, disadvantages, and problems associated with nine
different qualitative and quantitative methods of measuring patient satisfaction
with service quality and concludes with guidelines for measurement of patient
satisfaction and implementation of managerial follow-up.
PMID- 9543920
TI - Technology assessment in healthcare: a review and description of a "best
practice" technology assessment process.
AB - BACKGROUND: Technology assessment has become a rapidly growing component of the
healthcare system. It has assumed a functional role in operational settings and
is rapidly impacting decisions involving purchasing, coverage, and reimbursement.
This review is intended to assist the healthcare decision maker in considering
the application of technology assessment in healthcare, so as to maximize the
efficiency of future purchasing decisions. METHODS: This "best practice" was
synthesized after identifying key institutions performing technology assessment
in healthcare and analyzing their working processes, including literature review,
consensus panel discussions, and expert opinion. RESULTS: We describe this best
practice on a reiterative loop that consists of five processes: awareness,
strategic appropriateness, analysis versus need, acquisition and implementation,
and reassessment. Typical barriers to adoption of technology assessment are also
identified and discussed. CONCLUSIONS: This review suggests a common terminology
for the core processes involved in technology assessment, thereby facilitating a
more uniform understanding among the different components of the healthcare
system (i.e., payer, provider, and society) while recognizing their different
perspectives.
PMID- 9543921
TI - Disease management: Lovelace Health Systems episodes of care--a case study.
AB - The evolving paradigm shift in healthcare emphasizes population health status.
Disease management is gaining popularity as a means of providing cost-effective,
quality healthcare to an entire population at risk. Outcomes measurements,
standardized clinical protocols and commitment by physicians and staff are
crucial to a successful program. This article presents a case study from Lovelace
Health Systems in Albuquerque, N.M., and identifies key components, cost savings
and successes of one of its disease management programs.
PMID- 9543922
TI - Academic health center teaching hospitals in transition: a perspective from the
field.
AB - A study of 11 Academic Health Center Teaching Hospitals (ATHs) in 11 states found
that cost reduction programs, internal reorganizations, reengineering,
benchmarking, and broadened entrepreneurial activity were prominent among the
strategic initiatives reported in dealing with an increasingly turbulent
environment. Although none of the ATHs had experienced negative net margins, we
conclude that today's competitive healthcare system requires ATHs be reimbursed
separately for their educational and other societally related costs to assist
them in competing on a level playing fields.
PMID- 9543924
TI - Best practices in the best places: benchmarking in the emergency department.
PMID- 9543923
TI - Attracting RNs to nursing homes: nurses' work experience and perceived importance
of organization and job attributes.
AB - Applicant attraction theories stipulate that employment inducements be customized
to meet the desires and specific characteristics of potential applicants. This
study examined the relationship between nurses' level of work experience and
perceived importance of organization and job attributes in attracting them to
nursing home jobs. Importance ratings of recruitment factors varied significantly
by nurses' level of work experience. Unique variation was attributed to education
opportunities, potential for career advancement, compensation issues, benefits,
and work flexibility.
PMID- 9543925
TI - A brave New World.
PMID- 9543926
TI - Transmyocardial laser revascularisation in Edinburgh.
AB - This paper describes a feasibility study to evaluate the Xenon-Chloride Excimer
laser in patients requiring myocardial revascularisation. METHODS: Between
November 1995 and September 1997, 30 patients (aged 48 to 80 years) underwent
Transmyocardial Laser Revascularisation (TMR), either combined with coronary
artery bypass grafting (CABG) or as a sole procedure. These patients were
considered unsuitable for conventional coronary revascularisation on the basis of
angiographic findings. Evaluation included NYHA status, exercise tolerance test,
dobutamine stress echocardiography, Thallium myocardial perfusion scan, with
follow-up scan at 3 months and clinical review at 3, 6, 12 and 18 months.
Operative technique initially was standardised comprising median sternotomy, full
cardiopulmonary bypass, moderate systemic hypothermia and induced ventricular
fibrillation. This was later modified to mini-left anterior thoracotomy, femoral
cannulation with venous centrifugal assist. RESULTS: Patients undergoing TMR also
had conventional grafts whenever possible (18/30 (60%), 1 graft 12/30, 2 grafts
6/30). 14 patients were redo cases, and 12 were unsuitable for further grafts,
and therefore had TMR as a sole procedure. The number of channels created was
between 6 and 100 (mean 45.6 +/- 20.7). The majority of the cases had severe
angina (NYHA classes III or IV) at presentation, with an improvement of at least
2 points postoperatively (p < 0.001) which was sustained throughout the period of
follow-up. Objective evidence of improved myocardial perfusion and function
(dobutamine stress echocardiography and Thallium myocardial perfusion scan) was
obtained in a few patients. Complications following TMR were uncommon-one patient
developed complete AV dissociation requiring permanent pacemaker insertion. No
other specific TMR-related complications were identified. CONCLUSION: Despite
initial difficulties in recruiting adequate numbers of patients, TMR has proved
to be a useful adjunct in relieving angina in patients who are either poor
candidates for surgery or unsuitable for full revascularisation. Modification in
the technique has allowed a less invasive approach and improved recovery period.
PMID- 9543927
TI - Record keeping: legally and professionally important?
PMID- 9543928
TI - Alison Bell Memorial Writer's Award. Research and the practice of scrubbing up in
theatre.
PMID- 9543929
TI - Perioperative pain management: a gate control perspective.
AB - The assessment and management of perioperative pain are critical skills for the
surgical nurse, hence, the subjective nature of pain should be reflected in their
approach to pain control. Unfortunately, many studies (Seers 1987, Kuhns et al
1990, Royal College of Surgeons and Royal College of Anaesthetists 1990, Closs
1992 and Field 1996) suggest that the nurse's knowledge of perioperative
management is inadequate. However, as Carr (1997) reported, nurses are not the
only group of health care professionals who demonstrate a lack of 'expertise' in
providing analgesic relief. Carr reviewed the survey of 27 medical schools by
Marcer and Deighton in 1988 which revealed that 4 schools undertook no formal
teaching on pain control, and the remainder averaged only 3.5 hours during a four
year course. Clearly, perioperative pain management remains a major problem! We
have suggested that surgical nurses must have a sound knowledge of the
neurophysiology associated with this subjective phenomenon (Clancy and McVicar
1998) since such an understanding is paramount in assisting the decision making
process which underpins effective individualised perioperative pain management.
PMID- 9543930
TI - Are you research minded?
PMID- 9543931
TI - Rearranging the deckchairs on the Titanic.
PMID- 9543933
TI - Let the bank feed the river.
PMID- 9543934
TI - Spirituality and practice. Stories, barriers and opportunities. Interview by
Laurence A. Savett.
AB - What are "spiritual matters?" Are "spiritual matters" the same as "religious
matters?" What is spiritual inquiry? Are such questions appropriate for those of
us in the caring professions, other than clergy, to consider? If we accept that
role, how far should we go? When should we call for help? Whom should we call? We
convened a gathering of a hospital chaplain, a social worker, a hospice nurse and
a physician to discuss many of the dimensions of spirituality and then to apply
their personal and professional paradigms of care to a discussion of an actual
case. This article is a record of that conversation. It is actually several
articles in one, for it deals with their own views of the meaning of
spirituality, the degree to which their spirituality has impact on their
practice, what they see as the merit of spiritual matters in the caring
professions, barriers to collaboration among their professions and to addressing
these issues with patients, and boundaries beyond which one should not go. One
way to read this conversation is to include yourself; that is, to reflect on the
points the participants make and the ways in which you might integrate their
insights into your personal practice. We hope that you find this task worthwhile
and that it provokes further thought and discussion. The discussion began with
participant introductions.
PMID- 9543935
TI - Spiritual self-care: the healer's journey.
PMID- 9543936
TI - Hope in healthcare today.
PMID- 9543937
TI - The patient as focus in differentiating nursing practice.
PMID- 9543938
TI - Home care's situational crisis.
PMID- 9543939
TI - Nursing interventions with advanced osteoporosis.
AB - The patient with advanced osteoporosis presents with multisystem dysfunction, a
decrease in ability to perform activities of daily living (ADLs), and often both
acute and chronic pain. These men and women may experience depression and loss of
self-esteem as well as future disability and increasing physical dependence. In
the short time and limited visits allowed, the home care nurse can act as
advocate, teacher, and caregiver in helping these patients to reach the goals of
maintaining function and improving their quality of life.
PMID- 9543940
TI - The physical therapist as a member of the home healthcare team: caring for
patients with replacements.
AB - The projected life of a total knee and total hip replacement today is
approximately 15 years. Orthopedic surgeons are therefore very cautious to
replace joints in patients who are young, believing that if patients receive
joint replacements in their mild or early 60s, there is a good possibility they
may outlive the replacement and thereby require a revision. One role of physical
therapy with the postoperative replacement patient is education of the patient in
precautions that should be observed and guidelines to be followed for general
activities. This is very valuable information that should be shared with the
patient before surgery and reinforced afterward. In the changing healthcare
environment of the 1990s, home healthcare professionals are being challenged to
provide effective, skilled care that is the most cost effective and appropriate
for patients. It is important that all professional home healthcare personnel
work as a team to accomplish these goals. The PT is an important member of this
team. After an acute illness or injury, or throughout the course of a chronic
illness, there are numerous times when home healthcare patients will benefit from
skilled PT services. Home healthcare nurses are in a unique position to recognize
the need to work with the patient's physician for referral to other members of
the healthcare team.
PMID- 9543942
TI - Home care nursing as a philosophy of care.
PMID- 9543941
TI - Assessing the high-risk pregnant woman at home.
AB - Many women with high-risk pregnancies such as pregnancy-induced hypertension and
preterm labor are being managed in their homes. By using tools designed to detect
subtle changes in the health status of the woman and her fetus, the home
healthcare nurse can have a positive impact on the treatment and outcome of the
pregnancy.
PMID- 9543943
TI - Pharmacologic pain. Management for cancer patients at home.
AB - Pain management is one of the most important responsibilities of the home care
nurse serving cancer patients. Patients and caregivers often fear uncontrolled
pain, and need frequent reassurance that effective pain control can be achieved.
This article discusses the etiology and types of cancer pain, pain assessment,
pharmacologic pain management interventions, and evaluation of pain management
for home care patients.
PMID- 9543944
TI - Beyond venipuncture as the qualifying service for Medicare: seeing the forest for
the trees.
PMID- 9543946
TI - A message from a client.
PMID- 9543945
TI - Sexual activity and knowledge of safe sex reported by HIV-infected persons
receiving home care.
AB - Sexual activity and knowledge of safe sex were assessed for 57 human
immunodeficiency virus (HIV)-infected persons on admission to home care. More
than one third of the individuals providing information were sexually active; 72%
of the sexually active persons reported that they practiced safe sex. Definitions
of safe sex were inconsistent, particularly regarding safety of oral sex. Needs
for counseling on safe sex of HIV-infected persons receiving home care practices
were clearly evident.
PMID- 9543947
TI - Home care fraud & abuse: dishonest documentation.
PMID- 9543948
TI - The coffee connection: the benefits of memory.
PMID- 9543949
TI - The American Academy of Pediatrics recommendations on breastfeeding and the use
of human milk.
PMID- 9543951
TI - HIV transmission via breastfeeding: reflection on the issues.
PMID- 9543950
TI - Fortified human milk: nature's way to feed premature infants.
PMID- 9543952
TI - Rethinking latch-on problems.
PMID- 9543953
TI - Breastfeeding as the norm.
PMID- 9543954
TI - WIC-based interventions to promote breastfeeding among African-American Women in
Baltimore: effects on breastfeeding initiation and continuation.
AB - We evaluated the single and combined effects of introducing a motivational video
and peer counseling into four matched WIC clinics on breastfeeding initiation and
continuation at 7-10 days among African-American WIC participants. Of the 242
women with complete data, 48% initiated breastfeeding, but only 31% were still
breastfeeding at 7-10 days. Initiation was associated with cesarean delivery,
infant feeding instruction, no artificial milk discharge pack, attending the peer
counselor only-intervention site, and intention to breastfeed. Continuation was
influenced by infant feeding instruction, no artificial milk discharge pack, and
intention to breastfeed. Overall, trends toward a positive impact of the
breastfeeding promotion activities were evident but weak, and largely gone by 7
10 days postpartum.
PMID- 9543955
TI - The anticarcinogenic conjugated fatty acid, 9c, 11t-18:2, in human milk:
confirmation of its presence.
AB - The concentration of the anticarcinogenic fatty acid, 9c, 11t-18:2, in human milk
was determined by gas-liquid chromatography (GLC). The mean concentration of 20
samples from 5 women taken at 1, 7, 14, and 21 days was: 0.18% +/- 0.02; range,
0.14-0.28%. Identity was confirmed by GLC-mass spectrometry (MS). Conjugated
isomers other than 9c, 11t-18:2 were not detected. The amounts were not changed
by supplementation of the maternal diet with fish oil beginning on day 1 after
the milk sample was taken.
PMID- 9543956
TI - Breastfeeding of very low birth weight infants.
AB - This research examines the rate of breastfeeding among mothers of very low birth
weight infants (VLBW, < 1500 grams), and the correlates of breast milk pumping
and transition to nursing at the breast. Eighty-two mothers and their 69
singleton and 21 twin VLBW infants admitted to the Neonatal Intensive Care Unit
(January 1-June 30, 1995) of an urban tertiary care hospital. Maternal
demographic, infant birth, and neonatal data were compared according to breast or
bottle feeding, and a telephone interview was administered retrospectively to
mothers pumping breast milk at the time of the infant's discharge home. Of 39
mothers who chose to pump breast milk, 19 were still pumping at the time of the
infant's discharge home. Only 8 made a successful transition to nursing at the
breast. Mothers who continued pumping tended to be white, married, and older, and
their infants had fewer neonatal complications. The rates of prolonged breast
milk pumping and of nursing are very low. Specific interventions and better
support might improve the success rates.
PMID- 9543958
TI - The role of social support in breastfeeding promotion: a literature review.
AB - The current worldwide decline in the initiation and duration of breastfeeding has
increased the need for effective breastfeeding promotion. Promotion policies and
programs need to be sensitive to those factors that may help or hinder a mother
in her efforts to breastfeed. Such factors include sociodemographic
characteristics, maternal employment, and social support. Social support that
increases breastfeeding includes emotional, tangible, and educational components
from both informal social network members (male partner, mother, family/friends)
and professional network members (health care professionals, lactation
consultants). Conversely, negative social support may decrease breastfeeding.
PMID- 9543957
TI - Prenatal lactation advice and intention to breastfeed: selected maternal
characteristics.
AB - This study uses data from the NICHD/MMIHS to examine the relationship among
maternal characteristics and (a) whether mothers were asked by their prenatal
providers to consider breastfeeding and (b) mothers' prenatal plans on how to
feed their infants. Only 37% of the study population reported that their
providers advised them to consider breastfeeding. Proportions of women who
received prenatal advice to breastfeed and who intended to breastfeed were higher
among married, Caucasian non-Hispanic, primiparous mothers, and women who were
not enrolled in WIC. Women who received advice to breastfeed had significantly
higher rates of planning to breastfeed (61.1%) than women who did not receive
this advice (34.7%; p < 0.005). Efforts to meet the DHHS Healthy People 2000
objective for 75% of women to breastfeed in the early postpartum period will
require a concentrated effort by prenatal providers to help women overcome their
resistance to breastfeeding by offering support and encouragement.
PMID- 9543959
TI - Breastfeeding a baby with a cleft palate: a case report.
AB - A case report is presented on the experience of breastfeeding a baby with a cleft
palate. The importance of breastfeeding for the baby and the mother is discussed
as well as the importance of support from health care professionals. Problems are
described relating to (a) the long term maintenance of lactation by exclusive
breast pumping; and (b) the lack of information available on feeding techniques
and devices helpful in breastfeeding prior to and following palate repair.
Practical suggestions are proposed for expressing and feeding expressed milk to a
baby with a cleft palate.
PMID- 9543960
TI - A breastfeeding teaching tool using a sandwich analogy for latch-on.
AB - Effective latch-on is central to comfortable, efficient breastfeeding. Since
breastfeeding involves taking a large mouthful of an even larger object, a latch
on teaching model based on bottle-feeding or on suction alone may be
inappropriate. A model based on the way in which an adult approaches a large
sandwich, using a water balloon to demonstrate, can help a mother and baby
achieve an effective latch-on for breastfeeding.
PMID- 9543961
TI - Statistical report of the 1997 IBLCE Examination.
PMID- 9543962
TI - Sedatives and hypnotics in lactation.
PMID- 9543963
TI - How to order banked donor milk in the United States: what the health care
provider needs to know.
PMID- 9543964
TI - Effects of preoperative ambulatory gynecological education: clinical outcomes and
patient satisfaction.
AB - Because of the limited access to health care providers in ambulatory care,
individual patients must assume presurgical and postsurgical responsibility for
their own well-being. The purpose of this study was to identify optimal methods
of preparing patients for surgery. The clinical outcomes, length of stay in PACU,
and satisfaction of two groups of patients were compared using an experimental
design. Thirty patients who were scheduled for laparoscopic tubal ligation were
randomly assigned to either the experimental (structured) or control
(unstructured) education program. Clinical data about return to baseline vital
signs, use of analgesics, experiences of nausea and vomiting, and length of stay
in PACU were assessed via retrospective chart review. Patient satisfaction with
the instruction program was measured by a telephone interview using the Patient
Satisfaction Index. Results of t-tests, repeated measures (ANOVA), and sign tests
identified no significant differences concerning clinical outcomes except for
analgesics requested and received. Time between Phase I and Phase II and
discharge was not statistically significant. Future research is needed on major
ambulatory surgical procedures combined with an alternate method to assess
attitudinal data.
PMID- 9543965
TI - Factors influencing successful discharge after outpatient laparoscopic
cholecystectomy.
AB - Advanced laparoscopic and laser technologies have revolutionized the treatment of
gallbladder disease. A new treatment, laparoscopic cholecystectomy, allows direct
visualization of the abdominal cavity by means of a laparoscope and the removal
of the gallbladder with only four small 0.5-inch incisions. For the majority of
laparoscopic cholecystectomy patients, this service is provided in an ambulatory
surgery or free-standing outpatient surgery center. Ambulatory surgery patients
must meet established criteria before being discharged, but not all patients are
successful in meeting discharge criteria. Many must be admitted overnight for
further observation and treatment. Problems delaying discharge at one facility
related to pain control, inability to ambulate, or uncontrolled nausea. This
inability of patients to be discharged impacted on unit staffing, hospital
productivity and cost, and patient satisfaction. This article discusses the
factors that influenced the discharge outcome of patients undergoing elective
laparoscopic cholecystectomy surgery at an ambulatory surgery center in an urban
community hospital. Contributing factors included time of surgical procedure,
comorbidity, premedication for pain (preemptive analgesia), and incisional local
anesthesia. This information is important to providers caring for this patient
population. Careful screening processes and development of treatment protocols
related to the contributing factors will enhance the ability to safely discharge
laparoscopic cholecystectomy patients.
PMID- 9543966
TI - Perianesthesia care of adult and pediatric strabismus surgery patients.
AB - Strabismus procedures on children and adults are frequently performed in an
outpatient setting. Perianesthesia care of patients having strabismus procedures
may be optimized by recognizing the characteristics of strabismus patients, the
frequently associated diagnoses that may affect perioperative care, and the
specific surgical techniques used to treat strabismus. Complications including
postoperative nausea, pain, prolonged PACU stay, and unplanned postoperative
admissions can be minimized and treatment facilitated by preparing patients with
preoperative instructions, careful choice of anesthetic agents and postoperative
medications, and appropriate perioperative care. This report will provide a brief
review of surgical strabismus, including current techniques, and present
guidelines for perioperative care of pediatric and adult strabismus patients.
PMID- 9543967
TI - Computer and information technology: hardware.
AB - Computers open the door to an ever-expanding arena of knowledge and technology.
Most nurses practicing in perianesthesia setting were educated before the
computer era, and many fear computers and the associated technology. Frequently,
the greatest difficulty is finding the resources and knowing what questions to
ask. The following is the first in a series of articles on computers and
information technology. This article discusses computer hardware to get the
novice started or the experienced user upgraded to access new technologies and
the Internet. Future articles will discuss start up and usual software
applications, getting up to speed on the information superhighway, and other
technologies that will broaden our knowledge and expand our personal and
professional world.
PMID- 9543968
TI - Differentiation of atrioventricular blocks.
AB - In closing, it has been the purpose of this article to present and elaborate on
the types of AV blocks, their clinical significance and causes, nursing
interventions, and treatments associated with their management. The nurse that
has knowledge of these heart blocks will be well equipped and prepared to
promptly treat a patient suffering from AV block.
PMID- 9543969
TI - Science and theory.
AB - This manuscript presents some of the basic concepts of science and scientific
reasoning. Whether you are reading research or planning to do a Master's thesis,
understanding these concepts will be important. How theories differ from beliefs
and their ultimate practicality are discussed.
PMID- 9543971
TI - Forget authority--go for power.
AB - Real power comes from the ability to influence other people. The organization is
constantly changing, and when it gives a manager authority, it does not confer
power with it. With authority comes responsibility and accountability. What
managers need is power. Power comes from understanding values, and is the key to
bridging the gap between authority and accountability.
PMID- 9543970
TI - Postextubation laryngeal edema: a review with consideration for home discharge.
AB - Respiratory complications occurring in the immediate postoperative period are
well known to the seasoned postanesthesia care unit nurse. The most common
adverse respiratory events originating in this setting are airway obstruction,
hypoventilation, hypoxemia, and pulmonary aspiration of gastric contents. The
focus of this article details airway compromise secondary to edema of the larynx
and adjacent structures as a consequence of translaryngeal intubation.
Postextubation laryngeal edema is a relatively rare problem; however, severe
episodes may have life-threatening ramifications. A review of pertinent airway
anatomy and airflow dynamics as they relate to this compromised airway condition
is presented. Risk factors for the development of postextubation laryngeal edema
plus contemporary patient treatment strategies will be reinforced. Patient
management issues are addressed, with emphasis placed on the ambulatory patient
in which discharge to a remote location is anticipated.
PMID- 9543972
TI - Treat them tenderly.
PMID- 9543973
TI - The challenge of effective professional practice.
PMID- 9543974
TI - A comparison of dressings in the management of surgical abdominal wounds.
AB - This prospective randomised trial compared the performance of three dressing
protocols in the management of 36 dehisced surgical abdominal wounds: a standard
alginate; a gauze moistened with sodium hypochlorite (0.05%); and a combine
dressing pad. Outcomes assessed were: healing time (cm2 per day and cm3 per day),
patient comfort (pain and satisfaction) and cost. There were no statistically
significant differences in healing rates between the three groups but there was a
trend for the combine dressing pad protocol to produce a greater reduction in
wound area. The combine dressing pad protocol performed well when compared with
the calcium alginate in terms of healing time, patient comfort and cost. Maximum
pain was significantly greater (p = 0.011) and satisfaction significantly lower
among patients who received the sodium hypochlorite protocol. Costs during the in
patient phase were also substantially higher for the sodium hypochlorite
protocol. Trial results support the view that sodium hypochlorite dressing
protocols for surgical wounds should be abandoned.
PMID- 9543975
TI - A comparison of two amorphous hydrogels in the debridement of pressure sores.
AB - This study compared the efficacy of two hydrogel dressings in the debridement of
necrotic pressure sores. This randomised, controlled, assessor-blind, clinical
trial involved 50 patients whose wounds were assessed weekly using computerised
wound analysis for four weeks or until debrided. Debridement was identified when
there was 80% red granulation tissue present and no sign of necrosis. There were
no statistically significant differences in comfort, wound odour, surrounding
skin condition or time to debridement between the two groups.
PMID- 9543976
TI - An evaluation of hyper-oxygenated fatty acid esters in pressure sore management.
AB - The aim of this study was to use transcutaneous oxygen pressure (tcpO2)
measurements to evaluate the efficacy of a solution containing hyper-oxygenated
fatty acid esters in the prevention of pressure sores in 28 patients at high risk
of developing sores. Statistical analysis indicates a significant difference
between tcpO2 values during pressure exertion before and after application of the
product (p = 0.014). Oxygen pressure values decreased significantly when the
patient applied pressure to the sacral area before the test product was applied
whereas no difference in oxygen pressure values was noted after application of
the test product.
PMID- 9543977
TI - Hospital-acquired pressure sores in surgical patients.
AB - This study is based on a retrospective analysis of case notes of 314 elective and
emergency patients who underwent major surgical procedures between November 1995
and March 1996. The research is part of a larger project on pressure sores in
surgical patients. The effects of patient characteristics and the organisational
processes of care on the development of hospital-acquired pressure sores were
examined. Factors identified can be used as parameters in the assessment of
pressure sore risk in surgical patients. This report presents the preliminary
results of the univariate statistical analysis.
PMID- 9543978
TI - Wound-healing problems associated with cancers.
PMID- 9543979
TI - Minimising risk factors in pressure sore care.
PMID- 9543980
TI - Pressure sore risk assessment.
PMID- 9543981
TI - Community leg ulcer clinics and the effectiveness of care.
PMID- 9543982
TI - Healing in the nasal mucosa.
PMID- 9543983
TI - The pathophysiology and treatment of diabetic foot disease.
PMID- 9543985
TI - [The concept and practice of empowerment related to health promotion].
PMID- 9543984
TI - [Health promotion in health education].
PMID- 9543986
TI - [Self control and self care].
PMID- 9543987
TI - [Modeling theory and its future in health education].
PMID- 9543988
TI - [Diabetes education and self efficacy].
PMID- 9543989
TI - [Nursing care of children requiring home parental nutrition and their families:
descriptive study of 7 children with gastrointestinal disorders].
PMID- 9543991
TI - [Development of an observational method of sleep state].
PMID- 9543990
TI - [Relationship between the experience of steroids side effects and noncompliance
with oral steroids treatment in collagen disease patients].
AB - PURPOSE: To analyze the relationship between the experience of side effect and
the compliance with oral steroids drug treatment of the patients in Collagen
Disease Clinic. METHODS: A questionnaire survey through interview was conducted
on 165 outpatients with various collagen disease at Saga Medical School Hospital.
RESULTS: 94 patients (57%) had a history of noncompliance to the steroids drug.
49 patients (52.1%) adventitiously had forgotten to take the steroids as ordered
and 45 patients (47.9%) intentionally had regulated their steroids dose or had
discontinued the steroids drug treatment. Over 80% of the patients had
experienced side effects of the steroids. The patients who experienced one or
more of the following side effects, osteoporosis, bone fractures, menstrual
disorders, moon face, central obesity, alopecia, acnelike eruption, manic
depressive state, and insomnia, intentionally regulated, or discontinued the
steroids therapy. In addition, the patients who were not made cognizance about
side effects of the steroids by their physicians and nurse tended to
noncompliance group. CONCLUSION: To increase the compliance rate with oral
steroids drug treatment, we must make conscious efforts to inform the patients on
the condition of their medical states, the efficacy of the prescribed drugs, and
the side effects and risk concerning discontinuation of the steroids. It is Also
necessary to establish "Drug information and counseling day" in outpatient
Department.
PMID- 9543992
TI - [Quality of life of children and adolescents with cancer: telling diagnosis,
support systems, length of hospitalization, and home care].
PMID- 9543994
TI - [Survey and research (12). Steps in the survey process: testing reliability of
scales].
PMID- 9543993
TI - [Survey of studies on the role of play in child nursing].
AB - In this survey, 103 papers submitted to several nursing societies and published
in leading nursing journals are outlined and analyzed in terms of motives for
studies, kinds of play enjoyed by the subjects and effects of play on members of
ward staff, child patients and their family members. The articles are listed in
chronological order so that the changes and trends in the studies in this field
will be shown. Studies on play started and developed in the clinical field for
better ward management and more effective treatment. However, effects of play on
development of child patients gradually became the focus of the studies. In terms
of the subjects' level of health, it used to be limited to chronically
hospitalized patients who were not behaviorally limited. The scope of the
subjects has widened to include "every health level". It's now purported that
every patient regardless of his/her health level should enjoy the benefits of
play. Regarding kinds of play, indoor plays were initially predominant, but
subsequently outdoor activities became more popular with the playing repertoire
increasing. Infantile stage has been and still is most frequently discussed in
the field, while other developmental stages are now attracting more attention
than before.
PMID- 9543996
TI - Juggling work and the family.
PMID- 9543997
TI - Liability arising out of professional disciplinary law.
PMID- 9543998
TI - Dealing with chronic illness.
PMID- 9543999
TI - ANF Biennial Conference.
PMID- 9544000
TI - Inreach team's a winner.
PMID- 9544001
TI - Nurses' attitudes to voluntary euthanasia.
PMID- 9544003
TI - President's report.
PMID- 9544004
TI - Jo Leavy. Interview by Kimberly O'Sullivan.
PMID- 9544005
TI - Taking time for ourselves.
PMID- 9544006
TI - Breaking the boundaries: collaborating to develop a model ventilator training
program.
AB - Changes in the health care system have created new opportunities for acute care
nurses to establish collaborative relationships with their rehabilitation
partners. When a rehabilitation facility decided to establish a ventilator
weaning rehabilitation program, an acute care facility joined forces with the
institution to develop an educational plan for the nursing staff. The development
and implementation of the educational program as well as the collaborative
relationship established between the two facilities are highlighted in this
continuing education article.
PMID- 9544007
TI - The integration of a tuberculosis control plan into a standard of care for
tuberculosis.
AB - Tuberculosis is a significant public health problem. Health care agencies and
hospitals are mandated to have in place protocols to manage patients with
suspected or confirmed cases and to implement infection control measures to
prevent the spread of the disease. A facility with a high percentage of infected
patients developed and integrated a standard of care to improve the management
and outcomes of infected patients.
PMID- 9544008
TI - Implementing a residency program for the acute care nurse practitioner.
AB - A clinical residency program for acute care nurse practitioners (ACNPs) was
developed to facilitate the strengthening of practice competencies and role
performance. Strengthening collaboration between physicians and ACNPs and
supporting the growth of ACNPs through supportive and individualized learning
opportunities were key components to a highly successful initiative.
PMID- 9544009
TI - Nurses' perceptions of why medication administration errors occur.
AB - Nurses play a key role in medication administration in hospital settings. Five
categories of reasons for medication errors were identified in a survey of 1,384
nurses. These categories include physician, systems, pharmacy, individual, and
knowledge-related factors. In this article, issues surrounding the occurrence and
prevention of medication errors are discussed.
PMID- 9544010
TI - Describing pain management documentation.
AB - Managing postsurgical pain continues to be one of the nation's top clinical care
priorities and concerns. Despite widely publicized national care guidelines,
effective pain management for all patients is not a reality. This study explored
how nurses in a community hospital documented the process of pain management for
a group of postsurgical patients. The results have implications for all adult
health nurses.
PMID- 9544011
TI - In search of a 'magic' pill to treat obesity: the rise and fall of 'Fen-Phen'.
PMID- 9544012
TI - A road map for navigating end-of-life care.
AB - As nurses begin to develop the sensitivities and skills necessary to preserve the
integrity of clinical care and professional life, they must recognize the
legitimacy of their perspectives and the value and consequences they have for the
well-being of patient and family care. Nurses have much to contribute to the
development of ethical practice environments for patients, families,
multidisciplinary team members, and themselves. The frenzied, and at times
anesthetized, culture of clinical settings can mitigate against the kind of
deliberate reflection that is necessary if nurses are to act with ethical
integrity. Knowing the rules of the road for end-of-life care and being attentive
to common warning signs and addressing them proactively, enables nurses to
provide patients and families with the highest quality care at the end of life.
PMID- 9544013
TI - Transforming the workplace.
PMID- 9544014
TI - An update on nursing involvement in hospital governance: 1990-1996.
AB - The purpose of this study was to examine the nature and extent of nursing
involvement in hospital governance in 1994; compare the 1994 level of involvement
to 1990 levels; compare 1990 projections for 1995 to the actual state in 1994;
and examine CNEs' projections of the nature and extent of involvement in 1996.
The database compiled in the study and the author's earlier work (Havens, 1990,
1992) will assist in efforts to monitor nursing's status in hospital policy
making as monumental structural changes take place in health care organizations.
PMID- 9544015
TI - Managing change in health care redesign: a model to assist staff in promoting
healthy change.
PMID- 9544016
TI - Delegation skills and nurse job satisfaction.
AB - In this study, the mean age was 41 and these nurses had been out of school for
approximately 13 years. Over half of these RNs had never been taught delegation
skills in nursing school. Of those who were exposed to the concept of delegation,
their skills were not adequate to meet the patient care demands in the
restructured health care system. During these challenging periods in health care,
it is imperative that nursing service administrators provide RNs with the
continuing education necessary to develop delegation strategies to adapt to their
evolving professional roles. Continuing education classes on delegation skills
are requisite for RNs practicing in a competitive managed care environment. As we
approach the year 2000, the economic climate will dictate that RNs be skilled not
only as clinicians, but also as leaders of the health care team. The findings of
this study support that delegation decision-making skills enhance job
satisfaction in the areas of decision making and promotional opportunity.
Delegation knowledge is crucial to the successful direction of the health care
team in the managed care environment.
PMID- 9544017
TI - Facilitating instrument evaluation.
PMID- 9544018
TI - Information technology: strategies for success.
PMID- 9544019
TI - Awake and talking: ambulatory surgery and conscious sedation.
PMID- 9544021
TI - Are you aware?
PMID- 9544020
TI - Turnaround hospitals...
PMID- 9544022
TI - About being a nurse...
PMID- 9544023
TI - Does JCAHO require one nurse executive?
AB - Rumors have been flying that the Joint Commission is going to eliminate the
requirement for a single nurse executive as required by standard NR. 1 in the
Comprehensive Accreditation Manual for Hospitals (CAMH). This column clarifies
the JCAHO's intent in this regard.
PMID- 9544024
TI - Subacute care: creating alternatives. Reengineering: the key to survival and
growth under PPS.
AB - Many postacute care providers are concerned about the effects of the prospective
payment system on skilled nursing facilities. To retain their contractual
arrangements, physical, occupational and speech therapists are trying to develop
services within the financial constraints the PPS imposed. Management and staff
of SNFs also are struggling with the Resource Utilization Groups III and the
Minimum Data Set that will be the basis for the predetermined, per diem, all
inclusive fixed rate to be paid. The most logical approach to dealing with this
crisis is to reengineer all of the SNFs' processes.
PMID- 9544025
TI - Risk adjustment for health status.
AB - A managed care plan's capitation payments should include an adjustment for its
members' health status. Demographic and diagnostic information can be used to
make the adjustment, which would help to minimize a health plan's potential
financial liabilities. Without the adjustment, health plans have an incentive not
to enroll persons with the heaviest care needs.
PMID- 9544026
TI - A new millennium for health care IT: the year 2000 conversion.
AB - The new millennium. It means many things for many people, from astrologers to
information technology (IT) professionals. But the latter, especially those in
health care, have good reason to be concerned. Because for the majority of
computer systems, January 1,2000, marks both the beginning of a new decade and
total system chaos.
PMID- 9544027
TI - Liability for falls.
AB - Reengineering of roles, inexperienced personnel and poor communications among
departments has led to an increase in patient falls--a major source of liability.
While health care facilities are not liable for all falls, they are expected to
take precautions based on patients' deficits.
PMID- 9544028
TI - Competencies drive decision making.
AB - Staff nurses, using the Nursing Interventions Classification, selected the core
competencies, performance criteria and interventions relevant to their practice.
A performance-based approach highlights performance outcomes and previous
experience. A preceptor and self-directed learning activities help apply the
knowledge in the work setting.
PMID- 9544029
TI - A nursing fellowship--building leadership skills.
AB - A postgraduate nursing fellowship helps future nursing leaders deal with constant
change, focus on learning and development, think systemically and mobilize
resources through team building and goal directedness. An administrative
fellowship program helps to develop future leaders, with the skills necessary to
assume key positions in health care. Core competencies--leadership criteria,
roles of the fellow and preceptor, skills of the fellow and preceptor and
fellowship projects--are described.
PMID- 9544030
TI - The leader meter--a feedback survey.
AB - A survey rates leadership behavior at all levels. The confidential feedback
survey accomplishes three things: (1) it gives valuable feedback about leadership
skills; (2) it gives employees a voice or a chance to be heard; and (3) it
encourages teambuilding.
PMID- 9544031
TI - Continuing care beyond the hospital walls and onto the streets.
AB - Trauma center nurses joined forces with their city's leaders and organizations to
address juvenile violence and crime. Metropolitan Partners Against Crime's
primary initiatives focus on overcoming race, class and gender variances and
establishing community awareness programs.
PMID- 9544032
TI - A patient resource program--strengthening primary nursing.
AB - A patient resource program addresses fragmentation of care, duplication and
blurred accountability. This centralized referral service uses experts such as
clinical nurse specialists, enterostomal therapists and pain management nurses to
improve the primary nursing care model.
PMID- 9544033
TI - Managing nurse managers--what is the secret?
AB - What can managers do to ensure a nurse manager's competency and effectiveness in
today's dynamic health care environment? Strategies on how to lead nurse managers
and, in turn, help build a strong health care environment through effective
nursing management are given.
PMID- 9544034
TI - Nursing council ... coordination within decentralization.
AB - A nursing council modeled after the traditional five nursing roles--manager,
educator, practitioner, evaluator and researcher--improves patient outcomes and
enhances nurse work satisfaction. The council provides a participative forum to
address nursing and patient-care issues within a decentralized matrix
organization.
PMID- 9544035
TI - Peer interviewing: sharing the selection process.
PMID- 9544036
TI - Initiating action through understanding.
PMID- 9544037
TI - About preparing for managed care.
PMID- 9544038
TI - The time of their lives.
PMID- 9544039
TI - Debate of the age.
PMID- 9544041
TI - He's doing it my way.
PMID- 9544040
TI - Cradle to bus pass.
PMID- 9544042
TI - A healthy outlook?
PMID- 9544043
TI - A healthy outlook?. Interview by Charlotte Alderman.
PMID- 9544044
TI - Patients first.
PMID- 9544045
TI - Organising the workforce: annual hours in nursing.
PMID- 9544046
TI - Managing pressure sores.
PMID- 9544048
TI - The student's role in child nursing.
PMID- 9544047
TI - Learn about plans for the health service of tomorrow.
PMID- 9544049
TI - Forum bridges the divide.
PMID- 9544051
TI - Healthy practice is vital for teachers.
PMID- 9544050
TI - Clinical placements--are students treated properly?
PMID- 9544052
TI - Practical procedures for nurses. 9.2. Mouth care--2.
PMID- 9544053
TI - Nutrition in practice. 10. Nutrition and the elderly.
PMID- 9544054
TI - It's purely professional.
PMID- 9544055
TI - Calming measures.
PMID- 9544056
TI - Losing contact with ground control.
PMID- 9544057
TI - Legislation in the area of HIV infection.
PMID- 9544059
TI - Nursing management.
PMID- 9544058
TI - Mental health services.
PMID- 9544060
TI - Not a plain sailing.
PMID- 9544061
TI - Me and my doll.
PMID- 9544062
TI - On duty off shore.
PMID- 9544063
TI - Elderly care--waiting for a health return. Interview by Janet Snell.
PMID- 9544064
TI - Mental health--out of the darkness.
PMID- 9544065
TI - Face to face. Interview by Craig Kenny.
PMID- 9544066
TI - Forensic nursing.
PMID- 9544067
TI - Sexually transmitted diseases. Gonorrhoea: symptoms and treatment.
AB - This article continues our series looking at common sexually transmitted
infections. It focuses on gonorrhoea, its symptoms and treatment. The nursing
management and patient's experience are discussed in a case study.
PMID- 9544068
TI - Developing a reflective standard of care.
AB - Developing and monitoring effective practice is essential in health care
organisations. Reflective practice offers practitioners and organisations a means
to understand and learn through experience in complex care situations and develop
expertise. This paper describes standard-setting in a hospice to construct a
standard for managing patients who exhibit aggressive behaviour as part of their
terminal illness.
PMID- 9544069
TI - The care programme approach: a patient perspective.
AB - This study explores the attitudes and experiences of one group of patients on the
care programme approach living in an outer London borough. There was evidence to
suggest that patients were unfamiliar with their treatment programmes and lacked
knowledge regarding their care. Further research into patient attitudes to the
CPA would be beneficial, since it was not possible to make precise conclusions
based on this study.
PMID- 9544071
TI - Feed the patient, fool the pancreas.
PMID- 9544070
TI - Skills for preventing aggression.
AB - This case study shows how the assessment and action taken helped a person with
severe learning disabilities to adjust to life outside a hospital secure unit.
PMID- 9544072
TI - Know how nutritional assessment.
PMID- 9544073
TI - Gut instinct.
PMID- 9544074
TI - Feeding a habit.
PMID- 9544075
TI - Latex sensitisation--what causes it and what can be done to minimise the risks:
Part 2.
PMID- 9544076
TI - Advanced practice and consent.
PMID- 9544077
TI - Preventing skin cancer.
PMID- 9544078
TI - Clinical supervision for all.
PMID- 9544079
TI - Clinical supervision for specialist nurses.
AB - The UKCC has stated that every practitioner should have access to clinical
supervision. There is little literature on the supervision needs of specialist
nurses. Choosing the appropriate model of supervision and establishing formal
ground rules was essential to the success of the project.
PMID- 9544080
TI - Audit of nutritional practice and knowledge.
AB - An audit of nutritional practice was carried out in one NHS trust. Findings
demonstrated areas for improvement, particularly in the documentation of
nutritional status and in criteria for referral for specialist help. An
assessment sheet and a nursing care plan were developed to assess patients' risk
of being malnourished and to provide a recognised place for recording nutrition
related information.
PMID- 9544081
TI - Peripherally inserted central catheters.
AB - Peripherally inserted central catheters (PICCs) can meet the needs of patients
requiring short- to intermediate-term intravenous therapy in a variety of
settings. PICCs minimise insertion and catheter-related complications when
compared to other central venous access devices (CVADs). PICCs have been
introduced in the UK mainly through innovative advanced nursing practice.
PMID- 9544083
TI - Post-herpetic neuralgia.
PMID- 9544082
TI - Skin cancer.
PMID- 9544084
TI - Nurse prescribing in diabetes.
AB - The adjustment of diabetes medication is vital for the prevention of
complications. Insulin dose adjustment by diabetes specialist nurses is common
practice but its legality is questionable. Two surveys were undertaken to
identify common practice. The results were used to establish the basis for an
effective multiprofessional protocol for nurse administration of diabetes
medication.
PMID- 9544085
TI - Family attitudes to bed-wetting and their influence on treatment.
AB - Bed-wetting can have far-reaching social consequences for the whole family. Seven
types of attitude towards bed-wetting have been identified that can be strongly
predictive of behaviour, including the readiness to engage in and persist with
treatment. Understanding the family's perspective enables a dialogue to be
engaged in which takes account of the reality of the family's circumstances.
PMID- 9544086
TI - Consent and children.
AB - While children aged 16 and 17 years can consent to any surgical or medical
procedure, for those under 16, adults with parental responsibility may give
consent on their behalf. If parents and child disagree, however, the doctor
usually has a choice as to whose wishes he or she should follow.
PMID- 9544087
TI - Changing practice.
PMID- 9544088
TI - Ethics in action.
PMID- 9544089
TI - A CHF program that focuses on best practices and benchmarks.
PMID- 9544090
TI - New hypertension guidelines. Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure.
PMID- 9544091
TI - When your patient is on an insulin pump.
PMID- 9544092
TI - What's wrong with this patient?
PMID- 9544093
TI - Another way to open an airway.
PMID- 9544094
TI - As America ages. Assessing the older patient.
PMID- 9544095
TI - Getting a better read on thermometry.
PMID- 9544096
TI - The legal implications of genetic testing.
PMID- 9544097
TI - Making HIV therapy more manageable.
PMID- 9544098
TI - Keep your boss happy.
PMID- 9544099
TI - [Straight to a criminal case. Interview by Claus Leick].
PMID- 9544100
TI - [Management should take a stand. Interview by Claus Leick].
PMID- 9544101
TI - [Experiencing the situation differently. Interview by Claus Leick].
PMID- 9544102
TI - [There is a lack of discussion and frankness. Interview by Claus Leick].
PMID- 9544103
TI - [Regulations on the way about force against demented patients].
PMID- 9544104
TI - [Regulations ensure safety. Interview by Kirsten Bjornsson].
PMID- 9544105
TI - [Provide demented patients with a companion in the system. Interview by Kirsten
Bjornsson].
PMID- 9544106
TI - [Difficult with ban against code lockup. Interview by Kirsten Bjornsson].
PMID- 9544107
TI - [Overlook hidden medication].
PMID- 9544108
TI - [Farewell to telephone lines and TV lounges].
PMID- 9544109
TI - [Prevention--health gulf between rich and poor must be discarded].
PMID- 9544110
TI - [Observations on progress of care].
PMID- 9544111
TI - [Executive Board--members question services].
PMID- 9544112
TI - [Executive Board--close contact with employers].
PMID- 9544113
TI - [From the mail box].
PMID- 9544114
TI - [Nursing--failure can be prevented].
PMID- 9544115
TI - [Education--research: the young ones lack real knowledge about nursing].
PMID- 9544116
TI - [Education--campaign: new image of the profession].
PMID- 9544117
TI - [Education--research: a professorship in nursing].
PMID- 9544118
TI - [Membership in Norwegian Nurses' Association at any cost?].
PMID- 9544119
TI - [Snowed under by stress].
PMID- 9544120
TI - [Family influence greatly exaggerated].
PMID- 9544121
TI - [Nightmare for the health system].
PMID- 9544122
TI - [Close-up: Tom Ovlien, editorial secretary for Blikk. Tolerant--yet sharp around
the edges. Interview by Kari Anne Aase].
PMID- 9544123
TI - [The normal is problematic. Interview by Kari Anne Aase].
PMID- 9544124
TI - [My workplace: head nurse surgical department, Kongsvinger Hospital. A hazardous
position. Interview by Kjell Arne Bakke].
PMID- 9544126
TI - [Epilepsy--with thunderstorms in the head].
PMID- 9544125
TI - [From bygone days--social and economic conditions for nurses at the turn of the
century].
PMID- 9544127
TI - [Rape--volunteerism for care and support. Interview by Erik Dale].
PMID- 9544128
TI - [Education--where is "the real life"?. Interview by Erik Dale].
PMID- 9544129
TI - [History--cut healthy 60 years ago. Interview by Oddrunn Marie Dyrdal].
PMID- 9544130
TI - [USA--strict demand for licensure. Interview by Jan Erik Andreassen].
PMID- 9544131
TI - [Care of the elderly: geriatrics--only for those specially interested?].
PMID- 9544132
TI - [Care for the elderly--elderly persons needing care should select residential
community carefully].
PMID- 9544133
TI - [When you have power, you have responsibility!].
PMID- 9544134
TI - [Home care nursing--when care is experienced as an affront].
PMID- 9544135
TI - Aortoiliac occlusive disease and gastrointestinal malignancy: changing
therapeutic options.
AB - Treatment of gastrointestinal malignancy encountered unexpectedly during
procedures involving the abdominal aorta continues to be debated. Previously,
simultaneous vascular procedures with intra-abdominal malignancy were rare. Most
underwent vascular reconstruction followed by a delayed aortic procedure. With
recent improvement in axillobifemoral graft patency, a one-stage procedure for
aortoiliac disease should be entertained. We recently encountered a small bowel
lymphoma while beginning an aortic replacement for aortic occlusion. Resection of
a near-obstructing small bowel tumor immediately after axillofemoral
reconstruction provided treatment of both entities at one time. Since the early
description of axillofemoral bypass in 1963, varying success with extra-anatomic
bypass has been reported. Early data for axillofemoral bypass were dismal, but
with recent technical and graft improvements patency has been improved. Occult
malignancy during aortic procedures is uncommon, about 2 to 4 per cent, but when
met is usually dealt with after the patient recovers from the vascular procedure.
With improvements in extra-anatomic bypass results, a single operative period can
be entertained.
PMID- 9544136
TI - Gallbladder diverticulum: a case report and review of the literature.
AB - Gallbladder diverticulum is an unusual and uncommon disease process rarely
discussed in the literature. This disorder may not be diagnosed until surgically
resected. The presentation may entail nonspecific complaints over a prolonged
period as highlighted in a case report of a 17-year-old woman with this disease.
The incidence and pathophysiology of this disease process is correlated to the
symptoms and signs of this patient. The surgical findings, procedure, and outcome
are described.
PMID- 9544137
TI - Successful management of visceral Klippel-Trenaunay-Weber syndrome with the
antifibrinolytic agent tranexamic acid (cyclocapron): a case report.
AB - Klippel-Trenaunay-Weber syndrome (KTWS) is a rare, congenital disorder
characterized by vascular nevus formation, deep venous thrombosis, varicosities,
and hypertrophy of affected tissues. A patient with known thrombosis of his
splanchnic circulation and visceral KTWS presented with life-threatening
hemorrhage from rectosigmoid varices. Portosystemic shunting was not feasible.
Endoscopic sclerosis, variceal ligation, and proctocolectomy were not possible
due to the size and number of the varices. Previous treatment with epsilon
aminocaproic acid had been unsuccessful and complicated by thrombophlebitis.
Conservative treatment with blood transfusions, cryoprecipitate, fresh frozen
plasma, vitamin K, propanolol, and somatostatin analog failed to stop the
bleeding. The patient was given the antifibrinolytic agent, tranexamic acid, with
cessation of his hemorrhage. Serial thromboelastograms confirmed improved
reaction time, coagulation time, clot formation rate, and maximum amplitude. We
conclude that tranexamic acid may be a useful adjunct in the medical treatment of
high-risk patients with KTWS and other vascular nevi complicated by coagulopathy.
PMID- 9544139
TI - Mucoepidermoid carcinoma of the thyroid gland arising from a papillary epithelial
neoplasm.
AB - We report a case of mucoepidermoid carcinoma of the thyroid gland. The
simultaneous association of papillary and mucoepidermoid carcinoma in a
Hashimoto's thyroiditis makes the present observation unusual. Surgery was
limited due to local extension of the neoplasm. The patient consequently
underwent external radiotherapy followed by radiometabolic therapy. The patient
survived 11 months after diagnosis. As far as the histogenesis of the neoplasm is
concerned, we believe that mucoepidermoid areas correspond to squamous and
mucinous metaplasia of a preexisting papillary carcinoma. Transition areas
between elements morphologically characteristic of both neoplasms were observed.
Histochemical and immunohistochemical studies confirmed the diagnosis of a
carcinoma with multiple aspects showing a focal positive reaction for
thyroglobulin or keratin antisera. Therefore, this demonstrates different
functional activities of the neoplastic cells. There is still debate about
adjuvant therapies, the results of which appear for the moment very poor.
PMID- 9544138
TI - Ectopic thyroid nodular goiter presenting as a porta hepatis mass.
AB - An ectopic thyroid goiter was found in a 58-year-old woman who presented with
abdominal and low back pain, diarrhea, and generalized weakness. Initial workup,
including abdominal CT scan, revealed a mass extending from the duodenum to the
porta hepatis. After resection and upon pathologic examination of the tissue,
nodular arrangement of thyroid follicles and colloid lakes with focal
hyperplastic and nodular goiter changes were identified.
PMID- 9544140
TI - Small-bowel perforation secondary to metastatic carcinoma of the breast.
AB - Perforation from a solitary metastatic lesion of the small bowel is rare. We
report a case of acute perforation with no evidence of metastatic disease within
the abdomen. Resection of the small bowel was performed.
PMID- 9544141
TI - Nonsurgical pneumoperitoneum: a case report and a review.
AB - The finding of extraluminal gas on plain radiographs is usually associated with a
perforated viscus. But, as this case shows, the finding of pneumoperitoneum is
not pathogenic of a perforated viscus or even of a surgical emergency, because
there are many benign explanations for a pneumoperitoneum. Perhaps the most
important maneuver for differentiating between the two is by performing a through
history and physical examination. This in conjunction with either a diagnostic
peritoneal lavage, contrast studies, or endoscopic evaluation can help prevent a
patient from having needless surgery. The causes of a nonsurgical
pneumoperitoneum are described as well as a treatment plan for patients
presenting with a nonsurgical pneumoperitoneum.
PMID- 9544142
TI - Atherosclerotic aneurysm of the proximal subclavian artery: a case report.
AB - Aneurysms of the upper extremities, and particularly the intrathoracic segment of
the subclavian artery, are unusual. Surgical approach and timing of repair remain
controversial. We successfully treated a case of a large proximal subclavian
artery aneurysm, atherosclerotic in origin. In spite of the size, the symptoms
were vague. The patient underwent partial resection of the lesion located in the
proximal third of the right subclavian artery, and repair using 8 mm dacron
interposition graft. She did well postoperatively and remains symptom free at 1
year. A discussion of this disorder with the relevant literature review is herein
included.
PMID- 9544143
TI - Electrophysiologic nerve stimulation for identifying the recurrent laryngeal
nerve in thyroid surgery: review of 70 consecutive thyroid surgeries.
AB - To describe a simple technique for identifying the recurrent laryngeal nerve
(RLN) with a nerve stimulator to prevent damage to the nerve during thyroid
surgery. A retrospective review of 70 thyroidectomies performed from October 1989
to January 1995 by one surgeon using electrophysiologic nerve stimulation to
identify the RLN was conducted. The technique is described. Outpatient flexible
fiberoptic laryngoscopy was performed preoperatively and postoperatively in all
patients. From 70 thyroidectomies, 80 RLNs were identified to be at risk for
injury. Five patients had transient unilateral vocal cord paresis
postoperatively. No RLN transection or permanent vocal cord paralysis occurred.
This is the first large series of patients undergoing the use of
electrophysiologic nerve stimulation for identifying the RLN during thyroid
surgery. We found the technique to be useful and safe for identifying the RLN. We
present this technique as a less costly and time-consuming alternative to
intraoperative RLN monitoring.
PMID- 9544144
TI - Primary lymphoma of the thyroid.
AB - Primary lymphoma is an uncommon malignancy of the thyroid, comprising between 0.6
and 5 per cent of thyroid cancers in most series. This report is presented
because of a 10 per cent (6 of 60) incidence of this cancer at one institution. A
short history of a rapidly enlarging neck mass often associated with dyspnea,
difficulty swallowing, or voice change is the hallmark presentation of thyroid
lymphoma. The majority of patients are women with a mean age in the 6th decade.
Although fine-needle aspiration has become the procedure of choice for the
diagnosis of a thyroid nodule, it has yielded mixed results with the presence of
lymphoma. The majority of thyroid lymphomas are diffuse, large cell lesions of B
cell origin. Controversy remains as to the role of surgery in thyroid lymphomas.
Within the improvement in results with the use of radiotherapy and chemotherapy
alone or in combination, some authors have advocated relegating surgery to the
role of diagnosis only. This can be accomplished by fine-needle aspiration, core
biopsy, or open biopsy. Others have favored a more aggressive surgical approach,
showing that the amount of residual disease after debulking procedures was
directly correlated with local and distant recurrences. A lack of randomized
prospective studies makes it difficult to resolve this issue. The rates of
complications of surgery, including hypocalcemia and recurrent laryngeal nerve
damage, are higher than for operations for other types of thyroid malignancy.
Improved prognosis has been associated with the following factors: disease
limited to the thyroid, the absence of dysphagia, primary mass less than 10 cm,
tumors without necrosis, and tumors consisting of plasmacytomas.
PMID- 9544145
TI - Lower-extremity saphenous vein transposition arteriovenous fistula: an
alternative for hemodialysis access in AIDS patients.
AB - Arteriovenous access for long-term hemodialysis in patients with the acquired
immunodeficiency syndrome (AIDS) represents a special challenge. Many of these
patients are chronic intravenous drug abusers and do not have patent superficial
upper-extremity veins available for conventional arteriovenous fistulas. This
group of patients is also particularly prone to infections, which contraindicates
the use of prosthetic grafts. Over a period of 13 months, five lower-extremity
saphenous vein transposition arteriovenous fistulas (SVTAFs) were performed. Four
patients had a diagnosis of AIDS at the time of operation; all of these were
intravenous drug abusers. Three patients were male, two were female, and their
age ranged from 34 to 66 years (mean, 48). Three patients had a SVTAF as their
first hemodialysis access, and in two it was performed after multiple failed
upper-extremity accesses. Four fistulas remain patent to date, after a mean
follow-up of 11 months (range, 4 weeks to 16 months). One fistula thrombosed 4
weeks postoperatively, due to a hematoma that occurred after premature
venipuncture for dialysis. There were no other major complications. We conclude
that SVTAF is a suitable alternative to the limited hemodialysis venous access
sites, especially in the AIDS population.
PMID- 9544146
TI - Meandering bullet in the pericardial sac: to remove or not to remove.
AB - Patients with bullets in the pericardial sac without obvious myocardial injuries
are rare, making it difficult to analyze the natural history and propose
management approaches. We present the case of a meandering bullet in the
pericardial sac and a review of the literature.
PMID- 9544147
TI - The CVC removal distress syndrome: an unappreciated complication of central
venous catheter removal.
AB - The removal of a central venous catheter (CVC) can be complicated by rare but
potentially life-threatening neurocardiopulmonary distress. The clinical courses
of eight patients who had CVC removal complications are reviewed. Seven patients
had catheter removal from the right internal jugular vein, and one from the right
subclavian vein. The complications occurred after complete removal of the
catheter (four patients), after guidewire replacement for catheter change (three
patients), and after detachment of the hemostasis side port of the Swan
introducer during sheath removal (one patient). Each of them had more than one
complication. The major complications were: neurologic paresis or coma (four
patients), respiratory failure (four patients), and shock (two patients). One
patient died of pulmonary sepsis. The overall mortality rate was 12.5 per cent.
Guidelines for safe removal of central venous catheters are proposed. Possible
mechanisms of the complications are discussed. We refer to the observed
complications as the CVC removal distress syndrome.
PMID- 9544148
TI - Breaking strength and diameter of absorbable sutures after in vivo exposure in
the rat.
AB - Although absorbable sutures are commonly used in clinical practice, the rate of
decay of strength in various tissues has not been studied. The purpose of this
study was to assess breaking strength (BS) and diameter of monofilament (chromic
gut, polydiaxanone, Maxon, Monocryl) and multifilament (Vicryl, Dexon, Polysorb)
absorbable sutures implanted in various sites and measured at specific time
intervals. A 15 cm length of 4-0 suture from a single lot of each material was
implanted in the pleural space, rectus abdominus muscle, subcutaneous tissue,
intravascular space, peritoneal cavity, and stomach lumen in the rat. A
precipitous decrease in BS was noted in all multifilament sutures after 7 days,
and in chromic gut and Monocryl sutures after 1 day. Polydiaxanone and Maxon
sutures maintained the highest BS over the 28-day period, 71 per cent and 59 per
cent of their initial BS, respectively. Suture diameter remained essentially
unchanged except for chromic gut and the multifilament sutures which exhibited
increased diameter. This increase was attributed to inflammatory tissue
infiltration.
PMID- 9544149
TI - Adenocarcinoid tumor of the ampulla of Vater.
AB - We report a rare case of adenocarcinoid tumor of the ampulla of Vater. The tumor
contained an intermixture of adenocarcinoma and carcinoid tumor and was removed
successfully by pancreaticoduodenectomy. The characteristics of these rare tumors
are reviewed.
PMID- 9544150
TI - Intrathoracic aberrant thyroid: identification critical for appropriate operative
approach.
AB - True aberrant thyroid in the chest is a rarely described entity. More commonly,
"aberrant" thyroid is a substernal goiter that is an extension of the cervical
gland inferiorly and can be removed safely with the classic "collar" incision.
Aberrant intrathoracic thyroid typically derives its blood supply from
intrathoracic sources and requires an alternate surgical approach for adequate
exposure. The ability to identify these rare intrathoracic thyroids is critical
for safe surgical excision.
PMID- 9544151
TI - The role of liver transplantation in the subacute trauma patients.
AB - Two case reports are presented involving complex liver traumas requiring the need
for liver transplantation. Both of these patients were designated unsalvageable
until the transplant team was consulted. It is imperative that surgeons involved
with complex hepatic trauma not give up hope and include these patients as
potential liver recipients when irreversible liver failure occurs.
PMID- 9544152
TI - A Muir-Torre syndrome family.
AB - The Muir-Torre syndrome is a rare autosomal-dominant disease involving sebaceous
neoplasms as markers for multiple internal malignancies. Diagnostic criteria
include at least one sebaceous gland adenoma, epithelioma, or carcinoma and at
least one internal malignancy. The world literature contains 162 cases with 316
internal malignancies. Colorectal and urogenital malignancies predominate, and
nearly half the patients had two or more internal cancers. The discovery of a
Muir-Torre syndrome-associated sebaceous lesion is rare and should prompt an
evaluation for internal malignancies. We report a family over five generations
displaying this syndrome. The proband is a 44-year-old man with two skin and two
colon malignancies who presented to our clinic with the chief complaint of an
infected sebaceous cyst. The world literature is reviewed, and an emphasis on the
surgeon's role in evaluation and treatment is discussed.
PMID- 9544153
TI - Muscle-splitting thoracotomy.
AB - Muscle-splitting thoracotomy avoids transection of the latissimus dorsi and the
serratus anterior muscles, thereby decreasing post thoracotomy pain and
preserving the function and viability of these two muscles. The exposure provided
for most intrathoracic procedures is excellent.
PMID- 9544154
TI - The anterior extrapleural approach to the thoracolumbar junction revisited.
AB - General surgeons often provide the exposure for the anterior repair of vertebral
body lesions. The standard anterior approach to the thoracolumbar junction (T11
L1) is a transpleural 9th or 10th rib thoracoabdominal incision. From October
1995 through March 1997, 22 patients underwent anterior repair of thoracolumbar
junction vertebral lesions through an alternative 11th rib resection while
maintaining an extrapleural approach. Exposure was excellent, as judged by the
neurosurgical team completing the repairs. Chest tubes were not used routinely,
and all patients healed without complications. A major limitation of the 11th rib
extrapleural approach to the thoracolumbar junction has been poor exposure. This
problem is eliminated with the use of an abdominal self-retaining retractor
system. With many potential advantages to this 11th rib exposure (less pain,
fewer pulmonary problems, and better wound healing), we consider the 11th rib
incision to be the approach of choice to the thoracolumbar junction and recommend
renewed interest in this incision.
PMID- 9544156
TI - Clinical pathways for general surgeons: emergency appendectomy without rupture.
PMID- 9544155
TI - Howard Christian Naffziger: the surgeon and his syndrome.
PMID- 9544157
TI - Position statement for the need to define pediatric hematology/oncology programs:
a model of subspecialty care for chronic childhood diseases. Health Care Policy
and Public Issues Committee of the American Society of Pediatric
Hematology/Oncology.
PMID- 9544158
TI - Efficacy of surveillance radiographic imaging in detecting progressive disease in
children with advanced stage neuroblastoma.
AB - PURPOSE: Advanced stage neuroblastoma (NB) is generally associated with a grim
prognosis. Surveillance radiographic imaging is usually performed frequently to
detect progressive (PD) or recurrent disease (RD) and promptly begin salvage
therapy. We studied children with advanced stage NB to determine both how PD or
RD was detected and the impact of detection in asymptomatic versus symptomatic
children on outcome. STUDY DESIGN: A retrospective review of children with NB was
performed between 1984 and 1996. Children with advanced stage NB and RD or PD
were further studied. RESULTS: Thirty-two children with advanced stage NB and PD
or RD were identified. The median time to PD or RD after diagnosis was 1 year 2
months. Nine (28%) children progressed on therapy. One child underwent
confirmatory biopsy of residual scan abnormalities at the completion of planned
therapy. Disease recurred in 22 (67%) children after therapy (median time 6
months). Two children (6%) had RD detected by surveillance studies associated
only with elevated urinary catecholamines. Despite recent normal studies, 29 of
32 children (91%) had onset of new symptoms prompting confirmatory radiographic
studies. CONCLUSIONS: Surveillance radiographic imaging was insensitive in
detecting PD or RD in children with advanced stage NB. Careful history,
examination, and selective laboratory evaluation were sensitive and cost
effective in detecting PD or RD.
PMID- 9544159
TI - Combined RT-PCR and metaphase-FISH posttransplant studies in pediatric patients
with chronic myeloid leukemia.
AB - PURPOSE: To evaluate the use of a combined reverse-transcriptase polymerase chain
reaction (RT-PCR) and metaphase fluorescent in situ hybridization (FISH) approach
post-allogeneic marrow transplant in the detection of relapse in pediatric
patients with chronic myeloid leukemia (CML). PATIENTS AND METHODS: Five
pediatric patients with CML were monitored post-allogeneic transplant (two of
them also had received donor lymphocyte infusions) using the combined approach of
RT-PCR and metaphase FISH. Both the transplants and the follow-up were carried
out in a single institution setting. RESULTS: During the posttransplant
evaluation, a transiently positive signal for the Philadelphia chromosome but no
transcription of the bcr/abl-fusion message was detected in one patient currently
in remission. A posttransplant relapse was detected in two patients who
demonstrated the Philadelphia chromosome and the bcr/abl-fusion transcript; one
was successfully treated with donor lymphocyte infusions. The two patients
consistently negative for both the Philadelphia chromosome and the bcr/abl-fusion
transcript and currently in remission. CONCLUSION: Pediatric patients with CML
may transiently demonstrate cells positive for the Philadelphia chromosome but
not actively transcribing the bcr/abl-fusion message in their marrow during their
posttransplant evaluation but remain in remission. Recurrence is highly likely in
patients demonstrating positivity for both; these patients may be considered
candidates for donor lymphocyte transfusion therapy.
PMID- 9544160
TI - Identification of (CA/GT)n polymorphisms within the X-linked chronic
granulomatous disease (X-CGD) gene: utility for prenatal diagnosis.
AB - PURPOSE: The majority of known female carriers of X-linked chronic granulomatous
disease (X-CGD), a deficiency of the gp91-phox (phagocyte oxidase) subunit and
the most common genetic subtype of CGD, are not informative for the linked
restriction fragment length polymorphisms (RFLPs) described to date. The
isolation and characterization of two polymorphic (CA/GT)n repeats that lie
within the X-CGD gene are reported, which are a useful linked marker for prenatal
diagnosis. PATIENTS AND METHODS: cDNA for gp91-phox was used to probe a genomic
library. Genomic clones were isolated and screened for (CA/GT)n repeats. The
repeats were isolated and sequences surrounding the repeats were determined.
Oligonucleotide primer pairs surrounding the repeats were chosen to facilitate
polymerase chain reaction (PCR) across the repeat. RESULTS: Analysis of DNA
derived from over 100 individuals shows both markers to be highly polymorphic
with a resultant high proportion of heterozygosity in females. Several kindreds
affected by X-CGD were studied and the (CA/GT)n length polymorphisms were shown
to segregate with the clinical syndrome or biochemical carrier status. The
technique was prospectively applied to several kindreds containing a carrier
mother and an affected child. In a case where a male fetus was shown to carry the
unaffected allele, the pregnancy was carried to term and the child was not
affected. CONCLUSIONS: This approach is highly informative in a multiple allele
system, can provide a technical analysis in just hours, requires only a ng of
DNA, and permits the transport of diagnostic samples. Therefore, this method can
be used early in pregnancy on a chorionic villus biopsy sample for prenatal
diagnosis.
PMID- 9544161
TI - Clinical value of bone marrow cultures in childhood pure red cell aplasia.
AB - PURPOSE: We assessed the value of marrow cultures for defining the
pathophysiology, diagnosis, and therapeutic response to immunosuppressive therapy
in childhood pure red cell aplasia (PRCA). PATIENTS AND METHODS: Patients were
evaluated either at diagnosis (n = 23) or at the time of treatment failure (n =
2). Twelve patients had transient erythroblastopenia of childhood (TEC), 4 had
Diamont-Blackfan anemia (DBA), and 9 had acquired sustained PRCA (A-Su-PRCA).
Bone marrow mononuclear cells were cultured with combination of human recombinant
(rhu) erythropoietin (EPO), granulocyte monocyte colony stimulating factor (GM
CSF), granulocyte colony stimulating factor (G-CSF), Interleukin 3 (IL-3), either
with or without stem cell factor (SCF), and burst forming unit of erythroid (BFU
E) growth was assessed. RESULTS: The combination of growth factors without SCF
failed to induce any erythropoiesis (BFU-E < 10/10(5) mononuclear cells) in 10
patients (2 with TEC, 2 with DBA, and 6 with A-Su-PRCA), although the growth of
erythroid colonies was substantially lower in the remaining patients than in
controls (45.5 +/- 15.4 versus 91.7 +/- 12.7, p < 0.05). Addition of SCF restored
erythropoiesis in all but 6 patients (5 with A-Su-PRCA and 1 with DBA). Five of 6
nonresponders did not respond to any immunomodulating therapy; of the 5, 3 had or
developed some evidence of myelodysplasia. CONCLUSION: Our data indicate that in
vitro colony studies might prove to be a useful diagnostic tool, because
erythropoiesis' poor response to growth factors, including SCF, may suggest the
diagnosis of myelodysplasia. Moreover, it may have predictive value; in cases of
PRCA, regardless of etiology, poor growth of erythropoietic colonies may predict
refractoriness to immunomodulating therapy.
PMID- 9544162
TI - Postoperative chemotherapy in children less than 4 years of age with malignant
brain tumors: promising initial response to a VETOPEC-based regimen. A Study of
the Australian and New Zealand Children's Cancer Study Group (ANZCCSG).
AB - PURPOSE: Postoperative chemotherapy with indefinite postponement of radiation
therapy in children < 4 years old with brain tumors was investigated in a multi
institutional study. PATIENTS AND METHODS: From 1991 to 1995, 42 patients aged 3
to 47 months (median 20) with brain tumors were enrolled in a 2-phase
chemotherapy protocol: 16 patients had medulloblastoma (MB); 8 had supratentorial
primitive neuroectodermal tumor (PNET); 14 had ependymoma; and 4 had other
tumors. The initial phase was comprised of 4 courses of the 3-drug regimen:
vincristine (VCR), etoposide (VP-16), and intensive cyclophosphamide (CPA) in a
previously reported schedule (VETOPEC). The continuation phase was comprised of 2
drug courses: A, CPA + VCR; B, cisplatin + VP-16; and C, carboplatin + VP-16, for
a total duration of 64 weeks. RESULTS: Response to VETOPEC was evaluable in 28
patients with postresection residual (25) and/or metastatic (1 M2, 6 M3) tumor.
There were 9 complete responses (CR) and 9 partial responses (PR) with a combined
CR + PR of 64% (95% confidence interval [CI] 44 to 81). In 12 evaluable patients
with MB, CR + PR was 82% (48 to 98); in 6 patients with PNET, 50% (12 to 88);
and, in 8 patients with ependymoma, 86% (42 to 99). Of 40 patients eligible for
further analysis, 6 remain progression-free at a median of 30 months, 14 are
alive at a median of 38 months, 29 have progressed at a median of 7 months
(range, 2 to 37 months), and 26 have died. The progression-free and overall
survival rates at 36 months are estimated to be 11% (95% CI 1 to 22) and 34% (18
to 50), respectively. CONCLUSIONS: The initial response to the VETOPEC regimen is
encouraging and warrants study of further dose escalation. Survival remains poor
with current strategies in this high-risk population.
PMID- 9544163
TI - Effective adjuvant chemotherapy for advanced nasopharyngeal carcinoma in
children: a final update of a long-term prospective study in a single
institution.
AB - PURPOSE: The purpose of this study was to determine the efficacy and toxicity of
a doxorubicin/cyclophosphamide-based chemotherapy and local radiation therapy in
children with locally advanced or metastatic nasopharyngeal carcinoma (NPC).
PATIENTS AND METHODS: Twelve patients aged 6 to 20 years old were treated with a
chemotherapy regimen comprised of vincristine (1.5 mg/m2) and doxorubicin (45
mg/m2) on day 1 and cyclophosphamide (210 mg/m2) and 5-fluorouracil (240 mg/m2)
on days 1 to 5. Chemotherapy was administered every 3 weeks for 1 to 2 years.
Radiotherapy to the primary site (59 to 68 Gy) and to the neck (59 to 66 Gy) was
given before or after 2 to 4 courses of chemotherapy. RESULTS: All patients
achieved a complete response 4 to 16 months from the start of therapy (median 7
months). Nine patients have remained tumor free from 2 to 21 years (median 11
years) from diagnosis. One child was lost to follow-up and one died of
tuberculosis; both were disease-free. One child developed a secondary
osteosarcoma in the left mandible. Chemotherapy caused grade 4 neutropenia and
thrombocytopenia in four patients. There were no therapy-related deaths and the
most common late effect of therapy was neck fibrosis, which was observed in all
patients. We conclude that the chemotherapy and radiotherapy regimen used in this
study is highly effective for children and adolescents with locally advanced NPC
and is associated with tolerable toxicity.
PMID- 9544164
TI - In vitro antitumor activity of rebeccamycin analog (NSC# 655649) against
pediatric solid tumors.
AB - PURPOSE: This study determined the in vitro antitumor activity of a rebeccamycin
analog (NSC# 655649) using tetrazolium/formazan (MTT) and clonogenic assays
against established pediatric cell lines and solid tumor specimens obtained from
children. MATERIALS AND METHODS: Tumor cells from 14 established cell lines and
20 patient specimens were exposed in vitro for 1 hour to NSC# 655649 at
concentrations ranging from 0.015 to 15.0 microM. The cytotoxicity (IC50) of this
agent against established cell lines was determined using both the MTT
(cytotoxic) and clonogenic/soft agar cloning (cytostatic) assays. Tumor specimens
from children undergoing biopsy or surgical resection were also evaluated in
vitro against NSC# 655649 using the clonogenic assay. For studies using patient
specimens, antitumor activity was measured by comparing the number of tumor
colonies from NSC# 655649-treated cells with those from solvent-treated controls.
RESULTS: These studies showed that the mean IC50S using the MTT and clonogenic
assays using established solid tumor cell lines were 0.94 and 0.51 microM,
respectively. In general, for cell lines tested using both types of assays, the
clonogenic assay resulted in a smaller IC50. The overall in vitro responses (< or
= 50% survival compared to controls) using patient tumor specimens and the
clonogenic assay were 35% (1.5 microM), 60% (7.5 microM), and 80% (15.0 microM).
Of the 9 patients with neuroblastoma, responses to NSC# 655649 were seen in 33%
(1.5 microM), 58% (7.5 microM), and 92% (15.0 microM) of the specimens. Prior
chemotherapy did not appear to adversely affect in vitro responses. CONCLUSIONS:
NSC# 655649 appears to have broad antitumor activity in vitro against pediatric
malignancies at drug concentrations achieved during adult phase I clinical
trials. These studies support the further development of NSC# 655649 for solid
tumors in children.
PMID- 9544165
TI - Blunted serum erythropoietin response to anemia in patients polytransfused for
beta-thalassemia major.
AB - PURPOSE: To investigate the response of erythropoietin (EPO) to anemia in
patients polytransfused for beta-thalassemia major. PATIENTS AND METHODS: We
measured the serum EPO levels and the concurrent hemoglobin (Hb) concentrations
in 40 patients polytransfused for beta-thalassemia major, in 18 patients with
iron deficiency anemia (IDA), and 32 healthy subjects. Serum EPO levels were
assayed by an enzyme immunoassay. RESULTS: In both groups with beta-thalassemia
major and IDA, serum EPO levels were significantly elevated (114 +/- 71 and 239
+/- 217 mU/mL, respectively). There was a significant inverse correlation between
log EPO values and Hb concentrations in patients with beta-thalassemia major (r =
0.61; p < 0.01) and IDA (r = 0.81; p < 0.01). In a semilogarithmic plot, the
slope of the regression line obtained in patients with beta-thalassemia major was
significantly lower than that of IDA (p < 0.01), suggesting a blunted EPO
response to anemia in patients polytransfused for beta-thalassemia major. The
elevation of serum EPO in patients with beta-thalassemia major was poorly related
to clinical variables except serum ferritin. CONCLUSIONS: We conclude that a
significant inverse relationship between serum EPO levels and Hb concentration
exists in patients with beta-thalassemia major. However, this EPO response in
patients with anemia caused by beta-thalassemia major may be blunted when
compared to patients with IDA.
PMID- 9544166
TI - Donor lymphocyte infusions to displace residual host hematopoietic cells after
allogeneic bone marrow transplantation for beta-thalassemia major.
AB - PURPOSE: Donor lymphocyte infusion (DLI) was used to reverse relapse after
allogeneic bone marrow transplantation (BMT) in a patient with beta-thalassemia
major. PATIENTS AND METHODS: The patient with unstable mixed chimerism after BMT
was treated with graded increments of donor lymphocytes (10(5) T cells/kg to 5 x
10(7) T cells/kg) to displace residual hematopoietic host cells. RESULTS: DLI
resulted in complete donor-derived reconstitution of the hematopoietic
compartment. The patient developed mild graft-versus-host disease (GVHD) that
could be controlled by steroid treatment. CONCLUSIONS: This case report shows
that DLI can effectively eradicate host stem cells in mixed chimeras after BMT in
nonmalignant hematopoietic diseases.
PMID- 9544168
TI - Phenytoin-induced thrombocytopenia treated with intravenous immune globulin.
AB - PURPOSE: To describe the use of intravenous immune globulin (IVIG) in an 8-year
old girl with phenytoin-induced thrombocytopenia and leukopenia. PATIENTS AND
METHODS: An 8-year-old girl had fever, rash, thrombocytopenia, and leukopenia 18
days after initiation of phenytoin therapy. The phenytoin level was elevated. She
was treated with 1 g/kg of IVIG. RESULTS: The thrombocytopenia improved
dramatically after IVIG therapy. There was a slower response to the leukopenia.
CONCLUSIONS: Phenytoin hypersensitivity can present with thrombocytopenia and
leukopenia. Treatment with IVIG was associated with a rapid rise in the platelet
count in the patient in this report. IVIG should be considered for patients with
phenytoin-induced thrombocytopenia.
PMID- 9544167
TI - Hemolytic anemia associated with cold agglutinin during chickenpox and a review
of the literature.
AB - PURPOSE: To describe the findings and cause of anemia and jaundice in a 2-year
old boy. PATIENT AND METHODS: This boy was admitted with a hemoglobin of 7.8
g/dL, a bilirubin of 1.8 mg/dL, and increased urobilinogen. RESULTS: On the
second day after admission, hemolytic anemia associated with an anti-I cold
agglutinin was diagnosed, which was transient and recovered without any
treatment. CONCLUSION: This is a very rare complication of chickenpox; only five
cases have been previously reported and these were all characterized by anti-Pr
cold agglutinin with hemolytic anemia after the onset of chickenpox. We report
the first case of hemolytic anemia associated with an anti-I cold agglutinin
during the incubation period of chickenpox.
PMID- 9544169
TI - Pregnancy during therapy for childhood acute lymphoblastic leukemia: two case
reports and a review of the literature.
AB - PURPOSE: The incidence and consequences of pregnancy during therapy for childhood
acute lymphoblastic leukemia (ALL) are largely unknown. To explore the issues
involved in this complication of ALL treatment, two recent cases are presented.
PATIENTS: Two 15-year-old girls with "high risk" ALL became pregnant while
receiving maintenance therapy. RESULTS: In one case, the patient experienced a
spontaneous abortion at approximately 5 to 6 weeks gestation. The patient
completed maintenance therapy and is in remission 8 months after the end of
treatment. The second patient, known to be non-compliant during therapy, was
found to be 5 months pregnant at the end of maintenance therapy. She developed
HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), was
induced at approximately 34 weeks, and delivered an apparently normal baby girl.
Both the patient and her baby continue to do well 10 months after delivery.
CONCLUSIONS: A variety of factors may influence the incidence of pregnancy during
ALL therapy. Gonadal function, which is likely to return to normal during
maintenance therapy, may also be affected by alterations in the dose intensity of
treatment. Social factors may also alter the incidence of pregnancy. Adverse
effects on the fetus are more likely to occur in the first trimester, depending
on the drug or drugs used. Although all chemotherapies may have mutagenic and
teratogenic effects, they do not invariably cause abnormalities. Survival of
adolescents who become pregnant during treatment does not appear to be adversely
affected when therapy is not modified or discontinued.
PMID- 9544170
TI - Spindle cell sarcoma of the kidney with ganglionic elements (malignant
ectomesenchymoma) associated with chromosomal abnormalities and a review of the
literature.
AB - PURPOSE: Malignant ectomesenchymomas are tumors that exhibit both mesenchymal and
neuroectodermal elements (1). We report a case thought to represent a malignant
ectomesenchymoma arising in the kidney with cytogenetic abnormalities that may
provide insight into the biologic basis for this unusual tumor. METHODS: We
discuss the clinical features, histopathologic findings, cytogenetics, treatment,
and outcome of a child with a malignant ectomesenchymoma arising in the kidney.
RESULTS: An asymptomatic 16-month-old boy had a large abdominal mass. The
resected tumor contained sheets of spindled cells that expressed mesenchymal
markers and cartilaginous differentiation, interspersed with clusters of ganglion
cells that expressed neural markers. No blastemal or epithelial elements were
demonstrated. Cytogenetic analysis of the tumor revealed a hyperdiploid count
with multiple numerical and structural abnormalities, including a translocation
between chromosomes 12 and 15. In addition to the surgical resection, the patient
was successfully treated with adjuvant chemotherapy and local radiation therapy.
CONCLUSION: This is the first report of which we are aware of an ectomesenchymoma
arising within the kidney. A subset of malignant ectomesenchymomas may be related
to the Ewing's family of tumors (EFTs) (2), but this case did not exhibit
cytogenetic features consistent with EFT. Thus, the malignant ectomesenchymoma
phenotype probably represents a heterogeneous group of tumors with different
genotypes and origins. Cytogenetic analysis may be instrumental in determining
the appropriate therapeutic approach when faced with such a neoplasm. The
outcomes of 12 other children with ectomesenchymoma are reviewed.
PMID- 9544171
TI - Clear cell sarcoma of the kidney: an unusual presentation and review of the
literature.
AB - PURPOSE: To describe a child with clear cell sarcoma of the kidney (CCSK) with an
unusual presentation, including a primary tumor of the left kidney with
metastases to the right kidney and soft tissues of the lower extremities, and to
review the literature. PATIENT AND METHODS: An 8-month-old infant presented with
hypertension, an abdominal mass, and soft tissue masses in the left thigh and
right foot. Imaging studies revealed a large left-sided renal tumor, left
paravertebral soft tissue masses, and left thigh mass. At laparotomy, a lesion
was noted in the lower pole of the contralateral kidney. CCSK with metastases to
the contralateral kidney and to the soft tissues of left thigh, right foot, and
left paravertebral region was diagnosed on histopathologic examination. RESULTS:
Multimodal oncologic treatment included surgery, chemotherapy, and radiotherapy.
Three months after completion of therapy, a soft tissue lesion in the left arm
and, later, soft tissue lesions involving multiple parts of the body developed.
The patient died 18 months after diagnosis without clinical or radiographic
evidence of bone involvement. CONCLUSIONS: In a review of the literature, CCSK is
most commonly associated with bone and lung metastases. Soft tissue involvement
is uncommon. Metastasis to the contralateral kidney at initial diagnosis has not
previously been reported. This case represents an unusual metastatic pattern of
CCSK.
PMID- 9544172
TI - Nongestational choriocarcinoma in the postpartum period: a case report.
AB - PURPOSE: To determine the tissue of origin (gestational versus nongestational) of
an extensive metastatic choriocarcinoma in an 18-year-old woman to determine
prognosis and treatment. METHODS: DNA microsatellite polymorphisms after
polymerase chain reaction (PCR) amplification of the tumor tissue and blood from
the patient, husband, and daughter were used to determine the tissue of origin.
RESULTS: Molecular analyses revealed that the tumor shared the genetic features
of only the patient. She responded well to multiagent chemotherapy. CONCLUSIONS:
Molecular analysis is a useful tool to determine whether a choriocarcinoma
occurring in a female patient of child-bearing age is gestational or
nongestational when clinical findings are not clearly indicative of the primary.
PMID- 9544173
TI - Upstaging of non-Hodgkin's lymphoma in a child based on 67Gallium scintigraphy.
AB - PURPOSE: To describe a patient whose non-Hodgkin's lymphoma (NHL) appeared to be
localized by standard modalities but who was upstaged after Gallium scintigraphy
suggested disseminated disease. PATIENT AND METHODS: A patient with biopsy proven
NHL in the maxillary sinus was staged as having localized disease based on
computed tomography (CT) scans, bone scintigraphy, and evaluation of bone marrow
and spinal fluid. Open biopsy of a bony lesion, standard modalities for lymphoma
staging, and Gallium scintigraphy were obtained. RESULTS: Gallium scanning showed
bony lesions not previously seen with the standard modalities. Open biopsy of one
of these lesions confirmed disseminated disease. CONCLUSIONS: Gallium scanning
aids in the early identification of metastases in some patients with NHL and
should be included in a standard evaluation of apparently localized disease.
PMID- 9544174
TI - Ewing's tumor and papillary adenocarcinoma of the thyroid in a 14-year-old girl.
AB - PURPOSE: We describe an adolescent girl with Stage 1 Ewing's tumor and localized
papillary adenocarcinoma of the thyroid gland, a previously unreported
association. PATIENTS AND METHODS: A 14-year-old girl with right axillary
adenopathy was evaluated. RESULTS: Ewing's tumor was diagnosed after a lymph node
biopsy. A magnetic resonance imaging scan of the axilla, chest wall, and neck
demonstrated a nodule in the right lobe of the thyroid gland. A biopsy revealed
papillary adenocarcinoma. CONCLUSIONS: This is the first report of Ewing's tumor
and carcinoma of the thyroid in the same patient.
PMID- 9544175
TI - Highly probable anaphylactic reaction to systemic thrombolytic therapy with high
dose urokinase in a child with a prosthetic valve.
PMID- 9544176
TI - Pediatric residency training in an era of managed care: an introduction to
proceedings of a national conference.
AB - On May 4, 1996, a conference sponsored jointly by the Division of Medicine of the
Health Resources and Services Administration and the Ambulatory Pediatric
Association brought together pediatric educators from academic medical centers
and managed care organizations to address the challenges and opportunities for
pediatric residency training, given current trends toward increasing managed care
for children. This supplement is designed to bring the issues discussed there to
a broader audience of pediatricians and educators. The contributions are written
by the participants of that conference, with invited commentaries to add
additional perspectives on each topic. The papers were reviewed by an editorial
board of leaders in pediatric education with experience in relevant areas. This
introduction describes the impetus for the conference and highlights a number of
critical issues facing pediatric postgraduate training that are presented in
greater depth in the contributions that follow. Finally, this paper summarizes
the recommendations of the conference for meeting the challenges of training
pediatricians in these areas.
PMID- 9544177
TI - Pediatric education and managed care: a literature review.
AB - Managed care is becoming the dominant form of health care delivery and financing
in the United States, necessitating changes in pediatric education. This
transition is redefining the questions of what needs to be taught, who should be
teaching it, where it should be taught, and how to pay for this education. We
performed a literature review and examined reports from policy and professional
groups to seek answers to these questions. We have identified curricular,
administrative, and financial challenges to pediatric education in managed care.
Although road maps for innovation have been described, there is a deficiency of
research and information in key areas of pediatric education in the managed care
environment.
PMID- 9544178
TI - Child health care in changing times.
AB - Unprecedented transformations in the financing and organization of child health
care are driving change in the practice of pediatrics at a remarkably fast pace.
The health care needs of children also are evolving, reflecting changing disease
patterns, new technologies, and shifting socioeconomic and demographic
characteristics of children and families. Changes in the financing and
organization of child health services catalyzed by managed care and legislative
initiatives need to be responded to proactively by the pediatric community. Yet,
the anticipated health care needs of children also must be addressed as models
for both pediatric training and practice in the future are developed. This
article summarizes briefly these changes in health care services and in child
health needs, addresses training implications, and discusses several initiatives
the pediatric community is undertaking to develop guidelines for training
pediatricians for the 21st century.
PMID- 9544179
TI - Developing models for pediatric residency training in managed care settings.
AB - The preparation of pediatric residents to function optimally in managed care
environments challenges educators to create a new set of educational objectives
and competencies and to incorporate these into curricula that are already full.
Many of the skills needed to practice managed care are those that have been
required for the practice of pediatrics in any setting. Nevertheless, the
emergence of managed care requires the identification of new knowledge to be
acquired and new skills and attitudes to be incorporated into daily practice.
These competencies can be identified most thoroughly through collaboration among
physicians, educators, and leaders of managed care organizations. This joint
effort should also serve to establish a foundation on which collaborative,
mutually beneficial learning environments can be created. The development of
curricula that provide the opportunities needed to attain managed care
proficiencies requires an individualized approach for each program that takes
into account the degree of managed care penetration in each training environment.
Programs in which a managed care approach to patient care predominates will be
able to promote most easily their trainees' incorporation of these principles
into routine practice. Those with less regular exposure will be forced either to
promote managed care principles in an environment in which they may not be
accepted or practiced, or to join in partnership with managed care organizations
(MCOs) to train residents. Regardless of the setting, evaluation methodologies
must be developed to ensure that each of the core competencies has been learned,
can be applied to clinical situations, and is retained throughout the training
period. These efforts require the development of faculty who understand and can
model a managed care approach to patient management. The ongoing evolution of
managed care systems encourages the development of new, creative strategies to
train faculty, who may find themselves learning about this emerging environment
at the same time as are their trainees.
PMID- 9544180
TI - Teaching clinical decision-making to pediatric residents in an era of managed
care.
AB - The growth of managed care has brought a new focus on physician competency in the
appropriate use of resources to help patients. The community of pediatric
educators must improve residency curricula and teaching methodologies to ensure
that graduates of their programs can effectively and efficiently meet the needs
of children and their families. The educational approach in many pediatric
residency programs is an implicit apprenticeship model, with which the residents
follow the actions of attending physicians with little attention to scrutiny of
the clinical evidence for and against diagnostic and treatment strategies.
Evidence-based medicine stresses to the trainee the importance of the evaluation
of evidence from clinical research and cautions against the use of intuition,
unsystematic clinical experience, and untested pathophysiologic reasoning as
sufficient for medical decision-making. Managed care also has helped to create a
heightened awareness of the need to educate residents to incorporate the
preferences of patients and families into diagnostic and treatment decisions.
Trainees must know how to balance their duty to maximize the health of
populations at the lowest resource use with their duty to each individual patient
and family. Changes in the residency curriculum will bring change in educational
settings and the structure of rotations. Potential barriers to implementation
will include the need for faculty development and financial resources for
information technology.
PMID- 9544181
TI - Continuous improvement learning for residents.
AB - Physicians must be ready to assume an active role in the design, implementation,
and improvement of emerging models of health care delivery. Knowledge and skill
in continuous improvement prepare them to engage seriously in the processes of
change, on the basis of the same scientific principles they always have relied on
in the use of evidence to improve outcomes. This includes include the ability to
1) identify the health needs of the individuals and communities for which they
provide health services; 2) assess the impact of current practice with
appropriate outcome measures; 3) discover what in the process of health care may
be contributing to less than desired outcomes; 4) design and test interventions
to change the process of care to improve outcomes; 5) act as an effective member
of the interdisciplinary team required to complete these tasks; and 6) consider
ethical principles and professional values when making decisions about change in
health services delivery. Graduate medical education presents special
opportunities and challenges for learning about continuous improvement. Early
experiences at Rainbow Babies and Children's Hospital in Cleveland and Children's
Hospital in Boston suggest how we might prepare pediatricians and other
physicians to create positive change and continually improve health care.
PMID- 9544182
TI - General pediatric teaching clinics and managed care.
AB - Academic general pediatric divisions can function as effective primary care
providers in a managed care environment. Residents training in these programs are
expected to be better equipped to enter a work environment that is increasingly
structured in a managed care format. Positive and negative consequences of
managed care in an academic setting are discussed. Recommendations for successful
implementation of resident training in the world of managed care are shared.
PMID- 9544183
TI - Training pediatricians for the evolving generalist-specialist interface in the
managed care era.
AB - Managed care involves the linkage of service delivery and financing. One of the
outgrowths of the rapid expansion of managed care over the past decade has been
an increasing consensus that the generalist of the future will need to manage
more of the patients traditionally cared for by subspecialists. Subspecialty
education for pediatric residents becomes increasingly important as the role of
the pediatric generalist enlarges to include independent outpatient management of
some less complex but traditional subspecialty patients as well as collaborative
management of more complex patients. To prepare for this role, a balanced
exposure to subspecialty problems in outpatient as well as inpatient settings is
required. At the same time, however, the growth of managed care has led to
certain barriers for providing this enhanced training. This article describes the
effects of managed care on the role and scope of the pediatric subspecialist as
well as on educational strategies for coping with these changes while reshaping
the roles of both generalists and subspecialists for maximal effectiveness in
meeting the health care needs of children.
PMID- 9544184
TI - The impact of graduate medical education financing policies on pediatric
residency training.
AB - OBJECTIVE: To review special issues related to pediatric residency training in
managed care organizations, the effects of the changing health care system on the
demand for pediatricians and the potential impact on financial support for
residency training, current methods of financing graduate medical education
(GME), possible future approaches to financing GME, and policy directions to
support training of pediatricians well prepared for future practice. METHODS: We
reviewed current information on residency education in managed care settings,
including the rationale for training in such settings and the realities of such
educational experiences. We then assessed the evidence concerning the supply and
demand for pediatricians in the present health care marketplace, with its
evolution to managed systems of health care. We summarized current approaches to
financing GME through Medicare, Medicaid, private insurers and purchasers, and
direct federal and state support, with emphasis on the financing of ambulatory
training which could occur in managed care settings. Lastly, we described factors
influencing the upcoming revolution in GME financing and outlined possible new
policy directions for the financing of relevant GME training experiences.
RESULTS: Appropriate training experiences in managed care organizations may be a
valuable strategy to address the current disconnect between the traditional
hospital-based education of pediatricians and the expanded competencies necessary
to practice in intensively managed, integrated and accountable health systems.
Present pediatrician supply appears to be in relative balance with health
maintenance organization staffing patterns and with needs-based requirements
estimates. However, the pediatrician-to-child population ratio is predicted to
increase rapidly over the next decade, leading to an oversupply of pediatricians
under likely future health care delivery system scenarios. Medicare is the
largest explicit payer of GME training costs, historically directing
reimbursement primarily for hospital-based education. Numerous innovative
financing strategies are being considered to facilitate funding of GME training
in ambulatory settings and to open up funding to greater public scrutiny and
accountability. CONCLUSIONS: Although reforms in federal GME financing have been
limited to date and other significant changes have been largely state-based, it
is likely in the future that explicit funds will be targeted to specialties in
demand that prepare physicians well for future practice. Pediatricians and
medical educators must intensify their voices in the financing debate to ensure a
productive future for quality pediatric residency training.
PMID- 9544185
TI - The changing health care environment: implications for residency training.
AB - Throughout the United States, the growth of managed care is forcing pediatric
providers (physicians and hospitals) to reconstruct and integrate the health care
delivery system with a focus away from the academic center and toward the
community. Managed care also is forcing new financing approaches geared toward
the assumption of economic risk for patient management and utilization of
services. Radical changes in pediatric training programs will be necessary to
accommodate the strategic and operational changes being pursued in response to
these evolving market forces. These changes, while disruptive, will strengthen
the breadth and diversity of graduate medical education and will better prepare
trainees for the new delivery system in which they will practice. In this
article, we examine how the evolution of managed care is redefining the basic
financial and organizational framework for pediatric care and the implications of
this redefinition for children's hospitals and academic medical center-based
pediatric programs. We draw on our experience in the greater Philadelphia market
to illustrate the impact of these changes and discuss one pediatric system's
response. Finally, we review the educational opportunities provided by these
changes.
PMID- 9544186
TI - Organizational responses to managed care: issues for academic health centers and
implications for pediatric programs.
AB - The health care market dynamics that supported and directed the growth and
development of Academic Health Centers (AHCs) have changed dramatically in the
last 10 years. AHCs are struggling to adapt to new reimbursement mechanisms and
to compete effectively for limited dollars, but are constrained by administrative
and governance structures that are slow to evolve. Their multiple missions,
including education, research, and care for complex patients and underserved
populations, are at risk. Although most recognize the need for substantive
reorganization, available resources and market specifics vary dramatically from
one AHC to another. The current approaches to adaptation by four AHCs are
described, along with some of the unique challenges confronted by academic
pediatric programs.
PMID- 9544187
TI - Phenolphthalein: a sheep in wolf's clothing?
PMID- 9544188
TI - Psoralen photochemotherapy, clinical efficacy, and photomutagenicity: the role of
molecular epidemiology in minimizing risks.
AB - Photochemotherapy employing 8-methoxypsoralen and ultraviolet radiation (PUVA) is
widely used in the treatment of psoriasis. The photoactivation of psoralens in
skin cells leads to DNA photoadduct formation which may be responsible for the
efficacy of PUVA. Subsequent mutations may lead to the increased incidence of
squamous cell carcinoma (SCC). Mutations in the p53 tumor suppressor gene have
been detected in many human cancers. In this review, p53 mutation spectra in
murine and human SCC are compared to those obtained from murine cells and skin
treated with PUVA as well as to the p53 mutation spectrum in human solar SCC.
While the expected psoralen-type mutations at alternating AT sites were detected
in the treated cells and murine SCC (average frequency > 40%), such mutations
were not commonly detected in the human SCC (< 10%). Other common mutations in
the human SCC included: CG-->TA transitions (18%) and CG-->AT and TA-->GC
transversions (17 and 25%, respectively). In addition, the frequency of UVB-type
mutations at dipyrimidine sites (CC-->TT) in the SCC PUVA-treated psoriasis
patients was comparable to that in patients with SCC from only solar exposure. A
review of therapeutic history of these patients showed that many had also
received UVB phototherapy. Furthermore, because sunlight is thought to be
beneficial for psoriasis, nontherapeutic, casual UVB exposure cannot be excluded.
Thus, the PUVA SCC may have arisen from the solar mutations and PUVA may enhance
tumor progression by other epigenetic effects.
PMID- 9544189
TI - Measurement of micronucleated erythrocytes and DNA damage during chronic
ingestion of phenolphthalein in transgenic female mice heterozygous for the p53
gene.
AB - Phenolphthalein, a common ingredient in nonprescription laxatives and a multisex,
multispecies rodent carcinogen, was evaluated under chronic exposure conditions
for genotoxicity in transgenic female mice heterozygous for the p53 gene
(heterozygous TSG-p53 mice). Phenolphthalein was administered in the diet at 200,
375, 750, 3,000, and 12,000 ppm (corresponding to a time-weighted average of 37,
71, 146, 569, and 2,074 mg/kg/day, respectively) for 6 months (183 days). On days
39, 92, 137, and 183 of treatment, peripheral blood samples were collected and
evaluated for the frequency of micronucleated polychromatic and normochromatic
erythrocytes (MN-PCE and MN-NCE, respectively), the percentage of PCE (%PCE)
among total erythrocytes, and the extent of DNA damage (single strand breaks,
alkali labile sites, DNA crosslinking) in leukocytes. In addition, the extent of
DNA damage was evaluated in liver parenchymal cells sampled from mice at the end
of the 6-month treatment period. DNA damage was evaluated using the alkaline (pH
> 13) Single Cell Gel (SCG) assay. In addition, using a modified SCG technique,
the frequencies of leukocytes and liver parenchymal cells with extremely low
molecular weight DNA (indicative of apoptosis and/or necrosis) were determined.
At each sample time, phenolphthalein induced a highly significant, dose-dependent
increase in the frequency of MN-PCE and MN-NCE and in %PCE. Maximal induction of
MN-PCE and %PCE decreased with increasing treatment duration, most likely due to
a treatment duration-dependent decrease in the relative amount of ingested
phenolphthalein. A comparative analysis of the kinetochore status of MN in
erythrocytes sampled from control mice and mice ingesting phenolphthalein at
12,000 ppm for 183 days indicates that the induced MN resulted predominantly but
not exclusively from numerical chromosomal damage. The analysis for increased
levels of DNA damage in blood leukocytes was inconclusive, with a small but
statistically significant increase in DNA migration on days 39 and 137 but not on
days 92 and 183. The extent of DNA migration in liver parenchymal cells sampled
from mice at the end of treatment was not altered significantly. The frequencies
of apoptotic and/or necrotic leukocytes and liver parenchymal cells were not
increased among mice ingesting phenolphthalein. The lowest effective dose at
which a significant genotoxic response (i.e., the induction of MN-NCE) was
detected was 200 ppm, the lowest dose tested in this study. This dose in mice is
comparable to doses (on a mg/m2 basis) experienced by humans.
PMID- 9544190
TI - Epididymal sperm aneuploidies in three strains of rats detected by multicolor
fluorescence in situ hybridization.
AB - A multicolor fluorescence in situ hybridization (FISH) method was developed to
detect aneuploidy and diploidy in epididymal sperm of rats using DNA probes
specific for chromosomes 4 and Y. Fourteen healthy young-adult rats from three
strains were evaluated: inbred Fisher 344/N/ehs, outbred Sprague-Dawley, and
outbred WU Wistar/CPB. The hybridization efficiency of the FISH procedure was >
99.9%, the sex-ratio in sperm was approximately 1 as expected, and there was no
significant variation among two independent scorers. No significant variations
were detected within or among strains in the frequencies of sperm disomy for
chromosome 4 (1-6.5 per 10,000 cell per animal) or the Y chromosome (0-2.5 per
10,000 cells per animal). There was a trend toward increased variation among
Wistar rats. The frequencies of sperm-carrying hyper- and hypohaploidy for
chromosome 4 were similar, suggesting a symmetrical mechanism of chromosome gain
and loss during meiosis. The frequencies of Y-Y-4-4 sperm, which represent
genomic meiosis II errors, did not differ significantly across strains (0.1-0.7
per 10,000 cells per strain). This FISH method for detecting aneuploidy in rat
epididymal sperm provides a promising interspecies biomarker of male germ cell
aneuploidy and introduces the rat as an animal model for investigating the
heritable risk to offspring associated with paternal genotype, physiology, and
exposure to environmental mutagens. There appear to be no significant differences
among young healthy rats, mice, and men in the baseline frequencies of sperm with
Y chromosomal disomy, the only chromosome for which data currently exists for all
three species.
PMID- 9544191
TI - Apoptotic response of spermatogenic cells to the germ cell mutagens etoposide,
adriamycin, and diepoxybutane.
AB - In testis, apoptosis is a way to eliminate damaged germ cells during their
development. In this study, we evaluated the ability of three germ cell mutagens
to induce apoptosis (or programmed cell death) at specific stages of rat
seminiferous epithelial cycle. These chemicals include the cancer chemotherapy
drugs etoposide and adriamycin and the butadiene metabolite diepoxybutane.
According to our results, etoposide is a very potent inducer of apoptosis in male
rat germ cells and the cell types most sensitive to it include all types of
spermatogonia, zygotene, and early pachytene spermatocytes and meiotically
dividing spermatocytes. Also, adriamycin causes an increase in apoptosis at
specific stages of seminiferous epithelial cycle and the most sensitive cell
types are type A3-4 spermatogonia, preleptotene, zygotene, and early pachytene
spermatocytes. Diepoxybutane does not cause any significant increase in the
frequency of apoptosis in rat testis. In addition, we studied whether p53 is
taking part in the apoptotic response of spermatogenic cells by studying the
levels of p53 protein in testis before and after chemical treatment. No
accumulation of p53 in testis was seen after treatment with these three
chemicals. The expression of two p53-regulated genes, p21WAF1 and mdm2, was also
studied but no increase in the levels of mRNA of these genes was observed after
treatment. The results indicate that apoptosis should be taken into consideration
when the genotoxic effects of chemicals are evaluated in germ cells.
PMID- 9544192
TI - Comparison of the types of mutations induced by 7,12-dimethylbenz[a]anthracene in
the lacI and hprt genes of Big Blue rats.
AB - An important question regarding the use of transgenic reporter genes to detect
mutation in rodents is how the types of mutations recovered in transgenes compare
with the types of mutations found in endogenous genes. In this study, we examined
mutations induced by 7,12-dimethylbenz[a]anthracene in the lacI transgene and the
endogenous hprt gene of lymphocytes from Big Blue rats and in the hprt gene of
lymphocytes from nontransgenic Fischer 344 rats. The overall mutation profiles
found in these genes were remarkably similar: the majority of mutations were base
pair substitutions, with the most common mutation being A:T-->T:A transversion.
Differences were found for the mutational profiles in the endogenous gene and
transgene with respect to the location of the mutations and the orientation of
basepair substitutions in the DNA strands. In most cases, these differences could
be explained by the nature of the target genes. The results support the use of
the lacI transgene for detecting in vivo mutation.
PMID- 9544193
TI - Effects of germanium oxide and other chemical compounds on phenylmercury acetate
induced genotoxicity in cultured human lymphocytes.
AB - Phenylmercury acetate (PMA), which not only causes an elevation of sister
chromatid exchanges (SCEs) but also induces high frequency of endoreduplication
in human lymphocytes, may be genotoxic to humans. The major aim of our study was
to investigate the effects of germanium oxide (GeO2), D-penicillamine (D-PA),
dimercaprol (BAL), and diltiazem (DTM) on PMA-induced genotoxicity as quantified
by SCEs. All concentrations of the four chemical compounds tested alone did not
induce genotoxicity in cultured human lymphocytes. However, GeO2 significantly
inhibited PMA-induced genotoxicity in a concentration-dependent manner.
Similarly, D-PA at concentrations of 3 microM and 10 microM, and BAL at a
concentration of 30 microM produced the antigenotoxic effects. In addition, GeO2
(1.5 microM) significantly reversed an increase of endoreduplication frequency
caused by PMA. In a cell cycle kinetic study, GeO2 (0.5-5.0 microM) reversed the
inhibition of PMA on the proliferating rate index (PRI) of lymphocytes. On the
contrary, both D-PA and DTM at concentrations of 30-300 microM markedly
potentiated PMA-induced inhibition of PRI. These findings show that GeO2, D-PA
and BAL could antagonize PMA-induced genotoxicity, and GeO2 appears to be the
most effective.
PMID- 9544194
TI - Formation of direct-acting mutagens from mixtures of N-nitrosomorpholine and
carboxylates by UVA irradiation.
AB - Previously, we found that a directly mutagenic compound is produced from N
nitrosopiperidine (NPIP) in phosphate buffer on exposure to near-ultraviolet
light (UVA) and we identified its structure as alpha-hydroxy-N-nitrosopiperidine
phosphate ester. In the present study, we show that a similar photoactivation of
an N-nitrosamine can take place with carboxylates in place of phosphate. When a
neutral solution of a mixture of N-nitrosomorpholine (NMOR) and sodium acetate
was irradiated with UVA, the solution became directly mutagenic towards
Salmonella typhimurium TA1535. O6-Alkylguanine-DNA alkyltransferase-deficient
strains of S. typhimurium showed remarkably higher mutagenesis responses to this
mutagen than the proficient strains. Citrate, succinate, and several other
biological carboxylates were also effective in producing the mutagens. Since a
treatment of the "NMOR plus acetate" photoproduct with carboxylic ester hydrolase
resulted in a loss of the mutagenicity, the active principle is suggested to be
an acetate-esterified derivative of NMOR. The role of the esters as intermediates
in the photomutagenesis of nitrosamines is discussed.
PMID- 9544195
TI - Comparative studies of the mutagenicity of environmental tobacco smoke from
cigarettes that burn or primarily heat tobacco.
AB - The mutagenicity of particulate matter concentrated from environmental tobacco
smoke (ETS) from a prototype cigarette that primarily heats tobacco was compared
to that of four popular commercially available cigarettes that burn tobacco. ETS
was generated by six individuals simultaneously smoking 1 cigarette each in a 20
min time period in a 45 m3 environmental chamber operated in the static mode
(without ventilation). Respirable suspended particles (RSP) were collected on
polytetrafluoroethylene (PTFE) filters at a flow rate of 3 LPM for 120 min. Less
ETS-RSP (86-90%) was emitted by the prototype tobacco-heating cigarette than by
the tobacco-burning cigarettes. RSP was extracted from the filters by sequential
sonication in acetone and dichloromethane. The acetone extract was dried under
nitrogen and the dichloromethane filtrate was added and then dried to obtain ETS
RSP for testing. Mutagenicity was assessed in the microsuspension modification of
the Ames Salmonella/microsome assay with strains TA98 and YG1024 in the presence
of 5% S9 metabolic activation. The results show that the mutagenic activity of
RSP from the prototype cigarette was reduced by 75-83% on a per-mg basis when
compared to the commercially available cigarettes and was reduced by 96-98% when
calculated as revertants/m3 air under identical smoking conditions.
PMID- 9544196
TI - High production of nondisjunction mutants in the offspring of Drosophila
melanogaster females exposed to carbon dioxide at meiosis I.
AB - Drosophila melanogaster females homozygous for X-linked recessive markers, y and
wi, were exposed to CO2 and mated with y+ w+/Y males. The progeny were sampled
and inspected for y wi/y wi/Y (XXY) and y+ w+/O (XO) mutants. The frequency of
nondisjunction XXY mutants after a 90-min exposure to CO2 increased 100-fold
above the control level in the first-day brood but did not increase above the
control level in the second to sixth broods, showing that CO2 is an extremely
potent inducer of nondisjunction in mature oocytes during meiotic metaphase I but
is not harmful to immature oocytes. Nondisjunction-causing damage induced by CO2
in mature oocytes disappeared completely within one day after CO2 treatment, as
evidenced by a reduction of the number of XXY mutants to the control level when
the mating of CO2-treated females was delayed by one day. CO2-induced
nondisjunction is probably due to damage to spindle microtubules in mature
oocytes at metaphase I. N2 is a less potent inducer of nondisjunction than CO2.
Maternal X-irradiation with 4 Gy did not induce XXY mutants, showing that medium
level radiation does not induce nondisjunction. The results support Gaulden's
hypothesis that oxygen deficits and CO2 increases in the microenvironment of
mature oocytes can be potent inducers of nondisjunction. The possible
relationship to the cluster of Down syndrome seen in Berlin shortly after the
Chernobyl accident is discussed.
PMID- 9544197
TI - Genotoxic effects of heavy metals: comparative investigation with plant
bioassays.
AB - The potential use of micronucleus assays in plants for the detection of genotoxic
effects of heavy-metal ions was investigated. Three different plant systems were
comparatively investigated in micronucleus tests with Tradescantia pollen mother
cells (Trad MCN) and micronucleus tests with meristematic root tip cells of
Allium cepa and Vicia faba (Allium/ Vicia MCN). As3+, Pb2+, Cd2+, Zn2+ caused a
dose-dependent increase of MCN frequencies in all three test systems. Cu2+ gave
consistently negative responses in all three tests; Zn2+ caused only a moderate,
statistically not significant increase of MCN frequencies in Vicia. The ranking
of genotoxic potencies in all three tests was in the descending order: As3+ >
Pb2+ > Cd2+ > Zn2+ Cu2+. In experiments with Tradescantia, induction of MCN was
observed in a concentration range between 1 and 10 mM, whereas in tests with root
tip cells, higher concentrations (10-1,000 mM) were required to show significant
effects. Further increase of the exposure levels caused toxic effects (reduction
of root growth), cell division delays, and a decrease of MCN frequencies.
Comparisons by linear regression analyses indicated that the sensitivity of the
three bioassays for heavy metals decreases in the order: Trad MCN > Vicia root
MCN > Allium root MCN. In further experimental series, a soil sample which
contained high concentrations of the five metals and a control soil were
investigated. Aqueous soil extracts induced only weak effects in Trad MCN tests
and no effects in the root tip assays, whereas cultivation of the plants in the
soils resulted in a pronounced induction of MCN in the Tradescantia system and
moderate effects in Vicia and Allium. In conclusion, the results of the study
indicate that the Trad MCN assay detects the genotoxic effects of heavy metals
and can be used for biomonitoring metal-contaminated soils.
PMID- 9544198
TI - Transgenic model systems, National Institute of Environmental Health Sciences,
Research Triangle Park, North Carolina, March 17 and 18, 1997.
PMID- 9544199
TI - Physicochemical high throughput screening: parallel artificial membrane
permeation assay in the description of passive absorption processes.
PMID- 9544200
TI - Design of novel, potent, noncovalent inhibitors of thrombin with nonbasic P-1
substructures: rapid structure-activity studies by solid-phase synthesis.
AB - Study of surface representations of the inhibitor-bound thrombin P-1 pocket
revealed a lipophilic recess in this pocket which is not occupied by any known
inhibitor. Solid-phase synthesis was used to generate benzylamides of D
diphenylAlaPro by aminolysis of Boc dipeptide Kaiser resin. The resulting amides
inhibited thrombin in the range IC50 = 3-13,000 nM, and the structure-activity
relationships and molecular modeling suggest a unique fit of the benzyl side
chain into P-1 with the meta substituent occupying the recess.
PMID- 9544201
TI - Cytotoxic activities of Mannich bases of chalcones and related compounds.
AB - Various Mannich bases of chalcones and related compounds displayed significant
cytotoxicity toward murine P388 and L1210 leukemia cells as well as a number of
human tumor cell lines. The most promising lead molecule was 21 that had the
highest activity toward L1210 and human tumor cells. In addition, 21 exerted
preferential toxicity to human tumor lines compared to transformed human T
lymphocytes. Other compounds of interest were 38, with a huge differential in
cytotoxicity between P388 and L1210 cells, and 42, with a high therapeutic index
when cytotoxicity to P388 cells and Molt 4/C8 T-lymphocytes were compared. In
general, the Mannich bases were more cytotoxic than the corresponding chalcones
toward L1210 but not P388 cells. A ClusCor analysis of the data obtained from the
in vitro human tumor screen revealed that the mode of action of certain groups of
compounds was similar. For some groups of compounds, cytotoxicity was correlated
with the sigma, pi, or molar refractivity constants in the aryl ring attached to
the olefinic group. In addition, the IC50 values in all three screens correlated
with the redox potentials of a number of Mannich bases. X-ray crystallography and
molecular modeling of representative compounds revealed various structural
features which were considered to contribute to cytotoxicity. While a
representative compound 15 was stable and unreactive toward glutathione (GSH) in
buffer, the Mannich bases 15, 18, and 21 reacted with GSH in the presence of the
pi isozyme of glutathione S-transferase, suggesting that thiol alkylation may be
one mechanism by which cytotoxicity was exerted in vitro. Representative
compounds were shown to be nonmutagenic in an intrachromosomal recombination
assay in yeast, devoid of antimicrobial properties and possessing anticonvulsant
and neurotoxic properties. Thus Mannich bases of chalcones represent a new group
of cytotoxic agents of which 21 in particular serves as an useful prototypic
molecule.
PMID- 9544202
TI - Thiol-induced nitric oxide release from 3-halogeno-3,4-dihydrodiazete 1,2
dioxides.
AB - In this work we studied the mechanism of nitric oxide (NO) release underlying the
vasorelaxant and antiaggregant effect of 3,4-dihydrodiazete 1,2-dioxides (DD).
Six derivatives were included in the investigations, namely, 3-bromo- and 3
chloro-3,4,4-trimethyl-DD (1a,b), 3-bromo- and 3-chloro-4-methyl-3,4
hexamethylene-DD (2a,b), 3,3,4,4-tetramethyl-DD (3), and 3-methyl-3,4
hexamethylene-DD (4), and their reactivity toward thiols was analyzed. The 3
bromo- and 3-chloro-DD derivatives were found to react with thiols; this reaction
can lead to NO formation, DD 2a being the most reactive compound. 2
(Hydroxyamino)-2-methylbutan-3-one oxime (5a) and 2-hydroxy-2-methylbutan-3-one
oxime (6) were the main products isolated from the reaction of 1a with cysteine.
Reaction rates of DD with thiols were dependent upon pH and concentration of the
reagents. Maximum rates of NO release corresponded to thiol concentrations in the
range of 1 mM. Consistent with reaction kinetics data and products isolated, a
reaction mechanism was proposed. Addition of 2a to bovine aortic endothelial
cells led to strong NO release indicating a reaction with endogenous thiols. In
rat mesenterial arteries, the vasorelaxant action of 2a was only slightly
influenced by addition of thiol to the incubation medium. For the most reactive
DD derivatives, cytotoxic effects were observed at concentrations roughly 2
orders of magnitude higher than those inducing vasorelaxation.
PMID- 9544203
TI - Design and synthesis of enantiomers of 3,5-dinitro-o-tyrosine: alpha-amino-3
hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptor antagonists.
AB - The R- and S-isomers of 3,5-dinitro-o-tyrosine (6a,b) have been synthesized
through the use of chemoenzymatic synthesis and shown to bind differentially with
the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA, 3) receptors.
The phenolic functional group of these o-tyrosine analogues was designed to act
as a bioisostere of the gamma-carboxyl group of glutamate. The S-isomer of 3,5
dinitro-o-tyrosine (6b) was 6.5 times more potent than the R-isomer (6a) in
inhibiting [3H]AMPA binding with IC50 values of 13 +/- 7 and 84 +/- 26 microM,
respectively. The phenolic group was important for binding affinity since the
methoxy compound 7 was less potent than the phenolic compound 6 in inhibiting the
binding of AMPA. The free amino group was also shown to be important since the N
acetyl analogue 15 and the N-t-BOC compounds 16 and 17 exhibited very low
affinity for the AMPA receptors. AMPA receptor functional tests showed that the o
tyrosine analogues are antagonists and that the S-isomer 6b (IC50 = 630 +/- 140
microM) was more potent than the racemate 6 (IC50 = 730 +/- 88 microM) while the
R-isomer 6a was inactive up to 1 mM concentration, which is consistent with the S
isomer having higher binding affinity than the R-isomer.
PMID- 9544204
TI - Novel nonpeptide CCK-B antagonists: design and development of quinazolinone
derivatives as potent, selective, and orally active CCK-B antagonists.
AB - We have designed a novel series of CCK-B receptor antagonists by combining key
pharmacophores, an arylurea moiety of 1 and a quinazolinone ring of 3, from two
known series. Our earlier studies showed that compounds with methylene linkers in
our "target" produced moderate binding affinity and selectivity for CCK-B
receptors, whereas its higher and lower homologues resulted in loss of affinity.
Introduction of -NH- as a linker dramatically enhanced binding affinity and
selectivity for CCK-B receptors, thus providing several compounds with single
digit nanomolar binding affinity and excellent selectivity. Analogous to the
earlier studies of the series of quinazolinone derivatives 3, we also found 3
isopropoxyphenyl as a preferred substitution on the N-3 quinazolinone. Electron
withdrawing substitutions on the urea terminal phenyl ring enhanced the CCK-B
potency. Representative compounds of this series were tested in the functional
assay and showed pure antagonist profiles. Compounds 51 and 61 were orally active
in the elevated rat X-maze test. These compounds were also evaluated for their
pharmacokinetic profile. The absolute oral bioavailability of compound 61 was 22%
in rats.
PMID- 9544205
TI - Inhibition of Fc epsilon RI-mediated activation of mast cells by 2,3,4
trihydropyrimidino[2,1-a]isoquinolines.
AB - Assays based on reporter gene technology represent today an important tool in the
pharmaceutical industry for discovering novel compound classes interfering with
the activation and signaling of target cells after stimulation. Here we describe
a reporter gene assay targeting mast cell activation of IgE plus antigen,
established in an attempt to identify substances preventing type I allergy
(allergic rhinitis, allergic conjunctivitis, allergic asthma, and acute and
chronic urticaria). The assay is based on a murine mast cell line designated
CPII, stimulation by IgE plus antigen, and a reporter gene construct with the TNF
alpha promoter linked to luciferase as a read-out system. Via screening about
50,000 substances, compound 2 was found to inhibit the reporter gene induction in
the submicromolar range in this assay. Analogues of compound 2 of the 2,3,4
trihydropyrimidino[2,1-a]isoquinoline type were synthesized starting from 2-alkyl
substituted benzonitriles via aminolysis with 1,3-diaminopropane, dimetalation of
2-substituted 2-phenyl-1,4,5,6-tetrahydropyrimidines with n- and sec-butylithium,
reaction with carboxylic acid methyl esters, and finally acidic dehydration. From
about 50 derivatives, compound 41 was selected as a lead structure with an IC50
of 0.2 microM and a TC50 of 2.7 microM. In a first profiling in secondary assays,
it effectively interfered with the production of mediators such as TNF alpha, IL
4, IL-6, IL-13, and leukotriene synthesis as measured by the corresponding
ELISAs. In addition, a passive cutaneous anaphylaxis in mice (a typical type I
reaction) is inhibited to more than 90% by compound 41, when administered
intradermally 90 min before challenge.
PMID- 9544206
TI - 2-amino-4H-3,1-benzoxazin-4-ones as inhibitors of C1r serine protease.
AB - A series of 2-amino-4H-3,1-benzoxazin-4-ones have been synthesized and evaluated
as inhibitors of the complement enzyme C1r. C1r is a serine protease at the
beginning of the complement cascade, and complement activation by beta-amyloid
may represent a major contributing pathway to the neuropathology of Alzheimer's
disease. Compounds such as 7-chloro-2-[(2-iodophenyl)-amino]benz[d][1,3]oxazin-4
one (32) and 7-methyl-2-[(2-iodophenyl)amino]benz[d][1,3]oxazin-4-one (37) show
improved potency compared to the reference compound FUT-175. Many of these active
compounds also possess increased selectivity for C1r compared to trypsin and
enhanced hydrolytic stability relative to 2-(2-iodophenyl)-4H-3,1-benzoxazin-4
one (1).
PMID- 9544207
TI - Steroidal and nonsteroidal sulfamates as potent inhibitors of steroid sulfatase.
AB - Synthetic routes to potent steroidal and nonsteroidal sulfamate-based active site
directed inhibitors of the enzyme steroid sulfatase, a topical target in the
treatment of postmenopausal women with hormone-dependent breast cancer, are
described. Novel compounds were examined for estrone sulfatase (E1-STS)
inhibition in intact MCF-7 breast cancer cells and placental microsomes. Reaction
of the sodium salt of estrone with sulfamoyl chloride gave estrone 3-O-sulfamate
(EMATE, 2) which inhibits E1-STS activity potently (> 99% at 0.1 microM in intact
MCF-7 cells, IC50 = 65 pM) in a time- and concentration-dependent manner,
suggesting that EMATE is an active site-directed inhibitor. EMATE is also active
in vivo orally. 5,6,7,8-Tetrahydronaphthalene 2-O-sulfamate (7) and its N
methylated derivatives (8 and 9) were synthesized, and 7 inhibits the E1-STS
activity in intact MCF-7 cells by 79% at 10 microM. 4-Methylcoumarin 7-O
sulfamate (COUMATE) and its derivatives (14, 16, and 18) were prepared to extend
this series of nonsteroidal inhibitors, and COUMATE reduces the E1-STS activity
in placental microsomes by > 90% at 10 microM. Although the orally active COUMATE
is less potent than EMATE as an active site-directed inhibitor, it has the
important advantage of being nonestrogenic. Analogues (20, 22, 24, 26, 27, 31,
33, 39, and 44) of COUMATE were synthesized to study its structure-activity
relationships, and sulfamates of tetralones (46 and 48) and indanones (49, 51,
and 53) were also prepared. While most of these compounds were found to inhibit
E1-STS activity less effectively than COUMATE, one analogue, 3,4-dimethylcoumarin
3-O-sulfamate (24), was found to be some 12-fold more potent than COUMATE as an
E1-STS inhibitor in intact MCF-7 cells (IC50 = 30 nM for 24, cf. 380 nM for
COUMATE). Hence, highly potent sulfamate-based inhibitors of steroid sulfatase,
such as EMATE, COUMATE, and 24, possess therapeutic potential and will allow the
importance of estrogen formation in breast tumors via the E1-STS pathway to be
assessed. A pharmacophore for active site-directed sulfatase inhibition is
proposed.
PMID- 9544208
TI - Novel 5-(3-aryl-2-propynyl)-5-(arylsulfonyl)thiazolidine-2,4-diones as
antihyperglycemic agents.
AB - Novel 5-(3-aryl-2-propynyl)-5-(arylsulfonyl)thiazolidine-2,4-diones and 5-(3-aryl
2-propynyl)-5-(arylsulfanyl)thiazolidine-2,4-diones were prepared and evaluated
as oral antihyperglycemic agents in the obese, insulin resistant db/db mouse
model at 100 mg/kg and, if the analogue had sufficient potency, 20 mg/kg. The
sulfonylthiazolidinediones, 2, were more potent than the corresponding
sulfanylthiazolidinedione congeners, 1. With regard to substituent effects on the
3-propynyl phenyl ring (Ar') of 2, 4-halogen substitution generally resulted in
the more potent analogues. Substituent effects on the phenylsulfonyl moiety (Ar)
of 2 were less clear, although para-halogen substitution on Ar generally was
preferable. 2-Pyridinesulfonyl derivatives (Ar = 2-pyridine in 2) also had good
potency. Several compounds from series 2 were effective at lowering glucose and
insulin in the obese, insulin resistant ob/ob mouse at the 50 mg/kg oral dose.
Compound 20 significantly improved the glucose tolerance of obese, insulin
resistant Zucker rats at the 20 mg/kg dose level and had no effect on plasma
glucose or on glucose tolerance in normal rats fasted for 18 h at the 100 mg/kg
level.
PMID- 9544209
TI - Synthesis and endectocidal activity of novel 1-(arylsulfonyl)-1
[(trifluoromethyl)sulfonyl]methane derivatives.
AB - We have recently synthesized a series of novel disulfonylmethane compounds that
have shown anthelmintic and insecticidal (endectocidal) activity. Several
analogues have shown activity against the internal nematode Haemonchus contortus.
In sheep studies, these analogues have shown 100% control of this internal
parasite at a 10 mg/kg rate. In vitro activity against the biting flies, Stomoxys
calcitrans and Haematobia irritans, has been observed at rates as low as 25 and
2.3 ppm, respectively. Only marginal activity against the liver fluke Fasciola
hepatica and Trichostrongylus colubriformis was seen. Respiratory control index
values on rat liver mitochondria for this series suggested uncoupling of
oxidative phosphorylation as a mechanism of action. Compound 1 is considered to
be a promising agent for treatment of parasitized sheep.
PMID- 9544210
TI - Novel synthetic inhibitors of selectin-mediated cell adhesion: synthesis of 1,6
bis[3-(3-carboxymethylphenyl)-4-(2-alpha-D- mannopyranosyloxy)phenyl]hexane
(TBC1269).
AB - Reports of a high-affinity ligand for E-selectin, sialyl di-Lewis(x)
(sLe(x)Le(x), 1), motivated us to incorporate modifications to previously
reported biphenyl-based inhibitors that would provide additional interactions
with the protein. These compounds were assayed for the ability to inhibit the
binding of sialyl Lewis(x) (sLe(x), 2) bearing HL-60 cells to E-, P-, and L
selectin fusion proteins. We report that dimeric or trimeric compounds containing
multiple components of simple nonoligosaccharide selectin antagonists inhibit
sLe(x)-dependent binding with significantly enhanced potency over the monomeric
compound. The enhanced potency is consistent with additional binding interactions
within a single selectin lectin domain; however, multivalent interaction with
multiple lectin domains as a possible alternative cannot be ruled out. Compound
15e (TBC1269) showed optimal in vitro activity from this class of antagonists and
is currently under development for use in the treatment of asthma.
PMID- 9544211
TI - New cyclooxygenase-2/5-lipoxygenase inhibitors. 1. 7-tert-buty1-2,3-dihydro-3,3
dimethylbenzofuran derivatives as gastrointestinal safe antiinflammatory and
analgesic agents: discovery and variation of the 5-keto substituent.
AB - A series of 5-keto-substituted 7-tert-buty1-2,3-dihydro-3,3- dimethylbenzofurans
(DHDMBFs) were prepared and evaluated as potential nonsteroidal antiinflammatory
and analgesic agents. Interest in this class of compounds arose when a DHDMBF was
found to be an active metabolite of the di-tert-butylphenol antiinflammatory
agent tebufelone. We have now found that a variety of 5-keto-substituted DHDMBFs
have good in vivo antiinflammatory and analgesic activity after oral
administration. These compounds inhibit both cyclooxygenase (COX) and 5
lipoxygenase (5-LOX) in vitro. The cyclooxygenase inhibition was found to be
selective for the cyclooxygenase-2 isoform, and this combination of COX-2/5-LOX
inhibition may be responsible for the gastrointestinal safety of compounds such
as 30.
PMID- 9544213
TI - Synthesis and anticonvulsant activity of 2(3H)-benzoxazolone and 2(3H)
benzothiazolone derivatives.
AB - A series of 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives were
synthesized and evaluated for anticonvulsant activity. The compounds were
assayed, intraperitoneally in mice and per os in rats, against seizures induced
by maximal electroshock (MES) and pentylenetetrazole (scMet). Neurologic deficit
was evaluated by the rotarod test. The compounds were prepared to determine the
relationship between the 2(3H)-benzoxazolone and 2(3H)-benzothiazolone
derivatives' structures and anticonvulsant activity. Several of these compounds
showed significant anticonvulsant activity. Compounds 43 and 45 were the most
active of the series against MES-induced seizures with ED50 values of 8.7 and 7.6
mg/kg, respectively. Compound 45 displayed good protection against MES-induced
seizures and low toxicity in rats with an oral ED50 of 18.6 mg/kg and a
protective index (PI = TD50/ED50) of < 26.9. In vitro receptor binding studies
revealed that compounds 43 and 45 bind to sigma 1 receptors with nanomolar
affinities.
PMID- 9544212
TI - New cyclooxygenase-2/5-lipoxygenase inhibitors. 2. 7-tert-butyl-2,3-dihydro-3,3
dimethylbenzofuran derivatives as gastrointestinal safe antiinflammatory and
analgesic agents: variations of the dihydrobenzofuran ring.
AB - A series of 5-keto-substituted 7-tert-buty1-2,3-dihydro-3,3- dimethylbenzofurans
(DHDMBFs) were found to be nonsteroidal antiinflammatory and analgesic agents.
These compounds are inhibitors of 5-lipoxygenase (5-LOX) and cyclooxygenase (COX)
with selectivity for the COX-2 isoform. A series of analogues were prepared to
investigate the scope of this lead. Five ketone side chains from active DHDMBFs
were used to investigate the effects of changes in the DHDMBF "core": the size
and identity of the heterocycle and the substituent requirements of the
heterocycle and phenyl ring. Biological testing showed that a variety of
structural changes can be accommodated, but no structure was clearly superior to
the DHDMBF structure.
PMID- 9544214
TI - Potent antagonists of somatostatin: synthesis and biology.
AB - The search for synthetic analogues of somatostatin (SRIF) which exhibit selective
affinities for the five known receptor subtypes (sst1-5) has generated a large
number of potent agonist analogues. Many of these agonists display good subtype
selectivities and affinities for the subtypes 2, 3, and 5, with very few
selective for sst1 or sst4. Until the recent report by Bass and co-workers (Mol.
Pharmacol. 1996, 50, 709-715; erratum, Mol. Pharmacol. 1997, 51, 170), no true
antagonists had been discovered, let alone any displaying differential receptor
subtype selectivity. In this present study, we explore the effect of this
putative L5,D6 antagonist motif on various series of somatostatin agonist
analogues, both linear and cyclic. It was found that many D5,L6 agonists could be
converted into competitive antagonists by applying this motif, the most potent of
which was H-Nal-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-Nal-NH2 (32). This antagonist
was selective for hsst2 with an affinity of 75 nM and an IC50 of 15.1 nM against
SRIF-14 in a rat in vitro antagonist bioassay. Receptor-selective somatostatin
antagonists should provide valuable tools for characterizing the many important
physiological functions of this neuropeptide.
PMID- 9544215
TI - Antitumor agents. 181. Synthesis and biological evaluation of 6,7,2',3',4'
substituted-1,2,3,4-tetrahydro-2-phenyl-4-quinolones as a new class of
antimitotic antitumor agents.
AB - A novel series of 6,7,2',3',4'-substituted-1,2,3,4-tetrahydro-2-phenyl- 4
quinolones were synthesized and evaluated for interactions with tubulin and for
cytotoxic activity against a panel of human tumor cell lines, including ileocecal
carcinoma (HCT-8), breast cancer (MCF-7), lung carcinoma (A-549), epidermoid
carcinoma of the nasopharynx (KB), renal cancer (CAKI-1), and melanoma cancer
(SKMEL-2). Most compounds (18, 20, 22-27) showed potent cytotoxic and antitubulin
effects. The most active compounds (23, 26, 27) demonstrated strong cytotoxic
effects with ED50 values in the nanomolar or subnanomolar range in almost all
tumor cell lines. Three active racemates (20, 22, 25) were separated into the
enantiomers, and generally, the optically pure (-)-isomers (20a, 22a, 25a)
exhibited greater biological activity than the racemates or (+)-isomers.
Cytotoxicity and antitubulin activity were closely correlated, with the most
active compounds (23, 26, 27) having effects comparable to those of colchicine,
podophyllotoxin, and combretastatin A-4.
PMID- 9544216
TI - Synthesis and evaluation of compounds that facilitate the gastrointestinal
absorption of heparin.
AB - A family of novel compounds (delivery agents) that promote the gastrointestinal
absorption of USP heparin in rats and primates has been discovered. The delivery
agents in combination with heparin were administered either orally or
intracolonically in an aqueous propylene glycol solution and caused dramatic
increases in both plasma heparin concentrations (anti-Factor Xa) and clotting
times (APTT). Using one of the most effective delivery agents in this series, an
estimated relative bioavailability of 8% can be achieved following oral
administration to cynomolgus monkeys. To establish a correlation between the in
vivo data and an in vitro parameter, immobilized artificial membrane (IAM)
chromatography was performed. Log relative k' values were correlated to the
efficiency of oral heparin delivery.
PMID- 9544218
TI - Role of the C(6)-hydroxy group in bicyclomycin: synthesis, structure, and
chemical, biochemical, and biological properties.
AB - Bicyclomycin (1) is a commercial antibiotic whose primary site of action in
Escherichia coli is the transcription termination factor rho. A recent structure
activity relationship study of 1 showed that replacing the C(6)-hydroxy group
with alkoxy and thioalkoxy substituents led to dramatic losses of inhibitory
activity in rho biochemical assays. The origin for this structural specificity
has been explored by the synthesis and chemical, biochemical, and biological
evaluation of C(6)-amino- (13), C(6)-(hydroxylamino)-(14), and C(6)
mercaptobicyclomycin (15). These compounds, like 1, are capable of entering into
hydrogen bond donor interactions with rho and are capable of undergoing C(6) ring
opening to generate alpha, beta-unsaturated carbonyl, imine, or thione systems.
The chemical reactivity of 13-15 was compared with that of 1. We observed that 1,
upon treatment with EtSH under moderate and basic conditions, readily underwent
C(6) hemiaminal bond cleavage followed by conjugate addition to beta-methylene
alpha-ketoamide 2 to give Michael addition adducts whereas 13-15 reacted by
initial cleavage of the C(1)-O(2) bond. Biochemical and biological assays of 13
15 and related analogues demonstrated that the C(6) hydroxy group in 1 was
essential for activity. We found that replacing the C(6)-hydroxy group in 1 with
weaker hydrogen bond donors led to low inhibitory activities in the rho-dependent
ATPase and transcription termination assays. None of the bicyclomycin derivatives
exhibited antibiotic activity against E. coli W3350 cells at a 32 mg/mL
concentration. The apparent specificity for the C(6)-hydroxy group in 1 suggests
that an efficient hydrogen bond donor interaction from the C(6)-hydroxy group to
rho or the C(6) hemiaminal bond cleavage to 2 or both is necessary for drug
function.
PMID- 9544217
TI - (3R,4S)-3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol: a
conformationally restricted analogue of the NR2B subtype-selective NMDA
antagonist (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)- 1
propanol.
AB - (1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP
101,606, 1) is a recently described antagonist of N-methyl-D-aspartate (NMDA)
receptors containing the NR2B subunit. In the present study, the optimal
orientation of compounds of this structural type for their receptor was explored.
Tethering of the pendent methyl group of 1 to the phenolic aromatic ring via an
oxygen atom prevents rotation about the central portion of the molecule. Several
of the new chromanol compounds have high affinity for the racemic [3H]CP-101,606
binding site on the NMDA receptor and protect against glutamate toxicity in
cultured hippocampal neurons. The new ring caused a change in the stereochemical
preference of the receptor-cis (erythro) compounds had better affinity for the
receptor than the trans isomers. Computational studies suggest that steric
interactions between the pendent methyl group and the phenol ring in the acyclic
series determine which structures can best fit the receptor. The chromanol
analogue, (3R,4S)-3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1- yl]chroman-4,7-diol
(12a, CP-283,097), was found to possess potency and selectivity comparable to CP
101,606. Thus 12a is a new tool to explore the function of the NR2B-containing
NMDA receptors.
PMID- 9544219
TI - Pharmacophoric requirements for cannabinoid side chains: multiple bond and C1'
substituted delta 8-tetrahydrocannabinols.
AB - Accumulated evidence indicates that within the cannabinoid structure the
aliphatic side chain plays a pivotal role in determining cannabimimetic activity.
We describe the synthesis and affinities for the CB1 and CB2 receptors of a
series of novel delta 8-THC analogues in which the side-chain pharmacophores are
conformationally more defined than in the parent molecule. No analogue has the
side-chain pharmacophore in a fully restricted conformation. However, our design
serves to narrow down the scope of options for conformational requirements at the
receptor active sites. All the analogues tested showed nanomolar or subnanomolar
affinities for the receptors; 2-(6a,7,10,10a-tetrahydro-6,6,9-trimethyl-1-hydroxy
6H- dibenzo[b,d]pyranyl)-2-hexyl-1,3-dithiolane was found to possess very high
affinity for both cannabinoid receptors (CB1, Ki = 0.32 nM; CB2, Ki = 0.52 nM).
PMID- 9544220
TI - Simultaneous measurement of nineteen binding constants of peptides to vancomycin
using affinity capillary electrophoresis-mass spectrometry.
AB - On-line affinity capillary electrophoresis-electrospray ionization-mass
spectrometry (ACE-MS) was used for the simultaneous measurement of multiple
binding constants of an all-D-tetrapeptide library to the model receptor,
vancomycin. Determination of Kd values for the 19 peptides of the form Fmoc-DXYA
is demonstrated. The data are compared with the results obtained for individual
compounds using ACE-UV, and good correlation between the two detection methods is
shown. Simultaneous determination of multiple Kd values by ACE-MS is achieved in
one set of experiments, whereas only one Kd value can be obtained by ACE-UV
during the same time. ACE-MS measures multiple binding constants in solution in a
fast and reliable manner using femtomole amounts of samples.
PMID- 9544221
TI - The ultimate gift: mortui vivos docebunt.
PMID- 9544222
TI - Treatment of children with relapsed soft tissue sarcoma: report of the German
CESS/CWS REZ 91 trial.
AB - BACKGROUND: The present study was performed to evaluate the possibilities of
relapse treatment in patients heavily pretreated for a soft tissue sarcoma.
PATIENTS AND METHODS: Prospective, multicenter study in 44 soft tissue sarcoma
(STS) patients with first relapse. Primary diagnosis was embryonal
rhabdomyosarcoma (RME) in 17 patients, alveolar rhabdomyosarcoma (RMA) in 13,
primitive neuroectodermal tumor (PNET) in 6, and miscellaneous soft tissue
sarcomas in 8 patients. Initial chemotherapy consisted of carboplatin/etoposide
combination (150 mg/m2 each, days 1 to 4) followed by local therapy including
surgical treatment and, whenever possible, radiotherapy. RESULTS: In 11/17
patients without primary tumor resection, CR or PR was achieved following the
initial two cycles of chemotherapy (61%). The probability of event-free survival
(pEFS) for RME patients was 0.41 +/- 0.12 at 5 years, and 0.25 +/- 0.12 for RMA
patients. But, in contrast no PNET patient or patient with another soft-tissue
sarcoma achieved long-term remission. Additional local radiotherapy significantly
(P = 0.002) improved pEFS (3-year estimates of 0.23 +/- 0.2 vs. 0.1 +/- 0.1 in
patients without radiotherapy). CONCLUSIONS: In patients with RME, relapse
treatment employing a carboplatin/etoposide combination may induce a second
remission in approximately 40% of patients. Surgical excision and additional
local radiotherapy seem to be essential to maintain a stable remission. In
patients with RMA or PNET, however, this treatment strategy is of no long-term
benefit.
PMID- 9544223
TI - Clinical and epidemiologic studies of familial hemophagocytic lymphohistiocytosis
in Japan. Japan LCH Study Group.
AB - BACKGROUND AND PROCEDURE: The etiology of familial hemophagocytic
lymphohistiocytosis (FHL), which is characterized by fever, hepatosplenomegaly,
pancytopenia, and coagulopathy, remains unknown. We analyzed 43 FHL patients, all
with affected siblings, in 18 families who were identified during the period 1986
1995 in Japan. RESULTS: The presence of consanguinity was evident in two families
(11%). The majority of families lived in western Japan, where the frequency of
consanguineous marriage is high. The incidence of FHL was significantly higher in
the western island, Kyushu, than in other areas. The segregation ratio calculated
for these families was 0.35 by the Weinberg proband method, showing the autosomal
recessive inheritance of the disease. Since the diagnosis of an FHL patient
without affected siblings (sporadic case) is quite difficult, we calculated the
possible number of sporadic cases; approximately 122 patients could be identified
as sporadic FHL cases during the same period in Japan. Most of the clinical and
laboratory findings were not distinguishable from those of other types of
lymphohistiocytosis. However, atypical lymphoid cells with azurophilic granules
in peripheral blood were observed in half of the patients at diagnosis,
suggesting the clinical importance of this parameter for early diagnosis. Despite
intensive therapy, the prognosis of FHL was extremely poor; but 4 of the 8
patients who have survived had received bone marrow transplantation (BMT),
indicating the effectiveness of BMT for this disorder. CONCLUSIONS: The
distribution of FHL in areas of highly frequent consanguineous marriage and the
segregation analysis indicated a genetic factor in FHL. The identification of the
genes for FHL is expected to contribute to a cure for this disorder, and might
also enable FHL carrier detection and donor selection for BMT.
PMID- 9544224
TI - Autopsy in children with cancer who die while in terminal care.
AB - BACKGROUND: The purpose of this study was to find out whether autopsy of children
with cancer should be recommended after terminal care, or whether in those
circumstances it could be abandoned. PATIENTS AND METHODS: One hundred pediatric
patients with cancer treated at the Children's Hospital, University of Helsinki,
Finland, died during 1987-92. Seventy children died while in organized terminal
care. The underlying diagnoses were brain tumors (21), other solid tumors (24),
and leukemias (25). The method was a retrospective analysis of patients' records
and autopsy reports, in addition to a structured interview of the two parents
separately. RESULTS: Autopsy was performed in 40 (57%) of these 70 cases. It was
more often performed on children dying in hospital (69%) than in those dying at
home (39%). The autopsy rate also varied with the underlying disease: 68% of
patients with leukemia, 50% of those with solid tumors, and 52% of those with
brain tumors were autopsied. Autopsy afforded totally new medical information in
20% of cases, and important additional information in 55%. Nothing unexpected was
found in 25%. Almost all the parents (94%) who agreed to autopsy felt that it was
appropriate. Of both mothers and fathers, 50% felt that knowing the findings at
autopsy was helpful for them, and all the parents except one mother thought that
the autopsy of their child would at least be helpful to other patients.
CONCLUSIONS: Autopsy often provides important and even unexpected information in
those dying after terminal care. The majority of our parents felt that autopsy
was an acceptable and appropriate practice. We recommend that autopsies should be
performed, with the parents' consent, even after terminal care.
PMID- 9544226
TI - Childhood hemangiopericytoma.
AB - BACKGROUND: Hemangiopericytoma (HPC) is an uncommon tumor of childhood. PROCEDURE
AND RESULTS: This paper summarizes our experience with 5 children with
histologically proven HPC treated in a single institution, including 2 cases of
congenital HPC. This tumor has varying clinical presentations and biological
behavior. Congenital tumors have a better prognosis. Chemotherapy and
radiotherapy had little effect on outcome. CONCLUSION: Complete surgical excision
is the treatment of choice.
PMID- 9544225
TI - Rhabdomyosarcoma of extrahepatic biliary tree: initial treatment with
chemotherapy and conservative surgery.
AB - BACKGROUND: The very low frequency of rhabdomyosarcoma (RMS) of the extrahepatic
biliary tree has impeded the development of a standardized form of treatment.
PROCEDURE: Based on the good response of embryonal RMS to chemotherapy, we used a
multi-drug protocol as the initial treatment of a 3-year-old girl after obtaining
adequate transparietohepatic biliary drainage. The treatment achieved complete
remission. Later conservative laparoscopic surgery revealed only residual scar
tissue. The patient is alive and well 1 year after remission. DISCUSSION AND
CONCLUSIONS: Management of this difficult tumor using modern less invasive
techniques for diagnosis and treatment, with the help of preoperative
chemotherapy, prevented extensive damage to the biliary tree and allowed complete
recovery.
PMID- 9544227
TI - Misleading leads. Thallium-201 uptake in rebound thymic hyperplasia.
PMID- 9544228
TI - Primitive neuroectodermal tumor (PNET)/extraosseous Ewing sarcoma of the kidney.
PMID- 9544229
TI - Acute basal ganglia necrosis associated with cytarabine therapy.
PMID- 9544230
TI - Experience treating a patient with Bloom syndrome and acute myelogenous leukemia.
PMID- 9544231
TI - Chemotherapy for spinal cord astrocytoma.
PMID- 9544232
TI - The importance of molecular screening of 11q23 abnormalities in childhood acute
lymphoblastic leukemia: has the t(11;19)(q23;p13) a higher frequency than that
revealed by conventional cytogenetic techniques?
PMID- 9544233
TI - Bone marrow biopsy as prognostic indicator in childhood acute lymphoblastic
leukemia--another opinion.
PMID- 9544234
TI - The multi-epitope approach for immunotherapy for cancer: identification of
several CTL epitopes from various tumor-associated antigens expressed on solid
epithelial tumors.
AB - One approach to development of specific cancer immunotherapy relies on the
induction of cytotoxic T lymphocytes (CTL) specific for tumor-associated antigens
(TAA). Induction of TAA-specific CTL could be used towards the eradication of
established tumors, or to prevent their dissemination or recurrence after primary
treatment. The present study identifies a set of CTL epitopes from TAA frequently
found on solid epithelial tumors such as breast, lung and gastro-intestinal
tumors. Specifically, HLA-A2.1 binding peptides from the MAGE2, MAGE3, HER-2/neu
and CEA antigens were tested for their capacity to elicit in vitro anti-tumor CTL
using lymphocytes from normal volunteers and autologous dendritic cells as
antigen-presenting cells. A total of 6 new epitopes (MAGE2[10(157)],
MAGE3[9(112)], CEA[9(691)], CEA[9(24)], HER2[9(435)] and HER2[9(5)]) were
identified which were capable of specifically recognizing tumor cell lines lines
expressing HLA-A2.1 and the corresponding TAA. In one case (CEA[9(24)]),
induction of vigorous anti-tumor CTL responses required epitope engineering to
increase HLA-A2.1 binding affinity. Finally, most of the newly identified
epitopes (5 out of 6) were found to be highly crossreactive with other common HLA
alleles of the A2 supertype (A2.2, A2.3, A2.6 and A6802), thus demonstrating
their potential in providing broad and non-ethnically biased population coverage.
The results are discussed in the context of the development of multi-epitope
based therapies with broad applicability for patients suffering from commonly
found tumors.
PMID- 9544236
TI - Age-related defect of phospholipase C activity, differential expression of the
beta 2 isoform in active T lymphocytes from aged humans.
AB - The activation of phosphoinositide-specific PLC is one of the early cellular
responses to various growth factors and mitogens. It is known that these
functions are altered with ageing. Here we show that the beta 2 isozyme is
decreased with ageing in a peculiar T lymphocyte subpopulation involved in the
immune response, namely the active T lymphocytes. The presence and cellular
distribution of PLC isozymes were investigated with immunochemical and
immunocytochemical methods. The in situ immunocytochemistry displayed the
presence of the beta and gamma isoforms in the cytoplasm, while no reactivity for
the delta isoform was observed regardless of the age. The immunoblot analysis
showed an increased expression in the beta 2 isoform in the young and an equal
expression of the gamma 1 isoform in either age group. Our findings suggest that
the age-related defect of PLC activity is possibly due to an impaired expression
of isozymes in aged active T lymphocytes.
PMID- 9544235
TI - HLA-DP: a class II restriction molecule involved in epitope spreading during the
development of multiple sclerosis.
AB - Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central
nervous system. It is widely believed that complex polygenic inheritance patterns
involving HLA-DR and -DQ class II genes contribute to MS susceptibility, and
current evidence indicates that disease risk vs disease outcome may be associated
with distinctly different HLA class II alleles. We have recently shown that the
early development of MS is accompanied by an extensive plasticity of myelin self
recognition with the acquisition of neo-autoreactivity, or epitope spreading, as
a prominent feature. Although we did not observe a common determinant recognized
by patients sharing identical HLA-DR or -DQ class II alleles, we did observe
epitope spreading to the p50-63 determinant of myelin proteolipid protein (PLP)
in two study subjects showing complete disparity at HLA-DR and -DQ but identity
at the HLA-DP allele DPB1*0301. In the present study we show that self
recognition during the early stages in the development of MS involves HLA-DP
class II restricted responses to the PLP 50-63 spreading determinant. Our results
suggest that self-presentation by HLA-DP may play an important role in epitope
spreading and in the propagation of self-recognition during the clinical
progression of MS.
PMID- 9544237
TI - Kawasaki disease and the T-cell antigen receptor.
AB - We investigated the evidence for an infectious etiology of Kawasaki disease (KD),
an acute vasculitis of unknown etiology, by assessing the effects of KD on the T
cell antigen receptor variable beta region families (V beta). Using 3-color flow
cytometry, we studied KD patients pre- and post-intravenous gamma globulin (IVIG)
therapy and at > 40 days post therapy, additionally comparing them to matched
pediatric control patients (PCC) and their own healthy parents (one parent/KD
child). Of all the V beta families examined, only V beta 2 exhibited
statistically significant differences, between the pre- and post-IVIG samples and
preIVIG and parent samples. No associations were found between V beta 2 findings
and T cell memory, activation, or adhesion markers. For 2 KD patients, 4 parents,
and 1 PCC participant, > 15% of resting CD8+ lymphocytes and > 15% of blastic
CD8+ lymphocytes expressed a single V beta family, which varied by individual,
without similar expansions in the CD4+ cell populations. One of the participants
with this abnormality was the only one with significant cardiac abnormalities.
For all participants with the V beta abnormality, other T-cell abnormalities were
extensive and involved both CD4+ and CD8+ cells. We suggest that V beta 2 changes
do occur in KD, as previously reported. However, these may not be involved in
disease pathogenesis. Other V beta changes also occur. Those occurring in parents
may reflect asymptomatic reinfection with an infectious agent causing KD.
Further, some KD patients may have restricted cytotoxic T-cell responses to that
as yet unidentified agent; this restricted response may be associated with more
severe cardiac involvement.
PMID- 9544238
TI - Individuals from multiplex insulin-dependent diabetes mellitus (IDDM) families
express higher levels of TCRBV2S1 than controls.
AB - T lymphocytes recognise peptide antigens through the T cell antigen receptor,
which is composed of variable alpha and beta chains. There are forty-six
functional variable regions on the beta chain. In this study the expression of
the T cell receptor beta-chain variable regions 2S1 and 3S1, in a large cohort of
multiplex insulin-dependent diabetes mellitus families, have been determined by
use of monoclonal antibodies and flow cytometry. Peripheral blood was collected
from these multiplex families and three control groups, healthy individuals,
sporadic insulin-dependent diabetes mellitus patients and non-insulin-dependent
diabetes mellitus patients. The level of TCRBV2S1 expression in the multiplex
families was significantly higher than all the control groups for both the CD4+
and CD8+ T lymphocyte subsets. Detailed analysis of the family data showed that
this increased expression was not associated with age, sex, HLA type or the
diabetic phenotype. The TCRBV3S1 expression in all the diabetic cohorts was
significantly lower than the healthy controls, in the CD4 subset only. Detailed
analysis of the family data showed only the fathers TCRBV3S1 expression was lower
than the healthy controls. This study gives further insight into TCRBV usage
which could reflect the mechanism of the autoimmune response in IDDM multiplex
families.
PMID- 9544239
TI - Analysis of HLA class I and class II in Na-Dene and Amerindian populations from
British Columbia, Canada.
AB - We analyzed the distribution of HLA class II alleles and haplotypes in one Na
Dene (Athabaskan) group from British Columbia (Canada) by PCR amplification of
the DRB1, DQA1 and DQB1 second exon sequences. We extended the typing of the DRB1
in an Amerindian group (Penutian) from British Columbia. The presence of the
alleles DRB1* 0405, *0407 and *0410 only in Na-Dene and alleles DRB1*0408,
*1301*1302, *1304, *1305, *1502 and *1601 only in Amerindians suggests separate
origins of these two groups. There were fifteen different DRB1/DQA1/DQB1
haplotypes. One unique haplotype previously reported in Native Americans was
found. Thirty-four per cent of Athabaskans presented Native American haplotype
DRB1*1402/DQA1*0501/DQB1*0301. In addition, the results of this study are
compatible with previous evidence with mitochondrial (mtDNA) polymorphisms
indicating that Amerindians and Na-Dene populations derived from different
migrations from Asia.
PMID- 9544240
TI - MHC haplotype analysis by artificial neural networks.
AB - Conventional matching is based on numbers of alleles shared between donor and
recipient. This approach, however, ignores the degree of relationship between
alleles and haplotypes, and therefore the actual degree of difference. To address
this problem, we have compared family members using a block matching technique
which reflects differences in genomic sequences. All parents and siblings had
been genotyped using conventional MHC typing so that haplotypes could be assigned
and relatives could be classified as sharing 0, 1 or 2 haplotypes. We trained an
Artificial Neural Network (ANN) with subjects from 6 families (85 comparisons) to
distinguish between relatives. Using the outputs of the ANN, we developed a
score, the Histocompatibility Index (HI), as a measure of the degree of
difference. Subjects from a further 3 families (106 profile comparisons) were
tested. The HI score for each comparison was plotted. We show that the HI score
is trimodal allowing the definition of three populations corresponding to
approximately 0, 1 or 2 haplotype sharing. The means and standard deviations of
the three populations were found. As expected, comparisons between family members
sharing 2 haplotypes resulted in high HI scores with one exception. More
interestingly, this approach distinguishes between the 1 and 0 haplotype groups,
with some informative exceptions. This distinction was considered too difficult
to attempt visually. The approach provides promise in the quantification of
degrees of histocompatibility.
PMID- 9544241
TI - Investigation of two yeast genes encoding putative isoenzymes of phosphoglycerate
mutase.
AB - Our previous data indicated that GPM1 encodes the only functional
phosphoglycerate mutase in yeast. However, in the course of the yeast genome
sequencing project, two homologous sequences, designated GPM2 and GPM3, were
detected. They have been further investigated in this work. Key residues in the
deduced amino acid sequence, shown to be involved in catalysis for Gpm1 (i.e.
His8, Arg59, His181) are conserved in both enzymes. Overexpression of the genes
under control of their own promoters in a gpm1 deletion mutant did not complement
for any of the phenotypes. This could in part be attributed to a lack of
expression due to their weak promoters. Higher level expression under the control
of the yeast PFK2 promoter partially complemented the gpm1 defects, without
restoring detectable enzymatic activity. Nevertheless, deletion of either GPM2 or
GPM3, or the two deletions in concert, did not produce any obvious lesions for
growth on a variety of different carbon sources, nor did they change the levels
of key intermediary metabolites. We conclude that both genes evolved from
duplication events and that they probably constitute non-functional homologues in
yeast.
PMID- 9544242
TI - Post-translational fate of CAN1 permease of Saccharomyces cerevisiae.
AB - To study the post-translational fate of arginine permease (Can1p), the gene
coding for this transport protein was placed behind a constitutive promoter of
plasma membrane ATPase (PMA1) and furnished with a Myc tag. In exponential-phase
cells the amount of Can1p is constant, although turnover can be demonstrated. A
rapid decrease in transport activity during the early stationary phase is
paralleled by a corresponding net degradation of the protein. The amount of Can1p
present in exponential cells grown on various nitrogen sources is the same,
except in arginine-grown cells, in which the amount of the protein is markedly
lower. This occurs solely when arginine serves as nitrogen source but not as an
immediate consequence of, for example, arginine addition to cells growing on
other nitrogen sources. it was demonstrated that Can1p is phosphorylated. Since
Can1p expression under the PMA1 promoter is glucose-dependent, the amount of the
permease expressed in high-glucose-grown cells is higher than in low-glucose
grown ones. Only a part of the Can1p overexpressed in high-glucose-grown cells is
phosphorylated, while in low-glucose-grown cells the phosphorylated form probably
represents the majority of Can1p. The permease phosphorylation or
dephosphorylation is not related to transinhibition.
PMID- 9544243
TI - The Saccharomyces cerevisiae TGL2 gene encodes a protein with lipolytic activity
and can complement an Escherichia coli diacylglycerol kinase disruptant.
AB - Escherichia coli cells with a disrupted diacylglycerol kinase gene are unable to
grow on media containing arbutin due to a lethal accumulation of diacylglycerol.
In order to isolate genes from the yeast Saccharomyces cerevisiae involved in
diacylglycerol metabolism we complemented an E. coli diacylglycerol kinase
disruptant with a yeast genomic library and transformants were selected capable
of growing in the presence of arbutin. Using this method, a gene (TGL2) was
isolated coding for a protein resembling lipases from Pseudomonas. After
expression of the TGL2 gene in E. coli, lipolytic activity towards
triacylglycerols and diacylglycerols with short-chain fatty acids could be
measured. Therefore, it is very likely that the TGL2 gene can complement the E.
coli diacylglycerol kinase disruptant, because it encodes a protein that degrades
the diacylglycerol accumulated after growth in the presence of arbutin.
Disruption of the TGL2 gene in S. cerevisiae did not result in a detectable
phenotype. The role of the Tgl2 protein in lipid degradation in yeast is still
unclear.
PMID- 9544244
TI - Isolation and characteristics of yeasts able to grow at low concentrations of
nutrients.
AB - Seven oligotrophic yeasts, which can grow in a 10(4)-fold dilution of malt-yeast
glucose-peptone medium (10(-4) YM), were mainly isolated from soil. These yeasts
belong to the Cryptococcaceae. When inoculated at about 10(2) cells/ml in 10(-4)
YM, the isolates grew to 1.4 x 10(3)-2.4 x 10(5) cells/ml after 3 days. Some
culture collection yeasts fell into three groups according to their growth
characteristics in 10(-4) YM, one group showing characteristics of the
oligotrophic yeasts. The half-saturation values of uptake by the five isolated
oligotrophic yeasts for D-glucose, L-leucine and L-amino acids were 6.0-25.0, 1.7
43.3 and 3.5-21.6 microM, respectively. The oligotrophic yeasts suspended in 10
mM-phosphate buffer (pH 6.0) had high tolerances for starvation, and remained
more than 15% viable after 90 days of starvation.
PMID- 9544245
TI - Identification and kinetic analysis of a functional homolog of elongation factor
3, YEF3 in Saccharomyces cerevisiae.
AB - Yeast and other fungi contain a soluble elongation factor 3 (EF-3) which is
required for growth and protein synthesis. EF-3 contains two ABC cassettes, and
binds and hydrolyses ATP. We identified a homolog of the YEF3 gene in the
Saccharomyces cerevisiae genome database. This gene, designated YEF3B, is 84%
identical in protein sequence to YEF3, which we will now refer to as YEF3A. YEF3B
is not expressed during growth under laboratory conditions, and thus cannot
rescue growth of YEF3A deletion strains. However, YEF3B can take the place of
YEF3A in vivo when expressed from the YEF3A or ADH1 promoters. The products of
the YEF3A and YEF3B genes, EF-3A and EF-3B, respectively, were expressed from the
ADH1 promoter and purified. Both factors possessed basal and ribosomal-stimulated
ATPase activity, and had similar affinity for yeast ribosomes (103 to 113 nM).
K(m) values for ATP were similar, but the Kcat values differed significantly.
Ribosome-dependent ATPase activity of EF-3A was more efficient than EF-3B, since
the Kcat and Kcat/K(m) values for EF-3A were about two-fold higher; however, the
difference in Kcat/K(m) values between the two factors was small for basal ATPase
activity.
PMID- 9544246
TI - Generation of Saccharomyces cerevisiae deletants and basic phenotypic analysis of
eight novel genes from the left arm of chromosome XIV.
AB - The disruption of eight novel genes was realized in two genetic backgrounds.
Among these open reading frames, NO333, NO348 and NO364 presented homologies with
other proteins of yeast or other organisms, whereas NO320, NO325, NO339, NO384
and NO388 showed no similarity with any protein. Tetrad analysis of heterozygous
deletant strains revealed that NO348, NO364 and NO388 are essential genes for
vegetative growth, whereas NO320, NO325, NO333, NO339 and NO384 are non
essential. Basic phenotypic analyses of the non-lethal deletant strains as
suggested in the six-pack B0 programme did not reveal any significant differences
between parental and mutant strains.
PMID- 9544247
TI - Cloning, sequencing and disruption of the ARG8 gene encoding acetylornithine
aminotransferase in the petite-negative yeast Kluyveromyces lactis.
AB - A recombinant plasmid was isolated from a Kluyveromyces lactis genomic DNA
library which complements a Saccharomyces cerevisiae arg8 mutant defective in the
gene encoding acetylornithine aminotransferase. The complementation activity was
found to reside within a 2.0 kb DNA fragment. Nucleotide sequence analysis
revealed an open reading frame able to encode a 423-residue protein sharing 68.1%
and 35.0% sequence identities with the products of the ARG8 and argD genes of S.
cerevisiae and Escherichia coli. That the cloned gene, KlARG8, is the functional
equivalent of S. cerevisiae ARG8 was supported by a gene disruption experiment
which showed that K. lactis strains carrying a deleted chromosomal copy of KlARG8
are auxotrophic for arginine.
PMID- 9544248
TI - The SPL1 tRNA splicing gene of Candida maltosa and Candida albicans.
PMID- 9544249
TI - Current awareness on yeast.
PMID- 9544250
TI - Hexose recognition by the pancreatic beta-cell and the gustatory cell.
PMID- 9544251
TI - Glucose-induced time-dependent potentiation and "run down" of insulin secretion
in islets of young rats.
AB - A "run down" phenomenon in isolated islets from young rats has been detected, in
which the amount of insulin released in response to glucose decreases with time.
This has been studied in conjunction with glucose-induced time-dependent
potentiation (TDP) to see if the two are related. Islets, isolated from 7-day-old
rats, exposed to 16.7 mM glucose for the first time after 30, 75 and 120 minutes
of perifusion in Krebs-Ringer bicarbonate buffer (KRB) and 2.8 mM glucose, showed
a progressive loss of responsiveness, and less insulin was released at the later
times. This run down of the responses was prevented by successive challenges with
16.7 mM glucose and marked TDP was observed. The earlier the islets were exposed
to glucose the more effectively was the run down prevented. Also, and perhaps
causally related to the prevention of run down, the earlier the exposure to
glucose the greater the TDP of a subsequent response. The results could possibly
be explained in terms of a shift in metabolism in the isolated 7-day islets, with
resultant diminution of the signals for the stimulation of insulin release and
TDP. Early, and repeated exposure to high glucose would appear to minimize and
delay the metabolic shift.
PMID- 9544252
TI - ATP-sensitive K+ channel closure is not an obligatory step for glucose-induced
priming of pancreatic B-cell.
PMID- 9544254
TI - Modulation of three types of potassium selective channels by NAD and other
pyridine nucleotides in human pancreatic beta-cells. NAD and K+ channels in human
beta-cells.
PMID- 9544253
TI - Bursting electrical activity generated in the presence of KATP channel blockers.
Pharmacology, sensitivity to intracellular pH and modulation by glucose
metabolism.
PMID- 9544255
TI - Novel actions of the potassium channel modulator SDZ PCO 400 on ATP-regulated
potassium channels in insulin secreting cells. SDZ PCO 400 and beta-cells.
PMID- 9544256
TI - Effects of protein phosphorylation on the sulphonylurea receptor of the
pancreatic beta-cell.
PMID- 9544257
TI - Intracellular second messengers.
PMID- 9544258
TI - Immunological analysis of G-protein expression in the endocrine pancreas.
PMID- 9544259
TI - Calcyclin, a calcium-binding protein, which regulates insulin secretion from the
permeabilized pancreatic beta-cell.
PMID- 9544260
TI - Molecular cloning of the cDNA encoding beta-cell calcium/calmodulin-dependent
protein kinase II.
PMID- 9544261
TI - Trans-acting factor(s) confer glucose-responsive transcriptional regulation in
the insulin gene.
PMID- 9544262
TI - Extracellular messages for pancreatic B-cells.
PMID- 9544263
TI - The human glucagon-like peptide-1 (GLP-1) receptor. Cloning and functional
expression.
PMID- 9544264
TI - Islet release of ACTH-like peptides and their modulatory effect on insulin
secretion.
PMID- 9544265
TI - Chronic sympathetic innervation of islets in transgenic mice results in
differential desensitization of alpha-adrenergic inhibition of insulin secretion.
AB - The effects of chronic sympathetic hyperinnervation on pancreatic beta-cell
insulin secretion were investigated utilizing the in vitro perfused pancreas from
transgenic mice. These mice exhibit islet hyperinnervation of sympathetic neurons
resulting from overexpression of nerve growth factor in their beta-cells (1). The
goal was to determine whether sympathetic hyperinnervation increased classic
alpha-adrenergic inhibition of beta-cell insulin secretion or, in contrast, down
regulated beta-cell sensitivity to adrenergic input resulting in enhanced insulin
secretion. Both fasting and fed blood sugars and pancreatic insulin content were
normal in the transgenics. Response of the transgenic perfused pancreas to low
glucose (7 mM) was primarily first phase and normal whereas high glucose (22 mM)
caused enhanced, rather than reduced, insulin secretion of both first and second
phases. The alpha-antagonist, phentolamine, caused a six-fold increase in glucose
stimulated insulin secretion from the control pancreas, an effect that was
blunted for the transgenic pancreas. A similarly blunted response to phentolamine
occurred when this agent was superimposed on a combined glucose-forskolin
stimulus. (The positive effect on insulin secretion by phentolamine in normal
beta-cell preparations has arguably been ascribed to non-specific ionic effects.)
Therefore, as a test of possible changes in the ATP regulated K+ channel or the
linked Ca++ channels, glyburide was perfused during glucose stimulation. Insulin
secretion in response to glyburide was increased two fold in the control
pancreas. However, with the transgenic pancreas, in contrast to the enhanced
response to glucose, the effect of glyburide was almost completely inhibited. It
is concluded that: 1) chronic adrenergic hyperinnervation results in enhanced
glucose-stimulated insulin secretion by desensitization of a major alpha
adrenergic inhibitory site(s); and 2) adrenergic hyperinnervation acts directly
or indirectly on ion flux to partially inhibit insulin release, an effect which
is not desensitized. Since down-regulation of a single alpha-adrenergic receptor
would be expected to desensitize both phenomena the observed differential
desensitization indicates that different post receptor events or more than one
adrenergic receptor are involved.
PMID- 9544266
TI - Colocalization of WE-14 immunostaining with the classical islet hormones in the
porcine pancreas.
PMID- 9544267
TI - Pyridothiadiazines as potent inhibitors of glucose-induced insulin release.
PMID- 9544268
TI - Increase in [Ca2+]i and subsequent insulin release from beta TC3-cells with the L
type Ca(2+)-channel activator, FPL 64176.
PMID- 9544269
TI - Identification and characterization of non-adrenergic binding sites in insulin
secreting cells with the imidazoline RX821002.
PMID- 9544270
TI - PACAP as low as 10(-13) M raises cytosolic Ca2+ activity in pancreatic B-cells by
augmenting Ca2+ influx through L-type Ca2+ channels to trigger insulin release.
PMID- 9544271
TI - Characterization of purinergic receptor-evoked increases in intracellular Ca2+
transients in isolated human and rodent insulin-secreting cells. Purinergic
receptor signalling and [Ca2+]i in human beta-cells.
PMID- 9544272
TI - Reciprocal links between metabolic and ionic events in islet cells. Their
relevance to the rhythmics of insulin release.
PMID- 9544274
TI - Oscillations of cytosolic Ca2+ in pancreatic islets of Langerhans.
PMID- 9544275
TI - Effects of localized pulses of high K+ and carbachol on [Ca2+]i in pancreatic
islets of Langerhans.
PMID- 9544273
TI - Glyceraldehyde and the pancreatic beta-cell.
PMID- 9544276
TI - Cyclic AMP, a mediator of GLP-1, acts in concert with glucose and tolbutamide to
increase cytosolic Ca2+ in pancreatic B-cells.
PMID- 9544277
TI - Metabolism of phosphatidylcholine in mouse pancreatic islets.
PMID- 9544278
TI - Phe-Met-Arg-Phe-NH2 (FMRFa)-related peptides inhibit Na/Ca exchange in pancreatic
B cells.
PMID- 9544279
TI - Cell culture conditions influence glucose-induced [Ca2+]i responses in isolated
rat pancreatic B cells.
PMID- 9544280
TI - Glucose metabolism regulates cytosolic Ca2+ in the pancreatic beta-cell by three
different mechanisms.
PMID- 9544281
TI - Heterogeneity of beta-cell secretion. Possible involvement of K-ATP channels.
PMID- 9544282
TI - Heterogeneity of beta-cell Ca2+ responses to glucose.
PMID- 9544283
TI - Glucose-induced B-cell recruitment and the expression of hexokinase isoenzymes.
PMID- 9544284
TI - Physiological behavior of functional subpopulations of single pancreatic beta
cells.
PMID- 9544285
TI - Computer modeling of heterogeneous beta-cell populations.
PMID- 9544286
TI - Reconstructing islet function in vitro.
PMID- 9544287
TI - New aspects to the functioning and regeneration of pancreatic beta-cells. Cyclic
ADP-ribose and Reg gene.
PMID- 9544288
TI - A role for nitric oxide and other inflammatory mediators in cytokine-induced
pancreatic beta-cell dysfunction and destruction.
PMID- 9544289
TI - The REG gene and islet cell repair and renewal in type 1 diabetes.
PMID- 9544290
TI - DNA-damage and NAD(+)-depletion are initial events in oxygen radical induced
islet cell death.
PMID- 9544291
TI - Nitric oxide rather than superoxide or peroxynitrite inhibits insulin secretion
and causes DNA damage in HIT-T15 cells.
PMID- 9544292
TI - Activation of peritoneal macrophages during the prediabetic phase in low-dose
streptozotocin-treated mice.
PMID- 9544293
TI - Immunological reactivity of diabetes-prone BB/OK rats to syngeneic antigens.
Effect on beta-cell destruction and diabetes onset.
PMID- 9544294
TI - Effects of oxidants on membrane potential, K+ and Ca2+ currents of mouse
pancreatic B-cells.
PMID- 9544295
TI - IAPP and insulin regulation in human pancreatic islets.
PMID- 9544296
TI - Hyperproinsulinaemia and islet dysfunction in the NIDDM-like syndrome of
Psammomys obesus.
PMID- 9544297
TI - Altered secretory responsiveness of BRIN-BD11 cells cultured under hyperglycaemic
conditions is not readily reversed by subsequent culture in lower glucose
concentrations.
PMID- 9544298
TI - B-cell hyperresponsiveness to glucose in NIDDM during prediabetes.
PMID- 9544299
TI - Insulin treatment prevents adaptation of the endocrine pancreas to pregnancy.
PMID- 9544300
TI - Islet transplantation.
PMID- 9544301
TI - The syngeneic islet transplantation to study physiology and pathophysiology of
pancreatic beta-cells.
PMID- 9544302
TI - Islet growth after pancreatic fragments autotransplantation into the dog's
spleen. How can the engrafted islet mass satisfy the demand for its specific
products?
PMID- 9544303
TI - The use of immunomagnetic separation for secondary purification of pancreatic
islets. A comparison of different magnetic fields in the rat.
PMID- 9544304
TI - Transplantation of syngenic pancreatic islets into rats with streptozotocin
induced non insulin dependent diabetes mellitus.
PMID- 9544305
TI - Effects of caffeine on glucose-stimulated insulin release from islet transplants.
PMID- 9544306
TI - Prevention and treatment of respiratory syncytial virus infections (for advances
in pediatric infectious diseases).
PMID- 9544307
TI - Pertussis in older children and adults.
PMID- 9544308
TI - The athlete: an immunocompromised host.
PMID- 9544309
TI - Human parvovirus B19 infections in infants and children.
PMID- 9544310
TI - Controversies in Kawasaki syndrome.
PMID- 9544311
TI - Neisseria meningitidis in the 1990s.
PMID- 9544312
TI - Acute and chronic mastoiditis in children.
PMID- 9544313
TI - Tick-borne diseases.
PMID- 9544314
TI - Rabies risk and immunoprophylaxis in children.
PMID- 9544315
TI - Vancomycin resistant enterococci: impact and management in pediatrics.
PMID- 9544316
TI - Haemophilus influenzae vaccines: 1997.
PMID- 9544317
TI - Changing poliovirus vaccine policy can be controversial at best.
PMID- 9544318
TI - New vaccines against mucosal pathogens: rotavirus and respiratory syncytial
virus.
PMID- 9544319
TI - Selected topics in novel methods of antibiotic delivery: aerosolized antibiotics
and lipid preparations.
PMID- 9544320
TI - Seattle pilot project makes emergency contraception available directly from
pharmacists.
PMID- 9544321
TI - Wisconsin health plan rolls out comprehensive pharmacy provider contract.
PMID- 9544322
TI - First COMT inhibitor approved for Parkinson's disease.
PMID- 9544323
TI - New warnings issued for bromfenac, astemizole.
PMID- 9544324
TI - USP moves forward in providing information on botanical products.
PMID- 9544325
TI - University of Florida signs up Pharm.D. students for Texas, Illinois sites.
PMID- 9544326
TI - NCPA's TV network primes consumers, pharmacists for pharmaceutical care.
PMID- 9544327
TI - Assisted suicide: an issue for pharmacists.
PMID- 9544328
TI - Views on assisted suicide. Perspectives of the AMA and the NHO.
PMID- 9544329
TI - Views on assisted suicide. The aid-in-dying perspective.
PMID- 9544330
TI - Views on assisted suicide. An ethicist's perspective.
PMID- 9544331
TI - Topiramate: a new antiepileptic drug.
AB - The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug
interactions, and dosage of topiramate are reviewed. Topiramate is indicated for
use in the adjunctive treatment of adult partial-onset epilepsy. A sulfamate
substituted monosaccharide, it is structurally distinct from other antiepileptic
agents. Topiramate acts by blocking the spread of seizures. Oral topiramate has
high bioavailability and low protein binding, and as monotherapy its half-life
permits once- or twice-daily administration. The drug is excreted largely
unchanged in the urine. Clinical trials have shown that topiramate is effective
as adjunctive therapy in treating adult partial-onset epilepsy with or without
secondarily generalized seizures. In adults with refractory partial epilepsy,
topiramate has shown efficacy when carbamazepine or phenytoin has failed.
Topiramate may also be effective against partial-onset epilepsy and Lennox
Gastaut syndrome in children, but more pediatric studies are needed. CNS adverse
effects are the most common; weight loss and nephrolithiasis have also been
reported. The drug does not appear to interact significantly with other
antiepileptic agents, but enzyme inducers like phenytoin and carbamazepine can
decrease serum topiramate levels by 50%. The initial dosage is 50 mg nightly for
seven nights, followed by an increase weekly to 400 mg/day in two divided doses.
Topiramate is more costly than other anticonvulsants; however, drug therapy
accounts for less than 10% of the total direct cost of epilepsy treatment.
Topiramate offers an effective, well-tolerated option in patients with adult
partial-onset seizures.
PMID- 9544332
TI - Update on childhood immunization.
AB - Changes made in 1997 and 1998 in the U.S. childhood immunization schedule are
discussed, with a focus on the use of poliovirus, pertussis, and combination
vaccines. Oral poliovirus vaccine (OPV), the vaccine of choice for all four doses
in the polio immunization series since 1962, can cause vaccine-associated
paralytic poliomyelitis (VAPP). The inactivated poliovirus vaccine (IPV) has not
been associated with VAPP but must be administered by injection and provides
inferior intestinal immunity. With the reduced threat of poliovirus importation
into the United States, the risk of VAPP, although low, has become less
acceptable. The Centers for Disease Control and Prevention accordingly
recommended a shift from OPV to IPV in the childhood immunization schedule for
the United States, effective January 1997. A sequential OPV and IPV series is
recommended, but the schedule includes an OPV-only option, which may be preferred
in order to avoid the required injections, and an IPV-only option, which is
recommended for immunocompromised persons and their contacts. Concern over local
and systemic reactions associated with whole-cell pertussis vaccines, in addition
to controversy over a possible relationship between the whole-cell vaccine and
neurologic damage, has led to the development of new diphtheria and tetanus
toxoids and acellular pertussis vaccine products for use in the diphtheria and
tetanus toxoids and pertussis immunization series. Several combination products
were licensed in 1997, and more are on the way. This will mean fewer inoculations
for children. Increased use of IPV and acellular pertussis products could reduce
the frequency of VAPP due to OPV and the local and systemic reactions associated
with whole-cell pertussis vaccine.
PMID- 9544333
TI - 0.9% sodium chloride injection with and without heparin for maintaining
peripheral indwelling intermittent-infusion devices in infants.
AB - The use of 0.9% sodium chloride injection with and without heparin sodium for
maintaining peripheral indwelling intermittent-infusion devices (PIIIDs) in
infants was studied. In this double-blind study, children up to one year of age
who had a 24-gauge PIIID through which a continuous i.v. infusion was no longer
running were randomly assigned to have their PIIID capped with 0.9% sodium
chloride injection with or without heparin sodium 10 units/mL. PIIIDs were capped
every eight hours if no medications were administered; otherwise, they were
capped after each dose of an i.v. drug. The heparin group had 26 patients with 28
evaluable PIIIDs, and the 0.9% sodium chloride injection group had 32 patients
with 46 evaluable PIIIDs. The two groups did not differ significantly in
variables assessing the duration of PIIID use, reasons for removal of PIIIDs,
mean number of cappings, irritant potential of administered drugs, or severity of
medication-related irritation. There was no significant difference between 0.9%
sodium chloride injection with and without heparin sodium 10 units/mL in
maintaining 24-gauge PIIIDs in children younger than one year.
PMID- 9544334
TI - Stability of acyclovir sodium 1, 7, and 10 mg/mL in 5% dextrose injection and
0.9% sodium chloride injection.
PMID- 9544335
TI - Longing for mercy, requesting death: pharmaceutical care and pharmaceutically
assisted death.
PMID- 9544336
TI - Legal aspects of expanded prescribing authority for pharmacists.
PMID- 9544337
TI - Direct-to-consumer advertising: for better profits or for better health?
PMID- 9544338
TI - Albendazole versus praziquantel for neurocysticercosis.
PMID- 9544339
TI - Stability of carboplatin in polyvinyl chloride bags.
PMID- 9544340
TI - Paroxetine treatment of aggression and self-injury in persons with mental
retardation.
AB - An open, prospective assessment of the treatment of severe aggression and self
injurious behavior (SIB) with paroxetine, a serotonin re-uptake inhibitor, in 15
institutionalized persons with mental retardation was undertaken. Frequency and
severity of aggression and SIB were charted by trained staff members. Only
aggression severity was reduced over the entire 4-month follow-up period. Within
the limits of an open trial, this effect was significant at one month but did not
remain significant subsequently. The apparent diminution of effectiveness after 4
weeks of treatment may suggest adaptive changes warranting further study.
PMID- 9544341
TI - Cognitive representation of motion in individuals with mental retardation.
AB - Participants with and without mental retardation were compared on their tendency
to show the representational momentum effect when viewing a stimulus array that
implied motion. The representational momentum effect occurs when, due to implied
or apparent motion, an object is more likely to be remembered slightly shifted in
the direction of motion rather than against the direction of motion. Participants
with mental retardation showed the representational momentum effect as did
participants without mental retardation, though the magnitude of the memory shift
was smaller for participants with mental retardation. Results suggest that
individuals with mental retardation cognitively process motion information in the
same general way as do those without mental retardation, although less
efficiently.
PMID- 9544342
TI - Assessing perceived agency adherence to the values of community inclusion:
implications for staff satisfaction.
AB - Measures of staff members' knowledge (N = 518) of the values of community
inclusion, perception of agency adherence to community inclusion, and
satisfaction with relevant components of their jobs were developed. Staff
represented 130 agencies in a state-wide program of individualized community
living supports for adults with developmental and/or mental disabilities. Results
suggest relatively high levels of knowledge about values of inclusion and
perceived agency adherence to the inclusion philosophy among employees regarding
the need to provide individuals who have disabilities with opportunities for
engaging in community daily activities and their rights for services. Employees,
however, had significantly less knowledge of and noted less agency adherence to
activities intended to provide consumers with opportunities to make choices.
Staff who perceived more agency adherence to the philosophy of inclusion were
more satisfied with their jobs.
PMID- 9544344
TI - Matching training tasks to abilities of people with mental retardation: a
learning test versus experienced staff.
AB - Three sets of predictions were compared concerning the ability of 18 persons with
severe or moderate mental retardation to learn 12 training tasks. Predictions
were made by (a) experienced teachers who had worked with the clients for a
minimum of 8 months and (b) experienced teachers who did not know the clients
personally but who interacted with them for 30 minutes and by (c) consideration
of client performance on the Assessment of Basic Learning Abilities test. To
teach each task to a pass or fail criterion, we applied standard training
procedures. The Assessment of Basic Learning Abilities test was significantly
more accurate for predicting client performance than was either group of
experienced staff. Implications for decreasing the high cost of unproductive
training time were discussed.
PMID- 9544343
TI - Evolution of epilepsy in children with mental retardation: five-year experience
in 78 cases.
AB - Various aspects of epilepsy, including its evolution, were studied in 78 children
with mental retardation in a prospective 5-year (1989-1994) follow-up study.
Level of mental retardation was moderate or even more severe (IQ < 50) in 83% of
children, and 56% suffered from significant cerebral palsy. Epilepsy remained
uncontrolled in 28% of cases, 2-year remission was achieved by 26%, and mortality
was 12% during the study period. Associated cerebral palsy was the most important
single risk factor for severe epilepsy, and several handicaps seemed to have a
strong multiplicative effect. Complexity of epilepsy in children with mental
retardation was reflected by the evolutionary features described.
PMID- 9544345
TI - Confrontation naming of familiar sounds and pictures by individuals with Down
syndrome.
AB - We investigated whether adolescents and young adults with Down syndrome
experience difficulty in finding words to name familiar objects. In Experiment 1,
IQ- and MA-matched individuals with Down syndrome and with mental retardation due
to other causes orally identified familiar pictures and sounds. Results showed no
evidence of syndrome-specific word-finding difficulty in accuracy or speed.
Although both groups identified auditory stimuli less accurately and more slowly
than visual stimuli, results of Experiments 2 and 3 confirmed that young children
without mental retardation and college students showed the same pattern. Although
previous researchers have shown expressive speech deficits among people with Down
syndrome, these results suggest that adolescents and young adults with Down
syndrome show no syndrome-specific difficulty in finding words to label familiar
nonverbal sounds or pictures.
PMID- 9544346
TI - Longitudinal study of institutional downsizing: effects on individuals who remain
in the institution.
AB - In a 4-year study we examined the longitudinal effects of deinstitutionalization
programs on those who remain in institutions being downsized. Individual outcomes
investigated were community access, social activities, community inclusion,
family relationships, and choice. Effects of residential relocation on individual
outcomes such as adaptive behavior were evaluated and total daily per-person
expenditure on institutional services for participants was determined. Downsizing
was associated with decreased community integration but no change in most other
outcomes. Availability of therapy services fell over time, and individuals
experienced many residential and day program moves within the institution. Per
person expenditure on services increased substantially. Finally, no significant
changes in adaptive behavior were associated with intrainstitutional moves.
PMID- 9544347
TI - Implicit and explicit memory in individuals with mental retardation.
AB - Students with and without mental retardation from three age groups were compared
on implicit and explicit memory tasks. Consistent with previous research on
intelligence-related differences in controlled and automatic processes, students
without mental retardation performed better than those with mental retardation on
the explicit memory task, but there was no difference between groups on the
implicit memory task. For both groups implicit and explicit memory increased from
age 6 to 8 to age 10 to 12, but did not significantly increase to age 15 to 17.
Because implicit memory appears to be a relative strength for students with
mental retardation, we suggest further exploration into broader types of implicit
processes that may be useful in training situations.
PMID- 9544348
TI - The health care revolution: a catalyst for professional evolution.
PMID- 9544349
TI - Test-retest reliability of the evaluation tool of children's handwriting
manuscript.
AB - OBJECTIVE: This study examined the test-retest reliability of the legibility
portion of the Evaluation Tool of Children's Handwriting-Manuscript (ETCH-M).
METHOD: The sample consisted of 31 first-grade and second-grade students with
handwriting dysfunction. The ETCH-M was administered two times, 1 week apart, to
participants. The primary investigator acted as sole rater and followed standard
scoring procedures. RESULTS: The reliability coefficients were .63 for total
numeral legibility .77 for total letter legibility, and .71 for total word
legibility. Individual task reliability coefficients were generally lower and
ranged from .20 (near-point copy) to .76 (alphabet uppercase). CONCLUSION: Total
letter, total word, and uppercase letter legibility were more stable than total
numeral legibility scores and other individual tasks scores. When evaluating
handwriting for a child, it is important to consider ETCH legibility scores as
only one aspect of a comprehensive evaluation.
PMID- 9544350
TI - Clinical interpretation of "test-retest reliability of the Evaluation Tool of
Children's Handwriting-Manuscript".
PMID- 9544351
TI - The complexities embedded in family-centered care.
AB - The recent movement toward family-centered care, which has been propelled by the
implementation of the Education for All Handicapped Children Amendments of 1986,
poses considerable challenges to professionals trained in client-centered models
of service delivery. These challenges are compounded by the fact that our
understanding of family-centered care lags considerably behind our attempts to
implement responsive and efficacious services. When practitioners include family
members more integrally as collaborators in pediatric treatment, their
perceptions about families and the nature of the therapeutic experience is
affected. In this article, we present a number of critical dilemmas that are
based on data drawn from ethnographic research, descriptive studies, and training
seminars we conducted with pediatric practitioners and parents of children with
special health care needs. These dilemmas highlight the complexities involved in
building effective partnerships among all the key players, the influence of
multiple cultural worlds on everyday practices, and the need to provide supports
to practitioners for the emotional and social dimensions of practice.
Implications for practice and future research are presented.
PMID- 9544352
TI - Estimates of driving abilities and skills in different conditions.
AB - OBJECTIVES: This research was a preliminary effort to determine whether various
driving situations seemed to require different driving skills and abilities and
to identify the relative demands of specific physical, perceptual, cognitive,
behavioral, and operational skills and abilities in different driving situations.
METHOD: Experienced driver evaluators and trainers estimated the magnitude of
driving abilities and skills for different photographed driving situations.
Pictures of driving scenarios were counterbalanced for road type, traffic
condition, and weather condition. RESULTS: A multifactorial analysis of variance
of the total score for each scenario revealed significant main effects for road
type and traffic condition but not for weather condition. Highway and city
driving were rated as significantly more demanding overall than residential
driving, but no difference was found between city and highway driving. Estimates
of the overall demands for driving in heavy traffic were significantly greater
than in light traffic. However, driving in inclement weather was not regarded as
significantly more demanding than driving in sunny weather. Additionally,
significant interaction effects were found for road type by weather condition and
traffic by weather condition but not for road type by traffic condition. Through
multivariate methods to evaluate the significance of individual abilities and
skills across conditions, significant main and interactive effects were found for
road type, traffic condition, and weather condition. Post hoc analyses showed the
impact of these effects on such abilities and skills as scanning, attention and
concentration, information-processing speed, and others. CONCLUSION: Evaluators'
quantified estimates of driving demands showed driving as a complex task that (a)
requires high levels of abilities and skills in all situations; (b) demands
greater abilities in some situations than in others; and (c) involves different
kinds and various degrees of abilities and skills, depending on the demand
characteristics of the situation.
PMID- 9544353
TI - How occupational therapists teach older patients to use bathing and dressing
devices in rehabilitation.
AB - OBJECTIVE: This article describes the methods occupational therapists use to
teach bathing and dressing device use to older patients in rehabilitation
programs. The relationship of three patient characteristics to five aspects of
assistive device instruction was examined. METHOD: The study sample included 86
patients and 19 occupational therapists who provided the assistive device
training. Patients were 55 years of age or older and in rehabilitation for an
orthopedic deficit, cerebrovascular accident, or lower limb amputation.
Therapists recorded information on teaching methods, perceptions of patient
knowledge, and expectations for future device use after each treatment session.
RESULTS: Patients received an average of three dressing and two bathing devices
for home use. Therapists devoted an average of two and a half sessions (10 min
average duration) to teach dressing device use and an average of one session (9
min average duration) to teach bathing device use. Teaching occurred mostly in
the clinic setting through oral instruction and demonstration. At discharge,
patients who evaluated devices positively and were evaluated as having a positive
affect were perceived by the therapists as "having greater knowledge of device
use." More time was spent teaching those patients with lower Functional
Independence Measure scores, less positive evaluations of devices, and lower
affect scores. Family caregivers were involved in one or more dressing sessions
for 26% of patients and one or more bathing sessions for 36% of patients.
CONCLUSION: Assistive device training in rehabilitation centers consists largely
of simulated sessions in the occupational therapy clinic, and patients in the
study described the instruction they received as "satisfactory." More research is
needed to study the long-term effectiveness of assistive device training after
patients return home.
PMID- 9544355
TI - The fieldwork case study: writing for clinical reasoning.
PMID- 9544354
TI - The sensory profile: a discriminant analysis of children with and without
disabilities.
AB - OBJECTIVES: The purpose of this study was to determine which factors on the
Sensory Profile, a measure of children's responses to commonly occurring sensory
experiences, best discriminate among children with autism or pervasive
developmental disorder (PDD), children with attention deficit hyperactivity
disorder (ADHD), and children without disabilities. METHOD: Data for three groups
of children 3 to 15 years of age were used: 38 children with autism or PDD, 61
with ADHD, and 1,075 without disabilities. The researchers conducted a
discriminate analysis on the three groups, using group membership as the
dependent variable and the nine factors of the Sensory Profile as independent
variables. RESULTS: The analysis yielded two discriminant functions: one that
differentiated children with disabilities from children without disabilities and
another that differentiated the two groups of children with disabilities from
each other. Nearly 90% of the cases were correctly classified with these two
functions. CONCLUSION: The Sensory Profile is useful for discriminating certain
groups of children with disabilities. Children with disabilities are accurately
classified into disability categories with the factors described by previous
authors. This suggests that patterns of behavior associated with certain
developmental disorders are reflected in populations of children without
disabilities. It may be the frequency or intensity of certain behaviors that
differentiate the groups.
PMID- 9544356
TI - Covers for a powered wheelchair head-array system.
PMID- 9544357
TI - Occupational therapy after stroke: are we providing the right services at the
right time?
PMID- 9544358
TI - Metal-backed patellar component failure in total knee arthroplasty: a possible
risk for late infection.
AB - Between 1985 and 1987, 1837 primary total knee arthroplasty (TKA) prostheses were
implanted in 1503 patients. Group I included 843 knee with metal-backed patellar
components (MBPC), and group II included 994 knees with all polyethylene patellar
components (APPC). Follow-up averaged 5.7 years (range, 2 to 11 years). Twenty
four MBPC (2.9%) and 16 APPC TKA cases (1.6%) developed deep infection. In the
time interval between arthroplasty and 2-year follow-up, eight MBPC and 11 APPC
knees developed deep periprosthetic infection. The difference in the cumulative
probability of infection between the two groups during this time interval was not
significant (relative risk, 0.9; 95% confidence interval [CI], 0.3-2.1; P =
0.73). However, after the 2-year follow-up, 16 MBPC and 5 APPC knees developed
late infection, and the difference in the cumulative probability of infection
between the MBPC and APPC knees during this time interval was significant
(relative risk, 3.1; 95% CI, 1.1-8.5; P = 0.02). Although the mechanism for this
increased risk of these late infections is not well understood, the attendant
synovitis, effusion, and relative hyperemia of these knees in the presence of the
particulate metal and polyethylene debris may increase the potential of bacterial
seeding to these prostheses. Particulate metal debris has been previously shown
to suppress bacterial phagocytosis and may play a role in the pathogenesis of
these infections. We propose that the presence of metal-backed patellar failure
represents a "prosthesis at risk" for the development of late prosthetic
infection.
PMID- 9544359
TI - The effectiveness of gallium citrate Ga 67 radionuclide imaging in vertebral
osteomyelitis revisited.
AB - We investigated the role of gallium citrate Ga 67 scanning in diagnosing
spondylodiscitis. Scans of 41 patients with suspected spondylodiscitis showed
increased radionuclide uptake in 39 patients; these findings correlated with
those of magnetic resonance imaging and were proved by biopsy. Two patients with
negative findings on gallium scans had been strongly suspected of having
spondylodiscitis; biopsy findings in these patients showed degenerative changes.
Thirteen patients had negative cultures, while 22 had polygenic infections and 4
had granulomatous infections. Gallium scanning proved to be 100% sensitive,
specific, and accurate. The interrater accuracy was excellent. Follow-up scans
were used to track therapeutic progress. We recommend complementary bone and
gallium scans in cases of suspected spinal infections. If the scan is positive, a
biopsy should be done. If the scans are negative, no further investigation is
needed.
PMID- 9544360
TI - Percutaneous transpedicular discectomy and drainage in pyogenic spondylodiscitis.
AB - Spondylodiscitis normally heals itself, but it can cause bone destruction leading
to deformity and often pain. Debridement of these infections by percutaneous
transpedicular discectomy with access from adjacent caudal pedicles can
accelerate natural healing and prevent progression to bone destruction and
deformity. We outline this technique and discuss a series of 28 patients treated
using a percutaneous transpedicular approach to obtain culture and histopathology
specimens, permit drainage and antibiotic irrigation, and provide a channel for
granulation tissue to invade the infected space. This procedure is safe and
effective, but it is contraindicated for epidural abscess or granulation tissue
induced neurocompression and it is ineffective against extensive bone
destruction.
PMID- 9544361
TI - In vitro elution of tobramycin and vancomycin polymethylmethacrylate beads and
spacers from Simplex and Palacos.
AB - In vitro studies of antibiotic elution from polymethylmethacrylate cement
comparing Simplex (Howmedica, Rutherford, NJ) with Palacos brands (Richards,
Memphis, TN) have shown variable results. This study compares the elution of
tobramycin and vancomycin from Simplex and Palacos beads and spacers. Six
millimeter beads and spacers were incubated in phosphate-buffered saline, and the
solution was sampled and changed daily until the concentration of antibiotic fell
below the minimum inhibitory concentration (MIC) for Staphylococcus aureus. In
all groups, the Palacos PMMA beads and spacers showed elution at higher levels
and remained above the MIC longer than did the Simplex PMMA beads. Tobramycin had
superior elution to vancomycin in all groups. This in vitro study shows that
Palacos PMMA has superior elution properties to Simplex PMMA in tobramycin and
vancomycin beads and spacers.
PMID- 9544362
TI - Relation of surface area to in vitro elution characteristics of vancomycin
impregnated polymethylmethacrylate spacers.
AB - To study the relationship between surface area and antibiotic elution from
antibiotic-impregnated polymethylmethacrylate (PMMA) spacers, a standard block
spacer made of vancomycin (4 g) and 40 g of PMMA was compared with two unique
spacer designs, the "donut" and "fenestrated." The spacers were incubated in
phosphate-buffered saline, which was changed daily, and a microbiologic assay was
used to measure the antibiotic activity of the eluates. The donut and fenestrated
spacers had 12% and 40% more surface area than the standard spacer, respectively.
There was no significant difference, however, in daily elution levels of
antibiotic between the donut spacer and the standard spacer. The fenestrated
spacer displayed significantly better elution than either the standard or donut
spacers, with an average of 20% more antibiotic eluted on any given day.
PMID- 9544363
TI - The use of dynamic external fixation to obtain tibiocalcaneal fusion after Boyd's
amputation.
AB - Two patients sustained severe injuries of the foot and ankle, which were managed
with Boyd's amputation. A large-pin dynamic external fixator was used to obtain
fusion between the calcaneus and distal tibia. Boyd's amputation preserves limb
length and prevents posterior migration of the heel pad (both are disadvantages
of Syme's amputation). Use of a dynamic external fixator may result in reliable
and rapid consolidation of the fusion (thus overcoming the disadvantage
associated with Boyd's amputation).
PMID- 9544364
TI - Prosthetic joint infection due to Mycobacterium tuberculosis: a case series and
review of the literature.
AB - Prosthetic joint replacement is being performed more frequently for patients with
prior septic arthritis due to Mycobacterium tuberculosis. Prosthetic joint
infection due to Mycobacterium tuberculosis does occur, but is rare. We report
the clinical characteristics and outcome of seven cases of Mycobacterium
tuberculosis prosthetic joint infection seen at our institution over a 22-year
period and summarize the English-language literature regarding current
prophylaxis and treatment strategies. Tuberculous prosthetic joint infection most
often represents reactivation of prior tuberculous septic arthritis. The
diagnosis of tuberculous prosthetic joint disease is often delayed, because a
history of prior Mycobacterium tuberculosis septic arthritis is not known.
Treatment of tuberculous prosthetic joint infection requires a combined medical
and surgical approach. Removal of the prosthesis has been the traditional
surgical modality, followed by appropriate antituberculous therapy, but other
surgical methods have been used successfully in selected cases. To decrease the
risk of reactivation of infection after prosthesis implantation in patients with
quiescent tuberculous septic arthritis who have not received prior
antituberculous therapy, consideration should be given to preoperative or
perioperative antituberculous prophylaxis.
PMID- 9544365
TI - Isolated plantar fracture-dislocation of the middle cuneiform.
AB - A previously unreported case of plantar dislocation of the medial cuneiform is
described. The significance of this injury does not lie in its rarity, but in the
amount of force required to cause such an injury. This large force may cause bony
disruption, along with significant soft-tissue injury, and even compartment
syndrome. Analysis of the preoperative evaluation, including the importance of a
computed axial tomographicscan, operative intervention, and postoperative care
are discussed.
PMID- 9544366
TI - Technique for endoscopic femoral interference screw placement during anterior
cruciate ligament reconstruction.
AB - Proper femoral interference screw placement during endoscopic anterior cruciate
ligament reconstruction is technically demanding. Potential graft injury and the
high incidence of screw divergence can be decreased by using the tibial tunnel
for screw advancement, as described in this article.
PMID- 9544367
TI - Pain management in orthopedics.
PMID- 9544368
TI - Pain management in orthopedics.
PMID- 9544369
TI - Data about 154 children and adolescents reporting sexual assault.
AB - Sexual assaults on girls occur at an alarming rate representing a significant
public health problem, but difficulties in correctly identifying the problem,
managing the child and reporting for legal purposes have been recognized. We
describe data obtained on 154 recent cases of child and adolescent sexual
assault. Results indicate that those at highest risk of sexual assault are girls
at age of 11-15 years having a stepfather, although the most girls at age of > 15
were assaulted by strange men with higher incidence of cross-race assault. Over a
quarter of girls showed signs of physical trauma with face and neck as most
common site of contact. A total of 17.5% reported threat of violence or with
weapons and 9.7% had alcoholic influence. Pattern and incidence of genital
injuries were described.
PMID- 9544370
TI - Retrospective study of outcome on vaginal and abdominal delivery in twin
pregnancy in which twin 1 is presenting by the breech.
AB - We retrospectively reviewed the perinatal outcome of twin pregnancies cohere the
first baby was presenting by the breech. 21 were delivered vaginally and 37
abdominally. Differences in perinatal outcome, as measured by Apgar score and
mortality, were not apparently different.
PMID- 9544371
TI - A randomized study of local or general anesthesia for laser conization of the
cervix.
AB - Laser Conization of the cervix was performed in both inpatient and outpatient
settings with either local or general anesthesia. All of the patients included
had abnormal cervical smears, abnormal colposcopic findings and were allocated to
one of two groups, A and B. Patients in group A had general anesthesia while
patients in group B had only local anesthesia. A standard operative technique,
was used and all patients had estimation of blood loss, recording of operative
time, surgical suite time, anesthesia induction time, and assessment of
postoperative pain and morbidity. Statistical analysis was performed using the
student t-test. We concluded that laser conization of the cervix can be performed
more cheaply with local anesthesia than with general anesthesia and with little
discomfort, less nausea, and vomitting.
PMID- 9544372
TI - Endometrial cancer in patients undergoing diagnostic curettage.
AB - We made a retrospective review of in 2769 patients in whom curettage was
performed. Of 1468 women under 50 years of age, only one (0.08%) had endometrial
cancer. Of 834 patients presenting with postmenopausal bleeding 31, (3.7%) had
endometrial cancer.
PMID- 9544373
TI - Nine year survey of 138 ectopic pregnancies.
AB - During the nine years (1986-1994), 138 women underwent surgery for ectopic
pregnancies (One for every 213 deliveries). The commonest presenting symptom was
abdominal pain (96%) followed by vaginal bleeding (83%). Four patients were
asymptomatic and were diagnosed at a routine antenatal ultrasound scan. The most
frequent physical findings were abdominal tenderness (87%) and followed by
adnexal tenderness (57%). Histories of infertility in 17%, use of intrauterine
contraceptive device (13%), and previous ectopic pregnancy in 11% were elicited.
Eleven patients (8%) had a false negative urinary pregnancy test and subsequently
required surgery. The ectopic pregnancies were tubal in 97% of the cases. There
were 3 ovarian ectopics and one cervical ectopic.
PMID- 9544374
TI - Endometriosis diagnosed by laparoscopy in adolescent girls.
AB - 105 adolescent girls with mean age of 17.3 (11-19) years had
laparoscopy/pelviscopy between 1996 and 1997. In 37 cases, endometriosis was
diagnosed (35.2%). The majority of the girls (32.4%) presented with endoscopic
endometriosis classification (EEC) stage I. 2.8% of the girls had stage EEC II.
The lesions involved one site or pelvic organ (64.8%) with a mean age of 18.7 (14
19) years. In 35.2% of cases, the lesions were at multiple sites with a mean age
of 16.9 (11-19) years. Indications for laparoscopy included chronic or acute
pelvic pain and right-sided lower abdominal pain. Endometriotic lesions were
found in the pouch of Douglas (64.8%), uterosacral ligaments (37.8%), and ovarian
fossa (24.3%), 42.8% of directed biopsies were positive. Endocoagulation of the
endometriotic lesions was performed in 91.9% of cases.
PMID- 9544375
TI - Molecular analysis of the androgen receptor gene in 4 patients with complete
androgen insensitivity.
AB - Androgen insensitivity syndromes are due to defects in the androgen receptor
gene. In this study, we analyzed the androgen receptor gene in four cases with
complete androgen insensitivity syndrome. In patient 1, one substitutional
mutation [arginine (codon CGC) to cysteine (codon TGC) at position 774] of exon F
was identified. This position was located in the hormone binding domain and
appeared to be one hot spot of mutations because the mutations at the same
position in several unrelated cases were reported before. In patient 2, one
substitutional mutation [tyrosine (codon TAT) to cysteine (codon TGT) at position
571] of exon B was identified. This position was located in the DNA binding
domain. In patients 3 and 4 (siblings), one substitutional mutation [arginine
(codon CGA) to glutamine (codon CAA) at position 752] of exon E was identified.
Taken together, these abnormalities might be related to the pathogenesis of
complete androgen insensitivity.
PMID- 9544376
TI - Preeclampsia with fetal death in a patient with schistosomiasis japonica.
AB - A case of preeclampsia with fetal death at 32 weeks' gestation is reported. Liver
examination of the patient revealed network patterns on ultrasonography and
linear calcifications on unenhanced CT scans in the liver. These findings are
typical of those of chronic schistosomal infection. Indeed, liver biopsy
specimens showed eggs of schistosoma japonicum. We diagnosed her case as
preeclampsia with liver cirrhosis due to chronic schistosomiasis japonica.
Schistosomal placentitis may have been present and may have contributed to
preeclampsia and fetal death.
PMID- 9544377
TI - Persistent mullerian duct syndrome.
AB - We report an 18-month old male presenting with a right-sided inguinal hernia and
undescended testes. At herniotomy, a uterus and two fallopian tubes were found in
the pelvic peritoneum adjacent to the two gonads which received their blood
supply partly along the mullerian duct remnants. The gonads were testes by
histological examination. Bilateral orchiopexy was performed without removal of
the mullerian structures for fear of jeopardizing the testicular blood supply.
The diagnosis of persistent mullerian duct syndrome was confirmed postoperatively
by genetic and hormonal investigations.
PMID- 9544378
TI - Antimicrobial resistance and Helicobacter pylori: impacts on current and future
therapies.
PMID- 9544379
TI - Systemic lupus erythematosus (SLE): changing concepts and challenges for the new
millennium.
AB - SLE is still the prototype experimental animal and human autoimmune disease. The
clinical manifestations are so diverse that some have come to regard it as the
incumbent 'luetic heir apparent' of the late 20th century. The aberrations of the
immune disturbance have up until now defied clear explanation but have certainly
generated a level of academic and research interest far greater than the
frequency of the disease would initially suggest. The clear understanding of the
immune derangements in SLE will probably lead to the understanding of the core
mechanisms of the immune system and thus to better ways of its specific
manipulation in the management of many other conditions including cancer.
Research currently being undertaken on the mechanisms of control of
immunologically mediated inflammation and the possible use of immunogenetic
therapy in the treatment of various forms of SLE will hopefully further improve
SLE related morbidity and mortality.
PMID- 9544380
TI - Short duration therapy for Helicobacter pylori in Western Australia: the impact
of metronidazole resistance.
AB - BACKGROUND: Limited Australian data are available on either short duration
therapy for Helicobacter pylori infection, or the impact of metronidazole
resistance on the outcome of treatment. AIM: To compare the efficacy of two
treatment regimens and determine the influence metronidazole resistance has on
clearing H. pylori infection. METHODS: Eighty patients with H. pylori infection
proven at upper gastrointestinal endoscopy, none of whom had previously received
therapy for H. pylori, were randomised to one week therapy with either bismuth
subcitrate one tablet qid, tetracycline 500 mg qid and metronidazole 400 mg tds
(BTM), or lansoprazole 30 mg bd, amoxycillin 500 mg qid and metronidazole 400 mg
tds (LAM). Effectiveness of therapy was measured by C14-urea breath test at six
weeks. RESULTS: On an intention-to-treat basis, clearance of infection was
achieved in 17 of 32 (53%; 95% CI: 35-71%) evaluable patients receiving BTM and
32 of 46 (70%, 54-82%) patients receiving LAM (p = 0.16). Metronidazole
resistance was found in 32 of 65 (49%) patients in whom H. pylori was isolated by
culture. On a per-protocol basis, of patients who had metronidazole sensitive
strains of H. pylori 23 of 24 (96%) cleared infection after therapy with either
BTM or LAM, compared with 14 of 24 (58%) who were metronidazole resistant (p =
0.004). Clarithromycin resistance was not found in 45 patients tested.
CONCLUSIONS: In Western Australia clearance rates of H. pylori infection, after
one week of BTM or LAM, are lower than in other published series. The high
incidence of metronidazole resistance is the main determinant of our relatively
poor eradication rates.
PMID- 9544381
TI - Pregnancy outcome in systemic lupus erythematosus (SLE): a review of 54 cases.
AB - AIM: To compare the pregnancy outcome, in particular gestational age and birth
weight in women with systemic lupus erythematosus (SLE) diagnosed before and
after pregnancy, and to review data on presence or absence of the
antiphospholipid (aPL) antibody and flares of disease activity. METHOD: Case
histories were reviewed of women with a diagnosis of SLE and an obstetric event
attending Monash Medical Centre (MMC) over an eight year period (1988-96). Fifty
four pregnancies in 28 women were studied, with 44 occurring after the diagnosis
of SLE (Group 1) and ten prior to the diagnosis of SLE (Group 2). RESULTS: In
Group 1 there were 25 live births (63%) with 16 full term and nine premature
deliveries, 12 spontaneous abortions, three foetal deaths in utero and four
elective terminations. In Group 2 there were seven live births (70%), two
spontaneous abortions and one foetal death in utero. The mean gestational age of
live births was 35.8 weeks and 39.2 weeks respectively (p < 0.001). The mean
birth weight of live births was 2448 g and 3030 g respectively (p < 0.023). a PL
antibodies were positive in eight of 26 women tested with three live births and
were negative in 18 of 26 women with 12 live births. Flares of disease activity
occurred in 17 of 28 pregnancies. CONCLUSION: Pregnancy in women with a
predisposition to SLE have a high risk of an adverse outcome. Clinical disease
confers an additional risk. The mean gestational age and birth weight were
significantly less in women with established disease. Mild flares in disease
activity resulted in a favourable outcome while renal flares had a worse outcome.
PMID- 9544382
TI - Staphylococcal bacteraemia: the hospital or the home? A review of Staphylococcus
aureus bacteraemia at Concord Hospital in 1993.
AB - AIMS: To examine the risk factors for, and the complications and mortality of,
Staphylococcus aureus bacteraemia. METHODS: A retrospective case review of
patients with S. aureus bacteraemia in 1993 diagnosed at the Concord Repatriation
General Hospital, Sydney. RESULTS: Of 104 cases reviewed, 32 were due to
methicillin resistant S. aureus (MRSA), 73 were due to methicillin sensitive S.
aureus (MSSA) and one was a dual infection. Twenty-eight of the bacteraemias were
community-acquired, including one case of MRSA, and 76 were hospital-acquired;
38% had an implanted prosthetic device or graft. The average age (68 years),
incidence of underlying diseases and hospitalisation in the past month (26%) did
not differ between MRSA and MSSA groups. MRSA was more likely in patients with
recent broad-spectrum antibiotic use (53% vs 0, p < .01). Vascular access was the
commonest source of sepsis (61%) but in community-acquired cases the source was
unknown in 50%. Use of central line access was more predictive of MRSA infection
(75% vs 49%, p = .018). In hospital-acquired infection, MRSA sepsis occurred
later in the course of the admission (26 days vs eight days, p < .01). Directly
attributable mortality was highest in MRSA and community-acquired MSSA infection
(9% and 11%) compared with hospital-acquired MSSA infection (1%). CONCLUSIONS:
Nosocomial S. aureus bacteraemia, particularly MRSA, is a major source of
preventable morbidity, which could be addressed by improved infection control of
MRSA, antibiotic use and attention to central line catheter use.
PMID- 9544383
TI - Long term follow-up of CEOP in the treatment of HIV related non-Hodgkin's
lymphoma (NHL).
AB - BACKGROUND: The development of non-Hodgkin's lymphoma (NHL) in AIDS conveys a
poor prognosis with less than 10% of patients surviving beyond two years. These
tumours are generally aggressive and often require systemic chemotherapy to bring
about effective palliation. AIMS: To report on the long term follow-up of
patients with HIV related NHL treated with CEOP chemotherapy. METHODS: This is a
retrospective analysis of a group of 18 patients treated at two institutions
between October 1990 and 1992 with modified CEOP chemotherapy. Doses were
calculated using cyclophosphamide 750 mg/m2, epirubicin 50 mg/m2, vincristine 2
mg and prednisone 75-100 mg x five days, however initial doses of
cyclophosphamide and epirubicin were modified to 50-75% of calculated dose.
RESULTS: Seventeen of the 18 patients were male, one female; age range 26-79
(median 36 years); seven with immunoblastic, three Burkitt's, one Ki-1
(anaplastic), six diffuse large cell, and one mixed large and small cell. Eight
patients (44%) achieved a complete remission, with seven patients (39%) achieving
a partial remission, for an overall response rate of 83% (95% CI = 59-96%).
Survival ranged from three-35 months (median nine months). Interestingly, four
patients (22%) survived more than two years (median 31 months), three remaining
in complete remission at the time of death. Generally therapy was well tolerated
and toxicity was manageable. CONCLUSIONS: CEOP is an effective, tolerable and
safe regimen and our long term follow-up suggests that there is a small sub
population of patients with HIV and lymphoma who may have a better prognosis and
as such would clearly benefit from systemic chemotherapy as a means of prolonging
survival and not simply palliation.
PMID- 9544384
TI - Comparison of thallium-201 and gallium-67 scintigraphy in the evaluation of non
Hodgkin's lymphoma.
AB - BACKGROUND: Gallium-67 (Ga-67) is widely used in the assessment of patients with
lymphoma. Although highly sensitive in Hodgkin's disease and high grade non
Hodgkin's lymphoma (NHL), its sensitivity is reported to be reduced in lower
grades of NHL. Several series have suggested that thallium-201 (Tl-201) may be
more useful than Ga-67 in the evaluation of low and possibly intermediate grade
NHL. AIM: To compare the sensitivity and relative avidities (uptakes) of Tl-201
and Ga-67 in patients with NHL. METHODS: A total of 36 pairs of studies were
performed in 33 patients (14 male: 19 female; age range 16-84 years, mean 55
years). All had whole body Ga-67 (400 MBq) and Tl-201 (100-200 MBq) studies
(interval 0-three days) which were read by two experienced nuclear medicine
physicians blinded to clinical history and results of other investigations.
RESULTS: Tl-201 had a higher sensitivity and avidity than Ga-67 in patients with
low grade NHL. In contrast, Ga-67 was slightly more sensitive and had a higher
avidity in patients with both intermediate and high grade NHL. CONCLUSIONS: We
conclude that Tl-201 is more sensitive and avid for low grade NHL than Ga-67 and
that consideration should be given to its use in this condition in conjunction
with Ga-67 as it may provide complementary information. Routine use in
intermediate grade NHL is less convincing as Ga-67 was superior in most cases. Ga
67 is more sensitive than Tl-201 in assessment of high grade NHL.
PMID- 9544385
TI - Graves' ophthalmopathy: pathogenesis and clinical implications.
PMID- 9544386
TI - The Everett Magnus Oration. Euthanasia and the law: crossing the Rubicon?
PMID- 9544387
TI - Euthanasia--crossing the Rubicon or at the cross roads?
PMID- 9544388
TI - Euthanasia: over the Rubicon already?
PMID- 9544389
TI - Deliberate self-poisoning with eucalyptus oil in an elderly woman.
PMID- 9544390
TI - Heparin-induced skin lesions.
PMID- 9544391
TI - Very rapid echocardiographic appearance of Aspergillus endocarditis.
PMID- 9544392
TI - Skull metastases masquerading as cerebral secondaries in patients with cancer.
PMID- 9544393
TI - Acute rheumatic fever (ARF) in non-aboriginal patients in the Northern Territory.
PMID- 9544394
TI - Lupus anticoagulant antiprothrombin syndrome.
PMID- 9544395
TI - Implementation of guidelines for no-CPR orders.
PMID- 9544396
TI - Implementation of guidelines for no-CPR orders.
PMID- 9544397
TI - Haemolytic uraemic syndrome with acute oedematous pancreatitis.
PMID- 9544398
TI - Giant cell arteritis (GCA) presenting with severe aortic regurgitation and a
normal ESR.
PMID- 9544399
TI - Insulin requiring diabetes as a manifestation of Munchausen's syndrome.
PMID- 9544400
TI - Multi-focal Salmonella typhi infection.
PMID- 9544401
TI - Parallel implementations of individual-based models in biology: bulletin- and non
bulletin-board approaches.
AB - Particle-based models are simulations in which the discrete representation of
physical phenomenon involves interacting particles. This paper studies the
efficiency of two different methods of implementing these models on a network of
UNIX workstations. Two data parallel methods of modeling particles are tested:
bulletin-board and non-bulletin-board. In the former method, the programs
communicate through a logically shared, associative memory called a bulletin
board. The simulated particles are distributed among the workstations dynamically
as the processing load on the processors changes. In the latter method, the
particles are divided amongst the networked workstations statically at load time.
The simulated system is a collection of ants moving and foraging in a two
dimensional space. This paper analyzes and compares the execution times of both
implementations for different combinations of particles and number of
workstation, using speed-up, tuple granularity and communication cost as
measures. Analysis shows that the bulletin-board method is better for particle
based simulations when the correct granularity is chosen.
PMID- 9544402
TI - An interdisciplinary approach towards a theory of consciousness.
AB - Instead of attacking the difficult problem of consciousness or self-consciousness
directly, the theory is based on the more basic concept of reflection. A concept
of reflection is suggested on four levels (recursion, reflective thinking, self
reflection, intersubjective reflection). We propose the glial-neuronal
interaction as a neurobiological substrate for reflection processes. It is
assumed that glia have a boundary-setting function (scaffolding,
compartmentalization) in the spatio-temporal interaction with the neurons. This
function could be a possible mechanism of 'dividing' the brain into different
self-systems each with their own capacity of self-organization. Although the
brain's different self-systems are normally integrated, they may disintegrate and
show themselves in special states of the brain (e.g. multiple personality
disorder). A tree of reflection consisting of a number of places (ontological
loci) on which reflection processes of varying complexity take place, is
suggested as the formal model. Finally, the problem of self-conscious qualitative
experience (Qualia) is discussed in terms of the reflection model.
PMID- 9544403
TI - Characteristics of ionic transport processes in fish intestinal epithelial cells.
AB - A general mathematical version of the cell model of a leaky epithelium for the
NaCl absorption is presented, analysed and integrated numerically. The model
consists in the adequate differential equations that describe the rate of change
of the intracellular ion concentrations and are expressed in strict accordance
with the law of mass conservation. The model includes many state variables
representing ion concentrations, the cell volume, and membrane potentials. Ion
movements are described by the Michaelis-Menten kinetics or by the constant field
flux equation (Goldman-Hodgkin-Katz). In this paper, we model the intracellular
ion concentrations, change in the cell volume, the transmembrane flux and
membrane potentials of intestinal epithelium of both fresh water and sea water
fish, and generate several simulations (in both the steady state and the
transient state analysis) that appear to accord with prior experimental data in
this area. For the ion movements of the sea water fish intestine, there were
included a Na+/K+ pump, a K(+)-Cl- symport system, the K+ and Cl- channels in the
basolateral membrane, whereas a Na(+)-K(+)-2Cl- cotransporter for NaCl absorption
and K+ channels are located in the apical membrane. In the fresh water fish
intestinal cells, the NaCl absorption is performed by two coupled antiporters
Na+/H+ and Cl-/HCO3- presumably responsible for the intracellular pH regulation.
In this type of cells, Na+ and K+ channels are located within the apical
membrane, whereas Cl- channels are located within the basolateral membrane. The
osmotically induced water transport across the apical and basolateral membranes
has been taken into account as well. The simulations plot the steady state values
for membrane potential difference, short-circuit current and intracellular ionic
concentrations using the magnitude of the transmembrane flux through the Na+/K+
pump and Na(+)-K(+)-2Cl- cotransporter, or the basolateral Cl- permeability as
dependent variables. The model behaves appropriately with regard to several
experimental studies regarding the hyperpolarization (sea water fish intestine)
and depolarization (fresh water fish intestine) of the apical membrane potential
and inhibition of the short-circuit flux with reduced NaCl absorption. The model
is also used to make several analytical predictions regarding the response of the
membrane potential and ionic concentrations to variations in the basolateral Cl-
flux. Furthermore, maintaining conservation of both mass and electroneutrality
and taking into account the osmolar forces is an important advantage, because it
allows a rigorous analysis of the relationship between membrane potential
difference, volume and flux. The model can be used in the analysis and planning
of the experiments and is capable of predicting the instantaneous values of ionic
fluxes and intracellular concentrations and of cell volume.
PMID- 9544404
TI - Enzyme-dependent responses of stimuli-sensitive systems.
AB - The methods of creating of systems where properties depend both on an outer
physical signal and enzyme activity are discussed. The construction of a
conjugation chain between responses of stimuli-sensitive materials and urea
hydrolysis catalyzed with urease is demonstrated on the basis of light- and
thermoreversible polymeric matrices.
PMID- 9544405
TI - Diffusion theory, the cell and the synapse.
AB - The possibility exists that the cell internum is far more highly organised right
down to the molecular level than was hitherto appreciated, to the point where
ideas of a relatively solid-state chemistry model have been entertained (Coulson,
R.A., 1993. The flow theory of enzyme kinetics--a role of solid geometry in the
control reaction velocity in live animals. Int. J. Biochem. 25, 1445-1474). This
contrasts sharply with the traditional dogma that diffusion is the mechanism by
which molecules interact within an aqueous solution of the cell internum,
although it should have been clear from an early stage that diffusion could not
play other than a very restricted role in metabolic regulation. When physicists
began to question certain aspects of the fundamental Law of Heat Conductance
formulated over 170 years ago by Fourier, Diffusion Theory was also implicated
(Maddox, J., 1989. Heat conductance is a can of worms. Nature 338, 373), and
application of Fick's Laws of Diffusion to living systems criticised (Agutter
P.S., Malone, P.C., Wheatley, D.N., 1995. Intracellular transport mechanisms: a
critique of diffusion theory. J. Theoret. Biol. 176, 261-272). While we have
argued (Wheatley, D.N., Malone, P.C., 1993. Heat conductance, diffusion theory
and intracellular metabolic regulation. Biol. Cell 79, 1-5) that diffusion cannot
be prevented from occurring, we found that, irrespective of whether it was a
valid theory, diffusion was of little relevance in most actively metabolising
cell systems. However, diffusion is still perceived as essential for interacting
molecules to demonstrate their specificities. Any new model of the internal state
of the living cell has to resolve this dilemma. The question also relates to
molecular movement and ligand-receptor interactions outside the cell. In looking
at this situation, attention was paid to one site in the body in which diffusion
has long been assumed to be essential, namely in the passage of the chemical
transmitter between one neurone and the next across the synaptic cleft. A
detailed examination of this assumption has helped to identify one possible place
in which the importance of diffusion over a distance of no more than 20-30 nm
occurs, although objections to diffusion being involved have been raised. The
outcome, however, only re-enforces the conviction that diffusion has little role
in metabolic activity and is normally 'assisted' in almost all aspects of cell
physiology.
PMID- 9544406
TI - The role of the genetic code in generating new coding sequences inside existing
genes.
AB - The genetic code has a very interesting property--it generates an open reading
frame (ORF) inside a coding sequence, in a specific phase of the antisense strand
with much higher probability than in the random DNA sequences. Furthermore, these
antisense ORFs (A-ORFs) possess the same features as real genes--the asymmetry in
the nucleotide composition at the first and second positions in codons. About two
thirds of the 2997 overlapping ORFs in the yeast genome possess this feature.
Thus, the question arises: has this feature of the genetic code been exploited in
the evolution of genes? We have searched the FASTA data bases for homologies with
the antisense translation products of a specific class of genes and we have found
some sequences with relatively high homology. Many of them have scores which
could be randomly found in the searched data bases with a probability lower than
10(-6). We conclude that some genes could arise by positioning a copy of the
original gene under a promoter in the opposite direction in such a way that both,
the original gene and its copy initially use the same nucleotides in the third,
degenerated positions in codons.
PMID- 9544407
TI - Esophageal ulcer.
PMID- 9544408
TI - Collagenous colitis.
PMID- 9544409
TI - Methotrexate therapy.
AB - Methotrexate may be very helpful for your illness if proper care is taken in the
use of this medication. Follow your physician's instructions faithfully. Take
methotrexate weekly as directed. Notify your physician at once if an accidental
overdose is suspected or if you develop fever, cough or shortness of breath. If
you develop vomiting, there is a change in your pattern of diarrhea or you
suspect that you are dehydrated, notify your physician before taking the next
dose of methotrexate. Do not start or change any medicine without first checking
with your physician. Avoid or severely restrict alcohol, including wine and beer.
Obtain the blood tests ordered by your physician. Avoid pregnancy during and for
several months after taking methotrexate. Keep methotrexate out of the reach of
children. It has been prescribed for your current medical problem and must not be
given to other people.
PMID- 9544410
TI - Canadian Helicobacter pylori consensus conference. Canadian Association of
Gastroenterology.
AB - These guidelines were created to dispel confusion and provide guidance about how
the isolation of Helicobacter pylori infection has led to new opportunities and
initiatives to improve patient care. The guidelines are designed for practical
application in management decisions, but must remain flexible and amenable to
change with new information. Updated versions of the recommendations are
anticipated. Although it is now clear that H pylori is a major gastrointestinal
pathogen, the extent of the clinical consequences posed by this microorganism has
yet to be fully defined.
PMID- 9544411
TI - A cost-utility analysis comparing omeprazole with ranitidine in the maintenance
therapy of peptic esophageal stricture.
AB - BACKGROUND: Recent studies have suggested that patients receiving omeprazole for
prophylaxis against peptic esophageal stricture recurrence have less dysphagia
and require fewer repeat dilations than patients receiving ranitidine. OBJECTIVE:
To estimate the incremental utility gain and associated incremental cost of
omeprazole compared with those of ranitidine for the maintenance therapy of
patients with peptic stricture who required esophageal dilation. METHODS:
Decision analysis using SMLTREE software was used to compare the incremental cost
utility of omeprazole 20 mg once daily with that of ranitidine 150 mg bid for one
year. Variables were estimated from the literature, hospital data, and utility
analyses involving patients with peptic stricture and health professionals. The
primary outcome measure was cost per quality-adjusted life-years (QALYs) gained.
RESULTS: The incremental cost of omeprazole compared with that of ranitidine was
$556 per patient treated. The incremental utility gain of omeprazole was 0.0112
QALYs. Overall, the incremental cost:utility ratio of omeprazole in the
maintenance therapy of patients with peptic stricture was $49,600 per QALY
gained. A sensitivity analysis revealed that the estimates with the greatest
impact on the cost:utility ratio were disutility associated with dysphagia and
dilation, the probability of requiring redilation and the cost of medications.
CONCLUSIONS: Omeprazole 20 mg once daily is associated with greater utility and
higher cost than ranitidine 150 mg bid when used as prophylaxis against stricture
recurrence. Omeprazole may be considered clinically and economically sufficient
enough to warrant widespread use in this setting.
PMID- 9544412
TI - Combination ciprofloxacin and metronidazole for active Crohn's disease.
AB - Recent experimental evidence underscores the contribution of intestinal bacteria
to the inflammatory process of Crohn's disease. This open study examined the
efficacy and safety of combination ciprofloxacin and metronidazole for patients
with active Crohn's disease of the ileum and/or colon. Seventy-two patients with
active Crohn's disease of the ileum (n = 27), ileocolon (n = 22) or colon (n =
23) were treated with ciprofloxacin 500 mg bid and metronidazole 250 mg tid for a
mean of 10 weeks. Clinical remission was defined as a Harvey-Bradshaw index of
three points or less; an index reduction of at least three points indicated a
clinical response. Clinical remission was observed in 49 patients (68%), and 55
patients (76%) showed a clinical response. A clinical response was noted in 29 of
43 patients (67%) who were not taking concurrent prednisone treatment and in 26
of 29 patients (90%) receiving prednisone (mean dose of 15 mg/day). A clinical
response also occurred in a greater proportion of patients with colonic disease,
with or without ileal involvement (84%), compared with patients with ileal
disease alone (64%), and in patients without resection (86%) compared with those
with previous resection (61%). Five patients discontinued antibiotics because of
adverse events. After a mean follow-up of nine months, clinical remission was
maintained in 26 patients off treatment and in 12 patients who continued
antibiotic therapy. Ciprofloxacin in combination with metronidazole is well
tolerated and appears to play a beneficial role in achieving clinical remission
for patients with active Crohn's disease, particularly when there is involvement
of the colon.
PMID- 9544413
TI - Antibody levels in Ethiopian children five years after vaccination with two
different doses of hepatitis B vaccine: is there a need for booster vaccine?
AB - It was hypothesized that, following effective initial vaccination, a booster dose
of hepatitis B vaccine will not be necessary in areas of hyperendemicity for
hepatitis B virus (HBV) infection. A total of 314 Ethiopian children, ranging
from two to 14 years old, were alternatively vaccinated with 10 and 20 micrograms
hepatitis B vaccine doses, using the initial, one- and six-month schedule. Five
years later, 210 of the vaccinees were retested for anti-HBV surface antibody
titres. Both 10 and 20 micrograms doses of hepatitis B rDNA yeast vaccine were
equally immunogenic and protective against HBV infection for at least five years
despite marked reduction of mean antibody levels and geometric mean titres, with
11% of the vaccinees showing antibodies below the protective level. For firm
further recommendations a longer follow-up period of vaccinees is suggested.
PMID- 9544414
TI - Eligibility and exclusion of hemochromatosis patients as voluntary blood donors.
AB - BACKGROUND: Hereditary hemochromatosis patients are excluded in many countries as
voluntary blood donors. In 1991, changes in the Canadian Red Cross policy allowed
healthy hemochromatosis patients to become voluntary donors. STUDY DESIGN AND
METHODS: The medical histories of 208 hemochromatosis patients were evaluated for
eligibility for blood donation from a large prospective database of
hemochromatosis patients. A survey that determined the success or exclusion of 81
patients for blood donation and the reasons for their exclusion based on Canadian
Red Cross donor exclusion criteria was analyzed. RESULTS: Of 208 hemochromatosis
patients, 140 (67%) were eligible for blood donation. Criteria for exclusion were
other illnesses excluded by Canadian Red Cross criteria and the use of
contraindicated medications. Fifty-one per cent of patients had attempted to
donate blood, with only 7% being successful. CONCLUSIONS: A large number of
potential blood donors are excluded from blood donation inappropriately despite
changes in eligibility criteria to the contrary. Further public and health
education is needed to increase awareness and, thus, increase blood donation by
potential donors.
PMID- 9544415
TI - Liver transplantation for neuropsychiatric Wilson disease.
AB - Although neuropsychiatric manifestations are prominent in some patients with
Wilson disease, there is little published information regarding the efficacy of
liver transplantation for these patients. A 22-year-old male with advanced
neurological impairment and prominent psychiatric manifestations due to Wilson
disease who underwent liver transplantation is presented. After transplantation,
the ceruloplasmin and copper studies normalized and eventually the Kayser
Fleischer rings disappeared. Neurological recovery was very slow and incomplete,
and his behavioural and personality disorder was entirely unaffected. He
committed suicide 43 months post-transplantation. A review of the small number of
related published cases in the English language literature shows variable
neurological recovery post-transplantation, but the course of psychiatric
manifestations is virtually never described. This case suggests that one must be
cautious regarding liver transplantation for Wilson disease in patients with
prior psychiatric manifestations. Aggressive medical management is likely to be
preferable in most cases.
PMID- 9544416
TI - Hemorrhagic intestinal Henoch-Schonlein purpura complicated by cytomegalovirus
infection.
AB - A 54-year-old man on hemodialysis for acute chronic renal failure and on
corticosteroids for Henoch-Schonlein purpura developed massive hematochezia.
After extensive clinical investigation, an ileal bleeding site was identified and
surgically removed. Pathological examination of the diseased bowel segment
revealed an extensive vasculitis with mucosal ulceration attributable to Henoch
Schonlein purpura as well as florid cytomegalovirus infection.
PMID- 9544417
TI - Obscure gastrointestinal bleeding from an ampullary tumour in a patient with a
remote history of renal cell carcinoma: a diagnostic conundrum.
AB - Metastasis of renal cell carcinoma to the ampulla of Vater is a rare occurrence.
The outlined case, which presented as an upper gastrointestinal bleed, is only
the eighth such reported case in the English-language literature. This case is
the longest reported time interval between surgical nephrectomy to presentation
with ampullary metastasis at 17.5 years. The ampullary source of bleeding in this
case was initially obscure and missed by conventional gastroscopy. Diagnosis was
made with a side-viewing endoscope, emphasizing the usefulness of this instrument
in the investigation of active bleeding from a small bowel source.
PMID- 9544418
TI - A Canadian physician survey of dyspepsia management.
AB - OBJECTIVE: To determine the management of patients with new onset dyspepsia by
Canadian family physicians. METHODS: A survey was mailed to 195 family physicians
in August 1995 to identify how they manage dyspepsia in patients according to
four scenarios: based on presenting symptoms alone; assuming Helicobacter pylori
positive; known to be H pylori-negative; and endoscopically confirmed nonulcer
dyspepsia. RESULTS: A total of 170 of 195 physicians (87.2%) completed the
survey. Physicians reported that 7.3% of their practice is devoted to dyspepsia
and 23% of these dyspeptic patients present for the first time. Ninety-three per
cent of family physicians find a symptom classification of ulcer-, reflux- and
dysmotility-like dyspepsia helpful. The majority of patients are advised to make
life-style changes and are treated with antacids or empiric drug therapy. A H2
receptor antagonist was the drug of choice for ulcer and reflux-like dyspepsia,
while prokinetics were often used for reflux and dysmotility-like dyspepsia.
After failure of initial treatment, patients were given another course of empiric
treatment, commonly with cisapride or omeprazole. Family physicians estimated
that the mean time to obtain a gastrointestinal consult was five weeks, and 70%
indicated that this time to consult adversely influenced their decision to refer.
If this time was reduced to less than two weeks, responding physicians would
consider referring all eligible patients. On average, two to 2.5 courses of
empiric therapy were given before referral. If H pylori status was known, fewer
empiric treatments (mean 1.8) were given before gastroenterological referral
compared with the other scenarios. If the patient had nonulcer dyspepsia, 30% of
family physicians provided reassurance only and did not prescribe empiric drug
treatment. CONCLUSIONS: Most newly dyspeptic patients in Canada are treated with
empiric therapy according to symptom classification and referred for endoscopy
after an average two to 2.5 treatment courses.
PMID- 9544419
TI - Significance of nitric oxide in carcinogenesis, tumor progression and cancer
therapy.
PMID- 9544420
TI - Molecular biology of nitric oxide synthases.
AB - Nitric oxide (NO) is a potent biologic mediator with diverse physiologic and
pathophysiologic roles. NO is produced from L-arginine by the family of nitric
oxide synthase (NOS) enzymes, forming the free radical NO and citrulline as
byproduct. Three distinct isoforms of the NOS enzyme have been isolated and
represent the products of three different genes. Two of the NOS enzymes are
continuously present and are termed constitutive NOS (cNOS). One cNOS enzyme was
identified in neurons, and the other in endothelial cells. The two cNOS enzymes
are contrasted with the third NOS isoform, inducible NOS, which is not typically
expressed in resting cells and must first be induced by certain cytokines,
microbial products, or lipopolysaccharide. Since NO production has both
beneficial and detrimental consequences, understanding the molecular mechanisms
that regulate NOS expression is critical to the control of NO release in
homeostatic and pathophysiologic conditions. The purpose of this review is to
describe the molecular biology of NO synthases, with particular emphasis on the
regulation of the human NO synthase genes. Transcriptional and post
transcriptional regulation of neuronal and endothelial cNOS genes will be
reviewed first, followed by the molecular regulation of the inducible NOS gene.
PMID- 9544421
TI - Role of nitric oxide in genotoxicity: implication for carcinogenesis.
AB - Reactive oxygen species can initiate carcinogenesis by virtue of their capacity
to react with DNA and cause mutations. Recently, it has been suggested that
nitric oxide (NO) and its derivatives produced in inflamed tissues could
contribute to the carcinogenesis process. Genotoxicity of NO follows its reaction
with oxygen and superoxide. It can be due either to direct DNA damage or indirect
DNA damage. Direct damage includes DNA base deamination, peroxynitrite-induced
adducts formation and single strand breaks in the DNA. Indirect damage is due to
the interaction of NO reactive species with other molecules such as amines,
thiols and lipids. The efficiency of one pathway or another might depend on the
cellular antioxidant status or the presence of free metals.
PMID- 9544422
TI - Role of nitric oxide in mediation of macrophage cytotoxicity and apoptosis.
AB - Macrophages can recognize and eliminate tumor cells. To this effect, these cells
use a variety of cytotoxic effectors. Recent work has paid particular attention
to nitric oxide (NO) and its metabolic by-products in mediating macrophage tumor
cytotoxicity. Moreover, work from this and other laboratories have indicated that
macrophage-dependent, NO mediated tumor cell death meets the morphologic and
molecular criteria that define apoptotic cell death. This review will initially
discuss the characteristics of macrophage tumor cytotoxicity and the potential
mechanisms by which NO can induce apoptosis in tumor cells. In addition,
observations of spontaneous and acquired resistance to NO will be analyzed.
Lastly, the relevance of results obtained using animal cells to the biology of
the human macrophage will be considered.
PMID- 9544424
TI - Role of nitric oxide in angiogenesis and microcirculation in tumors.
AB - Nitric oxide (NO) is a free radical molecule with high reactivity, a short half
life and a variety of physiological activities. The role of NO in tumor
microcirculation, based on the data collected to date, can be summarized as
follows: 1) NO may partially mediate tumor angiogenesis; 2) endogenous NO derived
from tumor vascular endothelium and/or tumor cells increases and/or maintains
tumor blood flow via dilatation of arteriolar vessels, decreases leukocyte
endothelial interaction, and increases vascular permeability; 3) exogenous NO can
increase tumor blood flow via vessel dilatation, and reduce vessel tone; and 4)
NO production rates and vascular response to NO are heterogeneous and tumor
dependent. Modulation of NO level in tumor vessels can alter tumor hemodynamics
and thus augment oxygen, drug, gene vector and effector cell delivery to solid
tumors.
PMID- 9544423
TI - Therapy of cancer metastasis by activation of the inducible nitric oxide
synthase.
AB - The process of cancer metastasis consists of multiple sequential and highly
selective steps. The vast majority of tumor cells that enter the circulation die
rapidly; only a few survive to produce metastases. This survival is not random.
Metastases are clonal in origin and are produced by specialized subpopulations of
cells that preexist in a heterogeneous primary tumor. Experimental studies
concluded that metastatic cells survive in the circulation whereas nonmetastatic
cells do not. In part, this difference is due to an inverse correlation between
expression of endogenous inducible nitric oxide synthase (iNOS) and production of
nitric oxide (NO) and metastatic potential. Direct evidence for the role of iNOS
in metastasis has been provided by our data on transfection of highly metastatic
murine K-1735 clone 4 (C4.P) cells which express low levels of iNOS, with a
functional iNOS (C4.L8), inactive mutated iNOS (C4.S2), or neomycin resistance
(C4.Neo) genes in medium containing 3 mM of the specific iNOS inhibitor NG-L
methyl arginine (NMA). C4.P, C4.Neo, and C4.S2 cells were highly metastatic,
whereas C4.L8 cells were not. Moreover, C4.L8 cells produced slow-growing
subcutaneous tumors in nude mice, whereas the other 3 cell lines produced fast
growing tumors. In vitro studies indicated that the expression of iNOS in C4.L8.5
cells was associated with either cytostasis or cytolysis via apoptosis, depending
upon NO output. The tumor cells producing high levels of NO underwent
autocytolysis and produced cytolysis of bystander cells under both in vitro and
in vivo conditions. Multiple i.v. injections of liposomes containing a synthetic
lipopeptide upregulated iNOS expression in murine M5076 reticulum sarcoma cells
growing as hepatic metastases. The induction of iNOS was associated with the
complete regression of the lesions. Transfection of interferon-beta suppressed
tumor formation and eradicated metastases, which was apparently linked to iNOS
expression and NO production in host cells such as macrophage. Besides mediating
cell death, NO produced tumor suppression by regulating expression of genes
related to metastasis, e.g., survival, invasion, and angiogenesis. Suppression of
metastasis can be achieved through use of immunomodulators that induce iNOS
expression in tumor lesions or by the direct delivery of the iNOS gene to tumor
cells or host cells through liposome and/or viral vectors.
PMID- 9544425
TI - Role of nitric oxide in tumor progression: lessons from experimental tumors.
AB - Nitric oxide (NO), a potent biological mediator, plays a key role in
physiological as well as pathological processes, including inflammation and
cancer. The role of NO in tumor biology remains incompletely understood. While a
few reports indicate that the presence of NO in tumor cells or their
microenvironment is detrimental to tumor cell survival and consequently their
metastatic ability, a large body of clinical and experimental data suggest a
promoting role of NO in tumor progression and metastasis. We suggest that tumor
cells capable of very high levels of NO production die in vivo, and those
producing or exposed to lower levels of NO, or capable of resisting NO-mediated
injury undergo a clonal selection because of their survival advantage; they also
utilize certain NO-mediated mechanisms for promotion of growth, invasion and
metastasis. The possible mechanism(s) are: (a) a stimulatory effect on tumor cell
invasiveness, (b) a promotion of tumor angiogenesis and blood flow in the tumor
neovasculature, and (c) a suppression of host anti-tumor defense. In this review,
we discuss these mechanisms on the basis of data derived from experimental
models, in particular, a mouse mammary tumor model in which the expression of
eNOS by tumor cells is positively correlated with invasive and metastatic
abilities. Tumor-derived NO was shown to promote tumor cell invasiveness and
angiogenesis. The invasion-stimulating effects of NO were due to an upregulation
of matrix metalloproteases and a downregulation of their natural inhibitors.
Treatment of tumor-bearing mice with NO-blocking agents reduced the growth and
vascularity of primary tumors and their spontaneous metastases. We propose that
selected NO-blocking drugs may be useful in treating certain human cancers either
as single agents or as a part of combination therapies.
PMID- 9544426
TI - Role of nitric oxide in tumour progression: lessons from human tumours.
AB - Varied cellular expression and localisation of nitric oxide synthase (NOS)
isoforms has been shown in human cancers, including tumours of the breast, ovary,
stomach, cervix and central nervous system. Mapping of NOS expression within
tumour tissue from breast and gastric cancers shows inducible NOS (iNOS) is
expressed predominantly in stromal (macrophage and endothelial) cells, although
the level of NOS activity is at least 1-2 orders of magnitude lower than the
enzyme activity associated with cytotoxicity and apoptosis. There is evidence
that the intratumoural environment may provide chemoattractant signals for
monocyte-macrophage recruitment and their subsequent activation via expression of
interleukin-4, IgE, and CD23. Such signals lead to induction of iNOS in human
macrophages in vitro. The correlation between NOS activity and grade for breast
cancer suggests that NO may provide a positive growth signal within the tumour
microenvironment. In vivo studies showing increased growth rate, vascular density
and invasiveness of a human tumour cell line transfected to constitutively
express iNOS support this. Furthermore, in vivo administration of a highly
selective inhibitor of iNOS limited invasion and growth rate of iNOS transfected
tumours and other murine tumours expressing this isoform. Inhibition of NO
generation in the intratumoural microenvironment may prove a useful cancer
therapy by preventing angiogenesis, invasion and metastasis.
PMID- 9544427
TI - The role of nitric oxide in interleukin-2 therapy induced hypotension.
AB - Nitric oxide is an uncharged free radical that mediates a range of physiologic
processes in the vasculature. As a principal determinant of vascular tone, the
overproduction of nitric oxide has been implicated in the pathogenesis of sepsis-
and cytokine-induced hypotension. The enzyme that produces nitric oxide, nitric
oxide synthase, exists in three isoforms. One of the three isoforms, inducible
nitric oxide synthase, is expressed in many cell types only after stimulation by
cytokines and/or endotoxin. Compared to the constitutive nitric oxide synthase
enzymes, the inducible enzyme generates larger quantities of nitric oxide for
longer periods. Expression of the inducible isoform in vitro requires stimulation
by a mixture of cytokines including interferon-gamma, tumor necrosis factor
alpha, and interleukin-1 beta. These proinflammatory cytokines are known
mediators of sepsis and are also produced in the serum of cancer patients during
interleukin-2 therapy, thereby leading to excessive production of nitric oxide.
Interleukin-2 therapy is associated with a spectrum of cardiovascular toxicities
and hemodynamic alterations that are indistinguishable from those seen in septic
shock. Many of these hemodynamic effects have been linked to the overproduction
of nitric oxide via a cytokine-inducible nitric oxide pathway. In this regard,
inhibition of nitric oxide synthesis represents a novel approach to limit the
cardiovascular toxicity associated with interleukin-2 therapy and to improve its
therapeutic index. Clinical trials to evaluate the efficacy of nitric oxide
synthase inhibitors in reversing the hypotension associated with IL-2 therapy are
now underway.
PMID- 9544428
TI - Role of nitric oxide in IL-2 therapy-induced capillary leak syndrome.
AB - Nitric oxide (NO) is a potent short-lived and short range bioactive molecule,
which plays a key role in physiological and pathological processes including
inflammation and cancer. Detrimental effects of excessive NO production during
septic shock have been well recognized. We tested the hypothesis that 'capillary
leak syndrome' following systemic interleukin-2 (IL-2) therapy resulted from a
cascade of events leading to the induction of NO which, directly or indirectly,
injured capillaries and caused fluid leakage. Our results provided the first
direct evidence that the induction of active NO synthase (NOS) leading to the
overproduction of NO is instrumental in IL-2-induced capillary leakage in mice
and that successful blocking of this overproduction with chronic oral
administration of NOS inhibitors can mitigate this leakage without interfering
with the beneficial antitumor effects of IL-2 therapy. NO blocking agents can, in
fact, improve IL-2-induced antitumor effector cell activation, as well as tumor
regression. In our studies, NO blocking agents alone reduced the growth and
metastasis of a murine mammary carcinoma, at least in part, by mitigating the
invasion and angiogenesis-stimulating role of tumor-derived NO. Thus, NOS
inhibitors may be useful in treating certain tumors and serve as valuable
adjuncts to systemic IL-2 based immunotherapy of cancer and infectious diseases.
PMID- 9544429
TI - Evaluation of cell-mediated immunity and circulating immune complexes as
prognostic indicators in cancer patients.
AB - Cell-mediated immunity (CMI) and circulating immune complexes (CIC) were
estimated in 55 cancer patients and 25 control volunteers to evaluate their
prognostic significance. Cancer patients comprised head and neck cancer (11),
breast cancer (13), gastrointestinal cancer (10), genitourinary cancer (11), and
lymphomas and sarcomas (10). CMI was tested in vitro by early rosette-forming
cells (ARFC) and total rosette-forming cell (TRFC) counts. ARFC count in control
group was 758.1 +/- 78.09 cells/cumm. In advancing clinical stages of cancer (I
IV), ARFC counts were decreased (i.e., 601.12 +/- 74.96 [p < 0.01]; 494.8 +/-
71.83 [p < 0.001]; 432.44 +/- 36.05 [p < 0.001], and 438.55 +/- 69.99 [p < 0.001]
cells/cumm, respectively). TRFC count in control group was 1029 +/- 88.39
cells/cumm. In cancer stages I through IV, these counts decreased significantly
(i.e., 699.63 +/- 66.24; 597.55 +/- 82.9; 505.11 +/- 52.56; and 501.55 +/- 69.99
cells/cumm, respectively [p < 0.001]. Dinitrochlorobenzene cutaneous reactivity
in vivo was 100% positive in control group, 62.5% positive in cancer stage I, 5%
positive in stage II, and negative in stages III and IV. CIC of intermediate size
were estimated by polyethylene glycol precipitation (PEG pptn) technique, which
detects CIC in the ratio of 2:1 (Ag2Ab). Mean PEG index in control group was 39.5
+/- 4.65; sequential increase in CIC was observed in advancing clinical stages of
cancer (I-IV)(i.e., 49 +/- 7.03 [p < 0.01]; 75.38 +/- 44.01 [p < 0.001]; 93.38 +/
44.57 [p < 0.001]; and 216.00 +/- 147.05 [p < 0.001], respectively). Latex
agglutination inhibition (LAI) titer was done to detect CIC as small as 8s, which
constitute the opposite polar end of CIC spectrum. LAI titers in control group
were nil. However, LAI titers in cancer stages I through IV were 1 +/- 2.64; 8.6
+/- 5.6 (p < 0.001); 12.00 +/- 8.11 (p < 0.001); and 25.77 +/- 9.06 (p < 0.001),
respectively. Decrease in CMI and subsequent increase in CIC indicate unfavorable
prognosis in cancer patients, and also precede clinical manifestation of
increased tumor mass in vivo.
PMID- 9544430
TI - Risk factors for glioma in adults: a case-control study in northeast China.
AB - A case-control study of risk factors for glioma in adults was carried out in
Heilongjiang province in northeast China. Between September 1989 and May 1995,
218 histologically confirmed cases of glioma requiring surgery for tumor removal
(139 astrocytoma glioma and 79 other glioma) and 436 controls with non-neoplastic
and non-neurological disease were recruited and personally interviewed in the
wards of six major hospitals. Controls were matched by sex, age, and area of
residence. Occupational, lifestyle, and medical information was obtained through
a standardized questionnaire. Use of liquor was associated with cancer risk.
Compared with males who never drank liquor, males with total lifetime liquor
consumption of less than 1000 liters had an adjusted odds ratio (OR) of 1.60 (95%
CI: 0.89-2.88) and for more than 1000 liters, 2.73 (95% CI: 1.06-7.08).
Statistically significant associations were also found for diseases related to
the brain (OR: 5.75; 95% CI: 1.08-30.47) and trauma to the head requiring medical
attention (OR: 4.09; 95% CI: 2.51-10.31). Increased consumption of vegetables and
of fruit were each associated with decreased glioma risk. Compared with lowest
quartile intake, adjusted risks associated with highest quartile intake were 0.51
(95% CI: 0.29-0.89) for total vegetables and 0.28 (95% CI: 0.16-0.51) for total
fruit.
PMID- 9544431
TI - Cigarette smoking and cervical dysplasia among non-Hispanic black women.
AB - This is the first case-control study to determine whether smoking is associated
with cervical dysplasia, after adjustment for human papillomavirus (HPV)
infection, among a group of non-Hispanic black women. Subjects were interviewed
and asked questions about smoking and other risk factors for cervical cancer. HPV
infection was determined by hybrid capture. Thirty-two women with histologically
confirmed incident dysplasia and 113 control women with normal cytologic smears
were enrolled; all women were HIV negative. Smoking was more strongly associated
with dysplasia among women with high-grade lesions than among all case women
combined. After adjustment, women with high-grade lesions were roughly four times
more likely to be ever (odds ratio [OR]: 3.8; 95% confidence interval [CI]: 0.76
18.4) or current (OR: 4.3; 95% CI: 0.83-21.9) smokers, compared with control
women. Larger studies among black women that control for HPV infection are needed
to confirm these findings and to explore associations among black women with low
grade lesions.
PMID- 9544432
TI - Immunohistochemical prediction of radiation response and local control in
radiation therapy for cervical cancer.
AB - Prognosis of 64 cervical cancer patients treated with radiation therapy was
analyzed by tumor expressions of c-erbB-2 oncoprotein (CerbB-OPE) and p53 protein
(p53-PE), Ki-67 growth fraction (Ki-GF), and the mitotic index of proliferating
cell population (pMI). Positivity of CerbB-OPE and p53-PE was 42.4% and 84.6%,
respectively. Mean Ki-GF and pMI were 33.0% and 2.7%, respectively. Mean Ki-GF
for CerbB-OPE was 38.3%, significantly higher than the 26.2% for the negative
patients (p < 0.01). The mean pMI for CerbB-OPE was 2.00%, significantly lower
than the 3.70% of the negative patients (p < 0.05). The 5-year survival rate of
CerbB-OPE-positive patients was 44.4%, significantly lower than the 74.8% of
negative patients (p < 0.01). The survival rates of Ki-GF < 33% was 44.7%,
significantly lower than the 87.5% of Ki-GF > or = 33% (p < 0.01). The survival
rates of pMI > or = 3.5% was 0%, significantly lower than the 81.8% of pMI < 3.5%
(p < 0.001). The survival rates of p53-PE-positive and negative patients were
52.8% and 85.0%, respectively (p > 0.1). The poor prognosis of the cervical
cancer with CerbB-OPE, lower Ki-GF, and higher pMI were due to local recurrence
following radiation therapy. Multiple regression analysis indicated that pMI was
the strongest prognostic factor and was followed by CerbB-OPE, tumor volume, and
Ki-GF. In conclusion, the c-erbB-2 oncoprotein expression, Ki-67 growth fraction,
and the mitotic index of proliferating cell population were considered to be
effective prognostic factors in radiation therapy for cervical cancer.
PMID- 9544433
TI - GSTM1 and GSTT1 genes are potential risk modifiers for bladder cancer.
AB - The role of the polymorphic glutathione S-transferase genes GSTM1 and GSTT1 in
the development and in the clinicopathological outcome of bladder cancer was
investigated in 37 Egyptian bladder cancer patients and 34 matched controls. Of
the 37 patients studied, 26 had transitional cell carcinoma (TCC) and 11 had
squamous cell carcinoma (SCC). Fourteen out of twenty-six TCC and four out of
eleven SCC patients were infected with schistosoma. We observed an increased
relative risk for bladder cancer associated with the GSTM1 null genotype (OR =
2.99; 95% CL = 1.01-9.00; p = 0.02). The relative risk was more pronounced in
squamous cell carcinoma (SCC) (OR = 5.70; 95% CL = 0.91-36.70; p = 0.03) than in
transitional cell carcinoma (TCC) (OR = 2.39; 95% CL = 0.73-7.90; p = 0.08). Our
results also indicate that the GSTT1 polymorphism is individually associated with
increased risk for bladder cancer (OR = 4.93; 95% CL = 1.39-18.42; p = 0.004)
with no preferential increase in risk with respect to the type of the carcinoma.
Individuals with the null genotype for both GSTM1 and GSTT1 were at a
significantly higher risk for developing bladder cancer than individuals with
both genes present (OR = 9.92; 95% CL = 1.84-46.90; p = 0.001). These individuals
were more susceptible to developing SCC than TCC (OR = 14.16; 95% CL = 1.35
131.35; p = 0.01; and OR = 8.5; 95% CL = 1.38-60.10; p = 0.007, respectively). In
conclusion, our results indicate that the null genotypes for GSTM1 and GSTT1,
either individually or in combination, are important host risk factors for
bladder cancer. In addition, the null GSTM1 genotype may also affect the
clinicopathological tumor outcome. Since the deleted genotypes for GSTM1 and
GSTT1 are prevalent in the general population, the identification of these
individuals may provide a useful public health approach for early detection and
prevention of environmental cancers.
PMID- 9544434
TI - Prognostic significance of c-erbB-2 gene expression in the poorly differentiated
type of adenocarcinoma of the stomach.
AB - Prognostic significance of c-erbB-2 gene abnormalities is unclear in the poorly
differentiated type of gastric carcinoma, because the abnormalities of this gene
have been reported to be restricted to the differentiated type of gastric
carcinoma. In this study, correlation of c-erbB-2 gene
amplification/overexpression of mRNA and protein were studied in the poorly
differentiated type of gastric carcinoma. c-erbB-2 gene amplification determined
by the slot-blot hybridization was observed in 11 (13%) of 82 gastric cancer, and
8 of 11 tumors were poorly differentiated. In addition, c-erbB-2 mRNA expression
was studied by the reverse transcriptase-polymerase chain reaction. Four (17%) of
24 tumors showed overexpression of c-erbB-2 mRNA, and all these four exhibited
morphologically a poorly differentiated type. Among 157 poorly differentiated
gastric cancers, 20 (13%) tumors showed immunohistochemically c-erbB-2 protein
expression. These tumors had significantly higher incidences of larger tumor,
serosal invasion-positive tumors, node-positive tumor, or peritoneal
dissemination-positive tumor than those without c-erbB-2 expression. Furthermore,
patients with c-erbB-2 protein overexpression ran poorer prognoses than those
without c-erbB-2 expression. From these results, we conclude that expression c
erbB-2 tissue status may be a good prognostic indicator in poorly differentiated
gastric carcinoma.
PMID- 9544435
TI - Shared tumor antigens in colorectal carcinoma and neuroendocrine tumors.
AB - ND4 monoclonal antibody recognizes a tumor marker found on poorly differentiated
colorectal cancer. We demonstrate its expression in 25% of gastrointestinal
neuroendocrine tumors, which also express CEA in 37% of cases. As in colorectal
cancer the ND4 marker is predominantly membrane bound in a colonic neuroendocrine
tumor cell line, LCC-18 (p < 0.05). The ND4 marker is absent in a poorly
differentiated colorectal cancer cell line that does not express CEA or other
tumor antigens. Shed antigen in the serum of patients with neuroendocrine tumors
is detected in only five of seven patients with the carcinoid syndrome and two of
four of those without evidence of the syndrome. However, the reactivity was less
in the patients with localized disease, and this test is unlikely to be of
diagnostic utility in this group of patients. The sharing of this antigen in
colorectal cancer and neuroendocrine tumors is not universal, but does support
the common-cell progenitor theory for the origin of these tumors.
PMID- 9544436
TI - Effects of gamma-glutamylcysteine ethyl ester in cisplatin-induced changes in
prostanoid concentrations in rat gastric and colonic mucosa.
AB - We evaluated changes in gastric and colonic mucosal prostanoid contents in rats
treated with cisplatin. We also determined effects of gamma-glutamylcysteine
ethyl ester (GCE), a pro-drug of glutathione, on cisplatin-induced changes in
prostanoid concentrations. Rats were divided into three groups--the control: 0.5
ml of physiological saline was administered intraperitoneally (i.p.); the
cisplatin group: 0.5 ml of cisplatin, 10 mg/kg, was administered i.p.; the GCE +
cisplatin group: GCE, 30 min before cisplatin injection. In each group, rat
gastric and colonic mucosa were isolated and their prostanoid concentrations were
determined using high-performance liquid chromatography. 6-Keto-PGF1 alpha, PGF2
alpha, PGE2 were detected in gastric mucosa. In addition to these prostaglandins
(PGs), thromboxane (TX) B2 was also detected in the colonic mucosa. In the
cisplatin group, gastric mucosal 6-keto-PGF1 alpha concentration decreased
significantly 24 h after administration, while PGE2 and PGD2 concentrations were
increased significantly after 12 and 24 h, respectively. In colonic mucosa,
cisplatin increased PGE2 and PGD2 concentrations, while it decreased TXB2
concentration. 6-Keto-PGF1 alpha concentration was not affected by cisplatin in
colonic mucosa. GCE canceled out these changes in prostanoid concentrations in
both gastric and colonic mucosa. Changes in prostanoid concentrations might be
implicated in the adverse gastrointestinal effects of cisplatin, and clinical
application of GCE could be expected.
PMID- 9544437
TI - Screening mammography behavior after a false positive mammogram.
AB - This pilot study describes women's interpretations of the experience of a false
positive mammogram followed by a negative biopsy and the impact of this
experience on subsequent participation in screening mammography. A 25-min, open
ended telephone interview was administered in 1992 to 30 women over age 39 who
had negative biopsies in 1987 preceded by abnormal mammograms. Almost twice as
many women reported getting regular mammograms after the biopsy (60%) as did
before 1987 (33%). Most received their next mammogram after the biopsy within the
recommended interval (73%), and those getting regular mammograms prior to the
biopsy experience were more likely than those who did not have a prior habit of
undergoing mammography to continue to get them afterwards. These preliminary
findings suggest that a negative breast biopsy after a positive mammogram does
not reduce a patient's likelihood of undergoing screening in the future. In fact,
it may serve as an impetus for increased compliance with screening
recommendations.
PMID- 9544439
TI - Resistance of spontaneously transformed Syrian hamster embryo cells and their
malignant variants to cytotoxic activity of recombinant tumor necrosis factor
alpha.
AB - To study the possible role of the host macrophages in the selection of tumor
cells and tumor progression, a series of Syrian hamster tumor cell lines all
originating from a single spontaneously transformed Syrian hamster embryo cell
line (STHE strain) have been established. These STHE tumor cell variants,
selected either in vitro with resident and lipopolysaccharide-activated
macrophages or in vivo, differ in tumorigenic and metastatic activity. The
selected malignant STHE cells become resistant to cytotoxic activity of activated
peritoneal macrophages and of exogenous hydrogen peroxide (H2O2). Since activated
macrophages are a known source for both cytotoxic agents H2O2 and tumor necrosis
factor (TNF), the purpose of the present study was to define the sensitivity of
the STHE tumor cell lines to a direct cytotoxic activity mediated by recombinant
TNF-alpha in an attempt to understand the role of the cytokine in in vitro
selection of a malignant STHE cells by activated macrophages. The spontaneously
transformed STHE cells (selected in vivo and in vitro) as well as the hamster
embryo cells transformed in vitro by a tumorigenic Rous sarcoma virus (Schmidt
Ruppin strain) were used as targets. TNF-alpha-sensitive mouse L929 cells were
included in the study as a positive control. Sensitivity of actinomycin D
pretreated target cells studied for cytotoxic activity of a recombinant TNF-alpha
was examined over 21 h with a crystal violet dye assay. It was found that, in
contrast to L929 cells, the spontaneously transformed STHE cells as well as
tumorigenic Rous sarcoma virus hamster embryo transformants, were all
significantly resistant to the TNF-alpha-mediated cytolysis. This indicates that
TNF-alpha is not the single factor responsible in in vitro selection of malignant
STHE cell variants by activated macrophages. It appears that H2O2 is involved in
the selection of the hamster macrophage-resistant STHE tumor cells.
PMID- 9544438
TI - Enhancement of tumor cell lysis by natural killer cells after blocking of HLA
monomorphic determinant using F(ab')2 fragment of W6/32.
AB - It has been known that negative signal of natural killer (NK) cells is triggered
by HLA-polymorphic determinant (PMD) of target cells. However, it is not clear
whether or not the negative signal is triggered by HLA-monomorphic determinant
(MMD). In this study, we determined the interaction of NK receptor and MMD by
mean of a blocking test. For the blocking, W6/32, which is an antibody to the
MMD, was used. As target cells, we used a tumor cell line H42 and several cell
lines. The H42 was established from a bladder cancer patient after radiation
therapy. This cell line was demonstrated to be PMD negative but MMD positive and
showed NK sensitivity. We had established one more cell line, H41, from the same
patient before the radiation therapy. However, the H41 possessed both the PMD and
MMD and exhibited NK resistance. Thus, the NK sensitivity of the H42 may be due
to depression of the PMD. We performed a blocking test against the MMD of these
cell lines. When the H42 was pretreated with F(ab')2 fragment of the W6/32, the
killing by NK cells increased. Other cell lines, EB33, KMT-1, and HMy2-C1R, which
possessed low levels of PMD, were killed moderately after the pretreatment,
although the H41 and other cell lines (KO, MT-2, OKM-3T), which possessed high
levels of PMD, were killed only slightly. These findings suggest that the
negative signal may be triggered not only by the PMD but also by the MMD.
PMID- 9544440
TI - Families' experiences of caring at home for a technology-dependent child: a
review of the literature.
AB - Recent medical advances have led to the emergence of a group of chronically ill
children who are dependent upon technology for their survival. Many of these
children are cared for at home by their parents. This paper presents an overview
of the literature that has examined the experiences of families caring for a
technology-dependent child at home. The social, emotional and financial impact on
families and their perspectives on the services supporting them at home is
described. The paper concludes by identifying areas where further research is
needed.
PMID- 9544441
TI - Emotional and behavioural difficulties in children with diabetes: a controlled
comparison with siblings and peers.
AB - This study describes a comparison of children with insulin dependent diabetes
mellitus (IDDM) with two control groups: the sibling nearest to them in age, and
peers matched for gender and age. A broad range of emotional and behavioural
difficulties were assessed using the Conners' Teachers' and Parents' rating
scales (CTRS 39 and CPRS 93). Individually completed children's questionnaires
provided qualitative data about the children's problems. The results of the study
showed markedly higher scores for the children with diabetes on the parent scales
on factors such as hyperactivity, psychosomatic and restless/disorganized, in
comparison to their siblings, but not their peers. These differences were not
found on the Teachers' Scales. The findings are discussed in terms of parental
perceptions of children with diabetes and the difficulties these children and
their siblings experience in their lives. Suggestions are made for further
research.
PMID- 9544442
TI - The British Paediatric Surveillance Unit--a pioneering method for investigating
the less common disorders of childhood. Report of a seminar held in June 1995.
AB - The British Paediatric Surveillance Unit (BPSU) of the Royal College of
Paediatrics and Child Health is an 'active' case reporting scheme set up in 1986
to facilitate the investigation of uncommon childhood conditions of public health
and clinical importance in the UK and Ireland. Its methodology involves the
monthly mailing of a card containing a menu of up to 12 reportable conditions to
all clinically active paediatricians in the British Isles. Respondents either
indicate any cases seen in the past month or make a nil return. The BPSU forwards
details of respondents reporting cases to the investigators, who when obtain
information from the clinician. The menu changes from time to time and studies
undergo a rigorous selection process. In 1995, the BPSU held an international
seminar to review lessons learned during its first decade which would improve and
develop surveillance of paediatric disorders. Over the 9 years to mid-1995 a
total of 34 studies took place (25 completed, nine still in progress) with a high
respondent response rate (e.g. 90% in 1994). Underascertainment had been
addressed by seeking, in parallel, other sources of cases, e.g. death
registrations, laboratory reports, other relevant clinical specialists, and by
use of capture-recapture techniques. Other specialties and countries have since
followed the BPSU example providing opportunity for multispeciality and
international studies. The latter were valuable, but required careful planning to
standardize case definitions and laboratory techniques, otherwise geographical
differences in the incidence of study disorders were difficult to interpret. The
BPSU has facilitated studies which increased knowledge about a range of disorders
and informed national policy decisions. It also increased diagnostic awareness
and showed itself able to respond to public health emergencies. Its emulation in
further countries will have similar benefits.
PMID- 9544444
TI - Do the younger siblings of learning-disabled children see them as similar or
different?
AB - Pre-school siblings' comments about, and behaviour towards, their older, learning
disabled brothers and sisters are reported. Initially, some of the very young
siblings want to be similar, and attempt to imitate their brothers and sisters,
particularly if he or she is also physically disabled; this may be because of the
immediate visibility of physical disability, which makes it appear interesting
and important to the younger child. Before they are 2 years old, children are
able to recognize that their older brothers and sisters are different, and often
imitate the parents' behaviour towards the older child.
PMID- 9544443
TI - Short stature at school entry--an index of social deprivation? (The Wessex Growth
Study).
AB - This study was carried out to examine the biological and environmental variables
associated with non-organic short stature. We observed an unselected population
of very short normal children (SN) and their age- and sex-matched controls (C)
within the community. All 14,346 children in two health districts entering school
during 2 consecutive years were screened for short stature, and those whose
height lay below the 3rd centile, according to Tanner and Whitehouse standards (n
= 180) were identified. Excluding 32 with pathology, five from ethnic minorities
and three who refused to take part, the remaining SN children (mean height SDS
2.26) were matched with 140 age- and sex-matched controls (C) of average height
(mean height SDs 0.14). Birth weight, target height and predicted adult height
(based on parental height and bone age respectively), medical and social
background (obtained from parental interviews), and school performance (assessed
by class teachers) were the main outcome measures. Mean birth weight of the SN
children was significantly lower than C (SN = 2845 g, C = 3337 g, P < 0.001).
Mean mid-parental target height was also very different (SN = 162.0 cm, C = 170.9
cm, P < 0.001). Thirty-five per cent of SN children (C = 6%) had height SD scores
below parental target range, though only 10% had predicted heights below target
range (mean delay in bone age 0.68 years). There was a significant difference
between SN children and C in the number of children in the household (SN = 2.8, C
= 2.4 (P = 0.007) and in socio-economic status (P < 0.002). Many more SN children
were in social classes IV and V (SN = 31%, C = 13%, P < 0.002), and had an
unemployed father (SN = 22%, C = 10%, P < 0.010), highlighting the importance of
environmental influences on growth. One in four SN children was judged to have
serious psychosocial problems. However, the lower the socio-economic class, the
less likely the SN children were to be inappropriately short for parents.
Significantly more SN children were reported to have asthma (SN = 18%, C = 7%, P
< 0.007) and eczema (SN = 19%, C = 5%, P < 0.001), though only the latter was
significantly associated with stature below target height for both SN and C
groups. Biological variables are often insufficient to explain short stature. No
child, whatever the parental height, should be dismissed as normal without
careful evaluation, as poor growth in the early years may be an important pointer
to an adverse but potentially remediable environment.
PMID- 9544445
TI - An activity week for children with cancer: who wants to go and why?
AB - Many children now live with cancer rather than die from it, and such children
need both to continue their social, emotional and cognitive development and to
make long-term psychological adjustments. This paper presents the findings of a
research project set up to explore issues pertinent to the current provision of
an activity week experience for a group of British paediatric cancer patients.
The aims of the study included finding out which factors discriminate between
families who apply for a place to attend the week for their child and families
who do not, and to develop a knowledge of what factors are considered by parents
and children. The findings suggest that the week appeals to children who are
confident, active and able to separate from parents and whose parents are keen to
encourage independence and new experiences. Children diagnosed and treated at a
younger age and further away from treatment were more likely to express concerns
about being homesick and safety and to not apply for the week. Issues of
protection, independence and disability are discussed with reference to the
importance of parental attitude on children's psychological accommodation to
disease and treatment and to the experiences of adult survivors of childhood
cancer.
PMID- 9544446
TI - Alzheimer's amyloid beta interaction with normal human plasma high density
lipoprotein: association with apolipoprotein and lipids.
AB - We report studies of the interaction of Alzheimer's amyloid beta protein (A beta)
with normal human plasma high density lipoprotein (HDL), aiming to clarify to
which lipoprotein (LP) structural constituent (apolipoprotein or lipid) soluble A
beta is primarily bound. Purified HDLs were incubated with biotinylated A beta 1
40 followed by LP repurification by size exclusion (SE) HPLC. SDS-PAGE,
immunoblot and N-terminal sequence analysis of the biotin-A beta positive protein
bands revealed that A beta is bound to many apolipoproteins of the HDL, mainly
apoA-I, apoA-II, apoE and apoJ. On the other hand, reconstituted, protein-free
HDL lipid particles also bind A beta peptide and inhibit its aggregation, as
intact HDL does. This was assessed by SE-HPLC, SDS-PAGE, immunoblot analysis,
ultrastructural electron microscopy and Congo Red staining for beta amyloid
fibrils. Our data imply that A beta binding to lipids may play an important role
in maintaining the peptide in solution and thus be particularly relevant to A
beta normal and pathologic biochemistry and physiology.
PMID- 9544447
TI - A routine method for the simultaneous measurement of retinol, alpha-tocopherol
and five carotenoids in human plasma by reverse phase HPLC.
AB - We describe a simple isocratic HPLC method for the accurate and precise
measurement of retinol, alpha-tocopherol and the major carotenoids in plasma
using UV detection. Reference ranges for retinol, alpha-tocopherol and five
carotenoids are determined in a healthy population group. The most abundant
carotenoids found in plasma were beta-carotene, lycopene, lutein and
cryptoxanthin. Retinol, alpha-tocopherol and carotenoids were determined
simultaneously using two internal standards, retinol acetate for retinol and
tocopherol acetate for alpha-tocopherol and carotenoids. The use of echinenone as
an internal standard for carotenoids was investigated. The protective effect of
an antioxidant (ascorbic acid) on the stability of samples and extracted material
is documented. The method is useful for the routine measurement of plasma
retinol, alpha-tocopherol and carotenoids and could also be used in large scale
epidemiological studies.
PMID- 9544448
TI - An ultrasensitive, nonisotopic immunoassay for hyaluronan using the streptavidin
biotin system.
AB - A time-resolved fluoroimmunoassay for measuring hyaluronan concentrations in
plasma and several biological fluids is described. The solid-phase immunoassay is
based on the competition between aggregation of hyaluronan with the cartilage
proteoglycan monomer, followed by binding of a monoclonal antibody to keratan
sulfate of the proteoglycan and a biotinylated anti-mouse IgG. Fluorescence can
be measured by a time-resolved fluorometer after binding of Eu(3+)-labelled
streptavidin to the biotinylated IgG. The assay is precise and correlates well (r
= 0.986) with the only established radioimmunoassay known. The results show that
it is essential to perform a blank run without addition of proteoglycan, as
endogenous proteoglycan disturbs the measurement and causes underestimation of
plasma hyaluronan. The distinguishing feature of this assay is its extreme
sensitivity (< 0.24 microgram/l of plasma). The mean analytical recovery after
serial dilutions and addition was 100.3 and 101.3%, the within-assay and between
assay coefficients of variation were 3.67% and 7.02%, respectively.
PMID- 9544449
TI - Oxidation of erythrocyte glutathione by monocytes stimulated with interleukin-6.
Analysis by 1H spin echo NMR.
AB - 1H spin echo NMR was used to follow the release of reactive oxygen species (ROS)
from human monocytes by monitoring erythrocyte glutathione status, which is
sensitive to applied oxidative stress. This allowed the ability of the cytokine
interleukin-6 (IL-6) to stimulate release of ROS from monocytes to be assessed in
terms of oxidative damage to other cells, providing an estimation of its
importance in vivo. It was found that incubation of monocytes with erythrocytes
in the presence of IL-6 resulted in oxidation of the erythrocyte glutathione
pool, indicating that oxidants are released in sufficient amounts to cause
oxidative stress. High levels of IL-6 occurring in plasma of women with severe
pre-eclampsia could therefore be responsible for depleted plasma antioxidants and
haemolysis. The oxidation of erythrocyte glutathione was inhibited by the
presence of the cyclooxygenase inhibitor indomethacin, suggesting that this may
be of value in the treatment of oxidative pathologies.
PMID- 9544450
TI - Elimination of alkaline phosphatases from circulation by the galactose receptor.
Different isoforms are cleared at various rates.
AB - Three isoforms of human alkaline phosphatase (liver, bone and placental ALP) were
purified and their elimination studied after intravenous injection in rats. The
rates of elimination were significantly inhibited by prior injection of
asialofetuin, indicating that the uptake was mediated by the galactose receptor
in liver. Their relative clearance rates differed, being rapid for the bone ALP,
significantly slower for the liver isoform and very slow for the placental ALP.
The bone ALP showed a rapid initial clearance, apparently related to its large
glycan heterogeneity and to the presence of molecules with a low sialic acid
content. When isolated from serum the liver and bone ALP isoforms showed
clearance rates differing slightly from those of the organ derived forms. We
conclude that differences in carbohydrate structure and amount of sialic acid of
the three isoforms result in various clearance rates. These differences will also
affect their serum concentrations as well as the composition and heterogeneity of
the individual isoforms in serum.
PMID- 9544451
TI - Erythrocyte membrane lipids and serum selenium in post-viral and alcoholic
cirrhosis.
AB - Erythrocyte-membrane fatty acid composition and cholesterol content were
evaluated along with serum selenium in 33 patients with liver cirrhosis and in 40
normal subjects. Thirteen patients were suffering from post-viral (group V) and
20 from alcoholic (group A) cirrhosis. The aim of the study was to elucidate
whether membrane lipid abnormalities in cirrhosis were linked to the aetiology of
the disease or whether they were the results of the cirrhotic process itself. The
patients presented a significant increase in membrane cholesterol, palmitic acid
(C16:0) and saturated fatty acids (SFA), and a decrease in polyunsaturated fatty
acids (PUFA) and polyunsaturated/saturated fatty acids ratio (P/S) compared with
the control group. Serum selenium levels were significantly reduced. When
patients were subdivided according to aetiology, the alcoholic patients showed
greater lipid composition abnormalities than the viral cirrhotics (higher levels
of SFA and lower PUFA and P/S), while pathologic palmitic acid, membrane
cholesterol and serum selenium values were confirmed in both groups of patients.
In conclusion, low serum selenium and a series of erythrocytes membrane lipid
composition abnormalities would appear to be features peculiar to cirrhosis.
Alcoholic cirrhotics, on the other hand, show a more deranged erythrocyte
membrane lipid profile.
PMID- 9544452
TI - Specific interaction of food proteins with apical membranes of the human
intestinal cell lines Caco-2 and T84.
AB - A comparison between the intestinal epithelial cell lines Caco-2 and T84 was made
to assess the influence of enterocytic differentiation on food protein binding
capacities of the brush border membrane. Cell morphology and expression of brush
border-associated enzymes were studied as differentiation markers. Food protein
binding to isolated brush border membranes was measured with a dot blot
chemiluminescence assay. Early at confluence, Caco-2 cells exhibited a more
differentiated state compared to T84 cells. Brush border membranes of both cell
lines bound gliadin peptides, beta-lactoglobulin and ovalbumin specifically.
Binding capacities increased from gliadin peptides to ovalbumin to beta
lactoglobulin. There was correlation of membrane binding capacity with degree of
cell differentiation. Due to their similarity to small intestinal epithelial
cells, the colon carcinoma cell lines Caco-2 and T84 represent models for
studying food protein-enterocytic brush border membrane interactions in relation
to varying degrees of cell differentiation.
PMID- 9544453
TI - Identification and quantitative analysis of haptoglobin Johnson heterozygote.
PMID- 9544454
TI - The advantage of phenylalanine to tyrosine ratio for the early detection of
phenylketonuria.
PMID- 9544455
TI - Clinical specificity of a second-generation cardiac troponin T assay in patients
with chronic renal failure.
PMID- 9544456
TI - Stability of semicarbazide-sensitive amine oxidase in human blood and plasma.
PMID- 9544457
TI - Genetic variation in human serum albumin: a 313 Lys-->Asn mutation in albumin
reading identified by PCR analysis.
AB - An early case of bisalbuminaemia was reported in this journal in 1964, with the
name Albumin Reading added later. Its use in electrophoretic comparisons led to
some new variants being described as 'of the Reading type' on this basis alone.
Protein sequencing and DNA studies have since found the single point mutation 313
Lys-->Asn common to this type, but the eponymous variant has not, until recently,
been available for study. We now report on its characterisation using PCR
analysis with allele-specific oligonucleotide primers, a method also applicable
to studies of the population distribution of variants. We also draw attention to
the need to link clinically-significant effects to individual variants of known
structure.
PMID- 9544458
TI - [Measles outbreaks in the Bern canton].
AB - Currently, overall vaccination coverage against measles among infants ranges
between 77% and 89% in Switzerland. Experience in other countries has shown that
this level of vaccination is not sufficient to prevent measles outbreaks,
especially among schoolchildren. During 1992 surveillance for measles outbreaks
in closed populations was conducted in the Canton of Berne. Outbreaks were
investigated for vaccine efficacy. Two measles outbreaks in schoolchildren were
observed during the study period. In 2 Bernese suburban schools 6 measles cases
in children (median age 12.5 years) occurred over a period of 37 days. One of the
cases had been vaccinated. Vaccination rate in the healthy control children was
89.7%. Estimated vaccine efficacy was 97.7% (95% confidence interval [CI]: 68%,
99%). The second outbreak occurred in a rural region and comprised 21 measles
cases (median age 7.5 years) within 43 days. 10 (47.6%) of the cases attended the
same school. None of the cases had been vaccinated. Of the healthy control
children 82.6% had received measles vaccine. Estimated vaccine efficacy was 100%
(CI: 87%, 100%). These two measles outbreaks were due to failure to vaccinate
rather than low vaccine efficacy. Surveillance for measles cases is currently not
sufficient for the detection of measles outbreaks in our population. Laboratory
confirmation of measles, especially in vaccinated persons, has become more
important in a time of relatively low measles incidence.
PMID- 9544459
TI - Extreme hypercapnia is not a long-term prognostic factor after near-fatal asthma:
a 12-year follow-up study.
AB - QUESTION OF THE STUDY: Some patients experiencing near-fatal asthma present with
extreme hypercapnia (PaCO2 > or = 100 mm Hg), whereas others do not. The
influence of this factor on short- and long-term outcome and quality of life in
these patients is still unknown. PATIENTS AND METHODS: A series of 39 consecutive
patients who had had an episode of near-fatal asthma between 1978 and 1992 were
followed up. Long-term outcome and quality of life of the 12 patients who had
experienced extreme hypercapnia were compared with those of the 27 patients who
had not. RESULTS: Four patients died, but only 1 from asthma. Three patients were
lost to follow-up. The remaining 32 patients had a median observation period of
12.7 years. The hypercapnic patients did not significantly differ from the others
in past asthma history, subsequent hospitalizations, medication needs, pulmonary
function tests, quality of life and impairment/disability. In the event of
subsequent near-fatal asthma attacks, they tended to present with hypercapnia
levels similar to those observed during the first episode. DISCUSSION: Extreme
hypercapnia in near-fatal asthma tended to recur, but is not an aggravating long
term prognostic factor. Targeted surveillance of these high-risk patients should
make it possible to reduce relapses and death rates from asthma.
PMID- 9544460
TI - [Castleman disease: 2 unusual cases].
AB - Castleman's disease is a localized, rare and benign hyperplasia of the lymph
nodes, occurring mainly in the mediastinum. Three histologic types-
hyalinvascular, plasmacellular and intermediate--have been recognized. We report
on two patients with unusual locations of the disease, i.e. the pelvis and the
retroperitoneum respectively. These observations show that diagnosis is
difficult. They also indicate that, in selected patients, radiotherapy may induce
tumor regression and allow the resection of apparently inoperable lesions.
PMID- 9544461
TI - [Inflammatory mechanisms in the kidney].
AB - Diverse mechanisms regulate the infiltration of the kidney with leukocytes in
immune-mediated renal diseases. Chemotactic factors (chemokines) and
intercellular adhesion molecules are known to promote the anchoring of
infiltrating mononuclear cells in the kidney. We have recently shown that
fragments of the polysaccharide hyaluronan (HA), but not native high molecular
weight HA can cause prominent upregulation of the adhesion molecules ICAM-1 and
VCAM-1 in renal proximal tubular cells. HA is also capable of stimulating the
synthesis of chemokines in these cells. HA accumulates in many inflammatory renal
diseases and could cause a proinflammatory effect by promoting leukocyte
infiltration in the kidney after binding with its cellular receptor CD44. This
mechanism may play an important role in immune renal injury in various renal
diseases.
PMID- 9544462
TI - [Phlebitis after vinorelbine].
PMID- 9544463
TI - Risk equalization, competition and choice in Germany: a reply to Wysong and Abel.
PMID- 9544464
TI - Competition and "cream skimming" in Germany: incentives and opportunities.
PMID- 9544465
TI - Competition under a regime of imperfect risk adjustment: the Swiss experience.
PMID- 9544466
TI - [Asylum seekers and refugees: health management of a complex minority].
PMID- 9544467
TI - [Asylum seekers and refugees in general practice: problems and possible
developments].
AB - Health and health services provided to asylum seekers and refugees by the Swiss
National Health System have so far not been systematically investigated. The aim
of this cross-sectional study was to describe the attending asylum seekers and
refugees demographically and clinically, to identify main problem areas as
perceived by general practitioners and to highlight options and venues for
improvements. 272 questionnaires have been filled in by GPs of eight "federal
districts" (Kantone) and the consultations of 1477 asylum seekers and refugees
have been documented during one month in 193 surgeries. The documented asylum
seekers and refugees reflected the distribution of this population in
Switzerland. Low consultation rates of asylum seekers and refugees in the
majority of surgeries and high diversity of this population in respect to places
of origin, education and proficiency in languages appear to be the major
determinants of the difficulties in providing adequate health services to them.
Readily available information on the past medical history and on the ethnic
background of these patients and continuing education on specific topics
concerning health care for asylum seekers and refugees were thought to be
particularly useful. This needs to be considered in the planning of services for
this group. General practitioners specialized in health care for asylum seekers
and refugees is an option for providing improved specific services (interpreters,
institutional links, culturally adapted medical care).
PMID- 9544468
TI - [Asylum seekers and refugees in the medical polyclinic: a comparison between the
Basel, Bern and Geneva polyclinics].
AB - This cross-sectional study describes the state of health of asylum seekers and
refugees and the health services provided to them by the medical outpatient
departments of three major Swiss university hospitals, Basel, Berne and Geneva.
The comparison of outpatient departments differing in organisational structure
facilitated the identification of positive and negative determinants of health
service provision. Questionnaires have been filled in by all physicians of the
three medical outpatient departments (Basel: 10, Berne: 1, Geneva: 36). All
consultations of asylum seekers and refugees have been recorded during the study
period (Basel: 42, Berne: 93, Geneva: 187). Interviews have been done with the
physicians who coordinated the study. During the study period the majority of the
patients originated from former Yugoslavia, Turkey, Sri Lanka, Somalia, Angola
and Zaire. One of the most prominent features of the population investigated has
been its diversity in respect to countries of origin, languages, ability to
communicate and education. Diversity and low consultation rates per physician
could explain many of the problems which have been observed, e.g. the lack of
experience in specific approaches to these patients or difficulties to provide
interpreters. To improve the health care for this group of patients in medical
outpatient departments small teams of physicians should be selected. By these
means adequate levels of experience could be achieved and organizational problems
could be dealt with more effectively. In addition, the relationship between
specific problems of asylum seekers and refugees and more general issues of the
interaction between physicians and patients are discussed in view of tasks in
research and training.
PMID- 9544470
TI - [Medical faculty of the Vienna University and national socialists--a perspective
from a distance of 60 years].
PMID- 9544469
TI - [Asylum seekers and refugees in the emergency department].
AB - This cross-sectional study describes the health problems and the health care of
asylum seekers and refugees from the point of view of accident & emergency (A &
E) physicians at the major hospital in St. Gallen, Switzerland. The physicians
filled in a detailed questionnaire and documented all consultations of asylum
seekers/refugees and of a control group of patients during eleven weeks (2 x 98
consultations). 76% of these asylum seekers/refugees originated from former
Yugoslavia. The distribution of the main ICD-coded diagnoses did not differ
between asylum seekers/refugees and the control group after correction for age.
In comparison with the asylum seekers and refugees attending GPs, injuries were
much more common in the A & E department attenders (37% vs. 8%). Asylum
seekers/refugees and the patients in the control group did not differ in respect
to being classified as an emergency case (58% vs. 65%). There were also no
differences in hospitalisation rates (29% vs. 36%). Asylum seekers/refugees who
were registered with a GP attended the A & E department more often during the
night than during the day compared to patients who were not registered with a GP.
Consultations which have been classified as emergencies occurred more frequently
during the day than at night time. The time of residence in Switzerland was
negatively associated with the registration with a GP and with being classified
as an emergency case. A lack of experience in caring for asylum seekers and
refugees and of specific training in this field has been the major complaint by
the A & E physicians. Asylum seekers should be introduced to the tasks and
functions of the various sectors of the national health care system as early as
possible. Registration with a GP in the community should be promoted.
PMID- 9544471
TI - [Racial eugenics in Vienna 1938].
PMID- 9544472
TI - [Political misuse of science: biology in the Third Reich].
PMID- 9544473
TI - [Previously unrecognized significance of national socialism for Vienna medicine].
PMID- 9544474
TI - ["Guiding" instead of healing. On some discoveries from the Vienna Public Health
Office 1938-1945].
PMID- 9544475
TI - [Opportunists, sympathists and officials. Support of the national socialism
system at the Vienna Academy of Sciences, exemplified by the efforts of Nadler,
srbink and Meister].
PMID- 9544477
TI - [Arthur Schuller, father of neuroradiology or: an Austrian scientist's fate].
PMID- 9544478
TI - Edelweiss to kangaroo paw.
PMID- 9544476
TI - Austrian medical refugees in Great Britain: from marginal aliens to established
professionals.
AB - About 360 Austrian physicians were refugees in the UK between 1938 and 1945. This
paper traces their experiences. Apart from a scheme to admit only fifty
physicians and forty dental surgeons, support ranged from domestic service
permits to the backing from scientists keen to modernize British medicine. After
the wave of internments in 1940, it was possible for physicians to be placed on
the Temporary Register of Medical Practitioners. Three case studies of three
types of Austrian contributions to child health are presented. The position
improved after World War 2 when full registration of Austrian qualifications
became possible, and the National Health Service provided career opportunities
for clinical specialists. Only circa 10% of the medical refugees from Austria
returned there eventually. Examples are given of successful careers in a wide
range of medical specialties.
PMID- 9544479
TI - From personae non gratae in Vienna 1938 to respected citizens of Edinburgh: a
vignette of my parents Dr. Ernst Adler and Dr. Regina Kapeller-Adler.
PMID- 9544480
TI - The silence of words--some thoughts on the Pernkopf Atlas.
PMID- 9544481
TI - [The scientific development in dermatology in Germany in relation to the
emigration of Jewish dermatologists during national socialism].
AB - The anti-semitic laws let to the persecution of the Jews in Germany during the
time of National Socialism. About 600 Jewish dermatologists had to suffer from
the prohibition of their profession. 63% of them left Germany. The emigrants
mainly preferred to move out to the U.S. The policy of coordination and
elimination of the National Socialists led to the reappointment of dermatological
chairs in universities. The National Socialists also forced the change in the
boards of dermatological societies and the change of the editorial boards of
dermatological journals. All papers of the three leading dermatological journals
were analysed for the evaluation of the development of science. The assessment
included the number of articles, the origin of the authors and the contents of
articles (research, clinics, diagnostic, therapy). From 1933 to 1945 the number
of papers per year decreased consequently, especially during the Second World
War. During the whole time the number of German authors increased and the number
of abroad living authors decreased. There was a very good and interesting
international exchange of information in the journal "Archiv fur Dermatologie und
Syphilis". The activity reduced clearly after the beginning of the Second World
War in 1939. The analysis of contents resulted in a reduction of basis science
research and an orientation to the clinical research. Papers about therapeutical
possibilities were always published. The emigration of Jewish dermatologists led
to a continuous reduction of scientific activities and to an extensive
international isolation.
PMID- 9544482
TI - [Ernst Klee: Auschwitz, national socialist medicine and its victims].
PMID- 9544483
TI - Eduard Pernkopf's atlas of anatomy or: the fiction of "pure science".
PMID- 9544484
TI - The Wiener klinische Wochenschrift from 1938 to 1945. On the 50th anniversary of
its reappearance in 1946.
PMID- 9544486
TI - [The intestine as the cause of infection and multiple organ failure].
PMID- 9544487
TI - [Significance of small intestine mucosa as a metabolic organ].
PMID- 9544488
TI - [Physiology and pathophysiology of intestinal flora].
PMID- 9544489
TI - History of the Department of Pediatrics Yale University School of Medicine.
AB - The history of pediatrics at the Yale University School of Medicine can be
divided into eight historical eras. The "Paleohistorical Era" included colonial
figures such as Governor John Winthrop and Hezekiah Beardsley who wrote about
children's disease in colonial times. Eli Ives, Professor of the Diseases of
Children at Yale Medical School gave the first systematic pediatric course in
America in the first half of the nineteenth century. During the second era, from
1830-1920, the New Haven Hospital was opened. An affiliation between Yale
University and the New Haven Hospital led to the formal establishment of clinical
departments including pediatrics in the early 20th century. Six eras coinciding
with successive pediatric chairman have led the department to its present
respected position in American pediatrics. The department's 75th anniversary in
1996 is an occasion to recognize many of the department's accomplishments and
leaders over the years. It is also a time to reaffirm the mission of the
department: to the health needs of the children of Connecticut and beyond, to the
advancement of scientific knowledge of infants and children and their diseases,
and to the training and educational of the pediatric clinicians, educators and
investigators of the future.
PMID- 9544490
TI - Yale pediatrics: today and into the 21st century.
PMID- 9544491
TI - Building bridges between academia and industry: forms; foundations; functions.
PMID- 9544492
TI - Iron deficiency: lessons from anemic mice.
AB - Iron is an essential nutrient, and disorders of iron metabolism are common.
Nonetheless, intestinal iron absorption and cellular iron transport are poorly
understood. Biochemical approaches to elucidating these processes have yielded
little in the past decade. As an alternative approach, we have begun to study
spontaneous mouse mutants, that have inherited defects in key steps in iron
transport. We have undertaken positional cloning of the gene responsible for
microcytic anemia (gene symbol mk). This report describes the important
characteristics of these mice, and our progress in studying them.
PMID- 9544493
TI - Preventing preterm birth: are we making any progress?
AB - Most industrialized countries have reported recent decreases in the size of
infants born at term but no reduction, or even a rise in the incidence of preterm
birth. This paper reviews recent secular trends in preterm birth and the evidence
about possible reasons for those trends. The hypothesized reasons include
ignorance about the causal determinants of preterm birth, failure to reduce
exposure to recognized determinants, increases in multiple births, the use of
early ultrasound (rather than menstrual dates) to estimate gestational age, early
induction or cesarean section for pregnancy complications, and registration of
extremely immature births of borderline viability.
PMID- 9544495
TI - [Use of metal stents in gastroenterology].
AB - A variety of metal stents have been increasingly used for malignant esophageal,
biliary and colorectal stenoses. Esophageal self-expandable stents significantly
reduce the early morbidity after implantation compared to conventional plastic
prostheses. However they offer no benefit in the long-term due to various late
complications. Biliary stents offer a significantly longer patency than plastic
devices. This advantage is however clinically relevant only for patients with a
survival time of more than three months. Preliminary trials indicate promising
results for palliation of colorectal stenoses with metal stents in selected
cases. Due to a lack of comparative studies the different types of metal stents
must be selected on basis of their physical characteristics and clinical
experiences. Most of the prostheses are irremovable which is a limitation for use
in benign stenoses of the gastrointestinal and biliary tract. In addition metal
stents are extremely expensive so that carefully designed trials are warranted
for evaluation of the cost-benefit ratio.
PMID- 9544494
TI - [Guidelines of the German Society of Digestive and Metabolic Diseases. Guidelines
for endoscopic colorectal polypectomy with the sling. German Society of Digestive
and Metabolic Diseases].
PMID- 9544496
TI - Evaluation of a cacao drink as a simple oral stimulus to assess gallbladder
contraction.
AB - Gallbladder contractility plays an important role in the pathogenesis of
gallstones and in the course of cholelithiasis. Furthermore, a functioning
gallbladder is an important condition for performing a successful disolution of
gallstones by bile acids. Therefore, a reliable simple physiological test is
desired to assess gallbladder contractility. In ten volunteers gallbladder
contraction was stimulated by 50 g chocolate, 330 ml cacao drink or in comparison
by intramuscular injection of 0.3 microgram/kg ceruletide. Gallbladder volume was
measured sonographically and CCK in serum was determined by radioimmunoassay
(RIA) after 0, 15, 30 and 45 min. Additionally gallbladder contraction was
determined in 20 patients with symptomatic gallstones using cacao drink on
ceruletide. In health volunteers remaining gallbladder volume after 30 min was
28% +/- 5% using ceruletide and 37% +/- 7% using cacao. Stimulation by chocolate
resulted in a remaining volume of 59% +/- 12% after 45 min only. Simultaneously
to gallbladder contraction an increase of CCK in serum was registered. 30 min
after cacao CCK had increased from 0.9 to 3.3 pmol/l. Using chocolate an increase
of CCK amounted to 2.1 pmol/l after 45 min only. In patients with gallstones the
positive predictive value of the cacao test for a functioning gallbladder was 91%
and the negative predictive value was 78% in comparison to the unphysiologic
stimulation by ceruletide injection. CONCLUSION: Cacao test but not chocolate is
suitable and reliable to assess gallbladder contraction in patients with
symptomatic gallstones.
PMID- 9544497
TI - Evaluation of four methods for detection of Clostridium difficile or C. difficile
toxin: cytotoxin assay, culture, latex agglutination, and a new rapid immunoassay
(C. difficile toxin A test).
AB - The performance of C. difficile toxin A test (Oxoid, Basingstoke, UK), an
immunoassay for the detection of C. difficile toxin A in fecal samples, for the
diagnosis of C. difficile-associated diarrhea was compared with those of
cytotoxin assay, culture, and a latex agglutination assay (Culturette Brand CDT
Rapid Clostridium difficile test; Becton Dickinson, Cockeysville, MD). A total of
105 stool specimens from 71 patients were tested. Of the 105 specimens analyzed,
6 (5.7%) samples were positive by all four methods, 66 samples (62.9%) were
concordant negative. Two patients fulfilled all clinical criteria for C.
difficile-associated diarrhea but had negative results in the cytotoxicity tests.
The sensitivity and specificity, as determined against cytotoxin assay results,
were, respectively 52.4% and 93.9% for latex agglutination, 68.2% and 84.3% for
rapid immunoassay and 36.4% and 92.8% for culture. No single laboratory test
yields a definitive diagnosis of C. difficile-associated diarrhea at present.
Test results by any of these methods must be used in conjunction with patient
history when making the diagnosis to avoid indiscriminate treatment of
individuals without disease or the lack of treatment for individuals with a
serious infection. We consider the rapid and easy-to-perform C. difficile toxin A
test not to be an essential adjunct for the diagnosis of C. difficile-associated
diarrhea.
PMID- 9544498
TI - [Value of endosonography in diagnosis of diffusely growing stomach carcinomas].
AB - The diagnosis of diffuse type gastric carcinoma is very difficult. The delay of
diagnosis is often due to false-negative endoscopic and histologic evaluation.
The architecture of the stomach can be clearly visualized by endosonography.
Therefore, already minor destructions of the gastric layers can be found. The
endosonographic picture includes the presence of the layers, which are larger and
of irregular contour. In infiltrating gastric cancer typically the submucosal
layer and the muscularis are concentrically enlarged and appear folded. Based on
the endosonographic picture diffuse type gastric carcinoma has been diagnosed in
32 patients. When compared to the histologic diagnosis after gastrectomy or
autopsy the accuracy of the endosonographic diagnosis was 87.5%, (28 out of 32
patients). From the remaining four patients diagnosed to have diffuse type
gastric cancer by endosonography three patients turned out to have malignant
infiltrating tumors of different histologies. Therefore, the positive predictive
value of endosonography in detection of infiltrating malignant tumors was 96.8%
in our group. In contrast the accuracy of preoperative histologic diagnosis by
biopsies was only 58%. Suspicious results of gastroscopy, especially in
combination with a negative biopsy, should lead to further evaluation by
endosonography to detect diffuse type gastric cancer earlier.
PMID- 9544499
TI - Transjugular intrahepatic portosystemic stent-shunt after orthotopic liver
transplantation in a patient with early recurrence of portal hypertension of
unknown origin.
AB - A 65-year-old italian patient developed complicated portal hypertension
immediately after orthtopic liver transplantation (OLT) necessitating shunt
creation. One to five weeks after OLT, massive ascitic fluid losses of up to
121/day developed. Vascular and major hepatic-parenchymal abnormalities were
excluded by duplexsonography, angiography and initial histology, respectively. A
peritoneovenous shunt (Denver-shunt) on day 31 after OLT reduced (by about 50%)
but did not stop ascitic fluid losses. Furthermore, three variceal bleedings
occurred after implantation of the Denver-shunt. Direct portography on day 45
after OLT revealed portal hypertension (pressure gradient of 26 mmHg) requiring
the implantation of a transjugular intrahepatic portosystemic stent-shunt (TIPS)
leading to a reduction of the pressure gradient to 13 mmHg. Subsequently, ascites
resolved within ten days and esophageal varices improved. Liver function
parameters normalized inspite of recurrence of HCV infection with detection of
HCV RNA in serum already in the fifth week after OLT. During follow-up,
histological findings deteriorated from mild changes to extended fibrosis at day
61 after OLT, which might have contributed to the maintenance of portal
hypertension. The deterioration of liver histology was accompanied by an
improvement/normalization of liver graft function. There was no evidence for
additional viral liver infections, e.g. hepatitis B or cytomegalovirus infection.
This case illustrates an etiologically unclear syndrome developing directly after
OLT and reaffirms the effectiveness of TIPS in the treatment of complicated
portal hypertension even after liver transplantation.
PMID- 9544500
TI - [Protein-losing giant fold gastritis in childhood--a case report and
differentiation from Menetrier disease of adulthood].
AB - We report on a 2.5-year-old boy, who presented with vomiting since one week and
periorbital and pitting edema. Laboratory studies revealed hypoproteinemia and
hypoalbuminemia without signs of renal or liver disease. The cause of protein
loss was giant fold gastritis disclosed by upper endoscopy. Biopsies revealed
foveolar hyperplasia with cystic dilatation of the glands, identical to
Menetrier's disease in adulthood. About 55 cases of hypertrophic gastropathy in
children have been published. In contrast to the chronic course of Menetrier's
disease in adults, the pediatric cases are generally benign, self-limited with
complete resolution typically within a few weeks. While the etiology of
Menetrier's disease is still unknown, the benign pediatric hypertrophic
gastropathies have been associated with infections, primarily CMV and
occasionally helicobacter pylori, herpes simplex and mycoplasma. Supportive
treatment with a high-protein-diet and intravenous albumin transfusions is
recommended. H2-receptor antagonists might improve symptoms.
PMID- 9544501
TI - [A system of nonspecific defense in chronic inflammatory bowel diseases-
pathophysiologic and therapeutic aspects].
AB - Monocytes/macrophages are a prominent feature of the inflammatory infiltrate in
inflammatory bowel disease (IBD). Progress in the development of monoclonal
antibodies has provided a powerful means to identify and study various subsets of
macrophages in the intestinal mucosa. In both Crohn's disease and ulcerative
colitis distinct macrophage populations have been found being prominent in active
disease, but absent from normal mucosa. Studies of our group show that the Ca(2+)
binding proteins MRP8 and MRP14 as well as their heterocomplex MRP8/14 (27E10
epitope) can be immunolocalized in the majority of granulocytes and macrophages
in active but not inactive IBD. Serum MRP8/14 concentrations are significantly
increased in patients with active IBD compared with patients suffering from
inactive/mild disease. In vitro studies revealed that IL-13, IL-10 and IL-4
strongly suppress secretion of monocytic proteins. Differential responses of
monocytes and macrophages towards the inhibitory effects of TH2-cytokines can be
observed in both patients with IBD and control groups. Combined treatment with
TH2-cytokines may effectively suppress the response of activated
monocytes/macrophages thus being of potential therapeutic benefit for patients
with IBD.
PMID- 9544502
TI - [Treatment of primary sclerosing cholangitis: drug, endoscopic, combined or no
treatment at all?].
PMID- 9544503
TI - [Stress proteins and molecular chaperones--protectors of intestinal epithelial
damage?].
PMID- 9544504
TI - [Does liver transplantation have the greatest chance of healing in cirrhosis with
hepatocellular carcinoma?].
PMID- 9544505
TI - The effect of serial dilution error on calibration inference in immunoassay.
AB - A common practice in immunoassay is the use of sequential dilutions of an initial
stock solution of the antigen of interest to obtain standard samples in a desired
concentration range. Nonlinear, heteroscedastic regression models are a common
framework for analysis, and the usual methods for fitting the model assume that
measured responses on the standards are independent. However, the dilution
procedure introduces a propagation of random measurement error that may
invalidate this assumption. We demonstrate that failure to account for serial
dilution error in calibration inference on unknown samples leads to serious
inaccuracy of assessments of assay precision such as confidence intervals and
precision profiles. Techniques for taking serial dilution error into account
based on data from multiple assay runs are discussed and are shown to yield valid
calibration inferences.
PMID- 9544508
TI - Added risk and inverse estimation for count responses in reproductive aquatic
toxicology studies.
AB - One of the experimental designs used to evaluate the toxicity of certain
chemicals in aquatic organisms focuses on reproductive output. Toxic effects are
manifested through a reduced level of reproduction in exposed organisms.
Historically, evaluating risks in this context has focused on changes in the mean
reproduction in a population of organisms. In this paper, we focus on the toxic
effects at the level of the individual organism. This new method for count
responses involves added risk, the probability of the production of young being
suppressed below certain specified levels in individuals exposed to a particular
concentration level relative to the probability of that level of suppression in
control organisms. This probability serves as the basis of the individual-based
risk estimation procedures. In particular, inverse estimation of the
concentration associated with a specified added risk and estimates of the added
risk associated with a particular concentration are discussed in the context of a
negative binomial regression model. Confidence intervals are constructed for both
of these quantities using the delta method. These methods are illustrated with a
study of an aquatic organism, Ceriodaphnia dubia, exposed to the herbicide
nitrofen.
PMID- 9544509
TI - A method for parametric estimation of the number and size distribution of cell
clusters from observations in a section plane.
AB - The problem of finding the number and size distribution of cell clusters that
grow in an organ or tissue from observations of the number and sizes of
transections of such cell clusters in a planar section is considered. This
problem is closely related to the well-known corpuscle or Wicksell problem in
stereology, which deals with transections of spherical objects. However, for most
biological applications, it is unrealistic to assume that cell clusters have
spherical shapes since they may grow in various ways. We therefore propose a
method that allows for more general spatial configurations of the clusters. Under
the assumption that a parametric growth model is available for the number and
sizes of the cell clusters, expressions are obtained for the probability
distributions of the number and sizes of transections of the clusters in a
section plane for each point in time. These expressions contain coefficients that
are independent of the parametric growth model and time but depend on which model
is chosen for the configuration of the cell clusters in space. These results
enable us to perform estimation of the parameters of the growth model by maximum
likelihood directly on the data instead of having to deal with the inverse
problem of estimation of three-dimensional quantities based on two-dimensional
data. For realistic choices of the configuration model, it will not be possible
to obtain the exact values of the coefficients, but they can easily be
approximated by means of computer simulations of the spatial configuration. Monte
Carlo simulations were performed to approximate the coefficients for two
particular spatial configuration models. For these two configuration models, the
proposed method is applied to data on preneoplastic minifoci in rat liver under
the assumption of a two-event model of carcinogenesis as the parametric growth
model.
PMID- 9544510
TI - Change-point analysis of neuron spike train data.
AB - In many medical experiments, data are collected across time, over a number of
similar trials, or over a number of experimental units. As is the case of neuron
spike train studies, these data may be in the form of counts of events per unit
of time. These counts may be correlated within each trial. It is often of
interest to know if the introduction of an intervention, such as the application
of a stimulus, affects the distribution of the counts over the course of the
experiment. In such investigations, each trial generates a sequence of data that
may or may not contain a change in distribution at some point in time. Each
sequence of integer counts can be viewed as arising from a Poisson process and
are therefore independently distributed or as an integer-valued time series that
allows for correlations between these counts. The main aim of this paper is to
show how the ensemble of sample paths may be used to make inference about the
distribution of the instantaneous times of change in a given population. This
will be accomplished using a Bayesian hierarchical model for these change-points
in time. A bonus of these models is they also allow for inference about the
probability of a change in each unit and the magnitude of the effects, if any.
The use of such change-point models on integer-valued time series is illustrated
on neuron spike train data, although the methods can be applied to other
situations where integer-valued processes arise.
PMID- 9544511
TI - Three approaches to regression analysis of receiver operating characteristic
curves for continuous test results.
AB - The accuracy of a medical diagnostic test is typically summarized by the
sensitivity and specificity when the test result is dichotomous. Receiver
operating characteristic (ROC) curves are measures of test accuracy that are used
when test results are continuous and are considered the analogs of sensitivity
and specificity for continuous tests. ROC regression analysis allows one to
evaluate effects of factors that may influence test accuracy. Such factors might
include characteristics of study subjects or operating conditions for the test.
Unfortunately, regression analysis methods for ROC curves are not well developed
and methods that do exist have received little use to date. In this paper, we
propose and compare three very different regression analysis methods. Two are
modifications of methods previously proposed for radiology settings. The third is
a special case of a general method recently proposed by us. The three approaches
are compared with regard to settings in which they can be applied and
distributional assumptions they require. In the setting where test results are
normally distributed, we elucidate the correspondence between regression
parameters in the different models. The methods are applied to simulated data and
to data from a study of a new diagnostic test for hearing impairment. It is hoped
that the presentation in this paper will both encourage the use of regression
analysis for evaluating diagnostic tests and help guide the choice of the most
appropriate regression analysis approach in applications.
PMID- 9544512
TI - Inference for odds ratio regression models with sparse dependent data.
AB - Suppose the number of 2 x 2 tables is large relative to the average table size,
and the observations within a given table are dependent, as occurs in
longitudinal or family-based case-control studies. We consider fitting regression
models to the odds ratios using table-level covariates. The focus is on methods
to obtain valid inferences for the regression parameters beta when the dependence
structure is unknown. In this setting, Liang (1985, Biometrika 72, 678-682) has
shown that inference based on the noncentral hypergeometric likelihood is
sensitive to misspecification of the dependence structure. In contrast,
estimating functions based on the Mantel-Haenszel method yield consistent
estimators of beta. We show here that, under the estimating function approach,
Wald's confidence interval for beta performs well in multiplicative regression
models but unfortunately has poor coverage probabilities when an additive
regression model is adopted. As an alternative to Wald inference, we present a
Mantel-Haenszel quasi-likelihood function based on integrating the Mantel
Haenszel estimating function. A simulation study demonstrates that, in medium
sized samples, the Mantel-Haenszel quasi-likelihood approach yields better
inferences than other methods under an additive regression model and inferences
comparable to Wald's method under a multiplicative model. We illustrate the use
of this quasi-likelihood method in a study of the familial risk of schizophrenia.
PMID- 9544513
TI - Tests for homogeneity of the risk difference when data are sparse.
AB - Test statistics for the homogeneity of the risk difference for a series of 2 x 2
tables when the data are sparse is proposed. A weighted least squares statistic
is commonly used to test for equality of the risk difference over the tables;
however, when the data are sparse, this statistic can have anticonservative Type
I error rates. Simulation is used to compare the proposed test statistics to the
weighted least squares statistic. The weighted least squares statistic has the
most anticonservative Type I error rates of all the statistics compared. We
suggest the use of one of our proposed test statistics instead of the weighted
least squares statistic.
PMID- 9544514
TI - Interpreting the beta geometric in comparative fecundability studies.
AB - The beta distribution has often been used to describe variation in fecundability
between couples when modelling the number of menstrual cycles required for a
couple to achieve pregnancy. Groups are often compared for a condition or factor
that could affect conception rates. However, when heterogeneity is present in
each group, comparing group-specific parameters is not very informative on what
any differences might imply for the individual couples. We present a quantile
ratio that provides an individual level interpretation of any between-group
differences in the beta distribution. Our results are illustrated on the two
examples of Ridout and Morgan (1991, Biometrics 47, 1423-1433). The quantile
ratio suggests a simplification in one of the examples.
PMID- 9544515
TI - Permutational distribution of the log-rank statistic under random censorship with
applications to carcinogenicity assays.
AB - In the random censorship model, the log-rank test is often used for comparing a
control group with different dose groups. If the number of tumors is small, so
called exact methods are often applied for computing critical values from a
permutational distribution. Two of these exact methods are discussed and shown to
be incorrect. The correct permutational distribution is derived and studied with
respect to its behavior under unequal censoring in the light of recent results
proving that the permutational version and the unconditional version of the log
rank test are asymptotically equivalent even under unequal censoring. The log
rank test is studied by simulations of a realistic scenario from a bioassay with
small numbers of tumors.
PMID- 9544516
TI - Conditional logistic regression with sandwich estimators: application to a meta
analysis.
AB - Motivated by a meta-analysis of animal experiments on the effect of dietary fat
and total caloric intake on mammary tumorigenesis, we explore the use of sandwich
estimators of variance with conditional logistic regression. Classical
conditional logistic regression assumes that the parameters are fixed effects
across all clusters, while the sandwich estimator gives appropriate inferences
for either fixed effects or random effects. However, inference using the standard
Wald test with the sandwich estimator requires that each parameter is estimated
using information from a large number of clusters. Since our example violates
this condition, we introduce two modifications to the standard Wald test. First,
we reduce the bias of the empirical variance estimator (the middle of the
sandwich) by using standardized residuals. Second, we approximately account for
the variance of these estimators by using the t-distribution instead of the
normal distribution, where the degrees of freedom are estimated using
Satterthwaite's approximation. Through simulations, we show that these sandwich
estimators perform almost as well as classical estimators when the true effects
are fixed and much better than the classical estimators when the true effects are
random. We achieve simulated nominal coverage for these sandwich estimators even
when some parameters are estimated from a small number of clusters.
PMID- 9544517
TI - Prediction of cumulative incidence function under the proportional hazards model.
AB - In the presence of dependent competing risks in survival analysis, the Cox model
can be utilized to examine the covariate effects on the cause-specific hazard
function for the failure type of interest. For this situation, the cumulative
incidence function provides an intuitively appealing summary curve for marginal
probabilities of this particular event. In this paper, we show how to construct
confidence intervals and bands for such a function under the Cox model for future
patients with certain covariates. Our proposals are illustrated with data from a
prostate cancer trial.
PMID- 9544518
TI - Multiple imputation for early stopping of a complex clinical trial.
AB - It is desirable to have procedures available for stopping a clinical trial early
if there appears to be no treatment effect. Conditional power procedures allow
for early stopping in favor of the null hypothesis if the probability of
rejecting H0 at the planned end of the trial given the current data and a value
of the parameter of interest is below some threshold level. Lan, Simon, and
Halperin (1982, Communications in Statistics C1, 207-219) proposed a stochastic
curtailment procedure that calculates the conditional power under the alternative
hypothesis. Alternatively, predictive power procedures incorporate information
from the observed data by averaging the conditional power over the posterior
distribution of the parameter. For complex problems in which explicit evaluation
of conditional power is not possible, we propose treating the problem of
projecting the outcome of a trial given the current data as a missing data
problem. We then complete the data using multiple imputation and thus eliminate
the need for explicit calculation of conditional power. We apply this method to
AIDS Clinical Trials Group (ACTG) protocol 118 and to several simulated clinical
trials.
PMID- 9544519
TI - An optimal design for screening trials.
AB - Yao, Begg, and Livingston (1996, Biometrics 52, 992-1001) considered the optimal
group size for testing a series of potentially therapeutic agents to identify a
promising one as soon as possible for given error rates. The number of patients
to be tested with each agent was fixed as the group size. We consider a
sequential design that allows early acceptance and rejection, and we provide an
optimal strategy to minimize the sample sizes (patients) required using Markov
decision processes. The minimization is under the constraints of the two types
(false positive and false negative) of error probabilities, with the Lagrangian
multipliers corresponding to the cost parameters for the two types of errors.
Numerical studies indicate that there can be a substantial reduction in the
number of patients required.
PMID- 9544520
TI - A strategy for dose-finding and safety monitoring based on efficacy and adverse
outcomes in phase I/II clinical trials.
AB - We propose a design strategy for single-arm clinical trials in which the goals
are to find a dose of an experimental treatment satisfying both safety and
efficacy requirements, treat a sufficiently large number of patients to estimate
the rates of these events at the selected dose with a given reliability, and stop
the trial early if it is likely that no dose is both safe and efficacious.
Patient outcome is characterized by a trinary ordinal variable accounting for
both efficacy and toxicity. Like Thall, Simon, and Estey (1995, Statistics in
Medicine 14, 357-379), we use Bayesian criteria to generate decision rules while
relying on frequentist criteria obtained via simulation to determine a design
parameterization with good operating characteristics. The strategy is illustrated
by application to a bone marrow transplantation trial for hematologic
malignancies and a trial of a biologic agent for malignant melanoma.
PMID- 9544521
TI - A Bayesian framework for intent-to-treat analysis with missing data.
AB - In longitudinal clinical trials, one analysis of interest is an intention-to
treat analysis, which groups subjects according to the randomized treatment
regardless of whether they stayed on that treatment or not. When in addition to
going off the randomized treatment subjects may also drop out of the study and be
lost to follow-up, it is unclear what an intention-to-treat analysis should be.
If measurements are made after treatment drop-out on a random sample of subjects
who drop the treatment, then Hogan and Laird (1996, Biometrics 52, 1002-1017)
present a random effects model, well suited to this type of analysis, which fits
a two-piece linear spline to the data with the knot at the time the assigned
treatment is dropped. This article presents a Bayesian approach to fitting a
similar two-piece linear spline model and shows how the model can be applied to
data that have no off-treatment observations.
PMID- 9544522
TI - Sample size determination for phase II clinical trials based on Bayesian decision
theory.
AB - This paper describes an application of Bayesian decision theory to the
determination of sample size for phase II clinical studies. The approach uses the
method of backward induction to obtain group sequential designs that are optimal
with respect to some specified gain function. A gain function is proposed
focussing on the financial costs of, and potential profits from, the drug
development programme. On the basis of this gain function, the optimal procedure
is also compared with an alternative Bayesian procedure proposed by Thall and
Simon. The latter method, which tightly controls type I error rate, is shown to
lead to an expected gain considerably smaller than that from the optimal test.
Gain functions with respect to which Thall and Simon's boundary is optimal are
sought and it is shown that these can only be of the form considered, that is,
with constant cost for phase III study and cost of the phase II study
proportional to the sample size, if potential profit increases over time.
PMID- 9544523
TI - Inference using conditional logistic regression with missing covariates.
AB - When there are many nuisance parameters in a logistic regression model, a popular
method for eliminating these nuisance parameters is conditional logistic
regression. Unfortunately, another common problem in a logistic regression
analysis is missing covariate data. With many nuisance parameters to eliminate
and missing covariates, many investigators exclude any subject with missing
covariates and then use conditional logistic regression, often called a complete
case analysis. In this article, we derive a modified conditional logistic
regression that is appropriate with covariates that are missing at random.
Performing a conditional logistic regression with only the complete cases is
convenient with existing statistical packages, but it may give bias if
missingness is not completely at random.
PMID- 9544524
TI - Comparison of meta-analysis versus analysis of variance of individual patient
data.
AB - Meta-analysis is a method of synthesizing the results of independent studies. We
consider the case in which there are multiple treatments and a control, with the
goal of estimating the relative effect of each treatment based on continuous
outcomes. Even when all data are available, rather than only summary data, it has
become common to use meta-analytic estimators of treatment contrasts.
Alternatively, we could use a two-way analysis of variance model with no
interaction in which one factor is study and one factor is treatment. For the
unbalanced case, we obtain the surprising result that the standard meta-analysis
estimates of treatment contrasts are identical to the least squares estimators of
treatment contrasts in the linear model. Because a meta-analysis of individual
patient data can be considerably more costly in terms of data retrieval than a
meta-analysis of summary data, this equivalence provides for cost-efficient
analysis.
PMID- 9544525
TI - Sample size calculations based on slopes and other summary statistics.
AB - Sample size calculations based on two-sample comparisons of slopes have been
reported by many. This paper extends such discussions to include summary
statistics other than slopes, such as post-baseline means, change scores, and
final observations. Specifically, sample size formulas for analyses based on a
broad class of summary statistics are presented, with modifications proposed to
allow for missing data caused by staggered entry and random dropouts. The
formulas developed are used to illustrate how required sample size is affected by
summary statistic choice, variance parameters, the type of treatment difference
of interest, and the manner in which incomplete observations are used in the
analysis. An example based on longitudinal data from the Muscatine Study is
presented.
PMID- 9544526
TI - Power and sample size for stratified prospective studies using the score method
for testing relative risk.
AB - We derive the asymptotic power function of the score test for detecting a common
relative risk greater than unity from multiple 2 x 2 tables and formulate methods
of sample size determination for use when designing stratified prospective
studies. The stratified score test is more efficient than the unstratified test
when the latter is unbiased.
PMID- 9544527
TI - Analysis of compositional bone density data using log ratio transformations.
AB - In skeletal research, one of the techniques available to measure bone
mineralization produces compositional data, which consist of vectors of ordered
proportions of bone sample in prespecified density intervals. We investigated the
value of two multivariate data transformations, the cumulative log ratio and the
continuation log ratio, in the analysis of an experimental study of the dose
response effect of a drug treatment on bone mineralization. Based on a comparison
of alternative approaches to the analysis of compositional bone mineralization
data in the application and in a simulation study, we recommend the use of the
average of the cumulative log ratios over all the density intervals to detect
change in the density distribution. We also recommend the use of one of the
continuation log ratios when a specific density interval of interest can be
specified a priori.
PMID- 9544528
TI - Gibbs sampling for long-term survival data with competing risks.
AB - Many researchers use the 5-year survival probability as a measurement of cure for
long-term survival data. In addition to this probability, a mixture model with
possibility of cure provides a predictive probability of cure given that a
patient has survival to a period of time. Such probabilities are more realistic
in measuring the effectiveness of the treatment and predicting the long-term
survival of the patient than the 5-year survival rate. An extension of the cure
model to the competing risks data is developed. The extended model is a finite
mixtures model, where the independence of cause-specific failure times is not
assumed. A data set consisting of leukemia with bone marrow transplant is used
for illustration. Patients have three possible statuses after transplant: cured
by the treatment, relapse of leukemia, or non-relapse-related death. Only the
last two events are observable. Patients observed with these endpoints are
uncensored cases and the transplant is not successful for them. A case is
censored if the case is relapse-free and still alive at the end of its follow-up.
Only censored cases have the possibility of being cured, but cure is not assumed
to be observable. The status of cure is imputed by the posterior predictive
probability of cure given the lifetime and is implemented in the Gibbs sampling.
Cure is defined by assuming the risk for failure of a cured patient to be
approximately zero. The probability of cure for the leukemia patients after the
bone marrow transplant is about 27% for patients with the acute graft-versus-host
disease (GVHD) and 46% for the non-GVHD group. The probability of relapse, given
that one is not cured, is 0.50 for the non-GVHD group and 0.34 for the GVHD
group. The non-GVHD group has a better chance of survival, while the GVHD group
has a lower chance for relapse. This is known as the GVHD-versus-leukemia effect.
PMID- 9544529
TI - Mixed effects logistic regression models for longitudinal binary response data
with informative drop-out.
AB - A shared parameter model with logistic link is presented for longitudinal binary
response data to accommodate informative drop-out. The model consists of observed
longitudinal and missing response components that share random effects
parameters. To our knowledge, this is the first presentation of such a model for
longitudinal binary response data. Comparisons are made to an approximate
conditional logit model in terms of a clinical trial dataset and simulations. The
naive mixed effects logit model that does not account for informative drop-out is
also compared. The simulation-based differences among the models with respect to
coverage of confidence intervals, bias, and mean squared error (MSE) depend on at
least two factors: whether an effect is a between- or within-subject effect and
the amount of between-subject variation as exhibited by variance components of
the random effects distributions. When the shared parameter model holds, the
approximate conditional model provides confidence intervals with good coverage
for within-cluster factors but not for between-cluster factors. The converse is
true for the naive model. Under a different drop-out mechanism, when the
probability of drop-out is dependent only on the current unobserved observation,
all three models behave similarly by providing between-subject confidence
intervals with good coverage and comparable MSE and bias but poor within-subject
confidence intervals, MSE, and bias. The naive model does more poorly with
respect to the within-subject effects than do the shared parameter and
approximate conditional models. The data analysis, which entails a comparison of
two pain relievers and a placebo with respect to pain relief, conforms to the
simulation results based on the shared parameter model but not on the simulation
based on the outcome-driven drop-out process. This comparison between the data
analysis and simulation results may provide evidence that the shared parameter
model holds for the pain data.
PMID- 9544530
TI - To use or not to use? Backward equations in stochastic carcinogenesis models.
AB - The method based on the Kolmogorov backward equations of Little (1995, Biometrics
51, 1278-1291) for computing hazard functions for the multistage carcinogenesis
models fails when model parameters are time-dependent. In addition to suggesting
an alternative method based on the Kolmogorov forward equation, this note
highlights the interplay of the forward equation, the backward equation, and the
characteristic method. Advantages and disadvantages of the forward and backward
equations are discussed.
PMID- 9544531
TI - The phosphatase system in Saccharomyces cerevisiae.
AB - The yeast Saccharomyces cerevisiae has at least six species of acid and alkaline
phosphatases with different cellular localizations, as well as inorganic
phosphate (Pi) transporters. Most of the genes encoding these enzymes are
coordinately repressed and derepressed depending on the Pi concentration in the
growth medium. The Pi signals are conveyed to these genes through a regulatory
circuit consisting of a set of positive and negative regulatory proteins. This
phosphatase system is interested as one of the best systems for studying gene
regulation in S. cerevisiae due to the simplicity of phenotype determination in
genetic analysis. With this methodological advantage, considerable amounts of
genetic and molecular evidence in phosphatase regulation have been accumulated in
the past twenty-five years. This article summarizes the current progress of
research into this subject.
PMID- 9544532
TI - Presence of wheat retrotransposons in Gramineae species and the origin of wheat
retrotransposon families.
AB - Distribution of wheat retrotransposon families (families 1 to 7) was examined in
11 Gramineae species by the use of representative reverse transcriptase domain
clones selected from six of the seven wheat retrotransposon families previously
identified as probes. The homologues of families 3, 4, 5, and 7 retrotransposons
were detectable only in the Pooideae species, suggesting that the distribution of
the retrotransposons related to these families is restricted to the Pooideae
subfamily. The representatives of families 1 and 2, distantly related to families
3 to 7, revealed homologues additionally in the species outside the Pooideae
subfamily including rice. These results suggest that the retrotransposons related
to the former families have wider distribution than those related to families 3,
4, 5, and 7. Analysis of a wheat genomic clone confirmed that the family 1
representative reverse transcriptase domain clone is a Ty1-copia group
retrotransposon derivative, which we have named Tar1. On the basis of these
results, the origin of wheat retrotransposon families is discussed.
PMID- 9544534
TI - Cranial thickness in American females and males.
AB - To date, numerous studies have examined the range of cranial thickness variation
in modern humans. The purpose of this investigation is to present a new method
that would be easier to replicate, and to examine sex and age variation in
cranial thickness in a white sample. The method consists of excising four cranial
segments from the frontal and parietal regions. The sample consists of 165
specimens collected at autopsy and 15 calvarial specimens. An increase in cranial
thickness with age was observed. The results suggest that cranial thickness is
not sexually dimorphic outside the onset of hyperostosis frontalis interna (HFI).
PMID- 9544535
TI - Sex determination from the ribs of contemporary Turks.
AB - There have been several in-depth studies showing that the sternal extremity of
the fourth rib can be used in estimating age as well as in determining sex, as
illustrated in North American whites and blacks. Yet biological differences
between populations may preclude the cross-application of standards. To test this
hypothesis and develop a sex determination standard for the Turkish population, a
sample of the sternal ends of the fourth rib was collected from 294 individuals
autopsied in Istanbul, Turkey. Dimensions from the superior edge to the inferior
one (SI) and the anterior edge to its posterior edge (AP) were measured with a
caliper. The sample was divided into three age groups, "young," "old," and
"total." Using discriminant function analysis, three formulae were developed, one
for each group. The results indicated that SI height is the most dimorphic
dimension and that both dimensions together can given an accuracy of 86% to 90%.
To reach such an accuracy, the age of the unknown should be estimated, at least
whether it is phase 4 or above or below, using the age standards for ribs
developed by Iscan and associates. When cross-validation tests are carried out,
incorrect formulae reduce accuracy by as much as 20%. Furthermore, it was
observed that North American based white sex determination formulae assign many
Turkish males into a female category. In conclusion, it is important to note that
population and age specificity are essential in determining sex from the rib. Yet
its accuracy is as good as, if not better than, many bones of the postcranial
skeleton.
PMID- 9544536
TI - Excavation of a Vietnam-era aircraft crash site: use of cross-cultural
understanding and dual forensic recovery methods.
AB - The excavation of a 23 year-old aircraft crash site in the Socialist Republic of
Vietnam and the transformational processes preceding its excavation in 1995-1996
are detailed. The history of the site involved an initial catastrophic event,
with subsequent reclamation and disturbances. Ultimately, a recovery effort by a
joint U.S. team from the Central Identification Laboratory, Hawaii (CILHI). Joint
Task Force-Full Accounting (JTF-FA) and a Socialist Republic of Vietnam
contingent yielded numerous human remains, personal effects, and life-support
items from the crash site. This case study should be of interest to the
increasing number of forensic anthropologists who carry out work in international
contexts. The application of forensic anthropology in human rights abuse cases,
for example in Rwanda, Argentina, and Bosnia, provide examples of such cross
cultural endeavors. Cultural factors act in the development of a site and should
not be overlooked as significant taphonomic agents. The approach that an
indigenous person takes to a crash site or mass grave may be quite different from
our own approach, involving Western science. Holland, Anderson, and Mann (I)
describe the postmortem alternation of exhumed and/or curated bone caused by
indigenous South-east Asian peoples; the examples provided by these authors
demonstrate how culture affects the treatment of what we would call "evidence."
The international nature of an incident can add complicating "filters" to the
reconstruction of events, since reclamation responses by indigenous people vary
according to their interpretations of the scene. An investigating forensic
anthropologist needs to understand the emic viewpoint (the insider's view), as
cultural anthropologists do, when attempting to recover and reconstruct such an
incident. In response to the cultural (and natural) taphonomic agents at work on
such a site, the use of dual forensic recovery methods--simultaneously treating
the investigation scene like an aircraft crash and a clandestine burial site--is
advised. Employing a flexible set of methods will allow for maximal recovery of
evidence.
PMID- 9544537
TI - Short UV luminescence for forensic applications: design of a real-time
observation system for detection of latent fingerprints and body fluids.
AB - An assembly that allows a pseudo real-time (one second delay) observation of
latent fingerprints by their short ultraviolet luminescence was designed. It is
composed of a mercury-xenon lamp and a CCD camera, both water-cooled and computer
controlled. The system is used to study the behaviour of latent fingerprints and
stains of body fluids such as blood, semen and saliva under short-UV
illumination.
PMID- 9544538
TI - Evaluation of the human hair root for DNA typing subsequent to microscopic
comparison.
AB - Telogen human hairs are one of the most common useful evidence findings at crime
scenes and/or on homicide victims. Occasionally, the microscopic characterization
of the found telogen hair is the only physical evidence association to a victim
or suspect. Recently efforts to characterize these hairs by mitochondrial DNA
(mtDNA) methods have progressed. The nature of the telogen hair root morphology
and ultrastructure has, however, been largely ignored. Examiners have recognized
these hairs are unlikely to be typable by nuclear DNA (nuDNA) methods. Most
forensic biologists have little knowledge of the complex cellular composition of
anagen, catagen, and telogen hair roots or their morphogenesis. This paper
reviews ex situ human hair root morphology as it relates to the likelihood of
successful nuclear DNA typing. Dermatology texts of hair root morphology always
demonstrate their microscopic appearance in the skin. This study investigates the
use of fluorescence in situ hybridization (FISH) methods to sex type telogen head
hairs, and it further investigates hair root morphology as it relates to the
potential nuclear DNA content of evidence hairs. There is a need for the use of
appropriate, consensus terminology for describing hair root morphology. There is
also a need for standardized laboratory light microscopic methods in evaluating a
hair root for DNA typing. FISH was found to be an unsuitable technique for sex
determination of telogen hair clubs. It was determined that anagen/catagen hair
roots without translucent sheath material are excellent candidates for nuDNA PCR
based typing and that hairs with telogen club root material only should not be
submitted for nuDNA typing attempts.
PMID- 9544539
TI - Rapid PCR for identity testing using a battery-powered miniature thermal cycler.
AB - A microfabricated, battery-powered thermal cycler was implemented in PCR-based
DNA typing for human identification. HLA DQ alpha and an STR triplex were PCR
amplified using a device known as the Miniature Analytical Thermal Cycling
Instrument (MATCI). The extremely efficient heating properties of the MATCI
enabled thermal cycling to be completed in as little as 21 min. In addition, the
feasibility of using the real-time fluorescent detection system of the MATCI was
demonstrated. The successful application of this portable, prototype device to
forensic identity testing is a significant milestone towards the eventual
development of a completely integrated DNA testing instrument that would also
incorporate sample preparation and allele detection.
PMID- 9544540
TI - Post-traumatic movement disorders: effect of the legal system on outcome.
AB - Since patients with post-traumatic, neurologic, movement disorders often seek
legal counsel and become involved in litigation, we used this group of disorders
as a model for testing the hypothesis that an interaction with the legal system
may influence its outcome. We reviewed 100 consecutive medical records of
patients with post-traumatic movement disorders from the Movement Disorders
Clinic at the Baylor College of Medicine. Additionally, 40 patients completed a
detailed questionnaire and a health survey. Nineteen of the 40 respondents had
obtained legal representation in regards to compensation for their medical
problems. The group of patients with attorneys differed from those without legal
representation in that they were significantly younger and a significantly higher
percentage of these patients were disabled as compared to the group without
attorneys. While most were dissatisfied with the legal system, 68% were satisfied
with services provided by their attorneys. Although the patients with legal
aspects of their movement disorders seemed to have more severe and persistent
disability, we could not definitely conclude that the legal system had adversely
affected the outcome of the post-traumatic movement disorders.
PMID- 9544541
TI - Criminal and behavioral aspects of juvenile sexual homicide.
AB - This preliminary research provides a descriptive, systematic study of juvenile
sexual homicide. Fourteen incarcerated juveniles, identified through a department
of corrections computer search, were assessed using a structured diagnostic
interview, an author-designed clinical interview, and a review of correctional
files and other available records. Five of the offenders' victims survived the
homicidal attack, but their cases were nevertheless included in this study as the
offenders' intent was clearly to kill their victim, and the victim's survival was
merely by chance. All victims were female and all offenders were male. Their
crimes typically occurred in the afternoon, and involved a low-risk victim of the
same race who lived in the offender's neighborhood. The sexual component of the
crime consisted of vaginal rape in over one-half of the cases. Weapons, typically
a knife or bludgeon, were used in all but one case. Thirteen of these youths had
a prior history of violence, and twelve had previous arrests. Chaotic, abusive
backgrounds and poor adjustment in school were typical for these boys. A conduct
disorder diagnosis was present in twelve of the youths, and violent sexual
fantasies were experienced by one-half of the sample. The findings in this study
suggest that juvenile sexual murderers comprise less than 1% of juvenile
murderers, and are likely to be an emotionally and behaviorally disturbed
population with serious familial, academic, and environmental vulnerabilities.
PMID- 9544542
TI - Accuracy of bite mark overlays: a comparison of five common methods to produce
exemplars from a suspect's dentition.
AB - Physical comparison of a suspect's teeth to a bite mark injury using hollow
volume comparison overlays is a common forensic odontology technique. Several
methods are used to record characteristics of the size, shape and position of the
teeth and to generate overlays. These include computer-based, radiographic,
xerographic and hand-traced methods. Five common overlay production methods were
compared using digital images of dental study casts as a reference standard. Area
of the biting edges of the anterior teeth and relative rotation of each anterior
tooth were measured and compared. The computer-based production method was
determined to be the most accurate of those studied. It produced accurate
representations of the biting edges of the teeth in an objective manner. The
radiographic method was determined to be more accurate than the xerographic
method with respect to tooth area measurement. The opposite is true with respect
to tooth rotation. Hand-traced methods, from either wax impressions of teeth or
directly from study casts, were determined to be inaccurate and subjective. It is
recommended that forensic odontologists discontinue the use of hand-traced
overlays in bite mark comparison cases.
PMID- 9544543
TI - The natural decomposition of adipocere.
AB - Adipocere is a waxy substance which sometimes forms from the adipose tissue of
dead bodies, especially when they are under water. A disinterment in southern
Ontario lead to the recovery of extensive adipocere from an interment which
occurred in AD 1869. Subsequent laboratory research was designed to explore the
conditions under which adipocere will disappear, the goal being to identify
strategies for estimating a range of time since death in cases where adipocere is
present. Varieties of aerobic or facultatively anaerobic microorganisms from the
surface of the adipocere were separated and identified. In culture, the gram
positive bacteria were able to degrade the adipocere. We propose that the
persistence of adipocere is related to the exclusion of gram positive bacteria
from the burial environment. The role of bacteria in adipocere formation and
degradation must be understood before we can use the presence of adipocere to
extrapolate information about the post-death interval.
PMID- 9544544
TI - A 15 year retrospective review of homicide in the elderly.
AB - With constant improvements in socioeconomic conditions, the people of most
industrialized nations are living longer. Most elderly individuals lead
productive lives within the community. Unfortunately, when elderly individuals
suffer from a debilitating disease or injury, society seems ill-equipped to care
for them. The frailty and social isolation that comes with illness or advanced
age renders the elderly more vulnerable to crime. This study examines the
circumstances that surround homicides of those 65 years of age or older which
occurred in Jefferson County, Alabama over a 15 year span. We conducted a
retrospective study of all decedents brought to the Jefferson County
Coroner/Medical Examiner Office during the 15 years from 1981-1995. A computer
search identified 150 homicide victims who were 65 years or older. In these 150
cases the causes of death were as follows: gunshot wound 50%, blunt force
injuries 19%, knife wounds 14%, and asphyxiation 10%. Younger homicide victims
were much less likely to be killed as the result of a direct physical assault;
blunt force injuries and asphyxiation combined caused death in only 7% of the
younger population. Robbery was the most common motive for death in the elderly
population, which accounted for 37% of cases. The most common location for
homicides in the elderly population was in their own residence, which accounted
for 71% of cases. Four elderly homicide victims were shot by the police. Three
elderly decedents died as a result of abuse.
PMID- 9544545
TI - Subdural neomembranes and sudden infant death syndrome.
AB - Cranial dura maters of 36 consecutive infants with sudden infant death syndrome
(SIDS) and 16 control infants coming to the Department of Coroner were examined
microscopically to determine if subdural neomembranes are associated with cases
submitted as SIDS. Thirty-one percent (31%) of the infants with SIDS and 13% of
control infants had organizing subdural neomembranes (p > 0.05). Overall
prevalence of organizing subdural neomembranes was 25% in the group examined. In
all but two cases, birth trauma could be excluded as a cause of head trauma by
aging neomembranes histologically. No association was found between type of
delivery (vaginal or Cesarean) and presence of a subdural neomembrane. Subdural
neomembranes are common in infants autopsied in a forensic setting, but they may
be missed without a microscopic examination. Subdural neomembranes have no
demonstrated association with SIDS.
PMID- 9544546
TI - Death investigation in Canada.
AB - A survey of death investigation systems in Canada was conducted by questionnaire
and included questions on the type of system used (coroner or medical examiner),
budget, method of appointment and qualifications of coroners and medical
examiners, responsible department of government, training requirements,
laboratory facilities, and the utilization of investigators and pathologists by
each jurisdiction. Of the population of Canada 81.5% reside in coroner
jurisdictions, the primary death investigator in 81% of the population is a
licensed physician. The majority of jurisdictions either require or provide
training in death investigation. All death investigation systems are under the
respective provincial or territorial department of Justice or Attorney General
with the chief coroner or chief medical examiner appointed by their respective
provincial cabinet. The qualifications of the chief coroner vary with
jurisdiction, while in 75% of medical examiner jurisdictions the chief medical
examiner must be a pathologist. On a per capita basis medical examiner systems
are less expensive to operate than coroner systems.
PMID- 9544547
TI - Postmortem amitriptyline pharmacokinetics in pigs after oral and intravenous
routes of administration.
AB - In this study we have evaluated the postmortem pharmacokinetics of amitriptyline
(Ami) and metabolites in pigs after oral and intravenous administration, and the
results are compared with previous studies in rats and humans. In addition a
meticulous investigation of blood and tissue concentrations after postmortem
intravenous infusion of Ami was undertaken. Of a total of 9 over-night fasted
pigs, 3 were given 25 mg/Kg Ami orally, and another 3 pigs received an
intravenous infusion lasting 1 h of 3.3 mg/Kg Ami prior to death. The final 3
pigs were sacrificed and then given the intravenous infusion after death. After
approximately 5 h at room temperature, all carcasses were subsequently stored at
4-5 degrees C. Postmortem blood samples were collected at 0.25, 1, 2, 4, 8, 24,
48, and 96 h through an indwelling intracardial needle. Postmortem examination
with blood and tissue sampling was performed 96 h after death. Analysis was
carried out by high performance liquid chromatography with ultraviolet detection.
Postmortem blood samples from the heart of the orally dosed animals revealed
large and variable concentration increases of 99(30-243)% for Ami and 96(52-429)%
for the main metabolite 10-OH-Ami at 96 h. In the intravenously infused live pigs
heart blood Ami increased by 55(33-69)% and 10-OH-Ami increased by 232(76-240)%.
Blood from the atria had significantly higher Ami concentrations than blood from
both ventricles in the animals dosed while alive, and the drug concentration in
femoral blood was higher than in heart blood (p < 0.01). In the orally dosed pigs
the left lobe of the liver had significantly higher Ami levels than the right
lobe. Tissue/blood Ami concentration ratios were generally lower than previously
reported in rats and approximating the levels reported in humans. The animals
infused intravenously after death demonstrated high drug levels in blood samples
from central vessels, heart, lungs as well as cerebrospinal fluid and vitreous
humour. This implies that the presence of a lethal concentration of a drug in
just one sample of heart blood can prove worthless in a case where agonal drug
infusion may have occurred.
PMID- 9544548
TI - Considerations in the interpretation of urine analyses in suspected opiate
intoxications.
AB - Over the years, it has been observed that in many suspected opiate intoxications,
a urine screen using the standard 300 ng/mL cutoff has produced negative results.
Subsequent analysis of the blood in many of these cases, in fact, were positive
for morphine. To identify the frequency of this occurrence and to determine a
more appropriate urine screening cutoff, paired blood and urine specimens were
tested for opiates at the above cutoffs. Over the 6 months period of this study,
102 cases were identified where the blood morphine concentration by Roche
Abuscreen was greater than 100 ng/mL of "morphine equivalents." All positive
cases were confirmed as morphine by gas chromatography-mass spectrometry. Seventy
nine of these cases, or 77%, had urine concentrations by Abuscreen exceeding 300
ng/mL of "morphine equivalents." The remaining 23 cases had urine morphine
concentrations less than 300 ng/mL by Abuscreen. Urine specimens were then
reanalyzed by Abuscreen using dilutions of the 300 ng/mL calibrator: 50, 75, and
150 ng/mL. Even with the use of a 50 ng/mL cutoff, 9 of these 23 specimens tested
negative by Abuscreen. Moreover, 23 of the 67 cases or 34% in which the cause of
death was narcotic intoxication had urine opiate concentrations by Abuscreen less
than the recommended 300 ng/mL cutoff. These results indicate the critical
importance in cases of suspected narcotic intoxication of screening the blood in
addition to urine.
PMID- 9544549
TI - Setting cutoff concentrations for immunoassay screening of postmortem blood.
AB - The objective of this study was to establish the optimum immunoassay cutoff
concentrations for screening postmortem blood from coroner's cases for drugs of
abuse with a coated tube radioimmunoassay (RIA) to ensure that the results with
the coated tube RIA would be equal to or better than those with the previously
used double antibody RIA. Immunoassay results (positive or negative) blood were
compared to confirmed results on those cases by GC/MS alone or in combination
with GLC using either a NPD or FID detector. Four to seven potential cutoff
concentrations were evaluated for the drug classes opiates, amphetamines, cocaine
and metabolites, and barbiturates. Specimens were 350 postmortem blood specimens
and liver homogenates. The cutoffs chosen for the coated tube RIA using this
approach were 5 ng/mL morphine, 25 ng/mL methamphetamine, 500 ng/mL
benzoylecgonine, and 500 ng/mL secobarbital. These cutoffs corresponded to a
sensitivity and specificity of 94% and 96% for opiates, 93% and 86% for
amphetamines, 91% and 96% for cocaine and metabolites and 91% and 87% for
barbiturates. The double antibody RIAs were run on the same specimens with
cutoffs of 20 ng/mL morphine, 50 ng/mL methamphetamine, 50 ng/mL benzoylecgonine
and 1000 ng/mL phenobarbital. The sensitivity and specificity's for the double
antibody immunoassay were: > 99% and 96% for opiates, 83% and 89% for
amphetamines, 98% and 97% for cocaine, 79% and 95% for barbiturates.
PMID- 9544550
TI - Evaluation of the accuracy of on-site multi-analyte drug testing devices in the
determination of the prevalence of illicit drugs in drivers.
AB - A principal goal of this research was to conduct a field evaluation of "on-site"
multi-analyte drug testing devices to determine the most accurate, efficient, and
cost-effective device available for the purpose of rapidly detecting drivers
under the influence of drugs. Four on-site kits were selected and evaluated for
accuracy and efficiency for the detection of tetrahydrocannabinol (THC), the
cocaine metabolites (COC), and opiates (OPI). From 16 December 1995 to 17 March
1996, 303 voluntary urine specimens were collected by law enforcement officers
from persons arrested for driving-under-the-influence (DUI). These specimens were
tested using the four selected kits and aliquots of the specimens were sent to a
DHHS certified lab for "gold standard" comparison testing by immunoassay and Gas
Chromatography/Mass Spectrometry. On-site kit sensitivity ranged from 82.9% to
100% for THC, 82.5% to 100% for COC, and all were at 100% for OPI. Specificity,
and positive and negative predictive values were also determined. Accuracy ranged
from 94.0% to 98.3% for THC, 97.4% to 98.0% for COC, and 99.7% to 100% for OPI.
All four kits were in very close agreement on prevalence: 15.5% to 15.8% for THC,
all were at 13.2% for COC, and all were at 0.7% for OPI. For law enforcement
purposes, sensitivity may be the most important indicator in these kits.
PMID- 9544551
TI - Xylazine toxicity--literature review and report of two cases.
AB - Xylazine is a veterinary sedative, analgesic or general anesthetic. Its
pharmaceutical action results in sympathetic discharge via stimulation of alpha-2
adrenoceptors. In humans, toxicity consists of central nervous system depression,
bradycardia and hypotension. The dosages known to produce toxicity in humans vary
from 40 mg up to 2400 mg. Because of decomposition, xylazine blood concentrations
in two homicide victims were unknown; however, the concentrations in the brain,
liver, and kidneys were much higher in the 23-year-old female versus the 33-year
old male victim. A bottle of xylazine found on the crime scene had a
concentration of 100 mg/mL. This 50 mL bottle had 32 mL remaining. Therefore at
some point in time 18 mL had been utilized. The amount of available milligrams of
xylazine (1800 mg) were enough to cause toxicity in both the woman and the man.
Of interest was the fact that the partially skeletonized heads were found remote
from the torsos, however, the concentration of xylazine in the body tissues
provided a toxicological match of which head belonged to which body. Xylazine
toxicity in humans and its relationship to these homicides will be the focus of
this report.
PMID- 9544552
TI - Quechua Amerindian population characterized by HLA-DQ alpha, YNZ22, 3'APO B,
HUMTH01, and HUMVWA31A polymorphisms.
AB - Allele and genotype frequencies of DNA polymorphisms were determined in a
population sample of Quechua (n = 113) using the polymerase chain reaction (PCR).
We report data on the frequencies of HLA-DQ alpha, YNZ22, 3'ApoB, HUMTH01 and
HUMVWA31A alleles and the distribution of the different genotypes. No significant
deviations between observed and expected numbers were found, thus assuming the
Hardy-Weinberg equilibrium.
PMID- 9544553
TI - D4S43 locus DNA typing in the Japanese population and application to teeth with
degraded DNA.
AB - VNTR polymorphism at the D4S43 locus was investigated, and allele frequencies in
the Japanese population sample were determined by the polymerase chain reaction.
Eleven different alleles and 16 genotypes were observed in 131 unrelated
Japanese. The most common allele was one repeat unit (60.3%), the heterozygosity
index of the present study was 58.7%, and the polymorphic information content was
calculated at 0.55. In addition, we found four new size variations in the one
repeat-unit allele, which was the most common allele among the Japanese
population. These variations were believed to be different from variations by
repeats of the basic 14-bp unit. The one-repeat-unit allele at the D4S43 locus,
which comes in four sizes, was detected in all of the samples, including degraded
DNA samples obtained from hard tooth tissue. Therefore, this new variation is
useful in personal identification by DNA analysis using forensic scientific
degraded DNA samples.
PMID- 9544554
TI - The DRPLA CAG repeats in an Italian population sample: evaluation of the
polymorphism for forensic applications.
AB - The DRPLA CAG repeats polymorphism has been studied in an Italian population
sample. PCR amplification, manual PAGE and silver staining were employed. A total
of 16 different alleles, spanning the range from 5 to 21 CAG triplettes, was
observed. The heterozygosity was 0.81 and no significant deviation from Hardy
Weinberg equilibrium was found 81 meioses from parentage testing were also
analyzed and a Mendelian pattern of inheritance was observed in all cases. In
addition, we could successfully type DRPLA locus in some forensic specimens, 1 ng
of DNA allowing clear definition of alleles. The authors conclude that the DRPLA
CAG repeats analysis may be useful for forensic applications.
PMID- 9544555
TI - Human orosomucoid (ORM1) subtyping: further population genetic data and reports
on the feasibility to type aged blood samples and stains.
AB - Genetic polymorphism of serum orosomucoid (ORM1) was investigated in 1072
unrelated German Caucasians using isoelectric focusing followed by Western
blotting and EIA. The estimated allele frequencies were ORM1 *F1 = 0.5690, ORM1
*S = 0.3927, ORM1 *F2 = 0.0368, ORM1 *F2S = 0.0009 and ORM1 *F5 = 0.0005. The
method was successfully applied to determine ORM1 phenotypes in aged blood
samples and blood stains. The results indicated that the ORM protein is a
informative and remarkably robust blood group system.
PMID- 9544556
TI - Experimental single controlled study of burned bones: contribution of scanning
electron microscopy.
AB - Burned bones were studied using Scanning Electron Microscopy. The samples were
cut from a maxillary-mandibular block taken during an autopsy. These fragments
were heated in a furnace under controlled temperature conditions for 60 minutes.
The temperatures ranged from 150 to 1150 degrees Celsius. The results are as
following: (i) there are significant alterations of the bone, more and more
obvious as the temperature increases, (ii) it appears to be difficult to
establish a precise correlation between the temperature and the scanning electron
microscopy patterns.
PMID- 9544557
TI - Analysis of shrinkage in human fetal diaphyseal lengths from fresh to dry bone
using Petersohn and Kohler's data.
AB - Calculation of gestational age from forensic fetal remains may be problematic. If
soft-tissue indicators are not available, then diaphyseal lengths obtained
through sonograms on living fetuses in utero or radiographs of long bones can be
compared to known European standards, such as Fazekas and Kosa (1978) and Olivier
and Pineau (1958, 1960). Radiographic comparison to these European standards,
however, requires a correction factor for diaphyseal shrinkage from fresh to dry
states. Percent shrinkage is calculated for six diaphyses (humerus, ulna, radius,
femur, tibia and fibula) from Petersohn and Kohler's data published in Fazekas
and Kosa (1978:362-369). Average shrinkage, standard deviation, minimum and
maximum values are calculated for each diaphysis and for all diaphyses during 4
10 lunar months (LM) and newborns. Corresponding average and standard deviation
values are as follows: 4 LM-10.09% +/- 2.67%; 5 LM-5.74% +/- 0.84%; 6 LM-3.48% +/
0.49%; 7 LM-2.32% +/- 0.16%; 8 LM-2.18% +/- 0.51%; 9 LM-1.76% +/- 0.14%; 10 LM
1.90% +/- 0.59%; and newborns-1.28% +/- 0.55%. Analysis of these values suggests
that percent shrinkage steadily declines as the fetus ages. This pattern
presumably reflects calcification of bone during growth and development in utero.
These findings demonstrate a significant shrinkage in the diaphysis early in
development, which may alter accurate age estimation in the earliest fetal age
groups.
PMID- 9544558
TI - Correlation of body mass index with thoracic and abdominal panniculus.
AB - Obesity can play a significant role in chronic diseases, sudden unexpected death,
and morbid obesity may be important as a cause of death for forensic
pathologists. Our study attempted to determine if there is a correlation between
panniculus measurements and body mass index (BMI) since BMI has been used in most
studies to categorize obesity. Using data obtained from a review of 524 adult
autopsies conducted at the University of Michigan from 1990 to 1992 we were able
to show a correlation between both thoracic and abdominal panniculus and BMI (r2
= 0.335 and 0.296 respectively) which is statistically significant (p = 10(-47)
and 10(-41) respectively). A prospective study confirmed the correlation (r2 =
0.552 for thoracic and 0.436 for abdominal panniculus) when the measurements were
taken at the xyphoid process and 3 cm below the umbilicus. Using these data we
calculated a panniculus index (PI) which is equal to the thoracic + abdominal
panniculus in centimeters divided by the square of the height (in meters). The PI
strongly correlated with BMI and was able to predict obesity. Using a BMI cutoff
of 39 for morbid obesity, a PI value of 4.07 for females and 3.25 for males
predicted morbid obesity with the probability of a false positive less than or
equal to 2.5%. Mild and severe obesity could also be determined using the PI.
Based on these data we've concluded that a concise mathematical relationship does
exist between BMI and panniculus measurements. Therefore panniculus measurements
can be used either as a surrogate measurement of morbid obesity or to support BMI
calculations.
PMID- 9544559
TI - Origin and gender determination of dried blood on a statue of the Virgin Mary.
AB - In Italy, blood exudation from objects of worship recurs frequently in ancient
chronicles and literature, in popular beliefs, and even in modern mass-media
reports. This phenomenon, that was associated with epochal or catastrophic
events, has roots that reach classical antiquity. In the last few years, several
events connected with the detection of bloody "tears" on statues of the Virgin
Mary required forensic medicine investigations. In the present report we describe
genetic investigations conducted on dried blood of unknown derivation found on a
statuette representing the Virgin Mary. To test the human or animal origin of the
blood, we amplified Alu-specific sequences from DNAs obtained from the unknown
sample and from humans, large apes, various Old and New World monkeys, a
prosimian, mouse, common domestic artiodactyls and chicken. This investigation
restricted the range of possible origin of the statue blood to humans, apes and
Old World monkeys. To test the male or female origin of the blood, we used a
multiplex nested polymerase chain reaction method, that allows the simultaneous
amplification of the X-specific locus DXZ4 and of the Y-specific locus SRY.
Considering the unlikelihood of an origin from simian Old World primates, the
exclusive amplification of the X-specific product from the unknown sample and
from human female blood controls, compared to the amplification of distinct X-
and Y-specific bands from human male blood controls, strongly supports a human
female origin of the statue blood.
PMID- 9544560
TI - Evidence of polydrug use using hair analysis: a fatal case involving heroin,
cocaine, cannabis, chloroform, thiopental and ketamine.
AB - A case is presented involving a young woman on several illicit drugs (heroin,
cocaine and cannabis) as well as two medications and a solvent used for their
anesthetic and narcotic properties: thiopental, ketamine and chloroform. This
complex drug use was supported by hair analysis over a 10.5 cm segment of the
hair taken at autopsy. The average measured concentrations in hair were:
thiopental = 5.3 ng/mg, pentobarbital = 10.0 ng/mg, ketamine = 11.3 ng/mg
norketamine = 1.0 ng/mg, diazepam = 1.2 ng/mg, nordiazepam = 0.1 ng/mg, 6
acetylmorphine = 4.4 ng/mg, morphine = 3.4 ng/mg, codeine = 1.2 ng/mg, cocaine =
5.5 ng/mg, benzoylecgonine = 1.5 ng/mg and methylecgonine ester = 1.0 ng/mg.
While the ketamine/norketamine ratio is consistent with that already reported on
drug detection in hair, the thiopental/pentobarbital ratio seems to be inverted.
PMID- 9544561
TI - Croton ruizianus: platelet proaggregating activity of two new pregnane
glycosides.
AB - The MeOH extract of the aerial parts of Croton ruizianus afforded two new
pregnane glycosides 1 and 2, together with the morphinandienone alkaloids
flavinantine (3) and O-methylflavinantine (4). Their structures were elucidated
by NMR experiments including 1H-1H (1D TOCSY and 2D DQF-COSY) and 1H-13C (HSQC,
HMBC) spectroscopy. The proaggregating activity of the MeOH extract and the
isolates were evaluated. Although the MeOH extract and pregnane glycosides (at
different doses) were found to promote platelet aggregation, flavinantine (3) and
O-methylflavinantine (4) showed only slight activity. The ability of the MeOH
extract and the four compounds to act synergistically with thrombin was also
evaluated. All the tested compounds were successful in augmenting the aggregating
effect of thrombin, although to different degrees.
PMID- 9544562
TI - Triterpenoid saponins from Spergularia ramosa.
AB - Six new oleanene glycosides were isolated from the MeOH extract of the aerial
parts of Spergularia ramosa. They possess gypsogenin or quillaic acid as the
aglycons. The disaccharide moiety linked to C-3 of the aglycons is made up of
galactose (or glucose) and glucuronic acid (or glucose); the pentasaccharide
moiety linked to C-28 is made up of glucose (or galactose), xylose, rhamnose,
fucose, and arabinose. Their structures were elucidated by 1D and 2D NMR
experiments including 1H-1H (DQF-COSY, 1D TOCSY, 2D HOHAHA, ROESY) and 1H-13C
(HSQC, HMBC) spectroscopy.
PMID- 9544563
TI - Cardiovascular effects of aspidofractinine-type alkaloids from Kopsia.
AB - Intravenous injection of the aspidofractinine alkaloid, kopsingine (1, 0.2-10.0
mg/kg) from Kopsia teoi, produced dose-related decreases in the mean arterial
blood pressure and heart rate in anesthetized spontaneously hypertensive rats,
which were similar to those seen in normotensive controls. Minor modifications in
the molecular structure of kopsingine, as in kopsaporine (2, the 12-demethoxy
derivative of kopsingine) and 14,15-dihydrokopsingine (4), did not significantly
alter the hypotensive responses, whereas a more drastic change in the structure,
as in the heptacyclic kopsidine A (3) and the 3-to-17 oxo-bridged compound 5,
resulted in an increase in blood pressure. The antihypertensive effects of
kopsingine (1) and its congeners (2 and 4) along with the pressor effects
produced by the heptacyclic oxo-bridged compounds (5 and 3) could be ascribed to
central as well as peripheral actions.
PMID- 9544564
TI - 5-Lipoxygenase and cyclooxygenase-1 inhibitory active compounds from Atractylodes
lancea.
AB - Lipophilic extracts of Atractylodes lancea rhizomes exhibited potent inhibitory
activities in 5-lipoxygenase [IC50 (5-LOX) = 2.9 micrograms/mL (n-hexane
extract)] and cyclooxygenase-1 [IC50 (COX-1) = 30.5 micrograms/mL (n-hexane
extract)] enzymatic assays. Bioactivity-guided fractionation of the n-hexane
extract led to the isolation of a new compound atractylochromene (1), a potent
inhibitor in both test systems [IC50 (5-LOX) = 0.6 microM, IC50 (COX-1) = 3.3
microM]. Also obtained was 2-[(2E)-3,7-dimethyl-2,6-octadienyl]-6-methyl-2,5
cyclohexadiene-1 ,4-dione (2), which showed a selective inhibitory activity
against 5-LOX [IC50 (5-LOX) 0.2 microM, IC50 (COX-1) 64.3 microM]. The
sesquiterpene atractylon (3) and the coumarin osthol (4) turned out to be
moderate but selective 5-lipoxygenase inhibitors. Atractylenolides I (5), II (6),
and III (7) showed no significant inhibitory effects for either enzyme.
Structures were established by spectral data interpretation.
PMID- 9544565
TI - HIV-inhibitory and cytotoxic oligostilbenes from the leaves of Hopea malibato.
AB - Three new oligostilbenes, malibatols A (1) and B (2) and dibalanocarpol (3),
together with one known oligostilbene balanocarpol (4), were isolated from the
organic extract of the leaves of Hopea malibato. The structure elucidation of
these compounds was based on the interpretation of their chemical and spectral
data. Compounds 3 and 4 exhibited very modest HIV-inhibitory activity, while
compounds 1 and 2 were cytotoxic to the host cells (CEM SS) in the antiviral
assay.
PMID- 9544567
TI - New imidazole alkaloids and zinc complexes from the micronesian sponge Leucetta
cf. chagosensis.
AB - Four new imidazole alkaloids, 2-5, along with the known isonaamidine B (1) were
isolated from a Pacific sponge, Leucetta cf. chagosensis, collected from Yap,
Federated States of Micronesia. Among these, 4 and 5 are zinc complexes derived
from isonaamidine B and isonaamidine D. The structures of the new compounds were
elucidated from spectral data. Isonaamidine D (3) showed weakly antifungal
activity against Aspergillus niger with MIC = 100 micrograms/mL.
PMID- 9544566
TI - DNA polymerase and topoisomerase II inhibitors from Psoralea corylifolia.
AB - An ethanol extract of Psoralea corylifolia caused strong DNA polymerase
inhibition in a whole cell bioassay specific for inhibitors of DNA replication
enzymes. Bioassay-directed purification of the active compounds led to the
isolation of the new compound corylifolin (1) and the known compound bakuchiol
(2) as DNA polymerase inhibitors. On the basis of the structures of 1 and 2,
resveratrol (3) was tested and found to be active as a DNA polymerase inhibitor
in this bioassay. Neobavaisoflavone (4) was isolated as a DNA polymerase
inhibitor, daidzein (5) as a DNA polymerase and topoisomerase II inhibitor, and
bakuchicin (6) as a topoisomerase II inhibitor.
PMID- 9544568
TI - Antihyperglycemic effects of N-containing sugars from Xanthocercis zambesiaca,
Morus bombycis, Aglaonema treubii, and Castanospermum australe in streptozotocin
diabetic mice.
AB - The aqueous MeOH extract of the leaves and root of Xanthocercis zambesiaca
(Leguminosae) and eight structurally related nitrogen-containing sugars, fagomine
(1), 4-O-beta-D-glucopyranosylfagomine (2), 3-O-beta-D-glucopyranosylfagomine
(3), 3-epifagomine (4), 2,5-dideoxy-2,5-imino-D-mannitol (5), castanospermine
(6), alpha-homonojirimycin (7), and 1-deoxynojirimycin (8) were evaluated for
antihyperglycemic effects in streptozotocin (STZ)-diabetic mice. The insulin
releasing effects of 1 were also investigated. The blood glucose level fell after
i.p. injection of the extract (50 mg/kg). Compounds 1, 2, 5, and 6 reduced the
blood glucose level after i.p. injection of 150 mumol/kg. Compound 1 increased
plasma insulin level in STZ-diabetic mice and potentiated the 8.3-mM glucose
induced insulin release from the rat isolated-perfused pancreas. The 1-induced
potentiation of insulin release may partly contribute to antihyperglycemic
action.
PMID- 9544569
TI - Pseudopterane and norcembrane diterpenoids from the Caribbean sea plume
Pseudopterogorgia acerosa.
AB - A chemical study of the common Caribbean sea plume Pseudopterogorgia acerosa from
Puerto Rico has produced two previously undescribed secondary metabolites. One of
them, 1, is a new representative of the pseudopterane family of diterpenes
possessing the uncommon 3,4;5,6 diepoxyfuran moiety. The other metabolite, 2, is
a rare norcembranolide diterpene. Their chemical structures, including relative
stereochemistry, were established by detailed analysis of the spectral data in
addition to NMR spectral comparisons with known pseudopterane and cembrane
models.
PMID- 9544570
TI - Transcription factors that regulate monocyte/macrophage differentiation.
AB - Although all the cells in an organism contain the same genetic information,
differences in the cell phenotype arise from the expression of lineage-specific
genes. During myelopoiesis, external differentiating signals regulate the
expression of a set of transcription factors. The combined action of these
transcription factors subsequently determines the expression of myeloid-specific
genes and the generation of monocytes and macrophages. In particular, the
transcription factor PU.1 has a critical role in this process. We review the
contribution of several transcription factors to the control of macrophage
development.
PMID- 9544571
TI - The role of CD40/CD154 interactions in the priming, differentiation, and effector
function of helper and cytotoxic T cells.
AB - This review focuses on the emerging body of literature suggesting a critical role
for CD40/CD154 interactions in antigen-presenting cell (APC) activation, CD4+ and
CD8+ T cell priming, and effector T cell maturation. In this context effective
antigen presentation involves not only T cell expansion and long-term survival
but also the ability of the APC to guide the T cell response toward the Th1
(interferon-gamma producing) or the Th2 (interleukin-4 producing) phenotype. We
suggest a model to explain why CD40/CD154 interactions are critical for some
helper and cytotoxic T cell responses, whereas others occur independently of this
receptor/ligand pair. In addition, we will discuss the potential role for
CD40/CD154 interactions in effector T cell maturation and cytokine production.
PMID- 9544572
TI - Trypanosoma brucei infection elicits nitric oxide-dependent and nitric oxide
independent suppressive mechanisms.
AB - During murine Trypanosoma brucei infection, macrophages contribute significantly
to the inhibition of T cell responses. Although nitric oxide (NO) was shown to
play a central role in macrophage-mediated splenic suppression, macrophage
mediated lymph node suppression occurred in an interferon-gamma (IFN-gamma)
dependent manner. In this study, using NO inhibitor NG-monomethyl-L-arginine and
anti-IFN-gamma antibodies, the relative contribution of NO and IFN-gamma to the
active inhibition of ex vivo concanavalin A-induced T cell proliferation taking
place in the spleen and the lymph nodes of T. brucei-infected mice was
investigated. NO contributes to the suppressive activity of spleen and lymph node
cells only during early-stage infection. The existence of NO-independent
suppressive pathway was further evidenced in IFN-gamma(-/-)-infected mice. Spleen
cells from such animals do not produce NO but exert significant suppressive
activity during the whole course of infection. In contrast in the lymph nodes, no
suppressive activity is recorded at any moment of infection. Moreover, addition
of exogenous IFN-gamma to cultures containing lymph node cells from IFN-gamma(-/
)-infected mice does not impair proliferation despite NO production in such
cultures. Thus during late-stage infection, an IFN-gamma-independent suppressive
mechanism is elicited in the spleen, whereas in the lymph nodes, IFN-gamma is
required yet not sufficient to inhibit T cell proliferation.
PMID- 9544573
TI - Nonspecific and immune-specific up-regulation of cytokines in rabbit dermal
tuberculous (BCG) lesions.
AB - To our knowledge, this is the first sequential study of cytokines in tissue
sections of developing and healing tuberculous (BCG) lesions. In situ
hybridization, immunohistochemical, and RT-PCR techniques were used. Cytokine
mRNAs showed a biphasic pattern. The percentage of mononuclear cells (MN)
containing IL-1beta, TNF-alpha, MCP-1, and IL-8 mRNAs was highest in 1- to 3-day
lesions, apparently because of the nonspecific inflammatory response caused by
the tubercle bacilli in the BCG vaccine. At 5 days, this percentage was
significantly reduced. With IFN-gamma, the peak and trough were delayed by 2
days. By 9 days, the percentage of MN containing the mRNAs of all five cytokines
had again increased and the rabbits had become tuberculin-positive. In general,
MCP-1 and TNF-alpha proteins and the vascular adhesion molecules, ICAM, VCAM, and
perhaps ELAM, peaked at about 3 days. Many mononuclear cells surrounding the
central areas of solid and liquefied caseous necrosis contained chemokine IL-8
mRNA. IL-8 is known to attract PMN, and PMN were present nearby. In contrast, MN
containing chemokine MCP-1 mRNA were present more peripherally in areas rich in
macrophages and lymphocytes. The early nonspecific cytokine response seems to be
an adjuvant effect of the mycobacteria in BCG vaccine in that it causes a rapid
entry of macrophages, lymphocytes, granulocytes, and probably dendritic cells
into local sites of antigen deposition. This effect should be considered in
developing improved vaccines for the prevention of tuberculosis, because BCG
vaccines producing a strong early cytokine response should be more immunogenic
than BCG vaccines with similar antigens producing a weak response.
PMID- 9544574
TI - Collagenase expression by normal human eosinophils.
AB - Collagenolytic activity was detected in extracts from human blood eosinophilic
granulocytes. To characterize this collagenase, we compared extracts from
isolated populations of eosinophils and neutrophils. Significant collagenase
activity against type I and II collagens was present in extracts from both cell
populations. Although collagenase activity was present in eosinophils, the cells
did not stain with antibodies specific for fibroblast, neutrophil collagenase, or
collagenase-3. In contrast, neutrophils immunostained positively with antibody to
neutrophil collagenase. Western blot analysis confirmed the presence of
immunoreactive protein in neutrophil extracts but not in the eosinophil extracts.
Reverse transcription-polymerase chain reaction using primers specific for all
three known collagenases of an eosinophil cell suspension from peripheral blood
that had 3% contamination with immature neutrophils showed a polymerase chain
reaction product only with neutrophil collagenase oligonucleotide primers, but
not with fibroblast collagenase or collagenase-3 primers. Eosinophil collagenase
would appear to have a unique antigenic structure and may represent a new enzyme.
PMID- 9544575
TI - Processing of C5a by human polymorphonuclear leukocytes.
AB - Uptake of human C5a by neutrophils was monitored in vitro using both 125I-labeled
and unlabeled C5a. The ligand was internalized by the cells in a dose-dependent
manner and maximal binding/uptake was observed after 5 min of incubation.
Neutrophils were incubated with labeled C5a and the cytosol and supernatant were
analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and
autoradiography. C5a degradation products were primarily observed in the
supernatant, whereas most of the protein remained intact in the cytosol even
after 60 min of incubation. Cytosol from neutrophils incubated for 20 min with
unlabeled C5a was examined by radioimmunoassay and found to contain antigenically
intact C5a and retained the ability to induce a neutrophil (shape change)
response. The functional activity of C5a recovered from the cytosol was inhibited
by antibodies to either C5a or the C5a receptor (CD88). This data supports our
hypothesis that although C5a is internalized it remains antigenically intact and
functionally active inside the cell and is primarily degraded extracellularly.
PMID- 9544576
TI - HIV-1 induces human monocyte-derived macrophages to produce C3 and to fix C3 on
their surface.
AB - Complement components, particularly C3, are known to be involved in the
pathogenesis of AIDS and macrophages may serve as a source of C3 at sites of
infection. We investigated whether the interaction between HIV-1 and monocytes
has any effect on C3 production by the cells. Monocytes isolated from the blood
of healthy volunteers were incubated with monocytotropic and T lymphocytotropic
HIV-1 strains or with recombinant gp160 and cultured in serum-free medium up to 7
days. Supernatants were tested for secreted C3 by enzyme-linked immunosorbent
assay. Our data show that monocytes cultured with either the monocytotropic or
the T lymphocytotropic HIV-1 strains produce C3 in large amounts. The effect of
both viruses is dose dependent and the amount of C3 induced by HIV was up to 20
fold higher than in the control samples. C3 production was also enhanced by
gp160, the envelope protein of the virus. Secretion of IL-6 by the cells was also
measured and found to be elevated up to threefold as a consequence of the
interaction with the virus. HIV-1-activated monocyte-derived macrophages acquired
the capacity to cleave exogenous C3 and to fix generated C3 fragments on their
cell membrane.
PMID- 9544577
TI - Platelets induce monocyte differentiation in serum-free coculture.
AB - Terminal maturation of blood monocytes (MO) in vitro and in vivo into macrophages
(MAC) occurs as a result of interactions with various cell types. To characterize
some of the cell-cell connections that may be important for MO differentiation we
cocultured human MO with lymphocytes and/or with platelets. We found that intact
platelets strongly promoted MO maturation under serum-free conditions as evident
from the expression of differentiation-dependent antigens and morphology. To
further characterize the differentiation-inducing component(s) we prepared
membrane and cytosol fractions of platelets. Both fractions could induce MO
maturation, comparable to intact platelets. Further centrifugation of the
cytosolic fraction revealed that only the pellet of ultracentrifugation, e.g.,
membrane fragments, could induce MO differentiation. Digestion with either
trypsin or neuraminidase could only partially inhibit this effect. The same was
true for heat-treated fractions, indicating that this platelet-derived
differentiation stimulus is not solely an intact protein. Next we prepared
protein and lipid fractions of platelets. Treatment of MO with platelet proteins
or platelet lipids clearly showed that only the lipid components were able to
induce MO maturation. We propose components present in the lipid fraction of
platelet membranes as possible inducers of MO maturation in vitro.
PMID- 9544578
TI - Ligation of CR1 attenuates Fc receptor-mediated myeloperoxidase release and HOCl
production by neutrophils.
AB - Surface adherent immunoglobulins are potent stimuli for inducing neutrophil
release of myeloperoxidase and production of hypochlorous acid (HOCl), an oxidant
that promotes activity of neutrophil proteases. Opsonization of surface adherent
IgG (SAIgG) by complement results in attenuation of these responses, despite
augmenting neutrophil production of superoxide and release of specific granule
enzymes. The role of complement receptor ligation in modulating Fc receptor
triggered myeloperoxidase release and HOCl production by neutrophils was
determined by incubating neutrophils with SAIgG in the presence of complement
receptor ligating antibody reagents. Ligation of CR1 by F(ab')2 derived from CR1
specific monoclonal antibody (mAb 543) resulted in significant attenuation of
surface-associated IgG (SAIgG)-induced release of myeloperoxidase and HOCl
production but did not result in attenuation of SAIgG-induced superoxide or
hydrogen peroxide production; ligation of CR1 by mAb 543 F(ab')2 also attenuated
surface adherent IgA-induced myeloperoxidase release and HOCl production. HOCl
production was not significantly attenuated when neutrophils were activated with
SAIgG in the presence of surface adherent C1q or when CR3 was ligated by F(ab')2
derived from mAb having specificity for the CD11b (mAb M1/70) or CD18 (mAb TS1)
subunits of CR3. These results indicate that ligation of CR1 on neutrophils by
C3b fixed to IgG may alter signal transduction events linking ligation of
neutrophil Fc receptors to cellular events required for release of
myeloperoxidase and generation of HOCl.
PMID- 9544579
TI - Chemokine synthesis in the HSV-1-infected cornea and its suppression by
interleukin-10.
AB - Herpes simplex virus type 1 (HSV-1) infection of the murine cornea results in a
tissue-destructive inflammatory response. In this study we show that virus
infection induces the synthesis of macrophage inflammatory protein-2 (MIP-2), MIP
1alpha, and monocyte chemoattractant protein-1 (MCP-1). However, only the
production of MIP-2 and MIP-1alpha coincided with the influx of leukocytes into
the cornea. IL-10 treatment markedly suppressed chemokine message and protein
synthesis in vivo. Local administration of IL-10 also dramatically reduced the
number of T cells and neutrophils migrating into the cornea and suppressed the
severity of corneal disease. The inflammatory response could also be suppressed
by the passive transfer of neutralizing antibody to MIP-1alpha but not MCP-1. We
conclude that local IL-10 administration can suppress chemokine synthesis,
thereby ameliorating corneal disease. Furthermore, our results indicate that MIP
1alpha plays a major role in herpes stromal keratitis development, whereas MCP-1
does not.
PMID- 9544580
TI - Urinary levels of chemokines (MCAF/MCP-1, IL-8) reflect distinct disease
activities and phases of human IgA nephropathy.
AB - Leukocytes have been implicated to be involved in the pathogenesis of IgA
nephropathy (IgAN). To clarify the precise molecular mechanism of recruitment and
activation of leukocytes in the subgroups of IgAN, latent, acute, and chronic
types, we studied monocyte chemotactic and activating factor (MCAF/MCP-1) and
interleukin (IL)-8 in urines and renal expression of these cytokines. Urinary
MCAF levels were significantly higher in chronic type, and were correlated with
pathological progressive factors such as mesangial proliferation and interstitial
cellular infiltration associated with CD68-positive macrophage. On the other
hand, urinary IL-8 elevated only in acute type and were correlated with
glomerular endocapillary proliferation and the degree of hematuria. In
immunohistochemical study, IL-8 was mainly observed in glomeruli, otherwise MCAF
in vascular endothelial cells, tubular epithelial cells, and infiltrated
mononuclear cells in the interstitial lesions. These observations demonstrated
that MCAF and IL-8 were differentially expressed in kidneys with IgAN, and their
subtypes, and suggest that chemokines may be involved in the pathogenesis of IgAN
at distinct phases or pathological lesions, possibly through the recruitment and
activation of a distinct type of leukocyte.
PMID- 9544581
TI - Modulation of neutrophil adherence to endothelial cells by platelet-derived
adherence-inhibiting factor through interactions with selectin molecules.
AB - Platelet-derived adherence-inhibiting factor (AIF) has been demonstrated to
regulate the neutrophil binding to type IV collagen. In this study, we have
examined the effect of AIF on neutrophil adherence to confluently cultured human
umbilical vein endothelial cells (EC). AIF inhibited neutrophil adherence to
thrombin- or tumor necrosis factor alpha (TNF-alpha)-stimulated EC by 75 or 43%,
respectively, but hardly affected neutrophil adherence to resting EC. It is
interesting to note that the inhibitory activity of AIF was reduced by N-formyl
methionyl-leucyl-phenylalanine (fMLP) stimulation of neutrophils. Pretreatment of
neutrophils or EC with AIF inhibited neutrophil adherence to thrombin- or TNF
alpha-stimulated EC, suggesting that neutrophils and EC have AIF-binding
proteins. Using AIF-Sepharose affinity chromatography, AIF-binding proteins
containing L-selectin were isolated from 125I-labeled resting neutrophils.
However, L-selectin was markedly decreased in the AIF-binding fraction from fMLP
stimulated neutrophils. With the use of AIF-affinity chromatography, P- and E
selectins were obtained in the AIF-binding fractions from resting, thrombin-, and
TNF-alpha-stimulated EC. It is important to note that P- and E-selectin were
greatly increased in the AIF-binding fractions from thrombin- and TNF-alpha
stimulated EC, respectively. Furthermore, AIF was able to bind to L-selectin-IgG
chimeric protein and inhibit the binding of chimeric protein to thrombin or TNF
alpha-stimulated EC. In addition, AIF inhibited the binding of anti-P- or anti-E
selectin monoclonal antibody to the lysates of thrombin- or TNF-alpha-stimulated
EC. Together these observations indicate that AIF could recognize L-, P-, and E
selectins, and modulate neutrophil adherence to EC through interactions with
selectin molecules.
PMID- 9544582
TI - Inhibition of LPS-mediated activation in rat Kupffer cells by N-acetylcysteine
occurs subsequent to NF-kappaB translocation and requires protein synthesis.
AB - Activation of the resident hepatic macrophage population, Kupffer cells, leads to
production of mediators that initiate, potentiate, and modulate hepatic injury.
Recent studies have shown that activation of the pluripotent transcription factor
nuclear factor-kappaB (NF-kappaB) is an important step in the induction of
inflammatory cytokines, chemokines, growth factors, cell adhesion proteins, and
cytokine receptors, thus efforts have been focused to modulate its activity. A
common observation in diverse experimental systems is that oxidant stress
activates NF-kappaB and antioxidant drugs prevent activation and subsequent
inflammatory gene transcription. However, we have recently shown that the
inhibitory effect of N-acetylcysteine (NAC) is independent of its role as a
substrate of glutathione synthesis and NAC can inhibit Kupffer cell activation at
points beyond the initiation of activation. The goal of this study was to
characterize the mechanism for NAC-mediated inhibition of Kupffer cell
activation. We show for the first time that this process requires a cellular
synthetic response to prevent both NF-kappaB and tumor necrosis factor alpha (TNF
alpha) mRNA activation. Furthermore, NAC-mediated inhibition occurs after
degradation of IkappaB-alpha and nuclear translocation of NF-kappaB. These data
suggest that inhibition of Kupffer cell activation by NAC is a nuclear event and
offers a potential approach to modulate Kupffer cell activation during hepatic
injury.
PMID- 9544583
TI - Medals, memoirs--and Metchnikoff.
PMID- 9544584
TI - Mechanisms of neutrophil-induced parenchymal cell injury.
PMID- 9544585
TI - Methodological inquiries in health status assessment.
PMID- 9544586
TI - The risk of hospitalization for ischemic stroke among older adults.
AB - OBJECTIVES: The purpose of this study was to identify risk factors for stroke and
to estimate their relative importance in a large, nationally representative
sample of very old men and women. METHODS: The study was designed as a secondary
analysis of the Longitudinal Study on Aging. Baseline (1984) in-person interview
data were linked to Medicare hospitalization records for 1984 to 1991.
Participants were 6,071 noninstitutionalized adults 70 years old or older at
baseline. Hospitalization for ischemic stroke was defined as having one or more
episodes with a primary discharge diagnosis containing ICD-9-CM codes of 433.0
434.9, 436, and 437.0-437.1. Multivariable proportional hazards regression was
used to estimate the risks associated with previously identified epidemiologic
factors. RESULTS: Five hundred and three persons (8.3%) had at least one primary
discharge diagnosis of ischemic stroke. In descending order of importance-based
on the partial r statistics associated with their adjusted hazards ratios (AHRs),
the salient risk factors were having a previous history of stroke (AHR = 2.86),
age (AHR = 1.04 per year), diabetes (AHR = 1.78), male gender (AHR = 1.42), lower
body limitations (AHR = 1.09 per limitation), arthritis (AHR = 0.74),
hypertension (AHR = 1.29), and poverty (AHR = 1.33). CONCLUSION: Patients
presenting with the high risk factors identified in this study should be
considered for further evaluation and monitoring. Current protocols for the
therapeutic management of these higher risk patients should be considered, and
compliance should be encouraged.
PMID- 9544587
TI - The effectiveness of early endoscopy for upper gastrointestinal hemorrhage: a
community-based analysis.
AB - OBJECTIVES: The effectiveness of upper endoscopy in unselected patients with
upper gastrointestinal hemorrhage has not been well studied. This study was
undertaken to identify factors associated with the performance of early endoscopy
(ie, within 1 day of hospitalization) and, after adjusting for these factors, to
determine associations between early endoscopy and in-hospital mortality, length
of stay, and performance of surgery. METHODS: Subjects in this observational
cohort study were 3,801 consecutive admissions with upper gastrointestinal
hemorrhage to 30 hospitals in a large metropolitan region. Demographic and
clinical data were abstracted from hospital records. A multivariable model based
on factors that potentially could relate to the decision to perform endoscopy was
developed to determine the propensity (0 to 100%) for early endoscopy in each
patient. RESULTS: Early endoscopy was performed in 2,240 patients (59%), and
although it was not associated with mortality after adjusting for severity of
illness among all patients, it was associated with a higher risk of death for
patients in the lowest propensity group. Early endoscopy was associated with a
lower likelihood of upper gastrointestinal surgery in all patients and in the two
highest propensity groups and with a shorter length of stay in the entire cohort
and in all subgroups. CONCLUSIONS: In the absence of specific contraindications,
early endoscopy should be considered because of associated reductions in length
of stay and surgical intervention. Further studies are needed to identify
subgroups in whom the procedure may be associated with adverse effects on
survival.
PMID- 9544588
TI - The demand for post-acute and chronic care in nursing homes.
AB - OBJECTIVES: Nursing homes provide care for persons with both post-acute and
chronic conditions. In general, these two types of patients are associated with
short and long stays, respectively. They also tend to be covered by different
public or private insurance plans. The author investigated whether and how the
demand for these two types of nursing home care differ. How alternative
definitions of post-acute and chronic care nursing home stays affect estimates
also was explored. METHODS: Data on a sample of elderly persons from the National
Long-Term Care Channeling Demonstration was used. To account for market
disequilibrium, demand was estimated using a bivariate probit with partial
observability model. RESULTS: Differences were found in the demand for the two
types of nursing home care. For instance, economic factors and functional and
cognitive limitations were relatively more important in the demand for nursing
home care for chronic conditions. Further, chronic care patients appeared more
likely to face problems of access into nursing homes. Classifying nursing home
stays by payer, rather than by length of stay, captured expectations at admission
and appeared to reflect consumer behavior better. CONCLUSIONS: Differentiating
post-acute and chronic care nursing home stays provides more meaningful
information on consumer demand for nursing home care and will facilitate policy
analysis in this area.
PMID- 9544589
TI - Comparative responsiveness of generic versus disease-specific and weighted versus
unweighted health status measures in carpal tunnel syndrome.
AB - OBJECTIVES: The authors evaluated the relative responsiveness to change of
generic versus disease-specific and unweighted versus weighted health status
measures in carpal tunnel syndrome (CTS). METHODS: Data were obtained from 196
subjects followed in a prospective community-based cohort study in Maine who
underwent carpal tunnel release (The Maine Carpal Tunnel Syndrome Study).
Patients were evaluated before and 6 months after surgery. The disease-specific,
unweighted severity score was derived from the validated Carpal Tunnel Syndrome
Assessment Questionnaire. Patients were asked to rate the importance of each
symptom included in the severity score. Each severity question was weighted by
its importance, creating a disease-specific weighted score. Generic instruments
were the SF-36, SF-12, and a Quality of Life Rating Scale. Sensitivity to change
was calculated with the standardized response mean (SRM, mean change/standard
deviation of change) as well as the effect size (ES, mean change/standard
deviation of baseline values). The ability of the instruments to distinguish
clinically important differences was assessed by correlating the changes in
scores with global ratings on satisfaction and perceived improvement as external
criteria. RESULTS: The disease-specific weighted score (SRM: 1.56, ES: 1.99) was
more responsive than the unweighted score (SRM: 1.36, ES: 1.57). The Quality of
Life Rating Scale, SF-36, and SF-12 subscales were less sensitive to change, with
standardized response means and effect sizes that ranged from -0.23 to 0.88. The
ability to distinguish clinically important differences was higher for the two
disease-specific scales. The coefficients of correlation with the external
criteria ranged from 0.50 to 0.56 for the unweighted score and 0.56 to 0.62 for
the weighted score and were significantly stronger than the correlations between
external measures and the most responsive subscale of the SF-36 (Bodily Pain
subscale, r = 0.36). The SF-12 health survey performed as well as the SF-36 in
term of responsiveness and ability to distinguish clinically important change.
CONCLUSIONS: Disease-specific measures were superior to generic measures in
capturing clinical change after carpal tunnel release, and a weighted score was
slightly more responsive than the unweighted score. The SF-12 showed comparable
psychometric properties compared with the longer 36-item Short-Form Survey.
PMID- 9544590
TI - Access to public mental health services: determinants of population coverage.
AB - OBJECTIVES: This study examined factors that affect access to Veterans
Administration mental health services. METHODS: Data from national Veterans
Affairs databases and the 1990 Decennial Census were used to estimate rates of
Veterans Affairs mental health service use in each US county (n = 3,156) among
all US veterans and in three subpopulations defined by eligibility and clinical
status. Independent variables examined in standard multivariate analyses and
using hierarchical linear modeling techniques included county-level
sociodemographic characteristics (age, race, and income); "unmanaged" service
system characteristics (those not directly controlled by Veterans Affairs program
managers, eg, distance from residence to Veterans Affairs and to non-Veterans
Affairs services, local supply of non-Veterans Affairs services); and "managed"
service system factors (those directly controlled by Veterans Affairs program
managers, eg, per capita Veterans Affairs funding level and the efficiency of
Veterans Affairs service delivery). RESULTS: Altogether, 2.0% of US veterans used
Veterans Affairs mental health services. More than one third (36%) of the
variance in utilization was explained by sociodemographic factors; 8% was
explained by unmanaged service system factors and 7% was explained by managed
service system factors, with variations among subgroups. Substitution effects
were demonstrated between Veterans Affairs and non-Veterans Affairs systems and
appeared to be diagnosis-specific. CONCLUSIONS: Both per capita funding levels
and efficient service delivery were significantly associated with increased
access to mental health services. Implications for health system performance
assessment and management are discussed.
PMID- 9544591
TI - Outcomes for persons with rheumatoid arthritis with a rheumatologist versus a non
rheumatologist as the main physician for this condition.
AB - OBJECTIVE: The authors compared outcomes among persons with rheumatoid arthritis
(RA) with a rheumatologist versus a non-rheumatologist as the main physician for
this condition. METHODS: A cohort of 1,025 persons with rheumatoid arthritis were
followed for as long as 11 years. The principal measures were obtained from an
annual structured telephone interview conducted by a trained survey worker. All
persons with rheumatoid arthritis originally were selected from a random sample
of community rheumatologists, but some subsequently had migrated to the practices
of non-rheumatologists. The main outcome measures included the number of painful
and swollen joints, extent of morning stiffness, a global pain rating, functional
status, and a measure of global improvement. RESULTS: The persons with rheumatoid
arthritis treated by rheumatologists reported significantly better functional
status, fewer painful joints, and a lower overall pain rating, although the
magnitude of these differences was small. A significantly greater proportion of
the persons with rheumatoid arthritis treated by rheumatologists also reported
improvement in a global measure of rheumatoid arthritis outcome and simultaneous
improvement in all outcome measures. On all other outcome measures, the point
estimate favored those with a rheumatologist as the main rheumatoid arthritis
physician, although the differences did not reach statistical significance.
CONCLUSIONS: The evidence suggests an advantage for persons with a rheumatologist
as the main rheumatoid arthritis physician, but on several of the measures of
outcome, the magnitude of the advantage was small. Because the present study was
an observational design, the possibility that the advantage among persons with a
rheumatologist as the main rheumatoid arthritis physician is an artifact of
selection bias cannot be ruled out.
PMID- 9544592
TI - Heterogeneity in the relationship between the time tradeoff and Short Form-36 for
HIV-infected and primary care patients.
AB - OBJECTIVES: Evidence in the literature suggests that the overall correlation
between descriptive and valuational measures of health are weak to moderate. In
this study, the relationship between descriptive health status measures, obtained
using the Short-Form 36, and health values, measured with the time tradeoff, was
explored. METHODS: Two groups of patients matched for age and gender were
interviewed. One group comprised 139 human immunodeficiency virus (HIV)-infected
patients; the other group comprised 124 primary care patients. The relationship
between the SF-36 and the time tradeoff was estimated, assuming homogeneity
across patients, using multiple regression analysis. Subsequently, the
relationship was examined assuming heterogeneity across patients and using the
expectation maximization algorithm in a maximum likelihood context (latent class
analysis). RESULTS: Four classes, representing 47%, 13%, 8%, and 32% of the
population, respectively, were found. The overall percentage of variation
explained under the assumption of a homogeneous relationship was only 33% as
compared with 85% when heterogeneity was accounted for. Only three
characteristics (educational level, employment status, and the SF-36 social
functioning score) sufficed to generate a nearly perfect classification of the
patients. CONCLUSIONS: Heterogeneity across subjects should be taken into account
in describing the relationship between health values and health status
dimensions.
PMID- 9544593
TI - Functional status transitions and survival in HIV disease: evidence from the AIDS
Costs and Service Utilization Survey.
AB - OBJECTIVE: The authors examined the prevalence of limitations in physical
functioning in a large sample of people with human immunodeficiency virus (HIV)
infection and the patterns of change in their functional status with time.
METHODS: Patients receiving treatment for HIV infection were sampled from 26
providers in 10 cities across the United States; the analytic sample included
1,784 adults with HIV infection. Functional status was measured three times
during a 12-month period. Respondents indicated whether they were limited in
their ability to perform six activities, ranging from vigorous activities to
bathing and dressing. Responses to the six items were combined to form an index
of physical functioning. Medical records were used to determine stage of HIV
infection, and death records were used to determine vital status. Changes in
functional status during a 1-year period were assessed; correlates of change were
examined using multinomial logistic regression, with "deceased" included as an
outcome state. RESULTS: Limitation was most prevalent for vigorous activities
(55%) and least prevalent for activities of daily living (12%). For each
activity, the prevalence of limitations rose with increasing disease severity.
During 1 year, 43% of respondents did not change in functional status, whereas
42% became worse and 15% reported improved functioning. Controlling for prior
functional status, multivariate analyses showed that declines in functioning were
related to developing acquired immunodeficiency syndrome (AIDS), to prior reports
of fatigue, and to poor self-rated health. These same variables also predicted
mortality. CONCLUSIONS: Results suggest that the most prevalent types of home
care assistance needed by those with HIV disease involve help with energy
demanding activities, such as shopping, and that nonuniform patterns of change in
functioning necessitate flexible programs to meet frequently changing needs.
PMID- 9544594
TI - Employer-sponsored health insurance for chiropractic services.
AB - The use of chiropractors has increased substantially in recent years, and there
is growing scientific evidence on the effectiveness of chiropractic treatment for
common low back ailments. Despite the increased acceptance of chiropractic care,
little is known about the prevalence of chiropractic coverage in employer health
plans and the nature of such benefits when they are provided. This article
reports on the extent and composition of chiropractic insurance among workers
with employer-sponsored health insurance in 1993. The prevalence of the benefits
in employer plans was examined, as was the extent to which plans are in
compliance with state mandated benefits in this area. The authors also examined
what the actual benefits consist of and how they compare with those for physician
office visits and physical therapy.
PMID- 9544595
TI - An explanatory model of the dental care utilization of low-income children.
AB - OBJECTIVES: Factors related to the utilization of dental care by 5- to 11-year
old children from low-income households were investigated using a comprehensive
multivariate model that assessed the contribution of structure, history,
cognition, and expectations. The influence of dentist-patient interactions,
psychosocial and health beliefs, particularly fear of the dentist, on utilization
were investigated. METHODS: Children were chosen randomly from public schools,
and 895 mothers were surveyed and their children were interviewed in the home.
Utilization was studied during the 1991-1992 school year, including a 6-month
follow-up period after the interview. RESULTS: The overall utilization rate was
63.2%, and the rate for nonemergent (preventive) visits was 59.9%. Utilization
was unrelated to actual oral health status. Race and years the guardian lived in
the United States were predictive of an episode of care. Preventive medical
visits and perceived need were strong predictors of a visit to the dentist, as
were beliefs in the efficacy of dental care. Mothers who were satisfied with
their own care and oral health and whose children were covered by insurance were
more likely to utilize children's dental care. In contrast, child dental fear and
absences from school for family problems were associated with lower rates of
utilization. CONCLUSIONS: Mutable factors that govern the use of care in this
population were identified. These findings have implications for the design of
dental care delivery systems for children and their families.
PMID- 9544596
TI - SF-36 summary scores: are physical and mental health truly distinct?
AB - OBJECTIVES: Data from 536 primary care patients initiating antidepressant
treatment were used to examine the performance of the Medical Outcomes Study SF
36 Physical Component and Mental Component summary scores. METHODS: The SF-36 was
administered at baseline and readministered after 1 month and 3 months (n = 482).
RESULTS: At the baseline assessment, patients reported modest impairment on the
Physical Function, Role--Physical, Bodily Pain, and General Health Perceptions
subscales (0.10 to 0.68 standard deviations below national norms), but the
Physical Component summary (mean = 51) indicated no impairment based on a
population norm of 50. During 3 months of follow-up evaluation, the Physical
Function, Role--Physical, Bodily Pain, and General Health Perceptions subscales
all showed moderate and statistically significant improvement (range from 0.28 to
0.49 standard deviation units), whereas the Physical Component summary score was
essentially unchanged (mean = 50 at both 1-month and 3-month assessments). This
pattern of results is a natural consequence of the assumptions and methods used
to calculate these summary scores-orthogonal factor rotation and negative scoring
coefficients. CONCLUSIONS: These findings suggest caution in the interpretation
of Mental Component Summary and Physical Component Summary scores when the
condition or treatment of interest has strong effects on scales with negative
scoring coefficients (Mental Health and Role--Emotional for the Physical
Component; Physical Function, Role--Physical, and Bodily Pain for the Mental
Component).
PMID- 9544597
TI - Psychiatric morbidity and physician visits: lessons from Ontario.
AB - OBJECTIVES: The authors examine the association between psychiatric morbidity and
visits to general practitioners and family practitioners in Ontario, Canada.
METHODS: A nested set of hypotheses were posed to account for different levels of
use among persons with differing levels of psychiatric morbidity. The sample of
8,116 is drawn from a comprehensive household survey of physical and mental
health that included the UM-CIDI standardized diagnostic interview. RESULTS: The
findings suggest that persons with psychiatric disorders make more visits than
can be accounted for by sociodemographic factors, medical status, access, or by
intentional use of the general medical system for mental health treatment.
CONCLUSIONS: Psychiatric morbidity is associated with higher rates of health
service use. This effect is strongest among persons with multiple psychiatric
disorders.
PMID- 9544598
TI - An economic evaluation of home care for children with newly diagnosed diabetes:
results from a randomized controlled trial.
AB - OBJECTIVE: This study was undertaken to determine the health and cost effects of
using home care to treat newly diagnosed Type I diabetic children rather than
traditional inpatient hospital care. There had been no well-designed evaluations
of home care for such children, and very few for children with other health
conditions. METHODS: Sixty-three children seen at the Montreal Children's
Hospital were randomly assigned at diagnosis to home care or traditional
inpatient care. The children in the former group were discharged once their
metabolic condition stabilized; insulin adjustments and teaching were done in
their homes by a trained nurse. The children in the latter group remained
hospitalized for insulin adjustments and teaching. All were followed for 24
months. The cost effects were estimated using hospital and parental data.
RESULTS: Social costs were only $48 higher with home care. It had little effect
on social costs, because the increased costs of health care services with home
care ($768) were largely offset by parental cost savings ($720). Home care
improved the children's metabolic outcomes without adversely affecting their
psychosocial outcomes. CONCLUSIONS: Using home care to reduce hospital stays for
children with newly diagnosed Type I diabetes improved the children's health
outcomes without significantly increasing social costs.
PMID- 9544599
TI - Emergency Department Observation Unit versus hospital inpatient care for a
chronic asthmatic population: a randomized trial of health status outcome and
cost.
AB - OBJECTIVES: This study was designed to determine if an accelerated treatment
protocol administered to acute asthmatics presenting to a Hospital Emergency
Department Observation Unit (EDOU) can offset the need for inpatient admissions
and reduce total cost per episode of care without sacrificing patient quality of
life. METHODS: The authors used a prospective randomized controlled trial
comparing postintervention patient quality of life for EDOU care versus standard
inpatient care as measured by the standardized Medical Outcomes Study (MOS) SF-36
instrument. Other measures reported include: clinical status as measured by peak
flow rates, total cost per treatment arm using microcosting techniques, and
relapse-free survival 8 weeks after treatment. Eligible patients (n = 113) were
assigned randomly to an EDOU or inpatient care from a consecutive sample of 250
acute asthmatic patients presenting to an urban hospital emergency department who
could not resolve their acute asthma exacerbation after 3 hours of emergency
department therapy. RESULTS: Patients assigned to the EDOU had lower mean costs
of treatment (EDOU = $1,202 versus Hospital Inpatient = $2,247) and higher
quality of life outcomes after intervention in five of eight domains measured by
the MOS SF-36: Physical Functioning, Role Functioning-Emotional, Social
Functioning, Mental Health, and Vitality. No differences were found in clinical
outcomes as measured by peak flow rates or postintervention relapse-free
survival. Univariate comparative findings were re-examined and confirmed through
multivariable analysis when baseline SF-36 scores and postintervention peak
expiratory flow rates clinical status were used as covariates. CONCLUSIONS: The
study showed that the EDOU was a lower cost and more effective treatment
alternative for a refractory asthmatic population presenting to the Emergency
Department. Several baseline MOS SF-36 domains proved useful in predicting or
validating posttreatment clinical status, relapse, and total costs of care.
Outcome SF-36 domain scores were also useful in identifying patients with the
most favorable clinical, cost, and relapse rate outcomes at the study endpoint.
PMID- 9544601
TI - "Appearing twin": undercounting of multiple gestations on early first trimester
sonograms.
AB - An important role of first trimester sonography is to determine whether a
pregnancy is a singleton, twin, or higher order multiple gestation. We assessed
how frequently sonography at 5.0-5.9 weeks undercounts multiple gestations. We
identified all pregnancies at our institution since 1988 in which (1) an initial
sonogram obtained at 5.0-5.9 weeks demonstrated at least a singleton intrauterine
pregnancy and (2) a subsequent sonogram at 6.0 weeks or beyond demonstrated a
living multiple gestation. Twenty-four (11%) of 213 dichorionic twin gestations
were initially undercounted as singletons, as were six (86%) of seven
monochorionic twin gestations. Among 105 higher order multiples, 17 (16%) were
undercounted initially. All but one of the undercounted cases were scanned
transvaginally. Undercounting occurred in both natural and assisted conceptions,
and it occurred more frequently on sonograms obtained at 5.0-5.4 weeks than at
5.5-5.9 weeks (P = 0.02, Fisher's exact test). Prognosis for undercounted
multiple gestations was similar to that of correctly counted ones with respect to
several measures of pregnancy outcome, including the likelihood that all fetuses
would be delivered liveborn, gestational age at birth, and birth weight (P >
0.20, all comparisons). In conclusion, transvaginal sonography at 5.0-5.9 weeks
frequently undercounts multiple gestations. Initially undercounted multiple
gestations and those correctly counted have similar pregnancy outcomes.
PMID- 9544600
TI - Dimensions and correlates of physician work satisfaction in a midwestern city.
AB - OBJECTIVES: The purpose of this study was to examine the dimensions of physician
work satisfaction across a variety of medical specialties and practice settings.
METHODS: A modified version of the Scheckler et al survey instrument was mailed
to all physicians in Marion County, Indiana. Forty-two percent (777) of the
eligible physicians responded. Exploratory factor analysis and internal
consistency measures were used to assess the instrument's validity and
reliability. Multivariable linear regression was used to predict global and
summary scale scores. RESULTS: Four dimensions of physician work satisfaction
were identified: relationships with patients (k = 6, alpha = 0.81), autonomy in
clinical decision-making (k = 8, alpha = 0.81), office resources (k = 7, alpha =
0.87), and professional relationships (k = 5, alpha = 0.82). Most (73%) of the
physicians were satisfied with their overall practice, and the majority were also
satisfied with their income. Significant differences were observed in the sources
and magnitude of physician work satisfaction across medical specialty, practice
setting, and financial arrangement. Physicians in private practice were most
satisfied with their overall practice and office resources, whereas physicians in
health maintenance organizations (HMOs) were most satisfied with their autonomy
in clinical decision-making. Physicians not working in HMOs but having a large
percentage of patients with capitated reimbursement were not enthusiastic about
the effect of managed care on their medical practice. Among primary care
physicians, family practitioners and general internists were generally less
satisfied, and general pediatricians were generally more satisfied with most
aspects of their medical practices. CONCLUSIONS: The modified version of the
Scheckler et al instrument is a reliable and valid measure of physician work
satisfaction. Increases in the market share of managed care have differentially
affected the work satisfaction of physicians based on their medical specialty,
practice setting, and financial arrangements.
PMID- 9544603
TI - Distention of the fetal duodenum: abnormal finding?
AB - We investigated whether a fluid-filled duodenum is observed in normal fetuses. In
part 1 of the study a view in the region of the duodenum was obtained during
routine obstetric ultrasonography from 123 low-risk patients. All examinations
demonstrated a collapsed duodenum. No gastrointestinal abnormalities were found
in these infants. In part 2 of the study, 1163 fetuses (both high-risk and low
risk) were evaluated with real-time scanning, and duodenal fluid without a
"double bubble" was seen in one fetus who had a duodenal web. We conclude that a
nondistended fetal duodenum is the norm. If fetal duodenal dilation is
visualized, this may allow for earlier detection of duodenal obstructions.
PMID- 9544602
TI - Gallbladder polyps: prospective study.
AB - The aim of this study was to describe the natural history of gallbladder polyps.
Thirty-eight subjects who had been previously identified as having gallbladder
polyps in an epidemiologic study of gallstone prevalence in 627 diabetic subjects
and matched controls were followed longitudinally. Follow-up sonograms were
obtained on 33 and 22 of the 38 subjects at 2 and 5 years, respectively.
Prevalence for gallbladder polyps in this population was 6.7%, with a marked male
predominance (odds ratio 2.3). No statistical difference in prevalence was found
between diabetic subjects and nondiabetic controls. Ninety percent of the polyps
were less than 10 mm in diameter, with no polyp being larger than 12 mm. During
the follow-up period no changes suggestive of malignant transformation were
observed. In conclusion, we found that gallbladder polyps were relatively common
and that few significant changes occurred over a 5 year period. In asymptomatic
subjects in whom gallbladder polyps less than 10 mm in diameter are found
incidentally, the likelihood of malignant transformation is low.
PMID- 9544604
TI - Appendiceal ultrasonography performed by nonradiologists: does it help in the
diagnostic process?
AB - We performed a retrospective study to compare the sensitivity, specificity,
predictive value, and diagnostic accuracy of appendiceal ultrasonography
performed by unsupervised technicians during the nighttime hours with studies
performed during the day by supervised technicians. Fifty-nine percent of the 163
sonographic examinations were done during the day, and 41% were performed at
night. The sensitivity during the day (61%) was significantly higher than at
night (26%), as was the positive predictive value (93% day, 71% night). We
conclude that ultrasonography is an operator-dependent study. Its sensitivity is
so diminished when not performed by an experienced radiologist or technician that
a negative examination is not reliable.
PMID- 9544605
TI - Fetal cerebral and umbilical artery blood flow changes during pregnancy
complicated by malaria.
AB - The objectives of our study were to quantify the fetal cerebral artery and
umbilical artery blood flow changes daily during a malaria crisis in a pregnant
patient and evaluate the sensitivity and the specificity of Doppler indices for
the prediction of acute fetal distress at the end of the pregnancy. The study,
designed as a prospective and observational one, was carried out in the obstetric
department of a government hospital in French Guiana, on 23 women with
pregnancies complicated by malaria (age range, 23 +/- 5 years; primiparas, 30%);
crisis date: 30.8 +/- 2.5 weeks of gestation; start of treatment: 3.7 +/- 1.3
days after crisis started). The main measures of outcome consisted of daily
determinations of fetal Doppler indices during the crisis, evidence of fetal
distress (fetal heart rate decelerations) during labor, Apgar scores after birth,
gestational age at birth, mode of delivery, and birth weight. During the crisis
umbilical artery resistance index increased by 5 to 20% (P < 0.05), cerebral
artery resistance index decreased by 5 to 20% (P < 0.05), and CURR decreased by
10 to 35% (P < 0.01), indicating flow redistribution toward the brain. No
relationship was found between the CURR value and the following data: parasitemia
grade, parity, gestational age of the crisis, date and mode of delivery, and
fetal weight. A change in the hypoxia index (% change in CURR during the crisis x
number of days of crisis) greater than 150 was associated with abnormal fetal
heart rate in 75% of the cases, and a hypoxia index lower than 150 was associated
with normal fetal heart rate in 90% of the cases (sensitivity, 89%; specificity,
77%). Lastly, the combination (hypoxia index > 150 and CURR < 1) was associated
with abnormal fetal heart rate in 80% of the cases, and one or two of these
normal parameters were associated with normal fetal heart rate in 84.6% of the
cases (sensitivity, 80%; specificity, 84%). The CURR and the hypoxia index during
the malaria crisis can be used to predict acute fetal distress at delivery.
PMID- 9544606
TI - Sonographic analysis of gallbladder findings in Salmonella enteric fever.
AB - The purpose of this study was to analyze gallbladder sonographic findings
associated with Salmonella typhi enteric fever. Sixty-two patients with culture
positive Salmonella enteric fever were analyzed with serial sonography. The
following gallbladder sonographic findings were noted: globular gallbladder
distention (33 of 62 patients, 530%), positive sonographic Murphy sign (25
patients, 40%), pericholecystic edema or fluid (25 patients, 40%), gallbladder
wall thickening > 4 mm (21 patients, 34%), low-level nonshadowing intraluminal
echoes or sludge (nine patients, 15%), intramural linear sonolucency or striation
(eight patients, 13%), and mucosal irregularity or sloughed membrane (four
patients, 6%). Using the sonographic findings a gallbladder score was devised to
assess the severity of gallbladder changes, and the score was correlated with the
following clinical parameters--duration of fever, multidrug resistance, and
clinical outcome. An abnormal gallbladder score was noted in 37 patients (60%),
and multidrug resistance was noted in 35 of these patients (95%). The gallbladder
scores showed a strong positive correlation with the duration of fever and the
frequency of multidrug resistance. All 62 patients were treated with intensive
antibiotic therapy without any deaths.
PMID- 9544607
TI - Three-dimensional gray scale ultrasonographic imaging of the celiac axis:
preliminary report.
AB - The vessels of the celiac axis were evaluated in 16 healthy volunteers with three
dimensional gray scale ultrasonography. Sonographic volume data sets were
obtained from both sagittal and transverse planes. The visualization of specific
branches of the celiac artery (hepatic, splenic, left gastric, gastroduodenal,
left hepatic, right hepatic, right gastric) was evaluated, and each vessel was
placed in one of four categories on the basis of the appearance of the specific
vessel and image clarity (not seen, poorly seen, adequately seen, well seen).
Each vessel was evaluated on an initial two-dimensional scan and on a second scan
using the entire volume to optimize and follow the designated vessel using
rotating, referencing, and scrolling display capabilities. The ability to
manipulate an entire volume improved visualization of the selected vessels as
noted by an improved score. The proportion of vessels in the "not seen" and
"poorly seen" categories decreased from the initial scan (62.5%) to the scan
utilizing the entire volume (36%). Alternatively, the percentage of vessels in
the "adequately seen" to "well seen" categories improved from 37.50% on the
initial examination to 64% on the scans using the entire volume to depict
vascular anatomy. The optimal plane to image each vessel depended on the course
of a specific vessel. For optimal imaging of all the selected vessels, both
sagittal and transverse volume acquisitions and both sagittal and transverse
planes were needed. Three-dimensional imaging provided a new imaging plane
(coronal) that was useful in following and identifying vessels, especially those
vessels coursing in a right to left direction. Vascular variants were identified
by this technique in two of 16 subjects. Vascular imaging was improved with three
dimensional ultrasonography, and this imaging method may provide additional
assistance in decision making when evaluating abdominal vessels.
PMID- 9544608
TI - Ultrasonographic-surgical correlation of ankle tendon tears.
AB - This study evaluates the accuracy of ultrasonography in detecting ankle tendon
tears of the peroneal, posterior tibial, and flexor digitorum longus tendons
based on operative findings and clinical follow-up. A prospective study was
performed in 33 patients with clinically suspected tendon injury. Sixty-eight
tendons were evaluated sonographically. The diagnosis of an intrasubstance tear
was made when disruption of uniform tendon architecture by hypoechoic linear or
globular clefts was observed. Criteria used to diagnose complete tendon rupture
included discontinuity or gap within the tendon or complete nonvisualization of
the tendon. Treatment decisions were based on a combination of clinical
parameters and imaging studies. Twenty-six patients had the presence or absence
of tear confirmed at surgery. Five patients had a final diagnosis based on
clinical findings, and two were lost to follow-up. Of the 68 tendons evaluated
sonographically, 54 were directly inspected at surgery; 20 were found to be torn
and 34 were intact. Ultrasonography was able to identify all tears correctly with
an accuracy of 93%, a sensitivity of 100%, and a specificity of 88%. The positive
and negative predictive values were 83% and 100%, respectively. The combined
accuracy, sensitivity, and specificity of ultrasonography in detecting tendon
tears in all patients evaluated both surgically and by clinical follow-up were
94%, 100%, and 90%, respectively.
PMID- 9544609
TI - Iliotibial band friction syndrome: sonographic findings.
PMID- 9544610
TI - Congenital transverse vaginal septum: vaginal hydrosonographic diagnosis.
PMID- 9544611
TI - Prenatal ultrasonographic diagnosis of a simple umbilical hernia.
PMID- 9544612
TI - A photodetoxification mechanism of the cyanobacterial hepatotoxin microcystin-LR
by ultraviolet irradiation.
AB - When microcystin-LR was exposed to UV, three major nontoxic compounds were
formed. These compounds were identified as [4(E),6(Z)-Adda5]- and [4(Z),6(E)
Adda5]microcystin-LR, which are geometrical isomers of the Adda [3-amino-9
methoxy-2,6,8-trimethyl-10-phenyl-4(E),6(E)-decadienoic acid] moiety of
microcystin-LR, and a novel compound, tricyclo-Adda
[(2S,3S,1'R,3'S,4'S,5'R,6'R,7'R)-3-amino-5-(4',6'-dimethyl-3'-methoxy
tricyclo[5.4.0.0(1',5')]undeca-8',10'-dien-6'-yl)-2-methy l-4(E)-pentenoic acid]
containing microcystin-LR ([tricyclo-Adda5]microcystin-LR), which was formed by
[2 + 2] addition between the benzene ring and the double bond at position 6-7 of
the Adda moiety of the microcystin. The geometrical isomers were formed
reversibly, and their equilibrium constants were almost the same. [Tricyclo
Adda5]microcystin-LR was also formed reversibly and was decomposed under UV
light. These results suggest that the breakdown of microcystin-LR by UV
irradiation proceeds via [tricyclo-Adda5]microcystin-LR.
PMID- 9544613
TI - Immunochemical detection and identification of protein adducts of diclofenac in
the small intestine of rats: possible role in allergic reactions.
AB - Idiosyncratic adverse drug reactions are unpredictable, target multiple organ
systems, and often become life-threatening events. Although the causes of
idiosyncratic adverse drug reactions are not known in most cases, evidence
suggests that they may be mediated through immunological mechanisms. It is
generally thought that for a drug to lead to an immune response, it must first
become covalently bound to a carrier protein. Since most drugs are unreactive, it
is usually a reactive metabolite that is expected to form covalent adducts.
However, it is not clear why more people do not develop immune reactions against
drug-protein adducts. One possible explanation is that orally administered drugs
may lead to oral tolerance in most individuals through mechanisms similar to that
found with orally administered antigens. However, very little is known regarding
the interaction of drugs with gut-associated lymphoid tissue of the small
intestine, where oral tolerance can develop. As an initial step to test this
hypothesis, we have investigated whether diclofenac, a commonly used nonsteroidal
antiinflammatory drug, can lead to protein adducts in rat small intestine.
Diclofenac was administered to rats by gastric gavage. Immunoblot analysis of
small intestine homogenates and isolated enterocyte subcellular fractions with
drug-specific antiserum revealed 142-, 130-, 110-, and 55-kDa protein adducts of
diclofenac. The 142- and 130-kDa adducts of diclofenac were identified as
aminopeptidase N (CD13) and sucrase-isomaltase, respectively, by amino acid
sequence analyses and by their reactions with protein-specific antibodies. The
adducts were localized by immunohistochemistry and found primarily in the mid
villus and villus-tip enterocytes and also in the dome overlying Peyer's patches.
Similar adducts were detected immunochemically in villus-tip enterocytes of
animals treated with halothane or acetaminophen. These results show that
intestinal protein adducts of drugs can be formed in gut-associated lymphoid
tissue where they may lead to the down-regulation of drug-induced allergic
reactions in many individuals.
PMID- 9544614
TI - Drug-photosensitized protein modification: identification of the reactive sites
and elucidation of the reaction mechanisms with tiaprofenic acid/albumin as model
system.
AB - Certain drugs can photosensitive the formation of protein modifications, which
are thought to be responsible for the occurrence of photoallergy. In the present
work, the UV irradiation of serum albumin in the presence of tiaprofenic acid has
been studied as a model system for drug-photosensitized protein modifications.
The photolysates evidenced that His, Tyr, and Trp are the reactive sites of the
protein. The experimental results strongly suggest that formal hydrogen
abstraction from the OH or NH groups of Tyr or Trp by the excited drug is the key
photochemical process. Competition between cage escape and in cage recombination
of the resulting radical pairs governs the final outcome: protein photo-cross
linking versus drug-protein adduct formation. These findings are highly relevant
to understand the process of photohapten formation, the first event in the onset
of photoallergy.
PMID- 9544615
TI - Identification of a rat liver microsomal esterase as a target protein for
bromobenzene metabolites.
AB - The hepatotoxicity of bromobenzene and many other simple organic molecules has
been associated with their biotransformation to chemically reactive metabolites
and the subsequent covalent binding of those metabolites to cellular
macromolecules. To identify proteins targeted by bromobenzene metabolites, we
incubated [14C]bromobenzene in vitro with liver microsomes from phenobarbital
induced rats under conditions which typically led to covalent binding of 2-4 nmol
equiv of bromobenzene/mg of protein. Microsomal proteins were solubilized with
detergent, separated by chromatography and electrophoresis, and analyzed for 14C
by phosphorimaging of stained blots. Much of the radioactivity was associated
with several bands of proteins of ca. 50-60 kDa, plus another prominent band
around 70 kDa, but labeling density appeared to vary considerably overall. A
major radiolabeled protein was purified by preparative electrophoresis and
submitted to automated Edman microsequencing. Its N-terminal sequence was found
to correspond to that of a known rat liver microsomal carboxylesterase (E.C.
3.1.1.1) previously identified as a target for reactive metabolites of halothane.
The extent to which covalent modification of this protein by reactive metabolites
contributes to the production of hepatotoxic effects remains to be determined.
PMID- 9544616
TI - Immunochemical detection of hepatic cocaine-protein adducts in mice.
AB - Cocaine is capable of producing hepatic necrosis in laboratory animals and
humans. Studies in mice indicate that N-oxidative metabolism of cocaine is
required for hepatotoxicity and have suggested that toxicity may result from the
adduction of proteins by cocaine-reactive metabolites. To aid in identifying
protein targets for cocaine-reactive metabolites, an antibody was raised in
rabbits immunized with cocaine linked via the tropane nitrogen to a carrier
protein (bovine serum albumin). Hepatic proteins from cocaine-treated mice (ICR
males, 50 mg of cocaine/kg of body weight, ip) and saline-treated controls were
prepared from whole liver homogenate or following subcellular fractionation, and
Western blot analyses of hepatic proteins using this antibody were conducted
following one- and two-dimensional SDS-PAGE. Analysis of liver homogenate from
cocaine-treated mice revealed major protein targets with approximate molecular
masses of 20 kDa (pI = 6.0), 44 kDa (two proteins with pI's of 5.0 and 7.0), 52
54 kDa (pI = 4.5), and 64 kDa (pI = 5.5). These specific protein targets were
shown to be localized in the mitochondria and microsomes. Several minor bands of
immunoreactivity were also seen in mice treated with cocaine, but not in saline
treated controls. Pretreatment of mice with the P450 inhibitor SKF 525A
diminished or eliminated the formation of these cocaine-protein adducts. Liver
sections from cocaine-treated mice immunostained using the antibody indicated the
presence of cocaine-adducted proteins in the centrilobular and midzonal regions
of the lobule, corresponding to areas of hepatocyte swelling and necrosis. This
study indicates that reactive metabolites from cocaine bind to discrete proteins
in specific regions of the liver, consistent with a role for protein adduction in
cocaine hepatotoxicity.
PMID- 9544617
TI - Synthesis of enzymatically noncleavable carbocyclic nucleosides for DNA-N
glycosylase studies.
AB - Carbocyclic nucleosides have been of great interest as antiviral agents and in
studies in the area of antisense technology. The recent finding that the
replacement of a single 2'-deoxynucleoside in DNA by a carba analogue does not
alter the Watson-Crick base pairing, yet at the same time provides a chemically
and enzymatically stable "glycosidic" linkage, led us to examine this class of
compound as enzyme inhibitors of the DNA-repair enzymes involved in oxidative
damage. We now report the synthesis and incorporation into oligomeric DNA via
suitable derivatives, the carbanucleosides 8-oxo-7,8-dihydro-2'
deoxycarbainosine, 8-oxo-7,8-dihydro-2'-deoxycarbaguanosine, and 2'
deoxyaristeromycin. Aristeromycin (1) was deoxygenated at the 2'-position as
follows. Treatment of 1 with TPDSCl2 gave the 3',5'-protected derivative 3 (76%)
which on phenylthiocarbonylation at the 2'-position gave 4 in 51% yield. The
latter compound on reduction with Bu3SnH led to the 2'-deoxy derivative 5 (90%).
Benzoylation followed by deprotection with TBAF in THF then gave the desired
intermediate (6) in 65% yield. N2-Isobutyryl-8-oxo-7,8-dihydro-2'
deoxycarbaguanosine (16) was synthesized from 3-chloro-2'-deoxycarbainosine (9).
Treatment of 9, either with hydrazine followed by catalytic reduction of the 2
hydrazino derivative or with 1-(2-nitrophenyl)ethylamine followed by photolysis
of the resulting 2-substituted derivative, in both instances gave the desired 2'
deoxycarbaguanosine (12) in approximately 50% overall yield in each case.
Bromination of 12 gave 13 (90%) which, when treated with BnONa in DMSO at 65
degrees C, led to the 8-benzyloxy derivative 14 (46%). Isobutyrylation of 14
followed by catalytic reduction then afforded 16. 8-Oxo-7,8-dihydro-2'
deoxycarbainosine (23) was prepared in four steps. Bromination of 2'
deoxyaristeromycin (19) at the 8-position gave 20 (> 95%) which was converted to
the 8-benzyloxy derivative 21 (61%) using BnONa/DMSO at 80 degrees C. Reductive
debenzylation of 21 then led to 8-oxo-7,8-dihydro-2'-deoxyaristeromycin
(approximately 100%) which, when treated with adenosine deaminase, provided the
desired carbainosine derivative 23 in quantitative yield. Compounds 6, 16, and 23
were converted to their respective 5'-O-DMT, 3'-O-[(2-cyanoethoxy)-(N,N
diisopropylamino)phosphine] derivatives (8, 18, and 25) in excellent overall
yields. The latter were then used to synthesize a series of DNA oligomers by
automated procedures.
PMID- 9544618
TI - A mitomycin-N6-deoxyadenosine adduct isolated from DNA.
AB - A minor N6-deoxyadenosine adduct of mitomycin C (MC) was isolated from synthetic
oligonucleotides and calf thymus DNA, representing the first adduct of MC and a
DNA base other than guanine. The structure of the adduct (8) was elucidated using
submilligram quantities of total available material. UV difference spectroscopy,
circular dichroism, and electrospray mass spectroscopy as well as chemical
transformations were utilized in deriving the structure of 8. A series of
synthetic oligonucleotides was designed to probe the specificities of the
alkylation of adenine by MC. The nature and frequency of the oligonucleotide-MC
adducts formed under conditions of reductive activation of MC were determined by
their enzymatic digestion to the nucleoside level followed by quantitative
analysis of the products by HPLC. The analyses indicated the following: (i) (A)n
sequence is favored over (AT)n for adduct formation; (ii) the alkylation favors
the duplex structure; (iii) at adenine sites only monofunctional alkylation
occurs; (iv) the adenine-to-alkylation frequency in the model oligonucleotides
was 0.3-0.6 relative to guanine alkylation at the 5'-ApG sequence but only 0.02
0.1 relative to guanine alkylation at 5'-CpG. The 5'-phosphodiester linkage of
the MC-adenine adduct is resistant to snake venom diesterase. The overall ratio
of adenine to guanine alkylation in calf thymus DNA was 0.03, indicating that 8
is a minor MC-DNA adduct relative to MC-DNA adducts at guanine residues in the
present experimental residues in the present experimental system. However, the
HPLC elution time of 8 coincides with that of a major, unknown MC adduct detected
previously in mouse mammary tumor cells treated with radiolabeled MC [Bizanek,
R., Chowdary, D., Arai, H., Kasai, M., Hughes, C. S., Sartorelli, A. C.,
Rockwell, S., and Tomasz, M. (1993) Cancer Res. 53, 5127-5134]. Thus, 8 may be
identical or closely related to this major adduct formed in vivo. This
possibility can now be tested by further comparison.
PMID- 9544619
TI - Effect of cadmium exposure on background and anti-5 methylchrysene-1,2
dihydrodiol 3,4-epoxide-induced mutagenesis in the supF gene of pS189 in human
Ad293 cells.
AB - Cadmium is a toxic environmental contaminant that is carcinogenic in humans and
rodents. Although cadmium has proven to be mutagenic in a variety of assay
systems, exactly how cadmium achieves gentoxicity is poorly understood. To define
the mechanism(s) underlying the mutagenicity and comutagenicity of cadmium, human
Ad293 cells were exposed to subtoxic doses of the metal and transfected with
untreated or anti-5-methylchrysene-3,4-dihydrodiol 1,2-epoxide (5-MCDE)-treated
pS189 shuttle vector. Alterations in the frequency, types, and distribution of
mutations were subsequently assessed in the supF gene of pS189 that was
replicated in Ad293 cells and screened in indicator bacteria. Doses of 0.5 and 1
microM CdCl2 increased the mutation frequency of untreated pS189 by approximately
4- and 8-fold, respectively, with no apparent effect on the types of mutations
generated. In contrast, host-cell exposure to cadmium had little or no effect on
the frequency, types, or distribution of mutations generated with 5-MCDE-treated
pS189. These results indicate that cadmium increases mutagenesis of untreated
pS189 by affecting a process that is not involved in mutagenesis of the 5-MCDE
treated vector. Although it is not clear exactly how host-cell exposure to
cadmium increases background mutagenesis, presumably, the mutagenic effect does
not involve cadmium interaction with the cellular machinery used to replicate
past bulky DNA lesions.
PMID- 9544620
TI - Metabolism of the food-borne mutagen 2-amino-3,8-dimethylimidazo[4,5
f]quinoxaline in humans.
AB - The metabolism of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was
investigated in five human volunteers given a dietary equivalent of 14C-labeled
MeIQx. The amount of the dose excreted in urine ranged from 20.2% to 58.6%, with
unmetabolized MeIQx accounting for 0.7-2.8% of the dose. Five principal
metabolites were detected in urine, and four of the derivatives were
characterized by on-line UV spectroscopy and by HPLC-MS following immunoaffinity
chromatography. Two metabolites were identified as the phase II conjugates N2
(3,8-dimethylimidazo[4,5-f]quinoxalin-2-yl)sulfamic acid (MeIQx-N2-SO3(-)) and N2
(beta-1-glucosiduronyl)-2-amino-3,8-dimethylimidazo[4,5-f ]quinoxaline (MeIQx-N2
Gl). Two other metabolites were the cytochrome P450-mediated (P450) oxidation
products 2-amino-8-(hydroxymethyl)-3-methylimidazo[4,5-f]quinoxaline (8-CH2OH
MeIQx), and N2-(beta-1-glucosiduronyl)-N-hydroxy-2-amino-3,8-dimethylimidaz o[4,5
f]quinoxaline (NOH-MeIQx-N2-Gl). The latter product is a conjugate of the
genotoxic metabolite 2-(hydroxyamino)-3,8-dimethylimidazo-[4,5-f]quinoxaline
(NHOH-MeIQx). A large interindividual variation was observed in the metabolism
and disposition of MeIQx; these four metabolites and unchanged MeIQx combined
accounted for 6.3-26.7% of the total dose. The remaining principal metabolite
found in all subjects accounted for 7.6-28% of the dose. It has not been
previously identified in rodents or nonhuman primates, and its structure remains
unknown. P450-mediated ring oxidation of MeIQx at the C-5 position, a major
pathway of detoxication in rodents, was not detected in humans. Both 8-CH2OH
MeIQx formation and NHOH-MeIQx formation are catalyzed by P450 1A2 and may be
useful biomarkers of P450 1A2 activity in humans. The levels of NHOH-MeIQx-N2-Gl
found in human urine ranged from 1.4% to 10.0% of the dose, which is
significantly higher than that formed in rodents and nonhuman primates undergoing
cancer bioassays. Thus, bioactivation of MeIQx by P450-mediated N-oxidation is
extensive in humans.
PMID- 9544621
TI - Reaction of the potent bacterial mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy
2(5H)-furanone (MX) with 2'-deoxyadenosine and calf thymus DNA: identification of
fluorescent propenoformyl derivatives.
AB - The potent bacterial mutagen and drinking water disinfection byproduct 3-chloro-4
(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) was reacted with 2'-deoxyadenosine
and calf thymus DNA in aqueous solutions at neutral conditions. HPLC analyses of
the 2'-deoxyadenosine reaction mixtures showed that two previously unidentified
products were formed. The products were isolated by preparative C18
chromatography, and their structures were characterized by UV absorbance,
fluorescence emission, 1H and 13C NMR spectroscopy, and mass spectrometry. It was
concluded that in both products a propeno bridge had been incorporated between N
1 and N6 of the adenine unit. In one of the products, the propeno bridge carried
a formyl group [3-(2'-deoxy-beta-D-ribofuranosyl)-7H-8-formyl[2,1
i]pyrimidopurine++ + (pfA-dR)], and in the other the substituents consisted of a
formyl group and a chlorine atom [3-(2'-deoxy-beta-D-ribofuranosyl)-7H-8-formyl-9
chloro[2,1-i]pyrimid opurine (Cl-pfA-dR)]. These novel adducts exhibited
fluorescence in the visible region with emission maxima around 460 nm. The yields
of the products in reactions performed at pH 7.4 and 37 degrees C were about 0.03
mol %. In reaction of MX with calf thymus DNA, the adduct pfA-dR was formed and
its yield was about 0.6 adduct/10(5) nucleotides.
PMID- 9544622
TI - Structural characterization of contaminants found in commercial preparations of
melatonin: similarities to case-related compounds from L-tryptophan associated
with eosinophilia-myalgia syndrome.
AB - On-line HPLC/electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS) in
conjunction with NMR has been successfully employed to identify and structurally
characterize seven contaminants found in three different commercial preparations
of melatonin. Six of these contaminants were identified as analogues of
impurities found in contaminated L-tryptophan (an over-the-counter dietary
supplement) associated with the eosinophilia-myalgia syndrome (EMS) epidemic that
occurred in the United States during 1989. In particular, our studies identified
two compounds with MH+ = 249 to be hydroxymelatonin isomers. Four other compounds
with MH+ = 477 were identified as melatonin-formaldehyde condensation products.
These compounds are structural analogues of L-tryptophan contaminants, namely,
'peak C' and 'peak E' that were previously implicated as etiological agents
causing EMS. It has been reported that melatonin consumption has resulted in
eosinophilia in some humans taking high doses of this supplement. Although there
has not been a major outbreak of EMS-like symptoms from consumption of melatonin,
this study clearly suggests that tighter control and regulation of nutritional
supplements sold and used as drugs is necessary.
PMID- 9544623
TI - Glaucoma "valves"--truth versus myth.
PMID- 9544624
TI - Is advancing wave-like epitheliopathy distinct from whorled microcystic
dystrophy?
PMID- 9544625
TI - Decreasing blindness in developing countries.
PMID- 9544626
TI - Alternative treatment in retinoblastoma.
PMID- 9544627
TI - Second nonocular tumors in survivors of bilateral retinoblastoma: a possible age
effect on radiation-related risk.
AB - OBJECTIVE: This study aimed to investigate the relationship in bilateral
retinoblastoma survivors between the incidence of second tumors and the age when
external beam radiation (EBR) was used. DESIGN: A retrospective analysis of
patients diagnosed with retinoblastoma was performed by examining records for
background information and treatment information as well as reviewing
documentation of patients with second nonocular tumors. Two telephone interviews
were conducted for follow-up as well as inquiries directed to tumor registries
and state databases. PARTICIPANTS: The original study included 1729 patients
treated in New York and Boston; the current study includes only the 1506 patients
treated in New York. Of those, 816 patients were diagnosed with bilateral
retinoblastoma, had sufficient treatment data to be useful, and survived at least
1 year from diagnosis. MAIN OUTCOME MEASURES: The subjects were observed for
evidence of the development of second nonocular tumors. RESULTS: There was a
significant decrease in tumor-free survival among patients treated with EBR
before the age of 12 months, but no significant difference between the group
treated with EBR after the age of 12 months and the group not treated with EBR.
For tumors in the field of radiation, patients treated with early EBR showed a
significant decrease in tumor-free survival when compared to patients treated
with late EBR, with no significant difference between late radiation and no
radiation. There were no significant differences between groups for tumors out of
the field of radiation. Significant differences attributable to the use of EBR
were found only for tumors of the skull and face bones and for tumors of the soft
tissue of the head. CONCLUSIONS: The long-term effect of radiation treatment on
survivors of bilateral retinoblastoma is to increase the incidence and affect the
distribution of second tumors. However, no increased risk is observed for tumors
out of the field of radiation among patients who underwent radiation, and the
risk for tumors in the field of radiation is heavily dependent on the age at
which EBR is given and may be acceptably small to the patient after the age of 12
months.
PMID- 9544628
TI - Transpupillary thermotherapy for choroidal melanoma: tumor control and visual
results in 100 consecutive cases.
AB - OBJECTIVE: The authors evaluated the results of primary transpupillary
thermotherapy for choroidal melanoma in 100 cases. DESIGN: Prospective
nonrandomized analysis of treatment method. PARTICIPANTS: One hundred patients
with choroidal melanoma were studied. MAIN OUTCOME MEASURES: Tumor response,
ocular side effects, and visual results. RESULTS: Of 100 consecutive patients
with choroidal melanoma treated with transpupillary thermotherapy, the mean tumor
basal diameter was 7.1 mm and tumor thickness was 2.8 mm. The tumor margin
touched the optic disc in 34 eyes (34%) and was beneath the fovea in 42 eyes
(42%). Documented growth was present in 64 eyes (64%), and known clinical risks
for growth were present in all of the remaining 36 eyes (36%), with an average of
4 of 5 statistical risk factors for growth per tumor. After a mean of three
treatment sessions and 14 months of follow-up, the mean tumor thickness was
reduced to 1.4 mm. Treatment was successful in 94 eyes (94%) and failed in 6 eyes
(6%). Three patients with amelanotic tumors showed no initial response to
thermotherapy, but subsequent intravenous indocyanine green administration during
thermotherapy resulted in improved heat absorption and tumor regression to a flat
scar. The six eyes classified as treatment failures included four eyes with
tumors that showed partial or no response to thermotherapy, thus requiring plaque
radiotherapy or enucleation, and two eyes with recurrence, subsequently
controlled with additional thermotherapy. After treatment, the visual acuity was
the same (within 1 line) or better than the pretreatment visual acuity in 58 eyes
(58%) and worse in 42 eyes (42%). The main reasons for poorer vision included
treatment through the foveola for subfoveal tumor (25 eyes), retinal traction (10
eyes), retinal vascular obstruction (5 eyes), optic disc edema (1 eye), and
unrelated ocular ischemia (1 eye). Temporal location (versus nasal and superior,
P = 0.02) and greater distance from the optic disc (P = 0.04) were risks for
retinal traction. CONCLUSIONS: Transpupillary thermotherapy may be an effective
treatment for small posterior choroidal melanoma, especially those near the optic
disc and fovea. Despite satisfactory local tumor control, ocular side effects can
result in decreased vision. Longer follow-up will be necessary to assess the
impact of thermotherapy on ultimate local tumor control and metastatic disease.
PMID- 9544629
TI - The multidisciplinary management of psammomatoid ossifying fibroma of the orbit.
AB - OBJECTIVE: To discuss the multidisciplinary management of psammomatoid ossifying
fibroma (POF) of the orbit and to clarify the clinicopathologic terminology.
DESIGN: The authors present a cohort of cases of POF involving the frontal and
ethmoid sinuses and the orbit and discuss the nomenclature and literature.
PARTICIPANTS: Three patients with POF and their treatment are discussed.
INTERVENTION: Patients were worked up and treated by a multidisciplinary team
using imaging studies and histopathologic analysis. Reconstruction, if necessary,
was carried out at the time of excision or in a second-stage procedure. MAIN
OUTCOME MEASURES: In each case, the lesion was completely excised and has not
recurred. RESULTS: The diagnosis of POF was made in each case, and the patient
underwent successful resection of the tumor. CONCLUSION: The authors' experience
suggests that a multidisciplinary approach, including a radiologist, pathologist,
neurosurgeon, otolaryngologist, craniofacial surgeon, and orbital specialist, may
be useful in the evaluation and management of these lesions.
PMID- 9544630
TI - Malignant nonteratoid medulloepithelioma of the ciliary body in an adult.
AB - BACKGROUND: The authors describe a 62-year-old man with a malignant nonteratoid
malignant medulloepithelioma of the ciliary body with extension into the anterior
choroid and posterior chamber. He developed gradual loss of vision in his right
eye, and a clinical diagnosis of malignant melanoma of the ciliary body and
choroid was made. RESULTS: Histopathologic examination of the enucleated eye
showed a malignant nonteratoid medulloepithelioma of the ciliary body with
extension into the anterior choroid and posterior chamber. CONCLUSION: This
report provides clinicopathologic evidence that intraocular medulloepithelioma
can occur rarely in an adult. The lesion clinically may mimic a malignant
melanoma. The authors also summarize five previously reported cases of this
unusual lesion.
PMID- 9544632
TI - Results of laser in situ keratomileusis in different degrees of myopia.
AB - PURPOSE: This study aimed to analyze the results of laser in situ keratomileusis
(LASIK) in different degrees of myopia. MATERIAL AND METHODS: Three hundred
consecutive eyes were divided into 4 groups according to their degree of
preoperative myopia. Group I was between -3 and -6 diopters (D) (28 eyes), low
myopia. Group II was between -6.25 and -10 D (138 eyes), moderate myopia. Group
III was between -10.25 and -15 D (91 eyes), high myopia. Group IV was between
15.25 and -25.50 D (43 eyes), extremely high myopia. Patients were observed for 6
to 25 months. RESULTS: For group I, the preoperative spherical equivalent was
5.12 D +/- 0.81 standard deviation (SD), corrected visual acuity was 0.88 +/-
0.14 (SD), and keratometry was 44.09 D +/- 1.65 (SD). At the last check-up, the
spherical equivalent was -0.42 D +/- 0.98 (SD), corrected visual acuity was 0.89
+/- 0.15 (SD), keratometry was 39.11 D +/- 1.61 (SD). For group II, preoperative
spherical equivalent was -8.33 D +/- 1.24 (SD), corrected visual acuity was 0.72
+/- 0.22 (SD), keratometry was 44.34 D +/- 1.64 (SD). At last check-up, the
spherical equivalent was -0.19 D +/- 1.22 (SD), corrected visual acuity was 0.76
+/- 0.17 (SD), keratometry was 37.56 D +/- 1.90 (SD). For group III, the
preoperative spherical equivalent was -12.37 D +/- 1.49 (SD), corrected visual
acuity was 0.58 +/- 0.23 (SD), and keratometry was 44.06 D +/- 1.63 (SD). At last
check-up, spherical equivalent was -0.55 D +/- 1.63 (SD), corrected visual acuity
was 0.61 +/- 0.18 (SD), and keratometry was 35.88 D +/- 2.18 (SD). For group IV,
the preoperative spherical equivalent was -19.04 +/- 2.82 (SD), corrected visual
acuity was 0.37 +/- 0.17 (SD), and keratometry was 44.02 D +/- 1.30 (SD). At last
check-up, spherical equivalent was -1.49 D +/- 1.54 (SD), corrected visual acuity
was 0.44 +/- 0.18 (SD), and keratometry was 33.94 D +/- 2.54 (SD). CONCLUSION:
With some exceptions, LASIK results generally are acceptable and stable.
Nevertheless, the scatter of some cases shows that there is room for improvement,
even in the most sophisticated excimer software. The high regression of group I
proves the need to sample multizone software to determine whether stability is
improved. Although visual results are better in patients with lower myopia, the
patients whose eyes had higher ametropia more often showed improvement in their
visual acuity. This may be because of the greater postoperative size of the image
on the macula.
PMID- 9544631
TI - Cutaneous melanoma metastatic to the vitreous cavity.
AB - OBJECTIVE: The authors report their experience with cutaneous melanoma metastatic
to the vitreous and elaborate on the features of this entity. DESIGN: The study
design was a retrospective review. PARTICIPANTS: Three patients with four
affected eyes from cutaneous melanoma metastatic to the vitreous participated.
INTERVENTION: All three patients were white men, and their mean age was 58 years.
The previously excised cutaneous melanomas were all Clark level IV. The mean
interval from diagnosis of the primary cutaneous melanoma to vitreous metastasis
was 25 months. Ocular findings included clumps of cells arranged in sheets or
linear strands on the vitreous framework. The vitreous cells were nonpigmented in
two cases and pigmented in one case. Neovascular glaucoma was found in all three
cases. After the diagnosis of vitreous melanoma was made by cytopathologic
examination, external beam irradiation (5000 cGy) was given in all patients. MAIN
OUTCOME MEASURES: Local tumor control and survival were measured. RESULTS: At a
mean follow-up of 14 months from diagnosis of vitreous melanoma, tumor control
was achieved in only one of the four affected eyes. One eye was enucleated
because of painful neovascular glaucoma, and the other two eyes had progressive
vitreous disease. After a mean follow-up of 14 months (from ocular diagnosis),
all three patients had died. CONCLUSION: Cutaneous melanoma metastatic to the
vitreous can present with nonpigmented or pigmented cells. Neovascular glaucoma
frequently is found. External beam radiation therapy often is unsuccessful in
local tumor control, and systemic prognosis is poor.
PMID- 9544633
TI - Corneal topography of photorefractive keratectomy versus laser in situ
keratomileusis. Summit PRK-LASIK Study Group.
AB - OBJECTIVE: This study aimed to compare qualitative patterns of corneal topography
early in the postoperative course after excimer laser photorefractive keratectomy
(PRK) and laser in situ keratomileusis (LASIK) when used for the treatment of
myopia of 6.0 to 15.0 diopters. DESIGN: The study design was a prospective,
multicenter, randomized clinical trial. PARTICIPANTS: A total of 64 eyes were
treated with PRK and 54 eyes were treated with LASIK. INTERVENTION: Using the
Summit Apex excimer laser, patients received either PRK or LASIK using a single
pass, multizone excimer laser ablation. Computer-assisted videokeratography was
performed at designated postoperative examinations. MAIN OUTCOME MEASURES:
Videokeratography maps at 1 and 3 months after surgery were classified using a
standard classification scheme. The association of topography patterns to loss of
spectacle-corrected visual acuity was tested. RESULTS: At 1 month, for the PRK (n
= 60) and LASIK (n = 51) groups, respectively, 63.3% and 19.6% of eyes fell into
one of the four optically irregular groups (central island, keyhole,
semicircular, or irregularly irregular; P < 0.001). At 3 months, for the PRK (n =
49) and LASIK (n = 39) groups, respectively, 36.7% and 10.3% of eyes fell into
one of the optically irregular groups (P = 0.004). Comparing the 1- and 3-month
examination results in the PRK and LASIK groups, respectively, 19 (42%) of 45
eyes and 11 (31%) of 36 eyes had a change in topography, generally to an
optically smoother pattern. The irregular groups, taken together, were associated
with a greater tendency toward loss of spectacle-corrected visual acuity of two
or more Snellen lines (P = 0.01). There also was greater tendency toward loss of
spectacle-corrected visual acuity in the PRK group that diminished with time (P <
0.01 at 1 month, P = 0.05 at 3 months). CONCLUSIONS: After treatment for moderate
to-high myopia, LASIK topography patterns generally are more regular than are PRK
patterns. This may be a result either of masking of underlying topography
perturbations by the lamellar corneal flap, thus mitigating induced topography
changes, or differences in surface wound healing. This study suggests that more
rapid return of spectacle-corrected visual acuity found in patients treated with
LASIK may be a result of more regular topography patterns early in the
postoperative course.
PMID- 9544634
TI - Excimer laser photoastigmatic refractive keratectomy: eighteen-month follow-up.
AB - OBJECTIVE: To study the efficacy of photoastigmatic refractive keratectomy (PARK)
by the MEL 60 (Aesculap-Meditec, Jana, Germany) scanning excimer laser for the
treatment of myopic astigmatism, with follow-up of 18 months. PATIENTS AND
METHODS: One hundred and twenty-eight eyes of 102 patients with different degrees
of myopic astigmatism were treated by PARK and followed prospectively in an open
study. Ablations were performed with an MEL 60 excimer laser using an astigmatic
module. RESULTS: Mean preoperative refractive cylinder improved from a
preoperative value of -1.8 +/- 0.8 diopters (D; range, -1.0 to -6.0 D) to -0.3 +/
0.5 D (range, +1.0 to -2.5 D) at 18 months. The mean reduction in cylindrical
correction alone was 84 +/- 37% in the low astigmatism group (-1.0 to -1.5 D); 91
+/- 21% in the moderate astigmatism group (-1.75 to -2.5 D); and 75 +/- 25% in
the high astigmatism group (-2.75 to -6.0 D). One hundred and three eyes (80%) at
12 months and 100 eyes (85%) at 18 months were within +/-0.5 D of the intended
astigmatic correction, with more eyes in the low astigmatic group. One hundred
and nineteen eyes (93%) and 114 eyes (97%) at 12 and 18 months, respectively,
were within +/-1.0 D of the intended correction. Ninety-two percent to 95.7% of
the eyes in the different groups had a postoperative axis less than 10 degrees of
the preoperative and intended axis at 12 and 18 months after PARK. Uncorrected
visual acuity (UCVA) of 20/40 or better was achieved in nearly 84% of the eyes 12
and 18 months after PARK. A UCVA of 20/20 was achieved in 49% of eyes 18 months
after PARK. Ten eyes (8%) underwent reoperation at the end of 12 months.
CONCLUSIONS: The data indicate that PARK is an effective surgical tool for
correcting astigmatism, especially astigmatism of 1.0 to -2.5 D, with a success
rate of approximately 70%.
PMID- 9544635
TI - Refractive and keratometric results after the triple procedure: experience with
early and late suture removal.
AB - OBJECTIVE: The objective of this study was to determine the outcome of early and
late suture removal after the triple procedure (i.e., penetrating keratoplasty,
cataract extraction, lens implant). DESIGN AND PARTICIPANTS: The refractive and
keratometric results of 106 eyes undergoing the triple procedure were reviewed.
The target postoperative refractive error was -1 diopter (D). RESULTS: Average
length of follow-up was 40.3 months. Twenty eyes had sutures removed early (<18
months after surgery), 39 had sutures removed late (> or = 18 months after
surgery), and 47 had sutures still intact at last follow-up. A best spectacle
corrected visual acuity of 20/40 or better was achieved in 90% of eyes with
sutures removed early, 82.1% with sutures removed late, and 70.2% with sutures in
place. For all eyes, the mean spherical equivalent at last follow-up was -2.50 D,
with 75% of eyes falling between -4 and +2 D. The mean final refractive error was
-3.40 +/- 3.53 D for eyes with sutures removed early and -1.79 +/- 3.99 D for
eyes with sutures removed late. Eyes with sutures remaining had a mean final
refractive error of -0.33 +/- 2.25 D. There was an overall decrease in refractive
and keratometric astigmatism after both early and late suture removal with no
significant difference between groups. However, there was a wide range of change
with some eyes experiencing a decrease and others an increase in astigmatism.
Mean postoperative K readings increased significantly for both groups after
suture removal (final mean K, 47.00 D) but remained stable for eyes with sutures
in. CONCLUSION: The authors data suggest that the final refractive error and net
change in refractive and keratometric astigmatism after the triple procedure are
not dependent on the timing of suture removal.
PMID- 9544636
TI - Confocal microscopy of cystic disorders of the corneal epithelium.
AB - OBJECTIVE: This study aimed to describe the morphology of cystic disorders of the
corneal epithelium by confocal microscopy. DESIGN: The study design was a
prospective evaluation of confocal microscopic images of patients with cystic
corneal disorders. PARTICIPANTS: Thirteen patients (19 eyes) were included. The
corneal disorders included four patients with corneal decompensation (Fuchs'
dystrophy), five patients with epithelial basement membrane dystrophy (e.g.,
Cogan's microcystic and map-dot dystrophies), one patient with Meesmann's
dystrophy, and three patients with recurrent erosion syndrome of unknown
etiology. Confocal images of diseased corneas were compared with those of ten
normal control eyes (ten subjects). INTERVENTION: All patients were examined by
slit-lamp biomicroscopic analysis and confocal microscopic analysis (Tomey,
Erlangen-Temmenlohe, Germany). Image analysis was used to identify the corneal
epithelial structures correlated with the corresponding pathology. MAIN OUTCOMES
MEASURES: Confocal microscopy was used to assess the size, shape, light scatter,
and reflection of the cysts. RESULTS: Slit-lamp examination results showed
corneal epithelial cystic lesions in all cases. Confocal microscopy was able to
identify cystic lesions in 9 (69.2%) of 13 patients. Of the four patients in whom
lesions could not be found by confocal microscopy, three had recurrent erosion
syndrome and the other one had epithelial basement membrane dystrophy. The
confocal images were compatible with the clinical and histologic pictures of the
disease. Normal control eyes did not show any epithelial lesion, either by
biomicroscopy or confocal microscopy. CONCLUSIONS: Confocal microscopy provides
an in vivo evaluation of cystic epithelial corneal lesions. This study shows that
confocal microscopy is suitable for examining cystic lesions of the corneal
epithelium. Nevertheless, it is not as sensitive as biomicroscopy in detecting
cystic lesions in certain corneal conditions.
PMID- 9544637
TI - Long-term follow-up of patients with atopic keratoconjunctivitis.
AB - OBJECTIVE: This study aimed to review the presenting features, treatment
administered to, histopathologic findings, and complications encountered in a
cohort of patients with atopic keratoconjunctivitis. DESIGN: The study design was
a retrospective cohort series. PARTICIPANTS: The medical records of 20 patients
with atopic keratoconjunctivitis and a minimum follow-up of 3 years were
reviewed. MAIN OUTCOME MEASURES: Conjunctival and corneal complications, visual
acuity before and after surgery, and histopathologic features on conjunctival
biopsy were measured. RESULTS: Significant keratopathy developed in 70% of
patients, corneal neovascularization in 60%, fornix foreshortening in 25%, and
symblepharon in 20% during the course of their disease. Eleven patients (12 eyes)
required penetrating keratoplasty (3 for tectonic purposes and 8 for visual
rehabilitation). Vision improved by four or more lines of Snellen acuity in four
eyes, improved by two lines in two eyes, remained the same in five eyes, and
worsened by two lines in one eye after keratoplasty. Cataract surgery was
performed in seven patients (nine eyes) with vision improving by four or more
lines in six patients (eight eyes). CONCLUSION: Atopic keratoconjunctivitis is a
potentially blinding disease that may result in a poor visual outcome as a result
of corneal complications. Elective surgical intervention may be of benefit and
can be considered in those patients whose inflammation is well controlled.
PMID- 9544638
TI - Keratoconjunctivitis sicca associated with achalasia of the cardia,
adrenocortical insufficiency, and lacrimal gland degeneration:
Keratoconjunctivitis sicca secondary to lacrimal gland degeneration may parallel
degenerative changes in esophageal and adrenocortical function.
AB - OBJECTIVE/DESIGN: This study aimed to examine and describe three siblings with
alacrima, the eldest of whom had associated achalasia and adrenocortical
insufficiency. PARTICIPANTS: Three affected siblings and four age-matched control
subjects participated. INTERVENTION/MAIN OUTCOME MEASURES: The three children
underwent complete ophthalmologic examinations; computed tomographic scanning of
brain, orbit, chest, and abdomen; and measurement of serum cortisol. All three
were subjected to a short synacthen challenge. Lacrimal gland biopsies were
performed on the two younger subjects, and specimens were studied by light and
electron microscopy. RESULTS: All three children showed virtually absent tear
secretion as tested by the Schirmer test. The resulting keratopathy was most
severe in the oldest child, who developed bilateral corneal melting. The two
younger children showed interpalpebral corneal staining with rose bengal. All
three children improved after punctal occlusion. Addison's disease was present in
the oldest child. Computed tomographic scanning showed absent lacrimal and
shrunken adrenal glands in association with achalasia of the cardia in the oldest
child. The lacrimal glands were found to be reduced in size in the next eldest
child. When evaluated by electron microscopy, the lacrimal gland biopsy specimens
from the two younger children showed neuronal degeneration associated with
depletion of secretory granules in the acinar cells. CONCLUSION: In this disease,
radiologic evidence of reducing lacrimal gland size with increasing age could
represent a degenerative process. This may be paralleled by other signs and the
possibility of adrenocortical insufficiency and achalasia of the cardia should be
investigated in all children presenting with dry eyes. These children appear to
have a progressive neuronal disease.
PMID- 9544639
TI - Anterior uveitis and hypotony after intravenous cidofovir for the treatment of
cytomegalovirus retinitis.
AB - OBJECTIVE: This study aimed to describe the incidence and risk factors for the
development of anterior uveitis in patients receiving intravenous cidofovir for
the treatment of longstanding cytomegalovirus retinitis. DESIGN: The study design
was a retrospective cohort. PARTICIPANTS: Eighteen patients (30 eyes) receiving
parenteral cidofovir for the treatment of complicated cytomegalovirus retinitis
participated. MAIN OUTCOME MEASURES: The clinical response to parenteral
cidofovir; the occurrence of anterior uveitis, and the management and outcome of
patients with this complication; and the effect of cidofovir on intraocular
pressure measurements were measured. RESULTS: There was no progression or relapse
of retinitis in patients receiving intravenous cidofovir. Eight (44%) of the 18
patients developed anterior uveitis, which occurred after a median of 4 doses of
intravenous cidofovir. The median CD4+ cell count at the time of development of
iritis was 101/mm3. Patients who developed uveitis had a mean increase in serum
creatinine over baseline measurements (P = 0.05). The use of human
immunodeficiency virus type-1 (HIV-1) protease inhibitors was not different
between both groups of patients (P = 1.0). The development of anterior uveitis
and visually significant hypotony necessitated withdrawal of cidofovir in only
one patient. CONCLUSIONS: Anterior uveitis was a common complication after
intravenous cidofovir therapy. Despite the frequency of this complication,
continued treatment with intravenous cidofovir was possible in the majority of
patients. Patients with anterior uveitis after intravenous cidofovir may be
treated successfully with topical corticosteroid therapy and cycloplegic agents.
PMID- 9544640
TI - Pharmacokinetics of azithromycin in trachoma patients: serum and tear levels.
AB - OBJECTIVE: To determine the effectiveness of single-dose oral azithromycin in the
treatment of Chlamydia trachomatis through monitoring of tear and serum levels.
DESIGN: Nonrandomized, clinical trial. PARTICIPANTS: Fourteen school-age children
with active trachoma (one failed to complete the study). INTERVENTION: A single
dose of azithromycin (20 mg/kg) was administered orally to 14 patients, and tear
and serum levels were determined with high-performance liquid chromatography at
12, 24, 48, 72, 96, 120, and 144 hours after administration. MAIN OUTCOME
MEASURES: Azithromycin levels in tears and serum. RESULTS: Peak levels of 1.53
microg/ml (standard deviation [SD] +/- 0.94) and 0.15 microg/ml (SD +/- 0.04)
were obtained at 12 hours in both tears and serum, gradually decreasing over 144
hours. All patients were disease-free by 6 months. CONCLUSIONS: Levels of
azithromycin in patients with trachoma were found to be within minimum inhibitory
concentration range for Chlamydia trachomatis (0.03-0.25 microg/ml) throughout
the monitored period of 6 days.
PMID- 9544641
TI - Feeder vessel photocoagulation of subfoveal choroidal neovascularization
secondary to age-related macular degeneration.
AB - PURPOSE: This study aimed to assess the feasibility of laser photocoagulation of
feeder vessels of subfoveal choroidal neovascularization (CNV) secondary to age
related macular degeneration. PATIENTS AND METHODS: Of 170 consecutive patients
with subfoveal CNV secondary to age-related macular degeneration, feeder vessels
were detected in 37 patients by means of indocyanine green videoangiography using
a scanning laser ophthalmoscope. Dye laser photocoagulation was applied to
extrafoveal feeder vessels, with the fovea spared. RESULTS: Twenty-six (70%) of
those 37 patients had complete resolution of exudative manifestations. Persistent
or worsened manifestations were seen in 11 patients (30%) because of recurrent
CNV or persistent CNV. The visual acuity improved or stabilized in 25 patients
(68%). Ten patients (27%) had a final visual acuity of 20/40 or better and six
patients (16%) had a final visual acuity of 20/50 to 20/100. Significant factors
prognostic of the visual outcome of 20/100 or better were small CNV (2 disc areas
or smaller, Fisher's exact probability test, P = 0.041), the absence of white,
fibrous tissue in neovascular membranes (Fisher's exact probability test, P =
0.003), and the closest distance of laser burns to the center of the foveal
avascular zone (Fisher's exact probability test, P = 0.049). Preoperative visual
acuity had a significant positive correlation with final visual acuity
(Spearman's rank correlation test, P = 0.0076). CONCLUSION: Feeder vessel
photocoagulation should be considered as a treatment option for subfoveal CNV
secondary to age-related macular degeneration, because no other treatment method
has a better visual outcome.
PMID- 9544642
TI - Laser chorioretinal venous anastomosis for nonischemic central retinal vein
occlusion.
AB - OBJECTIVE: This study aimed to test the efficacy and safety of laser
chorioretinal anastomosis for central retinal vein occlusion (CRVO). DESIGN: The
study design was a consecutive case series. PARTICIPANTS: Eight eyes of eight
patients were treated. INTERVENTION: The argon laser was used in the method of
McAllister and Constable to attempt to form an anastomosis. The patients were
observed for 1 to 19 months (median, 11 months). MAIN OUTCOME MEASURES: Visual
acuity, anastomosis success, and complications were measured. RESULTS: Twenty
attempts to create anastomoses were made with 2 successful anastomoses but not of
a therapeutic type. Three patients developed rubeosis, retinal neovascularization
at the laser site, and vitreous hemorrhage. Traction retinal detachment occurred
twice and neovascular glaucoma occurred once. Secondary panretinal
photocoagulation, pars plana vitrectomy, and glaucoma seton were required in
three patients, one patient, and one patient, respectively. Visual acuity
improved in two patients independent of failed attempts at anastomosis creation
and did not improve or worsened in six patients, including the two patients with
the successfully created anastomoses. CONCLUSION: Laser chorioretinal anastomosis
for nonischemic CRVO has greater risks and less success than the initial report
suggested. Further refinement of the technique is needed before it is adopted
extensively. Even when successful, macular pigment epithelial scarring can limit
vision, implying a relatively short time window for its effective application in
the face of severe macular edema. Successful laser chorioretinal anastomosis does
not preclude development of anterior segment neovascularization.
PMID- 9544643
TI - Digital subtraction indocyanine green angiography of occult choroidal
neovascularization.
AB - OBJECTIVE: This study aimed to use a new technique for ocular imaging, digital
subtraction indocyanine green angiography (DS-ICGA), to evaluate patients with
occult choroidal neovascularization (CNV). DESIGN: The design was a cross
sectional study of patients with occult CNV. PARTICIPANTS: A total of 31 eyes of
31 patients were studied. INTERVENTION: Digital subtraction of sequentially
acquired indocyanine green angiographic frames was used to image the progression
of the dye front in eyes with occult CNV. A method of pseudocolor imaging of the
choroid was developed that allows differentiation and identification of
underlying choroidal arteries and veins. RESULTS: The DS-ICGA of occult CNV
showed consistent findings. Occult CNV was imaged with greater detail and in a
shorter period of time than with conventional indocyanine green angiography. The
fundus landmarks were retained with DS-ICGA much better than with conventional
indocyanine green angiography. CONCLUSIONS: The DS-ICGA uses time to dissect the
choroidal circulation. With DS-ICGA, occult CNV could be imaged more quickly and
in greater detail than with conventional imaging techniques. The DS-ICGA may
improve the authors ability to image, and subsequently treat, occult CNV.
PMID- 9544644
TI - Functional assessment of macular hole surgery by scanning laser ophthalmoscopy.
AB - OBJECTIVE: This study aimed to evaluate more precisely the benefit of macular
hole surgery. DESIGN: The design was a prospective study of 40 eyes in 40
patients examined before and after surgery of full-thickness macular holes with a
scanning laser ophthalmoscope (SLO). PARTICIPANTS: Forty patients with full
thickness macular holes participated. Three of the holes were stage 2, 23 were
stage 3, and 14 were stage 4. INTERVENTION: The SLO examination consisted of
macular imaging and assessment of macular function using tests produced by an
acousto-optical modulator. MAIN OUTCOME MEASURES: Preferred retinal locus (PRL)
was determined, visual acuity was measured, and scotoma was detected by
microscotometry and by the line test (modified Watzke-Allen test). RESULTS:
Anatomic success was achieved in 32 of 40 cases as assessed biomicroscopically.
On SLO examination before surgery, macular holes were seen as a central bright
round disc outlined by a thin dark edge surrounded by a dark ring and a less dark
area with ill-defined limits. In all cases, the PRL was located on the upper edge
of the hole, a scotoma was always detected inside the hole, and the line was seen
as broken in 26 of 32 cases. After surgery, the hole closed completely in 25 of
32 eyes; it disappeared from 14 of these 25 eyes and was replaced by a dark or
clear disc in 11. In the other seven successful cases, its size shrank and its
edge flattened but remained faintly visible. The hole remained unchanged in eight
cases. Eccentric PRL became central in 28 of 32 cases. The scotoma disappeared in
23 of 32 cases. The line was seen as continuous in 24 of 32 cases. Complete
anatomic and functional successes were achieved in 19 of the 32 cases of macular
hole closure. CONCLUSION: The SLO examination allows accurate assessment of the
anatomic and functional results of macular hole surgery. Various degrees of
functional success were recorded, depending on the test used.
PMID- 9544645
TI - Comparison of recombinant transforming growth factor-beta-2 and placebo as an
adjunctive agent for macular hole surgery.
AB - OBJECTIVE: This study aimed to compare the visual and anatomic results of macular
hole surgery in eyes treated with recombinant transforming growth factor-beta-2
(TGF-beta2) or placebo. DESIGN: The design was a prospective, multicenter,
randomized, double-masked, placebo-controlled clinical study. PARTICIPANTS: One
hundred thirty eyes with idiopathic macular holes of 1 year or less and a
refracted Early Treatment Diabetic Retinopathy Study visual acuity of 20/80 or
worse were treated with 1.1 microg recombinant TGF-beta2 or placebo to the
macular hole after fluid-gas exchange. INTERVENTION: The effect of recombinant
TGF-beta2 as an adjunctive agent for macular hole surgery was evaluated. MAIN
OUTCOME MEASURES: Closure of the macular hole and change in visual acuity at 3
months were measured. RESULTS: The 3-month visits were completed for 120 eyes.
The macular hole was closed at 3 months in 35 (61.4%) of 57 eyes treated with
placebo and 49 (77.8%) of 63 eyes treated with recombinant TGF-beta2 (P = 0.08).
The mean visual acuity gain was +6.4 letters in eyes receiving placebo and +8.9
letters in eyes treated with recombinant TGF-beta2 (P = 0.27). Visual acuity
improved 2 or more lines in 23 (40.4%) of 57 eyes treated with placebo and 30
(47.6%) of 63 eyes treated with recombinant TGF-beta2 (P = 0.42). Intraocular
pressure elevation greater than 30 mmHg was more common 2 weeks after surgery in
eyes treated with recombinant TGF-beta2 (P < 0.001). CONCLUSIONS: Recombinant TGF
beta2 resulted in a similar proportion of successful closure of macular holes as
placebo. There was no statistically significant visual acuity benefit with the
use of recombinant TGF-beta2 for the treatment of macular holes.
PMID- 9544646
TI - Additional procedures after the initial vitrectomy or tap-biopsy in the
Endophthalmitis Vitrectomy Study.
AB - OBJECTIVE: The study aimed to assess the frequency, indications, and outcome of
additional ocular procedures after initial treatment of vitrectomy (VIT) or tap
biopsy (TAP) for patients with endophthalmitis after cataract extraction. DESIGN:
The study design was an analysis of observational data collected as part of a
multicenter, randomized clinical trial. PARTICIPANTS: Of the 420 patients
enrolled in the Endophthalmitis Vitrectomy Study, the 148 who had additional
procedures were compared with the 272 who did not. MAIN OUTCOME MEASURES: The
types, indications, and number of additional ocular procedures were assessed. A
masked examiner measured visual acuity 9 to 12 months after study entry. RESULTS:
Within 1 week of study entry, 8% of VIT eyes and 13% of TAP eyes underwent
additional procedures, 14% for complications of the initial procedure and 86% for
worsening ocular inflammation or infection. Cultures were obtained in 33 of the
38 eyes operated on for worsening inflammation or infection and were positive in
42%. Cultures obtained from the early additional procedures were positive more
frequently in eyes with an initial TAP (71%) than in eyes with an initial VIT
(13%). Both virulence of initial microbiologic organism isolated and poor
presenting vision were risk factors for requirement of reoperation. In all cases
in which a single organism was cultured at the initial procedure, when the
reculture was positive, it was the same organism. Late additional procedures
(after 7 days) were required in 27% of patients. Visual outcome was much worse
for eyes that had an additional procedure compared to eyes that did not, and this
was especially the case for eyes that had an early additional procedure. Only 15%
of eyes that had an early additional procedure achieved 20/40 visual acuity as
compared to 57% of eyes that did not. CONCLUSION: Need for an additional
procedure was a marker of more severe disease, and patients who underwent
additional procedures achieved poorer visual acuity at final follow-up.
PMID- 9544647
TI - Hereditary external ophthalmoplegia synergistic divergence, jaw winking, and
oculocutaneous hypopigmentation: a congenital fibrosis syndrome caused by
deficient innervation to extraocular muscles.
AB - BACKGROUND: The congenital fibrosis syndrome is a hereditary form of external
ophthalmoplegia that is considered to be a primary myopathy. PURPOSE: To document
the coexistence of two distinct forms of ocular motor synkinesis in a subgroup of
patients with congenital fibrosis syndrome. METHODS: Clinical and intraoperative
examination results and extraocular muscle biopsy specimens from four patients
with congenital fibrosis syndrome were studied. RESULTS: Three patients displayed
a variant of synergistic divergence characterized by simultaneous abduction with
intorsion and depression of the synkinetically abducting eye. Three patients had
variant of Marcus Gunn jaw winking characterized by elevation of a ptotic eyelid
during mouth opening. Three patients had oculocutaneous hypopigmentation.
CONCLUSIONS: A subgroup of patients with congenital fibrosis syndrome display two
distinct synkinetic ocular movements in conjunction with oculocutaneous
hypopigmentation. The patterns of neuronal misdirection implicate a regional
innervational disturbance involving cranial nerves III through VI as the
underlying cause of diffuse hereditary ophthalmoplegia in these patients.
PMID- 9544648
TI - Comparative pupil dilation using phenylephrine alone or in combination with
tropicamide.
AB - OBJECTIVE: A prevalence survey of actinic and other eye diseases was conducted in
Nambour, Queensland, Australia, in 1992. Pupils were dilated with phenylephrine
alone for cataract identification because there were concerns that patient
discomfort, due to cycloplegia occurring with the usual dilating agents of
tropicamide and phenylephrine, may influence future compliance in an associated
intervention study. This validation study was undertaken to measure the possible
underestimation of cataract prevalence in this community study, which may have
occurred because of inadequate dilation from phenylephrine alone. DESIGN: The
study design was a repeated measures experimental design. PARTICIPANTS: Forty
seven normal subjects participated in the study. Both eyes were tested.
INTERVENTION: Pupil diameter after dilation with three drops of 10% phenylephrine
alone was compared with pupil diameter after dilation with three drops of 10%
phenylephrine together with three drops of 1% tropicamide. The two regimens were
given to the same subjects 1 week apart. Reversal was attempted with thymoxamine
hydrochloride 0.5%. MAIN OUTCOME MEASURES: Pupil diameter was assessed using a
Neitz cataract camera, and accommodation reserve also was measured. Subjects'
subjective appreciation of return of ocular function was assessed by a
questionnaire. Repeated measures analysis of variance, paired t test, McNemar's
test, and Wilcoxon signed rank test were used to analyze outcomes. RESULTS: Mean
maximum pupil size with 10% phenylephrine and 1% tropicamide was significantly
larger than pupil size after the use of 10% phenylephrine alone (F1,19 = 18.99, P
= 0.0003). However, there was no significant difference between the two dilation
regimens when comparing the proportion of subjects who dilated to 6 mm or more
(McNemar's X(2)1 = 2.7, P > 0.1). Compared with 10% phenylephrine and 1%
tropicamide, pupil diameters were significantly smaller (t46 = 16.77, P =
0.0001), and accommodation reserve greater (t46 = 4.14, P = 0.0001), 40 minutes
after reversal with thymoxamine in the group dilated with 10% phenylephrine
alone. CONCLUSION: Pupil dilation with 10% phenylephrine alone, if allowed at
least 40 minutes to act, will be as satisfactory for the identification of
cataracts in a normal population as 10% phenylephrine and 1% tropicamide and is
more acceptable because of reduced problems with glare and accommodation.
PMID- 9544649
TI - The prevalence of glaucoma in the Melbourne Visual Impairment Project.
AB - PURPOSE: The purpose of the study was to determine the prevalence of glaucoma in
Melbourne, Australia. METHODS: All subjects were participants in the Melbourne
Visual Impairment Project (Melbourne VIP), a population-based prevalence study of
eye disease that included residential and nursing home populations. Each
participant underwent a standardized eye examination, which included a Humphrey
Visual Field test, applanation tonometry, fundus examination including fundal
photographs, and a medical history interview. Glaucoma status was determined by a
masked assessment and consensus adjudication of visual fields, optic disc
photographs, intraocular pressure, and glaucoma history. RESULTS: A total of 3271
persons (83% response rate) participated in the residential Melbourne VIP. The
overall prevalence rate of definite primary open-angle glaucoma in the
residential population was 1.7% (95% confidence limits = 1.21, 2.21). Of these,
50% had not been diagnosed previously. Only two persons (0.1%) had primary angle
closure glaucoma and six persons (0.2%) had secondary glaucoma. The prevalence of
glaucoma increased steadily with age from 0.1% at ages 40 to 49 years to 9.7% in
persons aged 80 to 89 years. There was no relationship with gender. The authors
examined 403 (90.2% response rate) nursing home residents. The age standardized
rate for this component was 2.36% (95% confidence limits = 0, 4.88). CONCLUSION:
The rate of glaucoma in Melbourne rises significantly with age. With only half of
patients being diagnosed, glaucoma is a major eye health problem and will become
increasingly important as the population ages.
PMID- 9544650
TI - The role of adjunctive mitomycin C in secondary glaucoma triple procedure as
compared to primary glaucoma triple procedure.
AB - OBJECTIVE: This study aimed to investigate whether previously failed glaucoma
filtration surgery is a risk factor for filtration failure of subsequent
trabeculectomy combined with cataract surgery and to determine the role of
adjunctive mitomycin C (MMC) in the secondary glaucoma triple procedure (SGTP) as
compared to primary glaucoma triple procedure (PGTP). DESIGN: A prospective,
controlled study that was randomized with respect to assignment to adjunctive MMC
and a case-control design with respect to comparisons between SGTP and PGTP was
studied. PARTICIPANTS: The SGTP group consisted of 49 eyes of 49 consecutive
patients with primary open-angle glaucoma with a history of glaucoma filtration
surgery requiring glaucoma medical therapy and in need of cataract surgery,
randomized to adjunctive MMC (SGTP MMC subgroup of 21 eyes) and no adjunctive MMC
(SGTP control subgroup of 28 eyes). The PGTP group consisted of 49 PGTP cases
closely matched to the SGTP cases with respect to age, race, gender, MMC use, C:D
ratio, and systemic diseases. INTERVENTION: Trabeculectomy combined with
phacoemulsification and a small incision (5 x 6 mm), all polymethylmethacrylate
posterior chamber intraocular lens implantation with or without adjunctive MMC
(0.5 mg/ml for 1 minute), was performed. MAIN OUTCOME MEASURES: Surgery failure
was defined as the need of an additional intraocular procedure or the need of
more than one medication to achieve intraocular pressure control to the target
level. Intragroup and intergroup comparisons were made with respect to filtration
outcome among the SGTP and PGTP patients. RESULTS: Without adjunctive MMC,
filtration success was significantly less in SGTP than in PGTP (P = 0.03).
Adjunctive MMC significantly increased the success rate of SGTP (P = 0.02) but
not that of PGTP (P = 0.89) over the average follow-up period of 2 years.
CONCLUSIONS: Previously failed glaucoma filtration surgery is a significant risk
factor for the filtration failure of combined surgery. Intraoperative use of
adjunctive MMC significantly improves the filtration success rate of SGTP.
PMID- 9544651
TI - An ultrasound biomicroscopic study of eyes after deep sclerectomy with collagen
implant.
AB - OBJECTIVE: This study aimed to assess the natural history of eyes after deep
sclerectomy with collagen implant (DSCI), a nonperforating glaucoma-filtering
surgery. DESIGN: The design was a prospective, longitudinal, observational, and
nonrandomized study. PARTICIPANTS: Forty-five eyes of 41 patients with medically
uncontrolled open-angle glaucoma were studied. INTERVENTION: Deep sclerectomy
with collagen implant was performed. MAIN OUTCOME MEASURES: Ultrasound
biomicroscopy (UBM) of the sclerectomy site was performed 1, 2, 3, 6, 9, 12, and
18 months after surgery. The following parameters were assessed: length and
height of the collagen implant, thickness of the residual trabeculodescemetic
membrane, and bleb appearance. RESULTS: Mean intraocular pressure decreased from
a preoperative value of 26.3 +/- 3.5 mmHg (mean +/- standard deviation) to a
postoperative value of 16.6 +/- 3.1 mmHg (mean +/- standard deviation) at 18
months (P < 0.001). The UBM findings showed a subconjunctival filtration with a
nonperforated thin trabeculodescemetic membrane. In 23 eyes (51%), a hypoechoic
area in the suprachoroidal space was observed. The thickness of the
trabeculodescemetic membrane was stable throughout the study with a mean value of
0.13 mm +/- 0.02 (mean +/- standard deviation) at 18 months. The collagen implant
dissolved slowly within 6 to 9 months, leaving a tunnel in the sclera.
CONCLUSIONS: The UBM findings are consistent with intraocular pressure lowering
by aqueous filtration through the thin remaining trabeculodescemetic membrane to
an area under the scleral flap, which was maintained open by the collagen
implant. The authors speculate that aqueous humor then reached the
subconjunctival space and, eventually, was filtered through the thin scleral wall
into the suprachoroidal space. Complete resorption of the collagen implant
occurred between 6 and 9 months after surgery.
PMID- 9544652
TI - Glaucoma associated with keratoprosthesis.
AB - OBJECTIVE: This study aimed to review the authors clinical experience with
glaucoma associated with keratoprosthesis in patients with severe corneal
disease. DESIGN: The study design was a retrospective review of case series.
PARTICIPANTS: The authors studied 55 eyes in 52 patients with keratoprostheses
with follow-up of 21 +/- 16 months (range, 3-77 months). INTERVENTION: Glaucoma
drainage devices were implanted in 36 eyes (35 Ahmed valves, 1 Krupin valve) with
21 +/- 15 months' follow-up (range, 3-64 months). MAIN OUTCOME MEASURES: Clinical
outcome assessment included vision, intraocular pressure (IOP), visual fields,
optic disc appearance, and identification of complications. RESULTS: Glaucoma was
found in the majority (64%) of eyes treated with keratoprostheses, identified in
20 eyes (36%) before surgery and an additional 15 eyes (28%) after surgery. Of
the 36 eyes treated with glaucoma drainage devices, IOP was controlled in 29 eyes
(81%), with 9 eyes (25%) requiring additional medications. Continued progression
of glaucoma occurred in 5 (14%) of 36 eyes with keratoprostheses and glaucoma
drainage implants (4 of these eyes had advanced glaucomatous optic nerve damage
before surgery). There were nine nonvision-threatening complications due to
drainage implants. Compared with the preoperative visual acuity, vision was
markedly improved in 63%, unchanged in 17%, and worse in 20% of eyes after
keratoprosthesis surgery. CONCLUSION: Elevation of IOP is common in patients with
keratoprosthesis, and prevention or treatment with glaucoma drainage implants is
effective.
PMID- 9544653
TI - New isotope production company gearing up for nuclear medicine industry.
PMID- 9544654
TI - Investing in the future: MDS Nordion's Maple Medical Isotope Reactor Project.
PMID- 9544655
TI - Accelerator production of tritium as a future source of medical radionuclides.
PMID- 9544656
TI - Nuclear medicine pioneer: Joseph F. Ross. Focus and determination melded nuclear
medicine into recognized specialty.
PMID- 9544657
TI - Update on ambulatory payment classifications.
PMID- 9544658
TI - SNM house of delegates approves physician supervision guidelines; HCFA delays
physician supervision rule.
PMID- 9544659
TI - Prognostic value of myocardial perfusion imaging with exercise and/or
dipyridamole hyperemia in patients with preexisting left bundle branch block.
AB - The detection of myocardial ischemia in patients with preexisting left bundle
branch block (LBBB) remains problematic. Pharmacologic hyperemia with
dipyridamole is now used routinely in such patients for detection of significant
coronary artery disease. Little data exists on the prognostic value of cardiac
nuclear scintigraphy in patients with preexisting LBBB. The purpose of our study
was to determine the prognostic value of cardiac nuclear scintigraphy in patients
with preexisting LBBB. METHODS: Ninety-six patients with preexisting LBBB
underwent perfusion imaging between July 1987 and June 1995. Thirty-seven
underwent planar 201Tl imaging, and 59 underwent SPECT sestamibi imaging. Images
were interpreted by consensus of two experienced observers and classified as
normal, abnormal low risk and abnormal high risk. Outcomes measured were
survival, cardiac and noncardiac death. The final study group included 43 women
and 53 men, aged 42-83 (mean 66 +/- 9). Average follow-up was 3.4 +/- 2.1 yr.
RESULTS: Of the 96 patients examined, 31 had normal scans, 39 had low-risk scans
and 26 had high-risk scans. At the end of the study period, 27 patients with
normal scans were still alive while 2 suffered cardiac death and 2 suffered
noncardiac death. Of those with low-risk scans, 36 survived while 2 suffered
cardiac death and 1 suffered noncardiac death. Finally, of those with high-risk
scans, 17 survived while 8 suffered cardiac death and 1 suffered noncardiac death
(chi-square test, p = 0.020). CONCLUSION: Dipyridamole imaging is an important
prognostic tool for predicting future cardiac events in patients with preexisting
LBBB and aids in their risk stratification for coronary artery disease.
PMID- 9544660
TI - Myocardial tomography with technetium-99m-tetrofosmin during intravenous infusion
of adenosine triphosphate.
AB - The purpose of this study was to determine the biodistribution of 99mTc
tetrofosmin during intravenous infusion of adenosine triphosphate (ATP) and to
evaluate the potential diagnostic value of myocardial tomography with 99mTc
tetrofosmin during ATP infusion for the detection of coronary artery disease.
METHODS: Myocardial 99mTc-tetrofosmin imaging with ATP infusion and coronary
arteriography were performed on 65 patients with suspected coronary artery
disease. ATP was infused intravenously at a rate of 0.16 mg/kg/min for 5 min, and
370 MBq of 99mTc-tetrofosmin was injected 3 min after the start of ATP infusion.
Myocardial SPECT imags were obtained 60 min later. Then, 740 MBq of 99mTc
tetrofosmin was administered at rest, and myocardial SPECT was repeated. Regional
uptakes of 99mTc-tetrofosmin were scored from 4, normal, to 0, no activity.
Serial 5-min planar images were obtained in the anterior projection at 15, 30, 45
and 60 min after the 99mTc-tetrofosmin injection in 10 patients. Heart-to-lung
and heart-to-liver count ratios were defined from the serial planar images.
RESULTS: Adverse effects of ATP infusion were mild and transient. A heart-to-lung
ratio after ATP infusion was high even at 15 min (3.40 +/- 0.33) and gradually
increased with time. A heart-to-liver ratio after ATP was 0.53 +/- 0.40 at 15 min
and increased with time. A heart-to-liver ratio reached 0.99 +/- 0.25 (p < 0.01)
after 45 min and 1.32 +/- 0.36 (p < 0.01) after 60 min. The sensitivity and
specificity for detecting coronary artery disease by myocardial SPECT with ATP
were 89% (39/44) and 86% (18/21), respectively. CONCLUSION: This study shows the
favorable biodistribution of 99mTc-tetrofosmin after intravenous infusion of ATP.
A one-day imaging protocol of 99mTc-tetrofosmin tomography with ATP is feasible
and has high diagnostic accuracy for coronary artery disease.
PMID- 9544661
TI - The effect of coronary artery bypass surgery on brain perfusion.
AB - Coronary artery bypass grafting (CABG) is one of the major treatment methods of
coronary artery disease. CABG is an open-heart surgery that uses cardiopulmonary
bypass (CPB). After CPB, it is well known that neurological and
neuropsychological complications may occur. The purpose of this study was to
evaluate brain perfusion patterns before and after CPB and to locate brain
perfusion changes in patients with neurological and neuropsycological
complications after CPB. METHODS: Twenty-five patients who underwent open-heart
surgery (22 CABG, 3 valve replacement) and 5 patients (4 cholecystectomy, 1
periferic vascular surgery) as a control group were included in the study. The
99mTc-HMPAO injected dose was 925 MBq. Brain perfusion SPECT images were obtained
30-60 min postinjection using a dedicated triple-head brain SPECT camera. Imaging
was performed 1 wk before and 4-6 wk after surgery. Technetium-99m-HMPAO brain
SPECT slices were evaluated visually and semiquantitatively. RESULTS: None of the
patients had severe neurologic complications. Neuropsychological deficits
occurred in eight patients after CABG. Cognitive deterioration and depressive
mood occurred in five patients. Disorientation, agitation and confusion periods
were present in another two patients. Frontal hypoperfusion was found in these
patients by visual and semiquantitative evaluations (p = 0.0277) and left
parietal hypoperfusion was also present semiquantitatively (p = 0.0277). Visual
hallucinations occurred in one patient. Computed tomography of these patients was
normal. No perfusion abnormalities were observed in the patient with visual
hallucinations and in patients without symptoms after open-heart surgery nor in
the control group. Brain SPECT was repeated in two symptomatic patients 5 mo
after CABG. Frontal hypoperfusion became normal, and these patients' symptoms
disappeared. CONCLUSION: The results of this study indicate that regional
cortical hypoperfusion may occur in patients with neuropsychological
complications after CABG. Technetium-99m-HMPAO brain SPECT is a useful method to
locate and determine brain perfusion changes after CABG.
PMID- 9544662
TI - Dual spillover problem in the myocardial septum with nitrogen-13-ammonia flow
quantitation.
AB - Conventional cardiac PET modeling techniques for [13N]ammonia flow determination
do not fully account for the effects of spillover of activity from the right
ventricle (RV) onto the activity in the myocardial septum. The purpose of this
study was to investigate and to quantitatively account and correct for this
effect. METHODS: Simulations were performed to determine the error introduced by
conventional quantitation using septal time-activity curves, which only account
for left ventricle (LV) spillover. Furthermore, we explored two separate methods
to account for the dual spillover problem: direct estimation of the RV and LV
spillover fractions incorporated into the [13N]ammonia model by using the LV and
RV input functions in the fit and estimation of the relative dispersion and time
shift between the LV and RV input functions by fitting using only the LV input
function. The simulated curves were fitted using a two-compartment [13N]ammonia
model. Flow estimates from the conventional model and the models including either
of the two correction procedures were compared with canine microsphere data.
RESULTS: The influence of RV spillover on flow estimation in the septum is
determined by several parameters (e.g., dispersion between the RV and LV input
function). Depending on the value of these parameters, the septal flow may be
underestimated by 0%-30%. The applied methods for correction of the dual
spillover problem were comparable and allow for more accurate quantitation in the
septum. The canine microsphere data revealed that flow underestimation in the
septum is small but significant. CONCLUSION: Dual spillover in the myocardial
septum can introduce significant errors in the estimation of flow by the
conventional [13N]ammonia model fitting method, which does not properly account
for the RV spillover. Adjusting for the RV spillover in one of the two proposed
methods allows for more accurate quantitation of myocardial septal flow with
[13N]ammonia PET data.
PMID- 9544663
TI - Direct detection of regional myocardial ischemia with technetium-99m
nitroimidazole in rabbits.
AB - Conventional perfusion scintigraphy assesses disparities in regional myocardial
blood flow but does not directly detect hypoxic tissue. Nitroimidazoles labeled
with positron-emitting radionuclides have recently shown promise as direct
markers of myocardial hypoxia. This study evaluates a new 99mTc-labeled
nitroimidazole of potential benefit in standard myocardial scintigraphy. METHODS:
Technetium-99m-labeled nitroimidazole was administered to rabbits during the
early reperfusion phase after 10 min (Group 1) or 60 (Group 2) min of coronary
occlusion or after 10 min of a fixed coronary occlusion (Group 3). Tracer
retention at 1 hr was assessed in relation to microsphere-determined blood flow
during coronary occlusion and at tracer injection. The pattern of nitroimidazole
retention on autoradiographs was then compared with the pattern of myocardial
hypoperfusion defined by fluorescein photography to precisely define tracer
localization. RESULTS: The retention of nitroimidazole in Group 1 rabbits (brief
occlusion) was independent of both occlusion and reperfusion blood flow and was
uniformly distributed on the autoradiographs. In contrast, nitroimidazole
retention in Groups 2 and 3 increased with the severity of hypoperfusion during
the occlusion phase and precisely delineated the ischemic zone on all
autoradiographs. CONCLUSION: This 99mTc-labeled hypoxia-avid tracer delineates
severe ischemia even after blood flow to the compromised myocardium has been
restored. This class of compounds can potentially enhance the physiological
assessment of patients with ischemic heart disease.
PMID- 9544664
TI - Hypofrontality and negative symptoms in major depressive disorder.
AB - The purpose of the current study was to compare regional cerebral blood flow
(rCBF) in patients with major depressive disorder (MDD) to that of healthy
subjects and to examine the relationship between rCBF, depressive symptoms (DS)
and negative symptoms (NS) in these patients. METHODS: Eleven psychiatric
inpatients with diagnosed (MDD) and 15 normal control subjects were administered
the scale for the assessment of negative symptoms (SANS) and the modified
Hamilton rating scale for depression with items descriptive of NS excluded (HRSD
DS). Each patient underwent a SPECT scan using 99mTc-HMPAO at rest. Cortical and
subcortical regions of interest (ROIs) were symmetrically defined in each
hemisphere. Cortical-to-cerebellar perfusion ratios were established
quantitatively using ADAC software. RESULTS: Subjects in the MDD group had
significantly lower rCBF in the frontal cortex and cinglulate gyrus (MANOVA, p =
0.038) due to differences in dorsolateral prefrontal cortex bilaterally (right F
= 7.69, p = 0.01; left F = 8.41, p = 0.01) in the right orbitofrontal cortex (F =
6.79, p = 0.02) and in the cingulate gyrus (F = 5.34, p = 0.03). The MDD group
also had lower rCBF in the posterior cortical structures (MANOVA, p = 0.072),
which was due to decreased perfusion in the right parietal cortex (F = 7.54, p =
0.01). There were negative correlations between the SANS total score and rCBF in
both the left dorsolateral prefrontal cortex (Pearson's correlation coefficient r
= .-67, p < 0.05) and the left anterior temporal cortex (r = -0.71, p < 0.01) in
MDD patients. Additionally, there were positive correlations between HRSD scores
and rCBF in the left anterior temporal (r = 0.71, p < 0.01), left dorsolateral
prefrontal (r = 0.70, p < 0.01), right frontal (r = 0.82, p < 0.01) and right
posterior temporal (r = 0.74, p < 0.01) cortices. Cerebral blood flow was not
correlated with either mini-mental state examination scores or age. CONCLUSION:
This preliminary study replicates the finding of hypofrontality in MDD and
indicates that decreased perfusion is associated specifically with negative
symptom severity. These results support the hypothesis that, in MDD, negative
symptoms and symptoms of depression are distinct phenomena and underscore the
importance of negative symptom evaluation in neuroimaging studies of MDD and
other disorders.
PMID- 9544665
TI - Imaging of cerebral blood flow with technetium-99m-HMPAO and technetium-99m-ECD:
a comparison.
AB - Because 99mTc-HMPAO and 99mTc-ECD are both used for SPECT imaging of cerebral
blood flow, the question arises whether there are any differences in their
respective regional cerebral distribution. For that purpose, visual and
semiquantitative comparisons between 99mTc-HMPAO and 99mTc-ECD studies were
performed. METHODS: Seventeen patients (4 women; 13 men; age 45-89 yr; mean age
71 yr) with various neurological diseases, except acute/subacute stroke, were
investigated twice with 99mTc-HMPAO and 99mTc-ECD using a triple-headed rotating
SPECT camera. After image reorientation, the two studies were evaluated visually.
Seventy regions of interest (ROIs) were drawn manually and the same set of ROIs
was applied in both studies. Regional indices (RI) normalized to individual brain
values were calculated and first compared between two random patient groups.
Second, for all patients, RI for 70 and later for 27 regions (gained after
summing values of corresponding regions in different brain slices) were compared
by using a paired Student's t-test applying Bonferroni's correction. RESULTS:
Visual evaluation demonstrated relatively high 99mTc-ECD uptake in occipital and
comparatively low uptake in mediotemporal regions. Calculation of RI revealed
significantly higher values in the right cerebellum, brainstem, mediotemporal
regions, right basal ganglia and the thalamus in the 99mTc-HMPAO SPECT studies
and higher values in the occipital, supratemporal/inferior parietal and parietal
cortex in the 99mTc-ECD SPECT studies, respectively. CONCLUSION: Significant
differences in regional tracer distribution between 99mTc-HMPAO and 99mTc-ECD
could be detected, probably caused by different tracer kinetics. The results
indicate that direct comparisons of studies performed with 99mTc-HMPAO and 99mTc
ECD are not possible and the use of either tracer can be favorable in different
clinical questions.
PMID- 9544666
TI - Technetium-99m-ECD brain SPECT in cerebral palsy: comparison with MRI.
AB - Hypoxic brain injury is one of the major causes of cerebral palsy. Therefore,
this study was performed to evaluate cerebral perfusion impairments in these
patients using 99mTc-ECD brain SPECT. METHODS: Fifty-one patients (31 boys, 20
girls; age range 6 mo to 6 yr, 11 mo) with clinical manifestations of cerebral
palsy underwent brain SPECT after intravenous injection of 99mTc-ECD. The
clinical subtypes of cerebral palsy were spastic diplegia (n = 35), spastic
quadriplegia (n = 11), spastic hemiparesis (n = 2), choreoathetoid (n = 2) and
mixed (n = 1). Transaxial, coronal and sagittal images obtained with a brain
dedicated annular crystal gamma camera were qualitatively analyzed and compared
with the findings of magnetic resonance imaging (MRI). RESULTS: In SPECT,
thalamic hypoperfusion was seen in all patients except one (98%), followed by
hypoperfusion in the temporal lobe (52.9%, n = 27), basal ganglia (41.2%, n =
21), cerebellum (39.2%, n = 20) and extratemporal cortices (21.6%, n = 11).
However, MR imaging demonstrated thalamic abnormality in seven (13.7%), basal
ganglia in two (3.9%), extratemporal cortical defect in five (9.8%) and
cerebellar atrophy in one (1.9%). Instead, white matter changes such as
periventricular leukomalacia or ischemia (56.9%, n = 25) and thinning of corpus
callosum (49%, n = 25) were the major findings. CONCLUSION: Brain SPECT is useful
in the diagnosis of cerebral palsy and is more sensitive in the detection of
cortical, subcortical nuclei and cerebellar abnormalities. MRI is superior in the
detection of white matter changes.
PMID- 9544667
TI - Technetium-99m-HMPAO in Tourette's syndrome on neuroleptic therapy and after
withdrawal.
AB - Both decreased and increased perfusion and metabolism have been described with
PET and SPECT in different areas of the brain in patients with Gilles de la
Tourette's syndrome. The aim of this study was to define the regional cerebral
perfusion pattern in drug-free patients and the changes in perfusion with the
usual neuroleptic treatment. METHODS: A group of 13 normal control subjects and
15 unmedicated Gilles de la Tourette's syndrome patients were studied with 99mTc
HMPAO brain SPECT. Thirteen of the initial group of patients were retested on
neuroleptic treatment. A semiquantitative analysis of the images was performed.
RESULTS: Decreased perfusion in orbital and anterior medial regions of both
frontal lobes as well as in both temporal lobes was observed in the nontreated
group compared with control subjects. With treatment, a perfusion increase in
these frontal regions and in the left medial temporal cortex was observed.
CONCLUSION: Neuroleptic treatment could decrease the hyperactivity of the
dopaminergic system leading to improvement of the clinical symptoms and
reperfusion of some previously hypoperfused regions.
PMID- 9544668
TI - Cerebral perfusion imaging in asymptomatic carotid artery occlusion following gun
shot.
AB - Recognition of brain injury in asymptomatic carotid artery injuries with
conventional methods can be difficult. We present a case of angiographically
proven asymptomatic left internal carotid artery occlusion with normal CT after a
gunshot wound. The SPECT brain perfusion imaging showed mild generalized
supratentorial hypoperfusion of the bilateral cerebral cortices on the left side
and severe left temporal lobe hypoperfusion.
PMID- 9544669
TI - Cerebral perfusion impairment in a patient with toluene abuse.
AB - We report the case of a 17-yr-old man diagnosed as a toluene abuser. He had an 8
mo history of toluene inhalation exposure and was admitted to this hospital with
symptoms of auditory and visual hallucination. Magnetic resonance imaging (MRI)
revealed no structural abnormalities both on T1- and T2-weighted images, whereas
SPECT using 99mTc-ethyl cysteinate dimer (ECD) showed multifocally decreased
perfusion in the cerebral cortex, basal ganglia and thalami. Our case indicates
that SPECT detects early central nervous system injury from toluene inhalation
even when neurological examination and neuroanatomic imaging such as MRI are
normal.
PMID- 9544670
TI - In vivo detection of malignant thymic masses by indium-111-DTPA-D-Phe1-octreotide
scintigraphy.
AB - Many tumors with neuroendocrine characteristics express high amounts of
somatostatin receptors that enable in vivo imaging with [(111)In-DTPA-D-Phe1]
octreotide. In this study, we have analyzed the feasibility in detecting and
characterizing thymic masses by somatostatin receptor scintigraphy (SRS).
METHODS: Eighteen patients (13 women, 5 men, ages 18-78 yr; mean +/- s.d. = 42.1
+/- 17.6 yr) were enrolled in this study. Eleven patients were studied during
diagnosis and seven during routine follow-up. In seven patients, myasthenia
gravis was the presenting symptom. SRS was performed within 4 wk after CT and/or
MRI. Planar and tomographic images were acquired within 24 hr after the injection
of approximately 111 MBq of [(111)In-DTPA-D-Phe1]-octreotide. The scintigraphic
results were categorized according to the histologic findings. RESULTS: Histology
diagnosed 10 mixed epithelial/lymphoid thymomas (8 with prevalent epithelial
component), 2 thymic carcinomas, 1 thymic carcinoid, 1 lymphangioma and 4 thymic
hyperplasias. Two thymoma were Stage I, 3 were Stage II, 2 were Stage III and 5
were Stage IV, as was the thymic carcinoid. Indium-111-DTPA-D-Phe1-octreotide
concentrated in primary and/or metastatic sites of thymic tumors, thereby
enabling successful external gamma imaging of sites greater than 1.5 cm in size.
Tumor-to-lung (T/L) ratios were as high as 7.6-fold (range 1.7-7.6). Untreated
thymomas showed higher T/L (4.34 +/- 1.57) than treated ones (2.68 +/- 1.18). No
uptake was detectable in the four patients with benign thymic hyperplasia and the
patient with the lymphangioma. CONCLUSION: Indium-111-DTPA-D-Phe1-octreotide is
avidly concentrated within thymic tumors, but it is not concentrated by thymic
hyperplasia, which allows differential diagnosis. Thus, in patients with
myasthenia gravis, SRS may have a role in characterizing thymic masses, thereby
overcoming the limits of cross-sectional imaging modalities.
PMID- 9544671
TI - Combined fluorine-18-FDG and carbon-11-methionine PET for diagnosis of tumors in
lung and mediastinum.
AB - We evaluated the value of PET using 18F-fluorodeoxyglucose (FDG) and 11C
methionine, individually or in combination, to distinguish malignant from benign
tumors and to identify or exclude mediastinal metastases. METHODS: Seventeen
patients with a tumor in the lung or mediastinum were evaluated with 18F-FDG and
11C-methionine PET. For morphological comparison, we used CT, and all findings
were confirmed by histology of surgical resection specimens (n = 16) or by
cytology (n = 1). RESULTS: All tumors were visualized equally well with both
tracers, and there were no false-positive results. In 2 patients with a malignant
tumor, coexisting pneumonia was correctly diagnosed as an inflammatory lesion
because of its wedge-like shape. PET correctly excluded hilar invasion and
mediastinal lymph node metastases in 10 of 14 patients with primary lung tumor.
PET identified mediastinal metastases in 4 of 4 patients. CT failed to detect
mediastinal tumor spread in 2 patients and gave a false-positive reading in 2
others. Significantly higher uptake (SUV) and transport rate (slope) values were
obtained from malignant than benign lesions with both tracers. No major
differences were seen in either the levels of significance or accuracy when the
two tracers were compared. Slope values did not add further information to what
was obtained with SUV. Density correction of SUV and slope values, to avoid the
influence of surrounding air as well as tumor heterogeneity, increased these
differences somewhat. Both tracers distinguished malignant from benign lesions
with a 93% sensitivity and an accuracy of 89%-95%, but sensitivity improved to
100% when values from both tracers were combined. CONCLUSION: Fluorine-18-FDG and
11C-methionine PET visualized all tumors equally well and detected mediastinal
spread better than CT. For differentiation purposes, the problems of false
positive and false-negative PET findings could not be safely overcome in a
limited number of cases either by the use of both tracers, by the additional use
of slope values or by lesion density correction.
PMID- 9544672
TI - Iodine-131-metaiodobenzylguanidine uptake in metastatic carcinoid tumor to the
orbit.
AB - Metastatic tumor is one of several etiologies of space-occupying masses in the
orbit that accounts for 1%-13% of all orbital masses (1). In the adult patient
population, breast cancer is the most common tumor to metastasize to the orbit
followed by metastases from the lung, prostate and gastrointestinal tract (2). It
is rare for carcinoid tumors to metastasize to the eye or to the orbit. Carcinoid
tumors arise from Kulchitsky cells that originate in the neural crest.
Histologically, these tumors resemble, but are not as aggressive as,
adenocarcinomas. Most carcinoids arise in the gastrointestinal tract or the lung.
The most common site for carcinoid metastases is the liver. On anatomical imaging
studies, such as CT and magnetic resonance imaging, metastatic orbital carcinoid
tumors appear as nonspecific tumor masses. Carcinoid tumors have an affinity for
uptake of the radiopharmaceutical 131I-metaiodobenzylguanidine (MIBG) (3). We
report a case of a patient with a known carcinoid tumor who developed a left
orbital mass that demonstrated abnormal uptake of 131I-MIBG indicative of
metastatic carcinoid tumor to the orbit.
PMID- 9544673
TI - Prostate cancer abdominal metastases detected with indium-111 capromab pendetide.
AB - To provide appropriate therapy for prostate cancer, accurate staging of the
patient's disease is essential. Determination of tumor size, location,
periprostatic extension and metastatic disease in the skeleton and soft tissue
are needed to stage properly. Current diagnostic modalities may lead to
understaging in 40%-70% of prostate cancer. Detection of metastatic disease, both
at the time of initial diagnosis and in patients with suspected local recurrence,
can significantly alter the type of therapy given. Clinical studies using the
(111)In radiolabeled immunoconjugate, MAb 7E11-C5.3-GYK-DTPA (capromab
pendetide), have shown the superiority of radioimmunoscintigraphy over other
diagnostic modalities in the detection of both primary and metastatic prostate
cancer. Radioimmunoscintigraphy with capromab pendetide depends on expression of
tumor-associated antigen rather than lesion size. Earlier detection of
extraprostatic invasion and metastases by means of radioimmunoscintigraphy
provides valuable information for treatment decisions. A case of metastatic
prostate cancer in the abdomen of a patient without local disease, in which the
extent of disease was confirmed at autopsy after sudden cardiac arrest, is
presented.
PMID- 9544674
TI - Capromab pendetide imaging of occult lymph node metastases.
PMID- 9544675
TI - Fluorine-18-fluorodeoxyglucose dual-head gamma camera coincidence imaging of
recurrent colorectal carcinoma.
AB - We report our experience with coincidence detection imaging of 18F
fluorodeoxyglucose (FDG) using a dual-head gamma camera. Scanning of the pelvis
and abdomen of a patient with recurrent colorectal carcinoma showed recurrent
disease in the pelvic floor and the base of the urinary bladder and metastatic
disease in the retroperitoneal space of the pelvis. Although the tumor involving
the bladder and pelvic floor was detected by CT and magnetic resonance imaging
(MRI), metastatic spread to the retroperitoneal nodes on the left side was
detected only by 18F-FDG imaging. Based on the ultrasound, CT, MRI and
cystoscopy, a local recurrence of cancer was presumed in our patient. An
exploratory laparotomy was performed to resect the tumor in its entirety. At the
time of surgery, the retroperitoneal metastasis in the pelvis was confirmed. Had
the findings of the coincidence detection imaging study been considered, the
patient would have been spared the surgical procedure.
PMID- 9544676
TI - Accumulation of iodine-131-iodocholesterol in renal cell carcinoma adrenal
metastases.
AB - Adrenocortical scintigraphy is a useful technique for differentiating between
types of nonhyperfunctioning adrenal masses. Metastatic tumors do not normally
accumulate radioiodocholesterol and show discordant uptake on scintigrams. We
present two patients who showed accumulation of 131I-6beta-iodomethyl-19
norcholesterol (NP59) in the adrenal metastases from renal cell carcinoma. In one
patient with bilateral adrenal metastases, accumulation in the primary tumor as
well as adrenal metastases was demonstrated. The adrenal metastases in both
patients were resected and were histologically proven to be metastases from clear
cell renal carcinoma. Accumulation of NP59 in metastatic adrenal tumors, although
a very rare finding, suggests a pitfall in the differential diagnosis of adrenal
cortical tumors.
PMID- 9544677
TI - Rhenium-188(Sn)HEDP for treatment of osseous metastases.
AB - Rhenium-188 (tin) hydroxyethylidine diphosphonate [188Re(Sn)HEDP] is a new
radiopharmaceutical that localizes in skeletal metastases and emits beta
particles that may be therapeutically beneficial. METHODS: It was evaluated by in
vitro and in vivo testing in the laboratory, in animals and in humans using 188Re
from a variety of sources. It may be produced by a desk-top method developed
previously for 186Re(Sn)HEDP using 188Re produced through neutron irradiation of
either enriched 187Re or naturally occurring rhenium targets or the use of a
188W/188Re generator. RESULTS: So long as the mass of rhenium in the 188Re
perrhenate to be processed into 188Re(Sn)HEDP is at least 100 microg,
satisfactory radiochemical yields and purity may be obtained by all methods. The
188Re(Sn)HEDP has biodistribution and radiation dosimetry characteristics that
are similar to those noted previously for 186Re(Sn)HEDP and appears to result in
similar benefits and toxicities in patients with skeletal metastases. External
radiation exposure monitoring indicates that, only 4 hr after a therapeutic
administration of 1110 MBq (30 mCi) of 188Re(Sn)HEDP, average exposure rates at 1
meter from the patient would be only 0.5 mR/hr. CONCLUSION: Same-day, on-demand,
outpatient therapy of disseminated skeletal metastases appears to be feasible
with 188Re(Sn)HEDP.
PMID- 9544678
TI - Biodistribution studies on L-3-[fluorine-18]fluoro-alpha-methyl tyrosine: a
potential tumor-detecting agent.
AB - Iodine-123-alpha-methyl tyrosine has proven to be a promising SPECT agent for
imaging amino acid uptake in tumors. We developed L-[3-(18)F]-alpha-methyl
tyrosine (FMT) for PET studies. The aim of this study was to investigate its
potential use as a tumor-detecting agent by using tumor-bearing mice. METHODS: We
investigated the biodistribution in normal BALB/C mice and BALB/cA nude mice
bearing human rectal cancer cell line (LS180) until 120 min postinjection. FMT
tumor uptake at 60 min postinjection in mice with LS180 rectal cancer, RPM11788 B
cell lymphoma and MCF7 mammary cell carcinoma was assessed, and the results were
compared with 18F-fluoro-2-deoxy-D-glucose (FDG) tumor uptake. The effect of
competitive inhibition of large neutral amino acid transport system using
unlabeled L-alanine was also investigated. RESULTS: The amount of FMT in blood
fell to 1.05%ID/20 g at 60 min postinjection, whereas that in the pancreas was
15.2%ID/20 g, resulting in a high pancreas-to-blood ratio of 14.5. In other
organs, initial uptake peaked at 5 min postinjection and then declined with time.
In LS180 tumor-bearing mice, peak FMT uptake in tumor was observed at 60 min
postinjection. Tumor-to-blood and tumor-to-muscle ratios ranged from 1.60 to 2.94
and from 2.79 to 3.25 over the 120-min observation period. Tumor uptake of FMT
was clearly reduced by inhibition of the amino acid transport system. In mice
with LS180 and MCF7 tumors, FMT tumor uptake at 60 min postinjection was
significantly higher than FDG tumor uptake, whereas in RPM11788 lymphoma, uptake
of FDG was significantly higher than FMT tumor uptake. Tumor-to-blood ratios of
FMT in mice with LS180, RPMI1788 and MCF7 tumor at 60 min postinjection were
1.82, 5.88 and 3.56, respectively. CONCLUSION: FMT, like other fluorinated amino
acids, may become a promising tumor-detecting agent for PET, assuming that
efficient methods of radiosynthesis are developed.
PMID- 9544679
TI - Effects of radiolysis on yttrium-90-labeled Lym-1 antibody preparations.
AB - The physical half-life of 2.6 days and 2.2 MeV beta emissions of 90Y provide
excellent properties for radioimmunotherapy applications. However, the clinically
useful beta particles may be a source of radiation-induced damage of 90Y-labeled
immunoconjugate radiopharmaceuticals during preparation or short-term storage.
The stability of 90Y-labeled Lym-1 antibody was studied in standard radiopharmacy
conditions to establish a formulation at which radiolysis is not a problem.
METHODS: Lym-1-21T-BAD immunoconjugate intermediate was prepared according to our
standard procedure, then labeled with 90Y at 1, 2, 4 and 9.4 mCi/mg Lym-1 using
0.5 M tetramethylammonium acetate, pH 7, labeling buffer. Each mixture was
challenged in diethylenetriaminepentaacetic acid to remove nonspecifically bound
90Y. The 90Y-21T-BAD-Lym-1 products were purified by centrifuged molecular
sieving column chromatography. The radiochemical purity and immunoreactivity of
each preparation was monitored daily by high-performance liquid chromatography
(HPLC) and solid-phase radioimmunoassay, respectively, for 3 days. The
preparation at 2 mCi/mg was also formulated in 4% (wt/vol) human serum albumin
(HSA) overall and at 9.4 mCi/mg in five-fold water, 4 and 10% (wt/vol) HSA
overall; all were monitored as above. RESULTS: The monomeric quality and purity
profile of products at 1 and 2 mCi/mg were retained (> or = 80%) as was their
immunoreactivity (> or = 75%) over 3 days. The radiochemical purity and
immunoreactivity of the product at 4 mCi/mg declined to 65% and 28%,
respectively, by 3 days after preparation and in just 48 hr, the product at 9.4
mCi/mg had degraded to 21% in radiochemical purity with only 3% immunoreactivity.
The current HPLC data and earlier published chromatographic evidence did not
support a compromised radiochemical integrity of 90Y-DOTA complexes by loss of
90Y from the DOTA chelate. CONCLUSION: Radiolysis of 90Y-labeled antibody
preparations did not appear to be a problem at 90Y-21T-BAD-Lym-1 products < or =
2 mCi/mg. Human serum albumin proved to be an effective radioprotectant as the
initial 100% immunoreactivity of the product at 2 mCi/mg was retained for 72 hr.
The results underscore the need for appropriate formulations and dilutions of
clinical doses of 90Y immunopharmaceuticals immediately after manufacture.
PMID- 9544680
TI - Radiation absorbed dose estimates for indium-111-labeled B72.3, an IgG antibody
to ovarian and colorectal cancer: MIRD dose estimate report No. 18.
PMID- 9544681
TI - CuTira brachytherapy: a new combination of radioactive copper isotopes and the
hypoxic cytotoxin, tirapazamine, for targeted tumor therapy.
AB - We previously showed a significant enhancement of tirapazamine-induced
cytotoxicity and DNA damage after binding with copper. This result suggests that
conjugates of tirapazamine with radioactive copper, i.e., 64Cu and 67Cu, may
offer potential for targeted therapy of a wide range of advanced stage tumors
including a possible treatment for patients with solitary hepatocellular
carcinoma by intrahepatic arterial infusion. Major supporting considerations
include: (a) tirapazamine having a high selective toxicity against hypoxic cells;
(b) the nature of radioactive decay of these copper isotopes and obtainable high
specific activity; and (c) simple procedure for the production of copper
tirapazamine complex.
PMID- 9544683
TI - Health hazards of radiation exposure in the context of brain imaging research:
special consideration for children.
AB - This review provides information on health and biological effects of low-dose
radiation to help institutional review boards and investigators make educated
assessments of the risks of low-level radiation exposure involved in research,
particularly in children. METHODS: Studies of low-level radiation exposure with
large sample sizes and long follow-up were reviewed. To help interpret the
studies, we clarified the measures and measurement strategies of radiation
exposure and of health risks. The few large studies of risks of low-level
radiation in children have failed to detect an increased incidence of cancer.
Most studies of low-level radiation involve adults. RESULTS: The risk of
increased rates of cancer after low-level radiation exposure is not supported by
population studies of health hazards from exposure to background radiation, radon
in homes, radiation in the workplace or radiotherapy. Compared to the frequency
of daily spontaneous genetic mutations, the biological effect of low-level
radiation at the cellular level seems extremely low. Furthermore, the
potentiation of cellular repair mechanisms by low-level radiation may result in a
protective effect from subsequent high-level radiation. Studies approved by
institutional review boards in the U.S. that involve the exposure of healthy
normal children to ionizing radiation were reviewed. CONCLUSION: Health risks
from low-level radiation could not be detected above the "noise" of adverse
events of everyday life. In addition, no data were found that demonstrated higher
risks with younger age at low-level radiation exposure.
PMID- 9544682
TI - Current concepts on the diagnostic use of MIBG in children.
AB - Metaiodobenzylguanidine (MIBG) was developed 18 yr ago for scintigraphic imaging
of the adrenomedullary tumors pheochromocytoma and neuroblastoma. Many studies
have shown the usefulness of this agent for the management of patients with
neuroblastoma or pheochromocytoma, and the 131I-labeled form was recently
approved by the Food and Drug Administration for use in the U.S. This article
summarizes our current concepts on the diagnostic use of MIBG in children. The
radioisotopes available for labeling of MIBG and related compounds, the
dosimetry, metabolism and mechanisms of uptake and retention are discussed. Our
protocols for imaging both 131I-MIBG and 123I-MIBG, along with the normal
distribution of these compounds, are reviewed. The use of MIBG for the management
of neuroblastoma, and comparisons with other radiotracers available for imaging
neuroblastomas are also addressed.
PMID- 9544684
TI - Kinetic studies with iodine-123-labeled serum amyloid P component in patients
with systemic AA and AL amyloidosis and assessment of clinical value.
AB - In systemic amyloidosis, widespread amyloid deposition interferes with organ
function, frequently with fatal consequences. Diagnosis rests on demonstrating
amyloid deposits in the tissues, traditionally with histology although
scintigraphic imaging with radiolabeled serum amyloid P component (SAP) has
lately been developed as a specific noninvasive alternative. We report a detailed
analysis of the abnormal turnover of SAP in patients with systemic amyloidosis
and an assessment of its clinical value. METHODS: Iodine-123-labeled human SAP
(200 MBq) SAP was injected intravenously into 49 patients with histologically
proven systemic AA- or AL- amyloidosis and in 7 control subjects. Plasma
clearance and whole-body retention of labeled SAP were analyzed over 48 hr using
plasma sampling, whole-body gamma camera imaging and measurement of radioactivity
in the urine. The rate of SAP synthesis and interstitial exchange were
determined, and the size of the amyloid compartment was compared with clinical
estimates of whole-body amyloid load and patient survival. RESULTS: All plasma
time-activity curves were biphasic. In comparison with control subjects, patients
with amyloidosis showed significantly faster plasma disappearance [4-hr value: AA
48% +/- 18%, AL 45% +/- 15% versus 65% +/- 8% (p < 0.05)], higher total-body
retention 48 hr p.i. [AA 74% +/- 14%, AL 73% +/- 17% versus 46% +/- 15% (p <
0.01)] and especially higher extravascular retention 48 hr p.i. [AA 59% +/- 16%,
AL 58% +/- 19% versus 30% +/- 14% (p < 0.01)]. Extravascular retention correlated
with clinical estimation of the amyloid load. If extravascular retention values
in patients with AL amyloidosis were over 60%, survival was decreased (median 4
versus 23 mo, p < 0.001). Markedly increased interstitial exchange rates were
present in amyloidosis (AA 64 +/- 61, AL 50 +/- 37 versus 18 +/- 8 mg/hr),
whereas the SAP synthesis rate did not differ from the control values (AA 5.0 +/-
3.0, AL 5.5 +/- 3.2 versus 4.5 +/- 1.4 mg/hr). CONCLUSION: The presence of
systemic amyloidosis is characterized by accelerated initial clearance of 123I
SAP from the plasma and increased interstitial exchange rate and extravascular
retention. These findings reflect reversible binding of radiolabeled SAP to
amyloid deposits and provide clinically useful information for diagnosis,
monitoring of therapy and prognosis in patients with systemic amyloidosis.
PMID- 9544685
TI - Diagnostic evaluation of the adrenal incidentaloma: decision and cost
effectiveness analyses.
AB - The goal of this study was to examine the clinical and economic outcomes of
alternative diagnostic strategies for differentiating benign from malignant
adrenal masses. METHODS: We used cost-effectiveness assessment derived from
decision analysis and the economic perspective of the payer of health care
services. One-time evaluation with fine-needle aspiration (FNA) and combinations
of chemical-shift MRI, noncontrast CT, 131I-6beta-iodomethylnorcholesterol (NP
59) scintigraphy, with or without FNA, in a hypothetical cohort of 1000 patients
with incidentally discovered unilateral, nonhypersecretory adrenal masses. We
calculated and compared the diagnostic effectiveness, costs and cost
effectiveness of the alternative strategies based on estimates from published
literature and institutional charge data. RESULTS: At an assumed baseline
malignancy rate of 0.25, diagnostic utility varied from 0.31 (CT0) to 0.965 (NP
59) and diagnostic accuracy from 0.655 [noncontrast CT using a cut-off
attenuation value of > or = 0 (CT0)] to 0.983 (NP-59). The average cost per
patient per strategy ranged from $746 (NP-59) to $1745 (MRI +/- FNA). The best
and worst potential cost-to-diagnostic utility ratios were 773 (NP-59) and 2839
(CT0) and 759 (NP-59) and 1982 (MRI +/- FNA) for cost and diagnostic accuracy,
respectively. The NP-59 strategy was the optimal choice regardless of the
expected outcome examined: cost, diagnostic utility, diagnostic accuracy or cost
effectiveness. Varying the prevalence of malignancy did not alter the cost
effectiveness advantage of NP-59 over the other diagnostic modalities.
CONCLUSION: Based on available estimates of reimbursement costs and diagnostic
test performance and using reasonable clinical assumptions, our results indicate
that the NP-59 strategy is the most cost-effective diagnostic tool for evaluating
adrenal incidentalomas over a wide range of malignancy rates and that additional
clinical studies are warranted to confirm this cost-effectiveness advantage.
PMID- 9544686
TI - Radioiodine treatment outcomes in thyroid glands previously irradiated for
Graves' hyperthyroidism.
AB - Persistent or recurrent Graves' hyperthyroidism after an initial treatment dose
of radioactive iodine (RAI) is not uncommon and usually necessitates additional
administrations. The radiation sensitivity of the previously irradiated thyroid
gland is unknown but is of importance in selecting the retreatment dose. METHODS:
A retrospective analysis of patients receiving RAI for Graves' hyperthyroidism
was undertaken. A first treatment dose was given to 1076 patients, and 168 of
these patients subsequently required a second dose for persistent or recurrent
hyperthyroidism (interval between RAI treatments, 8.5 +/- 17.1 mo). RESULTS:
Paired comparisons for retreated patients showed similar RAI doses (291 +/- 95
MBq and 283 +/- 129 MBq; p = ns) and treatment intensities (3.26 +/- 1.87 MBq g(
1) and 3.48 +/- 1.88 MBq g(-1); p = ns) for first and second treatments.
Hypothyroidism occurred significantly earlier and more frequently after the first
RAI dose (p = 0.002), but there was no difference for persistent or recurrent
hyperthyroid events (p = 0.14). Multivariate regression established that the RAI
treatment number (first or second) was a significant independent determinant of
hypothyroid (p = 0.008) and combined (p = 0.001) events, whereas RAI dose and
dose intensity were not. CONCLUSION: We conclude that previous RAI treatment
failure does not lessen the chance of successfully eradicating Graves'
hyperthyroidism with additional RAI treatment. Furthermore, the previously
irradiated thyroid gland may be less susceptible to early hypothyroidism than the
RAI-naive thyroid gland.
PMID- 9544687
TI - Prediction of prognosis in peripheral facial nerve paralysis using submandibular
gland scintigraphy.
AB - In this study, we evaluated the ability of submandibular gland scintigraphy to
predict the prognosis of peripheral facial nerve paralysis. METHODS:
Submandibular gland scintigraphy was performed in 78 patients with acute
peripheral facial nerve paralysis. After injection of 180-370 MBq
[99mTc]pertechnetate, serial 1-min images were acquired for 25 min. At 15 min
after injection of radionuclide, ascorbic acid was administered intraorally to
stimulate salivary secretion. Regions of interest were set manually on both
submandibular glands, and time-activity curves were generated. The ratios of peak
count density (PCR) and washout (WR) of the affected side to the normal side were
calculated. Parameters of > or = 0.8 suggested normal affected submandibular
function and indicated a good prognosis. RESULTS: Complete recovery of facial
nerve paralysis was observed in 52 of 78 patients. The sensitivity, specificity
and accuracy of PCR for a good prognosis were 79%, 50% and 69%, and those of WR
were 85%, 77% and 82%, respectively. Positive and negative predictive values for
a good prognosis were 76% and 54% in PCR and 88% and 71% in WR, respectively.
When WR obtained within 14 days of the onset was used, positive and negative
predictive values for a good prognosis were 94% and 73%, respectively. None of
the eight patients who had values of <0.8 for both parameters within 14 days of
the onset recovered completely. CONCLUSION: Submandibular gland scintigraphy can
serve as a reliable indicator to predict the prognosis of acute peripheral facial
nerve paralysis in its early symptomatic period.
PMID- 9544688
TI - Pulmonary SPECT imaging and the stripe sign.
AB - A patient with high clinical suspicion for pulmonary embolism underwent a
diagnostic scintigraphic ventilation/perfusion scan. The planar images revealed
an unmatched perfusion defect with a stripe sign in the right middle lobe. A
stripe sign is the appearance of normally perfused tissue between the defect and
the pleural surface suggesting a nonpleural-based abnormality. SPECT images
acquired in the same study period, however, failed to demonstrate normally
perfused tissue between the defect and the pleural surface. Previous studies have
compared planar ventilation/perfusion studies with stripe sign perfusion defects
to pulmonary angiography. The results suggest that stripe sign perfusion defects
are generally not due to emboli. However, planar imaging is projectional and may
miss pleural contact in some perfusion lesions depending on the projection. In
the absence of SPECT data, the significance of the stripe sign may need to be
reassessed.
PMID- 9544689
TI - Early detection of bleomycin-induced lung injury in rat using indium-111-labeled
antibody directed against intercellular adhesion molecule-1.
AB - We have investigated whether an (111)In-labeled mouse monoclonal antibody to rat
intercellular adhesion molecule-1 ((111)In*aICAM-1) could detect lung injury
early in rats treated with bleomycin. METHODS: Rats received an intravenous
injection of either (111)In*aICAM-1 or (111)In-labeled normal mouse IgG
((111)In*nmIgG) and were imaged and killed 24 hr later. Lung injury was induced
by an intratracheal injection of bleomycin 4 or 24 hr before the rats were
killed. After death, tissue was removed and activity was measured, lungs were
cryostat-sectioned to detect the presence of ICAM-1 by immunofluorescence, and
the up-regulation of LFA-1alpha was examined on blood polymorphonuclear
leukocytes (PMNs) using fluorescence-activated cell-sorter (FACS) analysis.
RESULTS: In rats injected with (111)In*aICAM-1, the percent injected dose/organ
in lungs both at 4 and 24 hr postbleomycin increased significantly compared to
the values in either uninjured rats or rats that received (111)In*nmIgG. At 4 and
24 hr postinjury, the target-to-blood (T/B) ratio was 8/1 and 6/1, respectively.
For (111)In*nmIgG, the T/B ratio at 4 hr was 0.5/1 and 0.4/1 at 24 hr. In
(111)In*aICAM-1 rats injured at 4 or 24 hr, images could easily be distinguished
from uninjured rats. All images of (111)In*nmIgG rats showed only cardiac blood
pool and liver activity with little lung activity. Lung ICAM-1 immunofluorescence
intensity increased in the bleomycin-treated samples compared to uninjured lungs.
Expression of LFA-1alpha on PMNs increased 19% and 210% at 4 hr and 24 hr
postinjury, respectively, compared to control values. CONCLUSION: Biodistribution
and imaging data demonstrate that (111)In*aICAM-1 can detect early acute
bleomycin-induced lung injury. Immunofluorescence and FACS data suggest that
(111)In*ICAM-1 uptake is a specific process. This antibody has potential as an
early radionuclide detector of acute inflammations.
PMID- 9544690
TI - Noninvasive methods for quantitating blood time-activity curves from mouse PET
images obtained with fluorine-18-fluorodeoxyglucose.
AB - The mouse model is currently being explored for various applications with PET
imaging. Low resolution of current animal scanners relative to mouse size leads
to difficulty in quantitating data from mouse PET images. We have, therefore,
investigated methods for determining blood time-activity curves (TACs) from mouse
PET studies done with fluorine-18-fluorodeoxyglucose (FDG). METHODS: Eight mice
were fasted, the tail vein was injected with 150-300 microCi of FDG and dynamic
images were acquired with a CTI/Siemens (Knoxville, TN) animal tomograph for 64.5
min. Concurrently, 11-14 left ventricle (LV) blood samples were drawn directly
from the LV chamber. Organ TACs were obtained by drawing circular regions of
interest (ROIs) of various sizes on images of the heart, liver and brain. For
each mouse, the FDG model parameter K = (K1 x k3)/(k2 + k3) was estimated by a
Patlak algorithm with various estimates of the blood TAC and, as a reference
tissue TAC, the brain TAC. RESULTS: Most partial-volume-corrected heart ROI TACs
overestimated the LV samples. Blood TACs from heart images produced statistically
different estimates of K than did the LV samples. The liver image-derived blood
TACs yielded estimates of K that were comparable to those yielded by the LV
samples. Estimates of K determined with two directly sampled LV points in
conjunction with the liver image-derived TAC were not statistically different
from the estimates obtained with the LV samples. The size and location of ROIs on
images of the liver minimally affected the TACs. CONCLUSION: We have shown that
it is experimentally possible to obtain a blood TAC from mouse studies by
repeatedly sampling from the LV. We have also shown that images of the liver can
be used to reliably estimate the blood TAC. Future FDG PET studies with the mouse
model will benefit from this demonstrated ability to noninvasively quantitate
blood TACs directly from FDG PET images.
PMID- 9544691
TI - Artificial neural network as a tool to compensate for scatter and attenuation in
radionuclide imaging.
AB - This study investigates the ability of artificial neural networks (ANN) to
simultaneously correct for attenuation and Compton scattering in scintigraphic
imaging. METHODS: Three sets of experiments are conducted using images of
radioactive sources with various shapes and distributions in a homogeneous
medium. Numerical Monte Carlo simulations and physical phantom acquisitions of
radioactive geometric sources provide the basic material for correction. Our
method is based on the following assumptions: information needed to correct for
scattering can be extracted from the energy spectrum at each pixel without any
assumption concerning the source distribution, and two diametrically opposed
energy spectrum acquisitions yield enough information on the source location in
the diffusing medium for simultaneous correction for attenuation and scattering.
RESULTS: Qualitative and quantitative evaluations of scatter correction by ANN
demonstrate its ability to perform scatter correction from the energy spectra
observed in each pixel. By using the energy spectra of incident photons detected
in two diametrically opposed images, multilayer neural networks are able to
perform a proper restitution of projection images without any assumption on
geometry or position of radioactive sources in simple geometric cases. ANN
corrections compare favorably to those provided by five of the most popular
methods. A satisfying correction of both scatter and attenuation is observed for
a human pelvis scan obtained during routine clinical practice. CONCLUSION: An ANN
is an efficient tool for attenuation and Compton scattering in simple model
cases. The results obtained for routine scintigrams in a much more complex
situation are strong incentives for performing further studies.
PMID- 9544692
TI - Supercomputer description of human lung morphology for imaging analysis.
AB - A supercomputer code that describes the three-dimensional branching structure of
the human lung has been developed. The algorithm was written for the Cray C94. In
our simulations, the human lung was divided into a matrix containing discrete
volumes (voxels) so as to be compatible with analyses of SPECT images. The matrix
has 3840 voxels. The matrix can be segmented into transverse, sagittal and
coronal layers analogous to human subject examinations. The compositions of
individual voxels were identified by the type and respective number of airways
present. The code provides a mapping of the spatial positions of the almost 17
million airways in human lungs and unambiguously assigns each airway to a voxel.
Thus, the clinician and research scientist in the medical arena have a powerful
new tool to be used in imaging analyses. The code was designed to be integrated
into diverse applications, including the interpretation of SPECT images, the
design of inhalation exposure experiments and the targeted delivery of inhaled
pharmacologic drugs.
PMID- 9544693
TI - Inducible interleukin 4 (IL-4) production and mRNA expression following exposure
of mice to chemical allergens.
AB - Previous investigations have indicated that different classes of chemical
allergen provoke discrete immune responses in mice characterized by the
development of selective cytokine secretion patterns by draining lymph node
cells. It was found that, in mice exposed chronically to chemical respiratory
allergens, lymph node cells produced high levels of mitogen-inducible interleukin
4 (IL-4), a cytokine necessary for the development of IgE antibody responses. In
contrast, exposure of mice to contact allergens resulted in only low levels of IL
4 production. The studies described here were conducted to determine whether
differentially induced expression of IL-4 messenger RNA was independent of the
need for mitogen stimulation, unlike secretion of IL-4 protein. Mice were exposed
to concentrations of trimellitic anhydride (TMA), a respiratory allergen, or to
2,4-dinitrochlorobenzene (DNCB), a contact allergen, under conditions of
equivalent immunogenicity and where the former, but not the latter, resulted in
significant production of mitogen-inducible IL-4 protein. The steady state levels
of IL-4 mRNA in draining lymph nodes were measured by reverse transcription
polymerase chain reaction after a single or repeated daily application of the
test chemical to the ears of chronically sensitized mice. Expression of mRNA for
IL-4 was evaluated relative to the expression of a housekeeping gene,
glyceraldehyde 3-phosphate dehydrogenase. Both chemicals elicited increased
steady state levels of IL-4 mRNA by draining lymph node cells compared with
vehicle-treated and naive controls. However, using two different treatment
protocols, a chronic and an abbreviated chronic protocol and at all times
examined, the elevation in IL-4 mRNA steady state levels induced by TMA was
greater than that observed with DNCB. These data provide further support for the
differential stimulation by contact and respiratory chemical allergens of
cytokine secretion patterns in mice and demonstrate that the divergent production
of IL-4 in response to these classes of allergen is at least partly
transcriptionally regulated.
PMID- 9544695
TI - Hepatotoxicity of the drinking water disinfection by-product, dichloroacetic
acid, in the medaka small fish model.
AB - Recent studies have shown that dichloroacetic acid (DCA), a by-product of
chlorination of public water supplies, is carcinogenic to both rats and mice.
However, conflicting data have left the mechanism of DCA carcinogenicity, vital
to assessment of human health risk, unclear. Elucidation of this mechanism in
another animal model at a different phyletic level than rodents would advance the
risk assessment process for government agencies concerned with regulation and
provision of safe drinking water. The Japanese medaka (Oryzias latipes), a well
characterized small fish model, is being used increasingly for carcinogenicity
testing because of its low cost, ease of maintenance and carcinogen sensitivity.
In this study, 6-week-old medaka were exposed to diethylnitrosamine (DEN, a known
initiator), followed by continuous exposure to 0.5 or 2.0 g/l DCA in the ambient
water, over a 4 week period. At both exposure concentrations, changes in the
liver included marked hepatocellular cytoplasmic vacuolation, cytomegaly,
karyomegaly, nuclear atypia and multifocal areas of hepatocellular necrosis and
loss as early as week two of DCA exposure. The majority of the hepatocellular
cytoplasmic vacuoles were shown by periodic acid Schiff (PAS) staining to contain
large amounts of glycogen. These elevated glycogen levels may reflect a
disruption in the enzyme pathways for glycolysis. The total cellular changes seen
in this short-term exposure regimen are compatible with preneoplastic changes
seen in rats and mice exposed to DCA. The results of this study strengthen the
role of the Japanese medaka as a suitable species in carcinogenicity testing as
well as its implementation in the risk assessment process for DCA across several
phyletic levels.
PMID- 9544694
TI - Effects of 2-amino-7-phosphonohepatanoic acid, melatonin or NG-nitro-L-arginine
on cyanide or N-methyl-D-aspartate-induced neurotoxicity in rat cortical cells.
AB - When cortical neuronal cells were exposed to potassium cyanide (0.01, 0.05, 0.1,
0.5, or 1.0 mM) or N-methyl-D-aspartate (NMDA: 0.005, 0.01, 0.05, 0.1, or 0.2 mM)
for 24 h at 37 degrees C in a 95% air and 5% CO2 environment, lactate
dehydrogenase (LDH) efflux into the extracellular fluid from the cortical cells
was significantly increased in a concentration dependent manner and morphological
changes were observed. The increased LDH efflux and the morphological changes in
cortical cells induced by potassium cyanide or NMDA were blocked by co-exposure
to 2-amino-7-phosphonoheptanoic acid (AP7: 1.0 mM), a selective antagonist of the
NMDA receptor, melatonin (1.0 mM), a potent hydroxyl and peroxyl radical
scavenger, or NG-nitro-L-arginine (1.0 mM), an inhibitor of nitric oxide (NO)
synthase. These results suggest that activation of NMDA receptor and NO synthase
and/or free radical formation may contribute to the development of neurotoxicity
induced by cyanide or NMDA.
PMID- 9544696
TI - The effect of heptachlor, a chlorinated hydrocarbon insecticide, on p53 tumor
suppressor in human lymphocytes.
AB - Previous studies have shown that heptachlor, a chlorinated hydrocarbon
insecticide, is a liver tumor promoter in rats and mice and induces tumor
promoting-like alterations in human myeloblastic leukemia cells. The nature of
tumor promotion is multifaceted and has recently been shown to include
suppression of programmed cell death (apoptosis) as a mechanism by which a tumor
promoter can prolong cell viability. The ability of tumor promoters to suppress
apoptosis prompted us to address the question of whether heptachlor is capable of
effecting the expression of genes involved in lymphocyte apoptosis, in
particular, the p53 tumor suppressor gene. Experiments with a CEM x 174 cell
line, a hybrid of human T and B cells, revealed that heptachlor downregulated p53
gene expression at the post-transcriptional level without changing levels of mRNA
in the cells. The heptachlor-induced reduction in the basal levels of expression
of this gene was both in a concentration and time-dependent manner.
PMID- 9544697
TI - Momordica charantia (Bitter Gourd) peel, pulp, seed and whole fruit extract
inhibits mouse skin papillomagenesis.
AB - The present study was designed to elucidate the inhibitory potential of Momordica
charantia (Bitter Gourd) peel, pulp, seed and whole fruit extract on mouse skin
papillomagensis with the modulatory influence of biotransformation system
enzymes. Topical application of Momordica whole fruit extract (100 microl/animal
per day) during the peri-initiation stage (1 week before and 2 weeks after
initiation) by 7,12-dimethylbenz[a]anthracene (DMBA) and/or during the tumor
promotion stage reduced the (i) tumor burden to 4.26, 3.72 and 3.11 (positive
control value: 5.42); (ii) cumulative number of papillomas to 81, 67 and 53
(positive control value: 103); and (iii) percent incidence of mice bearing
papillomas to 100, 94 and 94, respectively (positive control value: 100). In a
comparison of the anticarcinogenic efficacy of Momordica peel, pulp, seed and
whole fruit extract (100 microl/animal per day), after topical treatment during
the peri-initiation and during the tumor promotion stage, revealed the modulation
of the (i) tumor burden (tumors/mouse) to 3.06, 3.61, 3.17 and 3.11; (ii)
cumulative number of papillomas to 49, 65, 54 and 53; and (iii) percent incidence
of mice bearing papillomas to 84, 100, 94 and 94, respectively. Significant
elevation in the sulfhydryl (-SH) level was observed in the liver and skin
tissues by the topical treatment of Momordica peel, pulp, seed and whole fruit
extract. Elevation in the hepatic levels of cytosolic glutathione S-transferase
(GST) and microsomal cytochrome b, was also observed by the topical treatment of
Momordica peel, seed and whole fruit extract. The results suggest the maximum
chemopreventive potential is in the Momordica peel. Equivocal efficacy is in the
Momordica seed and whole fruit extract. Biotransformation system enzymes may be
the cause of this reduced papillomagenesis.
PMID- 9544698
TI - Effect of chronic poisoning with aluminum on the renal handling of phosphate in
the rat.
AB - The effects of aluminum on renal function and phosphate handling were studied
using clearance techniques in chronically-intoxicated rats. Rats were given
aluminum hydroxide (80 mg/kg b.w., i.p.), three times per week during 6 months.
The phosphate tubular transport capacity was evaluated by determining the maximum
tubular transport (TmRPi) and the fractional excretion of phosphate (FE% Pi)
during the infusion of phosphate solutions with increasing concentrations (0, 9,
18, 33 mM). Parathyroid gland function was studied using indirect methods:
calcemia recovery after EDTA administration and the nephrogenic excretion of cAMP
as indicative of renal PTH actions, by RIA. The systemic acid base status was
determined and food intake and rat growth were controlled in both groups. No
changes were observed in the renal function. Pi reabsorption values per ml
glomerular filtration rate (TRPi/GFR microg/ml) for different Pi plasmatic
concentrations were distributed following a saturation curve compatible with a
saturation kinetics. Aluminum increased TmRPi/GFR in treated animals (T) 76+/-4
as compared with control animals (C) 57+/-7 microg/ml, without a statistical
modification in the apparent affinity. The FE% Pi and FE% Na were significantly
lower in treated animals than in control animals. There were neither systemic
variations in the acid-base balance nor in the Ca and Pi concentrations in
plasma. The calcemia recovery following a hypocalcemic stimulus and the
nephrogenic excretion of cAMP (T: 44+/-4; C: 91+/-7 pmol/min) were diminished.
Considering all these facts, it can be postulated that the aluminum renal effect
is associated from a decrease in PTH phosphaturic capacity. Nevertheless, other
associated factors like minor phosphate intestinal absorption rate may not be
disregarded, even though there were no significant intake variations.
PMID- 9544700
TI - The acetaminophen regioisomer 3'-hydroxyacetanilide inhibits and covalently binds
to cytochrome P450 2E1.
AB - 3'-Hydroxyacetanilide has been previously studied as a nontoxic regioisomer of
the analgesic acetaminophen (4'-hydroxyacetanilide). The radiolabeled derivative
has been shown to covalently bind to liver proteins at levels similar to that
observed with hepatotoxic doses of radiolabeled acetaminophen with no evidence of
hepatic damage. Using an anti-arylacetamide antiserum the primary protein adduct
detected following administration of 3'-hydroxyacetanilide (300 and 600 mg/kg) to
mice was a 50 kDa microsomal protein that co-migrated with cytochrome P450 2E1.
Cytochrome P450 2E1 enzyme activity (p-nitrophenol hydroxylase) was decreased by
79% in the mice treated with 3'-hydroxyacetanilide (600 mg/kg). Incubation of 3'
hydroxyacetanilide with hepatic microsomes resulted in a time dependent 47%
decrease in cytochrome P450 2E1 activity. Pre-incubation of acetaminophen with
microsomes did not result in covalent binding to the cytochrome P450 nor was
there a decrease in p-nitrophenol hydroxylase activity. These data suggest that
3'-hydroxyacetanilide covalently binds to cytochrome P450 2E1 with preferential
loss of activity.
PMID- 9544699
TI - Induction of heme oxygenase-1 in toxic renal injury: mercuric chloride-induced
acute renal failure in rat.
AB - It is known that mercuric chloride (HgCl2) is a nephrotoxicant. When HgCl2 (1
mg/kg body weight) was intraperitoneally injected into rats, acute renal failure
was induced. Histological changes in the kidneys were exclusively observed in the
proximal tubules and the severe necrosis was found as early as 24 h after HgCl2
injection. The heme oxygenase-1 (HO-1) mRNA was strongly and promptly induced at
about 2.5 h, the earliest time examined and abruptly decreased after the
injection. Whereas the time course of HO-1 protein level was delayed as compared
with that of HO-1 mRNA level. The levels of HO-1 mRNA and protein similarly
increased with dose-dependent manner. The localization of HO-1 protein was
restricted to the tubule cells. These findings suggest the potential involvement
of HO-1 induction in the response to HgCl2-induced acute renal injury.
PMID- 9544701
TI - Regions of the Escherichia coli primary sigma factor sigma70 that are involved in
interaction with RNA polymerase core enzyme.
AB - BACKGROUND: The sigma factors of bacterial RNA polymerase are required for
recognition of promoters in transcription initiation. Most sigma factors share
several regions with significant homology in their amino acid sequences (regions
1-4). Some primary sigma factors carry a large nonconserved segment between
regions 1 and 2. The binding of an sigma factor to the core enzyme alters the
structure and properties of the sigma factor, but little is known about the
binding mechanism and subsequent reactions. In this report, we employed the
protein footprinting method to investigate the alteration of the structure and
function of Escherichia coli sigma70 by binding to core enzyme and promoter DNA.
RESULTS: A segment between regions 1.1 and 1.2, and that in region 3.2, were
preferentially cleaved by hydroxyl radicals. Upon binding to the core enzyme,
segments in regions 1.1, 2, 3 and 4 were substantially protected, while cleavage
at a small segment in region 4.2 was weakly enhanced. In a binary complex of
holoenzyme and promoter DNA, additional segments in regions 2.4 and 4.2 were
protected, while the protection at region 1.1 disappeared. The nonconserved
acidic region of sigma70 in the holoenzyme became hypersensitive upon binding to
DNA. CONCLUSIONS: These results suggest that not only the conserved region 2, but
also regions 1.1, 3 and 4 of the sigma factor are involved in binding to the core
enzyme. The nonconserved acidic region is likely to be more exposed by further
binding of sigma factor to promoter DNA.
PMID- 9544702
TI - Roles of TraI protein with activities of cleaving and rejoining the single
stranded DNA in both initiation and termination of conjugal DNA transfer.
AB - BACKGROUND: The plasmid R100 encodes the TraI protein, which is required for
conjugal DNA transfer. TraI has the activity of site- and strand-specific nicking
of the supercoiled plasmid DNA. The molecular mechanism of this specific nicking,
which is supposed to be the initiation reaction of DNA transfer, is not
understood. RESULTS: We have demonstrated that TraI has the ability to cleave the
single-stranded DNA at the same site as the nicking site (nic) in a region, which
we here refer to as sbi. The product contained the TraI protein which was
covalently linked to the newly generated 5' end of the nicking reaction. Both the
cleaving and nicking reactions took place under almost the same conditions and
required the presence of the sbi region. DNase I-footprinting analysis revealed
that the TraI bound to the single-stranded DNA of the sbi region. TraI did not
cleave the double-stranded DNA fragment, but it did cleave the double-stranded
DNA with a single-stranded DNA portion in the sbi region. KMnO4 mapping analysis
revealed that TraI can melt the sbi region in the supercoiled DNA to generate a
single-stranded portion. We have also demonstrated that TraI was able to rejoin
the cleaved products. The rejoining reaction required the 5' end of one cleaved
product with the TraI covalently attached and the 3' end of the other product
containing the sbi region. CONCLUSIONS: Our results demonstrate that the nicking
reaction-the initiation reaction of DNA transfer-is actually the cleaving
reaction of the single-stranded DNA. TraI, which has both cleaving and rejoining
activities, is thought to be involved in the termination of DNA transfer, to give
a copy of the conjugative plasmid by joining the 5' end, which is generated by
the initiation reaction, with the 3' end, which will be generated upon cleavage
of the sbi region appearing after one round of the rolling circle replication of
the plasmid.
PMID- 9544703
TI - Gin4 of S. cerevisiae is a bud neck protein that interacts with the Cdc28
complex.
AB - BACKGROUND: A number of proteins make up the Cdc28 complex in Saccharomyces
cerevisiae, and regulate CDK activity. The cell cycle regulator Nik1 (Hsl1) is a
protein kinase that interacts with the Cdc28 complex. The growth inhibitor Gin4
is structurally similar to Nik1 and may play a redundant role in the regulation
of the cell cycle. We investigated the functions of Gin4 with respect to those of
Nik1. RESULTS: GIN4 was not essential for growth, and cells deficient in the GIN4
gene displayed no obvious defects in cell cycle regulation. The delta(gin)4
delta(nik)1 strain was temperature sensitive and showed an abnormal cell shape
and FACS profile at permissive temperatures. GFP-fused Gin4 was localized at the
bud-neck from late G1 to the M phase. Over-production of the C-terminal portion
of Gin4 was toxic for cell growth, and this domain was required for the bud-neck
localization of Gin4-GFP. High copy expression of Gin4-GFP disturbed the bud-neck
localization of Gin4 in the abnormally elongated cells. Cytokinesis was defective
in the delta(gin)4 cdc28 double mutants. The GST-Gin4 fusion protein physically
associates with the Cdc28 complex. CONCLUSIONS: Gin4 is a bud-neck protein. GIN4
and NIK1 have distinct but partially overlapping functions. The major function of
GIN4 is to ensure proper mitotic progression and cytokinesis.
PMID- 9544704
TI - Two mechanisms in the action of repressor deltaEF1: binding site competition with
an activator and active repression.
AB - BACKGROUND: Counteraction between activators and repressors is crucial for the
regulation of a number of cell-specific enhancers, where an activator and a
repressor are mutually competitive in binding to the same site. DeltaEF1 is a
repressor protein of delta1-crystallin minimal enhancer DC5 binding at the CACCT
site, and inhibits activator deltaEF3 from binding to the overlapped site. It has
two zinc finger clusters N-fin and C-fin, close to N- and C-termini,
respectively, and a homeodomain in the middle. deltaEF1 also binds to the E2-box
sequence CACCTG, and represses E2-box-dependent enhancers. RESULTS: The mechanism
of the repressor action of deltaEF1 was investigated by examining various
deletion mutants of deltaEF1 for their activity to repress delta1-crystallin
enhancer fragment HN which contained DC5 sequence and an additional activator
site. Both zinc finger clusters were found to be essential for DNA binding and
repression, but the homeodomain was not. In addition, the NR domain close to the
N-terminus was required for full repression. The NR domain showed active
repression when fused to the Gal4 DNA binding domain. Active repression by
deltaEF1, dependent on the NR domain, was also demonstrated in a situation where
the binding sites of deltaEF1 and deltaEF3 were separated. N-fin and C-fin in
their isolated forms bind the 5'-(T/C)ACCTG-3' and 5'-(t/C)ACCT-3' sequences,
respectively, while the homeodomain showed no DNA binding activity. An analysis
of DNA binding of the delta(Int)F form, having both N-fin and C-fin, indicated
that a single DNA binding domain is assembled from two zinc finger clusters.
CONCLUSION: Two mechanisms are involved in the repressor action of deltaEF1.
First, a binding site competition with an activator which depends on the
integrity of both zinc finger clusters, and second, an active repression to
silence an enhancer which is attributed to the NR domain.
PMID- 9544705
TI - Double-cleavage production of the CTL epitope by proteasomes and PA28: role of
the flanking region.
AB - BACKGROUND: Proteasomes are known to produce major histocompatibility complex
(MHC) class I ligands from endogenous antigens, and the gamma-interferon
inducible proteasome activator PA28 has been thought to play an important role in
the generation of immunodominant MHC ligands by proteasomes. Several attempts
have been made to show that proteasomes have the ability to yield cytotoxic T
lymphocyte (CTL) epitopes effectively from model polypeptides derived from viral
and intracellular proteins in vitro, but their antigen processing mechanism is
poorly understood. RESULTS: Proteasomes produce the tumour rejection antigen
precursor peptide pRL1b (SIIPGLPLSL), but not pRL1a (IPGLPLSL), bound to the H
2Ld molecule, from synthetic peptides covering the CTL epitope. This double
cleavage production of pRL1b by proteasomes seemed to depend on the length of the
flanking regions adjacent to either end of the CTL epitope, in which their
successive deletions caused the almost complete prevention of pRL1b excision. The
newly identified PA28 collaborates with proteasomes for efficient production of
pRL1b, by promoting not only single cleavage of all susceptible peptides, but
also dual cleavage in some peptides harboring certain characteristic lengths.
CONCLUSION: The flanking regions outside pRL1b of suitable length appear to be
essential for the correct CTL epitope production, possibly functioning as anchors
to trap target peptides for proteasomal degradation. We propose a novel mechanism
for dual-cleavage excision of immunodominant epitopes by proteasomes and PA28.
PMID- 9544706
TI - Induction of labor with intravaginal administration of misoprostol.
AB - OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of
intravaginal misoprostol for labor induction. METHODS: 110 singleton term
pregnancies with or without rupture of membranes were enrolled. Fractionated
doses of misoprostol were applied (50-100 microg), every 6 h until a maximum of
three doses or beginning of labor. RESULTS: The average interval (+/- S.D.) from
vaginal application to the beginning of active labor and to delivery were,
respectively, 9.5 +/- 5.7 h and 14.8 +/- 9.5 h. Failed labor induction was
observed in two cases (2%). Cesarean section rate was 14%. The incidence of
tachysystole was 18% and hypersystole 4%, but these situations were associated
with abnormal fetal heart rate pattern (hyperstimulation) in only 3%. No maternal
side effects and neonatal adverse effects were noted. CONCLUSIONS: Intravaginal
misoprostol administration with low doses is an effective and safe method for
labor induction in term pregnancies, with or without rupture of membranes.
PMID- 9544707
TI - Prenatal strategies for reducing severe thalassemia in pregnancy.
AB - OBJECTIVE: To describe the prenatal strategy in reducing new cases of severe
thalassemia at Maharaj Nakorn Chiang Mai Hospital. The study design involved a
prospective descriptive analysis set in Maharaj Nakorn Chiang Mai Hospital,
Chiang Mai University. SUBJECTS: Pregnant women attending antenatal clinic.
METHODS: The strategy included: (1) carrier identification by retrospective
(history review) and prospective screening program; (2) the couples at risk were
counseled and offered cordocentesis; (3) analysis of fetal blood with high
performance liquid chromatography (HPLC) or electrophoresis; and (4) counseling
for termination of pregnancy in case of affected fetus. The prospective screening
consisted of testing for a carrier by a simple erythrocyte osmotic fragility test
(EOFT) in women with no risk and testing the husbands of the women with abnormal
tests. A pregnancy in which both of the couple were carriers was considered a
risk. RESULTS: Cordocentesis was performed in 554 pregnancies at risk, 252 and
302 from retrospective and prospective screening, respectively. Sixty of 252 of
the first group had severe thalassemia. In the prospective screening program of
12 680 women, 459 risk couples were identified, 302 pregnancies underwent
cordocentesis and 53 (17.5%) had severe thalassemia. This strategy enabled us to
identify 113 cases of severe thalassemia (Hb Bart's; 60, beta-thal entities; 53)
from 554 cases at risk. CONCLUSION: The strategy proves valuable in the control
of severe thalassemia. This extensive experience suggests the strategy be
considered an effective way in the control of severe thalassemia in high
prevalence areas.
PMID- 9544708
TI - Birth weight, gestational age and medications during pregnancy.
AB - OBJECTIVE: To determine the effect of medication on birth weight and gestational
age in 29,004 healthy newborn infants born to mothers with or without treatment
of drugs. METHOD: Birth weight and gestational age were evaluated in healthy
control newborn infants in the population-based dataset of the Hungarian Case
Control Surveillance of Congenital Abnormalities (1980-1991) using multiple
regression analysis. RESULTS: Of 114 drugs used in more than 100 pregnant women,
19 had a positive or negative impact. CONCLUSIONS: Further studies should be
carried out to identify the possible mechanisms of medication and/or the maternal
disorder for which this medication was given.
PMID- 9544709
TI - Transcutaneous electrical nerve stimulation (TENS) for adjuvant pain-relief
during labor and delivery.
AB - OBJECTIVE: We examined the efficacy of transcutaneous electrical nerve
stimulation (TENS) in general and the new Freemom TENS device (LifeCare, Israel)
in particular, for pain relief during labor and delivery. METHODS: The study
group consisted of 104 women. Forty-six nulliparas (44.2%) and 58 multiparas
(55.8%), all of whom used the TENS device for pain relief during labor. All
participants completed a questionnaire on the degree of pain relief afforded them
by TENS during the delivery and related questions. The objective evaluation was
based on the documented labor and delivery parameters including medical
interventions during delivery. RESULTS: The majority of subjects (72% of the
nulliparas and 69% of the multiparas) considered TENS effective for the relief of
pain during labor. Most of them (67% of the nulliparas and 60% of the multiparas)
responded positively to the use of TENS in future deliveries. Sixty-five percent
of the multiparas considered TENS at least as effective as the other pain relief
methods they had used before. TENS significantly reduced the duration of the
first stage of labor P < 0.001 for nulliparas, P < 0.005 for multiparas and it
significantly decreased the amount of analgesics administered to individual
patients. No significant difference was found in fetal heart rate tracings, Apgar
scores and cord blood pH between the study group and an equal number of matched
controls who used other forms of pain management. CONCLUSIONS: TENS is an
effective non-pharmacological, non-invasive adjuvant pain relief modality for use
in labor and delivery. TENS application reduced the duration of the first stage
of labor and the amount of analgesic drug administered. There were no adverse
effects on mothers or newborns.
PMID- 9544710
TI - Erythropoietin in amniotic fluid as a marker of chronic fetal hypoxia.
AB - OBJECTIVE: To determinate the erythropoietin concentration in amniotic fluid in
normal pregnancies and pregnancies with suspected hypoxia. METHOD: The
erythropoietin concentration of 164 samples of amniotic fluid was determined by
ELISA. The samples were taken by amniotomy during birth, as well as amniocentesis
conducted during prenatal care. RESULTS: A distribution of 1.07-7.29 U/l (10th
90th percentile) within the normal group (n = 106) was determined. Significantly
elevated erythropoietin levels in amniotic fluid were determined in maternal
hypertension (P = 0.039) and low birth-weight children (P = 0.0032). A
correlation with the child's sex could be excluded. CONCLUSION: Elevated
erythropoietin levels in amniotic fluid indicated chronic fetal hypoxia.
PMID- 9544711
TI - Reproducibility of the revised American Fertility Society classification of
endometriosis using laparoscopy or laparotomy.
AB - OBJECTIVE: To assess the discrepancy between laparoscopic and laparotomic scoring
methods using the revised American Fertility Society (AFS) classification of
endometriosis. METHOD: In this prospective study, 84 patients with endometriosis
were scored twice (laparoscopically and laparotomically) by the same subspecialty
certified reproductive endocrinologist. The magnitude of inter-method variability
was reported quantitatively by the S.D. of the differences in scores between the
pairs. The differences in the mean endometriosis scores between the two methods
were assessed by the paired Student's t-test. P < 0.05 was considered as
statistically significant. Discrepancy between the two methods in the staging of
endometriosis patients was presented by kappa measure of agreement. RESULT: There
was considerable variability in the scores between the two scoring methods by the
same observer. Among individual components of the scoring system, the greatest
variability occurred in the ovarian endometriosis and cul-de-sac obliteration
subscores, with the least variability observed for peritoneum endometriosis. The
inter-method variation in score was sufficient to alter the endometriosis staging
in 34.5% of patients, including a difference of two stages in 3.6% of patients.
The kappa coefficient was 0.49, indicating fair-to-good agreement between the two
scoring methods. CONCLUSION: Inter-method variability between laparoscopic and
laparotomic scoring methods was high for ovarian endometriosis subscore using the
revised AFS classification of endometriosis. Agreement in endometriosis staging
between the two methods was fair to good.
PMID- 9544712
TI - Effect of long-term hormone replacement therapy on the bone in ovariectomized
women with cancer.
AB - OBJECTIVE: To evaluate longitudinally the effectiveness of long-term hormone
replacement therapy (HRT) in preserving the bone mineral density (BMD) over a 5
year period in ovariectomized patients treated for gynecologic malignancies.
METHODS: A total of 70 pre-menopausal women ovariectomized for gynecologic
malignancies at our hospital were divided non-randomly into two groups: HRT (+)
group (n = 59) and HRT (-) group (n = 11). HRT was administered in a sequential
regimen of 0.625-1.25 mg conjugated estrogen for 24 days and 5-10 mg
medroxyprogesterone acetate for 10 days. RESULTS: The BMD of the lumbar vertebrae
decreased significantly in the HRT (-) group (pre-operative BMD was 91.8%, 91.0%
and 91.3% at 1, 2 and 3 years post-ovariectomy), but no decrease in the BMD was
observed in the HRT (+) group (pre-operative BMD was 98.4%, 99.0%, 99.4%, 98.8%
and 98.7% at 1, 2, 3, 4 and 5 years post-ovariectomy); the difference in BMD
between the two groups was statistically significant (P < 0.01). Serum alkaline
phosphatase levels were significantly lower in the HRT (+) group than in the HRT
(-) group (P < 0.01). There were four recurrences of cancer in the HRT (+) group.
CONCLUSION: HRT appeared to have beneficial effects on bone metabolism by
maintaining BMD for 5 years in ovariectomized patients for gynecologic
malignancies.
PMID- 9544713
TI - Single dose methotrexate therapy: application to interstitial ectopic pregnancy.
AB - A woman with a small (6-mm gestational sac) interstitial pregnancy had complete
resolution after medical therapy alone. A single cycle of methotrexate 50 mg/m2
was used as outpatient treatment without any operative procedure either for
diagnosis or intervention. The guidelines that have evolved for selection of
women for single dose methotrexate treatment for both intrauterine and tubal
ectopic pregnancies may be applicable to interstitial ectopic pregnancy as well.
A suggested framework for treatment decisions is presented.
PMID- 9544714
TI - Ovarian carcinoma in the third trimester.
PMID- 9544715
TI - Perinatal Enterobius vermicularis infection.
PMID- 9544716
TI - Feasibility of photodynamic endometrial ablation without anesthesia.
PMID- 9544717
TI - Catamenial hemoptysis treated with a long-acting GnRH agonist.
PMID- 9544718
TI - Assessment of second-look operations in malignant ovarian germ cell tumors.
PMID- 9544719
TI - Pain control in abortion clinics.
PMID- 9544720
TI - ACOG educational bulletin. Sexual assault. Number 242, November 1997 (replaces
No. 172, September 1992). American College of Obstetricians and Gynecologists.
PMID- 9544721
TI - ACOG committee opinion. Physician/patient responsibility for follow-up of
diagnosis and treatment. Number 193, November 1997. Committee on Professional
Liability. American College of Obstetricians and Gynecologists.
PMID- 9544722
TI - ACOG practice patterns. Shoulder dystocia. Number 7, October 1997. American
College of Obstetricians and Gynecologists.
PMID- 9544723
TI - ACOG criteria set. Hysterectomy, abdominal or vaginal for abnormal uterine
bleeding. Number 28, November 1997. Committee on Quality Assessment. American
College of Obstetricians and Gynecologists.
PMID- 9544724
TI - ACOG criteria set. Hysterectomy, abdominal or vaginal for chronic pelvic pain.
Number 29, November 1997. Committee on Quality Assessment. American College of
Obstetricians and Gynecologists.
PMID- 9544725
TI - Lipid levels and peripheral vascular disease in diabetic and non-diabetic
subjects.
AB - Non-insulin dependent diabetes (NIDDM) is associated with an increased risk of
peripheral vascular disease (PVD), but within the diabetic population the
relationship between lipid profile and PVD has not been clearly defined. In this
study we examined the association of lipid parameters and in particular low
density lipoprotein (LDL) particle size, with the presence of PVD in subjects
with and without NIDDM. 41 NIDDM patients and 31 non-diabetic subjects with PVD
in the absence of rest pain or ulceration, defined by ankle-brachial index
measurements and duplex scanning, were compared with 41 NIDDM and 31 euglycemic
control subjects of comparable age and sex, without PVD. In both groups those
with PVD were found to have significantly elevated triglycerides (2.7 [2.2-3.3]
versus 1.9 [1.6-2.2] mmol/l; P < 0.05 in the diabetic group and 2.0 [1.6-2.3]
versus 1.4 [1.1-1.5] mmol/l; P < 0.05 in the non-diabetic group), decreased
apolipoprotein A1 (124 +/- 3 versus 139 +/- 5 mg/dl; P < 0.01 in the diabetic
group and 133 +/- 4 versus 147 +/- 4 mg/dl; P < 0.05 in the non-diabetic group)
and decreased LDL particle size (25.4 +/- 0.1 versus 25.8 +/- 0.1 nm; P < 0.01 in
the diabetic group and 26.0 +/- 0.1 versus 26.3 +/- 0.1 nm; P < 0.05 in the non
diabetic group). In the non-diabetic group apolipoprotein[a] (365 [239-554]
versus 184 [17-266] U/l; P < 0.01), total cholesterol (6.3 +/- 0.2 versus 5.6 +/-
0.2 mmol/l; P < 0.05), LDL cholesterol (4.1 +/- 0.2 versus 3.6 +/- 0.2 mmol/l; P
< 0.05) and apolipoprotein B (146 +/- 8 versus 117 +/- 5 mg/dl; P < 0.05) were
also found to be associated with PVD although these associations were not
observed in the group with diabetes. In addition, 11 NIDDM subjects and 11 non
diabetic subjects with rest pain or ulceration were compared to the corresponding
groups with uncomplicated PVD and had lipid profiles with significantly lower
levels of total cholesterol and LDL cholesterol. We conclude that the
dyslipidemic profile characterized by increased triglyceride level, decreased
apolipoprotein A1 level and small dense LDL is associated with uncomplicated PVD
in both NIDDM and non-diabetic subjects.
PMID- 9544726
TI - A novel mutation in Exon 4 of the low density lipoprotein receptor gene resulting
in heterozygous familial hypercholesterolemia associated with decreased ligand
binding.
AB - Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by
mutations in the low density lipoprotein (LDL) receptor gene. Currently,
diagnosis of heterozygous FH relies on clinical phenotype; however, the use of
clinical criteria for the diagnosis of heterozygous FH does not always permit
unequivocable diagnosis of the disease. Molecular diagnosis of FH is clinically
valuable especially in regions where founder mutations exist or where polygenic
hypercholesterolemia is prevalent. In this paper we report the identification of
a novel mutation, a cytosine to guanine substitution, at codon 152 in exon 4 of
the LDL receptor gene in a Nova Scotian family clinically diagnosed with
heterozygous FH. The mutation creates a recognition sequence for the restriction
endonuclease BsrI, and can be readily detected by BsrI restriction analysis of a
160 bp amplicon spanning the mutation. This analysis was used to show that the
mutation segregated with the disease in this family and is the probable cause of
FH in this kindred.
PMID- 9544727
TI - C57BL/6 mice fed high fat diets as models for diabetes-accelerated
atherosclerosis.
AB - Non-insulin-dependent diabetes mellitus (NIDDM) is a major risk factor for the
development of atherosclerosis in humans. The development of an animal model that
displays accelerated atherosclerosis associated with NIDDM will aid in
elucidating the mechanisms that associate these disorders. C57BL/6 mice may
provide such a model system. This strain becomes obese, hyperglycemic and insulin
resistant when fed a high fat diet (diabetogenic diet) and is susceptible to
atherosclerotic lesion development when fed a separate high fat diet containing
cholesterol and bile acids (atherogenic diet). This report tests whether a diet
commonly used to induce atherosclerosis also provokes a diabetic phenotype and
whether a diet used to induce diabetes provokes the development of aortic fatty
streak lesions. Mice of strains C57BL/6, C3H/He, BALB/c and seven recombinant
inbred (RI) strains were fed an atherogenic diet for 14 weeks and glucose
parameters were measured. No correlation was observed between atherosclerosis
susceptibility and fasting insulin or glucose levels, or glucose clearance
following short-term insulin or glucose treatment. Analysis of the RI strains
suggested that multiple genes control these glucose metabolic parameters. Feeding
the diabetogenic diet for 14 weeks to C57BL/6 mice induced obesity and diabetes
and 2-fold increases in plasma lipoprotein concentrations. Also, small aortic
sinus lipid deposits were observed in 40% of the mice. Thus, analysis of the
diabetogenic diet fed C57BL/6 mouse may provide an important tool for further
studies of diabetes accelerated vascular disease.
PMID- 9544728
TI - Cardiovascular risk factors in non-insulin-dependent diabetics compared to non
diabetic controls: a population-based survey among Asians in Singapore.
AB - Cardiovascular risk factors were compared between 126 people with non-insulin
dependent diabetes mellitus (NIDDM) and 530 non-diabetics (controls), in a random
sample of people (Chinese, Malays, and Asian Indians) aged 40-69 years from the
general population of Singapore. Data were adjusted for age and ethnicity. For
both genders, people with NIDDM had higher mean body mass indices, waist-hip
ratios and abdominal diameters. They also had a higher prevalence of
hypertension, higher mean levels of fasting serum triglyceride, slightly lower
mean levels of serum high-density-lipoprotein cholesterol, and higher mean levels
of plasma plasminogen activator inhibitor-1 and tissue plasminogen activator
(antigen). These factors are components of syndrome X (metabolic syndrome) and
increase the risk of atherosclerosis and thrombosis. In contrast, there were no
important differences for cigarette smoking, serum total and low-density
lipoprotein cholesterol, serum apolipoproteins A1 and B, plasma factor VIIc and
plasma prothrombin fragment 1 + 2. Females with NIDDM, but not males, had a
higher mean serum fibrinogen level than non-diabetics, which could explain why
NIDDM has a greater cardiovascular effect in females than males. Serum
lipoprotein(a) concentrations were lower in people with NIDDM. Mean levels of
serum ferritin, a pro-oxidant, were higher in people with NIDDM than controls,
but there were no important differences for plasma vitamins A, C and E, and serum
selenium, which are anti-oxidants.
PMID- 9544729
TI - Endothelial injury and leukocyte adherence in Hautchen preparations from coronary
arteries and aorta of cynomolgus monkeys.
AB - The aim was to describe the production of en face preparations (Hautchens) of the
endothelium from the aorta and the coronary arteries of cynomolgus monkeys
(Macaca fascicularis), to describe the morphology of the endothelium and to
estimate endothelial injury. The present study describes, for the first time, the
application of this technique to the coronary arteries. Numerous leukocytes
(peroxidase-positive and -negative cells) were observed on the endothelium and a
positive correlation between the numbers of adherent leukocytes and injured
endothelial cells was found. A relatively leukocyte-independent measure of
endothelial injury in the aorta was obtained by counting areas with a restricted
number of leukocytes. The results indicated an even distribution and a relatively
low frequency of injured endothelial cells along the arterial tree. The
percentage of injured endothelial cells in LAD and LCX was 0.18 and 0.16, and in
non-branched and circumostial areas of the descending thoracic aorta the
corresponding figures were 0.22 and 0.28. There were, on average, 344 and 236
adherent leukocytes/mm2 in the non-branched and circumostial areas of the
descending thoracic aorta, respectively, compared to 13 in the LAD and 23 in the
LCX. Proportionally more peroxidase-positive leukocytes (possibly granulocytes)
were found on the coronary endothelium than on the aortic endothelium, and the
peroxidase-positive cells were preferentially located around small artery
branches in the coronary arteries. The foregoing data provide an estimate of the
distribution and frequency of endothelial injury and adherent leukocytes at
pathobiologically relevant arterial sites in unmanipulated cynomolgus monkeys, an
animal frequently used in atherosclerosis research.
PMID- 9544730
TI - Oxidized cholesterol in oxidized low density lipoprotein may be responsible for
the inhibition of LPS-induced nitric oxide production in macrophages.
AB - Previous work has shown that oxidized low density lipoprotein (Ox-LDL) inhibited
lipopolysacchride (LPS)-induced nitric oxide (NO) production in macrophages. In
this paper, the role of different components of Ox-LDL in the inhibitory effect
was studied by measuring nitrite in media. Ox-LDL inhibited LPS-induced NO
production in macrophage cell line J774.A1. When compared with Ox-LDL, native and
acetylated LDL had a lesser effect on NO production. Pre-clearance of lipid
hydroperoxides (LOOH) in Ox-LDL and removal of soluble thiobarbituric acid
reactive substances (TBARS) in Ox-LDL solution by dialysis had no influence on
the inhibitory effect of Ox-LDL. The protein moiety of Ox-LDL had no effect on NO
production, but the lipid moiety inhibited NO production to about the same extent
as intact Ox-LDL. Linoleic acid and phosphatidylcholine, the main components of
LDL lipid, whether oxidized separately or together, had no effect on NO
production. However, if linoleic acid and cholesterol oxidized together, there
was very strong inhibition of NO production. Cholesterol oxidized alone also had
some inhibitory effect. These results suggest that oxidized cholesterol in Ox-LDL
might be responsible for the inhibition of NO production in macrophages.
PMID- 9544731
TI - Inhibitory effect of inducible type nitric oxide synthase on oxidative
modification of low density lipoprotein by vascular smooth muscle cells.
AB - Oxidative modification of low density lipoprotein (LDL) plays an important role
in atherogenesis. Inducible type nitric oxide synthase (iNOS) has been shown to
be expressed in vascular smooth muscle cells (VSMC) of atherosclerotic arteries.
Nitric oxide (NO) donors have been shown to inhibit metal ion- or cell-mediated
oxidation of LDL. To elucidate whether NO produced by iNOS in VSMC inhibit
oxidation of LDL, we investigated the effect of NO donors and iNOS-induction in
VSMC on oxidation of LDL. NO donor, S-Nitroso-n-acetylpenicillamine (SNAP) or 3
morpholinosydnonimine (SIN-1) (0.1-1.0 mmol/l) dose-dependently reduced copper
induced oxidation of LDL as demonstrated by the inhibition of electrophoretic
mobilities on agarose gels and the formation of thiobarbituric acid-reactive
substances (TBARS) and conjugated dienes. Moreover, treatment with IL-1beta (5-50
ng/ml) reduced the increases in electrophoretic mobilities on agarose gels and
TBARS formation in association with increases in NO production. In addition,
inhibition of NO production by NG-monomethyl-L-arginine monoacetate reduced the
inhibitory effect of IL-1beta on LDL oxidation. These results indicate that NO
release via iNOS action induced by cytokines in VSMC may play protective roles in
oxidative modification of LDL during the atherosclerosis process.
PMID- 9544732
TI - Amino-terminal fragment (1-34) of parathyroid hormone-related protein inhibits
migration and proliferation of cultured vascular smooth muscle cells.
AB - We investigated the effects of amino-terminal fragment (1-34) of parathyroid
hormone-related protein [PTHrP-(1-34)] on the migration and proliferation of
vascular smooth muscle cells (VSMCs). Cultured VSMCs (5-9th passage) obtained
from the aortas of male Wistar rats were used in this study. Migration of VSMCs
was assessed using a modified Boyden's chamber. Proliferation of VSMCs was
evaluated by measuring [3H]thymidine incorporation and counting cell numbers.
PTHrP-(1-34) inhibited 10% fetal bovine serum (FBS)-induced increase in migration
of VSMCs (61% of control at 1 micromol/l) in a concentration-dependent manner.
PTHrP-(1-34) also inhibited 5% FBS-induced increase in [3H]thymidine
incorporation (37% of control at 1 micromol/l) and cell number of VSMCs (33% of
control at 1 micromol/l) in a concentration-dependent manner. Parathyroid hormone
(PTH)-(1-34) inhibited the migration and DNA synthesis of VSMCs to a similar
extent. PTHrP-(7-34), a PTH/PTHrP receptor antagonist, significantly inhibited
these effects of PTHrP and PTH. PTHrP-(1-34) also inhibited platelet-derived
growth factor-BB (5 ng/ml)-induced migration and DNA synthesis of VSMCs. These
findings suggest that PTHrP-(1-34) inhibits the migration and proliferation of
VSMCs through PTH/PTHrP receptors.
PMID- 9544733
TI - Dietary L-arginine decreases myointimal cell proliferation and vascular monocyte
accumulation in cholesterol-fed rabbits.
AB - L-arginine, the precursor of endogenous nitric oxide (NO), has been shown to
enhance endothelial function and to reduce the progression of atherosclerosis in
cholesterol-fed rabbits. In the present study, we investigated whether myointimal
cell proliferation is enhanced in hypercholesterolaemic rabbit aorta and whether
chronic treatment of the rabbits with L-arginine or with the NO synthase
inhibitor L-NAME influences this proliferative response and vascular monocyte
accumulation. Rabbits were fed 1% cholesterol or normal rabbit chow for 12 weeks.
Subgroups of cholesterol-fed rabbits were treated with oral L-arginine (2.25%) or
L-NAME (3 mg/dl) in drinking water. Myointimal cell proliferation was quantified
in aortic segments by immunohistochemical detection of bromodeoxyuridine (BrdU)
incorporation into nuclear DNA; vascular monocyte accumulation was assessed by
immunohistochemistry using a monoclonal anti-macrophage/monocyte antibody (RAM
11). Plasma levels of L-arginine and the endogenous NO synthase inhibitor, ADMA,
were quantified by high-performance liquid chromatography (HPLC). Cholesterol
feeding increased the aortic intima/media (I/M) ratio, which was not measurable
in the control group, to 1.9 +/- 0.3. This was paralleled by enhanced cell
proliferation (cholesterol, 2.4 +/- 0.2%; P < 0.05; control, 0.02 +/- 0.001% BrdU
positive cells per 72 h) and vascular monocyte accumulation. Double
immunostaining for BrdU and alpha-actin showed that about two thirds of the
proliferating cells were smooth muscle cells. ADMA levels increased from 0.8 +/-
0.1 micromol/l to 2.2 +/- 0.2 micromol/l in cholesterol-fed rabbits, but were
unchanged by L-arginine or L-NAME treatment. Myointimal proliferation and
intima/media ratios were correlated with ADMA plasma levels. Dietary L-arginine
reduced monocyte accumulation by 85 +/- 2% (P < 0.05 vs cholesterol), myointimal
cell proliferation (1.8 +/- 0.3% per 72 h; P < 0.05) and intimal thickening (I/M
ratio: 0.7 +/- 0.2), whereas the inhibitor of NO synthase, L-NAME, further
increased cell proliferation to 3.1 +/- 0.4% per 72 h (P < 0.05). No significant
difference was observed in vascular monocyte infiltration between the cholesterol
and L-NAME groups. We conclude that cell proliferation and vascular monocyte
accumulation are enhanced in hypercholesterolaemic rabbit aorta. These
atherogenic effects can be attenuated by dietary L-arginine. Decreased NO
formation might underlie the enhanced monocyte accumulation and cell
proliferation in hypercholesterolaemic rabbit aorta. The observed inhibition of
cell proliferation adds to our understanding of the antiatherosclerotic effects
of L-arginine in vivo.
PMID- 9544734
TI - CI-1011 lowers lipoprotein(a) and plasma cholesterol concentrations in chow-fed
cynomolgus monkeys.
AB - Lipoprotein(a) (Lp(a)), which is generated through the covalent association of
apolipoprotein(a) (apo(a)) and apo B-100-LDL, is an independent risk factor for
several vascular diseases. Therefore, there is interest in developing therapies
for lowering Lp(a). This investigation was carried out to determine the effect of
CI-1011, a potent lipid regulator in rodents, on Lp(a) and other lipid parameters
in cynomolgus monkeys (Macaca fascicularis). Nine healthy male monkeys on a
normal chow diet were orally treated with CI-1011 at 30 mg/kg per day for 3
weeks. Lp(a) and total cholesterol levels were significantly decreased after 1
week and maximally reduced to 68 and 73% of control levels, respectively, after 3
treatment weeks. The decreases in total cholesterol were mainly due to changes in
low density lipoprotein (LDL). The LDL:HDL ratio decreased by 30%. Triglycerides
were unaffected by treatment. Lp(a) and total cholesterol levels returned to
pretreatment values after stopping treatment suggesting a direct effect of the
compound on their inhibition. Further studies demonstrated that CI-1011 was
effective at a low dose of 3 mg/kg per day after 1 week of administration. CI
1011 also decreased apo B-100 to 80% of control levels, but this change was not
sufficient to account for the Lp(a) lowering. There was also no correlation
between the changes in Lp(a) and apo B-100 levels. Treatment of cynomolgus monkey
primary hepatocyte cultures with CI-1011 resulted in a dose-dependent inhibition
of Lp(a) levels suggesting a direct hepatic effect of the compound. Western blot
analysis of the samples showed that changes in Lp(a) were associated mainly with
decreased apo(a) (47%), but not apo B-100 (17%). These results demonstrate that
CI-1011 effectively decreases Lp(a) levels both in vivo and in vitro.
PMID- 9544735
TI - Effect of naturally reduced ovarian function on plasma lipoprotein and 27
hydroxycholesterol levels in baboons (Papio sp.).
AB - Female baboons over 15 years of age develop irregular menstrual cycles, an
indication of declining ovarian function similar to that occurring in
perimenopausal women. To determine the effect of declining ovarian function on
plasma lipoprotein metabolism and plasma oxysterols, we measured plasma
lipoprotein and 27-hydroxycholesterol levels in 86 female baboons from 15-28
years of age with regular (n = 51) and irregular (n = 35) menstrual cycles. We
sampled blood and liver while they were consuming a basal diet and after
consuming a high cholesterol and high fat diet for 7 weeks. On the basal diet,
baboons with irregular cycles had higher VLDL + LDL/HDL cholesterol ratios (P =
0.034). After consuming the HCHF diet for 7 weeks, total plasma (P < 0.001) and
VLDL + LDL (P < 0.001) cholesterol concentrations and VLDL + LDL/HDL sterol
ratios (P < 0.001) increased in both cycle groups; whereas HDL cholesterol
concentrations increased only in baboons with regular cycles (P = 0.009). As a
result, HDL cholesterol concentrations (P = 0.006) were lower and VLDL + LDL/HDL
cholesterol ratios (P = 0.002) were higher in baboons with irregular cycles on
the HCHF diet. Plasma 27-hydroxycholesterol concentrations were higher in baboons
with regular cycles than in those with irregular cycles on both basal (P = 0.018)
and HCHF (P = 0.037) diets and were positively correlated (P < 0.001) with
hepatic sterol 27-hydroxylase activities on both diets. Hepatic sterol 27
hydroxylase activities were negatively correlated with the VLDL + LDL/HDL
cholesterol ratios on the HCHF diet (r = -0.342, P = 0.033). These results
suggest that declining ovarian function changes the plasma lipoprotein pattern to
one that is more atherogenic. Ovarian failure is also associated with decreased
concentrations of plasma 27-hydroxycholesterol (the major oxysterol of plasma),
and the decrease in plasma 27-hydroxycholesterol concentration was due to the
decrease in hepatic sterol 27-hydroxylase activity. The effects of ovarian
failure on plasma lipoprotein metabolism and plasma 27-hydroxycholesterol may be
mediated by the decreased production of estrogen in perimenopausal baboons. Thus,
the perimenopausal baboon is an excellent model for menopause and can be used for
studies that cannot be conducted in women.
PMID- 9544736
TI - Dehydroepiandrosterone protects low density lipoproteins against peroxidation by
free radicals produced by gamma-radiolysis of ethanol-water mixtures.
AB - Oxidized low density lipoproteins (LDL) are believed to play a central role in
the events that initiate atherosclerosis. Antioxidants have been shown to
decrease the oxidation of LDL, leading to the diminution of atherosclerosis.
Since it is well-known that decreased levels of dehydroepiandrosterone (DHEA) are
linked to the development of atherosclerosis, we studied the modulation of the
oxidation of LDL by DHEA. LDL were obtained from 10 healthy subjects and oxidized
by free radicals produced by gamma-radiolysis of ethanol-water mixtures. The
formation of conjugated dienes and thiobarbituric acid-reactive substances
(TBARS), the vitamin E content, as well as the incorporation of 4-[14C]DHEA in
LDL and the chemotactic effect of oxidized LDL in the presence of DHEA towards
monocytes, were investigated. It was found that DHEA was able to inhibit the
oxidation of LDL by reducing over 90% of the conjugated dienes and TBARS
formation, as well as by reducing the vitamin E disappearance and significantly
decreasing the chemotactic activity towards monocytes. Our results suggest that
DHEA exerts its antioxidative effect by protecting the endogenous vitamin E of
LDL.
PMID- 9544737
TI - The 4G/5G polymorphism of the plasminogen activator inhibitor gene is associated
with the time course of progression to acute coronary syndromes.
AB - The 4G allele of the plasminogen activator inhibitor (PAI-I) gene is associated
with increased PAI-I levels. Increased PAI-I levels have been reported to be
associated with atherothrombotic events. However, the significance of the 4G/5G
polymorphism of the PAI-I gene in the pathogenesis of ischemic heart diseases has
not been determined. We assessed the 4G/5G polymorphism of the PAI-I gene in 500
subjects including 148 normal controls, 23 subjects with normal coronary
arteries, 28 subjects with a paradoxical acetylcholine response, 97 subjects with
angina pectoris (AP) and 204 subjects with myocardial infarction (MI). We
assessed the length of time between the first anginal pain and the onset of acute
coronary syndromes (ACS) in the AP and MI subjects. Subjects who developed ACS
within 2 months from the first anginal pain were categorized to have a rapid
progression to ACS, and subjects who had had stable anginal pain more than 2
months were placed in the non-ACS group. Subjects in the ACS group were younger
than those in non-ACS group (P = 0.012) The frequency of the 5G/5G genotype of
the PAI-I gene was lower in the ACS (0.228) than in the non-ACS group (0.093) (P
= 0.003). Multiple logistic analyses revealed that a younger age (P = 0.028, odds
ratio = 1.03) and the (4G/5G + 4G/4G) genotype of the PAI-I gene (P = 0.008, odds
ratio = 2.68) were associated with the ACS group. We also assessed plasma PAI-I
antigen levels in 78 subjects. Plasma PAI-I antigen levels in the non-ACS group
were significantly lower than those in the ACS group (P = 0.050). Multiple
regression analyses revealed that plasma PAI-I levels were determined by plasma
insulin (P < 0.001) and the genotype of the PAI-I gene (P = 0.019). Higher plasma
insulin levels and the (4G/5G + 4G/4G) genotype of the PAI-I gene were associated
with higher plasma PAI-I levels. The 4G/5G polymorphism of the PAI-I gene
influenced not only plasma PAI-I antigen levels but also the time course of the
progression to ACS in patients with coronary atherosclerosis.
PMID- 9544738
TI - Poloxamer 407-induced atherogenesis in the C57BL/6 mouse.
AB - Poloxamer 407 (P-407) induces hyperlipidemia in the rat. It was the purpose of
this investigation to determine if chronic P-407 administration would produce
atherogenic arterial lesions in the C57BL/6 mouse, a strain reported to be
susceptible to hyperlipidemia-induced atherosclerotic plaque formation. One
injection (i.p.) of P-407 (0.5g/kg) produced hypercholesterolemia in the mouse
that peaked at 24 h and returned to control levels by 96 h following treatment.
Four groups of mice were maintained: (1) saline injected (C); (2) P-407-injected
(0.5g/kg every 3rd day) (P); (3) P-407 injected plus cholic acid in the diet
(PC); and (4) mice fed a high cholesterol (CHOL) diet containing cholic acid
(HF). Mice from each group were sacrificed following 90, 145, 200, or 300 days of
treatment. Plasma lipid concentrations, hepatic CHOL concentrations (145 and 300
day), and aortic atherogenic lesion areas were measured. Plasma CHOL and
triglyceride remained at control levels throughout the 300 days in the C group.
CHOL of the HF animals plateaued at approximately 225 mg/dl. P-407 produced CHOL
concentrations of 600 mg/dl in P mice and 1000-1500 mg/dl in PC animals. There
was no lesion formation in C mice. However, by 90 days lesions were present in
the three other groups. Size of the lesions progressed through day 300 with the
largest lesions (184.33 + 27.99 mu2 x 10(-3)) being present in the PC mice. HF
and P animals had lesions of 70.50 + 11.35 and 43.33 + 7.88 mu2 x 10(-3),
respectively. This study provides an animal model where atherogenesis has been
produced with hyperlipidemia induced using a chemical agent.
PMID- 9544739
TI - Aminoguanidine has an anti-atherogenic effect in the cholesterol-fed rabbit.
AB - Advanced glycosylation endproducts (AGEs) which result from the non-enzymatic
interaction of proteins and glucose are implicated in the vasculopathy of
diabetes and aging. Since aminoguanidine (A) inhibits the accumulation of AGEs,
we explored its effects on the development of atherosclerosis. Male New Zealand
white cross rabbits fed a high cholesterol (1%) diet were randomized to control
(C) or increasing doses of A treatment (25, 50 and 100 mg/kg A body weight). The
animals were sacrificed after 12 weeks. Sudan IV was used to stain the lipid
containing plaques of the aortic arch, thoracic and abdominal aorta and the
surface area occupied by atheroma was assessed. Increasing doses of A treatment
were associated with reduction in plaque formation in the aorta. At a dose of 100
mg/kg A, there was a 30, 49 and 48% reduction in plaque formation in the aortic
arch, thoracic and abdominal aorta, respectively. There was a correlation between
AGE levels and the degree of atheroma in these cholesterol fed rabbits (control,
r = 0.75, P < 0.01; 100 mg/kg A, r = 0.59, P = 0.02). These data suggest that
advanced glycation may participate in atherogenesis and raise the possibility
that inhibitors of advanced glycation may retard this process.
PMID- 9544740
TI - Elevated triglycerides and low HDL cholesterol in transgenic mice expressing
human apolipoprotein A-I(Milano).
AB - In general, plasma concentrations of high density lipoproteins (HDL) are
inversely related to the incidence of coronary artery disease. One exception to
this trend is individuals with apolipoprotein A-I(Milano) (apo A-IM), a molecular
variant of apo A-I, which results in very low plasma apo A-I and HDL-cholesterol
levels. Despite these low levels, and other lipoprotein defects, individuals with
this mutation have no increased risk for cardiovascular disease. As a first step
in proving why apo A-IM carriers appear to be protected from the pro-atherogenic
effect of a low HDL, transgenic mice expressing apo A-IM were generated. Mice
expressing either wild-type human apo A-I or apo A-IM, together with human apo A
II, were crossed into mice lacking murine apo A-I. Apo A-IM/A-II mice had lower
cholesterol and HDL plasma levels compared to apo A-I/A-II mice. Moreover, as in
human carriers, apo A-IM mice were characterized by elevated triglyceride plasma
levels and by the presence of a population of very small HDL particles. These
results indicate that the expression of apo A-IM in a mouse model reproduces the
major lipid/lipoprotein abnormalities observed in human carriers. Thus, apo A-IM
transgenic mice appear to be a suitable model in which to assess whether the
mutation has an anti-atherogenic effect.
PMID- 9544741
TI - Characterization of atherosclerotic lesions in apo E3-leiden transgenic mice.
AB - Apo E3-leiden transgenic mice express human dysfunctional apo E variant and
develop hyperlipidemia and atherosclerosis on a high fat/high cholesterol diet.
We characterized diet-induced atherosclerotic lesions in apo E3-leiden transgenic
mice using immunocytochemical methods in order to examine foam cell formation and
determine whether advanced atherosclerotic lesions develop in these animals.
Special attention was given to the presence of oxidized lipoproteins and
expression of lipoprotein receptors. Plasma cholesterol levels in apo E3-leiden
mice on an atherogenic diet increased from 2 to 36 mmol/l in 4 months. At this
time apo E3-leiden mice had developed lesions, which ranged from early fatty
streaks in thoracic and abdominal aorta to advanced lesions in aortic arch. Early
fatty streaks were entirely composed of macrophages which also expressed
scavenger receptors. Epitopes characteristic of oxidized LDL were present in
macrophage-rich foam cells. Advanced atherosclerotic lesions also developed in
apo E3-leiden mice including smooth muscle cell cap formation and erosion of the
media. Macrophages and epitopes characteristic of oxidized LDL were present in
core and shoulder regions. Scavenger receptors were expressed in macrophages in
advanced lesions, whereas LDL-receptor-related protein (LRP) was mainly expressed
in smooth muscle cells. It is concluded that: (1) macrophages are the major cell
type in both early and advanced atherosclerotic lesions; (2) scavenger receptors
and oxidized lipoproteins are present in lesion macrophages; and (3) LRP is
mostly expressed in smooth muscle cells. Thus, lesions in apo E3-leiden
transgenic mice have features in common with human atherosclerosis. Since lesion
macrophages also retain their ability to synthesize endogenous apo E, apo E3
leiden transgenic mouse may be a useful model for studies on the development and
genetics of atherosclerosis.
PMID- 9544742
TI - Psychosocial stress causes endothelial injury in cynomolgus monkeys via beta1
adrenoceptor activation.
AB - Current evidence links psychosocial factors to exacerbation of diet-induced
atherosclerosis in monkeys via activation of the sympathetic nervous system.
However, it is uncertain whether these factors can potentiate initial lesion
formation, and do so even in the absence of dietary provocation, and whether any
such effects can be prevented by beta-adrenergic blockade. As endothelial injury
has been considered an initiating event in atherogenesis, we studied the effect
of psychosocial stress on endothelial integrity in 48 adult male cynomolgus
monkeys (Macaca fascicularis). All animals were housed in 12 social groups of
four monkeys each for 11 weeks. The monkeys in half of the groups were exposed to
a socially unstable ('stressed') condition for 72 h and received saline (n = 8),
a lipophilic beta1-blocker (metoprolol, 0.30 mg/kg per h; n = 8), or hydrophillic
beta1-blocker (atenolol, 0.15 mg/kg per h; n = 8). The remaining six social
groups were assigned to the socially stable (non-stressed) condition; for 72 h
these animals all remained in their social groups and were similarly treated with
saline (n = 8), metoprolol (n = 8), or atenolol (n = 8). The frequency of IgG
positive (injured) endothelial cells was estimated on en face (Hautchen)
preparations from the thoracic aorta and coronary arteries. Psychosocial stress
caused a significant increase in the number of injured endothelial cells in the
circumostial areas of the descending thoracic aorta in the placebo group (0.3 vs.
0.8%, P < 0.02), an effect that had not been demonstrated previously. Moreover,
beta-blockade significantly (P < 0.01) inhibited the stress effect, with no
differences between the two beta-blocking agents. The number of injured
endothelial cells in the non-branched portions of the aorta and coronary arteries
were low and indistinguishable among groups; irregularities in the size and
location of branching points in the coronary arteries precluded analysis of these
sites. This study demonstrated that psychosocial stress induces endothelial
injury, and that this effect is mediated via beta1-adrenoceptor activation.
PMID- 9544743
TI - Troglitazone enhances glucose uptake and inhibits mitogen-activated protein
kinase in human aortic smooth muscle cells.
AB - The thiazolidinedione analogue troglitazone is an antidiabetic agent that
improves insulin resistance in rodents and humans. Although coronary artery
disease is common in patients with the insulin resistance syndrome, the effects
of troglitazone on smooth muscle cells (SMC) have not been fully elucidated. We
therefore examined the effects of troglitazone on cell growth and glucose uptake
in human aortic SMC. Mitogen-activated protein (MAP) kinase activity and glucose
transporter (Glut) 1 mRNA levels were also studied. In the absence of
troglitazone, insulin (10(-7) M) caused a 2-fold increase of DNA synthesis in SMC
and troglitazone suppressed the increase of DNA synthesis in a dose-dependent
manner. This growth suppression was accompanied by inhibition of MAP kinase
activity. On the other hand, troglitazone significantly increased Glut 1 mRNA and
enhanced glucose uptake in SMC. These results suggest that troglitazone affects
the insulin signaling pathways in SMC and suppresses growth while promoting
glucose uptake. Our findings support the application of troglitazone as an
inhibitor of SMC proliferation in patients with insulin resistance.
PMID- 9544744
TI - The effect of homocysteine on DNA synthesis in cultured human vascular smooth
muscle.
AB - Elevated plasma homocysteine is an established risk factor for vascular disease
although the mechanisms are unclear. Homocysteine has been reported to stimulate
DNA synthesis and proliferation in rat aortic smooth muscle cells. Human vascular
smooth muscle cells (HVSMC) from saphenous veins (n = 8), internal mammary
arteries (n = 6) and umbilical arteries (n = 2) were studied. To reflect DNA
synthesis, 3H-thymidine incorporation, during 24 h exposure to homocysteine in
concentrations from 0.0625 to 10 mM, was studied. Incorporation was significantly
increased up to 0.5 or 1 mM and thence was progressively depressed, the maximum
stimulation being 24 +/- 5(S.E.)% in vein (P < 0.005) and 34 +/- 4% in mammary
artery (P < 0.001) while incorporation fell to approximately 25% of the control
values at 10 mM (P < 0.001). Qualitatively similar results were obtained in
umbilical arteries. Homocysteine had a biphasic effect on DNA synthesis in
cultured HVSMC but the higher inhibitory concentrations are well above those
commonly found in vivo. While the conditions of exposure to homocysteine render
close analogy to the clinical situation impossible, homocysteine can stimulate
HVSMC, offering one possible mechanism for the involvement of homocysteine in the
pathogenesis of atherosclerosis.
PMID- 9544745
TI - Influence of genotype at the low density lipoprotein (LDL) receptor gene locus on
the clinical phenotype and response to lipid-lowering drug therapy in
heterozygous familial hypercholesterolaemia. The Familial Hypercholesterolaemia
Regression Study Group.
AB - The relationship between molecular defect and clinical phenotype has been
examined in 42 patients with heterozygous familial hypercholesterolaemia (FH) and
premature coronary heart disease. The defined defects included mutations in the
low density lipoprotein (LDL)-receptor gene (23/42) or the apolipoprotein B
Arg3500Gln mutation (5/42). Mean LDL-cholesterol was higher, both before and
during treatment with simvastatin and bile acid sequestrants, in patients
predicted as having a 'severe' mutation than in those with a 'mild' mutation
(8.72 +/- 2.02 mmol/l vs 6.63 +/- 1.8, P = 0.05 before and 4.51 +/- 0.90 mmol/l
vs 3.19 +/- 0.58, P = 0.05 during treatment). Maximum inducible LDL-receptor
activity in cultured lymphoblasts was inversely correlated with LDL-cholesterol
before (r2 = 0.499, P = 0.002) and during (r2 = 0.478, P = 0.004) treatment in
patients with a defined mutation in the LDL-receptor gene, but not in the 14
patients with no detectable molecular defect. LDL-cholesterol concentrations
before and during treatment were significantly correlated in patients with a
defined LDL-receptor gene mutation (r2 = 0.548, P = 0.0001), but not in those
with no detectable genetic defect. All these correlations were weak, however and
there were no differences in the response to treatment in terms of either
relative reduction or absolute decrease in LDL-cholesterol concentration between
patients with different LDL-receptor defects. We conclude that only part of the
variable phenotype of heterozygous FH patients is explained by different LDL
receptor defects and that other factors determine the severity of their
hypercholesterolaemia and the onset of coronary disease.
PMID- 9544747
TI - Why plasma should not be used to study paraoxonase.
PMID- 9544746
TI - Low density lipoprotein receptor mutations in a selected population of
individuals with moderate hypercholesterolemia.
AB - To evaluate mutations in the low density lipoprotein receptor (LDL-R) gene in
moderate primary hypercholesterolemia, a combination of polymerase chain reaction
(PCR), single-strand conformation polymorphism (SSCP) and direct sequencing, was
used to screen the LDL-R gene in a selected population of 82 unrelated
individuals with moderate elevation of plasma LDL-C [mean 4.55 +/- 0.55 mmol/l
(176.4 +/- 21.6 mg/dl)]. Four subjects (5%) were found to be heterozygotes for
missense mutations in the LDL-R gene. These mutations were located in four
different exons (exons 6, 7, 15 and 17) and all alters highly conserved residues
of LDL-R protein. None of these mutations were detected in 79
normocholesterolemic individuals. The mutation in exon 15 (T705I) was previously
reported in a compound heterozygote for familial hypercholesterolemia (FH). In
the proband carrying the mutation in exon 17 (R793Q), an in vivo LDL turnover
study was performed and it demonstrated a reduction of LDL catabolism. These
findings demonstrate that mutations in the LDL-R may occur in primary moderate
hypercholesterolemia. They also extend the concept that some FH patients may
present with a mild phenotype.
PMID- 9544748
TI - Can endothelial cells accumulate lipids?
PMID- 9544749
TI - A farewell to harms: experts debate global disease eradication efforts.
PMID- 9544751
TI - From the Centers for Disease Control and Prevention. Progress toward
poliomyelitis eradication--Bangladesh, 1995-1997.
PMID- 9544750
TI - FDA funding problems imperil safety of biological products in the United States.
PMID- 9544752
TI - From the Centers for Disease Control and Prevention. Enhanced medical assessment
strategy for Barawan Somali refugees--Kenya 1997.
PMID- 9544753
TI - A piece of my mind. After the miracle.
PMID- 9544754
TI - Gatekeeping: good or bad, but never indifferent.
PMID- 9544755
TI - Gatekeeping: good or bad, but never indifferent.
PMID- 9544756
TI - Gatekeeping: good or bad, but never indifferent.
PMID- 9544757
TI - Gatekeeping: good or bad, but never indifferent.
PMID- 9544758
TI - Gatekeeping: good or bad, but never indifferent.
PMID- 9544759
TI - Risk adjustment, quality assessment, and process of care.
PMID- 9544760
TI - Risk adjustment, quality assessment, and process of care.
PMID- 9544761
TI - Prevention and management of latex allergy.
PMID- 9544762
TI - Varicella infection in adults reporting prior varicella.
PMID- 9544763
TI - Medication dispensing and Medicaid managed care.
PMID- 9544764
TI - Reengineering quality in managed care.
PMID- 9544765
TI - Frequency of breast cancer attributable to BRCA1 in a population-based series of
American women.
AB - CONTEXT: Previous studies of BRCA1 mutation prevalence have been based on high
risk groups, yielding estimates that do not reflect the experience of the general
population of US patients with breast cancer. OBJECTIVE: To determine prevalence
of known disease-related mutations and other variants in BRCA1 and how it differs
by race, age at diagnosis, and family history status in a population-based sample
of white and black patients with breast cancer unselected for family history.
DESIGN: Case-control study. SETTING: A 24-county area of central and eastern
North Carolina. PARTICIPANTS: Cases were women aged 20 to 74 years diagnosed as
having a first invasive breast cancer between May 1993 and June 1996. Controls
were frequency matched to cases by 5-year age range and race. The first 211 cases
and 188 controls regardless of race and the subsequent 99 cases and 108 controls
of African American ancestry are included in this report. MAIN OUTCOME MEASURE:
Germline variants at any site in the coding sequence, splice junctions, 5'
untranslated region, or 3' untranslated region of the BRCA1 gene were analyzed in
cases, and selected variants were analyzed in controls. Screening was performed
using multiplex single-strand conformation analysis, with all potential variants
confirmed using genomic sequencing. RESULTS: Three of 211 patients with breast
cancer had disease-related variants at BRCA1, all of which were protein
truncating mutations. After adjustment for sampling probabilities, the proportion
of patients with breast cancer with disease-related variants was 3.3% (95%
confidence interval, 0%-7.2%) in white women and 0% in black women. Young age at
diagnosis alone did not predict BRCA1 carrier status in this population. In white
women, prevalence of inherited mutation was 23% for cases with family history of
ovarian cancer, 13% for cases from families with at least 4 cases of breast
cancer with or without ovarian cancer, and 33% for cases from families with both
breast and ovarian cancer and at least 4 affected relatives. Because these
results are based on few families at the highest levels of risk, confidence
intervals around these estimates are wide. An additional 5 patients had rare
missense mutations or a single amino acid deletion, the biological significance
of which is unknown. In black women, a variant in the 3' untranslated region was
statistically significantly more common in cases than in controls. CONCLUSIONS:
These data suggest that in the general US population, widespread screening of
BRCA1 is not warranted. In contrast, BRCA1 mutations are sufficiently frequent in
families with both breast and ovarian cancer, or at least 4 cases of breast
cancer (at any age), that genotyping might be considered. The emerging picture of
BRCA1 population genetics involves complex interactions of family history, age,
and genetic ancestry, all of which should be taken into account when considering
testing or interpreting results.
PMID- 9544766
TI - BRCA1 mutations and breast cancer in the general population: analyses in women
before age 35 years and in women before age 45 years with first-degree family
history.
AB - CONTEXT: Studies of high-risk families with multiple early-onset cases of breast
cancer have been useful for assessing the type and spectrum of germline mutations
on the BRCA1 gene, but do not provide guidance to women with modest family
history profiles. Thus, studies of women from the general population are needed
to determine the BRCA1 mutation frequency in women perceived to be at high risk,
and to develop profiles of those most likely to be carriers. OBJECTIVE: To
characterize frequency and spectrum of germline BRCA1 mutations in 2 categories
of women identified via population-based studies hypothesized to be at increased
risk of carrying such mutations: those diagnosed as having breast cancer before
age 35 years and those diagnosed before age 45 years who have first-degree breast
cancer family history. DESIGN: Study subjects were drawn from 2 population-based
case-control studies of breast cancer in young women on the basis of their family
history or their age of diagnosis. Cases were younger than 35 years or were
younger than 45 years with first-degree family history at the time of breast
cancer diagnosis and were ascertained via a population-based cancer registry, and
controls (women without breast cancer) were identified via random-digit dialing.
SETTING: Three counties in western Washington State. MAIN OUTCOME MEASURE: BRCA1
germline mutations in study subjects identified in DNA from peripheral blood
lymphocytes by single-strand conformation polymorphism analysis using primer
pairs that span the BRCA1 coding region and intron-exon boundaries. RESULTS: Of
193 women diagnosed as having breast cancer before age 35 years, none of whom
were selected on the basis of family history status, 12 (6.2%, 95% confidence
interval [CI], 3.2%-10.6%) had germline BRCA1 mutations. In 208 women diagnosed
before age 45 years who had first-degree breast cancer family history, 15 (7.2%,
95% CI,4.1%-11.6%) had germline mutations in BRCA1. In both groups, there were
variations in mutation frequency noted by age and by family history. Mutation
frequency decreased with increasing age of diagnosis. Higher proportions of
mutations were seen in cases with at least 1 relative diagnosed as having breast
cancer before age 45 years, in cases with greater numbers of affected relatives,
and those with ovarian cancer family history. Mutation frequency did not vary by
bilateral breast cancer family history. No frameshift or nonsense mutations were
observed in 71 control women with a first-degree family history, although
missense changes of unknown significance were seen in cases and controls.
CONCLUSIONS: Women with BRCA1 germline mutations lacked a common family history
profile. Also, a large proportion of the women with a first-degree breast cancer
family history and women diagnosed as having breast cancer before age 35 years
did not carry germline BRCA1 mutations. Hence, while early-onset disease and a
strong breast cancer family history may be useful guidelines for checking BRCA1
status, these findings on women drawn from the general population suggest that it
may be difficult to develop BRCA1 mutation screening criteria among women with
modest family history profiles.
PMID- 9544768
TI - Relationship of physical activity and television watching with body weight and
level of fatness among children: results from the Third National Health and
Nutrition Examination Survey.
AB - CONTEXT: Physical inactivity contributes to weight gain in adults, but whether
this relationship is true for children of different ethnic groups is not well
established. OBJECTIVE: To assess participation in vigorous activity and
television watching habits and their relationship to body weight and fatness in
US children. DESIGN: Nationally representative cross-sectional survey with an in
person interview and medical examination. SETTING AND PARTICIPANTS: Between 1988
and 1994, 4063 children aged 8 through 16 years were examined as part of the
National Health and Nutrition Examination Survey III. Mexican Americans and non
Hispanic blacks were oversampled to produce reliable estimates for these groups.
MAIN OUTCOME MEASURES: Episodes of weekly vigorous activity and daily hours of
television watched, and their relationship to body mass index and body fatness.
RESULTS: Eighty percent of US children reported performing 3 or more bouts of
vigorous activity each week. This rate was lower in non-Hispanic black and
Mexican American girls (69% and 73%, respectively). Twenty percent of US children
participated in 2 or fewer bouts of vigorous activity perweek, and the rate was
higher in girls (26%) than in boys (17%). Overall, 26% of US children watched 4
or more hours of television per day and 67% watched at least 2 hours per day. Non
Hispanic black children had the highest rates of watching 4 or more hours of
television per day (42%). Boys and girls who watch 4 or more hours of television
each day had greater body fat (P<.001) and had a greater body mass index (P<.001)
than those who watched less than 2 hours per day. CONCLUSIONS: Many US children
watch a great deal of television and are inadequately vigorously active. Vigorous
activity levels are lowest among girls, non-Hispanic blacks, and Mexican
Americans. Intervention strategies to promote lifelong physical activity among US
children are needed to stem the adverse health consequences of inactivity.
PMID- 9544767
TI - A randomized, double-blind trial comparing combinations of nevirapine,
didanosine, and zidovudine for HIV-infected patients: the INCAS Trial. Italy, The
Netherlands, Canada and Australia Study.
AB - CONTEXT: Current guidelines recommend that individuals infected with the human
immunodeficiency virus type 1 (HIV-1) be treated using combinations of
antiretroviral agents to achieve sustained suppression of viral replication as
measured by the plasma HIV-1 RNA assay, in the hopes of achieving prolonged
remission of the disease. However, until recently, many drug combinations have
not led to sustained suppression of HIV-1 RNA. OBJECTIVE: To compare the
virologic effects of various combinations of nevirapine, didanosine, and
zidovudine. DESIGN: Double-blind, controlled, randomized trial. SETTING:
University-affiliated ambulatory research clinics in Italy, the Netherlands,
Canada and Australia (INCAS). PATIENTS: Antiretroviral therapy-naive adults free
of the acquired immunodeficiency syndrome with CD4 cell counts between 0.20 and
0.60x10(9)/L (200-600/microL). INTERVENTION: Patients received zidovudine plus
nevirapine (plus didanosine placebo), zidovudine plus didanosine (plus nevirapine
placebo), or zidovudine plus didanosine plus nevirapine. MAIN OUTCOME MEASURE:
Plasma HIV-1 RNA. RESULTS: Of the 153 enrolled patients, 151 were evaluable. At
week 8, plasma HIV-1 RNA levels had decreased by log 2.18, 1.55, and 0.90 in the
triple drug therapy, zidovudine plus didanosine, and zidovudine plus nevirapine
groups, respectively (P<.05). The proportions of patients with plasma HIV-1 RNA
levels below 20 copies per milliliter at week 52 were 51%, 12%, and 0% in the
triple drug therapy, zidovudine plus didanosine, and zidovudine plus nevirapine
groups, respectively (P<.001). Viral amplification was attempted in 59 patients
at 6 months. Viral isolation was unsuccessful in 19 (79%) of 24, 10 (53%) of 19,
and 5 (31%) of 16 patients in the triple drug therapy, zidovudine plus
didanosine, and zidovudine plus nevirapine groups, respectively. Among patients
from whom virus could be amplified, resistance to nevirapine was found in all 11
patients receiving zidovudine plus nevirapine and in all 5 patients receiving
triple drug therapy. Rates of disease progression or death were 23% (11/47), 25%
(13/53), and 12% (6/51) for the zidovudine plus nevirapine, zidovudine plus
didanosine, and triple drug therapy groups, respectively (P=.08). CONCLUSIONS:
Triple drug therapy with zidovudine, didanosine, and nevirapine led to a
substantially greater and sustained decrease in plasma viral load than the 2-drug
regimens studied. Our results also suggest that suppression of viral replication,
as demonstrated by a decrease in the plasma HIV-1 RNA load below the level of
quantitation of the most sensitive test available, may at least forestall the
development of resistance.
PMID- 9544769
TI - Directly observed therapy for treatment completion of pulmonary tuberculosis:
Consensus Statement of the Public Health Tuberculosis Guidelines Panel.
AB - OBJECTIVE: To evaluate evidence on the relative effectiveness of directly
observed therapy in achieving treatment completion for pulmonary tuberculosis.
PARTICIPANTS: A panel of 11 practitioners representing the public health,
behavioral, and clinical management of tuberculosis was convened by the Council
on Linkages Between Academia and Public Health Practice in 1995 to develop public
health guidelines for tuberculosis treatment completion. EVIDENCE: English
language articles identified through MEDLINE (1966 to August 1, 1996) with
original data on directly observed therapy, supervised therapy, compliance,
treatment completion, case management, and treatment adherence for tuberculosis.
CONSENSUS PROCESS: Each eligible article underwent structured review by at least
2 panel members for study design, sample size, evaluation methods, and treatment
completion as the primary outcome. The full panel was convened twice, with
intercurrent small group meetings, conference calls, and summary workshop to
review findings. Recommendations made through this process were drafted by the
panel chair and circulated twice for additional panel comments. CONCLUSIONS:
Treatment completion rates for pulmonary tuberculosis are most likely to exceed
90%, as recommended by the Centers for Disease Control and Prevention, when
treatment is based on a patient-centered approach using directly observed therapy
with multiple enablers and enhancers. Other less intensive interventions,
including nonsupervised strategies and modified approaches to directly observed
therapy, are unlikely to achieve this recommended treatment completion goal.
Directly observed therapy also appears to be cost-effective compared with self
administered therapy, although data on cost-effectiveness are limited.
PMID- 9544770
TI - A 66-year-old woman with ulcerative colitis.
PMID- 9544771
TI - A 27-year-old woman with migraine headaches, 1 year later.
PMID- 9544772
TI - BRCA1 testing--advances and retreats.
PMID- 9544773
TI - HIV treatment strategies: planning for the long term.
PMID- 9544774
TI - Does television cause childhood obesity?
PMID- 9544775
TI - Attachment of group B streptococci to macrophages is mediated by a 21-kDa
protein.
AB - Group B Streptococcus (GBS) is able to bind to human macrophages in vitro in the
absence of exogenous opsonins. The exact mechanisms that mediate this attachment
are unclear. This study was undertaken to determine what protein adhesins are
present on the surface of GBS that mediate attachment to macrophages. We have
identified a 21-kDa protein from the envelope of GBS type III that directly binds
to macrophages as determined by Western blot analysis. Antiserum against this
protein was able to inhibit binding of GBS to macrophages by greater than 80% as
measured by flow cytometry. Antiserum against the 21-kDa protein cross-reacted
with 21-kDa proteins from GBS type Ib, type II, type III (COH31 and MR732) and
type IV, as well as Staphyloccus epidermidis, but not GBS type Ia, Listeria
monocytogenes or Enterococcus faecalis. This protein may be important in
mediating the attachment of GBS to macrophages in an opsonin-poor environment.
PMID- 9544776
TI - Effect of trifluoperazine on in vitro ATP synthesis by Mycobacterium leprae.
AB - The effect of trifluoperazine (TFP), a calmodulin antagonist, was investigated on
in vitro ATP levels of human derived Mycobacterium leprae. M. leprae were
obtained from biopsies from multi-bacillary forms of leprosy and were incubated
in a modified Dubos medium system which supports limited in vitro synthesis of M.
leprae. This incubation was carried out in the absence and presence of different
concentrations of trifluoperazine. Samples for estimation of bacillary ATP levels
were taken at day 0 and at 14 days of incubation. TFP inhibited ATP levels in M.
leprae and this inhibitory effect was marginal at 2.5 microg ml(-1) (35%
inhibition), highly significant at 5 microg ml(-1) (87% inhibition) and almost
total at 10 microg ml(-1) (98.5% inhibition). This compound appears to have
potential as an anti-leprotic drug and also as a broad spectrum anti
mycobacterial agent in view of its anti-tubercular activity reported earlier.
PMID- 9544777
TI - Sequence analysis of a compound coding-region microsatellite in Candida albicans
resolves homoplasies and provides a high-resolution tool for genotyping.
AB - Sequence diversity at a coding-region microsatellite locus of two diploid Candida
species was surveyed. Twenty-one alleles from fourteen strains of Candida
albicans and three alleles from two strains of the closely related Candida
dubliniensis were sequenced. Results show independent length variation in two
contiguous hexanucleotide repeats, one non-contiguous hexanucleotide repeat, and
two non-contiguous trinucleotide repeats within a 120 bp coding region. A
neighboring, non-repetitive 120 bp region showed no variation. The information
density of sequence polymorphisms in this region provides a powerful tool for
genotyping microorganisms in epidemiological studies, yielding detailed
resolution of closely related strains, and clearly distinguishing the two species
studied here. The individual length-variable repeat regions are very short (2-8
repeats), demonstrating that even very short microsatellites can show high levels
of length variability when surrounded by similarly repetitive DNA. Extensive
homoplasy was discovered among the C. albicans alleles, with the majority of
overall length categories consisting of alleles with more than one sequence. Our
results show that microsatellite length alone should not be used to assume either
sequence identity or identity by descent. Microsatellite length mutations appear
to have generated the high degree of both inter- and intraspecific polymorphism
seen at the ERK1 locus, and form an island of variability in an otherwise well
conserved gene.
PMID- 9544779
TI - Immunochemical characterization of an IgG-binding protein of Streptococcus suis.
AB - Several bacterial species express surface proteins with affinity for the constant
region (Fc) of immunoglobulin (Ig) of different animal species. Previous studies
from our group have reported the presence of an IgG-binding protein in various
serotypes of Streptococcus suis. This molecule was also shown to bind in a non
immune fashion chicken IgY and to our knowledge this characteristic is unique. In
the present study, by dot-blotting, we showed that the native protein, obtained
by affinity chromatography, reacted more strongly with IgG from various animal
species than the denatured material. Using a competitive enzyme-linked
immunosorbent assay the affinity of the native 60-kDa protein (previously
identified as a 52-kDa protein) towards IgG of various animal species was
compared to pig IgG. Bovine, goat and human IgG were able to compete effectively
with pig IgG whereas chicken IgY constituted a poor competitor. Peptide mapping
analysis using denatured protein indicated that pig and bovine IgG recognized the
same proteolytic fragment whereas chicken IgY did not. The smallest proteolytic
fragment that retained the binding activity towards the IgG of the different
animal species tested had a molecular mass of approximately 40 kDa. Fragments
with Mr < 40 kDa showed specific binding activities. That is, the smallest
fragment binding pig and bovine IgG had a Mr of 30 kDa whereas for goat and human
IgG a fragment of less than 16 kDa still showed binding activity. Finally, we
observed that antisera raised against a heat-shock protein of Pseudomonas
aeruginosa reacted with the 60-kDa S. suis protein indicating that the S. suis 60
kDa protein is a member of the 60-kDa hsp family that possesses the
characteristic of binding in a non-immune way mammalian IgG and chicken IgY.
PMID- 9544778
TI - A Salmonella typhimurium strain genetically engineered to secrete effectively a
bioactive human interleukin (hIL)-6 via the Escherichia coli hemolysin secretion
apparatus.
AB - Human interleukin-6 (hIL-6) cDNA was genetically fused with the Escherichia coli
hemolysin secretorial signal (hlyA[S]) sequence in a plasmid vector. Recombinant
E. coli XL-1 Blue and attenuated Salmonella typhimurium secreted a 30 kDa hIL-6
HlyA(S) fusion protein, with an additional form of higher apparent molecular mass
produced by S. typhimurium. In S. typhimurium cultures hIL-6-HlyA(S)
concentrations entered a plateau at 500 to 600 ng ml(-1) culture supernatant. In
contrast to E. coli XL-1 Blue, in S. typhimurium culture supernatants hIL-6
HlyA(S) was accumulated faster reaching three-fold higher maximal concentrations.
The cell proliferating activity of hIL-6-HlyA(S) fusion protein(s) was equivalent
to that of mature recombinant hIL-6. Furthermore. hIL-6-secreting S. typhimurium
were less invasive than the attenuated control strain. Therefore, the bulky
hemolysin secretorial peptide at the C-terminus of the fusion protein does not
markably affect hIL-6 activity, suggesting that the hemolysin secretion apparatus
provides an excellent system to study immunomodulatory effects of in situ
synthesized IL-6 in Salmonella vaccine strains.
PMID- 9544780
TI - Characterization of antigens recognized by new monoclonal antibodies raised
against culture filtrate proteins of Mycobacterium bovis bacillus Calmette
Guerin.
AB - Effective protection against Mycobacterium tuberculosis may be achieved in
experimental animals by immunization with proteins secreted by tuberculous
bacilli in the extracellular milieu during growth. In this study, monoclonal
antibodies were raised against Mycobacterium bovis bacillus Calmette-Guerin (BCG)
culture filtrate proteins or live BCG, in an attempt to identify novel
mycobacterial secretion antigens: the localization of the antigens recognized by
the monoclonal antibodies within the mycobacterial cell was studied and
interspecies reactivity was also investigated. The monoclonal antibodies obtained
recognized proteins of molecular mass ranging from 5 to 82 kDa, with a prevailing
frequency in the 30 kDa region. Three of the monoclonal antibodies recognized
proteins present only in culture filtrates, one reacted with a cytoplasmic
antigen, while the remaining antibodies recognized components which were mainly
associated with the cell wall and the cytoplasmic membrane. The chemical nature
and possible identity of the antigens was checked. Three monoclonal antibodies
are likely to react with novel mycobacterial antigens of 5, 42 and 82 kDa,
respectively.
PMID- 9544781
TI - Induction of abnormal respiratory sounds by capsaicin in rats previously infected
with Bordetella pertussis.
AB - Sprague Dawley rats, previously infected with Phase-I Bordetella pertussis,
developed more severe abnormal respiratory sounds than normal animals, but not
coughing, when exposed to aerosolized capsaicin, one of several cough-inducing
agents tested. Stethoscope examination suggested that greater production of
pulmonary mucus might be occurring after capsaicin challenge of the infected
animals, compared to the uninfected controls. Rats of three other strains gave
characteristically different responses from the Sprague Dawleys. The
administration of capsaicin to B. pertussis-infected rats may provide useful
insights into the pathophysiology of excess mucus secretion in human pertussis.
PMID- 9544782
TI - Identification of mycobacterial HSP70 reactive human T cell clones discriminating
between M. tuberculosis and M. leprae.
AB - M. tuberculosis reactive CD4+ T cell clones were established from a BCG
vaccinated donor and tested for proliferative responses against complex
mycobacterial antigens like M. tuberculosis, M. leprae, and PPD, as well as the
recombinant M. tuberculosis HSP70 and HSP65 antigens from both M. tuberculosis
and M. leprae. This screening permitted the identification of T cell clones
specifically recognizing the mycobacterial HSP70 or HSP65 antigen. All HSP65
reactive T cell clones were cross-reactive for M. tuberculosis and M. leprae,
whereas three HSP70 reactive T cell clones only recognized M. tuberculosis. In
addition, HLA typing and blocking experiments with anti-HLA antibodies revealed
that antigen presentation to all M. tuberculosis reactive T cell clones was
restricted by HLA-DR3 molecules. We have thereby demonstrated the presence of
human T cell specificities directed against the mycobacterial HSP70 antigen that
are able to discriminate between M. tuberculosis and M. leprae.
PMID- 9544783
TI - Antifungal antibiotic hamycin increases susceptibility of Candida albicans to
phagocytosis by murine macrophages.
AB - Hamycin is an antifungal antibiotic produced by Streptomyces pimprina Thirum. In
the present study, the effect of hamycin on (a) the phagocytosis of Candida
albicans by murine peritoneal macrophages and (b) the cell surface hydrophobicity
(CSH) of C. albicans was investigated. Addition of hamycin to the culture of
macrophages and Candida cells increased the susceptibility of Candida cells to
the phagocytosis by macrophages. Pretreatment of Candida cells with hamycin
increased their vulnerability to killing by macrophages. Examination of physico
chemical properties of Candida cell surface showed a significant decrease in the
CSH. These findings suggest that the binding of hamycin to Candida cells induces
biochemical/physico-chemical alterations of the surface, so that it becomes more
susceptible to phagocytosis by murine macrophages.
PMID- 9544784
TI - Neuropeptides in the livers of mice during bacterial infections.
AB - Neuropeptides such as substance P (SP) and vasoactive intestinal peptide (VIP)
are known to act as immunomodulators. We investigated the induction of SP and VIP
in the livers of mice infected with Listeria monocytogenes or injected with
Tsukamurella paurometabolum. VIP was detected in the livers of mice after L.
monocytogenes infection by an immunohistochemical technique and preproVIP mRNA,
which was detected by reverse transcription-polymerase chain reaction (PCR), was
induced post infection. However, no SP was detected. In contrast, SP, but not VIP
was detected within granulomas in the livers of T. paurometabolum-injected mice,
suggesting VIP and SP might be selectively induced in the liver by different
bacterial infections.
PMID- 9544785
TI - Genotypic and phenotypic characterization of two Swedish isolates and two
prototypic strains of Coxiella burnetii.
AB - Two Swedish isolates of Coxiella burnetii and the two prototype strains of the
species, Nine Mile and Priscilla, were characterized with regard to their
multiplication and cytopathic effect on BGM cells and by PCR-based amplification
of repetitive element DNA and the C. burnetii-specific plasmids QpH1 and QpRS.
Moreover, 1330 bp of each 16S rRNA gene were sequence-determined. All four
strains multiplied at virtually the same rate and displayed the same type of
vacuoles in the BGM cells. Genetic homogeneity was observed inasmuch as the 16S
rDNA sequences were identical and the strains showed identical PCR amplification
patterns using primers specific to enterobacterial repetitive intragenic
consensus DNA sequences. The two Swedish strains and the Priscilla strain also
showed identical patterns after PCR amplification of repetitive extragenic
palindromic DNA sequences, whereas the Nine Mile strain demonstrated a similar,
but not identical pattern. Thus, the investigated strains demonstrated very
similar phenotypic and genotypic characteristics. This finding is discussed in
view of the very rare occurrence of domestic Q fever in Sweden.
PMID- 9544786
TI - New visions in the pharmacology of anticonvulsion.
AB - Seizures are resistant to treatment with currently available anticonvulsant drugs
in about 1 out of 3 patients with epilepsy. Thus, there is a need for new, more
effective anticonvulsant drugs for intractable epilepsy. Furthermore, because of
the inadequacy of the currently available anticonvulsant armamentarium with
respect to safety, newly developed drugs should be less toxic than existing
drugs. Previous and current strategies for development of novel anticonvulsants
with improved efficacy or safety are critically discussed in this review. 'Old
drugs' (or 'first generation' drugs), which were developed and introduced between
1910 and 1970, are compared with new anticonvulsants both in terms of clinical
efficacy and safety and in terms of mechanisms of action. The new drugs are
referred to as 'second generation' drugs, i.e. anticonvulsants which have been
introduced into clinical practice in recent years, or 'third generation' drugs,
i.e. compounds in the pipeline of development. In spite of some 30 years of
'modern' neuroscientific epilepsy research, most novel, clinically effective
second generation anticonvulsants have been found by screening (i.e. serendipity)
or structural variation of known drugs and not by rational strategies based on
knowledge of processes involved in generation of seizures or in development of
epilepsy. An exception are only the GABA (gamma-aminobutyrate)-mimetic drugs
vigabatrin and tiagabine and, to some extent, gabapentin, which have been
developed by a rational strategy, i.e. the 'GABA hypothesis' of epilepsy. The
fact that preclinical seizure models used for identification and development of
novel drugs have been originally validated by old drugs, i.e. conventional
anticonvulsants, may explain that several of the new drugs possess mechanisms
which do not differ from those of the standard drugs. This may also explain that
none of the new drugs seems to offer any marked advantage towards the old, first
generation drugs with respect to the ultimate goal of drug treatment of epilepsy,
i.e. complete control of seizures, although some of the second generation drugs
may have benefits in terms of side effects and tolerability. It is to be hoped
that the various novel currently used or planned strategies for drug development
produce more effective and safe anticonvulsants than previous strategies. This
goal can only be achieved by strengthening our understanding of the fundamental
pathophysiology of seizure expression and epileptogenesis as theoretical
substrates for new pharmacological strategies, and by devising and refining
laboratory models for studying new agents obtained by such strategies.
PMID- 9544787
TI - Tetrahydroaminoacridine and D-cycloserine stimulate acquisition of water maze
spatial navigation in aged rats.
AB - We investigated the effect of tetrahydroaminoacridine, a cholinesterase inhibitor
and D-cycloserine (a partial glycine-B agonist of the NMDA receptor complex) on
the defect of water maze spatial navigation in rats induced by aging.
Tetrahydroaminoacridine (3 mg/kg, i.p.) or D-cycloserine (10 mg/kg, i.p.)
enhanced acquisition of the water maze task. A combination of subthreshold doses
of tetrahydroaminoacridine (1 mg/kg) and D-cycloserine (3 mg/kg) improved water
maze acquisition, but a combination of lower subthreshold doses
(tetrahydroaminoacridine 0.3 mg/kg + D-cycloserine 1 mg/kg) was ineffective.
Consolidation in water maze test was not improved by tetrahydroaminoacridine (3
mg/kg) and/or D-cycloserine (10 mg/kg). The results suggest that
tetrahydroaminoacridine and D-cycloserine synergistically enhance acquisition of
spatial navigation in aged rats.
PMID- 9544788
TI - The anxiolytic effect of gamma-hydroxybutyrate in the elevated plus maze is
reversed by the benzodiazepine receptor antagonist, flumazenil.
AB - The effects of gamma-hydroxybutyrate (GHB), a product of gamma-aminobutyric acid
(GABA) metabolism which possesses neuromodulatory properties in brain, were
investigated in the elevated plus maze in rats. The number of entries and the
time spent in the open arms of the maze were increased by GHB (50, 150, 250 mg/kg
i.p.). This is classically considered as indicative of an anxiolytic effect of
the drug. There was no sedative effect at these doses as measured by the
spontaneous locomotor activity in the actimeter or the total number of arm
entries. The anxiolytic properties of GHB were reversed by neither the GHB
receptor antagonist, NCS-382 (6,7,8,9-tetrahydro-5(H)-5-olylidene acetic acid)
(300 mg/kg i.p.), nor the opioid receptor antagonist, naloxone (10 mg/kg i.p.).
However the anti-anxiety effect of GHB was antagonized by the benzodiazepine
receptor antagonist, flumazenil (10 mg/kg i.p.), suggesting an interaction of GHB
with the GABA(A) receptor complex which mediates the anti-anxiety effect of
benzodiazepines.
PMID- 9544789
TI - Chronic exposure to melatonin receptor agonists does not alter their effects on
suprachiasmatic nucleus neurons.
AB - Previous studies have demonstrated that melatonin and a novel melatonin receptor
agonist, S20098 (N-[2-(7-methoxy-1-naphthyl) ethyl] acetamide), regulate neuronal
firing activity of photically responsive cells in the suprachiasmatic nucleus in
vivo. In the present study, we used several different methods to investigate the
effects of chronic daily treatment with melatonin, S20098 (1.0 mg/kg, s.c.) or
control vehicle for 14 d on responsiveness of suprachiasmatic nucleus cells to
these agonists. Both chronic and acute application of drugs were carried out
during the day-night transition period. We confirmed that suprachiasmatic nucleus
cells from control animals were most sensitive at this circadian phase. Chronic
drug treatments did not alter sensitivity of photically responsive
suprachiasmatic nucleus cells to S20098 or melatonin given intraperitoneally
(i.p.) or iontophoretically in vivo. Suprachiasmatic nucleus cells studied in
brain slice preparations also responded similarly to micropressure ejections of
melatonin receptor agonists regardless of drug pretreatment. These results
indicate that chronic melatonin receptor agonist pretreatment does not result in
desensitization of suprachiasmatic nucleus neuronal responses to these agonists
during the daily phase of maximum melatonin sensitivity.
PMID- 9544790
TI - Weak anticonvulsant effects of two novel glycineB receptor antagonists in the
amygdala-kindling model in rats.
AB - In the present work we evaluated the anticonvulsant effects of two novel
antagonists of the glycine co-agonist site (glycineB receptor) within the N
methyl-D-aspartate (NMDA) receptor complex, MRZ 2/576 (a tricyclic pyrido
phtalazin dione derivative) and L-701,324 (7-chloro-4-hydroxy-3-(3-phenoxy)phenyl
2(H)quinoline). As a model of epilepsy we used amygdala-kindled rats, which are
considered as a model to study the efficacy of drugs against human complex
partial seizures. MRZ 2/576 (2.5-10 mg/kg i.p. 15 min before testing) did not
influence afterdischarge threshold, which is believed to be the most subtle
indicator of efficacy against kindled seizures, nor did it affect other measures
of seizure activity such as seizure severity, seizure duration and afterdischarge
duration. However, MRZ 2/576 produced dose-dependent ataxia as measured in the
open field and rotarod test. The highest dose tested (10 mg/kg) also markedly
reduced rectal temperature (by about 1.5 degrees C). L-701,324 (2.5-10 mg/kg i.p.
30 min before testing) dose dependently and significantly increased
afterdischarge threshold, but other seizure parameters remained unchanged. The
ataxia produced by lower doses of L-701,324 (2.5 and 5 mg/kg) was more pronounced
than that caused by MRZ 2/576. However, the ataxia observed following the higher
dose of L-701,324 (10 mg/kg) was less intense than that elicited by MRZ 2/576.
The behavioral alterations produced by the two drugs did not resemble those
characteristic for classical competitive and uncompetitive NMDA receptor
antagonists. In conclusion, our data indicate that glycineB receptor antagonists
are not promising candidates for the treatment of complex partial seizures in
humans, at least as monotherapy.
PMID- 9544791
TI - Increase in nitric oxide in the hypoxic-ischemic neonatal rat brain and
suppression by 7-nitroindazole and aminoguanidine.
AB - We measured the changes in nitric oxide (NO) metabolites in the brains of
neonatal rats with hypoxic-ischemic damage. There were two peaks of NO
metabolites in the lesioned side of the cortex without treatment: one during
hypoxia and the other during the re-oxygenation period. Prehypoxic treatment with
7-nitroindazole, a selective neuronal NO synthase inhibitor, suppressed both
peaks of NO metabolites, whereas prehypoxic treatment with aminoguanidine, a
selective inducible NO synthase inhibitor, partially suppressed only the peak in
the re-oxygenation period. These data suggest different roles of neuronal and
inducible NO synthases in the pathogenesis of hypoxic-ischemic encephalopathy.
PMID- 9544792
TI - Effects of imipramine and sertraline on protein kinase activity in rat frontal
cortex.
AB - Three-week administration of sertraline or imipramine to rats (10 mg/kg,
intraperitoneally, twice a day) increased ex vivo cyclic AMP-dependent protein
kinase activity in the soluble but not in the particulate fraction of the frontal
cortex. However, cyclic AMP-dependent protein kinase activity was not affected in
either fraction of the parietotemporal cortex and hippocampus. Neither
antidepressant altered protein kinase C activity in the soluble and particulate
fractions or Ca2+/calmodulin-dependent protein kinase II activity in the frontal
cortex. Therefore, sertraline and imipramine both selectively enhance cyclic AMP
dependent protein kinase activity in the frontal cortex. This enhancement might
be involved in their biochemical mechanisms.
PMID- 9544793
TI - Activation of genes for growth factors and cyclooxygenases in rat gastric mucosa
during recovery from stress damage.
AB - Growth factors and prostaglandins protect the gastric mucosa against stress
induced lesions but their role in the recovery of the mucosa from these lesions
has been little studied. We evaluated gastric mucosa lesions, gastric blood flow,
mucosal generation of prostaglandin E2 and mucosal gene expression of epidermal
growth factor (EGF) and transforming growth factor alpha (TGF alpha) as well as
constitutive prostaglandin cyclooxygenase-1 and inducible cyclooxygenase-2 and
the effect of the inhibition of these enzymes on the recovery of mucosa from the
stress-induced lesions. Rats were exposed to 3.5 h of water immersion and
restraint stress and killed at 0, 2, 4, 6, 8, 12 and 24 h after stress. The
number of gastric lesions was determined and gastric blood flow was measured by
H2-gas clearance. Gastric acid secretion was tested in separate gastric fistula
rats. Gastric mucosa biopsies were taken for determination of immunoreactive EGF
and TGF alpha. Expression of EGF and TGF alpha mRNA and cyclooxygenase-1 and
cyclooxygenase-2 mRNA was also determined by reverse-transcriptase polymerase
chain reaction. The number of gastric lesions induced by 3.5 h stress averaged
approximately 20 per rat and declined significantly at 2, 4, 6, 8 and 12 h, to
disappear almost completely after 24 h. This was accompanied by a gradual rise in
gastric blood flow, mucosal generation of prostaglandin E2 and mucosal EGF and
TGF alpha contents, while the increased gastric acid secretion returned to
normal. In the intact mucosa, EGF mRNA was not detected but TGF alpha mRNA was
found in measurable amounts. Following exposure to stress, the expression of both
these factors was significantly increased. Similarly, the expression of cyclo
oxygenase-1 and cyclooxygenase-2 mRNA was detected in the oxyntic mucosa at all
time intervals after exposure to stress. Indomethacin (5 mg/kg i.p.), an
inhibitor of cyclooxygenase-1 and cyclooxygenase-2, and meloxicam (1 mg/kg i.p.),
an inhibitor of cyclooxygenase-2, both prolonged the healing of stress lesions
and reduced the gastric blood flow, while enhancing gastric acid secretion at all
times tested. We conclude that healing of stress lesions results in the
restoration gastric blood flow and mucosal prostaglandin generation and that
these effects are accompanied by overexpression of EGF and TGF alpha as well as
cyclooxygenase-1 and cyclooxygenase-2 mRNA and by increased biosynthesis of
gastroprotective prostaglandin.
PMID- 9544794
TI - Protective effects of 3-aminobenzamide, an inhibitor of poly (ADP-ribose)
synthase in a carrageenan-induced model of local inflammation.
AB - A cytotoxic cycle triggered by oxidant-induced DNA single strand breakage and
subsequent activation of the nuclear enzyme poly (ADP-ribose) synthetase have
been shown to contribute to the cellular injury during various forms of oxidant
stress in vitro. The aim of the present study was to investigate the role of poly
(ADP-ribose) synthetase in a model of acute local inflammation (carrageenan
induced pleurisy), where oxyradicals, nitric oxide and peroxynitrite are known to
play a crucial role in the inflammatory process. The results show that the poly
(ADP-ribose) synthetase inhibitor 3-aminobenzamide (given at 1-30 mg/kg) inhibits
the inflammatory response (pleural exudate formation, mononuclear cell
infiltration, histological injury). Moreover, 3-aminobenzamide reduces the
formation of nitrotyrosine, an indicator of the formation of peroxynitrite, in
the lung. The present results demonstrate that 3-aminobenzamide, presumably by
inhibition of poly (ADP-ribose) synthetase, exerts potent anti-inflammatory
effects. Part of the anti-inflammatory effects of 3-aminobenzamide may be related
to a reduction of neutrophil recruitment into the inflammatory site.
PMID- 9544795
TI - Nitrosative and oxidative stress induced heme oxygenase-1 accumulation in rat
mesangial cells.
AB - The formation of nitric oxide (NO.) and superoxide (O2-) promotes rat mesangial
cell death. Apoptotic death is characterized by DNA fragmentation, caspase-3
activation and concomitant poly(ADPribose) polymerase cleavage, as well as
accumulation of the tumor suppressor protein p53. In close association with
apoptotic parameters we noticed upregulation of heme oxygenase by the NO donor S
nitrosoglutathione (GSNO) and the redox cycler 2,3-dimethoxy-1,4-naphthoquinone
(DMNQ) in a time- and concentration-dependent manner. In response to the NO.
donor, heme oxygenase-1 expression was more easily obtained than initiation of
apoptosis. Radical (NO./O2-) cogeneration abrogated DNA fragmentation, suppressed
caspase activation and lowered p53 accumulation, thereby promoting cell survival
of mesangial cells. In contrast, heme oxygenase-1 expression remained elevated
under conditions of GSNO/DMNQ coadministration. Conclusively, heme oxygenase-1 is
a stress marker for both nitrosative and oxidative stress. Accumulation of heme
oxygenase-1 is found under conditions of both, apoptotic cell death and cell
survival, thereby questioning a specific cytoprotective role of heme oxygenase-1
under conditions of NO. and/or O2- formation in rat mesangial cells.
PMID- 9544796
TI - Differential alpha1-adrenoceptor labeling by [3H]prazosin and [3H]tamsulosin.
AB - The radioligand binding properties of [3H]prazosin and [3H]tamsulosin at alpha1
adrenoceptors of several rat tissues, human prostate and cloned rat and human
alpha1-adrenoceptor subtypes were compared in Tris/EDTA buffer unless otherwise
indicated. The affinity of [3H]tamsulosin at tissue and cloned alpha1A- and
alpha1B-adrenoceptors was somewhat greater and smaller, respectively, than that
of [3H]prazosin. In most rat tissues and at cloned rat alpha1A- and alpha1B
adrenoceptors, [3H]tamsulosin had a smaller Bmax than [3H]prazosin. Studies with
rat liver showed that this was due to considerably poorer labeling of agonist low
affinity sites, while both radioligands detected similar numbers of agonist high
affinity sites. Statistically significant differences in the number of binding
sites for both ligands were not detected in HEPES or glycylglycine buffer, as the
detectable receptor number for [3H]prazosin and [3H]tamsulosin tended to be
smaller and greater, respectively, in these than in Tris/EDTA buffer. Among human
alpha1-adrenoceptor subtypes [3H]tamsulosin labeled fewer sites than [3H]prazosin
for alpha1B- but more sites for alpha1A- and alpha1D-adrenoceptors. We conclude
that [3H]prazosin and [3H]tamsulosin do not detect the same number of alpha1
adrenoceptors under a variety of conditions. This should be taken into account in
the interpretation of data obtained with either radioligand.
PMID- 9544797
TI - Effects of bisaramil, a novel class I antiarrhythmic agent, on heart, skeletal
muscle and brain Na+ channels.
AB - The effects of bisaramil, a novel diazabicyclononane antiarrhythmic agent, were
compared to those of lidocaine, a clinically used class Ib antiarrhythmic agent,
on heart, skeletal muscle and brain Na+ channels expressed in Xenopus laevis
oocytes using a two-electrode voltage clamp. Both bisaramil and lidocaine
produced a concentration-dependent tonic block of Na+ current that was most
effective on cardiac channels, but bisaramil was more potent than lidocaine. Both
drugs produced a concentration-dependent shift in the voltage-dependence of
inactivation and delayed recovery from inactivation. Bisaramil produced marked
frequency-dependent block of heart channels and mild frequency-dependent block of
skeletal muscle and brain channels, whereas lidocaine produced marked frequency
dependent block of all three channel types. Therefore, bisaramil shows tonic and
frequency-dependent blockade that is most potent against the heart Na+ channel,
which may account for its potent antiarrhythmic efficacy in vivo, and may result
in reduced central nervous system toxicity compared to clinically used agents
such as lidocaine.
PMID- 9544798
TI - Effect of SA4503, a novel sigma1 receptor agonist, against glutamate
neurotoxicity in cultured rat retinal neurons.
AB - We examined the effects of sigma1 receptor agonists against glutamate-induced
neurotoxicity in cultured retinal neurons. Primary cultures obtained from fetal
rat retinas (16-19 d gestation) were used. The neurotoxic effect of glutamate was
quantitatively assessed using the trypan blue exclusion method. A brief exposure
of retinal cultures to glutamate (500 microM) led to delayed neuronal cell death.
The glutamate-induced neurotoxicity was inhibited by (5R,10S)-(+)-5-methyl-10,11
dihydro-5H-dibenzo-[a,b]-cyclohepten-5 ,10-imine hydrogen maleate (MK-801). The
sigma1 receptor agonists, 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)
piperazine dihydrochloride (SA4503) and (+)-pentazocine at a concentration range
of 0.1 approximately 100 microM reduced the glutamate-induced neurotoxicity in a
dose-dependent manner. In addition, the neuroprotective effects of both SA4503
and (+)-pentazocine were antagonized by co-treatment with N,N-dipropyl-2-[4
methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride (NE-100), a
putative sigma1 receptor antagonist. These findings suggest that sigma1 receptor
agonists protect retinal cells against glutamate-induced neurotoxicity.
PMID- 9544799
TI - Clotrimazole and bifonazole detach hexokinase from mitochondria of melanoma
cells.
AB - Cancer cells are characterized by a high rate of glycolysis. Hexokinase (ATP: D
hexose 6-phosphotransferase, EC 2.7.1.1), the only glycolytic enzyme which binds
to mitochondria, is exceptionally high in cancer cells, and believed to play a
key role in regulating cell energy metabolism and cancer cell growth rate. We
have previously found that clotrimazole (1-(alpha-2-chlorotrityl)imidazole) and
bifonazole (1-(alpha-biphenyl-4-ylbenzyl)imidazole), the antifungal azole
derivatives, which were recently recognized as calmodulin antagonists, are
calmodulin antagonists which most effectively reduce glycolysis and ATP level in
B16 melanoma cells. They act through allosteric regulation and detachment of
glycolytic enzymes from cytoskeleton. Here we report of a novel, additional,
mechanism of action of these drugs. We show that they induce a dose-dependent
detachment of hexokinase from mitochondria of B16 melanoma cells. This effect
preceded the decrease in cell viability. These results suggest that clotrimazole
and bifonazole may be promising drugs in treatment of melanoma.
PMID- 9544800
TI - Ca2+ release-activated channels in rat stomach smooth muscle cells.
AB - In rat stomach fundus, contractions induced by Ca2+ (1.8 mM) were strikingly
potentiated by thapsigargin. This potentiation was partially inhibited by the
blockers of Ca2+ release activated channels (CRACs), miconazole and SK&F96365 ([1
[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole, HCL]) and
slightly blocked by the antagonist of calcium voltage-operated channels (VOCs),
isradipine. In dissociated cells in a 0Ca solution, thapsigargin potentiated the
increase in intracellular calcium after reintroduction of Ca2+. This potentiation
was partially reduced by the CRAC blockers, but not by the VOC blockers. This
data suggests that calcium influx increased due to the depletion of intracellular
calcium by thapsigargin and that this influx occurs predominantly through CRACs.
PMID- 9544801
TI - Specific G protein activation and mu-opioid receptor internalization caused by
morphine, DAMGO and endomorphin I.
AB - Previous studies have shown that the agonist [D-Ala2, N-Me-Phe4, Gly
ol5]enkephalin (DAMGO) but not morphine induces mu-opioid receptor
internalization [Arden, J.R., Segredo, V., Wang, Z., Lameh, J., Sadee, W., 1995.
J. Neurochem. 65, 1636-1645]. In the present study we investigated the
relationship between internalization of the mu-opioid receptor and the specific G
proteins activated following treatment with morphine, DAMGO and endomorphin I
(Tyr-Pro-Trp-Phe-NH2) (a putative endogenous mu-opioid receptor agonist) in human
embryonic kidney (HEK) cells. Endomorphin I and DAMGO, but not morphine, caused
mu-opioid receptor internalization. Morphine, DAMGO and endomorphin I each
activated Gi1 alpha/Gi2 alpha, Go alpha and Gi3 alpha to a similar extent, but
not Gq alpha/G11 alpha or Gs alpha in HEK membranes. Therefore, the three ligands
tested differed in their ability to internalize mu-opioid receptors even though
they were similar in activating individual G proteins.
PMID- 9544802
TI - Capillary electrophoretic behavior of milk proteins in the presence of non-ionic
surfactants.
AB - The electrophoretic behavior of alpha-lactalbumin and beta-lactoglobulins (A and
B) in the presence of non-ionic surfactants was studied by capillary
electrophoresis (CE), using a poly(ethylene glycol) coated capillary column. The
surfactants (Tween 20, Brij 35 and 78) were used as buffer additives. The
separation is based on the difference in the strength of protein-surfactant
association complexes, which results in a change of the effective electrophoretic
mobility. The modification of the electrophoretic mobilities of proteins was
observed and this variation permitted the estimation of the interaction between
protein and surfactant. The effect of surfactant type and concentration on the
migration behavior of protein in CE is discussed. It is found that the retention
behavior of the milk proteins (the alpha-lactalbumin and the beta-lactoglobulins)
in CE is very different. The pH of the buffer and the surfactant type influence
significantly the protein-surfactant interactions.
PMID- 9544803
TI - Characterization and application of new macroporous membrane ion exchangers.
AB - A new ready-to-use unit for high-performance membrane chromatography has been
characterized. Its dynamic capacity, resolving power and protein recovery were
measured at different flow-rates. The binding capacity was 0.5-2 mg/cm2 with a
95% recovery at 10 ml/min irrespective of the protein concentration up to 10
mg/ml. For very-high flow-rates (50 and 100 ml/min) the recovery was 90% and 70%.
At these flow-rates, the maximum back-pressure was about 0.1 MPa and was
independent of the filtration area. By increasing the filtration area, a
proportional capacity increase was obtained, indicating an easy scale-up. High
flow-rates had only a slight effect on resolution. This new adsorber was able to
purify IgM from supernatant of cell culture of a human hybridoma in less than 8
min with a high degree of purity (95%).
PMID- 9544804
TI - Physico-chemical characterization of proteins by capillary electrophoresis.
AB - The electrophoretic mobility of proteins was successfully determined by means of
capillary electrophoresis (CE) with various background electrolytes (BGEs). The
objective was focused on the variation in BGE physico-chemical composition and
the consequential impact on the observed protein charge. Experimental and
calculated mobilities, according to Henry's equation, versus ionic strength have
been compared. For positively-charged lysozyme, a good agreement between observed
and calculated mobilities was observed using triethanolamine chloride at pH 7.0
as the BGE. Mobility close to zero was shown using borate (pH 8.0) and phosphate
(pH 7.0) at a low ionic strength of about 20 mmol l(-1), and as a consequence,
specific adsorption of oxyanions was evidenced. Lysozyme retention in the case of
reversed-phase high-performance liquid chromatography (RP-HPLC) was decreased by
the presence of phosphate ions. CE and HPLC are complementary tools for
characterizing the behaviour of lysozyme. On the other hand, the mobility of the
negatively-charged alpha-lactalbumin remained constant as regards phosphate at pH
7.0 in the 20-200 mmol l(-1) range, contrary to the decrease that had been
expected with the increasing ionic strength. beta-Lactoglobulin exhibited
increasingly lower mobilities than those expected of boric acid/borate at pH 7.0
and 8.0 (I=20 mmol l(-1)).
PMID- 9544805
TI - Influence of the nature of coupling agents on insulin adsorption on supports
grafted with sialic acid for high-performance affinity chromatography.
AB - Porous silica exhibits excellent mechanical properties for use as a stationary
phase for high-performance liquid chromatography. However, negative surface
charges make it unusable in its native state. For this reason, silica beads are
coated with dextran polymers carrying a calculated amount of diethylaminoethyl
groups. Both the minimization of non-specific interactions and the hydrophilic
character of such supports allow their functionalization with biospecific ligands
and finally their use in high-performance affinity chromatography of biological
products. The use of these modified supports in high-performance affinity
chromatography requires a better understanding of various characteristics of
stationary phases. For this purpose, several techniques were utilized, in
particular, size-exclusion chromatography and adsorption of radiolabelled
albumin. These methods provided complementary information on the structure of
these supports. Coated silica-based supports were functionalized with sialic acid
by means of different coupling agents. The affinity of these supports for insulin
was determined by the establishment of adsorption isotherms and by high
performance affinity chromatography, to evidence the relationships between
structural characteristics of the supports and their separation properties. The
study of interactions between these supports and insulin allowed us to show the
importance of the coupling method on the performances of supports in affinity
chromatography.
PMID- 9544806
TI - Preliminary report on fractionation of fucans by ion-exchange displacement
centrifugal partition chromatography.
AB - A new method combining ion-exchange displacement chromatography with centrifugal
partition chromatography (CPC) was used for the fractionation of partially
depolymerized fucans (polysulphated polysaccharides). The ion-exchanger was
Amberlite LA2, a high-molecular-mass liquid secondary amine miscible with most
common organic solvents and immiscible with aqueous solutions. Ion-exchange
displacement centrifugal partition chromatography was performed with LA2 in
methyl isobutyl ketone (MiBK) as the stationary phase, water as the mobile phase,
Cl- as the carrier and OH- as the displacer. A complex mixture of partially
depolymerized fucans was resolved into adjacent families characterized by their
peak molecular mass and polydispersity. The Dubois test (sugar) and the azur A
test (SO3-) confirmed the displacement mode of the process, and size-exclusion
chromatographic controls confirmed its efficiency.
PMID- 9544807
TI - High-performance affinity chromatography for the purification of heparin-binding
proteins from detergent-solubilized smooth muscle cell membranes.
AB - Heparin and heparan sulfates are regulators of cellular events including
adhesion, proliferation and migration. In particular, the antiproliferative
effect of heparin on smooth muscle cell (SMC) growth is well described. However,
its mechanism of action remains unclear. Numerous results suggest an endocytosis
mediated by a still unknown heparin receptor on vascular SMCs. In order to
identify a putative heparin receptor on SMCs that could be involved in heparin
signalling, affinity chromatography supports were developed. In this paper, we
describe high-performance liquid affinity chromatography (HPLAC) supports
obtained from silica beads coated with dextran polymer substituted by a
calculated amount of diethylaminoethyl functions. With a polysaccharide dextran
layer, this type of support can be grafted with specific ligands, such as
heparin, using conventional coupling methods. In a previous work, we
demonstrated, using butanedioldiglycidyl ether, that silica stationary phases
coupled to heparin could be used for the fast elution and good peak resolution of
heparin-binding proteins. In the present work, an affinity chromatographic
fraction of SMC membrane extracts was analyzed by sodium dodecyl sulfate
polyacrylamide gel electrophoresis (SDS-PAGE) and six heparin-binding proteins
from dodecyloctaethyleneglycol monoether-solubilized SMCs were observed. Their Mr
values were between 40 and 70 kDa, with three major protein bands at 66, 45 and
41 kDa. These results indicate the usefulness of the chromatographic method for
purifying heparin binding proteins from SMC membrane.
PMID- 9544808
TI - Purification of a 41 kDa cod-allergenic protein.
AB - Cod fish is one of the foods most frequently involved in allergy. Only the cod
allergen Gad c I, a 12.3 kDa parvalbumin, has been purified and characterized.
Recently, we have detected allergen bands which have not previously been
described, in particular a 41 kDa protein, by Western-blot. In the present work,
this protein has been purified from a crude cod extract by ammonium sulfate
fractionation, hydroxyapatite chromatography and preparative electrophoresis; a
single band with an Mr of 41 x 10(3) was found in silver-stained sodium dodecyl
sulfate-polyacrylamide gel electrophoresis. The amino acid composition and the
isoelectric point of the protein were determined. The purified protein (p41) was
shown to bind specifically to reaginic IgE from sera of cod-allergic individuals
and to a monoclonal anti-parvalbumin which recognizes specifically the first
calcium binding site of parvalbumins. p41 may therefore contain a calcium binding
site corresponding to an IgE-epitope similar to that of Gad c I.
PMID- 9544809
TI - Capillary zone electrophoresis in normal or reverse polarity separation modes for
the analysis of hydroxy acid oligomers in neutral phosphate buffer.
AB - Capillary zone electrophoresis (CZE) with neutral phosphate buffer as the
background electrolyte was used to analyse water-soluble oligomers obtained by
polycondensation of racemic lactic acid. Two CZE separation modes were tested.
The first mode was based on normal separation (injection at the anodic side)
using a fused-silica capillary. Eight peaks were observed within a 60-min
migration time range. They were ascribed to dimer and higher water-soluble
oligomers. Peaks from dimer to tetramer were split due to sensitivity for the
fine structures at the level of the distribution of chiral lactic acid moieties
in oligomer chains. The second mode was based on reverse separation (injection at
the cathodic side) using a fused-silica capillary modified by adsorption of a
polycation on its inner wall. Under these conditions, oligomers were rapidly
separated without peak splitting. Considering the forces which are involved in
CZE, data were plotted as a function of 1/t scale, according to the equation
[signal]=f((-1)(k)/t) where k=0 and k=1 for normal and reverse separation modes,
respectively. Such a plot allowed direct comparison between the various runs
after a simple translation along the 1/t axis, regardless of the separation mode
and the variation of electroosmotic flow. The second separation mode allowed
separation of 3-hydroxybutyric acid and 6-hydroxyhexanoic acid oligomers. For the
former series of oligomers, a side reaction generating crotyl bonds was observed
due to the high sensitivity of CZE. It was shown that separation was governed by
the ratio charge/mass of the oligoesters whatever their structure.
PMID- 9544810
TI - Covalent chromatography of influenza virus membrane M1 protein on activated
thiopropyl Sepharose-6B.
AB - The M1 protein of influenza virus is a highly hydrophobic polypeptide that is
resistant to enzyme cleavage during incubation in water solutions. We show here
that the M1 protein that is immobilized on an insoluble activated support
(thiopropyl Sepharose-6B) by means of a thiol-disulfide exchange reaction
acquires sensitivity to trypsin. After tryptic digestion noncysteine-containing
peptides of M1 were removed by washing the support, while cysteine-containing
ones were detached from the support by reduction. As a result, 24 unique tryptic
peptides of M1 protein were clearly separated by reversed-phase high-performance
liquid chromatography. The described method opens a new way to the investigation
of functional properties of distinct domains of viral thiol proteins.
PMID- 9544811
TI - Analytical development of electrospray and nanoelectrospray mass spectrometry in
combination with liquid chromatography for the characterization of proteins.
AB - Mass spectrometry has significantly extended its applicability in the area of
characterization of protein structures. Electrospray ionization enables on-line
coupling with liquid chromatography which has become a powerful tool for the
characterization of peptide and protein mixtures. The most recent development of
a nanoelectrospray source, using capillary forces for a particularly mild analyte
transport and ionization into the mass spectrometer, opens a wide field for
applications to protein structure analysis. In this paper, the analytical
development of liquid chromatography-electrospray ionization mass spectrometry
and nano-electrospray ionization mass spectrometry, adapted to an electrospray
ionization quadrupole mass spectrometer and its application to the
characterization of noncovalent protein complexes are described.
PMID- 9544812
TI - Isolation of the O-glycosidically linked oligosaccharides obtained by alkaline
borohydride degradation from oviducal mucins of the toad Bufo bufo.
AB - A combination of normal-phase high-performance liquid chromatography (HPLC) on
amino-bonded silica and reversed-phase HPLC on octadecylsilica has been used to
separate the reduced oligosaccharides produced by alkaline borohydride
degradation of oviducal mucins obtained from the jelly coat of Bufo bufo. The
former technique provides suitable separation on the basis of molecular size,
while the latter method offers selectivity for stereoisomers. Thirty-four
compounds, ranging in size from a trisaccharide to a dodecaoligosaccharide, have
been isolated preparatively using a Supelcosyl LC-NH2 normal-phase column eluted
with aqueous acetonitrile and a Zorbax ODS reversed-phase column eluted with
water.
PMID- 9544813
TI - Purification of a recombinant protein expressed in yeast: optimization of
analytical and preparative chromatography.
AB - The industrial production of recombinant proteins requires control of both
fermentation and purification steps. For the serodiagnosis of toxoplasmosis, the
main antigen is a membrane protein of 30 kDa (P30). The P30 gene was cloned and
expressed in Schizosaccharomyces pombe at 0.7 microg/ml in culture medium. Batch
fermentation was optimized by the specific choice of peptones, which enabled
optimum growth and protein expression without reducing the efficacy of the
purification step. Analytical purification was then carried out using cation
exchange chromatography. For larger volumes, scaling up was performed on expanded
mode by using a Streamline system (Pharmacia). This purification step allowed us
to obtain a 67.5% recovery with a purification factor greater than 27-fold.
Expanded bed adsorption technology is a convenient and effective technique for
protein capture directly from feedstock, and the eluted fraction is ready for a
second affinity chromatography step. This second step is performed with a yield
of 40% and provides a final purification factor of 2000-fold.
PMID- 9544814
TI - Qualitative and quantitative analysis of hemoglobin variants by capillary
isoelectric focusing.
AB - We developed two capillary isoelectric focusing (CIEF) assays, in narrow pH
gradients, with the aim of routinely separating and quantitating normal and
abnormal hemoglobins (Hbs): a one-step CIEF assay where residual electroosmotic
flow mobilizes the proteins during focalization, and a two-step CIEF assay where
focused Hbs are mobilized by low pressure by maintaining high-voltage. The
resolution of 0.10 pH unit obtained with the one-step assay allowed the
separation of the Hbs A, F, S and C; but Hb A2, which represents about 2-3% of
whole Hb, could not be quantitated. The better resolution of 0.02 pH unit
obtained with the two-step assay allowed the separation of some Hb variants of
very close isoelectric points. The reproducibility of retention times was
satisfactory (C.V.<5%). Moreover, in this configuration quantitation of Hb A2, Hb
F and Hb S led to a standard deviation of less than 5%, allowing the diagnosis of
thalassemias. The one-step assay could be useful only for the detection of
abnormal variants, while the two-step assay could be applied to the routine
analysis of Hbs, with quantitation of minor fractions and presumptive
identification of variants.
PMID- 9544815
TI - Characterization of the oligomeric behavior of a 16.5 kDa peanut oleosin by
chromatography and electrophoresis of the iodinated form.
AB - Oleosins are amphipathic proteins associated with oil bodies in seeds. We
purified the major 16,500 peanut oleosin by preparative SDS-PAGE. Autoradiography
after SDS-PAGE separation of the iodinated oleosin revealed covalently bound
oligomers with Mr of 21,000, 33,000, 44,000 and 51,000. The strong capacity of
these oligomers to form aggregates and to be incorporated into large-sized
detergent micelles was demonstrated by gel permeation and isoelectric focusing. A
50% ethanol concentration was necessary to elute the 16,500 oleosin from octyl
groups in hydrophobic interaction chromatography showing its natural tendency to
interact with lipid acyl chains. This oligomerization behavior in aqueous
solution is an indirect reflection of the interactions that occur in the oil
body.
PMID- 9544816
TI - Methodology for vesicle permeability study by high-performance gel exclusion
chromatography.
AB - A methodology based on high-performance gel exclusion chromatography (HPLC-GEC)
has been developed to perform permeability studies of vesicles. Encapsulation of
two marker isothiocyanate fluorescein (FITC) dextrans of 4400 and 40,500
molecular mass was used as a model system. Combination of two TSK-PW columns, one
efficient in vesicle sizing (G6000 PW), the other in that of dextrans (G4000 PW),
was required to achieve complete particle separation and to remove entirely the
unentrapped dextran after encapsulation into vesicles. Coupling fluorescence and
light scattering detection allowed to control the efficiency of the separation,
to quantify the vesicle leakage and to follow both the integrity of the vesicles
and changes in their size. This methodology can be applied to other fields such
as encapsulation of water soluble compounds and drug delivery systems.
PMID- 9544817
TI - Evaluation of coupling of cobalamin to antisense oligonucleotides by thin-layer
and reversed-phase liquid chromatography.
AB - We have evaluated by chromatography two strategies of oligonucleotide binding to
vitamin B12 (cobalamin). The first one was based on a covalent linkage of
aminooligonucleotide to carboxycobalamin in presence of 1-ethyl-3-(3
dimethylaminopropyl)-carbodiimide hydrochloride (EDC). Carboxycobalamin and EDC
cobalamin were eluted with a retention time of 16.5 and 21.6 min, respectively,
in RP-HPLC, while aminooligonucleotide and oligonucleotide-cobalamin were
coeluted at 19.4 and 19.8 min. In the second strategy, avidin was coupled to both
biotinylated oligonucleotide and vitamin B12. Aminocobalamin and biotinylated
cobalamin had respective retention times of 13 and 15.7 min in RP-HPLC and
respective Rf values of 0.3 and 0.8 in thin-layer chromatography. Incubation of
avidin with biotinylated cobalamin produced, in Superose 12 gel permeation, a
peak with a retention time of 28 min, which corresponded to avidin-biotinylated
cobalamin as it disappeared with an excess of either biotin or biotinylated
oligonucleotide. In conclusion, we have prepared and purified by RP-HPLC and gel
permeation chromatography an oligonucleotide-avidin-cobalamin complex which will
be used as a vector complex of antisense oligonucleotides.
PMID- 9544818
TI - Effect of salt concentration gradient on separation of different types of
specific immunoglobulins by ion-exchange chromatography on DEAE cellulose.
AB - A three-stage process, consisting of an ammonium sulfate precipitation step,
dialysis desalination with microporous anion-exchange Neosepta membranes and
anion-exchange chromatography on DEAE-cellulose DE-52 was used for the isolation
of mouse monoclonal antibodies specific against different antigens. The ascites
fluids contained monoclonal antibodies against human IgG, against horseradish
peroxidase and against the heavy chain of human IgM. The effect of the salt
concentration gradient in the elution buffer was examined with the aim of
optimizing chromatographic conditions. The quality of separation of protein zones
was determined using sodium dodecyl sulfate-polyacrylamide gel electrophoresis
under non-reducing conditions. The immunoreactivity of purified monoclonal
antibodies was determined by enzyme-linked immunosorbent assay using a solid
phase adsorbed antigens against which each monoclonal antibody type was directed.
PMID- 9544819
TI - Affinity purification and characterization of recombinant human galectin-1.
AB - Galectin-1, a polypeptidic factor that can have major effects on cell growth and
apoptosis, was overexpressed in E. coli. This protein was purified to homogeneity
by affinity chromatography on lactose coupled to divinylsulfone-activated
agarose. The recombinant galectin-1 (rGAL1) was compared with the homologous
protein purified from human brain tissue using two-dimensional electrophoresis on
immobilized pH gradient (IPG-DALT). rGAL1 had a major isoelectric point of 5.4
(major pI of tissular galectin-1, 5.1) and its subunit molecular mass was 14500.
Addition of rGAL1 to Jurkat T-lymphoblastoid cells induced cell death in a
concentration-dependent manner.
PMID- 9544820
TI - Gastrectomy in elderly patients.
PMID- 9544821
TI - Frequent expression of bcl-2 protein in solitary fibrous tumors.
AB - The distinction of solitary fibrous tumors from histologically similar neoplasms
is often difficult because they rarely occur at a variety of extrapleural sites.
CD34 immunoreactivity has recently been recognized to be an adjunct for the
diagnosis of solitary fibrous tumors. However, it is now known that CD34 staining
is not entirely specific for this entity. We evaluated 23 solitary fibrous tumors
and 54 other spindle cell tumors often considered in the differential diagnosis
for immunoreactivity using monoclonal antibodies directed against bcl-2 protein,
which protects cells from apoptosis and CD34. The patients with solitary fibrous
tumors comprised 11 men and 12 women, ranging in age from 35 to 85 years (mean,
57.6 years). Fourteen tumors arose in the pleura, four in the retroperitoneum,
three in the superficial soft tissue and one each in the mediastinum and uterine
cervix. Nineteen of 23 solitary fibrous tumors (83%), irrespective of tumor site,
demonstrated diffuse cytoplasmic staining for bcl-2 protein. bcl-2
immunoreactivity was also observed in five of seven neurofibromas (71%), eight of
10 synovial sarcomas (80%) and one of three spindle cell lipomas (33%). CD34
immunoreactivity was present in all but one solitary fibrous tumor (96%), seven
of seven neurofibromas (100%), three of three spindle cell lipomas (100%), five
of five dermatofibrosarcomas (100%), three of three hemangiopericytomas (100%)
and two of seven malignant fibrous histiocytomas (29%). To date, most of the
pleural and extrapleural cases have not shown aggressive features. We suggest
that bcl-2 protein can be used together with CD34 in the diagnosis of solitary
fibrous tumor to distinguish this entity from other spindle cell neoplasms.
PMID- 9544822
TI - Determination of cytosol c-erbB-2 protein in breast cancer by sandwich enzyme
immunoassay.
AB - We determined cytosol c-erbB-2 protein levels using a sandwich enzyme immunoassay
in benign breast disease and primary and recurrent breast cancer and analyzed the
relationship between c-erbB-2 protein levels and clinicopathological factors.
Overexpression of c-erbB-2 protein, the cut-off value being set at 18 ng/mg
protein, was observed in 26 of the 139 cases of stages I-IIIB breast cancer
(18.7%), four of the 12 cases of stage IV breast cancer (33.3%) and seven of the
13 recurrent breast cancer cases (53.8%). The levels of c-erbB-2 protein were
significantly different between the stages. Overexpression of c-erbB-2 protein in
stages I-IIIB breast cancer was associated with histological grade and serum CEA
level, but not with other clinicopathological factors. In addition, there was an
inverse correlation in the group of stages I-III plus IV breast cancer between c
erbB-2 protein expression and estrogen receptor status. Overexpression of c-erbB
2 protein can be easily determined in the cytosol fraction together with hormonal
receptor by this method. The prognostic importance will be evaluated in ongoing
adjuvant trials for operable breast cancer patients.
PMID- 9544823
TI - CD4- and TCRalphabeta-positive T lymphocytes predominantly infiltrated into well
moderately differentiated colon adenocarcinoma tissues.
AB - Intraepithelial T lymphocytes have been reported as being functional in the
growth of epithelial cells and also in the discrimination of aberrant cells,
whereas their function against colon adenocarcinoma cells is obscure. The
phenotype of colon intraepithelial T lymphocytes has been found in patients with
inflammatory bowel diseases but not in patients with colon adenocarcinoma. In
this study, we investigated cell surface markers of tumor-infiltrating T
lymphocytes of adenocarcinoma of the colon and rectum at various grades of
differentiation and intraepithelial T lymphocytes of adjacent normal colon by
enzyme immunostaining. Among intraepithelial T lymphocytes of the normal colon,
CD8-and TCRgammadelta-positive T lymphocytes were predominant as described. In
contrast, tumor-infiltrating T lymphocytes of well-moderately differentiated
adenocarcinoma of the colon and rectum were predominantly CD4- and TCRalphabeta
positive. The decrease of TCRgammadelta-positive T lymphocytes and the increase
of CD4 and TCRalphabeta-positive T lymphocytes in adenocarcinoma tissues of the
colon and rectum suggests that an alteration of the local immune system
participates in the formation of adenoma and/or adenocarcinoma of the colon and
rectum, resulting in infiltration of CD4-positive T lymphocytes that have certain
activity against transformed cells.
PMID- 9544824
TI - Gastrointestinal cancer metastasis and lymphogenous spread: viewpoint of animal
models of lymphatic obstruction.
AB - Primary gastrointestinal cancer frequently spreads to the mesentery, omentum and
other parts of the peritoneum and these deposits are generally considered to be
induced by intraperitoneal seeding from the primary lesion. In this work, we
examined the spread of gastrointestinal cancer from the viewpoint of lymphogenous
metastasis using a rat model of mesenteric lymph vessel obstruction. With these
models, we carried out mesenteric lymphangiography on the fourth and sixth
postoperative days (five animals each) to examine morphological changes in the
lymph vessels and lymph flow. In model animals with mesenteric lymph vessel
obstruction, re-celiotomy, performed on the fourth postoperative day, revealed
marked mesenteric edema and enlargement of the mesenteric lymph nodes, suggestive
of lymph retention. We also carried out mesenteric lymphangiography and obtained
images of extensive mesenteric lymph vessels and reflux of lymph distal to the
obstruction point in all five animals. On the sixth postoperative day, we
obtained lymphangiographic images of lymphatico-venous communication in the
mesentery in all five animals. Thus in animals with lymph vessel obstruction, the
lymph flow appeared to change to lymphatico-venous communication or reverse
lateral flow. In clinical cases, it is conceivable that lymph retention and
reflux of lymph induced by lymph vessel obstruction sometimes play a role in the
mechanism of intraperitoneal cancer dissemination and hematogenous metastasis.
PMID- 9544825
TI - Usefulness of magnetic resonance imaging with dynamic contrast enhancement and
fat suppression in detecting a pancreatic tumor.
AB - The purpose of this study was to compare the value of dynamic magnetic resonance
imaging (MRI) and fat suppression in detecting a pancreatic tumor. The subjects
were 19 patients with invasive ductal adenocarcinoma and six patients with islet
cell tumor where diagnosis was established pathologically. Breath-hold gradient
echo images, breath-hold gradient echo images with fat suppression and breath
hold gradient echo images with dynamic enhancement at 1.5 T were obtained for all
patients. The efficacies of these three imaging techniques were compared by
calculating the contrast-to-noise ratio, as indicative of conspicuousness between
a tumor-affected and a normal pancreas. As for adenocarcinoma, our results
indicated that the usefulness in detecting the tumor was high, decreasing in the
order dynamic contrast images > fat suppression images > plain images, and that
the difference between any two of these three types of image was statistically
significant. On the other hand, these imaging techniques showed no statistically
significant difference in detecting islet cell tumors. In conclusion, dynamic MRI
is the best method for detecting pancreatic adenocarcinoma. As the fat
suppression technique has the advantage of being non-invasive, this method is
suitable for screening studies of pancreatic adenocarcinoma. However, no
advantage was recognized in using the fat suppression technique for detecting an
islet cell tumor in comparison with plain MRI.
PMID- 9544826
TI - The outcome of surgical treatment for gastric carcinoma in the elderly.
AB - Surgeons are increasingly being faced with the problem of treating elderly
gastric carcinoma patients. The purpose of this study was to elucidate the
feasibility of surgical treatment for these patients. Among 4740 gastric
carcinoma patients treated from 1971 to 1990, 112 (2.4%) were aged 80 or over.
The results of treatment in this elderly group were compared retrospectively with
those in 2664 younger gastric carcinoma patients (aged 50-69, control group,
56.2%). The TNM stage distribution and the curative resection rates (75.9 vs
81.4%) were similar between the groups. Reduced nodal dissection was more common
in the elderly group. The elderly had a higher incidence of preoperative risk
factors (76.8 vs 53.1%) and 90-day mortality (10.7 vs 3.9%). However, the
postoperative complication rates were similar between the groups. The 90-day
mortality rates in the elderly group were higher in the subgroups undergoing
total gastrectomy or D2 dissection. In the patients without pre-existing
morbidity, the 30-day mortality, 90-day mortality and postoperative complications
were similar between the groups. The 5-year survival rate after curative
resection of the elderly group was significantly lower than that of the control
group (44.4 vs 74.0%). This difference lost significance when non-cancer death
was excluded (62.5 vs 79.9%). We believe that, although gastrectomy can be
carried out safely in elderly patients, extended surgery should be limited to
those without preoperative morbidity.
PMID- 9544827
TI - Complications after surgery for gastric cancer in patients aged 80 years and
over.
AB - Recent studies have shown a considerable increase in the number of aged patients
with gastric cancer. In this retrospective study, we report our 18-year
experience with 110 patients aged 80 years and over affected with this neoplasm.
Postoperative morbidity and mortality rates and risk factors affecting their
incidence were examined by univariate and multivariate analysis. Operability and
resectability rates were 70.9% and 47.3% respectively. Of the resective
procedures, 41 (78.8%) were subtotal gastrectomies. In five cases (9.6%), we
performed combined resections. Twenty-five patients (32.1%) experienced
postoperative complications; overall mortality rate was 12.8% (10 patients). In
resective procedures, morbidity and mortality were 26.9% and 3.8% respectively,
which are very low rates compared to other Western reports. Statistical analysis
identified the number of preexisting medical illnesses as an independent
predictor of morbidity and mortality. Crude five-year survival rate of curatively
resected cases was 43%. Although multiple medical illnesses involved much higher
operative mortality, neither the presence of postoperative complications nor the
number of preexisting medical illnesses significantly influenced five-year
survival rate of curatively resected patients. With careful evaluation and
selection of patients, correct treatment of concomitant diseases and adequate
peri- and postoperative care, gastric surgery provides good immediate and long
term results even in very old patients. Subtotal gastrectomy with limited
lymphadenectomy should be the preferred procedure; total gastrectomy, combined
resections and extended lymphadenectomy should be performed only when necessary,
in patients with fewer than two illnesses. Surgery should be avoided in patients
with highly advanced disease, if multiple medical illnesses are present.
PMID- 9544828
TI - Macroscopic features at the deepest site of tumor penetration predicting liver
metastases of colorectal cancer.
AB - Liver metastasis is the gravest prognostic factor in colorectal cancer. To
identify a reliable indicator for liver metastasis, we evaluated macroscopic
features and seven established histopathological findings at the cut section
containing the deepest penetration using univariate and multivariate analyses in
417 colorectal cancers. Macroscopic features were divided into two types, streak
type and non-streak type, according to the presence or absence of white streak(s)
at the advancing margin of tumor invasion. Streak type was observed in 109
patients (26%). The frequency of liver metastasis in streak type tumors (56%) was
significantly higher than that in non-streak type tumors (13%) (p < 0.001). The
white streak corresponded histologically with cancer cells showing focal
dedifferentiation with marked stromal and perivascular fibrosis extending towards
the serosa or adventitia. In 343 curatively treated patients, univariate analysis
showed that recurrent liver metastasis was significantly associated with
macroscopic features, venous invasion, focal dedifferentiation and lymph node
metastasis. Multivariate analysis disclosed that macroscopic features and lymph
node metastasis were independent indicators of liver metastasis. These
macroscopic features, corresponding histologically to stromal behavior against
invading cancer cells, are a simple and useful indicator of liver metastasis of
colorectal cancer.
PMID- 9544829
TI - Navoban (tropisetron, ICS 205-930) and dexamethasone combination in the
prevention of vomiting for patients receiving preconditioning high-dose
chemotherapy before marrow transplantation.
AB - The anti-emetic efficacy of a combination of tropisetron and dexamethasone was
studied in 33 patients who underwent bone marrow transplantation. Another 50
patients receiving conventional anti-emetic therapies in bone marrow
transplantation served as control. On the first and second days of
preconditioning chemotherapy, 51% and 36% respectively of patients in the
tropisetron and dexamethasone group did not experience vomiting, compared with
only 12% and 10% of control group patients (P < 0.001). The mean number of
episodes of vomiting in the tropisetron and dexamethasone group was also
significantly lower than in the control group (0.97+/-1.65 vs 3.50+/-2.45 and
1.30+/-1.40 vs 4.44+/-2.91 respectively, both P < 0.001). Control of vomiting in
the two groups was not significantly different during days 3-6. Analysis of
patients receiving busulfan and cyclophosphamide as the preconditioning regimen
still showed better anti-emetic control in the tropisetron and dexamethasone
group than in the control group on the first two days of treatment (total control
rate 33.3% vs 6.5% and 44.4% vs 12.9% respectively, P < 0.001). Patients given
tropisetron and dexamethasone combination more frequently suffered from dizziness
and burning sensation of the chest. However, diarrhea and extrapyramidal symptoms
were the most frequent adverse effects seen after using conventional anti-emetic
combination. The combination of tropisetron and dexamethasone was thus superior
to conventional anti-emetic combinations in preventing vomiting during
preconditioning period of bone marrow transplantation. The adverse effects of
this combination were minimal and well tolerated by patients.
PMID- 9544830
TI - Results of a qualitative and field study using the WHOQOL instrument for cancer
patients.
AB - The main purpose of the study was to evaluate quality of life (QOL) among cancer
patients using the WHOQOL-100 instrument and to see if any significant
differences were seen in cancer stages, treatment status and prognosis. This
study consisted of two parts; qualitative and quantitative. For the qualitative
study, two focus groups were conducted by medical professionals to establish the
applicability of the WHOQOL instrument in evaluating the QOL of cancer patients,
but most participants were negative about using a generic instrument such as
WHOQOL. For the quantitative study, 197 cancer patients (average age 55.86) from
eight medical centers using the WHOQOL instrument, in addition to each patient's
information sheet filled in by their own physicians, were analyzed. The average
overall QOL score was 3.39. There was high reliability (Cronbach's alpha =
0.9685) and a high correlation between the psychological and the environmental
domains (r = 0.7021), the physical domain and the level of independence (r =
0.6031) and social relations and the environment (r = 0.6856) and between health
conditions perceived by patients and QOL scores. In addition, differences by
gender, treatments and cancer sites were also found to be significantly different
at the 5% significance level. The results indicated that the WHOQOL core
instrument was sensitive enough to evaluate the QOL of cancer patients.
PMID- 9544831
TI - Primary seminoma in the middle mediastinum: case report in a 69-year-old male.
AB - Primary mediastinal seminoma is an uncommon tumor usually located in the anterior
mediastinum. The majority of cases occur in young males. We report here an
extremely rare case of a 69-year-old male with primary seminoma in the middle
mediastinum. The patient had no complaints, but an abnormal shadow was seen in a
routine chest X-ray. We performed a tumorectomy in the middle mediastinum, a
thymectomy and an orchidectomy and added postoperative chemotherapy. It seems
that the tumor was not associated with the thymus, so we believe the tumor did
not stem from the embryonic thymus. Our case demonstrated that mediastinal
seminoma does not always occur in the anterior mediastinum of young males.
Although this case is rare, seminoma should be included among the possible
diagnoses of a middle mediastinal mass.
PMID- 9544834
TI - Research programs in Japan.
PMID- 9544833
TI - Anastomotic recurrence after curative resection of a transverse colon carcinoma:
a case report.
AB - We report a case of anastomotic recurrence after curative surgery for transverse
colon cancer in a 53-year-old man. The recurrence was first detected as a
submucosal tumor 1.3 cm in diameter, located on the suture line, during an annual
follow-up barium enema and colonoscopy. A repeat examination 3 months later
showed the lesion to be a typical colon cancer, 2.5 cm in size, with a large
ulcerated area. Right hemicolectomy was performed with curative intent.
Anastomotic recurrence is much rarer after colonic resection than after anterior
resection. This was the first time that we had detected a recurrent lesion as a
submucosal tumor during annual follow-up examination.
PMID- 9544832
TI - A case of malignant peritoneal mesothelioma showed complete remission with
chemotherapy.
AB - A 71-year-old woman presented with an abdominal mass and ascites and was
subsequently admitted to our hospital in June 1995. Further examination revealed
that the mass was malignant and, as a result, surgery was indicated. However, the
mass demonstrated widespread peritoneal dissemination, which therefore could not
be resected, and pathological findings suggested a malignant peritoneal
mesothelioma. The patient showed a remarkable response to combined chemotherapy
with an accompanying intraperitoneal injection of cisplatin and etoposide and an
intravenous injection of caffeine. However, owing to side effects, this regimen
was discontinued. The patient was administered a combination drug of uracil and
tegafur (UFT) in addition to intraperitoneal injection of cisplatin as an
outpatient. By the 223rd day after surgery, the tumor mass and ascites had
completely disappeared according to the CT. Hence chemotherapy was judged to have
resulted in complete remission. Such a marked response to chemotherapy is rare in
an advanced malignant peritoneal mesothelioma such as the present case. Eight
months later, the tumor recurred in the pleura. Another regimen of chemotherapy
with cisplatin and CPT-11 was performed. However, this treatment proved
ineffective. The patient subsequently died of respiratory failure in January 1997
due to the mesothelioma. This is a case report of complete remission of malignant
peritoneal mesothelioma by combined chemotherapy.
PMID- 9544835
TI - A 50-year perspective of a family with chromosome-14-linked Alzheimer's disease.
AB - A Swedish family with two generations suffering from presenile dementia with an
unusually severe Alzheimer encephalopathy was first reported in 1946. The
hypothesis that the disease was inherited through a dominant gene is strongly
supported by the follow-up 50 years later of three additional generations and
molecular genetic findings of a novel presenilin-1 gene mutation in the family.
The pedigree contains six cases with well-documented dementia in four consecutive
generations. The Alzheimer encephalopathy was unusually severe in the three cases
studied post-mortem, with a pronounced involvement of the central grey
structures, such as the claustrum, the nuclei around the third ventricle, the
central thalamic nuclei and the brain stem. There were no vascular lesions and
little amyloid angiopathy. All six affected cases showed the typical
temporoparietal symptom pattern and other core symptoms of Alzheimer's disease,
such as logoclonia, myoclonic twitchings and major motor seizures. Other
predominant features were psychomotor slowness, increased muscular tension, a
stiff stooped gait and a rapid loss of weight. The symptom pattern is
convincingly explained by the consistent and severe involvement of cortical and
central grey structures and is probably linked to the presenilin-1 gene mutation.
PMID- 9544836
TI - Identification of CpG islands hypermethylated in human lung cancer by the
arbitrarily primed-PCR method.
AB - DNA hypermethylation is believed to be involved in human carcinogenesis, since it
suppresses the transcription of defined genes and is associated with chromosomal
instability. In this study, we identified CpG islands that are hypermethylated in
human lung cancer by a modified arbitrarily primed-polymerase chain reaction
method using genomic DNAs digested with a methylation-sensitive restriction
enzyme, HpaII, as templates. When we analyzed genomic DNAs from normal lung
tissues and non-small cell lung carcinoma cell lines using three arbitrary
primers, three DNA fragments were amplified from lung cancer DNAs but not from
normal lung DNAs. Restriction mapping and Southern blot analysis revealed that
all of these bands were amplified from CpG islands that were hypermethylated in
the lung cancer cell lines. These islands were mapped to chromosomes 4q34, 10q26
and 17p13.1-p13.2, respectively, and these chromosomal regions were also
hypermethylated in a subset of primary lung tumors in vivo. Thus, diverse
chromosomal regions are hypermethylated in lung cancer cells. The results also
indicate that this method is simple and effective for screening of CpG islands
that are hypermethylated in cancer cells.
PMID- 9544837
TI - Multiple different missense mutations in the pore region of HERG in patients with
long QT syndrome.
AB - Long QT syndrome (LQTS), is an inherited cardiac disorder in which ventricular
tachyarrhythmias predispose affected individuals to syncope, seizures, and sudden
death. Characteristic electrocardiographic findings include a prolonged QT
interval, T wave alternans, and notched T waves. We have screened LQTS patients
from 89 families for mutations in the pore region of HERG , the K+ channel gene
previously associated with chromosome 7-linked LQT2. In six unrelated LQTS
kindreds, single-strand conformation polymorphism analyses identified aberrant
conformers in all affected family members. These conformers were not seen in over
100 unaffected, unrelated control individuals, suggesting that they represent
pathogenic LQTS mutations. DNA sequence analyses of the aberrant conformers
demonstrated that they reflect five different missense mutations: V612L, A614V,
N629D, N629S, and N633S. The missense mutation A614V was found in two unrelated
families. Further functional studies will be required to determine what effect
each of these changes may have on HERG channel function.
PMID- 9544838
TI - Linkage of the apo CIII microsatellite with isolated low high-density lipoprotein
cholesterol.
AB - To evaluate whether a highly polymorphic microsatellite region within intron 3 of
the apolipoprotein (apo) CIII gene is linked to the isolated low HDL-C phenotype,
we studied eight unrelated probands (mean HDL-C = 10+/-5 mg/dl) and 157
biological family members. After PCR amplification of genomic DNA and denaturing
polyacrylamide gel electrophoresis, 26 alleles were identified in this
microsatellite including 9 alleles heretofore unreported. Quantitative sib-pair
linkage analysis demonstrated strong evidence of linkage between the isolated low
HDL-C phenotype and the apo CIII microsatellite region (P = 0.007). The
microsatellite was also linked to apo AI (P = 0.001), the primary apolipoprotein
of HDL-C. Therefore, this highly polymorphic microsatellite region is a
potentially important marker in the genetic evaluation of the isolated low HDL-C
phenotype.
PMID- 9544839
TI - Isolation of the human BACH1 transcription regulator gene, which maps to
chromosome 21q22.1.
AB - In order to contribute to the development of the transcriptional map of
chromosome 21, we performed exon trapping using cosmid clones mapped in the
region 21q22.1-22.2 and identified a number of potential exons. One of the
trapped exons (Genbank No. AF026200) showed a strong homology with the mouse
Bach1 gene (Genbank No. D86603), a transcription factor regulating gene
expression. We then isolated the full-length coding region of the human BACH1
gene using expressed sequence tags, reverse transcription-polymerase chain
reaction and rapid amplification of cDNA ends. The predicted BACH1 protein
contains 736 amino acids and is 88% identical to its mouse homolog. It contains
basic leucine zipper and BTB-zinc finger domains (which are directly involved in
DNA binding for transcription regulation). The BACH1 gene maps in a relatively
gene-poor region on 21q22.1 in yeast artificial chromosome 814c1 of the
collection of Chumakov et al. Northern blot analysis revealed that it is
expressed as an mRNA species of approximately 5.8 kb in all 16 adult and 4 fetal
tissues examined; an additional mRNA species of 2.8 kb was observed in adult
testis. The contribution of the BACH1 gene to the pathophysiology of trisomy or
monosomy 21 is unknown. In addition, no monogenic disorders associated with
mutations in the BACH1 gene have yet been identified.
PMID- 9544840
TI - Identification and characterization of a new human cDNA from chromosome 21q22.3
encoding a basic nuclear protein.
AB - Congenital heart disease (CHD) affects over 40% of Down syndrome (DS) patients.
The region proposed to contain the gene(s) for DS CHD has been restricted to
21q22.2-22.3, from D21S55 to MX1. The identification and functional
characterization of the genes mapping to this region is a necessary step to
understand the pathogenesis of CHD in DS. In an effort to contribute to the
construction of a transcriptional map of the DS CHD region we have performed
direct cDNA selection using a YAC contig that maps between ETS2 and D21S15 and
cDNAs synthesised from fetal heart structures. Here we describe the
identification and characterization of a new gene, WRB, that maps to 21q22.3
between ACTL5 and HMG 14 and appears to be widely expressed in adult and fetal
tissues. The new gene encodes a basic protein of unknown function containing a
tryptophan-rich carboxyl-terminal region and a potential nuclear localization
signal. Immunofluorescence analysis shows a predominant localization in the cell
nucleus. The understanding of the biological function of the protein product
should clarify the potential role of WRB in the pathogenesis of DS CHD.
PMID- 9544841
TI - Novel mutations of the peripheral myelin protein 22 gene in two pedigrees with
Dejerine-Sottas disease.
AB - Peripheral myelin protein 22 (PMP22), a membrane glycoprotein, plays a
significant role in the formation and/or maintenance of compact myelin in the
peripheral nervous system. We studied two pedigrees with Dejerine-Sottas disease
and identified two novel mutations in the PMP22 gene: one a 2-bp deletional
mutation at nucleotide positions 426 and 427 of exon 4 (this is predicted to
alter the reading frame at leucine 80 and thus to lead to frame-shifted
translation), and the other a guanine to thymine substitution at nucleotide
position 636 leading to a cysteine substitution for glycine 150. Both mutations
were located in the putative transmembrane domains reported in many cases of
Charcot-Marie-Tooth neuropathy, Dejerine-Sottas disease, and hereditary
neuropathy with liability to pressure palsies. The results suggest an important
role for the putative transmembrane domains of PMP22 in its function.
PMID- 9544842
TI - A high risk phenotype of hypertrophic cardiomyopathy associated with a compound
genotype of two mutated beta-myosin heavy chain genes.
AB - Hypertrophic cardiomyopathy (HCM) is a genetically and clinically heterogeneous
myocardial disease that is in most cases familial and transmitted in a dominant
fashion. The most frequently affected gene codes for the cardiac (ventricular)
beta-myosin heavy chain. We have investigated the genetic cause of an isolated
case of HCM, which was marked by an extremely severe phenotype and a very early
age of onset. HCM is normally not a disease of small children. The proband was a
boy who had suffered cardiac arrest at the age of 6.5 years (resuscitation by
cardioconversion). Upon screening of the beta-myosin heavy chain gene as a
candidate, two missense mutations, one in exon 19 (Arg719Trp) and a second in
exon 12 (Met349Thr), were identified. The Arg719Trp mutation was de novo, as it
was not found in the parents. In contrast, the Met349Thr mutation was inherited
through the maternal grandmother. Six family members were carriers of this
mutation but only the proband was clinically affected. Segregation and molecular
analysis allowed us to assign the Met349Thr mutation to the maternal and the
Arg719Trp de novo mutation to the paternal beta-myosin allele. Thus, the patient
has no normal myosin. We interpret these findings in terms of compound
heterozygosity of a dominant (Arg719Trp) and a recessive (Met349Thr) mutation.
Whereas a single mutated Arg719Trp allele would be sufficient to cause HCM, the
concurrent Met349Thr mutation alone does not apparently induce the disease.
Nevertheless, it conceivably contributes to the particularly severe phenotype.
PMID- 9544844
TI - Genetic and immunohistochemical detection of mutations inactivating the
keratinocyte transglutaminase in patients with lamellar ichthyosis.
AB - Autosomal recessive lamellar ichthyosis is a clinically heterogeneous group of
severe congenital keratinization disorders that is characterized by generalized
hyperkeratosis and variable erythema. About half of the patients have mutations
in the TGM1 gene, which encodes the keratinocyte transglutaminase. Linkage
studies have shown that at least two further loci for autosomal recessive
lamellar ichthyosis must exist. We present here two patients with lamellar
ichthyosis caused by mutations in the TGM1 gene. The first patient is compound
heterozygous for the novel missense mutation C53S and the splice mutation A3447G.
The second patient, a child of consanguineous parents from Tunisia, is homozygous
for the unknown nonsense mutation W263X. This is the first report of a mutation,
C53S, that affects the region of the keratinocyte transglutaminase that is
essential for anchorage of the enzyme to the plasma membrane. A novel, rapid in
situ transglutaminase activity assay revealed the absence of keratinocyte
transglutaminase activity in both patients. The mutations described are hence
causative for the ichthyosis phenotype.
PMID- 9544843
TI - Novel and recurrent tyrosine aminotransferase gene mutations in tyrosinemia type
II.
AB - Tyrosinemia type II (Richner-Hanhart syndrome, RHS) is a disorder of autosomal
recessive inheritance characterized by keratitis, palmoplantar hyperkeratosis,
mental retardation, and elevated blood tyrosine levels. The disease results from
deficiency in hepatic tyrosine aminotransferase (TAT). We have previously
described one deletion and six different point mutations in four RHS patients. We
have now analyzed the TAT genes in a further seven unrelated RHS families from
Italy, France, the United Kingdom, and the United States. We have established PCR
conditions for the amplification of all twelve TAT exons and have screened the
products for mutations by direct sequence analysis or by first performing single
strand conformation polymorphism analysis. We have thus identified the presumably
pathological mutations in eight RHS alleles, including two nonsense mutations
(R57X, E411X) and four amino acid substitutions (R119W, L201R, R433Q, R433W).
Only the R57X mutation, which was found in one Scottish and two Italian families,
has been previously reported in another Italian family. Haplotype analysis
indicates that this mutation, which involves a CpG dinucleotide hot spot, has a
common origin in the three Italian families but arose independently in the
Scottish family. Two polymorphisms have also been detected, viz., a protein
polymorphism, P15S, and a silent substitution S103S (TCG-->TCA). Expression of
R433Q and R433W demonstrate reduced activity of the mutant proteins. In all,
twelve different TAT gene mutations have now been identified in tyrosinemia type
II.
PMID- 9544845
TI - X chromosome-inactivation patterns in patients with Rett syndrome.
AB - Rett syndrome (RS) is a complex and severely disabling neurologic disorder,
restricted to females. As non-random X inactivation could indicate that the X
chromosome has a role in the etiology of the syndrome, we performed molecular
analysis based on the differential methylation of the active and inactive X
chromosomes with probe M27beta, taking into account the parental origin of the
two Xs, in 24 RS girls (including a pair of concordant monozygote twins), 22
mothers, and a control group of 30 normal women. The results showed a
significantly (Fisher's exact test) increased frequency of skewed X inactivation
in lymphocytes from 15/23 RS compared with 4/22 mothers (P = 0.0031) and 6/30
controls (P = 0.0021). Our results, together with those from the literature,
showed that as a group, RS patients are apparently more prone to skewed X
inactivation than their mothers and normal controls, and this suggests that the X
chromosome is somehow involved in RS etiology.
PMID- 9544846
TI - Exclusion of five subunits of cGMP phosphodiesterase in Leber's congenital
amaurosis.
AB - Leber's congenital amaurosis (LCA) is the earliest and most severe of all
inherited retinal dystrophies. Recently, we mapped an LCA gene to chromosome
17p13.1 (LCA1) and ascribed the disease to mutations of the retinal guanylate
cyclase (ret GC) gene in a subset of families of North African ancestry. Owing to
the genetic heterogeneity of LCA and considering that LCA1 results from an
impaired production of cGMP in the retina (with permanent closure of cGMP-gated
cation channels), we hypothesized that the activation of the cGMP
phosphodiesterase (PDE) could trigger the disease by lowering the intracellular
cGMP level in the retina. The rod and cone cGMP-PDE inhibitory subunits were
regarded therefore as candidate genes in LCA. Here, we report the exclusion of
five rod and cone cGMP-PDE subunits in LCA families unlinked to chromosome 17p13.
PMID- 9544848
TI - Allele frequencies of hereditary hemochromatosis gene mutations in a local
population of west Brittany.
AB - Hereditary hemochromatosis (HH) gene mutations, C282Y and H63D, have been
screened in a cohort of 254 presumably healthy persons originating from a western
region of France. The carrier frequencies of these mutations and the incidence of
HH have been estimated and compared with those of other studies. This cohort
contains two C282Y/C282Y genotypes and has the highest C282Y heterozygosity
frequency (17.46%) ever reported.
PMID- 9544847
TI - Familial mitochondrial DNA depletion in liver: haplotype analysis of candidate
genes.
AB - Two sons and one daughter of healthy consanguineous parents presented with fatal
hepatic failure in association with severe depletion of mitochondrial (mt)DNA in
liver; a third son is healthy. Other published cases of mtDNA depletion concern
single members of a family, which excludes the use of haplotype analysis. In the
family presented here, the inheritance of the genes for mitochondrial
transcription factor A (mtTFA), nuclear respiratory factor 1 (NRF-1),
mitochondrial single-stranded DNA-binding protein (mtSSBP), and endonuclease G
(EndoG) was studied using microsatellite markers linked to these genes. The
inheritance of the gene for mtDNA polymerase (pol gamma) was studied using a
polymorphic CAG repeat present within the coding region of the gene. EndoG and
mtSSBP were excluded, but mtTFA remains a candidate. Pol gamma or NRF-1
involvement would be compatible only with autosomal dominant inheritance. Coding
sequence analysis of NRF-1 and mtTFA revealed no novel mutations in affected
individuals.
PMID- 9544849
TI - Mutation analysis of the dystrophin gene in Southern French DMD or BMD families:
from Southern blot to protein truncation test.
AB - Data from 6 years of experience in molecular diagnosis of Duchenne (DMD) and
Becker (BMD) muscular dystrophy in Southern France are reported. DMD and BMD
patients have been extensively analyzed for deletions and for point mutations in
the dystrophin gene. By scanning the whole coding sequence as reverse-transcribed
from lymphocytes or muscular RNA by the protein truncation test, we have reached
a minimum of an 86% detection rate for point mutations responsible for DMD; these
mutations consist of nonsense, frameshifting, and splicing mutations. Four of 12
small alterations identified in our sample are novel and described in this study.
We also present an improved protocol for the automated detection of fluorescently
labeled duplex polymerase chain reactions of six known intragenic microsatellites
(Dys II, TG 15, STRs 44, 45, 49, and 50). Accurate sizing of the alleles at each
locus was performed, and we elucidated the sequence of several repeat units.
Allele frequencies at each of the six microsatellite loci and at one restriction
fragment length polymorphism site (intron 16/TaqI) were defined in a sample of
normal, DMD, and BMD X chromosomes from Southern France. The determination of the
grandparental origin of either deletions or point mutations revealed differences
depending on the type of the mutation, with most of the deletions occurring in
oogenesis and most of the point mutations occurring in spermatogenesis.
PMID- 9544850
TI - Analysis of low density lipoprotein receptor gene mutations and microsatellite
haplotypes in Greek FH heterozygous children: six independent ancestors account
for 60% of probands.
AB - This study reports the characterization of 60% of low density lipoprotein
receptor (LDLR) gene mutations in 150 unrelated Greek familial
hypercholesterolaemia (FH) heterozygous children by the analysis of six LDLR gene
mutations. The linkage disequilibrium of two polymorphic microsatellites (D19S394
and D19S221) flanking the LDLR gene on chromosome 19 to the four most common
mutations strongly suggests that each mutation is identical-by-descent in the
probands included in this study (this is also supported by the geographical
distribution of FH families with these mutations throughout Greece) and permits
an estimation of the number of generations from a common ancestor for each
mutation. The characterization of 60% of LDLR mutations in a representative
sample of Greek FH heterozygotes provides a basis for the diagnosis of FH through
DNA analysis in Greece, by using single-strand conformation polymorphism analysis
followed by allele-specific oligonucleotide hybridization (exon 6 mutations) or
restriction endonuclease analysis (C152R, V408M). A rapid diagnostic assay
positive for the mutation has been developed for the most common mutation, G528D.
The application of simple DNA diagnostic assays for LDLR mutation analysis are
appropriate for the early identification of FH heterozygotes in Greece and are
useful for the primary prevention of coronary artery disease.
PMID- 9544851
TI - Breast cancer risk assessment: use of complete pedigree information and the
effect of misspecified ages at diagnosis of affected relatives.
AB - Reliable risk estimates for hereditary breast cancer are important for the
genetic counseling of women who have one or more first- and/or second-degree
relatives affected by the disease. If no mutation analysis of known high
penetrance breast cancer genes is performed, risk estimation is often based on
published reference tables. These tables express a woman's age-specific risk of
breast cancer as a function of the ages at diagnosis of one or two affected
relatives with different degrees of relationship to the counselee. However,
unaffected relatives are not taken into account when these estimates are derived.
We report here the extent to which risk estimation is influenced by the number
and ages of any unaffected relatives and by the exact genealogical relationship
between the proband and affected relative rather than merely the degree.
Additionally, we describe the sensitivity of risk estimates when ages at
diagnosis of affected relatives are misspecified because of inaccurate
information supplied by the counselee. We determined a proband's probability of
being a carrier of a highly penetrant breast cancer susceptibility gene, such as
BRCA1 or BRCA2, by likelihood calculations that take into account information
from the entire pedigree. This genetic risk was used to estimate a phenotypic
lifetime breast cancer risk, which was compared with the risks derived from the
published reference tables. We demonstrate numerically that the tabulated values
tend to over-estimate the probands risk and that the extent of over-estimation
depends greatly on the number and ages of unaffected relatives. The validity of
the relatives ages at diagnosis can affect risk predictions considerably in small
families with two or three affected relatives. Furthermore, the magnitude of the
estimated breast cancer risks depends upon the assumed genetic model and can
therefore vary appreciably when different penetrance estimates are used.
PMID- 9544852
TI - Variable number tandem repeat polymorphism of the mucin genes located in the
complex on 11p15.5.
AB - A family of four genes that encode major secreted mucins (MUC6, MUC2, MUC5AC and
MUC5B) map to within 400 kb on chromosome 11p15.5. These genes contain long
stretches of tandem repeats of sequence that encode serine- and threonine-rich
domains but that otherwise show no similarity from gene to gene, and regions of
unique sequence domains that do show evidence of sequence homology. We have
previously reported the existence of polymorphism in three of these genes but the
extent and nature of this allelic variation is now described here in detail.
Variable number tandem repeat polymorphisms of MUC6, MUC2 and MUC5AC are
predicted to encode mucin polypeptides that differ in length. In the case of MUC2
and MUC6 these length differences are substantial (up to twofold). MUC5B in
contrast does not show common allele length variation. Three MUC2 mutations are
reported, none of which are associated with the meiotic recombinations previously
observed in this region of chromosome 11.
PMID- 9544853
TI - Two novel mutations in exons 19a and 20 and a BsaBI [correction of BsaI]
polymorphism in a newly characterized intron of the neurofibromatosis type 1
gene.
AB - Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder. It is
caused by mutations in the NF1 gene, which comprises 60 exons and is located on
chromosome 17q11.2. A total of 170 unrelated NF1 patients were screened for
mutations in four exons by temperature-gradient gel electrophoresis. Preparatory
work revealed the presence of a previously uncharacterized intron (19a) in what
was previously designated exon 19; this allowed us to develop assays for genomic
mutation screening in the newly defined exons 19a and 19b. Two novel NF1
mutations were detected: a single-base insertion in exon 19a creating a
frameshift, and a second mutation affecting the splice donor site of intron 20
and leading to skipping of exon 20. A novel BsaBI polymorphism was identified in
intron 19a.
PMID- 9544854
TI - Relationship of the angiotensin-converting enzyme gene polymorphism to glucose
intolerance, insulin resistance, and hypertension in NIDDM.
AB - The deletion (D) allele of the angiotensin-converting enzyme (ACE) gene
insertion/deletion (I/D) polymorphism has been shown to be associated with
cardiovascular and renal diseases in diabetes mellitus, but the mechanism
underlying this association is not known. In addition, recent studies of the
effect of the ACE gene on blood pressure have yielded conflicting results.
Therefore, we studied the association of the ACE gene I/D polymorphism with
glucose intolerance and insulin resistance, and the contribution of this locus to
genetic susceptibility to hypertension in non-insulin-dependent diabetic mellitus
(NIDDM). We analysed the ACE genotype in 84 unrelated NIDDM patients with a known
disease duration of less than 1 year and in 115 age- and sex-matched controls.
The I/D polymorphism was determined by the polymerase chain reaction. There were
no differences in ACE genotype distribution and allele frequencies between
patients with NIDDM and nondiabetic controls. The frequencies of the D and I
alleles in both groups were identical, viz., 0.65 and 0.35, respectively. The
NIDDM patients with the DD genotype had significantly higher blood glucose levels
in the oral glucose tolerance test than those with the other genotypes; the
incremental glucose area under the curve in the order of II, ID, and DD was 7.2+/
2.4, 9.2+/-4.0, and 10.7+/-2.7 mmol/l x h (II vs ID vs DD, P=0.0066 by ANOVA). No
significant difference was found between the ACE genotype and serum insulin
values. Similarly, there were no differences in body mass index, blood pressure,
or serum lipids between the three genotypes. Among the non-diabetic controls,
there was no statistically significant association of the I/D polymorphism with
serum lipids, blood glucose levels, serum insulin concentrations, or blood
pressure values. In conclusion, NIDDM patients with the DD genotype have higher
blood glucose levels and are more glucose intolerant; this may help to explain
the reported association between the D allele and vascular complications in
NIDDM.
PMID- 9544855
TI - A meta-analysis of clinical studies on the caries-inhibiting effect of fluoride
gel treatment.
AB - A meta-analysis was performed on published data on the caries-inhibiting effect
of fluoride gel treatment in 6- to 15-year-old children. The purposes of this
meta-analysis were: (1) to calculate the overall caries-inhibiting effect of
clinical fluoride gel treatment studies, based on explicit selection criteria,
and (2) to explore factors potentially modifying the effect of fluoride gel
treatment in caries prevention, concerning the baseline caries prevalence of the
target population, the general fluoride regimen, and application features. The
caries-inhibiting effect of fluoride gel application was assessed by the
prevented fraction and the 'number needed to treat'. The overall prevented
fraction of the fluoride gel treatment studies, indicating the reduction of
caries incidence by fluoride gel treatment relative to the incidence in the
control group, was 22% (95% CI = 18-25%). Multiple regression analysis showed no
significant influence on the prevented fractions for the variables 'baseline
caries prevalence', 'general fluoride regimen', 'application method', and
'application frequency'. The 'number needed to treat' (NNT), indicating the
number of patients that need to be treated in order to prevent 1 DMFS, estimated
the efficiency of fluoride gel treatment according to the caries incidence of the
target population, including cost/effect relations. It was found that the NNT =
18 in a population with caries incidence 0.25 DMFS per year, and NNT = 3 in a
population with caries incidence = 1.5 DMFS per year (treatment duration 1 year).
From the standpoint of cost-effectiveness, the additional effect of fluoride gel
treatment in current low and even moderate caries incidence child populations
must be questioned.
PMID- 9544857
TI - The isolation of Actinomyces naeslundii from sound root surfaces and root carious
lesions.
AB - The isolation of Actinomyces naeslundii from sound, exposed root surfaces (n =
56) and soft and leathery root carious lesions (n = 71) was investigated. Root
carious lesions were sampled after the removal of overlying plaque. Supragingival
plaque or carious dentine was sampled using a sterile excavator, the samples were
disaggregated and cultured on both selective and non-selective media. A.
naeslundii isolates were identified to the genospecies using specific antisera.
Significantly greater numbers and proportions of A. naeslundii genospecies 2 than
A. naeslundii genospecies 1 were isolated from all sites sampled. There was no
significant difference between the numbers and proportions of the two genospecies
isolated from leathery and soft lesions. The relationship between the presence of
A. naeslundii genospecies and aciduric and acidogenic organisms was investigated.
Those sound exposed root surfaces from which A. naeslundii genospecies 1 and/or 2
were isolated yielded significantly lower numbers of lactobacilli and yeasts than
the surfaces from which A. naeslundii were not isolated. This difference was also
found in leathery lesions but not soft root carious lesions. The microflora of
soft root carious lesions was found to comprise primarily gram-positive
pleomorphic rods which formed 70+/-7.8% of the flora, while in plaque from
exposed root surfaces and in infected dentine from leathery lesions the gram
positive pleomorphic rods represented only 35% of the flora.
PMID- 9544856
TI - Root caries and some related factors in 88-year-old carriers and non-carriers of
Streptococcus sobrinus in saliva.
AB - The prevalence of caries on exposed root surfaces in 88-year-old subjects with
and without salivary levels of Streptococcus sobrinus was studied. Ninety-two
individuals were examined with regard to root caries lesions and fillings. The
root caries index (RCI) was calculated and related to salivary flow rate and
buffer capacity, plaque score and salivary counts of Streptococcus mutans, S.
sobrinus and lactobacilli. In 89 subjects with exposed root surfaces, all but 2
harbored mutans streptococci; 51 subjects carried S. mutans only, 35 both S.
sobrinus and S. mutans, and 1 S. sobrinus only. The RCI was significantly higher
in persons with than those without S. sobrinus (p < 0.05). Subjects with both S.
sobrinus and S. mutans had higher counts of total mutans streptococci and
lactobacilli than subjects with only S. mutans (p < 0.05). The RCI was
significantly correlated to S. sobrinus and S. mutans (p < 0.05). The positive
correlation between the RCI and S. sobrinus was still significant when the other
tested variables were kept constant, whereas the correlation between the RCI and
S. mutans was weaker when S. sobrinus and lactobacilli were kept constant. The D
component of the RCI (DSr%) was significantly correlated to S. sobrinus, S.
mutans and lactobacilli, whereas the F-component of the RCI showed no significant
correlation to any of the tested variables. A stepwise multiple correlation
showed that the variance of DSr% was best explained in the S. sobrinus carriers
by S. sobrinus and the salivary buffer effect, and in the non-carriers by S.
mutans.
PMID- 9544858
TI - A descriptive report of the effects of a 16-month xylitol chewing-gum programme
subsequent to a 40-month sucrose gum programme.
AB - A previous caries trial (Belize studies) involved the usage of sucrose chewing
gum for a period of 40 months in one group of initially 10-year-old subjects in
an environment of high sugar consumption, high caries activity, and limited
access to restorative care. After the termination of the 40-month supervised
sucrose gum usage, the 109 subjects of the original sucrose group retrieved at
the endpoint of the original trial were invited to participate in a xylitol
chewing-gum programme (involving the usage of the '100% pellet-shaped formular')
for 16 months. The average daily consumption level of xylitol was up to 14 g per
subject, normally used in seven daily chewing episodes. Although most subjects
used chewing-gum at schools and received their gum portions from a school
official, gum chewing during these 16 months was mostly unsupervised. After 16
months, 83 subjects (76%; mean age 14.9 years) were retrieved. The caries status
of these subjects was examined by the same calibrated, blinded examiners as in
the original trial. To mask the examiners, 141 similar non-participating subjects
were recruited from the same school classes and were examined in a random order
with the gum-using subjects, according to the same standard routine. The
intensified xylitol gum usage for 16 months was associated with a reduction of
the mean DMFS score from 10.9 (at 40 months) to 9.3 (at 56 months, p = 0.0013)
and a reduction in caries rate from 20.1 caries onsets per 1,000 surface-years
(40-month period average rate) to 10.2 caries onsets per 1,000 surface-years. The
reduction in DMFS score resulted mostly from the change in the D component of the
index and possibly reflected a stabilisation of the caries process and
rehardening of some caries lesions to a non-progressive carious state.
PMID- 9544859
TI - Comparison of the efficacy of three different chlorhexidine preparations in
decreasing the levels of mutans streptococci in saliva and interdental plaque.
AB - The aim of the present study was to evaluate and compare the effects of three
different chlorhexidine (CHX)-containing preparations on mutans streptococci (MS)
levels in interdental plaque and whole saliva. Ninety-three healthy school
children (8-10 years old) with high scores of salivary MS were selected by a
screening procedure and randomised into three equally sized groups. MS were
enumerated at all mesial interdental sites of the first permanent molars with aid
of a modified chairside technique. The patients were then treated three times
within 2 weeks with either a 1% CHX/thymol-containing varnish (group A) or a 1%
CHX gel (group B), or they were subjected to daily supervised toothbrushing with
a 0.4% CHX dentifrice for 1 month (group C). Follow-up samples of saliva and
plaque from the interdental sites were collected 1 and 3 months after termination
of treatment. A statistically significant reduction of MS levels in saliva and
interdental plaque was found in all groups after 1 month. The CHX-containing
dentifrice (group C) was the most effective method in reducing MS levels in
saliva, and a significantly stronger (p < 0.05) suppression was found after 1 and
3 months when compared with the gel and the varnish forms. The gel (group B)
tended to be slightly more effective than the varnish (group A). In the
interdental plaque, the reduction of MS was less marked than in the saliva, and
the three groups exhibited MS reductions of similar magnitude (20%) and duration,
persisting up to 3 months. However, a high proportion (approximately 50%) of all
interdental sites were relatively unaffected by the treatments. In conclusion,
our results suggest that the interdental MS colonisation was difficult to combat,
irrespective of CHX preparation and method, while the salivary levels were more
easily affected. Daily tooth-brushing with a CHX-containing dentifrice was more
effective in reducing MS in saliva compared with the gel or varnish applications.
PMID- 9544860
TI - Three-year survival of one-surface ART restorations and glass-ionomer sealants in
a school oral health programme in Zimbabwe.
AB - An oral health care programme in secondary schools using the atraumatic
restorative treatment (ART) approach for dental caries was started in 1993. Glass
ionomer (restorative type II, 1) was used as the restorative and sealant
material. Sealants were placed using the 'press-finger' technique. Results after
3 years revealed a survival percentage for one-surface ART restorations of 85.3
(95% CL: 89.7-80.9%), which ranged from 96.1 to 69.3% per operator. Failures were
related to 'unacceptable marginal defects' (8.1%), 'falling out' (6.1%) and
'excessive wear' (2.5%). Of the 33 failed one-surface ART restorations, 17 were
material-related, 7 had caries and no information was available for 9
restorations. Sealants were placed only on surfaces diagnosed as early enamel
lesions and on some small dentinal lesions. After 3 years, 50.1% (95% CL: 55.1
45.1%) of the fully and partially retained sealants survived with a range of 68.5
25.9% per operator. Regardless of the low rate of retention, the sealed surfaces
had a 4 times lower chance of developing caries than unsealed surfaces with early
enamel lesions over the 3-year period. The retention of sealants and the survival
of one-surface ART restorations were influenced by an operator effect. The mean
treatment time for one-surface ART restorations without chairside assistance was
22.1 min (range per operator of 19.8-23.6 min), whilst the mean time for placing
sealants was 9.3 min (range per operator of 8.2-10.8 min). It is concluded that
the ART approach and the use of glass-ionomer sealants have made preventive and
restorative dental care available for this student population and further that
ART seems to be appropriate for population groups currently not receiving
preventive and restorative dental care.
PMID- 9544861
TI - The effect of a knowledge-based, image analysis and clinical decision support
system on observer performance in the diagnosis of approximal caries from
radiographic images.
AB - The aim of this study was to investigate the effect of a knowledge-based image
analysis and clinical decision support system (CariesFinder, CF) on diagnostic
performance and therapeutic decisions. The study material consisted of
radiographic images of 102 approximal surfaces, 35 sound, 67 caries (25 caries
and cavitated and 42 caries). Sixteen general practitioners were presented with
(1) radiographic film images and (2) digital filmless images with the results of
CF. The viewers were asked to respond whether approximal caries was present and
whether a restoration was indicated. Responses were analyzed for accuracy,
sensitivity, specificity and agreement. Further, the practitioners were ranked
according to the accuracy of their restorative decisions and assigned to ten
overlapping groups of 7 practitioners. For each group the diagnostic and
therapeutic decisions were then examined for unanimity. The parameters of
accuracy, sensitivity and specificity were then established for each group based
on only unanimous, correct decisions. The diagnostic and therapeutic accuracy of
CF alone was equal or superior to the decisions of the practitioners viewing film
images alone. For unanimous decisions, CF alone was more accurate than the most
accurate group of practitioners and made fewer incorrect decisions to restore non
cavitated surfaces than the practitioners. In general, dental practitioners
viewing the results of CF significantly increased their ability to diagnose
caries correctly, their overall diagnostic accuracy, and their ability to
recommend restorations for cavitated surfaces. There was a decrease in the
accuracy of their restorative decisions overall and in the specificity in
particular.
PMID- 9544862
TI - Human enamel as a substrate for in vitro acid dissolution studies: influence of
tooth surface and morphology.
AB - The variation in susceptibility of enamel to acid dissolution has been
quantitatively assessed in vitro by examination of different surfaces of both
maxillary and mandibular teeth of different morphology obtained from a pool of
sound human teeth. The lingual/palatal surfaces of all teeth showed greater
susceptibility to acid dissolution than the corresponding labial/buccal surfaces.
The palatal surface of the maxillary teeth appeared more susceptible to acid than
the lingual surface of the corresponding teeth in the mandible. The palatal
surfaces of the maxillary teeth showed least variation in acid susceptibility,
whilst the lingual surfaces of mandibular teeth and buccal/labial surfaces of
teeth from both jaws showed much more variation between teeth of different
morphology. These differences in susceptibility to acid dissolution probably
reflect both developmental differences and post-eruptive changes in enamel and
may contribute to the clinical presentation of dental disease. Importantly, the
data indicates that careful selection of teeth for in vitro study of enamel
dissolution processes is essential to minimise inter-sample variation. For such
purposes, the palatal surface of the maxillary teeth appears to be most suitable.
PMID- 9544863
TI - Inhibition of dentin demineralization by fluoride in vitro.
AB - Compared with the knowledge accumulated on enamel-fluoride interactions,
relatively little data is available regarding fluoride effects on dentin. This
applies to both laboratory and clinical studies into the efficacy of fluoride
schemes for the prevention of root surface caries. This study aimed to determine
the effects of fluoride and pH on the demineralization of dentin, such as to
provide information necessary to develop preventive programmes. Bovine dentin
blocks were subjected to undersaturated calcium- and phosphate-containing
solutions in the pH range 4.0-6.0 with fluoride added at concentrations between
0.5 and 10 ppm. Non-fluoride solutions served as controls. Mineral loss was
assessed chemically and by transversal microradiography. Comparisons were made
with similar studies on enamel demineralization. The results showed that
demineralization of dentin depends on both pH and fluoride concentration in the
demineralizing solution. Inhibition of demineralization that could be relevant
from a clinical point of view was found at fluoride values 5-10 times the
corresponding values for enamel. Also rapid depletion of fluoride from the
solutions was observed, indicating the high uptake capacity of dentin for
fluoride. Lesion depth depended on pH of the solution while the fluoride levels
were associated with the surface layer, both in mineral content and depth. For
dentin we propose a demineralization mechanism where acid penetrates rapidly into
the tissue, presumably through the tubules, after which the released calcium and
phosphate is partly trapped by the inward diffusing fluoride. This leads to the
formation of a surface layer, which may even be hypermineralized compared to
sound dentin.
PMID- 9544864
TI - The production of subsurface artificial caries lesions on third molar teeth.
PMID- 9544865
TI - Effect of antihypertensive treatment on cardiac and subcutaneous artery
structure: a comparison between calcium channel blocker and thiazide-based
regimens.
AB - The effects of two antihypertensive regimens (isradipine and hydrochlorothiazide
amiloride) on the ratio between media thickness and lumen diameter of
subcutaneous arteries and on left ventricular mass in essential hypertension were
compared. Fifty patients, aged 46.3+/-8 (mean+/-SD) years, with newly diagnosed
or poorly controlled essential hypertension were randomized to treatment with
either isradipine or hydrochlorothiazide-amiloride. Atenolol and hydralazine were
added in both groups as secondary and tertiary drugs, respectively, when needed
for normalization of diastolic blood pressure. A subcutaneous gluteal biopsy was
taken surgically before medication and again after 9 months of successful
antihypertensive treatment. Two small resistance arteries were isolated from each
biopsy and mounted in a Mulvany-Halpem isometric small vessel myograph. The media
thickness-to-lumen diameter ratio (percentage) of the vessels was measured under
standardized conditions and meaned. Left ventricular mass (LVM) index was
determined by echocardiography according to the Penn convention. Ten patients
were treated with isradipine as monotherapy, whereas only one patient was well
controlled on diuretics as monotherapy. Mean blood pressure was reduced equally
with the two regimens, from 131+/-9 mm Hg to 101+/-10 mm Hg with the isradipine
and from 128+/-9 mm Hg to 99+/-7 mm Hg with the thiazide/atenolol regimen. LVM
decreased significantly in both groups by 130+/-75 g with the isradipine-based
regimen and by 70+/-53 g with the hydrochlorothiazide/atenolol-based regimen. The
reduction of LVM was significantly greater on the isradipine-based regimen than
on the thiazide-based regimen (P < .01). There was a significant reduction of
media thickness-to-lumen diameter ratio during treatment with the isradipine
based regimen from 10.9% to 8.8% (P < .01). The reduction in the thiazide regimen
was from 9.7% to 8.5%, which was not significant (P = .07). The study
demonstrated significant reduction of hypertensive changes in peripheral
resistance artery structure during antihypertensive treatment with an isradipine
based regimen. The thiazide/betablocker-based regimen did not have a significant
effect on the vessels. Significant reduction of LVM was achieved with both
isradipine-based and thiazide/atenolol-based regimens. The reduction of LVM
obtained with the isradipine-based regimen was significantly greater than that of
the thiazide/atenolol-based regimen.
PMID- 9544866
TI - Little effect of ordinary antihypertensive therapy on nocturnal high blood
pressure in patients with sleep disordered breathing.
AB - The antihypertensive effects of four different antihypertensive medications (beta
blocking agent, atenolol 50 mg; calcium-antagonist, isradipine SRO [slow release]
2.5 mg; diuretic, hydrochlorothiazide [HCTZ] 25 mg; and angiotension converting
enzyme-inhibitor, spirapril 6 mg) on obese patients with sleep disordered
breathing and hypertension were compared by the ambulatory blood pressure
measurement (ABPM). Eighteen patients were randomized in a double-blind,
crossover fashion to receive each of the four different medications for 8 weeks.
ABPM was performed at baseline and after an 8-week treatment with these
medications. A 2- to 3-week washout period occurred both at baseline and between
each of the four medications. Three patients were omitted from statistical
analysis because of technical problems of ABPM. Atenolol, isradipine SRO, and
spirapril decreased significantly (P < .01) the mean 24-h systolic blood
pressure, whereas HCTZ did not. The mean 24-h diastolic blood pressure decreased
significantly after all four medications: 12 (SD+/-14) mm Hg with atenolol, 7
(SD+/-10) mm Hg with isradipine SRO, 3 mm Hg (SD+/-14) with HCTZ, and 6 (SD+/-15)
mm Hg with spirapril (P < .01). During nighttime none of the medications reduced
the mean diastolic or systolic blood pressure significantly. According to the 24
h blood pressure curve the influence of these four medications during the whole
measurement period was not similar. Atenolol and spirapril lost their
antihypertensive effect during the early morning hours. The antihypertensive
effect of HCTZ varied markedly from hour to hour. The trough-to-peak ratio of no
medication was >0.50. Negative correlation was observed between the apnea time
and the mean systolic 24-h (r = -0.604, P = NS) and the mean systolic nocturnal
blood pressure change (r = -0.590, P = NS). Our study revealed that the daytime
high blood pressure was quite easily controlled by the ordinary monotherapy in
these patients with partial upper airway obstruction and hypertension. Instead
none of the medications used decreased nocturnal high blood pressure markedly.
PMID- 9544867
TI - QT dispersion in dipper- and nondipper-type hypertension.
AB - The aim of this study was to identify the relationship of QT dispersion on 12
lead electrocardiograms and left ventricular mass index on echocardiograms
associated with the circadian rhythm of blood pressure (BP). Heart rate and BP
were monitored every 30 min for 48 h in 62 patients with essential hypertension
using an ambulatory BP monitoring device. The patients were divided into four
groups according to gender and circadian BP pattern (nocturnal BP dipper or
nondipper). The patients were classified as dippers if their daytime BP decreased
by at least 10% during the night and all the other subjects were classified as
nondippers. Age, body mass index, and 48-h mean BP were similar among the four
groups. During the night-rest period, the systolic and diastolic BP were
significantly decreased in dipper-type hypertensives. The maximum QTc interval
and QTc dispersion were longer in nondippers than in dippers. Left ventricular
mass index (LVMI) had a tendency to increase in nondippers. The nocturnal
reduction of BP significantly correlated with QTc dispersion and LVMI. The QTc
dispersion significantly correlated with LVMI and interventricular septum
thickness.
PMID- 9544868
TI - Left ventricular geometric patterns and QT dispersion in borderline and mild
hypertension: their evolution and regression.
AB - To investigate whether QT dispersion increases in borderline and mild
hypertension during a longitudinal observation of > 3 years and whether it is
improved with medications, left ventricular geometric patterns and QT dispersion
were studied with special regard to their longitudinal changes in 85 male
borderline and mild hypertensive subjects with left ventricular mass index < 125
g/m2. These subjects were followed for > 3 years without medication. Thirty-two
patients with a left ventricular mass index > 125 g/m2 at the end of follow-up
period were further observed using antihypertensive drugs for an additional 3
years. Echocardiograms and electrocardiograms were obtained at the beginning and
end of the follow-up period. At the end of the follow-up period, subjects were
classified into four groups based on ventricular geometric patterns determined by
left ventricular mass index and relative wall thickness in diastole. The QT
dispersion was greater in patients with concentric hypertrophy (56+/-18 msec)
than in patients with normal geometry (41+/-17 msec) (P < .05) and increased
significantly in the former group during the follow-up period. After medication,
the left ventricular mass index regressed and the QT dispersion decreased (from
55+/-21 to 50+/-26 msec, P < .01) in these patients. Thus, these findings suggest
that changes in the QT dispersion reflect both concentric evolution and
regression of left ventricular hypertrophy.
PMID- 9544869
TI - Aortic stiffening does not predict coronary and extracoronary atherosclerosis in
asymptomatic men at risk for cardiovascular disease.
AB - Stiffness of aortic walls has been shown to be a marker of coronary and
cerebrovascular diseases in patients with myocardial infarction or stroke.
However, its value for predicting preclinical atherosclerosis has not been
demonstrated. Therefore, this study tested the association of aortic wall
stiffness and coronary and extracoronary atherosclerosis in the absence of
clinical cardiovascular disease. In 190 asymptomatic men at cardiovascular risk,
carotid-to-femoral pulse wave velocity (PWV) was measured mechanographically and
the compliance of the aorta (C), as well as the intrinsic compliance (Ci), was
deduced after correction for the effect of blood pressure. Also determined
noninvasively were 1) the degree of coronary calcium deposit coded as grade 0, 1,
2, or 3 using ultrafast computed tomography; 2) the extent of extracoronary
plaque detected by B-mode echography at three different sites (carotid, abdominal
aorta, and femoral) coded as 0, 1, 2, or 3 diseased sites; and 3) the estimated
Framingham coronary risk. The grade of coronary calcium was not associated with
any aortic elastic parameter. The number of extracoronary diseased sites was not
associated with PWV and C but correlated negatively with Ci before but not after
age adjustment. The coronary risk correlated positively with PWV and negatively
with C before but not after age adjustment and was not associated with Ci. In
symptom-free subjects aortic stiffening does not predict the presence of coronary
and extracoronary atheroma and therefore cannot be considered as a useful
surrogate marker of early atherosclerosis.
PMID- 9544870
TI - Relationship between autonomic function and progression of renal disease in
diabetic proteinuria: clinical correlations and implications for blood pressure
control.
AB - The objective of this study was to test the relationship between neurologic and
microvascular complications of type 1 diabetes mellitus. It was hypothesized that
the mechanisms operative in autonomic dysfunction seen in diabetic patients with
microangiopathy play a role in the rapidity of progression to renal failure.
Twenty-six type 1 diabetic patients with proteinuria were studied with
computerized monitoring of heart rate variation during timed ventilation,
assumption of upright posture, and Valsalva maneuver and with 24-h ambulatory
blood pressure monitoring at baseline. Renal function was evaluated over the
ensuing 12 months of intensive insulin therapy. Blood pressure was treated so as
to achieve consistent 24-h readings < 140/90 mm Hg. Angiotensin converting enzyme
inhibitors were the preferred antihypertensive agents. Serial serum creatinine
concentrations were compared using repeated measures analysis of variance. Over
12 months there were no significant serum creatinine changes for any autonomic
test group with normal results at baseline. Groups with abnormal autonomic
results at baseline demonstrated statistically significant increases in serum
creatinine over 12 months compared to their baseline. Of the tests, Valsalva
separated groups of patients with similar degrees of baseline renal impairment.
Each of the sympathetic plus Valsalva combinations demonstrated a significant
difference in progression of serum creatinine increase over 12 months. In each
instance, if both sympathetic and Valsalva results were abnormal, there was a
statistically significant increase in serum creatinine over 12 months when
compared to groups in which one or both test results were normal. There is a
relationship between autonomic function and the progression of renal dysfunction.
The inability to vary the heart rate to a Valsalva maneuver identifies a degree
of parasympathetic dysfunction that permits unopposed sympathetic tone, heralding
more rapid renal destruction. A simple inexpensive bedside laboratory test
discerned a relatively low-risk group of diabetic patients with proteinuria that
demonstrated no deterioration in renal function over 12 months. When the Valsalva
maneuver was markedly abnormal the presence of a mean arterial pressure > 100 mm
Hg was associated with a greater likelihood of rapid renal deterioration. This
group at higher risk of renal deterioration should undergo aggressive lowering of
mean arterial blood pressure to < 95 mm Hg.
PMID- 9544872
TI - Angiotensin II type 1 receptor gene polymorphism is associated with increase of
left ventricular mass but not with hypertension.
AB - A genetic epidemiologic approach is useful to elucidate the genes responsible for
hypertension. Genetic analyses of the components of the renin-angiotensin system
have succeeded in showing an association between their polymorphism and
hypertension. Recently, two types of angiotensin II receptor were cloned and
characterized. To examine the genetic contribution of angiotensin II type 1
receptor (AT1) and type 2 receptor (AT2) genes in human essential hypertension, a
case-control study was performed in Japanese subjects. The study comprised 321
subjects with hypertension who satisfied the criteria for essential hypertension,
together with 215 age and sex matched controls. The significance of the
differences in genotype distribution between hypertensive and normotensive
subjects was examined by chi2 analysis. Neither AT1 nor AT2 gene variants were
associated with human essential hypertension in the Japanese subjects. However,
the AT1 receptor gene polymorphism was associated with left ventricular mass
index in normotensive subjects. The study results suggest that gene polymorphisms
of both angiotensin II receptors are not directly involved in the increase of
genetic risk for hypertension, but that the AT1 receptor gene might contribute
genetically to the increase of left ventricular mass.
PMID- 9544871
TI - The clinical utility of ambulatory blood pressure and heart rate monitoring in
psychiatric inpatients.
AB - Alterations in heart rate and blood pressure (BP) may occur in patients receiving
psychiatric medication. Twenty-four-hour ambulatory blood pressure (ABP)
monitoring was compared with nurses' conventional vital signs (CVS) for systolic
(SBP) and diastolic (DBP) and heart rate (HR) measurements in psychiatric
inpatients receiving multidrug treatments. Twelve consecutive subjects were
enrolled. ABP monitoring and CVS measurements were concurrent but independent in
each subject. Ambulatory BP monitoring recorded SBP, DBP, and HR thrice hourly
from 6:00 AM to 10:00 PM and once hourly between 10:00 PM and 6:00 AM; CVS were
obtained an average of 3.6 times/24 h. The frequency with which each BP and HR
measurement method detected Level-1 (SBP 90 to 100 or 180 to 209 mm Hg; DBP 40 to
60 or 110 to 119 mm Hg; HR 50 to 60 or 110 to 119 beats/min) or Level-2 (SBP < 90
or > or = 210 mm Hg; DBP < 40 or > or = 120 mm Hg; HR < 50 or > or = 120
beats/min) events was determined, and disagreements between the two measurement
systems were analyzed using the McNemar test for paired sample data. Ambulatory
BP monitoring detected significantly more Level-1 and Level-2 events than CVS. A
significant number of mostly low BP were documented by ABP monitoring and were
undetected by the CVS obtained by the nursing staff. This finding may be of
clinical relevance in view of the potential hemodynamic consequences of
hypotension, especially in older patients receiving psychotropic multidrug
treatment.
PMID- 9544873
TI - Effects of verapamil and trandolapril in the treatment of hypertension.
Trandolapril Study Group.
AB - The combination of an angiotensin converting enzyme inhibitor with a calcium
antagonist has become a common way of treating patients with essential
hypertension who respond insufficiently to monotherapy. This double-blind,
randomized, parallel, placebo-controlled, multicenter, outpatient study evaluated
the antihypertensive efficacy and safety of a calcium antagonist (verapamil SR)
and an angiotensin converting enzyme inhibitor (trandolapril) in patients with
mild-to-moderate (stages I and II) essential hypertension. Six hundred thirty-one
patients were enrolled in this 10-week study. After a 4-week single-blind placebo
phase, patients received one of the following daily dosage regimens in a double
blind fashion for 6 weeks: placebo, 4 mg of trandolapril, 240 mg of verapamil SR,
or a combination of 4 mg of trandolapril and 240 mg of verapamil SR. Trough
sitting diastolic blood pressure was lowered by 4.5 mm Hg, 4.3 mm Hg, and 8.1 mm
Hg more than placebo in the trandolapril, verapamil SR, and combination groups,
respectively. In the combination group, sitting diastolic blood pressure was
significantly lowered (P < .01) by 3.6 mm Hg more than in the trandolapril group
and by 3.8 mm Hg more than in the verapamil SR group. An analysis of the trough
to-peak ratio for sitting diastolic blood pressure revealed values of 0.75 and
0.67, for the 4-mg trandolapril and the combination groups, respectively, at end
point. The overall incidence of adverse reactions was similar for all treatment
groups. In this study the combination of an angiotensin converting enzyme
inhibitor and calcium antagonist was well tolerated and more effective than
either agent administered alone for the treatment of mild-to-moderate essential
hypertension.
PMID- 9544874
TI - Cardiovascular-renal responses to long-term nitric oxide inhibition during
angiotensin II-AT1 receptor inhibition.
AB - A previous study in conscious dogs showed that the normal hypertensive response
to short-term nitric oxide synthesis inhibition was markedly attenuated during
angiotensin II-AT1 receptor inhibition. However, whether angiotensin plays an
important cardiovascular role in the dog during long-term nitric oxide synthesis
inhibition has not been determined and was therefore the goal of this
investigation. Studies were conducted in 16 conscious dogs that received
angiotensin AT1 receptor inhibition with L158809 (N = 8) or vehicle (N = 8) for
12 d. During the last 6 d of this infusion, nitric oxide synthesis was inhibited
by infusing NG-nitro-L-arginine methyl ester intravenously at 37.1 nmol/kg/min.
In both the AT1 and vehicle groups, nitroarginine infusion significantly
decreased the acetylcholine depressor response, glomerular filtration rate, renal
plasma flow, and heart rate, and increased arterial pressure and renal vascular
resistance in a similar manner, whereas it caused little change in the urinary
excretion of sodium and water or in plasma renin activity. In conclusion, the
long-term responses of arterial pressure, renal hemodynamics, and the renal
excretion of sodium and water to nitric oxide synthesis inhibition were not
significantly influenced by blockade of angiotensin AT1 receptors with L158809 in
the dog.
PMID- 9544875
TI - Alterations in membrane fatty acid unsaturation and chain length in hypertension
as observed by 1H NMR spectroscopy.
AB - Alterations in fatty acids of membrane phospholipids in essential hypertension
may account for altered membrane ion transport, elasticity, and contractility
properties of hypertensive tissues. To investigate the abnormalities in membrane
fatty acids in essential hypertension, the degree of fatty acid unsaturation ([
CH=CH-]/[-CH3]), the average carbon chain length, ratio of glycerol to fatty acyl
chains, ratio of phosphatidylcholine to fatty acyl chains, and the ratio of free
and acylated cholesterol to fatty acyl chains in fatty acid fractions of membrane
phospholipids of aorta, kidney, and heart were determined in spontaneously
hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats by 1H nuclear magnetic
resonance (NMR) spectroscopy. The degrees of fatty acid unsaturation in the aorta
and the kidney membranes were significantly lower in SHR than in WKY rats (aorta,
0.53+/-0.01 v 0.63+/-0.01, n = 5, P = .01; kidney, 0.70+/-0.01 v 0.84+/-0.03, n =
10, P = .01). No significant difference could be detected in fatty acid
unsaturation in heart membranes between these two strains. For aorta, kidney, and
heart membranes, the average carbon chain lengths of fatty acid fractions of
membrane phospholipids were significantly shorter for SHR than for WKY rats
(aorta, 15.1+/-0.2 v 18.3+/-0.7, n = 5, P = .02; kidney, 14.5+/-0.2 v 16.4+/-0.4,
n = 10, P = .01; heart, 17.3+/-0.5 v 18.8+/-0.6, n = 10, P = .05). The lower
unsaturated fatty acid content in membrane phospholipids of the aorta and the
kidney, with concomitant reduction in average chain length, may arise from
increased oxidation of fatty acid double bonds in hypertensive tissues and may
account, in part, for the increased aortic stiffness and abnormal kidney function
associated with essential hypertension. Whether the lower unsaturated fatty acid
content and decreased carbon chain length of phospholipid membranes in the aorta
and the kidney are a cause or a consequence of the high blood pressure, however,
remains unknown.
PMID- 9544876
TI - Increased contraction of myocytes isolated from the young spontaneously
hypertensive rat: relationship between systolic and diastolic function.
AB - This study was designed to assess heart performance in young (10-week-old)
spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, in terms of
whole heart function in vivo and mechanics of isolated ventricular myocytes in
vitro. The data suggest that left ventricular pressure (LVP) generation is
greater, and the maximal velocities of LVP generation and decline are faster in
SHR than in WKY. Two-dimensional morphologic measurements show that SHR myocytes
are hypertrophied and that augmented contractile function is also present in
isolated cells as determined by the extent of shortening and velocity of
shortening. Relaxation is also faster at the myocyte level as determined by
velocity of relengthening. However, the slope of the relationship between myocyte
peak shortening and velocity of relaxation was similar in both groups. These
results suggest that hyperdynamic myocyte relengthening may reflect changes in
elastic recoil from increased shortening rather than intrinsic changes in
cellular mechanisms, which are independent of shortening.
PMID- 9544877
TI - Depressor role of angiotensin AT2 receptors in the (mRen-2)27 transgenic rat.
AB - The (mRen-2)27 transgenic rat (Tg+), a hypertensive model dependent on increased
expression of the renin angiotensin system, was used to explore the role of
angiotensin AT2 receptors in the control of cardiovascular and renal excretory
function. Experiments tested the effect of blockade of AT2 receptors on basal
blood pressure and the pressor, renal excretory, and vasopressin (VP) responses
to intravenous hypertonic saline (HS). Chronically catheterized male Tg+ and
normotensive Sprague-Dawley rats (Tg-) were housed in metabolic cages. PD123319
(AT2 antagonist) or 0.9% NaCl was given by intravenous bolus (3 mg/kg) followed
by infusion (50 microg/kg/ min). Blockade of AT2 receptors both in Tg+ and Tg-
rats produced no change in basal mean arterial pressure (MAP). The pressor
response to intravenous HS (10% NaCl; 325 microL/100 g body weight) was
significantly greater in Tg+ than in Tg- rats. PD123319 did not affect the peak
rise in MAP but extended the time course of the response only in Tg+ rats. MAP
was increased 39+/-4 and 36+/-3 mm Hg in Tg+ rats with and without the antagonist
as compared to 20+/-2 and 24+/-2 mm Hg in Tg- rats. In the antagonist-treated Tg+
rats, MAP remained elevated for 60 min as compared to 5 min for Tg+ control or Tg
control or antagonist-treated rats. Hypertonic saline caused similar increases
in plasma Na, VP, and in the natriuretic and diuretic responses in both Tg+ and
Tg- rats, with no effect of antagonist treatment. These results demonstrate that
Tg+ rats are sensitive to the effects of peripheral osmotic stimulation showing
an increased pressor response, not attributed to greater secretion of VP or
diminished natriuresis. These data also suggest that angiotensin AT2 receptors
play a depressor role in the sodium-induced pressor response in this model.
PMID- 9544878
TI - Effects of omapatrilat in low, normal, and high renin experimental hypertension.
AB - Combined inhibition of neutral endopeptidase (NEP) and angiotensin converting
enzyme (ACE) produces cardiovascular effects greater than those elicited by
selective inhibition of either enzyme alone. Dual metalloprotease inhibitors are
single molecules that inhibit both NEP and ACE and produce cardiovascular effects
in animal models similar to those elicited by the combination of NEP and ACE
inhibitors. The purpose of this study was to determined the duration of
antihypertensive activity of the dual metalloprotease inhibitor omapatrilat in
rodent models of hypertension. Omapatrilat inhibited NEP (Ki = 9 nmol/L) and ACE
(Ki = 6 nmol/L) activities in vitro and inhibited the pressor response to
angiotensin I in rats after intravenous administration with a potency and
duration of action similar to those of the long acting ACE inhibitor
fosinoprilat. After single dose administration, omapatrilat lowered mean arterial
blood pressure (aortic catheter) in sodium depleted spontaneously hypertensive
rats (high renin model) from 148+/-5 to 106+/-3 mm Hg (baseline to 24 h), in
deoxycorticosterone acetate-salt hypertensive rats (low renin) from 167+/-4 to
141+/-5 mm Hg and in spontaneously hypertensive rats (normal renin) from 162+/-4
to 138+/-3 mm Hg (P < .05 at 24 h v vehicle in all models). After oral
administration, omapatrilat (100 micromol/kg/day) persistently lowered systolic
blood pressure (tail cuff) in spontaneously hypertensive rats during 11 days of
treatment; at 24 h after dosing on day 12, mean arterial pressure (aortic
catheter) was lower (P < .05) in the group receiving omapatrilat (133+/-5 mm Hg)
than in the group receiving vehicle (149+/-2 mm Hg). The results indicate that
omapatrilat is a potent dual metalloprotease inhibitor of NEP and ACE with long
lasting, oral antihypertensive effects in low, normal, and high renin models of
hypertension. Omapatrilat has the potential to be an effective, broad spectrum
antihypertensive agent.
PMID- 9544879
TI - Absence of endogenous circadian rhythmicity in blood pressure?
AB - Currently available evidence reveals a predominant role of exogenous (so-called
"masking") factors in the 24 h variation of blood pressure in humans. The
existence of a (minor) endogenous circadian factor cannot be excluded, however.
This possibility was tested by applying the rigorous unmasking conditions of the
constant-routine protocol, that is, strict bed rest in a separate bedroom, total
sleep deprivation, constant ambient temperature and illumination, and hourly
equicaloric food and liquid intake. Twenty-five normotensive young individuals
were subjected to a 26 h constant-routine procedure while hourly measurements
were made of their blood pressure and heart rate. Repeated-measures analysis of
variance failed to show a significant 24 h variation of blood pressure. The power
of this test appeared satisfactorily high (>0.95). Heart rate, however, exhibited
a significant circadian pattern, with a range of 6.7 beats/min (10% of the 24 h
mean value). Moreover, the timing of the 24 h heart rate curves differed
significantly between so-called morning (n = 10) and evening (n = 9) individuals.
Mean peak values for the morning-types occurred at 11 AM, for the evening types
nearly 6 h later. In conclusion, no evidence was found for the involvement of a
circadian oscillator in the regulation of blood pressure.
PMID- 9544880
TI - Antihypertensive drug treatment and fibrinolytic function.
AB - Thromboembolic complications such as ischemic stroke and myocardial infarction
are significantly more frequent in patients with arterial hypertension. From the
available intervention studies, it appears that pharmacologic treatment of
hypertension-at least with diuretics and beta-blockers-may more effectively
protect against cerebrovascular as compared to coronary thromboembolic events.
Whether other antihypertensive substances provide a more effective protection
with respect to cardiac morbidity and mortality is the subject of numerous
studies presently underway. These studies will help to answer the question of
whether the extent of protection from coronary events during antihypertensive
treatment depends on factors beyond blood pressure control. The fibrinolytic
system is crucially involved in the pathogenesis of thromboembolic events. One
determinant of this system is the balance between plasminogen activators (tissue
type plasminogen activator [t-PA]) and inhibitors (plasminogen activator
inhibitor 1 [PAI-1]). Experimental and clinical evidence suggests that at least
some of the drugs used in the treatment of hypertension may alter the activity of
the fibrinolytic system. Scarce and controversial data with respect to such an
interaction exist with respect to diuretics, beta-blockers, and calcium
antagonists. In addition, experimental evidence demonstrates that PAI-1 is
stimulated by angiotensin II (A II), whereas t-PA is activated by bradykinin.
Thus, antihypertensive drugs acting within the renin angiotensin system should
exert effects also within the fibrinolytic system. However, results from clinical
studies with angiotensin converting enzyme (ACE) inhibitors and A II receptor
antagonists do not unequivocally support such a concept. The discrepancy in the
results may, at least in part, be explained by studies performed in healthy
volunteer subjects showing that ACE inhibition profoundly affected fibrinolysis
only during stimulation of the renin angiotensin system by NaCL restriction.
PMID- 9544881
TI - Regarding neonatal salt restriction.
PMID- 9544882
TI - Children at increased risk for Wilms tumor: monitoring issues.
PMID- 9544883
TI - Assessment of the respiratory status of infants and toddlers with cystic
fibrosis.
PMID- 9544884
TI - Inhaled steroids in children: risks versus rewards.
PMID- 9544885
TI - Overweight and cholesterol elevation: which is the chicken and which is the egg?
PMID- 9544886
TI - Dissecting the spectrum of fatty acid oxidation disorders.
PMID- 9544887
TI - Bone mineral content in patients with short bowel syndrome: the impact of
parenteral nutrition.
PMID- 9544888
TI - Childhood cancer predisposition: applications of molecular testing and future
implications.
PMID- 9544889
TI - Risk of cancer during the first four years of life in children from The Beckwith
Wiedemann Syndrome Registry.
AB - To determine the incidence and relative risk (RR) of cancer in children with
Beckwith-Wiedemann syndrome (BWS), children with BWS were followed up from birth
until death, diagnosis of cancer, fourth birthday, or last day of follow-up. A
total of 183 children with BWS were followed up for 482 person-years. The end
points were incidence of cancer, RR of cancer, and RR associated with specific
BWS phenotypic features. Thirteen children were identified with cancers before
the fourth year of life in comparison with fewer than one cancer expected in this
group on the basis of general population rates over the same period. The average
annual incidence of cancer in the first 4 years of life was 0.027 cancer per
person-year. The RR of Wilms tumor (RR = 816; 95% confidence interval [CI], 359
1156), neuroblastoma (RR = 197; 95% CI, 22-711), and hepatoblastoma (RR = 2280;
95% CI, 928-11,656) were statistically significant. Asymmetry of the limbs
(hemihypertrophy) was the only clinical feature associated with an increased RR
of cancer (RR = 4.6; 95% CI, 1.5-14.2). Given the high incidence of cancer in
infancy and early childhood of patients with BWS, a prospective study is
warranted to address the utility of screening for cancer.
PMID- 9544890
TI - Nephromegaly in infancy and early childhood: a risk factor for Wilms tumor in
Beckwith-Wiedemann syndrome.
AB - OBJECTIVE: Beckwith-Wiedemann Syndrome (BWS) is an overgrowth syndrome associated
with macrosomia, omphalocele, macroglossia, visceromegaly and Wilms tumor (WT).
We conducted a case-control study in children with BWS to examine whether
nephromegaly increases the risk of WT. METHODS: The BWS Registry was used to
identify control and case patients. Control patients were defined as children
with BWS who were older than 6 years and had no imaging evidence of renal disease
or previous WT and for whom complete records were available; 31 patients met
these criteria. Case patients were defined as children with BWS who had WT and
screening renal imaging before the diagnosis of WT; 12 of these patients had
serial screening images before diagnosis of WT and comprised the study
population. Only renal images obtained before the diagnosis of WT was made were
used to assess renal length. RESULTS: All 12 patients with WT had nephromegaly (>
or =95th percentile of age adjusted renal length) on serial screening studies.
Only four of 31 control patients (specificity = 86%) had nephromegaly resulting
in an odds ratio of 72 (95% confidence interval = 13-391) for the risk of WT with
nephromegaly. CONCLUSIONS: In patients with BWS, persistent nephromegaly is a
strong risk factor for the development of WT. If screening for WT is done in this
population, infants with nephromegaly should be considered those at greatest risk
for WT, and screening may be best targeted at this group.
PMID- 9544891
TI - Pulmonary function in hospitalized infants and toddlers with cystic fibrosis.
AB - In older children with cystic fibrosis (CF), well-documented improvements in lung
function occur during hospitalization for treatment of pulmonary exacerbations.
OBJECTIVES: (1) To test the hypothesis that improvement in lung function occurs
in infants and toddlers hospitalized because of CF pulmonary exacerbations. (2)
To compare changes in lung function measured during forced expiratory flow and
tidal breathing. STUDY DESIGN: Seventeen infants and toddlers with CF were
evaluated at the beginning and end of hospitalization by the rapid thoracic
compression technique to yield maximal flow at forced residual capacity. Tidal
mechanics were measured by the esophageal balloon technique to yield lung
conductance and compliance. RESULTS: Lung function improved during the course of
hospitalization. The greatest change was observed in measurements of maximal flow
at functional residual capacity (.VmaxFRC), increasing from 38.5% +/- 6%
predicted (mean +/- SEM) to 59.8% +/- 6% at the end (p < 0.005). Lung conductance
(GL) increased from 60% +/- 6% to 78% +/- 8% (p < 0.02); lung compliance (CL)
increased from 66% +/- 5% to 75% +/- 5% (p < 0.03). The degree of improvement of
.VmaxFRC, GL, and CL was related to baseline measurements; those with poorer
pulmonary function at baseline had the greatest degree of improvement during
hospitalization. CONCLUSION: Assessments of airflow obstruction from measurements
of .VmaxFRC and GL do not necessarily demonstrate similar findings in a given
infant with CF, perhaps because these two techniques measure different
physiologic properties. Changes in .VmaxFRC may best reflect the predominant
pathophysiology of lung disease in infants and toddlers with CF.
PMID- 9544892
TI - Collagen metabolism and growth in prepubertal children with asthma treated with
inhaled steroids.
AB - OBJECTIVE: To investigate growth and markers of collagen and bone metabolism in
prepubertal children with asthma. STUDY DESIGN: We measured growth velocity over
12 months and markers of collagen types I and III synthesis (PINP, PICP, PIIINP),
collagen type I degradation (ICTP), and bone metabolism (bone-specific alkaline
phosphatase and osteocalcin) on one occasion in 56 prepubertal children with
stable asthma, 39 of whom were treated with inhaled budesonide or beclomethasone.
Collagen data were compared with normal control values. RESULTS: Children treated
with inhaled steroids had reduced collagen synthesis (PINP, PIIINP) compared with
control subjects (p = 0.038, p = 0.045), although PICP was increased (p = 0.05).
Carboxyterminal telopeptide of type I collagen was reduced in patients treated
with inhaled steroids (p < 0.0005) compared with nonsteroid-treated patients.
Serum osteocalcin but not bone-specific alkaline phosphatase was significantly
reduced in children treated with inhaled steroids (p < 0.02). Significant
correlation was observed between PIIINP and ICTP and growth velocity. CONCLUSION:
Collagen turnover is reduced in children with asthma receiving long-term inhaled
steroid treatment. Markers of collagen synthesis provide a more accurate
reflection of growth disturbance than osteocalcin and bone-specific alkaline
phosphatase.
PMID- 9544894
TI - Low total body bone mineral content and high bone resorption in Korean winter
born versus summer-born newborn infants.
AB - Seasonal differences in newborn total body bone mineral content (TBBMC) have not
been studied, particularly in relation to alterations in vitamin D status in
winter. In vitamin D deficiency bone resorption may be high and bone
mineralization low. Bone resorption may be assessed by serum cross-linked
carboxyterminal telopeptide of type I collagen (ICTP) measures. Because vitamin D
supplements throughout pregnancy are uncommon in Korea, we hypothesized that in
Korean winter newborns, TBBMC is low and serum ICTP high from high bone
resorption and low 25-hydroxyvitamin D (25-OHD) compared with those in summer
newborns. Seventy-one Korean term infants were studied prospectively in summer
(July through September, n = 37) versus winter (January through March, n = 34);
TBBMC was measured before 3 days of age by dual-energy x-ray absorptiometry.
Significant seasonal differences were found: winter newborns had 6% lower TBBMC
(least squares means +/- SD; 86.7 +/- 7.7 gm vs 93.9 +/- 7.8 gm, p = 0.0002),
lower cord serum 25-OHD (10.7 +/- 8 nm vs 30 +/- 15 nm, p = 0.0001) and 1,25
dihydroxyvitamin D, and higher ICTP (96.4 +/- 20.3 microg/L vs 74.8 +/- 24
microg/L, p = 0.0002) and calcium than summer newborns. TBBMC correlated with
serum 25-OHD (r = 0.243, p = 0.047) and inversely with ICTP (r = -0.333, p =
0.008). We suggest that in Korea low maternal vitamin D status in winter results
in marked reduction in newborn TBBMC.
PMID- 9544893
TI - Age-related changes in cardiovascular disease risk factors of
hypercholesterolemic children.
AB - OBJECTIVE: To describe the age-related changes in cardiovascular disease risk
factors in young, hypercholesterolemic (HC) children. METHODS:
Hypercholesterolemic (n = 227) and nonhypercholesterolemic (NHC) (n = 80)
children between the ages of 4 and 10 years were identified. Height, weight, skin
fold and blood pressure measurements, and total cholesterol levels were measured.
The HC group also had insulin levels evaluated. The groups were compared by
analysis of variance. Simple Spearman correlations evaluated the associations
between factors within each group. RESULTS: The HC and NHC groups had similar
mean ages, heights, and weights, both contained 51% girls, and all were white
subjects. Percent weight-for-height median, and biceps, triceps, suprailiac and
subscapular skin-fold measurements were all larger for the HC group. A
significant age interaction demonstrated that the HC group's larger suprailiac
and sum of skin-fold measures were expressed in the 8.0- to 9.9-year-old
children, but not the 4.0- to 5.9-year-olds. For both groups, systolic blood
pressure was associated with the measures of adiposity. For the HC group, insulin
levels were also associated with adiposity. CONCLUSIONS: These results suggest
that: (1) children with HC have greater body fat, (2) the expression of the
hypercholesterolemia precedes the expression of increased body fat, (3) body fat
increases with age, and (4) altered insulin and blood pressure levels are
expressed in association with the increased body fat in children with HC.
Confirmation with longitudinal data is necessary.
PMID- 9544896
TI - Regional cerebral blood flow during seizures in neonates.
AB - With the use of 99mTc-D, L,-hexamethylpropylenamine oxime and single photon
emission computed tomography, regional cerebral blood flow was measured ictally
in 12 mature infants with recurrent seizures and compared with a reference group
of nine interictal studies. The study indicates that both clinical and electrical
seizures in neonates are associated with a focal cerebral hyperperfusion of the
same amount as seen in adults.
PMID- 9544895
TI - Feeding responses to free-flow formula in term and preterm infants.
AB - OBJECTIVES: Although introducing freely flowing formula into the infant's mouth
is a common feeding practice, its effect on feeding behavior is largely unknown.
We evaluated the effects of free flow of formula from the nipple on infant
feeding activity (sucking, swallowing, ingestion rate) and documented potential
adverse behaviors such as cough, restless behavior, drooling, apnea, and
bradycardia. METHODS: We studied 13 preterm and 7 term infants. During a feeding,
bottle pressure was adjusted every 2 to 3 minutes to increase or decrease free
flow from the nipple. RESULTS: Increase in free flow of formula from the nipple
caused rapid increases in suck and swallow frequency in term and preterm infants
and increased ingestion rate. The response was reversed by decreasing flow and
was repeatable throughout the feeding. Peak suck and swallow rates were highest
in term infants. Although drooling increased with increased milk flow, no effect
of flow on coughing, restless behavior, or apnea was observed. CONCLUSIONS: Free
flow formula is a potent stimulus for feeding activity in both preterm and term
infants and is not associated with increased apnea or other adverse behaviors.
The ability of the infant to divert excess formula flow by drooling is an
efficient airway protective behavior. Reduced maximum suck and swallow frequency
may be a primary basis for slow feeding in preterm infants.
PMID- 9544897
TI - Relationship of uric acid concentrations and severe intraventricular
hemorrhage/leukomalacia in the premature infant.
AB - The purine metabolite hypoxanthine accumulates with hypoxia ischemia and with
reperfusion is converted to uric acid (UA). We hypothesized that elevated UA
concentration is a marker of previous hypoxia ischemia and would identify infants
at greatest risk for having subsequent intraventricular hemorrhage
(IVH)/periventricular leukomalacia (PVL). We determined the relationship between
UA concentrations in the first postnatal day and the development of severe IVH,
PVL, or both in 58 infants of birth weight 865 +/- 177 gm and gestational age 27
+/- 2 weeks. Severe IVH developed in 10 (17%) infants and PVL in 3 (5.1%)
infants. UA concentrations on day 1 (obtained at 16 +/- 4 hours) were 7.9 +/- 2.8
mg/dl and increased to 9.5 +/- 2.58 mg/dl on day 2. UA concentrations on day 1
were higher in infants with severe IVH/PVL versus those in infants with neither
condition: 10.2 vs 7.3 mg/dl (p = 0.005). Infants with hyperkalemia on the second
postnatal day had higher UA concentrations on the first day versus infants with
normal potassium levels: 11.7 +/- 2 mg/dl versus 6.8 +/- 1.8 mg/dl (p < 0.0005).
Infants with severe IVH/PVL had higher potassium levels on day 2 versus infants
with neither condition: 11.9 vs 6.9 mg/dl (p < 0.048). By univariate analysis UA
concentrations were significantly related to gestational age (p = 0.005) and
birth weight (p = 0.03). Only UA concentration (p = 0.004) and gestational age (p
= 0.02) were related to IVH/PVL. By multivariate analysis UA remained
significantly related to IVH/PVL even when adjusted for other clinical variables,
with an odds ratio estimate of 1.63 (95% confidence interval 1.16 to 2.31). In
conclusion, higher UA concentrations on the first postnatal day were associated
with the subsequent development of severe IVH/PVL and with subsequent
hyperkalemia. Elevated UA concentrations in the first postnatal day may help to
identify a subset of premature infants at greatest risk for having subsequent
hemorrhagic ischemic injury.
PMID- 9544898
TI - Chest physiotherapy may be associated with brain damage in extremely premature
infants.
AB - OBJECTIVES: To determine whether a characteristic form of brain damage
(encephaloclastic porencephaly) was associated with chest physiotherapy treatment
in preterm babies. METHODS: A retrospective case-control study was undertaken
among 454 infants of birth weight less than 1500 gm cared for during the 3-year
period of 1992 to 1994. Thirteen babies of 24 to 27 weeks of gestation who
weighed 680 to 1090 gm at birth had encephaloclastic porencephaly. Twenty-six
control subjects were matched for birth weight and gestation. RESULTS: The
patients received two to three times as many treatments with chest physiotherapy
in the second, third, and fourth weeks of life as did control infants (median 79
vs 19 treatments in the first 4 weeks, p < 0.001). Patients also had more
prolonged and severe hypotension in the first week than did control subjects
(median duration of hypotension 4 vs 0.5 days, p < 0.01), and were less likely to
have a cephalic presentation (31% vs 81%, p < 0.01). Since December 1994 no very
low birth weight baby has received chest physiotherapy treatment in the first
month of life in our nursery, and no further cases have occurred. CONCLUSIONS:
Encephaloclastic porencephaly may be a previously unrecognized complication of
chest physiotherapy in vulnerable extremely preterm infants.
PMID- 9544899
TI - Neutrophil CD11b expression as a diagnostic marker for early-onset neonatal
infection.
AB - OBJECTIVES: To determine whether neutrophil surface expression of CD11b predicts
early-onset infection or suspected infection in at-risk infants. STUDY DESIGN:
CD11b expression on peripheral blood neutrophils was determined by flow cytometry
of whole blood samples. Blood (0.1 ml) was obtained from a convenience sample of
at-risk infants admitted to the neonatal intensive care unit, stained with
antibodies detecting CD11b and CD15, chilled, and analyzed within 8 hours. Blood
for culture, blood counts, and C-reactive protein (CRP) determination was
obtained simultaneously. Subjects were grouped on the basis of culture results
and clinical signs, and investigators were blinded to CD11b level. RESULTS: Of
106 subjects, seven had positive bacterial or viral cultures ("confirmed
infection"), 17 had clinical signs of infection but negative cultures ("suspected
infection"), and 82 had negative cultures and no clinical signs ("no infection").
Neutrophil CD11b was elevated in all infants with confirmed infection, 94% with
suspected infection, and none with no infection. The negative and positive
predictive values, sensitivity, and specificity were 100%, 99%, 96%, and 100%,
respectively, for diagnosis of neonatal infection at initial evaluation. CD11b
levels correlated with peak CRP (r2 = 0.76, p < 0.0001); however, CD11b was
elevated at the time of admission in all five infants with proven bacterial
infection, whereas CRP was normal until the second day in the neonatal intensive
care unit in three of these five. Both infants with positive viral cultures had
elevated CD11b, but the CRP levels remained within normal limits. The negative
predictive value of neutrophil CD11b for identifying suspected or confirmed
infection was 99%. CONCLUSION: This assay for neutrophil CD11b is a promising
test for exclusion of early-onset neonatal infection. If validated prospectively,
this assay may reduce hospital and antibiotic use in the population of neonates
at risk for early-onset infection.
PMID- 9544900
TI - Decreased growth hormone response to glucagon in infants after an apnea of
infancy.
AB - We studied glucagon-induced growth hormone secretion in 9 patients with apnea of
infancy and in 55 siblings of children who had died of sudden infant death
syndrome, who were included as a comparison group. We observed a 33% decrease in
growth hormone secretion in patients with apnea of infancy. However, linear
growth remained normal. This finding could be related to either repeated episodes
of hypoxia or to abnormal maturation of the autonomous nervous system.
PMID- 9544901
TI - Growth hormone therapy with three dosage regimens in children with idiopathic
short stature. European Study Group Participating Investigators.
AB - OBJECTIVE: In children with idiopathic short stature (ISS) we studied the growth
promoting effect at 4 years of recombinant human growth hormone (rhGH) therapy in
three dose regimens and evaluated whether increasing the dosage after the first
year could prevent a decline in height velocity (HV). DESIGN: Included were 223
patients who were treated with subcutaneous administrations of rhGH 6 days per
week. They were randomized to three groups: 3 IU/m2 body surface/day, 4.5
IU/m2/day, and 3 IU/m2/day during the first year and 4.5 IU/m2/day thereafter,
corresponding with dosages of 0.2 and 0.3 mg/kg body weight/week, respectively.
Growth was compared with a standard of 229 untreated children with ISS [ISS
standard]. RESULTS: During the first year of treatment HV almost doubled and was
higher with 4.5 IU/m2 than with 3 IU/m2. In the second year HV no longer differed
among the groups, but increasing the dosage slowed the rate of the fall of HV.
During 4 years of therapy the height SD score for age increased by a mean (SD) of
2.5 (1.0) [ISS standards], or 1.2 (0.7) (British standards), bone age increased
by 4.8 (1.3) years, and predicted adult height SD score increased by 1.5 (0.7).
After 4 years the results of the group with 4.5 IU/m2 were slightly better than
those of the other groups. When dropouts were included in the analysis (assuming
a stable height SD score after discontinuation of rhGH therapy), height gain was
still significant. CONCLUSIONS: During 4 years of rhGH therapy, growth and final
height prognosis improved, slightly more with 4.5 IU/m2 than with 3 IU/m2 or 3 to
4.5 IU/m2. However, bone age advanced on average 4.8 years during this period;
therefore, any effect on final height will probably be modest.
PMID- 9544902
TI - Long-term growth and development in children after home parental nutrition.
AB - Growth and development after the cessation of prolonged parenteral nutrition (PN)
has not been fully evaluated. Growth, body composition, and nutritional and
developmental status were documented in nine children (five boys, four girls) 2
to 6 years old (mean 4.9 +/- 1.0 years) who had previously received long-term PN
(mean 14.6 +/- 11.4 months). PN had been discontinued in all subjects for at
least 6 months (mean 3.4 +/- 1.4 years); they were receiving oral feedings only.
One subject had a significantly low height-for-age, and another had a low percent
ideal body weight; five subjects had low total body fat. Serum vitamin A was low
in six subjects. Seventy-two-hour fecal fat analysis was abnormal in two of eight
subjects. Abnormal bone mineral density was present in four of nine subjects.
Psychomotor development was normal in all nine subjects. Two had functional
difficulties in swallowing. One or more abnormalities were present in all nine
subjects. These findings suggest that children who require prolonged PN in early
life are at risk for abnormalities in growth and nutritional status in later
childhood; they require long-term dietary, growth, and nutritional monitoring.
PMID- 9544903
TI - Plasma zinc status, growth, and maturation in children with sickle cell disease.
AB - OBJECTIVE: The objective of this study was to determine the relation of plasma
zinc (Zn) status to growth and maturation in children with SS genotype sickle
cell disease. STUDY DESIGN: A cross-sectional study of 104 subjects who were 50%
female and ranged in age from 0.4 to 18 years was performed. Measures included
plasma Zn concentration (Znp), height, weight, skinfold thicknesses, elbow
breadth, upper arm muscle area, and fat-free mass and fat mass by total body
electrical conductivity. Skeletal maturation was assessed by hand-wrist x-ray
evaluation and sexual maturation by Tanner stage. RESULTS: A total of 44% of the
patients had low Znp (<10.7 micromol/L [70 microg/dl]); those with low Znp had
significantly lower SD scores for height (p = 0.003), weight (p = 0.003), upper
arm muscle area (p = 0.045), fat-free mass (p = 0.025), and elbow breadth (p =
0.017) and greater skeletal maturation delay (p = 0.04). In older children (>9
years) low Znp was associated with decreased Tanner scores for pubic hair (p =
0.001) and breast and genital maturation (p = 0.009). No significant differences
were seen in age, sex, or fat stores according to Zn status. CONCLUSIONS:
Decreased plasma Zn is common in children with SS genotype sickle cell disease
and is associated with decreased linear growth, skeletal growth, muscle mass, and
sexual and skeletal maturation.
PMID- 9544904
TI - Growth in asthmatic children treated with fluticasone propionate. Fluticasone
Propionate Asthma Study Group.
AB - OBJECTIVE: To determine whether inhaled fluticasone propionate has long-term
effects on growth in children with persistent asthma. STUDY DESIGN: In a double
blind, randomized, parallel-group, multicenter study, 325 prepubescent children
with persistent asthma and normal growth rates were treated with placebo or
inhaled fluticasone propionate powder 50 microg or 100 microg administered twice
daily by a breath-actuated device for 1 year. Growth was evaluated monthly,
whereas other safety variables and pulmonary function were evaluated
periodically. RESULTS: The prepubescent patients showed no statistically
significant differences in mean height, mean growth velocity, or mean skeletal
age between any of the treatment groups at any time. Over a period of 1 year,
mean height (+/- SE) increased 6.15 +/- 0.17 cm in the placebo group, 5.94 +/-
0.16 cm in the fluticasone propionate 50 microg group, and 5.73 +/- 0.13 cm in
the fluticasone propionate 100 microg group (p = 0.308, overall). CONCLUSIONS:
Prepubescent children treated with fluticasone propionate 50 microg and 100
microg administered twice daily for 1 year grew at rates similar to placebo
treated control subjects and at rates equal to expected growth velocity for age.
PMID- 9544905
TI - Growth status in children with cystic fibrosis based on the National Cystic
Fibrosis Patient Registry data: evaluation of various criteria used to identify
malnutrition.
AB - OBJECTIVES: The objectives of this study were to determine growth status and to
identify malnutrition with various anthropometric indicators in children with
cystic fibrosis (CF) based on cross-sectional analysis of the 1993 National CF
Patient Registry data. METHODS: Heights and weights of 13,116 children with CF
were evaluated with percentile, percent of reference median, Z-score, and percent
ideal weight-for-height based on National Center for Health Statistics/Centers
for Disease Control growth references. Malnutrition was defined by four criteria:
(1) height-for-age <5th percentile ("stunting") or weight-for-age <5th percentile
("wasting") (2) height-for-age <90% of reference median or weight-for-age <80% of
reference median, (3) height-for-age <5th percentile or percent ideal weight-for
height <85%, and (4) height-for-age <90% of reference median or weight-for-height
<85% of reference median. RESULTS: Mean and median height- and weight-for-age
were found to be at the 30th and 20th percentiles in children with CF.
Malnutrition (height- or weight-for-age <5th percentile) was particularly
pronounced in infants (47%) and adolescents (34%) and patients with newly
diagnosed CF (44%). A significant sex difference (p < 0.01) in the occurrence of
stunting (height-for-age <5th percentile) was observed during adolescence: boys
11 to 14 years of age showed lower occurrence of stunting (19%) compared with
girls (29%), whereas the opposite trend was observed at 15 to 18 years (34% in
male patients vs 28% in female patients). CONCLUSION: Twenty percent of all
children in the 1993 National CF Patient Registry were <5th percentile for height
or weight-for-age. A significant discrepancy was found when different criteria
were used to distinguish "stunting" versus "wasting" in malnourished children
with CF.
PMID- 9544906
TI - Nutrition intervention for weight gain in cystic fibrosis: a meta analysis.
AB - OBJECTIVES: A meta analysis of the literature on treatment approaches to
malnutrition in cystic fibrosis (CF) was conducted to evaluate the effectiveness
of oral supplementation, enteral nutrition, parenteral nutrition, and behavioral
intervention on weight gain before and after treatment. STUDY DESIGN: Eighteen
studies were reviewed: four behavioral, six supplement, five enteral nutrition,
and three parenteral nutrition. RESULTS: The weighted effect size for weight gain
was large for each intervention: 1.51 behavioral, 1.62 oral, 1.78 enteral, and
2.20 parenteral intervention. All interventions produced a large effect for
weight gain in patients with CF. A univariate analysis of variance indicated no
significant difference among the four interventions, F(3, 17) = 0.87, p > 0.05.
Effect size for calorie intake was also evaluated when data were available (N = 7
studies), yielding a sample size of three behavioral, two enteral, and two oral
supplement studies. Analysis of variance indicated a significant effect for
treatment, F(2,4) = 13.34, p < 0.05, with post hoc analysis indicating that the
behavioral intervention had a greater effect size for calorie intake than oral
supplement. CONCLUSIONS: All interventions were effective in producing weight
gain in patients with CF. Behavioral intervention appeared to be as effective in
improving weight gain in patients with CF as more invasive medical procedures.
These findings support continued research on nutrition intervention with patients
with CF including controlled clinical trials of the interventions and long-term
follow-up on the impact of nutrition on disease progression.
PMID- 9544907
TI - Acute pulmonary exacerbation is not associated with increased energy expenditure
in children with cystic fibrosis.
AB - OBJECTIVE: The objective of this study was to document alterations in resting
energy expenditure (REE), energy intake, and body composition that occur during
admission for management of a pulmonary exacerbation in children with cystic
fibrosis. STUDY DESIGN: A prospective study of 14 children with cystic fibrosis
(8 male, 12.5 +/- 3.3 years) was conducted throughout a 14-day hospitalization
and again 3 weeks after discharge. Repeated measures analysis of variance was
used to examine the change in variables across time. RESULTS: Significant
increases were documented from days 1 to 14 in weight (37.1 +/- 13.1 kg to 38.4
+/- 13.5 kg) and pulmonary function (forced expiratory volume in 1 second: 67.6%
+/- 19.8% to 78.5% +/- 24.5%). Energy intake was not different between
hospitalization and follow-up and averaged 175% of the Recommended Dietary
Allowance. REE on day 1 was elevated (122% +/- 11% predicted); however, when
expressed with fat free mass as a covariate, no significant changes were noted in
REE throughout the eight measurements. CONCLUSIONS: These data suggest that an
acute pulmonary exacerbation is not associated with an increase above a subject's
baseline REE in children with cystic fibrosis with mild to moderate lung disease.
Management of an acute pulmonary exacerbation should be associated with sustained
improvement in pulmonary function and nutritional status; in contrast, weight
loss or failure to improve pulmonary function should be seen as atypical.
PMID- 9544908
TI - Symptoms of pervasive developmental disorders as observed in prediagnostic home
videos of infants and toddlers.
AB - OBJECTIVES: The objectives of this study were (1) to show prediagnostic
abnormalities in social and communicative behaviors on home videos of children
who later received a diagnosis of one of the pervasive developmental disorders
(PDD) and (2) to demonstrate that prediagnostic abnormalities in social and
communicative behaviors for children with PDD not otherwise specified will be
less prominent than those in children with autistic disorder but still
distinguishable from those of typically developing peers. STUDY DESIGN: Parents
of children with PDD each submitted home videos of social events that were made
when their child was between the ages of 12 and 30 months, before diagnosis. Two
independent observers, unaware of the subjects' diagnoses or purpose of the
study, scored the rates of specific anomalies in social and communicative
behavior. Two additional observers scored the percentage of time the children
were engaged socially or with objects. Data from the experimental group were
compared with those of 25 age-matched children with no developmental
disabilities. RESULTS: Significant differences were found between the rates of
social engagement and 8 of the 25 specific behaviors of the children in whom PDD
was later diagnosed and those of the typical children. The children later given
the diagnosis of PDD not otherwise specified had mean frequencies of some social
interactions and communicative skills that fell between those of children later
given the diagnosis of autistic disorder and those of children with typical
development. CONCLUSION: In our sample children in whom PDD was later diagnosed
could be differentiated from their typically developing peers on the basis of
specific anomalies noted in their social and communicative behaviors, especially
joint attention. In our sample children with PDD not otherwise specified could
have been further differentiated on the basis of the rates of social interaction.
Careful assessment of social interaction and communicative behaviors may help to
identify children with PDD before the age of 30 months.
PMID- 9544909
TI - Presenting signs of retinoblastoma.
AB - A retrospective chart review was performed on the charts of 1265 patients with
retinoblastoma who were on file at New York Hospital and whose conditions had
been diagnosed between the years 1960 and 1990. The mean follow-up was 90 months,
ranging from 0 to 409 months. Thirty-two distinct presenting signs of
retinoblastoma were identified, the most common of which were leukocoria (56.2%),
strabismus (23.6%), poor vision (7.7%), and family history (6.8%). No correlation
was found between any of the presenting signs and laterality, sex, race, or
survival. Leukocoria correlated to Reese-Ellsworth Group Va or Vb, whereas
strabismus was invariably associated with either macular tumors or macular
retinal detachments. Eighty-three (96.5%) patients presenting with a family
history did so before the age of 24 months. The presenting sign leading to a
diagnosis of retinoblastoma was correlated with degree of advancement and tumor
location. Leukocoria and strabismus are the most common presenting signs, with
leukocoria correlated to more advanced disease and strabismus always associated
with macular involvement. Vitreous hemorrhage (1 case, 0.1%), microphthalmos (4
cases, 0.3%), and orbital cellulitis (3 cases, 0.2%) are extremely rare
presenting findings in retinoblastoma.
PMID- 9544910
TI - Risk factors for pediatric tuberculosis infection and disease after household
exposure to adult index cases in Alaska.
AB - OBJECTIVES: To determine risk factors for pediatric tuberculosis infection and
active tuberculosis. STUDY DESIGN: We examined medical records from multiple
sources for all 282 children younger than 15 years in Alaska during the period
1987 to 1994 who were household contacts of an adult with culture-positive
pulmonary tuberculosis. RESULTS: Infection developed in 25% of the children and
progressed to active disease in 9.6%. Risk factors for pediatric infection
included exposure to a parent who had active tuberculosis and exposure to any
adult with active tuberculosis who had a cough, smear positivity, or a left upper
lobe (LUL) chest lesion (odds ratios, 2.1 to 2.8). Among the 71 children in whom
infection developed, Alaska Natives and younger children were more likely to
progress to active tuberculosis, as were children exposed to a parent who had
active tuberculosis and children exposed to any adult who had a LUL chest lesion
(odds ratios, 1.5 to 12). CONCLUSIONS: Although all children with household
exposure to adults with active tuberculosis have a high risk of contracting the
infection and disease, specific risk factors can be identified and differ for
infection and disease. Alaska Natives have an increased risk of progression to
disease once infected.
PMID- 9544911
TI - A patient with carnitine-acylcarnitine translocase deficiency with a mild
phenotype.
AB - Carnitine-acylcarnitine translocase deficiency, a rare beta-oxidation defect, is
manifest in most cases by cardiomyopathy and death in early childhood. We report
an affected patient, 3 years of age, who has had no serious complications. The
residual enzyme activity in fibroblasts was higher than in previously reported
patients, which may explain the benign clinical course.
PMID- 9544912
TI - Bone mineral content in children with short bowel syndrome after discontinuation
of parental nutrition.
AB - To determine whether children with short bowel syndrome had evidence of metabolic
bone disease, total body bone mineral content was measured by dual-energy x-ray
absorptiometry in 18 patients and 36 age-, sex-, and race-matched control
subjects. Children with short bowel syndrome had decreased bone mineral content
compared with control subjects; however, it was not significant when adjusted for
differences in weight and height. Whether these children will have normal bone
accretion throughout puberty is not known.
PMID- 9544913
TI - 3-Methylcrotonyl-coenzyme A carboxylase deficiency in Amish/Mennonite adults
identified by detection of increased acylcarnitines in blood spots of their
children.
AB - Isolated 3-methylcrotonyl coenzyme A carboxylase (MCC) deficiency was documented
in four adult women from the Amish/Mennonite population of Lancaster County,
Pennsylvania. Metabolic and enzymatic investigations in these individuals were
instituted after the detection of abnormal acylcarnitine profiles in blood spots
obtained from their newborn children, in whom MCC activity was normal.
PMID- 9544914
TI - Calibrated-orifice nipples for measurement of infant nutritive sucking.
AB - To measure infant nutritive sucking reproducibly, nipple flow resistance must be
controlled. Previous investigators have accomplished this with flow-limiting
venturis, which has two limitations: flow resistance is highly dependent on fluid
viscosity and older infants often reject the venturi nipple. This report
describes the validation of calibrated-orifice nipples for the measurement of
infant nutritive sucking. The flow characteristics of two infant formulas and
water through these nipples were not different; those through venturi nipples
were (analysis of variance; p < 0.0001). Flow characteristics did not differ
among calibrated-orifice nipples constructed from three commercial nipple styles,
indicating that the calibrated-orifice design is applicable to different types of
baby bottle nipples. Among 3-month-old infants using calibrated-orifice nipples,
acceptability was high, and sucking accounted for 85% of the variance in fluid
intake during a feeding. We conclude that calibrated-orifice nipples are a valid
and acceptable tool for the measurement of infant nutritive sucking.
PMID- 9544916
TI - Increased risk of spastic diplegia among very low birth weight children after
preterm labor or prelabor rupture of membranes.
AB - Our objective was to study the association of spastic diplegia (SDP; N = 29) with
the initiator of preterm birth in a regional cohort of 312 6-year-old very low
birth weight children (< or =1500 gm). We determined the prevalence of SDP among
those children born after idiopathic preterm onset of labor (POOL) or prelabor
rupture of membranes (PROM) (12% SDP), and among those born after pregnancy
induced hypertension or other medical indications for preterm delivery (4% SDP).
Stratification showed that 83% of the children with diplegia were born after POOL
or PROM. The threefold increased risk of SDP among those children born after POOL
or PROM compared with the remainder of the cohort (crude odds ratio 3.2, 95%
confidence interval 1.2 to 8.5) remained elevated after controlling for perinatal
and neonatal variables (odds ratio 2.4 to 2.7) in logistic regression models. We
conclude that birth after POOL or PROM increases the risk of SDP among very low
birth weight children and speculate that this might be related to infectious
processes leading to both POOL or PROM and SDP.
PMID- 9544915
TI - Spastic diplegia as a complication of interferon Alfa-2a treatment of hemangiomas
of infancy.
AB - We report the development of spastic diplegia in infants during the course of
interferon Alfa-2a (IFN) therapy for potentially life-endangering hemangiomas.
Five infants who displayed diplegia were selected from a group of 26 infants
treated with IFN. Diplegia persisted in three infants, and in the remaining two
significant recovery occurred after IFN was discontinued. Magnetic resonance
imaging showed no significant brain or spinal abnormalities except minor to
moderate delayed myelination in two patients. Myelination was normal on
subsequent radiographic examination in all five patients. We conclude that IFN
can adversely affect the immature central nervous system and produce spastic
diplegia, which is potentially reversible. We recommend careful clinical
assessment of neurodevelopmental status during IFN therapy.
PMID- 9544917
TI - Successful treatment of a staphylococcal endocarditis vegetation with tissue
plasminogen activator.
AB - A 930 gm premature infant had Staphylococcal endocarditis with a tricuspid
valvular vegetation that was unresponsive to antibiotics and not amenable to
resection. Infusion of tissue plasminogen activator over a 3-day period
completely lysed the vegetation. The infection cleared with continued
antibiotics, and the infant recovered without sequelae.
PMID- 9544918
TI - Recurrent group B streptococcal disease in infants: Who should receive rifampin?
AB - A preterm breast-fed infant had three episodes of type Ia/c group B streptococcus
septicemia. After the second episode rifampin was given to the infant, but
further Ia/c exposure to maternal breast milk ensued. We propose rifampin
treatment for both the mother and infant in cases of recurrent group B
streptococcus disease.
PMID- 9544919
TI - Acute eosinophilic pneumonia: a cause of reversible, severe, noninfectious
respiratory failure.
AB - We report a case of acute eosinophilic pneumonia associated with adult
respiratory distress syndrome in an adolescent. This entity should be considered
in the differential diagnosis in previously well children and adolescents who are
seen with unexplained respiratory failure and who have many eosinophils in
bronchoalveolar lavage fluid. Prompt recognition of this rapidly reversible
noninfectious disorder and institution of corticosteroids may be lifesaving.
PMID- 9544920
TI - A pilot study of combination therapy with indinavir, stavudine (d4T), and
didanosine (ddI) in children infected with the human immunodeficiency virus.
AB - Twelve children infected with the human immunodeficiency virus were treated
orally with indinavir, stavudine, plus didanosine for 12 to 48 weeks. Therapy was
limited in some cases by nonadherence, intolerance, toxicity, and virologic
failure. Marked increases in CD4+ lymphocyte counts and decreases in plasma human
immunodeficiency virus RNA concentrations suggest that the regimen has potent
antiviral activity.
PMID- 9544921
TI - Pneumatosis intestinale in children with primary combined immunodeficiency.
AB - We report six episodes of pneumatosis intestinale (PI) in children with primary
combined immunodeficiency. PI was generally benign and responded to conservative
therapy. Increased risk of infection or disruption of gastrointestinal mucosa are
probable predisposing factors. A diagnosis of PI should be considered in children
with primary combined immunodeficiency who experience otherwise unexplained
gastrointestinal symptoms, particularly in the early post-transplant period.
PMID- 9544922
TI - Profound neonatal congestive heart failure caused by maternal consumption of blue
cohosh herbal medication.
AB - A newborn infant whose mother ingested an herbal medication, blue cohosh, to
promote uterine contractions presented with acute myocardial infarction
associated with profound congestive heart failure and shock. The infant remained
critically ill for several weeks, although he eventually recovered. Other causes
of myocardial infarction were carefully excluded. Blue cohosh, Caulophyllum
thalictroides, contains vasoactive glycosides and an alkaloid known to produce
toxic effects on the myocardium of laboratory animals. We believe this represents
the first described case of deleterious human fetal effects from maternal
consumption of blue cohosh.
PMID- 9544923
TI - Pediatric imaging perspective: acute head trauma--Is skull radiography useful?
PMID- 9544924
TI - Purpura fulminans skin lesions in a newborn with complete protein C deficiency.
PMID- 9544925
TI - Osteogenesis imperfecta: Are fractures and growth hormone treatment linked?
PMID- 9544926
TI - Oral feeding in low birth weight infants.
PMID- 9544927
TI - Spectrum of the X-linked hyper IgM syndrome.
PMID- 9544928
TI - Cyclization of alpha-aminoadipic acid into the the delta-lactam 6-oxo-piperidine
2-carboxylic acid by Penicillium chrysogenum.
PMID- 9544929
TI - TMC-49A, a novel transcriptional up-regulator of low density lipoprotein
receptor, produced by Streptomyces sp. AS1345.
AB - Microbial metabolites were screened for a transcriptional up-regulator of low
density lipoprotein (LDL) receptor by a reporter assay. TMC-49A was discovered as
an up-regulator obtained from the fermentation broth of Streptomyces sp. AS1345.
The structure of TMC-49A was elucidated to be butyl N-phenethylcarbamate by
spectroscopic analyses. This compound enhanced the synthesis of LDL receptor in
human hepatoma HepG2 cells as assessed by a receptor binding assay. Taxonomy of
the producing strain is also described.
PMID- 9544930
TI - CJ-12,373, a novel topoisomerase II inhibitor: fermentation, isolation, structure
elucidation and biological activities.
AB - A novel isochroman carboxylic acid CJ-12,373 was isolated from Penicillium sp.
CL22557. CJ-12,373 inhibits both DNA gyrase-mediated supercoiling and relaxation
without the formation of a cleavage intermediate, suggesting that CJ-12,373
inhibits DNA gyrase at a stage distinct from the religation step. CJ-12,373 is
not selective for procaryotic DNA gyrase as it also inhibits relaxation mediated
by eukaryotic topoisomerase II. The antimicrobial potency of CJ-12,373, however,
is largely attributed to its inhibition of DNA gyrase.
PMID- 9544931
TI - Glisoprenins C, D and E, new inhibitors of appressorium formation in Magnaporthe
grisea, from cultures of Gliocladium roseum. 1. Production and biological
activities.
AB - Glisoprenins C, D, and E, new glisoprenin derivatives, were isolated together
with glisoprenin A from submerged cultures of the deuteromycete Gliocladium
roseum HA190-95. All glisoprenins inhibited appressorium formation in Magnaporthe
grisea on inductive (hydrophobic) surfaces. The compounds exhibited moderate
cytotoxic, but no antifungal, antibacterial or phytotoxic activities.
PMID- 9544932
TI - Cremimycin, a novel 19-membered macrocyclic lactam antibiotic, from Streptomyces
sp.
AB - A novel 19-membered macrocyclic lactam antibiotic, cremimycin, was isolated from
the culture broth of an actinomycete strain. The producing organism, designated
MJ635-86F5, was identified as a member of Streptomyces. Cremimycin was isolated
from the mycelial cake by extraction with CHCl3-MeOH and precipitation with
hexane-MeOH. The structure of cremimycin was determined by spectroscopic study.
Cremimycin showed broad antimicrobial activities against Gram-positive bacteria
including MRSA.
PMID- 9544933
TI - Nothramicin, a new anthracycline antibiotic from Nocardia sp. MJ896-43F17.
AB - A new antibiotic designated nothramicin was isolated from the culture broth of
Nocardia sp. MJ896-43F17 which was closely related to Nocardia brasiliensis. It
was isolated by the Diaion HP-20 column chromatography, butyl acetate extraction
and purified by HPLC. It inhibited the growth of mycobacteria at the
concentration of 1.56 approximately 25 microg/ml. Nothramicin was revealed to be
a new member of anthracycline antibiotics by the various spectroscopies.
PMID- 9544934
TI - In vitro microbiological characterization of novel macrolide CP-163,505 for
animal health specific use.
AB - A novel 16-membered-ring macrolide agent (CP-163,505, a reductive amination
derivative of repromicin) was identified as an antibacterial against Pasteurella
haemolytica, P. multocida and Actinobacillus pleuropneumoniae, important
etiological agents of livestock respiratory disease. In vitro MIC50/90 analysis
revealed that CP-163,505 was more potent (4x) than tilmicosin against P.
multocida, and equivalent to tilmicosin against P. haemolytica and A.
pleuropneumoniae. In time kill kinetic studies, CP-163,505 showed bactericidal
activity against P. haemolytica, P. multocida and A. pleuropneumoniae and
bacteriostatic activity against E. coli at 8 times its MIC. In vitro, CP-163,505
was more potent in alkaline pH (16 approximately 32 x ) and less potent in the
presence of excess cations (Mg+2 and Ca+2, 4x). EDTA and PMBN increased CP
163,505 potency against E. coli (4x) but not against the other species. Similar
results were obtained with erythromycin A and tilmicosin, which were used as
controls. From our data, we hypothesize that Pasteurella and Actinobacillus have
an outer membrane significantly different from that of the typical enteric Gram
negative bacterium E. coli.
PMID- 9544935
TI - New quinolone compounds from Pseudonocardia sp. with selective and potent anti
Helicobacter pylori activity: taxonomy of producing strain, fermentation,
isolation, structural elucidation and biological activities.
AB - Eight novel quinolones with anti-Helicobacter pylori activity were isolated from
the actinomycete Pseudonocardia sp. CL38489. The quinolones were very potent
against H. pylori with MICs up to 0.1 ng/ml. The quinolones appear to be specific
for H. pylori, since they did not show antimicrobial activity when tested against
a panel of other microorganisms.
PMID- 9544936
TI - Antimalarial activity of radicicol, heptelidic acid and other fungal metabolites.
AB - In the course of our screening program for artemisinin-like antimalarial
compounds from microorganisms, seven fungal metabolites such as radicicol and
heptelidic acid were identified as active compounds. Some of them exhibited
antimalarial activity in vitro against the human malaria parasite Plasmodium
falciparum to the extent of approximately 1/10 as potent as artemisinin.
Radicicol was moderately active in vivo against Plasmodium berghei in mice.
PMID- 9544937
TI - Development of an improved cloning vector and transformation system in
Amycolatopsis mediterranei (Nocardia mediterranei).
AB - A versatile plasmid cloning vector pRL60 carrying kanamycin/neomycin resistance
(km/neo), erythromycin resistance (ermE) and alpha-amylase (alpha-amy) marker
genes that replicates in various Amycolatopsis mediterranei strains and
Escherichia coli has been constructed. This cloning vector has been derived from
a hybrid plasmid pRL50, which was developed by cloning ermE from pIJ4026 into a
pRL1 derivative pULAM2. While cloning ermE into the BamHI site of pULAM2, only a
hybrid plasmid pRL50 with an additional copy of pULAM2 was selected. Thus pRL50
(18.7 kb) contained two copies each of the km/neo, alpha-amy, and one copy of
ermE. When pRL50 was transformed into A. mediterranei DSM 40773 through
electroporation and selected under erythromycin resistance, the plasmid underwent
a spontaneous deletion of 8.5 kb fragment resulting in the formation of plasmid
pRL60. pRL60 (10.2 kb) is a shuttle vector between A. mediterranei and E. coli
with three marker genes: km/neo, ermE and alpha-amy. ermE is expressed in A.
mediterranei thus allowing good selection of transformants. The alpha-amy gene of
pRL60 is also expressed in A. mediterranei DSM 40773 and its activity can be
easily detected on starch containing medium after iodine staining. Most critical
parameters evaluated for electrotransformation using pRL60 in A. mediterranei
were growth phase, electrical field strength, pulse length, pretreatment of
mycelia with lysozyme and use of salt free water. At optimized parameters, a
transformation efficiency of 4.0 x 10(4) transformants/microg DNA was
reproducibly achieved for A. mediterranei DSM 40773. pRL60 could also be
transformed into A. mediterranei DSM 43304, DSM 46095, MTCC-17 and in mutants
F1/24 and T-195, (derived from an industrial strain of A. mediterranei N813). The
alpha-amy of pRL60 conferred an amylolytic phenotype to all these strains. With
the development of pRL60 and a reproducible transformation protocol, the
application of recombinant DNA techniques to these industrial microorganisms has
now become feasible.
PMID- 9544938
TI - Directed biosynthesis of peptaibol antibiotics in two Trichoderma strains. I.
Fermentation and isolation.
AB - Peptaibols are linear alpha-aminoisobutyric acid-containing peptide antibiotics
originating from soil fungi mainly of the genus Trichoderma and biosynthesized in
complex mixtures of closely related analogues by a polyenzymatic pathway.
Addition of amino acids such as alpha-aminoisobutyric acid (Aib), glutamic acid
or arginine, to the fermentation medium of two Trichoderma strains, T. harzianum
and T. longibrachiatum, has been shown to result in the simplification of the
natural peptaibol mixtures, leading in each case to the almost exclusive
biosynthesis of a single peptide. Surprisingly, the obtained peptides are Aib
enriched, whether the added amino acid is Aib, Glu or Arg. By adding Aib to the
fermentation medium of T. harzianum, two new Aib-rich peptaibols were isolated.
Moreover, adding glutamic acid to the culture medium of T. longibrachiatum, which
produces both neutral and acidic 20-residue peptaibols with either glutamine or
glutamic acid at position 18, increases the production of the acidic peptides.
However, arginine which is a positively charged amino acid generally absent from
peptaibol sequences, is not incorporated in trichorzins when added to the
fermentation medium of T. harzianum.
PMID- 9544939
TI - Directed biosynthesis of peptaibol antibiotics in two Trichoderma strains. II.
Structure elucidation.
AB - Alpha-aminoisobutyric acid-directed biosynthesis in two Trichoderma strains has
been shown to lead to the simplification of the natural peptaibol
microheterogeneous mixtures and to the production of new analogues. Hence, two
new peptides originating from T. harzianum, trichorzin PA(U) 4 and harzianin PCU
4, were isolated by HPLC. Their sequences were determined by positive liquid
secondary-ion mass spectrometry (LSI MS). Trichorzin PA(U) 4 and harzianin PC(U)
4 are 18- and 14-residue peptaibols, respectively, both containing a high
proportion of alpha-aminoisobutyric acid (Aib). LSI MS performed with lithium
cationized peptides, allowed to assign the relative position of
leucine/isoleucine isomeric residues, even without the use of tandem mass
spectrometry.
PMID- 9544940
TI - Synthesis and activities of bactobolin derivatives based on the alteration of the
functionality at C-3 position.
AB - Some derivatives of bactobolin were prepared from bactobolin (1) by radical
reduction and formation of the fused azetidine ring. The derivatives proved less
active than the parent antibiotic 1 against bacteria, indicating that
dichloromethyl group at C-3 position play an important role in biological
activity.
PMID- 9544941
TI - Synthesis and antimicrobial evaluation of TAN-1057A/B analogs.
AB - TAN-1057A-D, dipeptides isolated from bacteria Flexibacter sp. PK-74 and PK-176,
are new antibiotics with potent antibacterial activity against methicillin
resistant Staphylococcus aureus (MRSA). We describe, in detail, the synthesis of
several TAN-1057A/B analogs by a convergent route featuring a new method to
construct the cyclic amidinourea functional group. The biological activity of
these substances against methicillin-resistant Staphylococcus aureus (MRSA) is
reported.
PMID- 9544942
TI - Synthesis and activity of 3-epi-actinobolin.
AB - 3-epi-Actinobolin was synthesized by the chemical transformation of actinobolin
involving a key step of the reconstruction of fused delta-lacton skeleton via
intramolecular acylation reaction. The analogue with low toxicity weakly inhibits
Gram-positive and Gram-negative bacteria.
PMID- 9544944
TI - Sch 40832: a novel thiostrepton from Micromonospora carbonacea.
PMID- 9544943
TI - Novel C-2 substituted carbapenem derivatives. Part IV. Synthesis and biological
activity of five membered heteroaromatic derivatives.
AB - The synthesis, antibacterial activity, and stability to human dehydropeptidase-1
(DHP-1) of a novel series of (5R,6S)-6-[(1R)-1-hydroxyethyl]-2
heterocyclylcarbapen-2-em-3-carb oxylates are described. Of the compounds
investigated 1,5-disubstituted pyrazol-3-yl and 3-substituted isoxazol-5-yl
derivatives have the best combination of antibacterial activity and stability to
DHP-1. They are particularly active against community-acquired respiratory tract
pathogens and have stabilities to DHP-1 superior to that of meropenem.
PMID- 9544945
TI - Biosynthetic studies on the alpha-glucosidase inhibitor acarbose in Actinoplanes
sp.: glutamate is the primary source of the nitrogen in acarbose.
PMID- 9544946
TI - Glisoprenins C, D and E, new inhibitors of appressorium formation in Magnaporthe
grisea, from cultures of Gliocladium roseum. 2. Structure determination.
PMID- 9544947
TI - Structure of ericamycin having a 2-azahexaphene ring system.
PMID- 9544948
TI - Studies on the cytotoxicity of asterriquinone derivatives.
PMID- 9544949
TI - The synthesis and antifungal activity of nitrogen containing hemiaminal ethers of
LY303366.
PMID- 9544950
TI - Will xenotransplantation ever be feasible?
AB - In several recent conferences, the principal questions have been whether
xenotransplantation technology should be encouraged and, if so, how it should be
regulated. Because the prospect of successful transplantation of animal organs
into humans is still remote, the rush to achieve consensus about clinical
application would be inexplicable were it not for two ostensibly unrelated
issues. The first is the small but undeniable theoretical hazard of causing new
human infections with the intermingling of tissues from different species. The
second, advanced by animal-rights advocates, concerns the spiritual and ethical
relationship of humans to animals.
PMID- 9544951
TI - Genetic therapies for xenotransplantation.
PMID- 9544952
TI - The dialectic nature of xenotransplantation.
PMID- 9544953
TI - En bloc transplantation of infant kidneys: ten-year experience.
AB - BACKGROUND: Recent data have shown that en bloc infant kidneys transplanted to
adult recipients functioned well. Longterm graft survival and function are not
available, however. This study analyzes the 10-year experience with
transplantation of en bloc infant kidneys from 1987-1997. STUDY DESIGN: This is a
chart review of adult recipients of en bloc infant kidneys with respect to
donors' and recipients' age, weight, creatinine, HLA antigen matching, panel
reactive antibodies, cold ischemia time, surgical complications, original
disease, and longterm graft function and survival. RESULTS: Five en bloc kidneys
thrombosed (6.4%). Two ureteral fistulas were repaired successfully. Five
patients underwent dialysis (6.4%). Two patients died of infection, six of heart
attack and stroke, and one of cancer. All had excellent graft function at
patients' death. Renal artery stenosis was dilated in seven patients. Six grafts
were lost to rejection (one from noncompliance at 20 months). The original
disease recurred in three patients with massive proteinuria despite excellent
function. Graft survival at 43 months (range, 6-123 months) was 79%, with serum
creatinine levels at 1, 3, 9 and 10 years of 1.2, 1.0, 0.8 and 0.8 mg/dl,
respectively. Creatinine clearance averaged 88 mL/min (range, 34-188 mL) and 24
hour proteinuria was 146 mg (normal range, 10-150). CONCLUSIONS: In conclusion,
en bloc infant kidneys can be transplanted successfully with excellent longterm
function, hyperfiltration injury was not observed, and infant kidneys should be
used more frequently.
PMID- 9544954
TI - Intraoperative endovascular angioplasty and stenting of iliac artery: an adjunct
to femoro-popliteal bypass.
AB - BACKGROUND: With the rapid development of endovascular techniques, the management
strategy of patients with multilevel atherosclerotic arterial occlusive disease
is also evolving. Iliac artery stenting is a means whereby multiple bypass
operations can be avoided in such patients. The early results of preoperative
iliac artery stenting seem promising but the role of intraoperative iliac artery
angioplasty and stenting is less clear. STUDY DESIGN: This study was undertaken
to evaluate our early results of a combined endovascular and operative approach
to patients with multilevel atherosclerotic arterial occlusive disease. Between
June 1995 and March 1997, primary intraoperative iliac artery balloon angioplasty
and stent placement were performed on 13 affected limbs of 12 patients undergoing
an infrainguinal bypass operation. Indications for operation, patient
demographics, and risk factors were noted. The outcome of surgery and the patency
rates of bypass graft and stent were also recorded. RESULTS: The initial
technical success of primary iliac artery angioplasty and stenting was 93%. An
improvement of the ankle-brachial index by a mean value of 0.38 was attained
after operation (p < 0.001). Clinical success, based on the criteria suggested by
the Society for Vascular Surgery/International Society for Cardiovascular
Surgery, was achieved in all patients. There was no operative or hospital
mortality. Postoperative morbidity rate was 8% (n = 1). The cumulative 1-year
patency rates of iliac stent and infra-inguinal bypass grafts were 100% and 85%,
respectively. The limb loss rate was 7%. CONCLUSIONS: The technique of
intraoperative angioplasty and stenting can be easily mastered by an experienced
and skilled vascular surgeon, using a portable C-arm fluoroscopic unit, in the
operation theater. A combined endovascular and operative approach optimizes the
therapeutic option to this selected group of patients.
PMID- 9544955
TI - A comparative analysis of lobular and ductal carcinoma of the breast:
presentation, treatment, and outcomes.
AB - BACKGROUND: Compared with invasive ductal carcinoma, invasive lobular carcinoma
of the breast is considered by many to be a more indistinct and multicentric form
of cancer that is detected later and is treated less optimally by breast
preservation techniques. This study analyzed the presentation, treatment trends,
and survival rates of women who had invasive lobular and ductal breast carcinoma.
The objective was to determine the utility of breast-preservation therapy for
invasive lobular carcinoma by analysis of historic data on tumor features and
survival. STUDY DESIGN: Data on 291,273 women diagnosed with invasive carcinoma
between 1985 and 1993 were obtained from the National Cancer Data Base. Analysis
included the patient's age at diagnosis; tumor histology, anatomic site,
diameter, grade, and stage; treatment; and disease status 5 years after
diagnosis. RESULTS: The mean patient age at diagnosis was 61.0 years for invasive
ductal carcinoma, 63.0 years for invasive lobular carcinoma, and 60.6 years for
tumors with combined histology. The anatomic location, tumor diameter, and tumor
grade were similar for each histotype. Breast-preservation therapy was less
frequent for invasive lobular carcinoma. The 5-year overall survival and local
disease-free survival rates for women treated with breast preservation were
similar for invasive ductal carcinoma (84% overall survival; 97% disease-free
survival) and invasive lobular carcinoma (87% overall survival; 98% disease-free
survival). CONCLUSIONS: Invasive lobular carcinoma presents with a similar age
distribution, anatomic subsite, diameter, and grade as invasive ductal carcinoma.
Breast preservation is selected less commonly for women who have invasive lobular
carcinoma, but this choice of therapy does not compromise the disease-free or
overall survival status of this group of patients.
PMID- 9544956
TI - Sentinel lymph node biopsy in breast cancer: initial experience at Memorial Sloan
Kettering Cancer Center.
AB - BACKGROUND: Sentinel node biopsy (SNB) has emerged as a potential alternative to
routine axillary dissection in clinically node-negative breast cancer. STUDY
DESIGN: From September 1995 to June 1996 at Memorial Sloan-Kettering Cancer
Center, 60 patients with clinically node-negative cancer underwent SNB, which was
immediately followed by standard axillary dissection. Both blue dye and
radioisotope were used to identify the sentinel node. SNB was compared with
standard axillary dissection for its ability to accurately reflect the final
pathologic status of the axillary nodes. RESULTS: The sentinel node was
successfully identified by lymphoscintigraphy in 75% (42 of 56), by blue dye in
75% (44 of 59), by isotope in 88% (52 of 59), and by the combination of blue dye
and isotope in 93% (55 of 59) of all 59 evaluable patients. Of the 55 patients in
this study where sentinel nodes were identified, 20 (36%) were histologically
positive. The sentinel node was falsely negative in three patients, yielding an
accuracy of 95%. SNB was more accurate for T1 (98%) than for T2-T3 tumors (82%).
CONCLUSIONS: Lymphatic mapping is technically feasible, reliably identifies a
sentinel node in most cases, and appears more accurate for T1 tumors than for
larger lesions. Blue dye and radioisotope are complementary techniques, and the
overall success of the procedure is maximized when the two are used together.
PMID- 9544957
TI - Laparoscopic repair of paraesophageal hiatal hernias.
AB - BACKGROUND: Regardless of symptoms, paraesophageal hiatal hernias should be
repaired in order to prevent complications. This study reports the University of
California San Francisco experience with laparoscopic repair of paraesophageal
hiatal hernias, emphasizing the technical steps essential for good results.
PATIENTS AND METHODS: From May 1993 to September 1997, 55 patients, 27 women and
28 men, with a mean age of 67 years (range, 35-102 years) underwent laparoscopic
repair of paraesophageal hernias at the University of California San Francisco.
Symptoms, which had been present an average of 85 months before surgery,
consisted mainly of pain (55%), heartburn (52%), dysphagia (45%), and
regurgitation (41%). Of the four patients who presented with acute illness, two
had gastric obstruction, one had severe dyspnea, and one had gastric bleeding.
Endoscopy demonstrated esophagitis in 25 (69%) of 36 patients, and 24-hour pH
monitoring demonstrated acid reflux in 22 (67%) of 33 patients. Manometry
detected severely impaired distal esophageal peristalsis in 17 (52%) of 33
patients. The preferred operation consisted of reduction of the hernia, excision
of the sack and the gastric fat pad, closure of the enlarged hiatus without mesh,
and construction of a fundoplication anchored by sutures within the abdomen.
RESULTS: Of the 55 patients, the operations of 49 were completed laparoscopically
using the following reconstructions: Guarner (270-degree) fundoplication (30
patients); Nissen fundoplication (10 patients); and gastropexy (9 patients). Five
(9%) operations were converted to laparotomies. The average operating time was
219 minutes; the average blood loss was less than 25 mL; resumption of an
unrestricted diet, 27 hours; and mean hospital stay, 58 hours. Intraoperative
technical complications occurred in five (9%) patients. One patient died during
surgery from a sudden pulmonary embolus. Two (4%) patients required a second
operation for recurrent paraesophageal hernias. CONCLUSIONS: Laparoscopic repair
of paraesophageal hiatal hernias is safe and effective, but the operation is
difficult and good results hinge on details of the operative technique and the
surgeon's experience. In this series, the crus could always be closed securely
without using mesh. We realized early that a fundoplication should be a routine
step, because it corrects reflux and is the best method to secure the
gastroesophageal junction in the abdomen.
PMID- 9544958
TI - Gastric mucosal protection from enteral nutrients: role of motility.
AB - BACKGROUND: Cold restraint stress increases the force of gastric contractions and
produces gastric mucosal injury in rats. The aim of our study was to determine
whether enteral glucose or hyperglycemia alone would alter the stress-induced
gastric motility pattern and ameliorate the associated gastric mucosal injury.
METHODS: Adult male rats underwent surgical placement of gastric catheters,
jugular venous catheters, and gastric strain gauge transducers 5 days before cold
restraint. Three groups of rats received different substances during the same
cold restraint stress protocol. Group 1 received 0.9% NaCl, 2 mL/h infused both
intravenously (i.v.) and intragastrically (i.g.); group 2 received 0.9% NaCl, 2
mL/h i.g. plus 25% glucose, 2 mL/h i.v.; and group 3 received 0.9% NaCl, 2 mL/h
i.v. plus 25% glucose i.g. Following baseline gastric motility measurements, all
rats were restrained for 2 hours at 20 degrees C followed by 2 hours at 4 degrees
C. RESULTS: Restraint even at room temperature increased the force of gastric
contractions; the cold environment gradually prolonged gastric contractions.
Enteral glucose blunted the effects of stress on gastric motility, increased
gastric residual volume, decreased gastric acidity, and prevented gastric mucosal
injury. Parenteral glucose had little effect on any gastric parameters.
CONCLUSIONS: Enteral glucose prevents the abnormal gastric motility pattern that
is necessary to produce the gastric mucosal injury associated with cold restraint
stress, but hyperglycemia alone has little effect on the pathophysiology of cold
restraint.
PMID- 9544959
TI - Intraoperative abandonment of ileal pouch to anal anastomosis--the Mayo Clinic
experience.
AB - BACKGROUND: Completion of the ileal pouch to anal anastomosis (IPAA) is neither
always possible nor advisable based on intraoperative findings. This study was
undertaken to document the incidence of and reasons for intraoperative
abandonment of IPAA in a series of over 1,700 attempts. STUDY DESIGN: A
retrospective review of the Mayo Clinic surgical index from January 1981 through
December 1995. Patients with the preoperative diagnosis of chronic ulcerative
colitis or familial adenomatous polyposis for whom IPAA was planned but not
completed are the subject of this report. Comparison is made to patients with a
completed IPAA from the Mayo Clinic IPAA registry. RESULTS: During a 15-year
period, 1,789 IPAA attempts were made. Intraoperative abandonment occurred in 74
(4.1%). Patients in whom the operation was abandoned were older than patients in
whom it was not (38 versus 33 years, p < 0.01), with age older than 40 years
conferring a relative risk of 1.87 versus age younger than 40 (95% confidence
interval, 1.19-2.94%). IPAA was abandoned for technical reasons in 32 (43%),
intraoperative diagnosis of Crohn's disease in 27 (36%), colorectal cancer in 10
(14%), mesenteric desmoid in 3 (4%), and miscellaneous reasons in 2 (3%)
patients. Fifty-one (69%) patients underwent proctocolectomy and ileostomy and 23
(31%) underwent sphincter preserving procedures. Of these, 2 underwent subsequent
successful IPAA. CONCLUSIONS: Preoperative counseling for IPAA should include
discussion of the risk of intraoperative abandonment (4.1%). Older patients are
at increased risk. If the IPAA is abandoned for reversible reasons, preservation
of the anal sphincter preserves the option of a subsequent IPAA.
PMID- 9544960
TI - Three thousand one hundred seventy-five primary inguinal hernia repairs:
advantages of ambulatory open mesh repair using local anesthesia.
AB - BACKGROUND: Controversy exists over the relative advantages of open mesh repair
compared with open stitching methods and the laparoscopic approach. STUDY DESIGN:
Two thousand nine hundred six (2,906) consecutive unselected adult patients
underwent 3,175 primary inguinal hernia repairs using polypropylene mesh, under
local anesthesia on an ambulatory basis. The age range was 15-92 years. The study
specifically investigated the postoperative course with regard to pain,
complications, and time of return to work. RESULTS: There were no postoperative
deaths and no cases of urinary retention. Two percent of patients developed a
hematoma. The incidence of deep infection was 0.3%. No case of testicular atrophy
occurred. Postoperatively 19% of patients used no analgesia at all; 60% used oral
analgesics for up to 7 days. There was a gradual decrease in time of return to
work over four successive 1-year periods. Manual workers returned to work in 15
days (median) in the first year, reducing to 9 days in the fourth year. The
overall median time of return to work across the whole group was 9 days. There
were eight recurrences with an 18-month to 5-year followup. CONCLUSIONS: Open
mesh repair under local anesthesia is an effective day case technique,
particularly in the elderly and medically unfit. The economic benefits are
enhanced by low morbidity, early return to normal activities and low recurrence
rates.
PMID- 9544961
TI - The past is prologue: surgeons then and now.
PMID- 9544963
TI - Biology and treatment of peritonitis: the historic development of current
concepts.
PMID- 9544962
TI - Reflections on informed consent: 40 years after its birth.
PMID- 9544964
TI - Knot properties of alternating sliding knots with different patterns in
comparison to alternating and simple sliding knots.
AB - This study attempts to compare the alternating sliding knots with different
patterns with the alternating and simple sliding knots. Silk and nylon sutures of
2-0 and 4-0 United States Pharmacopeia (USP) sizes were mechanically tested. The
values of knot holding capacities (KHCs) varied depending on knot configuration,
suture material, and size. The parallel alternating knot with different patterns
showed a high KHC for silk suture of both sizes. For nylon, the alternating knots
with different patterns were comparable to the simple sliding knots. When we
compared silk with nylon in knots with different patterns we observed the
following. For size 2-0 loops, the nonidentical knot of nylon was higher in KHC
than that of silk, and the parallel knot of silk was higher in KHC than that of
nylon. Loops of 4-0 showed higher KHCs for the parallel knot in nylon than in
silk but similar values for both materials with the nonidentical knot. The
parallel alternating knot with different patterns was the most efficient for
nylon 4-0. The silk loops had good efficiencies for both sizes. The silk suture
knots were all reliable. The nylon suture showed unreliability for the parallel
and alternating nonidentical knots of both sizes and the alternating parallel
knot in 2-0 suture. The results section discusses the physical structure and
suture dimension. This study did not prove that the strength of the knot
increases with complexity.
PMID- 9544965
TI - Open technique during laparoscopic operations.
PMID- 9544966
TI - The hernia repair debate.
PMID- 9544967
TI - Aortic cannulation in organ donors with pathology of the infrarenal aorta.
PMID- 9544968
TI - Aortic cannulation in organ donors with pathology of the infrarenal aorta.
PMID- 9544969
TI - Combined effect of two different polymorphic sequences within the beta globin
gene cluster on the level of HbF.
AB - Beta thalassemia and Hb Lepore heterozygotes included in this study exhibit fetal
hemoglobin levels varying from trace quantities to 14% (1.74 g/dl) of total
hemoglobin in the adult. In this work, we have examined the correlation of DNA
sequence polymorphisms with the observed HbF level. The analysis of polymorphic
markers within the beta globin cluster in 39 individuals heterozygous for beta
thalassemia or Hb Lepore confirms the previous findings for homozygous beta
thalassemia: the presence of both an (AT)9 T5 sequence configuration at position
540 of the beta globin gene and a (C --> T) variation at -158 of the Ggamma
globin gene is associated with elevated expression of HbF. However, at least one
defective beta globin gene is required to reveal this association. The best
evidence is from the study of individuals heterozygous for Hb Lepore with various
levels of HbF. In these individuals it was possible to explore the effect of a
single (AT)x Ty motif (the other being absent from the rearranged Lepore
chromosome) on HbF expression. The presence of the (AT)9 T5 configuration
increases HbF level from a median of 0.515 g/dl observed in (AT)7 T7 subjects, to
1.39 g/dl. We confirm the existence of linkage disequilibrium between the (C -->
T) variation at -158 of Ggamma gene and the (TG)13 configuration at the second
intervening sequence (IVS-2) of Agamma gene and identify two new polymorphisms in
this region: (TG)7 (CG)5 (TG)8 linked to haplotype V and (TG)8 (CG)5 (TG)10
linked to haplotype II. This study suggests that two distinct regions of the beta
cluster, whether in cis or in trans to each other, can interact to enhance HbF
expression when a beta thalassemic determinant is present in heterozigosity.
PMID- 9544970
TI - Aspirin increases the bleeding side effects in essential thrombocythemia
independent of the cyclooxygenase pathway: role of the lipoxygenase pathway.
AB - Acetylsalicylic acid (ASA) is currently recommended as an antithrombotic for
patients with essential thrombocythemia (ET) who are at an increased risk of
thrombotic events. However, ASA is also associated with an increased risk of
bleeding in these patients as compared to the risk of bleeding in other patients
treated with ASA. Recent data suggest that while ASA inhibits platelet
thromboxane A2 (TxA2) synthesis in all individuals, ASA has little effect or
inhibits the lipoxygenase pathway (i.e., 12-hydroxyeicosatetranoic acid or 12
HETE synthesis) in some individuals, and enhances 12-HETE synthesis in others.
These differential effects are associated with a pronounced prolongation of the
bleeding time vs. no prolongation of the bleeding time, respectively, i.e., in
ASA responders and ASA nonresponders, respectively. To determine if the increased
risk of ASA-induced bleeding seen in ET patients is associated with an effect on
12-HETE synthesis, we compared the relative effects of ASA on the bleeding time,
platelet TxA2 and 12-HETE synthesis, and platelet aggregation and adhesion in ET
patients and healthy volunteers. ASA (300 mg, taken orally) prolonged the
bleeding time in 82% of the ET patients but only 27% of the healthy volunteers
although platelet TxA2 synthesis and ADP- and collagen-induced aggregation were
inhibited significantly in both groups. In contrast, platelet 12-HETE synthesis
was unchanged and platelet adhesion was decreased in those patients and
volunteers whose bleeding times were prolonged by ASA, whereas platelet 12-HETE
synthesis was increased significantly and platelet adhesion was unaffected in
those patients and volunteers whose bleeding times were not prolonged, and in
some cases shortened by ASA. These results confirm previous data that demonstrate
that ASA has different effects on platelet 12-HETE synthesis and platelet
adhesion in different individuals, i.e., inhibitory or no effect in ASA
responders (in whom ASA prolonged bleeding) vs. enhancing effects in ASA
nonresponders (in whom ASA did not prolong bleeding). These results also indicate
that there is a greater percentage of ASA responders in patients with ET than
that seen in the general population, a difference that is associated with an
effect of ASA on the lipoxygenase pathway. This may explain the increased
bleeding side effects seen in the ET patient population.
PMID- 9544971
TI - Detection of zeta-globin chains in the cord blood by ELISA (enzyme-linked
immunosorbent assay): rapid screening for alpha-thalassemia 1 (Southeast Asian
type).
AB - Fetuses with homozygous alpha-thalassemia 1, in which the deletion of all four
alpha-globin genes results in the absence of any alpha-globin chains, are
severely anemic with clinical features of hydrops fetalis. Definitive diagnosis
of alpha-thalassemia 1 carriers is difficult since there are few red cell
abnormalities. Recently Chui et al. found that minute amounts of embryonic zeta
globin chains are present in adult hemoglobin of the Southeast Asian type of
alpha-thalassemia 1 carriers. In this study, we screened 521 cord bloods for
alpha-thalassemia 1. Hemoglobin analysis, including quantitation of Hb Bart's,
was performed using the automated HPLC, alpha-thalassemia short program (VARIANT,
Bio-Rad, Hercules, CA). Of these, 200 cord blood samples in which Hb Bart's was
demonstrated were tested for the presence of zeta-globin chains by ELISA using
labeled anti-zeta monoclonal antibody. Zeta-globin ranged between 0.21 and 0.83%
in 19 specimens carrying alpha-thalassemia 1 gene. In the remaining 90 out of 109
specimens in which Hb Bart's was greater than 1.2%, zeta-globin was less than
0.17%. DNA analysis revealed the presence of normal alpha-genotype and other
types of alpha-thalassemia including alpha-thalassemia 2 and Hb Constant Spring.
One false positive was found in which the zeta-globin was 0.25% by ELISA but in
which PCR indicated an alpha-thalassemia 2 heterozygote. Ninety-one samples with
Hb Bart's of less than 1.2% by HPLC are most likely normal with a zeta-globin
range between 0 and 0.14%. This study also showed that the frequency of alpha
thalassemia 1 in Bangkok is 3.65%.
PMID- 9544972
TI - Decreased numbers of circulating B cells in myeloma patients with reduction after
conventional chemotherapy.
AB - Reports of high numbers of circulating monotypic B cells in patients with
multiple myeloma (MM) have recently been published. These cells, which were
identified by their expression of CD19, were reported to be resistant to
conventional chemotherapy and to represent the source of relapse. We examined
blood samples from 48 patients before and 53 patients after glucocorticoid
containing chemotherapy by dual color flow cytometry. The absolute count of
CD19+B cells in patients before treatment (212.6+/-24.8 x 10(6)/l) was decreased
compared to normal controls (P = .038). In the post-treatment group, circulating
B cells were highly significantly lower than in untreated patients (45.23+/-6.69
x 10(6)/l. P < .001). This reduction was also seen in 26 patients, that were
followed during chemotherapy. The cytoplasmic kappa/lambda ratio was within
normal range before and after treatment with no difference according to the light
chain isotype of the paraprotein. We conclude that circulating B cells are not
increased in patients with MM, that the majority of these cells are polyclonal,
and that conventional chemotherapy effectively reduces circulating B cells
without leading to dominance of resistant monotypic cells.
PMID- 9544973
TI - Increased von Willebrand factor binding to platelets in single episode and
recurrent types of thrombotic thrombocytopenic purpura.
AB - Extensive microvascular platelet aggregation is characteristic of thrombotic
thrombocytopenic purpura (TTP). Previous studies have indicated that
abnormalities of von Willebrand factor (vWf) are often present in TTP patient
plasma. There has not been previously any direct evidence linking these
abnormalities to the process of intravascular platelet aggregation in TTP. We
used flow cytometry to analyze the binding of vWf to single platelets, and the
presence of platelet aggregates, in the blood of 4 children with chronic
relapsing (CR) TTP and 5 adults with single episode or recurrent TTP. vWf on the
single platelets of CRTTP patients at all time points studied was significantly
increased compared to controls, and was increased further as platelet counts
decreased to levels below 40,000/microl. The single episode and recurrent adult
TTP patients had platelet aggregates in the blood, as well as increased vWf on
single platelets, before therapy commenced and thereafter until recovery was in
process. In the one unresponsive single episode TTP patient, vWf on single
platelets remained elevated, and platelet aggregates persisted, until her death.
The platelet alpha-granular protein, P-selectin, was not increased on the single
platelets of most TTP blood samples, suggesting that it is vWf from plasma
(rather than from alpha-granules) that attaches to platelet surfaces in
association with platelet aggregation. These results suggest that vWf-platelet
interactions are involved in the platelet clumping process that characterizes
TTP.
PMID- 9544974
TI - Recombinant human granulocyte colony-stimulating factor (G-CSF) combined
conditioning regimen for allogeneic bone marrow transplantation (BMT) in standard
risk myeloid leukemia.
AB - We previously suggested that using a combined conditioning regimen including rhG
CSF with allogeneic BMT in refractory AML and CML in blast crisis might reduce
the rate of relapse and improve disease-free survival, without any major side
effects. In this study, we used the same protocol for 10 AML patients in complete
remission (CR) and 6 CML patients in the chronic phase (CP). We compared disease
free survival as well as toxic side effects of the regimen with 6 AML patients in
CR and 6 CML patients in CP treated with chemoradiotherapy without G-CSF. The
conditioning regimen consisted of TBI and high-dose AraC. RhG-CSF was infused
continuously at a dose of 5 microg/kg/day, starting 24 hr before the initial dose
of total body irradiation (TBI) until the end of AraC therapy. In all 28 cases,
there were no early stage deaths due to regimen-related toxicity (RRT). None of
the 10 AML cases treated with the G-CSF combined regime relapsed. In 6 AML cases
treated conventionally without G-CSF, one patient died of infection and another
relapsed. There were no relapses in either CML group. In the combined G-CSF
group, one patient died of interstitial pneumonitis 48 days after BMT, while the
rest of the CML cases are still alive. There were no relapses with rhG-CSF and no
serious adverse effects in terms of RRT, acute graft vs. host disease (GVHD), or
leukocyte recovery.
PMID- 9544975
TI - Plasma fibronectin during myocardial ischemia-reperfusion: effects of magnesium,
diltiazem, and a novel Mac-1 inhibitor.
AB - The important role of fibronectin (Fn) has been recognized in patients with
ischemic heart disease. However, serial changes of Fn during both brief and
prolonged ischemia-reperfusion are poorly known. Plasma Fn was measured during
acute myocardial infarction (AMI) and myocardial stunning (MS), and in the
absence of myocardial injury. The effects of magnesium (Mg), diltiazem, and a Mac
1 inhibitor on the level of Fn were elucidated. Forty-nine swine underwent
prolonged (50 min) or brief (8 min) coronary artery occlusion followed by
reperfusion, while six control animals were free of ischemia. During the AMI
experiments, plasma Fn underwent a significant progressive increase. Mg or
diltiazem similarly affects the plasma Fn, reducing its release during the entire
reperfusion period, and did not influence the plasma Fn in the absence of
myocardial injury. Contrarily, Mac-1 inhibition resulted in the Fn elevation in
controls, and during the occlusion phase, with no significant effect during
reperfusion. There were no changes in the plasma Fn during MS, while inhibition
of Mac-1 was associated with the significant increase of Fn during ischemia
reperfusion. Ability of Mg, diltiazem, and leumedins to modulate plasma Fn level
may have direct clinical implications for the use of these agents in patients
with coronary artery disease.
PMID- 9544976
TI - Rapid detection of anticardiolipin antibodies.
AB - A rapid screening method for the detection of antiphospholipid antibodies is
described. Dense, red dyed polystyrene beads coated with cardiolipin were
incubated with test sera for a short period of time, then added to a microtube
containing anti-human IgG in a gel provided within a pre-cast card (DiaMed ID
Microtyping System). The card was centrifuged at 150g for 5 min and then examined
for movement of the beads through the gel. Beads without bound antibody travelled
through the gel and formed a pellet on the bottom of the tube. Anti-human IgG
within the gel matrix impeded cardiolipin-coated beads when antiphospholipid
antibodies bound to the beads. Positivity was indicated by the formation of a
layer of beads on the top of the gel matrix. Prospective analysis of 103 samples
for the presence of antiphospholipid antibodies by flow cytometry and the gel
card technique showed good correlation between the two methods. All samples found
to be positive by flow cytometry (23 of 103) were identified as positive by the
gel-card technique. Two samples were identified as positive by the gel-card
method but negative by flow cytometry. The technique is simple to perform and
should prove useful as a rapid screening method for the detection of
antiphospholipid antibodies.
PMID- 9544977
TI - Chronic myeloid leukemia with minor-bcr breakpoint developed hybrid type of blast
crisis.
AB - Although a breakpoint in the minor breakpoint cluster region (m-bcr) of the BCR
gene is observed in about two-thirds of patients with Philadelphia chromosome
positive acute lymphoblastic leukemia, this type of genomic rearrangement occurs
very rarely in chronic myeloid leukemia (CML). We describe here the eighth case
of m-bcr CML, and delineate unique clinical characteristics found in common to
the 7 cases reported previously. Monocytosis with a low neutrophil/monocyte ratio
resembling chronic myelomonocytic leukemia was the most striking feature of m-bcr
CML. Splenomegaly and basophilia were not conspicuous in chronic phase. A high
percentage of immature granulocytes and low neutrophil alkaline phosphatase score
were the findings in common with classical CML. Lymphoid and myeloid blast
changes have been observed at and shortly after presentation so far. We found a
hybrid type of blast crisis in the course of m-bcr CML.Thus, m-bcr CML may be a
definite subtype of CML, exhibiting distinct clinical characteristics. The
presence of fusion product of m-bcr mRNA in an earlier myeloid cell may involve
monocytic lineage in addition to myeloproliferative defects.
PMID- 9544978
TI - Transfusion management of an IgA deficient patient with anti-IgA and incidental
correction of IgA deficiency after allogeneic bone marrow transplantation.
AB - A patient with multiple myeloma was noted to have an IgA deficiency during
investigation of a possible transfusion reaction due to IgA deficiency and anti
IgA. Because of the patient's age, otherwise good health, and early stage of
disease, he was enrolled in a research treatment protocol that involved an
allogeneic bone marrow transplant (BMT). The BMT successfully put the patient in
complete remission from his multiple myeloma and corrected his IgA deficiency.
Class-specific IgG anti-IgA antibody that had been identified prior to BMT was no
longer detectable in his plasma. Anaphylactic transfusion reactions were
successfully avoided by using a combination of IgA-deficient and washed blood
components including the marrow graft, and IgA-reduced intravenous
immunoglobulin.
PMID- 9544980
TI - Immunologic thrombocytopenic purpura as presenting symptom of hepatitis C
infection.
AB - We report on 3 female patients with immunologic thrombocytopenic purpura (ITP)
for whom diagnostic procedures evidenced a chronic Hepatitis C virus (HCV)
infection. In 2 cases, a transfusion performed more than 10 years ago represented
the probable way of contamination. One patient received a course of steroids,
which normalized the platelet counts. Another one has been treated with repeated
IV immunoglobulins, which induced partial responses of variable duration. HCV is
responsible for many autoimmune manifestations and a search for this virus seems
warranted for exploring patients with ITP.
PMID- 9544979
TI - T-cell lymphoma associated with natural killer-like T-cell reaction.
AB - We report a case of T-cell lymphoma showing in the peripheral blood (PB)
exclusively T-lymphocytes with suppresser T-cell preponderance and a high
percentage of natural killer (NK) marker positive cells by flow cytometry. A T
cell receptor (TCR) gene analysis of the PB leukocytes demonstrated
rearrangements of TCRalpha, TCRbeta, and TCRgamma genes. Therefore, the phenotype
and genotype appeared to be consistent with an NK-like T-cell leukemia/lymphoma.
However, when the PB lymphocytes were separated by size, it was found that 80% of
NK marker positive cells were in the smaller cell population, while the
neoplastic cells were in the large cell gate. A diagnosis of T-cell lymphoma with
reactive NK-like T-cells was finally confirmed by demonstrating the presence of
both large atypical lymphoid cells and large granular lymphocytes (LGL) on PB
smears. Although immunoperoxidase stain of bone marrow and colon showed positive
T-cell markers in the tumor cell population, cytoplasmic granules could not be
identified in tissue sections and, thus, a distinction between T-cell lymphoma
and NK-like T-cell lymphoma could not be made by light microscopy until NK
markers were studied. CD57 was demonstrated immunohistochemically in small
lymphocytes but not in the large tumor cells in the colon. Electron microscopy,
however, demonstrated LGL reaction to the lymphoma cells in the colonic biopsy.
NK-like T-cell lymphoma usually carries a poorer prognosis than peripheral T-cell
lymphoma, thus the distinction of these neoplasms is important. This study
emphasizes that T-cell lymphoma may cause an LGL reaction or proliferation. If
the lymphoma cells were of the same size as LGL, flow cytometric studies may have
misled the diagnosis to NK-like T-cell-lymphoma.
PMID- 9544981
TI - Oxidized LDL damages endothelial cell monolayer and promotes thrombocyte
adhesion.
AB - The influence of oxidized low density lipoprotein (LDL) on a human endothelial
cell monolayer was examined. The resulting contraction of the oxidized LDL
damaged endothelial cells lets intercellular spaces become enlarged and therefore
visible via light microscopy. Electron microscopy reveals that the structural
damage facilitates thrombocyte adhesion and formation of microthrombi. Oxidized
LDL appears to play a pivotal role in initiating and deteriorating thromboembolic
complications.
PMID- 9544982
TI - Low risk of venous thrombosis in two families with combined type I plasminogen
deficiency and factor V R506Q mutation.
AB - Two families with type I plasminogen deficiency and APC resistance are reported.
The proposita of family A suffered from ischemic stroke when taking estrogen
progesterone-containing oral contraceptive. Several hemostatic challenges in the
past (ovariectomy, appendectomy, and two pregnancies) were without thrombosis.
Plasminogen activity and antigen (60 and 58%, normal range 72-136 and 69-135%,
respectively) were reduced, and an increased APC resistance (APC-SR= 1.55; normal
range 1.8-3.00) associated with G --> A change at 1,691 nucleotide position in
exon 10 of FV gene (FV Leiden) was observed. The asymptomatic son had isolated
plasminogen deficiency (activity 57% and antigen 60%) whereas the asymptomatic
daughter had isolated APC resistance (APC-SR = 1.61) and FV Leiden mutation. The
proposita of family B, referred for superficial thrombophlebitis, had low
plasminogen levels (activity 55% and antigen 53%) and APC resistance (APC-SR =
1.5) whereas the asymptomatic mother and the brother had isolated APC resistance
(APC-SR = 1.62 and 1.8, respectively) and the asymptomatic father isolated
plasminogen deficiency (activity 61% and antigen 62%). These data suggest that
the combination of plasminogen deficiency and APC resistance probably does not
significantly increase the risk of venous thrombosis. However, larger experience
with additional cases is needed to definitely assess the magnitude of thrombotic
risk in these families.
PMID- 9544983
TI - Oct-1 binds promoter elements required for transcription of the GnRH gene.
AB - The GnRH gene is exclusively expressed in a discrete population of neurons in the
hypothalamus. The promoter-proximal 173 bp of the rat GnRH gene are highly
conserved through evolution and are bound by multiple nuclear proteins found in
the neuronal cell line, GT1-7, a model for the GnRH-expressing hypothalamic
neuron. To explore the protein-DNA interactions that occur within this promoter
and the role of these interactions in targeting GnRH gene expression, we have
mutagenized individual binding sites in this region. Deoxyribonuclease I
protection experiments reveal that footprint 2, a 51-bp sequence that confers a
20-fold induction of the GnRH gene, is comprised of at least three independent
protein-binding sites. Transfections of the GnRH promoter-reporter plasmid
containing a series of block mutations of footprint 2 into GT1-7 neurons indicate
that each of the three putative component sites contributes to transcriptional
activity. Mutations in footprint 4 also decrease GnRH gene expression. Footprint
4 and the promoter-proximal site in footprint 2 contain octamer-like motifs, an
element that is also present in the neuron-specific enhancer of the rat GnRH gene
located approximately 1.6 kb upstream of the promoter. Previous studies in our
laboratory have demonstrated that two enhancer octamer sites are bound by the POU
homeodomain transcription factor Oct-1 in GT1-7 cells. We now show that Oct-1
binds the octamer motifs within footprints 2 and 4. Thus, Oct-1 plays a critical
role in the regulation of GnRH transcription, binding functional elements in both
the distal enhancer and the promoter-proximal conserved region.
PMID- 9544984
TI - Further characterization of the glucocorticoid response unit in the
phosphoenolpyruvate carboxykinase gene. The role of the glucocorticoid receptor
binding sites.
AB - Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the rate-limiting step of
gluconeogenesis. The activity of this enzyme is controlled by several hormones,
including glucocorticoids, glucagon, retinoic acid, and insulin, that principally
affect the rate of transcription of the PEPCK gene. Glucocorticoids induce PEPCK
gene transcription through a complex glucocorticoid response unit that consists
of, from 5' to 3', accessory factor elements AF1 and AF2; two noncanonical
glucocorticoid receptor-binding sites, GR1 and GR2; a third accessory factor
element, AF3; and a cAMP-response element, CRE. A complete glucocorticoid
response is dependent on the presence of both GR-binding sites, all three
accessory elements, and the CRE. In this study we assess the relative roles of
GR1 and GR2 in the context of the glucocorticoid response unit and use a
combination of binding and function assays to compare GR1 and GR2 to
glucocorticoid response elements (GREs) that conform closely to the consensus
sequence. The relative binding affinity of GR follows the order: consensus GRE >>
GR1 > GR2. Mutations that disrupt the binding of GR to GR1 result in a major
reduction of the glucocorticoid response, whereas similar mutations of GR2 have a
much smaller effect. Unlike the simple consensus GRE, neither GR1 nor GR2 mediate
a glucocorticoid response through a heterologous promoter. The accessory elements
appear to have different functional roles. AF2 is still needed for a maximal
glucocorticoid response when GR1 is converted to a high-affinity GR-binding
element, but AF1 and AF3 are not required.
PMID- 9544985
TI - Differential regulation and transcriptional control of immediate early gene
expression in forskolin-treated WEHI7.2 thymoma cells.
AB - Agents that increase intracellular cAMP are frequently growth inhibitory for
lymphocytes and induce apoptosis in cortical thymocytes by regulating gene
expression. In the present study, immediate early gene expression was examined in
WEHI7.2 thymoma cells undergoing cAMP-mediated apoptosis. Temporal differences in
c-fos, junB, and inducible cAMP early repressor (ICER) steady-state mRNA levels
were observed after forskolin exposure. Maximal induction of c-fos and junB
occurred within 1 h, returning to basal levels by 3.5 h. In contrast, a 1.5-h
time lag was observed before ICER transcript levels increased, reaching maximal
levels after 3.5 h. This rise in expression, correlating with the decrease in c
fos and junB levels, preceded apoptotic DNA fragmentation by 1.5 h. Transient
expression of ICER promoter constructs demonstrated that cAMP responsiveness
occurred through cAMP-autoregulatory response element (CARE)3/4, two of the four
proposed response elements in the ICER promoter. In contrast to the cAMP
responsive cell line JEG-3, CARE1/2 was not functional for cAMP-activated
transcription in WEHI7.2 cells. An observed differential binding pattern of WEHI
and JEG nuclear extracts to these elements may account for the cell-specific
differences in expression patterns. To determine the role of endogenous ICER in
regulating gene expression, cells were treated with two sequential doses of
forskolin after which ICER and c-fos mRNA levels were measured. The high levels
of cAMP-induced ICER expression dramatically reduced a second induction of c-fos.
These data suggest that ICER expression may function as an antioncogene to
attenuate the expression of certain protooncogenes, thereby preventing
transformation and oncogenesis due to continuous overexpression. Moreover,
inhibition of growth-stimulatory genes may be required for the activation of the
cell death machinery in specific cells.
PMID- 9544986
TI - Cell-specific inhibition of retinoic acid receptor-alpha silencing by the AF2/tau
c activation domain can be overcome by the corepressor SMRT, but not by N-CoR.
AB - The human retinoic acid receptor alpha (hRAR alpha) exhibits cell-specific
transcriptional activity. Previously, it was shown that in the absence of hormone
the wild-type receptor is a transcriptional silencer in L cells, whereas it lacks
silencing function and is a weak activator in CV1 cells. Addition of hormone
leads to a further increase in transactivation in CV1 cells. Thus, the retinoic
acid response mediated by RAR alpha is weak in these cells. It was shown that the
CV1-specific effect is due to the receptor C terminus. We show, that the failure
of silencing by RAR is not due to a general lack of corepressors in CV1 cells,
since the silencing domain of RAR is functionally active and exhibits active
repression in these cells. Furthermore, we show that the conserved AF2/tau c
activation function of RAR is responsible for the cell-specific inhibition of
silencing. Thereby, the CV1 cell specificity was abolished by replacing AF2/tau c
of RAR with the corresponding sequence of the thyroid hormone receptor. Thus, we
find a new role of the C-terminal conserved activation function AF2/tau c in
that, specifically, the RAR AF2/tau c-sequence is able to prevent silencing of
RAR in a cell-specific manner. In addition, we show that the inhibitory effect of
AF2/tau c in CV1 cells can be overcome by expression of the corepressor SMRT
(silencing mediator of retinoic acid and thyroid hormone receptor), but not by
that of N-CoR (nuclear receptor corepressor). The expression of these two
corepressors, however, had no measurable effect on RAR-mediated silencing in L
cells. Thus, the expression of a corepressor can lead to a dramatic increase of
hormonal response in a cell-specific manner.
PMID- 9544987
TI - A nuclear receptor corepressor modulates transcriptional activity of antagonist
occupied steroid hormone receptor.
AB - Synthetic steroid hormone antagonists are clinically important compounds that
regulate physiological responses to steroid hormones. The antagonists bind to the
hormone receptors, which are ligand-inducible transcription factors, and modulate
their gene-regulatory activities. In most instances, a steroid receptor, such as
progesterone receptor (PR) or estrogen receptor (ER), is transcriptionally
inactive when complexed with an antagonist and competitively inhibits
transactivation of a target steroid-responsive gene by the cognate hormone
occupied receptor. In certain cellular and promoter contexts, however, antagonist
occupied PR or ER acquires paradoxical agonist-like activity. The cellular
mechanisms that determine the switch from the negative to the positive mode of
transcriptional regulation by an antagonist-bound steroid receptor are unknown.
We now provide strong evidence supporting the existence of a cellular inhibitory
cofactor that interacts with the B form of human PR (PR-B) complexed with the
antiprogestin RU486 to maintain it in a transcriptionally inactive state. In the
presence of unliganded thyroid hormone receptor (TR) or ER complexed with the
antiestrogen 4-hydroxytamoxifen, which presumably sequesters a limiting pool of
the inhibitory cofactor, RU486-PR-B functions as a transcriptional activator of a
progesterone-responsive gene even in the absence of hormone agonist. In contrast,
hormone-occupied TR or ER fails to induce transactivation by RU486-PR-B. Recent
studies revealed that a transcriptional corepressor, NCoR (nuclear receptor
corepressor), interacts with unliganded TR but not with liganded TR.
Interestingly, coexpression of NCoR efficiently suppresses the partial agonistic
activity of antagonist-occupied PR-B but fails to affect transactivation by
agonist-bound PR-B. We further demonstrate that RU486-PR-B interacts physically
with NCoR in vitro. These novel observations suggest that the inhibitory cofactor
that associates with RU486-PR-B and represses its transcriptional activity is
either identical or structurally related to the corepressor NCoR. We propose that
cellular mechanisms that determine the switch from the antagonistic to the
agonistic activity of RU486-PR-B involve removal of the corepressor from the
antagonist-bound receptor so that it can effect partial but significant gene
activation.
PMID- 9544988
TI - Differential use of transcription activation function 2 domain of the vitamin D
receptor by 1,25-dihydroxyvitamin D3 and its A ring-modified analogs.
AB - Analogs of 1,25-dihydroxyvitamin D3 (1,25D3) can be used to elucidate details of
vitamin D receptor (VDR) activation. The A ring-modified analog, (TN-2) has 15
fold less affinity for VDR, but its transcriptional activity is diminished 1000
fold. Likewise, the ability of TN-2 to induce a protease-resistant conformation
in VDR is 1/1000 that of 1,25D3. The stability of the VDR-TN-2 complexes is also
significantly lower than VDR-1,25D3 complexes. Mapping the VDR-binding site of TN
2 showed that it had a significantly greater requirement for transcription
activation function 2 (AF-2) residues than 1,25D3 did. These results suggest that
the increased requirement for AF-2 residues that was induced by the A ring
modifications is associated with diminished receptor activation. To determine
whether restoring the potency of TN-2 by additional structural modifications
would change the requirements for AF-2 residues, we synthesized hybrid analogs
with 1beta-hydroxymethyl-3-epi groups and with dimethyl groups at positions 26
and 27 of the side chain, without or with a double bond between CD ring positions
16 and 17. We found that the side chain modification enhanced transcriptional
activity 150-fold, increased the ability of the receptor to form a protease
resistant conformation 100-fold, and stabilized the VDR-analog complexes. The
addition of the 16-ene group further reduced the analog's dissociation rate and
increased its potency in the protease assays. These functional changes in the
hybrid analogs were associated with a significant reduction in interaction with
AF-2 residues. We conclude that there is an inverse relationship between analogs'
potencies and their interaction with AF-2 residues of VDR.
PMID- 9544989
TI - Shc phosphotyrosine-binding domain dominantly interacts with epidermal growth
factor receptors and mediates Ras activation in intact cells.
AB - The adaptor protein Shc contains a phosphotyrosine binding (PTB) domain and a Src
homology 2 (SH2) domain, both of which are known to interact with phosphorylated
tyrosines. We have shown previously that tyrosine 1148 of the activated epidermal
growth factor (EGF) receptor is a major binding site for Shc while tyrosine 1173
is a secondary binding site in intact cells. In the present study, we
investigated the interaction between the PTB and SH2 domains of Shc and the
activated human EGF receptor. Mutant 52-kDa Shc with an arginine-to-lysine
substitution at residue 175 in the PTB domain (Shc R175K) or 397 in the SH2
domain (Shc R397K) was coexpressed in Chinese hamster ovary cells overexpressing
the wild-type or mutant EGF receptors that retained only one of the
autophosphorylation sites at tyrosine 1148 (QM1148) or 1173 (QM1173). Shc R397K
was coprecipitated with the QM1148 and QM1173 receptors, was tyrosine
phosphorylated, and associated with Grb2 and Sos. In contrast, coprecipitation of
Shc R175K with the mutant receptors was barely detectable. In cells expressing
the QM1173 receptor, Shc R175K was tyrosine-phosphorylated and associated with
Grb2, while association of Sos was barely detectable. In cells expressing the
QM1148 receptor, tyrosine phosphorylation of Shc R175K was markedly reduced. When
both Shc R175K and 46-kDa Shc R397K were coexpressed with the mutant receptors,
p46 Shc R397K was dominantly tyrosine-phosphorylated. In cells expressing the
wild-type receptor, Shc R397K, but not Shc R175K, translocated to the membrane in
an EGF-dependent manner. In addition, Ras activity stimulated by the
immunoprecipitates of Shc R397K was significantly higher than that by the
immunoprecipitates of Shc R175K. The present results indicate that tyrosine 1148
of the activated EGF receptor mainly interacts with the Shc PTB domain in intact
cells. Tyrosine 1173 interacts with both the PTB and SH2 domains, although the
interaction with the PTB domain is dominant. In addition, Shc bound to the
activated EGF receptor via the PTB domain dominantly interacts with Grb2-Sos
complex and plays a major role in the Ras-signaling pathway.
PMID- 9544990
TI - N-glycosylation of the prolactin receptor is not required for activation of gene
transcription but is crucial for its cell surface targeting.
AB - The functional importance of the three oligosaccharide chains linked to Asn35,
Asn80 and Asn108, of the long form of the PRL receptor (PRLR) was investigated by
individual or multiple substitutions of asparagyl residues using site-directed
mutagenesis and transient transfection of these mutated forms of PRLR in monkey
kidney cells, Chinese hamster ovary, and human 293 fibroblast cells that exhibit
different levels of protein expression. Scatchard analysis performed on monkey
kidney cells revealed that the mutants possess the same affinity for PRL as
compared with wild-type PRLR. A strong reduction (90%) of the aglycosylated PRLR
expression at the cell surface of monkey kidney or human 293 cells was observed.
Immunohistochemistry experiments using an anti-PRLR monoclonal antibody showed an
accumulation of the deglycosylated receptor in the Golgi area of transfected
monkey kidney cells. Upon PRL stimulation, the aglycosylated PRLR associated with
Janus kinase 2 was phosphorylated and was able to activate a beta-casein gene
promoter in transfected 293 fibroblast cells. The active form of the PRLR was
thus acquired independently of glycosylation. By contrast, no functional activity
was detectable in transfected Chinese hamster ovary cells that expressed low
levels of PRLR. These studies demonstrate that the glycosylation on the asparagyl
residues of the extracellular domain of the PRLR is crucial for its cell surface
localization and may affect signal transduction, depending on the cell line.
PMID- 9544991
TI - Dominant negative variants of the SHP-2 tyrosine phosphatase inhibit prolactin
activation of Jak2 (janus kinase 2) and induction of Stat5 (signal transducer and
activator of transcription 5)-dependent transcription.
AB - PRL plays a central role in the regulation of milk protein gene expression in
mammary epithelial cells and in the growth and differentiation of lymphocytes. It
confers its activity through binding to a specific transmembrane, class I
hematopoietic receptor. Ligand binding leads to receptor dimerization and
activation of the tyrosine kinase Jak (janus kinase) 2, associated with the
membrane-proximal, intracellular domain of the receptor. Jak2 phosphorylates and
activates Stat5, a member of the Stat (signal transducers and activators of
transcription) family. PRL receptor also activates SHP-2, a cytosolic tyrosine
phosphatase. We investigated the connection between these two signaling events
and derived a dominant negative mutant of SHP-2 comprising the two SH2 domains
[SHP-2(SH2)2]. An analogous variant of the SHP-1 phosphatase [SHP-1(SH2)2] was
used as a control. The dominant negative mutant of SHP-2 was found to inhibit the
induction of tyrosine phosphorylation and DNA-binding activity of m-Stat5a, m
Stat5b, and the carboxyl-terminal deletion variant m-Stat5adelta749, as well as
the transactivation potential of m-Stat5a and m-Stat5b. The dominant negative
mutant SHP-1(SH2)2 had no effect. The kinase activity of Jak2 is also dependent
on a functional SHP-2 phosphatase. We propose that SHP-2 relieves an inhibitory
tyrosine phosphorylation event in Jak2 required for Jak2 activity, Stat5
phosphorylation, and transcriptional induction.
PMID- 9544993
TI - The agonist-induced phosphorylation of the rat follitropin receptor maps to the
first and third intracellular loops.
AB - Previous results from this laboratory have shown that the rat FSH receptor
(rFSHR) becomes phosphorylated on S/T residues upon stimulation of transfected
cells with human (h)FSH and that a truncation of the C-terminal tail that removes
12 of the 25 intracellular S/T residues does not affect phosphorylation. Based on
the results of phosphopeptide-mapping experiments we analyzed three new mutants.
rFSHR-1L and rFSHR-3L were constructed by mutating the S/T residues in the first
intracellular loop or the third intracellular loop, respectively. rFSHR-(3L+CT)
was constructed by mutating all the S/T residues in the third loop as well as
S624, the only C-terminal tail residue that was not previously eliminated as a
potential phosphorylation site. All mutants were biologically active. The agonist
induced phosphorylation of rFSHR-3L and rFSHR-(3L+CT) were partially reduced,
while that of rFSHR-1L was almost completely lost. The agonist-induced uncoupling
of rFSHR-1L and rFSHR-3L are retarded to about the same extent, while the agonist
induced internalization is retarded only in rFSHR-1L. Four major conclusions can
be made from the present studies: 1) the phosphorylated rFSHR is a common
molecular intermediate in agonist-induced uncoupling and internalization; 2)
agonist-induced phosphorylation of the rFSHR maps to the first and third
intracellular loops; 3) the phosphorylation of the third intracellular loop
facilitates agonist-induced uncoupling but is not necessary for agonist-induced
internalization; 4) agonist-induced internalization is facilitated by
phosphorylation but it is not known if only the first loop, only the third loop,
or both the first and third loops need to be phosphorylated for this response.
PMID- 9544992
TI - Extinction of insulin-like growth factor-I mitogenic signaling by antiestrogen
stimulated Fas-associated protein tyrosine phosphatase-1 in human breast cancer
cells.
AB - Steroidal (ICI 182, 780) and nonsteroidal hydroxytamoxifen (OH-Tam) antiestrogens
inhibit growth factor-mitogenic activity in MCF 7 estrogen receptor-positive
human breast cancer cells. Cell inhibition is correlated with an increase in
membrane protein tyrosine phosphatase (PTP) activity, and the addition of
orthovanadate prevents OH-Tam inhibition. After RT-PCR cloning of PTPs expressed
in MCF 7 cells with primers to their catalytic domains, we have shown, by
differential screening, that the expression of two enzymes, leukocyte common
antigen-related PTP (LAR) and Fas-associated PTP-1 (FAP-1), was modulated by
antiestrogens. By comparative RT-PCR, in situ hybridization, and Northern blot,
LAR and FAP-1 mRNAs accumulation was found to be dose- and time-dependently
increased by antiestrogens. To further demonstrate that PTPs were key mediators
of antiestrogen-inhibitory action on the growth factor pathway, a panel of stable
FAP-1 transfectants expressing low to high levels of antisense mRNAs was
established. In these clones, the level of antisense RNA expression was
correlated with a reduction in basal levels and a complete inhibition of
antiestrogen-stimulated values of PTP activity. When FAP-1 expression was
abolished, OH-Tam was no longer able to block insulin-like growth factor I
mitogenic activity even though it remained strongly antiestrogenic. However, ICI
182,780 was still inhibitory, indicating that its effect was not exclusively
mediated by PTP. Our data first demonstrate that a specifically regulated
phosphatase (FAP-1) is implicated in the triggering of negative proliferation
signals in breast cancer cells.
PMID- 9544994
TI - A ligand-mimetic model for constitutive activation of the melanocortin-1
receptor.
AB - Dark coat color in the mouse and fox results from constitutively activated
melanocortin-1 receptors. Receptor mutations in the mouse (E92K, L98P), cow
(L99P), fox (C125R), and sheep (D119N) cluster near the membrane/extracellular
junctions of the second and third transmembrane domains, an acidic domain that is
the likely site of electrostatic interaction with an arginine residue in the
ligand, alpha-MSH. For transmembrane residues E92, D119, and C125, conversion to
a basic residue is required for constitutive activation. Unlike constitutively
activating mutations in many G protein-coupled receptors that increase agonist
efficacy and affinity, these MC1-R mutations have the opposite effect. Therefore,
these mutations do not activate the receptor by directly disrupting
intramolecular constraints on formation of the active high-affinity state, R*,
but do so indirectly by mimicking ligand binding.
PMID- 9544995
TI - Epithelial tight junction structure in the jejunum of children with acute and
treated celiac sprue.
AB - Tight junction morphology was analyzed in freeze fracture electron micrographs
from biopsies at two locations along the surface-crypt axis in the jejunum of
children with treated and untreated sprue and in control subjects. In control
jejunum, strand number, meshwork depth, and total depth of the tight junction
decreased from surface to crypt, consistent with the concept of the crypt being
more permeable than the surface epithelium. In acute sprue, strand number was
reduced in all regions along the surface-crypt axis, from 5.5+/-0.2 to 3.4+/-0.3
(surface) and from 4.7+/-0.2 to 3.6+/-0.1 (crypt). Meshwork depth was also
reduced at all regions along the surface-crypt axis. Strand discontinuities were
more frequent in acute sprue. Aberrant strands appeared below the main meshwork
of crypt tight junctions in acute sprue. In asymptomatic children treated with
the gluten-free diet, jejunal tight junctional structure only partially
recovered. Strand number was restored to normal at the surface, but was still
decreased in the crypts, from 4.7+/-0.2 to 3.9+/-0.3. We conclude that the
epithelial barrier function of the small intestine is seriously disturbed by
structural modifications of the tight junction in acute symptomatic celiac
disease, thereby accounting for increased ionic permeability noted in a parallel
study on identical specimens. This epithelial barrier defect may contribute to
diarrhea in celiac disease by a "leak flux mechanism." In children with sprue
treated with a gluten-free diet, barrier dysfunction was only partly recovered,
suggesting a level of "minimal damage."
PMID- 9544996
TI - Arginine-metabolizing enzymes in the developing rat small intestine.
AB - Before weaning, arginine biosynthesis from citrulline most likely takes place in
the small intestine rather than in the kidney. We studied the expression of
ornithine cycle enzymes in the rat small intestine during perinatal development.
The spatiotemporal patterns of expression of ornithine aminotransferase,
carbamoylphosphate synthetase, ornithine transcarbamoylase, argininosuccinate
synthetase, argininosuccinate lyase, and arginase mRNAs were studied by Northern
blot analysis and in situ hybridization. In addition, the expression of
carbamoylphosphate synthetase and argininosuccinate synthetase protein was
studied by immunohistochemistry. Before birth, the developmentally more mature
proximal loops of the intestine expressed the mRNAs at higher concentrations than
the more distal loops. After birth, this difference was no longer obvious. The
mRNAs of argininosuccinate synthetase and argininosuccinate lyase, the enzymes
that metabolize citrulline to arginine, were detectable only in the upper part of
the villi, whereas the other mRNAs were concentrated in the crypts. The
distribution of argininosuccinate synthetase protein corresponded with that of
the mRNA, whereas carbamoylphosphate synthetase protein was present in all
enterocytes of the crypts and villi. Hepatic arginase mRNA could not be detected
in the enterocytes. The spatial distribution of the respective mRNAs and proteins
along the villus axis of the suckling small intestine indicates that the basal
enterocytes synthesize citrulline, whereas the enterocytes in the upper half of
the villus synthesize arginine.
PMID- 9544997
TI - Metabolic and endocrine responses to cold exposure in chronically incubated
extrauterine goat fetuses.
AB - To investigate developmental aspects of metabolic and endocrine responses to cold
exposure in fetuses, we conducted experiments on six goat fetuses, three aged 95
116 d of gestation (dGA; group I), and three aged 122-134 dGA (group II), using
an extrauterine fetal incubation system that provided arterio-venous
extracorporeal membrane oxygenation (A-V ECMO). The fetuses were cannulated via
the umbilical vessels, and their blood gas exchange was totally supported by A-V
ECMO, while they were maintained in an isothermal incubator containing artificial
amniotic fluid. After confirming that fetuses were in metabolically stable
condition in the extrauterine incubation system, fetal core temperature was
lowered by 2 degrees C over 2 h by decreasing the temperature of incubating fluid
from 39.5 degrees C. During and after cold exposure, fetal heart rate and
arterial blood pressure remained unchanged. We observed significant increases in
oxygen consumption and plasma concentrations of norepinephrine, epinephrine,
adrenocorticotropic hormone, and cortisol in group II but not in group I fetuses.
In addition, based on regression analysis, maximal changes of these parameters
during cold exposure were linearly correlated with gestational age significantly,
and the regression lines were found to intersect the x (gestational age) axis at
around 98-106 dGA. These results suggest that metabolic and endocrine responses
to cold exposure develop with gestational age in the goat fetus, the responses
being manifested around 100 dGA.
PMID- 9544998
TI - Evidence that phenylalanine hydroxylation rates are overestimated in neonatal
subjects receiving total parenteral nutrition with a high phenylalanine content.
AB - Recent publications have indicated that the parenterally fed neonate has a
substantial ability to hydroxylate phenylalanine. Examination of these data
suggests that, at high phenylalanine intakes, estimated rates of hydroxylation
exceed rates of intake. This implies significant net tissue breakdown. However,
the quantitative validity of the estimates of phenylalanine hydroxylation cannot
be assessed without nitrogen balance data. We have recently developed a
parenterally fed neonatal piglet model and have used this to study aromatic amino
acid metabolism in piglets fed different amino acid solutions. Reappraisal of the
data from these studies has allowed us to estimate both phenylalanine
hydroxylation and tissue protein accretion. Piglets were parenterally fed Vamin
[292 micromol of Phe x kg(-1) x h(-1), 26 micromol of Tyr x kg(-1) x h(-1)],
Vaminolact + Phe [VLP, 277 micromol of Phe x kg(-1) x h(-1), 26 micromol Tyr x
kg(-1) x h(-1)], or Vaminolact + glycyl-L-tyrosine [VLGT, 152 micromol of Phe x
kg(-1) x h(-1), 159 micromol of Tyr x kg(-1) x h(-1)] for 8 d. Nitrogen balance
was measured over the last 5 study d, and aromatic amino acid kinetics were
determined using a primed continuous infusion of L-[1-4C]phenylalanine on d 8.
Average body protein gain, derived from nitrogen balance, was 11 g x kg(-1) x d(
1). For the Vamin and VLP groups, the rates of phenylalanine hydroxylation were
estimated to be 139 and 90% of intake, respectively. However, phenylalanine
hydroxylation was only 16% of intake for the VLGT group. In view of the tissue
protein accretion data, it appears that the rate of phenylalanine hydroxylation
may be overestimated in neonates fed high phenylalanine parenteral nutrition. The
extent to which the parenterally fed neonate can adapt to a high phenylalanine
intake, by increasing the rate of phenylalanine hydroxylation, remains to be
determined.
PMID- 9544999
TI - Factors affecting the 2H to 18O dilution space ratio in infants.
AB - In the doubly labeled water (DLW) method, for measurement of energy expenditure
in humans, calculation of carbon dioxide production rate is influenced by the
ratio (R) of the dilution spaces of the tracer isotopes 2H and 18O. Recent
publications have recommended use of a fixed value for R, using a mean population
value (meanR) rather than individually derived experimental values. However, most
of the data considered previously were derived from adults. Infants are
characterized by rapid rates of energy deposition and high body water content,
either of which could influence isotope kinetics. We have considered whether use
of a fixed R value is suitable for DLW studies of infants, and whether the adult
(meanR) value is appropriate. Data from 281 DLW measurements in healthy infants
aged 6 wk to 12 mo were analyzed. Mean R of all measurements was 1.036 (SD
0.019), very similar to (meanR) values recommended for adults. We found
analytical precision could account for almost all between-subject variation at a
single time point. However, we also found relationships between R and age and
weight gain, indicating that physiology does influence the space ratio. The
effect of weight gain on R was negligible, but changes of (meanR) with age,
reflecting changes in percentage body water during infancy, were of sufficient
magnitude to affect calculation of energy expenditure significantly. Our analysis
suggests that use of a fixed ratio at a single time point in infancy is
acceptable, but that the appropriate value of (meanR) changes over the first year
of life.
PMID- 9545000
TI - Hyperprolactinemia, a tool in treatment control of tetrahydrobiopterin
deficiency: endocrine studies in an affected girl.
AB - Severe tetrahydrobiopterin (BH4) deficiency is a naturally occurring model of
cerebral catecholamine and serotonin shortage. Examination of the stimulated
release and physiologic secretion pattern of several hormones in affected
individuals permits certain conclusions concerning the involvement of these
neurotransmitters in hormone regulation. Treatment, moreover, permits the ranking
of the quality of the therapeutic regimens in use according to the degree of
hormonal alteration. The 24-h secretion pattern of prolactin, GH, cortisol, and
melatonin and the stimulated release of prolactin, GH, TSH, and gonadotropins
were studied in an affected girl. Severe hyperprolactinemia with disruption of
the pulsatile and circadian secretion pattern was the prevailing feature. The GH
physiologic secretion pattern was not affected, but its stimulation was impaired.
Melatonin displayed a normal circadian secretion pattern; the rhythm, however,
was advanced by several hours. Conventional treatment of BH4 deficiency, i.e.
BH4, 5-hydroxytryptophan, and L-DOPA/carbidopa (the last named given in three
doses per day), suppresses prolactin levels merely for a few hours. L
DOPA/carbidopa given at shorter intervals or, even better, as a slow release
preparation, is more effective in suppressing prolactin levels. Our data indicate
immense hyperprolactinemia but few other hormonal disturbances in severe BH4
deficiency. Prolactin secretion may serve as an extremely sensitive marker for
the hypothalamic dopamine content under different therapeutic regimens. Treatment
with an L-DOPA/carbidopa slow release preparation produces virtually normal
prolactin levels.
PMID- 9545001
TI - Growth, insulin-like growth factor I (IGF-I), and IGF-binding proteins 1 and 3 in
children with severe liver disease before and after liver transplantation: a
longitudinal and cross-sectional study.
AB - We aimed to study the growth and growth factors of children with liver disease
before and after liver transplantation (LT). Three observation intervals: 1)
before LT (preLT), 2) after LT on daily prednisone treatment (dP), and 3) on
alternate day prednisone (adP). A longitudinal study (LS) involved 17 infants (9
male) aged 0.73-2.38 y at LT; mean (+/- SD) height (Ht) SD score (SDS) at LT was
2.02 (+/- 1.25). In a cross-sectional study, there were 123 children (73 male)
aged 0.16-14.88 y (mean 3.72 y). IGF-I and IGF binding proteins (BP) 1 and 3 were
measured at the same intervals. The results were, for LS, preLT height velocity
(HV) SDS (X +/- SD -0.8+/-1.4) lower (p < 0.01) than adP-HV SDS (3.1+/-1.8) but
not different from dP-HV SDS (-1.0+/-1.9). For the cross-sectional study, dP-Ht
SDS (X+/-SD -1.94+/-1.31) lower (p < 0.001) than preLT-Ht SDS (-1.03+/-1.06) and
adP-Ht SDS (-0.98+/-1.20). Parental target SDS was not different from adP-Ht SDS.
(Similar observations were made in the LS.) The dP- sitting height (SH) and
subischial leg length (SLL) SDS were significantly lower than both preLT- and adP
SH SDS and SLL SDS (p = 0.02 and 0.002, respectively). There was a significant
improvement of head circumference SDS and arm circumference SDS from preLT to
adP. The dP and adP IGF-I and IGF-BP3 levels were greater than preLT levels (p <
0.001); no differences were found between preLT, dP, and adP IGF-BP1 levels. We
conclude that growth in children with liver disease does not improve after LT on
dP, but catch-up growth is shown on adP, appearing to depend mainly on the
clinical course and corticosteroid regimen. IGF-I and IGF-BP3 increment on dP
(and sustained on adP) is possibly due to liver regeneration, in contrast with
inhibition of body growth on dP, possibly due to central and peripheral effects
of corticosteroid.
PMID- 9545002
TI - Treatment with recombinant human growth hormone in short children with
nephropathic cystinosis: no evidence for increased deterioration rate of renal
function. The European Study Group on Growth Hormone Treatment in Short Children
with Nephropathic Cystinosis.
AB - To evaluate the effect of long-term treatment with recombinant human GH (rhGH) on
renal function in short children with nephropathic cystinosis with and without
concomitant cysteamine treatment, 36 growth-retarded children with nephropathic
cystinosis (age 7.3+/-2.7 y; creatinine clearance [C(CR)] 50+/-27 mL (min x 1.73
m2)(-1) were treated with 1 IU rhGH/kg/wk for up to 5 y. The rise in serum
creatinine before and during rhGH treatment was compared with that in a
historical control group of cystinotic patients. The effect of concomitant
cysteamine treatment on the evolution of renal function before and after the
start of rhGH was evaluated separately in patients without (group A) and with
cysteamine treatment (group B). The decline of C(CR) was also compared with that
in noncystinotic patients with chronic renal failure with and without rhGH
treatment. At study entry, serum creatinine values in group A were similar to
those in the historical controls, whereas group B had significantly lower serum
creatinine values. Treatment with rhGH did not accelerate the rise in creatinine
independently of cysteamine treatment. There were no significant differences in
the mean decline of C(CR) per year in cystinotic compared with noncystinotic
patients with chronic renal failure with or without rhGH treatment. rhGH therapy
for up to 5 y does not accelerate the deterioration of renal function. This
justifies the continuation of controlled studies of rhGH treatment in these
patients. The study also provides further evidence that cysteamine therapy
reduces the progression of renal failure in children with cystinosis.
PMID- 9545003
TI - Effect of plasma from patients with idiopathic nephrotic syndrome on proteoglycan
synthesis by human and rat glomerular cells.
AB - In vivo and in vitro findings have shown that plasma of patients with idiopathic
nephrotic syndrome (INS) contain factors that increase glomerular permeability to
proteins. The effects of these factors on proteoglycan synthesis by glomerular
cells are unknown. To investigate the effect of plasma from patients with INS (n
= 23) and other glomerulopathies (n = 12) on the amount of proteoglycans
synthesized by cultured rat mesangial cells and human glomerular epithelial
cells, glomerular cells were cultured for 24 h with plasma from patients or
control subjects, and incorporation of Na2(35)SO4 in chondroitin dermatan sulfate
and heparan sulfate was assessed using a cationic nylon membrane. The mean ratio
of glycosaminoglycan produced by rat mesangial cells when in contact with plasma
(5%) from INS patients to the amount produced when in contact with control plasma
was 0.70+/-0.06. The mean ratio of heparan sulfate was 0.58+/-0.08. The decrease
of heparan sulfate production was present in the cellular and in the
extracellular fraction. It was observed when the cells were in contact with
plasma from patients in relapse but not when in remission. No decrease of heparan
sulfate production was observed with four of the five patients with membranous
glomerulonephritis (ratio of 1.27+/-0.03), IgA nephropathy (n = 5, ratio of
1.27+/-0.03), and membranoproliferative glomerulonephritis (n = 2, ratio of
1.39+/-0.34). When human glomerular epithelial cells were exposed to 5% plasma
from INS patients in relapse (n = 9), the mean ratio of heparan sulfate was
0.62+/-0.06 in the cellular fraction and 0.72+/-0.08 in the medium. When in
contact with plasma from patients in remission, no difference of
glycosaminoglycan production was observed. A factor present in plasma from
patients with INS during initial episodes or relapses is able to decrease the
proteoglycan production of glomerular cells.
PMID- 9545005
TI - Quantitative correlation between globin mRNAs and synthesis of fetal and adult
hemoglobins during hemoglobin switchover in the perinatal period.
AB - To determine whether a quantitative relationship existed between globin mRNAs and
their translation products during the period of switchover, the relative amounts
of the mRNAs of alpha-, beta-, and gamma-globins and their protein synthesis in
cord blood samples were measured and compared. The synthesis of globins in
immature red cells was measured by the incorporation of [3H]leucine followed by
separation and quantitation of the polypeptides on a C4-reverse phase HPLC. The
relative proportions of the mRNAs of globins were determined by RNase protection
assay. A comparison of cord blood samples from 45 newborn infants of different
gestational ages (25-41 wk; birth weight, 850-4695 g) revealed a very significant
correlation (r2 = 0.924) between the ratio of globin mRNAs encoding HbF
([gamma/(gamma + beta)] mRNAs) and HbA ([beta/(gamma + beta)] mRNAs) and the
ratio of de novo synthesis of HbF [gamma/(gamma + beta)] and HbA [beta/(gamma +
beta)]. There was a linear relationship between the proportions of globin mRNAs
encoding HbF with the proportional synthesis of HbF throughout the developmental
stage studied. The ratio of alpha2/alpha1-globin mRNAs increased from 2.0 +/- 0.2
between 24 and 36 wk of gestation to 2.3+/-0.4 (p = 0.02) during 37-41 wk of
gestation. These results of the complementary changes at alpha- and beta-loci
during fetal development may further the understanding of the coordinated
regulation of globin gene expression.
PMID- 9545004
TI - Characterization of early activation events in cord blood B cells after
stimulation with T cell-independent activators.
AB - Human neonates are immunologically immature, particularly in their humoral
antibody responses to T cell-independent antigens, as exemplified by their
increased susceptibility to infections with polysaccharide-encapsulated bacteria.
To clarify the mechanism(s) underlying the unresponsiveness of neonates to
polysaccharide antigens, we used an in vitro model with neonatal cord blood cells
that has been shown to mimic surface Ig-dependent signaling in the adult by T
cell-independent antigens. We studied the ability of cord blood human B cells to
become activated after ligation of their surface Ig by unconjugated anti-Ig,
dextran-conjugated anti-Ig, and Staphylococcus aureus Cowan A1, and compared
their response with that of adult B cells. After the addition of nanogram
concentrations of anti-Ig-dextran, neonatal cord blood B cells proliferated at
levels comparable to that observed with adult B cells. The majority of cord blood
B cells showed a marked rise in intracellular calcium, increased surface
expression of human leukocyte antigen DR, and an increase in cell size. Direct
activation of protein kinase C by phorbol esters in neonatal B cells led to
cellular proliferation, and when combined with anti-Ig, a synergistic effect on
proliferation was observed. These data suggest that the unresponsiveness of human
neonates to polysaccharide antigens does not represent an inability of these
antigens to induce early activation events in circulating B cells.
PMID- 9545006
TI - Human choriocarcinoma JAR cells constitutively express pro-interleukin-1beta that
can be released with Fc(gamma) receptor engagement.
AB - Some authors have suggested that fetally derived syncytiotrophoblasts, which form
the barrier between mother and the fetus, are an integral part of a complex
macrophage-cytokine network involving maternal leukocytes, decidual cells,
placental tissues, and even the fetus itself. We report here that
syncytiotrophoblast-like JAR cells, a human choriocarcinoma cell line, share
another feature common to cells of the monocyte-macrophage lineage, the ability
to secrete IL-1beta when stimulated through their Fc(gamma) receptors. We
incubated JAR cells with physiologically relevant concentrations of model BSA
rabbit IgG-anti-BSA immune complexes or monomeric rabbit IgG for periods of up to
72 h. Both monomeric IgG and immune complexes induced IL-1beta from JAR cells,
although levels produced by immune complexes were approximately twice those
induced by monomeric IgG. IL-1beta secretion was not inhibited by cycloheximide,
and Western blots of JAR cell lysates using pro-IL-1beta MAb revealed
constitutive expression of a 31-kD protein, whose levels declined within 2 h of
stimulation by either IgG or immune complexes, but returned to baseline within 18
h.
PMID- 9545007
TI - Responses to pulsatile flow in piglet isolated cerebral arteries.
AB - Because cerebrovascular hemorrhage in newborns is often associated with
fluctuations in cerebral blood flow, this study was designed to investigate the
effects of pulsatile flow in isolated cerebral arteries from neonatal piglets.
Arteries mounted on cannulas were bathed in and perfused with a physiologic
saline solution. An electronic system produced pulsations, the amplitude and
frequency of which were independently controlled. At constant mean transmural
pressure (20 mm Hg), increasing flow in steps from 0 to 1.6 mL/min under steady
flow conditions caused a biphasic response, constriction at low flow, and
dilation at high flow. Under pulsatile flow conditions (pulse amplitude 16-24 mm
Hg; 2 Hz), the arteries dilated upon flow initiation and continued to dilate as
mean flow increased. Dilation to pulsatile flow did not depend on the level of
mean flow because switching from steady to pulsatile flow at each flow step also
caused dilation. Arteries dilated further upon increasing either pulse amplitude
(12-28 mm Hg; 2 Hz) or frequency (16-24 mm Hg; 4 Hz). Inhibiting nitric oxide
synthesis with Nomega-nitro-L-arginine or perfusing with glutaraldehyde to
decrease endothelial cell deformability significantly reduced dilations to
pulsatile flow and to increased amplitude and frequency. These data suggest that
the arterial response to flow is highly dependent on the mode of flow. Dilation
induced by initiating pulsatile flow or increasing either pulse amplitude or
frequency appears to be mediated by augmented nitric oxide release as result of
shear stress-induced deformation of the endothelial cells.
PMID- 9545008
TI - Pressure overload induced in newborn rats: effects on left ventricular growth,
morphology, and function.
AB - Gradual pressure overload was induced by abdominal aortic constriction in male
rats on postnatal d 6 (AC6) or 2 (AC2). At the age of 8 wk, the systemic blood
pressure was measured, and the contractile performance of the left ventricle (LV)
was assessed after acute ligation of the ascending aorta in open chest
anesthetized animals. The LV free wall was used for the determination of collagen
concentration and morphometric analysis of cardiac myocytes and capillaries.
Aortic constriction resulted in LV hypertrophy, which was more pronounced in AC2
(by 71%) as compared with AC6 (by 34%) groups and correlated closely with the
degree of pressure overload (r = 0.88 and 0.80, respectively). The right
ventricular weight was increased by 13% in the AC2 group only. Contractile
performance of the LV of aortic constricted rats was significantly higher before
as well as after the acute load, but the average functional reserve was unchanged
in both experimental groups. Although the maximum value of the rate of pressure
development increased linearly with the degree of ventricular hypertrophy in the
AC6 group (r = 0.82), a negative correlation was observed in the AC2 animals (r =
-0.61). The density of myocytes was decreased, and the calculated average myocyte
cross-sectional area was increased in aortic constricted rats, but the coronary
capillary density and myocardial concentration of collagen remained constant.
Thus, in spite of the larger cardiac growth response in the younger age group,
the capillary proliferation and collagen formation were proportional to the
ventricular hypertrophy. Therefore, the degrees of overload and hypertrophy do
not seem to be limiting factors. Pressure overload induced in newborn rats can be
a useful model for the study of mechanisms that control either the growth and
differentiation of myocardium soon after birth, as well as the transition from
compensated to decompensated hypertrophy at later stages.
PMID- 9545009
TI - The relationship between temperature and calcium in acute cell damage after
exposure to radiofrequency or thermal energy in isolated neonatal and adult
rabbit cardiac myocytes.
AB - Radiofrequency (RF) ablation is a nonsurgical technique using catheter-directed
RF energy for treating cardiac arrhythmias in children and adults. Previous
reports have suggested that sequestration of calcium (Ca2+) by the sarcoplasmic
reticulum may partially protect mature cardiac myocytes from the effects of RF
energy. The purposes of this study were to determine whether differences exist
between neonatal and adult myocyte responses to RF energy and if myocyte damage
is a Ca2+-dependent process. Because immature myocardium is functionally
deficient in sarcoplasmic reticulum, we hypothesized that immature myocytes would
be more susceptible to damage induced by RF energy. Isolated ventricular myocytes
were obtained from neonatal and adult New Zealand White rabbits by enzymatic
dissociation, then placed in a perfusion chamber designed to deliver RF energy or
a heated perfusate solution. Measurements of bath temperature, cell morphology,
and contractile response to electrical stimuli were recorded. RF energy
application associated with increased perfusate temperature resulted in cell
death, but not when the temperature rise was inhibited. Thus, the acute damage to
cells exposed to RF energy appears to be mediated by thermal energy. After
exposure to thermal energy, neonatal cells underwent contracture at lower
temperatures than did adult cells. Perfusion with solutions containing low Ca2+
concentrations, comparable to intracellular diastolic Ca2+ levels, had a
protective effect for both neonatal and adult myocytes. These findings indicate
that acute cell damage after exposure to RF energy is mediated by a Ca2+
dependent process. Furthermore, immature myocardium is particularly susceptible
to RF-mediated cell damage, possibly secondary to reduced Ca2+ sequestration by
the sarcoplasmic reticulum.
PMID- 9545010
TI - Experimental study of coil embolization using a new atelocollagen spring coil.
AB - Spring steel coils have been used to occlude abnormal vessels in patients with a
congenital heart malformation. However, long-term adverse effects of steel spring
coils remain uncertain, although some long-term results appear to be good. The
purpose of this study was to evaluate the angiographic and histologic results of
coil embolization experimentally using a biodegradable atelocollagen coil that we
have recently developed. The spring coil was made from a 30% atelocollagen
solution mixed with a contrast medium. The delivery system consisted of a 5-F end
hole catheter and a 3-F modified biotome catheter as a catch and release system.
Coil embolization was percutaneously attempted in 12 dogs, and only one coil was
placed in each dog so that a variety of endothelial coverage could be evaluated
both in complete and incomplete occlusion. At 1 wk to 5 mo after the procedure,
the occluded vessels were resected and examined histologically. Postprocedural
angiography showed complete occlusion in 6 of the 12 vessels and partial
occlusion in 6. Follow-up angiography showed complete occlusion in 8 and
incomplete occlusion in 4. Histologic examination revealed that diffuse
thrombosis around the coil loops and the exchange between blood and contrast
medium were detectable as early as 7 d after embolization. Atelocollagen was
gradually replaced with fibrous tissue and became markedly degraded by 5 mo.
Atelocollagen spring coils can be used to occlude abnormal vessel effectively and
safely. The histologic reactions and the fate of the coil seem to be within
tolerable limits. This experimental study supports the feasibility of a clinical
trial of this coil embolization in patients with an aorticopulmonary collateral
artery.
PMID- 9545011
TI - Impaired gas mixing and low lung volume in preterm infants with mild chronic lung
disease.
AB - The aim of this study was to assess the possible role of gas mixing inefficiency
in spontaneously breathing infants with mild chronic lung disease (CLD) of
prematurity in relation to changes in other functional parameters. A simple
bedside technique for recording and analysis of multiple breath nitrogen washout
curves was applied together with occlusion mechanics. Fifteen preterm infants
with mild or moderately severe CLD were studied at a mean postconceptional age of
35 wk, together with 15 healthy preterm infants at the same maturity. All infants
breathed spontaneously, and the test was performed by a continuous bypass flow
system, connected to a face mask, a pneumotachograph, and a nitrogen meter. The
results showed impaired gas mixing with moment ratios above the 95th percentile
of the normal group in 11/15 infants with CLD. Functional residual capacity (FRC)
was low in 13/15 infants, but specific compliance and resistance of the
respiratory system did not differ between the groups. As FRC and moment ratios
were not correlated, it is suggested that they may reflect different aspects of
the pathophysiology in CLD. It is concluded that low FRC and disturbed gas mixing
are characteristic disturbances in CLD at different degrees of severity. The
multiple breath nitrogen washout test, followed by moment analysis of end-tidal
nitrogen concentrations, is a simple and sensitive method for detection of these
disturbances and for monitoring purposes.
PMID- 9545012
TI - Surfactant versus saline as a vehicle for corticosteroid delivery to the lungs of
ventilated rabbits.
AB - Local administration of steroids to the lungs in ventilated newborn infants can
minimize the harmful side effects that occur with systemic administration. An
efficient system of drug delivery that provides uniform distribution within the
lungs is essential for the treatment of bronchopulmonary dysplasia. In this study
we compare surfactant with 0.9% saline solution as vehicles for the direct
instillation of a steroid (budesonide) into the lungs. Twenty-two anesthetized,
ventilated rabbits received [3H]budesonide in either 0.9% saline or surfactant,
administered through an endotracheal tube. Before drug administration, bronchial
lavage was performed on half of the animals to serve as a model for surfactant
deficiency. Lung samples were analyzed by both autoradiography (alveolar versus
airway distribution) and liquid scintillation counting (central versus peripheral
deposition). As expected, the delivered concentration of [3H]budesonide decreased
as airway size decreased and branching increased. Significantly less
[3H]budesonide was deposited in the alveolar spaces of all study groups compared
with that deposited in the small and large airways (p < 0.05). However, both
vehicles were equally efficient in delivering [3H]budesonide to the lungs.
Although the alveolar and peripheral areas received less (4-11%) of the drug than
the central tissue (14-28%), this was consistent among all the groups and was not
affected by altered lung compliance. Therefore, either surfactant or saline could
be used to efficiently and reliably deliver budesonide to the lungs at a level
greater than that reported using nebulizers. Because normal saline is currently
used for tracheal toilette, it is likely to be preferred considering the
increased costs associated with surfactant.
PMID- 9545013
TI - Potassium channels in human fetal airway smooth muscle cells.
AB - Ion channels underlying the resting membrane potential were examined in human
fetal airway smooth muscle (ASM). Tissue was obtained from the Medical Research
Council Tissue Bank, London, UK. ASM cells were enzymatically dispersed, and ion
currents were examined using a patch clamp. Although all cells were of similar
size and stained intensely for vimentin, only approximately 50% stained intensely
for smooth muscle alpha-actin or myosin heavy chain. Depolarization induced a
tetraethylammonium (TEA)- and charybdotoxin (ChTX)-sensitive outward current that
varied widely among cells (<50 to >2000 pA at +100 mV), and a smaller
nonselective cation current that was similar in all cells (approximately 20 pA at
+100 mV). The TEA-sensitive current was associated with three types of large
conductance, ChTX-sensitive K+ channel: a 200-pS channel, which was active at
negative potentials and low [Ca2+], as described for freshly isolated adult ASM,
and two other K+ channels of 100 and 150 pS, previously observed only in adult
ASM proliferating in culture. ChTX, but not 4-aminopyridine, caused a substantial
depolarization in the current clamp mode, suggesting that, in contrast to ASM
from other species or vascular smooth muscle, large conductance K+ channels
rather than a delayed rectifier are the major determinant of membrane potential
in this tissue. Our results show a distinct similarity between fetal ASM and
adult ASM proliferating in culture. We suggest that the heterogeneity in current
density and staining reflect different degrees of differentiation, rather than
different cell types, and that the 100- and 150-pS K+ channels are specifically
associated with a proliferative phenotype in human ASM.
PMID- 9545014
TI - Presence of thyrotropin receptor in infant adipocytes.
AB - In healthy infants, the levels of TSH are known to peak at 50-100 times adult
values during the first days of life. In studies of isolated human infant
adipocytes, we have earlier shown that bovine TSH (bTSH) has a strong lipolytic
effect, accompanied by a blunted response of adipocytes to catecholamines. In
this study, we used human recombinant TSH (hTSH), and incubation of adipocytes
with hTSH induced a lipolytic response similar to that obtained with the beta
adrenergic receptor agonist isoprenaline in adipocytes isolated from three
infants. The lipolytic effect of hTSH was completely blocked by inhibitory TSH
receptor (TSHR) antibodies. The TSHR mediates the effects of TSH in the thyroid,
and it has been detected in some extrathyroid tissues, but not in isolated human
adipocytes or childhood adipose tissue. In this study, we found TSHR RNA in
infant and adult adipose tissues and isolated adipocytes with reverse
transcriptase-PCR. The sequence of the amplified PCR product agreed with the
published sequence. Northern blot hybridization on RNA prepared from infant
adipose tissue showed a transcript of the expected size, and the expression of
TSHR seemed higher in infant than in adult adipose tissue. In conclusion, this
study indicates that TSH plays an active role in the metabolic adaptation after
birth.
PMID- 9545015
TI - Current estimates of the economic cost of obesity in the United States.
AB - This study was undertaken to update and revise the estimate of the economic
impact of obesity in the United States. A prevalence-based approach to the cost
of illness was used to estimate the economic costs in 1995 dollars attributable
to obesity for type 2 diabetes mellitus, coronary heart disease (CHD),
hypertension, gallbladder disease, breast, endometrial and colon cancer, and
osteoarthritis. Additionally and independently, excess physician visits, work
lost days, restricted activity, and bed-days attributable to obesity were
analyzed cross-sectionally using the 1988 and 1994 National Health Interview
Survey (NHIS). Direct (personal health care, hospital care, physician services,
allied health services, and medications) and indirect costs (lost output as a
result of a reduction or cessation of productivity due to morbidity or mortality)
are from published reports and inflated to 1995 dollars using the medical
component of the consumer price index (CPI) for direct cost and the all-items CPI
for indirect cost. Population-attributable risk percents (PAR%) are estimated
from large prospective studies. Excess work-lost days, restricted activity, bed
days, and physician visits are estimated from 88,262 U.S. citizens who
participated in the 1988 NHIS and 80,261 who participated in the 1994 NHIS.
Sample weights have been incorporated into the NHIS analyses, making these data
generalizable to the U.S. population. The total cost attributable to obesity
amounted to $99.2 billion dollars in 1995. Approximately $51.64 billion of those
dollars were direct medical costs. Using the 1994 NHIS data, cost of lost
productivity attributed to obesity (BMI> or =30) was $3.9 billion and reflected
39.2 million days of lost work. In addition, 239 million restricted-activity
days, 89.5 million bed-days, and 62.6 million physician visits were attributable
to obesity in 1994. Compared with 1988 NHIS data, in 1994 the number of
restricted-activity days (36%), bed-days (28%), and work-lost days (50%)
increased substantially. The number of physician visits attributed to obesity
increased 88% from 1988 to 1994. The economic and personal health costs of
overweight and obesity are enormous and compromise the health of the United
States. The direct costs associated with obesity represent 5.7% of our National
Health Expenditure in the United States.
PMID- 9545016
TI - Evidence for multiple determinants of the body mass index: the National Heart,
Lung, and Blood Institute Family Heart Study.
AB - The body mass index (BMI) is a complex phenotype representing the amount of fat
mass, lean mass, body build and proportions, and it is likely to be affected by
various metabolic processes, hormonal effects, energy intake and expenditure, and
interactions within and among these broad categories of etiologic factors.
Nonetheless, several previous studies have reported evidence for major gene
segregation for the BMI in various populations. Data on a random sample of
Caucasian families participating in the National Heart, Lung, and Blood Institute
(NHLBI) Family Heart Study were analyzed to document the extent of familial
resemblance and to investigate whether a similar monogenic inheritance pattern
could be detected. Genetic analysis was carried out on age- and sex-adjusted BMI
values. Familial correlations were significant implying a maximal heritability,
including all genetic and environmentally inherited additive factors, of 41% to
59%. Segregation analysis revealed the presence of two maximum likelihood
solutions, one characterized as a recessive Mendelian gene and the other as a
major effect with an ambiguous transmission pattern. The presence of two such
solutions is consistent with detection of two separate factors, each influencing
the BMI distribution in a substantive manner. The evidence also supports a
multifactorial background for BMI and suggests that the frequencies of these two
factors, one of which appears to be a gene, may vary among diverse populations in
the United States.
PMID- 9545017
TI - Effects of sibutramine on resting metabolic rate and weight loss in overweight
women.
AB - Sibutramine, a monoamine re-uptake inhibitor, has recently been approved by the
Food and Drug Administration as a weight loss agent. Sibutramine lowers
bodyweight in rodents by reducing energy intake and increasing energy
expenditure. Sibutramine facilitates weight loss in human subjects, but it is not
clear whether it acts on energy intake, energy expenditure, or both. The present
study was a randomized clinical trial designed to assess the effects of
sibutramine (at 10 or 30 mg/day) on body weight and resting metabolic rate (RMR).
Forty-four overweight women were randomized to 1) placebo (n=15); 2) sibutramine
at 10 mg/day (n=15) or, 3) sibutramine at 30 mg/day (n=14). All subjects were
instructed to consume a 1200 kcal/day diet for 8 weeks while receiving drug or
placebo. RMR was assessed by indirect calorimetry at baseline, at 3 hours after
the first dose of drug (or placebo), and at the end of the 8-week weight-loss
period. Sibutramine reduced body weight-relative to placebo, but there was no
difference between weight loss on the two sibutramine doses. No significant
differences in RMR between sibutramine and placebo were seen, either 3-hour post
dose or after the 8-week weight-loss period. After the weight loss period, all
groups were taken off medication and kept weight stable for another 4 weeks. RMR
was measured again and was not different among groups. That there was no change
in RMR when sibutramine was stopped further suggests that the drug does not
directly affect RMR. In summary, while sibutramine was shown to be an effective
weight-loss agent over 8 weeks, we found no evidence that it increased RMR.
PMID- 9545018
TI - Leptin receptor gene in a large cohort of massively obese subjects: no indication
of the fa/fa rat mutation. Detection of an intronic variant with no association
with obesity.
AB - The massive obesity caused in rodents by the disruption of the leptin-receptor
signal through genetic defects at the level of either leptin (OB) or leptin
receptor (OB-R) has raised the question of the relevance of these genes to morbid
obesity in humans. In this study, we screened a large population of massively
obese subjects for the presence of a leptin receptor mutation homologous to that
of fa/fa rats, a single base substitution changing glutamine 269, a highly
conserved glutamine found at position 270 in the human sequence. After polymerase
chain reaction (PCR) amplification of a DNA region encompassing the end of exon
5, intron 5, and the beginning of exon 6, we performed restriction fragment
length polymorphism analysis. Within the limitations of this approach where only
mutations introducing restriction sites (5 of 8 possibilities) could be assessed,
no evidence of mutation at the codon gln 270 was found in 343 massively obese
subjects. However, a new OB-R gene variant in intron 5 was revealed by MaeII
digestion of the PCR products. MaeII/hOB-R genotyping revealed no difference in
the distribution of the genotypes between obese subjects and a group of 79
unrelated nonobese control subjects. In addition, no significant association
between various obesity-related metabolic phenotypes and the presence of
MaeII/hOB-R alleles was found. Thus, our results did not support a significant
role for the MaeII/hOB-R gene variant in the development of the obese phenotype
in the population we studied.
PMID- 9545019
TI - Relationship of leptin concentration to gender, menopause, age, diabetes, and fat
mass in African Americans.
AB - This investigation was designed to determine the relationship of leptin
concentration to gender, sex hormones, menopause, age, diabetes, and fat mass in
African Americans. Participants included 101 African Americans, 38 men (mean age,
34.2 +/- 7.4 years), 29 age-matched premenopausal women (mean age, 32.6 +/- 3.7
years), and 36 postmenopausal women (mean age, 57.8 +/- 5.9 years). The women
were not taking exogenous sex hormones, and 12 subjects were diabetic. Percent
body fat was calculated with the Siri formula, fat mass (FM) was calculated as
weight x percent body fat, and Fat-free mass (FFM) was calculated as weight minus
FM. Fasting plasma was assayed for leptin, estradiol, free testosterone, glucose,
and insulin concentrations. The nondiabetics had an oral glucose tolerance test
(OGTT). The diabetics compared with the non-diabetics had a higher central fat
index (p=0.04) but otherwise were similar to nondiabetics in all parameters
measured. Body mass index, percent body fat, and FM were greater in women than
men (p<0.001). Leptin concentrations in men, premenopausal, and postmenopausal
women were: 7.51 +/- 8.5, 33.9 +/- 17.3, 31.4 +/- 22.3 ng/mL. Leptin/FM x 100 in
the three groups were: 28.9 +/- 16.1, 98.65 +/- 44.9, 77.1 +/- 44.5 ng/mL/kg. The
gender difference in leptin concentration and leptin/FM was significant
(p<0.001), but the difference between premenopausal and postmenopausal women was
not. In each group, weight, percent body fat, and FM were highly correlated with
leptin concentration. Multiple regression analyses with leptin concentration as
the dependent variable and age, diabetic status, percent body fat, weight, FM,
FFM, estradiol, and free testosterone concentrations as independent variables
demonstrated that the determinants of leptin concentration in men was weight only
(R=0.83, p<0.001), in premenopausal women it was FM only (R=0.57, p<0.001), and
in postmenopausal women it was weight only (R=0.67, p<0.001). With diabetics
excluded, the multiple regression analysis was repeated with fasting insulin
concentration and the area under the insulin curve during the OGTT included as
independent variables. The results for this multiple regression analyses were the
same as the first. Therefore, leptin concentration in African Americans is
determined by gender and fat mass. Menopause, age, and diabetes do not affect
leptin concentration.
PMID- 9545020
TI - Demand characteristics of the research setting can influence indexes of negative
affect-induced eating in obese individuals.
AB - Measures of negative affect-induced eating (NAIE) are common in clinical research
with obese individuals. However, previous studies suggest that measures of NAIE
can be induced by social desirability tendencies or demand characteristics of the
research setting. Using an experimental design, the present study tested the
effects of demand characteristics of the research setting on self-report and
behavioral indexes of NAIE. Obese and nonobese subjects (n=107) were randomly
assigned to an experimental or control group. Experimental subjects received a
lecture indicating an association between emotional eating and obesity; control
subjects received no information. Outcome measures were indexes of NAIE from a
questionnaire, food diaries, and food intake during a laboratory "taste test." We
hypothesized that the association between relative body mass and NAIE would be
stronger among subjects receiving the lecture manipulation than control subjects.
Results indicated that NAIE indexes, particularly from food diaries, were
influenced modestly by research demand characteristics. We conclude that demand
characteristics of the research setting can affect indexes of NAIE among obese
persons.
PMID- 9545021
TI - Composition of dietary fat affects blood pressure and insulin responses to
dietary obesity in the dog.
AB - Cardiovascular and metabolic parameters were evaluated in 15 female spayed dogs
before and after they became obese on either a saturated fat (LD, lard, n=8) or
unsaturated fat (CO, corn oil, n=7) diet. Body weight and body fat increased
significantly in both groups, although no differences occurred between diet
groups. Dogs receiving the LD diet exhibited a greater increase in mean arterial
pressure than those receiving the CO diet (p<0.01; 15.9 +/- 2.1 vs. 9.8 +/- 3.3
mm Hg increase). The CO diet stimulated a greater increase in heart rate than the
LD diet (p<0.05; 32.8 +/- 7.8 vs. 14.1 +/- 5.8 bpm increase). Ganglionic blockade
with chlorisondamine caused an increase in HR in both lean groups and in the
obese CO group, but not the obese LD group, consistent with a decrease in
parasympathetic tone to the heart in the dogs overfed saturated fat. Obesity
enhanced the heart rate response to beta-adrenergic stimulation by isoproterenol
in the LD, but not CO group. The LD diet increased circulating insulin and
decreased insulin sensitivity, whereas the CO diet had no effect on either
parameter. These findings suggest that the composition of dietary fat can
modulate the autonomic and metabolic adaptations induced by dietary obesity.
PMID- 9545022
TI - Effect of chronic central administration of glucagon-like peptide-1 (7-36) amide
on food consumption and body weight in normal and obese rats.
AB - Glucagon-like peptide (7-36) amide (GLP-1) acutely inhibits food and water
consumption in rats after intracerebroventricular (icv) administration. To assess
the potential for desensitization of these effects, we investigated the effects
of chronic icv administration of GLP-1 on food consumption and body weight in
Sprague-Dawley (SD) rats and Zucker (fa/fa) obese rats. In vitro functional
densensitization of the GLP-1 receptor was not observed after overnight exposure
of Rin m5F insulinoma cells to GLP-1 at concentrations up to 10 nM.
Administration of GLP-1 to SD rats (30 microg icv twice a day for 6 days)
resulted in significant reductions in 24-hour food consumption each day (25 +/-
1%). Continuous icv infusion of GLP-1 for 7 and 14 days significantly inhibited
cumulative food consumption and reduced body weight in SD rats. In the
genetically obese Zucker rat, chronic dosing with GLP-1 (30 microg icv) once a
day for 6 days caused significant reductions in food consumption each day and a
reduction in body weight. These results indicate that the GLP-1 pathways in the
central nervous system controlling food consumption do not desensitize after
chronic exposure to GLP-1 and suggest that agonists of the central GLP-1 receptor
may be effective agents for the treatment of obesity.
PMID- 9545023
TI - The effect of glucose concentration on insulin-induced 3T3-L1 adipose cell
differentiation.
AB - We examined the effect of glucose concentration on insulin-induced 3T3-L1 adipose
cell differentiation. Oil Red O staining of neutral lipid, cellular triglyceride
mass, and glycerol phosphate dehydrogenase (GPDH) activity, were greater in 3T3
L1 cells cultured at 5 mM vs. 25 mM glucose. GPDH activity was 2- to 4-fold
higher at 5 mM vs. 25 mM glucose over a range of insulin concentrations (0.1 to
100 nM). Insulin-stimulated tyrosine phosphorylation of insulin receptor
substrate-1 (IRS-1) was 1.7-fold greater, and insulin-stimulated phosphoinositide
3-kinase association with IRS-1 was 2.3-fold higher, at 5 mM vs. 25 mM glucose.
These effects of glucose were not caused by alterations in IRS-1 mass or cell
surface insulin binding. In preadipose cells at 5 mM glucose, expression of the
leukocyte antigen-related (LAR) protein tyrosine phosphatase (negative regulator
of insulin signaling) was 63% of the level at 25 mM glucose. Our data demonstrate
that glucose concentration affects insulin-induced 3T3-L1 adipose cell
differentiation as well as differentiation-directed insulin signaling pathways.
Alterations in LAR expression potentially may be involved in modulating these
responses.
PMID- 9545024
TI - Hormonal regulation of leptin mRNA expression and preadipocyte recruitment and
differentiation in porcine primary cultures of S-V cells.
AB - The hormonal regulation of leptin mRNA expression and the association between
leptin expression and adipocyte differentiation were examined in primary cultures
of porcine S-V cells with Northern blot and immunocytochemical analysis. Seeding
for 3 days with fetal bovine serum (FBS) with varying levels of dexamethasone
(Dex) increased levels of leptin mRNA in a dose-dependent manner in parallel with
increases in the proportion of preadipocytes (AD-3 positive cells; AD-3, a
preadipocyte marker). Six-day treatment with 10 or 850 nM insulin after FBS+Dex
treatment resulted in a similar increase in leptin mRNA expression and
morphological differentiation. However, significantly lower levels of leptin mRNA
and smaller fat cells were observed in cultures treated with 1 nM insulin or 10
nM insulin-like growth factor-I (IGF-I). Dex-induced increases in leptin mRNA
levels and AD-3 cell numbers were blocked completely by the addition of
transforming growth factor-beta (TGF-beta) to FBS+Dex-treated cultures. However
TGF-beta significantly increased fat cell size and leptin mRNA expression when
added to ITS (insulin, 850 nM; transferrin, 5 microg/ml; and selenium, 5
microg/mL) treated cultures during the lipid-filling stage. When added with
FBS+DEX for the first 3 days, growth hormone (GH) did not influence the Dex
induced increase in AD-3 cells and leptin mRNA expression, but GH reduced leptin
mRNA levels when added with insulin for 6 days after FBS+Dex. These results
demonstrated that regulation of leptin mRNA expression by Dex, insulin, IGF-I,
TGF-beta, and GH may be associated with changes in preadipocyte number and fat
cell size.
PMID- 9545025
TI - The economic impact of obesity in the United States: whither?
PMID- 9545026
TI - Twisting DNA molecules.
PMID- 9545027
TI - Compliant realignment of binding sites in muscle: transient behavior and
mechanical tuning.
AB - The presence of compliance in the lattice of filaments in muscle raises a number
of concerns about how one accounts for force generation in the context of the
cross-bridge cycle--binding site motions and coupling between cross-bridges
confound more traditional analyses. To explore these issues, we developed a
spatially explicit, mechanochemical model of skeletal muscle contraction. With a
simple three-state model of the cross-bridge cycle, we used a Monte Carlo
simulation to compute the instantaneous balance of forces throughout the filament
lattice, accounting for both thin and thick filament distortions in response to
cross-bridge forces. This approach is compared to more traditional mass action
kinetic models (in the form of coupled partial differential equations) that
assume filament inextensibility. We also monitored instantaneous force
generation, ATP utilization, and the dynamics of the cross-bridge cycle in
simulations of step changes in length and variations in shortening velocity.
Three critical results emerge from our analyses: 1) there is a significant
realignment of actin-binding sites in response to cross-bridge forces, 2) this
realignment recruits additional cross-bridge binding, and 3) we predict
mechanical behaviors that are consistent with experimental results for velocity
and length transients. Binding site realignment depends on the relative
compliance of the filament lattice and cross-bridges, and within the measured
range of these parameters, gives rise to a sharply tuned peak for force
generation. Such mechanical tuning at the molecular level is the result of
mechanical coupling between individual cross-bridges, mediated by thick filament
deformations, and the resultant realignment of binding sites on the thin
filament.
PMID- 9545028
TI - Structure and dynamics of calmodulin in solution.
AB - To characterize the dynamic behavior of calmodulin in solution, we have carried
out molecular dynamics (MD) simulations of the Ca2+-loaded structure. The crystal
structure of calmodulin was placed in a solvent sphere of radius 44 A, and 6 Cl-
and 22 Na+ ions were included to neutralize the system and to model a 150 mM salt
concentration. The total number of atoms was 32,867. During the 3-ns simulation,
the structure exhibits large conformational changes on the nanosecond time scale.
The central alpha-helix, which has been shown to unwind locally upon binding of
calmodulin to target proteins, bends and unwinds near residue Arg74. We interpret
this result as a preparative step in the more extensive structural transition
observed in the "flexible linker" region 74-82 of the central helix upon complex
formation. The major structural change is a reorientation of the two Ca2+-binding
domains with respect to each other and a rearrangement of alpha-helices in the N
terminus domain that makes the hydrophobic target peptide binding site more
accessible. This structural rearrangement brings the domains to a more favorable
position for target binding, poised to achieve the orientation observed in the
complex of calmodulin with myosin light-chain kinase. Analysis of solvent
structure reveals an inhomogeneity in the mobility of water in the vicinity of
the protein, which is attributable to the hydrophobic effect exerted by
calmodulin's binding sites for target peptides.
PMID- 9545029
TI - Mathematical modeling and fluorescence imaging to study the Ca2+ turnover in
skinned muscle fibers.
AB - A mathematical model was developed for the simulation of the spatial and temporal
time course of Ca2+ ion movement in caffeine-induced calcium transients of
chemically skinned muscle fiber preparations. Our model assumes cylindrical
symmetry and quantifies the radial profile of Ca2+ ion concentration by solving
the diffusion equations for Ca2+ ions and various mobile buffers, and the rate
equations for Ca2+ buffering (mobile and immobile buffers) and for the release
and reuptake of Ca2+ ions by the sarcoplasmic reticulum (SR), with a finite
difference algorithm. The results of the model are compared with caffeine-induced
spatial Ca2+ transients obtained from saponin skinned murine fast-twitch fibers
by fluorescence photometry and imaging measurements using the ratiometric dye
Fura-2. The combination of mathematical modeling and digital image analysis
provides a tool for the quantitative description of the total Ca2+ turnover and
the different contributions of all interacting processes to the overall Ca2+
transient in skinned muscle fibers. It should thereby strongly improve the usage
of skinned fibers as quantitative assay systems for many parameters of the SR and
the contractile apparatus helping also to bridge the gap to the intact muscle
fiber.
PMID- 9545030
TI - Fabrication of a new substrate for atomic force microscopic observation of DNA
molecules from an ultrasmooth sapphire plate.
AB - A new stable substrate applicable to the observation of DNA molecules by atomic
force microscopy (AFM) was fabricated from a ultrasmooth sapphire (alpha-Al2O3
single crystal) plate. The atomically ultrasmooth sapphire as obtained by high
temperature annealing has hydrophobic surfaces and could not be used for the AFM
observation of DNA. However, sapphire treated with Na3PO4 aqueous solution
exhibited a hydrophilic character while maintaining a smooth surface structure.
The surface of the wet-treated sapphire was found by x-ray photoelectron
spectroscopy and AFM to be approximately 0.3 nm. The hydrophilic surface
character of the ultrasmooth sapphire plate made it easy for DNA molecules to
adhere to the plate. Circular molecules of the plasmid DNA could be imaged by AFM
on the hydrophilic ultrasmooth sapphire plate.
PMID- 9545031
TI - Computation of the internal forces in cilia: application to ciliary motion, the
effects of viscosity, and cilia interactions.
AB - This paper presents a simple and reasonable method for generating a
phenomenological model of the internal mechanism of cilia. The model uses a
relatively small number of parameters whose values can be obtained by fitting to
ciliary beat shapes. Here, we use beat patterns observed in Paramecium. The
forces that generate these beats are computed and fit to a simple functional form
called the "engine." This engine is incorporated into a recently developed
hydrodynamic model that accounts for interactions between neighboring cilia and
between the cilia and the surface from which they emerge. The model results are
compared to data on ciliary beat patterns of Paramecium obtained under conditions
where the beats are two-dimensional. Many essential features of the motion,
including several properties that are not built in explicitly, are shown to be
captured. In particular, the model displays a realistic change in beat pattern
and frequency in response to increased viscosity and to the presence of
neighboring cilia in configurations such as rows of cilia and two-dimensional
arrays of cilia. We found that when two adjacent model cilia start beating at
different phases they become synchronized within several beat periods, as
observed in experiments where two flagella are brought into close proximity.
Furthermore, examination of various multiciliary configurations shows that an
approximately antiplectic wave pattern evolves autonomously. This modeling
evidence supports earlier conjectures that metachronism may occur, at least
partially, as a self-organized phenomenon due to hydrodynamic interactions
between neighboring cilia.
PMID- 9545032
TI - Physical mechanisms for chemotactic pattern formation by bacteria.
AB - This paper formulates a theory for chemotactic pattern formation by the bacteria
Escherichia coli in the presence of excreted attractant. In a chemotactically
neutral background, through chemoattractant signaling, the bacteria organize into
swarm rings and aggregates. The analysis invokes only those physical processes
that are both justifiable by known biochemistry and necessary and sufficient for
swarm ring migration and aggregate formation. Swarm rings migrate in the absence
of an external chemoattractant gradient. The ring motion is caused by the
depletion of a substrate that is necessary to produce attractant. Several scaling
laws are proposed and are demonstrated to be consistent with experimental data.
Aggregate formation corresponds to finite time singularities in which the
bacterial density diverges at a point. Instabilities of swarm rings leading to
aggregate formation occur via a mechanism similar to aggregate formation itself:
when the mass density of the swarm ring exceeds a threshold, the ring collapses
cylindrically and then destabilizes into aggregates. This sequence of events is
demonstrated both in the theoretical model and in the experiments.
PMID- 9545033
TI - Numerical methods to determine calcium release flux from calcium transients in
muscle cells.
AB - Several methods are currently in use to estimate the rate of depolarization
induced calcium release in muscle cells from measured calcium transients. One
approach first characterizes calcium removal of the cell. This is done by
determining parameters of a reaction scheme from a fit to the decay of elevated
calcium after the depolarizing stimulus. In a second step, the release rate
during depolarization is estimated based on the fitted model. Using simulated
calcium transients with known underlying release rates, we tested the fidelity of
this analysis in determining the time course of calcium release under different
conditions. The analysis reproduced in a satisfactory way the characteristics of
the input release rate, even when the assumption that release had ended before
the start of the fitting interval was severely violated. Equally good
reconstructions of the release rate time course could be obtained when the model
used for the analysis differed in structure from the one used for simulating the
data. We tested the application of a new strategy (multiple shooting) for fitting
parameters in nonlinear differential equation systems. This procedure rendered
the analysis less sensitive to ill-chosen initial guesses of the parameters and
to noise. A locally adaptive kernel estimator for calculating numerical
derivatives allowed good reconstructions of the original release rate time course
from noisy calcium transients when other methods failed.
PMID- 9545034
TI - Molecular dynamics simulation of cytochrome c3: studying the reduction processes
using free energy calculations.
AB - The tetraheme cytochrome c3 from Desulfovibrio vulgaris Hildenborough is studied
using molecular dynamics simulation studies in explicit solvent. The high heme
content of the protein, which has its core almost entirely made up of c-type
heme, presents specific problems in the simulation. Instability in the structure
is observed in long simulations above 1 ns, something that does not occur in a
monoheme cytochrome, suggesting problems in heme parametrization. Given these
stability problems, a partially restrained model, which avoids destruction of the
structure, was created with the objective of performing free energy calculations
of heme reduction, studies that require long simulations. With this model, the
free energy of reduction of each individual heme was calculated. A correction in
the long-range electrostatic interactions of charge groups belonging to the redox
centers had to be made in order to make the system physically meaningful.
Correlation is obtained between the calculated free energies and the experimental
data for three of four hemes. However, the relative scale of the calculated
energies is different from the scale of the experimental free energies. Reasons
for this are discussed. In addition to the free energy calculations, this model
allows the study of conformational changes upon reduction. Even if the precise
details of the structural changes that take place in this system upon individual
heme reduction are probably out of the reach of this study, it appears that these
structural changes are small, similarly to what is observed for other redox
proteins. This does not mean that their effect is minor, and one example is the
conformational change observed in propionate D from heme I when heme II becomes
reduced. A motion of this kind could be the basis of the experimentally observed
cooperativity effects between heme reduction, namely positive cooperativity.
PMID- 9545035
TI - Glucose diffusion in pancreatic islets of Langerhans.
AB - We investigate the time required for glucose to diffuse through an isolated
pancreatic islet of Langerhans and reach an equilibrium. This question is
relevant in the context of in vitro electrophysiological studies of the response
of an islet to step changes in the bath glucose concentration. Islet cells are
electrically coupled by gap junctions, so nonuniformities in islet glucose
concentration may be reflected in the activity of cells on the islet periphery,
where electrical recordings are made. Using a mathematical model of hindered
glucose diffusion, we investigate the effects of the islet porosity and the
permeability of a surrounding layer of acinar cells. A major factor in the
determination of the equilibrium time is the transport of glucose into islet beta
cells, which removes glucose from the interstitial spaces where diffusion occurs.
This transport is incorporated by using a model of the GLUT-2 glucose
transporter. We find that several minutes are required for the islet to
equilibrate to a 10 mM change in bath glucose, a typical protocol in islet
experiments. It is therefore likely that in electrophysiological islet
experiments the glucose distribution is nonuniform for several minutes after a
step change in bath glucose. The delay in glucose penetration to the inner
portions of the islet may be a major contributing factor to the 1-2-min delay in
islet electrical activity typically observed after bath application of a
stimulatory concentration of glucose.
PMID- 9545036
TI - Strong precursor-pore interactions constrain models for mitochondrial protein
import.
AB - Mitochondrial precursor proteins are imported from the cytosol into the matrix
compartment through a proteinaceous translocation pore. Import is driven by
mitochondrial Hsp70 (mHsp70), a matrix-localized ATPase. There are currently two
postulated mechanisms for this function of mHsp70: 1) The "Brownian ratchet"
model proposes that the precursor chain diffuses within the pore, and that
binding of mHsp70 to the lumenal portion of the chain biases this diffusion. 2)
The "power stroke" model proposes that mHsp70 undergoes a conformational change
that actively pulls the precursor chain through the pore. Here we formulate these
two models quantitatively, and compare their performance in light of recent
experimental evidence that precursor chains interact strongly with the walls of
the translocation pore. Under these conditions the simulated Brownian ratchet is
inefficient, whereas the power stroke mechanism seems to be a plausible
description of the import process.
PMID- 9545037
TI - The effect of protein relaxation on charge-charge interactions and dielectric
constants of proteins.
AB - The effect of the reorganization of the protein polar groups on charge-charge
interaction and the corresponding effective dielectric constant (epsilon(eff)) is
examined by the semimicroscopic version of the Protein Dipole Langevin Dipoles
(PDLD/S) method within the framework of the Linear Response Approximation (LRA).
This is done by evaluating the interactions between ionized residues in the
reaction center of Rhodobacter sphaeroides, while taking into account the protein
reorganization energy. It is found that an explicit consideration of the protein
relaxation leads to a significant increase in epsilon(eff) and that
semimicroscopic models that do not take this relaxation into account force one to
use a large value for the so-called "protein dielectric constant," epsilon(p), of
the Poisson-Boltzmann model or for the corresponding epsilon(in) in the PDLD/S
model. An additional increase in epsilon(eff) is expected from the reorganization
of ionized residues and from changes in the degree of water penetration. This
finding provides further support for the idea that epsilon(in) (or epsilon(p))
represents contributions that are not considered explicitly. The present study
also provides a systematic illustration of the nature of epsilon(eff), supporting
our previously reported view that charge-charge interactions correspond to a
large value of this "dielectric constant," even in protein interiors. It is also
pointed out that epsilon(eff) for the interaction between ionizable groups in
proteins is very different from the effective dielectric constant, epsilon'(eff),
that determines the free energy of ion pairs in proteins (epsilon'(eff) reflects
the effect of preoriented protein dipoles). Finally, the problems associated with
the search for a general epsilon(in) are discussed. It is clarified that the
epsilon(in) that reproduces the effect of protein relaxation on charge-charge
interaction is not equal to the epsilon(in) that reproduces the corresponding
effect upon formation of individual charges. This reflects fundamental
inconsistencies in attempts to cast microscopic concepts in a macroscopic model.
Thus one should either use a large epsilon(in) for charge-charge interactions and
a small epsilon(in) for charge-dipole interactions or consider the protein
relaxation microscopically.
PMID- 9545038
TI - Thermally induced proliferation of pores in a model fluid membrane.
AB - The growth of thermally induced pores in a two-dimensional model fluid membrane
is investigated by Monte Carlo simulation. Holes appear in the membrane via an
activated process, and their subsequent growth is controlled by an edge energy
per unit length or line tension. The barrier height and line tension, together
with a lateral tension, are the independent parameters of the model. In the
resulting phase diagram, a rupture transition separates an intact membrane from a
disintegrated state. The approach to the ruptured state shows distinct regimes.
Reducing the barrier height at large line tension produces multiple, quasi
independent, small holes whose behavior is dominated by their edge energy,
whereas at lower line tensions shape fluctuations of the holes facilitate their
coalescence into a single large hole. At a small value of line tension and large
barrier height, a single hole spontaneously permeabilizes the membrane in an
entropically driven phase transition. Entropy dominates pore growth for line
tensions not far below those measured for artificial vesicles. Permeabilization
of lipid bilayers by certain peptides involves perturbing lipid-lipid cohesive
energies, and our simulations show that at small line tensions the entropy of
hole shape fluctuations destroys the model membrane's stability.
PMID- 9545039
TI - Depolarization increases the single-channel conductance and the open probability
of crayfish glutamate channels.
AB - We have studied the voltage sensitivity of glutamate receptors in outside-out
patches taken from crayfish muscles. We found that single-channel conductance,
measured directly at the single-channel level, increases as depolarization rises.
At holding potentials from -90 mV to approximately 20 mV, the conductance is 109
pS. At holding potentials positive to 20 mV, the conductance is 213 pS. This
increase in single-channel conductance was also observed in cell-attached
patches. In addition, desensitization, rise time, and the dose-response curve
were all affected by depolarization. To further clarify these multifaceted
effects, we evaluated the kinetic properties of single-channel activity recorded
from cell-attached patches in hyperpolarization (membrane potential around -75
mV) and depolarization (membrane potential approximately 105 mV). We found that
the glutamate dissociation rate constant (k_) was affected most significantly by
membrane potential; it declined 6.5-fold under depolarization. The rate constant
of channel closing (k(c)) was also significantly affected; it declined 1.8-fold.
The rate constant of channel opening (k(o)) declined only 1.2-fold. The possible
physiological significance of the depolarization-mediated changes in the above
rate constants is discussed.
PMID- 9545041
TI - Altered voltage dependence of fractional Ca2+ current in N-methyl-D-aspartate
channel pore mutants with a decreased Ca2+ permeability.
AB - The Ca2+ permeability properties of an N-methyl-D-aspartate (NMDA) channel pore
mutant (NR1E603K-NR2A) were studied using whole-cell patch-clamp recordings in
human embryonic kidney cells. Measurements of reversal potential shifts indicated
that the relative permeability of Ca2+ over monovalent ions, P(Ca)/P(M), was 1.6,
a value reduced by a factor of approximately 2 with respect to the wild-type
channel. The ratio of Ca2+ current over total current (fractional Ca2+ current),
however, was 19.7 +/- 1% at -50 mV and 2 mM external Ca2+ concentration, a value
similar to that of the wild-type channel, but 2.3-fold larger than that predicted
by simple permeation models for the corresponding P(Ca)/P(M) value. The deviation
from predicted values gradually disappeared with membrane depolarization. Similar
results were obtained for two cysteine mutations at asparagine residues of the
NR1 and NR2A subunits. When interpreted in terms of a two-barrier one-site model
for ion permeation, the results indicate that changes in the relative Ca2+
permeability occur close to an internal energy barrier limiting ion permeation.
PMID- 9545040
TI - Inactivation of Kv2.1 potassium channels.
AB - We report here several unusual features of inactivation of the rat Kv2.1 delayed
rectifier potassium channel, expressed in Xenopus oocytes. The voltage dependence
of inactivation was U-shaped, with maximum inactivation near 0 mV. During a
maintained depolarization, development of inactivation was slow and only weakly
voltage dependent (tau = 4 s at 0 mV; tau = 7 s at +80 mV). However, recovery
from inactivation was strongly voltage dependent (e-fold for 20 mV) and could be
rapid (tau = 0.27 s at -140 mV). Kv2.1 showed cumulative inactivation, where
inactivation built up during a train of brief depolarizations. A single
maintained depolarization produced more steady-state inactivation than a train of
pulses, but there could actually be more inactivation with the repeated pulses
during the first few seconds. We term this phenomenon "excessive cumulative
inactivation." These results can be explained by an allosteric model, in which
inactivation is favored by activation of voltage sensors, but the open state of
the channel is resistant to inactivation.
PMID- 9545042
TI - Effect of luminal calcium on Ca2+ release channel activity of sarcoplasmic
reticulum in situ.
AB - Ca2+ influx into empty SR in the absence of Ca2+ pump activity was determined in
skinned frog skeletal muscle fibers and compared with Ca2+ efflux from loaded SR
(i.e., Ca2+ release) to deepen our understanding of the properties of the Ca2+
release channel (CRC). Calcium content in SR increased approximately in a first
order kinetics and finally reached the equilibrium level determined by
cytoplasmic Ca2+ ([Ca2+]c). Because AMP caused an increase in the rate of Ca2+
influx, and procaine, Mg2+, and high concentrations of Ca2+ caused a
characteristic decrease, the major Ca2+ influx pathway was concluded to be the
CRC, as is true of Ca2+ release. The apparent rate constant (k(app)) of Ca2+
efflux did not significantly change when the loading level was decreased to one
third. At a given [Ca2+]c, the same equilibrium level of calcium in SR was
attained with a similar k(app) by both Ca2+ influx and Ca2+ efflux. The
relationship between [Ca2+]c and calcium in SR indicated the Ca2+ binding sites
in SR. These results, together with the anticipated effects of these Ca2+ buffer
sites on kinetics, are consistent with the idea that luminal Ca2+ inhibits the
CRC.
PMID- 9545043
TI - A permanent ion binding site located between two gates of the Shaker K+ channel.
AB - K+ channels can be occupied by multiple permeant ions that appear to bind at
discrete locations in the conduction pathway. Neither the molecular nature of the
binding sites nor their relation to the activation or inactivation gates that
control ion flow are well understood. We used the permeant ion Ba2+ as a K+
analog to probe for K+ ion binding sites and their relationship to the activation
and inactivation gates. Our data are consistent with the existence of three
single-file permeant-ion binding sites: one deep site, which binds Ba2+ with high
affinity, and two more external sites whose occupancy influences Ba2+ movement to
and from the deep site. All three sites are accessible to the external solution
in channels with a closed activation gate, and the deep site lies between the
activation gate and the C-type inactivation gate. We identify mutations in the P
region that disrupt two of the binding sites, as well as an energy barrier
between the sites that may be part of the selectivity filter.
PMID- 9545044
TI - Assembly of ROMK1 (Kir 1.1a) inward rectifier K+ channel subunits involves
multiple interaction sites.
AB - The ROMK1 (Kir 1.1a) channel is formed by a tetrameric complex of subunits, each
characterized by cytoplasmic N- and C-termini and a core region of two
transmembrane helices flanking a pore-forming segment. To delineate the general
regions mediating the assembly of ROMK1 subunits we constructed epitope-tagged N
terminal, C-terminal, and transmembrane segment deletion mutants. Nonfunctional
subunits with N-terminal, core region, and C-terminal deletions had dominant
negative effects when coexpressed with wild-type ROMK1 subunits in Xenopus
oocytes. In contrast, coexpression of these nonfunctional subunits with Kv 2.1
(DRK1) did not suppress Kv 2.1 currents in control oocytes. Interactions between
epitope-tagged mutant and wild-type ROMK1 subunits were studied in parallel by
immunoprecipitating [35S]-labeled oocyte membrane proteins. Complexes containing
both wild-type and mutant subunits that retained H5, M2, and C-terminal regions
were coimmunoprecipitated to a greater extent than complexes consisting of wild
type and mutant subunits with core region and/or C-terminal deletions. The
present findings are consistent with the hypothesis that multiple interaction
sites located in the core region and cytoplasmic termini of ROMK1 subunits
mediate homomultimeric assembly.
PMID- 9545045
TI - Both T- and L-type Ca2+ channels can contribute to excitation-contraction
coupling in cardiac Purkinje cells.
AB - Although L-type Ca2+ channels have been shown to play a central role in cardiac
excitation-contraction (E-C) coupling, little is known about the role of T-type
Ca2+ channels in this process. We used the amphotericin B perforated patch method
to study the possible role of T-type Ca2+ current in E-C coupling in isolated
canine Purkinje myocytes where both Ca2+ currents are large. T-type Ca2+ current
was separated from L-type Ca2+ current using protocols employing the different
voltage dependencies of the channel types and their different sensitivities to
pharmacological blockade. We showed that Ca2+ admitted through either T- or L
type Ca2+ channels is capable of initiating contraction and that the contractions
depended on Ca2+-induced Ca2+ release from the sarcoplasmic reticulum (SR). The
contractions, however, had different properties. Those initiated by Ca2+ entry
through T-type Ca2+ channels had a longer delay to the onset of shortening,
slower rates of shortening and relaxation, lower peak shortening, and longer time
to peak shortening. These differences were present even when L-type Ca2+ current
amplitude, or charge entry, was less than that of T-type Ca2+ current, suggesting
that Ca2+ entry through the T-type Ca2+ channel is a less effective signal
transduction mechanism to the SR than is Ca2+ entry through the L-type Ca2+
channel. We conclude that under our experimental conditions in cardiac Purkinje
cells Ca2+ entry through the T-type Ca2+ channel can activate cell contraction.
However, Ca2+ entry through the L-type Ca2+ channel is a more effective signal
transduction mechanism. Our findings support the concept that different
structural relationships exist between these channel types and the SR Ca2+
release mechanism.
PMID- 9545046
TI - Modulation of C-type inactivation by K+ at the potassium channel selectivity
filter.
AB - With prolonged or repetitive activation, voltage-gated K+ channels undergo a slow
(C-type) inactivation mechanism, which decreases current flow through the
channel. Previous observations suggest that C-type inactivation results from a
localized constriction in the outer mouth of the channel pore and that the rate
of inactivation is controlled by the-rate at which K+ leaves an unidentified
binding site in the pore. We have functionally identified two K+ binding sites in
the conduction pathway of a chimeric K+ channel that conducts Na+ in the absence
of K+. One site has a high affinity for K+ and contributes to the selectivity
filter mechanism for K+ over Na+. Another site, external to the high-affinity
site, has a lower affinity for K+ and is not involved in channel selectivity.
Binding of K+ to the high-affinity binding site slowed inactivation. Binding of
cations to the external low-affinity site did not slow inactivation directly but
could slow it indirectly, apparently by trapping K+ at the high-affinity site.
These data support a model whereby C-type inactivation involves a constriction at
the selectivity filter, and the constriction cannot proceed when the selectivity
filter is occupied by K+.
PMID- 9545047
TI - Mechanism of anode break stimulation in the heart.
AB - Anodal stimulation is routinely observed in cardiac tissue, but only recently has
a mechanism been proposed. The bidomain cardiac tissue model proposes that
virtual cathodes induced at sites distant from the electrode initiate the
depolarization. In contrast, none of the existing cardiac action potential models
(Luo-Rudy phase I and II, or Oxsoft) predict anodal stimulation at the single
cell level. To determine whether anodal stimulation has a cellular basis, we
measured membrane potential and membrane current in mammalian ventricular
myocytes by using whole-cell patch clamp. Anode break responses can be readily
elicited in single ventricular cells. The basis of this anodal stimulation in
single cells is recruitment of the hyperpolarization-activated inward current
I(f). The threshold of activation for I(f) is -80 mV in rat cells and -120 mV in
guinea pig or canine cells. Persistent I(f) "tail" current upon release of the
hyperpolarization drives the transmembrane potential toward the threshold of
sodium channels, initiating an action potential. Time-dependent block of the
inward rectifier, I(K1), at hyperpolarized potentials decreases membrane
conductance and thereby potentiates the ability of I(f) to depolarize the cell on
the break of an anodal pulse. Inclusion of I(f), as well as the block and unblock
kinetics of I(K1), in the existing Luo-Rudy action potential model faithfully
reproduces anode break stimulation. Thus active cellular properties suffice to
explain anode break stimulation in cardiac tissue.
PMID- 9545048
TI - Pressure effects on the lateral distribution of cholesterol in lipid bilayers: a
time-resolved spectroscopy study.
AB - The effects of hydrostatic pressure and temperature on the phase behavior and
physical properties of the binary mixture
palmitoyloleoylphosphatidylcholine/cholesterol, over the 0-40 molar % range of
cholesterol compositions, were determined from the changes in the fluorescence
lifetime distribution and anisotropy decay parameters of the natural lipid trans
parinaric acid (t-PnA). Pressurized samples were excited with a Ti-sapphire
subpicosecond laser, and fluorescence decays were analyzed by the quantified
maximum entropy method. Above the transition temperature (T(T) = -5 degrees C),
at atmospheric pressure, two liquid-crystalline phases, alpha and beta, are
formed in this system. At each temperature and cholesterol concentration below
the transition pressure, the fluorescence lifetime distribution pattern of t-PnA
was clearly modulated by the pressure changes. Pressure increased the fraction of
the liquid-ordered beta-phase and its order parameter, but it decreased the
amount of cholesterol in this phase.
Palmitoyloleoylphosphatidylcholine/cholesterol phase diagrams were also
determined as a function of temperature and hydrostatic pressure.
PMID- 9545049
TI - Studies of the binding and structure of adrenocorticotropin peptides in membrane
mimics by NMR spectroscopy and pulsed-field gradient diffusion.
AB - The partition and structure of three adrenocorticotropic hormone peptides ACTH(1
10), ACTH(1-24), and ACTH(11-24) in water and in sodium dodecylsulfate (SDS) and
dodecylphosphocholine (DPC) micelles were studied by 2D NMR and NMR gradient
diffusion measurements. The diffusion rates, the NH chemical shifts, and the
nuclear Overhauser effect patterns provided a coherent picture of binding of
these peptides. All three peptides are significantly partitioned in the
negatively charged SDS micelles and possess definite secondary structure, as
opposed to random structures in water. For ACTH (1-24), the hydrophobic 1-10
segment is partitioned in DPC micelles, but the charged 11-24 segment prefers to
remain in the aqueous region. ACTH(11-24) does not bind significantly to the DPC
micelles. The binding of the ACTH peptides in these two widely used "membrane
mimics" are substantially different from that in 1-palmitoyl-2-oleoyl-sn-glycero
3-phosphocholine (POPC) bilayers obtained by attenuated total reflection infrared
spectroscopy and from our preliminary diffusion studies of the same peptides in
POPC vesicles. This study showed that, in a given micellar medium, all
corresponding segments of these peptides are located in the same membrane
environment in the system, regardless of whether these segments exist by
themselves or are attached to other segments. This result may contradict the
membrane-compartments concept of Schwyzer, which suggests that ACTH(1-10) and
ACTH(1-24) are located in different membrane compartments because they have
different address segments, and consequently, bind to different receptors. The
present results also suggest that the assumption that micelles are good membrane
mimics should be carefully examined.
PMID- 9545050
TI - Correlation between electric field pulse induced long-lived permeabilization and
fusogenicity in cell membranes.
AB - Electric field pulses have been reported to induce long-lived permeabilization
and fusogenicity on cell membranes. The two membrane property alterations are
under the control of the field strength, the pulse duration, and the number of
pulses. Experiments on mammalian cells pulsed by square wave form pulses and then
brought into contact randomly through centrifugation revealed an even stronger
analogy between the two processes. Permeabilization was known to affect well
defined regions of the cell surface. Fusion can be obtained only when
permeabilized surfaces on the two partners were brought into contact.
Permeabilization was under the control of the pulse duration and of the number of
pulses. A similar relationship was observed as far as fusion is concerned. But a
critical level of local permeabilization must be present for fusion to take place
when contacts are created. The same conclusions are obtained from previous
experiments on ghosts subjected to exponentially decaying field pulses and then
brought into contact by dielectrophoresis. These observations are in agreement
with a model of membrane fusion in which the merging of local random defects
occurs when the two membranes are brought into contact. The local defects are
considered part of the structural membrane reorganization induced by the external
field. Their density is dependent on the pulse duration and number of pulses.
They support the long-lived permeabilization. Their number must be very large to
support the occurrence of membrane fusion.
PMID- 9545051
TI - Effects of a cationic and hydrophobic peptide, KL4, on model lung surfactant
lipid monolayers.
AB - We report on the surface behavior of a hydrophobic, cationic peptide, [lysine
(leucine)4]4-lysine (KL4), spread at the air/water interface at 25 degrees C and
pH 7.2, and its effect at very low molar ratios on the surface properties of the
zwitterionic phospholipid 1,2-dipalmitoylphosphatidylcholine (DPPC), and the
anionic forms of 1-palmitoyl-2-oleoylphosphatidylglycerol (POPG) and palmitic
acid (PA), in various combinations. Surface properties were evaluated by
measuring equilibrium spreading pressures (pi(e)) and surface pressure-area
isotherms (pi-A) with the Wilhelmy plate technique. Surface phase separation was
observed with fluorescence microscopy. KL4 itself forms a single-phase monolayer,
stable up to a surface pressure pi of 30 mN/m, and forms an immiscible monolayer
mixture with DPPC. No strong interaction was detected between POPG and KL4 in the
low pi region, whereas a stable monolayer of the PA/KL4 binary mixture forms,
which is attributed to ionic interactions between oppositely charged PA and KL4.
KL4 has significant effects on the DPPC/POPG mixture, in that it promotes surface
phase separation while also increasing pi(e) and pi(max), and these effects are
greatly enhanced in the presence of PA. In the model we have proposed, KL4
facilitates the separation of DPPC-rich and POPG/PA-rich phases to achieve
surface refinement. It is these two phases that can fulfill the important lung
surfactant functions of high surface pressure stability and efficient spreading.
PMID- 9545052
TI - Hydration of the dienic lipid dioctadecadienoylphosphatidylcholine in the
lamellar phase--an infrared linear dichroism and x-ray study on headgroup
orientation, water ordering, and bilayer dimensions.
AB - In the phospholipid 1,2-bis(2,4-octadecadienoyl)-sn-glycero-3-phosphorylcholine
(DODPC) in each of the fatty acid chains, a rigid diene group is inserted in a
position near the polar/apolar boundary that is exceptionally sensitive for
membrane stability. DODPC transforms upon gradual dehydration from the liquid
crystalline to a metastable gel state, which rearranges into two subgel phases at
low and intermediate degrees of hydration. The molecular dimensions of the
respective bilayers were determined by means of x-ray diffraction. Infrared
linear dichroism of selected vibrations of the phosphate and trimethylammonium
groups and of the nu13(OH) band of water adsorbed onto the lipid was used to
study the molecular order in the polar part of the bilayers in macroscopically
oriented samples. The dense packing of the tilted acyl chains in the subgel
causes the in-plane orientation of the phosphatidylcholine headgroups with direct
interactions between the phosphate and trimethylammonium groups, and a strong
orientation of adsorbed water molecules. In the more disordered gel, the
thickness of the polar part of the bilayer increases and the lateral interactions
between the lipid headgroups weaken. The higher order in the headgroup region of
the subgels correlates with shorter decay lengths of the repulsive forces acting
between opposite membrane surfaces. This result can be understood if the work to
dehydrate the lipid is determined to a certain degree by the work to break up the
lipid-water interactions without compensation by adequate lipid-lipid contacts.
Almost similar area compressibility moduli are found in the liquid-crystalline
and solid phases. Obviously, the lipid avoids lateral stress by the structural
rearrangement.
PMID- 9545053
TI - Membrane structure characterization using variable-period x-ray standing waves.
AB - The variable-period x-ray standing wave (XSW) technique is emerging as a powerful
tool for studying membrane structure. However, two significant problems arise
when the method is used to characterize membranes of thickness dL < 100 A. First,
the surface roughness, sigma(r), of the supporting reflecting mirror convolutes
with the intrinsic half-width of the marker atom distribution in the membrane,
sigma(in), and contributes to an apparent half-width, sigma, which is measured in
the XSW experiment. Here we show how the latter terms are related quantitatively
[sigma(in) = (sigma2 - sigma(r)2)(1/2)], such that rough mirrors give rise to
larger marker atom distribution widths, sigma, and how the required quantity
sigma(in) can be determined in the XSW measurement. Second, when the mean
position of the marker atom layer, (z), is close to one or both boundaries of the
membrane, its distribution function is truncated at the boundary. In such cases,
we show why marker atom distribution should be expressed in terms of its first
and second moments. We also demonstrate by numerical simulations of realistic
samples how the physical parameters, sigma(r), sigma, (z), and dL, affect x-ray
reflectivity and fluorescence yield profiles as an aid in their interpretation.
PMID- 9545054
TI - Electrochemical measurement of lateral diffusion coefficients of ubiquinones and
plastoquinones of various isoprenoid chain lengths incorporated in model
bilayers.
AB - The long-range diffusion coefficients of isoprenoid quinones in a model of lipid
bilayer were determined by a method avoiding fluorescent probe labeling of the
molecules. The quinone electron carriers were incorporated in supported
dimyristoylphosphatidylcholine layers at physiological molar fractions (<3 mol%).
The elaborate bilayer template contained a built-in gold electrode at which the
redox molecules solubilized in the bilayer were reduced or oxidized. The lateral
diffusion coefficient of a natural quinone like UQ10 or PQ9 was 2.0 +/- 0.4 x 10(
8) cm2 s(-1) at 30 degrees C, two to three times smaller than the diffusion
coefficient of a lipid analog in the same artificial bilayer. The lateral
mobilities of the oxidized or reduced forms could be determined separately and
were found to be identical in the 4-13 pH range. For a series of isoprenoid
quinones, UQ2 or PQ2 to UQ10, the diffusion coefficient exhibited a marked
dependence on the length of the isoprenoid chain. The data fit very well the
quantitative behavior predicted by a continuum fluid model in which the
isoprenoid chains are taken as rigid particles moving in the less viscous part of
the bilayer and rubbing against the more viscous layers of lipid heads. The
present study supports the concept of a homogeneous pool of quinone located in
the less viscous region of the bilayer.
PMID- 9545055
TI - The effects of solutes on the freezing properties of and hydration forces in
lipid lamellar phases.
AB - Quantitative deuterium nuclear magnetic resonance is used to study the freezing
behavior of the water in phosphatidylcholine lamellar phases, and the effect upon
it of dimethylsulfoxide (DMSO), sorbitol, sucrose, and trehalose. When sufficient
solute is present, an isotropic phase of concentrated aqueous solution may
coexist with the lamellar phase at freezing temperatures. We determine the
composition of both unfrozen phases as a function of temperature by using the
intensity of the calibrated free induction decay signal (FID). The presence of
DMSO or sorbitol increases the hydration of the lamellar phase at all freezing
temperatures studied, and the size of the increase in hydration is comparable to
that expected from their purely osmotic effect. Sucrose and trehalose increase
the hydration of the lamellar phase, but, at concentrations of several molal, the
increase is less than that which their purely osmotic effect would be expected to
produce. A possible explanation is that very high volume fractions of sucrose and
trehalose disrupt the water structure and thus reduce the repulsive hydration
interaction between membranes. Because of their osmotic effect, all of the
solutes studied reduced the intramembrane mechanical stresses produced in
lamellar phases by freezing. Sucrose and trehalose at high concentrations produce
a greater reduction than do the other solutes.
PMID- 9545056
TI - Energetics of inclusion-induced bilayer deformations.
AB - The material properties of lipid bilayers can affect membrane protein function
whenever conformational changes in the membrane-spanning proteins perturb the
structure of the surrounding bilayer. This coupling between the protein and the
bilayer arises from hydrophobic interactions between the protein and the bilayer.
We analyze the free energy cost associated with a hydrophobic mismatch, i.e., a
difference between the length of the protein's hydrophobic exterior surface and
the average thickness of the bilayer's hydrophobic core, using a (liquid-crystal)
elastic model of bilayer deformations. The free energy of the deformation is
described as the sum of three contributions: compression-expansion, splay
distortion, and surface tension. When evaluating the interdependence among the
energy components, one modulus renormalizes the other: e.g., a change in the
compression-expansion modulus affects not only the compression-expansion energy
but also the splay-distortion energy. The surface tension contribution always is
negligible in thin solvent-free bilayers. When evaluating the energy per unit
distance (away from the inclusion), the splay-distortion component dominates
close to the bilayer/inclusion boundary, whereas the compression-expansion
component is more prominent further away from the boundary. Despite this
complexity, the bilayer deformation energy in many cases can be described by a
linear spring formalism. The results show that, for a protein embedded in a
membrane with an initial hydrophobic mismatch of only 1 A, an increase in
hydrophobic mismatch to 1.3 A can increase the Boltzmann factor (the equilibrium
distribution for protein conformation) 10-fold due to the elastic properties of
the bilayer.
PMID- 9545057
TI - Prodan as a membrane surface fluorescence probe: partitioning between water and
phospholipid phases.
AB - Fluorescence spectral features of 6-propionyl-2-dimethylaminonaphthalene (Prodan)
in phospholipid vesicles of different phase states are investigated. Like the
spectra of 6-lauroyl-2-dimethylaminonaphthalene (Laurdan), the steady-state
excitation and emission spectra of Prodan are sensitive to the polarity of the
environment, showing a relevant shift due to the dipolar relaxation phenomenon.
Because of the different lengths of their acyl residues, the partitioning of the
two probes between water and the membrane bilayer differs profoundly. To account
for the contribution of Prodan fluorescence arising from water, we introduce a
three-wavelength generalized polarization method that makes it possible to
separate the spectral properties of Prodan in the lipid phase and in water, and
to determine the probe partitioning between phospholipid and water and between
the gel and the liquid-crystalline phases of phospholipids. In contrast to
Laurdan, Prodan preferentially partitions in the liquid-crystalline phase with
respect to the gel and is sensitive to the polar head pretransition, and its
partition coefficient between the membrane and water depends on the phase state,
i.e., on the packing of the bilayer. Prodan is sensitive to polarity variations
occurring closer to the bilayer surface than those detected by Laurdan.
PMID- 9545058
TI - Force regulation by Ca2+ in skinned single cardiac myocytes of frog.
AB - Atrial and ventricular myocytes 200 to 300 microm long containing one to five
myofibrils are isolated from frog hearts. After a cell is caught and held between
two suction micropipettes the surface membrane is destroyed by briefly jetting
relaxing solution containing 0.05% Triton X-100 on it from a third micropipette.
Jetting buffered Ca2+ from other pipettes produces sustained contractions that
relax completely on cessation. The pCa/force relationship is determined at 20
degrees C by perfusing a closely spaced sequence of pCa concentrations (pCa =
log[Ca2+]) past the skinned myocyte. At each step in the pCa series quick release
of the myocyte length defines the tension baseline and quick restretch allows the
kinetics of the return to steady tension to be observed. The pCa/force data fit
to the Hill equation for atrial and ventricular myocytes yield, respectively, a
pK (curve midpoint) of 5.86 +/- 0.03 (mean +/- SE.; n = 7) and 5.87 +/- 0.02 (n =
18) and an nH (slope) of 4.3 +/- 0.34 and 5.1 +/- 0.35. These slopes are about
double those reported previously, suggesting that the cooperativity of Ca2+
activation in frog cardiac myofibrils is as strong as in fast skeletal muscle.
The shape of the pCa/force relationship differs from that usually reported for
skeletal muscle in that it closely follows the ideal fitted Hill plot with a
single slope while that of skeletal muscle appears steeper in the lower than in
the upper half. The rate of tension redevelopment following release restretch
protocol increases with Ca2+ >10-fold and continues to rise after Ca2+ activated
tension saturates. This finding provides support for a strong kinetic mechanism
of force regulation by Ca2+ in frog cardiac muscle, at variance with previous
reports on mammalian heart muscle. The maximum rate of tension redevelopment
following restretch is approximately twofold faster for atrial than for
ventricular myocytes, in accord with the idea that the intrinsic speed of the
contractile proteins is faster in atrial than in ventricular myocardium.
PMID- 9545060
TI - Behavior of supercoiled DNA.
AB - We study DNA supercoiling in a quantitative fashion by micromanipulating single
linear DNA molecules with a magnetic field gradient. By anchoring one end of the
DNA to multiple sites on a magnetic bead and the other end to multiple sites on a
glass surface, we were able to exert torsional control on the DNA. A rotating
magnetic field was used to induce rotation of the magnetic bead, and reversibly
over- and underwind the molecule. The magnetic field was also used to increase or
decrease the stretching force exerted by the magnetic bead on the DNA. The
molecule's degree of supercoiling could therefore be quantitatively controlled
and monitored, and tethered-particle motion analysis allowed us to measure the
stretching force acting on the DNA. Experimental results indicate that this is a
very powerful technique for measuring forces at the picoscale. We studied the
effect of stretching forces ranging from 0.01 pN to 100 pN on supercoiled DNA (
0.1 < sigma < 0.2) in a variety of ionic conditions. Other effects, such as
stretching-relaxing hysteresis and the braiding of two DNA molecules, are
discussed.
PMID- 9545059
TI - Calcium regulation of tension redevelopment kinetics with 2-deoxy-ATP or low
[ATP] in rabbit skeletal muscle.
AB - The correlation of acto-myosin ATPase rate with tension redevelopment kinetics
(k(tr)) was determined during Ca(+2)-activated contractions of demembranated
rabbit psoas muscle fibers; the ATPase rate was either increased or decreased
relative to control by substitution of ATP (5.0 mM) with 2-deoxy-ATP (dATP) (5.0
mM) or by lowering [ATP] to 0.5 mM, respectively. The activation dependence of
k(tr) and unloaded shortening velocity (Vu) was measured with each substrate.
With 5.0 mM ATP, Vu depended linearly on tension (P), whereas k(tr) exhibited a
nonlinear dependence on P, being relatively independent of P at submaximum levels
and rising steeply at P > 0.6-0.7 of maximum tension (Po). With dATP, Vu was 25%
greater than control at Po and was elevated at all P > 0.15Po, whereas Po was
unchanged. Furthermore, the Ca(+2) sensitivity of both k(tr) and P increased,
such that the dependence of k(tr) on P was not significantly different from
control, despite an elevation of Vu and maximal k(tr). In contrast, lowering
[ATP] caused a slight (8%) elevation of Po, no change in the Ca(+2) sensitivity
of P, and a decrease in Vu at all P. Moreover, k(tr) was decreased relative to
control at P > 0.75Po, but was elevated at P < 0.75Po. These data demonstrate
that the cross-bridge cycling rate dominates k(tr) at maximum but not submaximum
levels of Ca(2+) activation.
PMID- 9545061
TI - PsaC subunit of photosystem I is oriented with iron-sulfur cluster F(B) as the
immediate electron donor to ferredoxin and flavodoxin.
AB - The PsaC subunit of photosystem I (PS I) binds two [4Fe-4S] clusters, F(A) and
F(B), functioning as electron carriers between F(X) and soluble ferredoxin. To
resolve the issue whether F(A) or F(B) is proximal to F(X), we used single
turnover flashes to promote step-by-step electron transfer between electron
carriers in control (both F(A) and F(B) present) and HgCl2-treated (F(B)-less) PS
I complexes from Synechococcus sp. PCC 6301 and analyzed the kinetics of P700+
reduction by monitoring the absorbance changes at 832 nm in the presence of a
fast electron donor (phenazine methosulfate (PMS)). In control PS I complexes
exogenously added ferredoxin, or flavodoxin could be photoreduced on each flash,
thus allowing P700+ to be reduced from PMS. In F(B)-less complexes, both in the
presence and in the absence of ferredoxin or flavodoxin, P700+ was reduced from
PMS only on the first flash and was reduced from F(X)- on the following flashes,
indicating lack of electron transfer to ferredoxin or flavodoxin. In the F(B)
less complexes, a normal level of P700 photooxidation was detected accompanied by
a high yield of charge recombination between P700+ and F(A)- in the presence of a
slow donor, 2,6-dichlorophenol-indophenol. This recombination remained the only
pathway of F(A)- reoxidation in the presence of added ferredoxin, consistent with
the lack of forward electron transfer. F(A)- could be reoxidized by methyl
viologen in F(B)-less PS I complexes, although at a concentration two orders of
magnitude higher than is required in wild-type PS I complexes, thus implying the
presence of a diffusion barrier. The inhibition of electron transfer to
ferredoxin and flavodoxin was completely reversed after reconstituting the F(B)
cluster. Using rate versus distance estimates for electron transfer rates from
F(X) to ferredoxin for two possible orientations of PsaC, we conclude that the
kinetic data are best compatible with PsaC being oriented with F(A) as the
cluster proximal to F(X) and F(B) as the distal cluster that donates electrons to
ferredoxin.
PMID- 9545062
TI - Association and dissociation kinetics of anti-hen egg lysozyme monoclonal
antibodies HyHEL-5 and HyHEL-10.
AB - The immunoglobulin G1 (IgG1) kappa antibodies HyHEL-5 and HyHEL-10 interact with
nonoverlapping epitopes on hen egg lysozyme (HEL); the HyHEL-5/HEL interface has
two energetically and structurally important salt links, whereas the HyHEL-10/HEL
interface involves predominantly hydrogen bonds and van der Waals interactions.
The kinetics of association and dissociation of antibodies HyHEL-5 and HyHEL-10
with HEL under a variety of conditions were investigated in this study. The
association of each antibody with HEL follows second-order kinetics. The
association process is significantly diffusion-limited, as indicated by the
viscosity dependence of the interaction of both antibodies with HEL, although
detailed energetics suggest that the association process may be more complex. The
association rate constant for the HyHEL-5/HEL system is within a factor of 2 of
the modified Smoluchowski estimate for proteins of this size, whereas HyHEL-10
interacts with HEL with an association rate an order of magnitude lower. The
association reactions are insensitive to ionic strength, showing only a twofold
decrease in the association rate constant when the ionic strength was increased
from 27 mM to 500 mM. Interestingly, the association rate constant for the
interaction of HyHEL-5 with HEL varies with pH in the range 6.0-10.0, whereas
HyHEL-10/HEL association is not affected by pH in the same range. The
dissociation of the HyHEL-5/HEL and HyHEL-10/HEL complexes follow first-order
kinetics with half-lives at 25 degrees C of approximately 3,150 s and
approximately 21,660 s, respectively.
PMID- 9545063
TI - Flavin fluorescence dynamics and photoinduced electron transfer in Escherichia
coli glutathione reductase.
AB - Time-resolved polarized flavin fluorescence was used to study the active site
dynamics of Escherichia coli glutathione reductase (GR). Special consideration
was given to the role of Tyr177, which blocks the access to the NADPH binding
site in the crystal structure of the enzyme. By comparing wild-type GR with the
mutant enzymes Y177F and Y177G, a fluorescence lifetime of 7 ps that accounts for
approximately 90% of the fluorescence decay could be attributed to quenching by
Y177. Based on the temperature invariance for this lifetime, and the very high
quenching rate, electron transfer from Y177 to the light-excited isoalloxazine
part of flavin adenine dinucleotide (FAD) is proposed as the mechanism of flavin
fluorescence quenching. Contrary to the mutant enzymes, wild-type GR shows a
rapid fluorescence depolarization. This depolarization process is likely to
originate from a transient charge transfer interaction between Y177 and the light
excited FAD, and not from internal mobility of the flavin, as has previously been
proposed. Based on the fluorescence lifetime distributions, the mutants Y177F and
Y177G have a more flexible protein structure than wild-type GR: in the range of
223 K to 277 K in 80% glycerol, both tyrosine mutants mimic the closely related
enzyme dihydrolipoyl dehydrogenase. The fluorescence intensity decays of the GR
enzymes can only be explained by the existence of multiple quenching sites in the
protein. Although structural fluctuations are likely to contribute to the
nonexponential decay and the probability of quenching by a specific site, the
concept of conformational substates need not be invoked to explain the
heterogeneous fluorescence dynamics.
PMID- 9545064
TI - Structural characterization of the hydrophobin SC3, as a monomer and after self
assembly at hydrophobic/hydrophilic interfaces.
AB - Hydrophobins are small fungal proteins that self-assemble at
hydrophilic/hydrophobic interfaces into amphipathic membranes that, in the case
of Class I hydrophobins, can be disassembled only by treatment with agents like
pure trifluoroacetic acid. Here we characterize, by spectroscopic techniques, the
structural changes that occur upon assembly at an air/water interface and upon
assembly on a hydrophobic solid surface, and the influence of deglycosylation on
these events. We determined that the hydrophobin SC3 from Schizophyllum commune
contains 16-22 O-linked mannose residues, probably attached to the N-terminal
part of the peptide chain. Scanning force microscopy revealed that SC3 adsorbs
specifically to a hydrophobic surface and cannot be removed by heating at 100
degrees C in 2% sodium dodecyl sulfate. Attenuated total reflection Fourier
transform infrared spectroscopy and circular dichroism spectroscopy revealed that
the monomeric, water-soluble form of the protein is rich in beta-sheet structure
and that the amount of beta-sheet is increased after self-assembly on a water-air
interface. Alpha-helix is induced specifically upon assembly of the protein on a
hydrophobic solid. We propose a model for the formation of rodlets, which may be
induced by dehydration and a conformational change of the glycosylated part of
the protein, resulting in the formation of an amphipathic alpha-helix that forms
an anchor for binding to a substrate. The assembly in the beta-sheet form seems
to be involved in lowering of the surface tension, a potential function of
hydrophobins.
PMID- 9545065
TI - Energy transfers in the B808-866 antenna from the green bacterium Chloroflexus
aurantiacus.
AB - Energy transfers within the B808-866 BChl a antenna in chlorosome-membrane
complexes from the green photosynthetic bacterium Chloroflexus aurantiacus were
studied in two-color pump-probe experiments at room temperature. The steady-state
spectroscopy and protein sequence of the B808-866 complex are reminiscent of well
studied LH2 antennas from purple bacteria. B808-->B866 energy transfers occur
with approximately 2 ps kinetics; this is slower by a factor of approximately 2
than B800-->B850 energy transfers in LH2 complexes from Rhodopseudomonas
acidophila or Rhodobacter sphaeroides. Anisotropy studies show no evidence for
intra-B808 energy transfers before the B808-->B866 step; intra-B866 processes are
reflected in 350-550 fs anisotropy decays. Two-color anisotropies under 808 nm
excitation suggest the presence of a B808-->B866 channel arising either from
direct laser excitation of upper B866 exciton components that overlap the B808
absorption band or from excitation of B866 vibronic bands in nontotally symmetric
modes.
PMID- 9545066
TI - Optical chemical imaging of tobacco mosaic virus in solution at 60-nm resolution.
AB - Scanning near-field optical microscopy can provide images with a resolution less
than the wavelength of light, and therefore ought in principle to be of great
value in studies of biological structures. In this work we show how for the first
time images have been obtained of tobacco mosaic virus particles at 60-nm
resolution, combined with chemical imaging using monoclonal antibodies under in
vitro conditions.
PMID- 9545067
TI - Micropipet-based pico force transducer: in depth analysis and experimental
verification.
AB - Measurements of forces in the piconewton range are very important for the study
of molecular adhesion and mechanics. Recently, a micropipet-based force
transducer for this type of experiment was presented (E. Evans, K. Ritchie, and
R. Merkel, 1995, Biophys. J., 68:2580-2587). In the present article we give a
detailed mechanical analysis of this transducer, including nonlinear effects. An
analytical expression for the transducer stiffness at small elongations is given.
Using magnetic tweezers (F. Ziemann, J. Radler, and E. Sackmann, 1994, Biophys.
J., 66:2210-2216), we were able to determine the force displacement relation of
this transducer experimentally. Forces from approximately 10 pN to 500 pN were
applied. Theoretical predictions and experimental results coincide remarkably
well.
PMID- 9545068
TI - Depolarized resonance light scattering by porphyrin and chlorophyll a aggregates.
AB - A quantum mechanical model is developed for the observed resonance enhancement of
light scattering by aggregates of electronically interacting chromophores.
Aggregate size, monomer oscillator strength, extent of electronic coupling, and
aggregate geometry are all important determinants of intensity in resonance light
scattering (RLS) spectra. The theory also predicts the value of the
depolarization ratio (rho(v)(90)) of RLS for a given aggregate geometry. These
results are used to interpret the RLS depolarization ratios of four aggregates:
tetrakis(4-sulfonatophenyl)porphine aggregated at low pH (rho(v)(90) = 0.17 at
488 nm), trans-bis(N-methylpyridinium-4-yl)-diphenylporphinato copper(II)
aggregated in 0.2 M NaCl solution (rho(v)(90) = 0.13 at 450 nm) and on calf
thymus DNA (rho(v)(90) = 0.20 at 454 nm), and chlorophyll a aggregates in
formamide/water (rho(v)(90) = 0.23 and 0.32 at 469 and 699 nm, respectively). The
analysis is consistent with a J-aggregate geometry for all four systems.
Furthermore, the specific values of rho(v)(90) allow us to estimate the
orientation of the monomer transition dipoles with respect to the long axis of
the aggregate. We conclude that depolarized resonance light scattering
spectroscopy is a powerful probe of the geometric and electronic structures of
extended aggregates of strong chromophores.
PMID- 9545069
TI - Comparison of secretory responses as measured by membrane capacitance and by
amperometry.
AB - We have compared capacitance and amperometric measurements in bovine chromaffin
cells when secretion was elicited by flash photolysis of caged-calcium or step
depolarizations. Total amperometric charge depended linearly on the amount of
capacitance increase in both types of experiments. Furthermore, the properties of
resolvable amperometric spikes after flashes were comparable to those observed
after depolarizations, and their timing was compatible with the rate of
capacitance increase. For a more detailed comparison, we used Monte Carlo
simulations of multiple amperometric events occurring randomly over the surface
of a sphere and summing together, to generate a reference amperometric signal for
a given measured capacitance increase. Even after correction for endocytotic
processes, the time courses of the integrated experimental records lagged behind
the integrated Monte Carlo records by approximately 50 ms in flash and
depolarization experiments. This delay was larger by approximately 40 ms than
what can be expected from the "pre-foot delay" or the foot duration. Possible
sources for the remaining delay could be diffusional barriers like the patch
pipette and the chamber bottom, which are not taken into account in the model. We
also applied a novel type of fluctuation analysis to estimate the relative
quantum size of an amperometric event. On average the estimates from experimental
amperometric traces, in both flash and depolarization experiments, were 3-5 times
smaller than estimates from simulated ones. This discrepancy can be due to
contributions to the amperometric current from small vesicles, preferred release
from cellular regions orientated toward the chamber bottom, or abundance of "foot
only" events. In conclusion, amperometric signals in flash and depolarization
experiments displayed similar delayed average time courses and a lower estimate
for the relative quantum size compared to the modeled amperometric signals.
However, individual amperometric spikes were in agreement with expectations
derived from capacitance signals.
PMID- 9545070
TI - Low frequency electrorotation of fixed red blood cells.
AB - Electrorotation of fixed red blood cells has been investigated in the frequency
range between 16 Hz and 30 MHz. The rotation was studied as a function of
electrolyte conductivity and surface charge density. Between 16 Hz and 1 kHz,
fixed red blood cells undergo cofield rotation. The maximum of cofield rotation
occurs between 30 and 70 Hz. The position of the maximum depends weakly on the
bulk electrolyte conductivity and surface charge density. Below 3.5 mS/m, the
cofield rotation peak is broadened and shifted to higher frequencies accompanied
by a decrease of the rotation speed. Surface charge reduction leads to a decrease
of the rotation speed in the low frequency range. These observations are
consistent with the recently developed electroosmotic theory of low frequency
electrorotation.
PMID- 9545072
TI - Imaging the permeability pore transition in single mitochondria.
AB - In mitochondria the opening of a large proteinaceous pore, the "mitochondrial
permeability transition pore" (MTP), is known to occur under conditions of
oxidative stress and matrix calcium overload. MTP opening and the resulting
cellular energy deprivation have been implicated in processes such as hypoxic
cell damage, apoptosis, and neuronal excitotoxicity. Membrane potential (delta
psi(m)) in single isolated heart mitochondria was measured by confocal microscopy
with a voltage-sensitive fluorescent dye. Measurements in mitochondrial
populations revealed a gradual loss of delta psi(m) due to the light-induced
generation of free radicals. In contrast, the depolarization in individual
mitochondria was fast, sometimes causing marked oscillations of delta psi(m).
Rapid depolarizations were accompanied by an increased permeability of the inner
mitochondrial membrane to matrix-entrapped calcein (approximately 620 Da),
indicating the opening of a large membrane pore. The MTP inhibitor cyclosporin A
significantly stabilized delta psi(m) in single mitochondria, thereby slowing the
voltage decay in averaged recordings. We conclude that the spontaneous
depolarizations were caused by repeated stochastic openings and closings of the
transition pore. The data demonstrate a much more dynamic regulation of membrane
permeability at the level of a single organelle than predicted from ensemble
behavior of mitochondrial populations.
PMID- 9545071
TI - High microvascular endothelial water permeability in mouse lung measured by a
pleural surface fluorescence method.
AB - Transport of water between the capillary and airspace compartments in lung
encounters serial barriers: the alveolar epithelium, interstitium, and capillary
endothelium. We previously reported a pleural surface fluorescence method to
measure net capillary-to-airspace water transport. To measure the osmotic water
permeability across the microvascular endothelial barrier in intact lung, the
airspace was filled with a water-immiscible fluorocarbon. The capillaries were
perfused via the pulmonary artery with solutions of specified osmolalites
containing a high-molecular-weight fluorescent dextran. An increase in perfusate
osmolality produced a prompt decrease in surface fluorescence due to dye dilution
in the capillaries, followed by a slower return to initial fluorescence as
capillary and lung interstitial osmolality equilibrate. A mathematical model was
developed to determine the osmotic water permeability coefficient (Pf) of lung
microvessels from the time course of pleural surface fluorescence. As predicted,
the magnitude of the prompt change in surface fluorescence increased with
decreased pulmonary artery perfusion rate and increased osmotic gradient size.
With raffinose used to induce the osmotic gradient, Pf was 0.03 cm/s at 23
degrees C and was reduced 54% by 0.5 mM HgCl2. Temperature dependence
measurements gave an Arrhenius activation energy (Ea) of 5.4 kcal/mol (12-37
degrees C). The apparent Pf induced by the smaller osmolytes mannitol and glycine
was 0.021 and 0.011 cm/s (23 degrees C). Immunoblot analysis showed approximately
1.4 x 10(12) aquaporin-1 water channels/cm2 of capillary surface, which accounted
quantitatively for the high Pf. These results establish a novel method for
measuring osmotically driven water permeability across microvessels in intact
lung. The high Pf, low Ea, and mercurial inhibition indicate the involvement of
molecular water channels in water transport across the lung endothelium.
PMID- 9545073
TI - First hominoid from the Miocene of Ethiopia and the evolution of the catarrhine
elbow.
AB - The first known fossil ape from the early-middle Miocene of Fejej, Ethiopia, is
described here. The specimen, FJ-18SB-68, is a partial ulna from a locality dated
by 40Ar/39Ar and paleomagnetic methods to a minimum age of 16.18 MYA. Compared to
a variety of extant and fossil ulnae, FJ-18SB-68 is most similar to
Turkanapithecus, Proconsul, and Pliopithecus, and appears to have been an
arboreal quadruped with substantial forearm rotational mobility. Among the extant
ulnae, canonical variates analysis successfully discriminates platyrrhines from
catarrhines and within the latter, cercopithecoids from hominoids. Basal
catarrhines (e.g., Aegyptopithecus) are platyrrhine-like in their morphology. Two
basic trends appear to evolve from this generalized template: one with less
mobile and more habitually pronated forearms, as seen in living and fossil
cercopithecoids (including Victoriapithecus and Paracolobus), and another with
greater forearm rotational mobility in fossil and modern hominoids. Primitive
Miocene apes, including Proconsul, Turkanapithecus, and FJ-18SB-68, share with
extant hominoids a more laterally positioned and laterally facing radial notch
and an incipient trochlear keel. This morphology, along with a large insertion
area for m. brachialis, suggests a departure from the more habitually pronated
hand posture of monkeys and may indicate greater climbing abilities in these
arboreally quadrupedal apes. Later Miocene apes, such as Oreopithecus and
Dryopithecus share additional morphological features with hominoids, indicating
considerable suspensory and climbing capabilities.
PMID- 9545074
TI - Restoration of the type and palate of Ankarapithecus meteai: taxonomic and
phylogenetic implications.
AB - A small number of large hominoid specimens are known from the late Miocene of
Turkey. (This paper focuses on the two specimens known until 1996. New fossils
described by Alpagut et al. ([1996] Nature 382:349-351) are briefly discussed in
this paper as well.) Among these, a fragmentary mandible is the type specimen of
Ankarapithecus meteai. Another specimen, a partial face, is from the same taxon.
Based on the morphology of this face, Ankarapithecus meteai was synonymized with
Sivapithecus (Andrews and Tekkaya [1980], Paleontology 23:85-95). The facial
specimen was recently restored by the authors, exposing much anatomy that had
previously been obscured. The new anatomical details reveal many important
differences from Sivapithecus and justify a revision of the nomen Ankarapithecus.
Ankarapithecus was a large hominid (great apes and humans) in the clade that also
includes Sivapithecus and Pongo. Sivapithecus and Pongo share derived characters
not found in Ankarapithecus, which is thus the sister clade to the Sivapithecus
Pongo clade. While the results of this analysis support the sister relationship
of Sivapithecus and Pongo, there is some uncertainty regarding paleobiogeographic
and taxonomic relationships to the large hominids from the Siwaliks. An
Ankarapithecus-like taxon may have been ancestral to Sivapithecus, or an early
Siwalik (Chinji formation) taxon, which predates both Sivapithecus sensu stricto
and Ankarapithecus, may be ancestral to both.
PMID- 9545075
TI - EMG study of hand muscle recruitment during hard hammer percussion manufacture of
Oldowan tools.
AB - The activity of 17 hand muscles was monitored by electromyography (EMG) in three
subjects during hard hammer percussion manufacture of Oldowan tools. Two of the
subjects were archaeologists experienced in the replication of prehistoric stone
tools. Simultaneous videotapes recorded grips associated with the muscle
activities. The purpose of the study was to identify the muscles most likely to
have been strongly and repeatedly recruited by early hominids during stone tool
making. This information is fundamental to the identification of skeletal
features that may reliably predict tool-making capabilities in early hominids.
The muscles most frequently recruited at high force levels for strong precision
pinch grips required to control the hammerstone and core are the intrinsic
muscles of the fifth finger and the thumb/index finger regions. A productive
search for skeletal evidence of habitual Oldowan tool-making behavior will
therefore be in the regions of the hand stressed by these intrinsic muscles and
in the joint configurations affecting the relative lengths of their moment arms.
PMID- 9545076
TI - Positional behavior and vertebral morphology in atelines and cebines.
AB - Atelines are of particular interest to primate evolutionary studies because they
converge with hominoids in postcranial anatomy, including the vertebral column.
Currently, our understanding of ateline vertebral morphology is limited to mainly
qualitative descriptions and functional interpretations based on general
categories of positional behavior. Even less is known about the vertebrae of
other platyrrhines. This study more closely examines vertebral form and function
in atelines and cebines by combining direct field observations of axial postures
and movements, assessments of spinal loading regimes, and a detailed vertebral
morphometric analysis. Field observations (Corcovado, Costa Rica) on Ateles
geoffroyi, Alouatta palliata, Cebus capucinus, and Saimiri oerstedii were
quantified in conjunction with a morphometric analysis of ateline and cebine
lumbar vertebrae. Hylobates was also included for comparison. Compared to Cebus
and Saimiri, atelines engage more frequently in postures and locomotor behaviors
that induce pronounced bending loads on the spine. All atelines share lumbar
adaptations for resisting bending, including ventrodorsally elongated vertebral
bodies and perpendicularly oriented transverse processes. Among atelines, lumbar
region lengths and vertebral bodies are shortest in Ateles and Brachyteles,
longest in Alouatta (resembling Cebus), and intermediate in Lagothrix. Compared
to Cebus and all atelines, Saimiri has a relatively longer lumbar region, longer
and less ventrodorsally expanded vertebral bodies, and more ventrally oriented
transverse processes. These features accentuate bending loads, but increase the
sagittal flexibility required for leaping. Vertebral convergence between
hylobatids and atelines is more readily interpretable as a product of shared
spinal loading patterns than shared positional behaviors.
PMID- 9545077
TI - Morphological diversity of anatomical strepsirrhinism and the evolution of the
lemuriform toothcomb.
AB - The hypothesis that the vomeronasal organ has an important functional
relationship with, and led to the evolution of, the prosimian toothcomb has not
been well tested. This paper examines the diversity of anatomical strepsirrhinism
across several mammalian taxa to determine if fossil and living strepsirrhine
primates exhibit any derived characters that may highlight the functional link
between the vomeronasal organ and the toothcomb, and to examine the potential
importance of anatomical strepsirrhinism to toothcomb origins. Results indicate
that extant gregarious lemuriforms are derived in having a relatively wide
interincisal gap, providing an unobstructed line of communication between the
vomeronasal organ and anterior rostral structures such as the toothcomb. This
finding is consistent with the proposal that anatomical strepsirrhinism is
functionally related to use of the toothcomb in grooming. However, the importance
of the vomeronasal organ to toothcomb origins is less clear. If the morphology of
adapiforms and non-gregarious lemuriforms is representative of the morphology of
basal lemuriforms, then it can be inferred that early lemuriforms did not possess
the wide-gap autapomorphy; hence, anatomical evidence discussed here cannot be
used to rule out non-social hypotheses of toothcomb origins.
PMID- 9545078
TI - Bicoronal synostosis in a child from historic Omaha Cemetery 25DK10.
AB - Fragmentary cranial remains of a child from a commingled burial in a historic
Omaha Cemetery (AD 1780-1800) exhibit bony fusion between the frontal, parietals,
and sphenoid. The child's remains are consistent with a developmental age between
newborn and 6 months postnatal. Radiological and morphological analyses confirm
that this individual exhibits osteological signs pathognomic of bicoronal sutural
synostosis, including deformation of the lateral orbital margin. This case,
although fragmentary, significantly augments other archaeological cases of
coronal synostosis reported in the literature. In addition, an extremely large
bregmatic fontanel, expanded anterior cranial fossa, and bossed forehead compared
with undeformed individuals suggest the child also suffered from increased
intracranial pressure perhaps related to an associated hydrocephaly. Despite the
deformity, the remains of this child were treated in much the same manner as
other infant remains from the site, including the presence of red mercury pigment
on the skeletal remains.
PMID- 9545079
TI - Finger ridge-count asymmetry and diversity in Andean Indians and interpopulation
comparisons.
AB - A separate analysis of ulnar and radial finger ridge-counts, obtained from 115
Aymara Indians (55 males and 60 females) of northern Chile, was performed. From
these variables, directional asymmetry, fluctuating asymmetry, indices of
bilateral asymmetry (square root of A2), and intraindividual diversity (s/square
root of 5) were calculated for each sex. The results show that most bimanual
differences for the ridge-counts are not statistically significant in the Aymara,
except for radial counts in female first and second fingers (right hand means are
larger), while most ulnar-radial differences are highly significant in both sexes
(radial values exceed ulnar ones). Most sex differences do not reach statistical
significance, although males have more ridge-counts, lower directional asymmetry,
somewhat lower fluctuating asymmetry, and lower indices of asymmetry and
diversity than females. As fluctuating asymmetry is not larger in males, the
dermatoglyphic findings do not indicate support for the hypothesis that males are
less canalized than females. In accordance with the findings of other authors,
interpopulation comparisons in the indices of asymmetry and diversity show ethnic
differences. Both indices tend to be low in samples of African ancestry, high in
samples of European origin, and intermediate in the Aymara, while Indian groups
are characterized by high asymmetry and low diversity values. Moreover, the data
reveal a geographical trend in that asymmetry and diversity values tend to
decrease from the northern to the southern hemisphere in populations of Europe,
the Middle East, and Africa, thus indicating greater ridge-count variability and
heterogeneity among fingers in northern populations. It is assumed that this
gradient primarily reflects different degrees of miscegenation and
heterozygosity.
PMID- 9545080
TI - Technical note: chromosomal and mtDNA analysis of Oliver.
AB - Oliver is an African ape whose species identity has been debated in the popular
media and by various scientists since the early 1970s. Although decisive
morphological data has never been adduced on Oliver, many reports indicated that
Oliver was morphologically unusual for a chimpanzee, particularly in his habitual
bipedal posture. In addition, his diploid chromosome number was reported to be
inconsistent with either human or chimpanzee, but instead intermediate between
those species. We performed standard chromosomal studies which demonstrated that
Oliver had the diploid number expected for a chimpanzee (2N = 48) and that the
banding patterns of his chromosomes were typical for a chimpanzee and different
from both humans and bonobos. We also sequenced a 312 bp region of his
mitochondrial DNA D-loop region. Results indicated a high sequence homology to
the Central African variety of chimpanzee, Pan troglodytes troglodytes. The
highest percent homology was observed with a previously characterized specimen
from Gabon, strongly suggesting that Oliver originated from this region.
PMID- 9545081
TI - How is membrane phospholipid biosynthesis controlled in neural tissues?
AB - Phospholipids are the major constituents of cell membranes, and have numerous
structural and functional roles in the nervous system. Although the metabolic
pathways responsible for the syntheses of the phosphatides phosphatidylcholine
(PtdCho), phosphatidylethanolamine (PtdEtn), and phosphatidylserine (PtdSer) are
well understood, the mechanisms controlling these pathways in neural tissue have
not been fully characterized. Recent studies have suggested that the main factors
controlling PtdCho and PtdEtn synthesis by the Kennedy cycle tend to be the
intracellular levels of key substrates for the biosynthetic enzymes, or changes
in the activities of the rate-limiting enzymes. Moreover, different control
mechanisms may operate, depending upon the functional state of the tissue.
PMID- 9545082
TI - Cell culture models for reactive gliosis: new perspectives.
AB - Reactive gliosis, which occurs in response to any damage or disturbance to the
central nervous system, has been recognized for many years, but is still not
completely understood. The hallmark is the increased expression of glial
fibrillary acidic protein (GFAP), yet studies in GFAP knockout mice suggest that
GFAP may not be required for an astrocyte to become hypertrophic. In this review,
we describe a series of tissue culture models that have been established in order
to address: 1) the biochemical phenotype of reactive astrocytes; 2) the factor
and/or cell responsible for induction of gliosis; 3) the mechanisms by which one
might block the induction. These models range from cultures of astrocytes, both
neonatal and adult, to co-cultures of astrocytes with either neurons or
microglia, to organ cultures. None is ideal: each addresses a different set of
questions, but taken together, they are beginning to provide useful information
which should allow a better understanding of the plasticity response of
astrocytes to brain injury.
PMID- 9545083
TI - Stimulation of L-type Ca2+ channel in growth cones activates two independent
signaling pathways.
AB - Although growth cones respond to various modulators of neurite outgrowth, such as
neurotrophins, neurotransmitters, and cell adhesion molecules, the signal
transducing mechanisms for these modulators in growth cones are unclear. Since
recent studies have suggested that the signals of these modulators are mediated
by Ca2+ influx through L-type voltage-sensitive Ca2+ channels (VSCCs) in the
growth cone, we examined L-type VSCC-dependent signaling pathways, using isolated
growth cones (IGCs) from developing rat forebrains. Binding assays revealed that
L-type VSCC is enriched in growth cone membrane and gradually decreased in amount
developmentally, while N-type VSCC has the opposite tendency. In intact IGCs, Bay
K 8644 (BK, an L-type agonist) induced much more rapid elevation of [Ca2+]i than
that in adult synaptosomes. Ca2+-dependent phosphorylation of GAP-43 and MARCKS
protein by protein kinase C (PKC) was enhanced in the IGC by BK, resulting in the
release of these proteins from the membrane, which is consistent with our recent
report. In addition, the Ca2+-dependent degradation of brain spectrin (fodrin) by
calpain was also enhanced by BK or GABA, consequently inducing the release of
alpha-actinin from the membrane skeleton of the growth cones. The activities of
PKC and calpain were not inhibited by inhibitors of the other, indicating that
these reactions occur independently. Our results suggest that Ca2+ influx through
L-type VSCCs activates two distinct signaling branches, probably in the different
domains of the growth cone, i.e., Ca2+-dependent phosphorylation of GAP-43 and
MARCKS protein, and Ca2+-dependent degradation of brain spectrin and the release
of alpha-actinin by calpain.
PMID- 9545084
TI - Granule cells of the internal granule layer have increased expression of GABA(A)
receptor beta 2/beta 3 subunits.
AB - We have examined the expression of GABA(A) receptor beta 2/beta 3 subunits from
postnatal day 4 (P4) to P23. beta 2/beta 3 subunits are not detected in
premigratory granule cells. Expression of beta 2/beta 3 was also low in granule
cells found in the internal granule layers (IGLs) of P7 and P10 cerebella.
However, between P10 and P16, the levels of beta 2/beta 3 increase substantially
and reach high levels at P16-23. Because granule cells continue to migrate from
the external granule layer (EGL) into the IGL after P10, this increase in the
number of cells and the intensity of beta 2/beta 3 expression could be the result
of a second wave of granule cells expressing beta 2/beta 3 that have migrated
from the EGL. To test this hypothesis, migrating granule cells after P10 were
eliminated by gamma-irradiation. Despite elimination of migrating granule cells,
beta2/3 expression remained high in the IGLs of P16 irradiated animals similar to
that observed in non-irradiated controls, suggesting that the increase of beta
2/beta 3 is not due to the arrival of a new population of granule cells
expressing GABA(A) receptors. To explore the possibility that the increase of
beta2/beta 3 is triggered by synaptic activity, we cultured P10 cerebellar
sections, free of mossy fiber inputs, for 6 days in vitro. As observed in vivo,
beta 2/3 expression in the IGL of cultured slices continued to increase,
suggesting that beta 2/3 expression could be triggered without synaptic inputs
from mossy fibers.
PMID- 9545085
TI - Bipotential roles of ceramide in the growth of hippocampal neurons: promotion of
cell survival and dendritic outgrowth in dose- and developmental stage-dependent
manners.
AB - Ceramide is now regarded as a lipid messenger molecule involved in a variety of
cellular processes, including growth, differentiation, and cell death.
Previously, we demonstrated that ceramide is required for cell survival and
dendritic growth of cerebellar Purkinje neurons (Furuya et al.: J Neurochem 65:
1551-1561, 1995). Here, we show that ceramide plays growth-supportive roles in
hippocampal neurons at immature stages of development. Application of cell
permeable N-hexanoyl-D-erythro-sphingosine (C6-ceramide) at a concentration of 3
microM promoted cell survival and dendritic outgrowth of the immature neurons. A
structurally related compound, N-hexanoyl-D-erythro-dihydrosphingosine (C6
dihydroceramide), was ineffective, showing a requirement of 4-5 double bonds in
the sphingosine moiety for activity. Incorporation of 5-bromo-2'-deoxyuridine
into neurons was not altered by the treatment with C6-ceramide, indicating that
C6-ceramide did not facilitate neuronal proliferation but protected hippocampal
neurons against basal cell death. The survival-promoting activity of C6-ceramide,
however, appeared to be biphasic; C6-ceramide at a concentration of 10 microM
caused retraction of the dendrites and detachment of the neurons from the culture
plate followed by cell death. In contrast to the immature neurons, the treatment
of mature hippocampal neurons with C6-ceramide did not support cell survival but
caused nonnecrotic cell death, even at a concentration of 3 microM. These results
suggest strongly that ceramide regulates the fate of hippocampal neurons,
depending on its concentration and on the developmental stage.
PMID- 9545086
TI - Axonal regrowth through a collagen guidance channel bridging spinal cord to the
avulsed C6 roots: functional recovery in primates with brachial plexus injury.
AB - Intraspinal implantation of a collagen guidance channel (CGC) to promote axon
regeneration was investigated in marmosets with brachial plexus injury. After
avulsion of the right C5, C6 and C7 spinal roots, a CGC containing (group B) or
not (group A) a nerve segment, or a nerve graft (group C), was ventro-laterally
implanted into the cord to bridge the ventral horn and the avulsed C6 roots. No
spinal cord dysfunction was observed following surgery. Two months later, the
postoperative flaccid paralysis of the lesioned arm improved. In five months, a
normal electromyogram of the affected biceps muscle was recorded in all repaired
animals. Motor evoked potentials were obtained with a mean amplitude of 13.37 +/-
13.66 microV in group A, 13.21 +/- 5.16 microV in group B and 37.14 +/- 35.16
microV in group C. The force of biceps muscle contraction was 27.33 +/- 20.03 g
(group A), 24.33 +/- 17.03 g (group B) and 37.38 +/- 21.70 g (group C).
Retrograde tracing by horseradish peroxidase showed labelled motoneurons
ipsilaterally located in the C5 and C6 ventral horn, nearby the implantation
site. The mean labelled neurons was 32.33 +/- 21.13, 219.33 +/- 176.29 and 64.33
+/- 23.54 in group A, B and C respectively. Histological analysis presented
numerous myelinated and unmyelinated regenerating axons in the implant of these
animals. Statistical analysis did not show significant difference among the three
repaired groups. Our results indicate that spinal neurons can regenerate through
a CGC to avulsed nerve roots and induce motor recovery in primates.
PMID- 9545087
TI - Differential distribution of beta-dystroglycan in rabbit and rat retina.
AB - The distribution of the dystrophin-associated glycoprotein complex was
investigated in rabbit and rat retina by using the monoclonal antibody 43DAG/8D5,
which specifically recognizes beta-dystroglycan, a central component of the
complex. In cryostat sections of retinae from both species, the authors observed
staining of blood vessels, continuous labeling around the vitreal border, and
strong immunoreactivity in the outer plexiform layer (OPL). Electron microscopy
showed that the immunoreactivity associated with the vitreal border of the retina
was the result of a subcellular concentration of beta-dystroglycan in the endfeet
of Muller glial cells. A similar concentration was observed in endfeet of
perivascular astrocytes in the region of contact with the capillary basal lamina.
In the OPL, beta-dystroglycan was associated with the terminals of both rods and
cones. The label was almost exclusively found outside the synaptic area and was
particularly strong in the extensions of the photoreceptor terminals protruding
into the OPL. In the OPL of the rabbit retina, the authors found additional
immunoreactivity associated with the tips of postsynaptic horizontal and bipolar
cell processes. These results show that the dystrophin-associated glycoprotein
complex is subcellularly concentrated in photoreceptor terminals and glial cell
endfeet, and that the rabbit retina differs from the rat retina by the additional
expression of this complex in bipolar and horizontal cells.
PMID- 9545088
TI - Mechanical injury to neuronal/glial cultures in microplates: role of NMDA
receptors and pH in secondary neuronal cell death.
AB - In vitro models of traumatic injury are useful adjuncts to animal models for
studying mechanisms of post-traumatic cell death. Here we describe a new in vitro
model in which reproducible levels of injury are delivered by a punch device that
produces 28 parallel cuts in individual wells of 96-well microplates. Cell loss
is measured by LDH assay or quantitative fluorometric assay for ethidium
homodimer staining. Glial cultures show cell death restricted to the initial
injury site, whereas neuronal/glial cultures demonstrate substantial spread of
cell loss over time. We used this model to examine the role of pH and NMDA
receptors in delayed post-traumatic injury. NMDA receptor blockade by dizocilpine
(MK-801) or treatment with antisense oligodeoxynucleotides directed against
NMDAR1 was neuroprotective. Decreased cell death was observed under acidic
conditions whereas increased extracellular pH was associated with increased, MK
801 sensitive cell loss. Advantages of our model include: reproducible trauma
induction; rapid measurements of cell injury; and use of 96-well microplates
which reduce time and cost. This model appears to be well-suited for the study of
selected mechanisms of post-traumatic neuronal injury as well as for screening
potential neuroprotective agents.
PMID- 9545089
TI - TCR repertoire and cytokine profiles of cerebrospinal fluid- and peripheral blood
derived T lymphocytes from patients with multiple sclerosis.
AB - The cerebrospinal fluid (CSF) represents an important source of T lymphocytes
that could be involved in the inflammatory response occurring in the central
nervous system in multiple sclerosis (MS). In order to investigate whether the
Vbeta gene usage of CSF T lymphocytes is restricted, we analyzed the TCR Vbeta
expression in twelve CSF expanded by in vitro culture compared to the paired in
vitro-stimulated peripheral blood T lymphocytes. The overexpression of one or two
Vbeta genes was demonstrated in ten CSF, but the type of Vbeta over expressed
varied from one patient to another. For one patient, the Vbeta repertoire was
also investigated by single cell cloning. High frequency of BV6S7-expressing T
cell clones was observed in the CSF while no BV6S7 clone was derived from the
peripheral blood T lymphocytes suggesting that these cells could be involved in
the immunopathological process in the central nervous system (CNS). The cytokine
patterns of the T cell clones derived from the CSF- and peripheral blood-T
lymphocytes of this patient were determined. The CSF T cell clones produced
higher levels of cytokines than the peripheral blood T cell clones. The high
frequency of IL-4-producing-T cell clones observed in CSF demonstrate that T
cells which could downregulate the inflammatory process are present in the CNS.
PMID- 9545090
TI - PCR detection of Y-specific sequences in patients with Ullrich-Turner syndrome:
clinical implications and limitations.
AB - Cytogenetic analysis of patients with Ullrich-Turner syndrome (UTS) may fail to
detect low levels of Y chromosome mosaicism or Y-derived marker chromosomes. More
sensitive polymerase chain reaction (PCR)-based tests have been developed;
however, applicability of these data to prognosis of virilization and
gonadoblastoma development has not been investigated adequately. We used a
multiplex PCR-based method to detect two Y-specific sequences, SRY and AMGLY.
Thirteen patients with UTS without cytogenetically detected Y chromosomes were
studied. Y-specific sequences were detected in 5 patients by multiplex PCR. A
cryptic translocation involving the Y chromosome was found in one patient with
severe virilization of external genitalia and a male phenotype. Y chromosomal
mosaicism was detected in peripheral blood and in both gonads of one patient, and
only in the left gonad of another patient. Existence of a Y-derived marker was
demonstrated in 2 patients, one of whom had no testicular tissue or virilization.
Consistent with previous reports, we conclude that PCR is more sensitive than
classical cytogenetic analysis and detects patients with Y-specific sequences in
blood cells. However, the absence of Y-specific material in blood is not a
sufficient reason to reject surgical treatment in case of virilization.
PMID- 9545091
TI - Sweat electrolyte and cystic fibrosis mutation analysis allows early diagnosis in
Brazilian children with clinical signs compatible with cystic fibrosis.
AB - A total of 540 individuals with clinical signs suggestive of cystic fibrosis (CF)
was studied. The sweat chloride was measured and the DF508, G542X, R553X, and
W1282X mutations of the CF gene were screened by polymerase chain reaction (PCR).
With this approach the diagnosis of CF was confirmed in 12 children, while 7
additional cases, who are heterozygous for the DF508 mutation, have had minor
clinical signs. The frequency of the DF508 allele among the 540 individuals was
approximately 3%. The mean age of children diagnosed with CF was 1.81 years,
which is significantly earlier than in other studies of the Brazilian population.
We also demonstrated that this approach has important clinical implications for
earlier and adequate treatment, which was shown to be fundamental for increasing
significantly the quality of life and life expectancy. This is particularly true
in countries such as Brazil where most CF cases remain undiagnosed, mainly in
families of low socio-economical status.
PMID- 9545092
TI - Errors of morphogenesis and developmental field theory.
AB - Field theory provides a rational basis for birth defects terminology. During
blastogenesis in higher metazoa, pattern formation in the primary field leads to
the establishment of upstream expression domains of growth and transcription
factors, which, in various permutations and at specific sites and times, lay down
the pattern of progenitor fields. Further spatially coordinated, temporally
synchronized, and epimorphically hierarchical morphogenetic events, mostly during
organogenesis, lead to the attainment of final form in the secondary, epimorphic
fields. Because of shared molecular determinants, spatial contiguity, and close
timing of morphogenetic events during blastogenesis, most malformations arising
during blastogenesis are polytopic, i.e., involving two or more progenitor
fields, e.g., acrorenal, cardiomelic, gastromelic, or splenomelic anomalies.
Defects of organogenesis tend to be monotopic malformations, e.g., cleft palate
or postaxial polydactyly. We suggest that what were called "associations" (e.g.,
VATER, schisis) be designated primary polytopic developmental field defects, or
simply polytopic field defects, and that the term "association" be reserved for
the original definition of a statistical combination of anomalies (mostly of
organogenesis) [Spranger et al. (1982): J Pediatr 100:160-165]. If genetically
caused or predisposed, all structures involved in a polytopic or monotopic
malformation are genetically abnormal, whereas the parts secondarily affected as
a consequence of a malformation sequence (e.g., spina bifida) are genetically
normal. Polytopic field anomalies, per se, must be distinguished from pleiotropy,
although such anomalies may constitute a part of pleiotropy (e.g., in trisomy
18). Because they are downstream from pattern-forming events in the primary
field, multiple anomalies of organogenesis more likely represent syndromal
pleiotropy.
PMID- 9545093
TI - Correlated heart/limb anomalies in Mendelian syndromes provide evidence for a
cardiomelic developmental field.
AB - Coordinated development of heart and limbs is suggested by a review of human
abortus, chromosomal, and teratogenic syndromes, and characterized by an analysis
of Mendelian disorders that affect the limbs, heart, or both (672, 202, or 107,
respectively). Mendelian syndromes with altered limb patterns often include
cardiac anomalies, as shown by limb duplications (34%), deficiencies (30%),
hypoplasias (23%), or dysplasias (9.3%). Syndromes with particular cardiac
anomalies, illustrated by VSD (85%) or ASD (90%), frequently include limb
defects. Positional correlations of anterior (preaxial/conotruncal), posterior
(postaxial/atrial), or lateral (mirror hand/atrial isometry) heart/limb anomalies
are consistent with the existence of a cardiomelic developmental field.
Vertebrate comparisons suggest an early D-V limb-heart gradient, influenced by
the neural crest, with distal limb segments (80% of syndromic defects) at its
dorsal extreme. The proposed cardiomelic field relates the genetic heterogeneity
of disorders such as Holt-Oram syndrome to a cascade of molecules, including the
brachyury, sonic hedgehog, bone morphogenetic protein, retinoic acid receptor,
and transforming growth factor-beta families.
PMID- 9545094
TI - Complex familial rearrangement of chromosome 9p24.3 detected by FISH.
AB - We describe a newborn male with minor facial anomalies, pyloric stenosis, and a
chromosome rearrangement that involves deletion and addition of material at
9p24.3. Routine studies showed a 46, XY, add (9) (p24) karyotype. Fluorescence in
situ hybridization (FISH) with two different whole chromosome probes for
chromosome 9 failed to identify whether the additional material was derived from
that chromosome. FISH with single copy YAC probes from 9p24 (D9S1858, D9S1813 and
D9S54) showed a more complex rearrangement involving a deletion at D9S1858 but
not at D9S1813 or D9S54. Parental chromosome studies demonstrated an apparently
identical 9p abnormality in the patient's mother. This report describes a
familial chromosome rearrangement in an abnormal child and his normal mother and
demonstrates the use and limitations of FISH in characterizing chromosomal
abnormalities.
PMID- 9545095
TI - Lack of association between mutations in the folate receptor-alpha gene and spina
bifida.
AB - Defects of neural tube closure are among the most common of all human
malformations. Epidemiological and genetic studies indicate that most of these
defects are multifactorial in origin with genetic and environmental causes.
Although periconceptional supplementation of the maternal diet with folic acid
has been shown to reduce the recurrence and occurrence of neural tube defects
(NTDs) by up to 70%, the underlying mechanism remains unknown. Folic acid enters
cells of certain tissues via a receptor-mediated process known as potocytosis.
The folate receptor alpha (FR-alpha) gene codes for the protein responsible for
binding folate, which is the first, and only, folate-dependent step in folate
transport. The FR-alpha exons, which code for mature protein and the intron-exon
boundaries, were examined for mutations in three separate studies. Initial
screening was performed by single-stranded conformational polymorphism (SSCP)
analysis in a subset of 1,688 samples obtained from a population-based case
control study of NTDs in California. In the second study, the DNA sequence of
exons 5 and 6 was determined in a group of 50 NTD affected individuals. The final
experiment involved using dideoxy fingerprinting (ddF) to screen a population
based case-control sample of 219 individuals who were stratified into four sub
groups on the basis of folate intake and pregnancy outcome. No polymorphism was
detected in any of the four exons examined. It is unlikely that the beneficial
effects of maternal folate supplementation in preventing NTDs acts through a
mechanism involving pharmacological correction of a variant form of folate
receptor alpha.
PMID- 9545096
TI - A multicenter investigation with interphase fluorescence in situ hybridization
using X- and Y-chromosome probes.
AB - Twenty-six laboratories used X and Y chromosome probes and the same procedures to
process and examine 15,600 metaphases and 49,400 interphases from Phaseolus
vulgaris-leucoagglutinin (PHA)-stimulated lymphocytes. In Part I, each laboratory
scored 50 metaphases and 200 interphases from a normal male and a normal female
from its own practice. In Part II, each laboratory scored 50 metaphases and 200
interphases on slides prepared by a central laboratory from a normal male and a
normal female and three mixtures of cells from the male and female. In Part III,
each laboratory scored 50 metaphases (in samples of 5, 10, 15, and 20) and 100
interphases (in samples of 5, 10, 15, 20, and 50) on new, coded slides of the
same specimens used in Part II. Metaphases from male specimens were scored as 98
99% XY with no XX cells, and 97-98% of interphases were scored as XY with 0.04%
XX cells. Metaphases from female specimens were scored as 96-97% XX with 0.03% XY
cells, and 94-96% of interphases were scored as XX with 0.05% XY cells.
Considering the data as a model for any probe used with fluorescence in situ
hybridization (FISH), a statistical approach assessing the impact of analytical
sensitivity on the numbers of observations required to assay for potential
mosaicisms and chimerisms is discussed. The workload associated with processing
slides and scoring 50 metaphases and 200 interphases using FISH averaged 27.1 and
28.6 minutes, respectively. This study indicates that multiple laboratories can
test/develop guidelines for the rapid, efficacious, and cost-effective
integration of FISH into clinical service.
PMID- 9545098
TI - Identification of heterozygotic carriers of 21-hydroxylase deficiency:
sensitivity of ACTH stimulation tests.
AB - Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is a common
autosomal-recessive disorder. To ascertain carrier status, adrenocorticotropin
(ACTH) stimulation tests are often used. To determine the sensitivity of ACTH
stimulation to detect heterozygotes and to correlate stimulated 17
hydroxyprogesterone responses with molecular genotype, we compared molecular
genetic analysis of the 21-hydroxylase (CYP21) gene with 17-hydroxyprogesterone
responses at 30 min in 51 individuals. Molecular genotype analysis and ACTH
stimulation tests were performed in healthy volunteers (n = 20) and relatives of
patients with congenital adrenal hyperplasia (n = 31). Polymerase chain reaction
(PCR) amplification, single-strand conformational polymorphism (SSCP) analysis,
allele-specific oligonucleotide hybridization (ASOH) analysis, and restriction
fragment length polymorphism (RFLP) analysis were utilized to screen for 14 CYP21
mutations which account for >90% of the mutations associated with 21-hydroxylase
deficiency. Molecular genotype analysis classified 28 individuals as
heterozygotic carriers and 23 individuals as normal for all mutations tested. As
a group, the heterozygotes had significantly greater stimulated 17
hydroxyprogesterone responses at 10 and 30 min (P < 0.0005). However, on an
individual basis, 14/28 (50%) genotyped heterozygotic carriers had stimulated 17
hydroxyprogesterone concentrations, 17-hydroxyprogesterone/cortisol ratios, and
17-hydroxyprogesterone incremental elevations indistinguishable from the
genotyped normal individuals. Thus, a normal 17-hydroxyprogesterone response to
ACTH stimulation testing does not exclude carrier status for 21-hydroxylase
deficiency. Molecular genotype analysis is a more reliable method to determine 21
hydroxylase heterozygotes.
PMID- 9545097
TI - Autism and maternally derived aberrations of chromosome 15q.
AB - Of the chronic mental disabilities of childhood, autism is causally least well
understood. The former view that autism was rooted in exposure to humorless and
perfectionistic parenting has given way to the notion that genetic influences are
dominant underlying factors. Still, identification of specific heritable factors
has been slow with causes identified in only a few cases in unselected series. A
broad search for genetic and environmental influences that cause or predispose to
autism is the major thrust of the South Carolina Autism Project. Among the first
100 cases enrolled in the project, abnormalities of chromosome 15 have emerged as
the single most common cause. The four abnormalities identified include deletions
and duplications of proximal 15q. Other chromosome aberrations seen in single
cases include a balanced 13;16 translocation, a pericentric inversion 12, a
deletion of 20p, and a ring 7. Candidate genes involved in the 15q region
affected by duplication and deletion include the ubiquitin-protein ligase (UBE3A)
gene responsible for Angelman syndrome and genes for three GABA(A) receptor
subunits. In all cases, the deletions or duplications occurred on the chromosome
inherited from the mother.
PMID- 9545099
TI - Caroline Crachami, the Sicilian dwarf (1815-1824): was she really nine years old
at death?
AB - Caroline Crachami (C.C.) considered to have had the Seckel syndrome was one of
the most extreme cases of dwarfism ever recorded. Reputedly born in Sicily in
1815, she attracted much attention when exhibited in England before her death on
3 June 1824. Although she is said to have been 9 years old at death, published
descriptions give her a dental age varying from 2 to 7 years. Examination of her
skull in the Royal College of Surgeons of England demonstrated a more or less
erupted complete deciduous dentition, with no erupted permanent teeth.
Radiographs showed agenesis of several permanent teeth. It was concluded that the
dental age of C.C. was 3 years (+/- 6 months). Perikymata were evident in the
surface enamel encircling the crown of the partially exposed maxillary left first
permanent molar. Their distribution and spacing were normal, with no evidence of
developmental retardation. The distance between the periradicular bands in the
root near the cement-enamel junction was also normal. We conclude that the dental
age of C.C. was similar to her chronological age and that at death she was about
3 and not 9 years old. The reason that she was said to be nearly 9 when exhibited
in England we believe was related to financial considerations, as people would be
generally less impressed with a dwarf only 3 years old. The new age we give C.C.
has implications on the diagnosis of her medical condition.
PMID- 9545100
TI - A growth on the tip of the nose, small appendages on both fifth fingers, and a
sign from heaven in a child born in 1738.
PMID- 9545102
TI - (Mis)classifying limb deficiencies: Reply to "Academicians are more likely to
share each other's toothbrush than each other's nomenclature (Cohen, 1982)".
PMID- 9545101
TI - Delineation of supernumerary marker chromosomes in 38 patients.
AB - We present cytogenetic and clinical data on 38 patients with supernumerary marker
chromosomes (SMCs). SMCs were characterized using a strategy combining classical
banding techniques and molecular cytogenetic studies. Cases were ascertained
prenatally, postnatally, and after fetal death. In 26 patients (68%), the SMC
originated entirely from acrocentric chromosomes. Among these, most patients
carried a der(15). In 11 patients (29%), they were of nonacrocentric origin,
including 9 autosomal and 2 gonosomal marker chromosomes. In 1 patient the SMC
was of partially acrocentric origin. Patients with small derivatives of
chromosome 15 [der(15)] had a normal phenotype. Those with a larger der(15)
showed phenotypical abnormalities. Patients with supernumerary marker chromosomes
derived from chromosomes 13 or 21, and 14 appeared to have a low risk of
abnormalities. Out of this group only 1 patient who carried an additional r(21)
had physical anomalies. Patients with an SMC originating from chromosome 22
showed physical abnormalities in 2 out of 6 cases. Supernumerary marker
chromosomes identified as i(9p), i(12p), and der(18) were all associated with an
abnormal phenotype. Two of the derivatives of chromosome 20 analyzed were
correlated with a normal phenotype, while the carrier of the third one showed
physical anomalies and motor retardation. Of 2 patients with an extra der(X), 1
was normal and 1 showed an abnormal phenotype.
PMID- 9545103
TI - FGFR2 gene mutation (Tyr375Cys) in a new case of Beare-Stevenson syndrome.
PMID- 9545104
TI - Mosaic trisomy 18 male with normal intelligence who fathered a normal baby girl.
PMID- 9545105
TI - Chronic thyroiditis as a favorable prognostic factor in papillary thyroid
carcinoma.
AB - A subgroup of patients with papillary thyroid carcinoma (PTC) also has chronic
thyroiditis (CT) as an associated disease of the thyroid. To assess the
prognostic value of CT in patients with PTC, we reviewed the histological slides
of 2225 patients with PTC who had undergone surgery between 1971 and 1992. Of the
2225 patients, 692 were excluded from the analysis because regional lymph nodes
and/or nonneoplastic thyroid tissues were unavailable for histological
assessment. The series included 281 patients with CT in nonneoplastic thyroid
tissue and 1252 without CT. We performed statistical analyzes by the log-rank
test and Cox's proportional-hazard method. Sixty-two (5.0%) of the 1252 patients
without CT died of metastatic disease during the follow-up period and the relapse
free 10-year survival rate was 85%. By contrast, only 2 (<1.0%) of the 281
patients with CT died, and their relapse-free 10-year survival rate was 95%. The
difference between patients with CT and those without CT in terms of relapse-free
and overall survival was statistically significant (p < 0.0001). Risk factors for
unfavorable outcome were age 45 years or more, absence of psammoma bodies, and
absence of CT (p < 0.0001), followed by vascular invasion (p = 0.0007), male sex
(p = 0.0013), and metastasis to regional lymph nodes (p = 0.047). Multivariate
analysis indicated that all of these factors with the exception of gender were
independent factors in the final model for overall survival. Chronic thyroiditis
in the nonneoplastic thyroid of patients with PTC is a powerful prognostic factor
for both relapse-free and overall survival.
PMID- 9545106
TI - mRNA levels of membrane-type 1 matrix metalloproteinase (MT1-MMP), MMP-2, and MMP
9 and of their inhibitors TIMP-2 and TIMP-3 in normal thyrocytes and thyroid
carcinoma cell lines.
AB - Thyroid cancer can degrade basement membranes and invade tissues. This depends on
a cascade of matrix metalloproteinases involving membrane-type 1 matrix
metalloproteinase (MT1-MMP), MMP-2, and MMP-9. We analyzed the expression and
role of these MMPs and their specific inhibitors TIMP-2 and TIMP-3 in human
highly purified thyroid epithelial, C 643, HTh 74, SW 1736, and 8505 C thyroid
carcinoma and thyroid-derived fibroblast cell cultures. The effect of phorbol
myristate acetate (PMA), and of the inflammatory cytokines interleukin-1 (IL-1)
and tumor necrosis factor-alpha (TNF-alpha) on MMP and TIMP mRNA levels were
monitored by semiquantitative reverse transcriptase-polymerase chain reaction (RT
PCR) including an internal homologous competitor fragment. The highest MT1-MMP
mRNA levels were found in thyroid-derived fibroblasts. The MT1-MMP mRNA
expression was increased up to 10-fold by PMA, while all other growth factors
tested had only negligible effects. The thyroid carcinoma cells themselves did
not seem to play a crucial role in the production of MT1-MMP in thyroid tumors.
Higher MMP-2 mRNA levels were found in all cell types investigated. The highest
MMP-2 mRNA levels were determined in thyroid-derived fibroblasts and HTh 74
cells. We found a lack of MMP-2 response to IL-1, TNF-alpha, and phorbol esters.
In unstimulated cells, MMP-9 mRNA was found near the detection limit or at low
levels. In nearly all cell types, treatment with PMA, IL-1, and TNF-alpha caused
an increase of the MMP-9 mRNA levels. The results of basal and stimulated MMP-2
and MMP-9 mRNA expression were confirmed at the protein level by gelatin
zymography. TIMP-2 and TIMP-3 mRNAs were expressed at high levels. In contrast to
the basal TIMP-3 mRNA levels, which varied over a great range, there were no
striking differences the cell types from analyzing TIMP-2 mRNA. There were no or
only slight stimulatory effects on TIMP-2 and TIMP-3 mRNA expression by IL-1, TNF
alpha, and PMA. Taken together, most enzymes of the MT-MMP/MMP class of proteases
facilitating invasion of thyroid tumor cells seem to have been produced by
fibroblasts, not by the tumor cells themselves. However, some dedifferentiated
thyroid tumor cell lines may be capable of secreting some of these enzymes, as in
the case of HTh 74 cells.
PMID- 9545107
TI - Treatment of micronodular lung metastases of papillary thyroid cancer: are the
tumors too small for effective irradiation from radioiodine?
AB - Our purpose was to determine if micronodular lung metastases from papillary
thyroid cancer had diameters that were less than 1 mm and therefore of a size for
which irradiation by radioiodine (131I) is inefficient. In five patients, lung
metastases seen on computed tomography (CT) were enumerated and sized in the
entire right lung and right upper lung giving volumes of measurable, ie, more
than 1 mm diameter, tumors. Concentrations of diagnostic 131I were quantified
scintigraphically in the same regions. Fractions of administered 131I per
milliliter of tumor and the absorbed radiation from the subsequent treatments
were calculated to see if the 131I levels in lungs were greater than expected for
the visible tumor volumes. Two other patients manifesting similar findings had
lung biopsies that were reviewed for size of metastases. The calculated fractions
of administered activity per milliliter of tumor and the absorbed radiations from
the treatments with 131I were exceptionally high. Biopsies revealed numerous
tumors below the resolution of CT. We conclude that the fractions of administered
activity and absorbed radiations of 131I in tumors were high because the measured
tumor volumes underestimated the total tumor volumes. Many lung metastases were
less than 1 mm in diameter.
PMID- 9545108
TI - Changes in the thyroid technetium-99m scintigram after antithyroid and subsequent
radioiodine treatment for solitary autonomous nodules.
AB - In patients with solitary autonomous thyroid nodules, the treatment of choice is
radioiodine (131I) therapy, eventually preceded by antithyroid drugs to avoid
aggravation of hyperthyroidism. The aim of this study was to evaluate the
scintigraphical results of 131I treatment when using antithyroid pretreatment.
Twenty-four patients having a solitary autonomous thyroid nodule were studied. A
technetium-99m (99mTc) pertechnetate scintigraphy was performed at the time of
diagnosis, when serum thyrotropin (TSH) had been normal for about 3 months on
antithyroid drug treatment, and finally when serum TSH was normalized after 131I
treatment. The primary scintigram showed suppression of 99mTc pertechnetate in
the paranodular thyroid tissue in all patients. The second scintigram showed
normal uptake in the paranodular tissue in 22 patients and a continuing
suppression of the paranodular tissue in 2 patients. The third scintigram showed
a solitary adenoma in 14 patients with none or almost no uptake in the
paranodular tissue, resembling the first scintigram. In 6 patients an adenoma was
still present, but uptake was seen in the paranodular tissue; in 3 patients a
homogenous uptake without any sign of the previous nodule, and in 1 patient very
low uptake in the gland was seen. Four patients developed hypothyroidism in the
follow-up period of approximately 1 year. Pretreatment with antithyroid drugs
induced an increase in serum TSH, stimulating the paranodular tissue. 131I will
therefore be distributed in the whole thyroid gland, and not only in the
autonomous solitary nodule. After 131I treatment, we continuously found a
solitary nodule with low uptake in the paranodular tissue in 20 of 24 patients.
PMID- 9545109
TI - Induction of oral tolerance in human autoimmune thyroid disease.
AB - Our laboratory has reported suppression of experimental autoimmune thyroiditis in
mice by oral feeding with antigen. Based on these data, we considered it possible
that oral feeding of animal thyroglobulin (TG) might induce tolerance to antigen
in human autoimmune thyroid disease (AITD). Thirteen patients receiving thyroid
hormone replacement with synthetic thyroxine (T4) (five patients with Graves'
disease, treated with radioiodine 4 to 11 years ago and eight patients with
Hashimoto's thyroiditis) were randomly assigned to a test group (switched to
replacement with desiccated thyroid from porcine thyroids) and a control group
(maintained on synthetic T4). Humoral and cellular immunologic parameters were
evaluated in addition to clinical parameters before and every 3 months after the
onset of study for a year. At the onset of study, there was no difference in
clinical parameters, or humoral and cellular immunity to thyroid autoantigens,
except a finding that one thyroid peroxidase (TPO) peptide (100 approximately
119) appeared to stimulate peripheral blood mononuclear cells (PBMC) during in
vitro microproliferation assay more in the test group than control group (p =
0.051 by t test). Additionally, almost all of TPO and thyrotropin receptor
extracellular domain (TSHR) peptides were slightly more stimulatory to PBMC from
the test group than the control group, although this was not statistically
significant. After treatment, all variables were analyzed at each time point
between groups (t test), and also were analyzed over time in each group (analysis
of variance, ANOVA). Among the clinical parameters, thyrotropin (TSH) levels were
unchanged and equal. Total serum T4 levels (p < 0.05 at 6 and 12 months after
treatment) and free thyroxine indices (FT4I) (p < 0.05 at all time points after
treatment) were lower in the test group than the control group. This is an
expected result of treatment with desiccated thyroid. We found no change over
time nor any difference between groups at time points for titers of antibodies to
thyroid autoantigens, ie, human TG, human TPO, and recombinant human TSHR from
Escherichia coli. However, cellular immunity, measured by in vitro
microproliferation of PBMC to peptides of TPO or TSHR, showed significant
differences between groups. At 12 months, stimulatory indices (SI) of PBMC to six
peptides, containing the indicated amino acids (764 approximately 95, 100
approximately 119, 110 approximately 129, 261 approximately 275, 441
approximately 448, 708 approximately 727) of 10 TPO peptides, and one peptide
(145 approximately 163) of 14 TSHR peptides were lower in the test group than
control group (p < 0.05). SI of PBMC to phytohemagglutinin, purified protein
derivative from mycobacteria, and tetanus toxoid were not different between
groups nor changed over time in any group. In conclusion, treating patients with
AITD with an antigen related to the autoantigen TG did not produce changes in
humoral immunity parameters, while cellular immunity to certain peptides were
apparently suppressed. While the results are both surprising and intriguing, we
need more evidence to justify the use of autoantigen as a form of immunospecific
therapy in patients with AITD.
PMID- 9545110
TI - Increased serum concentration of interleukin-5 in patients with Graves' disease
and Hashimoto's thyroiditis.
AB - We investigated serum levels of interleukin-5 (IL-5) in order to examine the role
of T-helper 2 (Th2)-type immune response in the pathogenesis of autoimmune
thyroid diseases. Serum levels of IL-5 were determined by a highly sensitive
sandwich enzyme-linked immunosorbent assay in 42 patients with Graves' disease,
32 patients with Hashimoto's thyroiditis, 12 patients with silent thyroiditis,
and 21 normal controls. Compared with serum levels in normal subjects (5.8 +/-
4.2 pg/mL), IL-5 was increased in patients with Graves' disease (16.4 +/- 16.7
pg/mL, p < .01), and in patients with Hashimoto's thyroiditis (10.0 +/- 7.6
pg/mL, p < .05), but not in patients with silent thyroiditis. There was no
correlation between serum free thyroxine (FT4) and IL-5 levels. These data
suggest an important role of the Th2-type immune response in the pathogenesis of
Graves' disease and Hashimoto's thyroiditis.
PMID- 9545111
TI - High frequency of T-cell lines responsive to immunodominant epitopes of
thyrotropin receptor in healthy subjects.
AB - In this study we analyzed the proliferative response to the extracellular domain
of thyrotropin receptor (TSHR-ECD) of T-cell lines raised from healthy subjects.
We found high frequencies of cell lines reactive to TSHR-ECD, ranging from 12% to
37%. The response of the cell lines to a set of overlapping peptides of TSHR-ECD
showed that the most recognized epitopes by T lymphocytes are on the C-terminal
portion. In particular, the regions of residues 360-396 and 258-277 are
immunodominant in T-lymphocyte reactivity. A group of cell lines specific for the
peptides of TSHR-ECD lost the response to the peptides during time in culture.
However, these lines were still responsive to TSHR extracellular domain. The
cloning of one of these lines showed three types of T-cell clones: (1) CD4+
clones (n = 4) highly responsive to the TSHR-ECD; (2) CD4+ clones (n = 4) low
responsive to TSHR-ECD; (3) CD8+ clones (n = 9) not responsive to TSHR-ECD. The
first group of clones was stable during time in culture, while the second group
was characterized by the loss of the specific response to TSHR-ECD after some
weeks from the first analysis. The observation of a spontaneous anergy in the
second group of CD4+ clones suggests that mechanisms of control of the lymphocyte
response to TSHR-ECD could be activated in vitro.
PMID- 9545112
TI - Simultaneous measurement of free thyroxine and free 3,5,3'-triiodothyronine in
undiluted serum by direct equilibrium dialysis/radioimmunoassay: evidence that
free triiodothyronine and free thyroxine are normal in many patients with the low
triiodothyronine syndrome.
AB - We have devised a practical, sensitive and specific method for simultaneous
measurement of free thyroxine (FT4) and free triiodothyronine (FT3) in undiluted
serum by direct equilibrium dialysis radioimmunoassay (RIA). Two hundred
microliters serum sample was dialyzed against buffer (pH 7.4) for 20 hours at 37
degrees C and approximately 800 microL of the dialysate was used for measuring
FT4 and FT3 simultaneously. The assay was set up in polystyrene tubes coated with
anti-T4 antibody and available commercially for FT4 measurement (Quest-Nichols
Institute, San Juan Capistrano, CA). The mean +/- SE (range) FT4 concentration
(ng/dL) was 1.2 +/- 0.04 (0.7.0 to 2.30) in 54 normal subjects. It was
significantly increased (3.6 +/- 0.4 [1.8 to 9.6], n = 20) in hyperthyroidism and
clearly decreased (0.40 +/- 0.04 [1.10 to 0.70], n = 26] in hypothyroidism. All
nonthyroid illness (NTI) patients had normal FT4 except 3, 2 of whom were on
amiodarone and 1 had received heparin. Serum FT4 concentration was minimally
elevated in 18 newborn cord blood serum (1.40 +/- 0.08 [0.90 to 2.2], cf. normal
p < .05). The mean serum FT3 concentration (pg/dL) was 285 +/- 10 (134 to 454) in
54 normal sera. It was clearly increased in hyperthyroidism (1033 +/- 98 [593 to
2134], n = 20, p < .001). However, serum FT3 varied widely in hypothyroidism (27
to 597, mean 235 +/- 24, NS) as did serum total T3 (19 to 175). Interestingly,
however, the mean serum FT3 concentration was normal (273 +/- 28 [62 to 575, NS])
in 25 NTI patients. All of these patients had low serum total T3 (46 +/- 5.0 [10
to 84], ng/dL; normal 84 to 160, p < 0.001), while FT3 was clearly normal in 21
of 25 patients and low in the remaining 4 patients. Similarly, among 18 newborn
cord blood sera serum FT3 concentration was normal in 15 and subnormal only in
the remaining 3 while all had clearly subnormal total T3 (28 to 74 ng/dL).
CONCLUSIONS: (1) A practical, sensitive, and specific assay for simultaneous
measurement of FT4 and FT3 is described; (2) FT3 is consistently elevated in
hyperthyroidism while FT4 is elevated in most (approximately 85%) cases; (3) FT4
is consistently decreased in hypothyroidism but FT3 varies widely; (4). Serum FT3
concentration is normal in approximately 83% of patients with the low T3 syndrome
in NTI and newborn cord blood serum. These data suggest that normal FT3 may
explain clinical euthyroidism in many patients with the low T3 syndrome.
PMID- 9545113
TI - Persistently increased gastrin and decreased pepsinogen concentrations in serum
from some patients with Graves' disease of triiodothyronine-predominant type and
common type.
AB - This study aimed to investigate the cause of persistently increased serum gastrin
concentration seen in some Graves' disease patients even when euthyroid during
antithyroid drug treatment. The subjects studied consisted of three groups: 33
patients with a common-type of Graves' disease, 14 with triiodothyronine (T3)
predominant Graves' disease (characterized from previous studies as having potent
immunologic abnormalities including greater concentrations of thyroid-stimulating
antibodies together with larger goiter size), and a group of 20 normal subjects.
Fasting serum gastrin concentrations in common Graves' disease patients were
significantly higher than those of normal subjects (58.4 +/- 38.9 pmol/L vs. 37.8
+/- 18.9 pmol/L [mean +/- SD], p < 0.05). The serum gastrin concentrations were
even greater in T3-predominant Graves' disease patients than common Graves'
disease patients (162.9 +/- 224.0 pmol/L vs. 58.4 +/- 38.9 pmol/L, p < .05).
Serum pepsinogen I (PGI) concentrations were significantly lower in the T3
predominant patient group than the common Graves' group (24.0 +/- 12.9 ng/mL vs.
39.7 +/- 19.6 ng/mL, p < .05). Serum ratios of PG I to PG II were significantly
lower in the T3-predominant Graves' disease patients than normal subjects (3.59
+/- 2.66 vs. 5.97 +/- 1.56, p < .01). The ratios also had a significant (p < .05)
inverse correlation with serum gastrin concentrations in T3-predominant Graves'
disease patients. The results suggest that autoimmune gastritis is associated
with Graves' disease, particularly in patients with potent thyroid-autoimmunity.
PMID- 9545114
TI - Pentagastrin testing in patients with renal insufficiency: normal responsivity of
mature calcitonin.
AB - Calcitonin (CT) is the most sensitive tumor marker for medullary thyroid
carcinoma available, but it lacks specificity. Chronic renal failure (CRF) is
known to be associated with elevations of serum immunoreactive calcitonin. Using
an immunoradiometric assay to detect only mature CT, we evaluated the basal CT
level and its response to pentagastrin in 30 patients with CRF and compared these
data with those obtained in 71 controls. Basal mature CT was significantly higher
(p < 0.05) in patients with CRF (3.55 pg/mL) than in controls (2.00). Among these
patients, 20% had basal CT levels more than 10 pg/mL with a maximum of 51 pg/mL.
Peak CT values (highest value obtained 3 or 5 minutes after pentagastrin) were
comparable in the two groups. Among patients with CRF, 10% had peak CT values
greater than 30 pg/mL with a maximum of 53 pg/mL. In this group of patients, no
correlation was found between CT (at any time during the test) and parathyroid
hormone, calcium, phosphate, or creatinine clearance. Men had significantly
higher CT values compared with women at each time point tested, including peak
values. Patients with CRF, who have not yet undergone dialysis, have moderately
elevated basal CT levels, but have normal pentagastrin-stimulated peak CT levels.
PMID- 9545115
TI - Adrenal insufficiency after recurrent post-partum thyroiditis (post-partum
Schmidt syndrome): a case report.
AB - Polyglandular autoimmune syndrome (PGAS) type 2 (Schmidt syndrome) is
characterized by the association of primary adrenocortical insufficiency with
autoimmune thyroid disease, and/or insulin-dependent diabetes mellitus (IDDM). In
this report we describe the occurrence of two episodes of post-partum thyroiditis
(PPT) after a first and second pregnancy as well the development acutely of
adrenal insufficiency after a second pregnancy. A family history of autoimmune
thyroid disease and IDDM as well as positive antiadrenal and antithyroid
antibodies and HLA typing is evidence for an underlying polyendocrine autoimmune
syndrome. This case report provides further evidence that the immune system that
is suppressed in pregnancy to tolerate the fetal allograft can rebound post
partum to unmask polyendocrine autoimmune disorders such as adrenalitis and PPT
in susceptible women.
PMID- 9545116
TI - Radiation-induced painless thyrotoxic thyroiditis followed by hypothyroidism: a
case report and literature review.
AB - A 68-year-old woman presented with a small painless goiter and thyrotoxic
symptoms immediately after 50-Gy external radiation for mucoepidermoid carcinoma
of the submandibular gland. Elevated serum thyroid hormone and thyroglobulin
levels, and undetectable serum thyrotropin level, together with extremely low
thyroidal radioiodine uptake established the diagnosis of painless thyrotoxic
thyroiditis. Thyroidal autoantibodies were negative. At follow-up without
medication, all the symptoms disappeared, and laboratory abnormalities normalized
within 6 months. One year later, the patient developed compensated hypothyroidism
as indicated by elevated serum thyrotropin level with low normal serum thyroid
hormone levels.
PMID- 9545117
TI - The medical costs of social deprivation--whose job is it anyway?
PMID- 9545118
TI - The emerging role of post-prandial hyperglycaemic spikes in the pathogenesis of
diabetic complications.
PMID- 9545119
TI - The blood glucose lowering effects of exercise and glibenclamide in patients with
type 2 diabetes mellitus.
AB - Physical exercise is associated with a fall in serum insulin levels, whereas
sulphonylurea administration increases insulin release. To date, the opposing
effects of exercise and sulphonylurea administration have not been systematically
studied in Type 2 diabetic patients, who are not infrequently treated with
sulphonylureas. In this study nine patients with Type 2 diabetes mellitus were
subjected to four treatments in random order on separate days: (A) endurance
exercise after the administration of 3.5 mg glibenclamide; (B) as A but given
only 1.75 mg glibenclamide; (C) as A but with placebo; (D) rest and
administration of 1.75 mg glibenclamide. Exercise and placebo resulted in only a
small decrease in glycaemia. Rest and administration of 1.75 mg glibenclamide led
to a moderate but steady fall in blood glucose concentrations. If glibenclamide
administration and exercise were combined, blood glucose concentrations declined
more markedly. Serum insulin concentrations showed a physiological decrease
during exercise and placebo administration. If patients rested after
administration of glibenclamide serum insulin levels rose and remained elevated.
When exercise and glibenclamide were combined the rise in serum insulin levels
was blunted and insulin levels fell once exercise was begun. Thus, exercise
attenuates the glibenclamide induced increase in serum insulin in moderately
hyperglycaemic Type 2 diabetic patients. Nevertheless, exercise has a substantial
hypoglycaemic effect in glibenclamide treated Type 2 diabetic patients.
PMID- 9545120
TI - Counterregulatory hormones in insulin-treated diabetic patients admitted to an
accident and emergency department with hypoglycaemia.
AB - The aim of the study was (1) to describe hormone responses in insulin-induced
hypoglycaemia and (2) to investigate if a combined treatment with intravenous
glucose and intramuscular glucagon (group A) would improve glucose recovery as
compared to treatment with intravenous glucose alone (group B). Eighteen adult
patients with insulin-treated diabetes mellitus admitted to the Accident and
Emergency Department with hypoglycaemia (plasma glucose 1.23 +/- 0.15 mmol l(-1)
on admission) were randomized to one of the above treatments and plasma glucose
and counterregulatory hormones were measured before and 30-120 min after
treatment. Pre-treatment counterregulatory hormone concentrations were
significantly lower than hormone concentrations during induced hypoglycaemia in
healthy control subjects but significantly higher than healthy fasting
concentrations for plasma adrenaline (p = 0.020), glucagon (p = 0.008), growth
hormone (p = 0.011), and cortisol (p<0.00001). Thus, although glucagon and
adrenaline responses may be absent when studying Type 1 diabetic patients in the
experimental setting, both hormones increase to a significant extent in 'real
life' hypoglycaemia in this patient group, although to a lesser degree than might
be expected. Plasma glucose did not differ significantly between the two
treatments at any time point. Despite access to food, one of four patients in
group B and one of five patients in group A had plasma glucose below 4.0 mmol l(
1) after 120 min. In conclusion, low yet significantly elevated concentrations of
adrenaline and glucagon were found in diabetic patients admitted with severe
hypoglycaemia to an Accident and Emergency Department.
PMID- 9545121
TI - Social deprivation and mortality in adults with diabetes mellitus.
AB - To investigate the relationship between measures of social deprivation and
mortality in adults with diabetes, data from 2104 randomly selected adults (> 16
years of age) with Type 1 and Type 2 diabetes mellitus from 8 hospital out
patient departments were analysed. A total of 38% of subjects had Type 1
(diagnosed before the age of 36 years and treated with insulin), 55% were male
and 85% Caucasian. During a follow-up period (mean (SD) of 8.4 (0.9) years), 293
(14%) of the subjects died, the most commonly recorded cause of death being
cardiovascular disease. Duration adjusted odds ratios (OR) and 95% confidence
intervals (CI) were calculated separately for Type 1 and Type 2 subjects. The
mortality rates for men were higher than for women (Type 1: OR 1.27, CI 0.61
2.62; Type 2: OR 1.79, CI 1.27-2.52); were higher for those of lower vs higher
social class (Type 1: OR 1.34, CI 0.61-2.96; Type 2: OR 2.0, CI 1.41-2.85); and
were higher for those who left school before 16 years of age compared to those
who left school at or after 16 years of age (Type 1: OR 3.98, CI 1.96-8.06; Type
2: OR 2.86, CI 1.93-4.25). Subjects who were unemployed had a higher mortality
rate than those employed at the time of the study (Type 1: OR 3.10, CI 1.67-5.79;
Type 2: OR 2.88, CI 2.12-3.91) and those living in council housing had a greater
mortality than those who were living in other types of housing (Type 1: OR 2.57,
CI 1.35-4.91, Type 2: OR 2.76, CI 2.05-3.73). Also for both Type 1 and Type 2
subjects mortality was significantly higher in those subjects who had a least one
diabetic complication at baseline and reported one or more hospital admissions in
the previous year and in Type 2 subjects with poor glycaemic control. After
adjusting for duration of diabetes, hospital admissions, and the presence of
diabetic complications, being unemployed, male, in poor glycaemic control (Type 2
only), and less educated were significant risk factors for mortality (p<0.001).
These results suggest that there are important indicators of social deprivation
which predict mortality over and above diabetic health status itself. Locally
targeted action will be required if these inequalities in health experienced by
people with diabetes are to be reduced.
PMID- 9545122
TI - Low educational status is a risk factor for mortality among diabetic people.
AB - Diabetes mellitus and its complications are an important cause of mortality in
Western populations. The purpose of the present study was to examine the
relationship between self-reported diabetes mellitus, gender, attained level of
education, and socio-economic resources to all-cause mortality risk in a simple
random sample of 39055 subjects, aged 25 to 74 years. Follow-up data were
obtained for a maximum of 16 years, from baseline (1979-1985) to 31 December
1995. Diabetic males (2.2% of the male study group) had a relative risk (RR) for
total mortality of 2.24 (CI = 1.96-2.57), adjusted for age, education, marital
status, housing tenure, and car ownership, compared with non-diabetic males. The
corresponding figure for females with diabetes (1.9%) was RR = 3.67 (CI = 3.16
4.27). Diabetic women had the highest age-adjusted mortality risk for coronary
heart disease (CHD) of 8 compared with non-diabetic women. The corresponding RR
for men was just below 3 (p<0.0001). Males and females (with and without
diabetes) of low attained educational level had a RR = 1.26 (CI = 1.15-1.39) and
RR = 1.54 (CI = 1.31-1.81), respectively. When analysing all people with diabetes
separately, adjusting for sex and age, low-educated subjects had a 40% excess all
cause mortality compared with high-educated subjects. We conclude that diabetic
women have a very high relative risk for CHD mortality compared to non-diabetic
women. Furthermore, diabetic people with a low attained level of education, have
an increased vulnerability to, and a higher total mortality.
PMID- 9545123
TI - Size at birth, maternal weight, and type 2 diabetes in South India.
AB - Recent research in Europe and the USA has shown that adults who had a low
birthweight or who were thin at birth with a low ponderal index
(birthweight/length3) tend to be insulin resistant and have an increased risk of
developing Type 2 diabetes mellitus. Low birthweight and Type 2 diabetes are
common in India. We have studied glucose and insulin metabolism in 506 men and
women (aged 39-60 years) born in a hospital in Mysore, South India, which kept
detailed obstetric records from 1934. The prevalence of Type 2 diabetes was 15%.
In contrast to Western populations, higher rates were found in men and women who
were short at birth (p = 0.07) and had a high ponderal index (p = 0.05). Their
mothers tended to be heavier than average during pregnancy (p = 0.004). Higher
ponderal index at birth was also associated with a lower 30 minute insulin
increment (p = 0.009), a marker of reduced beta cell function. We speculate that
the rise in Type 2 diabetes in Indian urban populations may have been triggered
by mild obesity in mothers, leading to glucose intolerance during pregnancy,
macrosomic changes in the fetus, and insulin deficiency in adult life.
PMID- 9545124
TI - Peripheral sensory nerve dysfunction in children and adolescents with type 1
diabetes mellitus.
AB - The aim of the present study was to investigate peripheral sensory nerve function
in diabetic children and adolescents without neurological symptoms. Ninety-two
children and adolescents with Type 1 (insulin-dependent) diabetes mellitus (mean
+/- SD age: 14.2 +/- 2.1 years, diabetes duration: 5.8 +/- 3.0 years) and 80
healthy control subjects (age: 13.8 +/- 2.2 years) matched for age, sex, body
mass index, and height standard deviation score were involved in the study. Using
a sine-wave transcutaneous stimulator, current perception threshold (CPT) testing
at 2000, 250 and 5 Hz was performed on the left median and peroneal nerves.
Diabetic children had increased CPT at 2000 Hz on both nerves as compared to the
control group (median (interquartile range), median nerve: 2.43 (2.20-3.43) vs
1.80 (1.51-2.60) mA, p = 0.02; peroneal nerve: 3.51 (2.81-4.82) vs 2.70 (2.04
3.70) mA, p = 0.01). Twenty-one (23%) of patients had CPT values higher than that
of any healthy individual. Of these, elevated CPT was observed in 9 (9.8%)
patients on the median nerve, in 8 (8.7%) patients on the peroneal nerve, and in
4 (4.3%) patients on both median and peroneal nerves. Using multiple logistic
regression analysis, worse long-term metabolic control and advanced puberty were
independently predictive of peripheral sensory nerve dysfunction as the dependent
variable (adjusted OR (95% CI): 3.4 (1.2-6.2), p = 0.01, and 2.8 (1.1-5.6), p =
0.03, respectively). In conclusion, evidence of peripheral sensory nerve
dysfunction is not rare in children and adolescents with diabetes and can be
demonstrated by CPT testing in asymptomatic patients. Poor metabolic control is a
risk factor for such subclinical neuropathy, and pubertal development may be
involved in the pathogenesis of diabetic peripheral neuropathy.
PMID- 9545125
TI - Reproducibility and comparability of insulin sensitivity indices measured by
stable-label intravenous glucose tolerance test.
AB - We have investigated the reproducibility of (1) insulin sensitivity (S*I) and
glucose effectiveness (S*G) as measured by the stable-label (one compartment)
minimal model, and (2) insulin sensitivity (S*Ib), plasma clearance rate (PCR),
basal hepatic output (HGOb), and total hepatic glucose output (HGO0-240) as
measured by the novel stable-label two compartment model of glucose disappearance
during labelled intravenous glucose tolerance test (IVGTT) using 6,6-(2)H
glucose. Ten normal male subjects were studied on two occasions one week apart.
Both models provided estimates of all indices with acceptable precision (CV of
parameter estimates < or =50%). The within subject CVs of S*I and S*Ib were
comparable (17% vs 19%) as were the within subject CVs of S*G and PCR (13% vs
16%). A highly significant linear relationship was observed between S*Ib and S*I
(0.303 +/- 0.046 ml kg(-1) min(-1) per mU l(-1) vs 13.04 +/- 1.89 10(-4) min(-1)
per mU l(-1), y = 0.0037 x + 0.0002, r = 0.90, p < 0.001; mean +/- SE), but not
between PCR and S*G (1.98 +/- 0.15 ml kg(-1) min(-1) vs 0.0089 +/- 0.0005 min(
1), rs = 0.34, NS). The two compartment model provided a plausible time-profile
of hepatic glucose output during IVGTT, reproducible estimates of HGOb (1.96 +/-
0.18 mg kg(-1) min(-1), 15%; mean +/- SE, within subject CV), and a highly
reproducible HGO0-240 (7%; within subject CV). We conclude that the stable-label
(one compartment) minimal model and the stable-label two compartment model
provide reproducible estimates of parameters of glucose kinetics in normal
subjects. Insulin sensitivity indices estimated by the two models are strongly
linearly related.
PMID- 9545126
TI - Human insulin analogue [LYS(B28), PRO(B29)]: the ideal pump insulin?
AB - The short-acting insulin analogue lispro ([LYS(B28), PRO(B29)] is absorbed from
the subcutis more rapidly than soluble insulin (S). To compare the clinical
effectiveness of lispro vs S, 11 Type 1 patients using continuous subcutaneous
insulin infusion (CSII) therapy (6 F, 5 M, age 30 +/- 2.5 years, diabetes
duration 14 +/- 1.0 years, BMI 24.0 +/- 0.8 kg m(-2), HbA1c 6.5 +/- 0.2%) were
studied in an open, randomized, crossover study for 6 months (3 months lispro and
3 months S or vice versa). During lispro treatment mean fasting and 2 h
postprandial blood glucose were lower compared to the S phase (fasting 6.5 +/-
0.4 vs 7.5 +/- 0.4 mmol l(-1) (NS), postprandial 6.8 +/- 0.3 vs 8.3 +/- 0.3 mmol
l(-1), p = 0.03). In patients treated first with lispro HbA1c levels improved
from 6.3 +/- 0.2% to 5.7 +/- 0.3%; On reversion to S HbA1c increased to 6.2 +/-
0.2%. In the group treated first with S, HbA1c fell (6.7 +/- 0.4% vs 6.5 +/-
0.3%) and then improved further to 6.3 +/- 0.3% with lispro. None of these
changes were significant. There was no significant difference with respect to
hypoglycaemic or other adverse events. It can be concluded that lispro in CSII
therapy is safe and may improve postprandial glucose excursions.
PMID- 9545127
TI - A comparison of digital retinal images and 35 mm colour transparencies in
detecting and grading diabetic retinopathy.
AB - We compared digital retinal images and 35 mm colour transparencies taken with the
Canon CR5 retinal camera for the detection and grading of diabetic retinopathy in
a clinical setting, in a randomized, blinded study of diabetic patients with a
spectrum of severity of diabetic retinopathy. Forty patients were photographed,
giving a total of 75 eyes including non-diabetic eyes as controls. Images were
graded according to the validated European guidelines. There was exact agreement
between grades obtained from both the 2 field 45 degrees 35 mm colour
transparencies and digital images in 93.3% (70/75) of eyes, with Cohen's Kappa
statistic for the comparison being 0.92. Overall, when grading from the digital
images 5.3% (4/75) eyes were undergraded with three cases of sight threatening
diabetic retinopathy (STDR) graded as non-sight threatening (NSTDR) (3/48, 6.3%).
One eye was overgraded (1/75, 1.3%). Two of the three cases of STDR undergraded
as NSTDR had small numbers of intra-retinal microvascular abnormalities (IRMA)
discernible on the colour transparencies but which were not visible from the
digital image. The third had multiple small cotton wool spots graded as laser
photocoagulation scars from the digital images. In conclusion there is good to
excellent agreement between retinopathy grades using the Canon CR5 digital
retinal imaging system compared to 35 mm colour transparencies.
PMID- 9545128
TI - Instant electronic imaging systems are superior to Polaroid at detecting sight
threatening diabetic retinopathy.
AB - Polaroid photography in diabetic retinopathy screening allows instant image
availability to enhance the results of ophthalmoscopy. Retinal cameras are now
being developed which use video/digital imaging techniques to produce an instant
enlarged retinal image on a computer monitor screen. We aimed to compare one such
electronic imaging system, attached to a Canon CR5 45NM, with standard Polaroid
retinal photography. Two hundred and thirteen eyes from 107 diabetic patients
were photographed through dilated pupils by both systems in random order and the
images were analysed blind. Diabetic retinopathy was present in 58 eyes of which
55/58 (95%) were detected on the electronic image and only 49/58 (84%) on the
Polaroid. Of 34 eyes requiring ophthalmologist referral according to standard
European criteria, 34/34 (100%) were detected on the electronic image and only
24/34 (71%) on the Polaroid. Side by side comparisons showed electronic imaging
to be superior to Polaroid at lesion detection. Using linear analogue scales, the
patients assessed the electronic imaging photographic flash as less uncomfortable
than the Polaroid equivalent (p < 0.0001). Other advantages of electronic imaging
include: ready storage of the images with other patient clinical data on the
diabetes computerized register/database; potential for image enhancement and
analysis using image analysis software and electronic transfer of images to
ophthalmologist or general practitioner. Electronic imaging systems represent a
potential major advance for the improvement of diabetic retinopathy screening.
PMID- 9545129
TI - Central pontine myelinolysis and ataxia: an unusual manifestation of
hypoglycaemia.
AB - Hypoglycaemia is common in people with diabetes who aim to achieve good blood
glucose control. Severe hypoglycaemia presents with evidence of neurological
dysfunction, such as inability to concentrate, confusion, seizures, and coma.
Such disturbances are reversible on correction of the hypoglycaemia. Infrequently
there may be a focal neurological deficit and we report one such case presenting
with cerebellar symptoms following an episode of severe hypoglycaemia. A magnetic
resonance scan showed features consistent with the presence of central pontine
myelinolysis. The symptoms resolved within a few months with only minimal
residual neurological deficit.
PMID- 9545130
TI - Use of a prostacyclin analogue in cholesterol crystal embolism.
AB - The prognosis of cholesterol embolism is often poor, and no treatment is
presently available. We report the use of a stable prostacyclin analogue in
treating cholesterol embolism in a diabetic patient with arteriopathy. As a sole
therapy, it improved cutaneous manifestations and pain, in parallel with an
increased transcutaneous oxymetry. We think that prostacyclin analogues are novel
candidates for the treatment of cholesterol embolism.
PMID- 9545131
TI - Porcine reproductive and respiratory syndrome.
AB - In 1987, porcine reproductive and respiratory syndrome (PRRS) was recognized in
the USA as a new disease of swine causing late-term reproductive failure and
severe pneumonia in neonatal pigs. The syndrome is caused by an RNA virus
referred to as PRRS virus (PRRSV), which is classified in the family
Arteriviridae. Swine macrophages are the only indigenous cell type known to
support PRRSV replication. Direct contact between infected and naive pigs is the
predominant route of PRRSV transmission. Exposure of a mucosal surface to PRRSV
leads to virus replication in regional macrophages, a prolonged viremia and
systemic distribution of virus to other macrophage populations. Reproductive
failure induced by PRRSV infection in late-gestation sows is characterized by
premature farrowing of stillborn, partially autolyzed, and mummified fetuses.
Pneumonia caused by PRRSV infection is more severe in young pigs compared to
adults and may be complicated by concurrent bacterial infections. Gross lung
lesions associated with PRRSV infection vary from none to diffuse consolidation.
In addition, multiple lymph nodes may be markedly enlarged. Microscopically,
PRRSV-pneumonia is characterized by multifocal, interstitial thickening by
macrophages and necrotic cell debris in alveoli. Other less common microscopic
lesions of PRRSV infection include myocarditis, vasculitis, encephalitis, and
lymphoid hypertrophy and hyperplasia. In acute or subacute PRRSV infections,
serum and lung are the best specimens for diagnosis. Persistent PRRSV infections
can be produced by transplacental or intranasal infection. Persistent PRRSV
infections are an important factor for virus survival and transmission within a
swine herd and will complicate control programs.
PMID- 9545132
TI - Lesions caused by cardiovascular flukes (Digenea: Spirorchidae) in stranded green
turtles (Chelonia mydas).
AB - Evidence of infection with spirorchid flukes (Digenea: Spirorchidae) was sought
at necropsy of 96 stranded green turtles, Chelonia mydas, that were examined
during the course of a survey of marine turtle mortality in southeastern
Queensland, Australia. Three species of spirorchid (Hapalotrema mehrai, H.
postorchis, and Neospirorchis schistosomatoides) were identified. Severe disease
due to spirorchid fluke infection (spirorchidiasis) was implicated as the
principal cause of mortality in 10 turtles (10%), and appeared to be one of
multiple severe problems in an additional 29 turtles (30%). Although flukes were
observed in only 45% of stranded C. mydas in this study, presumed spirorchid
fluke infection was diagnosed in an additional 53% of turtles, based principally
on characteristic necropsy lesions and to a lesser extent on the
histopathological detection of spirorchid eggs. Characteristic necropsy lesions
included miliary spirorchid egg granulomas, which were observed most readily on
serosal surfaces, particularly of the small intestine. Cardiovascular lesions
included mural endocarditis, arteritis, and thrombosis, frequently accompanied by
aneurysm formation. Resolution of thrombi was observed to occur via a combination
of granuloma formation about indigestible components (spirorchid fluke egg
shells) and exteriorization through the vessel wall, which resulted in
granulomatous nodules on the adventitial surface. Septic aortic thrombosis
complicated by disseminated bacterial infection, observed in five turtles, was
recorded for the first time. Egg granulomas were ubiquitous in turtle tissues
throughout this study. Although they generally appeared to be mild or incidental
lesions, they were occasionally associated with severe multifocal granulomatous
pneumonia or meningitis.
PMID- 9545133
TI - Vesicular and ulcerative dermatopathy resembling superficial necrolytic
dermatitis in captive black rhinoceroses (Diceros bicornis).
AB - The histopathology, clinical presentation, and epidemiology of a cutaneous and
oral mucosal disease affecting 40 black rhinoceroses (Diceros bicornis) at 21
zoological parks (50% of the captive US population) were investigated. Twenty
seven biopsies were examined from recent lesions, and clinical information was
available from 127 episodes. The cutaneous lesions began as plaques that
progressed to vesicles, bullae, or ulcers. Lesions waxed and waned in individual
cases. Lesions were predominantly bilaterally symmetrical, affecting pressure
points, coronary bands, tips of the ears and tail, and along the lateral body
wall and dorsum. Oral lesions were first noticed as ulcers and were present on
the lateral margins of the tongue, palate, and mucocutaneous junctions of the
lips. All recent lesions had similar histopathologic findings of prominent
acanthosis, hydropic degeneration of keratinocytes in the stratum spinosum,
spongiosis, intraepithelial vesicles, and parakeratosis without dermal
inflammation. Chronic lesions were ulcerated. No pathogens were identified by
culture or electron microscopy. Most episodes coincided with stress events
(transportation, sudden cold temperatures, intraspecific harassment, estrus,
advanced pregnancy) or concurrent diseases (toxic hepatopathy, hemolytic anemia,
respiratory or urinary tract infections). Affected rhinoceroses usually were
lethargic and had weight loss. Affected rhinoceroses also had lower hematocrit,
serum albumin, and cholesterol values than captive healthy or wild rhinoceroses.
The clinical patterns and histopathologic findings are similar to those of
superficial necrolytic dermatitis in dogs and necrolytic migratory erythema in
humans. The high prevalence of this skin disease in captive black rhinoceroses
under many circumstances suggests that their epidermis is acutely sensitive to
any disruption of metabolic homeostasis. We propose that metabolic changes
secondary to a stress response from maladaptation or nutritional inadequacy of
captive diets may contribute to the development of this disease in rhinoceroses
without hepatopathies.
PMID- 9545134
TI - Immunohistochemical characterization of inflammatory cells in brains of dogs with
granulomatous meningoencephalitis.
AB - The inflammatory cells of eleven dogs with canine granulomatous
meningoencephalitis were characterized immunohistochemically. Macrophages were
identified by antibodies directed against lysozyme and the DH82 antigen
(expressed by cells of a malignant histiocytosis). T cells were demonstrated by
CD3, CD43, and CD45R antigen, and B cells by immunoglobulin G and immunoglobulin
M expression. Furthermore, staining for the major histocompatibility complex
(MHC) class II antigen was evaluated. Diseased animals ranged from 1 to 9 years
of age. Small and medium-sized breeds were affected predominantly. Lesions were
widespread and localized mainly in the brain stem, less frequently in the
cerebrum or cerebellum. Alterations were represented by perivascular cuffs,
parenchymal granulomas, and leptomeningeal infiltrates. Lymphocytes and
macrophages comprised the dominant cell populations; their percentage varied
substantially between different animals and between sections from the same
individual. Immunohistochemically, the bulk of lymphocytes were CD3 antigen
positive T cells, while only a few cells were CD43 and CD45R antigen-positive or
were classified as B cells. The majority of macrophages expressed both lysozyme
and DH82 antigen; however, some were positive for only one antigen. MHC class II
antigen-expression, observed only within and in close proximity to the lesions,
was found on all inflammatory cells, pericytes/endothelial cells, and microglia.
Results were negative for canine distemper virus antigen and nucleoprotein mRNA,
rabies virus antigen, fungi, bacteria, and protozoal agents. This
immunomorphologic study reveals that inflammatory lesions in canine granulomatous
meningoencephalitis consist of a heterogeneous population of MHC class II antigen
positive macrophages and predominantly CD3 antigen-positive lymphocytes. The data
suggest a T cell-mediated delayed-type hypersensitivity of an organ-specific
autoimmune disease as a possible pathogenic mechanism for this unique canine
brain lesion.
PMID- 9545135
TI - The effects of the tremorgenic mycotoxin penitrem A on the rat cerebellum.
AB - Within 10 minutes of intraperitoneal injection of penitrem A (3 mg/kg), rats
develop severe generalized tremors and ataxia that persist for up to 48 hours.
These are accompanied by a three- to fourfold increase in cerebellar cortical
blood flow. Mitochondrial swelling occurs in cerebellar stellate and basket cells
within 30 minutes of dosing and persists for more than 12 hours without leading
to cell death. From 2 hours, Purkinje cell dendrites show early cytoplasmic
condensation accompanied by fine vacuolation of smooth endoplasmic reticulum and
enlargement of perikaryal mitochondria. From 6 hours, many Purkinje cells develop
intense cytoplasmic condensation with eosinophilia that resembles "ischemic cell
change," and from 12 hours, many other Purkinje cells show marked watery
swelling. Astrocytes begin to swell from 0.5 hours after injection and show
hypertrophy of organelles from 6 hours. Also from 6 hours onward, discrete foci
of necrosis appear in the granule cell layer, while permeability of overlying
meningeal vessels to horseradish peroxidase becomes evident at 8 hours. All
changes are more severe in vermis and paravermis. Despite widespread loss of
Purkinje cells, the animals' behavior becomes almost normal within a week. While
tremor occurs with doses of 1.5 and 0.5 mg/kg, cellular damage is minimal. The
tremor mechanism differs from that of harmaline since destruction of inferior
olivary nuclei abolishes neither the tremor response to penitrem A nor the
cellular damage. No morphological changes are found in other brain regions. The
affinities of penitrem A for high-conductance calcium-dependent potassium
channels and for gamma-aminobutyric acid receptors with the probability of
resultant excitotoxity are considered to be important underlying factors for
these changes.
PMID- 9545136
TI - Primitive neuroectodermal tumor in a two-month-old black and white Colobus
monkey.
AB - A 2-month-old male black and white Colobus monkey (Colobus guereza kikuyuensis)
was euthanatized because of progressive physical deterioration, rear limb
paralysis, lymphadenopathy, and the presence of facial and retroperitoneal lumbar
masses. At necropsy, soft white masses were present in and around lumbar
vertebrae, the subcutis of the face, multiple lymph nodes, and the fourth
ventricle of the brain. Histologic and immunohistochemical analysis of these
masses revealed a primitive neoplasm with both neuronal and glial
differentiation, consistent with a primitive neuroectodermal tumor (PNET) with
bipotential differentiation. The extracranial tumors were synaptophysin (SYN)
positive, glial fibrillary acidic protein (GFAP)-negative, and neurofilament
protein (NFP)-negative, while the intracranial tumor was SYN-positive, GFAP
positive, and NFP-negative.
PMID- 9545137
TI - Macroscopic and microscopic characterization of a uriniferous perirenal
pseudocyst in a Domestic Short Hair cat.
AB - The macroscopic and microscopic features of a uriniferous perirenal pseudocyst in
a castrated male 12-year-old American Domestic Short Hair cat are characterized.
The development in humans and animals of a perirenal pseudocyst due to the
accumulation of urine, lymph, or blood is discussed. In the presented case,
microscopic evidence suggests that the pseudocyst developed following formation
of a split in the kidney capsule. Emphasis is placed on the development of
uriniferous pseudocysts and three proposed criteria for their development:
trauma, abnormal openings that allow extravasation of urine, or urethral
obstruction.
PMID- 9545138
TI - Generalized AA-amyloidosis in Siberian tigers (Panthera tigris altaica) with
predominant renal medullary amyloid deposition.
AB - Generalized amyloidosis with predominant renal medullary amyloid deposition was
found in four closely related Siberian tigers (Panthera tigris altaica) suffering
from end stage kidney diseases. Only minimal to mild amounts of amyloid were
deposited in various organs outside the kidneys with individually variable organ
involvement. The Congo red staining affinity of amyloid deposits was sensitive to
potassium permanganate oxidation. The deposits were further characterized as
being of the amyloid-A (AA) type by immunohistochemistry using the mouse
monoclonal antibody mc4 directed against a conserved region of the human AA
protein. A combination of immunohistochemistry and Congo red staining was much
more sensitive for the diagnosis of amyloid deposits than Congo red staining
alone. With this combination, even minimal amyloid deposits were detected that
had been missed in the first reading using Congo-red-stained slides alone. Since
no common primary cause was identified, the amyloidosis was classified as
idiopathic generalized AA-amyloidosis with a potential familial predisposition.
PMID- 9545139
TI - Primary vascular neoplasms of lymph nodes in the dog.
AB - Primary vascular neoplasms of lymph nodes are rare, and appear not to have
previously been reported in domestic animals. This report describes hemangiomas
and a lymphangioma in lymph nodes of aged Beagle dogs. Eight hemangiomas (4.8%)
and one lymphangioma were present in 165 examined popliteal lymph nodes, and one
hemangioma occurred in a hepatic lymph node. The hemangiomas were cavernous and
benign.
PMID- 9545140
TI - Polycystic kidney and liver disease in two related West Highland White Terrier
litters.
AB - Polycystic kidney and liver disease was present in four of six female and three
of five male offspring born in two matings between the same pair of West Highland
White Terriers. Clinical signs were apparent and serum biochemistry analysis
consistent with liver failure was evident by 5 weeks of age. Affected pups were
euthanatized because of their disease. Renal cysts were confirmed to be of
collecting duct origin by Dolichos bifluros agglutinin lectin histochemistry, and
hepatic cysts were of biliary origin. The clinically unaffected parents were
related through multiple common ancestors, and there were no reports of similar
disease in related dogs. An autosomal recessive mode of inheritance is therefore
suggested. This is the first report of polycystic kidney and liver disease in the
West Highland White Terrier. The features of the disease in these pups are
similar to those of autosomal recessive polycystic kidney disease (ARPKD) in
humans. The West Highland White Terrier may therefore be a potential animal model
for ARPKD.
PMID- 9545141
TI - Current management of human bites.
AB - Human bites should be considered dangerous injuries with potentially serious
complications. Their characteristics vary from an uninfected abrasion to a
serious infection such as cellulitis or osteomyelitis. An estimated 10% of the
injuries become infected; suspected pathogens include oral and skin flora.
Management consists of history and examination, wound care, surgical intervention
if necessary, assessment of risk of disease transmission, and appropriate
antibiotic prophylaxis or treatment. The best choice for oral or intravenous
antibiotic therapy remains the combination of a beta-lactam antibiotic with a
beta-lactamase inhibitor. Among the most serious human bites are clenched fist
injuries, which often require surgical intervention and intravenous antibiotic
therapy.
PMID- 9545142
TI - Antiepileptic drug withdrawal--a good idea?
AB - Patients who are seizure free for 2 years or more are candidates for
antiepileptic drug (AED) withdrawal. A MEDLINE search of the English language
literature from 1980-1996 was performed to identify articles dealing with AED
withdrawal in both adults and children. Factors examined included advantages and
disadvantages of withdrawal, risks of relapse, prognostic factors of outcome, and
methods of withdrawal. Advantages include psychosocial benefits, cost savings
(direct drug costs, indirect monitoring costs), and avoidance of adverse effects
and toxicity. The benefits must be balanced against the risks and impact of
seizure relapse, which are different for each individual patient. A review of the
prognostic factors that influence the risk of relapse will aid clinicians in
determining appropriate candidates for AED withdrawal.
PMID- 9545143
TI - Statins in the prevention of coronary heart disease.
AB - Although epidemiologic studies proved that a causal relationship exists between
elevated serum cholesterol levels and coronary heart disease, it is only recently
that cholesterol-lowering strategies have shown significant reductions in total
mortality. In the last few years, three landmark coronary artery disease
reduction trials with HMG-coenzyme A reductase inhibitors (statins) showed
significant reductions in coronary heart disease and mortality. Statins have
beneficial effects on coronary heart disease and overall mortality in primary and
secondary prevention, including in women and the elderly. Angiographic studies
reveal the potential mechanisms through which statins exert their clinical
benefits.
PMID- 9545144
TI - The association between cryptococcal variety and immunocompetent and
immunocompromised hosts.
AB - The varieties of Cryptococcus neoformans serotypes are neoformans and gattii.
Data suggest an association between cryptococcal variety and host immune status.
In addition, the two varieties differ in their epidemiology and pathogenicity.
Furthermore, symptoms, outcome, and response of cryptococcosis to antifungal
therapy may vary. The two varieties also differ in immune-modulating effects.
Sparse clinical data suggest var. gattii is more virulent and may be more
recalcitrant to antifungal therapy. Also, its infections produce more sequelae. A
better understanding of how cryptococcal variety influences the clinical course
and response to the treatment of cryptococcosis is needed. Clinicians should be
aware of the association, especially in patients with refractory disease. It may
be useful to type the isolate to the variety level and administer prolonged
antifungal therapy.
PMID- 9545145
TI - Low-molecular-weight heparins in coronary arterial thrombus disease: a review of
the literature.
AB - Popularity of low-molecular-weight heparins (LMWH) continues to grow. Clinical
trials established their efficacy for various venous thromboembolic disease
states. Their use in arterial disorders is also becoming widespread.
Unfortunately, clinical trials in this population subgroup are either lacking or
show little or no benefit of LMWH. Specifically, they appear to offer no benefit
over antiplatelet agents, such as aspirin and ticlopidine, after percutaneous
transluminal coronary angioplasty. Conversely, they may have a role in the
management of unstable angina. At this time, however, their efficacy appears
equivalent only to therapeutic dosages of unfractionated heparin.
PMID- 9545147
TI - Cyclosporine trough concentrations in predicting allograft rejection and renal
toxicity up to 12 months after renal transplantation.
AB - STUDY OBJECTIVE: To evaluate the utility of cyclosporine (CsA) trough
concentrations as a monitoring tool for acute graft rejections and CsA
nephrotoxicity. DESIGN: Retrospective chart review. SETTING: University
affiliated teaching hospital. PATIENTS: One hundred thirty-seven adults who had
undergone kidney transplantation. MEASUREMENTS AND MAIN RESULTS: Clinical data
extracted from the charts were CsA dosage, CsA trough levels (whole blood, HPLC
method), biopsy findings to confirm acute rejections, and serum creatine to
determine clearance by the Jelliffe method. Data were collected at up to 1 month,
between 1 month and 3 months, and between 3 and 12 months after transplantation.
For each time period, receiver's operating characteristics curves were generated
to identify the optimum CsA concentration for avoiding acute rejection and CsA
nephrotoxicity. At up to 1 month, the CsA therapeutic response threshold was 182
ng/ml (sensitivity 69%, specificity 84%, p<0.0001) and toxicity threshold for CsA
nephrotoxicity was 204 ng/ml (sensitivity 89%, specificity 56%, p<0.0001).
Between 1 month and 3 months, the respective figures were 175 ng/ml (sensitivity
58%, specificity 89%, p<0.0002) and 189 ng/ml (sensitivity 87%, specificity 65%,
p<0.0001). Between 3 and 12 months, the CsA therapeutic response threshold
decreased to 135 ng/ml (sensitivity 56%, specificity 40%, p>0.1) and the toxicity
threshold for CsA nephrotoxicity remained relatively static at 204 ng/ml
(sensitivity 100%, specificity 14%, p<0.0001). CONCLUSION: Early in CsA therapy
it is essential to prevent graft rejection. Drug concentrations exceeding
approximately 182 ng/ml threshold accomplish this goal. Later, successful therapy
demands that CsA nephrotoxicity be avoided. This goal is accomplished by not
exceeding a CsA concentration of 204 ng/ml.
PMID- 9545146
TI - Population pharmacokinetics of carbamazepine in adults with epilepsy.
AB - STUDY OBJECTIVE: To conduct a population pharmacokinetic analysis of
carbamazepine (CBZ). DESIGN: Retrospective chart review. SETTING: Ambulatory
neurology clinics at three medical centers. PATIENTS: Patients diagnosed with
epilepsy from 1991-1995. The index set included 829 adults receiving CBZ. A
separate validation set consisted of 50 patients. INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: Final regression equations were apparent oral
clearance (Cl/F) (L/hr) = (0.0134 x TBW + 3.58), x 1.42 if receiving phenytoin
only; x 1.17 if receiving phenobarbital or felbamate; x 1.62 if receiving
phenytoin and phenobarbital or felbamate; x 0.749 if age > or = 70 years;
apparent volume of distribution (Vd/F) (L) = 1.97 x total body weight; absorption
rate constant [hr(-1)] = 0.441. Interindividual variability in Cl/F and Vd/F was
26% and 82%, respectively. Residual variability was 1.8 mg/L. Predictive
performance analysis of the validation set provided a mean prediction error of
0.6 mg/L and median absolute error of 2.4 mg/L. CONCLUSIONS: These routinely
collected data provided quantitative estimates of changes in CBZ Cl/F due to
comedication and an age-related decrease in Cl/F The derived regression equations
reasonably predicted concentrations in a separate validation set.
PMID- 9545148
TI - Relative bioavailability of ondansetron 8-mg oral tablets versus two
extemporaneous 16-mg suppositories: formulation and gender differences.
AB - STUDY OBJECTIVE: To compare the relative bioavailability of two 16-mg
extemporaneously prepared suppository formulations with that of an 8-mg
commercially available oral tablet. DESIGN: Prospective, crossover
bioavailability study. SETTING: Inpatient clinical research center. SUBJECTS:
Sixteen young, nonsmoking, healthy volunteers. INTERVENTIONS: Blood samples were
obtained 24 and 48 hours after administration of an 8-mg oral ondansetron tablet
and 16-mg suppository, respectively. Two 16-mg suppository formulations were
compounded using commercially available Fattibase and Polybase. MEASUREMENTS AND
MAIN RESULTS: Ondansetron was well absorbed by both routes of administration. The
following pharmacokinetic parameters (mean+/-SEM) were obtained for the 8-mg
tablet, 16-mg Fattibase suppository, and 16-mg Polybase suppository,
respectively: area under the curve (AUC) in men 154.2+/-21.77, 253.4+/-72.3,
304.8+/-62.2 ng x hr/ml; AUC in women 353.6+/-32.7, 561.6+/-103.6, and 768.7+/
117.9 ng x hr/ml; maximum concentration (Cmax) in men 45.5+/-7.0, 40.6+/-10.4,
and 51.2+/-6.7 ng/ml; Cmax in women 51.4+/-.8, 47.1+/-3.9, and 82.9+/-6.6 ng/ml.
Times to Cmax (Tmax; mean+/-SEM) for men were 1.5+/-0.3, 4.4+/-0.5, and 2.9+/-0.3
hours; Tmax for women were 1.8+/-0.3, 4.1+/-0.4, and 4.4+/-0.6 hours for the
three formulations, respectively. Women had a consistently higher AUC for all
three formulations than men (p<0.05). CONCLUSION: With the exception of the 16-mg
Polybase formulation in women, the two suppositories closely approximated the
pharmacokinetics of the 8-mg oral tablet. These results suggest that gender may
be a significant factor in ondansetron's disposition.
PMID- 9545149
TI - Food interaction and steady-state pharmacokinetics of itraconazole oral solution
in healthy volunteers.
AB - STUDY OBJECTIVES: To evaluate the effect of food on the bioavailability of
itraconazole (ITR) hydroxypropyl-beta-cyclodextrin (HP-beta-CD) solution under
multiple-dose to steady-state conditions, and to determine the pharmacokinetics
of ITR solution at steady state. DESIGN: Open-label, randomized, multiple-dose,
crossover study SETTING: University-affiliated health center. PATIENTS: Thirty
healthy men randomized to one of two treatment sequences (fasted-fed, fed
fasted). INTERVENTIONS: Subjects were either fasted or fed a standard breakfast
before receiving ITR oral solution 200 mg once/day for 15 days. Crossover phases
were separated by a 4-week washout period. MEASUREMENTS AND MAIN RESULTS: On day
1, blood samples were collected before the dose (time zero) and 0.5, 1, 2, 3, 4,
5, 6, 8, 12, and 24 hours after the dose. Trough samples were obtained before the
dose on days 4, 7, 12, 13, and 14. On day 15, samples were obtained at the same
times as day 1, and at 36, 48, 72, 96, 168, 240, and 360 hours. Samples were
analyzed by high-performance liquid chromatography for ITR and its major
metabolite hydroxyitraconazole (OH-ITR). Urine was collected on days 1 and 15
before and 0-8 and 8-24 hours after the dose; HP-beta-CD was measured by size
exclusion chromatography. Mean bioavailabilities of ITR and OH-ITR were 43% and
38% higher, respectively, when ITR solution was taken as a single dose under
fasted conditions. With multiple dosing, steady state was achieved by day 14. At
steady state, mean bioavailabilities were 29% and 17% higher, respectively, in
the fasted state; terminal half-life was similar under fasted and fed conditions
(mean 39.8 and 37.5 hrs for ITR, respectively; 27.3 and 26.2 hrs for OH-ITR,
respectively). HP-beta-CD was eliminated almost exclusively in urine. CONCLUSION:
The bioavailability of ITR and OH-ITR is enhanced when ITR oral solution is given
in the fasted state; this was true for both single and multiple dosing to steady
state.
PMID- 9545150
TI - 1995 National Clinical Pharmacy Services Study.
AB - To determine the extent of hospital-based clinical pharmacy services in 1995, we
surveyed 1109 United States acute care, general, medical-surgical, and pediatric
hospitals with 50 or more licensed beds. Fifteen clinical pharmacy services were
assessed to determine pharmacists' specific patient care responsibilities. The
percentage of hospitals offering services grew between 1992 and 1995:
pharmacokinetic consultations (16% increase), drug therapy protocol management
(15%), drug therapy monitoring (8%), drug counseling (13%), and parenteral
enteral nutrition team (6%). All other services increased 0-5%. Pharmacists
conducted clinical research in 14% of hospitals, averaging 6.3+/-22.1
protocols/department annually; total budget $96,219+/-$262,026. Patient-focused
care predominated in 20% of hospitals, although most pharmacists reported to
directors of pharmacy through traditional pharmacy department channels. Clinical
pharmacy services continue to expand, with pharmacists providing higher-level
direct patient care activities related to drug therapy management and monitoring.
PMID- 9545152
TI - Impact of patient knowledge, patient-pharmacist relationship, and drug
perceptions on adverse drug therapy outcomes.
AB - The purpose of this project was to determine the relationship between adverse
drug outcomes and knowledge of drugs, quality of a counseling relationship, and
perceptions about drugs in an ambulatory clinic population. The presence of these
three factors and other indicators of adverse outcomes were identified through a
structured interview of 78 patients. Medical records were reviewed 3, 6, and 12
months after the initial interview to determine the presence of adverse drug
outcomes. Four outcomes-hospitalizations, unscheduled clinic visits, emergency
room visits, and changes in drug regimen-were assessed and categorized according
to drug-related problem. Demographics of the group were recorded. Responses to
the interview were analyzed to determine differences in counseling relationships
between pharmacists and other health professionals. Logistic regression analysis
was performed to determine the influence of independent variables on outcome.
Relative risks for developing adverse outcomes given the presence of certain
independent variables were calculated for significant associations. Significant
relationships between predictor variables and adverse drug outcomes were
identified for the following independent variables: female gender (RR = 5.2, CI
1.11, 24.31), three or more diseases (RR = 3.3, CI 1.13, 9.75), more drug
knowledge and better perceptions (RR = 0.29, CI 0.10, 0.84), perception of no or
low drug interference (RR = 0.18, CI 0.044, 0.745), and inadequate data
collection by nurses and physicians as perceived by the patient (RR = 3.08, CI
1.09, 8.70). More knowledge and better perceptions about drugs were associated
with a reduced risk of therapy changes due to drug-related problems. No
association was found between the quality of the pharmacist-patient counseling
relationship and adverse drug outcomes.
PMID- 9545151
TI - The cost-effectiveness of a clinical pharmacist intervention among elderly
outpatients.
AB - We estimated the cost and cost-effectiveness of a clinical pharmacist
intervention known to improve the appropriateness of drug prescribing. Elderly
veteran outpatients prescribed at least five drugs were randomized to an
intervention (105 patients) or control (103) group and followed for 1 year. The
intervention pharmacist provided advice to patients and their physicians during
all general medicine visits. Mean fixed and variable costs/intervention patient
were $36 and $84, respectively Health services use and costs were comparable
between groups. Intervention costs ranged from $7.50-30/patient/unit change in
drug appropriateness. The cost to improve the appropriateness of drug prescribing
is thus relatively low.
PMID- 9545154
TI - Rifampin, a useful drug for nonmycobacterial infections.
AB - Rifampin has clinical efficacy against a wide variety of organisms, including
Staphylococcus aureus, Legionella pneumophila, group A Streptococcus, Brucella
sp, Haemophilus influenzae, and Neisseria meningitidis, as well as in vitro
activity against penicillin-resistant Streptococcus pneumoniae, Neisseria
gonorrhoeae, Chlamydia trachomatis, Haemophilus ducreyi, and many gram-negative
rods. Rifampin is a useful drug for several types of bacterial infections because
of its broad spectrum of activity, excellent tissue penetration, and low side
effect profile. In combination with other antibiotics, it may be effective when
conventional therapies are not.
PMID- 9545153
TI - Cyclosporine-induced beta-adrenergic receptor down-regulation in bovine pulmonary
artery smooth muscle cells: a pilot study.
AB - We attempted to determine the effects of cyclosporine on beta-adrenergic
receptors in bovine pulmonary artery smooth muscle cells. Bovine pulmonary artery
smooth muscle cells were exposed to cyclosporine at a concentration of 100 ng/ml
in culture media for 5 days, and control bovine pulmonary artery smooth muscle
cells were exposed to only culture media for the same 5-day period. Beta
adrenergic receptors were measured as total binding capacity (Bmax) by nonlinear
least squares fit of the specific binding curve. In a separate experiment beta1-
versus beta2-adrenergic receptor subtypes were identified by computer modeling
(LIGAND) of 17-19 point CGP20712A-125ICYP competition curves. Cyclosporine
significantly (p=0.02) decreased bovine pulmonary artery smooth muscle beta
adrenergic receptor density by 54%+/-7%. The Bmax for control versus treated
cells was 38.9+/-18 versus 17.7+/-12 fmol/mg protein, respectively. Subtype
determination of beta-receptors revealed 70% or more beta2- and 30% or less beta1
adrenergic receptors. Cyclosporine caused a 54% reduction in overall beta
adrenergic receptor density in bovine pulmonary artery smooth muscle cells. The
reduction in Bmax is suspected not to be a result of selective down-regulation of
beta1-adrenergic receptors alone. We believe that cyclosporine may also
contribute to a decrease in beta2-adrenergic receptors.
PMID- 9545155
TI - Patient recall of therapeutic paralysis in a surgical critical care unit.
AB - STUDY OBJECTIVE: To investigate patient recall of therapeutic paralysis (TP) in a
surgical critical care unit. DESIGN: Prospectively applied structured interview
of patients undergoing TP over 18 months. SETTING: Surgical critical care unit
with 27 beds at a tertiary care university teaching hospital. PATIENTS: Forty
patients admitted for postoperative care after coronary artery bypass graft
surgery, trauma, or gastrointestinal surgery. INTERVENTIONS: Patients received TP
and concurrent sedation with benzodiazepines, propofol, and narcotics.
MEASUREMENTS AND MAIN RESULTS: After the end of TP patients were asked to recall
the experience, and their responses were ranked on a four-point ordinal scale.
Four of 11 patients recalled mostly negative events and experiences with TP, such
as sleeplessness, discomfort, pain, anxiety, and inconsistent caregiver
communication. All patients with recall experienced fear, anxiety, and
sleeplessness. Single-drug therapy with propofol and inadequate benzodiazepine
dosing were linked to patient recall. CONCLUSIONS: Patient recollection from TP
may be more common than appreciated and is generally unpleasant. Adequate dosing
with benzodiazepines and narcotics is warranted to prevent recall and discomfort.
PMID- 9545156
TI - Circadian variations in the pharmacokinetics of a new microemulsion formulation
of cyclosporine in cardiac transplant recipients.
AB - We attempted to characterize circadian variations in pharmacokinetic parameters
of a new formulation of cyclosporine (CsA) in nine cardiac allograft recipients.
A secondary objective was to determine the sampling time that correlated best
with exposure of patients to the drug. This was a two-period study with each
period lasting 12 hours. All patients received two equal doses of a new
microemulsion of CsA 12 hours apart. Blood samples to measure drug levels were
obtained at administration and 1, 2, 3, 4, 6, 9, and 12 hours after each dose. We
found no statistically significant difference in pharmacokinetic parameters
(areas under the curve, minimum blood concentration, oral clearance) measured
during the day and during the night. However, maximum blood concentrations during
the day were 30% higher than those at night (p<0.05). We found a good correlation
between minimum concentrations in the morning and overall exposure of patients to
CsA (r=0.89). This new microemulsion appears to have few circadian variations of
blood concentrations in cardiac transplant recipients. The clinical significance
of higher maximum blood concentration during daytime remains to be elucidated.
Our results support the most widely accepted method for monitoring CsA, which is
based on minimum concentrations in the morning.
PMID- 9545157
TI - Effect of pharmacokinetic sampling methods on aminoglycoside dosing in critically
ill surgery patients.
AB - We compared pharmacokinetic parameters derived from three aminoglycoside serum
concentration sampling methods and evaluated their effects on recommended
aminoglycoside dosing regimens in 60 critically ill surgery patients. Patients
had presumed or documented gram-negative sepsis, and had at least 4
aminoglycoside serum concentrations measured. We used a one-compartment model for
peak and trough, 3-point series, and 4-point series sampling methods. Dosing
regimens were calculated for each patient based on values derived from each
method. We found differences in regimens for nearly 50% of patients if either 4-
or 3-point series sampling was used to calculate the recommended dosage rather
than peak and trough sampling. However, the 3-point method required a clinically
significant change in regimen in only 12% of patients compared with 4-point
sampling. The variability of all values derived from 3-point sampling were well
accounted for by the 4-point method (r2 > 0.80). In addition, we noted
significantly greater relative precision for 3-point sampling than peak and
trough sampling for estimates of clearance, elimination rate, recommended daily
dosage, and recommended dosing frequency. We recommend three optimally timed
samples be drawn instead of peak and trough levels in dosing aminoglycosides in
critically ill surgery patients.
PMID- 9545158
TI - Nefazodone: single versus twice daily dose.
AB - This pilot study involved six men with major depression treated with nefazodone
dosed either twice/day or once/day at bedtime. Depression was rated before
nefazodone therapy and at 4 weeks by the self-report version of the Hamilton
Depression Rating Scale. A simple 10-cm visual analog side effect scale for
daytime drowsiness was completed at the latter time. Dosages of nefazodone were
at least 400 mg/day. The results suggest that nefazodone given once/day at
bedtime may be as effective as the currently accepted twice/day regimen, with
less daytime drowsiness.
PMID- 9545159
TI - Prolongation of the QT interval related to cisapride-diltiazem interaction.
AB - Cisapride, a cytochrome P450 3A4 (CYP3A4) substrate, is widely prescribed for the
treatment of gastrointestinal motility disorders. Prolongation of QT interval,
torsades de pointes, and sudden cardiac death have been reported after
concomitant administration with erythromycin or azole antifungal agents, but not
with other CYP3A4 inhibitors. A possible drug interaction occurred in a 45-year
old woman who was taking cisapride for gastroesophageal reflux disorder and
diltiazem, an agent that has inhibitory effect on CYP3A4, for hypertension. The
patient was in near syncope and had QT-interval prolongation. After discontinuing
cisapride, the QT interval returned to normal and symptoms did not recur. We
suggest that caution be taken when cisapride is prescribed with any potent
inhibitor of CYP3A4, including diltiazem.
PMID- 9545160
TI - Delayed elevation of international normalized ratio with concurrent
clarithromycin and warfarin therapy.
AB - Clarithromycin is rarely reported to cause disturbances in anticoagulation.
Theoretically, clarithromycin administered concurrently with warfarin could
result in enhanced anticoagulation, since many properties of clarithromycin are
similar to those of erythromycin, which interacts with warfarin. A search of the
National Library of Medicine produced no published reports of an interaction
between the drugs. Erythromycin competitively inhibits hepatic metabolism of
warfarin, specifically the R-warfarin enantiomer, by the cytochrome P450 3A3 and
3A4 pathways, resulting in increased prothrombin time and international
normalized ratio (INR). Two men, age 61 and 70 years, who received stable
warfarin regimens, experienced supratherapeutic elevations in prothrombin time
(98.4 and 26.8 sec) and INR (90.3 and 5.6), respectively. While taking warfarin,
both patients experienced dramatically increased anticoagulation effects 5 days
after starting clarithromycin for atypical pneumonia. They were similarly managed
for overanticoagulation by discontinuing clarithromycin, holding warfarin, and
receiving intravenous phytonadione. Neither man suffered from medical
complications related to anticoagulation. Until clear documentation of the exact
mechanism and temporal relationship of this interaction is known, patients
receiving warfarin who require the concurrent clarithromycin should have
prothrombin time and INR closely monitored.
PMID- 9545161
TI - Fatal toxic epidermal necrolysis related to lamotrigine administration.
AB - Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are severe
life-threatening dermatologic conditions. To date, eight cases of TEN and one of
SJS related to lamotrigine administration have been reported in the literature.
Most patients were also taking concomitant valproic acid. It was hypothesized
that valproic acid may interfere with glucuronidation of lamotrigine, leading to
increased serum lamotrigine levels, or perhaps alter the drug's metabolism,
resulting in accumulation of a toxic intermediate metabolite. Ultimately, this
may possibly predispose a patient to increased dermatologic reactions, including
TEN. A 54-year-old man developed TEN 4 weeks after beginning lamotrigine for
complex partial seizures related to a glioblastoma multiforme brain tumor. The
patient had also been taking concomitant allopurinol and captopril for more than
4 years with no complications, and valproic acid 3 months before the cutaneous
event. Despite aggressive intensive care management, the patient died 17 days
from the onset of symptoms due to multiple organ failure. Administration of
lamotrigine, especially in combination with valproic acid, may lead to the
development of TEN.
PMID- 9545162
TI - Serotonin syndrome secondary to phenelzine-venlafaxine interaction.
AB - A 44-year-old woman accidentally ingested phenelzine along with venlafaxine.
Thirty minutes after the ingestion the woman began to feel nauseous and anxious.
Approximately 45 minutes later a friend noted that the woman had lower extremity
shaking and increasingly rapid respirations. The friend brought the woman to the
emergency department and she was subsequently diagnosed with serotonin syndrome.
Serotonin syndrome is usually precipitated by combinations of serotonin
potentiating agents and can lead to devastating outcomes. When using combinations
of drugs that elevate serotonin levels in the central nervous system, the
possibility of serotonin syndrome should be considered.
PMID- 9545163
TI - Famotidine-associated mental status changes.
AB - A 77-year-old man who had taken ranitidine for several years for dyspepsia was
prescribed alternative therapy with famotidine 20 mg twice/day. He subsequently
developed mental status changes, with confusion, disorientation, and nightmares.
The symptoms dissipated after he discontinued famotidine for 2 days. He
rechallenged himself and experienced return of the symptoms shortly thereafter,
with additional visual hallucinations. His therapy was changed to lansoprazole,
and his symptoms again disappeared and have not recurred. Case reports of central
nervous system effects with other histamine2 antagonists have been published.
Eight cases occurred with famotidine, all of which were in hospitalized patients
receiving intravenous famotidine. We believe this is the first report of mental
status changes in an ambulatory patient taking oral famotidine. The elderly may
be particularly susceptible to such changes.
PMID- 9545164
TI - Subcutaneous enoxaparin for outpatient anticoagulation therapy in a patient with
an aortic valve replacement.
AB - Low-molecular-weight heparins have been administered for a variety of clinical
conditions. A patient with a mechanical aortic valve replacement patient
underwent elective transurethral prostatectomy. Anticoagulation was managed with
unfractionated heparin immediately preoperatively and postoperatively. Warfarin
was begun on postoperative day 1. The patient had a prolonged hospitalization due
to subtherapeutic international normalized ratios (INR) despite warfarin
administration. Because he intended to leave the hospital against medical advice
before therapeutic INR was achieved, enoxaparin 1 mg/kg subcutaneously every 12
hours was prescribed to provide anticoagulation, facilitating discharge and
improving the patient's quality of life. Enoxaparin was associated with an
approximate saving of $4500 over warfarin. The only adverse event reported was
bruising at the injection site.
PMID- 9545165
TI - Octreotide-induced bradycardia.
AB - Because of deleterious hemodynamic effects of octreotide in a nonacromegalic
patient with a pancreatic fistula, we conducted a MEDLINE search of English
language journal articles to extract information on this complication of
octreotide or somatostatin therapy. Few data are available regarding patients
with disease states other than acromegaly. We believe octreotide should be
considered when determining the cause of bradycardia.
PMID- 9545166
TI - The strategic plan of the American College of Clinical Pharmacy 1998-2000.
PMID- 9545167
TI - Clinical utility research: an introduction.
AB - Clinical utility research is concerned with how one develops knowledge that can
be directly used for improving clinical practice. Some have referred to this
domain as "effectiveness" research, but clinical utility implies much more than
clinical effectiveness. It also addresses issues of access, transferability,
sample specificity, and the uniqueness of each human condition. This special
series of papers describe several research programs that have been conducted in
applied settings and that illustrate research on clinical utility. These
descriptions are modestly representative of the wide applicability of research
methods that address the uniqueness of each setting and population and the nature
of findings that can be used to guide clinical practice. The papers bridge
cultures, countries, settings, and problems. They illustrate some of the
advantages of, and some of the knowledge to be gained from conducting controlled
research in settings that are devoted to clinical service.
PMID- 9545168
TI - Diagnosis and treatment of depression in primary medical care practice: the
application of research findings to clinical practice.
AB - Approximately 50% of persons experiencing clinical depression seek help for this
disorder from their primary care physician. This pattern of help-seeking has
stimulated interest in providing appropriate treatment for depressed primary
medical care patients. While the efficacy of both psychotherapy and
pharmacotherapy for depression have been demonstrated in the mental health
specialty sector, current research endeavors to establish the effectiveness of
such treatments when provided to primary medical care patients. We review and
discuss the clinical, practical, and methodological issues pertaining to the
transfer of depression research to routine primary care practice. Possible
directions for future research which will inform the continued applicability of
research findings to routine practice are discussed.
PMID- 9545169
TI - Research in training clinics: a bridge between science and practice.
AB - Clinics associated with psychology training programs have potential to generate
important research data. The expectation that research be experimental in nature
has limited the pursuit of research in training clinics. This type of efficacy
study is not feasible in most clinics, where too much variation occurs as a
result of training and administrative demands. Numerous process-outcome studies
have been effectively conducted in training clinics. This article reviews some of
these studies, identifies problems related to research in training clinics, and
makes recommendations for the development of an enhanced research agenda for
training clinics.
PMID- 9545170
TI - Factors associated to outcome in psychotherapy: an effectiveness study in Puerto
Rico.
AB - Psychotherapy research has not received much attention among Latinos in the U.S.
or in Latin America including Puerto Rico. The present study explores factors
associated with the effectiveness of psychotherapy with a sample of Puerto
Ricans. Seventy-nine persons who received psychotherapy participated in a study
aimed at evaluating the process and outcome of psychotherapy. Participants
completed a questionnaire on the effects of treatment on the presenting problem.
Information from the questionnaire and other information from the clinical
records included the BDI and the Symptom Check List-36 scores, the number of
sessions received, etc. constituted the data set. The results show that
symptomatic severity, age. the number of sessions, and the therapeutic alliance
were associated with effectiveness. Also, the alliance explained 45% of the
variance in effectiveness. The results suggest that the therapeutic alliance
merits further study in psychotherapy research and in clinical training.
PMID- 9545171
TI - The research program at AIGLE.
AB - The purpose of this work is to present the research program of a Clinical Center,
the AIGLE Foundation in Buenos Aires, Argentina. It describes the potentialities
and advantages of research in this context. It also describes the institute, the
types of patients treated and its professional staff. The program covers four
areas: determining the demand for psychotherapeutic care in the population at
large, studying the conditions making participation in community mental health
possible, analyzing and follow-up on the outcomes and studying the personal
styles of the therapists. Finally, this work discusses the usefulness and
applicability of these results for clinical practice.
PMID- 9545172
TI - From the laboratory to the hospital, adults to adolescents, and disorders to
personality: the case of psychological reactance.
AB - Study 1 assessed whether trait reactance in disturbed adolescents (ages 12 to 17)
is part of the same constellation of personality variables associated with
reactance in adults, and Study 2 examined whether reactance predicts inpatient
treatment duration and outcomes. Correlations between reactance and MMPI-A
variables among 76 inpatients (41 girls) showed that reactance is associated with
oppositional, nonaffiliative, and narcissistic traits in disturbed adolescents as
well as adults. Reactance predicted longer hospital stays among 176 adolescents
(90 girls), and also changes in aggression, mood problems, and substance abuse
among those in middle (n=89) but not early (n=87) adolescence. Additional
analyses identified "typically male" and "typically female" patterns of reactance
change relationships. The clinical significance and utility of these findings are
discussed.
PMID- 9545173
TI - Using feedback on patient progress to predict the outcome of psychotherapy.
AB - The Dose-Response and Phase Models are useful for informing quality assurance
research on the expected patterns for separate categories of outcomes in
psychotherapy. Moreover, these models predict the sequence of change for outcomes
that may be differentially valued by patients, therapists, stakeholders, and cost
managers. Valid feedback on the progress of treatment is critical because
patients, therapists, and cost managers make decisions about continuation and
focus of treatment while psychotherapy is in progress. In this study, the focus
is on the validity of feedback data for therapist appraisal of patient progress.
Feedback at patient intake, in early sessions of psychotherapy, and at later
sessions of psychotherapy is considered. Among the variables examined are patient
and therapist agreement on severity, level of severity, evidence of
remoralization, and evidence of symptomatic remission. Data are drawn from
archived records of 243 psychotherapy cases conducted in several managed care
service delivery settings. The implications of a therapist's use of feedback to
adjust the therapeutic process in an individual case are discussed.
PMID- 9545174
TI - Congenital muscular dystrophies: 1997 update.
AB - The congenital muscular dystrophies (CMDs) comprise a heterogeneous group of
muscle disorders with onset in utero or during the first year of life. Several
forms of CMD show various types of brain involvement in addition to a muscular
dystrophy. Two forms are defined at the molecular level: merosin deficient-CMD
caused by mutations in the LAMA2-gene on chromosome 6q2. Fukuyama congenital
muscular dystrophy (FCMD) is prevalent in Japan and caused by an as yet
unidentified gene on chromosome 9q31. At least two further forms of CMD with
brain involvement are nosologically well defined: Walker--Warburg-CMD is
characterized by lissencephaly type 11, eye dysgenesis and muscular dystrophy.
This autosomal recessive disorder is fatal or results in complete lack of
development. A similar but much milder phenotype with pachygyria of the brain,
various degrees of eye changes and milder muscular dystrophy that is compatible
with achievement of simple motor milestones has been described under the name of
muscle-eye-brain disease (MEB) in Finland. A number of nosologically less
distinct forms of muscular dystrophy have been outlined such as 'pure' CMD
without brain involvement, CMD with cerebellar hypoplasia or CMD type Ullrich
with hyperelasticity of the distal joints. Several other CMD phenotypes are
known, some of which are suggestive of more distinctly separate nosological
entities due to their occurrence in siblings or due to a characteristic pattern
of clinical, histopathological and imaging features, and await further
clarification.
PMID- 9545175
TI - Mechanisms of generalized absence epilepsy.
AB - Absence seizures represent bilaterally synchronous burst-firing of an ensemble of
reciprocally connected neuronal populations located in the thalamus and
neocortex. Recent studies demonstrate that neurons in the reticular thalamic
nucleus (nRt), thalamic relay neurons (RNs), and neocortical pyramidal cells
comprise a circuit that sustains the thalamocortical oscillatory burst-firing of
absence seizures. Recent studies have focused on three intrinsic neuronal
mechanisms that increase the likelihood of thalamocortical oscillations. The
first mechanism involves T-currents elicited by activating the T-type calcium
channel, which appear to trigger sustained burst-firing of thalamic neurons
during absence seizures. A second intrinsic mechanism is GABA B receptors which
can elicit longstanding hyperpolarization in thalamic neurons required to 'prime'
T-channels for sustained burst-firing. A third mechanism involves the ability of
GABA A receptors, located on nRt neurons, to mediate recurrent inhibition.
Enhanced activation of GABA A receptors on nRt neurons decreases the pacemaking
capacity of these cells, therefore decreasing the likelihood of generating
absence seizures. Cholinergic mechanisms through modulating cortical excitability
and excitatory amino acid mediated mechanisms through depolarizing thalamic
neurons also play a role in absence seizures.
PMID- 9545176
TI - Reflex sympathetic dystrophy associated with deep peroneal nerve entrapment.
AB - Reflex sympathetic dystrophy (RSD or causalgia) has been rarely reported in
children. We now report a 10-year-old boy with RSD in whom we performed extensive
ancillary investigations including thermography, bone scintigraphy and dermo
echography. The clinical, laboratory and ancillary studies reported here
highlight the profound focal acquired autonomic disturbance in this disorder. The
patient presented a compression of the deep peroneal nerve at the inferior
extensor retinaculum in the affected limb. Surgical decompression lead to rapid
improvement of the patient's condition. Peripheral nerve decompression should be
considered as a possible treatment of RSD in children, particularly those that
are refractory to conservative maneuvers.
PMID- 9545177
TI - Panniculitis due to potassium bromide.
AB - Potassium bromide again is well known to be surprisingly effective in patients
with severe myoclonic epilepsy in infants (SME). Rare side effects on the skin
reappeared, such as the febrile nodular panniculitis (Weber-Christian syndrome).
In 1993 we described the first three cases of necrotizing panniculitis and
introduced the term 'halogen panniculitis'. It is a systemic disease with crops
of subcutaneous nodules, fever, elevated sedimentation rate, hepatosplenomegalia,
and abdominal pain. Later severe necrosis of the skin and adipose tissue may
happen with deep ulcerations. History and course of five cases, described in this
paper, suggest either an allergy or toxic reason. Histologic picture shows
inflammation of adipose tissues with infiltrating lymphocytes, but lymphocyte
transformation test (LTT) was not reliable in diagnosing the disease. Possibly,
bromides act as a chemokine and stimulate inflammatory processes. Bromide can be
transformed into a bromine radical/free electron pair under UV irradiation at
228.8 nm in aqueous solution. The bromine radical may have detrimental effects on
the tissue. However, despite some research, the origin of halogen panniculitis
and similar diseases remains unclear.
PMID- 9545178
TI - Neuronal nuclear antigen (NeuN): a marker of neuronal maturation in early human
fetal nervous system.
AB - Neuronal nuclear antigen (NeuN) immunocytochemistry was studied in 15 normal
human fetal nervous systems of 8-24 weeks gestation and in four term neonates.
Material was derived from products of conception or from autopsy. Antigen
retrieval was enhanced for immunocytochemistry by microwave heating of formalin
fixed paraffin sections. NeuN appears highly specific as a marker of neuronal
nuclei in human fetal brain. Only rare nuclei are recognized in the germinal
matrix. Cerebellar external granule cells are more strongly immunoreactive than
postmigratory internal granule cells until 24 weeks gestation; by term most
internal and only a few external granule cells are recognized by NeuN antibody.
In the cerebrum, some reactive nuclei are demonstrated along radial glial fibers,
particularly near the cortical plate. Within the cortical plate, only deep
neurons (future layers 4-6) are marked at 19-22 weeks, but by 24 weeks most
neurons in the cortical plate exhibit immunoreactivity, though at term some in
layer 2 are still non-reactive. Some neurons fail to be recognized by NeuN at all
ages: Cajal-Retzius cells, Purkinje cells, inferior olivary and dentate nucleus
neurons, and sympathetic ganglion cells are examples. Despite their common origin
in the cerebellar tubercle, basal pontine neurons are strongly reactive even
before midgestation, hence NeuN does not predict embryonic origin. Neurons of
dorsal root and cranial nerve ganglia are reactive even at 8 weeks. This study of
normal fetal central nervous system provides a basis for neuropathological
evaluation and as a prelude to applications in cerebral dysgeneses.
PMID- 9545179
TI - Increased levels of GM2 ganglioside in fibroblasts from a patient with juvenile
Niemann-Pick disease type C.
AB - A 15-year-old boy was suffering from splenomegaly and a 10-year history of a
neurologic disorder that included mental retardation, vertical supranuclear gaze
palsy, dysarthria, ataxia, and dystonia. Bone marrow aspirates revealed foamy
cells with storage materials which were positive with filipin staining. Cultured
skin fibroblasts derived from the patient showed moderate loss of
sphingomyelinase activity and the impairment of cholesterol esterification. The
characteristic clinical presentations and typical histochemical findings of this
patient met the diagnostic criteria of Niemann-Pick disease type C (NPC). In the
fibroblasts from the patient, there was an accumulation of GM2 ganglioside around
their cytoplasms. Increased levels of glycolipids. including GM2 ganglioside are
reported in the cerebral cortex of NPC, but not in the fibroblasts. The
fibroblasts derived from NPC may reflect the abnormal metabolism of glycolipids
in the central nervous system of NPC.
PMID- 9545180
TI - Neuropathological characteristics and alteration of the dopamine D2 receptor in
hypoxic-ischemic basal ganglia necrosis.
AB - The neuropathological characteristics and alteration of the dopamine D2 receptor
(D2R) were investigated in 27 cases of hypoxic-ischemic basal ganglia necrosis
(BGN) by means of neuropathological and immunohistochemical methods. Perinatal
hypoxic-ischemic BGN manifested neuronal karyorrhexis as well as eosinophilia,
karyorrhexis being more predominant in preterm infants and eosinophilia more
predominant in full-term infants. Immunoreactivity to D2R was detected in the
cytoplasm and dendrites of small and large neurons in the basal ganglia, and
increased with neuronal maturation during the late gestational period in normal
human basal ganglia. The number of D2R-positive neurons was smaller in all cases
of acute BGN than that in controls, the areas of decreased D2R-positive neurons
corresponding to the damaged regions observed on HE staining. Furthermore,
neurons showed high expression of D2R in a few cases of remote BGN, suggesting
some plasticity as to the recovery of D2R. Thus, the neuropathological
characteristics of perinatal hypoxic-ischemic BGN may be related to neuronal
maturation during different developmental stages in each region, and D2R
development may play a role in the basal ganglia vulnerability to hypoxic
ischemia.
PMID- 9545181
TI - Benign partial epilepsy in infancy with complex partial seizures (Watanabe's
syndrome): 12 non-Japanese new cases.
AB - International epilepsy classification includes different epileptic syndromes with
favourable outcomes in pediatric age. In addition to these, other forms probably
exist and in various papers in international literature they are proposed as new
entities. This article presents a survey of benign complex partial epilepsy in
infancy, a new epileptic syndrome first proposed by Watanabe, in 1987. Our work
represents the only description of non-Japanese cases although similar but
familial cases had been referred by Vigevano in 1992. We present data for 12
children (aged up to 9 years) followed over 2 years who had all the typical
clinical features characterizing Watanabe's cases. For all of them we obtained
EEG seizure recordings demonstrating the partial nature of their fits, arising
from occipital or temporal regions. Interictal EEG were completely normal, both
in waking and sleep. Evolution demonstrated benign outcome and all the children
are seizure-free (eight of them have already stopped all medication) and all have
normal psychomotor development.
PMID- 9545182
TI - Severe infantile congenital myopathy with nemaline and cytoplasmic bodies: a case
report.
AB - A Japanese boy had marked generalized hypotonia and weakness and progressive
respiratory failure since birth. Left biceps brachii muscle biopsy at 47 days of
age showed marked variation in muscle fiber size, and nemaline and/or cytoplasmic
bodies in approximately 10% of the muscle fibers. To our knowledge, the presence
of nemaline and cytoplasmic bodies in the same muscle has not been previously
reported. The severity of his respiratory failure and muscle weakness were
thought to be related to muscle immaturity since there were many undifferentiated
type 2C fibers.
PMID- 9545183
TI - Paroxysmal tonic upgaze of childhood with ataxia: a benign transient dystonia
with autosomal dominant inheritance.
AB - Paroxysmal tonic upgaze of childhood with ataxia is a rare form of age related
dystonia. Out of 12 previously reported cases, three had a clinical history of
similar symptoms occurring in at least one first degree relative belonging to the
same or two consecutive generations. Autosomal dominant inheritance was therefore
hypothesized. We report on a family in which the disorder appeared in three
consecutive generations between ages 6 and 11 months, disappearing gradually and
spontaneously between ages 18 to 24 months. All affected individuals had normal
neurologic development. The pedigree analysis of previously reported cases and of
the family reported herein provides strong evidence that the disorder may be
inherited as an autosomal dominant trait and represents a form of transient
paroxysmal dystonia with benign long-term prognosis.
PMID- 9545184
TI - Neuropsychological recovery from childhood moyamoya disease.
AB - These reports describe mental recovery from childhood moyamoya disease wherein
comprehensive and valid neuropsychological testing is administered in serial
fashion. Two young children diagnosed with moyamoya disease underwent procedures
to achieve bilateral revascularization. Neuropsychological studies were
administered pre-operatively in one case and in serial fashion post-operatively
through longer-term follow-up in both cases. Results indicated a trend of gradual
improvements in both cases. The disease process and its postulated
neuroanatomical and hemodynamic relationship to the psychometric findings are
discussed.
PMID- 9545185
TI - A case report of remarkable improvement of motor disturbances with L-dopa in a
patient with post-diffuse axonal injury.
AB - A 9-year-old girl with rigidospastic quadriplegia as post-traumatic sequela was
reported. The distribution of lesions observed on a MRI implied diffuse axonal
injury; involvement of the substantia nigra was also detected. L-Dopa
administration was remarkably effective for relief of the rigidity. As a result,
she became able to walk on her knees and communicate by writing letters. L-Dopa
administration should be considered for patients who show rigidity as sequela of
diffuse axonal injury with involvement of the substantia nigra.
PMID- 9545186
TI - Trisomy 12p and epilepsy with myoclonic absences.
AB - We report the case of a 6-year-2-month-old female affected by trisomy 12p
syndrome. Seizures were typical myoclonic absences from both the clinical and EEG
points of view. Our patient and other sporadic reports in the literature seem to
support the hypothesis that, at least in some cases, myoclonic absences can be a
direct or indirect effect of a chromosomopathy.
PMID- 9545187
TI - Developmental signalling: a careful balancing act.
AB - Embryos of arthropods and chordates are patterned along the dorso-ventral axis by
a gradient of secreted morphogens of the Bmp4/Dpp family. This gradient now
appears to be shaped by the opposing activities of Bmp-sequestering proteins, on
the one hand, and Bmp-releasing metalloproteases, on the other.
PMID- 9545188
TI - Zebrafish genetics: harnessing horizontal gene transfer.
AB - The promiscuous spread of Tc1/mariner transposons across species implies that
host factors are relatively unimportant for their transposition. Heterologous
elements can integrate on expression of the corresponding transposases, an
approach that should greatly facilitate genetic analysis in the zebrafish.
PMID- 9545189
TI - Visual attention: controlling what we see and do.
AB - Controlling what we see and do in complex environments depends upon the
interaction of top-down control mechanisms located in the prefrontal cortex, on
the one hand, and bottom-up competition between objects for limited perceptual
resources in posterior cortical areas, on the other.
PMID- 9545190
TI - Translation control: connecting mitogens and the ribosome.
AB - The identification of 3-phosphoinositide-dependent kinase 1 (PDK1) as one of the
elusive 70 kDa S6 kinase kinases has filled a gap in the signaling pathway by
which extracellular receptors regulate translation. Will it cause us to
reconsider the relationships between previously identified members of the
pathway?
PMID- 9545191
TI - Population genetics: surviving under mutation pressure.
AB - Concern has been voiced about the survival of endangered species, and even the
long-term prospects for humans, in the face of accumulating deleterious
mutations. Two experiments have investigated the mutation accumulation process in
laboratory Drosophila populations, with apparently conflicting results.
PMID- 9545193
TI - Obesity: progress through genetic manipulation.
AB - Transgenic mice have been produced that either lack or overproduce
neuroregulatory substances implicated in the control of food intake and body
weight. Are such mice useful models for understanding the underlying etiology of
obesity in humans?
PMID- 9545192
TI - Cancer predisposition: where's the phosphate?
AB - Mutations in a protein phosphatase and a protein kinase cause hamartomatous
polyposis syndromes, which are characterised by the formation of multiple benign
polyps and an increased susceptibility to some types of cancer.
PMID- 9545194
TI - Temporal precision of the encoding of motion information by visual interneurons.
AB - BACKGROUND: There is much controversy about the timescale on which neurons
process and transmit information. On the one hand, a vast amount of information
can be processed by the nervous system if the precise timing of individual spikes
on a millisecond timescale is important. On the other hand, neuronal responses to
identical stimuli often vary considerably and stochastic response fluctuations
can exceed the mean response amplitude. Here, we examined the timescale on which
neural responses could be locked to visual motion stimuli. RESULTS: Spikes of
motion-sensitive neurons in the visual system of the blowfly are time-locked to
visual motion with a precision in the range of several tens of milliseconds.
Nevertheless, different motion-sensitive neurons with largely overlapping
receptive fields generate a large proportion of spikes almost synchronously. This
precision is brought about by stochastic rather than by motion-induced membrane
potential fluctuations elicited by the common peripheral input. The stochastic
membrane-potential fluctuations contain more power at frequencies above 30-40 Hz
than the motion-induced potential changes. A model of spike generation indicates
that such fast membrane-potential changes are a major determinant of the precise
timing of spikes. CONCLUSIONS: The timing of spikes in neurons of the motion
pathway of the blowfly is controlled on a millisecond timescale by fast membrane
potential fluctuations. Despite this precision, spikes do not lock to motion
stimuli on this timescale because visual motion does not induce sufficiently
rapid changes in the membrane potential.
PMID- 9545195
TI - Histone-GFP fusion protein enables sensitive analysis of chromosome dynamics in
living mammalian cells.
AB - BACKGROUND: The amplification of oncogenes in cancer cells is often mediated by
paired acentric chromatin bodies called double minute chromosomes (DMs), which
can accumulate to a high copy number because of their autonomous replication
during the DNA synthesis phase of the cell cycle and their subsequent uneven
distribution to daughter cells during mitosis. The mechanisms that control DM
segregation have been difficult to investigate, however, as the direct
visualization of DMs in living cells has been precluded because they are far
smaller than normal chromosomes. We have visualized DMs by developing a highly
sensitive method for observing chromosome dynamics in living cells. RESULTS: The
human histone H2B gene was fused to the gene encoding the green fluorescent
protein (GFP) of Aequorea victoria and transfected into human HeLa cells to
generate a stable line constitutively expressing H2B-GFP. The H2B-GFP fusion
protein was incorporated into nucleosomes without affecting cell cycle
progression. Using confocal microscopy, H2B-GFP allowed high-resolution imaging
of both mitotic chromosomes and interphase chromatin, and the latter revealed
various chromatin condensation states in live cells. Using H2B-GFP, we could
directly observe DMs in living cancer cells; DMs often clustered during anaphase,
and could form chromosomal 'bridges' between segregating daughter chromosomes.
Cytokinesis severed DM bridges, resulting in the uneven distribution of DMs to
daughter cells. CONCLUSIONS: The H2B-GFP system allows the high-resolution
imaging of chromosomes, including DMs, without compromising nuclear and
chromosomal structures and has revealed the distinctive clustering behavior of
DMs in mitotic cells which contributes to their asymmetric distribution to
daughter cells.
PMID- 9545196
TI - Dissociation of the signalling and antiviral properties of SDF-1-derived small
peptides.
AB - BACKGROUND: The chemokine receptor CXCR4 (a receptor for the Cys-X-Cys class of
chemokines) is a CD4-associated coreceptor for T-cell-tropic strains of human
immunodeficiency virus 1 (HIV-1) and represents a target for antiviral therapy.
Infection by T-tropic HIV-1 can be blocked by stromal-cell-derived factor-1 (SDF
1), the natural ligand of CXCR4. The broad variety of cells expressing CXCR4 and
the perturbations observed in mice deficient for SDF-1 suggest that antiviral
compounds antagonizing the signalling activity of CXCR4 might have severe side
effects in vivo. Compounds that interfere selectively with HIV entry and not with
SDF-1 signalling would therefore be useful. RESULTS: A series of peptides, each
of 13 residues, spanning the whole SDF-1alpha sequence were tested for their
ability to block HIV-1 infection. The antiviral and signalling properties of SDF
1 were retained by a peptide corresponding to its amino terminus. Removal of the
first two residues resulted in an antiviral antagonist of the SDF-1-CXCR4
signalling pathway. We prepared 234 single-substitution analogues and identified
one antiviral analogue that had drastically reduced agonistic or antagonistic
properties. The antiviral peptides competed with the monoclonal antibody 12G5 for
CXCR4 binding. Their antiviral activity seems to be due to receptor occupancy
rather than induction of receptor endocytosis. CONCLUSIONS: The amino terminus of
the SDF-1 chemokine is sufficient for signal transduction via CXCR4 and for
inhibition of HIV-1 entry, but these activities could be dissociated in a peptide
analogue. This peptide represents a lead molecule for the design of low molecular
weight antiviral drugs.
PMID- 9545197
TI - Repair of oxidatively damaged guanine in Saccharomyces cerevisiae by an
alternative pathway.
AB - BACKGROUND: Transversion mutations are caused by 8-oxoguanine (OG), a DNA lesion
produced by the spontaneous oxidation of guanine nucleotides, which mis-pairs
with adenine during replication. Resistance to this mutagenic threat is mediated
by the GO system, the components of which are functionally conserved in bacteria
and mammals. To date, only one of three GO system components has been identified
in the budding yeast Saccharomyces cerevisiae, namely the OG:C-specific
glycosylase/lyase yOgg1. Furthermore, S. cerevisiae has been reported to contain
a unique glycosylase/lyase activity, yOgg2, which excises OG residues opposite
adenines. Paradoxically, according to the currently accepted model, yOgg2
activity should increase the mutagenicity of OG lesions. Here we report the
isolation of yOgg2 and the elucidation of its role in oxidative mutagenesis.
RESULTS: Borohydride-dependent cross-linking using an OG-containing
oligonucleotide substrate led to the isolation of yOgg1 and a second protein,
Ntg1, which had previously been shown to process oxidized pyrimidines in DNA. We
demonstrate that Ntg1 has OG-specific glycosylase/lyase activity
indistinguishable from that of yOgg2. Targeted disruption of the NTG1 gene
resulted in complete loss of yOgg2 activity and yeast lacking NTG1 had an
elevated rate of A:T to C:G transversions. CONCLUSIONS: The Ntg1 and yOgg2
activities are encoded by a single gene. We propose that yOgg2 has evolved to
process OG:A mis-pairs that have arisen through mis-incorporation of 8-oxo-dGTP
during replication. Thus, the GO system in S. cerevisiae is fundamentally
distinct from that in bacteria and mammals.
PMID- 9545198
TI - Exogenous phospholipase D generates lysophosphatidic acid and activates Ras, Rho
and Ca2+ signaling pathways.
AB - BACKGROUND: Phospholipase D (PLD) hydrolyzes phospholipids to generate
phosphatidic acid (PA) and a free headgroup. PLDs occur as both intracellular and
secreted forms; the latter can act as potent virulence factors. Exogenous PLD has
growth-factor-like properties, in that it induces proto-oncogene transcription,
mitogenesis and cytoskeletal changes in target cells. The underlying mechanism is
unknown, although it is generally assumed that PLD action is mediated by PA
serving as a putative second messenger. RESULTS: In quiescent fibroblasts,
exogenous PLD (from Streptomyces chromofuscus) stimulated accumulation of the GTP
bound form of Ras, activation of mitogen-activated protein (MAP) kinase and DNA
synthesis, through the pertussis-toxin-sensitive inhibitory G protein Gi.
Furthermore, PLD mimicked bioactive lysophospholipids (but not PA) in inducing
Ca2+ mobilization, membrane depolarization and Rho-mediated neurite retraction.
PLD action was mediated by Iysophosphatidic acid (LPA) derived from
Iysophosphatidylcholine acting on cognate G-protein-coupled LPA receptor(s).
There was no evidence for the involvement of PA in mediating the effects of
exogenous PLD. CONCLUSIONS: Our results provide a molecular explanation for the
multiple cellular responses to exogenous PLDs. These PLDs generate bioactive LPA
from pre-existing Iysophosphatidylcholine in the outer membrane leaflet,
resulting in activation of G-protein-coupled LPA receptors and consequent
activation of Ras, Rho and Ca2+ signaling pathways. Unscheduled activation of LPA
receptors may underlie, at least in part, the known pathogenic effects of
exogenous PLDs.
PMID- 9545199
TI - Wing development and specification of dorsal cell fates in the absence of
apterous in Drosophila.
AB - The development and patterning of the Drosophila wing relies on interactions
between cell populations that have the anteroposterior (AP) axis and dorsoventral
(DV) axis of the wing imaginal disc as frames of reference [1-3]. Each of these
cell populations gives rise to a compartment - a group of cells that have their
fates restricted by cell lineage - within which cells acquire specific identities
through the expression of 'selector' genes [1,2,4]. The genes engrailed (en) and
invected (inv), for example, label cells in the posterior compartment and mediate
a set of cell interactions that direct the patterning and growth of the wing
along the AP axis [1,2,4]. A similar situation has been proposed to exist across
the DV axis, along with apterous (ap) as a dorsal selector gene [5], mediating
cell interactions by regulating the expression of Serrate (Ser) [6] [7] and
fringe (fng) [8]. In ap mutants, the wing is lost [5] [9], and here we report
that this phenotype can be rescued by ectopic expression of either Ser or fng and
that, surprisingly, the resulting wings have both dorsal and ventral cell fates.
PMID- 9545200
TI - Direct isolation, phenotyping and cloning of low-frequency antigen-specific
cytotoxic T lymphocytes from peripheral blood.
AB - Cytotoxic T lymphocytes (CTLs) play an important role in controlling viral
infections and certain tumours, but characterising specific CTL responses has
always been technically limited. Fluorogenic 'tetramers' of major
histocompatibility complex (MHC) class I complexes have been exploited recently
to quantify the massive expansion of specific CTLs in human immunodeficiency
virus (HIV) infection [1]. Here, we use MHC class I complex tetramers to isolate
low-frequency antigen-specific CTLs directly from human peripheral blood,
allowing the simultaneous phenotypic and functional characterisation and cloning
of these CTLs. We synthesised a tetramer that specifically stained human
leukocyte antigen (HLA)-A2. 1-restricted CTL clones recognising the influenza
matrix protein peptide 58-66, matrix 58-66 [2]. This tetramer stained between 1
in 1,500 and 1 in 58,000 peripheral blood mononuclear cells (PBMCs) from HLA
A2.1+ individuals. The surface phenotype of these cells could be analysed by
fluorescence-activated cell sorting (FACS), and the cells could be directly
sorted into enzyme-linked immunospot (ELISpot) plates, where they released
interferon-gamma (IFN-gamma) within 1 day of antigen exposure. The same
population was cloned by FACS, and the specificity of several expanded clones was
confirmed. Cloning was greatly simplified and accelerated compared with standard
protocols, and was highly efficient. We also used tetramer-based sorting to
enrich melanoma-specific CTLs derived from a tumour-infiltrated lymph node.
Direct cloning of specific CTLs from peripheral blood can provide important
information about immunological memory, CTL responses against tumour antigens and
CTL proliferation and function, and opens up new possibilities for generating
CTLs for adoptive immunotherapy.
PMID- 9545201
TI - Use of a fusion protein between GFP and an actin-binding domain to visualize
transient filamentous-actin structures.
AB - Many important processes in eukaryotic cells involve changes in the quantity,
location and the organization of actin filaments [1] [2] [3]. We have been able
to visualize these changes in live cells using a fusion protein (GFP-ABD)
comprising the green fluorescent protein (GFP) of Aequorea victoria and the 25
kDa highly conserved actin-binding domain (ABD) from the amino terminus of the
actin cross-linking protein ABP-120 [4]. In live cells of the soil amoeba
Dictyostelium that were expressing GFP-ABD, the three-dimensional architecture of
the actin cortex was clearly visualized. The pattern of GFP-ABD fluorescence in
these cells coincided with that of rhodamine-phalloidin, indicating that GFP-ABD
specifically binds filamentous (F) actin. On the ventral surface of non-polarized
vegetative cells, a broad ring of F actin periodically assembled and contracted,
whereas in polarized cells there were transient punctate F-actin structures;
cells cycled between the polarized and non-polarized morphologies. During the
formation of pseudopods, an increase in fluorescence intensity coincided with the
initial outward deformation of the membrane. This is consistent with the models
of pseudopod extension that predict an increase in the local density of actin
filaments. In conclusion, GFP-ABD specifically binds F actin and allows the
visualization of F-actin dynamics and cellular behavior simultaneously.
PMID- 9545203
TI - Curiosity and a dash of good luck
PMID- 9545204
TI - A lust for science
PMID- 9545202
TI - Identification of a common docking topology with substantial variation among
different TCR-peptide-MHC complexes.
AB - Whether T-cell receptors (TCRs) recognize antigenic peptides bound to major
histocompatability complex (MHC) molecules through common or distinct docking
modes is currently uncertain. We report the crystal structure of a complex
between the murine N15 TCR [1-4] and its peptide-MHC ligand, an octapeptide
fragment representing amino acids 52-59 of the vesicular stomatitis virus nuclear
capsid protein (VSV8) bound to the murine H-2Kb class I MHC molecule. Comparison
of the structure of the N15 TCR-VSV8-H-2Kb complex with the murine 2C TCR-dEV8-H
2Kb [5] and the human A6 TCR-Tax-HLA-A2 [6] complexes revealed a common docking
mode, regardless of TCR specificity or species origin, in which the TCR variable
Valpha domain overlies the MHC alpha2 helix and the Vbeta domain overlies the MHC
alpha1 helix. As a consequence, the complementary determining regions CDR1 and
CDR3 of the TCR Valpha and Vbeta domains make the major contacts with the
peptide, while the CDR2 loops interact primarily with the MHC. Nonetheless, in
terms of the details of the relative orientation and disposition of binding,
there is substantial variation in TCR parameters, which we term twist, tilt and
shift, and which define the variation of the V module of the TCR relative to the
MHC antigen-binding groove.
PMID- 9545205
TI - Negative equity
PMID- 9545206
TI - Hidden agenders
PMID- 9545208
TI - Cell asymmetry in development.
PMID- 9545210
TI - Stormy weather in galaxy clusters
AB - Recent x-ray, optical, and radio observations coupled with particle and gas
dynamics numerical simulations reveal an unexpectedly complex environment within
clusters of galaxies, driven by ongoing accretion of matter from large-scale
supercluster filaments. Mergers between clusters and continuous infall of dark
matter and baryons from the cluster periphery produce long-lived "stormy weather"
within the gaseous cluster atmosphere-shocks, turbulence, and winds of more than
1000 kilometers per second. This weather may be responsible for shaping a rich
variety of extended radio sources, which in turn act as "barometers" and
"anemometers" of cluster weather.
PMID- 9545207
TI - The NB-ARC domain: a novel signalling motif shared by plant resistance gene
products and regulators of cell death in animals.
PMID- 9545211
TI - Protactinium-231 and thorium-230 abundances and high scavenging rates in the
western arctic ocean
AB - The Canadian Basin of the Arctic Ocean, largely ice covered and isolated from
deep contact with the more dynamic Eurasian Basin by the Lomonosov Ridge, has
historically been considered an area of low productivity and particle flux and
sluggish circulation. High-sensitivity mass-spectrometric measurements of the
naturally occurring radionuclides protactinium-231 and thorium-230 in the deep
Canada Basin and on the adjacent shelf indicate high particle fluxes and
scavenging rates in this region. The thorium-232 data suggest that offshore
advection of particulate material from the shelves contributes to scavenging of
reactive materials in areas of permanent ice cover.
PMID- 9545212
TI - Is GRO J1744-28 a strange star?
AB - The unusual hard x-ray burster GRO J1744-28 recently discovered by the Compton
Gamma-Ray Observatory can be modeled as a strange star with a dipolar magnetic
field of =10(11) gauss. According to this model, when the accreted mass of the
star exceeds some critical mass, its crust breaks, resulting in the conversion of
the accreted matter into strange matter and a release of energy. Subsequently, a
fireball forms and expands relativistically outward. The expanding fireball
interacts with the surrounding interstellar medium, causing its kinetic energy to
be radiated in shock waves and producing a burst of x-ray radiation. The burst
energy, duration, interval, and spectrum derived from such a model are consistent
with the observations of GRO J1744-28.
PMID- 9545213
TI - Two-fraction model of initial sediment motion in gravel-Bed rivers
AB - The prediction of sediment transport in gravel-bed rivers is essential to the
management of land, water, and ecological resources in mountain regions. Dividing
the bed sediment into two populations-sand and gravel-permits realistic and
useful predictions of the onset of sediment transport. The critical flow
initiating grain motion decreases rapidly with sand content over the transition
from a gravel-framework bed to a sand-matrix bed. The two-fraction model provides
a simple means of forecasting the movement of excess fine sediment supply. The
model also helps to explain the development of the abrupt gravel-sand transition
commonly observed in natural rivers.
PMID- 9545214
TI - Formation of carbonates in the Tatahouine meteorite.
AB - The Tatahouine meteorite, in southern Tunisia, shows terrestrial contamination
that developed during 63 years of exposure on Earth's surface. Samples collected
on the day of the fall in 1931 contained fractures, with no secondary minerals,
whereas samples collected in 1994 contain calcite aggregates (70 to 150
micrometers) and rod-shaped forms (100 to 600 nanometers in length and 70 to 80
nanometers in diameter) on the fractures. Carbon isotope analysis of the
carbonates within the Tatahouine meteorite [delta13C = -2.0 per mil Pee Dee
belemnite standard (PDB)] and the underlying ground (delta13C = -3.2 per mil PDB)
confirm their terrestrial origin.
PMID- 9545216
TI - Osmium isotopic evidence for ancient subcontinental lithospheric mantle beneath
the kerguelen islands, southern indian ocean
AB - Upper mantle xenoliths found in ocean island basalts are an important window
through which the oceanic mantle lithosphere may be viewed directly. Osmium
isotopic data on peridotite xenoliths from the Kerguelen Islands, an archipelago
that is located on the northern Kerguelen Plateau in the southern Indian Ocean,
demonstrate that pieces of mantle of diverse provenance are present beneath the
Islands. In particular, peridotites with unradiogenic osmium and ancient rhenium
depletion ages (to 1.36 x 10(9) years old) may be pieces of the Gondwanaland
subcontinental lithosphere that were incorporated into the Indian Ocean
lithosphere as a result of the rifting process.
PMID- 9545215
TI - Oxygen isotopic abundances in calcium- aluminum-rich inclusions from ordinary
chondrites: implications for nebular heterogeneity.
AB - The oxygen isotopic compositions of two calcium-aluminum-rich inclusions (CAIs)
from the unequilibrated ordinary chondrite meteorites Quinyambie and Semarkona
are enriched in 16O by an amount similar to that in CAIs from carbonaceous
chondrites. This may indicate that most CAIs formed in a restricted region of the
solar nebula and were then unevenly distributed throughout the various chondrite
accretion regions. The Semarkona CAI is isotopically homogeneous and contains
highly 16O-enriched melilite, supporting the hypothesis that all CAI minerals
were originally 16O-rich, but that in most carbonaceous chondrite inclusions some
minerals exchanged oxygen isotopes with an external reservoir following
crystallization.
PMID- 9545218
TI - A monolithic photovoltaic-photoelectrochemical device for hydrogen production via
water splitting
AB - Direct water electrolysis was achieved with a novel, integrated, monolithic
photoelectrochemical-photovoltaic design. This photoelectrochemical cell, which
is voltage biased with an integrated photovoltaic device, splits water directly
upon illumination; light is the only energy input. The hydrogen production
efficiency of this system, based on the short-circuit current and the lower
heating value of hydrogen, is 12.4 percent.
PMID- 9545217
TI - Unitary control in quantum ensembles: maximizing signal intensity in coherent
spectroscopy
AB - Experiments in coherent magnetic resonance, microwave, and optical spectroscopy
control quantum-mechanical ensembles by guiding them from initial states toward
target states by unitary transformation. Often, the coherences detected as
signals are represented by a non-Hermitian operator. Hence, spectroscopic
experiments, such as those used in nuclear magnetic resonance, correspond to
unitary transformations between operators that in general are not Hermitian. A
gradient-based systematic procedure for optimizing these transformations is
described that finds the largest projection of a transformed initial operator
onto the target operator and, thus, the maximum spectroscopic signal. This method
can also be used in applied mathematics and control theory.
PMID- 9545220
TI - Association of the AP-3 adaptor complex with clathrin.
AB - A heterotetrameric complex termed AP-3 is involved in signal-mediated protein
sorting to endosomal-lysosomal organelles. AP-3 has been proposed to be a
component of a nonclathrin coat. In vitro binding assays showed that mammalian AP
3 did associate with clathrin by interaction of the appendage domain of its beta3
subunit with the amino-terminal domain of the clathrin heavy chain. The beta3
appendage domain contained a conserved consensus motif for clathrin binding. AP-3
colocalized with clathrin in cells as observed by immunofluorescence and
immunoelectron microscopy. Thus, AP-3 function in protein sorting may depend on
clathrin.
PMID- 9545219
TI - Gastrointestinal tract as a major site of CD4+ T cell depletion and viral
replication in SIV infection.
AB - Human and simian immunodeficiency virus (HIV and SIV) replicate optimally in
activated memory CD4(+) T cells, a cell type that is abundant in the intestine.
SIV infection of rhesus monkeys resulted in profound and selective depletion of
CD4+ T cells in the intestine within days of infection, before any such changes
in peripheral lymphoid tissues. The loss of CD4+ T cells in the intestine
occurred coincident with productive infection of large numbers of mononuclear
cells at this site. The intestine appears to be a major target for SIV
replication and the major site of CD4+ T cell loss in early SIV infection.
PMID- 9545221
TI - NMR structure of a classical pseudoknot: interplay of single- and double-stranded
RNA.
AB - Pseudoknot formation folds the 3' ends of many plant viral genomic RNAs into
structures that resemble transfer RNA in global folding and in their reactivity
to transfer RNA-specific proteins. The solution structure of the pseudoknotted T
arm and acceptor arm of the transfer RNA-like structure of turnip yellow mosaic
virus (TYMV) was determined by nuclear magnetic resonance (NMR) spectroscopy. The
molecule is stabilized by the hairpin formed by the 5' end of the RNA, and by the
intricate interactions related to the loops of the pseudoknot. Loop 1 spans the
major groove of the helix with only two of its four nucleotides. Loop 2, which
crosses the minor groove, interacts closely with its opposing helix, in
particular through hydrogen bonds with a highly conserved adenine. The structure
resulting from this interaction between the minor groove and single-stranded RNA
at helical junctions displays internal mobility, which may be a general feature
of RNA pseudoknots that regulates their interaction with proteins or other RNA
molecules.
PMID- 9545222
TI - Autoinducer of virulence as a target for vaccine and therapy against
Staphylococcus aureus.
AB - Staphylococcus aureus causes pathologies ranging from minor skin infections to
life-threatening diseases. Pathogenic effects are largely due to production of
bacterial toxin, which is regulated by an RNA molecule, RNAIII. The S. aureus
protein called RAP (RNAIII activating protein) activates RNAIII, and a peptide
called RIP (RNAIII inhibiting peptide), produced by a nonpathogenic bacteria,
inhibits RNAIII. Mice vaccinated with RAP or treated with purified or synthetic
RIP were protected from S. aureus pathology. Thus, these two molecules may
provide useful approaches for the prevention and treatment of diseases caused by
S. aureus.
PMID- 9545223
TI - Impacts of rising atmospheric carbon dioxide on model terrestrial ecosystems
AB - In model terrestrial ecosystems maintained for three plant generations at
elevated concentrations of atmospheric carbon dioxide, increases in
photosynthetically fixed carbon were allocated below ground, raising
concentrations of dissolved organic carbon in soil. These effects were then
transmitted up the decomposer food chain. Soil microbial biomass was unaffected,
but the composition of soil fungal species changed, with increases in rates of
cellulose decomposition. There were also changes in the abundance and species
composition of Collembola, fungal-feeding arthropods. These results have
implications for long-term feedback processes in soil ecosystems that are subject
to rising global atmospheric carbon dioxide concentrations.
PMID- 9545224
TI - Control of alternative splicing of potassium channels by stress hormones.
AB - Many molecular mechanisms for neural adaptation to stress remain unknown.
Expression of alternative splice variants of Slo, a gene encoding calcium- and
voltage-activated potassium channels, was measured in rat adrenal chromaffin
tissue from normal and hypophysectomized animals. Hypophysectomy triggered an
abrupt decrease in the proportion of Slo transcripts containing a "STREX" exon.
The decrease was prevented by adrenocorticotropic hormone injections. In Xenopus
oocytes, STREX variants produced channels with functional properties associated
with enhanced repetitive firing. Thus, the hormonal stress axis is likely to
control the excitable properties of epinephrine-secreting cells by regulating
alternative splicing of Slo messenger RNA.
PMID- 9545225
TI - Maternal control of embryogenesis by MEDEA, a polycomb group gene in Arabidopsis.
AB - The gametophytic maternal effect mutant medea (mea) shows aberrant growth
regulation during embryogenesis in Arabidopsis thaliana. Embryos derived from mea
eggs grow excessively and die during seed desiccation. Embryo lethality is
independent of the paternal contribution and gene dosage. The mea phenotype is
consistent with the parental conflict theory for the evolution of parent-of
origin-specific effects. MEA encodes a SET domain protein similar to Enhancer of
zeste, a member of the Polycomb group. In animals, Polycomb group proteins ensure
the stable inheritance of expression patterns through cell division and regulate
the control of cell proliferation.
PMID- 9545226
TI - Cathepsin L: critical role in Ii degradation and CD4 T cell selection in the
thymus.
AB - Degradation of invariant chain (Ii) is a critical step in major
histocompatibility complex class II-restricted antigen presentation. Cathepsin L
was found to be necessary for Ii degradation in cortical thymic epithelial cells
(cTECs), but not in bone marrow (BM)-derived antigen-presenting cells (APCs).
Consequently, positive selection of CD4+ T cells was reduced. Because different
cysteine proteinases are responsible for specific Ii degradation steps in cTECs
and BM-derived APCs, the proteolytic environment in cells mediating positive and
negative selection may be distinct. The identification of a protease involved in
class II presentation in a tissue-specific manner suggests a potential means of
manipulating CD4+ T cell responsiveness in vivo.
PMID- 9545227
TI - Perturbation of beta1-integrin function alters the development of murine mammary
gland.
AB - The expression of a transgene coding for a chimeric molecule, containing the
cytoplasmic and transmembrane domains of the beta1-integrin chain and the
extracellular domain of the T-cell differentiation antigen CD4, was targeted to
the mouse mammary gland by the mouse mammary tumor virus (MMTV) promoter. The
chimera does not interact with the extracellular ligands; however, its expression
in cultured cells was shown to interfere with focal adhesion kinase (FAK)
phosphorylation following ligation of endogenous beta1-integrin. Therefore,
expression of the transgenic protein on the cell surface should uncouple adhesion
from intracellular events associated with the beta1-cytoplasmic domain and thus
perturb beta1-integrin functions. Although most of the transgenic females were
able to lactate, their mammary glands had a phenotype clearly distinct from that
of wild-type mice. At mid-pregnancy and the beginning of lactation, transgenic
glands were underdeveloped and the epithelial cell proliferation rates were
decreased, while the apoptosis levels were higher than in wild-type glands. In
lactation, the amounts of the whey acidic protein (WAP) and beta-casein gene
transcripts were diminished, and the basement membrane component, laminin and the
beta4-integrin chain accumulated at the lateral surface of luminal epithelial
cells, revealing defects in polarization. Our observations prove that in vivo,
beta1-integrins are involved in control of proliferation, apoptosis,
differentiation and maintenance of baso-apical polarity of mammary epithelial
cells, and therefore are essential for normal mammary gland development and
function.
PMID- 9545228
TI - Dileucine-based sorting signals bind to the beta chain of AP-1 at a site distinct
and regulated differently from the tyrosine-based motif-binding site.
AB - In previous work, we showed that peptides from endocytosed proteins containing
the tyrosine YXXphi sorting motif are recognized by the mu 2 subunit of AP-2, the
plasma membrane clathrin adaptor protein complex. This interaction is activated
by phosphoinositide lipids that are phosphorylated at the D-3 position of the
inositol ring, and is also enhanced by the formation of clathrin-AP-2 coats.
Here, we describe the detection of a specific interaction between peptides
containing a second sorting motif, the dileucine motif, and AP-1, the clathrin
adaptor complex responsible for sorting proteins at the trans-Golgi network
(TGN). Surprisingly, the site of dileucine binding is the beta1 subunit, not mu
1. A YXXphi-containing peptide from a protein trafficked within the TGN does bind
to mu 1, however. Phosphatidylinositol 3,4-diphosphate and 3,4, 5-triphosphate
did not activate the interaction between dileucine-containing peptides and AP-1
but instead inhibited it, and clathrin-AP-1 coat formation did not alter the
interaction. Thus, there are at least two physically separate binding sites for
sorting signals on APs, which are also regulated independently.
PMID- 9545229
TI - Initial docking of ER-derived vesicles requires Uso1p and Ypt1p but is
independent of SNARE proteins.
AB - ER-to-Golgi transport in yeast may be reproduced in vitro with washed membranes,
purified proteins (COPII, Uso1p and LMA1) and energy. COPII coated vesicles that
have budded from the ER are freely diffusible but then dock to Golgi membranes
upon the addition of Uso1p. LMA1 and Sec18p are required for vesicle fusion after
Uso1p function. Here, we report that the docking reaction is sensitive to excess
levels of Sec19p (GDI), a treatment that removes the GTPase, Ypt1p. Once docked,
however, vesicle fusion is no longer sensitive to GDI. In vitro binding
experiments demonstrate that the amount of Uso1p associated with membranes is
reduced when incubated with GDI and correlates with the level of membrane-bound
Ypt1p, suggesting that this GTPase regulates Uso1p binding to membranes. To
determine the influence of SNARE proteins on the vesicle docking step,
thermosensitive mutations in Sed5p, Bet1p, Bos1p and Sly1p that prevent ER-to
Golgi transport in vitro at restrictive temperatures were employed. These
mutations do not interfere with Uso1p-mediated docking, but block membrane
fusion. We propose that an initial vesicle docking event of ER-derived vesicles,
termed tethering, depends on Uso1p and Ypt1p but is independent of SNARE
proteins.
PMID- 9545230
TI - A novel EspA-associated surface organelle of enteropathogenic Escherichia coli
involved in protein translocation into epithelial cells.
AB - Enteropathogenic Escherichia coli (EPEC), like many bacterial pathogens, employ a
type III secretion system to deliver effector proteins across the bacterial cell.
In EPEC, four proteins are known to be exported by a type III secretion
system_EspA, EspB and EspD required for subversion of host cell signal
transduction pathways and a translocated intimin receptor (Tir) protein (formerly
Hp90) which is tyrosine-phosphorylated following transfer to the host cell to
become a receptor for intimin-mediated intimate attachment and 'attaching and
effacing' (A/E) lesion formation. The structural basis for protein translocation
has yet to be fully elucidated for any type III secretion system. Here, we
describe a novel EspA-containing filamentous organelle that is present on the
bacterial surface during the early stage of A/E lesion formation, forms a
physical bridge between the bacterium and the infected eukaryotic cell surface
and is required for the translocation of EspB into infected epithelial cells.
PMID- 9545231
TI - Ramifications of kinetic partitioning on usher-mediated pilus biogenesis.
AB - The biogenesis of diverse adhesive structures in a variety of Gram-negative
bacterial species is dependent on the chaperone/usher pathway. Very little is
known about how the usher protein translocates protein subunits across the outer
membrane or how assembly of these adhesive structures occurs. We have discovered
several mechanisms by which the usher protein acts to regulate the ordered
assembly of type 1 pili, specifically through critical interactions of the
chaperone-adhesin complex with the usher. A study of association and dissociation
events of chaperone-subunit complexes with the usher in real time using surface
plasmon resonance revealed that the chaperone-adhesin complex has the tightest
and fastest association with the usher. This suggests that kinetic partitioning
of chaperone-adhesin complexes to the usher is a defining factor in tip
localization of the adhesin in the pilus. Furthermore, we identified and purified
a chaperone-adhesin-usher assembly intermediate that was formed in vivo. Trypsin
digestion assays showed that the usher in this complex was in an altered
conformation, which was maintained during pilus assembly. The data support a
model in which binding of the chaperone-adhesin complex to the usher stabilizes
the usher in an assembly-competent conformation and allows initiation of pilus
assembly.
PMID- 9545232
TI - ER-60, a chaperone with thiol-dependent reductase activity involved in MHC class
I assembly.
AB - The assembly of newly synthesized MHC class I molecules within the endoplasmic
reticulum and their association with the transporter associated with antigen
processing (TAP) is a process involving the chaperones calnexin and calreticulin.
Using peptide mapping by matrix-assisted laser desorption/ionization (MALDI) mass
spectrometry to identify a new component, we now introduce a third molecular
chaperone, the thiol-dependent reductase ER-60 (ERp57/GRP58/ERp61/HIP-70/Q2),
into this process. ER-60 is found in MHC class I heavy chain complexes with
calnexin that are generated early during the MHC class I assembly pathway. The
thiol reductase activity of ER-60 raises the possibility that ER-60 is involved
in the disulfide bond formation within heavy chains. In addition, ER-60 is part
of the late assembly complexes consisting of MHC class I, tapasin, TAP,
calreticulin and calnexin. In a beta2-microglobulin (beta2m)-negative mouse cell
line, S3, ER-60-calnexin-heavy chain complexes are shown to bind to TAP,
suggesting that beta2m is not required for the association of MHC class I heavy
chains with TAP.
PMID- 9545234
TI - A novel protein modification pathway related to the ubiquitin system.
AB - Ubiquitin conjugation is known to target protein substrates primarily to
degradation by the proteasome or via the endocytic route. Here we describe a
novel protein modification pathway in yeast which mediates the conjugation of
RUB1, a ubiquitin-like protein displaying 53% amino acid identity to ubiquitin.
We show that RUB1 conjugation requires at least three proteins in vivo. ULA1 and
UBA3 are related to the N- and C-terminal domains of the E1 ubiquitin-activating
enzyme, respectively, and together fulfil E1-like functions for RUB1 activation.
RUB1 conjugation also requires UBC12, a protein related to E2 ubiquitin
conjugating enzymes, which functions analogously to E2 enzymes in RUB1-protein
conjugate formation. Conjugation of RUB1 is not essential for normal cell growth
and appears to be selective for a small set of substrates. Remarkably,
CDC53/cullin, a common subunit of the multifunctional SCF ubiquitin ligase, was
found to be a major substrate for RUB1 conjugation. This suggests that the RUB1
conjugation pathway is functionally affiliated to the ubiquitin-proteasome system
and may play a regulatory role.
PMID- 9545233
TI - Mtr10p functions as a nuclear import receptor for the mRNA-binding protein Npl3p.
AB - MTR10, previously shown to be involved in mRNA export, was found in a synthetic
lethal relationship with nucleoporin NUP85. Green fluorescent protein (GFP)
tagged Mtr10p localizes preferentially inside the nucleus, but a nuclear pore and
cytoplasmic distribution is also evident. Purified Mtr10p forms a complex with
Npl3p, an RNA-binding protein that shuttles in and out of the nucleus. In mtr10
mutants, nuclear uptake of Npl3p is strongly impaired at the restrictive
temperature, while import of a classic nuclear localization signal (NLS)
containing protein is not. Accordingly, the NLS within Npl3p is extended and
consists of the RGG box plus a short and non-repetitive C-terminal tail. Mtr10p
interacts in vitro with Gsp1p-GTP, but with low affinity. Interestingly, Npl3p
dissociates from Mtr10p only by incubation with Ran-GTP plus RNA. This suggests
that Npl3p follows a distinct nuclear import pathway and that intranuclear
release from its specific import receptor Mtr10p requires the cooperative action
of both Ran-GTP and newly synthesized mRNA.
PMID- 9545235
TI - IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct
inhibition of distinct caspases.
AB - Inhibitor of apoptosis (IAP) gene products play an evolutionarily conserved role
in regulating programmed cell death in diverse species ranging from insects to
humans. Human XIAP, cIAP1 and cIAP2 are direct inhibitors of at least two members
of the caspase family of cell death proteases: caspase-3 and caspase-7. Here we
compared the mechanism by which IAPs interfere with activation of caspase-3 and
other effector caspases in cytosolic extracts where caspase activation was
initiated by caspase-8, a proximal protease activated by ligation of TNF-family
receptors, or by cytochrome c, which is released from mitochondria into the
cytosol during apoptosis. These studies demonstrate that XIAP, cIAP1 and cIAP2
can prevent the proteolytic processing of pro-caspases -3, -6 and -7 by blocking
the cytochrome c-induced activation of pro-caspase-9. In contrast, these IAP
family proteins did not prevent caspase-8-induced proteolytic activation of pro
caspase-3; however, they subsequently inhibited active caspase-3 directly, thus
blocking downstream apoptotic events such as further activation of caspases.
These findings demonstrate that IAPs can suppress different apoptotic pathways by
inhibiting distinct caspases and identify pro-caspase-9 as a new target for IAP
mediated inhibition of apoptosis.
PMID- 9545236
TI - Caspase-mediated activation and induction of apoptosis by the mammalian Ste20
like kinase Mst1.
AB - Mst1 is a ubiquitously expressed serine-threonine kinase, homologous to the
budding yeast Ste20, whose physiological regulation and cellular function are
unknown. In this paper we show that Mst1 is specifically cleaved by a caspase 3
like activity during apoptosis induced by either cross-linking CD95/Fas or by
staurosporine treatment. CD95/Fas-induced cleavage of Mst1 was blocked by the
cysteine protease inhibitor ZVAD-fmk, the more selective caspase inhibitor DEVD
CHO and by the viral serpin CrmA. Caspase-mediated cleavage of Mst1 removes the C
terminal regulatory domain and correlates with an increase in Mst1 activity in
vivo, consistent with caspase-mediated cleavage activating Mst1. Overexpression
of either wild-type Mst1 or a truncated mutant induces morphological changes
characteristic of apoptosis. Furthermore, exogenously expressed Mst1 is cleaved,
indicating that Mst1 can activate caspases that result in its cleavage. Kinase
dead Mst1 did not induce morphological alterations and was not cleaved upon
overexpression, indicating that Mst1 must be catalytically active in order to
mediate these effects. Mst1 activates MKK6, p38 MAPK, MKK7 and SAPK in co
transfection assays, suggesting that Mst1 may activate these pathways. Our
findings suggest the existence of a positive feedback loop involving Mst1, and
possibly the SAPK and p38 MAPK pathways, which serves to amplify the apoptotic
response.
PMID- 9545237
TI - Cell wall integrity modulates RHO1 activity via the exchange factor ROM2.
AB - The essential phosphatidylinositol kinase homologue TOR2 of Saccharomyces
cerevisiae controls the actin cytoskeleton by activating a GTPase switch
consisting of RHO1 (GTPase), ROM2 (GEF) and SAC7 (GAP). We have identified two
mutations, rot1-1 and rot2-1, that suppress the loss of TOR2 and are synthetic
lethal. The wild-type ROT1 and ROT2 genes and a multicopy suppressor, BIG1, were
isolated by their ability to rescue the rot1-1 rot2-1 double mutant. ROT2 encodes
glucosidase II, and ROT1 and BIG1 encode novel proteins. We present evidence that
cell wall defects activate RHO1. First, rot1, rot2, big1, cwh41, gas1 and fks1
mutations all confer cell wall defects and suppress tor2(ts). Second,
destabilizing the cell wall by supplementing the growth medium with 0.005% SDS
also suppresses a tor2(ts) mutation. Third, disturbing the cell wall with SDS or
a rot1, rot2, big1, cwh41, gas1 or fks1 mutation increases GDP/GTP exchange
activity toward RHO1. These results suggest that cell wall defects suppress a
tor2 mutation by activating RHO1 independently of TOR2, thereby inducing TOR2
independent polarization of the actin cytoskeleton and cell wall synthesis.
Activation of RHO1, a subunit of the cell wall synthesis enzyme glucan synthase,
by a cell wall alteration would ensure that cell wall synthesis occurs only when
and where needed. The mechanism of RHO1 activation by a cell wall alteration is
via the exchange factor ROM2 and could be analogous to signalling by integrin
receptors in mammalian cells.
PMID- 9545238
TI - Membrane-targeting sequences on AKAP79 bind phosphatidylinositol-4, 5
bisphosphate.
AB - Protein kinases and phosphatases are targeted through association with anchoring
proteins that tether the enzymes to subcellular structures and organelles.
Through in situ fluorescent techniques using a Green Fluorescent Protein tag, we
have mapped membrane-targeting domains on AKAP79, a multivalent anchoring protein
that binds the cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and
protein phosphatase 2B, calcineurin (CaN). Three linear sequences termed region A
(residues 31-52), region B (residues 76-101) and region C (residues 116-145)
mediate targeting of AKAP79 in HEK-293 cells and cortical neurons. Analysis of
these targeting sequences suggests that they contain putative phosphorylation
sites for PKA and PKC and are rich in basic and hydrophobic amino acids similar
to a class of membrane-targeting domains which bind acidic phospholipids and
calmodulin. Accordingly, the AKAP79 basic regions mediate binding to membrane
vesicles containing acidic phospholipids including phosphatidylinositol-4, 5
bisphosphate [PtdIns(4,5)P2] and this binding is regulated by phosphorylation and
calcium-calmodulin. Finally, AKAP79 was shown to be phosphorylated in HEK-293
cells following stimulation of PKA and PKC, and activation of PKC or calmodulin
was shown to release AKAP79 from membrane particulate fractions. These findings
suggest that AKAP79 might function in cells not only as an anchoring protein but
also as a substrate and effector for the anchored kinases and phosphatases.
PMID- 9545240
TI - Calmodulin controls the rod photoreceptor CNG channel through an unconventional
binding site in the N-terminus of the beta-subunit.
AB - Calmodulin (CaM) controls the activity of the rod cGMP-gated ion channel by
decreasing the apparent cGMP affinity. We have examined the mechanism of this
modulation using electrophysiological and biochemical techniques. Heteromeric
channels, consisting of alpha- and beta-subunits, display a high CaM sensitivity
(EC50 =5 nM) similar to the native channel. Using surface plasmon resonance
spectroscopy, we identified two unconventional CaM-binding sites (CaM1 and CaM2),
one in each of the N- and the C-terminal regions of the beta-subunit. Ca2+ co
operatively stimulates binding of CaM to these sites exactly within the range of
[Ca2+] occurring during a light response. Deletion of the N-terminal CaM1 site
results in channels that are no longer CaM-sensitive, whereas deletion of CaM2
has only minor effects. We discuss different models to explain the high-affinity
binding of CaM.
PMID- 9545239
TI - A novel lipid-anchored A-kinase Anchoring Protein facilitates cAMP-responsive
membrane events.
AB - Compartmentalization of protein kinases with substrates is a mechanism that may
promote specificity of intracellular phosphorylation events. We have cloned a low
molecular weight A-kinase Anchoring Protein, called AKAP18, which targets the
cAMP-dependent protein kinase (PKA) to the plasma membrane, and permits
functional coupling to the L-type calcium channel. Membrane anchoring is mediated
by the first 10 amino acids of AKAP18, and involves residues Gly1, Cys4 and Cys5
which are lipid-modified through myristoylation and dual palmitoylation,
respectively. Transient transfection of AKAP18 into HEK-293 cells expressing the
cardiac L-type Ca2+ channel promoted a 34 9% increase in cAMP-responsive Ca2+
currents. In contrast, a targeting-deficient mutant of AKAP18 had no effect on
Ca2+ currents in response to the application of a cAMP analog. Further studies
demonstrate that AKAP18 facilitates GLP-1-mediated insulin secretion in a
pancreatic beta cell line (RINm5F), suggesting that membrane anchoring of the
kinase participates in physiologically relevant cAMP-responsive events that may
involve ion channel activation.
PMID- 9545241
TI - Two distantly positioned PDZ domains mediate multivalent INAD-phospholipase C
interactions essential for G protein-coupled signaling.
AB - Drosophila INAD, which contains five tandem protein interaction PDZ domains,
plays an important role in the G protein-coupled visual signal transduction.
Mutations in InaD alleles display mislocalization of signaling molecules of
phototransduction which include the essential effector, phospholipase C-beta (PLC
beta), which is also known as NORPA. The molecular and biochemical details of
this functional link are unknown. We report that INAD directly binds to NORPA via
two terminally positioned PDZ1 and PDZ5 domains. PDZ1 binds to the C-terminus of
NORPA, while PDZ5 binds to an internal region overlapping with the G box-homology
region (a putative G protein-interacting site). The NORPA proteins lacking
binding sites, which display normal basal PLC activity, can no longer associate
with INAD in vivo. These truncations cause significant reduction of NORPA protein
expression in rhabdomeres and severe defects in phototransduction. Thus, the two
terminal PDZ domains of INAD, through intermolecular and/or intramolecular
interactions, are brought into proximity in vivo. Such domain organization allows
for the multivalent INAD-NORPA interactions which are essential for G protein
coupled phototransduction.
PMID- 9545242
TI - Xvent-1 mediates BMP-4-induced suppression of the dorsal-lip-specific early
response gene XFD-1' in Xenopus embryos.
AB - Ectopic expression of the ventralizing morphogen BMP-4 (bone morphogenetic
protein-4) in the dorsal lip (Spemann organizer) of Xenopus embryos blocks
transcription of dorsal-lip-specific early response genes. We investigated the
molecular mechanism underlying the BMP-4-induced inhibition of the fork head gene
XFD-1'. The promoter of this gene contains a BMP-triggered inhibitory element
(BIE) which prevents activation of this gene at the ventral/vegetal side of the
embryo in vivo. In the present study, we show that BMP-4-induced inhibition is
not direct but indirect, and is mediated by Xvent homeobox proteins. Micro
injections of Xvent-1 RNA and XFD-1' promoter deletion mutants demonstrate that
Xvent-1 mimics the effect of BMP-4 signalling not only by suppression of the XFD
1' gene, but also by utilizing the BIE. Suppression could be reverted using a
dominant-negative Xvent-1 mutant. The repressor domain was localized to the N
terminal region of the protein. Gel-shift and footprint analyses prove that Xvent
1 binds to the BIE. Moreover, PCR-based target-site selection for the Xvent-1
homeodomain confirms distinct motifs within the BIE as preferential binding
sites. Thus, biological and molecular data suggest that Xvent-1 acts as direct
repressor for XFD-1' transcription and mediates BMP-4-induced inhibition.
PMID- 9545243
TI - A phosphorylation site in the ftz homeodomain is required for activity.
AB - The Drosophila homeodomain-containing protein Fushi tarazu (Ftz) is expressed
sequentially in the embryo, first in alternate segments, then in specific
neuroblasts and neurons in the central nervous system, and finally in parts of
the gut. During these different developmental stages, the protein is heavily
phosphorylated on different subsets of Ser and Thr residues. This stage-specific
phosphorylation suggests possible roles for signal transduction pathways in
directing tissue-specific Ftz activities. Here we show that one of the Ftz
phosphorylation sites, T263 in the N-terminus of the Ftz homeodomain, is
phosphorylated in vitro by Drosophila embryo extracts and protein kinase A. In
the embryo, mutagenesis of this site to the non-phosphorylatable residue Ala
resulted in loss of ftz-dependent segments. Conversely, substitution of T263 with
Asp, which is also non-phosphorylatable, but which successfully mimics
phosphorylated residues in a number of proteins, rescued the mutant phenotype.
This suggests that T263 is in the phosphorylated state when functioning normally
in vivo. We also demonstrate that the T263 substitutions of Ala and Asp do not
affect Ftz DNA-binding activity in vitro, nor do they affect stability or
transcriptional activity in transfected S2 cells. This suggests that T263
phosphorylation is most likely required for a homeodomain-mediated interaction
with an embryonically expressed protein.
PMID- 9545245
TI - Erythroid Kruppel-like factor (EKLF) is active in primitive and definitive
erythroid cells and is required for the function of 5'HS3 of the beta-globin
locus control region.
AB - Disruption of the gene for transcription factor EKLF (erythroid Kruppel-like
factor) results in fatal anaemia caused by severely reduced expression of the
adult beta-globin gene, while other erythroid-specific genes, including the
embryonic epsilon- and fetal gamma-globin genes, are expressed normally. Thus,
EKLF is thought to be a stage-specific factor acting through the CACC box in the
beta-gene promoter, even though it is already present in embryonic red cells.
Here, we show that a beta-globin gene linked directly to the locus control region
(LCR) is expressed at embryonic stages, and that this is only modestly reduced in
EKLF-/- embryos. Thus, embryonic beta-globin expression is not intrinsically
dependent on EKLF. To investigate whether EKLF functions in the locus control
region, we analysed the expression of LCR-driven lacZ reporters. This shows that
EKLF is not required for reporter activation by the complete LCR. However,
embryonic expression of reporters driven by 5'HS3 of the LCR requires EKLF. This
suggests that EKLF interacts directly with the CACC motifs in 5'HS3 and
demonstrates that EKLF is also a transcriptional activator in embryonic
erythropoiesis. Finally, we show that overexpression of EKLF results in an
earlier switch from gamma- to beta-globin expression. Adult mice with the EKLF
transgene have reduced platelet counts, suggesting that EKLF levels affect the
balance between the megakaryocytic and erythroid lineages. Interestingly, the
EKLF transgene rescues the lethal phenotype of EKLF null mice, setting the stage
for future studies aimed at the analysis of the EKLF protein and its role in beta
globin gene activation.
PMID- 9545244
TI - Identification of BSAP (Pax-5) target genes in early B-cell development by loss-
and gain-of-function experiments.
AB - The Pax-5 gene codes for the transcription factor BSAP which is essential for the
progression of adult B lymphopoiesis beyond an early progenitor (pre-BI) cell
stage. Although several genes have been proposed to be regulated by BSAP, CD19 is
to date the only target gene which has been genetically confirmed to depend on
this transcription factor for its expression. We have now taken advantage of
cultured pre-BI cells of wild-type and Pax-5 mutant bone marrow to screen a large
panel of B lymphoid genes for additional BSAP target genes. Four differentially
expressed genes were shown to be under the direct control of BSAP, as their
expression was rapidly regulated in Pax-5-deficient pre-BI cells by a hormone
inducible BSAP-estrogen receptor fusion protein. The genes coding for the B-cell
receptor component Ig-alpha (mb-1) and the transcription factors N-myc and LEF-1
are positively regulated by BSAP, while the gene coding for the cell surface
protein PD-1 is efficiently repressed. Distinct regulatory mechanisms of BSAP
were revealed by reconstituting Pax-5-deficient pre-BI cells with full-length
BSAP or a truncated form containing only the paired domain. IL-7 signalling was
able to efficiently induce the N-myc gene only in the presence of full-length
BSAP, while complete restoration of CD19 synthesis was critically dependent on
the BSAP protein concentration. In contrast, the expression of the mb-1 and LEF-1
genes was already reconstituted by the paired domain polypeptide lacking any
transactivation function, suggesting that the DNA-binding domain of BSAP is
sufficient to recruit other transcription factors to the regulatory regions of
these two genes. In conclusion, these loss- and gain-of-function experiments
demonstrate that BSAP regulates four newly identified target genes as a
transcriptional activator, repressor or docking protein depending on the specific
regulatory sequence context.
PMID- 9545246
TI - Rb binds c-Jun and activates transcription.
AB - The retinoblastoma protein (Rb) acts as a critical cell-cycle regulator and loss
of Rb function is associated with a variety of human cancer types. Here we report
that Rb binds to members of the AP-1 family of transcription factors, including c
Jun, and stimulates c-Jun transcriptional activity from an AP-1 consensus
sequence. The interaction involves the leucine zipper region of c-Jun and the B
pocket of Rb as well as a C-terminal domain. We also present evidence that the
complexes are found in terminally differentiating keratinocytes and cells
entering the G1 phase of the cell cycle after release from serum starvation. The
human papillomavirus type 16 E7 protein, which binds to both c-Jun and Rb,
inhibits the ability of Rb to activate c-Jun. The results provide evidence of a
role for Rb as a transcriptional activator in early G1 and as a potential
modulator of c-Jun expression during keratinocyte differentiation.
PMID- 9545247
TI - Structure of wild-type yeast RNA polymerase II and location of Rpb4 and Rpb7.
AB - The three-dimensional structure of wild-type yeast RNA polymerase II has been
determined at a nominal resolution of 24 A. A difference map between this
structure and that of the polymerase lacking subunits Rpb4 and Rpb7 showed these
two subunits forming part of the floor of the DNA-binding (active center) cleft,
and revealed a slight inward movement of the protein domain surrounding the
cleft. Surface plasmon resonance measurements showed that Rpb4 and Rpb7 stabilize
a minimal pre-initiation complex containing promoter DNA, TATA box-binding
protein (TBP), transcription factor TFIIB and the polymerase. These findings
suggest that Rpb4 and Rpb7 play a role in coupling the entry of DNA into the
active center cleft to closure of the cleft. Such a role can explain why these
subunits are necessary for promoter-specific transcription in vitro and for a
normal stress response in vivo.
PMID- 9545248
TI - Mechanism of translational coupling in the nifLA operon of Klebsiella pneumoniae.
AB - The nifLA operon of Klebsiella pneumoniae encodes the sensor-activator pair
involved in the regulation of other nif genes. Balanced synthesis of both
proteins, which is required for correct regulation, is achieved by coupling
translation of nifA to that of nifL. The mechanism of translational coupling at
the nifLA operon was analysed using a specialized ribosome system, and the effect
of substituting the natural Shine-Dalgarno of nifL or nifA for specialized Shine
Dalgarno sequences was determined. Our results indicate that translational
coupling occurs in this operon by a reinitiation mechanism. Additionally,
reinitiation at the nifA can happen even in the absence of good Shine-Dalgarno
recognition by the reinitiating ribosome, although its efficiency is lower. The
effect of a putative translational enhancer sequence (downstream box) on
translational coupling efficiency was also determined. Mutations that reduce the
homology of the putative downstream box to the consensus had only a minor effect
on nifA translation by wild-type ribosomes. However, they had a significant
effect on nifA translation by specialized ribosomes, suggesting that recognition
of the downstream box may compensate inefficient ribosomal interactions with the
Shine-Dalgarno sequence.
PMID- 9545249
TI - Tertiary structure formation in the hairpin ribozyme monitored by fluorescence
resonance energy transfer.
AB - The complex formed by the hairpin ribozyme and its substrate consists of two
independently folding domains which interact to form a catalytic structure.
Fluorescence resonance energy transfer methods permit us to study reversible
transitions of the complex between open and closed forms. Results indicate that
docking of the domains is required for both the cleavage and ligation reactions.
Docking is rate-limiting for ligation (2 min-1) but not for cleavage, where
docking (0.5 min-1) precedes a rate-limiting conformational transition or slow
reaction chemistry. Strikingly, most modifications to the RNA (such as a G+1A
mutation in the substrate) or reaction conditions (such as omission of divalent
metal ion cofactors) which inhibit catalysis do so by preventing docking. This
demonstrates directly that mutations and modifications which inhibit a step
following substrate binding are not necessarily involved in catalysis. An
improved kinetic description of the catalytic cycle is derived, including
specific structural transitions.
PMID- 9545250
TI - Dissecting RNA recombination in vitro: role of RNA sequences and the viral
replicase.
AB - Molecular mechanisms of RNA recombination were studied in turnip crinkle
carmovirus (TCV), which has a uniquely high recombination frequency and non
random crossover site distribution among the recombining TCV-associated satellite
RNAs. To test the previously proposed replicase-driven template-switching
mechanism for recombination, a partially purified TCV replicase preparation
(RdRp) was programed with RNAs resembling the putative in vivo recombination
intermediates. Analysis of the in vitro RdRp products revealed efficient
generation of 3'-terminal extension products. Initiation of 3'-terminal extension
occurred at or close to the base of a hairpin that was a recombination hotspot in
vivo. Efficient generation of the 3'-terminal extension products depended on two
factors: (i) a hairpin structure in the acceptor RNA region and (ii) a short base
paired region formed between the acceptor RNA and the nascent RNA synthesized
from the donor RNA template. The hairpin structure bound to the RdRp, and thus is
probably involved in its recruitment. The probable role of the base-paired region
is to hold the 3' terminus near the RdRp bound to the hairpin structure to
facilitate 3'-terminal extension. These regions were also required for in vivo
RNA recombination between TCV-associated sat-RNA C and sat-RNA D, giving crucial
and direct support for a replicase-driven template-switching mechanism of RNA
recombination.
PMID- 9545251
TI - Ku80 is required for immunoglobulin isotype switching.
AB - Isotype switching is the DNA recombination mechanism by which antibody genes
diversify immunoglobulin effector functions. In contrast to V(D)J recombination,
which is mediated by RAG1, RAG2 and DNA double-stranded break (DSB) repair
proteins, little is known about the mechanism of switching. We have investigated
the role of DNA DSB repair in switch recombination in mice that are unable to
repair DSBs due to a deficiency in Ku80 (Ku80(-/-)). B-cell development is
arrested at the pro-B cell stage in Ku80(-/-) mice because of abnormalities in
V(D)J recombination, and there are no mature B cells. To reconstitute the B-cell
compartment in Ku80(-/-) mice, pre-rearranged VB1-8 DJH2 (mu i) and V3-83JK2
(kappa i) genes were introduced into the Ku80(-/-) background (Ku80(-/-)mu
i/+kappa i/+). Ku80(-/-)mu i/+ kappai/+ mice develop mature mIgM+ B cells that
respond normally to lipopolysaccharide (LPS) or LPS plus interleukin-4 (IL-4) by
producing specific germline Ig constant region transcripts and by forming switch
region-specific DSBs. However, Ku80(-/-)mu i/+kappa i/+ B cells are unable to
produce immunoglobulins of secondary isotypes, and fail to complete switch
recombination. Thus, Ku80 is essential for switch recombination in vivo,
suggesting a significant overlap between the molecular machinery that mediates
DNA DSB repair, V(D)J recombination and isotype switching.
PMID- 9545252
TI - Regulation of DNA replication and repair proteins through interaction with the
front side of proliferating cell nuclear antigen.
AB - The DNA polymerase accessory factor proliferating cell nuclear antigen (PCNA) has
been caught in interaction with an ever increasing number of proteins. To
characterize the sites and functions of some of these interactions, we
constructed four mutants of human PCNA and analysed them in a variety of assays.
By targeting loops on the surface of the PCNA trimer and changing three or four
residues at a time to alanine, we found that a region including part of the
domain-connecting loop of PCNA and loops on one face of the trimer, close to the
C-termini, is involved in binding to all of the following proteins: DNA
polymerase delta, replication factor C, the flap endonuclease Fen1, the cyclin
dependent kinase inhibitor p21 and DNA ligase I. An inhibition of DNA ligation
caused by the interaction of PCNA with DNA ligase I was found, and we show that
DNA ligase I and Fen1 can inhibit DNA synthesis by DNA polymerase delta/PCNA. We
demonstrate that PCNA must be located below a 5' flap on a forked template to
stimulate Fen1 activity, and considering the interacting region on PCNA for Fen1,
this suggests an orientation for PCNA during DNA replication with the C-termini
facing forwards, in the direction of DNA synthesis.
PMID- 9545253
TI - Initiation of DNA replication at CpG islands in mammalian chromosomes.
AB - CpG islands are G+C-rich regions approximately 1 kb long that are free of
methylation and contain the promoters of many mammalian genes. Analysis of in
vivo replication intermediates at three hamster genes and one human gene showed
that the CpG island regions, but not their flanks, were present in very short
nascent strands, suggesting that they are replication origins (ORIs). CpG island
like fragments were enriched in a population of short nascent strands from human
erythroleukaemic cells, suggesting that islands constitute a significant fraction
of endogenous ORIs. Correspondingly, bulk CpG islands were found to replicate
coordinately early in S phase. Our results imply that CpG islands are initiation
sites for both transcription and DNA replication, and may represent genomic
footprints of replication initiation.
PMID- 9545254
TI - Devoted to the lagging strand-the subunit of DNA polymerase III holoenzyme
contacts SSB to promote processive elongation and sliding clamp assembly.
AB - Escherichia coli DNA polymerase III holoenzyme contains 10 different subunits
which assort into three functional components: a core catalytic unit containing
DNA polymerase activity, the beta sliding clamp that encircles DNA for processive
replication, and a multisubunit clamp loader apparatus called gamma complex that
uses ATP to assemble the beta clamp onto DNA. We examine here the function of the
psi subunit of the gamma complex clamp loader. Omission of psi from the
holoenzyme prevents contact with single-stranded DNA-binding protein (SSB) and
lowers the efficiency of clamp loading and chain elongation under conditions of
elevated salt. We also show that the product of a classic point mutant of SSB,
SSB-113, lacks strong affinity for psi and is defective in promoting clamp
loading and processive replication at elevated ionic strength. SSB-113 carries a
single amino acid replacement at the penultimate residue of the C-terminus,
indicating the C-terminus as a site of interaction with psi. Indeed, a peptide of
the 15 C-terminal residues of SSB is sufficient to bind to psi. These results
establish a role for the psi subunit in contacting SSB, thus enhancing the clamp
loading and processivity of synthesis of the holoenzyme, presumably by helping to
localize the holoenzyme to sites of SSB-coated ssDNA.
PMID- 9545255
TI - Interaction of Drosophila inhibitors of apoptosis with thick veins, a type I
serine/threonine kinase receptor for decapentaplegic.
AB - Decapentaplegic (Dpp) is a Drosophila member of bone morphogenetic proteins,
which belong to the transforming growth factor-beta superfamily. Members of this
family regulate a variety of biological processes such as cell proliferation,
morphogenesis, immune response, and apoptosis. Dpp plays a critical role in many
aspects of Drosophila development. Members of the transforming growth factor-beta
superfamily bind to two different types of serine/threonine kinase receptors,
termed type I and type II. Type I receptors act as downstream components of type
II receptors in the receptor complexes. Therefore, intracellular proteins that
interact with the type I receptors are likely to play important roles in
signaling. Several proteins have been identified through protein-protein
interaction screenings. We identified Drosophila inhibitor of apoptosis (DIAP) 1
as an interacting protein of a Dpp type I receptor, Thick veins (Tkv). DIAP1
associates with Tkv in vivo. The binding region in DIAP1 is mapped to its C
terminal RING finger region. DIAP2, another Drosophila member of the inhibitor of
apoptosis protein family, also interacts with Tkv in vivo. These data suggest
that DIAP1 and DIAP2 may be involved, possibly as negative regulators, in the Dpp
signaling pathway, which leads to cell apoptosis.
PMID- 9545256
TI - Caspase-3 is required for DNA fragmentation and morphological changes associated
with apoptosis.
AB - Interleukin 1beta-converting enzyme-like proteases (caspases) are crucial
components of cell death pathways. Among the caspases identified, caspase-3
stands out because it is commonly activated by numerous death signals and cleaves
a variety of important cellular proteins. Studies in caspase-3 knock-out mice
have shown that this protease is essential for brain development. To investigate
the requirement for caspase-3 in apoptosis, we took advantage of the MCF-7 breast
carcinoma cell line, which we show here has lost caspase-3 owing to a 47-base
pair deletion within exon 3 of the CASP-3 gene. This deletion results in the
skipping of exon 3 during pre-mRNA splicing, thereby abrogating translation of
the CASP-3 mRNA. Although MCF-7 cells were still sensitive to tumor necrosis
factor (TNF)- or staurosporine-induced apoptosis, no DNA fragmentation was
observed. In addition, MCF-7 cells undergoing cell death did not display some of
the distinct morphological features typical of apoptotic cells such as shrinkage
and blebbing. Introduction of the CASP-3 gene into MCF-7 cells resulted in DNA
fragmentation and cellular blebbing following TNF treatment. These results
indicate that although caspase-3 is not essential for TNF- or staurosporine
induced apoptosis, it is required for DNA fragmentation and some of the typical
morphological changes of cells undergoing apoptosis.
PMID- 9545257
TI - A calcium-dependent tyrosine kinase splice variant in human monocytes. Activation
by a two-stage process involving adherence and a subsequent intracellular signal.
AB - Freshly isolated human monocytes do not express p125(FAK) but upon adherence to
substrata activate the highly related calcium-dependent tyrosine kinase (CADTK),
also known as Pyk2, CAKbeta, RAFTK, and FAK2. The monocyte CADTK was 5 kDa
smaller than protein from epithelial cells; isolation and sequencing of the
monocyte CADTK cDNA revealed a predicted 42-amino acid deletion between the two
proline-rich domains of the enzyme. The nucleic acid sequence suggests that the
deletion is caused by alternative RNA splicing. This species was also found in T
and B lymphocytes and appears to be the predominant form of cytoskeletal
associated tyrosine kinase in non-neoplastic, circulating, hematopoietic cells.
CADTK was not activated when monocytes maintained in suspension were treated with
agents that produce an intracellular calcium (thapsigargin) or protein kinase C
(phorbol 12-myristate 13-acetate) signal including a chemokine, RANTES, that
binds to the HIV co-receptor, CCK5. In contrast, monocyte adherence to tissue
culture plastic-stimulated CADTK tyrosine phosphorylation, a process that was
enhanced by thapsigargin, phorbol 12-myristate 13-acetate, and RANTES but that
was completely blocked by preincubation with cytochalasin D. When compared with
plastic, adherence to fibronectin- or collagen-coated surfaces produced only
minimal CADTK activation but permitted significant stimulation by added
thapsigargin. These data suggest that in a cell type that lacks p125(FAK), CADTK
plays an early role in post-adherence signaling. Its activation involves two
stages, cytoskeletal engagement, which is permissive, and co-stimulatory signals
(calcium or protein kinase C) generated by extensive cell surface engagement,
agonists, or inflammatory chemokines.
PMID- 9545258
TI - A novel protein distinguishes between quiescent and activated forms of the type I
transforming growth factor beta receptor.
AB - Transforming growth factor beta (TGFbeta) signal transduction is mediated by two
receptor Ser/Thr kinases acting in series, type II TGFbeta receptor (TbetaR-II)
phosphorylating type I TGFbeta receptor (TbetaR-I). Because the failure of
interaction cloning, thus far, to identify bona fide TbetaR-I substrates might
reasonably have been due to the use of inactive TbetaR-I as bait, we sought to
identify molecules that interact specifically with active TbetaR-I, employing the
triple mutation L193A,P194A,T204D in a yeast two-hybrid system. The Leu-Pro
substitutions prevent interaction with FK506-binding protein 12 (FKBP12), whose
putative function in TGFbeta signaling we have previously disproved; the charge
substitution at Thr204 constitutively activates TbetaR-I. Unlike previous screens
using wild-type TbetaR-I, where FKBP12 predominated, none of the resulting
colonies encoded FKBP12. A novel protein was identified, TbetaR-I-associated
protein-1 (TRAP-1), that interacts in yeast specifically with mutationally
activated TbetaR-I, but not wild-type TbetaR-I, TbetaR-II, or irrelevant
proteins. In mammalian cells, TRAP-1 was co-precipitated only by mutationally
activated TbetaR-I and ligand-activated TbetaR-I, but not wild-type TbetaR-I in
the absence of TGFbeta. The partial TRAP-1 protein that specifically binds these
mutationally and ligand-activated forms of TbetaR-I can inhibit signaling by the
native receptor after stimulation with TGFbeta or by the constitutively activated
receptor mutation, as measured by a TGFbeta-dependent reporter gene. Thus, TRAP-1
can distinguish activated forms of the receptor from wild-type receptor in the
absence of TGFbeta and may potentially have a functional role in TGFbeta
signaling.
PMID- 9545259
TI - Urea transporter UT3 functions as an efficient water channel. Direct evidence for
a common water/urea pathway.
AB - A family of molecular urea transporters (UTs) has been identified whose members
appear to have an exceptionally high transport turnover rate. To test the
hypothesis that urea transport involves passage through an aqueous channel,
osmotic water permeability was measured in Xenopus oocytes expressing UTs. The
UT3 class of urea transporters functioned as efficient water channels.
Quantitative measurement of single channel water permeability (pf) using epitope
tagged rat UTs gave pf (in cm3/s x 10(-14)) of 0.14 +/- 0.11 (UT2) and 1.4 +/-
0.2 (UT3), compared with 6.0 and 2.3 for water channels AQP1 and AQP3,
respectively. Relative single channel urea permeabilities (purea) were 1.0 (UT2),
0.44 (UT3), and 0.0 (AQP1). UT3-mediated water and urea transport were weakly
temperature-dependent (activation energy <4 kcal/mol), inhibited > 75% by the
urea transport inhibitor 1,3-dimethylthiourea, but not inhibited by the water
transport inhibitor HgCl2. To test for a common water/urea pore, the urea
reflection coefficient (sigmaurea) was measured by independent induced osmosis
and solvent drag methods. In UT3-expressing oocytes, the time course of oocyte
volume in response to different urea gradients (induced osmosis) gave sigmaurea
approximately 0.3 for the UT3 pathway, in agreement with sigmaurea determined by
the increase in uptake of [14C]urea during osmotic gradient-induced oocyte
swelling (solvent drag). In oocytes of comparable water and urea permeability
coexpressing AQP1 (permeable to water, not urea) and UT2 (permeable to urea, not
water), sigmaurea = 1. These results indicate that UT3 functions as a urea/water
channel utilizing a common aqueous pathway. The water transporting function and
low urea reflection coefficient of UT3 in vasa recta may be important for the
formation of a concentrated urine by countercurrent exchange in the kidney.
PMID- 9545260
TI - The phosphorylation of eukaryotic initiation factor eIF4E in response to phorbol
esters, cell stresses, and cytokines is mediated by distinct MAP kinase pathways.
AB - Initiation factor eIF4E binds to the 5'-cap of eukaryotic mRNAs and plays a key
role in the mechanism and regulation of translation. It may be regulated through
its own phosphorylation and through inhibitory binding proteins (4E-BPs), which
modulate its availability for initiation complex assembly. eIF4E phosphorylation
is enhanced by phorbol esters. We show, using specific inhibitors, that this
involves both the p38 mitogen-activated protein (MAP) kinase and Erk signaling
pathways. Cell stresses such as arsenite and anisomycin and the cytokines tumor
necrosis factor-alpha and interleukin-1beta also cause increased phosphorylation
of eIF4E, which is abolished by the specific p38 MAP kinase inhibitor, SB203580.
These changes in eIF4E phosphorylation parallel the activity of the eIF4E kinase,
Mnk1. However other stresses such as heat shock, sorbitol, and H2O2, which also
stimulate p38 MAP kinase and increase Mnk1 activity, do not increase
phosphorylation of eIF4E. The latter stresses increase the binding of eIF4E to 4E
BP1, and we show that this blocks the phosphorylation of eIF4E by Mnk1 in vitro,
which may explain the absence of an increase in eIF4E phosphorylation under these
conditions.
PMID- 9545261
TI - Two novel odorant receptor families expressed in spermatids undergo 5'-splicing.
AB - We report the identification of two novel families of odorant receptor (OdR)-like
proteins, termed spermatid chemoreceptors (SCRs), in rat spermatids of the
testis. The full-length genomic clones encode seven transmembrane domain
receptors that share 35-40% identity with certain OdRs and are among the most
divergent members of the OdR superfamily based on phylogenetic analysis. RNase
protection assays and in situ hybridization studies confirmed the expression of
SCRs in spermatids, the post-meiotic, differentiating cell population in the
testis. SCR transcripts were undetectable in the prepubertal testis but were
readily identified in spermatids of sexually maturing and mature testis. Rapid
amplification of cDNA end-polymerase chain reaction and genomic clone sequencing
led to the discovery that SCRs are spliced upstream of their presumptive starting
methionines. 5'-Splicing of OdRs may regulate the expression of functional
chemoreceptors.
PMID- 9545262
TI - Heterochromatin organization of a natural yeast telomere. Changes of nucleosome
distribution driven by the absence of Sir3p.
AB - We have defined the in vivo heterochromatin structure of the left telomere of
Saccharomyces cerevisiae chromosome III (LIII). Analysis of heterochromatin of a
single telomere was so far lacking, due to the difficulties intrinsic to the
highly repetitive nature of telomeric sequences. In LIII, the terminal (C1-3A)n
repetitive sequences are followed by a complete X element and by the single copy
Ty5-1 retrotransposon. Both the telosome and the X element exhibit overall
resistance to micrococcal nuclease digestion reflecting their tight chromatin
structure organization. The X element contains protein complexes and irregularly
distributed but well localized nucleosomes. In contrast, a regular array of
phased nucleosomes is associated with the promoter region of Ty5-1 and with the
more centromere-proximal sequences. The lack of a structural component of yeast
telomeres, the SIR3 protein, does not alter the overall tight organization of the
X element but causes a nucleosome rearrangement within the promoter region of Ty5
1 and releases Ty5-1 silencing. Thus, Sir3p links the modification of the
heterochromatin structure with loss of transcriptional silencing.
PMID- 9545263
TI - FcgammaRI coupling to phospholipase D initiates sphingosine kinase-mediated
calcium mobilization and vesicular trafficking.
AB - Aggregation of receptors specific for the constant region of immunoglobulin G
activates a repertoire of monocyte responses that can lead ultimately to targeted
cell killing via antibody-directed cellular cytotoxicity. The high affinity
receptor, FcgammaRI, contains no recognized signaling motif in its cytoplasmic
tail but rather utilizes the gamma-chain of FcepsilonRI as an accessory molecule
to recruit tyrosine kinases for signal transduction. We show here that, in a
human monocytic cell line primed with interferon-gamma, FcgammaRI mobilizes
intracellular calcium stores using a novel pathway that involves tyrosine kinase
coupling to phospholipase D and resultant downstream activation of sphingosine
kinase. Moreover, FcgammaRI is not coupled to phospholipase C; hence, calcium
release from intracellular stores occurred in the absence of any measurable rise
in inositol triphosphate. Finally, as this novel activation pathway is also shown
to be responsible for mediating the vesicular trafficking of internalized immune
complexes for degradation, it is likely to play a key role in controlling
intracellular events triggered by FcgammaRI.
PMID- 9545264
TI - Converse modulation of IRP1 and IRP2 by immunological stimuli in murine RAW 264.7
macrophages.
AB - Iron regulatory proteins (IRP1 and IRP2) are two cytoplasmic RNA-binding proteins
that control iron metabolism in mammalian cells. Both IRPs bind to specific
sequences called iron-responsive elements (IREs) located in the 3' or 5'
untranslated regions of several mRNAs, in particular mRNA encoding ferritin and
transferrin receptor. In this study, we followed in parallel the in vivo
regulation of the two IRPs in physiologically stimulated macrophages. We show
that stimulation of mouse RAW 264.7 macrophage-like cells increased IRP1 IRE
binding activity 4-fold, whereas IRP2 activity decreased 2-fold 8 h after
interferon-gamma/lipopolysaccharide treatment. Decrease in IRP2 was not due to
nitric oxide (NO) production and did not require de novo protein synthesis. Our
data therefore indicate that the two IRPs can be conversely regulated in response
to the same stimulus. In addition, the effect of endogenously produced NO on IRP1
was further characterized in an activated macrophage/target cell system. We show
that NO acts as an intercellular signal to increase IRP1 activity in adjacent
cells. As the effect was detectable within 1 h and did not require de novo
protein synthesis, this result supports a direct action of NO on IRP1.
PMID- 9545265
TI - Stimulation of replication efficiency of a chromatin template by chromosomal
protein HMG-17.
AB - The effect of chromosomal protein HMG-17 on the replication of a chromatin
template was studied with minichromosomes containing the SV40 origin of
replication. The minichromosomes were assembled from M13 DNA in Xenopus egg
extracts in either the absence or presence of HMG-17. Structural data show that
HMG-17 was efficiently incorporated into the chromatin and induced an extended
chromatin structure. Using an in vitro SV40 replication system, we find that
minichromosomes containing HMG-17 replicate with higher efficiency than
minichromosomes deficient of HMG-17. The replicational potential of chromatin was
enhanced only when HMG-17 was incorporated into the template during, but not
after, chromatin assembly. HMG-17 stimulated replication only from a chromatin
template, but not from protein-free DNA. Thus, HMG-17 protein enhances the rate
of replication of a chromatin template by unfolding the higher order chromatin
structure and increasing the accessibility of target sequences to components of
the replication machinery.
PMID- 9545266
TI - Interactions of chaperone alpha-crystallin with the molten globule state of
xylose reductase. Implications for reconstitution of the active enzyme.
AB - alpha-Crystallin is a multimeric protein that has been shown to function as a
molecular chaperone. Present investigations were undertaken to understand its
mechanism of chaperoning. For this functional in vitro analysis of alpha
crystallin we used xylose reductase (XR) from Neurospora crassa as the model
system. Denaturation studies using the structure-perturbing agent guanidinium
chloride indicated that XR folds through a partially folded state that resembles
the molten globule. Fluorescence and delay experiments revealed that alpha
crystallin interacts with the molten globule state of XR (XR-m) and prevents its
aggregation. Cold lability of alpha-crystallin.XR-m interaction was revealed by
temperature shift experiments implicating the involvement of hydrophobic
interactions in the formation of the complex. Reconstitution of active XR was
observed on cooling the alpha-crystallin.XR-m complex to 4 degrees C or on
addition of ATP at 37 degrees C. ATP hydrolysis is not a prerequisite for XR
release since the nonhydrolyzable analogue 5'-adenylyl imidodiphosphate (AMP-PNP)
was capable of reconstitution of active XR. Experimental evidence has been
provided for temperature- and ATP-mediated structural changes in the alpha
crystallin.XR-m complex that shed some light on the mechanism of reconstitution
of active XR by this chaperone. The relevance of our finding to the role of alpha
crystallin in vivo is discussed.
PMID- 9545268
TI - Effects of FK506-binding protein 12 and FK506 on autophosphorylation of epidermal
growth factor receptor.
AB - FK506-binding proteins and cyclophilins are intracellular proteins that express
peptidylproline cis-trans-isomerase (PPIase) activity. The effects of FK506
binding protein 12 (FKBP12) and the cyclophilins 18 and 23 on autophosphorylation
of the epidermal growth factor (EGF) receptor prepared from plasma membranes of
the human epidermoid cell line A431 have been investigated. Whereas FKBP12
inhibited EGF receptor tyrosine kinase activity in a concentration-dependent
manner, the cyclophilins did not affect autophosphorylation. In contrast to the
wild-type enzyme, several variants of FKBP12 with greatly reduced PPIase activity
were unable to suppress EGF receptor tyrosine kinase significantly. Pervanadate
an inhibitor of protein tyrosine phosphatases, abolished the effect of FKBP12 on
EGF receptor autophosphorylation. Finally, FK506 and rapamycin, which are known
to block the PPIase activity of FKBP12, induced a significant stimulation of EGF
receptor autophosphorylation in intact A431 cells suggesting suppression of EGF
receptor autophosphorylation by intracellular FKBP12 in vivo. Taken together the
data point to an inhibitory function of FKBP12 in EGF receptor signaling,
possibly induced by stimulation of a protein tyrosine phosphatase coupled to the
EGF receptor. Both PPIase activity and substrate specificity of FKBP12 seem to be
indispensable for this effect.
PMID- 9545267
TI - dGNaC1, a gonad-specific amiloride-sensitive Na+ channel.
AB - Amiloride-sensitive sodium channels have been implicated in reproductive and
early developmental processes of several species. These include the fast block of
polyspermy in Xenopus oocytes that follows the sperm binding to the egg or
blastocoel expansion in mammalian embryo. We have now identified a gene called
dGNaC1 that is specifically expressed in the gonads and early embryo in
Drosophila melanogaster. The corresponding protein belongs to the superfamily of
cationic channels blocked by amiloride that includes Caenorhabditis elegans
degenerins, the Helix aspersa FMRF-amide ionotropic receptor (FaNaC), the
mammalian epithelial Na+ channel (ENaC), and acid-sensing ionic channels (ASIC,
DRASIC, and MDEG). Expression of dGNaC1 in Xenopus oocytes generates a
constitutive current that does not discriminate between Na+ and Li+, but is
selective for Na+ over K+. This current is blocked by amiloride (IC50 = 24
microM), benzamil (IC50 = 2 microM), and ethylisopropyl amiloride (IC50 = 49
microM). These properties are clearly different from those obtained after
expression of the previously cloned members of this family, including ENaC and
the human alphaENaC-like subunit, deltaNaC. Interestingly, the pharmacology of
dGNaC1 is not very different from that found for the Na+ channel characterized in
rabbit preimplantation embryos. We postulate that this channel may participate in
gametogenesis and early embryonic development in Drosophila.
PMID- 9545269
TI - Two efficiency elements flanking the editing site of cytidine 6666 in the
apolipoprotein B mRNA support mooring-dependent editing.
AB - Normally, apolipoprotein B (apoB) mRNA editing deaminates a single cytidine
(C6666) in apoB mRNA. However, when the catalytic subunit of the editing enzyme
complex, APOBEC-1, was overexpressed in transgenic mice and rabbits, numerous
cytidines in the apoB mRNA and in a novel mRNA, NAT1, were aberrantly
hyperedited, and the animals developed liver dysplasia and hepatocellular
carcinomas. To identify the RNA motifs in the apoB mRNA that support
physiological editing and those that support aberrant hyperediting, we
constructed rabbit apoB RNA substrates and tested them in vitro for physiological
editing and hyperediting. Three previously unrecognized RNA elements that are
critical for efficient physiological editing at C6666 were identified. In concert
with the mooring sequence (6671-6681), the 5' efficiency element (6609-6628), an
A-rich region (6629-6640), and the 3' efficiency element (6717-6747) increased
editing at C6666. The 5' efficiency element was the most potent, elevating
physiological editing to wild-type levels in combination with the mooring
sequence. The 3' efficiency element was somewhat less important but increased
physiological editing to levels approaching wild type. These elements encompass
139 nucleotides on the apoB RNA transcript and are sufficient for editing with
the efficiency of full-length apoB mRNA. Furthermore, a distal downstream apoB
region (6747-6824) may function as a recognition element in the apoB mRNA.
Hyperediting at C6802 in the rabbit apoB mRNA is mediated by RNA elements similar
to those required for normal physiological editing at C6666. Similarly sized
upstream and downstream flanking regions of C6802 are necessary for hyperediting
in combination with a degenerate mooring sequence.
PMID- 9545270
TI - Stabilization of alpha-synuclein secondary structure upon binding to synthetic
membranes.
AB - alpha-Synuclein is a highly conserved presynaptic protein of unknown function. A
mutation in the protein has been causally linked to Parkinson's disease in
humans, and the normal protein is an abundant component of the intraneuronal
inclusions (Lewy bodies) characteristic of the disease. alpha-Synuclein is also
the precursor to an intrinsic component of extracellular plaques in Alzheimer's
disease. The alpha-synuclein sequence is largely composed of degenerate 11
residue repeats reminiscent of the amphipathic alpha-helical domains of the
exchangeable apolipoproteins. We hypothesized that alpha-synuclein should
associate with phospholipid bilayers and that this lipid association should
stabilize an alpha-helical secondary structure in the protein. We report that
alpha-synuclein binds to small unilamellar phospholipid vesicles containing
acidic phospholipids, but not to vesicles with a net neutral charge. We further
show that the protein associates preferentially with vesicles of smaller diameter
(20-25 nm) as opposed to larger (approximately 125 nm) vesicles. Lipid binding is
accompanied by an increase in alpha-helicity from 3% to approximately 80%. These
observations are consistent with a role in vesicle function at the presynaptic
terminal.
PMID- 9545271
TI - Deletion and site-directed mutagenesis of the ATP-binding motif (P-loop) in the
bifunctional murine ATP-sulfurylase/adenosine 5'-phosphosulfate kinase enzyme.
AB - The P-loop is a common motif found in ATP- and GTP-binding proteins. The recently
cloned murine ATP-sulfurylase/adenosine 5'-phosphosulfate (APS) kinase contains a
P-loop (residues 59-66) in the APS kinase portion of the bifunctional protein. A
series of enzymatic assays covering the multiplicity of functions of this unique
protein (reverse ATP-sulfurylase, APS kinase, and an overall assay) were used to
determine the effect of deleting or altering specific residues constituting this
motif. In addition to the full-length cDNA construct (1MSK), two deletion mutants
that progressively shortened the N terminus by 34 amino acids (2MSK) and 70 amino
acids (3MSK) were designed to examine the effects of translation initiation
before (2MSK) and after (3MSK) the P-loop. The 2MSK protein possessed sulfurylase
and kinase activity equivalent to the full-length construct, but 3MSK exhibited
no kinase activity and reduced sulfurylase activity. In light of the evident
importance of this motif, a number of site-directed mutants were designed to
investigate the contribution of key residues. Mutation of a highly conserved
lysine in the P-loop to alanine (K65A) or arginine (K65R) or the following
threonine (T66A) to alanine ablated APS kinase activity while leaving ATP
sulfurylase activity intact. Three mutations (G59A, G62A, and G64A) addressed the
role of the conserved glycines as follows: G64A showed diminished APS kinase
activity only, whereas G62A had no effect on either activity. G59A caused a
significant decrease in ATP-sulfurylase activity without effect on APS kinase
activity. A series of highly conserved flanking cysteines (Cys-53, Cys-77, and
Cys-83) were mutated to alanine, but none of these mutations showed any effect on
either enzyme activity.
PMID- 9545272
TI - Genomic organization, chromosomal mapping, and promoter analysis of the mouse
dentin sialophosphoprotein (Dspp) gene, which codes for both dentin sialoprotein
and dentin phosphoprotein.
AB - Our laboratory has reported that two major noncollagenous dentin proteins, dentin
sialoprotein and dentin phosphoprotein, are specific cleavage products of a
larger precursor protein termed dentin sialophosphoprotein (MacDougall, M.,
Simmons, D., Luan, X., Nydegger, J., Feng, J. Q., and Gu, T. T. (1997) J. Biol.
Chem. 272:835-842). To confirm our single gene hypothesis and initiate in vitro
promoter studies, we have characterized the structural organization of the mouse
dentin sialophosphoprotein gene. This gene has a transcription unit of
approximately 9.4 kilobase pairs and is organized into 5 exons and 4 introns.
Exon 1 contains a noncoding 5' sequence, and exon 2 contains the transcriptional
start site, signal peptide, and first two amino acids of the NH2 terminus. Exons
3 and 4 contain coding information for 29 and 314 amino acids, respectively. The
remainder of the coding information and the untranslated 3' region are contained
in exon 5. Chromosomal mapping localized the gene to mouse chromosome 5q21 in
close proximity to other dentin/bone matrix genes. Computer analysis of the
promoter proximal 1.6-kilobase pair sequence revealed a number of potentially
important cis-regulatory sequences; these include the recognition elements of AP
1, AP-2, Msx-1, serum response elements, SP-1, and TCF-1. In vitro studies showed
that the DSPP promoter is active in an odontoblast cell line, MO6-G3, with basal
activity mapped to -95 bp. Two potential enhancer and suppresser elements were
identified in the regions between -1447 and -791 bp and -791 and -95 bp,
respectively. The structural organization of the dentin sialophosphoprotein gene
confirms our finding that both dentin sialoprotein and dentin phosphoprotein are
encoded by a single gene with a continuous open reading frame.
PMID- 9545273
TI - Interactions of phosducin with the subunits of G-proteins. Binding to the alpha
as well as the betagamma subunits.
AB - The high affinity interactions of phosducin with G-proteins involve binding of
phosducin to the G-protein betagamma subunits. Here we have investigated whether
phosducin interacts also with G-protein alpha subunits. Interactions of phosducin
with the individual subunits of Go were measured by retaining phosducin-G-protein
subunit complexes on columns containing immobilized anti-phosducin antibodies.
Both the alpha and the beta subunits of trimeric Go were specifically retained by
the antibodies in the presence of phosducin. This binding was almost completely
abolished for both subunits following protein kinase A-mediated phosphorylation
of phosducin and was reduced, more for alpha than for beta subunits, by the
stable GTP analog guanosine 5'-(3-O-thio)triphosphate. Isolated alphao was also
retained on the columns in the presence of phosducin but not in the presence of
protein kinase A-phosphorylated phosducin. Likewise, purified G-protein betagamma
subunit complexes as well as purified alpha subunits of Go and Gt were
precipitated together with His6-tagged phosducin with nickel-agarose; this co
precipitation occurred concentration-dependently, with apparent affinities for
phosducin of 55 nM (Gbetagamma), 110 nM (alphao), and 200 nM (alphat). In
functional experiments, the steady state GTPase activity of isolated alphao was
inhibited by phosducin by approximately 60% with an IC50 value of approximately
300 nM, whereas the GTPase activity of trimeric Go was inhibited by approximately
90% with an IC50 value of approximately 10 nM. Phosducin did not inhibit the GTP
hydrolytic activity of isolated alphao as measured by single-turnover assays, but
it inhibited the release of GDP from alphao; the rate constant of GDP release was
decreased approximately 40% by 500 nM phosducin, and the inhibition occurred with
an IC50 value for phosducin of approximately 100 nM. These data suggest that
phosducin binds with high affinity to G-protein betagamma subunits and with lower
affinity to G-protein alpha subunits. We propose that the alpha subunit-mediated
effects of phosducin might increase both the extent and the rapidity of its
inhibitory effects compared with an action via the betagamma subunit complex
alone.
PMID- 9545274
TI - Amino acid residues that define both the isoprenoid and CAAX preferences of the
Saccharomyces cerevisiae protein farnesyltransferase. Creating the perfect
farnesyltransferase.
AB - Studies of the yeast protein farnesyltransferase (FTase) have shown that the
enzyme preferentially farnesylates proteins ending in CAAX (C = cysteine, A =
aliphatic residue, X = cysteine, serine, methionine, alanine) and to a lesser
degree CAAL. Furthermore, like the type I protein geranylgeranyltransferase
(GGTase-I), FTase can also geranylgeranylate methionine- and leucine-ending
substrates both in vitro and in vivo. Substrate overlap of FTase and GGTase I has
not been determined to be biologically significant. In this study, specific
residues that influence the substrate preferences of FTase have been identified
using site-directed mutagenesis. Three of the mutations altered the substrate
preferences of the wild type enzyme significantly. The ram1p-74D FTase
farnesylated only Ras-CIIS and not Ras-CII(M,L), and it geranylgeranylated all
three substrates as well or better than wild type. The ram1p-206DDLF FTase
farnesylated Ras-CII(S,M,L) at wild type levels but could no longer
geranylgeranylate the Ras-CII(M,L) substrates. The ram1p-351FSKN FTase
farnesylated Ras-CIIS and Ras-CIIM but not Ras-CIIL. The ram1p-351FSKN FTase was
not capable of geranylgeranylating the Ras-CII(M,L) substrates, giving this
mutant the attributes of the dogmatic FTase that only farnesylates non-leucine
ending CAAX substrates and does not geranylgeranylate any substrate. These
results suggest that the isoprenoid and protein substrate specificities of FTase
are interrelated. The availability of a mutant FTase that lacked substrate
overlap with the protein GGTase-I made possible an analysis of the role of
substrate overlap in normal cellular processes of yeast, such as mating and
growth at elevated temperatures. Our findings suggest that neither farnesylation
of leucine-ending CAAX substrates nor geranylgeranylation by the FTase is
necessary for these cellular processes.
PMID- 9545275
TI - The importance of two conserved arginine residues for catalysis by the ras GTPase
activating protein, neurofibromin.
AB - Ras proteins are guanine-nucleotide binding proteins that have a low intrinsic
GTPase activity that is enhanced 10(5)-fold by the GTPase-activating proteins
(GAPs) p120-GAP and neurofibromin. Comparison of the primary sequences of RasGAPs
shows two invariant arginine residues (Arg1276 and Arg1391 of neurofibromin). In
this study, site-directed mutagenesis was used to change each of these residues
in the catalytic domain of neurofibromin (NF1-334) to alanine. The ability of the
mutant proteins to bind to Ras.GTP and to stimulate their intrinsic GTPase rate
was then determined by kinetic methods under single turnover conditions using a
fluorescent analogue of GTP. The separate contributions of each of these residues
to catalysis and binding affinity to Ras were measured. Both the R1276A and the
R1391A mutant NF1-334 proteins were 1000-fold less active than wild-type NF1-334
in activating the GTPase when measured at saturating concentrations. In contrast,
there was only a minor effect of either mutation on NF1-334 affinity for wild
type Ha-Ras. These data are consistent with both arginines being required for
efficient catalysis. Neither arginine is absolutely essential, because the mutant
NF1-334 proteins increase the intrinsic Ras.GTPase by at least 100-fold. The
roles of Arg1276 and Arg1391 in neurofibromin are consistent with proposals based
on the recently published x-ray structure of p120-GAP complexed with Ras.
PMID- 9545276
TI - Characterization of a nucleoside/proton symporter in procyclic Trypanosoma brucei
brucei.
AB - Adenosine transport at 22 degrees C in procyclic forms of Trypanosoma brucei
brucei was investigated using an oil-inhibitor stop procedure for determining
initial rates of adenosine uptake in suspended cells. Adenosine influx was
mediated by a single high affinity transporter (Km 0.26 +/- 0.02 microM, Vmax
0.63 +/- 0.18 pmol/10(7) cells s-1). Purine nucleosides, with the exception of
tubercidin (7-deazaadenosine), and dipyridamole inhibited adenosine influx (Ki
0.18-5.2 microM). Purine nucleobases and pyrimidine nucleosides and nucleobases
had no effect on adenosine transport. This specificity of the transporter appears
to be similar to the previously described P1 adenosine transporter in bloodstream
forms of trypanosomes. Uptake of adenosine was Na+-independent, but ionophores
reducing the membrane potential and/or the transmembrane proton gradient
(monitored with the fluorescent probes bis-(1,3-diethylthiobarbituric acid)
trimethine oxonol and 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein
acetoxymethyl ester, respectively) inhibited adenosine transport. Similarly, an
increase in extracellular pH from 7.3 to 8.0 reduced adenosine influx by 30%. A
linear correlation was demonstrated between the rate of adenosine transport and
the protonmotive force. Adenosine uptake was accompanied by a proton influx in
base-loaded cells and was also shown to be electrogenic. These combined results
indicate that transport of adenosine in T. brucei brucei procyclics is
protonmotive force-driven and strongly suggest that the adenosine transporter
functions as an H+ symporter.
PMID- 9545277
TI - Regulation of mammary differentiation by extracellular matrix involves protein
tyrosine phosphatases.
AB - Extracellular matrix and growth factors cooperate to regulate signaling pathways
and gene transcription in adherent cells. However, the mechanism of extracellular
matrix signaling is poorly defined. In mammary gland, the expression of milk
protein genes is controlled by cross-talk between signals derived from the
basement membrane protein, laminin, and the lactogenic hormone, prolactin.
Signals from basement membrane are transduced by beta1 integrins and are required
for prolactin to activate DNA binding of the milk protein gene transcription
factor, Stat5. Here we show that basement membrane is necessary for tyrosine
phosphorylation of the prolactin receptor and thus directly affects cytokine
signaling and differentiation at the level of the plasma membrane. Prolactin does
not induce tyrosine phosphorylation of its receptor, Jak2, or Stat5 in
nondifferentiated breast epithelia cultured on collagen I, and we show that this
is due to a vanadate-sensitive activity that inhibits the prolactin pathway. We
suggest that protein-tyrosine phosphatases are novel targets for regulation by
extracellular matrix and in mammary cells represent an additional control to the
requirement of integrins for milk protein production.
PMID- 9545278
TI - Proteasome activation by REG molecules lacking homolog-specific inserts.
AB - The peptidase activities of eukaryotic proteasomes are markedly activated by the
11 S REG or PA28. The three identified REG subunits, designated alpha, beta, and
gamma, differ significantly in sequence over a short span of 15-30 amino acids
that we call homolog-specific inserts. These inserts were deleted from each REG
to produce the mutant proteins REGalphaDeltai, REGbetaDeltai, and REGgammaDeltai.
The purified recombinant proteins were then tested for their ability to
oligomerize and activate the proteasome. Both REGalphaDeltai and REGgammaDeltai
formed apparent heptamers and activated human red cell proteasomes to the same
extent as their full-length counterparts. By contrast, REGbetaDeltai exhibited,
at low protein concentrations, reduced proteasome activation when compared with
the wild-type REGbeta protein. REGbetaDeltai was able to form hetero-oligomers
with a single site, monomeric REGalpha mutant and with REGalphaDeltai. At low
concentrations, the REGalphaDeltai/REGbetaDeltai hetero-oligomers stimulated the
proteasome less than REGalpha/REGbeta oligomers formed from wild-type subunits,
and the reduced activation by REGalphaDeltai/REGbetaDeltai was due to removal of
the REGbeta insert, not the REGalpha insert. These studies demonstrate that the
REGalpha and REGgamma inserts play virtually no role in oligomerization or in
proteasome activation. By contrast, removal of REGbeta insert reduces binding of
this subunit and REGalpha/REGbeta oligomers to proteasomes. On the whole,
however, our findings show that REG inserts are not required for binding and
activating the proteasome. We speculate that they serve to localize REG
proteasome complexes within cells, possibly by binding components in endoplasmic
reticulum membranes.
PMID- 9545279
TI - Circadian periodicity of intestinal Na+/glucose cotransporter 1 mRNA levels is
transcriptionally regulated.
AB - Intestinal expression of the high affinity Na+/glucose cotransporter 1 (SGLT1),
which absorbs dietary glucose and galactose, exhibits both circadian periodicity
in its activity and induction by dietary carbohydrate. Because the daily
variation in SGLT1 activity is established by the feeding schedule (whether ad
libitum or imposed) and persists in the absence of food, this variation has been
described as anticipatory. To delineate the mechanisms regulating SGLT1, its
expression was examined in rats maintained in a 12-h photoperiod with free access
to chow. SGLT1 mRNA levels varied significantly, with the maximum abundance
occurring near the onset of dark and the minimum near the onset of light. The
SGLT1 transcription rate was 7-fold higher in the morning (1000-1100 h) than in
the afternoon (1600-1700 h). An element for hepatocyte nuclear factor 1 (HNF-1)
was identified in the SGLT1 promoter that formed different complexes with small
intestinal nuclear extracts, depending on the time when the source animal was
killed. Serological tests indicated that HNF-1alpha was present in complexes
throughout the day, while HNF-1beta binding exhibited circadian periodicity. We
propose that exchange of HNF-1 dimerization partners contributes to circadian
changes in SGLT1 transcription. Because SGLT1 mRNA levels also varied in rhesus
monkeys (offset by approximately one-half day from rats), a similar mechanism
appears to be present in primates.
PMID- 9545280
TI - Solution and crystal structures of a sperm whale myoglobin triple mutant that
mimics the sulfide-binding hemoglobin from Lucina pectinata.
AB - The bivalve mollusc Lucina pectinata harbors sulfide-oxidizing chemoautotrophic
bacteria and expresses a monomeric hemoglobin I, HbI, with normal O2, but
extraordinarily high sulfide affinity. The crystal structure of aquomet Lucina
HbI has revealed an active site with three residues not commonly found in
vertebrate globins: Phe(B10), Gln(E7), and Phe(E11) (Rizzi, M., Wittenberg, J.
B., Coda, A., Fasano, M., Ascenzi, P., and Bolognesi, M. (1994) J. Mol. Biol.
244, 86-89). Engineering these three residues into sperm whale myoglobin results
in a triple mutant with approximately 700-fold higher sulfide affinity than for
wild-type. The single crystal x-ray structure of the aquomet derivative of the
myoglobin triple mutant and the solution 1H NMR active site structures of the
cyanomet derivatives of both the myoglobin mutant and Lucina HbI have been
determined to examine further the structural origin of their unusually high
sulfide affinities. The major differences in the distal pocket is that in the
aquomet form the carbonyl of Gln64(E7) serves as a H-bond acceptor, whereas in
the cyanomet form the amido group acts as H-bond donor to the bound ligand.
Phe68(E11) is rotated approximately 90 degrees about chi2 and located
approximately 1-2 A closer to the iron atom in the myoglobin triple mutant
relative to its conformation in Lucina HbI. The change in orientation potentially
eliminates the stabilizing interaction with sulfide and, together with the
decrease in size of the distal pocket, accounts for the 7-fold lower sulfide
affinity of the myoglobin mutant compared with that of Lucina HbI.
PMID- 9545281
TI - Flavohemoglobin expression and function in Saccharomyces cerevisiae. No
relationship with respiration and complex response to oxidative stress.
AB - The yeast Saccharomyces cerevisiae contains a flavohemoglobin, encoded by the
gene YHB1, whose function is unclear. Previous reports presented evidence that
its maximal expression requires disruption of mitochondrial respiration and that
it plays a role in the response to oxidative stress. We have studied the
expression of YHB1 in respiratory deficient cells and in cells exposed to various
compounds causing oxidative stress. Several different strains and approaches
(spectroscopic detection of the oxygenated form of Yhb1p, beta-galactosidase
activity of a YHB1-lacZ fusion, and Northern blot analysis) were used to
demonstrate that YHB1 expression and Yhb1p production are not increased by
respiration deficiency. YHB1 expression was unchanged in cells challenged with
antimycin A or menadione, while it decreased in cells exposed to H2O2, diamide,
dithiothreitol, and Cu2+. Transcription of YHB1 is not under the control of the
transcriptional factor Yap1p. These results do not support a participation of
YHB1 in the genetic response to oxidative stress. We also analyzed the growth
phenotypes associated with altered Yhb1p production using YHB1-deleted strains
and strains that greatly overproduced Yhb1p. Yhb1p appears to protect cells
against the damage caused by Cu2+ and dithiothreitol, while sensitizing them to
H2O2. Yhb1p overproduction in a glucose-6-phosphate dehydrogenase-deficient
mutant decreased its growth rate. These data indicate that there is a complex
relationship(s) between Yhb1p function(s) and cell defense reactions against
various stresses.
PMID- 9545282
TI - Functional correlation among Gal11, transcription factor (TF) IIE, and TFIIH in
Saccharomyces cerevisiae. Gal11 and TFIIE cooperatively enhance TFIIH-mediated
phosphorylation of RNA polymerase II carboxyl-terminal domain sequences.
AB - Saccharomyces cerevisiae Gal11, a component of the holoenzyme of RNA polymerase
II, interacts through its functional domains A and B with the small (Tfa2) and
large (Tfa1) subunits of the general transcription factor (TF) IIE, respectively.
We have recently suggested that Gal11 functions through a common pathway with
TFIIE in transcriptional regulation (Sakurai, H., and Fukasawa, T. (1997) J.
Biol. Chem. 272, 32663-32669). Here, we report that the activity of the TFIIH
associated kinase, responsible for phosphorylation of the largest subunit of RNA
polymerase II at the carboxyl-terminal domain (CTD), is enhanced cooperatively by
Gal11 and TFIIE. The enhancement of CTD phosphorylation was observed in the
holoenzyme of RNA polymerase II, but not in its core enzyme. The stimulatory
effect was completely abolished in the absence of either domain B of Gal11 or the
Tfa1 subunit of TFIIE, suggesting that the domain B-Tfa1 interaction is
necessary, if not sufficient, for an extensive phosphorylation of the CTD by
TFIIH. Stimulation of basal transcription by Gal11 was coupled with enhancement
of TFIIH-catalyzed CTD phosphorylation in a cell-free transcription system,
suggesting that Gal11 activates transcription by stimulating the CTD
phosphorylation in the cell.
PMID- 9545283
TI - Activation of the leukocyte NADPH oxidase by phorbol ester requires the
phosphorylation of p47PHOX on serine 303 or 304.
AB - The leukocyte NADPH oxidase is an enzyme in phagocytes and B lymphocytes that
when activated catalyzes the production of O-2 from oxygen and NADPH. During
oxidase activation, serine residues in the C-terminal quarter of the oxidase
component p47(PHOX) become extensively phosphorylated, the protein acquiring as
many as 9 phosphate residues. In a study of 11 p47(PHOX) mutants, each containing
an alanine instead of a serine at a single potential phosphorylation site, we
found that all but S379A corrected the defect in O-2 production in Epstein-Barr
virus (EBV)-transformed p47(PHOX)-deficient B cells (Faust, L. P., El Benna, J.,
Babior, B. M., and Chanock, S. J. (1995) J. Clin. Invest. 96, 1499-1505). In
particular, O-2 production was restored to these cells by the mutants S303A and
S304A. Therefore, apart from serine 379, whose state of phosphorylation in the
activated oxidase is unclear, no single potential phosphorylation site appeared
to be essential for oxidase activation. We now report that the double mutant
p47(PHOX) S303A/S304A was almost completely inactive when expressed in EBV
transformed p47(PHOX)-deficient B cells, even though it was expressed in normal
amounts in the transfected cells and was able to translocate to the plasma
membrane when the cells were stimulated. In contrast, the double mutant p47(PHOX)
S303E/S304E was able to support high levels of O-2 production by EBV-transformed
p47(PHOX)-deficient B cells. The surprising discovery that the double mutant
S303K/S304K was also able to support considerable O-2 production suggests either
that the effect of phosphorylation is related to the increase in hydrophilicity
around serines 303 and 304 or that activation involves the formation of a metal
bridge between the phosphorylated serines and another region of the protein.
PMID- 9545284
TI - Role of transcriptional repressor ICER in cyclic AMP-mediated attenuation of
cytokine gene expression in human thymocytes.
AB - Proliferating human medullary thymocytes can exhibit characteristic T helper cell
type 1 cytokine responses exemplified by the immediate early expression of
interleukin-2, interferon-gamma, tumor necrosis factor-alpha, and lymphotoxin
beta. Here we report that cAMP-mediated attenuation of the transcription of T
helper-1-specific cytokine genes in human medullary thymocytes correlates with
the induction of the cAMP-mediated transcriptional repressor ICER (inducible cAMP
early repressor). We show that ICER binds specifically to several NFAT/AP-1
(nuclear factor of activated T cells/activating protein-1) composite DNA sites
essential for the activation of the interleukin (IL)-2 promoter as well as to a
homologous DNA motif present in the proximal segment of the interferon-gamma
promoter. In the presence of the minimal NFAT DNA-binding domain, which is
sufficient for both DNA binding and AP-1 complex formation, ICER and NFAT form
NFAT/ICER ternary complexes on several NFAT/AP-1 DNA composite sites previously
identified as essential for the expression of the immunoregulatory cytokines such
as IL-2, IL-4, granulocyte-macrophage colony-stimulating factor, and tumor
necrosis factor-alpha. In extracts prepared from human medullary thymocytes
treated with forskolin and ionomycin, these composite sites bind endogenously
expressed ICER either singly or in complexes. Moreover, in Jurkat cells,
ectopically expressed ICER represses transcription from NFAT-mediated, phorbol
ester/ionophore-activated IL-2, granulocyte-macrophage colony-stimulating factor,
and tumor necrosis factor-alpha promoters. We present evidence that ICER
interactions with NFAT/AP-1 composite DNA sites correlate with its ability to
repress transcription. These findings provide further insight into the mechanisms
involved in cAMP-mediated transcriptional attenuation of cytokine expression.
PMID- 9545285
TI - Inhibition of CCAAT/enhancer-binding protein alpha and beta translation by
upstream open reading frames.
AB - CCAAT/enhancer-binding protein (C/EBP) alpha is a bZIP transcription factor whose
expression is restricted to specific cell types. Analysis of C/EBPalpha mRNA and
protein levels in various mammalian cells indicates that expression of this gene
is controlled both transcriptionally and post-transcriptionally. We report here
that C/EBPalpha translation is repressed in several cell lines by an
evolutionarily conserved upstream open reading frame (uORF), which acts in cis to
inhibit C/EBPalpha translation. Mutations that disrupt the uORF completely
abolished translational repression of C/EBPalpha. The related c/ebpbeta gene also
contains an uORF that suppresses translation. The length of the spacer sequence
between the uORF terminator and the ORF initiator codon (7 bases in all
c/ebpalpha genes and 4 bases in c/ebpbeta homologs) is precisely conserved. The
effects of insertions, deletions, and base substitutions in the C/EBPalpha spacer
showed that both the length and nucleotide sequence of the spacer are important
for efficient translational repression. Our data indicate that the uORFs regulate
translation of full-length C/EBPalpha and C/EBPbeta and do not play a role in
generating truncated forms of these proteins, as has been suggested by start site
multiplicity models.
PMID- 9545286
TI - Characterization of the p125 subunit of human DNA polymerase delta and its
deletion mutants. Interaction with cyclin-dependent kinase-cyclins.
AB - The catalytic subunit of human DNA polymerase (pol) delta was overexpressed in an
active, soluble form by the use of a baculovirus system in insect cells. The
recombinant enzyme was separated from endogenous DNA polymerases by
phosphocellulose, Mono Q-Sepharose, and single-stranded DNA-cellulose
chromatography. Recombinant DNA pol delta was also purified by immunoaffinity
chromatography. The enzymatic properties of the purified catalytic subunit were
characterized. The enzyme was active and possessed both DNA polymerase and
associated 3' to 5' exonuclease activities. NH2-terminal deletion mutants
retained polymerase activity, whereas the core and COOH-terminal deletion mutants
were devoid of any measurable activities. Coinfection of Sf9 cells with
recombinant baculovirus vectors for pol delta and cyclin-dependent kinase (cdk)
cyclins followed by metabolic labeling with 32Pi showed that the recombinant
catalytic subunit of pol delta could be hyperphosphorylated by G1 phase-specific
cdk-cyclins. When cdk2 was coexpressed with pol delta in Sf9 cells, pol delta was
found to coimmunoprecipitate with antibodies against cdk2. Experiments with
deletion mutants of pol delta showed that the NH2-terminal region was essential
for this interaction. Coimmunoprecipitation and Western blot experiments in Molt
4 cells confirmed the interaction in vivo. Preliminary experiments showed that
phosphorylation of the catalytic subunit of pol delta by cdk2-cyclins had little
or no effect on the specific activity of the enzyme.
PMID- 9545287
TI - Dynamic cross-linking by alpha-actinin determines the mechanical properties of
actin filament networks.
AB - We used smooth muscle alpha-actinin to evaluate the contribution of cross-linker
dynamics to the mechanical properties of actin filament networks. Recombinant
actin-binding domain (residues 2-269) binds actin filaments with a Kd of 1 microM
at 25 degrees C, 20 times stronger than actin-binding domain produced by
thermolysin digestion of native alpha-actinin (residues 25-257). Between 8 and 25
degrees C the rate constants for recombinant actin-binding domain to bind to (0.8
2.7 microM-1 s-1) and dissociate from (0.2-2.4 s-1) actin filaments depend on
temperature. At 8 degrees C actin filaments cross-linked with alpha-actinin are
stiff and nearly solid, whereas at 25 degrees C the mechanical properties
approach those of actin filaments alone. In these experiments, high actin
concentrations kept most of the alpha-actinin bound to actin and temperature
varied a single parameter, cross-linker dynamics, because the mechanical
properties of pure actin filaments (a viscoelastic gel) or biotinylated actin
filaments cross-linked irreversibly by avidin (a stiff viscoelastic solid) depend
little on temperature. These results show that the rate of exchange of dynamic
cross-links between actin filaments is an important determinant of the mechanical
properties of the networks.
PMID- 9545288
TI - The guanylyltransferase domain of mammalian mRNA capping enzyme binds to the
phosphorylated carboxyl-terminal domain of RNA polymerase II.
AB - We have conducted a biochemical and genetic analysis of mouse mRNA capping enzyme
(Mce1), a bifunctional 597-amino acid protein with RNA triphosphatase and RNA
guanylyltransferase activities. The principal conclusions are as follows: (i) the
mammalian capping enzyme consists of autonomous and nonoverlapping functional
domains; (ii) the guanylyltransferase domain Mce1(211-597) is catalytically
active in vitro and functional in vivo in yeast in lieu of the endogenous
guanylyltransferase Ceg1; (iii) the guanylyltransferase domain per se binds to
the phosphorylated RNA polymerase II carboxyl-terminal domain (CTD), whereas the
triphosphatase domain, Mce1(1-210), does not bind to the CTD; and (iv) a mutation
of the active site cysteine of the mouse triphosphatase elicits a strong growth
suppressive phenotype in yeast, conceivably by sequestering pre-mRNA ends in a
nonproductive complex or by blocking access of the endogenous yeast
triphosphatase to RNA polymerase II. These findings contribute to an emerging
model of mRNA biogenesis wherein RNA processing enzymes are targeted to nascent
polymerase II transcripts through contacts with the CTD. The phosphorylation
dependent interaction between guanylyltransferase and the CTD is conserved from
yeast to mammals.
PMID- 9545289
TI - Identifying Lys359 as a critical residue for the ATP-dependent reactions of
Drosophila DNA topoisomerase II.
AB - Substituting Lys359 with either Gln or Glu in the highly conserved QTK-loop in
the DNA gyrase B protein homologous domain of Drosophila topoisomerase II
inactivates its catalytic activities. Although strand passage and DNA-dependent
ATPase activities are affected in these mutant proteins, their DNA cleavage
activity is comparable with the wild-type enzyme and can be stimulated to the
same level by topoisomerase-targeting anticancer drugs. The sequence specificity
in the DNA cleavage reaction remains unaltered for the mutant proteins. We have
used both glass fiber filter binding assay and CsCl density gradient
ultracentrifugation to monitor the formation of a salt-stable, protein-clamp
complex. Both Gln and Glu mutant proteins can form a clamp complex in the
presence of 5'-adenylyl-beta,gamma-imidodiphosphate, albeit with a lower
efficiency than the wild-type enzyme. However, the mutant proteins can form a
stable complex either in the presence of ATP or in the absence of any cofactors.
These results are in an interesting contrast with the wild-type enzyme, which
cannot form a stable complex under similar conditions. Our data suggest that
Lys359 is critical for the catalytic activity of topoisomerase II and may have an
important function in the ATP signaling process.
PMID- 9545290
TI - Rationale for reclassification of a distinctive subdivision of mammalian class Mu
glutathione S-transferases that are primarily expressed in testis.
AB - A rat testicular Mu-class glutathione S-transferase (GST) resolved by reversed
phase high performance liquid chromatography cross-reacted with peptide sequence
specific antisera raised against the human hGSTM3 subunit. Electrospray
ionization mass spectrometry indicated that this rat GST subunit (designated
rGSTM5 in this report) has a significantly greater molecular mass (26,541 Da)
than the other rat GST subunits. The mouse homologue (mGSTM5 subunit) was also
identified and characterized by high performance liquid chromatography and
electrospray ionization mass spectrometry. Sequence analysis of rGSTM5 peptide
fragments and the sequence deduced from a cDNA clone showed that the protein is
highly homologous to the hGSTM3 and murine mGSTM5 subunits. All three GSTs of
this subclass have N- and C-terminal extensions with C-terminal cysteine
residues, but the two penultimate amino acids near the C terminus are divergent
in the three species. The proteins of this class Mu subfamily have similar
catalytic specificities and mechanisms, are all cysteine rich, are found mainly
in testis, and share characteristics that distinguish them from other GSTs.
Moreover, the rGSTM5 subunit isolated from rat testis was not found in
heterodimeric combination with other common Mu-class GST subunits. As the rGSTM5,
mGSTM5, and hGSTM3 subunits are structurally more closely related to each other
than they are to other Mu GSTs, it is proposed that they be considered a
functionally distinct and separate subfamily within class Mu. The identification
of this unique mammalian GST subclass could advance strategies for interspecies
comparisons of GSTs and provides a rodent model for studies on functions and
regulatory mechanisms for human GSTs.
PMID- 9545291
TI - Re-evaluating the role of His-143 in the mechanism of type I dehydroquinase from
Escherichia coli using two-dimensional 1H,13C NMR.
AB - Type I dehydroquinase from the shikimate pathway of Escherichia coli dehydrates
dehydroquinate to dehydroshikimate. pH/log Vmax profiles of the enzyme indicate
the presence of a single ionizing group with a pKa of 6.2. Chemical modification
experiments with diethyl pyrocarbonate have identified the conserved residue His
143 as essential for catalysis in this enzyme and the pKa for this modification
is also 6.2, implying that this is the single ionizing residue in dehydroquinase
that may be acting as a general base in the catalytic mechanism. Subsequent
mutagenesis of this residue (Leech, A. P., James, R., Coggins, J. R., and
Kleanthous, C. (1995) J. Biol. Chem. 270, 25827-25836) further suggested that His
143 may be involved in Schiff base formation/breakdown as well as being the
proton abstracting general base. The importance of this residue was confirmed by
recent x-ray crystallographic data showing His-143 to be at the center of a
hydrogen-bonded triad, flanked by the essential Schiff base forming residue Lys
170 and Glu-86. In the present study, we have used mutagenesis and 1H and 13C NMR
to assign the resonance of His-143 and probe its ionization state to define more
precisely its role in the mechanism of type I dehydroquinase. Following isotopic
enrichment of wild-type and H143A dehydroquinase enzymes with [2-13C]histidine,
the resonance for His-143 was assigned by comparing their 1H,13C heteronuclear
single quantum correlation NMR spectra. pH titrations revealed that whether in
the liganded or unliganded state, His-143 does not ionize over the pH range 6-9.5
and so cannot possess a pKa of 6.2. The NMR data are consistent with this residue
remaining unprotonated at pH values optimal for the activity of this enzyme (pH >
7). The role of His-143 is re-evaluated in light of these and the recent
structural data, and an alternative candidate for the pKa of 6.2 is discussed.
PMID- 9545292
TI - Mutation of the sialyltransferase S-sialylmotif alters the kinetics of the donor
and acceptor substrates.
AB - Protein sequence analysis of the cloned sialyltransferase gene family has
revealed the presence of two conserved protein motifs in the middle of the
lumenal catalytic domain, termed L-sialylmotif and S-sialylmotif. In our previous
study (Datta, A. K., and Paulson, J. C. (1995) J. Biol. Chem. 270, 1497-1500) the
larger L-sialylmotif of ST6Gal I was analyzed by site-directed mutagenesis, which
provided evidence that it participates in the binding of the CMP-NeuAc, a common
donor substrate for all the sialyltransferases. However, none of the mutants
tested in this motif had any significant effect on their binding affinities
toward the acceptor substrate asialo alpha1-acid glycoprotein. In this study, we
have investigated the role of the S-sialylmotif of the same enzyme ST6Gal I. In
total, nine mutants have been constructed by changing the conserved amino acids
of this motif to mostly alanine by site-directed mutagenesis. Kinetic analysis
for the mutants which retained sialyltransferase activity showed that the
mutations in the S-sialylmotif caused a change of Km values for both the donor
and the acceptor substrates. Our results indicated that this motif participates
in the binding of both the substrates. A sequence homology search also supported
this finding, which showed that the downstream amino acid sequence of the S
sialylmotif is conserved for each subgroup of this enzyme family, indicating its
association with the acceptor substrate.
PMID- 9545293
TI - Identification of the N-linked oligosaccharide sites in chick corneal lumican and
keratocan that receive keratan sulfate.
AB - Corneal proteoglycans have chondroitin/dermatan and keratan sulfate (KS) chains
and belong to the leucine-rich proteoglycan gene family. Corneal KS is N-linked
to Asn of an NX(S/T) site through a complex oligosaccharide linkage region. Only
some sites receive KS, whereas others remain in a high mannose form. To determine
whether the attachment of KS was biased toward specific sites, we isolated
trypsin-digested KS-containing fragments of chick corneal proteoglycans and
sequenced the peptides. Results showed that all of the peptides sequenced aligned
to the deduced amino acid sequence of either chick lumican or chick keratocan at
the first, third, and fourth potential N-linked sites. Sites 1 and 4 in lumican
and keratocan are in a homologous location. By analogy with the structure of
ribonuclease inhibitor (a Leu-rich repeat containing protein), the KS chains
would extend outward on the outer face of a horseshoe-like structure. The amino
acid sequences surrounding the potential N-linked sites were also compared. Sites
receiving KS tend to have a higher occurrence of aromatic residues, in particular
Phe, located within 3 amino acids of NX(S/T). These conserved Phe residues may
have a role in the conversion of high mannose N-linked oligosaccharides to
polylactosamine and/or keratan sulfate.
PMID- 9545294
TI - A novel -2Fe-2S- ferredoxin from Pseudomonas putida mt2 promotes the reductive
reactivation of catechol 2,3-dioxygenase.
AB - Catechol 2,3-dioxygenase (XylE) is a component of the TOL plasmid-encoded pathway
for the degradation of toluene and xylenes and catalyzes the dioxygenolytic
cleavage of the aromatic ring. Purified XylE is oxygen-sensitive and unstable in
vitro, particularly in the presence of substituted catechol substrates, but it is
stabilized in vivo by another protein, XylT, encoded by the xylT gene located
just upstream of xylE. In this study, we have purified to homogeneity the XylT
product from a recombinant Escherichia coli strain containing a hyperexpressible
xylT gene and characterized it as a novel [2Fe-2S] ferredoxin. It is the first
example of a soluble ferredoxin with a net positive charge at neutral pH. The EPR
signal of the iron sulfur cluster has rhombic symmetry as is the case for plant
type ferredoxins, but the XylT absorbance spectrum resembles more closely that of
adrenodoxin. The midpoint redox potential was determined to be -373 +/- 6 mV, at
pH 8. 5. XylT was unusually unstable for a [2Fe-2S] ferredoxin, with half-lives
of 69 min at 25 degrees C in air and 70 min at 37 degrees C in argon. With
photochemically reduced 5-deazaflavin for the controlled generation of reductant,
it was demonstrated that XylT mediates the rapid reactivation of purified
inactive catechol 2,3-dioxygenase in vitro. Inactivation of XylE by 4
methylcatechol resulted in oxidation of the active site iron to a high spin
ferric state that was detectable by EPR. Spectroscopic evidence presented here
demonstrates that XylT reactivates XylE through reduction of the iron atom in the
active site of the enzyme. It is the first instance of a ferredoxin-mediated
reactivation of an enzyme. The level of expression of XylT in Pseudomonas putida
mt2 cells is low and the calculated XylT/XylE molar ratio is consistent with the
proposal that XylE reactivation involves catalytic nonstoichiometric amounts of
XylT.
PMID- 9545295
TI - Expression of a plastidic ATP/ADP transporter gene in Escherichia coli leads to a
functional adenine nucleotide transport system in the bacterial cytoplasmic
membrane.
AB - Recently, a second type of eucaryotic adenine nucleotide transporter located in
the inner envelope membrane of higher plants has been identified at the molecular
level (Neuhaus, H. E., Thom, E., Mohlmann, T., Steup, M., and Kampfenkel, K.
(1997) Plant J. 11, 73-82). Here we have analyzed the biochemical properties of
this ATP/ADP transporter from Arabidopsis thaliana (AATP1, At). This analysis was
carried out by expressing a cDNA encoding this carrier as a histidine-tagged
chimeric protein heterologously in Escherichia coli. Isopropyl-1-thio-beta-D
galactopyranoside (IPTG)-induced E. coli cells were able to import radioactively
labeled [alpha-32P]ATP. Uninduced E. coli cells did not import [alpha-32P]ATP.
Further control experiments revealed that IPTG induction did not promote import
of other phosphorylated or unphosphorylated metabolites into the bacterial cell
indicating the specificity of [alpha-32P]ATP transport. [alpha-32P]ATP uptake
into induced E. coli cells was linear with time for several minutes allowing for
determination of kinetic constants. The apparent Km for ATP was 17 microM which
is close to values reported on the authentic protein in isolated plastids. ADP
was a strong competitive inhibitor of -alpha-32P-ATP uptake (Ki ADP 3.6 microM).
Other metabolites like AMP, ADP glucose, UTP, UDP, NAD, and NADP did not
influence [alpha-32P]ATP uptake. IPTG-induced E. coli cells preloaded with [alpha
32P]ATP exported radioactively labeled adenylates after exogenous addition of
unlabeled ATP or ADP indicating a counter exchange mechanism of transport. The
biochemical properties of the heterologously expressed AATP1 gene product
demonstrated that the protein is functionally integrated in the cytoplasmic
membrane of E. coli. This is the first report of the functional expression of a
plant membrane protein in E. coli leading to new transport properties across the
cytoplasmic membrane. The functional integration of a plant membrane protein in
the cytoplasmic membrane of E. coli offers new possibilities for future studies
of the structural and mechanistic properties of this transporter. Since IPTG
induction allowed synthesis of a 67-kDa protein in E. coli, which was
subsequently specifically enriched by metal-chelate chromatography, this
procaryotic heterologous expression system might provide a suitable system for
overproduction of membrane proteins of eucaryotic origin in the near future.
PMID- 9545296
TI - Protein disulfide isomerase acts as a molecular chaperone during the assembly of
procollagen.
AB - Protein-disulfide isomerase (PDI) has been shown to be a multifunctional enzyme
catalyzing the formation of disulfide bonds, as well as being a component of the
enzymes prolyl 4-hydroxylase (P4-H) and microsomal triglyceride transfer protein.
It has also been proposed to function as a molecular chaperone during the
refolding of denatured proteins in vitro. To investigate the role of this
multifunctional protein within a cellular context, we have established a semi
permeabilized cell system that reconstitutes the synthesis, folding,
modification, and assembly of procollagen as they would occur in the cell. We
demonstrate here that P4-H associates transiently with the triple helical domain
during the assembly of procollagen. The release of P4-H from the triple helical
domain coincides with assembly into a thermally stable triple helix. However, if
triple helix formation is prevented, P4-H remains associated, suggesting a role
for this enzyme in preventing aggregation of this domain. We also show that PDI
associates independently with the C-propeptide of monomeric procollagen chains
prior to trimer formation, indicating a role for this protein in coordinating the
assembly of heterotrimeric molecules. This demonstrates that PDI has multiple
functions in the folding of the same protein, that is, as a catalyst for
disulfide bond formation, as a subunit of P4-H during proline hydroxylation, and
independently as a molecular chaperone during chain assembly.
PMID- 9545297
TI - Purification and characterization of the Sgs1 DNA helicase activity of
Saccharomyces cerevisiae.
AB - The yeast Saccharomyces cerevisiae Sgs1 protein is a member of a family of DNA
helicases that include the Escherichia coli RecQ protein and the products of
human Bloom's syndrome and Werner's syndrome genes. To study the enzymatic
characteristics of the protein, a recombinant Sgs1 fragment (amino acids 400-1268
of the 1447-amino acid full-length protein) was overexpressed in yeast and
purified to near homogeneity. The purified protein exhibits an ATPase activity in
the presence of single- or double-stranded DNA. In the presence of ATP or dATP,
unwinding of duplex DNA or a DNA-RNA heteroduplex by the recombinant Sgs1
fragment was readily observed. Similar to the E. coli RecQ helicase, displacement
of the DNA strand occurs in the 3' to 5' direction with respect to the single
stranded DNA flanking the duplex. The efficiency of unwinding was found to
correlate inversely with the length of the duplex region and was enhanced by the
presence of E. coli single-stranded DNA-binding protein. In addition, the
recombinant Sgs1 fragment was found to bind more tightly to a forked DNA
substrate than to either single- or double-stranded DNA.
PMID- 9545298
TI - Up-regulation of glucosylceramide synthase expression and activity during human
keratinocyte differentiation.
AB - During keratinocyte differentiation, the glycolipid, glucosylceramide (GlcCer),
is thought to be synthesized, stored in intracellular lamellar granules and
eventually extruded into the intercellular space where GlcCer is hydrolyzed to
ceramide, a major component of the epidermal permeability barrier. Previous
studies showed that GlcCer synthase (GCS) activity increases during keratinocyte
differentiation; however, the mechanism by which GCS activity is regulated was
not established. In the present study, we prepared anti-peptide antibodies and
amplified cDNA probes based on the cDNA sequence for human GCS (Ichikawa, S.,
Sakiyama, H., Suzuki, G., Hidari, K. I.-P. J., and Hirabayashi, Y. (1996) Proc.
Natl. Acad. Sci. U. S. A. 93, 4638-4643) in order to study GCS expression during
keratinocyte differentiation. Confluent human keratinocytes in culture were
induced to terminally differentiate by elevation of Ca+2 in the medium without
exogenous hormones or growth factors. GlcCer synthesis assayed in situ using a
fluorescent ceramide analog increased approximately 5-fold during keratinocyte
differentiation, peaking at day 6. Fluorescence microscopy studies of living
keratinocytes showed that fluorescent ceramide and/or its metabolites accumulated
in the Golgi in undifferentiated cells but targeted to unique vesicular
structures that may be derived from the trans-Golgi region. Expression of both
GCS mRNA, a approximately 3. 8-kilobase transcript on Northern blots, and GCS
protein, a approximately 38-kDa polypeptide detected by Western blotting,
increased dramatically (approximately 5-fold) during differentiation, reaching a
maximum at about day 8. These results suggest that GCS is up-regulated at the
transcriptional level during keratinocyte differentiation and provide the first
direct evidence for GCS up-regulation in any cell type.
PMID- 9545299
TI - Crystal structure of human RhoA in a dominantly active form complexed with a GTP
analogue.
AB - The 2.4-A resolution crystal structure of a dominantly active form of the small
guanosine triphosphatase (GTPase) RhoA, RhoAV14, complexed with the
nonhydrolyzable GTP analogue, guanosine 5'-3-O-(thio)triphosphate (GTPgammaS),
reveals a fold similar to RhoA-GDP, which has been recently reported (Wei, Y.,
Zhang, Y., Derewenda, U., Liu, X., Minor, W., Nakamoto, R. K., Somlyo, A. V.,
Somlyo, A. P., and Derewenda, Z. S. (1997) Nat. Struct. Biol. 4, 699-703), but
shows large conformational differences localized in switch I and switch II. These
changes produce hydrophobic patches on the molecular surface of switch I, which
has been suggested to be involved in its effector binding. Compared with H-Ras
and other GTPases bound to GTP or GTP analogues, the significant conformational
differences are located in regions involving switches I and II and part of the
antiparallel beta-sheet between switches I and II. Key residues that produce
these conformational differences were identified. In addition to these
differences, RhoA contains four insertion or deletion sites with an extra helical
subdomain that seems to be characteristic of members of the Rho family, including
Rac1, but with several variations in details. These sites also display large
displacements from those of H-Ras. The ADP-ribosylation residue, Asn41, by C3
like exoenzymes stacks on the indole ring of Trp58 with a hydrogen bond to the
main chain of Glu40. The recognition of the guanosine moiety of GTPgammaS by the
GTPase contains water-mediated hydrogen bonds, which seem to be common in the Rho
family. These structural differences provide an insight into specific interaction
sites with the effectors, as well as with modulators such as guanine nucleotide
exchange factor (GEF) and guanine nucleotide dissociation inhibitor (GDI).
PMID- 9545300
TI - A novel lectin from Sarcophaga. Its purification, characterization, and cDNA
cloning.
AB - A novel C-type lectin that agglutinates rabbit red cells was purified from NIH
Sape-4 cells derived from the flesh fly (Sarcophaga peregrina), and its cDNA was
isolated. This lectin, named granulocytin, appeared to be a trimer of a 20-kDa
subunit consisting of 151 amino acid residues. The gene for granulocytin was
activated in third instar larvae, and its expression was enhanced when the larval
body wall was injured. In third instar larvae, granulocytin was found to be
synthesized by hemocytes and secreted into the hemolymph. The molecular mass and
gene expression patterns of granulocytin were very similar to those of Drosophila
lectin that we reported previously (Haq, S., Kubo, T., Kurata, S., Kobayashi, A.,
and Natori, S. (1996) J. Biol. Chem. 271, 20213-20218). However, these two
lectins showed amino acid identities of 20% at most, and no significant hapten
sugar for granulocytin was identified.
PMID- 9545301
TI - The 55-kDa tumor necrosis factor receptor induces clustering of mitochondria
through its membrane-proximal region.
AB - The cytokine tumor necrosis factor (TNF) activates diverse signaling molecules
resulting in gene expression, differentiation, and/or cell death. Here we report
a novel feature induced by TNF, namely translocation of mitochondria from a
dispersed distribution to a perinuclear cluster. Mitochondrial translocation
correlated with sensitivity to the cell death-inducing activity of TNF and was
mediated by the 55-kDa TNF receptor (TNF-R55), but not by Fas, indicating that
the signaling pathway requires a TNF-R55-specific but death domain-independent
signal. Indeed, using L929 cells that express mutant TNF-R55, we showed that the
membrane-proximal region of TNF-R55 was essential for signaling to mitochondrial
translocation. In the absence of translocation, the cell death response was
markedly delayed, pointing to a cooperative effect on cell death. Translocation
of mitochondria, although dependent on the microtubules, was not imposed by the
latter and was equally induced by TNF-independent immunoinhibition of the motor
protein kinesin. Additionally, immunoinhibition with antibody directed against
the tail domain of kinesin synergized with TNF-induced cell death. Based on this
functional mimicry, we propose that a TNF-R55 membrane-proximal region-dependent
signal impedes mitochondria-associated kinesin, resulting in cooperation with the
TNF-R55 death domain-induced cytotoxic response and causing the observed
clustering of mitochondria.
PMID- 9545302
TI - Oxidized low density lipoprotein induces apoptosis in cultured human umbilical
vein endothelial cells by common and unique mechanisms.
AB - Oxidized low density lipoprotein (oxLDL) induces apoptosis in vascular cells. To
elucidate the mechanisms involved in this apoptosis, we studied the apoptosis
inducing activity in lipid fractions of oxLDL and the roles of two common
mechanisms, ceramide generation and the activation of caspases, in apoptosis in
human umbilical vein endothelial cells treated with oxLDL. We also studied the
effects of antioxidants and cholesterol. oxLDL induced endothelial apoptosis in a
time- and dose-dependent fashion. Apoptosis-inducing activity was recovered in
the neutral lipid fraction of oxLDL. Various oxysterols in this fraction induced
endothelial apoptosis. Neither the phospholipid fraction nor its component
lysophosphatidylcholine induced apoptosis. oxLDL induced ceramide accumulation
temporarily at 15 min in a dose-dependent fashion. Two inhibitors of acid
sphinogomyelinase inhibited both the increase in ceramide and the apoptosis
induced by oxLDL. Furthermore, a membrane-permeable ceramide (C2-ceramide)
induced endothelial apoptosis. These findings demonstrated that ceramide
generation by acid sphingomyelinase is indispensable for the endothelial
apoptosis induced by oxLDL. Inhibitors of both caspase-1 and caspase-3 inhibited
the apoptosis, suggesting that oxLDL induced apoptosis by activating these
cysteine proteases. The antioxidants butylated hydroxytoluene and superoxide
dismutase but not catalase inhibited the apoptosis induced by oxLDL or 25
hydroxycholesterol. This suggests not only that superoxide plays an important
role but also that a critical interaction between oxLDL and the cell takes place
on the outer surface of the membrane, because superoxide dismutase is not
membrane-permeable. Exogenous cholesterol also inhibited the apoptosis. Our study
demonstrated that neutral lipids in oxLDL induce endothelial apoptosis by
activating membrane sphingomyelinase in a superoxide-dependent manner, as well as
by activating caspases.
PMID- 9545303
TI - Site-directed mutagenesis of essential residues involved in the mechanism of
bacterial glycosylasparaginase.
AB - Flavobacterium glycosylasparaginase was cloned in an Escherichia coli expression
system. Site-directed mutagenesis was performed at residues suggested to be
important in the catalytic mechanism based on the crystal structure of the human
enzyme and other biochemical studies. In vitro autoproteolysis allowed the mutant
enzymes to be activated, including those that were slow to self-cleave. Based on
the activity of the mutant enzymes, six catalytically essential amino acids were
identified: Trp-11, Asp-66, Thr-152, Thr-170, Arg-180, and Asp-183. Kinetic
analysis of each mutant further defined the function of these residues in
substrate specificity and reaction rate. Mutagenesis of the N-terminal
nucleophile residue Thr-152 confirmed the key function of its side-chain hydroxyl
group. Partial activities of mutants T152S/C were in agreement with the general
mechanism of N-terminal nucleophile (Ntn)-amidohydrolases. The side-chain
hydroxyl of Thr-170 contributes to the reaction rate based on studies of mutants
T170S/C/A. Residues Asp-183 and Arg-180 were found to H-bond, respectively, with
the charged alpha-amino and alpha-carboxyl group of the substrate (Asn-GlcNAc).
Mutants R180Q/L and D183E/N had greatly decreased substrate affinity and reduced
reaction rates. Kinetic studies also showed that Trp-11 is involved in regulation
of the enzyme reaction rate, contradictory to a previous suggestion that this
residue is involved in substrate binding. Asp-66 is a new residue found to be
important in enzyme activity. The overall active site structure involving these
catalytic residues resembles the glutaminase domain of glucosamine 6-phosphate
synthase, another member of the Ntn-amidohydrolase family of enzymes.
PMID- 9545304
TI - Characterization and functional analysis of the cis-autoproteolysis active center
of glycosylasparaginase.
AB - Glycosylasparaginase is an N-terminal nucleophile hydrolase and is activated by
intramolecular autoproteolytic processing. This cis-autoproteolysis possesses
unique kinetics characterized by a reversible N-O acyl rearrangement step in the
processing. Arg-180 and Asp-183, involved in binding of the substrate in the
mature enzyme, are also involved in binding of free amino acids in the partially
formed substrate pocket on certain mutant precursors. This binding site is
sequestered in the wild-type precursor. Binding of free amino acids on mutant
precursors can either inhibit or accelerate their processing, depending on the
individual mutants and amino acids. The polypeptide sequence at the processing
site, which is highly conserved, adopts a special conformation. Asp-151 is
essential for maintaining this conformation, possibly by anchoring its side chain
into the partially formed substrate pocket through interaction with Arg-180. The
reactive nucleophile Thr-152 is activated not only by deprotonation by His-150
but also by interaction with Thr-170, suggesting a His-Thr-Thr active triad for
the autoproteolysis.
PMID- 9545305
TI - Activation of phosphatidylinositol 3-kinase through glycoprotein 130 induces
protein kinase B and p70 S6 kinase phosphorylation in cardiac myocytes.
AB - Phosphatidylinositol (PI) 3-kinase is known to be activated by cytokine
stimulation through different types of receptors to transduce intracellular
responses. We have previously reported that leukemia inhibitory factor (LIF)
induces the activation of Janus kinase signal transducer and activator of
transcription (JAK-STAT) and mitogen-activated protein (MAP) kinase pathways
through glycoprotein (gp) 130 in cardiac myocytes. However, whether PI 3-kinase
is involved in regulation of gp130 signaling and the activation mechanisms by
which it associates with other tyrosine-phosphorylated proteins remain unknown.
We found that LIF induced the activation of PI 3-kinase in cardiac myocytes.
Moreover, JAK1 binds to PI 3-kinase, and LIF stimulation increases the PI 3
kinase activity in JAK1 immunoprecipitates. Activation of MAP kinase and protein
kinase B by LIF was attenuated by wortmannin. LIF-induced p70 S6 kinase
activation, protein synthesis, and c-fos mRNA expression were inhibited by
wortmannin and rapamycin. Both inhibitors failed to appreciably affect the
phosphorylation of STAT3. In conclusion, PI 3-kinase is activated with LIF in
cardiac myocytes, and JAK1 is found to associate with this enzyme. PI 3-kinase
provides a crucial link between gp130, MAP kinase, protein kinase B, and p70 S6
kinase in cardiac myocytes.
PMID- 9545306
TI - Cleavage of BP180, a 180-kDa bullous pemphigoid antigen, yields a 120-kDa
collagenous extracellular polypeptide.
AB - The hemidesmosome (HD) is a cell-to-substrate adhesion apparatus found in
stratified and complex epithelia. One of the putative cell-matrix adhesion
molecules present in the HD is the 180-kDa bullous pemphigoid antigen (BP180),
also termed type XVII collagen. In our previous study, using a monoclonal
antibody (mAb) 1337, we have detected a 120-kDa collagenase-sensitive polypeptide
in the HD fraction (Uematsu, J. and Owaribe, K. (1993) Cell Struct. Funct. 18,
588 (abstr.)). The present study was undertaken to assess the relation of the 120
kDa polypeptide to this BP180. Immunofluorescence microscopy of bovine skin
revealed the basement membrane zone of skin to be stained clearly with mAb 1337,
whereas the lateral surfaces of basal cells, which were decorated by typical
antibodies against BP180, were not. The antibody did not detect HDs in cultured
cells but rather in the culture medium. These results indicate a localization of
mAb 1337 antigen distinct from BP180. However, the same polypeptide was also
recognized by monoclonal antibodies to the extracellular but not the cytoplasmic
part of BP180, and found to react with a polyclonal antibody against the non
collagenous 16A domain of BP180. Therefore, the polypeptide was identified as an
extracellular fragment of BP180. mAb 1337 immunoprecipitated the 120-kDa fragment
from the medium, but not the 180-kDa molecule of BP180 extracted from cultured
cells, indicating that the antibody specifically recognizes the fragment. The mAb
1337 apparently recognizes a unique epitope that is exposed or formed by the
cleavage. Hence, the staining pattern observed for bovine skin demonstrated the
presence of the 120-kDa extracellular fragment. Rotary shadow electron microscopy
of affinity-purified 120-kDa fragments demonstrated that they have the unique
molecular shape consisting of a central rod and a flexible tail, without the
globular head that is present in the BP180 molecule. From these results, we
conclude that mAb 1337 shows unique epitope specificity, recognizing only the 120
kDa extracellular fragment of BP180, which is constitutively cleaved on the cell
surface as a 120-kDa fragment both in in vivo and in vitro.
PMID- 9545307
TI - A peptide sequence of heparin/heparan sulfate (HP/HS)-interacting protein
supports selective, high affinity binding of HP/HS and cell attachment.
AB - We previously have identified a novel cell surface heparan sulfate/heparin
(HS/HP)-interacting protein (HIP) found in human uterine epithelia and a variety
of other human epithelial and endothelial cells and cell lines (Liu, S., Smith,
S. E., Julian, J., Rohde, L. H., Karin, N. J., and Carson, D. D. (1996) J. Biol.
Chem. 271, 11817-11823; Rohde, L. H., Julian, J., Babaknia, A., and Carson, D. D.
(1996) J. Biol. Chem. 271, 11824-11830). The amino acid sequence predicted for
HIP revealed a potential HS/HP-binding motif. In the present studies, a synthetic
peptide corresponding to this putative HS/HP-binding motif, HIP peptide, was
synthesized and examined with regard to its HS/HP binding and cell attachment
promoting activity. Results using solid phase binding assays demonstrate that HIP
peptide binds HS/HP with high selectivity and has high affinity for bulk HP (50%
saturation congruent with 300 nM) and even higher affinity for a subset of
polysaccharides found in commercial [3H]HP (half-saturation congruent with 10
nM). Moreover, HIP peptide binds subsets of cell and extracellular matrix
associated HS and dermatan sulfate expressed by RL95 cells, a human uterine
adenocarcinoma cell line. HIP peptide also binds a similar fraction of HS as well
as dermatan sulfate expressed by JAR cells, a human choriocarcinoma cell line. In
contrast to binding of cell- or extracellular matrix-associated HS, HIP peptide
does not bind secreted or released forms of HS or DS from either RL95 or JAR
cells to a significant extent. HS species that bind to HIP peptide are generally
larger, have a higher negative charge density, and have a larger proportion of di
and trisulfated disaccharide units than HS species that do not bind to HIP
peptide, demonstrating structural differences among these polysaccharides. This
same peptide supports HS-dependent JAR cell attachment. Collectively, these data
demonstrate that a linear peptide sequence found within HIP can account, at least
in part, for the HS/HP binding and cell adhesion promoting activities of this
protein.
PMID- 9545308
TI - Increased expression of acetylcholinesterase T and R transcripts during
hematopoietic differentiation is accompanied by parallel elevations in the levels
of their respective molecular forms.
AB - Differentiation of hematopoietic cells is known to be accompanied by profound
changes in acetylcholinesterase (AChE) enzyme activity, yet the basic mechanisms
underlying this developmental regulation remain unknown. We initiated a series of
experiments to examine the molecular mechanisms involved in regulating AChE
expression during hematopoiesis. Differentiation of murine erythroleukemia (MEL)
cells using dimethyl sulfoxide resulted in a 5- and 10-fold increase in
intracellular and secreted AChE enzyme activity, respectively. Interestingly,
these increases resulted from a preferential induction of the globular molecular
form G1 and a slight increase in G4 instead of an increase in the levels of the
G2 membrane-bound form, a molecular form expressed in mature erythrocytes.
Concomitantly, expression of the two predominant AChE transcripts (R and T, for
read-through and tail, respectively) in MEL cells was induced to a similar extent
with differentiation. Nuclear run-on assays performed with nuclei isolated from
induced versus uninduced MEL cells revealed that in contrast to the large
increases seen in the transcription of the beta-globin gene, the transcriptional
activity of the AChE gene remained largely unaffected after differentiation.
Determination of the half-lives of the R and T transcripts demonstrated that they
both exhibited an increase in stability in induced MEL cells. Taken together,
results from these studies indicate that post-transcriptional regulatory
mechanisms account for the increased expression of AChE in differentiated
hematopoietic cells.
PMID- 9545310
TI - Visualization of a slow, ATP-induced structural transition in the bacterial
molecular chaperone DnaK.
AB - Recent reports have shown that the binding of ATP to a 70-kDa molecular chaperone
induces a rapid global conformational transition from a "high affinity" state to
a "low affinity" state, where these states are defined by tight and weak binding
to (poly)peptides, respectively. To complete the activity cycle, a chaperone
molecule must ultimately return to the high affinity state. In this report, this
return to the high affinity state was studied using a chemical cross-linking
assay in conjunction with SDS-polyacrylamide gel electrophoresis. The basis for
this assay is that in the absence of nucleotide or in the presence of ADP,
conditions that stabilize the high affinity state, cross-linking of the
Escherichia coli molecular chaperone DnaK yielded two monomeric forms, with
apparent molecular masses of 70 kDa (77%) and 90 kDa (23%), whereas cross-linking
yielded only the 70-kDa monomeric form in the presence of ATP. This ATP-dependent
difference in cross-linking was used to follow the kinetics of the low affinity
to high affinity transition under single turnover conditions. The rate of this
transition (kobs = 3.4 (+/-0.6) x 10(-4) s-1 at 25 degrees C) is almost identical
to the reported rate of ATP hydrolysis (khy = 2.7 (+/-0.7) x 10(-4) s-1 at 22
degrees C). These results are consistent with a two-step sequential reaction
where rate-limiting ATP hydrolysis precedes the conformational change. Models for
the formation of two cross-linked DnaK monomers in the absence of ATP are
discussed.
PMID- 9545309
TI - Ubiquitination is required for the retro-translocation of a short-lived luminal
endoplasmic reticulum glycoprotein to the cytosol for degradation by the
proteasome.
AB - In the endoplasmic reticulum (ER), an efficient "quality control system" operates
to ensure that mutated and incorrectly folded proteins are selectively degraded.
We are studying ER-associated degradation using a truncated variant of the rough
ER-specific type I transmembrane glycoprotein, ribophorin I. The truncated
polypeptide (RI332) consists of only the 332 amino-terminal amino acids of the
protein corresponding to most of its luminal domain and, in contrast to the long
lived endogenous ribophorin I, is rapidly degraded. Here we show that the
ubiquitin-proteasome pathway is involved in the destruction of the truncated
ribophorin I. Thus, when RI332 that itself appears to be a substrate for
ubiquitination was expressed in a mutant hamster cell line harboring a
temperature-sensitive mutation in the ubiquitin-activating enzyme E1 affecting
ubiquitin-dependent proteolysis, the protein is dramatically stabilized at the
restrictive temperature. Moreover, inhibitors of proteasome function effectively
block the degradation of RI332. Cell fractionation experiments indicate that
RI332 accumulates in the cytosol when degradation is prevented by proteasome
inhibitors but remains associated with the lumen of the ER under ubiquitination
deficient conditions, suggesting that the release of the protein into the cytosol
is ubiquitination-dependent. Accordingly, when ubiquitination is impaired, a
considerable amount of RI332 binds to the ER chaperone calnexin and to the Sec61
complex that could effect retro-translocation of the polypeptide to the cytosol.
Before proteolysis of RI332, its N-linked oligosaccharide is cleaved in two
distinct steps, the first of which might occur when the protein is still
associated with the ER, as the trimmed glycoprotein intermediate efficiently
interacts with calnexin and Sec61. From our data we conclude that the steps that
lead a newly synthesized luminal ER glycoprotein to degradation by the proteasome
are tightly coupled and that especially ubiquitination plays a crucial role in
the retro-translocation of the substrate protein for proteolysis to the cytosol.
PMID- 9545311
TI - Promoter structures and differential responses to viral and nonviral inducers of
chicken type I interferon genes.
AB - Two serologically distinct type I interferons (IFNs), designated ChIFN1 and
ChIFN2, are known in the chicken. ChIFN1 is encoded by a family of 10 or more
genes, whereas ChIFN2 is encoded by a single gene. We show here that ChIFN1 and
ChIFN2 transcripts are both strongly induced by Newcastle disease virus in
primary chicken macrophages. By contrast, oral administration of the
imidazoquinoline S-28463, which selectively induces IFN-alpha in mammals, led to
a rapid accumulation of ChIFN1 (but not ChIFN2) transcripts in adult chicken
spleen and thymus. The 5'-upstream region of the ChIFN2 gene contains a NF-kappaB
consensus motif flanked by a sequence element that could serve as a binding site
for transcription factor IRF-1, reminiscent of mammalian IFN-beta promoters, and
it mediated powerful virus inducibility in a duck fibroblast cell line when
cloned in front of a promoterless luciferase reporter gene. The 5'-upstream
region of the cloned ChIFN1 gene contains two putative binding sites for IRF-1,
but lacks NF-kappaB-binding sites, and it did not respond well to virus in
transfected cells. Thus, the promoters of ChIFN1 and ChIFN2 genes not only
exhibited differential responses to nonviral inducers in vivo, but also differed
in structure and response to virus in transfected cells. These findings indicate
that ChIFN2 represents the avian homolog of mammalian IFN-beta, whereas ChIFN1
seems to correspond to mammalian IFN-alpha.
PMID- 9545312
TI - Enhancement of serum-response factor-dependent transcription and DNA binding by
the architectural transcription factor HMG-I(Y).
AB - The mechanisms by which HMG-I proteins regulate cell growth are unknown, and
their effects on gene expression have only been partially elucidated. We explored
the potential interaction between HMG-I proteins and serum-response factor (SRF),
a member of the MADS-box family of transcription factors. In cotransfection
experiments, HMG-I(Y) potentiated SRF-dependent activation (by more than 5-fold)
of two distinct SRF-responsive promoters, c-fos and the smooth muscle-specific
gene SM22alpha. This effect was also observed with a heterologous promoter
containing multiple copies of the CC(A/T)6GG (CArG) box. HMG-I proteins bound
specifically to the CArG boxes of c-fos and SM22alpha in gel mobility shift
analysis and enhanced binding of SRF to these CArG boxes. By chelating peptide
immobilized metal affinity chromatography, we mapped the domain of HMG-I(Y) that
interacts with SRF to amino acids 50-81, a region that does not bind specifically
to DNA in electrophoretic mobility shift assays even though it includes the third
AT-hook DNA-binding domain. Surprisingly, HMG-I(Y) mutants that failed to bind
DNA still enhanced SRF binding to DNA and SRF-dependent transcription. In
contrast, deletion of the HMG-I(Y) 50-81 domain that bound SRF prevented
enhancement of transcription. To our knowledge, this is the first report of an
HMG-I protein interacting with a MADS-box transcription factor. Our observations
suggest that members of the HMG-I family play an important role in SRF-dependent
transcription and that their effect is mediated primarily by a protein-protein
interaction.
PMID- 9545313
TI - Collapsin response mediator protein-2 is associated with neurofibrillary tangles
in Alzheimer's disease.
AB - Intraneuronal accumulation of paired helical filaments (PHF) is considered to be
closely related to the neuronal loss observed in brains of patients affected with
Alzheimer's disease. The central issue is whether PHF formation itself causes or
accelerates the neuronal perikaryal and neuritic degeneration or whether they are
simply the consequence of preceding degeneration. We sought to address the issue
in part by characterizing the PHF-associated molecules and thus raised a number
of monoclonal antibodies to neurofibrillary tangles. One monoclonal antibody,
3F4, strongly reacted with neurofibrillary tangles and some plaque neurites but
few neuropil threads. This monoclonal antibody labeled a 65-kDa protein, but not
tau or ubiquitin, on a Western blot of human brain extract and immunoprecipitated
the same protein. The peptides released from the purified 65-kDa protein had the
same sequences as those of a newly identified protein, human collapsin response
mediator protein-2. Incorporation into neurofibrillary tangles may deplete
soluble, cytosolic human collapsin response mediator protein-2 and lead to
abnormal neuritic and/or axonal outgrowth of the tangle-bearing neuron, thus
accelerating the neuritic degeneration in Alzheimer's disease.
PMID- 9545314
TI - Differential effects of transforming growth factor-beta on the expression of
collagenase-1 and collagenase-3 in human fibroblasts.
AB - Collagenase-3 (MMP-13) is a matrix metalloproteinase (MMP) originally identified
in breast carcinomas which is also produced at significant levels during fetal
ossification and in arthritic processes. In this work, we have found that
transforming growth factor beta1 (TGF-beta1), a growth factor widely assumed to
be inhibitory for MMPs, strongly induces collagenase-3 expression in human KMST
fibroblasts. In contrast, this growth factor down-regulated the expression in
these cells of collagenase-1 (MMP-1), an enzyme highly related to collagenase-3
in terms of structure and enzymatic properties. The positive effect of TGF-beta1
on collagenase-3 expression was dose- and time-dependent, but independent of the
effects of this growth factor on cell proliferation rate. Analysis of the signal
transduction mechanisms underlying the up-regulating effect of TGF-beta1 on
collagenase-3 expression demonstrated that this growth factor acts through a
signaling pathway involving protein kinase C and tyrosine kinase activities.
Functional analysis of the collagenase-3 gene promoter region revealed that the
inductive effect of TGF-beta1 is partially mediated by an AP-1 site. Comparative
analysis with the promoter region of the collagenase-1 gene which contains an AP
1 site at equivalent position, confirmed that TGF-beta1 did not have any effect
on CAT activity levels of this promoter. Finally, by using electrophoretic
mobility shift assays and antibody supershift analysis, we propose that c-Fos, c
Jun, and JunD may play major roles in the collagenase-3 activation by TGF-beta1
in human fibroblasts.
PMID- 9545315
TI - Molecular cloning of the helodermin and exendin-4 cDNAs in the lizard.
Relationship to vasoactive intestinal polypeptide/pituitary adenylate cyclase
activating polypeptide and glucagon-like peptide 1 and evidence against the
existence of mammalian homologues.
AB - Helodermin and exendin-4, two peptides isolated from the salivary gland of the
Gila monster, Heloderma suspectum, are approximately 50% homologous to vasoactive
intestinal peptide (VIP) and glucagon-like peptide-1 (GLP-1), respectively, and
interact with the mammalian receptors for VIP and GLP-1 with equal or higher
affinity and efficacy. Immunohistochemical studies suggested the presence of
helodermin-like peptides in mammals. To determine whether helodermin and exendin
4 are present in mammals and their evolutionary relationship to VIP and GLP-1,
their cDNAs were first cloned from Gila monster salivary gland. Northern blots
and reverse transcription-polymerase chain reaction of multiple Gila monster
tissues identified approximately 500-base pair transcripts only from salivary
gland. Both helodermin and exendin-4 full-length cDNAs were approximately 500
base pairs long, and they encoded precursor proteins containing the entire amino
acid sequence of helodermin and exendin-4, as well as a 44- or 45-amino acid N
terminal extension peptide, respectively, having approximately 60% homology. The
size and structural organization of these cDNAs indicated that they were closely
related to one another but markedly different from known cDNAs for the VIP/GLP-1
peptide family previously identified in both lower and higher evolved species.
Cloning of the Gila monster VIP/peptide histidine isoleucine, pituitary adenylate
cyclase activating polypeptide, and glucagon/GLP-1 cDNAs and Southern blotting of
Gila monster DNA demonstrate the coexistence of separate genes for these peptides
and suggests, along with the restricted salivary gland expression, that
helodermin and exendin-4 coevolved to serve a separate specialized function.
Probing of a variety of rat and human tissues on Northern blots, human and rat
Southern blots, and genomic and cDNA libraries with either helodermin- or exendin
4-specific cDNAs failed to identify evidence for mammalian homologues. These data
indicate that helodermin and exendin-4 are not the precursors to VIP and GLP-1
and that they belong to a separate peptide family encoded by separate genes.
Furthermore, the existence of as yet undiscovered mammalian homologues to
helodermin and exendin-4 seems unlikely.
PMID- 9545316
TI - An enzymatically active chimeric HIV-1 reverse transcriptase (RT) with the RNase
H domain of murine leukemia virus RT exists as a monomer.
AB - The existence of retroviral reverse transcriptases as monomers or dimers is
rather intriguing. A classical example of the former is murine leukemia virus
reverse transcriptase (MuLV RT), while human immunodeficiency virus type 1 (HIV
1) RT represents the latter. A careful scrutiny of the amino acid sequence
alignment of the two enzymes pinpoints the region tentatively responsible for
this phenomenon. We report here the construction of a chimeric enzyme containing
the first 425 amino acid residues from the N-terminal domain of HIV-1 RT and 200
amino acid residues from the C-terminal domain of MuLV RT. The chimeric enzyme
exists as a monomer with intact DNA polymerase and RNase-H functions.
PMID- 9545317
TI - Analysis of the DNA-binding site for Xenopus glucocorticoid receptor accessory
factor. Critical nucleotides for binding specificity in vitro and for
amplification of steroid-induced fibrinogen gene transcription.
AB - In addition to the glucocorticoid receptor, DNA-binding proteins called accessory
factors play a role in hormone activation of many glucocorticoid-responsive
genes. Hormonal regulation of the gamma-fibrinogen subunit gene from the frog
Xenopus laevis requires a novel DNA sequence that binds a liver nuclear protein
called Xenopus glucocorticoid receptor accessory factor (XGRAF). Here we
demonstrate that the recognition site for XGRAF encompasses GAGTTAA at positions
175 to -169 relative to the start site of transcription. This sequence is not
closely related to the binding sites for known transcription factors. The two
guanosines make close contact with XGRAF, as shown by the methylation
interference assay. Single-point mutagenesis of every nucleotide in the 9-base
pair region from positions -177 to -169 showed an excellent correlation between
ability to bind XGRAF in vitro and ability to amplify hormone-induced
transcription from DNA transfected into Xenopus primary hepatocytes. Conversely,
XGRAF had little or no effect on basal transcription of the gamma-fibrinogen
gene. Maximal hormonal induction also requires three half-glucocorticoid response
elements (half-GREs) homologous to the downstream half of the consensus GRE.
Interestingly, the XGRAF-binding site is immediately adjacent to the most
important half-GRE. This close proximity suggests a new mechanism for activation
of a gene lacking a conventional full GRE.
PMID- 9545318
TI - Kinesin is a candidate for cross-bridging microtubules and intermediate
filaments. Selective binding of kinesin to detyrosinated tubulin and vimentin.
AB - We showed previously that stable, detyrosinated (Glu) microtubules function to
localize vimentin intermediate filaments in fibroblasts (Gurland, G., and
Gundersen, G. G. (1995) J. Cell Biol. 131, 1275-1290). To identify candidate
proteins that mediate the Glu microtubule-vimentin interaction, we incubated
microtubules with microtubule-interacting proteins and saturating levels of
antibodies to Glu or tyrosinated (Tyr) tubulin. Antibodies to Glu tubulin
prevented the microtubule binding of kinesin obtained from fibroblast or brain
extracts more effectively than antibodies to Tyr tubulin. Scatchard plot analysis
showed that kinesin heads bound to Glu microtubules with an approximately 2.8
fold higher affinity than to Tyr microtubules. Purified brain kinesin
cosedimented with vimentin, but not with neurofilaments, indicating that kinesin
specifically associates with vimentin without accessory molecules. Kinesin
binding to vimentin was not sensitive to ATP, and kinesin heads failed to bind to
vimentin. By SDS-polyacrylamide gel electrophoresis, a kinesin heavy chain of
approximately 120 kDa and a light chain of approximately 64 kDa were detected in
vimentin/kinesin pellets. The light chain reacted with a general kinesin light
chain antibody, but not with two other antibodies that recognize the two known
isoforms of kinesin light chain in brain, suggesting that the kinesin involved in
binding to vimentin may be a specific one. These results demonstrate a kinesin
based mechanism for the preferential interaction of vimentin with detyrosinated
microtubules.
PMID- 9545319
TI - Mechanisms involved in the acidosis enhancement of the isoproterenol-induced
phosphorylation of phospholamban in the intact heart.
AB - Previous experiments have shown that acidosis enhances isoproterenol-induced
phospholamban (PHL) phosphorylation (Mundina-Weilenmann, C., Vittone, L.,
Cingolani, H. E., Orchard, C. H. (1996) Am. J. Physiol. 270, C107-C114). In the
present experiments, performed in isolated Langendorff perfused rat hearts,
phosphorylation site-specific antibodies to PHL combined with the quantitative
measurement of 32P incorporation into PHL were used as experimental tools to gain
further insight into the mechanism involved in this effect. At all isoproterenol
concentrations tested (3-300 nM), phosphorylation of Thr17 of PHL was
significantly higher at pHo 6.80 than at pHo 7.40, without significant changes in
Ser16 phosphorylation. This increase in Thr17 phosphorylation was associated with
an enhancement of the isoproterenol-induced relaxant effect. In the absence of
isoproterenol, the increase in [Ca]o at pHo 6.80 (but not at pHo 7.40) evoked an
increase in PHL phosphorylation that was exclusively due to an increase in Thr17
phosphorylation and that was also associated with a significant relaxant effect.
This effect and the phosphorylation of Thr17 evoked by acidosis were both offset
by the Ca2+/calmodulin-dependent protein kinase II inhibitor KN-62. In the
presence of isoproterenol, either the increase in [Ca]o or the addition of a 1
microM concentration of the phosphatase inhibitor okadaic acid was able to mimic
the increase in isoproterenol-induced Thr17 phosphorylation produced by acidosis.
In contrast, these two interventions have opposite effects on phosphorylation of
Ser16. Whereas the increase in [Ca]o significantly decreased phosphorylation of
Ser16, the addition of okadaic acid significantly increased the phosphorylation
of this residue. The results are consistent with the hypothesis that the increase
in phospholamban phosphorylation produced by acidosis in the presence of
isoproterenol is the consequence of two different mechanisms triggered by
acidosis: an increase in [Ca2+]i and an inhibition of phosphatases.
PMID- 9545320
TI - Identification of a novel type of alternatively spliced exon from the
acetylcholinesterase gene of Bungarus fasciatus. Molecular forms of
acetylcholinesterase in the snake liver and muscle.
AB - The venom of the snake Bungarus fasciatus contains a hydrophilic, monomeric
species of acetylcholinesterase (AChE), characterized by a C-terminal region that
does not resemble the alternative T- or H-peptides. Here, we show that the snake
contains a single gene for AChE, possessing a novel alternative exon (S) that
encodes the C-terminal region of the venom enzyme, located downstream of the T
exon. Alternative splicing generates S mRNA in the venom gland and S and T mRNAs
in muscle and liver. We found no evidence for the presence of an H exon between
the last common "catalytic" exon and the T exon, where H exons are located in
Torpedo and in mammals. Moreover, COS cells that were transfected with AChE
expression vectors containing the T exon with or without the preceding genomic
region produced exclusively AChET subunits. In the snake tissues, we could not
detect any glycophosphatidylinositol-anchored AChE form that would have derived
from H subunits. In the liver, the cholinesterase activity comprises both AChE
and butyrylcholinesterase components; butyrylcholinesterase corresponds
essentially to nonamphiphilic tetramers and AChE to nonamphiphilic monomers
(G1na). In muscle, AChE is largely predominant: it consists of globular forms
(G1a and G4a) and trace amounts of asymmetric forms (A8 and A12), which derive
from AChET subunits. Thus, the Bungarus AChE gene possesses alternatively spliced
T and S exons but no H exon; the absence of an H exon may be a common feature of
AChE genes in reptiles and birds.
PMID- 9545321
TI - Combinatorial action of HNF3 and Sp family transcription factors in the
activation of the rabbit uteroglobin/CC10 promoter.
AB - It has been reported that respiratory epithelium-specific transcription is
mediated by thyroid transcription factor 1 and members of the HNF3/forkhead
family of transcription factors. Here, we show that the uteroglobin/Clara cell 10
kDa promoters from rabbit and man are regulated by HNF3alpha and HNF3beta but not
by HFH-4 and TTF-1. We have identified two HNF3-responsive elements in the rabbit
uteroglobin/CC10 promoter located around 95 and 130 base pairs upstream of the
transcriptional start site. Both elements contribute to promoter activity in H441
cells expressing uteroglobin/CC10 and HNF3alpha. Gene transfer experiments into
Drosophila Schneider cells that lack many mammalian transcription factor homologs
revealed that HNF3alpha and HNF3beta on their own cannot activate the
uteroglobin/CC10 promoter. However, HNF3alpha and HNF3beta strongly enhanced Sp1
mediated promoter activation. Synergistic activation by HNF3alpha and Sp1 was
absolutely dependent on the integrity of two Sp1 sites located at around -65 and
230. We show further that multiple activation domains of Sp1 are required for
cooperativity with HNF3alpha. These studies demonstrate that transcription from
the rabbit uteroglobin/CC10 promoter in lung epithelium is controlled by the
combinatorial action of the cell-specific factor HNF3alpha and the ubiquitous
factor Sp1.
PMID- 9545322
TI - The PEL1 gene (renamed PGS1) encodes the phosphatidylglycero-phosphate synthase
of Saccharomyces cerevisiae.
AB - Phosphatidylglycerophosphate (PG-P) synthase catalyzes the synthesis of PG-P from
CDP-diacylglycerol and sn-glycerol 3-phosphate and functions as the committed and
rate-limiting step in the biosynthesis of cardiolipin (CL). In eukaryotic cells,
CL is found predominantly in the inner mitochondrial membrane and is generally
thought to be an essential component of many mitochondrial functions. We have
determined that the PEL1 gene (now renamed PGS1), previously proposed to encode a
second phosphatidylserine synthase of yeast (Janitor, M., Jarosch, E., Schweyen,
R. J., and Subik, J. (1995) Yeast 13, 1223-1231), in fact encodes a PG-P synthase
of Saccharomyces cerevisiae. Overexpression of the PGS1 gene product under the
inducible GAL1 promoter resulted in a 14-fold increase in in vitro PG-P synthase
activity. Disruption of the PGS1 gene in a haploid strain of yeast did not lead
to a loss of viability but did result in a dependence on a fermentable carbon
source for growth, a temperature sensitivity for growth, and a petite lethal
phenotype. The pgs1 null mutant exhibited no detectable in vitro PG-P synthase
activity and no detectable CL or phosphatidylglycerol (PG); significant CL
synthase activity was still present. The growth arrest phenotype and lack of PG-P
synthase activity of a pgsA null allele of Escherichia coli was corrected by an N
terminal truncated derivative of the yeast PG-P synthase. These results
unequivocally demonstrate that the PGS1 gene encodes the major PG-P synthase of
yeast and that neither PG nor CL are absolutely essential for cell viability but
may be important for normal mitochondrial function.
PMID- 9545323
TI - ATP-dependent assembly of a ternary complex consisting of a DNA mismatch and the
yeast MSH2-MSH6 and MLH1-PMS1 protein complexes.
AB - MSH2 and MSH6 proteins exist as a stable complex, as do the MLH1 and PMS1
proteins. To study the mismatch binding properties of the MSH2-MSH6 complex and
to examine its functional interaction with the MLH1-PMS1 complex, these protein
complexes were purified to near homogeneity from overproducing yeast strains. As
has been reported previously, the purified MSH2-MSH6 complex binds DNA substrates
containing a G/T mismatch and insertion/deletion mismatches, but the binding
affinity for the latter decreases as the size of the extrahelical loop increases.
Addition of ATP or the nonhydrolyzable ATPgammaS reduces binding of the MSH2-MSH6
complex to the DNA substrates markedly. Here, we show that MSH2-MSH6 forms a
ternary complex with MLH1-PMS1 on a mismatch containing DNA substrate. The
formation of this ternary complex requires ATP, which can be substituted by
ATPgammaS, suggesting that ATP binding alone is sufficient for ternary complex
formation. Thus, it appears that ATP binding by the MSH2-MSH6 complex induces a
conformation that is conducive for the interaction with MLH1-PMS1 complex,
leading to the formation of the ternary complex.
PMID- 9545324
TI - Lysosomal enzyme trafficking between phagosomes, endosomes, and lysosomes in J774
macrophages. Enrichment of cathepsin H in early endosomes.
AB - In this study we take advantage of recently developed methods using J774
macrophages to prepare enriched fractions of early endosomes, late endosomes,
dense lysosomes, as well as phagosomes of different ages enclosing 1-micron latex
beads to investigate the steady state distribution and trafficking of lysosomal
enzyme activity between these organelles. At steady state these cells appear to
possess four different cellular structures, in addition to phagolysosomes, where
acid hydrolases were concentrated. The first site of hydrolase concentration was
the early endosomes, which contained the bulk of the cellular cathepsin H. This
enzyme was acquired by phagosomes significantly faster than the other hydrolases
tested. The second distinct site of lysosomal enzyme concentration was the late
endosomes which contain the bulk of cathepsin S. The third and fourth large pools
of hydrolases were found in two functionally distinct types of dense lysosomes,
only one of which was found to be secreted in the presence of chloroquine or
bafilomycin. Among this secreted pool was soluble furin, generally considered
only as a membrane-bound trans-Golgi network resident protein. Thus, the
organelles usually referred to as "lysosomes" in fact encompass a growing family
of highly dynamic but functionally distinct endocytic organelles.
PMID- 9545325
TI - Metastasis-associated Mts1 (S100A4) protein modulates protein kinase C
phosphorylation of the heavy chain of nonmuscle myosin.
AB - Mts1 protein (S100A4 according to a new classification) has been implicated in
the formation of the metastatic phenotype via regulation of cell motility and
invasiveness. Previously we have demonstrated that Mts1 protein interacted with
the heavy chain of nonmuscle myosin in a calcium-dependent manner. To elucidate
the role of the Mts1-myosin interaction, we mapped the Mts1-binding region on the
myosin heavy chain molecule. We prepared proteolytically digested platelet myosin
and a series of overlapped myosin heavy chain protein fragments and used them in
a blot overlay with Mts1 protein. Here we report that the Mts1-binding site is
located within a 29-amino acid region, at the C-terminal end of the myosin heavy
chain (between 1909-1937 amino acids). Two-dimensional phosphopeptide analysis
showed that Mts1 protein inhibits protein kinase C phosphorylation of the
platelet myosin heavy chain at Ser-1917. We hypothesize that Mts1 protein
regulates cytoskeletal dynamics of the metastatic cells through modulation of the
myosin phosphorylation by protein kinase C in calcium-dependent fashion.
PMID- 9545326
TI - ERcalcistorin/protein-disulfide isomerase acts as a calcium storage protein in
the endoplasmic reticulum of a living cell. Comparison with calreticulin and
calsequestrin.
AB - ERcalcistorin/protein-disulfide isomerase (ECaSt/PDI), a high capacity low
affinity Ca2+-binding protein in the endoplasmic reticulum of sea urchin eggs
(Lebeche, D., and Kaminer, B. (1992) Biochem. J. 287, 741-747), shares 55%
sequence identity with mammalian PDI and has PDI activity (Lucero, H., Lebeche,
D., and Kaminer, B. (1994) J. Biol. Chem. 269, 23112-23119). We report on
ECaSt/PDI functioning as a Ca2+ storage protein in the endoplasmic reticulum (ER)
of a living cell and compare it with calsequestrin and calreticulin, high
capacity low affinity Ca2+-binding proteins in the sarcoplasmic reticulum and ER,
respectively. Stably transfected Chinese hamster ovary cell clones expressed
these proteins, which were localized in the ER of the cell. Microsomes from cells
expressing ECaSt/PDI, calreticulin, and calsequestrin accumulated 17.2 +/- 0.27,
20.0 +/- 0.82, and 38.0 +/- 0.28 nmol of Ca2+/mg of protein, respectively;
control microsomes accumulated from 2.6 +/- 0.17 to 2.9 +/- 0.14 nmol of Ca2+/mg
of protein. The initial rate of Ca2+ uptake was similar in microsomes from
transfected and control cells. Microsomes containing an ECaSt/PDI mutant in which
45% of the acidic residue pairs in the C terminus were truncated had a reduced
Ca2+ storage capacity. This supports our previous hypothesis that the degree of
low affinity Ca2+ binding is dependent on the number of pairs of carboxyl groups
in the molecule. The maximal Ca2+ accumulation by microsomes containing the
expressed ECaSt/PDI, C-terminally truncated ECaSt/PDI, calreticulin, or
calsequestrin correlates approximately with the Ca2+ binding capacity of the
respective proteins.
PMID- 9545327
TI - Regulation of interleukin-13 receptor constituents on mature human B lymphocytes.
AB - Human B cells stimulated through both their immunoglobulin and CD40 receptors up
regulate 745 +/- 51 interleukin (IL)-13 ligand binding sites with an affinity of
0.91 +/- 0.08 nM within 24 h. IL-13 binds primarily to the IL-13Ralpha1 with
subsequent sequestration of the IL-4Ralpha into the complex. IL-13Ralpha1 may
also be found in those receptors capable of binding IL-4. gamma chain (gammac)
participates in receptors capable of binding IL-4 but is not found in association
with bound IL-13. Dimeric receptors composed of the IL-4Ralpha complexed with
either the IL-13Ralpha1 or gammac occur simultaneously within defined B cell
populations. mRNAs for all receptor constituents are increased subsequent to
immunoglobulin stimulation alone, while maximal expression of IL-13Ralpha1 is
more dependent upon co-stimulation of immunoglobulin and CD40 receptors. mRNA
levels for IL-13Ralpha1 vary over a wider range subsequent to surface stimulation
than other receptor components. Although gammac is not bound to IL-13 in B cells
under the conditions evaluated, it may influence IL-13 binding by competing with
IL-13Ralpha1 for association/sequestration with the IL-4Ralpha chain. IL
13Ralpha2 does not participate in the IL-13 receptor that is up-regulated upon
activation of quiescent tonsillar B lymphocytes, although mRNA for the protein
may be found in the centroblastic fraction of tonsillar cells.
PMID- 9545328
TI - Reduction in abortive transcription from the lambdaPR promoter by mutations in
region 3 of the sigma70 subunit of Escherichia coli RNA polymerase.
AB - Transcription initiation by Escherichia coli RNA polymerase at most promoters is
associated with a reiterative synthesis and release of short abortive RNA
products. We have investigated the mechanism of abortive RNA synthesis by using
holoenzymes containing mutant sigma70 subunits with changes in region 3 (S506F
and P504L), which reduce the ratio of abortive to full-length products. Binary
complexes formed by these mutant enzymes at a modified lambdaPR promoter
contained a smaller fraction of open complexes than for normal polymerase,
suggesting an involvement of region 3 in melting duplex DNA or in maintenance of
the open complex. The half-lives of the majority of binary complexes formed by
the mutant enzymes were less than 1 min, in contrast to 30 min for the wild-type
complexes. The time courses of transcription and pulse-labeling assays showed
that moribund complexes, which generate only abortive products (Kubori, T., and
Shimamoto, N. (1996) J. Mol. Biol. 256, 449-457), were formed by the mutant
enzymes. However, they accumulated to a lesser extent than for the wild-type
enzyme, due both to faster dissociation and conversion into inactive complexes.
This is the main cause of the low degree of abortive transcription displayed by
the mutant enzymes on this promoter.
PMID- 9545329
TI - Agonist-induced sequestration, recycling, and resensitization of platelet
activating factor receptor. Role of cytoplasmic tail phosphorylation in each
process.
AB - Agonist-induced sequestration, recycling, and resensitization of platelet
activating factor (PAF) receptor were characterized in transfected Chinese
hamster ovary cells. Exposure of the cells to PAF led to rapid sequestration of
the receptors into the intracellular compartment and desensitization of the
response to PAF. The sequestration was inhibited by pretreatments that perturbed
the clathrin-mediated pathway. Subsequent removal of PAF by washing with receptor
antagonists led to rapid recycling of the sequestered receptors to the cell
surface accompanied by resensitization to PAF. To evaluate the potential role of
phosphorylation in the receptor cytoplasmic tail during these processes, mutant
receptors in which the tails were truncated or substituted, so as to lack
serine/threonine residues, were created. PAF phosphorylated the wild-type
receptor rapidly and strongly, but the mutants did not. The maximal extent of
sequestration of each mutant was lower than that of the wild-type, and one of the
substituted mutants showed no sequestration. Furthermore, the sequestration
defective mutant showed evidence of desensitization after agonist stimulation but
not resensitization after agonist removal. Thus, agonist-induced phosphorylation
of the cytoplasmic tail facilitates but is not essential for receptor
sequestration, and sequestration/recycling appears important in receptor
resensitization.
PMID- 9545330
TI - Subcellular localization of prostaglandin endoperoxide H synthases-1 and -2 by
immunoelectron microscopy.
AB - Prostaglandin endoperoxide H synthases-1 and -2 (PGHS-1 and -2) are the major
targets of nonsteroidal anti-inflammatory drugs like aspirin and ibuprofen. These
enzymes catalyze the committed step in the formation of prostanoids from
arachidonic acid. Although PGHS-1 and -2 are similar biochemically, a number of
studies suggest that PGHS-1 and PGHS-2 function independently to form prostanoids
that subserve different cellular functions. We have hypothesized that these
isozymes may reside, at least in part, in different subcellular compartments and
that their compartmentation may affect their access to arachidonic acid and serve
to separate the functions of the enzymes. To obtain high resolution data on the
subcellular locations of PGHS-1 and -2, we employed immunoelectron microscopy
with multiple antibodies specific to each isozyme. Both PGHS-1 and -2 were found
on the lumenal surfaces of the endoplasmic reticulum (ER) and nuclear envelope of
human monocytes, murine NIH 3T3 cells, and human umbilical vein endothelial
cells. Within the nuclear envelope, PGHS-1 and -2 were present on both the inner
and outer nuclear membranes and in similar proportions. Western blotting data
showed a similar distribution of PGHS-1 and -2 in subcellular fractions, and
product analysis using isozyme-specific inhibitors suggested that both enzymes
generate the same products in NIH 3T3 cells. Thus, we are unable to attribute the
independent functioning of PGHS-1 and PGHS-2 to differences in their subcellular
locations. Instead, the independent operation of these isozymes may be
attributable to subtle kinetic differences (e.g. negative allosteric regulation
of PGHS-1 at low concentrations of arachidonate (500-1000 nM)). A further
conclusion of importance from a cell biological perspective is that membrane
proteins such as PGHS-1 and -2, which are located on the lumenal surface of the
ER, are able to diffuse freely among the ER and the inner and outer membranes of
the nuclear envelope.
PMID- 9545331
TI - Direct photoaffinity labeling of cysteine-295 of alpha-tubulin by guanosine 5'
triphosphate bound in the nonexchangeable site.
AB - The alphabeta-tubulin heterodimer has two high affinity guanosine 5'-triphosphate
binding sites, so that purified tubulin usually contains two molecules of bound
guanosine nucleotide. Half this nucleotide is freely exchangeable with exogenous
guanine nucleotide, and its binding site has been readily localized to the beta
subunit. The remaining nonexchangeable guanosine 5'-triphosphate can only be
released from tubulin by denaturing the protein. We replaced the exchangeable
site nucleotide of tubulin with 2'-deoxyguanosine 5'-diphosphate, exposed the
resulting tubulin to ultraviolet light, degraded the protein, and isolated ribose
containing peptide derived from the nonexchangeable site. A large cyanogen
bromide peptide was recovered, and its further degradation with endoproteinase
Glu-C established that cysteine-295 of alpha-tubulin was the major reactive amino
acid cross-linked to guanosine by ultraviolet irradiation.
PMID- 9545332
TI - A role for the insulin-interleukin (IL)-4 receptor motif of the IL-4 receptor
alpha-chain in regulating activation of the insulin receptor substrate 2 and
signal transducer and activator of transcription 6 pathways. Analysis by
mutagenesis.
AB - The interleukin (IL)-4 receptor alpha-chain (IL-4Ralpha) contains a sequence
motif (488PLVIAGNPAYRSFSD) termed the insulin IL-4 receptor motif (I4R motif).
Mutation of the central Tyr497 to Phe blocks the tyrosine phosphorylation of the
insulin receptor substrate 1 (IRS1) and diminishes proliferation in response to
IL-4. Recent data suggest that the I4R motif encodes binding sites for several
protein tyrosine binding (PTB) domain-containing proteins such as IRS1 and Shc
and potentially for the Src homology 2 domain of signal transducer and activator
of transcription 6 (STAT6). To analyze the function of the I4R motif in
regulating IL-4 signaling, we changed conserved residues upstream and downstream
of the central Tyr to Ala in the human IL-4Ralpha. We analyzed the ability of
these constructs to signal the tyrosine phosphorylation of IRS2 and STAT6, the
induction of DNA binding activity, and CD23 induction in response to human IL-4
(huIL-4) in transfected M12.4.1 cells. Mutagenesis of residues downstream of
Tyr497, such as Arg498 or Phe500, to Ala had no effect on any of these responses,
suggesting that the I4R motif may not be important for functional Src homology 2
domain interactions. However, mutagenesis of Pro488 to Ala (P488A) greatly
diminished the tyrosine phosphorylation of IRS2 and abolished tyrosine
phosphorylation of STAT6, induction of DNA binding activity, and CD23 induction
in response to huIL-4. By contrast, a P488G mutant signaled these responses to
huIL-4. Mutagenesis of hydrophobic amino acids previously shown to contact the
PTB domain of IRS1, Leu489 or Ile491, to Ala had only minimal effects on
responses to huIL-4. However, changing both Leu498 and Ile491 to Ala greatly
diminished the tyrosine phosphorylation of IRS2 and abolished STAT6 activation.
Taken together, these results indicate the important role of the I4R motif in
regulating IRS docking and suggest that I4R docking to a PTB domain-containing
protein regulates activation of the STAT6 pathway.
PMID- 9545333
TI - Cell growth inhibition by a novel vitamin K is associated with induction of
protein tyrosine phosphorylation.
AB - We have shown that a synthetic vitamin K analog, 2-(2-mercaptoethanol)-3-methyl
1,4-naphthoquinone or compound 5 (Cpd 5), potently inhibits cell growth and
suggested that the analog exerts its effects mainly via sulfhydryl arylation
rather than redox cycling. Since protein-tyrosine phosphatases (PTPases), which
have pivotal roles in many cellular functions, have a critical cysteine in their
active site, we have proposed PTPases as likely targets for Cpd 5. To test this
hypothesis, we examined the effects of Cpd 5 on protein tyrosine phosphorylation
of cellular proteins and on the activity of PTPases. We found that Cpd 5 rapidly
induced protein tyrosine phosphorylation in a human hepatocellular carcinoma cell
line (Hep3B) at growth inhibitory doses, and the effect was blocked by thiols but
not by non-thiol antioxidants or tyrosine kinase inhibitors. Cpd 5 inhibited
PTPase activity, which was also significantly antagonized by reduced glutathione.
Furthermore, the well studied PTPase inhibitor orthovanadate also induced protein
tyrosine phosphorylation and growth inhibition in Hep3B cells. These results
suggest that inhibition of cellular PTPases by sulfhydryl arylation and
subsequent perturbation of protein tyrosine phosphorylation may be involved in
the mechanisms of Cpd 5-induced cell growth inhibition.
PMID- 9545335
TI - RhoB is stabilized by transforming growth factor beta and antagonizes
transcriptional activation.
AB - Transforming growth factor beta (TGF-beta) is the prototype for an evolutionarily
conserved superfamily of secreted factors implicated in diverse biological
phenomena. The pleiotropic responses to TGF-beta are initiated by a heteromeric
receptor complex that binds and phosphorylates downstream effectors. Among these,
the Smads have been extensively studied. However, less attention has been
directed toward alternative downstream effectors and their participation in TGF
beta signal transduction. We show that TGF-beta promotes accumulation of the
labile monomeric GTPase RhoB by antagonizing its normal proteolytic destruction,
presumably via the 26 S proteasome. RhoB accumulates in its isoprenylated form.
Transient overexpression of wild type RhoB but not its dominant negative mutant
RhoB-N19 antagonizes TGF-beta-mediated transcriptional activation. These results
suggest a novel mechanism of regulation by TGF-beta and implicate RhoB as a
negative regulator of TGF-beta signal transduction.
PMID- 9545334
TI - Palindrome with spacer of one nucleotide is characteristic of the cis-acting
unfolded protein response element in Saccharomyces cerevisiae.
AB - When unfolded proteins are accumulated in the endoplasmic reticulum (ER), an
intracellular signaling pathway termed the unfolded protein response (UPR) is
activated to induce transcription of ER-localized molecular chaperones and
folding enzymes in the nucleus. In Saccharomyces cerevisiae, at least six lumenal
proteins including essential Kar2p and Pdi1p are known to be regulated by the
UPR. We and others recently demonstrated that the basic-leucine zipper protein
Hac1p/Ern4p functions as a trans-acting factor responsible for the UPR. Hac1p
binds directly to the cis-acting unfolded protein response element (UPRE)
responsible for Kar2p induction. Moreover, we showed that the KAR2 UPRE contains
an E box-like palindrome separated by one nucleotide (CAGCGTG) that is essential
for its function. We report here that the promoter regions of each of five target
proteins (Kar2p, Pdi1p, Eug1p, Fkb2p, and Lhs1p) contain a single UPRE sequence
that is necessary and sufficient for induction and that binds specifically to
Hac1p in vitro. All of the five functional UPRE sequences identified contain a
palindromic sequence that has, in four cases, a spacer of one C nucleotide. This
unique characteristic of UPRE explains why only a specific set of proteins are
induced in the UPR to cope with ER stress.
PMID- 9545336
TI - The proton motive force, acting on acidic residues, promotes translocation of
amino-terminal domains of membrane proteins when the hydrophobicity of the
translocation signal is low.
AB - We have shown previously that the first transmembrane segment of leader peptidase
can function to translocate the polar amino-terminal Pf3 domain across the
membrane into the periplasm independently of the proton motive force (pmf) (Lee,
J. I., Kuhn, A., and Dalbey, R. E. (1992) J. Biol. Chem. 267, 938-943). We now
show that when the first transmembrane segment lacks a strong hydrophobic
character, the pmf is required for translocation. In addition, we find that the
amino-terminal acidic residue proximal to the transmembrane domain plays a
critical role in pmf-dependent amino-terminal translocation. Moreover, the pmf is
required to hold the amino-terminal domain in the periplasm to prevent it from
slipping such that the amino terminus is no longer exposed to the periplasm. In
all cases, translocation occurs under conditions in which the function of the Sec
machinery is impaired. These studies show that the low hydrophobicity of the
first apolar domain (the translocation signal) can be compensated for by a
negative charge in the amino-terminal region, upon which the pmf acts.
PMID- 9545337
TI - Glycosaminoglycan binding properties of annexin IV, V, and VI.
AB - We have previously demonstrated that annexin IV, one of the calcium/phospholipid
binding annexin family proteins, binds to glycosaminoglycans (GAGs) in a calcium
dependent manner (Kojima, K., Yamamoto, K., Irimura, T., Osawa, T., Ogawa, H.,
and Matsumoto, I. (1996) J. Biol. Chem. 271, 7679-7685). In this study, we
investigated the GAG binding specificities of annexins IV, V, and VI by affinity
chromatography and solid phase assays. Annexin IV was found to bind in a calcium
dependent manner to all the GAG columns tested. Annexin V bound to heparin and
heparan sulfate columns but not to chondroitin sulfate columns. Annexin VI was
adsorbed to heparin and heparan sulfate columns in a calcium-independent manner,
and to chondroitin sulfate columns in a calcium-dependent manner. An N-terminal
half fragment (A6NH) and a C-terminal half fragment (A6CH) of annexin VI, each
containing four units, were prepared by digestion with V8 protease and examined
for GAG binding activities. A6NH bound to heparin in the presence of calcium but
not to chondroitin sulfate C, whereas A6CH bound to heparin calcium-independently
and to chondroitin sulfate C calcium-dependently. The results showed that annexin
IV, V, and VI have different GAG binding properties. Some annexins have been
reported to be detected not only in the cytoplasm but also on the cell surface or
in extracellular components. The findings suggest that the some annexins function
as recognition elements for GAGs in extracellular space.
PMID- 9545338
TI - Mechanisms for the processing of a frozen topoisomerase-DNA conjugate by human
cell-free extracts.
AB - The metabolic fate of covalently linked DNA-protein complexes (cross-links) is
not clearly understood. Our aim was to investigate the processing of protein-DNA
cross-links by cellular enzymes. As an example of a DNA-protein cross-link, we
have constructed frozen topoisomerase-DNA conjugates and investigated their
processing by human cell-free extracts. A suicide DNA substrate was constructed
that upon reaction with vaccinia type I topoisomerase yielded a highly stable
covalent DNA-protein cross-link. When this conjugate was treated with human
nuclear or whole cell extracts, two sites of DNA breakpoints were detected: one
set of double-stranded breaks occurred close to the 3' side of the topoisomerase
(topo) conjugation site, and there was another set of nicks about 30 nucleotides
3' to the topo site. The double-stranded breaks were not made by extracts from
xeroderma pigmentosum group A mutant cells, suggesting that the xeroderma
pigmentosum group A damage recognition protein may be required for the occurrence
of DNA breakage. In addition to these DNA breakage reactions, there was an
activity that resulted in the delinking of the frozen topoisomerase (or
proteolytic fragments thereof) from the DNA substrate, which was followed by a
ligation step that restored the continuity of the broken DNA strand at the
erstwhile topo attachment site. We suggest that frozen topoisomerase-DNA
conjugates (and perhaps other types of covalent DNA-protein complexes) are
processed by multiple pathways that may involve the cleavage of the DNA in the
covalent protein-DNA complex and/or enzymatic delinking followed by ligation of
the broken DNA ends. These processes may represent the "repair" of DNA-protein
cross-links.
PMID- 9545339
TI - Characterization of V3 loop-Pseudomonas exotoxin chimeras. Candidate vaccines for
human immunodeficiency virus-1.
AB - To develop a candidate vaccine for human immunodeficiency virus, type 1 (HIV-1),
chimeric proteins were constructed by inserting sequences derived from the V3
loop of gp120 into a nontoxic form of Pseudomonas exotoxin (PE). Inserts of 14 or
26 amino acids, constrained by a disulfide bond, were introduced between domains
II and III of PE. V3 loop-toxin proteins expressed in Escherichia coli and
corresponding to either MN (subtype B) or Thai (subtype E) strains, were
recognized by strain-specific monoclonal anti-gp120 antibodies. When loop
sequences were introduced into an enzymatically active form of the toxin, there
was no loss of toxin-mediated cell killing, suggesting that these sequences were
co-transported to the cytosol. Sera from rabbits injected with nontoxic PE-V3
loop chimeras were reactive for strain-specific gp120s in Western blots,
immunocapture assays, enzyme-linked immunosorbent assays, and neutralized HIV-1
infectivity. Since toxin vectors were designed to receive oligonucleotide
duplexes encoding any V3 loop sequence, this approach should allow for the
production of V3 loop-toxin chimeras corresponding to multiple HIV isolates.
PMID- 9545340
TI - Involvement of Sp1 elements in the promoter activity of the alpha1-proteinase
inhibitor gene.
AB - The transcripts of the alpha1-proteinase inhibitor in the cornea are different
from those in hepatocytes and monocytes, suggesting that alpha1-proteinase
inhibitor gene transcription may respond to different cell-specific regulatory
mechanisms. Although information on alpha1-proteinase inhibitor gene structure
has been obtained, little is known regarding the cis- and trans-acting factors
that regulate its expression. In this study, we cloned and sequenced a 2. 7
kilobase 5'-flanking region upstream from the corneal transcription initiation
site of the gene, demonstrated functional promoter activity, and identified the
regulatory elements. Sequencing revealed that the 5'-flanking element was highly
G/C-rich in regions proximal to the corneal transcription start site. DNase I
footprinting located 10 potential Sp1-binding sites between nucleotides -1519 and
+44. The putative promoter was functional in human corneal stromal cells, but not
in human skin, scleral, and conjunctival fibroblasts, suggesting that the
promoter may be corneal cell-specific. The promoter activity in the corneal cells
was repressed when Sp1 was coexpressed. In the cornea-thinning disease
keratoconus, down-regulation of the alpha1-proteinase inhibitor gene and
increased Sp1 expression have both been demonstrated. The current results suggest
that down-regulation of the inhibitor in keratoconus corneas may be related
directly to overexpression of the Sp1 gene. This information may help elucidate
the molecular pathways leading to the altered alpha1-proteinase inhibitor
expression in keratoconus.
PMID- 9545341
TI - Inhibition of the mitogen-activated protein kinase pathway triggers B16 melanoma
cell differentiation.
AB - In B16 melanoma cells, mitogen-activated protein (MAP) kinases are activated
during cAMP-induced melanogenesis (Englaro, W., Rezzonico, R., Durand-Clement,
M., Lallemand, D., Ortonne, J. P., and Ballotti, R. (1995) J. Biol. Chem. 270,
24315-24320). To establish the role of the MAP kinases in melanogenesis, we
studied the effects of a specific MAP kinase kinase (MEK) inhibitor PD 98059 on
different melanogenic parameters. We showed that PD 98059 inhibits the activation
of MAP kinase extracellular signal-regulated kinase 1 by cAMP, but does not
impair the effects of cAMP either on the morphological differentiation,
characterized by an increase in dendrite outgrowth, or on the up-regulation of
tyrosinase that is the key enzyme in melanogenesis. On the contrary, PD 98059
promotes by itself cell dendricity and increases the tyrosinase amount and
activity. Moreover, down-regulation of the MAP kinase pathway by PD 98059, or
with dominant negative mutants of p21(ras) and MEK, triggers a stimulation of the
tyrosinase promoter activity and enhances the effect of cAMP on this parameter.
Conversely, activation of the MAP kinase pathway, using constitutive active
mutants of p21(ras) and MEK, leads to an inhibition of basal and cAMP-induced
tyrosinase gene transcription. These results demonstrate that the MAP kinase
pathway activation is not required for cAMP-induced melanogenesis. Furthermore,
the inhibition of this pathway induces B16 melanoma cell differentiation, while a
sustained activation impairs the melanogenic effect of cAMP-elevating agents.
PMID- 9545342
TI - A cyclic AMP response element in the angiotensin-converting enzyme gene and the
transcription factor CREM are required for transcription of the mRNA for the
testicular isozyme.
AB - The angiotensin-converting enzyme (ACE) gene produces two mRNA species from
tissue-specific promoters. The transcription start site of the mRNA for the
smaller testicular isozyme (ACET) is located within an intron of the larger
transcription unit that encodes the pulmonary isozyme (ACEP).We have previously
demonstrated that a 298-base pair DNA fragment, 5' to the rabbit ACET mRNA
transcription initiation site, can activate the testicular expression of a
transgenic reporter gene. In the current study, using the same transgenic
reporter system, we identified a putative cyclic AMP response element present
within this DNA fragment to be absolutely essential for transcriptional
activation. Moreover, we observed that ACET mRNA was not expressed in the testes
of mice homozygous for a null mutation in the transcription factor CREM. However,
in the same mice, ACEP mRNA was abundantly expressed in the lung. Our
observations indicate that ACET mRNA expression in the testes is regulated by the
putative cyclic AMP response element present 5' to the transcription start site
and the corresponding transcription factor CREM.
PMID- 9545343
TI - Characterization of RNA strand displacement synthesis by Moloney murine leukemia
virus reverse transcriptase.
AB - The RNase H activity of reverse transcriptase (RT) is presumably required to
cleave the RNA genome following minus strand synthesis to free the DNA for use as
a template during plus strand synthesis. However, since RNA degradation by RNase
H appears to generate RNA fragments too large to spontaneously dissociate from
the minus strand, we have investigated the possibility that RNA displacement by
RT during plus strand synthesis contributes to the removal of RNA fragments. By
using an RNase H- mutant of Moloney murine leukemia virus (M-MuLV) RT, we
demonstrate that the polymerase can displace long regions of RNA in hybrid duplex
with DNA but that this activity is approximately 5-fold slower than DNA
displacement and 20-fold slower than non-displacement synthesis. Furthermore, we
find that although certain hybrid sequences seem nearly refractory to the
initiation of RNA displacement, the same sequences may not significantly impede
synthesis when preceded by a single-stranded gap. We find that the rate of RNA
displacement synthesis by wild-type M-MuLV RT is significantly greater than that
of the RNase H- RT but remains less than the rate of non-displacement synthesis.
M-MuLV nucleocapsid protein increases the rates of RNA and DNA displacement
synthesis approximately 2-fold, and this activity appears to require the zinc
finger domain.
PMID- 9545344
TI - Tissue plasminogen activator binding to the annexin II tail domain. Direct
modulation by homocysteine.
AB - Tissue plasminogen activator binds to endothelial cells via the calcium-regulated
phospholipid-binding protein annexin II, an interaction that is inhibited by the
prothrombotic amino acid homocysteine. We sought to identify the tissue
plasminogen activator binding domain of annexin II and to determine the mechanism
of its modulation by homocysteine. Tissue plasminogen activator binding to
immobilized annexin II was inhibited by intact fluid phase annexin II but not by
its "core" fragment (residues 25-339). Two overlapping "tail" peptides
specifically blocked 65-75% of binding. Localization of the tissue plasminogen
activator binding domain was confirmed upon specific inhibition by the
hexapeptide LCKLSL (residues 7-12). Expressed C9G annexin II protein failed to
support tissue plasminogen activator binding, while binding to C133G, C262G, and
C335G was equivalent to that of wild type annexin II. Upon exposure to
homocysteine, annexin II underwent a 135 +/- 4-Da increase in mass localizing
specifically to Cys9 and a 60-66% loss in tissue plasminogen activator-binding
capacity (I50 = 11 microM). Upon treatment of cultured endothelial cells with
[35S]homocysteine, the dithiothreitol-sensitive label was recovered by
immunoprecipitation with anti-annexin II IgG. These data provide a potential
mechanism for the prothrombotic effect of homocysteine by demonstrating direct
blockade of the tissue plasminogen activator binding domain of annexin II.
PMID- 9545345
TI - Insulin receptor substrate-1 is the predominant signaling molecule activated by
insulin-like growth factor-I, insulin, and interleukin-4 in estrogen receptor
positive human breast cancer cells.
AB - Because insulin-like growth factor-I (IGF-I), insulin, and interleukin-4 (IL-4)
have known biological effects in breast cancer cells and signal through insulin
receptor substrate (IRS) adaptor proteins, we examined the expression and
function of IRS-1 and IRS-2 in breast tumors and cell lines. IRS-1 and IRS-2 were
expressed by cell lines and primary breast tumor specimens. IGF-I, insulin, and
IL-4 treatment of MCF-7 and ZR-75, and IGF-I treatment of T47-D breast cancer
cells, resulted in much greater tyrosine phosphorylation of IRS-1 compared with
IRS-2. Furthermore, IGF-I stimulated greater tyrosine phosphorylation of IRS-1
than either insulin or IL-4. IGF-I treatment also enhanced association of the p85
regulatory subunit of phosphatidylinositol 3-kinase with IRS-1 and stimulated
increased enzymatic activity compared with IL-4 and insulin in all three cell
lines. Similarly, mitogen-activated protein kinase activity was greater in IGF-I
stimulated cells. To determine the functional significance of the activation of
these pathways, we inhibited activation of phosphatidylinositol 3-kinase with
wortmannin and mitogen-activated protein kinase with PD098059. Both compounds
inhibited IGF-stimulated growth, suggesting that both pathways contributed to the
mitogenic response to IGF-I. We conclude that IRS-1, and not IRS-2, is the
predominant signaling molecule activated by IGF-I, insulin, and IL-4.
Furthermore, enhanced tyrosine phosphorylation of IRS-1 by IGF-I, compared with
either insulin or IL-4, is associated with greater activation of mitogenic
downstream signaling pathways resulting in enhanced cell growth.
PMID- 9545346
TI - Overexpression of C-terminal Src kinase homologous kinase suppresses activation
of Lyn tyrosine kinase required for VLA5-mediated Dami cell spreading.
AB - The Csk homologous kinase (Chk), which is co-expressed with C-terminal Src kinase
(Csk) in hematopoietic cells, negatively regulates Src family kinases in vitro
with selectivity toward Lyn but not c-Src in platelets. To explore the role of
Src family kinases in hematopoietic cell adhesion, we overexpressed Chk in the
megakaryocytic cell line Dami and established clones exhibiting a 10-fold
increase in the amount of Chk. Overexpression of Chk was found to suppress VLA5
integrin-mediated cell spreading, but not cell attachment, throughout fibronectin
(FN) stimulation. Deletion and point mutagenesis analyses of Chk showed that this
suppression was dependent upon both the SH3 domain, which is responsible for
membrane anchoring, and kinase activity. FN-induced cell spreading accompanied a
sustained increase in Lyn activity with coincidental kinetics and the activation
of Lyn was also suppressed by overexpression of Chk but not a Chk mutant lacking
the SH3 domain. Expression of a truncated Lyn mutant lacking the kinase domain
inhibited both cell spreading and Lyn activation upon stimulation with FN. These
results suggest that sustained activation of Lyn, which is regulated by membrane
anchored Chk, plays a crucial role in VLA5-mediated cell spreading but not cell
attachment to a FN substrate.
PMID- 9545347
TI - Molecular cloning and characterization of a novel human classic cadherin
homologous with mouse muscle cadherin.
AB - We used a novel cDNA cloning method based on the cadherin-beta-catenin protein
interaction and identified a new human classic-type cadherin, which we named
cadherin-15, from adult brain and skeletal muscle cDNA libraries. Sequence
analysis revealed that this cadherin was closely related to mouse muscle cadherin
and seemed to be its human counterpart. However, its deduced amino acid sequence
differed from that of mouse muscle cadherin in that it had an extra 31-amino acid
sequence at its C terminus that has been found neither in mouse muscle cadherin
nor in any other known classic cadherin. Analysis of cadherin-15 protein
expressed in L fibroblasts showed that it was cleaved proteolytically, expressed
on the cell surfaces as a mature form of about 124-kDa, and functioned as a cell
cell adhesion molecule in a homophilic and specific manner, but Ca2+ did not
protect it against degradation by trypsin. Our findings also suggest that
cadherin-15 mediates cell-cell adhesion with a binding strength comparable to
that of E-cadherin.
PMID- 9545348
TI - The identification, purification, and characterization of CooJ. A nickel-binding
protein that is co-regulated with the Ni-containing CO dehydrogenase from
Rhodospirillum rubrum.
AB - CooJ, a nickel-binding protein from the CO dehydrogenase system of Rhodospirillum
rubrum, was purified by immobilized metal affinity chromatography. CooJ is a CO
induced protein predicted to contain a nickel binding motif composed of 16
histidine residues in the final 34 amino acids of the 12.5-kDa protein. When
cells grown in the presence of CO were fractionated on an immobilized metal
affinity chromatography column and analyzed by SDS-polyacrylamide gel
electrophoresis, the major protein observed in the effluent migrated at an
apparent molecular mass of 19 kDa. The 19-kDa protein was absent in extracts of
cells grown in the absence of CO and the mutant strain, UR294, which lacks a
functional cooJ gene. N-terminal sequence analysis confirmed that the 19-kDa
protein is the product of the cooJ gene. Purified CooJ was shown to bind four
nickel atoms per CooJ monomer with a Kd of 4.3 microM. Other divalent metals
competed with the following order of affinity and corresponding Ki: Zn2+ (5
microM) > Cd2+ (19 microM) > Co2+ (23 microM) > Cu2+ (122 microM). CooJ
chromatographed on a calibrated Superose 12 gel filtration column eluted at 39
kDa, a position consistent with a multimeric native molecular mass for CooJ.
PMID- 9545350
TI - Properties of pervanadate and permolybdate. Connexin43, phosphatase inhibition,
and thiol reactivity as model systems.
AB - Pervanadate and permolybdate are irreversible protein-tyrosine phosphatase
inhibitors, with IC50 values of 0.3 and 20 microM, respectively, in intact cells.
Maximal inhibition was obtained within 1 min at higher concentrations of the
compounds. They induced prominent changes in the phosphorylation status of the
gap junction protein, connexin43. These effects were utilized as model systems to
assess the stability and inactivation of the compounds. Although the concentrated
stock solutions were relatively stable, the diluted compounds were unstable. The
biological activity had decreased to 20-30% after 6 h of incubation in a
phosphate buffer, 1 h in phosphate buffer with 10% fetal calf serum, and 1-3
minutes in culture medium. Thiols reacted rapidly with the compounds and
inactivated them (initial reaction rates with cysteine: permolybdate >
pervanadate > H2O2). Catalase inactivated the compounds, and permolybdate was the
more sensitive. The cells inactivated permolybdate faster than pervanadate.
Cellular inactivation of permolybdate, and to a lesser degree pervanadate,
appeared to be partly dependent on catalase and thiols. However, a general
decrease in cellular thiols was not the mediator of the biological effects of
pervanadate or permolybdate. Mathematical modeling of the thiol reactivity
suggested that monoperoxovanadate at maximum could possess 20% of the biological
activity of diperoxovanadate.
PMID- 9545349
TI - Enzymatic processing of uracil glycol, a major oxidative product of DNA cytosine.
AB - A major stable oxidation product of DNA cytosine is uracil glycol (Ug). Because
of the potential of Ug to be a strong premutagenic lesion, it is important to
assess whether it is a blocking lesion to DNA polymerase as is its structural
counterpart, thymine glycol (Tg), and to evaluate its pairing properties. Here, a
series of oligonucleotides containing Ug or Tg were prepared and used as
templates for a model enzyme, Escherichia coli DNA polymerase I Klenow fragment
(exo-). During translesion DNA synthesis, Ug was bypassed more efficiently than
Tg in all sequence contexts examined. Furthermore, only dAMP was incorporated
opposite template Ug and Tg and the kinetic parameters of incorporation showed
that dAMP was inserted opposite Ug more efficiently than opposite Tg. Ug opposite
G and A was also recognized and removed in vitro by the E. coli DNA repair
glycosylases, endonuclease III (endo III), endonuclease VIII (endo VIII), and
formamidopyrimidine DNA glycosylase. The steady state kinetic parameters
indicated that Ug was a better substrate for endo III and formamidopyrimidine DNA
glycosylase than Tg; for endonuclease VIII, however, Tg was a better substrate.
PMID- 9545351
TI - The sister of P-glycoprotein represents the canalicular bile salt export pump of
mammalian liver.
AB - Canalicular secretion of bile salts is a vital function of the vertebrate liver,
yet the molecular identity of the involved ATP-dependent carrier protein has not
been elucidated. We cloned the full-length cDNA of the sister of P-glycoprotein
(spgp; Mr approximately 160,000) of rat liver and demonstrated that it functions
as an ATP-dependent bile salt transporter in cRNA injected Xenopus laevis oocytes
and in vesicles isolated from transfected Sf9 cells. The latter demonstrated a 5
fold stimulation of ATP-dependent taurocholate transport as compared with
controls. This spgp-mediated taurocholate transport was stimulated solely by ATP,
was inhibited by vanadate, and exhibited saturability with increasing
concentrations of taurocholate (Km approximately 5 microM). Furthermore, spgp
mediated transport rates of various bile salts followed the same order of
magnitude as ATP-dependent transport in canalicular rat liver plasma membrane
vesicles, i.e. taurochenodeoxycholate > tauroursodeoxycholate = taurocholate >
glycocholate = cholate. Tissue distribution assessed by Northern blotting
revealed predominant, if not exclusive, expression of spgp in the liver, where it
was further localized to the canalicular microvilli and to subcanalicular
vesicles of the hepatocytes by in situ immunofluorescence and immunogold labeling
studies. These results indicate that the sister of P-glycoprotein is the major
canalicular bile salt export pump of mammalian liver.
PMID- 9545352
TI - Modulation of E2F activity via signaling through surface IgM and CD40 receptors
in WEHI-231 B lymphoma cells.
AB - Stimulation of the phenotypically immature B cell lymphoma WEHI-231 with anti-IgM
induces G1 arrest followed by apoptotic cell death, which can be reversed by
stimulation via the CD40 receptor. Here, we show that cells expressing bcl-xL
(WEHI-bcl-xL) arrest at G0/G1 following culture with anti-IgM but do not undergo
apoptosis. These arrested cells can be induced to reenter the cell cycle by
ligation of CD40. We have therefore used these cells as a model to study the
regulation of the transcription factor E2F, which is critically involved in
transit through the cell cycle. We found that anti-IgM treatment induces the
appearance of an inhibitory DNA binding complex containing the pRB-related pocket
protein p130 together with E2F and a concomitant decrease in "free" E2F,
consisting of E2F1 and its partner DP1; these effects were reversed following
stimulation via CD40. These changes in free E2F levels were regulated by changes
in E2F1 gene transcription, which is at least partly a result of control of E2F1
promoter activity through its E2F binding sites. Transient transfection
experiments showed that either E2F1 or the viral oncoprotein E1A, which
sequesters pocket proteins, including p130, overcame anti-IgM-induced cell cycle
arrest in WEHI-bcl-xL. Taken together, these results indicate that in WEHI-231
sIgM ligation induces the accumulation of hypophosphorylated p130 with consequent
inhibition of E2F1 gene transcription and cell cycle arrest. Conversely, ligation
of CD40 causes hyperphosphorylation of p130, thereby releasing the repression of
E2F1 and other E2F-regulated genes, enabling the cells to reenter the cycle.
These results, therefore, provide novel insights into the mechanisms whereby
antigen receptors on immature B cells deliver inhibitory signals (leading to
negative selection of self-reactive B cells) and how these signals can be
modulated by positive signals generated via CD40.
PMID- 9545353
TI - Comparison of promoters for the murine and human P-selectin genes suggests
species-specific and conserved mechanisms for transcriptional regulation in
endothelial cells.
AB - P-selectin, an adhesion receptor for leukocytes, is constitutively expressed in
megakaryocytes and endothelial cells. Tumor necrosis factor-alpha (TNF-alpha) or
lipopolysaccharide (LPS) increases synthesis of P-selectin in murine but not in
human endothelial cells. To identify potential species-specific and conserved
mechanisms for regulation of expression of P-selectin, we cloned the 5'-flanking
region of the murine P-selectin gene and compared its features with those
previously reported for the human gene. The murine and human genes shared
conserved Stat-like, Hox, Ets, GATA, and GT-IIC elements. In the murine gene, a
conserved GATA element bound to GATA-2 and functioned as a positive regulatory
element, whereas a conserved Ets element bound to GA-binding protein and
functioned as a negative regulatory element. Significantly, the murine P-selectin
gene had several features not found in the human gene. These included an
insertion from -987 to -649 that contained tandem GATA and tandem AP1-like
sequences, which resembled enhancers in beta-globin locus control regions. Both
tandem elements bound specifically to nuclear proteins. The murine gene lacked
the unique kappaB site specific for p50 or p52 homodimers found in the human
gene. Instead, it contained two tandem kappaB elements and a variant activating
transcription factor/cAMP response element site, which closely resembled sites in
the E-selectin gene that are required for TNF-alpha- or LPS-inducible expression.
TNF-alpha or LPS augmented expression of a reporter gene driven by the murine,
but not the human, P-selectin promoter in transfected endothelial cells.
Deletional analysis of the murine 5'-flanking region revealed several sequences
that were required for either constitutive or inducible expression. These data
suggest that both species-specific and conserved mechanisms regulate
transcription of the human and murine P-selectin genes.
PMID- 9545354
TI - Tumor necrosis factor-alpha- or lipopolysaccharide-induced expression of the
murine P-selectin gene in endothelial cells involves novel kappaB sites and a
variant activating transcription factor/cAMP response element.
AB - Tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS) increases
expression of the P-selectin gene in murine, but not in human, endothelial cells.
These mediators augment expression of a reporter gene driven by the murine, but
not the human, P-selectin promoter in transfected endothelial cells. The regions
from -593 to -474 and from -229 to -13 in the murine P-selectin promoter are
required for TNF-alpha or LPS to stimulate reporter gene expression. Within these
regions, we identified two tandem kappaB elements, a reverse-oriented kappaB site
and a variant activating transcription factor/cAMP response element (ATF/CRE),
that participate in TNF-alpha- or LPS-induced expression. The tandem kappaB
elements bound to NF-kappaB heterodimers and p65 homodimers, the reverse-oriented
kappaB site bound to p65 homodimers, and the variant ATF/CRE bound to nuclear
proteins that included activating transcription factor-2. Mutations in each
individual element eliminated binding to nuclear proteins and decreased by 20-60%
the TNF-alpha- or LPS-induced expression of a reporter gene driven by the murine
P-selectin promoter in transfected endothelial cells. Simultaneous mutations of
all elements further decreased, but did not abolish, induced expression. Co
overexpression of p50 and p65 enhanced murine P-selectin promoter activity in a
kappaB site-dependent manner. These data indicate that the kappaB sites and the
variant ATF/CRE are required for TNF-alpha or LPS to optimally induce expression
of the murine P-selectin gene. The presence of these elements in the murine, but
not the human, P-selectin gene may explain in part why TNF-alpha or LPS
stimulates transcription of P-selectin in a species-specific manner.
PMID- 9545355
TI - Absence of soluble leptin receptor in plasma from dbPas/dbPas and other db/db
mice.
AB - The leptin receptor (Ob-R) is alternatively spliced into at least five different
RNAs designated Ob-R(a-e). Ob-R(a-d) predict receptors with a single
transmembrane domain, and Ob-Re predicts a secreted form of the receptor. The
presence of an approximately 120-kDa soluble leptin receptor in mouse plasma was
confirmed by precipitation with leptin-Sepharose beads followed by immunobloting
with anti-leptin receptor antibodies. The soluble leptin receptor is larger than
that predicted by the primary sequence. Deglycosylation of the receptor with
peptide N:glycosidase F results in a decrease in molecular mass to a size
consistent with that of the primary sequence. The secreted receptor was present
in plasma from wild type mice but was truncated in plasma from db3J/db3J and
absent in dbPas/dbPas plasma. Although db3J/db3J mice are known to have a
frameshift mutation at amino acid 625, the basis for the mutation in dbPas/dbPas
mice was not known. Further studies indicated that dbPas/dbPas mice carry a
duplication of exons 4 and 5 of Ob-R. This mutation introduces a premature stop
codon into the protein at amino acid 281. The absence of Ob-R in db3J/db3J and
dbPas/dbPas mice confirm the identify of the 120-kDa plasma protein as Ob-Re.
PMID- 9545356
TI - Ten-year risk of false positive screening mammograms and clinical breast
examinations.
AB - BACKGROUND: The cumulative risk of a false positive result from a breast-cancer
screening test is unknown. METHODS: We performed a 10-year retrospective cohort
study of breast-cancer screening and diagnostic evaluations among 2400 women who
were 40 to 69 years old at study entry. Mammograms or clinical breast
examinations that were interpreted as indeterminate, aroused a suspicion of
cancer, or prompted recommendations for additional workup in women in whom breast
cancer was not diagnosed within the next year were considered to be false
positive tests. RESULTS: A total of 9762 screening mammograms and 10,905
screening clinical breast examinations were performed, for a median of 4
mammograms and 5 clinical breast examinations per woman over the 10-year period.
Of the women who were screened, 23.8 percent had at least one false positive
mammogram, 13.4 percent had at least one false positive breast examination, and
31.7 percent had at least one false positive result for either test. The
estimated cumulative risk of a false positive result was 49.1 percent (95 percent
confidence interval, 40.3 to 64.1 percent) after 10 mammograms and 22.3 percent
(95 percent confidence interval, 19.2 to 27.5 percent) after 10 clinical breast
examinations. The false positive tests led to 870 outpatient appointments, 539
diagnostic mammograms, 186 ultrasound examinations, 188 biopsies, and 1
hospitalization. We estimate that among women who do not have breast cancer, 18.6
percent (95 percent confidence interval, 9.8 to 41.2 percent) will undergo a
biopsy after 10 mammograms, and 6.2 percent (95 percent confidence interval, 3.7
to 11.2 percent) after 10 clinical breast examinations. For every 100 dollars
spent for screening, an additional 33 dollars was spent to evaluate the false
positive results. CONCLUSIONS: Over 10 years, one third of women screened had an
abnormal test result that required additional evaluation, even though no breast
cancer was present. Techniques are needed to decrease false positive results
while maintaining high sensitivity. Physicians should educate women about the
risk of a false positive result from a screening test for breast cancer.
PMID- 9545357
TI - Quality of life and clinical outcomes in elderly patients treated with
ventricular pacing as compared with dual-chamber pacing. Pacemaker Selection in
the Elderly Investigators.
AB - BACKGROUND: Standard clinical practice permits the use of either single-chamber
ventricular pacemakers or dual-chamber pacemakers for most patients who require
cardiac pacing. Ventricular pacemakers are less expensive, but dual-chamber
pacemakers are believed to be more physiologic. However, it is not known whether
either type of pacemaker results in superior clinical outcomes. METHODS: The
Pacemaker Selection in the Elderly study was a 30-month, single-blind,
randomized, controlled comparison of ventricular pacing and dual-chamber pacing
in 407 patients 65 years of age or older in 29 centers. Patients received a dual
chamber pacemaker that had been randomly programmed to either ventricular pacing
or dual-chamber pacing. The primary end point was health-related quality of life
as measured by the 36-item Medical Outcomes Study Short-Form General Health
Survey. RESULT: The average age of the patients was 76 years (range, 65 to 96),
and 60 percent were men. Quality of life improved significantly after pacemaker
implantation (P<0.001), but there were no differences between the two pacing
modes in either the quality of life or prespecified clinical outcomes (including
cardiovascular events or death). However, 53 patients assigned to ventricular
pacing (26 percent) were crossed over to dual-chamber pacing because of symptoms
related to the pacemaker syndrome. Patients with sinus-node dysfunction, but not
those with atrioventricular block, had moderately better quality of life and
cardiovascular functional status with dual-chamber pacing than with ventricular
pacing. Trends of borderline statistical significance in clinical end points
favoring dual-chamber pacing were observed in patients with sinus-node
dysfunction, but not in those with atrioventricular block. CONCLUSION: The
implantation of a permanent pacemaker improves health-related quality of life.
However, the quality-of-life benefits associated with dual-chamber pacing as
compared with ventricular pacing are observed principally in the subgroup of
patients with sinus-node dysfunction.
PMID- 9545358
TI - A comparison of recombinant urokinase with vascular surgery as initial treatment
for acute arterial occlusion of the legs. Thrombolysis or Peripheral Arterial
Surgery (TOPAS) Investigators.
AB - BACKGROUND: Recent controlled trials suggest that thrombolytic therapy may be an
effective initial treatment for acute arterial occlusion of the legs. A major
potential benefit of initial thrombolytic therapy is that limb ischemia can be
managed with less invasive interventions. METHODS: In this randomized,
multicenter trial conducted at 113 North American and European sites, we compared
vascular surgery (e.g., thrombectomy or bypass surgery) with thrombolysis by
catheter-directed intraarterial recombinant urokinase; all patients (272 per
group) had had acute arterial obstruction of the legs for 14 days or less.
Infusions were limited to a period of 48 hours (mean [+/-SE], 24.4+/-0.86), after
which lesions were corrected by surgery or angioplasty if needed. The primary end
point was the amputation-free survival rate at six months. RESULTS: Final
angiograms, which were available for 246 patients treated with urokinase,
revealed recanalization in 196 (79.7 percent) and complete dissolution of
thrombus in 167 (67.9 percent). Both treatment groups had similar significant
improvements in mean ankle-brachial blood-pressure index. Amputation-free
survival rates in the urokinase group were 71.8 percent at six months and 65.0
percent at one year, as compared with respective rates of 74.8 percent and 69.9
percent in the surgery group; the 95 percent confidence intervals for the
differences were -10.5 to 4.5 percentage points at six months (P=0.43) and -12.9
to 3.1 percentage points at one year (P=0.23). At six months the surgery group
had undergone 551 open operative procedures (excluding amputations), as compared
with 315 in the thrombolysis group. Major hemorrhage occurred in 32 patients in
the urokinase group (12.5 percent) as compared with 14 patients in the surgery
group (5.5 percent) (P= 0.005). There were four episodes of intracranial
hemorrhage in the urokinase group (1.6 percent), one of which was fatal. By
contrast, there were no episodes of intracranial hemorrhage in the surgery group.
CONCLUSIONS: Despite its association with a higher frequency of hemorrhagic
complications, intraarterial infusion of urokinase reduced the need for open
surgical procedures, with no significantly increased risk of amputation or death.
PMID- 9545359
TI - A multicenter trial of two dexamethasone regimens in ventilator-dependent
premature infants.
AB - BACKGROUND: Ventilator-dependent premature infants are often treated with
dexamethasone. However, the optimal timing of therapy is unknown. METHODS: We
compared the benefits and hazards of initiating dexamethasone therapy at two
weeks of age and at four weeks of age in 371 ventilator-dependent very-low-birth
weight infants (501 to 1500 g) who had respiratory index scores (mean airway
pressure x the fraction of inspired oxygen) of 52.4 at two weeks of age. One
hundred eighty-two infants received dexamethasone for two weeks followed by
placebo for two weeks, and 189 infants received placebo for two weeks followed by
either dexamethasone (those with a respiratory-index score of > or =2.4 on
treatment day 14) or additional placebo for two weeks. Dexamethasone was given at
a dose of 0.25 mg per kilogram of body weight twice daily intravenously or orally
for five days, and the dose was then tapered. RESULTS: The median time to
ventilator independence was 36 days in the dexamethasone-placebo group and 37
days in the placebo-dexamethasone group. The incidences of chronic lung disease
(defined as the need for oxygen supplementation at 36 weeks' postconceptional
age) were 66 percent and 67 percent, respectively. Dexamethasone was associated
with an increased incidence of nosocomial bacteremia (relative risk, 1.5; 95
percent confidence interval, 1.1 to 2.1) and hyperglycemia (relative risk, 1.9;
95 percent confidence interval, 1.2 to 3.0) in the dexamethasone-placebo group,
elevated blood pressure (relative risk, 2.9; 95 percent confidence interval, 1.2
to 6.9) in the placebo-dexamethasone group, and diminished weight gain and head
growth (P< 0.001) in both groups. CONCLUSIONS: Treatment of ventilator-dependent
premature infants with dexamethasone at two weeks of age is more hazardous and no
more beneficial than treatment at four weeks of ages.
PMID- 9545360
TI - Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy.
AB - BACKGROUND: Globoid-cell leukodystrophy is caused by a deficiency of
galactocerebrosidase, which results in progressive central nervous system
deterioration. We investigated whether allogeneic hematopoietic stem-cell
transplantation can provide a source of leukocyte galactocerebrosidase and
thereby prevent the decline of central nervous system function in patients with
the disease. METHODS: Five children with globoid-cell leukodystrophy (one with
the infantile type and four with late-onset disease) were treated with allogeneic
hematopoietic stem-cell transplantation. Measurement of leukocyte
galactocerebrosidase levels, neurologic examinations, neuropsychological tests,
magnetic resonance imaging of the central nervous system, cerebrospinal fluid
protein assays, and neurophysiologic measurements were performed before and after
transplantation, with follow-up ranging from one to nine years. RESULTS:
Engraftment of donor-derived hematopoietic cells occurred in all patients and was
followed by restoration of normal leukocyte galactocerebrosidase levels. In the
four patients with late-onset disease, the central nervous system deterioration
was reversed, and in the patient with the infantile form of the disease, signs
and symptoms have not appeared. Magnetic resonance imaging showed a decrease in
signal intensity in the three patients with late-onset disease who were assessed
both before and after transplantation. Abnormalities in cerebrospinal fluid total
protein levels were corrected in three patients with late-onset disease and
substantially reduced in the patient with the infantile form. CONCLUSIONS:
Central nervous system manifestations of globoid-cell leukodystrophy can be
reversed by allogeneic hematopoietic stem-cell transplantation.
PMID- 9545361
TI - Images in clinical medicine. Unilateral livedo reticularis.
PMID- 9545362
TI - Drugs in pregnancy.
PMID- 9545364
TI - Benefit and harm associated with screening for breast cancer.
PMID- 9545365
TI - Do patients prefer physiologic pacing?
PMID- 9545366
TI - Thrombolysis for acute arterial occlusion of the legs.
PMID- 9545367
TI - Should all people over the age of 50 have regular fecal occult-blood tests?
Postpone population screening until problems are solved.
PMID- 9545368
TI - Equine infectious anemia virus transactivator is a homeodomain-type protein.
AB - Lentiviral transactivator (Tat) proteins are essential for viral replication. Tat
proteins of human immunodeficiency virus type 1 and bovine immunodeficiency virus
form complexes with their respective RNA targets (Tat responsive element, TAR),
and specific binding of the equine anemia virus (EIAV) Tat protein to a target
TAR RNA is suggested by mutational analysis of the TAR RNA. Structural data on
equine infectious anemia virus Tat protein reveal a helix-loop-helix-turn-helix
limit structure very similar to homeobox domains that are known to bind
specifically to DNA. Here we report results of gel-shift and footprinting
analysis as well as fluorescence and nuclear magnetic resonance spectroscopy
experiments that clearly show that EIAV Tat protein binds to DNA specifically at
the long terminal repeat Pu.1 (GTTCCTGTTTT) and AP-1 (TGACGCG) sites, and thus
suggest a common mechanism for the action of some of the known lentiviral Tat
proteins via the AP-1 initiator site. Complex formation with DNA induces specific
shifts of the proton NMR resonances originating from amino acids in the core and
basic domains of the protein.
PMID- 9545369
TI - Tandem 5'-GA:GA-3' mismatches account for the high stability of the fold-back
structures formed by the centromeric Drosophila dodeca-satellite.
AB - The centromeric dodeca-satellite of Drosophila forms unusual DNA structures in
which its purine-rich strand (GTACGGGACCGA)n folds into very stable
intramolecular hairpins. These intramolecular hairpins contain groups of tandem
5'-GA:GA-3' mismatches that, as judged by gel electrophoresis analysis and UV
melting studies, have a determinant contribution to their stability. Duplexes of
the dodeca-satellite purine-rich strand, carrying tandem 5'-GA:GA-3' mismatches,
are as stable as equivalent fully Watson-Crick duplexes containing tandem 5'
TA:TA-3' Watson-Crick pairs in place of the non-Watson-Crick G.A pairs. On the
other hand, duplexes carrying any of the other three possible tandem combinations
of purine.purine mismatches, including G.A pairs on the opposite orientation 5'
AG:AG-3', are very unstable. The high stability of the dodeca-satellite hairplus
suggests that the tandem G.A pairs are on the sheared configuration although they
are found within the less favourable 5'-G-(G-A)-C-3' sequence context. Other
centromeres DNA sequences, including the AAGAG satellite of Drosophila and the
mammalian CENP-B box sequence, have the potential of forming intramolecular
hairpins stabilised by similar purine.purine interactions.
PMID- 9545370
TI - Human T cell cyclophilin18 binds to thiol-specific antioxidant protein Aop1 and
stimulates its activity.
AB - Cyclophilins (CyPs) define a family of proteins binding to the immunosuppressive
drug cyclosporin A (CsA). They are evolutionary highly conserved proteins being
present in both pro- and eukaryotes and in different subcellular locations. CyPs
possess enzymatic activity, namely peptidyl-prolyl cis-trans isomerase (PPIase)
activity and are involved in cellular protein folding and protein interactions.
Here we describe a novel interaction of human T cell cyclophilin18 (hCyP18).
Abundant cytosolic hCyP18 binds to the thiol-specific antioxidant protein Aop1
and stimulates its enzymatic activity. Aop1 belongs to a family of proteins
thought to be involved in defense of oxidative stress. The interaction of both
proteins seem to be specific, since other PPIases do not have any stimulatory
effect on Aop1.
PMID- 9545371
TI - Plugging interactions of HAP2 pentamer into the distal end of flagellar filament
revealed by electron microscopy.
AB - Bacterial flagellum has a cap structure tightly attached to its distal end. The
cap is an oligomeric assembly of HAP2 protein (also called FliD) and plays an
essential role in the filament growth in vivo by preventing flagellin monomers
from leaking out without polymerization. Electron micrographs of the HAP2 complex
formed in solution showed exclusively a pentagonal shape, called "star-cap",
which was thought to be the end-on view of the cap. The molecular mass roughly
corresponded to a dodecamer of HAP2, and therefore a double-layered star-cap was
modeled to be the cap. Here, we have observed the side view of the complex in
electron micrographs. The images clearly show a rectangular shape, about 80 A
wide and 180 A long, with a bipolar feature in its long axis, indicating that the
complex is a bipolar pair of pentamers. A thin plate feature is identified at
each end of the particle, which looks exactly like the one observed as the
structure of the native filament cap. Together with the structure of the filament
previously analyzed by electron cryomicroscopy, the results suggest that the cap
is a pentamer with its thin plate exposed to the solvent and the other half
plugged into the hole at the distal end of the filament, which is almost twice
wider than its central channel. This also allows us to model the axial domain
arrangement of flagellin subunit in the filament.
PMID- 9545372
TI - Role of protein-induced bending in the specificity of DNA recognition: crystal
structure of EcoRV endonuclease complexed with d(AAAGAT) + d(ATCTT).
AB - The crystal structure of EcoRV endonuclease has been determined at 2. 1 A
resolution complexed to two five-base-pair DNA duplexes each containing the
cognate recognition half-site. The highly localized 50 degrees bend into the
major groove seen at the center TA-step of the continuous GATATC site is
preserved in this discontinuous DNA complex lacking the scissile phosphates.
Thus, this crystal structure provides evidence that covalent constraints
associated with a continuous target site are not essential to enzyme-induced DNA
bending, even when these constraints are removed directly at the locus of the
bend. The scissile phosphates are also absent in the crystal structure of EcoRV
bound to the non-specific site TCGCGA, which shows a straight B-like
conformation. We conclude that DNA bending by EcoRV is governed only by the
sequence and is not influenced by the continuity of the phosphodiester backbone.
Together with other data showing that cleavable non-cognate sites are bent, these
results indicate that EcoRV bends non-cognate sites differing by one or two base
pairs from GATATC, but does not bend non-specific sites that are less similar.
Structural and thermodynamic considerations suggest that the sequence-dependent
energy cost of DNA bending is likely to play an important role in determining the
specificity of EcoRV. This differential cost is manifested at the binding step
for bent non-cognate sequences and at the catalytic step for unbent non-specific
sequences.
PMID- 9545373
TI - Transcription activation at promoters carrying tandem DNA sites for the
Escherichia coli cyclic AMP receptor protein: organisation of the RNA polymerase
alpha subunits.
AB - We have constructed a family of promoters carrying tandem DNA sites for the
Escherichia coli cyclic AMP receptor protein (CRP), with one of the sites centred
between base-pairs 41 and 42 upstream from the transcription start site, and the
second site located further upstream. In vivo activity measurements show that the
activity of these promoters is completely dependent on CRP and that, depending on
the precise location, CRP bound at the upstream site increases transcription
activation. Hydroxyl radical footprinting was exploited to investigate the
binding of CRP and RNA polymerase holoenzyme (RNAP) to these promoters. The study
shows that the C-terminal domains of the RNAP alpha subunits bind adjacent to the
upstream CRP and that their precise positioning depends on the location of
upstream-bound CRP. The C-terminal domains of the RNAP alpha subunits interact
with both the upstream and downstream-bound CRP via activating region 1 of CRP.
PMID- 9545374
TI - The arginine repressor of Escherichia coli K-12 makes direct contacts to minor
and major groove determinants of the operators.
AB - In order to gain further insight into the molecular mechanism of arginine
dependent operator recognition by the hexameric Escherichia coli arginine
repressor we have probed protein-DNA interactions in vitro and in vivo. We have
extensively applied the chemical modification-protection and premodification
interference approach to two operators, the natural operator overlapping the P2
promoter of the carAB operon and a fully symmetrical consensus sequence. Backbone
contacts were revealed by hydroxyl radical footprinting and phosphate ethylation
interference. Base-specific contacts to purines and pyrimidines were revealed by
methylation protection and premodification interference, KMnO4 and NH2OH.HCl
specific modification of thymine and cytosine residues, base-removal
(depurination and depyrimidation), and base substitution (uracil and inosine).
Additional information on the groove specificity of repressor binding was
obtained by small ligand binding interference (distamycin and methyl green). In
vivo, we measured the effects on the repressibility of 24 single base-pair
substitutions obtained by saturation mutagenesis of half an Arg box in the carAB
operator. The results of these experiments point to the conclusion that a
hexameric arginine repressor molecule covers four turns of the helix, makes base
specific contacts to at least one guanine (G4 or G4') and two thymine (T3, T13',
or T3', T13) residues in each one of four consecutive major grooves on one face
of the helix and with four A-T/T-A base-pairs, comprising the adenine residues
A9, 9', 12, 12' and the thymine residues T10, 10', 11, 11', in the two outermost
minor grooves of the operator, on the very same face of the DNA molecule. The
hydrophobic 5-methyl groups of four thymine residues (T3, 3', 13, 13') in each
Arg box contribute to major groove-specific recognition via hydrophobic and/or
van der Waals interactions. The importance of minor groove contacts was further
supported by the drastic effect of distamycin binding interference. In vivo, the
most pronounced drops in repressibility were occasioned by mutations at positions
10 (A-->G or C), 11 (T-->A or G) and 12 (A-->G, T or C).
PMID- 9545375
TI - ATP-independent DNA unwinding by the adenovirus single-stranded DNA binding
protein requires a flexible DNA binding loop.
AB - The adenovirus DNA binding protein (DBP) binds cooperatively to single-stranded
(ss) DNA and stimulates both initiation and elongation of DNA replication. DBP
forms protein filaments via a C-terminal arm that hooks into a neighbouring
molecule. This multimerization is the driving force for ATP-independent DNA
unwinding by DBP during elongation. Another conserved part of DBP forms an
unstructured flexible loop that is probably directly involved in contacting DNA.
By making appropriate deletion mutants that do not distort the overall DBP
structure, the influence of the C-terminal arm and the flexible loop on the
kinetics of ssDNA binding and on DNA replication was studied. Employing surface
plasmon resonance we show that both parts of the protein are required for high
affinity binding. Deletion of the C-terminal arm leads to an extremely labile DBP
ssDNA complex indicating the importance of multimerization. The flexible loop is
also required for optimal stability of the DBP-ssDNA complex, providing
additional evidence that this region forms part of the ssDNA-binding surface of
DBP. Both deletion mutants are still able to stimulate initiation of DNA
replication but are defective in supporting elongation, which may be caused by
the fact that both mutants have a reduced DNA unwinding activity. Surprisingly,
mixtures containing both mutants do stimulate elongation. Mixing the purified
mutant proteins leads to the formation of mixed filaments that have a higher
affinity for ssDNA than homogeneous mutant filaments. These results provide
evidence that the C-terminal arm and the flexible loop have distinct functions in
unwinding during replication. We propose the following model for ATP-independent
DNA unwinding by DBP. Multimerization via the C-terminal arm is required for the
formation of a protein filament that saturates the displaced strand. A high
affinity of a DBP monomer for ssDNA and subsequent local destabilization of the
replication fork requires the flexible loop.
PMID- 9545376
TI - TAPASIN, DAXX, RGL2, HKE2 and four new genes (BING 1, 3 to 5) form a dense
cluster at the centromeric end of the MHC.
AB - TAPASIN, a gene recently shown to be required for antigen presentation through
MHC class I molecules, is located 180 kbp centromeric of HLA-DP in a region
linked to several diseases, and associated with altered developmental phenotypes
in the mouse. We present the genomic analysis of a 70 kbp gene-dense segment
flanking the TAPASIN locus, including sequence, structure and preliminary
characterisation of seven additional genes. BING1 is a Zn finger gene containing
a POZ motif. BING3 is similar to myosin regulatory light chain. BING4 shows
homologies only to hypothetical yeast and Caenorhabditis elegans proteins. BING5
is found within an intron of BING4 on the complementary strand, and encodes a
molecule with no homologies to database proteins. Another three genes were
identified whose full sequence was not previously known; namely, RGL2, DAXX
(BING2) and HKE2. RGL2 encodes an effector of Ras, homologous to the mouse RalGDS
protein, Rlf. DAXX encodes an effector of Fas that stimulates apoptosis through
the Jun kinase (JNK) pathway. The location of DAXX is of interest given the
linkage of autoimmune disease to the MHC and to apoptosis.
PMID- 9545377
TI - Processing of Escherichia coli alkaline phosphatase: role of the primary
structure of the signal peptide cleavage region.
AB - A wide range (69) of mutant Escherichia coli alkaline phosphatases with single
amino acid substitutions at positions from -5 to +1 of the signal peptide were
obtained for studying protein processing as a function of the primary structure
of the cleavage region. Amber suppressor mutagenesis, used to create mutant
proteins, included: (i) introduction of amber mutations into respective positions
of the phoA gene; and (ii) expression of each mutant phoA allele in E. coli
strains producing amber suppressor tRNAs specific to Ala, Cys, Gln, Glu, Gly,
His, Leu, Lys, Phe, Pro, Ser and Tyr. Most amino acid substitutions at positions
3 and -1 resulted in a complete block of protein processing. These data give new
experimental support for the "-3, -1 rule". Only Ala, Gly and Ser at position -1
allowed protein processing, and Ala provided the highest rate of processing. The
results revealed the more conservative nature of the amino acids at the -1
position of signal peptides of Gram-negative bacteria as compared with those of
eukaryotic organisms. Position -3 was less regular, since not only Ala, Ser and
Gly, but also Leu and Cys at this position, allowed the processing. Mutations at
position -4 had an insignificant effect on the processing. Surprisingly,
efficient processing was provided mainly by large amino acid residues at position
-2 and by middle-sized residues at position -5, indicating that the processing
rate is affected by the size of amino acid residues not only at positions -1 and
3. Conformation analysis of the cleavage site taken together with the mutation
and statistical data suggests an extended beta-conformation of the -5 to -1
region in the signal peptidase binding pocket.
PMID- 9545378
TI - Effect of cellular level of FliK on flagellar hook and filament assembly in
Salmonella typhimurium.
AB - Frameshift mutations in the fliK gene of Salmonella result in abnormal elongation
of the hook and the failure to assemble filament (polyhook phenotype). Second
site suppressor mutations restore filament assembly, but the cells often remain
defective in hook-length control (polyhook-filament phenotype). Where the
suppressor mutations are intragenic, the second mutation restores the original
frame, generating a region of frameshifted sequence, but restoring the natural C
terminus. Some of these frameshifted sequences contain a UGA (opal) termination
codon. These cells have few flagella and swarm poorly. We suspected that
readthrough of UGA by tRNATrp might be the reason for the partial function. When
the UGA codon was changed to the Trp codon UGG, flagellar assembly and function
were restored to wild-type levels. Conversely, underexpression of the wild-type
fliK gene, achieved by changing the sole Trp codon in the sequence (Trp271) to
UGA, decreased both the number of flagella and the ability to swarm. These
results validate the readthrough hypothesis and indicate that low levels of FliK
sustain some degree of flagellation and motility. At low levels of FliK, most
flagella had polyhooks. With increasing amounts, the morphology progressively
changed to polyhook-filament, and eventually to wild-type hook-filament. When
FliK was overproduced, the hook length was slightly shorter (46(+/-7) nm) than
that of the wild-type strain (55(+/-9) nm). FliK levels were measured by
immunoblotting. Wild-type levels were about 40 to 80 molecules/cell. FliK
synthesized by UGA readthrough could be detected when overproduced from plasmid
fliK-W271opal, and the levels indicated a probability of readthrough of 0.002 to
0.01. This value was used to estimate the cellular level of underexpressed FliK,
which could partly restore function to a fliK mutant, at about 0.07 to 0.8
molecule/cell. These results suggest that FliK does not form a large structure in
the cytoplasm and may function as a regulatory protein for protein export. A
model for hook-length control is presented that involves feedback from the
assembly point to the export apparatus.
PMID- 9545379
TI - Assembly characteristics of flagellar cap protein HAP2 of Salmonella: decamer and
pentamer in the pH-sensitive equilibrium.
AB - The cap of the bacterial flagellum is an oligomeric assembly of HAP2 protein
(also called FliD), tightly attached to the tip of the flagellar filament.
Flagellar growth does not occur in fliD-deficient mutants because flagellin
monomers transported through the central channel of the flagellum leak out
without polymerizing at the distal end. The structure of the cap complex is not
known yet. An in vitro assembly of HAP2 proteins was found to have a pentagonal
shape, while its molecular mass corresponded roughly to that of a dodecamer. To
characterize the structure and assembly behavior of the complex formed in vitro
in more detail, the stoichiometry of the complex and the association equilibrium
have been studied. Crosslinking experiments now clearly show that the HAP2
complex is decameric. The assembly equilibrium is mainly between the monomer and
decamer with a minor population of intermediate oligomers involved, and is highly
dependent on the solution pH as well as the salt concentration: the fraction of
the decamer sharply rises as the pH decreases from 8.5 to 8.0; the physiological
concentration of salt partially suppresses the decamer formation. A preferential
crosslinking within a pentameric unit together with a bipolar feature of the
complex particle observed by electron microscopy suggests that the decamer is a
bipolar pair of pentamers. Because of the polar nature of the filament cap
structure, the pentamer is suggested to be the cap complex with its decamer
forming surface involved in interactions with the filament.
PMID- 9545380
TI - Stochastic modeling and optimization of phage display.
AB - Phage display, SELEX and other methods of combinatorial chemistry have become
very popular means of finding ligands with high affinities to given targets.
Despite their success, they suffer from numerous sources of error and bias, such
as very low initial concentrations of species, non-specific binding, and the
sampling of only a tiny fraction of the library at the end of an experiment. To
understand the interaction of these errors and to better devise molecular search
strategies that take the errors into account, I devise and analyze a highly
detailed model of phage display. The model is specifically designed to study the
influence of the stochastic nature of each laboratory step. The model includes
phage multivalency, multiple classes of targets, and solid-phase equilibrium and
washing, yet it is amenable to analytic results and rapid computer simulation.
With both analytic and simulation approaches, I: (1) describe the effects of
target concentration, phage valency, degree of background binding and other
laboratory parameters on the probabilities of phage binding and of being
selected; (2) show the effects of an increasing selection stringency strategy and
how it results in a tradeoff between rapid library enrichment and high
probability of sampling the best ligands; and (3) show how the number of phage
sampled for detailed study at the end of a search alters search success. The work
concludes with several practical suggestions for the control of selection
stringency.
PMID- 9545381
TI - Structures of the Erythrina corallodendron lectin and of its complexes with mono-
and disaccharides.
AB - The structures of the Erythrina corallodendron lectin (EcorL) and of its
complexes with galactose, N-acetylgalactosamine, lactose and N-acetyllactosamine
were determined at a resolution of 1.9 to 1.95 A. The final R-values of the five
models are in the range 0.169 to 0.181. The unusual, non-canonical, dimer
interface of EcorL is made of beta-strands from the two monomers, which face one
another in a "hand-shake" mode. The galactose molecule in the primary binding
site is bound in an identical way in all four complexes. Features of the
electrostatic potential of the galactose molecule match those of the potential in
the combining site, thus probably pointing to the contribution of the
electrostatic energy to determining the orientation of the ligand. No
conformational change occurs in the protein upon binding the ligand. Subtle
variations in the binding mode of the second monosaccharide (glucose in the
complex with lactose and N-acetylglucosamine in the complex with N
acetyllactosamine) were observed. The mobility of Gln219 is lower in the
complexes with the disaccharides than in the complexes with the monosaccharides,
indicating further recruitment of this residue to ligand binding through more
extensive hydrogen bonding in the former complexes. Water molecules that have
been located in the combining sites of the five structures undergo rearrangement
in response to binding of the different ligands. The new structural information
is in qualitative agreement with thermodynamic data on the binding to EcorL.
PMID- 9545382
TI - The changing nature of the protein folding transition state: implications for the
shape of the free-energy profile for folding.
AB - According to landscape theory proteins do not fold by localised pathways, but
find their native conformation by a progressive organisation of an ensemble of
partly folded structures down a folding funnel. Here, we use kinetics and protein
engineering to investigate the shape of the free-energy profile for two-state
folding, which is the macroscopic view of the funnel process for small and
rapidly folding proteins. Our experiments are based mainly on structural changes
of the transition state of chymotrypsin inhibitor 2 (CI2) upon destabilisation
with temperature and GdnHCl. The transition state ensemble of CI2 is a localised
feature in the free-energy profile that is sharply higher than the other parts of
the activation barrier. The relatively fixed position of the CI2 transition state
on the reaction coordinate makes it easy to characterise but contributes also to
overshadow the rest of the free-energy profile, the shape of which is
inaccessible for analysis. Results from mutants of CI2 and comparison with other
two-state proteins, however, point at the possibility that the barrier for
folding is generally broad and that localised transition states result from minor
ripples in the free-energy profile. Accordingly, variabilities in the folding
kinetics may not indicate different folding mechanisms, but could be accounted
for by various degrees of ruggedness on top of very broad activation barriers for
folding. The concept is attractive since it summarises a wide range of folding
data which have previously seemed unrelated. It is also supported by theory.
Consistent with experiment, broad barriers predict that new transition state
ensembles are exposed upon extreme destabilisation or radical mutations.
PMID- 9545383
TI - Topology of the calmodulin-melittin complex.
AB - The topology of the Ca2+-calmodulin-melittin ternary complex has been
investigated by a combined strategy which integrates limited proteolysis and
cross-linking experiments with mass spectrometric methodologies. The rationale
behind the methods is that the interface regions of two interacting proteins are
accessible to the solvent in the isolated molecules, whereas they become
protected following the formation of the complex. Therefore, when limited
proteolysis experiments are carried out on both the isolated proteins and the
complex, differential peptide maps are obtained from which the interface regions
can be inferred. Alternatively, cross-linking reactions performed under strictly
controlled conditions lead to the identification of spatially closed amino acid
residues in the complex. Mass spectrometry can be employed in both procedures for
the definition of the cleavage sites and to identify covalently linked residues.
Our results show that melittin interacts with calmodulin by adopting a parallel
orientation, i.e. the N and C-terminal halves of the peptide are anchored to the
amino and carboxy-terminal domains of the protein, respectively. This orientation
is inverted with respect to all the peptide substrates examined so far. A model
of the complex was designed and refined on the basis of the experimental results,
supporting the above conclusions. This finding reveals a further dimension to the
already remarkable capability of calmodulin in binding different protein
substrates, providing this protein with the capability of regulating an even
larger number of enzymes.
PMID- 9545384
TI - Influence of cofactor binding and active site occupancy on the conformation of
the macromolecular substrate exosite of factor VIIa.
AB - The catalytic activity of the trypsin-like serine protease coagulation factor
VIIa is allosterically regulated. In this work, we employed monoclonal antibodies
as probes to analyze conformational changes in the VII protease domain that are
induced by zymogen activation, cofactor tissue factor (TF) binding, and active
site occupancy. The epitopes of three monoclonal antibodies were mapped using a
panel of 57 individual alanine replacement mutants in the protease domain. Two of
the antibodies had typical "hot spot" epitopes in a basic cluster above the
active site cleft and antibody binding to these epitopes was not affected by
zymogen activation, TF binding, or active site occupancy. In contrast, the
binding kinetics of VII/VIIa to a monoclonal antibody that mapped to an extended
epitope overlapping with the macromolecular substrate exosite was affected by
each of the conformational transitions of the VIIa protease domain. The changes
in antibody affinity are consistent with a transition from zymogen VII to the
TF.VIIa complex, with free enzyme VIIa as an intermediate that retains some
zymogen-like features responsible for its low catalytic activity. In contrast,
active site occupancy resulted in effects that were qualitatively different from
the effects of zymogen activation on the antibody epitope. This provides novel
insight into the conformational interdependence between the active site, the
region for macromolecular substrate recognition, and the cofactor binding exosite
of this allosterically regulated serine protease.
PMID- 9545385
TI - Molecular mechanisms for cooperative folding of proteins.
AB - The folding of single-domain globular proteins exhibits the character of first
order or two-state thermodynamics. The origin of such high cooperativity in
relatively small polymer systems is still not well understood. Recently, the
statistical mechanics of protein folding has been studied extensively with simple
protein models such as short cubic-lattice chains with contact-based
interactions. While many valuable insights about protein folding were gained with
such models, some concerns have also arisen, viz. that they lack the character of
protein backbones whose interactions would limit the folding patterns of
proteins. Here, a comparative study of the conventional cubic-lattice chain model
and a fine-grained more realistic lattice protein model with both backbone and
side-chain interactions is carried out. It is found that, even though both types
of models exhibit a cooperative two-state folding transition to the native
structure with optimized force fields, the character and origin of cooperativity
of the two models are different. In the simple contact-based model, the free
energy barrier occurs at the low end of the energy scale, and the cooperativity
arises from a concerted formation of native contacts among many residues in a
compact state. In the other more complicated model, the free-energy barrier
occurs in the intermediate energy region, and the folding cooperativity arises
from collective orientational arrangements of locally structured units in semi
open conformational states. On the basis of these results, two limiting molecular
mechanisms for protein folding emerge, which can be used for analyzing the
folding process of real proteins.
PMID- 9545386
TI - Contact order, transition state placement and the refolding rates of single
domain proteins.
AB - Theoretical studies have suggested relationships between the size, stability and
topology of a protein fold and the rate and mechanisms by which it is achieved.
The recent characterization of the refolding of a number of simple, single domain
proteins has provided a means of testing these assertions. Our investigations
have revealed statistically significant correlations between the average sequence
separation between contacting residues in the native state and the rate and
transition state placement of folding for a non-homologous set of simple, single
domain proteins. These indicate that proteins featuring primarily sequence-local
contacts tend to fold more rapidly and exhibit less compact folding transition
states than those characterized by more non-local interactions. No significant
relationship is apparent between protein length and folding rates, but a weak
correlation is observed between length and the fraction of solvent-exposed
surface area buried in the transition state. Anticipated strong relationships
between equilibrium folding free energy and folding kinetics, or between chemical
denaturant and temperature dependence-derived measures of transition state
placement, are not apparent. The observed correlations are consistent with a
model of protein folding in which the size and stability of the polypeptide
segments organized in the transition state are largely independent of protein
length, but are related to the topological complexity of the native state. The
correlation between topological complexity and folding rates may reflect chain
entropy contributions to the folding barrier.
PMID- 9545387
TI - A simple method for analyzing microsatellite allele image patterns generated from
DNA pools and its application to allelic association studies.
AB - Allelic association studies provide the most powerful method for locating genes
of small effect contributing to complex diseases and traits. However, in outbred
populations, allelic association is usually maintained only over distances of <=1
cM. Therefore, systematic searches over large regions are costly. Here we present
a method involving DNA pooling that can be used as a rapid preliminary screen for
allelic association with the most common class of polymorphic markers, single
sequence repeats. Patient and control samples are pooled separately, and markers
are typed in the two pools. By use of primers with fluorescent 5' ends, PCR
products can be analyzed on an automated sequencing apparatus. Allele image
patterns (AIPs) produced for the two groups are overlaid and differences in
pattern area between pools computed. From this, a DeltaAIP statistic is
calculated from the difference in areas between the two AIPs expressed as a
fraction of the total shared and nonshared area. AIPs of a range of different
sized pools were generated by computer simulation for markers with a range of
allele sizes and frequencies. DeltaAIPs from pools and chi2 values for individual
genotypings were compared, with both simulated and real data from microsatellite
markers. The results demonstrated a high correlation between DeltaAIP and chi2
values. DeltaAIP analysis of real microsatellite data indicated the feasibility
of using this method in systematic searches for allelic association and generated
a small number of false positives but few false negatives. We conclude that
DeltaAIP analysis of DNA pools can be used effectively and efficiently as a rapid
screen for allelic association in case-control studies.
PMID- 9545388
TI - An analysis of linkage disequilibrium in the interleukin-1 gene cluster, using a
novel grouping method for multiallelic markers.
AB - In population- and family-based association studies, it is useful to have some
knowledge of the patterns of linkage disequilibrium that exist between markers in
candidate regions. When such studies are carried out with multiallelic markers,
it is often convenient to group the alleles into a biallelic system, for
analysis. In this study, we specifically examined the interleukin-1 (IL-1) gene
cluster on chromosome 2, a region containing candidates for many inflammatory and
autoimmune disorders. Data were collected on eight markers, four of which were
multiallelic. Using these data, we investigated the effect of three allele
grouping strategies, including a novel method, on the detection of linkage
disequilibrium. The novel approach, termed the "delta method," measures the
deviation from the expected haplotype frequencies under linkage equilibrium, for
each allelic combination. This information is then used to group the alleles, in
an attempt to avoid the grouping together of alleles at one locus that are in
opposite disequilibrium with the same allele at the second locus. The estimate
haplotype frequencies (EH) program was used to estimate haplotype frequencies and
the disequilibrium measure. In our data it was found that the delta method
compared well with the other two strategies. Using this method, we found that
there was a reasonable correlation between disequilibrium and physical distance
in the region (r=-.540, P=.001, one-tailed). We also identified a common, eight
locus haplotype of the IL-1 gene cluster.
PMID- 9545389
TI - Genotype/phenotype correlation in autosomal recessive lamellar ichthyosis.
AB - Autosomal recessive lamellar ichthyosis is a severe congenital disorder of
keratinization, characterized by variable erythema of the whole body surface and
by different scaling patterns. Recently, mutations have been identified in
patients with lamellar ichthyosis in the TGM1 gene coding for keratinocyte
transglutaminase, and a second locus has been mapped to chromosome 2. We have now
analyzed the genotype/phenotype correlation in a total of 14 families with
lamellar ichthyosis. Linkage analyses using microsatellites in the region of the
TGM1 gene confirmed genetic heterogeneity. In patients not linked to the TGM1
gene, the second region identified on chromosome 2 and a further candidate region
on chromosome 20 were excluded, confirming as well the existence of at least
three loci for lamellar ichthyosis. Sequence analyses of the TGM1 gene in
families compatible with linkage to this locus revealed seven different missense
mutations, five of these unpublished so far, and one splice mutation. No
genotype/phenotype correlation for mutations in the TGM1 gene was found in this
group of patients, which included two unrelated patients homozygous for the same
mutation. Similarly, no clear difference in the clinical picture was seen between
patients with TGM1 mutations and those unlinked to the TGM1 locus. Comparison of
genetic and clinical classifications for patients with lamellar ichthyosis shows
no consistency and thus indicates that clinical criteria currently in use cannot
discriminate between the molecularly different forms of the disease.
PMID- 9545390
TI - Segregation of a PRKCG mutation in two RP11 families.
PMID- 9545393
TI - Statistical evaluation of age-at-onset anticipation: a new test and evaluation of
its behavior in realistic applications.
AB - The discovery that microsatellite repeat expansions can cause clinical disease
has fostered renewed interest in testing for age-at-onset anticipation (AOA). A
commonly used procedure is to sample affected parent-child pairs (APCPs) from
available data sets and to test for a difference in mean age at onset between the
parents and the children. However, standard statistical methods fail to take into
account the right truncation of both the parent and child age-at-onset
distributions under this design, with the result that type I error rates can be
inflated substantially. Previously, we had introduced a new test, based on the
correct, bivariate right-truncated, age-at-onset distribution. We showed that
this test has the correct type I error rate for random APCPs, even for quite
small samples. However, in that paper, we did not consider two key statistical
complications that arise when the test is applied to realistic data. First,
affected pairs usually are sampled from pedigrees preferentially selected for the
presence of multiple affected individuals. In this paper, we show that this will
tend to inflate the type I error rate of the test. Second, we consider the
appropriate probability model under the alternative hypothesis of true AOA due to
an expanding microsatellite mechanism, and we show that there is good reason to
believe that the power to detect AOA may be quite small, even for substantial
effect sizes. When the type I error rate of the test is high relative to the
power, interpretation of test results becomes problematic. We conclude that, in
many applications, AOA tests based on APCPs may not yield meaningful results.
PMID- 9545391
TI - A syndrome of severe mental retardation, spasticity, and tapetoretinal
degeneration linked to chromosome 15q24.
AB - Nine affected individuals are described from a large extended Pakistani family
manifesting a syndrome characterized by a triad of varying degrees of spasticity,
severe mental retardation, and visual impairment resulting from tapetoretinal
degeneration. In all cases, the parents were at least first cousins, since there
was complex consanguinity within the pedigree. The clinical features differ from
previously reported syndromes involving pigmentary retinal degeneration and
appear to represent a new recessively inherited neurodegenerative condition.
Linkage to a 4-5 cM-region between markers D15S211 and D15S152 on 15q24 has been
established by autozygosity mapping.
PMID- 9545392
TI - mtDNA analysis reveals a major late Paleolithic population expansion from
southwestern to northeastern Europe.
AB - mtDNA sequence variation was studied in 419 individuals from nine Eurasian
populations, by high-resolution RFLP analysis, and it was followed by sequencing
of the control region of a subset of these mtDNAs and a detailed survey of
previously published data from numerous other European populations. This analysis
revealed that a major Paleolithic population expansion from the "Atlantic zone"
(southwestern Europe) occurred 10,000-15,000 years ago, after the Last Glacial
Maximum. As an mtDNA marker for this expansion we identified haplogroup V, an
autochthonous European haplogroup, which most likely originated in the northern
Iberian peninsula or southwestern France at about the time of the Younger Dryas.
Its sister haplogroup, H, which is distributed throughout the entire range of
Caucasoid populations and which originated in the Near East approximately 25,000
30,000 years ago, also took part in this expansion, thus rendering it by far the
most frequent (40%-60%) haplogroup in western Europe. Subsequent migrations after
the Younger Dryas eventually carried those "Atlantic" mtDNAs into central and
northern Europe. This scenario, already implied by archaeological records, is
given overwhelming support from both the distribution of the autochthonous
European Y chromosome type 15, as detected by the probes 49a/f, and the synthetic
maps of nuclear data.
PMID- 9545394
TI - Autozygosity mapping, to chromosome 11q25, of a rare autosomal recessive syndrome
causing histiocytosis, joint contractures, and sensorineural deafness.
AB - We describe a highly consanguineous family, originating from Pakistan, displaying
histiocytosis, joint contractures, and sensorineural deafness. The form of
histiocytosis exhibited by this family does not fit readily into any of the
recognized classes of this disease. It appears to represent a novel form of
familial histiocytosis demonstrating autosomal recessive inheritance. Using
autozygosity mapping, we have identified a homozygous region of approximately 1
cM at chromosome 11q25, in affected individuals. A maximum two-point LOD score of
3.42 (recombination fraction straight theta = .00) was obtained with marker
D11S968. This is the first genetic locus to be described that is involved in the
molecular pathogenesis of histiocytosis.
PMID- 9545395
TI - A second common mutation in the methylenetetrahydrofolate reductase gene: an
additional risk factor for neural-tube defects?
AB - Recently, we showed that homozygosity for the common 677(C-->T) mutation in the
methylenetetrahydrofolate reductase (MTHFR) gene, causing thermolability of the
enzyme, is a risk factor for neural-tube defects (NTDs). We now report on another
mutation in the same gene, the 1298(A-->C) mutation, which changes a glutamate
into an alanine residue. This mutation destroys an MboII recognition site and has
an allele frequency of .33. This 1298(A-->C) mutation results in decreased MTHFR
activity (one-way analysis of variance [ANOVA] P < .0001), which is more
pronounced in the homozygous than heterozygous state. Neither the homozygous nor
the heterozygous state is associated with higher plasma homocysteine (Hcy) or a
lower plasma folate concentration-phenomena that are evident with homozygosity
for the 677(C-->T) mutation. However, there appears to be an interaction between
these two common mutations. When compared with heterozygosity for either the
677(C-->T) or 1298(A-->C) mutations, the combined heterozygosity for the 1298(A-
>C) and 677(C-->T) mutations was associated with reduced MTHFR specific activity
(ANOVA P < .0001), higher Hcy, and decreased plasma folate levels (ANOVA P <.03).
Thus, combined heterozygosity for both MTHFR mutations results in similar
features as observed in homozygotes for the 677(C-->T) mutation. This combined
heterozygosity was observed in 28% (n =86) of the NTD patients compared with 20%
(n =403) among controls, resulting in an odds ratio of 2.04 (95% confidence
interval: .9-4.7). These data suggest that the combined heterozygosity for the
two MTHFR common mutations accounts for a proportion of folate-related NTDs,
which is not explained by homozygosity for the 677(C-->T) mutation, and can be an
additional genetic risk factor for NTDs.
PMID- 9545396
TI - A susceptibility locus for bipolar affective disorder on chromosome 4q35.
AB - Bipolar affective disorder (BAD) affects approximately 1% of the population and
shows strong heritability. To identify potential BAD susceptibility loci, we
undertook a 15-cM genome screen, using 214 microsatellite markers on the 35 most
informative individuals of a large, statistically powerful pedigree. Data were
analyzed by parametric two-point linkage methods under several diagnostic models.
LOD scores >1.00 were obtained for 21 markers, with four of these >2.00 for at
least one model. The remaining 52 individuals in the family were genotyped with
these four markers, and LOD scores remained positive for three markers. A more
intensive screen was undertaken in these regions, with the most positive results
being obtained for chromosome 4q35. Using a dominant model of inheritance with
90% maximum age-specific penetrance and including bipolar I, II,
schizoaffective/mania, and unipolar individuals as affected, we obtained a
maximum two-point LOD score of 2.20 (theta = .15) at D4S1652 and a maximum three
point LOD score of 3.19 between D4S408 and D4S2924. Nonparametric analyses
further supported the presence of a locus on chromosome 4q35. A maximum score of
2.62 (P=.01) was obtained between D4S1652 and D4S171 by use of the GENEHUNTER
program, and a maximum score of 3.57 (P=.0002) was obtained at D4S2924 using the
affected pedigree member method. Analysis of a further 10 pedigrees suggests the
presence of this locus in at least one additional family, indicating a possible
predisposing locus and not a pedigree-specific mutation. Our results suggest the
presence of a novel BAD susceptibility locus on chromosome 4q35.
PMID- 9545399
TI - Mutational mechanisms for generating microsatellite allele-frequency
distributions: an analysis of 4,558 markers.
PMID- 9545397
TI - Human meiotic recombination products revealed by sequencing a hotspot for
homologous strand exchange in multiple HNPP deletion patients.
AB - The HNPP (hereditary neuropathy with liability to pressure palsies) deletion and
CMT1A (Charcot-Marie-Tooth disease type 1A) duplication are the reciprocal
products of homologous recombination events between misaligned flanking CMT1A-REP
repeats on chromosome 17p11. 2-p12. A 1.7-kb hotspot for homologous recombination
was previously identified wherein the relative risk of an exchange event is 50
times higher than in the surrounding 98.7% identical sequence shared by the CMT1A
REPs. To refine the region of exchange further, we designed a PCR strategy to
amplify the recombinant CMT1A-REP from HNPP patients as well as the proximal and
distal CMT1A-REPs from control individuals. By comparing the sequences across
recombinant CMT1A-REPs to that of the proximal and distal CMT1A-REPs, the
exchange was mapped to a 557-bp region within the previously identified 1.7-kb
hotspot in 21 of 23 unrelated HNPP deletion patients. Two patients had recombined
sequences suggesting an exchange event closer to the mariner-like element
previously identified near the hotspot. Five individuals also had interspersed
patches of proximal or distal repeat specific DNA sequence indicating potential
gene conversion during the exchange of genetic material. Our studies provide a
direct observation of human meiotic recombination products. These results are
consistent with the hypothesis that minimum efficient processing segments, which
have been characterized in Escherichia coli, yeast, and cultured mammalian cells,
may be required for efficient homologous meiotic recombination in humans.
PMID- 9545398
TI - Mutations in btk in patients with presumed X-linked agammaglobulinemia.
AB - In 1993, two groups showed that X-linked agammaglobulinemia (XLA) was due to
mutations in a tyrosine kinase now called Btk. Most laboratories have been able
to detect mutations in Btk in 80%-90% of males with presumed XLA. The remaining
patients may have mutations in Btk that are difficult to identify, or they may
have defects that are phenotypically similar to XLA but genotypically different.
We analyzed 101 families in which affected males were diagnosed as having XLA.
Mutations in Btk were identified in 38 of 40 families with more than one affected
family member and in 56 of 61 families with sporadic disease. Excluding the
patients in whom the marked decrease in B cell numbers characteristic of XLA
could not be confirmed by immunofluorescence studies, mutations in Btk were
identified in 43 of 46 patients with presumed sporadic XLA. Two of the three
remaining patients had defects in other genes required for normal B cell
development, and the third patient was unlikely to have XLA, on the basis of
results of extensive Btk analysis. Our techniques were unable to identify a
mutation in Btk in one male with both a family history and laboratory findings
suggestive of XLA. DNA samples from 41 of 49 of the mothers of males with
sporadic disease and proven mutations in Btk were positive for the mutation found
in their son. In the other 8 families, the mutation appeared to arise in the
maternal germ line. In 20 families, haplotype analysis showed that the new
mutation originated in the maternal grandfather or great-grandfather. These
studies indicate that 90%-95% of males with presumed XLA have mutations in Btk.
The other patients are likely to have defects in other genes.
PMID- 9545400
TI - Some underlooked properties of the multifactorial/threshold model.
PMID- 9545401
TI - Dual origins of Finns revealed by Y chromosome haplotype variation.
AB - The Finnish population has often been viewed as an isolate founded 2, 000 years
ago via a route across the Gulf of Finland. The founding event has been
characterized as involving a limited number of homogeneous founders, isolation,
and subsequent rapid population growth. Despite the purported isolation of the
population, levels of gene diversity for the Finns at autosomal and mitochondrial
DNA loci are indistinguishable from those of other Europeans. Thus, mixed or dual
origins for the Finns have been proposed. Here we present genetic evidence for
the dual origins of Finns by evaluating the pattern of Y chromosome variation in
280 unrelated males from nine Finnish provinces. Phylogenetic analysis of 77
haplotype configurations revealed two major star-shaped clusters of Y haplotypes,
indicative of a population expansion from two common Y haplotypes. Dramatic and
quite significant differences in Y haplotype variation were observed between
eastern and western regions of Finland, revealing contributions from different
paternal types. The geographic distribution and time of expansion for the two
common Y haplotypes correlate well with archeological evidence for two culturally
and geographically distinct groups of settlers. Also, a northeastern to
southwestern gradient of Y haplotype frequencies provides convincing evidence for
recent male migration from rural areas into urban Finland.
PMID- 9545402
TI - Linkage-disequilibrium mapping of autistic disorder, with 15q11-13 markers.
AB - Autistic disorder is a complex genetic disease. Because of previous reports of
individuals with autistic disorder with duplications of the Prader-Willi/Angelman
syndrome critical region, we screened several markers across the 15q11-13 region,
for linkage disequilibrium. One hundred forty families, consisting predominantly
of a child with autistic disorder and both parents, were studied. Genotyping was
performed by use of multiplex PCR and capillary electrophoresis. Two children
were identified who had interstitial chromosome 15 duplications and were excluded
from further linkage-disequilibrium analysis. Use of the multiallelic
transmission-disequilibrium test (MTDT), for nine loci on 15q11-13, revealed
linkage disequilibrium between autistic disorder and a marker in the gamma
aminobutyric acidA receptor subunit gene, GABRB3 155CA-2 (MTDT 28.63, 10 df,
P=.0014). No evidence was found for parent-of-origin effects on allelic
transmission. The convergence of GABRB3 as a positional and functional candidate
along with the linkage-disequilibrium data suggests the need for further
investigation of the role of GABRB3 or adjacent genes in autistic disorder.
PMID- 9545403
TI - Linkage disequilibrium analysis in a recently founded population: evaluation of
the variegate porphyria founder in South African Afrikaners.
PMID- 9545404
TI - Localization of the gene for congenital dyserythropoietic anemia type I to a <1
cM interval on chromosome 15q15.1-15.3.
AB - Congenital dyserythropoietic anemias (CDA) are a rare group of red-blood-cell
disorders of unknown etiology that are characterized by ineffective
erythropoiesis, pathognomonic cytopathology of the nucleated red blood cells in
the bone marrow, and secondary hemochromatosis. In CDA type I, bone-marrow
electron microscopy reveals characteristic findings in erythroid precursors,
including spongy heterochromatin and enlarged nuclear pores. Since the genetic
basis of CDA type I is not evident, we used homozygosity and linkage mapping to
localize the genetic defect responsible for CDA type I in 25 Bedouins from four
large consanguineous families. We report the linkage of this disease to markers
on chromosome 15 located at q15. 1-q15.3. Fourteen markers within a 12-cM
interval were typed in the relevant family members. Nine of the markers yielded
maximum LOD scores of 1.625-12.928 at a recombination fraction of .00. Linkage
disequilibrium was found only with marker D15S779. Haplotype analysis revealed
eight different carrier haplotypes and highlighted the existence of a founder
haplotype. Identification of historical crossover events further narrowed the
gene location to between D15S779 and D15S778. The data suggest localization of
the CDA type I gene within a 0.5-cM interval. The founder mutation probably
occurred >/= 400 years ago. Sequence analysis of the coding region of protein
4.2, the only known erythroid-specific gene in the locus, did not reveal any
change in the CDA type I patients. Future analysis of this locus may lead to the
identification of a gene essential to normal erythropoiesis.
PMID- 9545406
TI - Worldwide distribution of a common methylenetetrahydrofolate reductase mutation.
PMID- 9545405
TI - Renpenning syndrome maps to Xp11.
AB - Mutations in genes on the X chromosome are believed to be responsible for the
excess of males among individuals with mental retardation. Such genes are
numerous, certainly >100, and cause both syndromal and nonsyndromal types of
mental retardation. Clinical and molecular studies have been conducted on the
Mennonite family with X-linked mental retardation (XLMR) reported, in 1962, by
Renpenning et al. The clinical phenotype includes severe mental retardation,
microcephaly, up-slanting palpebral fissures, small testes, and stature shorter
than that of nonaffected males. Major malformations, neuromuscular abnormalities,
and behavioral disturbances were not seen. Longevity is not impaired. Carrier
females do not show heterozygote manifestations. The syndrome maps to Xp11.2
p11.4, with a maximum LOD score of 3.21 (recombination fraction 0) for markers
between DXS1039 and DXS1068. Renpenning syndrome (also known as "MRXS8"; gene
RENS1, MIM 309500) shares phenotypic manifestations with several other XLMR
syndromes, notably the Sutherland-Haan syndrome. In none of these entities has
the responsible gene been isolated; hence, the possibility that two or more of
them may be allelic cannot be excluded at present.
PMID- 9545407
TI - The Bjornstad syndrome (sensorineural hearing loss and pili torti) disease gene
maps to chromosome 2q34-36.
AB - We report that the Bjornstad syndrome gene maps to chromosome 2q34-36. The
clinical association of sensorineural hearing loss with pili torti (broken,
twisted hairs) was described >30 years ago by Bjornstad; subsequently, several
small families have been studied. We evaluated a large kindred with Bjornstad
syndrome in which eight members inherited pili torti and prelingual sensorineural
hearing loss as autosomal recessive traits. A genomewide search using polymorphic
loci demonstrated linkage between the disease gene segregating in this kindred
and D2S434 (maximum two-point LOD score = 4.98 at theta = 0). Haplotype analysis
of recombination events located the disease gene in a 3-cM region between loci
D2S1371 and D2S163. We speculate that intermediate filament and intermediate
filament-associated proteins are good candidate genes for causing Bjornstad
syndrome.
PMID- 9545409
TI - A gene for autosomal dominant hypohidrotic ectodermal dysplasia (EDA3) maps to
chromosome 2q11-q13.
AB - Autosomal dominant hypohidrotic ectodermal dysplasia (ADHED) is a disorder
characterized by fine, slow-growing scalp and body hair, sparse eyebrows and
eyelashes, decreased sweating, hypodontia, and nail anomalies. By genetic linkage
analysis of a large ADHED kindred, we have mapped a gene for ADHED (EDA3) to the
proximal long arm of chromosome 2 (q11-q13). Obligate recombinations localize
EDA3 to an approximately 9-cM interval between D2S1321 and D2S308, with no
apparent recombinations with markers D2S1343, D2S436, D2S293, D2S1894, D2S1784,
D2S1890, D2S274, and CHLC.GAAT11C03.
PMID- 9545408
TI - mtDNA analysis of a prehistoric Oneota population: implications for the peopling
of the New World.
AB - mtDNA was successfully extracted from 108 individuals from the Norris Farms
Oneota, a prehistoric Native American population, to compare the mtDNA diversity
from a pre-Columbian population with contemporary Native American and Asian mtDNA
lineages and to examine hypotheses about the peopling of the New World.
Haplogroup and hypervariable region I sequence data indicate that the lineages
from haplogroups A, B, C, and D are the most common among Native Americans but
that they were not the only lineages brought into the New World from Asia. The
mtDNA evidence does not support the three-wave hypothesis of migration into the
New World but rather suggests a single "wave" of people with considerable mtDNA
diversity that exhibits a signature of expansion 23,000-37,000 years ago.
PMID- 9545411
TI - Mapping of a congenital microcoria locus to 13q31-q32.
AB - Congenital microcoria is an autosomal dominant disorder characterized by a pupil
with a diameter <2 mm. It is thought to be due to a maldevelopment of the dilator
pupillae muscle of the iris, and it is associated with juvenile-onset glaucoma. A
total genome search for the location of the congenital microcoria gene was
launched in a single large family. We found linkage between the disease and
markers located on 13q31-q32 (Zmax = 9.79; theta = 0). Haplotype analysis
narrowed the linked region to an interval <8 cM between markers D13S1239
proximally and D13S1280 distally.
PMID- 9545410
TI - A gene for familial juvenile polyposis maps to chromosome 18q21.1.
AB - Familial juvenile polyposis (FJP) is a hamartomatouspolyposis syndrome in which
affected family members develop upper and lower gastrointestinal juvenile polyps
and are at increased risk for gastrointestinal cancer. A genetic locus for FJP
has not yet been identified by linkage; therefore, the objective of this study
was to perform a focused genome screen in a large family segregating FJP. No
evidence for linkage was found with markers near MSH2, MLH1, MCC, APC, HMPS,
CDKN2A, JP1, PTEN, KRAS2, TP53, or LKB1. Linkage to FJP was established with
several markers from chromosome 18q21.1. The maximum LOD score was 5.00, with
marker D18S1099 (recombination fraction of .001). Analysis of critical
recombinants places the FJP gene in an 11.9-cM interval bounded by D18S1118 and
D18S487, a region that also contains the tumor-suppressor genes DCC and DPC4.
These data demonstrate localization of a gene for FJP to chromosome 18q21.1 by
linkage, and they raise the possibility that either DCC or DPC4 could be
responsible for FJP.
PMID- 9545412
TI - Diversity of cystic fibrosis mutation-screening practices.
PMID- 9545413
TI - A locus for autosomal recessive congenital microphthalmia maps to chromosome
14q32.
AB - Congenital microphthalmia (CMIC) (OMIM 309700) may occur in isolation or in
association with a variety of systemic malformations. Isolated CMIC may be
inherited as an autosomal dominant, an autosomal recessive, or an X-linked trait.
On the basis of a whole-genome linkage analysis, we have mapped the first locus
for isolated CMIC, in a five-generation consanguineous family with autosomal
recessive inheritance, to chromosome 14q32. All affected individuals in this
family have bilateral CMIC. Linkage analysis gave a maximum two-point LOD score
of 3.55 for the marker D14S65. Surrounding this marker is a region of
homozygosity of 7.3 cM, between the markers D14S987 and D14S267, within which the
disease gene is predicted to lie. The genes for several eye-specific
transcription factors are located on human chromosome 14q and in the syntenic
region of mouse chromosome 12. However, both CHX10 (14q24.3), mutations of which
give rise to CMIC in mouse models, and OTX2 (14q21-22) can be excluded as
candidates for autosomal recessive congenital microphthalmia (arCMIC), since they
map outside the critical disease region defined by recombination events. This
suggests that arCMIC is caused by defects in a novel developmental gene that may
be important or even essential in eye development.
PMID- 9545414
TI - Multipoint quantitative-trait linkage analysis in general pedigrees.
AB - Multipoint linkage analysis of quantitative-trait loci (QTLs) has previously been
restricted to sibships and small pedigrees. In this article, we show how variance
component linkage methods can be used in pedigrees of arbitrary size and
complexity, and we develop a general framework for multipoint identity-by-descent
(IBD) probability calculations. We extend the sib-pair multipoint mapping
approach of Fulker et al. to general relative pairs. This multipoint IBD method
uses the proportion of alleles shared identical by descent at genotyped loci to
estimate IBD sharing at arbitrary points along a chromosome for each relative
pair. We have derived correlations in IBD sharing as a function of chromosomal
distance for relative pairs in general pedigrees and provide a simple framework
whereby these correlations can be easily obtained for any relative pair related
by a single line of descent or by multiple independent lines of descent. Once
calculated, the multipoint relative-pair IBDs can be utilized in variance
component linkage analysis, which considers the likelihood of the entire pedigree
jointly. Examples are given that use simulated data, demonstrating both the
accuracy of QTL localization and the increase in power provided by multipoint
analysis with 5-, 10-, and 20-cM marker maps. The general pedigree variance
component and IBD estimation methods have been implemented in the SOLAR
(Sequential Oligogenic Linkage Analysis Routines) computer package.
PMID- 9545415
TI - Replicative senescence in the immune system: impact of the Hayflick limit on T
cell function in the elderly.
PMID- 9545416
TI - ACMG/ASHG statement. Laboratory guidelines for Huntington disease genetic
testing. The American College of Medical Genetics/American Society of Human
Genetics Huntington Disease Genetic Testing Working Group.
PMID- 9545417
TI - Molecular classification of the inherited hamartoma polyposis syndromes: clearing
the muddied waters.
PMID- 9545418
TI - The genetics of cellular senescence.
PMID- 9545420
TI - Pharmaceutical biotechnology.
PMID- 9545421
TI - Cytoskeleton.
PMID- 9545419
TI - Causes, effects, and constraints in the genetics of human longevity.
PMID- 9545422
TI - Cytoskeleton.
PMID- 9545423
TI - Solution structure of a synthetic lytic peptide: the perforin amino terminus.
AB - BACKGROUND: Killer lymphocytes secrete perforin, a 67 kDa protein that initiates
T-cell cytolysis following aggregation and pore formation in target membranes.
The resulting pores cause a breakdown of the transmembrane osmotic gradient and
allow other cytolytic mediators to enter the target cell and initiate apoptosis.
The cytolytic domain resides within the first 34 residues of the amino terminus
of perforin, with residues 1-19 being sufficient for cytolytic activity. RESULTS:
The solution structure of a 22-residue synthetic peptide (P22), corresponding to
the amino terminus of human perforin, has been determined using high resolution
nuclear magnetic resonance spectroscopy in the presence and absence of
perdeuterated detergent (SDS) micelles. In aqueous solution, P22 exists mainly in
a random conformation. However, it adopts a hook-like structure at the carboxyl
terminus in the presence of SDS micelles when the positively charged residues
cluster to form a turn that provides a binding surface to the negatively charged
sulfate headgroups. CONCLUSIONS: The strong electrostatic interaction between the
cationic region of the P22 peptide and the lipid headgroups probably weakens the
membrane, facilitating insertion of the relatively neutral/hydrophobic stretch of
P22, and is representative of the initial step of the lytic pathway. The
structural model described here is probably relevant to understanding the
mechanisms of other cationic antimicrobial peptides.
PMID- 9545424
TI - Heterologously expressed acyl carrier protein domain of rat fatty acid synthase
functions in Escherichia coli fatty acid synthase and Streptomyces coelicolor
polyketide synthase systems.
AB - INTRODUCTION: Fatty acid synthases (FASs) catalyze the de novo biosynthesis of
long-chain saturated fatty acids by a process common to eubacteria and
eukaryotes, using either a set of monofunctional proteins (Type II FAS) or a
polypeptide containing several catalytic functions (Type I FAS). To compare the
features of a Type I domain with its Type II counterpart we expressed and
characterized an acyl carrier protein (ACP) domain of the Type I rat FAS.
RESULTS: An ACP domain of rat FAS was defined that allows expression of a small
percentage of active holo-ACP both in Escherichia coli, increasing fivefold upon
co-expression with an E. coli holo-ACP synthase, and in Streptomyces coelicolor.
The rat ACP domain functions with some components of the E. coli FAS, and can
replace the actinorhodin polyketide synthase (PKS) ACP in S. coelicolorA3(2).
Purification of the rat ACP domain from E. coli resulted in loss of its
functionality. Purified apo-ACP could be converted to its holo-form upon
incubation with purified E. coli holo-ACP synthase in vitro, however, suggesting
that the loss of functionality was not due to a conformational change.
CONCLUSIONS: Functionality of the recombinant rat ACP was shown in distantly
related and diverse enzyme systems, suggesting that Type I and Type II ACPs have
a similar conformation. A procedure was described that might permit the
production of rat FAS holo-ACP for structural and further biochemical
characterization.
PMID- 9545425
TI - Visualizing metal-ion-binding sites in group I introns by iron(II)-mediated
Fenton reactions.
AB - BACKGROUND: Most catalytic RNAs depend on divalent metal ions for folding and
catalysis. A thorough structure-function analysis of catalytic RNA therefore
requires the identification of the metal-ion-binding sites. Here, we probed the
binding sites using Fenton chemistry, which makes use of the ability of Fe2+ to
functionally or structurally replace Mg2+ at ion-binding sites and to generate
short-lived and highly reactive hydroxyl radicals that can cleave nucleic acid
and protein backbones in spatial proximity of these ion-binding sites. RESULTS:
Incubation of group I intron RNA with Fe2+, sodium ascorbate and hydrogen
peroxide yields distinctly cleaved regions that occur only in the correctly
folded RNA in the presence of Mg2+ and can be competed by additional Mg2+,
suggesting that Fe2+ and Mg2+ interact with the same sites. Cleaved regions in
the catalytic core are conserved for three different group I introns, and there
is good correlation between metal-ion-binding sites determined using our method
and those determined using other techniques. In a model of the T4 phage-derived
td intron, cleaved regions separated in the secondary structure come together in
three-dimensional space to form several metal-ion-binding pockets. CONCLUSIONS:
In contrast to structural probing with Fe2+/EDTA, cleavage with Fe2+ detects
metal-ion-binding sites located primarily in the inside of the RNA. Essentially
all metal-ion-binding pockets detected are formed by tertiary structure elements.
Using this method, we confirmed proposed metal-ion-binding sites and identified
new ones in group I intron RNAs. This approach should allow the localization of
metal-ion-binding sites in RNAs of interest.
PMID- 9545426
TI - Sequencing and analysis of genes involved in the biosynthesis of a vancomycin
group antibiotic.
AB - BACKGROUND: The emergence of resistance to vancomycin, the drug of choice against
methicillin-resistant Staphylococcus aureus, in enterococci has increased the
need for new antibiotics. As chemical modification of the antibiotic structure is
not trivial, we have initiated studies towards enzymatic modification by
sequencing the DNA coding for the biosynthesis of chloroeremomycin (also known as
A82846B and LY264826). RESULTS: Analysis of 72 kilobases of genomic DNA from
Amycolatopsis orientalis, the organism that produces chloroeremomycin, revealed
the presence of 39 putative genes, including those coding for the biosynthesis of
the antibiotic. Translation and subsequent comparison with known proteins in
public databases identified enzymes responsible for the biosynthesis of the
heptapeptide backbone and 4-epi-vancosamine, as well as those for chlorination
and oxidation reactions involved in the biosynthesis of chloroeremomycin.
CONCLUSIONS: The genes responsible for the biosynthesis of chloroeremomycin have
been identified, and selective expression of these genes could lead to the
synthesis of new potent glycopeptide antibiotics.
PMID- 9545427
TI - Transforming the cell surface through proteolysis.
AB - Protein shedding, or the proteolytic cleavage of a protein from the surface of a
cell, is emerging as an important mechanism in the regulation of cellular
activity but it is poorly understood. Growing evidence suggesting that protein
shedding and protein function are closely linked may lead to new strategies for
the treatment of a wide range of diseases.
PMID- 9545428
TI - Self-assembly and steric stabilization at heterogeneous, biological surfaces
using adsorbing block copolymers.
AB - BACKGROUND: We present the synthesis, characterization and initial structure
function analysis of a new class of bioactive agent that allows the application
of techniques from colloid science to biological surfaces. Stable colloidal
suspensions can be generated by immobilizing a dense brush of soluble polymer at
the colloidal surface, creating a zone protected against the adhesion of
approaching particles, a phenomenon termed polymeric steric stabilization. This
is often accomplished for aqueous colloidal dispersions using adsorbing block
copolymers. We demonstrate that water-soluble block copolymers can be designed to
adsorb onto heterogeneous biological surfaces and block cell-cell and cell
surface adhesion, using polymer compositions and architectures that are quite
different from surfactants used for stabilizing nonbiological colloidal
dispersions. RESULTS: Comb copolymers were synthesized having polycationic
backbones (poly-L-lysine, PLL), serving as the anchor for binding to the net
negatively charged biological surfaces, grafted with water-soluble polynonionic
chains (polyethylene glycol, PEG), to block biological recognition, producing PLL
graft-PEG copolymers. Specific copolymers were found to sterically stabilize red
blood cells from lectin-induced hemagglutination and fibroblasts from adhesion to
fibronectin-coated surfaces. The polymer design principles, which appear to be
unique for adsorption to heterogeneous biological surfaces, require the use of
very high molecular weight comb copolymers, perhaps because anionic sites are non
uniformly distributed on biological surfaces, and the ability of larger
copolymers to span between highly anionic sites. CONCLUSIONS: Water-soluble
copolymers were produced that can block recognition at biological surfaces, on
the basis of nonspecific physicochemical phenomena rather than specific
biochemical interactions.
PMID- 9545429
TI - Inhibition of major-groove-binding proteins by pyrrole-imidazole polyamides with
an Arg-Pro-Arg positive patch.
AB - BACKGROUND: Gene-specific targeting of any protein-DNA complex by small molecules
is a challenging goal at the interface of chemistry and biology. Polyamides
containing N-methylimidazole and N-methylpyrrole amino acids are synthetic
ligands that have an affinity and specificity for DNA comparable to many
naturally occurring DNA-binding proteins. It has been shown that an eight-ring
hairpin polyamide targeted to a specific minor-groove contact within a
transcription factor binding site can inhibit protein-DNA binding and gene
transcription. Polyamides and certain major-groove-binding proteins have been
found to co-occupy the DNA helix, however. To expand the number of genes that can
be targeted by pyrrole/imidazole polyamides, we set out to develop a class of
polyamides that can selectively inhibit major-groove-binding proteins. RESULTS:
An eight-ring hairpin polyamide conjugated to a carboxy-terminal Arg-Pro-Arg
tripeptide was designed to deliver a positive residue to the DNA backbone and
interfere with protein-phosphate contacts. Gel mobility shift analysis
demonstrated that a polyamide hairpin-Arg-Pro-Arg binding in the minor groove
selectively inhibits binding of the transcription factor GCN4 (222-281) in the
adjacent major groove. Substitution within the Arg-Pro-Arg revealed that each
residue was required for optimal GCN4 inhibition. CONCLUSIONS: A pyrrole
imidazole polyamide that binds to a predetermined site in the DNA minor groove
and delivers a positive patch to the DNA backbone can selectively inhibit a DNA
binding protein that recognizes the adjacent major groove. A subtle alteration of
the DNA microenvironment targeted to a precise location within a specific DNA
sequence could achieve both gene-specific and protein-specific targeting.
PMID- 9545430
TI - Rainforest remedies Shaman Pharmaceuticals, Inc
PMID- 9545431
TI - Active-site mutants of the VanC2 D-alanyl-D-serine ligase, characteristic of one
vancomycin-resistant bacterial phenotype, revert towards wild-type D-alanyl-D
alanine ligases.
AB - BACKGROUND: The rising number of vancomycin-resistant enterococci (VREs) is a
major concern to modern medicine because vancomycin is currently the 'last
resort' drug for life-threatening infections. The D-alanyl-D-X ligases (where X
is an hydroxy or amino acid) of bacteria catalyze a critical step in bacterial
cell-wall peptidoglycan assembly. In bacteria that produce glycopeptide
antibiotics and in opportunistic pathogens, including VREs, D-, D-ligases serve
as switches that confer antibiotic resistance on the bacteria themselves.
Peptidoglycans in vancomycin-sensitive bacteria end in D-alanyl-D-alanine,
whereas in vancomycin-resistant bacteria they end in D-alanyl-D-lactate or D
alanyl-D-serine. RESULTS: We demonstrate that the selective utilization of D
serine by the Enterococcus casseliflavus VanC2 ligase can be altered by
mutagenesis of one of two residues identified by homology to the X-ray structure
of the Escherichia coli D-alanyl-Dalanine ligase (DdlB). The Arg322-->Met (R322M)
and Phe250-->Tyr (F250Y) ligase mutants show a 36-44-fold decrease in the use of
D-serine, as well as broadened specificity for utilization of other D-amino acids
in place of D-serine. The F250Y R322M double mutant is effectively disabled as a
D-alanyl-D-serine ligase and retains 10% of the catalytic activity of wild-type D
alanyl-D-alanine ligases, reflecting a 6,000-fold switch to the D-alanyl-D
alanine peptide. Correspondingly, the Leu282-->Arg mutant of the wild-type E.
coli DdlB produced a 560-fold switch towards D-alanyl-D-serine formation.
CONCLUSIONS: Single-residue changes in the active-site regions of D-, D-ligases
can cause substantial changes in recognition and activation of hydroxy or amino
acids that have consequences for glycopeptide antibiotic efficacy. The
observations reported here should provide an approach for combatting antibiotic
resistant bacteria.
PMID- 9545433
TI - Analysis of the conversion of delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D-alpha
aminobutyrate by active-site mutants of Aspergillus nidulans isopenicillin N
synthase.
AB - BACKGROUND: Penicillins and cephalosporins constitute a major class of clinically
useful antibiotics. A key step in their biosynthesis involves the oxidative
cyclisation of delta-(Lalpha-aminoadipoyl)-L-cysteinyl-D-valine to isopenicillin
N by isopenicillin N synthase (IPNS). This chemically remarkable transformation
has been extensively studied using substrate analogues. The conversion of an
analogue in which the valine is replaced by alpha-aminobutyrate results in three
products, two epimeric penams and a cepham. The ratio of these products in
reactions catalysed by four different IPNS isozymes has been used previously to
probe the thermicity of the chemical mechanism. But how IPNS restricts the
products from the natural substrate to a single penam (isopenicillin N) has
remained unknown. RESULTS: A key active-site residue, Leu223, identified
according to a model of enzyme-substrate binding, has been altered to sterically
less demanding residues. As the steric constraints on the upper part of the
active site are reduced, the ratio of the beta-methyl penam to the cepham
increases when the alpha-aminobutyrate-containing substrate analogue is used.
These results suggest a mechanism for processing of the natural substrate in
which IPNS uses steric control to restrict the conformational freedom of an
intermediate such that the only product is the penam. CONCLUSIONS: Using steric
pressure to control conformation, and hence to disfavour reactions leading to
alternate products, is probably the result of evolutionary selection for a
biologically active product at the expense of biologically inactive byproducts.
It is likely that this sort of enzymatic catalysis is used in situations where
substrate conversion is highly exothermic and a variety of products are possible.
PMID- 9545432
TI - Antibiotic sensitization using biphenyl tetrazoles as potent inhibitors of
Bacteroides fragilis metallo-beta-lactamase.
AB - BACKGROUND: High level resistance to carbapenem antibiotics in gram negative
bacteria such as Bacteroides fragilis is caused, in part, by expression of a wide
spectrum metallo-beta-lactamase that hydrolyzes the drug to an inactive form. Co
administration of metallo-beta-lactamase inhibitors to resistant bacteria is
expected to restore the antibacterial activity of carbapenems. RESULTS: Biphenyl
tetrazoles (BPTs) are a structural class of potent competitive inhibitors of
metallo-beta-lactamase identified through screening and predicted using molecular
modeling of the enzyme structure. The X-ray crystal structure of the enzyme bound
to the BPT L-159,061 shows that the tetrazole moiety of the inhibitor interacts
directly with one of the two zinc atoms in the active site, replacing a metal
bound water molecule. Inhibition of metallo-beta-lactamase by BPTs in vitro
correlates well with antibiotic sensitization of resistant B. fragilis.
CONCLUSIONS: BPT inhibitors can sensitize a resistant B. fragilis clinical
isolate expressing metallo-beta-lactamase to the antibiotics imipenem or
penicillin G but not to rifampicin.
PMID- 9545434
TI - Bicyclo[3.2.1]-DNA, a new DNA analog with a rigid backbone and flexibly linked
bases: pairing properties with complementary DNA.
AB - BACKGROUND: The structural and conformational variety in nucleic acid complexes
is largely controlled by the sugar-phosphate backbone. In order to modulate
specific features such as strength or selectivity of complex formation by
designing nucleotide analogs, a deeper understanding of the relationship between
mononucleotide structures and the properties of their oligomers is necessary. One
approach involves comparing the properties of DNA analogs displaying well defined
modifications in their backbone structure with those of natural DNA and RNA.
RESULTS: We have designed and synthesized a new DNA analog, 'bicyclo[3.2.1]-DNA',
which has a rigid phosphodiester backbone that emulates a B-DNA-type
conformation, to which the nucleobases are attached via a flexible open-chain
linker. A UV-melting curve analysis shows that bicyclo[3.2.1]-DNA forms stable
duplexes with complementary DNA, although generally with lower Tm values than
pure DNA duplexes. Duplex formation is strictly constrained to antiparallel
complementary sequences, and base-mismatch discrimination is slightly enhanced
compared to pure DNA duplexes. In addition, bicyclo[3.2.1]-DNA sequences are
resistant to a 3'-exonuclease. CONCLUSIONS: The furanose unit present in natural
nucleosides is not necessary for a competent and stable phosphodiester-based
pairing system, provided that the backbone is conformationally constrained. The
information for the preference of antiparallel strand association in B-DNA is not
merely a consequence of bases being attached to a specific side of the furanose
unit, but is also encoded in the backbone itself. Furthermore, conformational
flexibility in the base-pairing region does not lead to a loss of selectivity in
base-pair formation.
PMID- 9545436
TI - Atopic allergy and other hypersensitivities.
PMID- 9545435
TI - Role of the microcin B17 propeptide in substrate recognition: solution structure
and mutational analysis of McbA1-26.
AB - BACKGROUND: The peptide antibiotic microcin B17 (MccB17) contains oxazole and
thiazole heterocycles formed by the post-translational modification of four
cysteine and four serine residues. An amino-terminal propeptide targets the 69
amino acid precursor of MccB17 (preproMccB17) to the heterocyclization enzyme
MccB17 synthetase. The mode of synthetase recognition has been unclear, because
there has been limited structural information available on the MccB17 propeptide
to date. RESULTS: The solution structure of the MccB17 propeptide (McbA1-26),
determined using nuclear magnetic resonance, reveals that McbA1-26 is an
amphipathic alpha helix. Mutational analysis of 13 propeptide residues showed
that Phe8 and Leu12 are essential residues for MccB17 synthetase recognition. A
domain of the propeptide was putatively identified as the region that interacts
with the synthetase. CONCLUSIONS: MccB17 synthetase recognizes key hydrophobic
residues within a helical propeptide, allowing the selective heterocyclization of
downstream cysteine and serine residues in preproMccB17. The determination of the
solution structure of the propeptide should facilitate the investigation of other
functions of the propeptide, including a potential role in antibiotic secretion.
PMID- 9545437
TI - RB and apoptotic cell death.
AB - Homeostasis of cell numbers is achieved by balancing the proliferative and death
states of cells. Proper regulation in a cell requires an accurate coordination
between these two processes. Indeed, dysregulation of cell cycle progression is
essential for the initiation of apoptosis. Retinoblastoma protein (RB) is an
important tumor suppressor and a cell cycle regulator. Most recent studies
suggest that RB also plays a regulatory role in the process of apoptosis. During
the onset of apoptosis, the hyperphosphorylated form of RB (p120/hyper) is
converted to a hypophosphorylated form (p115/hypo), which is mediated by a
specific protein-serine/ threonine phosphatase activity. Accompanied by the
internucleosomal fragmentation of DNA, the newly formed p115/hypo/RB is
immediately cleaved by a protease that has properties of the caspase family.
During apoptosis, RB is also cleaved in its carboxyl terminus by a caspase-3-like
activity. By contrast, the unphosphorylated form of RB (p110/unphos) remains
uncleaved during apoptosis. Further studies suggest that p110/unphos/RB functions
as an inhibitor of apoptosis. Therefore, regulation of the RB proteolytic
activities and consequent RB levels is important for the determination of
cellular fate.
PMID- 9545438
TI - The essential role of inflammation and induced gene expression in the pathogenic
pathway of Alzheimer's disease.
AB - Alzheimer's disease is among the most common diseases of advanced age affecting
almost one out of ten individuals who survive beyond the age of 65 years, and an
another 10% for each additional decade of the life-span. The prognosis of the
disease is an inexorable decline of mental functions leading to complete
dependence on caretakers in the late stages of the disease. Alzheimer's disease
will become a steadily increasing financial health-care problem in the
industrialized world with the increasing longevity and ageing of the population.
To-date there are no effective therapeutics. However, during the last years
promising findings suggest that anti-inflammatory treatment strategies might be
efficient. Here, we will review the experimental and epidemiological findings
which support the idea that inflammatory mechanisms play an important role in
Alzheimer's disease pathogenesis. The review of the experimental findings will be
focussed on the amyloid-associated proteins, alpha1-antichymotrypsin and
apolipoprotein E, as well as the major cytokines. In addition, the
epidemiological studies on non-steroidal anti-inflammatory drugs and traumatic
head injury will be summarized. We hypothesize a pathogenic model for Alzheimer's
disease in which the expression of amyloid-associated proteins/pathological
chaperones, induced by inflammatory cytokines, plays an essential role in
accelerating the disease progress, and suggest potential targets for drug
discovery based on such a model.
PMID- 9545439
TI - The neuro-immunological interface in an evolutionary perspective: the dynamic
relationship between effector and recognition systems.
AB - The evolutionary perspective indicates that an immune-neuroendocrine effector
system integrating innate immunity, stress and inflammation is present in
invertebrates. This defense network, centered on the macrophage and exerting
primitive and highly promiscuous recognition units, is very effective, ancestral
and appears to have been conserved throughout evolution from invertebrates to
higher vertebrates. It would seem that there was a "big bang" in the recognition
system of lower vertebrates, and T and B cell repertoires, MHC and antibodies
suddenly appeared. We argue that this phenomenon is the counterpart of the
increasing complexity of the internal circuitry and recognition units in the
effector system. The immediate consequences were a progressive enlargement of the
pathogen repertoire and new problems regarding self/not-self discrimination.
Probably not by chance, a new organ appeared, capable of purging cells able of
excessive self recognition. This organ, the thymus, appears to be the result of a
well known evolutionary strategy of re-using pre-existing material
(neuroendocrine cells and mediators constituting the thymic microenvironment).
This bricolage at an organ level is similar to the effect we have already
described at the level of molecules and functions of the defense network, and has
a general counterpart at genetic level. Thus, in vertebrates, the conserved
immune-neuroendocrine effector system remains of fundamental importance in
defense against pathogens, while its efficiency has increased through synergy
with the new, clonotipical recognition repertoire.
PMID- 9545440
TI - In search of an animal model for postmenopausal diseases.
AB - The purpose of this review is to discuss the use of the aged ovariectomized ewe
as a cost-effective large animal model to study coronary artery disease (CAD),
osteoporosis, osteoarthritis (OA), and oral bone loss--conditions seen after
menopause. Earlier studies from our laboratory showed a significant decline in
the bone mineral density (BMD) of the iliac crest following ovariectomy in sheep,
while subsequent studies demonstrated decreased bone loss (measured by dual
energy X-ray absorptiometry (DXA)) in the lumbar vertebrae following ovariectomy.
We examined the effects of estrogen deficiency and estrogen therapy on the
terminal aorta of the aged ovariectomized (OVX) ewes and demonstrated subintimal
thickening in the distal aorta of animals that were estrogen deficient when
compared to the control groups. A popular model to study OA is the knee joint of
sheep following medial or lateral meniscus removal combined with exercise, but
there is a need for an estrogen-deficient large animal model of OA to study
articular cartilage changes occurring after menopause. We saw an effect of
ovariectomy on the biomechanical properties (aggregate modulus and shear modulus)
of articular cartilage. Estrogen deficiency had a detrimental effect on the
articular cartilage of the knee even though the cartilage of the OVX animals
appeared grossly normal. In another study, 13.5 months following ovariectomy, we
found an increase in estrogen receptor binding capacity of the articular
cartilage suggesting that articular cartilage is a sex-hormone sensitive tissue.
There is intense interest in the correlation between systemic osteoporosis and
bone loss of the mandible and maxilla. We studied mandibular bone loss in OVX
sheep using DXA. The mean BMD of the OVX group versus sham and estradiol-treated
animals was lower, indicating that systemic bone loss in OVX ewes may be
accompanied by oral bone loss. Coronary artery disease, osteoporosis,
osteoarthritis (OA) and oral bone loss all have a major impact on women's heath
after menopause and we found that certain characteristics of these conditions can
be reproduced in the skeletally mature or aged estrogen-deficient sheep. It is
premature to promote the sheep as the only model to study estrogen deficiency and
the many differences from small animal omnivores and non-human primates need to
be overcome and a search for more economical models must continue. This model,
however, may offer the opportunity to study postmenopausal conditions and the
safety and efficacy of new therapeutic agents.
PMID- 9545441
TI - Mapper: an intelligent restriction mapping tool.
AB - MOTIVATION: To determine the most powerful artificial intelligence techniques for
automated restriction mapping, and use them to create a powerful multiple-enzyme
restriction mapping tool. RESULTS: The most effective search engine utilized
model-driven exhaustive search and a form of binary logic pruning based on
Pratt's separation theory. Additional experimentation led to the development of
an input preprocessing module which significantly speeds up searches, and an
output post-processing module which enables users to analyze large solution sets
and reduce their apparent complexity. AVAILABILITY: An executable version of the
resultant tool, Mapper, can be downloaded from our Web site
(http://www.ai.eecs.uic.edu) by selecting the 'Software' option. CONTACT:
nelson@eecs.uic.edu (http://www.ai.eecs.uic.edu/nelson).
PMID- 9545442
TI - Design and implementation of a CORBA-based genome mapping system prototype.
AB - MOTIVATION: CORBA (Common Object Request Broker Architecture), as an open
standard, is considered to be a good solution for the development and deployment
of applications in distributed heterogeneous environments. This technology can be
applied in the bioinformatics area to enhance utilization, management and
interoperation between biological resources. RESULTS: This paper investigates
issues in developing CORBA applications for genome mapping information systems in
the Internet environment with emphasis on database connectivity and graphical
user interfaces. The design and implementation of a CORBA prototype for an animal
genome mapping database are described. AVAILABILITY: The prototype demonstration
is available via: http://www.ri.bbsrc.ac.uk/ark_corba/. CONTACT:
jian.hu@bbsrc.ac.uk
PMID- 9545443
TI - Prediction of MHC class II-binding peptides using an evolutionary algorithm and
artificial neural network.
AB - MOTIVATION: Prediction methods for identifying binding peptides could minimize
the number of peptides required to be synthesized and assayed, and thereby
facilitate the identification of potential T-cell epitopes. We developed a
bioinformatic method for the prediction of peptide binding to MHC class II
molecules. RESULTS: Experimental binding data and expert knowledge of anchor
positions and binding motifs were combined with an evolutionary algorithm (EA)
and an artificial neural network (ANN): binding data extraction --> peptide
alignment --> ANN training and classification . This method, termed PERUN, was
implemented for the prediction of peptides that bind to HLA-DR4(B1*0401). The
respective positive predictive values of PERUN predictions of high-, moderate-,
low- and zero-affinity binders were assessed as 0.8, 0.7, 0.5 and 0.8 by cross
validation, and 1.0, 0.8, 0.3 and 0.7 by experimental binding. This illustrates
the synergy between experimentation and computer modeling, and its application to
the identification of potential immunotherapeutic peptides. AVAILABILITY:
Software and data are available from the authors upon request. CONTACT:
vladimir@wehi.edu. au
PMID- 9545444
TI - Analysis of DNA curvature using artificial neural networks.
AB - MOTIVATION: Our aim is to utilize an artificial neural network (ANN) for the
prediction of DNA curvature in terms of retardation anomaly. RESULTS: An ANN
capturing the role of phasing, increased helix flexibility, run of poly(A) tracts
and flanking base pair effects in determining the extent of DNA curvature has
been developed. The network predictions validate the known experimental results
and also explain how the base pairs other than ApA affect the curvature. The
results suggest that ANN can be used as a model-free tool for studying DNA
curvature. AVAILABILITY: The optimal weights and the procedure to compute the
retardation anomaly value are available on request from the authors. CONTACT:
bdk@ems. ncl.res.in
PMID- 9545445
TI - Feature selection for genetic sequence classification.
AB - MOTIVATION: Most of the existing methods for genetic sequence classification are
based on a computer search for homologies in nucleotide or amino acid sequences.
The standard sequence alignment programs scale very poorly as the number of
sequences increases or the degree of sequence identity is <30%. Some new
computationally inexpensive methods based on nucleotide or amino acid
compositional analysis have been proposed, but prediction results are still
unsatisfactory and depend on the features chosen to represent the sequences.
RESULTS: In this paper, a feature selection method based on the Gamma (or near
neighbour) test is proposed. If there is a continuous or smooth map from feature
space to the classification target values, the Gamma test gives an estimate for
the mean-squared error of the classification, despite the fact that one has no a
priori knowledge of the smooth mapping. We can search a large space of possible
feature combinations for a combination which gives a smallest estimated mean
squared error using a genetic algorithm. The method was used for feature
selection and classification of the large subunits of rRNA according to RDP
(Ribosomal Database Project) phylogenetic classes. The sequences were represented
by dinucleotide frequency distribution. The nearest-neighbour criterion has been
used to estimate the predictive accuracy of the classification based on the
selected features. For examples discussed, we found that the classification
according to the first nearest neighbour is correct for 80% of the test samples.
If we consider the set of the 10 nearest neighbours, then 94% of the test samples
are classified correctly. AVAILABILITY: The principal novel component of this
method is the Gamma test and this can be downloaded compiled for Unix Sun 4,
Windows 95 and MS-DOS from http://www.cs.cf.ac.uk/ec/ CONTACT:
s.margetts@cs.cf.ac.uk
PMID- 9545446
TI - DIVCLUS: an automatic method in the GEANFAMMER package that finds homologous
domains in single- and multi-domain proteins.
AB - MOTIVATION: Large-scale determination of relationships between the proteins
produced by genome sequences is now common. All protein sequences are matched and
those that have high match scores are clustered into families. In cases where the
proteins are built of several domains or duplication modules, this can lead to
misleading results. Consider the very simple example of three proteins: 1, formed
by duplication modules A and B; 2, formed by duplication modules B' and C; and 3,
formed by duplication modules C' and D. Duplication modules B and B' are
homologous, as are C and C'. Matching the sequences of 1, 2 and 3 followed by
simple single-linkage clustering would put all three in the same family, even
though proteins 1 and 3 are not related. This is because the different parts of 2
match 1 and 3. This paper describes a procedure, DIVCLUS, that divides such
complex clusters of partially related sequences into simple clusters that contain
only related duplication modules. In the example just given, it would produce two
groups of sequences: the first with domains B of sequence 1 and B of sequence 2,
and the second with domain C of sequence 2 and C of sequence 3. DIVCLUS is part
of a package called GEANFAMMER, for GEnome ANalysis and protein FAMily MakER. The
package automates the detection of families of duplication modules from a protein
sequence database. RESULTS: DIVCLUS has been applied to the division of single
linkage clusters generated from the protein sequences of six completely sequenced
bacterial genomes. Out of 12 013 genes in these six genomes, 4563 single- and
multi-domain sequences formed 1071 complex clusters. Application of the DIVCLUS
program resolved these clusters into 2113 clusters corresponding to single
duplication modules. AVAILABILITY: The perl5 program and its documentation are
available at the following address: http://www.mrc-lmb.cam.ac.uk/genomes/ and by
anonymous ftp at ftp.mrc-lmb.cam.ac.uk in the directory /pub/genomes/Software/.
CONTACT: sat@mrc-lmb.cam.ac.uk; jong@mrc-lmb. cam.ac.uk
PMID- 9545447
TI - A major component approach to presenting consensus sequences.
AB - MOTIVATION: Summarizing and displaying the information contained in a set of
aligned sequences is an important aid to identifying patterns within the
sequences. A variety of forms of consensus sequences have been used previously to
provide this information. However, these methods can cause a loss of information
or introduce ambiguities into the consensus sequence, and some graphical
approaches may become difficult to interpret due to visual distortion. RESULTS:
We have developed a method to present a more precise and graphically clear view
of a consensus sequence by using an approach based on defining the major
components at each position in a sequence set. The major components are given in
an ordered list and their frequencies are shown as histograms which can be colour
coded to reflect conservative groupings. Minor components, a one-line character
based consensus sequence and information statistics can also be presented. As
well as identifying the dominant sources of variation and conservation in the
sequence set, the method also enables similarities and differences between
subgroups of a sequence set to be readily assessed. AVAILIABILITY: On request
from the authors. CONTACT: bcsmith@usthk.ust.hk, hxue@usthk. ust.hk
PMID- 9545448
TI - Rose: generating sequence families.
AB - MOTIVATION: We present a new probabilistic model of the evolution of RNA-, DNA-,
or protein-like sequences and a software tool, Rose, that implements this model.
Guided by an evolutionary tree, a family of related sequences is created from a
common ancestor sequence by insertion, deletion and substitution of characters.
During this artificial evolutionary process, the 'true' history is logged and the
'correct' multiple sequence alignment is created simultaneously. The model also
allows for varying rates of mutation within the sequences, making it possible to
establish so-called sequence motifs. RESULTS: The data created by Rose are
suitable for the evaluation of methods in multiple sequence alignment computation
and the prediction of phylogenetic relationships. It can also be useful when
teaching courses in or developing models of sequence evolution and in the study
of evolutionary processes. AVAILABILITY: Rose is available on the Bielefeld
Bioinformatics WebServer under the following URL: http://bibiserv.TechFak.Uni
Bielefeld.DE/rose/ The source code is available upon request. CONTACT:
folker@TechFak.Uni-Bielefeld.DE
PMID- 9545449
TI - Automated protein sequence database classification. I. Integration of
compositional similarity search, local similarity search, and multiple sequence
alignment.
AB - MOTIVATION: Genome sequencing projects require the periodic application of
analysis tools that can classify and multiply align related protein sequence
domains. Full automation of this task requires an efficient integration of
similarity and alignment techniques. RESULTS: We have developed a fully automated
process that classifies entire protein sequence databases, resulting in alignment
of the homologous sequences. The successive steps of the procedure are based on
compositional and local sequence similarity searches followed by multiple
sequence alignments. Global similarities are detected from the pairwise
comparison of amino acid and dipeptide compositions of each protein. After the
elimination of all but one sequence from each detected cluster of closely related
proteins, the remaining sequences are compiled in a suffix tree which is self
compared to detect local sequence similarities. Sets of proteins which share
similar sequence segments are then weighted according to their closeness and
multiply aligned using a fast hierarchical dynamic programming algorithm.
Computational strategies were devised to minimize computer processing time and
memory space requirements. The accuracy of the sequence classifications has been
evaluated for 12 462 primary structures distributed over 341 known families. The
percentage of sequences with missed or incorrect family assignments was 6.8% on
the test set. This low error level is only twice that of the manually constructed
PROSITE database ( 3.4% ) and is substantially better than that found for the
automatically built PRODOM database ( 34.9% ). AVAILABILITY: The resulting
database, called DOMO, is available through database search routine SRS at
Infobiogen (http://www.infobiogen.fr/srs5/), EBI (http://srs.ebi.ac.uk:5000/) and
EMBL (http://www.embl-heidelberg.de/srs5/) World Wide Web sites. CONTACT:
gracy@infobiogen.fr
PMID- 9545450
TI - Automated protein sequence database classification. II. Delineation Of domain
boundaries from sequence similarities.
AB - MOTIVATION: Decomposing each protein into modular domains is a basic prerequisite
to classify accurately structural units in biological molecules. Boundaries
between domains are indicated by two similar amino acid sequence segments located
within the same protein (repeats) or within homologous proteins at notably
different distances from their respective N- or C-termini. RESULTS: We have
developed an automated method that combines such positional constraints derived
from various detected pairwise sequence similarities to delineate the modular
organization of proteins. The procedure has been applied to a non-redundant data
set of 26 990 proteins whose sequences were taken from the PIR and SWISS-PROT
databanks and shared <60% sequence identity amongst pairs. The resultant
clustering, delineation and multiple alignment of 24 380 sequence fragments
yielded a new database of 4364 domain families. Comparison of the domain
collection with that of PRODOM indicates a clear improvement in the number and
size of domain families, domain boundaries and multiple sequence alignments. The
accuracy and sensitivity of the method are illustrated by results obtained for
ankyrin-like repeats and EGF-like modules. AVAILABILITY: The resulting database,
called DOMO, is available through the database search routine SRS at Infobiogen
(http://www.infobiogen.fr/srs5/), EBI (http://srs.ebi.ac.uk:5000/) and EMBL
(http://www.embl-heidelberg.de/srs5/) World Wide Web sites. CONTACT:
gracy@infobiogen.fr
PMID- 9545451
TI - 3DinSight: an integrated relational database and search tool for the structure,
function and properties of biomolecules.
AB - MOTIVATION: Although a large amount of information on the structure, function and
properties of biomolecules is becoming available, it is difficult to understand
the relationship between them. Thus, we have attempted to create an integrated
relational database, search and visualization tool, 3DinSight, to help
researchers to gain insight into their relationship. RESULTS: We have gathered
data on the structure, function and properties of biomolecules, and implemented
them into a relational database system. The structural data contain several
subset data such as protein homologues, protein-DNA complex, in order to enable
searching within a specific class of data. The functional data include motif
sequence and mutation data of proteins. Also, various amino acid properties are
implemented as a relational table. The World Wide Web (WWW) interfaces enable
users to carry out various kinds of searches among these data. The locations of
motif sequences and mutations are automatically mapped on the structure, and
visualized in three-dimensional (3D) space by interactive viewers, VRML (Virtual
Reality Modeling Language) and RasMol. In the case of VRML, the mapped 3D objects
are hyper-linked to the corresponding document data. Also, amino acid properties,
linked with structure, functional and mutation sites, can be displayed as graph
plots. AVAILABILITY: 3DinSight is freely accessible through the Internet
(http://www.rtc.riken.go.jp/3DinSight.h tml). CONTACT: sarai@rtc.riken.go.jp
PMID- 9545452
TI - Estimation and filtering of potential protein-protein docking positions.
AB - MOTIVATION: Software systems predicting automatically whether and how two
proteins may interact are highly desirable, both for understanding biological
processes and for the rational design of new proteins. As a part of a future
complete solution to this problem, a bundle of programs is presented designed (i)
to estimate initial docking positions for a given pair of docking candidates,
(ii) to adjust them, and (iii) to filter them, thus preparing more detailed
computations of free energies. RESULTS: The system is evaluated on a test set of
51 co-crystallized complexes aiming at redocking the subunits. It works
completely automatically and the evaluation is performed using one single set of
parameters for all complexes in the test set. The number of solutions is fixed to
50 positions with a median CPU time of 26 min. For 30 complexes, these contain a
near-correct solution with root mean square deviation ( RMSD ) =5.0 A, which is
ranked first in five cases. For all complexes, the best solution is scored on
rank 16 as the worst case, and has a median RMSD of 4.3 A. Alternatively to this
initial estimation of docking positions, a global sampling of rotations was
tested. Whereas this yields top-ranked solutions with RMSD =3.0 A for all 51
complexes, the median CPU time increases to 11 h. This shows that this blind
sampling is not feasible for most applications. AVAILABILITY: The system and its
components are available on request from the authors. CONTACT:
friedric@techfak.uni-bielefeld or posch@techfak.uni-bielefeld.de
PMID- 9545453
TI - Incremental threading optimization (TITO) to help alignment and modelling of
remote homologues.
AB - MOTIVATION: Protein sequence comparison has become a major tool for biologists.
Various methods have been designed in order to reveal even remote homologies
among proteins. Sequence analyses are powerful, but the lower the identity score,
the more skill and time are required to perform them accurately. While necessary
to confirm the sequence comparison through the potential of mean force, sequence
alignment and molecular modelling are still tedious and time-consuming tasks.
RESULTS: In order to help sequence threading onto known three-dimensional (3D)
structures, we have developed a new program, named TITO (Tool for Incremental
Threading Optimization), which uses a multiple alignment to validate and help the
refinement of a sequence/structure comparison. It measures the compatibility of a
family of related sequences with a known 3D structure. The coordinates of the
common core are extracted, allowing further molecular modelling and 3D survey.
AVAILABILITY: TITO is available by anonymous ftp at: ftp://lmcp.jussieu.
fr/pub/tito CONTACT: labesse@lmcp.jussieu.fr SUPPLEMENTARY INFORMATION:
http://www.lmcp.jussieu.fr/ approximately labesse/TITO/TITO.html
PMID- 9545454
TI - Fast computation of 3D radon transform via a direct Fourier method.
AB - MOTIVATION: Arrays of three-dimensional (3D) data are ubiquitous in structural
biology, biomedicine and clinical imaging. The Radon transform can be implied in
their manipulation mainly for the solution of the inverse tomographic problem,
since experimental data are often collected as projections or as samples of the
Radon space. In electron tomography, new applications of the transform may become
convenient if a fast and accurate transformation algorithm is adopted. RESULTS: A
direct Fourier method (DFM) is proposed to compute the 3D Radon transform from a
sampled function with compact support. This paper describes an already known two
step algorithm and illustrates its DFM implementation by coordinate
transformations in 2D Fourier space. The algorithm is easily inverted to obtain a
density distribution from the Radon transform. The main applications are in the
field of electron tomography, especially in processes of angular refinement,
since whatever projection of a structure can be retrieved from its Radon
transform in a fast and accurate way. The times required to compute a number of
projections with use of the Radon transform are compared with those required by
other algorithms. Further uses of the Radon transform can be foreseen in
applications based on 'projection onto convex sets' (POCS). AVAILABILITY:
Software is available free of charge upon request to the authors. CONTACT:
salvator@csmtbo.mi.cnr.it
PMID- 9545455
TI - Automated management of gene discovery projects.
AB - The paper reports on programs, organization and Hypertext Mark-up Language (HTML)
presentation provided by the Hierarchical Automated Gene Identification System
(HAGIS) designed for managing sequencing projects. AVAILABILITY: On request from
the authors. CONTACT: st23646@ggr.co.uk
PMID- 9545456
TI - TOPAL: recombination detection in DNA and protein sequences.
AB - TOPAL scans a multiple sequence alignment for evidence of recombinant sequences,
prior to phylogenetic analysis. AVAILABILITY: The TOPAL package may be accessed
at http://www.bioss.sari.ac.uk/grainne, and by anonymous ftp at ftp.bioss.
sari.ac.uk in the directory pub/phylogeny/topal. CONTACT:
grainne@bioss.sari.ac.uk
PMID- 9545457
TI - STRIRED: graphical analysis of string repeats.
AB - STRIRED is a toolkit to generate a graphical picture of the distribution of 4- to
6-mer repeats in a set of user-defined nucleic acid sequences. AVAILABILITY: The
STRIRED package can be downloaded as self-extracting archive (strired.exe) by
anonymous FTP from biol.dgbm.unina.it (143.225.252.1), in the directory
/software/win95/STRIRED. CONTACT: calogero@biol.dgbm.unina. it.
PMID- 9545458
TI - GeneFIND web server for protein family identification and information retrieval.
AB - An integrated database and search system has been developed for protein family
identification and information retrieval, as an approach to undertake the highly
complex, genomic-scale problem of molecular sequence database search and
organization. AVAILABILITY: http://diana.uthct.edu CONTACT: wu@uthct.edu
PMID- 9545459
TI - MEICPS: substitution mutations to engineer intracellular protein stability.
AB - In MEICPS, results from earlier analyses are utilized to suggest possible
substitution point mutations to engineer intracellular stability using a given
sequence or structure of the protein. AVAILABILITY: From bvbreddy@ccmb.ap.nic.in.
This program needs data from other software, PSA and SSTRUC, available from
sali@tamika.rockefeller.edu and tom@cryst.bioc.cam.ac.uk, respectively. CONTACT:
bvbreddy@ccmb.ap.nic.in
PMID- 9545460
TI - An EXCEL template for calculation of enzyme kinetic parameters by non-linear
regression.
AB - MOTIVATION: An EXCEL template has been developed for the calculation of enzyme
kinetic parameters by non-linear regression techniques. The tool is accurate,
inexpensive, as well as easy to use and modify. AVAILABILITY: The program is
available from http://www.ebi.ac.uk/biocat/biocat.html CONTACT: agustin.
hernandez@bio.kuleuven.ac.be
PMID- 9545461
TI - A new aspect to the origin and evolution of eukaryotes.
AB - One of the most important omissions in recent evolutionary theory concerns how
eukaryotes could emerge and evolve. According to the currently accepted views,
the first eukaryotic cell possessed a nucleus, an endomembrane system, and a
cytoskeleton but had an inefficient prokaryotic-like metabolism. In contrast, one
of the most ancient eukaryotes, the metamonada Giardia lamblia, was found to have
formerly possessed mitochondria. In sharp contrast with the traditional views,
this paper suggests, based on the energetic aspect of genome organization, that
the emergence of eukaryotes was promoted by the establishment of an efficient
energy-converting organelle, such as the mitochondrion. Mitochondria were
acquired by the endosymbiosis of ancient alpha-purple photosynthetic Gram
negative eubacteria that reorganized the prokaryotic metabolism of the
archaebacterial-like ancestral host cells. The presence of an ATP pool in the
cytoplasm provided by this cell organelle allowed a major increase in genome
size. This evolutionary change, the remarkable increase both in genome size and
complexity, explains the origin of the eukaryotic cell itself. The loss of cell
wall and the appearance of multicellularity can also be explained by the
acquisition of mitochondria. All bacteria use chemiosmotic mechanisms to harness
energy; therefore the periplasm bounded by the cell wall is an essential part of
prokaryotic cells. Following the establishment of mitochondria, the original
plasma membrane-bound metabolism of prokaryotes, as well as the funcion of the
periplasm providing a compartment for the formation of different ion gradients,
has been transferred into the inner mitochondrial membrane and intermembrane
space. After the loss of the essential function of periplasm, the bacterial cell
wall could also be lost, which enabled the naked cells to establish direct
connections among themselves. The relatively late emergence of mitochondria may
be the reason why multicellularity evolved so slowly.
PMID- 9545462
TI - Evolution of the cytochrome c oxidase proton pump.
AB - The superfamily of quinol and cytochrome c terminal oxidase complexes is related
by a homologous subunit containing six positionally conserved histidines that
ligate a low-spin heme and a heme-copper dioxygen activating and reduction
center. On the basis of the structural similarities of these enzymes, it has been
postulated that all members of this superfamily catalyze proton translocation by
similar mechanisms and that the CuA center found in most cytochrome c oxidase
complexes serves merely as an electron conduit shuttling electrons from
ferrocytochrome c into the hydrophobic core of the enzyme. The recent
characterization of cytochrome c oxidase complexes and structurally similar
cytochrome c:nitric oxide oxidoreductase complexes without CuA centers has
strengthened this view. However, recent experimental evidence has shown that
there are two ubiquinone(ol) binding sites on the Escherichia coli cytochrome bo3
complex in dynamic equilibrium with the ubiquinone(ol) pool, thereby
strengthening the argument for a Q(H2)-loop mechanism of proton translocation
[Musser SM et al. (1997) Biochemistry 36:894-902]. In addition, a number of
reports suggest that a Q(H2)-loop or another alternate proton translocation
mechanism distinct from the mitochondrial aa3-type proton pump functions in
Sulfolobus acidocaldarius terminal oxidase complexes. The possibility that a
primitive quinol oxidase complex evolved to yield two separate complexes, the
cytochrome bc1 and cytochrome c oxidase complexes, is explored here. This idea is
the basis for an evolutionary tree constructed using the notion that respiratory
complexity and efficiency progressively increased throughout the evolutionary
process. The analysis suggests that oxygenic respiration is quite an old process
and, in fact, predates nitrogenic respiration as well as reaction-center
photosynthesis.
PMID- 9545463
TI - Estimation of the transition/transversion ratio.
AB - A simple method for estimating the transition/transversion ratio was developed.
This method can be applied to not only two sequences but also more than two
sequences. The statistical properties of the method and some other methods were
examined by numerical computation and computer simulation. The results obtained
showed that, in terms of bias and variance, the new method gives a better
estimate of the transition/transversion ratio than do the other examined methods.
The new method was applied to human and chimpanzee mitochondrial control region
sequences.
PMID- 9545464
TI - Patterns of base composition within the genes of Drosophila melanogaster.
AB - Base composition is not uniform across the genome of Drosophila melanogaster.
Earlier analyses have suggested that there is variation in composition in D.
melanogaster on both a large scale and a much smaller, within-gene, scale. Here
we present analyses on 117 genes which have reliable intron/exon boundaries and
no known alternative splicing. We detect significant heterogeneity in G+C content
among intron segments from the same gene, as well as a significant positive
correlation between the intron and the third codon position G+C content within
genes. Both of these observations appear to be due, in part, to an overall
decline in intron and third codon position G+C content along Drosophila genes
with introns. However, there is also evidence of an increase in third codon
position G+C content at the start of genes; this is particularly evident in genes
without introns. This is consistent with selection acting against preferred
codons at the start of genes.
PMID- 9545465
TI - Transcription and splicing patterns of M- and O-type P elements in drosophila
bifasciata, D. helvetica, and scaptomyza pallida
AB - RT-PCR was applied to analyze the splicing patterns of P-element-derived mRNAs in
Drosophila bifasciata, D. helvetica, and Scaptomyza pallida. D. melanogaster was
used as a control. The experiments revealed that P elements are transcribed in
all species investigated. However, there are differences in the splicing patterns
of IVS3, which has to be removed in order to produce transposase mRNA instead of
repressor mRNA. These differences are observed among species as well as between
the P element subfamilies, the M and the O type, which coexist in the genomes of
D. bifasciata and S. pallida. In D. helvetica M-type transposase mRNA was found
in the germline and repressor mRNA in the soma, as has been previously described
for the canonical (M-type-related) P element of D. melanogaster. In contrast, in
S. pallida only repressor mRNA of M-type elements was detected in all tissues. In
D. bifasciata, M-type IVS3, although activated both in the soma and the germline,
is never completely excised. Instead, two alternative double-spliced variants
occur in which two small introns are removed within the IVS3 region. One of these
variants codes for a protein 12 aa longer than the regular transposase. Taking
these findings together, transposase production and transpositional activity of M
type elements seem to be limited to D. helvetica and D. melanogaster, whereas M
type elements have become immobile in D. bifasciata and S. pallida. Unlike the M
type, the splicing of O-type transcripts in D. bifasciata and S. pallida follows
the classical rules of tissue-specific P element regulation: transposase mRNA is
produced exclusively in the germline whereas repressor mRNA is formed in somatic
cells. Thus O-type elements are thought to be still transpositionally active in
both species. This finding is in accordance with the postulated recent transfer
of O-type elements between the gene pools of D. bifasciata and S. pallida. In
addition, we were able to show that the IVS3 double-spliced variants of both P
element types are produced regularily in all species of the genus Drosophila
investigated so far, but not in S. pallida.
PMID- 9545466
TI - The molecular clock runs at different rates among closely related members of a
gene family.
AB - The serum albumin gene family is composed of four members that have arisen by a
series of duplications from a common ancestor. From sequence differences between
members of the gene family, we infer that a gene duplication some 580 Myr ago
gave rise to the vitamin D-binding protein (DBP) gene and a second lineage, which
reduplicated about 295 Myr ago to give the albumin (ALB) gene and a common
precursor to alpha-fetoprotein (AFP) and alpha-albumin (ALF). This precursor
itself duplicated about 250 Myr ago, giving rise to the youngest family members,
AFP and ALF. It should be possible to correlate these dates with the phylogenetic
distribution of members of the gene family among different species. All four
genes are found in mammals, but AFP and ALF are not found in amphibia, which
diverged from reptiles about 360 Myr ago, before the divergence of the AFP-ALF
progenitor from albumin. Although individual family members display an
approximate clock-like evolution, there are significant deviations-the rates of
divergence for AFP differ by a factor of 7, the rates for ALB differ by a factor
of 2.1. Since the progenitor of this gene family itself arose by triplication of
a smaller gene, the rates of evolution of individual domains were also calculated
and were shown to vary within and between family members. The great variation in
the rates of the molecular clock raises questions concerning whether it can be
used to infer evolutionary time from contemporary sequence differences.
PMID- 9545467
TI - A concertedly evolving region in Chironomus, unique within the telomere.
AB - Chromosome terminal, complex repeats in the dipteran Chironomus pallidivittatus
show rapid concerted evolution during which there is remarkably efficient
homogenization of the repeat units within and between chromosome ends. It has
been shown previously that gene conversion is likely to be an important component
during these changes. The sequence evolution could be a result of different
processes-exchanges between repeats in the tandem array as well as information
transfer between units in different chromosomes-and is therefore difficult to
analyze in detail. In this study the concerted evolution of a region present only
once per chromosome, at the junction between the telomeric complex repeats and
the subtelomeric DNA was therefore investigated in the two sibling species C.
pallidivittatus and C. tentans. Material from individual microdissected
chromosome ends was used, as well as clones from bulk genomic DNA. On the
telomeric side of the border pronounced species-specific sequence differences
were observed, the patterns being similar for clones of different origin within
each species. Mutations had been transmitted efficiently between chromosomes also
when adjoining, more distally localized DNA showed great differences in sequence,
suggesting that gene conversion had taken place. The evolving telomeric region
bordered proximally to subtelomeric DNA with high evolutionary constancy. More
proximally localized, subtelomeric DNA evolved more rapidly and showed
heterogeneity between species and chromosomes.
PMID- 9545468
TI - Phylogenetic and functional classification of mitogen- and stress-activated
protein kinases.
AB - All currently sequenced stress-activated protein kinases (SAPKs), extracellular
signal-regulated kinases (ERKs), and other mitogen-activated protein kinases
(MAPKs) were analyzed by sequence alignment, phylogenetic tree construction, and
three-dimensional structure modeling in order to classify members of the MAPK
family. Based on this analysis the MAPK family was divided into three subgroups
(SAPKs, ERKs, and MAPK3) that consist of at least nine subfamilies. Members of a
given subfamily were exclusively from animals, plants, or yeast/fungi. A single
signature sequence, [LIVM][TS]XX[LIVM]XT[RK][WY]YRXPX[LIVM] [LIVM], was
identified that is characteristic for all MAPKs and sufficient to distinguish
MAPKs from other members of the protein kinase superfamily. This signature
sequence contains the phosphorylation site and is located on loop 12 of the three
dimensional structure of MAPKs. I also identified signature sequences that are
characteristic for each of the nine subfamilies of MAPKs. By modeling the three
dimensional structure of three proteins for each MAPK subfamily based on the
resolved atomic structures of rat ERK2 and murine p38, it is demonstrated that
amino acids conserved in all MAPKs are located primarily in the center of the
protein around the catalytic cleft. I conclude that these residues are important
for maintaining proper folding into the gross structure common to all MAPKs. On
the other hand, amino acids conserved in a given subfamily are located mainly in
the periphery of MAPKs, indicating their possible importance for defining
interactions with substrates, activators, and inhibitors. Within these subfamily
specific regions, amino acids were identified that represent unique residues
occurring in only a single subfamily and their location was mapped in three
dimensional structure models. These unique residues are likely to be crucial for
subfamily-specific interactions of MAPKs with substrates, inhibitors, or
activators and, therefore, represent excellent targets for site-directed
mutagenesis experiments.
PMID- 9545469
TI - Molecular evolution of the globin gene cluster E in two distantly related midges,
Chironomus pallidivittatus and C. thummi thummi.
AB - We have studied the evolutionary dynamics of a cluster of insect globin genes by
comparing the organization and sequence of the gene group in two distantly
related species, Chironomus pallidivittatus and C. t. thummi. Although the
general architecture of the globin gene cluster has been conserved, we have found
an additional, previously undescribed gene (named Cpa F) in C. pallidivittatus
which shows signs of accelerated sequence evolution at nonsynonymous codon
positions. This new gene is clearly functional, as demonstrated by Northern
analysis. Comparison of paralogous and orthologous genes reveals patterns of
intraspecific sequence homogenization. The head-to-head-oriented globin 3 and 4
gene pairs in C. t. thummi and the gb 4 gene pair in C. pallidivittatus have been
efficiently homogenized, probably by gene conversion, in their promoter and
coding regions. Inverted transcriptional orientation seems to favor efficient
conversion. The orthologous genes from C. t. thummi and C. pallidivittatus reveal
different levels of sequence conservation, ranging from 85.3 to 94.7% amino acid
identity. Surprisingly, globin gene E, for which up to now no corresponding
protein has been detected in the larval hemolymph of C. t. thummi, shows the
highest degree of interspecies sequence conservation. This points to an
essential, as yet unknown function of this globin. The usefulness of globin gene
comparisons for dating speciation events in Chironomus is discussed.
PMID- 9545470
TI - Evolutionary rate and genetic heterogeneity of human T-cell lymphotropic virus
type II (HTLV-II) using isolates from European injecting drug users.
AB - Seven new Italian and two new British HTLV-II isolates were obtained from
injecting drug users and the entire long terminal repeat (LTR) region was
sequenced. Restriction analysis showed that all the Italian isolates are of the
IIb subtype, whereas the British isolates are of the IIa subtype. To understand
whether the further differentiation of each two principal HTLV-II subtypes in
several subgroups could be statistically supported by phylogenetic analysis, the
neighbor-joining, parsimony, and maximum likelihood methods were used. The
separation between IIa and IIb is very well supported by all three methods. At
least two phylogenetic subgroups exist within the HTLV-IIa and at least three
within the HTLV-IIb subtype. In the present analysis, no statistical support was
obtained for additional phylogroups. Two particular subgroups seem interesting
because they include all European and North American injecting drug user strains
within the IIa and IIb subtypes, respectively. These data confirm that European
HTLV-II infection among drug users is probably derived from North America. They
also suggest that though a certain differentiation by restriction analysis in
different subgroups is possible, carefully interpreted phylogenetic analyses
remain necessary. Using the likelihood ratio test, a molecular clock for the drug
user strains was calibrated. A fixation rate between 1.08 x 10(-4) and 2.7 x 10(
5) nucleotide substitutions per site per year was calculated for the IIa and IIb
injecting drug user strains. This is the lowest fixation rate so far reported for
RNA viruses, including for HIV, which typically range between 10(-2) and 10(-4).
PMID- 9545471
TI - Presence of a fibronectin type III domain in a plant protein.
AB - A hidden Markov model (HMM) approach was used to identify potential candidates in
sequence databases for fibronectin type III domains in plants, a kingdom
heretofore bereft of these structures. Fortuitously, one of the proteins
uncovered had already had a crystal structure published, allowing direct
structural confirmation of the existence of this domain in plants.
PMID- 9545472
TI - Magnetic resonance imaging of the fetus.
AB - Fetal magnetic resonance imaging (FMRI) has gained considerable interest during
the last decade, especially in its intracranial applications. Due to its high
soft-tissue contrast and presumed safety, FMRI should be accepted as a
complementary technique in prenatal diagnosis, useful either to elucidate
equivocal findings on routine US studies or to further delineate some
pathological entities. Normal patterns of fetal brain maturation, as shown by
FMRI, are described because they are of paramount importance to accurately
evaluate intracranial diseases. To date, however, FMRI requires specialised
facilities and should be considered as an evolving clinical research modality and
performed within precise guidelines in a multidisciplinary approach to prenatal
pathology.
PMID- 9545473
TI - MR imaging of fetal cerebral anomalies.
AB - BACKGROUND: Prenatal diagnosis of fetal brain anomalies relies mainly upon
ultrasonography. However, even in the most experienced hands, the technique has
limitations for some difficult diagnoses. MRI is an excellent imaging modality
for the paediatric and adult brain. OBJECTIVE: To assess the value of prenatal
MRI when a cerebral anomaly was detected by US and where the prognosis depended
on the identification of other anomalies undetectable by US, or where fetuses
were at risk for a CNS lesion even when the US was normal. MATERIALS AND METHODS:
Four hundred prenatal MRI examinations were performed since 1988, and confirmed
by postnatal follow-up or pathological examination. Two-thirds of the
examinations were performed after 25 weeks of gestation, one-third between 21 and
26 weeks. Fetal immobilisation was obtained by maternal premedication with
flunitrazepam, administered orally 1 h before the examination. The examinations
were performed on 1.5 T scanners using one or two surface coils. RESULTS:
Prenatal MRI allowed the diagnosis of serious unsuspected lesions such as
neuronal migration disorders, ischaemic and haemorrhagic lesions and the
abnormalities observed in tuberous sclerosis. It helped to characterise
ventricular dilatation and anomalies of the corpus callosum and of the posterior
fossa. CONCLUSIONS: MRI is a valuable complementary tool when prenatal US is
incomplete, doubtful or limited. Prenatal MRI is particularly useful for the
detection of ischaemic and haemorrhagic lesions, neuronal migration disorders and
tuberous sclerosis lesions. Detection of these associated anomalies worsens the
fetal prognosis, has medico-legal implications and modifies obstetric management.
Normal prenatal MRI does not exclude an anomaly.
PMID- 9545474
TI - Intracranial aneurysms in infants and children.
AB - BACKGROUND: The diagnosis and imaging of pediatric aneurysms has changed since
the advent of MR and MRA. OBJECTIVE: To update the literature on pediatric
aneurysms and better define the appropriate work-up of childhood aneurysms in
1997. MATERIALS AND METHODS: Retrospective review of 21 children (12 boys, 9
girls) with 25 aneurysms from three institutions over a 20-year period was
performed. Imaging studies were mixed and included CT (19 patients), MR (11
patients), MRA (6 patients) and angiography (18 patients). RESULTS: Eighteen of
25 aneurysms were congenital saccular, 6 were mycotic, and 1 was post-traumatic.
Of these, 44 % were in the posterior circulation. Nine aneurysms arose from
distal arterial branches. Forty percent were large (between 1-2.5 cm) and 16 %
were giant (> 2.5 cm). CT and MR showed hemorrhage, and frequently revealed the
aneurysms as a focal mass with or without enhancement and flow void. Six children
had MRA which revealed aneurysms in four patients. All patients with MRA had
corresponding conventional angiography. CONCLUSION: Characteristics of pediatric
aneurysms include diversity of type, increased incidence in the posterior fossa,
peripheral location, and large size. CT, MR and MRA are useful in the diagnosis
with conventional angiography essential for preoperative planning.
PMID- 9545475
TI - Ultrasound and MR imaging of fibromatosis colli (sternomastoid tumor of infancy).
AB - The sonographic and CT findings of fibromatosis colli (sternomastoid tumor of
infancy) have been described, but the MRI appearance has been reported in only
one case in which the mass resolved over time. This case describes the detailed
MRI findings in a biopsy-proven case of fibromatosis colli; the signal intensity
of the mass on T2-weighted images was slightly less than on gradient-recalled T1
weighted images, consistent with the presence of some fibrous tissue within the
muscle mass. The involved portion of the muscle was better defined on MRI than
sonography. MRI was helpful in demonstrating the signal characteristics of the
mass; localizing the mass to within the sternocleidomastoid muscle; and
demonstrating clear surrounding fascial planes with lack of associated
lymphadenopathy, airway compression, vascular encasement, bone involvement or
intracranial/intraspinal extension associated with other neck masses.
PMID- 9545476
TI - Complete calcification of an aneurysm of the vein of Galen.
PMID- 9545477
TI - Skeletal tuberculosis: dactylitis and involvement of the skull.
AB - A re-emergence of tuberculosis (TB) is occurring world wide in both developed and
developing countries. The clinical picture caused by infection with M.
tuberculosis may simulate many other disease entities and may result in
unnecessary investigations with a delay in diagnosis and treatment. Skeletal TB
tends to be isolated to one anatomical site. We report a 6-year-old boy with
disseminated skeletal TB with dactylitis resembling sickle cell anaemia and lytic
lesions similar to those which are often seen in neuroblastoma, Langerhans' cell
histiocytosis and leukaemia. The clinician should be aware that TB can mimic
almost any disease and recognise the radiographic appearances of skeletal
tuberculous lesions.
PMID- 9545478
TI - Reconversion of bone marrow in Gaucher disease treated with enzyme therapy
documented by MR.
AB - BACKGROUND: Skeletal complications are responsible for significant morbidity in
Gaucher patients. Plain radiographs have been unreliable in assessing bone marrow
infiltration and activity. A way to assess bone marrow improvement is needed
during enzyme therapy. OBJECTIVE: The purpose of this paper is to assess the
usefulness of MR in following improvement of abnormal bone marrow in Gaucher
patients on enzyme therapy. MATERIALS AND METHODS: Three patients aged 2, 7, and
24 years underwent serial MR scans of the lower extremities before and during
treatment with Alglucerase (two patients) and Imiglucerase (one patient). T1
weighted, T2-weighted, STIR and FSE T2-weighted images were utilized. Two
patients were imaged after 16 months of therapy, and one patient was imaged after
6 months of therapy. RESULTS: All patients had improvement in marrow signal
consistent with partial reconversion to fatty marrow during treatment. The
findings were more marked after prolonged therapy. T1-weighted images
demonstrated findings most clearly. CONCLUSION: MR consistently showed
improvement in marrow signal in Gaucher patients on enzyme therapy. As smaller
doses of enzyme therapy are the trend, MR can be utilized to determine if therapy
is effecting a change in the bone marrow.
PMID- 9545480
TI - The role of ultrasound in the follow-up of postoperative changes after
pyeloplasty.
AB - BACKGROUND: Pyeloplasty is an established treatment for pelviureteric junction
(PUJ) obstruction. The postoperative change in the size of the renal pelvis and
the kidney parenchyma are variable. OBJECTIVE: To document the changes in renal
pelvic size and renal parenchymal thickness following pyeloplasty and to
establish that improvement of both parameters are good markers for improved urine
flow. MATERIALS AND METHODS: A group of 267 newborns and young infants with
suspected PUJ obstruction were investigated by ultrasound. Pyeloplasty was
performed on 102 babies, and 165 patients were followed conservatively.
Postoperative ultrasonography at 6 and 12 months was available in 88 patients.
RESULTS: One year after surgery, the renal pelvis was smaller in 76 % of the
cases. The renal parenchyma was normal or had increased in 92 % of cases.
CONCLUSION: Resolution of hydronephrosis after surgery is relatively slow, but
renal parenchymal growth is rapid. Mild postoperative pelvic dilatation is
frequent and does not indicate continued obstruction.
PMID- 9545479
TI - Lateral femoral scan: an alternative method for assessing bone mineral density in
children with cerebral palsy.
AB - BACKGROUND: Children with cerebral palsy (CP), often nonambulatory and/or on
anticonvulsants, are at increased risk for fractures. Bone mineral density (BMD)
measured by the conventional techniques of dual-energy X-ray absorptiometry (DXA)
often cannot be reliably or easily measured in these patients. OBJECTIVE: To find
an alternative site to whole body, spine and hip that can be conveniently used to
measure BMD in CP patients. MATERIALS AND METHODS: Having observed that CP
patients prefer to lie on their sides, we explored measuring BMD at the distal
femur in the lateral projection. A total of 92 scans were performed without
sedation in 34 children and adolescents with CP, aged 4-19 years. Four femoral
shaft subregions were created: two trabecular and two cortical. RESULTS: The
coefficients of variation (CV %) were generally higher for opposite-side
comparisons (n = 12 patients) than for same-side comparisons (n = 16 patients).
For intra- and interobserver analyses, CV % were higher for cortical regions than
for trabecular regions. Overall, the CV % were similar to those for hip and
spine. CONCLUSION: This peripheral site in the femur should be considered as an
alternative for patients with CP when whole-body, hip and spine DXA are not
practical.
PMID- 9545481
TI - Cystosonography with echocontrast: a new imaging modality to detect
vesicoureteric reflux in children.
AB - BACKGROUND: Conventionally, vesicoureteric reflux (VUR) is assessed by
fluoroscopic micturating cystourethrography (MCU) or direct or indirect
radionuclide cystography (RNC). There is preliminary experience with contrast
enhanced sonography for the detection of VUR. OBJECTIVE: To evaluate the
usefulness of contrast-enhanced ultrasonography using galactose suspension as an
echogenic contrast medium. MATERIALS AND METHODS: In this study a galactose
suspension was instilled into the bladder in 58 neonates, infants and children
along with normal saline to detect the presence and the severity of VUR through
the enhanced US signal. The results were compared with those of MCU and RNC. One
ml/kg of echocontrast in the neonatal age group, and 0.5 ml/kg thereafter, were
slowly instilled through a 4-F catheter after preliminary supine and prone
urinary tract US. Indications for the investigation were antenatally diagnosed
pyelectasis (21 cases) and pyelonephritis (37 cases). In 38 patients echocontrast
cystosonography (ECS) was performed before, and in 20 patients after, MCU or RNC.
RESULTS: ECS detected 76 refluxing units in 50 patients. In eight patients, no
VUR was shown, and none of these developed a urinary tract infection in 18 months
of follow-up. In 43 patients, MCU or RNC detected 62 refluxing units, while in 15
no VUR was shown. Taking MCU as the gold standard and using the same grading
scale, the sensitivity of ECS was 100 %. No side effects were observed. Several
urinary tract abnormalities were detected by ECS. The male urethra was studied by
ECS, both by retrograde infusion and during micturition. CONCLUSIONS: ECS is a
promising imaging technique for detecting and grading VUR without exposing
patients to ionising radiation.
PMID- 9545482
TI - Idiopathic arterial calcification of infancy: sonographic and magnetic resonance
findings with pathologic correlation.
AB - Idiopathic arterial calcification of infancy is a rare condition characterized by
extensive arterial calcification and stenoses of large and medium sized arteries.
We report the sonographic and magnetic resonance angiographic findings of this
entity and correlate them with the findings at autopsy.
PMID- 9545483
TI - Pseudolymphoma of the breast in a 4-year-old boy.
PMID- 9545484
TI - Pulmonary oedema associated with mitral regurgitation: prevalence of predominant
right upper lobe involvement in children.
AB - OBJECTIVE: To evaluate the hypothesis that pulmonary venous congestion and oedema
manifested predominantly in the right upper lobe in children with mitral
regurgitation occur more frequently than previously thought. MATERIALS AND
METHODS: Three radiologists retrospectively and independently reviewed the plain
chest radiographs of 54 children (26 girls, 28 boys, age range 2 days-18 years,
median 9.5 years) with mitral regurgitation admitted to our institution during a
5-year period. Radiographs showing pulmonary venous congestion and oedema
manifested predominantly in the right upper lobe were identified. Clinical
records of these patients were studied to exclude other causes of pulmonary
disease. RESULTS: Radiographic signs of pulmonary venous congestion and oedema
were present in all patients, with redistribution of flow and interstitial oedema
in 39 patients (72 %) and alveolar oedema in 15 children (28 %). In 12 (22 %) of
54 children, these findings were localised or predominant in the upper lobe of
the right lung; none of the children had predominantly left-sided involvement.
CONCLUSIONS: Pulmonary venous congestion and oedema involving predominantly the
upper lobe of the right lung in children with mitral regurgitation occur more
frequently than previously thought. This finding is useful in the differential
diagnosis of right upper lobe abnormalities, such as pneumonia.
PMID- 9545485
TI - Magnetic resonance imaging of a left circumflex aortic arch and aberrant right
subclavian artery: the other vascular ring.
AB - We present a case of a rare congenital cardiac anomaly. Magnetic resonance
imaging accurately demonstrated a left circumflex aortic arch. This finding was
not apparent on a prior conventional angiogram or echocardiography. Magnetic
resonance imaging documentation of this anomaly is uncommon. Review of the
embryonic development, clinical presentation of complete and incomplete vascular
rings, and additional associated cardiac anomalies are discussed. This is one of
only a few reported cases of a left circumflex aortic arch.
PMID- 9545486
TI - Spontaneous involution of pulmonary sequestration in children: a report of two
cases and review of the literature.
AB - BACKGROUND: Two cases of pulmonary sequestration which regressed spontaneously
are presented. OBJECTIVE: To demonstrate the value of imaging studies in the
diagnosis and follow-up of some forms of congenital masses of the lung in
asymptomatic patients. MATERIAL AND METHODS: We reviewed the clinical records and
imaging studies of two asymptomatic children, one newborn and the other 3 months
old, with thoracic masses which demonstrated variable degrees of spontaneous
involution. RESULTS: Abdominal ultrasound performed on the newborn with a
palpable mass showed a triangular echogenic mass with a large central feeding
vessel arising from the aorta. The mass had disappeared on follow-up US exam
performed 6 years later. CT was performed in the 3-month-old patient with a
persistent retrocardiac mass. A soft-tissue density mass in the left pulmonary
base with a large feeding vessel arising from the aorta was visualised on
contrast-enhanced CT. Five years later, a new CT scan showed significant
shrinkage of the mass and no vessel. CONCLUSION: Radiological techniques such as
real-time US with Doppler imaging and contrast-enhanced CT may establish the
diagnosis of pulmonary sequestration by demonstrating the mass and its systemic
vessel, thereby eliminating the need for more aggressive imaging procedures.
Partial or total disappearance of these masses represents a further example of
involutive pathology and suggests that not all cases of pulmonary sequestration
should be surgically treated.
PMID- 9545487
TI - Post-operative intussusception: often an elusive diagnosis.
PMID- 9545488
TI - MR imaging of a pilomatrixoma.
PMID- 9545489
TI - Meeting report: 11th International Mouse Genome Conference.
PMID- 9545490
TI - Location of mouse and human genes corresponding to conserved canine olfactory
receptor gene subfamilies.
AB - Olfactory receptors are G protein-coupled, seven-transmembrane-domain proteins
that are responsible for binding odorants in the nasal epithelium. They are
encoded by a large gene family, members of which are organized in several
clusters scattered throughout the genomes of mammalian species. Here we describe
the mapping of mouse sequences corresponding to four conserved olfactory receptor
genes, each representing separate, recently identified canine gene subfamilies.
Three of the four canine genes detected related gene clusters in regions of mouse
Chromosomes (Chrs) 2, 9, and 10, near previously mapped mouse olfactory genes,
while one detected a formerly unidentified gene cluster located on mouse Chr 6.
In addition, we have localized two human gene clusters with homology to the
canine gene, CfOLF4, within the established physical map of Chr 19p. Combined
with recently published studies, these data link the four conserved olfactory
gene subfamilies to homologous regions of the human, dog, and mouse genomes.
PMID- 9545491
TI - Factors affecting ectopic gene conversion in mice.
AB - Duplicated genes and repetitive sequences are distributed throughout the genomes
of complex organisms. The homology between related sequences can promote
nonallelic (ectopic) recombination, including gene conversion and reciprocal
exchange. Resolution of these events can result in translocations, deletions, or
other harmful rearrangements. In yeast, ectopic recombination between sequences
on nonhomologous chromosomes occurs at high frequency. Because the mammalian
genome is replete with duplicated sequences and repetitive elements, high levels
of ectopic exchange would cause aneuploidy and genome instability. To understand
the factors regulating ectopic recombination in mice, we evaluated the effects of
homology length on gene conversion between unlinked sequences in the male
germline. Previously, we found high levels of gene conversion between lacZ
transgenes containing 2557 bp of homology. We report here that genetic background
can play a major role in ectopic recombination; frequency of gene conversion was
reduced by more than an order of magnitude by transferring the transgenes from a
CF1 strain background to C57BL/6J. Additionally, conversion rates decreased as
the homology length decreased. Sequences sharing 1214 bp of sequence identity
underwent ectopic conversion less frequently than a pair sharing 2557 bp of
identity, while 624 bp was insufficient to catalyze gene conversion at
significant levels. These results suggest that the germline recombination
machinery in mammals has evolved in a way that prevents high levels of ectopic
recombination between smaller classes of repetitive sequences, such as the Alu
family. Additionally, genomic location appeared to influence the availability of
sequences for ectopic recombination.
PMID- 9545492
TI - Structural characterization of the mouse long-chain acyl-CoA dehydrogenase gene
and 5' regulatory region.
AB - Long-chain acyl-CoA dehydrogenase (LCAD) is one of four enzymes involved in the
initial step of mitochondrial beta-oxidation of straight-chain fatty acids. It is
a member of the acyl-CoA dehydrogenase (Acad or ACAD) gene family of enzymes,
which also includes very-long-chain (VLCAD), medium-chain (MCAD), and short-chain
(SCAD) acyl-CoA dehydrogenases. These enzymes all have similar activity but
differ only in the chain length specificity for their substrate. Mitochondrial
beta-oxidation provides an important source of energy especially during times of
fasting. In order to understand the role of LCAD in this pathway, we have cloned
and characterized the entire mouse (Mus musculus) gene encoding LCAD (Acadl).
Acadl is a single-copy, nuclear encoded gene approximately 35 kb in size. We have
sequenced the entire coding region, all intron/exon boundaries, 1.7 kb of its 5'
regulatory region, and mapped the transcription start site. The gene contains 11
coding exons ranging in size from 67 bp to 275 bp, interrupted by 10 introns
ranging in size from 1.0 kb to 6.6 kb in size. The Acadl 5' regulatory region,
like other members of the Acad family, lacks a TATA or CAAT box and is GC rich.
This region does contain multiple, putative cis-acting DNA elements recognized by
either SP1 or members of the steroid-thyroid family of nuclear receptors, which
has been shown with other members of the ACAD gene family to be important in
regulated expression. The characterization of the mouse Acadl gene will allow
further study of LCAD in an in vivo model, and how its expression may be
coordinated with other members of the Acad gene family.
PMID- 9545493
TI - Improvement of the porcine transcription map: localization of 33 genes, of which
24 are orthologous.
AB - From a resource of porcine ESTs, 52 transcripts were selected for regional
chromosomal assignments in a somatic cell hybrid panel. Except for six ESTs, the
chosen transcripts represented genes where the BLASTX database searches showed
high similarity scores (>90%) with a part of the single pass 5' sequence to
human, bovine, mouse, or pig entries. PCR primers for hybrid cell analysis of the
ESTs were positioned in the 3'UTR of the sequences. Confident regional
assignments to pig chromosomes were obtained for 33 of the 52 porcine ESTs.
Comparative human mapping data were available for 27 of these. Twenty-four proved
to be orthologous genes now placed on the porcine transcription map. The data
presented provide further comparative data for 13 autosomes and the X chromosome.
PMID- 9545494
TI - CSF2RA, ANT3, and STS are autosomal in marsupials: implications for the origin of
the pseudoautosomal region of mammalian sex chromosomes.
AB - The X and Y Chromosomes (Chrs) of eutherian ("placental") mammals share a pseudo
autosomal region (PAR) that pairs and recombines at meiosis. In humans and other
eutherians, the PAR contains several active genes and has also been thought to be
critical for pairing and fertility. In order to explore the origin of the PAR, we
cloned and mapped three human or mouse pseudoautosomal genes in marsupials, a
group of mammals that diverged from eutherians about 130 (MYrBP). All three genes
were autosomal in marsupials, and two co-localized with other human Xp genes on
an autosome. This implies that the human PAR, like most of human Xp, represents a
relic of an autosomal region added to both X and Y Chrs between 80 and 150 MYrBP.
PMID- 9545495
TI - Genetics of susceptibility to radiation-induced apoptosis in colon: two loci on
chromosomes 9 and 16.
AB - Apoptosis, a mechanism for removal of genetically damaged cells and for
maintenance of desired size of cell populations, has been implicated in tumor
development. Previously, we defined polymorphic loci for susceptibility to
apoptosis of thymocytes Rapop1, Rapop2, and Rapop3 on mouse Chromosomes 16, 9,
and 3, respectively, using recombinant congenic CcS/Dem strains, each of which
contains a random set of 12.5% STS/A genome in the genetic background of
BALB/cHeA. The STS/A alleles at these loci confer lower susceptibility to
radiation-induced apoptosis of thymocytes than the BALB/cHeA. In the present
study, we tested susceptibility of colon crypt cells to radiation-induced
apoptosis. In contrast to apoptosis in thymus, the STS/A mice were more
susceptible to apoptosis in colon than the BALB/cHeA. Among the CcS/Dem strains,
CcS-4, CcS-7, and CcS-16 were more susceptible to apoptosis in colon than the
BALB/cHeA; in thymus, the CcS-7 mice are less susceptible, and the CcS-4 and CcS
16 are not different from the BALB/cHeA. Thus, individual CcS/Dem strains showed
different apoptosis susceptibility in the two organs. Analysis of (CcS-7 x
BALB/cHeA)F2 hybrids revealed linkage of susceptibility to radiation-induced
apoptosis of colon crypt cells to two loci on Chrs 9 and 16, to which Rapop2 and
Rapop1 are mapped. The STS/A allele at the locus on chromosome 9 results in high
susceptibility to apoptosis of colon crypt cells in mice homozygous for the
BALB/cHeA allele at the locus on Chr 16. Although these two loci may be identical
to Rapop1 and Rapop2, they affect apoptosis in colon in a way different from that
in thymus.
PMID- 9545496
TI - A genetic linkage map of the mouse chromosome 9 region encompassing the Friend
virus susceptibility gene 2.
PMID- 9545497
TI - Evaluation of mouse Sfrp3/Frzb1 as a candidate for the lst, Ul, and Far mutants
on chromosome 2.
PMID- 9545498
TI - Mapping, cloning, cDNA sequence, and expression of the gene encoding the mouse
micromolar calpain large subunit.
PMID- 9545499
TI - A high-resolution genetic map of mouse chromosome 19 encompassing the muscle
deficient osteochondrodystrophy (mdf-ocd) region.
PMID- 9545500
TI - Long CAG/CTG repeats in mice.
PMID- 9545501
TI - Chromosomal assignments of 19 porcine cDNA sequences by FISH.
PMID- 9545502
TI - TBX10, a member of the Tbx1-subfamily of conserved developmental genes, is
located at human chromosome 11q13 and proximal mouse chromosome 19.
PMID- 9545503
TI - Comparison of the human and murine ATRX gene identifies highly conserved,
functionally important domains.
PMID- 9545504
TI - A potential human axonemal dynein heavy-chain gene maps to 17q25.
PMID- 9545505
TI - Genomic structure of the human KDR/flk-1 gene.
PMID- 9545506
TI - Cellular apoptosis susceptibility gene capts maps to mouse chromosome 2.
PMID- 9545507
TI - Isolation and localization of the skeletal myosin heavy chain 2X gene on pig
chromosome 12q1.4-q1.5.
PMID- 9545508
TI - The gene encoding PRBP, the mouse homolog of human TRBP, maps to distal
chromosome 15.
PMID- 9545510
TI - Role of chondroitin sulfate-hyaluronan interactions in the viscoelastic
properties of extracellular matrices and fluids.
AB - The purpose of this study was to investigate the role of chondroitin sulfate
hyaluronan interactions in the viscoelastic properties of tissues and fluids,
using capillary and cone-on-plate viscometers. Chondroitin sulfate markedly
increased the viscosity of hyaluronan solutions at a wide range of hyaluronan
mass (50-1900 kDa) under physiological conditions of pH, temperature, ionic
strength and glycosaminoglycan concentration (0.5-40 mg/ml), although the
viscosity of the chondroitin sulfate solutions themselves was very low. In the
assay using a cone-on-plate viscometer, chondroitin sulfate increased the
viscosity of hyaluronan solutions at various shear rates. At low shear rates, the
viscosity of a chondroitin sulfate (5 mg/ml)-hyaluronan (0.5 mg/ml) mixture was
about 40% of that of an aggrecan (5 mg/ml)-hyaluronan (0.5 mg/ml) mixture, and at
2.8-fold higher concentrations, chondroitin sulfate elicited the same effect on
the viscosity of hyaluronan solutions (5 mg/ml) as an aggrecan monomer. In the
presence of oscillatory motion, the addition of aggrecan increased the elasticity
(storage) modulus G' and the viscosity (loss) modulus G" of hyaluronan solutions
and markedly decreased the loss tangent G"/G' at frequencies corresponding to
normal joint movements. In contrast, chondroitin sulfate had only a marginal
effect on the loss tangent G"/G', although it increased G' and G". These findings
demonstrated that chondroitin sulfate, as well as aggrecan, increases the
viscosity of hyaluronan solutions, although chondroitin sulfate has less effect
on the elasticity of hyaluronan solutions than that of aggrecan, and suggest that
chondroitin sulfate may play an important physiological role in determining the
viscoelastic properties of extracellular matrices and fluids.
PMID- 9545511
TI - Molecular cloning and functional expression of chicken luteinizing hormone
receptor.
AB - A complementary DNA for chicken luteinizing hormone (LH) receptor containing the
entire coding region was isolated from chicken F1 granulosa cell cDNA library.
Nucleotide sequence analysis revealed that there are characteristic GC-rich
regions around the N-terminal part. Chicken LH receptor consists of a 19-residue
signal peptide, a 366-residue extracellular domain, a 267-residue region
containing seven transmembrane segments, and a 76-residue cytoplasmic C-terminal
tail. The deduced amino acid sequence of the chicken LH receptor shares 67%, 69%,
and 69% identity with the human, rat and porcine LH receptor sequences,
respectively, and 51% with chicken FSH receptor. However, an insertion of about
30 amino acid residues is found in chicken LH receptor in the extracellular
domain about 44 amino acid residues upstream of the first transmembrane segment.
In addition, alternative splicing seems likely to occur at the point where the
insertion starts (nucleotide position 933), resulting in the truncated forms of
chicken LH receptor with only the extracellular domain. Northern blot analysis
revealed the presence of multiple transcripts of LH receptor, a major 3.0-kb and
minor 7-kb and 1.5-kb bands, in chicken F1 to F3 granulosa cells. The full length
chicken LH receptor cDNA was transiently expressed in COS-7 cells and the
transfected cells displayed a concentration-dependent increase in cAMP production
when exposed to varying concentrations of chicken LH. This clearly indicates that
the cloned cDNA encodes a functional chicken LH receptor protein.
PMID- 9545512
TI - Saguenay Lac Saint Jean cytochrome oxidase deficiency: sequence analysis of
nuclear encoded COX subunits, chromosomal localization and a sequence anomaly in
subunit VIc.
AB - A biochemically distinct form of cytochrome oxidase (COX) deficiency found in the
Saguenay region of Quebec is an autosomal recessive trait. The cDNA sequences of
all 10 nuclear-encoded subunits from a patient's fibroblasts showed normal coding
sequence. Sequences for subunit VIc in two atypical patients showed a
heterozygous base substitution. Subunit VIc was localized to chromosome 18.
PMID- 9545513
TI - The generation and interpretation of positional information within the vertebrate
myotome.
AB - How somitic cells become restricted to the muscle fate has been investigated on a
number of levels. Classical embryological manipulations have attempted to define
the source of inductive signals that control the formation of the myotome.
Recently, these studies have converged with others dissecting the role of
secreted proteins in embryonic patterning to demonstrate a role for specific
peptides in inducing individual cell types of the myotome. Collectively, these
investigations have implicated the products of the Wnt, Hedgehog (Hh) and Bone
morphogenetic protein (Bmp) gene families as key myogenic regulators;
simultaneously controlling both the initiation of myogenesis and the fate of
individual myoblasts.
PMID- 9545514
TI - Molecular cloning of human caveolin 3.
AB - We isolated a full-length cDNA encoding human caveolin 3, which is 72% and 59%
homologous to human caveolin 1 and caveolin 2, respectively. Human caveolin 3
protein contains the 'caveolin signature sequence' and the 33 amino acids
spanning intramembrane domain common to all caveolins. Northern blot analysis
indicates that the caveolin 3 transcript is 1.6 kb in size and exclusively
detectable in muscle tissue.
PMID- 9545515
TI - cDNA cloning and expression of a novel CYP3A from the Syrian hamster, CYP3A31.
AB - A clone, encoding a cytochrome P450 protein consisting of 501 amino acids, was
isolated from a cDNA library constructed from mRNA of Syrian hamster liver. The
deduced amino acid sequence of this clone showed a high homology (65 to 81%) with
other mammalian CYP3As and hence, this novel isozyme was named CYP3A31. By
Northern blotting, using an oligonucleotide specific to CYP3A31, the mRNA for
this isozyme was shown to be expressed constitutively in liver and induced by
treatment with phenobarbital but repressed by 3-methylcholanthrene or
dexamethasone treatments. The increase in mRNA expression by phenobarbital and
decrease by dexamethasone corresponded to changes in CYP3A protein as analysed by
Western blotting. These indicate that CYP3A31 might constitute one of the major
CYP3A isozymes in the hamster.
PMID- 9545516
TI - Molecular basis for evasion of host immunity and pathogenesis in malaria.
AB - The article relates the ability of the malaria parasite Plasmodium falciparum to
avoid a protective immune response, and to induce pathological changes, to the
properties of specific parasite molecules. Cytoadherence and rosetting are
important features of cerebral malaria and involve proteins located on the
surface of the infected red blood cell. Proinflammatory cytokines, particularly
tumour necrosis factor (TNF), play a role in protective immunity and in inducing
pathology. Glycophosphatidyl inositol membrane anchors of parasite proteins
possess insulin like activity and induce TNF synthesis. People subject to
repeated infections in malaria endemic areas rarely develop complete or sterile
immunity to malaria. They frequently carry small numbers of parasites in the
blood, with little symptoms of the disease, illustrating a phenomenon termed semi
immunity. The basis for semi-immunity is incompletely understood. Malaria
parasites are susceptible to several immunological effector mechanisms. The
presence of extensive repetitive regions is a feature of many P. falciparum
proteins. Available evidence suggests that the structural characteristics of the
repeats and their location on the surface of parasite proteins promote
immunogenicity. The repeats may help the parasite evade host immunity by (i)
exhibiting sequence polymorphism, (ii) preventing the normal affinity and isotype
maturation of an immune response, (iii) functioning possibly as B cell
superantigens, (iv) generating predominantly thymus independent antibody
responses, and (v) acting as a sink for binding protective antibodies. Sequence
diversity in non-repetitive regions and antigenic variation in parasite molecules
located on the surface of infected red blood cells also play a role in immune
evasion. Some sequence homologies between parasite and human proteins may be due
to molecular mimicry. Homologies in other instances can cause autoimmune
responses. The immune evasion mechanisms of the parasite need to be considered in
developing vaccines. Protective immunity and pathology may be delicately balanced
in malaria.
PMID- 9545517
TI - The complex between retinol and retinol-binding protein is formed in the rough
microsomes of liver following repletion of vitamin A-depleted rats.
AB - Retinol-binding protein (RBP), the plasma transport protein for vitamin A, is
primarily synthesized in the rough endoplasmic reticulum of the liver. RBP then
passes through the smooth endoplasmic reticulum and into the Golgi apparatus
where vesicles form and transport the protein to the cell membrane. When rats
were depleted of their vitamin A stores, RBP accumulated in the liver microsomes,
particularly in the rough microsomes. To identify the organelle(s) where retinol
initially binds to RBP, vitamin A-depleted rats were given an i.v. injection of
[3H]retinol suspended in Tween 40. After intervals of 2, 3, 4, 5, 6, 8, 10, 15
and 20 min, liver fractions enriched in rough and smooth microsomes and Golgi
apparatus were prepared. The retinol/RBP complex (holoRBP) was detected in the
rough microsomes within 3 min post injection. HoloRBP later appeared in the
smooth microsomes and Golgi fraction, and then the serum at time intervals
consistent with the known secretion rate for RBP. HoloRBP was detected in the
rough microsomes at all times after 3 min, whether or not the complex was present
in the other subcellular fractions. Thus, the holoRBP complex can form in the
rough endoplasmic reticulum of the liver.
PMID- 9545518
TI - Cloning and characterization of vascular endothelial growth factor (VEGF) from
zebrafish, Danio rerio.
AB - We have cloned and sequenced a zebrafish (Danio rerio) Vascular Endothelial
Growth Factor (vegf) cDNA. It encodes a precursor protein of 188 amino acids with
a putative 23 amino acids signal peptide. Sequence comparison analysis indicates
that the zebrafish vegf cDNA corresponds to the human VEGF165 isoform and shows
about 52% identity to human VEGF165 at the amino acid level. A 2.8 kb vegf
message RNA was detected in adult zebrafish by Northern blot analysis. Expression
of vegf165 is also detected by RT-PCR in adult fish and throughout the zebrafish
embryonic development. Whole mount in situ hybridization of zebrafish embryos
indicates strong expression in four areas of the 18-19 h post-fertilization (hpf)
embryo: within the anterior central nervous system in the prospective optic
stalk, in mesoderm overlapping the bilaterally located merging heart fields, in
mesoderm underlying and flanking the hindbrain posterior to rhombomere 4, and in
medial regions of the somites. The study of vegf function in zebrafish embryonic
vascular development will contribute to our understanding of the mechanisms of
vertebrate endothelial cell differentiation and vasculature formation.
PMID- 9545519
TI - Characterisation of non-transferrin-bound iron (ferric citrate) uptake by rat
hepatocytes in culture.
AB - Under conditions of iron overload plasma transferrin can be fully saturated and
the plasma can transport non-transferrin-bound Fe which is rapidly cleared by the
liver. Much of this Fe is complexed by citrate. The aim of the present work was
to characterise the mechanisms by which Fe-citrate is taken up by hepatocytes
using a rat hepatocyte cell culture model. The cells, after one day in culture,
were incubated with 59Fe-labelled Fe-citrate for varying time periods, then
washed and Fe uptake to the membrane and intracellular compartments of the cell
was determined by radioactivity measurements. Maximal rates of internalisation of
Fe occurred at a Fe:citrate molar ratio of 1:100 or greater, a pH of
approximately 7.4 and an extracellular Ca2+ concentration of 1.0 mM. Fe uptake
showed Michaelis-Menten kinetics and was a temperature-dependent process. The
K(m) and Vmax for Fe internalisation by the cells at 37 degrees C were
approximately 7 microM and 2 nmol/mg DNA/min (25 x 10(6) atoms/cell/min),
respectively; and the Arrhenius activation energy was 35 kJ/mol. The transition
metals, Zn2+, Co2+ and Ni2+, inhibited Fe uptake when used at 10 and 100 times
the concentration of Fe. The rate of Fe internalisation from Fe-citrate was found
to be approximately 20 times as great as that from Fe-transferrin with Fe
concentrations of 1 and 2.5 microM for both forms of Fe. The rate of Fe uptake by
iron-loaded hepatocytes obtained from rats which had been fed carbonyl Fe was not
significantly different from that by normal hepatocytes. These experiments show
that rat hepatocytes in primary culture have a high capacity to take up non
transferrin-bound Fe in the form of Fe-citrate and that uptake occurs by
facilitated diffusion. The iron transport process does not appear to be regulated
by cellular Fe levels.
PMID- 9545520
TI - Molecular analysis of a glucose-regulated gene (grp78) of Neurospora crassa.
AB - The nucleotide sequence of the gene encoding the glucose-regulated protein 78
(GRP78) of Neurospora crassa was determined. The ORF codes for a protein of 662
amino acids (72 kDa) and belongs to the heat shock protein 70 (hsp70) gene
family, which is characterized by three HSP70 'signature sequences'. The grp78
gene contains 5 introns. The protein carries the ER retention signal HDEL at its
carboxy terminus and is most homologous to the KAR2/GRP78 protein of
Saccharomyces cerevisiae (78%) and to KAR2/BiP of Yarrowia lipolytica (76%). The
expression of grp78 is constitutive and can be enhanced by starvation, treatment
with tunicamycin, the calcium ionophore A23187 or elevated temperatures (40
degrees C). An uninterrupted ORF was found on the reverse cDNA strand of grp78.
The putative peptide shows 47% homology to the NAD-specific glutamate
dehydrogenase of Achlya klebsiana.
PMID- 9545521
TI - Capsulin: a novel bHLH transcription factor expressed in epicardial progenitors
and mesenchyme of visceral organs.
AB - Members of the basic helix-loop-helix (bHLH) family of transcription factors have
been shown to control development and differentiation of a variety of cell types.
We describe a novel bHLH protein, called capsulin, which is expressed
specifically in mesodermally-derived cells that surround the epithelium of the
developing gastrointestinal, genitourinary and respiratory systems during mouse
embryogenesis. Capsulin transcripts also mark the spiral septum of the heart and
progenitor cells that give rise to the pericardium and coronary arteries.
Capsulin shares high homology with a recently identified bHLH protein from
Drosophila, called bHLH102C, which is expressed in visceral muscle cells that
surround the midgut. Capsulin binds a specific E-box consensus sequence (CANNTG)
as a heterodimer with the widely-expressed bHLH protein E12, but it does not
activate transcription through that sequence on its own. Its restricted
expression pattern and DNA binding activity suggest that capsulin regulates gene
expression in specific subtypes of visceral mesodermal cells involved in
organogenesis and in precursor cells that contribute to the pericardium, coronary
arteries and regions of the heart.
PMID- 9545522
TI - Sequencing and high level expression in Escherichia coli of the tropomyosin
allergen (Der p 10) from Dermatophagoides pteronyssinus.
AB - The cDNA encoding an allergen from the dust mite Dermatophagoides pteronyssinus
has been cloned and sequenced. The allergen (Der p 10) is a tropomyosin that
shared more than 65% identical residues with other invertebrate tropomyosins. The
final recovery of recombinant Der p 10 from the culture media after a single
purification step was as much as 26 mg/l. The recombinant allergen is reactive to
shrimp antitropomyosin IgG antibodies and has a 5.6% frequency of IgE reactivity
in sera from mite-allergic patients.
PMID- 9545523
TI - Appearance of cross linked proteins in human atheroma and rat pre-fibrotic liver
detected by a new monoclonal antibody.
AB - A new monoclonal antibody against malondialdehyde (MDA)-treated low density
lipoprotein (LDL) was raised using homogenate of human atheroma as immunogen.
This antibody, DLH2, was obtained by selecting the clones which did not react to
native LDL but did react to copper-induced oxidized LDL (OxLDL). DLH2 showed a
greater reactivity to MDA-LDL than to OxLDL. When LDL was treated with various
aldehyde containing reagents, treatment of LDL with glutaraldehyde or MDA greatly
increased the reactivity to the antibody, while LDL treated with 2,4-hexadienal
or 4-hydroxynonenal was not reactive. Among many proteins tested, high density
lipoprotein, bovine serum albumin and hemoglobin showed significant reactivity to
DLH2 after they were treated with MDA or glutaraldehyde. When low density and
high density lipoproteins treated with MDA were subjected to immunoblot analysis,
newly formed products larger than the original apolipoproteins were detected with
the antibody, suggesting that this antibody recognizes aggregated proteins with
divalent short chain cross linkers. The antigenic materials were shown by
immunohistochemical analysis to be present in foamy macrophages in human
atheromatous lesions. DLH2 antigen did not colocalize either with apolipoprotein
B. Furthermore, we found a massive accumulation of the antigenic material in
Kupffer cells in the liver of rats treated with alcohol and carbonyl iron, a
model of hepatic fibrosis due to oxidative stress. These results suggest the
presence of cross linked proteins in damaged tissues.
PMID- 9545524
TI - Effects of cyclopentenone prostaglandins and related compounds on insulin-like
growth factor-I and Waf1 gene expression.
AB - The molecular pathways by which the cyclopentenone prostaglandins (PGA and PGJ
series) inhibit cell growth and tumorigenicity are poorly understood. These
cellular responses may be caused by specific regulation of growth-related and
stress-induced genes. A variety of prostaglandins were tested for their ability
to regulate insulin-like growth factor-I (IGF-I) and Waf1 gene expression in C6
rat glioma cells. The prostaglandins (in order of potency) PGJ2 > PGA1 > PGA2,
approximately PGD2 >> PGE2 all significantly repressed IGF-I gene expression.
With the exception of PGE2, the same prostaglandins that repressed IGF-I also
induced Waf1 gene expression. However, the order of potency for Waf1 induction
was different than for IGF-I repression: PGA2 > PGA1 approximately PGJ2 > PGD2.
The different order of potency of the prostaglandins in regulating IGF-I and Waf1
gene expression suggests that different intracellular signals may be involved in
regulating the two genes. Augmentation of glutathione levels by pretreatment of
cells with N-acetyl-L-cysteine attenuated the effect of PGA2 on IGF-I and Waf1
gene expression. conversely, depletion of the intracellular glutathione pool by
pretreatment with buthionine sulfoximine potentiated the effect of PGA2 on the
expression of both genes. These results suggest that conjugation with glutathione
prevents the regulation of gene expression by PGA2. We also tested the effect of
several simpler compounds that contain a five-membered ring system on IGF-I and
Waf1 gene expression. 2-Cyclopenten-1-one, but not cyclopentene or cyclopentene,
repressed IGF-I and induced Waf1 gene expression, demonstrating the requirement
for an alpha, beta-unsaturated carbonyl for regulation of the two genes. The
dione compound 4-cyclopentene-1,3-dione, which has two potentially reactive
carbons rather than one, was considerably more potent than 2-cyclopentene-1-one
in repressing IGF-I gene expression (IC50 = 30 microM for 4-cyclopentene-1,3
dione as compared with 167 microM for 2-cyclopentene-1-one). Additional results
indicated that diethyl maleate, which has two alpha,beta-unsaturated carbonyls in
a non-cyclic configuration, also repressed IGF-I gene expression (IC50 = 214
microM) and induced Waf1 gene expression, indicating that the cyclic structure is
not required for either effect.
PMID- 9545525
TI - Oriented growth of calcium oxalate monohydrate crystals beneath phospholipid
monolayers.
AB - Oriented calcium oxalate crystals have been grown beneath phospholipid monolayers
at the air-solution interface from supersaturated calcium oxalate solutions.
Mature calcium oxalate crystals grown beneath zwitterionic
dipalmitoylphosphatidylcholine (DPPC) monolayers exhibit the characteristic
morphology of calcium oxalate monohydrate (COM) crystals with the elongated (101)
crystal face preferentially oriented parallel to the plane of the monolayer.
Calcium oxalate crystals grown beneath negatively-charged
dimyristoylphosphatidylserine (DMPS) monolayers also show a preferential
orientation with respect to the monolayer; they do not, however, exhibit the
characteristic COM morphology. Raman spectroscopy strongly suggests that the
crystals grown beneath either DPPC or DMPS monolayers are the monohydrate phase
of calcium oxalate; therefore, differences in crystal morphology are not due to
differences in the crystalline phase. Dimyristoylphosphatidylethanolamine (DMPE),
dimyristoylphosphatidic acid (DMPA), eicosanoic acid (C20), and eicosanol (C20
OH) monolayers have also been studied to help elucidate the mechanisms of
interaction between the lipid monolayers and the calcium oxalate crystals. We
discuss the roles of lattice matching, hydrogen bonding, stereochemistry and
electrostatics on crystal orientation and morphology.
PMID- 9545526
TI - Cloning of capsulin, a basic helix-loop-helix factor expressed in progenitor
cells of the pericardium and the coronary arteries.
AB - The basic helix-loop-helix (bHLH) class of transcription factors have been linked
to a variety of cellular differentiation processes, including myogenesis,
neurogenesis and hematopoiesis. Here we report the cloning of a new member of
this family of factors, capsulin. Capsulin was shown to be expressed as early as
9.5 days of mouse development, with expression in mesodermal cells that are
progenitors of the epicardium and the coronary arteries. At later stages of
development, expression is seen in mesenchymal cells that are closely associated
with the epithelium of the developing lung, gut and kidney. In the proepicardial
organ, and in the organs where it is expressed in later development, capsulin is
expressed in cells that give will give rise to smooth muscle. Given the likely
expression of capsulin in smooth muscle cell progenitors, and significant
sequence similarity through the bHLH domain, capsulin may be a functional
ortholog of a Drosophila gene that is expressed in cells that give rise to the
longitudinal visceral muscle. Capsulin alone or in combination with other bHLH
proteins, was shown to function as a transcription factor by its ability to
transactivate both a synthetic and a native promoter, each of which contains
multiple E-boxes. These studies extend the growing family of bHLH factors that
are expressed in the early mesoderm, and suggest that capsulin may have a
functional role in development of the coronary vasculature and organs containing
epithelial lined tubular structures.
PMID- 9545527
TI - Stringent structural requirements for anti-Ras activity of S-prenyl analogues.
AB - The carboxy terminal S-farnesylcysteine of Ras oncoproteins is required for their
membrane anchorage and transforming activities. We showed previously that S
farnesylthiosalicylic acid (FTS) affects the membrane anchorage of activated H
Ras in EJ cells and inhibits their growth. We report here on structural elements
in S-prenyl derivatives that specifically inhibit the growth of EJ cells, but not
of untransformed Rat-1 cells. Inhibition of the Ras-dependent extracellular
signal-regulated protein kinase (ERK), of DNA synthesis and of EJ cell growth
were apparent after treatment with FTS or its 5-fluoro, 5-chloro and 4-fluoro
derivatives or with the C20 S-geranylgeranyl derivative of thiosalicylic acid.
The 4-Cl-FTS analogue was a weak inhibitor of EJ cell growth. The 3-Cl-FTS
analogue and the FTS carboxyl methyl ester were inactive, as were the C10 S
geranyl derivative of thiosalicylic acid, farnesoic acid, N-acetyl-S-farnesyl-L
cysteine and S-farne-sylthiopropionic acid. The structural requirements for anti
Ras activity of S-prenyl analogues thus appear to be rather stringent. With
regard to chain length, the C15 farnesyl group linked to a rigid backbone seems
to be necessary and sufficient. A free carboxyl group in an appropriately rigid
orientation, as in thiosalicylic acid, is also required. Halogenic substitutents
on the benzene ring of the thiosalicylic acid are tolerated only at position 5 or
4. This information may facilitate the design of potent Ras antagonists and
deepen our understanding of the mode of association of Ras with the plasma
membrane.
PMID- 9545528
TI - Characterization of HSE sequences in human Hsp40 gene: structural and promoter
analysis.
AB - We have recently cloned a gene of Hsp40, a human homologue of bacterial DnaJ.
Here we describe the structural and promoter analysis of human Hsp40 gene.
Analysis of Hsp40 transcripts by 5' and 3' RACE suggested that they have
different 3' ends, and primer extension studies revealed that the major
transcription initiation site was localized 47 bp upstream of the ATG translation
initiation codon. Promoter analysis using deletion derivatives defined a minimal
region which was active in response to heat shock. The region contained the
consensus heat shock element (HSE) sequences. The factor bound to these sequences
was suggested to be a heat shock factor 1 (HSF1) by gel mobility supershift
assay. In vivo footprinting and promoter analysis revealed that the HSEs in 5'
upstream region of human Hsp40 gene were composed of eight contiguous (A/G)GAAN
motifs and were essential for heat shock response. These results indicate that
Hsp40 is a real heat shock protein. It is also shown that the HSE found in the
first intron might not be the essential element for heat shock response.
PMID- 9545529
TI - Expression of two zebrafish homologues of the murine Six3 gene demarcates the
initial eye primordia.
AB - The murine homeobox gene Six3 and its Drosophila homologue sine oculis both have
regulatory functions in eye development. We report the isolation and
characterization of two zebrafish genes, six3 and six6, that are closely related
to the murine Six3 gene. Zebrafish six3 may be the structural orthologue, while
the six6 gene is more similar with respect to embryonic expression. Transcripts
of both zebrafish six genes are first detected in involuting axial mesendoderm
and, subsequently, in the overlying anterior neural plate from which the optic
vesicles and the forebrain will develop. Direct correspondence between six3/six6
expression boundaries and the optic vesicles indicate essential roles in defining
the eye primordia. During later stages only the six6 gene displays similar
features of expression in the eyes and rostral brain as reported previously for
murine Six3.
PMID- 9545530
TI - Protective effects of carnosine against protein modification mediated by
malondialdehyde and hypochlorite.
AB - Malondialdehyde (MDA) and hypochlorite anions are deleterious products of oxygen
free-radical metabolism. The effects of carnosine, a naturally occurring
dipeptide (beta-alanyl-L-histidine), on protein modification mediated by MDA and
hypochlorite have been studied. MDA and hypochlorite induced formation of
carbonyl groups and high molecular weight and cross-linked forms of crystallin,
ovalbumin and bovine serum albumin. The presence of carnosine effectively
inhibited these modifications in a concentration-dependent manner. It is proposed
that relatively non-toxic carnosine and related peptides might be explored as
potential therapeutic agents for pathologies that involve protein modification
mediated by MDA or hypochlorite.
PMID- 9545531
TI - Granule associated DNase in T4 and T8 lymphocytes from patients with autoimmune
diseases.
AB - The presence of a DNase activity associated with secretion granules was detected
in T4 and T8 lymphocytes from patients with autoimmune diseases. This activity
was much higher in primary biliary cirrhosis (PBC) than in Graves' disease (GD)
and multiple sclerosis (MS) or in healthy subjects. This granule associated DNase
activity was Ca(2+)-dependent, inhibited by Zn2+, and higher at low pH; its
molecular weight corresponded to 66kDa; it was more active with double-strand
than single-strand DNA. Judging from its properties this enzyme differed from the
three types of endonucleases described as involved in DNA fragmentation (DNase I,
DNase II and NUC18). Flow cytometry analysis of T lymphocytes showed that DNase
activity associated with CD4+ lymphocyte granules correlated with the ratio
CD4+CD45RO+/CD4+CD45RA+ (memory and cytotoxic cells/naive cells, inducers of
suppression). In contrast, T8 lymphocyte DNase activity correlated with the
proportion of CD4+ lymphocytes with CD4+CD45RA- phenotype (helpers and inducers
of cytotoxicity). The possible role of this DNase activity in the mechanisms of
lysis or apoptosis mediated by CTL is discussed. We suggest that this DNase
activity could be implicated in some of the alterations of the autoimmune
response depending on cytotoxic T lymphocytes or T cell inducers of apoptosis.
PMID- 9545532
TI - Hydroxyl radical formation resulting from the interaction of nitric oxide and
hydrogen peroxide.
AB - The highly reactive and cytotoxic hydroxyl radical (OH) was found by
electrochemical detection to be produced in reactions involving hydrogen peroxide
(H2O2) and the nitric oxide (NO) donor diethylamine- NO complex. Using aromatic
hydroxylation of salicylate as a specific indicator of OH, three salicylate
hydroxylation products were identified; catechol, 2,3- and 2,5-dihydroxybenzoic
acid. Four additional compounds were detected but not identified. The
interactions of H2O2 and NO represent a biologically feasible reaction mechanism
that can account for OH-induced damage in cellular environments where transition
metal ions are unavailable for participation in the superoxide-mediated Fenton
reaction. The ability of the NO/H2O2 complex to generate OH independently of iron
or other transition metals provides a new focus for studies concerned with the
origin of tissue-specific damage caused by oxygen-derived species.
PMID- 9545533
TI - Design of metal-binding green fluorescent protein variants.
AB - Diglycylcysteine motifs bind reduced oxo-compounds of technetium-99m, an
important isotope in nuclear imaging. We suggested a system for detecting gene
expression employing the effect of oxo[99mTc]technetate (Tc(V)O3+) transchelation
and coordination with redox amino acid motifs. DNA fragments encoding
diglycylcysteine (GGC) binding motifs were prepared by PCR and positioned
downstream from the green fluorescent protein (GFP) cDNA insert. Using a
Bluescript (+) vector with the fusion protein positioned under the control of a
lac promoter, we obtained several E. coli clones expressing the following GFP
fusion peptides: (1) GFP-P1 bearing a 'hydrophilic' C-terminal peptide
(LEGGGCEGGC) containing two residues of glutamic acid and C-terminal cysteine (2)
GFP-P2 carrying a 'hydrophobic' (LGGGGCGGGCGI) peptide (3) a control GFP fusion
peptide with deleted C-terminal portion. Bacterial lysates obtained from the
corresponding clones were tested for oxo[99mTc] technetate transchelation from a
glucoheptonate complex. We found, using a solid phase assay, that radioactivity
associated with protein lysates obtained from clones expressing GFP-P2 fusions
were 3-4 fold higher than lysates prepared from a clone expressing a truncated
GFP fusion protein lacking the C-terminal GGC motifs. High expression of GFP
fusions (5-21% of total protein) was demonstrated by electrophoresis and verified
by immunoblotting. Specific association of the isotope with GFP-P2 fusion
proteins was detected upon incubation of gels in the presence of
[99mTc]glucoheptonate, while no binding of oxo[99mTc]technetate to GFP-P1 was
revealed. We demonstrated, by using semi-quantitative autoradiography, that there
is a 10-fold higher binding of oxotechnetate to GFP-P2 than to a control GFP
fusion protein. The implications of the study for in vivo gene expression imaging
are discussed.
PMID- 9545534
TI - Abnormalities of floor plate, notochord and somite differentiation in the loop
tail (Lp) mouse: a model of severe neural tube defects.
AB - Mouse embryos homozygous for the loop-tail (Lp) mutation fail to initiate neural
tube closure at E8.5, leading to a severe malformation in which the neural tube
remains open from midbrain to tail. During initiation of closure, the normal
mouse neural plate bends sharply in the midline, at the site of the future floor
plate. In contrast, Lp/Lp embryos exhibit a broad region of flat neural plate in
the midline, displacing the sites of neuroepithelial bending to more lateral
positions. Sonic hedgehog (Shh) and Netrin1 are expressed in abnormally broad
domains in the ventral midline of the E9.5 Lp/Lp neural tube, suggesting over
abundant differentiation of the floor plate. The notochord is also abnormally
broad in Lp/Lp embryos with enlarged domains of Shh and Brachyury expression. The
paraxial mesoderm shows evidence of ventralisation, with increased expression of
the sclerotomal marker Pax1, and diminished expression of the dermomyotomal
marker Pax3. While the expression domain of Pax3 does not differ markedly from
wild-type, there is a dorsal shift in the domain of Pax6 expression in the neural
tube at caudal levels of Lp/Lp embryos. We suggest that the Lp mutation causes
excessive differentiation of floor-plate and notochord, with over-production of
Shh from these midline structures causing ventralisation of the paraxial mesoderm
and, to a lesser extent, the neural tube. Comparison with other mouse mutants
suggests that the enlarged floor plate may be responsible for the failure of
neural tube closure in Lp/Lp embryos.
PMID- 9545535
TI - Regulation of pyruvate dehydrogenase activity and glucose metabolism in post
ischaemic myocardium.
AB - Pyruvate dehydrogenase (PDH) is regulated both by covalent modification and
through modulation of the active enzyme by metabolites. In the isolated heart,
post-ischaemic inhibition of PDH, leading to uncoupling of glycolysis and glucose
oxidation and a decrease in cardiac efficiency, has been described. In vivo, post
ischaemic reperfusion leads to metabolic abnormalities consistent with PDH
inhibition, but the effects of ischaemia/reperfusion on PDH are not well
characterized. We therefore investigated PDH regulation following transient
ischaemia in vivo. In 33 open-chest dogs, the left anterior descending (LAD) was
occluded for 20 min followed by 4 h reperfusion. In 17 dogs, dichloroacetate
(DCA) was injected prior to reperfusion, while 16 dogs served as controls. In
dogs without DCA, glucose oxidation and lactate uptake were lower in reperfused
than in remote tissue, suggesting reduced flux through PDH. However, percent
active and total PDH measured in myocardial biopsies were similar in both
territories, excluding covalent enzyme modification or loss of functional enzyme.
DCA activated PDH activity similarly in both regions and abolished differences in
glucose oxidation and lactate uptake. Thus, decreased PDH flux in reperfused
myocardium does not result from covalent modification or loss of total enzyme
activity, but more likely from metabolite inhibition of the active enzyme. DCA
leads to essentially complete activation of PDH, increases overall glucose
utilization and abolishes post-ischaemic inhibition of glucose oxidation.
PMID- 9545536
TI - Time resolved absorption study of the reaction of hydroxyurea with sickle cell
hemoglobin.
AB - Hydroxyurea has been mixed with hemoglobin S and the reaction was studied using
electronic absorption spectroscopy as a function of time and wavelength. The rate
of conversion of oxyhemoglobin S to other species was determined and the nature
of the reaction products was studied. We also report the formation of
methemoglobin (and other reaction products) when deoxyhemoglobin S is combined
with hydroxyurea. The probable increase in the formation of methemoglobin, and
other potential reaction products such as nitric oxide-hemoglobin, in patients
with sickle cell anemia who are taking hydroxyurea as a therapeutic drug is
discussed in terms of the pathophysiology of the disease. It is proposed that
methemoglobin and possibly nitric oxide-hemoglobin formation may partially
explain beneficial effects observed in these patients before their levels of
fetal hemoglobin have increased.
PMID- 9545537
TI - Repressible antisense inhibition in B lymphocytes.
AB - The tetracycline-responsive promoter (TRP) system has been adopted in an attempt
to obtain repressible antisense inhibition in a B lymphocyte model in vitro.
Levels of secreted IgM protein and mRNA were assessed following the stable
transfection of B cell line, HO-2.2, with a series of plasmid constructs
containing antisense or sense target sequence DNA (the 3'-untranslated region
adjacent to the secreted exon of IgM gene) under the control of the TRP.
Significant reduction (approximately 90%) in IgM secretion was observed for
clones transfected with antisense plasmids driven by the TRP and containing the
IgH enhancer element and the polyadenylation signal sequence from membrane IgM,
when compared with untransfected and sense controls. Tetracycline (1
microgram/ml) addition to the culture medium restored the level of IgM secretion
in these clones to control values, demonstrating repressibility of antisense
inhibition. Transfection of HO-2.2 cells with antisense (or sense) constructs had
no detectable effect on membrane IgM protein levels. Hybridisation studies
demonstrated that decreased protein production observed in the antisense
transfected clones was most likely attributable to reduced RNA levels. These data
show that the TRP can be used for repressible and specific antisense inhibition
of gene product expression in B lymphocytes.
PMID- 9545538
TI - Duplication and triplication with staggered breakpoints in human mitochondrial
DNA.
AB - We identified a tandem duplication and triplication of a mitochondrial DNA
(mtDNA) segment in the muscle of a 57-year-old man with no evidence of a
neuromuscular disorder. A large triplication of a mtDNA coding region has not
been previously reported in humans. Furthermore, the rearrangements (comprising
10-12% of the muscle mtDNA pool in the propositus) were unique because the
breakpoints were staggered at both ends (between mtDNA positions 3263-3272 and
16,065-16,076) and contained no identifiable direct repeats. Both sides of the
breakpoint were located approximately 35 bp downstream of regions that undergo
frequent strand displacement by either transcription (positions 3263-3272) or
replication (positions 16,065-16,076), suggesting that topological changes
generated by the movement of RNA/DNA polymerases may be associated with the
genesis of a subclass of mtDNA rearrangements. The presence of low levels of
these rearrangements in other normal adults also suggest that these mutations are
not rare. The characterization of these rearrangements shed light on potential
alternative mechanisms for the genesis of mtDNA rearrangements.
PMID- 9545539
TI - The Xenopus Emx genes identify presumptive dorsal telencephalon and are induced
by head organizer signals.
AB - We have isolated and studied the expression pattern of Xemx1 and Xemx2 genes in
Xenopus laevis. Xemx genes are the homologues of mouse Emx genes, related to
Drosophila empty spiracles. They are expressed in selected regions of the
developing brain, particularly in the telencephalon, and, outside the brain, in
the otic vesicles, olfactory placodes, visceral arches and the developing
excretory system. We also report on experiments concerning the tissue and
molecular signals responsible for their activation in competent ectoderm. Xemx
genes are activated in ectoderm conjugated with head organizer tissue, but not
with tail organizer tissue. Furthermore, they are not activated in animal cap
either by noggin or by Xnr3, thus suggesting that a different inducer or the
integration of several signals may be responsible for their activation.
PMID- 9545540
TI - Direct structural evidence for formation of a stem-loop structure involved in
ribosomal frameshifting in human immunodeficiency virus type 1.
AB - Programmed ribosomal frameshifting in viral messenger RNA occurs in response to
neighboring sequence elements consisting of: a frameshift site, a spacer, and a
downstream enhancer sequence. In human immunodeficiency virus type 1 (HIV-1)
mRNA, this sequence element has a potential to form either a stem-loop or a
pseudoknot structure. Based on many mutational studies, the stem-loop structure
has been proposed for the downstream enhancer region of the HIV-1 mRNA. This
stimulatory stem-loop structure is separated from the shift site by a spacer of
seven nucleotides. In contrast, a recent report has proposed an alternative model
in which the bases in the spacer sequence form a pseudoknot structure as the
downstream enhancer sequence [Du et al., Biochemistry 35 (1996) 4187-4198.].
Using UV melting and enzymatic mapping analyses, we have investigated the
conformation of the sequence region involved in ribosomal frameshifting in HIV-1.
Our S1, V1, and T1 endonuclease mappings, together with UV melting analysis,
clearly indicate that this sequence element of the HIV-1 mRNA frameshift site
forms a stem-loop structure, not a pseudoknot structure. This finding further
supports the stem-loop structure proposed by many mutational studies for the
downstream enhancer sequence of the HIV-1 mRNA.
PMID- 9545542
TI - Interaction between N-terminal domain of H4 and DNA is regulated by the
acetylation degree.
AB - To study whether the acetylation of one or more of the four acetylatable lysines
of histone H4 affects its binding to DNA, we have designed a protection
experiment with a model system consisting in phage lambda DNA as substrate, StuI
as restriction endonuclease and histone H4 with different degrees of acetylation
as the protective agent. It can be deduced from the experimental data that the
protection afforded by the histone is not dependent on the number of positive
charges lost by acetylation. Thus, non-acetylated H4 and mono-acetylated H4 cause
similar protection, while di-acetylation of the histone seems to be the crucial
step in significantly weakening the interaction between H4 and DNA. This is
confirmed by the results obtained in protection experiments carried out using H4
peptide (1-24) with different degrees of acetylation as the protecting agent. As
restriction enzyme can imitate any trans-acting factor with sequence recognition,
the di-acetylated isoform of histone H4 can be the starting point, through
acetylation, to unmask DNA sequences, allowing the accessibility of regulatory
factors to DNA in the chromatin.
PMID- 9545541
TI - Induction of prothrombin synthesis by K-vitamins compared in vitamin K-deficient
and in brodifacoum-treated rats.
AB - Vitamin K is a group name for a number of prenylated 2-methyl-1,4-naphtoquinones,
which may differ in their ability to function as a cofactor for prothrombin
biosynthesis. To quantify the bioactivity of different forms of vitamin K, two
experimental animal systems are frequently used: vitamin K-deficient rats and
anticoagulated rats. In this paper both models are compared, and it is shown that
the results obtained depend on the model used. The main reason for this
discrepancy is the difference in recycling of vitamin K-epoxide, which results in
a 500 times higher vitamin K requirement in anticoagulated rats. Absorption and
hepatic accumulation of long chain menaquinones seem to be restricted to a
maximum, whereas also the lipophilic nature of long chain menaquinones may hamper
the quinone-quinol reduction in anticoagulated animals. If these data may be
extrapolated to patients, food items rich in K1 and MK-4 would be expected to
influence the stability of oral anticoagulation to a much larger extent than food
items primarily containing higher menaquinones.
PMID- 9545543
TI - Identification of new mutations in the adenylosuccinate lyase gene associated
with impaired enzyme activity in lymphocytes and red blood cells.
AB - We determined the DNA sequence of the adenylosuccinate lyase (ASL) gene from a 13
year-old female, who showed a reduced ASL enzymatic activity in lymphocytes and
red blood cells and suffered from severe psychomotor retardation. The patient was
the offspring of a non-consanguineous marriage. She was found to be compound
heterozygous for two missense-mutations located on different alleles (C300-G and
G1266-T): the first mutation replaces Pro75 by Ala, the second mutation replaces
Asp397 by Tyr.
PMID- 9545544
TI - Quantitative measurements of the interaction between monosialoganglioside
monolayers and wheat germ agglutinin (WGA) by a quartz-crystal microbalance.
AB - Monosialogangliosides (GM1, GM2, GM3 and GM4) were reconstituted in lipid
monolayers at the air-water interface. The binding amounts and the initial
binding rates of wheat germ agglutinin (WGA) to the monosialoganglioside
monolayers were quantitatively studied by use of a quartz-crystal microbalance
(QCM). A QCM was horizontally attached to the monolayer from the air phase, and
the binding behavior (mass increase) was followed by the frequency decrease of
the QCM. WGA binding affinities for the ganglioside monolayers were influenced by
hydrophilic head groups of lipid matrices, densities of gangliosides, and
sequences of oligosaccharide in gangliosides. Binding of WGA to the gangliosides
reconstituted in a phosphatidylcholine (sphingomyelin and
distearoylphosphatidylcholine) matrix was strongly suppressed, but not in a
neutral glycolipids (GlcCer, GalCer, and LacCer),
dipalmitoylphosphatidylethanolamine, and dipalmitoylphosphatidylethanolamine
matrix. WGA showed high affinity for monolayers containing 20 mol% gangliosides,
but only low affinity for 100% ganglioside monolayers. WGA preferably binds to
gangliosides in the following sequence: GM3 > GM4 >> GM2 = GM1. No affinities of
WGA for GM2 and GM1 were observed. The combined techniques of monolayer and QCM
have the advantages of investigating recognition properties of gangliosides.
PMID- 9545545
TI - Mitochondrial gene expression and respiratory enzyme activities in cardiac
diseases.
AB - Respiratory enzyme activities and steady-state level of two mitochondrial-encoded
transcripts were quantified in heart muscle biopsies from patients suffering
various types of cardiomyopathies unrelated to mitochondrial primary disorders.
We have found that although the mitochondrial DNA copy number and the
concentration of COI and ND4 transcripts remain fairly constant, there is an
important increase (up to 6-fold) in respiratory enzyme activities affecting to
several oxidative phosphorylation complexes. Idiopathic dilated cardiomyopathy
shows the greatest increase, followed by ischemic heart and ventricular
hypertrophy due to aortic stenosis. The results suggest an energetic compensatory
mechanism in the heart muscle, in the absence of mitochondrial proliferation or
activation of mitochondrial gene expression.
PMID- 9545547
TI - Inhibition of nuclear factor kappa B attenuates proinflammatory cytokine and
inducible nitric-oxide synthase expression in postischemic myocardium.
AB - We have previously reported that induction of nuclear factor-kappa B (NF-kappa B)
occurs in a biphasic manner in postischemic myocardium. Because interleukin-1 (IL
1), IL-6, tumor necrosis factor-alpha (TNF-alpha), and inducible nitric-oxide
synthase (iNOS) contain kappa B-response elements, and since transforming growth
factor-beta 1 (TGF-beta 1) down-modulates both cytokine and iNOS expression, we
studied their temporal expression during myocardial ischemia/reperfusion (I/R).
Northern and Western analyses showed low levels of IL-6 and no signal for IL-1
beta, TNF-alpha and iNOS under basal conditions. Their expression rose
significantly over sham-operated controls by 1 h reperfusion, and persisted high
for various periods. Under basal conditions, low levels of TGF-beta 1 were
detected, which rose significantly at 3 h reperfusion, and remained high until 24
h reperfusion. Administration of diethyldithiocarbamate (DDC) inhibited induction
of NF-kappa B and concomitantly the expression of IL-1 beta, IL-6, TNF-alpha as
well as iNOS. However, expression of TGF-beta was not altered. Our results
indicate that ischemia/reperfusion induces NF-kappa B, and upregulates kappa B
response genes. Administration of DDC inhibits NF-kappa B levels, and attenuates
expression of inflammatory cytokines and iNOS.
PMID- 9545546
TI - Nkx2-9 is a novel homeobox transcription factor which demarcates ventral domains
in the developing mouse CNS.
AB - Nkx homeobox transcription factors are expressed in diverse embryonic cells and
presumably control cell-type specification and morphogenetic events. Nkx2-9 is a
novel family member of NK2 genes which lacks the conserved TN-domain found in all
hitherto known murine Nkx2 genes. The prominent expression of Nkx2-9 in ventral
brain and neural tube structures defines a subset of neuronal cells along the
entire neuraxis. During embryonic development, Nkx2-9-expressing cells shift from
the presumptive floor plate into a more dorsolateral position of the
neuroectoderm and later become limited to the ventricular zone. Nkx2-9 expression
overlaps with that of Nkx2-2 but is generally broader. While initially Nkx2-9 is
expressed in close proximity to sonic hedgehog, its expression domain clearly
segregates from sonic hedgehog at later developmental stages. The dynamic
expression pattern of Nkx2-9 in ventral domains of the CNS is consistent with a
possible role in the specification of a distinct subset of neurons.
PMID- 9545548
TI - Selection of monoclonal antibodies for probing of functional intermediates in
incision of UV-irradiated DNA by Uvr(A)BC endonuclease from Escherichia coli.
AB - Monoclonal antibodies (mAbs) were generated that recognize UvrA and UvrB
proteins. These proteins are components of the Uvr(A)BC endonuclease, which
initiates nucleotide excision repair in Escherichia coli. mAbs, which can be used
for probing of structural intermediates of Uvr(A)BC endonuclease functioning,
were selected for their ability to: (i) recognize different epitopes; (ii) have a
high-affinity for native antigenic protein; (iii) preserve functionality of the
Uvr protein in immunocomplex. The adherence of anti-Uvr mAbs with these criteria
was verified by additivity and competition tests, and by their influence on the
ATPase activities of UvrA and UvrB*, the functionally active proteolytic fragment
of UvrB. Two out of twelve anti-UvrA and seven out of thirteen anti-UvrB/anti
UvrB* hybridoma lines were shown to satisfy these criteria. Recognition of UvrA
and UvrB deletion mutant proteins by mAbs was used to map their epitopes.
Epitopes of A2D1 and A2B1 mAbs were mapped to regions of amino acids 230-281 and
560-680 of UvrA, respectively. Epitopes of anti-UvrB/UvrB* mAbs were assigned to
the following amino acid regions of UvrB: B2A1, 8-61; B2C5 and B*2E3, 171-278;
B2E2, 631-673; B3C1, 1-7 and/or 62-170; B*2B9, 473-630; B*3E11, 379-472. The
ability of selected mAbs to neutralize the incision function of Uvr(A)BC was
analyzed. The results are discussed in terms of the applicability of these mAbs
to probe the structures of intermediates in the functioning of Uvr(A)BC.
PMID- 9545549
TI - Identification of carbohydrate deficient transferrin forms by MALDI-TOF mass
spectrometry and lectin ELISABiochim Biophys Acta 1998 Aug 24;1381(3):356.
AB - Transferrin was isolated from sera of patients with severe alcohol abuse and from
control sera by affinity chromatography using an immobilized polyclonal antibody
from sheep, followed by gel filtration. The purified transferrin was then
separated by MonoQ chromatography. Compared to the controls, sera from heavy
alcohol consumers showed two additional transferrin peaks, eluting earlier than
the three main transferrin forms present in all sera. Further analysis of the
isolated transferrin forms by matrix assisted laser desorption/ionization time of
flight mass spectrometry (MALDI-TOF-MS) and enzyme linked immunosorbent assay
with different digoxigenylated lectins (lectin ELISA) revealed that the main
carbohydrate deficient transferrin (CDT) forms are lacking either one or both of
the N-Glycan chains.
PMID- 9545550
TI - Apparent continuity between the messenger transport organizer and late RNA
localization pathways during oogenesis in Xenopus.
AB - The localization of RNAs at the vegetal cortex in Xenopus oocytes is a complex
process, involving at least two different pathways. The early, or messenger
transport organizer (METRO), pathway, localizes RNAs such as Xlsirts, Xcat2 and
Xwnt11 during stages 1 and 2 of oogenesis, while the late pathway localizes RNAs
such as Vg1 during stages 2-4. We demonstrate that the onset of Vg1 localization
is characterized by its microtubule-independent binding to a subdomain of the
endoplasmic reticulum (ER). The formation of this unique ER structure is
intimately associated with the movement of the mitochondrial cloud toward the
vegetal cortex. In addition, we demonstrate that the mitochondrial cloud contains
a gamma-tubulin-positive structure that may function as a microtubule organizing
center for establishing microtubule tracks for Vg1 localization. These data,
support, although they do not prove, a model in which the development of the late
pathway machinery relies upon the prior functioning of the early pathway.
PMID- 9545551
TI - Modulation of DNA polymerases alpha, delta and epsilon by lactate dehydrogenase
and 3-phosphoglycerate kinase.
AB - Literature documents that glycolytic enzymes (among them lactate dehydrogenase
and 3-phosphoglycerate kinase) can reside in nuclei of mammalian cells and exert
functions in DNA replication, transcription and DNA repair, in addition to their
role as catalysts in the cytoplasm. Transfer of glycolytic enzymes to cell nuclei
requires modification, for example phosphorylation. We studied the effects of
phosphorylated lactate dehydrogenase and 3-phosphoglycerate kinase on (i) UV
induced DNA repair, using permeabilized human fibroblasts, and (ii) in vitro DNA
synthesis catalyzed by purified DNA polymerases alpha, delta, and epsilon from
proliferating rat liver. (i) Phosphorylated lactate dehydrogenase stimulated UV
induced DNA repair synthesis in normal fibroblasts in a dose-dependent manner;
the unphosphorylated enzyme slightly inhibited. In repair-deficient xeroderma
pigmentosum fibroblasts reparative synthesis was not enhanced whether lactate
dehydrogenase was phosphorylated or not, indicating that reparative DNA synthesis
must be possible in order to be stimulated. (ii) Activity of purified DNA
polymerases alpha, delta, and epsilon was differentially stimulated or inhibited,
according to the phosphorylation status of lactate dehydrogenase. DNA polymerases
were also modulated by 3-phosphoglycerate kinase, depending on the primer
templates used which were gapped DNA (mimicking a repair mode of DNA synthesis)
or single-stranded M13 DNA (representing the replicative mode of DNA synthesis).
Since glycolytic enzymes in cell nuclei retain binding ability for their
cofactors, cytoplasmic substrates and inhibitors, a regulatory linkage might
exist between the energy state of a cell and its replicative and reparative
functions.
PMID- 9545552
TI - Reactive iron species in biological fluids activate the iron-sulphur cluster of
aconitase.
AB - Low molecular mass iron (LMrFe) can appear in plasma when the transferrin becomes
fully iron loaded. Such iron poses a risk factor for oxidative damage, and for
microbial virulence. A previous novel approach to the detection and measurement
of LMrFe in plasma was the use of the iron-binding properties of the glycopeptide
antitumour antibiotic bleomycin and its ability to degrade DNA in the presence of
oxygen, bound iron, and an iron reducing agent. Since bleomycin is a non
physiological ligand with iron-binding and redox cycling properties, it has been
suggested that it may not be a valid biological model for detecting and measuring
LMrFe. To address these concerns we have developed a biological approach to the
detection and measurement of LMrFe based on the activation of iron-requiring
aconitase. Parallel measurements, in a variety of clinical conditions in which
there was a complete saturation of the plasma transferrin, showed that the
bleomycin assay and the aconitase assay can give similar results for LMrFe.
PMID- 9545553
TI - Structure and expression of Wnt13, a novel mouse Wnt2 related gene.
AB - We have identified a novel mouse member of the Wnt family, Wnt13. Among mouse Wnt
genes, Wnt13 is most closely related to Wnt2. Sequence comparisons and
chromosomal localization strongly suggest that Wnt13, rather than Wnt2, is the
mouse orthologue of both the human WNT13 and Xenopus XWnt2 genes. Wnt13 is
expressed in the embryonic mesoderm during gastrulation. At later stages,
transcripts are detected in the dorsal midline of the diencephalon and
mesencephalon, the heart primordia, the periphery of the lung bud and the otic
and optic vesicles. These data suggest that Wnt13 function might partially
overlap with those of other Wnt genes in the cell signaling mechanisms
controlling mesoderm specification during gastrulation and some aspects of brain,
heart and lung formation.
PMID- 9545554
TI - Inhibition of migration and proliferation of vascular smooth muscle cells by
dehydroepiandrosterone sulfate.
AB - Dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) are the most abundant
steroids in humans, and their serum concentrations progressively decrease with
age. Although relationships between DHEA(-S) and many age-related illnesses have
been postulated, the mechanisms for their effects remain unknown, and specific
receptors for these molecules have not been identified. In this paper, to
investigate the role of DHEA(-S) in atherogenesis, we studied the proliferation
and migration of a rabbit vascular smooth muscle cell line, SM-3, in the presence
of DHEA(-S). Cellular proliferation was inhibited by DHEA-S, and to a lesser
extent by DHEA. Modified Boyden's chamber assays revealed that DHEA-S inhibited
the migration of SM-3 cells toward PDGF-BB. In cell attachment assays, DHEA-S
inhibited the attachment of SM3 cells to fibronectin. It was suggested that the
inhibitory effect of DHEA-S for SM-3 proliferation and migration was due to the
decreased interaction with fibronectin. Scatchard analysis revealed the presence
of two populations of DHEA-S binding sites in the nuclear fraction, and a smaller
number in the cytosolic fraction. Since the dissociation constant of the higher
affinity site was similar to the serum DHEA-S concentration in humans (Kd = 5.8
microM), this binding site could be functional under physiologic conditions.
These findings suggest that there may be receptor-mediated anti-atherogenic
actions of DHEA-S.
PMID- 9545555
TI - Bilirubin as an anti precipitant against copper mediated denaturation of bovine
serum albumin: formation of copper-bilirubin complex.
AB - BR forms a beautiful 1:1 greenish complex with Cu2+, having a characteristic
absorption maximum at 343 nm. To our knowledge, this is the first metal complex
of bilirubin in aqueous solution so far to be reported. It has also been shown
that bilirubin (BR) at a concentration more than protein binding capacity has a
definite role as an anti precipitant of bovine serum albumin by excess copper. At
a concentration of 1 x 10(-3) moll-1 of the Cu-BR complex, the colour becomes
greenish black. The rate of formation of this Cu-BR complex when BR extracts
copper from copper-albumin complex as obtained in our experiment is 34.981 mol-1
s-1. The Cu-BR complex is stable at a pH ranging from 3.5 to 13.2, and also can
scavenge radicals like CCl3OO., eaq- and OH.. Addition of excess copper sulfate
to the solution of this complex causes a greenish black precipitate which can be
re dissolved in HCl but insoluble in 99% ethanol. The complex does not give
positive test in Gmelin reaction for bile pigments. The fluorescence spectrum of
the complex in solution exhibits a peak at 450 nm when excited at 343 nm. The
precipitated complex is insoluble in a number of solvents like ether, xylene,
benzene, acetone, chloroform-methanol mixture and DMSO. These results show that
BR may protect mammals from copper poisoning.
PMID- 9545556
TI - Repressed beta-1,3-galactosyltransferase in the Tn syndrome.
AB - The human hematopoietic disorder named Tn syndrome has been ascribed to an
acquired stem cell mutation resulting in loss of beta-1,3-galactosyltransferase
activity in affected Tn+ cells of the hematopoietic lineages. Recently, we could
demonstrate that this deficiency is due to a repression of a functional allele of
the beta-1,3-Gal-T gene since treatment of Tn+ T-lymphocytes from a patient
(R.R.) afflicted with the Tn-syndrome with 5-azacytidine or Na n-butyrate
resulted in re-expression of the Thomsen-Friedenreich (TF) antigen, the product
of beta-1,3-Gal-T activity [M. Thurnher, S. Rusconi, E.G. Berger. Persistent
repression of functional allele can be responsible for galactosyltransferase
deficiency in Tn syndrome. J. Clin. Invest. 91 (1993) 2103-2110]. To reduce these
observations to a common pathogenetic mechanism responsible for the Tn-syndrome,
more Tn patients need to be investigated. Here, we describe similar Tn+ T
lymphocytes cultured ex vivo from patient M.Z. whose Tn+ syndrome was newly
recognized. Tn+ and TF+ T-lymphocyte cultures were characterized by flow
cytometry and measurement of beta-1,3-Gal-T and shown to be deficient in Tn+
cells. Furthermore, Tn+ cells were treated with 5-azacytidine and Na n-butyrate
as described before. Reoccurrence of beta-1,3-Gal-T activity dependent epitopes
on the cell surface of Tn+ cells was shown by flow cytometry. These support the
notion of beta-1,3-Gal-T gene repression as a common pathogenetic mechanism
underlying the Tn-syndrome.
PMID- 9545557
TI - Stereochemistry and biological activities of constituents from Cynanchum
taiwanianum.
AB - The stereochemistry of new acetophenones, cynandione B-D (2-4), isolated from
Cynanchum taiwanianum, elucidated by computer modelling calculation and NOESY
spectrum. It establishes the absolute configurations of cynandiones B-D (2-4) as
7R; 7"S, 7S; 7"S and 7R; 7"R, respectively. Cynandione B (2) strongly inhibited
the release of beta-glucuronidase and lysozyme in formyl-methionyl-leucyl
phenylalanine (fMLP)-stimulated rat neutrophils in a concentration-dependent
manner with IC50 values of 1.5 +/- 0.2 and 1.6 +/- 0.2 microM, respectively. 2,5
Dihydroxyacetophenone (6) strongly inhibited the aggregation of washed rabbit
platelets induced by arachidonic acid in a concentration-dependent manner with an
IC50 value of about 4.8 microM. In human citrated platelet-rich plasma, 2,5
dihydroxyacetophenone (6) inhibited the secondary phase, but not the primary
phase, of aggregation induced by adrenaline and ADP. These results suggest that
the antiplatelet effect of 2,5-dihydroxyacetophenone (6) is due to inhibition of
the formation of thromboxane A2.
PMID- 9545558
TI - Expression of ARNT, ARNT2, HIF1 alpha, HIF2 alpha and Ah receptor mRNAs in the
developing mouse.
AB - The basic helix-loop-helix-PAS (bHLH-PAS) protein ARNT is a dimeric partner of
the Ah receptor (AHR) and hypoxia inducible factor 1 alpha(HIF1 alpha). These
dimers mediate biological responses to xenobiotic exposure and low oxygen
tension. The recent cloning of ARNT and HIF1(homologues (ARNT2 and HIF2 alpha)
indicates that at least six distinct bHLH-PAS heterodimeric combinations can
occur in response to a number of environmental stimuli. In an effort to
understand the biological relevance of this combinatorial complexity, we
characterized their relative expression at a number of developmental time points
by parallel in situ hybridization of adjacent tissue sections. Our results reveal
that in general there is limited redundancy in the expression of these six
transcription factors and that each of these bHLH-PAS members displays a unique
pattern of developmental expression emerging as early as embryonic day 9.5.
PMID- 9545559
TI - Concentration-dependent differential effects of N-acetyl-L-cysteine on the
expression of HSP70 and metallothionein genes induced by cadmium in human
amniotic cells.
AB - Cadmium induces the expression of the 70 kDa heat shock protein (HSP70) and
metallothionein (MT), both of which are considered to be associated with
intracellular glutathione (GSH) metabolism in the cellular protection mechanism
against cadmium-induced cellular injury. We determined the effects of N-acetyl-L
cysteine (NAC), which increases the intracellular GSH levels, on the induction of
HSP70 and MT gene expression in a cultured cell line of human amniotic cells
(WISH) exposed to CdCl2. The mRNA level of MT-II, a major isoform of MT genes,
was more prominently increased than that of HSP70 when WISH cells were exposed to
CdCl2 (5-15 microM, for 6 h). The treatment of WISH cells with 1.5 and 30 mM NAC
for 2 h increased the intracellular GSH levels by 1.4- and 3.1-fold,
respectively. Pretreatment of cells with 30 mM NAC significantly reduced both
HSP70 and MT-II mRNA levels in the cells exposed to 50 microM CdCl2. This
concentration of NAC also efficiently suppressed the cadmium-induced lethality.
On the contrary, pretreatment with 1.5 mM NAC suppressed only the induction of
HSP70 gene expression in the 50 microM CdCl2-treated cells, and did not inhibit
the metal toxicity. However, this low concentration of NAC efficiently suppressed
lipid peroxidation which was increased by 50 microM CdCl2. Furthermore, this low
concentration of NAC also decreased the CdCl2-induced gene expression of HSP32
which represents a general response to oxidative stress. Taken together, NAC
seems to have at least two concentration-dependent functions in WISH cells
exposed to CdCl2; the low concentration of NAC can suppress the induction of
HSP70 gene expression as well as the increase of lipid peroxidation via an
antioxidant pathway, while the high concentration of NAC can suppress the
induction of MT-II mRNA as well as cadmium-induced cell death. Our present data
suggest that changes in intracellular redox status, as reflected by GSH
concentration, have more important effects on the induction of HSP70 mRNA rather
than that of MT-II mRNA in human amniotic cells exposed to cadmium.
PMID- 9545560
TI - Expression of NK-2 class homeobox gene Nkx2-6 in foregut endoderm and heart.
AB - NK-2 class homeobox genes are candidate patterning and lineage regulators in
diverse organisms. We report here the embryonic expression pattern of murine
member, Nkx2-6. In keeping with its vertebrate relatives, Nkx2-6 was transcribed
in ventrolateral embryonic structures. Expression was first detected at E8.0 in
endodermal walls of the foregut pocket, tissue destined to become pharyngeal
floor. From E8.0-10.5, transcripts were concentrated in pharyngeal pouches and
juxtaposed arch ectoderm and mesoderm, as well as in more caudal gut segments.
Expression was also seen at opposite poles of the developing heart from E8-8.5 in
posterior myocardial progenitors, then sinus venosa and dorsal pericardium, and
from E9.5 in outflow tract myocardium.
PMID- 9545561
TI - Expression of the mouse Fkh1/Mf1 and Mfh1 genes in late gestation embryos is
restricted to mesoderm derivatives.
AB - We have compared the expression patterns of the mouse Forkhead homologue 1/
mesoderm/mesenchyme forkhead 1 (Fkh1/Mf1) gene with that of the highly related
winged helix gene Mfh1 in late gestation mouse embryos. Transcripts for both
genes are restricted to derivatives of the mesoderm. Co-expression was found in
cartilage primordia of the head, ribs, vertebra and bones. However, in several
structures analyzed, Fkh1/Mf1 signals are lower in the inner layers of the
developing cartilage than those of Mfh1.
PMID- 9545562
TI - Antioxidant capacity is correlated with steroidogenic status of the corpus luteum
during the bovine estrous cycle.
AB - The reactions of steroid hormone biosynthesis are accompanied by formation of
oxygen radicals. We determined the levels of some antioxidants and antioxidative
enzymes at different developmental stages of bovine corpora lutea to examine
their correlation with steroidogenic status. Plasma progesterone concentrations
of estrous cycle synchronized cows increased until day 16, and then decreased
rapidly during luteal regression. The levels of steroidogenic cytochrome P450scc
and adrenodoxin paralleled the changes in plasma progesterone. Among the
antioxidative enzymes examined, the SOD and catalase activities showed patterns
most similar to plasma progesterone. Catalase and SOD activities increased 6-8
fold from day 6 to 16 of the estrous cycle and then decreased during the luteal
regression. Ascorbate and beta-carotene showed low but significant correlation
with P450scc and plasma progesterone levels. The profiles of two lipophilic
antioxidants in corpora lutea were very different. beta-carotene concentration
increased by approximately 6 fold from day 6 to 16, and decreased in regressive
tissue. alpha-tocopherol showed a 3 fold increase between days 6 and 9 followed
by a rapid decrease. Thus, at the peak of steroidogenesis at mid-luteal phase
alpha-tocopherol levels decreased, but beta-carotene levels increased. The
correlation between the levels of some antioxidant enzymes and compounds with
progesterone levels indicates that antioxidative mechanisms are activated to cope
with steroidogenesis dependent oxyradical formation in the bovine corpus luteum.
PMID- 9545563
TI - Purification and characterization of two insecticyanin-type proteins from the
larval hemolymph of the Eri-silkworm, Samia cynthia ricini.
AB - Two different biliverdin-binding proteins, designated BBP-I and BBP-II, were
purified from the larval hemolymph of the Eri-silkworm, Samia cynthia ricini.
These proteins were readily isolated from the hemolymph of fifth instar larvae
using two chromatographic steps, hydrophobic interaction chromatography and ion
exchange chromatography. Both BBPs were easily separated by Q-Sepharose HP column
chromatography. BBP-I has an apparent molecular weight of 24 kDa, as determined
by gel-filtration and sodium dodecyl sulfate-polyacrylamide gel electrophoresis
(SDS-PAGE). Native BBP-II had a molecular weight of 48 kDa estimated by gel
filtration. SDS-PAGE revealed a single band with a molecular weight of 26 kDa.
Moreover, the molecular weights of BBP-I and BBP-II were determined to be 20,468
and 22,708 by MALDI-TOF/MS (matrix-assisted laser desorption ionization-time of
flight/mass spectrometry), respectively. On this basis, BBP-I and BBP-II
molecules are assumed to be a monomer and a dimer, respectively. The blue color
of BBPs collected from the hemolymph is attributed to the presence of biliverdin
IX gamma, which is non-covalently and stoichiometrically bound to the apoprotein,
based on absorbance maxima at 359 and 695 nm in methanol:HCl (95:5, v/v). One
molecule of BBP-I contains one molecule of biliverdin IX gamma, whereas BBP-II
contains two molecules of biliverdin IX gamma. The amino acid compositions of BBP
I and BBP-II are different, although the N-terminal sequences of both BBPs have a
48% identity. These BBPs were found in the hemolymph of fourth and fifth instar
larvae. The newly molted fifth instar larvae had the highest concentration of BBP
I in the hemolymph. This gradually decreased during larval development. In
contrast to BBP-I, the level of BBP-II was low, and increased slightly at the
same developmental stage in S. cynthia ricini larvae.
PMID- 9545564
TI - ERD6, a cDNA clone for an early dehydration-induced gene of Arabidopsis, encodes
a putative sugar transporter.
AB - Previously, we constructed a cDNA library from Arabidopsis plants that were
exposed to dehydration stress for 1 h and obtained the ERD6 clone. Here we report
that the ERD6 cDNA consists of 1741 bp and encodes a polypeptide of 496 amino
acids having a predicted molecular weight of 54,354. The putative polypeptide of
ERD6 is related to those of sugar transporters of bacteria, yeasts, plants and
mammals. Hydropathy analysis revealed that ERD6 protein has 12 putative
transmembrane domains and a central hydrophilic region. Sequences that are
conserved at the ends of the 6th and 12th membrane-spanning domains of sugar
transporters are also present in ERD6. These data suggest that ERD6 encodes a
sugar transporter. Genomic Southern blots indicate that the ERD6 gene is a member
of a multigene family in the Arabidopsis genome. The expression of the ERD6 gene
was induced not only by dehydration but also by cold treatment.
PMID- 9545565
TI - Transport mechanisms of a glycoside, p-nitrophenyl-beta-D-glucopyranoside, across
rat small intestinal brush-border membranes.
AB - We examined the mechanism of p-nitrophenyl-beta-d-glucopyranoside (p-NP-beta-d
Glc) transport in brush-border membrane vesicles from rat small intestine. The
initial uptake rate showed an overshoot phenomenon in the presence of an inwardly
directed sodium-ion concentration gradient. The overshoot disappeared when the
sodium-ion concentration gradient was replaced with a potassium ion concentration
gradient. d-Glucose and p-NP-beta-D-Glc analogues inhibited the uptake, whereas
uridine, leucine and disaccharide did not. Data on the concentration dependence
of p-NP-beta-D-Glc uptake indicated that two carrier-mediated systems are
involved. The uptake via the high-affinity site required an inwardly directed
sodium-ion concentration gradient, while the uptake via the low-affinity site
proceeded such a gradient. D-Glucose competitively inhibited the initial uptake
of p-NP-beta-D-Glc via the high-affinity site with a Ki value of 301 microM. The
p-NP-beta-D-Glc is transported in the small intestine via both the same carrier
mediated transport system that takes up D-glucose and a distinct low-affinity
carrier-mediated transport system.
PMID- 9545566
TI - Determination of the depth of penetration of the alpha subunit of retinal G
protein in membranes: a spectroscopic study.
AB - This paper reports the fluorescence quenching of the alpha subunit of retinal rod
outer segment G protein (Gtalpha) by vesicles of brominated phospholipids. Two
different brominated phospholipids with the bromine quencher groups attached at
the 6-7 and 9-10 positions in one of the fatty acyl chains have been used to
estimate the depth of penetration of the Gtalpha protein in the lipid vesicles
using steady-state fluorescence quenching techniques. Our studies provide
evidence of the interaction between Gtalpha protein, in its active conformation,
with the lipid vesicles mimicking natural membranes. This study demonstrates that
in vitro the distance between fluorescent tryptophan site of Gtalpha and the
membrane surface is approximately 6.5 A.
PMID- 9545567
TI - Role of cholesterol in the modulation of interdigitation in phosphatidylethanols.
AB - Phosphatidylethanol (Peth) is formed in biological membranes when ethanol
replaces water in the transphosphatidylation reaction catalyzed by phospholipase
D. This charged lipid accumulates in the presence of ethanol, and it has unusual
properties that can influence membrane structure and function. We have previously
shown that dimyristoylphosphatidylethanol (DMPeth) and
dipalmitoylphosphatidylethanol (DPPeth) form the interdigitated gel phase in the
presence of Tris-HCl [O.P. Bondar, E.S. Rowe, Biophys. J., 71 (1996) 1440-1449].
In the present investigation, differential scanning calorimetry (DSC) and
fluorescence have been used to investigate the effect of cholesterol on the phase
behavior of DPPeth and DMPeth. Our results show that cholesterol prevents the
formation of the interdigitated phase in the presence of Tris-HCl, and that
ethanol counters this influence and restores the ability of these lipids to
interdigitate. Pyrene-PC fluorescence probe was used in this investigation and
gave results that were in agreement with the conclusions based on the DSC study.
PMID- 9545569
TI - Quantification of concanavalin A binding to rat brain microsomal membranes
detected by fluorescence polarization technique.
AB - A high sensitive method for detecting the change of microsomal membrane surface
oligosaccharides was developed to study the regulatory role of lipid- or peptide
linked mannoside of endoplasmic reticulum in synaptic functions. The binding of
concanavalin A to the microsomal membrane surface was measured quantitatively
using a microgram-order of rat brain microsomal proteins. The fluorescence
polarization of concanavalin A (Con A)-fluorescein isothiocyanate (FITC)
conjugate bound to the membrane was analyzed to quantitate the change of binding
constant and the number of binding sites. As a control, the non-specific binding
of bovine serum albumin-FITC conjugate was measured by the same technique. We
measured the change of fluorescence intensity of membrane-bound FITC conjugates
by the flow cytometry and found that the intensity of FITC conjugate bound to the
membrane increased more than that of free form of the probe. We observed that the
alpha-mannosidase-treatment of rat brain microsomes resulted in the increase of
binding constant of Con A to the microsomal surface without significant loss of
binding sites.
PMID- 9545568
TI - The aminosterol antibiotic squalamine permeabilizes large unilamellar
phospholipid vesicles.
AB - The ability of the shark antimicrobial aminosterol squalamine to induce the
leakage of polar fluorescent dyes from large unilamellar phospholipid vesicles
(LUVs) has been measured. Micromolar squalamine causes leakage of
carboxyfluorescein (CF) from vesicles prepared from the anionic phospholipids
phosphatidylglycerol (PG), phosphatidylserine (PS), and cardiolipin. Binding
analyses based on the leakage data show that squalamine has its highest affinity
to phosphatidylglycerol membranes, followed by phosphatidylserine and cardiolipin
membranes. Squalamine will also induce the leakage of CF from phosphatidylcholine
(PC) LUVs at low phospholipid concentrations. At high phospholipid
concentrations, the leakage of CF from PC LUVs deviates from a simple dose
response relationship, and it appears that some of the squalamine can no longer
cause leakage. Fluorescent dye leakage generated by squalamine is graded,
suggesting the formation of a discrete membrane pore rather than a generalized
disruption of vesicular membranes. By using fluorescently labeled dextrans of
different molecular weight, material with molecular weight =4000 g/mol is
released from vesicles by squalamine, but material with molecular weight
>/=10,000 is retained. Negative stain electron microscopy of squalamine-treated
LUVs shows that squalamine decreases the average vesicular size in a
concentration-dependent manner. Squalamine decreases the size of vesicles
containing anionic phospholipid at a lower squalamine/lipid molar ratio than pure
PC LUVs. In a centrifugation assay, squalamine solubilizes phospholipid, but only
at significantly higher squalamine/phospholipid ratios than required for either
dye leakage or vesicle size reduction. Squalamine solubilizes PC at lower
squalamine/phospholipid ratios than PG. We suggest that squalamine complexes with
phospholipid to form a discrete structure within the bilayers of LUVs, resulting
in the transient leakage of small encapsulated molecules. At higher
squalamine/phospholipid ratios, these structures release from the bilayers and
aggregate to form either new vesicles or squalamine/phospholipid mixed micelles.
PMID- 9545570
TI - Cloning differentially regulated genes from chondrocytes using agarose gel
differential display.
AB - The technique of RNA differential display has been used extensively to clone
differentially expressed genes from a wide variety of cells and tissues.
Recently, a simplified method of cloning differential display products, separated
on agarose gels, was described. Here we report an adaption of this method, using
total RNA, to clone differentially expressed genes. The approach is simple and
rapid, and requires only small quantities of total RNA. Utilising this approach,
we have cloned three differentially regulated genes from chondrocytes stimulated
to hypertrophy in vitro, and confirmed their pattern of expression by Northern
blotting. These gene fragments were sequenced and found to correspond to known
genes, although only one has previously been isolated from chondrocytes.
PMID- 9545571
TI - Isolation of novel human cDNA (hGMF-gamma) homologous to Glia Maturation Factor
beta gene.
AB - A novel full-length human cDNA homologous to Glia Maturation Factor-beta (GMF
beta) gene was isolated. Sequence analysis of the entire cDNA revealed an open
reading frame of 426 nucleotides with a deduced protein sequence of 142 amino
acid residues. The deduced amino acid sequences of its putative product is highly
homologous to human GMF-beta (82% identity) and named for GMF-gamma. Northern
blot analysis indicated that a message of 0.9 kb long, but not 4.1 kb of GMF
beta, is predominantly expressed in human lung, heart, and placenta.
PMID- 9545572
TI - The development of IL-2 conjugated liposomes for therapeutic purposes.
AB - A unique immunoliposome has been developed as a drug delivery vehicle for
immunotherapy. Human recombinant interleukin-2 (IL-2) has been chemically coupled
to the external surface of small unilamellar vesicles (SUVs) containing
methotrexate as a candidate immunosuppresive agent in order to specifically
direct the drug-bearing liposome to activated T-cells expressing the high
affinity IL-2 receptor. This drug delivery system is designed to deliver an
immunosuppressive agent to those cells that actively participate in disorders
such as graft rejection without delivering an effective but potentially toxic
drug to all cells of the immune system as well as other healthy tissues. IL-2 was
chemically modified with succinimidyl 4-[p-maleidophenyl butyrate](SMPB) while
the receptor binding domain on IL-2 was protected by monoclonal anti-IL-2 bound
to Protein A-Silica Gel. The antibody recognizes the receptor binding domain of
the IL-2 molecule. The IL-2 was derivatized with S-succinimidyl-S-thioacetate
(SATA) in order to add an acetyl thioester group to the lipid and create the
complex. The derivatized lipid (SATA-PE) was then part of the liposome
formulation containing DSPC:cholesterol: SATA-PE at a mole ratio of 1.5:1.0:0.26.
SMPB-IL-2 was covalently coupled to the external surface of the SUV after
deacetylation of the thioester moiety at pH 7.4 in PBS. Liposomes prepared by
sonication or extrusion had an average diameter of 46-50 nm. SUV-IL-2 bound to
the high affinity IL-2 receptor as measured by competitive binding assays and
Scatchard analysis using 111InCl2-loaded liposomes The preparation exhibited a
binding constant of 30 pM, consistent with values for free IL-2 cited in the
literature. SUV IL-2 could be used as the sole source of IL-2 for the murine CTLL
2 T-cell line or for human mitogen-activated PBLs. The presence of IL-2 coupled
to the surface was absolutely required for delivery of the drug to the cell. When
methotrexate was encapsulated within the internal aqueous space, receptor
mediated endocytosis led to the inhibition of proliferation due to delivery of
MTX to the cytoplasm of the cell. More than 90% of the methotrexate was retained
within the liposome during storage over a 24-h period at 4 degrees C. This
immunoliposome represents a new class of cell specific immunoliposomes whose
entry into the cell is controlled by a cell surface receptor.
PMID- 9545573
TI - Molecular cloning of a human cDNA for the 41-kDa phosphoribosylpyrophosphate
synthetase-associated protein.
AB - A human cDNA encoding 41-kDa phosphoribosylpyrophosphate (PRPP) synthetase (PRS)
associated protein (PAP41) was cloned from two expressed sequence tag (EST)
clones having the nucleotide similarity of 61.5 and 70.0% to human PAP39 cDNA.
The predicted open reading frame of 1107 base pairs (bp) has the nucleotide
identity of 91.8% to rat PAP41 and encodes a protein of 369 amino acids with a
calculated molecular weight (MW) of 40,925. The deduced amino acid sequence
exhibits the 98.9% identity to rat PAP41 and 72.2, 50.6, and 50.0% identity with
human PAP39, PRS I, and PRS II, respectively, but lacks the PRPP binding site.
Southern blot analysis suggested that the PAP41 gene exists as a single copy in
the human genome. The single PAP41 mRNA of about 2.1 kb was shown to be present
in five human cell lines by Northern blot analysis.
PMID- 9545574
TI - Identification of two new members of the mouse prolactin gene family.
AB - The prolactin (PRL) family consists of a collection of genes expressed in the
uterus, placenta, and anterior pituitary. These cytokines/hormones participate in
the control of maternal-fetal adaptations to pregnancy. In this report, we
establish the presence of two new members of the mouse PRL family. Novel
expressed sequence tags (ESTs) with significant homology to PRL were isolated
from embryonic, ectoplacental cone, and placental cDNA libraries. The cDNAs were
sequenced and compared to other members of the PRL family. The two new cDNAs were
assigned to the PRL family based on sequence homology and were referred to as PRL
like protein-F (PLP-F) and PRL-like protein-G (PLP-G). PLP-F cDNA encodes for a
predicted 267 amino acid protein containing a 30 amino acid signal peptide and
three putative N-linked glycosylation sites. PLP-G cDNA encodes for a predicted
266 amino acid protein containing a 30 amino acid signal peptide and six putative
N-linked glycosylation sites. Sequence alignments of these proteins with other
members of the PRL family suggest some unique features. Both sequences contain an
extra amino acid segment located between exons two and three of the prototypical
PRL gene and a nine amino acid carboxy terminal extension. PLP-F contained an
additional 15 amino acid region situated between exons four and five of the
prototypical PRL gene. Both PLP-F and PLP-G mRNAs were expressed in the placenta
but not in other tissues (uterus, brain, thymus, heart, lung, diaphragm, liver,
kidney, and ovary). In summary, the two newly identified members share
approximately 50% amino acid sequence identity, are specifically expressed in the
placenta, and represent a new subfamily within the PRL family.
PMID- 9545575
TI - Mechanism of the inhibitory effect of imipramine on the Na+-dependent transport
of L-glutamic acid in rat intestinal brush-border membrane.
AB - The mechanism of the inhibitory effect of imipramine, a lipophilic organic cation
on the Na+-dependent transport of L-glutamic acid across intestinal brush-border
membrane was investigated. The uptake of L-glutamic acid by intestinal brush
border membrane vesicles was dependent on the concentration of Na+. Fitting of
the uptake data in the presence of various concentrations of Na+ using Hill
equation yielded a Hill coefficient of 2.18. This result suggest that the carrier
system of L-glutamic acid has at least two sites for Na+-binding. By the analysis
of double reciprocal plot and Dixon-type plot, it was found that imipramine
inhibits the transport of L-glutamic acid by interacting competitively with the
binding sites of Na+, but not inhibit L-glutamic acid binding site. Moreover, the
effect of imipramine on the transport of L-alanine and D-glucose which are co
transported with only one Na+ molecule was also suggestive of interaction with
the Na+-binding sites on the carrier. These results indicate that the mechanism
of the inhibitory effect of imipramine on the Na+-dependent carrier systems is
common for all systems regardless of the stoichiometry or substrates.
PMID- 9545576
TI - Lymphatic uptake and biodistribution of liposomes after subcutaneous injection .
IV. Fate of liposomes in regional lymph nodes.
AB - The ability of clodronate-containing liposomes to deplete lymph nodes of
macrophages was used as a tool to investigate the fate of liposomes in regional
lymph nodes after subcutaneous (s.c.) administration. Reduced lymph node
localization of liposomes in macrophage-depleted lymph nodes confirmed that
phagocytosis by macrophages plays an important role in lymph node retention of
liposomes. Depletion of macrophages had less effect on lymph node localization of
small liposomes than on the lymph node localization of large liposomes. Inclusion
of distearoylphosphatidylethanolamine (DSPE)-poly(ethyleneglycol) (PEG-PE) into
the liposomes, which is known to oppose macrophage uptake, did not affect lymph
node localization in macrophage-depleted or control lymph nodes. We conclude that
PEG-liposomes retained by lymph nodes are also taken up by lymph node
macrophages. Morphological observations visualizing the uptake of PEG-liposomes
by lymph node macrophages support this conclusion.
PMID- 9545577
TI - Cloning of the cDNA encoding rat presenilin-2.
AB - We report here the cDNA sequence of rat homologue of presenilin-2 (PS-2). The rat
PS-2 cDNA encoded 448 amino acids, and the deduced amino acid sequence was highly
homologous to those of the human (94.9%), mouse (96.4%) and Xenopus (70.8%). A
minor splicing variant lacking a single glutamate was detected, while the product
corresponding to the exon 9 deleted splicing variant observed in human was not
detected.
PMID- 9545578
TI - Cloning of chicken and mouse alpha 1b adrenergic receptor.
AB - A partial cDNA encoding most of the third intracellular loop of the chicken alpha
1b adrenergic receptor subtype, obtained by reverse transcription-polymerase
chain reaction (RT-PCR) techniques using degenerate primers derived from
mammalian sequences, was used to isolate an alpha 1b adrenergic receptor cDNA
from brain. The cDNA encodes a potential protein of 507 amino acids and Northern
hybridization of poly(A)+ RNA from chicken brain of different developmental
stages detected a single 3.5 kb transcript. Analysis of receptor expression
indicated that the alpha 1b adrenergic receptor is widely distributed in chicken
tissues, specially kidney and liver. cDNA and genomic clones encoding sequences
of the mouse alpha 1b adrenergic receptor were also isolated.
PMID- 9545579
TI - Characterization of the 5' flanking region of the human NPT-1 Na+/phosphate
cotransporter gene.
AB - To elucidate the expression and regulation of the human type I Na+/phosphate
transporter gene (NPT-1), the 5' flanking region of the NPT-1 gene was cloned,
and its nucleotide sequence and function were determined. A genomic clone that
contained approximately 14.0 kb of the 5'-flanking region of the NPT-1 gene was
isolated. A single transcription start site was located 104 base pairs (bp)
upstream of the 3' end of exon 1. In addition to the sequence of the 5'-flanking
region contained a sequence weakly homologous to a TATA box at position -41 to
36 and many transcriptional regulatory elements. Transient expression revealed
that a 45-bp region of proximal to exon 1, which contained TATA-like sequence,
was sufficient for promoting luciferase expression in OK-cells derived from
opossum kidney proximal tubule.
PMID- 9545580
TI - Isolation of cDNA encoding a novel human CC chemokine NCC-4/LEC.
AB - We have determined the entire sequence of human cDNA encoding a novel CC
chemokine NCC-4 by 5' and 3' RACE methods. Two types of transcripts, 579 bp and
1503 bp long, respectively, are generated through alternative polyadenylation
sites. Both species contain an open reading frame encoding 120 amino acids with
19-38% identity to other human CC chemokines. The short and long transcripts are
expressed highly selectively in the liver at nearly equivalent levels. There
seems to be one copy of the gene per haploid genome. We now designate NCC-4 as
LEC from liver-expressed chemokine.
PMID- 9545581
TI - Palmitic acid is associated with halorhodopsin as a free fatty acid.
Radiolabeling of halorhodopsin with 3H-palmitic acid and chemical analysis of the
reaction products of purified halorhodopsin with thiols and NaBH4.
AB - Halorhodopsin, isolated from Halobacterium salinarium cells incubated with
tritiated palmitic acid, co-elutes with labeled palmitate in phenylsepharose CL
4B chromatography. Halorhodopsin-bound 3H-palmitate is not readily displaced by
prolonged exposure to a large excess of detergents and by re-chromatography of
radiolabeled halorhodopsin on phenylsepharose. On other hand, the association of
labeled palmitate with purified halorhodopsin is not resistant to denaturation
induced either by isopropanol/hexane or by SDS gel electrophoresis. We have
tested the hypothesis that tightly associated palmitate is bound to halorhodopsin
through a thioester bond, which is unstable in denaturing conditions. Using
GC/MS, we have analysed the reaction products of native halorhodopsin with
specific thioester reagents, thiols and NaBH4, which are inactive on free fatty
acids. The results of this analytical approach indicate that there is no
thioester bond between halorhodopsin and palmitic acid and that palmitic acid is
associated with halorhodopsin as a free fatty acid.
PMID- 9545582
TI - Analysis of expression of the gene encoding for the nuclear autoantigen La/SS-B
using reporter gene constructs.
AB - In earlier studies mRNA isoforms encoding for the nuclear autoantigen La were
identified. In an alternative La mRNA form the exon 1 was replaced with the exon
1'. Moreover, exon 1' La mRNAs were found to start at different 5'-regions. In
dependence on the 5'-start the exon 1' La mRNAs encoded for up to three open
reading frames upstream of the La frame, which starts in the exon 2. The exon 1'
was located in the intron about 70 nts downstream of the exon 1. The exon 1' La
mRNA was proposed to be the result of a promoter switch in combination with an
alternative splicing mechanism. The commonly used technique to study the
expression of a eucaryotic gene is to fuse a reportergene immediately downstream
of the proposed regulatory elements. Due to (i) the short distance between exon 1
and exon 1', (ii) the varying 5'-starts of the exon 1' La mRNAs, and (iii) the
upstream open reading frames in the exon 1' La mRNAs this technique appeared to
be difficult to apply to the La gene. In order to overcome these problems a
luciferase reportergene construct was cloned which started about 2500 nts
upstream of the exon 1 and contained the exon 1, the intron including the exon
1', and a portion of the exon 2. Luciferase was fused into the exon 2. This
construct was used to prepare 5'-deletion mutants. The constructs were
transiently transfected into HeLa cells. RNAs were isolated from the transiently
transfected cells and analyzed using the 5'-Rapid Amplification of cDNA End
technique. The PCR products were subcloned and sequenced. This analysis showed
that exon 1 and exon 1' transcripts were correctly transcribed and spliced from
the La luciferase fusion construct. Moreover, the 5'-start of the respective
transcript allowed to identify those genomic regions in the La gene that were
most likely being involved in determining the respective transcription initiation
site. In parallel to the estimation of the 5'-start of the transcripts, the
luciferase activity was measured. Thereby we detected a cryptic promoter element
in the intron between the exon 1 and exon 2.
PMID- 9545583
TI - Self-assembled alpha-hemolysin pores in an S-layer-supported lipid bilayer.
AB - The effects of a supporting proteinaceous surface-layer (S-layer) from Bacillus
coagulans E38-66 on a 1,2-diphytanoyl-sn-glycero-3-phosphatidylcholine (DPhPC)
bilayer were investigated. Comparative voltage clamp studies on plain and S-layer
supported DPhPC bilayers revealed no significant difference in the capacitance.
The conductance of the composite membrane decreased slightly upon
recrystallization of the S-layer. Thus, the attached S-layer lattice did not
interpenetrate or rupture the DPhPC bilayer. The self-assembly of a pore-forming
protein into the S-layer supported lipid bilayer was examined. Staphylococcal
alpha-hemolysin formed lytic pores when added to the lipid-exposed side. The
assembly was slow compared to unsupported membranes, perhaps due to an altered
fluidity of the lipid bilayer. No assembly could be detected upon adding alpha
hemolysin monomers to the S-layer-faced side of the composite membrane.
Therefore, the intrinsic molecular sieving properties of the S-layer lattice do
not allow passage of alpha-hemolysin monomers through the S-layer pores to the
lipid bilayer. In comparison to plain lipid bilayers, the S-layer supported lipid
membrane had a decreased tendency to rupture in the presence of alpha-hemolysin.
PMID- 9545584
TI - Successful recovery of the normal electrophysiological properties of PorB (class
3) porin from Neisseria meningitidis after expression in Escherichia coli and
renaturation.
AB - Neisseria meningitidis PorB class 3 porins obtained either from native membranes
(wild-type) or recovered from inclusion bodies following expression in
Escherichia coli (recombinant), have been reconstituted into solvent-free planar
phospholipid membranes. The wild-type and recombinant porins exhibited the same
single-trimer conductance (1-1.3 nS in 200 mM NaCl), tri-level closure pattern,
characteristic of functional channel trimers, and pattern of insertion into
planar membranes. Both proteins were open at low voltages and displayed two
voltage-dependent closure processes, one at positive and the other at negative
potentials. Both showed asymmetric voltage dependence such that one gating
process occurred at lower voltages (Vo=15 mV) than the other (Vo=25 mV). The sign
of the potential that resulted in closure at low voltages varied from membrane to
membrane indicating that they may have the property of auto-directed insertion
(in analogy to the mitochondrial channel, VDAC). In the case of the recombinant
porin, the steepness of the voltage dependence of one gating process was slightly
less (n=1.3) than that observed for the other process or for the wild-type
channel (n=1.5-1.7). Both channels have a high (40%) probability of closure even
at 0 mV. While both channels show a slight selectivity for Cl- over Na+, the
selectivity of the recombinant porin is a bit higher (permeability ratio of 2.8
vs. 1.6) as measured using a 2-fold salt gradient. Thus, the method employed to
refold the recombinant porin was successful in not only restoring wild-type
structure [H.L. Qi, J.Y. Tai, M.S. Blake, Expression of large amounts of
Neisserial porin proteins in Escherichia coli and refolding of the proteins into
native trimers, Infect. Immun. 62 (1994) 2432-2439; C.A.S.A. Minetti, J.Y. Tai,
M.S. Blake, J.K. Pullen, S.M. Liang, D.P. Remeta, Structural and functional
characterization of a recombinant PorB class 2 protein from Neisseria
meningitidis. Conformational stability and porin activity, J. Biol. Chem. 272
(1997) 10710-10720] but also the overall electrophysiological function.
PMID- 9545585
TI - Gene expression of mouse M1 and M2 pyruvate kinase isoenzymes correlates with
differential poly[A] tract extension of their mRNAs during the development of
spermatogenesis.
AB - In eukaryotes, different isoenzymes for pyruvate kinase have been characterized.
M2-type Pk cDNA from a mouse fetal ovary library was isolated and differential
expression for M1 and M2-types during testis development was observed. While the
presence of M2 mRNAs decreases throughout the development of spermatogenesis, we
deduced that M1 type expression increases in adult testis coinciding with the
presence of elongating spermatids in the seminiferous epithelium. Polyadenylation
tests showed a concurrent increase in the length of the polyadenylation tail of
transcribed M1-type pyruvate kinase mRNAs in prepuberal to adult seminiferous
tubules. A similar relationship between poly[A] tail extension and differential
increase of gene expression was detected for M1-type mRNA in adult brain and
muscle. Length of poly[A] tail of M2-type transcripts is shown to decrease during
the development of mouse testis. These results suggest that changes in the length
of the poly[A] tail of transcripts are associated with differential expression of
both regulated isoenzymes during testicular development.
PMID- 9545587
TI - Temperature-responsive size-exclusion chromatography using poly(N
isopropylacrylamide) grafted silica.
AB - Silica-based packing materials induce non-specific interactions with proteins in
aqueous media because of the nature of their surface, mainly silanol groups.
Therefore, the silica surface has to be modified in order to be used as
stationary phase for the High Performance Size-Exclusion Chromatography (HPSEC)
of proteins. For this purpose, porous silica beads were coated with hydrophilic
polymer gels (dextrans of different molecular weights) carrying a calculated
amount of diethyl-aminoethyl groups (DEAE). Actually, as shown by HPSEC, these
dextran modified supports minimize non-specific adsorption for proteins and
pullulans in aqueous solution. Then, in order to change the pore size in response
to temperature, temperature responsive polymer of poly(N-isopropylacrylamide)
(PIPAAm) was introduced into the surface of dextran-DEAE on porous silica beads.
The structure of these supports before and after modification was alternately
studied by Scanning Electronic Microscopy (SEM) and Scanning Force Microscopy
(SFM). An adsorption of radiolabelled albumin was performed to complete our
study. Silica modifications by dextran-DEAE and PIPAAm improve the neutrality of
the support and minimize the non-specific interactions between the solid support
and proteins in solution. At low temperature, the support having PIPAAm exhibits
a high resolution domain in HPSEC and finally permits a better resolution of
proteins and pullulans. At higher temperature, hydrophobic properties of PIPAAm
produce interactions with some proteins and trigger off a slight delay of their
elution time.
PMID- 9545588
TI - Functional expression of a mammalian acetylcholinesterase in Pichia pastoris:
comparison to acetylcholinesterase, expressed and reconstituted from Escherichia
coli.
AB - The mature rat brain acetylcholinesterase gene (T subunit, AChE) was subcloned
downstream of the temperature-inducible lambda promoter PL and fused to the
signal peptide of the OmpA protein. Three different expression vectors were
constructed: (i) pCompmA containing the mature AChE, (ii) pComp delta TA
containing a truncated AChE and (iii) pComp delta TAH containing the truncated
AChE C-terminal fused to a 6xHis-tag. With all expression vectors the
overexpression of AChE in Escherichia coli resulted mainly in cytoplasmic
inclusion bodies (IB). However, some activity was found in the periplasmic space.
The inclusion bodies were refolded in vitro, yielding up to 1.42 U/mg IB of
active AChE. The refolded AChE was partially purified (approx. 300-fold) by
affinity chromatography with a specific activity of approx. 250 U/mg. Removing
the cysteine residue near the C-terminus (truncated AChE, delta TAChE) assuming
to affect the refolding, did not increase the amount of active enzyme obtained
after refolding. Purification of denatured delta TAChE-6xHis prior to refolding
by Ni-NTA-chromatography increased the refolding efficiency by a factor of 1.5.
Functional expression and secretion of rat brain acetylcholinesterase into the
medium was achieved in Pichia pastoris. By optimizing the culture conditions, 100
mU/ml AChE in the medium was produced. In this work we are describing the
functional expression of a mammalian AChE in a microbial host in good yields for
the first time. The physico-chemical properties of both, the bacterial and yeast
expressed AChE were compared with those of the native AChE. The properties of the
yeast expressed AChE and the native AChE were similar, whereas the E. coli
expressed enzyme was found to be less stable and had different inhibition
properties.
PMID- 9545586
TI - Where does cholesterol act during activation of the nicotinic acetylcholine
receptor?
AB - Why agonist-induced activation of the nicotinic acetylcholine receptor (nAcChoR)
fails completely in the absence of cholesterol is unknown. Affinity-purified
nAcChoRs from Torpedo reconstituted into 1,2-dioleoyl-sn-glycero-3
phosphatidylcholine/1, 2-dioleoyl-sn-glycero-3-phosphate/steroid bilayers at mole
ratios of 58:12:30 were used to distinguish between three regions of the membrane
where cholesterol might act: the lipid bilayer, the lipid-protein interface, or
sites within the protein itself. In the bilayer, the role of fluidity has been
ruled out and certain neutral lipids can substitute for cholesterol [C. Sunshine,
M.G. McNamee, Biochim. Biophys. Acta 1191 (1994) 59-64]; therefore, we first
tested the hypothesis that flip-flop of cholesterol across the membrane is
important; a plausible mechanism might be the relief of mechanical bending strain
induced by a conformation change that expands the two leaflets of the bilayer
asymmetrically. Cholesterol analogs prevented from flipping by charged groups
attached to the 3-position's hydroxyl supported channel opening, contrary to this
hypothesis. The second hypothesis is that interstitial cholesterol binding sites
exist deep within the nAcChoR that must be occupied for channel opening to occur.
When cholesterol hemisuccinate was covalently 'tethered' to the glycerol backbone
of phosphatidylcholine, channel opening was still supported. Thus, if there are
functionally important cholesterol sites, they must be very close to the lipid
protein interface and might be termed periannular.
PMID- 9545589
TI - In vivo activation of yeast plasma membrane H+-ATPase by ethanol: effect on the
kinetic parameters and involvement of the carboxyl-terminus regulatory domain.
AB - The in vivo activation of Saccharomyces cerevisiae plasma membrane H+-ATPase by
ethanol was observed during ethanol-stressed cultivation or following the rapid
incubation of cells with ethanol (6% (v/v)). Ethanol activated both the basal and
the glucose-activated forms of the enzyme being the H+-ATPase fully activated by
glucose (5% (w/v)) still additionally activable by ethanol. The kinetic
parameters of ethanol-activated and non-activated H+-ATPase were calculated based
directly on Michaelis-Menten equation (with MgATP concentrations in the range 0.
16-8.18 mM and 7.5 mM of free Mg2+); the rectangular hyperbolic function was
solved using iterative procedures. Ethanol-induced stimulation of plasma membrane
H+-ATPase activity was associated to the increase of Vmax whereas the Km for
MgATP increased. Results obtained with mutants constructed and used in previous
studies envisaging the analysis of the molecular mechanisms underlying plasma
membrane ATPase activation by glucose, external acidification and nitrogen
starvation, suggested that the carboxyl-terminus (C-terminus) regulatory domain
may also be involved in the in vivo activation by ethanol.
PMID- 9545590
TI - The effect of ethanol on pancreatic enzymes--a dietary artefact?
AB - The effects of ethanol on pancreatic digestive and lysosomal enzymes may be
relevant to the pathogenesis of alcoholic pancreatitis since pancreatic enzymes
are thought to play an important role in the development of pancreatic injury.
Previous studies, using the Lieber-DeCarli pair-feeding model of ethanol
administration, have demonstrated that ethanol significantly increases the
content and gene expression of pancreatic enzymes. However, these findings have
been questioned because, in the Lieber-DeCarli model, ethanol-fed rats have a
lower carbohydrate intake than their pair-fed controls, making it difficult to
ascribe any observed changes to ethanol alone. This study was designed to
distinguish between the effects of ethanol and those of reduced dietary
carbohydrate on pancreatic enzymes, using a quartet-feeding model of ethanol
administration. Rats were fed liquid diets containing low (11%) and high (47%)
amounts of carbohydrate, with and without ethanol, for four weeks. The effects of
ethanol on pancreatic content and messenger RNA levels for digestive enzymes
(trypsinogen, chymotrypsinogen and lipase) and a lysosomal enzyme (cathepsin B)
were assessed. Ethanol feeding resulted in a significant increase in glandular
content with a corresponding increase in mRNA levels for all four enzymes
studied. By contrast, a reduction in dietary carbohydrate intake alone did not
alter pancreatic content or gene expression for the above enzymes. These results
indicate that (i) ethanol significantly increases the capacity of the acinar
cells to synthesise digestive enzymes and the lysosomal enzyme cathepsin B, and
(ii) these changes are due to ethanol itself and are not due to variations in
dietary carbohydrate intake.
PMID- 9545591
TI - Verapamil enhances the uptake and the photocytotoxic effect of PII, but not that
of tetra(4-sulfonatophenyl)porphine.
AB - The influence of the calcium channel blocker verapamil on the sensitivity of
mouse fibrosarcoma cells of the line EMT-6 to treatment with Photofrin II (PII)
or tetra(4-sulfonatophenyl)porphine (TPPS4) and light has been assessed. Cells
were treated with 1.5 microg/ml PII or 75 microg/ml TPPS4 overnight in the
absence or presence of 50 microg/ml verapamil and subsequently exposed to light.
Verapamil increased the sensitivity of the EMT-6 cells to PII-induced
photoinactivation by a factor of 2. In contrast, verapamil decreased the
sensitivity of the cells to TPPS4-induced photoinactivation by 50-60%. Both
sensitizers were found to be located to a large extent in lysosomes as revealed
by fluorescence microscopy and by photochemical inactivation of the lysosomal
marker enzyme beta-N-acetyl-D-glucosaminidase. Verapamil increased the uptake of
PII by 30% and reduced the uptake of TPPS4 by 20%. Furthermore, verapamil
enhanced the binding and uptake of LDL by about 40%. In conclusion, the effects
of verapamil-induced sensitization of EMT-6 cells treated with PII or TPPS4 and
light can to a large extent be attributed to the modulatory effects of verapamil
on endocytosis.
PMID- 9545592
TI - IGF-1, PDGF and CD18 are adherence-responsive genes: regulation during monocyte
differentiation.
AB - Unstimulated mononuclear cells express IGF-1, PDGF-A and PDGF-B mRNA, but not a
number of other genes coding for growth factors or cytokines, as we demonstrated
previously. The main focus of the present investigation was to compare gene
expression of mononuclear cells unstimulated in suspension with gene expression
of monocytes stimulated by adherence. mRNA levels of IGF-1-A and -B, PDGF-A, -B,
PD-ECGF, basic FGF, acidic FGF, TGF-alpha, TGF-beta 1, and IGF-2 were sought for
and quantified with our sensitive RT-PCR method (3n-PCR). The respective mRNAs of
basic FGF, acidic FGF, TGF-alpha and IGF-2 were not detected, independent of the
culture conditions. In suspension culture, mRNA levels of IGF-1A and -B, PDGF-A,
B, and CD18 remained unchanged. Monocyte adherence regulated IGF-1A, PDGF-A, and
B mRNA levels. In parallel, mRNA levels of the monocyte adhesion molecule CD18
increased rapidly (4.5-fold). In contrast, independent of the presence of an
adherence stimulus, the mRNAs for the cytoskeletal structure protein beta-actin
and PD-ECGF remained constant, whereas mRNA for growth factors TGF-beta 1 and IGF
1B, respectively, was increased. Thus, monocyte adherence selectively regulates
IGF-1, PDGF-A, PDGF-B and CD18 mRNAs (adherence-responsive genes) in a
coordinated manner. This led us to identify two novel consensus elements within
their respective functional promoters. Both motifs, an 11 bp purine-rich sequence
and a 13 bp pyrimidine-rich segment, respectively, are absent from the genes that
were not specifically activated by adherence. The identified elements are
potential binding sites for transcription factors that may define a common basis
for the regulation of the adherence-responsive genes IGF-1A, PDGF-A, PDGF-B and
CD18.
PMID- 9545593
TI - Oligomerization of beta-dystroglycan in rabbit diaphragm and brain as revealed by
chemical crosslinking.
AB - The surface component beta-dystroglycan is a member of the dystrophin
glycoprotein complex providing a trans-sarcolemmal linkage between the actin
membrane cytoskeleton and the extracellular matrix component laminin-alpha2.
Although abnormalities in this complex are involved in the pathophysiology of
various neuromuscular disorders, little is known about the organization of
dystrophin-associated glycoproteins in diaphragm and brain. We therefore
investigated the oligomerization of beta-dystroglycan and its connection with the
most abundant dystrophin homologues in these two tissues. Employing detergent
solubilization and alkaline extraction procedures of native membranes, it was
confirmed that beta-dystroglycan behaves like an integral surface molecule as
predicted by its cDNA sequence. Immunoblot analysis following chemical
crosslinking of native membranes showed that beta-dystroglycan has a tendency to
form high-molecular-mass complexes. Within these crosslinkable complexes, immuno
reactive overlaps were observed between beta-dystroglycan, alpha-dystroglycan,
laminin and 427 kDa dystrophin in diaphragm and skeletal muscle. In synaptosomes,
the major brain dystrophin isoform Dp116 also exhibited an immuno-reactive
overlap with members of the dystroglycan complex. These findings demonstrate that
beta-dystroglycan does not exist as a monomer in native membranes and imply that
certain dystrophin isoforms and dystrophin-associated components interact with
this surface protein in diaphragm and brain as has been previously shown for
skeletal and heart muscle.
PMID- 9545594
TI - Effects of the sulforaphane analog compound 30, indole-3-carbinol, D-limonene or
relafen on glutathione S-transferases and glutathione peroxidase of the rat
digestive tract.
AB - Several dietary compounds have been demonstrated to reduce gastrointestinal
cancer rates in both humans and animals. We showed that high human
gastrointestinal tissue levels of glutathione S-transferase (GST), a family of
detoxification enzymes consisting of class Alpha, Mu, Pi and Theta isoforms, were
inversely correlated with cancer risk. We now investigated whether the
sulforaphane analog compound 30, indole-3-carbinol, D-limonene or relafen,
supplemented in the diet for two weeks at 1450, 250, 10,000, and 200 ppm,
respectively, influenced (i) GST activity, (ii) GST isoenzyme levels, (iii) GSH
levels, or (iv) glutathione peroxidase (GPx) activity in the gastrointestinal
tract of male Wistar rats. Sulforaphane analog compound 30 enhanced GST activity
in all organs studied (1.2-2.4 x). It induced GST Alpha levels in small intestine
and liver, GST Mu levels in stomach and small intestine, GST Pi levels in stomach
and small and large intestine, and GSH levels in stomach and proximal and middle
small intestine. Indole-3-carbinol induced gastric GST Mu and hepatic GST Alpha
levels. D-limonene induced hepatic GST Alpha, colonic GST Pi levels and proximal
small intestinal GST enzyme activity and GST Pi levels. Relafen induced hepatic
GST Alpha levels, distal small intestinal and gastric GST Pi levels, and
oesophageal and proximal small intestinal GSH levels. GPx activity was enhanced
by relafen in oesophagus, and in distal small intestine by sulforaphane analog
compound 30. Enhancement of GSTs and to a lesser extent GPx and GSH, resulting in
a more efficient detoxification, may explain at least in part the
anticarcinogenic properties of sulforaphane analog compound 30, and to a much
lesser extent of indole-3-carbinol and D-limonene.
PMID- 9545595
TI - Structure of the human Nkx2.1 gene.
AB - NKX2.1 is a member of the NK2 family of homeodomain-containing transcriptional
factors which binds to and activates the promoters of thyroid and pulmonary
epithelial genes. We have cloned and sequenced twelve human lung NKx2.1 cDNAs. To
elucidate the origin of Nkx2.1 transcripts, we also cloned and sequenced a 12 kb
human Nkx2.1 genomic clone. Alignment of cDNA sequences with the genomic clone
showed that contrary to previous reports, the human Nkx2.1 gene is organized into
three exons and two introns. The newly discovered exon I contains an ATG codon
that falls in frame with the previously identified Nkx2.1 initiator ATG codon on
one of the cDNAs, designated 5E. Northern blot analysis shows that an mRNA of
approximately 2.5 kb in size, homologous to 5E, is expressed in both lung and
thyroid. The deduced amino acid sequence of the longest open reading frame on 5E
is identical to NKX2.1 with the exception of a 30 amino acid N-terminal
extension. Coupled in vitro transcription/translation of the 5E cDNA confirms
that the open reading frame is translated into a contiguous polypeptide of 44
kDa. Analysis of Nkx2.1 genomic DNA fragments suggest that at least two
independent regions, one within the first intron and the other 5' of the first
exon may mediate the basal promoter activity of the Nkx2.1 gene in lung
epithelial cells.
PMID- 9545597
TI - Control analysis of metabolic systems involving quasi-equilibrium reactions.
AB - Reactions for which the rates are extremely sensitive to changes in the
concentrations of variable metabolite concentrations contribute little to the
control of biochemical reaction networks. Yet they do interfere with the
calculation of the system's behaviour, both in terms of numerical integration of
the rate equations and in terms of the analysis of metabolic control. We here
present a way to solve this problem systematically for systems with time
hierarchies. We identify the fast reactions and fast metabolites, group them
apart from the other ("slow") reactions and metabolites, and then apply the
appropriate quasi-equilibrium condition for the fast subsystem. This then makes
it possible to eliminate the fast reactions and their elasticity coefficients
from the calculations, allowing the calculation of the control coefficients of
the slow reactions in terms of the elasticity coefficients of the slow reactions.
As expected, the elasticity coefficients of the fast reactions drop out of the
calculations, and they are irrelevant for control at the time resolution of the
steady state of the slow reactions. The analysis, when applied iteratively, is
expected to be particularly valuable for the control analysis of living cells,
where a time hierarchy exists, the fastest being at the level of enzyme kinetics
and the slowest at gene expression.
PMID- 9545596
TI - Molybdate binding by ModA, the periplasmic component of the Escherichia coli mod
molybdate transport system.
AB - ModA, the periplasmic-binding protein of the Escherichia coli mod transport
system was overexpressed and purified. Binding of molybdate and tungstate to ModA
was found to modify the UV absorption and fluorescence emission spectra of the
protein. Titration of these changes showed that ModA binds molybdate and
tungstate in a 1:1 molar ratio. ModA showed an intrinsic fluorescence emission
spectrum attributable to its three tryptophanyl residues. Molybdate binding
caused a conformational change in the protein characterized by: (i) a shift of
tryptophanyl groups to a more hydrophobic environment; (ii) a quenching (at pH
5.0) or enhancement (at pH 7.8) of fluorescence; and (iii) a higher availability
of tryptophanyl groups to the polar quencher acrylamide. The tight binding of
molybdate did not allow an accurate estimation of the binding constants by these
indirect methods. An isotopic binding method with 99MoO42- was used for accurate
determination of KD (20 nM) and stoichiometry (1:1 molar ratio). ModA bound
tungstate with approximately the same affinity, but did not bind sulfate or
phosphate. These KDs are 150- to 250-fold lower than those previously reported,
and compatible with the high molybdate transport affinity of the mod system. The
affinity of ModA for molybdate was also determined in vivo and found to be
similar to that determined in vitro.
PMID- 9545598
TI - Kinetics of lactone hydrolysis in antitumor drugs of camptothecin series as
studied by fluorescence spectroscopy.
AB - Potent antitumor activity exhibited by 20-S-camptothecin (CPT) and numerous
derivatives is known to be lost upon opening of the alpha-hydroxy-lactone ring of
these drugs, hydrolyzable at neutral and basic pH. To quantify in 'real time' the
lactone hydrolysis reaction in CPTs under physiological conditions, we have
applied a non-perturbing approach by fluorescence spectroscopy. CPT and a set of
its derivatives (21-lactam-S-CPT, 10,11-(methylenedioxy)-CPT, CPT-11, SN-38,
topotecan, tricyclic ketone-CPT) with antitumor activity varying from negligible
to 10 times that of CPT have been studied. Prior to the kinetic measurements, the
effects of substitutions, pH, polarity of molecular environment, lactone ring
opening (lactone-carboxylate transition) have been investigated in terms of the
UV-visible absorption and fluorescence emission spectra of CPTs. Then the
determined parameters of the fluorescence emission spectra corresponding to the
respective lactone and carboxylate forms have been used to estimate the residual
lactone percentage as a function of time. The reproducibility of the obtained
data demonstrates that the spectroscopic approach provides a satisfactory
precision for this kind of measurements. For CPT at pH 7.3, the lactone half-life
was 29.4 +/- 1.7 min and the lactone percentage at equilibrium was 20.9 +/- 0.3%.
Within a series of derivatives with substitutions at quinoline rings, the lactone
half-life varied from 29 to 32 min and the equilibrium lactone content varied
from 15% to 23%. For each compound, even slight increase of pH from 7.1 to 7.3 or
from 7.3 to 7.6 logically leads to a remarkable decrease of both lactone half
life and equilibrium lactone percentage.
PMID- 9545599
TI - High resolution 1H NMR spectroscopic studies on dynamic biochemical processes in
incubated human seminal fluid samples.
AB - High resolution 600 MHz 1H NMR spectroscopy was used to investigate the changes
in biochemical composition of whole human seminal fluid (SF) and an artificial
mixture of prostatic (PF) and seminal vesicle fluid (SVF). A variety of time
related biochemical changes were monitored simultaneously and non-invasively in
SF, including enzymatic hydrolysis of phosphorylcholine to choline and
polypeptides to amino acids. The fastest NMR-observable reactions in SF were the
conversion of phosphorylcholine to choline (t1/2 approximately equal to 9 min)
and uridine-5'-monophosphate (UMP) to uridine (t1/2 < 2 min). UMP has not
previously been detected in SF because of its rapid hydrolysis. Artificial
mixtures of separately obtained prostatic and SVF showed very similar biochemical
changes to those observed in whole SF. Addition of EDTA to SF incubated for 2 min
post ejaculation strongly inhibited peptide hydrolysis. Zn2+, present in whole SF
was shown to be non EDTA-chelatable 2 min after ejaculation, whereas after 7 min,
a singlet signal from the ethylenic protons of the Zn-EDTA2- complex was clearly
observed which remained constant after 7 min. This indicates that soon after
ejaculation (< 5 min) Zn2+ is immobilised in a macromolecular complex which is
rapidly broken down by proteolytic enzymes, the released Zn2+ then being free to
react with EDTA. Mg- and Ca-EDTA2- complexes were observed at 2 min and remained
constant (at 1.4 and 2.1 mM, respectively) throughout the entire time course of
the experiment. These studies cast new light on the time-related biochemical
changes occurring in the post-ejaculatory SF which may have an important role in
reproductive function.
PMID- 9545600
TI - Electrochemical analysis of the interactions of laccase mediators with lignin
model compounds.
AB - The mechanism of oxidation of lignin by laccase and mediator has been
investigated by cyclic voltammetry and bulk electrolysis. Electrochemical
properties and reactivities of the two mediators 2,2'-azinobis-(3
ethylbenzthiazoline-6-sulfonate) (ABTS) and 1-hydroxybenzotriazole (HBT) were
studied and their intermediates responsible for lignin oxidation were
characterized. ABTS was oxidized first to the cation radical (ABTS+.) and then to
the dication (ABTS2+). The two oxidized species are relatively stable and
electrochemically reversible, with formal redox potentials (E0' vs Ag/AgCl) of
472 mV for ABTS/ABTS+. and 885 mV for ABTS+./ABTS2+. The dication was shown to be
the intermediate responsible for the oxidation of the non-phenolic lignin model
compound veratryl alcohol, whereas the cation radical reacted only with phenolic
structures in lignin. Cyclic voltammetry of HBT shows only one oxidation peak at
878 mV, but unlike ABTS, the oxidized intermediate was not stable and decayed
rapidly. The radical intermediate of HBT was shown to catalyze the oxidation of
veratryl alcohol to veratraldehyde. The kinetics of homogeneous redox catalysis
of mediators and veratryl alcohol were estimated. ABTS-mediated lignin oxidation
at the redox potential of laccase (585 mV) was shown to be possible, but at a
very slow rate, as previously reported for laccase and mediator.
PMID- 9545601
TI - 2-Methoxy-4-nitroaniline and its isomers induce cytochrome P4501A (CYP1A) enzymes
with different selectivities in the rat liver.
AB - We reported previously that 2-methoxy-4-nitroaniline (2-MeO-4-NA) is a selective
inducer of cytochrome P4501A2 (CYP1A2) in the rat liver, and its molecular size
is the smallest among known CYP1A2-selective inducers. In the present study, a
structure-activity relationship on the CYP1A2-selective induction has been
investigated using isomeric nitroanisidines and their related chemicals. Western
blot analyses revealed that the chemicals removed a substituent (amino, methoxyl
or nitro group) from a 2-MeO-4-NA molecule had no capacity for inducing CYP1A
enzymes in rat livers. On the other hand, isomeric nitroanisidines such as 2-MeO
4-NA, 2-MeO-5-NA and 4-MeO-2-NA induced both CYP1A2 and CYP1A1 enzymes with
different selectivities. As judged from the induced levels of CYP1A proteins, 2
MeO-4-NA (CYP1A2/CYP1A1 ratio; 9.5) and 4-MeO-2-NA (0.3) were the most selective
inducers of CYP1A2 and CYP1A1, respectively, among the isomeric nitroanisidines
(0.44 mmol/kg) used. The induced level of CYP1A2 protein was in the order 2-MeO-4
NA > 2-MeO-5-NA > 4-MeO-2-NA, although no significant difference was observed on
their CYP1A2 mRNA level. On the contrary, increases in the levels of CYP1A1 mRNA
and protein were in the order 4-MeO-2-NA > 2-MeO-5-NA > 2-MeO-4-NA. The present
findings indicate that all three substituents (amino, methoxyl and nitro groups)
are necessary components of nitroanisidines for induction of CYP1A enzymes, and
also show that regio-isomeric positions of these substituents determine the
selectivity in the induction of CYP1A enzymes.
PMID- 9545602
TI - Peroxisomal localization of D-aspartate oxidase and development of peroxisomes in
the yeast Cryptococcus humicolus UJ1 grown on D-aspartate.
AB - The peroxisomal localization of D-aspartate oxidase (EC. 1.4.3.1) was
demonstrated in the yeast Cryptococcus humicolus UJ1 cells grown in the medium
containing D-aspartate as a nitrogen source. The conclusion is based on the
identical behavior of the enzyme with those of peroxisomal marker enzymes,
catalase and urate oxidase, during all steps of subcellular fractionations.
Supporting evidence was provided by the morphometric analysis of the peroxisomes
with electron microscopy, showing that the cells grown on D-aspartate contained
more and larger peroxisomes than those grown on L-aspartate, consistent with the
500-fold and 3-fold, higher contents of D-aspartate oxidase and catalase
activities, respectively, in the former cells than the latter.
PMID- 9545603
TI - The Web, communication trends, and children's health. Part 1: Development and
technology of the Internet and Web.
AB - The Internet and The World Wide Web are changing the way pediatricians find
medical information and provide care. This article, the first in a four-part
series on The Web, Communication Trends, and Children's Health, published in
consecutive issues of this journal, describes how the Web was created and how its
multimedia capabilities are affecting information exchange.
PMID- 9545605
TI - Lack of evidence of transmission of HIV-1 to family contacts of HIV-1 infected
children.
AB - Although a number of studies have documented that casual household contact does
not result in the transmission of HIV, isolated cases of person-to-person
transmission have been reported. We report a study of household transmission in
which the families were unaware the children were infected with HIV and thus took
no precautions to prevent transmission. Twenty-two family members of nine
transfusion-associated HIV-infected children were studied for transmission of HIV
in households. There was a total of 174 person-year of household exposure; 76 of
these exposure years were before the diagnosis of HIV infection in the index
child. All family members tested negative for HIV by ELISA. Sharing household
facilities, and interactions with the infected child including kissing, bathing,
sleeping with, and helping to bathe, dress, and eat, did not result in
transmission. Interactions that could theoretically result in person-to-person
transmission occurred in these households such as caring for nose bleeds, biting,
and home health care procedures. The findings of this and other studies support
the participation of HIV-infected infants and children in out-of-home care
programs. It remains prudent, however, to observe current recommendations for
prevention of HIV-1 for all individuals regardless of whether HIV status is
known.
PMID- 9545604
TI - CHARGE association: an update and review for the primary pediatrician.
AB - CHARGE association is a nonrandom pattern of congenital anomalies that occurs
together more frequently than one would expect on the basis of chance. This
common multiple anomaly condition has an estimated prevalence of 1:10,000. The
number of children diagnosed with CHARGE association is increasing, owing
presumably to greater awareness of this condition and advances in the care of
complex, chronically ill children, resulting in improved survival and outcome.
This review of CHARGE association presents diagnostic criteria that may define a
concise, recognizable syndrome with a single pathogenetic basis. This review also
summarizes our current understanding of the management for this complex and
chronic multiple congenital anomaly condition and discusses the pathogenetic
basis for this condition.
PMID- 9545606
TI - Infectious diseases presentations of Munchausen syndrome by proxy: case report
and review of the literature.
AB - Munchausen syndrome by proxy is a form of abuse, usually of a child by a parent,
in which a factitious illness is reported or produced in the child, resulting in
unnecessary medical evaluations and treatments. A dramatic case of a 17-month-old
infant with recurrent polymicrobial bacteremia prompted a review of cases
diagnosed by the Pediatric Infectious Diseases consultation service at our
referral children's hospital and a review of the infectious diseases
presentations in the medical literature. The infectious diseases presentations of
the syndrome as well as criteria for the diagnosis are reviewed and discussed.
PMID- 9545607
TI - A physician's perspective on dealing with cases of Munchausen by proxy.
PMID- 9545608
TI - Normal 17-month outcome of a severely hypothermic term neonate.
PMID- 9545609
TI - Dubowitz syndrome and achalasia: two rare conditions in a child.
PMID- 9545610
TI - Stool withholding masquerading as seizure disorder.
PMID- 9545611
TI - Congenital ranula.
PMID- 9545612
TI - Resident rounds on infant botulism.
PMID- 9545613
TI - The uncertain diagnosis.
PMID- 9545614
TI - Iodine intake is a main determinant of thyroid hypersensitivity to acute iodine
overload.
PMID- 9545615
TI - The role of quantitative ultrasound in the assessment of bone: a review.
AB - Quantitative ultrasound (QUS) bone measurement is a promising, relatively new
technique for the diagnosis of osteoporosis. Unlike to the more established
method of bone densitometry [measurement of bone mineral density (BMD) e.g. using
dual X-ray absorptiometry (DEXA)], QUS does not use ionizing radiation. It is
cheaper, takes up less space and is easier to use than densitometry techniques.
The two QUS parameters currently measured are broadband ultrasound attenuation
(BUA) and speed of sound (SOS). The reported age-related changes for healthy
women range from -0.27% to -1.62% per year for BUA and from -0.06% to -0.19% per
year for SOS. Precision ranges from 1.0 to 3.8% (CV) for BUA and from 0.19 to
0.30% (CV) for SOS. The new method of imaging ultrasound has improved the
precision of QUS measurements. QUS is significantly correlated with BMD. Studies
with the latest equipment have shown r-values between 0.6 and 0.9 in site
specific measurements, and QUS is thus believed to reflect mainly BMD. However,
other studies indicate that QUS measures something other than the actual mineral
content of bone, namely bone quality, e.g. in vitro studies have shown that QUS
reflects trabecular orientation independently of BMD. In both cross-sectional and
prospective studies, QUS seems to be as good a predictor of osteoporotic
fractures as BMD. In two large prospective studies, QUS also predicted fracture
risk independently of BMD. QUS has just begun to be used systematically for
monitoring the response to anti-osteoporotic treatments in prospective trials. In
the studies performed, QUS has been found to be useful in the follow-up of
patients. QUS is thus a promising new technique for bone assessment.
PMID- 9545616
TI - Calf vein compliance increases following bed rest after aortocoronary bypass
surgery.
AB - Early post-operative ambulation (< 3 days) is expected to decrease the risk of
venous thrombosis, whereas late ambulation (> 7 days) increases the risk of
orthostatic hypotension. The effect of post-operative bed rest on calf vein
compliance was studied before (D - 1) and 7 days (D + 7) after aortocoronary
bypass surgery in 50 patients (41 men and nine women, 65 +/- SD 10 years). Calf
vein compliance was measured by strain gauge plethysmography and stepwise
increases in thigh congestive pressure from 20 to 60 mmHg. Calf compliance
[median (25 percentile-75 percentile)] increased significantly by 48% from D - 1
to D + 7 [0.044 (0.039-0.051) vs. 0.065 (0.048-0.083) ml (100 ml mmHg)-1, P <
0.001]. This increase was reflected as increased calf volume for the 50 mmHg [D-1
2.10 (1.75-2.65) vs. D + 7 2.60 (1.70-3.00) ml 100 ml-1, P < 0.01] and 60 mmHg [D
- 1 2.50 (2.10-2.95) vs. D + 7 3.20 (2.30-4.00) ml 100 ml-1, P < 0.001] occlusion
pressure levels. The associated pathologies (diabetes and arterial hypertension)
and NYHA grades had no significant influence on the increase in compliance. Among
the vasoactive therapeutic regimens, calcium channel blockers contributed
significantly to the increased calf compliance, but only on D-1. The increase in
venous compliance following aortocoronary bypass surgery is multifactorial but
should be considered for prophylactic management of these patients.
PMID- 9545617
TI - Effect of the H1 blocker d-chlorpheniramine on cerebral blood flow in the
conscious dog during normocapnic hypoxia.
AB - The mechanism causing cerebral vasodilatation during hypoxia remains unclear. A
role for histamine is suspected because H2 receptor-blocking drugs blunt the
hypoxia-induced increase in cerebral blood flow (CBF). Moreover, in vitro
blockade of H1 receptors by chlorpheniramine decreases the vasodilatation of
cerebral arteries that is induced by histamine. The present study tested the
hypothesis that an H1 receptor blocker (d-chlorpheniramine) would have a similar
effect in vivo during hypoxia. Isocapnic hypoxia (inspired oxygen fraction, FIO2
= 0.10; inspired carbon dioxide fraction, FICO2 = 0.035) was induced in 16
conscious dogs randomly divided into two groups: eight dogs received saline
intravenously (controls) at time 0 (normoxia) and after 2 h and 4 h hypoxia, and
the other eight dogs received d-chlorpheniramine intravenously (0.5 mg kg-1) to
block the H1 receptors. Regional CBF was measured by the radioactive microspheres
technique 15 min after each injection of d-chlorpheniramine or saline. In the
control group, CBF increased during hypoxia in all regions of the brain. In the d
chlorpheniramine group, total CBF increased similarly after 2 h of hypoxia. After
4 h of hypoxia, the increase was limited, especially in the pons, cerebral
peduncles, hippocampus, hypothalamus, thalamus, and occipital lobes (six out of
12 studied regions). It is concluded that the H1 blocker d-chlorpheniramine did
not strongly inhibit the increase in CBF during hypoxia. After cumulative doses,
however, as in the fourth hour of hypoxia, the increase in total CBF was limited.
PMID- 9545618
TI - Lower leg electrical impedance after distal bypass surgery.
AB - Electrical impedance was determined in 13 patients following distal bypass
surgery to evaluate lower leg oedema as reflected by its circumference. Tissue
injury was assessed by the plasma concentration of muscle enzymes. After surgery,
the volume of the control lower leg increased from 1250 (816-2373) to 1384 (874
2345) ml (median and range; P < 0.05), where the impedance did not change
significantly from 140 (92-181) ohms. The volume of the operated leg increased
more [from 1129 (824-2373) to 1600 (1090-2837) ml], and the decrease in
electrical impedance was also pronounced [137 (125-169) to 83 (69-104) ohms (P <
0.001)]. Tissue injury after surgery was indicated by an increase in total
creatine kinase (n = 17) and MB isoenzyme of creatine kinase (n = 8) (P < 0.05).
Myoglobin (n = 8) had increased already during surgery (P < 0.05), whereas there
was no significant change in the plasma concentration of troponin I (n = 8). In
conclusion, tissue injury was reflected by increases in muscle enzymes in plasma.
We found an inverse correlation between lower leg electrical impedance and
volume, but the deviation in electrical impedance was approximately twice that of
the leg volume. Electrical impedance appears to be a useful method for the
evaluation of lower leg oedema after distal bypass surgery.
PMID- 9545619
TI - Effect of head-upright tilt on the dynamic of cerebral autoregulation.
AB - The effect of head-upright tilting on the rate of cerebral autoregulation was
studied in 12 healthy volunteers (nine men and three women; age range 20-36
years). The dynamics of cerebral autoregulation was determined from the rate of
change in cerebral resistance (RoR) during a drop in arterial blood pressure
induced by rapid deflation of a 3-min ischaemic thigh cuff and from the ratio of
changes in cerebral blood flow and arterial blood pressure (CAI) during the
recovery period after the drop in arterial blood pressure. The test was performed
supine and with 40 degrees head-up tilt (40 degrees HUT). Middle cerebral artery
mean blood flow velocity was measured by transcranial Doppler simultaneously with
peripheral arterial blood pressure using Finapres. The thigh cuff deflation
induced a larger drop in arterial pressure during 40 degrees HUT [median -28% (25
percentile -36, 75 percentile -19)] than in the supine position [-16% (-23, -15)]
(P < 0.01) and in cerebral resistance [supine: -12% (-15, -6); 40 degrees HUT:
15% (-20, -12); P < 0.05]. There was no significant change in RoR [15% s-1 (12,
15)] and CAI [1.9 (1.5, 3.1)] measured supine and during 40 degrees HUT [RoR: 13%
s-1 (12, 15); CAI: 1.3 (0.99, 1.9)]. During the drop in arterial pressure, the
relationship between arterial blood pressure and systolic peak-to-peak interval
exhibited an hysteresis loop, indicating a cardiopulmonary and/or baroreflex
activation that was not observed with cerebral resistance. The rate of
autoregulation is an intrinsic property of the cerebral vascular bed and is not
affected by the vasodilator state in the range of arterial blood pressure changes
induced by the tight cuff method.
PMID- 9545620
TI - Diagnostic role of residual volume in paediatric patients with chronic symptoms
of the lower airways.
AB - In bronchial asthma, measurement of absolute lung volumes may reveal lung
dysfunction more readily than forced expiratory spirometry. Sixty-one children
(aged 4-16 years) with mild to moderate bronchial asthma and 35 children (aged 7
16 years) with other symptoms of the lower airways (OSLA) were studied, and the
plethysmographic results were compared with data obtained from 36 healthy
volunteers aged 6-16 years. In the first test session, repeatability of forced
expiratory volume in one second (FEV1), forced vital capacity (FVC), residual
volume (RV), functional residual capacity (FRC) and total lung capacity (TLC)
were good. Control subjects were also tested the next day, and intra-subject
variability of repeat pulmonary function testing was in the normal range. The
FEV1/FVC ratio was significantly higher in control subjects than in patients with
asthma or OSLA, but only the decrease in RV after bronchodilator challenge
separated patients with asthma from patients with OSLA. Changes in FEV1 and RV
after bronchodilator challenge had a significant, although low, inverse
correlation. An increase of > or = 5% in FEV1 had a positive predictive value of
44% and a negative predictive value of 68% for the clinical diagnosis of
bronchial asthma; for a decrease of > or = 24% in RV, the figures were 86% and
71% respectively. The support of baseline absolute lung volumes on clinical
decision-making is not necessarily great. Bronchodilator response, particularly
in RV, is more pertinent and may enhance the detection of reversible lung
dysfunction.
PMID- 9545621
TI - Selectivity of superficial vein occlusion at the ankle and calf level: a
methodological study in healthy volunteers.
AB - Judgement of deep venous function may be necessary before surgery for superficial
vein incompetence is performed. Assessment of deep venous function needs
selective entrapment of superficial venous compartments between the ankle and
knee, which may not be guaranteed if conventional tourniquets are used. This
study was, therefore, aimed at modifying the technique of selective compression
of superficial vein compartments. Twenty apparently normal legs of 10 volunteers
were investigated on two study days. The subjects were in a supine position with
the feet resting 30 cm above heart level. Ankle cuffs (3 cm wide) were placed
just above the malleoli and stepwise inflated with air. The steady-state venous
volume of the forefoot as a function of the pressure within the ankle cuff was
measured with a mercury-in-rubber strain gauge. The maximum venous outflow
velocity from the foot was also measured at each cuff pressure step after the
addition of conventional thigh vein occlusion. The same protocol was used on the
second study day: calf cuffs (3 cm wide) were then used instead of the ankle
cuffs. In the forefoot, venous volume increased and the maximum venous outflow
velocity decreased significantly either at ankle cuff pressures > 30 mmHg or at
calf cuff pressures of > 60 mmHg. By using small cuffs, selective superficial
vein occlusion seems to occur at cuff pressures ranging between 10 and 30 mmHg
(ankle) and between 30 and 60 mmHg (calf), provided the feet are 30 cm above
heart level. Higher cuff pressures seem to interact with deep venous function.
PMID- 9545622
TI - The C-terminal fragment of big endothelin-1 does not potentiate the vasoactive
effects of endothelin-1.
AB - The aim was to study the cardiovascular effects of the C-terminal (22-38)
fragment of big endothelin-1, which is produced by the cleavage of big endothelin
1 (big ET-1) to endothelin-1 (ET-1). An intravenous infusion of the (22-38)
fragment (4, 8 and 12 pmol kg-1 min-1, each dose for 10 min) was given to 10
healthy subjects. Four control subjects received 0.9% saline. Two additional
subjects received ET-1 1 (0.2 and 4 pmol kg-1 min-1, each dose for 20 min) alone
or combined with an equimolar infusion of the (22-38) fragment on two separate
occasions. The fragment infusion did not alter heart rate, mean arterial blood
pressure, cardiac output, systemic or pulmonary vascular resistance, splanchnic,
cerebral or forearm blood flow. Renal blood flow showed a slight fall (11%, P <
0.001) in the fragment group of the same magnitude as in a previous control
study. After the fragment infusion, a decrease in mean pulmonary arterial
pressure (MPAP) by 12% (P < 0.01) and in pulmonary capillary wedge pressure
(PCWP) by 31% (P < 0.001) was noted, which did not differ from the pulmonary
pressures in the saline-infused control group. The (22-38) fragment, when
combined with ET-1, was not able to modify the effects of ET-1 on heart rate,
mean arterial blood pressure, splanchnic and renal blood flow. Consequently, the
exogenous (22-38) fragment does not seem to cause any significant cardiovascular
effects in healthy humans.
PMID- 9545623
TI - Cardiovascular effects of ephedrine, caffeine and yohimbine measured by thoracic
electrical bioimpedance in obese women.
AB - Low caloric diet is a commonly accepted treatment in obesity. However, owing to
moderate results, a pharmacological support has been proposed. As some
efficacious drugs activate overall sympathetic activity, they might modify
functions of the cardiovascular system. Three groups of subjects were studied:
(1) nine obese women receiving only a standard hypocaloric diet; (2) nine obese
women receiving a standard hypocaloric diet and ephedrine (2 x 25 mg) with
caffeine (2 x 200 mg); (3) nine obese women receiving a standard hypocaloric diet
and ephedrine (2 x 25 mg) with caffeine (2 x 200 mg) and yohimbine (2 x 5 mg).
The cardiovascular state was evaluated by thoracic electrical bioimpedance,
automatic sphygmomanometry and continuous ECG recording. In each patient, the
haemodynamic study was performed twice: at rest, i.e. before treatment; and after
10 days of treatment. On the same days in each patient, the haemodynamic tests
were performed during physical exercises (handgrip stress and cycloergometer
exercise). Caffeine and ephedrine had no haemodynamic effect in resting patients.
These two drugs led to an increase in ejection fraction during cycloergometer
exercise. Addition of yohimbine increased diastolic pressure and heart rate but
decreased ejection fraction and stroke index during rest. We also observed that
addition of yohimbine decreased ejection fraction during the handgrip and
cycloergometer exercise and increased cardiac load during dynamic exercise.
Pharmacological supplement of ephedrine and caffeine to a low caloric diet
modified the cardiovascular system weakly, but the addition of yohimbine to this
regimen attenuated cardiac performance during rest and handgrip and increased
cardiac work during dynamic exercise.
PMID- 9545624
TI - Explaining fertility transitions.
AB - In this essay, I suggest that the crisis in our understanding of fertility
transitions is more apparent than real. Although most existing theories of
fertility transition have been partially or wholly discredited, this reflects a
tendency to assume that all fertility transitions share one or two causes, to
ignore mortality decline as a precondition for fertility decline, to assume that
pretransitional fertility is wholly governed by social constraints rather than by
individual decision-making, and to test ideas on a decadal time scale. I end the
essay by suggesting a perceptual, interactive approach to explaining fertility
transitions that is closely allied to existing theories but focuses on conditions
that lead couples to switch from postnatal to prenatal controls on family size.
PMID- 9545625
TI - The rise of divorce and separation in the United States, 1880-1990.
AB - I use the Integrated Public Use Microdata Series to assess the potential effects
of local labor-market conditions on long-term trends and race differences in
marital instability. The rise of female labor-force participation and the
increase in nonfarm employment are closely associated with the growth of divorce
and separation. Moreover, higher female labor-force participation among black
women and lower economic opportunities for black men may account for race
differences in marital instability before 1940, and for most of such differences
in subsequent years. However, unmeasured intervening cultural factors are
probably responsible for at least part of these effects.
PMID- 9545626
TI - Migration, fertility, and state policy in Hubei Province, China.
AB - Despite China's one-child family planning policy, the nation experienced a slight
rise in the birth rate in the mid-1980s. Many observers attributed this rise to
the heightened fertility of those rural-to-urban migrants who moved without a
change in registration (temporary migrants), presumably to avoid the surveillance
of family planning programs at origin and destination. Using a sequential logit
analysis with life-history data from a 1988 survey of Hubei Province, we test
this possibility by comparing nonmigrants, permanent migrants, and temporary
migrants. While changing family planning policies have a strong impact on timing
of first birth and on the likelihood of higher-order births, migrants generally
do not have more children than nonmigrants. In fact, migration tends to lower the
propensity to have a child. More specifically, the fertility of temporary
migrants does not differ significantly from that of other women.
PMID- 9545627
TI - Sibling models of socioeconomic effects on the timing of first premarital birth.
AB - Data on 1,000 pairs of sisters from the National Longitudinal Survey of Youth are
used to estimate the effects of observed individual-level factors, common family
level variables, and shared unobserved family-level traits on the timing of
premarital births. Results show a moderate correlated risk of premarital
childbearing among siblings after controlling for the effects of measured
covariates. The effect of older sisters' out-of-wedlock childbearing on the
timing of younger sisters' premarital birth is overestimated when shared
unmeasured family-level traits are ignored. Public policy measures designed to
reduce premarital births have a smaller multiplier effect via reduced younger
sisters' premarital births because unmeasured family-level factors are less
amenable to policy measures. However, because the older-sibling effect is large
when other sources of variability in premarital birth timing are controlled,
interventions may be effective in reducing premarital births among young women in
high-risk families.
PMID- 9545628
TI - Effect of provider characteristics on choice of contraceptive provider: a two
equation full-information maximum-likelihood estimation.
AB - We use surveys of households and health-care facilities conducted in the same
area at the same time to determine which characteristics of providers attract
users of contraceptives. By using the full-information maximum-likelihood
technique to jointly estimate choice of contraceptive method and choice of
provider, we avoid self-selection bias. Results support the need for modeling
quality and for jointly estimating the choice of contraceptive method and the
choice of provider to avoid biased estimates of coefficients. The results suggest
that for the Cebu, Philippines region, small local clinics that focus on family
planning tend to be most favored by clients.
PMID- 9545629
TI - Residential mobility between cities and suburbs: race, suburbanization, and back
to-the-city moves.
AB - Information from the 1979 to 1986 waves of the Panel Study of Income Dynamics is
merged with data on respondents' tract and metropolitan area of residence to
examine patterns and determinants of residential mobility between central cities
and suburbs. Consistent with the life-cycle model of residential mobility,
mobility in both directions declines with age, but on balance the presence of
young children deters moving to the suburbs. Among blacks, education increases
the probability of moving from cities to suburbs, while high income retains
blacks and whites in suburbs. Consistent with the place stratification model,
blacks are substantially less likely than whites to move from cities to suburbs,
and substantially more likely to move from suburbs to cities, even after
standardizing for racial differences in sociodemographic characteristics. High
levels of violent crime and unemployment in cities relative to suburbs also tend
to spur city-to-suburb mobility or inhibit suburb-to-city moves.
PMID- 9545630
TI - An occupational tale of two cities: minorities in London and New York.
AB - In this paper, queuing theory is tested through an examination of the
occupational attainment of six groups of non-whites in London and New York.
Workers in the dominant economy are distinguished from those in the niche economy
and emphasis is placed on the former. Black male immigrants in New York and black
female immigrants in London hold more favorable occupational status. These
results reflect differences in (1) the presence of indigenous minorities--African
Americans and Puerto Ricans--in New York but not London, and (2) the relatively
low position of indigenous minority males compared to the relatively middling
position of indigenous minority females in New York's labor queue.
PMID- 9545631
TI - Age-distribution dynamics and aging indexes.
AB - I analyze the dynamics of the age distribution as some vital rates change. When
the fertility or mortality rate declines, the age distribution often manifests a
dynamic stochastic-dominance relationship. I also propose some alternative
indexes for measuring population aging. These indexes are closely connected with
the age-distribution dynamics and contain more refined information about the
distribution of age among the old.
PMID- 9545632
TI - Structure and methylation-based silencing of a gene (DBCCR1) within a candidate
bladder cancer tumor suppressor region at 9q32-q33.
AB - Loss of heterozygosity (LOH) on chromosome 9q is the most frequent genetic
alteration in transitional cell carcinoma (TCC) of the bladder, indicating the
presence of one or more relevant tumor suppressor genes. We previously mapped one
of these putative tumor suppressor loci to 9q32-q33 and localized the candidate
region within a single YAC 840 kb in size. This locus has been designated DBC1
(for deleted in bladder cancer gene 1). We have identified a novel gene, DBCCR1,
in this candidate region by searching for expressed sequence tags (ESTs) that map
to YACs spanning the region. Database searching using the entire DBCCR1 cDNA
sequence identified several human ESTs and a few homologous mouse. ESTs. However,
the predicted 761-amino-acid sequence had no significant homology to known
protein sequences. Mutation analysis of the coding region and Southern blot
analysis detected neither somatic mutations nor gross genetic alterations in
primary TCCs. Although DBCCR1 was expressed in multiple normal human tissues
including urothelium, mRNA expression was absent in 5 of 10 (50%) bladder cancer
cell lines. Methylation analysis of the CpG island at the 5' region of the gene
and the induction of de novo expression by a demethylating agent indicated that
this island might be a frequent target for hypermethylation and that
hypermethylation-based silencing of the gene occurs in TCC. These findings make
DBCCR1 a good candidate for DBC1.
PMID- 9545634
TI - Cloning and localization of the murine Xpct gene: evidence for complex
rearrangements during the evolution of the region around the Xist gene.
AB - The overall organization of the X-inactivation center (XIC/Xic) candidate region
seems poorly conserved between human and mouse. The orientation of a region
containing the X-inactive-specific transcript (Xist/ XIST) gene and three genes
located 3' of Xist/XIST has been shown to be inverted between the two species,
although the actual extent of this rearrangement is unknown. We have cloned and
mapped the mouse homolog of the human XPCT (X-linked PEST-containing transporter)
gene, which encodes a putative transmembrane transporter. Human XPCT is located
about 200 kb outside of the XIC candidate region and 600 kb 5' of or telomeric to
the XIST gene. The mouse Xpct gene, which lies approximately 300 kb 5' of and
centromeric to Xist, displays 85% identity at the nucleotide level with the human
gene, and the overall protein structure is conserved. The transcriptional
orientation of mouse Xpct with respect to Xist is the opposite of that in human.
Consequently, the evolution of the region between human and mouse appears to be
highly complex, with structural rearrangements involving a region of up to 600 kb
or more around the Xist gene.
PMID- 9545633
TI - Partial deletion of both the spermine synthase gene and the Pex gene in the X
linked hypophosphatemic, gyro (Gy) mouse.
AB - Gy, along with Hyp, is a dominant mutation of the normal gene Pex causing X
linked hypophosphatemia in the mouse. Hemizygous Gy male mice, however, have
greater defects in survival, bodily growth, skeletal mineralization, and
neurological function than those found in heterozygous Gy females or in Hyp mice.
Since the gene for spermine synthase is immediately upstream of the homologous
human gene PEX, we compared the effects of the Gy and Hyp mutations on both the
spermine synthase gene and the Pex gene. Barely detectable levels of spermine (<
5% of normal) with elevated levels of its precursor, spermidine, were found in
organs of Gy male mice compared to normal male littermates. Neither Gy females
nor Hyp male mice were significantly affected. Four missing introns of the
spermine synthase gene were identified in Gy male mice, suggesting extensive gene
disruption. A pseudogene for spermine synthase was also identified in the mouse
genome. Pex mRNA was found in several but not all tissues studied in adult normal
mice. Pex mRNA was altered in both Gy and Hyp mice. All male Hyp mice were
lacking the 3' end of the Pex message, whereas all male Gy mice were deficient at
the 5' end. In summary, the Gy mutation is associated with a recessively
expressed mutation of the spermine synthase gene, leading to spermine deficiency,
and a dominantly expressed mutation of the Pex gene, leading to hypophosphatemia.
Alterations in two contiguous genes in Gy may explain the additional phenotypic
abnormalities present in the Gy male mouse.
PMID- 9545636
TI - Genomic DNA sequence, promoter expression, and chromosomal mapping of rat muscle
carnitine palmitoyltransferase I.
AB - Carnitine palmitoyltransferase I (CPT-I) is a key enzyme involved in the
regulation of fatty acid oxidation. CPT-IA and CPT-IB are isoforms of carnitine
palmitoyltransferase I, of which CPT-IA is expressed in liver, kidney,
fibroblasts, and heart and CPT-IB is expressed in skeletal muscle, heart, brown
and white adipocytes, and testes. Although the genomic DNA sequence of human CPT
IB is available, the transcription start site and upstream regulatory sequences
are not known. For rat CPT-IB, only the cDNA sequence has been published. We have
cloned the entire rat CPT-IB gene from a Lambda fix II rat kidney genomic
library. The genomic structure contains 19 exons, with the transcription start
site for CPT-IB located in a short first exon, which is a 13-bp extension to the
previously published cDNA 5' sequence. The coding sequence is identical with the
rat muscle cDNA. The rat CPT-IB gene contains 18 introns and 19 exons, the latter
18 exons showing 85% homology to the human CPT-IB cDNA. CPT-IB maps to rat
chromosome 7 at band q34. A putative promoter region was identified to within 391
bp of the transcription start site. The muscle specificity of the 5' flanking
region was verified by comparison of luciferase expression to that of beta
galactosidase in cardiac myocytes and in HepG2 cells.
PMID- 9545635
TI - The mouse Y chromosome: enrichment, sizing, and cloning by bivariate flow
cytometry.
AB - In this report, we demonstrate the utility of interleukin-2 (IL-2) stimulation of
spleen cell cultures and bivariate flow cytometry in the analysis and
purification of the C57BL/6J mouse Y Chromosome. We determined that the DNA
content of the C57BL/6J Y Chromosome is approximately 94.7 Mb, making it similar
in size to human Chromosome 16 and significantly larger than previous estimates.
In addition, we describe the bulk isolation of mouse Y Chromosomes and
demonstrate enrichment of the isolated material using a fluorescence in situ
hybridization strategy. We detail the construction of two small insert Y
Chromosome-specific libraries, ideal for sampling Y Chromosome sequences. From
these libraries 1566 clones were analyzed. We provide a detailed characterization
of 103 clones, generating nearly 50 kb of sequence. For 30 of these clones, we
identify regions of homology to known Y chromosomal sequences, confirming the
enrichment of the sorted DNA. From the remaining characterized clones, we
describe the development of 15 male-specific PCR assays and 19 male-female PCR
assays potentially originating from the pseudoautosomal region or other areas of
X-Y or autosome-Y homology.
PMID- 9545639
TI - Homozygosity mapping of autosomal recessive retinitis pigmentosa locus (RP22) on
chromosome 16p12.1-p12.3.
AB - Autosomal recessive retinitis pigmentosa (arRP) is a genetically and clinically
heterogeneous and progressive degenerative disorder of the retina, leading
usually to severe visual handicap in adulthood. To date, disease loci/genes have
been mapped/identified only in a minority of cases. DNA samples were collected
from 20 large consanguineous Indian families, in which arRP segregated and that
were suitable for homozygosity mapping of the disease locus. After excluding
linkage to all known arRP loci, a genome-wide scan was initiated. In two
families, homozygosity mapping, haplotype analysis, and linkage data mapped the
disease locus (RP22) in an approximately 16-cM region between D16S287 and D16S420
on the proximal short arm of chromosome 16. No mutation has been found by direct
sequencing in the gene (CRYM) encoding micron crystallin, which maps in the
critical region.
PMID- 9545638
TI - Identification and characterization of two putative human arginine
methyltransferases (HRMT1L1 and HRMT1L2).
AB - RNA-binding proteins such as heterogeneous nuclear ribonucleoproteins (hnRNPs),
which contain the bulk of methylated arginine residues in eukaryotic cells, play
many essential roles in the metabolism of nuclear pre-mRNA. Arginine
methyltransferase activity has also been implicated in signal transduction events
with components of the cellular growth and viral response pathways. We recently
characterized a single yeast hnRNP methyltransferase (HMT1). We now present the
identification and characterization of two putative human arginine
methyltransferases termed HRMT1L1 and HRMT1L2. In addition to methyltransferase
similarities, the N-terminal region of the HRMT1L1 protein contains an Src
homology 2 domain. HRMT1L1 maps to a YAC containing the telomere of chromosome
21q. Three alternatively spliced HRMT1L2 transcripts with variable 5'-ends were
observed, encoding proteins of 343, 347, and 361 amino acids, respectively.
HRMT1L2 maps to human chromosome 19q. Recombinant HRMT1L2 protein encoded by the
most common 5'-variant exhibited methyltransferase activity in vitro.
Furthermore, in vivo activity was demonstrated by complementation of a yeast HMT1
mutant strain. The identification of highly conserved Hmt1p human homologues that
function in yeast indicates that analyses of this class of enzymes in yeast may
be directly applicable to higher eukaryotes. The possible roles of HRMT1L1 and
HRMT1L2 in human disease are currently unknown.
PMID- 9545637
TI - Molecular cloning, structural characterization, and chromosomal mapping of the
human LECT2 gene.
AB - We originally isolated LECT2 (leukocyte cell-derived chemotaxin 2) as a 16-kDa
secreted protein having a human neutrophil chemotactic activity, then cloned
human and bovine LECT2 cDNAs and demonstrated the liver-specific expression of
the protein. LECT2 is thought to be a multifunctional protein, because it was
recently found to be identical to chondromodulin-II a growth stimulator of
chondrocyte cells. We report here the cloning and the structural analysis of the
human LECT2 gene. The gene spans approximately 8 kb and consists of four exons
and three introns. Primer extension analysis revealed that several transcription
initiation sites occur within 70-230 nucleotides upstream of the translation
initiation codon. Several transcriptional control sequences relevant to the liver
specific expression have been identified at the 5' untranslated region of the
human LECT2 gene. The human LECT2 gene was mapped to chromosome 5q31.1-q32 by
fluorescence in situ hybridization. This region contains a cluster of cytokine
genes including IL-4, IL-5, and IL-9.
PMID- 9545640
TI - A high-resolution genetic map of the nervous locus on mouse chromosome 8.
AB - The nervous (nr) mutant mouse displays two gross recessive traits: both an
exaggeration of juvenile hyperactivity and a pronounced ataxia become apparent
during the third and fourth postnatal weeks. Using an intersubspecific
intercross, we have established a high-resolution map of a segment of mouse
chromosome 8 that places the nr locus in a genomic segment defined by D8Rck1 on
the centromeric end and D8Mit3 on the telomeric end. This map position places the
nr locus within the BALB/cGr congenic region of the C3HeB/ FeJ-nr strain,
confirming the accuracy of our study. We used this map position to identify and
evaluate three genes-ankyrin 1, cortexin, and farnesyltransferase-as candidates
for the nr gene. These three genes were eliminated from consideration but allowed
us to establish the conservation of synteny between the region containing the nr
locus and a segment of the short arm of human chromosome 8 (8p21-p11.2). Finally,
the incomplete penetrance of the nr phenotype led us to perform a screen for
modifier loci, and we present evidence that such a nervous modifier locus may
exist on mouse chromosome 5.
PMID- 9545642
TI - Physical linkage of the B29/Ig-beta (CD79B) gene to the skeletal muscle, sodium
channel, and growth hormone genes in rat and human.
AB - In the region between the polyadenylation site of the rat skeletal muscle (SkM)
Na-channel gene and the 5' end of the growth hormone (GH) gene, a gene coding for
B-cell-specific membrane protein B29/Ig-beta was found and noted to have the same
orientation as the Na-channel and GH genes. Rat B29/Ig-beta gene was 3.1 kb in
length with six exons and was separated by 3.3 and 9.3 kb from Na-channel and GH
genes, respectively. Rat B29/Ig-beta protein comprised 228 amino acids, and its
amino acid sequence was 85 and 69% identical with the mouse and human
counterparts, respectively. With the long-area PCR method, genomic DNA connecting
human SkM Na-channel (SCN4A) and B29/Ig-beta (CD79B) genes and CD79B and GH (GH1)
genes was amplified, and the physical linkage of SCN4A/CD79B/ GH1 genes in the
human genome was established. The human CD79B gene was separated by 6.3 and 10.5
kb from the SCN4A and GH1 genes, respectively.
PMID- 9545641
TI - Human GFRA1: cloning, mapping, genomic structure, and evaluation as a candidate
gene for Hirschsprung disease susceptibility.
AB - Congenital aganglionic megacolon, commonly known as Hirschsprung disease (HSCR),
is the most frequent cause of congenital bowel obstruction. Germline mutations in
the RET receptor tyrosine kinase have been shown to cause HSCR. Knockout mice for
RET and for its ligand, glial cell line-derived neurotrophic factor (GDNF),
exhibit both complete intestinal aganglionosis and renal defects. Recently, GDNF
and GFRA1 (GDNF family receptor, also known as GDNFR-alpha), its GPI-linked
coreceptor, were demonstrated to be components of a functional ligand for RET.
Moreover, GDNF has been implicated in rare cases of HSCR. We have mapped GFRA1 to
human chromosome 10q25, isolated human and mouse genomic clones, determined the
gene's intron-exon boundaries, isolated a highly polymorphic microsatellite
marker adjacent to exon 7, and scanned for GFRA1 mutations in a large panel of
HSCR patients. No evidence of linkage was detected in HSCR kindreds, and no
sequence variants were found to be in significant excess in patients. These data
suggest that GFRA1'S role in enteric neurogenesis in humans remains to be
elucidated and that RET signaling in the gut may take place via alternate
pathways, such as the recently described GDNF-related molecule neurturin and its
GFRA1-like coreceptor, GFRA2.
PMID- 9545643
TI - Construction of a 1.5-Mb bacterial artificial chromosome contig in Xp11.23, a
region of high gene content.
AB - To generate sequence-ready templates for the gene-rich Xp11.23 region, we have
constructed a 1.5-Mb bacterial artificial chromosome (BAC) contig spanning the
interval between the DNA markers OATL1 and DXS255. The contig includes 28 BACs,
ranging in size from 58 to 258 kb with an average size of 135 kb, which provide
2.5-fold coverage of the region. The BAC contig was constructed based entirely on
the content of 40 DNA markers from a previously established YAC contig and 11 new
markers developed from BAC-end DNA sequences, 4 of which were required to close
gaps in the map. There was no evidence of rearrangement, instability, or
chimerism in any of the BAC clones. The BAC cloning system appears to provide
robust and total physical coverage of this gene-rich region with clones that are
suitable for DNA sequencing.
PMID- 9545644
TI - Identification and characterization of the human ortholog of rat STXBP1, a
protein implicated in vesicle trafficking and neurotransmitter release.
AB - In a screen designed to identify genes expressed preferentially in retina, we
identified a cDNA encoding the human ortholog of rat STXBP1 (n-Sec1, Munc-18-1,
rbSec1), a protein implicated in vesicle trafficking and neurotransmitter
release. This protein also has similarity to Drosophila Rop (65% aa identity) and
Caenorhabditis elegans UNC-18 (58% aa identity). The major human cDNA encodes a
protein of 594 amino acids which has 100 % amino acid identity with its rat and
murine counterparts. Additionally, there is an alternative splice form in humans,
arising from the inclusion of an additional exon, which encodes a protein of 603
amino acids and is also 100% identical to the corresponding rat isoform. We found
expression of the shorter cDNA in all tissues and cell lines we examined with
highest levels in retina and cerebellum. By RT-PCR analysis, we found expression
of the longer cDNA in neural tissues only. We mapped the structural gene to
9q34.1, a region without obvious candidate phenotypes. However, due to its
evolutionary conservation and abundant expression in retina and brain, STXBP1
should be considered a candidate gene for retinal and/or neural disorders mapping
to 9q34.1.
PMID- 9545645
TI - Genomic organization of the human SPOCK gene and its chromosomal localization to
5q31.
AB - SPOCK, previously identified as testican, is a modular proteoglycan that carries
both chondroitin and heparan sulfate glycosaminoglycan side chains. The overall
genomic organization has been established. The SPOCK gene spans at least 70 kb
and is composed of 11 exons: the first half of the gene is dramatically expanded,
but the second half is more compact. In situ hybridization and YAC mapping
independently linked the SPOCK gene to 5q31, a region containing an impressive
number of genes encoding growth factors, cytokines, and neurotransmitter and
hormone receptors. The gene is located between the IL9 and the EGR1 genes,
bordering the smallest commonly deleted region of chromosome 5.
PMID- 9545646
TI - The identification and localization of a human gene with sequence similarity to
Polycomblike of Drosophila melanogaster.
AB - The Drosophila Polycomb group (PcG) of genes is required for the epigenetic
regulation of a number of important developmental genes, including the homeotic
(Hox) genes. The members of this gene family encode proteins that do not share
sequence similarity, implying that each plays a unique role in this epigenetic
repression mechanism. Polycomblike (Pcl) was the second PcG gene to be
identified. We report here the isolation and characterization of a human cDNA,
termed PHF1, which encodes a protein with significant sequence similarity to
Drosophila Polycomblike (PCL). The region of similarity between PHF1 and PCL
includes the two PHD fingers (C4-H-C3 motif), the region between them, and
sequences C-terminal to the PHD fingers. PHF1 and PCL are 34% identical over this
258-residue region. PHF1 was mapped to 6p21.3 by fluorescence in situ
hybridization. While several genetic diseases that are likely to result from
developmental abnormalities map to this region, PHF1 is not a clear candidate
gene for any of them.
PMID- 9545648
TI - Endothelial Tie2/Tek ligands angiopoietin-1 (ANGPT1) and angiopoietin-2 (ANGPT2):
regional localization of the human genes to 8q22.3-q23 and 8p23.
PMID- 9545647
TI - Chromosomal locations of three human nuclear genes (RPSM12, TUFM, and AFG3L1)
specifying putative components of the mitochondrial gene expression apparatus.
AB - We have mapped the chromosomal locations of three human nuclear genes for
putative components of the apparatus of mitochondrial gene expression, using a
combination of in situ hybridization and interspecies hybrid mapping. The genes
RPMS12 (mitoribosomal protein S12, a conserved protein component of the
mitoribosomal accuracy center), TUFM (mitochondrial elongation factor EF-Tu), and
AFG3L1 (similar to the yeast genes Afg3 and Rca1 involved in the turnover of
mistranslated or misfolded mtDNA-encoded polypeptides) were initially
characterized by a combination of database sequence analysis, PCR, cloning, and
DNA sequencing. RPMS12 maps to chromosome 19q13.1, close to the previously mapped
gene for autosomal dominant hearing loss DFNA4. The TUFM gene is located on
chromosome 16p11.2, with a putative pseudogene or variant (TUFML) located very
close to the centromere of chromosome 17. AFG3L1 is located on chromosome 16q24,
very close to the telomere. By virtue of their inferred functions in
mitochondria, these genes should be regarded as candidates of disorders sharing
features with mitochondrial disease syndromes, such as sensorineural deafness,
diabetes, and retinopathy.
PMID- 9545649
TI - Individual differences and cardiovascular responsivity.
PMID- 9545650
TI - Psychosocial influences on blood pressure during daily life.
AB - Ambulatory blood pressure (ABP) monitoring allows frequent non-invasive blood
pressure (BP) recordings in a variety of settings. Emerging evidence suggests
that ABP is a better predictor of cardiovascular morbidity than clinic BP.
Ambulatory blood pressure is influenced by a variety of physical, psychological
and behavioral factors that comprise an individual's daily life. The present
article reviews psychosocial research relating ABP to psychological factors (e.g.
Type A behavior pattern, anger/hostility) and environmental influences (e.g. job
strain). Psychological factors and environmental factors alone and in interaction
with each other appear to substantially influence ABP. Interacting physical,
psychosocial and behavioral factors that comprise daily life provide unique
methodological challenges to ABP research. Methodological considerations (e.g.
activity patterns, caffeine and alcohol consumption) for performing ABP research
are discussed. Evidence outlined in this review suggests that psychosocial
factors contribute to ABP level. To the extent that psychosocial factors
contribute to ABP cardiac disease, it will be important to analyze their effects
on underlying disease processes.
PMID- 9545651
TI - Sociotropic cognition moderates blood pressure response to interpersonal stress
in high-risk adolescent girls.
AB - This article tests the hypothesis that 'sociotropic cognition'--heightened
preoccupation with being accepted by others--increase vulnerability to
cardiovascular stress in females. Adolescent girls (55 African-American; 23
Caucasian) at increased risk of developing essential hypertension due to
persisting high normal blood pressure, completed measures of sociotropic
cognition, social competence, trait affect and social support. Later, their blood
pressure and heart rate were measured during non-social stress (mirror image
tracing) and interpersonal stress [Social Competence Interview (SCI)].
Comparisons of blood pressure responses to the tasks disclosed a significant Task
main effect, replicating a previous finding that blood pressure is elevated more
by SCI than by non-social stress. When Sociotropy was introduced as a moderator,
however, a significant Task by Sociotropy interaction indicated that the
comparatively greater reactivity to SCI occurred mainly in girls who exhibited
high levels of sociotropic thinking. Cognitive sociotropy was associated with a
profile of social emotional and environmental deficits suggesting increased
susceptibility to chronic stress and impaired coping.
PMID- 9545652
TI - Stress and personality as factors in women's cardiovascular reactivity.
AB - An experiment was conducted to investigate the relationships among Type A
behavior, hostility and cardiovascular reactivity (CVR) in women. Changes in
heart rate, blood pressure and skin conductance from baseline to task levels were
used to assess reactivity. These measures were obtained from 96 women during a
seated baseline period, a reaction time task and during an oral IQ quiz. Analyses
indicated that Type A and high hostile women were more reactive to an oral IQ
quiz and reaction time stressors than Type B and low hostile women. Specifically,
Type As showed significantly greater increases in systolic blood pressure in the
reaction time task and greater mean arterial pressure and systolic blood pressure
increases in the IQ quiz. High hostiles evidenced significantly higher systolic
blood pressure and diastolic blood pressure in the RT task and higher mean
arterial pressure and diastolic blood pressure in the IQ quiz. It was concluded
that Type A personality and hostility can predict greater reactivity in women to
two different stressors. The oral quiz generated greater reactivity than the RT
task and thus may be a more stressful task.
PMID- 9545653
TI - Enhanced cardiovascular and catecholamine responses in women with depressive
symptoms.
AB - To test the hypothesis that cardiovascular and sympathetic nervous system
responses before and during behavioral stressors are exaggerated among subjects
with depressed mood who do not have clinical depressive disorder. Sixty healthy
women aged 18-49 were initially asked to complete the Beck Depression Inventory
(BDI). The 15 with the highest (Depressive Symptom group) and the 15 with the
lowest BDI scores (Control group) underwent stress testing including baseline,
postural challenge, a speech task describing responses to a recent anger-arousing
experience and recovery. Both systolic and diastolic blood pressure levels were
higher in the Depressive Symptom group during baseline, challenges and recovery.
This group also showed shorter pre-ejection period (a marker of enhanced cardiac
sympathetic activation) and lesser heart rate variability across all test
periods. During the speech task only, the Depressive Symptom group exhibited
greater increases in plasma norepinephrine and higher cardiac output responses
associated with decreased interbeat interval (faster heart rate). These results
support the a priori hypothesis regarding enhanced sympathetic and cardiovascular
activity. Finally, the BDI scores correlated very highly with lack of perceived
emotional social support, reinforcing prior research on the linkage between
social isolation and severity of depressive symptoms.
PMID- 9545654
TI - Serum lipid concentrations, hostility and cardiovascular reactions to mental
stress.
AB - The objective of the present study was to determine whether serum lipid
concentrations interact with hostility to affect cardiovascular responses to
mental stress. One-hundred and seventy-four male subjects were screened with the
Cook and Medley hostility scale (Ho), the anger expression inventory by
Spielberger and a general health questionnaire. Subjects in the upper (n = 22)
and lower (n = 22) quartile of the Ho score distribution were asked to take part
in a laboratory experiment. Continuous measures of heart rate, blood pressure,
respiration and electrodermal activity were taken while participants carried out
a series of behavioral maneuvres, including mental arithmetic and mirror star
tracing. Prior to the experiment fasting blood samples were taken for lipid
determinations. The results show higher heart rate reactivity in high hostile
than low hostile subjects. High hostile subjects also reported more anger and
frustration in response to tasks. Hostility groups differed in lipid levels in
that high hostiles had higher triglyceride and VLDL-c concentrations than low
hostiles. Cholesterol levels showed an inverse association with cardiovascular
reactivity but only in low hostile subjects. No such associations could be found
in high hostiles. We conclude that there is partial support for both, the
hyperreactivity and the health behavior model linking hostility and
cardiovascular disorder.
PMID- 9545656
TI - Parental history of hypertension and hostility moderate cardiovascular responses
to interpersonal conflict.
AB - A parental history of hypertension has been implicated in the development of
hypertension, perhaps by virtue of an elevated cardiovascular response to stress.
Similarly, hostility has been hypothesized to be linked to cardiovascular disease
through cardiovascular hyperreactivity. The interaction of parental history and
hostility in moderating cardiovascular response has been infrequently examined,
though research suggests the two may be linked through familial factors. The
present study examined the cardiovascular response of 98 healthy young adult
males categorized as offspring of hypertensive subjects (PH+) or offspring of
normotensive subjects (PH-) and as high or low hostile, based on Cook-Medley
Hostility scores (HiHo vs. LoHo). Subjects were exposed to either an harassment
or non-harassment stressor. Results indicated elevated cardiac output and forearm
blood flow responses in PH+/HiHo subjects who were harassed as compared to any
other harassed subject and all non-harassed individuals. This hemodynamic
response pattern of elevated blood flow suggests a mechanism of hypertensive
disease development.
PMID- 9545655
TI - Interactive effects of trait hostility and anger expression on cardiovascular
reactivity in young men.
AB - Hostility and anger-expression style are personality traits often associated with
elevated cardiovascular reactivity and potential heightened risk for
cardiovascular disease. In the present study a sample of 50 young, healthy men
were divided into groups low or high on the Cook-Medley Hostility scale and on
anger-out from Spielberger's Anger Expression scale. Subjects worked on mental
arithmetic and public speaking tasks in counterbalanced order. Heart rate,
systolic and diastolic blood pressure and hemodynamic indices were measured at
baseline and during the tasks. Hostility and anger-out interacted in their
effects on cardiovascular responses. The High Anger-Out/Low-Hostile group
displayed the greatest increases in heart rate and blood pressures, while the
High Anger-Out/High-Hostile group was least reactive. Furthermore, the High Anger
Out/Low-Hostile group showed a distinct fight/flight response pattern during
public speaking, indicated by increases in stroke volume and cardiac output and a
decrease in systemic vascular resistance. These results suggest that a mismatch
between hostile cognitions and habitual anger expression leads to greater
cardiovascular reactivity to challenging tasks, potentially enhancing risk for
development of cardiovascular diseases.
PMID- 9545657
TI - Family history of hypertension: a psychophysiological analysis.
AB - Family history of hypertension (positive and negative) and gender groups were
compared on cardiovascular responses at rest, during stressors and during
recovery. Two tasks were employed, mental arithmetic and an anger recall
interview. Both levels and reactivity measures of blood pressure, heart rate,
cardiac output and total peripheral resistance were included. In addition,
participants filled out several questionnaires measuring state feelings during
the task and recovery periods, trait anger/hostility and emotions. Both men and
women with a positive family history of hypertension exhibited higher tonic
levels of blood pressure and heart rate at rest, recovery and during both tasks.
They also exhibited greater heart rate reactivity during the mental arithmetic
task and greater blood pressure reactivity to both tasks when post-math recovery,
but not initial rest, was used as a covariate. Positive family history
individuals reported less trust and gregariousness, more depression and
aggression, less awareness of somatic responses to the tasks and less effort to
relax during the post-task rest periods. Finally, significant correlations were
found between low anger expression how anger experience and high anger control
and task SBP levels in positive family history individuals.
PMID- 9545658
TI - Effects of threat of shock, shock electrode placement and darkness on startle.
AB - Fear can be elicited by physically-presented explicit threat stimuli or by more
static contextual stimuli that are not an immediate source of danger. Research in
both humans and animals suggest that fear produced by these two types of stimuli
represents separate processes mediated by different brain structures. The present
study used the startle reflex methodology to examine affective responses elicited
by an explicit threat cue signalling a period of shock anticipation and by two
types of contextual stimuli; darkness and attaching the shock electrodes. As
expected, shock anticipation potentiated startle (fear-potentiated startle).
Startle was also facilitated by darkness and by the placement of shock
electrodes. Further, darkness increased fear-potentiated startle to an explicit
threat cue, but did not affect the facilitation of startle produced by attaching
the shock electrodes. It is suggested that affective responses to contextual
stimuli should be considered when investigating both normal and pathological
fear.
PMID- 9545660
TI - Responses to irrelevant probes during task-induced negative and positive shifts.
AB - The functional significance of task-induced negative and positive cortical shifts
were tested with the probe-stimulus method. Both shifts were induced within the
same experimental situation in three variants of a CNV paradigm, where a slow
positive wave (a variant of P300) appeared following S2. In Experiment I and II,
S2 called for making or withholding a motor response (go/no-go); in Experiment
III, S2 informed the subject about the correctness of a previous guess.
Irrelevant probe-stimuli were applied in conjunction with the task during the
CNV, the post-S2 positivity and the intertrial interval (ITI). The probe-evoked
vertex EPs were smaller during the post-S2 positivity as compared to the CNV and
the ITI. This was true not only for the motor task but also for the guessing
task, where the effect is unlikely to have been contaminated by motor potentials.
This indicates that positive shifts have an inhibitory effect on the processing
of irrelevant probe-stimuli and possibly on information-processing in general.
PMID- 9545659
TI - P300 correlates of simulated malingered amnesia in a matching-to-sample task:
topographic analyses of deception versus truthtelling responses.
AB - Two experiments using a P300-enhanced Forced Choice Procedure (P3FCP)
investigated simulated amnesia in a matching-to-sample task. In Experiment 1,
successful manipulation of subjects towards different behavioral hit rates (75
80% vs. 85-90%) did not adversely affect the diagnostic sensitivity of match
mismatch Pz-P300 amplitude analyses, allowing detection of 69% of simulators.
P300 amplitudes of simulators (Malinger group) were as large as those of truth
tellers (truth group, a control), indicating no dual task-related (Malingering)
reduction across different behavioral hit rates. Experiment 2 found no main
effect of oddball type, match vs. mismatch, on P300 (P3) amplitude with a
mismatch-rare variant of the P3FCP. This study also revealed larger Pz-P3s in the
Malingering (vs. Truth-telling) condition. Subsequent topographic analyses
suggested different Truth and Malinger scaled P3 amplitude topographies in both
these sets of P3FCP data and in those from a previous autobiographical memory
paradigm. Further analysis yielded preliminary evidence for a common deception
related P3 amplitude topography across different paradigms/conditions.
PMID- 9545661
TI - Psychophysiological effects of interviews about emotional events on offspring of
hypertensives and normotensives.
AB - Normotensive individuals with a parental history of hypertension have been found
to exhibit greater cardiovascular reactivity to a variety of laboratory stressors
than offspring of normotensives. To examine the possible generalization of these
differences to real-life stressors, subjects were administered four brief
interviews about different emotional events in their lives. Regardless of
emotional content, offspring of hypertensives displayed greater systolic blood
pressure responses to the non-verbal recollection and verbal description of
personal emotional events, but not to the imagination of standardized emotional
scenes or reading a non-emotional advertisement. This suggests that group
differences in reactivity may generalize to real-world situations. Evidence of
significantly greater vasoconstriction during interviews about sad topics was
also observed, contributing to the literature on the physiological
differentiation of emotional states.
PMID- 9545663
TI - Steady-state visual evoked potentials to computer monitor flicker.
AB - In the present study, steady-state visual evoked potentials (S-VEP) in response
to amplitude-modulated light from a computer monitor (colour sVGA, 15-inch tube)
have been examined. S-VEPs to computer monitors with different refresh rates (60
Hz or 72 Hz) and screen brightness (65 cd/m2 or 6 cd/m2) were recorded in 13
subjects with normal or corrected-to-normal vision. EEG samples were amplified,
averaged and stored using Cadwell Excel EMG-EP recorder and a regression model
was applied for the amplitude analysis. The mean values of S-VEP amplitude at 60
Hz were found to be significantly higher at 60 Hz refresh rate vs. 72 Hz (F1,12 =
14.1; P = 0.003). Effect of screen brightness (F2,24 = 6.5; e = 0.62; P =
0.00075) as well as the interaction effect of refresh rate and screen brightness
(F2,24 = 11.6; P = 0.0003) were also found to be significant. Data obtained show
that the characteristics of amplitude-modulated light from a computer monitor
(frequency, brightness, waveform) are sufficient to elicit S-VEP, and the
influence is not only restricted to the peripheral divisions of the visual system
as it was shown earlier, but also extends to the central brain structures.
PMID- 9545662
TI - Cardiac response induced by voluntary self-paced finger movement.
AB - Cardiac responses induced by slow and brisk voluntary self-paced index finger
movements of the dominant and non-dominant hand were investigated in a group of
12 right-handed subjects. Since subjects synchronised movement and respiration,
initiating movement preferably during inspiration, a novel method of evaluating
the movement-induced cardiac response was used. This method allows one to
distinguish the differential effects on the cardiac response due to movement and
respiration. The effect of type of movements (slow vs. brisk) and hand (right vs.
left) were analysed. Slow movements induced a monophasic cardiac response,
consisting of cardiac deceleration preceding and accompanying movement. Brisk
movements induced a biphasic cardiac response, consisting of preparatory
deceleration followed by slight post-movement cardiac acceleration. Hand
dominance did not influence the movement-induced cardiac response. The results
suggest that neocortical structures involved in planning and execution of
voluntary movement impinge upon brainstem cardiovascular nuclei. Vagal cardiac
outflow is affected and gives rise to movement-induced changes in cardiac
chronotropism.
PMID- 9545664
TI - Physiological responses in high-P subjects during active and passive coping.
AB - There have been relatively few studies of the psychophysiological correlates of
Eysenck's dimension of psychoticism (P) and those which do not exist report
findings which cannot be readily integrated to isolate a distinctive
physiological basis of P. The present study investigated differences between
subjects scoring high and low on the P scale of the Eysenck Personality
Questionnaire (EPQ) in relation to sympathetic and parasympathetic arousal
following aversive stimulation. An active-passive coping paradigm using an
aversive tone was selected to elicit responses and cardiovascular measures (heart
period, heart period variance, T-wave amplitude) and a skin conductance measure
(event-related skin conductance) were obtained. The findings show that
differences between high- and low-P subjects are specific to the coping
condition. Under active coping, high-P subjects exhibited greater sympathetic
arousal following the aversive tone than low-P subjects. There was no significant
difference between the high-P and low-P subjects on any physiological variable
under the passive coping condition. It is suggested that if there is differential
functioning of the divisions of the autonomic nervous system in subjects
differing in P, that these differences may only manifest themselves under
specific situations.
PMID- 9545666
TI - Intracranial recording during hypnotic analgesia.
PMID- 9545665
TI - Effects of memory load on event-related patterns of 40-Hz EEG during cognitive
and motor tasks.
AB - The present study describes a phasic event-related synchronization (ERS) in the
gamma band (36-44 Hz) induced by the onset of probe visual stimuli. The
experiment consisted of two experimental tasks with high and low memory-load in
which a geometrical figure (S1) was held in memory for comparison with a
subsequent stimulus (S2). In each task a Go-NoGo paradigm was used with a Same
Different discrimination task. The aim of the study was to examine the influence
on 40-Hz ERS of stimulus type ('Same-Different') and of response (Go-NoGo) task
as moderated by activation or effort level (high/low memory-load). The
investigation was carried out in 27 women. The EEG was recorded from FP1, FP2,
F3, F4, P3, P4, O1 and O2 scalp sites referenced to linked earlobes. As a
manipulation check for activation level, we recorded heart rate (HR) during the
S1-S2 period. A main peak of activity was found around 160 ms with a maximum at
occipital sites. The amplitude of this peak was higher in the high memory-load as
compared to the low memory-load condition. This difference was manifested mainly
at F3 and O2 scalp sites. A larger 40-Hz peak at F3 was also found in the Go
compared to the NoGo condition. No 40-Hz ERS differences between Same and
Different trials were observed. The HR was found sensitive to the stimulus type
showing a greater HR deceleration response to S2 for Same trials, as compared to
Different ones. In parallel with 40-Hz ERS response, the HR deceleration was more
pronounced for the high memory-load as compared to the low memory-load condition.
The results indicate that the 40-Hz ERS is dependent upon both memory-load and
motor responding. The influence of memory load on cognitive (Same-Different) and
motor response (Go-NoGo) variables is discussed.
PMID- 9545667
TI - [Effects of dosing regimen on the effectiveness and safety of aminoglycosides
(discussion)].
PMID- 9545668
TI - [The in vitro antibacterial activity of cefozopran against clinically isolated
bacteria].
AB - The in vitro antibacterial activity of cefozopran (CZOP) against recent clinical
isolates was evaluated and compared with those of ceftazidime (CAZ), cefpirome
(CPR), cefepime (CFPM), cefotaxime (CTX), sulbactam/cefoperazone (S/C), imipenem
(IPM), oxacillin (MPIPC), and flomoxef (FMOX). MIC80 values of CZOP for
methicillin-susceptible Staphylococcus aureus (MSSA, n = 41), methicillin
resistant Staphylococcus aureus (MRSA, n = 57), Streptococcus pneumoniae (n =
45), Enterococus faecalis (n = 49), Enterobacter cloacae (n = 50), Citrobacter
freundii (n = 45), Serratia marcescens (n = 45), and Pseudomonas aeruginosa (n =
100) were 1, 32, 2, 16, 4, 1, 0.25, 8 micrograms/ml, respectively. CZOP was more
active than CPR against P. aeruginosa and exhibited similar activity to CPR
against other species. CZOP was especially active against S. marcescens with MIC
values lower than 1 microgram/ml against all strains tested. CZOP was similarly
active to or more active than CFPM against all species except for C. freundii.
CZOP was not active against MRSA. Thus, we investigated the in vitro combination
effects of CZOP/vancomycin (VCM) and CZOP/arbekacin (ABK) using the checkerboard
method. The interaction between CZOP and VCM ranged from additive activity (0.5 <
FIC index < or = 1.00, n = 37) to synergistic activity (FIC index < 0.50, n = 1),
except for one strain showing indifference (1.00 < FIC index < or = 2.00). The
interaction between CZOP and ABK ranged from additive activity (n = 22) to
synergistic activity (n = 1). These date suggest the potential effect of
combination therapy of (CZOP) and VCM or ABK against MRSA. The combined therapy
is suggested to be useful to reduce side effects in patients with impared renal
function, to reduce the administration dose of VCM or to treat infections of
sites where achievable drug concentrations are lower than those commonly achieved
in the bloodstream. We also investigated the combination effects of CZOP/AMK and
CZOP/GM against CZOP-resistant P. aeruginosa (MIC > 16 micrograms/ml). The
combination of CZOP/AMK showed additive activity (n = 9) to synergistic activity
(n = 2). The combination of CZOP/GM showed additive activity (n = 5). These
results suggest that combinations of CZOP with AMK or GM are effective in
treating P. aeruginosa.
PMID- 9545669
TI - [Fundamental and clinical evaluation of cefozopran in low birth weight infants
and neonates].
AB - We conducted fundamental and clinical evaluations of a cephem antibiotic,
cefozopran (SCE-2787, CZOP), in infants with low birth weights and mature
infants. (1) Blood concentrations CZOP was intravenously given in bolus dose of
20 mg/kg to the newborn. The blood antibiotic concentrations were 69.7
micrograms/ml at 30 minutes after administration and the elimination half life
was 2.99 hours in mature infants aged 1 to 3 days. They were 38.7 micrograms/ml
and 2.85 hours in those aged 4 to 7 days, and 40.8 micrograms/ml and 3.81 hours
in those aged 8 days or elder, respectively. In infants with lower birth weights
aged 4 to 7 days the blood antibiotic concentrations were 48.6 micrograms/ml at
30 minutes after i.v. administration and the elimination half life was 3.77
hours. The blood antibiotic concentrations at 30 minutes after intravenous doses
of 10, 20 and 50 mg/kg in mature infants aged 8 days or elder were 21.1, 40.8 and
153.6 micrograms/ml (value at 60 minutes) and the elimination half lives were
2.24, 3.81 and 3.07 hours, respectively. Administration of CZOP at doses of 20
and 40 mg/kg by intravenous drip infusion over 30 minutes gave the blood drug
concentrations of 48.0 and 103.2 micrograms/ml at the end of the infusion and the
half lives were 2.60 and 3.33 hours, respectively. (2) Urinary excretion The
urinary excretion rates after i.v. bolus doses of 10, 20 and 40 mg/kg were 28.4
to 58.6% of dose. The urinary excretion rate after i.v. drip infusion of 40 mg/kg
over 30 minutes was 49.0% of dose. (3) Transfer into cereblospinal fluid The
transfer of the antibiotic into cereblospinal fluid in patients with serous
meningitis was 4.1 to 15.5 micrograms/ml at 1 hours after administration. (4)
Clinical results The clinical efficacy was judged "good" or "excellent" in 2 of
the 3 patients with septicemia and in all of the 10 patients with suspected
septicemia. It was judged "excellent" in all of the 9 patients with pneumonia, 3
with urinary tract infections and 3 with intrauterine infections. Prophylactic
use of the antibiotic was effective in all of the 12 patients. Of the patients in
whom bacteriological evaluation was successful, 7 of the 10 causative organisms
were confirmed to be eradicated. No adverse drug reactions of signs and symptoms
were recognized. Fourteen abnormal alterations of the laboratory test values such
as elevation of gamma-GTP and that of GPT were recognized in 8 patients (16.7%).
None of them were particularly serious. These results indicate that CZOP is a
drug useful for treatment and prevention of infections in infants with lower
birth weights as well as in mature infants.
PMID- 9545670
TI - [Pharmacokinetic, bacteriological and clinical studies on cefozopran in
neonates].
AB - Cefozopran (CZOP) was administered to nine newborn patients with infections at a
dose of 20 mg/kg twice or three times daily for 5 to 6 days to evaluate the
efficacy, safety and pharmacokinetics of cefozopran. 1. Blood concentrations CZOP
was intravenously given to 6 newborn patients by drip infusion at a dose of 20
mg/kg over 30 minutes. The maximum blood concentrations (Cmax) were 38.4
micrograms/ml in a patient aged 0 day, 37.7 and 54.3 micrograms/ml in two
patients aged 1 day, 51.3 and 64.1 micrograms/ml in two patients aged 3 days and
51.0 micrograms/ml in a patient aged 5 days. Cmax was lower in the patient aged 0
day. The elimination half life (T 1/2) was 9.2 hours in the patient aged 0 day,
4.9 and 3.7 hours in the patients aged 1 day, 3.1 and 2.4 hours in the patients
aged 3 days and 2.9 in the patient aged 5 days, showing a prolongation of T 1/2
in patients of lower age. 2. Urinary excretion Of the 6 patients given CZOP at a
dose of 20 mg/kg by intravenous drip infusion over 30 minutes, urine was
collected in 5 patients. The cumulative excretion rate within 6 hours after
infusion was as low as 19.8% of dose in the patient aged 0 day. The rates were
elevated as high as 46.3 and 57.0% of dose in the patients aged 1 day. In the
patient aged 3 days, the recovery within 4 hours after infusion was 47.3%. It was
70.6% of dose within 6 hours after dosing in the patient aged 5 days. The urinary
recovery within 6 hours after dosing increased with the advance of age. 3.
Clinical results Efficacy was evaluable in 7 patients. Of them, 3 had suspected
septicemia, 2 pneumonia, 1 intrauterine infection and 1 urinary tract infection.
The clinical efficacy was judged "excellent" in all the evaluable patients.
Neither adverse drug reactions of signs and symptoms nor abnormal alterations of
the laboratory test values were recognized in the 9 patients evaluable for
safety. These results suggest that CZOP is an effective and safe drug for
treatment of infections in the newborns. As for the dosage and method of
administration from the view of the pharmacokinetic data obtained, intravenous
drip infusion of 20 mg/kg once or twice daily was considered to be sufficient for
patients aged 0 day. For patients aged 1 to 7 days and those aged 8 days or
elder, the administration of twice to 3 times daily and 3 to 4 times daily were
considered to be sufficient, respectively.
PMID- 9545671
TI - [Pharmacokinetic, bacteriological and clinical studies on cefozopran in
neonates].
AB - The efficacy, safety and pharmacokinetics of cefozopran (CZOP) were evaluated in
neonates and the following results were obtained: 1. Of the 12 patients treated
with CZOP, judgment of clinical efficacy was evaluable in 10 patients (including
5 with pneumonia and 3 with urinary tract infections). The treatment was
effective and the causative organism was eradicated in 100% of the patients. 2.
No adverse signs and symptoms were recognized during the treatment with CZOP. A
slight elevation of direct bilirubin was recognized as an abnormal alteration of
laboratory test values in one patient. The value, however, returned to the normal
range after the completion of treatment. 3. The pharmacokinetic evaluation was
made in 3 of the 12 patients. The blood CZOP levels were recognized in proportion
with the dosages. The elimination half lives (T 1/2) in those patients were 8.92,
2.90 and 2.76 hours. Prolongation of T 1/2 was recognized in the patient aged 0
day. It was possible to examine the urinary excretion only in one patient aged 18
days. The excretion rate of the drug was 68.6% of dose by 8 hours after
administration. These results suggest that CZOP is a drug useful for treatment of
infections in neonates as well, with high efficacy and safety.
PMID- 9545672
TI - [Pharmacokinetic and clinical evaluation of cefozopran in premature and newborn
patients].
AB - Cefozopran (SCE-2787, CZOP), which is already on the market with a variety of
approved indications in infectious diseases for adult patients, was administered
to premature and newborn patients to evaluate the pharmacokinetics and the
clinical efficacy. 1. Pharmacokinetics CZOP was intravenously administered at
doses of 10.0 mg/kg, 21.4 mg/kg and 40.0 mg/kg to premature and newborn patients,
and the blood concentrations and urinary excretion rate were examined. The blood
CZOP concentrations were 31.7 and 65.5 micrograms/ml at 30 minutes after
administration of 10.0 mg/kg and 40.0 mg/kg, respectively. The elimination half
life was 1.78 hours and 2.31 hours, and the urinary recovery was 110.7% and 53.7%
within 6 hours after administration, respectively. In the patient given 21.4
mg/kg, the blood CZOP concentration was 36.4 mg/kg at 1 an hour after
administration and the elimination half life was 3.97 hours. The urinary recovery
was 29.6% within 5 hours after administration. 2. Clinical results The clinical
efficacy was evaluated in 19 patients and judged "good" or better in 13 of them
with the efficacy rate or 68.4%. The bacteriological response was evaluated in 10
patients from whom Gram-positive cocci of S. aureus (6 strains), S. pneumoniae (1
strain) and E. faecalis (1 strain) and Gram-negative bacilli of H. influenzae (2
strains) and E. coli (2 strains) were isolated as possible causative organisms.
With exception of 1 strain each of S aureus and H influenzae, which were not
tested after the treatment with CZOP, all of these strains were found to be
eradicated. 3. Adverse drug reactions (ADRs) of signs and symptoms and abnormal
alterations of laboratory test values. Safety evaluation was made in 24 patients.
ADRs of signs and symptoms were recognized in none of them. As abnormal
alterations of laboratory test values, increased eosinophils in 3 patients,
elevated GOT in one and elevated GPT in one were recognized. These results
indicate that CZOP is a drug useful for treatment of infections in premature and
newborn patients.
PMID- 9545673
TI - [Pharmacokinetic and clinical evaluation of cefozopran in newborn patients].
AB - Pharmacokinetic and clinical evaluation of an injectable cephem antibiotics,
cefozopran (SCE-2787, CZOP), was conducted in newborn patients and the following
results were obtained: 1. Clinical results The clinical efficacy of CZOP was
evaluated in one each patient with intrauterine infection and suspected
septicemia. The efficacy was "excellent" in both patients. No clinically serious
adverse drug reactions of signs and symptoms and abnormal alterations of the
laboratory test values were recognized. 2. Pharmacokinetics CZOP was
intravenously given to newborn patients at doses of 25.0, 20.0, and 18.75 mg/kg.
The blood CZOP concentrations were 44.7 +/- 7.0 micrograms/ml (n = 3), 48.3
micrograms/ml and 48.2 micrograms/ml at one hour after administration,
respectively. The elimination half life (T 1/2) was 4.22 +/- 1.17 hours (n = 3)
in the patients given 25.0 mg/kg and 2.74 hours in the patient given 20.0 mg/kg.
The urinary drug excretion rate was 44.5 +/- 8.7% and 31.3 +/- 9.7% of dose
within 8 hours after administration of 25.0 mg/kg and 20.0 mg/kg, respectively.
PMID- 9545674
TI - Tactile sensitivity of gloved hands in the cold operation.
AB - In this study, tactile sensitivity of gloved hand in the cold operation has been
investigated. The relations among physical properties of protective gloves and
hand tactile sensitivity and cold protection were also analysed both objectively
and subjectively. Subjects with various gloves participated in the experimental
study during cold exposure at different ambient temperatures of -12 degrees C and
-25 degrees C. Tactual performance was measured using an identification task with
various sizes of objects over the percentage of misjudgment. Forearm, hand and
finger skin temperatures were also recorded throughout. The experimental data
were analysed using analysis of variance (ANOVA) model and the Tukey's multiple
range test. The results obtained indicated that the tactual performance was
affected both by gloves and by hands/fingers cooling. Effect of object size on
the tactile discrimination was significant and the misjudgment increased when
similar sizes of objects were identified, especially at -25 degrees C.
PMID- 9545675
TI - Control of liquid cooling garments: technical control of mean skin temperature
and its adjustments to exercise.
AB - This paper describes an automatic control concept for liquid cooling garments.
The concept consists of an own controller for mean skin temperature whose
setpoint is either fixed or adjusted to the metabolic heat production by means of
the heart rate signal. The controller for mean skin temperature included both a
proportional and an integral signal path (PI-type), the latter being able to
eliminate any load error within the control loop. This means that the actual skin
temperature will always match the given setpoint irrespective of the amount and
the origin of the heat gain at the body shell. Experiments were carried out to
test the operation of the skin temperature controller. There the setpoint was
fixed while metabolic heat production was changing. After a transient period with
deviations, the load error was always eliminated by the skin temperature
controller. With this result one can also imagine the controllers ability to
compensate changing heat gains from the environment. Despite this behaviour, the
amount of heat removal was not high enough to prevent sweating and warm
discomfort during all exercise levels. Therefore we draw the conclusion that, in
addition, the setpoint of the skin temperature should be adjusted to the
metabolic rate/heat production. A convenient physiological signal that reflects
the current level of metabolic rate is the heart rate signal. After being
filtered the heart rate signal was used during some experiments to change the
setpoint of the skin temperature controller. The reason for this filtering
(lowpass, time constant = 10 min) was, firstly, the necessity of attenuating the
consequences of short-term psychological effects on the heart rate and secondly,
the avoidance of vasoconstriction due to too fast changes of the exercise/heart
rate induced cooling rate. In the following experiments it became clear that the
adjustment of the skin temperature setpoint to the exercise level was an
improvement as there was less sweating and the subjects felt more comfortable.
PMID- 9545676
TI - Blood lactate disappearance during breathing hyperoxic gas after exercise in two
different physical fitness groups--on the work load fixed at 70% VO2max.
AB - The purpose of this study is to evaluate effects of breathing hyperoxic gas on
blood lactate disappearance after submaximal exercise in two different physical
fitness groups and to clarify the most effective oxygen concentration in each
group. Fourteen healthy male students participated as subjects in this study.
They were divided in two groups by difference in their anaerobic threshold (AT).
Seven males were treated as Higher AT group and the others as Lower AT group.
Subjects wore a T-shirt, short pants and sports shoes and performed three
sessions; each consisting of five minutes of exercise and six minutes of rest, at
a workload of 70%VO2max on a bicycle ergometer. Hyperoxic gas was breathed only
during recovery periods. Oxygen rates of 21, 30, 40, 60, 80 and 100% in inspired
gas were employed. According to the results of blood lactate (BLA), the most
effective oxygen condition on BLA disappearance was obtained over 60% in Higher
AT group and at 30% oxygen in Lower AT group. Thus, it was especially noteworthy
that the effects of hyperoxic gas in Higher AT group were different from those of
Lower AT group. It is thought that the effects of breathing hyperoxic gas were
dependent on physical fitness, which have caused many reports to be in conflict
hitherto.
PMID- 9545677
TI - Physical fitness and psychological benefits of strength training in community
dwelling older adults.
AB - Previous studies concerning psychological benefits of exercise among the elderly
has focused predominantly on the effects of aerobic exercise. In the present
study, psychological and behavioral adaptations in response to 12-weeks of
strength training were examined in medically healthy but sedentary 42 older
adults (mean age = 68 years). The purpose of this study was to evaluate the
effects of high and low intensity resistance training intensity on a) muscular
fitness, b) psychological affect, and c) neurocognitive functioning. Subjects
were randomly assigned to high intensity/low volume (EXH: 2 sets of 8 to 10
repetitions for 75 to 85% of 1 RM), low intensity/high volume (EXL: 2 sets of 14
to 16 repetitions for 55 to 65% of 1 RM), or no exercise control programs. Prior
to and following the 12-week program, subjects underwent comprehensive
physiological and psychological evaluations. Physiological assessment included
measurements of blood pressure, heart rate, arm and leg muscle strength, body
composition, and oxygen consumption (VO2max). Psychological measures included
evaluations of mood, anxiety, and physical self-efficacy as well as cognitive
functioning. The results of this study indicated that both high and low intensity
strength programs were associated with marked improvements in physiological
fitness and psychological functioning. Specifically, subjects in the strength
training programs increased overall muscle strength by 38.6% and reduced percent
body fat by 3.0%. Favorable psychological changes in the strength-trained
subjects included improvements in positive and negative mood, trait anxiety, and
perceived confidence for physical capability. The treatment effects of
neurocognitive functioning were not significant. In summary, this study
demonstrated that participation in 12-weeks of high or low intensity strength
training can improve overall physical fitness, mood, and physical self-efficacy
in older adults while cognitive functioning remains constant.
PMID- 9545678
TI - [Clinical usefulness of scatter and attenuation correction for brain single
photon emission computed tomography (SPECT) in pediatrics].
AB - This investigation was undertaken to study clinical usefulness of scatter and
attenuation correction (SAC) of brain SPECT in infants to compare the standard
reconstruction (STD). The brain SPECT was performed in 31 patients with 19
epilepsy, 5 cerebro-vascular disease, 2 brain tumor, 3 meningitis, 1
hydrocephalus and psychosis (mean age 5.0 +/- 4.9 years old). Many patients was
necessary to be injected sedatives for restraining body motion after Technetium
99m hexamethylpropylene amine oxime (99mTc-HMPAO) was injected at the convulsion
or rest. Brain SPECT data were acquired with triple detector gamma camera (GCA
9300 Toshiba Japan). These data were reconstructed by filtered backprojection
after the raw data were corrected by triple energy windows method of scatter
correction and Chang filtered method of attenuation correction. The same data was
reconstructed by filtered backprojection without these corrections. Both SAC and
STD SPECT images were analyzed by the visual interpretation. The uptake ratio of
cerebral basal nuclei was calculated by the counts of the thalamus or lenticular
nuclei divided by the cortex. All images of SAC method were excellent than that
of STD method. The thalamic uptake ratio in SAC method was higher than that of
STD method (1.22 +/- 0.09 > 0.87 +/- 0.22 p < 0.01). The lenticular nuclear
uptake ratio in SAC method was higher than that of STD method (1.26 +/- 0.15 >
1.02 +/- 0.16 p < 0.01). Transmission scan is the most suitable method of
absorption correction. But the transmission scan is not adequate for examination
of children, because this scan needs a lot of time and the infants are exposed by
the line source radioisotope. It was concluded that these scatter and absorption
corrections were most suitable method for brain SPECT in pediatrics.
PMID- 9545680
TI - [Simplified method to quantitate regional cerebral blood flow by 123I-IMP
microsphere model: validity of input counts by using the whole brain time
activity curve and one point arterial blood sampling].
AB - We developed a new microsphere method using 123I-IMP in which arterial blood is
collected at one time point early after 123I-IMP injection instead of
conventional continuous arterial blood sampling, and the input count is estimated
using a whole brain time-activity curve until that time point. The differential
curve dCb(t)/dt of the brain time-activity curve Cb(t) early after 123I-IMP
injection (when the microsphere model is established) approximates the arterial
time-activity curve Ca(t) as an input function. The input count as the integral
value of Ca(t) at 0-5 min was estimated using the 50 min whole brain activity
Cb(5 min) and the differential value dCb(5 min/dt and the 5-min octanol-extracted
count of arterial samples obtained at one time point Ca(5 min). The input counts
calculated by this method were very closely correlated with measurement values
obtained by continuous arterial sampling. This method is more convenient and less
invasive than the continuous arterial sampling method.
PMID- 9545679
TI - [Estimation of integral value of input function for the quantification of
cerebral blood flow with 123I-IMP using one-point arterial blood sampling].
AB - Cerebral blood flow (CBF) has been measured using a microsphere model with
octanol-extracted radioactivity counts (integral value of input function). We
developed a new method estimating the integral value of input function. First, we
fitted the whole brain time-activity curves early after intravenous injection of
N-isopropyl-p-[123I]iodoamphetamine (123I-IMP) by the least-squares method.
Second, we differentiated this equation. Third, we calibrated it using octanol
extracted radioactivity counts of the arterial blood sampled at 5 min. Finally,
we integrated it. A significant correlation was found between the integral values
obtained using a new method and those obtained using the continuous arterial
blood sampling data (y = 1.048x-1206, r = 0.984). The errors between the CBF
values obtained using a new method and those obtained using the 5-min continuous
arterial blood sampling was 6.88 +/- 4.78%. Measurement of integral values of the
input function using a new method with one-point arterial blood sampling is less
invasive and convenient, and is not influenced by cardiopulmonary disease or
smoking. Therefore, it would be useful for the routine measurement of CBF.
PMID- 9545682
TI - [Analysis of cerebral blood flow SPECT imaging on standard brain atlas in
patients with dementia of Alzheimer type].
AB - Statistical parametric map (SPM) has been developed by Friston et al. to analyze
focal changes in rCBF induced by brain activation. This automated and objective
approach has the potential of being applied to SPECT image data sets. This study
evaluated an automated analysis of brain SPECT imaging in patients with dementia
of Alzheimer type (DAT) using SPM95. Seventeen patients with clinically diagnosed
moderate to severe DAT and nine normal control subjects were studied. The SPECT
device used was a triple-headed rotation gamma camera GCA9300A/HG. All images
were transformed into the standard anatomical space of the stereotactic brain
atlas of Talairach and Tournoux, and then smoothed. Statistical analysis was made
between DAT and normal control groups. SPM analysis of SPECT images revealed that
the parieto-temporal areas and posterior cingulate gyrus of both cerebral
hemispheres were significantly decreased in DAT patients compared to normal
controls. In conclusion, SPM analysis of SPECT images proved to be useful in the
evaluation of abnormal perfusion areas of demented patients.
PMID- 9545681
TI - [Cardiac sympathetic denervation after aortic surgery in a patient with thoracic
dissecting aneurysm: a case report].
AB - We experienced a case of a 60 year-old man with cardiac sympathetic denervation
after aortic graft replacement of ascending aorta for a dissecting aneurysm
(Debakey type II). Fourteen years after pheochromocytomectomy (paraganglioma),
the patient developed a severe chest pain, and admitted to the hospital for the
diagnosis of dissecting aneurysm. CT scan with contrast enhancement revealed
thrombosed dissecting aneurysm in the region of ascending aorta to aortic arch.
Graft replacement was undergone on the same day. 123I-MIBG imaging 20 days after
the operation showed severely attenuated myocardial uptake (heart to mediastinum
ratio 1.19), although the MIBG imaging before the operation showed normal
myocardial uptake (heart to mediastinum ratio 1.55). Heart rate variability
analysis in Holter ECG showed that the power of the low frequency (LF), that of
the high frequency (HF) and L/H ratio were severely decreased. MIBG and heart
rate variability analysis indicated that cardiac sympathetic and parasympathetic
nerve were denervated. This is the first report of cardiac sympathetic
denervation after aortic vascular surgery. Clinical significance of cardiac
sympathetic denervation after aortic vascular surgery is uncertain, and further
investigation will be required.
PMID- 9545683
TI - [Enterohemorrhagic Escherichia coli O157 outbreak in Obihiro-City--study on
antibiotic susceptivity and plasmid profiles].
AB - The drug-resistance patterns and plasmid profiles of 147 isolates (patient origin
142 and food origin 5 isolates) from the outbreak of enterohemorrhagic
Escherichia coli (EHEC) O157:H7 infection in Obihiro-city Hokkaido in late
October, 1996, were examined. Thirty-six isolates were resistant to tetracycline
(TC) (24.5%), 15 of which were resistant to both streptomycin and TC. The minimal
growth inhibitory concentration (MIC) of fosfomycine (FOM) was examined,
confirming that MIC changed by the cultivation conditions, that is 12.5
micrograms/ml at the aerobic condition, 1.6 micrograms/ml at the anaerobic
condition and 3.2 micrograms/ml on blood agar plates. Furthermore, though E. coli
O157 could not be detected once by the FOM medication, FOM sensitivity of the
patient origin O157 isolates who became O157-positive again was examined. Any
changes in FOM sensitivity were not observed. Plasmid profiles of all isolates
were divided by 4 patterns from A to D. The most dominant pattern was type A, and
plasmid profiles of food origin O157 belonged to pattern A. In 9 examples of the
person-to-person infection in the family, plasmid patterns of O157 isolates were
the same to each other, even though drug-resistant patterns were different. In 13
patients developing the duration of excretion of EHEC, the changes of the drug
resistance patterns were correlated with the changes of plasmid profiles. By
comparing plasmid profiles and TC resistance, it was suggested that TC resistance
was controlled on a plasmid. Since food origin O157 isolates were sensitive to
all drugs and presenting the same plasmid profiles, demonstrating that TC
resistance and plasmid are newly added to the bacterial cells while food origin
O157 isolates passe inside the human body.
PMID- 9545684
TI - [Ionic binding of 3H-gentamicin and short-term bactericidal activity of
gentamicin against Pseudomonas aeruginosa isolates differing in
lipopolysaccharide structure].
AB - The clinical isolates of Pseudomonas aeruginosa can be roughly classified into
long- and short-lipopolysaccharide (LPS) strains and LPS-deficient strains, based
on the silver-stained patterns of their LPSs after SDS-PAGE. The ionic binding of
3H-gentamicin, a polycationic antibiotic, to the negatively charged sites on the
surface structures of P. aeruginosa strains, often differing in LPS structure,
was the highest in the long-LPS strains followed in descending order by the short
LPS strains and LPS-deficient strains. It was presumed that a clinical isolate of
P. aeruginosa No. 45 is lacking in the O-polysaccharide chains and some
structures of the core-regions consisting of its LPS-structure after SDS-PAGE. On
the other hand, the binding of 3H-gentamicin to this strain was quite. high,
i.e., similar to that to of the long-LPS strains. To clarify this finding, P.
aeruginosa PAC1R and its LPS-deficient mutants were used as reference strains
because the chemical structures of their LPSs containing the repeated units of O
polysaccharides and the neutral sugar contents in the core-regions were
previously confirmed. The PAC605 strain of the LPS-mutants of the PAC series, was
completely lacking in the repeated units of O-polysaccharide and also lacking in
some neutral sugar residues of the core-oligosaccharide region. However, this
strain was highly bound to 3H-gentamicin, suggesting that the negatively charged
sites on the deep core-oligosaccharide region and/or on lipid A participated in
the binding of 3H-gentamicin. This manner of binding may be also applied to P.
aeruginosa No. 45. When P. aeruginosa PAC1R, PAC605 and No. 45 strains were each
exposed to gentamicin (20 micrograms/ml) for 10 minutes, the viable cell counts
of PAC1R decreased to about 70% of the initial count, whereas the viable cell
counts of PAC605 and No. 45 strains decreased to 3.6 and 11.0% respectively,
indicating the vulnerability of both types of the strains to be enhanced by the
bactericidal action of gentamicin with short-term incubation.
PMID- 9545685
TI - [Survey of fungemia cases during the past seventeen years at Teikyo University
Hospital].
AB - Fungi were isolated from 642 cases (3.5%) of 18,403 blood samples at Teikyo
University Hospital during the 17-years period between 1979 and 1995. The number
of fungemia cases began to increase around 1985, reached a peak in 1988, and
since then, it has been gradually decreasing. The fungal species of isolates
were: (1) Candida albicans in 224 cases (34.9%), (2) C. parapsilosis in 149 cases
(23.2%), (3) C. tropicalis in 87 cases (13.6%), (4) C. glabrata in 65 cases
(10.1%), (5) Hansenula anomala in 58 cases (9.0%), (6) C. guilliermondii in 24
cases (3.7%), (7) C. famata in 14 cases (2.1%), (8) Trichosporon beigelii in 11
cases (1.7%), (9) C. inconspicua in 5 cases (0.8%) and C. lusitaniae in 5 cases
(0.8%), and other yeasts in 33 causes (5.1%). The number of isolates of C.
albicans has been decreasing since 1989, concomitant with the clinical
introduction of fluconazole in this hospital. However, the number of fluconazole
insusceptible fungi such as non-albicans Candida and Trichosporon spp. has
increased. Fungemia cases infected concomitantly or sequentially with two or more
different fungal species have been found occasionally since 1983 and have shown a
high mortality rate. The spectrum of the causative organisms of fungemia appears
to be, at least, partly influenced, by the usage of antifungal agents,
particularly fluconazole.
PMID- 9545686
TI - Sensitive detection of Helicobacter pylori in gastric aspirates by polymerase
chain reaction.
AB - The detection of Helicobacter pylori in gastric aspirate was examined by using
the polymerase chain reaction (PCR) method for amplifying a specific fragment of
the urease gene A. The ability of PCR to amplify H. pylori-specific DNA was
analyzed by Southern hybridization with an internal oligonucleotide probe. Twenty
two H. pylori strains from clinical isolates and reference strains were studied,
and all H. pylori strains yielded a 356-bp product that hybridized with the
oligonucleotide probe, whereas no amplification was evident with 18 non-H. pylori
strains. This could detect as little as 50 CFU of H. pylori in pure culture and
0.1 pg of purified chromosomal DNA. A total of 50 dyspeptic patients were
examined for the presence of H. pylori by culture, the rapid urease test and
histological examination of antral biopsy samples as well as by PCR in gastric
juice aspirate samples. The gold standard for the presence of H. pylori was
established by minimum concordance of two of three tests performed on biopsy
specimens. With this gold standard, 34 of the 50 patients were considered to
harbor H. pylori infection. PCR correctly identified 32 (94.1%) of these 34
infected patients. PCR had the best combination of sensitivity and specificity in
assessing the correct diagnosis of H. pylori as compared with those of the rapid
urease test and culture. Moreover, we established a fast and simple method for
use by improvement of DNA extraction. PCR of the gastric aspirate was shown to be
a sensitive and specific procedure which may be an attractive alternative to
methods currently used for diagnosis of H. pylori infection.
PMID- 9545687
TI - [Inflammatory reactions and microorganisms cultured from sputum and blood in
association with terminal stage infection of patients with lung cancer].
AB - We reviewed our experience with terminal stage infections in patients with lung
cancer over an 11 year period at Kurume University Hospital. In patients with end
stage lung cancer, the infection is common and a mortal disease. We examined the
clinical features and significance of pathogenic microbes isolated from sputum
and blood in patients with lung cancer during their last month. Bacteriological
examinations from blood done frequently in patients with episodes of fever
revealed that bacteremia was one of the most important disease in terminal stage
infection. In the blood cultures from the 22 patients various species of
pathogenic microbes were recovered, and nine of which were fungi; five Candida
albicans, three Candida tropicalis and one Candida parapsilosis. The major
species of bacteria isolated from sputum were Staphylococcus aureus, including
methicillin-resistant strain, and Gram-negative bacilli; P. aeruginasa, A.
calcoaceticus, K. pneumoniae and E. cloacae, which are known to be frequently
involved in hospital-acquired infections. However, S. pneumoniae and H.
influenzae which were well known to be microbes of respiratory infections were
rare. We concluded that we had to reveal the feature of terminal stage infection
in order to reduce the fee for medical treatment and improve the QOL of patients
with terminal stage lung cancer.
PMID- 9545688
TI - [Detection of intrathoracic infectious lesions using In-diethylenetriamine
pentaacetic bicyclic anhydride-IgG (111In-DTPA-IgG) scintigraphy].
AB - The utility of 111In-DTPA-IgG imaging for the detection of intrathoracic lesions
was evaluated in 10 patients with the suspicion of inflammatory or infectious
diseases. They were intravenously administered 40 or 80 MBq of 111In-DTPA-IgG,
and scanned after 24 or 48 hours. Of these, 8 cases, consisted of 4 cases with
pneumonia and 2 cases with lung abscess and one case of pulmonary tuberculosis
and one of a tuberculous pleuritis, showed true positive results. Others were one
false negative case of pneumonia and one true negative case of lung cancer.
Overall sensitivity and specificity were 88.9% and 100%, respectively. There were
no cases which showed side effects or abnormal laboratory findings caused by the
radiopharmaceuticals administered. Thus, 111In-DTPA-IgG imaging is a useful tool
for the detection of intrathoracic infectious lesions.
PMID- 9545689
TI - [Detection of enterovirus 70 in acute hemorrhagic conjunctivitis by PCR-stringent
microplate hybridization method].
AB - The surveillance of acute hemorrhagic conjunctivitis (AHC) caused by enterovirus
70 (EV70) is insufficient because of the difficulties of virus isolation using
conventional methods. In this study, reverse transcription-polymerase chain
reaction (RT-PCR) and stringent microplate hybridization (SMH) methods were
assessed for the detection of EV70 in conjunctival swabs collected from the
patients of AHC which broke out in Miyazaki Prefecture in 1990 and Okinawa
Prefecture in 1994. Furthermore, with the use of the SMH method, we compared the
genetic homogeneity of EV70 detected from the samples collected in 1990 and 1994
to the J670/71 strain isolated approximately 25 years ago. A similar
investigation was performed between recent coxsackievirus A24 variant (CA24v) and
EH24/70 strain, a standard strain of CA24v that was isolated approximately 25
years ago. As a result, RT-PCR products were detected in 26 of 34 conjunctival
swabs collected in Miyazaki Prefecture in 1990. Likewise, RT-PCR products were
detected in 9 of 10 conjunctival swabs collected in Okinawa Prefecture in 1994,
and these RT-PCR products were all identified as EV70 by SMH method. Such a high
level of virus recovery from specimen shows the evidence of usefulness of these
techniques. Recent EV70 showed a reaction of about 60% to a probe synthesized
with J670/71. Likewise, recent CA24v showed a reaction of about 30% to a probe
synthesized with EH24/70. These finding are highly suggestive of the progress of
viral mutation.
PMID- 9545690
TI - [Acute respiratory distress syndrome complicating imported Plasmodium falciparum
malaria].
AB - A 25-year-old male, who had returned from the Republic of Mali in Africa, was
admitted to our hospital because of a 3-day history of high fever, on the first
of October 1996. He was diagnosed as Plasmodium falciparum malaria by peripheral
blood smear. From the admission day he was treated with quinine HCL, 1,500 mg per
day, and sulfamethoxazole 2,400 mg trimethoprim 480 mg per day, but on October
2nd blood examination showed 35% parasite density and he was given mefloquine.
However he was complicated with DIC on October 3rd, ARDS on October 5th. By anti
coagulant therapy and methylprednisolone pulse therapy he became afebrile and
respiratory function improved rapidly. ARDS should be emphasized as a severe
complication of imported severe malaria.
PMID- 9545691
TI - [A case of tuberculous pyothorax after an interval of four years of finishing
with the first treatment for pulmonary tuberculosis].
AB - We reported a case of tuberculous pyothorax which developed at four years after
finishing with the first treatment for pulmonary tuberculosis. A 50-year-old
female was admitted to our hospital with right chest pain. Tuberculous pyothorax
was diagnosed by means of polymerase chain reaction (PCR method) of pleural
effusion and of histological findings of the pleural section. She was cured by
operation, pleural drainage and anti-tuberculous drugs. The bone scincigram of
99mTc revealed accumulation in the right 9th rib, tuberculous empyema might have
been a secondary development from osteomyelitis.
PMID- 9545692
TI - Severe malaria from a new beach resort.
PMID- 9545693
TI - [Retropharyngeal abscess in an adult and an elderly woman].
AB - Retropharyngeal abscess is reported to be decreasing in frequency in recent
years. We report two cases of retropharyngeal abscess that were diagnosed within
four years in Department of Otorhinolaryngology, Gifu University Hospital. Case 1
was a 36-year-old male who was suggested to have an abscess as primary infection
and case 2 was a 71-year-old female whose abscess seemed to be a secondary
infection following unknown primary infection. Endoscopic or open neck drainage
as well as antibacterial chemotherapy mainly with combinations of flomoxef and
clindamycin in the case 1 and piperacillin and clindamycin in the case 2 was
successfully carried out. They were discharged an 15-day and 24-day after
operation in the cases 1 and 2, respectively. A 30 min. culture after sample
collection on operation demonstrated aerobe-anaerobe mixed infection in both
cases; three aerobes and four anaerobes in the case 1 and three aerobes and two
anaerobes in the case 2. These results suggest that retropharyngeal abscess may
be a complicated infection involving more bacterial species than has been
commonly believed. Measuring susceptibility of isolates to antimicrobial agents,
a strain of Capnocytophaga sp. and a strain of anaerobic gram-negative rod were
highly resistant to piperacillin, cefroxine and ofloxacin. It is important for
adequate antibacterial chemotherapy to grasp the bacteriology of retropharyngeal
abscess and analyze susceptibility of antimicrobial agents.
PMID- 9545694
TI - Hemolytic uremic syndrome in a patient with Bacteroides fragilis infection.
PMID- 9545695
TI - [Carrier state of escherichia coli O157:H7 in cattle].
PMID- 9545696
TI - [Usefulness of MycoDot test for the detection of anti-mycobacterial antibodies as
an aid in the diagnosis of experimental Mycobacterium tuberculosis and
Mycobacterium avium complex infections in mice].
AB - The MycoDot is a new diagnostic kit for tuberculosis which was devised by DynaGen
Inc., USA. The MycoDot test is based on the detection of anti-mycobacterial
antibodies in the serum samples of patients by employing plastic combs coated
with lipoarabinomannan (LAM) antigen which is a highly immunogenic
lipopolysaccharide presenting in the cell wall of all species of mycobacteria. It
has been reported that healthy infected and BCG-vaccinated individuals do not
react to the MycoDot test, while a positive reaction occurs in patients with
active tuberculosis or atypical mycobacteriosis with good sensitivity and
specificity. In this study, we evaluated the efficacy of MycoDot test for the
detection of anti-LAM antibodies in sera of mice infected with Mycobacterium
tuberculosis or M. avium complex (MAC). By using the MycoDot test, anti-LAM
antibodies were positive in 2 out of 4 mice infected with M. tuberculosis 2 weeks
before, while all of M. intracellulare-infected mice were negative at the same
phase of infection. On the other hand, anti-mycobacterial (MB) antibodies were
detected in the serum samples of mice infected with M. intracellulare as well as
M. tuberculosis by home-made ELISA testing using whole cells of test mycobacteria
as antigen. In the next experiment, mice were infected with M. avium. All the
serum samples of mice obtained at 13 weeks after infection were negative for anti
LAM antibodies in MycoDot test, whereas they reacted positively to anti-MB
antibodies in ELISA test. These results indicate that the MycoDot test is capable
of detecting M. tuberculosis infection but not MAC infection induced in mice.
PMID- 9545697
TI - [Therapeutic efficacy of benzoxazinorifamycin KRM-1648 against experimental
murine tuberculosis: (1). A study on the efficacy of short course treatment with
the intratracheal and intravenous infection model].
AB - OBJECTIVES: This study aims to compare in vivo activity of benzoxazinorifamycin
KRM-1648 (KRM) with those rifampicin (RFP) and rifabutin (RBT) against
experimental murine tuberculosis. STUDY DESIGN: Mice were infected with
Mycobacterium tuberculosis or M. bovis by the intratracheal (i.t.) or intravenous
(i.v.) routes, and treated for 10 days with various doses of each drug starting
from the 9th or 11th day after the TB-infection. RESULTS: (A) A rapid test for in
vivo evaluation of three rifamycins was conducted by examining the survival days
of treated mice infected with 106 cfu of M. bovis Ravenel. Mice treated with KRM
exhibited 2.13.7 times longer survival times, in comparison with those treated
with RFP or RBT. (B) In the i.t.-model of M. bovis Ravenel infection, three
rifamycin derivatives gave "distinctive dose-response curves" in the correlation
of dose sizes with the mean survival times or "log10CFU/lungs reductions". (C) In
M. tuberculosis Kurono infection models, the ranking of the anti-TB activity of
the three rifamycins in each organ was as follows: i.t.-and i.v.-lungs: KRM >>
RFP not equal to RBT, i.v.-spleen: KRM not equal to RBT > RFP, i.v.-liver: KRM
not equal to RBT > RFP. (D) Based on the results of "log10CFU reduction" in
different organs in M. tuberculosis Kurono infection models, "characteristic in
vivo activity patterns of each rifamycin" were obtained. (E) The therapeutic
efficacy of KRM in lungs was greater than in spleen and liver with any dose. In
contrast, RBT exhibited more remarkable in vivo activity in the spleen and liver
than in lungs. CONCLUSION: The prominent in vivo activity of KRM may allow small
dose for effective therapy; 1/3 dose or less in comparison with those of RFP or
RBT, or intermittent therapy of tuberculosis.
PMID- 9545698
TI - [Biochemical and immunological properties of the fractions of tubercle bacilli].
AB - In 1954, Dr. Yuichi Yamamura and his coassociates, National Sanatorium Toneyama
Hospital, has reported the formation of experimental tuberculous cavity in
rabbits. This work was a milestone of the researches in the field of cellular
immunology. In 1960, I have started my scientific carrier in Kyushu University
Medical School as the post-graduate student under the guidance of Prof. Yamamura.
Since then, I have worked on the field of biochemical and immunological
properties of tubercle bacilli. The arabinose mycolate, polysaccharides, cell
wall skeleton (CWS) and trehalose dimycolate (TDM) were purified from tubercle
bacilli and their Chemical structures and biological activities were investigated
in detail in our laboratory. In 1971, we have reported that adjuvant active
principle of tubercle bacilli was a CWS fraction, and the details of chemical
structure and adjuvantity of mycobacterial CWS were investigated in our research
group. The application of BCG-CWS to cancer immunotherapy was also studied. In
1974, Prof. E. Lederer and his coworkers, University of Paris, have reported that
N-acetyl muramyl-L-alanyl-D-isoglutamine (MDP) was the minimum adjuvant-active
structure of bacterial cell wall. We have synthesized several hundreds of MDP
derivatives and selected, MDP-Lys(L18), romurtide, as the candidate of cytokine
inducer for the clinical application. Romurtide is applied in cancer patients for
the recovery of the number and functions of monocytes, neutrophils and platelets.
These results suggest that the tubercle bacilli, especially, CWS and related
synthetic MDP derivatives, are effective for the potentiation of host resistance
against infectious diseases and cancer.
PMID- 9545699
TI - [Nontuberculous mycobacteriosis; the present status and in the future. Mechanisms
of host resistance to Mycobacterium avium complex and Mycobacterium tuberculosis
infection].
AB - In order to know profiles of the antimicrobial action of some microbicidal
effector molecules against Mycobacterium avium complex (MAC) and M. tuberculosis
(MTB), profiles of collaborating effects among reactive nitrogen intermediates
(RNI), free fatty acids (FFA), and reactive oxygen intermediates (ROI) were
studied, RNI and FFA exerted synergistic effects in killing MAC and MTB, while
the combination of ROI (H2O2-mediated halogenation system) with FFA conversely
caused antagonism. The combination of RNI with ROI displayed additive effects in
killing MTB, whereas the same combination showed antagonistic effects against
MAC. Murine peritoneal macrophages (M phi s) produced and/or released these three
antimicrobial effectors in the order ROI, FFA, and RNI in response to cellular
stimulation induced by their contact with MAC or MTB organisms. These findings
indicate that the collaborating effect of RNI with FFA is crucial for M phi
mediated intracellular killing of MAC and MTB. Secondly, we examined the modes of
bacterial growth of MAC and MTB in murine peritoneal M phi s and A-549 type II
alveolar epithelial cell line. The growth rate of these organisms was much larger
in A-549 cells than in M phi s. In addition, the growth rate of high-virulence
MAC (N-260 strain) was significantly larger than that of low-virulence MAC (N-444
strain), when they were residing in M phi or A-549 cells. Although a high
virulence MTB (strain Kurono) also showed much more rapid growth in M phi s than
did low-virulence MTB (strain H37Ra), such a phenomenon was not observed for
their intracellular growth in A-549 cells. MTB exhibited strong cytotoxic effects
against M phi s but not against A-549 cells when resided in these cells. On the
other hand, MAC organisms did not cause cytotoxicity even in M phi s. Although
MAC and MTB infections caused significant increase in RNI production by M phi s
but not by A-549 cells, there was no significant relationship between the degree
of M phi RNI production by a given mycobacterial organism and its virulence.
These findings indicate some important roles of type II alveolar epithelial cells
as a target cell for primary invasion and transient growth of mycobacterial
organisms in the host lungs.
PMID- 9545701
TI - [Nontuberculous mycobacteriosis; the present status and in the future. 3-(2) Long
term prognosis of Mycobacterium avium complex disease].
AB - This paper shows long-term course of 71 patients with Mycobacterium avium complex
(MAC) disease treated in National Hiroshima Hospital between 1977 and 1991 and
were observed for more than 5 years or died between 6 months and years from the
onset. In the patients who were not treated with chemotherapeutic agent or
treated with less than 3 drugs, about 60 per cent deteriorated and few obtained
persistent negativity of bacteria. In patients treated with at least 3 drugs out
of isoniazid, rifampicin, ethambutol, ethionamide, cycloserine, clarithromycin
and new-quinolones for more than 12 months, 59.2 per cent deteriorated, while
29.6 per cent obtained negative conversion of bacteria by initial chemotherapy.
However only 18.5 per cent remained negative during long term observation. In
patients treated with at least 3 drugs including one aminoglycoside such as
streptomycin for more than 12 months, 64.7 per cent obtained negative conversion
and 35.5 per cent remained negative bacteriologically, while 23.5 per cent
deteriorated. In twelve patients who were operated, only one patient
deteriorated. The long-term prognosis of MAC disease under the chemotherapy
mainly by antituberculous agents up to this time was still poor compared to that
by short-term observation. Anticipated new regimens for MAC should be multidrug,
to prevent secondary drug resistance.
PMID- 9545700
TI - [Nontuberculous mycobacteriosis; the present status and in the future. 3--(1).
The view of development of new drugs against nontuberculous mycobacterial
infections].
AB - It is obvious that the number of patients with pulmonary nontuberculous
mycobacterial infections is increasing gradually in Japan. Of these infections,
M. avium complex (MAC) is the most common cause, and is known to be resistant to
many antimicrobial drugs. At present, no standard regimen which is able to
control MAC infections completely is established. For these reasons, the
development of new drugs with strong antimycobacterial activity which are not
cross-resistant to conventional antimycobacterial drugs is urgently desired.
Thus, we studied in vitro activities of various drugs which are expected to be a
new promising drug against nontuberculous mycobacterial infections, and reviewed
clinical impact of these drugs. 1) New quinolones New quinolones including
ofloxacin, ciprofloxacin, levofloxacin and sparfloxacin (SPFX), are considered to
be active against M. tuberculosis, M. kansasii, M. fortuitum, but are inactive
against MAC, M. chelonae, M. abscessus, M. scrofulaceum. Both AM-1155 and Du
6859a, newer quinolones, seemed to be comparable to or more active than SPFX
which is considered to be most active now. 2) New macrolides Clarithromycin (CAM)
has in vitro activities against various nontuberculous mycobacteria including
MAC, and also has proven to have clinical potential not only for disseminated MAC
infections in AIDS but also for pulmonary MAC infections. Therefore, CAM seems to
be a candidate for one of the key drugs in the treatment of MAC infections.
3)Rifamycins Rifabutin (RBT) and rifapentine exhibited more potent in vitro and
in vivo antimycobacterial activities than rifampicin. RBT has already
demonstrated clinical effect against intractable tuberculosis and MAC infections.
Thus, RBT is recommended for the prophylaxis of M. tuberculosis and MAC
infections in AIDS patients in US. KRM-1648 displayed much more potent in vitro
and in vivo activities than rifampicin against both M. tuberculosis and MAC. It
is needed an effort to confirm its therapeutic efficacies. Now clinical phase
study is going on in US. 4) Phenazines Clofazimine (CFZ), an effective
antileprosy drug, is known to be active in vitro against various mycobacteria
including MAC, and often used as a component of combination chemotherapy for
disseminated MAC infections in AIDS patients in US. Recently, CFZ new analogs
have been developed, and it is necessary to evaluate its activities against
nontuberculous mycobacteria.
PMID- 9545702
TI - [Nontuberculous mycobacteriosis; the present status and in the future. Infection
with human immunodeficiency virus (HIV) and nontuberculous mycobacteriosis].
AB - Disseminated Mycobacterium avium-intracellulare complex (DMAC) infection is a
common complication of AIDS. The cumulative incidence is 40% in patient surviving
2 years after diagnosis of AIDS. AIDS patients with DMAC reduced life expectancy
compared with those without. Antimycobacterial therapy with Clarithromycin (CAM)
can significantly reduce bacteremia and improve symptoms, quality of life, and
survival of patients with DMAC. Prophylactic therapy with Rifabutin, CAM and
Azithromycin is effective and Synergic effect can be expected as Rifabutin and
Azithromycin are administered together. But it is serious problem to get
resistance to CAM when prophylactic therapy with CAM failed because we lose one
of the most effective medicines against DMAC. It is recommended to start
prophylactic therapy when CD4 Lymphocyte count falls below 50-75/microliters in
patients who had opportunistic infection. In Japan, 32 cases of AIDS with NTM are
reported. All of them are male and mean count of CD4+lymphocyte was
11/microliters. Twenty three out of 32 were MAC and 6 were M. kansasii. Cases of
NTM bacteremia were 9 (69.2%) and cases of those without bacteremia were 4
(30.8%). Three out of 4 were cases of M. kansasii.
PMID- 9545703
TI - [Short-term triple therapy with pantoprazole, amoxicillin and metronidazole in
Helicobacter pylori infection].
AB - BACKGROUND: The present study was conducted to investigate the efficacy and
tolerability of a 7-day treatment with pantoprazole, amoxicillin and
metronidazole for the eradication of Helicobacter pylori (H. pylori) infection.
PATIENTS AND METHODS: Fifty patients (26 male, 24 female, age 18 to 86, mean 54
years) with an active duodenal (n = 25) or gastric ulcer (n = 25) were recruited
into the study, 48 patients being H. pylori positive at the study start. Patients
were treated with pantoprazole (40 mg bid), amoxicillin (1 g bid) and
metronidazole (500 mg bid) for 7 days and for another 21 days with pantoprazole
(40 mg/od). Four weeks after the end of study medications the patients were re
examined endoscopically and their H. pylori status was re-assessed using urease
test, histology and 13C-urea-breath test. RESULTS: In 39 of 48 intention to treat
patients, H. pylori infection was cured, according to 81% (95%-CI = 67 to 91%).
In the per protocol population in 35 of 41 patients H. pylori was eradicated,
which results in an eradication rate of 85% (95%-CI = 71 to 94%). Ulcer healing
was endoscopically confirmed in 45 of 48 patients (94%; 95%-CI = 83 to 99%) after
8 weeks. Six of 50 patients (12%) reported mild to moderate probable side-effects
of the study medication. Cure of the infection was associated with a distinct
reduction of the gastritis grade and activity. CONCLUSION: A 7-day triple therapy
using pantoprazole, amoxicillin and metronidazole is an effective and cost
effective alternative to regimens including clarithromycin for the treatment of
H. pylori infection.
PMID- 9545704
TI - [1997 gastroenterology update--I].
PMID- 9545705
TI - [Space-occupying lesion of the liver hilus].
PMID- 9545706
TI - [Pathogenesis and therapy of Hodgkin lymphoma].
AB - Although the pathogenesis of Hodgkin's disease is not clear, molecular analyses
reveal characteristic features. EBV infection can be demonstrated in more than
50% of cases at the DNA or protein level. Recently, immunoglobulin gene
rearrangements were found in single Hodgkin and Reed-Sternberg cells. Sequence
analyses revealed that the rearranged Ig genes have frequently somatic mutations,
which indicate that the cells are derived from the germinal center. These
rearrangements may be used as defined markers to detect residual disease after
chemotherapy. Modern polychemotherapy regimen and radiotherapy are very
effective, and 60-90% of patients, depending on stage of the disease and risk
factors, can be cured. Salvage therapy for relapsed patients including high-dose
chemotherapy with autologous stem cell support frequently results in remission
although duration is frequently short. New immunotherapy strategies with
immunotoxins or bispecific antibodies are currently analysed in clinical studies.
PMID- 9545707
TI - [Outcome of intensive care].
AB - BACKGROUND: The mean hospital mortality of patients after intensive therapy in
Germany is about 15%, the mortality within the intensive care unit about 8%.
Short-term prognosis is mainly determined by severity of disease, type of disease
and patient age. FACTORS IN INTENSIVE CARE: The impact of disease severity is
measured by acute physiology score systems. The significance of disease
categories becomes apparent in disease states with a continuing high mortality.
Age is an independent risk factor. The higher risk of older patients cannot be
explained by different diagnosis, and it is not secondary to a less aggressive
therapy. The same factors mainly determine long-term prognosis. The 5-year
survival rate after intensive therapy is around 60%, a 3-fold increase as
compared to the general population. Dependent upon the disease category, survival
curves of intensive care patients parallel survival curves of the general
population 2 years after admission. Analysis of quality of life is based upon
objective measurement and subjective estimation of health-related life quality in
the physical, psychological, and social life domain. Patients after intensive
therapy experience a moderate but significant decrease in quality of life. This
is the case in global estimations of quality of life as well as in investigations
of different life domains. CONCLUSION: The remaining quality of life is
tolerable. This is in accordance with the positive overall judgement of intensive
care by patients themselves. The chief problem of intensive care remain diseases
with continuing high mortality.
PMID- 9545708
TI - [Illnesses caused by amalgam?].
AB - BACKGROUND: As side effects of dental amalgam have been mentioned allergy, oral
lichen, electro-galvanism, amalgam tattoos of gingiva or oral mucosa, and
undesirable esthetics. Patients with amalgam restorations show increased mercury
levels in different body fluids compared to amalgam-free controls. An
intoxication due to dental amalgam fillings, however, is not to be expected
despite equivocal statements in the literature. SCIENTIFIC RESULTS: In contrast,
recent studies revealed that dental amalgam contributes to mercury exposure less
than assumed few years ago. Therefore, amalgam will stay an option as a
restorative material in future. The removal of intact amalgam fillings in the
intention of "detoxification" is not science-based. CONCLUSION: Successful caries
prevention (e.g. due to the widespread use of fluoride) and the further
development of esthetic restorative materials based on composite resins will
limit the utilisation of amalgam. Thus, alternative materials have not been shown
to have a lower rate of side effects (e.g. allergy) compared to amalgam.
PMID- 9545710
TI - [Supraventricular tachycardia, II: Atrioventricular nodal reentry tachycardia:
diagnosis and therapy].
PMID- 9545709
TI - [Pseudoaneurysm with associated arteriovenous fistula after transfemoral
puncture].
AB - BACKGROUND: Local vascular complications after transfemoral cardiac
catheterization occur with an incidence of 5%. Most commonly these lesions are
pseudoaneurysms, av-fistulas, arterial dissections or direct vascular injuries.
Undiagnosed vascular lesions can lead to fatal consequences especially in
patients with chronic heart failure by av-fistula with significant shunt volume.
CASE REPORT: We report a vascular complication of combined pseudoaneurysm and av
fistula originated from the pseudoaneurysm. The lesion was diagnosed by color
Doppler ultrasound. CONCLUSION: The suspicion of a vascular lesion after vascular
catheterization should immediately lead to color Doppler ultrasound. Noninvasive
duplexsonography will lead to early diagnosis of vascular complications and
prompt further surgical or conservative intervention with reduction of long-term
sequela and morbidity.
PMID- 9545711
TI - [Poison and nocebo--2 aspects of toxicology].
AB - BACKGROUND: Erroneously it is assumed that drugs promote health exclusively by
interacting with the organism through chemical or physical forces. However,
placebo phenomena are omnipresent in patients who believe in the value of a
treatment, be it medical or paramedical. Conversely, nocebo phenomena originate
from fear of detrimental effects attributed to a putative poison. Thus, both
drugs and poisons release two different messages, the one being physicochemical,
the other psychosocial. The latter is fostered by the public opinion, and man is
a sensitive receiver. TYPICAL NOCEBO PHENOMENA: Here some epidemiological
examples of nocebo phenomena will be presented. Each society selects the matching
nocebos, today mainly as chemical exposures from oecological sources such as
environment, buildings, emissions and industrial products. THERAPEUTICAL
APPROACH: Suspicion of nocebo should not hamper the search for chemical poisons.
Anxiety and fear furnish the neurobiological and evolutionary basis of the nocebo
phenomena. Hence behavioural and conversational therapy, supported by
antidepressants if needed, should be tried. Unfortunately, most patients expect
their psychosocial problems instead to be declared as chemical.
PMID- 9545712
TI - [Structure and activities of drug committees in Germany. Results of a survey of
143 hospitals. Pharmaco-economic Study Group and Rational Drug Therapy of the
German Society of Clinical Pharmacology and Therapy].
AB - BACKGROUND: To obtain information on the structure, present activities and
decision making process of hospital drug committees in Germany in 1995 a
questionnaire with 36 items was designed and sent to 450 hospitals in Germany
with more than 400 beds. 143 returned questionnaires could be evaluated. RESULTS:
According to hospital size the median value of the annual drug budget 1993 ranged
between DM 2.4 Mio for hospitals with less than 500 beds and DM 30.0 Mio for
university hospitals with more than 1,000 beds (including blood and blood derived
products). In 53% of drug committees a pharmacist held the position of the
chairman, followed by medical specialists (32%), (clinical) pharmacologists held
this position only in 8% of the hospitals, but in almost 50% of the university
hospitals. In most cases all clinical specialties are represented in the drug
committee, the number of members ranging between 5 and 40 (median 12). The number
of drugs included in the internal drug list ranging between 400 in hospitals with
< 500 beds and about 700 in university hospitals was strongly correlated with the
number of beds and, interestingly, with the number of drug committee members.
Treatment guidelines were implemented mainly for antiinfectives (87%), infusion
solutions (30%), antiemetic drugs (5-HT3-receptor antagonists, 27%) and blood and
blood-derived products such as intravenous immunoglobulins (23%). However,
effective control of these guidelines was only performed in about 50% of the
hospitals. A drug information service was provided in most hospitals, where 95%
of queries were answered by pharmacists. CONCLUSION: The results of our survey
showed, that German hospital drug committees vary considerably with regard to
their function and control mechanisms on drug use. Most of the responders would
appreciate a more intensive exchange of current problems and treatment
guidelines.
PMID- 9545713
TI - [Eczema of the nipple: cancer or not?].
AB - Paget disease of the nipple is a rare unique presentation of breast cancer. The
main differential diagnosis is dermatitis. We describe two patients with mammary
Paget: one, a women aged 41, with limited ductal carcinoma in situ and the other,
a women of 56 years, with invasive carcinoma. A third patient, a woman of 46
years, had typical eczema of the areola. This disease usually leads to less well
circumscribed lesions than Paget. The treatment of Paget disease is not
essentially different from that of any other mammary carcinoma. Eczema of the
areola is treated with corticosteroids, to which the disease should respond
favourably within three weeks.
PMID- 9545714
TI - [The value of roentgen pictures in rheumatoid arthritis].
AB - Rheumatoid arthritis leads to many abnormalities in radiographs as a result of
irreversible destruction of cartilage or underlying bone. Radiographs of hands
and feet provide the most useful information. Erosions and joint space narrowing
in particular can be assessed reliably, and give a good impression of the
destruction of the joints. Several validated scoring methods are available to
assess the severity and progression of joint damage. Abnormalities are already
present shortly after onset of the disease. About 70% of the patients develop
erosive disease and in the majority of the cases erosions are present one year
after onset. Patients who are rheumatoid factor positive in particular develop
erosions. Damage occurs earlier and is often more severe in the joints of the
feet than in joints of the hands. The early occurrence of irreversible joint
destruction and the availability of treatment effective in reducing this damage
necessitates early treatment of patients with RA.
PMID- 9545715
TI - [Complications, hospital mortality and survival following partial
pancreaticoduodenectomy].
AB - OBJECTIVE: To analyse hospital mortality, complications and survival of patients
after subtotal pancreaticoduodenectomy in the Academic Medical Centre, Amsterdam,
the Netherlands, 1983-1996. DESIGN: Partly retrospective (1983-August 1987),
partly prospective (September 1987-1996). METHOD: Patient characteristics,
indication for surgery, postoperative complications, mortality and survival of
patients who underwent subtotal pancreaticoduodenectomy were recorded in a
computer database. Patients were subdivided into three groups (1983-September
1992; October 1992-1994; 1995-September 1996) to analyse the influence of change
in surgical technique and the increase of experience. RESULTS: From 1983-to
September 1996, 312 consecutive patients underwent a subtotal
pancreaticoduodenectomy. Hospital mortality decreased from 4.9% to 1.4% in the
last period (1995-1996). The complication rate decreased from 60% to 41%. The
hospital stay decreased from median 24 days to 16 days. The actualized 5-year
survival analysed for patients operated from 1983-to September 1992 was 31%.
Patients with ampullary tumours had a 5-year survival of 50%. The 5-year survival
of patients with bile duct and pancreatic carcinoma was 24% and 15% respectively.
CONCLUSIONS: Subtotal pancreaticoduodenectomy can be performed safely with a low
mortality (< 2%) in specialised centres. The morbidity is still substantial
(40%). The survival is mainly dependent on type of tumour and patient selection
and is approximately 50% for patients with ampullary tumours. The pylorus
preserving procedure has become the standard operation.
PMID- 9545716
TI - [Hospital experience and hospital mortality following partial
pancreaticoduodenectomy in The Netherlands].
AB - OBJECTIVE: To analyse the effect of hospital experience on mortality after
subtotal pancreaticoduodenectomy in the Netherlands. DESIGN: Retrospective
evaluation. METHOD: Information on hospital mortality and pancreatic resection in
1994 and 1995 in the Netherlands was obtained from the National Medical Register.
Subanalysis was carried out of surgical mortality by age and hospital experience.
RESULTS: Approximately 50% of the pancreaticoduodenectomies in the Netherlands
were performed in hospitals with limited experience (< 5 procedures per year).
Hospital mortality was higher in small-volume hospitals than in hospitals with
experience (> 25 procedures per year): in 1994 17.2 and 0% and in 1995 14.6 and
2.9%, respectively (p < 0.05). Mortality was higher in patients older than 70
years compared with patients younger than 55 (p < 0.05). CONCLUSION: There was a
correlation between mortality after pancreaticoduodenectomy and hospital
experience. Therefore these procedures should be performed in centres with
experience.
PMID- 9545717
TI - [Ascites due to hypothyroidism].
AB - A 77-year-old man presented with ascites which was due to hypothyroidism. After
the ascites had been brought into remission by salt restriction, diuretics and
paracentesis, monotherapy with levothyroxine prevented recurrence. Ascites
reappeared as soon as levothyroxine was withdrawn due to the patient's non
compliance. Distinctive aspects of this type of ascites are the high
concentration of total protein in the ascites and the high serum-to-ascites
albumin gradient (SAAG). The pathogenesis of ascites in hypothyroidism is
unknown. Possible hypotheses include increased capillary permeability,
obstruction to lymphatic flow caused by hyaluronic acid-albumin complexes, and
diminished water diuresis due to excess antidiuretic hormone. A patient with
unexplained ascites should be tested for hypothyroidism, especially when the SAAG
is high (> 11 g/l).
PMID- 9545718
TI - [Influenza in the 1996/'97 season; vaccine composition for the 1997/'98 season].
AB - The first indication of flu activity in the Netherlands in the 1996/'97 season
was the isolation of an A/H3N2 influenza virus in week 48 of 1996. In subsequent
weeks influenza viruses were isolated sporadically. The clinical influenza
activity increased from week I of 1997 and reached its peak in week 4 of 1997.
Simultaneously with the increase of clinical influenza activity, an increasing
number of influenza viruses were isolated. The epidemic had a relatively small
extent. Initially, A/H3N2 influenza viruses were predominant, but in the second
half of the epidemic an increasing number of influenza B viruses were isolated as
well. The A/H3N2 viruses were antigenically fairly strongly distinct from the
variants prevalent in the preceding years. This season influenza A/HINI viruses
did not play a significant role and only one virus of this subtype was isolated.
All influenza A/H3N2, A/HINI and B viruses isolated were antigenically similar to
the vaccine strains.
PMID- 9545719
TI - [Statement of ingredients of cosmetics].
AB - Since January 1st 1997 there is European legislation labelling that cosmetic
products are supplied with a list of their ingredients. The ingredients are given
in order of decreasing concentration using the nomenclature 'International
nomenclature cosmetic ingredient' (INCI). This enables dermatologists to identify
the allergenic components of cosmetic products in patients with allergic contact
dermatitis caused by cosmetics, and enables allergic patients to purchase other
cosmetic products without risking a recurrence of dermatitis.
PMID- 9545720
TI - [Syncopes with simultaneous use of terfenadine and itraconazole].
PMID- 9545721
TI - [Syncopes with simultaneous use of terfenadine and itraconazole. Drug Monitoring
Board].
PMID- 9545722
TI - [Diagnostic and therapeutic dilemmas in malignancy during pregnancy].
AB - In four pregnant women, aged 28, 29, 30, and 35, malignancies were diagnosed:
synoviosarcoma, gastric carcinoma, non-Hodgkin B cell lymphoma and
undifferentiated adenocarcinoma in one of the labia vulvae, respectively. The
first three women eventually died, the first before giving birth, the last woman
was treated surgically and was alive without recurrence two years after
treatment. Pregnancy can lead to diagnostic dilemma and delay as many symptoms of
a malignancy are not recognised as such but are attributed to the pregnant state
and because of reluctance to apply diagnostic tools which can be harmful to the
foetus. It can also lead to therapeutic dilemma and delay because several
therapies may also harm the foetus.
PMID- 9545723
TI - [Malaria therapy; ups and downs, how much longer?].
AB - The natural products quinine and artemisinine have been effective antimalarials
for centuries. Most synthetic antimalarials were developed because of pressure of
war; against all some degree of resistance has developed. The newer drugs are too
expensive for large-scale use. Development of new antimalarials is financially
too risky for the pharmaceutical industry. Co-operation among industries,
research institutes, governments and international organizations is coming off
the ground. Dutch researchers should contribute to international malaria research
for humanitarian reasons and out of self-interest, for the benefit of public
health.
PMID- 9545724
TI - [Immunology in medical practice. I. Introduction].
AB - Fundamental immunology has seen a tremendous development in the past decades.
This has resulted in a large body of knowledge, part of which has led to
applications in laboratory diagnosis, but of which little has made its way to the
clinic in terms of new therapies. The progress in understanding pathogenesis of
diseases is also slow. This journal is planning a series of articles that
highlight the recent achievements of immunology and their consequences for
understanding and treating disease.
PMID- 9545725
TI - [Immunology in medical practice. II. Antiphospholipid antibodies in pregnancy].
AB - Antibodies against phospholipids are a risk factor for thrombotic disorders, but
also for foetal death, pre-eclampsia, foetal distress and dysmaturity. This group
of antibodies (aPLab) includes lupus anticoagulant (LAC) and anticardiolipin
antibodies (aCL). These antibodies are encountered in patients with systemic
lupus erythematosus (SLE), but also in patients with lupus-like disease and in
women with (a history of) symptoms compatible with the antiphospholipid syndrome.
Screening for a aPLab is advisable in these patients when they want to conceive
and in women with recurrent foetal death after the 12th week of pregnancy. It is
not clear if the antibodies exert a direct noxious action or are an accompanying
phenomenon. Secondary prevention is possible with acetylsalicylic acid (80
mg/day), if desired in combination with subcutaneous heparin (5000-12,000 units
twice daily). The thrombosis prophylaxis should be continued for 6 weeks after
delivery.
PMID- 9545726
TI - [The treatment of malaria].
AB - The diagnosis of malaria should include the species involved and in case of P.
falciparum infection the parasitaemia index: the percentage of the infected red
cells. P. vivax, ovale and malariae infection are treated with chloroquine, in
case of P. vivax and ovale malaria followed by primaquine. Mefloquine and
halofantrine are indicated for chloroquine-resistant vivax infections. Advice on
management and treatment is different for mild and severe (> or = 5% infected
erythrocytes or presence of complications) P. falciparum infections. Mild
infections may be treated on an outpatient basis. In severe infections quinine
has to be started immediately, while frequent checks of vital functions and blood
parameters are indicated. New treatment options are the use of artemisinine
(preparations) or atovaquone, both efficacious and low in adverse effects and
toxicity.
PMID- 9545727
TI - [Consensus prevention of crib death. CBO (Central Guidance Organization for Peer
Review)].
AB - The sudden and unforeseen death of a child in the first two years, usually
happening during a sleeping period, is known as cot death. As cot death is a very
tragic and dramatic experience for the family, it is important to reduce its
incidence. In the period between 1972 and 1987, the number of cot deaths
initially increased, but during the last decade a substantial reduction could be
observed. This fluctuation can be connected with the position in which the baby
is put to sleep. From 1970 the prone sleeping position was strongly recommended.
Since then, the number of cot death cases increased. From 1987, a causal
relationship between the prone sleeping position and cot death was suspected. As
a result the prone sleeping position was strongly advised against. A reduction of
cot death cases was then observed. By now, the role of many other factors in cot
death has been perceived. The risk of cot death is increased if these factors act
at the same time. Some of these factors that promote cot death come from the
child's environment and can be influenced when kept in mind. Apart from the prone
or side sleeping position, heat congestion, unsafe bed material and smoking in
the presence of the child substantially increase the risk of cot death. The main
recommendations of the committee which drew up the Dutch consensus report on
prevention of cot death are therefore aimed at avoiding the above mentioned risk
factors. Continuation of research is necessary to further reduce the current
number of some 50 cases of cot death which happen yearly in the Netherlands.
PMID- 9545729
TI - [Chronic fatigue syndrome].
PMID- 9545731
TI - [Suppurative hidradenitis].
PMID- 9545730
TI - [Chronic fatigue syndrome].
PMID- 9545728
TI - [Recurrent Plasmodium vivax malaria in spite of primaquine follow-up treatment].
AB - Two patients, a 25-year-old woman and a 62-year-old man, with Plasmodium vivax
infection, suffered repeated attacks of malaria despite standard treatment with
chloroquine and subsequently primaquine. The relapses were due to a combination
of decreased primaquine sensitivity and incorrect prescription of primaquine.
Primaquine is administered as diphosphate (salt), but the required amount has to
be prescribed as base (26.3 mg diphosphate corresponds to 15 mg base).
PMID- 9545732
TI - [Genetic counseling: should side issues become main issues?].
AB - Three people applied for genetic counselling, but during the consultations the
clinical geneticist discovered other problems for which advice could have been
given but was not asked. This caused a serious dilemma. The first person was a
woman who wanted to know the risks of epilepsy for her potential offspring, but
then it became clear that she appeared to have Huntington's disease in the
family. The second person was a man who wanted to know about the genetic risks
for his offspring of a borderline psychiatric disorder, but the geneticist,
seeing that the partner had severe limb defects, wondered whether these were
caused by a genetic disorder. The third patient was a pregnant woman who came
asking about the risks caused by mental retardation in one of her ancestors, but
who appeared to be a heavy drinker and user of cocaine and ecstasy. In dealing
with such 'secondary' problems, it should be kept in mind that persons seeking
advice must decide for themselves whether or not they want to be informed
regarding these problems or not.
PMID- 9545733
TI - [Optimal world-wide obstetrical care; a WHO report].
AB - 'Safe motherhood; care in normal birth: a practical guide' is a document produced
by an international technical working group of the World Health Organization.
This report addresses issues of care during normal birth irrespective of country
or region. Routine interventions and non-interventions in the physiological
processes of pregnancy and labour are analysed and assessed for their scientific
validity. Scientific foundation of obstetric practice is considered an important
step towards worldwide demystification of obstetric practice, which now often
relies on authority, culture and habit. For risk assessment, the cornerstone of
the Dutch system of obstetric care, an evidence-based strategy is imperative.
This requires scientific training in schools of midwifery.
PMID- 9545734
TI - [Endothelins: possibly a new pharmacological approach in cardiovascular diseases,
kidney diseases and oncological disorders].
AB - Only 10 years ago, the vasoconstricting peptide endothelin was discovered; it is
produced by endothelial cells. Different isoforms and receptors of endothelin
have been identified. The effects of endothelin-I, the most important isoform,
are mainly vasoconstriction and proliferation of cells. In the last few years
endothelin receptor antagonists have become available, which can delineate the
clinical importance of the endothelin system. Possible indications for endothelin
receptor blockers are renal disease (acute and chronic renal failure) and
cardiovascular disease (heart failure; restenosis after percutaneous transluminal
coronary angioplasty (PTCA); pulmonary hypertension; systemic hypertension).
There is also a possible role for endothelin receptor blockers in oncology
(prostatic carcinoma). Currently clinical trials are being carried out to
determine the efficacy of these compounds for the above-mentioned indications.
PMID- 9545735
TI - [Pleurodesis in malignant pleural effusion].
AB - About 50% of the pleural effusions diagnosed are caused by a malignancy,
especially by thoracic, pulmonary and ovarian cancer and lymphomas. The
accumulation of fluid is caused by metastasization to the pleura and obstruction
of lymph vessels and nodes. The effusion generally decreases if the tumour
responds to systemic treatment. However, frequently this does not occur and the
fluid has to be removed, to alleviate symptoms such as dyspnoea, coughing and a
heavy sensation in the chest. Possible surgical therapies are draining through a
needle or a drain, (partial) pleural resection and the creation of a pleuro
peritoneal shunt. Disadvantages of these are early recurrences, the severity of
the intervention and (or) the high morbidity and mortality. The current standard
treatment is pleurodesis brought about by a sclerosing agent, usually via a
drain. The substances preferably used for this purpose are, in the order of
decreasing importance, tetracycline, bleomycin or talc, doxycycline or
minocycline. The most frequent adverse effects are chest pain and fever during
and after the pleurodesis.
PMID- 9545736
TI - [Relationship between air pollution due to traffic, decreased lung function and
airway symptoms in children].
AB - OBJECTIVE: To assess whether air pollution by traffic was related to lung
function and chronic respiratory symptoms in children living. DESIGN:
Descriptive. SETTING: The province of South Holland, the Netherlands. METHODS: In
the period May through July of 1995 pulmonary function tests and questionnaires
were obtained from 1,092 and 1,068 children respectively in six city districts
near busy motorways in the province of South Holland. In the same period, indoor
measurements were performed at 12 schools of NO2, black smoke and PM10 dust
density. Lung function data were analysed by multiple linear regression and
respiratory symptoms were analysed by multiple logistic regression. As
independent variables, distance between motorway and home, passenger car traffic
density and lorry traffic density on the motorway, and black smoke and NO2
concentrations in schools were taken. RESULTS: Significant differences in lung
function and respiratory symptoms were found between children living in different
city districts. Lung function as well as symptoms were associated with lorry
traffic density on the motorway. The validity of these findings was supported by
associations between black smoke concentrations (representative for diesel soot)
and lung function as well as respiratory symptoms. In contrast, there was no
association between passenger car traffic counts or NO2 and lung function or
respiratory symptoms. CONCLUSION: The results suggest that air pollution by lorry
traffic can lead to reduced lung function and to an increased prevalence of
chronic respiratory symptoms in children living near major motorways.
PMID- 9545738
TI - [Asystole due to complex partial epilepsy].
AB - A 56-year-old man was seen in the Emergency Room because of sudden and transient
loss of consciousness. An asystole was diagnosed with 10 S duration after which a
pacemaker was implanted. The patient had experienced such collapses before,
preceded by odd smell sensations. After the implantation of the pacemaker, the
patient did not collapse again but still experienced attacks of the same smell
sensations combined with a strange feeling in his stomach. An EEG, recorded
during such an attack, showed epileptic activity predominantly over the right
hemisphere while at the same moment a pacemaker rhythm was observed. After the
epileptic activity had stopped, normal sinus rhythm reappeared. On anticonvulsant
therapy the attacks disappeared completely.
PMID- 9545739
TI - [Cancer incidence in the area of Schiphol in 1988-1993].
PMID- 9545740
TI - [Puerperal fever: an old enemy in aggressive form].
AB - Two previously healthy women, aged 30 and 35 years, suffered pain in the lower
abdomen, one before and the other after spontaneous delivery at 40 and 33 4/7
weeks of amenorrhoea, respectively, while a third woman, aged 33, at 36 weeks of
amenorrhoea developed pain in the lower abdomen, fever, vomiting, and diarrhoea.
All three women were found to have a uterine infection caused by streptococci of
Lancefield group A (group A Streptococcus, GAS). In one woman, the diagnosis was
made rapidly so that antibiotic treatment could be instituted in time; the other
two developed sepsis and multiorgan failure, with a fatal issue in one of them.
The three children also were septic, two recovered after treatment and one died.
Since the eighties, serious GAS infection has been on the increase. The worst
manifestation is the toxic shock syndrome caused by streptococci. Abdominal pains
after delivery may be a first sign of this, and should not too readily be
interpreted as just after pains. The condition may also develop before delivery.
In view of the high mortality rate, early diagnosis and antibiotic treatment are
of vital importance for mother and child.
PMID- 9545741
TI - [Is the pulmonary artery catheter discredited because of ignorance?].
AB - Recently in an observational study the use of a pulmonary artery catheter in
critically ill patients was associated with an increase in both mortality and
utilization of resources when compared with case-matched control patients. The
authors corrected for selection bias by using a propensity score. The publication
of this article elicited a flood of commentary in both medical journals and the
lay press. Critical assessment of this study and other studies about pulmonary
artery catheterization in our opinion supports the view that it is probably not
the use of the catheter itself, but physicians' insufficient knowledge of right
heart catheterization and the specific treatment resulting from its use that is
at fault.
PMID- 9545742
TI - [Immunology in medical practice. III. Disseminated lupus erythematosus: disturbed
apoptosis?].
AB - The main feature of systemic lupus erythematosus (SLE) is formation of
antinuclear antibodies, particularly against double-stranded (ds) DNA. This
autoimmune response is T cell- and (auto)antigen-dependent, but dsDNA is very
poorly immunogenic. Recent data suggest that the nucleosome is the principal
autoantigen in SLE. DNA is present in the circulation of SLE patients in the form
of nucleosomes. In vivo, nucleosomes can only be generated through apoptosis.
There is increasing evidence that apoptosis is disturbed in murine and human SLE.
Nucleosomes have a high affinity for heparan sulphate in the glomerular basement
membrane. By forming complexes with nucleosomes, antinuclear antibodies (both
nucleosome-specific and anti-dsDNA autoantibodies) acquire a high affinity for
the glomerular basement membrane, an initial key event in the development of
lupus nephritis.
PMID- 9545743
TI - [Drug treatment of prostatic carcinoma].
AB - The basis for the medical treatment of prostate cancer is inhibition of the
influence of testosterone on the prostate. Surgical castration is in 1997 still
the gold standard; it reduces the testosterone level by 90% and the level of
dihydrotestosterone (the active metabolite) by 60%. In the eighties luteinising
hormone releasing hormone (LH-RH) analogues were introduced to avoid the
psychological burden of castration. After an initial stimulation (the flare-up)
testosterone decreases to castrate level within 3 weeks. Recently (non-steroidal)
anti-androgens, competitive inhibitors of dihydrotestosterone on receptor level
were introduced. There are also drugs which inhibit the conversion of
testosterone to dihydrotestosterone: 5 alpha-reductase inhibitors. Non-steroidal
anti-androgens and 5 alpha-reductase inhibitors do not decrease the testosterone
level and therefore cause less loss of libido and energy than castration.
Combination of (chemical) castration and anti-androgens is called maximum
androgen blockade. This treatment has limited additional value in proportion to
the increase in side effects and costs. A new form of treatment is intermittent
androgen blockade. With this strategy growth of hormone-insensitive cells in the
prostate, which is considered the main determinant of the poor prognosis, might
be delayed with reduction of side effects and costs. The role of imidazoles is
still investigated; the role of cytotoxic drugs is mainly palliative.
PMID- 9545745
TI - [Alleviation of inoperable malignant colon stenosis using endoscopic placement of
an endoprosthesis].
AB - Treatment modalities for patients with an obstruction due to an irresectable
malignant stenosis of the colon are: a palliative colostomy proximal of the
obstruction, radiotherapy, laser therapy, cryosurgery, and photodynamic therapy.
In 4 patients, 3 men and 1 woman of 70, 66, 74, and 38 years respectively with
obstruction ileus caused by an irresectable distal colonic carcinoma, a self
expanding wallstent was successfully placed endoscopically in the stenosis of the
latter three as a palliative measure, resulting in the unimpeded passage of
faeces and intestinal gas.
PMID- 9545746
TI - [Abdominal wall metastasis following surgical removal of colorectal carcinomas].
AB - Abdominal wall metastases after laparoscopic resection of colorectal cancer have
been reported by various authors. It appeared that abdominal wall metastases
occur more frequently after laparoscopic than after conventional, open resection
of colorectal cancer. However, the frequency of abdominal wall metastases after
laparoscopic surgery varies from only 0 to 1.9% in centres with sufficient
relevant experience, whereas after conventional resections the frequency is 0.8
3.3%. A randomized clinical study comparing laparoscopic with conventional
resection of colon cancer is necessary to assess the optimal surgical approach to
colon cancer. Such a trial has been set up.
PMID- 9545747
TI - [The 'Colon cancer laparoscopic or open resection' (COLOR) trial].
AB - The value of laparoscopic surgery for colorectal malignancy as compared with open
surgery will be determined in the COLOR-trial. The disease-free survival time is
the primary end point. Twenty-one hospitals in the Netherlands and Scandinavia
will participate in the trial. In the COLOR trial 1500 patients with colon
carcinoma will be randomised for either a laparoscopic or open colon resection.
PMID- 9545748
TI - [Temperature measurement using the tympanic membrane infrared meter].
PMID- 9545749
TI - [The 'medical work disability criterion'].
PMID- 9545750
TI - [Hodgkin's disease].
PMID- 9545751
TI - [Communication between treating physician and occupational physician in the
monitoring of illness absenteeism].
PMID- 9545752
TI - [Amebic abscess in the liver; early suspicion, late detection].
PMID- 9545754
TI - Plasma concentrations of antipsychotic drugs in psychiatric inpatients.
AB - In current psychiatric therapy, two or more kinds of antipsychotic drugs are
usually prescribed in Japan. However, there are few data on the therapeutic
plasma concentrations of antipsychotic drugs or on the correlation between the
daily dose and the plasma concentration, in cases where several antipsychotic
drugs had been prescribed for each patient. We measured the therapeutic plasma
concentrations of 9 antipsychotic drugs in 24 psychiatric inpatients during a 6
month period. They were treated with fixed dosages of antipsychotic drugs. Plasma
samples were collected early in the morning once a month, and the concentrations
of antipsychotic drugs were determined by gas chromatography with nitrogen
phosphorus detection, high-performance liquid chromatography (HPLC) with
fluorescence detection and HPLC with UV detection. The plasma levels of
chlorpromazine, levomepromazine, thioridazine, haloperidol, bromperidol,
zotepine, oxypertine, sulpiride and sultopride were 21.8-92.4, 31.7-156, 101-203,
16.4-56.2, 2.72-11.7, 13.6-84.0, 29.9-80.4, 70.1-1,120 and 35.7-2,990 ng/ml,
respectively. A linear correlation between the daily dose and the plasma
concentration was noted for sultopride, levomepromazine, sulpiride, haloperidol,
chlorpromazine and zotepine.
PMID- 9545753
TI - Genetic polymorphisms detectable in human urine: their application to forensic
individualization.
AB - This review describes several types of genetic polymorphism, which have recently
been identified in human urine in our laboratory, and have also been found in
other human body fluids such as blood, saliva and semen. These include
uropepsinogen, ribonuclease, deoxyribonuclease I (DNase I), deoxyribonuclease II
(DNase II), 43-kDa glycoprotein, alpha-L-fucosidase, glutamate pyruvate
transaminase, alpha-2-HS-glycoprotein, transferrin and vitamin D-binding protein.
Several substances can be detected more easily in urine than in plasma. The
concentrations of uropepsinogen, DNase I and DNase II in blood plasma are too low
for analysis, whereas those in urine are high enough for easy typing. In
practice, DNase I-polymorphism is one of the most useful genetic markers for
practical purposes, because of its higher content in various body fluids
including urine, a well-balanced gene frequency, and its easy and accurate
detectability. Furthermore, several genetic markers previously identified in
blood and/or other forensic samples can be phenotyped reproducibly and easily
from the corresponding urine samples. Thus, urine, in addition to the convenience
and non-invasive nature of its collection, is by no means inferior to blood as a
sample source for typing in the field of forensic science. Biochemical and
serological typing of genetic polymorphisms present in human urine could offer
useful information to practising forensic biologists for forensic
individualization of urine samples.
PMID- 9545755
TI - [Analysis of sudden death caused by intestinal obstruction].
AB - Five autopsy cases of sudden death caused by intestinal obstruction are reported.
The causes of death of the cases were duodenal obstruction of impacted food
stuff, ileocaecal obstruction caused by Crohn's disease, incarceration of
inguinal hernia, intestinal obstruction caused by heterotopic pancreas and
paralytic ileus. In three cases, the patient was in cardiopulmonary arrest on
arrival at hospital, and in the remaining cases the patient died within 12 hours
from the beginning of treatment; therefore, a correct clinical diagnosis was not
made before the death in all cases. All the patients had from one to three days
history of nausea and abdominal pain, major complications of intestinal
obstruction. Among all cases, the duration from the onset to death was the
shortest in the case of a patient complicated with schizophrenia. It is
characteristic that the patients of all cases died suddenly and resuscitation was
not successful. Regarding the laboratory data of a hospitalized patient, marked
hemoconcentration and an increased level of BUN/Cr ratio and blood sugar were
shown. The patient who died from duodenal obstruction caused by impacted food
stuff had suffered from depression for six years, and the patient who died from
paralytic ileus had suffered from schizophrenia for about 23 years. In both
cases, it is characteristic that the complaints of the patient were poorer than
what would be expected. Furthermore, these patients had been taking medication of
psychotic, anti-depressant and anti-parkinsonism drugs; therefore the combination
of these drugs was thought to be reflected in the bowel movement.
PMID- 9545756
TI - Determination of sibship by microsatellite typing in a deficiency case of
disputed maternity: further study.
AB - In a deficiency case of maternity dispute where the father and his two wives were
dead and only the six children were available for testing, we analyzed three sex
linked short tandem repeat (STR) loci DYS19, HPRT, and AR. On the basis of the
typing results of the HPRT and AR loci, we obtained probabilities of maternity
ranging from 0.9256 to 0.9724 for five of the six children. The results supported
those of typing for 24 conventional hemogenetic markers and 11 autosomal STRs,
enabling us to establish maternity. The present study demonstrates the utility of
sex-chromosomal STR typing in the solution of deficiency cases of disputed
parentage.
PMID- 9545757
TI - [A simple technique for the genotyping of TH01 locus].
AB - It is difficult to differentiate between type 9.3 and 10 at the TH01 locus.
Therefore, we designed three primers including allele-specific primer for the
type 9.3. Our primer sets gave shorter fragments ranging from 62 to 81 bp than
those in other reports, allowing each allelic band to be resolved by 10% non
denaturing polyacrylamide gel electrophoresis and stained with SYBR Green I. TH01
typing was successfully applied to human remains such as sera, whole bloods and
blood stains made about 80 years ago without extracting DNA from them. The simple
and fast methods for TH01 typing as demonstrated herein will be useful in the
field of forensic practice.
PMID- 9545758
TI - A case of disseminated intravascular coagulation probably arising from sudden
infant death syndrome.
AB - The cause of death in a 45-day-old male infant who was found apneic at home and
died 21 hours later was disseminated intravascular coagulation (DIC). The patient
was admitted to a hospital in a state of cardio-respiratory arrest. The initial
diagnosis was interrupted sudden infant death syndrome. The patient remained
apneic, and recurrent discharge of bloody stool was the dominant clinical
findings. He died without spontaneous respiration being restored. The autopsy
revealed hemorrhages in the lungs and the ventricular septum and the free wall of
the left ventricle of the heart. Microscopically, fibrin thrombi were noted in
the large intestine and heart. The DIC was probably triggered by a widespread
endothelial injury caused by severe hypoxia and acidosis originating from the
apnea and cardiac arrest lasting longer than 30 min.
PMID- 9545759
TI - A sudden death case from retropharyngeal abscess.
AB - A sudden death case, a 21-year-old man, from retropharyngeal abscess is reported.
It seemed to be caused by an injury in the posterior wall of the pharynx by an
ingested foreign body. Because he had never consulted a doctor, it had grown
large in several days and ruptured into the pharynx, and he died suddenly from
airway obstruction by the inhaled pus.
PMID- 9545760
TI - [An autopsy case of carbon dioxide intoxication].
AB - A 44-year-old male, engaged in the transportation of dry ice, was found dead on
the floor of the freezer of his refrigerator car which was parked in front of the
place where he was scheduled to make a delivery. Autopsy was performed to
investigate the cause of death. Apart from the signs of acute death, no other
significant findings were obtained, either macro or microscopically; carbon
dioxide poisoning was thus strongly suspected. We created a simulation experiment
by using the refrigerator car to reproduce the events of the accident. The oxygen
concentration in the freezer was 21.0% as indicated by oxygen sensors, but
decreased to 17.1-17.4% when the engine was stopped. This decrease in oxygen
concentration supposedly results from the production of carbon dioxide by the
vaporization of dry ice. Carbon dioxide concentration in the air could be
calculated from the change in the oxygen concentration in the closed space of the
freezer. The concentration was assessed at 17.1-18.6%. An oxygen concentration of
17.1-17.4% does not of itself cause serious hypoxia, but a carbon dioxide
concentration of 17.1-18.6% probably causes serious intoxication, because this
value is beyond that of intoxication levels published in references. Therefore,
we concluded that the cause of death in this case was carbon dioxide
intoxication.
PMID- 9545761
TI - [A case of dural sinus thrombosis during the medication of medroxyprogesterone
acetate].
AB - It is reported that medroxyprogesterone acetate (MPA) causes venous thrombosis as
one of the side effects. A 49-year-old woman suffering from metastatic lung
carcinoma from breast carcinoma was administered MPA 1200 mg/day for about four
months. Thereafter she complained of dizziness about two weeks but the general
practitioners could detect no abnormality on physical examinations and on brain
CT X-ray findings. Six days later, she died suddenly at her home. Forensic
autopsy findings revealed the marked superior sagital sinus thrombosis and the
malignant lymphadenomatosis caused by metastatic lung carcinoma. As the patient
had not disease or trauma causing dural sinus thrombosis except for the
administration of MPA, we concluded that superior sagital sinus thrombosis was
due to the medication of MPA. This case illustrates that forensic pathologist
should consider the major side effect of some drugs like our case.
PMID- 9545763
TI - [The influence of age and sex on the results of otosclerosis surgery].
AB - The influence of age and sex on auditory improvement after stapes surgery was
investigated retrospectively on 127 otosclerotic ears (99 subjects) that were
followed up for 6 months postoperatively. The prostheses used were the Shuknecht
type Teflon wire piston (87 ears), the House-type wire loop (29 ears), and the
Cawthone-type Teflon piston (11 ears). While closure of the air-bone gap after
surgery was good at 2 kHz, it was poor at 8 kHz and frequencies lower than 1 kHz,
and especially poor at 250 Hz. At all frequencies, both air and bone thresholds
were significantly improved by the surgery, but the greatest improvements in air
and bone thresholds resulted from the use of Teflon wire pistons. Ears receiving
Teflon wire prostheses were divided into 5 age groups: under 20 years, 20-29, 30
39, 40-49, and 50 or above. Both air and bone thresholds at higher frequencies
before surgery worsened with increasing age. However, there were no significant
differences among age groups in the postsurgical improvement of either air or
bone thresholds. Similarly, no gender-related differences in either air or bone
thresholds were recognized postsurgically. The authors speculate that light cases
of otosclerosis are common among Japanese patients, while severe cases are rare
even among the elderly.
PMID- 9545762
TI - Forced double suicide by fire revealed by autopsy and toxicological examination:
a case report.
AB - We report here a forced double suicide by fire. Two burned bodies discovered in
the debris of a house fire were identified as a father and his son by
odontological findings. In the father, the concentration of carboxyhemoglobin (CO
Hb) in the left ventricle was over 90% and endrin, an organochlorine pesticide,
was also detected in the stomach contents. However, 30.5% of CO-Hb in left
ventricular blood and gasoline traces from an intratracheal puncture were
detected in the son who had been undergoing treatment at a neuropsychiatric
clinic. From these results, we determined this case to be a double suicide forced
by the father in which the father set a fire with gasoline, thus burning his son
to death, and then died in the fire himself after ingestion of Endrin. This case
suggests the importance of integration of the results from the detailed forensic
pathological and toxicological examinations and the scene investigation.
PMID- 9545764
TI - [Facial nerve anomalies of children with congenital anomalies].
AB - It is well known that congenital anomalies are often associated with malformation
of the inner, middle and external ear. In temporal bone studies, it has been
found that abnormality of the facial nerve often occurs in patients with
congenital aberrations. The temporal bone collections of the Teikyo University
School of Medicine include 32 human temporal bones obtained from 19 infants
ranging in age from one day to 7 months, who had chromosomal aberration and
severe visceral anomalies. We histologically studied routinely processed sections
of these temporal bones under a light microscope. Facial anomaly was observed in
20 of the 32 ears (63%). An abnormal course was observed in 18 ears (56%); 5 ears
showed hypoplastic development, 4 showed displacement of geniculate ganglion
cells into the internal auditory meatus, and 3 ears showed bifurcation. Abnormal
course of the facial nerve was found in a significant number of ears with aural
and mandibulal abnormalities (76%). However patients with multiple inner ear
anomalies showed an abnormal course and hypoplasia of the facial nerve. There was
no correlation between the incidence of facial abnormalities and inner ear
anomalies.
PMID- 9545765
TI - [Silicon of the medium in the postoperative maxillary cyst].
AB - As part of a study on chronic inflammatory disease of the mucous membrane,
silicon of the medium in postoperative maxillary cysts and in other cysts was
measured, and following results were obtained. Silicon concentrations of the
medium in the postoperative maxillary cysts and in the postoperative ethmoidal
cysts were 34.5 ppm and 42.9 ppm (geometrical mean) respectively, and they were
higher than in other primary cysts such as frontal cyst, nasal vestibular cyst,
and dental cyst. The silicon content of the medium in the postoperative maxillary
cyst varied with the water content of the medium; the lower the water content the
higher was the silicon content and the relationship was expressed by the
following equation. log S = 7.43 + 7.14 log d-6.14 log w, where S = Si (mcg), d =
dry weight (g.) and w = wet weight (g.). The high concentration of silicon in the
postoperative cyst was considered to be due to the large amount of silicon
transudate from the surrounding fibrous tissue through a highly damaged or
missing epithelial wall of the cyst.
PMID- 9545766
TI - [Telomerase activity of tumors in the head and neck].
AB - Telomerase is a maintaining enzyme of telomere repeats. Telemorase is expressed
in immortal and cancer cells, but not in the normal tissues. We investigated
telomerase activity of tumors in the head and neck. Telomerase activity was found
in all of the cell lines derived from squamous cell carcinomas of the head and
neck. Six of 9 (67%) primary fresh tissues from squamous cell carcinomas of the
head and neck contained detectable telomerase activity. There were no apparent
relationship between telomerase activity and clinical stage. Telomerase activity
differed, depend on the responses to chemotherapy and radiotherapy: complete
response, 0 of 3(0%); partial response; 0 of 1(0%); no change; 7 of 7 (100%).
Therapy-resistant tumor seemed to have much telomerase activity and much
malignant potential. In benign tumors, neither of 2 benign parotid tumors
expressed telomerase activity, but one of 2(50%)papillomas had the telomerase
activity. Telomerase is considered useful tumor marker for the diagnosis and
prognosis.
PMID- 9545767
TI - [Cyclin D1 overexpression in laryngeal carcinomas].
AB - Overexpression of cyclin D1 has been found in a variety of malignancies and is
suggested to be related to tumor progression. We immunohistochemically
investigated the overexpression of cyclin D1 protein in 92 laryngeal carcinomas.
Twenty-eight (30.4%) of the carcinoma specimens showed overexpression of cyclin
D1. This overexpression was not related to the tumor stage, lymph node
metastasis, or clinical outcome. However, the overexpression of cyclin D1 in
patients with local recurrence was significantly higher than in patients with no
recurrence. Cyclin D1 immunohistochemical staining is considered to be a useful
marker for predicting tumor recurrence.
PMID- 9545768
TI - [Clinical investigation of lymph node metastasis in carcinoma of the
hypopharynx].
AB - Carcinoma of the hypopharynx has a great tendency to metastasize to the neck. In
addition it often metastasizes to the upper retropharyngeal lymph nodes
(Rouviere's lymph nodes) and to the paratracheal lymph nodes. In this study, in
order to determine the pattern of lymph node metastasis, 112 patients with
carcinoma of the hypopharynx who had undergone bilateral radical neck dissection,
bilateral paratracheal dissection, bilateral dissection of retropharyngeal nodes
as an initial treatment between January 1982 and June 1997 in the Kurume
University Hospital, were retrospectively reviewed in detail. Special attention
was paid to retropharyngeal nodes and paratracheal lymph nodes. In N0 cases neck
metastases were seen in more than one-quarter of the patients. Metastasis to
retropharyngeal lymph nodes and to the paratracheal lymph nodes was seen in 5.4%
and 12.5% of the patients, respectively. The frequency of metastasis to
paratracheal lymph nodes had a significantly close relationship with that to the
upper and lower jugular lymph nodes. The frequency of metastasis to
retropharyngeal lymph nodes also had significantly close relationship with that
to paratracheal lymph nodes, while having no relationship with that to other neck
lymph nodes. These results suggest the following: 1) In patients with T1 or T2 PS
type carcinoma of the hypopharynx, in which the lesion is confined unilaterally
and is presumed to have been successfully treated by laser surgery prior to
radiotherapy, unilateral neck dissection alone will be sufficient. In all the
other patients with carcinoma of the hypopharynx bilateral neck dissection must
be performed. 2) In all patients retropharyngeal lymph nodes and paratracheal
lymph nodes should be dissected as much as possible and postoperative irradiation
to both areas will be necessary.
PMID- 9545769
TI - [Optokinetic nystagmus under prolonged alteration in the direction of gravity].
AB - Optokinetic Nystagmus (OKN) exhibit different responses depending on the
direction of gravity, with respect to head and body. In 13 normal healthy
volunteers (10 experimental subjects and 3 controls), we studied the OKN evoked
by horizontal and vertical stimuli, in upright, side-lateral, and repeated
upright positions during a long time course of six test stages. Stage 1 was an
upright sitting position. Stage 2 was a 90-degree recumbent lateral position
immediately after Stage 1. Stage 3 was the same position as in Stage 2, but 2h
later. Stage 4 was the same position, another 2h later (total of 4h). Stage 5 was
a return to the upright position (the same as Stage 1) immediately after Stage 4.
Stage 6 was a return to the same upright position, 2h after Stage 5. The results
showed continuous modifications of OKN. A lateral tilt produced different effects
on the horizontal and vertical optokinetic oculomotor systems. The gain in
horizontal OKN (HOKN) decreased during Stages 2-4 with time, and returned to
normal in Stages 5 and 6. As for vertical OKN (VOKN), the gain of upward (the
direction by slow phase) OKN increased during Stages 2-4, and returned to normal
in Stages 5 and 6. But the gain of downward OKN did not show any clear
modulation. We showed that the change in gravity direction has a clear effect on
OKN, and that it takes some time to reach the maximal and desirable level of
modification. The difference in time-dependent modifications between HOKN and
VOKN should be due to the difference in OKN-producing mechanisms and velocity
storage systems.
PMID- 9545770
TI - Staged intact canal wall tympanoplasty for treatment of middle ear cholesteatoma.
AB - Results of surgery for middle ear cholesteatoma were investigated in 202 ears of
197 patients who had undergone surgery by the staged intact canal wall technique.
Surgical procedures used in the second stage for prevention of a retraction
pocket were classified into three types: Type S1, no scutumplasty; Type S2,
scutumplasty; Type S3, scutumplasty plus mastoid obliteration. Recurrent
cholesteatoma was found in 9 ears (4%) and retraction pocket in 47 ears (23%).
They occurred between 2 and 120 months (average: 26 months) after the second
stage, most frequently at 1 to 3 years. The incidence was higher after Type S3
surgery than after the other types, probably because the middle ear was severely
involved in patients who were indicated Type S3 surgery. For prevention of a
retraction pocket, bone putty and cartilage were proved to be appropriate
materials for scutumplasty, and hydroxyapatite for mastoid obliteration. As the
retraction pocket tended to recur in patients with the pocket at the second
stage, these patients needed obliteration of the mastoid cavity to prevent a
retraction pocket. Postoperative hearing was evaluated according to the criteria
proposed by the Japan Society of Clinical Otology. Of 145 ears of the 142
patients who were followed for more than 1 year, 118 ears (81%) the surgery was
judged successful. The success rate in hearing was in good accordance with the
condition of the tympanic membrane.
PMID- 9545771
TI - [Molecular biology of hereditary dystonia].
AB - The causative genes of hereditary dystonia (hereditary progressive dystonia, HPD;
dopa-responsive dystonia, DRD) were discovered in 1994-1995. HPD/DRD is caused by
the deficiency of dopamine to less than 20% of the normal level in the nigro
striatum of the brain owing to the mutations of the dopamine synthesizing
enzymes. Autosomal dominant dystonia (Segawa's disease) was found to be caused by
mutations of GTP cyclohydrolase I which synthesizes tetrahydrobiopterin, the
cofactor of tyrosine hydroxylase, by Ichinose et al. (Nature Genetics, 1994) in
Japan. Autosomal recessive dystonia was reported to be caused by mutations of
tyrosine hydroxylase by Ludecke et al. (Human Genetics, 1995) in Germany.
Hereditary dystonia, especially autosomal dominant Segawa's disease can be
completely controlled by L-dopa administration. Measurement of the activity of
GTP cyclohydrolase I in mononuclear blood cells is useful for the diagnosis of
Segawa's disease.
PMID- 9545772
TI - [Bioethics in severely neurologically disturbed children].
AB - Informed consent is essential for bioethical considerations when physicians treat
severely neurologically disturbed children. Because these patients are immature
for their decision-making, proxy consent must be given to their physicians by
their guardian to accept within agreeable limits of treatments and care for them.
Prior to obtaining the consent, given by their guardians, physicians are obliged
to provide their guardians with necessary informations regarding patients'
physical conditions and details of procedures for proposed treatments, as well as
possible risks involved in these treatments and care to be provided. Clinical
applications of bioethical considerations are given to the patients with
following diseases: spina bifida cystica and other neural tube defects,
congenital metabolic disorders such as cretinism and phenylketonuria, malignant
tumors such as neuroblastoma and retinoblastoma, and intractable epilepsy.
Bioethical considerations are also given to prenatal diagnosis for early
discovery, diagnosis and possible treatments of severely neurologically disturbed
fetuses.
PMID- 9545773
TI - [The results of recent research in neurocutaneous syndromes].
AB - Identification of NF1, TSC2 and TSC1 genes has enabled us to focus on their
function and regulation. Evidence suggests that these genes are tumor suppressor
genes. Malignant tissues in NF1 and hamartomatous tissues in TSC show "loss of
heterozygosity" in NF1 and TSC1, 2 genes, respectively. In addition, in the Eker
rat with hereditary renal carcinoma, a mutation in the TSC2 gene has been
identified. In this review I mentioned briefly several issues to be clarified in
the near future.
PMID- 9545774
TI - [Pathophysiology and therapeutic approach in inflammatory demyelinating
polyneuropathy--recent advances].
AB - Recent advances on pathogenetic mechanism and therapeutic approach for Guillain
Barre syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIPD)
were briefly reviewed. As for GBS, an axonal form has been recognized as a
clinicopathological variant, in which Campylobacter jejuni infection and elevated
anti-GM1 antibody tires are frequently observed. Other anti-glycolipid antibodies
to GQ1b, GD1b and GM2 would also be significant as a determinant factor for a
clinical phenotype. Beneficial effects of IVIg therapy and plasmapheresis have
been established. Although CIDP has also been considered to be demyelinating
neuropathy, axonal pathology is frequently noted, and in such cases, a
substantial motor neuron loss is present. Clinical recovery in the cases with
high anti-MAG and anti-SGPG titers is not necessarily favorable. Corticosteroid
therapy, plasmapheresis and IVIg have been all established as therapies
beneficial for CIDP.
PMID- 9545776
TI - [The progress and strategy of molecular diagnosis for human genetic diseases].
AB - Recently, the human genome project has progressed and the responsible genes for
many diseases have been discovered. Molecular diagnosis based on gene analysis
techniques has developed. In this paper, the methods in molecular diagnosis were
explained, taking as examples of several pediatric neurological diseases such as
GM1- gangliosidosis, fragile X syndrome and congenital myotonic dystrophy. Next,
we stressed the importance of the study on the gene function in related to the
gene mutation. Finally the strategy to establish the molecular diagnosis of
polygenic diseases, such as mental retardation and autism, was considered.
PMID- 9545777
TI - [Molecular analysis of peroxisomal disorders].
AB - Peroxisome biogenesis disorders (PBD) include Zellweger syndrome (ZS), neonatal
adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD). They are
classified into ten complementation groups. Five pathogenic genes have been
identified using different model systems of peroxisome deficient mutants. PAF-1
and 2 were identified from CHO mutants and were responsible genes for PBD group F
and C. Human PEX 5, 12 and 1, responsible genes for group 2, 3 and 1,
respectively, were cloned by homology search between yeast PEX genes and human
genes on the cDNA data base. Adrenoleukodystrophy (ALD), the most frequent
peroxisomal disorder, shows phenotypic heterogeneity. Its responsible gene was
cloned by positional cloning. It encodes a 75 kDa peroxisomal membrane protein
(ALDP) that is a member of the ATP-binding cassette transporter family. There are
about 120 different mutations including missense, nonsense and splice mutations,
as well as insertions and deletions of a few base pairs. There is no correlation
between the clinical phenotype and the ALDP gene mutation. Recently, animal
models have been produced by targeted mutation of the PBD and ALD genes. The
mouse model should facilitate researches on PBD and ALD, especially those on
regulatory factors of their phenotypic heterogeneity and on new therapeutic
approaches.
PMID- 9545778
TI - [Molecular diagnosis of mitochondrial disorders].
AB - Mitochondrial disorders are caused by either nuclear or mitochondrial DNA
abnormalities. The latter but not the former can be examined as a means of
diagnosis at present. The peculiarities and problems of the mtDNA test depend
strongly on the characteristics of mtDNA itself, such as the multiplicity in
number, vulnerability to mutation, and maternal transmission. The mtDNA
abnormalities observed in patients with mitochondrial disorders indicate
heteroplasmy, tissue/cell specificity, and threshold effects. It should be
stressed that the presence of mutant mtDNA in an individual does not mean that he
or she is ill. The problems of the mtDNA test could be solved if the genotype
phenotype relationship is farther elucidated in the future study.
PMID- 9545779
TI - [Genetic diagnosis of Duchenne/Becker muscular dystrophy; clinical application
and problems].
AB - Duchenne/Becker muscular dystrophies (DMD/BMD) are the most common inherited
muscular disease and caused by mutations in the dystrophin gene. A half to two
thirds of DMD and BMD patients carry deletions (usually of several kilobases of
genomic DNA). The clinical progression in DMD and BMD patients with deletions can
be predicted in 92% of cases based on whether the deletion maintains or disrupts
the translational reading frame (frame-shift hypothesis). However, some
exceptional cases have been reported in which some posttranscriptional
modifications were suggested, such as alternative splicing and reinitiation of
translation. Splicing mutation is one kind of mutations of dystrophin gene, and
usually induced by a small mutation of exon-intron boundary sequence. However,
intraexonal small mutation also induces exon skipping, due to disruption of an
exon recognition sequence, which is an intraexonal sequence and necessary for
splicing of the upstream intron. Carrier diagnosis is one of the important
clinical application of genetic diagnosis. In the case of DMD/BMD with deletions
of the dystrophin gene, carrier diagnosis is difficult because of the existence
of normal X chromosome. In these cases a linkage analysis is useful, and in some
cases non-carriers can be directly diagnosed on the basis of microsattelite
polymorphism detected in deleted region of patient. For the molecular diagnosis
of DMD/BMD it is important to analyze not only at the genomic DNA level, but also
at the mRNA, protein, and clinical levels. And the relationship between the
molecular abnormality and clinical phenotype should be examined, especially
extramuscular symptoms such as heart failure and mental retardation.
PMID- 9545780
TI - [GM1-gangliosidosis knockout mouse].
AB - We generated a beta-galactosidosis mouse by gene targeting in an embryonic stem
cell. Clinical, pathological, and biochemical analyses revealed that this mouse
is a useful animal model to study the pathogenesis and therapy of human GM1
gangliosidosis.
PMID- 9545781
TI - [Topography, size and number of cortical tubers in tuberous sclerosis with West
syndrome].
AB - To predict the prognosis of tuberous sclerosis with West syndrome, we studied the
relation between the cortical tubers and the neurological evolution. We reviewed
the clinical data on the seizure evolution and developmental status of 7 patients
(3 males and 4 females) and estimated the number, size and location of cortical
tubers on 5 mm-thick T2-weighted MR images. The cortical tubers were grouped into
categories: small (10 mm or less in maximum diameter), medium (10 to 25 mm) and
large (25 mm or more). The first MRI study was performed at ages form 3 months to
18 years, and the follow-up study was performed on 6 out of the 7 patients. We
also estimated the interval change of cortical tubers. The average number of
cortical tubers was 12.1 per patient, being larger than the values previously
reported for the patients of tuberous sclerosis without West syndrome. However,
the numbers varied widely from 1 to 29. Two patients with good outcome had more
than 10 tubers, whereas two patients with poor outcome had less than 5 tubers.
All the patients with good outcome were female. Follow-up MRI in one patient
revealed a marked increase in the number of cortical tubers, from 15 (at the age
of 5 months) to 23 (at 4 years 2 months), which probably resulted from
physiological hypomyelination during infancy. Some tubers corresponded to a
electroencephalographic focus, whereas others did not. There was no difference in
the topography of cortical tubers between the patients with good prognosis and
those with poor prognosis. Thus, it was hard to make the prognosticate a case of
tuberous sclerosis based solely on the number and topography of cortical tubers
on MRI.
PMID- 9545782
TI - [Nonconvulsive status epilepticus in a patient with atypical severe myoclonic
epilepsy in infancy].
PMID- 9545783
TI - [Characteristics of drusen and changes in Bruch's membrane in eyes with age
related macular degeneration. Histological study].
AB - BACKGROUND: Different types of drusen and changes in Bruch's membrane have been
associated with age-related macular degeneration (AMD). METHODS: We compared 51
eyes with different stages of AMD with 40 age-matched controls using light
microscopy. The degree of calcification of Bruch's membrane, fragmentation of
Bruch's membrane, number of different types of drusen, and basal laminar deposit
(BLD) were assessed. RESULTS: In the macular area, the presence of basal laminar
deposit was most strongly associated with the presence of AMD. There was a
statistically significant difference observed in the degree of calcification and
fragmentation of Bruch's membrane in eyes with AMD as compared to controls. Eyes
with AMD displayed significantly more soft, confluent, and large drusen as
compared to controls. CONCLUSION: Calcification and fragmentation of Bruch's
membrane, soft, confluent, and large drusen and BLD but not hard drusen
correlated strongly with the histologic presence of AMD. Calcification and
fragmentation of Bruch's membrane seem to facilitate ingrowth of choroidal
neovascular membranes with consecutive development of exudative AMD.
PMID- 9545784
TI - [Epidermal growth factor (EGF) in tears in excimer laser photorefractive
keratectomy. Responsible for postoperative refraction and "haze"?].
AB - BACKGROUND: Corneal wound healing is of critical importance for the postoperative
outcome of excimer laser PRK. Wound healing is a complex biological process that
is well characterised at the microscopic level, but its regulation is poorly
understood at the molecular level. Among various cytokines, epidermal growth
factor (EGF) plays an important role in superficial wound healing. The synthesis
of EGF varies individually; therefore, by determining the EGF concentration in
the tear fluid, patients with increased wound healing activity might be traced.
METHODS: In this study we measured the EGF concentration pre- and postoperatively
in the tear fluid of 50 eyes using a ELISA test. The preoperative refraction was
between -2.00 and -10.00 dioptres. The maximum follow-up was 6 months. RESULTS:
Preoperatively, in all eyes the EGF concentration in the tear fluid was between
0.2 and 1.7 ng/ml. In contrast, 1 week postoperatively, these values increased
(0.21-22.50 ng/ml); 4 weeks postoperatively, the EGF concentration was in all
eyes back to preoperative levels. In eyes with high EGF tear fluid concentration
1 week after surgery, refraction at 6 months was outside the intended correction
of +/- 1.0 D. We could not find any correlation between EGF concentration and
"corneal haze". CONCLUSIONS: EGF may play an important role in postoperative
wound healing after excimer laser PRK. Investigations concerning a pharmaceutical
control of EGF should be undertaken.
PMID- 9545785
TI - [Capsular sack-fixed IOL implantation in pediatric cataract. Visual prognosis and
complications].
AB - BACKGROUND: The aim of the study was to evaluate results of visual acuity and
binocularity and complications after cataract surgery with primary capsular bag
fixated IOL implantation in children. MATERIALS AND METHODS: Thirty-three
children [mean age (+/- SEM) 6.9 +/- 2.9 years, range 3-12 years] accounting for
43 eyes, were examined before and after surgery (15 traumatic, 19 developmental,
and 9 congenital cataracts, of the latter two groups 9 unilateral and 19
bilateral cataracts). RESULTS: All eyes had a best corrected postoperative visual
acuity of 0.5 +/- 0.05. The postoperative visual acuity of the traumatic
cataracts was 0.6 +/- 0.07, of the developmental cataracts 0.5 +/- 0.07, and of
the congenital cataracts 0.2 +/- 0.05. Of the 43 eyes, 17 (40%) showed a best
corrected visual acuity of 0.5 or better. There was a positive correlation
between morphology (lamellar versus subcapsular opacification) and visual acuity
(0.7 +/- 0.07 versus 0.5 +/- 0.05; P < 0.05). Bilateral cataracts had a better
postoperative visual acuity than unilateral cataracts (0.7 +/- 0.07 versus 0.2 +/
0.05 P< 0.001) Stereopis was found postoperatively in 62% of the children. In
one eye a capsular bag-fixated IOL implantation was not possible, and so the IOL
was inserted in the sulcus. Four children presented with postoperative fibrin
formation. Posterior capsule opacification occurred in 19% of the eyes in which a
primary posterior capsulotomy had been performed. CONCLUSIONS: The prognosis of
visual acuity and the results of stereopsis in children older than 3 years
following capsular bag-fixated IOL implantation are very good. Both the
intraoperative and postoperative complication rates were low.
PMID- 9545786
TI - [Threshold-oriented suprathreshold perimetry and threshold value perimetry with
the Tubigen CC Automated Perimeter. A comparative study].
AB - BACKGROUND: We compared the standard suprathreshold strategy to the so-called
threshold splitting strategy with 5 and 2 dB steps. The aim of the study was to
establish whether the threshold splitting strategy had advantages over the
suprathreshold strategy that has been used to date. METHOD: We examined the 30
degrees visual field in 49 volunteers using suprathreshold perimetry and on the
same day threshold splitting perimetry on the Tubinger Automatic Perimeter CC. A
total of 191 test points were examined in suprathreshold strategy. Using the
threshold splitting strategy, 67 test points were examined, with a test-point
design similar to other perimeters with the threshold splitting strategy. The
criteria for inclusion in the study were central light sensitivity differences
greater than 25 dB, fixation better than 80% and an illumination class density <
2. RESULTS/DISCUSSION: The average duration of the examination using the
suprathreshold strategy was 2-3 min quicker than the threshold splitting strategy
in normal visual fields or small scotomas, but it took up to 15 min longer if
large scotomas were presents. Interpretation of the scotoma configuration showed
subjective differences: the smaller the scotoma, the greater the differences
because of the fact that threshold splitting perimetry utilizes test points that
are farther apart than those used in suprathreshold perimetry.
PMID- 9545787
TI - [Risks of 360 degree suture trabeculotomy].
AB - BACKGROUND: In 1995, Beck and Lynch reported a method to perform a 360 degrees
trabeculotomy by prolene suture introduced into Schlemm's canal. Because this
type of surgery has proved to have perils and can lead to extreme hypotony, even
a small series of cases must be reported. PATIENTS: Suture trabeculotomy was
planned in five eyes of four patients, 5 and 7 months old and 6 and 51 years old,
with primary congenital glaucoma, but completed in only two eyes. RESULTS: In one
child, suture trabeculotomy could be accomplished easily in both eyes. In the
first eye a 360 degrees-tomy was performed, in the second eye only a 180 degrees
tomy was done. Both eyes remained extremely hypotonic (4 mm Hg). In one eye
Schlemm's canal could not be disrupted by the suture; in another eye, Schlemm's
canal could be probed only for a short distance, and in one eye the suture went
the wrong way. CONCLUSIONS: Because a suture trabeculotomy can be transformed
into a normal trabeculotomy any time, the main problems of the 360 degrees-suture
trabeculotomy are not the possible technical difficulties, but that a successful
suture trabeculotomy is followed by extreme hypotony.
PMID- 9545788
TI - [Imaging the tear film and in vivo cornea. Initial results with a modified
confocal laser scanning ophthalmoscope].
AB - BACKGROUND: As the slit-lamp technique is an restrictive method for the in-vivo
examination and documentation of the multi-layer structure and the dynamics of
the tear film and the cornea, e.g. during wound-healing processes, our aim was to
find out whether it is possible to change the confocal laser scanning
ophthalmoscope (CLSO; Zeiss) into a high-resolution confocal laser scanning
microscope (CLSM) for the visualization of the anterior segments of the eye and
the tear film by adapting a special objective system. In order to gain
information concerning the function of such a cornea microscope we examined
selected patients with erosion or pterygium before and after operation and
subsequent phototherapeutic keratectomy (PTK), as well as some in-vitro corneal
surfaces after photorefractive keratectomy (PRK). MATERIAL AND METHODS: We
developed an objective adapter for the CLSO in order to focus the laser beam onto
anterior segments of the eye to visualize the tear film and the layer structure
of the cornea. By combining the long-distance objective or a contract objective
with different zoom-optic lenses it was possible to alter the scan field size and
so the magnification of the CLSM by a factor of up to 1000. RESULTS: The CLSM
provides a new method for the in-vivo examination of the tear film and its
dynamics as well as the thin layers of the cornea in real-time imaging technique
with high contrast and resolution in non-contact or contact procedures.
CONCLUSION: This system is a unique took for evaluating and monitoring the effect
of excimer laser ablation after PTK and PRK on the corneal surface and the
dynamics of the tear film. The application of this method causes no pain for the
patient.
PMID- 9545789
TI - [Image flicker frequency of television reading aids. Effect on reading comfort
for visually handicapped patients].
AB - PURPOSE: To compare reading speed and reading comfort between closed-circuit
television systems (CCTVs) with different image refresh rates. METHODS: Reading
speed was measured with three CCTVs that only differed in repeat frequency (50,
60 and 70 Hz) in 21 patients with age-related macular degeneration and 10
controls. We compared reading speed measured in syllables per minute of 16
different reading templates with about 500 syllables each. RESULTS: Reading speed
was equal with all CCTVs. Eighteen of 21 patients identified and disliked 50 Hz
CCTVs because the image quality was worse. An image quality of 70 HZ enabled
patients to use positive contrast with the best reading speed. CONCLUSIONS:
Although reading speed does not improve with increasing frequency, flickering of
50 Hz CCTVs is critical for low-vision patients. The preference of low-vision
patients for negative contrast image is more likely due to flickering with a
lower repeat rate and 70 Hz CCTVs may allow more comfortable reading in positive
contrast.
PMID- 9545790
TI - [Transplantation of amniotic membrane for reconstruction of the eye surface].
AB - Persistent defects of the ocular surface remain a therapeutic challenge that
often requires surgical intervention. Recently, the transplantation of human
amniotic membrane has been added to our therapeutic armentarium. This thick
basement membrane has distinct biological properties that influence cellular
differentiation and proliferation. Amniotic membrane obtained from cesarean
deliveries is prepared and cryopreserved under sterile conditions and can be
sutured onto the ocular surface. This procedure allows for reepithelialization of
persistent corneal ulcerations as well as filling of stromal defects. Amniotic
membrane can successfully be employed for ocular surface reconstruction following
large corneal excisions and in the context of limbal stem cell disease for
pterygium surgery as well as for various kinds of reconstruction of the
conjunctiva. Taken together, amniotic membrane transplantation can serve as a
valuable tool for ocular surface reconstruction, especially in the context of
impaired epithelial function.
PMID- 9545791
TI - [Comment on the contribution by C.-D. Quentin and H. Reiber: Aqueous humor
analysis in intraocular toxoplasmosis].
PMID- 9545792
TI - [Swelling in the area of a scar after injury to the orbital wall. Occult foreign
body].
PMID- 9545793
TI - [Immune privilege of the eye].
PMID- 9545794
TI - [Current principles of diagnosis and treatment of chronic lymphocytic B-cell
leukemia].
AB - Chronic lymphocytic leukaemia is the most frequent form of malignant
hematological diseases in the Western countries, it comprises 30-40% of all the
leukaemias and it manifests itself between 60-65 years of age. Clinical features
are caused in 93% of the cases by the accumulation and proliferation of
immunologically incompetent, anergic, long lived, CD5 positive B-lymphocytes,
expressing monoclonal IgM or IgD immunglobulin, in the bone marrow, the
peripheral blood, the lymphoid and in other organs. In the etiology genetic basis
is highly supposed, whereas affect of toxic agents and radiation exposure can be
neglected. The prognosis of patients is variable and is determined by the
clinical stage and the proliferative activity of the disease. Treatment is
indicated in intermediate and high-risk clinical stages only with signs of
disease activation on the basis of individual patient's risk. As first line
treatment, Chlorambucil is indicated in high doses. Results achieved by combined
chemotherapy are generally not superior compared to high-dose Chlorambucil
treatment. For patients who developed resistance to alkilating agents purin
analogues are recommended. Out of them the most favorable results had been
accumulated with Fludarabine as second line treatment. For minority of the cases
hemopoetic stem cell transplantation as the only curative therapeutic measure is
being introduced in an increasing number. This review gives an account of the
recent advances in the diagnosis and therapy of the disease.
PMID- 9545795
TI - [Assessment of cerebrovascular reactivity in patients with symptomatic and
asymptomatic atherosclerotic carotid artery lesions].
AB - AIMS: Strokes caused by hemodynamically significant internal carotid artery
stenoses and occlusions are believed to be embolic or hemodynamic of origin. The
aim of the study was to assess cerebral hemodynamic compromises of significant
carotid artery stenosis of occlusion using vasodilatory testing (acetazolamide
test) in asymptomatic and symptomatic patients. PATIENTS AND METHODS: 36 patients
with unilateral, hemodynamically significant carotid stenosis were investigated
using transcranial Doppler acetazolamide-test. There were 12 asymptomatic and 24
symptomatic patients. The middle cerebral artery mean blood flow velocity was
measured at rest and after intravenous injection of 1 g acetazolamide. The
absolute mean blood flow velocities and the cerebrovascular reactivity was
compared at the stenotic and non-stenotic side. In a further analysis the mean
velocities and the cerebrovascular reactivity values of the stenotic side were
compared. Results of acetazolamide test performed on 28 healthy volunteers were
used as control values. RESULTS: There were no side-differences between the
middle cerebral artery mean blood flow velocity and cerebrovascular reactivity
values in the asymptomatic group. In the symptomatic group, however middle
cerebral artery mean velocity and cerebrovascular reactivity after acetazolamide
was significantly lower on the stenotic side, than on the non-stenotic one.
Comparing the different groups non-stenotic sides did not differ to each other in
their cerebral blood flow velocity and cerebrovascular reactivity. In the
symptomatic patients, however, cerebral blood flow velocity and cerebrovascular
reserve capacity after acetazolamide was lower, than that of the stenotic side of
asymptomatic patients and controls. CONCLUSIONS: The transcranial Doppler is a
suitable method for detecting altered cerebral hemodynamics in significant
carotid stenosis. Impaired cerebrovascular reactivity may refer to the impairment
of cerebral autoregulatory mechanisms.
PMID- 9545796
TI - [Endoscopic subfascial vein dissection].
AB - Endoscopic subfascial dissection is an effective method for the interruption of
incompetent perforating veins. From 15th October to 15th December of 1995 11
patients underwent endoscopic subfascial sectioning. It is the first time to
apply this procedure in Hungary. A venous ulcer was found in 5 patients.
Endoscopic sectioning supplemented by extensive fasciotomy, without any
substantial complication. The method is recommended due to its reduced
invasiveness and fair results.
PMID- 9545797
TI - [Regulation of the cell cycle].
AB - The basic steps of the eukaryotic cell cycle process have been known for almost
half a century. The development of the molecular biological methods allowed the
identification of the cell cycle regulatory genes and their products. The cycline
dependent kinases as catalytic subunits of the multiprotein nuclear enzyme
complexes, regulate the cell cycle machinery in a direct way in complex with the
cyclins which appear periodically and the negatively modulating cyclin
inhibitors. To assure strategy of the cell for global survival during the DNA
injury, the Ataxia Teleangiectasia Mutator gene function has a supervisory role
in the coordination and parallel activation of the checkpoint control, p53 tumor
suppressor gene, GADD45 protein and of the DNA repair, thus prevents the
activation of the cell death program. The outlined regulator system gives an
opportunity to explain some of the phenomena related to tumor biology and
pharmacology.
PMID- 9545799
TI - [Pathogenesis of ophthalmopathy].
PMID- 9545798
TI - [Severe genital mycoplasma infection following cesarean section].
AB - Authors report a serious case of post-caesarean delivery endometritis caused,
probably exclusively, by genital mycoplasmas: Ureaplasma urealyticum and
Mycoplasma hominis. The initial treatment of the patient with various
penicillins, ceftriaxone, gentamicin, metronidazole and nystatine proved
ineffective. Subsequently, as microbiological tests turned out positive for
genital mycoplasmas, a therapy of doxycyclin was introduced and a full recovery
could be attained. Authors' experience is consistent with the observation of
American scientists that U. urealyticum is an important pathogen in post
caesarean delivery endometritis. Since the carriage of U. urealyticum in women is
frequent in Hungary, it is suggested that microbiological investigations related
to sectio caesarea always include tests for genital mycoplasmas.
PMID- 9545800
TI - [Questions about scientometry].
PMID- 9545801
TI - [FISH, interphase cytogenetics, gene rearrangements].
PMID- 9545802
TI - [Future development of platelet transfusion].
PMID- 9545803
TI - [Signal transduction BCR-ABL fusion protein: analysis of BCR-ABL functional
domains].
PMID- 9545804
TI - [Internal tandem duplication in the juxtamembrane domain of the Flt3 gene found
in leukemias].
PMID- 9545806
TI - [Constitutive activation of B cell antigen receptor-associated tyrosine kinases
in B cell leukemia/lymphoma lines].
PMID- 9545805
TI - [Constitutive activation of MAP kinase pathway and STAT pathway in AML].
PMID- 9545808
TI - [Regulation system of apoptosis contributes to the human pro-B leukemogenesis].
PMID- 9545807
TI - [Overexpression of differentiation inhibitory factor/nm23 in acute myeloid
leukemia].
PMID- 9545809
TI - [Scoring systems for predicting prognoses of the patients with AML treated
according to the Japan Adult Leukemia Study Group (JALSG) protocols].
PMID- 9545810
TI - [Short-term intensive therapy for adult AML].
PMID- 9545811
TI - [Leukemia specific chimeric protein as a target molecule for chemotherapy].
PMID- 9545812
TI - [Individualized treatment of leukemia patients by monitoring of minimal residual
disease (MRD) based on WT1 assay].
PMID- 9545813
TI - [Is the ABVD an optimal regimen for Hodgkins disease?].
PMID- 9545814
TI - [Long-term follow up of aggressive lymphoma patients treated with CAMBO-VIP-
clinical significance of a residual mass after otherwise successful
chemotherapy].
PMID- 9545816
TI - [Clinical significance of platelet-derived microparticles in thrombotic disease].
PMID- 9545815
TI - [Interaction between platelets and oxidised-lipid in thrombus formation].
PMID- 9545817
TI - [Basis of molecular cell biology on thrombosis: in the cases of protein C
deficiency and protein S deficiency].
PMID- 9545818
TI - [Potential mechanisms of thrombogenesis in antiphospholipid syndrome].
PMID- 9545819
TI - [Fluid shear stress-mediated signal transduction in endothelial cells: temporal
signaling events].
PMID- 9545820
TI - [Adenovirus-mediated local expression of TFPI eliminates shear stress-induced
recurrent thrombosis in the injured arteries].
PMID- 9545821
TI - [Molecular analysis and gene therapy in Fanconi anemia].
PMID- 9545822
TI - [Gene analysis of hereditary red cell membrane disorders].
PMID- 9545823
TI - [Prospects for gene therapy for chronic granulomatous disease with gp91-phox
deficiency].
PMID- 9545824
TI - [Mutation of WASP in Wiskott-Aldrich syndrome and it's effect on
megakaryopoiesis].
PMID- 9545825
TI - [Mechanism of tumorigenesis and cell cycle dysregulation in ataxia
telauqiectasia].
PMID- 9545826
TI - [Molecular analysis of hemophilia A].
PMID- 9545827
TI - [Severe hepatic veno-occlusive disease (VOD) which was successfully treated with
supportive therapy, but subsequently developed late-recurrence].
AB - A 40-year-old man with chronic myelogenous leukemia in chronic phase received an
allogeneic marrow graft from his HLA identical brother. He was conditioned with
busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg). Graft-versus-host disease
(GVHD) prophylaxis was attempted with cyclosporine A (CYA) and methotrexate. On
day 30, weight gain, ascites and hepatomegaly developed in addition to an
elevation of total bilirubin (TB). He was diagnosed as having veno-occlusive
disease (VOD) and treated conservatively. The TB level increased up to 20.1 mg/dl
on day 66, then reduced to 2.1 mg/dl on day 129. By that time ascites and
hepatomegaly also had completely resolved. However, on day 134. The TB level
started to increase again, when the lesions of chronic GVHD were observed in the
eye, the mouth, and the skin. CYA was started on day 142, and FK506 was
substituted for CYA on day 161. Despite the improvement of oral and skin lesions,
TB level continued to rise, and he died of respiratory failure due to ARDS on day
186. Autopsy revealed both acute and old hepatic VOD lesions, suggesting the
occurrence of late-onset VOD which probably contributed to the liver dysfunction
observed after clinical resolution of the first episode of VOD.
PMID- 9545829
TI - [Fatal pulmonary thromboembolism in a patient with paroxysmal nocturnal
hemoglobinuria].
AB - A 38 year old woman with paroxysmal nocturnal hemoglobinuria was admitted to our
hospital because of hemoptysis. Pulmonary infarction was diagnosed by the
perfusion lung scan. In spite of the administration of prednisolone, dextran, low
molecular weight heparin, and warfarin, she died of pulmonary infarction and
secondary pulmonary hypertension. Autopsy revealed thromboembolism of both
pulmonary arteries and hepatic central vein thrombosis. Recent understanding of
the pathogenesis and incidence of thromboembolism in paroxysmal nocturnal
hemoglobinuria was discussed.
PMID- 9545828
TI - [Abnormal hemoglobinopathy (HbE) diagnosed from microcytic hypochromic red blood
cells in a 31 year-old Bangladeshian male].
AB - Microcytic hypochromic red blood cells (RBC) were discovered in a 31 year-old
Bangladeshi man. Additional laboratory data revealed only slight elevations of
LDH and transaminase activities. The patient was clinically asymptomatic and
showed no signs of anemia. On this basis, along with biochemical genetic analysis
of hemoglobin, a diagnosis of hemoglobinopathy (HbE) was made. HbE is common in
southeast Asia with over 30% of the population affected. Most people are
asymptomatic. In northern Asia, including Japan, HbE is found in only 0.001% of
the population. With ther recent influx of southeast Asians to Japan, care must
be taken not to overlook the diagnosis of hemoglobinopathies.
PMID- 9545830
TI - [Successful syngeneic peripheral blood stem cell transplantation for protracted
myelosuppression after chemotherapy in a patient with acute myelogenous
leukemia].
AB - Acute myelogenous leukemia (M2) with translocation of 8;21. Was diagnosed in 61
year-old man. He was successfully treated and obtained complete remission. After
consolidation therapy, myeloid suppression and maturation arrest at the myelocyte
level were recognized. Following intensive chemotherapy, he received rhG-CSF
mobilized peripheral blood stem cell transplantation (PBSCT) from an identical
twin because he had life threatening infectious events and protracted
myelosuppression. Transplantation of 2.5 x 10(6)/kg CD34+ cells resulted in a
rapid normal tri-lineage hematologic reconstitution. Syngeneic PBSCT appears to
be a substitute for syngeneic bone marrow transplantation in certain situations.
PMID- 9545831
TI - [Pharmacologic pain treatment].
AB - Pharmacotherapy of chronic pain uses the following groups of drugs: simple
analgesics, NSAID's, opioids, calcitonin, antidepressants, neuroleptic drugs and
myorelaxants. Diseases of the locomotor system are very often chronic or
chronically recurrent. We therefore need a tailored longterm therapy. We have to
consider not only the effect but also side effects of the different drugs. The
aim of the therapy is an optimal quality of life for the individual patient. To
this end we have to avoid polypragmasia.
PMID- 9545832
TI - [Opioids in treatment of chronic noncancer pain].
AB - Opioids have been accepted as appropriate analgesic treatment for pain associated
with cancer. However, controversy exists about their use for chronic noncancer
pain. Reasons for reluctance are concerned about efficacy and potential adverse
effects such as respiratory depression, addiction, physical dependence or
intolerance. Many physicians worry about liability and legal restrictions.
Nevertheless, pain management of chronic severe pain with opioids can be the only
help when alternative methods are too risky of fail to be effective. This article
briefly reviews the published literature on this topic and discusses some
practical guidelines for the use of opioids in the treatment of non-cancer pain.
PMID- 9545833
TI - [Sacral block: indications and effectiveness].
AB - It has been shown that during injection of 17 to 20 ml local anesthetics combined
with a corticosteroid via the hiatus canalis sacralis that the solution is
distributed up to the level of the thoraco-lumbar junction. The indication for
therapeutical peridural injection are radicular symptoms as a result of disc
herniation, foraminal stenosis as well as neurogenic claudicatio.
Contraindications are anticoagulation, local infection as well as suspicion of
systemic inflammatory disease of the peripheral nervous system. With proper
technique and adequate desinfection, complications and side effects are very
rare.
PMID- 9545834
TI - [Manual medicine in pain treatment].
AB - To diagnose the source of pain, a very refined segmental technique is employed in
manual medicine. The evaluation of static and dynamic functions is complemented
by palpatory and functional testing of the joint mechanics. A reversible
hypomobility of a joint causes a swelling of the surrounding soft tissue, a
stiffening of the muscle tissue and a change in turgor and trophicism. The
various techniques of manual medicine restore the physiological joint play,
causing thereby reflectory phenomena, often the source of pain, to disappear
quickly. Trivial trauma or inappropriate coordination of movement sequences
interfere with joint mechanics. The nociceptive stimulus from all joint
structures activates segmentally connected muscular fiber bundles through the
posterior horn complex via alpha- and gamma-motoneurons. The joint play of other
segments and/or peripheral components can be disturbed via interneurons and
become a source of pain. Mobilisation of the joint activates inhibitory neurons,
the normal joint mechanics are reestablished and the nociceptive stimulus
reduced.
PMID- 9545835
TI - [Intracerebral neurosurgery in the treatment of chronic pain].
AB - Brain surgery is generally considered a treatment of last resort for chronic pain
resistant to all other therapeutic measures. The neurosurgical treatment of pain
may be either destructive (e.g., thalamotomy) or augmentative (e.g., electrical
stimulation through an electrode connected to an implanted neurologic pacemaker).
For pain of the neurogenic type (neuropathic or deafferentation pain), the
preferred target is either the sensory nucleus of the thalamus, at a site
corresponding somatotopically to the location of the pain, or the precentral
cortex. For somatic (nociceptive) pain, stimulation of the periventricular or
periaqueductal gray matter, or intraventricular infusion of morphine, may be
useful. These operations are now indicated only in exceptional cases, as will be
explained with reference to the author's long experience.
PMID- 9545836
TI - [Febrile state, bloody diarrhea and megacolon].
AB - We report about a forty year old female patient with severe bloody diarrhoea and
fever over a period of 14 days due to an infection with Salmonella enteritidis. X
ray of the abdomen showed a toxic megacolon. With the diagnosis of an infectious
colitis we started therapy with ciprofloxacin i/v. The toxic megacolon progressed
despite intensive care and parenteral nutrition. Additionally the patient
received metronidazole i/v and in combination with a roll technique in bed in the
knee-elbow-position the leucocytosis and the megacolon decreased. A toxic
megacolon is in about 3% associated with an infection with Salmonella
enteritidis. It is essentially diagnosed by X-ray. Patients should receive
intensive care, and because of the high mortality rate an interdisciplinary
management is required. The article discusses the major differential diagnosis of
the toxic megacolon, as well as the pathogenesis and therapy of Salmonella ent,
infection. In case of an infection with Salmonella ent. physicians should
acknowledge the possibility of development of a toxic megacolon.
PMID- 9545837
TI - [Stage II sarcoidosis].
PMID- 9545838
TI - [What is your diagnosis? Information regarding the examination of his daughter
(virginity)].
PMID- 9545839
TI - [Generic drugs: curse or blessing?].
PMID- 9545840
TI - [Value of thoracoscopy and talc pleurodesis in diagnosis and palliative treatment
of malignant pleural mesothelioma].
AB - Malignant pleural mesothelioma (MPM) remains a disease of very poor prognosis
despite all new therapeutic approaches. We describe here 13 cases with MPM. The
main symptoms at presentation were dyspnea (12/13) followed by weight loss
(7/13), cough (3/13) and thoracic pain (2/13). On chest X-ray, all patients had
pleural effusion associated with pleural thickening in 8/13 cases (62%). A
definitive diagnosis was brought by thoracoscopy in 11/12 cases (diagnostic
sensitivity 92%). In one patient, thoracoscopy was technically impracticable
because of very important obesity. By thoracoscopic talc pleurodesis, we were
able to control the pleural effusion in all patients with suppression of dyspnea
(11). The mean survival after diagnosis was 6.8 +/- 5.0 months (range 1-16). At
the present time, we believe that thoracoscopy is well indicated in any suspicion
of MPM not only for diagnosis but also for palliative treatment of this pleural
disease. However, there is a need for well controlled studies to improve the
outcome of MPM.
PMID- 9545841
TI - [Iatrogenic disease and self-injury: significant factors in hospital admission?].
AB - The frequency of adverse effects caused by doctors may serve as a quality
control. We therefore assessed the number of adverse effects leading to a
hospital admission and occurring during a six-month period in the medical
department of a district hospital. We compared these figures with the number of
admissions caused by substance-abuse by the patient himself. RESULTS: At
admission to hospital 35 patients (6.4%) suffered from adverse effects. In 89% of
these, the adverse effect was the leading factor to admit the patient; in the
remaining 4 patients (11%) the adverse effect was detected by routine-screening
upon admission. Further 8.6% developed adverse effects in the hospital which in
12.5% had consequences upon course and duration of the hospitalization. Self
afflicted hospital-admissions (substance-abuse, suicide-attempts) were found in
13%. Iatrogenic adverse effects brought 3.5% of the patients to the hospital.
CONCLUSIONS: Adverse effects caused by diagnostic and therapeutic activities of
doctors considerably contribute to hospital-admissions and course of hospital
stay, but even more often the patient himself is responsible by his self-damaging
behavior.
PMID- 9545842
TI - [Withdrawal syndrome caused by selective serotonin reuptake inhibitors: apropos
of a case].
AB - During the past 4 years, several case reports have been published on the
withdrawal syndrome which may be observed after acute interruption of a treatment
with selective serotonin reuptake inhibiting antidepressants (SSRI). Paroxetine
is the most frequently cited antidepressant in the literature, whereas fluoxetine
is the less frequently cited of this type of drugs. The withdrawal symptoms
appear a few days after stopping treatment or after a decrease of the dose. The
typical symptoms are of the gastro-intestinal type, such as loss of appetite,
nausea, vomiting, diarrhea and abdominal cramps. Other symptoms are sensation of
instability, vertigo, dizziness, headache, malaise, muscular pains, asthenia, as
well as a syndrome of pseudo-influenza. Brief electric shocks throughout the
body, which last one or two seconds, have also been reported. A case is reported
in detail by the authors, who observed some of these symptoms in a patient after
stopping his treatment with paroxetine. This withdrawal syndrome may be due to a
rebound phenomenon of the serotonergic systems after interruption of the
treatment with SSRIs. It is, therefore, recommended that treatment with SSRIs is
progressively stopped over a period of several weeks.
PMID- 9545843
TI - [Abdominal pain and flatulence. Intestinal and pulmonary tuberculosis. IgG kappa
paraproteinemia].
AB - A 21-year-old woman suffered from cramplike abdominal pain, flatulence and
occasional diarrhoea for about one year. Over the past few weeks the abdominal
symptoms exacerbated, besides productive cough and subfebrile temperatures
developed. Coloscopy revealed two isolated, short ulcers in the proximal colon.
The histological examination of the biopsies taken from these ulcers indicated
granulomatous inflammation. Moreover small acinar infiltrates in both pulmonary
apices were visualized. The findings in this patient originating from Turkey were
suspicious for intestinal and pulmonary tuberculosis. Though sensitive methods
were used (Ziehl-Neelson stam, amplified M. tuberculosis direct test, a
polymerase chain reaction) direct tests allowed no detection of mycobacteria.
Antituberculous therapy was initiated on a probatory basis to which the patient
responded well and promptly. The diagnosis was confirmed by culture results: M.
tuberculosis was grown from colonic biopsies, morning sputa and bronchioalveolar
lavage.
PMID- 9545844
TI - [Ascites. Tuberculous peritonitis].
AB - Because of deteriorating general health, weight loss of 5 kg and leftsided
epigastric pain a 44 year old innkeeper was evaluated unsuccessfully for 1 month.
Thereafter a protein- and lymphocyte-rich ascites developed. CT-scans revealed a
thickened visceral peritoneum and multiple, marginally increased retroperitoneal
lymph nodes. The history of the patient originating from former Jugoslavia was
suspicious for inadequately treated tuberculous pericarditis. Hence this
diagnosis tuberculous peritonitis became probable but for practical reasons could
not be proven neither by biopsy nor by culture. Under probatory antituberculous
treatment the patient's general condition improved rapidly, the ascites
disappeared and initially elevated parameters for infection normalized.
PMID- 9545845
TI - [Increase in transaminases in HIV infection. Toxic liver cell damage with
trimethoprim/sulfamethoxazole administration in HIV infection].
PMID- 9545846
TI - [Surgical and conservative treatment of liver diseases].
PMID- 9545847
TI - [Therapy of viral hepatitis].
AB - The therapy of viral hepatitis has great medical and socioeconomic impact. Today
chronic viral hepatitis is the most important cause for chronic liver disease,
liver cirrhosis, and hepatocellular carcinoma. Hepatitis A and E cause acute
courses exclusively whereas infection with the hepatitis B, C, and D virus might
result in chronic hepatitis as well. The goal of therapy of chronic viral
hepatitis has to be a reduction/normalisation of elevated transaminases, decrease
of the serologic parameters of active viral replication, improvement of histology
and prevention of complications of chronic hepatitis. The only drug with proven
benefit in the treatment of chronic viral hepatitis is interferon alpha. This
therapy results in a sustained response in 25 to 40% for hepatitis B and 10 to
25% for hepatitis C infection. New developments under clinical evaluation are
Lamivudine and Famciclovir in the treatment of HBV-infection and Ribavirin in
combination with INFa for chronic HCV-infection.
PMID- 9545848
TI - [Treatment of alcoholic liver diseases and psychiatric and psychosocial
problems].
AB - Only about 15% of the subjects abusing ethanol will eventually develop cirrhosis
of the liver, suggesting that other factors in addition to the consumption of
large quantities of ethanol play a role in the pathogenesis of alcoholic
cirrhosis. Important contributors may be infection with hepatitis viruses, in
particular HCV, protein-calorie malnutrition and immunologic factors. Abstinence
improves the prognosis of patients with alcoholic cirrhosis, provided that the
liver disease is not too far advanced. No pharmacotherapeutic intervention has
shown a convincing improvement of the prognosis of alcoholic liver disease, so
that the therapeutic efforts should be mainly directed towards abstinence. The
patient with alcoholic liver disease needs support and guidance by the treating
physicians. Supportive treatment with Disulfiram, Acamprosate or Naltrexon can
help with achieving durable abstinence.
PMID- 9545849
TI - [Non-surgical treatment of portal hypertension].
AB - The choice of methods for the treatment of acute variceal hemorrhage critically
depends on the locally available expertise. Vasoactive drugs or balloon tamponade
may bridge the time to more definitive measures such as sclerotherapy or band
ligation. Drugs (nonselective beta-adrenergic blockers and long-acting nitrates)
are almost equivalent to endoscopic sclerotherapy for the prevention of recurrent
bleeding, while band ligation offers both increased efficacy (reduced rate of
rebleeding and death) and decreased complication rates when compared to
sclerotherapy. Thus, ligation will predominantly be used for the prevention of
recurrent bleeding. Alternatively, drugs may be applied when acute bleeding was
effectively stopped without the use of endoscopic means. Endoscopic sclerotherapy
and surgery have no place in the primary prophylaxis of variceal hemorrhage in
patients who have not bled before. Prevention of the first bleed is clearly the
field for beta-blockers or nitrates. The role of banding ligation in this
situation remains to be defined.
PMID- 9545850
TI - [Treatment of portal hypertension by portosystemic shunts].
AB - The use of shunts for the treatment of portal hypertension has been revived after
the introduction of the transjugular intrahepatic portosystemic shunt (TIPS) into
clinical practice. This interventional procedure has mainly been used as rescue
treatment for variceal bleeding resistant to endoscopic therapy and for ascites
refractory to diuretic treatment and paracentesis. With respect to variceal
bleeding TIPS has a low rate of "operative" mortality of < 1% and variceal
rebleeding of 6 to 18%. In patients with refractory ascites the response to
treatment is 50 to 92%. The major problems of the TIPS procedure are the
increased incidence of hepatic encephalopathy and the high rate of shunt
insufficiency of about 50%. Therefore, control of shunt function by duplex
sonography is essential to detect malfunction of the shunt. Radiological revision
is then indicated if the clinical symptoms of portal hypertension (varices,
ascites) reappear. The TIPS treatment has partially replaced the surgical
shunting procedures. This decision is based on the potentially higher mortality
of the surgical procedure. However, this has not been proven by randomized
studies and, therefore, surgical shunts may also be indicated in selected
patients with low operative mortality.
PMID- 9545851
TI - [Cholestasis: therapeutic options].
AB - Ursodeoxycholic acid (UDCA) has been shown to be both an effective and well
tolerated treatment of primary biliary cirrhosis, a model chronic cholestatic
liver disease. Beneficial effects of UDCA have also been observed in other
cholestatic disorders such as primary sclerosing cholangitis, cystic fibrosis, or
intrahepatic cholestasis of pregnancy. Liver transplantation is the treatment of
choice in end stage chronic cholestatic liver disease. Symptomatic therapeutic
concepts include the treatment of cholestasis-associated problems such as
pruritus, osteopathy and vitamin deficiency.
PMID- 9545852
TI - [Diagnosis and therapy of obstructive jaundice].
AB - Obstructive jaundice is a sign of intra- or posthepatic blockage of bile flow.
This diagnosis has to be differentiated from various other diagnoses such as
disorders of bilirubin metabolism or hepatocellular causes of jaundice. An
accurate evaluation of the past medical history and clinical examination of the
patient can already establish obstruction as the cause of jaundice in most cases.
For prevention of a cholangitis further imaging procedures should focus on
rapidly establishing the cause and the location of obstruction. Further
therapeutic procedures are dependent on the type of obstruction and the condition
of the patient. Most importantly there should be a decompression of the biliary
tree with ES or PTBD.
PMID- 9545853
TI - [Cholelithiasis--laparoscopy or laparotomy?].
AB - Between 10% and 15% of the adult population have gallstones and therefore
symptomatic cholelithiasis is the second most common indication for surgery in
general practice. It's diagnosis depends on the patients history, clinical
findings, laboratory tests and ultrasound. In case of symptomatic gallstones
surgery offers the only permanent cure and specific complications due to
gallstones such as ileus or fistula are becoming rare. With the introduction of
minimal invasive surgery at the end of this century laparoscopic cholecystectomy
is now considered to be the standard treatment for symptomatic gallstones. This
approach can be offered to > 90% of patients in elective cases and in between 60%
80% of patients having acute cholecystitis with a low morbidity and mortality
rate. The main advantages of the laparoscopic approach are the overall increased
patients comfort with less postoperative pain, shorter hospital stay, recovery
and off work time. Although the rate of common bile duct injury appears to be
increased using this minimal invasive approach, this rate is still sufficiently
small to justify the use of laparoscopic cholecystectomy for symptomatic disease.
Open cholecystecomy remains the treatment of choice for complicated gallstone
disease (i.e. cancer, Mirizzi syndrome, severe inflammation) and high risk
patients. In case of acute cholecystitis the laparoscopic treatment with all it's
advantages may also be offered to many patients. However, in those cases the
conversion rate to the open approach may be markedly increased which has not to
be considered as a complication of the laparoscopic approach but as a
maximization of safety and effectiveness of the treatment.
PMID- 9545854
TI - [Treatment of choledocholithiasis].
AB - Passage of gallstones into the common bile duct occurs in 10-15% of patients with
cholecystolithiasis. The incidence of common bile duct stones increases with age
of the patient and can reach up to 50% in certain series. The diagnosis of
choledocholithiasis is usually made by endoscopic retrograde cholangiography
(ERC), either preoperatively or intraoperatively at the time of laparoscopic
cholecystectomy. Endoscopic sphincterotomy followed by balloon or basket
extraction is the method of choice for the management of patients with common
duct stones.
PMID- 9545855
TI - [Differential diagnosis and therapy of benign liver tumors].
AB - Hemangioma, focal nodular hyperplasia (FNH) and hepatocellular adenoma represent
the most common and clinically relevant benign liver tumors. Improved diagnostic
imaging procedures as well as the broad use of oral contraceptives resulted in an
increased detection rate during the past 25 years. Focal liver diseases are
primarily diagnosed by ultrasonography, while a specific diagnosis can be
established by contrast enhanced magnetic resonance imaging. Hepatocellular
adenomas should be resected, since they bear the potential of a malignant
transformation as well as the risk of rupture and intraperitoneal hemorrhage.
Conversely, a conservative approach is advocated for hemangioma and FNH. However,
surgical procedures may be justified when a mass becomes symptomatic, and should
be applied liberally when the diagnosis remains uncertain.
PMID- 9545856
TI - [Diagnosis and treatment of hepatocellular carcinoma].
AB - Worldwide, hepatocellular carcinoma is one of the most common intra-abdominal
malignancy. It occurs mostly in patients who are carriers of the hepatitis B or C
virus and/or have liver cirrhosis. There is no screening-test for early
recognition of the development of liver cancer and this delays often an accurate
diagnosis and early treatment. Resection is the best form of treatment offering a
chance of cure. In the last decades, considerable progress has been made in the
field of liver diagnostic and operative techniques for liver resection. This has
been followed by an increase in the resection rate of patients with malignant
liver tumours and by a decrease in postoperative morbidity and mortality.
Nowadays, after curative resection, 5-year survival rates up to 30% can be
achieved. Promising results are also obtained by new adjuvant therapeutic
modalities demonstrating improvement in survival. Therefore, in the field of
malignant liver tumours there is no more space for therapeutic nihilismus.
PMID- 9545857
TI - [Indications and results of liver transplantation].
AB - Liver transplantation offers cure and high a quality of life to patients with
otherwise incurable diseases. For patients suffering from chronic liver diseases
or metabolic disorders, a life expectancy of less than one year or an
unacceptable quality of life are considered to be indications for
transplantation. For unresectable primary liver tumors without vascular invasion
or tumor manifestations outside the liver long-term survival can be achieved with
transplantation. Because of the enormous regenerative capacity of the liver,
indication for transplantation can be difficult in case of fulminant hepatic
failure, for which own criteria have been defined. In relation to the under-lying
liver disease one-year patient survival varies from 60%-80%. Recurrence of tumors
or viral hepatitis may have a negative impact of long-term outcome. Various
indications and results are discussed in detail.
PMID- 9545858
TI - [Management of the liver transplant patient].
AB - The general practitioner plays a crucial role in the care for the liver
transplant recipient. The number of liver transplant recipients increasing
steadily by about 50 a year in Switzerland, the practitioner will increasingly be
confronted with such patients. A close cooperation between general practitioner
and transplant center is mandatory and the key to success. This paper aims at
introducing the general practitioner to the care for the liver transplant
recipient.
PMID- 9545859
TI - [Establishment of Sendai virus gene manipulation and its applications].
PMID- 9545860
TI - [Structure/function analysis of rice dwarf phytoreovirus genome and its
proteins].
PMID- 9545861
TI - [Structure-function relationship of the influenza virus RNA polymerase].
PMID- 9545862
TI - [NO in the pathogenesis of viral infections].
PMID- 9545863
TI - [Viral ion channel: structure and function of influenza virus M2 protein].
PMID- 9545864
TI - [Neuropathogenic murine retrovirus].
PMID- 9545865
TI - [Current status of gene therapy and viral vectors].
PMID- 9545866
TI - [Process development for large scale procreation of retroviral vectors].
PMID- 9545867
TI - [Gene transfer into non-dividing cells by a lentiviral vector].
PMID- 9545868
TI - [Adeno-associated virus vectors and gene therapy].
PMID- 9545869
TI - [Next generations of adenovirus vector: present and future].
PMID- 9545870
TI - [Herpes simplex virus as a vector for gene therapy].
PMID- 9545871
TI - [Gene transfer into mammalian cells by baculovirus vector and its applications].
PMID- 9545872
TI - [Glycoprotein C of herpes simplex virus].
PMID- 9545873
TI - [Hemagglutinating virus of Japan].
PMID- 9545874
TI - Phenolic constituents of licorice (Glycyrrhiza species).
PMID- 9545875
TI - Antibacterial effect of propolis and honey on oral bacteria.
AB - PURPOSE: To investigate the antibacterial properties of propolis and honey
against oral bacteria in vitro and in vivo. MATERIALS AND METHODS: In vitro
study: The antibacterial effects of propolis and honey on oral streptococci were
determined using the broth method. Clinical study: The short-term antibacterial
effect of propolis solution and honey on salivary total bacteria and
Streptococcus mutans was tested in 10 volunteers. RESULTS: Propolis demonstrated
an antibacterial effect both in vitro on isolated oral streptococci and in the
clinical study on salivary bacterial counts. Honey induced bacteria growth at low
concentrations, while at high concentrations honey had an inhibitory effect on
bacterial growth in vitro. Salivary counts of total bacteria and Streptococcus
mutans were lower for 1 hour after application of honey. The antibacterial effect
of the honey tested may be attributed to its osmolarity effect.
PMID- 9545876
TI - Dentin infiltration by three adhesive systems in clinical and laboratory
conditions.
AB - PURPOSE: To evaluate in vivo and in vitro the formation of hybrid layer, resin
tags and adhesive lateral branches, by use of three different enamel dentin
bonding systems. MATERIALS AND METHODS: The dentin adhesives were tested on flat
dentin preparations made on buccal surfaces of vital, periodontally compromised
teeth. The samples were randomly divided in four groups: Group 1: Prime & Bond
2.0; Group 2: Scotchbond Multi-Purpose Plus; Group 3: Clearfil Liner Bond 2 (the
self-etching primer was applied for 30 seconds on the enamel and dentin); Group
4: Clearfil Liner Bond 2 (the self-etching primer was applied for 60 seconds on
the enamel and dentin). The sample teeth were extracted immediately after the
bonding was cured. The same procedure described for the in vivo samples was
performed in vitro on extracted molars. All the samples were split-fractured
along their long axis. Half of the samples were used to visualize the hybrid
layer and the other half to observe the morphology of resin tags by use of
scanning electron microscopy. RESULTS: All the tested products formed a hybrid
layer, both in vivo and in vitro. In many areas of the samples of Groups 1, 2 and
4, characteristic reverse cone-shaped tags with their corresponding adhesive
lateral branches were evident. In contrast to this, resin tags found in samples
of Group 3 were narrower at the tubule orifices, and adhesive lateral branches
were scarce. The length of the resin tags observed in the samples of Groups 1 and
2 were longer than those found in Groups 3 and 4. The morphology of the hybrid
layer of the in vivo samples was similar to that of the in vitro samples.
PMID- 9545877
TI - Microleakage of multi-step and simplified-step bonding systems.
AB - PURPOSE: To measure and compare the microleakage of Class V resin composite
restorations using the following three pairs of multi- and simplified-step dentin
bonding systems (DBS): OptiBond vs. OptiBond FL, All-Bond 2 vs. One-Step, and
Tenure vs. Tenure Quik. MATERIALS AND METHODS: V-shaped cavities were prepared in
the mesial and distal surfaces of 30 extracted human mandibular molars with
margins in both enamel and cementum, and randomly assigned into three equal
groups of 10 each. All DBSs were applied strictly following manufacturers'
specifications before three incremental layers of resin composite (Pertac-Hybrid)
were applied in all cavities. Specimens were stored for 7 days in 37 degrees C
water, thermocycled for 300 cycles between 5 degrees C and 55 degrees C, immersed
in 0.5% basic fuchsin solution for 24 hours, and embedded in resin before being
sectioned longitudinally in multiple sections. Dye solution penetration at the
tooth/composite interface was scored from 0 to 4 under a microscope at x100 at
both enamel (E) and cementum (C) margins. Data were analyzed by Kruskal-Wallis
and Mann-Whitney U tests with alpha = 0.05. RESULTS: OptiBond FL and One-Step
showed less microleakage at the cementum margins compared to their multi-step
versions. At the enamel margins Tenure Quik showed less microleakage compared to
Tenure, and none of the other DBSs tested showed significant dye penetration at
that interface. All DBSs showed significantly less microleakage at the enamel
margins compared to the cementum margins except for OptiBond FL and One-Step that
did not show any significant dye penetration at the cementum margins as well.
PMID- 9545878
TI - Microleakage of dentin bonding systems used with spherical and admixed amalgams.
AB - PURPOSE: To evaluate the effectiveness of the dentin bonding systems (DBS)
Tenure, Syntac, Amalgambond and All-Bond 2 using a resin-lined amalgam technique
in preventing short-term microleakage in Class V cavity preparations restored
with a spherical and an admixed alloy. MATERIALS AND METHODS: Class V cavity
preparations were made on the mesial and distal surfaces of non-carious human
mandibular molars with the occlusal margins in enamel and gingival margins in
cementum. Prepared teeth were randomly assigned to 12 treatment groups (n = 10)
consisting of each DBS, no liner and Copalite for both amalgam alloys. Samples
were thermocycled, stained and sectioned to evaluate microleakage. RESULTS: The
DBS-lined restorations had significantly less microleakage at both occlusal and
gingival margins than the Copalite and unlined restorations. Among DBS, Syntac
had significantly more microleakage with both alloys than either All-Bond 2 or
Amalgambond. These results do not totally correlate to a previous study which
used the same experimental design but included viscous liners in addition to the
same DBS, indicating a potential difference between resin-lined versus resin
bonded amalgam techniques in preventing microleakage.
PMID- 9545879
TI - Marginal adaptation of resin-bonded light-cured glass ionomers in dentin
cavities.
AB - PURPOSE: To investigate the marginal adaptation of resin-modified glass ionomer
cements in dentin cavities placed with or without additional application of resin
bonding systems. MATERIALS AND METHODS: Three resin-modified materials (Fuji II
LC, Photac-Fil, Vitremer), one compomer (Dyract) and as reference an adhesively
bonded resin composite system (Gluma CPS-Pekafill) were used. Flat peripheral
dentin surfaces on human molar teeth were produced by wet grinding on SiC paper.
Cylindrical cavities, 3.5 mm wide, were prepared in these dentin areas and
restored with the individual materials. Sixty cavities were pretreated and
restored as requested by the respective manufacturers. Following water storage of
the specimens for 15 minutes or 24 hours, excess was gently removed by wet
grinding for microscopic inspection of the marginal area. Additionally, in 30
cavities an experimental one-component adhesive resin system, a proprietary
dimethacrylate and HEMA mixture dissolved in acetone, was combined with each of
the restoratives for evaluation after 15-minutes water storage. Finally, in six
cavities each, Dyract was combined with Prime and Bond 2.0, and Vitremer with
Scotchbond Multi-Purpose Plus for assessment after 15 minutes. Maximum marginal
gap widths (MGW) were measured. One-way ANOVA by ranks (Kruskal-Wallis-Test)
followed by Wilcoxon's Two-Sample test were used to study the statistical
difference of MGW among the treatment groups at a rejection level P = 0.05.
RESULTS: Neither the conventionally placed material systems nor the restorations
in combination with adhesives showed consistently gap-free margins after 15
minute water storage. After 24-hour storage with Vitremer 4 of the 6 restorations
were gap-free, whereas with all other materials only perfect margins were
registered. There was, however, no significant difference between the groups.
Application of the experimental and/or the specific resin bonding agents had no
effect on early MGW except for the Photac-Fil group, which was significantly
reduced.
PMID- 9545880
TI - Compomers and glass ionomers: bond strength to dentin and mechanical properties.
AB - PURPOSE: To compare compomers and conventional and resin-modified glass ionomer
cements (GIC) with respect to bond strength to dentin and mechanical properties.
MATERIALS AND METHODS: Seven conventional GICs (BaseLine, ChemFil Superior, Fuji
II, Fuji IX, Ketac-Fil, Ketac-Silver, and Miracle Mix), three resin-modified GICs
(Fuji II LC, Photac-Fil, and Vitremer), and two compomers (Dyract and Compoglass)
were investigated. Bond strength was determined to untreated as well as pre
treated human dentin. The mechanical properties tested were flexural strength and
flexural modulus. RESULTS: Mean bond strengths to untreated dentin ranged from
0.0 MPa (Photac-Fil) to 8.5 MPa (Fuji IX). Generally, the bond strengths of the
compomers and resin-modified GICs were lower than those of the conventional GICs.
Mean bond strengths to pre-treated dentin ranged from 0.5 MPa (Photac-Fil) to
13.7 MPa (Compoglass). No clear-cut bond strength pattern was observed for the
three types of materials. Pretreatment improved the bond strength of nine out of
12 materials. Flexural strengths ranged from 13 MPa (Miracle Mix) to 180 MPa
(Dyract). Generally, the compomers were stronger than the resin-modified GICs,
which were much stronger than the conventional GICs. Flexural moduli ranged from
4.0 GPa (Miracle Mix) to 7.2 GPa (Fuji IX and Dyract) with no typical variations
between the three categories of materials.
PMID- 9545881
TI - Effect of polymerization mode of a dual-cured resin cement on time-dependent
shear bond strength to porcelain.
AB - PURPOSE: To evaluate the shear bond strengths to porcelain and setting times of a
dual-cured resin cement with light/chemical curing (dual) or chemical only curing
versus time. MATERIALS AND METHODS: Variolink resin cement was bonded to
specimens of etched, silanated porcelain. Groups of specimens were cured by dual
cured or by chemical curing only. Shear bond strengths were recorded at 2, 3, 5,
60 minutes and 24 hours for dual cured and at 10, 20, 40, 50, 60 minutes and 24
hours for chemical-cured only after mixing. Kinetic-temperature profiles of dual
and chemical curing modes of cement were calculated. RESULTS: Maximum bond
strengths and time to attainment were 17.5 +/- 2.7 MPa at 60 minutes for chemical
cured and 26.1 +/- 2.3 MPa at 5 minutes for dual-cured. The peak in the kinetic
temperature setting profiles were 14.1 +/- 0.9 minutes for chemical curing and
52.2 +/- 5.2 seconds for dual curing. Dual curing provided significantly higher
shear bond strengths versus chemical curing at both the 60-minute and 24-hour
time periods.
PMID- 9545882
TI - Bond strength of multi-step and simplified-step systems.
AB - PURPOSE: To measure and compare the in vitro shear bond strength (SBS) of the
following three pairs of multi- and simplified-step dentin bonding systems:
OptiBond vs. OptiBond FL, All-Bond 2 vs. One-Step, and Tenure vs. Tenure Quik.
MATERIALS AND METHODS: 60 extracted human mandibular molars were sectioned
perpendicular to the long axis 1 mm above the CEJ to expose the dentin bonding
surface. After being wet-ground to 600 grit with SiC abrasive papers, rinsed and
dried, the teeth were individually mounted in phenolic rings with epoxy resin,
and randomly assigned into six equal groups of 10 each. The dentin surfaces were
treated with the above mentioned dentin bonding systems, and a gelatin cylinder
filled with resin composite (Pertac-Hybrid) was directly bonded to each
pretreated surface. After 7-day storage in 37 degrees C water followed by
thermocycling, the specimens were shear tested to failure on an Instron machine.
Data were analyzed by independent t-tests, one-way ANOVA, and Duncan's Multiple
Comparison tests at alpha = 0.05. RESULTS: Except for the pair Tenure/Tenure
Quik, the differences between the pairs All-Bond 2/One-Step and OptiBond/OptiBond
FL were statistically significant with All-Bond 2 and OptiBond FL yielding higher
shear bond strength (P < 0.05). Findings of this study indicated that OptiBond FL
was the only simplified-step system showing improved bond strength.
PMID- 9545883
TI - Wet bonding: effect of drying time and distance.
AB - PURPOSE: To examine the effect of various drying times and air syringe-to-tooth
distances on the shear bond strength of a dentin adhesive that requires a wet
surface for maximum effectiveness. MATERIALS AND METHODS: Seventy extracted human
molars were acid etched. The surface of the etched dentin was rinsed and dried
with compressed air for 1, 3, or 5 seconds from a distance from either a distance
of 1 or 10 cm. The adhesive One-Step was then applied, composite cylinders were
attached and shear bond strengths were obtained. RESULTS: Drying time and
distance had a significant impact on the resultant shear bond strengths. Longer
drying times and shorter syringe-to-tooth distances negatively affected the bond
strength of the adhesive studied.
PMID- 9545884
TI - 2-year clinical performance of a fluoride-containing fissure sealant in young
schoolchildren at caries risk.
AB - PURPOSE: To evaluate the clinical performance of Helioseal-F, a fluoride
containing fissure sealant, in school children at caries risk. MATERIALS AND
METHODS: A caries risk assessment based on past caries experience, saliva
microbial tests, buffer capacity and frequency of sugar intake was carried out in
204 healthy children, 6-7 years of age. Children exhibiting one or more risk
factors were considered at caries risk (n = 121) and their permanent molars were
sealed with a fluoride-containing fissure sealant, thus forming a fissure sealant
group (FSG). The remaining 83 children with low caries risk received no fissure
sealants and constituted a reference group (RG). Both groups were followed for 2
years. From 15 children of both groups, unstimulated whole saliva was collected 1
month after sealant placement in order to determine fluoride levels. In another
20 children, a split-mouth study design was utilized to compare the colonization
of mutans streptococci adjacent to and on F-containing sealants and conventional
controls. The sealants were placed by dental hygienists according to the
manufacturers' instructions. RESULTS: A total of 431 fissure sealants were placed
at baseline. Complete retention was found in 76.6% during the study period while
22.0% were partially lost. Six sealants (1.4%) were completely lost. The enamel
caries incidence was 45% lower (P < 0.05) in the permanent molars of the caries
risk FSG compared with the low risk RG. There was no significant increase in
saliva fluoride concentration following placement of the sealants and the
proportion of mutans streptococci in relation to total viable counts was
unaffected by type of material. The levels of salivary mutans streptococci were
mainly unchanged in both groups during the study period, while the levels of
salivary lactobacilli decreased in the FSG.
PMID- 9545885
TI - Manipulation effects on fluoride release from chemically-cured and resin-modified
glass ionomers.
AB - PURPOSE: To examine the effect of mixing techniques (hand-mixing vs. trituration)
on fluoride release from chemically-cured (Fuji II) and resin-modified (Fuji II
LC) glass ionomer products. MATERIALS AND METHODS: Fluoride measurements were
determined and comparisons made between hand-mixed-type materials that were both
hand-mixed (60 seconds) and triturated (10 seconds). Hand-mixed specimens were
made using the manufacturer's recommended powder/liquid ratio. Triturated
specimens of the same material were made using the same powder/liquid ratio. Disk
specimens (8.5 mm diameter, 2 mm thickness; n = 6) were stored in deionized water
for 23 hours to obtain Day 1 solutions. Solutions were also obtained at 2, 3, 4,
5, 6, 7, 14, 21, and 28 days after fabrication and were changed 24 hours before
fluoride concentration was determined using a fluoride ion selective electrode.
Daily rates of fluoride release and 28-day cumulative fluoride totals were
calculated. Cumulative data were analyzed by two-way ANOVA and Scheffe's test
(alpha = 0.05). Daily results were analyzed by the Mann-Whitney U-test. RESULTS:
A significant difference was observed between materials (P < 0.001). Depending on
the kind of material used, the method of manipulation affected the fluoride
release. Data analysis revealed that: (1) Fuji II LC released significantly more
fluoride than Fuji II for both triturated (P = 0.005) and hand-mixed (P < 0.005);
(2) the triturated Fuji II released significantly more fluoride than the hand
mixed (P = 0.02); and (3) the hand-mixed Fuji II LC released more fluoride than
the triturated, but was not statistically significant (P = 0.16).
PMID- 9545886
TI - VariGlass fluoride release and uptake by an adjacent tooth.
AB - PURPOSE: To quantitatively analyze in vitro the fluoride release from proximal
VariGlass restorations and resulting uptake by the enamel of adjacent teeth.
MATERIALS AND METHODS: Sixty impacted third molars were used and assigned to
three groups: C: control, teeth without restorations; RC: teeth with resin
composite restorations (Prisma APH); and PMRC: teeth with polyacid-modified resin
composite restorations (VariGlass). Each group consisted of four sets of five
teeth each. In the latter two sets, by alternating restored and unrestored teeth,
the proximal surfaces of three unrestored teeth with an area of exposed enamel
were in contact with the restored proximal surfaces of two other teeth. The sets
were submitted to high caries challenge conditions with demineralizing and
remineralizing solutions for 14 days. The fluoride of each solution and the
fluoride uptake were determined and statistical analyses were carried out (ANOVA
and Tukey's test). RESULTS: The highest mean fluoride concentration occurred with
Group PMRC in both kinds of solutions (P < 0.01), but this value was higher in
the demineralizing solution (P < 0.01). Over the 14 days, however, this mean
gradually decreased in both solutions (P < 0.01). Group PMRC also showed the
highest mean fluoride uptake (P < 0.01), which gradually decreased with depth in
the enamel (P < 0.01).
PMID- 9545887
TI - Bond strength and interface micromorphology of an improved resin-modified glass
ionomer cement.
AB - PURPOSE: To evaluate the influence of surface treatment with 20% polyacrylic acid
containing 3% aluminum chloride (AlCl3) on the shear bond strength of an improved
resin-modified glass ionomer cement to enamel and dentin, and to analyze the
micromorphology of the cement-tooth interface. MATERIALS AND METHODS: Flat enamel
and dentin surfaces of bovine incisors were ground up with sequentially finer
abrasives to 1000-grit silicon carbide paper. Each surface was treated with 10%
polyacrylic acid (Dentin Conditioner: DC) for 20 seconds or with 20% polyacrylic
acid containing 3% aluminum chloride (Cavity Conditioner: CC) for 10 seconds,
rinsed, and gently air-dried. A resin-modified glass ionomer cement (Fuji II LC)
and its improved version (Fuji II LC-I) were applied to the tooth substrate, and
bond strengths measured at periods of 5 minutes, 1 day, and 1 week after light
curing. As a control, the resin-modified glass ionomer cements were applied to
untreated surfaces and were tested at 1 day. To evaluate the interface
micromorphology, specimens were prepared following the adhesive-sandwich
technique, cut in equal halves, and observed under a scanning electron microscope
(SEM). Additionally, in order to observe the effect of surface pre-treatment of
each conditioner on dentin, pre-treated dentin disks were freeze-dried,
fractured, and the morphology of the treated and fractured surfaces were
observed. RESULTS: Shear bond strength of CC+ Fuji II LC-I to enamel was
significantly higher than that of DC+ Fuji II LC at 1 day and 1 week (P <
0.0001). As for dentin, the improved system showed significantly higher bond
strength at 5 minutes after light curing (P < 0.001), but bond strengths were not
statistically different at 1 day and 1 week. Fracture patterns, examined with a
stereomicroscope, were mixed adhesive/cohesive within the cement for all groups.
Interface micromorphology, observed with an SEM, suggested the formation of a
resin-rich layer and an indistinct zone between the resin-modified glass ionomer
cements and the underlying dentin.
PMID- 9545888
TI - Changes to Dyract restorative resin immersed in various media.
AB - PURPOSE: To examine changes in weight, strength, fluoride release, and surface
changes to the polyacid-modified resin composite Dyract after immersion in
various media for periods up to 16 weeks. MATERIALS AND METHODS: Properties
investigated were change in weight, strength, release of fluoride ions, and
surface changes. Specimens were immersed in reverse osmosis deionized water (ROW)
and in acetate buffer solutions containing calcium hydrogen orthophosphate. The
acetate media were of pH3, pH5 and pH7. All solutions were maintained at 37
degrees C without agitation. Solutions were changed weekly and retained for
fluoride analysis and specimens were weighed each week. After periods of 1, 2, 3,
4, 8, 12 and 16 weeks, some specimens were subjected to shear punch testing and
SEM examination. RESULTS: All specimens except those in pH3 medium gained weight
for the first 2-5 weeks after which weight was lost until all specimens weighed
less than at the commencement of the study. The specimens in pH3 medium lost
considerable weight from weeks 1 and 2. SEM examination showed disintegration of
the surface of all specimens examined. Fluoride release peaked at 1 week in all
specimens except those in pH3 medium. Fluoride release was highest in pH3 media
(approximately 46 ppm) after 1 week and remained high for 7 weeks, after which it
was reduced to about 50% of the initial release. Specimens stored in ROW and pH5
media released approximately 5 ppm after 1 week, and this was reduced to
approximately 1 ppm (pH7) and 2 ppm (ROW) by week 6.
PMID- 9545889
TI - Surface finishing of glass ionomer.
AB - PURPOSE: To evaluate the surface roughness and staining of a glass ionomer cement
when subjected to different finishing procedures. MATERIALS AND METHODS: Sixty
four discs of Chem-Fil II glass ionomer cement were submitted to staining test
with methylene blue by spectrophotometry and roughness test by profilometry. Four
groups were evaluated: Mylar matrix (control). Sof-Lex discs, Enhance points, and
diamond bur. RESULTS: Staining and roughness test, analyzed by ANOVA and Tukey's
test, showed that the best surface was obtained when the material cured in
contact with the Mylar matrix strip or when treated with Sof-Lex discs. The
poorest results were obtained after using the diamond bur.
PMID- 9545890
TI - Laboratory evaluation of compomers in Class V restorations.
AB - PURPOSE: To evaluate the in vitro microleakage, marginal morphology and resin
tags configuration of a compomer restorative material (Dyract) alternatively used
with two different bonding systems (Dyract-PSA and Prime & Bond 2.0). A hybrid
resin composite (Prisma TPH) used with two different bonding systems (Universal
Bond 3 and ProBond) was evaluated as control material. MATERIALS AND METHODS:
Class V non-retentive restorations were made in vitro at CEJ and divided at
random in four groups: Dyract/PSA, Dyract/P&B 2.0, Prisma TPH/UB3, and Prisma
TPH/ProBond. The latter two groups were as controls. After finishing the
restorations, an impression material was used to obtain an epoxy resin replica
for SEM analysis of margin alterations. Percentage of perfect margin was
evaluated under SEM and calculated comparing it with the width/length of
restoration margin. The presence of gaps, enamel fractures and other marginal
alterations was also recorded inspecting under SEM replicas. Each tooth was then
immersed for 24 hours in erythrosin B dye solution at room temperature and
evaluated at superficial margins as marginal leakage (ML) for dye penetration.
Each sample was then longitudinally sectioned, and leakage was expressed as % dye
penetration of the total cavity wall, longitudinal leakage (LL). Finally, each
tooth was dissolved (10%H3PO4 for 48 hours and NaOCl solution for additional 24
hours) to leave only the resin restoration. The internal walls of each
restoration were then inspected by SEM at x1,000-15,000 to evaluate the presence
of resin-dentin infiltrated layer (hybrid layer) and to calculate the ability of
primer/bonding to infiltrate peritubular dentin and to form resin tags. RESULTS:
Gap widths were 2-6 microns at dentin and lower at enamel. Several enamel
fractures along the margin were observed. Resin tags were observed only in deeper
dentin. Only Prime & Bond 2.0/Dyract formed resin tags at medium-superficial
dentin. The length of resin tags ranged from 1-6 microns for Dyract-PSA primer to
100 microns for Prime & Bond 2.0. Marginal and longitudinal leakage was observed
both at dentin and enamel levels. The best dentin seal was obtained with Prime &
Bond 2.0/Dyract, while enamel seals were equivalent with both bonding systems (P
> 0.05). No correlations were demonstrated between leakage and SEM observations.
PMID- 9545891
TI - Effect of HEMA-containing dentin desensitizers on shear bond strength of a resin
cement.
AB - PURPOSE: To determine whether the use of two HEMA-containing dentin desensitizing
agents [Health-Dent Desensitizer with fluoride (H) or Gluma Desensitizer (G)],
when applied at simulated "cavity preparation" and "cementation" appointments,
affects the bond strength of lab processed resin composite restorations cemented
to dentin. MATERIALS AND METHODS: The occlusal surfaces of 70 teeth were ground
flat to expose dentin and polished to 600 grit. Teeth were randomly assigned to
seven groups (n = 10). The treatments were applied in two sessions in order to
simulate cavity preparation and cementation appointments. Water (W) was applied
as a control instead of a desensitizing agent. H or G were applied for 30 seconds
with a rubbing motion (1) at preparation appointment (HW and GW), or (2) at
cementation appointment, after etching (WH and WG), or (3) at both sessions (HH
and GG). In the control group, water was applied at both sessions (WW). All-Bond
2 and Dual Cement were used according to manufacturers' instructions to cement
pre-polymerized resin composite cylinders (4 mm diameter) to the dentin surfaces
using a force of 1.0 MPa. Specimens were thermocycled 300x and tested in shear
until failure. Data was analyzed using one-way ANOVA and Tukey's HSD test at
alpha = 0.05. RESULTS: Mean bond strength and standard deviations are reported in
MPa: GW = 7.4 +/- 6.0; WW = 7.7 +/- 5.8; HW = 8.2 +/- 4.3; WH = 10.8 +/- 6.2; GG
= 13.5 +/- 6.0; HH = 13.8 +/- 7.1; WG = 19.9 +/- 8.8. There were no significant
differences in bond strengths for GW, WW, HW, WH and GG. Shear bond strength for
WG and HH was significantly higher than all groups except for GG. Results of this
in vitro study indicate that the use of desensitizers at the preparation and/or
cementation appointment does not interfere with bond strengths of resin cement to
dentin.
PMID- 9545892
TI - Effect of two etching times on the sealing ability of Clearfil Liner Bond 2 in
Class V restorations.
AB - PURPOSE: To investigate the sealing ability of the Clearfil Liner Bond 2 self
etching primer in Class V restorations placed under clinical and laboratory
conditions. MATERIALS AND METHODS: Firstly, the influence of two etching times of
the self-etching primer were tested in vitro. In 10 Class V cavities (Group 1),
the self-etching primer was applied for 30 seconds on the enamel and dentin,
while in another 10 Class V cavities (Group 2) the etching time was 60 seconds.
Since the Group 2 samples showed the best in vitro sealing ability at both the
enamel and cementum-dentin sites, the teeth of Group 3 (10 restorations) were
restored as in Group 2 under clinical conditions, applying the self-etching
primer for 60 seconds. The sample teeth were extracted after 65-90 days, and then
processed for leakage. Two other groups of 10 samples each were prepared under
laboratory conditions to investigate hybrid layer, resin tags and adhesive
lateral branch formation. A flat buccal surface on each extracted tooth was
prepared. Group 4 samples were conditioned for 30 seconds, and those of Group 5
for 60 seconds. RESULTS: In Group 1, 40% of the restorations showed leakage at
the cementum-dentin site and 40% at the enamel site. Groups 2 and 3 showed
statistically significant difference (less leakage) than Group 1. In Group 2 and
3 no leakage was found at the enamel site, and only a moderate leakage (10% and
20% of restorations, respectively) was found at the cementum-dentin site. The
scanning electron microscopy observations of Group 4 samples showed a thin hybrid
layer, with well-fitting and smooth resin tags and adhesive lateral branches only
sporadically. Group 5 samples presented a thicker hybrid layer, rough and deep
resin tags with many adhesive lateral branches. The etch enamel pattern was more
uniform and rougher in Group 5 than in Group 4. The 60-second application time of
the self-etching primer seems to be more reliable than a shorter conditioning
time in day-to-day practice.
PMID- 9545893
TI - Bond strength of one-bottle dentin bonding agents on human dentin.
AB - PURPOSE: To evaluate the shear bond strength of one-bottle dentin bonding agents
(DBA's) (Prime & Bond 2.1, ART Experimental, Syntac Single Component) on
pressurized human dentin. MATERIALS AND METHODS: Freshly prepared dentin
specimens of human teeth were perfused with horse serum which was diluted 1:5 in
physiologic saline. Three different types of surface treatment were evaluated on
the freshly prepared dentin. Group 1: One of the three one-bottle DBA's was
applied onto freshly prepared dentin together with a cylinder of composite luting
resin and cured. Group 2: A provisional cement (Freegenol, without eugenol, or
Temp Bond, containing eugenol) was applied first on the dentin surface for 24 h.
Only then was one of the three the one-bottle DBA's added onto the dentin
together with a cylinder of composite luting resin after cleaning the dentin
surface with pumice. Group 3: One of the three one-bottle DBA's was applied first
on the dentin surface and light-cured. Then a provisional cement (Freegenol,
without eugenol, or Temp Bond, containing eugenol) was added for 24 h. After
cleaning with pumice, the respective one-bottle DBA was applied for a second time
onto the dentin together with a cylinder of composite luting resin and light
cured. As control for Group 1 (freshly prepared dentin), the two- or three-step
DBA's ART Bond and Syntac were used in a similar way. As control for Group 2
(single application of the DBA's after contamination of the dentin with a
provisional cement) and Group 3 (dual application of the DBA's with intermediate
contamination of the dentin with a provisional cement) the two-step DBA ART Bond
was used. After 1500 thermal cycles with constant imitation of intrapulpal
pressure, shear bond strengths were measured. Resulting shear bond strength
values were displayed by means of a box plot and they were analyzed statistically
by Student's t-Test or one-way ANOVA. RESULTS: Lowest and highest mean shear bond
strength values were 0.26 +/- 0.47 MPa (single use of ART Bond with prior
application of Temp Bond) and 16.34 +/- 5.02 MPa (dual use of ART Bond with
intermediate application of Temp Bond). With respect to the surface treatment
significant differences between the DBA's could be found in all groups.
PMID- 9545894
TI - Ultrastructure of the resin-dentin interface following reversible and
irreversible rewetting.
AB - PURPOSE: This study investigated the effect of reversible and irreversible
rewetting on the application of One-Step, single-bottle, water-free, acetone
based primer/adhesive. MATERIALS AND METHODS: Thirty 1 mm dentin discs prepared
from third molars were each conditioned with 10% H3PO4 for 20 seconds and rinsed
for 20 seconds. They were randomly divided into five groups: Group 1 (positive
control): conditioned dentin bonded visibly moist; Group 2: bonded after drying
for 3 seconds; Group 3: drying for 3 seconds and rewetting with distilled water;
Group 4 (negative control): drying for 3 seconds, stored in 8% glutaraldehyde for
15 minutes, rinsed with distilled water and dried for 3 seconds; and Group 5:
drying for 3 seconds, stored in glutaraldehyde for 15 minutes, rinsed with
distilled water and bonded visibly moist. One-Step was applied in two coats
according to the manufacturer's recommendation and discs in each group were
further bonded together to form a disc-pair using a chemical cure resin,
demineralized in EDTA and prepared for TEM examination. RESULTS: Complete resin
infiltration into the zone of demineralized dentin was observed in Group 1 and 3.
In Group 2, resin infiltration was limited to the surface and base of the
demineralized network apparently along the lateral branches of the dentin
tubules. A middle zone of suboptimal infiltration was observed. In Group 4 and 5,
minimal resin infiltration was only observed along the base of the demineralized
network upon their fixation in a collapsed state with glutaraldehyde.
PMID- 9545895
TI - Saliva contamination and bond strength of single-bottle adhesives to enamel and
dentin.
AB - PURPOSE: To determine and compare the shear bond strength of four single-bottle
adhesives to enamel and dentin contaminated with human saliva. MATERIALS AND
METHODS: Prime & Bond 2.1, One Step, Tenure Quik and Syntac Single Component were
evaluated. Ninety-six sound molars were divided into three subgroups for each of
the four adhesives. Small flat areas on the buccal and lingual surfaces were
ground in enamel. Small flat areas on the mesial and distal surfaces were ground
on the middle dentin of the same teeth. Each adhesive was tested under:
uncontaminated conditions (Group 1), contamination of the bonding surface with
fresh whole saliva for 20 seconds and removing the excess with cotton pellets
(Group 2), and contamination of the bonding surface with fresh whole saliva for
20 seconds and rinsing the saliva for 20 seconds before adhesive application
(Group 3). After adhesive application, a plastic mold was filled with composite,
applied to the bonding surface and light-cured. The teeth were thermocycled
(1,000 cycles) and sheared using an Instron testing machine. The results were
analyzed using a three-way ANOVA. RESULTS: Saliva contamination of enamel or
dentin did not affect the shear bond strength of the adhesives tested except for
Syntac SC with contaminated dried enamel. One Step displayed similar bond
strengths to both enamel and dentin; P & B 2.1, Tenure Q and Syntac SC displayed
higher bond strength to enamel than to dentin. P & B 2.1 showed significantly
higher bond strengths to enamel than the other adhesives, but there was no
significant difference for dentin bond strength under the uncontaminated
condition.
PMID- 9545896
TI - Effect of composite type, light intensity, configuration factor and laser
polymerization on polymerization contraction forces.
AB - PURPOSE: To investigate the effect of composite type, light intensity,
configuration factor and laser polymerization on polymerization contraction
force. MATERIALS AND METHODS: Glass rods (10 pairs/group) were etched with HF
acid, silanated, unfilled resin applied and light cured for 20 s. Rods were held
vertically in chucks on a Zwick machine. A cylindrical matrix was filled with
Silar chemical cure, Silux Plus microfill or Z-100 hybrid composite and the
crosshead of the UTM positioned at an inter-rod distance corresponding to a
specific ratio of bound to unbound composite surface area (configuration factor
or C). Exposure time with the Demetron 401 conventional visible light curing unit
(D401) was 40 s/side (80 s total). Exposure times for the ILT Model D5500 air
cooled laser (LAC) and Model 5500ABL water cooled laser (LWC) was 20 s/side (40 s
total). Experimental groups, n = 10 with constant factors in parentheses,
included: (1) Silar chemical-cured (C = 3); (2) Z-100 hybrid (C = 3, D401, 100%
intensity); (3) Silux Plus microfill (C = 3, D401, 100% intensity); (4) D401 100%
light intensity = 476 mW (Z-100, C = 3, D401); (5) D401 50% intensity = 238 mW (Z
100, C = 3, D401); (6) D401 25% intensity = 119 mW (Z-100, C = 3, D401); (7-9) C
= 5, 3 & 1 respectively (Z-100, D401, 100% intensity); (10) D401 with 13 mm tip =
391 mW/cm2 (Z-100, C = 3; D401); (11) D401 with Turbo Tip = 811 mW/cm2 (Z-100, C
= 3; D401); (12) LAC = 265 mW, 689 mW/cm2 (Z-100, C = 3); (13) LWC = 365 mW, 1100
mW/cm2 (Z-100, C = 3). One Way ANOVA and Duncan's Multiple Range Test (alpha =
0.05) were performed separately for each variable. RESULTS: Homogeneous subsets
by variable were: composite type Group 1 (25N) < Group 3 (65.8N) < Group 2
(90.4N); intensity Group 6 (73.9N) = Group 5 (77.7N) < Group 4 (90.4N); C-Factor
Group 7 (81.8N) < Group 8 (90.4N) < Group 9 (103.4N); light source Group 12
(77.4N) = Group 13 (79.1N) < Group 10 (90.4N) = Group 11.(89.4N). The chemical
cured composite had the lowest maximum polymerization contraction force, the
microfill was intermediate and the hybrid composite had the highest recorded
force. Increases in light intensity increased the maximum force on the force/time
curve. Maximum forces were inversely related to C-factor (C5 < C3 < C1) and
directly related to composite volume in a non-rigid system which allowed
compliance. Maximum force was not significantly different with the two tips
tested on the conventional curing light. Forces obtained with laser
polymerization were similar for the two laser groups, which were both
statistically lower than the conventional light tested.
PMID- 9545897
TI - Cavosurface margin geometry in conventional and air abrasion Class V cavity
preparations.
AB - PURPOSE: To compare cavosurface angle and area of missing tooth structure at the
cavosurface margin in cross-sections of Class V cavity preparations made with a
conventional carbide bur and with an air abrasive cavity preparation system.
MATERIALS AND METHODS: Class V cavity preparations were made with a #56 carbide
bur or with a KCP 1000 air abrasive unit. They were restored and sectioned
longitudinally, providing 43 margins for study. Cavo-surface angle and area of
missing tooth structure were measured for each margin from digital images of the
sections. The angle and area data was grouped according to margin location and
cavity preparation system and analyzed for differences using the Kruskal-Wallis
test. To determine if there was a relationship between the missing area and the
angle at the cavosurface margin, Lomb periodograms were analyzed. RESULTS:
Conventional cavity preparation margins had an average cavosurface angle less
than 90 degrees while the air abrasion margin angle was greater than 90 degrees.
Cavo-surface angles for conventional cavity preparations were significantly
different from cavosurface angles for air abrasion cavity preparations. Missing
areas at the cavosurface margin for conventional cavity preparations were not
significantly different from missing areas at the cavosurface margin for air
abrasion cavity preparations. Lomb periodograms showed no trend concerning the
missing area as a function of the angle. CONCLUSIONS: There was no significant
difference between the area of missing tooth structure at the cavosurface margin
in conventional vs. air abrasion cavity preparation. Cavosurface angle in
conventional preparations was less than 90 degrees, and greater than 90 degrees
in air abrasion cavity preparations. Cavosurface angle and area of missing tooth
structure at the cavosurface margin varied independently.
PMID- 9545898
TI - Surface integrity of composite inlays following ultrasonic vibration.
AB - PURPOSE: To assess the effect of ultrasonic vibration on the surface integrity of
a resin composite inlay. MATERIALS AND METHODS: Ultrasonic vibration in the form
of a scaling tip oriented either parallel or perpendicular to the surface was
applied to 2 mm thick, 10 mm wide composite discs and the experiment was repeated
with the probe oriented perpendicular using composite or rubber shields. The
indentations produced were measured using a form Talysurf profilometer. The
surfaces of the discs were also observed using scanning electron microscopy. Five
discs were used for each experiment. RESULTS: Both parallel and perpendicular
orientations produced an indentation with a scattering of composite debris. A
significant increase in the depth of indentation occurred if the vibrations of
the ultrasonic scaler were oriented parallel to the composite surface (Two sample
t- test, P < 0.01). The presence of a composite shield significantly reduced
(Mann-Whitney, P < 0.05) the depth of indentation but produced roughening of the
surface with impaction of material from the shield onto the surface. The rubber
shield, however, polished the surface significantly smoother than the control
specimens (Mann-Whitney, P < 0.05). Microscope slide separation was used to
measure the thickness of composite luting agent following vibration with an
ultrasonic scaling tip with and without a protective sleeve. There was a
significantly thinner film of luting agent when an unsleeved scaler was used
(ANOVA, P < 0.001). Although an unguarded tip oriented perpendicular to the
surface appears to result in the best energy transfer for a thin layer of
composite luting agent, it does, however, create minimal surface damage.
PMID- 9545899
TI - Effects of subgingival chlorhexidine irrigation on peri-implant maintenance.
AB - PURPOSE: To evaluate the effect of irrigation with 0.06% chlorhexidine
(PerioGard) (CHX) using a powered oral irrigator (Water Pik) with a special
subgingival irrigating tip (Pik Pocket Subgingival Tip) compared to rinsing with
0.12% chlorhexidine gluconate once daily. MATERIALS AND METHODS: Following a
prophylaxis, patients were randomly assigned to an irrigation or a rinse group.
The following clinical parameters were measured at baseline and at the 3-month
end of the study: Modified Gingival Index (MGI), Plaque Index (PI), Bleeding
Index (BI), and Calculus Index (CI). Also, a Stain Index (SI) was measured at 3
months. RESULTS: Patients irrigating with diluted CHX showed a statistically
significant reduction (P < 0.05) from their baseline in the MGI, PI, BI, and CI
scores at 3 months. In the rinse group both MGI and BI showed statistically
significant reduction from their baseline (P < 0.05) at 3 months. The rinse group
showed a nonsignificant (P > 0.05) increase from baseline in CI and a
nonsignificant decrease in PI. Intergroup comparisons showed that CHX irrigation
produced statistically significantly greater reductions than CHX rinsing in the
PI, MGI, and SI. The irrigation group also showed a greater reduction in BI and
CI than the rinsing group but these differences were not statistically
significant (P = 0.12). The results of this study suggest that use of diluted
0.06% CHX when used in a powered irrigator may be a valuable adjunct to oral
health in patients with implants.
PMID- 9545900
TI - Use of a clear matrix to minimize finishing of a posterior resin composite.
AB - This article describes the use of a clear matrix to duplicate the original
occlusal anatomy before placing a posterior resin composite. The technique
minimizes finishing procedures after the resin composite is placed.
PMID- 9545901
TI - Dental caries and sugar consumption into the 21st century.
AB - New trends towards the effect and role of sugar consumption in the etiology of
dental caries into the 21st century are presented, analyzed and discussed. Many
factors such as the amount of sugar consumed, the frequency of sugar intake and
the kind of sugars ingested have to be taken into consideration. Over the years,
the relative importance of these factors has changed. For a very long time, sugar
has been "blamed" as a primary etiological factor in the development of dental
caries. However, a number of recent reports have attributed a much less important
role to carbohydrates. Sugar consumption only does not affect caries prevalence
as much as it used to. It is obvious that the role of sugar in the etiology of
caries must be reviewed. Additional factors like overall nutrition, the number of
meals and snacks per day, education and motivation, fluoride (in tablets or
drops, in mouthwashes, toothpastes, baby foods, formulas, beverages, milk,
vitamin supplements and/or fluoridated water ingested), socioeconomic group,
ethnicity, oral hygiene status, use of preventive methods and sweeteners other
than sucrose are presented.
PMID- 9545902
TI - 2-year clinical evaluation of a gallium restorative alloy.
AB - PURPOSE: To assess the clinical performance of 2-year old gallium alloy
restorations. Parameters evaluated include: (1) fracture at the margins, (2)
tarnish, (3) surface roughness, (4) tooth fracture, (5) fracture through the body
of the restoration, and (6) any medical or dental conditions arising during the
study. MATERIALS AND METHODS: Nine patients received 30 Class I restorations of
Galloy gallium alloy. These were placed as conservatively as possible under a
rubber dam. Fifteen of the preparations were lined with a Bis-GMA resin to seal
the restoration from moisture. The other 15 preparations were sealed with
Amalgambond. After placement of the gallium alloy, the exposed surfaces of all
restorations were sealed with the Bis-GMA resin, and the occlusion was checked.
The restorations were examined at 2 weeks, 3 months, 6 months, 1 year and 2
years. RESULTS: At the 2-year recall, all restorations were intact with the
exception of one tooth fracture (cause unknown). Forty-five percent of the
restorations exhibited tarnish and 60% had a rough surface. The fracture at the
margins of these restorations was minimal, and no significant difference could be
found between those using Amalgambond and those sealed with the resin system. No
medical problems were reported by the patients, and postoperative sensitivity was
minimal.
PMID- 9545904
TI - Physical properties of composites cured with conventional light or argon laser.
AB - PURPOSE: To evaluate and compare diametral tensile strength (DTS), compressive
strength (CS) and flexural strength (FS) of a hybrid and a microfill resin
composite restorative material polymerized by an argon laser for 10 seconds
(AL10) and 20 seconds (AL20) vs. a conventional visible light for 40 seconds
(VL40). MATERIALS AND METHODS: Five specimens of resin composite, Herculite XRV,
shade A-2 and Durafill VS, shade B-2, were made for each set of physical
properties tested, for a total of 18 groups and 90 specimens. ANSI/ADA
Specification #27 for direct filling resins was used as the protocol for specimen
preparation and physical properties testing. An argon laser at approximately 285
mW, 6 mm beam size, power density of approximately 1,000 mW/cm2, and a
conventional visible light at approximately 470 mW, 13 mm beam size, power
density of approximately 354 mW/cm2, were used to polymerize the composite.
Samples were stored in water in light-proof containers at 37 degrees C for at
least 7 days and then tested on a Zwick universal testing machine. Mean DTS, CS
or FS (MPa) values were calculated for each group. RESULTS: Herculite XRV's
physical properties were not significantly affected by light source or exposure
time. Light source or exposure time had no significant effect on DTS for Durafill
VS. Significantly lower FS was found for Durafill VS, when cured for 10 seconds
with the argon laser compared to 20 seconds with the laser or 40 seconds with the
conventional light. In addition, significantly lower CS was found for the
Durafill VS when polymerized with the laser at 10 seconds compared to the
conventional light at 40 seconds.
PMID- 9545903
TI - 3-year clinical evaluation of a compomer, a resin-modified glass ionomer and a
resin composite in Class III restorations.
AB - PURPOSE: To evaluate and compare intra-individually a polyacid-modified resin
composite, commonly called compomer (Dyract), a resin-modified glass ionomer
cement (RM GIC)(Fuji II LC) and a resin composite (Pekafill) in Class III
cavities. MATERIALS AND METHODS: In 50 patients, 154 Class III restorations were
placed. Most patients received one of each of the experimental materials. At
baseline, 6 months, 1, 2 and 3 years the restorations were evaluated by slightly
modified USPHS criteria. RESULTS: At 3 years, 152 restorations were evaluated.
Two restorations were replaced, one due to fracture and one due to secondary
caries. The resin composite showed significantly better color match. A slight but
still acceptable color shift and increased surface roughness was seen for the RM
GIC. The compomer and the resin composite performed significantly better than the
RM GIC. No postoperative sensitivity was reported and no loss of vitality was
seen after use of the three different total etch techniques.
PMID- 9545905
TI - Handling and clinical performance of a glass ionomer sealant.
AB - PURPOSE: To compare the handling and 6-month clinical performance of an
experimental resin-modified glass ionomer cement (K-512 = Fuji III LC) with that
of a light-cured resin-based sealant (Delton Opaque) when used as a pit and
fissure sealant in 15-27 year old subjects. MATERIALS AND METHODS: Seventeen
patients with 65 cement and 55 resin-based sealants were recalled after 6 months
for clinical examination and color photographs. RESULTS: Sealant retention
failures requiring retreatment were 74% for the glass ionomer cement sealant and
11% for the resin-based sealant, with one instance of fissure caries being found
for each material. The resin-modified glass ionomer cement sealant showed a
slight darkening from its initial placement, and was also more difficult to
handle than the resin-based sealant.
PMID- 9545906
TI - Laboratory evaluation of one-component enamel/dentin bonding agents.
AB - PURPOSE: To evaluate the bonding efficacy of five commercial and one experimental
one-component enamel/dentin adhesives. MATERIALS AND METHODS: The adhesives One
Step (BOS), Primabond (PAB), Prime & Bond 2.0 (PB2), Solist (SOL), Tenure Quik
(TEQ), and an experimental compound (EXP) were investigated. The adhesives were
used to bond a hybrid-type resin composite to enamel and dentin. Shear bond
strength (SBS) to human teeth was determined after 24-hour storage in water. The
marginal performance was evaluated on restorations in 3.5 mm wide cylindrical
dentin cavities as the maximum gap width found 15 minutes after light activation.
The hybrid layer thicknesses at the cavity margin were measured by light
microscopy. RESULTS: Mean SBSs to enamel were between 23 and 35 MPa, those to
dentin between 3.5 and 25 MPa. BOS and EXP showed the highest bond strengths to
dentin and consistently gap-free restorations. PB2 mediated significantly lower
SBS to dentin; only three of the six restorations were gap-free. SOL exhibited
poor marginal quality (mean MGW 7.5 microns) despite 15 MPa dentin bond strength.
PAB and TEQ demonstrated very low SBS to dentin. None of the restorations with
these products was gap-free. All adhesives produced hybrid layers between 2 and
10 microns thick, as a coupling zone between dentin and restoration. Adhesives
with the essential components of wetting monomer, well-polymerizing
dimethacrylate, and acetone as the water-chasing solvent, performed very well
when used with a moist bonding technique.
PMID- 9545907
TI - Variation in phosphoric acid concentration and treatment time and HEMA diffusion
through dentin.
AB - PURPOSE: The effects of phosphoric acid concentration and time of dentin
treatment on the movement of 2-hydroxyethylmethacrylate (HEMA) from a bonding
resin-resin composite combination through dentin were investigated in vitro.
MATERIALS AND METHODS: Freshly extracted human third molar teeth were divided
into seven groups each of 10 teeth. A closed chamber was attached to the CEJ of
each tooth to contain 1 ml distilled water. An occlusal cavity of 6 mm diameter
and remaining dentin thickness of 1.0-1.5 mm was prepared in each tooth. Dentin
was treated with either 10% phosphoric acid for 15, 30 or 60 seconds or with 37%
phosphoric acid for 15, 30 or 60 seconds. A control group not treated with acid
was also prepared. The cavities were rinsed, dried and then treated with the HEMA
containing Scotchbond Multi-Purpose bonding resin which was light-cured for 10
seconds. The cavities were then restored with Z100 and light-cured for 30
seconds. Water samples were retrieved from the chambers over a time course (4.32,
14.4, 43.2, 144 & 432 minutes; 1, 3 and 10 days) and analyzed by high performance
liquid chromatography. RESULTS: HEMA was detected in the pulp chambers of all
teeth from 4.32 minutes after resin placement. Mean total (cumulative) release at
10 days for all groups was in the 2-4 mumol range. The highest HEMA diffusion
rate was 4.32 minutes after placement and were in the range 6-13 times greater
than control in the 10%-15 seconds, 10%-30 seconds, 10%-60 seconds, 37%-15
seconds, and 37%-30 seconds groups. Unexpectedly, by far the lowest early rate at
4.32 minutes was in the 37%-60 seconds group (0.6 times of no-acid control).
PMID- 9545908
TI - Effects of viscosity and surface moisture on bond strengths of resin-modified
glass ionomers.
AB - PURPOSE: To evaluate the effects of surface moisture and material viscosity on
the shear bond strength of resin-modified glass ionomers to dentin. MATERIALS AND
METHODS: Sixty human teeth were mounted in phenolic rings and ground to obtain
flat facial and lingual dentin surfaces. The specimens were assigned to six
treatment groups. Three groups were first conditioned with 10% polyacrylic acid.
On one surface of each specimen, dentin was left visibly moist prior to
application of the restorative material. On the opposite surface the dentin was
dried, but not desiccated, after conditioning. For these three groups, Fuji II LC
resin-modified glass ionomer was mixed at powder/liquid (P/L) ratios of 1.4, 3.0
and 3.6 and applied to the conditioned dentin in 2.5 mm diameter molds. The other
three groups were treated with Vitremer primer. One surface of each specimen was
"dry" and one surface was "moist" before primer application. Vitremer restorative
material was mixed at P/L ratios of 2.2, 2.5 and 2.8 and applied to the primed
surfaces. Shear bond strengths were measured using a universal testing machine.
Data were subjected to three-way ANOVA and Tukey's multiple comparisons test.
RESULTS: Mean shear bond strengths of the two materials ranged from 6.9 to 10.4
MPa and varied little regardless of the viscosity of the materials or the degree
of surface moistness. The differences among viscosities and surface moistness
were not statistically significant. IN this in vitro study, the shear bond
strengths of two resin-modified glass ionomers were unaffected by the viscosity
of the materials and the surface moisture of the dentin substrate.
PMID- 9545909
TI - Bond strengths of fluoride-releasing restorative materials.
AB - PURPOSE: To compare the shear bond strengths to dentin of four tooth-colored
fluoride-releasing restorative materials that utilize different mechanisms of
dentin-bonding. MATERIALS AND METHODS: Four materials were tested: a chemically
cured glass ionomer (Ketac-Fil); a light-cured resin-modified glass ionomer
(Photac-Fil); a light-cured resin-modified glass ionomer in conjunction with a
resin dentin-bonding agent (Vitremer); and a light-cured resin composite in
conjunction with a resin dentin-bonding agent (Tetric). The enamel was removed
from four sides of the twenty human noncarious extracted molars which had their
roots embedded in acrylic blocks. Cylindrical samples of the materials were
prepared in plastic molds and bonded to the dentin surface according to the
manufacturers' instructions. After 24 hours of storage in a humidor, the samples
were sheared with an Instron testing machine at a crosshead speed of 0.5
mm/minute. RESULTS: Statistical evaluation (ANOVA and Duncan's test) suggests
that the fluoride-releasing resin composite material utilizing a resin dentin
bonding agent provided a significantly greater mean shear bond strength (16.5
MPa) after 24 hours storage than any of the selected glass ionomer materials. Of
the three glass ionomer materials compared, the light-cured resin-modified
material with a resin dentin-bonding agent provided a significantly greater mean
shear bond strength (6.7 MPa) than the light-cured resin-modified material
without a resin dentin-bonding agent (3.0 MPa) or the chemically-cured material
(3.8 MPa).
PMID- 9545911
TI - A fiber composite laminate endodontic post and core.
AB - The goals of endodontic post and core procedures are to provide maximum retention
of the post and resistance to fracture of the roots. Presented is a recently
developed fiber composite laminate (FCL) post and core technique which results in
a bonded structure that is conservative, morphologic, retentive, versatile,
esthetic, and helps resist root fracture. To ascertain the durability of FCL
posts and cores, an in vitro pilot study with stress testing is included. The
results of the study are compared to other post and core materials to show how
well this technique approaches the ideal characteristics for endodontic post and
cores.
PMID- 9545910
TI - Bond strength to crown and root dentin.
AB - PURPOSE: To investigate (1) the tensile bond strengths of four commercial dentin
bonding systems to bovine crown and root dentin and (2) the structure of the
hybrid layers for each system bonded to the two dentin substrates. MATERIALS AND
METHODS: Superficial surfaces were exposed in bovine crown and root dentin. The
teeth were embedded in plaster and a 3 mm diameter bonding area was demarcated.
The four bonding systems used were All-Bond 2, Super-Bond D-Liner Plus, Clearfil
Liner Bond II, and ProBond. Bonding procedures followed the manufacturers'
instructions with the exception of Super-Bond D-Liner Plus where the primer was
left in situ for 60 seconds. Tensile bond strengths were tested after 24-hour
storage in 37 degrees C deionized water. Specimens were also prepared for SEM
observation of the hybrid layer, after treatment with 10% phosphoric acid, and
10% phosphoric acid and 5% sodium hypochlorite. RESULTS: Statistically lower bond
strengths to crown dentin when compared with root dentin were observed for All
Bond 2, whereas Liner Bond II showed the opposite (P < 0.01). Both ProBond and
Super-Bond D-Liner Plus showed no statistical differences between crown and root
dentin (P > 0.05). Hybrid layers could be observed for All-Bond 2, Liner Bond II
and Super-Bond D-Liner Plus, with no apparent differences between the hybrid
layers of crown and root dentin. In the case of ProBond, where the smear layer
was not removed during the priming stage, it appeared that the primer had
infiltrated and caused hybridization of the smear layer. The differences in bond
strength were thought to be related to the different bonding mechanisms of each
material, as well as possible variations in the crown and root dentin substrates.
PMID- 9545912
TI - One step bond strength to enamel and dentin.
AB - PURPOSE: To evaluate the shear bond strength over a variety of conditions of a
new dental adhesive having the primer and bonding resin in a single bottle.
MATERIALS AND METHODS: Facial surfaces of extracted human molars for the dentin
study and labial surfaces of incisors were treated with the One-Step adhesive
after both etching and nonetching, variable etching times and variable rinsing
times. Composite cylinders were attached and shear bond strengths were obtained.
RESULTS: The bond strength data was quite consistent over a wide variety of
conditions. The bond strengths were in the range of 23-29 MPa to dentin, and
compared favorably with the performance of the adhesive to etched enamel
surfaces.
PMID- 9545913
TI - Surface treatment effects on amalgam repair strength.
AB - PURPOSE: To determine whether the use of microetching and bonding agents could
improve the shear bond strength between aged and freshly added dental amalgam,
simulating an amalgam repair. MATERIALS AND METHODS: Aged amalgam surfaces were
treated with either a carbide bur or carbide bur + microetcher (Al2O3 abrasive).
Five commercially-available adhesive systems were tested. Fresh amalgam was
condensed through a split mold onto each prepared amalgam surface. Two control
groups were included: a positive control consisting of non-repaired amalgam, and
a negative control consisting of aged specimens which received neither carbide
bur nor microetching preparation prior to the addition of fresh amalgam. In
addition, one group received only carbide bur and another received only carbide
bur and microetching treatments, without any adhesive. Following storage and
thermocycling, each specimen was tested for shear bond strength. RESULTS: The
mean shear bond strength of the repaired samples treated with carbide bur alone
(25.8 MPa) was not exceeded by any of the other treatments. Neither microetching
nor use of an adhesive agent significantly improved amalgam-to-amalgam shear bond
strength. In some cases, use of an adhesive agent significantly decreased the
shear bond strength of repaired amalgam samples.
PMID- 9545914
TI - Surface hardness and wear of glass ionomers and compomers.
AB - PURPOSE: To determine the surface hardness and in vitro wear of glass ionomer
cements (GIC) and compomers in comparison with a resin composite and to test for
a possible correlation between the determined hardness and wear values. MATERIALS
AND METHODS: Samples were made of conventional GIC (Ketac-Fil, Fuji II, Fuji IX,
Ketac-Prototype = Ketac-Molar), resin-modified GIC (Photac-Fil, Fuji II LC,
Vitremer), compomers (Dyract, Compoglass) and resin composite (Z100) for the
hardness test (n = 10) and for the wear test (n = 3). The materials were handled
according to the manufacturers' instructions. The samples were stored in
deionized water for 48 hours at 37 degrees C prior to the determination of
Rockwell hardness and three-body in vitro wear. RESULTS: Hardness could not be
measured on Ketac-Fil and Fuji II as the samples fractured before a reading was
obtainable. Statistically significant differences were found in hardness and wear
between brands and between the four types of material. Surface hardness: resin
modified GIC < conventional GIC = compomers < resin composite. In vitro wear:
resin-modified GIC > compomers > conventional GIC > resin composite. A negative
correlation between hardness and wear was recorded.
PMID- 9545915
TI - Clinical evaluation of glass ionomers and compomers in Class V carious lesions.
AB - PURPOSE: To evaluate the 2-year clinical performance of two polyacid-modified
resin composites and two resin-modified glass ionomers in Class V carious
cavities. MATERIALS AND METHODS: A total of 120 Class V cavities were selected
and 30 cavities were restored with one of two resin-modified glass ionomer
materials (Fuji II LC Improved and Vitremer) and two polyacid-modified resin
composites (Dyract and Compoglass) in Class V carious cavities after 2 years. The
restorations were clinically evaluated after 1 and 2 years using the USPHS
criteria. RESULTS: One-year findings revealed a significant difference in color
match between Vitremer and other materials (P < 0.05) and no significant
difference was found for the other criteria. Two-year results indicated a
significant difference between resin-modified glass ionomers and polyacid
modified resin composite materials. The difference between Compoglass and Dyract
was not statistically significant whereas the difference between Vitremer and
Fuji II LC was statistically significant. Caries was not recorded at any
evaluation period.
PMID- 9545916
TI - Dentin desensitizing agents: SEM and X-ray microanalysis assessment.
AB - PURPOSE: To evaluate the effect of four proprietary dentin desensitizing agents
on dentin tubular occlusion, chemical composition changes on the dentin surface,
and the effect of saliva and toothbrushing on these agents. MATERIALS AND
METHODS: Fifty dentin discs, obtained from 50 freshly extracted human premolar
and molar teeth were used in this study. These were divided into five groups of
10 discs each. Five discs from each group were treated with the desensitizing
agents, viewed under the SEM and subjected to energy dispersive X-ray analysis.
The other five discs were treated with the desensitizing agents, immersed in
artificial saliva, subjected to simulated toothbrushing equivalent to 3 weeks of
normal brushing and viewed under the SEM. The agents studied were Sensodyne
Dentin Desensitizer, Therma-Trol Desensitizer Gel, Gluma Desensitizer and All
Bond DS. RESULTS: The Kruskal-Wallis test followed by the Wilcoxon signed-rank
test showed that Sensodyne Dentin Desensitizer exhibited the greatest amount of
tubular occlusion among the unbrushed samples, followed by Therma-Trol
Desensitizer Gel, Gluma Desensitizer and All-Bond DS (P < 0.05) in that order.
Toothbrushing increased tubular occlusion in all cases except the Sensodyne
Dentin Desensitizer treated samples.
PMID- 9545917
TI - Dentin bond strength of Dyract Cem.
AB - PURPOSE: To evaluate the influence of provisional cements and of a dentin bonding
agent on the adhesion of a self-curing polyacid-modified resin composite (Dyract
Cem) on pressurized human dentin. MATERIALS AND METHODS: Freshly prepared dentin
specimens of human teeth were perfused with physiologic saline. Three different
types of surface treatment were evaluated. (1) Dyract Cem was applied to freshly
prepared dentin without (Group 1.1) or with (Group 1.2) the respective dentin
bonding agent (Prime & Bond 2.0) and cured. (2) Freegenol (Groups 2.1 and 2.2) or
Temp Bond (Groups 2.3 and 2.4) were applied first on the dentin surface for 24
hours. Only then was Dyract Cem (with or without Prime & Bond 2.0) added onto the
dentin after cleaning the dentin surface with pumice. 3) Prime & Bond 2.0 was
applied first on the dentin surface and cured. Then Freegenol (Group 3.1) or Temp
Bond (Group 3.2) were added for 24 hours. After cleaning with pumice, Prime &
Bond 2.0 was applied for a second time on the dentin (= dual application) and
finally Dyract Cem was added. As control, a conventional glass ionomer cement
(Ketac-Cem Maxicap; Groups 4.1-4.3) was used in a similar way. After 1,500
thermal cycles with constant imitation of intrapulpal pressure, shear bond
strengths were measured. Resulting shear bond strength values were displayed by
means of a box plot and they were analyzed statistically by Mann-Whitney, Kruskal
Wallis or one way ANOVA tests. RESULTS: Lowest and highest mean shear bond
strength values were 0.27 +/- 0.42 MPa (Group 2.4; single use of Prime & Bond 2.0
with prior application of TempBond) and 5.84 +/- 3.36 MPa (Group 3.1; dual use of
Prime & Bond 2.0 with intermediate application of Freegenol). A clearly
significant difference between groups could only be found when a single or dual
use of the dentin bonding agent Prime & Bond 2.0 were combined with either
Freegenol (Groups 2.1, 2.2 and 3.1; Kruskal-Wallis: P < 0.01) or Temp Bond
(Groups 2.3, 2.4 and 3.2; Kruskal-Wallis: P < 0.001) as additional dentin surface
treatment.
PMID- 9545918
TI - Effect of cavity design on microleakage of resin-modified glass ionomer
restorations.
AB - PURPOSE: To investigate cavity sealing with resin-modified glass ionomer cements
(RGIC) and a compomer relative to the design of Class V cavities crossing the
CEJ. MATERIALS AND METHODS: Three types of cavities, 6 x 3 x 1.5 mm, were
prepared buccally in human molars. Type 1: semicircular with 90 degrees cavo
surface angle; Type 2: as type 1, but with bevelled enamel margin; Type 3: V
shaped. The cavities were restored with the compomer Dyract (DYR), with one of
the RGIC, Fuji II LC (FUJ), Photac-Fil (PHF) or Vitremer (VIT), or with the
bonded resin composite system Gluma-CPS/Pekafill (GLP) as a reference. Six
restorations in each group were finished immediately after curing and
thermocycled 1500 between 5 degrees C and 55 degrees C. For Type 1 restorations,
another set of six samples was stored in 23 degrees C water for 24 hours. After
thermocycling and water storage, respectively, the specimens were immersed in
0.1% fuchsin. Two sections were made through the restoration to register
microleakage on the four surfaces produced as depth of dye penetration coronally
and apically by scores 0 (no) to 4 (beyond deepest part of cavity). The results
were statistically analyzed by cavity type, site, and restorative material using
Kruskal-Wallis ANOVA and Wilcoxon's two sample test at P = 0.05. RESULTS: When
compared with water storage, thermocycling had no effect on dye penetration with
FUJ and PHF, yet more pronounced microleakage at the enamel site was noted with
DYR and VIT, and apically with DYR and GLP. Type 1 restorations leaked more than
type 2 and 3 cavities for FUJ, VIT and GLP.
PMID- 9545919
TI - Rechargeability of fluoride releasing pit and fissure sealants and restorative
resin composites.
AB - PURPOSE: To evaluate the effect of exposure of 1.23% acidulated phosphate
fluoride gel on fluoride release from fluoride releasing pit and fissure sealants
and restorative resin composites. MATERIALS AND METHODS: Specimens of four
fluoride releasing pit and fissure sealants (Helioseal F, Ultraseal XT, Seal Rite
Low Viscosity and Seal Rite-Regular Viscosity) and two fluoride releasing
restorative resin composites (Tetric and Heliomolar Radiopaque) were prepared
using a Teflon mold. The specimens were divided into two groups. The experimental
group was exposed to 1.23% acidulated phosphate fluoride gel and the control
group was exposed to 1.23% acidulated phosphate gel without fluoride. The
specimens were stored in deionized water and the fluoride concentration of the
solution was measured every 24 hours. On day 7, the discs were exposed to the
respective gel for 4 minutes and then rinsed in a continuous stream of deionized
water for 30 seconds. The fluoride concentration was then measured for another 7
days. RESULTS: There was a significant increase after the fluoride gel treatment
in the amount of fluoride released from all of the materials studied. When the
cumulative amount of fluoride released was evaluated, Tetric, Heliomolar
radiopaque, Helioseal F, and Ultraseal XT released significantly (P < 0.01) more
fluoride than the respective control groups. There was no significant difference
between groups from day 8 to day 14 for Seal Rite-Regular Viscosity and Seal Rite
Low Viscosity.
PMID- 9545920
TI - Effect of implant curets on titanium implant surfaces.
AB - PURPOSE: To compare the surface roughness produced by various implant curets on
titanium implant abutment surfaces. MATERIALS AND METHODS: Each of six titanium
implants was divided into four quadrants, three experimental and an untreated
control surface. The three experimental surfaces were instrumented with a gold
platinum curet, an unreinforced resin curet, or a reinforced resin curet. Two
implants were assigned to each of the following treatments: 128, 256 or 512
scaling strokes within a 4 mm wide area. Photographs were taken of the surfaces
with a scanning electron microscope at approximately x500 magnification and
classified by six investigators according to surface roughness. RESULTS: The
surfaces were different at 8 and 16 years with P < 0.01 and P < 0.0005,
respectively. At 8 years, the surface roughness was significant between the
treatments in the following ascending order: untreated, unreinforced resin curet,
reinforced resin curet and gold platinum curet. Significant roughness was
observed for surfaces treated by only the gold platinum curet and the reinforced
resin curet at 16 years. The gold platinum curet created the roughest surface P <
0.0006.
PMID- 9545921
TI - Effect of fit adjustment on CEREC CAD-CAM veneers.
AB - PURPOSE: To measure and compare the adaptation of CEREC CAD-CAM porcelain veneers
with and without fit adjustment. MATERIALS AND METHODS: Two groups of porcelain
veneers were fabricated using the CEREC CAD-CAM technique for standardized
preparations on 10 artificial teeth. Mesial preparation contacts were broken, but
distal contacts remained intact. One group was adjusted using a disclosing spray
to improve fit, another group made for the same teeth was not adjusted before
cementation. The veneers were cemented in a standardized manner to their teeth.
The veneers and their attached cement were retrieved, embedded in epoxy resin and
sectioned twice to produce eight sections. Each section was measured at three
defined points from the external surface inwards. RESULTS: Three-way ANOVA
disclosed that fit adjustment was relatively ineffective (P approximately 0.05),
but that measurement section location, measurement point location and their
interaction significantly affected fit (P < 0.05). Restoration of the broken
proximal contact, or simulated diastema closure did not compromise fit. Incisal
margins ranked worst for fit. Surface measurement point locations ranked worse
than internal points. The fit of these CEREC CAD-CAM veneers was not
substantially different from previously published fit values for conventional
porcelain veneers.
PMID- 9545922
TI - Clinical application of a direct placement mercury-free alloy.
AB - This article provides information about a recently introduced, mercury-free
restorative alloy. This direct placement alloy uses gallium rather than mercury
to mix the alloy particles. The material has recently been approved for use in
the United States. Although its handling and physical properties are similar in
most ways to amalgam, there are a few differences that require careful attention
to assure success for the restoration. This article discusses these handling
characteristics, the procedures for placement, and offers specific directions and
recommendations to avoid potential problems with its use. Information on recent
clinical research is included in the article.
PMID- 9545923
TI - One visit composite onlay utilizing a new flexible model material.
AB - Fabrication of a composite inlay/onlay utilizing a flexible model is described as
a direct alternative to direct composite placement.
PMID- 9545924
TI - The need for well-controlled clinical studies.
PMID- 9545925
TI - Immediate loading of Branemark implants in edentulous mandibles: a preliminary
report.
AB - A study involving the immediate loading of Branemark implants in the edentulous
mandibles of 10 patients is reported. The design involved the immediate loading
of four widely distributed implants with a transitional fixed implant-supported
prosthesis at first-stage surgery, avoiding the need for a removable prosthesis.
A sufficient number of additional implants are allowed to heal in the
conventional manner to provide sufficient support for a definitive fixed
prosthesis even if all of the immediately loaded implants fail. Preliminary
results have been favorable, with all patients functioning with a fixed implant
prosthesis from the day of first-stage surgery.
PMID- 9545926
TI - Osteoconductive properties and efficacy of resorbable bioactive glass as a bone
grafting material.
AB - The height of the available bone between the alveolar ridge and the sinus is
often insufficient for placing endosseous implants in the posterior maxilla.
Subantral augmentation after sinus elevation can be performed using bone-grafting
materials such as autogenous bone, allografts, and alloplasts. The properties and
performance of a recently developed resorbable bioactive glass (BioGran) were
investigated with regard to bioactivity and bone-forming capability. The
bioactive glass was grafted into the sinus cavities of 25 patients and biopsies
were taken after 7 months. The samples were examined by conventional histologic
techniques, elemental composition and distribution assayed by an electron probe
microanalyzer, and comparative biomechanical data for BioGran and bone tissue
gathered. Histologic and biomechanical examination indicated bone formation in
all cases, with biomechanical properties of the regenerated bone close to those
of bone tissue. The results of this study suggest that BioGran exhibits
osteoconductive properties and efficacy as an alloplastic bone-grafting material.
PMID- 9545928
TI - Long-term efficacy of hydroxyapatite-coated cylindrical implants.
AB - A two-site clinical study of hydroxyapatite-coated cylindrical titanium alloy
implants was undertaken to evaluate their efficacy. Observations were recorded
before surgery, at first-stage surgery, at second-stage surgery, at loading, and
at quarterly postrestoration prophylactic examinations and annual comprehensive
patient visits. Implant failure criteria included mobility, peri-implant
radiolucency, fracture, exfoliation, removal for any reason, and patient reported
pain on palpation. Soft tissue indices were monitored as part of the study.
Postrestoration implant performance was analyzed using life table methodology.
From the 316 implants restored in 154 patients, 11 implants in 8 patients failed
before prosthetic attachment, for a surgical success rate of 96.4 percent. Four
implants failed during an observation period extending up to 85 months after
completion of prosthetic treatment. The Cutler-Ederer life table success rate
after 6 years was 97.8 percent. No significant adverse events were reported
during the observation period. Results of this investigation suggest that
hydroxyapatite-coated cylindrical titanium alloy implants are an effective
treatment modality.
PMID- 9545927
TI - Reconstruction of a severely atrophic maxilla using a Le Fort I downgraft and
dental implants: clinical report.
AB - A 55-year-old woman developed chronic infections of the maxillary sinuses with
osteomyelitis resulting in extensive bone destruction and atrophy from a failed
subperiosteal implant. After surgical removal of the subperiosteal implant,
extensive debridement of the maxilla, and long-term antibiotic therapy, maxillary
reconstruction was initiated. A Le Fort I osteotomy and downgraft was performed,
and a posterior iliac bone graft was harvested and grafted to reconstruct the
severely atrophic maxilla. In a later surgical procedure, maxillary and
mandibular implants were placed. Implant-retained overdentures were fabricated to
restore function and esthetics.
PMID- 9545929
TI - Fitting and securing abutments to implant heads: technical note.
AB - Access and visualization in the implant-abutment area are often compromised.
Tissue impingement and lack of abutment position verification may result in
inaccurate fit.
PMID- 9545930
TI - The Second International Implantology Congress. Bangkok, Thailand, January 18-20,
1997. Abstracts.
PMID- 9545931
TI - Evaluation of the antibacterial activities of calcium hydroxide, chlorhexidine,
and camphorated paramonochlorophenol as intracanal medicament. A clinical and
laboratory study.
AB - The antibacterial activities of camphorated paramonochlorophenol, chlorhexidine,
and calcium hydroxide were compared using a clinical and laboratory evaluation.
In the clinical experiment, root canals that yielded positive cultures a week
after complete chemomechanical preparation and camphorated paramonochlorophenol
dressing were medicated with one of the three substances tested. Postmedication
samples were taken from the canal 1 week later. In the laboratory experiment, the
agar diffusion test was used to evaluate the inhibitory activity of the
medicaments against bacteria commonly found in endodontic infections. The results
of the clinical evaluation showed that all medicaments were effective in reducing
or eliminating the endodontic microbiota, as demonstrated by the incidence of
negative cultures. There was no statistically significant difference among the
medicaments tested. In the laboratory evaluation, camphorated
paramonochlorophenol showed the largest zones of bacterial inhibition against all
bacterial strains tested.
PMID- 9545932
TI - Root canal cleanliness after preparation with different endodontic handpieces and
hand instruments: a comparative SEM investigation.
AB - The root canals of 150 extracted mandibular incisors were prepared to ISO 30
using eight different automated devices and hand instruments. The automated
devices investigated were: Endoplaner, Excalibur, Ultrasonics (Piezon Master 400)
with H2O2 (5%), or NaOCl (1%) as irrigants, Giromatic, Intra-Endo 3-LDSY, Canal
Finder System, Canal Leader 2000, and Endolift. Hand instrumentation was
performed using reamers and Hedstroem files. Fifteen teeth were instrumented with
each device, cracked longitudinally, and investigated under the scanning electron
microscope using five category scoring systems based on reference photographs for
debris and smear layer. No preparation system or technique resulted in complete
removal of smear layer and debris. The ultrasonic unit performed best followed by
the Canal Leader 2000 and hand instrumentation, whereas the use of the Giromatic,
the Endolift, the Canal Finder System, and the Intra-Endo-3-LDSY-handpiece
resulted in insufficiently cleaned root canal walls.
PMID- 9545933
TI - Warm vertical compaction sequences in relation to gutta-percha temperature.
AB - The aim of this study was to analyze warm vertical compaction sequences in
relation to the temperature variations of gutta-percha. Twenty-four maxillary
incisors were obturated according to two different instrumentation techniques:
Compaction and heating were performed with either the monomanual classical or
bimanual method. To evaluate gutta-percha temperature, thermocouples (TC) were
introduced into channels bored through the dentin into the root canal system or
fixed on the root surface at 8 (TC8), 4 (TC4), 2 (TC2), and 0 mm (TC0) from the
apex. Maximal temperature was 118 degrees C for TC8, 52 degrees C for TC4, and 44
degrees C for TC2 and TC0. At TC0, the temperature remained above 42.9 degrees C
for 10 +/- 5 s. These results show the importance of heating down to a distance
of 7 mm to ensure a significant increase in apical gutta-percha temperature. They
further indicate that the last compaction should last more than 15 s to avoid
detrimental cooling and dimensional variations. The principal differences between
the monomanual and bimanual methods were the compaction time (5.07 +/- 0.2 min vs
4.02 +/- 0.3 min) and the number of compactions (8 +/- 1 vs 12 +/- 2).
PMID- 9545934
TI - An in vitro comparison of apical microleakage after obturation with JS Quick-Fill
or lateral condensation.
AB - Thirty extracted human single-root teeth were instrumented to #45 file size while
creating a continuous coronal taper. Canals were obturated with Roth 801 sealer
and either JS Quick-Fill or lateral condensation of gutta-percha. Mean apical
linear microleakage of India Ink was evaluated in cleared teeth using a
stereomicroscope. Significantly less leakage (p < 0.1) occurred with lateral
condensation than with JS Quick-Fill.
PMID- 9545935
TI - Comparison of the intraosseous biocompatibility of Dyract and Super EBA.
AB - The purpose of this study was to compare the intraosseous biocompatibility of
Dyract, a new hydrophilic glass-ionomer cement, to that of Super EBA. Twenty-four
New Zealand rabbits were anesthetized, one leg was shaved, the femur exposed, and
two holes were drilled through the cortical plate. The materials were loaded into
silicone carriers and inserted into the femur. Half of the rabbits were killed 4
weeks after implantation and the other half at 12 weeks and the femurs were
prepared using standard histological procedures. The tissue reactions were graded
from none to severe. At 4 weeks both materials showed slight to moderate
reactions, characterized by the presence of fibrous tissue interposition and
inflammatory cells. At 12 weeks, bone healing had occurred, despite the
persistence of some fibrous tissue interposition, and the reactions were
classified as slight. At both observation periods, statistical analysis failed to
show any difference between the two materials indicating that Dyract and Super
EBA had similar intraosseous biocompatibility.
PMID- 9545936
TI - Microleakage of temporary restorations after thermocycling and mechanical
loading.
AB - The marginal seal of four temporary filling materials in endodontic access
cavities was examined in vitro after thermocycling and mechanical loading using
dye penetration tests and a quantitative marginal analysis of replicas in the
SEM. Class I cavities were prepared in 44 extracted human molars and filled
either with Cavit, Kalsogen, IRM, or TERM. After setting the reaction and
thermocycling procedure, Cavit showed less microleakage in the dye penetration
test and fewer marginal crevices in the quantitative marginal analysis. After
loading, two Cavit fillings collapsed into the endodontic cavity. The marginal
conditions of TERM were comparable to Cavit after thermocycling and mechanical
loading. Kalsogen and IRM restorations demonstrated significantly increased
microleakage and a higher percentage of marginal crevices after thermocycling and
loading. In contrast to dye penetration tests, the effects of different factors
on the marginal integrity of temporary fillings can be examined with the replica
technique and quantitative marginal analysis.
PMID- 9545937
TI - Evaluation for cracks associated with ultrasonic root-end preparation of gutta
percha filled canals.
AB - Many clinicians use ultrasonics for root-end preparations. The purpose of this
study was to evaluate resected root-end surfaces of bilaterally matched human
teeth for cracks before and after ultrasonic root-end preparation. Twenty matched
pairs of extracted single rooted teeth were divided into two experimental groups.
In group 1, root-end resection was performed on uninstrumented teeth. In group 2,
root-end resection was performed after the canals were instrumented and filled
with gutta-percha. All teeth in both groups received root-end preparations using
ultrasonic instrumentation at low power. Two examiners evaluated the root-ends
after root-end resection and again after root-end preparation using zoom
magnification of 20x to 63x. The number, types, and location of cracks were
mapped. There were no significant differences when gutta-percha filled roots were
compared to uninstrumented roots with regard to the number or type of cracks
after root-end resection or root-end preparation. In addition, there were no
significant differences in the number or type of cracks following root resection
and ultrasonic root-end preparation when compared to teeth with root resection
alone.
PMID- 9545938
TI - An ultrastructural study of root canal walls in contact with endodontic
biomaterials.
AB - The aim of this in vitro study was to compare structural and ultrastructural
changes to the unmineralized extracellular matrix after using two root canal
restoration materials, one calcium hydroxide based and the other calcium oxide
based. Pig teeth were restored with no preliminary root canal preparation. The
filling materials were left in the root canals for 3, 8, 15, or 21 days.
Observations were carried out by scanning electron microscopy. Results showed
that when the calcium oxide-based material was used, it penetrated tubules and
the unmineralized extracellular matrix material was reduced to a minimum. Teeth
filled with the calcium hydroxide-based material were similar to control samples
with an intact predentine. These observations suggest that the calcium oxide
based material induces changes in the unmineralized extracellular matrix of the
endodontium.
PMID- 9545939
TI - Leakage of AH26 and Ketac-Endo used with injected warm gutta-percha.
AB - Condensing warm gutta-percha (GP) can greatly reduce the distance between the GP
and the root canal walls (RCW). Different sealers with different film thicknesses
may seal such close fits differently. With the use of a fluid transport model,
leakage of AH26 and Ketac-Endo used with injected warm GP to fill root canals was
measured. The distance between the condensed GP and RCW and the film thickness of
the two sealers was determined as well. After condensation, the distance between
GP and RCW was mostly less than 25 microns. AH26, with a film thickness of 39
microns, leaked more than Ketac-Endo (p < 0.05) of which the film thickness was
22 microns. It seems that film thickness of sealer is an influencing factor on
the sealing ability of a root canal filling when condensation of
thermoplasticized GP is performed.
PMID- 9545940
TI - Atypical odontalgia misdiagnosed as odontogenic pain: a case report and
discussion of treatment.
AB - Atypical odontalgia is characterized by prolonged periods of throbbing or burning
pain in the teeth or alveolar process, which occurs in the absence of any
identifiable odontogenic etiology. The pain may be bilateral and change in
location. This article presents two cases of atypical odontalgia that were
misdiagnosed and initially treated as pain of odontogenic origin. A therapeutic
regimen of tricyclic antidepressants alleviated the pain in one patient and was
unsuccessful in the second. These two cases demonstrate the importance of having
a thorough knowledge of both odontogenic and nonodontogenic causes of orofacial
pain as well as the need for careful diagnosis before undertaking any treatment.
PMID- 9545941
TI - Analysis of forces developed during obturations. Comparison of three gutta-percha
techniques.
AB - The aim of this study was to compare the forces developed during three obturation
techniques: warm vertical compaction (WVC), lateral condensation (LC), and
thermomechanical compaction (TMC). A force-analyzer device allowed us to record
and analyze the forces exerted during the obturations. The different methods,
which varied in instrumentation, duration, and compaction load, were studied from
graphs representing the force application sequences. In addition, the graphs
resulting from specific modifications in the LC technique (use of a single
spreader) and deliberately induced failures with TMC (with a too-small condensor
or with excessive load) were analyzed. The mean values for the vertical forces
for WVC, LC, and TMC were, respectively, 2.5 +/- 0.4 kg, 1.1 +/- 0.3 kg, and 1.65
+/- 0.2 kg. The mean values for the lateral forces were, respectively, 0.85 +/-
0.2 kg, 0.35 +/- 0.1 kg, and 0.5 +/- 0.2 kg. The use of graphs provides a new
approach to the analysis of obturation methods and may find its greatest
application in the teaching of these techniques. It also has the potential to
improve research into obturation technique.
PMID- 9545942
TI - Comparison between Sulphorhodamine-B dye staining and 51Cr-release method in
cytotoxicity assay of endodontic sealers.
AB - The aim of this study was to evaluate Sulphorhodamine-B (SRB) staining against
51Cr-release in cytotoxicity tests of six endodontic sealers, namely, MU sealer
(Mahidol University) ROCANAL 2, ROCANAL 3, Apexit, Endomethasone, and AH-26.
Monolayers (5 x 10(5) cells/ml) of the mouse cell line Mu-mu-1 were used as test
cells. Following incubation at 37 degrees C in 5% CO2 for 24 h in the presence of
each sealer, cells were stained with 0.4% SRB and the absorbance at 540 nm
determined as measure of cell viability. For 51Cr-release assay, cells were
labelled with 51Cr before testing with sealers, and radioactivity in the
supernatant was measured in a liquid scintillation counter. Both techniques
indicated that Apexit was the least toxic sealer. In view of the ease of
conducting SRB staining for tests of cell viability, this may be the method of
choice over 51Cr-release assay in the evaluation of endodontic sealer
cytotoxicity.
PMID- 9545943
TI - The degrees and configurations of mesial canal curvatures of mandibular first
molars.
AB - The objective of this study was to determine the frequency, degree of curvature,
and the configuration of mesiobuccal and mesiolingual root canals of mandibular
first molars. The degree of curvature and configuration of root canals creates
some technical difficulties to the clinician during biomechanical preparation.
Therefore this knowledge is essential for successful endodontic therapy. Six
hundred and ninety-seven freshly extracted mandibular first molars were used in
this study. After introducing 0.8 to 15 K reamers into the mesial root canals,
the teeth were radiographed in buccolingual (clinical) and mesiodistal (proximal)
directions. All samples showed curvatures at varying degrees in both views. There
was a significant correlation between the degree of primary curvature of
mesiobuccal and mesiolingual canals in clinical directions for total samples.
When the primary curvature values of the mesial root canals were evaluated in
Vertucci classification, the mesiobuccal and mesiolingual canals in Vertucci type
VI were found as significantly correlated (r = 0.7173, p < 0.05). A significant
correlation was seen between the secondary curvature values of clinical and
proximal views of mesiolingual canal in Vertucci type VI (r = 0.9891, p < 0.05).
The secondary curvature values in the clinical views of mesiobuccal and
mesiolingual canals were found as significantly correlated in Vertucci type II.
PMID- 9545944
TI - Detection of human IL-2 in normal and inflamed dental pulps.
AB - Irreversible pulpitis has been associated with an increase in the number of
pulpal T-cells. Interleukin-2 (IL-2) stimulates T-cell proliferation and signals
the release of other proinflammatory mediators associated with connective tissue
degradation. IL-2 has been suggested to be a useful marker of pathologic
inflammatory activity in periodontal and systemic disease conditions. The purpose
of this study was to analyze normal and inflamed dental pulps for the presence of
immunoreactive IL-2 (iIL-2). Normal healthy pulpal tissue was obtained from 17
impacted third molars and inflamed samples were obtained from 12 symptomatic
carious molars clinically diagnosed with irreversible pulpitis. Pulpal tissues
were collected, prepared, and analyzed for histological status and iIL-2
concentration by a modified ELISA technique. iIL-2 was detected in all vital
pulpal tissues. A t-test revealed significant differences in iIL-2 concentrations
when inflamed pulpal tissues were compared to normal healthy samples (T = -2.75,
p < 0.05). These results suggest that iIL-2 may serve as a marker of pathologic
inflammatory activity in irreversible pulpitis.
PMID- 9545945
TI - Cytotoxicity of Ketac Silver cement.
AB - The aim of this experiment was to investigate the effect of a glass ionomer
cement with silver particles (Ketac Silver) on pulp tissue. Class V cavities were
prepared in 60 healthy teeth scheduled for extraction for orthodontic reasons. A
base of Dycal was placed in each cavity. Thirty teeth were filled with Ketac
Silver and 30 with ZOE. Ten teeth of each group were extracted 15, 30, and 60
days later. At 15 days, the pulps in the Ketac group showed vacuolization and
disruption of the odontoblastic layer, edema, vasodilation, chronic inflammatory
infiltrate (CII), and necrosis. At 30 days, a necrotic odontoblastic layer,
severe CII, and extensive areas of necrosis were seen. At 60 days, pulp tissue
was almost completely necrotic. The ZOE control group showed a slight CII at 15
days. Our results suggest that under these experimental conditions, this cement
is highly toxic and induces irreversible pulpal damage.
PMID- 9545946
TI - Osteocalcin expression in young and aged dental pulps as determined by RT-PCR.
AB - Dental pulps were obtained from third molars of young adults (17-25 yr) or from
molar teeth of individuals > 50 yr of age and examined for the expression of
osteocalcin (OC) mRNA by RT-PCR. OC was selected as a determinant of pulp
vitality, because it has long been associated with the production of hard tissue
matrix in teeth and bone. For comparative purposes, the expression of OC in each
pulp was normalized relative to its housekeeping gene-product GAPDH by the
establishment of a OC/GAPDH ratio. This study demonstrated that OC expression,
presumably by cells of odontoblast lineage, does not diminish relative to the
extant cell population. Our findings suggest, despite a reduction in volume and
cell numbers, that the pulps of aging teeth retain a capacity for dentin
deposition and a potential for caries and trauma resistance.
PMID- 9545947
TI - Recombinant human osteogenic protein-1 induces dentin formation: an experimental
study in miniature swine.
AB - It was the aim of the present study to investigate the induction of dentin
formation by recombinant human osteogenic protein-1 (hOP-1). In 4 adult miniature
pigs a total of 16 teeth with artificially exposed dental pulps were capped with
3 mg of a complex of recombinant hOP-1 in collagen matrix (2.5 micrograms/mg),
collagen matrix alone, or calcium hydroxide paste. Teeth were removed in block
section after a healing period of 5 weeks. Decalcified sections were processed
for light microscopy and histomorphometric analysis. In hOP-1 treated teeth
substantial amounts of hard tissue formation (osteodentin and tubular dentin) had
consistently led to a complete bridging of the defects. Less dentin formation was
seen after calcium hydroxide application. In control defects collagen matrix
alone failed to form complete dentin bridges. Recombinant human osteogenic
protein-1 in a collagen carrier matrix appeared to be suitable as a bio-active
capping agent for surgically exposed dental pulps.
PMID- 9545948
TI - A comparison of molar root canal preparations using six instruments and
instrumentation techniques.
AB - Six different instruments (Flexofile, Canal Master U, Heliapical, Flexogate,
Ultraflex, and Lightspeed) were evaluated in 240 mesial canals of extracted
mandibular molars (40 canals per instrument type). After instrumentation, the
roots were cross-sectioned 2, 5, and 9 mm from the apex. The cross sections were
evaluated to determine the quality of canal preparation (round, oval, irregular).
The best results were obtained with nickel-titanium, a short cutting blade and a
rotary rather than a filing motion. The Canal Master U, Flexogate, and Lightspeed
instruments had significantly more round canals than the Flexofile, Heliapical
and Ultraflex instruments at all levels. The Lightspeed had the largest number of
round canals at all levels. Instrumentation time was also recorded. The Canal
Master U and Flexogate were significantly slower than the Flexofile, heliapical,
Ultraflex, and Lightspeed instruments. There were no statistically significant
differences within the faster group.
PMID- 9545949
TI - In vitro study of intradentinal calcium diffusion induced by two endodontic
biomaterials.
AB - The aim of this in vitro study was to assess intratubular calcium penetration
induced by two root canal restoration materials, one calcium oxide based, and the
other calcium hydroxide based. Pig teeth were restored with no preliminary root
canal preparation. The filing materials were left in place for 8, 15, or 21 days.
The samples were then examined using various microanalytical techniques and, in
parallel, by backscattered electron image (BEI) scanning electron microscopy. The
Ca/P ratios obtained by microanalysis were higher for samples restored with
calcium oxide. In addition, the distances over which the ratios increased were
also greater than those obtained using calcium hydroxide. BEI photographs confirm
these results and show corresponding retrodiffusion fringes.
PMID- 9545950
TI - Penetration of constricted canals with modified K files.
AB - A technique using K files with modified tips has been developed for the
penetration of constricted canals. The tip of a #10 K file was sliced diagonally
to make it thinner. Because this modified K file has an especially fine tip and
an appropriate stiffness, it followed constricted or sharply curved canals well
and had a high penetration potential. The author attempted to penetrate to the
apical foramen in all 1844 canals of 977 teeth treated from 1987 to 1994. In 263
canals (14.3%) that could not be penetrated with conventional #10 K files,
further attempts were made with the modified K files. As a result, the number of
the nonpenetrated canals was reduced to 75 (4.1%). There were 7 file breakages
and 14 accidental perforations.
PMID- 9545951
TI - Prevalence of teaching apical patency and various instrumentation and obturation
techniques in United States dental schools.
AB - Maintaining an open apex beyond the apical constriction with an endodontic file
during canal instrumentation is a concept that has been advocated by several
authors and clinicians. To ascertain the prevalence of teaching the patency
concept as well as various instrumentation and obturation techniques in the
United States dental schools, a survey was conducted. Forty-eight out of a total
of 53 dental schools (91%) responded to the survey. Results indicate that 50% of
the schools surveyed teach the concept of patency to their undergraduates or
graduates or both; 83% teach a step-back instrumentation technique; and 89.6%
teach lateral condensation of gutta percha as their primary obturation technique.
PMID- 9545952
TI - Hardness and stress-corrosion of rubber dam clamps.
AB - Rubber dam clamps fracture infrequently during use. There are no American
National Standards Institute or International Standards Organization standards
for their manufacture. The purpose of this study was to measure the hardness of
the clamps and test their resistance to a stress-corrosion test. Upper molar,
lower molar, and premolar clamps were obtained from two manufacturers (A, B). The
Rockwell C hardness at four sites on the bow of each clamp was then determined.
Fresh clamps were placed on blocks corresponding to the average buccal-lingual
dimension of the tooth on which they would be used. These blocks were then
submerged in room temperature 5.25% sodium hypochlorite for 20 min and then
allowed to air dry for 30 min. This was repeated 10 times. Rockwell C hardness
values ranged from C30 to 38, with the clamps of manufacturer B being
significantly harder. None of the clamps from manufacturer B cracked or corroded.
When a third batch received from manufacturer A was tested in the same manner,
none of the clamps fractured or corroded either.
PMID- 9545954
TI - Informed consent in orthodontics.
AB - Informed consent is a process of communication between a health care provider and
patient that educates the patient as to the patient's needs and the potential
solutions for those needs, and leads to the endorsement of a health care
treatment plan. A claim of lack of informed consent may be brought by a patient
when there is a perceived failure in the disclosure of adequate information to
make a reasoned decision whether to consent to treatment. This article provides
the foundation of the informed consent doctrine, delineates the essential
elements of a lack of informed consent claim, and identifies the parties and
their roles in the informed consent process.
PMID- 9545953
TI - Endodontic treatment in three cases of dens invaginatus.
AB - Three cases of dens invaginated teeth with periapical lesions are presented in
this article. In the first case the maxillary canine was treated with
conventional endodontic treatment. The second and third cases, in mandibular and
maxillary central incisors respectively, were treated surgically. Six months
postoperatively all cases appeared radiographically to be improved.
PMID- 9545955
TI - The standard of care: the orthodontist's tort liability.
PMID- 9545956
TI - Basic contract law.
PMID- 9545957
TI - Bracing yourself to deal with the top 10 employment law problems.
AB - Orthodontists face a number of legal problems in dealing with employment issues.
Some of them are similar to those effecting other professionals, whereas other
problems are peculiar to the practice of orthodontia. An experienced employment
attorney offers recommendations to deal with 10 common issues confronting
orthodontists in the workplace.
PMID- 9545958
TI - Temporomandibular joint litigation: resolving issues of medical necessity and
contract ambiguity.
AB - Courts routinely award coverage for TMJ disorders under medical plans, despite
exclusionary language and evidence that the insured failed to disclose
preexisting treatment as required by the plan and neglected to attempt more
conservative treatment first. Such decisions adversely affect both the health
carrier and the plan participants. Various states have enacted legislation
mandating coverage of TMJ; however, TMJ issues still exist and will remain a
frequent topic for litigation until the judiciary recognizes that validating
contract language ultimately benefits insureds as consumers and reinforces the
integrity of the industry as a whole.
PMID- 9545959
TI - State regulation of the practice of dentistry.
AB - Dentistry in today's world is a highly regulated industry. It is governed
primarily by the state, but the federal government also controls certain aspects
of a dental practice. This article focuses on the ways in which state government
regulates the practice of dentistry. It explains the purpose of a state licensing
board, as well as the authority a licensing board derives from state statute-
including the authority to take disciplinary action against practitioners who
engage in misconduct, and the authority to promulgate rules.
PMID- 9545960
TI - Basic insurance concepts for dentists.
AB - Dentists cannot afford to be ignorant about insurance. Insurance is an important
risk-management tool, minimizing the exposure for catastrophic claims and losses.
Patient insurance is also a major source of revenue for most dental practices.
PMID- 9545961
TI - Simple solutions.
PMID- 9545963
TI - Medicare. Challenges ahead.
PMID- 9545964
TI - Medicaid. Low outreach.
PMID- 9545966
TI - Mergers. Big year for deals.
PMID- 9545965
TI - Finance. Health care's rainmakers.
PMID- 9545967
TI - Consumerism. Hearing voices.
PMID- 9545968
TI - Employers. Mandate-busters.
PMID- 9545969
TI - Management. VA performance.
PMID- 9545970
TI - Managed care. Small-biz enrollments up.
PMID- 9545971
TI - Mental health. Research project.
PMID- 9545972
TI - End-of-life care. Off-site DNRs.
PMID- 9545973
TI - Kaiser's labor pains.
PMID- 9545974
TI - Gen-X meets Medicare. Interview by Jan Greene.
PMID- 9545975
TI - Fields of vision. Virginia system's outreach to migrants brings health care
directly to their camps.
PMID- 9545976
TI - The health care 100.
AB - They may not be the biggest health systems, the most profitable, or even those
with the most doctors. They are the most integrated, having gone the furthest in
building organizations that boast of geographic reach and coordinated systems of
care. Unlike rankings that focus on size, our listing looks at health care
enterprises that are pioneering change.
PMID- 9545977
TI - Choice words on open access.
AB - Drawn by rates only slightly higher than traditional HMOs, consumers have hurried
to sign up for open-access plans. Yet what works for patients may work against
doctors who assume the financial risks.
PMID- 9545978
TI - Trendspotting.
AB - All health care isn't local. To make the right strategic moves, you need to
understand the bigger picture. A new environmental assessment from Deloitte &
Touche and VHA, released first to Hospitals & Health Networks, sizes up the
national scene.
PMID- 9545979
TI - Health care costs. Twin Cities' setback.
PMID- 9545980
TI - Consumerism. Satisfaction guaranteed.
PMID- 9545981
TI - Access to care. Less trouble in paradise.
PMID- 9545983
TI - Mergers. Or forever hold your peace.
PMID- 9545982
TI - Doctor dispute. Turf's up.
PMID- 9545984
TI - Cost control. Drain stopper on water bills.
PMID- 9545985
TI - Hospital pulse ... September 1997.
PMID- 9545986
TI - Child and adolescent psychiatry research remains a challenge.
PMID- 9545987
TI - The crisis in clinical research.
PMID- 9545988
TI - Images in psychiatry. The West Riding Pauper Lunatic Asylum.
PMID- 9545989
TI - A new intellectual framework for psychiatry.
AB - In an attempt to place psychiatric thinking and the training of future
psychiatrists more centrally into the context of modern biology, the author
outlines the beginnings of a new intellectual framework for psychiatry that
derives from current biological thinking about the relationship of mind to brain.
The purpose of this framework is twofold. First, it is designed to emphasize that
the professional requirements for future psychiatrists will demand a greater
knowledge of the structure and functioning of the brain than is currently
available in most training programs. Second, it is designed to illustrate that
the unique domain which psychiatry occupies within academic medicine, the
analysis of the interaction between social and biological determinants of
behavior, can best be studied by also having a full understanding of the
biological components of behavior.
PMID- 9545990
TI - Site of opioid action in the human brain: mu and kappa agonists' subjective and
cerebral blood flow effects.
AB - OBJECTIVE: Humans experience the subjective effects of mu and kappa opioid
agonists differently: mu agonists produce mainly euphoria, while kappa agonists
are more likely to produce dysphoria. This study tested the hypothesis that these
subjective effects would be associated with anatomically distinct changes in
regional cerebral blood flow (CBF) relative to baseline as assessed with single
photon emission computed tomography (SPECT). METHOD: Nine nondependent opioid
abusers participated in the study. In the first phase of the study, the
participants were acclimated to effects of the study drugs. In the second phase
they underwent repeat challenges with the study drugs followed by an assessment
of CBF with use of the SPECT tracer [99mTc]HMPAO. Medications tested were the
prototypic mu agonist hydromorphone, the mixed agonist/antagonist butorphanol
(which has a kappa agonist component of activity), and saline placebo. RESULTS:
Subjective effects of the drugs were distinctly different. Hydromorphone produced
increased ratings of "good effects," while butorphanol led to more "bad effects."
Hydromorphone significantly increased regional CBF in the anterior cingulate
cortex, both amygdalae, and the thalamus--all structures belonging to the limbic
system. Butorphanol caused a less distinct picture of regional CBF increases,
mainly in the area of both temporal lobes. CONCLUSIONS: This study demonstrates
that opioids with different subjective effects also produce statistically
significant patterns of change in regional CBF from baseline, and the regions of
statistical significance appear in different brain regions. In addition, these
results demonstrate the applicability of SPECT functional neuroimaging in the
study of medications with potential abuse liability.
PMID- 9545991
TI - Modification of alcohol withdrawal by the A9 allele of the dopamine transporter
gene.
AB - OBJECTIVE: Determinants of individual vulnerability to alcohol withdrawal
symptoms are largely unknown. Because of the substantial role of monoaminergic
transporters in limiting time and space effects of synaptic neurotransmission,
the dopamine transporter gene (DAT1; locus symbol: SLC6A3) was studied as a
candidate gene possibly related to symptoms of uncomplicated alcohol withdrawal.
METHOD: In 48 chronically intoxicated alcoholics (diagnosed according to ICD-10),
withdrawal symptoms were examined and the presence of a variable-number tandem
repeat in the 3' untranslated region of the DAT1 gene was determined. RESULTS:
Withdrawal syndromes were more pronounced in the 22 patients carrying the nine
copy repeat than in the 26 patients without this variant. Multiple regression
analysis revealed that 4% of the variance of withdrawal was explained by this
genotype, whereas 16% was due to the amount of alcohol the patients reported
having consumed in the month before detoxification. CONCLUSIONS: The A9 allele of
the dopamine transporter gene is associated with more severe effects of alcohol
withdrawal, possibly because of modifications of the brain's capacity to
compensate for long-term effects of ethanol on cerebral function.
PMID- 9545992
TI - Progression from conduct disorder to antisocial personality disorder following
treatment for adolescent substance abuse.
AB - OBJECTIVE: This study investigated the progression from conduct disorder to
antisocial personality disorder among individuals treated for adolescent
substance abuse. This issue is important because of the poor outcomes observed
among individuals with antisocial pathology after treatment for alcohol and drug
problems. The utility of factors assessed at the time of treatment in predicting
progression to adult antisocial personality disorder was evaluated in the context
of developmental models of antisocial behavior. METHOD: This was a prospective
longitudinal study of 137 substance-abusing adolescents (53 female and 84 male),
whose average age was 15.9 years and who met the DSM-III-R criteria for conduct
disorder. Consecutively admitted patients were recruited from two adolescent
inpatient alcohol and drug treatment facilities. Participants were interviewed
again 4 years after treatment. RESULTS: Four years after treatment, 61% of the
study group met the DSM-III-R criteria for antisocial personality disorder.
Results of a logistic regression analysis indicated that onset of deviant
behavior at or before age 10, a greater diversity of deviant behavior, and more
extensive pre-treatment drug use best predicted progression to antisocial
personality disorder. At 4-year follow-up, the subjects with an antisocial
personality disorder diagnosis exhibited more involvement with alcohol and drugs
and poorer functioning across important life domains than the subjects without
antisocial personality disorder. CONCLUSIONS: This study found a high rate of
progression to antisocial personality disorder among substance-abusing
adolescents and identified factors predictive of this progression. Careful
assessment of conduct disorder history at the time of treatment may be valuable
for treatment planning and intervention.
PMID- 9545993
TI - DSM-IV substance use disorder criteria for adolescents: a critical examination
based on a statewide school survey.
AB - OBJECTIVE: The DSM-IV criteria for substance use disorders were incorporated into
the 1995 Minnesota Student Survey in order to estimate the need for alcohol/drug
treatment among adolescents in the state. This study used data from the survey to
examine the utility of individual diagnostic criterion items, diagnostic
categories, and diagnostic thresholds in a general adolescent population. METHOD:
The survey was administered to ninth- and 12th-grade public school students.
Participation was voluntary, and survey questionnaires were anonymous. The survey
included questions about the use of substances during the past year and the
presence of DSM-IV criterion symptoms for substance abuse and dependence. This
study was based on responses from 74,008 students who answered these questions.
RESULTS: Of the students who reported any substance use in the past 12 months,
13.8% of the ninth graders and 22.7% of the 12th graders met the criteria for a
substance abuse diagnosis, and 8.2% of the ninth graders and 10.5% of the 12th
graders met the criteria for dependence. The presence of multiple criterion
symptoms was strongly associated with the use of multiple drugs. Analyses of
positive and negative predictive value, sensitivity, and specificity did not
support the diagnostic distinction between dependence criteria and abuse
criteria. CONCLUSIONS: A combined set of criteria, with empirically derived
diagnostic threshold categories based on total number of symptoms, may be more
suitable for estimates of substance use disorders and need for treatment among
adolescents.
PMID- 9545994
TI - Adult psychiatric status of hyperactive boys grown up.
AB - OBJECTIVE: Numerous studies have examined the adolescent and young adult fate of
children with attention deficit hyperactivity disorder (ADHD). In marked
contrast, relatively little is known about the adult outcome of these children.
There have been only two controlled, prospective studies of psychiatric status
into adulthood. The present study was conducted to gain further understanding of
the natural course of this common childhood condition. METHOD: This was a
prospective follow-up of clinically diagnosed, white boys of average intelligence
who were referred by teachers to a child psychiatric research clinic at an
average age of 7.3 years. At a mean age of 24.1 years, 85 probands (82% of the
childhood cohort) and 73 comparison subjects (94% of adolescent comparison
subjects) were directly interviewed by trained clinicians who were blind to group
status. RESULTS: Evaluations of the probands and comparison subjects indicated
significantly higher prevalences of antisocial personality disorder (12% versus
3%) and nonalcohol substance abuse (12% versus 4%) in the probands, whereas mood
disorders (4% versus 4%) and anxiety disorders (2% versus 7%) were not
significantly different. At adult follow-up, ADHD was rare, occurring in only 4%
of the probands (no comparison subjects). CONCLUSIONS: The results of the present
study are consistent with the authors' previously reported major findings. They
strongly suggest that children with ADHD are at significantly higher risk for a
specific negative course marked by antisocial and substance-related disorders.
PMID- 9545995
TI - Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a
randomized double-blind study. The Risperidone Study Group.
AB - OBJECTIVE: The purpose of this study was to compare the short-term efficacy and
safety of risperidone and clozapine in treatment-resistant chronic schizophrenic
patients. METHOD: In a controlled double-blind, multicenter study, 86 inpatients
with chronic schizophrenia (DSM-III-R), who were resistant to or intolerant of
conventional neuroleptics, were randomly assigned to receive risperidone or
clozapine for 8 weeks after a 7-day washout period. After a 1-week dose-titration
phase, doses were fixed at 6 mg/day of risperidone and 300 mg/day of clozapine
for 1 week and then adjusted according to each patient's response. The final mean
doses were 6.4 mg/day of risperidone and 291.2 mg/day of clozapine. Treatment
efficacy and safety were evaluated with several well-known rating scales.
RESULTS: Both risperidone and clozapine significantly reduced the severity of
psychotic symptoms (scores on the Positive and Negative Syndrome Scale and the
Clinical Global Impression scale) from baseline, with no significant between
group differences. At endpoint, 67% of the risperidone group and 65% of the
clozapine group were clinically improved (reduction of 20% or more in total
Positive and Negative Syndrome Scale score). Risperidone appeared to have a
faster onset of action. In both groups extrapyramidal symptoms and other adverse
events were few, and their severity was generally mild. Neither group showed
evidence of a relation between drug plasma concentrations and clinical
effectiveness. CONCLUSIONS: Risperidone was well tolerated and as effective as
medium doses of clozapine in patients with chronic schizophrenia who had been
resistant to or intolerant of conventional neuroleptics.
PMID- 9545996
TI - Binding of antipsychotic drugs to cortical 5-HT2A receptors: a PET study of
chlorpromazine, clozapine, and amisulpride in schizophrenic patients.
AB - OBJECTIVE: This study examined the binding to cortical serotonin 5-HT2A receptors
of conventional doses of the typical neuroleptic chlorpromazine in comparison
with clozapine, the prototype atypical antipsychotic, and amisulpride, a specific
dopamine D2-D3 blocker. METHOD: Seventeen schizophrenic patients treated with
chlorpromazine (75-700 mg/day), four treated with clozapine (200-600 mg/day), and
five treated with amisulpride (200-1200 mg/day) were studied. Cortical 5-HT2A
binding was estimated by reference to the values for 14 antipsychotic-free
schizophrenic subjects with the use of positron emission tomography and
[18F]setoperone, a high-affinity radioligand for cortical 5-HT2A receptors.
RESULTS: A dose-dependent decrease in the number of available cortical binding
sites for [18F] setoperone was demonstrated in the chlorpromazine group; for the
highest dose, there was a virtual lack of sites available for binding. A very low
percentage of available binding sites was also observed in the clozapine-treated
patients at all doses. This suggests a high level of 5-HT2A blockade with both
clozapine and high doses of chlorpromazine. No significant binding of amisulpride
to 5-HT2A receptors was detected. CONCLUSIONS: A high level of 5-HT2A receptor
blockade does not appear specific to clozapine in comparison with high doses of
chlorpromazine, suggesting that the distinct clinical profiles of both drugs are
unrelated to 5-HT2A blockade itself.
PMID- 9545998
TI - Randomized trial of general hospital and residential alternative care for
patients with severe and persistent mental illness.
AB - OBJECTIVE: Severe and persistent mental illnesses are often lifelong and
characterized by intermittent exacerbations requiring hospitalization. Providing
needed care within budgetary constraints to this largely publicly subsidized
population requires technologies that reduce costly inpatient episodes. The
authors report a prospective randomized trial to test the clinical effectiveness
of a model of acute residential alternative treatment for patients with
persistent mental illness requiring hospital-level care. METHOD: Patients
enrolled in the Montgomery County, Md., public mental health system who
experienced an illness exacerbation and were willing to accept voluntary
treatment were randomly assigned to the acute psychiatric ward of a general
hospital or a community residential alternative. There were no psychopathology
based exclusion criteria. Treatment episode symptom improvement, satisfaction,
discharge status, and 6-month pre- and postepisode acute care utilization,
psychosocial functioning, and patient satisfaction were assessed. RESULTS: Of 185
patients, 119 (64%) were successfully placed at their assigned treatment site.
Case mix data indicated that patients treated in the hospital (N = 50) and the
alternative (N = 69) were comparably ill. Treatment episode symptom reduction and
patient satisfaction were comparable for the two settings. Nine (13%) of 69
patients randomly assigned to the alternative required transfer to a hospital
unit; two (4%) of 50 patients randomly assigned to the hospital could not be
stabilized and required transfer to another facility. Psychosocial functioning,
satisfaction, and acute care use in the 6 months following admission were
comparable for patients treated in the two settings and did not differ
significantly from functioning before the acute episode. CONCLUSIONS:
Hospitalization is a frequent and high-cost consequence of severe mental illness.
For patients who do not require intensive general medical intervention and are
willing to accept voluntary treatment, the alternative program model studied
provides outcomes comparable to those of hospital care.
PMID- 9545997
TI - MRI study of cavum septi pellucidi in schizophrenia, affective disorder, and
schizotypal personality disorder.
AB - OBJECTIVE: A cavum between the septi pellucidi may reflect neurodevelopmental
anomalies in midline structures of the brain. The authors examined cavum septi
pellucidi in subjects with schizophrenia, affective disorder, and schizotypal
personality disorder and in normal subjects. METHOD: Thirty schizophrenic
patients (15 chronic, 15 first-episode), 16 patients with affective disorder
(first-episode), 21 patients with schizotypal personality disorder, and 46 normal
subjects were evaluated with magnetic resonance imaging. Cavum septi pellucidi
was assessed by counting the number of 1.5-mm slices containing cavum septi
pellucidi. RESULTS: The presence or absence of cavum septi pellucidi did not
differentiate among groups. However, the prevalence of abnormal cavum septi
pellucidi (i.e., cavum septi pellucidi contained on four or more slices) was
30.4% for schizophrenic patients (36.4% for chronic, 25.0% for first-episode),
20.0% for patients with affective disorder, 18.8% for patients with schizotypal
personality disorder, and 10.3% for normal subjects. When the authors used the
Nopoulos et al. criteria for rating cavum septi pellucidi, which omitted
borderline cases with cavum septi pellucidi on three slices, the prevalence of
abnormal cavum septi pellucidi increased to 35.0% for schizophrenia (40.0% for
chronic, 30.0% for first-episode), 25.0% for affective disorder, 27.3% for
schizotypal personality disorder, and 13.0% for normal subjects. There was a
statistically significant difference in ratings between schizophrenic and normal
subjects. CONCLUSIONS: The results suggest that alterations in midline structures
during the course of neurodevelopment may play a role in the pathogenesis of
schizophrenia.
PMID- 9545999
TI - Cost comparison of state hospital and community-based care for seriously mentally
ill adults.
AB - OBJECTIVE: In 1989, Philadelphia began a bold experiment involving the total
shutdown of a 500-bed state hospital. This study examines the service utilization
and cost of treating individuals with serious mental illness in a community-based
care system in which the state hospital was replaced with 60 extended acute care
beds in general hospitals and 583 residential beds. METHOD: A pre-post study
design was used to determine the utilization and cost differences before and
after the state hospital closed for individuals with a diagnosis of schizophrenia
who required extended psychiatric hospitalization following an acute care crisis
episode in a general hospital. The number and cost of days spent in general and
in extended hospital and residential treatment were compared on an episode and an
annual basis. RESULTS: The results of this analysis showed that after the state
hospital closed, the direct treatment cost of an episode of care increased from
$68,446 to $78,929, and the average annual cost of care per patient increased
from $48,631 to $66,794 because of an increase in acute care hospitalization.
CONCLUSIONS: This study suggests that an "admission" cohort of seriously mentally
ill patients requires an optimal mix of acute care, extended care, and
residential beds, as well as ambulatory services, in order for cost-efficient
care to be delivered during a crisis period. Determining the appropriate
allocation and supply of beds in different settings is essential if community
mental health systems are to manage the care of individuals with serious mental
illness outside of institutional settings.
PMID- 9546000
TI - Clinical interview skills and identification of emotional disorders in primary
care.
AB - OBJECTIVE: The aim of this research was to study the relationship between the
clinical interview skills of primary care physicians and their psychodiagnostic
ability during office visits. METHOD: Ten doctors took part in the study, and 233
patients were assessed. The patients were seen and diagnosed by their physicians
and interviewed afterward by a psychiatrist using the Present State Examination.
All the interviews with the primary care physicians were recorded on videotape,
and the Physician's Skills Observation Scale was used to analyze 10 interviews
per doctor, five psychiatric cases and five nonpsychiatric cases. RESULTS: The
physician's active listening (eye contact, posture, and absence of verbal
interruptions) and ability to ask questions with psychological content were
associated with the ability to identify the patient's emotional problems. This
association was shown to be independent of the physician's characteristics
(social, academic, attitudinal, and professional), the sociodemographic
characteristics of the patients, the time spent in exploration during the office
visit, and the severity of the emotional or somatic disorder. CONCLUSIONS: The
findings of this research highlight the need to train primary care physicians in
specific interview skills, in order to improve their ability to identify mental
disorders in their practices.
PMID- 9546001
TI - Religiosity and remission of depression in medically ill older patients.
AB - OBJECTIVE: The effects of religious belief and activity on remission of
depression were examined in medically ill hospitalized older patients. METHOD:
Consecutive patients aged 60 years or over who had been admitted to medical
inpatient services at a university medical center were screened for depressive
symptoms. Of 111 patients scoring 16 or higher on the Center for Epidemiologic
Studies Depression Scale, 94 were diagnosed with depressive disorder (DSM-III
major depression or subsyndromal depression) by a psychiatrist using a structured
psychiatric interview. After hospital discharge, depressed patients were followed
up by telephone at 12-week intervals four times. At each follow-up contact,
criterion symptoms were reassessed, and changes in each symptom over the interval
since last contact were determined. The median follow-up time for 87 depressed
patients was 47 weeks. Religious variables were examined as predictors of time to
remission by means of a multivariate Cox model, with controls for demographic,
physical health, psychosocial, and treatment factors. RESULTS: During the follow
up period, 47 patients (54.0%) had remissions; the median time to remission was
30 weeks. Intrinsic religiosity was significantly and independently related to
time to remission, but church attendance and private religious activities were
not. Depressed patients with higher intrinsic religiosity scores had more rapid
remissions than patients with lower scores. CONCLUSIONS: In this study, greater
intrinsic religiosity independently predicted shorter time to remission. To the
authors' knowledge, this is the first report in which religiosity has been
examined as a predictor of outcome of depressive disorder.
PMID- 9546002
TI - Reduction by paroxetine of suicidal behavior in patients with repeated suicide
attempts but not major depression.
AB - OBJECTIVE: Suicidal behavior has been associated with reduced central
serotonergic function. Because selective serotonin reuptake inhibitors (SSRIs)
enhance serotonergic function, the authors studied the efficacy of an SSRI,
paroxetine, in the prevention of recurrent suicidal behavior. METHOD: They
conducted a 1-year double-blind study comparing paroxetine (40 mg/day) and
placebo in 91 patients who had recently attempted suicide for at least a second
time. None of the patients had experienced a major depressive episode or had any
other major DSM-III-R axis I diagnoses. At least one cluster B personality
disorder was present in 74 patients. RESULTS: With adjustment for the number of
previous suicide attempts, paroxetine showed significant efficacy in the
prevention of recurrent suicidal behavior. Among the patients who had attempted
suicide fewer than five times, 12 (36%) in the placebo group (N = 33) and five
(17%) in the paroxetine group (N = 30) made a subsequent suicide attempt.
Paroxetine was also significantly more effective in patients who met fewer than
15 criteria for cluster B personality disorders than in those who met more than
15 criteria. Overall, paroxetine was not significantly different from placebo in
its effect on depressive mood, hopelessness, and anger. However, the data suggest
that paroxetine may have some temporary effect in reducing anger. CONCLUSIONS:
This study indicates that enhancing serotonergic function with an SSRI may reduce
suicidal behavior in a subgroup of patients who have attempted suicide more than
once but who do not suffer from major depression.
PMID- 9546003
TI - Does fluoxetine augment the inpatient treatment of anorexia nervosa?
AB - OBJECTIVE: While pharmacological interventions are of established utility in
bulimia nervosa, medications have no clear role in the treatment of anorexia
nervosa. Because patients with anorexia nervosa frequently exhibit mood
disturbances and symptoms of obsessive-compulsive disorder, the authors tested
the utility of fluoxetine in the treatment of women participating in an inpatient
program for anorexia nervosa. METHOD: The authors conducted a randomized, placebo
controlled, double-blind, 7-week study of fluoxetine at a target daily dose of 60
mg in 31 women with anorexia nervosa receiving treatment for their eating
disorder on a clinical research unit. Body weight and measures of eating behavior
and psychological state were obtained at baseline and at termination. RESULTS:
There were no significant differences in clinical outcome on any measure between
patients receiving fluoxetine and patients receiving placebo. CONCLUSIONS:
Fluoxetine does not appear to add significant benefit to the inpatient treatment
of anorexia nervosa.
PMID- 9546004
TI - Mental illness in adults with fetal alcohol syndrome or fetal alcohol effects.
AB - OBJECTIVE: The authors' goal was to use structured clinical interviews to
characterize the type and frequency of mental illness in adults with fetal
alcohol syndrome or fetal alcohol effects. METHOD: Twenty-five subjects who met
criteria for fetal alcohol syndrome or fetal alcohol effects, who were older than
18 years old, and who had an IQ of greater than 70 were interviewed with the
Structured Clinical Interview for DSM-IV Axis I Disorders and the Structured
Clinical Interview for DSM-III-R Personality Disorders. RESULTS: Eighteen of the
25 subjects had received psychiatric treatment. The most common axis I disorders
were alcohol or drug dependence (15 subjects), depression (11 subjects), and
psychotic disorders (10 subjects). The most common axis II disorders were
avoidant (six subjects), antisocial (four subjects), and dependent (three
subjects) personality disorders. CONCLUSIONS: This study suggests that adults
with fetal alcohol syndrome or fetal alcohol effects suffer from substantial
mental illness.
PMID- 9546005
TI - Higher prevalence of obsessive-compulsive symptoms in patients with blepharospasm
than in patients with hemifacial spasm.
AB - OBJECTIVE: The prevalences of obsessive-compulsive symptoms in patients suffering
from blepharospasm and in those with hemifacial spasm were determined. The two
conditions have similar symptoms, but only blepharospasm is etiologically linked
to basal ganglia dysfunction. METHOD: After being interviewed with the Structured
Clinical Interview for DSM-III-R, 13 patients with blepharospasm and 13 with
hemifacial spasm completed the SCL-90-R and the Hamburg Obsession/Compulsion
Inventory-Short Form. RESULTS: Patients in the blepharospasm group had
significantly more obsessive-compulsive symptoms, as indicated by higher scores
on the Hamburg Obsession/Compulsion Inventory-Short Form, than the patients with
hemifacial spasm. SCL-90-R scores were in the normal range for nine and eight
categories, respectively (out of nine). CONCLUSIONS: The findings provide
additional support for the hypothesis that obsessive-compulsive symptoms are
related to basal ganglia dysfunction.
PMID- 9546006
TI - Defense mechanism changes in successfully treated patients with obsessive
compulsive disorder.
AB - OBJECTIVE: Changes in defense mechanisms after treatment of patients with
obsessive-compulsive disorder (OCD) were measured by using an established rating
scale. METHOD: Before and after 7-week group behavior therapy, 17 patients with
DSM-III-R OCD were assessed with the Defense Style Questionnaire, Yale-Brown
Obsessive Compulsive Scale, and Beck Depression Inventory. RESULTS: After
behavior therapy the patients evidenced significant decreases in Yale-Brown
Obsessive Compulsive Scale scores and significant increases in the use of more
adaptive defense mechanisms. There were no significant changes in three
maladaptive defense mechanism categories. The improvement in adaptive defenses
was independently linked to improvement both in OCD and in depression.
CONCLUSIONS: Personality as defined by defense mechanisms may be more amenable to
brief behavioral treatment than previously thought. The permanence of these
changes must be further assessed.
PMID- 9546007
TI - Retrospective review of treatment outcome for 63 patients with trichotillomania.
AB - OBJECTIVE: The authors' goal was to assess naturalistic treatment outcome in
trichotillomania. METHOD: Sixty-three patients who had been treated in a
specialty clinic for trichotillomania over a period of 6 years were contacted.
The patients were given paper-and-pencil instruments that assessed current
severity of hairpulling, depression, anxiety, self-esteem, and psychosocial
functioning. RESULTS: Significant mean improvement was found on measures of
hairpulling, depression, anxiety, self-esteem, and psychosocial functioning.
Improvement in hairpulling was associated with greater depression at the time of
their index clinic evaluation as well as more improvement in depression after
treatment. CONCLUSIONS: State-of-the-art behavioral and pharmacological
treatments offer substantial clinical benefit to patients with trichotillomania,
both in hairpulling symptoms and ancillary measures of functioning.
PMID- 9546008
TI - PTSD symptoms in Bosnian refugees 1 year after resettlement in the United States.
AB - OBJECTIVE: The authors' goal was to describe the characteristics of posttraumatic
stress disorder (PTSD) symptoms on resettlement in the United States and at 1
year follow-up among Bosnian refugees as well as possible factors affecting the
PTSD symptom profile among these refugees. METHOD: They used standardized
instruments to assess 34 Bosnian refugees for PTSD at resettlement in the United
States and 1 year later. RESULTS: Fifteen of the refugees were diagnosed with
PTSD at 1-year follow-up, compared with 25 at initial assessment. The average
PTSD severity score at follow-up was 12.5, compared with 20.6 at initial
assessment. At 1-year follow-up, 25 of the refugees experienced a decrease in
severity of PTSD symptoms, one remained the same, and eight experienced an
increase in severity. Older refugees were significantly more likely to have PTSD
than younger refugees, and older refugees had more severe symptoms. CONCLUSIONS:
The level of PTSD diagnosis and symptoms in Bosnian refugees remained substantial
1 year after their resettlement in the United States, although there were notable
overall decreases. Older refugees appeared to be at greater risk.
PMID- 9546010
TI - Interaction of fluoxetine and valproic acid.
PMID- 9546009
TI - Intermittent neuroleptic treatment and risk for tardive dyskinesia: Curacao
Extrapyramidal Syndromes Study III.
AB - OBJECTIVE: The authors examined the association between three lifetime medication
variables (cumulative amount of neuroleptics, number of interruptions in
neuroleptic treatment, cumulative amount of anticholinergics) and the occurrence
and severity of tardive dyskinesia. METHOD: The study was conducted in the only
psychiatric hospital of a well-defined catchment area (the Netherlands Antilles).
For all patients who had a history of taking neuroleptics for at least 3 months
and were currently using neuroleptics (N = 133, mean age = 51.5 years), the
presence and severity of tardive dyskinesia were measured with the Abnormal
Involuntary Movement Scale. RESULTS: Of the three lifetime medication variables,
only the number of neuroleptic interruptions was significantly related to tardive
dyskinesia. The risk of tardive dyskinesia was three times as great for patients
with more than two neuroleptic interruptions as for patients with two or fewer
interruptions. CONCLUSIONS: This finding supports the schizophrenia protocol of
long-term neuroleptic treatment rather than targeted or intermittent neuroleptic
treatment.
PMID- 9546011
TI - Ethics in forensic psychiatry.
PMID- 9546012
TI - Utilization management criteria for psychiatry.
PMID- 9546013
TI - Squamous cells as predictors of bacterial contamination in urine samples.
AB - STUDY OBJECTIVE: To determine whether squamous cells in urine indicate bacterial
contamination. METHODS: We prospectively studied 105 consecutive women who
presented to the emergency department with symptoms suggestive of a urinary tract
infection. Two urine samples were collected from each woman, a midstream clean
catch (MSCC) sample and a catheterized (CATH) sample. Microscopic urinalyses to
assess for squamous cells and urine cultures to assess for bacterial
contamination were performed on all samples. Bacterial contamination was defined
as growth of fewer than 10,000 colonies of a single species per milliliter or
growth of three or more species of commensal bacteria (mixed flora) in a urine
sample. RESULTS: Squamous cells were found in 99 of 105 CATH samples (94%);
however, no CATH samples had bacterial contamination. Squamous cells were found
in 101 of 105 MSCC samples (96%); however, only 22 MSCC samples (21%) had
bacterial contamination. CONCLUSION: The presence of squamous cells in CATH urine
samples obtained from women is not indicative of bacterial contamination. The
presence of squamous cells in MSCC urine samples obtained from women also is not
a good indicator, with an overall predictive value for bacterial contamination of
21%.
PMID- 9546014
TI - Comparison of arterial and venous blood gas values in the initial emergency
department evaluation of patients with diabetic ketoacidosis.
AB - STUDY OBJECTIVE: To determine whether venous blood gas values can replace
arterial gas values in the initial emergency department evaluation of patients
with suspected diabetic ketoacidosis. METHODS: This prospective comparison was
performed in an adult university teaching hospital ED. Samples for arterial and
venous blood gas analysis were obtained during initial ED evaluations. The venous
gas samples were collected with samples for other blood tests at the time of
intravenous line insertion. Both arterial and venous samples were obtained before
the initiation of treatment. RESULT: Data from 44 episodes of diabetic
ketoacidosis in 38 patients were analyzed. Laboratory findings of those patients
with diabetic ketoacidosis were as follows (mean +/- SD): arterial pH, 7.20 +/-
14; venous pH, 7.17 +/- 13; serum glucose, 33.8 +/- 16 mmol/L (609 +/- 288
mg/dL); arterial HCO3-, 11.0 +/- 6.0 mmol; venous HCO3-, 12.8 +/- 5.5 mmol/L;
serum CO2, 11.8 +/- 5.0 mmol/L; and anion gap, 26.7 +/- 7.6 mmol/L. The mean
difference between arterial and venous pH values was 0.03 (range 0.0 to 0.11).
Arterial and venous pH results (r = .9689) and arterial and venous HCO3- results
(r = .9543) were highly correlated and showed a high measure of agreement.
CONCLUSION: Venous blood gas measurements accurately demonstrate the degree of
acidosis of adult ED patients presenting with diabetic ketoacidosis.
PMID- 9546015
TI - Organ procurement in an urban level I emergency department.
AB - STUDY OBJECTIVE: To determine whether an intensive educational campaign of
emergency department personnel on the organ donor and procurement process would
result in both increased organ donor referrals and organs procured. METHODS: A
retrospective review of the performance of an urban teaching ED in identifying
and referring potential organ donor candidates was performed. Subsequently an
intensive educational campaign of all ED staff, in conjunction with the Regional
Organ Procurement Agency of Southern California (ROPA), was initiated. Physicians
and nurses were educated about the procurement process, and a ROPA representative
was on call 24 hours a day to assist in this process. The need for aggressive
resuscitation and vital sign maintenance in potential donors as a strategy to
promote organ recovery was emphasized. Reeducation by ROPA occurred every 2 to 3
months. The identification and referral rates were then retrospectively reviewed
to evaluate any improvement. RESULTS: In 1994 the initial referral rate of
potential organ donors from the ED was 30% (3 of 10) resulting in no organs
procured. After the intervention the referral rate increased to 100% (25 of 25)
in 1995 (P < .0001). The number of actual donors procured was 0 in 1994, 5 in
1995, and 9 in 1996. The increased ED referrals resulted in 14 and 32 organs
procured in 1995 and 1996, respectively. CONCLUSION: Emergency physicians are in
a unique position as first caregivers to interact with both potential donors and
their families. With intensive education of ED staff, proper identification and
referral, as well as timely intervention by organ procurement representatives,
the consent and donation rate of organs for transplantation can be increased and
maintained.
PMID- 9546016
TI - Effects of adding links to "the chain of survival" for prehospital cardiac
arrest: a contrast in outcomes in 1975 and 1995 at a single institution.
AB - STUDY OBJECTIVE: The concept of a "chain of survival" to improve outcome from
prehospital cardiac arrest has been defined and promulgated over the last two
decades. The purpose of this study was to compare outcomes of prehospital cardiac
arrest in 1975 and 1995 at a single institution. METHODS: This longitudinal,
before-after study compares published data collected at our municipal, tertiary
care in 1974-1975 with data collected prospectively in 1995. The 1975 study group
served as control subjects (n = 120). We enrolled an equal number of consecutive
patients who met inclusion criteria in the 1995 cohort (consecutive patients who
experienced prehospital arrest and who received prehospital Advanced Cardiac Life
Support (ACLS) measures during the two study periods). Patients younger than 18
years or with posttraumatic arrest were excluded. Between 1975 and 1995 the
following "links" in the "chain of survival" were added to the prehospital care
system: (1) 911 access and dispatch, (2) paramedic endotracheal intubation, (3)
EMT automated defibrillation, (4) standing out-of-hospital orders before hospital
radiotelemetry contact, and (5) introduction of American Heart Association ACLS
algorithms. RESULTS: The following significant differences (chi 2) were observed
between the study periods: prevalence of ventricular fibrillation or tachycardia
(42% in 1975 versus 28% in 1995, P = .021), prevalence of asystole or pulseless
electrical activity as the first documented rhythm (58% versus 72%, P = .021),
survival to hospital discharge (22% versus 9%, P = .007), and percent of
survivors of ventricular fibrillation or tachycardia (30% versus 0%, P = .004).
Eighty-six percent of the 1995 cohort had advanced chronic disease and 29%
experienced cardiopulmonary arrest in a nursing home. CONCLUSION: Survival
decreased dramatically during the 20-year study period. This may be because of
the high incidence of chronic disease, the greater frequency of asystole and
pulseless electrical activity, and the inclusion of patients with "end-of-life"
arrests in which ACLS protocol was initiated in the 1995 cohort. The patient
population in which ACLS is initiated is the weakest link in the "chain of
survival."
PMID- 9546017
TI - Race and survival after out-of-hospital cardiac arrest in a suburban community.
AB - STUDY OBJECTIVE: To determine whether race, when controlled for income, is an
independent predictor of survival to hospital discharge after out-of-hospital
cardiac arrest (OHCA). METHODS: Prospective OHCA data were collected over 4 years
(1991-1994) from a convenience sample of OHCA patients transported to nine
hospitals in three suburban counties. Race was determined from hospital and vital
statistics records. The average household income was identified from ZIP codes
and used as a marker of socioeconomic status. Demographic data and known
predictors of survival were compared between blacks and whites. A logistic
regression analysis was used to assess the association between race, income, and
survival. RESULTS: Of the 1,690 patients, 223 (13%) were blacks and 1,467 (87%)
were whites. Average household income was less for blacks than for whites
($40,225 versus $46,193; P < .001), but both populations were affluent by
national standards (national percentile ranks were 73% and 88%, respectively).
The populations were no different in percentage of witnessed arrests (57% versus
61%; P = .465). Blacks were younger (mean +/- SD, 62 +/- 16 versus 68 +/- 15
years; P < .001); less frequently received bystander CPR (11% versus 20%; P =
.002); less often had ventricular tachycardia or ventricular fibrillation (37%
versus 50%; P < .001); and had a shorter advanced life support call-response
interval (median, 4 versus 6 minutes; P < .001). The odds ratio for survival
(white/black) was .931 (95% confidence interval, .446 to 1.945). CONCLUSION: Race
was not found to predict adverse OHCA outcomes in this affluent population.
PMID- 9546018
TI - Synchronization of timepieces to the atomic clock in an urban emergency medical
services system.
AB - STUDY OBJECTIVE: Erroneous time documentation of emergency treatment caused by
the variation in the accuracy of timepieces has profound medical, medicolegal,
and research consequences. The purpose of this study was to confirm the variation
of critical timepiece settings in an urban emergency care system noted in
previous studies and to implement and monitor the results of a prospective
program to improve time synchronization. METHODS: Timepieces (n = 393) used by
firefighters, paramedics, and emergency physicians and nurses were randomly
sampled immediately before and at two time intervals (1 and 4 months) after
attempted synchronization to the US atomic clock standard. The setting on each
timepiece was compared with the atomic clock. From the data, a mathematical
simulation estimated the number of time-related documentation errors that would
occur in 2,500 simulated cardiac arrest cases using timepieces with accuracy
similar to those found in the EMS system before and after attempted
synchronization. RESULTS: Before attempted synchronization, the timepieces had a
mean error of 2.0 (95% confidence interval 1.8 to 2.3) minutes. One month after
attempted synchronization, the mean error decreased significantly to .9(.8 to
1.1) minute. However, it increased to 1.7 (1.5 to 1.9) minutes within 4 months.
Mathematical simulation before attempted synchronization predicted that 93% of
cardiac arrest cases would contain a documentation error of 2 minutes or more and
that 41% of cases would contain a documentation error of 5 minutes or more.
Attempted synchronization cut the 2-minute documentation error rate in half and
reduced the 5-minute documentation error rate by three fourths. However, the
error rates were predicted to return to baseline 4 months after attempted
synchronization. CONCLUSION: Emergency medical timepieces are often inaccurate,
making it difficult to reconstruct events for medical, medicolegal, or research
purposes. Community synchronization of timepieces to the atomic clock can reduce
the problem significantly, but the effects of a one-time attempted
synchronization event are short-lived.
PMID- 9546019
TI - Failure of the mandatory domestic violence reporting law to increase medical
facility referral to police.
AB - STUDY OBJECTIVE: To assess the effect of California's 1994 mandatory domestic
violence reporting law on Los Angeles Sheriff's Department dispatches to medical
facilities for domestic violence incidents. METHODS: This ecological time-trend
study analyzed data from the Los Angeles Sheriff's Department for the period
January 1, 1993, to December 31, 1995. All 26,051 dispatches for domestic
violence offenses during the study period were analyzed. The outcome measures
were changes in biweekly department dispatches for domestic violence offenses
resulting from the implementation of the mandatory domestic violence reporting
law adjusted for seasonal variation and the Simpson/Goldman murders. RESULTS: The
percentage of biweekly dispatches to medical facilities for domestic violence
offenses did not increase in response to the law (beta = -.0072, P = .095). Total
domestic violence dispatches increased significantly after the Simpson/Goldman
murders but not after passage of the law (beta = 82.7, P < .0001 versus beta =
10.1, P = .2205). CONCLUSION: The mandatory domestic violence reporting law in
California did not increase medical personnel reporting of domestic violence
situations to the Sheriff's Department during the 2 years after its
implementation.
PMID- 9546020
TI - Comparison of domestic violence screening methods: a pilot study.
AB - STUDY OBJECTIVE: Previous studies have indicated a number of barriers to
screening for domestic violence (DV) in an emergency department setting. These
barriers result in inconsistencies which determine who is screened as well as the
content and quality of the information obtained, and if uncontrolled they are
likely to affect measurements of DV incidence in ED populations. The objectives
of this project were to design a screening tool that circumvented these barriers
and sources of error; to assess whether such an alternative method of screening
for DV was acceptable to our patients; and to determine whether the alternative
and traditional methods of screening for DV would yield comparable results. Our
hypotheses were that the alternative screening tool would be acceptable to our
patients and that no significant differences would be found between the two
methods. METHODS: The study took place in a rural, university-affiliated ED with
approximately 36,000 annual patient visits. The study population consisted of 186
women older than 18 years of age who were treated by one designated physician.
Approximately half of these subjects were screened for DV in a face-to-face
interview. The other half listened to a tape-recorded questionnaire and recorded
their responses on a coded answer sheet. RESULTS: There were 175 completed
screenings. The average age of all respondents was 34 years, and 90 (51%)
indicated a cumulative lifetime experience of DV of some sort. Overall, 3% of the
respondents indicated they were in the ED for injuries received as a result of
DV. No significant differences were found between the two methods of screening
for DV on any measurement, including refusals. No problems hearing the tape or
understanding the instructions were reported. CONCLUSION: These results indicate
that the alternative method of employing a recorded questionnaire was no less
effective than the best efforts of a designated and conscientious physician. As a
means of quickly assessing the prevalence of DV in an ED setting, we find much to
recommend such an approach.
PMID- 9546021
TI - Emergency department-based study of risk factors for acute injury from domestic
violence against women.
AB - STUDY OBJECTIVES: To evaluate the associations between selected socioeconomic
risk factors and acute injury from domestic violence against women. METHODS: We
conducted a preliminary matched case-control study to measure the association of
selected predictor variables with acute injury from domestic, violence against
women. Patients identified as cases were Hispanic or white female emergency
department patients, 16 to 65 years of age, with acute injury sustained from
physical assault by an intimate male partner. Cases were selected for inclusion
in the study if they reported or admitted acute physical assault by their male
partners. Controls were selected from non-case female ED patients so as to
represent the base population of the cases and enhance comparability. Two
controls were matched to each case. The socioeconomic predictor variables
examined were the education level, employment status, history of alcohol abuse,
and history of drug abuse of the male partner and the education level and
cohabitation status of the female partner. RESULTS: Forty-six cases were
identified and included in the study. The age range was 16 to 51 years (mean, 33
years). There were 26 (57%) Hispanic and 20 (43%) white cases. The strongest
predictor for acute injury from domestic violence in these patients was a history
of alcohol abuse by the male partner, as reported by the female partner (odds
ratio, 12.9). The remaining predictor variables were weakly associated or not
associated with domestic violence. One half of the cases stated that their male
partners were intoxicated with alcohol at the time of assault. CONCLUSION: Of the
socioeconomic variables examined in this preliminary study, a history of alcohol
abuse by the male partner, as reported by the female partner, was the strongest
predictor for acute injury from domestic violence. A large-scale, multicenter, ED
based study is needed to clarify the relation between alcohol abuse, other
socioeconomic factors, and acute physical assaults against women by their
intimate male partners.
PMID- 9546022
TI - Evaluation of orthotopic liver transplant recipients presenting to the emergency
department.
AB - Improved survival rates and more centers performing liver transplantation have
resulted in increasing numbers of liver transplant recipients presenting to
emergency departments. This article familiarizes emergency physicians with
orthotopic liver transplantation and complications that cause liver transplant
recipients to visit EDs.
PMID- 9546023
TI - National Highway Traffic Safety Administration (NHTSA) notes. 1996 Motor Vehicle
Occupant Safety Survey.
PMID- 9546024
TI - National Highway Traffic Safety Administration (NHTSA) notes. Commentary: and who
is my neighbor?
PMID- 9546025
TI - Pediatric death and fluoride-containing wheel cleaner.
PMID- 9546026
TI - Ammonium bifluoride causes another pediatric death.
PMID- 9546027
TI - Pulse oximetry gap in carbon monoxide poisoning.
PMID- 9546029
TI - Health care guidelines for cruise ship medical facilities. American College of
Emergency Physicians.
PMID- 9546028
TI - Regional intravenous infusion of calcium gluconate for hydrofluoric acid burns of
the upper extremity.
PMID- 9546030
TI - Familial dysautonomia: a 47-year perspective. How technology confirms clinical
acumen.
AB - A historical perspective of familial dysautonomia is presented, highlighting the
early contributions of Dr. Joseph Dancis. As further investigations proceeded,
his original observations have withstood the test of time and may contribute to
determining the molecular abnormality in this rare genetic disorder. Dr. Dancis's
work in this area serves as a model of how observations based on clinical acumen
and critical thinking can be verified by future technological advances.
PMID- 9546031
TI - Nutritional studies of the embryo during early organogenesis with normal embryos
and embryos exhibiting yolk sac dysfunction.
AB - In 1961 we reported that heterologous kidney antiserum when injected into
pregnant rats resulted in wide spectrum of congenital malformations. Further
studies identified that it was the IgG component of the antiserum that was
teratogenic and that complement was not necessary to produce the teratogenic
effect. Labeled antibody studies demonstrated that the kidney antiserum localized
in the kidney and in the visceral yolk sac (VYS) and parietal yolk sac placentas.
Preparation of yolk sac (YS) antiserum proved to be more potent than the kidney
antiserum. Adsorption studies with VYS and parietal yolk sac antiserum revealed
that the site of the teratogenic process was located in the VYS. In vitro embryo
culture experiments demonstrated that direct injection of the teratogenic
antibody into the amniotic or YS cavity did not injure the embryo, thus
indicating that the teratogenic antibody had to come in contact with the
absorptive surface of the VYS. Collaboration with Dr. John Lloyd demonstrated
that teratogenic antibody interfered with the process of pinocytosis and the
delivery of amino acids (AA) to the developing embryo. Our studies into the
nature of the source of AA for the embryo indicated that in some instances > 95%
of the AA present in the developing embryo were derived from maternal proteins
and the remainder from free AA in the maternal serum. We also demonstrated that
embryonic methionine was derived primarily from the digestion of maternal serum
proteins but that more of the methionine was diverted from the synthesis of
embryonic proteins, supporting the view that it has important functions other
than the synthesis of proteins. All these studies focus on the role of the YS in
human development and whether human YS dysfunction may play a role in the
pathogenesis of congenital malformations. Further studies on the delivery of AA
to the embryo are warranted to determine whether certain AA are in short supply
in maternal serum and place the embryo at risk if nutritional alterations in the
maternal environment occurs. Furthermore, the YS may be an organ whose role might
offer opportunities for pregnancy control.
PMID- 9546032
TI - Maple syrup urine disease: it has come a long way.
AB - Maple syrup urine disease (MSUD) was first described in 1954 by Menkes et al. as
a progressive neurologic degenerative disorder. In 1960, Dancis et al.
established that the metabolic block in MSUD is at the decarboxylation of
branched-chain alpha-ketoacids derived from leucine, isoleucine, and valine. The
multienzyme complex affected in MSUD, the mitrochondrial branched-chain alpha
ketoacid (BCKD) dehydrogenase complex was purified in 1978 to homogeneity in
Reed's laboratory. This led to the later cloning of cDNAs and genes for subunits
of the human BCKD complex. Genetic heterogeneity in MSUD is now explained by the
various mutations that occur in the E1 alpha, E1 beta, E2, and E3 loci of the
BCKD complex. Recently, we found that bacterial chaperonins GroEL and GroES
promote folding and assembly of E1 decarboxylase component of the BCKD complex in
Escherichia coli. Pulse-chase labeling in this system showed that a subset of E1
alpha mutations, notably the homozygous Y393N-alpha in Mennonite MSUD patients,
impedes the assembly of the mutant E1 alpha subunit with normal E1 beta. The
assembly defect is associated with a rapid degradation of the normal E1 beta
subunit in MSUD cells. Retrovirus-mediated transduction of lymphoblasts from a
Mennonite MSUD patient with a normal E1 alpha cDNA resulted in a complete
restoration of BCKD activity. This was accompanied by a stabilization of the
normal E1 beta subunit through assembly with recombinant E1 alpha. The results
demonstrated the feasibility of stable correction of E1 alpha-deficient (type IA)
MSUD and provided a basis for the development of gene therapy.
PMID- 9546033
TI - Genetic analysis of iron uptake in the yeast Saccharomyces cerevisiae.
AB - OBJECTIVE: We used the methods of yeast genetics to identify genes involved in
acquisition of iron by eukaryotic cells. METHODS: Mutants were identified with
defects in cellular iron uptake. These were organized into an upstream group and
a downstream group. The upstream group was involved in the delivery of copper to
the multicopper oxidase FET3. Mutants of this group were characterized by
defective iron uptake that could be corrected by exposure of the cells to large
amounts of copper. The downstream group was more directly involved in iron
uptake. Mutant phenotypes from these genes could not be corrected by copper
exposure. RESULTS: Genes in the upstream group encoded the regulator of copper
transport, MAC1, and two copper transporters, CTR1 and CCC2. Genes in the
downstream group encoded the multicopper oxidase FET3 and its partner the iron
permease FTR1. In addition, the downstream genes encoded the surface reductases
FRE1 and FRE2 and the iron regulatory protein AFT1. CONCLUSIONS: The iron and
copper uptake processes in yeast intersect because the FET3 gene encodes a
multicopper oxidase that is required for iron transport. In human beings, an
analogous function may be served by ceruloplasmin, a multicopper oxidase with a
role in iron homeostasis.
PMID- 9546034
TI - Mechanisms of cerebral injury in perinatal asphyxia and strategies for
prevention.
AB - We have investigated the mechanisms of hypoxic brain cell injury in the immature
animal by examining (1) the role of excitatory amino acid neurotransmitter
receptors, (2) the receptor-mediated increase in intracellular Ca2+, and (3) the
generation of oxygen free radicals. We examined the effect of brain tissue
hypoxia on the NMDA receptor-ion channel complex including the glutamate, Mg2+,
spermine, CPP, and the non-NMDA receptor kainate sites. Brain tissue hypoxia
resulted in modification of the NMDA receptor ion channel and its modulatory
sites. Hypoxia increased the affinity of both the ion channel and the glutamate
recognition site. Pretreatment of animals with the glutamate antagonist CPP
prevented hypoxia-induced modification of the channel. Similarly, pretreatment of
animals with Mg2+, a blocker of the NMDA receptor ion channel, prevented the
hypoxia-induced modification of the receptor. In addition, an increased agonist
dependent entry of Ca2+ into synaptosomes was observed in hypoxic animals
compared with normoxic animals. Increased free radical generation in the cerebral
cortex during hypoxia was demonstrated using spin labeling technique and electron
spin resonance spectroscopy. We conclude that hypoxia-induced modification of the
NMDA receptor-ion channel complex leads to increased intracellular Ca2+
potentiating free radical generation and resulting in hypoxic cell injury.
PMID- 9546035
TI - Transport and endogenous release of vitamin B12 in the dually perfused human
placenta.
AB - The kinetics for vitamin B12, cobalamin (Cbl), transfer across the human
placenta, and the retention of the endogenous Cbl and its release into the
maternal and fetal compartments were investigated in a dually perfused human term
placenta in vitro. After 4 hours of perfusion following a single bolus injection
(peak maternal perfusate 94 fmol/ml) of 57Co-Cbl into the maternal reservoir, the
maternal [57Co-Cbl] rapidly decreased whereas the fetal [57Co-Cbl] was only 9% of
the final maternal [57Co-Cbl]. Even though there was a limited transfer of 57Co
Cbl to the fetus, the placenta rapidly accumulated Cbl. At 4 hours, 18% of the
initial 57Co-Cbl dose was in the placenta; only 3% of the initial dose was in the
fetal perfusate. Also after 4 hours, [57Co-Cbl] was bound > 95% to transcobalamin
(TC)I/III-like proteins in the maternal perfusate, whereas Cbl was bound to
TCI/III- and TCII-like proteins with some free in the fetal perfusate. In the
cytosol, > 95% of the [57Co-Cbl] was bound (80% to TCII-like and 19% to TCI/III
like proteins). When no exogenous Cbl was added, total endogenous [Cbl] in the
maternal circulation increased with time during 8 hours of perfusion at a rate of
0.25 +/- 0.12 pmol/gm per hour. Only 2% of this Cbl was free, whereas 98% was
bound to specific binding proteins. Neither plateau values nor equilibration with
the fetal side were noted. In the fetal circulation, there was a release of Cbl
at a rate of 0.015 +/- 0.003 pmol/gm per hour, which was 99.99% bound. Thus the
human placenta rapidly concentrates Cbl in the perfused lobule with little
distribution of Cbl to nonperfused areas. Therefore, the human placenta modulates
the asymmetric transfer of vitamin B12 on the basis of release of specific Cbl
binding proteins (TCI/III- and TCII-like) into the maternal and fetal perfusates.
PMID- 9546036
TI - Aging, changes in the cardiovascular system, and responses to stress.
AB - I have presented a picture of cardiovascular aging that resembles the situation
with vision, where in the absence of actual disease, near vision changes with age
and cataracts appear with age but after these are corrected, vision remains
markedly unchanged with age. For the undiseased heart, intrinsic cardiac muscle
function and the inotropic response to nonsympathetic mediators, along with
coronary perfusion, are well maintained with age. There are, however, some
changes that do occur with age. Cellular hypertrophy occurs, both because of cell
drop out and because of some chamber hypertrophy secondary to increased impedance
to left ventricular ejection. As a result of the hypertrophy, there is some
prolongation of systole secondary to delayed relaxation. This is typical of what
occurs in hypertension induced hypertrophy as well. These age-related changes are
of critical importance and are the background for the entire discussion of the
interplay between hypertension and disease. The large arteries do in fact stiffen
with age. Thus, even without hypertension, there is an age-related increased
impedance to ejection, a greater systolic load, a lower coronary perfusion
pressure, and an increased pulse wave velocity. Added to this is the failure of
the entire beta-sympathetic system to respond as well in the elderly as in the
younger individuals with a resultant decrease in the vasodilating response. Both
the chronotropic and inotropic response to sympathetic mediation is diminished so
that states that put sudden loads on the left ventricle, such as accelerated
hypertension or myocardial infarction, have more severe results in the elderly.
Also acute hypertension may produce less hypertrophy in the elderly and therefore
place more hemodynamic stress on the left ventricle than in young adults.
PMID- 9546037
TI - Renal disease and renal artery stenosis in the elderly.
PMID- 9546038
TI - Uncommon forms of secondary hypertension in older patients.
PMID- 9546039
TI - Quality of life during antihypertensive treatment. Lessons from the Systolic
Hypertension in the Elderly Program.
PMID- 9546040
TI - Individualized selection of antihypertensive drug therapy for older patients.
PMID- 9546041
TI - Cloning and sequence analysis of the cDNA encoding the elongation factor-1 beta
of Dictyostelium discoideum.
AB - A cDNA encoding elongation factor-1 beta (DdEF-1 beta) for protein synthesis was
isolated from Dictyostlium discoideum cells by the differential display (DD)
method. The DdEF-1 beta cDNA sequence with a length of 733 bp encodes a protein
(M(r) 24.1 kDa) consisting of 214 amino acids. Comparison of the predicted amino
acid sequence revealed relatively high homology to that of DdEF-1 beta from
silkworm (59%), human (57%) and Xenopus (55%). Northern analysis showed that the
DdEF-1 beta mRNA is maximally expressed during the vegetative growth phase,
followed by marked decrease in response to cell differentiation induced by
starvation.
PMID- 9546042
TI - Isolation of a new member of DnaJ-like heat shock protein 40 (Hsp40) from human
liver.
AB - A new member of Hsp40, HLJ1, consisting of 337 amino acids, was cloned from a
human liver cDNA library. The deduced amino acid sequence of HLJ1 has an 84%
homology (69% identity) with that of HDJ-1 isolated from human placenta. Northern
analysis showed that expression of the HLJ1 gene is heat-inducible and its
transcription shows some degree of preference in heart, skeletal muscle, and
pancreas.
PMID- 9546044
TI - Melatonin and serotonin interactions with calmodulin: NMR, spectroscopic and
biochemical studies.
AB - It has been reported that the hormone melatonin binds tightly to the ubiquitous
calcium-regulatory protein, calmodulin (CaM) with a Kd value around 0.1 nM
[Benitez-King et al., Biochim. Biophys. Acta, 1290 (1993) 191-196]. Normally CaM
only binds to target proteins and various 20-residue synthetic peptides
encompassing the CaM-binding domain of these target proteins with K(d) values
ranging between 1.0 microM and 0.1 nM. Here we have studied the interaction of
melatonin and several structurally related compounds--serotonin, 5
hydroxytryptophan, and tryptophan--to CaM through gel band shift assays,
enzymatic competition assays with calcineurin, fluorescence spectroscopy, far and
near UV circular dichroism spectropolarimetry and NMR spectroscopy. Fluorescence
spectra show that the binding is calcium dependent. NMR studies with
biosynthetically labelled methyl-13C-Met CaM show that melatonin and the other
compounds interact with the hydrophobic cleft regions of the protein. Our NMR
data show that melatonin binds to both domains of the dumbbell-shaped CaM, while
serotonin appears to bind only to the C-terminal domain. This binding mode is
further substantiated by fluorescence and gel band shift competition experiments
with synthetic peptides from myosin light chain kinase and constitutive nitric
oxide synthase. Circular dichroism spectra indicate that the secondary structure
of CaM is not altered by addition of melatonin. Our data are internally
consistent and reveal Kd values in the mM range for melatonin. Thus the binding
of these compounds to CaM is substantially weaker than was previously reported
and is unlikely to be of physiological significance.
PMID- 9546043
TI - Legume lectin structure.
AB - The legume lectins are a large family of homologous carbohydrate binding proteins
that are found mainly in the seeds of most legume plants. Despite their strong
similarity on the level of their amino acid sequences and tertiary structures,
their carbohydrate specificities and quaternary structures vary widely. In this
review we will focus on the structural features of legume lectins and their
complexes with carbohydrates. These will be discussed in the light of recent
mutagenesis results when appropriate. Monosaccharide specificity seems to be
achieved by the use of a conserved core of residues that hydrogen bond to the
sugar, and a variable loop that determines the exact shape of the monosaccharide
binding site. The higher affinity for particular oligosaccharides and
monosaccharides containing a hydrophobic aglycon results mainly from a few
distinct subsites next to the monosaccharide binding site. These subsites consist
of a small number of variable residues and are found in both the mannose and
galactose specificity groups. The quaternary structures of these proteins form
the basis of a higher level of specificity, where the spacing between individual
epitopes of multivalent carbohydrates becomes important. This results in
homogeneous cross-linked lattices even in mixed precipitation systems, and is of
relevance for their effects on the biological activities of cells such as
mitogenic responses. Quaternary structure is also thought to play an important
role in the high affinity interaction between some legume lectins and adenine and
a series of adenine-derived plant hormones. The molecular basis of the variation
in quaternary structure in this group of proteins is poorly understood.
PMID- 9546045
TI - Substrate specificity of cellobiose dehydrogenase from Phanerochaete
chrysosporium.
AB - Substrate structural mapping suggests that the catalytic site of cellobiose
dehydrogenase from Phanerochaete chrysosporium forms a narrow cave with two
hexose binding subsites. Kinetic data also show that beta-di or oligosaccharides
are favored electron donors with respect to both KM and kcat. Surprisingly,
thiocellobiose showed an even higher kcat than cellobiose, although the KM value
was somewhat higher. The CDH was purified using an updated protocol.
PMID- 9546046
TI - Primary structures of Arenicola marina isomyoglobins: molecular basis for
functional heterogeneity.
AB - The primary structures of isomyoglobins MbI and MbII from the body wall
musculature of the polychaete Arenicola marina were investigated, aiming to trace
the molecular basis for their functional differentiation. Unexpectedly, five
chains, MbIa, MbIb, MbIIa, MbIIb and MbIIc, each consisting of 145 amino-acid
residues and occurring in a ratio of = 33:17:25:12.5:12.5 were found. All
substitutions can be explained by one-point mutations. With the exception of the
41(C6)Asn-->Asp(MbI/MbII) exchange that appears to be the basis for the
electrophoretic separation of MbI and MbII, the substitutions do not involve
drastic changes in the character of the side-chains. Pairwise comparison of MbIa
and MbIIa with other invertebrate globin chains indicate the following sequence
of decreasing identities: Aplysia (mollusc) Mb, Chironomus (insect) CTT III
hemoglobin, whale Mb and Ascaris (nematode) Mb. The marked difference in O2
affinities between MbI and MbII appears attributable to 62Pro which distorts the
E helix around E6 and occurs in all MbII chains, but in only 33% of the MbI
chains (MbIb).
PMID- 9546047
TI - Catalytic properties of the cysteine aminopeptidase PepC, a bacterial bleomycin
hydrolase.
AB - PepC is a cytoplasmic thiol aminopeptidase widely conserved among lactic acid
bacteria. PepC from Lactococcus lactis shares 35-38% identity with
aminopeptidases of eukaryotic origins: the yeast and mammalian bleomycin
hydrolases (BLMase). In this work we investigated the hydrolytic activity of PepC
towards various substrates: bleomycin A2, aminoacyl-p-nitroanilides (pNA) and
peptides. First, we found the bleomycin hydrolase activity of lactococcal PepC
and measured similar kinetics parameters to those reported for the mammalian
BLMase. Second, the results obtained on aminoacyl-pNA confirmed the capacity of
the enzyme to release a broad range of amino acids and the pH activity profile
suggests the presence of an ionic interaction between the enzyme and the free
alpha-amino group of the substrate. Third, the aminopeptidase activity measured
on peptide substrates revealed that PepC possesses an extended binding site which
interacts with the peptidic backbone of the substrate. The hydrolytic efficiency
is highly dependent on the length of the peptide, optimal for tetrapeptides and
further enhanced by the presence of hydrophobic residues in the P' positions of
the substrate. These enzymatic properties are of importance for the design of
specific inhibitors and the biological function of the bleomycin hydrolases.
PMID- 9546048
TI - Dual effect of actin on the accessibility of myosin essential light chain A1 to
papain cleavage.
AB - The influence of various amounts of actin on the proteolytic susceptibility of
myosin essential light chain (ELC) A1, the binding of isolated A1 light chain and
the N-peptide spanning N-terminal sequence of A1 to actin is studied to obtain
more information on the role of the N-terminus of A1 light chain in the myosin
actin interaction. Low ratios of actin to myosin (1:1) lead to stimulate
cleavage, whereas higher ratios (4:1) lead to protection of A1. Exposure of A1 by
actin is especially seen in heavy meromyosin (HMM) and monomeric myosin and this
is probably related to the full saturation of actin protomers with myosin heads.
The protecting action of actin on A1 cleavage is more pronounced in myosin
filaments. Conditions favoring the saturation of myosin regulatory light chain
(RLC) with calcium ions instead of magnesium ions promotes the protection of A1.
Cross-linking of HMM and actin results in higher yields of A1-actin product at
high actin to myosin heads ratios. Isolated A1 light chain is pelleted by actin.
A synthetic peptide spanning the N-terminal sequence of A1 can be cross-linked to
actin. It is postulated that the protective action of actin on A1 papain cleavage
is caused by the binding of the A1 N-terminus to actin. Changes in the RLC
phosphorylation level and magnesium-for-calcium exchange in RLC may affect the
probability of this interaction.
PMID- 9546049
TI - Interaction of quinones with Arabidopsis thaliana thioredoxin reductase.
AB - In view of the ubiquitous role of the thioredoxin/thioredoxin reductase (TRX/TR)
system in living cells, the interaction of Arabidopsis thaliana NADPH-thioredoxin
reductase (EC 1.6.4.5) with quinones, an important class of redox cycling and
alkylating xenobiotics, was studied. The steady-state reactions of A. thaliana TR
with thioredoxin (TRX) and reaction product NADP+ inhibition patterns were in
agreement with a proposed model of E. coli enzyme (B.W. Lennon, C.H. Williams,
Jr., Biochemistry, vol. 35 (1996), pp. 4704-4712), that involved enzyme cycling
between four- and two-electron reduced forms with FAD being reduced. Quinone
reduction by TR proceeded via a mixed single- and two-electron transfer, the
percentage of single-electron flux being equal to 12-16%. Bimolecular rate
constants of quinone reduction (kcat/km) and reaction catalytic constants (kcat)
increased upon an increase in quinone single-electron reduction potential. E(1)7.
In several cases, the kcat of quinone reduction exceeded kcat of TRX reduction,
suggesting that quinones intercepted electron flux from TR to TRX. Incubation of
reduced TR with alkylating quinones resulted in a rapid loss of TRX-reductase
activity, while quinone reduction rate was unchanged. In TRX-reductase and
quinone reductase reactions of TR, NADP+ exhibited different inhibition patterns.
These data point out that FAD and not the catalytic disulfide of TR is
responsible for quinone reduction, and that quinones may oxidize FADH2 before it
reduces catalytic disulfide. Most probably, quinones may oxidize the two-electron
reduced form of TR, and the enzyme may cycle between two-electron reduced and
oxidized forms in this reaction. The relatively high rate of quinone reduction by
A. thaliana thioredoxin reductase accompanied by their redox cycling, confers pro
oxidant properties to this antioxidant enzyme. These factors make plant TR an
attractive target for redox active and alkylating pesticide action.
PMID- 9546050
TI - X-ray crystal structure of papain complexed with cathepsin B-specific covalent
type inhibitor: substrate specificity and inhibitory activity.
AB - The Ile-Pro sequence of CA074, potent covalent-type inhibitor, is necessary to
exhibit the specificity for cathepsin B, but not for papain. In order to
elucidate how its sequence binds to papain and why such binding does not exhibit
the specificity for papain at the atomic level, two CA074-related compounds, 1 (N
(L-3-carboxyloxirane-2-carbonyl)-L-isoleucyl-L-proline) and 2 (N-(L-3
carboxyloxirane-2-carbonyl)-L-isoleucyl-diethylamide), were designed and their
structure--inhibitory activity relationship was investigated by the X-ray crystal
analyses of the complexes with papain. The Ile-Pro moiety of 1 was located at the
S2 and S3 subsites consisting of Val-133, Val-157, and Asp-158 and of Tyr-61, Gly
66, and Tyr-67 residues of papain, respectively, which is in contrast with the
binding of CA074 to S'n (n = 1 approximately 2) subsites in the complex with
cathepsin B. Although 2 in the complex with papain showed the similar binding
pattern to 1, its inhibitory activity was about two-fold higher than of 1,
suggesting the importance of tight S3-P3 hydrophobic interaction for the
activity. The difference of the substrate specificity between papain and
cathepsin B has also been discussed based on the X-ray results of the present and
cathepsin B-inhibitor complexes.
PMID- 9546051
TI - The purification and characterization of a Trichoderma harzianum exochitinase.
AB - A chitinolytic enzyme was purified from the culture filtrate of T. harzianum
(T198) by precipitation with ammonium sulphate followed by affinity binding to
swollen chitin and release with 10% (v/v) acetic acid. The molecular weight of
the enzyme was calculated to be 28 and 27.5 kD by gel filtration chromatography
and SDS-PAGE, respectively. The isoelectric point of the enzyme was 7.4. The pH
optimum for activity was 3.5 and maximum activity was obtained at 50 degrees C.
The enzyme displayed activity on a wide array of chitin substrates of more than
two N-acetylglucosamine units in length. HPLC analysis of hydrolysis products
demonstrated that the enzyme was an exochitinase releasing N-acetylglucosamine
only.
PMID- 9546052
TI - Probing the ATP binding site of tubulin with thiotriphosphate analogues of ATP.
AB - Tubulin assembly studies with GTP alpha S diastereoisomers have shown that there
is stereoselectivity at the alpha-phosphate binding region of tubulin. GTP alpha
S(Sp) bound tighter than GTP alpha S(Rp) and promoted nucleation and assembly
better than GTP and GTP alpha S(Rp). ATP and dATP have been reported to bind
weakly to tubulin and to be less effective than GTP and dGTP in promoting tubulin
assembly. This study was done to learn if ATP alpha S(Sp) and dATP alpha S(Sp)
are good promoters of tubulin assembly and to compare these ATP thiotriphosphate
analogues to the corresponding GTP analogues in tubulin assembly. Studies were
also done with ATP alpha S(Rp), GTP, ATP beta S(Sp) and ATP gamma S. At least
three cycles of tubulin (25 microM) assembly-disassembly were found with 1 mM ATP
alpha S(Sp) and dATP alpha S(Sp) and both nucleotides were incorporated and
hydrolyzed in the polymers. Less dATP alpha S(Sp) (25 microM) than ATP alpha
S(Sp) (100 microM) promoted assembly to 50% of the maximum value. The critical
concentrations (Cc) for assembly with 1 mM nucleotide were low for ATP alpha
S(Sp) (3 microM) and dATP alpha S(Sp) (2 microM) and compared favorably with GTP
(5 microM), GTP alpha S(Sp) (2 microM) and dGTP alpha S(Sp) (1 microM). Both 1 mM
ATP and dATP were poor promoters of tubulin assembly and were not detected in the
polymers. The predominant structures induced by 1 mM (ATP alpha S(Sp) and dATP
alpha S(Sp) were bundles of sheets and microtubules, which were more stable to
the cold and to Ca(II) than microtubules assembled with GTP, ATP or dATP. ATP
alpha S(Rp) (1 mM) did not promote assembly suggesting that there is
stereoselectivity at the ATP alpha S alpha-phosphate binding region of tubulin as
there is with GTP alpha S diastereoisomers. ATP alpha S(Sp) and dATP alpha S(Sp)
mimic GTP alpha S(Sp) and dGTP alpha S(Sp) in tubulin assembly since all four
nucleotides promote bundles of tubulin in buffer with glycerol, and the deoxy
nucleotides have lower Cc, shorter lags and faster rates for tubulin assembly.
PMID- 9546053
TI - Interaction of M1 and M2 isozymes pyruvate kinase from human tissues with
phospholipids.
AB - The effect of pH and the presence of FBP on the interaction of skeletal muscle
(PK-M1) and kidney or tumor meningioma (PK-M2) pyruvate kinase with the
phospholipids liposomes were investigated by ultracentrifugation and steady-state
kinetics and were compared with those results obtained using the bovine heart (PK
M1) isoenzyme which we previously studied. Pyruvate kinase specific activity
increases upon the interaction with liposomes. The activation is specifically
sensitive to presence of phosphatidylserine (PS) in liposomes. Liposomes made of
phosphatidylcholine + phosphatidylserine mixture are good adsorptive systems for
both human and bovine of M-type isozymes at low ionic strength. Interaction of PK
M1 with PS liposomes results in the change of Vmax and K(m) values for PEP
without marked effect on Hill coefficients. Addition of PS liposomes to PK-M2
induces hyperbolic saturation curves for PEP.
PMID- 9546054
TI - A molecular model for the d chain of the giant haemoglobin from Lumbricus
terrestris and its implications for subunit assembly.
AB - A structural model for the monomeric d chain of the giant haemoglobin from
Lumbricus terrestris is described. Based on the crystal structures of other
globins, the model provides evidence for the existence of a novel tryptophan-haem
interaction. The observation that all three tryptophans are buried within the
hydrophobic core is consistent with fluorescence data on the isolated monomer and
the intact molecule. The model has also been used to predict the probable
arrangement of the abcd tetramer as being similar to that observed in the clam Hb
II structure. Such predictions allow the identification of four residues of
particular importance in stabilising one of the subunit-subunit interfaces:
Arg48, Arg97, His89 and Gln93. The latter two may be of special importance in the
mediation of cooperative effects within the tetramer and indeed the intact
molecule.
PMID- 9546055
TI - An electrospray ionization mass spectrometric study of the extracellular
hemoglobins from Chironomus thummi thummi.
AB - The aquatic larvae of the dipteran, Chironomus thummi thummi contain
extracellular hemoglobins which exhibit stage-specific expression. We have used
maximum entropy-based deconvolution of the complex, multiply charged electrospray
ionization mass spectra, to demonstrate the presence of more than 20 components,
ranging in mass from 14,417.3 Da to 17,356.5 Da in the 4th instar larvae. Of the
15 major peaks with intensities > 10 relative to 100 for the 14,417.3 Da
component (CTT-IV), only the 15,528.2-Da peak does not correspond to a known
amino acid sequence. Since the number of C. thummi thummi globin genes now stands
at 27, including one cDNA and not counting three that must encode known globins,
our results suggest that only a limited number of the globin genes are expressed
in the 4th instar larvae.
PMID- 9546056
TI - Long-lifetime Ru(II) complexes for the measurement of high molecular weight
protein hydrodynamics.
AB - We describe the synthesis and characterization of two asymmetrical ruthenium(II)
complexes, [Ru(dpp)2(dcbpy)]2+ and [Ru(dpp)2(mcbpy)]2+, as well as the water
soluble sulfonated derivatives [Ru(dpp(SO3Na)2)2(dcbpy)]2+ and
[Ru(dpp(SO3Na)2)2(mcbpy)]2+ (dpp is 4,7-diphenyl-1,10-phenanthroline, dcbpy is
4,4'-dicarboxylic acid-2,2'-bipyridine, mcbpy is 4-methyl,4'-carboxylic acid-2,2'
bipyridine, and dpp(SO3Na)2 is the disulfonated derivative of dpp) as probes for
the measurement of the rotational motions of proteins. The spectral (absorption,
emission, and anisotropy) and photophysical (time-resolved intensity and
anisotropy decays) properties of these metal-ligand complexes were determined in
solution, in both the presence and absence of human serum albumin (HSA). These
complexes display lifetimes ranging from 345 ns to 3.8 microseconds in
deoxygenated aqueous solutions under a variety of conditions. The carboxylic acid
groups on these complexes were activated to form N-hydroxysuccinimide (NHS)
esters which were used to covalently lable HSA, and were characterized
spectroscopically in the same manner as above. Time-resolved anisotropy
measurements were performed to demonstrate the utility of these complexes in
measuring long rotational correlation times of bioconjugates between HSA and
antibody to HSA. The potential usefulness of these probes in fluorescence
polarization immunoassays was demonstrated by an association assay of the Ru(II)
labeled HSA with polyclonal antibody.
PMID- 9546057
TI - Redox potential of the haem c group in the quinocytochrome, lupanine hydroxylase,
an enzyme located in the periplasm of a Pseudomonas sp.
AB - The quinocytochrome c, lupanine hydroxylase, was shown to be located in the
periplasm of a Pseudomonas sp. The midpoint redox potential of the haem in the
purified enzyme was measured by potentiometric titration and shown to be +193 mV.
PQQ was removed from the enzyme by isoelectric focusing to give inactive
apoenzyme. This resulted in a shift in the midpoint redox potential of the haem
to +98 mV. Full activity was recovered by the addition of PQQ to apoenzyme that
also restored the original potential.
PMID- 9546058
TI - Effect of pressure on the catalytic activity of subtilisin Carlsberg suspended in
compressed gases.
AB - We studied the effect of pressure up to 300 bar on the catalytic efficiency of
subtilisin Carlsberg suspended in compressed propane, near-critical ethane, near
critical carbon dioxide and tert-amyl alcohol, at constant temperature and fixed
enzyme hydration. Increasing pressure lowered the catalytic efficiency of the
enzyme in all the solvents, resulting in positive activation volumes, delta V#.
The delta V# values in compressed propane and in tert-amyl alcohol were similar
and larger in magnitude than the value reported in the literature for the same
reaction in an aqueous buffer, although within the range of typical delta V#
values in aqueous media. In the near-critical fluids, the delta V# were much
larger, e.g., an increase in pressure of only 200 bar causing a sixfold decrease
in the catalytic efficiency of subtilisin in carbon dioxide. These data should
reflect the proximity of ethane and carbon dioxide to the critical point, and the
resulting condensation of solvent molecules about the solutes, yielding negative
solute partial molar volumes.
PMID- 9546059
TI - Pediatric brain tumors: loss of heterozygosity at 17p and TP53 gene mutations.
AB - Cytogenetic and molecular analyses of primitive neuroectodermal tumors (PNETs) of
the central nervous system (CNS) have demonstrated material losses of 17p, the
region that contains the TP53 gene, as the most frequent abnormality. Mutations
in the TP53 gene are, however, very rare in these tumors. These findings strongly
suggest that another, as yet unidentified, gene on 17p may be involved. We
performed a search for loss of heterozygosity (LOH) on 17p by microsatellite
markers on 26 childhood CNS tumors as well as TP53 gene mutations (exons 5-8) by
single-strand conformational polymorphism analysis on 41 pediatric brain tumor
samples of distinct histologic types. LOH was detected in 10 cases: 7 PNET, 2
astrocytomas, and 1 glioblastoma multiforme. In 4 of the PNETs the losses were
limited to more distal markers. On the other hand, TP53 mutations were detected
in 6 of 41 samples studied. Our results not only confirm the low penetrance of
the TP53 gene on pediatric CNS tumors, but also provide further evidence of a
putative tumor suppressor gene distal to TP53, between markers (D17S938, D17S926)
and 17pter, specifically taking part in the development of PNET.
PMID- 9546060
TI - Characterization of a malignant eccrine poroma by cytogenetic and fluorescence in
situ hybridization techniques.
AB - We have cytogenetically and by fluorescence in situ hybridization (FISH) analyzed
short-term cultures from a malignant eccrine poroma, a type of tumor in which
chromosomal abnormalities have previously not been reported. Combining the
results from G-banding and FISH, the karyotype was interpreted as
50,XX,t(3;11;12)(q21;p15;q15),+5,+7,+9,
+9,t(12;22)(q13;q13),+del(12)(q15),der(15)t(3;15)
(q23;p13),der(17)t(8;17)(q22;p13),-20,add(22)(q13).
PMID- 9546061
TI - Normal and rearranged PAX3 expression in human rhabdomyosarcoma.
AB - PAX3, a member of the PAX-gene family, encodes a nuclear transcription factor
that is transiently expressed in the neural tube and in muscle progenitor cells
and regulates embryonal development in the mouse. Together with the FKHR gene it
is involved in the t(2;13)(q35;q14), a specific translocation associated with
alveolar rhabdomyosarcoma (ARMS). As a consequence of the rearrangement two
chimeric transcripts originate: FKHR-PAX3 and PAX3-FKHR. We studied the
expression of wild type PAX3 and the chimeric transcripts originating from the
t(2;13) in a series of 23 rhabdomyosarcomas (RMS) of childhood, by reverse
transcriptase polymerase chain reaction (RT-PCR). Wild type PAX3 was detected in
48% of the RMS, whereas another 39% were positive only after nested PCR. Normal
adult-skeletal muscle showed a very weak expression of PAX3, but fetal muscle did
not express PAX3. PAX3-FKHR was found in 11 of 15 alveolar RMS, 7 of which were
positive also for the reciprocal transcript, whereas no RMS expressed FKHR-PAX3
alone. These results confirm that the PAX3-FKHR transcript is specifically
associated with the alveolar RMS and that it is a more sensitive marker of the
t(2;13) than the reciprocal product FKHR-PAX3. Furthermore, the finding of PAX3
expression with or without PAX3-FKHR transcript in the great majority of the
cases raises the question of whether PAX3 expression could play a role in the
pathogenesis of RMS.
PMID- 9546062
TI - Mutation of the 5' noncoding region of the BCL-6 gene in low-grade gastric
lymphoma of the mucosa-associated lymphoid tissue.
AB - BCL-6 gene rearrangement and hypermutations were investigated in four Hong Kong
Chinese patients with low-grade gastric lymphoma of the mucosa-associated
lymphoid tissue (MALToma). The former was studied by Southern analysis and the
latter by the technique of polymerase chain reaction and denaturing gradient gel
electrophoresis. BCL-6 gene rearrangement was not detectable in any of the four
cases. However, mutations at both the E1.11 and E1.12 segments of the 5'
noncoding region of the BCL-6 gene were found in two patients. This preliminary
observation suggests that the mutations of the 5' noncoding region of the BCL-6
gene rather than gene rearrangement may be playing a more important role in the
tumorigenesis of low-grade gastric MALToma. Further confirmation of this finding
by studying a larger number of patients will be required.
PMID- 9546063
TI - Fluorescence in situ hybridization to assess aneuploidy for chromosomes 7 and 8
in hematologic disorders.
AB - Stored, fixed cell suspensions of bone marrows from 70 patients karyotyped over a
three-year period for myelodysplastic syndrome (MDS) or related hematologic
conditions were retrospectively studied in two series using centromeric probes
for chromosomes 7 and 8. Series I consisted of patient samples with numerical
and/or structural abnormalities of chromosomes 7 or 8, matched with chromosomally
normal samples from about the same time period. Series II consisted of
consecutive MDS patient samples as well as patient samples in which one or more
cells had numerical or structural abnormalities of 7 and 8. In both series,
probes for chromosomes 7 and 8 were applied in each case and at least 100 nuclei
were scored for each probe for the distribution of one, two, or three signals.
Twenty-seven cases had clonal abnormalities by routine cytogenetics (RC): 12 with
monosomy 7; one with monosomy 8; five with trisomy 8; nine with clonal
abnormalities other than 7 or 8 aneuploidy. Eleven cytogenetically normal cases
gave abnormal interphase FISH (IF) results; one was subsequently confirmed by
metaphase FISH analysis to have a clonal structural abnormality of chromosome 7;
one case with a trisomy 8 clone, in remission by RC, showed 35% of cells by IF
with three signals for chromosome 8; one case had heteromorphic chromosomes by
FISH. Of eight remaining cases, five (four with -7 and one with +8 by IF) were
among 22 cases of cytogenetically normal MDS. Three remaining cases (two with +8
and one with both +7 and +8 by IF) had AML or MPD. The high rate of possible
undetected monosomy 7, among MDS cases in particular, suggests all MDS cases
should be screened by IF.
PMID- 9546065
TI - Two new cases of near-tetraploidy in adult acute myeloid leukemia.
AB - Tetraploid or near-tetraploid karyotype has been described rarely in hematologic
neoplasms. Herein we report two new cases of adult acute myeloblastic leukemia,
M0 and M1 FAB subtypes that showed near-tetraploid clones that were studied with
conventional cytogenetics and in situ hybridization (ISH). We compare our new
cases with those previously reported.
PMID- 9546064
TI - Chromosomal abnormalities in two bladder carcinomas with secondary squamous cell
differentiation.
AB - Two secondary squamous cell carcinomas of the bladder (i.e., tumors that
originated from primary transitional cell carcinomas) were examined
cytogenetically. Both tumors showed complex karyotypes with many of the same
aberrations that have formerly been described in transitional cell carcinomas.
Monosomy 9, trisomy 7, and rearrangements of chromosomes 3, 8, 10, 13, and 17
were common to both tumors. Among other changes that have been implicated in
bladder carcinogenesis, an isochromosome for 5p was seen in one tumor and loss of
11p material in the other. Our findings indicate that secondary squamous cell
carcinomas of the bladder are karyotypically indistinguishable from advanced
transitional cell carcinomas of the same organ. The putative genetic changes that
steer the differentiation of the neoplastic epithelium in the direction of
squamous cells thus remain unknown.
PMID- 9546066
TI - Gastrointestinal stromal tumor, uncommitted type, with monosomies 14 and 22 as
the only chromosomal abnormalities.
AB - Karyotypic analysis of a gastric stromal tumor with the histologic and
immunohistochemical features of a malignant, uncommitted lesion revealed clonal
monosomies of chromosomes 14 and 22. Such changes, together with loss of
chromosomes 15 and 18, as well as structural rearrangements involved chromosome
1, have been previously reported in gastrointestinal stromal tumors with smooth
muscle differentiation. We suggest that monosomies of chromosomes 14 and 22 are
early events in the malignant transformation of the mesenchymal cell-originating
gastrointestinal stromal tumors.
PMID- 9546067
TI - Cytogenetic chromosomal preparations using 2-methoxyestradiol.
AB - The antimitotic drug 2-methoxyestradiol is an end metabolite of catechol
estrogens. In vivo, it arrests cells in mitosis by interfering with the dynamics
of the mitotic spindle without disrupting tubulin formation. It has a mitotic
index similar to that of Colcemid in different cell lines. Here we report that 2
methoxyestradiol can be used for making cytogenetic preparations of comparable
quality to that of colcemid. In addition, 2-methoxyestradiol is devoid of the
toxicity associated with Colcemid, which may make 2-methoxyestradiol useful in
slowly growing samples often found in primary solid tumor cultures where a
sufficient number of mitotic cells is difficult to obtain.
PMID- 9546068
TI - Cytogenetic findings in an embryonal sarcoma of the liver.
AB - An undifferentiated embryonal sarcoma (malignant mesenchymoma) of the liver from
a 5-year-old girl was found to have near-triploid and near-hexaploid clones with
several chromosomal rearrangements. This is the first description of the
chromosomal changes in this tumor type.
PMID- 9546069
TI - Splenic lymphoma with villous lymphocytes showing del(7) and inv(10).
AB - A 49-year-old woman presented with splenic lymphoma with villous lymphocytes
(SLVL) that showed a clonal abnormality of del(7)(q22q32) in addition to
inv(10)(p13q23), the latter being a previously undescribed abnormality in chronic
lymphoproliferative disorders. A review of the literature on cytogenetic
abnormalities of SLVL indicates that del(7q) is strongly associated with SLVL and
may be important in the pathogenesis of this disorder.
PMID- 9546070
TI - Fluorescence in situ hybridization reveals trisomy 2q by insertion into 9p in
hepatoblastoma.
AB - Cytogenetics and fluorescence in situ hybridization (FISH) of a hepatoblastoma
are presented. The results of standard chromosome analysis were as follows:
47,XY,+2,add(4)(q35),-9,+20[10]. FISH with the use of whole-chromosome paints
revealed partial trisomy of the long arm of chromosome 2 by insertion into
chromosome 9. Comparison of the G-banded metaphases with metaphase FISH led to a
reinterpretation of the karyotype as:
47,XY,add(4)(q35),der(9)ins(9;2)(p22;q?21q?25),+20. This case supports previous
observations that the critical region of trisomy 2 lies between 2q21 and 2qter
and shows how partial trisomy 2q may evade detection in G-banded metaphases.
PMID- 9546071
TI - Rare constitutional Robertsonian translocation in a childhood acute lymphoblastic
leukemic patient.
PMID- 9546072
TI - True extended haplotypes of p53: indicators of breast cancer risk.
PMID- 9546073
TI - Cytogenetic analysis of cells from endometriotic cysts of the human ovary.
PMID- 9546074
TI - Correction of the Bloom syndrome cellular phenotypes.
AB - Bloom syndrome (BLM) is a genetic disorder associated with predisposition to
cancer and chromosome instability. However, the most readily recognized clinical
feature of the syndrome is growth retardation. Introduction of the previously
cloned BLM gene into BLM cells yielded correction of the chromosome instability
and slow growth phenotypes. Additionally, asynchronous cultures of complemented
clones revealed a lower percentage of cells in S-phase than uncomplemented BLM
cells. These results support the notion that BLM is a defect in which short
stature, chromosome instability and cancer predisposition are all associated with
an error in DNA replication.
PMID- 9546075
TI - Cell cycle control is aberrant in Chinese hamster ovary cell mutants exhibiting
apoptosis after serum deprivation.
AB - We isolated mutants of Chinese hamster ovary cells that exhibit excessive
apoptosis after serum deprivation. In the medium containing 10% serum, the growth
rates of the mutants were 1.4 to 1.5-fold faster than those of wild-type cells.
Whereas the cell cycle of wild-type cells was arrested at the G1 phase after
serum deprivation, the cell cycle of the mutant cells was not fully arrested at
this phase, suggesting that cell cycle regulation was disorganized in the
mutants. The mutants were highly sensitive to a nucleotide-analogue 5
fluorouracil in the absence of serum, whereas wild-type cells were resistant to
the drug. Based on the sensitivity to the drug after serum deprivation, we could
classify the mutants into dominant groups and at least two recessive
complementation groups. Thus, these mutants presumably contain different lesions
in gene(s) required for cell cycle regulation and apoptosis.
PMID- 9546076
TI - Applications of green fluorescent protein as a marker of retroviral vectors.
AB - The Green Fluorescent Protein (GFP) of Aequorea victoria is used as a vital
fluorescent tag for the detection and isolation of genetically modified cells.
Several modified variants of GFP were tested as marker genes in retroviral
vectors containing different backbones and promoter combinations. Constructs
allowing for reliable detection of GFP fluorescence and the expression of a
cotransduced gene from a strong promoter were identified. Cells harboring such
constructs are detectable by flow cytometry, fluorescence microscopy and multi
well fluorescence reading. GFP expression in transduced cells is stable both in
vitro and in vivo, and long-term dynamics of GFP-positive fractions in a mixed
population can be used to monitor the biological effects of a cotransduced gene.
Selection of cells with the highest GFP fluorescence enriches for multiply
infected cells. The use of different GFP variants allows one to monitor
simultaneously two cell populations transduced with vectors carrying GFPs that
differ in their fluorescence intensity or spectral properties and to identify
doubly transduced cells. In addition, transcription of an inducible promoter
positioned in the opposite orientation to GFP can be monitored by the inhibition
of GFP fluorescence. Thus, GFP provides a useful marker for gene transfer by
retroviral vectors and extends the range of applications for retroviral
transduction.
PMID- 9546078
TI - Assignment of three human markers in chromosome 21q11 to mouse chromosome 16.
AB - Three unique sequence microclones from human chromosome region 21q11 were
assigned to mouse chromosome 16 using a mouse/Chinese hamster cell hybrid 96Az2
containing a single mouse chromosome 16. This comparative mapping provides
further homology between human chromosome 21 and mouse chromosome 16 to include
the very proximal portion of the long arm of human chromosome 21. Since this part
of human chromosome 21 is associated with mental retardation in Down syndrome
individuals, its homologous mouse region should also be included in the
construction of mouse models for studying Down syndrome phenotypes including
mental retardation.
PMID- 9546077
TI - Phenotypic correction of ataxia-telangiectasia cellular defect by exogenously
introduced human or mouse subchromosomal fragments.
AB - A human-mouse hybrid containing a human 11q22-23 fragment including the ATM locus
was used to examine its capability to correct the cellular defect of ataxia
telangiectasia (A-T). Examination of 21 A-T-derived hybrids indicated that the
acquired radioresistance was observed in the clones where the 11q22-23 fragment
was transferred intact, but not in those where donor-derived 11q segment was
lost. In one exceptional clone, the ATM locus was deleted from the transferred
fragment, while it was still partially radioresistant. This partially
radioresistant clone was found to include the mouse-derived fragment containing
the Atm gene, the mouse homologue of human ATM gene. Similar association of
partial radioresistance with the presence of mouse Atm gene was observed in three
additional hybrids. The results indicate that the cellular A-T defect can be
corrected by the mouse subchromosomal fragment containing the Atm gene as well as
by the human 11q22-23 fragment containing the ATM gene, but apparently to a
lesser extent in the former.
PMID- 9546079
TI - [The knowledge of pediatricians in Salvador, Brazil about measles vaccine].
AB - The success of international initiatives for the eradication of measles depends
in large part on knowledge about vaccination. In 1992, a cross-sectional study
was carried out to evaluate knowledge about measles vaccine among pediatricians
in the Brazilian city of Salvador, Bahia. Of the 506 pediatricians residing in
the city, 299 (59%) could be located and responded to a questionnaire containing
15 questions that posed hypothetical situations regarding indications and
contraindications for this vaccine. The average number of correct responses was
9.3 out of 15, which illustrates the pediatricians' poor knowledge of measles
vaccine. Conditions commonly seen in pediatric practice in Brazil--malnutrition,
upper respiratory tract infection, diarrhea, and prematurity--were often
erroneously considered contraindications for immunization. More than half (62%)
of the pediatricians did not know the correct way to administer the vaccine.
Knowledge about the vaccine did not differ according to the length of time that
had elapsed since the physicians' university training in pediatrics or as a
result of working in health centers operated by the State Health Secretariat.
University professors, pediatricians with a postgraduate degree, and those
pursuing postgraduate studies scored slightly higher than the rest. These results
point to the need to strengthen training on measles vaccination in medical
schools and programs of continuing education for pediatricians.
PMID- 9546080
TI - [The prevalence of non-insulin-dependent diabetes mellitus in the rural
population of Durango, Mexico].
AB - This study was carried out to determine the prevalence of non-insulin-dependent
diabetes mellitus (NIDDM) in rural inhabitants of Durango, Mexico, and some of
the risk factors for the disease. A random samples of 30,996 individuals aged 30
years and over was selected from 627 rural communities in Durango. These persons
were interviewed between November 1993 and December 1994 to obtain information on
several sociodemographic variables. A capillary blood sample was collected from
each individual to determine his or her glucose level after 10-12 hours of
fasting. Measures of central tendency and dispersion were calculated, and
percentage distributions for the study variables were determined. Comparisons
among proportions were made utilizing the chi-square test, and means were
compared using Student's t test. The strength of associations was estimated with
odds ratios, and 95% confidence intervals (CI 95%) were calculated for
proportions. The final sample consisted of 31,028 persons, of whom 22,890 (73.8%)
were women and 8,138 (26.2%) were men. A total of 1,004 cases of NIDDM were
detected (3.2%; CI 95%:3.0 to 3.4), 767 in women and 237 in men. Only 9.2% of the
study population was obese. The highest frequency of NIDDM was documented in
persons 60 to 69 years of age. Family history of NIDDM was identified in 59.5% of
the persons with the disease (CI 95%: 58.9 to 60.0) and in 26.3% of the healthy
persons (CI 95%: 25.8 to 26.8). The low prevalence of NIDDM found in this study
may be related to the low level of obesity in the population surveyed.
PMID- 9546081
TI - [Enteroparasitoses in food handlers of the public schools in Uberlandia (Minas
Gerais), Brazil].
AB - A prospective study based on a parasitologic survey was carried out with a view
toward controlling enteroparasitoses in food handlers who work in public primary
schools in Uberlandia, Minas Gerais, Brazil. The study subjects were 264
individuals from 57 schools, from whom three fecal samples (C) were collected: C1
in September 1989, C2 in April 1990, and C3 in September 1990. The participants
were predominantly female (259 women and 5 men) and ranged in age from 20 to 66
years. A total of 792 samples were preserved in 10% formalin and analyzed using
the method of Hoffman, Pons, and Janer. Intestinal parasites were found in 17%,
10%, and 10% of the C1, C2, and C3 samples, respectively. The following organisms
were found in C1: Giardia lamblia (8%), ancylostomids (6%), Ascaris lumbricoides
(3%), Entamoeba histolytica (2%), Strongyloides stercoralis, Hymenolepis nana,
Taenia sp., and Trichuris trichiura (less than 1% each). Parasites found in C2
were: ancylostomids (5%), G. lamblia (2%), A. lumbricoides (1%), S. stercoralis,
H. nana, Taenia sp., and Enterobius vermicularis (less than 1% each). In C3, the
parasites observed were: ancylostomids (5%), G. lamblia (3%), A. lumbricoides
(2%), S. stercoralis, and E. vermicularis (less than 1% each). After each
collection, the individuals found to be infected received specific treatment. The
authors recommend the establishment of epidemiologic surveillance through
periodic parasitologic exams, specific treatment, and training on hygienic food
handling and personal hygiene for all food handlers.
PMID- 9546082
TI - [A combined methodology for understanding the duration of breast feeding the poor
neighborhoods of Managua, Nicaragua].
AB - This study examined the relationship of several maternal variables to the
duration of exclusive breast-feeding and the total duration of breast-feeding,
along with attitudes, perceptions, and beliefs about breast-feeding among women
living in poor neighborhoods of Managua, Nicaragua. The field work was carried
out in December 1992 and January 1993 using qualitative and quantitative methods.
A structured questionnaire was administered in interviews with 556 mothers of
children under 12 months of age, and meetings of four directed discussion groups
were held, in which a total of 20 women participated. At one week of age, almost
all the children of the mothers who were surveyed had been breast-fed, but only
45% had been exclusively breast-fed. At 12 weeks old, 30% were already completely
weaned. The discussion groups revealed the coexistence of positive opinions about
both breast-feeding and bottle-feeding. However, exclusive breast-feeding was
considered harmful for the mother, and breast milk was not thought to be
sufficient nourishment for the child. Previous experience was strongly related to
the duration of exclusive breast-feeding and to total breast-feeding duration.
Attitudes, social support, and work situation were important factors influencing
the total length of time women breast-fed a child. In general, the results
obtained through the interviews and in the discussion groups were in agreement
and showed that the elements needed to promote exclusive breast-feeding were
social support, a favorable community environment, and policies that dealt with
problems faced by working mothers. The complementary research methods were useful
for obtaining information about the relative importance of different factors that
determine the duration of breast-feeding and for understanding that practice in
greater depth from the mother's point of view.
PMID- 9546083
TI - Abdominal pain during pregnancy.
AB - In evaluating the pregnant patient with abdominal pain, the physician is
presented with a wide range of diagnostic possibilities, including disorders that
can occur in nonpregnant individuals and disorders that are unique to pregnancy.
The development of modern laboratory testing methods and diagnostic imaging
techniques has led to a decline in the morbidity and mortality from many of these
disorders. With an understanding of the physiologic changes occurring during
pregnancy, a careful history and physical examination, and judicious use of
laboratory tests and imaging studies, the physician should be able to determine
the cause of the patient's pain in the great majority of cases and, in the words
of Babler, avoid "the mortality of delay."
PMID- 9546084
TI - The safety and efficacy of gastrointestinal endoscopy during pregnancy.
AB - More than 12,000 pregnant patients in the United States per year have conditions
normally evaluated by esophagogastroduodenoscopy (EGD). More than 6000 pregnant
patient in the United States per year have conditions normally evaluated by
sigmoidoscopy or colonoscopy. Endoscopy during pregnancy raises the unique issue
of fetal safety, and endoscopic medications comprise a significant component of
fetal risks from endoscopy. This article analyzes the safety of endoscopic
medications during pregnancy, reviews the literature on the safety of
gastrointestinal endoscopy during pregnancy, proposes guidelines for endoscopic
indications during pregnancy, and describes modifications of gastrointestinal
endoscopy during pregnancy to increase fetal and maternal safety.
PMID- 9546085
TI - Gastrointestinal surgery during pregnancy.
AB - Gastrointestinal surgical problems often mimic symptoms and signs of nonsurgical
conditions that occur during pregnancy. This mimicry presents a particular
challenge to diagnosis because avoiding a delay in treatment is critical to
successful management. Some of these conditions, such as acute appendicitis and
biliary colic, are common in younger women; however, the anatomic and physiologic
changes of pregnancy can alter their usual manner of presentation. Many elective
and urgent operations can be performed during pregnancy with minimal risk to the
mother and fetus. The mother's condition should always take priority because her
proper treatment usually benefits the fetus as well.
PMID- 9546086
TI - Nutritional assessment and support during pregnancy.
AB - Proper nutrition during pregnancy is critically important to mother and fetus.
For most healthy women, the only nutritional intervention required may be
adequate iron and folate intake; however, for others, who begin pregnancy in a
malnourished state or whose nutritional intake deteriorates during pregnancy,
invasive nutritional support, including tube feeding or parenteral nutrition, may
be indicated. To guide nutritional therapy and to avoid its potential
complications, it is necessary to evaluate the patient's nutritional state. Such
evaluation must focus not only on body composition and substrate reserves but
also on the patient's changing nutrient requirements and any impediments to the
patient's capacity to ingest and assimilate food.
PMID- 9546087
TI - Nausea and vomiting of pregnancy.
AB - NVP is a spectrum of disorders ranging from the physiologically typical mild to
moderate nausea and vomiting that is usually self-limited, to the pathologic,
intractable symptoms of hyperemesis gravidarum that are associated with metabolic
and electrolyte disturbances and weight loss. Up to 90% of pregnant women
experience NVP. The pathogenesis remains poorly understood with multifactorial
theories proposed combining both biologic and psychological factors. Diagnosing
this syndrome is straightforward, but other organic sources should be excluded
when symptoms are severe or prolonged. The overall prognosis is excellent for
typical NVP, but whether hyperemesis gravidarum increases the risk to the fetus
is controversial. Initial management should be conservative, including
reassurance of the transient nature of the symptoms and the good prognosis, in
addition to dietary modifications. Pharmacologic therapy is reserved for patients
with persistent symptoms and is appropriate after discussion of the risks and
benefits with informed consent. Alternative treatments, including psychotherapy
and other nonpharmacologic modalities, are less proven but potentially safe and
effective, thus providing additional therapeutic options. In refractory cases,
nutritional supplementation becomes life-saving for both the mother and the
fetus. Therapeutic abortion is a rare and last resort, to be used only when
maternal life is threatened.
PMID- 9546088
TI - Gastroesophageal reflux disease during pregnancy.
AB - Pregnant patients with symptomatic GERD should be managed aggressively with
lifestyle modification and dietary changes. Antacids and antacids/alginic acids
combination or sucralfate should be considered first-line medical therapy. If
symptoms are not adequately relieved or complications develop, treatment with
cimetidine or ranitidine should be considered; these H2 receptor antagonists are
preferred during pregnancy. Nizatidine cannot be recommended. Proton-pump
inhibitors should be used with caution because little human experience is
available. Despite this caveat, both proton-pump inhibitors are likely to be safe
during pregnancy.
PMID- 9546089
TI - Gastric and duodenal ulcers during pregnancy.
AB - The frequency, symptoms, and complication rate of peptic ulcer disease appear to
decrease during pregnancy significantly. Clinicians, however, often have to treat
dyspepsia or pyrosis of undetermined cause because the frequency of pyrosis
increases during pregnancy. Physicians are reluctant to perform
esophagogastroduodenoscopy (EGD) during pregnancy for pyrosis to reliably
differentiate gastroesophageal reflux from peptic ulcer disease. Dyspepsia or
pyrosis during pregnancy first should be treated with dietary and lifestyle
changes, together with antacids or sucralfate. When symptoms persist, H2 receptor
antagonists are recommended. If symptoms continue and are severe despite these
interventions, the patient should be evaluated for possible EGD or proton pump
inhibitor therapy during the second or third trimester.
PMID- 9546090
TI - Constipation and diarrhea in pregnancy.
AB - Constipation and diarrhea are common during pregnancy, occurring in up to one
third of women. Constipation is often the result of physiologic changes that
occur during pregnancy, usually from hormonal effects on gastrointestinal
motility. Diarrhea, on the other hand, is often caused by the same disorders
responsible for diarrhea in the nonpregnant patient. The incidence,
pathophysiology, evaluation, and treatment of constipation and diarrhea during
pregnancy are reviewed in this article.
PMID- 9546091
TI - Inflammatory bowel disease and pregnancy.
AB - Despite the lack of prospective studies on the relationship between inflammatory
bowel disease (IBD) and pregnancy, the evidence strongly supports the conclusions
that fertility is compromised in active Crohn's disease; heredity plays an
important role in type and location of disease; fetal outcome is essentially no
different than in the general population, except in the presence of active
Crohn's disease during pregnancy; and the course of IBD during pregnancy is
influenced by disease activity or lack of it before pregnancy. The major
influence on outcome of pregnancy, fetal outcome, and course of IBD is the
favorable effect of drug therapy on the disease. Most drugs, including
sulfasalazine, 5ASA products, corticosteroids, and immunosuppressives, are safe,
certainly safer than permitting the disease to be active and allowing for the
possibility of surgical intervention during pregnancy. Episiotomy is
contraindicated in women with Crohn's disease and perirectal complications.
Cesarean section probably is indicated in most patients with Crohn's disease with
colonic involvement.
PMID- 9546092
TI - Colon cancer during pregnancy. The gastroenterologist's perspective.
AB - Colon cancer during pregnancy is uncommon but not rare, with an estimated
incidence of several hundred cases per year in the United States. This type of
cancer tends to have a poor prognosis that is attributable to delays in diagnosis
and advanced disease at diagnosis. The diagnosis frequently is delayed because
symptoms of colon cancer, such as rectal bleeding, nausea and vomiting, and
constipation, often are attributed to normal pregnancy or minor complications of
pregnancy. Pregnancy affects the diagnostic evaluation and therapy of colon
cancer because of fetal risks of diagnostic tests and therapy. Appropriate
medical evaluation of significant lower gastrointestinal complaints during
pregnancy can lead to an earlier and improved diagnosis.
PMID- 9546093
TI - Cancer of the colon, rectum, and anus during pregnancy. The surgeon's
perspective.
AB - Colorectal carcinoma presenting during pregnancy is uncommon. Most patients
present late in pregnancy, and greater than 80% have rectal tumors. Pregnant
patients with unexplained rectal bleeding should be evaluated by anorectal
examination and flexible sigmoidoscopy. Treatment is individualized to each
patient, but a strategy of proceeding immediately with a surgical resection when
a diagnosis is made early in pregnancy and allowing the fetus to develop to safe
delivery before treating when the diagnosis is made late in pregnancy is
recommended. Most patients present with advanced tumors and have a poor
prognosis, but prognosis by stage is not different from that in the general
population. Adjuvant radiation and chemotherapy have limited roles in the
treatment of pregnant women with colon and rectal carcinoma. Future challenges
are aimed at improving survival through earlier diagnosis and the development of
adjuvant therapies that are effective in patients with advanced disease.
PMID- 9546094
TI - HIV in pregnancy.
AB - Pregnancy in individuals infected with HIV has become an important problem
because of a fourfold rise of infection in women of childbearing age in the
developed world. The incidence of vertical transmission varies in different
continents and is highest in Africa. Transmission may occur in utero
(antepartum), during delivery (intrapartum), or after birth (postpartum),
occurring during the latter period, in many cases, through breastfeeding.
Maternal viral burden around the time of delivery is the strongest determinant of
the risk of disease transmission. While breastfeeding may account for up to one
third of cases of vertical transmission in Africa, the benefits of breastfeeding
outweigh its risks, even in HIV infection, and breastfeeding is recommended in
those areas. Treatment of the mother with antiretroviral agents significantly
decreases the risk of vertical transmission.
PMID- 9546095
TI - [Limits of exposure in the prevention of damage of reproduction: an operational
proposal].
AB - Recent studies have shown that the reproductive system may be particularly
vulnerable to some environmental agents. This requires the definition of specific
exposure limits to safeguard the reproductive health of both males and females
and, not only of pregnant women. The paper presents such limits of exposure for a
number of reproductive toxicants. These were defined on the basis of experimental
and epidemiological evidence, taking into consideration the precautionary
principle.
PMID- 9546096
TI - Biological monitoring of acrylonitrile exposure.
AB - This study reports the results obtained with the environmental and biological
monitoring of 34 workers exposed to acrylonitrile (ACN). Occupational exposure
was monitored during 8-h work shifts with both active and diffusive personal
samplers which yielded comparable results. The median exposure was 78
micrograms/m3. The ACN concentration in urine collected at the end of the work
shifts correlated significantly with the environmental exposure. The ACN
concentration in the pre-shift urine samples (median 3.6 micrograms/l) was lower
than that found in the post-shift samples (median 10.9 micrograms/l), but higher
than in the urine of non-exposed people (median 0.45 microgram/l). Smoking is an
important confounding factor in monitoring exposure to ACN. The ACN concentration
in urine provides reliable information about occupational and non-occupational
exposure to ACN. Aspects of the mechanism of ACN excretion in urine are also
discussed.
PMID- 9546097
TI - [Risk of infection in a hospital environment].
AB - The infectivologic risk in hospital environment. After a brief introduction on
the historical development of the question of infectivologic risk in health
services in general, and, in particular, in hospitals, the principal
epidemiologic characteristics of viral hepatitis B and C, of HIV/AIDS and of TBC
are examined as well as the potential cancerogenic role of the viral hepatitis.
Guide-lines on staff health observation are also presented along with work
fitness criteria.
PMID- 9546098
TI - [An ergonomic study of postures of toll collectors].
AB - The working activities of operators in the workstations along the italian motor
ways involve repetitive movements of upper limbs and neck with asymmetric
postures of the trunk. The tasks examined are characterized by factors
potentially dangerous for developing musculo-skeletal disorders, such as
repetitivity, and prolonged constrained postures. It is therefore crucial that
dimensional and structural characteristics of the workplace are adequately
designed, with regard to the anthropometric parameters and the type of activity
performed. The results of our "on-site" investigation, using an observational
method (OCRA), dedicated computerized modules for postural analysis (software
"Vision 3000", Promatek, Ltd.), and recordings of myoelectrical activity (surface
EMG) in the muscles of the shoulder girdle, have shown the need of a partial re
designing of the man-workstation system under investigation.
PMID- 9546099
TI - [Functional state and indications for a rehabilitation program of patients in a
dialysis center: a multidisciplinary study with ergonomic, physiatrical and
psychological evaluation].
AB - The following study describes the functional status of the entire chronic
hemodialysis ambulatory population in treatment at our center. The patients were
evaluated from 3 points of view: ergonomic, phyiatric and psychological, thus
going a snapshot picture in time of their status. Based on these three
evaluations, the need for rehabilitation intervention was determined and
rehabilitation treatment program was elaborated. The ergonomic evaluation
determined the maximal sustained workload (MSW) from O2 consumption, minute
ventilation, heart rate, subjective perception of fatigue and dyspnea. The
phyiatric examination included a thorough musculoskeletal examination,
application of a functional ability instruments (Karnofsky + FIM) and then
integrated the results with the ergonomic + psychologic testing in order to
generate phyiatric prescription. The psychologist had a conversation with all
patients and applied 2 instruments for evaluation of health-related quality of
life (CBA-H + SIP). The results of these studies indicated a markedly compromised
aerobic capacity, which worsened with age in years rather than with years in
dialysis. Phyiatric prescription were considered necessary in 78% of the patients
with major goals being re-conditioning and joint mobilization in order to
diminish the fragility of independence in this population. The psychological arm
of the study revealed good adaptation to chronic dialysis in 75% of the
population, with however absorption of a passive lifestyle. The remaining 25% of
the population showed severe psychological distress and social withdrawal.
Psychological support for this population is necessary to identify families at
risk for stress and poor adaptability as well as to help motivate patients who
require rehabilitation to participate in therapy.
PMID- 9546100
TI - [Evaluation of the capacity of work using upper limbs after radical latero
cervical surgery].
AB - Evaluation of arm work capacity after radical neck surgery. The aim of this paper
is to describe an approach for the assessment of work capacity in patients who
underwent radical neck surgery, including those treated with radiation therapy.
Nine male patients, who underwent radical neck surgery 2 months before being
referred to our Unit, participated in the study. In addition to manual muscle
strength test, we performed the following functional evaluations: 0-100 Constant
scale for shoulder function; maximal shoulder strength in adduction/abduction and
intrarotation/extrarotation; instrumental. We measured maximal isokinetic
strength (10 repetitions) with a computerized dynamometer (Lido WorkSET) set at
100 degrees/sec. During the rehabilitation phase, the patients' mechanical
parameters, the perception of effort, pain or discomfort, and the range of
movement were monitored while performing daily/occupational task individually
chosen on the simulator (Lido WorkSET) under isotonic conditions. On this basis,
patients were encouraged to return to levels of daily physical activities
compatible with the individual tolerable work load. The second evaluation at 2
month confirmed that the integrated rehabilitation protocol successfully
increased patients' capacities and "trust" in their physical capacity. According
to the literature, the use of isokinetic and isotonic exercise programs appears
to decrease shoulder rehabilitation time. In our experience an excellent
compliance has been noted. One of the advantages of the method proposed is to
provide quantitative reports of the functional capacity and therefore to
facilitate return-to-work of patients who underwent radical neck surgery.
PMID- 9546101
TI - The biological monitoring of inhalation anaesthetics.
AB - The biological monitoring of inhalation anaesthetics. Occupational exposure to
inhalation anaesthetics is an undesired consequence of the work in the operating
theatre. Anaesthesia is currently practised using nitrous oxide associated with
one or more potent anaesthetics (halothane, enflurane, isoflurane). In the
present study we evaluated the occupational exposure to inhalation anaesthetics
during anaesthesia in 190 operating theatres of 41 hospitals in Italy. Nitrous
oxide, halothane, enflurane, isoflurane were detected in the urine of 1521
exposed subjects (anaesthetists, surgeons and nurses). Significant correlations
were found between the anaesthetic concentrations in urine produced during the
shift (Cu) and anaesthetic environmental concentrations (CI). The results show
that the urinary anaesthetic concentration can be used as an appropriate
biological exposure index. The biological threshold values (urinary concentration
values) proposed are the following: nitrous oxide, 15, 28 and 57 micrograms/L for
an environmental exposure of 25, 50 and 100 ppm respectively; halothane, 97
micrograms/L (for an environmental exposure of 50 ppm), 6.1 micrograms/L (for an
environmental exposure of 2 ppm) and 3.3 micrograms/L (for an environmental
exposure of 0.5 ppm); enflurane, 145 micrograms/L (for an environmental exposure
of 50 ppm), 22.7 micrograms/L (for an environmental exposure of 10 ppm), 3.7
micrograms/L (for an environmental exposure of 1 ppm); isoflurane, 5.3
micrograms/L (for an environmental exposure of 2 ppm) and 1.8 micrograms/L (for
an environmental exposure of 0.5 ppm). These values apply to urine samples
collected at the end of 4-hours' exposure to the anaesthetics.
PMID- 9546102
TI - Analysis of growth rate of pediatric kidneys transplanted into juveniles or
adults.
AB - Estimation of renal length was carried out during radionuclide function studies,
in cases of pediatric kidneys transplanted into adolescents or adults. In all 24
cases of single kidney transplants, the kidneys eventually increased in size, but
at varying rates. From 5 cases with repeat studies close in time, and shortly
after transplantation, an apparent maximal growth rate was estimated. In 3 pairs
of dual renal transplants, with both kidneys surviving, marked differences in
growth of each member of the pair was noted. The present initial description, of
rates of change in size of the transplanted pediatric kidneys, may serve as a
baseline from which to sort out the contributions of pre- and post-transplant
factors.
PMID- 9546103
TI - Late embryonic and early posthatch growth of heart and lung in White Leghorn
lines of chickens.
AB - Growth and development of heart and lungs were measured from day 15 of incubation
to 25 days after hatch in lines of chickens that had undergone long-term
selection for high (HAS) or low (LAS) antibody titers to sheep erythrocytes. A
correlated response to this selection was heavier 28-day body weights for LAS
than HAS chickens. In this experiment body weights were heavier in line LAS than
HAS from 15 days of incubation to 5 days after hatch and again at 25 days after
hatch. Absorption of residual yolk was greater in HAS than LAS chicks. Although
there were no differences between lines for absolute heart weights, lungs were
heavier in line LAS than HAS at all ages except 20 days after hatch. Relative to
body weight, both heart and lung weights declined with age, however, the pattern
of decline differed. For this criterium, hearts were larger in line HAS than LAS
to 5 days after hatch with no difference thereafter; for lungs lines were similar
until 5 days after hatch after which they were larger in LAS than HAS chicks. In
all but one case (HAS at hatch) the left:right relationship for lung weights
exhibited fluctuating asymmetry with the left minus right character difference
having a normal distribution and mean zero. The degree of fluctuating asymmetry,
however, varied with age.
PMID- 9546104
TI - Ontogenetic limb bone scaling in basic fibroblast growth factor (FGF-2)
transgenic mice.
AB - Basic fibroblast growth factor (FGF-2) is a potent mitogen which is required for
normal development, particularly the development of the skeletal system, where
the inhibition of FGF binding to its receptor results in various skeletal
malformations. The present study employed a newly engineered line of FGF-2
transgenic mice to determine the effects of overexpressing FGF-2 on limb bone
ontogeny. We collected radiographic and weight data longitudinally and obtained
the length, proximal, distal, and minimum diaphyseal widths of the humerus,
femur, and tibia. Because growth is nonlinear with respect to time, we used the
Gompertz mathematical model to obtain parameters describing rate and timing for
each individual for each measurement. Differences in the parameters due to
genotype and sex were subsequently tested with ANOVA. Transgenic animals
exhibited consistently shorter limb bones which were generally wider at the
epiphyses than those of controls. Parameters of early growth, including initial
size and proportional rate of growth, appeared to be most directly responsible
for significant differences in final size; however, exponential decay of growth
was also a marginally significant factor. There were no differences between the
genotypes in body weight, indicating that the shape anomalies observed in
transgenic mice were a direct result of the action of FGF-2 rather than a general
runting phenomenon.
PMID- 9546105
TI - Variability of embryonic development among three inbred strains of mice.
AB - We examined the relationships between litter size, embryonic growth, days of
gestation, onset and duration of morphological stages and development of the
first arch skeleton in three inbred strains of mice--C57BL/6, CBA/J and C3H/He.
Detailed embryonic staging was based on craniofacial development between 11 and
18 days of gestation. Considerable intra- and interlitter variation of
morphological stages of embryonic development exists in all three inbred strains.
The relationship of morphological stages to days of gestation reveals that each
stage has a different duration, being shortest at Theiler's stage 18 and longest
at stage 21 in all three inbred strains. Embryos of CBA/J mice tend to reach each
stage later than do embryos of the other two strains, i.e., morphological
development is slowest in CBA/J. The greatest length, a measurement of embryonic
growth, increases at a constant rate during gestation in all three strains. In
C57BL/6 and CBA/J, more embryos tend to be implanted in the right horn of the
uterus than in the left, whereas in C3H/He an even number of embryos tends to be
implanted in both horns. Timing of the development of Meckel's cartilage differs
between the three inbred strains: both condensation and onset of matrix
deposition begin one stage earlier in C57BL/6 than in CBA/J and C3H/He. On the
other hand, alkaline phosphatase, one of the earliest markers for bone
development, is expressed at the same time in all three inbred strains.
Differences in timing of skeletal development between the strains may be
attributed in part to the genealogical closeness OF CBA/J and C3H/He mice.
PMID- 9546106
TI - 6R-L-erythro-5,6,7,8-tetrahydrobiopterin is involved in brain vulnerability of
senescence-accelerated mouse during the processes of aging.
AB - The effects of age on the dopamine (DA) turnover and 6R-L-erythro-5,6,7,8
tetrahydrobiopterin (6R-BH4), a cofactor for monooxygenases, were investigated in
the striatum and midbrain of the senescence accelerated mouse (SAM) at 6, 12 and
15 months old. 6R-BH4 and DA levels were decreased significantly in the striatum
of 15-month-old SAM-P/1 (senescence accelerated prone) mice. At 12 months old, DA
level was decreased significantly in the striatum of SAM-P/1 compared with SAM
R/1 (senescence accelerated resistant) mice. The reduction of striatal DA level
was shown to be related to the depletion of 6R-BH4 in the striatum during the
processes of aging. Age-related decreases in striatal dopamine function occurred
in SAM-P/1 mice earlier than in the SAM-R/1 mice. The striatal [DOPAC]/[DA]
ratio, as the index of DA turnover, was increased significantly in the 15-month
old SAM-P/1 mice. On the other hand, the DA, 6R-BH4 levels and the ratio of
[DOPAC]/[DA] did not show any changes in the midbrain of SAM-P/1 and SAM-R/1
during the processes of aging. It was suggested that brain vulnerability with
aging may be associated with the levels of 6R-BH4.
PMID- 9546107
TI - Animal models showing "accelerated aging" are more likely to be useful for
pathology than for mechanisms of aging.
PMID- 9546108
TI - Body composition of inactivated growth hormone (oMt1a-oGH) transgenic mice:
generation of an obese phenotype.
AB - The consequences of a 42 d exposure to elevated growth hormone (GH) on adipose
tissue were assessed using the regulatable ovine metallothionein- ovine GH (oMt1a
oGH) transgene in male and female GH transgenic (TG) mice. Activation of
transgene expression at 21 d of age followed by inactivation of transgene
expression at 63 d of age (TG-on/off) increased individual white adipose tissue
(WAT) depots and total body lipid stores in both males and females. WAT,
expressed as a percentage of fasted body weight, did not differ in wildtype (WT)
and continuously activated TG males and females up to 105 d of age, but was
increased approximately 270% following inactivation of the transgene. Inguinal
depot adipocytes were more numerous in both male and female TG +/- relative to WT
or TG animals. The ensuring obesity was not accompanied by a decrease in
thermogenic capacity of brown adipose tissue, as indexed by uncoupling protein
quantity. GH transgene expression was accompanied by elevated insulin levels that
were restored to WT levels upon cessation of transgene expression (p > 0.1).
Early, transient exposure to elevated GH increased total body lipid by nearly
threefold independent of gender; the increased lipid content was sustained and
reflected WAT hypertrophy and hyperplasia. The oMt1a-oGH mouse provides a novel
model of induced obesity in response to inactivation of a GH-transgene by the
withdrawal of the transgene stimulus.
PMID- 9546109
TI - Whole body bone resorption in the growing pig.
AB - Our knowledge of total body bone resorption during growth is limited. The primary
purpose of this study was to determine if a commercially available bone
resorption assay, developed for measuring human bone resorption, could be used to
measure whole body bone resorption in young, growing pigs. A secondary purpose
was to evaluate if this method could detect changes in bone resorption in
response to certain dental appliances which have been shown to change mandibular
and maxillary growth. Five growing 4-month-old male Hanford minipigs (Sus scrofa)
were housed in metabolic cages for 24 h, every other day, over a period of 1
month. Three of the animals were fitted with a mandibular protrusive orthodontic
appliance. Total 24 h urines were collected in which the concentration of
creatinine and collagen type I N-telopeptide crosslinks (NTx, a marker of bone
resorption) were measured. The NTx immunoassay was originally developed for the
analysis of human urine. Pig bone was powdered, defatted, and decalcified, and
the resulting powder digested with bacterial collagenase. The digest was screened
for NTx content, in the same fashion as the pig urines. Bone extract and pig
urines were cross-calibrated to a standard of adolescent human urine. This
allowed calculation of the daily quantity of pig bone resorbed. Daily metabolite
excretion was quite variable in these growing animals; for NTx the CV was 31%,
for creatinine the CV was 25%. The mean daily quantities of bone resorption
ranged between 26 and 46 grams of bone which amounted to 1.2-1.7% of estimated
total skeletal mass. The protrusive appliances increased bone resorption
significantly during the first two weeks of the trial. IN CONCLUSION: the NTx
assay can be used to measure bone resorption in pigs; the assay is sensitive
enough to indicate changes in bone resorption, such as those caused by an
orthodontic mandibular protrusive appliance. During growth, bone resorption
varies greatly from day to day. On average, every 24 h, 1.4% of the skeletal mass
is resorbed.
PMID- 9546110
TI - Localization and treatment of an oxidation-sensitive defect within the TCR
coupled signalling pathway that is associated with normal and premature
immunologic aging.
AB - The age-dependent decline in the ability of T-cells to mount a proliferative
response both to mitogens and to receptor ligation is due to an age-related
defect in signal transduction, since functional expression of receptors displayed
by aged T-cells is not reduced. We show here that, although turnover of
phosphatidylinositol is not diminished, total inositol-trisphosphate generation
decreases after T-cell receptor (TCR) ligation, resulting in reduced flux of
calcium. Defective inositol-trisphosphate generation may result from impaired
activation of phospholipase C due to decreased tyrosine phosphorylation of this
enzyme after ligation of CD3 in aged cells. Proliferation of aged T-cells, which
is normally 10-30% of the level of young controls, was enhanced almost tenfold by
glutathione or its precursor N-acetyl L-cysteine (NAC), reached levels of young
controls and was accompanied by restoration of normal inositol-trisphosphate
generation and calcium flux. These findings suggest that the T-cell antigen
receptor is associated with at least two types of signal transduction modules.
The first depends on synthesis and phosphorylation of phosphatidylinositol that
is independent of sulphydryl groups and is not affected by senescence. The second
transduction module includes tyrosine phosphorylation and activation of
phospholipase C. This module is regulated by glutathione levels and is diminished
in aged T-cells, that are deficient in reducing equivalents which support the PLC
gamma-dependent generation of inositol-trisphosphate from phosphatidylinositol
derivatives. This underlying biochemical defect also occurs earlier in strains
which display premature aging due to differences in the H-2 region of MHC I.
PMID- 9546111
TI - How do practicing clinicians manage Helicobacter pylori-related gastrointestinal
diseases in Germany? A survey of gastroenterologists and family practitioners.
AB - BACKGROUND: Since the bacterium H. pylori was identified in 1982, overwhelming
evidence has implicated it as the causal factor in the occurrence and relapse of
peptic ulcer disease. The major objective of this study was to examine the extent
to which physicians recognize H. pylori as a causal agent in peptic ulcer disease
or as potential cofactor in other gastrointestinal diseases, and the extent to
which this knowledge has influenced diagnostic and therapeutic practices.
MATERIALS AND METHODS: Using a national mail survey in Germany in September 1995,
1197 family practitioners and 1197 gastroenterologists were selected for the
study. RESULTS: Of the surveyed physicians, 756 (32%) responded. Family
practitioners treated almost 50% of their patients with initial presentation of
suspected ulcer disease without ordering further diagnostic tests. More than 25%
of the family practitioners and 14% of the gastroenterologists reported that they
do not treat diagnosed H. pylori infection in the first presentation of duodenal
ulcer. At the time we conducted the study, 22% of responding family practitioners
and 5% of responding gastroenterologists treated the first presentation of H.
pylori-positive ulcer disease with regimens determined to be ineffective
according to the available literature. CONCLUSIONS: Gastroenterologists preferred
to treat H. pylori infection when the associated disease was one for which a
causal relationship had been more clearly established, while family practitioners
showed less discrimination. In order to provide optimal therapy aimed at
minimizing the course and consequences of H. pylori-related diseases, researchers
in the field must ensure continuous dissemination of current knowledge.
PMID- 9546112
TI - Comparison of Helicobacter pylori infection between Fukuoka, Japan and Chinju,
Korea.
AB - BACKGROUND: Helicobacter pylori is the causative agent of type B chronic
gastritis, and plays a major role in the pathogenesis of gastroduodenal ulcer and
gastric cancer. Because gastric cancer has been the leading cause of cancer
mortality in Japan and Korea, we conducted a seroepidemiological study to
estimate the prevalence of H. pylori infection in Japan and Korea in order to
explain the current change in the gastric cancer incidences between two
countries. MATERIALS AND METHODS: Samples used for this study included 1204 sera
from Chinju, Korea and 580 sera from Fukuoka, Japan. Immunoblotting, using a
sonicated crude H. pylori antigen and 1:5 dilution of serum, was performed,
considering the immunoblot shows reactivity to the 120 Kd antigen of H. pylori as
a specific marker of H. pylori infection. RESULTS: Seroepidemiology data from
Fukuoka, Japan showed a prevalence of H. pylori infection of 20% before school
age, 40% by teenage years, and over 80% beyond 20 years of age. Seroepidemiology
data from Chinju, Korea, showed a 50% infection rate in preschool ages, and over
80% prevalence rate after 7 years of age. CONCLUSIONS: Lower rates of childhood
H. pylori infection in Fukuoka may explain the recent decline and shift in the
incidence of stomach cancer in Japan, supporting the hypothesis that H. pylori is
a major determinant in the pathogenesis of stomach cancer.
PMID- 9546113
TI - Serologic detection of CagA positive Helicobacter pylori infection in a northern
Italian population: its association with peptic ulcer disease.
AB - BACKGROUND: About 60-70% of Helicobacter pylori strains possess cagA (cytotoxin
associated gene A) gene and express its product CagA, a highly immunogenic 128
140 kD protein. Patients infected with CagA positive strains develop serum IgG
anti-CagA. A serologic response to CagA has been detected in Helicobacter pylori
infected patients with peptic ulcer more frequently than in those with gastritis
alone. It is nuclear whether this finding is consistent in different geographical
populations. We investigated the relationship between anti-CagA seropositivity
and peptic ulcer disease in a Northern Italian population. MATERIALS AND METHODS:
We studied 135 H. pylori infected patients: 65 with duodenal ulcer (DU), 28 with
gastric ulcer (GU) and 42 with non ulcer dyspepsia (NUD). Sera from these
patients were assayed by EIA (enzyme immunoassay) for anti-CagA IgG. RESULTS: A
high prevalence of anti-CagA was found associated with DU (86.1%) and GU (96.4%),
while NUD patients showed anti-CagA seropositivity of 52.4% (Odd ratio, 5.66; 95%
confidence interval, 2.23 to 14.32; p < .001, DU vs. NUD; Odd ratio, 24.5; 95%
confidence interval, 3.05 to 197.6; p = .003, GU vs. NUD). DU patients showed
anti-CagA seropositivity titer (1.15 (0.61 OD, mean (SD) higher than that of NUD
patients (0.78 (0.60 OD, mean (SD) (p < .05). CONCLUSIONS: These data demonstrate
in a Northern Italian population that anti-CagA seropositivity is strongly
associated with peptic ulcer disease and suggest that CagA might play an
important role in ulcer pathogenesis.
PMID- 9546114
TI - Growth inhibitory and bactericidal activities of lansoprazole compared with those
of omeprazole and pantoprazole against Helicobacter pylori.
AB - BACKGROUND: Helicobacter pylori plays a role in the pathogenesis of both duodenal
and gastric ulcers. The aim of this study was to evaluate the effect of the
proton pump inhibitor (PPI), lansoprazole, commonly used in eradication regimens,
on growth, bactericidal activity and morphology of H. pylori in vitro in
comparison with other PPIs. MATERIALS AND METHODS: Growth inhibitory activity of
each of the PPIs was evaluated by determining minimum inhibitory concentrations
using an agar dilution method. Bactericidal activity was determined by analysis
of the viable cells in culture at various time points after incubation with
different concentrations of the PPIs. Bacterial morphology was examined using
scanning electron microscopy of fixed cells after exposure to the test
substances. Urease activity in cell extracts of H. pylori that had been incubated
with increasing concentrations of the PPIs was determined by colorimetry.
RESULTS: The growth inhibitory activity of lansoprazole was significantly more
potent than that of omeprazole or pantoprazole (MIC90 6.25 vs. 25 and 100
micrograms/ml, respectively). Exposure of H. pylori to lansoprazole produced loss
of viability and an aberrant bacterial morphology, which was more extensive than
seen with omeprazole or pantoprazole. Lansoprazole dose dependently inhibited
urease activity; its effectiveness was comparable with omeprazole but more potent
than pantoprazole. CONCLUSIONS: The mechanism of action that leads to loss of
viability of H. pylori cells appears to differ between the three PPIs
investigated; lansoprazole was the most potent of the three agents in terms of
growth inhibition and disruption of bacterial morphology.
PMID- 9546115
TI - An investigation of the molecular basis of the spontaneous occurrence of a
catalase-negative phenotype in Helicobacter pylori.
AB - BACKGROUND: The discovery of a highly active catalase in Helicobacter pylori that
in some strains may lose its activity has generated strong scientific interest.
We have characterized a spontaneous catalase-negative isolate of H. pylori (UNSW
RU1) and sequenced katA in the parent strain and the promoters of both phenotypes
as a prelude to understanding the genetic processes leading to the failure to
express catalase. MATERIALS AND METHODS: Protein extracts from both phenotypes
were examined for catalase on 2D-PAGE and analyzed by Western blot-based immuno
analysis. Presence of catalase mRNA was detected by Northern blot. Hi-Fidelity
PCR was used to sequence the katA promoter while katA was sequenced using cycle
sequencing. The transcription start site was located by primer extension.
RESULTS: Catalase protein was absent in UNSW-RU1 (KatA-) by 2D-PAGE and Western
blot, as was catalase mRNA by Northern blot, indicating that the cause of the
KatA- phenotype was at the level of transcription. No mutations were found in the
promoter region of the KatA- isolate. The transcription start site was identified
55 bp upstream of the ATG site and putative RNA polymerase binding sites were
mapped at "-10" and "-35". A Fur box was identified 181 bp upstream of the
transcription start site. The sequences of an 876 bp ORF and a 366 bp Escherichia
coli phnA homologue were identified. CONCLUSIONS: The UNSW-RU1 (KatA-) phenotype
does not express KatA or transcribe katA. The absence of defects in its promoter
and a large part of its ORF indicates that loss of activity may be due to a
mutation in an accessory gene essential for catalase expression, or to the
binding of a repressor preventing katA transcription.
PMID- 9546116
TI - Follow-up of Helicobacter pylori positive gastritis and argyrophil cells pattern
during the natural course of gastric ulcer.
AB - BACKGROUND: A follow-up of argyrophil cell hyperplasia in Helicobacter pylori
positive corpus gastritis in gastric ulcer patients during the natural course of
ulcer disease. METHODS: Endoscopic biopsies (4 specimens) were obtained step-wise
from the posterior wall of the corpus mucosa in 55 gastric ulcer (GU) patients.
The natural course of GU was followed up in 38 patients during more than 10 years
(maximum 19 years), and altogether 115 endoscopic examinations were made: 20
patients were re-examined once, 14 twice, and 4 three times. A total of 364
biopsies from 307 biopsy sites were stained by Grimelius' silver, hematoxylin
eosin, and Giemsa method for the analysis of the argyrophil endocrine cells,
chronic gastritis, and H. pylori colonization, respectively, according to the
Sydney System. RESULTS: Of 307 biopsy sites, 153 (50%) showed some grade of ACH.
Focal (linear/micronodular) hyperplasia was found in 118 (77%) of biopsy sites;
it was detected in 78 (66%) cases of atrophic corpus mucosa, but was present in
only 14 (12%) cases of gastritis without atrophy or in the normal mucosa. In the
follow-up patients, ACH evolved in 17 and progressed in 6 cases, and a
simultaneous development of atrophic corpus gastritis was found in 20 cases.
CONCLUSION: This study demonstrates that ACH evolves during the natural course of
GU, alongside the development of chronic atrophic gastritis.
PMID- 9546117
TI - A modified McMullen's staining for Helicobacter pylori: a high-contrast, visibly
prominent method.
AB - BACKGROUND: Many stains can be used for the histological assessment of
Helicobacter pylori, but all have defects from the standpoint of sensitivity,
convenience, stability, visible prominence and cost. This paper describes a stain
which produces satisfactory results on all the above accounts. MATERIALS AND
METHODS: Paraffin-embedded sections were dewaxed and treated with 0.2% w/v carbol
fuchsin for two min; then 1.0% w/v malachite green was applied for two minutes.
RESULTS: This technique stained the bacterial from a deep magenta against a light
green background. The characteristic morphology of H. pylori was identified very
easily as a stumpy curved rod, and the coccoid forms were also identified.
Staining was not specific with mixed samples of bacteria, but it was sufficient
to identify H. pylori in the gastric mucosa. CONCLUSION: We have established an
easy, stable, convenient, low-cost, and easily recognizable staining method for
H. pylori in paraffin-embedded tissue.
PMID- 9546118
TI - The UBiT-100 13CO2 infrared analyzer: comparison between infrared spectrometric
analysis and mass spectrometric analysis.
AB - BACKGROUND: Although the 13C-urea breath test is the most accurate noninvasive
method for detecting the presence of H. pylori infection, the requirement for an
expensive mass spectrometer to analyze breath samples has prevented physicians
from providing rapid results near the patient. Recently, a new type of infrared
spectrometric analyzer, the UBiT-100, was developed for analyzing 13CO2 in
breath. The purpose of this study is to compare results analyzed by the UBiT-100
to those analyzed by the mass spectrometric method. METHODS: Four hundred and
fifty-three subjects participated in this study. Breath samples were collected
before administration of 100 mg of 13C-urea and at 10, 20, 30, 45 and 60 min
after administration. Subjects were asked to hold their breath for 10 sec and
then exhale in order to collect breath samples containing more than a 2%
concentration of CO2. Samples were then analyzed by both methods. RESULTS: The
correlation analysis using values at 20 min after the administration of the study
drug (433 points) was excellent with the regression equation of Y = 1.034x -
0.203; r = .996. The results of the UBiT-100 were available in 6 min, making the
entire testing procedure less than 30 min. CONCLUSIONS: The UBiT-100 infrared
analyzer provides a simple and accurate method of performing the urea breath test
while the patient is still in the doctor's office.
PMID- 9546119
TI - Amoxicillin/metronidazole/omeprazole/clarithromycin: a new, short quadruple
therapy for Helicobacter pylori eradication.
AB - BACKGROUND: Triple therapy regimens including two antibiotics plus acid
suppression have become the new standard therapy in Helicobacter pylori
eradication because of success rates of about 90%. However, these regimens are
still costly, duration is about one week or less, and side-effects are not
negligible. We therefore evaluated a new quadruple therapy, because theoretically
a shorter duration of treatment may result in reduced costs, fewer side-effects,
and possibly in a lower potential for antibiotic resistances. METHODS:
Controlled, prospective pilot study including H. pylori-positive patients with
gastric or duodenal ulcers or erosive gastritis, treated after failure of dual
therapy (proton-pump-inhibitors or ranitidine plus amoxicillin) or for the first
time. They were assigned to a one week triple standard therapy, consisting of
metronidazole 400 mg bid + omeprazole 20 mg bid + clarithromycin 250 mg bid, or a
newly created quadruple-regimen, which adds amoxicillin (1 g bid) to the above
triple regimen. Each of the four drugs was given for 5 days. H. pylori status was
checked by 13C urea breath test before and after four weeks of therapy. RESULTS:
A total of 71 patients were treated by quadruple therapy, and 42 patients were
treated by triple therapy. The eradication rate of H. pylori for patients under
quadruple treatment, without vs. with previous dual therapy, were 96% vs. 92%
(42/44 vs. 22/24) by per protocol and 91% vs. 88% (42/46 vs. 22/25) by intention
to treat analysis (comparisons not significant). No major side-effects were
reported. CONCLUSIONS: Five-day quadruple therapy (with omeprazole,
metronidazole, clarithromycin and amoxicillin) represents an effective and safe
new regimen for H. pylori eradication.
PMID- 9546120
TI - Assessment of a new triple agent regimen for the eradication of Helicobacter
pylori and the nature of H. pylori resistance to this therapy in Japan.
AB - BACKGROUND: Multiple regimens for the eradication of Helicobacter pylori have
been tested, but the best therapy has not been determined yet. To determine the
efficacy of a new triple agent regimen using a combination of lansoprazole,
amoxicillin, and clarithromycin against Helicobacter pylori (H. pylori), and to
examine H. pylori resistance to this therapy in ineffective cases. METHODS: We
studied a total of 71 patients infected with H. pylori who had gastric ulcer (n =
37) or duodenal ulcer (n = 34) as confirmed by endoscopy. Patients received 1500
mg amoxicillin, 400 mg clarithromycin and 30 mg lansoprazole for 2 weeks followed
by 30 mg lansoprazole for 6 weeks in patients with gastric ulcer or for 4 weeks
in those with duodenal ulcer. Endoscopic examination was performed before
treatment and at 1 month, 2 months, and 5 months after initiating treatment to
check the status of ulceration and H. pylori infection. RESULTS: The eradication
rate of H. pylori was 92% (CI, 83-100%) in the gastric ulcer group and 94% (CI,
86-100%) in the duodenal ulcer group at 5 months, as determined by per-protocol
analysis. Resistance to clarithromycin was present in 1 of 71 (1%) patients
before treatment and in 2 of 5 (40%) patients after treatment. No resistance to
amoxicillin and lansoprazole was found in patients before or after treatment. The
resistance to clarithromycin changed during the observation period. CONCLUSIONS:
The new triple agent regimen was effective against H. pylori. Resistance to
clarithromycin may not be permanent and it might be one of the risk factors which
affect the efficacy of a clarithromycin-based therapy.
PMID- 9546121
TI - The serum 13C-bicarbonate assay: a replacement for urea breath tests?
PMID- 9546122
TI - Vector potential of houseflies (Musca domestica) for Helicobacter pylori.
PMID- 9546123
TI - [Imaging studies of excretory urography and computed tomography scan for patients
suffering from renal colic].
AB - Renal colic mainly due to urolithiasis is one of the most common morbid
conditions in urology and commonly seen in the urology emergency clinic. Imaging
studies were performed to evaluate the upper urinary tract of 29 patients
suffering from renal colic in the 2 years between November, 1994 and October,
1996. After intramuscular injection of the analgesic (pentazocine, 15 mg), all 29
patients were examined by excretory urography (IVP) at the time of the first
visit. In some patients abdominal plain computed tomography (CT) scan was
performed consecutively even when extravasation of the contrast medium was not
seen. Spontaneous peripelvic extravasation was seen in 14 patients (11 males and
3 females) with urolithiasis; 7 of them were diagnosed by IVP, 5 by IVP plus CT
scan and 2 with CT scan only. IVP imaging study followed by plain abdominal CT
scan is useful even when the contrast medium is not extravasated on IVP in
patients suffering from renal colic.
PMID- 9546124
TI - [Clinical study on 17 cases of genitourinary tuberculosis].
AB - Between 1987 and 1995, 17 patients with genitourinary tuberculosis were treated
at Iwate Prefectural Central Hospital. The incidence of newly diagnosed
genitourinary tuberculosis was 17 out of 16,363 outpatients (0.1%) during the 9
year period. Twelve patients had urinary tuberculosis and genital as well as
urinary organs were affected in 5. Six (35%) patients presented in their fifties
and 5 (29%) each in their forties and sixties. Nine (53%) patients had irritative
voiding symptoms as the chief complaint. Only 29% had a known history of extra
genitourinaty tuberculosis. In addition to the standard multidrug chemotherapy,
nephrectomy was performed in 5 patients and orchiectomy in 2 with epididymal
tuberculosis. The incidence of tuberculosis has recently increased in many parts
of our country and more attention should be paid to genitourinary tuberculosis.
PMID- 9546125
TI - [PSA-doubling time immediately before the diagnosis of prostate cancer].
AB - PSA-doubling time (PSA-DT) immediately before the diagnosis of prostate cancer
was calculated in 8 prostate cancer patients in whom PSA was checked three or
more times with the same kit during a period of 6 months or more. The correlation
between PSA-DT and clinical stage or pathological differentiation was analyzed.
In most patients, PSA correlated well showing a straight regression line to the
observation period on a hemi-logarithmic scale. The correlation coefficient was
high, almost 0.9 or more except in one patient. PSA-DT ranged from 5.1 to 64.9
months, averaging 23.1 months. There was no significant correlation between
clinical stage or pathological differentiation and PSA-DT. However, PSA-DT in
stage D patients tended to be shorter than that of stage B + C patients. One
patient who had stage D poorly differentiated carcinoma died of cancer
recurrence. In this patient, PSA-DT was short (5.1 months).
PMID- 9546126
TI - [A case of renal cell carcinoma with synchronous contralateral adrenal
metastasis].
AB - A 73-year-old female visited our department with right incidentally-found renal
tumor, which was revealed by follow-up computed tomography (CT) on an annual
physical check-up. CT also showed a left adrenal mass that was 4 cm. Further
evaluation suggested right renal cell carcinoma and left adrenal metastasis. The
patient, therefore, underwent right-adrenal-gland-sparing radical nephrectomy and
left adrenalectomy. The pathology report indicated renal cell carcinoma with
contralateral adrenal metastasis. A case of contralateral adrenal metastasis from
renal cell carcinoma is not common clinically. Furthermore, whether ipsilateral
adrenalectomy should be performed in such a case is still controversial at this
stage.
PMID- 9546127
TI - [Renal cell carcinoma detected by metastasis to the frontal sinus: a case
report].
AB - A 58-year-old man was admitted with a swelling in the frontal region.
Computerized tomography scan, magnetic resonance imaging and angiography revealed
a tumor in the right frontal sinus. The surgically extirpated specimen showed
clear cell carcinoma which was suspected to be a metastasis from renal cell
carcinoma. Subsequent urologic examination disclosed the right renal tumor. Since
there were no other systemic metastases, right nephrectomy was performed.
Pathologically, the renal tumor was clear cell subtype renal cell carcinoma and
had the same histology as the frontal sinus tumor.
PMID- 9546128
TI - [A case of renal cell carcinoma in a nonfunctioning kidney caused by staghorn
calculus].
AB - A 62-year-old man was referred to our clinic with a chief complaint of gross
hematuria. He had bilateral renal staghorn calculi at the age of 50 years and had
undergone left nephrolithotomy. However, no treatment had been given to the right
staghorn calculi associated with nonfunctioning kidney. Imaging diagnosis
demonstrated no mass lesions in the bilateral kidneys. Right nephrectomy revealed
renal cell carcinoma, tubular type, mixed subtype, G2, INF-beta with lymph node
metastasis to the renal hilum. Cancer cells infiltrated diffusely throughout the
entire renal parenchyma. He died of progressive metastases 15 months
postoperatively.
PMID- 9546129
TI - [Clinical application of intraoperative ultrasonography for bilateral
multilocular cystic renal cell carcinoma: a case report].
AB - A 45-year-old man was referred to our department for further examination of the
renal complicated cyst which was found incidentally by ultrasonography. Another
complicated cyst in the left kidney was detected by subsequent dynamic CT and
ultrasonography, which suggested bilateral cystic renal cell carcinoma. Bilateral
partial nephrectomy was performed. Intraoperative ultrasonography was useful for
diagnosis of multilocular cystic renal cell carcinoma (MCRCC). It disclosed
multiple septa of the right renal complicated cyst which were not revealed by any
preoperative examinations. It was also a useful adjunct to partial nephrectomy.
It helped to identify the extent of deep intra-parenchymal lesions. The final
diagnosis was bilateral synchronous multilocular cystic renal cell carcinoma.
This is the second case of bilateral synchronous multilocular cystic renal cell
carcinoma reported in Japan. We reviewed the clinical characteristics of 59 cases
of MCRCC in the Japanese literature including the present case.
PMID- 9546130
TI - [Kidney-sparing surgery for recurrent ureteral and bladder cancers in an aged
patient with functionally solitary horseshoe kidney].
AB - A 79-year-old woman was admitted with recurrent ureteral and bladder cancers. She
had a horseshoe kidney with a non-functioning right renal unit. Fifteen months
earlier, multiple urothelial tumors had first developed in the left upper ureter
and bladder. Transurethral resection of bladder tumor (TUR-Bt) and partial
ureterectomy (2 cm) had been performed. Presently, the recurrent tumors were
located at the left lower ureter and bladder. Considering the high age of the
patient, TUR-Bt and partial ureterectomy (5 cm) were performed. Besides
urothelial cancers, she had been operated for carcinomas of the colon, uterus and
stomach. Kidney-sparing therapy has successfully maintained her quality of life.
PMID- 9546131
TI - [Retrovesical liposarcoma: a case report].
AB - A case of retrovesical liposarcoma is reported. The patient was a 41-year-old man
who complained of left scrotal pain and of hip discomfort. Digital rectal
examination revealed a hen's egg-sized mass with an elastic hard consistency at
the left side of the normal prostate. Pelvic CT and MRI showed a heterogeneous
tumor in the retrovesical region. Transperineal biopsy revealed liposarcoma.
Pelvic exenteration, colostomy and ileal conduit were performed. The resected
weight was 1,680 grams, and the histopathological diagnosis was myxoid type of
liposarcoma, grade II. Postoperatively, a metastatic lesion to vertebrae
thoracicae I developed causing radiculoneuropathy of the left superior limb. Spot
radiation (50 Gy) was administered to the lesion, but there was no response.
Currently, the patient is being treated with combination chemotherapy consisting
of dacarbazine, vincristine, adriamycin, and cyclophosphamide. Cases of
retrovesical liposarcomas reported in Japan are reviewed and discussed.
PMID- 9546132
TI - [A case of multiple organ failure with massive intestinal bleeding caused by
methicillin-resistant Staphylococcus aureus in a postcystectomy patient--efficacy
of mask continuous positive airway pressure training and intraarterial
embolization].
AB - A 51-year-old man underwent radical cystectomy with tubeless cutaneous
ureterostomy. Methicillin-resistant Staphylococcus aureus (MRSA) enteritis
developed postoperatively. MRSA caused critical infections such as pneumonia and
sepsis, which subsequently progressed to adult respiratory distress syndrome,
massive melena and multiple organ failure. The patient was rescued by intensive
management including mask continuous positive airway pressure, systemic
vancomycin administration and intraarterial embolization to stop jejunal
bleeding.
PMID- 9546133
TI - [A case of poorly differentiated adenocarcinoma of prostate with neuroendocrine
differentiation].
AB - A 59-year-old man was diagnosed with clinical stage D1 poorly differentiated
prostatic adenocarcinoma (PAC). The patient was treated with total androgen
blockade therapy. The tumor recurred 18 months later. Digital rectal examination
revealed a large, stony-hard prostate. The serum PSA level was within normal
limits. Pathological examination of the prostate revealed conventional
adenocarcinoma with large numbers of neuroendocrine (NE) cells. The patient died
3 months after the diagnosis of PAC with NE differentiation, 22 months after the
initial diagnosis of prostate cancer.
PMID- 9546134
TI - [A case of prostatic tuberculosis: usefulness of transrectal ultrasound in
diagnosis].
AB - A case of prostatic tuberculosis is reported. A 61-year-old male visited our
clinic complaining of urinary retention. On digital rectal examination, the
prostate was found to be enlarged, hard, and uneven. Transrectal ultrasound
revealed a large hypoechoic lesion in the posterior aspect of the prostate.
Transrectal ultrasound guided systematic biopsies of the prostate were performed.
The specimens obtained from the hypoechoic lesion, were diagnosed
histopathologically as prostatitis with epithelioid granuloma, Langhans' type
giant cells, and caseous necrosis. Mycobacterium tuberculosis was detected in the
physiological saline solution injected into the urethra after prostatic massage.
The patient was diagnosed as having prostatic tuberculosis and underwent
antituberculotic therapy with INH and RFP. Transrectal ultrasound seemed to be
useful in detecting histopathological changes associated with tuberculosis in the
prostate.
PMID- 9546135
TI - Leiomyoma of the spermatic cord extending along the vas deferens.
AB - We report an unusual case of a leiomyoma of the spermatic cord. The tumor did not
present as a mass but presented as a hard structure along the spermatic cord. To
our knowledge, this is the first case report of a leiomyoma of the spermatic cord
with such an unusual appearance.
PMID- 9546136
TI - [Chronic perianal pyoderma with urethrocutaneous fistula: a case report].
AB - A 65-year-old male was hospitalized because of micturition pain and urinary
oozing from several fistulas on the perineal and the left gluteal skin. Oozing
had been present for about 50 years, after receiving mass resection of his left
scrotum or perineum, and left orchiectomy. The main focus was on the left dorsal
site of the anus. Compression around this area produced malodorous grayish pus
discharge from many fistulas, although the anus was intact. Although he had
histories of spinal caries and renal tuberculosis, both pus and urine cultures
showed Staphylococcus spp. and no growth of Mycobacterium tuberculosis.
Urethrocystography showed urethral stenosis at bulbar urethra and leakage from a
site just proximal to the stenosis. Antibiotics for tuberculosis were
administrated for fear of recurrent tuberculosis for 6 months. Cystostomy
formation and debridement were performed, followed by en-bloc resection and mesh
skin graft after two weeks. Internal urethrotomy was performed six months after
the surgery, and subsequently cystostomy removed. After three and a half years,
although there was no local recurrence and no difficulty of urination, he died of
cholangio-carcinoma. There are many reports of chronic perianal pyoderma
subsequent to hemorrhoid or subcutaneous abscess; however, this might be the
first report on a case originating from fistulas in the urinary tract.
PMID- 9546138
TI - [Informed consent in the terminal care].
AB - One of the biggest problems to perform terminal care is how to communicate with
patient's families. Mental stresses of patients who are expected to die and of
their families are extremely serious. To release their stresses, kind and
detailed explanation of patient condition should be given every day by the
clinical team consisted of doctors and nurses. We should realize that mental
support given by the clinical staff would be an important care point to alleviate
the stresses of patients and to alleviate the stresses and the strains of their
families. And we can say that performing terminal care is essential to promote
informed consent.
PMID- 9546137
TI - [A case of labial adhesions in an elderly woman].
AB - A 90-year-old woman was admitted with a chief complaint of difficulty in
urination. She had severe labial adhesions with a pin point opening. Urinary
tract infection was detected by urine examination. The adhesions were surgically
dissected under local anesthesia and recurrence was not seen at follow-up 6
months after the operation. Labial adhesions in adult women are rare and only 28
cases of labial adhesions in adults have been reported in the Japanese
literature. Labial adhesions in adults may be more closely related with chronic
inflammation such as recurrent urinary tract infections and vulvovaginitis than
in pediatric cases.
PMID- 9546139
TI - [Surgery for cancer patients and informed consent].
AB - Cancer treatment in medical centers traditionally provide high-quality medical
care but are often perceived by patients to be lacking in humanity, respect for
individual dignity, and personal comfort. The most important features of approach
are that patients are more informed about their condition and medical options
than before, and another point is growing recognition of the importance of caring
not only for the body but also for the personal, emotional, educational needs of
cancer patients and their families.
PMID- 9546140
TI - [The importance of informed consent in the field of ophthalmology].
AB - Ocular diseases have some characteristics that are different from diseases of
other organs. First, patients clearly can judge for themselves whether or not
they can see better postoperatively. Second, because several parameters such as
visual acuity and intraocular pressure, are obtained from patients, patient's
families and others can objectively judge the post-treatment status. Therefore,
clinical information is easily available to others besides the physician. Third,
except for acute ocular diseases such as retinal detachment, acute glaucoma, and
ocular trauma that easily can result in blindness, ophthalmologists usually treat
eyes that will maintain a certain visual acuity level. These are the primary
reasons why patients and families complain about unfavorable post-treatment
subjective symptoms. Because of these three characteristics of ocular disease,
informed consent (IC) is extremely important in the field of ophthalmology. I
studied ophthalmology and IC at Harvard Medical School, Boston, from 1980 to
1983, and again in 1989. Strict IC is mandatory in the United States. However,
the concept of IC in the US cannot always be adapted to fit Japanese culture. The
different legal concepts of IC in the two countries are discussed in this paper.
Since I returned to Japan, our Department of Ophthalmology incorporated several
new concepts into our clinical practice. For example, we now broadcast live
surgeries of patients with severe proliferative diabetic retinopathy by closed
circuit TV to their families in the hospital. This has fostered great
communication and confidence among patients, their families, and doctors. In
1994, we also began inter-hospital and international IC via telemedicine and
telescience. The video conferencing system VisionSeries (Panasonic Broadcast and
Television System Company) is used to communicate between Asahikawa Medical
University and 10 branch hospitals. INS net 1500 or INS net 64 (3 lines)
transmits full-motion (30 frames/second) color fundus images and biomicroscopic
images. Ocular surgeries performed by ophthalmologists using operating
microscopes at each branch hospital also are transmitted to Asahikawa Medical
University to facilitate consultation with more experienced ophthalmologists. The
transmitted images of the fundus and biomicroscopic findings are satisfactory,
and they allow surgeons to conduct useful discussions among themselves and with
the family members during the surgeries in real time. When the patients' families
are in local cities, surgeons can transmit the operations via the telemedicine
system link to the nearby hospital, and the ophthalmologists there can narrate
the surgeries in real time. On November 14, 1996, our technology was used
internationally for the first time to transmit ocular images and live ocular
surgeries between Asahikawa Medical University, Japan, and the Schepens Eye
Research Institute, Harvard Medical School, Boston, MA, USA. Telemedicine and
telesurgery will be useful scientific tools in the field of Ophthalmology in the
near future. We believe that this technology literally opens up the world to
scientific and medical collaboration. Patients with vision deficiencies and
blinding disease are certain to be the ultimate beneficiaries of these
interactions. Lastly, ideal implementation of IC in the field of Ophthalmology
are discussed in this paper.
PMID- 9546141
TI - [Role of nursing informed consent].
AB - Informed consent is important for medical practice. Pilot study of comprehensive
discharge planning at Higashi Sapporo Hospital suggested that there was a
relationship between informed consent and patients' length of stay. Also in a
study of home care systems for advanced cancer patients, it was one of the most
important factors that they knew their true diagnoses, especially in young cancer
patients. Informed consent, that is shared decision making, is an important
communication process between patients and professional care givers. We consider
the roles of nursing for informed consent are as follows: 1. Support of patients'
decision making; 1) promotion of patients' understanding of their own situation,
a. active listening, b. information disclosure, c. psychological support, 2)
advocation, 3) assisting patients understanding of doctor's explanations, 2.
Promotion of good relationships between patients and professional staff, 3.
Coordination with patients and/or their families and/or professional care givers,
4. Ethical issues, and 5. Education for health promotion. However there are some
problems remaining: for example, 1. Nurses after feel then have little role in
informed consent, which is an issue for physicians. 2. Nurses must improve their
professional skill and knowledge, 3. Nurses must perform more actively and
independently.
PMID- 9546142
TI - [The medical health care of the elderly and the informed consent].
PMID- 9546143
TI - [Informed consent in psychosomatic medicine].
AB - Obtaining informed consent perfectly is very difficult from the view of
psychosomatic medicine. Medical education regarding informed consent is generally
of a low level. However as it is important to defend patients' human rights, we
must educate them as to the precise meaning of both "informed" and "consent". In
this report I have tried to demonstrate that both the education of medical
students and their social consciousness are very important. I examined students'
opinions regarding the care of a sudden case of hysterectomy (Porro's emergent
operation). The following students were involved: 1st year medical students (N =
73), 4th year (N = 85) and 6th year (N = 119), and 3rd year nursing students (N =
42) and midwife students (N = 27). I examined their answers by transactional
analysis. The answers of the 1st year medical students reflecting the view of the
child ego state were significantly greater than those of the other students (P <
0.01). But following my lecture the answers of the same 1st year students altered
to reflect the view of the adult ego more (P < 0.05). We opened "the key center
of psychosomatic women's health in Japan" in our clinic two years ago. Since then
we have talked every month to people in general about various women's diseases,
and also discussed various problems of the doctor-patient relationships during
these talks. I feel that public awareness concerning informed consent has
increased gradually recently in Japan.
PMID- 9546144
TI - [Informed consent--on the right of self-determination].
AB - The idea of informed consent asks for the right of self-determination which is
very difficult to achieve. Human life does not depend on one's will, and neither
does suffering. That is human being does not control one's own life, even though
one must be responsible for it. The right of self-determination has long and
struggling history. As a result we have acquired the concept of informed consent.
And then the physician-patient relationship is no longer considered to be based
on paternalism and now the new model is seeked for. All human beings are mortal
and cannot inevitably escape suffering. Therefore we must consider the physician
patient relationship as the one based on equality. The problem of self
determination should arise from this understanding.
PMID- 9546145
TI - [Experimental study on the therapeutic effects of SMS201-995 on bile-induced
acute pancreatitis in the dog].
AB - We studied the effects of SMS201-995, a long-acting somatostatin analogue, on
bile-induced acute pancreatitis in the dog. According to morphometrical study,
parenchymal necrotic ratio, zymogen granules area and zymogen granules occupied
ratio of acinus were significantly decreased in SMS-treated pancreatitis. These
results suggests that SMS-treated pancreatitis showed less damage than non
treated ones and decreased secretion of pancreatic enzyme. On the other hand,
pancreatic blood flow showed a stronger decrease in SMS-treated dogs than in non
treated ones, and a significant difference was observed at 15 minutes and 1 hour
after induction of pancreatitis. Many clinical and experimental evidences suggest
that pancreatic ischemia causes acute pancreatitis. Pancreatitis may be worsened
by an early phase treatment with SMS201-995, because this substance reduces
pancreatic tissue blood flow. The harmful effect of this substance on pancreatic
tissue blood flow must be kept in mind when SMS201-995 is used for therapeutic
purpose of acute pancreatitis.
PMID- 9546146
TI - Emergency appendectomy in a patient with Eisenmenger's syndrome.
AB - For the successful management of an emergency appendectomy and abscess drainage
in an Eisenmenger's patient with diffuse peritonitis, it may be preferable to use
general anesthesia with awake intubation. Epidural anesthesia is commonly
combined with this anesthetic management for emergency abdominal surgery.
However, the combination of topical anesthesia with epidural anesthesia should be
avoided for fear of toxicity of local anesthetics in a patient with complications
due to Eisenmenger's syndrome.
PMID- 9546147
TI - [Morphological studies on lower margins of nasal aperture in the skull of
Hokkaido Japanese].
AB - It is well-known that the lower margins of nasal aperture in the human skull may
be classified into the following four types, i.e., Forma anthropina, Forma
infantilis, Fossae praenasales and Clivus nasoalveolaris, and that the rates of
appearance of these four types differ with races. In the present study we made
morphological studies on the lower margins of nasal aperture of 465 Hokkaido
Japanese skulls, 463 skulls with symmetrical nasal aperture and 2 skulls with
asymmetrical one, and compared the findings with those of all races in the world,
especially of the Japanese, Ainu, Moyoro Man, Hamanaka Site Man and Eskimo. Forma
anthropina was found in 330 skulls (71.27 +/- 2.10%) among the 463, marking the
highest rate. Forma infantilis, found in 74 skulls (15.98 +/- 1.70%) among the
463, marked the second highest rate. Fossae praenasales, found in 42 skulls (9.07
+/- 1.33%) among the 463, marked the third highest rate. These 42 cases of Fossae
praenasales were further classified into three types, i.e., sub-Forma infantilis,
17 (40.48%), typical Fossae prenasales, 23 (54.76%) and sub-Clivus
nasoalveolaris, 2 (4.76%). Clivus nasoalveolaris, found in 17 skulls (3.67 +/-
0.87%) among the 463, marked the lowest rate. As a whole, the rates of the four
types in the Hokkaido Japanese were close to those in the other groups of the
Japanese in Kinai and Hokkaido (Ito).
PMID- 9546148
TI - [Effects of physical exhaustion on immune systems].
AB - The present study was performed to elucidate the effects of physical fatigue on
immune parameters of peripheral blood and splenic T cells in rats. Male Wistar
rats aged 20 to 45 weeks were used for the experiment. Swimming was employed as a
physical fatigue load. The rats in the single-load group with a weight equal to
3% of the body weight of each rat connected to the tails were exhausted by two
hours of swimming in one day. The rats in the consecutive-load group were
exhausted by three hours of swimming for 7 consecutive days with a weight equal
to 5% of the body weight of each rat. Absolute numbers of total white blood cells
(WBCs) and peripheral blood lymphocytes decreased significantly just after
swimming and returned to the baseline one day after swimming in both the single-
and consecutive-load groups. However, in the consecutive-load group WBCs and
lymphocytes decreased 7 days after swimming. Concentrations of plasma
corticosterone increased significantly just after swimming, and returned to the
baseline one day after swimming in both groups. Percentages of peripheral blood
CD5+ cells, CD4+ cells and CD8+ cells in the single-load group increased
significantly just after swimming. The percentage of peripheral blood CD5+ cells
and CD4+ cells increased significantly one day after swimming in the consecutive
load group. Percentages of splenic CD5+ cells and CD4+ cells increased
significantly in the single-load group. However, only that of CD4+ cells
increased significantly just after swimming in the consecutive-load group. A
single load affected the proportions of CD5+ cells, CD4+ cells and CD8+ cells
just after the load but the consecutive load affected CD5+ cells and CD4+ cells
and the effect persisted until the next day. These results indicate that the
effect of fatigue on immune parameters depends on the level of fatigue, and that
measurement of subsets of peripheral blood T cells is useful for evaluating
various levels of fatigue.
PMID- 9546149
TI - [Morphometrical analysis of projection neurons in reeler mutant mice].
AB - The projection neurons in the cerebral cortex are localized in the specific
layers, and present the characteristic shape of cell bodies and dendritic
arborization according to their properties. To examine what factors could cause
the morphological characteristics of the reeler neurons, of which cortical layers
are generally inverted, we morphometrically analyzed three types of projection
neurons, callosal (CC-neurons), corticospinal (CS-neurons), and corticothalamic
neurons (CT-neurons), by the retrograded labeling method. The results were as
follows: 1) Although in the normal mice, the CC-neuron cell bodies in the layer 2
+ 3 were significantly smaller than ones in the layer 5, the reeler CC-neurons
were uniform regardless of their intracortical positions. 2) The cell bodies of
the reeler CS-neurons were normal in size throughout the entire cortex. 3) The
cell bodies of reeler CT-neurons were generally larger than normal ones, and they
were larger in the location near the pia mater. 4) The apical dendrites of the
normal CC-, CS- and CT-neurons were generally directed toward the layer 1 of
neocortex, which is the plexiform zone (PZ) in the embryo stage, whereas those of
the reeler CC- and CS-neurons were directed toward the upper-middle zone of
neocortex, which is the interplexiform zone (IPZ) that corresponds with the
normal PZ; however, those of the reeler CT-neurons were not oriented toward
dominant direction. These results suggest that the sizes of CS-neurons vary
depending upon the target of the projection, whereas CC- and CT-neurons are
influenced by the volume of afferent inputs as well as the target of the
projection. The afferent factors, especially thalamocortical fibers, may also
influence the direction of the apical dendrites of CT-neurons.
PMID- 9546151
TI - Alkane hydroxylase from Acinetobacter sp. strain ADP1 is encoded by alkM and
belongs to a new family of bacterial integral-membrane hydrocarbon hydroxylases.
AB - Degradation of long-chain alkanes by Acinetobacter sp. strain ADP1 involves
rubredoxin and rubredoxin reductase. We complemented a mutant deficient in alkane
utilization and sequenced four open reading frames (ORFs) on the complementing
DNA. Each of these ORFs was disrupted by insertional mutagenesis on the
chromosome. As determined from sequence comparisons, ORF1 and ORF4 seem to encode
a rotamase of the PpiC type and an acyl coenzyme A dehydrogenase, respectively.
Disruption of these ORFs does not affect alkane utilization. In contrast, the two
other ORFs, alkR and alkM, are essential for growth on alkanes as sole carbon
sources. alkR encodes a polypeptide with extensive homology to AraC-XyIS-like
transcriptional regulators. It is located next to alkM, which encodes the
terminal alkane hydroxylase, but is in the opposite orientation. Sequence
homologies with other bacterial integral-membrane hydrocarbon hydroxylases
suggest that AlkM may be the first member of a new protein family. The genes
identified here are not linked to the rubredoxin- and rubredoxin reductase
encoding genes on the Acinetobacter sp. strain ADP1 chromosome.
PMID- 9546150
TI - Differential transmission of the genospecies of Borrelia burgdorferi sensu lato
by game birds and small rodents in England.
AB - The genetic diversity of Borrelia burgdorferi sensu lato was assessed in a focus
of Lyme borreliosis in southern Britain dominated by game birds. Ticks, rodents,
and pheasants were analyzed for spirochete infections by PCR-targeting the 23S-5S
rRNA genes, followed by genotyping by the reverse line blot method. In questing
Ixodes ricinus ticks, three genospecies of B. burgdorferi sensu lato were
detected, with the highest prevalences found for Borrelia garinii and Borrelia
valaisiana. B. burgdorferi sensu stricto was rare (< 1%) in all tick stages.
Borrelia afzelia was not detected in any of the samples. More than 50% of
engorged nymphs collected from pheasants were infected with borreliae, mainly B.
garinii and/or B. valaisiana. Although 19% of the rodents harbored B. burgdorferi
sensu stricto and/or B. garinii in internal organs, only B. burgdorferi sensu
stricto was transmitted to xenodiagnostic tick larvae (it was transmitted to 1%
of the larvae). The data indicate that different genospecies of B. burgdorferi
sensu lato can be maintained in nature by distinct transmission cycles involving
the same vector tick species but different vertebrate host species. Wildlife
management may have an influence on the relative risk of different clinical forms
of Lyme borreliosis.
PMID- 9546153
TI - Effects of bacterial host and dichloromethane dehalogenase on the competitiveness
of methylotrophic bacteria growing with dichloromethane.
AB - Methylobacterium sp. strain DM4 and Methylophilus sp. strain DM11 can grow with
dichloromethane (DCM) as the sole source of carbon and energy by virtue of
homologous glutathione-dependent DCM dehalogenases with markedly different
kinetic properties (the kcat values of the enzymes of these strains are 0.6 and
3.3 S-1, respectively, and the Km values are 9 and 59 microM, respectively).
These strains, as well as transconjugant bacteria expressing the DCM dehalogenase
gene (dcmA) from DM11 or DM4 on a broad-host-range plasmid in the background of
dcmA mutant DM4-2cr, were investigated by growing them under growth-limiting
conditions and in the presence of an excess of DCM. The maximal growth rates and
maximal levels of dehalogenase for chemostat-adapted bacteria were higher than
the maximal growth rates and maximal levels of dehalogenase for batch-grown
bacteria. The substrate saturation constant of strain DM4 was much lower than the
Km of its associated dehalogenase, suggesting that this strain is adapted to
scavenge low concentrations of DCM. Strains and transconjugants expressing the
DCM dehalogenase from strain DM11, on the other hand, had higher growth rates
than bacteria expressing the homologous dehalogenase from strain DM4. Competition
experiments performed with pairs of DCM-degrading strains revealed that a strain
expressing the dehalogenase from DM4 had a selective advantage in continuous
culture under substrate-limiting conditions, while strains expressing the DM11
dehalogenase were superior in batch culture when there was an excess of
substrate. Only DCM-degrading bacteria with a dcmA gene similar to that from
strain DM4, however, were obtained in batch enrichment cultures prepared with
activated sludge from sewage treatment plants.
PMID- 9546155
TI - Self-transmissible mercury resistance plasmids with gene-mobilizing capacity in
soil bacterial populations: influence of wheat roots and mercury addition.
AB - A set of mercury resistance plasmids was obtained from wheat rhizosphere soil
amended or not amended with mercuric chloride via exogenous plasmid isolation by
using Pseudomonas fluorescens R2f, Pseudomonas putida UWC1, and Enterobacter
cloacae BE1 as recipient strains. The isolation frequencies were highest from
soil amended with high levels of mercury, and the isolation frequencies from
unamended soil were low. With P. putida UWC1 as the recipient, the isolation
frequency was significantly enhanced in wheat rhizosphere compared to bulk soil.
Twenty transconjugants were analyzed per recipient strain. All of the
transconjugants contained plasmids which were between 40 and 50 kb long. Eight
selected plasmids were distributed among five groups, as shown by restriction
digestion coupled with a similarity matrix analysis. However, all of the plasmids
formed a tight group, as judged by hybridization with two whole-plasmid probes
and comparisons with other plasmids in dot blot hybridization analyses. The
results of replicon typing and broad-host-range incompatibility (Inc) group
specific PCR suggested tht the plasmid isolates were not related to any
previously described Inc group. Although resistance to copper, resistance to
streptomycin, and/or resistance to chloramphenicol was found in several plasmids,
catabolic sequences were generally not identified. One plasmid, pEC10,
transferred into a variety of bacteria belonging to the beta and gamma
subdivisions of the class Proteobacteria and mobilized as well as retromobilized
the IncQ plasmid pSUP104. A PCR method for detection of pEC10-like replicons was
used, in conjunction with other methods, to monitor pEC10-homologous sequences in
mercury-polluted and unpolluted soils. The presence of mercury enhanced the
prevalence of pEC10-like replicons in soil and rhizosphere bacterial populations.
PMID- 9546154
TI - Population dynamics of phenol-degrading bacteria in activated sludge determined
by gyrB-targeted quantitative PCR.
AB - A method for quantifying bacterial populations introduced into an activated
sludge microbial community is described. The method involves extraction of DNA
from activated sludge, appropriate dilution of the extracted DNA with DNA
extracted from nonintroduced activated sludge, PCR amplification of a gyrB gene
fragment from the introduced strain with a set of strain-specific primers, and
quantification of the electrophoresed PCR product by densitometry. The adequacy
of the method was examined by analyzing the population dynamics of two phenol
degrading bacteria, Pseudomonas putida BH and Comamonas sp. strain E6, that had
been introduced into phenol-digesting activated sludge. The density of each of
the two populations determined by the PCR method immediately after the
introduction was consistent with the density estimated from a plate count of the
inoculum. This quantitative PCR method revealed different population dynamics for
the two strains in the activated sludge under different phenol-loading
conditions. The behavior of both of these strains in the activated sludge
reflected the growth kinetics of the strains determined in laboratory axenic
cultures.
PMID- 9546156
TI - Production of the carotenoids lycopene, beta-carotene, and astaxanthin in the
food yeast Candida utilis.
AB - The food-grade yeast Candida utilis has been engineered to confer a novel
biosynthetic pathway for the production of carotenoids such as lycopene, beta
carotene, and astaxanthin. The exogenous carotenoid biosynthesis genes were
derived from the epiphytic bacterium Erwinia uredovora and the marine bacterium
Agrobacterium aurantiacum. The carotenoid biosynthesis genes were individually
modified based on the codon usage of the C. utilis glyceraldehyde 3-phosphate
dehydrogenase gene and expressed in C. utilis under the control of the
constitutive promotes and terminators derived from C. utilis. The resultant yeast
strains accumulated lycopene, beta-carotene, and astaxanthin in the cells at 1.1,
0.4, and 0.4 mg per g (dry weight) of cells, respectively. This was considered to
be a result of the carbon flow into ergosterol biosynthesis being partially
redirected to the nonendogenous pathway for carotenoid production.
PMID- 9546157
TI - Specificity of milk peptide utilization by Lactococcus lactis.
AB - To study the substrate specificity of the oligopeptide transport system of
Lactococcus lactis for its natural substrates, the growth of L. lactis MG1363 was
studied in a chemically defined medium containing milk peptides or a tryptic
digest of alpha s2-casein as the source of amino acids. Peptides were separated
into acidic, neutral, and basic pools by solid-phase extraction or by cation
exchange liquid chromatogrpaphy. Their ability to sustain growth and the time
course of their utilization demonstrated the preferential use of hydrophobic
basic peptides with molecular masses ranging between 600 and 1,100 Da by L.
lactis MG1363 and the inability to use large, acidic peptides. These peptide
utilization preferences reflect the substrate specificity of the oligopeptide
transport system of the strain, since no significant cell lysis was inferred.
Considering the free amino acid content of milk and these findings on peptide
utilization, it was demonstrated that the cessation of growth of L. lactis MG1363
in milk was due to deprivation of leucine and methionine.
PMID- 9546158
TI - PCR for detection of Shigella spp. in mayonnaise.
AB - The use of PCR to amplify a specific virA gene fragment serves as a highly
specific and sensitive method to detect virulent bacteria of the genus Shigella
and enteroinvasive Escherichia coli. Amplification of a 215-bp DNA band was
obtained by using isolated genomic DNA of Shigella, individual cells of Shigella
dysenteriae, and mayonnaise contaminated with S. dysenteriae. Moreover, a
multiplex PCR with specific (virA) and bacterium-restricted (16S ribosomal DNA)
primers generated an amplification product of approximately 755 bp for all
bacteria tested and an additional 215-bp product for Shigella and enteroinvasive
E. coli.
PMID- 9546160
TI - 19F nuclear magnetic resonance as a tool to investigate microbial degradation of
fluorophenols to fluorocatechols and fluoromuconates.
AB - A method was developed to study the biodegradation and oxidative
biodehalogenation of fluorinated phenols by 19F nuclear magnetic resonance (NMR).
Characterization of the 19F NMR spectra of metabolite profiles of a series of
fluorophenols, converted by purified phenol hydroxylase, catechol 1,2
dioxygenase, and/or by the yeast-like fungus Exophiala jeanselmei, provided
possibilities for identification of the 19F NMR chemical shift values of
fluorinated catechol and muconate metabolites. As an example, the 19F NMR method
thus defined was used to characterize the time-dependent metabolite profiles of
various halophenols in either cell extracts or in incubations with whole cells of
E. jeanselmei. The results obtained for these two systems are similar, except for
the level of muconates observed. Altogether, the results of the present study
describe a 19F NMR method which provides an efficient tool for elucidating the
metabolic pathways for conversion of fluorine-containing phenols by
microorganisms, with special emphasis on possibilities for biodehalogenation and
detection of the type of fluorocatechols and fluoromuconates involved. In
addition, the method provides possibilities for studying metabolic pathways in
vivo in whole cells.
PMID- 9546161
TI - Grazing of Tetrahymena sp. on adhered bacteria in percolated columns monitored by
in situ hybridization with fluorescent oligonucleotide probes.
AB - Predation of attached Pseudomonas putida mt2 by the small ciliate Tetrahymena sp.
was investigated with a percolated column system. Grazing rates were examined
under static and dynamic conditions and were compared to grazing rates in batch
systems containing suspended prey. The prey densities were 2 x 10(8) bacteria per
ml of pore space and 2 x 10(8) bacteria per ml of suspension, respectively.
Postingestion in situ hybridization of bacteria with fluorescent oligonucleotide
probes was used to quantify ingestion. During 30 min, a grazing rate of 1,382 +/-
1,029 bacteria individual-1 h-1 was obtained with suspended prey; this was twice
the grazing rate observed with attached bacteria under static conditions.
Continuous percolation at a flow rate of 73 cm h-1 further decreased the grazing
rate to about 25% of the grazing rate observed with suspended prey. A
considerable proportion of the protozoans fed on neither suspended bacteria nor
attached bacteria. The transport of ciliates through the columns was monitored at
the same time that predation was monitored. Less than 20% of the protozoans
passed through the columns without being retained. Most of these organisms
ingested no bacteria, whereas the retained protozoans grazed more efficiently.
Retardation of ciliate transport was greater in columns containing attached
bacteria than in bacterium-free columns. We propose that the correlation between
grazing activity and retardation of transport is a consequence of the interaction
between active predators and attached bacteria.
PMID- 9546162
TI - Characterization of the rrnB operon of the plant pathogen Rhodococcus fascians
and targeted integrations of exogenous genes at rrn loci.
AB - A 6.0-kb SalI DNA fragment containing an entire rRNA operon (rrnB) was cloned
from a cosmid gene bank of the phytopathogenic strain Rhodococcus fascians D188.
The nucleotide sequence of the 6-kb fragment was determined and had the
organization 16S rRNA-spacer-23S rRNA-spacer-5S rRNA without tRNA-encoding genes
in the spacer regions. The 5' and 3' ends of the mature 16S, 23S, and 5S rRNAs
were determined by alignment with the rrn operons of Bacillus subtilis and other
gram-positive bacteria. Four copies of the rrn operons were identified by
hybridization with an rrnB probe in R. fascians type strain ATCC 12974 and in the
virulent strain R. fascians D188. However, another isolate, CECT 3001 (= NRRL
B15096), also classified as R. fascians, produced five rrn-hybridizing bands. An
integrative vector containing a 2.5-kb DNA fragment internal to rrnB was
constructed for targeted integration of exogenous genes at the rrn loci.
Transformants carrying the exogenous chloramphenicol resistance gene (cmr)
integrated in different rrn operons were obtained. These transformants had normal
growth rates in complex medium and minimal medium and were fully stable for the
integrated marker.
PMID- 9546163
TI - Characterization of the dominant and rare members of a young Hawaiian soil
bacterial community with small-subunit ribosomal DNA amplified from DNA
fractionated on the basis of its guanine and cytosine composition.
AB - The small-subunit ribosomal DNA (rDNA) diversity was found to be very high in a
Hawaiian soil community that might be expected to have lower diversity than the
communities in continental soils because the Hawaiian soil is geographically
isolated and only 200 years old, is subjected to a constant climate, and harbors
low plant diversity. Since an underlying community structure could not be
revealed by analyzing the total eubacterial rDNA, we first fractionated the DNA
on the basis of guanine-plus-cytosine (G + C) content by using bisbenzimidazole
and equilibrium centrifugation and then analyzed the bacterial rDNA amplified
from a fraction with a high biomass (63% G + C fraction) and a fraction with a
low biomass (35% G + C fraction). The rDNA clone libraries were screened by
amplified rDNA restriction analysis to determine phylotype distribution. The
dominant biomass reflected by the 63% G + C fraction contained several dominant
phylotypes, while the community members that were less successful (35% G + C
fraction) did not show dominance but there was a very high diversity of
phylotypes. Nucleotide sequence analysis revealed taxa belonging to the groups
expected for the G + C contents used. The dominant phylotypes in the 63% G + C
fraction were members of the Pseudomonas, Rhizobium-Agrobacterium, and
Rhodospirillum assemblages, while all of the clones sequenced from the 35% G + C
fraction were affiliated with several Clostridium assemblages. The two-step rDNA
analysis used here uncovered more diversity than can be detected by direct rDNA
analysis of total community DNA. The G + C separation step is also a way to
detect some of the less dominant organisms in a community.
PMID- 9546164
TI - Pyruvate decarboxylase catalyzes decarboxylation of branched-chain 2-oxo acids
but is not essential for fusel alcohol production by Saccharomyces cerevisiae.
AB - The fusel alcohols 3-methyl-1-butanol, 2-methyl-1-butanol, and 2-methyl-propanol
are important flavor compounds in yeast-derived food products and beverages. The
formation of these compounds from branched-chain amino acids is generally assumed
to occur via the Ehrlich pathway, which involves the concerted action of a
branched-chain transaminase, a decarboxylase, and an alcohol dehydrogenase.
Partially purified preparations of pyruvate decarboxylase (EC 4.1.1.1) have been
reported to catalyze the decarboxylation of the branched-chain 2-oxo acids formed
upon transamination of leucine, isoleucine, and valine. Indeed, in a coupled
enzymatic assay with horse liver alcohol dehydrogenase, cell extracts of a wild
type Saccharomyces cerevisiae strain exhibited significant decarboxylation rates
with these branched-chain 2-oxo acids. Decarboxylation of branched-chain 2-oxo
acids was not detectable in cell extracts of an isogenic strain in which all
three PDC genes had been disrupted. Experiments with cell extracts from S.
cerevisiae mutants expressing a single PDC gene demonstrated that both PDC1- and
PDC5-encoded isoenzymes can decarboxylate branched-chain 2-oxo acids. To
investigate whether pyruvate decarboxylase is essential for fusel alcohol
production by whole cells, wild-type S. cerevisiae and an isogenic pyruvate
decarboxylase-negative strain were grown on ethanol with a mixture of leucine,
isoleucine, and valine as the nitrogen source. Surprisingly, the three
corresponding fusel alcohols were produced in both strains. This result proves
that decarboxylation of branched-chain 2-oxo acids via pyruvate decarboxylase is
not an essential step in fusel alcohol production.
PMID- 9546165
TI - The Desulfuromonas acetoxidans triheme cytochrome c7 produced in Desulfovibrio
desulfuricans retains its metal reductase activity.
AB - Multiheme cytochrome c proteins that belong to class III have been recently shown
to exhibit a metal reductase activity, which could be of great environmental
interest, especially in metal bioremediation. To get a better understanding of
these activities, the gene encoding cytochrome c7 from the sulfur-reducing
bacterium Desulfuromonas acetoxidans was cloned from genomic DNA by PCR and
expressed in Desulfovibrio desulfuricans G201. The expression system was based on
the cyc transcription unit from Desulfovibrio vulgaris Hildenborough and led to
the synthesis of holocytochrome c7 when transferred by electrotransformation into
the sulfate reducer Desulfovibrio desulfuricans G201. The produced cytochrome was
indistinguishable from the protein purified from Desulfuromonas acetoxidans cells
with respect to several biochemical and biophysical criteria and exhibited the
same metal reductase activities as determined from electrochemical experiments.
This suggests that the molecule was correctly folded in the host organism.
Desulfovibrio desulfuricans produces functional multiheme c-type cytochromes from
bacteria belonging to a different genus and may be considered a suitable host for
the heterologous biogenesis of multiheme c-type cytochromes for either structural
or engineering studies. This report, which presents the first example of the
transformation of a Desulfovibrio desulfuricans strain by electrotransformation,
describes work that is the first necessary step of a protein engineering program
that aims to specify the structural features that are responsible for the metal
reductase activities of multiheme cytochrome c7.
PMID- 9546166
TI - Detection of mRNA by reverse transcription-PCR as an indicator of viability in
Escherichia coli cells.
AB - The relationship between the detection of mRNA and cellular viability in
Escherichia coli was investigated in cells killed by heat or ethanol. Reverse
transcription-PCR (RT-PCR) methods were developed for detecting mRNA from rpoH,
groEL, and tufA genes. mRNA from all three genes was detected immediately after
the cells had been killed by heat or ethanol but gradually disappeared with time
when dead cells were held at room temperature. In heat-killed cells, some mRNA
targets became undetectable after 2 to 16 h, whereas after ethanol treatment,
mRNA was still detected after 16 h. In contrast, 16S rRNA was detected by RT-PCR
in all samples containing dead cells and did not disappear during a subsequent
incubation of 16 h at room temperature. Of the different types of nucleic acid,
mRNA is the most promising candidate for an indicator of viability in bacteria,
but its persistence in dead cells depends on the inactivating treatment and
subsequent holding conditions.
PMID- 9546167
TI - Biodegradation of metal-EDTA complexes by an enriched microbial population.
AB - A mixed culture utilizing EDTA as the sole carbon source was isolated from a
mixed inoculum of water from the River Mersey (United Kingdom) and sludge from an
industrial effluent treatment plant. Fourteen component organisms were isolated
from the culture, including representatives of the genera Methylobacterium,
Variovorax, Enterobacter, Aureobacterium, and Bacillus. The mixed culture
biodegraded metal-EDTA complexes slowly; the biodegradability was in the order Fe
> Cu > Co > Ni > Cd. By incorporation of inorganic phosphate into the medium as a
precipitant ligand, heavy metals were removed in parallel to EDTA degradation.
The mixed culture also utilized a number of possible EDTA degradation
intermediates as carbon sources.
PMID- 9546168
TI - A competitive microflora increases the resistance of Salmonella typhimurium to
inimical processes: evidence for a suicide response.
AB - The presence of a viable competitive microflora at cell densities of 10(8) CFU ml
1 protects an underlying population of 10(5) CFU of Salmonella typhimurium ml-1
against freeze injury. The mechanism of enhanced resistance was initially
postulated to be via an RpoS-mediated adaptive response. By using an spvRA::
luxCDABE reporter we have shown that although the onset of RpoS-mediated gene
expression was brought forward by the addition of a competitive microflora, the
time taken for induction was measured in hours. Since the protective effect of a
competitive microflora is essentially instantaneous, the stationary-phase
adaptive response is excluded as the physiological mechanism. The only
instantaneous effect of the competitive microflora was a reduction in the percent
saturation of oxygen from 100% to less than 10%. For both mild heat treatment (55
degrees C) and freeze injury this change in oxygen tension affords Salmonella a
substantive (2 orders of magnitude) enhancement in survival. By reducing the
levels of dissolved oxygen through active respiration, a competitive microflora
reduces oxidative damage to exponential-phase cells irrespective of the inimical
treatment. These results have led us to propose a suicide hypothesis for the
destruction of rapidly growing cells by inimical processes. In essence, the
suicide hypothesis proposes that a mild inimical process leads to the growth
arrest of exponential-phase cells and to the decoupling of anabolic and catabolic
metabolism. The result of this is a free radical burst which is lethal to
unadapted cells.
PMID- 9546169
TI - Bacterial oxidation of mercury metal vapor, Hg(0).
AB - We used metalloregulated luciferase reporter fusions and spectroscopic
quantification of soluble Hg(II) to determine that the hydroperoxidase-catalase,
KatG, of Escherichia coli can oxidize monatomic elemental mercury vapor, Hg(0),
to the water-soluble, ionic form, Hg(II). A strain with a mutation in katG and a
strain overproducing KatG were used to demonstrate that the amount of Hg(II)
formed is proportional to the catalase activity. Hg(0) oxidation was much
decreased in stationary-phase cells of a strain lacking KatG, suggesting that the
monofunctional hydroperoxidase KatE is less effective at this reaction.
Unexpectedly, Hg(0) oxidation also occurred in a strain lacking both KatE and
KatG, suggesting that activities other than hydroperoxidases may carry out this
reaction. Two typical soil bacteria, Bacillus and Streptomyces, also oxidize
Hg(0) to Hg(II). These observations establish for the first time that bacteria
can contribute, as do mammals and plants, to the oxidative phase of the global Hg
cycle.
PMID- 9546171
TI - Buffering capacity and membrane H+ conductance of neutrophilic and alkalophilic
gram-positive bacteria.
AB - Buffering capacity and membrane H+ conductance were examined in three gram
positive bacteria, Staphylococcus aureus, Bacillus subtilis, and Bacillus
alcalophilus. An acid pulse technique was used to measure both parameters. The
buffering capacity and membrane H+ conductance of B. alcalophilus are influenced
by the pH of the medium and the culture conditions. Suspensions of B.
alcalophilus cells from both H. A. medium and L-malate medium cultures grown at
pH 10.5 exhibited higher values for these parameters than cells grown at pH 8.5.
B. alcalophilus grown aerobically had a lower buffering capacity and a lower
membrane conductance for protons than the neutrophilic bacteria S. aureus and B.
subtilis. Fermenting cells exhibited significantly higher values for both
variables than respiring cells.
PMID- 9546170
TI - A novel sensitive bioassay for detection of Bacillus cereus emetic toxin and
related depsipeptide ionophores.
AB - Of the toxins produced by Bacillus cereus, the emetic toxin is likely the most
dangerous but, due to the lack of a suitable assay, the least well known. In this
paper, a new, sensitive, inexpensive, and rapid bioassay for detection of the
emetic toxin of B. cereus is described. The assay is based on the loss of
motility of boar spermatozoa upon 24 h of exposure to extracts of emetic B.
cereus strains or contaminated food. The paralyzed spermatozoa exhibited swollen
mitochondria, but no depletion of cellular ATP or damage to plasma membrane
integrity was observed. Analysis of the purified toxin by electrospray tandem
mass spectrometry showed that it was a dodecadepsipeptide with a mass
fragmentation pattern similar to that described for cereulide. The 50% effective
concentration of the purified toxin to boar spermatozoa was 0.5 ng of purified
toxin ml of extended boar semen-1. This amount corresponds to 10(4) to 10(5) CFU
of B. cereus cells. No toxicity was detected for 27 other B. cereus strains up to
10(8) CFU ml-1. The detection limit for food was 3 g of rice containing 10(6) to
10(7) CFU of emetic B. cereus per gram. Effects similar to those provoked by
emetic B. cereus toxin were also induced in boar spermatozoa by valinomycin and
gramicidin at 2 and 3 ng ml of extended boar semen-1, respectively. The symptoms
provoked by the toxin in spermatozoa indicated that B. cereus emetic toxin was
acting as a membrane channel-forming ionophore, damaging mitochondria and
blocking the oxidative phosphorylation required for the motility of boar
spermatozoa.
PMID- 9546172
TI - Pichia stipitis genes for alcohol dehydrogenase with fermentative and respiratory
functions.
AB - Two genes coding for isozymes of alcohol dehydrogenase (ADH); designated PsADH1
and PsADH2, have been identified and isolated from Pichia stipitis CBS 6054
genomic DNA by Southern hybridization to Saccharomyces cerevisiae ADH genes, and
their physiological roles have been characterized through disruption. The amino
acid sequences of the PsADH1 and PsADH2 isozymes are 80.5% identical to one
another and are 71.9 and 74.7% identical to the S. cerevisiae ADH1 protein. They
also show a high level identity with the group I ADH proteins from Kluyveromyces
lactis. The PsADH isozymes are presumably localized in the cytoplasm, as they do
not possess the amino-terminal extension of mitochondrion-targeted ADHs. Gene
disruption studies suggest that PsADH1 plays a major role in xylose fermentation
because PsADH1 disruption results in a lower growth rate and profoundly greater
accumulation of xylitol. Disruption of PsADH2 does not significantly affect
ethanol production or aerobic growth on ethanol as long as PsADH1 is present. The
PsADH1 and PsADH2 isozymes appear to be equivalent in the ability to convert
ethanol to acetaldehyde, and either is sufficient to allow cell growth on
ethanol. However, disruption of both genes blocks growth on ethanol. P. stipitis
strains disrupted in either PsADH1 or PsADH2 still accumulate ethanol, although
in different amounts, when grown on xylose under oxygen-limited conditions. The
PsADH double disruptant, which is unable to grow on ethanol, still produces
ethanol from xylose at about 13% of the rate seen in the parental strain. Thus,
deletion of both PsADH1 and PsADH2 blocks ethanol respiration but not production,
implying a separate path for fermentation.
PMID- 9546173
TI - Oxygen-dependent regulation of the expression of the catalase gene katA of
Lactobacillus sakei LTH677.
AB - The catalase gene katA of Lactobacillus sakei LTH677 was cloned and expressed in
Escherichia coli UM2, Lactobacillus casei LK1, and Lactobacillus curvatus
LTH1432. The last host is a catalase-deficient plasmid-cured derivative of a
starter organism used in meat fermentation. The regulation of katA expression was
found to be the same in L. sakei LTH677 and the recombinant strains. The addition
of H2O2 to anaerobic cultures, as well as a switch to aerobic conditions,
resulted in a strong increase in KatA activity. The expression was investigated
in more detail with L. sakei LTH677 and L. curvatus LTH4002. The recombinant
strain LTH4002 did not accumulate H2O2 under glucose-limited aerobic conditions
and remained viable in the stationary phase. Under inductive conditions, the katA
specific mRNA and the apoenzyme were synthesized de novo. Deletion derivatives of
the katA promoter were produced, and the regulatory response was investigated by
fusion to the beta-glucuronidase reporter gene gusA and expression in L. sakei
LTH677. The fact that gene expression was subject to induction was confirmed at
the level of transcription and protein synthesis. A small putative regulatory
sequence of at least 25 bp was identified located upstream of the -35 site.
Competition experiments performed with L. sakei LTH677 harboring the fusion
constructs consisting of the katA promoter and gusA revealed that an activator
protein is involved in the transcriptional induction of katA.
PMID- 9546174
TI - Purification and characterization of a nylon-degrading enzyme.
AB - A nylon-degrading enzyme found in the extracellular medium of a ligninolytic
culture of the white rot fungus strain IZU-154 was purified by ion-exchange
chromatography, gel filtration chromatography, and hydrophobic chromatography.
The characteristics of the purified protein (i.e., molecular weight, absorption
spectrum, and requirements for 2,6-dimethoxyphenol oxidation) were identical to
those of manganese peroxidase, which was previously characterized as a key enzyme
in the ligninolytic systems of many white rot fungi, and this result led us to
conclude that nylon degradation is catalyzed by manganese peroxidase. However,
the reaction mechanism for nylon degradation differed significantly from the
reaction mechanism reported for manganese peroxidase. The nylon-degrading
activity did not depend on exogenous H2O2 but nevertheless was inhibited by
catalase, and superoxide dismutase inhibited the nylon-degrading activity
strongly. These features are identical to those of the peroxidase-oxidase
reaction catalyzed by horseradish peroxidase. In addition, alpha-hydroxy acids
which are known to accelerate the manganese peroxidase reaction inhibited the
nylon-degrading activity strongly. Degradation of nylon-6 fiber was also
investigated. Drastic and regular erosion in the nylon surface was observed,
suggesting that nylon is degraded to soluble oligomers and that nylon is degraded
selectively.
PMID- 9546176
TI - Longitudinal study of Escherichia coli O157:H7 dissemination on four dairy farms
in Wisconsin.
AB - A 14-month longitudinal study was conducted on four dairy farms (C, H, R, and X)
in Wisconsin to ascertain the source(s) and dissemination of Escherichia coli
O157:H7. A cohort of 15 heifer calves from each farm were sampled weekly by
digital rectal retrieval from birth to a minimum of 7 months of age (range, 7 to
13 months). Over the 14 months of the study, the cohort heifers and other
randomly selected cattle from farms C and H tested negative. Farm R had two
separate periods of E. coli O157:H7 shedding lasting 4 months (November 1995 to
February 1996) and 1 month (July to August 1996), while farm X had at least one
positive cohort animal for a 5-month period (May to October 1996). Heifers shed
O157:H7 strains in feces for 1 to 16 weeks at levels ranging from 2.0 x 10(2) to
8.7 x 10(4) CFU per g. E. coli O157:H7 was also isolated from other noncohort
cattle, feed, flies, a pigeon, and water associated with the cohort heifers on
farms R and/or X. When present in animal drinking water, E. coli O157:H7
disseminated through the cohort cattle and other cattle that used the water
source. E. coli O157:H7 was found in water at < 1 to 23 CFU/ml. Genomic subtyping
by pulsed-field gel electrophoresis demonstrated that a single O157:H7 strain
comprised a majority of the isolates from cohort and noncohort cattle, water, and
other positive samples (i.e., from feed, flies, and a pigeon, etc.) on a farm.
The isolates from farm R displayed two predominant XbaI restriction endonuclease
digestion profiles (REDP), REDP 3 and REDP 7, during the first and second periods
of shedding, respectively. Six additional REDP that were > or = 89% similar to
REDP 3 or REDP 7 were identified among the farm R isolates. Additionally, the
REDP of an O157:H7 isolate from a heifer on farm R in 1994 was indistinguishable
from REDP 3. Farm X had one O157:H7 strain that predominated (96% of positive
samples had strains with REDP 9), and the REDP of an isolate from a heifer in
1994 was indistinguishable from REDP 9. These results suggest that E. coli
O157:H7 is disseminated from a common source on farms and that strains can
persist in a herd for a 2-year period.
PMID- 9546177
TI - COVASIAM: an image analysis method that allows detection of confluent microbial
colonies and colonies of various sizes for automated counting.
AB - In this work we introduce the confluent and various sizes image analysis method
(COVASIAM), an automated colony count technique that uses digital imaging
technology for detection and separation of confluent microbial colonies and
colonies of various sizes growing on petri dishes. The proposed method takes
advantage of the optical properties of the surfaces of most microbial colonies.
Colonies in the petri dish are epi-illuminated in order to direct the reflection
of concentrated light coming from a halogen lamp towards an image-sensing device.
In conjunction, a multilevel threshold algorithm is proposed for colony
separation and counting. These procedures improved the quantification of colonies
showing confluence or differences in size. We tested COVASIAM with a sample set
of microorganisms that form colonies with contrasting physical properties:
Saccharomyces cerevisiae, Aspergillus nidulans, Escherichia coli, Azotobacter
vinelandii, Pseudomonas aeruginosa, and Rhizobium etli. These physical properties
range from smooth to hairy, from bright to opaque, and from high to low
convexities. COVASIAM estimated an average of 95.47% (sigma = 8.55%) of the
manually counted colonies, while an automated method based on a single-threshold
segmentation procedure estimated an average of 76% (sigma = 16.27) of the
manually counted colonies. This method can be easily transposed to almost every
image-processing analyzer since the procedures to compile it are generically
standard.
PMID- 9546178
TI - Structural and kinetic properties of nonglycosylated recombinant Penicillium
amagasakiense glucose oxidase expressed in Escherichia coli.
AB - The gene coding for Penicillium amagasakiense glucose oxidase (GOX; beta-D
glucose; oxygen 1-oxidoreductase [EC 1.1.3.4]) has been cloned by PCR
amplification with genomic DNA as template with oligonucleotide probes derived
from amino acid sequences of N- and C-terminal peptide fragments of the enzyme.
Recombinant Escherichia coli expression plasmids have been constructed from the
heat-induced pCYTEXP1 expression vector containing the mature GOX coding
sequence. When transformed into E. coli TG2, the plasmid directed the synthesis
of 0.25 mg of protein in insoluble inclusion bodies per ml of E. coli culture
containing more than 60% inactive GOX. Enzyme activity was reconstituted by
treatment with 8 M urea and 30 mM dithiothreitol and subsequent 100-fold dilution
to a final protein concentration of 0.05 to 0.1 mg ml-1 in a buffer containing
reduced glutathione-oxidized glutathione, flavin adenine dinucleotide, and
glycerol. Reactivation followed first-order kinetics and was optimal at 10
degrees C. The reactivated recombinant GOX was purified to homogeneity by mild
acidification and anion-exchange chromatography. Up to 12 mg of active GOX could
be purified from a 1-liter E. coli culture. Circular dichroism demonstrated
similar conformations for recombinant and native P. amagasakiense GOXs. The
purified enzyme has a specific activity of 968 U mg-1 and exhibits kinetics of
glucose oxidation similar to those of, but lower pH and thermal stabilities than,
native GOX from P. amagasakiense. In contrast to the native enzyme, recombinant
GOX is nonglycosylated and contains a single isoform of pI 4.5. This is the first
reported expression of a fully active, nonglycosylated form of a eukaryotic,
glycosylated GOX in E. coli.
PMID- 9546181
TI - Use of 13C nuclear magnetic resonance to assess fossil fuel biodegradation: fate
of [1-13C]acenaphthene in creosote polycyclic aromatic compound mixtures degraded
by bacteria.
AB - [1-13C]acenaphthene, a tracer compound with a nuclear magnetic resonance (NMR)
active nucleus at the C-1 position, has been employed in conjunction with a
standard broad-band-decoupled 13C-NMR spectroscopy technique to study the
biodegradation of acenaphthene by various bacterial cultures degrading aromatic
hydrocarbons of creosote. Site-specific labeling at the benzylic position of
acenaphthene allows 13C-NMR detection of chemical changes due to initial
oxidations catalyzed by bacterial enzymes of aromatic hydrocarbon catabolism.
Biodegradation of [1-13C]acenaphthene in the presence of naphthalene or creosote
polycyclic aromatic compounds (PACs) was examined with an undefined mixed
bacterial culture (established by enrichment on creosote PACs) and with isolates
of individual naphthalene- and phenanthrene-degrading strains from this culture.
From 13C-NMR spectra of extractable materials obtained in time course
biodegradation experiments under optimized conditions, a number of signals were
assigned to accumulated products such as 1-acenaphthenol, 1-acenaphthenone,
acenaphthene-1,2-diol and naphthalene 1,8-dicarboxylic acid, formed by benzylic
oxidation of acenaphthene and subsequent reactions. Limited degradation of
acenaphthene could be attributed to its oxidation by naphthalene 1,2-dioxygenase
or related dioxygenases, indicative of certain limitations of the undefined mixed
culture with respect to acenaphthene catabolism. Coinoculation of the mixed
culture with cells of acenaphthene-grown strain Pseudomonas sp. strain A2279
mitigated the accumulation of partial transformation products and resulted in
more complete degradation of acenaphthene. This study demonstrates the value of
the stable isotope labeling approach and its ability to reveal incomplete
mineralization even when as little as 2 to 3% of the substrate is incompletely
oxidized, yielding products of partial transformation. The approach outlined may
prove useful in assessing bioremediation performance.
PMID- 9546179
TI - Molecular cloning and transcriptional regulation of the Aspergillus nidulans xlnD
gene encoding a beta-xylosidase.
AB - The xlnD gene encoding the 85-kDa beta-xylosidase was cloned from Aspergillus
nidulans. The deduced primary structure of the protein exhibits considerable
similarity to the primary structures of the Aspergillus niger and Trichoderma
reesei beta-xylosidases and some similarity to the primary structures of the
class 3 beta-glucosidases. xlnD is regulated at the transcriptional level; it is
induced by xylan and D-xylose and is repressed by D-glucose. Glucose repression
is mediated by the product of the creA gene. Although several binding sites for
the pH regulatory protein PacC were found in the upstream regulatory region, it
was not clear from a Northern analysis whether PacC is involved in
transcriptional regulation of xlnD.
PMID- 9546182
TI - Influence of water temperature and salinity on Vibrio vulnificus in Northern Gulf
and Atlantic Coast oysters (Crassostrea virginica).
AB - This study investigated the temperature and salinity parameters associated with
waters and oysters linked to food-borne Vibrio vulnificus infections. V.
vulnificus was enumerated in oysters collected at three northern Gulf Coast sites
and two Atlantic Coast sites from July 1994 through September 1995. Two of these
sites, Black Bay, La., and Apalachicola Bay, Fla., are the source of the majority
of the oysters implicated in V. vulnificus cases. Oysters in all Gulf Coast sites
exhibited a similar seasonal distribution of V. vulnificus: a consistently large
number (median concentration, 2,300 organisms [most probable number] per g of
oyster meat) from May through October followed by a gradual reduction during
November and December to < or = 10 per g, where it remained from January through
mid-March, and a sharp increase in late March and April to summer levels. V.
vulnificus was undetectable (< 3 per g) in oysters from the North and South
Carolina sites for most of the year. An exception occurred when a late-summer
flood caused a drop in salinity in the North Carolina estuary, apparently causing
V. vulnificus numbers to increase briefly to Gulf Coast levels. At Gulf Coast
sites, V. vulnificus numbers increased with water temperatures up to 26 degrees C
and were constant at higher temperatures. High V. vulnificus levels (> 10(3) per
g) were typically found in oysters from intermediate salinities (5 to 25 ppt).
Smaller V. vulnificus numbers (< 10(2) per g) were found at salinities above 28
ppt, typical of Atlantic Coast sites. On 11 occasions oysters were sampled at
times and locations near the source of oysters implicated in 13 V. vulnificus
cases; the V. vulnificus levels and environmental parameters associated with
these samples were consistent with those of other study samples collected from
the Gulf Coast from April through November. These findings suggest that the
hazard of V. vulnificus infection is not limited to brief periods of unusual
abundance of V. vulnificus in Gulf Coast oysters or to environmental conditions
that are unusual to Gulf Coast estuaries.
PMID- 9546184
TI - Cocoa fermentations conducted with a defined microbial cocktail inoculum.
AB - Cocoa fermentations were performed in wooden boxes under the following four
experimental regimens: beans naturally fermented with wild microflora;
aseptically prepared beans with no inoculum; and beans inoculated with a defined
cocktail containing microorganisms at a suitable concentration either at zero
time or by using phased additions at appropriate times. The cocktail used
consisted of a yeast, Saccharomyces cerevisiae var. chevalieri, two lactic acid
bacterial species, Lactobacillus lactis and Lactobacillus plantarum, and two
acetic acid bacterial species, Acetobacter aceti and Gluconobacter oxydans subsp.
suboxydans. The parameters measured were cell counts (for yeasts, filamentous
fungi, lactic acid bacteria, acetic acid bacteria, and spore formers, including
reisolation and identification of all residual cell types), sugar, ethanol,
acetic acid, and lactic acid contents (and contents of other organic acids), pH,
and temperature. A cut test for bean quality and a sensorial analysis of
chocolate made from the beans were also performed. The natural fermentation
mimicked exactly the conditions in 800-kg boxes on farms. The aseptic box
remained largely free of microflora throughout the study, and no significant
biochemical changes occurred. With the zero-time inoculum the fermentation was
almost identical to the natural fermentation. The fermentation with the phased
addition inoculum was similar, but many changes in parameters were slower and
less pronounced, which led to a slightly poorer end product. The data show that
the nearly 50 common species of microorganisms found in natural fermentations can
be replaced by a judicious selection and concentration of members of each
physiological group. This is the first report of successful use of a defined,
mixed starter culture in such a complex fermentation, and it should lead to
chocolate of more reliable and better quality.
PMID- 9546183
TI - Gene cloning, transcriptional analysis, purification, and characterization of
phenolic acid decarboxylase from Bacillus subtilis.
AB - Bacillus subtilis displays a substrate-inducible decarboxylating activity with
the following three phenolic acids: ferulic, p-coumaric, and caffeic acids. Based
on DNA sequence homologies between the Bacillus pumilus ferulate decarboxylase
gene (fdc) (A. Zago, G. Degrassi, and C. V. Bruschi, Appl. Environ. Microbiol.
61:4484-4486, 1995) and the Lactobacillus plantarum p-coumarate decarboxylase
gene (pdc) (J.-F. Cavin, L. Barthelmebs, and C. Divies, Appl. Environ. Microbiol.
63:1939-1944, 1997), a DNA probe of about 300 nucleotides for the L. plantarum
pdc gene was used to screen a B. subtilis genomic library in order to clone the
corresponding gene in this bacterium. One clone was detected with this
heterologous probe, and this clone exhibited phenolic acid decarboxylase (PAD)
activity. The corresponding 5-kb insertion was partially sequenced and was found
to contain a 528-bp open reading frame coding for a 161-amino-acid protein
exhibiting 71 and 84% identity with the pdc- and fdc-encoded enzymes,
respectively. The PAD gene (pad) is transcriptionally regulated by p-coumaric,
ferulic, or caffeic acid; these three acids are the three substrates of PAD. The
pad gene was overexpressed constitutively in Escherichia coli, and the stable
purified enzyme was characterized. The difference in substrate specificity
between this PAD and other PADs seems to be related to a few differences in the
amino acid sequence. Therefore, this novel enzyme should facilitate
identification of regions involved in catalysis and substrate specificity.
PMID- 9546185
TI - Targeted mutants of Cochliobolus carbonum lacking the two major extracellular
polygalacturonases.
AB - The filamentous fungus Cochliobolus carbonum produces endo-alpha 1,4
polygalacturonase (endoPG), exo-alpha 1,4-polygalacturonase (exoPG), and pectin
methylesterase when grown in culture on pectin. Residual activity in a pgn1
mutant (lacking endoPG) was due to exoPG activity, and the responsible protein
has now been purified. After chemical deglycosylation, the molecular mass of the
purified protein decreased from greater than 60 to 45 kDa. The gene that encodes
exoPG, PGX1, was isolated with PCR primers based on peptide sequences from the
protein. The product of PGX1, Pgx1p, has a predicted molecular mass of 48 kDa, 12
potential N-glycosylation sites, and 61% amino acid identity to an exoPG from the
saprophytic fungus Aspergillus tubingensis. Strains of C. carbonum mutated in
PGX1 were constructed by targeted gene disruption and by gene replacement. Growth
of pgx1 mutant strains on pectin was reduced by ca. 20%, and they were still
pathogenic on maize. A double pgn1/pgx1 mutant strain was constructed by
crossing. The double mutant grew as well as the pgx1 single mutant on pectin and
was still pathogenic despite having less than 1% of total wild-type PG activity.
Double mutants retained a small amount of PG activity with the same cation
exchange retention time as Pgn1p and also pectin methylesterase and a PG activity
associated with the mycelium. Continued growth of the pgn1/pgx1 mutant on pectin
could be due to one or more of these residual activities.
PMID- 9546186
TI - Recovery of humic-reducing bacteria from a diversity of environments.
AB - To evaluate which microorganisms might be responsible for microbial reduction of
humic substances in sedimentary environments, humic-reducing bacteria were
isolated from a variety of sediment types. These included lake sediments,
pristine and contaminated wetland sediments, and marine sediments. In each of the
sediment types, all of the humic reducers recovered with acetate as the electron
donor and the humic substance analog, 2,6-anthraquinone disulfonate (AQDS), as
the electron acceptor were members of the family Geobacteraceae. This was true
whether the AQDS-reducing bacteria were enriched prior to isolation on solid
media or were recovered from the highest positive dilutions of sediments in
liquid media. All of the isolates tested not only conserved energy to support
growth from acetate oxidation coupled to AQDS reduction but also could oxidize
acetate with highly purified soil humic acids as the sole electron acceptor. All
of the isolates tested were also able to grow with Fe(III) serving as the sole
electron acceptor. This is consistent with previous studies that have suggested
that the capacity for Fe(III) reduction is a common feature of all members of the
Geobacteraceae. These studies demonstrate that the potential for microbial humic
substance reduction can be found in a wide variety of sediment types and suggest
that Geobacteraceae species might be important humic-reducing organisms in
sediments.
PMID- 9546187
TI - Extremely barophilic bacteria isolated from the Mariana Trench, Challenger Deep,
at a depth of 11,000 meters.
AB - Two strains of obligately barophilic bacteria were isolated from a sample of the
world's deepest sediment, which was obtained by the unmanned deep-sea submersible
Kaiko in the Mariana Trench, Challenger Deep, at a depth of 10,898 m. From the
results of phylogenetic analysis based on 16S rRNA gene sequences, DNA-DNA
relatedness study, and analysis of fatty acid composition, the first strain
(DB21MT-2) appears to be most highly similar to Shewanella benthica and close
relatives, and the second strain (DB21MT-5) appears to be closely related to the
genus Moritella. The optimal pressure conditions for growth of these isolates
were 70 MPa for strain DB21MT-2 and 80 MPa for strain DB21MT-5, and no growth was
detected at pressures of less than 50 MPa with either strain. This is the first
evidence of the existence of an extreme-barophile bacterium of the genus
Moritella isolated from the deep-sea environment.
PMID- 9546188
TI - Spatial patterns of alkaline phosphatase expression within bacterial colonies and
biofilms in response to phosphate starvation.
AB - The expression of alkaline phosphatase in response to phosphate starvation was
shown to be spatially and temporally heterogeneous in bacterial biofilms and
colonies. A commercial alkaline phosphatase substrate that generates a
fluorescent, insoluble product was used in conjunction with frozen sectioning
techniques to visualize spatial patterns of enzyme expression in both Klebsiella
pneumoniae and Pseudomonas aeruginosa biofilms. Some of the expression patterns
observed revealed alkaline phosphatase activity at the boundary of the biofilm
opposite the place where the staining substrate was delivered, indicating that
the enzyme substrate penetrated the biofilm fully. Alkaline phosphatase
accumulated linearly with time in K. pneumoniae colonies transferred from high
phosphate medium to low-phosphate medium up to specific activities of 50 mumol
per min per mg of protein after 24 h. In K. pneumoniae biofilms and colonies,
alkaline phosphatase was initially expressed in the region of the biofilm
immediately adjacent to the carbon and energy source (glucose). In time, the
region of alkaline phosphatase expression expanded inward until it spanned most,
but not all, of the biofilm or colony depth. In contrast, expression of alkaline
phosphatase in P. aeruginosa biofilms occurred in a thin, sharply delineated band
at the biofilm-bulk fluid interface. In this case, the band of activity never
occupied more than approximately one-sixth of the biofilm. These results are
consistent with the working hypothesis that alkaline phosphatase expression
patterns are primarily controlled by the local availability of either the carbon
and energy source or the electron acceptor.
PMID- 9546189
TI - Enterohemorrhagic Escherichia coli O157:H7 present in radish sprouts.
AB - Using cultivation, immunofluorescence microscopy, and scanning electron
microscopy, we demonstrated the presence of viable enterohemorrhagic Escherichia
coli O157:H7 not only on the outer surfaces but also in the inner tissues and
stomata of cotyledons of radish sprouts grown from seeds experimentally
contaminated with the bacterium. HgCl2 treatment of the outer surface of the
hypocotyl did not kill the contaminating bacteria, which emphasized the
importance of either using seeds free from E. coli O157:H7 in the production of
radish sprouts or heating the sprouts before they are eaten.
PMID- 9546190
TI - Development of a direct in situ PCR method for detection of specific bacteria in
natural environments.
AB - We applied HNPP (2-hydroxy-3-naphthoic acid-2'-phenylanilide phosphate) to direct
in situ PCR for the routine detection of specific bacterial cells at the single
cell level. PCR was performed on glass slides with digoxigenin-labeled dUTP. The
digoxigenin-labeled PCR products were detected with alkaline phosphatase-labeled
antidigoxigenin antibody and HNPP which was combined with Fast Red TR. A bright
red fluorescent signal was produced from conversion to HNP (dephosphorylated
form) by alkaline phosphatase. We used the ECOL DNA primer set for amplification
of ribosomal DNA of Escherichia coli to identify cells specifically at the single
cell level in a bacterial mixture. High-contrast images were obtained under an
epifluorescence microscope with in situ PCR. By image analysis, E. coli cells in
polluted river water also were detected.
PMID- 9546191
TI - An origin of transfer (oriT) on the conjugative element pRS01 from Lactococcus
lactis subsp. lactis ML3.
AB - Previous analysis of the Tra1 region of the conjugative element pRS01 from
Lactococcus lactis subsp. lactis ML3 suggested that an origin of transfer (oriT)
was present. Deletion derivatives of this cloned Tra1 region were assayed for
mobilization in the presence of the wild-type pRS01 element in trans. The pRS01
oriT was localized to a 446-nucleotide segment in the intergenic region between
open reading frames ltrD and ltrE. Sequence analysis of this region revealed a
cluster of direct and inverted repeat structures characteristic of oriT regions
associated with other conjugative systems.
PMID- 9546193
TI - High-pressure inactivation and sublethal injury of pressure-resistant Escherichia
coli mutants in fruit juices.
AB - The potential of high-pressure-resistant mutants of Escherichia coli to survive
high-pressure pasteurization in fruit juices and in low-pH buffers was
investigated. Treatments with up to 500 MPa of pressure caused only a limited
direct inactivation of the mutants but resulted in an accelerated low-pH
inactivation during subsequent storage.
PMID- 9546192
TI - Transformation of Acinetobacter sp. strain BD413 by transgenic sugar beet DNA.
AB - The ability of Acinetobacter sp. strain BD413(pFG4 delta nptII) to take up and
integrate transgenic plant DNA based on homologous recombination was studied
under optimized laboratory conditions. Restoration of nptII, resulting in
kanamycin-resistant transformants, was observed with plasmid DNA, plant DNA, and
homogenates carrying the gene nptII. Molecular analysis showed that some
transformants not only restored the 317-bp deletion but also obtained additional
DNA.
PMID- 9546194
TI - Sonication-dependent electroporation of the erythromycin-producing bacterium
Saccharopolyspora erythraea.
AB - We report the development of an electrotransformation method applicable to all
strains of Saccharopolyspora erythraea examined to date. Vegetatively grown
mycelia were rendered electrocompetent by subjecting mycelial suspensions to
ultrasound pulses. The protocol provides an alternative route for the
introduction of DNA into filamentous microorganisms otherwise recalcitrant to
transformation techniques.
PMID- 9546195
TI - DNA sequence similarity between California isolates of Cryptosporidium parvum.
AB - We evaluated whether nucleic acid amplification with primers specific for
Cryptosporidium parvum followed by automated DNA sequence analysis of the PCR
amplicons could differentiate between California isolates of C. parvum obtained
from livestock, humans, and feral pigs. Almost complete sequence identity existed
among the livestock isolates and between the livestock and human isolates. DNA
sequences from feral pig isolates differed from those from livestock and humans
by 1.0 to 1.2%. The reference sequence obtained by Laxer et al. (M. A. Laxer, B.
K. Timblin, and R. J. Patel, Am. J. Trop. Med. Hyg. 45:688-694, 1991.) differed
from California isolates of C. parvum by 1.8 to 3.2%. These data suggest that DNA
sequence analysis of the amplicon of Laxer et al. does not allow for
differentiation between various strains of C. parvum or that our collection of
isolates obtained from various hosts from across California was limited to one
strain of C. parvum.
PMID- 9546197
TI - Catalytic mechanism of aldose reductase studied by the combined potentials of
quantum mechanics and molecular mechanics.
AB - The catalytic reduction of D-glyceraldehyde to glycerol by aldose reductase has
been investigated with the combined potentials of quantum mechanics (QM) and
molecular mechanics (MM) to resolve the question of whether Tyr48 or His110
serves as the proton donor during catalysis. Site directed mutagenesis studies
favor Tyr48 as the proton donor while the presence of a water channel linking the
N delta 1 of His110 to the bulk solvent suggests that His110 is the proton donor.
Utilizing the combined potentials of QM and MM, the binding mode of substrate D
glyceraldehyde was investigated by optimizing the local geometry of Asp43, Lys77,
Tyr48, His110 and NADPH at the active site of aldose reductase. Reaction pathways
for the reduction of D-glyceraldehyde to glycerol were then constructed by
treating both Tyr48 and His110 as proton donors. Comparison of energetics
obtained from the reaction pathways suggests His110 to be the proton donor. Based
on these findings, a reduction mechanism of D-glyceraldehyde to glycerol is
described.
PMID- 9546196
TI - Statistical analysis of data pertaining to complex state systems by stepwise
regression with reformulated parameters; application to spectroscopically
monitored hemoglobin oxygen binding data.
AB - A method is described for the statistical analysis of data pertaining to complex
state systems, based on the concept of reformulating the parameters describing
the system as a hierarchy of interactions, and this method demonstrated on the
analysis of spectroscopically monitored hemoglobin oxygen binding data [K. Imai,
Biophys. Chem. 37 (1990) 197-210]. The concept of reformulation was first
extended to state parameters other than delta G degree s, such as the extinction
coefficients (epsilon s) associated with different ligation states during
hemoglobin oxygen binding. The reformulated parameters are incrementally allowed
to vary in the data fitting procedure, and the statistical significance of the
added parameters tested by F and Kolmogorov-Smirnov tests. The result of this
method is the minimal set of statistically significant parameters required to
describe the data. The hierarchical nature of reformulated parameters allows the
physical significance of the subset of statistically significant parameters to be
discussed even when all reformulated terms may not be statistically significant.
Applying this method to hemoglobin oxygen binding data with the reformulated
Adair model demonstrated that at least two, and at most three, of the four
reformulated Adair constants are statistically significant. A reformulated square
model was found to give a statistically indistinguishable fit from the Adair
model, with the statistically significant thermodynamic terms essentially those
proposed by Linus Pauling in 1935. A change in delta epsilon with subsequent
oxygen binding events was found to be significant in both models. These results
are consistent with a model for hemoglobin oxygen binding where a subunit changes
its conformation upon oxygen binding, and affects the conformation of adjacent
subunits.
PMID- 9546198
TI - The PHBH fold: not only flavoenzymes.
AB - p-Hydroxybenzoate hydroxylase, D-amino acid oxidase, cholesterol oxidase and
glucose oxidase form a family of structurally related flavoenzymes. Comparison of
their three-dimensional structures reveal how the same FAD-binding scaffold has
been employed to implement diverse active-site architectures, suited for
different types of catalytic reactions. The substrate binding mode differs in
each of these enzymes, with the catalytically relevant residues not located on
homologous positions. A common feature is provided by the ability of these enzyme
to bury their substrates beneath the protein surface. In D-amino acid oxidase and
cholesterol oxidase, a loop forms a 'lid' controlling the active site
accessibility, whereas in p-hydroxybenzoate hydroxylase is the flavin itself,
which swings out to allow substrate binding. The crystallographic analysis has
revealed that the GTP-dissociation inhibitor of RAB GTPases has a folding
topology remarkably similar to p-hydroxybenzoate hydroxylase. This finding
highlights the versatile nature of this folding topology, which in addition to
flavin-dependent catalysis, is suited for diverse functions, such as the
regulation of GTPases.
PMID- 9546199
TI - Interaction of Doxorubicin with phospholipid monolayer and liposomes.
AB - The effect of Doxorubicin which is (an anthracycline antibiotic with a broad
spectrum of antitumor activity) on the monolayer and bilayer in the form of large
Multilamellar Vesicles (MLV's) of Dipalmitoyl phosphatidylcholine (DPPC) were
studied by means of monolayer techniques (surface pressure, penetration kinetics,
and association constant) and light scattering technique. The monolayer technique
showed that addition of DXR to a lipid film composed of (DPPC/CHOL/PEG-PE) at a
molar ratio of (100:0:0) produced a less condensed Monolayer. In the (pie-A)
curves, DXR induced shift towards larger area/molecule, where the area/molecule
was shifted from 61 to 89 A2, and 116 A2 in the presence of 20 and 40 nM DXR,
respectively. The three curves collapsed at a pressure pi = 45 mN/m. In
penetration kinetics experiment (delta pi-t), the change in pressure with time
was 8 and 14 mN/m for a DXR concentration of 20 and 40 nM, respectively, and the
increase in surface pressure presented a plateau over a period of 30 min. The
measured association constant (K) was found to be 5 x 10(5)/M. In the light
scattering experiment, there was a shift of the transition temperature (Tm) of
(MLV's) of the same composition of the monolayer towards a smaller value from
40.5 degrees to 34.5 degrees C. Incorporation of CHOL and PEG-PE as DPPC/CHOL/PEG
PE at a molar ratio of (100:20:0), (100:20:4) and (100:20:4) greatly counteracted
the effect of DXR and made the lipid membrane more condense and rigid. Moreover,
the penetration of DXR into the membrane was greatly reduced. There was a very
small shift for the (pi-A) and (delta pi-t) curves, and the association constant
of the drug for these different lipid compositions was greatly reduced down to
2.5 x 10(5)/M and the transition temperature (Tm) was increased up to (42.5
degrees C) in the presence of 40 nM DXR. Our results suggest that DXR has a great
effect on the phospholipid membrane, and that addition of CHOL or PEG-PE to the
phospholipid membrane causes stabilization for the membrane, and reduces the
interaction with Doxorubicin.
PMID- 9546200
TI - NMR triple-quantum filtered relaxation analysis of 17O-water in insulin
solutions: an insight into the aggregation of insulin and the properties of its
bound water.
AB - Transverse triple-quantum filtered NMR spectroscopy (TTQF) of 17O-water was used
to study the properties of water in insulin solutions at different Zn2+
concentrations and pH values. It was established that strongly bound water
molecules are already present in Zn-free insulin. On the assumption that the
effective correlation time of a strongly bound water molecule, tau sb, is 10 ns,
the apparent number of strongly bound water molecules was approximately 3 to 4
per insulin monomer. Addition of Zn2+ equivalent to approximately 2 g-atoms per
hexamer did not produce substantial increases in the overall 17O-water TTQF
signal intensity and apparent fraction of bound water. The dramatic enhancement
of the TTQF signals observed for samples with a Zn2+/hexamer ratio greater than
approximately 2:1 could be attributed to the increase in correlation time of the
strongly bound water, due to the formation of higher-order oligomers of the
protein.
PMID- 9546201
TI - Staggered movement of an actin filament sliding on myosin molecules in the
presence of ATP.
AB - An actin filament sliding on myosin molecules in the presence of an extremely low
concentration of ATP exhibited a staggered movement. Longitudinally sliding
movement of the filament was frequently interrupted by its non-sliding,
fluctuating movements both in the longitudinal and transversal directions.
Intermittent sliding movements of an actin filament indicate establishment of a
coordination of ATP-mediated active sites distributed along the filament.
PMID- 9546202
TI - Irreversible thermal denaturation of uridine phosphorylase from Escherichia coli
K-12.
AB - Thermal denaturation of uridine phosphorylase from Escherichia coli K-12 has been
studied by differential scanning calorimetry. The excess heat capacity vs.
temperature profiles were obtained at temperature scanning rates of 0.25, 0.5,
and 1 K/min. These profiles were analysed using three models of irreversible
denaturation which are approximations to the whole Lumry-Eyring model, namely,
the one-step model of irreversible denaturation, the Lumry-Eyring model with the
fast equilibrating first step, and the model involving two consecutive
irreversible steps. In terms of statistics the latter model describes the
kinetics of thermal denaturation of uridine phosphorylase more satisfactorily
than the two other models. The values of energy activation for the first and
second steps calculated for the model involving two consecutive irreversible
steps are the following: Ea,1 = 609.3 +/- 1.8 kJ/mol and Ea,2 = 446.8 +/- 3.2
kJ/mol.
PMID- 9546204
TI - Characterization of repetitive DNA sequences carrying 5S rDNA of the triploid
ginbuna (Japanese silver crucian carp, Carassius auratus langsdorfi).
AB - Repetitive DNA sequences (Hi-b; 209 bp in length) were isolated from the HindIII
digests of the genomic DNA of the triploid ginbuna, Carassius auratus langsdorfi.
Sequence analyses revealed that the Hi-b repetitive units were comprised of the
complete coding regions of 5S rDNA (120 bp in size) and their 5'flanking regions.
The sequences of the Hi-b units from the same individual were highly homogeneous.
Southern blot hybridization to the Hi-b probe displayed intricate patterns that
represented the presence of other repetitive units containing the Hi-b related
sequences. A major family of repetitive sequences related to the Hi-b was then
obtained by the polymerase chain reaction using asymmetry primers for the 5S
coding regions. These 331-bp sequences (AZ5S's) contained 5S pseudogenes as well
as the almost entire Hi-b sequences, and seemed to be the true 5S rDNAs. The
tandem arrangements of the AZ5S sequences explained most of the complex results
of Southern blots. Another class of intriguing repeat units (Hi-b-beta and Hi-b
gamma) were also isolated. Fluorescence in situ hybridization data revealed two
major signals on a pair of homologous chromosomes and several minor signals on
other chromosomes in the triploid ginbuna, indicating the existence of the 5S
related sequences as several separate clusters. The major spots were shared with
the tetraploid ginbuna and goldfish, but not with the diploid ginbuna. When the
genomic organization of the Hi-b related sequences in other cyprinid fishes was
examined, the hybridization patterns of the ginbuna were very similar to those of
the goldfish, but were clearly different from those of the gengorobuna. The carp
genome showed less complex patterns. Thus, the present 5S rDNA-related sequences
could be candidates for phylogenetic molecular markers for the crucian carp.
PMID- 9546203
TI - Germline cell formation in Drosophila embryogenesis.
AB - The classical term germ cell determinant was defined to cover whole function of
germ plasm, or morphologically remarkable cytoplasm localized in oocytes and germ
cells. Since early 1970 consequential advances in technology, including
microsurgery, genetic anatomy and gene manipulation, have allowed cytological and
molecular analyses of pole plasm (germ plasm) in Drosophila embryos. A series of
recent work has revealed that multiple factors or molecule species in pole plasm
participate in a consecutive reactions resulting in germline formation. Two
molecule species have been specified as playing roles in germline cell formation.
One that participates in sequestering pole plasm from somatic environment is
mitochondrial large ribosomal (mtlr) RNA, and the other involved in driving pole
cells into the germline pathway is Nanos protein. Studies disclosed the roles of
those two molecules are reviewed.
PMID- 9546205
TI - Decreased physical performance of congenic mice with mismatch between the nuclear
and the mitochondrial genome.
AB - Maternal transmission of mitochondrial DNA (mtDNA) allows us to generate mtDNA
congenic strain by repeating backcrosses of female mice to male mice of an inbred
strain, which carries different mtDNA haplotype from that of the female
progenitor. Since genetic backgrounds of inbred strains commonly used (e.g.,
C57BL/6J [B6] and BALB/c) are mainly derived from an European subspecies of Mus
musculus domesticus, congenic strains, in which mtDNA originated from an Asian
subspecies M. musculus musculus or an European species M. spretus, give in vivo
condition that mismatch occurs between the mitochondrial and the nuclear genome.
So far, little has been known how the mismatch condition affects the
physiological phenotype of the mice. To address this question, we established two
mtDNA congenic strains, C57BL/6J(B6)-mtSPR and BALB/c-mtSHH, which carry M.
spretus- and M. m. musculus-derived mtDNAs, representing the conditions of
interspecific and intersubspecific mitochondrial-nuclear genome mismatch,
respectively. Using these congenic strains, we examined their physical
performance by measuring their running time on a treadmill belt until exhaustion.
The result clearly showed that the mtDNA congenic strains manifested a
significant decrease in the level of physical performance, when compared with
their progenitor strains. It also appeared that the congenic mice manifested
growth rate. Thus, all results indicated that mismatch between the mitochondrial
and the nuclear genome causes phenotypic changes in individuals of mice.
PMID- 9546206
TI - Characterization of the heterochromatic chromosome regions in sheep.
AB - In order to elucidate the structural chromosome organization of the
heterochromatic regions in sheep, we have used C-banding, silver-staining,
sequential CDD technique and restriction endonuclease banding. By these banding
techniques we obtained four fractions of repetitive DNA, the autosomal fractions
A and B, the C fraction in the X chromosome, and the D fraction in the Y
chromosome. Silver staining revealed active nucleolus organizer regions (NOR's)
on the telomeric GC-rich areas of chromosomes 1, 2, 3, 4, and 25 which were
digested with HaeIII restriction endonuclease.
PMID- 9546207
TI - Drugs, money and deposition.
PMID- 9546209
TI - Breaking up is easy with esters.
AB - Formation of an internal (thio)ester bond activates numerous in vivo protein
autoprocessing pathways including pyruvoyol group synthesis, autoproteolysis,
protein splicing, enzyme activation and protein targeting. Structural analysis of
precursors, intermediates and products is fine tuning our understanding of the
mechanisms of these reactions.
PMID- 9546208
TI - Oxidative modifications in nitrosative stress.
AB - The molecular basis of redox sensitivity in proteins is not well understood. Here
we consider a continuum of NO- and O2-related modifications of cysteine residues
that constitute biological signaling events on the one hand and hallmarks of
nitrosative and oxidative stresses on the other.
PMID- 9546210
TI - All wrapped up.
AB - How is it possible that nine small repeated 'zinc finger' units (each spanning
just 3 or 4 base pairs) can protect the whole 50 base pair binding site of TFIIIA
and why should such a periodic protein structure give rise to such an asymmetric
footprint on DNA? The crystal structure of the first six fingers of TFIIIA bound
to 31 base pairs of DNA explains everything: not all zinc fingers act alike.
PMID- 9546211
TI - Ankyrin(g) ETS domains to DNA.
PMID- 9546212
TI - The alpha and beta of turning on a molecular switch.
AB - The crystal structures of RCC1 and the Sec7 domain of human Arno, nucleotide
exchange factors for the Ras-related GTPases Ran and ARF, reveal two very
different folds, the former a seven-bladed beta-propeller, the latter a capped
right-handed superhelix. Both are also unrelated to the folds of Mss4 and
elongation factor Ts, nucleotide exchange factors for Rab and elongation factor
Tu.
PMID- 9546213
TI - Recognition of DNA methylation by zinc fingers.
PMID- 9546214
TI - Picture story. A long unwinding road.
PMID- 9546215
TI - Enzyme inactivation through sulfhydryl oxidation by physiologic NO-carriers.
AB - Nitric oxide (NO) is a pluripotent regulatory molecule, yet the molecular
mechanisms by which it exerts its effects are largely unknown. Few physiologic
target molecules of NO have been identified, and even for these, the
modifications caused by NO remain uncharacterized. Human glutathione reductase
(hGR), a central enzyme of cellular antioxidant defense, is inhibited by S
nitrosoglutathione (GSNO) and by diglutathionyl-dinitroso-iron (DNIC-[GSH]2), two
in vivo transport forms of NO. Here, crystal structures of hGR inactivated by
GSNO and DNIC-[GSH]2 at 1.7 A resolution provide the first picture of enzyme
inactivation by NO-carriers: in GSNO-modified hGR, the active site residue Cys 63
is oxidized to an unusually stable cysteine sulfenic acid (R-SOH), whereas
modification with DNIC-[GSH]2 oxidizes Cys 63 to a cysteine sulfinic acid (R
SO2H). Our results illustrate that various forms of NO can mediate distinct
chemistry, and that sulfhydryl oxidation must be considered as a major mechanism
of NO action.
PMID- 9546216
TI - Structure of a stereoregular phosphorothioate DNA/RNA duplex.
AB - In this work, we present the first NMR solution structure of a DNA/RNA hybrid
containing stereoregular Rp-phosphorothioate modifications of all DNA backbone
linkages. The complex of the enzymatically synthesized phosphorothioate DNA
octamer (all-Rp)-d(GCGTCAGG) and its complementary RNA r(CCUGACGC) was found to
adopt an overall conformation within the A-form family. Most helical parameters
and the sugar puckers of the DNA strand assume values intermediate between A- and
B-form. The close structural similarity with the unmodified DNA/RNA hybrid of the
same sequence may explain why both the natural and the sulfur-substituted complex
can be recognized and digested by ribonuclease H.
PMID- 9546217
TI - Capture of an early fusion-active conformation of HIV-1 gp41.
AB - Using an inhibitory synthetic peptide (DP-178) from HIV-1 gp41, we have trapped
HIV-1 envelope glycoprotein (Env) undergoing conformational changes during virus
entry. Our data show that DP-178 binds gp41 and inhibits Env-mediated membrane
fusion after gp120 interacts with cellular receptors, indicating that
conformational changes involving the coiled coil domain of gp41 are required for
entry. Capture of this fusion-active conformation of Env provides insights into
the early events leading to Env-mediated membrane fusion.
PMID- 9546218
TI - Hydrolysis of a slow cyclic thiophosphate substrate of RNase T1 analyzed by time
resolved crystallography.
AB - Here we present a time-resolved crystallographic analysis of the hydrolysis of
exo (Sp) guanosine 2',3'-cyclophosphorothioate by RNase T1. The use of a slow
substrate and fast crystallization methods made it possible to perform the study
with conventional data-collection techniques. The results support the idea that
the hydrolysis reaction proceeds through a mechanism that is the inverse of the
transesterification reaction. In addition, the structures provide an explanation
for the differential behavior of RNase T1 towards exo- and endo-cyclic
thiophosphates.
PMID- 9546219
TI - Unusual beta-sheet periodicity in small cyclic peptides.
AB - Cyclic peptide homologs of gramicidin S containing 6, 8, 10, 12, 14 and 16
residues were synthesized and characterized using circular dichroism (CD) and 1H
NMR spectroscopy. Based on the three-dimensional structures generated from these
data we have found strong evidence of a periodic sequence-length dependence on
beta-sheet content. In particular, peptides of length 6, 10 and 14 residues
exhibit a high beta-sheet content, while peptides of 8, 12 and 16 residues appear
to exist as random coils. This unusual beta-sheet periodicity may have important
implications in our understanding of beta-sheet formation and in the design of
constrained beta-sheet and beta-hairpin mimics.
PMID- 9546220
TI - Crystal structure of aspartate decarboxylase at 2.2 A resolution provides
evidence for an ester in protein self-processing.
AB - The structure of L-aspartate-alpha-decarboxylase from E. coli has been determined
at 2.2 A resolution. The enzyme is a tetramer with pseudofour-fold rotational
symmetry. The subunits are six-stranded beta-barrels capped by small alpha
helices at each end. The active sites are located between adjacent subunits. The
electron density provides evidence for catalytic pyruvoyl groups at three active
sites and an ester at the fourth. The ester is an intermediate in the
autocatalytic self-processing leading to formation of the pyruvoyl group. This
unprecedented structure provides novel insights into the general phenomenon of
protein processing.
PMID- 9546221
TI - The crystal structure of Dps, a ferritin homolog that binds and protects DNA.
AB - The crystal structure of Dps, a DNA-binding protein from starved E. coli that
protects DNA from oxidative damage, has been solved at 1.6 A resolution. The Dps
monomer has essentially the same fold as ferritin, which forms a 24-mer with 432
symmetry, a hollow core and pores at the three-fold axes. Dps forms a dodecamer
with 23 (tetrahedral) point group symmetry which also has a hollow core and pores
at the three-folds. The structure suggests a novel DNA-binding motif and a
mechanism for DNA protection based on the sequestration of Fe ions.
PMID- 9546222
TI - Crystal structures of a nitric oxide transport protein from a blood-sucking
insect.
AB - The nitrophorins are heme-based proteins from the salivary glands of the blood
sucking insect Rhodnius prolixus that deliver nitric oxide gas (NO) to the victim
while feeding, resulting in vasodilation and inhibition of platelet aggregation.
The nitrophorins also bind tightly to histamine, which is released by the host to
induce wound healing. Here we present three crystal structures of nitrophorin 1
(NP1): bound to cyanide, which binds in a manner similar to NO (2.3 A
resolution); bound to histamine (2.0 A resolution); and bound to what appears to
be NH3 from the crystallization solution (2.0 A resolution). The NP1 structures
reveal heme to be sandwiched between strands of a lipocalin-like beta-barrel, and
in an arrangement unlike any other gas-transport protein discovered to date. The
heme is six-coordinate with a histidine (His 59) on the proximal side, and ligand
in a spacious pocket on the distal side. The structures confirm that NO and
histamine compete for the same binding pocket and become buried on binding. The
dissociation constant for histamine binding was found to be 19 nM, approximately
100-fold lower than that for NO.
PMID- 9546223
TI - Crystal structure of the type-2 Cu depleted laccase from Coprinus cinereus at 2.2
A resolution.
AB - Laccase catalyses the oxidation of a variety of organic substrates coupled to the
reduction of oxygen to water. It is widely believed to be the simplest
representative of the ubiquitous blue multi-copper oxidase family. Laccase is
implicated in a wide spectrum of biological activities and, in particular, plays
a key role in morphogenesis, development and lignin metabolism in fungi and
plants. The structure of laccase from the fungus Coprinus cinereus has been
determined by X-ray crystallography at a resolution of 2.2 A. Laccase is a
monomer composed of three cupredoxin-like beta-sandwich domains, similar to that
found in ascorbate oxidase. In contrast to ascorbate oxidase, however, the
mononuclear type-1 Cu site lacks the axial methionine ligand and so exhibits
trigonal planar coordination, consistent with its elevated redox potential.
Crucially, the structure is trapped in a Cu depleted form in which the putative
type-2 Cu atom is completely absent, but in which the remaining type-1 and type-3
Cu sites display full occupancy. Type-2 Cu depletion has unexpected consequences
for the coordination of the remaining type-3 Cu atoms.
PMID- 9546224
TI - Crystal structure of the hCASK PDZ domain reveals the structural basis of class
II PDZ domain target recognition.
AB - PDZ domain containing proteins assist formation of cell-cell junctions and
localization of membrane protein receptors and ion channels. PDZ domains interact
with the C-terminal residues of a particular target membrane protein. Based on
their binding specificities and sequence homologies, PDZ domains fall into two
classes. The first crystal structure of a class II PDZ domain, that of hCASK, has
been solved by multi-wavelength anomalous dispersion phasing. Complex formation
with the C-terminus of a neighboring non-crystallographically related PDZ domain
reveals interactions between hCASK and its ligand. Class II PDZ domains differ
from class I domains by formation of a second hydrophobic binding pocket. The C
terminal carboxylate binding loop of the PDZ domain is structurally conserved in
both classes suggesting a generalized carboxylate binding motif (h-Gly-h) where h
is a hydrophobic residue.
PMID- 9546225
TI - Vein graft surveillance: is graft revision without angiography justified and what
criteria should be used?
AB - PURPOSE: The objective of this study was to assess the accuracy of color-flow
duplex surveillance parameters to detect infrainguinal vein graft stenoses and to
investigate whether graft revision without angiography is justified. METHODS: In
a prospective study in which three centers participated, the data of graft
surveillance in 300 patients were analyzed. For the evaluation of surveillance
criteria all patients underwent a digital subtraction angiography if a graft
stenosis was suspected. To create a control group, in patients with normal grafts
a consented digital subtraction angiography was performed also. From these data
the accuracy of seven duplex and three ankle blood pressure-derived variables was
assessed. The relation between various surveillance criteria and continued graft
patency was determined with life table analysis with the transient state method.
RESULTS: The mean follow-up period was 20 months (range, 1 to 40 months). At
univariate and multivariate analysis the peak systolic velocity (PSV) ratio
provided the best correlation with angiographic stenoses > or = 70% (PSV ratio
cutoff 3.0: sensitivity 80%, specificity 84%). This finding did not differ
between the participating centers. With life table methods it was demonstrated
that the best combination of efficacy (limitation of the number of unnecessary
revisions), safety (minimal number of correctable lesions missed), and reduction
of angiograms was obtained by a two-parameter surveillance algorithm. This
algorithm included a PSV ratio < 2.5 to delineate patients in whom a conservative
approach without angiography or revision was appropriate, a PSV ratio > or = 4.0
to indicate patients in whom vein graft revision without angiography could be
scheduled, and a group with PSV ratios between 2.5 and 4.0 in whom angiography
was to be performed to determine clinical management on the basis of the stenosis
severity. This algorithm had a positive predictive value of 93% and a negative
predictive value of 89%. In addition, it resulted in a reduction of the number of
angiograms of 49% compared with a policy of angiographies in all patients with a
PSV ratio > or = 2.5. CONCLUSIONS: The best criterion to identify a failing graft
is the PSV ratio. With a two-parameter algorithm for vein graft surveillance, the
incidence of unnecessary revisions and of missed high-grade lesions was
acceptably low, whereas the number of angiograms was reduced by one half.
PMID- 9546226
TI - Contralateral symptoms after unilateral intervention for peripheral occlusive
disease.
AB - OBJECTIVE: The objectives of this study were (1) to determine the incidence of
contralateral symptoms in patients with a unilateral intervention for peripheral
arterial occlusive disease and (2) to identify characteristics that predict these
symptoms. SUBJECTS AND SETTING: We included patients who had a unilateral
surgical or percutaneous intervention for peripheral arterial occlusive disease
at the Brigham and Women's Hospital (Boston) between 1990 and 1995 (n = 532).
MAIN OUTCOME MEASURE: The main outcome measure was the first occurrence of
contralateral critical ischemia or intermittent claudication. RESULTS: The annual
incidence rate of contralateral critical ischemia was considerable, ranging from
3.3% to 8.3% during the first 4 years after the initial ipsilateral intervention.
The annual incidence rate of contralateral critical ischemia and claudication
combined varied from 7.7% to 21.3%. Cox regression analysis indicated that the
initial ipsilateral symptoms and the initial contralateral ankle/brachial index
can be used to predict the occurrence of contralateral symptoms. After correction
was done for these two variables, we found no statistically significant effects
for other factors including age, sex, diabetes, smoking, antihypertensive
medication, history of coronary artery disease, the type of intervention, and the
arterial level of the intervention. CONCLUSIONS: The results of our analysis
emphasize that peripheral arterial occlusive disease is essentially a two-limb
problem. Especially patients with previous ipsilateral critical ischemia and
patients with a poor initial contralateral ankle/brachial index have a high risk
for contralateral critical ischemia.
PMID- 9546227
TI - Intermittent claudication: symptom severity versus health values.
AB - OBJECTIVE: The objective of this study was to obtain health values from patients
with intermittent claudication with five different instruments and to study the
construct validity of these measures of health-related quality of life by
examining their relation with symptom severity. METHODS: We included all patients
with intermittent claudication who participated in an exercise program of the
Department of Internal Medicine at our university hospital (n = 92). Health value
instruments included the verbal rating scale, time trade-off, standard gamble,
EuroQol, and the Health Utilities Index (Mark III). Symptom-free walking distance
was used as a measure of symptom severity. RESULTS: For all instruments the
average health values in groups of patients with a symptom-free walking distance
< or = 150 m were lower than the average values in patients with a greater walk
distance, but the differences for the time trade-off and the standard gamble were
small, and only the differences for the verbal rating scale and the EuroQol were
statistically significant. At the individual patient level considerable
heterogeneity was seen, and the statistical association of the symptom-free
walking distance with health values varied from poor to moderate (Spearman rank
correlations, 0.03 to 0.48; p values, 0.003 to 0.78). CONCLUSION: At least for
the verbal rating scale and the EuroQol, the results of our study provide
evidence of the validity of the various health value instruments in a population
of patients with peripheral arterial occlusive disease.
PMID- 9546228
TI - The value of computed tomography in the assessment of suspected ruptured
abdominal aortic aneurysm.
AB - OBJECTIVE: The objective of this study was to determine the diagnostic value of
computed tomography (CT) in patients with suspected ruptured abdominal aortic
aneurysm. STUDY DESIGN: The study was an interrogation of a prospectively
gathered computerized database. SETTING: The study was performed at a regional
vascular surgery unit. SUBJECTS: Six hundred fifty-two consecutive patients were
admitted to this unit with suspected ruptured abdominal aortic aneurysm between
January 1, 1989, and December 31, 1996. Seventy-four patients (11.3%) in whom the
diagnosis was in doubt on clinical grounds alone underwent urgent CT. A total of
47 men and 27 women with a median age of 73 years (range, 52 to 86 years) were
evaluated. MAIN OUTCOME MEASURES: CT and operative findings were compared.
RESULTS: CT correctly diagnosed rupture in 22 of 28 patients who underwent
operation and correctly excluded rupture in 30 of 39 patients who underwent
operation. The sensitivity and specificity of CT when compared with operative
findings were therefore 79% and 77%, respectively. CONCLUSIONS: These data
indicate that CT has little additional diagnostic value. If in the opinion of an
experienced vascular surgeon rupture cannot be excluded on clinical grounds
alone, and the patient has no medical contraindications to abdominal aortic
aneurysm repair, then the patient should be taken directly to the operating
department.
PMID- 9546229
TI - Anastomotic aneurysms after surgical treatment of Takayasu's arteritis: a 40-year
experience.
AB - PURPOSE: To evaluate the clinical characteristics of anastomotic aneurysms that
develop in surgically treated patients with Takayasu's arteritis. METHODS: Among
103 patients with Takayasu's arteritis treated surgically over 40 years, 91
patients with 259 anastomoses (allowing for exclusion of 12 operative deaths)
participated in follow-up study from 1 month to 37.3 years with a mean value +/-
SEM of 17.3 +/- 1.1 years with a follow-up completion rate of 93% at 30 years.
The clinical characteristics of anastomotic aneurysms were clarified, and the
influences of several factors (sites of anastomoses, occlusive or aneurysmal
disease, suture material, preoperative systemic inflammation, and administration
of corticosteroids) on formation of anastomotic aneurysms were analyzed by means
of life-table method and Cox regression analysis. RESULTS: Twenty-two uninfected
anastomotic aneurysms were found among 14 patients (22 of 259 anastomoses, 8.5%).
The interval between the previous operation and diagnosis varied from 1.6 to 30
years with a mean value +/- SEM of 9.8 +/- 1.8 years. The cumulative incidence of
anastomotic aneurysm at 20 years was 12.0%. Systemic inflammation or steroid
administration had little influence on formation of anastomotic aneurysm.
Instead, anastomotic aneurysm tended to occur after operations for aneurysmal
lesions. CONCLUSIONS: Anastomotic aneurysm can occur anytime after operations for
Takayasu's arteritis. The development of anastomotic aneurysm is not influenced
by any factor specific to this disease except the presence of an aneurysmal
lesion.
PMID- 9546230
TI - Endoleak after endovascular graft repair of experimental aortic aneurysms: does
coil embolization with angiographic "seal" lower intraaneurysmal pressure?
AB - PURPOSE: To investigate the relation between endoleaks and intraaneurysmal
pressure (IAP) and the effect of coil embolization in the management of
endoleaks. METHODS: The infrarenal aorta of a dog (n = 15) was replaced by a
polytetrafluoroethylene aneurysm containing a pressure transducer. Group I (n =
4) had untreated aneurysms. Group II (n = 4) had endovascularly excluded
aneurysms without an endoleak. Group III (n = 7) had aneurysms excluded by means
of grafts with a defect that represented the source of an endoleak. After 4 weeks
of follow-up study, the endoleaks in group III dogs were subjected to coil
embolization. Systolic IAP was measured daily and expressed as a ratio of
systolic blood pressure obtained from a forelimb cuff. Arteriography, duplex
ultrasonography, and spiral contrast computed tomography were performed to
evaluate endoleaks. RESULTS: In group I, the LAP remained close to systolic blood
pressure (ratio of 0.96 +/- 0.06), whereas in group II the IAP ratio showed a
decline to 0.34 +/- 0.16 (p = 0.0009 group I versus II). After an initial
decrease, the IAP ratio in group III stabilized at 0.75 +/- 0.18 (p = 0.003,
group II versus III). Aneurysms with an endoleak remained pulsatile with a pulse
pressure of 30 +/- 16 mm Hg, which was less than that of untreated aneurysms (62
+/- 15 mm Hg; p < 0.0001 group I versus III). Arteriography and computed
tomography revealed "sealing" of endoleaks after coil embolization, but IAP ratio
did not decrease (0.76 +/- 0.14) after coil embolization. CONCLUSIONS: Incomplete
endovascular aneurysm exclusion caused by an endoleak fails to reduce IAP ratio
and may subject the aneurysm to a continued risk for rupture. Although coil
embolization resulted in angiographic and computed tomographic sealing, it failed
to reduce IAP ratio.
PMID- 9546231
TI - Ex vivo human carotid artery bifurcation stenting: correlation of lesion
characteristics with embolic potential.
AB - PURPOSE: To develop an ex vivo human carotid artery stenting model that can be
used for the quantitative analysis of risk for embolization associated with
balloon angioplasty and stenting and to correlate this risk with lesion
characteristics to define lesions suitable for balloon angioplasty and stenting.
METHODS: Specimens of carotid plaque (n = 24) were obtained circumferentially
intact from patients undergoing standard carotid endarterectomy. Carotid lesions
were prospectively characterized on the basis of angiographic and duplex findings
before endarterectomy and clinical findings. Specimens were encased in a
polytetrafluoroethylene wrap and mounted in a flow chamber that allowed access
for endovascular procedures and observations. Balloon angioplasty and stenting
were performed under fluoroscopic guidance with either a Palmaz stent or a
Wallstent endoprosthesis. Ex vivo angiograms were obtained before and after
intervention. Effluent from each specimen was filtered for released embolic
particles, which were microscopically examined, counted, and correlated with
various plaque characteristics by means of multivariate analysis. RESULTS:
Balloon angioplasty and stenting produced embolic particles that consisted of
atherosclerotic debris, organized thrombus, and calcified material. The number of
embolic particles detected after balloon angioplasty and stenting was not related
to preoperative symptoms, sex, plaque ulceration or calcification, or artery
size. However, echolucent plaques generated a higher number of particles compared
with echogenic plaques (p < 0.01). In addition, increased lesion stenosis also
significantly correlated with the total number of particles produced by balloon
angioplasty and stenting (r = 0.55). Multivariate analysis revealed that these
two characteristics were independent risk factors. CONCLUSIONS: Echolucent
plaques and plaques with stenosis > or = 90% produced a higher number of embolic
particles and therefore may be less suitable for balloon angioplasty and
stenting. This ex vivo model can be used to identify high-risk lesions for
balloon angioplasty and stenting and can aid in the evaluation of new devices
being considered for carotid balloon angioplasty and stenting.
PMID- 9546232
TI - Duplex ultrasound in the hemodynamic evaluation of the late sequelae of deep
venous thrombosis.
AB - PURPOSE: The use of duplex ultrasound scanning to evaluate the hemodynamic
outcome of deep venous thrombosis 7 to 13 years after the original diagnosis.
METHODS: Duplex ultrasound was used to re-examine 1212 segments of vein from 72
patients (49 men, 23 women) with deep venous thrombosis previously diagnosed by
means of phlebography to detect reflux and obstruction and evaluate flow; 611
segments were initially thrombosed and 601 segments were open. To define reflux,
reversed flow in 31 healthy persons was measured. RESULTS: In a review of all
veins of the 72 patients, 8 patients (11%) had completely normal duplex results
in all veins, 33 (46%) had reflux, 6 (8%) had at least one noncompressible vein
segment, and 25 (35%) had a combination of both. In the proximal vein segments
without initial thrombosis a higher percentage was normal (73%) than in segments
with initial thrombosis (46%). There was a significantly higher frequency of
reflux (46%, p = 0.05) and noncompressibility (12%, p < 0.01) in initially
thrombosed proximal vein segments than in vein segments without initial
thrombosis (reflux 25%, noncompressibility 3%). Distal to the knee 125 (17%) of
720 vein segments were not traceable. Significantly more initially thrombosed
vein segments were not traceable (p < 0.01). In distal vein segments there was no
significant difference in reflux (7% versus 5%) and noncompressibility (10%
versus 5%) between vein segments with and without initial thrombosis. Flow was
present in 99% of the 611 previously thrombosed proximal and distal segments.
CONCLUSIONS: Most patients with deep venous thrombosis still had venous
abnormalities 7 to 13 years after the initial diagnosis. The most common
abnormality was reflux. Significantly more abnormalities were found in initially
thrombosed segments. The abnormalities were found in the proximal vein segments
and in the distal vein segments, although less frequently in the latter.
PMID- 9546233
TI - Overestimation of a stenosis in the internal carotid artery by duplex sonography
caused by an increase in volume flow.
AB - PURPOSE: The accuracy of duplex sonography in predicting the degree of an
internal carotid artery (ICA) stenosis is decreased when a contralateral high
grade stenosis or occlusion is present. The purpose of this study was to
determine whether this overestimation of the stenosis by duplex sonography is
associated with an increase in volume flow through the ipsilateral ICA. METHODS:
Forty-seven patients (89 vessels) with a symptomatic ICA stenosis or occlusion
who underwent duplex sonography, intraarterial digital subtraction angiography,
and magnetic resonance angiography flow quantification of the ICAs were
evaluated. RESULTS: With the use of peak systolic velocity criteria, duplex
overestimated stenoses more frequently (chi2: p = 0.03) in vessels with high
volume flow (= mean volume flow in control group + 2 SD (>274 ml/min), 46%
overestimation) than in vessels with normal or low volume flow (<274 ml/min, 20%
overestimation). A correlation coefficient of 0.75 (p < 0.001) was found between
volume flow and peak systolic velocity in the distal ICA, indicating that
increased volume flow causes the peak systolic velocity to increase. Compared
with volume flow in the control group (mean +/- SD = 198 +/- 38 ml/min), volume
flow was increased in vessels with a 0% to 49% stenosis (mean +/- SD = 272 +/-
100 ml/min, p < 0.05) and in vessels with a 50% to 69% stenosis (mean +/- SD =
291 +/- 79 ml/min, p < 0.01) when the contralateral ICA had a 70% to 99% stenosis
or occlusion. CONCLUSIONS: Increase in volume flow through the ICA frequently
causes overestimation of stenoses in the ICA. Increased volume flow is frequently
found in ICAs with a <70% stenosis that are contralateral to ICAs with a >70%
stenosis or an occlusion.
PMID- 9546234
TI - Validation of automated contour analysis of intravascular ultrasound images after
vascular intervention.
AB - PURPOSE: The purpose of this study was to determine the feasibility of automated
contour analysis of intravascular ultrasound images obtained after vascular
intervention. STUDY DESIGN: This was a descriptive study. METHODS: Intravascular
ultrasound images obtained from patients after balloon angioplasty (n = 10),
stent (n = 10), or stent graft placement (n = 10) were analyzed. A comparison was
made between lumen area measured with an automated and a manual system. The
location showing the smallest lumen area derived from the automated system was
compared with the smallest lumen area selected by visual estimation. RESULTS:
Images containing a dissection as a result of balloon angioplasty could not be
analyzed by the automated system. The coefficient of variation between the lumen
area measurements obtained with the automated system and the manual tracing
system of images with a stent (n = 76) or stent graft (n = 79) was 2.7% and 2.1%,
respectively. Correlation between the two systems was high (r = 1.00, p < 0.01)
both for images containing stents or stent grafts. Minimum lumen area measured
with the automated analysis system was smaller than minimum lumen area selected
by visual estimation (mean difference 0.8 mm2 (4.9%) for stents and 2.4 mm2
(10.9%) for stent grafts). The location of the smallest lumen area determined
with both systems was the same (<1 cm) in 16 cases and differed more than 1 cm in
4 other cases. CONCLUSIONS: The automated analysis system shows good agreement
with manual contour analysis of lumen area in images with a stent or stent graft
and is a reliable tool for determination of the smallest lumen area. The system
is not able to analyze an irregular-shaped lumen area caused by a dissection.
PMID- 9546235
TI - Human saphenous vein allograft bypass grafts: immune response.
AB - Although it has been claimed that allografts of blood vessels might be successful
because of minimal immunogenicity, they are subject to frequent and early
failure, the cause of which has not been thoroughly investigated. We sought to
define the immune response to allograft bypass. In a prospective trial, 40
patients underwent cryopreserved venous allograft bypass. Allograft biopsies were
performed at implantation and at allograft explantation in instances of graft
failure. Tissues were evaluated in a blinded manner by means of standard
histologic examination and paraffin immunohistochemical analysis with monoclonal
antibodies against a variety of immune markers. During the 31-month follow-up
period, 22 allografts were removed, and 19 were suitable for immunohistochemical
study. Of these 19, 6 (32%) had moderate or severe infiltrates, which were evenly
distributed throughout the intima, media, and adventitia. Immunohistochemical
study of the explants demonstrated all of these infiltrates to be leukocytes
(+LCA), which were predominantly activated T lymphocytes (+CD3, CD8, CR3)
containing cytotoxic granules (+TIA-1). Macrophages were uncommon (+CD68); B
cells (+L26, CD79) and natural killer cells (+CD56) were rare. Immunosuppression
was associated with decreased presence of cytotoxic granules (TIA-1). Human
venous allografts are immunogenic and prompt a T cell-mediated response.
Allografts also fail without strong evidence of rejection, presumably because of
local injury, hypercoagulability, or stasis. It may be possible to modify the
contribution of rejection to venous allograft failure by means of
immunosuppression and to modify the contribution of local hypercoagulability by
means of anticoagulation.
PMID- 9546236
TI - Genetic risk factor for abdominal aortic aneurysm: HLA-DR2(15), a Japanese study.
AB - PURPOSE: Autoimmunity has been proposed to play a role in the pathogenesis of the
abdominal aortic aneurysm (AAA). Several autoimmune diseases are associated with
specific HLA DR alleles. These experiments were carried out to determine whether
the same HLA DR types that have been reported to be associated with AAA in a
mixed North American population are similarly associated with AAA in a more
homogeneous group of patients in Japan. METHOD: HLA DR typing was performed by a
serologic method on samples of peripheral blood of patients with nonspecific
infrarenal AAA in Nagasaki University Hospital in Japan. The frequencies of HLA
DR antigens were compared with those of volunteers approximately matched for age
and sex from the same referral area. RESULTS: HLA DR haplotypes were determined
in 46 Japanese patients with AAA and in 50 patients in a control group. The HLA
DR2(15) antigen was observed in 27 (58.7%) patients (29 alleles 31.5%) with AAA
and in 14 (28%) subjects (16 alleles 26.0%) in the control group (p < 0.005).
CONCLUSIONS: The data suggest that HLA-DR2(15) has an important role as a genetic
risk factor for AAA in Japanese patients, as previously reported in a mixed North
American population.
PMID- 9546237
TI - In vitro evaluation of electrostatic endothelial cell transplantation onto 4 mm
interior diameter expanded polytetrafluoroethylene grafts.
AB - PURPOSE: To perform an in vitro evaluation of electrostatic endothelial cell
transplantation of human umbilical vein endothelial cells (HUVEC) onto segments
of 4 mm internal diameter expanded polytetrafluoroethylene (ePTFE) vascular
prostheses. METHODS: This evaluation consisted of exposing vascular graft
segments that had been subjected to either electrostatic or gravitation
transplantation with HUVEC to a physiologic shear stress (15 dynes/cm2) under
steady flow conditions within a flow loop system. Biochemical assays were
performed on freshly transplanted grafts by means of radioimmunoassay for
prostacyclin and thromboxane A2. RESULTS: There was a 30% loss of HUVEC after 30
minutes of shear stress exposure from the grafts subjected to gravitational
transplantation with no additional significant (alpha = 0.05) loss after 120
minutes. Grafts subjected to electrostatic transplantation had no significant
(alpha = 0.05) loss of HUVEC during exposure to physiologic shear stress.
Furthermore, after 120 minutes of shear-stress exposure, the grafts subjected to
electrostatic transplantation (78,420 +/- 6274 HUVEC/cm2) retained 2.3 times more
HUVEC than the counterparts subjected to gravitational transplantation (34,427 +/
4637 HUVEC/cm2). The biochemical assay results indicated no significant (alpha =
0.05) production of prostacyclin or thromboxane A2 regardless of the method of
cell transplantation. CONCLUSIONS: (1) The electrostatic transplantation
technique was superior to the gravitational transplantation technique in terms of
cellular retention when the ePTFE grafts were exposed to physiologic shear
stress. (2) Production of prostacyclin and thromboxane A2 did not differ between
transplanted HUVEC subjected to gravitational or electrostatic procedures.
PMID- 9546238
TI - Heparin inhibits thrombin-induced mitogen-activated protein kinase signaling in
arterial smooth muscle cells.
AB - PURPOSE: Smooth muscle cell proliferation is a key event in the development of
intimal hyperplasia after arterial injury. Heparin can suppress smooth muscle
cell proliferation in vitro and prevents intimal hyperplasia after arterial
injury, but the mechanisms of action are poorly understood. Recently, we observed
that heparin inhibited serum-induced activation of mitogen-activated protein
kinase in smooth muscle cells, but heparin did not inhibit signaling induced by
platelet-derived growth factor BB and basic fibroblast growth factor, both
ligands of tyrosine kinase receptors. Here, we examined the possibility that
heparin inhibits signaling by thrombin and other activators of heterotrimeric G
proteins. DESIGN OF STUDY: Baboon aortic smooth muscle cells were stimulated with
thrombin, angiotensin II, endothelin-1, and lysophosphatidic acid in the presence
or absence of heparin. After stimulation, mitogen-activated protein kinase
activity was measured with an in-gel phosphorylation assay, mitogen-activated
protein kinase kinase-1 was immunoprecipitated from the same samples, and
activity was measured with recombinant mitogen-activated protein kinase as a
substrate. DNA synthesis was measured by 3H-thymidine labeling and scintillation
counting. RESULTS: Heparin inhibited sustained activity of mitogen-activated
protein kinase kinase-1 and mitogen-activated protein kinase and prevented DNA
synthesis induced by thrombin, angiotensin II, endothelin-1, and lysophosphatidic
acid. CONCLUSIONS: Heparin inhibits growth of baboon smooth muscle cells by
preventing prolonged mitogen-activated protein kinase activation elicited by
ligands of seven transmembrane domain receptors and heterotrimeric G-proteins.
The results indicate that heparin interferes with a specific pathway in smooth
muscle cell growth, which could be a future target in attempts to inhibit lesion
development after vascular surgery.
PMID- 9546239
TI - Enhancement of tissue factor expression by vein segments exposed to coronary
arterial hemodynamics.
AB - PURPOSE: Although saphenous vein is the most reliable conduit for arterial
interposition procedures in the coronary circulation, graft thrombosis remains a
clinical problem. We hypothesized that an important factor in early graft
thrombosis is sudden change in the hemodynamic environment of the vein as it is
placed in the coronary circulation. METHODS: We used an ex vivo perfusion system
to study freshly excised segments of human saphenous vein (HSV) and pig internal
jugular vein. For coronary graft (CAVG) simulation, sections of HSV were
subjected to arterial pulsatile pressure and flow and twisting and stretching to
mimic deformations caused by the beating heart. Using functional and
immunohistochemical assays, we investigated the effect of these conditions on
expression of tissue factor (TF), an important prothrombotic surface molecule.
RESULTS: In each of 11 experiments (6 human, 5 porcine), vein segments from a
single donor were subjected to venous conditions (VEN), CAVG perfusion, or no
perfusion. Expression of TF was measured as the amount of factor Xa generated per
unit area of luminal vein surface. VEN perfusion did not cause a significant
change in mean TF expression over nonperfused control values (human: 14.3 +/- 1.5
versus 11.4 +/- 2.3 U/cm2, p = 0.31; pig: 11.6 +/- 1.5 versus 12.5 +/- 1.4 U/cm2,
p = 0.70). CAVG perfusion led to significant enhancement of TF expression over
VEN perfusion (human: 36.8 +/- 6.2 versus 14.3 +/- 1.5 U/cm2, p < 0.05; pig: 40.0
+/- 9.9 versus 11.6 +/- 1.5 U/cm2, p < 0.05). Immunohistochemical analysis showed
positive TF staining on the luminal side of a CAVG-stimulated HSV segment, but
not on a VEN-stimulated segment. In four additional studies, HSV segments were
subjected to arterial perfusion without twist and stretch to mimic lower
extremity arterial interposition grafts. TF expression for lower extremity venous
graft perfusion was significantly higher than for VEN perfusion (25.3 +/- 2.5
versus 14.3 +/- 1.5, p < 0.01) but not significantly different from CAVG
perfusion. CONCLUSIONS: Our studies in a unique perfusion system suggest that
exposure of vein to coronary arterial hemodynamic conditions results in elevated
expression of the important prothrombotic molecule TF. This phenomenon may
contribute to early graft thrombosis.
PMID- 9546240
TI - Functional activity and transmembrane signaling mechanisms after cryopreservation
of human internal mammary arteries.
AB - PURPOSE: Cryopreserved human blood vessels are important tools in bypass surgery.
However, several in vitro studies have demonstrated diminished postthaw
functional activity. Therefore the aim of this study was to investigate the
consequences of various freezing/thawing protocols and the role of protein kinase
C in the postthaw functional activity of cryopreserved human arteries. METHODS:
In vitro responses of frozen/thawed human internal mammary arteries (IMA) were
used to investigate the functional activity after thawing at 15 degrees, 30
degrees, and 100 degrees C/min and after different prefreezing equilibration
times (10, 60, 120, 240 minutes) with the cryomedium (Krebs-Henseleit solution
containing 1.8 mol/L dimethyl sulfoxide and 0.1 mol/L sucrose) at room
temperature followed by cryostorage at -196 degrees C. RESULTS: Prefreezing
equilibration for 10 to 120 minutes diminished maximal alpha-adrenoceptor
mediated responses to noradrenaline to approximately 60%, and equilibration for
240 minutes attenuated noradrenaline effects to less than 25% of that produced by
unfrozen controls. Contractile responses were slightly better when thawing was
performed at 15 degrees C/min compared with 100 degrees C/min. The postthaw
sensitivity to direct activation of protein kinase C by phorbol 12,13-dibutyrate
was enhanced. Compared with unfrozen tissues (pD2 = 7.36 +/- 0.07, n = 32)
maximal sensitization to phorbol 12,13-dibutyrate was observed in IMA that had
been frozen after 60 minutes of equilibration with the cryomedium (pD2 = 8.31 +/-
0.09, n = 30). Responses to phorbol 12,13-dibutyrate of cryopreserved IMA were
highly susceptible to blockade of calcium influx by nifedipine, whereas those of
unfrozen IMA were resistant to nifedipine. Against noradrenaline nifedipine was
equipotent in cryopreserved (pD'2 = 7.75 +/- 0.15, n = 8) and unfrozen IMA (pD'2
= 7.70 +/- 0.10, n = 6). Endothelium-dependent relaxant responses to
acetylcholine were significantly attenuated after cryopreservation (Emax = 26% +/
5%, n = 4) compared with unfrozen IMA (Emax = 71% +/- 4%, n = 4, p < 0.001);
endothelium-independent relaxant responses to sodium nitroprusside were
unchanged. CONCLUSIONS: Cryopreservation of human IMA under the conditions
applied in this study (1) attenuated endothelial cell function and (2) induced an
activation of protein kinase C, thereby increasing calcium influx through
dihydropyridine-sensitive calcium channels. These experimental data suggest that
postoperative administration of calcium channel blockers alone or combined with
long-acting nitrates should effectively prevent the development of spasms in
arterial grafts.
PMID- 9546241
TI - Acute traumatic rupture of the thoracic aorta: delayed treatment with endoluminal
covered stent. A report of two cases.
PMID- 9546242
TI - Iliac and femoral artery occlusion by thromboemboli from an abdominal aortic
aneurysm in the setting of blunt abdominal trauma.
AB - The abdominal aorta is injured infrequently in blunt trauma to the abdomen. When
injury does occur, aortic rupture, dissection, and traumatic aneurysm most
commonly result. An aneurysmal abdominal aorta would appear to be at increased
risk for injury from blunt abdominal trauma. This case report appears to be the
first description of iliac and femoral artery occlusion by thromboemboli
dislodged from an atherosclerotic abdominal aortic aneurysm at the time of a
motor vehicle accident. We believe that this peripheral embolization was caused
by direct compression of the abdominal aortic aneurysm by a seatbelt.
PMID- 9546243
TI - Subclavian artery pseudoaneurysm in type IV Ehlers-Danlos syndrome.
AB - We report case of a subclavian artery pseudoaneurysm in a patient with type IV
Ehlers-Danlos Syndrome. A 16-year-old boy underwent successful repair of a
subclavian artery pseudoaneurysm that occurred after a cervical hyperextension
injury. Subsequent workup included skin biopsy and fibroblast culture, which were
consistent with a diagnosis of type IV Ehlers-Danlos Syndrome. This condition is
a dominantly inherited connective tissue disorder, which in this patient was
found to be caused by a spontaneous point mutation in the COL3A1 gene that
encodes the chains of type III procollagen. The clinical, genetic, and molecular
characteristics of type IV Ehlers-Danlos Syndrome are briefly reviewed.
PMID- 9546244
TI - Successful delayed bilateral renal revascularization during active phase of
Takayasu's arteritis.
AB - Successful bilateral renal revascularization was performed 24 days after the
development of angiotensin converting enzyme-inhibitor-induced bilateral renal
artery thrombosis and anuric acute renal failure in a patient with Takayasu's
arteritis. Excellent results were obtained after an unusually long ischemic time
for a patient with active-phase disease. The outcome suggests that aggressive
surgical revascularization can benefit patients with renal failure caused by
renal arterial occlusion during the active phase of Takayasu's arteritis.
PMID- 9546245
TI - Primary aortic intimal sarcoma of the endothelial cell type with long-term
survival.
AB - Primary tumors of the aorta are rare and are difficult to diagnose
preoperatively. These tumors are malignant and ultimately fatal. A patient had
initial evidence of aortoiliac obstructive disease. Aortic endarterectomy
produced an excellent postoperative clinical result until the pathology report
from the endarterectomy specimen revealed aortic sarcoma. The patient refused a
second operation for en bloc aortic resection. One year later with recurrent
symptoms, the patient underwent en bloc resection of the aorta and common iliac
vessels until clear margins were obtained. The tumor was found to be intimal
aortic sarcoma of endothelial cell origin. The only metastasis was to bone, and
it was controlled with radiation and chemotherapy. The patient lived a total of 8
years from the time of initial diagnosis. Abdominal aortic intimal sarcoma of the
endothelial cell type is a rare variety of aortic sarcoma that can be managed
successfully if diagnosed early. This specific type of tumor has a longer
survival period and better prognosis than other types of aortic sarcoma when
managed with aggressive surgical resection, radiation, and chemotherapy.
PMID- 9546246
TI - Superior mesenteric arterial occlusion from a leiomyoma.
AB - We report a solitary leiomyoma of the superior mesenteric artery resulting in
arterial occlusion and gangrenous bowel. On histologic evaluation the lesion
extended into the vessel lumen off its stalk and showed immunostaining for smooth
muscle antigen and desmin. Leiomyomas can arise anywhere there is smooth muscle
and occur most commonly in the uterus followed by the skin and gastrointestinal
tract. We could not identify any previous case in the literature of a leiomyoma
arising from within the wall of a mesenteric vessel.
PMID- 9546247
TI - Spontaneous tibial artery thrombosis associated with varicella pneumonia and free
protein S deficiency.
AB - Pneumonia is the most common serious complication of varicella infection in
adults. A variety of thrombotic complications including purpura fulminans and
disseminated intravascular coagulation have been reported in children with
varicella but not in adults. Two men with varicella pneumonia who had profound
lower extremity ischemia caused by thrombosis of the profunda femoris and tibial
arteries are reported. Both patients had free protein S deficiency and vascular
thrombosis in association with varicella pneumonia without overt evidence of
disseminated intravascular coagulation or purpura fulminans. Antiphospholipid
immunoglobulin G and immunoglobulin M antibodies were present in one, whereas the
other had evidence of the lupus anticoagulant. The proposed pathogenesis and
management options including intraarterial thrombolytic therapy with urokinase
and the need for long-term anticoagulation are discussed.
PMID- 9546248
TI - Intraoperative monitoring of danaparoid sodium anticoagulation during
cardiovascular operations.
AB - PURPOSE: Patients with cardiovascular disorders frequently need anticoagulation
for diagnostic studies, surgical procedures, and therapy. Heparin-induced
thrombocytopenia is a relatively common complication of heparin therapy that can
result in thrombosis and subsequent limb loss or death, necessitating use of
alternative anticoagulants. METHODS: Two patients who needed cardiac surgery had
thrombocytopenia induced by exposure to heparin and heparin-coated tubing.
Several assays were examined for their ability to monitor intraoperative
anticoagulation of a factor Xa inhibitor, danaparoid sodium. RESULTS: In vitro,
celite and kaolin activated dotting times and activated partial thromboplastin
time were prolonged linearly in the presence of increasing concentrations of
danaparoid sodium. Aprotinin did not alter the linearity of the response but did
alter its slope. In vivo, activated clotting times and activated partial
thromboplastin time were insensitive to clinically significant changes in
danaparoid sodium plasma levels during cardiopulmonary bypass. Correction in
activated partial thromboplastin time lagged 2 hours behind clinically important
changes in anti-factor Xa levels. Only anti-factor Xa levels were adequate to
monitor intraoperative danaparoid sodium levels. CONCLUSION: Anticoagulation for
cardiopulmonary bypass can be successfully performed with danaparoid sodium and
intraoperative anti-factor Xa monitoring.
PMID- 9546249
TI - A new surgical approach to the innominate and subclavian vein.
AB - A new technique extending the incision used for thoracic outlet decompression
with a subclavicular approach to the first rib is presented. After the first rib
and scalenotomy are removed, the subclavicular incision is continued into the
sternum medially and superiorly to the sternal notch. This gives easy access to
the innominate-subclavian-axillary vein segment. Eight patients with extensive
chronic fibrotic obstruction of the subclavian-innominate vein segment underwent
operation with this technique. It allows placement of either long patches of
saphenous vein to reestablish normal caliber or replacement, as is our choice,
with a small-sized cryopreserved descending thoracic aortic homograft. The
operation is carried out in an extrapleural plane preserving the sternoclavicular
joint, avoiding the deformity caused by transclavicular techniques. Repair of the
sternotomy creates a stable incision. Follow-up to 14 months shows patency of the
venous channel with no complications. This surgical approach is recommended to
solve the problem of satisfactory exposure of the subclavian-innominate venous
channel after decompression of the thoracic outlet.
PMID- 9546250
TI - Technique for obtaining proximal intraluminal control when arteries are
inaccessible or unclampable because of disease or calcification.
AB - When proximal arterial control cannot be obtained by standard methods, it may be
achieved safely and bloodlessly by intraluminal routes with balloon catheters,
hemostatic sheaths, and catheter-guide wire techniques. This method was used
successfully in 20 patients to achieve proximal arterial control without
complications in a variety of locations. Use of this method or its modifications
may facilitate and simplify a variety of vascular operations that would otherwise
be difficult or hazardous.
PMID- 9546251
TI - Regarding "Detection of active cytomegalovirus infection in inflammatory aortic
aneurysms with RNA polymerase chain reaction".
PMID- 9546252
TI - Use of an internal saphenous varicose vein covered by a polytetrafluoroethylene
prosthesis in a femoropopliteal bypass graft.
PMID- 9546253
TI - Ultrasound-guided interstitial Nd: YAG laser treatment of voluminous hemangiomas
and vascular malformations in 92 patients.
AB - In many cases voluminous vascular anomalies of the head and neck region are still
treated with conventional surgery, although neodymium:yttrium-aluminum-garnet
(Nd:YAG) laser therapy offers a valuable treatment alternative. Ninety-two
patients with voluminous hemangiomas and vascular malformations were treated with
interstitial Nd:YAG laser therapy (power density, 1300 to 3300 W/cm2), partly
complemented by a noncontact-mode Nd:YAG laser light application (energy density,
1000 to 2500 J/cm2). The vascular tumors had a diameter of more than 3 cm in at
least two dimensions. Treatment was carried out under ultrasound and manual
control. Nearly 60% of the patients (n = 55) showed a complete clinical
regression. Thirty-three patients (35.8%) had a partial regression and were
satisfied with the treatment outcome. Four patients were treated unsuccessfully
with the laser, and three of them subsequently underwent conventional surgery.
Only nine of the 92 patients (9.8%) showed cosmetic or functional impairments.
The results of this first consecutive series study with a retrospective clinical
evaluation of the interstitial Nd:YAG laser therapy of voluminous hemangiomas and
vascular malformations in a large patient group demonstrate a high effectiveness
of this novel therapy modality.
PMID- 9546254
TI - Diagnosis of head and neck precancerous lesions in an animal model using
fluorescence spectroscopy.
AB - Laser-induced fluorescence (LIF) of tissues depends on their biochemical and
histomorphologic characteristics. LIF spectroscopic properties of 9,10-dimethyl
1,2-benzanthracene (DMBA)-induced precancerous and early cancerous lesions in a
hamster buccal pouch mucosa model were studied. Fluorescence spectra from
neoplastic lesions showed a characteristic fluorescence peak in the red region of
the visible spectrum centered between 630 and 640 nm when excited with 410-nm
light. Using this as a diagnostic criterion, 45 of 49 lesions studied were
correctly diagnosed, including early dysplastic lesions. Follow-up study of four
dysplastic lesions over 2 weeks revealed an increase in red fluorescence
intensity. The findings of these experiments suggest that LIF spectroscopy may be
a valuable noninvasive technique not only for early diagnosis of head and neck
cancer, but also to probe a possible biochemical surrogate biomarker in the
follow-up of suspected lesions.
PMID- 9546255
TI - Reconstruction after temporal bone resection.
AB - Reconstruction of soft tissue defects after temporal bone resection can vary from
simple closure of the external auditory canal to complex flap coverage of
extensive defects. Between 1987 and 1996, 34 patients underwent lateral skull
base resections and reconstruction for invasive carcinoma of the temporal bone.
Seven underwent sleeve resection and/or radical mastoidectomy. Sleeve resection
was managed with tympanoplasty, canalplasty, or obliteration of the external
auditory canal (10). There were 24 lateral temporal bone resections and four
subtotal temporal bone resections. Larger defects created by lateral and subtotal
temporal bone resections required closure with a combination of temporalis flaps
and local rotational cutaneous flaps (13). Lower island trapezius flaps (five),
free flaps (four), and pectoralis major flaps (two) were also used. Indications
and efficacy of each method are discussed, and treatment outcomes are presented.
PMID- 9546256
TI - Combining free flap reconstruction and craniofacial prosthetic technique for
orbit, scalp, and temporal defects.
AB - OBJECTIVES: To identify factors leading to successful application of prosthetic
techniques following free flap reconstruction of the orbit, scalp, and temporal
region. STUDY DESIGN: Retrospective review. METHODS: Twenty-eight patients who
underwent free flap reconstruction for defects of these regions between 1989 and
1996 were reviewed for clinical parameters, flap loss, patient survival, and
implant loss rate. Prosthetic usage rates were compared before and after
introduction of a site-specific reconstructive algorithm. RESULTS: Free flap
success rate was 93%, whereas osseointegrated implant loss rate was 11%. In
addition to implants, a reconstructive strategy that provided thin, vascular
tissue between bone and skin, a flat platform in the temporal region, and
preservation of orbital cavity depth led to increased prosthetic usage.
CONCLUSIONS: Craniofacial prosthetic techniques can significantly augment the
results of free flap surgery for the orbit, scalp, and temporal region.
Successful combination of these techniques requires a site-specific surgical
approach.
PMID- 9546257
TI - Interactive magnetic resonance imaging-guided biopsy in the head and neck:
initial patient experience.
AB - Because of its excellent soft tissue resolution, magnetic resonance imaging (MRI)
can optimize image guidance for interventional and surgical procedures. Notably,
needle biopsy of head and neck lesions has been used for years, deeper lesions
often requiring some form of image guidance. The closed space of diagnostic MRI
scanners proves cumbersome for intervention. The authors report on the first head
and neck image-guided biopsies performed in a new, investigational "open
configuration" intraoperative MRI scanner. Vertical space between the scanner's
upright coils gives access to the patient while imaging; image acquisition is as
fast as 2 sec/image. Biopsies were performed on seven patients (parotid,
parapharyngeal space, second cervical vertebra); five specimens were diagnostic.
Both general anesthesia and intravenous sedation were used. The procedures were
without complications. Imaging provided definition of anatomy to direct needle
placement. Access to the patient allowed for both percutaneous and transoral
approaches. The environment of the open magnet is well suited for biopsy of the
head and neck, and near real-time intraoperative MRI has promise for guiding more
complex head and neck procedures. Further study should optimize the quality of
the images and the interactibility of localization and targeting and fully
utilize MRI's three-dimensional imaging capabilities.
PMID- 9546258
TI - Relative accuracy of fine-needle aspiration and frozen section in the diagnosis
of well-differentiated thyroid cancer.
AB - The need for and extent of thyroid surgery for a thyroid nodule is usually
primarily based on fine-needle aspiration (FNA) and frozen section diagnosis. The
relative role of these modalities in 66 patients who had undergone FNA and
subsequent thyroidectomy with frozen section was investigated. Cases that
demonstrated discordance between FNA and frozen section (n = 22; 33%) were
identified, and all slides were re-reviewed by a cytopathologist using current
established cytologic criteria. A change in diagnosis was made in 13 cases with
an increase in accuracy of FNA from 71% to 88%. The accuracy of frozen section
(92%) did not change appreciably with re-review (94%). The accuracy of FNA and
frozen section combined was found to be 98%. The rate of discordance decreased
from 33% to 13% with re-review. When strict histologic and cytologic criteria are
applied, FNA and frozen section are accurate and complementary methods that help
in determining the operative management of thyroid masses. However, when FNA
yields a diagnosis of "follicular neoplasm," frozen section is unlikely to change
this diagnosis.
PMID- 9546259
TI - Identification of p53 and human papilloma virus in Schneiderian papillomas.
AB - Schneiderian papilloma of the nose is an unusual neoplasm with the propensity for
local tissue destruction, recurrence, and malignant degeneration. Human papilloma
virus (HPV) is related to a subset of sinonasal papillomas and has been
implicated in the pathogenesis of cancer by interaction with the host p53
protein. Detection of p53 and HPV could be clinically useful as tumor markers for
lesions with oncogenic potential. Thirty specimens for p53 were studied and nine
(30%) stained positive. HPV was detected in six (20%). In the presence of p53, an
odds ratio for carcinoma was 1.19:1, or 19% higher than expected. In the presence
of HPV the odds ratio for carcinoma was 11.5:1, or 11.5 times higher than
expected. In the presence of HPV an odds ratio for finding an elevated amount of
p53 was 2.2:1. The data support the hypothesis that HPV and p53 may interact in a
novel manner and elevate the risk for neoplasia.
PMID- 9546261
TI - Identification of obstructive sleep apnea in patients who snore.
AB - As the field of sleep medicine has evolved, the clinical implications of
obstructive sleep apnea (OSA) in snoring patients have become well accepted.
Recent advances in surgical therapy for snoring allow otolaryngologists to offer
simple outpatient treatment to patients with this problem. However, because the
incidence of OSA in snorers seeking medical attention is unknown, the appropriate
pretreatment evaluation of these patients is a subject of continued debate.
Ninety-four snoring patients were recruited for a study to determine the
incidence of OSA in this highly selected population. Subjects answered an
extensive sleep questionnaire to determine factors that might suggest a diagnosis
of OSA. Level III ambulatory sleep studies were performed on each participant.
The incidence of OSA in this group was 72% (42% severe and 30% mild to moderate).
Twenty of the subjects with OSA also underwent formal level I sleep studies, and
the diagnosis of OSA was confirmed in each instance. Although there was a
relationship between body mass index and OSA and certain questions correlated
with OSA, the sensitivity and specificity of these data alone or in combination
were too low to recommend their use in lieu of a formal sleep study. Given the
remarkably high incidence of OSA in this group, which may reflect that seen by
otolaryngologists who treat snoring, a sleep study should be performed to
diagnose OSA and institute therapy for this condition. Level III ambulatory
monitoring devices may be the most cost-effective alternative for evaluating this
high-risk population.
PMID- 9546260
TI - Histology and histomorphometry of ethmoid bone in chronic rhinosinusitis.
AB - Mucosal changes have been well described in chronic sinusitis, yet little is
known about the underlying bone, despite clinical and experimental evidence
suggesting that bone may be involved in chronic sinusitis. Techniques of
undecalcified bone analysis were used for detailed histologic examination of
ethmoid bone in chronic sinusitis compared with controls. Bone synthesis,
resorption, and inflammatory cell presence were specifically assessed.
Additionally, histomorphometry techniques were used to determine ethmoid bone
physiology in individuals undergoing surgery for chronic sinusitis. Overall,
individuals undergoing surgery for chronic sinusitis were found to have evidence
of marked acceleration in bone physiology with histologic changes including new
bone formation, fibrosis, and presence of inflammatory cells. These findings are
compared with osteomyelitis in long bone and the jaw. The suggestion that
underlying bone may serve as a catalyst for chronic sinusitis is supported and
implications for therapy are discussed.
PMID- 9546262
TI - Influence of size and etiology of glottal gap in glottic incompetence dysphonia.
AB - This study investigates the relationship between glottal gap and vocal function
in patients with glottic incompetence dysphonia. Twenty patients with vocal fold
paralysis (VFP), 17 patients with vocal fold atrophy (VFA), and five patients
with sulcus vocalis (SV) were examined. Glottal gap area at the most closed point
of vibration was measured using digitized videostroboscopic images. Glottal gap
area was correlated with acoustic and aerodynamic measures of vocal function.
Patients with VFP had the largest glottal gaps and had significantly worse vocal
function than did the patients with VFA or SV. Regardless of groups, however,
where glottal gap size was similar, there was no difference in vocal function.
Therefore vocal function was mainly influenced by glottal gap size, not by
whether glottic incompetence was the result of VFP, VFA, or SV.
PMID- 9546264
TI - Lipoperoxidation as a measure of free radical injury in otitis media.
AB - Free radical damage, as evidenced by lipoperoxidation, has previously been
demonstrated to contribute to the inflammatory changes associated with acute
otitis media. The present study was undertaken to evaluate whether
lipoperoxidation continues to be present for a period of time after middle ear
infection. Eighty-two 300- to 400-g guinea pigs were injected with Streptococcus
pneumoniae in the left ear and sterile saline in the right ear as a control.
Animals were examined and sacrificed on day 5, 10, 20, or 30; middle ear mucosa
was harvested and assayed for lipid hydroperoxide content. A statistically
significant increase in lipoperoxidation was seen at each time point studied,
compared with controls. Lipoperoxidation was highest at days 5 and 10; a
significant decrease was seen at days 20 and 30. Histologic sections of middle
ear mucosa of two animals per group were prepared and evaluated for inflammation.
These results demonstrate that lipoperoxidation may contribute to middle ear
inflammation for a significant period of time after acute infection; the findings
are discussed in light of other work on the role of free radicals in otitis
media.
PMID- 9546263
TI - Pediatric bilateral facial paralysis.
AB - Bilateral facial paralysis is an unusual clinical entity that occurs in less than
1% of patients with facial paralysis. In children bilateral facial paralysis is
even more rare, and establishing its etiology can be challenging. Four pediatric
patients ranging in age from 3 to 17 years are presented who developed bilateral
facial paralysis as a result of acute otitis media, Lyme disease, recurrent
central nervous system leukemia, and acute disseminated encephalomyelitis. The
diagnosis and treatment of pediatric bilateral facial paralysis are reviewed, as
well as the pertinent literature.
PMID- 9546265
TI - Hearing results with the Dornhoffer ossicular replacement prostheses.
AB - The "ideal" prosthesis for ossicular reconstruction should, from a surgical
standpoint, require easy manipulation, reduce surgeries to partial or total
variants, and be constructed of stable, biocompatible material. From an acoustic
standpoint, a prosthesis should weigh 10 to 40 mg, provide proper tension between
the tympanic membrane (TM) and stapes, form less than a 30-degree angle with the
TM, and accommodate the malleus. Work was conducted with Smith & Nephew Richards,
Inc. (Memphis, TN), to develop a partial ossicular replacement prosthesis (PORP)
and a total ossicular replacement prosthesis (TORP) that combined the majority of
these features. This retrospective study used a computerized otologic database to
identify patients implanted with a Dornhoffer HAPEX PORP or TORP from June 1995
to March 1997. The surgical procedures utilizing these prostheses were primary
cholesteatoma and revision surgery of previously performed modified or radical
mastoidectomies complicated by poor hearing or chronically draining cavities.
Preoperative and postoperative air and bone conduction four-frequency (500, 1000,
2000, and 3000 Hz) pure-tone averages (PTAs) were used to calculate the PTA air
bone gaps (ABGs). Results in 52 cases (follow-up, 1 year) showed a statistically
significant improvement in hearing (P < 0.05) for each group. Excellent hearing
results (< or = 10 dB PTA-ABG) were seen in 69% of PORP cases and in 35% of TORP
cases, and good results (11 to 20 dB PTA-ABG) were seen in 31% and 50% of PORP
and TORP cases, respectively. Designing an ossicular replacement prosthesis with
both surgical and acoustic factors in mind has led to encouraging short-term
hearing results.
PMID- 9546266
TI - A study on epidermal proliferation ability in cholesteatoma.
AB - With the objective of estimating proliferation ability of epidermis of middle ear
cholesteatoma, the difference in proliferating cell nuclear antigen (PCNA)
staining between the skin of the bone region of the external ear canal (control
skin) and cholesteatoma epidermis and the effects on PCNA staining of
subepidermal inflammatory cell infiltration of cholesteatoma were
immunohistochemically studied using an antibody against PCNA. Transforming growth
factor-alpha (TGF-alpha) is known to promote epidermal proliferation based on
autocrine mechanism. But it is not clear that cholesteatoma epidermis is actually
in the state of hyperproliferation under the effect of this growth factor. To
estimate the effect of TGF-alpha on epidermal proliferation ability, the authors
compared the location of PCNA and TGF-alpha in the same specimen. Unlike the
control skin, not only epidermal basal cell layer and suprabasal cell layer, but
also more superior layers were found to have high levels of PCNA staining in the
epidermis of cholesteatoma. However, in the same cholesteatoma epidermal tissue,
the PCNA staining was varied and the difference was ascribable to subepidermal
cell inflammation. It appeared that the proliferation ability was high in regions
where subepidermal inflammatory cell infiltration was severe. These differences
in microenvironment are inferred to greatly affect proliferation ability of
cholesteatoma epidermis.
PMID- 9546268
TI - Audiometric results of bilateral bone-anchored hearing aid application in
patients with bilateral congenital aural atresia.
AB - The effect of bilateral application of bone-anchored hearing aids (BAHAs) was
examined in terms of directional hearing and speech recognition in quiet and in
noise in four patients with bilateral congenital atresia who, out of pure
necessity, had been using a unilateral bone-conduction hearing aid since early
life. This study comprised a prospective clinical evaluation in a single subject
design; four patients with bilateral congenital atresia originating from the
Nijmegen BAHA series participated. Three patients had Treacher Collins syndrome.
All four patients had conductive, most probably, symmetrical, hearing loss.
Recently these patients had applied for a second BAHA and were subsequently
fitted bilaterally. With two BAHAs, all four patients showed significant
improvement in sound localization. Also, speech perception in quiet showed
significant improvement with bilateral application, and a significant improvement
was found in speech perception in noise in three patients. These results suggest
that patients with congenital conductive, symmetrical hearing loss will benefit
from bilateral BAHAs.
PMID- 9546267
TI - Effect of intratympanic steroid application on the development of experimental
cholesteatoma.
AB - By introducing certain irritants into the middle ear it is possible to produce
cholesteatoma. Propylene glycol, the main agent used for this purpose, produces a
long-standing inflammation that causes hyperplasia and migration of the
epithelium through an intact tympanic membrane. In the present investigation
topical prednisolone was used in order to inhibit the production of
cholesteatoma. The results indicate that there is a marked decrease in
inflammation and hence experimental cholesteatoma production when prednisolone is
administered into the middle ear.
PMID- 9546269
TI - Correlation between electrical auditory brainstem response and perceptual
thresholds in Digisonic cochlear implant users.
AB - OBJECTIVES: To examine the relationships between psychophysical perceptions and
the electrically evoked auditory brainstem responses (EABRs) in multichannel
cochlear implant (CI) users and to determine the effectiveness of EABRs in
electrode failure. DESIGN: A descriptive study reported the EABR characteristics
while the different electrodes were activated. Characteristics of the EABR and of
the perceptual measures served as compared variables in a correlational study.
SETTING: The study was carried out in the audiology clinic of an otolaryngology
department at a university hospital. PATIENTS: The subjects consisted of nine
consecutively selected habitual Digisonic DX1OR multichannel CI users. Seven
patients were postlinguistically deafened adult patients; two were congenitally
deaf children. MAIN OUTCOME MEASURES: Ipsilateral recordings were performed using
a previously published method. Morphology, latency, and amplitude measures of the
EABR recordings were described, computed, and compared with the literature data
for EABRs obtained while activating other types of CI and for acoustically evoked
ABRs. Correlations between EABRs and behavioral perception thresholds were
analyzed using the parametric Pearson's correlation test. RESULTS: EABRs allowed
the authors to detect failure of no. 10 electrode integrity in one child.
Perceptual threshold measures were found to be highly significantly related to
the EABR threshold across subjects and electrode position (n = 31, r = 0.98; P <
0.001; linear regression equation: perceptual threshold = 1.06 EABR threshold +
0.76). The latencies and amplitudes were found to be similar to those described
in the literature. CONCLUSIONS: EABRs may be used to estimate settings for the
Digisonic DX10 CI even in a pediatric population, although they cannot entirely
replace behavioral measurements, especially in children. The EABR can be employed
for electrode dysfunction diagnosis. Further studies are needed to determine
whether recordings of EABR quality could contribute to the evaluation of
functional prognosis during the rehabilitation.
PMID- 9546270
TI - Optimization of speech processor fitting strategies for Chinese-speaking cochlear
implantees.
AB - OBJECTIVES: To compare speech recognition performance in Chinese-speaking
cochlear implant patients with a speech processor program selected by the
clinical audiologist in Taiwan and with a new speech processor program based on
the Washington University clinical procedure developed by Skinner et al. STUDY
DESIGN: Six adult Chinese-speaking patients implanted with the Nucleus cochlear
implant system participated in this study. METHODS: A fitting procedure developed
in 1995 by Skinner et al. at Washington University School of Medicine was used to
create a new speech processor program to optimize each patient's hearing in
everyday life. Speech tests (vowels, consonants, tones, and words), sound-field
thresholds, and a self-report questionnaire were used to evaluate each patient's
performance with his or her previous speech processor program and a new one.
RESULTS: Four of the six patients had significant changes from the previous to
the new speech processor program. These changes were associated with improvement
in score on at least one speech test, more sensitive sound field thresholds, and
reported improvement in some everyday listening situations on the questionnaire.
CONCLUSIONS: These results suggest that use of this procedure with adult cochlear
implantees may improve benefit in everyday life. Analysis of the speech test
stimuli and patients' responses provides a basis for modification or creation of
new Mandarin Chinese speech tests for preoperative and postoperative evaluation
of adult cochlear implant patients.
PMID- 9546271
TI - Short- and long-term results of stapedectomy in children.
AB - Studies have indicated that stapedectomy can be an effective procedure in
children for correcting conductive hearing losses due to juvenile otosclerosis.
However, because childhood otosclerosis is rare and children commonly choose to
use hearing aids in lieu of undergoing surgery, little outcome data are
available. The purpose of this retrospective study was to provide additional
outcome data in both the short and the long term. Stapedectomies were performed
on 47 children. Preoperative hearing results were compared with 6-month
postoperative hearing results. Hearing results for the children who had long-term
follow-up (5 years or more) were compared with the 6-month postoperative results.
Stapedectomy was successful (postoperative air conduction pure-tone average [PTA]
within 10 dB of the preoperative bone conduction PTA) in 91.7% of the cases. The
mean overclosure of the preoperative bone conduction PTA by the postoperative air
conduction PTA was 0.2 dB. The mean PTA hearing improvement was 32.8 dB. Results
from the 21 children (28 ears) who had long-term follow-up indicated an average
0.7 dB/year PTA worsening from the 6-month postoperative PTA. Results from this
study provide additional evidence that stapedectomy can be an effective procedure
for correcting conductive hearing losses due to juvenile otosclerosis.
PMID- 9546272
TI - Idiopathic facial paralysis: a randomized, prospective, and controlled study
using single-dose prednisone versus acyclovir three times daily.
AB - In a prospective, controlled, and randomized study, we compared the outcome of
101 Bell's palsy patients treated with acyclovir (54 patients) or prednisone (47
patients). The acyclovir dosage was 2400 mg (800 mg three times a day) for 10
days, and prednisone was given as a single daily dose of 1 mg/kg of body weight
for 10 days and tapered to 0 over the next 6 days. Minimum follow-up was 3 months
in all patients. Patients in the prednisone group had better clinical recovery
than those treated with acyclovir. Less degree of neural degeneration was
observed in the prednisone group compared with acyclovir patients. The incidence
of sequelae was the same in both groups. According to these results, in a 10-day
treatment cycle acyclovir given 800 mg three times is not as useful as prednisone
given 1 mg/kg of body weight once a day in patients with idiopathic facial nerve
paralysis.
PMID- 9546273
TI - Blood distribution in the facial nerve in temporal bones acquired from cases with
subarachnoid hemorrhage.
AB - The objectives of this study, conducted in eight temporal bones from five
autopsied cases of subarachnoid hemorrhage, were to delineate the communication
between the cerebrospinal fluid space and each space of the epineurium,
perineurium, and area surrounding the nerve fibers in the facial nerve and to
identify the site of hypertonic diuretic solution infusion most likely to
decrease the facial nerve swelling at the initial stage of facial palsy. In all
eight specimens, blood cells had directly entered into each space from the
labyrinthine segment of the facial nerve. The subarachnoid space extended to the
first genu of the nerve. The genu, which is the site of the initial lesion in
Bell's palsy, is concluded to be the most effective site of intracanal
decompression of the facial nerve with hypertonic diuretic solution.
PMID- 9546274
TI - Mitochondrial DNA deletion is a predisposing cause for sensorineural hearing
loss.
AB - Composed of a postmitotic stable tissue, the inner ear is a target organ for
mitochondrial DNA (mtDNA) mutation. To determine whether mtDNA mutation is a
predisposing factor in patients with sensorineural hearing loss (SNHL), the
authors assessed the mtDNA4977 deletion from 60 patients with SNHL and 47 normal
control subjects. All cases had no past history of ototoxic or noise exposure,
middle ear disease, or other known etiological factors for SNHL. DNA specimens
extracted from peripheral blood leukocytes were used for detection of mtDNA4977
deletion by polymerase chain reaction. Patients with SNHL had a significantly
higher rate of the mtDNA4977 deletion than did controls (75% vs. 30%, P <
0.0001). The detection rate of mtDNA4977 deletion was significantly increased
with the deterioration of the hearing threshold. Aging did not influence the
detection rate of mtDNA4977 deletion in either the control or SNHL group. The
authors have described high detection rates of the mtDNA4977 deletion in patients
with idiopathic bilateral SNHL and propose that at least some of the advanced
SNHL cases should be categorized as mitochondrial oxidative phosphorylation
diseases. This inference would offer novel possibilities for treatment and
prevention of SNHL including presbycusis.
PMID- 9546275
TI - Changes in immunostaining of inner ears after antigen challenge into the scala
tympani.
AB - To study the mechanisms of immune responses and immune injuries in inner ears,
labyrinthitis was induced by inoculation of keyhole limpet hemocyanin (KLH) into
the scala tympani of systemically sensitized guinea pigs. Inner ears were then
immunostained for KLH, immunoglobulin G (IgG), albumin, connexin26 (Cx26), and
sodium-potassium adenosine triphosphate (Na,K-ATPase). Inflammatory cells
containing KLH were observed in the scala tympani and in the collecting venule of
the spiral modiolar vein (SMV). Spiral ligament, spiral limbus, and blood vessels
including the SMV were diffusely positive for IgG and albumin. Immunoreactivity
for Cx26 and Na,K-ATPase was decreased compared with the normal ears in the
fibrocytes of the spiral ligament. These results suggest that inflammatory cells
and blood constituents could extravasate into the cochlea from blood vessels and
that fibrocyte damage in the spiral ligament could cause cochlear dysfunction.
PMID- 9546276
TI - Effect of locally applied drugs on the endolymphatic sac potential.
AB - In Meniere's disease, an inner ear disorder related to an endolymphatic hydrops,
an alteration of the functioning of the endolymphatic sac has been proposed. The
endolymphatic sac is assumed to be involved in the secretion/resorption of
endolymph. The epithelial transport systems have been indirectly studied by the
recording of the endolymphatic sac transepithelial potential (ESP) in control
conditions and after the local injection of drugs such as diuretics that have
been proposed in the treatment of Meniere's disease. The ESP was recorded, in
vivo, in guinea pigs up to 150 minutes after the perisaccular injection of 5
microL of a 150 mmol/L (mM) NaCl solution containing various drugs known to
inhibit ionic transport systems. The initial ESP was +8.4+/-0.3 mV (mean +/- SEM,
n = 78). The basolateral injection of 5 microL of 150 mM NaCl induced an ESP
decrease of 64%+/-6.0% (n = 12), 5 minutes after the end of the injection. Then
ESP increased, returning to its initial value at 60 minutes and surpassing it at
120 minutes. Diuretics such as acetazolamide (10[-3] mol/L [M]), an inhibitor of
carbonic anhydrase, and amiloride (10[-4] M), an inhibitor of Na channel or Na/H
exchanger, decreased the ESP recovery. At variance, bumetanide (10[-6] M, 10[-4]
M), the Na-K-Cl cotransport inhibitor, and chlorothiazide (10[-4] M), a Na-Cl
cotransporter inhibitor, failed to alter the ESP as compared with the control
group. Ouabain (10[-3] M), the Na+,K+-adenosine triphosphatase (ATPase)
inhibitor, prevented the ESP recovery otherwise observed 60 minutes after the
NaCl injection. Bafilomycin A1, the inhibitor of the vacuolar-type H+-ATPase,
prevented the recovery of the ESP with a log-dose/effect (10[-5] M, 10[-6] M, 10[
8] M). Disulfonic acid stilbene (DIDS) (10[-4] M), an inhibitor of transporters
involving HCO3-, also prevented the ESP recovery. These results suggest that the
genesis of the ESP was highly dependent on acid-base transport systems including
carbonic anhydrase, a vacuolar-type H+-ATPase, and an anionic transport system
blocked by DIDS. Further studies are needed to confirm the alteration of the acid
base balance in this epithelium and its possible involvement in the pathogenesis
of Meniere's disease.
PMID- 9546278
TI - Is the presence of transient evoked otoacoustic emmissions in ears with acoustic
neuroma significant?
AB - One hundred sixty-eight patients admitted for acoustic neuroma removal were
involved in this study. In all cases, the size of the tumor and the presence or
absence of tinnitus and vertigo or dizziness were evaluated. Investigated
functional procedures included bilateral measures of pure-tone audiometry (PTA),
auditory brainstem response (ABR), electronystagmography (ENG), and transient
evoked otoacoustic emissions (TEOAEs). Thirty-five patients (21%) had normal
preoperative TEOAEs in the affected ear, whereas 133 patients (79%) failed to
show reproducible responses. The aims of this study were 1. to evaluate what
distinguishes patients with preoperative TEOAEs in the pathological ear (group A)
from those who had no TEOAE (group B); and 2. to determine in cases of attempted
hearing preservation whether preoperative TEOAE presence in the neuroma ear
(group C) was predictive of postoperative hearing preservation compared with the
group of patients without TEOAEs (group D). The presence of vertigo or dizziness
was significantly less frequent, the age was lower, and preoperative mean PTA
loss in both ears was lower in group A compared with group B. Frequency of the
other studied parameters and ABR threshold were similar in both groups. When
hearing preservation was attempted, the mean preoperative PTA loss of group C
patients was lower in both ears compared with group D. However, postoperative
mean PTA loss did not significantly differ in the two groups. In group C, the
percentage of hearing preservation (66.6%) was significantly higher than the
percentage of deafness (33.4%), whereas in group D the percentage of
postoperative preserved audition and deafness did not significantly differ
(respectively 44.4% and 55.6%). The findings suggest that 1. TEOAEs in ears with
acoustic neuromas are found in younger patients with a lower preoperative mean
PTA loss and are accompanied by fewer functional complaints, perhaps because
preserved TEOAEs indicate a better preservation of inner ear vasculature; and, 2.
along with radiological and electrophysiological investigations, TEOAE presence
in the pathological ear could provide an additional criterion or predictive
factor for the successful outcome of attempted hearing-conservation surgery in
ears with acoustic neuromas.
PMID- 9546277
TI - Imaging destructive lesions of the petrous apex.
AB - Cholesterol granuloma and cholesteatoma are the two most common destructive
lesions of the petrous apex. Arachnoid cyst is less common. These three expansile
lesions are often indistinguishable on clinical grounds. Cholesterol granulomas
can be treated effectively through internal drainage into the mastoid cavity or
middle ear. Cholesteatomas, however, are managed by more aggressive and
complicated removal, which often mandates the sacrifice of hearing. Symptomatic
arachnoid cysts are amenable to simple surgical drainage. Therefore, accurate
preoperative recognition on computed tomography (CT) and magnetic resonance
imaging (MRI) is important in planning proper treatment. Thirteen cases of
destructive lesions of the petrous apex are analyzed. The authors' experience
illustrates that the "typical" CT and MRI radiographic features are diagnostic in
some cases, but not in all. In this study the pathologic findings have been
correlated with the radiologic features on both MRI and CT.
PMID- 9546279
TI - Vestibular disease unmasked by hyperventilation.
AB - Hyperventilation-induced dizziness is often thought to be psychogenic, but its
effects in the presence of known vestibular disease have not been adequately
examined. In this study hyperventilation was tested in two models of vestibular
disease. These were, first, patients with profound unilateral vestibular deficit
(prior translabyrinthine acoustic neuroma resection [postsurgery group]) and,
second, patients with variable unilateral vestibular deficit (unoperated
unilateral acoustic neuroma [presurgery group]). Patients were hyperventilated
for 90 seconds. Using infrared videonystagmography, 100% of the 32 postsurgery
patients and 82% of the 28 presurgery patients developed nystagmus with
hyperventilation. Hyperventilation was more sensitive than head shake for
eliciting nystagmus in these models. The false-positive rate for nystagmus in 29
normal volunteers was 3.5% for hyperventilation and 10% for head shake. Our
results show that hyperventilation can unmask underlying vestibular disease.
PMID- 9546280
TI - Angiographic embolization for epistaxis: a review of 114 cases.
AB - Angiography with selective embolization has become an accepted method of treating
posterior epistaxis that is not controlled with conservative measures. The
authors reviewed 112 cases of patients who had received selective angiographic
embolization for refractory epistaxis from January 1990 to December 1995. There
were 114 embolizations over this 5-year period. The immediate success rate was
93%, with long-term success achieved in 88% of patients. The overall complication
rate was 17%, with the long-term morbidity rate less than 1%. Selective
angiographic embolization is a safe and effective method that should be
considered in the treatment of refractory epistaxis.
PMID- 9546281
TI - Pseudoepitheliomatous hyperplasia versus squamous cell carcinoma of the external
auditory canal.
AB - Four case reports are presented to demonstrate the clinical and histopathologic
similarity of pseudoepitheliomatous hyperplasia (PH) to squamous cell carcinoma
(SCC) in the external auditory canal (EAC). In all four cases the original report
of SCC on a biopsy specimen of an EAC lesion was corrected on review to PH. In
one patient conservative management resulted in resolution of the EAC lesion. A
second patient underwent radiation therapy and partial temporal bone resection
with no SCC found in the surgical specimen. A third patient's ear canal had
healed with conservative treatment and repeated biopsy revealed no malignancy.
After a 6-year symptom-free interval, she developed invasive SCC with bone
involvement that required surgery and radiation treatment. A fourth patient
underwent a sleeve resection of the skin of the EAC that proved to be PH, and no
evidence of SCC was found. A thoughtful clinical history, careful physical
examination, response to conservative treatment, and close communication with the
pathologist should be exercised in the evaluation of EAC lesions.
PMID- 9546282
TI - Three-dimensional analysis of cricoarytenoid joint motion.
AB - The normal motion of the cricoarytenoid joint was characterized and analyzed in
this study using seven fresh cadaver larynges mounted rigidly in an external
fixator apparatus after radiopaque markers were attached to laryngeal landmarks.
Fluoroscopic imaging and recording was performed of top, front, and side views
while the arytenoid cartilages of each larynx were manipulated through the full
range of motion from adduction to abduction. Computer video capture was performed
of the recordings and editing of still frames accomplished to generate three
dimensional plots of cricoarytenoid joint motion, which are shown in the
manuscript. Selective and varying sequential disconnection of muscular and
ligamentous structures to the arytenoid cartilage was achieved to determine their
contributions to cricoarytenoid joint motion limitations and stability. The
vocalis ligament, cricoarytenoid ligament, and conus elasticus are most important
in controlling abduction, whereas the posterior cricoarytenoid muscle and conus
elasticus are crucial in limiting adduction. The vocalis ligament prevents
posterior displacement of the vocal process, while the cricoarytenoid ligament
and a newly described ligament, the posterior capsular ligament, restricts
anterior vocal process migration. Another ligament, the anterior capsular
ligament, is described, which limits backward arytenoid cartilage tilting and
lateral movement of the arytenoid cartilage on the cricoid cartilage facet.
Section of the vocalis ligament with underlying conus elasticus produced
reducible lateral arytenoid cartilage subluxation. Confirmation of cricoarytenoid
joint facet relationships in full adduction and abduction was accomplished by
fixation of the cricoarytenoid joints of one larynx in the two positions with
adhesive, and subsequent exposure of the joint surfaces. Review of literature
detailing human laryngeal embryological development shows that the glottis and
arytenoid cartilages are formed in adduction, which explains how cricoarytenoid
joint ligaments collaborate to achieve accurate vocal process approximation in
adduction despite side-to-side asymmetries of the cricoarytenoid joint structures
in the same larynges.
PMID- 9546283
TI - Neuropathy associated with hyperoxaluria: improvement after combined renal and
liver transplantations.
AB - Little is known about oxaluria-associated neuropathy, and no effective treatments
have been described. We report two patients with clinically severe and
progressive sensorimotor polyneuropathy associated with oxaluria.
Electrodiagnostic testing and sural nerve histopathology revealed evidence of
severe axon loss and demyelination. In addition, birefringent crystalline
deposits were identified within endoneurial and perineurial blood vessel walls,
axon cylinders, and perimysial blood vessel walls. Electron probe microscopy
confirmed that calcium (consistent with calcium oxalate) was a major constituent
of the crystals. Both patients had substantial improvement in neuropathic signs
and symptoms after kidney and liver transplantations despite no prior improvement
with hemodialysis. Our results confirm previous reports of a mixed axonal and
demyelinating neuropathy with calcium oxalate deposition in association with
oxaluria. In addition, our findings suggest that renal and liver transplantation
may be potential treatments for the associated neuropathy.
PMID- 9546284
TI - BDNF up-regulates TrkB protein and prevents the death of CA1 neurons following
transient forebrain ischemia.
AB - The neurotrophin family of growth factors, which includes Nerve Growth Factor
(NGF), Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT3) and
Neurotrophin-4/5 (NT4/5) bind and activate specific tyrosine kinase (Trk)
receptors to promote cell survival and growth of different cell populations. For
these reasons, growing attention has been paid to the use of neurotrophins as
therapeutic agents in neurodegeneration, and to the regulation of the expression
of their specific receptors by the ligands. BDNF expression, as revealed by
immunohistochemistry, is found in the pre-subiculum, CA1, CA3, and dentate gyrus
of the hippocampus. Strong TrkB immunoreactivity is present in most CA3 neurons
but only in scattered neurons of the CA1 area. Weak TrkB immunoreactivity is
found in the granule cell layer of the dentate gyrus. Unilateral grafting of BDNF
transfected fibroblasts into the hippocampus resulted in a marked increase in the
intensity of the immunoreaction and in the number of TrkB-immunoreactive neurons
in the granule cell layer of the dentate gyrus, pre-subiculum and CA1 area in the
vicinity of the graft. No similar effects were produced after the injection of
control mock-transfected fibroblasts. Delayed cell death in the CA1 area was
produced following 5 min of forebrain ischemia in the gerbil. The majority of
living cells in the CA1 area at the fourth day were BDNF/TrkB immunoreactive.
Unilateral grafting of control mock-transfected or BDNF fibroblasts two days
before ischemia resulted in a moderate non-specific protection of TrkB-negative,
but not TrkB-positive cells, in the CA1 area of the grafted side. This finding is
in line with a vascular and glial reaction, as revealed, by immunohistochemistry
using astroglial and microglial cell markers. This astroglial response was higher
in the grafted side than in the contralateral side in ischemic gerbils, but no
differences were seen between BDNF-producing and non-BDNF-producing grafts.
However, grafting of BDNF-producing fibroblasts two days before ischemia
significantly and specifically prevented nerve cells from dying in the CA1 area
of the ipsilateral hippocampus. Cell survival was associated with increased TrkB
immunoreactivity as the majority of living cells were TrkB immunoreactive. Thus,
our results show that BDNF is able to up-regulate the expression of TrkB in
control and pathological states, and that BDNF prevention of neuronal death
following transient forebrain ischemia is associated with increased expression of
its specific receptor.
PMID- 9546285
TI - Frequent inactivation of CDKN2A and rare mutation of TP53 in PCNSL.
AB - Twenty primary central nervous system lymphomas (PCNSL) from immunocompetent
patients (nineteen B-cell lymphomas and one T-cell lymphoma) were investigated
for genetic alterations and/or expression of the genes BCL2, CCND1, CDK4, CDKN1A,
CDKN2A, MDM2, MYC, RB1, REL, and TP53. The gene found to be altered most
frequently was CDKN2A. Eight tumors (40%) showed homozygous and two tumors (10%)
hemizygous CDKN2A deletions. Furthermore, methylation analysis of six PCNSL
without homozygous CDKN2A loss revealed methylation of the CpG island within exon
1 of CDKN2A in three instances. Reverse transcription PCR analysis of CDKN2A mRNA
expression was performed for 11 tumors and showed either no or weak signals.
Similarly, immunocytochemistry for the CDKN2A gene product (p16) remained either
completely negative or showed expression restricted to single tumor cells. None
of the PCNSL showed amplification of CDK4. Similarly, investigation of CCND1
revealed no amplification, rearrangement or overexpression. The retinoblastoma
protein was strongly expressed in all tumors. Only one PCNSL showed a mutation of
the TP53 gene, i.e., a missense mutation at codon 248 (CGG to TGG:Arg to Trp). No
evidence of BCL2 gene rearrangement was found in 11 tumors investigated. The bcl
2 protein, however, was strongly expressed in most tumors. None of the 20 PCNSL
demonstrated gene amplification of MDM2, MYC or REL. In summary, inactivation of
CDKN2A by either homozygous deletion or DNA methylation represents an important
molecular mechanism in PCNSL. Mutation of the TP53 gene and alterations of the
other genes investigated appear to be of minor significance in these tumors.
PMID- 9546286
TI - Distribution of brain HIV load in AIDS.
AB - Approximately one quarter of patients with AIDS develop severe cognitive deficits
called HIV-associated dementia complex (ADC). There is some controversy regarding
the importance of viral load in mediating neurologic disease. With the advent of
sensitive, quantitative and reproducible RNA assays for HIV load in plasma and
CSF, we quantified viral load in brains from 10 autopsied HIV-infected subjects
and 2 non-infected controls. The new quantitative HIV RNA assays showed general
agreement with previously used semi-quantitative immunocytochemical assessments
of HIV envelope protein, and were performed without professional subjective
interpretation. All cases with very high levels of HIV in the CSF, had high
overall levels in the brain, suggesting that CSF viral loads exceeding 10(6)
copies per mL may be a surrogate marker of high viral load in the brain. Levels
of virus in the spleen showed no clear association with those found in the brain.
HIV RNA was not uniformly distributed throughout the brain. Selective regions,
including basal ganglia and hippocampus, showed higher levels of virus than the
cerebellar cortex and mid-frontal cortical gray matter. Assessment of overall
brain viral load requires careful attention to regional quantitation.
PMID- 9546288
TI - Non-Alzheimer degenerative dementias.
PMID- 9546287
TI - CD95 ligand: lethal weapon against malignant glioma?
AB - CD95 (Fas/APO-1) and its ligand (CD95L) belong to a growing cytokine and cytokine
receptor family that includes nerve growth factor (NGF) and tumor necrosis factor
(TNF) and their corresponding receptors. CD95 expression increases during
malignant progression from low-grade to anaplastic astrocytoma and is most
prominent in perinecrotic areas of glioblastoma. There is, however, no evidence
that CD95 expression in malignant gliomas is triggered by hypoxia or ischemia.
Agonistic antibodies to CD95, or the natural ligand, CD95L, induce apoptosis in
human malignant glioma cells in vitro. Glioma cell sensitivity to CD95-mediated
apoptosis is regulated by CD95 expression at the cell surface and by the levels
of intracellular apoptosis-regulatory proteins, including bcl-2 family members.
Several cytotoxic drugs synergize with CD95L to kill glioma cells. For as yet
unknown reasons, glioma cells may co-express CD95 and CD95L in vitro without
undergoing suicide or fratricide. Yet, they kill T cells via CD95/CD95L
interactions and are sensitive to exogenously added CD95L. Since CD95L is
expressed in gliomas in vivo, too, forced induction of CD95 expression might
promote therapeutic apoptosis in these tumors. That glioma cells differ from
nontransformed T cells in their sensitivity to CD95 antibodies or recombinant
ligand, may allow the development of selective CD95 agonists with high antitumor
activity that spare normal brain tissue. A family of death ligand/receptor pairs
related to CD95L/CD95, including APO2L (TRAIL) and its multiple receptors is
beginning to emerge. Although several issues regarding glioma cell sensitivity to
CD95L/CD95-mediated apoptosis await elucidation, CD95 is a promising target for
the treatment of malignant glioma.
PMID- 9546289
TI - Dementia with Lewy bodies. A distinct non-Alzheimer dementia syndrome?
AB - Lewy body formation is central to the pathological phenotype of a spectrum of
disorders. The most familiar of these is the extrapyramidal syndrome of
idiopathic Lewy-body Parkinson's disease (PD). Studies of dementia in the elderly
suggest that another manifestation of Lewy body pathology is equally or more
common than Parkinson's disease. This syndrome of Dementia with Lewy bodies (DLB)
has been given a number of diagnostic labels and is characterised by dementia,
relatively mild parkinsonism, visual hallucinations, and fluctuations in
conscious level. Although many of these features can arise in Parkinson's
disease, the patients with DLB tend to have early neuropsychiatric features which
predominate the clinical picture, and the diagnosis of the syndrome in practice
is more concerned with the differential diagnosis of Alzheimer's disease (AD).
Distinction from AD has clinical importance because of potentially differing
therapeutic implications. Diagnostic guidelines for the clinical diagnosis and
pathological evaluation of DLB are reviewed. Research into the disorder has
centered around characterising the clinical, neuropsychological, pathological,
neurochemical and genetic relationships with Alzheimer's disease on the one hand,
and Parkinson's disease on the other. Many cases of DLB have prominent
pathological features of AD and there are some shared genetic risk factors.
Differences from the pathology of PD are predominantly quantitative rather than
qualitative and evidence is discussed which suggests that DLB represents a
clinicopathological syndrome within the spectrum of Lewy body disorders. The
possibility that the syndrome represents a chance association of PD and AD is not
supported by published studies.
PMID- 9546290
TI - Dementia of frontal type and dementias with subcortical gliosis.
AB - The group of Frontotemporal dementias (FTD) is composed of non-Alzheimer forms of
dementia characterized clinically by behavioural and personality change leading
to apathy and mutism. The disorder is associated with a progressive atrophy of
the frontal, anterior temporal and anterior parietal lobes of the brain with
several types of underlying pathology. One type (frontal lobe degeneration) is
characterized by a microvacuolar degeneration of the outer cortical laminae along
with a mild and mainly subpial gliosis and a loss of nerve cells, mostly from
layers II and III. Another type shows transcortical tissue cavitation and florid
gliosis with neuronal degeneration characterized by the presence of tau and
ubiquitin positive inclusion bodies and alpha beta-crystallin-positive ballooned
neurones: such changes have been termed 'Pick-type histology', and form the basis
for the modern definition of 'Pick's disease'. The aetiological relationship
between these two histological types is presently unknown. Both histologies can
be differently distributed topographically throughout the brain to produce
syndromes of progressive language disorder, when affecting bitemporal lobes or
the left hemisphere preferentially, or progressive apraxia when parietal and
motor regions are involved. Either pathology can be combined with or overlaps
with that of classical motor neurone disease to produce motor neurone disease
dementia. The underlying cause of FTD is unknown but genetic factors are strongly
implicated. About half of cases show a previous family history of a similar
disorder. In several families bearing a FTD clinical and pathological phenotype,
linkage to chromosome 17 has been established but the pathology of this group
appears distinctive and its relation to other forms of FTD awaits further
elucidation. It is still possible that the many clinical and pathological
variants of FTD may reflect different phenotypic expressions of a particular
genetic change(s) at a single locus on this chromosome.
PMID- 9546291
TI - Pick's disease: a modern approach.
AB - Pick's disease is a rare dementing disorder that is sometimes familial. The
cardinal features are circumscribed cortical atrophy most often affecting the
frontal and temporal poles and argyrophilic, round intraneuronal inclusions (Pick
bodies). Clinical manifestations reflect the distribution of cortical
degeneration, and personality deterioration and memory deficits are often more
severe than visuospatial and apraxic disorders that are common in Alzheimer's
disease, but clinical overlap with other non-Alzheimer degenerative disorders is
increasingly recognized. Neuronal loss and degeneration are usually maximal in
the limbic system, including hippocampus, entorhinal cortex and amygdala.
Numerous Pick bodies are often present in the dentate fascia of the hippocampus.
Less specific features include leukoencephalopathy and ballooned cortical neurons
(Pick cells). Glial reaction is often pronounced in affected cerebral gray and
white matter. Tau-immunoreactive glial inclusions are a recently recognized
finding in Pick's disease, and neuritic changes have also recently been
described. Variable involvement of the deep gray matter and the brainstem is
typical, with a predilection for the monoaminergic nuclei and nuclei of the
pontine base. Neurochemical studies demonstrate deficits in intrinsic cortical
neurotransmitter systems (e.g., somatostatin), but inconsistent loss of
transmitters in systems projecting to the cortex (e.g., cholinergic neurons of
the basal nucleus). Biochemical and immunocytochemical studies have demonstrated
that abnormal tau proteins are the major structural components of Pick bodies. A
specific tau protein immunoblotting pattern different from that seen in
Alzheimer's disease and certain other disorders has been suggested in some
studies. A specific molecular marker and a genetic locus for familial cases are
not known.
PMID- 9546292
TI - Corticobasal ganglionic degeneration and progressive supranuclear palsy
presenting with cognitive decline.
AB - Corticobasal ganglionic degeneration (CBGD) and progressive supranuclear palsy
(PSP) were originally described in the sixties as predominantly motor syndromes.
Over the years, the detailed study of additional cases of CBGD has shown that it
is a distinctive histological entity which can often present as dementia or
aphasia. Although some pathological features of CBGD overlap with those of other
forms of non-Alzheimer non-Lewy body dementia, the distribution and relative
number of these abnormalities and the distinctive pattern of tau immunodeposits
allows the distinction of CBGD from Pick's disease and fronto-temporal dementia.
In contrast, PSP only rarely presents with prominent dementia or behavioral
changes. In these unusual PSP cases, care must be taken to exclude the diagnoses
of CBGD and familial tangle-only dementia.
PMID- 9546293
TI - Senile dementia with tangles (tangle predominant form of senile dementia).
AB - Senile dementia with tangles is a sporadic subset of very late onset dementia
with preponderance in females over age 80 years. Neuropathology shows diffuse
cerebral atrophy with neurofibrillary tangles, often ghost tangles, and neuropil
threads almost limited to limbic areas (transentorhinal, entorhinal area,
hippocampuS--not exclusively sector CA 1--and amygdala) with only rare and mild
involvement of the neocortex, basal ganglia and brainstem (except nucleus basalis
and locus ceruleus), absence of neuritic plaques and absence or scarcety of
amyloid deposits. This pattern of fibrillary pathology corresponds to Braak
stages III and IV or the "limbic" type of Alzheimer disease that is considered
the main form in the oldest-old but escapes the current criteria for the
morphologic diagnosis of Alzheimer disease. It is distinct from other tau- or
tangle-pathology related conditions, e.g. progressive supranuclear palsy,
autosomal dominant dementia with tangles, and diffuse tangles with calcification.
Very low prevalence of ApoE e4 allele (0.03-0.11%) and higher frequency of ApoE
e3 and/or e2 suggest a lack of promoting effect of e4 and a possible protecting
effect of e2/3 on amyloidogenesis. Senile dementia with tangles is suggested to
be a variant of Alzheimer disease occurring in the oldest-old, but its
nosological position within aging disorders of the brain is still controversy.
PMID- 9546294
TI - Dementia with grains (argyrophilic grain disease).
AB - Dementia with grains, also referred to as argyrophilic grain disease, is a
morphological condition in elderly individuals histologically characterised by
the widespread occurrence of minute, spindle or comma-shaped argyrophilic, tau
immunoreactive structures distinct from neuropil threads that are predominantly
located in the hippocampus and related limbic areas including the amygdala. They
are suggested to arise mainly in dendrites of neurons showing accumulation of
hyperphosphorylated tau proteins (pretangle stage) but not necessarily forming
paired helical filaments. Argyrophilic grains are associated with argyrophilic,
tau-positive oligodendroglial inclusions ("coiled bodies") in the white matter,
while astroglia are not affected. Argyrophilic grain disease is considered to be
a progressive disorder that may or may not be associated with dementia, the
grains occasionally being the only morphologic substrates of cognitive decline.
They often occur in combination with neuritic Alzheimer-type lesions (many
corresponding to "limbic" Braak stages III and IV) or other neurodegenerative
disorders, such as progressive supranuclear palsy, corticobasal degeneration, or
Pick's disease. The prevalence and pathogenesis of this condition, its
clinicopathologic correlations and nosological position among tau-pathology
related disorders await further elucidation.
PMID- 9546295
TI - Frontotemporal dementia and Parkinsonism linked to chromosome 17: a new group of
tauopathies.
AB - Frontotemporal dementia is a neurological disorder characterised by personality
changes, deterioration of memory and executive functions as well as stereotypical
behaviour. Sometimes a Parkinsonian syndrome is prominent. Several cases of
frontotemporal dementia are hereditary and recently families have been identified
where the disease is linked to chromosome 17q21-22. Although, there is clinical
and neuropathological variability among and within families, they all
consistently present a symptomathology that has led investigators to name the
disease "Frontotemporal Dementia and Parkinsonism linked to chromosome 17."
Neuropathologically, these patients present with atrophy of frontal and temporal
cortex as well as of basal ganglia and substantia nigra. In the majority of cases
these features are accompanied by neuronal loss, gliosis and microtubule
associated protein tau deposits which can be present in both neurones and glial
cells. The distribution, structural and biochemical characteristics of the tau
deposits differentiate them from those present in Alzheimer's disease,
corticobasal degeneration, progressive supranuclear palsy and Pick's disease. No
beta-amyloid deposits are present. The clinical and neuropathological features of
the disease in these families suggest that Frontotemporal Dementia and
Parkinsonism linked to chromosome 17 is a distinct disorder. The presence of
abundant tau deposits in the majority of these families define this disorder as a
new tauopathy.
PMID- 9546296
TI - Establishing a pathological diagnosis in degenerative dementias.
AB - While clinicopathological studies have confirmed that Alzheimer's disease (AD) is
the most common neurodegenerative cause of dementia, these same studies have also
revealed that other degenerative pathologies account for a significant proportion
of patients with cognitive decline. Because pathological assessment of non
Alzheimer neurodegenerative diseases now demands routine use of a costly panel of
immunohistochemical techniques a scheme for staged examination of brain tissue
has been developed. This scheme is weighted to initially screen out cases of
Alzheimer's disease, dementia with Lewy bodies and vascular dementia using
conventional staining methods and established diagnostic protocols, bringing in
immunochemical techniques to discriminate between non-Alzheimer degenerative
dementias. Diagnosis of pathologies causing the clinical syndrome of
frontotemporal dementia can be ascertained using conventional staining
supplemented by immunochemical detection of ubiquitin, tau protein and alpha beta
crystallin. The diagnosis of prion disease is reliably confirmed by
immunohistochemical detection of prion protein. This morphological assessment
complements emerging genetic insights into many of these neurodegenerative
diseases.
PMID- 9546297
TI - Early Intervention Project: can its claims be substantiated and its effects
replicated?
AB - A comprehensive report to the National Institute of Health on the diagnosis,
etiology, epidemiology, and treatment of autism indicated that early intervention
has the potential of being an effective intervention (Bristol et al., 1996). In
spite of this positive outlook, several research and methodological questions
remain regarding time of treatment initiation, intensity of treatment and
duration of treatment, random assignment, comparative treatment designs, and
treatment integrity. Against this backdrop we consider the claims made by the
Early Intervention Project (EIP; Lovaas, 1987, 1993; McEachin, Smith, & Lovaas,
1993). The EIP claims to produce recovery from autism in 47% of the cases and to
greatly reduce its severity in an additional 42% of cases. This article evaluates
the EIP against threats to internal and external validity and is found to suffer
from a number of methodological problems. Based on rebuttals to criticisms of
their program, the EIP authors seem unwilling to admit any methodological flaws
in the sampling, design, and analysis of data of the EIP. It is recommended that
parents and fair hearing officers adopt an attitude of healthy skepticism before
proceeding to an unqualified endorsement of the EIP as a treatment for autism.
PMID- 9546298
TI - Home-based behavioral treatment of young children with autism.
AB - This study evaluated the impact of intensive behavioral treatment on the
development of young autistic children. The treatment reported in this study was
home based and was implemented by parents of autistic children with the
assistance of community-based clinicians. Although treatment was unable to be
observed directly, parents reported that therapy was based on methods developed
by Lovaas et al. (1981). Treatment differed from that described in previous
reports of intensive behavior therapy for this population in that it was
implemented outside an academic setting and for a shorter period. In addition,
children received fewer hours per week of therapy than in previous reports.
Children in the experimental treatment group were pairwise matched to children in
a control group (who received conventional school-based and brief one-on-one
interventions) on the basis of pretreatment chronological and mental age,
diagnosis (autism vs. PDD), and length of treatment. The groups did not differ on
pretreatment IQ. Children receiving the experimental treatment had significantly
higher posttreatment IQ scores. Smaller, but still statistically significant
effects on symptom severity were also found, though experimental subjects still
met diagnostic criteria for autism or PDD.
PMID- 9546299
TI - Effectiveness of a home program intervention for young children with autism.
AB - This project evaluated the effectiveness of a TEACCH-based home program
intervention for young children with autism. Parents were taught how to work with
their preschool autistic child in the home setting, focusing on cognitive,
academic, and prevocational skills essential to later school success. To evaluate
the efficacy of the program, two matched groups of children were compared, a
treatment group and a no-treatment control group, each consisting of 11 subjects.
The treatment group was provided with approximately 4 months of home programming
and was tested before and after the intervention with the Psychoeducational
Profile-Revised (PEP-R). The control group did not receive the treatment but was
tested at the same 4-month interval. The groups were matched on age, pretest PEP
R scores, severity of autism, and time to follow-up. Results demonstrated that
children in the treatment group improved significantly more than those in the
control group on the PEP-R subtests of imitation, fine motor, gross motor, and
nonverbal conceptual skills, as well as in overall PEP-R scores. Progress in the
treatment group was three to four times greater than that in the control group on
all outcome tests. This suggests that the home program intervention was effective
in enhancing development in young children with autism.
PMID- 9546300
TI - Does a photographic cue facilitate false belief performance in subjects with
autism?
AB - The posting manipulation, which Mitchell and Lacohee (1991) successfully employed
to facilitate false belief (FB) task performance in normally developing 3-year
olds, was employed with subjects with autism. There was no autism-specific
impairment on the standard FB task, compared to mental handicap and normal
controls: All groups performed poorly, with the autism and normal groups
performing significantly worse than chance and the mental handicap group
performing at chance. However, a facilitative effect was found on the posting FB
task for all subject groups. On the posting task the mental handicap and normal
controls groups performed significantly better than chance and the autism group
performed at chance. The facilitative effect reached significance for the autism
and normal groups. The lack of an autism-specific deficit on the standard task is
discussed in relation to the somewhat variable findings of past studies of FB
performance in autism. The facilitative effect of the posting manipulation may
tell us something about the task demands required to pass a false belief task
itself, and suggestions are made for future research to clarify how the
facilitative effect operates.
PMID- 9546301
TI - Source monitoring by children with autism.
AB - The term "source monitoring" refers to the ability to distinguish the origins of
memories. One type of source monitoring is reality monitoring-which means
distinguishing internally and externally generated memories. This experiment
examined reality monitoring by children with autism (with a mean mental age of 7
years 8 months). The children said several words and listened to another person
say similar words. The children were then given a surprise memory test and asked
to identify which words they had said and which the other person had said. The
children with autism were compared to matched groups of normal children and
children with mental retardation. There were no differences between the groups
and, at least for this task, there was no evidence that children with autism have
a deficit in their reality monitoring abilities.
PMID- 9546302
TI - Following the child's lead: mothers' interactions with children with autism.
AB - This study examined the extent to which mothers of preschool children with autism
use language that is related to the child's focus of attention. Fourteen mother
child dyads involving preschool children with autism participated in this study,
along with 14 matched dyads involving typically developing preschool children.
Both groups were observed during 15 minutes of free play. Results revealed that
the mothers of children with autism directed verbalizations to something within
the child's focus of attention as frequently as the mothers of typically
developing children. Thus, children with autism had as many opportunities to
benefit from verbal input related to their focus of attention as did typically
developing children. However, mothers of children with autism directed
verbalizations to something not within the child's focus of attention more
frequently than mothers of typically developing children. This nonrelated input
may have reflected the mothers' attempts to adapt to their children's
difficulties in attention and interaction.
PMID- 9546303
TI - Abnormal saccadic eye movements in autistic children.
AB - The saccadic eye movements, generated during a visual oddball task, of autistic
children, normal children, children with attention deficit disorder and
hyperactivity (ADDH), and dyslexic children were examined to determine whether
autistic children differed from these other groups in saccadic frequency.
Autistic children made more saccades during the presentation of frequent stimuli
(than normals and ADDH children), and between stimulus presentations. Also,
unlike the normal and dyslexic groups, their saccadic frequency did not depend on
stimulus type. This abnormal pattern of saccades may negatively influence the
ability to attend to stimuli, and thereby learning processes. Suggestions are
made with respect to possible abnormalities in subcortical mechanisms involved in
saccade generation.
PMID- 9546304
TI - The Swedish version of the Childhood Autism Rating Scale in a clinical setting.
AB - The Childhood Autism Rating Scale (CARS) is an instrument for screening and
diagnosis of autism. The present study was performed to assess the interrater
reliability of a Swedish version of the CARS when used in a clinical setting. The
procedure used mimicked a frequent form of consultation in neuropsychiatry and
pediatric neurology. During a restricted time period, both an interview with the
parents and observation of the child take place. Often this assessment is an
important screening procedure and directs further investigation. CARS was used
for rating autistic behavior by two investigators in 25 children. A variant of
the weighted kappa statistic (correcting for chance and for degrees of
disagreement) showed values between .53 and .75 (indicating fair to excellent
agreement). Aspects of validity and reliability are discussed.
PMID- 9546305
TI - Validity of the Autism/Pervasive Developmental Disorder subscale of the
Diagnostic Assessment for the Severely Handicapped-II.
AB - This study was designed to establish the empirical validity of the Diagnostic
Assessment for the Severely Handicapped-II (DASH-II) to screen for the presence
of autism in severely and profoundly mentally retarded adults. Participants
included 51 individuals residing in a large developmental center in Central
Louisiana. The Autism/Pervasive Developmental Disorder subscale of the DASH-II
was internally consistent. Additionally, the DASH-II was just as likely as the
Childhood Autism Rating Scale (CARS) to classify autistic and control
individuals. Specific items on the subscale were examined to identify those items
most associated with a diagnosis of autism.
PMID- 9546306
TI - Brief report: Control in highly focused top-spinning.
PMID- 9546307
TI - Brief report: Degree of facilitator influence in facilitated communication as a
function of facilitator characteristics, attitudes, and beliefs.
PMID- 9546308
TI - Will your journal support parents advocating for intensive behavior therapy (the
Lovaas method) as an entitlement under Part H of the Individuals with
Disabilities Education Act?
PMID- 9546309
TI - Does angiotensin I-converting enzyme inhibitor therapy have an antiproliferative
effect on blood-forming bone marrow?
PMID- 9546310
TI - Selective proliferation of lymphoid cells from lineage-c-Kit+ Sca-1+ cells by a
clonal bone marrow stromal cell line.
AB - To understand the regulatory mechanisms involved in the development of
hematopoietic stem cells, we cultured lineage-negative, c-Kit+ Sca-1+ stem cells
sorted from bone marrow cells by a fluorescence-activated cell sorter (FACS) on
layers of bone marrow stromal cell lines established from SV40 T-antigen gene
transgenic mice. We previously reported that the TBR59 stromal cell line induced
two sequential cobblestone formations: the first formation committed to the
myeloid and the second to the lymphoid lineage. After examination of many other
bone marrow stromal cell lines, we found that TBR31-1 stromal cells supported
only lymphoid development of the sorted stem cells. The sorted stem cells
proliferated by forming cobblestones and the cells were released from the
cobblestones. Most released cell populations were B220-positive lymphoid cells;
cell production continued for 2 months. Addition of G-CSF or M-CSF produced only
a slight effect on myeloid development. FACS analysis of the released cells
showed that the B-lymphoid-committed progenitors developed into mature B-cells by
expressing surface immunoglobulin M. These results indicate that TBR31-1 bone
marrow stromal cells selectively support B-lymphoid development, whereas TBR59
cells support both myeloid and lymphoid development of stem cells.
PMID- 9546311
TI - Multiparameter-fluorescence activated cell sorting analysis of retroviral vector
gene transfer into primitive umbilical cord blood cells.
AB - Retroviral vector gene transfer strategies are currently being developed to treat
a variety of hematopoietic disorders. To date, genetic modification of human
pluripotent hematopoietic stem cells has been inefficient. In the present study
we developed reagents and procedures for rapidly screening retroviral vector gene
transfer conditions using a multiparameter fluorescence-activated cell sorting
(FACS) assay. To identify transduced cells using FACS analysis, we developed a
retroviral vector, termed MN, which stably expressed high levels of a truncated
version of the low-affinity nerve growth factor receptor (LNGFR). In addition,
procedures were developed for enriching CD34+ cells from cryopreserved umbilical
cord blood. These cells were transduced with MN and evaluated using
multiparameter FACS analysis for expression of CD34, CD38, and LNGFR. Stem cell
maintenance was determined by measuring the CD34hi and CD34hiCD38lo/- cells
remaining after ex vivo gene transfer. Gene transfer into these cells was
measured by evaluating cells expressing high levels of LNGFR. Initial studies
with this assay and with in vitro functional assays indicated that retroviral
gene transfer following pre-incubation with a variety of cytokines in serum
containing conditions resulted in 1) poor maintenance of hematopoietic stem cells
and 2) gene transfer predominantly in relatively mature cells. When gene transfer
in serum-free conditions was performed, some improvement was observed in the
maintenance of cells retaining primitive immunophenotypes with no reduction in
the gene transfer efficiency. The MN vector and multiparameter FACS analysis will
be useful in efficiently screening ongoing efforts designed to improve stem cell
gene transfer.
PMID- 9546312
TI - IL-10 as an autocrine regulator of CSF secretion by monocytes: disparate effects
on GM-CSF and G-CSF secretion.
AB - In previous studies of endogenous granulocyte-macrophage colony-stimulating
factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) production, we
found several differences in the secretion pattern within and between different
cell systems; for example, CSF secretion by endothelial cells is not affected by
any major downregulatory factors, whereas monocyte CSF secretion is modulated by
several mechanisms. In this study, we characterized the factors that inhibit CSF
secretion by monocytes. Three cytokines have inhibitory effects: interleukin (IL)
4, IL-10, and IL-13. Among these, IL-4 and IL-10 have higher potency than IL-13.
IL-4 and IL-13 affect GM-CSF and G-CSF secretion to the same extent. In contrast,
exogenously added IL-10 has a stronger inhibitory effect on GM-CSF secretion than
on G-CSF secretion. We also found that monocytes produce IL-10 with an autocrine
downregulatory effect, and that this autocrine IL-10 reaches concentrations at
which in most cases only GM-CSF (not G-CSF) secretion is significantly affected.
We postulate that the disparate effect of IL-10 on monocyte secretion of the two
CSFs reflects their physiological functions, with GM-CSF being mainly a
proinflammatory cytokine working in the local compartment and G-CSF functioning
mainly as a cell recruiting factor.
PMID- 9546313
TI - Comparative phenotype mapping of normal vs. malignant pediatric B-lymphopoiesis
unveils leukemia-associated aberrations.
AB - Leukemic cells of B-lineage acute lymphoblastic leukemia (ALL) are regarded as
the malignant counterparts of immature, physiologic B cell precursors (BCPs). To
determine whether phenotypic differences exist between these corresponding cell
types, we investigated samples of normal pediatric bone marrow (n=30) as well as
of B-precursor ALL at diagnosis (n=53; common and pre-B subtype). Using three
color multiparameter flow cytometric analysis, we compared the leukemic
populations with the physiologic BCPs of corresponding maturity with respect to
the intensity with which they expressed a series of antigens. In some of these
antigens, leukemia-associated aberrations were frequently observed. In
particular, overexpression of CD10 was displayed by 65% of ALL samples, whereas
58% of leukemic cases aberrantly exhibited very low or no CD45RA expression.
Regarding CD11a and CD44, 47% and 35% of ALL populations were aberrant as defined
by either the absence or significant overexpression of the antigen. In contrast,
antigen densities of CD49d, CD49e, and CD99 on leukemic cells were in the normal
range of values for BCPs. Combining the patterns of frequently aberrant markers
in a comprehensive analysis, we were able to identify individual phenotypic
leukemic cell aberrations in up to 98% of investigated cases. CD10 and/or CD45RA
were aberrant in 86% of cases overall, emphasizing the high discriminative
potential of these two markers. Using comparative phenotype mapping based on
quantitatively aberrant, leukemia-associated antigenic patterns, we were able to
detect leukemic blasts among normal bone marrow cells at frequencies as low as
10(-5). We speculate that our approach may have a profound impact on the
development of new strategies for minimal residual disease investigations in
patients with BCP-ALL.
PMID- 9546314
TI - Sickling of nucleated erythroid precursors from patients with sickle cell anemia.
AB - The pathophysiology of sickle cell anemia is primarily explained in terms of the
oxygen-dependent polymerization of sickle hemoglobin (HbS) followed by sickling
of erythrocytes. Since the rate and extent of HbS polymerization depend on its
intracellular concentration, it has been generally assumed that sickling occurs
primarily in mature erythrocytes with their high intracellular hemoglobin
concentration. In the present study, we investigated the propensity of nucleated
erythroid precursors to undergo sickling; both cultured and fresh marrow-derived
erythroid precursors from patients with homozygous sickle cell anemia were
studied. The results revealed that upon deoxygenation cultured erythroblasts
underwent characteristic morphological deformation in the form of fine, fragile,
elongated spicules. Ultrastructural analysis demonstrated highly organized and
tightly aligned hemoglobin fibers in the protruded regions. Bone marrow cells
examined under partial or complete deoxygenated conditions displayed similar
morphological changes. When cultured SS erythroid precursors were exposed to
hydroxyurea or butyrate, drugs that may increase fetal hemoglobin (HbF) and
inhibit intracellular polymerization, a significant decrease was observed in the
propensity of these precursors to undergo sickling, accompanied by a three- to
fivefold increase in HbF. These results suggest that, in addition to mature
erythrocytes, nucleated erythroid precursors in the bone marrow have the capacity
to undergo characteristic sickling as a result of HbS polymerization and may be
involved in several aspects of the pathophysiology of sickle cell anemia.
Treatment with HbF-stimulating drugs may benefit patients with this disease by
inhibiting polymerization-induced sickling of erythroid precursors in the marrow
as well as mature erythrocytes in the peripheral blood.
PMID- 9546315
TI - Repetitive bone marrow transplantation in nonmyeloablated recipients.
AB - Transplantation of 200 million male BALB/c marrow cells into normal
nonmyeloablated female BALB/c hosts results in relatively high levels of
engraftment, whether the cells are infused repetitively over time or in a single
infusion. These high engraftment rates suggested that repetitive injections of
high levels of male BALB/c cells might be able to totally replace host marrow.
Accordingly, we transplanted 40x10(6) male BALB/c bone marrow cells into female
BALB/c recipients over a 7-week period for a total of 20 injections (800x10[6]
marrow cells). Engraftment in this experimental group was compared to that seen
when female recipients received 2x10(6) male marrow cells or phosphate-buffered
saline (PBS) over the same injection schedule. Engraftment was quantitated at 5
and 7 weeks after the final infusion by detection of male-specific sequences in
female host marrow, spleen, and thymus by Southern blot analysis using a Y
specific cDNA probe. Male DNA levels were quantitated with a Molecular Dynamics
phosphorimager. Engraftment of male cells into female marrow at 5 and 7 weeks
posttransplantation ranged from 19 to 88%, whereas that in spleen and thymus
ranged between 30 and 100% and 28 and 50%, respectively. The mean percent
engraftments for marrow, spleen, and thymus were 41, 69, and 39%, respectively.
Mean percent engraftments for 2x10(6) cell infusions at 5 and 7 weeks for marrow,
spleen, and thymus were 4, 6, and 4%, respectively. Marrow and spleen cellularity
and total high proliferative potential colony-forming cell numbers were
determined in PBS- and cell-injected mice. No significant differences between
these groups were observed. For marrow engraftment, 20 injections of 40x10(6)
cells was not more effective than five, but donor DNA in thymus and spleen was
increased with 20 injections. Primitive progenitor cell levels and marrow
cellularity do not increase in mice injected with large numbers of marrow cells,
suggesting that host marrow cells are replaced rather than augmented by infused
donor cells.
PMID- 9546316
TI - Induction of L-histidine decarboxylase in a human mast cell line, HMC-1.
AB - Histamine is an important mediator in allergic reactions, gastric acid
secretions, and neurotransmission in the central nervous system. Basophils and
mast cells are the main sources of histamine, which is formed from L-histidine by
histidine decarboxylase (HDC). However, the regulatory mechanism of HDC in these
cells remains unclear. We examined the regulation of HDC activity and gene
expression using a unique human mast cell line, HMC-1, after stimulation with
phorbol 12-myristate 13-acetate (PMA) or ionomycin. HDC activity was increased
from 52.1+/-0.4 (mean+/-standard deviation) to 154+/-6.9, or 105.6+/-6.2
pmol/min/mg protein (n = 3), 4 hours after stimulation with PMA (10 ng/mL) or
ionomycin (10[-6] M). Although actinomycin D had no effect on this increase,
cycloheximide completely inhibited the increase caused by these stimuli. The
population of HMC-1 cells containing HDC protein was increased after stimulation
with either PMA or ionomycin as evaluated by immunocytochemical analysis with
anti-HDC antibody as a marker. HMC-1 constitutively expressed HDC mRNA, and its
level was not increased with these stimuli. These results suggest that the
increase of HDC activity in HMC-1 induced by PMA or ionomycin is regulated at the
translational level.
PMID- 9546317
TI - Mature human hematopoietic cells in donor bone marrow complicate interpretation
of stem/progenitor cell assays in xenogeneic hematopoietic chimeras.
AB - Xenogeneic hematopoietic chimeras have been used to assay the growth and
differentiation of human stem/progenitor cells. The presence of human
hematopoietic cells in immunodeficient mice transplanted with human marrow cells
may be caused by proliferation and differentiation of early stem/progenitor cells
and/or proliferation of mature cells. Unpurified human marrow mononuclear cells,
T cell-depleted, or stem/progenitor cell-enriched (CD34+ or CD34+CD38-)
populations were injected into sublethally irradiated NOD/LtSz scid/scid
(NOD/SCID) mice. High levels of human cells were detected in mice (hu/mu
chimeras) transplanted with each of the above human marrow populations. Large
numbers of mature human T lymphocytes were found in marrow, spleens, and thymuses
from hu/mu chimeras that had been transplanted with unpurified human mononuclear
marrow cells. Human immunoglobulin was detected in sera from these chimeras, and
some exhibited a clinical syndrome suggestive of graft-versus-host disease. In
contrast, in hu/mu chimeras that had received T cell-depleted or stem/progenitor
cell-enriched populations, multilineage hematopoiesis (myeloid, B lymphoid, and
progenitor cells by immunophenotype) was detected but T lymphocytes and human
immunoglobulin were not; in addition, no human cells were detected in the
thymuses. Thus, injection of adult human marrow cells into immunodeficient mice
can result in hematopoietic chimerism for at least 3 months after transplant.
However, the types of cells present in hu/mu chimeras differ depending on the
human cell population transplanted. This should be taken into account when
hematopoietic chimeras are used to assess human stem/progenitor cell function.
PMID- 9546318
TI - Distinct actions of Flt3 ligand and stem cell factor on myeloid lineage selection
and maturation of granulocytes versus macrophages.
AB - Flt3/Flk2 ligand (FL) and stem cell factor (SCF; c-kit ligand) interact with
different but related surface receptor tyrosine kinases expressed on early
hematopoietic cells. Both FL and SCF stimulate the proliferation of stem cells
and progenitors, but the mechanisms by which these cytokines exert their
functions are currently unknown. Here we show that FL and SCF have different
effects on myeloid differentiation and lineage selection of early hematopoietic
cells using a defined subpopulation of mouse bone marrow (BM) expressing c-Kit
but lacking mature lineage markers (c-Kit+Lin-). SCF, together with IL-6, induced
the differentiation of a large fraction of these progenitor cells toward mature
granulocytes and to a lesser extent toward monocytes. In contrast, FL combined
with IL-6 favored differentiation into mature monocytes and macrophages, and very
few if any granulocytes could be identified. When FL and SCF were analyzed for
their ability to support growth of multilineage erythroid colonies (pre-CFCmulti)
and myeloid-committed colony-forming progenitors of granulocytes and monocytes
(CFC-G/M), a clear discrepancy was also found. Both FL and SCF had synergistic
effects on the proliferation of immature cells with blast-like morphology, but
the expansion of pre-CFCmulti and CFC-G/M was favored by SCF but not by FL. FL
synergized with both SCF and IL-6 with respect to proliferative response and
maintenance of undifferentiated cells; however, the numbers of CFC-G/M after 7 or
14 days in culture were significantly lower than those observed with SCF combined
with IL-6. Interestingly, in contrast to SCF, no pre-CFCmulti was recovered from
BM cells expanded in the presence of FL and IL-6.
PMID- 9546319
TI - Human bone marrow CD34- cells engraft in vivo and undergo multilineage expression
that includes giving rise to CD34+ cells.
AB - We used the human/sheep competitive engraft model to investigate the in vivo
engraftment potential of human CD34-, Lin- cells. In three separate studies,
transplantation of CD34+, Lin- and CD34-, Lin- cells from the same normal human
donors into preimmune fetal sheep resulted in long-term engraftment and
multilineage hematopoietic cell/progenitor expression. Human cell/progenitor
activities of the CD34+ group were CD3, 0.52%; CD13, 0.36%; CD45, 1.02%; glyA,
1.78%; HLA-DR, 0.99%; colony-forming units (CFU)-Mix, 7.1%; and granulocyte
macrophage CFU (CFU-GM), 13.7%; those of the CD34- group were CD3, 0.24%; CD45,
2.49%; glyA, 0.75%; HLA-DR, 0.3%; CFU-Mix, 7.1%; and CFU-GM, 4.3%. Of special
interest was the detection of highly significant numbers (1 x 10[9] cells) of
human CD34+ cells in animals transplanted with CD34- cells. Secondary
transplantation and limiting dilution studies confirmed the presence of cells
with long-term engraftment potential in CD34- populations. The results presented
here demonstrate that the CD34- fraction of normal human bone marrow contains
cells capable of engraftment and differentiation into CD34+ progenitors and
multiple lymphohematopoietic lineages in primary and secondary hosts.
PMID- 9546320
TI - Prolonged febrile seizures and mesial temporal sclerosis.
PMID- 9546321
TI - Magnetic resonance imaging evidence of hippocampal injury after prolonged focal
febrile convulsions.
AB - Magnetic resonance imaging (MRI) was performed after complex febrile convulsions
(CFCs) in 27 infants. Definite MRI abnormalities were seen in 6 of the 15 infants
with focal or lateralized CFCs and in none of the 12 infants with generalized
CFCs. In 2 of the 6 infants with lateralized CFCs and abnormal MRIs, the MR
images showed preexisting bilateral hippocampal atrophy consistent with the
history of perinatal insults in these infants. However, the remaining 4 infants
with MRI abnormalities and lateralized CFCs had significantly longer seizures
than other infants and had MRI changes suggesting acute edema with increased
hippocampal T2-weighted signal intensity and increased volume predominantly in
the hippocampus in the hemisphere of seizure origin. Of those with acute edema, 1
had electrographical seizure activity recorded in the temporal region and another
had a choroid fissure cyst displacing the affected hippocampus; both infants had
follow-up MRIs showing that hippocampal atrophy had developed. These patients
demonstrate that prolonged and focal CFCs can occasionally produce acute
hippocampal injury that evolves to hippocampal atrophy. Finally, evidence of
preexisting hippocampal abnormalities in several infants and electrographical
temporal lobe seizure activity in 1 suggests the possibility that CFCs actually
originated in the temporal lobes in some patients.
PMID- 9546323
TI - Epilepsies in twins: genetics of the major epilepsy syndromes.
AB - We studied twins to examine the genetics of epilepsy syndromes. We ascertained
358 twin pairs in whom one or both reported seizures. After evaluation, 253 of
358 (71%) had seizure disorders and 105 pairs were false positives. Among the
monozygous (MZ) pairs, more were concordant for seizures (48 of 108; casewise
concordance = 0.62 +/- 0.05) than among the dizygous (DZ) pairs (14 of 145;
casewise concordance = 0.18 +/- 0.04). In 94% of concordant MZ pairs, and 71% of
concordant DZ pairs, both twins had the same major epilepsy syndrome. When
analyzed according to major epilepsy syndrome, the casewise concordances for
generalized epilepsies (MZ = 0.82; DZ = 0.26), both idiopathic (MZ = 0.76; DZ =
0.33) and symptomatic (MZ = 0.83; DZ = 0), were greater than those for partial
epilepsies (MZ = 0.36; DZ = 0.05), with intermediate values seen for febrile
seizures (MZ = 0.58; DZ = 0.14) and unclassified epilepsies (MZ = 0.53; DZ =
0.18). We conclude that genetic factors are particularly important in the
generalized epilepsies but also play a role in the partial epilepsies. The high
frequency of concordant MZ pairs with the same major syndrome strongly suggests
there are syndrome-specific genetic determinants rather than a broad genetic
predisposition to seizures.
PMID- 9546322
TI - Matrix metalloproteinases MMP-9 and MMP-7 are expressed in experimental
autoimmune neuritis and the Guillain-Barre syndrome.
AB - Matrix metalloproteinases (MMPs) are a family of enzymes that may be implicated
in the pathogenesis of inflammatory demyelinating disorders such as multiple
sclerosis. The present study investigated the expression of 92-kd gelatinase (MMP
9) and five other MMPs in sciatic nerve from Lewis rats with autoimmune
experimental neuritis (EAN), an experimental model of the Guillain-Barre syndrome
(GBS). Quantitative polymerase chain reaction analysis revealed an up-regulation
of MMP-9 mRNA with peak levels concurrent with maximal disease severity.
Increased mRNA expression was associated with enhanced enzyme activity, as
detected by gelatin zymography. Immunohistochemically, MMP-9 could be localized
primarily around blood vessels within the epineurium and endoneurium in diseased
but not normal sciatic nerve. Among all other MMPs investigated, mRNA levels of
matrilysin (MMP-7) were found to be up-regulated at the peak of the disorder,
remaining at high levels throughout the clinical recovery phase of the disease.
To apply these findings to human disease, sural nerve biopsies from GBS patients
were examined. By using immunohistochemistry, positive immunoreactivity against
MMP-9 and MMP-7 was noted and corroborated by demonstrating augmented mRNA
expression in comparison with noninflammatory neuropathies. Furthermore,
increased MMP-9 activity was detected by zymography. These findings indicate that
92-kd gelatinase and matrilysin are selectively up-regulated during EAN and
expressed in nerves of GBS patients and thus may contribute to the pathogenesis
of inflammatory demyelination of the peripheral nervous system.
PMID- 9546325
TI - Increased sensitivity of fibroblasts from amyotrophic lateral sclerosis patients
to oxidative stress.
AB - Although the cause of amyotrophic lateral sclerosis (ALS) is unkNown, free
radical toxicity is thought to play a pathogenic role. We investigated whether
cells from ALS patients are more vulnerable to exogenously induced oxidative
stress than cells from controls. We therefore studied the sensitivity of
fibroblasts from patients with sporadic ALS (SALS), and from patients with
familial ALS (FALS) associated with copper/zinc superoxide dismutase (Cu/ZnSOD)
mutations (SOD1-FALS), to the free radical-generating agents 3
morpholinosydnonimine (SIN-1) and hydrogen peroxide (H2O2), and to serum
withdrawal. SOD1-FALS and SALS fibroblasts were significantly more sensitive than
controls to SIN-1 but not to serum withdrawal. In addition, SOD1-FALS fibroblasts
were more sensitive to H2O2 than SALS fibroblasts and than fibroblasts of
controls. These results suggest that the mechanism underlying both SOD1-FALS and
SALS jeopardizes the cell's defense against free radical stress, and that SOD1
FALS cells are particularly sensitive to H2O2. The latter finding is compatible
with biochemical data on the increased affinity of the mutated Cu/ZnSOD for H2O2.
PMID- 9546326
TI - Purified IgG from seropositive and seronegative patients with mysasthenia gravis
reversibly blocks currents through nicotinic acetylcholine receptor channels.
AB - The mechanism of block of nicotinic acetylcholine receptor (nAChR) channels by
purified antibodies from patients with myasthenia gravis (MG) was investigated by
using an ultrafast system for solution exchange at outside-out patches. IgG of MG
patients and controls was purified by using protein A-Sepharose columns. Probes
from 9 seropositive MG patients and 3 seronegative MG patients were tested. As a
preparation, cultured mouse myotubes expressing the embryonic-type nAChR channels
were used. Twenty-millisecond pulses of 1.0 mM ACh were applied repetitively to
outside-out patches. Outside-out patches were preexposed with IgG in
concentrations between 0.1 and 200 mg/L during application of ACh pulses. The
peak current amplitude was reduced to values between 6% and 71% of control for
the 9 seropositive and 3 seronegative MG patients. The block was concentration
dependent and fully reversible after washout of antibodies. Incubation with IgG
from different control patients did not reduce the peak current amplitude. In
addition, our findings with purified IgG from seronegative MG patients support
the idea of the immunopathogenesis of this disorder and may allow the development
of a diagnostic test for seronegative MG patients.
PMID- 9546324
TI - Valproate, lamotrigine, and insulin-mediated risks in women with epilepsy.
AB - We recently reported the frequent occurrence of polycystic ovaries and
hyperandrogenism associated with weight gain and hyperinsulinemia in women taking
valproate for epilepsy. The purpose of this study was to evaluate the risks
related to valproate-induced hyperinsulinemia and their reversibility after
discontinuing the medication. Sixteen women with valproate-related polycystic
ovaries or hyperandrogenism participated in the study. Vaginal ultrasonography
was performed, and endocrine and lipid parameters were measured. Thereafter,
lamotrigine was substituted for valproate and the patients were observed for 12
months. Twenty-four healthy age-matched women served as control subjects. Twelve
women completed the 12-month follow-up. While still on valproate they had
centripetal obesity with associated hyperinsulinemia and unfavorable serum lipid
profiles. The body-mass index and fasting serum insulin and testosterone
concentrations decreased during the first year after replacing valproate with
lamotrigine whereas the HDL-cholesterol/total cholesterol ratios increased from
0.17 +/- 0.06 to 0.26 +/- 0.05. The total number of polycystic ovaries in these
women decreased from 20 during valproate medication to 11 one year after
replacing valproate with lamotrigine. Valproate induces a metabolic syndrome with
centripetal obesity, hyperinsulinemia, lipid abnormalities, and polycystic
ovaries/hyperandrogenism in women with epilepsy. These valproate-related risks
can be reduced by substituting lamotrigine for valproate.
PMID- 9546327
TI - Multiple sclerosis: in situ evidence for antibody- and complement-mediated
demyelination.
AB - We describe a case of multiple sclerosis characterized by deposition of
immunoglobulin and complement in the areas of active demyelination. This was
particularly evident for the C9neo antigen, which is a marker for the activated
lytic complement complex and was exclusively deposited in the areas of active
myelin destruction. In addition, macrophages in the lesions contained degradation
products that were immunoreactive for myelin antigens, immunoglobulins, and C9neo
antigen. Destruction of myelin sheaths was associated with incomplete loss of
oligodendrocytes in the active areas and reappearance of oligodendrocytes with
remyelination in the inactive plaque center.
PMID- 9546328
TI - Cortical reflex myoclonus in Rett syndrome.
AB - Rett syndrome (RS) is one of the most frequent causes of mental retardation in
females. As there are no known biochemical, genetic, or morphological markers,
diagnosis is based on clinical phenotype including severe dementia, autism,
truncal ataxia/apraxia, loss of purposeful hand movements, breathing
abnormalities, stereotypies, seizures, and extrapyramidal signs. Myoclonus,
although reported in some series, has never been characterized. We studied 10 RS
patients, age 3 to 20 years, and observed myoclonus in 9. Severity of myoclonus
did not correlate with that of the other symptoms or with age. Multifocal,
arrhythmic, and asynchronous jerks mainly involved distal limbs.
Electromyographic bursts lasted 48 +/- 12 msec. Burst-locked
electroencephalographic averaging generated a contralateral centroparietal
premyoclonus transient preceding the burst by 34 +/- 7.2 msec. Motor evoked
potentials showed normal latencies, indicating integrity of the corticospinal
pathway. Somatosensory evoked potentials were enlarged. The C-reflex was
hyperexcitable and markedly prolonged (62 +/- 4.3 msec), mainly due to increase
in cortical relay time (28.4 +/- 4.5 msec). We conclude that RS patients show a
distinctive pattern of cortical reflex myoclonus with prolonged intracortical
delay of the long-loop reflex.
PMID- 9546329
TI - Quinidine sulfate therapy for the slow-channel congenital myasthenic syndrome.
AB - The slow-channel congenital myasthenic syndrome (SCCMS) is caused by gain of
function mutations in subunits of the end-plate acetylcholine receptor (AChR).
The mutations prolong the opening episodes of the AChR channel, leading to a
depolarization block and an end-plate myopathy. Because levels of quinidine
sulfate attainable in clinical practice shorten the opening episodes of
genetically engineered mutant SCCMS receptors in vitro, we tested the notion that
the drug can be of benefit in SCCMS. We treated 6 SCCMS patients with quinidine
sulfate in an open-label trial, using objective clinical measures of muscle
strength and repetitive stimulation studies as end points. One patient became
allergic to quinidine after 7 days. The remaining patients tolerated the drug
well and after 30 days of continuous therapy showed statistically significant
improvement in muscle strength and in decrement of the compound muscle action
potential elicited by rapid rates of stimulation.
PMID- 9546330
TI - Angelman syndrome: correlations between epilepsy phenotypes and genotypes.
AB - We compared epilepsy phenotypes with genotypes of Angelman syndrome (AS),
including chromosome 15q11-13 deletions (class I), uniparental disomy (class II),
methylation imprinting abnormalities (class III), and mutation in the UBE3A gene
(class IV). Twenty patients were prospectively selected based on clinical
cytogenetic and molecular diagnosis of AS. All patients had 6 to 72 hours of
closed-circuit television videotaping and digitized electroencephalogrpahic (EEG)
telemetry. Patients from all genotypic classes had characteristic EEGs with
diffuse bifrontally dominant high-amplitude 1- to 3-Hz notched or triphasic or
polyphasic slow waves, or slow and sharp waves. Class I patients had severe
intractable epilepsy, most frequently with atypical absences and myoclonias and
less frequently with generalized extensor tonic seizures or flexor spasms.
Epileptic spasms were recorded in AS patients as old as 41 years. Aged-matched
class II, III, and IV patients had either no epilepsy or drug-responsive mild
epilepsy with relatively infrequent atypical absences, myoclonias, or atonic
seizures. In conclusion, maternally inherited chromosome 15q11-13 deletions
produce severe epilepsy. Loss-of-function UBE3A mutations, uniparental disomy, or
methylation imprint abnormalities in AS are associated with relatively mild
epilepsy. Involvement of other genes in the chromosome 15q11-13 deletion, such as
GABRB3, may explain severe epilepsy in AS.
PMID- 9546331
TI - The role of type III collagen in spontaneous cervical arterial dissections.
AB - A case-control study was carried out to investigate whether type III collagen
deficiency plays a role in the pathogenesis of spontaneous cervical arterial
dissections. In 16 patients with spontaneous cervical arterial dissections and in
41 healthy controls, protein analysis of type III collagen (ratio of type
III/type I collagen) was performed. Furthermore, single-stranded conformation
polymorphism/heteroduplex analysis was used to investigate the type III collagen
gene in the 16 patients with spontaneous cervical dissections to detect
mutations. The ratios of type III/type I collagen in the controls ranged from 5.5
to 19.8% (median, 10%). The ratios of type III/type I collagen in the patients
with spontaneous cervical arterial dissections ranged from 3.2 to 17.9% (median,
9.3%). Two patients had a low ratio of type III/type I collagen (<5.5%). No
abnormalities suggesting a mutation in the gene of type III collagen were
demonstrated in any of the 16 patients. Our findings are in keeping with the
hypothesis that a reduced production of type III collagen may contribute to the
formation of spontaneous cervical arterial dissections in some patients. The
absence of a responsible mutation indicates that the coding sequence of the type
III collagen gene is not involved.
PMID- 9546332
TI - Guidelines for using quantitative measures of brain magnetic resonance imaging
abnormalities in monitoring the treatment of multiple sclerosis.
AB - The change of brain lesion load, measured on T2-weighted magnetic resonance
imaging (MRI) using computer-assisted techniques, is a widely used secondary
endpoint for phase III clinical trials in multiple sclerosis (MS). Collection,
transfer, and analysis of the electronic data across multiple centers have all
proved challenging and give rise to potential errors. However, many new
acquisition schemes and postprocessing techniques have been developed; these may
reduce scan times and result in better lesion conspicuity or lessen the human
interaction needed for data analysis. This review considers many aspects of the
use of MRI in clinical trials for MS and provides international consensus
guidelines, derived from a task force of the European Magnetic Resonance Networks
in Multiple Sclerosis (MAGNIMS) together with a group of North American experts.
The main points considered are the organization of correctly powered trials and
selection of participating sites; the appropriate choice of pulse sequences and
image acquisition protocol given the current state of technology; quality
assurance for data acquisition and analysis; accuracy and reproducibility of
lesion load assessments; and the potential for the application of quantitative
methods to other MRI-derived measures of disease burden.
PMID- 9546333
TI - Adenosine A2A antagonist: a novel antiparkinsonian agent that does not provoke
dyskinesia in parkinsonian monkeys.
AB - Treatment of Parkinson's disease with L-dopa therapy leads to long-term
complications, including loss of drug efficacy and the onset of dyskinesia.
Adenosine A2A receptors in striatum are selectively localized to GABAergic output
neurons of the striato-pallidal pathway and may avoid such problems. The novel
adenosine A2A receptor antagonist KW-6002 has been examined for antiparkinsonian
activity in MPTP-treated primates. Oral administration of KW-6002 reversed motor
disability in MPTP-treated common marmosets in a dose-dependent manner. However,
KW-6002 only modestly increased overall locomotor activity and did not cause
abnormal movement, such as stereotypy. The ability of KW-6002 to reverse motor
disability was maintained on repeated daily administration for 21 days, and no
tolerance was observed. KW-6002 induced little or no dyskinesia in MPTP-treated
primates previously primed to exhibit dyskinesia by prior exposure to L-dopa.
These results suggest that selective adenosine A2A receptor antagonists represent
a new class of antiparkinsonian agents that improve disability without producing
hyperactivity and without inducing dyskinesia.
PMID- 9546334
TI - Paroxysmal tonic upgaze: a reappraisal of outcome.
AB - Paroxysmal tonic upgaze (PTU) of childhood is a distinctive neuro
ophthalmological syndrome of unknown etiology and pathogenesis that is
characterized by episodes of sustained upward deviation of the eyes, often with
incomplete downward saccades on attempted downgaze. It is generally regarded as
having a benign outcome. We observed 16 children with PTU, from 10 months to 11
years from onset (mean, 5.4 years), to study the natural history and possible
etiology. Five cases were from two unrelated families. Onset of PTU occurred
either during or after an intercurrent infection or vaccination in 5 children. No
antecedent was identifiable in the rest. PTU had completely resolved in 10
children (62%) (mean age at offset, 2.5 years), whereas 2 children intermittently
manifest a modified form of the disorder. At follow-up, 11 children (69%) had
developmental delay, intellectual disability, or language delay and 9 (56%) had
ocular motility problems other than PTU. Only 3 children (19%) had normal
development and neurological findings. PTU is a heterogeneous syndrome with
respect to associations and outcome and may simply be an age-dependent
manifestation of a variety of disorders affecting corticomesencephalic control of
vertical eye movement. This disorder may be an early sign of more widespread
neurological dysfunction.
PMID- 9546335
TI - Cerebrospinal fluid homovanillic acid levels in rapid-onset dystonia
parkinsonism.
AB - Rapid-onset dystonia-parkinsonism (RDP) is characterized by sudden onset over
hours to days of dystonia, dysphagia, dysarthria, and parkinsonism. RDP has been
reported by our group in two apparently unrelated families. We now report
analysis of cerebrospinal fluid metabolites of dopamine, norepinephrine, and
serotonin for mild and severely affected individuals, known asymptomatic gene
carriers, and at-risk individuals from both families with RDP. Levels of the
dopamine metabolite homovanillic acid (HVA) were decreased in severely affected
patients and in some asymptomatic gene carriers. HVA levels increased with
treatment in some affected individuals, but this increase did not predict
clinical response to carbidopa/levodopa. We suggest that a low HVA level is a
biological marker with modest association to the diagnosis of RDP.
PMID- 9546336
TI - A permanent pure amnestic syndrome of insidious onset related to Alzheimer's
disease.
AB - A 55-year-old patient experienced a pure amnestic syndrome of insidious onset
that worsened progressively. Subsequently, her memory disorder stabilized and
remained her only cognitive impairment for several years. She ultimately
developed more widespread cognitive decline and terminal dementia. Postmortem
examination 18 years after the onset revealed numerous senile plaques and
neurofibrillary tangles consistent with Alzheimer's disease. A permanent pure
amnestic syndrome of insidious onset may represent a further type of focal
cerebral degeneration.
PMID- 9546337
TI - Clinical demographics of multiplex families with multiple sclerosis. Multiple
Sclerosis Genetics Group.
AB - The demographic and clinical characteristics of 89 multiplex families whose
affected members meet proposed diagnostic criteria for multiple sclerosis (MS)
genetic research are described and compared with 425 sporadic cases of MS and
other published collections of MS multiplex families. The proportion of affected
multiplex family members who experienced gradual progression of disability from
onset (primary progressive MS) is lower than reported by other investigators.
Different phenotypes of MS may reflect genetic heterogeneity that may partially
explain inconsistencies in the results of genetic linkage studies. Clinical
details of affected multiplex family members must be described so that
comparisons of genetic results across studies can be properly interpreted.
PMID- 9546338
TI - Optic neuritis heralding varicella zoster virus retinitis in a patient with
acquired immunodeficiency syndrome.
AB - We report on a 29-year-old severely compromised acquired immunodeficiency
syndrome patient who developed retrobulbar optic neuritis 5 weeks after an
episode of cutaneous herpes zoster infection. During the optic neuritis,
varicella zoster virus could be demonstrated in the cerebrospinal fluid. The
neuritis responded well to treatment with foscarnet, but, 3 weeks into therapy,
varicella zoster retinitis developed. Additional treatment with intravenous
acyclovir stopped progression of the retinitis and resulted in healing of the
retinal lesions. This case suggests that retrobulbar optic neuritis can be
regarded as a prodrome of imminent acute retinal necrosis. Early recognition and
prompt therapy with combined antivirals may prevent the development of this
devastating ocular complication of varicella zoster infection.
PMID- 9546340
TI - Very long chain acyl-coenzyme A dehydrogenase deficiency with adult onset.
AB - Very long chain acyl-coenzyme A (acyl-CoA) dehydrogenase (VLCAD) deficiency is a
severe disorder of mitochondrial beta-oxidation in infants. We report adult onset
of attacks of painful rhabdomyolysis. Gas chromatography identified strongly
elevated levels of tetradecenoic acid, 14:1(n-9), tetradecadienoic acid, 14:2(n
6), and hexadecadienoic acid, 16:2(n-6). Palmitoyl-CoA and behenoyl-CoA
dehydrogenase in fibroblasts were deficient. Muscle VLCAD activity was very low.
DNA analysis revealed compound heterozygosity for two missense mutations in the
VLCAD gene. The relatively mild clinical course may be due to residual enzyme
activity as a consequence of the two missense mutations. Treatment with L
carnitine and medium chain triglycerides in the diet did not reduce the attacks
of rhabdomyolysis.
PMID- 9546339
TI - Neurotrophin-4 is up-regulated in ragged-red fibers associated with pathogenic
mitochondrial DNA mutations.
AB - Ragged-red fibers (RRFs) are found more frequently in highly oxidative type I
fibers than in glycolytic type II fibers in the muscle of many patients with
mitochondrial myopathies. Neurotrophin-4 (NT-4), a neuronal signaling molecule,
is also expressed in skeletal muscle, predominantly in type I fibers. We found
that NT-4 protein and mRNA were present in both type I and type II fibers but
were up-regulated in RRFs of patients with mitochondrial encephalomyopathies; it
is noteworthy that NT-4 was not up-regulated in muscle fibers from healthy
aerobically trained athletes. Thus, NT-4 might represent a member of a new class
of candidate molecules involved in the compensatory adjustments of muscle fibers
to oxidative dysfunction, and may even play a role as a signaling molecule for
mitochondrial proliferation.
PMID- 9546341
TI - APOE allele frequencies in demented and nondemented elderly Jamaicans.
PMID- 9546342
TI - Preserved tendon reflexes in Campylobacter neuropathy.
PMID- 9546343
TI - Gap junction function: the messenger and the message.
PMID- 9546344
TI - Regulation of uveal melanoma interconverted phenotype by hepatocyte growth
factor/scatter factor (HGF/SF).
AB - Human uveal melanoma disseminates initially and preferentially to the liver. This
study describes the relationship between the expression of the c-met proto
oncogene (receptor for hepatocyte growth factor/scatter factor (HGF/SF)) in
interconverted uveal melanoma cells (co-expressing vimentin and keratin
intermediate filaments) and the regulation of their motogenic response to HGF/SF,
a key step in local invasion and targeted dissemination to the liver. Expression
of c-met in uveal melanoma cell lines correlates with both the appearance of an
interconverted phenotype and invasive ability (measured in vitro). Using
chemotactic checkerboard analysis, the greatest motogenic response to HGF/SF was
achieved by invasive, interconverted, c-met-positive uveal melanoma cells. C-met
was observed histologically in a uveal melanoma containing interconverted cells
but was absent in a tumor composed of non-interconverted cells (vimentin
positive/keratin negative). The c-met ligand, HGF/SF, although not expressed by
uveal melanoma cell lines, was localized in tissue sections of primary uveal
melanomas and metastatic melanoma to the liver. In the primary tumor, staining
for HGF/SF was most intense at the level of the choriocapillaris, a finding that
is significant because 1) highly remodeled neovascular loops and networks, which
appear in tumors likely to disseminate, can be traced to the choriocapillaris and
the draining vortex veins and 2) HGF/SF plays a role in tumor angiogenesis. Foci
of metastatic melanoma to the liver stain diffusely for HGF/SF. Regulation of the
uveal melanoma interconverted phenotype by HGF/SF may play an important role in
the dissemination of this tumor.
PMID- 9546345
TI - Nasopharyngeal carcinomas frequently lack the p16/MTS1 tumor suppressor protein
but consistently express the retinoblastoma gene product.
AB - The p16/MTS1 gene is altered by deletion, mutation, or hypermethylation in a wide
variety of human cancers. As a result of deficient p16 protein, these cancers
lack a critical mechanism for halting G1/S cell cycle progression. In the current
study, 59 cases of nasopharyngeal carcinoma were evaluated for expression of the
p16 tumor suppressor protein by immunohistochemical analysis of paraffin-embedded
tissue. There was no detectable p16 in 38/59 cases (64%), which implies a very
high rate of p16 inactivation in this type of cancer. On the other hand, the
retinoblastoma gene product, which also regulates the G1 to S phase transition of
the cell cycle, was consistently expressed in nasopharyngeal carcinomas by
immunohistochemical analysis. These results implicate p16 inactivation but not Rb
alteration in the stepwise progression of nasopharyngeal carcinogenesis.
PMID- 9546346
TI - Evidence of oxidative stress and in vivo neurotoxicity of beta-amyloid in a
transgenic mouse model of Alzheimer's disease: a chronic oxidative paradigm for
testing antioxidant therapies in vivo.
AB - Increased expression of antioxidant enzymes and heat-shock proteins are key
markers of oxidative stress. Such proteins are abnormally present within the
neuropathological lesions of Alzheimer's disease (AD), suggesting that oxidative
stress may play significant but yet undefined roles in this disorder. To gain
further insight into the role of oxidative stress in AD, we studied the
expression of CuZn superoxide dismutase (SOD) and hemoxygenase-1 (HO-1), two
established markers of oxidative stress, in a transgenic mouse model of AD.
Immunohistochemistry with anti-SOD and anti-HO-1 antibodies revealed a very
pronounced increase of these proteins only in aged transgene-positive mice.
Interestingly, the distribution of the oxidative burden was largely overlapping
with dystrophic neuritic elements in the mice as highlighted with anti-ubiquitin
antibodies. Because the most conspicuous alterations were identified around
amyloid (Abeta) deposits, our results provide strong support for the hypothesis
that Abeta is neurotoxic in vivo and that such toxicity is mediated by free
radicals. To obtain additional experimental evidence for such an interpretation
(ie, a cause-effect relationship between Abeta and oxidative neurotoxicity), PC12
cells were exposed to increasing concentrations of Abeta or to oxidative stress.
In agreement with the in vivo findings, either treatment caused marked induction
of SOD or HO-1 in a dose-dependent fashion. These results validate the transgenic
approach for the study of oxidative stress in AD and for the evaluation of
antioxidant therapies in vivo.
PMID- 9546347
TI - Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and
dementia with Lewy bodies.
AB - Lewy bodies (LBs) are hallmark lesions of degenerating neurons in the brains of
patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB).
Recently, a point mutation in the gene encoding the presynaptic alpha-synuclein
protein was identified in some autosomal-dominantly inherited familial PD
pedigrees, and light microscopic studies demonstrated alpha-synuclein
immunoreactivity in LBs of sporadic PD and DLB. To characterize alpha-synuclein
in LBs, we raised monoclonal antibodies (MAbs) to LBs purified from DLB brains
and obtained a MAb specific for alpha-synuclein that intensely labeled LBs. Light
and electron microscopic immunocytochemical studies performed with this MAb as
well as other antibodies to alpha-and beta-synuclein showed that alpha-synuclein,
but not beta-synuclein, is a component of LBs in sporadic PD and DLB. Western
blot analyses of highly purified LBs from DLB brains showed that full-length as
well as partially truncated and insoluble aggregates of alpha-synuclein are
deposited in LBs. Thus, these data strongly implicate alpha-synuclein in the
formation of LBs and the selective degeneration of neurons in sporadic PD and
DLB.
PMID- 9546348
TI - RNA synthesis and splicing interferes with DNA in situ end labeling techniques
used to detect apoptosis.
AB - The detection of DNA fragmentation by the use of the TUNEL technique has become a
standard technique for the detection of apoptosis in tissue sections. DNA
cleavage, detected by the TUNEL technique, is the last irreversible stage of the
apoptosis cascade. When the nuclear DNA is cleaved in oligonucleosomal-sized
fragments, processes such as transcription are completely abolished. The values
of apoptotic cell death that were obtained for atherosclerotic plaques by the
TUNEL technique ranged from less than 2% up to 60%. The latter value would
indicate that plaques are in an imminent state of collapse, which is certainly
not the case. Other factors that could result in TUNEL labeling have to be
considered. Therefore, we developed a co-localization system and studied TUNEL
labeling together with markers of RNA transcription and splicing. The present
study demonstrates that, besides apoptotic nuclei, non-apoptotic nuclei that show
signs of active gene transcription are labeled by the TUNEL technique. The fact
that the TUNEL technique is not specific for the executive phase of apoptosis is
not surprising, as the technique is only selective (rather than specific) for
apoptotic nuclei as these contain a far greater degree of DNA fragmentation than
non-apoptotic nuclei. Therefore, we think that the TUNEL technique should be
combined with additional techniques, such as markers of transcription and
morphological criteria.
PMID- 9546350
TI - Biotin-labeled hairpin oligonucleotides: probes to detect double-strand breaks in
DNA in apoptotic cells.
AB - Hairpin oligonucleotides were synthesized with stems ending in a double-stranded
structure, which can be ligated to double-strand breaks in DNA, and with loops
that contain nucleotides modified by the attachment of biotin. These probes
specifically and sensitively detect double-strand breaks in apoptotic cells.
Localization of these probes is restricted to areas of chromatin characteristic
of apoptosis, whereas much more diffuse labeling was obtained when all available
3' DNA ends were labeled by terminal transferase. In principle, hairpin
oligonucleotide probes can be designed with any type of 3' or 5' overhang
complementary to double-strand DNA termini being detected.
PMID- 9546349
TI - Light and electron microscopic immunolocalization of presenilin 1 in abnormal
muscle fibers of patients with sporadic inclusion-body myositis and autosomal
recessive inclusion-body myopathy.
AB - Sporadic inclusion-body myositis (s-IBM) is the most common progressive muscle
disease of older persons. The muscle biopsy demonstrates mononuclear cell
inflammation and vacuolated muscle fibers containing paired helical filaments and
6- to 10-nm fibrils, both resembling those of Alzheimer disease brain and Congo
red positivity. The term hereditary inclusion-body myopathies (h-IBMs) designates
autosomal-recessive or autosomal-dominant disorders with muscle biopsies
cytopathologically similar to s-IBM but without inflammation. Vacuolated muscle
fibers of both s-IBM and the h-IBMs contain accumulations of several "Alzheimer
characteristic proteins" including beta-amyloid protein and beta-amyloid
precursor protein, and their paired helical filaments are composed of
phosphorylated tau. We used six well characterized antibodies against several
residues of presenilin 1 (PS1) to immunostain muscle biopsies of 12 patients with
s-IBM, 5 patients with autosomal-recessive inclusion-body myopathy, and 16 normal
and disease controls. Seventy to eighty percent of the vacuolated muscle fibers
of both s-IBM and autosomal-recessive inclusion-body myopathy had inclusions that
were strongly PS1-immunoreactive, which by immunoelectron microscopy localized
mainly to paired helical filaments and 6- to 10-nm filaments. None of the control
biopsies had PS1-positive inclusions characteristic of the s- and h-IBM abnormal
muscle fibers. Mutations of the newly discovered PS1 gene are responsible for
early-onset familial Alzheimer disease (AD), and PS1 is abnormally accumulated in
sporadic and familial AD brain. Our study provides the first demonstration of PS1
abnormality in non-neural tissue and in diseases other than AD and suggests that
the cytopathogenesis in AD brain and IBM muscle may share similarities.
PMID- 9546351
TI - A quantitative method for determination of endothelial mRNA expression in vivo:
induction of platelet-derived growth factor by endotoxin.
AB - Quantitation of mRNA expression by endothelial cells in vivo has been limited to
larger animals from which sufficient amounts of RNA could be isolated for
Northern blot analysis. In the present study, we established a technique to
isolate endothelial RNA from rat aortas using en face preparations. This RNA was
not contaminated with RNA from smooth muscle cells as demonstrated by the absence
of smooth muscle alpha-actin RNA. Following lipopolysaccharide (LPS)
administration to rats, quantitation of platelet-derived growth factor (PDGF)
ligand and receptor mRNA expression was carried out by competitive reverse
transcriptase-polymerase chain reaction and normalized to glyceraldehyde-3
phosphate dehydrogenase. The results of the competitive reverse transcriptase
polymerase chain reaction were compared with those obtained by en face in situ
hybridization. Aortic endothelium showed a 140-fold increase in PDGF-A mRNA
expression 4 hours after LPS injection. Expression levels of this growth factor
declined to near base line levels within 36 hours of the LPS injection. A 52-fold
increase in PDGF-B mRNA was seen at 12 hours after LPS injection but expression
levels were approximately 300-fold lower than for PDGF-A. These data indicate
that changes in PDGF expression by endothelium in vivo can greatly exceed those
observed in cultured cells. This method should permit study of endothelial gene
regulation in a variety of pathological conditions in vivo.
PMID- 9546352
TI - Clonal architecture of normal and atherosclerotic aorta: implications for
atherogenesis and vascular development.
AB - X chromosome inactivation studies indicate that smooth muscle cells in human
atherosclerosis are monoclonal. Monoclonality could arise either by 1)
proliferation of a single cell in the adult intima, eg, by selection or mutation,
or 2) proliferation of many cells within a large, pre-existing clonal patch that
formed during development. To determine whether clonal expansion occurs
concomitantly with plaque growth or as part of normal development, X chromosome
inactivation patterns were mapped in microdissected samples of aortic smooth
muscle, using the human androgen receptor locus as a marker. As expected, 43% of
plaque samples were skewed toward one X chromosome, indicating a monoclonal
population. Surprisingly, 25% of normal medial samples and 31% of diffuse intimal
thickening samples also were skewed toward one X chromosome, indicating a
relatively large patch size. Furthermore, 30% of diffuse intimal thickening and
22% of medial samples showed contiguous regions of 4 mm skewed to the same
allele, showing that patch length often exceeded 4 mm. Intima and overlying media
typically were skewed to the same allele (73% concordance), suggesting common
cells of origin. Because patch size is large in normal arteries, X-inactivation
analysis cannot discriminate between a monoclonal and a polyclonal origin of
plaque smooth muscle cells. We propose that human arteries grow by expanding
coherent smooth muscle clones, with little mixing of adjacent clones. Determining
whether plaques arise by clonal expansion will require other approaches, such as
analysis of somatic mutations; the finding of large X-inactivation patches raises
the possibility that plaques arise from a pre-existing (developmental) clone.
PMID- 9546353
TI - Temporal expression of pro-inflammatory cytokines and inducible nitric oxide
synthase in experimental acute Chagasic cardiomyopathy.
AB - To characterize the kinetics of myocardial cytokine and inducible nitric oxide
synthase (iNOS) expression in acute Chagasic cardiomyopathy, we studied a rat
model of acute Trypanosoma cruzi infection. Rats were euthanized 36 hours and 5,
10, and 15 days after infection, and hearts were collected for histology, mRNA,
and protein analyses. Histological analysis of myocardium showed a progressive
increase in the number of amastigotes and mononuclear inflammatory cells.
Organisms were first detected 5 days after intraperitoneal inoculation as
isolated nests and became numerous by day 15. Northern blot analysis of total RNA
revealed no signal for interleukin (IL)-1beta or tumor necrosis factor (TNF)
alpha and a weak signal for IL-6 in control hearts. High levels of expression for
the three genes were detected in the infected animals at 36 hours after
infection. Although IL-1beta and IL-6 levels increased steadily up to 10 days,
TNF-alpha levels were the highest at 5 days, remained high at 10 days, and
declined thereafter. Western blot analysis showed similar results to that of mRNA
expression. No signal was detected for iNOS in the controls, but both its mRNA
and protein were found in the infected animals, with levels being highest at 15
days after infection. Immunohistochemistry revealed no iNOS immunoreactivity in
uninfected animals, but intense iNOS staining was detected in blood vessels of
infected animals, which decreased progressively with period of infection.
Positive staining for iNOS in cardiomyocytes was first detected at 36 hours after
infection (at a time when there was no histological inflammatory reaction), which
steadily increased, being the highest at 15 days after infection. These results
indicate that, in addition to mechanical damage by T. cruzi, substantial pro
inflammatory cytokine production within the myocardium is likely to participate
in the pathophysiology of acute Chagasic cardiomyopathy.
PMID- 9546354
TI - Compound heterozygosity for missense (L156P) and nonsense (R554X) mutations in
the beta4 integrin gene (ITGB4) underlies mild, nonlethal phenotype of
epidermolysis bullosa with pyloric atresia.
AB - Mutations in the genes encoding the subunit polypeptides of the alpha6beta4
integrin (ITGA6 and ITGB4, respectively) have been previously demonstrated in
patients with a lethal form of epidermolysis bullosa with congenital pyloric
atresia (OMIM #226730). In this study, we demonstrate for the first time ITGB4
mutations in nonlethal phenotype of epidermolysis bullosa with congenital pyloric
atresia. Specifically, the proband was shown to be a compound heterozygote for a
missense mutation (L156P) and a nonsense mutation (R554X). The leucine
substitution by proline was shown to affect a residue, which was precisely
conserved in different human, rodent, and drosophila integrin-beta polypeptides,
and consequently disrupts the alpha-helix formation of the polypeptide segment as
determined by Garnier alpha-helicity plot. The nonsense mutation in another
allele was accompanied by undetectable levels of the corresponding mRNA
transcript, as determined by reverse transcription-polymerase chain reaction. The
presence of a missense mutation, when combined with a premature termination codon
mutation, may explain the milder blistering tendency of the skin in this patient.
PMID- 9546355
TI - Identification of cell types responsible for bone resorption in rheumatoid
arthritis and juvenile rheumatoid arthritis.
AB - Focal resorption of bone at the bone-pannus interface is common in rheumatoid
arthritis (RA) and juvenile rheumatoid arthritis (JRA) and can result in
significant morbidity. However, the specific cellular and hormonal mechanisms
involved in this process are not well established. We examined tissue sections
from areas of bone erosion in patients with RA and JRA. Multinucleated cells
(MNCs) were present in resorption lacunae in areas of calcified cartilage and in
subchondral bone immediately adjacent to calcified cartilage, as previously
described. mRNA for the calcitonin receptor (CTR) was localized to these MNCs in
bone resorption lacunae, a finding that definitively identifies these cells as
osteoclasts. These MNCs were also positive for tartrate-resistant acid
phosphatase (TRAP) mRNA and TRAP enzymatic activity. Occasional mononuclear cells
on the bone surface were also CTR positive. Mononuclear cells and MNCs not on
bone surfaces were CTR negative. The restriction of CTR-positive cells to the
surface of mineralized tissues suggests that bone and/or calcified cartilage
provide signals that are critical for the differentiation of hematopoietic
osteoclast precursors to fully differentiated osteoclasts. Some MNCs and
mononuclear cells off bone and within invading tissues were TRAP positive. These
cells likely represent the precursors of the CTR-TRAP-positive cells on bone.
Parathyroid hormone receptor mRNA was present in cells with the phenotypic
appearance of osteoblasts, in close proximity to MNCs, and in occasional cells
within pannus tissue, but not in the MNCs in bone resorption lacunae. These
findings demonstrate that osteoclasts within the rheumatoid lesion do not express
parathyroid hormone receptor. In conclusion, the resorbing cells in RA exhibit a
definitive osteoclastic phenotype, suggesting that pharmacological agents that
inhibit osteoclast recruitment or activity are rational targets for blocking
focal bone erosion in patients with RA and JRA.
PMID- 9546357
TI - Human CTLA-4 is expressed in situ on T lymphocytes in germinal centers, in
cutaneous graft-versus-host disease, and in Hodgkin's disease.
AB - Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4, CD152) is a molecule
expressed on in vitro activated T cells. CTLA-4 shares important sequence
homology with CD28 and binds to the same ligands, CD80 (B7-1) and CD86 (B7-2).
CTLA-4 probably functions as a negative regulator of T lymphocyte activation in
the mouse, although this remains to be proven for human T lymphocytes. We have
developed new monoclonal antibodies against human CTLA-4 and have investigated
the in situ expression of CTLA-4 in a wide variety of normal and pathological
human tissues expressing CD80 and CD86. As revealed in this study, CTLA-4 is
expressed on thymocytes in thymic medulla, on a subset of CD4+ T lymphocytes in
germinal centers of follicular hyperplasia, on T cells, mainly CD8+, infiltrating
skin affected by graft-versus-host disease, and on T cells, mainly CD4+,
infiltrating Hodgkin's disease lesions. In immunoelectron microscopy, CTLA-4 was
found on the plasma membrane as well as in the hyaloplasm and cytoplasmic
vesicles, in agreement with its pattern of expression on in vitro activated T
cells. Interestingly, no or at most scarce expression of CTLA-4 was found in
granulomatous lymph nodes, T-cell-mediated inflammatory diseases, or non
Hodgkin's lymphomas, regardless of their expression of CD80 or CD86. Thus,
expression of CTLA-4 appears to be induced in selective pathological conditions
in vivo. The pathways leading to selective induction of CTLA-4 and its role in
the pathophysiology of these conditions need to be further investigated.
PMID- 9546358
TI - Time course and cellular localization of interleukin-10 mRNA and protein
expression in autoimmune inflammation of the rat central nervous system.
AB - Experimental autoimmune encephalomyelitis of the Lewis rat is a T-cell-mediated
autoimmune disease of the central nervous system characterized by a self-limiting
monophasic course. In this study, we analyzed the expression of the anti
inflammatory cytokine interleukin (IL)-10 at the mRNA and protein level in
experimental autoimmune encephalomyelitis actively induced with the
encephalitogenic 68-86 peptide of guinea pig myelin basic protein.
Semiquantitative reverse transcriptase-polymerase chain reaction revealed that IL
10 mRNA expression peaked during the acute phase of the disease at days 11 and
13. IL-10 mRNA was synchronously induced with mRNA for the proinflammatory
cytokine interferon-gamma. Immunocytochemistry with a monoclonal antibody against
rat IL-10 showed that the peak of IL-10 mRNA was accompanied by an abundant
expression of IL-10 protein during the acute stage of the disease. Both in situ
hybridization and double labeling immunocytochemistry in combination with
confocal microscopy identified T cells, macrophages/microglia, and astrocytes as
major cellular sources of IL-10 in vivo. The early peak of IL-10 production was
unexpected in light of its well-documented anti-inflammatory properties.
Additional studies are required to determine whether endogenous IL-10 contributes
to rapid clinical remission typical for Lewis rat experimental autoimmune
encephalomyelitis or if it plays other, yet undefined, roles in central nervous
system autoimmunity.
PMID- 9546356
TI - Tubular up-regulation of clusterin mRNA in murine lupus-like nephritis.
AB - Clusterin, a widely distributed glycoprotein, is detected in most tissues and in
numerous physiological fluids. In the kidney, this protein is constitutively
expressed in tubular epithelial cells, and its expression is enhanced following
tubular injuries. In addition, clusterin has been detected in glomerular immune
deposits of glomerulonephritis. The present study was designed to define the
sites of clusterin mRNA accumulation in murine lupus-like nephritis in comparison
with murine tubulopathies. In lupus-like nephritis, a significant increase of
clusterin mRNA abundance was demonstrated. This up-regulation was localized
exclusively in tubular epithelial cells exhibiting tubulointerstitial
alterations, whereas no clusterin mRNA was detectable in diseased glomeruli,
excluding an active synthesis of clusterin by glomerular cells. A similar tubular
increase of clusterin mRNA abundance was observed in myeloma-like cast
nephropathy induced by IgG3 monoclonal cryoglobulins and even in the absence of
any detectable histological alterations in a model of septic shock induced by the
injection of bacterial lipopolysaccharides. Our results suggest that tubular
epithelial cells are the only sites of clusterin mRNA accumulation during the
course of lupus-like nephritis and that the tubular up-regulation of clusterin
gene expression may reflect the cellular response to various types of tubular
injuries.
PMID- 9546359
TI - Astrocytes containing amyloid beta-protein (Abeta)-positive granules are
associated with Abeta40-positive diffuse plaques in the aged human brain.
AB - Amyloid beta-protein (Abeta) is the major component of senile plaques that emerge
in the cortex during aging and appear most abundantly in Alzheimer's disease. In
the course of our immunocytochemical study on a large number of autopsy cases, we
noticed, in many aged nondemented cases, the presence of unique diffuse plaques
in the cortex distinct from ordinary diffuse plaques by immunocytochemistry. The
former were amorphous, very faintly Abeta-immunoreactive plaques resembling
diffuse plaques, but they stained for Abeta40 and were associated with small
cells containing Abeta-positive granules. A panel of amino- and carboxyl-terminal
specific Abeta antibodies showed that such Abeta40-positive diffuse plaques and
cell-associated granules were composed exclusively of amino-terminally deleted
Abeta terminating at Abeta40, -42, and -43. Double immunostaining also showed
that those Abeta-immunoreactive granules are located in astrocytes and not in
microglia or neurons. Immunoelectron microscopy revealed that nonfibrillar Abeta
immunoreactivity was located within lipofuscin-like granules in somewhat swollen
astrocytes. These findings raise the possibility that astrocytes take up Abeta
and attempt to degrade it in lysosomes in the aged brain.
PMID- 9546360
TI - Connexin43 gap junctions in normal, regenerating, and cultured mouse bone marrow
and in human leukemias: their possible involvement in blood formation.
AB - Communicating channels called gap junctions are thought to play a ubiquitous part
in cell growth and development. Based on earlier work, we have recently found
functional evidence of their presence in human and mouse bone marrow. In this
study we studied the cell-type association of the gap junction channel-forming
protein, connexin, in mouse and human bone marrow under different physiological
and pathological conditions and tested the pathway of communication in bone
marrow cultures. For high-resolution antigen demonstration we took advantage of
semi-thin resin sections, antigen retrieval methods, immunofluorescence, and
confocal laser scanning microscopy. Connexin43 (Cx43) and its mRNA were
consistently expressed in human and rodent marrow. Cx37 was found only in the
arteriolar endothelium, but neither Cx32 nor -26 were expressed. In tissue
sections, the immunostained junctions appeared as dots, which were digitally
measured and counted. Their average size was 0.40 mm in human and 0.49 mm in mice
marrow. There were at least twice as many gap junctions in the femoral midshaft
of 6-week-old mice (1.75 x 10(5)/mm3) as in those older than 12 weeks (0.89 x
10(5)/mm3). Most Cx43 was associated with collagen III+ endosteal and adventitial
stromal cells and with megakaryocytes. Elsewhere, they were few and randomly
distributed between all kinds of hematopoietic cells. In the femoral epiphysis of
juvenile mice, stromal cell processes full of Cx43 enmeshed three to six layers
of hematopoietic cells near the endosteum. The same pattern was seen in the
midshaft of regenerating mouse marrow 3 to 5 days after cytotoxic treatment with
5-fluorouracil. Functional tests in cultures showed the transfer of small
fluorescent dyes, Lucifer Yellow and 2',7'-bis-(2-carboxyethyl)-5, 6
carboxyfluorescein, between stromal cells and in rare cases between stromal and
hematopoietic cells too. The stromal cells were densely packed with Cx43 and we
found aggregates of connexon particles in their membrane replicas. In
normocellular human bone marrow, gap junctions were as rare as in adult mouse and
similarly distributed, except that they were also on adipocytic membranes. In a
few leukemic samples, characterized by an increased stromal/hematopoietic cell
ratio, there were two- to fourfold more Cx43 (2.8 x 10(5) to 3.9 x 10(5)/mm3)
than in the normal (1.0 x 10(5) to 1.2 x 10(5)/mm3). The cases included a
hypoplastic acute lymphoblastic leukemia, an acute myeloid leukemia (French
American-British classification M4-5), a case of myelodysplastic syndrome with
elevated number of megakaryocytes, and a CD34+ acute hemoblastosis, probably
acute myeloid leukemia (French-American-British classification M7). Taken
together, our results indicate that direct cell-cell communication may be
involved in hematopoiesis, ie, in developmentally active epiphyseal bone marrow
and when there is a demand for progenitors in regeneration. However, gap
junctions may not play as important a role in resting adult hematopoiesis and in
leukemias.
PMID- 9546361
TI - Distinct expression profiles of stromelysin-2 (MMP-10), collagenase-3 (MMP-13),
macrophage metalloelastase (MMP-12), and tissue inhibitor of metalloproteinases-3
(TIMP-3) in intestinal ulcerations.
AB - Programmed expression of matrix metalloproteinases is involved in wound healing
in various organs. We have previously demonstrated enhanced expression of
collagenase-1, stromelysin-1, matrilysin, and tissue inhibitor of
metalloproteinases (TIMP-1) in gastrointestinal ulcerations. To further define
the role of matrix-degrading enzymes and their inhibitors in intestinal
inflammation and ulcerations, the expression of stromelysin-2 (MMP-10),
collagenase-3 (MMP-13), macrophage metalloelastase (HME, MMP-12), and TIMP-3
mRNAs was studied using in situ hybridization and immunohistochemistry in 38
samples representing ulcerative colitis, Crohn's disease, ischemic colitis, and
normal intestine. As controls for normally healing intestinal wounds, 12
postoperative samples of rat experimental jejunal anastomoses were also examined.
The colitis types studied did not essentially differ in their MMP expression. We
found stromelysin-2 mRNA in laminin-5-positive and Ki-67-negative enterocytes
bordering the ulcerations. HME was abundantly expressed by macrophages in the
vicinity of shedding mucosal epithelium and beneath the necrotic surface of the
ulcers. Collagenase-3 and TIMP-3 were expressed by fibroblast-like cells deeper
in the remodeling intestinal wall. Expression for stromelysin-2 and collagenase-3
was observed in granulation tissue, but not the epithelium, of the rat
anastomoses. Our results suggest a role for stromelysin-2 in epithelial migration
and for metalloelastase in macrophage movement and epithelial cell shedding.
PMID- 9546362
TI - Post-transcriptional induction of p21cip1 protein in condylomata and dysplasias
is inversely related to human papillomavirus activities.
AB - Infections of the genital and oral epithelia by human papillomaviruses cause
condylomata, papillomas, and squamous intraepithelial neoplasms, some of which
can progress to invasive cancers. We describe an induction of p21cip1/WAF1/sdi1
protein in a fraction of the spinous cells in benign lesions and in cervical
intraepithelial neoplasia grades I and II. The induction appears to be post
transcriptional and independent of p53. p21cip1 antigen-positive cells were
sporadic in cervical intraepithelial neoplasia III and rare and focal in
carcinomas. In contrast, p21cip1 protein was below or at the threshold of
detection in the differentiated cells of normal squamous epithelia from different
body sites despite an up-regulation of p21cip1 RNA. In cervical intraepithelial
neoplasias from patients who were also positive for the human immunodeficiency
virus, there was an additional increase in p21cip1 RNA in the upper spinous cells
without concomitant p21cip1 protein induction. A consistent inverse relationship
was observed between the p21cip1 protein induction and abundant human
papillomavirus DNA and RNAs. We propose that p21cip1 protein induction is a novel
host response that inhibits viral DNA replication and thus prevents elevated
viral transcription. This hypothesis can partly account for the heterogeneity and
the differentiation-dependent viral activities commonly observed in benign human
papillomavirus lesions.
PMID- 9546363
TI - Insulinomas derived from hyperplastic intra-hepatic islet transplants.
AB - Insulinomas were induced in a new animal model by transplanting a low number of
isologous pancreatic islets via the portal vein into the livers of 66
streptozotocin-induced diabetic rats. In contrast to high-number islet
transplantation, which restored normoglycemia in 25 control animals, the low
number islet transplantation was followed by persisting hyperglycemia for at
least 13 months. Hyperplasia of islet cells developed in the transplanted islets
as a consequence of hyperglycemia, which for the beta cells is not only a
secretory but also a proliferative stimulus. Six of thirty-three animals between
the 18th and the 24th month after islet transplantation changed from
hyperglycemia to severe hypoglycemia, due to insulinomas that had developed in
the liver from the transplanted islets. In contrast to other animal models,
insulinoma development in this new model does not result from DNA damage by
chemicals or radiation or from the expression of transgenes, but starts from
apparently normal islets prepared from untreated isologous donors, which are
exposed to an imbalance in glucose metabolism. The persistent proliferative
stimulus and the metabolic alterations caused by the longstanding hyperglycemia
seem to be the most relevant oncogenic factors in this model.
PMID- 9546364
TI - The gamma-glutamyl transpeptidase gene is transcribed from a different promoter
in rat hepatocytes and biliary cells.
AB - Gamma-glutamyl transpeptidase (GGT) activity is commonly used to follow the
differentiation of liver precursor cells into the biliary lineage. However, the
GGT expression in immature hepatocytes or its induction in adult hepatocytes
following diverse carcinogenic or noncarcinogenic treatments has questioned the
reliability of GGT expression as a biliary marker. In the present study, we
investigated the GGT gene expression from its five different promoters in the
late fetal, neonatal, and adult rat liver by Northern blot, reverse transcription
polymerase chain reaction, and in situ hybridization analysis. We show that the
GGT activity in the 18-day-old fetus results from the transcription of the gene
from the promoter P3 in the hepatocytes. In contrast, the GGT promoter P4
activity appears to be specific of biliary cells in normal as well in cholestatic
liver. Thus, sequences unique to the GGT transcripts initiated on these two
alternate promoters provide unique molecular probes to discriminate between the
biliary and the hepatocytic phenotypes in liver differentiation and cell lineage
studies.
PMID- 9546366
TI - Analysis and clinical implications of p53 gene mutations and human papillomavirus
type 16 and 18 infection in primary adenocarcinoma of the uterine cervix.
AB - Mutant p53 is frequently detected in endometrial and ovarian carcinoma, but it is
rare in cervical cancers. Previous reports focused on cervical squamous cell
carcinoma, whereas cervical adenocarcinoma was given little attention. We
searched for p53 gene mutations in 74 primary cervical adenocarcinomas with known
human papillomavirus (HPV) status. Our aim was to evaluate the prevalence of p53
mutations and to investigate their possible role as an independent prognostic
factor. We found mutations in 13.5% with a high rate of G:C --> A:T transitions
as observed in endometrial adenocarcinoma. As p53 mutations are more frequently
detected in malignancies of high grade, high stage, and large size, this
molecular event seems to play a role in the progression rather than in the
induction of cervical adenocarcinoma. In our series, patients with HPV-negative
tumors and patients with mutated neoplasms, irrespective of HPV infection, had a
shorter survival. Yet the absence of HPV infection and presence of p53 mutations
are not independent risk factors for tumor-related death after adjustment for
clinicopathological confounders. The only significant and independent predictors
of survival are age of patient, stage of disease, tumor grade, and presence of
lymph node metastases.
PMID- 9546365
TI - Accelerated methylmercury elimination in gamma-glutamyl transpeptidase-deficient
mice.
AB - The disposition and toxicity of methylmercury, a ubiquitous environmental
pollutant, is modulated by binding to the endogenous tripeptide glutathione (GSH)
and metabolism of the resulting methylmercury-glutathione complex by the
ectoproteins gamma-glutamyl transpeptidase (GGT) and dipeptidase. To evaluate the
role of GGT in the whole-body disposition of methylmercury, we compared the
elimination of [203Hg]methylmercury in GGT-deficient mice with that in wild-type
mice and mice heterozygous for this deficiency. The effects of N-acetylcysteine
(NAC), a drug used to maintain the cysteine and GSH levels of GGT-deficient mice,
were also examined. Female mice were treated with either 0.5 or 25 micromol of
CH3 203HgCl/kg body weight, in the presence and absence of 10 mg/ml NAC in the
drinking water. There were no differences in methylmercury excretion between the
wild-type and heterozygous mice; however, the GGT-deficient mice excreted
methylmercury more rapidly at both dose levels. Wild-type and heterozygous mice
excreted from 11 to 24% of the dose in the first 48 hours, whereas the GGT
deficient mice excreted 55 to 66% of the dose, with most of the methylmercury
being excreted in urine. Urinary methylmercury excretion was further accelerated
in mice that received NAC. In contrast to methylmercury, the whole-body
elimination of inorganic mercury was not affected by GGT deficiency, although the
tissue distribution of inorganic mercury was markedly different in GGT-deficient
male mice, with only 13% of the 203Hg body burden in the kidneys of GGT-deficient
mice versus approximately 50% in kidneys of wild-type male mice. These findings
provide direct evidence for a major role of GGT in regulating the tissue
distribution and elimination of methylmercury and inorganic mercury and provide
additional support for the use of NAC as an antidote in methylmercury poisoning.
PMID- 9546367
TI - Monoclonality of both pale cells and cuboidal cells of sclerosing hemangioma of
the lung.
AB - Sclerosing hemangioma of the lung remains poorly understood, and it is still
unclear whether this lesion is neoplastic or not. It consists of two major cell
types, pale cells and cuboidal cells. We analyzed the clonality of each cell
types from six female cases of surgically resected sclerosing hemangioma. The
pale cells and cuboidal cells were separated by microdissection from methanol
fixed sections, and DNA was extracted for clonal analysis based on an X
chromosome-linked polymorphic marker, the human androgen receptor (HUMARA) gene
or the phosphoglycerate kinase (PGK) gene. The HUMARA and PGK genes were found to
be amplified with or without digestion by the methylation-sensitive restrictive
endonuclease HpaII. Five of six cases were informative. Pale cells and cuboidal
cells showed the same monoclonality in all of the informative cases, whereas the
control cells showed a polyclonal pattern. Our results demonstrated that
sclerosing hemangioma is caused by monoclonal expansion of cells, confirming that
it is a neoplasia. Moreover, the present data indicate that both pale cells and
cuboidal cells are derived from the same cell.
PMID- 9546368
TI - Methylation alterations of the MyoD1 upstream region are predictive of
subclassification of human rhabdomyosarcomas.
AB - MyoD1 expression is a distinguishing characteristic of rhabdomyosarcoma. In this
study, distinct methylation alterations were identified in the 5' flanking region
of the MyoD1 gene from the two major subtypes, ie, alveolar and embryonal
rhabdomyosarcoma. The MyoD1 methylation patterns of 26 rhabdomyosarcomas were
compared with that of normal skeletal muscle and nonmuscle specimens by Southern
blot analysis using methylation-sensitive restriction enzymes HhaI and HpaII. A 5
kb region immediately upstream of the MyoD1 coding sequence was found to be
methylated in adult muscle and all nonmuscle tissues tested. The MyoD1 upstream
region was unmethylated in the majority of the alveolar rhabdomyosarcomas (13 of
15, 87%) examined in this study. In contrast, 10 of 11 (91%) embryonal
rhabdomyosarcomas showed a methylation pattern that was also observed in fetal
muscle cells, in which the CpG sites in the MyoD1 upstream region were partially
methylated. Our data suggest that the methylation status of the MyoD1 upstream
CpG sites may be related to rhabdomyosarcoma tumorigenesis and may have valuable
implications for its differential diagnosis.
PMID- 9546370
TI - Regulation of synoviocyte proliferation, apoptosis, and invasion by the p53 tumor
suppressor gene.
AB - Recent studies show that 1) the p53 tumor suppressor protein is overexpressed by
rheumatoid arthritis (RA) synovium and fibroblast-like synoviocytes (FLS) and 2)
somatic mutations previously identified in human tumors are present in RA
synovium and FLS. We have hypothesized that abnormalities in p53 can contribute
to chronic destructive RA synovitis. To understand the functional consequences of
p53 abnormalities in FLS, RA and normal FLS expressing wild-type p53 were
transduced with a retroviral vector encoding the human papilloma virus 18 E6
gene, which inactivates endogenous p53 protein. Three RA and one normal FLS lines
were infected with recombinant retrovirus encoding the neomycin resistance gene
(neo) or E6+neo. FLS proliferation, apoptosis, and invasion was studied in E6,
neo, and uninfected parental strains (PS). The growth rate for E6 was
significantly increased with a sixfold increase in cell number after 7 days
compared with a twofold to threefold increase in neo and PS. When FLS were
treated with cytokines, proliferative response of E6, neo, and PS to interleukin
1 and transforming growth factor-beta were similar. However, response to platelet
derived growth factor was significantly greater in E6 FLS compared with neo or
PS. Apoptosis was studied by incubating FLS with sodium nitroprusside as a source
of nitric oxide or hydrogen peroxide for 8 hours and examining DNA fragmentation
and E6 cells were significantly less susceptible to cell death. In addition, E6
FLS were more invasive into cartilage extracts than neo or PS using an in vitro
cell invasion assay. These data suggest that p53 is a critical regulator of FLS
proliferation, apoptosis, and invasiveness. Abnormalities of p53 function might
contribute to synovial lining expansion and joint destruction in RA.
PMID- 9546371
TI - A rat model of spontaneous myopathy and malignant hyperthermia.
AB - Malignant hyperthermia is a main cause of death during general anesthesia,
particularly in children. However, research has been hampered by the lack of a
convenient animal model, the only one available being a special strain of pig. In
this study, we describe spontaneous myopathy and a fatal syndrome of generalized
muscle rigidity triggered by halothane in an outbred strain of rat. Histological
examination of skeletal muscle reveals severe abnormalities indicating chronic
underlying myopathy. The association of histological abnormalities with an acute,
fatal syndrome clinically resembling malignant hyperthermia provides a strong
basis for a new and extremely useful animal model to study this fatal disorder.
PMID- 9546369
TI - Heterogeneity in Lewis-X and sialyl-Lewis-X antigen expression on monocytes in
whole blood: relation to stimulus-induced oxidative burst.
AB - By using flow cytometric analysis of cells in whole blood expressing high levels
of CD14, we found a subpopulation of monocytes (8% of total) with higher scatter
parameters, high capacity to produce reactive oxygen species (ROS), stronger
expression of Lewis-X (CD15), sialyl-Lewis-X, CD11b and CD18 antigens, as well as
an increased polymerized actin content. The size of this subpopulation increased
after stimulation with lipopolysaccharide at the expense of the remaining
monocytes, suggesting that its features were inducible. The membrane increase in
Lewis-X and sialyl-Lewis-X expression observed during this conversion was largely
due to the translocation of these carbohydrate structures from intracellular
pools. Moreover, this subpopulation behaved as a primed monocyte subpopulation
producing large amounts of H2O2 in response to N-formyl-methionyl-leucyl
phenylalanine. Increased H2O2 production was inhibited not only by anti-CD14 but
also by anti-CD15 and anti-sialyl-Lewis-X monoclonal antibodies when added before
lipopolysaccharide. These results show that lipopolysaccharide priming is
regulated, at least in part, by Lewis-X and sialyl-Lewis-X structures expressed
on the monocyte membrane. All together, this highly reactive and inducible
subpopulation of monocytes, which share phenotypic and functional characteristics
with neutrophils, might play an important role in host defenses and inflammatory
responses.
PMID- 9546372
TI - Development of the cardiac conduction system.
PMID- 9546373
TI - Formation of the atrioventricular septal structures in the normal mouse.
AB - It is sometimes thought that formation of the atrioventricular septum is equated
with fusion of the endocardial cushions and that failure of fusion can explain
all deficiencies of atrioventricular septation. Clearly, this is simplistic, but
the exact contribution of different primordia to atrioventricular septation is
not well understood. To clarify this, we studied normal mouse embryos (days 10 to
15 of gestation), which were serially sectioned and examined by light microscopy.
Another group of embryos was examined by scanning electron microscopy after
microdissection. Our results show that development of the atrioventricular septal
area is highly complex. Proper formation requires the following: remodeling of
the inner heart curvature, rotation of the horns of the systemic venous sinus
around the pulmonary portal, expansion of the right atrioventricular junction,
formation of the muscular atrial and ventricular septa, bridging by the
dextrodorsal outflow ridge and the superior endocardial cushion, fusion with the
inferior margins of the venous valves, and formation of the mouth of the coronary
sinus from the cranial muscular wall of the left sinus horn. Multiple primordia
contribute to a central mesenchymal mass (the "septum intermedium"), including
the mesenchyme on the leading edge of the primary atrial septum, the
atrioventricular endocardial cushions, and the cap of mesenchyme on the spina
vestibuli. Fusion of these components closes the ostium primum, completing atrial
and atrioventricular septation. Additionally, the spina vestibuli has a
mesodermal core, which contributes to the muscularization of the lower margin of
the oval fossa. This contrasts with the formation of the upper rim, which occurs
as a result of an infolding of the atrial wall itself.
PMID- 9546374
TI - Effects of overexpression of the Na+-Ca2+ exchanger on [Ca2+]i transients in
murine ventricular myocytes.
AB - We measured [Ca2+]i and [Na+]i in isolated transgenic (TG) mouse myocytes
overexpressing the Na+-Ca2+ exchanger and in wild-type (WT) myocytes. In TG
myocytes, the peak systolic level and amplitude of electrically stimulated (ES)
[Ca2+]i transients (0.25 Hz) were not significantly different from those in WT
myocytes, but the time to peak [Ca2+]i was significantly prolonged. The decline
of ES [Ca2+]i transients was significantly accelerated in TG myocytes. The
decline of a long-duration (4-s) caffeine-induced [Ca2+]i transient was markedly
faster in TG myocytes, and [Na+]i was identical in TG and WT myocytes, indicating
that the overexpressed Na+-Ca2+ exchanger is functionally active. The decline of
a short-duration (100-ms) caffeine-induced [Ca2+]i transient in 0 Na+/0 Ca2+
solution did not differ between the two groups, suggesting that the sarcoplasmic
reticulum (SR) Ca2+-ATPase function is not altered by overexpression of the Na+
Ca2+ exchanger. There was no difference in L-type Ca2+ current density in WT and
TG myocytes. However, the sensitivity of ES [Ca2+]i transients to nifedipine was
reduced in TG myocytes. This maintenance of [Ca2+]i transients in nifedipine was
inhibited by Ni2+ and required SR Ca2+ content, consistent with enhanced Ca2+
influx by reverse Na+-Ca2+ exchange, and the resulting Ca2+-induced Ca2+ release
from SR. The rate of rise of [Ca2+]i transients in nifedipine in TG myocytes was
much slower than when both the L-type Ca2+ current and the Na+-Ca2+ exchange
current function together. In TG myocytes, action potential amplitude and action
potential duration at 50% repolarization were reduced, and action potential
duration at 90% repolarization was increased, relative to WT myocytes. These data
suggest that under these conditions, overexpression of the Na+-Ca2+ exchanger in
TG myocytes accelerates the decline of [Ca2+]i during relaxation, indicating
enhanced forward Na+-Ca2+ exchanger function. Increased Ca2+ influx also appears
to occur, consistent with enhanced reverse function. These findings provide
support for the physiological importance of both these modes of Na+-Ca2+
exchange.
PMID- 9546375
TI - Angiotensin II activates RhoA in cardiac myocytes: a critical role of RhoA in
angiotensin II-induced premyofibril formation.
AB - The organization of actin into striated fibers (myofibrils) is one of the major
features of cardiac hypertrophy. However, its signal transduction mechanism is
not well understood. Although Rho-family small G proteins have been implicated in
actin organization in many cell types, it is not fully elucidated whether Rho
mediates the organization of actin fibers by hypertrophic stimuli in cardiac
myocytes. Therefore, we examined (1) whether Rho is activated by the hypertrophic
stimulus, angiotensin II (Ang II), and (2) whether Rho mediates the Ang II
induced organization of actin fibers in cultured neonatal rat cardiac myocytes.
Treatment of myocytes with Ang II caused a rapid formation of both striated
(mature myofibrils) and nonstriated (premyofibrils) actin fibers within 30
minutes, as determined by phalloidin stainings of the polymerized actin and
troponin T stainings. Immunoblot analyses and immunostainings have indicated that
cardiac myocytes express RhoA, but RhoB is undetectable. In the control state,
RhoA was observed predominantly in the cytosolic fraction, but it was
translocated in part to the particulate fraction in response to Ang II,
consistent with activation of RhoA by Ang II. Incubation of myocytes with
exoenzyme C3 for 48 hours completely ADP-ribosylated Rho in vivo. The C3
treatment abolished formation of premyofibrils induced by Ang II, suggesting that
Ang II causes premyofibril formation via a Rho-dependent mechanism. The Ang II
induced mature myofibril formation was only partly abolished by C3. Expression of
constitutively active RhoA (V14RhoA) caused the formation of premyofibrils but
not mature myofibrils. The C3 treatment inhibited Ang II-induced atrial
natriuretic factor induction, whereas it had no effect on c-fos induction. These
results indicate that RhoA is activated by Ang II and mediates the Ang II-induced
formation of premyofibrils and induction of a subset of genes. Distinct signaling
mechanisms seem to be responsible for striated mature myofibril formation by Ang
II.
PMID- 9546376
TI - Acute glucose overload abolishes Ca2+ oscillation in cultured endothelial cells
from bovine aorta: a possible role of superoxide anion.
AB - Effects of acute glucose overload on [Ca2+]i were investigated in cultured
endothelial cells from bovine aorta. Application of 0.1 micromol/L ATP elicited
an oscillatory increase in [Ca2+]i (Ca2+ oscillation) in Krebs solution
containing 11.5 mmol/L glucose. The frequency of Ca2+ oscillation induced by ATP
increased in a concentration-dependent manner, ranging between 0.03 and 1
micromol/L. When cells were preincubated with 23 mmol/L glucose-containing Krebs
solution (high glucose solution) for 3 hours, 0.1 micromol/L ATP failed to induce
Ca2+ oscillation but evoked only a phasic followed by sustained increase in
[Ca2+]i. Application of a higher concentration of ATP (10 micromol/L) evoked a
transient increase in [Ca2+]i both in control and high glucose-treated cells.
However, the falling phase of [Ca2+]i was prolonged in high glucose-treated
cells. Thapsigargin (1 micromol/L), an inhibitor of endoplasmic Ca2+-ATPase,
induced a transient followed by a sustained increase in [Ca2+]i in control cells.
Preincubation with high glucose solution increased the rate of rise of the
thapsigargin-induced increase in [Ca2+]i and abolished the sustained increase,
suggesting that glucose overload accelerates Ca2+ leak from intracellular store
sites and impairs Ca2+ release-activated Ca2+ entry. We found that all of the
glucose overload-induced changes in Ca2+ mobilization could be mimicked by
xanthine with xanthine oxidase and abolished by superoxide dismutase. These
results indicate that acute glucose overload accumulates superoxide anion in
bovine aortic endothelial cells, thereby diminishing ATP-induced Ca2+ oscillation
through the impairment of Ca2+ homeostasis.
PMID- 9546377
TI - Ca2+-independent activation of the endothelial nitric oxide synthase in response
to tyrosine phosphatase inhibitors and fluid shear stress.
AB - Fluid shear stress enhances NO formation via a Ca2+-independent tyrosine kinase
inhibitor-sensitive pathway. In the present study, we investigated the effects of
the protein tyrosine phosphatase inhibitor phenylarsine oxide and of fluid shear
stress on endothelial NO production as well as on the membrane association and
phosphorylation of the NO synthase (NOS) III. Phenylarsine oxide (10 micromol/L)
induced an immediate and maintained NO-mediated relaxation of isolated rabbit
carotid arteries, which was insensitive to the removal of extracellular Ca2+ and
the calmodulin antagonist calmidazolium. This phenylarsine oxide-induced
vasodilatation was unaffected by genistein but abrogated by the tyrosine kinase
inhibitor erbstatin A. Incubation of native or cultured endothelial cells with
phenylarsine oxide resulted in a time-dependent tyrosine phosphorylation of
mainly Triton X-100-insoluble (cytoskeletal) proteins, along with a parallel
change in the detergent solubility of NOS III, such that the enzyme was recovered
in the cytoskeletal fraction. A similar, though slightly delayed, phenomenon was
also observed after the application of fluid shear stress but not in response to
any receptor-dependent agonist. Although Ca2+-independent NO formation was
sensitive to erbstatin A, phenylarsine oxide treatment was associated with the
tyrosine dephosphorylation of NOS III rather than its hyperphosphorylation.
Proteins that also underwent redistribution in response to the tyrosine
phosphatase inhibitor included paxillin, phospholipase C-gamma1, mitogen
activated protein kinase, and the tyrosine kinases Src and Fyn. We envisage that
fluid shear stress and tyrosine phosphatase inhibitors may alter the conformation
and/or protein coupling of NOS III, facilitating its interaction with specific
phospholipids, proteins, and/or protein kinases that enhance/maintain its Ca2+
independent activation.
PMID- 9546378
TI - Pulsatile stretch in coronary arteries elicits release of endothelium-derived
hyperpolarizing factor: a modulator of arterial compliance.
AB - To date, the release of the endothelium-derived hyperpolarizing factor (EDHF) has
been demonstrated only in response to receptor-dependent Ca2+-elevating agonists.
Since endothelial cells in situ are continuously subjected to rhythmic
distension, we investigated the effect of rhythmic stretch on the release of EDHF
from isolated porcine coronary arteries. In the combined presence of diclofenac
and N(G)-nitro-L-arginine (L-NNA), sinusoidal pressure oscillations (from 40 to
50 mm Hg, 4 minutes, 1.5 Hz) led to simultaneous oscillations in the external
diameter of coronary artery segments, the amplitude of which were decreased by
iberiotoxin and apamin and also by endothelial denudation. In order to directly
demonstrate the release of EDHF, the intraluminal solution from endothelium
intact coronary segments exposed to pulsatile stretch was applied to detector rat
aortic smooth muscle cells, the membrane potential of which was continuously
measured using the patch-clamp technique. The hyperpolarization of detector cells
induced by the intraluminal solution was proportional to the amplitude of the
pressure oscillations applied to the donor artery and was attenuated by either
preincubation of donor arteries with 17-octadecynoic acid or application of
either tetrabutylammonium or iberiotoxin to detector cells. In contrast to the
bradykinin-induced release of EDHF, the EDHF synthesized in response to pulsatile
stretch did not exhibit any tachyphylaxis. These findings demonstrate for the
first time that the synthesis of EDHF in coronary arteries can be mechanically
stimulated by rhythmic vessel wall distension and suggest that the continuous
release of EDHF may contribute to the adjustment of an adequate vascular
compliance and to the control of coronary blood flow.
PMID- 9546379
TI - Cooperative interactions between RB and p53 regulate cell proliferation, cell
senescence, and apoptosis in human vascular smooth muscle cells from
atherosclerotic plaques.
AB - Compared with vascular smooth muscle cells (VSMCs) from normal vessels, VSMCs
from human atherosclerotic plaques proliferate more slowly, undergo earlier
senescence, and demonstrate higher levels of apoptosis in culture. The tumor
suppressor genes p105RB (retinoblastoma, acting through the E2F transcription
factor family) and p53 regulate cell proliferation, cell senescence, and
apoptosis in many cell types. We have therefore determined whether these stable
growth properties of plaque VSMCs reflect altered activity of RB and/or p53.
VSMCs were derived from coronary atherectomies or from normal coronary arteries
from transplant recipients. Compared with normal VSMCs, plaque VSMCs showed a
higher ratio of the active (hypophosphorylated) to the inactive (phosphorylated)
form of RB and a lower level of E2F transcriptional activity. Cells were stably
transfected with retrovirus constructs that inhibited RB or p53 alone or in
combination. Suppression of RB alone increased rates of cell proliferation and
apoptosis and inhibited cell senescence in normal VSMCs. Suppression of p53 and
RB together had similar effects but, additionally, resulted in immortalization of
normal VSMC cultures. In contrast, inhibition of RB binding to E2F or ectopic
expression of E2F-1 in plaque VSMCs induced massive apoptosis, which required
suppression of p53 to rescue cells. Suppression of RB and p53 together increased
cell proliferation and delayed senescence but failed to immortalize plaque VSMCs.
Inhibition of p53 alone had minimal effects on plaque VSMCs but increased the
lifespan of normal VSMCs. We conclude that human plaque VSMCs have slower rates
of cell proliferation and earlier senescence than do cells from normal vessels
because of a defect in phosphorylation of RB. Furthermore, both disruption of
RB/E2F and inhibition of p53 are required for plaque VSMCs to proliferate without
apoptosis. This observation may explain the relatively low level of cell
proliferation and high level of apoptosis seen in VSMCs in human atherosclerotic
plaques.
PMID- 9546381
TI - Response of intra-acinar pulmonary microvessels to hypoxia, hypercapnic acidosis,
and isocapnic acidosis.
AB - To elucidate the differential reactivity of pulmonary microvessels in the acini
to hypoxia, excessive CO2, and increased H+, we investigated changes in the
diameter of precapillary arterioles, postcapillary venules, and capillaries in
isolated rat lungs on exposure to normocapnic hypoxia (2% O2), normoxic
hypercapnia (15% CO2), and isocapnic acidosis (0.01 mol/L HCl). Microvascular
diameters were precisely examined using a real-time confocal laser scanning
luminescence microscope coupled to a high-sensitivity camera with an image
intensifier. Measurements were made under conditions with and without
indomethacin or N(omega)-nitro-L-arginine methyl ester to assess the importance
of vasoactive substances produced by cyclooxygenase (COX) or NO synthase (NOS) as
it relates to the reactivity of pulmonary microvessels to physiological stimuli.
We found that acute hypoxia contracted precapillary arterioles that had diameters
of 20 to 30 microm but did not constrict postcapillary venules of similar size.
COX- and NOS-related vasoactive substances did not modulate hypoxia-elicited
arteriolar constriction. Hypercapnia induced a distinct venular dilatation
closely associated with vasodilators produced by COX but not by NOS. Arterioles
were appreciably constricted in isocapnic acidosis when NOS, but not COX, was
suppressed, whereas venules showed no constrictive response even when both
enzymes were inhibited. Capillaries were neither constricted nor dilated under
any experimental conditions. These findings suggest that reactivity to hypoxia,
CO2, and H+ is not qualitatively similar among intra-acinar microvessels, in
which COX- and NOS-associated vasoactive substances function differently.
PMID- 9546380
TI - Cell replication in the arterial wall: activation of signaling pathway following
in vivo injury.
AB - This study examined intracellular signal events of arterial cells following
balloon catheter injury to rat carotid artery. Within 30 minutes, a marked
increase in extracellular signal-regulated kinase-1/2 (ERK1/2) activity was
observed. This activity remained elevated for 12 hours but had decreased to
control levels by day 1. No increase in ERK1/2 was detected at any later times.
Injection of anti-fibroblast growth factor 2 antibody (60 mg i.v.) significantly
inhibited the activation of ERK1/2 at 30 minutes after the injury. PD98059 (80
micromol/L), a selective inhibitor of mitogen-activated protein kinase/ERK kinase
1 (MEK1), decreased ERK1/2 activity in injured arteries and also reduced the
medial cell replication. In contrast, PD98059 did not block the intimal cell
replication at day 8. Mitogen-activated protein kinase phosphatase-1 (MKP-1) was
expressed within hours after injury but only weakly at later times; MKP-1 was
again expressed after 7 and 14 days. The expression of MKP-1 was associated with
an activation of c-Jun amino-terminal kinase. Injury to the arterial wall also
stimulated the activity of p70 S6 kinase from 30 minutes to 12 hours, suggesting
an alternative pathway in mitogenic signaling of early cell replication. These
findings demonstrate that fibroblast growth factor 2-induced ERK1/2 activation
promotes medial cell replication after balloon injury; however, signaling of
intimal cell replication may not be linked to the MEK1-dependent ERK pathway.
PMID- 9546382
TI - Increased expression of Ca2+-sensitive K+ channels in the cerebral
microcirculation of genetically hypertensive rats: evidence for their protection
against cerebral vasospasm.
AB - The Ca2+-sensitive K+ channel (K(Ca) channel) plays a key role in buffering
pressure-induced constriction of small cerebral arteries. An amplified current
through this channel has been reported in vascular smooth muscle cells obtained
from hypertensive animals, implying that the expression or properties of K(Ca)
channels may be regulated by in vivo blood pressure levels. In this study, we
investigated this hypothesis and its functional relevance by comparing the
properties, expression levels, and physiological role of K(Ca) channels in
cerebral resistance arteries from normotensive and genetically hypertensive rats.
Whole-cell patch-clamp experiments revealed a 4.7-fold higher density of
iberiotoxin-sensitive K(Ca) channel current at physiological membrane potentials
in spontaneously hypertensive rat (SHR) compared with Wistar-Kyoto (WKY) rat
cerebrovascular smooth muscle cells (n = 18 and 21, respectively). However,
additional single-channel analysis in detached patches showed similar levels of
unitary conductance, voltage, and Ca2+ sensitivity in K(Ca) channels from WKY and
from SHR membranes. In contrast, Western analysis using an antibody directed
against the K(Ca) channel alpha-subunit revealed a 4.1-fold increase in the
corresponding 125-kD immunoreactive signal in cerebrovascular membranes from SHR
compared with WKY rats. The functional impact of this enhanced K(Ca) channel
expression was assessed in SHR and WKY rat pial arterioles, which were monitored
by intravital microscopy through in situ cranial windows. Progressive
pharmacological block of K(Ca) channels by iberiotoxin (0.1 to 100 nmol/L) dose
dependently constricted pial arterioles from SHR and WKY rats (n = 6 to 8). The
arterioles in SHR constricted 2- to 4-fold more intensely, and vasospasm occurred
in some vessels. These data provide the first direct evidence that elevated
levels of in situ blood pressure induce K(Ca) channel expression in
cerebrovascular smooth muscle membranes. This homeostatic mechanism may
critically regulate the resting tone of cerebral arterioles during chronic
hypertension. Furthermore, the overexpression of distinct K+ channel types during
specific cardiovascular pathologies may provide for the upregulation of novel
disease-specific membrane targets for vasodilator therapies.
PMID- 9546383
TI - Wag the tail: structural dynamics of actomyosin.
PMID- 9546384
TI - Kinesin: what gives?
PMID- 9546386
TI - RNA polymerase as a molecular motor.
PMID- 9546385
TI - Staying on track: common features of DNA helicases and microtubule motors.
PMID- 9546387
TI - The turn of the screw: the bacterial flagellar motor.
PMID- 9546388
TI - F1-ATPase: a rotary motor made of a single molecule.
PMID- 9546389
TI - The transfer of left-right positional information during chick embryogenesis.
AB - The earliest known left-right asymmetric genes are expressed at Hensen's node
during chick gastrulation. Gene expression following reorientation of the node
shows asymmetry is instructed by adjacent tissue, hence left-right information
originates outside the node. Subsequently, the node signals back to the lateral
tissue, initiating a cascade leading to left-sided expression of nodal in the
lateral plate mesoderm. Loss of nodal expression in the presence of blocking
antibodies confirms that Sonic hedgehog is the key signal conveying left-right
information from the node; however, manipulation of explant cultures suggests
that the induction of nodal requires secondary signals produced in the paraxial
mesoderm. These experiments establish the time of action of these signals to and
from Hensen's node in establishing left-right asymmetry.
PMID- 9546390
TI - The left-right coordinator: the role of Vg1 in organizing left-right axis
formation.
AB - The asymmetries of internal organs are consistently oriented along the left-right
axis in all vertebrates, and perturbations of left-right orientation lead to
significant congenital disease. We propose a model in which a "left-right
coordinator" interacts with the Spemann organizer to coordinate the
evolutionarily conserved three-dimensional asymmetries in the embryo. The Vg1
cell-signaling pathway plays a central role in left-right coordinator function.
Antagonists of Vg1 alter left-right development; antagonists of other members of
the TGFbeta family do not. Cell-lineage directed expression of Vg1 protein can
fully invert the left-right axis (situs inversus), can randomize left-right
asymmetries, or can "rescue" a perturbed left-right axis in conjoined twins to
normal orientation (situs solitus), indicating that Vg1 can mimic left-right
coordinator activity. These are the first molecular manipulations in any
vertebrate by which the left-right axis can be reliably controlled.
PMID- 9546391
TI - Odorant receptors govern the formation of a precise topographic map.
AB - Olfactory neurons expressing a given odorant receptor project with precision to 2
of the 1800 glomeruli within the olfactory bulb to create a topographic map of
odor quality. We demonstrate that deletions or nonsense mutations in the P2
odorant receptor gene cause the axons of these cells to wander rather than
converge on a specific glomerulus. Receptor substitution experiments that replace
the P2 gene with the coding region of the P3 gene result in the projection of P3-
>P2 axons to a glomerulus touching the wild-type P3 glomerulus. These data, along
with additional receptor substitutions, indicate that the odorant receptor plays
an instructive role in the establishment of the topographic map.
PMID- 9546392
TI - Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause
combined deficiency of coagulation factors V and VIII.
AB - Combined deficiency of factors V and VIII is an autosomal recessive bleeding
disorder resulting from alterations in an unknown gene on chromosome 18q,
distinct from the factor V and factor VIII genes. ERGIC-53, a component of the ER
Golgi intermediate compartment, was mapped to a YAC and BAC contig containing the
critical region for the combined factors V and VIII deficiency gene. DNA sequence
analysis identified two different mutations, accounting for all affected
individuals in nine families studied. Immunofluorescence and Western analysis of
immortalized lymphocytes from patients homozygous for either of the two mutations
demonstrate complete lack of expression of the mutated gene in these cells. These
findings suggest that ERGIC-53 may function as a molecular chaperone for the
transport from ER to Golgi of a specific subset of secreted proteins, including
coagulation factors V and VIII.
PMID- 9546393
TI - The C. elegans spe-9 gene encodes a sperm transmembrane protein that contains EGF
like repeats and is required for fertilization.
AB - In the nematode worm C. elegans, individuals with mutations in the spe-9 gene
produce spermatozoa with wild-type morphology and motility that cannot fertilize
oocytes even after contact between gametes. Therefore, disruption of spe-9
function affects either gamete recognition, adhesion, signaling, and/or fusion.
The spe-9 gene encodes a sperm transmembrane protein with an extracellular domain
that contains ten epidermal growth factor-like repeats. A common feature of
proteins that include epidermal growth factor-like motifs is their involvement in
extracellular functions such as adhesive and ligand-receptor interactions.
Additionally, the overall structure of the predicted SPE-9 protein is similar to
that of ligands for the Notch/LIN-12/GLP-1 family of transmembrane receptors.
These results suggest that SPE-9 functions in the specialized cell-cell
interactions required for fertilization.
PMID- 9546394
TI - Human T cell leukemia virus type 1 oncoprotein Tax targets the human mitotic
checkpoint protein MAD1.
AB - In searching for cellular targets of the HTLV-I oncoprotein Tax, we identified
TXBP181, which we characterized as the human homolog of yeast mitotic checkpoint
MAD1 protein. Evidence supporting TXBP181 as HsMAD1 includes sequence
conservation with yeast MAD1, hyperphosphorylation during S/G2/M phases and upon
treatment of cells with nocodazole, and binding to HsMAD2. HsMAD1 functions as a
homodimer. It localizes to the centrosome during metaphase and to the spindle
midzone and the midbody during anaphase and telophase. Expression of either Tax
or a transdominant-negative TXBP181 results in multinucleated cells, a phenotype
consistent with a loss of HsMAD1 function. We propose a model of viral
transformation in which Tax targets TXBP181, thereby abrogating a mitotic
checkpoint.
PMID- 9546395
TI - A novel and ubiquitous system for membrane targeting and secretion of cofactor
containing proteins.
AB - We report the identification of the proteins encoded by the mttABC operon
(formerly yigTUW), which mediate a novel Sec-independent membrane targeting and
translocation system in Escherichia coli that interacts with cofactor-containing
redox proteins having a S/TRRXFLK "twin arginine" leader motif. A pleiotropic
negative mutant in mttA prevents the periplasmic localization of twin arginine
redox enzymes, including nitrate reductase (NapA) and trimethylamine N-oxide
reductase (TorA). The mutation also prevents the correct localization of the
integral membrane molybdoenzyme dimethylsulfoxide reductase (DmsABC). The DmsA
subunit has a twin arginine leader. Proteins with a Sec-dependent leader or which
assemble spontaneously in the membrane are not affected by this mutation. MttA,
B, and C are members of a large family of related sequences extending from
archaebacteria to higher eukaryotes.
PMID- 9546396
TI - The unusual active site of Gal6/bleomycin hydrolase can act as a
carboxypeptidase, aminopeptidase, and peptide ligase.
AB - The Gal6 protease is in a class of cysteine peptidases identified by their
ability to inactivate the anti-cancer drug bleomycin. The protein forms a barrel
structure with the active sites embedded in a channel as in the proteasome. In
Gal6 the C termini lie in the active site clefts. We show that Gal6 acts as a
carboxypeptidase on its C terminus to convert itself to an aminopeptidase and
peptide ligase. The substrate specificity of the peptidase activity is determined
by the position of the C terminus of Gal6 rather than the sequence of the
substrate. We propose a model to explain these diverse activities and Gal6's
singular ability to inactivate bleomycin.
PMID- 9546397
TI - Crystal structure of the hemochromatosis protein HFE and characterization of its
interaction with transferrin receptor.
AB - HFE is an MHC-related protein that is mutated in the iron-overload disease
hereditary hemochromatosis. HFE binds to transferrin receptor (TfR) and reduces
its affinity for iron-loaded transferrin, implicating HFE in iron metabolism. The
2.6 A crystal structure of HFE reveals the locations of hemochromatosis mutations
and a patch of histidines that could be involved in pH-dependent interactions. We
also demonstrate that soluble TfR and HFE bind tightly at the basic pH of the
cell surface, but not at the acidic pH of intracellular vesicles. TfR:HFE
stoichiometry (2:1) differs from TfR:transferrin stoichiometry (2:2), implying a
different mode of binding for HFE and transferrin to TfR, consistent with our
demonstration that HFE, transferrin, and TfR form a ternary complex.
PMID- 9546398
TI - Crystal structure of the thermosome, the archaeal chaperonin and homolog of CCT.
AB - We have determined to 2.6 A resolution the crystal structure of the thermosome,
the archaeal group II chaperonin from T. acidophilum. The hexadecameric homolog
of the eukaryotic chaperonin CCT/TRiC shows an (alphabeta)4(alphabeta)4 subunit
assembly. Domain folds are homologous to GroEL but form a novel type of inter
ring contact. The domain arrangement resembles the GroEL-GroES cis-ring. Parts of
the apical domains form a lid creating a closed conformation. The lid substitutes
for a GroES-like cochaperonin that is absent in the CCT/TRiC system. The central
cavity has a polar surface implicated in protein folding. Binding of the
transition state analog Mg-ADP-AIF3 suggests that the closed conformation
corresponds to the ATP form.
PMID- 9546399
TI - Human Tra2 proteins are sequence-specific activators of pre-mRNA splicing.
AB - The RNA-binding protein Tra2 is an important regulator of sex determination in
Drosophila. Recently, two mammalian Tra2 homologs of unknown function have been
described. Here, we show that human Tra2 proteins are present in HeLa cell
nuclear extracts and that they bind efficiently and specifically to a previously
characterized pre-mRNA splicing enhancer element. Indeed, both purified proteins
bound preferentially to RNA sequences containing GAA repeats, characteristic of
many enhancer elements. Neither Tra2 protein functioned in constitutive splicing
in vitro, but both activated enhancer-dependent splicing in a sequence-specific
manner and restored it after inhibition with competitor RNA. Our findings
indicate that mammalian Tra2 proteins are sequence-specific splicing activators
that likely participate in the control of cell-specific splicing patterns.
PMID- 9546400
TI - Receptor-specific adhesion and clinical disease in Plasmodium falciparum.
PMID- 9546401
TI - A geographic information system applied to a malaria field study in western
Kenya.
AB - This paper describes use of the global positioning system (GPS) in differential
mode (DGPS) to obtain highly accurate longitudes, latitudes, and altitudes of
1,169 houses, 15 schools, 40 churches, four health care centers, 48 major
mosquito breeding sites, 10 borehole wells, seven shopping areas, major roads,
streams, the shore of Lake Victoria, and other geographic features of interest
associated with a longitudinal study of malaria in 15 villages in western Kenya.
The area mapped encompassed approximately 70 km2 and included 42.0 km of roads,
54.3 km of streams, and 15.0 km of lake shore. Location data were entered into a
geographic information system for map production and linkage with various
databases for spatial analyses. Spatial analyses using parasitologic and
entomologic data are presented as examples. Background information on DGPS is
presented along with estimates of effort and expense to produce the map
information.
PMID- 9546402
TI - The historical question of acquired immunodeficiency syndrome in the 1960s in the
Congo River basin area in relation to cryptococcal meningitis.
AB - In Europe before the advent of the acquired immunodeficiency syndrome (AIDS),
fatal cases of infection with Cryptococcus neoformans resembling acute meningitis
were rarely described and never in young adults. However, rapidly fatal
cryptococcal meningitis in young Africans has been known to exist in central
Africa for at least 30 years, mainly in the lower area of the Congo River basin.
Cases have been reported in this area since 1953, particularly in young patients
during the 1950s. It is also known that central African AIDS patients frequently
suffer from cryptococcosis, and there is a possibility that earlier clinical
reports of encephalitis were actually fatal cases of AIDS in young Africans. It
appears possible that the central part of the African continent is the area where
human immunodeficiency virus originated.
PMID- 9546403
TI - Aedes aegypti survival and dispersal estimated by mark-release-recapture in
northern Australia.
AB - The survival and dispersal of adult Aedes aegypti were estimated in northern
Australia where sporadic outbreaks of Ae. aegypti-borne dengue viruses have
occurred in recent years. Standard mark-release-recapture methods were used. In
addition, a new sticky trap was used to capture the mosquitoes. Prior to the
field study, the survival and effect of marking Ae. aegypti with fluorescent
powder were determined in the laboratory. Mortality was age-dependent and the
marked cohorts had higher survival rates than the untreated cohorts. Recapture
rates of 13.0% and 3.6% over a seven-day period were achieved for two batches of
marked Ae. aegypti released simultaneously at the field site. More males than
females were recaptured although the proportion of females increased with time.
The probability of daily survival was 0.91 and 0.86 for the blue- and pink-marked
females, respectively, and 0.57 and 0.70 for the blue- and pink-marked and males,
respectively. The mean distance traveled of recaptured Ae. aegypti was 56 m and
35 m for females and males, respectively. The maximum observed distance traveled
of 160 m was the same for both sexes. The warm to hot and dry climatic conditions
may have restricted the dispersal of released mosquitoes in this study. The
frequency of recaptures at certain trap locations suggested that shade, wind, and
the availability of hosts affected the distribution of Ae. aegypti within the
study site.
PMID- 9546404
TI - Effect of size and geographic origin of Aedes aegypti on oral infection with
dengue-2 virus.
AB - Differences in larval habitats cause variation in the size of Aedes aegypti (L.)
adults. We suspected that such size variation was related to the ease with which
the mosquitoes could be infected with dengue virus. Using a rearing procedure
that produced three distinct size classes of mosquitoes, we determined the
percentage of mosquitoes that developed disseminated dengue-2 infection following
oral feeding with a suspension containing 3.3 x 10(7) plaque-forming units/ml.
Mosquitoes were reared from eggs deposited by females captured in either of two
villages in Chachoengsao Province or in Bangkok, Thailand. More of the larger
mosquitoes (10.7%) were infected than the medium (5.6%) or small (5.7%)
mosquitoes. Mosquitoes from Bangkok were less easily infected (5.0%) than
mosquitoes from either of the two villages (8.5% and 10.7%). These results
suggest that quantitative risk assessment of dengue transmission may be very
difficult unless inoculation rate is measured directly. Also, control procedures
that reduce density of larvae in individual containers may exacerbate dengue
transmission by creating larger mosquitoes that are more easily infected.
PMID- 9546405
TI - Exploratory space-time analysis of reported dengue cases during an outbreak in
Florida, Puerto Rico, 1991-1992.
AB - The spatial and temporal distributions of dengue cases reported during a 1991
1992 outbreak in Florida, Puerto Rico (population = 8,689), were studied by using
a Geographic Information System. A total of 377 dengue cases were identified from
a laboratory-based dengue surveillance system and georeferenced by their
residential addresses on digital zoning and U.S. Geological Survey topographic
maps. Weekly case maps were generated for the period between June and December
1991, when 94.2% of the dengue cases were reported. The temporal evolution of the
epidemic was rapid, affecting a wide geographic area within seven weeks of the
first reported cases of the season. Dengue cases were reported in 217 houses; of
these 56 (25.8%) had between two and six reported cases. K-function analysis was
used to characterize the spatial clustering patterns for all reported dengue
cases (laboratory-positive and indeterminate) and laboratory-positive cases
alone, while the Barton and David and Knox tests were used to characterize spatio
temporal attributes of dengue cases reported during the 1991-1992 outbreak. For
both sets of data significant case clustering was identified within individual
households over short periods of time (three days or less), but in general, the
cases had spatial pattern characteristics much like the population pattern as a
whole. The rapid temporal and spatial progress of the disease within the
community suggests that control measures should be applied to the entire
municipality, rather than to the areas immediately surrounding houses of reported
cases. The potential for incorporating Geographic Information System technologies
into a dengue surveillance system and the limitations of using surveillance data
for spatial studies are discussed.
PMID- 9546406
TI - Diarrheal disease incidence and morbidity among United States military personnel
during short-term missions overseas.
AB - Outpatient medical surveillance of U.S. troops was conducted during 11 different
overseas missions between 1981 and 1990. In addition, at the end of each of 18
overseas missions during the same period, a sample of troops was queried
regarding illnesses and exposures experienced in the preceding time overseas.
Diarrhea was among the leading causes of morbidity during all of these short-term
missions. Diarrhea incidence rates were found to be highest during summer months,
and were higher during missions to Thailand (median = 25%, range = 20-29%), Latin
America (median = 26%, range = 1-43%), and northeastern Africa and southwest Asia
(median = 19%, range = < 1-52%). Rates were lowest in troops deployed to the
Republic of South Korea (median = 16%, range = 8-27%). During April and May 1990,
a focused surveillance and questionnaire study was conducted during a five-week,
joint U.S.-Thai military training exercise in central Thailand. Among 2,600 U.S.
personnel, diarrheal illness was found to be the most common medical problem for
troops (estimated cumulative incidence = 29%). Travel outside of the base of
operations and consumption of ice were found to be important risk factors. The 10
year database analyzed for this report is the largest, published summary showing
the significant impact of diarrheal diseases on U.S. military forces during short
term deployments to less developed areas.
PMID- 9546408
TI - Risk factors for primary pulmonary coccidioidomycosis hospitalizations among
United States Navy and Marine Corps personnel, 1981-1994.
AB - Recent coccidioidomycosis outbreaks among military personnel have alarmed public
health officials. We used computerized hospitalization records to identify risk
factors for coccidioidomycosis hospitalizations among active-duty United States
Navy and Marine Corps personnel for the years 1981 to 1994. Primary pulmonary
disease was the most common form of disease, accounting for 82 (73%) of the 113
first admissions. Crude annual rates of primary pulmonary disease increased
markedly in 1992 and 1993 in concert with an epidemic in the United States.
Demographic data from the pulmonary admissions were combined with that of a 2%
random sample of the entire Navy and Marine Corps population for multivariate
risk factor modeling. Persons from junior paygrades, older age groups, and those
reporting a race/ethnicity other than Caucasian or Hispanic were most likely to
be hospitalized with this disease. These risk factor data should be considered in
designing coccidioidomycosis surveillance and prevention programs.
PMID- 9546407
TI - Helicobacter pylori serostatus in backpackers following travel to tropical
countries.
AB - The mode of transmission of Helicobacter pylori is unknown. The seroprevalence of
H. pylori and the rate of transmission of feco-oral pathogens in developing
countries are both high. Long-term travelers to these regions, who come from
developed countries are thus potentially at increased risk of an infection with
this bacterium. We studied the H. pylori serology status before and after travel
of 104 backpackers who traveled to tropical countries; 76 medical students who
did not leave Israel served as controls. Southeast Asia (70%) and South America
(24%) were the major destinations, but the area of travel had no effect on the
seroconversion rate. The total time spent abroad was 53 person-years. Thirty six
of the travelers and 30 controls were positive at the outset. Seropositivity at
entry was significantly associated with being a Sepharadic Jew or having a parent
with a peptic ulcer disease. The majority of travelers (86.5%) and controls
(92.1%) did not change their serostatus. Four travelers seroconverted, but 10
seroreverted, while three controls seroconverted, and three others seroreverted.
No significant association with gastroenteritis was found. Serostatus may have
been affected by mefloquine use because none of the four seroconverters, but
eight of 10 seroreverters used it as malaria prophylaxis. In vitro studies
demonstrated that mefloquine has anti-H. pylori activity. Feco-oral transmission
is apparently not an important route of transmission of this organism among
travelers.
PMID- 9546409
TI - Application of the enzyme-linked immunoelectrotransfer blot to filter paper blood
spots to estimate seroprevalence of cysticercosis in Bolivia.
AB - An enzyme-linked immunoelectrotransfer blot (EITB) assay was used to study the
prevalence of cysticercosis in rural Bolivia. Dried blood spots on filter paper
from fingersticks were used as assay samples. Before the serosurvey, experiments
were performed to show that samples eluted from dried whole blood on filter paper
exhibited no decrease in sensitivity when compared with the more traditional
serum samples used in the EITB. Fingerstick blood dried on filter paper is a
convenient, economical way of transporting and storing field samples for
epidemiologic surveys of cysticercosis in developing countries. This report shows
the utility of this sample collection method in underdeveloped countries where
refrigeration is not possible and where venipuncture is a problem. Blood was
obtained from randomly selected residents in three rural regions of Bolivia:
Chuquisaca (n = 1,859), Cochabamba (n = 1,516), and Tarija (n = 1,010). The
estimated seroprevalence on 10% of the sample collected for the three regions
were 9%, 4.5%, and 2%, respectively.
PMID- 9546410
TI - Short report: gnathostomiasis in Mexico.
AB - Gnathostomiasis is an important food-borne parasitic zoonosis that is endemic
mainly in Asian countries where some people prefer to eat raw freshwater fish. In
North America, the first recorded case of gnathostomiasis was in Mexico in 1970,
and the numbers of gnathostomiasis patients in Mexico seems to be increasing
dramatically with time. However, the epidemiology of this disease in Mexico has
never been described in detail. Here we review the current status of
gnathostomiasis in Mexico.
PMID- 9546411
TI - Postpartum cardiac failure in Sudanese-Sahelian Africa: clinical prevalence in
western Niger.
AB - Postpartum cardiac failure (PPCF) is the most frequent clinical form of heart
failure in hospitalized women in Sudanese-Sahelian Africa. We have previously
studied this disease in a hospital setting. Although the incidence is relatively
high in rural areas, no systematic field study has been carried out. In this
report, we describe a retrospective study conducted in the western part of Niger
in July-August 1991. Sixty-two villages were visited and a thorough search for
patients was initiated (from a population of 79,941 inhabitants, 19,941 females
14-40 years of age, corrected census of 1988). Twenty-eight patients from 27
villages were included. The subject patients were those presenting with
predefined symptoms (dyspnea and cough) and physical signs (edema of the legs) of
congestive heart failure during the six-month period following delivery. Apart
from arterial hypertension and previous PPCF, diagnosis of another cardiac
disease was an exclusion criterion. The prevalence of PPCF was 1.40 per 1,000
females of child-bearing age. The clinical profiles of these cases were in
accordance with those of a previous study in 1989 carried out at Niamey Hospital.
These results were a mean +/- SD age of 28 +/- 7 years, multiparity (mean = 4
children), poor socioeconomic status, postpartum ablutions with hot water, and a
high sodium intake. This is the first study on the clinical prevalence of PPCF in
a Sudanese/Sahelian population living in a rural area.
PMID- 9546413
TI - Role of hepatitis E virus in sporadic cases of acute and fulminant hepatitis in
an endemic area (Chad).
AB - Forty-one patients with acute or fulminant hepatitis and 86 control patients were
entered into a study of sporadic, acute, and fulminant hepatitis in the N'Djamena
area of Chad in 1993. Acute hepatitis B was diagnosed in nine (22%) patients and
acute hepatitis E in 27 (66%) patients. No acute hepatitis A was observed and 10%
of the patients had serologic markers of hepatitis C virus (HCV) infection. Dual
acute hepatitis B and E were observed in four patients (10%) and acute HEV
infection was associated with chronic hepatitis B surface antigen carriage in 16
(39%). Epidemiologic findings concerning HBV from Chad suggest that these
patients had undiagnosed chronic liver disease due to HBV, with acute
deterioration caused by superimposed HEV replication. Moreover, it is obvious
that in developing countries only the most severe cases of hepatitis are seen in
hospital settings and a large proportion of them are related to superinfection
with HBV and HEV. Antibody to HEV was observed in 22% of the control patients.
This observation and the fact that epidemic and sporadic cases of HEV are
observed in Chad indicates that HEV is highly endemic in this country.
PMID- 9546412
TI - Japanese encephalitis among hospitalized pediatric and adult patients with acute
encephalitis syndrome in Hanoi, Vietnam 1995.
AB - The etiologic spectrum of acute encephalitis syndrome (AES) has not been well
defined in Vietnam. Cohort and case-control studies were performed on all adult
and pediatric AES patients admitted to the Neurology Service of Bach Mai Hospital
between June 5 and August 3, 1995. Among pediatric AES patients, 31 (67%) of 46
had acute Japanese encephalitis (JE), compared with only two (6%) of 33 adult AES
patients (P < 0.0001). For confirmed JE cases, serum specimens obtained 15-21
days after symptom onset had the highest mean anti-JE IgM signal-to-noise (P/N)
ratios (8.08 + 1.09 SE). A serosurvey of adult household members did not reveal
any cases of recent subclinical JE infection, although 26% had evidence of past
JE infection. The use of bed netting was nearly universal but did not appear to
reduce the risk of AES or JE. Given the high incidence of JE, particularly among
children, Vietnam seems well suited for the development of a targeted JE
vaccination strategy.
PMID- 9546414
TI - A case study of cytokine profiles in acute human babesiosis.
AB - The immune response in a patient with acute babesiosis was determined by
measurements of lymphocyte subpopulations, serum levels of cytokines, and
adhesion molecules. The ratio of CD4+:CD8+ lymphocytes was reduced early in the
infection, but returned to a normal value after treatment with azithromycin and
quinine. Natural killer (NK) cells markedly increased in the acute phase but
progressively decreased and to the normal range in the convalescent phase. Serum
levels of tumor necrosis factor-alpha, interferon-gamma, interleukin-2 (IL-2), IL
6, E-selectin, vascular cell adhesion molecule-1, and intercellular adhesion
molecule-1 were highly elevated in the acute phase while normal levels of these
mediators were observed one month after treatment. These results suggest that
CD8+ T cells and NK cells may be involved in the host defense mechanisms against
acute babesiosis.
PMID- 9546415
TI - Increase in asialoganglioside- and monosialoganglioside-reactive antibodies in
chronic Chagas' disease patients.
AB - Antibodies reactive with the core glycan of asialoganglioside (GA1),
monosialoganglioside (GM1), and disialoganglioside (GD1a) were studied in human
sera. In healthy individuals, GA1-, GM1-, and GD1a-reactive antibodies were
mainly of the IgM class, but also of the IgA and IgG classes, and were present at
low titers in the serum of 68%, 79%, and 91% of the individuals studied,
respectively. Levels of anti-GA1 and anti-GM1 antibodies, mainly of the IgA and
IgG classes, were significantly elevated (P < 0.001) in 62% and 72% of subjects,
respectively, chronically infected with Trypanosoma cruzi, with no association
found with the degree of myocardial damage. No significant increase in anti-GA1
and anti-GM1 antibodies was found in dilated cardiomyopathy patients. The level
of anti-GD1a antibody was not significantly different between healthy controls
and chronic chagasic or dilatatory cardiomyopathy patients. Since the peripheral
nervous system is very rich in gangliosides, it is possible that the increases in
GA1- and GM1-specific antibodies that develop during chronic T. cruzi infection
are involved in the pathology of peripheral neuropathy in Chagas' disease.
PMID- 9546416
TI - Effect of pentoxifylline on cytokine patterns in the therapy of complicated
Plasmodium falciparum malaria.
AB - The effect of pentoxifylline (PTX) was tested for its capacity to modulate
cytokine responses during therapy of severe Plasmodium falciparum malaria in a
placebo-controlled, randomized study in 45 adult patients in Bangkok, Thailand.
The patients received standard antimalarial treatment with artesunate (120 mg
intravenously given immediately, then 60 mg every 12 hr for a total dose of 600
mg). The patients received either low-dose PTX (20 mg/kg/day, n = 15), high-dose
PTX (40 mg/kg/day, n = 15), or placebo (n = 15) as continuous infusion for the
first three days of antimalarial treatment. Tumor necrosis factor (TNF) and
interleukin-6 (IL-6) plasma levels were markedly elevated in all patients prior
to treatment. After 6 hr of high-dose PTX treatment, TNF and IL-6 levels
significantly decreased while an increase in TNF and IL-6 levels was seen after 6
hr of low-dose PTX or placebo treatment (P < 0.01). After 12 and 24 hr of high
dose PTX infusion, TNF-receptor plasma concentrations were lower than in low-dose
PTX- or placebo-treated patients (P < 0.01), whereas no differences between the
groups with regard to IL-6 receptor levels were observed. We conclude that 40
mg/kg/day of PTX reduces plasma levels of TNF, IL-6, and TNF-receptor in patients
with severe malaria. Whether this reduction improves clinical outcome remains to
be determined.
PMID- 9546417
TI - Pentoxifylline as an ancillary treatment for severe falciparum malaria in
Thailand.
AB - Pentoxifylline, an inhibitor of tumor necrosis factor, has been evaluated as an
antimalarial agent in combination with artesunate in 45 patients with severe
falciparum malaria. Patients were admitted to the intensive care unit at the
Hospital for Tropical Diseases in Bangkok, Thailand, and randomly assigned to
treatment for 72 hr with a combination of intravenously administered artesunate
and 1) placebo, 2) low-dose pentoxifylline (0.83 mg/kg/hr), or 3) high-dose
pentoxifylline (1.67 mg/kg/hr). All 45 patients had one or more manifestations of
severe malaria such as cerebral malaria (n = 18), renal failure requiring
hemodialysis (n = 9), azotemia (n = 8), jaundice (n = 25), or hyperparasitemia (n
= 30). The overall severity was comparable in the three groups. Clinical outcome
was assessed with respect to the parasite clearance time and the fever clearance
time in all patients. In addition, a number of subsidiary outcome variables were
examined in specific subgroups, including the recovery time from coma for
patients with cerebral malaria, the duration of intubation in patients with
respiratory distress, the number of hemodialysis treatments needed for patients
with acute renal failure, and the number of units of blood administered to
patients requiring transfusion. Concentrations of tumor necrosis factor were
reduced in all three groups at 48 hr after treatment. No significant differences
among the three treatment groups were found for any of the outcome variables
examined. We conclude that the addition of pentoxifylline to artesunate therapy
for severe malaria produced no evident clinical benefit.
PMID- 9546418
TI - In vitro activity of artemether against African isolates (Senegal) of Plasmodium
falciparum in comparison with standard antimalarial drugs.
AB - The in vitro activity of artemether against 56 African isolates of Plasmodium
falciparum from Senegal was evaluated using an isotope-based drug susceptibility
semi-microtest. The 50% inhibitory concentration (IC50) values for artemether
were in a narrow range from 0.8 to 15.2 nM (mean IC50 = 3.43 nM) and the 95%
confidence interval (CI) was 2.50-4.36 nM. Artemether was equally effective on
chloroquine-sensitive and chloroquine-resistant isolates (mean IC50 = 346 nM, 95%
CI = 2.08-4.84 nM versus mean IC50 = 2.80 nM, 95% CI = 2.00-3.60 nM). There was a
significant positive correlation between responses to artemether and mefloquine
(r2 = 0.36, P < 0.001), artemether and quinine (r2 = 0.085, P < 0.05), artemether
and halofantrine (r2 = 0.075, P < 0.05), quinine and mefloquine (r2 = 0.205, P <
0.01), quinine and halofantrine (r2 = 0.124, P < 0.05), and mefloquine and
halofantrine (r2 = 0.801, P < 0.001). A positive correlation between these drugs
suggests in vitro cross-resistance or at least in vitro cross-susceptibility.
PMID- 9546419
TI - Assessment of the effect of the oral iron chelator deferiprone on asymptomatic
Plasmodium falciparum parasitemia in humans.
AB - While the parenteral iron-chelating agent desferrioxamine B has anti-malarial
activity in humans, the usefulness of an orally active chelator for this
indication has not been investigated previously in vivo. We conducted a
prospective, double-blind, placebo-controlled, cross-over trial of deferiprone
(L1; CP20; 1,2-dimethyl-3-hydroxypyridin-4-one) in 25 adult Zambians with
asymptomatic Plasmodium falciparum parasitemia. Deferiprone was administered
daily for three or four days in divided doses of 75 or 100 mg/kg of body weight,
dosages that are effective for treating iron overload. No reduction in asexual
intra-erythrocytic parasites was observed during or after deferiprone treatment.
The mean peak plasma concentration of deferiprone (108.9 +/- 24.9 micromol/L)
achieved was within the range demonstrated to inhibit the growth of P. falciparum
in vitro, but the systemic exposure as determined by the 24-hr plasma
concentration-time curve would not be predicted inhibit growth in vivo. No
evidence of deferiprone-associated hematological toxicity was noted in this short
term study of these subjects, all of whom had clinical evidence of normal body
iron stores. Because of the risk of neutropenia and other adverse effects with
higher doses or prolonged use of the chelator, additional trials of deferiprone
as a sole anti-malarial agent would not seem to be justified. In contrast,
further efforts are needed to develop other orally active iron-chelating agents
specifically for their anti-malarial action.
PMID- 9546420
TI - Plasma levels of artesunate and dihydroartemisinin in children with Plasmodium
falciparum malaria in Gabon after administration of 50-milligram artesunate
suppositories.
AB - A thermostable suppository of artesunate (artesunic acid) has been developed. In
Gabon, 12 children with Plasmodium falciparum malaria received two
administrations of this suppository in a 4-hr interval. Parasitemia and fever
were then measured and the plasma levels of artesunate and its active metabolite,
dihydroartemisinin, were determined by means of a reversed phase high-pressure
liquid chromatography method using reductive electrochemical detection.
Substantial parasite clearance (97-100%) was noted 24 hr after the beginning of
the treatment and body temperature had returned to normal. Absorption,
metabolism, and elimination of artesunate were rapid. Mean values of maximum
plasma levels (Cmax) and maximum concentration peak times (tmax) were evaluated.
The Cmax of dihydroartemisinin (0.18 +/- 0.10 microg/ml [mean +/- SE]) was higher
than the Cmax of artesunate (0.09 +/- 0.04 microg/ml) and the tmax of
dihydroartemisinin (1.13 +/- 0.58 hr) was higher than the tmax of artesunate
(0.58 +/- 0.19 hr). Plasma levels 30 min after the second suppository
administration were not consistently higher than those found 30 min after the
first administration.
PMID- 9546421
TI - Molecular epidemiology of malaria in Yaounde, Cameroon I. Analysis of point
mutations in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium
falciparum.
AB - Resistance to antifolate antimalarial drugs (cycloguanil, a biologically active
metabolite of proguanil, and pyrimethamine) is associated with a Ser- to Asn-108
point mutation in the dihydrofolate reductase-thymidylate synthase gene of
Plasmodium falciparum. The frequency of this mutation was studied in 127 clinical
isolates obtained in Yaounde, Cameroon using a simple and rapid molecular
technique based on the polymerase chain reaction and restriction fragment length
polymorphism. Of the 127 isolates, pure wild-type Ser-108 codon, pure mutant-type
Asn-108 codon, and mixed codons were observed in 66, 55, and six parasites,
respectively. The proportion of antifolate-resistant, pure mutant-type codon,
with respect to pure wild-type or mixed alleles, was 43% (55 of 127). The results
of the molecular assay were compared with those of semimicro isotopic in vitro
assay in 34 isolates. All 17 pure Ser-108 isolates and two isolates with mixed
alleles were sensitive to both pyrimethamine (50% inhibitory concentration [IC50]
< 100 nM) and cycloguanil (IC50 < 50 nM). Fourteen of 15 isolates with the mutant
type Asn-108 codon were resistant to pyrimethamine and cycloguanil. One isolate
with Asn-108 showed a slightly elevated pyrimethamine IC50 (78 nM), which was
within the sensitive range. This study provides further evidence that antifolate
resistant P. falciparum isolates are already present in Yaounde, Cameroon.
PMID- 9546422
TI - Molecular epidemiology of malaria in Yaounde, Cameroon II. Baseline frequency of
point mutations in the dihydropteroate synthase gene of Plasmodium falciparum.
AB - Sulfadoxine-pyrimethamine is one of the alternative antimalarial drugs used to
treat chloroquine-resistant Plasmodium falciparum malaria. The molecular target
of sulfadoxine, an analog of p-aminobenzoic acid that inhibits the folate
biosynthetic pathway, is dihydropteroate synthase (DHPS). The nucleotide sequence
of the DHPS gene was determined in 32 clinical isolates obtained in Yaounde,
Cameroon, and compared with the sequence of reference clones and Cambodian
strains of P. falciparum. Of the 32 Cameroonian isolates, 31 displayed one of the
sulfadoxine-sensitive mutation patterns: Ala-436/Ala-437/Ala-581/Ala-613 (n =
20), Ser-436/Gly-437/Ala-581/Ala-613 (n = 6), Ser-436/Ala-437/Ala-581/Ala-613 (n
= 4), and Ala-436/Gly-437/Ala-581/Ala-613 (n = 1). One isolate had a sulfadoxine
resistant profile characterized by a double mutation: Phe-436/Ala-437/Ala-581/Ser
613. Although the majority of the isolates had a sulfadoxine-sensitive genetic
profile, further studies are needed to correlate the mutation patterns and in
vitro and in vivo sulfadoxine sensitivity.
PMID- 9546423
TI - Evaluation of SPf66 malaria vaccine efficacy in Brazil.
AB - This paper reports the efficacy results of the randomized, placebo-controlled,
field trial of SPf66 malaria vaccine in Costa Marques, Rondonia, Brazil. This
region is characterized by the seasonal distribution of Plasmodium falciparum and
P. vivax infections, and the recent occupation by migrants from nonendemic areas.
A total of 800 individuals of both sexes, ranging in age from seven to 60 years,
were included in the study. Of the initial cohort, 572 participants completed the
vaccination schedule. Clinical and parasitologic evaluations were obtained by
active and passive searches on a periodic basis. The overall protective efficacy
against P. falciparum infections was -1.6% (-32.9% to 22.4%), and 14.1% (-17.0%
to 36.9%) for the first episode. The overall protective efficacy for P. vivax
infections was -19.7% (-44.8% to 1.03%), and -10.8% (-41.1% to 12.8%) for the
first episode. No statistical evidence of an overall significant protective
effect of SPf66 malaria vaccine against P. falciparum and P. vivax malaria was
obtained in this trial.
PMID- 9546424
TI - Identification of Tyr-762 in the platelet-derived growth factor alpha-receptor as
the binding site for Crk proteins.
AB - Tyr-762 is an autophosphorylation site in the human platelet-derived growth
factor (PDGF) alpha-receptor. In order to investigate whether phosphorylated Tyr
762 serves as a docking site for downstream signal transduction molecules,
affinity purification using an immobilized synthetic peptide containing
phosphorylated Tyr-762 and its surrounding amino acid residues was performed.
Proteins in HeLa cell lysate of molecular sizes 27, 38 and 40 kDa bound to the
phosphorylated, but not to the unphosphorylated peptide. Analyses of partial
amino acid sequences of the purified proteins indicated that they were identical
to CrkI, CrkII and CrkL respectively. The wild-type PDGF alpha-receptor, when
expressed in porcine aortic endothelial cells, formed complexes with CrkII and
CrkL upon ligand stimulation, which was specifically inhibited by a synthetic
peptide containing phosphorylated Tyr-762. Replacement of Tyr-762 with a
phenylalanine residue in the PDGF alpha-receptor abrogated ligand-induced binding
of Crk proteins. Tyrosine phosphorylation of CrkII and CrkL increased by 1.8- and
1.3-fold, respectively, upon ligand stimulation of the wild-type alpha-receptor.
In contrast, the Y762F mutant PDGF alpha-receptor failed to induce tyrosine
phosphorylation of Crk proteins. CrkII and CrkL constitutively formed complex
with the guanine nucleotide exchange factor C3G, in unstimulated as well as PDGF
stimulated cells. Moreover, the activated wild-type PDGF alpha-receptor but not
the Y762F mutant receptor was found in a C3G immunoprecipitate, suggesting that a
ternary complex between the activated PDGF alpha-receptor, Crk and C3G was
formed. DNA synthesis stimulated by PDGF-BB as well as PDGF-induced MAP kinase
activation was similar in cells expressing wild-type and mutant receptors.
Interestingly, the activated PDGF beta-receptor was found not to bind Crk
proteins. Instead, Tyr-771 of the beta-receptor, which is localized at an
analogous position to Tyr-762 in the alpha-receptor, binds RasGAP. RasGAP is not
bound to the alpha-receptor. Thus, this region in the kinase inserts of the two
receptors may be important for the divergency in signaling from the two PDGF
receptors.
PMID- 9546425
TI - Slow repair of bulky DNA adducts along the nontranscribed strand of the human p53
gene may explain the strand bias of transversion mutations in cancers.
AB - Using UvrABC incision in combination with ligation-mediated PCR (LMPCR) we have
previously shown that benzo(a)pyrene diol epoxide (BPDE) adduct formation along
the nontranscribed strand of the human p53 gene is highly selective; the
preferential binding sites coincide with the major mutation hotspots found in
human lung cancers. Both sequence-dependent adduct formation and repair may
contribute to these mutation hotspots in tumor tissues. To test this possibility,
we have extended our previous studies by mapping the BPDE adduct distribution in
the transcribed strand of the p53 gene and quantifying the rates of repair for
individual damaged bases in exons 5, 7, and 8 for both DNA strands of this gene
in normal human fibroblasts. We found that: (i) on both strands, BPDE adducts
preferentially form at CpG sequences, and (ii) repair of BPDE adducts in the
transcribed DNA strand is consistently faster than repair of adducts in the
nontranscribed strand, while repair at the major damage hotspots (guanines at
codons 157, 248 and 273) in the nontranscribed strand is two to four times slower
than repair at other damage sites. These results strongly suggest that both
preferential adduct formation and slow repair lead to hotspots for mutations at
codons 157, 248 and 273, and that the strand bias of bulky adduct repair is
primarily responsible for the strand bias of G to T transversion mutations
observed in the p53 gene in human cancers.
PMID- 9546427
TI - Mismatch repair deficiency leads to a unique mode of colorectal tumorigenesis
characterized by intratumoral heterogeneity.
AB - In order to determine the effects of mismatch repair (MMR) deficiencies in
sporadic colorectal carcinomas, 45 such cancers were examined using a sensitive
method called crypt isolation technique. Loss of heterozygosity (LOH) in the MSH2
or MLH1 gene was more frequently observed in replication error (RER) (+)
carcinomas than in RER (-) carcinomas, which implied that loss of one normal
allele could partly affect repair capacity. MSH2 gene defects at both alleles
were observed in two carcinomas, which showed severe repair deficiencies.
Interestingly, unlike the situation observed in the p53 gene, the MSH2 and MLH1
genes did not show complete LOH. Novel crypt isolation-based subpopulation (CISP)
analysis demonstrated that at least two distinct carcinoma subpopulations existed
in most carcinomas that showed incomplete LOH; one with and one without LOH. In
one carcinoma that had germline mutation and somatic incomplete LOH of the MSH2
gene, the mutator phenotype was only observed in populations affected in both
alleles. Thus, the MSH2 gene appears to possess the two hits mechanism of tumor
suppressor genes. However, unlike the tumor suppressor genes, MMR gene defects
lead to a unique mode of colorectal tumorigenesis characterized by intratumoral
heterogeneity.
PMID- 9546426
TI - The oncogenic ErbB-2/ErbB-3 heterodimer is a surrogate receptor of the epidermal
growth factor and betacellulin.
AB - The ErbB-1 receptor tyrosine kinase binds to six different growth factors, whose
prototype is the epidermal growth factor (EGF). Two homologous epithelial
receptors, ErbB-3 and ErbB-4, bind all isoforms of another family of growth
factors, the Neu differentiation factors (NDFs/neuregulins). The fourth member of
the ErbB family, ErbB-2, acts as the preferred heterodimeric partner of ligand
occupied complexes of the three other ErbB proteins. Here we report that at high
concentrations, EGF can induce cell growth and differentiation in the absence of
ErbB-1. This function is shared by betacellulin, but not by three other ligands,
including the transforming growth factor alpha (TGFalpha). The functional
receptor was identified as a heterodimer between ErbB-3 and ErbB-2, a previously
identified oncogenic complex. When singly expressed, neither ErbB-3 nor ErbB-2
can mediate signaling by EGF. In addition, when co-expressed, blocking either
receptor by using site-specific antibodies inhibited EGF and betacellulin
activities, indicating strict cooperativity between ErbB-3 and ErbB-2. Through
analysis of chimeras between EGF and TGFalpha, we identified the middle portion
of EGF (loop B) as the site that enables activation of ErbB-2/ErbB-3. In
conclusion, cooperative and promiscuous binding of stroma-derived growth factors
by the epithelium-expressed ErbB-2/ErbB-3 heterodimer may be significant to
cancer development. The mechanistic implications of our results for a model that
attributes receptor dimerization to ligand bivalency, as well as to a recently
proposed mechanism of secondary dimerization, are discussed.
PMID- 9546428
TI - Deregulated expression of E2F1 induces hyperplasia and cooperates with ras in
skin tumor development.
AB - In cell culture studies, overexpression of the E2F1 transcription factor has been
shown to stimulate proliferation, induce apoptosis, and cooperate with an
activated ras gene to oncogenically transform primary rodent cells. To study the
effect of increased E2F1 activity on epithelial growth and tumorigenesis in vivo,
transgenic mice expressing E2F1 under the control of a keratin 5 (K5) promoter
were generated. Expression of E2F1 in the epidermis results in hyperplasia but
does not inhibit terminal differentiation. In a transgenic line expressing high
levels of E2F1, mice have decreased hair growth likely as a result of aberrant
apoptosis in developing hair follicles. Coexpression of a cyclin D1 transgene
with E2F1 augments epidermal hyperplasia and further disrupts hair follicle
development suggesting that hypophosphorylated Rb antagonizes the proliferative
and apoptotic-promoting activities of E2F1. Finally, the E2F1 transgene is found
to cooperate with a v-Ha-ras transgene to induce skin tumors in double transgenic
animals. These findings confirm that many of the activities ascribed to E2F1
through in vitro studies can be reproduced in vivo and demonstrate for the first
time that deregulated E2F activity can contribute to tumor development.
PMID- 9546429
TI - Oncogenic activation of a human cyclin A2 targeted to the endoplasmic reticulum
upon hepatitis B virus genome insertion.
AB - Cyclins are major cell cycle regulators which role in malignant transformation
remains controversial. In this report we describe a new mechanism of cyclin
oncogenic activation. We demonstrate that an altered form of cyclin A2 (S2A)
which N-terminal part is replaced by the hepatitis B virus envelope protein
transforms normal rat kidney cells and cooperates with ras to transform rat
embryo fibroblasts. In contrast, neither the viral moiety, nor a full length or N
terminally deleted cyclin A2 show these oncogenic properties. S2A oncogenicity
arises from its binding to cyclin dependent kinases, since mutation in the MRAIL
sequence abolishes transformation and correlates with an abnormal cellular
localization in the endoplasmic reticulum membrane. Together, these results
implicate modification in the cellular distribution of a cell cycle regulator as
a mechanism of virally-induced transformation.
PMID- 9546430
TI - E2F-3 accumulation is regulated by polypeptide stability.
AB - E2F is a complex family of transcription factors which appears to regulate the
transcription of genes required for the S phase of the mammalian cell cycle. In
the present work, we have examined the mechanisms regulating E2F-3 accumulation
in mouse fibroblasts. We have determined that E2F-3 DNA binding activity is
restricted to the G1/S transition and S phase in both normal BALB/c-3T3
fibroblasts and in an SV40 virus-transformed BALB/c-3T3 derivative. Immunoblot
analysis indicates that G0 and G1 cells have little or no E2F-3 polypeptide and
that the increase in the DNA binding activity of E2F-3 at the G1/S boundary is
reflected by an increase in total E2F-3 protein. In contrast to the E2F-3
polypeptide, RNAse protection assays demonstrate that the E2F-3 mRNA is clearly
present in G0 and G1 cells. Finally, pulse/chase experiments indicate that the
half-life of E2F-3 is approximately 40-fold greater in cells blocked in S phase
relative to asynchronously growing cells. Together, these results indicate that
the accumulation E2F-3 at S phase may be regulated, at least in part, at the
level of protein stability.
PMID- 9546431
TI - Human smooth muscle alpha-actin gene is a transcriptional target of the p53 tumor
suppressor protein.
AB - Smooth muscle (sm) alpha-actin is expressed in vascular smooth muscle cells and
fibroblast cells. Its expression is regulated by cell proliferation and repressed
during oncogenic transformation. In this study, we demonstrate that p53
activation is associated with a dramatic increase in organized microfilament
bundles and an increase in sm alpha-actin mRNA level. Wild-type p53, but not
mutant p53, strongly stimulated human sm alpha-actin promoter activity in p53
null cell lines. The sequences homologous to the p53 consensus sequence and to
the p53 binding sequence from the muscle creatine kinase, were found within a
specific region of the sm alpha-actin promoter. This sequence was sufficient to
confer p53-dependent activation to a heterologous promoter and p53 was capable of
binding to this sequence as assessed by gel shift analysis. Ionizing irradiation
of colorectal tumor cells caused an increase in alpha-actin mRNA level in a p53
dependent manner. Taken together, these results demonstrate that human sm alpha
actin gene is a transcriptional target for p53 tumor suppressor protein and
represents the first example of a cytoskeletal gene with a functionally defined
p53 response element.
PMID- 9546432
TI - Molecular analysis of the IL-2 receptor beta chain gene expressed in human tumor
cells.
AB - Interleukin-2 (IL-2) is recognized as a T cell growth factor. We have previously
reported that human carcinoma cell lines are inhibited in growth by exogenous IL
2, which binds to the IL-2 receptor beta (IL-2Rbeta) chain ubiquitously expressed
on the surface of tumor cells. A possibility was considered that IL-2Rbeta on
carcinomas responsible for negative signaling was different from that expressed
on hematopoietic cells. To investigate this possibility, mRNA for the IL-2Rbeta
chain was amplified and compared in carcinoma and lymphoid cells. Using RT-PCR
with pairs of sense-antisense oligonucleotide primers specific for the various
regions of extracellular, transmembrane and intracellular domains of the IL
2Rbeta chain, we amplified mRNA obtained from three human carcinoma cell lines
and human lymphoid cells as controls. The identity of the amplicons was confirmed
by Southern analysis with the 32P-labeled cDNA probe coding for the entire span
of the IL-2Rbeta chain. In addition, genomic DNA obtained from the tumor cell
lines was sequenced to examine the possibility that a mutation is present in the
gene coding for the intracellular IL-2Rbeta chain domain. No mutations or
deletions were detected. The message for all three domains of the beta chain was
identical in tumor cells and in normal lymphoid cells used as controls. Also, by
Western blot and northern analyses no differences between IL-2Rbeta chain in
tumors vs that expressed in lymphoid cells were demonstrable. The IL-2Rgamma
chain, which participates in IL-2/IL-2R signaling pathway, was expressed in tumor
cells. Expression of JAK1 transcripts in these cells was comparable to that in
lymphocytes. However, RT-PCR analysis identified differences in expression of
JAK3 splice variants (B and M) in tumor cells. These differences may be
responsible for altered downstream signaling by IL-2. Overall, our data indicate
that the same IL-2/IL-2R pathway is operative in human carcinomas and in normal
epithelial or lymphoid cells.
PMID- 9546433
TI - Abl protein kinase abrogates the response of multipotent haemopoietic cells to
the growth inhibitor macrophage inflammatory protein-1 alpha.
AB - The clonogenic cells of chronic myeloid leukaemia (CML), unlike normal
haemopoietic progenitor cells, are resistant to the growth inhibitory effects of
the chemokine macrophage inflammatory protein-1 alpha (MIP-1alpha). CML is also
relatively resistant to chemotherapy and the disease is difficult to cure using
conventional therapeutic routes. CML is associated with increased abl oncogene
protein tyrosine kinase (PTK) activity. Here, we have tested the hypothesis that
these aberrant responses to MIP-1alpha and the relative resistance to
chemotherapy are directly related to this increased abl PTK activity in primitive
haemopoietic cells. To do this we have expressed a temperature sensitive abl PTK
in a growth factor dependent, multipotent stem cell line (FDCP-Mix) in which
growth is normally suppressed by MIP-1alpha. In FDCP-Mix cells expressing the ts
v-abl PTK and grown at the restrictive temperature for PTK activity the cells
were relatively sensitive to cytotoxic agents such as cytosine arabinoside and 5
fluorouracil but MIP-1alpha could induce growth inhibition and confer some degree
of protection from these agents. At the permissive temperature for abl PTK, the
cells were relatively resistant to cytotoxic drugs and MIP-1alpha treatment
neither induced growth inhibition nor protected the cells from cytotoxic drug
induced cell death. This lack of response to MIP-1alpha was not due to receptor
down modulation as neither the affinity nor the number of 125I-MIP-1alpha binding
sites was altered by activating Abl PTK. However, MIP-1alpha mediated increases
in cytosolic Ca2+ levels were abrogated by switching cells to the permissive
temperature for Abl PTK activity. These data suggest that the relative resistance
of CML progenitor cells to therapeutic drugs and the lack of response to MIP
1alpha occurs as a direct consequence of abl PTK activity and involves
desensitisation of signal transduction events stimulated by MIP-1alpha receptors.
Thus one contributory mechanism to transformation of primitive haemopoietic cells
is abrogation of response to a growth inhibitor.
PMID- 9546434
TI - MMSP tumor cells expressing the EWS/ATF1 oncogene do not support cAMP-inducible
transcription.
AB - Malignant Melanoma of Soft Parts (MMSP) is associated with the EWS/ATF1 fusion
protein that arises due to chromosomal fusion of the Ewings Sarcoma oncogene
(EWS) and the cellular transcription factor ATF1. EWS/ATF1 can activate several
cAMP-inducible promoters, suggesting that cellular transformation in MMSP might
involve constitutive activation of cAMP-inducible promoters. To assess this
possibility we have examined the status of the cAMP-signaling pathway in the
available MMSP-derived cell lines (DTC1 and Su-ccs-1) and find that both cell
lines share several features. First, in contrast to previous effects observed in
transient assays, three chromosomal promoters containing ATF binding sites are
not constitutively activated by endogenous EWS/ATF1 in MMSP cells. Second, all
the components that are known to be required for cAMP-inducible transcription are
present. Third, phosphorylation of the cAMP-response-element-binding protein
(CREB) can be efficiently induced by cAMP. Fourth, cAMP is unable to activate
transcription, as assessed by a GAL4/ATF1 reporter assay and analysis of the c
fos and adenovirus early promoters. Thus, cell lines derived from MMSP have a
block to cAMP-signaling that lies downstream of CREB phosphorylation. In light of
the cAMP-responsiveness of almost all mammalian cell types, our findings suggest
that the inability to respond to cAMP might be an important feature of MMSP
cells.
PMID- 9546435
TI - Expression of a novel form of p21Cip1/Waf1 in UV-irradiated and transformed
cells.
AB - The tumor suppressor p53 and its target the CDK inhibitor p21 (Cip1/Waf1) are key
components of the cellular response to DNA damage. Insight into how p21 is
regulated in normal cells, and how it may be deregulated in tumor cells is
important for the understanding of tumorigenesis. p21 was induced in normal human
diploid fibroblasts after UV irradiation-induced DNA damage, but, at a high dose
of UV irradiation, a faster mobility form of p21 on SDS-PAGE (designated
p21delta) was expressed. Surprisingly, in a variety of growing transformed cell
lines, the level of p21 was low but p21delta was prominent. We found that
p21delta appeared to be derived through a loss of around 10 amino acids from the
C-terminus of p21, which theoretically would remove the PCNA binding domain, a
second cyclin binding domain and the nuclear localization signal sequence.
Several characteristics distinguish p21 from p21delta. Both the full length p21
and p21delta could be stabilized by a proteasome inhibitor, but only the full
length p21 was associated with Cdk2 and PCNA. Consistent with this, gel
filtration chromatography revealed that all the full length p21 in the cell was
complexed to other proteins, whereas a significant portion of p21delta was in
monomeric form. Moreover, p21 was mainly localized to the nucleus, but p21delta
was mainly localized to the cytoplasm. We propose that the decrease in p21 and
increase in p21delta could contribute to the deregulation of the cell cycle, and
could be a mechanism involved in cellular transformation.
PMID- 9546436
TI - Cloning and characterization of human and mouse telomerase RNA gene promoter
sequences.
AB - Variation in telomerase activity is correlated with cellular senescence and
tumour progression. However, although the enzymatic activity of telomerase has
been well studied, very little is known about how expression of telomerase genes
is regulated in mammalian cells. We have therefore cloned the promoter regions of
the human (hTR), and mouse, (terc), telomerase RNA genes in order to identify the
regulatory elements controlling telomerase RNA gene transcription. 1.76 kb
encompassing the hTR gene promoter region was sequenced, as was 4 kb encompassing
the terc promoter. No significant sequence similarity could be detected in
comparisons between human and mouse 5'-regions, flanking the transcribed
sequences. However, both the human and mouse telomerase RNA genes are within CpG
islands and may therefore be under the regulation of DNA methylation. Transient
expression of hTR-reporter gene constructs in HeLa and GM847 cells identified the
elements responsible for promoter activity are contained in a 231 bp region
upstream of the transcriptional start site. Transient expression of terc-reporter
gene constructs in Swiss3T3 and A9 cells identified the elements responsible for
promoter activity are contained in a 73 bp region upstream of the transcriptional
start site. These studies have implications for novel transcription targeted
cancer therapies.
PMID- 9546437
TI - Potential role for wild-type p53 in leukemias with MLL gene translocations.
AB - We used single-strand conformation polymorphism (SSCP) analysis of p53 exons 4-8
to screen for possible mutations in 25 pediatric de novo leukemias with
translocations of the MLL gene at chromosome band 11q23. Of the 25 patients, 21
were infants. Fifteen cases were acute myeloid leukemia (AML), eight were acute
lymphoblastic leukemia (ALL), and two cases were biphenotypic. Nineteen cases
were studied at diagnosis and six at time of relapse. p53 mutations were absent
in all 19 cases studied at the time of diagnosis. The only mutation was a TGC-
>TTC transversion (cys-->phe) at codon 141 in exon 5 in a case of infant ALL at
relapse that occurred by subclone evolution after MLL gene translocation. We
previously showed that p53 mutations are also absent in pediatric treatment
related leukemias with MLL gene translocations. The absence of p53 mutations at
initial transformation may suggest that the anti-apoptotic effect of mutant p53
is not important in leukemias with MLL gene translocations. Alternatively,
exogenous DNA damage may be the common feature in treatment-related and de novo
cases. Since MLL gene translocations may occur through DNA repair and wild-type
p53 is central to DNA repair, the absence of p53 mutations raises the possibility
that wild-type p53, not mutant p53, may be important in the genesis of leukemias
with these translocations.
PMID- 9546438
TI - Isolation and characterization of a chicken homologue of the Spi-1/PU.1
transcription factor.
AB - Spi-1/PU.1 is a member of the Ets family of transcription factors important in
regulation of hematopoiesis. We have isolated a chicken cDNA homologuous to the
mammalian Spi-1/PU.1 gene with an open reading frame of 250 amino acids (aa). The
chicken Spi-1/PU.1 protein is 14 aa and 16 aa shorter than its human and mouse
counterparts but is extremely well conserved with 78.8% and 75.2% identity
respectively. The carboxy terminal DNA binding region, or ETS binding domain, is
100% identical to that of human and mouse. Some differences with the mammalian
homologues are seen in the N-terminal part of the protein and in the PEST
connecting domain. However, the differences are mainly conservative and all the
features underlying functional aspects seem preserved. The major discrepancy lies
in a 12 aa deletion in an already poorly conserved part of the PEST sequence. Spi
1/PU.1 transcripts were detected at high levels in spleen and Fabricius bursa of
chick embryos by Northern blot and in situ hybridization. Our results show that
the chicken Spi-1/PU.1 protein behaves like a bonafide Spi-1/PU.1 transcription
factor in its DNA binding and transactivating properties.
PMID- 9546439
TI - Identification of human p53 mutations with differential effects on the bax and
p21 promoters using functional assays in yeast.
AB - Recent studies have suggested that a rare class of p53 mutants found in tumours
has a subtle transcriptional defect affecting bax induction but not p21
induction. We have therefore developed simple functional assays in yeast which
can be used to identify these mutants. Analysis of 51 different mutations
observed in human tumours showed that all mutants tested scored as mutant with
the bax reporter strain but nine scored as wild-type with the p21 reporter
strain. These results, which can be explained by the lower affinity of the p53
protein for the bax site, may suggest that p21 is not the key target of p53
mutations in tumours. Since p21 status has recently been shown to modulate the
chemotherapeutic and radiotherapeutic sensitivities of cancerous cells, the
functional assays described here may have important clinical implications.
PMID- 9546440
TI - Anterior cruciate ligament reconstruction.
PMID- 9546441
TI - Wear of polyethylene in artificial hip joints: superolateral wear of the
acetabulum.
PMID- 9546442
TI - Management of the orthopaedic complications of haemophilia.
PMID- 9546443
TI - Superolateral wear of the acetabulum.
PMID- 9546444
TI - Microsurgical excision of lateral lumbar disc herniation through an interlaminar
approach.
AB - We made a prospective study of 43 consecutive patients treated for intraforaminal
(34) or extraforaminal (9) herniations of a lumbar disc by excision through an
interlaminar approach, using an operating microscope. The intraforaminal
herniations were contained or extruded in 52% and sequestrated in 47%; for
extraforaminal herniation the proportions were 66% and 33%, respectively. There
was additional posterolateral protrusion or spinal stenosis at the level of the
lateral herniation in seven and four cases, respectively. The patients were
reviewed at three months and two years after surgery. Radiographs showed three
grades of facetectomy: grade I, removal of 50% or less, grade II, excision of 51%
to 75%, and grade III, subtotal or total facetectomy. For intraforaminal
herniations the results were excellent or good in 88% of patients when reviewed
at three months and in 91% at two years. For extraforaminal herniations, there
was an excellent or good outcome in 89% of patients in the short term and in all
in the long term. The facetectomy had been grade I in 14 and grade II in 25; it
had been grade III in four, but only one had had total facetectomy. No patient
had developed vertebral hypermobility as a result of the operation. An
intralaminar approach using an operating microscope can provide adequate access
to a lateral protrusion. It has the advantage of allowing the treatment of
posterolateral protrusion or posterior annular bulge and of spinal stenosis at
the same level.
PMID- 9546445
TI - Orientation of lumbar pars defects: implications for radiological detection and
surgical management.
AB - Lateral oblique radiographs are considered important for the identification of
spondylolytic lesions, but these projections will give a clear view only when the
radiological beam is in the plane of the defect. We studied the variation in
orientation of spondylolytic lesions on CT scans of 34 patients with 69 defects.
There was a wide variation of angle: only 32% of defects were orientated within
15 degrees of the 45 degrees lateral oblique plane. Lateral oblique radiographs
should not be considered as the definitive investigation for spondylolysis. We
suggest that CT scans with reverse gantry angle are now more appropriate than
oblique radiography for the assessment of spondylolysis. Variation in the angle
of the defect may also need consideration when direct repair is being planned.
PMID- 9546446
TI - Idiopathic scoliosis in twins studied by DNA fingerprinting: the incidence and
type of scoliosis.
AB - We investigated 21 pairs of twins for zygosity and idiopathic scoliosis. DNA
fingerprinting confirmed that 13 pairs were monozygotic and eight were dizygotic.
There was concordance for idiopathic scoliosis in 92.3% of monozygotic and 62.5%
of dizygotic twins. Of the 12 pairs of monozygotic twins concordant for
idiopathic scoliosis, six showed discordant curve patterns but eight had
differences in Cobb angle of less than 10 degrees. Seven of the ten pairs of
monozygotic twins had similar back shapes. Our findings suggest that there is a
genetic factor in the aetiology of idiopathic scoliosis; they also indicate that
there is a genetic factor in both the severity of the curve and the general shape
of the back.
PMID- 9546447
TI - The anatomy of acute scaphoid fractures: a three-dimensional analysis of
patterns.
AB - Various classifications of scaphoid fractures have been based on plain
radiography, but there are difficulties in defining the actual fracture line
without an appreciation of the three-dimensional anatomy. Radiological fracture
lines were therefore mapped on transparent methylmethacrylate models of the bone.
An analysis of 91 acute fractures showed that 11 were apparently incomplete. The
other 80 showed three basic anatomical patterns: transverse through the waist,
oblique in the plane of the dorsal sulcus, or of the proximal pole. There was
some variation and comminution in these patterns, but no distal fractures of the
body were seen. The interpretation of different radiological projections is
discussed. The findings have implications for the management and the assessment
of outcome.
PMID- 9546448
TI - Rupture of flexor pollicis longus tendon: a complication of volar plating of the
distal radius.
AB - We report three complete ruptures and one partial rupture of the flexor pollicis
longus tendon in association with the insertion of a volar plate for the
treatment of fracture of the distal radius. Rupture was associated with the
chronic use of steroids.
PMID- 9546449
TI - External fixation for phalangeal and metacarpal fractures.
AB - From 1987 to 1993 we treated 33 patients with 29 phalangeal and seven metacarpal
fractures by external fixation using a mini-Hoffmann device. There were 27 open
and 25 comminuted fractures. In 12 patients one or more tendons was involved. The
mean follow-up was 4.4 years. Complications occurred in ten fractures; two
required repositioning of the fixator. All the fractures healed. The functional
results after metacarpal fractures were better than those after phalangeal
fractures and fractures of the middle phalanx had better recovery than those of
the proximal phalanx. Twenty-eight of the 33 patients were satisfied with their
result. External fixation proved to be a suitable technique for stabilising
unstable, open fractures with severe soft-tissue injuries.
PMID- 9546450
TI - Resection of the radial head after Mason type-III fractures of the elbow: follow
up at 16 to 30 years.
AB - We reviewed 21 patients with Mason type-III fractures of the radial head treated
by resection, evaluating the results at 16 to 30 years by a standard
questionnaire and clinical and radiological examination of the elbow and wrist.
Seventeen patients had an excellent result, three were good and one fair.
Resection of the radial head is a satisfactory method of treatment of such
fractures. Prosthetic replacement seems to be indicated only when there is valgus
instability of the elbow.
PMID- 9546451
TI - Non-constrained elbow arthroplasty for mutilans deformity in rheumatoid
arthritis: a report of six cases.
AB - Six highly unstable elbows with severe bone loss due to rheumatoid arthritis were
replaced by a non-constrained, unlinked prosthesis. Bone defects were filled with
autogenous bone grafts. The mean follow-up was 4.5 years (2 to 8). The clinical
results were excellent in four elbows and good in two, with good varus-valgus
stability in all. Radiological follow-up showed no appreciable signs of
loosening, and the bone grafts had retained most of their original size, with
minimal resorption. There were no major complications such as dislocation, skin
necrosis, infection or ulnar neuropathy. The study has shown that the so-called
mutilans elbow can be successfully replaced using a properly selected type of non
constrained, unlinked prosthesis with bone grafting of the major defects.
PMID- 9546452
TI - The posterior interosseous nerve and the posterolateral approach to the proximal
radius.
AB - We dissected 21 cadaver elbows to determine the relationship of the posterior
interosseous nerve to the posterolateral approach to the elbow and head of the
radius. At the distal end of the exposure the first branches at risk, those to
extensor carpi ulnaris, were on average 6.0 +/- 1.0 cm (4.0 to 8.4) from the
articular surface of the radial head. When using the posterolateral approach it
is important that the interval between extensor carpi ulnaris and anconeus is
clearly identified with the forearm fully pronated. The supinator should be
released close to its ulnar border. It is safe to expose the proximal radius as
far as the distal aspect of the bicipital tuberosity.
PMID- 9546453
TI - Epidemiology of fractures in 15,000 adults: the influence of age and gender.
AB - We report a prospective study of the incidence of fractures in the adult
population of Edinburgh, related to age and gender. Over a two-year period,
15,293 adults, 7428 males and 7865 females, sustained a fracture, and 5208
(34.0%) required admission. Between 15 and 49 years of age, males were 2.9 times
more likely to sustain a fracture than females (95% CI 2.7 to 3.1). Over the age
of 60 years, females were 2.3 times more likely to sustain a fracture than males
(95% CI 2.1 to 2.4). There were three main peaks of fracture distribution: the
first was in young adult males, the second was in elderly patients of both
genders, mainly in metaphyseal bone such as the proximal femur, although
diaphyseal fractures also showed an increase in incidence. The third increase in
the incidence of fractures, especially of the wrist, was seen to start at 40
years of age in women. Our study has also shown that 'osteoporotic' fractures
became evident in women earlier than expected, and that they were not entirely a
postmenopausal phenomenon.
PMID- 9546454
TI - The epidemiology of humeral shaft fractures.
AB - We have analysed 249 consecutive fractures of the humeral shaft treated over a
three-year period. The fractures were defined by their AO morphology, position,
the age and gender of the patient and the mechanism of injury. Open fractures
were classified using the Gustilo system and soft-tissue injury, and closed
fractures using the Tscherne system. The fractures were classified as AO type A
in 63.3%, type B in 26.2% and type C in 10.4%. Most (60%) occurred in the middle
third of the diaphysis with 30% in the proximal and 10% in the distal third. The
severity of the fracture and soft-tissue injury was greater with increasing
injury severity. Less than 10% of the fractures were open. There was a bimodal
age distribution with a peak in the third decade as a result of moderate to
severe injury in men and a larger peak in the seventh decade after a simple fall
in women.
PMID- 9546455
TI - Vascular injuries in compound fractures of the leg with initially adequate
circulation.
AB - We carried out a randomised, controlled trial in 157 patients who had isolated
severe Gustilo type-IIIa and type-IIIb fractures of the metaphysis or diaphysis
of the leg to determine the prevalence of vascular injuries and the role of
vascular repair. All patients had stable vital signs and clinically adequate
circulation in their legs before operation. In a control group of 64 patients we
performed conventional surgery with systematic debridement and primary
stabilisation of the fractures. In the trial group of 93 patients the major
vessels and nerves adjoining the compound fracture were routinely explored and
repaired when necessary after the initial procedure. Two of the 28 control
patients (7.1%) with type-IIIb compound fractures had signs of inadequate
circulation after the first operation. Both had major vascular injuries which
were demonstrated at a second procedure. In the trial group, major vascular
injuries were found in two of 54 patients (3.7%) with type-IIIa and 11 of 39
patients (28.2%) with type-IIIb compound fractures. Compared with the control
group the trial group showed improved results at both the immediate and long-term
follow-up. Routine exploration and early repair of injured major vessels of the
leg in severe compound fractures gave encouraging results.
PMID- 9546456
TI - Indomethacin versus radiation therapy for prophylaxis against heterotopic
ossification in acetabular fractures: a randomised, prospective study.
AB - We report a prospective, randomised, blinded clinical comparison of the use of
indomethacin or radiation therapy for the prevention of heterotopic ossification
(HO) in 75 adults who had open reduction and internal fixation of acetabular
fractures through either a Kocher-Langenbeck, a combined ilioinguinal and Kocher
Langenbeck, or an extended iliofemoral approach. Indomethacin, 25 mg, was given
three times daily for six weeks. Radiation with 800 cGy was delivered within
three days of operation. Plain radiographs were reviewed and given Brooker
classification scores by three independent observers who were unaware of the
method of prophylaxis. One patient died from unrelated causes and two were lost
to follow-up, leaving 72, 33 in the radiation group and 39 in the indomethacin
group, available for evaluation at a mean of 12 months (6 to 48). There was no
significant difference in the two groups in terms of age, gender, injury severity
score, estimated blood loss, delay to surgery, head injury, presence of femoral
head dislocation, or operating time, and no complications due to either method of
treatment. The final extent of HO was already present by six weeks in all
patients who were followed up. Three patients in the radiation group and five who
received indomethacin developed HO of Brooker grade III. Two patients in the
indomethacin group developed Brooker IV changes; both had failed to receive
proper doses of the drug. Cochran-Armitage analysis showed no significant
difference between the two treatment groups as regards the formation of HO.
Indomethacin and single-dose radiation therapy are both safe and effective for
the prevention of HO after operation for acetabular fractures. Radiation therapy
is, however, approximately 200 times more expensive than indomethacin therapy at
our institution and has other risks.
PMID- 9546457
TI - Pelvic insufficiency fracture with diastasis of the pubic symphysis after
irradiation: a case report.
AB - A 61-year-old woman was seen with diastasis of the symphysis pubis and
insufficiency fractures of the wings of both ilia after irradiation for carcinoma
of the cervix. The characteristics and treatment of these fractures are
discussed.
PMID- 9546459
TI - Stem fixation in the Charnley low-friction arthroplasty in young patients using
an intramedullary bone block.
AB - We report a prospective study of the use of intramedullary bone blocks to improve
the fixation of a matt-finish femoral stem in Charnley low-friction
arthroplasties. There were 379 patients (441 hips), but at a minimum follow-up of
ten years there were 258 arthroplasties in 221 patients including some which had
been revised. The mean age at surgery was 41 years (17 to 51) and the mean follow
up was 13.4 years (1 to 20 including the early revisions). Nine stems (3.5%) had
been revised for aseptic loosening, but there were no stem fractures.
Survivorship of stems was 99.2% at ten years and 94.35% at 15 and 20 years. We
found that the patient's gender, the position of the stem and the experience of
the surgeon all influenced the outcome. Our findings suggest that using our
method of stem fixation, follow-up of over 11 years was needed to reveal the
effects of endosteal cavitation of the femur, and of over 13 years to assess any
divergence between the clinical and the radiological outcomes of stem fixation.
PMID- 9546458
TI - Severe osteolysis after third-body wear due to hydroxyapatite particles from
acetabular cup coating.
AB - One concern about the fixation of HA-coated implants is the possible
disintegration of the surface, with the migration of HA granules into the joint
space, producing third-body wear. We report a study of six revisions of HA-coated
polyethylene RM cups at 9 to 14 years after successful primary arthroplasty. In
all six hips, we found HA granules embedded in the articulating surface of the
polyethylene, with abrasive wear of the cup and the metal femoral head. The cup
had loosened in four hips and three showed severe osteolysis of the proximal
femur. Third-body wear due to HA particles from implant coating may produce
severe clinical problems with few early warning signs. Further clinical,
radiological and histological observations are needed to determine the possible
incidence of this late complication in the various types of coating of a variety
of substrates.
PMID- 9546460
TI - Diagnostic value of intra-articular anaesthetic in primary osteoarthritis of the
hip.
AB - We investigated 42 patients who were being considered for primary total hip
arthroplasty (THA), but in whom it was uncertain whether the hip was the source
of their pain. They were given an injection of local anaesthetic into the joint
space. Of 33 patients who gained pain relief from their injection, 32
subsequently had successful THA. The remaining patient has not had surgery. The
intra-articular injection of local anaesthetic is thus at least 96% sensitive. Of
the nine patients who had no or only minimal pain relief from injection, one has
had an unsuccessful THA, three have been successfully treated for other
conditions and five have unresolved pain for which no organic basis has been
established. We believe that the injection of local anaesthetic into the hip is a
reliable test, with low morbidity. In difficult cases it will aid in the
clarification of the cause of pain which possibly arises from the hip.
PMID- 9546461
TI - Retrograde nailing of femoral fracture below a hip prosthesis: a case report.
AB - In a frail elderly patient a pathological fracture of the femur at the lower end
of a loose femoral stem was treated by the retrograde insertion of an
intramedullary nail over the tip of the prosthesis.
PMID- 9546462
TI - Function of reinserted abductor muscles after femoral replacement.
AB - We compared two methods of reconstruction of the abductor mechanism in 15
patients after prosthetic replacement of the upper femur, to assess abductor
strength and function. Six patients in group I had direct fixation of the gluteus
medius tendon and a segment of the original bone to the prosthesis. Nine patients
in group 2 had the abductor tendon fixed to the iliotibial band. We assessed
clinical function, isometric muscle strength and muscle cross-sectional area for
each patient. The patients in group 1 had better clinical and functional results
(p = 0.059), with average peak torques for hip abduction of 92% of that in the
non-operated leg in group 1, and of 57% in group 2. Group 1 had a mean muscle
cross-sectional area of 69% and a mean value of strength per cross-sectional area
of 134% when compared with the control side. The respective values for group 2
were 52% and 91%. Direct fixation of the abductor muscles to the prostheses gave
improved function and higher isometric abductor muscle force.
PMID- 9546463
TI - Endoscopic reconstruction for isolated anterior cruciate ligament rupture.
AB - We treated 90 patients with an isolated injury to the anterior cruciate ligament
(ACL) by reconstruction using a patellar tendon autograft and interference screw
fixation. Of these, 82 (91%) were available for review at 24 months. Two grafts
and two contralateral ACLs had ruptured during sport and there was one case of
atraumatic graft resorption. Using the assessment of the International Knee
Documentation Committee (IKDC), 86% of the remaining patients were normal or
nearly normal. The median Lysholm knee score was 95/100 and 84% of patients were
participating in moderate to strenuous activity. All had grade-0 or grade-1
Lachman, pivot-shift and anterior-drawer tests. Measurement with the KT1000
arthrometer gave a side-to-side difference of <3 mm of anterior tibial
displacement in 90%. Sixty-six radiographs were IKDC grade A and one was grade B.
Pain on kneeling was present in 31% and graft site pain in 44%. At 24 months
after operation all patients had excellent knee stability, a high rate of return
to sport and minimal radiological evidence of degenerative change. Our series
therefore represents a basis for comparison of results using other techniques and
after more severe injuries.
PMID- 9546464
TI - Fixation of the tibial component of total knee arthroplasty after high tibial
osteotomy: a matched radiostereometric study.
AB - To assess migration of the tibial component we used roentgen
stereophotogrammetric analysis in 40 patients who had had a total knee
arthroplasty after failure of a closing wedge osteotomy and compared them with 40
matched patients after primary total knee arthroplasty. We found no difference in
migration over time or in the tendency for continuous migration between the two
groups. There were no differences in alignment or position of the knee prosthesis
or in the clinical outcome. Our findings show that revision of a failed high
tibial osteotomy to a total knee arthroplasty is effective.
PMID- 9546465
TI - Lipoma arborescens of the knee.
AB - Lipoma arborescens is a rare intra-articular lesion, characterised by diffuse
replacement of the subsynovial tissue by mature fat cells, producing prominent
villous transformation of the synovium. The aetiology of this benign condition is
unknown. We describe six cases involving the knee, discussing the symptoms,
diagnosis and treatment.
PMID- 9546466
TI - Is there a future for hinged prostheses in primary total knee arthroplasty? A 20
year survivorship analysis of the Blauth prosthesis.
AB - The Blauth prosthesis is a hinged total knee replacement. We have evaluated 422
consecutive primary total knee arthroplasties using this design in 330 patients
with a maximum follow-up of 20 years (mean 6). The mean age of the patients at
the time of operation was 70 years (29 to 87). Using endpoints of infection,
removal because of aseptic loosening, removal for any cause, and the worst case
as definitions of failure, the cumulative rates of survival at 20 years were
93.6%, 96.0%, 94.4% and 86.8%, respectively. The cumulative rate of survival of
the patients themselves was 14.4% (24% in patients with osteoarthritis and 9% in
these with rheumatoid arthritis) after 20 years. Our survivorship analysis shows
that hinged knee prostheses, when they are biomechanically well designed, can
yield a satisfactory long-term outcome, similar to those of the best prostheses
of the resurfacing type. Hinged knee prostheses continue to be of value in
patients with severe deformity or instability of the knee.
PMID- 9546467
TI - Prognosis in Perthes' disease: a comparison of radiological predictors.
AB - We compared the prognostic value of the Catterall grouping, the Salter-Thompson
grading, the arthrographic shape of the femoral head, and the Herring lateral
pillar grouping during the fragmentation stage of Perthes' disease in 73 patients
with 81 affected hips. Radiographs were available for study from the onset of the
disease until skeletal maturity. We used the Stulberg classification to assess
outcome. The Herring grade and arthrographic sphericity proved to be the best
predictors of final outcome. Combining these two values further increased the
predictive value. All but one patient in Herring group A achieved an excellent
outcome. In Herring group B, the age of the child and the sphericity of the
femoral head influenced the end result. If the child was less than seven years
old at the onset of symptoms the prognosis was invariably good and all spherical
hips in group B had a good outcome with Stulberg grades 1 or 2. Moderately and
severely deformed hips on arthrography resulted in Stulberg 3 and 4 hips. None of
the hips in Herring group C had a normal appearance at maturity and the outcome
was not significantly influenced by the age at onset or the arthrographic
appearance.
PMID- 9546468
TI - Development of the hip in diastrophic dysplasia.
AB - We examined 50 patients with diastrophic dysplasia both clinically and
radiologically. Two legally aborted fetuses were dissected. The mean age of the
patients was 16.2 years (newborn to 38) and the mean follow-up was 11.4 years (3
months to 34 years). The fetal hips and MRI of newborn infants showed congruity
and no significant joint deformity. Flexion contracture of the hip became evident
later in 93% and was progressive. The radiological appearance of the proximal
femoral ossific nuclei was delayed and in 17% of males and 28% of females the
ossific nuclei had not appeared by the age of 12 years. Radiological measurements
differed considerably from reference values and were related to the rapid and
progressive restriction of rotational movement and the increase in flexion
contracture. The typical findings were flattening and inferomedial bulking of the
femoral head and a double-hump deformation. The changes in the hip led to
secondary osteoarthritis before early middle age. We describe the clinical and
radiological measurements which define the early degeneration of the joint.
PMID- 9546469
TI - Ultrasonography of the hip in developmental hip dysplasia.
AB - Ultrasonography of the hip was performed sequentially by two different examiners
in 75 infants. The ultrasound strips were reviewed twice by three paediatric
orthopaedic surgeons and classified by the Graf method. The intraobserver and
interobserver agreement between the interpretations was analysed using simple and
weighted kappa coefficients calculated for agreement on the Graf classification
and for grouping as normal (types 1A to 2A), and abnormal requiring treatment
(types 2B to 4). When examining the same ultrasound strip, intraobserver
agreement for the Graf classification was substantial (mean kappa 0.61), but
interobserver agreement was only moderate (kappa 0.50). For the grouping into
normal and abnormal, the mean kappa value for intraobserver agreement was 0.67
and for interobserver agreement 0.57. Because of the significant differences in
agreement between normal and abnormal hips, we analysed a subgroup of those with
at least one abnormal interpretation. Intraobserver agreement within this
subgroup showed moderate reliability (kappa 0.41), but interobserver agreement
was only fair (kappa 0.28). Interpretations of two different strips performed
sequentially showed significantly lower agreement with an intraobserver kappa
value of 0.29 and an interobserver value of 0.28. In the subgroup with at least
one abnormal reading, the intraobserver kappa was 0.09 and the interobserver 0.1.
Our findings suggest that both the technique of performing ultrasonography and
the interpretation of the image may influence the result.
PMID- 9546470
TI - The Singapore operation for recurrent dislocation of peroneal tendons: long-term
results.
AB - Recurrent dislocation of peroneal tendons is uncommon and there are few reports
of the long-term results after repair. The Singapore operation, first described
in 1985, is an anatomical repair based on the Bankart-like lesion seen in the
superior peroneal retinaculum. We reviewed 21 patients after a mean follow-up of
9.3 years, and found no recurrence. Eighteen had good functional results and had
returned to their previous levels of vocational and sports activities. The three
fair results were due to painful scars or neuromas.
PMID- 9546471
TI - Ankle arthroplasty for rheumatoid arthritis and osteoarthritis: prospective long
term study of cemented replacements.
AB - We performed 52 cemented ankle arthroplasties for painful osteoarthritis (OA)
(25) or rheumatoid arthritis (RA) (27) using an ankle prosthesis with a near
anatomical design. We assessed the patients radiologically and clinically for up
to 14 years using an ankle scoring system. The preoperative median scores were 29
for the OA group and 25 for the RA group and at ten years were 93.5 and 83,
respectively. Six ankles in the OA group and five in the RA group required
revision or arthrodesis. Survivorship analysis of the two groups showed no
significant differences with 72.7% survival for the OA group and 75.5% for the RA
group at 14 years.
PMID- 9546472
TI - Osteoarthritis of the ankle after foreign-body reaction to absorbable pins and
screws: a three- to nine-year follow-up study.
AB - Between 1985 and 1994, 1223 patients with malleolar fractures of the ankle were
treated by open reduction and internal fixation with absorbable pins and screws,
of whom 74 (6.1%) had an obvious inflammatory foreign-body reaction to the
implants. Of these 74, ten later developed moderate to severe osteoarthritis of
the ankle despite no evidence of incongruity of the articular surface. The
implants used in these patients were made from polyglycolide, polylactide or
glycolide-lactide copolymer. The joint damage seemed to be due to polymeric
debris entering the articular cavity through an osteolytic extension of an
implant track. The ten patients had a long clinical course which included a
vigorous local foreign-body reaction, synovial irritation and subsequent
degeneration. At a follow-up of three to nine years, ankle arthrodesis had been
necessary in two patients and is being considered for another two. The incidence
of these changes in the whole series was 0.8%, which is not high, but awareness
of this possible late complication is essential.
PMID- 9546473
TI - Quantitative comparison of wear debris from UHMWPE that has and has not been
sterilised by gamma irradiation.
AB - Ultra-high-molecular-weight polyethylene (UHMWPE) components for total joint
replacement generate wear particles which cause adverse biological tissue
reactions leading to osteolysis and loosening. Sterilisation of UHMWPE components
by gamma irradiation in air causes chain scissions which initiate a long-term
oxidative process that degrades the chemical and mechanical properties of the
polyethylene. Using a tri-pin-on-disc tribometer we studied the effect of ageing
for ten years after gamma irradiation in air on the volumetric wear, particle
size distribution and the number of particles produced by UHMWPE when sliding
against a stainless-steel counterface. The aged and irradiated material produced
six times more volumetric wear and 34 times more wear particles per unit load per
unit sliding distance than non-sterilised UHMWPE. Our findings indicate that
oxidative degradation of polyethylene after gamma irradiation in air with ageing
produces more wear.
PMID- 9546474
TI - Wear in uncemented porous and cemented polyethylene sockets: a randomised,
radiostereometric study.
AB - We used radiostereometric analysis to compare wear rates between uncemented
porous sockets and cemented all-polyethylene sockets in a series of 102 hips
randomised for either a Harris-Galante or a Charnley cup. Wear was evaluated in
95 hips at a mean of five years (2 to 7). All hips had a cemented, 22 mm head
mono-bloc Charnley stem. The mean annual wear rate was 0.09 mm in the Charnley
sockets and 0.10 mm in the Harris-Galante sockets, with no statistically
significant differences in wear, migration or rotation. We conclude that, up to
five years, the wear characteristics of the modular and porous Harris-Galante
socket resemble that of the Charnley socket.
PMID- 9546475
TI - Interbody cage stabilisation in the lumbar spine: biomechanical evaluation of
cage design, posterior instrumentation and bone density.
AB - We performed a biomechanical study on human cadaver spines to determine the
effect of three different interbody cage designs, with and without posterior
instrumentation, on the three-dimensional flexibility of the spine. Six lumbar
functional spinal units for each cage type were subjected to multidirectional
flexibility testing in four different configurations: intact, with interbody
cages from a posterior approach, with additional posterior instrumentation, and
with cross-bracing. The tests involved the application of flexion and extension,
bilateral axial rotation and bilateral lateral bending pure moments. The relative
movements between the vertebrae were recorded by an optoelectronic camera system.
We found no significant difference in the stabilising potential of the three cage
designs. The cages used alone significantly decreased the intervertebral movement
in flexion and lateral bending, but no stabilisation was achieved in either
extension or axial rotation. For all types of cage, the greatest stabilisation in
flexion and extension and lateral bending was achieved by the addition of
posterior transpedicular instrumentation. The addition of cross-bracing to the
posterior instrumentation had a stabilising effect on axial rotation. The bone
density of the adjacent vertebral bodies was a significant factor for
stabilisation in flexion and extension and in lateral bending.
PMID- 9546476
TI - Health status after Ilizarov reconstruction of post-traumatic lower-limb
deformity.
AB - Previous studies of the Ilizarov procedure have concentrated on musculoskeletal
assessments rather than the opinions of patients. In a prospective trial of 25
consecutive patients, we evaluated the effect of Ilizarov reconstruction of post
traumatic deformity on general health status using the SF36 and Nottingham Health
Profile (NHP). The patients had very low preoperative scores, which remained low
during treatment and correction, but increased postoperatively. The mean overall
SF36 score improved from 36 +/- 3 to 58 +/- 7 (p = 0.031) and the NHP score from
39 +/- 11 to 67 +/- 10 (p = 0.002). The improvements in scores were not limited
to the physical components and were equal or better than the improvements
reported for other orthopaedic procedures, including total joint arthroplasty.
Ilizarov-type reconstruction of deformity of the lower limb not only restores
bony configuration, but also produces a large improvement in the general health
status of patients.
PMID- 9546477
TI - Laser Doppler flowmetry in the diagnosis of chronic compartment syndrome.
AB - Chronic compartment syndrome (CCS) is usually considered to be due to ischaemia
of muscle. We have attempted to use the direct measurement of muscle blood flow
for diagnosis since the assessment of intracompartmental pressure does not
provide accurate knowledge of the vascular state. We recorded simultaneously
continuous measurements of the laser Doppler flow (LDF) in muscle and the
intracompartment pressure (ICP) after exercise in seven patients with CCS, and in
seven control subjects. The mean ICP was 74.1 +/- 4.4 mmHg in CCS patients and
24.2 +/- 3.4 mmHg in control subjects one minute after exercise, decreasing to
34.6 +/- 2.3 mmHg and 15.0 +/- 1.6 mmHg at 20 min, respectively. The LDF was 0.80
+/- 0.11 arbitrary units (AU) in control subjects and 1.09 +/- 0.14 AU in CCS
patients one minute after exercise, and 0.41 +/- 0.11 AU and 0.27 +/- 0.04 AU,
respectively, at the end of the recovery period. The ICP showed a progressive
decrease over time in both groups. The LDF decreased sharply during the first
minutes of recovery in control subjects, but in patients with CCS there was a
delayed hyperaemic peak with blood flow reaching 0.84 +/- 0.10 AU at nine minutes
as against 0.33 +/- 0.06 AU for control subjects (p < 0.01). The ICP increased in
both control subjects and CCS patients after exercise with no clear cut-off point
between the groups. By contrast, changes in muscle blood flow over time were
clearly different between control subjects and patients with CCS. For this
reason, LDF should be investigated further as a technique for the diagnosis of
CCS.
PMID- 9546478
TI - Recurrence of giant-cell tumour of bone after the use of cement.
PMID- 9546480
TI - MRI can prevent unnecessary arthroscopy.
PMID- 9546479
TI - Thromboprophylaxis and death after total hip replacement.
PMID- 9546481
TI - MRI can prevent unnecessary arthroscopy.
PMID- 9546482
TI - MRI can prevent unnecessary arthroscopy.
PMID- 9546483
TI - Early tourniquet release during total knee arthroplasty.
PMID- 9546484
TI - Alternative treatments for meniscal injuries.
PMID- 9546485
TI - The role of electromyography in neurology.
AB - A review is given of the role of electromyography (EMG) for diagnosis,
pathophysiological description and monitoring of patients with disorders of the
peripheral nervous system. Various EMG methods are presented and their principal
differences are discussed. The usefulness of these methods varies depending on
the pathology to be studied. With modern quantitative methods for analysis, EMG
has become more sensitive and accurate and is therefore an important part in the
evaluation of the neurologic patient. EMG results are usually combined with
findings from other neurophysiological investigations (neurography, evoked
potentials), histochemistry, biochemistry and most importantly with the clinical
signs to give as complete a picture of the condition as possible. The usefulness
of EMG depends on a number of factors other than the quality of the investigation
as such. These aspects are discussed briefly.
PMID- 9546486
TI - The largest Lyapunov exponent of the EEG during ECT seizures as a measure of ECT
seizure adequacy.
AB - Attributes of the electroencephalogram (EEG) recorded during electroconvulsive
therapy (ECT) seizures appear promising for decreasing the uncertainty that
exists about how to define a therapeutically adequate seizure. In the present
report we study whether one promising and not yet tested ictal EEG measure, the
largest Lyapunov exponent (lambda1), is useful in this regard. We calculated
lambda1 from 2 channel ictal EEG data recorded in 25 depressed subjects who
received right unilateral ECT. We studied the relationship of lambda1 to
treatment therapeutic outcome and to an indirect measure of treatment therapeutic
potency, the extent to which the stimulus intensity exceeds the seizure
threshold. We found lambda1 could be reliably calculated from ictal EEG data and
that the global mean, maximum, and standard deviation of lambda1 were smaller in
the more therapeutically potent moderately suprathreshold ECT and in therapeutic
responders. These results imply a more predictable or consistent pattern of EEG
seizure activity over time in more therapeutically effective ECT seizures. These
findings also suggest the promise of lambda1 as a marker of ECT seizure
therapeutic adequacy and build on our previous work suggesting that lambda1 may
be useful for classifying seizures and for reflecting the relative physiologic
impact of seizure activity.
PMID- 9546488
TI - Neurophysiologic surgical monitoring staffing patterns in the USA.
AB - Staffing patterns for intraoperative EEG and somatosensory evoked potential
monitoring were assessed in a survey of 150 US board certified clinical
neurophysiologists. Whether or not a clinical neurophysiology physician needs to
be in the operating room throughout monitoring has been a point of disagreement
and debate. The data here provide evidence that most US clinical
neurophysiologists send non-physician staff to monitor EEG during carotid
endarterectomies. Similar results were found for somatosensory evoked potential
spinal cord monitoring during scoliosis procedures. By describing current
staffing practices, these data can promote a more informed debate on this
controversial topic.
PMID- 9546487
TI - Early detection of vasospasm after acute subarachnoid hemorrhage using continuous
EEG ICU monitoring.
AB - The neurologic morbidity of delayed ischemic deficits from vasospasm following
aneurysmal subarachnoid hemorrhage (SAH) continues to be the most debilitating
complication from this devastating illness. Neurologic critical care is focused
on recognition and treatment of these secondary insults but often the treatment
is withheld until an irreversible deficit becomes manifest. Continuous EEG (cEEG)
monitoring provides a unique potential to recognize early secondary insults and
offers an opportunity for early intervention. We studied 32 SAH patients using
cEEG and trending of the quantitative measure, relative alpha (RA), to determine
if reductions in RA variability occurred with documented vasospasm. In 19/19
patients with angiographically documented vasospasm, we found that RA variability
was decreased by a mean of two grades and improved with resolution of vasospasm.
In 10/19 this reduction in RA variability preceded the diagnosis of vasospasm by
a mean of 2.9 days (SD 1.73). The positive predictive and negative predictive
values are 76% and 100%, respectively. Non-diagnostic clinical signs at the time
of RA variability reduction and vasospasm were present in 12/19 patients. Thus
decreased RA variability is able to provide early detection of neurologic
complications such as vasospasm in patients before clear clinical symptoms and
signs occur.
PMID- 9546489
TI - Dynamics of EEG background activity level during quiet sleep in multiple
nocturnal sleep episodes in infants.
AB - The study reported in this paper investigated the dynamics of EEG background
activity during quiet sleep (QS) in the first year of life. These dynamics have
been previously shown to follow an intra-sleep trend within a single sleep
episode, and the aim of this study was to show whether they were similar in two
successive nocturnal sleep episodes interrupted by a waking episode, or whether
they exhibited a progressive trend across the two episodes. The polygraphic
recordings of two groups of 6 infants aged from 9 to 15 weeks old and from 25 to
47 weeks old, whose nocturnal sleep organisation was spontaneously interrupted,
were selected. Three indicators of the time course of the parameter value,
obtained from automatic analysis and reflecting the degree of synchronisation of
the EEG activity recorded by the centro-occipital lead, were computed for the
first two QS periods of two successive sleep episodes: the parameter range
(difference between the EEG parameter value at the QS onset and that at the
trough); the trough latency (time interval between QS onset and trough); and rate
of synchronisation (range/trough latency). All 3 indicators differed between the
first and the second QS period of both sleep episodes independently of age. The
rate of synchronisation (but not the parameter range and the trough latency) was
higher in the first sleep episode than in the second one, showing an over-night
decreasing trend. Those results show that, when nocturnal sleep in infants is
split into two episodes separated by an intervening waking, also the second sleep
episode displays an internal organisation of its EEG dynamics. Moreover, an
across-night trend in the rate of synchronisation can be observed from an early
age, a finding which suggests, again, the early emergence of homeostatic
regulation of sleep.
PMID- 9546490
TI - Relationship between muscle tone changes, sawtooth waves and rapid eye movements
during sleep.
AB - 'Sawtoothed' waves occur during rapid eye movement (REM) sleep, but their source
as well as their function is not known. We studied the onset of sawtooth waves
(STW) in relation to the onset of muscle tone reduction (MTR) and to REM during
20 polysomnographic recordings in 11 normal volunteers. Seventy-seven (85%) of a
total of 91 REM sleep cycles were used for further analysis, because within a
1000 s interval they showed a relatively stereotyped sequence of events: a
generalized body movement, followed by MTR, then the appearance of STW, and
ending with the first REM. The first STW often occurred during the electrographic
stage II period prior to the beginning of the REM, by which time muscle tone was
either already at or close to the tone level of the REM sleep period in all
subjects. The overall mean onset time of MTR was 267 s (range 89-660 s), STW was
378 s (range 169-779), and REM was 448 s (range 265-849); their differences were
highly significant (F = 27.1, df 2,20, P < 0.001). Our data suggest that a
predictable sequence of muscle tone reduction, then STW, and then REM, precedes
the generally accepted onset of the REM sleep period, and may have implications
for the redesignation of physiologic REM sleep onset.
PMID- 9546491
TI - Auto power and coherence analysis of delta-theta band EEG during the waking
sleeping transition period.
AB - To evaluate the spatio-temporal variation of delta and theta band EEGs during the
waking-sleeping transition period, auto power and coherence analyses of scalp
EEGs were carried out on 12 male subjects. The 7 auto power and 21 coherence
values obtained from the 7 areas were studied every 20 s from 5 min before stage
1 onset to 24 min after stage 1 onset. The consecutive samples of spectra were
computed for two frequency bands (delta: 2.5-3.5 Hz; theta: 4.0-7.5 Hz). Auto
power started to increase after stage 1 onset and terminated 8.4 min after stage
2 onset. Topograms of each band power changed with progression towards deep sleep
from the flat or relatively low voltage pattern without any focus to the
frontopolar-parietal pattern or the fronto-parietal dominant pattern. Principal
component analysis of the coherence values revealed generalized and localized
components in each band. The generalized component was distributed across scalp
areas, while the localized component was distributed in frontopolar-frontal
areas. The generalized component decreased to the plateau level of non-rapid eye
movement (NREM) sleep 5.4 min after stage 2 onset. The localized component
started to increase after stage 1 onset and reached the plateau level of NREM
sleep 2.4 min after stage 2 onset. These results indicate that the delta-theta
band EEG structures of the waking-sleeping transition period may not be uniform
across the scalp areas and the hypnagogic period may start after stage 1 onset
and continue for 8.4 min after stage 2 onset.
PMID- 9546492
TI - EEG-based discrimination between imagination of right and left hand movement.
AB - Three subjects were asked to imagine either right or left hand movement depending
on a visual cue stimulus. The interval between two consecutive imagination tasks
was > 10 s. Each subject imagined a total of 160 hand movements in each of 3-4
sessions (training) without feedback and 7-8 sessions with feedback. The EEG was
recorded bipolarly from left and right central and parietal regions and was
sampled at 128 Hz. In the feedback sessions, the EEG from both central channels
was classified on-line with a neural network classifier, and the success of the
discrimination between left and right movement imagination was given within 1.5 s
by means of a visual feedback. For each subject, different frequency components
in the alpha and beta band were found which provided best discrimination between
left and right hand movement imagination. These frequency bands varied between 9
and 14 Hz and between 18 and 26 Hz. The accuracy of on-line classification was
approximately 80% in all 3 subjects and did not improve with increasing number of
sessions. By averaging over all training and over all feedback sessions, the EEG
data revealed a significant desynchronisation (ERD) over the contralateral
central area and synchronisation (ERS) over the ipsilateral side. The ERD/ERS
patterns over all sessions displayed a relatively small intra-subject variability
with slight differences between sessions with and without feedback.
PMID- 9546493
TI - Reproducibility and validity of electric source localisation with high-resolution
electroencephalography.
AB - The present study investigates the reproducibility and validity of the EEG source
localisation of somatosensory evoked potentials (SEPs) using high-resolution EEG
(61 scalp electrodes) and a source reconstruction on the basis of the individual
brain morphology as obtained from magnetic resonance images (MRIs). The
somatosensory evoked potentials (SEPs) to electrical stimulation of the right
median nerve were repeatedly collected from the scalp of one healthy subject in 9
replications run on 9 different days. The source reconstruction for the 19 ms SEP
component was performed by using a single moving dipole model as a source model.
Two different head models were used: a spherical 3 shell model and a more
realistically shaped 3 compartment model computed using the boundary element
method (BEM). The source locations of the 19 ms SEP component were found to be
highly reproducible using both head models: the mean standard deviation of the
dipole locations was found to be 2.6 mm for the 3 shell model and 4 mm for the
more realistically shaped head model. By projection into the individual MRI, the
dipoles resulting from either head models were found to be located within the
postcentral gyrus. The electric source locations were consistent with the maximum
of the task-specific changes seen in a functional magnetic resonance imaging
(fMRI) experiment when using the same somatosensory stimulation protocol.
PMID- 9546494
TI - Bicoherence of intracranial EEG in sleep, wakefulness and seizures.
AB - The hypothesis that the intracranial EEG has local structure and short-term non
stationarity is tested with a little-studied measure of non-linear phase
coupling, the bicoherence in human subdural and deep temporal lobe probe data
from 11 subjects during sleeping, waking and seizure states. This measure of
cooperativity estimates the proportion of energy in every possible pair of
frequency components, F1, F2 (from 1 to 50 Hz in this study), that satisfies the
definition of quadratic phase coupling (phase of component at F3, which is F1 +
F2, equals phase of F1 + phase of F2). Derived from the bispectrum, which
segregates the non-Gaussian energy, auto-bicoherence uses the frequency
components in one channel; cross-bicoherence uses one channel for F1 and F2 and
another for F3. These higher order spectra are used in physical systems for
detection of episodes of non-linearity and transients, for pattern recognition
and robust classification, relatively immune to Gaussian components and low
signal to noise ratios. Bicoherence is found not to be a fixed character of the
EEG but quite local and unstable, in agreement with the hypothesis. Bicoherence
can be quite different in adjacent segments as brief as 1.6 s as well as adjacent
intracranial electrodes as close as 6.5 mm, even when the EEG looks similar. It
can rise or fall steeply within millimeters. It is virtually absent in many
analysis epochs of 17s duration. Other epochs show significant bicoherence with
diverse form and distribution over the bifrequency plane. Isolated peaks,
periodic peaks or rounded mountain ranges are either widely scattered or confined
to one or a few parts of the plane. Bicoherence is generally an invisible
feature: one cannot usually recognize the responsible form of non-linearity or
any obvious correlate in the raw EEG. During stage II/III sleep overall mean
bicoherence is generally higher than in the waking state. During seizures the
diverse EEG patterns average a significant elevation in bicoherence but have a
wide variance. Maximum bispectrum, maximum power spectrum, maximum and mean
bicoherence, skewness and asymmetry all vary independently of each other. Cross
bicoherence is often intermediate between the two auto-bicoherence spectra but
commonly resembles one of the two. Of the known factors that contribute to
bicoherence, transient as distinct from ongoing wave forms can be more important
in our data sets. This measure of non-linear higher moments is very sensitive to
weak quadratic phase coupling; this can come from several kinds of waveforms. New
methods are needed to evaluate their respective contributions. Utility of this
descriptor cannot be claimed before more carefully defined and repeatable brain
states are studied.
PMID- 9546495
TI - Stimulus-evoked electrographic patterns in neonates: an abnormal form of
reactivity.
AB - Stimulus-evoked electrographic patterns are described for 12 neonates, coincident
with tactile or painful stimulation. Four newborns had stimulus-evoked
electrographic seizures with and without concomitant clinical seizure behaviors.
Eight neonates had generalized or focal stimulus-evoked discharges, with or
without coincident movements, which did not evolve into electrographic seizures.
Nine infants were less than 36 weeks estimated gestational age at the time
stimulus-evoked discharges were noted. Eleven neonates were comatose or
phamacologically paralyzed at the time the stimulus-evoked patterns were
initially noted. All neonates had moderate or severe interictal EEG background
abnormalities at the time these patterns were observed. All patients had brain
lesions documented by either cranial imaging or neuropathological examinations.
Eleven patients died or have significant neurological handicaps. These phenomena
represent an abnormal form of cortical reactivity to sensory stimuli in the
developing brain. Most neonates with these patterns have significant diffuse or
multifocal damage to the neocortex.
PMID- 9546497
TI - Changing, from top to bottom.
PMID- 9546498
TI - Pallidotomy for Parkinson's disease: hitting the target?
PMID- 9546496
TI - Topographic distribution of seizure onset and hippocampal atrophy: relationship
between MRI and depth EEG.
AB - Medial temporal lobe epilepsy (MTLE) is associated with hippocampal cell loss and
organization of the dentate gyrus. Some studies suggest a correlation between the
topographic distribution of cell loss and site of epileptogenesis. We studied the
relationship between the site of ictal onset with the presence of segmental
atrophy in patients with non-lesional MTLE using magnetic resonance imaging (MRI)
and depth EEG. Ictal recordings were obtained from 27 patients with longitudinal
hippocampal depth electrodes and variable combinations of subdural strips
sampling medial temporal structures. The location of the depth electrode contacts
was correlated with anatomical landmarks. Seizures were analyzed for the
distribution of onset along the long axis of the hippocampus. MRI analysis were
performed to detect segmental atrophy. Outcome was assessed 1 year or more
following anterior temporal lobectomy. Twenty-five patients had unilateral, and
two had bilateral, hippocampal atrophy. One hundred and forty-seven seizures were
reviewed: 21 showed focal onset and 126 showed regional onset. Ictal onset
involved the amygdala and anterior half of the hippocampus in 80% of the seizures
while only 40% of patients had atrophy of these segments. Most patients had
excellent outcome. In patients with MTLE the primary area of epileptogenesis does
not parallel the hippocampal segments with the greatest degree of volume loss.
PMID- 9546499
TI - Electrovaporisation of the prostate.
PMID- 9546500
TI - Vein quality in vascular surgery.
PMID- 9546501
TI - Statins for prevention of stroke.
PMID- 9546502
TI - Nomenclature of enterotoxins.
PMID- 9546503
TI - Conditions in prisons.
PMID- 9546504
TI - Continuing medical education: shibboleth or necessity?
PMID- 9546505
TI - Randomised controlled trial of prophylactic antibiotics before insertion of
intrauterine devices. IUD Study Group.
AB - BACKGROUND: The value of antibiotic prophylaxis before insertion of an
intrauterine device (IUD) remains uncertain. We undertook a triple-masked,
randomised, placebo-controlled trial to find out whether such prophylaxis reduces
the rate of IUD removal within 90 days. METHODS: 11 clinic sites in southern
California enrolled women who requested IUD insertion and were at low risk of
sexually transmitted infection according to self-reported medical history. We
randomly assigned 1985 participants either 500 mg azithromycin or placebo
capsules of identical appearance taken about 1 h before insertion of a Copper T
380A IUD. 118 women did not have an IUD inserted. We followed up 1833 of the
remaining 1867 (98%) participants for at least 90 days after insertion. FINDINGS:
The rate of IUD removal for any reason other than partial expulsion was 3.8%
(35/918) in the antibiotic group and 3.4% (31/915) in the placebo group (relative
risk 1.1 [95% CI 0.7-1.8]). The two treatment groups sought medical attention
with equal frequency (mean 38 visits per 100 women). During the 90 days after IUD
insertion, only one woman from each assignment group had salpingitis, as defined
by established criteria. INTERPRETATION: Prophylaxis with azithromycin did not
affect the likelihood that a woman would retain her IUD at 90 days or the
frequency of postinsertion medical attention. In appropriately screened women,
the risk of upper-genital-tract infection is negligible after IUD insertion, with
or without the administration of prophylactic antibiotics.
PMID- 9546506
TI - Inequalities in self-rated health: explanations from different stages of life.
AB - BACKGROUND: Inequalities in health are a major public-health concern. A greater
understanding is needed on the relative importance of different causes. We
investigated the contribution of risk factors identified at different life stages
to inequalities in self-rated health. METHODS: We used data from 5606 men and
5799 women in the 1958 British birth cohort followed-up to age 33 years, on
health behaviour, education, adolescent health, family structure and social
support, work characteristics, and material circumstances. We assessed the
contribution of different factors to social-class differences in self-rated
health by adjustment of odds ratios (classes IV and V vs I and II). FINDINGS:
Odds ratios of poor-rated health at age 33 were 3.15 for men and 2.30 for women,
which decreased to 2.06 and 1.34, respectively, after adjustment for previously
identified factors from birth to early adulthood. Adjustment for adult work
characteristics, material circumstances, and health behaviour between ages 23
years and 33 years further decreased the odds ratios to 1.64 (men) and 1.11
(women). Most factors contributed to the reduction in odds ratios, although
adolescent socioemotional adjustment, class at birth, educational qualifications,
and psychosocial job strain were especially important. Additional key factors for
men were adult smoking and job insecurity, and for women, housing during
childhood, adult income, and age at first child. INTERPRETATION: There was no
single cause of health inequality at age 33 years. Explanations spanned from
early life to young adulthood. Policy implications include reduction of social
differences in material circumstances and of differences in individual skills and
resources acquired in early life.
PMID- 9546507
TI - Effects of resective surgery for left-sided intracranial tumours on language
function: a prospective study.
AB - BACKGROUND: Although language disorders occur in about 50% of patients with a
left hemispheric tumour and are a significant cause of morbidity, the effects of
resective neurosurgery and their relation to tumour pathology are unclear. We
report the immediate effects of resective surgery on language functions in a
heterogeneous group of patients with left-sided intracranial tumours. METHODS: 40
patients were studied. The Western Aphasia Battery (WAB) and Boston Naming Test
(BNT) were administered preoperatively and before discharge following resective
neurosurgery. Dexamethasone dose at time of testing was recorded, as was time
taken to complete the tests, and tumour neuropathology. FINDINGS: 15 patients
with normal aphasia quotients and language quotients before resective surgery all
had normal quotients postoperatively. 25 who were dysphasic (ie, aphasia quotient
<93.8) preoperatively showed significant postoperative improvements in both their
mean aphasia quotient (from 81.8 to 89.1, p=0.004) and their mean language
quotient (from 73.4 to 85.4, p=0.001), though 13 remained dysphasic. Two of the
25 dysphasic patients had their WAB scores lowered by tumour resection. The
findings and postoperative changes in BNT scores were almost identical to the
pattern of those in WAB scores. At second assessment, dexamethasone therapy was
significantly (p<0.01) lower than preoperative dose (reduction from mean 10.3
mg/day to 0.7 mg/day in the dysphasic group). Patients with glioblastoma were
more likely to have lower aphasia quotients, language quotients, and BNT scores
than patients with anaplastic glioma, metastasis, or meningioma. Although the
glioblastoma group had the greatest improvements in WAB operative scores, 57%
remained dysphasic after resective surgery. Two additional patients declined
postoperative assessment. INTERPRETATION: Resective surgery for left-sided
intracranial tumours significantly improves language function in dysphasic
patients, and is unlikely to impair language functions in non-dysphasic patients.
Dysphasia and its response to resective surgery are related to the tumour
neuropathology.
PMID- 9546509
TI - First-trimester transabdominal fetal echocardiography.
AB - BACKGROUND: Fetal echocardiography is usually done during the second trimester of
pregnancy, but waiting until that time can lead to anxiety for the parents if the
fetus is at high risk of having cardiac abnormalities. We report the feasibility
of transabdominal first-trimester fetal echocardiography for early reassurance of
normality or a prenatal diagnosis of a cardiac malformation. METHODS: We did
first-trimester fetal echocardiography and colour-flow mapping with a 5 MHz
curvilinear transducer at 13 weeks' gestation (range 12-13+6 days) in 15 fetuses
at risk of cardiac defects. The fetus was judged to be normal if the
investigation showed normal visceral situs, four-chamber view, and two normally
related great arteries of similar size. We did second-trimester scans and
neonatal follow-up for the women who continued with their pregnancies; necropsy
was done in two cases of pregnancy termination. FINDINGS: Ten fetuses had normal
hearts at the time of the first scan, which was confirmed during second-trimester
assessment. In one fetus, the four-chamber view was asymmetrical and a moderate
sized apical muscular ventricular septal defect (VSD) was diagnosed after birth.
In another two fetuses we diagnosed small muscular VSD on the second-trimester
scans. A complex cardiac malformation was correctly diagnosed in one fetus at 12
weeks of gestation. Thus, in 11 fetuses, the imaging was of sufficient quality to
reassure the family or to diagnose an abnormality. In the other four fetuses, the
investigation was judged to be incomplete, but no definite cardiac abnormality
was identified. INTERPRETATION: Transabdominal fetal echocardiography in the
first trimester of pregnancy is feasible. In most patients the resolution of
images is sufficient to allow assessment of basic cardiac anatomy, when normal,
or detection of complex malformations, when present.
PMID- 9546508
TI - Risk factors for and prevention of sporadic infections with vero cytotoxin (shiga
toxin) producing Escherichia coli O157.
AB - BACKGROUND: Recent outbreaks of vero cytotoxin (shiga toxin) producing
Escherichia coli O157 (VTEC O157) infection have stimulated debate on food
safety. However, 90% of cases in England and Wales are sporadic. We report a case
control study of sporadic VTEC O157 infection. METHODS: We compared 85 sporadic
cases of VTEC O157 infection, identified through population surveillance, with
142 controls, randomly selected from general practitioners' lists. We matched
cases and controls for age, sex, and family doctor's practice. Exposures to
foods, water, animals, farms, and environmental factors were recorded. We visited
the premises concerned when cases had eaten beefburgers or cooked sliced meats
from caterers or had had contact with a farm. FINDINGS: Consumption of a
beefburger from a catering premises other than from a fast-food chain A (a
national chain) and consumption of cold cooked sliced meat (eg, in a salad or
sandwich) from caterers, but not butchers, was associated with VTEC O157
infection (odds ratios 4.63 [95% CI 1.33-30.14] and 3.36 [1.04-12.74],
respectively). Policies for ensuring thorough cooking of burgers by one national
fast-food chain differed from the other catering premises we visited. There was
evidence of person-to-person spread and transmission of VTEC O157 infection from
animals. INTERPRETATION: Local inspection of catering establishments that serve
cooked meats together with public education to prevent spread on farms and in
houses would reduce the burden of VTEC O157 infection by about 10% for each risk
factor.
PMID- 9546510
TI - A brain haemorrhage?
PMID- 9546511
TI - Intracerebral haemorrhage caused by drug abuse.
PMID- 9546512
TI - Antiretrovirals during pregnancy in HIV-1-positive women in New York City.
PMID- 9546513
TI - Outbreak of Legionnaires' disease at a bar after basement flooding.
PMID- 9546514
TI - Aplastic anaemia during treatment with fluoxetine.
PMID- 9546515
TI - Familial leg ulcers.
PMID- 9546516
TI - Neuroleptic sensitivity in dementia with Lewy bodies and Alzheimer's disease.
PMID- 9546517
TI - Increased urinary retinol loss in children with severe infections.
PMID- 9546518
TI - Does the salmon patch reappear?
PMID- 9546519
TI - ATLAS shows global undertreatment of heart failure.
PMID- 9546521
TI - Meditating on yogic science.
PMID- 9546522
TI - War surgery continues in Sri Lanka.
PMID- 9546523
TI - "Disgust" at Canada's tainted-blood settlement.
PMID- 9546524
TI - US court to rule whether HIV infection constitutes disability.
PMID- 9546526
TI - Migraine.
PMID- 9546527
TI - The oasis.
PMID- 9546528
TI - Eating for two: are guidelines for weight gain during pregnancy too liberal?
PMID- 9546529
TI - Highly active antiretroviral therapy.
PMID- 9546530
TI - Highly active antiretroviral therapy.
PMID- 9546531
TI - Highly active antiretroviral therapy.
PMID- 9546532
TI - Highly active antiretroviral therapy.
PMID- 9546533
TI - Highly active antiretroviral therapy.
PMID- 9546534
TI - Highly active antiretroviral therapy.
PMID- 9546535
TI - Septic arthritis.
PMID- 9546536
TI - Septic arthritis.
PMID- 9546537
TI - Magnesium sulphate in eclampsia.
PMID- 9546539
TI - Meta-analyses, multivariate analyses, and coping with the play of chance.
PMID- 9546538
TI - Magnesium sulphate in eclampsia.
PMID- 9546540
TI - Biochemical detection of systolic dysfunction.
PMID- 9546541
TI - Biochemical detection of systolic dysfunction.
PMID- 9546542
TI - Lung transplantation.
PMID- 9546543
TI - Maternal inheritance of longevity.
PMID- 9546544
TI - Ethics review and clinical trials.
PMID- 9546545
TI - Ethics review and clinical trials.
PMID- 9546546
TI - Ethics review and clinical trials.
PMID- 9546547
TI - Hyphenosis.
PMID- 9546548
TI - Switching sides.
PMID- 9546549
TI - A piece of my mind. The teaching case.
PMID- 9546550
TI - Emerging infections on center stage at first major international meeting.
PMID- 9546551
TI - Acne drug depression warnings highlight need for expert care.
PMID- 9546552
TI - From the Centers for Disease Control and Prevention. Mortality among children
with sickle cell disease identified by newborn screening during 1990-1994-
California, Illinois, and New York.
PMID- 9546553
TI - From the Centers for Disease Control and Prevention. HIV/AIDS among American
Indians and Alaskan Natives--United States, 1981-1997.
PMID- 9546554
TI - From the Centers for Disease Control and Prevention. Administration of zidovudine
during late pregnancy and delivery to prevent perinatal HIV transmission-
Thailand, 1996-1998.
PMID- 9546555
TI - From the Centers for Disease Control and Prevention. Self-assessed health status
and selected behavioral risk factors among persons with and without health-care
coverage--United States, 1994-1995.
PMID- 9546556
TI - Palliative options at the end of life.
PMID- 9546557
TI - Palliative options at the end of life.
PMID- 9546558
TI - Palliative options at the end of life.
PMID- 9546559
TI - Palliative options at the end of life.
PMID- 9546560
TI - Standards for scientific behavior and research integrity.
PMID- 9546561
TI - Screening for cystic fibrosis.
PMID- 9546562
TI - Screening for cystic fibrosis.
PMID- 9546563
TI - Effect of vitamins C and E on vascular reactivity.
PMID- 9546564
TI - Clinical Crossroads: a 73-year-old man with symptomatic benign prostatic
hyperplasia.
PMID- 9546565
TI - Prevalence of hearing loss among children 6 to 19 years of age: the Third
National Health and Nutrition Examination Survey.
AB - CONTEXT: Hearing loss in children influences the development of communication and
behavioral skills, but few studies in the United States have used pure-tone
audiometry to derive hearing loss prevalence estimates for children. OBJECTIVE:
To describe the prevalence of hearing loss among US children by sociodemographic
characteristics, reported hearing loss, and audiometric screening factors.
DESIGN: National population-based cross-sectional survey with an in-person
interview and audiometric testing at 0.5 to 8 kHz. SETTING/PARTICIPANTS: A total
of 6166 children aged 6 to 19 years completed audiometry in the mobile
examination center of the Third National Health and Nutrition Examination Survey
conducted between 1988 and 1994. MAIN OUTCOME MEASURE: Hearing loss, defined as
audiometric threshold values of at least 16-dB hearing level based on a low or
high pure-tone average. RESULTS: A total of 14.9% of children had low-frequency
or high-frequency hearing loss of at least 16-dB hearing level, 7.1% had low
frequency hearing loss of at least 16-dB hearing level, and 12.7% had high
frequency hearing loss of at least 16-dB hearing level. Most hearing loss was
unilateral and slight in severity (16- to 25-dB hearing level). Of those with
measured hearing loss, 10.8% were reported to have current hearing loss during
the interview. CONCLUSIONS: This analysis indicates that 14.9% of US children
have low-frequency or high-frequency hearing loss of at least 16-dB hearing level
in 1 or both ears. Among children in elementary, middle, and high school,
audiometric screening should include low-frequency and high-frequency testing to
detect hearing loss.
PMID- 9546566
TI - Preemptive epidural analgesia and recovery from radical prostatectomy: a
randomized controlled trial.
AB - CONTEXT: Preemptive analgesia can decrease the sensitization of the central
nervous system that would ordinarily amplify subsequent nociceptive input, but a
clear demonstration of its clinical efficacy is necessary for it to become a
routine component of acute pain therapy. OBJECTIVE: To determine the impact of
preemptive epidural analgesia on postoperative pain and other clinically
important outcome variables after radical retropubic prostatectomy. DESIGN AND
SETTING: A block randomized double-blind clinical trial lasting 20 months at a
single academic medical center. PATIENTS: A total of 100 generally healthy and
neurologically intact patients scheduled for radical retropubic prostatectomy for
the treatment of prostate cancer in whom an epidural catheter for treating
postoperative pain was to be placed prior to the induction of general anesthesia.
INTERVENTIONS: Epidural bupivacaine, epidural fentanyl, or no epidural drug was
administered prior to induction of anesthesia and throughout the entire
operation, followed by aggressive postoperative epidural analgesia for all
patients. MAIN OUTCOME MEASURES: Daily pain scores during hospitalization and
pain scores obtained 3.5, 5.5, and 9.5 weeks after hospital discharge. RESULTS:
The patients who received epidural fentanyl or bupivacaine prior to surgical
incision (preemptive analgesia) experienced 33% less pain while hospitalized
(P=.007). Pain scores in those receiving preemptive analgesia were significantly
lower at 9.5 weeks (P=.02), but were not significantly different at 3.5 or 5.5
weeks. At 9.5 weeks, 32 (86%) of 37 patients receiving preemptive analgesia were
pain-free compared with 9 (47%) of 19 control patients (P=.004). Patients
receiving preemptive analgesia were more active 3.5 weeks after surgery (P=.01),
but not at 5.5 or 9.5 weeks. CONCLUSIONS: Even in the presence of aggressive
postoperative pain management, preemptive epidural analgesia significantly
decreases postoperative pain during hospitalization and long after discharge, and
is associated with increased activity levels after discharge.
PMID- 9546567
TI - Visual processing impairment and risk of motor vehicle crash among older adults.
AB - CONTEXT: Motor vehicle crash risk in older drivers has been associated with
visual acuity loss, but only weakly so, suggesting other factors contribute. The
useful field of view is a measure that reflects decline in visual sensory
function, slowed visual processing speed, and impaired visual attention skills.
OBJECTIVE: To identify whether measures of visual processing ability, including
the useful field of view test, are associated with crash involvement by older
drivers. DESIGN: Prospective cohort study with 3 years of follow-up, 1990-1993.
SETTING: Ophthalmology clinic assessment of community-based sample. PATIENTS: A
total of 294 drivers aged 55 to 87 years at enrollment. MAIN OUTCOME MEASURE:
Motor vehicle crash occurrence. RESULTS: Older drivers with a 40% or greater
impairment in the useful field of view were 2.2 times (95% confidence interval,
1.2-4.1) more likely to incur a crash during 3 years of follow-up, after
adjusting for age, sex, race, chronic medical conditions, mental status, and days
driven per week. This association was primarily mediated by difficulty in
dividing attention under brief target durations. CONCLUSION: Reduction in the
useful field of view increases crash risk in older drivers. Given the relatively
high prevalence of visual processing impairment among the elderly, visual
dysfunction and eye disease deserve further examination as causes of motor
vehicle crashes and injury.
PMID- 9546568
TI - Issues in comparisons between meta-analyses and large trials.
AB - CONTEXT: The extent of concordance between meta-analyses and large trials on the
same topic has been investigated with different protocols. Inconsistent
conclusions created confusion regarding the validity of these major tools of
clinical evidence. OBJECTIVE: To evaluate protocols comparing meta-analyses and
large trials in order to understand if and why they disagree on the concordance
of these 2 clinical research methods. DESIGN: Systematic comparison of protocol
designs, study selection, definitions of agreement, analysis methods, and
reported discrepancies between large trials and meta-analyses. RESULTS: More
discrepancies were claimed when large trials were selected from influential
journals (which may prefer trials disagreeing with prior evidence) than from
already performed meta-analyses (which may target homogeneous trials) and when
both primary and secondary (rather than only primary) end points were considered.
Depending on how agreement was defined, kappa coefficients varied from 0.22 (low
agreement) to 0.72 (excellent agreement). The correlation of treatment effects
between large trials and meta-analyses varied from -0.12 to 0.76, but was more
similar (0.50-0.76) when only primary end points were considered. When both the
magnitude and uncertainty of treatment effects were considered, large trials
disagreed with meta-analyses 10% to 23% of the time. Discrepancies were
attributed to different disease risks, variable protocols, quality, and
publication bias. CONCLUSIONS: Comparisons of large trials with meta-analyses may
reach different conclusions depending on how trials and meta-analyses are
selected and how end points and agreement are defined. Scrutiny of these 2 major
research methods can enhance our appreciation of both for guiding medical
practice.
PMID- 9546569
TI - Does this patient have deep vein thrombosis?
AB - OBJECTIVE: To review the validity of the clinical assessment and diagnostic tests
in patients with suspected deep vein thrombosis (DVT). METHODS: A comprehensive
review of the literature was conducted by searching MEDLINE from 1966 to April
1997. RESULTS: Individual symptoms and signs alone do not reliably predict which
patients have DVT. Overall, the diagnostic properties of the clinical examination
are poor; the sensitivity of the clinical examination ranges from 60% to 96%, and
the specificity ranges from 20% to 72%. However, using specific combinations of
risk factors, symptoms, and physical signs for DVT, clinicians can reliably
stratify patients with suspected DVT into low, moderate, or high pretest
probability categories of actually suffering from DVT. This stratification
process in combination with noninvasive testing, such as compression
ultrasonography, simplifies the management strategies for patients with suspected
DVT. CONCLUSIONS: Use of a clinical prediction guide that includes specific
factors from both the history and physical examination in combination with
noninvasive tests simplifies management strategies for patients with suspected
DVT.
PMID- 9546570
TI - Diagnosis and treatment of attention-deficit/hyperactivity disorder in children
and adolescents. Council on Scientific Affairs, American Medical Association.
AB - OBJECTIVE: To deal with public and professional concern regarding possible
overprescription of attention-deficit/hyperactivity disorder (ADHD) medications,
particularly methylphenidate, by reviewing issues related to the diagnosis,
optimal treatment, and actual care of ADHD patients and of evidence of patient
misuse of ADHD medications. DATA SOURCES: Literature review using a National
Library of Medicine database search for 1975 through March 1997 on the terms
attention deficit disorder with hyperactivity, methylphenidate, stimulants, and
stimulant abuse and dependence. Relevant documents from the Drug Enforcement
Administration were also reviewed. STUDY SELECTION: All English-language studies
dealing with children of elementary school through high school age were included.
DATA EXTRACTION: All searched articles were selected and were made available to
coauthors for review. Additional articles known to coauthors were added to the
initial list, and a consensus was developed among the coauthors regarding the
articles most pertinent to the issues requested in the resolution calling for
this report. Relevant information from these articles was included in the report.
DATA SYNTHESIS: Diagnostic criteria for ADHD are based on extensive empirical
research and, if applied appropriately, lead to the diagnosis of a syndrome with
high interrater reliability, good face validity, and high predictability of
course and medication responsiveness. The criteria of what constitutes ADHD in
children have broadened, and there is a growing appreciation of the persistence
of ADHD into adolescence and adulthood. As a result, more children (especially
girls), adolescents, and adults are being diagnosed and treated with stimulant
medication, and children are being treated for longer periods of time.
Epidemiologic studies using standardized diagnostic criteria suggest that 3% to
6% of the school-aged population (elementary through high school) may suffer from
ADHD, although the percentage of US youth being treated for ADHD is at most at
the lower end of this prevalence range. Pharmacotherapy, particularly use of
stimulants, has been extensively studied and generally provides significant short
term symptomatic and academic improvement. There is little evidence that
stimulant abuse or diversion is currently a major problem, particularly among
those with ADHD, although recent trends suggest that this could increase with the
expanding production and use of stimulants. CONCLUSIONS: Although some children
are being diagnosed as having ADHD with insufficient evaluation and in some cases
stimulant medication is prescribed when treatment alternatives exist, there is
little evidence of widespread overdiagnosis or misdiagnosis of ADHD or of
widespread overprescription of methylphenidate by physicians.
PMID- 9546572
TI - Preempting the memory of pain.
PMID- 9546571
TI - HIV infection and AIDS in the public health and health care systems: the role of
law and litigation.
AB - The AIDS Litigation Project has reviewed nearly 600 reported cases involving
individuals with human immunodeficiency virus (HIV) infection and acquired
immunodeficiency syndrome (AIDS) in the federal and state courts in the United
States between 1991 and 1997. Cases were identified through a federal and 50
state computer and library search. An important subset of litigation relates to
HIV/AIDS in the public health and health care systems, since the law affects
health care institutions and professionals, patients, and public health policy in
America. This subset of HIV/AIDS litigation includes testing and reporting;
privacy, the duty to warn, and the right to know; physician standards of care in
prevention and treatment; and discrimination and access to health care. In broad
terms, the review demonstrates a reliance on voluntary testing and protection of
patient privacy through HIV-specific statutes and the common law. Negligence with
potential civil and criminal liability has been alleged in cases of erroneous or
missed diagnosis of HIV infection. In the first AIDS case to be considered by the
Supreme Court, the Court will decide whether patients with asymptomatic HIV
infection are protected under the Americans With Disabilities Act. Considerable
progress has been made, both socially and legally, during the first 2 decades of
the epidemic, but much still needs to be accomplished to protect privacy, prevent
discrimination, and promote tolerance.
PMID- 9546573
TI - Profiles in primary care.
PMID- 9546574
TI - Eugene McGregor, MD: a legacy of general practice.
PMID- 9546575
TI - Protective effect of an SDF-1 variant in HIV disease: abstract and commentary.
PMID- 9546576
TI - Hormone response units: one plus one equals more than two.
AB - The transcription rate of many genes, and particularly those which code for
metabolically important proteins, is regulated by various hormones. Detailed
analysis of the promoters of these genes has shown that, while functional
'Hormone response elements' exist, the hormonal responsiveness of many promoters
is often synergistically mediated by several cis-elements, collectively referred
to as a hormone response unit. The utilization of a hormone response unit to
mediate a response offers several regulatory advantages, including an expansion
of the range of transcriptional responses and modulation of the response by
tissue- and developmental-specific cues. Furthermore, the presence of Hormone
Response Units may provide a mechanism for the coordination of information from
two or more signaling pathways into a single, integrated and exquisitely
controlled transcriptional response. The protein-protein interactions that likely
mediate many of the synergistic functional characteristics of Hormone Response
Units may provide unique targets for therapeutic intervention.
PMID- 9546578
TI - Comparison of biochemical effects produced by calcium ions and by monomers of
polyacrylamide (acrylamide and bisacrylamide) on strains of Saccharomyces
cerevisiae used for production of chiral synthons.
AB - The biochemical behaviour of four commercial strains of Saccharomyces cerevisiae
was studied in the presence of calcium ions, acrylamide and bisacrylamide.
Calcium ions at a concentration of 300 microM induced an increase of NAD(P)+
reduction in commercial Turkish and American strains, while in Chilean and
Brazilian commercial strains, it diminished NAD(P)+ reduction. On the other hand,
polyacrylamide monomers (acrylamide and bisacrylamide) induced a decrease of
NAD(P)+ reduction in all strains studied in this paper. When membrane potential
(delta psi) and oxygen consumption were measured in the presence of
polyacrylamide monomers, a decrease of both was observed in all strains studied.
PMID- 9546579
TI - Diazepam induced early oxidative changes at the subcellular level in rat brain.
AB - Studies were conducted to ascertain any involvement of free radical mediated
prooxidative processes in different brain regions following diazepam
administration. A significant decrease in TBA reactive substance formation was
observed in cerebral cortex, cerebellum and brain stem regions after single doses
of 1.5, 3 and 6 mg/kg b.wt. For further studies rats were given diazepam (i.p.)
at 3 mg/kg body weight dose and sacrificed after 1 h to follow changes in the
pro/antioxidant status. An enhancement in the TBARS formation was found in the
mitochondrial fractions from cerebral cortex and brain stem. This effect was
highest in brain stem being 107% as compared to controls. In the post
mitochondrial fraction, cerebellum showed 49% enhancement whereas decreased
formation of thiobarbituric acid reactive substances was observed in cerebral
cortex and brain stem. Isozymes of superoxide dismutase showed a decrease in
activity which was region dependent. Even though, total thiols were not
significantly altered, free thiols showed depletion in cerebellum (39.8%) and
brain stem (50%). Glutathione reductase activity was also decreased in cerebellum
and brain stem. The results indicate that a single dose of diazepam causes free
radical mediated changes and the modulatory response of antioxidant defences
appears to be region specific.
PMID- 9546580
TI - G-CSF receptor-mediated up-regulation of c-fos but not c-raf mRNA expression in
myeloid cells.
AB - Granulocyte colony stimulating factor (G-CSF) regulates survival, proliferation,
and differentiation of myeloid precursor cells. One of the signaling mechanisms
for the G-CSF receptor (G-CSF-R) involves the activation of Ras/MAP kinase (MEK)
pathway. Since Raf is an important, common link between Ras and MEK in the Ras
Raf-MEK cascade, we studied the expression of c-raf mRNA in G-CSF-treated myeloid
precursor cell lines--NFS-60 and HL-60. G-CSF did not alter c-raf mRNA expression
in these cells up to 24 h, but induced a transient up-regulation of c-fos mRNA
expression between 15-60 min post-treatment. Our results show that G-CSF triggers
a de novo induction of c-fos but not c-raf mRNA, and suggests that G-CSF-R
mediated activation of Ras/MEK pathway may involve post-transcriptional
mechanisms of Raf regulation.
PMID- 9546581
TI - Increased mRNA expression of cardiac renin-angiotensin system and collagen
synthesis in spontaneously hypertensive rats.
AB - Hypertensive cardiac hypertrophy is associated with the accumulation of collagen
in the myocardial interstitium. Previous studies have demonstrated that this
myocardial fibrosis accounts for impaired myocardial stiffness and ventricular
dysfunction. Although cardiac fibroblasts are responsible for the synthesis of
fibrillar collagen, the factors that regulate collagen synthesis in cardiac
fibroblasts are not fully understood. We investigated the effects of angiotensin
II on cardiac collagen synthesis in cardiac fibroblasts. Cardiac fibroblasts of
10 week old spontaneously hypertensive rats and age-matched Wistar-Kyoto rats
were prepared and maintained in culture medium supplemented with 10% fetal calf
serum. The expression of mRNA of the renin-angiotensin system (renin,
angiotensinogen, angiotensin converting enzyme) was determined by using a
ribonuclease protection assay. Basal collagen synthesis in cardiac fibroblasts
from spontaneously hypertensive rats was 1.6 fold greater than that in the cell
of Wistar-Kyoto rats. Angiotensin II stimulated collagen synthesis in cardiac
fibroblasts in a dose-dependent manner. The responsiveness of collagen production
to angiotensin II was significantly enhanced in cardiac fibroblasts from
spontaneously hypertensive rats (100 nM angiotensin II resulted in 185 +/- 18%
increase above basal levels, 185 +/- 18 versus 128 +/- 19% in Wistar-Kyoto rats p
< 0.01). This effect was receptor-specific, because it was blocked by the
competitive inhibitor saralasin and MK 954. These results indicate that collagen
production was enhanced in cardiac fibroblasts from spontaneously hypertensive
rats, that angiotensin II had a stimulatory effect on collagen synthesis in
cardiac fibroblasts, and that cardiac fibroblasts from spontaneously hypertensive
rats were hyper-responsive to stimulation by angiotensin II. Level of angiotensin
and renin mRNA expressed in ventricles, and angiotensinogen mRNA expressed in
fibroblasts from SHR were higher than those from WKY. These findings suggest that
the cardiac renin-angiotensin system may play an important role in collagen
accumulation in hypertensive cardiac hypertrophy.
PMID- 9546583
TI - Muscle metabolism and quality (MQI) in prediabetic sedentary man.
AB - Twelve pairs of healthy sedentary males matched for their body mass index (BMI)
with either a low insulin response (LIR; a stage of prediabetes) or a high (HIR;
controls) to a standardized glucose infusion test (GIT) were studied in respect
to their exercise capacities (W(OBLA), W(SL) and relative W(OBLA):W(OBLA) x
W(SL)(-10 x 100), muscle fiber composition (%ST), muscle citrate synthase
activity (CS), muscle ubiquinone (MUQ), MUQ over %ST (muscle quality index, MQI),
and peripheral insulin sensitivity (PIS) as described with insulin-clamp
techniques (SIGITmean). LIR and HIR displayed normal PIS and positive
relationships versus exercise capacity. LIR's but not HIR's relative W(OBLA) was
related to CS as earlier only documented in endurance athletes but at a lower
level than in athletes. This pointed at a poor peripheral oxygen delivery in LIR.
LIR's MQI decreased relative to HIR's the higher the muscle CS indicating radical
related muscle trauma in LIR as in athletes. LIR representing prediabetes
described muscle anomalies, which could represent prestages of the lesions
observed in type-2 diabetes. They are claimed to be responsible for insulin-,
glucose-, lipid-resistance, and peripheral circulatory resistance.
PMID- 9546582
TI - Identification and activation of mitogen-activated protein (MAP) kinase in normal
human osteoblastic and bone marrow stromal cells: attenuation of MAP kinase
activation by cAMP, parathyroid hormone and forskolin.
AB - The mitogen-activated protein (MAP) kinases (p44mapk and p42mapk), also known as
extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2), are activated in
response to a variety of extracellular signals, including growth factors,
hormones and, neurotransmitters. We have investigated MAP kinase signal
transduction pathways in normal human osteoblastic cells. Normal human bone
marrow stromal (HBMS), osteoblastic (HOB), and human (TE85, MG-63, SaOS-2), rat
(ROS 17/2.8, UMR-106) and mouse (MC3T3-E1) osteoblastic cell lines contained
immunodetectable p44mapk/ERK1 and p42mapk/ERK2. MAP kinase activity was measured
by 'in-gel' assay using myelin basic protein as the substrate. Mainly ERK2 was
rapidly activated (within 10 min) by bFGF, IGF-I and PDGF-BB in normal HOB, HBMS
and human osteosarcoma cells, whereas both ERK1 and ERK2 were activated by growth
factors in rat osteoblast-like cell lines, ROS 17/2.8 and UMR-106. The ERK1
activation was greater than the ERK2 in ROS 17/2.8 cells. Furthermore, ERK2 was
also activated by bFGF and PDGF-BB in the mouse osteoblastic cell line, MC3T3-E1.
This is the first demonstration of inter-species differences in the activation of
MAP kinases in osteoblastic cells. Cyclic AMP derivatives or cAMP generating
agents such as PTH and forskolin inhibited ERK2 activation by bFGF and PDGF-BB
suggesting a 'cross-talk' between the two different signalling pathways activated
by receptor tyrosine kinases and cAMP-dependent protein kinase. The accumulated
results also suggest that the MAP kinases may be involved in mediating mitogenic
and other biological actions of bFGF, IGF-I and PDGF-BB in normal human
osteoblastic and bone marrow stromal cells.
PMID- 9546584
TI - Effects of peroxide on the fluorescence of the Ca2+ probe Fluo 3 and the pH probe
BCECF.
AB - Fluorescence probes are invaluable tools in monitoring intracellular ion
concentrations. They have also been used for studying how reactive oxygen species
alter these concentrations and yet there are no studies indicating how reactive
oxygen species directly affect the characteristics of the probes. Our concern was
that if reactive oxygen were to affect characteristics of these probes, these
measurements would be inconsequential. Therefore, we examined the effects of
peroxide on the Ca2+-sensitive dye Fluo 3 and the pH sensitive dye BCECF.
Peroxide concentrations below 10 mM did not alter fluorescence or binding
characteristics of either dye. Since the concentrations of peroxide used in most
pathophysiological experiments are in the micromolar range, we conclude that
these probes are appropriate for monitoring the effects of peroxide on
intracellular ion concentrations.
PMID- 9546585
TI - Reduced 40S initiation complex formation in skeletal muscle during sepsis.
AB - Severe muscle wasting is a characteristic feature of sepsis. We have previously
established that the rate of protein synthesis in muscles composed of fast-twitch
fibers is severely diminished in response to sepsis. The present studies
investigate the biochemical reactions responsible for the decreased rate of
protein synthesis using gastrocnemius from control and septic rats perfused in
situ. Analysis of free ribosomal subunits indicated peptide-chain initiation was
impaired by infection. To characterize biochemical reactions in the pathway of
peptide-chain initiation affected, the effect of sepsis on the incorporation of
initiator [35S]methionyl-tRNA (met-tRNA(imet)) into the 40S initiation complex
was examined. Sepsis caused a 65% decrease in the binding of radiolabelled met
tRNA(imet) to the 40S initiation complex compared with controls. The binding of
met-tRNA(met) to the 40S ribosome is regulated by eukaryotic initiation factor
eIF-2B, whose activity can be modulated in part by the redox state of pyridine
dinucleotides. The mean cytoplasmic NADH/NAD+ ratio was increased 2 fold in
sepsis, while the NADPH/NADP+ ratio was unchanged. These findings identify the
formation of the 40S initiation complex as a defect in the protein synthesis
machinery during sepsis. The decreased formation of the 40S initiation complex in
muscle could not be explained by changes in the cytoplasmic redox state.
PMID- 9546586
TI - Heterogeneous cellular expression of creatine kinase isoenzyme during normal rat
heart development.
AB - The degree to which developmentally related alterations in cardiac creatine
kinase (CK) activity reflect modification of CK isoenzyme gene expression remains
uncertain. The present studies addressed this question by assessing multiple
aspects of CK in rat heart during the perinatal to adult transition. In addition
to whole tissue, isolated and purified muscle and nonmuscle cells were studied,
as well as myofibrillar, mitochondrial, and cytosolic subcellular fractions.
Whole homogenate CK enzyme specific activity nearly doubled during the weanling
to adult developmental period. Muscle cell CK activity increased by a similar
magnitude. Nonmuscle cell activity decreased. In the adult heart, both
myofibrillar and mitochondrial CK activities were augmented versus the weanling
heart. The cytoplasmic fraction activity held constant during development.
Electrophoretic isoenzyme analyses of both weanling and adult cardiac muscle
cells indicated the presence of mitochondrial CK and MM-CK isoforms. Weanling
heart nonmuscle cells contained mitochondrial, MM, MB, and BB isoforms; however,
BB isoform was not detected in the adult heart nonmuscle cells. Arrhenius plots
provided information regarding heart muscle and nonmuscle cell alterations during
development. CK activation energies were also determined for whole tissue,
muscle/nonmuscle cells, myofibrils, mitochondria, and cytosol. Results
demonstrate that heterogeneous muscle/nonmuscle cellular composition and
differential myofibrillar/mitochondrial subcellular composition account for
normal, developmentally related changes in heart CK enzyme activity. CK isoenzyme
gene expression changes were not detected in cardiac muscle cells, and transition
of CK-B to CK-M gene expression is limited to nonmuscle cells during normal,
weanling to adult development in the rat heart.
PMID- 9546577
TI - Biochemical and molecular mechanisms regulating apoptosis.
AB - In eukaryotes, the regulation of tissue cell numbers is a critical homeostatic
objective that is achieved through tight control of apoptosis, mitosis and
differentiation. While much is known about the genetic regulation of cell growth
and differentiation, the molecular basis of apoptosis is less well understood.
Genes involved in both cell proliferation and apoptosis reflect the role of some
stimuli in both of these processes, the cell response depending on the overall
cellular milieu. Recent research has given fascinating insights into the complex
genetic and molecular mechanisms regulating apoptosis. A picture is emerging of
the initiation in certain cells, after an apoptotic trigger, of sequential gene
expression and specific signal transduction cascades that guide cells along the
cell death pathway. Changes in gene expression precede the better known
biochemical and morphological changes of apoptosis. It seems possible that, as a
result of increased understanding of the cellular events preceding cell death,
apoptosis may become more amenable to manipulation by appropriate drug- and gene
based therapies.
PMID- 9546587
TI - Characterization of the phosphorylation state of natriuretic peptide receptor-C.
AB - Many internalized receptors are known to be phosphorylated within their
cytoplasmic domain. Natriuretic peptide receptor-C (NPR-C) is a covalent
homodimer primarily involved in the internalization of bound ligand resulting in
tissue uptake and degradation of natriuretic peptides. In this report, we have
investigated the phosphorylation state of NPR-C receptors present at high level
in rat aortic smooth muscle cells (RASM). 32P labeled cells, NPR-C purification
and phosphoamino acid analysis clearly demonstrate that NPR-C exists as a
phosphoprotein in RASM cells and that phosphorylation occurs exclusively on
serine residues. Transient expression of bovine NPR-C in Cos-P cells of kidney
origin confirmed that phosphorylation occurs within the cytoplasmic domain of the
receptor. These results provide the first evidence for NPR-C phosphorylation as
well as a model for future studies of its role in altering receptor function.
PMID- 9546588
TI - Potential role of NF-kB and RXR beta like proteins in interferon induced HLA
class I and beta globin gene transcription in K562 erythroleukaemia cells.
AB - Positive effects of biological response modifiers on cancer cells are usually
measured using markers for increased immunogenicity as well as those for
increased differentiation of the cells. An increase in levels of HLA class I
antigens and the adult (beta) globin molecules are two such markers that may be
used to assess the effect of modulators like interferons on the K562
erythroleukaemia cell line. Although interferon mediated up regulation of gene
expression is thought to be primarily regulated by binding of proteins to the
Interferon responsive cis elements in the promoters of IFN responsive genes,
recent evidence has shown the induction of other transcriptional activators in
response to IFN treatment. We present evidence for one such instance wherein up
regulation of HLA class I and beta globin gene transcription are accompanied by
induction of binding activities similar to RXR beta and kB proteins in K562
cells.
PMID- 9546589
TI - Characterization of free and glyceride-esterified long chain fatty acids in
different skeletal muscle types of the rat.
AB - The plasma-borne long-chain free fatty acids (FFA) enter skeletal muscle cells.
Upon entering they are oxidized or esterified and a fraction remains free (non
esterified). The data on free fatty acids in skeletal muscles remain highly
controversial. Furthermore, the composition of individual fatty acids in various
lipid fractions including free fatty acids, monoglyceride and diglyceride in
muscles has not been characterized. Also data on the composition of fatty acids
esterified into muscle triglycerides and phospholipids are incomplete. The
present study was undertaken to examine a composition of fatty acids in lipid
fractions of different skeletal muscle types. For this purpose, samples of the
rat soleus, red and white portions of gastrocnemius were excised, trimmed of
visible fat and fascias and immediately frozen in liquid nitrogen. Samples were
then pulverized and, lipids were extracted and fractionated by thin-layer
chromatography. Individual long-chain fatty acids in different fractions were
identified, characterized and quantitated by gas-liquid chromatography. FFA
composition in the plasma was also determined. The total FFA content in the
soleus, red and white gastrocnemius was 69.1 +/- 10.8, 49.0 +/- 13.6 and 22.7 +/-
8.6 nmol/g, respectively. Palmitic and oleic acids were the major fatty acids in
the muscles FFA fraction. Monoglyceride fraction of each muscle contained
palmitic, stearic and linoleic acid as the major fatty acids, Diglyceride
fraction contained mostly palmitic and oleic acid whereas triglyceride fraction
mostly palmitic and linoleic acid.. The fraction of phospholipids was composed
mostly of palmitic and linoleic acid but contained also considerable percentage
of archidonic acid. Total plasma FFA/muscle FFA ratio depended on a muscle type
and was: 2.4 in the soleus, 3.5 in the red and 7.4 in the white gastrocnemius.
This assured transport of FFA to the myocytes. However, there were great
differences in the ratio between particular FFA within the same muscle as well
between the muscles. It indicates that individual FFA are either selectively
transported from the plasma to the muscles or selectively used within the
myocytes or both.
PMID- 9546590
TI - Evidence for HSP70-like protein in the RBC membrane of the hereditarily anemic
Belgrade laboratory (b/b) rat.
AB - We have demonstrated that in normal and b/b rat red blood cells (RBCs) hsp70-like
protein (heat shock protein 70-like) is localized in the cytosol and it is
exported via exosomes during in vivo reticulocytes maturation. As we have
presumed, in the mutant (b/b) rat, hsp70-like protein transfers from cytosol to
the RBC membrane. In the normal rat RBCs this happens when those cells are
submitted to heat stress conditions. Our study indicates that the presence of
hsp70-like protein in the b/b rat RBC plasma membrane is consistent with a
primary defect and is not a consequence of life long stress, i.e. hypoxia.
PMID- 9546592
TI - Pharmacological characterization of an endogenous negative inotrophic factor
(ENIF) from porcine heart.
AB - Recently we have been successful in isolating an endogenous negative inotropic
factor (ENIF) from porcine left ventricular tissue. In this study, we have
characterized its pharmacological properties. The results of the study
demonstrated that ENIF produces a concentration-dependent negative inotropic
response on both guinea pig left atria and right ventricular trabeculae. The
maximal reduction in contractile force produced by 300 ul of ENIF (5 ml bath) on
atria and trabeculae were 90.0 +/- 0.8% and 77.5 +/- 6%. Atria, however, was
significantly more sensitive to ENIF than trabeculae. The ED 50 of ENIF for atria
was found to be 38 ul as opposed to ED 50 of 100 ul of ENIF for trabeculae.
Acetylcholine (ACh), a muscarinic receptor agonist, decreased the contractile
force of guinea pig atria in a dose-dependent manner with a maximal decline in
the contractile force of 90%. However, none of the concentration of ACh used
affected the contractile function of the trabeculae. Atropine (1 uM) completely
blocked the negative inotropic response on atria of all the doses of ACh used.
The same dose of atropine, however, was unable to influence the negative
inotropic effect of any of the doses of ENIF used on either the atria or
trabeculae preparations in our study. The maximal decline in the contractile
force of atria was e.g. 94 and 95% in the presence and absence of atropine
respectively. These data demonstrate that the myocardial negative inotropic
effect of ENIF is not mediated via the cholinegic receptor mechanism.
PMID- 9546591
TI - Protection by ebselen against cisplatin-induced nephrotoxicity: antioxidant
system.
AB - This study was designed to investigate the cisplatin-induced alteration in renal
antioxidant system and the nephroprotection with ebselen. Male Wistar rats were
injected with (1) vehicle control; (2) cisplatin; (3) ebselen; and (4) cisplatin
plus ebselen. Rats were sacrificed three days post-treatment and plasma as well
as kidney were isolated and analyzed. Plasma creatinine increased 598% following
cisplatin administration alone which decreased by 158% with ebselen pretreatment.
Cisplatin-treated rats showed a depletion of renal glutathione (GSH) levels (52%
of control), while cisplatin plus ebselen injected rats had GSH values close to
the controls. Antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and
glutathione peroxidase (GSH-Px) activities decreased 38, 75 and 62% of control,
respectively, and malondialdehyde (MDA) levels increased 174% of control
following cisplatin administration, which were restored to control levels after
ebselen treatment. The renal platinum level did not significantly change with
ebselen pretreatment. This study suggests that the protection offered by ebselen
against cisplatin-induced nephrotoxicity is partly related to the sparing of
antioxidant system.
PMID- 9546594
TI - Antioxidant properties of indapamide, 5-OH indapamide and hydrochlorothiazide
evaluated by oxygen-radical absorbing capacity and electron paramagnetic
resonance.
AB - The aim of these experiments was to investigate the radical scavenging properties
of three diuretics: indapamide (IND) and its major metabolite, 5-OH indapamide (5
OH IND), compared to a reference diuretic, hydrochlorothiazide (HTZ). Electron
Paramagnetic Resonance (EPR) was used to determine the scavenging abilities of
these compounds on enzymatically produced superoxide radical anion, with 5,5
dimethyl-1-pyrroline N-oxide (DMPO) used as a spin-trap. These experiments
revealed that IND and specially 5-OH IND were effective superoxide radical anion
scavengers at 0.2 mg/ml. In the second part of these studies, allophycocyanin was
used as an indicator of free radical mediated protein damage. In the assay, 2,2'
azobis(2-amidinopropane) hydrochloride (AAPH) was used as a peroxyl radical
generator, Trolox (a water-soluble analogue of vitamin E) as a control standard,
and the loss of allophycocyanin fluorescence was monitored. The antioxidant
effects of the diuretics were expressed in oxygen-radical absorbing capacity
(ORAC), where one ORAC unit equals the net protection produced by 1 microM
Trolox. HTZ showed no protection up to 100 microM final concentration, whereas
IND and 5-OH IND showed linear correlation with respect to concentration when
expressed in ORAC units: 5-OH IND induced the highest protection against peroxyl
radical. The above observations suggested that IND and 5-OH IND are potent
radical scavengers, with the metabolite 5-OH IND having a superior antioxidant
potency than IND. By contrast, HTZ had no effect. These radical scavenging
properties of 5-OH IND may be of clinical interest for vascular protection and
may help to protect the heart from oxidative injury.
PMID- 9546593
TI - Chemical hypoxia triggers apoptosis of cultured neonatal rat cardiac myocytes:
modulation by calcium-regulated proteases and protein kinases.
AB - Myocardial infarctions and stroke arise primarily as a result of hypoxia/ischemia
induced cell injury. However, the molecular mechanism of cardiac cell death due
to hypoxia has not been elucidated. We showed here that chemical hypoxia induced
by 1 mM azide triggered apoptosis of isolated neonatal rat ventricular cardiac
myocytes but had no effect on cardiac fibroblasts. The azide-induced
cardiomyocyte apoptosis could be characterized by a reversible initiation phase
(0-46 h after azide exposure) during which cytosolic ATP levels remained little
affected. This was followed by an irreversible execution phase (12-18 h)
exhibiting prominent internucleosomal DNA fragmentation, cell membrane leakage,
mitochondrial dysfunction, and increased calpain messenger RNA. Blocking
extracellular calcium influx or intracellular calcium release was each effective
in suppressing myocyte apoptosis. Cell death was also found to be mediated by
calcium sensitive signal transduction events based on the use of specific
antagonists. Consistent with the induction of calpain expression during
apoptosis, blocking de novo protein synthesis and calpain activity inhibited cell
death. These regulatory features coupled with the ease of the cell system suggest
that the myocyte apoptosis model described here should be useful in the study of
events leading to the demise of the myocardium.
PMID- 9546595
TI - Protein tyrosine phosphatase gene expression analysis in Swiss 3T3 fibroblasts.
AB - The aim of this study was to identify protein tyrosine phosphatases (PTPs)
expressed in Swiss 3T3 fibroblasts and to examine their expression levels as well
as to characterize quantitative aspects of RT-PCR based on degenerate
deoxyoligonucleotides. By using an RT-PCR assay based on degenerate
deoxyoligonucleotide primers, expression of mRNAs for two cytoplasmic- and six
transmembrane-type PTPs in Swiss 3T3 cells was detected. The sequences of two of
them are new. Among nine analyzed PTPs expressed to widely varied extends, only
three have mRNA levels high enough to be seen on Northern blots with 10 microg of
total RNA per lane. The frequencies with which the examined PTPs are represented
among the PCR amplification products, correlate stronger with the primer
fidelity, defined as the number of mismatches between the primer- and the cDNA
target-sequences, rather than with the PTP expression levels. In conclusion, an
RT-PCR assay based on degenerate primers can be successfully used to sample the
expressed PTPs and to identify new members of this gene family. However, reliable
quantification of their mRNA levels can only be achieved using the classical
approaches, like Northern, RNase protection assay or nondegenerate quantitative
RT-PCR.
PMID- 9546596
TI - Purification and characterization of the rat liver gamma-butyrobetaine
hydroxylase.
AB - The biosynthesis of carnitine from lysine and methionine involves five enzymatic
reactions. Gamma-butyrobetaine hydroxylase (BBH; EC 1.14.11.1) is the last enzyme
of this pathway. It catalyzes the reaction of hydroxylation of gamma
butyrobetaine to carnitine. This enzyme had never been purified to homogeneity
from rat tissue. This paper describes the purification and characterization of
the rat liver BBH. This protein has been purified some 413 fold by ion exchange,
affinity and gel-filtration chromatographies and appears as a dimere of 43,000
Daltons subunits by PAGE. The affinity chromatography column used in the
purification process utilizes 3-(2,2,2-trimethylhydrazinium)propionate (THP), a
BBH inhibitor, as the ligand. Polyclonal antibodies were raised against the liver
enzyme. They were able to precipitate BBH activity in either a crude liver
extract or a purified fraction of the enzyme. Furthermore, it crossreacts with a
43 kDa protein in the liver. No evidence for extra hepatic enzyme was found.
PMID- 9546597
TI - Shigella dysenteriae type 1 toxin induced lipid peroxidation in enterocytes
isolated from rabbit ileum.
AB - To evaluate the role of reactive oxygen species (ROS) in Shigella dysenteriae 1
toxin (STx) mediated intestinal infection, the ligated rabbit small intestinal
loops were injected with STx. The enterocytes isolated from STx treated rabbit
ileal loops had a significantly higher level of lipid peroxidation as compared to
enterocytes isolated from control rabbit ileum. To study the role of second
messengers in STx mediated intestinal damage, the in vivo and in vitro effects of
modulators of lipid peroxidation of enterocytes were used. The presence of Ca2+
ionophore A23187 enhanced the extent of lipid peroxidation in enterocytes
isolated from the control and STx treated rabbit ileum. However, 1-verapamil only
marginally decreased the lipid peroxidation level of enterocytes isolated from
STx treated rabbit ileum. The in vitro effect of modulators was in agreement with
in vivo studies. Dantrolene significantly decreased the extent of lipid
peroxidation of enterocytes isolated from STx treated rabbit ileum. PMA
significantly increased the lipid peroxidation level of enterocytes isolated from
control ileum. However, PMA could not further enhance the lipid peroxidation
level of enterocytes isolated from STx treated rabbit ileum. The presence of H-7
significantly decreased the extent of lipid peroxidation of enterocytes isolated
from STx treated rabbit ileum. In vitro effect of PMA and H-7 was in agreement
with that of in vivo findings. The role of arachidonic acid metabolites,
prostaglandins (PGs), in mediating STx induced lipid peroxidation was also
studied. The presence of indomethacin (a PG synthesis inhibitor) significantly
decreased the lipid peroxidation induced by STx. These findings suggest that
lipid peroxidation induced by STx is mediated through cytosolic calcium. The
increase in (Ca2+)i leads to activation of PKC. A significant decrease in the
enterocyte levels of antioxidant enzymes superoxide dismutase, catalase and
reduced glutathione in STx treated rabbit ileum as compared to control was seen.
A significant decrease in vitamin E levels was also observed. This suggests that
there is decreased endogenous intestinal protection against ROS in STx mediated
intestinal infection which could contribute to enterocyte membrane damage that
ultimately leads to changes in membrane permeability and thus to fluid secretion.
PMID- 9546598
TI - Lipoperoxidation of rod outer segments of bovine retina is inhibited by soluble
binding proteins for fatty acids.
AB - In the present study it was investigated if soluble-binding proteins for fatty
acids (FABPs) present in neural retina show protection from in vitro
lipoperoxidation of rod outer segment membranes (ROS). After incubation of ROS in
an ascorbate-Fe++ system, at 37 degrees C during 90-120 min, the total cpm
originated from light emission (chemiluminescence) was found to be lower in those
membranes incubated in the presence of soluble binding proteins for fatty acids.
The fatty acid composition of rod outer segment membranes was substantially
modified when subjected to non-enzymatic lipoperoxidation with a considerable
decrease of docosahexaenoic acid (22:6 n-3) and arachidonic acid (20:4 n-6). As a
result of this, the unsaturation index, a parameter based on the maximal rate of
oxidation of specific fatty acids was higher in the native and control membranes
when compared with peroxidized ones. A similar decrease of chemiluminescence was
observed with the addition of increasing concentrations of native or delipidated
FABP retinal containing fractions to rod outer segment membranes. These results
indicate that soluble proteins with fatty acid binding properties may act as
antioxidant protecting rod outer segment membranes from deleterious effect.
PMID- 9546599
TI - Histone H1 isoforms purified from rat liver bind nonspecifically to the nuclear
factor 1 recognition sequence and serve as generalized transcriptional
repressors.
AB - Two polypeptides with molecular masses of 34 and 30 kDa were copurified from rat
liver during DNA affinity purification of a sequence-specific transcription
factor binding to the footprint II sequence within the P2 promoter of the rat
alpha1B adrenergic receptor (alpha1B AR) gene, and were identified by
microsequencing their endoproteinase Lys-C-derived peptides as histone H1d and
histone H1c, respectively. Histone H1 was previously reported to bind to the
nuclear factor 1 (NF1) recognition sequence, although the specificity of this
binding has been controversial. Here, DNA mobility shift and supershift assays,
DNase I footprinting and mutational analyses indicated that the binding of
histone H1 to the NF1 sites located within footprint II of the alpha1B AR gene P2
promoter is nonspecific. Transient cotransfections into Hep3B cells of histone
H1d cDNA with CAT constructs containing promoter regions of different genes
resulted in generalized and non-specific suppression of CAT activity. The histone
H1d-mediated repression of the activities of the alpha1B AR gene P2/CAT or beta2
AR gene P(-186/1307)/CAT constructs was reversed by the cotransfection of a cDNA
encoding the sequence-specific transcription factor NF1/X, and the fold increase
in CAT activities was similar to that obtained in the absence of histone H1d.
These results suggest that sequence-specific transcription factors counteract the
histone H1-mediated transcriptional repression in vivo by a true activation,
which is different from the in vitro antirepression in histone H1-repressed
chromatin templates (Laybourn and Kadonaga, (1991) Science 254: 238-245).
PMID- 9546600
TI - Study on lipid peroxidation potential in different tissues induced by ascorbate
Fe2+: possible factors involved in their differential susceptibility.
AB - Susceptibility of four major rat tissues to oxidative damage in terms of lipid
peroxidation induced by in vitro by ascorbate-Fe2+ in homogenates and
mitochondria has been examined. Lipid peroxidation, as assessed by thiobarbituric
acid reactive substances (TBARS) and conjugated dienes was maximum in brain
followed by liver, kidney and heart. However, the time course of lipid
peroxidation showed different patterns in tissues examined. The higher
susceptibilities of brain and liver can be explained by substrate availability
and to a lesser extent the level of antioxidants. The differences observed in the
tissues studied may reflect their susceptibility to degenerative diseases and
xenobiotic toxicity which are considered as a result of oxidative damage to
membranes.
PMID- 9546602
TI - Steady state changes in mitochondrial electrical potential and proton gradient in
perfused liver from rats fed a high fat diet.
AB - In this work the protonmotive force (delta p), as well as the subcellular
distribution of malate, ATP, and ADP were determined in perfused liver from rats
fed a low fat or high fat diet, using density gradient fractionation in non
aqueous solvents. Rats fed a high fat diet, despite an enhanced hepatic oxygen
consumption, exhibit similar delta p to that found in rats fed a low fat diet,
but when we consider the two components of delta p, we find a significant
decrease in mitochondrial/cytosolic pH difference (delta pH(m)) and a significant
increase in mitochondrial membrane potential (delta psi(m)) in rats fed a high
fat diet compared to rats fed a low fat diet, which tend to compensate each
other. In rats fed a high fat diet the concentration ratio of malate and ATP/ADP
does not reflect the changes in delta pH(m) and delta psi(m), which represent the
respective driving force for their transport. The findings are in line with an
increase in substrate supply to the respiratory chain which is, however,
accompanied by a higher energy turnover in livers from HFD rats. By this way the
liver could contribute to the lack of weight gain from the high caloric intake in
HFD rats.
PMID- 9546601
TI - Inhibition of human topoisomerase II by anti-neoplastic benzazolo[3,2
alpha]quinolinium chlorides.
AB - Previously we reported [20] that there is no correlation between the cytotoxic
activity of four new structural analogs of the antitumor DNA intercalator 3
nitrobenzothiazolo[3,2-a]quinolinium chloride (NBQ-2) and their interaction with
DNA. In the present study, we present evidence suggesting that the molecular
basis for the anti-proliferative activity of these drugs is the inhibition of
topoisomerase II. The NBQ-2 derivatives inhibited the relaxation of supercoiled
DNA plasmid pRYG mediated by purified human topoisomerase II. Inhibition of the
decatenation of kinetoplast DNA mediated by partially purified topoisomerase II
extracted from the human histiocytic lymphoma U937 (a cell line previously shown
to be sensitive to the drugs) was also caused by these drugs. The potency of the
benzazolo[3,2-a]quinolinium drugs against topoisomerase II in vitro was the
following: 7-(1-propenyl)-3-nitrobenzimidazolo[3,2-a]quinolinium chloride (NBQ
59) > 4-chlorobenzothiazolo[3,2-a]quinolinium chloride (NBQ-76) > 7-ethyl-3
nitrobenzimidazolo[3,2-a]quinolinium chloride (NBQ-48) > 7-benzyl-3
nitrobenzimidazolol[3,2-a]quinolinium chloride (NBQ-38). This rank of potency for
topoisomerase II inhibition correlated very well with the cytotoxicity elicited
by these drugs. Furthermore, significant levels of topoisomerase II/DNA cleavage
complex induced by these drugs in vivo were detected when U937 cells were treated
with NBQ-59 and NBQ-76 whereas NBQ-38 and NBQ-48 produced negligible amounts of
the cleavage complex. Our results strongly suggest that topoisomerase II is the
major cellular target of this family of compounds.
PMID- 9546603
TI - Use of competitive dead-end inhibitors to determine the chemical mechanism of
action of yeast alcohol dehydrogenase.
AB - In this work, we have postulated a comprehensive and unified chemical mechanism
of action for yeast alcohol dehydrogenase (EC 1.1.1.1, constitutive,
cytoplasmic), isolated from Saccharomyces cerevisiae. The chemical mechanism of
yeast enzyme is based on the integrity of the proton relay system: His
51....NAD+....Thr-48....R.CH2OH(H2O)....Zn++, stretching from His-51 on the
surface of enzyme to the active site zinc atom in the substrate-binding site of
enzyme. Further, it is based on extensive studies of steady-state kinetic
properties of enzyme which were published recently. In this study, we have
reported the pH-dependence of dissociation constants for several competitive dead
end inhibitors of yeast enzyme froin their binary complexes with enzyme, or their
ternary complexes with enzyme and NAD+ or NADH; inhibitors include: pyrazole,
acetamide, sodium azide, 2-fluoroethanol, and 2,2,2-trifluorethanol. The unified
mechanism describes the structures of four dissociation forms of apoenzyme, two
forms of the binary complex E.NAD+, three forms of the ternary complex
E.NAD+.alcohol, two forms of the ternary complex E.NADH.aldehyde and three binary
complexes E.NADH. Appropriate pKa values have been ascribed to protonation forms
of most of the above mentioned complexes of yeast enzyme with coenzymes and
substrates.
PMID- 9546604
TI - Differential expression and localization of annexin V in cardiac myocytes during
growth and hypertrophy.
AB - Recently it was shown that annexin V is the most prominent member of the annexin
family in the adult heart [1]. Amongst others, annexin V has been suggested to
play a role in developmental processes. The aim of the present study was to
explore whether in the heart annexin V content and localization change during
maturational and hypertrophic growth, in order to obtain indications that annexin
V is involved in cardiac growth processes. First, in the intact rat heart annexin
V content and localization were studied during perinatal development. It was
clearly demonstrated that annexin V content in total heart transiently increased
in the first week after birth, from 0.79 +/- 0.06 microg/mg protein at 1 day
before birth to a peak value of 1.24 +/- 0.08 microg/mg protein 6 days after
birth, whereafter annexin V protein levels declined to a value of 0.70 +/- 0.06
microg/mg protein at 84 days after birth (p < 0.05). Differences in annexin V
content were also observed between myocytes isolated from neonatal and adult
hearts [0.81 +/- 0.09 and 0.17 +/- 0.08 microg/mg protein, respectively (p <
0.05)]. Moreover, during cardiac maturational growth the subcellular localization
of annexin V might change from a cytoplasmic to a more prominent sarcolemmal
localization. Second, in vivo hypertrophy induced by aortic coarctation resulted
in a marked degree of hypertrophy (22% increase in ventricular weight), but was
not associated with a change in annexin V localization or content. The
quantitative results obtained with intact hypertrophic rat hearts are supported
by findings in neonatal ventricular myocytes, in which hypertrophy was induced by
phenylephrine (10(-5) M). In the latter model no changes in annexin V content
could be observed either. In conclusion, the marked alterations in annexin V
content during the maturational growth in the heart suggest a possible
involvement of this protein in this process. In contrast, the absence of changes
in annexin V content and localization in hypertrophied hearts compared to age
matched control hearts suggests that annexin V does not play a crucial role in
the maintenance of the hypertrophic phenotype of the cardiac muscle cell. This
notion is supported by observations in phenylephrine-induced hypertrophied
neonatal cardiomyocytes.
PMID- 9546605
TI - Protective effects of nicaraven, a new hydroxyl radical scavenger, on the
endothelial dysfunction after exposure of pig coronary artery to hydroxyl
radicals.
AB - Recently, we have reported that a new synthetic compound, 1,2bis(nicotinamido)
propane (nicaraven), improved cardiac function following preservation and
reperfusion. In this study, we investigated the efficacy of nicaraven as a
radical scavenger by using an in vitro model of oxidative stress, to clarify
mechanisms of the protective effect of this new compound on reperfusion injury in
rat heart. Ring segments of epicardial right coronary arteries (RCA) of pig were
suspended in organ chambers and exposed to hydroxyl radicals (.OH), generated (by
two different systems) by 0.28 mM FeSO4/0.28 mM H2O2 and DHF/Fe3+-ADP (2.4 mM, 43
nM, and 1.56 uM, respectively) to the bathing solution for 60 min. Prior exposure
of the coronary arteries to .OH significantly produced right-ward shift of the
dose-response curves of the bradykinin-induced endothelium-dependent relaxations
(an increase in the ED50 value for bradykinin by 4.37 and 1.98 times than control
in two different .OH generating systems, respectively), but did not affect the
maximum relaxation responses. The presence of nicaraven (10(-4) and 10(-5) M) in
the .OH generating system, shifted the dose-response curves to bradykinin to the
control level, suggesting a significant hydroxyl radical scavenging effect of the
drug. These results indicate that nicaraven, a new hydroxyl radical scavenger,
exhibits a protective effect on hydroxyl radical-induced endothelial dysfunctions
of pig coronary artery.
PMID- 9546606
TI - Apparent cleavage of poly(ADP-ribose) polymerase in non-apoptotic mouse LTA
cells: an artifact of cross-reactive secondary antibody.
AB - Proteolytic cleavage of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) to
fragments of 89 kD and 24 kD is widely observed during apoptotic cell death. In
the present study, labelling of a Mr approximately 89000 polypeptide was
demonstrated in untreated mouse LTA cells during probing of immunoblots with C-2
10 monoclonal anti-PARP antibody. The source of the labeling was traced to the
secondary antibody preparation, which labeled a Mr approximately 89000
polypeptide in murine LTA cells but not in human cells. These observations
indicate that assessment of PARP cleavage must be (1) performed with appropriate
controls when new cell lines are investigated and (2) carefully interpreted in
light of additional biochemical or morphological data demonstrating apoptotic
changes.
PMID- 9546607
TI - Third calcium-modulated rod outer segment membrane guanylate cyclase transduction
mechanism.
AB - Ca2+-modulated rod outer segment membrane guanylate cyclase (ROS-GC1) has been
cloned and reconstituted to show that it is regulated by two processes: one
inhibitory, the other stimulatory. The inhibitory process is consistent with its
linkage to phototransduction; the physiology of the stimulatory process is
probably linked to neuronal transmission. In both regulatory processes, calcium
modulation of the cyclase takes place through the calcium binding proteins;
guanylate cyclase activating proteins (GCAP1 and GCAP2) in the case of the
phototransduction process and calcium-dependent GCAP (CD-GCAP) in the case of the
stimulatory process. The cyclase domains involved in the two processes are
located at two different sites on the ROS-GC1 intracellular region. The GCAP1
modulated domain resides within the aa 447-730 segment of ROS-GC1 and the CD-GCAP
modulated domain resides within the aa 731-1054 segment. In the present study the
GCAP2-dependent Ca2+ modulation of the cyclase activity has been reconstituted
using recombinant forms of GCAP2 and ROS-GC1, and its mutants. The results
indicate that consistent to phototransduction, GCAP2 at low Ca2+ concentration
(10 nM) maximally stimulates the cyclase activity of the wild-type and its
mutants: ext (deleted aa 8-408), kin (deleted aa 447-730) and hybrid consisting
of the ext, transmembrane and kin domains of ANF-RGC and the C-terminal domain,
aa 731-1054, of ROS-GC1. In all cases, it inhibits the cyclase activity with an
IC50 of about 140 nM. A previous study has shown that under identical conditions
the kin and the hybrid mutant are at best only minimally stimulated. Thus, the
GCAP1 and GCAP2 signal transduction mechanisms are different, occurring through
different modules of ROS-GC1. These findings also demonstrate that the
intracellular region of ROS-GC1 is composed of multiple modules, each designed to
mediate a particular calcium-specific signalling pathway.
PMID- 9546608
TI - Binding of Shigella to rat and human intestinal mucin.
AB - Invasion of epithelial cells by Shigella is an early step in their pathogenesis.
Adherence is generally presumed to be a prerequisite for invasion. This study
examined the possibility of intestinal mucins serving as initial binding sites
for clinical isolates of S. boydii and S. sonnei. The interactions of Shigella
with rat and human small intestinal and colonic mucin were investigated. In solid
phase binding assays, [35S] labelled Shigella did not show any preferential
binding to rat/human small intestinal mucin or to rat colonic mucin. On the other
hand, Shigella bound specifically to human colonic mucin in a concentration
dependent manner. This specific binding to human colonic mucin was not by weak
hydrophobic interactions and could not be attributed to the presence of
contaminating glycolipids in the mucin preparation. The human colonic mucin
receptor was sensitive to periodate treatment suggesting the involvement of the
carbohydrate portion of the mucin. Reduction and alkylation of mucin enhanced
adherence probably by exposing buried binding sites. The monosaccharides present
in mucins were ineffective as hapten inhibitors as was the lectin wheat germ
agglutinin suggesting that the mucin receptor is a more complex one. This study
identifies, for the first time, the presence of a specific Shigella-binding site
on the carbohydrate portion of human colonic mucin, which is not present in rat
colonic mucin or in rat/human small intestinal mucin.
PMID- 9546609
TI - Expression of C/EBP alpha, beta and delta in fetal and postnatal subcutaneous
adipose tissue.
AB - The C/EBP (CCAAT/enhancer binding protein) family of transcription factors (C/EBP
alpha, beta, and delta) has been implicated in the development and the metabolic
regulation of adipocytes from in vitro studies, yet the function of these
factors, particularly CEBP beta and delta, in vivo has not been characterized. To
assess the role of these factors in vivo, subcutaneous adipose, tissue from fetal
and postnatal pigs was examined for C/EBP alpha, beta, and delta expression in
developing and mature adipocytes. Western blot analysis of fetal adipose tissue
showed a progressive increase of C/EBP alpha expression in 50, 75 and 95 day old
fetuses. C/EBP beta and delta proteins were not observed in fetal adipose tissue.
These results were confirmed with immunohistochemical studies of fetal adipose
showing enhanced C/EBP alpha expression in the nuclei of adipocytes and cells
closely associated with adipose cell clusters from 75 and 95 day old fetuses. For
the same tissues only light background staining with no differential enhancement
was found for C/EBP beta and delta. In postnatal adipose tissue C/EBP alpha and
C/EBP beta protein were expressed in both 8 day old postnatal and mature (180
day) pigs. C/EBP delta reactive products were found in postnatal tissues however,
their molecular weights were lower than that found in fetal pig liver. Our data
suggest that adipose cell terminal differentiation proceeds in the pig fetus
without the expression of C/EBP beta and delta and that these factors may have a
more important role in fully differentiated adipose cells in postnatal tissue.
PMID- 9546610
TI - Stimulatory effect of calcium administration on regucalcin mRNA expression is
attenuated in the kidney cortex of rats ingested with saline.
AB - The expression of calcium-binding protein regucalcin mRNA in the kidney cortex of
rats ingested with saline was investigated. The alteration in regucalcin mRNA
levels was analyzed by Northern blotting using liver regucalcin complementary DNA
(0.9 kb of open reading frame). Rats were freely given saline as drinking water
for 7 days. Regucalcin mRNA levels in the kidney cortex were suppressed by saline
ingestion. When calcium chloride (10 mg Ca/100 g body weight) was
intraperitoneally administered to rats ingested with saline for 7 days, the
effect of calcium administration to increase regucalcin mRNA levels was weakened
by saline ingestion. Such effect was also seen by the administration of 2.5 and 5
mg Ca/100 g. Regucalcin mRNA levels in the kidney cortex of spontaneous
hypertensive rats (SHR) were not appreciably increased by the administration of
calcium (10 mg/100 g). Meanwhile, calcium content in the kidney cortex was
significantly elevated by the administration of calcium (10 mg/100 g) to normal
rats. This increase was weakened in saline-ingested rats. Moreover,
Ca2+/calmodulin-dependent protein kinase activity in the cytosol of kidney cortex
was significantly decreased by saline ingestion. These results suggest the
possibility that saline ingestion-induced suppression of regucalcin mRNA
expression in the kidney cortex is partly involved in the attenuation of Ca2+
signalling.
PMID- 9546611
TI - Expression of calcium-binding protein regucalcin mRNA in fetal rat liver is
stimulated by calcium administration.
AB - The expression of hepatic calcium-binding protein regucalcin mRNA in fetal rats
was investigated. The alteration in regucalcin mRNA levels was analyzed by
Northern blotting using liver regucalcin cDNA (0.9 kb with complete open reading
frame). Hepatic regucalcin mRNA levels were progressively increased with fetal
development; the mRNA was clearly expressed at 15 and 21 days of pregnancy but
only slightly at the 8 days. Meanwhile, beta-actin mRNA levels in the fetal liver
were remarkable at 8 and 15 days of pregnancy. The fetal liver regucalcin mRNA
levels at 15 days of pregnancy were significantly decreased by overnight-fasting
of maternal rats. The oral administration of calcium chloride (50 mg Ca/100 g
body weight) to maternal rats at 15 days of pregnancy caused a remarkable
elevation (about 2 fold) of regucalcin mRNA levels in the fetal liver; this
increase was seen 60 and 180 min after the calcium administration. After birth,
regucalcin mRNA was increasingly expressed in the livers of newborn and weanling
rats, while hepatic beta-actin mRNA expression was not appreciably altered with
increasing ages. These findings demonstrate that the expression of hepatic
regucalcin mRNA is increased with fetal development, and that the gene expression
may be stimulated by the ingestion of dietary calcium.
PMID- 9546612
TI - Characterization of the reciprocal binding sites on human alpha-thrombin and
factor XIII A-chain.
AB - Solution- and solid-phase techniques were used to probe Factor XIII A-chain-alpha
thrombin interactions. Alpha-thrombin activated Factor XIII more efficiently (Km
= 0.83 +/- 0.08 x 10(-7) M; V/K = 14.90 +/- 3.20 x 10(-3) min(-1)) than beta
thrombin (Km = 6.14 +/- 1.26 x 10(-7) M; V/K = 3.30 +/- 1.00 x 10(-3) min(-1)) or
gamma-thrombin (Km = 6.25 +/- 1.15 x 10(-7) M; V/K = 3.00 +/- 0.80 x 10(-3) min(
1)). Immobilized FPR-alpha-thrombin bound plasma Factor XIII (Kd = 0.17 +/- 0.04
x 10(-7) M) > Factor XIIIa (Kd = 0.69 +/- 0.18 x 10(-7) M) > liver
transglutaminase (Kd = 4.73 +/- 1.01 x 10(-7) M) > Factor XIII A-chain (Kd =
49.00 +/- 9.40 x 10(-7) M). FPR-alpha-thrombin and alpha-thrombin also bound
immobilized Factor XIII A-chain with affinities inversely related to protease
activity: maximal binding at 1.36 x 10(-7) M and 13.6 x 10(-7) M, respectively.
Plasma Factor XIII, transglutaminase, and dithiothreitol competitively inhibited
Factor XIII A-chain binding to FPR-alpha-thrombin: IC50 = 1.0 x 10(-7) M, 3.0 x
10(-6) M and 1.52 x 10(-4) M, respectively. Transglutaminase also inhibited
Factor XIII binding to alpha-thrombin (IC50 = 2.0 x 10(-6) M). Thrombin-binding
site was localized to G38-M731 fragment of Factor XIII A-chain, probably within
homologous regions (N72-A493) of transglutaminase. R320-E579 of alpha-thrombin
was Factor XIII A-chain binding site. Intra-B-chain disulfides in alpha-thrombin
were essential for binding but not catalytic H363 or residues R382-N394 and R443
G475. These studies propose a structural basis for Factor XIII activation,
provide a regulatory mechanism for Factor XIIIa generation, and could eventually
help in the development of new structure-based inhibitors of thrombin and Factor
XIIIa.
PMID- 9546614
TI - Tissue-specific binding of nuclear factors to the 5'-flanking region of the rat
gene for calcium-binding protein regucalcin.
AB - The existence of nuclear factors which bind to the 5'-flanking region of calcium
binding protein regucalcin gene in rats was investigated. We previously reported
that rat regucalcin mRNA is expressed in a highly tissue-specific manner; the
mRNA was mainly present in the liver but only slightly in the kidney. When the
nuclear proteins extracted from the liver and kidney of rats were used in the gel
mobility shift assays, a protein-DNA complex was uniquely formed with the DNA
fragment containing the upstream region from the first exon of rat regucalcin
gene. On the other hand, this complex was not found by using the nuclear extracts
from rat brain, spleen, and heart. The nuclear proteins of these extracts,
however, could specifically bind to the DNA fragment containing the first exon
region of rat regucalcin gene, although Northern blot analysis did not show
detectable amount of regucalcin mRNA levels in rat brain, spleen, and heart. The
present study demonstrates that the existence of nuclear protein components which
bind to the regucalcin gene. These identified components may be involved in the
tissue-specific regulation of regucalcin gene expression.
PMID- 9546613
TI - Melatonin reduces the increase in 8-hydroxy-deoxyguanosine levels in the brain
and liver of kainic acid-treated rats.
AB - In the present study, the effect of melatonin on oxidative DNA damage induced by
kainic acid (KA) treatment was investigated. 8-hydroxy-deoxyguanosine (8-OH-dG)
is a main product of oxidatively damaged DNA and was used as the endpoint in
these studies. The levels of 8-OH-dG were found to be elevated in the hippocampus
and frontal cortex of rats treated with KA. These elevated levels were
significantly reduced in animals that were co-treated with melatonin. Thus, there
was no difference in 8-OH-dG levels in the brain of control rats compared to
those treated with KA (10 mg/kg) plus melatonin (10 mg/kg). The levels of 8-OH-dG
also increased in the liver of rats treated with KA. This rise in oxidatively
damaged DNA was also prevented by melatonin administration. Melatonin's ability
to reduce KA-induced increases in neural and hepatic 8-OH-dG levels presumably
relates to its direct free radical scavenging ability and possibly to other
antioxidative actions of melatonin.
PMID- 9546615
TI - Streptozotocin-induced diabetes increases (Ca2+-Mg2+)-ATPase activity in hepatic
plasma membranes of rats: involvement of protein kinase C.
AB - The alteration in calcium transport in the liver of rats with streptozocin(STZ)
diabetic state was investigated. STZ (6 mg/100 g body weight) was subcutaneously
administered in rats, and 1 or 2 weeks later they were sacrificed by bleeding.
STZ administration caused a remarkable elevation of serum glucose concentration.
Liver calcium content was significantly increased by STZ administration. Hepatic
plasma membrane (Ca2+-Mg2+)-ATPase activity was markedly elevated by STZ
administration. This increase was completely abolished by the presence of
staurosporine (10(-7)-10(-5) M), an inhibitor of protein kinase C, in the enzyme
reaction mixture, suggesting an involvement of protein kinase C signalling.
Moreover, the STZ-induced increase in liver plasma membrane (Ca2+-Mg2+)-ATPase
activity was significantly raised by the presence of okadaic acid (10(-5) and 10(
4) M). Meanwhile, the STZ-increased (Ca2+-Mg2+)-ATPase activity was not
appreciably altered by the presence of anti-regucalcin IgG in the reaction
mixture, indicating that the activatory protein regucalcin does not participate
in the elevation of the enzyme activity. The present study demonstrates that STZ
induced diabetes causes the increase in hepatic plasma membrane (Ca2+-Mg2+)
ATPase activity of rats.
PMID- 9546616
TI - Receptor-specific ligands distinguish natriuretic peptide receptors-A and -C in
primate tissues.
AB - Systemic clearance of atrial natriuretic peptide (ANP) is in part due to neutral
endopeptidase (NEP) proteolysis and natriuretic peptide receptor-C (NPR-C)
mediated endocytosis. Biological responses to ANP are primarily mediated by the
membrane guanylyl cyclase-A/natriuretic peptide receptor-A (NPR-A). Analogs of
ANP selective for NPR-A and/or resistant to NEP may have increased activity in
those tissues where NPR-C and NEP are coexpressed with NPR-A. The analog of ANP
termed vANP; [(R3D, G9T, R11S, M12L, G16R)ANP] is selective for human NPR-A with
at least 10,000 fold reduction in affinity for human NPR-C. We report that rat
NPR-A is insensitive to 10 nM vANP, demonstrating the limitations of this species
in evaluating human therapeutic candidates. As an alternative approach we tested
the binding and potency of receptor-selective and NEP-resistant ANP analogs in
rhesus monkey tissues. Competition binding studies with a simplified version of
vANP, sANP [(G9T, R11S, G16R)rANP], in rhesus monkey kidney and lung membrane
preparations shows displacement of 125I-ANP from only a fraction of the total ANP
receptor population, 30 and 85%, respectively. The remaining ANP binding sites
can be occupied with the NPR-C selective ligand cANP(4-23). These data strongly
suggest that only two classes of ANP receptor are present in these membrane
preparations, NPR-A and NPR-C. The NEP resistant sANP derivative called
sANP(TAPR) was 8 fold more potent (ED50 = 0.6 nM) than rANP (ED50 = 5 nM) in
stimulating cGMP production in the lung membrane preparation. Our results
demonstrate that the rhesus monkey natriuretic peptide receptors reflect the
pharmacology of the human receptors, and that this species may be suitable to
determine the role of NPR-C and NEP in peptide clearance and attenuating
functional responses.
PMID- 9546617
TI - The effect of dexamethasone treatment on the expression of the regulatory genes
of ketogenesis in intestine and liver of suckling rats.
AB - The influence of the injection of dexamethasone on ketogenesis in 12 day old
suckling rats was studied in intestine and liver by determining mRNA levels and
enzyme activity of the two genes responsible for regulation of ketogenesis:
carnitine palmitoyl transferase I (CPT I) and mitochondrial HMG-CoA synthase.
Dexamethasone produced a 2 fold increase in mRNA and activity of CPT I in
intestine, but led to a decrease in mit. HMG-CoA synthase. In liver the mRNA
levels and activity of both CPT I and mit. HMG-CoA synthase decreased. Comparison
of these values with the ketogenic rate of both tissues following dexamethasone
treatment suggests that mit. HMG-CoA synthase could be the main gene responsible
for the regulation of ketogenesis in suckling rats. The changes produced in serum
ketone bodies by dexamethasone, with a profile that is more similar to the
ketogenic rate in the liver than that in the intestine, indicate that liver
contributes more to ketone body synthesis in suckling rats. Two day treatment
with dexamethasone produced no change in mRNA or activity levels for CPT I in
liver or intestine. While mRNA levels for mit. HMG-CoA synthase changed little,
the enzyme activity is decreased in both tissues.
PMID- 9546618
TI - Pranidipine, a new 1,4-dihydropyridine calcium channel blocker, enhances cyclic
GMP-independent nitric oxide-induced relaxation of the rat aorta.
AB - Pranidipine, a new calcium channel blocker, prolonged endothelium-dependent
relaxation induced by acetylcholine in an aortic ring preparation, contracted
with prostaglandin F2alpha. This action was not shared by amlodipine. The effect
was not modified by indomethacin, suggesting that the action of pranidipine does
not involve prostanoid metabolism. N(G)-nitro-L-arginine completely prevented the
action of Pranidipine. The drug affected neither nitric oxide (NO) synthase
activity nor the level of cyclic GMP in the vessel. Pranidipine did not affect
the sensitivity of the contractile proteins to calcium. Pranidipine also did not
alter cyclic GMP-induced relaxation in alpha-toxin-skinned vascular preparations.
Pranidipine also prolonged glyceryl trinitrate-induced relaxation in the
endothelium denuded rat aorta. Furthermore, pranidipine enhanced relaxation of
the aorta induced by glyceryl trinitrate even in the presence of methylene blue,
a guanylyl cyclase inhibitor. This action was not modified by iberiotoxin or by
charybdotoxin, two inhibitors of the calcium-activated potassium channel. The
results strongly suggest that pranidipine enhances cyclic GMP-independent NO
induced relaxation of smooth muscle by a mechanism other than through NO-induced
hyperpolarization. These effects were in direct contrast to amlodipine, another
new 1,4-dihydropyridine calcium antagonist.
PMID- 9546619
TI - Intestinal mucosal lipid peroxidation and absorptive function in Salmonella
typhimurium mediated intestinal infection.
AB - S. typhimurium infection is associated with neutrophil infiltration within the
intestinal mucosa. Neutrophil activation provides a major source of reactive
oxygen species (ROS). The mucosal pathology of S. typhimurium infection may be in
part due to the excessive production of these reactive species. This study was
carried out to investigate if ROS play a role in mediating the changes in the
structural components and functional properties of brush border membrane (BBM) in
rats during S. typhimurium infection. This was done by determining the changes in
the BBM extent of lipid peroxidation and absorptive function. A significant
increase in the extent of lipid peroxidation of BBM during S. typhimurium
infection was observed as judged by malondialdehyde (MDA) and conjugated diene
formation and depletion of alpha-tocopherol and protein associated thiol groups.
A significant decrease in the BBMV (brush border membrane vesicle) transport of
amino acids was also observed. However there was no change in the transport of D
glucose. The decrease in amino acid transport further led to a significant
decrease in the enterocyte level of protein synthesis. Exposure of BBMV to a free
radical donor, cumene hydroperoxide, also led to an increase in the extent of
lipid peroxidation and a decrease in the amino acid transport. Possibly ROS might
play a significant role in mediating the mucosal damage during S. typhimurium
infection.
PMID- 9546620
TI - Is a dietary n-3 fatty acid supplement able to influence the cardiac effect of
the psychological stress?
AB - Epidemiological studies suggest that n-3 polyunsaturated fatty acids (PUFA) are
involved in the prevention of cardiovascular disease. Stress is known to increase
the incidence of CVD and the present study was realised to evaluate some
physiological and biochemical effects of dietary docosahexaenoic acid (DHA) in
male Wistar rats subjected to a psycho social stress. Rats were fed for 8 weeks a
semi-purified diet containing 10% of either sunflower seed oil or the same oil
supplemented with DHA. This food supply represented 50% of their daily
requirement. The remaining 50% were supplied as 45 mg food pellets designed to
induce stress in rats by an intermittent-feeding schedule process. The control
group (n = 12) was fed the equivalent food ration as a single daily feeding. The
physiological cardiovascular parameters were recorded by telemetry through a
transmitter introduced in the abdomen. At the end of the experimentation, the
heart and adrenals were withdrawn and the fatty acid composition and the
catecholamine store were determined. Dietary DHA induced a pronounced alteration
of the fatty acid profile of cardiac phospholipids (PL). The level of all the n-6
PUFAs was reduced while 22:6 n-3 was increased. The stress induced a significant
increase in heart rate which was not observed in DHA-fed group. The time
evolution of the systolic blood pressure was not affected by the stress and was
roughly similar in the stressed rats of either dietary group. Conversely, the
systolic blood pressure decreased in the unstressed rats fed DHA. Similar data
were obtained for the diastolic blood pressure. The beneficial effect of DHA was
also observed on cardiac contractility, since the dP/dt(max) increase was
prevented in the DHA-fed rats. The stress-induced modifications were associated
with an increase in cardiac noradrenaline level which was not observed in DHA-fed
rats. The fatty acid composition of adrenals was significantly related to the
fatty acid intake particularly the neutral lipid fraction (NL) which incorporated
a large amount of DHA. Conversely, n-3 PUFAs were poorly incorporated in adrenal
phospholipids. Moreover the NL/PL ratio was significantly increased in the DHA
fed rats. The amount of adrenal catecholamines did not differ significantly
between the groups. These results show that a supplementation of the diet with
DHA induced cardiovascular alterations which could be detected in conscious
animals within a few weeks. These alterations were elicited by a reduced heart
rate and systolic and diastolic blood pressure.
PMID- 9546621
TI - Stimulation of MAP kinase and S6 kinase by vanadium and selenium in rat
adipocytes.
AB - To explore the mechanism underlying the insulin-mimetic actions of vanadium and
selenium we examined their effects on the mitogen activated protein/myelin basic
protein kinases (MAPK) and ribosomal S6 protein kinases, which are among the best
characterized of the kinases that comprise the phosphorylation cascade in insulin
signal transduction. We observed a transient activation of MAPK and S6 kinases by
insulin in rat adipocytes, while both sodium selenate and vanadyl sulphate
produced prolonged activation of the kinases. Vanadyl sulphate stimulated the
activity of MAPK and S6 kinase by as much as 6 fold and 15 fold, respectively.
Pretreatment of the cells with genistein did not affect the activation of MAPK by
insulin, but partially blocked the effects of sodium selenate and vanadyl
sulphate. Genistein did not change the activation of S6 kinase by insulin, but
blocked the activation in vanadyl sulphate- and sodium selenate-treated-cells,
suggesting that a genistein sensitive tyrosine kinase may be involved in the
activation by these two compounds. Rapamycin, a specific inhibitor of the p70s6k
isoform of S6 kinase, partially reduced the activation of S6 kinase activity by
sodium selenate, indicating a role for this kinase in the overall activity of the
S6 kinase in sodium selenate-treated cells. A similar trend was noted in vanadyl
sulphate-treated cells. Thus, this study supports the involvement of MAPK and S6
kinases in the insulin-mimetic actions of vanadium and selenium.
PMID- 9546622
TI - Anabolic effect of genistein and genistin on bone metabolism in the femoral
metaphyseal tissues of elderly rats: the genistein effect is enhanced by zinc.
AB - The effect of genistein and genistin on bone components in the femoral
metaphyseal tissues obtained from elderly female rats was investigated in vitro.
The metaphyseal tissues were cultured for 24 h in a medium containing either
vehicle, genistein (10(-8)-10(-5) M) or genistin (10(-7)-10(-5) M). The presence
of genistein or genistin caused a significant increase in alkaline phosphatase
activity, deoxyribonucleic acid (DNA) and calcium contents in the metaphyseal
tissues. The effect of genistein was greater than that of genistin. The bone
components increased by genistein (10(-5) M) or genistin (10(-5) M) were
completely blocked by the presence of cycloheximide (10(-6) M). The presence of
zinc sulfate (10(-5) M) caused a significant increase in the genistein (10(-5) M)
elevated alkaline phosphatase activity, DNA and calcium contents. The enhancement
with zinc was not seen by genistin (10(-5) M). The stimulatory effect of zinc on
the genistein-induced increase in bone components of the metaphyseal tissues was
completely blocked by the presence of cycloheximide (10(-6) M). The present
results suggest that genistein and genistin have an anabolic effect on bone
metabolism in the femoral-metaphyseal tissues of elderly rats, and that the
genistein effect is enhanced by zinc, an essential trace element.
PMID- 9546623
TI - Human platelets contain a novel 47 kDa thiol-oxidase having affinity for genomic
sterol-regulatory sequence.
AB - The present study provides evidence to support that human platelets possess a 47
kDa dual functional molecule having thiol-oxidase activity as well as high
affinity for the SRE sequence in the human genome. On the basis of these as well
as earlier results, we propose that Receptor 'Ck' dependent regulation of this
dual functional 47 kDa molecule may provide a mechanism for the maintenance of
cellular cholesterol homeostasis. Further, this mechanism may also explain the
molecular basis of cholesterol-feedback lesion observed under premalignant
conditions.
PMID- 9546624
TI - Glutathione involvement on the intestinal Na+-dependent D-glucose active
transporter.
AB - Glutathione and its related enzymes are present in intestinal epithelium.
Depletion or alteration of glutathione levels have been related to different
physiological and pathological conditions. Glutathione also seems to be related
to the regulation of some protein activities. The present study, by in vivo
experiments, shows a specific relationship between D-glucose Na+-dependent active
transporter activity in rat intestine brush-border membranes and reduced
glutathione/oxidized glutathione ratio levels. Changes of the kinetic parameters
show that an increase of this ratio is related to an increase of the affinity of
glucose for its binding sites and a higher transport capacity of the transporter.
Neither alteration in the activity of other substrate transport systems nor
change in the specific activity of the key enzymes related to glutathione and
glucose metabolism are found. These findings suggest the possibility that D
glucose transporter activity is modulated through the change in the redox status
of glutathione.
PMID- 9546625
TI - Phosphopeptides derived from in vitro phosphorylated E. coli RNA polymerase bind
to DNA and affect DNA transcription.
AB - E. Coli RNA polymerase was phosphorylated with protein kinase CKII and allowed to
bind to pBR322. After digestion of the RNA polymerase-pBR322 complex with
proteinase K, the phosphopeptides that remained bound to DNA were extracted and
analyzed. These phosphopeptides are able to bind again to DNA and to inhibit
transcription.
PMID- 9546627
TI - Differential regulation in the heart of mitochondrial carnitine
palmitoyltransferase-I muscle and liver isoforms.
AB - Carnitine palmitoyltransferase-I (CPT-I) plays a crucial role in regulating
cardiac fatty acid oxidation which provides the primary source of energy for
cardiac muscle contraction. CPT-I catalyzes the transfer of long chain fatty
acids into mitochondria and is recognized as the primary rate controlling step in
fatty acid oxidation. Molecular cloning techniques have demonstrated that two CPT
I isoforms exist as genes encoding the 'muscle' and 'liver' enzymes. Regulation
of fatty acid oxidation rates depends on both short-term regulation of enzyme
activity and long-term regulation of enzyme synthesis. Most early investigations
into metabolic control of fatty acid oxidation at the CPT-I step concentrated on
the hepatic enzyme which can be inhibited by malonyl-CoA and can undergo dramatic
amplification or reduction of its sensitivity to inhibition by malonyl-CoA. The
muscle CPT-I is inherently more sensitive to malonyl-CoA inhibition but has not
been found to undergo any alteration of its sensitivity. Short-term control of
activity of muscle CPT-I is apparently regulated by malonyl-CoA concentration in
response to fuel supply (glucose, lactate, pyruvate and ketone bodies). The liver
isoform is the only CPT-I enzyme present in the mitochondria of liver, kidney,
brain and most other tissues while muscle CPT-I is the sole isoform expressed in
skeletal muscle as well as white and brown adipocytes. The heart is unique in
that it contains both muscle and liver isoforms. Liver CPT-I is highly expressed
in the fetal heart, but at birth its activity begins to decline whereas the
muscle isoform, which is very low at birth, becomes the predominant enzyme during
postnatal development. In this paper, the differential regulation of the two CPT
I isoforms at the protein and the gene level will be discussed.
PMID- 9546628
TI - Carnitine deficiency-induced cardiomyopathy.
AB - The results of clinical and animal studies suggest that a short term period of
moderate secondary carnitine deficiency, in and of itself, does not have a major
effect on the cardiac contractile function, although substrate oxidation may be
altered. However, with longer durations of carnitine deficiency, alterations
occur within the heart that may result in impaired contractile performance,
particularly at high workloads. At this point, the mechanisms responsible for the
cardiac depression are uncertain. We hypothesize that the alterations in
substrate metabolism produced by the carnitine deficient state results in
inadequate ATP production under high workload conditions which result in impaired
cardiac contractile performance. Carnitine deficiency may also induce a number of
changes in gene expression of key enzymes required for normal cardiac contractile
function and metabolism.
PMID- 9546626
TI - Glucose and glycogen utilisation in myocardial ischemia--changes in metabolism
and consequences for the myocyte.
AB - Experimentally, enhanced glycolytic flux has been shown to confer many benefits
to the ischemic heart, including maintenance of membrane activity, inhibition of
contracture, reduced arrhythmias, and improved functional recovery. While at
moderate low coronary flows, the benefits of glycolysis appear extensive, the
controversy arises at very low flow rates, in the absence of flow; or when
glycolytic substrate may be present in excess, such that high glucose
concentrations with or without insulin overload the cell with deleterious
metabolites. Under conditions of total global ischemia, glycogen is the only
substrate for glycolytic flux. Glycogenolysis may only be protective until the
accumulation of metabolites (lactate, H+, NADH, sugar phosphates and Pi )
outweighs the benefit of the ATP produced. The possible deleterious effects
associated with increased glycolysis cannot be ignored, and may explain some of
the controversial findings reported in the literature. However, an optimal
balance between the rate of ATP production and rate of accumulation of
metabolites (determined by the glycolytic flux rate and the rate of coronary
washout), may ensure optimal recovery. In addition, the effects of glucose
utilisation must be distinguished from those of glycogen, differences which may
be explained by functional compartmentation within the cell.
PMID- 9546629
TI - Fatty acid-binding proteins in the heart.
AB - Long-chain fatty acids are important fuel molecules for the heart, their
oxidation in mitochondria providing the bulk of energy required for cardiac
functioning. The low solubility of fatty acids in aqueous solutions impairs their
cellular transport. However, cardiac tissue contains several proteins capable of
binding fatty acids non-covalently. These fatty acid-binding proteins (FABPs) are
thought to facilitate both cellular uptake and intracellular transport of fatty
acids. The majority of fatty acids taken up by the heart seems to pass the
sarcolemma through a carrier-mediated translocation mechanism consisting of one
or more membrane-associated FABPs. Intracellular transport of fatty acids towards
sites of metabolic conversion is most likely accomplished by cytoplasmic FABPs.
In this review, the roles of membrane-associated and cytoplasmic FABPs in cardiac
fatty acid metabolism under (patho)physiological circumstances are discussed.
PMID- 9546630
TI - Metabolic disturbances in diabetic cardiomyopathy.
AB - It has been established that diabetes results in a cardiomyopathy, and increasing
evidence suggests that an altered substrate supply and utilization by cardiac
myocytes could be the primary injury in the pathogenesis of this specific heart
muscle disease. For example, in diabetes, glucose utilization is insignificant,
and energy production is shifted almost exclusively towards beta-oxidation of
free fatty acids (FFA). FFA's are supplied to cardiac cells from two sources:
lipolysis of endogenous cardiac triglyceride (TG) stores, or from exogenous
sources in the blood (as free acid bound to albumin or as TG in lipoproteins).
The approximate contribution of FFA from exogenous or endogenous sources towards
beta-oxidation in the diabetic heart is unknown. In an insulin-deficient state,
adipose tissue lipolysis is enhanced, resulting in an elevated circulating FFA.
In addition, hydrolysis of the augmented myocardial TG stores could also lead to
high tissue FFA. Whatever the source of FFA, their increased utilization may have
deleterious effects on myocardial function and includes the abnormally high
oxygen requirement during FFA metabolism, the intracellular accumulation of
potentially toxic intermediates of FFA, a FFA-induced inhibition of glucose
oxidation, and severe morphological changes. Therapies that target these
metabolic aberrations in the heart during the early stages of diabetes could
potentially delay or impede the progression of more permanent sequelae that could
ensue from otherwise uncontrolled derangements in cardiac metabolism.
PMID- 9546631
TI - Diabetes mellitus and cardiac function.
AB - Cardiovascular complications are the most common causes of morbidity and
mortality in diabetic patients. Coronary atherosclerosis is enhanced in
diabetics, whereas myocardial infarction represents 20% of deaths of diabetic
subjects. Furthermore, re-infarction and heart failure are more common in the
diabetics. Diabetic cardiomyopathy is characterized by an early diastolic
dysfunction and a later systolic one, with intracellular retention of calcium and
sodium and loss of potassium. In addition, diabetes mellitus accelerates the
development of left ventricular hypertrophy in hypertensive patients and
increases cardiovascular mortality and morbidity. Treating the cardiovascular
problems in diabetics must be undertaken with caution. Special consideration must
be given with respect to the ionic and metabolic changes associated with
diabetes. For example, although ACE inhibitors and calcium channel blockers are
suitable agents, potassium channel openers cause myocardial preconditioning and
decrease the infarct size in animal models, but they inhibit the insulin release
after glucose administration in healthy subjects. Furthermore, potassium channel
blockers abolish myocardial preconditioning and increase infarct size in animal
models, but they protect the heart from the fatal arrhythmias induced by ischemia
and reperfusion which may be important in diabetes. For example, diabetic
peripheral neuropathy usually presents with silent ischemia and infarction.
Mechanistically, parasympathetic cardiac nerve dysfunction, expressed as
increased resting heart rate and decreased respiratory variation in heart rate,
is more frequent than the sympathetic cardiac nerve dysfunction expressed as a
decrease in the heart rate rise during standing.
PMID- 9546633
TI - The role of glucose metabolism in a pig heart model of short-term hibernation.
AB - Previously, we reported, alterations in glucose metabolism in a 4 day model of
chronic coronary stenosis similar to those described in patients with hibernating
hearts. The purpose of this study was 2 fold: (1) to identify whether an acute
model of mild, sustained ischemia could effect similar changes, and (2) to
determine the effects of pharmacological inhibition of glycolysis. In the first
group, extracorporeally perfused, intact pig hearts were subjected to 85 min of a
40% reduction in left anterior descending (LAD) coronary arterial blood flow. A
second group was subjected to the same protocol, except after 40 min of LAD
regional ischemia, iodoacetate (IAA) was administered to block glycolysis.
Ischemia reduced MVO2 by 10% in both groups with a further 20% reduction noted
following IAA treatment. Regional systolic shortening was reduced nearly 50% by
ischemia and decreased an additional 40% following treatment with IAA. Glycolysis
was increased by over 700% with ischemia in the first group. IAA caused a 3 fold
reduction in glycolysis as compared to the preceding ischemic period and
inhibited lactate production. Fatty acid metabolism was significantly reduced by
ischemia in the first group, but was not reduced in the IAA group. Activity of
creatine kinase associated with myofibrils was reduced and may have contributed
to the contractile dysfunction. In conclusion, this acute model of short-term
hibernation demonstrates several metabolic changes previously reported in chronic
hibernation and may prove useful in determining mechanisms of substrate
utilization in simulated conditions of chronic coronary stenosis and hibernation.
PMID- 9546632
TI - Phospholipase A2-mediated hydrolysis of cardiac phospholipids: the use of
molecular and transgenic techniques.
AB - Under pathophysiological conditions, like myocardial ischemia and reperfusion,
cardiac phospholipid homeostasis is severely disturbed, resulting in a net
degradation of phospholipids and the accumulation of degradation products, such
as lysophospholipids and (non-esterified) fatty acids. The derangements in
phospholipid metabolism are thought to be involved in the sequence of events
leading to irreversible myocardial injury. The net degradation of phospholipids
as observed during myocardial ischemia may result from increased hydrolysis
and/or reduced resynthesis, while during reperfusion hydrolysis is likely to
prevail in this net degradation. Several studies indicate that the activation of
phospholipases A2 plays an important role in the hydrolysis of phospholipids. In
this review current knowledge regarding the potential role of the different types
of phospholipases A2 in ischemia and reperfusion-induced damage is being
evaluated. Furthermore, it is indicated how recent advances in molecular
biological techniques could be helpful in determining whether disturbances in
phospholipid metabolism indeed play a crucial role in the transition from
reversible to irreversible myocardial ischemia and reperfusion-induced injury,
the knowledge of which could be of great therapeutic relevance.
PMID- 9546634
TI - Glucose metabolism, H+ production and Na+/H+-exchanger mRNA levels in ischemic
hearts from diabetic rats.
AB - Glycolysis uncoupled from glucose oxidation is a major reason for the
intracellular acidosis that occurs during severe myocardial ischemia. The
imbalance between glycolysis and glucose oxidation, and the resultant H+ produced
from glycolytically derived ATP hydrolysis in the diabetic rat heart is the focus
of this study. Isolated working hearts from 6 week streptozotocin diabetic rat
hearts were perfused with 11 mM glucose and 1.2 mM palmitate and subjected to a
25 min period of global ischemia. A second series of experiments were also
performed in which hearts from control, diabetic, and islet-transplanted diabetic
rats were subjected to a 30 min aerobic perfusion, followed by a 60 min period of
low-flow ischemia (coronary flow = 0.5 ml/min) and 30 min of aerobic reperfusion.
H+ production from glucose metabolism was measured throughout the two protocols
by simultaneous measurement of glycolysis and glucose oxidation using perfusate
labelled with [5-3H/U-14C]-glucose. Rates of H+ production were calculated by
measuring the difference between glycolysis and glucose oxidation. The H+
production throughout the perfusion was generally lower in diabetic rat hearts
compared to control hearts, while islet-transplantation of diabetic rats
increased H+ production to rates similar to those seen in control hearts. This
occurred primarily due to a dramatic increase in the rates of glycolysis. Despite
the difference in H+ production between control, diabetic and islet-transplanted
diabetic rat hearts, no difference in mRNA levels of the cardiac Na+/H+-exchanger
(NHE-1) was seen. This suggests that alterations in the source of protons (i.e.
glucose metabolism) are as important as alterations in the fate of protons, when
considering diabetes-induced changes in cellular pH. Furthermore, our data
suggests that alterations in Na+/H+-exchange activity in the diabetic rat heart
occur at a post-translational level, possibly due to direct alterations in the
sarcolemmal membranes.
PMID- 9546635
TI - Regulation of carbohydrate and fatty acid utilization by L-carnitine during
cardiac development and hypoxia.
AB - This study is designed to investigate whether substrate preference in the
myocardium during the neonatal period and hypoxia-induced stress is controlled
intracellularly or by extracellular substrate availability. To determine this,
the effect of exogenous L-carnitine on the regulation of carbohydrate and fatty
acid metabolism was determined during cardiac stress (hypoxia) and during the
postnatal period. The effect of L-carnitine on long chain (palmitate) and medium
chain (octonoate) fatty acid oxidation was studied in cardiac myocytes isolated
from less than 24 h old (new born; NB), 2 week old (2 week) and hypoxic 4 week
old (HY) piglets. Palmitate oxidation was severely decreased in NB cells compared
to those from 2 week animals (0.456+/-0.04 vs. 1.207+/-0.52 nmol/mg protein/30
min); surprisingly, cells from even older hypoxic animals appeared shifted toward
the new born state (0.695+/-0.038 nmol/mg protein/30 min). Addition of L
carnitine to the incubation medium, which stimulates carnitine palmitoyl
transferase I (CPTI) accelerated palmitate oxidation 3 fold in NB and
approximately 2 fold in HY and 2 week cells. In contrast, octanoate oxidation
which was greater in new born myocytes than in 2 week cells, was decreased by L
carnitine suggesting a compensatory response. Furthermore, oxidation of
carbohydrates (glucose, pyruvate, and lactate) was greatly increased in new born
myocytes compared to 2 week and HY cells and was accompanied by a parallel
increase in pyruvate dehydrogenase (PDH) activity. The concentration of malonyl
CoA, a potent inhibitor of CPTI was significantly higher in new born heart than
at 2 weeks. These metabolic data taken together suggest that intracellular
metabolic signals interact to shift from carbohydrate to fatty acid utilization
during development of the myocardium. The decreased oxidation of palmitate in NB
hearts probably reflects decreased intracellular L-carnitine and increased
malonyl-CoA concentrations. Interestingly, these data further suggest that the
cells remain compliant so that under stressful conditions, such as hypoxia, they
can revert toward the neonatal state of increased glucose utilization.
PMID- 9546636
TI - Identification of nucleoside transport binding sites in the human myocardium.
AB - The role of nucleoside transport in ischemia-reperfusion injury and arrhythmias
has been well documented in various animal models using selective blockers.
However, clinical application of nucleoside transport inhibitors remains to be
demonstrated in humans. It is not known whether human heart has nucleoside
transport similar to that of animals. The aim of this study is to
pharmacologically identify the presence of nucleoside transport binding sites in
the human myocardium compared to animals. Myocardial tissue was obtained from
guinea pig left and right ventricle, canine left ventricle, human intraoperative
right atrium and human cadaveric right atrium and right and left ventricles.
Myocardial preparations were obtained from tissue samples after homogenized and a
differential centrifugation. Equilibrium binding assays were performed using [3H]
p-nitrobenzylthioinosine (NBMPR) at room temperature in the presence or absence
of non-radioactive NBMPR or other nucleoside transport blockers such as p
nitrobenzylthioguanosine dipyridamole, lidoflazine, papaverin, adenosine and
doxorubcine. From saturation curves and inhibition kinetics, we determined the
relative maximal binding (Bmax) and dissociation constant (Kd) of [3H]-NBMPR
binding of human myocardial preparations. Results demonstrated that the fresh
human myocardial preparations have a specific binding site for NBMPR with a Bmax
of 283+/-32 fmol/mg protein and Kd of 0.56+/-0.12 nM. These values are lower than
those obtained from guinea pigs (Bmax = 1440+/-187 fmol/mg protein and Kd =
0.21+/-0.03 nM) and canine atrium (Bmax 594+/-73 fmol/mg protein, and Kd = 1.12+/
0.22 nM). Displacement kinetics studies revealed the relative potencies (of
certain unrelated drugs as follow: p-nitrobenzylthioguanosine > dipyridamole >
lidoflazine > pavaverine > Diltazam > adenosine > doxyrubicin. It is concluded
that human myocardium contains an active nucleoside transport site which may play
a crucial role in post-ischemic reperfusion-mediated injury in a wide spectrum of
ischemic syndromes.
PMID- 9546637
TI - Mutagenesis and characterization of specific residues in fatty acid ethyl ester
synthase: a gene for alcohol-induced cardiomyopathy.
AB - Fatty acid ethyl ester synthase-III metabolizes both ethanol and carcinogens.
Structure-function studies of the enzyme have not been performed in relation to
site specific mutagenesis. In this study, three residues (Gly 32, Cys 39 and His
72) have been mutated to observe their role in enzyme activity. Gly to Gln, Cys
to Trp and His to Ser mutations did not affect fatty acid ethyl ester synthase
activity, but His to Ser mutant had less than 9% of control glutathione S
transferase activity. The apparent loss of transferase activity reflected a 28
fold weaker binding constant for glutathione. Thus, this study indicates that Gly
and Cys may not be important for synthase or transferase activities however,
histidine may play a role in glutathione binding, but it is not an essential
catalytic residue of glutathione S-transferase or for fatty acid ethyl ester
synthase activity.
PMID- 9546638
TI - Palmitate oxidation by the mitochondria from volume-overloaded rat hearts.
AB - In this work, an attempt was made to identify the reasons of impaired long-chain
fatty acid utilization that was previously described in volume-overloaded rat
hearts. The most significant data are the following: (1) The slowing down of long
chain fatty acid oxidation in severely hypertrophied hearts cannot be related to
a feedback inhibition of carnitine palmitoyltransferase I from an excessive
stimulation of glucose oxidation since, because of decreased tissue levels of L
carnitine, glucose oxidation also declines in volume-overloaded hearts. (2)
While, in control hearts, the estimated intracellular concentrations of free
carnitine are in the range of the respective Km of mitochondrial CPT I, a kinetic
limitation of this enzyme could occur in hypertrophied hearts due to a 40%
decrease in free carnitine. (3) The impaired palmitate oxidation persists upon
the isolation of the mitochondria from these hearts even in presence of
saturating concentrations of L-carnitine. In contrast, the rates of the
conversion of both palmitoyl-CoA and palmitoylcarnitine into acetyl-CoA are
unchanged. (4) The kinetic analyses of palmitoyl-CoA synthase and carnitine
palmitoyltransferase I reactions do not reveal any differences between the two
mitochondrial populations studied. On the other hand, the conversion of palmitate
into palmitoylcarnitine proves to be substrate inhibited already at physiological
concentrations of exogenous palmitate. The data presented in this work
demonstrate that, during the development of severe cardiac hypertrophy, a
fragilization of the mitochondrial outer membrane may occur. The functional
integrity of this membrane seems to be further deteriorated by increasing
concentrations of free fatty acids which gives rise to an impaired cooperation
between palmitoyl-CoA synthase and carnitine palmitoyltransferase I. In intact
myocardium, the utilization of the in situ generated palmitoyl-CoA can be further
slowed down by decreased intracellular concentrations of free carnitine.
PMID- 9546639
TI - Effects of phosphodiesterase inhibitors on glucose utilization in isolated
cardiac myocytes.
AB - The phosphodiesterase (PDE) inhibitor, enoximone, enhances the oxidation of fatty
acids in cardiac myocytes. Since carbohydrate oxidation is tightly coupled and
inversely related in cardiac tissue to fatty acid oxidation, this study was
designed to investigate enoximone's effects on glucose metabolism in the heart.
To determine if enoximone alters this reciprocal relationship, the effects of
enoximone on [U-14C]glucose and [2-14C]pyruvate oxidation were determined in
isolated cardiac myocytes. The effect of PDE inhibitors was also examined on
pyruvate dehydrogenase complex (PDH) activity, a key component of oxidative
glucose metabolism. Two PDE inhibitors, enoximone and milrinone, decreased PDH
activity by 69 and 64%, respectively at 0.5 mM. This inhibition of PDH activity
by enoximone was completely reversed after removing enoximone from the myocyte
medium. PDH activity was unaffected by agents which alter cyclic nucleotide
signaling: cGMP, dibutyryl cyclic AMP, and AMP. The effect of enoximone on [2
14C]pyruvate oxidation was similar to that on PDH. Interestingly, the oxidation
of glucose was decreased 35% by 0.5 mM enoximone. In isolated rat heart
mitochondria (RHM), enoximone decreased PDH activity by 37%. These studies
suggest that PDE inhibitors decrease carbohydrate utilization by inhibiting the
PDH complex in the heart. The inhibition of PDH by PDE inhibitors appears
unrelated to their effects on cAMP or cGMP. This inhibition of PDH by PDE
inhibitors may occur, at least in part, secondary to stimulating fatty acid
oxidation.
PMID- 9546640
TI - Energy metabolism and mechanical recovery after cardioplegia in moderately
hypertrophied rats.
AB - It is well established that severe hypertrophy induces metabolic and structural
changes in the heart which result in enhanced susceptibility to ischemic damage
during cardioplegic arrest while much less is known about the effect of
cardioplegic arrest on moderately hypertrophied hearts. The aim of this study was
to elucidate the differences in myocardial high energy phosphate metabolism and
in functional recovery after cardioplegic arrest and ischemia in mildly
hypertrophied hearts, before any metabolic alterations could be shown under
baseline conditions. Cardiac hypertrophy was induced in rats by constriction of
the abdominal aorta resulting in 20% increase in heart weight/body weight ratio
(hypertrophy group) while sham operated animals served as control. In both
groups, isolated hearts were perfused under normoxic conditions for 40 min
followed by infusion of St.Thomas' Hospital No. 1 cardioplegia and 90 min
ischemia at 25 degrees C with infusions of cardioplegia every 30 min. The changes
in ATP, phosphocreatine (PCr) and inorganic phosphate (Pi) were followed by 31P
nuclear magnetic resonance (NMR) spectroscopy. Systolic and diastolic function
was assessed with an intraventricular balloon before and after ischemia. Baseline
concentrations of PCr, ATP and Pi as well as coronary flow and cardiac function
were not different between the two groups. However, after cardioplegic arrest PCr
concentration increased to 61.8+/-4.9 micromol/g dry wt in the control group and
to 46.3+/-2.8 micromol/g in hypertrophied hearts. Subsequently PCr, pH and ATP
decreased gradually, concomitant with an accumulation of Pi in both groups. PCr
was transiently restored during each infusion of cardioplegic solution while Pi
decreased. PCr decreased faster after cardioplegic infusions in hypertrophied
hearts. The most significant difference was observed during reperfusion: PCr
recovered to its pre-ischemic levels within 2 min following restoration of
coronary flow in the control group while similar recovery was observed after 4
min in the hypertrophied hearts. A greater deterioration of diastolic function
was observed in hypertrophied hearts. Moderate hypertrophy, despite absence of
metabolic changes under baseline conditions could lead to enhanced functional
deterioration after cardioplegic arrest and ischemia. Impaired energy metabolism
resulting in accelerated high energy phosphate depletion during ischemia and
delayed recovery of energy equilibrium after cardioplegic arrest observed in
hypertrophied hearts could be one of the underlying mechanisms.
PMID- 9546641
TI - Role of nucleoside transport and purine release in a rabbit model of myocardial
stunning.
AB - Previously, we have demonstrated the role of nucleoside transport and purine
release in post-ischemic reperfusion injury (myocardial stunning) in several
canine models of ischemia. Since rabbits are deficient of xanthine oxidase, it is
not known whether selective blockade of purine release is beneficial in a rabbit
model of coronary artery occlusion and reperfusion (stunning). Therefore, we
determined the hemodynamic and metabolic correlates in response to myocardial
stunning in the presence or absence of selective nucleoside transport blocker (p
nitrobenzylthioinosine, NBMPR) and adenosine deaminase inhibitor (erythro-9-(2
hydroxy-3-nonyl)adenine, EHNA). Sixty adult anaesthetized rabbits were surgically
prepared for hemodynamic measurements. After stabilization period, the left
anterior descending coronary artery was occluded for 15 min and reperfused for 30
min. Transmural myocardial biopsies were obtained from the ischemic LAD area and
from the non-ischemic posterior (circumflex, CFX) segment of the myocardium.
Rabbits (n = 60) were randomly assigned to either the control or the EHNA/NBMPR
treated group (n = 30 each). Each group was further divided to either functional
or metabolic groups (n = 15 each subgroup). Each animal received intravenously 30
ml of either a vehicle solution or 100 M EHNA and 25 M NBMPR 10 min before
ischemia. Although administration of EHNA/NBMPR did not affect the heart rate, it
did cause mild hypotension (about 20-30%). Fifteen minutes of LAD occlusion
resulted in significant ATP depletion and concomitant accumulation of nucleosides
in both groups (p < 0.05 vs. baseline and non-ischemic CFX segment). AMP was
higher in the LAD compared to the CFX segment. Significant accumulation of
adenosine was observed in the treated group compared to the control group. It is
concluded that EHNA/NBMPR induced site specific entrapment of adenosine of
nucleoside transport in the rabbit heart, in vivo.
PMID- 9546642
TI - Ischemic preconditioning in rat heart: no correlation between glycogen content
and return of function.
AB - We tested the hypothesis that glycogen levels at the beginning of ischemia affect
lactate production during ischemia and postischemic contractile function.
Isolated working rat hearts were perfused at physiological workload with
bicarbonate buffer containing glucose (10 mmol/L). Hearts were subjected to four
different preconditioning protocols, and cardiac function was assessed on
reperfusion. Ischemic preconditioning was induced by either one cycle of 5 min
ischemia followed by 5, 10, or 20 min of reperfusion (PC5/5, PC5/10, PC5/20), or
three cycles of 5 min ischemia followed by 5 min of reperfusion (PC3 x 5/5). All
hearts were subjected to 15 min total, global ischemia, followed by 30 min of
reperfusion. We measured lactate release, timed the return of aortic flow,
compared postischemic to preischemic power, and determined tissue metabolites at
selected time points. Compared with preischemic function, cardiac power during
reperfusion improved in groups PC5/10 and PC5/20, but was not different from
control in groups PC5/5 and PC3 x 5/5. There was no correlation between
preischemic glycogen levels and recovery of function during reperfusion. There
was also no correlation between glycogen breakdown (or resynthesis) and recovery
of function. Lactate accumulation during ischemia was lowest in group PC5/20 and
highest in the group with three cycles of preconditioning (PC3 x 5/5). Lactate
release during reperfusion was significantly higher in the groups with low
recovery of power than in the groups with high recovery of power. In glucose
perfused rat heart recovery of function is independent from both pre- and
postischemic myocardial glycogen content over a wide range of glycogen levels.
The ability to utilize lactate during reperfusion is an indicator for
postischemic return of contractile function.
PMID- 9546644
TI - Human myocardial ATP content and in vivo contractile function.
AB - The study was designed to characterize the relationship between the metabolite
content of human cardiac muscle and in vivo cardiac function. ATP, total adenine
nucleotides, and NAD were quantified in human myocardial biopsies using high
performance liquid chromatography. Right ventricular endomyocardial biopsies were
obtained from 43 patients with dilated cardiomyopathy, 6 with restrictive
cardiomyopathy, 10 with normal systolic and diastolic function, and from 24 cold
preserved human donor hearts. Transmural samples of failing right and left
ventricular free walls were obtained during cardiac transplantation surgery in 8
patients. ATP, total adenine nucleotides, and NAD were similar in the cold
preserved donor hearts and in right ventricular endomyocardial biopsies from the
10 individuals with normal systolic and diastolic function. In contrast, these
values were significantly depressed in tissue samples from patients with dilated
or restrictive cardiomyopathy. There was a significant correlation between ATP
and pulmonary capillary wedge pressures but not ejection fractions. Declines in
the sizes of myocardial ATP, adenine nucleotide, and pyridine nucleotide pools in
the human myocardium are associated primarily with diastolic but not systolic
dysfunction.
PMID- 9546643
TI - The liver isoform of carnitine palmitoyltransferase I is activated in neonatal
rat cardiac myocytes by hypoxia.
AB - Fatty acids are the preferred substrate of ischemic, reperfused myocardium and
may account for the decreased cardiac efficiency during aerobic recovery.
Neonatal cardiac myocytes in culture respond to hypoxia/serum- and glucose-free
medium by a slow decline in ATP which reverses upon oxygenation. This model was
employed to examine whether carnitine palmitoyltransferase I (CPT-I) modulates
high rates of beta-oxidation following oxygen deprivation. After 5 h of hypoxia,
ATP levels decline to 30% control values and CPT-I activity is significantly
stimulated in hypoxic myocytes with no alteration in cellular carnitine content
or in the release of the mitochondrial matrix marker, citrate synthase. This
stimulation was attributed to an increase in the affinity of hypoxic CPT-I for
carnitine, suggesting that the liver CPT-I isoform is more dominant following
hypoxia. However, there was no alteration in hypoxic CPT-I inhibition by malonyl
CoA. DNP-etomoxiryl-CoA, a specific inhibitor of the liver CPT-I isoform,
uncovered identical Michaelis kinetics of the muscle isoform in control and
hypoxic myocytes with activation of the liver isoform. Northern blotting did not
reveal any change in the relative abundance of mRNA for the liver vs. the muscle
CPT-I isoforms. The tyrosine phosphatase inhibitor, pervanadate, reversed the
hypoxia-induced activation of CPT-I and returned the affinity of cardiac CPT-I
for carnitine to control. Reoxygenation was also associated with a return of CPT
I activity to control levels. The data demonstrate that CPT-I is activated upon
ATP depletion. Lower enzyme activities are present in control and reoxygenated
cells where ATP is abundant or when phosphatases are inhibited. This is the first
suggestion that phosphorylation may modulate the activity of the liver CPT-I
isoform in heart.
PMID- 9546645
TI - Differential cardioprotection with selective inhibitors of adenosine metabolism
and transport: role of purine release in ischemic and reperfusion injury.
AB - In a previous report, we have demonstrated that simultaneous inhibition of
nucleoside transport and adenosine deaminase accumulates endogenous adenosine and
protects the myocardium against stunning. The differential cardioprotective
effects of erythro-9(2-hydroxy-3-nonyl)-adenine (EHNA), a potent inhibitor of
adenosine deamination but not transport, and p-nitrobenzylthioinosine (NBMPR), a
selective blocker of adenosine and inosine transport, are not known. Thirty-seven
anaesthetized adult dogs were instrumented to monitor left ventricular
performance using sonomicrometery. Dogs were randomly assigned into four groups.
The control group (n = 8) received only the vehicle solution. Treated groups
received saline containing 100 microM EHNA (EHNA-group, n = 7), 25 microM NBMPR
(NBMPR-group, n = 7), or a combination of 100 microM EHNA and 25 microM NBMPR
(EHNA/NBMPR-group, n = 10). Hearts were subjected to 30 min of normothermic
global ischaemia and 60 min of reperfusion while on bypass. Adenine nucleotides,
nucleosides, oxypurines and NAD+ were determined in extracts of transmural
myocardial biopsies using HPLC. TTC staining revealed the absence of necrosis in
this model. Drug administration did not affect myocardial ATP metabolism and
cardiac function in the normal myocardium. Ischemia caused about 50% ATP
depletion and accumulation of nucleosides. The ratio between adenosine/inosine at
the end of ischemia was 1:10, 1:1, 1:1 and 10:1 in the control, EHNA-, NBMPR- and
EHNA/NBMPR-group, respectively. Upon reperfusion, both nucleosides washed out
from the myocardium in the control and EHNA-group while retained in the
myocardium in the NBMPR and EHNA/NBMPR groups. Ventricular dysfunction 'stunning'
persisted in the control group (52%) and in the EHNA-treated group (32%) after 30
min of reperfusion. Significant improvement of function was observed in the EHNA
group only after 60 min of reperfusion. LV function recovered in the NBMPR- and
EHNA/NBMPR-treated groups during reperfusion. ATP recovery occurred only when
animals were pretreated with the combination of EHNA/NBMPR and remained depressed
in the control group and EHNA and NBMPR-treated groups. At post mortem, TTC
staining revealed the absence of myocardial necrosis. Superior myocardial
protection was observed with inhibition of nucleoside transport by NBMPR alone or
in combination with inhibition of adenosine deaminase by EHNA. Selective blockade
of nucleoside transport by NBMPR is more cardioprotective than inhibition of
adenosine deaminase alone in attenuating myocardial stunning. It is not known why
EHNA partially inhibit adenosine deaminase, in vivo.
PMID- 9546646
TI - Effects of nucleoside transport inhibitors and adenine/ribose supply on ATP
concentration and adenosine production in cardiac myocytes.
AB - Adenosine plays an important role in protection of the heart before, during and
after ischemia. Nucleoside transport inhibitors (NTI) increase adenosine
concentration without inducing ischemia by preventing its uptake and metabolism
in cardiac cells. However, prolonged effects of nucleoside transport inhibitors
on adenosine and nucleotide metabolism and its combined effect with nucleotide
precursors has not been established in cardiomyocytes. The aim of this study was
to investigate the effect of two nucleoside transport inhibitors, dipyridamole
(DIPY) and nitrobenzylthioinosine (NBTI) alone or combined with adenine and
ribose on adenosine production and ATP content in cardiomyocytes. Rat
cardiomyocytes were isolated using collagenase perfusion technique. Isolated cell
suspensions were incubated for up to 480 min with different substrates and
inhibitors as follows: (1) control; (2) 100 microM adenine and 2.5 mM ribose; (3)
10 microM DIPY; (4) 1 microM NBTI; (5) DIPY, adenine and ribose and (6) NBTI,
adenine and ribose. Five microM EHNA (erythro-9(2-hydroxy-3-nonyl)adenine, an
inhibitor of adenosine deaminase) was added to all incubations. After incubation,
extracts of myocyte suspension were analysed by HPLC for adenine nucleotides and
metabolite concentrations. ATP content decreased in cardiomyocytes after 8 h of
incubation with DIPY, while no change was observed with NBTI or without
inhibitors. Adenosine concentration increased with both DIPY and NBTI. In the
presence of adenine and ribose an elevation in ATP concentration was observed,
but no significant change in adenosine content. In the presence of DIPY or NBTI
together with adenine and ribose, an enhancement in cardiomyocyte ATP
concentration was observed together with an increase in adenosine content. This
increase in adenosine production was especially prominent with DIPY. In
conclusion, dipyridamole causes a decrease in ATP concentration in isolated
cardiomyocytes by mechanisms other than nucleoside transport inhibition. Addition
of adenine/ribose with dipyridamole prevents the depletion of ATP. Combination of
adenine/ribose with nucleoside transport inhibitors may also further enhance
adenosine concentration and thus, could be more effective as pharmacological
agents for treatment.
PMID- 9546647
TI - Inter-alpha-trypsin inhibitor proteoglycan family--a group of proteins binding
and stabilizing the extracellular matrix.
AB - Extracellular matrix (ECM) is composed of several macromolecules associated in a
complex network. This structure allows cells to adhere, migrate and interact.
Hyaluronic acid (HA) is a glycosaminoglycan (GAG) and a major representative of
ECM. HA-binding proteins such as CD44, aggrecan, and versican, have been
implicated in structuring the ECM by stabilizing large macromolecular aggregates.
They also play an important role in tumor metastasis and cell motility. Recently,
further HA-binding proteins were identified: the inter-alpha-trypsin
inhibitor(ITI)-related proteins. ITI is a glycoprotein composed of three
polypeptides: two heavy chains (HC1 and HC2) and one light chain (bikunin).
Bikunin confers the protease-inhibitor function. The heavy chains' function was
unknown. Recent studies have shown that HC1 and HC2 are linked in vivo and in
vitro to hyaluronic acid. This linkage greatly improves extracellular matrix
stability. It also demonstrates that ITI-related proteins might be considered as
HA-binding proteins (HABP). The ITI related proteins are composed of four
polypeptides (HC1, HC2, HC3 and the bikunin) encoded by four genes H1, H2, H3 and
L. Unlike the majority of plasma protein a non-disulfide covalent linkage exists
between heavy chains and bikunin. This review presents the recent progress
concerning the interactions between ITI and ECM showing that ITI-related proteins
are HABP members. We will focus on the heavy chain linkage with HA, which
represents the demonstration of covalent binding between proteins and HA.
PMID- 9546648
TI - Evaluation of the impact of S-adenosylhomocysteine metabolic pools on cytosine
methylation of the tobacco genome.
AB - We explored the possibility that the cytosine DNA methylation might be regulated
by S-adenosyl-L-methionine (AdoMet) and S-adenosyl-L-homocysteine (AdoHcy) pools
in plant cells. In order to change the AdoHcy/AdoMet ratio (methylation index),
(S)-9-(2,3-dihydroxypropyl)adenine was employed, a selective reversible inhibitor
of cellular S-adenosyl-L-homocysteine hydrolase. Micromolar concentrations of the
inhibitor increased dramatically (more than 1000-fold) intracellular AdoHcy
levels (and concominantly the AdoHcy/AdoMet ratio) in tobacco TBY-2 cells. No
toxic effect of the drug was observed and the cells displayed only marginal
inhibition of growth at high AdoHcy levels. At near equal intracellular
concentrations of AdoHcy and AdoMet, a significant reduction of cytosine
methylation in transcribed (5SrDNA) and non-transcribed (HRS60, NTRS) sequences
was observed. Interestingly, the CpCpG and CpApG trinucleotide targets appeared
to be most sensitive to changes in the methylation index. Methylation of cytosine
residues at CpG sites was not affected even at AdoHcy/AdoMet ratio of > 10. These
results support the possible regulation of DNA methylation via AdoHcy/AdoMet
metabolic pathways in plant cells.
PMID- 9546649
TI - Occurrence of two plastidic ATP/ADP transporters in Arabidopsis thaliana L.-
molecular characterisation and comparative structural analysis of similar ATP/ADP
translocators from plastids and Rickettsia prowazekii.
AB - Recently, we sequenced a cDNA clone from Arabidopsis thaliana L. encoding an
ATP/ADP transporter protein (AATP1) located in the plastid envelope membrane. The
deduced amino acid sequence of AATP1 exhibits a high degree of similarity (> 66%)
to the ATP/ADP transporter from the obligate intracellular gram-negative
bacterium Rickettsia prowazekii. Here we report a second plastidic ATP/ADP
carrier from A. thaliana (AATP2). As deduced from the amino acid sequence, AATP2
exhibits 77.6% identity to AATP1 and 36% to the rickettsial protein. Hydropathy
analysis indicates that all three translocators are highly hydrophobic membrane
proteins, which exhibit marked similarities and differences. The AATP1
translocator lacks the sixth transmembrane domain that is present in AATP2 and
the bacterial transporter in R. prowazekii. In contrast to AATP1 and the
bacterial transport protein, only AATP2 exhibits a truncated C-terminal end. To
compare the general biochemical properties of AATP2 with the known transport
properties of AATP1 we cloned the entire AATP2 cDNA into plasmid pJT118, leading
to the presence of an additional N-terminal histidine tag of 10 amino acids. For
heterologous expression of His10-AATP2 we chose the Escherichia coli strain C43,
which was reported recently to allow overproduction of eucaryotic membrane
transport proteins. After transformation and subsequent induction by
isopropylthio-2-D-galactopyranoside intact E. coli cells harbouring plasmid
pJT118 showed import of radioactively labelled ATP and ADP. As deduced from a
Lineweaver-Burk analysis His10-AATP2 exhibited apparent Km values for ATP and ADP
of 22 microM and 20 microM, respectively. Import of ADP into His10-AATP2
expressing E. coli cells occurred at a rate of 24 nmol x mg protein(-1) x h(-1),
which was about threefold faster than import of ATP. These biochemical
characteristics are similar to transport properties of the heterologously
expressed His10-AATP1 protein.
PMID- 9546651
TI - In vitro characterisation of the interaction between newly synthesised proteins
and a pancreatic isoform of protein disulphide isomerase.
AB - The lumen of the endoplasmic reticulum (ER) contains an array of molecular
chaperones and folding factors that modulate the folding and assembly of newly
synthesised proteins entering the secretory pathway. One of these components,
protein disulphide isomerase (PDI), facilitates the formation of the correct
disulphide bonds within newly synthesised polypeptides, and is the archetype for
a family of sequence related PDI-like proteins. We have investigated the
interaction between a recently identified, pancreas-specific PDI-like protein
(PDIp), and in vitro synthesised secretory and membrane proteins produced in the
presence of ER-derived canine pancreatic microsomes. We have previously
established that a second PDI-like protein, ERp57, interacts specifically with N
glycosylated proteins. In contrast, we find that the interaction of PDIp with
newly synthesised proteins occurs independently of any requirement for N-linked
glycosylation. In this respect, the properties of PDIp mirror those of archetypal
PDI. When the carbohydrate-dependent interactions between glycoproteins and ERp57
are blocked by drug treatment, the association of these precursors with both PDIp
and PDI is enhanced. We propose that PDI-like proteins have overlapping
specificity and may exhibit some degree of functional redundancy.
PMID- 9546650
TI - Effect of reversible reactions on isotope label redistribution--analysis of the
pentose phosphate pathway.
AB - The pentose phosphate pathway plays several key roles in metabolism including
supply of biosynthetic carbon skeletons and reducing power. Previous research has
focused on determining the fluxes through the reactions of this pathway using
carbon-labeled substrates and models that make certain assumptions about the
reversibility of the transketolase and transaldolase reactions in the
nonoxidative pathway. These assumptions, however, have resulted in
inconsistencies between the predicted carbon label distributions using these
models and those determined experimentally. A general metabolic reaction network
model developed in this paper and applied to the pentose phosphate pathway not
only incorporates reaction reversibility but also accounts for the effect of
individually varying extents of reaction reversibility on labeled carbon
fractional enrichment values for intermediate metabolites. In addition, an
algorithm is presented that can be used to calculate the three individual
transaldolase and transketolase extents of reversibility. The results of this
method show that varying extents of reaction reversibility have an observable
effect on the metabolite carbon label distributions which can in turn affect flux
calculation for other parts of the metabolic network such as the tricarboxylic
acid cycle. In addition, the observability of reversibility extent and accuracy
of flux calculations depend on the particular choice of metabolite carbon
enrichments measured. In particular, [6-13C]hexose 6-phosphate and [4
13C]erythrose 4-phosphate carbon enrichment values resulting from [1-13C]glucose
feeding contained more information as compared to those from ribose 5-phosphate.
This analysis was applied to literature data of metabolite carbon labeling that
resulted from supplying either 13C- or 14C-enriched substrates to several cell
types growing under various conditions. The specific activities of metabolite
carbon atoms taken from rat epididymal adipose tissue, goosefish islet cells,
Corynebacterium glutamicum, and Escherichia coli supplied with either [2
14C]glucose or [1-13C]glucose demonstrate how reversibility is present in the
pentose phosphate pathway and the extents of reversibility can be estimated from
labeled carbon data sets.
PMID- 9546652
TI - Atherogenic concentrations of native low-density lipoproteins down-regulate
nitric-oxide-synthase mRNA and protein levels in endothelial cells.
AB - The nitric oxide synthase family of proteins is the unique class of mammalian
enzymes that metabolizes L-arginine to form nitric oxide (NO). The atherogenic
action of low-density lipoproteins (LDL) may be mediated, in part, by its effects
on endothelial-derived nitric oxide. To determine whether native LDL (nLDL), at
atherogenic concentrations, are capable of modulating NO synthase expression, we
treated human umbilical vein endothelial cells with increasing concentrations of
human nLDL (0-240 mg cholesterol/dl) for various time periods (2-48 h). Northern
and western blot analyses indicate that both endothelial NO-synthase mRNA and
protein are down-regulated by atherogenic concentrations of nLDL (180 and 240 mg
cholesterol/dl) after 48 h of incubation. Cycloheximide and actinomycin D
experiments suggest that this down-regulation operates at a transcriptional
level. Additionally, treatment of the cells with high-density lipoproteins, at
human physiological concentrations (45 mg cholesterol/dl), does not appear to
alter the expression of endothelial NO synthase which seems to indicate that nLDL
affect the gene transcription rate by a specific and concentration-dependent
mechanism. These findings may have important implications because they provide a
novel mechanism by which hypercholesterolemia induces early changes on
endothelial cells that could have pathophysiological significance in the
atherosclerotic process.
PMID- 9546653
TI - Detection of abscisic-acid-binding proteins in the microsomal protein fraction of
Arabidopsis thaliana with abscisic-acid-protein conjugates used as affinity
probes.
AB - A family of affinity probes has been generated to detect and purify abscisic-acid
(ABA)-binding proteins, by coupling ABA onto carrier proteins (ovalbumin or BSA)
through the C1 carboxyl group or the C4' carbonyl group of ABA. ELISA detection
showed that these ABA-protein conjugates bound efficiently to the solubilized
microsomal protein fraction of Arabidopsis thaliana, but not to the soluble
protein fraction. Heat or proteolytic treatments inhibited the binding of the
conjugates, indicating the protein nature of these binding sites. After membrane
purification of the microsomes, the binding sites were found to be preferentially
located in the plasma membrane fraction. The binding of the conjugates was
independent of the nature of the carrier protein or the ABA-carrier protein
linker, but was competitively inhibited with an anti-ABA mAb. Furthermore, the
competitive inhibition of the binding of the conjugates with ABA, but not with
the inactive ABA methyl ester analog, demonstrated the specificity of the binding
and the saturability of the binding sites. The binding of the conjugates was
strictly correlated to the ABA/carrier protein molar coupling ratio, confirming
that the affinity of the conjugates to the ABA-binding proteins was enhanced by
the increase in the probability of binding events. The experimental approach
permits a new insight into the nature of membrane-associated ABA-binding
proteins.
PMID- 9546654
TI - Functional expression of recombinant N-methyl-D-aspartate receptors in the yeast
Saccharomyces cerevisiae--localization and pharmacological characterization.
AB - The yeast Saccharomyces cerevisiae was used for expressing the genes encoding the
ionotropic N-methyl-D-aspartate (NMDA) receptor subunits from rats (NR1a, NR2A,
NR2C) and mice (NR2B). Four plasmids were constructed by cloning the different
NMDA receptor genes in the two multi-copy yeast-Escherichia coli shuttle vectors
pMB01 (--> NR1a gene) and pMB02 (--> NR2A-2C genes). The protease-deficient S.
cerevisiae strain cI3-ABYS-86 (leu-, ura-) was transformed or co-transformed with
the resulting plasmids pMBNR1a (leu+) or pMBNR1a/pMBNR2A-C (ura+) respectively.
Western blotting analysis with antibodies raised against amino acid sequences at
the C-termini of the respective subunits revealed that the recombinant receptor
proteins were differently expressed and only partially glycosylated in the cell
membranes of the recombinant yeast strains. The expression and localization of
the recombinant NMDA receptor proteins were also proved by immunofluorescence
microscopy which indicated a distinct expression of the different NMDA receptor
subunits in the plasma membrane of the transformed yeast cells. Pharmacological
characterization of crude membrane preparations of the recombinant yeast cells
showed saturable binding of the glycine antagonist [3H]MDL105,519 with Kd values
of 56.9 +/- 6.19 nM (NR1a/NR2A), 26.72 +/- 2.13 nM (NR1a/NR2B), and 21.22 +/-
1.64 nM (NR1a/NR2C), and bound capacities of 17.94 +/- 1.24 pmol/mg membrane
protein (NR1a/NR2A), 11.45 +/- 0.67 pmol/mg (NR1a/NR2B), and 16.15 +/- 0.86
(NR1a/NR2C) pmol/mg. The [3H]MDL105,519 binding was inhibited by the glycine
antagonist 5,7-dichlorokynurenate, ethyl-2-carboxy-4,6-dichloro-3-indoleacetate,
and itself, but not by glycine, D-serine or 1-amino-cyclopropanecarboxylic acid.
Specific binding of [3H]glycine or the NMDA channel blocker [3H]dizolcipine were
not observed.
PMID- 9546655
TI - Galectin-1 from ovine placenta--amino-acid sequence, physicochemical properties
and implications in T-cell death.
AB - In the present study we report the amino-acid sequence, carbohydrate specificity
and overall biochemical and physicochemical properties of galectin-1, a beta
galactoside-binding lectin from ovine placenta. The complete amino-acid sequence,
obtained by tryptic and chymotryptic digestion, revealed that this carbohydrate
binding protein shares all the absolutely preserved and critical residues found
in other members of the mammalian galectin-1 subfamily. Moreover, conformational
changes induced by protein interaction with its specific disaccharide were
investigated by fourth-derivative spectral analysis, intrinsic tryptophan
fluorescence measurements and circular dichroism. The first two methods indicated
changes in the environment of aromatic residues, in agreement with the role of
Trp in carbohydrate binding. The quenching of the fluorescence emission upon
addition of lactose, allowed us to calculate the Kd for its interaction with the
galectin, which was 0.157 +/- 0.02 mM. The far-ultraviolet CD spectra is
consistent with the large extent of beta-sheet structure described for other
galectins. Addition of lactose produced no significant changes, suggesting that
it causes no modifications in the secondary structure of the lectin. In addition,
we explored its potential cell-growth inhibitory activity and implications in T
cell death. Finally, we also provide evidence showing that antagonic properties
of galectins-1 and -3 are reciprocally neutralized in a natural mixture of both
proteins, suggesting that they could play an important role in the regulation of
cell proliferation and death, according to physiological requirements at
particular developmental stages of the placenta, thus allowing successful
pregnancy to occur.
PMID- 9546656
TI - Oligomeric structure of the repressor of the bacteriophage Mu early operon.
AB - The regulation of the lytic and lysogenic development in the life cycle of
bacteriophage Mu is regulated in part by its repressor, c, which binds to three
operator sites, O1, O2 and O3, overlapping two divergent promoters. The
oligomeric structure of this repressor protein was investigated by hydrodynamic
and biochemical methods. Size-exclusion chromatography, analytical
ultracentrifugation, dynamic light scattering, crosslinking and direct electron
microscopy observations suggest that c exists primarily as a hexamer with a
molecular mass of 120-140 kDa at low concentrations, i.e. in the 10-microM range.
This molecule undergoes a self-assembly process leading to dodecamers and higher
order species as the concentration is further increased in a manner depending on
the nature of the solvent. Our results also suggest that these species have an
elongated structure, and a possible arrangement of the subunits within the
hexamer is proposed. The implication of this unusual quaternary structure for a
repressor in its interaction with the operator sites O1 and O2 remains to be
elucidated.
PMID- 9546657
TI - Conformer selection and differential restriction of ligand mobility by a plant
lectin--conformational behaviour of Galbeta1-3GlcNAcbeta1-R, Galbeta1
3GalNAcbeta1-R and Galbeta1-2Galbeta1-R' in the free state and complexed with
galactoside-specific mistletoe lectin as revealed by random-walk and
conformational-clustering molecular-mechanics.
AB - To study conformational parameters of ligands before and after complex formation
with the galactoside-binding agglutinin of Viscum album L. (VAA) in solution,
combined computer-assisted random walk molecular mechanics (RAMM) calculations
extended by conformational clustering analysis (CCA), molecular dynamics (MD)
simulations as well as two-dimensional rotating-frame nuclear Overhauser effect
(ROE) and two-dimensional nuclear Overhauser effect (NOE) spectroscopy NMR
experiments were employed. Derivatives of the naturally occurring disaccharides
Galbeta1-3GlcNAcbeta1-R and Galbeta1-3GalNAcbeta1-R as well as of a synthetic
high-affinity binding partner, i.e. the disaccharide Galbeta1-2Galbeta1-R', were
chosen as ligands in this study. The disaccharides displayed inherent flexibility
in the valley of the global minimum between phi/psi combinations of (40
degrees/60 degrees) and (40 degrees/-60 degrees). Calculations of the de-N
acetylated sugars revealed that presence of this group did not markedly influence
the distribution of low-energy conformers in the phi, psi, epsilon plot.
Occupation of side minima at phi/psi (180 degrees/0 degrees) or (0 degrees/180
degrees) is either unlikely or low according to the results of MD simulations and
RAMM calculations extended by CCA. Notably, these side minima define
conformations which are not stable during a MD simulation. Transitions to other
minima occur already a few picoseconds after the start of the simulation. NMR
experiments of the free-state ligand confirmed the validity of the data sets
obtained by the calculations. Following the description of the conformational
space in the free-state NMR experiments were performed for these disaccharides
complexed with VAA. They yielded two interresidual contacts for Galbeta1
3GlcNAcbeta1-R and Galbeta1-2Galbeta1-R'. The ligand conformations in the complex
did not deviate markedly from those of a minimum conformation in the free state.
One- and two-dimensional transferred nuclear Overhauser enhancement (TRNOE)
experiments at different mixing times excluded the influence of spin-diffusion
effects. When the NOE build-up curves in the three studied cases were compared,
the residual mobility of the penultimate carbohydrate unit of Galbeta1
3GalNAcbeta1-R was observed to be higher than that of the respective hexopyranose
unit of the other two bound ligands. Due to the availability of the
conformational parameters of Galbeta1-2Galbeta1-R' in association with a
galectin, namely the beta-galactoside-binding protein from chicken liver, it is
remarkable to note that this ligand displays different conformations in the
binding sites of either the plant or the animal lectin. They correspond to local
energy-minimum conformations in the phi,psi, epsilon plot and substantiate
differential conformer selection by these two lectins with identical nominal
monosaccharide specificity.
PMID- 9546658
TI - Conformation of desmopressin, an analogue of the peptide hormone vasopressin, in
aqueous solution as determined by NMR spectroscopy.
AB - Desmopressin (1-desamino-[DArg8]vasopressin, is a synthetic analogue of the
neurohypophyseal peptide hormone vasopressin which has high antidiuretic and
antibleeding potency. The structure of desmopressin has been determined in
aqueous solution by two-dimensional NMR techniques and molecular dynamics
simulations. Both standard and time-averaged distance restraints were used in
structure calculations because of the inherent flexibility in small peptides. 21
models calculated with standard restraints were compared with structures refined
with time-averaged distance restraints and were found to be good representatives
of the conformational ensemble of desmopressin. The macrocyclic ring forms an
inverse gamma-turn centered around Gln4. Residues 1 and 2, the disulphide bridge
and the three-residue acyclic tail were found to be flexible in solution.
Residues 4-6 in the ensemble of calculated structures contain essentially the
same backbone conformation as in the crystal structure of pressinoic acid, the
cyclic moiety of vasopressin, whereas residues 2-6 superimpose on the NMR-derived
conformation of oxytocin bound to neurophysin. The results presented in this work
suggest that, in addition to the differences in sequence between desmopressin and
vasopressin, differences in conformational and dynamic properties between the two
compounds explain their pharmacological differences.
PMID- 9546659
TI - The V3 loop of human immunodeficiency virus type-1 envelope protein is a high
affinity ligand for immunophilins present in human blood.
AB - Human immunodeficiency virus type-1 (HIV-1) infection requires binding of the
envelope protein gp120 to host CD4 receptors and the action of the chemokine
receptors CXCR4 or CCR5, which define cell tropism. The proline-containing V3
loop of gp120 determines the selection of the chemokine receptor and participates
in conformational changes on binding of gp120 to CD4. In this study, we show that
macrophage-tropic and T-cell-tropic V3 loop peptides bind specifically to the
active site of the immunophilins FK506-binding protein (FKBP12), and cyclophilins
A and B. Macrophage-tropic and T-cell-tropic V3 loop peptides inhibited the
peptidyl-prolyl cis-trans isomerase (PPIase) activities of the immunophilins. Kd
values in the range 0.036-4.1 microM were determined with V3 loop peptides
labeled with an environmentally sensitive fluorophore. The observed binding
properties of the V3 loop peptides reveal structural motifs of linear water
soluble peptidic substrates for tight interaction with immunophilins. FKBP12, and
cyclophilins A and B were found to be present in normal human blood in the ranges
0.8-1.7, 1.4-2.3 and 2.4-3.1 nM, respectively, as demonstrated by PPIase activity
measurements and western blot analysis. Cyclophilins A and B levels in serum of
HIV-1-infected individuals were increased 3.6-fold and 1.6-fold. Due to the
interaction of immunophilins with V3 loop peptides and with the envelope protein
gp120, a role of immunophilins in HIV pathogenesis as conformases or docking
mediators seems possible, since immunophilin receptors on cell membranes and
immunophilin-related virulence factors of pathogens have been identified.
PMID- 9546660
TI - Comparative study of the catalytic domain of phosphorylating glyceraldehyde-3
phosphate dehydrogenases from bacteria and archaea via essential cysteine probes
and site-directed mutagenesis.
AB - Phosphorylating glyceraldehyde-3-phosphate dehydrogenase (GraP-DH) catalyzes the
oxidative phosphorylation of D-glyceraldehyde-3-phosphate to form 1.3
diphosphoglycerate. The currently accepted mechanism involves an oxidoreduction
step followed by a phosphorylation. Two essential aminoacids, Cys149 and His176
are involved in the chemical mechanism of bacterial and eukaryotic GraP-DHs.
Roles have been assigned to the His176 as (a) a chemical activator for enhancing
the reactivity of Cys149, (b) a stabilizator of the tetrahedral transition
states, and (c) a base catalyst facilitating hydride transfer towards NAD. In a
previous study carried out on Escherichia coli GraP-DH [Soukri, A., Mougin, A.,
Corbier, C., Wonacott, A. J., Branlant, C. & Branlant, G. (1989) Biochemistry,
28, 2586-2592], the role of His176 as an activator of the reactivity of Cys149
was studied. Here, we further investigated the role of the His residue in the
chemical mechanism of phosphorylating GraP-DH from E. coli and Bacillus
stearothermophilus. The chemical reactivity of Cys149 in the His176Asn mutant was
reinvestigated. At neutral pH, its reactivity was shown to be at least as high as
that observed in the Cys-/His+ ion pair present in the wild type. No pre-steady
state burst of NADH was found with the His176Asn mutant in contrast to what is
observed for the wild type, and a primary isotope effect was observed when D-[1
2H]glyceraldehyde-3-phosphate was used as the substrate. Therefore, the major
role of the His176 in the catalytic mechanism under physiological conditions is
not to activate the nucleophilicity of Cys149 but first to facilitate the hydride
transfer. These results hypothesized that a phosphorylating GraP-DH possessing a
different protein environment competent to increase the nucleophilic character of
the essential Cys residue and to favor the hydride transfer in place of His,
could be enzymically efficient. This is most likely the case for archaeal
Methanothermus fervidus GraP-DH which shares less than 15% amino-acid identity
with the bacterial or eukaryotic counterparts. No Cys-/His+ ion pair was
detectable. Only one thiolate entity was observed with an apparent pKa of 6.2.
This result was confirmed by the fact that none of the mutations of the five
invariant His changed the catalytic efficiency.
PMID- 9546661
TI - Conferring aldosterone synthesis to human CYP11B1 by replacing key amino acid
residues with CYP11B2-specific ones.
AB - Performing residue-swapping experiments between the highly conserved human
steroidogenic proteins CYP11B1 and CYP11B2 we recently demonstrated that
replacement of specific residues at position 301, 302 and 320 in the aldosterone
producing CYP11B2 protein for such residues that were specific for the highly
similar cortisol-producing CYP11B1 protein elevated the 11beta-hydroxylase
activity dramatically. Conversely, aldosterone synthesis in the triple mutant was
severely impaired. Here we provide evidence that in a reciprocal experiment,
CYP11B2-specific amino acids at position 320 and 335 endowed CYP11B1 with an 18
oxidase function amounting to 20% of the CYP11B2 wild-type activity, thus
changing the specificity of steroid hydroxylation by only one point mutation.
Combining substitutions at positions 296, 301, 302, 320, 335 and 339 did,
however, not result in further enhancement. Paradoxically, 11beta-hydroxylation
was not or only marginally affected in CYP11B1 mutants, indicating an alternative
structural basis for this activity in CYP11B1 compared with the engineered
CYP11B2 variant. Our results suggest that the sequence spanned by amino acids 301
and 335 constitutes part of the substrate-binding site in CYP11B1 and CYP11B2 as
well. By constructing chimeric proteins we further investigated the effect of the
C-terminal portions of both proteins and found that diverging residues at
positions 471, 472, 492, 493 and 494 were insignificant for the stereospecificity
and regiospecificity of steroid hydroxylation.
PMID- 9546662
TI - An Escherichia coli hydrogenase-3-type hydrogenase in methanogenic archaea.
AB - Methanogenic archaea are known to contain two types of [NiFe] hydrogenases
designated F420-reducing hydrogenase and F420-non-reducing hydrogenase. We report
here that they additionally contain Escherichia coli hydrogenase-3-type [NiFe]
hydrogenases. The evidence is based on biochemical studies and analysis of the
subunit primary structure of this hydrogenase (designated Ech) purified from
membranes of acetate-grown cells of Methanosarcina barkeri. The subunits EchE and
EchC of the EchABCDEF complex showed 34% and 45% sequence identity to the nickel
containing large subunit HycE and to the iron-sulfur cluster containing small
subunit HycG, respectively, of the hydrogenase in the formate hydrogen lyase
complex from E. coli. Analysis of the totally sequenced genomes of Methanococcus
jannaschii and Methanobacterium thermoautotrophicum strain deltaH revealed that
these organisms contain similar open reading frames, indicating the presence of
an E. coli hydrogenase-3-type hydrogenase also in these methanogenic archaea.
PMID- 9546663
TI - Fatty acid elongation in yeast--biochemical characteristics of the enzyme system
and isolation of elongation-defective mutants.
AB - Elongation of long-chain fatty acids was investigated in yeast mutants lacking
endogenous de novo fatty acid synthesis. In this background, in vitro fatty acid
elongation was dependent strictly on the substrates malonyl-CoA, NADPH and a
medium-chain or long-chain acyl-CoA primer of 10 or more carbon atoms. Maximal
activity was observed with primers containing 12-14 carbon atoms, while shorter
chain-length acyl-CoA were almost (octanoyl-CoA) or completely (hexanoyl-CoA,
acetyl-CoA) inactive. In particular, acetyl-CoA was inactive as a primer and as
extender unit. The Michaelis constants for octanoyl-CoA (0.33 mM), decanoyl-CoA
(0.83 mM) lauroyl-CoA (0.05 mM), myristoyl-CoA (0.4 mM) and palmitoyl-CoA (0.13
mM) were determined and were comparable for fatty acid synthesis and elongation.
In contrast, the affinity of malonyl-CoA was 17-fold lower for elongation (Km =
0.13 mM) than for the fatty acid synthase (FAS) system. With increasing chain
length of the primer (> or = 12:0), fatty acid elongation becomes increasingly
sensitive to substrate inhibition. Due to the activation of endogenous fatty
acids, ATP exhibits a stimulatory effect at suboptimal but not at saturating
substrate concentrations. In the yeast cell homogenate, the specific activity of
fatty acid elongation is about 10-20-fold lower than that of de novo fatty acid
synthesis. The same elongation activity is observed in respiratory competent and
in mitochondrially defective cells. The products of in vitro fatty acid
elongation are fatty acids of 15-17 or 22-26 carbon atoms, depending on whether
tridecanoyl-CoA or stearoyl-CoA is used as a primer. In vitro, the elongation
products are converted in part, by alpha-oxidation, to their odd-chain-length
lower homologues or are hydrolyzed to fatty acids. In contrast, no odd-chain
length elongation products or very-long-chain fatty acids (VLCFA) shorter than
26:0 are observed in vivo. Hence, VLCFA synthesis exhibits a higher processivity
in vivo than in the cell homogenate. In addition, the in vivo process appears to
be protected against side reactions such as hydrolysis or alpha-oxidation. Yeast
mutants defective in 12:0 or 13:0 elongation were derived from fas-mutant strains
according to their failure to grow on 13:0-supplemented media. In vivo, 12:0
elongation was reduced to 0-10% of the normal level, while 16:0 elongation and
VLCFA synthesis were unimpaired. It is concluded that yeast contains either two
different elongation systems, or that the respective mutation interferes
differentially with medium-chain and long-chain fatty acid elongation. The yeast
gene affected in the elongation-defective mutants was isolated and, upon
sequencing, identified as the known ELO1 sequence. It encodes a putative membrane
protein of 32-kDa molecular mass with no obvious similarity to any of the known
FAS component enzymes.
PMID- 9546664
TI - Purification and properties of an extremely thermostable membrane-bound sulfur
reducing complex from the hyperthermophilic Pyrodictium abyssi.
AB - The chemolithoautotrophic archaeon Pyrodictium abyssi isolate TAG 11 gains energy
by reducing sulfur with H2 to H2S. From this hyperthermophile, a sulfur-reducing
complex catalyzing this reaction was purified 13.5-fold. The native complex
exhibited a brownish-yellow colour and showed an apparent molecular mass of 520
kDa. SDS/PAGE revealed the presence of nine different major polypeptides with
apparent molecular masses of 82, 72, 65, 50, 47, 42, 40, 30 and 24 kDa. The
native complex contained 50-55 mol acid-labile sulfur, 50-55 mol iron, 1.6 mol
nickel, 1.2 mol copper, 2.8 mol cytochrome b and 0.3 mol cytochrome c (all per
mol native complex). The temperature optimum of the H2:sulfur oxidoreductase
complex was 100 degrees C, which is consistent with the physiological growth
optimum of the native organism. The complex is extremely heat stable. During 5 h
incubation at 100 degrees C, no decrease in H2S-forming activity could be
observed.
PMID- 9546665
TI - Localization of carbohydrate chains of pig sperm ligand in the glycoprotein ZPB
of egg zona pellucida.
AB - The three glycoproteins of pig zona pellucida (ZPA, ZPB and ZPC) can be separated
into ZPA and a mixture of ZPB/ZPC by gel-filtration HPLC. We have shown
previously that the neutral complex-type N-linked carbohydrate chains obtained
from ZPB/ZPC possess sperm-binding activity. Intact ZPB and ZPC cannot be
separated from each other unless acidic N-acetyllactosamine regions of their
carbohydrate chains are removed by endo-beta-galactosidase digestion. The endo
beta-galactosidase-digested ZPB retains the sperm-binding activity. Recently, we
have reported that N-linked carbohydrate chains of N-terminal fragment (residues
137-247) obtained from endo-beta-galactosidase-digested ZPB are involved mainly
in sperm binding [Yonezawa, N., Mitsui, S., Kudo, K. & Nakano, M. (1997) Eur. J.
Biochem. 248, 86-92]. In this study, we separated the intact neutral N-linked
chains from the ZPB/ZPC mixture into diantennary chains and triantennary and
tetraantennary chains by affinity chromatography on Concanavalia ensiformis
agglutinin. An in vitro competition assay revealed that triantennary and
tetraantennary chains possess a sperm-binding activity stronger than that of
diantennary chains. Three glycopeptides, having one Asn residue to which the
carbohydrate chain is linked, were obtained by lysyl endopeptidase digestion of
the heat-solubilized zonae containing intact ZPB and lysyl endopeptidase and
chymotrypsin A digestion of endo-beta-galactosidase-digested ZPB. From sugar
mapping analysis of the carbohydrate chains from these glycopeptides and
comparison with the carbohydrate structures of the main intact neutral N-linked
chains of ZPB/ZPC, the triantennary and tetraantennary chains were shown to be
localized mainly at Asn220 of ZPB, and diantennary chains were present on all the
three potential residues (Asn203, Asn220 and Asn333). These results suggest that
the carbohydrate chains linked to Asn220 of ZPB participate predominantly in
sperm-egg binding.
PMID- 9546666
TI - Three-dimensional structure of moenomycin A--a potent inhibitor of penicillin
binding protein 1b.
AB - The first three-dimensional structure of moenomycin A in aqueous solution based
on NMR-derived distance constraints and molecular dynamics simulations is
presented. The antibiotic moenomycin A was obtained from the FlavomycinR complex
by ultrafiltration, chromatography on a DEAE-cellulose ion exchanger and reverse
phase chromatography in 98% purity. In contrast to the previously reported
behaviour, the compound gave rise to well-resolved NMR spectra in standard
solvents. Using several two-dimensional experiments, a complete assignment of
proton and carbon chemical shifts was achieved in (CD3)2SO, CD3OD and H2O/D2O
(9:1, pH 7.3). A total of 175 interproton distances were determined from 600-MHz
rotating-frame NOE (ROE) spectra and were used as restraints in molecular
dynamics calculations. These restraints included 84 ROEs between protons of the
moenocinol part leading to a very well-defined structure of the lipid part of the
molecule. The relative orientation of the subunits was determined by 66 ROEs
among different sugar rings and between the sugar rings and moenocinol. As a
result of the molecular dynamics calculation, rings D, E, and F as well as the
moenocinol part are very well-defined (average rms deviation over all heavy atoms
0.48 A) whereas rings A, B and C display a higher degree of conformational
flexibility which might be an artefact due to the lower number of ROEs in this
part of the molecule. A three-dimensional pharmacophore hypothesis comprising
functional groups of rings E and F and the carboxyl group of glyceric acid is
presented on the basis of the degradation and derivatization studies of Welzel
and coworkers [Welzel, P., Kunisch, F., Kruggel, F., Stein, H., Scherkenbeck, J.,
Hiltmann, A., Duddeck, H., Muller, D., Maggio, J. E., Fehlhaber, H.-W., Seibert,
G., van Heijenoort, Y. & van Heijenoort, J. (1987) Moenomycin A: Minimum
structural requirements for biological activity, Tetrahedron 43, 585-598; Welzel,
P. (1993) Transglycosylase inhibition, in Antibiotics and antiviral compounds-
Chemical synthesis and modifications (Krohn, K., Kirst, H. A. & Maag, H., eds)
pp. 373-378, VCH Weinheim].
PMID- 9546667
TI - Effect of the extramitochondrial adenine nucleotide pool size on oxidative
phosphorylation in isolated rat liver mitochondria.
AB - The effect of the concentration of extramitochondrial adenine nucleotides on
oxidative phosphorylation was studied in isolated rat liver mitochondria.
Mitochondria were incubated with succinate and hexokinase or creatine kinase at
constant or varying extramitochondrial adenine nucleotide concentrations ranging
over 0.3-5 mM. As parameters of oxidative phosphorylation, rate of respiration,
membrane potential as well as intra- and extra-mitochondrial adenine nucleotide
concentrations were determined. Below a threshold concentration of
extramitochondrial adenine nucleotides of 2 mM, the free Gibb's energy for the
adenine nucleotide transport increased but the extramitochondrial ATP/ADP ratio
decreased at intermediate rates of respiration with decreasing extramitochondrial
adenine nucleotide concentrations. In this range the rate of respiration was
dependent on the extramitochondrial ADP concentration. No effect of the
extramitochondrial adenine nucleotide concentration on the relationships between
the rate of respiration and the membrane potential, the intramitochondrial
adenine nucleotide pool and the intramitochondrial ATP/ADP ratio was found. This
suggests that the decline of extramitochondrial ATP due to adenine nucleotide
degradation and the limitation of adenine nucleotide transport may be of
importance in the postischemic phase as nucleotide resynthesis and reorganization
of physiological ion distribution are ATP consuming processes.
PMID- 9546668
TI - Biosynthesis of C18 polyunsaturated fatty acids in microsomal membrane
preparations from the filamentous fungus Mucor circinelloides.
AB - The biosynthesis of C18 polyunsaturated fatty acids has been studied in the
fungus Mucor circinelloides. Microsomal membrane preparations contained delta9,
delta12 and delta6 desaturase activities. The delta9 desaturase exhibited
characteristics similar to those of the animal and yeast delta9 desaturases in
being membrane bound and utilising stearoyl-CoA as substrate. Cytochrome b5 (a
soluble form lacking the 20-amino-acid hydrophobic C-terminus) stimulated
desaturation and was identified as a major cytochrome component of the membranes.
A high ferricyanide reductase activity (indicative of NADH:cytochrome b5
reductase activity) coupled to inhibition by cyanide further supported the
similarity with the mammalian and yeast enzymes. Time-course studies with
radiolabelled oleoyl-CoA showed that the oleate [18:1(9)] was transferred to
position sn-2 of phosphatidylcholine (PtdCho) and was desaturated to linoleoyl
PtdCho. Removal of the excess oleoyl-CoA from the membranes prior to addition of
reductant confirmed that oleoyl-PtdCho is a substrate for the delta12 desaturase.
The entry of oleate at this position of the phospholipid was facilitated by the
activity of lyso-PtdCho:acyl-CoA acyltransferase (LPCAT), which readily
transferred oleate from oleoyl-CoA to lyso-PtdCho. Desaturation of oleate at the
sn-1 position of PtdCho was also demonstrated after the entry of oleate in to the
phospholipid by the enzymes of the Kennedy pathway. Thus oleate at sn-1 and sn-2
positions served as substrate for the delta12 desaturase and is consistent with
observations in oil seed tissues. LPCAT activity was substantially higher than
that observed with lysophosphatidylethanolamine:acyl-CoA acyltransferase (LPEAT)
indicating that oleate is less effectively channelled to phosphatidylethanolamine
for linoleate synthesis. No desaturation on phosphatidylinositol could be
demonstrated. Delta6 desaturase utilised linoleate at the sn-2 position of
exogenously supplied PtdCho presented to the membranes in the presence of
reductant. Thus, the entry of substrates into PtdCho via LPCAT and the synthesis
of linoleate [18:2(9,12)] and gamma-linolenate [18:3(6,9,12)] on this
phospholipid is similar to that reported for oil seed membranes.
PMID- 9546669
TI - Analysis of stress in the active site of myosin accompanied by conformational
changes in transient state intermediate complexes using photoaffinity labeling
and 19F-NMR spectroscopy.
AB - Myosin forms stable ternary complexes with ADP and the phosphate analogues,
fluoroaluminate (Al F4-), fluoroberyllate (BeFn) or orthovanadate (Vi); these
ternary complexes mimic transient intermediates in the myosin ATPase cycle.
Moreover, we previously demonstrated that these complexes may mimic different
myosin ATPase reaction intermediates corresponding to separate steps in the cross
bridge cycle [Maruta, S., Henry, G. D., Sykes, B. D. & Ikebe, M. (1993) J. Biol.
Chem. 268, 7093-7100]. Park et al. suggested that the changing conformation of
ATP during hydrolysis stresses the active site of myosin subfragment-1 (S-1)
through protein-nucleotide contacts at the gamma-phosphate and nucleotide base,
and the stress-induced strain in the cross-bridge may be the mechanism by which
energy in ATP is transferred to the myosin structure [Park, S., Ajtai, K. &
Burghardt, T. P. (1997) Biochemistry 36, 3368-3372]. In the present study, the
photoactive ADP analogue, 3'-O-(N-methylanthraniloyl)-2-azido-ADP (Mant-2-N3
ADP), and the 19F-labeled ADP analogue, 2
[(trifluoromethylnitrophenyl)aminoethyl]diphosphate, were employed to examine
conformational differences in protein-nucleotide contact in the ATP-binding site
that may correlate with energy transduction. Mant-2-N3-ADP was trapped within the
active site of skeletal and smooth muscle myosin in the presence of AlF4-, BeFn
or Vi. For both skeletal and smooth muscle myosins, trapped Mant-2-N3-ADP was
covalently linked to the 25-kDa N-terminal fragment of S-1 of both myosin/Mant-2
N3-ADP/AlF4- and BeFn complexes, presumably at Trp130. However, the efficiency of
the incorporation was much higher for skeletal than for smooth muscle myosin
suggesting that the conformations of the adenine-binding pockets of the two
myosins are somewhat different. Although the amount of Mant-2-N3-ADP trapped in
the presence of AlF4- and BeFn was the same for both myosins, the efficiency of
photolabeling skeletal muscle myosin was approximately two times higher for BeFn
complex than for AlF4- complex. The 19F-NMR spectra of the bound 2
[(trifluoromethylnitrophenyl)aminoethyl]diphosphate in the ternary complexes
formed in the presence of AlF4-, BeFn or Vi showed small but distinguishable
differences. Taken together, these results indicate that there is some variation
in the protein-nucleotide contacts at the nucleotide base among the ternary
complexes studied, and these differences mimic separate steps occurring
transiently during the contractile cycle.
PMID- 9546670
TI - One-step purification of cathepsin D by affinity chromatography using immobilized
propeptide sequences.
AB - In vivo, active cathepsin D proteinase is generated by removal of a 44-residue
propeptide at its N-terminus. Here we report that mature cathepsin D and
pseudocathepsin D (a partially activated form of cathepsin D with 25 amino acid
residues removed from the propeptide) bind to the immobilized propeptide, while
procathepsin D does not. The N-terminal 25 amino acid residues of the propeptide
are sufficient for this binding. Based on this observation, a simple one-step
procedure was developed to purify mature cathepsin D from whole cell extracts to
near homogeneity. This method has the advantage over existing affinity
purification systems that active forms of the proteinase can be separated from
inactive precursors and other aspartic proteinases. Furthermore, this technique
was effective for pepsin as well, suggesting it may have general utility for all
activated aspartic proteinases and perhaps other families of proteinases.
PMID- 9546671
TI - Non-detergent sulphobetaines enhance the recovery of membrane and/or cytoskeleton
associated proteins and active proteases from erythrocytes infected by Plasmodium
falciparum.
AB - A better understanding of the causative agent's biology and the definition of new
targets for the development of drugs and/or specific immune responses is
necessary to face the spred of drug-resistant malaria in developing countries and
the absence of an efficient vaccine against this most important infectious
disease. Non-detergent sulphobetaines enhance the recovery and isoelectric
focussing of active Plasmodium falciparum proteases, cytoskeleton-associated
proteins and Maurer's cleft-associated proteins. This is a significant advantage
for the purification of such proteins and might help pinpoint their role for red
blood cell rupture and merozoite release.
PMID- 9546672
TI - Sequential phosphorylation of Tau by glycogen synthase kinase-3beta and protein
kinase A at Thr212 and Ser214 generates the Alzheimer-specific epitope of
antibody AT100 and requires a paired-helical-filament-like conformation.
AB - AT100 is a monoclonal antibody highly specific for phosphorylated Tau in
Alzheimer paired helical filaments. Here we show that the epitope is generated by
a complex sequence of sequential phosphorylation, first of Ser199, Ser202 and
Thr205 (around the epitope of antibody AT8), next of Thr212 by glycogen synthase
kinase (GSK)-3beta (a proline-directed kinase), then of Ser214 by protein kinase
A (PKA). Conversely, if Ser214 is phosphorylated first it protects Thr212 and the
Ser-Pro motifs around the AT8 site against phosphorylation, and the AT100 epitope
is not formed. The generation of the AT100 epitope requires a conformation of tau
induced by polyanions such as heparin, RNA or poly(Glu), conditions which also
favor the formation of paired helical filaments. The Alzheimer-like
phosphorylation can be induced by brain extracts. In the extract, the kinases
responsible for generating the AT100 epitope are GSK-3beta and PKA, which can be
inhibited by their specific inhibitors LiCl and RII, respectively. A cellular
model displaying the reaction with AT100 is presented by Sf9 insect cells
transfected with Tau. Knowledge of the events and kinases generating the AT100
epitope in cells might allow us to study the degeneration of the cytoskeleton in
Alzheimer's disease.
PMID- 9546673
TI - Selection of a RNA aptamer that binds to human activated protein C and inhibits
its protease function.
AB - A high-affinity RNA aptamer to human activated protein C (APC) was selected from
a pool of random sequences using in vitro selection. Activated protein C, a
trypsin-like serine protease plays an important role along with thrombin as a
regulator in blood clotting cascade. After seven rounds of selection and
amplification, a single predominant nucleic acid sequence APC-167, a 167-base
oligonucleotide with a random sequence core of 120 bases, was obtained. The
selected aptamer did not bind to thrombin or factor Xa and thus demonstrated
specificity to APC. Furthermore, this aptamer was a non-competitive inhibitor to
the cleavage reaction of a fluorogenic substrate catalyzed by APC. The inhibition
constant (Ki) of APC-167 was 83 nM. The 99-base oligonucleotide (APC-99) derived
from APC-167 by deleting both primer binding sites, was also found to inhibit APC
strongly (Ki = 137 nM). Two stem-loop structures and at least one G x U wobble
base pair in the stem were elucidated as important structural motifs for binding.
PMID- 9546674
TI - Lipocalins of boar salivary glands binding odours and pheromones.
AB - Large amounts of an odorant-binding protein have been isolated from submaxillary
glands of mature male pig. This polypeptide molecule is sex-specific, being
absent in females. On electrophoretic gels under denaturing conditions it
migrated as a broad band with an apparent molecular mass of around 20 kDa.
Electrospray mass spectrometry revealed the presence of three main components,
whose mass differences are not interpretable as result of any common post
translational modifications, indicating the presence of distinct polypeptide
chains. N-terminal Edman degradation yielded a single sequence of 29 amino acids.
It includes the lipocalin signature (-G-X-W-) and shows clear homology with a
subclass of odorant-binding proteins present in mouse saliva, nasal mucus and
urine. The purified protein still retained small ligands tightly bound; among
them 5alpha-androst-16-en-3-one and 5alpha-androst-16-en-3alpha-ol, both known
sex pheromones for the pig, were identified. The protein also binds 2-isobutyl-3
methoxypyrazine, a good ligand for most odorant-binding proteins, with a
dissociation constant of 5 microM.
PMID- 9546675
TI - Purification and amino acid sequence of halystase from snake venom of Agkistrodon
halys blomhoffii, a serine protease that cleaves specifically fibrinogen and
kininogen.
AB - We have isolated a serine protease, halystase, from Agkistrodon halys blomhoffii
venom by chromatography on DEAE-Sepharose, heparin-Sepharose and Q-Sepharose
columns, and have determined the complete amino acid sequence by Edman
degradation and by mass spectral analysis of peptides generated by enzymatic and
chemical cleavage. The 238-residue sequence of halystase, containing N-linked
carbohydrates (about 13%) at two sites showed significant similarity to other
thrombin-like snake venom serine proteases (66-72%), mammalian tissue kallikrein
(42%) and thrombin (26%). Halystase contained the tentative catalytic triad of
His43, Asp88 and Ser184 common to all serine proteases and Asp178 in the primary
substrate-binding site. Although halystase contained an RGD sequence at residues
181-183, it did not inhibit platelet aggregation induced by ADP or collagen. It
hydrolyzed most efficiently a tissue-kallikrein substrate,
prolylphenylalanylarginyl-4-methyl-coumaryl-7-amide, and released bradykinin from
bovine kininogen. Halystase did not coagulate human plasma, but it cleaved the
fibrinogen B beta chain at the carboxyl side of Arg42 and cleaved slowly the
fibrogen A alpha chain. Fibrinogen thus treated gradually became insensitive to
thrombin. The proteolytic activity was inhibited with diisopropyl
fluorophosphate, phenylmethylsulfonyl fluoride or leupeptin. These results
indicate that halystase is a serine protease structurally similar to coagulating
thrombin-like snake venom proteases, but it specifically cleaves fibrinogen at
sites different from thrombin without inducing fibrin clotting, and hydrolyzes
kininogen to produce bradykinin, resulting in the reduction of blood pressure.
PMID- 9546676
TI - Selective reduction of 6-O-sulfation in heparan sulfate from transformed mammary
epithelial cells.
AB - Heparan sulfate at cell surfaces and in the extracellular matrix regulates cell
proliferation and adhesion by binding to growth factors and matrix proteins via
structurally specific oligosaccharide domains. We have used the hormonally
regulated mouse mammary carcinoma cell line S115 as a model to elucidate the
effect of malignant transformation on the structure of heparan sulfate. When
cultured in the presence of testosterone, S115 cells form tumor cell colonies in
soft agar and exhibit fibroblast-like morphology; withdrawal of testosterone
results in a loss of the tumorigenic capacity and a switch towards epithelial
morphology. Metabolically 35SO4-labeled heparan sulfate was isolated from
testosterone-treated and non-treated S115 cells and subjected to structural
analysis. We found that the testosterone-dependent malignant transformation was
associated with reduced sulfation of heparan sulfate due to a approximately 40%
decrease in the amount of GlcN6S units. By contrast, no significant differences
were observed in the amounts of 2-O-sulfate or N-sulfate groups. The reduced 6-O
sulfation of GlcN units in heparan sulfate from transformed S115 cells led to a
marked decrease in the amount of trisulfated IdoA2S-GlcNS6S units (IdoA, L
iduronic acid), implicated in many heparan sulfate-protein interactions.
PMID- 9546677
TI - Demonstration of a Ca2+ requirement for thyroglobulin dimerization and export to
the golgi complex.
AB - We have examined the effects of depleting the endoplasmic reticulum Ca2+ store on
the maturation of newly synthesized thyroglobulin molecules, their export to the
Golgi complex, and their secretion by FRTL-5 cells. An inhibitor of the
endoplasmic reticulum Ca2+ pump, thapsigargin, and the Ca2+ ionophore A23187
depleted the endoplasmic reticulum Ca2+ store and strongly inhibited
thyroglobulin secretion in cells chased in medium containing 0.1 mM Ca2+.
Inhibition of thyroglobulin secretion was caused by a block in the export of
newly synthesized thyroglobulin molecules from the endoplasmic reticulum to the
Golgi complex, as shown by cell-fractionation experiments and the intracellular
accumulation of endoH-sensitive thyroglobulin. The thyroglobulin molecules
retained in the endoplasmic reticulum of cells treated with the drugs were found
to assemble more slowly into dimers than thyroglobulin in control cells. Protease
sensitivity experiments demonstrated that thyroglobulin dimers assembled in the
presence of thapsigargin had a different conformation with respect to dimers
assembled in controls cells.
PMID- 9546678
TI - Guanylate-cyclase-inhibitory protein is a frog retinal Ca2+-binding protein
related to mammalian guanylate-cyclase-activating proteins.
AB - Two guanylate-cyclase-activating proteins (GCAP) encoded by a tail-to-tail gene
array have been characterized in the mammalian retina. Using frog retina as a
model, we obtained evidence for the presence of a photoreceptor Ca2+-binding
protein closely related to GCAP. This protein (206 amino acids) does not
stimulate guanylate cyclase (GC) in low [Ca2+], but inhibits GC in high [Ca2+],
and is therefore termed guanylate-cyclase-inhibitory protein (GCIP). Sequence
analysis indicates that GCIP and GCAP1 and GCAP2 have diverged substantially, but
conserved domains present in all vertebrate GCAP are present in GCIP. Moreover,
partial characterization of the GCIP gene showed that the positions of two
introns in the GCIP gene are identical to positions of corresponding introns of
the mammalian GCAP gene array. As to the major differences between GCIP and GCAP,
the fourth EF hand Ca2+-binding motif of GCIP is disabled for Ca2+ binding, and
GCIP does not stimulate GC. Monoclonal and polyclonal antibodies raised against
recombinant GCIP identified high levels of GCIP in the inner segments, somata and
synaptic terminals of frog cone photoreceptors. The results suggest that GCIP is
a Ca2+-binding protein of the GCAP/recoverin subfamily. Its localization in frog
cones closely resembles that of GC in mammalian cones. GCIP inhibits GC at high
free [Ca2+], competing with GCAP1 and GCAP2 for GC regulatory sites.
PMID- 9546679
TI - Tryptophan mutants of troponin C from skeletal muscle--an optical probe of the
regulatory domain.
AB - We have generated a series of chicken skeletal muscle troponin C mutants to study
the conformation of the regulatory domain in the N-terminal half of the molecule.
These mutants each contained a single Trp at position 22 (helix A), 52 (linker of
helices B and C), or 90 (central helix). Some of these mutants also contained
additional mutations to introduce a single Cys at a desired position. The mutants
were characterized by molecular graphics and CD and found to have a minimum of
structural perturbations when compared with the native structure. They also
retained the ability to regulate myofibrillar ATPase activity. The fluorescence
of Trp22 was sensitive to Ca2+ binding only to the regulatory sites, whereas
Trp52 and Trp90 responded to Ca2+ binding to both the regulatory and the
Ca2+/Mg2+ sites. The tryptophan quantum yield (Q) of all Trp22-containing mutants
was very high (0.33) in the absence of bound Ca2+, compared to that of L
tryptophan in aqueous solution (0.14). Q decreased 25% upon binding of Ca2+ to
the regulatory sites. The quantum yields of Trp52 and Trp90 in apo mutants were
close to 0.14. In the presence of bound Ca2+ at the regulatory sites, the quantum
yield of Trp52 decreased 16%, whereas that of Trp90 increased 25%. Results from
acrylamide quenching of the fluorescence of the three Trp residues indicated that
Trp22 was the least exposed and Trp52 was the most exposed, consistent with other
spectral data that Trp22 was in a relatively nonpolar environment and Trp52 was
in a highly polar environment. The ability of Trp52 and Trp90 to sense Ca2+
binding to sites located at both domains suggests inter-domain communication in
the protein. These single Trp TnC mutants provide specific signals for probing
Ca2+-induced conformational changes in the regulatory domain.
PMID- 9546681
TI - Advances in the understanding of the nephrotoxicity of radiocontrast media.
PMID- 9546680
TI - How Drosophila species acquire cold tolerance--qualitative changes of
phospholipids.
AB - Phospholipids of many cold-tolerant organisms have been reported to contain more
unsaturated fatty acids than cold-susceptible organisms, a phenomenon known to
maintain membrane fluidity at low temperature. However, we have obtained results
to the contrary through a comparison of the membrane phospholipids of six
temperate and subtropical species belonging to the Drosophila melanogaster
species group. With enhancement of cold tolerance, the percentages of monoenoic
acids increased but the percentages of dienoic acids decreased, that is, the
number of double bonds in the phospholipid decreased without a marked variation
in the percentages of unsaturated fatty acids. Concomitantly, the percentage of
fatty acids containing 16 carbon atoms increased, while that of fatty acids with
18 carbon atoms decreased. Since phosphatidylethanolamine is a dominant
phospholipid in Drosophila, these changes probably contribute to keeping the
homeoviscosity of the cellular membranes in a manner different to that in
phosphatidylcholine-rich membranes, thereby increasing cold tolerance.
PMID- 9546683
TI - The relationship between pentosidine and hemodialysis-related connective tissue
disorders.
AB - Dialysis-related amyloidosis (DRA), such as destructive spondyloarthropathy (DSA)
and carpal tunnel syndrome (CTS), occurs in the connective tissues of patients on
long-term hemodialysis (HD). Recently, it was suggested that advanced glycation
end products (AGEs) and beta2-microglobulin (beta2m) modified with AGEs are
related to DRA. The aim of this study is to elucidate whether serum levels of
pentosidine, which is an AGE, relate to the occurrence of DRA in patients with
long-term HD. 127 end-stage renal failure patients, with DSA or CTS and
undergoing HD, were examined. Serum pentosidine was measured by the HPLC method
with column switching. Beta2m and intact parathyroid hormone (i-PTH) were
measured. Pentosidine levels were significantly elevated in the DSA, CTS, and DRA
groups (patients in the DRA group had either DSA and/or CTS). There were no
significant differences in the beta2m and i-PTH levels between any group. The
duration of HD did not correlate with either pentosidine or beta2m levels, but
did with i-PTH. Receiver-operating characteristic (ROC) analysis was performed to
examine the discriminatory ability of pentosidine, beta2m, and i-PTH for DRA. The
area under the ROC curve was the greatest for pentosidine. Serum beta2m levels
were not related with the occurrence of DRA. The fact that serum pentosidine was
higher in DRA than in non-DRA indicates that it has potential as an indicator of
the occurrence of DRA in long-term HD patients.
PMID- 9546682
TI - Improvement of nutritional status in patients receiving maintenance hemodialysis
after correction of renal anemia with recombinant human erythropoietin.
AB - Despite a large body of evidence showing the beneficial effects of successful
treatment of anemia with recombinant human erythropoietin (EPO) in patients with
end-stage renal disease, controversy remains as to whether EPO treatment of
anemia can improve the nutritional status in patients on maintenance
hemodialysis. This prompted us to conduct a prospective study in 41 hemodialysis
patients with basal hemoglobin less than 9 g/dl. The dose of EPO was increased
for 12 weeks to achieve the target hemoglobin concentration of 10 g/dl and then
titrated in the following 12 weeks to maintain the target value. Nutritional
status was assessed at baseline and after 6 months of follow-up, using the global
protein-calorie malnutrition (PCM) index proposed by Bilbrey and Cohen. A low
global PCM score indicates better nutrition. The results showed that hemoglobin
values significantly increased from 8.7 +/- 0.8 g/dl at baseline to 10.7 +/- 0.5
g/dl in the 6th month (p < 0.001). No significant changes were observed in the
normalized protein catabolic rate and Kt/V during the study period. Global PCM
scores improved from 30.0 +/- 7.5 to 23.6 +/- 3.1 (p < 0.001) and paralleled the
correction of anemia by EPO treatment. The data were consistent with a major
improvement in the nutritional markers of relative body weight, triceps skinfold,
midarm circumference, midarm muscle circumference, serum albumin, serum
transferrin and total lymphocyte count in the 6th month as compared to baseline.
The percentages of mild and moderate-severe PCM at baseline were 32 and 58%,
respectively. These percentages were significantly reduced during the 6th month
to 20 and 30%, respectively (p = 0.0004). In summary, correction of renal anemia
with EPO improves the nutritional status in hemodialysis patients. A postulated
mechanism is that EPO may exhibit anabolic effects, with a better utilization of
ingested protein.
PMID- 9546684
TI - Association of apolipoprotein E polymorphism with lipoprotein glomerulopathy.
Report of 2 cases with a new genotype and comparison of the relative frequencies
of apolipoprotein E isoforms in lipoprotein glomerulopathy and in the general
population.
AB - Two cases of lipoprotein glomerulopathy with a new apolipoprotein E (Apo E)
genotype, epsilon3/epsilon4, were diagnosed recently. These 2 cases, together
with other cases documented in English literature made a total of 6 common
isoforms of Apo E encountered in lipoprotein glomerulopathy. Although the
calculated allele frequency of epsilon2 is relatively high in cases with
lipoprotein glomerulopathy as compared with that in the general population (39.3
vs. 6.4-11.4%), the gradual emergence of Apo E isoforms other than E2/E3 in
lipoprotein glomerulopathy implicates that the genetic susceptibility of certain
Apo E isoforms may not be a crucial factor. An alteration in the local
environment of glomerular capillaries may be more important in the pathogenesis
of lipoprotein glomerulopathy.
PMID- 9546685
TI - Lipid composition of platelets in patients with uremia.
AB - AIMS: The lipid composition of platelets and the function of these cells in
patients with uremia were studied. METHODS: Fourteen patients and 14 normal
volunteers were studied. Platelet lipids including phospholipids and cholesterol,
as well as the platelet aggregation response to agonists, were studied. RESULTS:
The amount of platelet phospholipids was decreased in patients compared to
controls (338.0 +/- 79 vs. 511.6 +/- 125 nmol/10(9) cells; p < 0.001), while the
percentage of the five main specimens of these compounds was normal. The content
of platelet cholesterol in patients (97.8 +/- 17.0 microg/10(9) cells) was
similar to that in controls (91.7 +/- 26.0 microg/10(9) cells). Consequently, the
cholesterol:phospholipid ratio in uremic platelets was increased (0.75 +/- 0.1
vs. 0.46 +/- 0.1; p < 0.01). Although this feature is associated with
hyperreactive platelets, the aggregation tests were defective for adenosin
diphosphate (p < 0.01), arachidonic acid (p < 0.01), epinephrine (p < 0.01) and
collagen (p < 0.001). This behavior is probably due to the multifactorial
platelet defect described in uremia.
PMID- 9546686
TI - Accidental aluminum intoxication in patients undergoing acetate-free
biofiltration.
AB - Eight patients undergoing acetate-free biofiltration (AFB) suffered aluminum
intoxication. The source of this outbreak was parenteral exposition to high
concentrations of aluminum in sodium bicarbonate solutions. The manufacturer of
bicarbonate solutions used in AFB was substituted in May 1994 and the solutions
were stored in glass containers. At the peak of intoxication (July 1994) serum
aluminum determination revealed an average value of 147.3 +/- 21 microg/l.
Aluminum levels in bicarbonate solutions were 400 microg/l. Serum ferritin rose
from 307.4 +/- 161 to 735.6 +/- 206 ng/ml, whereas MCV decreased significantly
from 98.4 +/- 9 to 90.1 +/- 10 fl. No significant changes were found in
hemoglobin, neither in plasma iron, nor in iron transferrin saturation. The doses
of recombinant human erythropoietin showed a considerable increase. The
replacement solutions were changed and a new solution, stored in plastic
containers and with aluminum levels lower than 10 microg/l, was used. The
biochemical parameters were normalized. This outbreak demonstrates the need for a
stringent control of aluminum-containing replacement fluids.
PMID- 9546687
TI - Anticardiolipin antibodies in classic pediatric hemolytic-uremic syndrome: a
possible pathogenic role.
AB - Anticardiolipin (aCL) antibodies have been associated with thrombocytopenia,
hemolytic anemia and an increased risk of thrombosis in different vascular
locations, even in the absence of lupus. The classic hemolytic-uremic syndrome is
a postinfectious acute renal failure characterized by hemolytic anemia,
thrombocytopenia and the presence of widespread glomerular thrombosis in the
kidney, with pathogenic mechanisms that remain to be identified. In order to
establish the frequency of aCL antibodies in this syndrome and to identify a
possible role in the pathogenesis and clinical manifestations, 17 patients were
studied during the reactant phase of the disease looking for an association
between the presence of aCL antibodies (isotypes IgG, IgA and IgM) and the main
clinical variables of the syndrome. In 8 patients IgG aCL was present, 2 patients
had IgM aCL, and 1 had IgA antibodies on the solid-phase ELISA aCL assays, but no
association could be demonstrated with the clinical variables studied. Although
it might correspond to an epiphenomenon related to the triggering intestinal
infection, a pathogenic role cannot be discarded and additional studies should be
performed.
PMID- 9546688
TI - Mesangial expression of a nonmuscle myosin heavy chain, SMemb, is associated with
glomerular sclerosis and renal prognosis in IgA nephropathy.
AB - To characterize the phenotypic alteration in mesangial cells in human
glomerulonephritis, we investigated the expression of nonmuscle-type myosin heavy
chain, SMemb, and alpha-smooth muscle actin (alpha-SM actin) in IgA nephropathy.
The expression of SMemb and alpha-SM actin was examined by immunohistochemistry
in biopsy specimens from 45 patients with IgA nephropathy. We examined a total of
489 glomeruli representing all patients enrolled, and found that mesangial
expression of SMemb and alpha-SM actin was associated with mesangial
proliferation. Only mesangial expression of SMemb showed a significant
relationship with mesangial matrix accumulation. Semiquantitative evaluation
using composite expression scores showed that the expression of SMemb was
elevated in the patients with poor renal prognosis. The expression of alpha-SM
actin showed no significant relationship with renal prognosis. These results
suggest that mesangial expression of SMemb is an important factor in the
progression of IgA nephropathy, and that SMemb and alpha-SM actin are associated
with the activation of mesangial cells by different mechanisms.
PMID- 9546689
TI - Sera of IgA nephropathy patients contain a heterogeneous population of relatively
cationic alpha-heavy chains.
AB - Sera of IgA nephropathy (IgAN) patients and normal subjects were analysed by two
dimensional (2-D) gel electrophoresis. Densitometric analysis of the 2-D gels of
IgAN patients and normal subjects revealed that their protein maps were
comparable. There was no shift of pI values in the major alpha-heavy chain spots.
However, the volume of the alpha-heavy chain bands were differently distributed.
Distribution was significantly lower at the anionic region in IgAN patients (mean
anionic:cationic ratio of 1.184 +/- 0.311) as compared to normal healthy controls
(mean anionic:cationic ratio of 2.139 +/- 0.538). Our data are in support of the
previously reported findings that IgA1 of IgAN patients were lacking in sialic
acid residues.
PMID- 9546690
TI - Development of calcium oxalate crystals on urothelium: effect of free radicals.
AB - The effects of free radicals on the development of crystals attached to the
living epithelium have been studied using an experimental model that enables
close simulation of the conditions prevailing in the kidney. The results obtained
clearly demonstrate that free radical-damaged cells produce a favorable
environment for crystal development. At low free radical concentrations, crystals
develop on calcium-enriched zones, whereas at higher concentrations, crystals
develop on areas with a destroyed monolayer of superficial cells. Evaluation of
the action of some products with antioxidant action and/or crystallization
inhibitory capacity is also included. Antioxidants, such as ascorbic acid and
mannitol, exerted the most remarkable effects in avoiding calcium oxalate crystal
development, whereas crystal inhibitors, such as citric acid, did not produce any
remarkable reduction in calcium oxalate crystallization. Phytic acid notably
decreased calcium oxalate crystal development. The ability of phytic acid to
diminish calcium oxalate crystallization must be attributed to the combination of
its inhibitory capacity of calcium oxalate crystallization and its preventive
antioxidant action.
PMID- 9546691
TI - Urinary transforming growth factor-beta (TGF-beta) excretion and renal production
of TGF-beta in rats with subtotal renal ablation: effect of enalapril and
nifedipine.
AB - The aim of the present study was to investigate the effect of enalapril and
nifedipine on renal transforming growth factor-beta (TGF-beta) production and on
the rate of urinary TGF-beta excretion in rats with subtotal renal ablation.
After subtotal nephrectomy some animals were treated with enalapril or
nifedipine. Renal cortical TGF-beta mRNA levels were 68% higher in untreated
nephrectomized rats (p < 0.05) and 39% higher in rats treated with nifedipine (p
< 0.05) compared with controls. There was no difference in renal cortical TGF
beta mRNA content between the nephrectomized rats treated with enalapril and sham
animals, showing that enalapril treatment prevented the increase of TGF-beta mRNA
in nephrectomized rats. The rate of urinary TGF-beta excretion was 2.2 +/- 0.8
pg/min in sham animals, 61.5 +/- 40.1 pg/min in untreated nephrectomized rats,
9.6 +/- 4.2 pg/min in nephrectomized rats treated with enalapril, and 55.2 +/-
24.46 pg/min in rats treated with nifedipine. The immunohistochemical reaction
for TGF-beta in the renal cortex was less intense in the nephrectomized rats
treated with enalapril than in the other groups of rats with subtotal renal
ablation. These data show that enalapril induces a decrease in renal TGF-beta
production and in urinary TGF-beta excretion in rats with subtotal renal
ablation, an effect associated with the protective action of this treatment on
renal structure and function and suggest that the determination of the rate of
urinary TGF-beta could be a useful procedure for the evaluation of disease
progression and therapeutic efficacy in the remnant kidney model.
PMID- 9546692
TI - Anti-CD8 monoclonal antibody protects against spontaneous IgA nephropathy in ddY
mice.
AB - We investigated the effects of anti-CD4 monoclonal antibody (mAb) and/or anti-CD8
mAb in ddY mice, an animal model of spontaneous IgA nephropathy. Female ddY mice
were treated with 18 intravenous injections of anti-CD4 and/or anti-CD8 mAb at 2
week intervals. This was based on our observation that a single injection of anti
CD4 mAb or anti-CD8 mAb caused a selective depletion in CD4+ T cells for 2 weeks
and CD8+ T cells for 4 weeks, respectively. The level of proteinuria, serum IgA,
and changes in the histopathological features of renal tissue samples were
assessed in treated mice between the age of 4 and 40 weeks. The level of
proteinuria increased with age, but there was not significant difference among
the groups. No animal developed microhematuria throughout the study. Treatment
with anti-CD4 mAb produced a mild to moderate level of mesangial hypertrophy at
20 and 40 weeks, similar to the results in untreated mice. The lowest degree of
mesangial hypertrophy occurred in mice treated with anti-CD8 mAb up to the age of
40 weeks. Treatment with a combination of anti-CD4 and anti-CD8 mAbs produced
effects that were similar to those observed on treatment with anti-CD8 mAb alone.
Our results suggest that CD8+ T cells mediate mesangial proliferation and the
progression of nephropathy in ddY mice.
PMID- 9546694
TI - Castleman's disease and mesangial proliferative glomerulonephritis: the role of
interleukin-6.
AB - Renal complications of Castleman's disease (angiofollicular lymph node
hyperplasia) are uncommon. The reported cases are very heterogeneous and their
renal pathology ranged from minimal change disease, mesangial proliferative
glomerulonephritis, to amyloidosis. We have previously reported two cases of
Castleman's disease with renal complications. We now present two more such cases.
In contrast to other reports, all our cases are of the plasma cell type and their
renal pathology showed remarkable similarities, namely mesangial proliferation,
interstitial plasma cell infiltration and negative immunofluorescence. The level
of serum interleukin-6 (IL-6) in both patients was elevated at presentation and
came down with immunosuppressive therapy.
PMID- 9546693
TI - Crescentic glomerulonephritis due to rifampin treatment in a patient with
pulmonary atypical mycobacteriosis.
AB - A 64-year-old male was treated continuously with rifampin, isoniazid and
streptomycin for pulmonary atypical mycobacteriosis, Mycobacterium kansasii. Five
weeks after beginning the treatment, the patient suddenly developed acute renal
failure. A renal biopsy showed crescentic lesions characteristic of rapidly
progressive glomerulonephritis with moderate interstitial changes. Serum
antirifampin antibody was detected, and the cessation of rifampin treatment was
followed by a rapid spontaneous recovery of the patient's renal function. This
is, to our knowledge, the first case of rapidly progressive crescentic
glomerulonephritis associated with rifampin treatment where circulating
antirifampin antibody is demonstrated and the renal function spontaneously
improved after discontinuing rifampin treatment.
PMID- 9546695
TI - Soyprotein diet therapy in renal disease.
PMID- 9546696
TI - Does hypertension cause end-stage renal disease in older white patients?
PMID- 9546697
TI - Excessive polyuria after renal transplantation.
PMID- 9546698
TI - Acute rhabdomyolysis after bezafibrate re-exposure.
PMID- 9546699
TI - Safe use of gemfibrozil in uremic patients on continuous ambulatory peritoneal
dialysis.
PMID- 9546700
TI - Urinary acidification and renal sodium handling in a case of renal Fanconi
syndrome.
PMID- 9546701
TI - Bone loss in children with idiopathic hypercalciuria.
PMID- 9546702
TI - A case of unusual anomalies of the abdominal aorta, renovascular hypertension,
and disappearance of hypertension right after nephrectomy: an incomplete Ask
Upmark kidney?
PMID- 9546703
TI - Prevalence of gallstone disease in hemodialysis patients.
PMID- 9546704
TI - Nature of membrane, permeability, and biocompatibility in hemodialysis.
PMID- 9546705
TI - Effects of amlodipine and enalapril alone and in combination on glomerular
hemodynamics in a hypertensive patient with unilaterally contracted kidney.
PMID- 9546706
TI - Effect of omeprazole on the urinary excretion of aluminum and phosphorus in
chronic renal failure.
PMID- 9546707
TI - Erythropoietin-induced epilepsy in hemodialysis patients?
PMID- 9546708
TI - Microscopic poliangiitis and human immunodeficiency virus infection.
PMID- 9546709
TI - Isolated diffuse mesangial sclerosis in three siblings.
PMID- 9546710
TI - Antioxidant status in Balkan endemic nephropathy.
PMID- 9546711
TI - Ultrasonographic evaluation of the bursae in patients with dialysis-related
amyloidosis.
PMID- 9546712
TI - An analysis of the effect of routine medications on hemodialysis vascular access
survival.
PMID- 9546713
TI - Hypertension, lipid abnormalities and cardiovascular changes in autosomal
dominant polycystic kidney disease.
PMID- 9546714
TI - Acute tubulo-interstitial nephritis and uveitis with anti-neutrophil cytoplasmic
antibodies in an adult: an autoimmune disorder?
PMID- 9546715
TI - Nitric oxide as a regulator of embryonic development.
AB - The role of nitric oxide (NO) in activation of cGMP is well established. It has
been proposed that the ratio of cAMP to cGMP may be important in the regulation
of preimplantation embryonic growth and differentiation. Therefore, we determined
the ability of murine preimplantation embryos to produce NO. In addition, NO as
an endogenous smooth muscle relaxant and vasodilator is a candidate for
involvement in embryo implantation because this process requires increased
vascular permeability and uterine quiescence at the sites of blastocyst
apposition. Nitrite assays, an indirect measure of NO production, indicate that
preimplantation murine embryos produce NO. This production was reversibly
inhibited by culture of embryos in medium containing a nonspecific NO synthase
(NOS) inhibitor (NG-nitro-L-arginine). Additionally, inhibition of normal
development was observed in embryos cultured with NOS inhibitor. NO levels
increased in culture medium when ovariectomized progesterone-treated animals were
exposed to estrogen for 1 h in utero. Such hormonal treatment induces
implantation. These data indicate that NO levels are regulated by estrogen and
may be important in regulation of implantation. In addition, these data
demonstrate for the first time that NO production appears to be required for
normal embryonic development.
PMID- 9546716
TI - Transient exposure of rhesus macaque oocytes to calyculin-A and okadaic acid
stimulates germinal vesicle breakdown permitting subsequent development and
fertilization.
AB - Exposure of mammalian oocytes to the protein phosphatase (PP)-1 (PP1) and PP2A
inhibitor okadaic acid (OA) stimulates oocyte meiosis. However, treated oocytes
do not develop beyond metaphase I (MI), and they display morphological
aberrations. Experiments were conducted to define inhibitor treatment conditions
for macaque oocytes that would result in germinal vesicle breakdown (GVB)
stimulation and completion of meiosis without significant cytoplasmic
abnormalities. As described above for OA, continual exposure of macaque oocytes
to 50 nM calyculin-a (CL-A) significantly enhanced GVB at 24 h compared to that
in controls, and the majority of the treated oocytes displayed cytoplasmic
abnormalities. However, transient exposure (10 min) of rhesus macaque oocytes to
either 50 nM CL-A or 1.0 microM OA enhanced GVB rates compared to that in
controls and did not increase the incidence of cytoplasmic abnormalities. Meiotic
maturation from germinal vesicle-intact oocytes to MII was enhanced following
transient treatment with CL-A or OA compared to that in controls; however,
development from MI to MII occurred at a similar frequency. In vitro-matured
oocytes transiently exposed to OA and CL-A were capable of fertilization. In
addition, ovarian immunohistochemical analysis revealed that both PP1 and PP2A
were present in macaque oocytes. PP1 was localized throughout the cytoplasm with
a predominance in the nucleus, whereas PP2A was evenly distributed throughout the
cytoplasm with a reduction in the nuclear area. These results taken together
differential developmental responses to inhibitor treatment and intracellular
enzyme localizations-may be indicative of multiple regulatory roles of PP1 and/or
PP2A during meiosis.
PMID- 9546717
TI - Characterization of a ribonucleic acid transcript from the brook trout
(Salvelinus fontinalis) ovary with structural similarities to mammalian
adipsin/complement factor D and tissue kallikrein, and the effects of kallikrein
like serine proteases on follicle contraction.
AB - A 2.4-kilobase (kb) clone (kallikrein trout #14; KT-14) was isolated from a brook
trout ovulatory cDNA library. KT-14 contains an open reading frame (ORF) of 768
base pairs (bp), presumably encoding a protein of 255 amino acids. The KT-14 cDNA
also contains a 711 -bp 5' untranslated region and a 793-bp region downstream of
the ORF that includes a 66-bp sequence repeated 12 times. The amino acid sequence
of the KT-14 ORF is 41 % identical to that of porcine complement factor D and 33%
identical to that of porcine pancreatic kallikrein. On Northern blots of ovarian
tissue, KT-14 hybridized with four transcripts of 1.8, 2.4, 2.9, and 3.2 kb.
While the 3.2- and 2.4-kb transcripts were present in the ovary prior to meiotic
maturation, they were significantly up-regulated at ovulation and at 12 h
postovulation, respectively. Antibodies constructed against the recombinant KT-14
protein recognized one 30-kDa immunogenic protein in ovarian tissue and fluid.
This immunogenic protein was significantly elevated in the tissue by ovulation.
Using a follicle weight loss bioassay, we provide indirect evidence that
mammalian kallikrein and related serine proteases can stimulate brook trout
follicle contraction. Thus, one possible function of the KT-14 protein may be the
regulation of oocyte expulsion at ovulation.
PMID- 9546718
TI - Pregnancy and interferon-tau induce conjugation of bovine ubiquitin cross
reactive protein to cytosolic uterine proteins.
AB - Conceptus-derived interferon-tau (IFN-tau) induces bovine endometrial ubiquitin
cross-reactive protein (UCRP) mRNA and protein on Days 15-21 of pregnancy. Bovine
UCRP retains the Leu-Arg-Gly-Gly C-terminal sequence of ubiquitin that ligates to
and directs degradation of cytosolic proteins. The objectives of the present
experiments were to determine whether UCRP became conjugated to endometrial
cytosolic proteins during early pregnancy and in response to recombinant bovine
(rbo) IFN-tau. Ubiquitin (8 kDa), UCRP (17 kDa), and conjugates thereof (> or =
30 kDa) were quantitated using Western blotting and densitometry. Endometrial
ubiquitin and its conjugates did not differ between Day 18 pregnant and
nonpregnant cows, or between control and rboIFN-tau-treated (25 nM) explant
cultures (Day 14; nonpregnant). Bovine UCRP was induced in endometrium from
pregnant as compared with nonpregnant cows. Conjugation of endometrial proteins
to UCRP was induced in pregnant as compared to nonpregnant cows. Recombinant
boIFN-tau induced UCRP and its conjugates in cultured endometrial explants from
nonpregnant cows. It is concluded that UCRP, in response to rboIFN-tau, becomes
conjugated to endometrial cytosolic proteins during early pregnancy. The
regulation of uterine proteins by UCRP may be integral to the maintenance of
early pregnancy in ruminants.
PMID- 9546719
TI - Development of Meishan and Yorkshire littermate conceptuses in either a Meishan
or Yorkshire uterine environment to day 90 of gestation and to term.
AB - To investigate the impacts of uterine type and conceptus genotype on development
through late gestation, Meishan and Yorkshire embryos were co-transferred into
the uteri of either Meishan or Yorkshire recipients that were subsequently
slaughtered on Day 90 of gestation. At slaughter, regardless of conceptus
genotype, fetuses and placentae were markedly smaller when recovered from Meishan
than from Yorkshire recipients. Whereas Meishan and Yorkshire fetuses recovered
from Meishan uteri were similar in weight, Meishan fetuses were markedly lighter
than littermate Yorkshire fetuses when recovered from Yorkshire uteri. Because of
the marked differences between fetal weights observed in Yorkshire recipients on
Day 90 of gestation, Meishan and Yorkshire embryos were co-transferred to
Yorkshire recipients that were allowed to farrow. Surprisingly, Meishan and
Yorkshire fetuses cogestated in Yorkshire recipients were born at similar
weights, whereas Meishan placentae were markedly smaller. The weight of Meishan
placentae were similar on Day 90 and at term, whereas the weight of Yorkshire
placentae were markedly larger (approximately 70%) at term than on Day 90. The
constant weight of Meishan placentae from Day 90 to farrowing appears to result
from an ability to increase their vascularity during this interval. In contrast,
Yorkshire placentae may be forced to increase their weight to keep pace with
fetal growth during this period. Because uterine capacity sets the upper limit on
litter size, the decreased endometrial surface area required per conceptus in the
Meishan pig seems to explain its greater potential for increased litter size.
PMID- 9546720
TI - Uterine environment and breed effects on erythropoiesis and liver protein
secretion in late embryonic and early fetal swine.
AB - In this study we investigated erythropoiesis and fetal liver protein secretion
during late embryonic (Day 24 and Day 30) and early fetal (Day 40) development in
pigs from domestic white crossbred (WC) gilts with a normal (intact; INT) or
crowded (unilateral hysterectomized/ovariectomized; UHO) uterine environment, or
from prolific Chinese Meishan (MS) gilts. Increased fetal weight, fetal liver
weight, placental weight, total red blood cells, hematocrit, blood hemoglobin
content, and maternal plasma erythropoietin (EPO) levels were observed as
gestation advanced. Cultured fetal liver secretion of transferrin and a protein
of Mr 12500 and pI 7.5 also increased as gestation advanced. Fetal plasma EPO
declined between Day 30 and Day 40. Differential counts of circulating erythroid
precursors revealed a decline in basophilic erythroblasts and polychromatic
erythroblasts between Day 24 and Day 40, an increase in orthochromatic
erythroblasts on Day 30 followed by a drop on Day 40, and an increase in the
percentage of reticulocytes/ erythrocytes from < 1.0% to approximately 90% of
circulating red blood cells between Day 24 and Day 40. Differences among the
treatment groups included a lower fetal survival percentage in UHO (vs. INT or
MS) on Day 40, and higher maternal hematocrits, fetal weights, fetal hematocrits,
fetal EPO levels, and liver transferrin secretion in WC vs. MS pigs. MS pigs had
a lower percentage of polychromatic erythroblasts overall and a higher percentage
of orthochromatic erythroblasts on Day 24 followed by a higher percentage of
erythrocytes on Day 40 than WC pigs, suggesting a more mature erythron
(circulating red blood cells plus erythropoietic tissue) in the MS pigs.
Covariate analysis indicated that MS had larger placentae per unit of body weight
than did WC. Conclusions were that 1) Days 24-40 of gestation is a critical time
for fetal erythropoiesis in pigs as well as survival in a crowded uterine
environment, 2) the MS breed may differ in the development of the fetal
erythropoietic system because of altered fetal or uterine physiology, and 3) the
UHO procedure did not significantly affect erythropoiesis in the fetuses studied
but did alter fetal survival and the relationship between fetal weight and both
hematocrit and hemoglobin on Day 40.
PMID- 9546721
TI - Expression and immunolocalization of functional cytochrome P450 aromatase in
mature rat testicular cells.
AB - Aromatase activity has been measured in Leydig cells and Sertoli cells from both
immature and mature rats. Cytochrome P450 aromatase (P450arom) has been
immunolocalized in germ cells of the rodent, bear, and rooster. Our purpose was
to investigate expression of and to immunolocalize P450arom in adult rat
testicular cells. After Western blotting with a specific anti-cytochrome P450arom
antibody, we demonstrated the presence of a 55-kDa protein in mature rat
seminiferous tubules and crude germ cell preparations. Immunoreactive aromatase
was detected both in cultured rat Leydig cells and in testis sections
(interstitial tissue and elongated spermatids showed positive immunoreactivity
for P450arom). We next used reverse transcription-polymerase chain reaction to
localize and quantify the P450arom mRNA in the various testicular cells. In rat
Leydig cells, the amount of P450arom mRNA was 15 times higher than in Sertoli
cells (34.1+/-3.2 to 2.3 +/-0.2 x 10(-3) amol/10(6) cells, respectively). In
pachytene spermatocytes, round spermatids, and testicular spermatozoa the
P450arom mRNA levels were 38.7+/-8.1, 20.4+/-3.8, and < 1.3 x 10(-3) amol/10(6)
cells, respectively. The aromatase activity was 2.5-4 times higher in testicular
spermatozoa (8.48+/-1.98 fmol/10(6) cells per hour) than in other germ cells.
These results indicate that in mature rats, not only Leydig cells and Sertoli
cells but also germ cells have the capacity to express functional P450arom.
According to the germ cell maturation state, there was an inverse relationship
between P450arom mRNA content and the biological activity of the protein. The
expression of the functional P450arom in mature rat germ cells confirms the
existence of an additional source of estrogens within the genital tract of the
male.
PMID- 9546722
TI - Immunoregulatory activity in adult rat testicular interstitial fluid: roles of
interleukin-1 and transforming growth factor beta.
AB - Studies on the effect of rat testicular interstitial fluid (IF) on T-cell
function have reported both stimulatory and inhibitory actions. Specific
cytokines produced within the testis, particularly interleukin-1 (IL-1) and
transforming growth factor beta (TGFbeta), may contribute to these apparently
conflicting observations. In proliferation assays employing lectin- or antibody
activated thymocytes or mature T cells in vitro, adult rat testicular IF
stimulated T-cell activation and/or proliferation at low assay doses and was
inhibitory at higher doses. The stimulatory activity was blocked by recombinant
IL-1 receptor antagonist. The inhibitory activity was not affected by a
polyspecific TGFbeta antiserum. The biological characteristics of the inhibitor
were distinct from those of a similar, but considerably less potent, activity in
platelet-depleted serum. These data demonstrate that rat testicular IF contains
biologically significant concentrations of IL-1 but has a predominantly
inhibitory action on T-cell responses. The factor predominantly responsible for
this inhibitory activity displays a relatively large apparent molecular weight,
is protease sensitive and partially heat labile, but does not appear to be one of
the known mammalian TGFbeta isoforms.
PMID- 9546723
TI - Immunoregulatory activity in adult rat testicular interstitial fluid:
relationship with intratesticular CD8+ lymphocytes following treatment with
ethane dimethane sulfonate and testosterone implants.
AB - Regulation of T-cell traffic and function in the adult rat testis was assessed
following treatment with the specific Leydig cell cytoxin, ethane dimethane
sulfonate (EDS), and s.c. testosterone implants to prevent Leydig cell recovery.
The distribution of T-cell subsets in the testis was determined
immunohistochemically using stereological techniques. Testicular T cell
inhibiting activity in the interstitial fluid was measured using a
phytohemagglutinin-activated rat thymocyte proliferation bioassay. The mostly
cytotoxic CD8+ T-cell subset predominated over the CD4+ (regulatory) T-cell
subset in the normal rat testis. Destruction of the Leydig cells caused a rapid
preferential increase in testicular CD4+ T cells, which was followed by an
increase in both the CD8+ subset and T cell-inhibiting activity in the Leydig
cell-deficient testis. After Leydig cell recovery, there was a significant shift
toward the CD8+ T-cell subset in the EDS-treated testis but not in the EDS
treated/testosterone-implanted testis. Total T-cell numbers and inhibitory
activity in the testis returned to control levels regardless of whether the
Leydig cells were allowed to recover. The level of inhibitory activity was
closely related to the number of CD8+ T cells in the testis across all
experimental groups, but it showed no relationship with pituitary hormones,
macrophage numbers, or intratesticular testosterone levels. The data suggest that
1) cytotoxic lymphocytes have a potentially significant role in testicular
function and 2) T cell-inhibiting activity in the testis interstitium is not
substantially affected by changes in pituitary hormones or Leydig cell function,
but appears to be related to local changes in immune activity.
PMID- 9546724
TI - Characterization of lymphocytes in the adult rat testis by flow cytometry:
effects of activin and transforming growth factor beta on lymphocyte subsets in
vitro.
AB - The rat testis is considered to be an immunologically privileged site because of
its reduced capacity to support antigen-specific immune responses. To understand
this phenomenon, it is essential to characterize both the lymphocyte
subpopulations normally present in the testis and their regulation by testicular
cytokines. Peripheral blood was obtained from adult male Dark Agouti or Sprague
Dawley rats, and testicular interstitial tissue was collected after perfusion of
the testes to remove blood. Blood and testis lymphocytes were isolated using
discontinuous Percoll density gradients, and the testicular lymphocytes were
further purified by selective adherence to remove mononuclear phagocytes. The
isolated lymphocytes were analyzed by flow cytometry using specific monoclonal
antibodies and fluorescein labeling and were enumerated as total T cells, CD4+ T
cells, CD8+ T cells, B cells, and natural killer (NK) cells. In contrast to
peripheral blood, in which the CD4+ T-cell subset was the major lymphocyte
subset, rat testis T cells were predominantly of the CD8+ subset, and a large
population of NK cells also were present. Subsequently, peripheral blood
lymphocytes were stimulated with the polyclonal T-cell activator,
phytohemagglutinin, and cultured in the presence of activin, inhibin, or
transforming growth factor beta (TGFbeta) prior to flow cytometric analysis.
Activin and TGFbeta suppressed T-cell proliferation without any selective effect
on either T-cell subset, and inhibin had no effect. The predominance of CD8+ T
cells and NK cells, and the relatively minor proportion of CD4+ T cells, are
consistent with both increased cellular immune surveillance and a reduced
capacity for initiating antigen-specific immune responses in the adult rat
testis.
PMID- 9546725
TI - Developmental consequences of karyokinesis without cytokinesis during the first
mitotic cell cycle of bovine parthenotes.
AB - Bovine parthenogenetic embryos and bovine embryos produced by in vitro
fertilization were compared for chromosomal complement and developmental
potential. Oocytes (n = 1885) were matured in vitro, fertilized (n = 1151) or
activated (n = 734) by exposure to 5 microM ionomycin for 4 min, and then treated
with 1.9 mM 6-dimethylaminopurine for 5 h to inhibit protein kinase functions and
promote mitosis. Mean cleavage rates at 48 h were 76.3+/-4.7% for fertilization
and 60.1+/-4.2% for activation (p < 0.05). A similar percentage of embryos had
reached the blastocyst stage on Day 8 post fertilization/postactivation (16.4+/
3.3%) and (15.8+/-1.0%), respectively. Blastocysts (n = 53) produced by in vitro
fertilization had higher total cell numbers (116.9+/-5.5) than parthenotes (n =
71, 67.2+/-3.5 cells, p < 0.05). Differential staining indicated a significant
reduction in the number of blastomeres allocated to both the inner cell mass and
trophectodermal lineages in parthenotes (p < 0.05). All parthenotes (n = 65) were
polyploid or mixoploid, with observed karyotypes of 4n (61.53%), 2n/4n (30.76%),
2n/8n (4.61%), and 3n (3.07%). In contrast, only 9 control blastocysts (n = 53)
revealed abnormal metaphases (16.9%). At 6 h postactivation (hpa), 70.7% of
parthenotes (n = 65) demonstrated a fully formed pronucleus; and at 10 hpa (n =
86), 89% had completed pronuclear formation. Pronuclear DNA replication was
observed by 6 hpa and resulted in the formation of a second pronucleus in 76.9%
of activated oocytes (n = 104) by 24 hpa. These pronuclear kinetics lead to a
high number of embryos with binucleate blastomeres upon cleavage. Thus,
alterations in the DNA content (ploidy) of bovine parthenogenetic blastocysts
reflect ongoing karyokinesis without cytokinesis during the first mitotic cell
cycle after exposure to a protein kinase inhibitor.
PMID- 9546726
TI - Spatial and temporal patterns of expression of cellular retinol-binding protein
and cellular retinoic acid-binding proteins in rat uterus during early pregnancy.
AB - Retinoic acid, perhaps the most potent hormonal form of the naturally occurring
retinoids (retinol and derivatives), is required in vivo for the maintenance of
normal pregnancy and embryo development. However, little is known about the
specific sites of action and metabolism in the uterus during pregnancy. In this
study we describe the pattern of temporal and cell-specific expression of
cellular retinol-binding protein (CRBP) and cellular retinoic acid-binding
proteins type I and type II (CRABP and CRABP[II], respectively) in the rat uterus
during the periimplantation period (Day 1 to Day 7 of pregnancy; Day 1 = presence
of vaginal plug). Immunohistochemical studies showed that there were dramatic and
rapid changes in expression pattern of the retinoid-binding proteins after mating
as early as Day 1, as well as a differential expression of these proteins when
the mesometrial side and antimesometrial side of the uterus were examined during
the periimplantation period. CRABP(II), whose presence has been previously shown
to correlate with retinoic acid synthesis in the uterine epithelium, was
specifically localized to the luminal epithelium at Day 1, being stronger on the
mesometrial side, and then fell to lower levels. CRBP was also expressed in the
luminal epithelium on the mesometrial side at Day 1 as well as in some stromal
cells, declining at these sites over the next several days. CRABP was localized
to some of the stromal cells at Day 1, overlapping CRBP expression. Embryonic
implantation was accompanied by the appearance of CRBP and CRABP(II) in the
decidual cells. CRBP and CRABP were also present in both smooth muscle layers of
the uterus. The changes in the temporal and cell-specific distribution of
retinoid-binding proteins imply a multifunctional role of vitamin A in uterine
cell proliferation, differentiation, and embryonic implantation. The presence of
CRABP(II) suggests that local generation of retinoic acid is important in these
processes.
PMID- 9546727
TI - Morphine inhibits nocturnal oxytocin secretion and uterine contractions in the
pregnant baboon.
AB - Morphine is a potent inhibitor of nocturnal uterine contractions (UCs) in the
pregnant baboon, and these contractions are known to be induced by oxytocin (OT).
The purpose of this study was to determine the mode of action of morphine in
inhibiting nocturnal UCs by examining the effect of morphine on OT secretion, OT
clearance, and uterine responsiveness to OT. A tethered pregnant baboon model
during the last third of gestation was used for these experiments. In study 1,
the effects of morphine or control saline on OT release and on spontaneous
nocturnal UCs were examined. Study 2 determined the effects of morphine or
control saline on the pharmacokinetics of OT after a bolus injection of OT. To
exclude/include direct opiate effects on UCs, study 3 examined the responsiveness
of the uterus to exogenous OT after morphine or control saline administration.
Plasma OT levels were analyzed by RIA after extraction. UCs were assessed by
frequency, amplitude, duration, and area under the curve. During nocturnal UCs,
morphine, but not saline, administration resulted in the precipitous suppression
of integrated OT levels (p < 0.05) to 42% of pretreatment values at 0-15 min
postinjection and 17% at 30-45 min. Simultaneously, UCs were significantly
suppressed (p < 0.05) by 75% at the 30- to 45-min interval. By 1 h, 5 of 7
animals showed no UCs. In study 2, morphine consistently increased the metabolic
clearance rate (MCR) of OT in all trials (p < 0.05), although the magnitude of
this effect was small (median 9%). Finally, study 3 demonstrated that myometrial
responsiveness to the challenge of exogenous OT was not depressed by opiate
administration (p > 0.05). To summarize, the decrease in nocturnal UCs after
morphine is primarily due to an inhibition of OT release, and perhaps, but to a
much lesser extent, an increase in OT MCR. There was no evidence of a direct
tocolytic effect of morphine on the uterus. In conclusion, opioids such as
morphine are potent inhibitors of nocturnal UCs and act by suppressing OT release
in the pregnant baboon.
PMID- 9546728
TI - Relaxin inhibits the pulsatile release of oxytocin but increases basal
concentrations of hormone in lactating rats.
AB - The effects of porcine relaxin were examined in urethane-anesthetized, lactating
rats to clarify the actions of relaxin on basal levels and the pulsatile release
of oxytocin during suckling. Baseline plasma oxytocin concentrations were 27.6+/
2.9 pM in unsuckled rats. They were significantly increased in rats after the
onset of suckling (34.5+/-2.4 pM) compared with unsuckled animals. Oxytocin
concentrations were increased further during reflex milk ejection (41.2+/-2.7
pM). Treatment with porcine relaxin (5 microg in 0.1 ml saline) caused a
significant (p < 0.05) increase in plasma oxytocin compared with pretreatment
concentrations or saline injection in all three groups. Frequent blood samples
were taken before and during milk ejection to confirm pulsatile oxytocin
associated with reflex milk ejection. Short-lived (5-10-sec) pulses with peak
concentrations of oxytocin 392.4+/-122.1 pM were observed shortly before or at
the time of the peak rise in intramammary pressure associated with reflex milk
ejection. Relaxin (5 microg i.v.) completely suppressed the pulsatile release of
oxytocin. These data suggest that relaxin increases basal secretion of oxytocin
but inhibits the pulsatile secretion associated with reflex milk ejection.
PMID- 9546729
TI - Functional studies of human decidua in spontaneous early pregnancy loss: effect
of soluble factors and purified CD56+ lymphocytes on killing of natural killer-
and lymphokine-activated killer-sensitive targets.
AB - Inappropriate leukocyte activation and disturbance of the delicate cytokine
balance within the uterus during early human pregnancy may initiate spontaneous
abortion. The purpose of the present study was to assess whether decidual soluble
factors from women suffering sporadic spontaneous early pregnancy loss could
enhance the cytotoxic activity of peripheral blood lymphocytes (PBL), and to
investigate the lytic activity of endometrial granulated lymphocytes (eGL)
purified from decidua against natural killer (NK)- and lymphokine-activated
killer (LAK)-sensitive targets. Decidual cell culture supernatants from sporadic
spontaneous abortion cases did not have any effect on PBL cytotoxic activity
against the NK-sensitive target cells K562. Endometrial GL purified from decidua
of spontaneous aborters were unable to lyse the LAK-sensitive target cells Raji
and, in contrast with eGL from decidua of first-trimester therapeutic aborters,
approximately 50% of the cases also failed to kill K562 cells. These results do
not provide evidence to implicate either cell-mediated or cytokine-mediated
cytolytic mechanisms in early spontaneous pregnancy loss, thus strengthening the
possibility that other damaging effects are operating. Nevertheless, the
deficient cytotoxic activity in a proportion of spontaneous abortion decidua
merits further investigation.
PMID- 9546730
TI - Endometriotic lesions synthesize and secrete a haptoglobin-like protein.
AB - To explore the identity and possible function of endometriosis protein-I (ENDO
I), which is an acidic glycoprotein synthesized and secreted by endometriotic
lesions, partial amino acid sequence and cDNA sequence were determined. Partially
purified, de novo-synthesized rat endometriosis glycoproteins were separated by
two-dimensional SDS-PAGE, transferred to polyvinyl difluoride membranes, and
stained with Coomassie blue. Protein corresponding to the size and pI of ENDO-I
was cut from the membranes and analyzed by automated Edman degradation. ENDO-I
amino acid sequence analysis identified 15 residues that shared significant
homology with the beta-chain of rat, mouse, and human haptoglobin (Hp) and human
Hp-related protein. Western blot analyses using anti-Hp antibody demonstrated
cross-reactivity with de novo-synthesized ENDO-I protein in endometriosis culture
media. For nucleotide sequence analysis, poly A-enriched mRNA was isolated from
rat endometriotic tissues. A gene-specific oligonucleotide primer was designed
and used for 3' rapid amplification of cDNA ends (RACE). Automated sequencing of
RACE cDNA fragments identified 859 base pairs, of which 858 were identical to rat
Hp. Reverse transcription-polymerase chain reaction was used to demonstrate that
ENDO-I transcripts are differentially expressed by endometriosis but not by
uterine tissues. In the human, distinct subtypes of Hp as well as proteins
sharing epitopes with Hp have been used to diagnose a variety of diseases;
therefore, Hp-like ENDO-I may prove to be a nonsurgical diagnostic tool to assess
endometriosis. Hepatic Hp, induced by acute-phase stimuli, modulates macrophage
function and angiogenic activity. If ENDO-I possesses similar activities, it may
be involved with anomalies of the immune system or the etiology and
pathophysiology of endometriosis.
PMID- 9546732
TI - Expression of intercellular adhesion molecule-1 messenger ribonucleic acid and
protein in human term placental cells and its modulation by pro-inflammatory
cytokines (interleukin-1beta and tumor necrosis factor alpha).
AB - Intercellular adhesion molecule-1 (ICAM-1) is a ligand for the integrins
lymphocyte function-associated antigen-1 (LFA-1) and complement receptor-3 (Mac
1), making it an important participant in many immune and inflammatory processes.
Previous studies suggested that lack or reduced expression of ICAM-1 on
trophoblast might partially explain its resistance to lysis by cytotoxic
effectors. However, whether or not the adhesion molecule is expressed on
placental cells is still a matter of debate. In this study, we determined ICAM-1
expression at mRNA, surface, and soluble protein levels on human trophoblasts
throughout their functional differentiation in culture from cytotrophoblasts into
syncytiotrophoblasts. Placental cells were obtained from 6 term placentas derived
from normal pregnancies. ICAM-1 mRNA was detected by reverse transcription
polymerase chain reaction using two oligonucleotide primers specific for the
human ICAM-1 gene. A single major DNA band of the expected size (943 base pairs)
was obtained in both cytotrophoblasts and syncytiotrophoblasts. Flow cytometric
analysis demonstrated expression of surface ICAM-1 protein on 45.5+/-3.5% of
cytotrophoblasts. No changes were observed during differentiation in culture.
Levels of the soluble form of ICAM-1 (sICAM-1) released by placental cells were
undetectable when assessed by a specific ELISA. Finally, we investigated the
effect of pro-inflammatory cytokines on placental ICAM-1 expression. Treatment of
cultured trophoblasts for 24 h with interleukin-1beta (1 ng/ml) or tumor necrosis
factor alpha (1 ng/ml) increased surface expression of ICAM-1 without inducing
sICAM-1 shedding. However, on placental cells, the two cytokines exerted
stimulatory effects lower than those detected on endometrial cells used as
positive control. These observations document that the ICAM-1 gene is expressed
in both cytotrophoblasts and syncytiotrophoblasts, suggesting that the molecule
may be of value for some immune-mediated processes. On the other hand, the low
sensitivity of trophoblasts to cytokine-mediated induction of ICAM-1 expression
might represent a functional mechanism contributing to maternal tolerance for
fetal graft.
PMID- 9546731
TI - Apoptosis, bcl-2 expression, and proliferative activity in human endometrial
stroma and endometrial granulated lymphocytes.
AB - Human endometrial leukocytes undergo regular cyclical changes during the
menstrual cycle, with a striking increase in the phenotypically unusual
population of CD56+ CD16- endometrial granulated lymphocytes (eGLs) in the late
secretory phase and early pregnancy. The factors that regulate this increase in
eGL numbers are unclear; their unusual morphology, however, has led to the
suggestion that they undergo apoptosis at the end of the menstrual cycle.
Apoptosis, bcl-2 expression, and proliferative activity were examined in the
stroma of normal cycling, progesterone-treated, and early-pregnancy endometrium.
The expression of bcl-2 and the Ki67 proliferation marker by highly purified (>
98% CD56+) eGLs from endometrium during the menstrual cycle and from first
trimester decidua was also studied. Apoptotic cells were rarely observed in the
endometrial stroma of any of the samples examined. Stromal bcl-2 expression,
however, increased from the proliferative to the premenstrual phase, and double
immunohistochemical labeling demonstrated large numbers of bcl-2+ CD56+ eGLs. In
contrast, Ki67 expression was high in the endometrial stroma during the
proliferative phase, fell during the secretory phase, and rose again
premenstrually, because of expression by eGLs. Isolated CD56+ eGLs also showed
high bcl-2 and Ki67 expression at the end of the menstrual cycle. Unlike
premenstrual endometrium, progesterone-treated endometrium and first-trimester
decidua contained few proliferating cells, expressed high levels of bcl-2, and
showed no evidence of apoptosis. Thus, eGLs do not undergo apoptosis in
premenstrual endometrium, and their regulatory mechanisms remain to be clarified.
PMID- 9546733
TI - Ovary-independent estrogen receptor expression in neonatal porcine endometrium.
AB - Effects of age and ovariectomy (OVX) at birth on uterine growth, endometrial
development, and estrogen receptor (ER) expression were determined for intact and
OVX gilts (n = 5 per day) hysterectomized on postnatal days (PND) 0, 15, 30, 60,
90, or 120. Uteri were evaluated histologically, and ER protein and mRNA
expression were characterized immunohistochemically and by in situ hybridization.
OVX did not affect uterine weight or endometrial thickness until after PND 60,
when both increased more rapidly in intact gilts. Neither did it affect genesis
of uterine glands, which were present and which proliferated after PND 0, or
endometrial ER expression patterns in glandular epithelium (GE), luminal
epithelium (LE), or stroma (S) between PND 0 and 120. Endometrium was ER negative
at birth. On PND 15, the ER signal was strong in GE, weak in S, and effectively
absent in LE. Thereafter, although the ER signal remained strong in GE and
increased through PND 60 in S, it was not evident consistently until after PND 30
in LE. The data indicate that 1) porcine uterine growth and endometrial
morphogenesis are ovary-independent processes before PND 60; 2) uterine gland
genesis is associated temporally with development of ER-positive endometrial GE
and S; and 3) regulation of endometrial ER expression is ovary independent
between PND 0 and 120. The results establish the ER as a marker of GE
differentiation and implicate this receptor in mechanisms regulating endometrial
morphogenesis in the neonatal pig.
PMID- 9546734
TI - Regulation of anion secretion by prostaglandin E2 in the mouse endometrial
epithelium.
AB - The present study was an investigation of the regulation of anion secretion
across cultured mouse endometrial epithelium by prostaglandin E2 (PGE2) using the
short-circuit current (ISC) technique. The cultured endometrial monolayers
responded to both apical and basolateral application of PGE2 with a sustained
rise in ISC in a concentration-dependent manner. However, the potencies of apical
and basolateral addition of PGE2 were different, with apparent EC50 of 200 and 4
nM, respectively. Replacement of Cl- or HCO3- in the bathing solution
significantly reduced the ISC responses to both apical and basolateral addition
of PGE2; however, the apical response exhibited greater dependence on HCO3- .
Pretreatment with diphenylamine 2,2'-dicarboxylic acid, a Cl- channel blocker,
significantly reduced both PGE2-induced ISC responses, while pretreatment with
amiloride, a Na+ channel blocker, did not exert any effect. Forskolin, an
adenylate cyclase activator, and 3-isobutyl-dihydro-testosterone-1-methyl
xanthine, a cAMP phosphodiesterase inhibitor, mimicked the ISC response to PGE2
while MDL12330A, an adenylate cyclase inhibitor, completely abolished the PGE2
induced ISC. The results of the present study indicate that the anion secretion
across the mouse endometrial epithelium may be regulated by PGE2 involving a cAMP
dependent mechanism predominantly. The differential responses to apical and
basolateral challenge with PGE2 also suggest that PGE2 of different origins may
play different roles in uterine function.
PMID- 9546735
TI - Intrauterine infusion of high doses of pig trophoblast interferons has no
antiluteolytic effect in cyclic gilts.
AB - In the pig species, the preimplanting trophoblast is known to synthesize and
secrete high amounts of interferon during early development. Previous experiments
in cyclic gilts using total conceptus secretory proteins suggested that porcine
trophoblastic interferons, unlike those of ruminants, exert no effect on the
luteal cycle. In the present experiment, cyclic Meishan gilts were divided into
two groups, cannulated on both uterine horns, and given daily injections of
either a placebo or increasing doses of a mixture of recombinant interferon-gamma
and interferon-delta, on Days 11-14 of the estrous cycle. In treated gilts, the
injected doses were much higher than those previously found in uterine perfusates
from pregnant gilts. However, no significant differences could be found between
the control (n = 4) and the treated (n = 5) group concerning the days of the
estrous cycle for mid-decrease of progesterone (control: Day 14.5+/-0.57 [mean+/
SD]; treated: Day 15+/-1.25), the day of estrus (control: Day 19+/-0.96; treated:
Day 19.6+/-0.55), and the subsequent ovulation rate (control: 14+/-2.2 corpora
lutea; treated: 13.1+/-1.1 corpora lutea). These data confirm that pig
trophoblastic interferons, unlike those of ruminants, do not themselves exert an
antiluteolytic effect. A possible synergistic effect of embryonic estrogens on
the luteal functions of nonpregnant sows remains to be determined.
PMID- 9546736
TI - Prostaglandin F2alpha-induced luteolysis of aging corpora lutea in
hysterectomized pigs.
AB - Prostaglandins primarily of uterine origin play an important role in parturition.
Hysterectomy of nongravid pigs early in the luteal phase maintains luteal
function until about Day 150, whereas the duration of normal pregnancy is about
114 days. A precisely timed peak release of relaxin and coincident decrease in
progesterone secretion in unmated hysterectomized gilts are similar to hormonal
changes that occur a few hours before parturition. It is hypothesized that
prostaglandin F2alpha (PGF2alpha) in hysterectomized pigs mimics abrupt changes
in ovarian and pituitary hormone secretion seen before normal parturition and in
early lactation. Unmated Yorkshire gilts were hysterectomized on Days 6-8 of a
normal estrous cycle, and at 1200 h on Day 113, they were given an i.m. injection
of 30 mg PGF2alpha-trihydroxymethylaminomethane (THAM) salt or PBS. None of these
gilts expressed behavioral estrus immediately after PGF2alpha or vehicle
treatment. On Day 113, PGF2alpha increased peak relaxin (60 ng/ml) compared with
that of controls (34 ng/ml; p < 0.01), whereas progesterone decreased abruptly (4
vs. 16 ng/ml in PGF2alpha and PBS; p < 0.01). Prolactin remained at < 5 ng/ml
from Day 98 to 120 in controls but peaked at 33 ng/ml immediately after PGF2alpha
treatment on Day 113, and then decreased to levels similar to those of controls
on Day 120. Sequential bleeding revealed an acute growth hormone release (4.5
ng/ml) immediately after PGF2alpha injection and return to basal levels (< 0.6
ng/ml) on Days 114-120. PGF2alpha induced abrupt shifts in progesterone, relaxin,
prolactin, and growth hormone secretion in hysterectomized gilts that mimicked
hormone changes seen in late pregnancy, parturition, and early lactation. These
findings provide new insight into the role of PGF2alpha in abruptly changing
hormone secretions by aging corpora lutea and the pituitary gland even in the
absence of conceptuses or the uterus in the pig.
PMID- 9546737
TI - Effects of dialyzing gamma-aminobutyric acid receptor antagonists into the medial
preoptic and arcuate ventromedial region on luteinizing hormone release in male
sheep.
AB - We investigated the effects of microdialyzing alpha-aminobutyric acid (GABA)
receptor antagonists into either the medial preoptic area (mPOA) or the arcuate
ventromedial region (ARC-VMR) on LH secretion. Bicuculline methiodide (BMI,
GABA(A) receptor antagonist), and either 2-hydroxysaclofen (SAC) or CGP 55845A
(CGP, GABA(B) receptor antagonists) were used. In experiment 1, castrated rams
received 4-h dialysis into either the mPOA (n = 5) or ARC-VMR (n = 4) of
artificial cerebrospinal fluid (aCSF) followed by 4 h of either BMI (aCSF-BMI,
375 microM in mPOA, 1 mM in the ARC-VMR for 2-1/2 h), or aCSF-SAC (5 mM). In
experiment 2, castrated rams received dialysis only in the ARC-VMR (n = 5) of
aCSF-aCSF, aCSF-BMI (375 microM), or aCSF-CGP (50 microM). In experiment 3,
untreated or testosterone (T)-treated castrated rams (n = 6/group) received
dialysis only in the ARC-VMR of aCSF-aCSF, aCSF-BMI (375 microM), or aCSF-CGP
(500 microM). Jugular blood was collected at 10-min intervals. In experiment 1,
BMI suppressed mean plasma LH (p < 0.05) and increased interpulse interval (IPI,
p < 0.05) at both sites. In experiment 2, BMI significantly reduced mean LH and
increased IPI (p < 0.01). In experiment 3, BMI reduced mean LH in both the
presence (p < 0.05) and absence of T (p < 0.01) and increased IPI (p < 0.01) in
the absence of T. SAC, CGP, and aCSF did not affect LH in any experiment. These
results show that dialysis of BMI, into either the mPOA or the ARC-VMR of either
castrated or T-treated castrated rams decreased LH release, whereas dialysis of
GABA(B) antagonists at these sites was without detectable effect.
PMID- 9546738
TI - Identification of cigarette smoke components that alter functioning of hamster
(Mesocricetus auratus) oviducts in vitro.
AB - Previous studies have shown that solutions of mainstream and sidestream cigarette
smoke decrease both ciliary beat frequency and oocyte cumulus complex pick-up
rate of hamster oviducts in vitro. The purpose of this study was to identify the
component(s) in smoke that produces these effects. Chemicals reported to be
ciliotoxic in other systems were tested on hamster infundibula at various
concentrations to determine whether a dose-response inhibition of ciliary beat
frequency occurred. In addition, the concentration of each test component was
measured in mainstream and sidestream smoke solutions (whole, particulate, and
gas phase). All test components (acrolein, formaldehyde, phenol, acetaldehyde,
and potassium cyanide [KCN]) inhibited ciliary beat frequency in a dose-dependent
manner. Inhibition of ciliary beat frequency was at least partially reversible
for all test compounds except acrolein. The concentrations of acrolein,
formaldehyde, and phenol that were required to inhibit beat frequency were at
least 3-50 times higher than their corresponding concentrations in smoke
solutions. In contrast, cyanide was present in all smoke solutions at
concentrations sufficient to inhibit ciliary beat frequency. Cilia on the outer
surface of the infundibulum function in picking up the oocyte cumulus complex.
Oocyte cumulus complex pick-up rate was measured in vitro at KCN concentrations
shown to inhibit ciliary beat frequency. Pick-up rate was likewise inhibited by
KCN and remained significantly depressed after washout of KCN. These data show
that cyanide is a potent inhibitor of both ciliary beat frequency and oocyte
cumulus complex pick-up rate and that its concentration in smoke solutions is
sufficiently high to explain the previously reported inhibition of these
oviductal processes.
PMID- 9546739
TI - Metabolism of pyruvate by the early human embryo.
AB - Pyruvate is added to all media used for human in vitro fertilization and embryo
culture, but its function(s) in the early embryo is unknown. We tested the
possibility that pyruvate can act as an oxidizable energy source by measuring the
consumption of pyruvate and oxygen by Day 2 and Day 3 human embryos, using
microfluorometric techniques. Oxygen consumption (19.6 pmol/embryo per hour)
could account for the oxidation of only 56% of the pyruvate consumed (13.9
pmol/embryo per hour). Oxygen was also consumed in the absence of exogenous
substrates. Lactate appeared in the incubation medium with pyruvate (0.47 mM) as
sole exogenous substrate at a rate of 12.1 pmol/embryo per hour, at a similar
rate (10.85 pmol/embryo per hour) in the presence of 1 mM glucose and 0.47 mM
pyruvate, and at 2.25 pmol/embryo per hour in the absence of exogenous
substrates, suggesting that a high proportion of the pyruvate taken up by early
human embryos is converted to lactate. Pyruvate uptake in the presence of UK5099,
a pyruvate transport inhibitor, was reduced to 10% of control values, consistent
with the presence of the monocarboxylate carrier in the human embryo plasma
membrane.
PMID- 9546740
TI - Molecular cloning and characterization of P47, a novel boar sperm-associated zona
pellucida-binding protein homologous to a family of mammalian secretory proteins.
AB - P47, a peripherally associated 47-kDa protein of porcine spermatozoa, was
identified by affinity chromatography in the fraction of solubilized plasma
membrane proteins bound to immobilized porcine zona pellucida glycoproteins. N
terminal and internal amino acid sequences revealed structural similarity between
P47 and rat O-acetyl ganglioside synthase, bovine mammary gland protein
(MGP)57/53 and mouse milk fat globule protein E8-polypeptides of unknown function
secreted by mammary gland epithelial cells in both species. A polyclonal antibody
directed against bovine MGP57/53 displayed cross-reactivity with P47. Indirect
immunofluorescence analysis located porcine P47 on the acrosomal cap of
testicular sperm and on sperm recovered along different sections of the ductus
epididymidis, as well as on swim-up and in vitro-capacitated sperm. Porcine P47
was demonstrated on sperm bound to the zona pellucida of a homologous oocyte.
Western blot analysis identified P47 (or MGP57/53) homologous proteins in porcine
and human milk. Like the sperm-associated protein, porcine milk P47 possesses
affinity for isolated, biotinylated sow oocyte zona pellucida glycoproteins.
Reverse transcription-polymerase chain reaction was used to isolate P47
homologous cDNAs from porcine testis and mammary gland tissues as well as from
bovine, mouse, and human testis. P47 proteins deduced from these cDNA sequences
showed 60-100% amino acid sequence identity. These proteins display a mosaic
structure organized into two N-terminal, tandemly arranged epidermal growth
factor (EGF)-like domains followed by a region with similarity to C1 and C2
domains found in blood clotting factors V and VII. The second EGF-like domain
contains an arginine-glycine-aspartic acid sequence, a motif often found in
integrin receptor ligands. P47-like proteins are not expressed solely in
testicular and mammary gland tissues. Northern blot analysis showed that P47 mRNA
is transcribed in several porcine and bovine tissues. These data indicate a
potential role for boar sperm-associated P47 in membrane remodeling and/or as a
zona pellucida binding protein.
PMID- 9546741
TI - Fetal and maternal endocrine changes approaching parturition in the goat: lack of
evidence for prostaglandins E2 and F2alpha as signals for luteolysis.
AB - We investigated the temporal relationship of fetal cortisol secretion to
circulating concentrations of fetal ACTH1-39 and its high-molecular weight
precursors in goats. We also measured the concentrations of progesterone,
estradiol-17beta estrone sulfate, prostaglandin (PG) E, PGF2alpha, and PGF2alpha
metabolite (PGFM) in maternal arterial plasma over the last month of gestation.
Prostaglandin concentrations were also measured in utero-ovarian venous plasma.
There was a positive association between ACTH1-39 in fetal plasma and the
prepartum surge in fetal cortisol that commenced 8 days before labor. The fetal
cortisol surge was followed by a simultaneous decrease in maternal progesterone
and an increase in plasma estrogens commencing 3-4 days before labor. No change
in basal prostaglandin concentration occurred before this time. There was a
positive veno-arterial difference of PGE and PGF2alpha across the uterine
vascular bed, confirming the uteroplacental unit as a major source of these
eicosanoids in the plasma of the pregnant doe. We conclude that the fetal signal
for parturition precedes luteolysis by some 5 days and find no evidence of
changes in the basal concentrations of PGE and PGF2alpha in maternal plasma at
the time of luteolysis.
PMID- 9546742
TI - Cryopreservation and orthotopic transplantation of mouse ovaries: new approach in
gamete banking.
AB - Mouse half ovaries were cryopreserved and orthotopically transplanted into
ovariectomized recipients genetically identical to ovary donors except for the
coat color gene. Fertility was reestablished in 57% of the female recipients,
which became pregnant in an average of 40 days after transplantation of frozen
thawed half ovaries. These experiments demonstrate that ovary cryopreservation
can be a very useful option for banking mouse germplasm, or managing subfertile
animal colonies, when embryo or sperm freezing cannot be used or is not cost
effective.
PMID- 9546743
TI - Complementary expression of HIP, a cell-surface heparan sulfate binding protein,
and perlecan at the human fetal-maternal interface.
AB - The human hemochorial placenta is a structure formed by the invasion of
cytotrophoblasts into the uterus. Previous studies from our laboratory have
demonstrated a role for heparan sulfate proteoglycans (HSPGs) and their binding
proteins in interactions between human trophoblastic and uterine cell lines in
vitro. In this study, expression of both mRNA and protein of a novel, cell
surface, heparin/heparan sulfate interacting protein (HIP), by human
trophoblastic cell lines-i.e., JAR, JEG, and BeWo-and by human cytotrophoblast
was examined throughout gestation. Immunohistochemistry of the human fetal
maternal interface demonstrated abundant HIP expression in cytotrophoblast cells,
with lesser staining in syncytiotrophoblast and little or no staining in
surrounding stromal or decidual cells. Staining with antibodies to the basement
membrane HSPG, perlecan, demonstrated a pattern of staining complementary to that
of HIP. Cytotrophoblasts in the uterine stroma, not affiliated with attached
villi, displayed a less intense deposition of perlecan. In vitro binding studies
of 125I-perlecan to a 17-amino acid synthetic peptide sequence of HIP, which has
a high affinity and specificity for heparin/heparan sulfate, indicates that
perlecan binds to the HIP peptide with high affinity (KDapp = 0.6 nM) and in a
heparin-inhibitable manner. Furthermore, HIP antibodies inhibited by 61-88% in
vitro invasion by trophoblasts in assays using primary cultures of normal human
cytotrophoblasts. Consistent with this was the observation that
immunohistochemically detectable HIP expression was greatly reduced in pre
eclamptic cytotrophoblasts, a condition in which trophoblast invasion is
abnormally shallow. It is suggested that HIP potentiates human cytotrophoblast
interactions with HSPGs, in vivo, and facilitates trophoblast invasion processes.
PMID- 9546744
TI - Meiotic induction in cumulus cell-enclosed mouse oocytes: involvement of the
pentose phosphate pathway.
AB - In this study we tested the hypothesis that the pentose phosphate pathway (PPP)
participates in the meiotic induction of mouse oocytes. The electron acceptors
methylene blue, phenazine ethosulfate (PES), and pyrroline-5-carboxylate (P5C)
oxidize NADPH to NADP and activate the NADP-dependent enzymes of the PPP. Each of
these compounds triggered a dose-dependent increase in meiotic maturation in
hypoxanthine-arrested cumulus cell-enclosed oocytes during 17- to 18-h cultures.
More than 96% of the oocytes underwent germinal vesicle breakdown (GVB) at the
highest concentrations of P5C and PES tested (250 and 1 microM, respectively) as
compared to only 45-52% of control oocytes. P5C was also stimulatory to denuded
oocytes. Analysis of energy substrates in microdrop cultures revealed a 3.6-fold
increase in glucose consumption by PES-treated oocyte-cumulus cell complexes that
was associated with stimulation of GVB. On the other hand, 2-deoxyglucose, which
interferes with glucose utilization, prevented the induction of maturation
brought about by P5C. Apocynin and diphenyleneiodonium, inhibitors of NADPH
oxidase, prevented meiotic maturation in the presence or absence of FSH.
Gonadotropin-induced maturation was also prevented by 6-aminonicotinamide (6-AN)
and dehydroepiandrosterone (DHEA), inhibitors of the two NADP-dependent enzymes
of the PPP, and this was accompanied by suppression of glucose consumption.
Phosphoribosyl-pyrophosphate (PRPP) is an important compound required in purine
metabolism and can be formed from the end product of the oxidative arm of the
PPP, ribose-5-phosphate. Ribose, which can be metabolized to PRPP, increased PRPP
synthesis in complexes and induced meiotic maturation when added to hypoxanthine
arrested cumulus cell-enclosed oocytes in glucose-free medium in both the
presence and absence of FSH. PRPP levels within complexes were also increased by
glucose and FSH, but were reduced by hypoxanthine, 6-AN, and DHEA. In addition,
exogenous PRPP stimulated maturation in hypoxanthine-arrested oocytes. These
results support the proposition that glucose metabolism through the PPP is
important in the meiotic induction mechanism and may involve the generation of
PRPP that acts, at least in part, through the purine metabolizing pathways.
PMID- 9546745
TI - Silicosis in mice: effects of dose, time, and genetic strain.
AB - Experimental silicosis allows study of the mechanisms of lung injury,
inflammation, and fibrosis. Inbred mice are an attractive species in which to
study these mechanisms because of recent progress in murine immunology, molecular
biology, and genetics. We exposed mice to an aerosol of silica and examined the
effects of exposure dose, the evolution of disease features over time, and the
variation in responses among four inbred strains. In C3H/HeN mice incremental
cumulative exposure doses of cristobalite silica caused increased initial lung
dust burden 12 to 16 weeks post-exposure, progressively intense pathological
responses, and increased total lung collagen (hydroxyproline). The
histopathological changes and total lung collagen increased progressively over
time after exposure. We compared the features of silicosis in four strains of
inbred mice selected for common use or immunologic reactivity 16 weeks after
aerosol inhalation exposure to crystalline cristobalite silica (70 mg/m3, 5
hours/day, 12 days). C3H/HeN mice demonstrated histopathological silicotic
lesions and enlarged intrapulmonary lymphoid tissue, and increased lung wet
weight, bronchoalveolar lavage (BAL) recovery of macrophages, lymphocytes, and
neutrophils, and total lung collagen (hydroxyproline). BALB/c mice developed
slight pulmonary lesions; MRL/MpJ mice demonstrated prominent pulmonary
infiltrates with lymphocytes; New Zealand Black mice developed extensive alveolar
proteinaceous deposits, inflammation, and fibrosis. Our findings demonstrate
orderly dose-time-response relationships, and a substantial variation of
responses among inbred strains of mice. This model should prove valuable for
future experimental interventions into the mechanisms of silicosis.
PMID- 9546746
TI - Persistent overexpression of interleukin-1beta and tumor necrosis factor-alpha in
murine silicosis.
AB - The cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha
(TNFalpha), derived from macrophages and other cells, may promote mononuclear
cell inflammation and fibrosis in pulmonary silicosis. C3H/HeN mice were exposed
to control air or to an aerosol of 70 mg/m3 cristobalite silica for 5 h/d for 12
days and examined at 2 and 16 weeks after exposure. This exposure resulted in
murine silicosis, as manifested by focal mononuclear cell accumulations, diffuse
interstitial fibrosis, lymphoid tissue enlargement, recruitment of inflammatory
cells into BAL fluid, and increased total lung collagen. Semiquantitative reverse
transcription-polymerase chain reaction (RT-PCR) with designed primers and
membrane hybridization with biotinylated cDNA probes were used to assess the
abundance of IL-1beta and TNFalpha mRNA. In situ hybridization with digoxigenin
labeled cDNA probes was used to localize gene expression. Persistent
overexpression of both IL-1beta and TNFalpha were found at 2 and 16 weeks in the
lungs of silica-exposed mice compared with air-sham control mice. IL-1beta and
TNFalpha expression localized to individual mononuclear cells in the alveolar
spaces, groups of cells within the aggregate lesions, and scattered mononuclear
cells in BALT and lymphoid nodules. Thus, cells producing IL-1beta and TNFalpha
appear to be intimately associated with the evolving lesions of silicosis, and
the lymphoid tissue of the lung may be important in driving the pathogenesis of
this disease.
PMID- 9546747
TI - Effects of radiation on wound healing.
AB - The pathological changes of radiation on wound healing in rats were observed by
macroscopic, microscopic, and electronmicroscopic examination and detection of
collagen types. We found that the wound healing process was obviously delayed by
irradiation. First, the early phase inflammatory response was severely inhibited.
In particular, the number of infiltrating macrophages and neutrophils was
decreased, blood vessels were injured, and hemorrhage was evident. Second, the
formation and maturation of granulation tissue were slowed down, fibroblasts were
injured, and transcription of types and collagen mRNAs and synthesis and
secretion of collagen were reduced. Finally, the reepithelialization process was
delayed and the healing time was prolonged.
PMID- 9546748
TI - Overexpression of MDM2, p53, and NCAM proteins in human radiation-induced skin
ulcers.
AB - Using immunohistochemistry, we studied the overexpression of MDM2, p53, and NCAM
proteins in human radiation-induced skin ulcers. We found that the positive rate
of overexpression of MDM2, p53, and NCAM was 36%, 8%, and 32%, respectively. The
overexpression of MDM2 protein was mainly observed in the nuclei of fibroblasts
in the deeper part of the ulcer; that of p53 protein was in the nuclei of the
epidermis and in the cytoplasm of fibroblasts and endothelial cells, whereas that
of NCAM was located in the cytoplasm of squamous epithelial cells of the
epidermis and in fibroblasts, fibrocytes, endothelial cells, and leiomyocytes in
the media of arteriolar walls. The overexpression of MDM2, p53, and NCAM may be
related to the poor healing of radiation-induced skin ulcers and the cancer
transformation.
PMID- 9546749
TI - The changes and significance of c-kit expression in the irradiated bone marrow of
mice.
AB - There have been only a few studies on the expression of c-kit in bone marrow
after radiation and radiation-induced apoptosis of hematopoietic cells. LACA mice
were examined after irradiation with a dose of 60Co gamma-rays. Using a light
microscope, electron microscope, and immunohistochemistry, we studied radiation
induced apoptosis of hematopoietic cells and the expression of c-kit. We found
that 5.5 Gy total body irradiation was a sublethal dose for LACA mice, induced
suppression of leukocytes in blood, and of nucleated cells in bone marrow.
Apoptosis of the hematopoietic cells occurred within 1 day after irradiation. The
expression of c-kit was related to the recovery of hematopoiesis and played an
important role in early hematopoiesis.
PMID- 9546750
TI - Interleukin-3 gene expression in irradiated mouse bone marrow.
AB - The expression of endogenous interleukin-3 (IL-3) gene in mouse bone marrow after
whole body irradiation was assessed by immunocytochemistry, in situ hybridization
(ISH), and in situ reverse transcription PCR (IS RT-PCR). The results showed
obvious injury to the bone marrow followed by recovery 4 weeks after radiation.
IL-3 protein was increased in the cytoplasm of recovering hematopoietic cells,
especially at 21 days after radiation, while the mRNA was negative, except at 15
days when the mRNA was weakly positive by ISH. IS RT-PCR showed that IL-3 mRNA
was strongly positive in the cytoplasm of recovering hematopoietic cells,
especially at 10 to 15 days after radiation. We postulate that endogenous IL-3
gene may accelerate hematopoietic recovery in irradiated bone marrow and that IS
RT-PCR may objectively report the regulation of IL-3 gene expression.
PMID- 9546751
TI - Kinetic alterations of angiotensin-II and nitric oxide in radiation pulmonary
fibrosis.
AB - We studied the kinetic alterations of angiotensin-II (A-II) and nitric oxide (NO)
in radiation pulmonary fibrosis (RPF) to determine the roles of these two types
of vasoactive substances in the pathogenesis of RPF. We irradiated the right
hemithorax of male Wistar rats with single doses of 0, 15, and 30 Gy of 60Co
gamma rays and we examined the lung parenchyma at 1, 3, 5, and 7 months following
the radiation. The rats were killed at the stated intervals and samples were
obtained from the right lung. We measured types I and III procollagen mRNA by in
situ hybridization and demonstrated the synthesis and distribution of A-II in the
pulmonary tissue by immunohistochemistry. The formation and kinetic alterations
of types I and III collagen were analyzed under polarized light microscope using
Sirius Red stain. The hydroxyproline (Hyp) content was measured in the pulmonary
tissue after digestion with HCl. A-II radiation immunoactivity (RIA) was assayed
in pulmonary tissue homogenate. Pulmonary NO content, NO synthase (NOS), and the
angiotensin converting enzyme (ACE) activities were also measured. Our results
showed that types I and III collagen genes began to be expressed 1 month after
irradiation. Type I collagen gene increased significantly, reaching its peak 3
months after irradiation. As the irradiation dosage was increased from 15 to 30
Gy, the type I collagen gene content increased significantly, while type III
significantly decreased. The Hyp content increased with the passage of time after
irradiation. Pulmonary A-II RIA increased significantly with the dose of
irradiation and was chiefly produced by fibroblasts and macrophages in the
interstitium, bronchiolar epithelium, and the anteriolar wall. Pulmonary NO and
NOS activities decreased following irradiation. One month following irradiation,
the expression of the type I collagen gene begins to increase, with a significant
increase in both Hyp and type I collagen 3 months after irradiation. The
histogenesis of RPF may be related to A-II. The interstitial cells, the
bronchiolar epithelium, and the arteriolar wall can produce A-II and need not
pass through the ACE pathway. Our results suggest that the A-II increase and NO
decrease may have a role in the pathogenesis of RPF.
PMID- 9546752
TI - The protective action of taurine and L-arginine in radiation pulmonary fibrosis.
AB - Taurine has the ability to resist the action of oxygen-free radicals by
protecting cytomembranes. L-arginine increases the nitric oxide in the organism,
inhibiting some types of abnormal cell proliferation. We examined the actions and
protective mechanisms of these two substances against radiation pulmonary
fibrosis. The mRNA transcription and the distribution of pulmonary types I and
III procollagen were measured by in situ hybridization. Type I and type III
collagen in the interalveolar septa and the change ratio between the two types
were assayed using Sirius Red staining and polarizing microscopy. Angiotensin
converting enzyme (ACE), hydroxyproline (Hyp), malondialdehyde (MDA), and nitric
oxide (NO) were measured in lung tissue after irradiation. We found that,
following administration of taurine or arginine, the mRNA transcription of
procollagen types I and III significantly decreased in the pulmonary tissue 3
months after irradiation and the Hyp content was lower, especially after the
administration of arginine. The extent of the radiation-induced decrease in ACE
activity was markedly attenuated. As a substrate of NO production, arginine can
significantly increase the pulmonary NO content. We conclude that the
administration of taurine or arginine can significantly decrease the mRNA
transcription of procollagen and the synthesis of type I collagen in the
interalveolar septa and can decrease the Hyp content of the pulmonary tissue.
Following irradiation, NO can attenuate the radiation-induced decrease in ACE
activity. Our study suggests that exogenous NO and taurine significantly protect
against radiation pulmonary injury.
PMID- 9546753
TI - Preventive effects of selenium-enriched spiruline (SESP) on radiation
pneumonitis.
AB - We studied the early effects of selenium-enriched spiruline (SESP) on radiation
induced pulmonary fibrosis using histopathology, cDNA-mRNA dot-blot
hybridization, and a biochemical technique for quantifying the hydroxyproline
content. We found marked lung injury in the irradiated group, whereas only slight
hyperemia, hemorrhage, exudation, and thickness of the interalveolar wall in the
lung in the selenium-treated group. The hydroxyproline (hyp) content in the lungs
and the synthesis of type III collagen mRNA decreased in the SESP-treated group.
Selenium-enriched spiruline may have a protective effect on the development of
radiation pneumonitis.
PMID- 9546754
TI - Dursban revisited: birth defects, U.S. Environmental Protection Agency, and
Centers for Disease Control.
PMID- 9546755
TI - Measurement of nasal irritant sensitivity to pulsed carbon dioxide: a pilot
study.
AB - Nasal irritation and associated symptoms (e.g., nasal congestion, rhinorrhea,
sinus headache) are important air-pollution-related health complaints,
particularly in so-called problem buildings. Individual differences in nasal
irritant sensitivity are therefore of both clinical and regulatory interest. To
document such differences, one must first functionally define perceptual acuity
to airborne irritants. In an adaptation of an established sensory testing method,
the authors used the odorless irritant carbon dioxide in an electronically
controlled dilution apparatus to deliver brief (approximately 3 s) pulses at
controlled levels (10%-70%, vol/vol), synchronized with the inspiratory phase of
the respiratory cycle. Investigators who use this apparatus can use a variant of
the forced-choice paradigm for threshold determination to document nasal irritant
sensitivity. The authors recruited 30 adult volunteers (17 males, 13 females;
average age = 41 y, range = 19-79 y) from a university laboratory complex and
from the general community. Within this group, there was a skewed distribution of
carbon dioxide thresholds (arithmetic mean = 28%, geometric mean = 27%
[vol/vol]). In univariate analyses, geometric mean carbon dioxide thresholds
differed significantly with respect to smoking status (36% carbon dioxide in
smokers versus 25% in nonsmokers; p < .005), but not with respect to age, gender,
or self-reported history of allergic rhinitis. In a multivariate analysis, gender
also approached significance; females tended to show better perceptual acuity
than males (p = .06). Neither self-reported "vasomotor rhinitis" symptoms nor
self-reported symptomatic reactivity to environmental tobacco smoke predicted
carbon dioxide thresholds. Pulsed carbon dioxide is well tolerated by subjects
who participate in a threshold detection task; the procedure yields a potential
endpoint with which to compare individuals (and groups) with respect to nasal
irritant perceptual acuity. The relationship between such acuity and nasal
physiologic reactivity-as well as the generalizability of such measures to other,
more environmentally realistic irritants-has yet to be defined.
PMID- 9546756
TI - Maternal exposure to exogenous nitrogen compounds and complications of pregnancy.
AB - Increased lipid peroxidation and reduced antioxidant activity have been reported
with pregnancy complications. Given that exogenous oxidants stimulate formation
of lipid peroxides, the authors investigated the relationship between exposure to
nitrogen-oxidizing species and pregnancy complications and took into account
markers of antioxidant and oxidant status. The study sample included pregnant
women who were from an area polluted by oxidized nitrogen compounds.
Methemoglobin, a biomarker of individual exposure, was determined, as were
measures of oxidant/antioxidant status, including glutathione balance and lipid
peroxide levels. Only 10 women experienced normal pregnancies. The most common
complications were anemia (67%), threatened abortion/premature labor (33%), and
signs of preeclampsia (23%). Methemoglobin was elevated significantly in all
three conditions, compared with normal pregnancies. Reduced:total glutathione
decreased, whereas lipid peroxide levels increased. These results suggest that
maternal exposure to environmental oxidants can increase the risk of pregnancy
complications through stimulation of the formation of cell-damaging lipid
peroxides and from a decrease in maternal antioxidant reserves.
PMID- 9546757
TI - Trichloroethylene, tetrachloroethylene, nitrates, and other chemicals in well
water in the Fresno-Clovis Metropolitan Area.
AB - In this study, the author examined the spatial and temporal distribution of
tetrachloroethylene, trichloroethylene, nitrate, and several other organic and
inorganic chemicals in large community wells in the Fresno-Clovis Metropolitan
Area and estimated the lifetime cancer risk associated with exposure to
tetrachloroethylene and trichloroethylene. By 1992-1993, investigators found the
industrial solvent tetrachloroethylene in 34 wells and found trichloroethylene in
16 wells. All wells had detectable levels of nitrate. In addition, investigators
found radon, arsenic, cadmium, iron, manganese, trihalomethanes, and several
other volatile organic chemicals in the wells, but only radon and arsenic posed a
significant health risk. In 1995, 16 wells were closed because chemicals were
found in them. Twenty-six of 248 (10.5%) active wells and 24 of 43 (55.8%) closed
wells contained multiple contaminants, excluding nitrate. Between 1988 and 1993,
concentrations of trichloroethylene, tetrachloroethylene, and nitrates increased
in selected wells. Daily, monthly, and bimonthly variations in the concentrations
of tetrachloroethylene, trichloroethylene, and nitrate were often considerable.
Granulated activated carbon filtration reduced trichloroethylene levels in well
water by 91%-95%, and the author examined its usefulness as a remedial measure.
Estimated lifetime cancer risks for tetrachloroethylene and trichloroethylene
were 1 excess cancer death per 9.5 million people and 1 excess death per 250
million, respectively. The author also included recommendations for the conduct
of further epidemiological and environmental studies.
PMID- 9546758
TI - Long-term follow-up after methyl chloride intoxication.
AB - In this study, the authors investigated mortality and cancer patterns among a
group of individuals accidentally exposed to methyl chloride 32 y earlier. This
group of 24 persons had survived the immediate intoxication, which had occurred
on a trawler during a fishing trip. The authors selected a reference group, which
contained five times as many individuals as the study group, from registers of
crews, and they controlled for age, occupation, social class, and lifestyle
factors. The authors established a record linkage through personal identification
numbers with the national death register and cancer register, thus securing 100%
follow-up. The Mantel-Haenszel point estimate (M-H) was 2.2, and the 95%
confidence interval (CI) was 1.3-3.1 for all causes of death. There was an excess
of deaths from cardiovascular diseases (M-H = 2.1, 95% CI = 1.2-3.8). This excess
mortality was more prominent among deckhands who had been subject to higher
exposure; risk ratios (RRs) were elevated for all causes of death (RR = 2.5, 95%
CI = 1.0-5.7), as well as for cardiovascular diseases (RR = 3.9, 95% CI = 1.0
14.4). In addition, the authors noted elevated risks for all cancers (M-H = 1.5,
95% CI = 0.3-5.6) and for lung cancer (M-H = 2.7, 95% CI = 0.1-52.6). The authors
concluded that exposure to methyl chloride may have contributed to the risk of
cardiovascular disease. Investigators need to conduct further studies on groups
exposed to methyl chloride to refute or confirm this result.
PMID- 9546759
TI - Effect of a new ventilation system on health and well-being of office workers.
AB - Sick building syndrome is the term given to a heterogeneous constellation of
symptoms that affects workers in modern mechanically ventilated office buildings.
Although the cause is unknown, there is evidence that the local environment of
the work station is an important determinant of symptoms. In this study,
investigators examined the effect of a new, individually controlled ventilation
system on workers' symptoms. Investigators studied two groups of workers in one
mechanically ventilated office building: (1) a control group at whose worksite no
intervention was made and (2) an intervention group. The intervention consisted
of installation of a device that allowed each worker control over the ventilation
supplied to his or her worksite. Just before, and 4 and 16 mo after installation
of this device, workers completed self-administered questionnaires regarding
occurrence of symptoms. The new ventilation system resulted in higher air
velocities, more variable temperatures, and higher concentrations of airborne
dust and fungal spores. Four months after installation, workers with the new
ventilation system reported fewer symptoms that were (a) work-related (p < .05)
and that were work-related and frequent (p < .05); in addition, they reported
fewer symptoms that reduced their capacity to work (p < .01). Sixteen months
after installation, workers with the new device reported fewer symptoms than at
baseline (although not as significantly), and they indicated that the indoor air
quality improved their productivity by 11%, compared with a 4% reduction of
productivity among the control group of workers (p < .001). Investigators
concluded that the new ventilation system, which provided the workers with
individual control over ventilation, was associated with important and sustained
reduction in symptoms.
PMID- 9546760
TI - Effects of intermittent ozone exposure on peak expiratory flow and respiratory
symptoms among asthmatic children in Mexico City.
AB - In a panel study of Mexican children (5-13 y of age) with mild asthma, the
authors studied the relationship between ozone exposure and the course of
childhood asthma. Decrements in peak expiratory flow rate were associated with
ozone, and respiratory symptoms were associated with both ozone level and ambient
particulate matter (< 10 microm) level. After the authors adjusted for minimum
temperature and autocorrelation in the data, they determined that an increase of
50 ppb in a daily ozone 1-h maximum was related to an 8% increase in cough (95%
confidence interval = 2, 15); a 24% increase in phlegm (95% confidence interval =
13, 35); and an 11% increase in low respiratory symptoms index (95% confidence
interval = 5, 19). The authors concluded that children with mild asthma who
resided in the south of Mexico City were affected adversely by the high ozone
ambient levels observed in this area.
PMID- 9546761
TI - Effects of lead on the somatic growth of children.
AB - Studies on the effects of lead on the somatic growth of children are limited and
contradictory. The authors investigated the adverse effects of blood lead
concentration on the somatic growth of primary-school-age children. In this
study, there was a total of 522 children, aged 6-9 y, who resided in three areas
of Greece (i.e., Loutraki, Lavrion, and Elefsina). The medical evaluation
included medical history; physical examination; and measurements of height, head
circumference, and chest circumference. The authors also evaluated dietary
information, socioeconomic status, and height of parents. The authors conducted
laboratory tests for hematological parameters and blood lead levels. The mean
blood lead level was 12.3 microg/dl (standard deviation = 8.9 microg/dl), and
levels ranged from 1.3 microg/dl to 51.2 microg/dl. There were negative monotonic
relationships between growth parameters and blood lead levels, even after the
authors allowed for confounding effects. An increase in blood lead level of 10
microg/dl was associated with a decrease of (a) 0.33 cm in head circumference
(95% confidence interval = 0.12, 0.55; p = .002); (b) 0.86 cm in height (95%
confidence interval = 0.14, 1.16; p = .020); and (c) 0.40 cm in chest
circumference (95% confidence interval = -0.22, 1.02; p = .207). These findings
led the authors to conclude that a decrease in growth in children may be
associated with blood lead concentrations.
PMID- 9546762
TI - Mineral particles in bronchoalveolar lavage fluid (BALF): an attempt at designing
a quantitative model.
AB - The author examined by morphology, chemical composition, and crystalline
structure, approximately 2 500 mineral particles from bronchoalveolar lavage
fluids obtained from 25 residents of Rome. In addition, the author obtained the
same structural data for approximately 3000 inhalable particles present in the
atmosphere in Rome. The author constructed a model of the concentration and
granulometry of the different types of mineral particles in bronchoalveolar
lavage fluids, by estimating the clearance times of the different particle
classes. The author based the model on the following: (a) data relative to the
inhalable particulate to which involved subjects were exposed, (b) updated
knowledge about the processes of deposition and retention of the mineral
particulate in the human respiratory tract, and (c) the hypothesis that the
mineral particle pattern in bronchoalveolar lavage fluid reflects the pattern of
particulate in lung parenchyma. Finally, the author compared the model with the
particulate pattern observed in the bronchoalveolar lavage fluid samples. Despite
some drastic approximations, the model satisfactorily fits the data obtained from
the experimental research on mineral particulate in bronchoalveolar lavage fluid.
PMID- 9546764
TI - Anonymous anti-HIV agent.
PMID- 9546763
TI - Response to the June 13, 1996, draft report of the Commission on Risk Assessment
and Risk Management.
PMID- 9546765
TI - Xenotransplantation--caution, but no moratorium.
PMID- 9546767
TI - Britain establishes Academy of Medical Sciences.
PMID- 9546766
TI - Poor reporting of oocyte apoptosis.
PMID- 9546768
TI - IOM panel has begun NIH spending investigation.
PMID- 9546769
TI - Letter from Shalala feeds organ feud.
PMID- 9546770
TI - Fight to develop drug addiction therapy.
PMID- 9546772
TI - German/US health research agreement lacks substance.
PMID- 9546771
TI - Indian state plans compulsory HIV testing, segregation and branding.
PMID- 9546773
TI - Tipping the scales of herpes simplex virus reactivation: the important responses
are local.
PMID- 9546774
TI - A serious target for laughing gas.
PMID- 9546775
TI - Orexins and appetite: the big picture of energy homeostasis gets a little bigger.
PMID- 9546776
TI - Microchimerism: friend or foe?
PMID- 9546777
TI - Two strings to the bow of Ebola virus.
PMID- 9546778
TI - Mother knows best.
PMID- 9546779
TI - Retroviral zoonoses.
PMID- 9546780
TI - COX-2 inhibitors for colorectal cancer.
PMID- 9546781
TI - Monster plaques: what they tell us about Alzheimer's disease.
PMID- 9546782
TI - Death to a blood vessel, death to a tumor.
PMID- 9546783
TI - Enhanced immunogenicity for CD8+ T cell induction and complete protective
efficacy of malaria DNA vaccination by boosting with modified vaccinia virus
Ankara.
AB - Immunization with irradiated sporozoites can protect against malaria infection
and intensive efforts are aimed at reproducing this effect with subunit vaccines.
A particular sequence of subunit immunization with pre-erythrocytic antigens of
Plasmodium berghei, consisting of single dose priming with plasmid DNA followed
by a single boost with a recombinant modified vaccinia virus Ankara (MVA)
expressing the same antigen, induced unprecedented complete protection against P.
berghei sporozoite challenge in two strains of mice. Protection was associated
with very high levels of splenic peptide-specific interferon-gamma-secreting CD8+
T cells and was abrogated when the order of immunization was reversed. DNA
priming followed by MVA boosting may provide a general immunization regime for
induction of high levels of CD8+ T cells.
PMID- 9546784
TI - Identification of a human population infected with simian foamy viruses.
AB - Studying the transmission of simian retroviruses to humans can help define the
importance of these infections to public health. We identified a substantial
prevalence (4/231, 1.8%) of infection with simian foamy viruses (SFV) among
humans occupationally exposed to nonhuman primates. Evidence of SFV infection
included seropositivity, proviral DNA detection and isolation of foamy virus. The
infecting SFV originated from an African green monkey (one person) and baboons
(three people). These infections have not as yet resulted in either disease or
sexual transmission, and may represent benign endpoint infections.
PMID- 9546785
TI - Evidence for the involvement of endothelial cell integrin alphaVbeta3 in the
disruption of the tumor vasculature induced by TNF and IFN-gamma.
AB - Administration of tumor necrosis factor (TNF) and gamma interferon (IFN-gamma) to
melanoma patients causes selective disruption of the tumor vasculature but the
mechanism of this disruption is unknown. Here we report that exposure of human
endothelial cells to TNF and IFN-gamma results in a reduced activation of
integrin alphaVbeta3, an adhesion receptor that plays a key role in tumor
angiogenesis, leading to a decreased alphaVbeta3-dependent endothelial cell
adhesion and survival. Detachment and apoptosis of angiogenic endothelial cells
was demonstrated in vivo in melanoma metastases of patients treated with TNF and
IFN-gamma. These results implicate integrin alphaVbeta3 in the anti-vascular
activity of TNF and IFN-gamma and demonstrate a new mechanism by which cytokines
control cell adhesion.
PMID- 9546786
TI - TNFalpha regulation of Fas ligand expression on the vascular endothelium
modulates leukocyte extravasation.
AB - It is generally believed that the vascular endothelium serves as an inflammatory
barrier by providing a nonadherent surface to leukocytes. Here, we report that
Fas ligand (FasL) is expressed on vascular endothelial cells (ECs) and that it
may function to actively inhibit leukocyte extravasation. TNFalpha downregulates
FasL expression with an accompanying decrease in EC cytotoxicity toward co
cultured Fas-bearing cells. Local administration of TNFalpha to arteries
downregulates endothelial FasL expression and induces mononuclear cell
infiltration. Constitutive FasL expression markedly attenuates TNFalpha-induced
cell infiltration and adherent mononuclear cells undergo apoptosis under these
conditions. These findings suggest that endothelial FasL expression can
negatively regulate leukocyte extravasation.
PMID- 9546787
TI - Antigenic stimulation by BCG vaccine as an in vivo driving force for SIV
replication and dissemination.
AB - The impact of antigenic stimulation on the dynamics of simian immunodeficiency
virus (SIV) replication was studied following repeated intravenous BCG
inoculation of a SIV infected macaque. At the site of a delayed type
hypersensitivity reaction to purified protein derivative of M. tuberculosis, a
distinctive SIV variant was noted, probably as a result of the infiltration of
activated antigen-specific T cell clones as opposed to infection by blood borne
virus in situ. The dynamics of SIV quasispecies in peripheral blood suggests
sequential waves of viral replication, illustrating the role of antigenic
stimulation as a driving force in viral dissemination and pathogenesis.
PMID- 9546788
TI - Effects of a urinary factor from women in early pregnancy on HIV-1, SIV and
associated disease.
AB - The effects of clinical grade crude preparations of human chorionic gonadotropin
(hCG) on Kaposi's sarcoma, HIV, SIV and hematopoiesis were examined in vitro and
in vivo. In contrast to previous studies, we report that the antiviral activity
of hCG associated factors is not due to the native hCG heterodimer, including its
purified subunits or its major degradation product, the beta-core. Using gel
permeation chromatography of the clinical grade hCG and urine concentrates from
pregnant women, we demonstrate that an as yet unidentified hCG associated factor
(HAF) with anti-HIV, anti-SIV, anti-KS and pro-hematopoietic activities elutes as
two peaks corresponding to 15-30 kDa and 2-4 kDa.
PMID- 9546789
TI - Deregulation of cell growth by the K1 gene of Kaposi's sarcoma-associated
herpesvirus.
AB - At a position equivalent to the gene encoding the saimiri transforming protein
(STP) of herpesvirus saimiri (HVS), Kaposi's sarcoma-associated herpesvirus
(KSHV) contains a distinct open reading frame called K1. Although KSHV and HVS
are related members of the rhadinovirus subgroup of gamma herpesviruses, K1 and
STP exhibit no similarity in amino acid sequence or in structural organization.
Since STP is required for the oncogenic potential of HVS, we investigated the
functional consequence of K1 expression. Expression of the K1 gene in rodent
fibroblasts produced morphologic changes and focus formation indicative of
transformation. A recombinant herpesvirus in which the STP oncogene of HVS was
replaced with K1, immortalized primary T lymphocytes to IL-2 independent growth
and induced lymphoma in common marmosets. These results demonstrate the
transforming potential of the K1 gene of KSHV.
PMID- 9546790
TI - Novel role of human CD4 molecule identified in neurodegeneration.
AB - The human CD4 molecule (hCD4) is expressed on T lymphocytes and macrophages and
acts as a key component of the cellular receptor for HIV. At baseline, hCD4
transgenic mice expressed hCD4 on microglia, the resident mononuclear phagocytes
of the brain, and showed no neuronal damage. Activation of brain microglia by
peripheral immune challenges elicited neurodegeneration in hCD4 mice but not in
nontransgenic controls. In post-mortem brain tissues from AIDS patients with
opportunistic infections, but without typical HIV encephalitis, hCD4 expression
correlated with neurodegeneration. We conclude that hCD4 may function as an
important mediator of indirect neuronal damage in infectious and immune-mediated
diseases of the central nervous system.
PMID- 9546791
TI - Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides.
AB - Alzheimer's disease (AD) is characterized by the accumulation of cerebral plaques
composed of 40- and 42-amino acid beta-amyloid (Abeta) peptides, and autosomal
dominant forms of AD appear to cause disease by promoting brain Abeta
accumulation. Recent studies indicate that postmenopausal estrogen replacement
therapy may prevent or delay the onset of AD. Here we present evidence that
physiological levels of 17beta-estradiol reduce the generation of Abeta by
neuroblastoma cells and by primary cultures of rat, mouse and human embryonic
cerebrocortical neurons. These results suggest a mechanism by which estrogen
replacement therapy can delay or prevent AD.
PMID- 9546792
TI - A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due
to deletion of exon 9 of presenilin 1.
AB - We describe a novel variant of Alzheimer's disease (AD) in a Finnish pedigree
with 17 affected individuals of both sexes in three generations. The disease is
characterized by progressive dementia which is, in most cases, preceded by
spastic paraparesis. Neuropathological investigations revealed numerous,
distinct, large, round and eosinophilic plaques as well as neurofibrillary
tangles and amyloid angiopathy throughout the cerebral cortex. The predominant
plaques resembled cotton wool balls and were immunoreactive for Abeta but lacked
a congophilic dense core or marked plaque-related neuritic pathology. Molecular
genetic analysis revealed that the disease was caused by a deletion of exon 9
(delta9) of the presenilin 1 (PS1) gene from the mRNA: unlike previous examples
of the delta9 variant, the deletion was not caused by a splice acceptor site
mutation.
PMID- 9546793
TI - Local paracrine effects of estradiol are central to parturition in the rhesus
monkey.
AB - The central biochemical mechanisms involved in primate parturition are still
unclear. Studies in both humans and nonhuman primates such as the baboon and
rhesus monkey indicate that many factors play a part in the cascade of
interactive positive feedforward loops that progressively promote parturition:
changes in maternal endocrinology, a nocturnal switch in myometrial activity from
low amplitude, infrequent contractures to high amplitude, high frequency
contractions (see Fig. 1), dilation of the cervix and biochemical changes in the
fetal membranes that lead to rupture. Here we demonstrate that infusion of the
aromatase inhibitor 4-hydroxyandrostenedione (4OHA) inhibits conversion of
androgen to estrogen and prevents premature delivery caused by administration of
androgen to pregnant rhesus monkeys at 0.8 of pregnancy term. 4OHA also inhibited
the androstenedione induced maternal endocrine and fetal membrane biochemical
changes, and alteration of myometrial activity patterns. Secondly, peripheral
estrogen infusions increased myometrial activity but did not produce preterm
delivery or fetal membrane changes. We conclude that paracrine functions of
estrogen at its site of production play critical and central roles in delivery in
the non-human primate.
PMID- 9546794
TI - Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and
neurotoxin.
AB - Extensive research has failed to clarify the mechanism of action of nitrous oxide
(N2O, laughing gas), a widely used inhalational anesthetic and drug of abuse.
Other general anesthetics are thought to act by one of two mechanisms-blockade of
NMDA glutamate receptors or enhancement of GABAergic inhibition. Here we show
that N2O, at anesthetically-relevant concentrations, inhibits both ionic currents
and excitotoxic neurodegeneration mediated through NMDA receptors and, like other
NMDA antagonists, produces neurotoxic side effects which can be prevented by
drugs that enhance GABAergic inhibition. The favorable safety record of N2O may
be explained by the low concentrations typically used and by the fact that it is
usually used in combination with GABAergic anesthetics that counteract its
neurotoxic potential.
PMID- 9546795
TI - In vivo imaging of oligonucleotides with positron emission tomography.
PMID- 9546796
TI - Features of the SIVmac transmembrane glycoprotein cytoplasmic domain that are
important for Env functions.
AB - The cytoplasmic domain (CD) of the SIVmac transmembrane protein (TM) can affect
viral infectivity by modulating several Env functions, notably fusogenic capacity
and incorporation into virions. In addition, envelopes with a truncated CD are
counterselected in primary cells in culture and in vivo in rhesus macaques,
suggesting a role for this domain in viral persistence. Here, we have used
mutagenesis to examine specific features of the SIVmac TM CD, including the
conserved C-terminal alpha helix and the overall length of the CD. Several
mutations dramatically reduced and/or delayed virus infectivity in lymphoid cell
lines. Detailed analysis of mutants revealed defects in envelope stability,
fusogenic capacity, and virion incorporation. The primary defect associated with
an envelope containing a 64-residue CD was rapid degradation. A mutant Env
lacking the C-terminal alpha helix but encoding an exceptionally long CD (373
residues) was highly fusogenic but inefficiently incorporated into virions. A
third mutant, containing amino acid substitutions designed to alter the charge
density of the C-terminal helix, retained cytopathic properties and showed
enhanced fusogenic capacity but replicated with delayed kinetics. Taken together,
these results demonstrate that CD sequence variation entails functional
"tradeoffs" that can involve optimization of certain Env functions at the expense
of others.
PMID- 9546797
TI - Efficacy of fusion peptide homologs in blocking cell lysis and HIV-induced
fusion.
AB - Contrary to earlier reports, we have found that tri- and hexapeptides analogous
or homologous with segments of the 23-residue N-terminal fusion sequence (FS) of
the viral transmembrane glycoprotein gp41 (residues 517-539) did not
significantly inhibit HIV-1-induced syncytium formation, using an uninfected cell
infected cell fusion assay. In contrast, we found that the high molecular weight
apolipoprotein A-1 and a 23-residue analog of the FS, with the phenylalanine
residues at positions 524 and 527 replaced with alanine residues, were effective
inhibitors. Although the tripeptides were ineffective as inhibitors of syncytium
formation, we found a number of them inhibited red cell lysis induced by the
synthetic peptide AVGIGALFLGFLGAAGSTMGARS (based on the HIV-1 gp41 FS). This
effect was also seen with apolipoprotein A-1. The Ala524,527 analog of the fusion
sequence could not be tested in this system because it was hemolytic. We
concluded that the smaller peptides were effective inhibitors of hemolysis
because they interfered with pore formation by the fusion sequence peptide,
either by disrupting the pores or by preventing the peptide from adopting the
alpha-helical conformation found in the pores. On the other hand, membrane
fusion, which is a prelude to syncytium formation, has been shown to require the
fusion sequence in the beta-strand conformation. We argue that small peptides
would be unable to block interaction between such strands, although larger
molecules, such as apolipoprotein A-1 and the Ala524,527 analog, would be able to
do so and thus inhibit fusion. It seems, therefore, that a successful drug
directed against the FS-cell membrane interaction stage of syncytium formation
would need to be of relatively high molecular weight and complexity.
PMID- 9546798
TI - Administration of recombinant human interleukin 12 to chronically SIVmac-infected
rhesus monkeys.
AB - With the demonstration that interleukin 12 can enhance natural killer (NK) cell
activity and drive CD4+ lymphocytes toward T helper type 1 (Thl) responses, there
is a strong rationale for exploring the use of this cytokine as an
immunomodulatory therapy in HIV-1-infected individuals. To assess its potential
safety and effects on both immune and virologic aspects of HIV-1 infection,
recombinant human IL-12 (rhIL-12) was assessed in rhesus monkeys chronically
infected with the simian immunodeficiency virus of macaques (SIVmac). The
activity of rhIL-12 on rhesus monkey lymphocytes was confirmed with the
demonstration that peripheral blood lymphocyte lysis of the NK-sensitive cell
line Colo was enhanced by this recombinant cytokine. Further, rhIL-12 was shown
to induce interferon-gamma production by rhesus monkey lymphocytes in vitro.
Then, in separate studies, two treatment regimens of rhIL-12 were assessed in
SIVmac-infected monkeys: a low-dose regimen (0.1 microg/kg, daily for 4 weeks)
and a high-dose regimen (2.5 microg/kg, every 3-4 days, for 3 weeks). Both rhIL
12 treatment regimens were well tolerated by these virus-infected animals. The
high-dose regimen of rhIL-12 induced transient decreases in circulating
lymphocytes in the SIVmac-infected monkeys. Furthermore, no changes in lymphocyte
associated SIVmac DNA or SIVmac plasma RNA levels were seen in the treated
monkeys. These studies indicate that short-term treatment with rhIL-12 is well
tolerated and causes no measurable changes in virus load in chronically SIVmac
infected rhesus monkeys.
PMID- 9546799
TI - An experimental prime-boost regimen leading to HIV type 1-specific mucosal and
systemic immunity in BALB/c mice.
AB - Induction of mucosal as well as systemic immunity to HIV-1 is considered to have
high priority in current concepts of future AIDS vaccines. Here we show that the
desired immune responses can be elicited by an experimental prime-boost regimen
consisting of mucosal (intragastric) application of a recombinant vaccinia virus
carrying the HIV-1 env gene (vSC25), followed by parenteral (intradermal)
immunization with the recombinant HIV-1 glycoprotein 160 (rgp160). Following
intragastric immunization of mice with vSC25 in combination with the mucosal
adjuvant cholera toxin (CT), HIV-1 env-specific IgA was secreted by B cells of
Peyer's patches and the lamina propria. Moreover, mucosal (intragastric and
intranasal) application of vSC25 (both in presence or absence of CT) induced a
long-lasting, HIV-1 env-specific systemic cytotoxic T cell response. Subsequent
intradermal boosters with rgp160 led to HIV-1-specific T cell memory and serum
antibodies.
PMID- 9546800
TI - Immunoliposomes containing antibodies to costimulatory molecules as adjuvants for
HIV subunit vaccines.
AB - Immunoliposomes containing monoclonal antibodies (MAbs) to the costimulatory
molecules CD28 and CTLA4 and their counterreceptors B7-1 (CD80) and B7-2 (CD86)
were evaluated for the ability to increase the immune response to recombinant
envelope protein rgp120 of the MN strain of human immunodeficiency virus type 1
(HIV-1) during vaccination. MAbs were attached to rgp120-containing liposomes via
a biotin-avidin-biotin bridge. Mice vaccinated with immunoliposomes were found to
have a strong delayed-type hypersensitivity (DTH) response to the weakly
immunogenic gp120 that was dependent on the presence of the MAbs. However, this
vaccination protocol did not induce humoral immunity. The DTH response was not
accompanied by increased production of interferon gamma (IFN-gamma) or
interleukin 4 (IL-4), implying that the primary cellular interaction was between
the immunoliposomes and cells of the reticuloendothelial system and not helper T
(Th) cells. This strategy of incorporating antibodies to costimulatory molecules
on the surface of antigen-containing particulates, such as liposomes or
microspheres, can be used to increase DTH immune responses to protein or peptide
vaccines.
PMID- 9546801
TI - Immunologic cross-reaction between HIV type 1 p17 and Mycoplasma hyorhinis
variable lipoprotein.
AB - Monoclonal antibodies directed against the HIV-1 matrix protein p17 that react
with a component present on the surface of HIV-1-infected cells have previously
been described. In this study we show that one of these monoclonal antibodies
binds to persistently HIV-1-infected cell lines that are coinfected with
Mycoplasma hyorhinis, but not to cell lines that are uninfected with mycoplasma.
Mycoplasma-infected cells secrete HIV-1 at a higher rate, have a slight increase
in cell surface expression of gp120 and gp41, and are less sensitive to
immunotoxins than uninfected cells. The anti-p17 antibody binds to a protein of
M. hyorhinis grown in cell-free culture. The variable expression and size of the
protein among strains is typical of the variable lipoprotein (Vlp) system of M.
hyorhinis. Confirmation of the reactivity of the antibody with a Vlp was provided
by demonstrating its specific binding to recombinant VlpF expressed in E. coli,
and to a synthetic peptide representing the carboxy-terminal region of VlpF, but
not to other recombinant Vlp products or peptides. This is a true cross-reaction
because the antibody also binds to recombinant p17 expressed in E. coli and the
binding is inhibited by the VlpF peptide. These analyses highlight the potential
of mycoplasma contamination of tissue culture cell lines to cause anomalous
results. With regard to HIV-1, mycoplasma infection of cells results in increased
rates of virus secretion, and introduces a potential confounding immunologic
cross-reaction as well. The existence of a cell surface form of p17 is unlikely.
PMID- 9546802
TI - HIV type 1 infection of human macrophages induces an upregulation of manganese
superoxide dismutase gene that may protect cells from death.
AB - It has been previously demonstrated that HIV-1 infection induces a downregulation
of MnSOD transcription in CD4+ lymphocytes. Using clinical isolates of macrophage
tropic HIV-1 strains we report here that conversely, purified normal human
monocyte-derived macrophages (MDMs) overexpress the manganese superoxide
dismutase (MnSOD) gene in response to infection and viral replication. This
upregulation of MnSOD gene expression is concomitant with tumor necrosis factor
alpha (TNF-alpha) and interleukin 6 (IL-6) production and treatment of HIV-1
infected MDMs with a specific transcriptional inhibitor of TNF-alpha synthesis
counteracts the HIV-1-induced MnSOD gene activation. Moreover, TNF-alpha but not
IL-6 addition mimicks the effects of HIV-1 infection on MnSOD gene regulation in
normal MDM cultures. These observations strongly suggest that the MnSOD gene
induction detected in HIV-1-infected MDMs is triggered by TNF-alpha produced in
culture supernatants in parallel to HIV-1 particle release. In contrast to MnSOD,
HIV-1 infection or replication in human MDMs has no effect on copper-zinc
superoxide dismutase (Cu/ZnSOD) gene expression.
PMID- 9546803
TI - Macrophage protection against human immunodeficiency virus or herpes simplex
virus by red blood cell-mediated delivery of a heterodinucleotide of
azidothymidine and acyclovir.
AB - Human herpesvirus (HSVs) are distributed worldwide and are among the most
frequent causes of viral infection in HIV-1-immunocompromised patients. Hence,
therapeutic strategies able to inhibit HSV-1 and HIV-1 replication are sorely
needed. Until now, the most common therapies against HSV-1 and HIV-1 infectivity
have been based on the administration of nucleoside analogs; however, to be
active, these antiviral drugs must be converted to their triphosphorylated
derivatives by viral and/or cellular kinases. At the cellular level, the main
problems involved in the use of such drugs are their limited phosphorylation in
some cells (e.g., antiretroviral drugs in macrophages) and the cytotoxic side
effects of nucleoside analog triphosphates. To overcome these limitations, a new
heterodinucleotide (AZTp2ACV) consisting of both an antiretroviral and an
antiherpetic drug, bound by a pyrophosphate bridge, was designed and synthesized.
The impermeant AZTp2ACV was encapsulated into autologous erythrocytes modified to
increase their recognition and phagocytosis by human macrophages. Once inside
macrophages, metabolic activation of the drug occurred. The addition of AZTp2ACV
loaded erythrocytes to human macrophages provided effective and almost complete
in vitro protection from HIV-1 and HSV-1 replications, respectively. Therefore,
AZTp2ACV acts as an efficient antiviral prodrug following selective targeting to
macrophages by means of loaded erythrocytes.
PMID- 9546804
TI - Phenotypic variability of lymphocyte populations in peripheral blood and lymph
nodes from HIV-infected individuals and the impact of antiretroviral therapy.
DATRI 003 Study Group. Division of AIDS Treatment Research Initiative.
AB - This study presents immunophenotypic variation in lymphocyte populations obtained
from peripheral blood and lymph nodes from individuals with early HIV disease who
were enrolled in a prospective, open-label study. At baseline, there was a
significantly greater percentage of B cells and significantly smaller percentage
of CD8+ cells in lymph nodes compared with peripheral blood. Evaluation of
lymphocyte phenotypic markers of function, maturation, and activation at baseline
revealed a significantly higher percentage of activated CD4+ cells in lymph nodes
compared with peripheral blood, whereas the percentages of activated CD8+ cells
were similar in both compartments. After an 8-week period of randomly assigned
treatment, peripheral blood phenotypic marker changes included (1) a reduced
proportion of activated cells (HLA-DR+) in antiretroviral-naive patients who
received zidovudine (ZDV), and (2) as increased proportion of "naive" cells
(CD45RA+) in individuals, previously administered ZDV alone, who received ZDV and
didanosine (ddI) therapy. The lymph node phenotypic marker analysis showed no
significant changes over the 8-week treatment period. Overall, the study
demonstrates significant differences in lymphocyte subsets from lymph nodes
compared with peripheral blood and suggests that further studies be performed to
determine the functional significance of these phenotypic subsets.
PMID- 9546805
TI - Failure to quantify viral load with two of the three commercial methods in a
pregnant woman harboring an HIV type 1 subtype G strain.
AB - The level of HIV-1 RNA in plasma has become one of the most important markers in
the follow-up of HIV-infected patients. Three techniques are commercially
available: both the Amplicor HIV Monitor and the NASBA HIV-1 RNA QT are target
amplification methods, whereas the Quantiplex HIV RNA assay is a branched DNA
signal amplification technique. Detection in both target amplification techniques
is based on a single primer pair and a single probe in the gag region, whereas
multiple probes capture the pol region of the viral RNA in the branched DNA
assay. We investigated the discrepant observation of an undetectable viral load
in an immunodeficient pregnant HIV-1-infected patient of African origin with no
prior antiretroviral treatment. Although clinical progression was present in this
patient with tuberculosis and a low CD4 cell count, viral load determinations
with both the Amplicor Monitor and NASBA assays revealed no detectable RNA
levels. The presence of HIV-1 RNA in the plasma of the patient was demonstrated
by an in-house RNA-PCR. Subsequent HIV-1 RNA quantification with the branched DNA
method revealed a high viremia (460,000 copies/ml). DNA sequence analysis of the
gag gene identified a subtype G HIV-1 strain (HIV-1BL). To our knowledge this is
the first report of a patient harboring an HIV-1 genotype of the main group with
a high viral load as quantified by the branched DNA assay, but undetectable with
the two commercial HIV RNA amplification techniques because of genetic
divergence. In the case of discrepant low viral loads determined by one
amplification technique in patients with advanced clinical stage one should use
an alternative quantification technique for confirmation.
PMID- 9546806
TI - Complete nef gene sequence of HIV type 1 subtype B' from professional plasma
donors in the People's Republic of China.
PMID- 9546808
TI - ATP-dependent transport of lipophilic cytotoxic drugs by membrane vesicles
prepared from MRP-overexpressing HL60/ADR cells.
PMID- 9546807
TI - HIV type 2 Vif proteins have specific conserved amino acid motifs.
PMID- 9546810
TI - Structure and in vitro substrate specificity of the murine multidrug resistance
associated protein.
PMID- 9546809
TI - Cellular and in vitro transport of glutathione conjugates by MRP.
PMID- 9546811
TI - Cytokine profiles of in vivo activated thyroid-infiltrating T cells cloned in the
presence or absence of interleukin 4.
AB - We compared Th1 and Th2 cytokines secreted by randomly selected, intrathyroidal
CD4+ T cell clones isolated from a patient with Graves' disease using IL-4 + IL-2
versus IL-2 alone. Prior to T cell isolation, PCR of cDNA from the intact thyroid
tissue generated IL-4 and IL-10, but not IFN-gamma, products. As controls, IL-4,
IFN-gamma and IL-10 cDNA was amplified from stimulated, but not unstimulated,
PBMC. All 21 of the nine IL-2 clones and twelve IL-2 + IL-4 clones isolated from
the thyroid tissue were CD4+. With the exception of one clone in the IL-2 group,
all clones produced IL-10 on stimulation with anti-CD3 and phorbol-12-myristate
13-acetate (PMA) with similar mean values for both groups. The majority of clones
in both groups also produced IFN-gamma and IL-4 after stimulation. However, the
IL-4:IFN-gamma ratios were significantly higher in clones isolated using IL-2 +
IL-4 than in those isolated with IL-2 alone. Furthermore, the distribution of
Th1, Th0 and Th2 type clones, defined by their IL-4:IFN-gamma ratios, was also
significantly different between those isolated using IL-2 alone and those
isolated using IL-2 + IL-4. Of note, although Th0 clones predominated in both
groups, Th1 clones were only obtained using IL-2 alone and Th2 clones were only
obtained with IL-2 + IL-4. In conclusion, the presence of IL-4 together with IL-2
induces a shift away from a Th1-towards a Th2-response in T cells cloned from in
vivo-activated thyroid-infiltrating lymphocytes. This difference in cytokine
profile emphasizes that IL-4 is required for cloning T cells representative of a
response involving both Th1 and Th2 cells, as occurs in autoimmune thyroid
disease.
PMID- 9546812
TI - Autoimmunity to ryanodine receptor and titin in myasthenia gravis is associated
with GM allotypes.
AB - Myasthenia gravis (MG) is mediated by autoantibodies against the acetylcholine
receptor at the muscle endplate. Some MG patients have in addition antibodies
(Ab) to the skeletal muscle proteins ryanodine receptor (RyR) and titin. We have
examined GM and KM allotypes, RyR and titin Ab in 44 MG patients (37 thymoma
patients and 7 non-thymoma, late-onset patients) and 292 non-MG controls to see
if GM/KM allotypes associate with differences in autoantibody production. All
patients had titin Ab, and 15 thymoma patients had also RyR Ab. The phenotype GM
1, 2, 3 23 5, 21 was significantly increased in the patients with titin Ab
compared with the non-MG controls (chi2 = 4.93, p < 0.05). Thymoma patients with
RyR Ab had a higher frequency of the GM 3 23 5 phenotype compared with RyR Ab
negative patients and controls (chi2 = 7.1, p < 0.05). KM allotypes did not
differ between RyR Ab positive or titin Ab positive patients and controls. GM
phenotypes may thus be associated with an autoimmune response against the muscle
proteins titin and RyR in MG patients.
PMID- 9546813
TI - Beta-cell rest: a strategy for the prevention of autoimmune diabetes.
AB - An autoantigen being recognized by specific receptors is the key reaction of an
autoimmune disease. Whereas much efforts have been made to develop
immunosuppressive regimens which reduce the amount of effector cells, and/or
inhibit receptor activation, surprisingly little attention has been paid to
reduce the ligand-receptor interaction by interfering with the amount of antigen
being presented from the target cells. In this review, we discuss clinical
observations in autoimmune endocrine disease which illustrate that target cell
alterations can modify the disease activity and comment on recent clinical trials
which indicate that beta-cell rest may be beneficial to the course of human
autoimmune diabetes mellitus.
PMID- 9546814
TI - HLA-DR and the development of rheumatoid arthritis.
AB - Susceptibility to develop Rheumatoid arthritis (RA) maps to a highly conserved
amino acid motif ("the shared epitope") expressed in the third hypervariable
region of different HLA-DRB1 alleles. This motif, namely QKRAA, QRRAA or RRRAA
helps the development of RA by an unknown mechanism. However, it is now
established that the shared epitope can 1. Shape the T cell repertoire. 2.
Interact with 70 kD heat shock proteins.
PMID- 9546815
TI - Cytokines in the evolution of Graves' ophthalmopathy.
AB - Infiltration of the retroocular space by inflammatory cells and the accumulation
of glycosaminoglycans are histological characteristics of Graves' ophthalmopathy.
Various cytokines, released by infiltrating immunocompetent cells and resident
connective tissue cells, play a pivotal role in the evolution of this disease.
The predominant cytokines secreted by orbital T cells during the course of the
disease may govern the activity and stage of the local autoimmune process.
Cytokine effects of potential relevance to the pathogenesis of Graves'
ophthalmopathy include their ability to stimulate orbital fibroblasts to
proliferate and secrete excess quantities of glycosaminoglycans. The edema
associated with these hydrophilic macromolecules is directly responsible for many
of the characteristic clinical features of the disease. In addition, certain
cytokines induce or enhance the expression on orbital fibroblasts of
immunomodulatory proteins. We review current evidence supporting the notion that
cytokines are central to the development and evolution of Graves' ophthalmopathy.
PMID- 9546816
TI - Characterisation of the antibody response to the extracellular region of
recombinant thyrotropin receptor.
AB - Autoantibodies to the human thyrotropin receptor (TSH-R) are pathogenic in a
number of autoimmune thyroid diseases including Graves' disease. We have
characterised polyclonal antisera to TSH-R for antibodies which may mimic those
present in autoimmune thyroid disease. For immunisations, recombinant
extracellular region of human TSH-R which does not interact with its ligand TSH
was used. The induced antibodies react with the full length membrane receptor in
transfected mammalian cells by flow cytometry showing the presence of antibody
capable of recognising the native functional receptor. The properties of the
generated antibodies have been compared after two injections or following a
multiple immunisation protocol with the receptor in adjuvant. High titre antisera
were readily generated after the short injection protocol and further
immunisations did not lead to any change in antibody titers. Analysis of the
epitopes recognised using synthetic peptides confirmed previous observations that
the immunodominant determinants localise to the amino and the carboxyl terminal
part of the extracellular region of the receptor. Antisera from both rabbits
contain TSH blocking antibody as assessed by inhibition of TSH mediated cAMP
stimulation. There was an increase in TSH binding inhibitory immunoglobulin
(TBII) activity with multiple injections. Furthermore, the increase in TBII
activity was not related to spreading of the antibody response to new
determinants on TSH-R. Our results support previous observations on the
difficulties in reproducing, by adjuvant immunisation with recombinant TSH-R
preparations, the fine specificity of antibodies to TSH-R present in autoimmune
disorders such as Graves' disease or primary myxoedema.
PMID- 9546817
TI - X-chromosome inactivation in monozygotic twins with systemic lupus erythematosus.
AB - The hypothesis that a low concordance rate in monozygotic (MZ) twins with
systemic lupus erythematosus (SLE) may be accounted for by differences in X
chromosome inactivation was examined. Five MZ twin pairs, four discordant and one
concordant, were recruited, zygosity confirmed by DNA fingerprinting, and their
pattern of X-chromosome inactivation in DNA samples prepared from peripheral
blood and buccal cells were examined. X-chromosome inactivation was assessed by
the methylation status of the CpG region near trinucleotide repeats in exon 1 of
the androgen receptor gene on X-chromosome after digestion with the methylation
sensitive enzyme HpaII or HhaI and PCR amplification. X-chromosome inactivation
patterns were found to be the same between affected and non-affected twins in all
four discordant twin pairs, with random patterns in two pairs and skewed patterns
in the others. The concordant twins demonstrated the same random patterns. X
chromosome inactivation was also examined from buccal smear DNA and shown to have
the same pattern as that noted from peripheral blood DNA in one informative twin
pair. Differences in X-chromosome inactivation patterns were not observed in
these five MZ twin pairs. The results could not support the hypothesis that
differences in X-chromosome inactivation is the mechanism accounting for the low
concordance rate noted in MZ twins with SLE.
PMID- 9546818
TI - Neonatal lupus erythematosus: studies on HLA class II genes and autoantibody
profiles in Japanese mothers.
AB - Neonatal lupus erythematosus (NLE) is a rare disorder of neonates characterized
by two major clinical manifestations: congenital heart block and cutaneous lupus
lesions. The disease is associated with placentally transferred maternal anti
Ro/SSA and/or La/SSB antibodies. To clarify possible class II HLA associations
with maternal autoantibody responses, haplotypic and allelic distributions, along
with the polymorphism of the MHC class II HLA alleles, were analyzed based on PCR
RFLP results in 25 Japanese mothers of two groups defined by precipitating
autoantibody profiles. Among mothers with both anti-Ro/SSA and anti-La/SSB
antibodies, but not those with anti-Ro/SSA alone, the class II haplotypes
DRB1*1101-DQA1*0501-DQB1*0301 and DRB1*08032-DQA1*0103-DQB1*0601 as well as
individual class II alleles DRB1*1101, DRB1*08032 and DQB1*0301 showed
significantly increased frequencies compared to those in normal controls. All
anti-Ro/SSA and anti-La/SSB positive mothers carried DRB1 alleles that shared the
same amino acid residues at positions 14-31 and 71 of the DRB1 chain. These
mothers also carried homozygous or heterozygous DQ6 and DQ3 alleles that shared
the same amino acid residues at positions 27-36 and 71-77 of hypervariable
regions of the DQB1 chain. Furthermore, all mothers with both anti-Ro/SSA and
anti-La/SSB were homozygous for DPB1*0501. Nine of 10 anti-Ro/SSA and anti-La/SSB
positive mothers, but only 6 of 15 mothers with anti-Ro/SSA alone, had affected
infants. Thus, our findings suggest that there may be immunogenetic differences
among mothers according to their autoantibody profiles, and that mothers with
both anti-Ro/SSA and anti-La/SSB are more likely to have infants with NLE than
mothers with anti-Ro/SSA alone.
PMID- 9546819
TI - Contribution of structural neuroimaging to the early diagnosis of Alzheimer's
disease.
AB - There is compelling evidence for the early involvement of the hippocampal
formation in the natural history of Alzheimer's disease (AD). The evidence comes
from recent neuropathology, neuropsychology, and neuroimaging studies. AD-type
histopathologic changes limited to the hippocampus have been described and may be
seen in normal aging subjects. The sites of maximal neuronal loss in the
hippocampal formation are in the CA1, subiculum, and entorhinal cortex. Minimally
cognitively impaired (MCI) individuals (defined by ratings of functional capacity
and psychiatric symptomatology) exhibit a neuropsychological profile that is
distinct from that of the unimpaired elderly. Pathologic evidence suggests that
most of these cases already have AD brain changes accentuated in the hippocampal
region, and our own longitudinal studies reveal that 70% of this group develop
dementia within a 4-year period. We have developed a negative-angle axial view
designed to cut parallel to the anterior-posterior plane of the hippocampus.
Using this modified axial plane of section in conjunction with computed
tomography (CT) and magnetic resonance imaging (MRI), we estimated the prevalence
of hippocampal atrophy in normal aging and across severity levels of cognitively
impaired elderly patients. Longitudinal study shows that hippocampal atrophy is a
sensitive and specific predictor of future AD for patients with MCI. MRI volume
study of AD patients, controls, and MCI patients shows specific hippocampal
volume loss in MCI. We conclude that the atrophic changes associated with early
AD can be visualized using qualitative techniques and are readily quantifiable
with volumetry. This article is not intended to be comprehensive, but to provide
an overview of some of the structural neuroimaging data from our laboratory.
PMID- 9546820
TI - Are the hypervariable regions of S RNases sufficient for allele-specific
recognition of pollen?
PMID- 9546821
TI - A full genome screen for autism with evidence for linkage to a region on
chromosome 7q. International Molecular Genetic Study of Autism Consortium.
AB - Autism is characterized by impairments in reciprocal social interaction and
communication, and restricted and sterotyped patterns of interests and
activities. Developmental difficulties are apparent before 3 years of age and
there is evidence for strong genetic influences most likely involving more than
one susceptibility gene. A two-stage genome search for susceptibility loci in
autism was performed on 87 affected sib pairs plus 12 non-sib affected relative
pairs, from a total of 99 families identified by an international consortium.
Regions on six chromosomes (4, 7, 10, 16, 19 and 22) were identified which
generated a multipoint maximum lod score (MLS) > 1. A region on chromosome 7q was
the most significant with an MLS of 3.55 near markers D7S530 and D7S684 in the
subset of 56 UK affected sib-pair families, and an MLS of 2.53 in all 87 affected
sib-pair families. An area on chromosome 16p near the telomere was the next most
significant, with an MLS of 1.97 in the UK families, and 1.51 in all families.
These results are an important step towards identifying genes predisposing to
autism; establishing their general applicability requires further study.
PMID- 9546822
TI - Proceedings of the 1997 International Symposium, Exhibit and Workshop on
Preparative Chromatography, Ion Exchange and Adsorption/Desorption Processes and
Related Techniques. Washington, DC, USA. 1-4 June 1997.
PMID- 9546823
TI - Benign form of congenital angulation of long bones associated with shortening of
soft tissues.
AB - We report a benign form of congenital angulation of long bones associated with
shortening of soft tissues. The patients were three males and four females
including two siblings. The average age at first examination was 6 months (range,
1-17 months) and that at the time of follow-up was 7 years (range, 13 months-11
years). The characteristics were short-limb type short stature, congenital
multiple angulation deformities of the long bones of both upper and lower
extremities, with almost the same angulation directions for all the patients and
improvement of the deformities with age. There was also accelerated skeletal
maturation, lack of epi-metaphyseal lesions, skin dimples, limitation of the
ankle joint dorsiflexion, and inconspicuousness of skin creases on the flexor
side of the elbow and knee. This phenotype is not consistent with any of the bent
bone dysplasia group. Caffey's report [Caffey J (1947). Am J Dis Child 74:543
5621 included two different subtypes of bent bones, round bowing and sharp
angulation, and the latter are similar to this report. However, Caffey's cases
lack limitation of ankle dorsiflexion and reduced skin creases. An autosomal
recessive mode of inheritance could be present in this subtype.
PMID- 9546824
TI - Autosomal dominant Klippel-Feil anomaly with cleft palate.
AB - Klippel-Feil anomaly is characterized by the fusion of two or more cervical
vertebrae. Most cases are sporadic but dominant and recessive inheritance are
well described. Associated anomalies such as a cleft palate are common. We
describe a unique family with autosomal dominantly inherited Klippel-Feil anomaly
in six individuals associated with a cleft palate in four. One patient, a child,
has a cleft palate only but may develop radiological cervical fusion with time,
as documented in two other family members.
PMID- 9546826
TI - A boy with severe manifestations of type A1 brachydactyly.
AB - We describe a male with type A1 brachydactyly, a descendant of Drinkwaters second
family. In addition to absence of the middle phalanges of his hands and feet he
has generalised skeletal abnormalities, nystagmus and a squint. We suggest that
his clinical findings represent the more severe manifestations of this autosomal
dominant gene.
PMID- 9546825
TI - Mutation of the MITF gene in albinism-deafness syndrome (Tietz syndrome).
AB - A mother and her son with albinism and sensorineural deafness compatible with
Tietz syndrome (MIM 103500) are reported. An in-frame deletion of the MITF gene
that is identical at the molecular level to the mouse mi mutant allele has been
found in this family. MITF gene mutations account for 20% of Waardenburg syndrome
(WS) type II. These data, together with the wide spectrum of mutant alleles
reported in mi mice (which have pigmentary disorders), suggest that MITF could be
regarded as a candidate gene in various pigmentation disorders in man.
PMID- 9546827
TI - Brachydactyly type A1 with abnormal menisci and scoliosis in three generations.
AB - We report a three-generation family in which four members had brachydactyly type
A1, degenerative arthritis of the knee as a complication of abnormal menisci, and
variable scoliosis. Nine of the 15 individuals in the two generations preceding
the proband had brachydactyly. Three of these nine had degenerative arthritis of
the knee including the proband's father who had meniscal degeneration with tears.
One other had radiologically confirmed discoid menisci. Of those with
brachydactyly, five also had scoliosis. Although autosomal dominant inheritance
of brachydactyly A1 and discoid menisci have been reported separately,
cosegregation of these features in one family has not previously been described
and seems to comprise a unique autosomal dominant condition. The combination of
brachydactyly, meniscal abnormalities including discoid meniscus, and scoliosis
suggests that this disorder represents a new osteochondrodysplasia syndrome.
PMID- 9546828
TI - Four cases of amelia of the upper limb associated with anal atresia--is this
VACTERL with extreme limb involvement?
AB - Amelia is an extremely rare abnormality with a highest reported incidence of 1 in
67,500 liveborn infants. We now report four cases in each of which amelia
involving one upper limb occurred in association with anal atresia. The pattern
of other abnormalities present in these cases suggests that this combination of
amelia and anal atresia falls within the spectrum of the VACTERL association.
PMID- 9546829
TI - Cerebellar hypoplasia, facial dysmorphism and internal abnormalities: a new
recessive syndrome?
AB - Three female sibs had cerebellar hypoplasia, facial dysmorphism comprising a high
forehead, lowset posteriorly rotated ears, a prominent upper lip and receding
chin, and variable internal abnormalities. Two of the cases had deficient
lobulation of the lungs, two had an atrial septal defect of the heart and
developmental abnormalities of the urinary system or internal genitalia, one had
holoprosencephaly. All had normal chromosomes. This syndrome does not seem to
have been reported before and may be inherited in an autosomal recessive manner.
PMID- 9546830
TI - Two sisters with growth failure, microcephaly, peculiar facies and apical
dystrophy: the presentation of brachymorphism-onychodysplasia-dysphalangism
syndrome?
AB - We report two sisters with growth failure, relative microcephaly, peculiar facies
and apical dystrophy (brachydactyly type B). They had shortness and clinodactyly
of the 5th fingers, aplasia or hypoplasia of the distal phalanges of 5th fingers,
short medial phalanges of the 2nd and 5th fingers, hypoplasia or aplasia of
distal phalanges of 2-5th toes, with tiny toenails, and aplasia or nails of 5th
fingers and right 5th toe in the younger sister. Dysmorphic facial features
included high forehead, sparse hair, blepharophimosis, telecanthus, epicanthic
folds, a low nasal bridge, a broad nasal tip and micrognathia. Their ears were
low-set and malformed. The older sister additionally had a high-pitched voice and
eczema on the face and limbs. In the younger sister a cardiac defect was
diagnosed--ventricular and atrial septal defect, patent ductus arteriosus. They
had some clinical features of Coffin-Siris syndrome, but with a milder phenotype
and much less severe mental handicap. Their clinical picture resembles more the
brachymorphism-onychodysplasia-dysphalangism (BOD) syndrome.
PMID- 9546831
TI - Unusual association of congenital malformations: craniosynostosis, heart defect,
abnormal intestinal innervation and urogenital abnormalities.
AB - Monozygotic male twins and an unrelated boy are described who have an unusual
association of malformations, i.e. craniosynostosis of the sagittal suture, a
cardiac malformation, urogenital anomalies, intestinal malformations and a single
umbilical artery. The twins are discordant for these features, except for
Hirschsprung disease. No similar cases could be traced in literature. The
possible genetic background is discussed.
PMID- 9546832
TI - Oral-facial-digital (OFD) syndrome with associated features: a new syndrome or
genetic heterogeneity and variability?
AB - We report a male patient with clinical characteristics compatible with an OFD
syndrome and previously unassociated findings such as myelomeningocele, stenosis
of aqueduct of Sylvius and heart anomalies, that we feel that may represent a new
type of OFD syndrome (XII).
PMID- 9546833
TI - Azoospermia and segmentation abnormalities of the cervicothoracic spine ('MURCS
in the male').
AB - The MURCS association is traditionally regarded as a disorder limited to the
female sex. It has been hypothesized that men displaying the combination of
azoospermia, segmentation abnormalities of the cervicothoracic spine and renal
anomalies may have a male analogue of MURCS. Here we describe a patient with non
obstructive azoospermia and Klippel-Feil anomaly type II and suggest that this
may represent another case of 'MURCS in the male'.
PMID- 9546834
TI - Congenital ptosis and blepharophimosis in a mentally retarded girl: a new case of
Ohdo syndrome?
AB - A mentally retarded girl with congenital blepharophimosis, ptosis, hypoplastic
teeth and other traits consistent with Ohdo syndrome is reported. Her mother had
had surgery for blepharophimosis as a small child, but did not fulfil the other
criteria for Ohdo syndrome. The mother had also been abusing alcohol prior to the
pregnancy. Differential diagnoses and possible modes of inheritance are
discussed.
PMID- 9546835
TI - Re: Spondylometaphyseal dysplasia with characteristic facial appearance.
PMID- 9546836
TI - Enchondromatosis with features of dysspondyloenchondromatosis and Maffucci
syndrome.
AB - We report a girl with multiple enchondromatosis, unequal leg length, short
stature, congenital scoliosis, lymphangioma, and cutaneous hemangiomata. The
skeletal findings were consistent with the clinical and radiological features of
dysspondyloenchondromatosis except that short stature was not apparent in the
neonatal period. Dysspondyloenchondromatosis is a rare disorder, one of the
several types of multiple enchondromatosis with spinal abnormalities. In previous
reports of this condition the association of vascular lesions usually found in
Maffucci syndrome has not been described.
PMID- 9546838
TI - A new case of the acromegaloid facial appearance syndrome?
AB - An apparently new case of the acromegaloid facial appearance syndrome is
reported. The main clinical findings were coarse facies and thickened lips, oral
mucosa and upper eyelids. The patient also had macrocephaly with an arachnoid
cyst in the right middle fossa, an anomaly not previously described in
association with this syndrome.
PMID- 9546837
TI - Livedo reticularis, developmental delay and stroke-like episode in a 7-year-old
male.
AB - Livedo reticularis is a vascular abnormality of the skin resulting in an
erythematous reticular rash. The combination of livedo reticularis and stroke
like episodes in adults is known as Sneddon syndrome [Sneddon, IB (1965). Br J
Dermatol 77:180-188]. A similar combination of stroke-like episodes and livedo
reticularis has been reported to occur in children [Baxter P et al. (1993). Dev
Med Child Neuro 35:917-926]. We present here a 7-year-old male with congenital
livedo reticularis, obesity, developmental delay, stroke-like episode,
hypertension and cystic kidneys. We summarize our patient's findings and family
history, and compare his disorder to other possibly related conditions.
PMID- 9546839
TI - Waardenburg syndrome: variable phenotypic expression in monozygotic twins.
PMID- 9546840
TI - The hand arm vibration syndrome: a review.
AB - Since its first description over eight decades ago, the hand arm vibration
syndrome-- vibration white finger as it was previously known--has become one of
the most common prescribed diseases in the industrialized world. This article is
intended to provide a broad review of existing evidence and knowledge regarding a
disease which, for medicolegal reasons, demands attention from all medical
personnel. Detailed discussion is presented regarding: the multifactorial
aetiology of the syndrome; suggestions for clinical assessment, laboratory
investigations and classification of disease severity; and strategies for the
prevention and treatment of the syndrome.
PMID- 9546841
TI - The antiphospholipid syndrome and vascular surgery.
PMID- 9546842
TI - Interposition vein cuffs--are they effective?
PMID- 9546843
TI - Patency of infrainguinal polytetrafluoroethylene bypass grafts with distal
interposition vein cuffs.
AB - Polytetrafluoroethylene (PTFE) prosthetic bypasses in the lower extremity have
poor patency rates, particularly in limb salvage cases. Patency and limb salvage
rates of PTFE bypasses supplemented by distal interposition vein cuffs were
assessed in patients requiring revascularization for critical limb ischemia, in
the absence of a suitable autologous saphenous vein. Between October 1993 and
April 1996, 163 patients underwent 185 infrainguinal bypasses. Forty-three limbs
in 42 patients (12 women, 30 men; mean age 67 years) did not have a suitable
autologous saphenous vein (24%) and had femoropopliteal (20) and infrapopliteal
(23) bypasses performed. Patients were examined prospectively at 3-month
intervals during the first year and at 6-month intervals thereafter to determine
graft patency and limb salvage. Postoperative anticoagulation with warfarin was
used in 26 patients. Indications for operation included limb salvage in 41
extremities (21 rest pain/ulceration or gangrene, 20 rest pain alone), and
disabling claudication in two. Patients were followed clinically for 2-30 months
(mean 10 months). Cumulative 2-year life-table patencies for all grafts,
femoropopliteal and infrapopliteal bypasses were 64%, 75% and 62%, respectively.
Previous primary patencies at the authors' institution for PTFE bypasses without
vein cuffs were 35%, 46% and 12% for the same categories. Cumulative life-table
limb salvage for all PTFE/vein cuff bypasses in the present series was 76%
compared with 37% in previous PTFE bypasses without vein cuffs. Adjunctive use of
distal interposition vein cuffs improves prosthetic graft patency, while
producing satisfactory limb salvage. Postoperative anticoagulation did not
influence graft patency. PTFE/vein cuff for lower-extremity revascularization
shows good 2-year patency and is an acceptable alternate conduit in patients with
critical limb ischemia when autologous saphenous vein is absent.
PMID- 9546844
TI - Nondissection method for tibial bypass surgery using Esmarch's rubber bandage or
an automatic sequential pneumatic tourniquet: long-term results.
AB - It is suspected that operative injury to the native arteries during a vascular
bypass procedure causes periarterial fibrosis contributing to late graft failure.
A a nondissection method for tibial artery bypass has been developed using
Esmarch's rubber bandage or an automatic sequential pneumatic tourniquet. This
retrospective study examined patency and other late results in distal bypass
operations using the nondissection method. Between June 1982 and July 1995, 78
tibial bypasses were performed using reversed autogenous saphenous vein grafts in
70 patients (57 men, 13 women; mean age 57.4 years). Graft patency was assessed
angiographically. When a stenotic lesion was recognized, the graft was revised
and considered an assisted primary patency. Primary patency rates at 1, 3, 5, and
10 years were 82.8%, 75.3%, 63.4% and 63.4%, respectively, by life-table
analysis. Six grafts required revision for stenosis; one involved distal
anastomotic stenosis. As a result, assisted primary patency rates resembled
secondary patency rates of 87.7%, 84.3%, 80.3%, and 80.3% at the same respective
intervals. In conclusion, the nondissection method improved long-term patency by
preventing late distal anastomotic stenosis.
PMID- 9546845
TI - Mesenteric bypass for chronic mesenteric ischaemia.
AB - Chronic mesenteric ischaemia is an uncommon disease that requires treatment to
relieve the symptoms of abdominal angina and to prevent intestinal infarction.
Over a period of 3 years, 12 patients with visceral artery stenosis or occlusion
were referred to the authors' service and 10 underwent mesenteric bypass
grafting. Both the coeliac and the superior mesenteric arteries were
revascularized in four patients, and the superior mesenteric artery alone in six
patients, using a variety of grafts and graft configurations. This was done in
conjunction with aortic graft placement in four cases and with renal bypass in
three. All patients survived the procedure. At a mean follow-up of 28 months, one
patient died of myocardial infarction 42 months after surgery, while all
survivors are symptom-free. Chronic mesenteric ischaemia can be treated safely
and effectively. The variation in the pattern of mesenteric occlusions and the
frequent association with aortic and renovascular disease does not allow for a
single 'best' technical solution but requires the surgical procedure to be
individually tailored.
PMID- 9546846
TI - Some popliteal aneurysms are congenital.
AB - Although the majority of popliteal aneurysms are of atherosclerotic origin and
are discovered in patients aged more than 50, the aetiology of a small minority
may be attributed to arterial trauma, septic disruption, Behcet's disease, a
medial fibromuscular dysplasia, or popliteal entrapment. The aim of this study
was to propose a possible congenital origin for popliteal aneurysms without
evidence of any other aetiology. A retrospective review of five younger patients
(aged 20-45 years) with seven non-atherosclerotic popliteal aneurysms was
performed. In patient nos 1 and 2, histological examination showed that the
arterial wall had been replaced by an abundant collagenic tissue. After
replacement by a saphenous bypass graft, these patients did well with a follow-up
ranging from 1 to 15 years. Patient no. 3 was not operated on because of a
symptomless occlusion of the tibial and peroneal arteries, and remains well 10
years later. Patients nos 4 and 5 were treated with a saphenous bypass graft. The
last patient also had associated bilateral congenital anomalies of the division
of the popliteal arteries. In the absence of any evidence of any classical
aetiology, particularly fibromuscular dysplasia and popliteal entrapment, a
congenital aetiology is proposed in aneurysms diagnosed in younger patients. The
complex composition of the popliteal artery, being composed by an association of
three original segments, may induce a fragility of the arterial wall that may be
responsible for aneurysmal deterioration as well as abnormal branching or
popliteal artery entrapment. These aneurysms are associated with the same risk of
thrombosis as atherosclerotic aneurysms and therefore, they should be subjected
to the same therapeutic considerations.
PMID- 9546847
TI - Correction of total anomalous pulmonary venous connection of the cardiac type.
AB - Surgical treatment of the cardiac type of total anomalous pulmonary venous
connection requires special techniques. The treatment and outcome in 17
consecutive patients who had undergone primary repairs of the cardiac type
between 1965 and 1996 were reviewed. The median age was 3 months and median
weight 4.2 kg. The connection was the coronary sinus in ten patients, and the
right atrium in six. Interatrial communication was routinely augmented. The right
atrial cavity was partitioned using a patch to direct the anomalous pulmonary
veins into the left atrium through the atrial septal defect in the first 13
patients. In the last four patients, the free wall flap of the right atrium was
developed as a neoseptum. There were three early postoperative deaths during the
early period of conventional repair. Two patients developed residual or recurrent
diffuse obstruction in the individual lobar veins; reoperation to relieve the
obstruction was attempted but unsuccessful. One sudden death occurred in a
patient with occasional heart block. Ten survivors have been asymptomatic during
follow-up, but two incomplete heart blocks and one atrial flutter were noted
among patients who underwent conventional repair. The right atrial wall flap
technique was not associated with any mortality or morbidity, such as arrhythmia
and recurrent pulmonary vein stenosis during 12 to 63 months of postoperative
obstruction. In conclusions, a flap technique using the right atrial wall appears
to be a promising method to decrease the incidence of supraventricular
arrhythmias and pulmonary vein drainage obstruction following repair of the
cardiac type.
PMID- 9546848
TI - Predicting outcome after myocardial revascularization in patients with left
ventricular dysfunction.
AB - In order to identify the risk factors which could predict outcome after coronary
artery bypass grafting in patients with left ventricular dysfunction, 80
consecutive patients with an ejection fraction < or = 30%, who underwent isolated
coronary artery bypass grafting at the authors' centre between January 1994 and
May 1996 were evaluated. Preoperatively, mean(s.d.) ejection fraction was
27.1(3.8)%, 56 patients (70%) had angina, and 56(70%) were in New York Heart
Association (NYHA) functional class III or IV. There were five operative deaths,
with a hospital mortality rate of 6.3%. Significant risk factors for hospital
death were NYHA class IV, preoperative ventricular arrhythmias and left
ventricular end-diastolic volume index > 110 ml/m2. At mean follow-up of 15(7)
(range 6-30) months, there were six late deaths, five of which were from cardiac
causes. Actuarial survival rate at 2 years was 82(5)% and freedom from cardiac
death 84(5)%. Risk factors for overall mortality from cardiac causes were
preoperative grade 2 mitral regurgitation, associated with left ventricular
dilatation, and renal dysfunction (creatininaemia > or = 180 micromol/l). At
follow-up, mean ejection fraction was 37.5(8.4)%, and the overall functional
status had improved: 12 patients (18%) had angina and eight (12%) were in NYHA
class III and IV. Myocardial revascularization in patients with left ventricular
dysfunction can be performed with acceptably low operative risk, good survival
rate at 2 years, and functional status improvement. Patients with extensive
ventricular dilatation, associated with significant mitral regurgitation, have a
lower life expectancy and less functional benefits from coronary artery bypass
grafting. These patients are better treated by cardiac transplantation.
PMID- 9546849
TI - Na+/H+ exchange inhibition improves post-transplant myocardial compliance in 4
hour stored donor hearts.
AB - Na+/H+ exchange inhibitors have cardioprotective properties. The effects of the
new Na+/H+ exchange inhibitor, HOE642 on myocardial function were assessed after
transplantation of canine brain-dead and non-brain-dead donor hearts preserved
for 4 h. Four groups were studied: brain-dead donors; non-brain-dead donors;
brain-dead donors and recipients treated with HOE642 (2 mg/kg); and treated non
brain-dead donors and recipients. Donor hearts were stored in NIH2. At the end of
60 min reperfusion after transplantation, pressure-volume curves were
constructed. Biopsies were analysed histologically and ultrastructurally.
Afterwards, weaning from cardiopulmonary bypass was accomplished. HOE642 improved
compliance in hearts from both brain-dead and non-brain-dead donors. No
differences in myocardial water content nor in myocardial performance were
detected. No irreversible damage was seen ultrastructurally. It is concluded that
myocardial compliance after transplantation was improved by administration of
HOE642. The use of this inhibitor might improve the current myocardial
preservation technique for transplantation.
PMID- 9546850
TI - Predictors of hospital mortality in type A aortic dissections: a retrospective
analysis of 148 consecutive surgical patients.
AB - Reports in the literature frequently concern miscellaneous types of dissections.
This makes correct interpretation of data difficult. In order to assess the
determinants of hospital mortality, the results of 148 consecutive patients over
a 23-year period, all operated on for a type A dissection, were reviewed.
Mean(s.d.) age was 56(13.1) years, 64% were male. An acute dissection (surgery
within 14 days after onset of symptoms) was performed in 139 patients. Stigmata
of the Marfan syndrome were present in 6.1% (n = 9). Peripheral vascular
ischaemic complications were observed in 27.7%. Nowadays, diagnosis is primarily
confirmed using transoesophageal echocardiography (75 correct diagnoses among 76
performed). Operation consisted of repair or replacement of the ascending aorta.
Resuspension of the aortic valve was performed in 74 patients, and arch
replacement in 25. In 74 patients, distal repair was done under deep hypothermic
circulatory arrest. Hospital mortality rate was 23.6% (35 patients), though
mortality rate calculated over the period 1990-1993 was 17.4% (P = n.s.).
Univariate analysis revealed the following variables to be statistically
significant predictors of hospital mortality (P < 0.05): preoperative ischaemic
complications, preoperative resuscitation, haemopericardium, postoperative
neurological complications, rethoracotomy, renal insufficiency and intestinal
ischaemia. Multivariate stepwise logistic regression indicated preoperative
resuscitation, postoperative haemodialysis and postoperative neurological
complications as the only independent predictors of hospital death. Dissections
arising from a primary intimal tear in the descending aorta had a more favourable
outcome (P = 0.06, odds ratio 0.1). Although hospital mortality has declined over
the past few years, no decline was seen in operative mortality since gelatine
resourcine-formol (GRF) glue is used as a routine. Transoesophageal
echocardiography is the first choice in confirming diagnosis. Early operation is
advocated, with careful haemostasis, before the development of cardiac tamponade
or end-organ ischaemia, as the cornerstone of a successful treatment of a type A
dissection. Reduction of neurological complications will further improve the
results.
PMID- 9546851
TI - Coronary bypass with arterial conduits.
AB - To assess the efficacy of arterial revascularization 368 patients were studied
who underwent myocardial revascularization with two or more arterial conduits
(group M) and compared with 2092 patients in whom a single internal mammary
artery +/- veins (group S), and to a third group in which only saphenous vein
conduits (group V, n = 602) were used. Group M patients were younger (aged
54.0(9.5) years; 4.1% aged > 70 years) than either group V (67.6(8.9) years,
40.7% > 70 years, P < 0.0001) or group S patients (62.0(8.5) years, 15.7% > 70
years, P < 0.0001). Furthermore, this cohort group had the lowest percentage of
females (8.4%), of urgent cases (21.7%), of preoperative myocardial infarction
(6.0%), and of redo surgery (0.8%). In contrast, patients who received only
saphenous vein conduits had the highest proportion of female patients (29.2%), of
urgent cases (47.4%), of preoperative myocardial infarction (16.5%), and of redo
surgery (5.5%). By multivariate logistic regression analysis (odds ratio in
parentheses), redo surgery (6.06, P = 0.0001), preoperative intra-aortic balloon
pump assist (6.11, P = 0.0001), diabetes (1.97, P = 0.03), urgent surgery (1.80,
P = 0.05), and advanced age (2.14, P = 0.01) were all predictors of operative
mortality. In contrast, while choice of conduit appeared to influence outcome by
univariate analysis (4.2% mortality in group V, P < 0.001), it was not found to
be a predictor of either mortality or morbidity by regression analysis. The
present results indicate that, in carefully selected patients, despite increased
technical demands with longer periods of aortic occlusion and longer pump times,
multi-arterial grafting (compared with conventional revascularization) is a safe
and efficacious procedure. Whether or not this approach to revascularization will
increase long-term survival and freedom from reoperation will require further
study.
PMID- 9546852
TI - Coronary artery bypass grafting in a patient with type II heparin associated
thrombopenia.
AB - Two types of heparin-associated thrombopenia can be distinguished. Patients with
the type II condition present a particularly difficult management problem when
they require full anticoagulation. There is no consensus about the proper
anticoagulation management for type II patients who have to undergo
cardiopulmonary bypass. The case is reported of a type II heparin-associated
thrombopenia patient who underwent successful aortocoronary saphenous vein
grafting. Sodium-danaparoid was used for anticoagulation. The anti-factor Xa
level was kept below the value reported in the literature for patients undergoing
cardiopulmonary bypass. No fibrin formation was observed during the time of
cardiopulmonary bypass, nor was any severe postoperative haemorrhage seen, as is
frequently described in the literature.
PMID- 9546853
TI - Primary palmar hyperhidrosis presenting with unilateral symptoms: a report of two
cases and review of the literature.
AB - Two cases of primary palmar hyperhidrosis are presented. T2-T3 sympathetic
ganglionectomy of the affected side completely alleviated perspiration of the
palms, but oversweating of the contralateral palms appeared a few weeks later. A
similar sympathetic ganglionectomy of the second side, 1 month and 1 year later,
resulted in renewed oversweating of the palm on the first operated side within 3
months of the second operation. During the same period, 127 other patients with
primary palmar hyperhidrosis underwent a bilateral upper dorsal sympathectomy,
though the condition did not recur in any of these patients. The possible
mechanism(s) of why overperspiration of the second hand developed after the first
sympathectomy in these two patients, and why it recurred in the first hand after
the second operation are examined, but remain obscure.
PMID- 9546854
TI - [VII Congress of the Spanish Society of Neuroscience. Santander, Spain, 22-26
September 1997. Abstracts].
PMID- 9546855
TI - [Efficacy of the meningococcal vaccine from Group C capsular polysaccharide].
AB - BACKGROUND: This report is a systematic review of the effect intensity and
duration of the immune response to meningococcal serogroup C vaccine. The vaccine
safety, efficacy and effectiveness are also analyzed. METHODS: MEDLINE literature
search in the period 1970-1996. Meningoccocal polysaccharide vaccine clinical
trials and human prospective studies were specifically searched. Quality of the
retrieved studies were analyzed. Information available was integrated. RESULTS:
Group C meningoccal polysaccharide vaccine is a safe product. Its efficacy is
over 85% among adults and children over 5 years old. 70% (CI 95%: 5-91%) under 5
years old, and 55% among children 2-3 years old. The vaccine is not effective
under 2 years. The duration of protective antibody levels decrease with age. The
proportion of vaccinated children effectively protected one year after
vaccination is low. Vaccination does not affect the immune response to ulterior
revaccination. CONCLUSIONS: Group C meningococcal polysaccharide vaccine is
indicated in adults and children over 2 years old to protect them from
meningococcal disease due to group C when exposed to high risk of infection. The
outbreaks control is the main indication for the use of this vaccine. Routine
immunization in not outbreak situation is not recommended due to the small
vaccine protection in children under 2 years old, the limited efficacy in
children under 5, and the short duration of the immunity in children.
PMID- 9546857
TI - [Mortality among young people and its impact on life expectancy in Andalusia
during 1980-1992].
AB - BACKGROUND: From the middle eighties, mortality in the age group 15 to 39 years
in Andalusia has experienced an important increase; the object of this work is to
analyse mortality in this age group, in order to discover the causes which have
brought about this increase in mortality and to assess its impact on life
expectancy in the eighties. METHODS: Using the mortality data and the population
of Andalusia from 1980 to 1992, specific rates have been calculated, both for
mortality by age and cause as well as those adjusted for age. To quantify the
impact of the causes of death with respect to life expectancy development, the
Pollard method was used. RESULTS: There was a relative increase in the mortality
of Andalusian young people between the three-yearly periods 1980-1982 and 1990
1992. The causes contributing to this increase, amongst the male population,
were: Aids with an excess of 825 deaths, 575 in traffic accidents, 155 suicides
and 147 deaths from drug overdoses. These same causes of death led to total
losses of 0.46% years in the gain of life expectancy. Amongst women, on the other
hand, the causes of death maintained relatively stable rates, with an almost
imperceptible effect on life expectancy at birth. CONCLUSIONS: The increase in
mortality in the 15-40 age group for causes mentioned previously, is an almost
exclusive phenomenon amongst young Andalusian men. This produced a slow-down in
any gain in life expectancy during the eighties.
PMID- 9546856
TI - [Disability evaluation: Barthel's index].
AB - In Public Health exists a growing tendency to evaluate the impact of health
problems both on the quality of life of the persons involved as well as the use
of health services. In this sense, the evaluation of incapacity is acquiring ever
greater relevance. The Barthel Index is an instrument widely used to this end and
measures the capacity of the person for the execution of ten basic activities in
daily life, obtaining a quantitative estimation of the subject's level of
dependency. The Barthel Index has been used, since its introduction in 1955,
resulting in numerous versions, as well as serving as a standard of comparison
with other scales. It is an easily applicable method, with a high level of
reliability and validity, capable of detecting changes, easy to interpret and the
application of which is not problematic. On the other hand, its adaptation to
different cultural environments is almost immediate. Although it has a few
limitations, the Barthel Index may be recommended as a selection method for
measuring physical incapacity, both in clinical practice as well as in
epidemiological investigation and Public Health.
PMID- 9546859
TI - [Healthy aging and functional disability among the elderly inhabitants of the
Canary Islands (Spain)].
AB - BACKGROUND: Among the elderly, health is usually measured in terms of ability for
both the Basic and Instrumental Activities of Daily Living. The objective of this
work is to estimate the percentage of healthy elderly among the population of the
Canary Islands (Spain) and the factors associated with functional disability in
this older population. METHODS: We randomly sampled 411 elderly from the whole
population of the Canary Islands, of whom 97 had died or could not be located. Of
the 314 people approached, 29 (9.2%) denied participation. The 285 participants
were interviewed with the Spanish version of Pfeiffer's Functional Assessment
Inventory previously adapted and validated in our habitat. RESULTS: Up to 53% of
the elderly (61% of males and 47% of females) were disability-free. Greater
disability was associated with higher age, lesser education, worse subjective
health, worse subjective vision, and worse subjective hearing. No association of
disability with female gender and cognitive deficit was found when including age
and education in the logistic model. CONCLUSIONS: Health status among the elderly
in the Canaries is similar to that in developed countries. In contrast with other
studies, we found functional ability associated with poor hearing and dissociated
from cognitive deficit.
PMID- 9546858
TI - [Daily mortality in the Madrid community during 1986-1991 for the group between
45 and 64 year of age: its relationship to air temperature].
AB - BACKGROUND: There are many types of work which relate mortality with different
environmental factors. These focus on the general population or in the over-65
age-group, but are relatively few in those with reference to the 45-64 age group
in which mortality has a large economic and social impact. The object of the
present article is to analyse the existant association between daily mortality,
from both diverse specific causes, as well as the air temperature in this group
in Madrid. Madrid's extreme climatic characteristics make this work of special
interest. METHODS: The ARIMA model was used according to the Box-Jenkins
methodology for the infiltration of the daily series of mortality regarding
temperature. Amongst the residuals, interrelated functions were established which
establish an association between series eliminating communal seasonal factors as
well as determining the length of disequilibrium between thermal extremes and
excesses in mortality. RESULTS: There is a V-shaped relationship between total
daily mortality and temperature. The minimum mortality rate is established at a
maximum daily temperature of 33 degrees C. Excess mortality is 0.8% for each
degree below 33 degrees C, while that for each degree above is 3.0%. The
functions of interrelated correlation indicate that this association is clear in
males regarding general mortality as well as for circulatory diseases. In the
case of high temperature the effect is immediate, while in lower temperatures we
have to add a delay of 10-13 days. CONCLUSION: There is a significant statistical
association between mortality and temperature extremes in people of this age
group. Lost life expectancy indicates the extent of the problem and the need to
implement preventative measures.
PMID- 9546860
TI - [Seroprevalence of the infections caused by Borrelia Burgdorferi and Rickettsia
Conorii in humans and dogs in primary health care of San Andreas del Rabanedo
(Leon, Spain)].
AB - BACKGROUND: Positive results in infections of borrelia burgdorferi and Rickettsia
conorii in human and canine population is studied in order to understand the
situation of both in humans, and at the same time discover the importance of the
dog as an indicator of these agents among those in the Health Area of San Andres
del Rabanedo, Leon. METHODS: A study was made of 98 human serums and 95 canine
serums (dogs of different breeds and capabilities) as regards B. burgdorferi
(positive results 1/128 and 1/64, respectively) and 104 human serums and 84
canine serums as regards R. conorii (positive results at range 1/64 in both
species) by means of indirect Immunofluorescence (IFI). RESULTS: Positivity in
both infections was discovered in both humans and dogs. With regard to B
burgdorferi it was higher in humans than in dogs and with regard to R. conorii it
was higher in dogs than in humans. In humans it was 4.08% as regards B.
burgdorferi and 1% with respect to R. conorii: in dogs it was 2.10% as regards B.
burgdorferi and 14.28% regarding R. conorii. The highest values were discovered
in the Spring-Summer months except in the case of B. burgdorferi in dogs. Serum
prevalence was greater in dogs used to guard other animals (sheep) than those
involved in hunting and security. CONCLUSIONS: The percentages of positive
results discovered in our work, in humans as well as dogs, estimated in the
territorial area of a geographical zone in a semi-rural Leon province, were equal
or inferior to those discovered in other provinces, including ours. In dogs there
were larger positive results regarding R. conorii than B. burgdorferi, which
indicates that it is the most extended agent within our Province, as other
authors have pointed out. The values discovered in humans as regards B.
burgdorferi were higher than those in dogs; the existence of reactions crossed
with other microorganisms may have influenced these results. For this reason, we
consider it necessary to conduct more studies on the prevalence to these
infections to obtain an appropriate epidemiological surveillance and control of
these zoonosis, given their impact on public health.
PMID- 9546861
TI - [The evaluation of epidemiological services related to brucellosis in the
Autonomous Community of the Basque Country].
AB - BACKGROUND: Spain's Epidemiologic Notifiable Disease Surveillance System (ENDSS)
was evaluated by reference to Brucellosis, the zoonoses with greatest incidence
countrywide and a disease that is notifiable on a case by case basis in the
Basque Autonomous Region (BAR). METHODS: ENDSS information and the use to which
it was put, were analysed. Active case searching was carried out via the
Microbiologic Information System (MIS), public hospitals and the Occupational
Disease Registry (ODR). A comparison was run between reported and search data.
The capture-recapture method was used to compare ENDSS against hospital cases.
RESULTS: Risks and outbreaks wee detected. Suspect cases were not reported. There
was a 40% post-search increase in cases, i.e., 40 versus a previous figure of 24.
Sensitivity was estimated at 60%. Predictive Value Positive could not be computed
however. No case definition was in force. As estimated by the capture-recapture
method, overall sensitivity for both ENDSS and hospital-based surveillance was
84% (95% IC: 70-100). The number of cases estimated by this method was 38 +/- 8.
CONCLUSIONS: Underreporting is in evidence and, as a consequence, sensitivity is
low. A case definition is called for. Response time is slowed by awaiting
confirmation before reporting. The number of cases detected through active
searching is compatible with that calculated by the capture-recapture method
using only two sources.
PMID- 9546862
TI - [The evaluation of hospital management of sanitary waste in the principality of
Asturias].
AB - BACKGROUND: With the object of evaluating the management of sanitary waste of 12
publicly funded Asturian hospitals, a visit was paid to the hospital services,
particularly significant as regards the generation of waste (a total of 91
services). The evaluated hospitals represent 75.10% of the total hospital beds in
the Principality. METHODS: Interviews with personnel from 91 different services
were undertaken, always by the same interviewer, and according to the rules of
the Joint Commission of Health Care Organizations. The information obtained was
afterwards verified by the interviewer by means of direct observation. RESULTS:
Amongst the most relevant results, the absence of adequate containers for
"clinical" waste in 28.5% of the services visited, stands out. Into the bargain,
82.4% of the services classify this type of waste incorrectly. The percentage of
incorrect classification is 1.1% for "special" waste. In large hospitals (with
over 300 beds), 60% of the services have information on the handling of waste,
but only 40% of these hospitals have adequate supervision over the management of
waste by the Service of Preventive Medicine or another equivalent service.
CONCLUSIONS: The level of incorrect classification of sanitary waste which has
been discovered suggests that, in order to improve the intra-hospital management
of waste, it is necessary to increase the amount of information, modify certain
attitudes of the hospital staff and reinforce the level of supervision executed
by the Services of Preventive Medicine.
PMID- 9546863
TI - [The role of the sanitary authorities in the public health network in the 21st
century].
PMID- 9546864
TI - [Gastro-hemorrhagic Escherichia coli].
AB - Groups of Escherichia coli enteropathogen are described, with special attention
to Escherichia coli enterohaemorragic. Some serotypes of Escherichia coli
verocitotoxin-producing are able to produce haemorrhagic enteritis, which can
develop a complication with hemolityc uraemic syndrome. This complication is most
frequent in children and has a high mortality rate. The transmission takes place
via food and its capacity to cause epidemic outbreaks together with the
seriousness of the complications caused by enteritys make this microorganism of
great importance to Public Health. The epidemiology of this microorganism in
Spain is reviewed.
PMID- 9546865
TI - [Tobacco use disorder prevalence among hospital workers].
AB - BACKGROUND: In Spain, as in other countries, numerous studies on tobaccoism have
been carried out. The purpose of this survey was to evaluate the prevalence of
tobaccoism in a representative sample of hospital employees and its association
with age, sex, profession level and attitudes. METHODS: Following a pilot study,
a survey was carried out amongst a representative and random sample (n = 360) of
hospital personnel, who were asked about their attitudes towards smoking,
classified according to age, sex and professional level. RESULTS: The total
percentage of smokers was 36.4%, but no significant statistical differences were
found between sex or age group. The professional levels with the highest
percentage of smokers are ATS/DUE and clerks. 42.8% of non-smokers declared
having smoked in the past. ATS/DUE, clerks and doctors showed the highest
percentage. 40.5% of smokers declare that they were willing to give up smoking,
whereas people over 50 were the most reluctant. The majority of cigarette smokers
admitted that they smoke in the hospital. Most of them are intermediate smokers
(10-20 cigarettes per day) and have been so for many years. The majority of
former smokers gave up smoking in recent years. CONCLUSIONS: These results prove
that a large number of hospital employees are smokers. However, many are willing
to give up the habit. We should therefore encourage these people to give up
smoking and help them by different means such as: anti-smoking advice, medical
advice and health education. We propose to declare hospitals as "Non-Smoking
Area" as of the year 2000 which includes employees, patients and visitors,
according to the WHO "Health for All." program.
PMID- 9546866
TI - [Epidemiology of leprosy through the study of frequency of visits to the Trillo
Specialized Hospital in 1943-1995].
AB - BACKGROUND: The purpose of this study is to describe the social-demographic and
clinical profile of hospitalised leprosy patients and to check whether typology
has changed during the history of the centre. METHODS: Descriptive and
retrospective study, performed by means of reviewing a sample of the patient
records registered at the Centre since it was founded in 1943 until 1995. 366
cases were chosen by means of a systematic random sample and questionnaires
completed on social-demographic and clinical variables. RESULTS: Most of the
patients were male (71.9%, IC: 67.3-76.4), young (39.6 years of age, IC: 37.9
41.4), single (46.2%, IC: 41-51.3%) with low levels of education (illiteracy:
54.1%, IC: 40-69) with occupations relating to farming (35.5%, IC: 30.6-40.4)
from Southern Spanish regions (patients from Andalucia 52.8%, IC: 45.8-54). The
disease showed a family background in 31.1% of cases (IC: 26.4-35.9) and serious
multibacillary forms (Lepromatose Leprosy 66.1%, IC: 61.2-71), which affected
lower limbs in 72.1% of cases, heads in 63.1% and upper limbs in 64.4%. Global
mortality of people admitted to hospital was 31.1% (IC: 26.4-35.9). During the
surveyed period, patient age increased, and symptoms and mortality decreased. In
general, hospital stays were for long periods (7.1 years, IC: 6.1-8.1), although
at the end of the surveyed period, stays decreased considerably, in accordance
with the duration of treatment (2.2 years). CONCLUSIONS: A Young male, in a
precarious financial situation living in the South of Spain appear to be the
patient profile which, with severe initial anatomical symptoms and later
favourable results may represent the disease in a country with an autocuthonous
endemy and characteristic epidemiology, which is in the pre-eradication phase.
PMID- 9546867
TI - [Continuity and longitudinal aspects of care in general practice in four European
countries].
AB - BACKGROUND: The objective of the study was to compare continuity and
longitudinality of care in general practice in four European countries with a
public salary model. METHODS: Descriptive and prospective study. 63 general
practitioners/family physicians working in public health centers registered all
encounters (direct and indirect) over a period of one week in Spain, Finland,
Portugal and Sweden. RESULTS: 92% of the contacts were office encounters: 75%
were direct (face to face), the average number of encounters per doctor, per week
was 103. The principal problem was chronic in 42% of cases and acute in 31%. The
physician has previous knowledge of the principal problem in 63% of the
encounters and previous knowledge of concurrent problems in 79%. In 66% of cases
the doctor has previous knowledge of the patient relatives. CONCLUSIONS: The
level of continuity and longitudinality is variable; from high to low: Portugal,
Spain, Sweden and Finland. In Spain the duration of the encounter is short and
repeated prescription are infrequent. In Portugal there are waitings lists which
implies low accessibility for acute problems. In Finland general practitioners
have no patients lists and the care is des-personalized. In Sweden there are
waiting lists and high use of telephone encounters.
PMID- 9546868
TI - [Eating and life style habits in primary school student population from Mataro
(Barcelona) associated with consumption of sugar and TV watching].
AB - BACKGROUND: Most important trends of knowledge and behaviour are built on
childhood and adolescence. Thus, to act on non healthy habits at early ages
should have more impact in the development of later diseases. METHODS: 2,898
primary school students answered a written self administered questionnaire
containing items about Dietary habits life-style habits, and familiar
socioeconomic level. Cluster analysis was used to obtain the profile of student
groups with higher probabilities to develop the risk habits studied. RESULTS:
High consumption of television is associated with older ages, refreshments
intake, and moderate consumption of sugar. On the other hand, high consumption of
sugar is associated with older ages, usual intake of candies, type of school, low
intake of raw vegetables, and low consumption of fruits. CONCLUSIONS: Other non
healthy dietary and lifestyle habits show clustering in high consumers of
television and/or sugar. The influence of socioeconomic level on getting risk
habits is well stated; however, the role played by this variable in the results
of our study remains uncertain, probably due to the utilization of indirect data.
The resultants profiles suggest that the presence of some non healthy lifestyle
habits, such as high television and sugar consumption, tends to cluster other
risk habits in the same person.
PMID- 9546869
TI - Presence of peptide synthetase gene transcripts and accumulation of ergopeptines
in Claviceps purpurea and Neotyphodium coenophialum.
AB - The production of toxic ergopeptine alkaloids by the fungi Claviceps purpurea and
Neotyphodium coenophialum involves the activity of one or more nonribosomal
peptide synthetases. Claviceps purpurea and N. coenophialum each have several
different peptide synthetase genes, fragments of which have been cloned
previously. An additional Claviceps purpurea peptide synthetase gene was cloned
by hydridization with one of the N. coenophialum peptide synthetase gene
fragments. We detected the presence of mRNA from the peptide synthetase genes in
cultures of different ages grown under conditions favorable or unfavorable for
ergopeptine production. All four peptide synthetase genes from Claviceps purpurea
were transcribed under at least some of the experimental conditions. Transcripts
from three of the four genes were detected under conditions consistent with their
potential involvement in ergopeptine biosynthesis. All three peptide synthetase
genes previously identified in N. coenophialum were transcribed during symbiotic
growth of this fungus with tall fescue, as well as ergopeptine-producing
cultures. The data show that all of the peptide synthetase genes are transcribed,
that one of the peptide synthetase genes is dissociated from ergopeptine
biosynthesis, and, as a result, prioritize the remaining genes for functional
analyses by transformation-mediated gene disruption.
PMID- 9546870
TI - Headache and menstrually related disorders: in search of a consensus. Naples,
Italy, 14 November 1995.
PMID- 9546871
TI - Review of chronic pelvic pain.
PMID- 9546873
TI - Iraqi time to PAUSE?
PMID- 9546872
TI - The use of uterine thermal balloon for treatment of menorrhagia.
PMID- 9546874
TI - A classic medical mystery.
PMID- 9546875
TI - Women and herbal medicine in Africa.
PMID- 9546876
TI - The method and role of mediastinoscopy.
PMID- 9546877
TI - Infection control: HIV/AIDS and other bloodborne pathogens.
PMID- 9546878
TI - Nursing informatics--what on earth?
PMID- 9546879
TI - Unannounced JCAHO survey.
PMID- 9546880
TI - MI mortality outpacing growth of chest pain centers.
PMID- 9546881
TI - Divers' treasure--hyperbaric oxygen therapy.
PMID- 9546882
TI - Nursing under pressure.
PMID- 9546883
TI - Mutual recognition practice model a step closer to reality.
PMID- 9546884
TI - Volunteers are angels.
PMID- 9546886
TI - A run in the sun.
PMID- 9546885
TI - Relief for migraine sufferers.
PMID- 9546887
TI - Humility--a misplaced virtue.
PMID- 9546888
TI - Mentoring APRN students.
PMID- 9546889
TI - Programs that will certainly benefit the patients in our service area.
PMID- 9546890
TI - An Octopus in the OR.
PMID- 9546891
TI - High-tech nursing in interventional radiology.
PMID- 9546892
TI - A critical care nurse tries home care.
PMID- 9546894
TI - Humility--a misplaced virtue.
PMID- 9546893
TI - Respiratory syncytial virus: a new approach to an old disease.
PMID- 9546895
TI - Coming to America.
PMID- 9546896
TI - Breaking barriers: a Robinson family tradition. Interview by Catherine Campion.
PMID- 9546897
TI - I.v nurses celebrate.
PMID- 9546898
TI - Recipe for health: laughter and killer cells.
PMID- 9546899
TI - Behavioral modification program equals healthy lifestyle.
PMID- 9546900
TI - APRNs tap vast Internet resources.
PMID- 9546901
TI - ANAC conference highlights innovations in HIV/AIDS care.
PMID- 9546902
TI - Infection control: HIV/AIDS and other bloodborne pathogens.
PMID- 9546903
TI - Home care conference update.
PMID- 9546904
TI - A look at umbilical cord blood.
PMID- 9546905
TI - Medical news rings in 1998.
PMID- 9546906
TI - Rehab nursing: more than you may think.
PMID- 9546907
TI - MI mortality outpacing growth of chest pain centers.
PMID- 9546908
TI - Assisted suicide: an "answer" fraught with questions.
PMID- 9546909
TI - Acute myocardial infarction in a young woman with systemic lupus erythematosus.
AB - A young woman was diagnosed with systemic lupus erythematosus at the age of 7
years and incurred an acute myocardial infarction at the age of 17 years. Her
risk factors for coronary artery disease include hypertension,
hypercholesterolemia, a relatively long disease duration, a fairly active disease
as evidenced by the history of nephrotic syndrome and other organ system
involvement, and a long history of prednisone use. It is difficult to determine
the etiology of this patient's acute myocardial infarction without coronary
artery histopathology, but aspects of her presentation (a history of virulent
systemic lupus erythematosus, and the angiographic findings of ectasia and
aneurysm) suggest that coronary arteritis was the etiology of her accelerated
coronary artery disease and subsequent myocardial infarction. Acute myocardial
infarction is an uncommon occurrence in premenopausal women less than 30 years
old.35 These patients are typically found to have an associated systemic disease
such as diabetes mellitus or familial hypercholesterolemia. Systemic lupus
erythematosus is a less common systemic disease associated with premature
coronary artery disease. Mechanisms of acute coronary syndromes in these patients
include accelerated atherosclerosis, active coronary vasculitis, and/or vasospasm
with superimposed thrombosis.
PMID- 9546911
TI - Quality of life in patients with intermittent claudication: relationship with
laboratory exercise performance.
AB - In patients with peripheral arterial disease, limitation of exercise capacity
will reduce the level of everyday physical activity and affect the quality of
life. This study was designed (1) to examine the health-related quality of life
of patients with intermittent claudication, and (2) to verify whether treadmill
performance is related to the patient's perceived ability to function in the
community. In 251 patients with intermittent claudication and 89 matched normal
subjects, quality of life was assessed by a general health index questionnaire,
the McMaster Health Index Questionnaire (MHIQ), which covers three dimensions of
life (physical, social and emotional function). The maximal walking capacity of
intermittent claudication patients was measured by the treadmill test. When
controls were compared to intermittent claudication patients using the MHIQ, it
was found that intermittent claudication patients showed a significant (p < 0.01)
impairment of 'general health' and lower scores for physical (0.90 +/- 0.17 vs
0.65 +/- 0.17; p < 0.01), social (0.71 +/- 0.11 vs 0.63 +/- 0.12; p < 0.01) and
emotional (0.75 +/- 0.17 vs 0.65 +/- 0.15; p < 0.01) function. Age, gender and
work status had a significant impact upon health scores in several areas.
Treadmill performance did not correlate with social or emotional function,
whereas there was a small but significant relationship between maximal walking
capacity and physical function scores (r = 0.197; p < 0.01). This study suggests
that impairment in quality of life experience by patients with intermittent
claudication poorly correlates with the reduced exercised capacity assessed by
the treadmill test. Therefore, the evaluation of medical and surgical treatment
of intermittent claudication should include the administration of a questionnaire
for quality of life assessment.
PMID- 9546910
TI - The vascular biology of S-nitrosothiols, nitrosated derivatives of thiols.
AB - Nitric oxide (NO) is a simple heterodiatomic molecule with a broad range of
biologic actions. In the cardiovascular system NO serves as an endothelium
dependent vasodilator, an antithrombotic agent, an antiproliferative molecule,
and a regulator of cardiac contractility. Owing to its reactivity under
physiologic conditions, accumulating data suggest that NO forms derivatives with
several classes of biologic compounds. One group of biochemical functionalities
that serves this role is that of thiols, which can form thionitrites or S
nitrosothiols with NO. In this paper we will examine the effects of the
biologically known and the chemically produced S-nitrosothiols on the
cardiovascular system in order to understand better what role these compounds may
play in physiologic and pathologic states.
PMID- 9546912
TI - Images in vascular medicine. Adventitial cystic disease of the popliteal artery.
PMID- 9546913
TI - Claudication as an 'orphan disease': rationale and goals of drug therapy for
peripheral arterial disease.
AB - Patients with peripheral arterial disease are often perceived to suffer from a
disorder whose pathogenesis and symptoms are not amenable to drug therapies. This
clinical misperception remains prevalent despite an abundance of data suggesting
that diverse pharmacotherapies may modulate the natural history of this disease.
Patients with chronic limb arterial occlusive disease suffer from a disease that
is characterized by: (1) a prolonged asymptomatic state that can be identified by
simple physical examination and confirmed by measurement of the ankle brachial
index; (2) a multi-year period of symptomatic claudication; and (3) a variable
rate of progression to critical limb ischemia or acute arterial occlusion. This
stage-dependent disease progression is mediated via the dynamic, but as yet
incompletely understood, interaction of factors that elicit endothelial
dysfunction, atherogenesis, and thrombosis. Current data suggest that each of
these contributory disease processes can be modulated by extant
pharmacotherapies. Additionally, many novel pharmacotherapeutic agents that are
currently under investigation may further improve the ability of clinicians to
modulate these fundamental biologic processes. Pharmacologic therapies should be
targeted to decrease the rate of limb arterial disease progression, to improve
limiting symptoms, and to prolong life. Symptoms of claudication can be
objectively assessed via both exercise testing and disease-specific
questionnaires. The presence of lower extremity atherosclerotic disease is
predictive of the presence of coronary heart disease and a foreshortened five
year survival. Current data suggest that clinical investigations should be able
to effectively stratify this relative risk via use of both clinical variables
(e.g., age, diabetes mellitus, tobacco use, etc.) or by measurement of the ankle
brachial index (ABI). The role of the physician is to decrease suffering and to
prolong life. Judicious administration of medical therapies can play a critical
role in helping the vascular practitioner accomplish these goals.
PMID- 9546914
TI - Experimental models of chronic lower extremity arterial occlusive disease:
lessons for drug development.
AB - Peripheral vascular disease is the result of chronic vascular insufficiency. As
the vascular insufficiency of the lower limbs progressively deteriorates, the
condition progresses from intermittent claudication (pain upon exercise) to pain
at rest and gangrene. In very severe cases amputation of the leg may be
necessary. Whilst dieting, cessation of smoking and physical exercise all
beneficially affect the progression of the disorder, the available drug therapy
is of limited benefit. Very effective pharmacological agents capable of
alleviating the symptoms of chronic peripheral vascular disease have not been
developed. In order to mimic the vascular insufficiency of intermittent
claudication, an animal model was developed in rats. This involves short-term and
long-term 6-10 weeks ligation of the femoral artery of the rat. As demonstrated
using measurements of hindlimb skeletal muscle, blood flow, pO2, metabolism and
function, a model of intermittent claudication was produced. Using this model,
the beneficial effects of physical training was demonstrated. Physical training
induced an increase in blood flow and a greater capacity for aerobic metabolism
in the partially ischaemic skeletal muscle. The effect of vasodilators has also
been examined in this model; in contrast to agents such as Ca2+ antagonists, K+
channel openers appear to improve nutritional blood flow and metabolism in the
afflicted skeletal muscle. This model can also be utilized to demonstrate the
effects of haemorrheological interventions and of agents modulating muscle
metabolism. However, additional effort is required to develop models for the
evaluation of efficacy of antiatherothrombotic drugs.
PMID- 9546915
TI - Microvascular changes in arterial occlusive disease: target for pharmacotherapy.
AB - The main techniques which have been used to study skin microcirculation in
patients with peripheral arterial occlusive disease include intravital microscopy
with and without the use of fluorescent dyes, laser Doppler fluxmetry and
transcutaneous oximetry. In patients with severe ischaemia (rest pain or
incipient gangrene) the number of perfused skin capillaries is reduced. Parallel
to the decreased number of microvessels containing blood, transcutaneous oxygen
tension is low or even approaches the zero level. The tendency to oedema
formation is documented by increased leakage of intravenously injected sodium
fluorescein at the capillary apex of foot skin ('candlelight phenomenon'). Laser
Doppler flux at rest may still be within the normal range even in advanced
disease, since the sample volume of these instruments also contains non-nutritive
shunt vessels. However, reactive hyperaemia after arterial occlusion is decreased
and delayed in peripheral ischaemia. Whereas rhythmic low-frequency vasomotion is
significantly enhanced in patients with intermittent claudication, vasoparalysis
with no flux fluctuations prevails in patients with critical ischaemia.
PMID- 9546916
TI - Skeletal muscle metabolism as a target for drug therapy in peripheral arterial
disease.
AB - Peripheral arterial disease (PAD) is an atherosclerotic disease which modifies
lower extremity hemodynamics. There is considerable evidence that skeletal muscle
metabolism is altered in PAD. Several studies have demonstrated altered
mitochondrial enzyme content in PAD muscle as compared with controls, and enzyme
activity may not increase normally in PAD with exercise training. A variety of
metabolic intermediates, including acylcarnitines, accumulate in muscle of PAD
patients, suggesting incomplete oxidative metabolism. Studies employing 31P-NMR
(nuclear magnetic resonance) also suggest a metabolic myopathy in PAD.
Strikingly, while hemodynamics do not predict claudication-limited performance,
metabolic injury as evidenced by acylcarnitine accumulation is strongly
correlated with patients' functional status in PAD. Further, exercise
rehabilitation improves claudication-limited performance without modifying large
vessel hemodynamics. The stress placed on skeletal muscle during exercise in PAD
and the observed evidence of metabolic dysfunction is similar to
ischemia/reperfusion injury in cardiac muscle. Recognition of the role of
cellular metabolic injury and function in PAD has formed the basis for novel
therapeutic strategies in this disease.
PMID- 9546917
TI - The demographics of claudication and the aging of the American population.
AB - Most peripheral artery disease is of ischemic atherosclerotic etiology and
manifested as intermittent claudication (IC). Death and disability from
atherosclerotic cardiovascular disease (CVD) is a growing problem because of the
rapidly increasing elderly segment of the population. By the year 2015 the
elderly will constitute 14.8% of Americans. Of the total 255 million, 13.8
million are over age 75 years and 9 million are women. On reaching age 65 years,
the average remaining lifetime is 17.4 years. In the USA this 11% of the
population accounts for 29% of the health costs and 70% of all deaths are
attributable to cardiovascular disease. About 9.6% of cardiovascular events are
due to peripheral artery disease manifested as IC requiring 777,000 office visits
and 63,000 hospitalizations. Also, 17,400 deaths each year are attributed
directly to this cause. The biennial incidence of IC in the Framingham Study was
7.1 per 1000 for men and 3.6% for women, increasing with age in both sexes up to
age 75 years. At all ages there is a distinct male predominance. In the 35-64
year age range IC incidence is virtually identical to that of cardiac failure and
stroke, but only one-third of CHD incidence. Beyond age 65 years IC incidence is
only half that of other atherosclerotic cardiovascular conditions. The incidence
of carotid bruits and non-palpable pedal pulses is virtually identical in the two
sexes; only femoral bruits are male predominant. At time of diagnosis of IC one
in three already have overt evidence of CHD, stroke or congestive heart failure
(CHF). In those free of these at outset CHD and strokes occur at two to three
times the general population rate and CHF 3.5-4.5 times the rate of persons
without IC. Within 10 years of IC onset 43% develop CHD, 21% strokes and 24%
cardiac failure. Carotid and femoral bruits are likewise harbingers of other
atherosclerotic CVD. As many as 45% of IC victims lose their symptoms for
extended periods. Survival following onset of IC is only two-thirds of that
general population; after 10 years 60% died. This high mortality is largely
attributable to coexistent cardiovascular impairments. A risk profile comprising
the major cardiovascular risk factors predicts occurrence of IC even better than
CHD. IC risk increases progressively with burden of the risk factors. With an
aging population of increased size peripheral artery disease is a problem of
increasing dimensions. Attention to comorbid conditions is essential if survival
is to be improved. Because IC shares many of the same risk factors, measures to
prevent CHD, CHF and strokes should also reduce IC risk.
PMID- 9546918
TI - The correlation between symptoms and non-invasive test results in patients
referred for peripheral arterial disease testing.
AB - The WHO/Rose questionnaire has served as the epidemiologic and clinical standard
in the assessment of leg pain in patients with peripheral arterial disease (PAD)
for over three decades. However, the structure of this questionnaire does not
allow assessment of leg-specific (i.e. right versus left) symptoms. We studied
508 patients aged 39-95 years (mean 68 years), initially referred for PAD non
invasive testing. A revised questionnaire, the San Diego Claudication
Questionnaire, was administered which allowed determination of leg-specific
symptoms and evaluated thigh and buttock as well as calf pain. Leg-specific
symptoms were categorized into no pain, pain at rest, non-calf claudication, non
Rose calf claudication, and Rose claudication. At the same visit, the ankle
brachial index, the toe brachial index, and peak posterior tibial flow velocity
were measured by Doppler ultrasound and five categories of non-invasive results
by type and severity of PAD were defined. Legs with previous intervention (Rx),
surgery or angioplasty, were evaluated separately. Claudication was reported in
42% of no Rx legs and 50% of Rx legs; 40% of claudication was atypical (not
Rose); 64% of no Rx and 81% of Rx legs had PAD by non-invasive testing, and 27%
of affected legs had severe PAD. The correlation between the severity of symptoms
and the severity of ipsilateral PAD in no Rx legs was r = -0.40, p < 0.001. In Rx
legs, this correlation was somewhat less (r = 0.27, p < 0.001) due to more
symptomatology at lesser degrees of PAD, suggesting reporting bias and/or more
residual disease than evident from non-invasive testing. To our knowledge, these
results provide the first comparison between a standardized assessment of leg
pain and the severity of ipsilateral PAD by non-invasive testing.
PMID- 9546919
TI - New antithrombotics for the treatment of acute and chronic arterial ischemia.
AB - The established antithrombotic agents are effective but they have limitations
which have provided opportunities for the development of new antithrombotic
compounds. Of these new agents, the antithrombin III-independent thrombin
inhibitors and the platelet GPIIb/IIIa receptor antagonists are the most advanced
in their development. Other new antithrombotic agents include the antithrombin
III-independent factor Xa inhibitors, activated protein C, soluble thrombomodulin
and tissue factor pathway inhibitor. Of the GPIIb/IIIa antagonists, the humanized
7E3 antibody and integrin have been evaluated in phase III studies. The 7E3
antibody was effective in preventing both short-term and longer-term
complications of coronary angioplasty. The antithrombin III-independent thrombin
inhibitors hirudin and hirulog have also been evaluated in phase III studies. The
studies with hirudin as an adjuvant to coronary thrombolysis had to be terminated
and restarted at lower dosages because of an unacceptable incidence at
intracranial hemorrhage and the study with hirulog produced equivocal results.
PMID- 9546920
TI - Therapeutic angiogenesis: a new frontier for vascular therapy.
AB - Angiogenic cytokines constitute a potentially novel form of therapy for patients
with cardiovascular disease. The feasibility of using recombinant formulations of
angiogenic growth factors to expedite and/or augment collateral artery
development in animal models of myocardial and hindlimb ischemia--'therapeutic
angiogenesis'--has now been well established. These studies have suggested that
two angiogenic growth factors in particular--basic fibroblast growth factor and
vascular endothelial growth factor--are sufficiently potent to merit further
investigation. More recently, experiments performed in our laboratory have
indicated that, in the case of vascular endothelial growth factor--a secreted
protein--similar results may be achieved by percutaneous arterial gene transfer.
Further laboratory and clinical studies may yield promising insights into the
fundamental basis for native as well as therapeutic angiogenesis, and at the same
time more explicitly define the manner in which therapeutic angiogenesis may be
successfully incorporated into clinical practice.
PMID- 9546921
TI - The influence of apolipoprotein E on the interactions between normal human very
low density lipoproteins and U937 human macrophages: heterogeneity among persons.
AB - Apolipoprotein E (apo E) can mediate the cell binding of normal human very low
density lipoproteins (VLDL). However, the extent to which apo E is involved in
the cell binding and uptake of VLDL from different normolipidemic persons is not
well defined. The VLDL (d < 1.006 g/l) of eight subjects were fractionated into
VLDL with apo E and without apo E using a monoclonal antibody that binds to the
LDL receptor recognition region of apo E. VLDL particles that expressed the 1D7
binding region of apo E comprised an average of 34% (range 7-51%) of the VLDL
particles. Anti-apo E blocked an average of 43% (range 8-63%) of the binding of
unfractionated VLDL to U937 cells. Anti-apo E blocked a similar proportion of
binding to U937 cells of three VLDL subfractions of different density ranges
(Sf20-60, Sf60-100, Sf100-400). The proportion of the VLDL particles that
contained apo E correlated with the extent of uptake of the total VLDL by U937
cells, but not with stimulation by total VLDL of cholesterol ester formation. The
binding to cells of VLDL without apo E varied by six-fold among persons, and
caused most of the binding of the total VLDL of some subjects. Therefore,
normolipidemic VLDL contains particles across its density range that use apo E to
bind to U937 macrophages. In some VLDL samples, apo E provides most of the cell
binding activity, whereas in others the binding activity occurs by other means.
PMID- 9546922
TI - Hypothermia and rewarming after hypothermic exposure alter venous relaxation.
AB - Hypothermia has pathophysiological consequences on endothelial and smooth muscle
cell function. This study investigates the impact on venous relaxation of
hypothermia and rewarming following hypothermic exposure. In vitro isometric
relaxation responses of norepinephrine precontracted rabbit external jugular
veins to a panel of endothelium-dependent and -independent agonists were assessed
in controls at 37 degrees C, and in an experimental group after cooling to 20
degrees C and after rewarming to 37 degrees C. On cooling, the endothelium
dependent responses to acetylcholine became multiphasic with initial contraction
at low concentrations followed by relaxation at higher concentrations, the
maximum of which was significantly diminished compared to controls. Incubation
with indomethacin did not affect this response. Rewarming re-established a
monophasic dose-dependent acetylcholine induced relaxation response but the
maximal response was significantly augmented. This augmentation in relaxation on
rewarming could be prevented by preincubation with indomethacin. The maximal
response to calcium ionophore was reduced at 20 degrees C and augmented upon
rewarming to 37 degrees C. All veins relaxed in a dose-dependent manner to the
non-endothelium-dependent agonists forskolin and sodium nitroprusside; the
maximal responses were significantly reduced at 20 degrees C and returned to
normal upon rewarming. This study suggests that short-term exposure of venous
tissue to hypothermia impairs the vessel's ability to produce endothelium
dependent relaxation. Rewarming does not re-establish normal endothelium
dependent relaxation but results in an enhanced, partially indomethacin
sensitive, response which appears to be independent of changes in non-endothelium
dependent mediated relaxation.
PMID- 9546923
TI - The impact of angiotensin converting enzyme inhibitors on the arterial wall.
AB - There is recent interest in the possibility that angiotensin converting enzyme
inhibitors (ACE inhibitors) may reduce the damage inflicted on the arterial wall
by common cardiovascular risk factors such as hypertension, hyperlipidaemia and
ageing. The efficacy of these drugs in blood pressure reduction is accepted, but
whether there is an excess benefit on arterial structure and function, conferred
by use of ACE inhibitors over more traditional antihypertensives, is still under
debate. There is also evidence in animal models to suggest that ACE inhibition is
effective in reduction of arterial damage due to experimental hyperlipidaemia.
ACE inhibitors not only reduce the conversion of angiotensin I and angiotensin
II, which can interact with the sympathetic nervous system, but also prevent the
degradation of bradykinin. This means that ACE inhibitors have several potential
mechanisms through which they could suppress intimal hypertrophy and prevent
endothelial dysfunction, which is believed to precede arteriosclerosis in man.
Although much further work is needed to clarify the mechanism underlying the
beneficial effects on the arterial wall of this group of drugs, they do appear to
have significant potential in the effort to reduce cardiovascular mortality and
morbidity, especially in high risk groups.
PMID- 9546924
TI - Can lower limb ultrasonography replace arteriography?
AB - Although duplex ultrasonography offers a number of theoretical and practical
advantages over arteriography for the assessment of lower limb arterial disease,
it has not yet been widely accepted into clinical practice. This article reviews
the current status of lower limb arterial duplex and concludes that arteriography
should no longer be regarded as the diagnostic 'gold-standard' and that duplex
ultrasonography should now be the first line investigation in patients with lower
limb arterial disease.
PMID- 9546925
TI - Carotid angioplasty.
AB - Aspirin and carotid endarterectomy represent the current method of prophylaxis
against stroke in patients with symptomatic high grade carotid stenoses. Whilst
balloon dilatation and stent placement is an accepted form of recannalization,
elsewhere in the arterial circulation the technique is in its infancy within the
supra-aortic vessels. Carotid endarterectomy is expensive, requires a general
anaesthetic and is associated with an acceptable complication rate as
demonstrated by the ECST and NASCET studies. The author's experience in 55
patients with symptomatic high grade atherosclerotic disease is described with a
disabling stroke rate at 30 days similar to the surgical series (5%). Long-term
follow-up is awaited. Metallic intra-arterial stents provide the opportunity to
reduce the immediate postintervention residual stenosis and possibly reduce the
long-term restenosis rate. Modifications of the technique are in development and
may reduce the cerebral embolization that occurs during the procedure.
PMID- 9546926
TI - Quality control during carotid endarterectomy.
AB - Although some form of quality control assessment is standard practice following
virtually all forms of peripheral vascular reconstruction, it is seldom applied
to carotid endarterectomy. This is despite the fact that the complications
following endarterectomy can be catastrophic, are often related to technical
error and are not easily remedied. A number of novel quality control techniques
are now available. This review article summarizes the application of these
methods to ensuring optimal surgical practice in patients undergoing carotid
endarterectomy.
PMID- 9546927
TI - Images in vascular medicine. Buerger's disease (thromboangiitis obliterans).
PMID- 9546928
TI - The PACK trial: morbidity and mortality effects of ketanserin. Prevention of
Atherosclerotic Complications.
AB - A total of 3899 patients over 40 years old who had documented intermittent
claudication for at least 2 months and in whom the ratio of systolic blood
pressure in the ankle to that in the arm was < 0.85 in both arteries of at least
one foot were recruited in a double-blind, randomized, placebo-controlled trial
after a single-blind run-in period of placebo treatment for 1 month. Trial drug
was ketanserin 40 mg three times daily. The first primary event after
randomization was the endpoint. Primary events were definite myocardial
infarction, major stroke, amputation above the ankle, excision of ischaemic
viscera, and death due to other vascular causes. There were 136 study endpoints
in the 1930 patients treated with ketanserin, who were followed up for 2063
patient-years, and 132 study endpoints in the 1969 patients treated with placebo,
who were followed up for 2129 patient-years. A harmful interaction of ketanserin
and potassium-losing diuretics resulted in an increase in the number of deaths.
After patients taking potassium-losing diuretics or antiarrhythmic agents were
excluded, a secondary analysis showed that there were 65 endpoints in 1514
patients taking ketanserin and 87 in 1577 patients taking placebo, a reduction of
23% in the number of study endpoints in those taking ketanserin. The treadmill
walking distance and ankle systolic pressure were measured in a predetermined
subset of 594 patients. Complete datasets at the beginning and end of 1 year's
treatment with ketanserin or placebo were available in 436 patients. There was no
difference between the groups in the improvement in pain-free treadmill walking
distance. The placebo effect on treadmill walking distance increased continuously
for at least 1 year at the rate of about 15% every 6 months. There was no
significant change in either group in the ankle systolic pressure at the end of
the treatment period, but, in the group given ketanserin, brachial systolic
pressure was decreased and the ankle/arm systolic pressure ratio therefore
increased.
PMID- 9546929
TI - The STIMS trial: the ticlopidine experience and its clinical applications.
Swedish Ticlopidine Multicenter Study.
AB - The mortality in patients with intermittent claudication can be reduced by
treatment with ticlopidine. This is the clinically most significant result from
STIMS, the Swedish Ticlopidine Multicenter Study. During an average treatment
period of 5.6 years, 153 of the 687 patients died, 26.1% in the placebo group and
18.5% in the ticlopidine group (RR0.7, p = 0.015). The incidence of fatal
vascular events in the two groups was 12% and 6%. In terms of lives saved per
years of treatment, STIMS showed that by treating 200 claudicants for 5 years one
can save 13 from a cardiovascular death, not merely dying from something else as
treatment was associated with a reduced total mortality as well. The
interpretation of the on-treatment analysis is that for those who tolerate the
drug the combined vascular morbidity and mortality rate is lowered from 24% to
14%. The disadvantage is that many patients do not tolerate ticlopidine. In
STIMS, 22% (2.5 times as many as in the control group) had to stop medication
because of gastrointestinal side-effects. Although ticlopidine is associated with
an increased risk of leukopenia, the risk in absolute numbers is small: according
to STIMS, 4% during 5.6 years. All events were reversible. The 1.4% incidence of
thrombocytopenia did not seem to be associated with ticlopidine treatment.
PMID- 9546930
TI - The pentoxifylline experience: exercise testing reconsidered.
AB - This paper critically reviews the methodology used in clinical trials in chronic
occlusive arterial disease (COAD) stage II (intermittent claudication) patients.
The reasons for choosing internationally accepted standard treadmill settings as
well as its limitations are discussed. Emphasis is put on the discussion of valid
trial endpoints such as hemodynamic surrogates and clinically oriented
parameters. Reasons for a spontaneous and treatment-unrelated improvement in
claudication distance are elucidated, and variables which may be used for the
definition of patient subsamples showing a high frequency of a pronounced
treatment response (treatment responder populations) are presented. The magnitude
of claudication distance improvement that might be considered clinically relevant
is discussed in the light of the European Union guidelines for clinical trials in
COAD patients. Results achieved with pentoxifylline are presented in context with
all variables mentioned above.
PMID- 9546931
TI - Prostanoid drug therapy for peripheral arterial occlusive disease--the European
experience.
AB - The most serious threat to a claudicant is not the possible future need for a
major amputation, but rather that the medium-term mortality is two to three times
that of the general age-matched population. In patients with more severe disease
in the legs, approximately 45% will have had a major amputation or be dead within
a year of developing rest pain, ulcers or gangrene. These are the challenges for
pharmacotherapy in peripheral arterial occlusive disease. In the short and medium
term, pharmacotherapy can only have a significant effect by modifying the
microcirculatory response to the low perfusion pressure caused by the arterial
disease. The microcirculatory changes in the leg in severe leg ischaemia are ill
understood, but theoretically a number of pharmacological effects could be
beneficial. In practice, the only type of drugs widely tested clinically in
severe leg ischaemia are prostacyclin and its analogues. In the last 12 years the
results of properly controlled randomized trials involving patients with chronic
limb ischaemia have been carried out in approximately 2000 patients in Europe.
The largest number were entered into trials using the prostacyclin analogue
iloprost. Some of these trials have shown a significant benefit compared to
placebo in terms of major amputation or death during the 6 months following a 2-4
week course of intravenous iloprost. The possible future indications for this
type of therapy, as well as the use for prostaglandins in claudicants, is
discussed.
PMID- 9546932
TI - Thrombolysis or operation for peripheral arterial occlusion.
AB - Patients with peripheral arterial occlusion may be treated with one of three
distinct treatment strategies: observation and/or anticoagulation alone,
operative intervention, or catheter-directed thrombolytic therapy. The severity
of symptoms is the most important clinical parameter with which to formulate
clinical strategies. Patients with non-lifestyle limiting claudication may be
best managed without arteriographic investigation, managing symptoms
conservatively with exercise, cessation of smoking, and occasionally the oral
pharmacologic agent pentoxifylline. Patients with threatened limbs in the form of
rest pain or tissue loss carry a high risk of limb loss without intervention.
These patients should undergo arteriography with consideration of endovascular
intervention for focal lesions and bypass grafting for more diffuse disease.
Patients with more acute symptoms may be best treated with catheter-directed
thrombolytic therapy, addressing unmasked lesions responsible for the occlusion
with an operative or endovascular approach. In all cases, the appropriate therapy
must be tailored to the clinical presentation, the anatomic distribution of
disease, and the experience of the clinical team.
PMID- 9546933
TI - Practical equations to predict claudication pain distances from a graded
treadmill test.
AB - Treadmill testing is used to estimate the severity of claudication, but routine
use is not practical or cost-effective in all settings. Thus, the purposes of
this study were: (1) to develop and cross-validate prediction equations for
treadmill claudication pain distances in a heterogeneous cohort of peripheral
arterial occlusive disease patients, and (2) to determine if the regression
equations were more accurate in assessing claudication distances than self
reported distances of patients. Medical history, vital signs, resting
ankle/brachial systolic pressure index (ABI), and claudication distances during a
graded treadmill test were obtained on a validation group of 178 claudicants and
on a cross-validation group of 94 claudicants. The independent predictors of
claudication pain distances of the validation group were ABI, body mass index,
gender, and current smoking status, with multiple correlation coefficients of R =
0.73 and R = 0.82 for the distances to onset and to maximal pain, respectively.
These equations were successfully cross-validated on an independent group of
claudicants, as the predicted distances to onset of claudication pain (167.2 +/-
102.6 m) and to maximal pain (354.6 +/- 154.3 m) were similar (p = 0.99) to
measured distances (169.1 +/- 127.8 m and 356.6 +/- 181.0 m, respectively).
However, the self-reported distances to onset (89.5 +/- 126.3) and to maximal
claudication pain (189.2 +/- 284.3) were 1-2 blocks less than either the measured
or predicted distances (p < 0.01). It is concluded that claudication pain
distances during an incremental treadmill test can be more accurately estimated
from a composite of variables obtained during medical screening than by relying
on the self-report of patients. Consequently, in clinical settings where
treadmill testing is impractical, the functional severity of claudication can be
assessed without exercise testing.
PMID- 9546934
TI - Heparin administration via nomogram versus a standard approach in venous and
arterial thromboembolic disease.
AB - To determine whether heparin administered by continuous intravenous infusion
using a nomogram is superior to a random dosing scheme, we performed a
prospective, randomized comparative trial in 161 patients. Patients were
prospectively randomized to one of three groups. Group I received an intravenous
bolus of 5000 IU of heparin followed by heparin administration according to a
modification of a previously published nomogram. Group II patients received a
5000 IU intravenous bolus of heparin followed by continuous intravenous heparin
infusion with dosage adjustment at the discretion of the treating physician.
Group III patients received a continuous intravenous heparin infusion with dosage
adjustments at the discretion of the treating physician without the prior
administration of a bolus dose. Activated partial thromboplastin time (APTT) was
obtained at baseline, 6 h after each heparin dose adjustment and every morning.
The mean percent of each patient's APTTs in the subtherapeutic range (< 50 sec)
over the course of treatment was 9% for group I and 24% for groups II and III, p
= 0.0001. The three groups had a similar percentage of each patient's APTTs
within the therapeutic range (50-80 sec). There was a larger percentage of APTTs
> 80 sec in group I (46%) compared to group II (31%) or group III (32%), p =
0.01. There were no clinically recurrent deep venous thrombi or arterial
thromboemboli in any of the groups. Two patients had documented pulmonary emboli
during heparin therapy (one in group I; one in group II). There was no difference
in the complication rates of heparin therapy or the need for blood transfusions
among the three groups. Patients randomized to the heparin nomogram (group I)
achieved an APTT > 50 sec more frequently than patients in the other two groups.
Overall, fewer patients in the nomogram group were subtherapeutic, and, when APTT
levels fell in the subtherapeutic range, the nomogram restored APTTs to the
therapeutic range faster than the standard methods. The heparin nomogram was
clearly more effective as a method of heparin dosing than standard methods of
anticoagulation dosing.
PMID- 9546935
TI - Felodipine inhibits intimal lesion formation in the hypercholesterolemic rabbit:
differential effects on endothelial and monocyte determinants of atherogenesis.
AB - The purpose of this study was to determine if the calcium entry antagonist
felodipine inhibited intimal lesion formation in hypercholesterolemic rabbits,
and to determine if this was due to an effect upon monocyte and/or endothelial
determinants of this interaction. Twenty-three male New Zealand White rabbits
received the following treatment regimen for 10 weeks: normal chow (NP, n = 3);
normal chow with felodipine infusion (NF, n = 6); 0.5% cholesterol chow (CP, n =
7); or 0.5% cholesterol chow and felodipine infusion (CF, n = 7). After 10 weeks
blood was collected for biochemical measurements and mononuclear cell binding
assays, and thoracic aortae were harvested for vascular reactivity studies and
histomorphometry. In the animals receiving normal chow, felodipine did not
significantly affect blood pressure, plasma cholesterol levels, binding studies,
vascular reactivity, or structure; therefore these animals were analyzed as one
group (N). Plasma cholesterol levels were significantly elevated in groups
receiving the 0.5% cholesterol diet (N, 29 +/- 3 mg/dl; CP, 1221 +/- 73 mg/dl;
CF, 979 +/- 108 mg/dl). High-density lipoprotein cholesterol was not different
between the groups (25 +/- 4 vs 23 +/- 4 vs 27 +/- 4 mg/dl; N vs CF vs CP
respectively; p = NS). Cholesterol feeding markedly augmented the adhesiveness of
mononuclear cells, as demonstrated by a 250% increase in cell binding. Felodipine
did not alter the adhesiveness of mononuclear cells in hypercholesterolemic
animals. Cholesterol feeding significantly impaired endothelium-dependent
relaxations. Endothelium-dependent relaxations were restored by felodipine
treatment as reflected by the maximal responses to acetylcholine (40 +/- 7% vs 58
+/- 4% vs 67 +/- 5%; CP vs CF vs N respectively). The improvement in endothelium
dependent relaxation in the felodipine-treated animals was associated with a 2.2
fold reduction in lesion surface area of the thoracic aorta (8.2 +/- 6.3% vs 18.2
+/- 9.5%; CF vs CP; p < 0.01). Moreover, the intima/media ratio reflecting lesion
thickness was substantially reduced by felodipine treatment (0.05 +/- 0.02 vs
0.20 +/- 0.07; CF vs CP; p = 0.006). Ex vivo studies revealed that felodipine
inhibited the adhesiveness of vascular endothelium, but not mononuclear cells,
derived from hypercholesterolemic animals. Low-dose felodipine appears to inhibit
monocyte-endothelial interaction, as indicated by a reduction in the formation of
lesions in hypercholesterolemic animals. This effect is not due to an alteration
in adhesiveness of mononuclear cells. The salutary effect of felodipine is
associated with an increase in vascular nitric oxide activity which may reduce
endothelial adhesiveness.
PMID- 9546936
TI - The effect of cigarette smoking on exercise capacity in patients with
intermittent claudication.
AB - The purposes of this study were: (1) to determine whether peripheral arterial
occlusive disease (PAOD) patients who smoked had more severe claudication pain,
reduced peripheral circulation, and poorer cardiopulmonary measurements at peak
exercise than non-smoking patients, and (2) to determine whether the differences
between the smoking and non-smoking patients persisted after controlling for the
resting ankle/brachial systolic pressure index (ABI). Thirty-eight PAOD patients
(ABI = 0.59 +/- 0.15, mean +/- SD) who smoked an average of 1.5 packs of
cigarettes per day over 42 years and 100 PAOD patients (ABI = 0.74 +/- 26) who
had quit smoking for an average of 7 years were recruited. Smokers refrained from
smoking on the day of testing. Claudication pain times, oxygen uptake,
ventilation, leg oximetry, and ankle systolic pressure responses to peak exercise
were recorded. The smoking group had more severe claudication pain, as maximal
pain occurred 1:37 min:s sooner during exercise (p < 0.05), and the pain took
2:21 min:s longer to subside (p < 0.01) compared to the non-smoking group.
Additionally, at peak exercise the smoking group had a lower oxygen uptake (12.8
+/- 2.6 vs 13.9 +/- 2.4 ml/kg/min, p < 0.01), a higher ventilation (31.7 +/- 9.2
vs 27.9 +/- 7.1 liters/min, p < 0.05), and a higher oximeter electrode power (409
+/- 55 vs 385 +/- 37 mW, p < 0.01) than the non-smoking group. Differences
between the groups persisted (p < 0.05) after adjusting for resting ABI. It is
concluded that cigarette smokers with PAOD had more severe claudication pain,
reduced peripheral circulation, and poorer cardiopulmonary measurements at peak
exercise than non-smoking patients. These differences were independent of resting
ABI. Thus, cigarette smoking reduces the exercise capacity of claudicants,
placing patients who smoke at an even greater risk of living a functionally
dependent lifestyle.
PMID- 9546937
TI - Vasodilator responses in the forearm skin of patients with insulin-dependent
diabetes mellitus.
AB - The integrity of endothelium-dependent vasodilation in the skin of patients with
insulin-dependent diabetes mellitus (IDDM) is unclear, especially with respect to
the role of nitric oxide. To examine this, forearm skin blood flow by laser
Doppler flowmetry and total blood flow by venous occlusion plethysmography was
measured in response to brachial artery infusions of an endothelium-dependent
(methacholine) and -independent (sodium nitroprusside) vasodilator. Peak
hyperemic forearm blood flow, following 5 min of arterial occlusion, was also
determined. Responses were compared in 11 control subjects and 16 patients with
insulin-dependent diabetes mellitus. In ten normal subjects, co-infusion of NG
monomethyl-L-arginine with methacholine produced a significant reduction in total
forearm blood flow response to methacholine (p < 0.002), measured by venous
occlusion plethysmography, as well as vascular conductance (p < 0.001),
confirming that nitric oxide contributes to this response. In contrast, NG
monomethyl-L-arginine had no significant effect on the methacholine-induced
increase in forearm skin blood flow measured by laser Doppler flowmetry
indicating that factors other than nitric oxide may be involved. Increases in
forearm skin blood flow in response to methacholine, sodium nitroprusside and to
an ischemic stimulus were not significantly different between the normal subjects
and patients with IDDM. Dose-related increases in total forearm blood flow and
vascular conductance were not significantly different between control subjects
and diabetic patients during infusions of methacholine. The increases in these
parameters during infusions of sodium nitroprusside, however, were significantly
less in the diabetic group than in the control group (p < 0.05) as was the peak
reactive hyperemic blood flow (p < 0.05). Since skin blood flow was not affected,
the reduced vasodilator responses to sodium nitroprusside and an ischemic
stimulus in the diabetic group are in forearm skeletal muscle. The reduced muscle
blood flow does not reflect a decreased vasodilatory capacity, but rather a
functional impairment in response to nitric oxide and ischemia since the
methacholine dilation was normal. The normal vasodilator responses in the forearm
skin, which is predominantly capillary as opposed to arteriovenous anastomatic
blood flow, indicate that the response to nitric oxide and an ischemic stimulus
in this vascular bed is intact in patients with IDDM. This is, therefore, an
unlikely cause of diabetic skin, complications in these areas.
PMID- 9546938
TI - Oxidative stress and lipids in diabetes: a role in endothelium vasodilator
dysfunction?
AB - Endothelial dysfunction is a key feature of diabetes mellitus and is thought to
be the major cause of vascular complications associated with the disease. The
vascular endothelium demonstrates impaired synthesis of vasodilators and
increased release of procoagulants and vasoconstrictors, defects which
theoretically could explain the increased incidence of atherosclerosis and
hypertension found within this patient group. The pathways mediating endothelial
cell layer dysfunction are unknown, although many candidates have been proposed.
This review concentrates on the hypothesis that increased oxidative stress
combined with abnormal plasma lipid composition leads to reduced synthesis of
endothelial vasodilators and hence endothelial dysfunction. Free radical
generation is undoubtedly raised in diabetes but the evidence for decreased
antioxidant status is debatable. The role of antioxidant and lipid-lowering
therapy is considered, but few studies have directly investigated the effect of
treatment on vascular function. Concern arises from individual studies of vitamin
E in diabetic animals which have proved deleterious. Current literature implies
that a combination therapy of vitamin E and vitamin C may be beneficial, but this
needs to be investigated further in both animal and human diabetes.
PMID- 9546940
TI - Current puzzles presented by postmastectomy oedema (breast cancer related
lymphoedema).
PMID- 9546939
TI - Prophylaxis against deep venous thrombosis and pulmonary embolism in patients
with stroke.
PMID- 9546941
TI - Takayasu arteritis: clinical characteristics and the role of genetic factors in
its pathogenesis.
AB - Takayasu arteritis is a chronic vasculitis, the aetiology of which is still
unknown. Several characteristic clinical manifestations have led scientists to
consider the possibility of the genetic factors in the aetiology, conjecture
which is supported by HLA analysis. Recent attention has focused on the different
clinical manifestations among Asian and South American countries and further
progress is likely to stem from international network studies.
PMID- 9546942
TI - Images in vascular medicine. Multiple aortic aneurysms.
PMID- 9546943
TI - Role of digital artery adrenoceptors in Raynaud's disease.
AB - Raynaud's disease is characterized by excessive cutaneous vasoconstriction in
response to ambient cold. A functional disturbance in the local regulation of
digital vasomotion has been proposed. The purpose of this study was to determine
whether there is an alteration in the postjunctional adrenergic receptors in the
digital circulation of patients with Raynaud's disease. Furthermore, we sought to
determine whether this abnormality was responsible for the excessive cold-induced
vasoconstriction in these patients. Finger blood flow was measured by strain
gauge venous occlusion plethysmography in 10 patients with Raynaud's disease and
in 10 normal volunteers in a 22 degrees C room. Measurements of finger blood flow
and mean systemic arterial pressure were made during intra-arterial infusions of
the alpha 1-adrenergic antagonist, prazosin, or the alpha 2-adrenergic
antagonist, yohimbine, at room temperature and during local cooling of the hand.
Basal finger blood flow in normal subjects was significantly greater than that of
patients (8.6 +/- 2.7 vs 1.7 +/- 0.5 ml/100 ml per min; normal vs Raynaud's
subjects; p < 0.05). In normal subjects, either prazosin or yohimbine induced
dose-dependent increases in finger blood flow. The maximal increase in finger
blood flow induced by prazosin was significantly greater than that in response to
yohimbine (29.2 +/- 10.1 vs 2.8 +/- 2.1 ml/100 ml per min; prazosin vs yohimbine;
p < 0.05). By contrast, in the Raynaud's patients, prazosin or yohimbine induced
maximal increases in finger blood flow that were not significant (7.1 +/- 1.8 vs
5.0 +/- 2.2 ml/100 ml per min; prazosin vs yohimbine; p = NS). The response to
prazosin in Raynaud's patients was significantly less than that of the normal
volunteers (p < 0.05). In normal subjects, during intra-arterial infusion of
vehicle alone, cooling induced a 52.6 +/- 5.8% reduction in finger blood flow.
This cold-induced vasoconstriction was blunted, but not qualitatively altered, by
either adrenergic antagonist. In the Raynaud's patients, during the intra
arterial infusion of the vehicle, cooling induced a 68.2 +/- 7.8% reduction in
finger blood flow. Infusion of either adrenergic antagonist blunted, but did not
qualitatively alter, the response to cold. Finger blood flow is less in patients
with Raynaud's disease than in normal subjects when studied in a 22 degrees C
room. In normal subjects, postjunctional alpha 1-adrenergic receptors appear to
predominate in the control of digital vasoconstriction. Postjunctional alpha 1-
and alpha 2-adrenoceptors play an equal role in adrenergic regulation of finger
blood flow in patients with Raynaud's disease. In both normal and Raynaud's
subjects, selective antagonism of alpha 1- or alpha 2-adrenergic receptors does
not abolish local cold-induced vasoconstriction. Therefore, it is likely that a
nonadrenergic mechanism contributes to local cold-induced vasoconstriction.
PMID- 9546945
TI - Changes in the amplitude of cyclic load biphasically modulate endothelial cell
DNA synthesis and division.
AB - Several physical factors, including shear stress and cyclic load, modulate the
ability of endothelial cells to respond to injury. The objective of these
experiments was to test the hypothesis that cyclic mechanical load stimulates
endothelial cell DNA synthesis and division in vitro. Rabbit aortic endothelial
cells were cultured on Flex I flexible-bottomed culture plates, and subjected to
load amplitudes of increasing magnitude (0, 0.18, 0.24 and 0.27 load at 1 Hz)
using a Flexercell strain unit. Cells were harvested enzymatically and cell
numbers determined on days 1, 3 and 5 after initiating the load regimen. DNA
synthesis was quantified after trichloroacetic acid precipitation of
[3H]thymidine-labeled cells from: (1) whole culture wells and (2) areas of
minimum and maximum strain in culture cells. Data were analyzed using analysis of
variance and a Tukey's test (n = 6 observations/strain regimen per day in
triplicate). Results from analysis of endothelial cells in whole, subconfluent
cultures showed that cells subjected to strains of 0.18 had a decreased rate of
cell division (76% of control) and DNA synthesis (63% of control), while cells
subjected to strains of 0.24 and 0.27 had an increased rate of cell division (108
and 83% increase, respectively, compared with control; p < 0.001) and DNA
synthesis (39 and 172% increase, respectively, compared with control; p < 0.001
for 0.27) on day 3 when compared with control cells. The results indicate that
endothelial cells respond to various physiologic levels of cyclic load in a
biphasic manner to initiate DNA synthesis and cell division. These data suggest
that endothelial cell mitogenesis may be modulated by specific levels of cyclic
load.
PMID- 9546944
TI - Effect of felodipine on regional blood supply and collateral vascular resistance
in patients with peripheral arterial occlusive disease.
AB - This double-blinded, randomized, placebo-controlled study was designed to
investigate the acute effect of felodipine on regional blood supply and
collateral vascular resistance in patients with peripheral arterial occlusive
disease (PAOD). Thirty men with PAOD were treated with a single dose of 5 mg
felodipine or placebo. Systolic blood pressure (SBP), Doppler ankle pressure
(DAP), calf blood flow (CBF) by venous occlusion plethysmography and calf
transcutaneous oxygen tension (tcpO2) were measured during a cycle ergometry.
Felodipine reduced SBP significantly (from 149 to 136 mmHg, p < 0.05), while
placebo did not. DAP increased slightly but not significantly in both groups. The
pressure gradient between SBP and DAP fell significantly in the felodipine group
(60 vs 39 mmHg, p < 0.01) but not in the placebo group (59 vs 56 mmHg). There was
a trend for lower velocity in tcpO2 decrease during the stress test and higher
velocity of tcpO2 increase during recovery from exercise in the felodipine group
although the differences between both groups were not significant. In the
felodipine group, CBF increased by 35.6% (p < 0.05) whereas it did not change in
the placebo group. In conclusion, while lowering SBP, felodipine increased
slightly, or at least maintained, the blood supply to the calves in PAOD
patients, which probably results from reducing collateral vascular resistance.
PMID- 9546946
TI - Cost-effective strategies for the management of vascular disease.
AB - Cardiovascular disease accounts for over 950,000 deaths and an estimated $151
billion in direct and indirect costs. Because of this escalating clinical and
financial burden, economic analysis has become essential for the evaluation of
preventative therapies for vascular disease. Economic analysis compares competing
interventions or management strategies for costs and benefits; more specifically,
cost-effectiveness analysis compares cost in financial terms like dollars to
measures of effectiveness like years of life saved. Important concepts in the
creation of a valid cost-effectiveness analysis include perspective, time
horizon, measurement of costs and effectiveness and sensitivity analysis. In
patients with peripheral arterial occlusive disease, most morbidity and mortality
arises from complications of coronary artery disease. Because coronary artery
disease and peripheral arterial occlusive disease commonly occur together and
share risk factors, pathophysiology and response to preventative therapy,
economic evaluations of preventative therapies for coronary artery disease have
relevance for patients with vascular disease. Cost-effectiveness analysis reveals
that modification of vascular risk factors like tobacco use, hypertension and
hypercholesterolemia improve clinical outcomes at acceptable cost-effectiveness
ratios, usually less than $20,000 per year of life saved. More importantly,
interventions like smoking cessation or lipid modification in high-risk groups
may be cost saving, with treatment costs outweighed by financial benefits. From
the patient, clinician and societal perspective, cost-effectiveness analysis
supports the aggressive modification of cardiovascular risk factors in patients
with peripheral arterial occlusive disease.
PMID- 9546947
TI - The endothelin system in cardiovascular physiology and pathophysiology.
AB - Endothelin-1, a member of a novel family of regulatory peptides, is the most
potent vasoconstrictor and pressor substance known. Endothelin-1 is a 21-amino
acid endothelium-derived peptide causing uniquely sustained vasoconstriction. In
addition, endothelin-1 has pronounced effects on the coronary, renal and cerebral
circulations, enhances responses to other vasoconstrictors, and is comitogenic.
Recent studies have shown that the endothelins are essential for normal fetal
development, and that endothelin-1 plays an important physiological role in the
regulation of basal vascular tone and blood pressure in healthy humans. There is
now also a wealth of evidence suggesting that endothelin-1 is a key mediator in a
range of cardiovascular diseases associated with sustained vasoconstriction, such
as chronic heart failure, and with vasospasm, such as subarachnoid haemorrhage.
In addition, endothelin-1 appears to act in opposition to nitric oxide to promote
the atherosclerotic process. There are a large number of oral and intravenously
active endothelin antagonists entering clinical development and a number of
clinical studies, particularly with endothelin receptor antagonists, are now
under way. Such studies are beginning to define the role of the endothelins in
cardiovascular disease and to confirm the potential of the endothelin system as
an important new therapeutic target.
PMID- 9546948
TI - Physiologic aspects of drug therapy and large artery elastic properties.
AB - Vasoactive drugs alter smooth muscle tone not only in arterial resistance
vessels, but also in large conduit arteries. The resultant changes in smooth
muscle tone alter both conduit vessel size and stiffness and hence influence
pulsatile components of left ventricular afterload. The effects of smooth muscle
relaxation and contraction on arterial elastic properties are complex and have
not been fully characterized. Several recent studies have utilized a new
intravascular ultrasound technique to study the effects of changes in smooth
muscle tone on brachial artery elastic mechanics in normal human subjects in
vivo. Smooth muscle relaxation with nitroglycerin improves isobaric brachial
artery compliance without significantly altering arterial wall stiffness as
measured by incremental elastic modulus (Einc). The improvement in compliance
with smooth muscle relaxation is the net result of factors that: (1) increase
wall stiffness (increased tension in parallel elastin and collagen fibers); (2)
decrease wall stiffness (decreased tension in the smooth muscle and its
associated series elastic component); and (3) increase vessel lumen size. Using a
modified Maxwell model for the arterial wall, smooth muscle relaxation is also
shown to shift the predominant elements contributing to wall stress and Einc from
smooth muscle and the collagen fibers in series with the smooth muscle to
collagen fibers in parallel with the smooth muscle. A better understanding of the
mechanisms contributing to changes in arterial elastic mechanics following
alterations in smooth muscle tone will help in developing pharmacologic therapies
aimed at reducing pulsatile components of left ventricular afterload.
PMID- 9546949
TI - Intravenous thrombolytic therapy in acute stroke.
AB - The article reviews the experimental basis of thrombolytic therapy, and
summarizes the results of the recent trials of thrombolysis. Five large clinical
trails have evaluated intravenous thrombolytic therapy for the treatment of
hyperacute (< 6 h) stroke. Three of these studies were negative, one was
equivocal, and one was strongly positive. The failure of demonstrate efficacy
definitively in four of these trials may be related to a number of methodological
factors, including the type and dose of drug administered, the timing of drug
administered, and the method of patient selection for treatment. The NINDS
recombinant tissue plasminogen activator (rt-PA) study showed that thrombolytic
therapy can be of substantial benefit when administered within 3 h of stroke
onset using strict patient selection criteria and rt-PA is now FDA approved for
treatment of acute stroke. However, the risk of clinically significant bleeding
is elevated. To achieve the favorable risk/benefit ratio demonstrated in the
NINDS trial, patients must be screened by experienced clinicians for
contraindications to thrombolysis and the acute computerized tomography (CT)
brain scan must be carefully evaluated for radiographic features that increase
the risk of cerebral hemorrhage. Guidelines for the use of rt-PA are provided, as
well as insights into future thrombolytic treatment strategies.
PMID- 9546950
TI - Thromboangiitis obliterans (Buerger's disease).
AB - Thromboangiitis obliterans (TAO) is a nonatherosclerotic segmental inflammatory
obliterative disease that most commonly affects the small- and medium-sized
arteries and veins in both upper and lower extremities. In the past, TAO was
exclusively a disease confined to men; however, recently more women have been
diagnosed with TAO. Most patients are heavy users of tobacco, and usually
cigarette smokers.
PMID- 9546951
TI - Radial artery compliance in patients with peripheral vascular disease.
AB - Compliance in largely central arteries of patients with peripheral vascular
disease (PVD) has been reported to be reduced. However, the arterial tree is an
inhomogeneous system, and there remains uncertainty about whether the peripheral
arteries (e.g. the medium-sized muscular radial artery) undergo a similar change
to the central arteries. The aim of this study was to investigate the radial
artery elasticity in 19 patients with PVD compared with 18 normal subjects of
comparable age and sex. Using a noninvasive high-resolution echo-tracking device
coupled to a photoplethysmograph (Finapres system) allowing simultaneous arterial
diameter and finger blood pressure monitoring, we measured the radial artery
compliance by determining the diameter-pressure, compliance-pressure and
distensibility-pressure curves. The results showed that the diameter of the
radial artery was similar in the two groups, but that the compliance and
distensibility were not further reduced in patients with PVD than in the normal
controls at 100 mmHg and for a common blood pressure range. The present studies
demonstrate that in patients with PVD the radial arterial compliance is not
reduced, which indicates that the change in arterial elasticity is not identical.
The potential mechanisms involved in this change in radial artery compliance are
discussed.
PMID- 9546952
TI - Role of endothelial cells in allograft rejection.
AB - The immunological properties of endothelial cells suggest they perform a pivotal
role in acute and chronic rejection following solid organ transplantation. Their
constitutive expression of MHC class II molecules (which initiate allograft
rejection by activating CD4 T cells) and accessory molecules allows them to
present foreign antigen by both the direct and indirect route to the recipient's
immune system. The costimulatory molecules used by endothelial cells appear to
differ from those used by traditional antigen-presenting cells such as B cells
and dendritic cells. Release of non-HLA antigens from damaged endothelial cells
results in a chronic antibody response--possibly contributing to graft
vasculopathy and chronic rejection. Further understanding of the factors that
regulate MHC class II and accessory molecule expression on endothelial cells
could lead to novel strategies of therapeutic intervention.
PMID- 9546953
TI - Fibrinogen and cardiovascular risk.
AB - The hypothesis that fibrinogen is closely related to cardiovascular risk has been
strengthened through the results of various lines of research, which this review
will aim to unravel. Several prospective epidemiological studies convincingly
show elevated fibrinogen to represent a major, independent cardiovascular risk
factor. Cross-sectional studies strongly associate fibrinogen and conventional
cardiovascular risk factors. Clinical cohort studies demonstrate that increased
fibrinogen is also a risk factor for the sequelae of cardiovascular disease. Our
knowledge about the determinants of the variable plasma level of fibrinogen in
health and disease is incomplete. Understanding of the mechanisms that might be
involved in the atherothrombogenic action of fibrinogen is also fragmentary.
Fibrinogen strongly affects blood coagulation, blood rheology and platelet
aggregation. In addition, it has direct effects on the vascular wall and is a
prominent acute phase reactant. All of these phenomena might constitute
pathophysiological mechanisms involved in the association between fibrinogen and
cardiovascular events. Their relative importance is unclear at present. Even
though many crucial questions await conclusive answers, little doubt exists that
fibrinogen represents a major, independent risk factor.
PMID- 9546954
TI - The challenge and importance of defining critical limb ischemia.
AB - Patients with critical limb ischemia are at risk of limb loss and have very high
cardiovascular and total mortality rates, which are greater than can be accounted
for by the usual risk factors for atherosclerosis. A definition of critical
ischemia is necessary to determine the natural history of the disease and to
assess and compare the efficacy of various forms of therapy. The definition needs
to be based on hemodynamic criteria because clinical manifestations and outcomes
are not reliable. The reasons for the difficulties in arriving at a generally
acceptable definition are explored. Building on the previous work of others,
modified hemodynamic definitions for critical and subcritical ischemia, which
include measurements of pressures and of indices of microcirculation, are
proposed.
PMID- 9546955
TI - Development of vascular complications in diabetes.
AB - Chronic complications of diabetes are dominated by disorders of the vascular
system. They are a much larger burden on both diabetic patients and overall
medical costs than diabetes itself. Large vessel problems are far more frequent
than microvascular disorders. Loss of arterial elasticity alters arterial flow
patterns and increases microcirculatory peak flow rates. Hyperglycemia may
directly disrupt elastin formation. Diabetic leg artery disease may be generated
by nerve damage, reversing this interactive contribution sequence. The major
anatomic feature of microangiopathy in long-term diabetes is an unevenly
distributed thickening of the intima of smaller arterioles. The thickening is
primarily due to accumulation of type IV (basement membrane) collagen. Arterioles
change local vessel diameter to adjust blood distribution to meet current needs.
The thickening compromises the maximum local blood flow that may be achieved by
this means. Compromise of maximal arteriolar dilatation does not disrupt
exercising muscle but in the kidney, retina, and possibly in nerve, local
circumstances can generate serious damage. Each of these system's responses has
unique features that mediate its vulnerability, but all these organs show
arteriolar hyalinization. The increased arteriolar accumulation of type IV
collagen appears to be a response to the tangential force generated by flow over
local endothelial cells. An increase in peak arteriolar wall force is mediated by
a diabetes-specific doubling of erythrocyte membrane curvature change resistance.
Red cell aggregation rate determines the rate of damage. The same nonspecific
burden may also predispose to heart disease and stroke. Intensive metabolic
control improves red cell deformability and protects against arteriolar damage.
Therapies that address the rheologic problem more directly may add to the
effectiveness of good diabetes control in the future.
PMID- 9546956
TI - A case of scurvy rarely encountered in Japan.
AB - We report a case of scurvy, which is rarely encountered in Japan. A 75-year-old
male was hospitalized with diffuse subcutaneous hemorrhaging of both feet, pain
on walking, and shortness of breath. A remarkably low serum level of vitamin C
was confirmed. Administration of ascorbic acid dramatically improved his clinical
symptoms. Improvement paralleled the increase of serum vitamin C level. This case
underscores the important role of vitamin C on the integrity function of the
vessel wall.
PMID- 9546957
TI - Exercise testing and exercise rehabilitation for patients with peripheral
arterial disease: status in 1997.
AB - Intermittent claudication is a common manifestation of peripheral arterial
occlusive disease (PAOD). Patients with claudication are limited in terms of
work, housework and leisure activities so that functional status is very
impaired. Therefore, the goals for treatment should focus on improving the
functional impairment as well as on modifying risk factors. Evaluation of the
functional status is of critical importance before beginning any therapy so that
any resultant changes can be assessed. A validated graded treadmill protocol and
validated questionnaires are used for this purpose. Three questionnaires that are
currently used include the Walking Impairment Questionnaire, the PAOD Physical
Activity Recall and the Medical Outcomes Study SF-36. Exercise rehabilitation is
a method that has been particularly efficacious for treating the functional
impairment associated with intermittent claudication. Exercise rehabilitation has
been shown to improve pain-free treadmill walking distance by 44% to 300% and
absolute walking distance by 25% to 442%. In addition, improvements have also
been reported (using questionnaire data) in the ability to walk distances and
speeds, in amount of habitual physical activity and in physical functioning.
Thus, exercise rehabilitation has caused improvements not only in exercise
capacity but also in community-based functional status. Because of the benefits
of this treatment, in addition to the low associated morbidity, exercise therapy
is recommended as an important treatment option for people with intermittent
claudication due to PAOD.
PMID- 9546958
TI - Images in vascular medicine. Internal iliac artery aneurysm.
PMID- 9546959
TI - Carnitines increase plasma levels of adenosine and ATP in humans.
AB - In order to help to clarify the mode of action of carnitine derivatives, plasma
levels of adenosine, ATP and inosine were evaluated following the infusion of
0.75, 0.50 and 0.25 mg/kg/min propionyl-L-carnitine (PLC) for 30 min in patients
affected with peripheral arterial disease. Moreover, the effects of 0.75
mg/kg/min acetyl-L-carnitine (ALC) and L-carnitine (LC) were studied in the same
conditions. Finally, the activity of 7.5 mg/kg/min PLC administered for 3 min was
also evaluated. PLC and ALC produced a significant increase in plasma levels of
adenosine and ATP, whereas LC induced less relevant changes. The administration
of the compounds did not affect the adenosine/inosine ratio. Peak plasma levels
of adenosine preceded in any case those of ATP. The possibility can be suggested
that the pharmacological activity of PLC, ALC, and LC may be mediated, at least
in part, by an interference with the endogenous purine system. Since these
effects may be related to physiological mechanisms of tissue protection, new
pharmacological perspectives for the compounds may arise.
PMID- 9546961
TI - Noninvasive assessment of endothelium-dependent flow-mediated dilation of the
brachial artery.
AB - Coronary atherosclerosis is characterized by an early loss of endothelium
dependent vasodilation. However, the methods of assessing coronary endothelial
function are invasive and difficult to repeat over time. Recently, a noninvasive
ultrasound method has been widely used to measure flow-mediated dilation in the
brachial artery as a surrogate test for endothelial function. We seek to further
validate this method of measuring vascular function. The brachial artery
diameters and blood flow of 20 normal volunteers (10 males and 10 females) were
measured using high resolution (7.5 MHz) ultrasound and strain gauge
plethysmography. Flow-mediated endothelium-dependent vasodilation was measured in
the brachial artery during reactive hyperemia after 5 minutes of cuff occlusion
in the upper arm. The brachial artery diameter increased maximally by 9.7 +/-
4.3% from baseline at 1 min after cuff release and blood flow increased by 1002
+/- 376%. Five min of cuff occlusion was sufficient to achieve 97 +/- 6% of
maximal brachial artery dilation and degree of dilation was not different whether
the cuff was inflated proximally or distally to the image site. The intraobserver
variability in measuring brachial diameters was 2.9% and the variability of the
hyperemic response was 1.4%. In young, healthy men and women, the baseline
brachial artery diameter was the only factor that was predictive of the flow
mediated vasodilation response. The brachial noninvasive technique has been
further validated by the determination of flow-mediated dilation. This method of
assessing endothelial function may help to determine the importance of
vasodilator dysfunction as a risk factor in the development of atherosclerosis.
PMID- 9546960
TI - Cutaneous vascular responses to acetylcholine are mediated by a prostanoid
dependent mechanism in man.
AB - Approximately 50% of the forearm vasodilatation to intra-arterial infusions of
acetylcholine is mediated by endothelium-derived nitric oxide. These conclusions
have been derived from venous occlusion plethysmographic measurements of total
forearm blood flow during co-infusions of acetylcholine and NG-monomethyl-L
arginine (L-NMMA), an inhibitor of nitric oxide synthase. Since venous occlusion
plethysmography measures total limb blood flow, the relative proportion of the
measurement from skin cannot be determined precisely. To determine the effects of
acetylcholine on skin specifically, we have used laser Doppler flowmetry to
measure vascular responses to local iontophoresis of acetylcholine in the forearm
of normal male volunteers. To elucidate the possible mechanisms of cutaneous
vasodilatation to acetylcholine, vascular responses were measured before and
after systemic inhibition of prostanoid production and nitric oxide synthesis by
oral aspirin (600 mg daily for 3 days) and intravenous L-NMMA (3 mg/kg for 60
min), respectively. After aspirin administration, dose-dependent vascular
responses to acetylcholine were reduced significantly by approximately 53% (p <
0.005, ANOVA). In contrast, intravenous L-NMMA appeared to have no significant
effect on cutaneous vascular responses to acetylcholine. While the role of nitric
oxide is uncertain, vasodilatation to acetylcholine in the forearm skin is
mediated largely by a prostanoid-dependent mechanism. Assessment of cutaneous
vascular responses to iontophoresis of acetylcholine may, therefore, be useful in
diseases where abnormal endothelium-dependent prostanoid function has been
implicated.
PMID- 9546962
TI - Comparison of graded versus constant treadmill test protocols for quantifying
intermittent claudication.
AB - The standard method for quantifying the symptoms of intermittent claudication is
by using treadmill walking distance. It has recently been suggested that a graded
exercise test is much more reproducible than a constant load exercise test.
Graded protocols have also been claimed to abolish the placebo effect that has
been reported with the constant load test. The reproducibility of absolute
claudication distance (ACD) and initial claudication distance (ICD) using a
constant load was compared to the graded load treadmill protocol. Fourteen
patients (mean age 66 years) with varying severity of stable intermittent
claudication were tested using a constant load (3.2 km/h, 10% gradient) and a
graded load (3.2 km/h, 0% gradient increasing by 3.5% every 3 min). Patients were
tested twice using each protocol in a random sequence, with a minimum 2 day
interval between visits. Intra-class correlation coefficient (R) with a constant
load protocol for ICD and ACD was R = 0.68, R = 0.93, respectively. With a graded
protocol R = 0.84 for ICD and R = 0.98 for ACD. Relative coefficient of
repeatability for ICD and ACD during constant load tests were 1.47 and 1.90
respectively and with a graded load test were 1.69 and 1.52 respectively. It was
concluded that the graded load test was more reproducible than the constant load
test but only by a small margin, whilst ACD was much more reproducible than ICD
using either protocol.
PMID- 9546963
TI - Thoracic aortic aneurysm repair with endovascular stent-grafts.
AB - The purpose of the study was to describe the clinical experience is using
endoluminal stent-grafts for the treatment of thoracic aortic aneurysms in high
risk patients. Patients with aneurysms of the descending thoracic aorta who were
considered high surgical risks underwent evaluation for endoluminal repair. The
prosthesis was constructed from Z stents covered with polyester fabric using
dimensions based upon preprocedural computed tomography scans and angiography.
Through a femoral arteriotomy or left retroperitoneal flank incision, a 22-24 Fr
delivery catheter was inserted and advanced through the aorta to the target site
under fluoroscopic guidance in the operating suite. The stent-graft prosthesis
was deployed at the site of the aneurysm. 44 patients (36 male, 8 female; mean
age 36 years) underwent stent-graft repair for thoracic aneurysms (mean diameter
6.3 cm). The deployment was technically successful in all cases, with complete
aneurysm thrombosis in 88%. The 30-day perioperative mortality rate was 6.8% and
35-month actuarial survival was 82%. There were no cases of stent migration,
surgical conversion or intraprocedural death. Paraplegia occurred in two patients
who underwent simultaneous surgical infrarenal aortic aneurysm repair immediately
followed by stent-graft placement for a coexisting thoracic aneurysm. The
conclusion was that placement of endoluminal stent-grafts for repair of thoracic
aortic aneurysms is technically feasible in high-risk patients in whom
conventional surgery is contraindicated. Long-term studies are needed to
determine protection against aneurysm rupture and patient survival.
PMID- 9546964
TI - Soluble form of selectins in blood of patients with acute myocardial infarction
and coronary intervention.
AB - Soluble (s) P-selectin, sE-selectin, sL-selectin and soluble intercellular
adhesion molecule-1 (sICAM-1) levels were examined by monoclonal antibody-based
enzyme immunoassay on serum samples taken from nine patients with acute
myocardial infarction (AMI) and eight patients with stable angina pectoris (SAP)
before and after the successful percutaneous transluminal coronary angioplasty
(PTCA). In patients with acute phase of AMI, the levels (mean +/- SEM) of sP
selectin (110 +/- 18 ng/ml) and sE-selectin (54 +/- 15 ng/ml) before PTCA, were
significantly higher than those in the SAP group, the values being 44 +/ 27 and
21 +/- 4 ng/ml (p < 0.05), respectively. After recanalization, the levels of sE
selectin and sL-selectin were significantly decreased (sE-selectin 54 +/- 15 to
42 +/- 11 ng/ml, sL-selectin 1104 +/- 106 to 891 +/- 59 ng/ml, P < 0.05,
respectively). These findings suggest that the presence of activated and/or
injured endothelial cells, which may be involved in the plaque disruption or
intraluminal thrombosis in AMI region and that the inflammatory process may be
altered after reperfusion therapy.
PMID- 9546965
TI - Decreased ankle/brachial indices in relation to morbidity and mortality in
patients with peripheral arterial disease.
AB - To determine the relationship between ankle/brachial indices (ABIs) and morbidity
and mortality in patients with peripheral arterial disease (PAD), a historical
cohort study was performed. A total of 154 patients who had undergone noninvasive
arterial assessment of the lower extremities in 1989 and 1990 were selected for
this purpose. Selection criteria were age > 40 years at the time of
investigation, a resting ABI < 0.90 and the availability of an ABI after exercise
or arterial occlusion. Mortality and vascular events were recorded after an
average follow-up period of 6 years. A vascular event was defined as an
intervention because of PAD, the occurrence of a nonfatal myocardial infarction
or stroke, a transient ischaemic attack or a coronary artery bypass graft (CABG)
or percutaneous transluminal coronary angioplasty (PTCA) procedure. During the
period studied, 44 patients died and 111 patients suffered a vascular event. The
relative risk for mortality was 3.1 per 0.50 decrease of the ABI at rest (95%
confidence interval (CI) 1.1-8.7, p = 0.03) and 2.4 per 0.50 decrease of the ABI
after exercise or arterial occlusion (95% CI 0.9-6.4, p = 0.08). The relative
risk for mortality or the occurrence of a vascular event was 3.3 per 0.50
decrease of the resting ABI (95% CI 1.7-6.3, p < 0.001) and 2.5 per 0.50 decrease
of the ABI after exercise or occlusion (95% CI 1.5-4.4, p < 0.001). After
standardization, the prognostic power of the two types of ABIs was equivalent.
The cumulative survival after 5 years was 63% for patients with resting ABIs <
0.50, 71% for patients with ABIs 0.50-0.69 and 91% for those with ABIs of 0.70
0.89. There were obvious differences between the mean initial ABIs of patients
who suffered a vascular event and/or died and those of survivors, who did not
suffer an event. A relatively simple measurement like the determination of the
resting ABI can give valuable information about the prognosis for vascular
related morbidity and mortality. This can be of help in the approach of patients
with PAD and assist in therapeutical decision making. Determination of the ABI
after exercise or occlusion has no additional value for this purpose.
PMID- 9546966
TI - Oxygen uptake during constant-intensity exercise in patients with peripheral
arterial occlusive disease.
AB - The purpose of the present study was to evaluate the oxygen uptake (VO2) response
to walking in patients with peripheral arterial occlusive disease (PAOD) at a
constant velocity and to determine whether the oxygen uptake observed during
constant-intensity exercise in this population is associated with the severity of
PAOD. Forty-nine PAOD patients with intermittent claudication were recruited
(values are mean +/- SD) [age = 66.4 +/- 8.0 years, weight = 83.3 +/- 16.0 kg,
body mass index = 28.8 +/- 5.6, ankle/brachial systolic blood pressure index
(ABI) = 0.63 +/- 0.18, VO2peak = 13.02 +/- 2.99 ml/kg/min]. Patients were
evaluated during a 2.0 miles/h walk on a treadmill until maximal claudication
pain or for a maximum of 20 minutes. On average, patients walked for a duration
of 10.3 +/- 5.8 min. Despite the constant absolute intensity during the exercise
bout, there was a significant (p < 0.01) 4.0% increase in VO2 from min 3 of
exercise (10.58 +/- 2.02 ml/kg/min) to min 5 (11.01 +/- 2.18 ml/kg/min) and a
further 4.0% increase from min 5 to the end of exercise (11.46 +/- 2.32
ml/kg/min). Expressed as relative exercise intensity, this represented an
increase from 80.8 +/- 18.3% to 87.1 +/- 18.0% of VO2peak from min 3 to the end
of exercise. The magnitude of increase in VO2 during the exercise bout was not
correlated with resting ABI (r = 0.00, p = 0.68) or post-exercise ABI (r = 0.04,
p = 0.73). There was a nonsignificant trend towards a correlation between the
time to onset of claudication pain and the magnitude of increase in VO2 (r =
0.25, p = 0.08). Results of this study suggest that an increase in VO2 occurs
during constant-velocity walking at a high relative intensity in PAOD patients.
This increase in VO2 does not appear to be related to the severity of PAOD.
PMID- 9546967
TI - Mechanisms of neointima formation--lessons from experimental models.
AB - The lamina intima of an artery is the region between the endothelial cell surface
and the internal elastic lamina, which forms the luminal margin of the media. In
humans the intima of atherosclerosis-prone arteries becomes thicker due to
accumulation of smooth muscle cells, which originate from the media. The
introduction of percutaneous transluminal coronary angioplasty (PTCA) boosted
scientific interest in intimal thickening, because restenosis remains an
unresolved problem of this intervention. In order to unravel the mechanisms of
intimal thickening there is a need for appropriate animal models. A brief
overview of these models is given together with factors that control
proliferation and/or migration. Despite intensive research on neointima
formation, an effective therapy for restenosis has not emerged to date. This may
be due to the fact that other processes, such as acute elastic recoil and chronic
constrictive remodeling may contribute to lumen narrowing as well. Other
limitations of neointima models are related to species and anatomical
differences. Most studies are performed in arteries that are either lesion-free,
or contain relatively mild plaques, in contrast to the complicated, stenotic
lesions that are the substrate for human PTCA. Other differences are the severity
of the injury and incorporation of a mural fibrin-rich thrombus. Nevertheless,
studies based on superficial injury, like the frequently used balloon denudation
model, are useful. There are similarities with angioplasty, such as endothelial
cell damage and proliferation of medial and intimal smooth muscle cells. The use
of techniques such as differential display, gene transfer and application of
antisense oligonucleotides may provide new therapeutic approaches to reduce
neointima formation.
PMID- 9546968
TI - New developments in nitrosovasodilator therapy.
AB - Under basal conditions, nitric oxide (NO) modulates vascular tone, serves as an
antithrombotic agent, and inhibits vascular smooth muscle cell proliferation. NO
deficiency has been implicated in the pathophysiology of several vascular
disorders, including hypertension, atherosclerosis, and restenosis, and provides
a plausible biologic basis for the use of NO replacement therapy in these
conditions. Treatment with conventional nitrate preparations is limited by a
short therapeutic half-life, systemic absorption with potentially adverse
hemodynamic effects, and drug tolerance. To overcome these limitations, novel
delivery systems and novel NO donors have been developed that offer selective
effects, a prolonged half-life, and a reduced incidence of tolerance.
PMID- 9546969
TI - The microcirculation in venous hypertension.
AB - Venous ulceration is a common problem in western countries and results in large
costs to healthcare systems. A number of hypotheses of the mechanisms of
development of venous ulceration have been advanced, but this question has not
been fully resolved. In recent years research effort has focused on the
microcirculation of the skin and many methods of investigation have been employed
to study this. Some of the principal findings described in published work are
reviewed in this article. It seems unlikely from the available evidence that
venous ulceration is attributable solely to failure of diffusion of oxygen and
other small nutritional molecules to the tissues of the skin. The microvascular
changes in the skin are characterised by activated endothelium and perivascular
inflammatory cells. It is much more likely that leucocytes attach themselves to
the cutaneous microcirculation, become activated and produce endothelial injury.
Repeated over many months or years, this chronic inflammatory process leads to be
tissues changes of lipodermatosclerosis. Although there is evidence of leucocyte
involvement in the pathogenesis of venous ulceration, the exact mechanisms remain
to be resolved. Improved treatment for patients may be devised once a better
understanding of the basic causes of this condition has been reached.
PMID- 9546970
TI - Images in vascular medicine. Incomplete (latent) subclavian steal syndrome.
PMID- 9546971
TI - The epidemiology of peripheral arterial disease: importance of identifying the
population at risk.
AB - Data from the Framingham Study and other population studies indicate that
intermittent claudication (IC) sharply increases in late middle age and is
somewhat higher among men than women. Noninvasive testing in populations
indicates that the true prevalence of peripheral arterial disease (PAD) is at
least five times higher than would be expected based on the reported prevalence
of IC. Peripheral arterial disease correlates most strongly with cigarette
smoking and either diabetes or impaired glucose tolerance. Other risk factors for
PAD include hypertension; low levels of high-density lipoprotein cholesterol; and
high levels of triglycerides, apolipoprotein B, lipoprotein(a), homocysteine,
fibrinogen and blood viscosity. Individuals with PAD are more likely to have
coronary heart disease and cerebrovascular disease than those without PAD.
Because of the high risk of both nonfatal and fatal cardiovascular disease (CVD)
events in PAD patients, individuals with evidence of PAD should undergo both a
careful examination of the entire cardiovascular system and aggressive
modification of CVD risk factors.
PMID- 9546972
TI - The pathophysiology of peripheral arterial disease: rational targets for drug
intervention.
AB - The most common cause of peripheral arterial disease (PAD) is atherosclerosis,
which begins with an alteration in endothelial biology due to
hypercholesterolemia, diabetes mellitus, hypertension, tobacco use, elevated
levels of lipoprotein(a) or homocystinemia. With chronic and severe arterial
disease, changes begin to occur in the microcirculation, including obstruction at
the microvascular level and tissue injury. Based on insights into the vascular
biology of PAD, new therapies have been developed and are at various stages of
clinical trials. Future pharmacotherapy for PAD will include agents that have one
or more of the following attributes; (1) reduce, or even reverse, the progression
of atherosclerosis; (2) inhibit plaque rupture; (3) inhibit thrombosis by a novel
mechanism; (4) induce angiogenesis; (5) reverse microvascular derangements; (6)
affect blood rheology; and (7) enhance skeletal muscle's ability to use available
nutrients.
PMID- 9546973
TI - Clinical assessment of the patient with claudication: the role of the vascular
laboratory.
AB - The noninvasive vascular laboratory aids in the evaluation of patients with
peripheral arterial disease (PAD). Several qualitative and quantitative
noninvasive tests are useful for diagnosing PAD and monitoring patients' response
to treatment. These tests include Doppler ultrasonography, pulse volume
recording, segmental blood pressure measurement, exercise testing, post-occlusive
reactive hyperemia testing, transcutaneous oximetry and color-assisted ultrasound
imaging. Each test has specific utility and can be used either individually or in
combination with other noninvasive tests to obtain information about the
hemodynamic and functional severity of peripheral atherosclerosis in patients
with claudication.
PMID- 9546974
TI - Exercise in the treatment of claudication: assessment and treatment of functional
impairment.
AB - Claudication is an important cause of impaired exercise capacity, which limits a
patient's ability to walk and thus to meet the personal, social and occupational
demands of daily life. Given that improvement of the walking impairment is the
primary goal of treating claudication, exercise performance and functional status
of patients with claudication should be measured before and after any
intervention. Assessment of functional status in both the laboratory and
community settings is important so that the various treatments can be judged as
to relative efficacy. Studies have shown that exercise training programs have a
clinically important impact on functional capacity in persons with claudication.
A meta-analysis showed that pain-free walking time increased 180% and maximal
walking time increased 120% in claudicants who participated in an exercise
program. Substantial improvements have been found in walking speeds and distances
(65% and 44%, respectively), caloric expenditure (31%) and physical functioning
(67%).
PMID- 9546975
TI - The role of tobacco cessation, antiplatelet and lipid-lowering therapies in the
treatment of peripheral arterial disease.
AB - Despite the widely held belief that there are no effective medical therapies for
peripheral arterial disease (PAD), current data suggest that medical therapies
can effectively modify the natural history of atherosclerotic lower extremity
arterial occlusive disease. The ideal medical therapy would improve claudication,
forestall the onset of limb-threatening events, decrease rates of invasive
interventional therapies and improve long-term patient survival. These ideal
outcomes might be achieved through the use of smoking cessation interventions,
including behavioral and pharmacological therapy, and the administration of
antiplatelet and lipid-lowering medications in patients with PAD.
PMID- 9546976
TI - Role of revascularization in the treatment of claudication.
AB - Intermittent claudication is a relative indication for vascular reconstruction.
Conservative management with a combination of risk factor control, exercise
training and medical therapy will relieve or at least improve claudication in
some patients. If claudication precludes gainful employment or imposes an
unacceptable alteration in lifestyle, surgical revascularization should be
considered. Surgical bypass for claudication will produce optimal results in
younger patients, in whom near-normalization of the ankle/brachial index can be
anticipated. Proximal axial (in-line) reconstructions maintain their patencies
longer than more distal, and often technically more challenging, bypasses. These
tenets also apply well to percutaneous transluminal angioplasty. Both surgical
and catheter-based interventions carry potential risks of short- and long-term
morbidity, although overall morbidity associated with surgery for claudication is
acceptably low. Interventions are justified only if they are safe, effective and
durable, and if they are performed after the long-term prognosis for both life
and limb is considered.
PMID- 9546977
TI - Current and future drug therapies for claudication.
AB - The primary objectives of claudication treatment are to reduce cardiovascular
mortality and improve walking ability. Patients with claudication have 60%
mortality over 10 years, with most deaths due to myocardial infarction and
stroke. Aggressive risk-factor modification is required in all these patients,
particularly smoking cessation, lipid modification, and treatment of
hypertension, diabetes and elevated homocysteine levels. Aspirin, ticlopidine and
clopidogrel are all effective in reducing the risk of myocardial infarction,
stroke and vascular death, and thus antiplatelet therapy should be considered in
all claudicants. Patients with disabling claudication should be considered for
therapies that relieve claudication pain and improve exercise performance, the
most effective being exercise training and smoking cessation. Pentoxifylline, the
only approved claudication drug in the United States, has modest efficacy in
improving treadmill exercise performance. Other drugs shown to be of some benefit
in patients with claudication include propionyl-L-carnitine, cilostazol and
possibly prostaglandin derivatives. Several antiplatelet agents and angiogenic
growth factors are also being evaluated for the treatment of claudication.
PMID- 9546978
TI - Clinical use of intravascular ultrasound.
AB - Intravascular ultrasound has dramatically changed our view of atherosclerotic
disease and has helped to define mechanisms of therapeutic interventions,
providing a new rationale for selection of appropriate devices. Currently, this
technology is used for sizing and orientation of commonly performed interventions
such as balloon angioplasty and directional atherectomy. The information from
intravascular ultrasound has also led to a dramatic change in the deployment
algorithm of stents. Further improvements in catheter design and the findings
from clinical trials utilizing intravascular ultrasound will help define a
practical role for this new technology.
PMID- 9546979
TI - Application of intravascular ultrasound in remodelling studies.
AB - Arterial remodelling is an important determinant of luminal narrowing in de novo
atherosclerosis as well as in restenosis following balloon angioplasty. To date,
intravascular ultrasound is the best diagnostic modality to study changes in
arterial size in vivo. The role of arterial wall remodelling in de novo
atherosclerosis and restenosis has been well established by intravascular
ultrasound studies. Single intravascular ultrasound studies have demonstrated
that the artery may enlarge, fail to enlarge or even shrink if plaque
accumulates. In restenosis studies, serial intravascular ultrasound studies have
allowed examination of the remodelling process over time and have shown that
arterial shrinkage and not intimal hyperplasia is the predominant factor
responsible for luminal narrowing after balloon angioplasty. This article will
focus on the applicability of intravascular ultrasound to the study of vascular
remodelling in de novo atherosclerosis, in restenosis after balloon angioplasty,
atherectomy and stenting, in saphenous vein grafts and in the coronary arteries
of transplanted hearts.
PMID- 9546980
TI - The latest in electronic imaging.
AB - Development of new transducer and system technologies has led to major advances
in image quality for electronic imaging catheters. New, 64-element arrays have
increased sensitivity and optimized image resolution. System technology has
advanced to include high speed reconstruction using 'complete data sets' of
information. The incorporation of personal computer technology has enabled new
user interfaces and digital image archiving. New, combined imaging and therapy
catheters allow for efficient usage of devices. The debut of intravascular colour
flow imaging technology promises a new dimension in the treatment of coronary
artery disease.
PMID- 9546981
TI - Quantitative three-dimensional intravascular ultrasound.
AB - Three-dimensional (3-D) intravascular ultrasound (IVUS) allows for the
visualization of entire coronary segments, provides more detailed insights into
the geometry of atherosclerotic plaques and facilitates serial studies. Automated
quantitative 3-D IVUS methods reduce the analysis time and the subjectivity of
boundary tracing, and permit complex IVUS studies. The 3-D IVUS approach is not
restricted to research applications, but may be used as a valuable clinical tool.
Evaluation of the coronary segment of interest before catheter-based coronary
interventions provides information which may facilitate the selection of
interventional devices. Moreover, 3-D IVUS allows for a careful assessment of the
procedural results and potential post-procedural complications. ECG-gated image
acquisition, automated contour detection, and approaches using data of both 3-D
IVUS and biplane angiography represent the recent progress in this field. Three
dimensional IVUS will surely gain further importance and become a routine
technique, if the interest and research effort is sustained.
PMID- 9546982
TI - High-frequency intracoronary ultrasound imaging.
AB - Intravascular ultrasound is playing an increasingly important role in the
clinical management of coronary interventions. In the past few years the
technology for intracoronary ultrasound, in response to clinical pressure, has
moved towards lower profile probes with improved handling. While new catheter
designs are markedly improved on their predecessors, image quality has not seen
significant gains due to the primitive nature of the ultrasound transducer
designs. In this article, the potential for improving image quality by increasing
the frequency and focusing the ultrasound beam is explored. Basic aspects of
transducer implementation are discussed and the acoustic properties of vascular
tissues and blood are reviewed. A variety of instruments are used to image
coronary and femoral arteries at frequencies ranging from 40 to 200 MHz. These
studies serve to illustrate the trade-offs in the development of high frequency
IVUS systems. There would appear to be no fundamental reason why frequencies in
excess of 50 MHz could not be implemented. Studies using prototype IVUS
instruments in the 50 MHz range demonstrate significant improvements in image
quality.
PMID- 9546983
TI - True reconstruction of vessel geometry from combined X-ray angiographic and
intracoronary ultrasound data.
AB - At present a rapidly expanding variety of methods appear to provide three
dimensional (3-D) reconstructions of blood vessels in a patient. Generally the
results of such methods look very realistic. However, only a few produce a true 3
D reconstruction. We strongly suggest that for a true 3-D reconstruction of a
blood vessel the following criteria should at least be fulfilled: (1) the
arterial wall rather than the lumen must be reconstructed; (2) the spatially
curved course of the vessel must be included; and (3) the orientation of local
vessel wall characteristics, for example, plaque eccentricity, with respect to
the luminal course must be correctly maintained. Currently, only methods
combining biplane X-ray angiography and intravascular ultrasound imaging (IVUS)
have succeeded in providing true 3-D reconstruction of a segment of a vessel.
Accuracy of those reconstructions is derived from studies using phantoms having
precisely known geometry. In patients, data on accuracy are more difficult to
obtain. Nevertheless, a comparison can be made between the actual length of an
IVUS pull-back trajectory and its reconstructed length showing relative
differences of less than 3%. Further knowledge can be obtained by comparing
simulated angiograms derived from the 3-D reconstruction with the real contrast
angiograms. True 3-D reconstruction methods of the vessel wall and lumen,
applicable in the individual patient, have become feasible and produce accurate
results. Application of such a method will be helpful to understand immediate and
long-term vessel remodelling induced by all types of catheter interventions and
in the study of progression or regression of atherosclerotic wall disease.
PMID- 9546984
TI - Potentials of volumetric blood-flow measurement.
AB - Current intravascular ultrasound techniques produce real-time imaging of a vessel
cross-section with a scan plane normal to blood flow. When randomly distributed
blood particles travel through this ultrasound imaging plane, the received echo
signals decorrelate as a function of time. The speed of such a decorrelation
procedure is proportional to the flow velocity. This phenomenon provides a
potential to estimate blood velocities by means of decorrelation analysis. In
this paper, we present a method for measuring local blood velocity and
quantifying volume flow directly from cross-sectional intravascular ultrasound
data. This method is based on multiple decorrelation assessments with a sequence
of radio frequency echo signals. The velocity measurement is obtained by
comparing the measured decorrelation value with the prior knowledge of the beam
characteristics of an intravascular ultrasound transducer. Volume flow is derived
by integrating the cross-sectional area and its corresponding velocity vector
over the vessel lumen. The decorrelation-based method was tested in vitro with a
flow phantom. Measurements were also carried out in vivo in pig experiments to
determine the usefulness of this method in clinical settings. Preliminary results
of these experiments indicate that the proposed decorrelation method is able to
extract cross-sectional velocity profiles and volumetric flow both in vitro and
in vivo.
PMID- 9546985
TI - Intravascular elastography: principles and potentials.
AB - Many intravascular therapeutic techniques for the treatment of significant
atherosclerotic lesions are mechanical in nature: angioplasty, stenting and
atherectomy. The selection of the most adequate treatment would be advantageously
aided by knowledge of the mechanical properties of the lesion. Based on the
success of conventional intravascular ultrasound (IVUS) imaging in accurately
depicting the morphology of atheromatous lesions, ultrasonic tissue
characterization has been proposed to determine the composition of
atherosclerotic plaques. Elastography is an ultrasound-based imaging technique
capable of producing cross-sectional elasticity images called elastograms. The
technique involves analysis of echo signals obtained at two states of incremental
intravascular pressure. High resolution, local tissue displacement estimation by
cross-correlation is followed by computation of local strain. Strain is utilized
as an indicator of the local compliance of tissue under the assumption of
constant stress within the scan plane. Using vessel-mimicking phantoms, we
demonstrate the feasibility of intravascular elastography experimentally. The
elastograms are able to depict lesions of different elasticity independently of
the echogenicity contrast, since the information provided by the elastograms is
generally independent of that obtained from the conventional IVUS image. Thus,
the elastogram can complement the characterization of lesions from the
conventional IVUS image. Progress to in vitro and in vivo testing is expected in
conjunction with ongoing improvements in the current instrumentation and
processing.
PMID- 9546986
TI - Technical aspects of ultrasound imaging guidewires.
AB - In many interventional catheterization laboratories around the world the use of
intravascular ultrasound (IVUS) has become a routine addition to the catheter
based interventional procedures. IVUS catheters, for coronary use, typically of a
size around 3 French, provide images that assist in diagnosing the coronary
obstructive disease, choosing the most appropriate recanalization method,
monitoring the recanalization process and evaluating the end result. The downside
of the use of IVUS, apart from additional cost to the procedure, is the
additional exchange of catheters during the procedure. Several designs of hybrid
catheters have been proposed, combining IVUS imaging with a therapeutic de
obstruction method in one catheter. A more modular approach is to equip the
guidewire with imaging capability. Such a guidewire would provide an image of the
stenotic region as well as guide the recanalization catheter to its location. It
will, however, require further miniaturization of the ultrasound imaging
technology, which already is scaled down considerably to enable coronary imaging.
In addition, the ultrasound imaging guidewire (UIG) would have to possess
specific qualities in bending and torque to act as a true guidewire. A first step
to modularity is the separately used 'imaging core', which is advanced into the
guidewire lumen of a therapeutic catheter, but cannot guide this catheter to the
desired location. The combination of both imaging and mechanical requirements
would yield a true UIG, but constitutes major technical challenges.
PMID- 9546987
TI - First experience with imaging core wires.
AB - This study is the first assessment of feasibility and clinical usefulness of an
imaging wire. The device used is a 0.018" flexible cable mounting a 30 MHz
piezoelectric crystal at the end. The only possible application of the wire in
its current configuration is the assessment of balloon expansion with over-the
wire balloon catheters. In this study, 17 lesions were examined in 14 patients.
Despite careful removal of the air, no image could be obtained with the balloon
deflated or through the shaft of conventional balloon catheters. When the balloon
was inflated to 1-4 atm the circular echo-free cross-section of the balloon
became visible, surrounded by the dense line of the balloon membrane and by the
vessel wall. By examining the stent area at different balloon pressures, it was
possible to determine the stent recoil between maximal balloon expansion and
lowest balloon pressure allowing a readable ultrasound image. These encouraging
preliminary observations confirm the feasibility of the use of an ultrasound
guidewire for monitoring balloon expansion during stent implantation. After high
pressure inflation, a moderate reduction of the stent lumen was observed during
deflation, compatible with the small recoil predicted for the stainless-steel
mesh stent used.
PMID- 9546988
TI - Forward-looking catheters.
AB - Current intravascular ultrasound catheters provide a cross-sectional view of the
blood vessel that limits their ability to visualize severely stenosed or occluded
vessels. Forward-looking ultrasound catheters can overcome these limitations.
Development of a practical forward-looking ultrasound catheter requires solutions
to address the need for improved lateral resolution and depth of penetration
presented by the forward-looking format. Methods are also needed to generate the
forward-looking scan within the space constraints of a catheter. New developments
using mechanical scanning methods suggest that a practical device appears
achievable. Two-dimensional, as well as three-dimensional imaging, may be
possible. Early efforts towards a phased array scanner have also begun.
PMID- 9546989
TI - Irradiation and stenting.
AB - Intravascular irradiation by both gamma and beta sources has been shown to
prevent neointimal proliferation after balloon injury in the overstretch pig
coronary model. A number of clinical studies are underway that involve
brachytherapy from gamma sources in vessels that have been stented. The purpose
of this review is to analyse the physical nature of the interaction of various
forms of radiation with stent materials and to summarize the available
experimental information for relevant clinical correlates of these effects. The
ultimate use of vascular radiation in the presence of metallic stents will
require knowledge of the possible dose alterations, and where possible,
techniques to compensate for these effects.
PMID- 9546990
TI - Advantages and limitations of radioactive stents.
AB - The concept of radioactive stents was initiated to prevent restenosis after
angioplasty in patients with coronary artery disease. We review the modes of
fabrication, dosimetry and the biological effects of radioactive stents.
Radioactive stents deliver ionizing radiation continuously at very low-dose rates
according to the half-life of the incorporated radioisotopes. The activity levels
of radioactive stents are up to 10,000 times lower than activity levels of
sources used for catheter-based vascular brachytherapy. Radioactive stents allow
uniform dose distribution and precise dosimetry because of the direct source
contact with the circumference of the vessel. Animal studies show that these
stents can potently inhibit smooth muscle cell proliferation and neointimal
hyperplasia. A persistent inhibition of neointimal hyperplasia appears to be dose
dependent. Local or systemic side effects related to the irradiation were not
observed. A limitation of radioactive stents could be the dose-dependent delay in
stent endothelialization which, however, did not cause thrombotic vessel
occlusion in animal experiments. Whether a delay in stent endothelialization is
associated with an increased rate of occlusive stent thrombosis in humans
requires further studies.
PMID- 9546991
TI - Basis of endovascular radiation therapy in human coronary arteries.
AB - Restenosis is the major limitation to a full expansion of all revascularization
procedures. Elastic coil, unfavorable remodeling and a proliferative response to
injury are the more importune mechanisms to restenosis. Ionizing radiation based
on the inhibitory effect on cellular proliferation has been widely used in the
treatment of numerous neoplastic and non neoplastic conditions. Experimental
brachytherapy has demonstrated to reduce restenosis in peripheral arteries and
coronary arteries in animal models and gamma-radiation therapy decrease
restenosis after stent implantation in femoral-popliteal arteries in patients. We
developed to evaluate the feasibility, safety and effects of gamma intracoronary
radiation therapy after coronary angioplasty a protocol and used a wire 0.018 and
0.014 inches in diameter and 30 mm active length with 192 Iridium into the closed
channel polyethylene catheter was not centered the source within the vessel wall.
We prescribed 25 Gy and 20 Gy to the diameter of the reference artery to 21
patients. The 24 hours, two months and after six months angiographic follow up
demonstrated that intracoronary radiation therapy was feasible and safe and
preliminary analysis point out a reduction in late loss. The efficacy and safety
of the different sources and procedures should be well established. There is a
great expectation regarding the efficacy and safety of vascular brachytherapy to
increasing the use of endovascular recanalization procedures.
PMID- 9546992
TI - Physics and safety aspects of a coronary irradiation pilot study to inhibit
restenosis using manually loaded 192Ir ribbons.
AB - Radiation therapy has been successfully used in controlling some forms of benign
tissue growth. A pilot study has been launched to evaluate the usefulness of
localized radiation therapy in reducing restenosis after coronary angioplasty. In
this randomized, double-blind study, patients with known restenosis received
balloon angioplasty or additional stent implantation and were then randomized to
receive either radiation or placebo treatment. Active sources consisted of 192Ir
in the form of cylindrical seeds (0.3 x 0.05 cm). The seeds are embedded in a
nylon ribbon. The nylon ribbon is passed through an indwelling coronary catheter.
For this pilot trial, radioactive sources were exposed to blood elements and,
therefore, required sterilization. A method of sterilization is described. A
working team was developed to perform coronary radiation procedures at our
institution. A description of the procedure is provided.
PMID- 9546994
TI - Five year follow-up after brachytherapy for restenosis in peripheral arteries.
AB - Restenosis in peripheral vessels caused by intimal hyperplasia after stent
implantation, PTA, atherectomy or laser treatment ranged up to 40%. In order to
avoid the hyperplastic reaction with restenosis we treated our patients with
prophylactic endovascular afterloading therapy after failure of PTA in case of
recurrent stenosis. We had 30 patients with up to 4 recurrent stenoses between 4
and 7 months due to intimal hyperplasia in the stented area. To minimize the
reocclusion rate we performed an irradiation with 12 Gy surface dose in one
session using the endovascular afterloading method with 192 Iridium HDR following
re-PTA in the stented vessel segment. The longest follow up is 68 months. The
histological analyses of tissue years after irradiation showed a thinner, more
compact cellular layer of the myofibroblasts with less myxoid degeneration
between the cells compared to intimal hyperplasia and plaques in not irradiated
vessel segments. The follow up showed a significant effect of endovascular
radiotherapy. The histological findings after irradiation were a diminished
growth in the cellular population of the analysed vessel wall compared to not
irradiated vessel wall segments of the same patient. These findings may be
explained by a reduced migration and mitosis rate of myofibroblastic cells after
irradiation. The method may be an interesting alternative to stent implantation
alone. Even vessel segments like the Hunter's channel will be patent for a long
time follow up. Because of the steep decay in the dose using the endovascular
irradiation method with 192 iridium HDR, the method can be used with minimal risk
for the surrounding tissue.
PMID- 9546993
TI - Feasibility and safety of beta irradiation in human coronary arteries.
AB - We have developed a technique of endoluminally centred endovascular beta
irradiation aimed at preventing restenosis after PTCA. The source consists of a
pure metallic 90-Yttrium coil that can be positioned within the lumen at the
target site by the use of a centering device and an afterloading console.
Experimental evaluation of this approach showed that a dose of 18 Gy delivered at
the inner arterial surface was highly effective in preventing fibrointimal
hyperplasia in rabbit carotid and iliac arteries. A pilot clinical evaluation in
the coronary arteries of 15 patients using the same dose demonstrated excellent
feasibility and no unexpected side-effects. A dose-finding evaluation in the
clinical setting is now planned.
PMID- 9546995
TI - Clinical trial design.
AB - Clinical trials of radiation therapy provide the first opportunity to examine a
device therapy in a truly blinded manner. Observational studies suggest that
moderate-sized clinical trials can adequately test the ability of the method to
reduce restenosis. The mechanism by which such reduction is achieved should be
studied by angiographic and intravascular ultrasound methods although clinical
outcomes will be uniquely valuable because of the blinding.
PMID- 9546996
TI - The vessel wall reaction in restenosis.
AB - Coronary angioplasty imposes injury on the coronary artery during the procedure
to achieve adequate revascularization. The arterial response to that injury is
critical to both the acute and long-term success or failure of the procedure. As
newer technologies become clinically available, it is increasingly evident that a
final common response to angioplasty is neointimal formation, and adventitial
contraction known as remodelling. Both procedures appear to occur to varying
degrees, and similarly appear dependent on the degree of injury. Neointimal
hyperplasia is a major factor in the restenosis problem, although others are
clearly important. Additional factors include thrombus, intimal and medial
dissections and elastic recoil of the arterial wall. The proportion of the
restenosis problem caused by each is unclear, but current efforts to solve
restenosis centre on limiting neointimal hyperplasia, the primary response to
injury of the vessel. This paper will review arterial injury during
revascularization in both patients and animal models, with special emphasis of
the nature and formation of neointimal hyperplasia.
PMID- 9546997
TI - Basic physics and biology of radiation therapy.
AB - The therapeutic use of ionizing radiation followed shortly after the discovery of
X-rays by Roentgen in 1895. The radiobiological principles that underlie the
clinical use of ionizing radiation have been ablated slowly over the past
century. Ionizing radiation, which is used therapeutically for benign and
malignant conditions, is characterized by the localized release of large amounts
of energy. These radiations may be electromagnetic (X- or gamma rays) or
particulate (electrons, protons, alpha particles, neutrons, etc.). In this paper
we will review some basic radiation physics and radiation biology principles
which might be unfamiliar to the interventional cardiologist interested in this
evolving application of radiation to prevent restenosis.
PMID- 9546998
TI - Response to radiation therapy in animal restenosis models.
AB - Intracoronary radiation therapy for prevention of restenosis is a new emerging
technology which is tested nowadays in clinical trials. Several methods of
radiation and a variety of isotopes have been tested in different animal models
in order to prove the concept and to find a friendly user system for this
application. Using the same treatment doses both gamma and beta emitters
demonstrated similar results despite differences in isotope characteristics:
penetration, activity, dose rate and treatment time. In addition, intracoronary
radiation delivered via a catheter-based system prior to coronary stenting showed
reduction of neointimal hyperplasia in the porcine coronary stent model and may
further reduce restenosis coupled to stent implantation. The value of radioactive
stents is also considered especially in large vessels with regard to their low
activity and their proximity to the vessel wall. Adventitial labeling and
immunostaining suggested the mechanism by which radiation reduces smooth muscle
cell proliferation at the adventitia and affects on favorable vessel remodeling.
These studies which were pioneered in this new field and have facilitated the
clinical trials of using radiotherapy for prevention of restenosis are reviewed
and discussed in this paper.
PMID- 9546999
TI - The neurotoxicity of amyloid beta protein in aged primates.
AB - Amyloid beta protein deposition is a universal feature of Alzheimer's disease
brain. To investigate the effects of amyloid beta protein in aged primates,
intracerebral microinjections of solubilized amyloid beta (A beta (1-40)) and
control peptides were made into the frontal cortex of 7 primates under
stereotactic guidance. Control injections consisted of vehicle alone, a 37 amino
acid non toxic peptide (A37), scrambled peptide (CA4), and reverse peptide (A
beta (40-1)). Amyloid beta peptide produced dose-dependent cortical lesions that
were significantly larger than those produced by vehicle or by isomolar control
peptides (3.28 and 2.20 fold larger respectively) (p = < 0.005). In 5 aged
primates, the cortex surrounding the amyloid beta lesions contained argyrophilic,
thioflavine S fluorescent, Alz 50 and ubiquitin immunoreactive neurons and
perikarya. The number of Alz 50 immunoreactive neurons surrounding the amyloid
beta injections was significantly greater (mean 127 +/- 39) than the number found
surrounding reverse peptide injections (mean 20 +/- 13) and other control
peptides (mean 0.8 +/- 0.3) (p < 0.05). Neuronal and neuritic alterations were
not found adjacent to the amyloid beta peptide lesions in young monkeys and
control injections produced insignificant Alz 50 neuronal positivity. These
findings suggest that amyloid beta peptide is neurotoxic in primate brain and
that the cytoskeletal response to amyloid beta protein is specific and age
related.
PMID- 9547000
TI - Effects of beta-amyloid peptides on the fluidity of membranes from frontal and
parietal lobes of human brain. High potencies of A beta 1-42 and A beta 1-43.
AB - beta-amyloid peptide (A beta) and several A beta-fragments decrease the fluidity
of human cortex membranes in a concentration dependent fashion. The effect of A
beta on membrane fluidity increases with peptide length, is most pronounced for A
beta 1-43 and can be seen at concentrations as low as 100 nmol/l. While the
fragment A beta 25-35 is active, scrambled peptide (A beta 35-25) when
investigated under similar conditions shows no effects on membrane fluidity. The
effect of A beta peptides on fluidity of the phospholipid bilayer is more
pronounced in the hydrocarbon core (labeled with the fluorescence probe 1,6
diphenylhexa-1,3,5-triene) than in the region of the hydrophilic heads (labeled
with the fluorescence probe 1-[4'-(trimethylamino)phenyl]-6-phenylhexa-1,3,5
triene). It is suggested that the effect of A beta on neuronal membranes is
probably a major initial mechanism in a cascade of events finally leading to
neurotoxicity and cell death in Alzheimer's disease.
PMID- 9547001
TI - Laminin blocks the assembly of wild-type A beta and the Dutch variant peptide
into Alzheimer's fibrils.
AB - Amyloid fibril formation is believed to be a nucleation-dependent polymerization
process which may be influenced by various other factors with important
consequences for the development, prevention or treatment of amyloidosis. We have
previously shown that laminin inhibits A beta peptide fibril formation in vitro.
Here we present a kinetic study that indicates laminin to be a potent anti
amyloidosis factor, as it not only inhibited A beta 1-40 fibril aggregation, but
also inhibited the aggregation of the Dutch A beta 1-40 variant, a peptide with a
higher capacity to aggregate than the wild-type A beta 1-40. The inhibitory
effect of laminin on amyloid fibril formation was not overcome by the addition of
pre-formed A beta fibrils, suggesting that laminin inhibits the fibril elongation
process. At the present time, however, we cannot rule out the possibility that
laminin also affects the initial nucleation process of A beta fibril formation.
On other hand, laminin was not able to counteract the amyloid fibril formation
promoted by acetylcholinesterase (AChE), another component of the amyloid
deposits found in AD brains. The effect of laminin may be important as an
inhibitor of A beta amyloidogenesis in vivo, specifically at the level of
cerebral blood vessels.
PMID- 9547003
TI - Transthyretin mutation (serine 84) associated with familial amyloid
polyneuropathy in a Hungarian family.
AB - A Hungarian family with familial amyloid polyneuropathy (FAP) was studied. The
disease presented in two individuals with carpal tunnel syndrome in the fourth
and fifth decades of life. The proband subsequently developed vitreous opacities
requiring vitrectomy and now has evidence of cardiomyopathy. Single strand
conformation polymorphism analysis and direct DNA sequencing revealed a variant
AGC (serine) codon at amino acid position 84 of the amyloid precursor protein,
transthyretin (TTR). The same single amino acid substitution in TTR was detected
in an Indiana kindred with Swiss/German origin. Six individuals of the 11 tested
being at risk for FAP proved to have the mutation in the present Hungarian
kindred. This is the first description of this TTR gene mutation in Europe.
Despite TTR gene haplotype analysis which suggests that the Hungarian and Indiana
kindreds may have a common origin, no genealogical link has been identified
between the families living in Indiana and Hungary.
PMID- 9547002
TI - Synovial inflammatory cells captured 131I-beta 2-microglobulin in patients with
dialysis related amyloidosis.
AB - Dialysis related amyloidosis (DRA) is a major complication of long term
hemodialysis therapy. It is well recognized that scintigraphic study using
radioisotope-labeled beta 2-microglobulin (beta 2M) as a tracer is a sensitive
and specific technique to diagnose DRA non-invasively. The aim of this study is
to clarify the mechanism of 131I-beta 2M accumulation around the amyloid tissue.
Three dialysis patients with carpal tunnel syndromes were examined for
consecutive 131I-beta 2M scintigraphies every 24 hours for 3 days till the carpal
tunnel synovectomy. Removed synovial tissues were processed for histological
study. The scintigraphic study demonstrated tracer accumulations in the joints
involved with DRA and the intensity increased in a time dependent fashion.
Microscopic observations revealed many inflammatory cells presenting CD68
monocytes/macrophages antigen infiltrated into the synovial tissues. 131I-beta 2M
was evident in the cytoplasm of the infiltrating cells, while no radioactivity
was detected above background in the amyloid tissues. In conclusion, the tracer
accumulations observed in the 131I-beta 2M scintigraphic studies were the
consequence of circulating beta 2M assimilated by the infiltrating
monocytes/macrophages. Thus, the undetermined elimination pathway of circulating
beta 2M in the dialysis patients was identified as the storage pool in those
inflammatory cells. The inflammatory change may play a crucial role in the local
progression of DRA through the accumulation of circulating beta 2M around the
established amyloid tissues.
PMID- 9547004
TI - Ultrastructural evidence for the formation of amyloid fibrils within
cardiomyocytes in isolated atrial amyloid.
AB - Isolated atrial amyloid (IAA) frequently affects elderly human hearts in which
only the atria are involved by the deposits. Biochemical analysis has indicated
that the major subunit protein of IAA is alpha-human atrial natriuretic peptide
(alpha-ANP), which is synthesized by the atrial muscle cells. To define the exact
location of the formation of IAA fibrils, right atria from 25 patients undergoing
cardiac surgery have been examined by an immunohistochemistry and immunoelectron
microscopy with anti-alpha-ANP, apolipoprotein E, amyloid P component,
transthyretin, and cathepsin B antisera. Of 25 patients, 19 were involved with
IAA deposits which reacted with anti-alpha-ANP, apolipoprotein E, amyloid P
component antisera but not with anti-transthyretin antiserum. In 8 of them,
amyloid fibrils were seen not only in the interstitium of the atrial myocardium
but also in the dilated transverse tubules of the cardiomyocytes. In some
cardiomyocytes, amyloid fibrils were also demonstrated within the organelles such
as coated and uncoated secretory vesicles or lysosomes. These findings lead to
the inescapable conclusion that the polymerization of amyloid fibrils in IAA
occurs within the cytoplasm of cardiomyocytes under some conditions.
PMID- 9547005
TI - An ultrastructural study of the colocalization of biglycan and decorin with AA
amyloid fibrils in human renal glomeruli.
AB - An investigation was undertaken on paraformaldehyde-fixed, Lowicryl resin
embedded renal biopsies from patients with AA amyloidosis to study the
association of two small chondroitin sulphate/dermatan sulphate proteoglycans,
decorin and biglycan, with amyloid fibrils using an ultrastructural immunogold
technique. Biglycan was present in glomerular endothelial cells in both normal
kidney and in amyloidosis, but little biglycan or decorin was present in the
normal mesangial matrix. By contrast, conspicuous amounts of both biglycan and
decorin were seen to be associated with amyloid fibrils in the glomerular matrix
in cases of renal AA amyloidosis. The results further emphasise the close
association between amyloid and extracellular matrix components which are now
considered to be an integral part of the amyloid fibrils.
PMID- 9547006
TI - Local synthesis of amyloid fibril precursor in AL amyloidosis of the urinary
tract.
AB - An amyloid tumor localized to the urethra was resected and shown by
immunohistochemistry to contain fibril deposits that stained with antisera
specific for lambda VI immunoglobulin light chain. The amino acid sequence of the
fibril protein was homologous to lambda VI Positive staining of subepithelial
plasma cells with lambda VI specific monoclonal antibody was consistent with the
hypothesis that the fibril precursor light chain protein is synthesized and
processed locally to give this type of localized amyloidosis.
PMID- 9547007
TI - Gelsolin-related familial amyloidosis, Finnish type (FAF), and its variants found
worldwide.
AB - Gelsolin-related familial amyloidosis, Finnish type, occurs worldwide, most
likely as a result of sporadic low-frequency mutations. Two mutations at
nucleotide 654 in the gelsolin gene have been demonstrated, which result in a
characteristic triad of ophthalmologic, neurologic and dermatologic
manifestations distinct from other amyloidoses. Some phenotypic variation,
particularly in the age of onset and severity of manifestations, occurs but in
general the disease is clinically rather homogeneous. Systemic deposition of
amyloid is found in most tissues, predominantly in blood vessel walls and
associated with basement membranes. The mutations result in amino acid
substitutions with a charge change in the gelsolin molecule, postulated to alter
the susceptibility for proteases thereby rendering the molecule amyloidogenic.
Gelsolin fragments constitute the amyloid fibrils, but abnormal fragments also
occur in patients' plasma and CSF providing evidence for the role of aberrant
proteolysis in the disease pathomechanism. This is further strengthened by in
vitro expression analyses showing both disease-related mutations to result in
secretion of an abnormal gelsolin fragment, the likely precursor protein of
gelsolin amyloid. Of the two forms of gelsolin, secretory and cytoplasmic, the
secretory plasma form is the likely source of amyloid. The origin of the systemic
amyloid deposits is not known but, beside a circulatory origin, local synthesis
and deposition is an attractive pathomechanical alternative. The final goal of
preventing or curing this disease has come closer, but still awaits further
comprehensive pathological, functional and experimental studies in order to
dissect all pathogenetically important events.
PMID- 9547008
TI - Tenth and eleventh Amyloidforum at the 80th and 81st annual meeting of the German
Society for Pathology, June 1, 1996 in Dresden and May 24, 1997 in Berlin,
Germany.
PMID- 9547009
TI - Localized genitourinary amyloidosis: a new form of light chain disease.
PMID- 9547011
TI - Oxazole yellow dye interactions with short DNA oligomers of homogeneous base
composition and their hybrids.
AB - Interactions between short single-stranded DNA oligomers of homogeneous base
composition and the fluorescent probes oxazole yellow (YO) and its homodimer YOYO
are described. The oligomers included 15-mers and 30-mers of polydA, polydT,
polydG, and polydC. Interactions between the dyes and DNA hybrids formed from
complementary homogeneous strands of equal length were also investigated. No
interactions were observed between the dyes and the monomeric monophosphate
nucleosides A, G, T, or C. The dyes were found to interact much more strongly
with the purine oligomers polydA and polydG than with the pyrimidine oligomers
polydT and polydC. PolydA of both lengths has strong interactions with YOYO,
whereas the polydG 30-mer interacts strongly with monomeric YO. The 15-mers of
polydG and polydC of both lengths show little interaction with either dye.
Interactions of the dyes with the polydA/polydT and polydG/polydC hybrids tend to
be dominated by interactions with polydA and polydG, respectively. Although dye
interactions generally were facilitated by hybridization, particularly for
polydA/polydT, the interactions were similar to those with the single strands and
different from those that have been observed in long double-stranded DNA.
PMID- 9547010
TI - Cyanide binding and active site structure in heme-copper oxidases: normal
coordinate analysis of iron-cyanide vibrations of a3(2+)CN- complexes of
cytochromes ba3 and aa3.
AB - The cyanide isotope-sensitive low-frequency vibrations of ferrous cyano complexes
of cytochrome a3 are studied for cytochrome ba3 from Thermus thermophilus and
cytochrome aa3 from bovine heart. Cyanide complexes of ba3 display three isotope
sensitive frequencies at 512, 485, and 473 cm-1. The first is primarily an Fe-C
stretching motion, whereas the lower wavenumber modes are bending motions. These
iron-cyanide vibrations are independent of the redox levels of the other metal
centers in the protein. On the other hand, the fully reduced bovine derivative
complexed with cyanide gives rise to a bending vibration at 503 cm-1 and a
stretching vibration at 469 cm-1. That is, the ordering of the stretching and
bending frequencies is reversed from that of the bacterial protein. These results
are analyzed by normal coordinate calculations to obtain comparative models for
the binuclear O2 reducing site of the two proteins. We find that the observed
frequencies are consistent with a linear Fe-C-N group and larger Fe-C stretching
force constant (2.558 mdyn/A) for ba3 and a slightly bent Fe-C-N group (angle
approximately 170 degrees) and a smaller Fe-C stretching force constant (2.335
mdyn/A) for aa3. Thus, there are significant differences in the interaction of
cyanide with ferrous a3 in the two proteins that are most likely caused by a
weaker proximal histidine interaction and stronger peripheral heme electron
withdrawing effects in ba3. Possible sources of these protein-induced effects are
discussed. Using the analysis developed here, comparison of the FeCN stretching
and bending frequencies of the ferrous bovine a3-CN complex to those obtained
from the ferric a3-CN complex suggests that upon conversion of the resting to the
fully reduced protein, a conformational change occurs that constrains the ligand
binding site.
PMID- 9547012
TI - Spectroscopic studies of single-stranded DNA ligands and oxazole yellow dyes.
AB - Interactions between short single-stranded DNA ligands and fluorescent DNA
indicator dyes were used to investigate binding selectivity of the ligands.
Conformational differences among four DNA ligands of different sequence and
structure, including two that form a G-quartet and two that do not, were
confirmed by circular dichroism spectroscopy. Their interactions with indicator
dyes YO-pro-1 iodide (YO) and YOYO-1 iodide (YOYO) were probed using measurements
of dye absorbance; induced circular dichroism; and fluorescence spectra,
anisotropy, and lifetime. Equilibrium binding constants and stoichiometry were
determined as well. Results indicate significant differences among the dye
interactions and binding stoichiometries of the four ligands. One of the G
quartet forming ligands, a 20-mer of sequence 5'-GGTTTTGGTTTTGGTTTTGG-3', shows
distinctly different interactions from the other three ligands, all of which are
15-mers. These studies illustrate the importance of sequence and conformation in
determining the binding interactions of short single-stranded DNA.
PMID- 9547013
TI - Cancer grading by Fourier transform infrared spectroscopy.
AB - Thirty-nine freeze-dried tissue samples from 17 lymphoid tumors (nine malignant
non-Hodgkin's lymphomas) were studied by Fourier transform infrared (FTIR)
spectroscopy. The absorbance ratio A1121/A1020 increased, along with the
emergence of an absorbance pulse at 1121 cm-1, with increasing
clinicopathological grade of malignant lymphoma. An increasing A1121/A1020 ratio
from benign to malignant is evident in literature spectra from several different
tissues; however, the present study is the first to comment on this effect and to
propose it as an index of the cellular RNA/DNA ratio after subtraction of
overlapping absorbances, if present, due to collagen or glycogen. Absorbance
attributable to collagen increased with lymphoma grade and was greater in benign
inflammatory tumors than in low-grade lymphomas. The A1121/A1020 trend observed
here may form the basis of a universal cancer-grading parameter to assist with
cancer treatment decisions and may also be useful in the analysis of cellular
growth perturbation induced by drugs or other therapies. Our spectral findings
may potentially be applied to cell clusters and discrete areas of tumor tissue
sections using the FTIR microscope, allowing correlation with morphology and a
high degree of spatial resolution.
PMID- 9547014
TI - Infrared spectroscopy of human tissue. I. Differentiation and maturation of
epithelial cells in the human cervix.
AB - Infrared spectral results for the different epithelial layers of human cervical
squamous tissue are reported. The layers, representing different cellular
maturation stages, exhibit quite different spectral patterns. Thus, infrared
spectroscopy presents a powerful tool to monitor cell maturation and
differentiation. Furthermore, a detailed understanding of the spectra of the
individual layers of tissue permit a proper interpretation of the state of health
of cells exfoliated from such tissue. Part II of this series describes the use of
the spectral information presented here to interpret the infrared spectra of
exfoliated cells.
PMID- 9547015
TI - Infrared spectroscopy of human tissue. II. A comparative study of spectra of
biopsies of cervical squamous epithelium and of exfoliated cervical cells.
AB - A comparison of infrared absorption spectra obtained from the different layers of
squamous epithelium from the human cervix, and infrared spectra obtained from
exfoliated cervical cells, is presented. Infrared spectroscopy has been shown (in
part I of this series) to be a sensitive tool to monitor maturation and
differentiation of human cervical cells; therefore, this spectroscopic technique
provides new insights into the composition and state of health of exfoliated
cells.
PMID- 9547016
TI - Raman scattering tensors of tyrosine.
AB - Polarized Raman scattering measurements have been made of a single crystal of L
tyrosine by the use of a Raman microscope with the 488.0-nm exciting beam from an
argon ion laser. The L-tyrosine crystal belongs to the space group P2(1)2(1)2(1)
(orthorhombic), and Raman scattering intensities corresponding to the aa, bb, cc,
ab and ac components of the crystal Raman tensor have been determined for each
prominent Raman band. A similar set of measurements has been made of L-tyrosine
d4, in which four hydrogen atoms on the benzene ring are replaced by deuterium
atoms. The effects of NH3-->ND3 and OH-->OD on the Raman spectrum have also been
examined. In addition, depolarization ratios of some bands of L-tyrosine in
aqueous solutions of pH 13 and pH 1 were examined. For comparison with these
experimental results, on the other hand, ab initio molecular orbital calculations
have been made of the normal modes of vibration and their associated
polarizability oscillations of the L-tyrosine molecule. On the basis of these
experimental data and by referring to the results of the calculations,
discussions have been presented on the Raman tensors associated to some Raman
bands, including those at 829 cm-1 (benzene ring breathing), 642 cm-1 (benzene
ring deformation), and 432 cm-1 (C alpha-C beta-C gamma bending).
PMID- 9547017
TI - The diversity of volume regulatory mechanisms.
AB - Mammalian cells utilize a wide variety of cell volume regulatory mechanisms. For
rapid adjustment of cell volume cells release or accumulate ions through
respective channels and transport systems across the cell membrane. The most
widely used mechanisms of cell volume regulatory ion release include ion channels
and KCl symport. Ion uptake is most frequently mediated by Na+ channels, Na+, K+,
2Cl- cotransport, and Na+/H+ exchange. Chronic adjustment of cell osmolarity is
accomplished by the formation or accumulation of organic osmolytes, molecules
specifically designed to create intracellular osmolarity without interfering with
cellular function. The most widely occurring osmolytes are sorbitol, inositol,
glycerophosphorylcholine, betaine, taurine, and amino acids. The osmolytes are
either synthesized by or transported into shrunken cells. During cell swelling
osmolytes can be rapidly degraded or released. Any given cell may utilize several
volume-regulatory mechanisms. Moreover, different mechanisms are utilized in
different tissues. The diversity of cell volume regulatory mechanisms allows the
cells to defend the constancy of cell volume against a myriad of challenges with
relatively little impairment of cellular function.
PMID- 9547018
TI - Endogenous angiotensin II and cell hypertrophy in vascular smooth muscle cultures
from hypertensive Ren-2 transgenic rats.
AB - We investigated the possible role of a tissular renin-angiotensin system in
promoting the growth of vascular smooth muscle cells (VSMCs) from hypertensive
transgenic rats (TGRs) with the mouse renin gene Ren-2. Mean arterial pressure
values were 99.4 +/- 2.8 and 186.7 +/- 5.0 mm Hg for control Sprague-Dawley rats
(SDs) and TGRs, respectively (p < 0.05). The tunica media of femoral arteries
obtained from hypertensive TGRs was found to be thickened compared to that of age
matched normotensive SDs. Angiotensin II could be detected by dot blot and
immunocytochemistry and quantified by radioimmunoassay in transgenic VSMCs, but
not in control SD ones. Under serum-free conditions, VSMCs derived from TGRs
showed a higher protein content than those derived from SDs (337 +/- 19 vs. 269
+/- 14 pg/cell, p < 0.05, n = 3). Under the same basal conditions, the mean
planar cell surface area was significantly higher in TGR VSMCs than in SD ones
(4,764 +/- 204 vs. 4,074 +/- 238 micron 2, p < 0.05). In addition, TGR VSMCs
showed an enhanced [14C]-leucine uptake but SD VSMCs did not (13,188 +/- 663 vs.
7,633 +/- 713 dpm/well, p < 0.05). VSMCs showed a concentration-dependent
proliferative response to fetal calf serum (FCS) that was more marked in TGRs
than in SDs. In the absence of FCS, c-fos and c-jun mRNAs were expressed only in
transgenic cultures. From the present results, we can hypothesize that cultured
TGR VSMCs are able to synthesize angiotensin II that, being almost exclusive into
the cells, contributes to produce VSMC growth in the absence of FCS stimulation.
PMID- 9547019
TI - Functional evidence for a pH sensor of erythrocyte K-Cl cotransport through
inhibition by internal protons and diethylpyrocarbonate.
AB - The sidedness of proton modulation of K-Cl cotransport (K-Cl COT) was studied in
low K sheep red blood cells stripped of cellular Mg, Mgi, at alkaline medium pH,
pHo, by the divalent ionophore A23187 and a chelator. This procedure activates K
Cl COT, presumably, by inhibition of MgATP-dependent kinases. Ouabain-resistant K
efflux and Rb influx were measured in Cl or NO3 either at variable pHi and fixed
pHo, or vice versa, in erythrocytes pH- and volume-clamped with the anion
exchange inhibitor 4,4'-diisothiocyanato-2,2'-disulfonic stilbene (DIDS) and
sucrose. Between pHi 9 and 6, and at constant pHo 9, K effluxes decreased
hyperbolically in Cl and linearly in NO3 whereas Rb influxes fell almost linearly
in Cl and asymptotically in NO3. Thus, saturation of outward and inward K-Cl COT,
the calculated difference of the fluxes in Cl and NO3, occurred at slightly
different pHi values. Hill plots revealed pKa values of 6.5 and 7.0, and Hill
coefficients of > 1 for outward and inward K-Cl COT, respectively. Raising pHo
from 6 to 9 at fixed pHi slightly increased K and Rb fluxes in both Cl or NO3,
but not K-Cl COT. The histidine reagent diethylpyrocarbonate (DEPC) inhibited low
Mgi-activated K-Cl COT at approximately 4 mM, an effect partially reversible by
subsequent treatment with hydroxylamine. It is concluded that protons inhibit
erythrocyte K-Cl COT through internal histidine(s) which may be part of a pH
sensor.
PMID- 9547020
TI - Expression of cystic fibrosis transmembrane conductance regulator alters the
responses to hypotonic cell swelling and ATP of Chinese hamster ovary cells.
AB - The aim of this study was to examine whether the stable expression of wild-type
cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese hamster
ovary (CHO) cells alters the properties of these cells towards hypotonic cell
swelling and ATP. According to many previous studies this was not expected a
priori, since overexpression of CFTR should not affect the conductive pathways
upregulated by the purinergic agonist or cell swelling. Three types of CHO cells
were examined: a control group of normal CHO cells; a group of CFTR-CHO cells
stably expressing wild-type CFTR at high levels (CHO-CFTR), and a group delta
F508-CFTR-CHO cells, stably expressing the frequent mutation delta F508 CFTR (CHO
delta F508). Whole cell patch-clamp studies were performed to measure the
membrane voltage (Vm), the membrane conductance (Gm), and the membrane
capacitance (C(m)). Hypotonic cell swelling (Hypo, 150 mosm/l) was used, because
it activates Cl- and K+ channels and enables the cell to extrude KCl in many
cells, and ATP because it is known to activate Ca(2+)-regulated channels in a
large variety of cells. Hypo depolarized all three types of cells. This
depolarization was accompanied by an increase in Cl- conductance. The selectivity
of the conductance was I- > or = Br- > or = Cl- in CHO cells, but Cl- = Br- = I-
in the CFTR cells. Even more surprising: ATP (100 mumol/l) hyperpolarized CHO and
delta F508 cells and predominantly enhanced K+ conductance, whilst it depolarized
and increased mostly a Cl- conductance in CFTR cells. The selectivity of this
anion conductance was atypical for ATP: Br- > Cl- > I-. C(m) was increased by ATP
and Hypo in all three types of cells. ATP enhanced cytosolic Ca2+ ([Ca2+]i) in
all three types of cells but did not enhance cAMP. These data indicate that the
expression of CFTR profoundly alters the properties of CHO cells. Agonists which
stimulate characteristic Ca(2+)-regulated channels now enhance a Cl- conductance
resembling the properties of CFTR-Cl- conductance.
PMID- 9547021
TI - Influence of hypoxia and glucose deprivation on tumour necrosis factor-alpha and
granulocyte-macrophage colony-stimulating factor expression in human cultured
monocytes.
AB - Ischaemia in wounds may modulate the expression of tumour necrosis factor-alpha
(TNF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The
release of these and other cytokines by stimulated macrophages influences wound
healing. Our aim was to examine the separate and combined effects of hypoxia and
glucose deprivation on TNF-alpha and GM-CSF mRNA levels in human monocytes
isolated from peripheral blood by density gradient centrifugation and purified by
adherence. Cells were incubated for a 16-hour period in a hypoxic (3% O2) or
normoxic (21% O2) environment in the presence or absence of glucose followed by a
further 4 h under normoxic conditions in the presence or absence of
lipopolysaccharide (LPS, 100 pg/ml). These different incubation conditions had no
effect on cell viability, cell number, lactate dehydrogenase release or
superoxide anion generation (n = 5, p > 0.05, paired t test). However, Northern
hybridisation showed that hypoxia decreased the expression of GM-CSF mRNA in LPS
stimulated human monocytes by 46% (n = 9, p < 0.05, paired t test) and increased
the expression of TNF-alpha by 102% (n = 7, p < 0.05, paired t test). The
increase in the level of immunoreactive TNF-alpha in the cell supernatants
paralleled the increase in TNF-alpha mRNA. The combination of glucose deprivation
and hypoxia decreased the expression of both GM-CSF and TNF-alpha mRNA in LPS
stimulated human monocytes. Similarly, a decrease in the level of TNF-alpha in
the cell supernatants was observed (n = 3-5, p < 0.05, two-way ANOVA). These data
suggest that incubation conditions simulating ischaemia reduce LPS-induced
cytokine expression.
PMID- 9547022
TI - A Ba(2+)-insensitive K+ conductance in the basolateral membrane of rabbit
cortical thick ascending limb cells.
AB - The nature of the K+ exit across the basolateral membrane of microperfused rabbit
cortical thick ascending limbs (cTALs) was investigated using the transepithelial
and transmembrane potential difference (PDte, PDbl) and conductance measurements.
An increase in bath K+ concentration from 4 to 10, 25, 50 mmol/l depolarized the
basolateral membrane in a concentration-dependent manner, accompanied by a
decrease in the fractional resistance of the basolateral membrane (FRbl). The Cl-
channel blocker, 5-nitro-2-(3-phenylpropyl-amino)-benzoic acid (NPPB), did not
prevent these effects. The effect of Ba2+ on PDbl was bimodally distributed:
paradoxically, in the tubules in which Ba2+ largely depolarized, the effects on
PDbl of the bath K+ concentration increases were not inhibited by extracellular
Ba2+, in tubules in which Ba2+ moderately depolarized, Ba2+ partially inhibited
the K+ concentration increase-induced depolarization of the basolateral membrane.
However, the parallel decrease in FRbl was Ba2+ insensitive, indicating that the
K+ channel of the basolateral membrane was not modified by extracellular Ba2+.
The Ba(2+)-induced depolarizations were prevented by furosemide suggesting that
Ba2+ acts by inhibiting basolateral KCl extrusion. Finally, the K+ concentration
increase-induced depolarizations were insensitive to tetraethylammonium,
charybdotoxin, apamin and verapamil. In conclusion, the present study provides
evidence that, in addition to a Ba(2+)-sensitive KCl cotransport system, the
basolateral membrane of rabbit cTAL cells possesses a K+ conductance which is
insensitive to extracellular Ba2+.
PMID- 9547024
TI - Pathophysiology of acute ischemic stroke: new concepts in cerebral embolism.
PMID- 9547023
TI - Are more complex study designs needed for future acute stroke trials?
PMID- 9547025
TI - Ancrod in the treatment of acute ischemic stroke. A review of clinical data.
PMID- 9547026
TI - Controlling acute elevation of plasma fibrinogen with ancrod.
PMID- 9547027
TI - The pharmacology of thrombolytic and fibrinogen-depleting agents in the treatment
of acute ischaemic stroke.
PMID- 9547029
TI - Is there a need to reclassify acute stroke patients?
PMID- 9547028
TI - Acute stroke therapy in Europe today.
PMID- 9547030
TI - Occupational stress and health care use.
AB - This study investigated the relationship between health care use and (a)
stressful work events; (b) strain; (c) social support; (d) type of job and
industry; and (e) the individual characteristics of control, commitment, and
length of time in position. A sample of 260 individuals (95 men, 165 women) from
two different industries was used. Correlational analyses suggested that health
care claims and costs were positively related to stressful work events and strain
and negatively related to employees' length of time in position. Industry type
also played a role in predicting the health care variables. Multivariate analyses
suggested that environmental, stressor, and strain variables accounted for up to
16% of the variance in health care costs and 21.5% of the variance in number of
health care claims.
PMID- 9547031
TI - Adverse health effects of high-effort/low-reward conditions.
AB - In addition to the person-environment fit model (J. R. French, R. D. Caplan, & R.
V. Harrison, 1982) and the demand-control model (R. A. Karasek & T. Theorell,
1990), a third theoretical concept is proposed to assess adverse health effects
of stressful experience at work: the effort-reward imbalance model. The focus of
this model is on reciprocity of exchange in occupational life where high-cost/low
gain conditions are considered particularly stressful. Variables measuring low
reward in terms of low status control (e.g., lack of promotion prospects, job
insecurity) in association with high extrinsic (e.g., work pressure) or intrinsic
(personal coping pattern, e.g., high need for control) effort independently
predict new cardiovascular events in a prospective study on blue-collar men.
Furthermore, these variables partly explain prevalence of cardiovascular risk
factors (hypertension, atherogenic lipids) in 2 independent studies. Studying
adverse health effects of high-effort/low-reward conditions seems well justified,
especially in view of recent developments of the labor market.
PMID- 9547032
TI - Occupational health psychology (OHP) is moving forward from the crossroads of
health psychology and public health.
PMID- 9547033
TI - The influence of the work environment on cardiovascular health: a historical,
conceptual, and methodological perspective.
AB - The framework of psychosocial epidemiology is used to examine research
developments that characterize the accumulation of knowledge regarding the role
of the work environment in cardiovascular health and disease. The discussion of
current programs of research focuses on the work of T. Theorell and R. Karasek
(1996) and J. Siegrist (1996) as exemplars of European and American studies that
have contributed the most to the understanding of occupational cardiovascular
health. It is argued that researchers need to maintain and nurture relatively
broad conceptual models of etiology because cardiovascular disease involves
multiple biomedical risk factors and because specific aspects of the work
environment are embedded in a large, complex matrix of other psychosocial
influences. At the same time, investigators need to push ahead with focused
research strategies to clarify the precise nature of the work environmental risk
factors that emerge in the broad, somewhat imprecise epidemiologic study designs.
PMID- 9547034
TI - Work-family conflict, gender, and health-related outcomes: a study of employed
parents in two community samples.
AB - On the basis of identity theory and research on sex role socialization, it was
predicted that both work interfering with family (W-->F conflict) and family
interfering with work (F-->W conflict) are uniquely related to depression, poor
physical health, and heavy alcohol use (Hypothesis 1). It also was predicted that
gender would moderate these relationships, such that W-->F conflict is more
strongly related to the outcomes among women (Hypothesis 2a) and F-->W conflict
is more strongly related to the outcomes among men (Hypothesis 2b). Survey data
were obtained from 2 random community samples of employed parents (Ns = 496 and
605). Hierarchical regression analyses supported Hypothesis 1 but failed to
support Hypotheses 2a and 2b.
PMID- 9547035
TI - Conceptual and methodological developments in occupational stress research: an
introduction to state-of-the-art reviews. I.
AB - This article introduces the first special section of state-of-the-art reviews.
The historical origins of occupational health psychology are briefly discussed to
establish a context for the present contributions that focus on job strain,
effort-reward imbalance, and methodological problems.
PMID- 9547036
TI - Organizational impact of workaholism: suggestions for researching the negative
outcomes of excessive work.
AB - Excessive work can be viewed as an addictive behavior, and, as such, it will have
a negative impact on the setting in which it occurs, as well as on the
individual. This change in perspective is needed to address dysfunctional
behavior patterns that interfere with organizational operations. Similarities
with other addictions include identity issues, rigid thinking, withdrawal,
progressive involvement, and denial. These factors influence decision making and
goals of the workaholic. They also interfere with effectiveness by distorting
interpersonal relations. Suggestions for further research build on established
organizational topics that coincide with characteristics of an addictive pattern.
PMID- 9547037
TI - Behavioral determinants of occupational exposure to chemical agents.
AB - In the demand-control model (see T. Theorell & R. A. Karasek, 1996), it is
hypothesized that workers in active jobs (high demands-high decision latitude)
can exert effective coping strategies when confronted with environmental
stessors. Thus, when exposed to similar levels of a chemical agent, lower
concentrations of this agent in blood could be expected in these workers in
comparison with workers in passive jobs. This theory was tested in 2 studies of
lead-exposed workers: 18 male Caucasian workers from an electric accumulatory
factory and 18 male Caucasian workers from a lead smelting factory. The results
did not follow the hypothesized outcomes. In the work environment of the workers
in active jobs, lower concentrations of lead in air were measured, but higher
levels of lead in blood were observed in these workers. The opposite was true of
workers in passive jobs. Differences in hygienic behavior at work may explain
these unexpected results.
PMID- 9547038
TI - Current issues relating to psychosocial job strain and cardiovascular disease
research.
AB - The authors comment on recent reviews of cardiovascular job strain research by P.
L. Schnall and P. A. Landsbergis (1994), and by T. S. Kristensen (1995), which
conclude that job strain as defined by the demand-control model (the combination
of contributions of low job decision latitudes and high psychological job
demands) is confirmed as a risk factor for cardiovascular mortality in a large
majority of studies. Lack of social support at work appears to further increase
risk. Several still-unresolved research questions are examined in light of recent
studies: (a) methodological issues related to use of occupational aggregate
estimations and occupational career aggregate assessments, use of standard scales
for job analysis and recall bias issues in self-reporting; (b) confounding
factors and differential strengths of association by subgroups in job strain
cardiovascular disease analyses with respect to social class, gender, and working
hours; and (c) review of results of monitoring job strain-blood pressure
associations and associated methodological issues.
PMID- 9547039
TI - Employee drug use, demographic characteristics, work reactions, and absenteeism.
AB - Employees in a large work organization participated in an investigation of
relationships between drug use and absenteeism and tardiness. Specifically, the
study investigated the extent to which both self-reported and urine-screened drug
use accounted for variance in several types of absenteeism, as well as tardiness,
above and beyond that accounted for by demographic and work reaction variables.
The results showed that employee drug use accounted for additional statistically
significant variance in overall absenteeism and in absenteeism due to injuries
and suspensions, as well as days tardy. Implications of these findings for
organizational drug testing are discussed.
PMID- 9547040
TI - Extending the boundaries of occupational health psychology: state-of-the-art
reviews. II.
AB - The nature of work changes over the life course for both men and women, yet the
substance and meaning of both paid and unpaid activities varies considerably by
gender. The articles in this special section extend the study of work and health
by applying an ecology of the life course perspective to retirement, by extending
the definition of work to include unpaid activity outside formal employment, and
by examining the elements of causal analysis in longitudinal studies.
PMID- 9547041
TI - Influence of paid and unpaid work on psychophysiological stress responses of men
and women.
AB - Female labor force participation has increased considerably, but women's
traditional responsibility for home and family has not changed accordingly.
Although women's employment per se does not seem to have negative health
consequences, studies show that stress from role conflicts and work overload is
reflected in women's elevated psychophysiological arousal not only at work but
also off work, which may induce psychosomatic symptoms (e.g., cardiovascular and
musculoskeletal disorders). In addition, multiple role demands reduce women's
possibilities to make a professional career on the same terms as men. Data
emphasize the need for a new allocation of work functions between the sexes and
the need for organizational changes leading to more influence and control over
work to make it possible for both men and women to combine a qualified job with a
meaningful family life.
PMID- 9547042
TI - A life course perspective on retirement, gender, and well-being.
AB - The existing research literature on the links between retirement and physical and
psychological health is examined. This synthesis characterizes the complexity of
the relationship between retirement and health; points out potential gender
differences in the nature, experience, and implications of retirement; and
develops a life course model of the pathways through occupational career and
retirement leading to health. Such a life course model suggests a research agenda
that can produce important insights on the dynamics and consequences of the
retirement transition, including the mechanisms and conditions linking withdrawal
from employment to changes in health and well-being.
PMID- 9547043
TI - Longitudinal studies in organizational stress research: a review of the
literature with reference to methodological issues.
AB - Demonstrating causal relationships has been of particular importance in
organizational stress research. Longitudinal studies are typically suggested to
overcome problems of reversed causation and third variables (e.g., social
desirability and negative affectivity). This article reviews the empirical
longitudinal literature and discusses designs and statistical methods used in
these studies. Forty-three longitudinal field reports on organizational stress
were identified. Most of the investigations used a 2-wave panel design and a
hierarchical multiple regression approach. Six studies with 3 and more waves were
found. About 50% of the studies analyzed potential strain-stressor (reversed
causation) relationships. In about 33% of the studies there was some evidence of
reverse causation. The power of longitudinal studies to rule out third variable
explanations was not realized in many studies. Procedures of how to analyze
longitudinal data are suggested.
PMID- 9547044
TI - The effect of stress inoculation training on anxiety and performance.
AB - Stress inoculation training is an intervention that has shown considerable
promise; however, many questions arise regarding the application of this
clinically based approach to more applied workplace settings. A meta-analysis was
conducted to determine the overall effectiveness of stress inoculation training
and to identify conditions that may moderate the effectiveness of this approach.
The analysis was based on a total of 37 studies with 70 separate hypothesis
tests, representing the behavior of 1,837 participants. Results indicated that
stress inoculation training was an effective means for reducing performance
anxiety, reducing state anxiety, and enhancing performance under stress.
Furthermore, the examination of moderators such as the experience of the trainer,
the type of setting in which training was implemented, and the type of trainee
population revealed no significant limitations on the application of stress
inoculation training to applied training environments.
PMID- 9547045
TI - Self-esteem and the occupational stress process: testing two alternative models
in a sample of blue-collar workers.
AB - Blue-collar workers (4,523 men and 927 women) participated in a survey comparing
two alternative models, one assuming the level of self-esteem (SE) to result to a
significant extent from the strain induced by occupational stressors and the
other stating the level of SE as a determinant of stressor perception and
experienced strain. The results of multiple regression analyses did not support
the latter model, whereas the first model was partially supported: Monotony was
associated with increased strain and decreased SE among younger (< or = 35 years)
male participants and older (> 35 years) female participants, and lack of control
related to increased strain and decreased SE among older male participants. These
observations were made in the context of psychological strain symptoms but not in
the context of physiological strain symptoms.
PMID- 9547047
TI - Dual-earner families: the importance of work stress and family stress for
psychological well-being.
AB - Scales of work stress and family stress as well as outcome measures of depression
and self-esteem were completed by 94 mothers and 48 fathers in dual-earner
families. Working mothers and working fathers reported equivalent levels of
family stress, work stress, job-family interference, and psychological well
being, although mothers did report a higher level of lack of task sharing. Self
esteem and depression of dual-earner mothers and fathers were affected by both
job and family stress. Insignificance within their work role affected both self
esteem and depression. Lack of task sharing significantly predicted depression
among dual-earner mothers. Lack of challenge in their work role appeared to be a
positive characteristic for dual-earner fathers.
PMID- 9547046
TI - Correlates and consequences of workplace violence.
AB - A random telephone survey was used to interview 598 employees about instances, if
any, when they had been physically attacked or threatened in the workplace.
Demographic and workplace characteristics are analyzed as correlates of these
forms of violence. The only characteristic consistently associated with higher
risk is a work schedule that included nighttime hours. However, although few
strong or consistent correlates of workplace violence were found, there were
clear negative consequences associated with being victimized at work: lower job
satisfaction, greater job stress, increased considerations of job change, and an
increased likelihood of bringing mace, a gun, or another weapon to work.
PMID- 9547048
TI - Gender and ethnic differences in social constraints among a sample of New York
City police officers.
AB - Gender and ethnic differences in social constraints on and off the job among a
sample of 372 police officers was examined. Positive and negative social
interactions with supervisors and coworkers, and perceptions of the work
environment as well as support and resentment of the job from family and
significant others, was included. As hypothesized, women and minority men
reported more negative social interactions on the job, such as criticism, bias,
and sexual harassment. Few differences were observed for positive social
interactions on or off the job, and where differences emerged, women and minority
men reported more favorable social interactions. These findings are discussed in
terms of implications for intervention, policy, and future research.
PMID- 9547049
TI - Contributing concepts and methods across disciplinary boundaries: state-of-the
art reviews. III.
AB - This article introduces the third special section of state-of-the-art reviews.
The conceptual and methodologic contributions of the 3 articles in this section
are framed, noting the importance of the public health, preventive medicine, and
sociological disciplines represented.
PMID- 9547050
TI - Job stress and cardiovascular disease: a theoretic critical review.
AB - During the last 15 years, the research on job stress and cardiovascular diseases
has been dominated by the job strain model developed by R. Karasek (1979) and
colleagues (R. Karasek & T. Theorell, 1990). In this article the results of this
research are briefly summarized, and the theoretical and methodological basis is
discussed and criticized. A sociological interpretation of the model emphasizing
theories of technological change, qualifications of the workers, and the
organization of work is proposed. Furthermore, improvements with regard to
measuring the job strain dimensions and to sampling the study base are suggested.
Substantial improvements of the job strain research could be achieved if the
principle of triangulation were used in the measurements of stressors, stress,
and sickness and if occupation-based samples were used instead of large
representative samples.
PMID- 9547051
TI - Occupational stress, safety, and health: conceptual framework and principles for
effective prevention interventions.
AB - The authors present an overarching conceptual model of occupational stress,
safety, and health, incorporating multiple factors from diverse disciplines. They
examine specific implications of the model for the development of prevention
interventions (e.g., context-specific interventions and primary, secondary, and
tertiary prevention). They review prevention interventions and describe and
analyze 4 case studies that address exposure to environmental, ergonomic, and
psychosocial stressors and a combination of physical-environmental and
psychosocial stressors. The authors examine lessons learned from these
interventions in light of the conceptual model (e.g., role of top management and
integrating research and intervention).
PMID- 9547052
TI - Work-related stress and blood pressure: current theoretical models and
considerations from a behavioral medicine perspective.
AB - There is extensive evidence that the prevalence of human hypertension is related
to psychosocial factors, possibly including chronic exposure to stress. A
tripartite model, consistent with the literature on stress and health, may help
to define this relationship better. Its 3 components are environmental stressors,
individual factors affecting the perception of stress, and the individual's
physiological susceptibility. To date, researchers have looked at individual
parts of this model, but rarely at all 3. Some models of work stress (e.g., the
job strain, effort-reward, and person-environment fit models) focus on work
related stressors alone or in conjunction with individual characteristics. Other
models (e.g., the defense-defeat, John Henryism, and reactivity models) focus on
individual differences in response, with little attention paid to the nature of
the stressors. The authors suggest that it is timely to integrate these
approaches and to look for physiological mechanisms.
PMID- 9547053
TI - Eldercare responsibilities, interrole conflict, and employee absence: a daily
study.
AB - A model was developed specifying that the number of hours employees spend
providing care to or interacting with elderly parents predicts conflict between
the roles of employee and caregiver. Interrole conflict was subsequently expected
to predict partial absence from work (e.g., arriving late). Seventeen employed
eldercare providers completed a daily questionnaire for 20 work days. The data
were standardized and pooled, and the proposed model was tested by using
structural equation modeling. The proposed model provided a good fit to the data.
A competing model that added the direct effects of hours of interacting with and
hours of providing care to parents on partial absence provided a significantly
better fit. The potential impact of the findings on employees and organizations
is discussed.
PMID- 9547054
TI - Perceived race-based discrimination, employment status, and job stress in a
national sample of black women: implications for health outcomes.
AB - Previous research has not systematically examined the relationship of perceived
race-based discriminations to labor force participation or job related stresses
problems experienced by Black women. The present study investigated the relative
contributions of perceived race-based discriminations and sociodemographic
characteristics to employment status and job stress in a national probability
sample (the National Survey of Black Americans; J. S. Jackson, 1991) of Black
women in the United States. Logit and polychotomous logistic regression analyses
revealed that Black women's current employment status was best explained by
sociodemographic measures. In contrast, the combination of perceived
discrimination and sociodemographics differentially affects patterns of
employment status and perceived job stress in the work environment of Black
women. Implications of these findings for the health of African American women
are discussed.
PMID- 9547055
TI - Construct validity of a Physical Work Environment Satisfaction Questionnaire.
AB - Many theories of behavior at work fail to consider the effects of the physical
environment on employees' behavior and attitudes. The purpose of this research
was to gather evidence of the construct validity of the Physical Work Environment
Satisfaction Questionnaire (PWESQ) and of the validity of the physical work
environment satisfaction construct. Evidence of the construct validity of the
PWESQ was sought through its administration, along with a number of established
measures of work attitudes, to 641 employees in 8 organizations. The data
provided evidence of the validity of both the physical work environment
satisfaction construct and the PWESQ as a valid measure of that construct.
Practical and theoretical implications, as well as implications for future
research, are discussed.
PMID- 9547056
TI - Advancing public policy, social science, and biomedical inquiry: state-of-the-art
reviews. IV.
AB - In this article, the author introduces the fourth special section of state-of-the
art reviews. He discusses the public policy and epistemological contributions of
the 2 articles in this section in terms of the translation of scientific research
findings into public policy actions.
PMID- 9547057
TI - Public policy and occupational health psychology in Europe.
AB - Increasing evidence exists that workplace absence due to stress-related
conditions is a growing problem in Europe. However, the priority on the issue
varies between countries. The costs of occupational stress are difficult to
accurately quantify, and the incentives for investing in stress-prevention
activities are less apparent at an organizational level than in the United
States. Consequently, expansion in this area has been considerably slower. The
authors present an overview of the problems of occupational stress within Europe.
They discuss the response and intervention characteristics of European employers
and policymakers and possible developments. If organizations are to become more
proactive in their approach to stress prevention, there needs to be a framework
for assessing, implementing, and evaluating interventions. The authors outline a
framework to adopt.
PMID- 9547058
TI - Dialectic between conceptual and causal inquiry in psychosocial work-environment
research.
AB - In this article, the authors discuss the ongoing tension between etiologically
oriented research--particularly that focused on the demand-control model--and the
need to conceptually expand the work stress field to include gender and class
specific exposure contexts. Epidemiological research on the effects of low levels
of work control is critically reviewed, and new methods of long-term psychosocial
work-exposure assessment are presented. The process of conceptually expanding the
demand-control model is discussed with respect to including other important
variables, such as work-related social support, and specifying the nature of the
gendered work process that involves developing new concepts and measures of the
invisible and emotional labor often performed by women.
PMID- 9547059
TI - Hostility and hearing protection behavior: the mediating role of personal beliefs
and low frustration tolerance.
AB - The authors examined whether hostility would negatively be associated with
occupational health behavior, namely, the use of hearing protection devices
(HPDs). Also examined as possible mediators were the protection motivation theory
(PMT) components and low frustration tolerance (LFT). Participants were 226 male
industrial workers, all exposed to potentially hearing-damaging noise. Hostility
was negatively related to HPD use. It moderately correlated with the PMT
components: negatively with perceived susceptibility, severity, effectiveness,
and self-efficacy and positively with perceived barriers. Hostility correlated
highly with LFT. Regression analyses confirmed the mediating role of perceived
barriers, low self-efficacy, and LFT in the negative relationship between
hostility and the use of HPDs. Thus, intrapsychic characteristics of hostile
people may be significant for hearing protection behavior.
PMID- 9547060
TI - Leadership behavior and subordinate stress: a 360 degrees view.
AB - Relationships between leader behavior and subordinate work stress were examined
from the perspectives of 343 leaders, their bosses, and their subordinates.
Leader behaviors did relate to stress experienced by staff; however, leaders'
views of what related to subordinate stress did not always coincide with the
factors that subordinates themselves associated with stress. The relationships of
leader delegation and subordinate participation to lower subordinate reports of
stress were particularly underestimated by leaders. Implications for developing
leaders as agents for employee stress reduction are discussed.
PMID- 9547062
TI - Relation of negative affectivity to self-reports of job stressors and
psychological outcomes.
AB - A total of 250 new women teachers participated in a longitudinal study of the
influence of negative affectivity (NA) on the relation of self-report work
environment measures to psychological outcomes. Three "neutrally worded" work
environment measures were specially constructed to minimize confounding with NA.
The work-environment measures were moderately related to postemployment
depressive symptoms, job satisfaction, and, among Whites but not among a
principally Black and Hispanic subsample, motivation. Correlation and regression
coefficients were largely unchanged when the preemployment psychophysiologic
symptoms scale and the Center for Epidemiologic Studies-Depression Scale (L. S.
Radloff, 1977), factors that tap NA, were controlled. Findings suggest NA does
not overly distort the relation of some self-report work-environment measures to
depressive symptoms, satisfaction, and motivation.
PMID- 9547061
TI - Work-related stress and psychological distress in emergency medical technicians.
AB - Emergency medical technicians (N = 65) participated in a study on work
environment characteristics, work-related stress, and psychological distress.
Data were collected at baseline and 6 months. Work-related stress was associated
with lower work group support and poor supervisory behavior. Work-related stress
was strongly related to psychological distress. Changes in work-related stress
were significantly related to changes in psychological distress. Findings support
the work-related stress, psychological distress model.
PMID- 9547063
TI - C band variation in polytene chromosomes of Chironomus riparius (Diptera,
Chironomidae) from a polluted Piedmont station (Italy).
AB - C banding in polytene chromosomes of Chironomus riparius from a Santena polluted
station of the river Po, Italy was described. A large variation in the appearance
of C bands was established. The process involved the transformation of
euchromatin into heterochromatin. Activation of all chromosomes at telomeres was
found. A structural modification of telomeric heterochromatin may exist. The
centromeric heterochromatin was rarely observed. A high percentage of an
amplification (88%) in arm F, B3h, was recorded. These changes in the appearance
of heterochromatin in the population studied could be considered as a type of
polymorphic system, existing in the polluted population. For the first time in C.
riparius two types of position effect variegation are reported. In arm E the
euchromatin near to the centromere became inactive due to a heterozygous
inversion and in arms D and F the opposite phenomenon was observed in which a
heterozygous inversion partly suppressed the inactivation of heterochromatin.
PMID- 9547064
TI - Effect of Peganum harmala extract on root tips of Allium cepa.
AB - Treatment with Peganum harmala extract remarkably increased the mitotic index in
Allium cepa root tips with increasing treatment duration at all exposure times
used and with almost all concentrations. The extract caused a relatively high
increase in the mitotic index after a long period of treatment with some low
concentrations.
PMID- 9547065
TI - Causes and consequences of intrauterine growth retardation. Proceedings of an
IDECG Workshop. Baton Rouge, Louisiana, USA. November 11-15, 1996.
PMID- 9547066
TI - Changes in synaptology of adult cat spinal alpha-motoneurons after axotomy.
AB - The aim of this electron-microscopic study was to analyze the distribution of
synaptic contacts on the cell bodies and dendrites of permanently axotomized
adult cat spinal alpha-motoneurons. Following transection and ligation of the
medial gastrocnemius nerve, the synaptic covering of the cell bodies and three
different dendritic compartments of homonymous alpha-motoneurons was analyzed
quantitatively at 3, 6, and 12 weeks postoperatively. The synaptic boutons were
classified according to their size and the shape of their synaptic vesicles. On
the soma, a transient increase in the number of boutons was noted at 3 weeks and
6 weeks postoperatively, while after 12 weeks the bouton number had decreased to
half of its normal value. The transient increase was mainly due to an increase in
the number of F-type boutons. At 12 weeks postoperatively, the synaptic covering
was reduced by 83% on the soma and by 57% on the proximal dendrites. In the
distal dendritic regions, the values for synaptic covering remained largely
unchanged. In summary, axotomized motoneurons exhibit a reduction in synaptic
covering which is maximal on the cell body and becomes less pronounced
centrifugally along the dendrites. However, if also taking into account the loss
of distal dendritic branches that occurs in axotomized motoneurons, the total
loss of boutons is several times larger in the dendrites than on the soma.
PMID- 9547067
TI - Movements modulate the reflex responses of human flexor pollicis longus to
stretch.
AB - The reflex responses to brisk, ramp stretch perturbations of the human flexor
pollicis longus muscle (FPL) were recorded during isometric and slow concentric
or eccentric contractions at similar levels of muscle excitation. The subjects
flexed their thumb to push down against a thumb-rest, whose position was
controlled by a servo-controlled motor. In different runs, the stretch
perturbations were imposed when the thumb-rest was stationary (isometric) or was
flexing or extending the interphalangeal joint of the thumb at a constant
velocity, i.e. during concentric or eccentric contractions of FPL. The latency of
the most prominent component of the electromyographic reflex in the isometrically
contracting muscle was about 60 ms, measured from the command signal. The
amplitude of this response was sharply reduced during the non-isometric
contractions. While not dependent on the direction, this modulation of the reflex
response increased with the speed of active movement of the interphalangeal joint
(flexion or extension). The response was greatly reduced during concentric or
eccentric movements as slow as 1.6 mm x s[-1] (approximately 5 degrees x s (-1)
at the joint). When the force rather than the position of the thumb-rest was
servo-controlled, the stretch response to perturbation again diminished with
speed in a self-paced flexion task, compared with an isometric "hold" condition.
PMID- 9547068
TI - Depletion of calcitonin gene-related peptide from the caudal trigeminal nucleus
of the rat after electrical stimulation of the Gasserian ganglion.
AB - Electrical stimulation of the Gasserian ganglion resulted in partial depletion of
calcitonin gene-related peptide (CGRP) from ipsilateral central terminals of
pseudounipolar primary sensory ganglion cells. Affected terminals exhibit
decreased CGRP immunoreactivity as shown by cytophotometric densitometry of the
caudal trigeminal nucleus. The decrease in CGRP immunoreactivity is statistically
significant only in the medial one-third of the caudal trigeminal nucleus. Since
earlier studies have shown that electrical stimulation of the Gasserian ganglion
induces first accumulation then depletion of CGRP from perivascular sensory
terminals in the dura mater, the present experiments suggest that CGRP is
depleted also from central terminals of primary sensory trigeminal neurons, which
might be of importance in the pathogenesis of migraine headache.
PMID- 9547069
TI - Canal-otolith interactions in the squirrel monkey vestibulo-ocular reflex and the
influence of fixation distance.
AB - Natural head movements include angular and linear components of motion. Two
classes of vestibulo-ocular reflex (VOR), mediated by the semicircular canals and
otoliths (the angular and linear VOR, or AVOR and LVOR, respectively), compensate
for head movements and help maintain binocular fixation on targets in space. In
this study, AVOR/LVOR interactions were quantified during complex head motion
over a broad range of fixation distances at a fixed stimulus frequency of 4.0 Hz.
Binocular eye movements were recorded (search-coil technique) in squirrel monkeys
while fixation distance (assessed by vergence) was varied using brief
presentations of earth-fixed targets at various distances. Stimuli consisted of
rotations around an earth-vertical axis and therefore always activated the AVOR.
Horizontal and vertical AVORs were assessed when the head was centered over the
axis of rotation and oriented upright (UP) and right-side-down (RD),
respectively. AVOR gains increased slightly with increasing vergence in darkness,
as expected given the small anterior position of the eyes in the head. Combined
AVOR/LVOR responses were recorded when subjects were displaced eccentrically from
the rotation axis. Eccentric rotations activated the AVOR just as when the head
was centered, but added a translational stimulus which generated an LVOR
component in response to interaural (IA) or dorsoventral (DV) tangential
accelerations, depending on whether the head was UP or RD, respectively. When the
head was eccentric and facing nose-out, the AVOR and LVOR produced ocular
responses in the same plane and direction (coplanar and synergistic), and
response magnitudes increased with increasing vergence. With the head facing nose
in, AVOR and LVOR response components were oppositely directed (coplanar and
antagonistic). The AVOR dominated the response when fixation distance was far,
and phase was compensatory for head rotation. As fixation distance decreased
toward the rotation axis, responses declined to near zero, and when fixation
distance approached even closer, the LVOR component dominated and response phase
inverted. The same pattern was observed for both horizontal (head UP) and
vertical (head RD) responses. The LVOR was recorded directly by rotating subjects
eccentrically but in the nose-up (NU) orientation. The AVOR then generated
torsional responses to head roll, coexistent with either horizontal or vertical
LVOR responses to tangential acceleration when the subject was oriented head-out
or right-side-out, respectively. Only the LVOR response components were modulated
by vergence. A vectorial analysis of AVOR, LVOR, and combined responses supports
the conclusion that AVOR and LVOR response components combine linearly during
complex head motion.
PMID- 9547070
TI - Adaptational effects during human split-belt walking: influence of afferent
input.
AB - The modification of the normal locomotor pattern of humans was investigated using
a split-belt locomotion protocol (treadmill belt speeds of 4.5 km/h and 1.5 km/h
for the right and left legs, respectively) and also by changing afferent input
from the legs (30% reduction or increase in body weight by suspending subjects in
a parachute harness or by wearing a lead-filled vest). After a control-speed
training period (10 min) of symmetrical walking (3 km/h each leg) and a period
(10 min) of split-belt walking, the adjustment back to the control speed resulted
in a mean speed difference between the right leg and the left leg of 0.85 km/h.
Adjustment of belt speed on either side was performed by the hands using a
potentiometer. For comparison, also speed adjustment by the feet via feedback
derived from changes in the treadmill drive current was studied. No significant
difference was obtained when both modes of adjustment were compared. Body
unloading or loading during the training period resulted in an improved
adjustment of treadmill belt speed. This suggests that load receptor information
plays a major role in the programming of a new walking pattern.
PMID- 9547071
TI - Perceptual learning in tactile hyperacuity: complete intermanual transfer but
limited retention.
AB - We investigated intermanual transfer and long-term retention of practice-related
perceptual learning in the domain of tactile hyperacuity. Subjects discriminated
a row of three dots in which the central dot was offset laterally from a row
without such offset. Performance at the right index fingerpad improved with
practice. Practice effects transferred essentially completely to the left index
fingerpad. When tested some months later at the right index fingerpad, long-term
retention of learning was limited and further practice was required to stabilize
discrimination thresholds. Intermanual transfer of tactile learning appears to be
a general phenomenon, while long-term retention appears to be limited in
hyperacuity tasks.
PMID- 9547073
TI - Differential activation of spinal dorsal horn units by subcutaneous formalin
injection in the cat: an electrophysiological study.
AB - In our previous report we found that subcutaneous (s.c.) formalin injection into
the cutaneous receptive field (RF) of dorsal horn wide-dynamic-range (WDR) units
and nociceptive primary afferent units resulted in a tonic, long-lasting increase
in firing. However, s.c. formalin injection only resulted in a short-lasting
increase in firing of non-nociceptive primary afferent units. In the present
study, by using extracellular single-unit recording techniques we further studied
effects of s.c. formalin on response properties of identified superficial-layer
nociceptive-specific (NS) units and deeper-layer, low-threshold mechanoreceptive
(LTM) units of L7 dorsal horn in urethane-chloralose-anesthetized cats. s.c.
formalin injection into the RF of NS units resulted in a tonic, long-lasting
increase in firing (7.08+/-0.42 spikes/s, n = 5), for more than 1 h, compared
with the spontaneous background (1.42+/-0.03 spikes/s, n = 5). Formalin injection
into the RF of LTM units also resulted in an increase in firing; however, the
duration was short-lasting, for 25-520 s (152.92+/-46.73 s, n = 12). The present
study demonstrated that s.c. injection of dilute formalin solution resulted in
activation of not only nociceptive but also non-nociceptive dorsal horn units,
suggesting that tissue injury caused by s.c. formalin results in vigorous injury
discharges of peripheral nerve terminals, which subsequently leads to activation
of primary afferent neurons and secondary dorsal horn neurons.
PMID- 9547072
TI - Visual fixation offsets affect both the initiation and the kinematic features of
saccades.
AB - It is well known that the removal of a fixation point prior to the presentation
of a peripheral target dramatically reduces saccadic reaction time (SRT). This
effect has become known as the "gap effect". The present study examined several
detailed kinematic variables to determine whether the removal of the fixation
point also affects the manner in which saccades are produced. The findings
indicate that saccades that were initiated after the removal of the fixation
point had higher average velocities and reached greater peak velocities,
accelerations, and decelerations than did saccades produced in the presence of
the fixation point. The results suggest that the removal of the fixation point
may affect the force-time curves of saccades in addition to affecting the time
needed to initiate the saccades.
PMID- 9547074
TI - Transient visual field defects induced by transcranial magnetic stimulation over
human occipital pole.
AB - Transient visual field defects (VFDs) and phosphenes were induced in normal
volunteers by means of transcranial magnetic stimulation (TMS) using a circular
magnetic coil of 12.5 cm diameter placed with its lower rim 2-4 cm above the
inion in the midline. Subjects had to detect small, bright dots presented
randomly for 14 ms in one of 60 locations on a computer screen resulting in a
plot of the central 9 degrees of the visual field. In 8 of 17 subjects, transient
VFDs were inducible at peak magnetic field strenghts of 1.1-1.4 T. In the central
1-3 degrees, detection of targets was impaired in both the upper and lower visual
field, whereas at 4-9 degrees large parts of only the lower visual field were
affected with a sharp cut-off along the horizontal meridian. Targets at 1 degree
in the lower field were affected with lower TMS intensities than corresponding
locations in the upper or peripheral locations in the lower field. Detection of
central targets was affected at more caudal stimulation sites than detection of
peripheral targets. Phosphenes were elicitable in 14 of 17 subjects at clearly
lower field strengths of 0.6-1.0 T. Many subjects perceived chromatophosphenes.
From a discussion of the literature on patients with VFDs and the known
topography of the human visual system, it is concluded that the transient VFDs at
1-3 degrees are probably due to stimulation of both striate cortex (V1) and
extrastriate areas (V2/V3), while VFDs in the lower visual field at
eccentricities 4-9 degrees are due to stimulation of V2/V3 but not V1.
PMID- 9547075
TI - Event-related potentials associated with correct and incorrect responses in a
cued antisaccade task.
AB - In an antisaccade task, subjects are instructed to inhibit a reflexive saccade
towards a peripheral stimulus flash and to generate a saccade in the opposite
direction. It has been shown recently that normal subjects will generate a high
number of incorrect prosaccades in an antisaccade task if the fixation point is
extinguished 200 ms before the stimulus appears and if a valid cue for the
subsequent antisaccade is given during this gap period. In the present study we
recorded cerebral event-related potentials from 19 scalp electrodes from normal
subjects prior to correct and incorrect responses in a cued antisaccade task to
investigate the neural processes associated with correct antisaccades and
incorrect prosaccades in this task. Correct antisaccades and incorrect
prosaccades were associated with a negative potential with a maximal amplitude
around stimulus onset over the dorsomedial frontal cortex. This potential was
higher prior to correct antisaccades than prior to incorrect prosaccades. The
execution of a correct antisaccade was preceded by a shift of a negative
potential from the parietal hemisphere contralateral to the visual stimulus
towards the parietal hemisphere ipsilateral to the stimulus. These results
support the view that the supplementary eye fields participate in the inhibition
of incorrect saccades in a cued antisaccade task and show that the parietal
cortex participates in generating a neural representation of the visual stimulus
in the hemifield ipsilateral to the stimulus before generating a motor response.
PMID- 9547077
TI - Pain and Stroop interference tasks activate separate processing modules in
anterior cingulate cortex.
AB - Investigations of pain using functional imaging techniques have revealed an
extensive central network associated with nociception. This network includes the
thalamus, insula, prefrontal cortex and anterior cingulate cortex (ACC) as well
as the somatosensory cortices. Positron emission tomography (PET) of regional
cerebral blood flow (rCBF) has demonstrated activation of the ACC during
cognitively challenging tasks such as the Stroop interference task and divided
attention. One interpretation of this research is that ACC is involved in the
general features of attention and that it does not play a specific role in pain
processing per se. Three-dimensional PET imaging provides a method for
assessments of rCBF in a single individual during multiple tasks. In addition,
coregistration of PET and magnetic resonance (MR) images allows for better
localisation of the PET signals so that differences in cortical activation sites
can be more accurately determined. This approach was used to assess rCBF during
the experience of pain by subtracting images collected during heat from those
during noxious heat stimulation. Two regions of the ACC had elevated rCBF, one in
the perigenual region and one in the mid-rostrocaudal region (i.e. midcingulate
cortex). During the execution of the Stroop task, the group result showed the
midcingulate region overlapping with the site seen during the experience of pain.
This group result, however, was not confirmed in the individual subject analysis,
which revealed widespread and independent areas of ACC response to pain and
Stroop. It is concluded that the ACC contributes to multiple cognitive
procedures. It is inadequate to describe the primary contribution of ACC to pain
processing as "attention" because it is unlikely that the multiple small and
independent activation sites produced by pain and Stroop subserve attentive
processing throughout the brain.
PMID- 9547076
TI - Common principles underlying the control of rapid, single degree-of-freedom
movements at different joints.
AB - Studies of rapid, single degree-of-freedom movements have shown different changes
in electromyographic patterns for movement tasks that appear very similar (e.g.,
movements over different ranges of distance). However, it is not clear whether
these differences are a result of joint-specific control schemes or whether they
are instead due to the limited range of task parameters studied relative to the
mechanical constraints of each joint (e.g., short compared with long movements
relative to the range of motion of a particular joint). In this study, we
measured and compared the kinematic trajectories and electromyograms recorded
during various movement tasks at the wrist, elbow, and ankle. Subjects performed
movements over a wide range of distances "as fast as possible," "at a comfortable
speed," and against two inertial loads (at the elbow only), and they performed
movements over a fixed distance at three different speeds at the wrist and ankle.
For fast movements we show that, in spite of some joint-specific differences, the
basic pattern of electromyographic (EMG) modulation is similar at all three
joints; for example, the agonist EMG burst transitions from a fixed duration to
an increasing duration with increasing movement distance at all three joints.
Moreover, the distance at which this transition occurs in one joint relative to
the distance at which this transition occurs in the other two joints is
consistent across subjects. The transition occurs at the shortest distance at the
ankle and the longest distance at the wrist. In general we suggest that the data
are consistent with a single set of control rules applied at all three joints,
with the biomechanical constraints at each joint accounting for the differences
in the EMG and kinematic patterns observed across joints.
PMID- 9547078
TI - 5-Hydroxytryptamine modifies neuronal responses to glutamate in the red nucleus
of the rat.
AB - The effects of 5-hydroxytryptamine (5-HT) on the responses of red nucleus (RN)
neurones to glutamate (glu) and its agonists were studied using a
microiontophoretic technique in anaesthetised rats. Extracellular unitary
recordings of RN neuronal activity showed that 5-HT application induced a
significant and reversible depression of glu-evoked excitations in 85% of the RN
units tested. This effect was independent of the action of the amine on
background firing, which appeared enhanced in the majority of cases but was
either depressed or uninfluenced in other cases. Microiontophoretic 5-HT also
depressed the excitatory responses evoked in RN neurones by electrical
stimulation of sensorimotor cortex. Methysergide application, which prevented the
enhancing effects of 5-HT on the background firing, was scarcely effective in
antagonising the depression of glu responses. In contrast, the serotonergic
effects on the glu responses were reduced by the iontophoretically applied
antagonist of 5-HT1A receptors, NAN-190. Microiontophoretic 5-HT was also able to
influence the neuronal responses evoked by glu agonists quisqualate (quis) and N
methyl-D-aspartate (NMDA), acting on non-NMDA and NMDA receptors respectively. In
fact 5-HT depressed quis-evoked excitations and induced mixed effects on NMDA
responses, which were reduced in 45%, enhanced in 34% and unmodified in 21% of
the units tested. These results suggest that 5-HT is able to modulate the motor
glutamatergic input to RN by acting mostly on non-NMDA receptors. The modulation
of non-NMDA and NMDA receptors by 5-HT in the RN appears significant and its
functional meaning is discussed.
PMID- 9547079
TI - On the cutaneous receptors contributing to withdrawal reflex pathways in the
decerebrate spinal rat.
AB - Previous studies indicate that the withdrawal reflex system in the rat has a
"modular" organization, each reflex pathway performing a specific sensorimotor
transformation. Here, we wished to clarify which cutaneous receptors contribute
to this system and to determine whether there are differences in this respect
between reflex pathways of different muscles. Withdrawal reflexes of the peroneus
longus, extensor digitorum longus, and semitendinosus muscles were recorded with
EMG techniques during high reflex excitability in decerebrate spinal rats (n=26).
While maintained innocuous pressure on glabrous skin could elicit a sustained
reflex activity in all muscles studied, vibration of glabrous skin (10-300 Hz)
always failed to evoke a reflex response, suggesting that slowly adapting, but
not rapidly adapting, low-threshold mechanoreceptive fibers from this type of
skin contribute to withdrawal reflex pathways. Thermal stimulation in the
innocuous range, i.e., cooling from 32 to 17 degrees C, or warming the skin from
32 to 41 degrees C, always failed to produce reflex responses, indicating that
neither cold nor warm receptors contribute to withdrawal reflex pathways. When
either cooling or warming the skin to the noxious temperatures of 1 degrees C or
above 45 degrees C, respectively, a reflex discharge was often evoked in the
muscles studied. Intradermal administration of histamine, a potent pruritogenic
substance, produced very weak, or no, reflex response. In contrast, mustard oil
produced vigorous reflex responses in all muscles studied. These findings suggest
that some chemonociceptors contribute only weakly, or not at all, to withdrawal
reflex pathways. The present data suggest that a selective set of cutaneous
receptors contribute to withdrawal reflex pathways and that different withdrawal
reflex pathways receive input from essentially the same cutaneous receptor types.
PMID- 9547080
TI - Distinguishing between the effects of frequency and amplitude on interlimb
coupling in tapping a 2:3 polyrhythm.
AB - Rhythmic interlimb coordination is characterized by attraction to stable phase
and frequency relations. Sudden, unintended transitions between such coordination
patterns have been observed in iso- and multifrequency tasks when movement
frequency was gradually increased. These transitions have been accounted for by
modeling the two limbs as nonlinearly coupled oscillators. The prevailing form of
the coupling function is based on time derivatives, but an alternative
formulation can be derived by incorporating time delays. These time delays may be
related to the neurophysiological delays associated with the use of kinesthetic
afferences. The two ways of deriving coupling functions for interlimb
coordination allow for different predictions with respect to the effects of
movement frequency and amplitude on the strength of interaction between the
limbs. In the current experiment, the effects of amplitude and frequency were
dissociated experimentally, so as to arrive at an empirically motivated choice
between the two ways of formalizing interlimb coupling. Subjects tapped the
polyrhythm 2:3 at five different frequencies under three amplitude conditions.
Whereas no effects of amplitude were observed, the strength of interaction
between the hands decreased with increasing movement frequency. These results
support the time-delay version of the model, in which differential (loss of)
stability of coordination modes results from differential dependence on movement
amplitude, but overall coupling strength is related reciprocally to movement
frequency squared. This version of the model was related tentatively to three
proposed aspects of interlimb coordination: (1) neurophysiological delays
associated with the use of kinesthetic afferences; (2) rate-dependent decrease in
pattern stability; and (3) differential entrainment influences of kinesthetic
signals.
PMID- 9547081
TI - Distribution, size and number of axons in the optic pathway of ground squirrels.
AB - The present study has examined the distribution of axons of differing sizes in
the optic pathway of the ground squirrel. Axon diameters were measured from
electron micrographs at various locations across sections of the optic nerve and
tract, and total distributions and numbers were estimated. In both the nerve and
tract, roughly 1.2 million optic axons were present. The population of optic
axons had a unimodal size distribution, peaking at 0.9 microm in diameter and
having an extended tail toward larger diameters. Local axon diameter
distributions in the optic tract indicated distinct (though partially
overlapping) axon diameter classes, including one of fine sizes peaking at 0.8
0.9 microm, a second of medium sizes peaking around 1.7-1.8 microm, and a third
composed of the larger fibers with diameters up to 4.8 microm. The fine-caliber
axons were found at all locations in the tract, and were the only axons present
immediately adjacent to the pia, while the medium- and coarse-caliber axons were
found at deeper locations. Curiously, the larger axons were found primarily in
the medial parts of the tract, where axons from the dorsal retina normally
course. A similarly restricted distribution of the larger axons was observed in
the dorsotemporal parts of the optic nerve, suggesting that this difference in
the tract may relate to an asymmetric distribution of ganglion cells on the
retina giving rise to these axons. Measurements of axonal size taken within the
optic fiber layer in dorsal and ventral parts of the retina confirmed this
asymmetry, consistent with previous demonstrations of soma size differences in
the dorsal versus ventral retina. The partial segregation of axons by size in the
optic tract of the ground squirrel then reflects both the asymmetric distribution
of retinal ganglion cell classes and the chronotopic reordering of optic axons
that occurs within the chiasmatic region.
PMID- 9547082
TI - The central pattern generator for vomiting may exist in the reticular area
dorsomedial to the retrofacial nucleus in dogs.
AB - There is some controversy over whether or not a discrete site that integrates
vomiting activities in somatic and autonomic nerves is present in the medulla
oblongata. On the basis of our previous studies, we hypothesized that the
temporal patterns of muscle contractions in vomiting are generated by a central
pattern generator in the retrofacial area of the rostral medulla. To investigate
this hypothesis further, the effects of electrical and chemical lesions of the
medullary area were observed in decerebrate paralyzed dogs. Efferent activities
of the phrenic and abdominal muscle nerves were recorded to recognize fictive
vomiting. The right half of the medulla oblongata was transversely severed about
3 mm rostral to the obex. Fictive vomiting responses to vagal stimulation still
appeared after hemisection in all 11 dogs. In addition, stimulation of the
contralateral reticular area dorsomedial to the retrofacial nucleus produced
fictive vomiting even after hemisection. An electrical lesion or injection of
kainic acid (0.5-1.0 microl) was applied at the point where reticular stimulation
induced fictive vomiting. After this destruction, no activities that corresponded
to fictive vomiting could be induced by stimulation of vagal afferents or the
reticular site. Salivation was decreased by hemisection, and decreased further,
but was not completely abolished, with destruction of the reticular area. Kainic
acid is known to selectively destroy neural cell bodies. Therefore, we concluded
that neuronal somata in the reticular formation dorsomedial to the retrofacial
nucleus play an essential role in the central patterning of vomiting activities
in peripheral motor nerves.
PMID- 9547083
TI - Development of action potentials and apamin-sensitive after-potentials in mouse
vestibular nucleus neurones.
AB - The postnatal maturation of medial vestibular nucleus (MVN) neurones was examined
in slices of the dorsal brainstem prepared from balb/c mice at specific stages
during the first postnatal month. Using spike-shape averaging to analyse the
intracellularly recorded action potentials and after-hyperpolarizations (AHPs) in
each cell, all the MVN neurones recorded in the young adult (postnatal day 30;
P30) mouse were shown to have either a single deep AHP (type A cells), or an
early fast and a delayed slow AHP (type B cells). The relative proportions of the
two subtypes were similar to those in the young adult rat. At P5, all the MVN
cells recorded showed immature forms of either the type A or the type B action
potential shape. Immature type A cells had broad spontaneous spikes, and the
characteristic single AHP was small in amplitude. Immature type B cells had
somewhat narrower spontaneous spikes that were followed by a delayed, apamin
sensitive AHP. The delayed AHP was separated from the repolarisation phase of the
spike by a period of isopotentiality. Over the period P10-P15, the mean resting
potentials of the MVN cells became more negative, their action potential fall
times became shorter, the single AHP in type A cells became deeper, and the early
fast AHP appeared in type B cells. Until P15 cells of varying degrees of
electrophysiological maturity were found in the MVN but by P30 all MVN cells
recorded were typical adult type A or type B cells. Exposure to the selective
blocker of SK-type Ca-activated K channels, apamin (0.3 microM), induced
depolarising plateaux and burst firing in immature type B cells at rest. The
duration of the apamin-induced bursts and the spike frequency during the bursts
were reduced but not abolished after blockade of Ca channels in Ca-free
artificial cerebrospinal fluid containing Cd2+. By contrast, in mature type B
cells at rest apamin selectively abolished the delayed slow AHP but did not
induce bursting activity. Apamin had no effect on the action potential shape of
immature type A cells. These data show that the apamin-sensitive I(AHP) is one of
the first ionic conductances to appear in type B cells, and that it plays an
important role in regulating the intrinsic rhythmicity and excitability of these
cells.
PMID- 9547084
TI - Time-course expression of vascular endothelial growth factor as related to the
development of the retinochoroidal vasculature in rats.
AB - Growth factors involved in angiogenesis are critical to both the normal and
pathological vascular development in the retina and choroid. In the present
experiment, the relationship between the vascular endothelial growth factor
(VEGF) expression and the retinochoroidal vasculogenesis in Sprague-Dawley rats
was investigated using in situ hybridization and immunohistochemistry. It was
found that VEGF was produced mainly by astrocytes and Muller cells in the neural
retina, and this was correlated temporally and spatially with the retinal
vasculogenesis. In addition, it was observed that, although the VEGF expression
in the retinal pigment epithelium (RPE) decreased with increasing age, it
persisted from the embryonic stage to adulthood. These findings indicate that the
VEGF expression in RPE may play a role in the development of the choroidal
vessels as well as in the maintenance of the normal structure and permeability of
the choriocapillaris in adults.
PMID- 9547085
TI - Sinusoidal forearm tracking with delayed visual feedback. I. Dependence of the
tracking error on the relative delay.
AB - During forearm tracking of a sinusoidally moving target matching of
proprioceptive and visual feedback was altered by introducing different visual
delays. In five normal subjects seven target frequencies were tested ranging from
0.3 to 1.5 Hz. For each target frequency nine different delays were used ranging
from 0 to 120% of the cycle duration with target frequency and delay being varied
randomly. Tracking error revealed a cyclic behaviour with an increase up to
delays of about 50% of the target cycle duration and an improvement for delays
larger than 50%. Modulation of response frequency was less pronounced compared
with tracking error variation but also was dependent on relative phase. The
response frequency matched the target frequency at delays of 0 and 100% of cycle
duration and was slightly lower than the target frequency with relative delays of
about 50%. The introduction of a visual delay during sinusoidal forearm tracking
leads to a spatial in addition to the temporal mismatch between proprioception
and vision. The temporal and the spatial incompatibility influence the tracking
performance differentially.
PMID- 9547086
TI - Sinusoidal forearm tracking with delayed visual feedback. II. Dependence of the
relative phase on the relative delay.
AB - The influence of delayed visual feedback on the phase relationships between
target and response signal during a sinusoidal tracking task was analysed in five
normal subjects. Target frequency was varied systematically between 0.3 and 1.5
Hz, and the delay between 0 and 120% of the target cycle duration. For each
subject, 63 trials were recorded. Phase parameters (relative phase, absolute
relative phase and percentage of positive relative phases) revealed a clear
dependence on relative delay but not on target frequency. With relative delays
close to 0 and 100% of the target cycle duration, subjects successfully tracked
the target signal with a small phase lag. With delays in the 30-90% range, larger
phase differences were observed. Furthermore, the (delayed) response signal
usually preceded the target signal in this delay range. These findings provide
further evidence for a dependence of tracking error on external delays in the
visual feedback loop, and indicate that delays of about 50% of the movement cycle
are more difficult to handle than are smaller or larger delays. The results are
discussed with regard to the influence of different control strategies (feedback,
feedforward) and different types of feedback (such as vision and proprioception)
on motor control.
PMID- 9547087
TI - Somatotopic consolidation: a third phase of reorganization after peripheral nerve
injury in adult squirrel monkeys.
AB - It has previously been demonstrated that the central somatosensory topographic
reorganization within deprived cortex that follows peripheral nerve injury in
adult monkeys occurs in at least two stages: an immediate unmasking period; and a
more prolonged period where deprived areas of cortex come to express new
receptive fields in a topographically arranged manner. In the present
experiments, we have compared cortical topography many months after combined
median and ulnar nerve transection with "complete" reorganization evident at
relatively short (i.e., 2-5 months) survival times. We find further
reorganizational changes in cortical topography with longer survival times. That
is, the roughly somatotopic, generally multiple-digit receptive fields frequently
observed at the shorter survival times are generally sharpened to more distinct,
single-digit receptive fields at longer survival times. We hypothesize that the
early crudely topographic maps reflect all available inputs while the refined map
is the outcome of an extraction process where only the most useful subset of
available inputs is expressed. It is further suggested that this distillation
process is a use-dependent phenomenon.
PMID- 9547088
TI - Effects of repetitive transcranial magnetic stimulation over dorsolateral
prefrontal and posterior parietal cortex on memory-guided saccades.
AB - We investigated the role of the dorsolateral prefrontal cortex (DLPFC) and the
posterior parietal cortex (PPC) in a visuospatial delayed-response task in
humans. Repetitive transcranial magnetic stimulation (20 Hz, 0.5 s) was used to
interfere temporarily with cortical activity in the DLPFC and PPC during the
delay period. Omnidirectional memory-guided saccades with a 3-s delay were used
as a quantifiable motor response to a visuospatial cue. The question addressed
was whether repetitive transcranial magnetic stimulation (rTMS) over the DLPFC or
PPC during the sensory of memory phase affects accuracy of memory-guided
saccades. Stimulation over the primary motor cortex served as control.
Stimulation over the DLPFC significantly impaired accuracy of memory-guided
saccades in amplitude and direction. Stimulation over the PPC impaired accuracy
of memory-guided saccades only when applied within the sensory phase (50 ms after
cue offset), but not during the memory phase (500 ms after cue offset). These
results provide further evidence for a parieto-frontal network controlling
performance of visuospatial delayed-response tasks in humans. It can be concluded
that within this network the DLPFC is mainly concerned with the mnemonic
representation and the PPC with the sensory representation of spatially defined
perceptual information.
PMID- 9547089
TI - The NMDA receptor participates in respiration-related mitral cell synchrony.
AB - The N-methyl-D-aspartate (NMDA)-type glutamate receptor participates in the
excitation of olfactory bulb mitral cells and is important in granule-cell
mediated feedback-inhibition. In the present study, extracellular unit recordings
were made in vivo to demonstrate that the firing rates of mitral cells are not
affected by peripheral administration of the non-competitive NMDA receptor
antagonist MK-801. However, while over 50% of odor-driven mitral cell activity is
normally correlated with the respiratory cycle, only about 10% of mitral cell
activity is correlated with the respiratory cycle 30 min after MK-801
administration. Thus, the NMDA receptor is a participant in normal respiration
related mitral cell activity and may have an important role in the formation of
bulb oscillations that encode olfactory information. Furthermore, the NMDA
receptor is in a position to mediate activity-dependent changes in the bulb that
rely on synchronous activity.
PMID- 9547090
TI - Axial synergies during human upper trunk bending.
AB - Upper trunk bending movements were accompanied by opposite movements of the lower
body segments. These axial kinematic synergies maintained equilibrium during the
movement performance by stabilizing the center of gravity (CG), which shifted on
average across all the subjects by 1 +/- 4 cm in the anteroposterior direction
and thus always remained within the support area. The aim of the present
investigation was to provide an insight into the central control responsible for
the performance of these synergies. The kinematic analysis was performed by the
method of principal components (PC) analysis applied to the covariation between
ankle, knee and hip joint angles and compared with CG shifts during upper trunk
bending. Subjects were asked to perform backward or forward upper trunk bending
in response to a tone. They were instructed to move as fast as possible or slowly
(2 s), with high or low movement amplitudes. PC analysis showed a strong
correlation between hip, knee and ankle joint changes. The first principal
component (PC1) representing a multijoint movement with fixed ratios between
joint angular changes, accounted, on average, for 99.7% +/- 0.2% of the total
angular variance in the forward trunk movements and for 98.4% +/- 1.4% in the
backward movements. The instructed voluntary regulation of the amplitude and
velocity of the movement was achieved by adapting the bell-shaped profile of the
velocity time course without changes in interjoint angular relations. Fixed
ratios between changes in joint angles, represented by PC1, ensured localization
of the CG within the support area during trunk bending. The ratios given by PC1
showed highly significant dependence on subjects, suggesting the adaptability of
the central control to each subject's biomechanical peculiarities. Subject's
intertrial variability of PC1 ratios was small, suggesting a stereotyped
automatic interjoint coordination. When changing velocity and amplitude of the
movement, the ratios remained the same in about half the subjects while in others
slight variations were observed. A weak second principal component (PC2) was
shown only for fast movements. In forward movements PC2 reflected the early knee
flexion that seems related to the disturbances caused by the passive interaction
between body segments, rather than to the effect of a central command. In fast
backward movements, PC2 reflected the delay in hip extension relative to the
movement onset in the ankle and knee that mirrors intersubject differences in the
initiation process of the axial synergy. The results suggest that PC1 reflects
the centrally controlled multijoint movement, defining the time course and
amplitude of the movement and fixing the ratios between changes in joint angles.
They support the hypothesis that the axial kinematic synergies result from a
central automatic control that stabilizes the CG shift in the anteroposterior
direction while performing the upper trunk bending.
PMID- 9547092
TI - Functional evidence for the differential control of superficial and deep blood
vessels by sympathetic vasoconstrictor and primary afferent vasodilator fibres in
rat hairless skin.
AB - We quantitatively investigated sympathetic vasoconstriction and antidromic
vasodilation mediated by small-diameter primary afferents on the plantar hairless
skin of the hindpaws in Wistar rats using laser Doppler (LD) flowmetry and an
infrared thermometer. Sympathetic vasoconstriction was elicited by electrical
stimulation of the centrally cut ipsilateral lumbar sympathetic trunk (LST) with
50-s trains at 0.1-20 Hz. Antidromic vasodilation was evoked by electrical
stimulation of the dorsal root (DR) L5 with 20-s or 50-s trains at 1-4 Hz.
Cutting the LST resulted in increases in skin temperature (SKT) by 6.1 +/- 1.0
degrees C (mean +/- SEM) and in LD flow by 128 +/- 20%. Stimulation of the LST
resulted in a graded decrease in LD flow and SKT that was most pronounced between
0 and 0.1 Hz. However, DR stimulation evoked a large increase in LD flow but only
little change in SKT in rats with sectioned LST. When the DR was stimulated
either in animals with intact LST or during continuous stimulation of
vasoconstrictor fibres in the sectioned LST, i.e. while baseline temperature was
relatively low (26.3 +/- 1.1 degrees C), DR stimulation still resulted in large
increases in LD flow, but only minor changes in SKT. These results suggest that
blood flow through both deep and superficial layers of rat hairless skin is
regulated by activity in sympathetic postganglionic vasoconstrictor fibres,
whereas small-diameter primary afferent fibres appear to influence predominantly
the blood flow through superficial layers of rat plantar skin.
PMID- 9547091
TI - The gap effect and express saccades in the auditory modality.
AB - Latencies of eye movements to peripheral targets are reduced when there is a
short delay (typically 200 ms) between the offset of a central visual fixation
point and the target onset. This has been termed the gap effect. In addition,
some subjects, usually with practice, exhibit a separate population of very short
latency saccades, called express saccades. Both these phenomena have been
attributed to disengagement of visual attention when the fixation point is
extinguished. A competing theory of the gap effect attributes it to disengagement
of oculomotor fixation during the temporal gap. It is known that auditory targets
are effective in eliciting saccadic eye movements, and also that covert attention
operates in the auditory modality. If the gap effect and express saccades are due
to disengagement of spatial attention, both should persist in the auditory
modality. However, fixation of gaze is largely under visual control. If the gap
effect results from disengagement of fixation, then at least a reduced effect
should be seen in the auditory modality. Human subjects performed the gap task
and a control task in the dark, using auditory fixation points and saccadic
targets, on five successive days. Despite this practice, express saccades were
not observed. There was a reliable gap effect, but the reduction in saccadic
latency was only 17 ms, compared with 32 ms for the same subjects in the visual
modality. This suggests that about half the gap effect is due to disengagement of
visual fixation. The remainder was not due to non-specific warning effects and
could be attributed to offset of the auditory fixation stimulus.
PMID- 9547093
TI - Induction of microglial and astrocytic response in the adult rat lumbar spinal
cord following middle cerebral artery occlusion.
AB - The response of microglia and astrocytes, as detected immunohistochemically by
the monoclonal antibody OX-42 and anti-glial fibrillary acidic protein (GFAP)
respectively, was studied in the rat lumbar spinal cord following focal cerebral
ischaemia produced by permanent occlusion of the middle cerebral artery (MCA)
above the rhinal fissure. At 1 and 2 days after right-sided MCA occlusion, OX-42
immunoreactivity of microglia in both the contralateral dorsal and ventral horns
of the lumbar spinal cord was moderately increased compared with cells of the
ipsilateral side. The microglial reaction was progressive, with some cells
transformed into amoeboid form considered to be macrophages at day 3. By 5 days,
many of the reactive microglia, notably in the ventral horn, appeared to encircle
the soma of motoneurons. At 7 days, the microglial reaction had subsided while
astrocytes in the same area were hypertrophied to replace the perineuronal
microglia. The microglial response in both the cerebral cortex and lumbar spinal
cord was effectively reduced by the N-methyl-D-aspartate (NMDA) receptor
antagonist, MK-801. Present results suggest that following MCA occlusion, the
vigorous response of microglia, and subsequently astrocytes, in the spinal cord
in extra-focal areas far removed from the primary site of ischaemia may be
mediated by glutamate released from the ischaemic corticospinal neurons through
NMDA receptors on the postsynaptic spinal cord neurons.
PMID- 9547094
TI - Analysis of double-joint movements in controls and in parkinsonian patients.
AB - The motor performance of seven patients with Parkinson's disease and seven
control subjects was tested in a choice reaction aiming task. The subjects were
instructed to aim as fast and as accurately as possible to a light stimulus,
which defined one of eight possible target positions. In order to reach the
targets, elbow flexions had to be combined with forearm supinations or with
forearm pronations. For single-joint movements, forearm supinations or pronations
were executed faster than the long elbow flexions in both groups. In the double
joint movements of the control group, the flexion movement times (flex.MTs) and
the supination movement times (sup.MTs) or pronation movement times (pron.MTs)
were similar to the MTs of the corresponding single-joint movements. MTs of
parkinsonian patients were significantly longer than those of control subjects.
MTs were most increased in the forearm supination and forearm pronation of double
joint movements. In contrast to the controls, sup.MT and pron.MT were
significantly increased in double-joint movements as compared to single-joint
movements. The variations in the flex.MT and sup.MT of the double-joint movements
neither correlated for a control subject nor for a parkinsonian patient. For
controls, the independent MTs in double-joint movements cannot be explained by
minimal principles (minimum energy, minimal torque change), but suggest that two
separate motor programs are superimposed. In Parkinson's disease, there seems to
be a deficit in superimposing two separate motor programs.
PMID- 9547095
TI - Reach-to-grasp movements during obstacle avoidance.
AB - The transport and grip components are two controlled components of a prehensile
movement. These components are coordinated so that objects of varying size and
shape resting in diverse locations can be grasped easily. It has been suggested
that the timing between these two components is a specified parameter, although
the origin of such timing is unknown. The present study examines the
interdependency of the reach and grasp components when the transport component is
modified by placing an obstacle of varying height (9 cm and 11 cm) in the hand
path between the starting position and the target object location. Subjects were
asked to reach over a Plexiglas barrier and grasp a 2-cm dowel. To reach the
object, the subject had to elevate the hand. At issue in this experiment is
whether changes in hand path trajectory caused by obstacle avoidance produce
corresponding changes in the kinematics of grip aperture. The findings showed
that reaching in the presence of an obstacle resulted in the prolongation of most
transport component time parameters except peak acceleration and a few amplitude
parameters. Changes in the transport component also produced systematic
prolongation in all time parameters of grip kinematics, including grip closure
time. Temporal prolongation was also reflected in a significant decrease in grip
opening and closing velocity; only relative time-to-peak closing velocity was
maintained. Closure distance and maximum grip aperture were smaller for the
obstacle conditions. Together with the observed smaller variability for the
distance to peak aperture, these findings suggest that spatial localization of
the hand aperture is an important prehensile movement control feature.
Parameterization processes for the grip component are closely linked to those of
the transport component, and their organization appears to be interdependent.
PMID- 9547096
TI - Evidence that spinal endogenous opioidergic systems control the expression of
chronic pain-related behaviors in spinally injured rats.
AB - We have previously reported that ischemic spinal cord injury in rats leads to
chronic pain-related behaviors. Thus, rats exhibited aversive reactions to
innocuous mechanical stimuli (mechanical allodynia) applied to a body area at or
rostral to the dermatomes innervated by the injured spinal segments. The
responses of the rats to cold are also markedly enhanced (cold allodynia).
Interestingly, more than 50% of spinally injured rats did not develop these
abnormal pain-related behaviors after spinal cord injury. In the present study,
we showed that the extent of injury is similar between allodynic and non
allodynic rats. Furthermore, intrathecal (i.t.) naloxone, a broad-spectrum opioid
receptor antagonist, reversibly provoked mechanical and cold allodynia-like
responses in spinally injured rats that did not develop such behaviors
spontaneously. However, naloxone did not elicit such reactions in normal rats and
did not alter the tail-flick latency in normal or spinally injured rats.
Furthermore, i.t. D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) or naltridole,
selective antagonists of mu and delta opioid receptors, respectively, also
triggered pain-related behaviors similarly to naloxone. Although
norbinaltorphimine (nor-BIN), a selective kappa-receptor antagonist, also
elicited such responses, the time course of the effect makes it unlikely that
spinal kappa-receptors were involved. These results suggested that the expression
of abnormal pain-related behaviors in some spinally injured rats is tonically
suppressed by the spinal opioidergic system. Interindividual differences that
lead to lack or dysfunction of such inhibition may underly the appearence of pain
related behavior in some, but not all, spinally injured rats. It is suggested
that such inhibition is exerted through spinal mu and delta, but not kappa,
opioid receptors. The endogenous opioidergic control appears to be only active
against abnormal painrelated behaviors in spinally injured rats. Our results are
relevant for the clinical observation that only a subgroup of patients with nerve
injury suffers from neuropathic pain.
PMID- 9547097
TI - A comparison of jaw-opener and jaw-closer muscle activity in humans to overcome
an external force counteracting jaw movement.
AB - In contrast to the jaw-closer muscles, no or very few spindles are present in the
jaw-opening digastric muscle. Therefore sensory feedback to the digastric muscle
may be different from feedback to the jaw-closer muscles, resulting in a
different reaction when jaw movement is perturbed. This possible difference was
investigated by comparing the reaction of the digastric muscle when jaw opening
is perturbed, with the reaction of the masseter muscle when jaw closing is
perturbed. Subjects made rhythmic, 1-Hz open-close movements of the jaw under
control of a metronome. During jaw opening (digastric muscle) or, in the other
experiments, during jaw closing (masseter muscle), an external force
counteracting jaw movement could appear. Series of movements without the force
were unexpectedly alternated by series with the force. In both muscles sensory
induced activity started approximately 25 ms after the onset of the force and
consisted of two phases. In the masseter muscle the maximum of the first increase
was reached significantly sooner (37 +/- 2 ms SEM) than in the digastric muscle
(54 +/- 3 ms). The second increase appeared much sooner in the masseter muscle
(73 +/- 4 ms) than in the digastric muscle (159 +/- 10 ms). When the force was
expected, in both muscles an increase in preprogrammed muscle activity was
observed. Also an increase in reflex activity, generated before 120 ms after the
onset of the force, was observed, compared with when the force appeared
unexpectedly. The relative increase in reflex activity was approximately 2 times
larger than the relative increase in preprogrammed activity. Therefore, the
increase in reflex activity when the force was expected may have been caused not
only by an increase in recruitment, but also by an increase in the gain of the
reflex loops. Reflex activity relative to preprogrammed activity was on average 4
times larger in the masseter muscle than in the digastric muscle. This indicates
that the masseter muscle can react more adequately to disturbances of jaw
movement than the digastric muscle.
PMID- 9547098
TI - Receptive field properties of visual neurons in the avian nucleus lentiformis
mesencephali.
AB - The receptive field (RF) properties of visual neurons extracellularly recorded
from the nucleus lentiformis mesencephali (nLM) in pigeons (Columba livia) were
quantitatively analyzed using a workstation computer. These cells were actively
spontaneous, and direction-and velocity-selective. Using spatial gratings as
visual stimuli, these cells could be divided into three groups: uni- (74%), bi-
(17%), and omnidirectional (9%) cells in terms of their directionality. On the
basis of their velocity selectivity, they could be named slow cells (84%),
preferring low velocity (0.1-11 degrees/s), and fast cells (14%), preferring
rapid motion (34-67 degrees/s), with one cell (2%) responding maximally to an
intermediate velocity of 18 degrees/ s. These two properties were correlated in
the way that all unidirectionals were slow cells, omnidirectionals were fast
cells, and bidirectionals were either slow or fast cells including the
intermediate cell. Using small targets as visual stimuli, it was found that the
majority of cells examined had RFs that each consisted of an excitatory RF (ERF)
and an inhibitory RF (IRF) that overlapped. The unidirectionals were mainly of
this type of RF structure, whereas the omnidirectionals apparently had ERFs
alone. The direction preference of ERF was opposite to that of IRF for
unidirectional cells tested, whereas they were perpendicular to each other for
one bidirectional cell. The overall responses of these cells resulted from
interaction between excitation and inhibition induced by directionally different
motion. Under certain conditions, visual responses of a particular cells to a
small target moving through its ERF were equal in responsive strength to those to
whole-field gratings swept over the screen. It was suggested that optokinetic
nystagmus produced by wholefield gratings results from population activity of
large group(s) of neurons in some optokinetic nuclei, at least one of which is
nLM.
PMID- 9547099
TI - Coordination of hand aperture with the spatial path of hand transport.
AB - We have investigated the coordination of hand aperture with the spatial path of
hand transport in prehensile movement by comparing straight prehensile movements
with curved movements, in which subjects had to pass over a "via point" marked on
the work surface before picking up an object in the target location. Spatial
plots of hand aperture against hand transport showed that the preshaping of the
hand to prepare an appropriate grasp was delayed in the curved movements relative
to the straight movements, with most of the preshaping of the hand occurring
after passing the via point, even when the via point occurred late in the course
of the movement. The postponement of hand preshaping was apparently not due to
subjects' segmenting the movement into two completely separate portions preceding
and following the via point, since some degree of hand opening often occurred
before the via point. We suggest that the delay in hand opening in curved
movements involves a scheduling process, which uses information about hand
transport to set an appropriate hand aperture.
PMID- 9547101
TI - Helicobacters and biliary tract disease.
PMID- 9547100
TI - Regulation of hepatic chylomicron remnant uptake: effects of obesity and insulin
resistance.
PMID- 9547102
TI - Steatohepatitis: a tale of two "hits"?
PMID- 9547103
TI - Recurrent bleeding from peptic ulcers: sticky problem, sticky solution?
PMID- 9547104
TI - Evaluating TIPS trials: the devil is in the details?
PMID- 9547105
TI - Gastroesophageal reflux-induced asthma: new insights.
PMID- 9547106
TI - One if by mouth and two if IV.
PMID- 9547107
TI - 13C-Octanoic acid breath test for gastric emptying rate of solids.
PMID- 9547108
TI - 13C-Octanoic acid breath test: valueless test for gastric emptying?
PMID- 9547109
TI - Pancreatic disease: does "itis" lead to "oma"?
PMID- 9547110
TI - Unreliable pancreatitis epidemiology captures the wrong population.
PMID- 9547111
TI - Treatment of short-bowel syndrome.
PMID- 9547112
TI - Arterioportal fistula in a child with biliary atresia.
PMID- 9547113
TI - Are normal hearing thresholds a sufficient condition for click-evoked otoacoustic
emissions?
AB - Transiently evolked otoacoustic emissions (TEOAE) have been reported in several
studies as absent in a small minority of normal ears. Other studies have reported
TEOAEs in all normal ears. Differences between studies may arise directly from
criteria for TEOAE identification, criteria for selection of normals, or
statistically due to limited sample sizes. In order to understand and model
cochlear processes involved in TEOAE generation, it needs to be known whether the
presence of normal hearing leads automatically to generation of TEOAEs. The
present study set out to establish in a large sample if any ears could be found
that lacked TEOAEs despite normal hearing threshold levels (HTL). A total of 397
ears from highly cooperative adult subjects were examined under laboratory
conditions. Using cross correlation between replicate nonlinear waveforms as the
criterion, TEOAEs were present in 99.2% of the sample (lower CI 98.1%). However,
careful visual assessment of the recorded waveforms for the remaining ears did
not unequivocally show absence of TEOAE characteristics in any ear with normal
HTLs. While TEOAE strength varies widely among ears, no clear evidence was found
to show that TEOAEs can be absent when HTLs are normal.
PMID- 9547114
TI - Treatment resistant depression in the elderly: a review of its conceptualisation,
management and relationship to organic brain disease.
PMID- 9547115
TI - Disinhibition syndromes, secondary mania and bipolar disorder in old age.
AB - BACKGROUND: The neurological literature concerning disinhibition syndromes and
secondary mania has run in parallel to clinical reports of bipolar disorder in
old age. METHODS: A critical review was conducted of both the neurological and
geriatric psychiatry literature in an attempt to integrate the two streams.
RESULTS: Disinhibition syndromes include lateralization to the right hemisphere
and localization of lesions to the orbito-frontal and basotemporal cortex
involving limbic and frontal connections (orbito-frontal circuit). Mania in old
age is associated with late onset, heterogeneous neurological disorders and poor
outcome. CONCLUSION: Bipolar disorders in old age may be understood in the
context of affective vulnerability influenced by a specific neurobiologic
substrate. LIMITATIONS: The clinical literature consists predominantly of small
case series and anecdotal reports. CLINICAL RELEVANCE: Improved understanding of
these syndromes may elucidate the pathogenesis and etiology of bipolar disorders
and the neuropsychiatric syndromes affecting mood, motivation and behavioural
disinhibition.
PMID- 9547116
TI - Anxiety disorders in the elderly: DSM-IV and other barriers to diagnosis and
treatment.
AB - Traditional lore suggests that anxiety disorders are less prevalent in elderly
than in younger adults, and late-onset anxiety disorders are especially rare. We
question these assumptions, and suggest that these conditions are underdiagnosed
in late life. A common problem in the literature is the application of DSM-IV
like criteria developed from studies of younger adults to geriatric samples
without regard for atypical symptom presentations, high occurrence of depressive
and medical co-morbidity, and influence of aging-related psychosocial changes on
the clinical picture. Diagnostic problems are further compounded by therapeutic
ones. Clinicians are often forced to make treatment decisions for their elderly
patients based on uncontrolled clinical observations or questionable
extrapolation of treatment data in younger adults. An open-minded approach
unhinged by 'conventional wisdom' is warranted.
PMID- 9547117
TI - The efficacy, safety and tolerability of antidepressants in late life depression:
a meta-analysis.
AB - BACKGROUND: To determine the efficacy, safety and tolerability of antidepressants
in depressed elderly patients. METHODS: Search for randomized controlled double
blind studies evaluating atypical antidepressants (ATYPs), reversible inhibitors
of monoamine oxidase-A, selective serotonin reuptake inhibitors (SSRIs) and
tricyclic antidepressants in moderate/severe depressed patients > or = 60 years
for > or = four weeks. The random effects model (single-arm; comparative) was
used to aggregate efficacy, safety and dropout. RESULTS: No difference in single
arm aggregation of outcomes for four antidepressant classes. Comparative analyses
showed no statistical difference between outcomes, except SSRIs had a higher
response rate than ATYPs. CONCLUSION: Elderly show no differences in
antidepressant class outcomes. LIMITATIONS: Heterogeneity and lack of power.
CLINICAL RELEVANCE: There is little advantage for antidepressant classes over
another in the aged.
PMID- 9547119
TI - Depression, diagnostic sub-type and death: a 25 year follow-up study.
AB - We assessed mortality rates over 25 years in 212 patients admitted for depression
or depressive symptoms. More patients had died than expected (80 including 13
suicides; SMR = 1.40, P < 0.01). Females, but not males, experienced
significantly higher mortality than the general population. When suicides were
excluded, neither the group as a whole, nor females solely, demonstrated excess
mortality. Rigorously diagnosed depressive sub-type did not predict mortality.
Mortality, particularly from suicide, was disproportionately greater in the first
2 years after index admission, suggesting that the follow-up of patients
hospitalised with depression must be especially assiduous during the years
immediately after admission.
PMID- 9547118
TI - Depression and physical health in later life: results from the Longitudinal Aging
Study Amsterdam (LASA).
AB - BACKGROUND: In later life, declining physical health is often thought to be one
of the most important risk factors for depression. Major depressive disorders are
relatively rare, while depressive syndromes which do not fulfill diagnostic
criteria (minor depression) are common. METHODS: Community-based sample of older
adults (55-85) in the Netherlands: baseline sample n = 3056; study sample in two
stage screening procedure n = 646. Both relative (odds ratios) and absolute
(population attributable risks) measures of associations reported. RESULTS: In
multivariate analyses minor depression was related to physical health, while
major depression was not. General aspects of physical health had stronger
associations with depression than specific disease categories. Significant
interactions between ill health and social support were found only for minor
depression. Major depression was associated with variables reflecting long
standing vulnerability. CONCLUSION: Major and minor depression differ in their
association with physical health. LIMITATION: Cross-sectional study relying
largely on self-reported data. CLINICAL RELEVANCE: In major depression, with or
without somatic co-morbidity, primary treatment of the affective disorder should
not be delayed. In minor depression associated with declining physical health,
intervention may be aimed at either or both conditions.
PMID- 9547120
TI - Depression in male geropsychiatric inpatients with and without dementia: a
naturalistic study.
AB - The authors compared the presentation and course of major depression in male
geriatric inpatients with and without a diagnosis of dementia. Of 326 consecutive
admissions to an inpatient geropsychiatry unit, 22 (7%) had a diagnosis of major
depression without dementia, 35 (11%) had major depression with dementia. Both
groups presented with similar types and severity of depressive symptoms, which
improved substantially with treatment in both groups, as measured by Hamilton
Depression Rating Scale scores. In addition, agitation, psychiatric, and side
effects symptoms decreased significantly in both groups. Our naturalistic results
suggest the clinical value of intensive treatment of depressive symptoms in
elderly demented patients, whether or not they meet the criteria for major
depressive episode.
PMID- 9547121
TI - Co-occurrence of disadvantage conditions in elderly subjects with depressive
symptoms.
AB - The aim of this survey study is to describe the association of symptomatic
depression with the co-occurrence of psycho-social, functional, and somatic
disadvantage conditions in 390 over 70 subjects living at home. The most
disadvantaged tertile of various conditions (age, social support, cognition,
social interactions, self evaluation of health, disability, number of diseases,
and somatic symptoms) was associated with greater risk of symptomatic depression.
A subset of conditions that might be causally related to depression (age, social
support, financial welfare, diseases, and disability) was used to divide subjects
into five levels of increasing multiple disadvantage conditions (MDC). Increasing
severity of MDC level was associated with greater risk of symptomatic depression
even after adjustment for gender and all five conditions used to define MDC
levels (odds ratios ranging from 2.7 to 11.3).
PMID- 9547123
TI - Changes in auditory P300 in patients with major depression and silent cerebral
infarction.
AB - We examined event-related potentials in patients with senile depression and
silent cerebral infarction (SCI) to clarify the features of the P300 component.
P300 event-related potentials were recorded in drug-free depressed patients (N =
16) and normal controls (N = 17). All patients underwent magnetic resonance
imaging and were classified as SCI-positive (N = 7) or SCI-negative (N = 9). In
depressed patients, the P300 was reexamined after antidepressant treatment. Prior
to treatment, P300 amplitudes in depressed patients were significantly smaller
than those in normal controls (P < 0.01). P300 amplitudes increased significantly
in SCI-negative patients following recovery (P < 0.05), but did not change in SCI
positive patients. SCI may interrupt the treatment-related P300 amplitude
increase in depressed patients.
PMID- 9547122
TI - The natural history of depression and the anxiety disorders in older people: the
Islington community study.
AB - BACKGROUND: This study reports the outcome of depression and anxiety disorders in
older people. METHODS: Follow-up of 165 subjects age 65 or over, initially
identified in a community study in inner London as depressed or having an anxiety
disorder. RESULTS: 117 subjects still living in the area; 25 had died. Death was
predicted only by activity limitation at first interview and not by other
demographic or morbidity variables. Eighty-six subjects reinterviewed; 21 males,
65 females. Of the depressed, 34% had recovered, 39% were depressed and 27% were
dead. Predictors from initial interview of continuing depression were female
gender and more severe depression. Of those with phobic anxiety, 16% had
recovered, 18% died and 66% were still phobic. Predictors of continuing phobic
anxiety from initial interview were female gender and "stand-alone" phobic
anxiety, i.e., not being depressed at initial interview. Sixty percent of those
with early onset phobias had specific phobias; 82% of those with late-onset
phobias had agoraphobia. Twenty-two subjects were prescribed psychotropics. The
only significant predictor of psychotropic prescription was having sleep
disturbance at initial interview. A low score on life satisfaction was
significantly correlated with depression but not with phobic disorder. A high
score was correlated with not having a current psychiatric disorder. LIMITATIONS:
Some subjects were lost to follow-up. Those on psychotropics were particularly
likely to refuse an interview. CONCLUSION AND CLINICAL RELEVANCE: In older
people, neither depression nor the anxiety disorders generally remit
spontaneously. Those with a particularly poor prognosis are women and those with
a more severe depression. Agoraphobia may be precipitated in older people by
stressful events and interferes with life satisfaction. There is potential for
increased pharmacological treatment of older people with affective disorders.
PMID- 9547124
TI - Ruminative thinking in older inpatients with major depression.
AB - Ruminative thinking, the tendency to dwell on particular ideas or themes, can be
a prominent part of the phenomenology of major depression, but it rarely has been
the focus of empirical research. We attempted to replicate (in adult psychiatric
inpatients age > or = 50 years with DSM-III-R major depression) the previously
published finding that ruminative thinking was associated with melancholia and
with psychosis. In our sample, these associations were not present. In addition,
we explored the relationships of ruminative thinking to specific areas of thought
content (e.g., suicidal ideation, somatic worry), cognitive function and overall
functional status; ruminative thinking was not associated with suicidal ideation,
but was associated with greater somatic worry and with poorer functional status,
although these associations were not independent of overall depressive severity.
A substantial proportion of subjects were unable to complete the cognitive
measures; ruminative thinking was independently associated with inability to
complete these tasks. We conclude that ruminative thinking is a meaningful and
common clinical phenomenon among severely depressed older inpatients. Further
investigations in inpatients and other populations examining its relationships to
other phenomenology, to course and outcome, and to putative underlying mechanisms
of depression are warranted.
PMID- 9547125
TI - An intervention study with husband and wife carers of older people with a
psychiatric illness.
AB - BACKGROUND: Individual packages of care were devised for spouses of older people
with psychiatric illness. METHOD: Randomised controlled trial with blind follow
up. Intervention group members were offered multidisciplinary packages while
controls received no extra help. Both groups were reassessed 12-14 weeks later.
The initial control group then received intervention; both were reassessed at 24
28 weeks. RESULTS: Although no significant differences emerged in group mean
scores for affective illness or social difficulties, carers who were mentally ill
at outset improved significantly. CONCLUSION: Interventions targeted at
caregiving spouses with affective disorder are acceptable and efficacious.
LIMITATION: It was impossible to compare treatment with no treatment.
PMID- 9547126
TI - Effects of comorbidity and polypharmacy on the clinical usefulness of sertraline
in elderly depressed patients: an open multicentre study.
AB - Antidepressant therapy in the elderly age group is frequently complicated by
medical comorbidity, polypharmacy and increased sensitivity to drug effects. A
nonblind, noncomparative, observational, multicentre study over 8 weeks was
conducted to assess the effectiveness and tolerability of sertraline (50-200
mg/day) in 1437 elderly depressed outpatients with a mean (S.D.) age of 68 (6.3)
years (range 60-92) in routine clinical practise. Depressive symptoms were
monitored using the Montgomery Asberg Depression Rating Scale (MADRS) at baseline
and at weeks 2, 4, 6 and 8. The mean dose of sertraline at the final visit was
85.2 mg/day (48% of patients were given the initial dose throughout the study).
At the end of the study, mean percentage change of MADRS score from baseline was
61% (P < 0.001). A > or = 50% decrease in MADRS score was obtained in 70% of
patients. Sertraline was well tolerated. Side effects occurred in 23% of
patients, although only 5.1% withdrew because of adverse events. There were no
significant differences in the antidepressant effectiveness or occurrence of side
effects when patients with and without concomitant pathologic conditions or with
and without concurrent medications were compared. These findings indicate the
absence of clinically important drug interaction and confirm the effectiveness
and safety of sertraline in routine clinical practise for treating elderly
depressed outpatients.
PMID- 9547127
TI - Long-term treatment of geropsychiatric depressed patients with venlafaxine.
AB - Twenty-eight psychiatric patients older than 65 years with major depression with
high probability of recurrence were enrolled in a 24-month open label clinical
trial aimed at evaluating the long-term efficacy and safety of venlafaxine. All
patients completed the acute phase of the study; 21 were responders and entered
the follow-up period. During the continuation phase no relapse was observed.
During the maintenance period, 20% of the patients had a single new recurrence.
No significant side effects were observed. The results demonstrate that
venlafaxine is both effective and safe in the long-term treatment of major
depression in geropsychiatric patients.
PMID- 9547128
TI - Are personality disorders more frequent in early onset geriatric depression?
AB - This preliminary study evaluates the prevalence of personality disorders (PD) in
a sample of 37 elderly recovered depressed and non-demented patients, using the
French version of the Vragenlijst voor Kenmezken van de Persoonlijkheid (VKP) or
Questionnaire on Personality Traits (QPT). The prevalence of definite personality
disorder was 65% with predominance of Cluster C and particularly dependent and
avoidant PD. The rate of PDs was higher in early onset (73%) than in late onset
(45%) geriatric depression, even though there is only a trend towards statistical
significance (Chi square = 2.588, p = 0.107). These results are consistent with
those of previous reports using different PD assessment methods, supporting
evidence that the QPT could be useful in PD assessment of elderly French speaking
patients.
PMID- 9547129
TI - Does a teaching programme improve general practitioners' management of depression
in the elderly?
AB - General Practitioners have a central role to play in the management of depression
in their older patients. However, studies suggest that GPs tend to underdiagnose
and undermanage depression in this age group. Continuing Medical Education is an
important part of helping GPs keep up to date and improve their practice. We set
out to see what effect a half a day postgraduate training course had on the views
and knowledge of a group of local GPs on the management of depression in the
elderly. Twenty-one general practitioners attended the course and of these
fifteen completed a questionnaire with clinical vignettes before and six weeks
after the course. Analysis of the questionnaire and vignette data showed
significant improvements in a number of areas: in particular, GPs' knowledge
about antidepressant treatment increased, as did their preference for cognitive
behavioural therapy out of a range of psychological treatments. This study
indicates that a teaching package on depression in the elderly can improve
general practitioner's management knowledge. It also suggests that old age
psychiatrists can play an important part in the education of their GP colleagues.
Nevertheless, further studies are needed to ensure that educational programmes
make an effective impact on the underdiagnosis and undertreatment of depression
in the elderly.
PMID- 9547130
TI - Response characteristics to antidepressants and placebo in post-traumatic stress
disorder.
AB - Characteristic response patterns are described for two antidepressant drugs and
placebo in post-traumatic stress disorder. Early onset and steady improvement
occurred on a global rating scale for both drugs and placebo in those who
ultimately met responder criteria at the end of treatment. In certain cases, the
magnitude of global response was greater for drug than for placebo. At weeks 2 or
4, the Clinical Global Impressions score for fluoxetine but not for
amitriptyline, served as a good predictor of eventual response. In a review of
numerous completed placebo-controlled trials, antidepressants were superior to
placebo in seven out of eight comparisons using the Clinical Global Impressions,
although specific effects on post-traumatic stress disorder scales were more
variable. Drug response rates are similar for combat and civilian trauma samples,
but placebo response rates may be higher in the latter. Effect sizes suggested a
moderate-to-good effect for drug therapy.
PMID- 9547131
TI - The dopamine hypothesis of schizophrenia: current status, future prospects.
AB - The dopamine hypothesis of schizophrenia is reviewed in the context of recent
advances in dopamine research. These include the following: the discovery that
there are several subtypes of dopamine receptor, the recognition that the
activity of dopamine neurons is controlled by negative feedback systems; insights
into the functions of different subsystems of dopamine neurons; the discovery
that different subsystems of dopamine neurons interact with one another; and a
growing understanding of the functions and mode of operation of the forebrain
regions that the dopamine projections innervate. The paper reviews some of the
complexities that the dopamine hypothesis has encountered, and continues to
encounter, with a particular focus on three issues: the adequacy of our
understanding of neuroleptic drug action, the heterogeneity of schizophrenic
symptoms and the paucity of direct evidence to support the hypothesis. It is
concluded that schizophrenia does not reflect primary abnormalities of dopamine
transmission, but probably does reflect abnormalities in systems that have an
intimate interaction with the dopamine system. The primary substrates for
schizophrenia will probably be found within the major targets of the ascending
dopamine projections: the fronto-striato-pallido-thalamic loops, and the limbic
structures, such as amygdala and hippocampus, with which the fronto-striatal
system interacts.
PMID- 9547132
TI - A 2-year study of sertraline in the treatment of obsessive-compulsive disorder.
AB - The present study investigated the tolerability, safety profile, and anti
obsessional efficacy of sertraline, a selective serotonin reuptake inhibitor,
during long-term treatment of patients with obsessive-compulsive disorder (OCD).
Fifty-nine OCD patients who had completed a 1 year double-blind, fixed dose study
comparing sertraline and placebo subsequently entered a 1-year open extension.
Among the 51 patients who had been treated with sertraline during the double
blind phase, the mean total duration of sertraline treatment was 690 days. Only
treatment responders who completed the 52-week double-blind treatment phase were
permitted to enter the open extension. The higher rate (p < 0.02) of sertraline
patients (51 out of 241) than of placebo patients (eight out of 84), who
responded to treatment and entered the open-label phase is therefore consistent
with the greater mean improvement observed in the sertraline group during double
blind treatment. Placebo responders differed from sertraline responders in that
they were less impaired at baseline of the double-blind study [Yale-Brown
Obsessive-Compulsive Scale (Y-BOCS) of 18.5 versus 23.4] and they exhibited less
improvement during double-blind treatment (-6.1 versus -11.4). In the open-label
phase all patients received sertraline at a starting dose of 50 mg once a day,
titrated in 50 mg increments to a maximum dose of 200 mg according to clinical
response. At end-point the mean Y-BOCS score for all patients decreased by a
further 3.6 points. Patients previously treated with placebo showed greater
improvement after being switched to sertraline than those who received continued
sertraline treatment. Patients who completed the study and received 2 full years
of sertraline treatment (n = 38) exhibited a mean improvement of 15.6 points
using the Y-BOCS. Sertraline was well tolerated during both the double-blind
phase and the open extension, and the incidence of adverse experiences was
generally reduced during the second year of treatment. Three patients
discontinued open treatment because of adverse experiences. Long-term sertraline
treatment did not appear to be associated with the emergence, increased
incidence, or increased severity of adverse experiences or clinically significant
abnormalities in laboratory tests, vital signs, or the electrocardiogram. The
study supports the long-term safety and tolerability of sertraline over a 2-year
treatment course and the sustained efficacy of sertraline in patients with OCD.
PMID- 9547133
TI - Moclobemide effects on prolactin plasma levels in healthy individuals: the
hormonal increase induced by a single dose is maintained during a 4-week period
of drug intake.
AB - Neuroendocrine challenge studies are frequently used to study the pathophysiology
of psychiatric illnesses and the effects of psychotropic drug treatment on brain
monoamine function. Moclobemide, a reversible inhibitor of monoamine oxidase,
with predominant effects on the A-type of the enzyme, was administered to 15
healthy men. Seven out of the 15 also received single blind placebo a week before
the moclobemide. The individuals received moclobemide as a single dose (150 mg),
followed by doses of 150 mg three times a day, during a 4-week period. Plasma
prolactin was measured in the morning over a 150-min period, following the single
dose, and then at the end of weeks 1, 2 and 4 of moclobemide intake. The present
data show an acute and transitory increase of plasma prolactin levels after the
single dose, and also during the long-term moclobemide administration. It might
indicate that steady-state moclobemide levels, during the long-term drug
administration, were low and thus large fluctuations of drug levels occurred
between doses. Thus, it is suggested that larger doses or administering smaller
doses more frequently, or both, may induce hyperprolactinaemia with clinical
consequences.
PMID- 9547134
TI - A double-blind multicenter trial comparing sertraline and citalopram in patients
with major depression treated in general practice.
AB - The purpose of this double-blind, multicenter trial was to compare the efficacy
and safety of sertraline (50-150 mg/day) with those of citalopram (20-60 mg/day)
in patients with major depression in general practice during 24 weeks of
treatment. The patients were assessed using the Montgomery-Asberg Depression
Rating Scale and the Clinical Global Impressions of severity and improvement
scales. Observed and spontaneously reported adverse events were recorded and side
effects were assessed by means of the UKU Side-Effect Scale. Altogether 400
patients were randomized into the study. A total of 308 patients completed the 24
week study in accordance with the protocol. A significant reduction in the total
Montgomery-Asberg Depression Rating Scale scores was observed in both treatment
groups as early as 2 weeks, with no statistically significant differences between
the drugs. In the intention to treat-last observation carried forward analysis
76% responded to treatment in the sertraline and 81% in the citalopram group. The
final mean doses were 82 mg/day (64% higher than baseline) in the sertraline
group and 34 mg/day (70% higher than baseline) in the citalopram group. The
response rate in completers in accordance with protocol was 90% in the sertraline
group and 93% in the citalopram group. The side-effects were those usually seen,
and both sertraline and citalopram were considered to be well tolerated. It was
concluded that patients with major depression in general practice respond well to
24 weeks of treatment with sertraline or citalopram. With regard to efficacy, no
statistically significant differences were found between the drugs.
PMID- 9547135
TI - Long-term risperidone treatment in bipolar disorder: 6-month follow up.
AB - Antipsychotic agents, such as clozapine and risperidone, have been reported to be
beneficial in the treatment of some bipolar patients. Many bipolar patients
experience 'breakthrough episodes' of mood disorder, with mania or depression
recurring despite adequate ongoing levels of one or more mood-stabilizing
medications. There are no controlled studies of breakthrough episodes, and there
is little open experience to guide clinicians in pharmacotherapy of breakthrough
episodes. This report describes the outcome of adjunctive risperidone treatment
in breakthrough episodes of bipolar disorder. We assessed the outcome of openly
adding risperidone to the medication regimen of 12 outpatients with bipolar
disorder, type I, who suffered breakthrough episodes despite adequate maintenance
medication (lithium, valproate, or carbamazepine, or a combination of these).
Prospective ratings were made at each clinical visit using the Clinical Global
Impressions and Global Assessment of Functioning scales. Patients received
risperidone for a mean of 6.0 months (23.96 weeks, range 0.5-72 weeks) at a mean
dose of 2.75 mg/day (range 1-4.5 mg/day). Four patients discontinued medication
(two because of lack of efficacy at weeks 6 and 64, and two because of adverse
events at weeks 0.5 and 23). Among the remaining eight patients, four experienced
a 10-25 point improvement in Global Assessment of Functioning scores and were
rated much better on the Clinical Global Impression-Improvement scale. Although
one patient suffered a major depressive recurrence (at week 22), no patient
experienced worsening of mania. This small open series suggests a subgroup of
bipolar patients with breakthrough episodes may benefit from treatment with
risperidone.
PMID- 9547136
TI - Serotonin syndrome--clomipramine too soon after moclobemide?
PMID- 9547137
TI - The ribosomal RNA gene region of Nosema apis (Microspora): DNA sequence for small
and large subunit rRNA genes and evidence of a large tandem repeat unit size.
AB - The ribosomal RNA (rRNA) gene region of the microsporidium, Nosema apis, has been
examined. A new method for extracting microsporidian genomic DNA from infected
host tissue is described. Complete DNA sequence data are presented for the small
subunit gene (1242 bp), the internal transcribed space (33 bp), and the large
subunit gene (2481 bp to a putative termination point). This is the first time
that the complete large subunit rRNA gene has been published for any
microsporidian species. DNA sequence is also presented for the regions flanking
the 5' end of the small subunit gene and the 3' end of the large subunit gene.
The intergenic spacer is shown to be heterogeneous, showing variation in sequence
and restriction sites rather than length and containing sequence repeats, which
are a characteristic feature of intergenic spacers. The rRNA gene region of N.
apis is shown to occur in a head-to-tail, tandemly repeated manner, as in other
eukaryotes. This repeat unit is shown to be approximately 18 kb in length. The
nucleotide sequence presented has been submitted to the Genbank database under
the accession number U97150.
PMID- 9547138
TI - Fabrication of a guide for nonradiographic evaluation of bone contour.
PMID- 9547139
TI - Functional analysis of the cellobiohydrolase I promoter of the filamentous fungus
Trichoderma reesei.
PMID- 9547140
TI - Case records of the Massachusetts General Hospital. Weekly clinicopathological
exercises. Case 12-1998. A 68-year-old man with a rash, diabetes insipidus, and
laryngeal stenosis.
PMID- 9547141
TI - Should all people over the age of 50 have regular fecal occult-blood tests? If it
works, why not do it?
PMID- 9547142
TI - The obesity problem.
PMID- 9547143
TI - The obesity problem.
PMID- 9547144
TI - The obesity problem.
PMID- 9547145
TI - The obesity problem.
PMID- 9547146
TI - The obesity problem.
PMID- 9547147
TI - The obesity problem.
PMID- 9547148
TI - The obesity problem.
PMID- 9547149
TI - Age, body-mass index, and mortality.
PMID- 9547150
TI - Age, body-mass index, and mortality.
PMID- 9547151
TI - Age, body-mass index, and mortality.
PMID- 9547152
TI - Six years' follow-up after hepatitis A vaccination.
PMID- 9547153
TI - Accidental deep hypothermia.
PMID- 9547154
TI - Accidental deep hypothermia.
PMID- 9547155
TI - Accidental deep hypothermia.
PMID- 9547156
TI - Circulating endothelial cells in sickle cell anemia.
PMID- 9547157
TI - Circulating endothelial cells in sickle cell anemia.
PMID- 9547158
TI - Evaluating CME speakers.
PMID- 9547159
TI - Melatonin induces hyporeactivity caused by type II collagen in peripheral blood
lymphocytes from patients with autoimmune hearing losses.
AB - We have studied the behavior of peripheral blood lymphocytes in healthy controls
and in patients with various hearing losses. These hearing losses were of an
autoimmune origin in which type II collagen and melatonin were either present or
absent, activated or not with concanavalin A (Con A). In patients with autoimmune
hearing losses, the results showed lymphocytes that displayed hyporeactivity to
type II collagen in terms of their proliferative activity in the presence of Con
A. The hyporeactivity is specially relevant in those cells which are melatonin
incubated. When different nosologic entities were studied, we observed similar
lymphocyte hyporeactivity to type II collagen in bilateral sensorineural hearing
loss, Meniere's disease and otosclerosis. We conclude that in the lymphocytes of
patients with autoimmune hearing losses, there is hyporeactivity to type II
collagen when compared to the hyporeactivity of lymphocytes in control groups.
This hyporeactivity is revealed when the lymphocytes are activated in the
presence of melatonin.
PMID- 9547160
TI - Corticosubthalamic input zones from forelimb representations of the dorsal and
ventral divisions of the premotor cortex in the macaque monkey: comparison with
the input zones from the primary motor cortex and the supplementary motor area.
AB - Employing double anterograde axonal tracing in combination with intracortical
microstimulation, we examined the distribution patterns of corticosubthalamic
inputs from forelimb representations of the dorsal (PMd) and ventral (PMv)
divisions of the premotor cortex in the macaque monkey. The inputs from the PMd
and PMv were distributed mainly in the medial aspect of the subthalamic nucleus
(STN), in which their distribution areas overlapped each other. By the same
experimental approach, we further compared corticosubthalamic input zones from
the PMd/PMv with those from the primary motor cortex (MI) and the supplementary
motor area (SMA). The input zones from the PMd/PMv and SMA largely overlapped in
the medial aspect of the STN, whereas the input zones from the PMd/PMv and MI
were virtually segregated mediolaterally in the STN.
PMID- 9547161
TI - Expression of Ly-6C on microglia in the developing and adult mouse brain.
AB - Expression of Ly-6C, a murine homolog of human CD59, in the brain was examined
immunologically using an ER-MP20 monoclonal antibody both in vitro and in vivo.
Ly-6C was expressed both on the isolated microglia and on microglia in the
developing and adult cerebellum. The number of cerebellar microglia expressing Ly
6C markedly increased during the first postnatal week in mouse development. The
expression of Ly-6C on microglia in the developing and adult brain may be related
to the unique role(s) of microglia under normal and/or pathological conditions of
the brain.
PMID- 9547162
TI - Developmental changes in distribution patterns of phencyclidine-induced c-Fos in
rat forebrain.
AB - In the forebrain of 56-day-old rats, histochemical studies revealed that the
subcutaneous injection of a psychotomimetic phencyclidine (PCP; 1 and 10 mg/kg)
induced a dose-related and dense nuclear c-Fos-like immunoreactivity in the
pyriform cortex, layers IV-VI of the neocortex and septum, but a sparse c-Fos
immunostaining in the olfactory tubercle and mid-lateral striatum. Infant rats at
postnatal day 8 expressed much fewer and more confined c-Fos-positive cells in
the neocortex than young adult rats following PCP injection. However, a similar
expression pattern of PCP-induced c-Fos was observed in the pyriform cortex, mid
lateral striatum, olfactory tubercle and septum between the infant and adult
periods. These developmental changes in the regional distribution of a neuronal
activity marker, c-Fos, suggest that neuronal populations involved in PCP-induced
abnormal behavior are influenced by postnatal development, at least, in the
neocortex.
PMID- 9547163
TI - Motor unit discharge rate is not associated with muscle relaxation time in
sustained submaximal contractions in humans.
AB - The muscle wisdom hypothesis suggests that motor unit discharge rates decrease in
parallel with the slowing of muscle contractile properties during fatigue. In
this study, the discharge rates of single motor units and the muscle contractile
properties were measured during a sustained submaximal contraction. The majority
of motor units that were active from the beginning of the task demonstrated a
decline in discharge rate in the absence of any slowing of muscle relaxation
time. These findings suggest that the muscle wisdom hypothesis may not apply to
sustained submaximal contractions.
PMID- 9547164
TI - Interleukin-6 (IL-6) and soluble forms of IL-6 receptors are not altered in
cerebrospinal fluid of Alzheimer's disease patients.
AB - We quantitated interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R) and soluble
form of the IL-6 signal-transducing protein gp130 (sgp130) in cerebrospinal fluid
(CSF) of patients with Alzheimer's disease (AD) (n = 17) and control subjects (n
= 18) using sensitive enzyme-linked immunosorbent assays (ELISA). Our results
show that none of the parameters examined was significantly different in CSF of
AD patients as compared to control age-matched non-demented patients. We conclude
that CSF levels of IL-6 and their soluble receptors do not necessarily reflect
local changes of the IL-6 system that has been shown to be involved in
neurodegenerative events occurring in AD. Levels of sgp130 are substantially high
(approximately 100 ng/ml) in the CSF of all individuals probably representing a
high antagonistic potential.
PMID- 9547165
TI - Reduced cholinergic function in normal and Alzheimer's disease brain is
associated with apolipoprotein E4 genotype.
AB - Apolipoprotein E (ApoE) is a potent risk factor for Alzheimer's disease. Since
the loss of cholinergic function in Alzheimer's disease is known to occur at an
early stage in the disease we have examined this function in normal subjects with
an Apoepsilon4 allele to see if the deficit occurs in the absence of Alzheimer
pathology or symptoms. We report that brain tissue obtained post-mortem from
normal subjects and Alzheimer patients with an Apoepsilon4 allele has a lower
cholinergic activity than tissue from those subjects without this allele. This
has important significance for the interpretation of the cholinergic deficits
found in Alzheimer's disease.
PMID- 9547166
TI - Nociceptin hyperpolarises neurones in the rat ventromedial hypothalamus.
AB - Patch-clamp recording techniques were used to examine the effect of nociceptin
upon neurones contained in slices from the rat ventromedial hypothalamus (VMH).
Bath application of 50-300 nM nociceptin hyperpolarised neurones in a
concentration-dependent manner that was not affected by either tetrodotoxin (TTX)
or naloxone. In voltage-clamp studies nociceptin induced an outward current at
60mV that had a reversal potential of -100.2 +/- 4.6 mV and was abolished by bath
application of 2 mM BaCl2.
PMID- 9547167
TI - Paired helical filament morphology varies with intracellular location in
Alzheimer's disease brain.
AB - Paired helical filaments (PHFs) are one of the hallmark pathologies of
Alzheimer's disease (AD). PHFs occur in three intracellular locations, although
hitherto, it was not known whether all PHFs are structurally homogeneous.
Parietal cortex biopsies were taken from five patients with a clinical and
histopathological diagnosis of AD and processed for electron microscopy.
Photomicrographs were then taken of PHFs in neurofibrillary tangles (NFTs),
neuropil threads (NTs) and neuritic plaque (NP) neurites and their dimensions
measured. The mean half period, maximum and minimum widths of PHFs in NFTs were
significantly smaller than those in NTs or NP neurites. The mean half period and
maximum width of PHFs in NTs were similar to those in NP neurites. These results
reveal the presence of two distinct PHF populations and investigation of their
relationship may shed light on the pathogenesis of AD.
PMID- 9547168
TI - NACP, a presynaptic protein, immunoreactivity in Lewy bodies in Parkinson's
disease.
AB - NACP, originally identified as a precursor of the non-Abeta component of
Alzheimer's disease amyloid (NAC), is now known to be identical to alpha
synuclein, a presynaptic protein in the human brain. Recently, a mutation in the
alpha-synuclein gene in families with autosomal dominant Parkinson's disease (PD)
was identified. We carried out immunohistochemical examinations of the brains of
sporadic PD patients using anti-NACP and anti-ubiquitin antibodies. Consistent
with previous studies, the anti-NACP antibody immunostained the neuropil in a
punctate pattern throughout the brain. Moreover, much stronger NACP
immunoreactivity was found in Lewy bodies and degenerating neurites in the
brainstem. Serial sections immunolabeled with anti-ubiquitin or anti-NACP showed
that all ubiquitin-immunoreactive LBs were also NACP-immunoreactive. These
findings suggest that alteration of NACP metabolism is involved in the
pathogenesis of PD, particularly in Lewy body formation, leading to
neurodegeneration.
PMID- 9547169
TI - mRNA distribution in adult human brain of GRIN2B, a N-methyl-D-aspartate (NMDA)
receptor subunit.
AB - The expression of the N-methyl-D-aspartate (NMDA) receptor subunit NR2B/epsilon2
(GRIN2B) in the human adult brain was assayed by in situ hybridisation, by using
a specific cRNA probe. The full length GRIN2B cDNA was cloned and sequenced. It
showed a 90% nucleotide conservation when compared to the rodent homologue.
GRIN2B gene is expressed at high levels in the fronto-parieto-temporal cortex and
hippocampus pyramidal cells and, at a lower extent, in the basal ganglia
(amygdala and striatum). The cerebellar granule cells does not show any mRNA
expression. The non-ubiquitous anatomical distribution of the GRIN2B mRNA in the
central nervous system suggests that the gene could be involved in specific
functions pertaining to the expressing cell groups.
PMID- 9547170
TI - Lack of translation of normal 7B2 mRNA levels in hypothalamic mutant vasopressin
cells of the homozygous Brattleboro rat.
AB - The homozygous Brattleboro rat (di/di) synthesizes a vasopressin (VP) precursor
with an aberrant C-terminus, which causes a hypothalamic form of diabetes
insipidus. The neuroendocrine polypeptide 7B2 is present in VP and oxytocin (OT)
neurons of the supraoptic and paraventricular nucleus of the hypothalamus in wild
type rats. However, in the di/di rat 7B2 immunoreactivity is absent in the VP
cell population, whereas 7B2 levels within the OT cells are unaffected.
Remarkably, there is no obvious difference in 7B2 transcript levels between VP
and OT neurons in the di/di rat hypothalamus. This study shows that the presence
of mRNA does not automatically result in the subsequent synthesis of its protein.
Cellular mechanisms underlying this discrepancy are discussed.
PMID- 9547171
TI - Age changes in dopamine levels in the corpus striatum of Albino Swiss (AS) and
AS/AGU mutant rats.
AB - The AS/AGU rat is characterised by an ungainly, staggering gait, hind-limb
rigidity, whole body tremor and (in older animals) difficulty in initiating
movement. Brains of AS and AS/AGU males aged between 3 and 12 months (n = 10 per
group) were sectioned transversely on a cryostat (-20 degrees C) to produce two
successive cut faces (corresponding approximately to Bregma +1.2 and -0.5 mm) and
1 mm diameter x 1 mm deep micropunches were taken from four areas of the caudate
putamen. Levels of dopamine in all four areas (measured by HPLC-ECD followed by
protein estimation) peaked at around 6 months and then declined in AS and AS/AGU
rats. In the dorsal and lateral caudate-putamen, dopamine levels were
significantly reduced in AS/AGU rats compared to AS controls from 6 months
onwards. This provides further evidence that the AS/AGU mutant has impairment of
its striatal dopaminergic systems.
PMID- 9547172
TI - Pentylenetetrazol kindling decreases N-methyl-D-aspartate and kainate but
increases gamma-aminobutyric acid-A receptor binding in discrete rat brain areas.
AB - Pentylenetetrazol is a convulsive drug acting on gamma-aminobutyric acid-A
(GABA[A]) gated-chloride receptors. In this study we used a subconvulsive dose
(30 mg/kg) of pentylenetetrazol to induce a fully kindled state in rats.
Glutamate receptors were evaluated using [3H]-[1(2-thienylcyclohexyl)]-piperidin
(TCP) and [3H]kainate receptor autoradiography and [3H]muscimol autoradiography
was used to study GABA(A) receptors. In fully kindled rats decreased N-methyl-D
aspartate receptor binding was found in parietal cortex, area CA2 of hippocampus
and piriform cortex. Decreased kainate receptor binding was observed in all areas
of the hippocampus, the medial amygdala and in the piriform cortex in the kindled
rats. In contrast, GABA(A) receptor binding increased in the dentate gyrus. It is
concluded that modulatory neuronal plasticity events are induced in fully
pentylenetetrazol kindled rats, which appears to lead to decreased glutamatergic
excitation and increased GABAergic inhibition in brain regions implicated in the
development of seizure activity.
PMID- 9547173
TI - [Bone substitution materials].
PMID- 9547174
TI - Urine testing--2. urinalysis.
PMID- 9547175
TI - She can't help it. Fetal alcohol syndrome haunts those who watch but can't change
things.
PMID- 9547176
TI - Optical character recognition. Let a scanner spare you those inputting ordeals.
PMID- 9547177
TI - Monitor chamber backscatter for intensity modulated radiation therapy using
multileaf collimators.
AB - Backscattered radiation into the machine monitor chamber can affect the machine
output variation, with changes in field size and shape. For intensity modulated
radiation therapy (IMRT) where many field, which may have small dimensions, are
summed to give an intensity modulated field, the magnitude of backscatter will be
different due to both the backscattering surface area changing, and the delivered
monitor units being larger than for the equivalent static field. The effect of
backscatter variation with field size for a Philips SL15 accelerator has been
investigated at 8 MV for static and IMRT fields both in the standard clinical
operating condition where an anti-backscatter plate is fitted, and also for a
case where the anti-backscatter plate has been removed. The results show that in
the absence of the anti-backscatter plate the variation in output between a 4 cm
by 4 cm field and a 40 cm by 40 cm field size due to backscattered radiation was
5% for static fields. The anti-backscatter plate reduced this variation to less
than 1%. When the accelerator operated in IMRT mode, with the backscatter plate
in place, changes in the output due to additional backscattered radiation were
less than 0.3%. With the backscatter plate removed, the outputs were lower,
indicating the presence of additional backscattered radiation. It can be
concluded that for the Philips MLC and SL accelerator with its anti-backscatter
plate, the effects of backscattered radiation can be ignored for both static and
IMRT fields.
PMID- 9547178
TI - [Progress in research on etiopathogenesis of schizophrenia in recent decades].
AB - In this paper, a progress in research on etiopathogenesis of schizophrenia made
in the recent decade was presented. Two main etiopathogenetic factors in this
illness include genetic predisposition and brain damage in early period of life,
leading to a disorder of brain development and lateralization, and to an
increased susceptibility to stress. The use of new methods of genetic studies
brought about a significant progress as to identification of relationship between
schizophrenia and various changes within genotype. In the 1990s, many data have
been obtained concerning possible brain damaging factors as well as the existence
of structural and functional brain abnormalities in this illness. Impaired brain
development in schizophrenia results in disturbances of neuronal connection in
the cortical structures and in cortical-limbic transmission, what may underlie
the appearance of psychopathological symptoms. New neuroleptic drugs introduced
in the recent years show more complete therapeutic action against schizophrenic
symptoms compared with drugs used so far. This may result from their broader
influence on the pathogenetic processes of schizophrenia, which may be due, apart
from their effect on dopaminergic system, also to their action on some elements
of serotonergic neurotransmission.
PMID- 9547179
TI - [Neurodevelopmental schizophrenia: the concept of developmental origins of
certain forms of schizophrenia].
AB - This article presents the concept of neurodevelopmental schizophrenia and reviews
the studies that contributed to its formulation. According to this concept some
forms of schizophrenia (early onset, with predominating negative symptoms) are
conditioned by distorted CNS development, probably in prenatal period. Such
pathogenesis of certain forms of the disease is suggested by the following
results of the studies on the CNS structure and function in schizophrenia: 1)
structural abnormalities on in vivo brain imaging and postmortem studies 2)
cytoarchitectural distortions in some brain regions, suggestive of disruption of
cell migration during the CNS developmental processes 3) co-occurrence of the CNS
congenital anomalies, minor physical anomalies and schizophrenia 4) neurological
defects and psychosocial childhood dysfunction in individuals with adult onset
schizophrenia. Genetical conditions, viral infections in prenatal period,
obstetric complications or combination of the mentioned factors are considered as
the factors disturbing the CNS developmental processes.
PMID- 9547180
TI - [Structural brain changes in the computerized tomography of schizophrenic
patients].
AB - VBR was higher and the cortical atrophy more frequent in the schizophrenic
patients as compared to the control group. VBR correlated negatively with SANS
and PANSS (negative) scores, especially with alogia and inattention, it also
correlated positively with female sex. Positive intercorrelations were found
between VBR and other ratios concerning lateral ventricles and no correlations
were found between them and cortical atrophy.
PMID- 9547182
TI - [Social functioning of schizophrenic patients after 15 years from the first
hospitalization (Part I -- evaluation of social functioning)].
AB - Catamnestic data concerning 109 patients, inhabitants of Warsaw-Praga,
hospitalized for the first time in the years 1978-79 with schizophrenia (92
persons) or paranoid psychosis-ICD IX number 297.9 (17 persons), were collected
in 1993-94. Smaller number and shorter duration of hospitalisations has been
observed during 15 years, in comparison with other Polish data. Twenty persons
died during the period of observation. In the group of 85 investigated persons
69% were not working at all-15% were fully and 18% partially unable to meet their
basic needs on their own-29% were temporarily or permanently unable to function
adequately in their marital and/or parental roles, 31% were single and childless.
Taking into account the mortality among 109 observed persons (18.7% during 15
years); good prognosis according to social functioning has been found in 48.6% of
the group observed at first hospitalisation.
PMID- 9547181
TI - [Cortical atrophy in MRI, mental status and neuroleptic treatment effect in
schizophrenia].
AB - MR imaging of the head was performed in forty schizophrenics (DSM-IV). Mental
status was evaluated before and during 8-weeks of neuroleptic treatment. Cortical
atrophy in frontal and temporal regions was found in 40% of subjects. They were
older, had longer history of schizophrenia, were less active professionally and
were more frequently hospitalized. Patients with and without cortical atrophy in
MRI did not differ in the severity of schizophrenic psychopathology at baseline.
During neuroleptic treatment negative schizophrenia symptoms were significantly
better diminished in patients without cortical atrophy than in subjects with
cortical atrophy in MRI; this regarded specially the severity of emotional
blunting. Clinical improvement after 8-weeks of neuroleptic administration was
less favorable in patients with cortical atrophy.
PMID- 9547183
TI - [Social functioning of schizophrenic patients after 15 years from the first
hospitalization (Part II -- the evaluation of needs for community care)].
AB - The description of the studied group was given in the first part of the paper.
Some of the factors having been present at the first hospitalization were found
to be important for the patients' functioning 15 years later. On the basis of the
collected regarding data 85 patients, significant coincidence has been found
between more intensive use of extramural services, more frequent and longer
hospitalizations, and worse social functioning during 15 years' period in
individual cases. The conclusion has been assumed that there exists obvious need
for more intensive community care for such patients. On the basis of 0.15%
morbidity index the number of schizophrenics needing social support, sheltered
accommodation and sheltered working conditions were estimated. According to the
Mental Health Care Act of 1994 such services have to be organized within social
care system.
PMID- 9547185
TI - [Psychoeducation in schizophrenia relapse prevention].
AB - Schizophrenia is a chronic disease, with phase course. Most of patients (about
78%) experience more than one episode of the disease in the course of life.
Pharmacotherapy is the standard method of troating schizophrenia. Since the
middle of the 70 a new orientation of therapy of schizophrenia has been
developing. Its main goal is prophylaxis, which combines pharmacotherapy and
psychosocial treatment. In the paper we discuss the term "relapse of
schizophrenia" and researches concerning the index of relapses and dynamics of
the disease. We present theoretical presumptions which are the base of
psychoeducational programs, that is, stress-vulnerability model. The main
purposes of psychoeducation in schizophrenia are also discussed. The article
contains current review of the researches relative to effectiveness of
psychoeducational programs in relapse of schizophrenia prevention.
PMID- 9547184
TI - [Comparison of quality of life of schizophrenic patients in different forms of
psychiatric care].
AB - Health related quality of life and severity of psychopathological symptoms were
evaluated in 90 patients with schizophrenia, hospitalized in a psychiatric ward
in a day hospital or followed by the therapist in a community care center. No
statistical differences were found in the quality of life evaluation between
patients from all three settings. The quality of life did not correlate with the
severity of schizophrenic symptoms. Older patients and those more frequently
hospitalized were more pessimistic in evaluation of their quality of life. Health
status transition, as compared to the situation one year before, correlated
inversely with patients' age. Male patients as well as patients from
schizophrenic families evaluated their quality of life as worse.
PMID- 9547186
TI - [Negative symptoms with relation to the remission in the early stage of
schizophrenic psychosis].
AB - 103 patients were admitted for the first time to the psychiatric hospital
(Institute of Psychiatry and Neurology in Warsaw) between 1976-1983 and received
a research diagnosis of schizophrenia (in accordance with the ICD-9 criteria).
The course and clinical pattern of the illness were analyzed at a follow-up in 65
patients-rehospitalized in the 5th year from their first admission and in 10
patients not rehospitalized during catamnestic period. As regards the clinical
pattern analysis, it was focussed on negative symptoms occurrence, as assessed
using the Andreasen Scales (SANS). The quality of remission was evaluated. The
data obtained from the case reports were statistically tested and the results
were presented in the tables according to the research questions. The occurrence
of negative symptoms (affective blunting, alogia, apathy, anhedonia, attention)
at first hospitalization had no relation to the quality of the remission at the
five-year follow-up.
PMID- 9547187
TI - [Follow-up studies of psychotic patients receiving inpatient treatment or
alternative forms of psychiatric care].
AB - An analysis of populations treated in the III Department of Psychiatry indicates
that 12 years since the transformation of the organizational model of care for
patients from sub-regionalized catchment area, inpatient treatment continues to
be of major importance, as it was provided to over half of all referrals.
Intermediate forms of care, replacing a half of the former number of psychiatric
beds, were offered mainly to schizophrenic patients, with the exclusion of those
with a marked agitation, psychomotor retardation, or aggressive, presenting
imminent danger to self or others. At one-year follow-up J.E. Overall's scale was
used to examine 39 schizophrenic patients treated at the inpatient ward, day
hospital, or by a community treatment team. Patients treated at the day hospital
providing an intense therapeutic program manifested a significantly more marked
improvement in respect of 6 symptoms: autism, affective bluntness, guilt
feelings, tension, suspiciousness, and bizarre thoughts. No significant
differences were found between the compared forms of care as regards the degree
of other symptoms amelioration. Thus, the day hospital turned out to be a more
effective form of care in case of schizophrenic patients manifesting the cluster
of symptoms listed above.
PMID- 9547188
TI - [Family burden of patients receiving inpatient treatment or alternative forms of
psychiatric care].
AB - Professionals working with chronic patients are usually aware of vast deficitis
in what is called in the literature "natural support networks". The deficits
generally increase over time, as is the case with broadly defined social skills.
Although the efficacy of biological treatment was similar in all the three forms
of care, nevertheless, patients and their families, when left without
psychotherapeutic support provided to them by the day hospital or community
treatment team, at one-year follow-up indicated lack of any satisfactory
improvement in many dimensions of their functioning, and in some aspects-even a
progressive deterioration.
PMID- 9547189
TI - [Foreign bodies in trachea and bronchi].
PMID- 9547190
TI - [Non-small cell bronchopulmonary carcinoma. In search of a precise prognosis].
PMID- 9547191
TI - [Hypertriglyceridemia and plasma insulin in combined familial hyperlipidemia].
AB - Changes in insulin secretion were investigated in a group of non obese subjects
with combined familial hyperlipidemia (CFH), with normal glucose tolerance,
relating the observed changes with plasma triglycerides and lipoprotein
phenotype. MATERIALS AND METHODS: The study was conducted with 21 subjects (16
males and 5 females; mean age: 45.9 +/- 9.1 years), diagnosed of CFH after the
clinical and analytical study of patients and their first degree relatives (9
with phenotype IIa, 8 IIb, and 4 IV) and 21 healthy control subjects, of similar
age, sex and body weight. In both groups, lipids, plasma lipoproteins, glucose,
basal plasma insulin, and insulin after and oral glucose overload (OGO) were
quantitated. RESULTS: Diastolic blood pressure was higher (p < 0.01) in CFH group
compared with controls (means: 132/80 vs 123/71 mmHg, respectively). TC, TG and
Apo B were also higher in the CFH group. With OGO significantly higher serum
insulin levels were observed at 0, 30, 60, 90 and 120 minutes in CFH subjects
compared with control group. Basal serum insulin and the area under the curve of
insulin secretion after OGO was higher in subjects with triglycerides (45,579 +/-
13,056 in controls, 61,385 +/- 22,254 in CFH IIa, 70,645 +/- 17,271 IIb and
124,884 +/- 36,944 in CFH IV. Insulin secretion correlated significantly (p <
0.01) with plasma triglycerides. As conclusion, hyperinsulinism is a finding in
CFH non obese subjects and with normal glucose tolerance, and has an increasing
frequency in subjects with high triglycerides levels.
PMID- 9547192
TI - [Percutaneous implant of Hickman catheters and reservoirs. Long-term experience].
AB - OBJECTIVE: To report our experience with long term external catheters and
implantable ports in the last 8 years. MATERIAL AND METHODS: From December 1987
to August 1995 a total of 617 central venous catheters were implanted in 541
patients in our Interventionist Vascular Radiology Unit, 265 men (49%) and 276
women (51%), with a mean age of 46 years. A total of 335 (54%) were partially
implantable external catheters and 241 (39%) implantable ports in chest and 41
(7%) in the forearm. RESULTS: A technical success--defined as the possibility of
implanting the catheter--was achieved in 98% of cases. Immediate complications
included 5 pneumothorax (0.8%), 11 accidental carotid artery puncture (2%) with
no clinical relevance, 18 catheter misplacement (3%), and 8 vein spasm (1%).
Fifty-two catheters (8%) were removed on account of infectious complications.
Currently, 71 catheters are still in use (12%), 433 (70%) have been removed or
the catheter was patent until patients's death. CONCLUSIONS: Partially
implantable central venous catheters and totally implantable ports are a safe
alternative in patients requiring a central venous access for prolonged
treatments. The low number of immediate complications renders the Interventionist
Vascular Radiology Unit the proper place where to perform these procedures.
PMID- 9547193
TI - [Medical rhabdomyolysis in the elderly].
AB - BACKGROUND: To investigate the characteristics of medical rhabdomyolysis (RM) in
the elderly, as well as differences compared with those observed in younger
patients. PATIENTS AND METHODS: Prospective study of 56 elderly patients (> or =
65 years) with RM and 73 younger patients (> 7 years and < 65 years) with RM for
43 months. The RM characteristics were analyzed in the elderly group (ERM) and
compared with those in the younger group (YRM). RESULTS: Fifty-six elderly
patients with RM (38 males and 18 females, with a mean age of 76.3 +/- 7.6 years;
range: 65-92 years) and 73 younger patients (57 males and 16 females, with a mean
age of 37.9 +/- 15.6 years; range: 13-63 years), made up the 129 patients in the
study. The most common cause for RM in the ERM was muscle compression due to
immobilization and the multicausative group, both with 9 (16%) cases, followed by
respiratory infection with 8 (14.2%) cases. In the YRM, the most common cause was
physical exertion with 15 patients (20.5%) and multicausative with 18 patients
(24.6%). Myalgia predominated in the YRM group, with 25 vs. 9 (odds ratio [OR]:
2.7; 95% confidence interval [CI]: 1.0-7.3; p < 0.05). Acute renal failure (ARF)
occurred in 13 patients in the ERM group compared with 4 in the YRM group (OR:
5.2; 95% CI: 1.4-23; p < 0.01). In the logistic regression analysis an
association was found between hypoalbuminemia and ARF for the ERM group. In the
presence of ARF, both ERM and YRM had decreased serum calcium levels, deeper in
YRM and more prolonged in the ERM. Six patients in the ERM died, and four of them
had developed ARF. In contrast, none of the two deceased patients in the YRM had
the complication of ARF. CONCLUSION: Almost half of cases of RM occur in elderly
patients, which is mostly due to muscle compression and infections, particularly
in the respiratory tract. Symptoms are usually mild and the development of ARF is
more common than in younger patients, and its presence is associated with
hypoalbuminemia. Hypocalcemia associated with ARF was less deep in the elderly,
but more persistent than in younger patients. Most deceased patients in the
elderly group previously developed ARF.
PMID- 9547194
TI - [Treatment of Hodgkin's disease with bulky mediastinal involvement. Study of 28
cases].
AB - BACKGROUND: Bulky mediastinal involvement in Hodgkin disease (HD) is usually
considered an adverse prognostic factor. Patients treated with radiotherapy alone
(RT) or chemotherapy alone (CT) have a high relapse rate. The combined
chemotherapy plus radiotherapy is the therapy of choice. The objective of the
present study was to report our results and complications in the treatment of 28
patients with HD with bulky mediastinal involvement. MATERIALS AND METHODS: A
retrospective analysis was made of a series of 28 patients with bulky mediastinal
disease treated in our hospital from 1973-1993, with RT, CT or combined therapy.
The overall survival rate and free of disease, the presence of residual mass, as
well as therapy toxicity were studied. RESULTS: The overall remission rate was
85.7%. The overall survival rates and free of disease were 76% and 78% at 19
years. Five patients died due to progression of disease, and one due to pulmonary
toxicity. Neither heart disease nor secondary neoplasms were documented.
CONCLUSION: Our results, in agreement with those reported in literature, support
the combined therapy, chemotherapy plus radiotherapy, as the therapy of choice
for patients with HD and bulky mediastinal involvement.
PMID- 9547195
TI - [Circadian rhythm and lacunar syndromes].
AB - BACKGROUND: There is scarce knowledge on the mode of onset of disease related to
circadian rhythm in lacunar syndromes. METHODS: A prospective clinical analysis
was conducted in 181 patients with lacunar infarcts (LI) and 47 patients with
lacunar syndromes not due to lacunar infarcts. In every patient the onset of the
disease was recorded for each of the four 6-hour equal periods of the day. The
injure volume of the LI was measured by means of a computer and image analyzer. A
descriptive analysis of the hour of onset of the disease and a comparative
analysis of clinical differences and injure size for each day period, relating to
circadian rhythm were made. RESULTS: For LI, the onset occurred during nocturnal
sleep in 32.5% and during wakening hours in 67.5%. The morning onset of the
disease was significantly more frequent in lacunar syndromes by cerebral
hemorrhage (55.5%) than in LI (24.5%) (p < 0.001). For LI, the mean injure volume
was significantly larger when associated with a morning onset (2,574 mm3), during
the afternoon (1,678 mm3) or during the night (1,328 mm3) (p < 0.04). At
discharge, no significant differences were documented between hospital stay
length and also between functional disability, when compared with disease onset
and circadian rhythm. CONCLUSIONS: A third of patients with LI had their onset of
symptoms during nocturnal sleep. The morning onset of the disease regarding
circadian rhythm in LI is associated with a larger injure volume.
PMID- 9547196
TI - [Maternal mortality in Spain, 1980-1992. Relationship with birth distributions
according to the mother's age].
AB - The maternal mortality evolution in Spain during the 1980-1992 period is
reported. The influence of birth distribution according to maternal age is
analyzed. The information was gathered from vital statistics published by
Instituto Nacional de Estadistica. The mortality rates have stabilized since 1985
(4.8 per 10(5) for 1992) associated with the increase in the proportion of births
in women aged > or = 30 years (40.6% for 1992). Birth distributions according to
maternal age account for 13.1% of the deaths observed. The predictions point to
an increase in maternal mortality for the year 2000.
PMID- 9547197
TI - [Back pain, intervertebral calcifications, and pubic osteitis].
PMID- 9547198
TI - [Tumor in the left iliac fossa].
PMID- 9547199
TI - [Obstructive pneumonia in a former smoker].
PMID- 9547200
TI - [Assessment of operativity in bronchogenic carcinoma surgery].
PMID- 9547202
TI - [Size decrease as a factor associated with reduction of sensitivity to insulin in
normoglycemic progeny of patients with non-insulin dependent diabetes mellitus].
PMID- 9547201
TI - [Indications for combined treatment in Hodgkin's disease. Review of the
literature].
PMID- 9547203
TI - [Bilateral myelomatous pleural effusion].
PMID- 9547204
TI - [Treatment of erythromelalgia with buprenorphine].
PMID- 9547205
TI - [Hypopotassemia caused by cloxacillin: a new case].
PMID- 9547206
TI - [Bronchial stenosis secondary to aspiration of a ferrous sulfate tablet].
PMID- 9547207
TI - [Jan Bedrna. 16 August 1897, Cesky Brod--25 August 1956, Podebrady].
PMID- 9547208
TI - [P. K. Anokhin: his physiological, general biological and philosophical ideas (on
the centenary of his birth)].
PMID- 9547209
TI - [An epidemic outbreak of an acute intestinal infection in a children's center].
PMID- 9547210
TI - [The centenary anniversary of the Merieux Institute].
PMID- 9547212
TI - [Psychiatric disorders and cognitive deterioration in Friedreich ataxia].
AB - The present study was designed with the aim of examining the presence of
psychiatric diagnosis and intellectual impairment in a sample of patients with
Friedreich's ataxia. A consecutive sample of 21 patients presenting with
Friedreich's Ataxia were evaluated by means of a neuropsychiatric interview. Only
one patient was diagnosed as mentally retarded. Out of the 15 patients of the
sample who were evaluated with be WAIS, all of them fell within a normal
intellectual range. The idea that Friedreich's Ataxia produces cognitive
impairment and serious psychiatric symptoms came from the earliest descriptions
of the disease at the beginning of this century, which probably included many
patients in their samples who had other diseases.
PMID- 9547211
TI - ["Nervous breakdown": a diagnostic characterization study].
AB - An evaluation was made of the influence of different psychiatric co-morbidities
on the symptoms of the disorder popularly known as "ataque de nervios" (nervous
breakdown) among the US Hispanic population. Using a self-completed instrument
designed specially for both traditional nervous breakdown and for panic symptoms,
and structured or semi-structured psychiatric interviews for Axis I disorders,
and evaluation was made of Hispanic subjects who sought treatment for anxiety in
a clinic (n = 156). This study centered on 102 subjects who presented symptoms of
"nervous breakdown" and comorbidity with panic disorder, other anxiety disorders,
or affective disorder. Variations in co-morbidity with "nervous breakdown"
enabled the identification of different patterns of "nervous breakdown"
presenting symptoms. Individuals with "nervous breakdown" and panic disorder
characteristically expressed a greater sense of asphyxiation, fear of dying, and
growing fear (panic-like) during their breakdowns. Subjects with "nervous
breakdown" and affective disorder had a greater sensation of anger and more
tendency toward screaming and aggressive behavior such as breaking things during
the breakdown (emotional anger). Finally, subjects with "nervous breakdown" and
co-morbidity with another anxiety disorder had fewer "paniclike" or "emotional
anger" symptoms. These findings suggest that: a) the widely used term "nervous
breakdown" is a popular label for different patterns of loss of emotional
control; b) the type of loss of emotional control is influenced by the associated
psychiatric disorder; and c) the symptoms characteristics of the "nervous
breakdown" can be useful clinical markers for associated psychiatric disorders.
Future research is needed to determine whether the known Hispanic entity "ataque
de nervios" is simply a popular description for different aspects of well-known
psychiatric disorders, or if it reflects specific demographic, environmental,
personality and/or clinical characteristics of the population.
PMID- 9547213
TI - [Positive and negative symptoms in schizophrenia: standards of change during
acute exacerbation].
AB - INTRODUCTION AND OBJECTIVES: The temporal stability of the positive and negative
symptoms in schizophrenia deserves a special interest due to its consequences in
the outcome and the treatment of the disease. This study determines the temporal
stability of positive/negative subtypes in schizophrenia during the acute phase.
MATERIAL AND METHODS: This is a clinical, observational and prospective study of
a dynamic cohort of patients with acute exacerbation of schizophrenia defined by
DSM III-R criteria. Patients with severe and unstable organic pathology,
substance dependence, mental organic disorder, mental retardation, depression, or
medicamentous parkinsonism were excluded. Clinical assessment was performed with
the PANSS scale. Schizophrenic subtypes were established according to inclusive
and restrictive criteria of PANSS. All patients were treated with new
antipsycotics and biperiden if necessary. RESULTS: 51 patients were assessed for
8 weeks. In the baseline, the negative subtype (63.3% and 52.5% by inclusive and
restrictive system respectively) and paranoid form (45.1%) were predominant.
Three types of analysis were performed to determine the temporal stability: 1.
Concordance (Kappa index). The concordance of the inclusive and restrictive
System, regarding to the baseline assessment, indicated that both criteria had a
low temporal stability. 2. Mc Nemar Ji Square. This test showed that these
changes were bi-directional except for the first visit, which was significant
through the restrictive system (higher change from the negative to other
subtypes). 3. Transition analysis among groups by First Order Morkov Chains
analysis indicated that this change was stationary (the change was the same in
all phases). CONCLUSIONS: 1o The variable "time" has to be considered for the
definition of subtypes in schizophrenia. 2o The restrictive system is more
specific. It allows to identify a subgroup of patients with "Negative"
schizophrenia with a high specificity and validity in clinical and
epidemiological studies. 3o The use of the baseline visit as a reference (gold
standard) is recommended because it exits a higher concordance among criteria and
a more florid psychopathology.
PMID- 9547214
TI - [Neuropsychological deficits, obstetric complications and premorbid adjustment in
patients with the first psychotic episode].
AB - In spite of the great number of studies that have proved the existence of
cognitive disturbances in schizophrenic subjects, conflicting results have not
allowed to glimpse a typical pattern of neuropsychological deficits in
schizophrenia. On the contrary, these results have raised important controversies
regarding the nature of such cognitive impairment. Thus, questions concerning the
existence of generalized versus focal cognitive impairment or in relation lo the
static versus progressive nature of these deficits remain unresolved. In the
middle of these debates, the need for prospective research, which focuses on the
neuropsychological deficits of schizophrenia and other psychotic disorders from
the beginning of the illness, has been pointed out. In these lines we present the
results obtained in our study in which 59 subjects, who were admitted in our
hospital for presenting a first psychotic episode, were assessed. Measures of
premorbid adjustment, obstetric complications and clinical symptoms were taken
and correlated to measures of cognitive performance obtained by using a
minibattery of neuropsychological tests at time of dismissal. Results showed, as
in previous research, that neuropsychological deficits are already present in
psychotic patients at the beginning of the illness. These deficits in our sample
were related lo obstetric complications especially in males, and disturbances of
premorbid adjustment occurred in early stages of development. These results
support the neurodevelopmental hypothesis of schizophrenia.
PMID- 9547215
TI - [Descriptive epidemiology of suicide in Spain (1906-1990)].
AB - INTRODUCTION: In Spain, suicide as a cause of death is increasing in different
age groups in both sexes. The aim of the present work is to characterize the
phenomenon of suicide. MATERIALS AND METHODS: A retrospective descriptive
epidemiological study was carried out. Data periodically published by the
National Institute of Statistics (INE) on the statistical Incidence of Suicides
in Spain (1906-1990) were analyzed, processed and tabulated. RESULTS: Suicide
increases with age and this increase is more pronounced as from 40 years of age.
The ratio between sexes is 3:1 in favour of men, although with a tendency to
decrease. The most important causes of suicide are: physical suffering (27%),
psychopathy (18%) and Daily Activities (DA) (17.5%). The method most used is
hanging, which has been the case of 37% of the suicides committed in Spain during
the study period (1906-1990). CONCLUSIONS: The risk factors associated with
suicide are age, male sex, and physical and mental suffering.
PMID- 9547217
TI - Errata: Analysis of semen constantly changing social context of medicine.
PMID- 9547216
TI - [Delirium in delusions of negations of Cotard: syndrome versus disorder].
AB - This article constitutes the first of a series directed to review fundamental
disorders in clinical psychogeriatrics. This sort of publication is intended to
retrieve clinical practice as the cornerstone for research and teaching in
psychiatry. Besides, and particularly in geriatry, we try to expand the strategy
of liaison work with primary physicians. In this case, a nosological review of
the so called "delusion of negations" is presented. The Jules Cotard's original
concept of subtype of delusional melancholia is contrasted to the view of
numerous authors in this century who have described it as a form of non-specific
delusional syndrome.
PMID- 9547218
TI - In vitro and in vivo regulation of assimilatory nitrite reductase from Candida
utilis.
PMID- 9547219
TI - The experience of schizophrenia.
PMID- 9547220
TI - Disruption of mitochondrial respiration inhibits volume-regulated anion channels
and provokes neuronal cell swelling.
AB - Hypoxia and inhibitors of mitochondrial respiration impair the regulatory volume
decrease (RVD) of cerebellar granule neurons after hypotonic swelling. RVD is
linked to the opening of volume-regulated anion channels (VRACs). VRACs are
outwardly rectifying, inactivate slowly during maintained depolarization, and are
permeable to the cellular organic osmolyte taurine. Channel activation requires
nonhydrolytic ATP binding and is not modulated by intracellular ADP. VRAC opening
is reversibly depressed by hypoxia and by mitochondrial inhibitors such as
oligomycin, rotenone, and antimycin A. These results demonstrate that neuronal
VRAC activation and swelling are both tightly linked to cellular energy.
Moreover, the findings reported in this work may have a particular significance
for inherited mitochondrial human diseases, such as mitochondrial myopathy,
encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), which cause
brain swelling and edema.
PMID- 9547221
TI - Somatodendritic depolarization-activated potassium currents in rat neostriatal
cholinergic interneurons are predominantly of the A type and attributable to
coexpression of Kv4.2 and Kv4.1 subunits.
AB - Unlike other neostriatal neurons, cholinergic interneurons exhibit spontaneous,
low-frequency, repetitive firing. To gain an understanding of the K+ channels
regulating this behavior, acutely isolated adult rat cholinergic interneurons
were studied using whole-cell voltage-clamp and single-cell reverse transcription
PCR techniques. Cholinergic interneurons were identified by the presence of
choline acetyltransferase (ChAT) mRNA. Depolarization-activated potassium
currents in cholinergic interneurons were dominated by a rapidly inactivating, K+
selective A current that became active at subthreshold potentials. Depolarizing
prepulses inactivated this component of the current, leaving a delayed, rectifier
like current. Micromolar concentrations of Cd2+ dramatically shifted the voltage
dependence of the A current without significantly affecting the delayed
rectifier. The A-channel antagonist 4-aminopyridine (4-AP) produced a voltage
dependent block (IC50, approximately 1 mM) with a prominent crossover at
millimolar concentrations. On the other hand, TEA preferentially blocked the
sustained current component at concentrations <10 mM. Single-cell mRNA profiling
of subunits known to give rise to rapidly inactivating K+ currents revealed the
coexpression of Kv4.1, Kv4.2, and Kv1.4 mRNAs but low or undetectable levels of
Kv4.3 and Kv3.4 mRNAs. Kv1.1, beta1, and beta2 subunit mRNAs, but not beta3, were
also commonly detected. The inactivation recovery kinetics of the A-type current
were found to match those of Kv4.2 and 4.1 channels and not those of Kv1.4 or
Kv1. 1 and beta1 channels. Immunocytochemical analysis confirmed the presence of
Kv4.2 but not Kv1.4 subunits in the somatodendritic membrane of ChAT
immunoreactive neurons. These results argue that the depolarization-activated
somatodendritic K+ currents in cholinergic interneurons are dominated by Kv4.2-
and Kv4. 1-containing channels. The properties of these channels are consistent
with their playing a prominent role in governing the slow, repetitive discharge
of interneurons seen in vivo.
PMID- 9547222
TI - G-Protein-coupled modulation of presynaptic calcium currents and transmitter
release by a GABAB receptor.
AB - Presynaptic GABAB receptors play a regulatory role in central synaptic
transmission. To elucidate their underlying mechanism of action, we have made
whole-cell recordings of calcium and potassium currents from a giant presynaptic
terminal, the calyx of Held, and EPSCs from its postsynaptic target in the medial
nucleus of the trapezoid body of rat brainstem slices. The GABAB receptor agonist
baclofen suppressed EPSCs and presynaptic calcium currents but had no effect on
voltage-dependent potassium currents. The calcium current-EPSC relationship
measured during baclofen application was similar to that observed on reducing
[Ca2+]o, suggesting that the presynaptic inhibition generated by baclofen is
caused largely by the suppression of presynaptic calcium influx. Presynaptic
loading of the GDP analog guanosine-5'-O-(2-thiodiphosphate) (GDPbetaS) abolished
the effect of baclofen on both presynaptic calcium currents and EPSCs. The
nonhydrolyzable GTP analog guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS)
suppressed presynaptic calcium currents and occluded the effect of baclofen on
presynaptic calcium currents and EPSCs. Photoactivation of GTPgammaS induced an
inward rectifying potassium current at the calyx of Held, whereas baclofen had no
such effect. We conclude that presynaptic GABAB receptors suppress transmitter
release through G-protein-coupled inhibition of calcium currents.
PMID- 9547223
TI - Calcium-dependent regulation of rab3 in short-term plasticity.
AB - The Rab3 proteins are monomeric GTP-binding proteins associated with secretory
vesicles. In their active GTP-bound state, Rab3 proteins are involved in the
regulation of hormone secretion and neurotransmitter release. This action is
thought to involve specific effectors, including two Ca2+-binding proteins,
Rabphilin and Rim. Rab3 acts late in the exocytotic process, in a cell domain in
which the intracellular Ca2+ concentration is susceptible to rapid changes.
Therefore, we examined the possible Ca2+-dependency of the regulatory action of
GTP-bound Rab3 and wild-type Rab3 on neuroexocytosis at identified cholinergic
synapses in Aplysia californica. The effects of recombinant GTPase-deficient
Aplysia-Rab3 (apRab3-Q80L) or wild-type apRab3 were studied on evoked
acetylcholine release. Intraneuronal application of apRab3-Q80L in identified
neurons of the buccal ganglion of Aplysia led to inhibition of neurotransmission;
wild-type apRab3 was less effective. Intracellular chelation of Ca2+ ions by EGTA
greatly potentiated the inhibitory action of apRab3-Q80L. Train and paired-pulse
facilitation, two Ca2+-dependent forms of short-term plasticity induced by a rise
in intraterminal Ca2+ concentration, were increased after injection of apRab3
Q80L. This result suggests that the inhibition exerted by GTP-bound Rab3 on
neuroexocytosis is reduced during transient augmentations of intracellular Ca2+
concentration. Therefore, a Ca2+-dependent modulation of GTP-bound Rab3 function
may contribute to short-term plasticity.
PMID- 9547224
TI - Extrasynaptic glutamate diffusion in the hippocampus: ultrastructural
constraints, uptake, and receptor activation.
AB - Fast excitatory synapses are generally thought to act as private communication
channels between presynaptic and postsynaptic neurons. Some recent findings,
however, suggest that glutamate may diffuse out of the synaptic cleft and bind to
several subtypes of receptors, either in the perisynaptic membrane or at
neighboring synapses. It is not known whether activation of these receptors can
occur in response to the release of a single vesicle of glutamate. Here we
estimate the spatiotemporal profile of glutamate in the extrasynaptic space after
vesicle exocytosis, guided by detailed ultrastructural measurements of the CA1
neuropil in the adult rat. We argue that the vicinity of the synapse can be
treated as an isotropic porous medium, in which diffusion is determined by the
extracellular volume fraction and the tortuosity factor, and develop novel
stereological methods to estimate these parameters. We also estimate the spatial
separation between synapses, to ask whether glutamate released at one synapse can
activate NMDA and other high-affinity receptors at a neighboring synapse. Kinetic
simulations of extrasynaptic glutamate uptake show that transporters rapidly
reduce the free concentration of transmitter. Exocytosis of a single vesicle is,
however, sufficient to bind to high-affinity receptors situated in the immediate
perisynaptic space. The distance separating a typical synapse from its nearest
neighbor is approximately 465 nm. Whether glutamate can reach a sufficient
concentration to activate NMDA receptors at this distance depends critically on
the diffusion coefficient in the extracellular space. If diffusion is much slower
than in free aqueous solution, NMDA receptors could mediate crosstalk between
neighboring synapses.
PMID- 9547225
TI - Reversal of age-related alterations in synaptic plasticity by blockade of L-type
Ca2+ channels.
AB - The role of L-type Ca2+ channels in the induction of synaptic plasticity in
hippocampal slices of aged (22-24 months) and young adult (4-6 months) male
Fischer 344 rats was investigated. Prolonged 1 Hz stimulation (900 pulses) of
Schaffer collaterals, which normally depresses CA3/CA1 synaptic strength in aged
rat slices, failed to induce long-term depression (LTD) during bath application
of the L-channel antagonist nifedipine (10 microM). When 5 Hz stimulation (900
pulses) was used to modify synaptic strength, nifedipine facilitated synaptic
enhancement in slices from aged, but not young, adult rats. This enhancement was
pathway-specific, reversible, and impaired by the NMDA receptor (NMDAR)
antagonist DL-2-amino-5-phosphonopentanoic acid (AP5). Induction of long-term
potentiation (LTP) in aged rats, using 100 Hz stimulation, occluded subsequent
synaptic enhancement by 5 Hz stimulation, suggesting that nifedipine-facilitated
enhancement shares mechanisms in common with conventional LTP. Facilitation of
synaptic enhancement by nifedipine likely was attributable to a reduction (
approximately 30%) in the Ca2+-dependent K+-mediated afterhyperpolarization
(AHP), because the K+ channel blocker apamin (1 microM) similarly reduced the AHP
and promoted synaptic enhancement by 5 Hz stimulation. In contrast, apamin did
not block LTD induction using 1 Hz stimulation, suggesting that, in aged rats,
the AHP does not influence LTD and LTP induction in a similar way. The results
indicate that, during aging, L-channels can (1) facilitate LTD induction during
low rates of synaptic activity and (2) impair LTP induction during higher levels
of synaptic activation via an increase in the Ca2+-dependent AHP.
PMID- 9547226
TI - Increased synaptic sprouting in response to estrogen via an apolipoprotein E
dependent mechanism: implications for Alzheimer's disease.
AB - Estrogen replacement therapy appears to delay the onset of Alzheimer's disease
(AD), but the mechanisms for this action are incompletely known. We show how the
enhancement of synaptic sprouting by estradiol (E2) in response to an entorhinal
cortex (EC) lesion model of AD may operate via an apolipoprotein E (apoE)
dependent mechanism. In wild-type (WT) mice, ovariectomy decreased
commissural/associational sprouting to the inner molecular layer of the dentate
gyrus, with synaptophysin (SYN) as a marker. E2 replacement returned SYN in the
inner layer to levels of EC-lesioned, ovary-bearing controls and increased the
area of compensatory synaptogenesis in the outer molecular layer. In EC-lesioned
apoE-knock-out (KO) mice, however, E2 did not enhance sprouting. We also examined
apoJ (clusterin) mRNA, which is implicated in AD by its presence in senile
plaques, its transport of Abeta across the blood-brain barrier, and its induction
by neurodegenerative lesioning. ApoJ mRNA levels were increased by E2 replacement
in EC-lesioned WT mice but not in apoE-KO mice. These data suggest a mechanism
for the protective effects of estrogens on AD and provide a link between two
important risk factors in the etiology of AD, the apoE epsilon4 genotype and an
estrogen-deficient state. This is also the first evidence that SYN, a presynaptic
protein involved in neurotransmitter release, is regulated by E2 in the adult
brain, and that apoE is necessary for the induction of apoJ mRNA by E2 in brain
injury.
PMID- 9547227
TI - Type I adenylyl cyclase mutant mice have impaired mossy fiber long-term
potentiation.
AB - Long-term potentiation (LTP) at the mossy fiber-->CA3 pyramidal cell synapse in
the hippocampus is an NMDA-independent form of LTP that requires cAMP-dependent
protein kinase (PKA) activity and can be induced by forskolin, a general
activator of adenylyl cyclases. Presynaptic Ca2+ influx and elevated cAMP may be
obligatory for mossy fiber LTP. Because the Ca2+-stimulated type 1 adenylyl
cyclase (AC1) is expressed in the dentate gyrus and CA3 pyramidal cells, it is
hypothesized that AC1 may be critical for mossy fiber LTP. To test this
hypothesis, we examined several forms of hippocampal LTP in wild-type and AC1
mutant mice. Wild-type and AC1 mutant mice exhibited comparable perforant path
LTP recorded in the dentate gyrus as well as decremental LTP at the Schaffer
collateral-->CA1 pyramidal cell synapse. Although the mutant mice exhibited
normal paired pulse facilitation, mossy fiber LTP was impaired significantly in
AC1 mutants. High concentrations of forskolin induced mossy fiber LTP to
comparable levels in wild-type and AC1 mutant mice, indicating that signaling
components downstream from the adenylyl cyclase, including PKA, ion channels, and
secretory machinery, were not affected by disruption of the AC1 gene. These data
indicate that coupling of Ca2+ to activation of AC1 is crucial for mossy fiber
LTP, most likely via activation of PKA and enhancement of excitatory amino acid
secretion.
PMID- 9547228
TI - Calcium-sensitive particulate guanylyl cyclase as a modulator of cAMP in
olfactory receptor neurons.
AB - The second messengers cAMP and inositol-1,4,5-triphosphate have been implicated
in olfaction in various species. The odorant-induced cGMP response was
investigated using cilia preparations and olfactory primary cultures. Odorants
cause a delayed and sustained elevation of cGMP. A component of this cGMP
response is attributable to the activation of one of two kinetically distinct
cilial receptor guanylyl cyclases by calcium and a guanylyl cyclase-activating
protein (GCAP). cGMP thus formed serves to augment the cAMP signal in a cGMP
dependent protein kinase (PKG) manner by direct activation of adenylate cyclase.
cAMP, in turn, activates cAMP-dependent protein kinase (PKA) to negatively
regulate guanylyl cyclase, limiting the cGMP signal. These data demonstrate the
existence of a regulatory loop in which cGMP can augment a cAMP signal, and in
turn cAMP negatively regulates cGMP production via PKA. Thus, a small, localized,
odorant-induced cAMP response may be amplified to modulate downstream
transduction enzymes or transcriptional events.
PMID- 9547229
TI - Experience-induced neurogenesis in the senescent dentate gyrus.
AB - We demonstrate here that under physiological conditions neurogenesis continues to
occur in the dentate gyrus of senescent mice and can be stimulated by living in
an enriched environment. Neurogenesis was investigated by confocal microscopy of
three-channel immunofluorescent staining for the proliferation marker
bromodeoxyuridine (BrdU) and neuronal and glial markers. Quantification was
performed with unbiased stereological counting techniques. Neurogenesis decreased
with increasing age. Stimulation of adult and aged mice by switching from
standard housing to an enriched environment with opportunities for social
interaction, exploration, and physical activity for 68 d resulted in an increased
survival of labeled cells. Phenotypic analysis revealed that, in enriched living
animals, relatively more cells differentiated into neurons, resulting in a
threefold net increase of BrdU-labeled neurons in 20-month-old mice (105 vs 32
cells) and a more than twofold increase in 8-month-old mice (684 vs 285 cells)
compared with littermates living under standard laboratory conditions.
Corresponding absolute numbers of BrdU-positive astrocytes and BrdU-positive
cells that did not show colabeling for neuronal or glial markers were not
influenced. The effect on the relative distribution of phenotypes can be
interpreted as a survival-promoting effect that is selective for neurons.
Proliferation of progenitor cells appeared unaffected by environmental
stimulation.
PMID- 9547230
TI - Stable complexes involving acetylcholinesterase and amyloid-beta peptide change
the biochemical properties of the enzyme and increase the neurotoxicity of
Alzheimer's fibrils.
AB - Brain acetylcholinesterase (AChE) forms stable complexes with amyloid-beta
peptide (Abeta) during its assembly into filaments, in agreement with its
colocalization with the Abeta deposits of Alzheimer's brain. The association of
the enzyme with nascent Abeta aggregates occurs as early as after 30 min of
incubation. Analysis of the catalytic activity of the AChE incorporated into
these complexes shows an anomalous behavior reminiscent of the AChE associated
with senile plaques, which includes a resistance to low pH, high substrate
concentrations, and lower sensitivity to AChE inhibitors. Furthermore, the
toxicity of the AChE-amyloid complexes is higher than that of the Abeta
aggregates alone. Thus, in addition to its possible role as a heterogeneous
nucleator during amyloid formation, AChE, by forming such stable complexes, may
increase the neurotoxicity of Abeta fibrils and thus may determine the selective
neuronal loss observed in Alzheimer's brain.
PMID- 9547231
TI - High constitutive NF-kappaB activity mediates resistance to oxidative stress in
neuronal cells.
AB - Selected clones of the sympathetic precursor-like cell line PC12 (rCl8) are
resistant to oxidative cell death induced by the Alzheimer's disease-associated
amyloid beta protein (Abeta) and hydrogen peroxide (H2O2). Here, we show that the
transcriptional activity and DNA binding activity of the redox-sensitive
transcription factor NF-kappaB and its nuclear expression are constitutively
increased in rCl8 cells compared with their nonresistant parental PC12 cell
(PC12p) counterpart. Suppression of the transcriptional activity of NF-kappaB in
rCl8 cells with the synthetic glucocorticoid dexamethasone or by direct
overexpression of a super-repressor mutant form of IkappaBalpha, a specific
inhibitor of NF-kappaB, reversed the oxidative stress resistance phenotype of
these cells and ultimately led to increased cell death after the challenge with
H2O2. Dexamethasone treatment also caused an increase in the protein level of
IkappaBalpha. Our data show that an increased baseline of NF-kappaB activity may
mediate the resistance of these cells of neuronal origin to oxidative stress.
Therefore, the presented model may help to identify possible neuronal target
genes of NF-kappaB and to further elucidate the molecular basis of the
differential sensitivity of neurons in neurodegenerative conditions associated
with an increased oxidative burden, such as in Alzheimer's disease.
PMID- 9547232
TI - Attenuated influx of calcium ions at nerve endings of csp and shibire mutant
Drosophila.
AB - Previous work has shown that cysteine-string proteins (csps) are synaptic vesicle
proteins that are important for evoked neurotransmitter release at Drosophila
neuromuscular junctions. Indirect evidence has implicated csps in a regulatory
link between synaptic vesicles and presynaptic calcium (Ca) channels. In this
report, we use Ca Crimson to monitor stimulus-dependent changes of cytosolic Ca
at motor nerve terminals of csp mutant Drosophila. These mutants display
temperature-sensitive (TS) paralysis and a presynaptic failure of evoked synaptic
transmission. We show that this TS inhibition of neuromuscular transmission is
correlated with a block of Ca ion entry at nerve endings of csp mutants. These
data support the hypothesis that csps mediate a regulatory interaction between
synaptic vesicles and presynaptic Ca channels. Moreover, these results predict
that if one depletes nerve endings of synaptic vesicles, one may see a reduction
of presynaptic Ca ion entry. Defects of the dynamin gene in TS shibire mutant
Drosophila interfere with synaptic vesicle recycling and lead to an activity
dependent depletion of these organelles. Our results show that Ca influx is
blocked at nerve terminals of shibire mutant larvae at the same time that
synaptic transmission fails in these organisms. Thus, using two completely
independent Drosophila mutants, we demonstrate that synaptic vesicles and csps
are vital for the function of presynaptic Ca channels.
PMID- 9547233
TI - Massive mitochondrial degeneration in motor neurons triggers the onset of
amyotrophic lateral sclerosis in mice expressing a mutant SOD1.
AB - Amyotrophic lateral sclerosis (ALS) involves motor neuron degeneration, skeletal
muscle atrophy, paralysis, and death. Mutations in Cu,Zn superoxide dismutase
(SOD1) are one cause of the disease. Mice transgenic for mutated SOD1 develop
symptoms and pathology similar to those in human ALS. To understand the disease
mechanism, we developed a simple behavioral assay for disease progression in
mice. Using this assay, we defined four stages of the disease in mice expressing
G93A mutant SOD1. By studying mice with defined disease stages, we tied several
pathological features into a coherent sequence of events leading to motor neuron
death. We show that onset of the disease involves a sharp decline of muscle
strength and a transient explosive increase in vacuoles derived from degenerating
mitochondria, but little motor neuron death. Most motor neurons do not die until
the terminal stage, approximately 9 weeks after disease onset. These results
indicate that mutant SOD1 toxicity is mediated by damage to mitochondria in motor
neurons, and this damage triggers the functional decline of motor neurons and the
clinical onset of ALS. The absence of massive motor neuron death at the early
stages of the disease indicates that the majority of motor neurons could be
rescued after clinical diagnosis.
PMID- 9547234
TI - Traumatic spinal cord injury induces nuclear factor-kappaB activation.
AB - Inflammatory responses are a major component of secondary injury and play a
central role in mediating the pathogenesis of acute and chronic spinal cord
injury (SCI). The nuclear factor-kappaB (NF-kappaB) family of transcription
factors is required for the transcriptional activation of a variety of genes
regulating inflammatory, proliferative, and cell death responses of cells. In
this study we examined the temporal and cellular expression of activated NF
kappaB after traumatic SCI. We used a contusion model (N.Y.U. Impactor) to
initiate the early biochemical and molecular changes that occur after traumatic
injury to reproduce the pathological events associated with acute inflammation
after SCI. The activation and cellular distribution of activated NF-kappaB was
evaluated by using a monoclonal antibody that selectively recognizes activated
p65 in a NF-kappaB dimer. Immunohistochemical and Western blot analyses
demonstrated that NF-kappaB activation occurred as early as 0.5 hr postinjury and
persisted for at least 72 hr. Using electrophoretic mobility shift assays (EMSA),
we demonstrate that NF-kappaB is activated after SCI. In our immunohistochemical,
Western, and EMSA experiments there are detectable levels of activated NF-kappaB
in our control animals. Using double-staining protocols, we detected activated NF
kappaB in macrophages/microglia, endothelial cells, and neurons within the
injured spinal cord. Colocalization of activated NF-kappaB with the NF-kappaB
dependent gene product, inducible nitric oxide synthase (iNOS), suggests
functional implications for this transcription factor in the pathogenesis of
acute spinal cord injury. Although there is considerable evidence for the
involvement of an inflammatory reaction after traumatic SCI, this is the first
evidence for the activation of NF-kappaB after trauma. Strategies directed at
blocking the initiation of this cascade may prove beneficial as a therapeutic
approach for the treatment of acute SCI.
PMID- 9547235
TI - Glial fibrillary acidic protein-apolipoprotein E (apoE) transgenic mice:
astrocyte-specific expression and differing biological effects of astrocyte
secreted apoE3 and apoE4 lipoproteins.
AB - The epsilon4 allele of apolipoprotein E (apoE) is associated with increased risk
for Alzheimer's disease (AD) and poor outcome after brain injury. In the CNS,
apoE is expressed by glia, predominantly astrocytes. To define the potential
biological functions of different human apoE isoforms produced within the brain,
transgenic mice were generated in which human apoE3 and apoE4 expression is under
control of the astrocyte-specific glial fibrillary acidic protein (GFAP)
promoter. These animals were then bred back to apoE knock-out mice. Human apoE
protein is found within astrocytes and the neuropil throughout development and
into the adult period, as assessed by immunocytochemistry and immunoblot analysis
in several GFAP-apoE3 and E4 lines. Cultured astrocytes from these mice secrete
apoE3 and apoE4 in lipoproteins that are high-density lipoprotein-like in size.
When primary hippocampal neurons are grown in the presence of astrocyte
monolayers derived from these transgenic mice, there is significantly greater
neurite outgrowth from neurons grown in the presence of apoE3-secreting
astrocytes compared with apoE4-secreting or apoE knock-out astrocytes. These
effects are not dependent on direct astrocyte-neuron contact and appear to
require the low-density lipoprotein receptor-related protein. These data suggest
that astrocyte-secreted, apoE3-containing lipoproteins have different biological
effects than apoE4-containing lipoproteins. In addition to providing information
regarding the role of astrocyte-secreted apoE lipoproteins in the normal brain,
these animals will also be useful in models of both AD and CNS injury.
PMID- 9547236
TI - Competitive signaling between TrkA and p75 nerve growth factor receptors
determines cell survival.
AB - In addition to its role as a survival factor, nerve growth factor (NGF) has been
implicated in initiating apoptosis in restricted cell types both during
development and after terminal cell differentiation. NGF binds to the TrkA
tyrosine kinase and the p75 neurotrophin receptor, a member of the tumor necrosis
factor cytokine family. To understand the mechanisms underlying survival versus
death decisions, the TrkA receptor was introduced into oligodendrocyte cell
cultures that undergo apoptosis in a p75-dependent manner. Here we report that
activation of the TrkA NGF receptor in oligodendrocytes negates cell death by the
p75 receptor. TrkA-mediated rescue from apoptosis correlated with mitogen
activated protein kinase activation. Concurrently, activation of TrkA in
oligodendrocytes resulted in suppression of c-jun kinase activity initiated by
p75, whereas induction of NFkappaB activity by p75 was unaffected. These results
indicate that TrkA-mediated rescue involves not only activation of survival
signals but also simultaneous suppression of a death signal by p75. The selective
interplay between tyrosine kinase and cytokine receptors provides a novel
mechanism that achieves alternative cellular responses by merging signals from
different ligand-receptor systems.
PMID- 9547237
TI - Regeneration of cochlear efferent nerve terminals after gentamycin damage.
AB - Chickens recover auditory function after hair cell loss caused by ototoxic drug
damage or acoustic overstimulation, indicating that mechanisms exist to
reestablish appropriate neuronal connections to regenerated hair cells. However,
despite similar hair cell regeneration times, hearing recovery takes
substantially longer after aminoglycoside than after sound damage. We have
therefore begun examining damage and regeneration of efferent nerve terminals by
immunolabeling whole-mount cochleae for differentially localized synaptic
proteins and by visualizing the distribution of label with confocal microscopy.
In undamaged cochleae, the synaptic proteins synapsin and syntaxin show similar
distribution patterns corresponding to the large cup-like terminals on short hair
cells. After gentamycin administration, these terminals are disrupted as hair
cells are lost, leaving smaller, more numerous synapsin-reactive structures in
the sensory epithelium. Syntaxin reactivity remains associated with the extruded
hair cells, indicating that the presynaptic membrane is still attached to the
postsynaptic site. In contrast, after sound damage, both synapsin and syntaxin
reactivity are lost from the epithelium with extruded hair cells. As regenerated
hair cells differentiate after gentamycin treatment, the synapsin labeling
associated with cup-like efferent endings reappears but is not completely
restored even after 60 d of recovery. Thus, efferent terminals are reestablished
much more slowly than after sound damage (), consistent with the prolonged loss
of hearing function. This in vivo model system allows comparison of axonal
reconnection after either complete loss (sound damage) or partial disruption
(gentamycin treatment) of axon terminals. Elucidating the differences in recovery
between these injuries can provide insights into reinnervation mechanisms.
PMID- 9547238
TI - Selective fasciculation and divergent pathfinding decisions of embryonic chick
motor axons projecting to fast and slow muscle regions.
AB - Proper motor function requires the precise matching of motoneuron and muscle
fiber properties. The lack of distinguishing markers for early motoneurons has
made it difficult to determine whether this matching is established by selective
innervation during development or later via motoneuron-muscle fiber interactions.
To examine whether chick motoneurons selectively innervate regions of their
target containing either fast or slow muscle fibers, we backlabeled neurons from
each of these regions with lipophilic dyes. We found that motor axons projecting
to fast and slow muscle regions sorted into separate but adjacent fascicles
proximally in the limb, long before they reached the muscle. More distally, these
fascicles made divergent pathfinding decisions to course directly to the
appropriate muscle fiber region. In contrast, axons projecting to different areas
of an all-fast muscle did not fasciculate separately and became more intermingled
as they coursed through the limb. Selective fasciculation of fast- and slow
projecting motoneurons was similar both before and after motoneuron cell death,
suggesting that motoneurons specifically recognized and fasciculated with axons
growing to muscle regions containing the appropriate muscle fiber type. Taken
together, these results strongly support the hypothesis that "fast" and "slow"
motoneurons are molecularly distinct before target innervation and that they use
these differences to selectively fasciculate, pathfind to, and branch within the
correct muscle fiber region from the outset of neuromuscular development.
PMID- 9547239
TI - Development of bone morphogenetic protein receptors in the nervous system and
possible roles in regulating trkC expression.
AB - Characterization of bone morphogenetic protein receptor (BMPR) expression during
development is necessary for understanding the role of these factors during
neural maturation. In this study, in situ hybridization analyses demonstrate that
BMP-specific type I (BMPR-IA and BMPR-IB) and type II (BMPR-II) receptor mRNAs
are expressed at significant levels in multiple regions of the CNS, cranial
ganglia, and peripheral sensory and autonomic ganglia during the embryonic and
neonatal periods. All three BMP receptor subunits are expressed within
periventricular generative zones. BMPR-IA is more abundant than the other
receptor subtypes, with widespread expression in the brain, cranial ganglia, and
peripheral ganglia. By contrast, BMPR-IB mRNA displays significant expression
within more restricted regions, including the anterior olfactory nuclei. BMPR-II
mRNA exhibits peak expression within the cerebellar Purkinje cell layer and the
hippocampus, as well as within cranial ganglia. The distribution of BMP receptors
within large neurons in adult dorsal root ganglia suggested a possible role in
regulating expression of the neurotrophin receptor trkC. This hypothesis was
tested in explant cultures of embryonic day 15 (E15) and postnatal day 1 (P1)
sympathetic superior cervical ganglia (SCG). Treatment of the E15 or the P1 SCG
with BMP-2 induced expression of trkC mRNA and responsiveness of sympathetic
neurons to NT3 as measured by neurite outgrowth. The pattern of expression of BMP
receptors in embryonic brain suggests several potentially novel areas for further
developmental analysis and supports numerous recent studies that indicate that
BMPs have a broad range of cellular functions during neural development and in
adult life.
PMID- 9547240
TI - Development of the mouse inner ear and origin of its sensory organs.
AB - The molecular mechanisms dictating the morphogenesis and differentiation of the
mammalian inner ear are largely unknown. To better elucidate the normal
development of this organ, two approaches were taken. First, the membranous
labyrinths of mouse inner ears ranging from 10.25 to 17 d postcoitum (dpc) were
filled with paint to reveal their gross development. Particular attention was
focused on the developing utricle, saccule, and cochlea. Second, we used bone
morphogenetic protein 4 (BMP4) and lunatic fringe (Fng) as molecular markers to
identify the origin of the sensory structures. Our data showed that BMP4 was an
early marker for the superior, lateral, and posterior cristae, whereas Fng served
as an early marker for the macula utriculi, macula sacculi, and the sensory
portion of the cochlea. The posterior crista was the first organ to appear at
11.5 dpc and was followed by the superior crista, the lateral crista, and the
macula utriculi at 12 dpc. The macula sacculi and the cochlea were present at 12
dpc but became distinguishable from each other by 13 dpc. Based on the gene
expression patterns, the anterior and lateral cristae may share a common origin.
Similarly, three sensory organs, the macula utriculi, macula sacculi, and
cochlea, seem to arise from a single region of the otocyst.
PMID- 9547241
TI - Light-induced retinal degeneration suppresses developmental progression of flip
to-flop alternative splicing in GluR1.
AB - AMPA receptors are hetero-oligomers composed of subsets of four distinct
subunits, termed GluR1, GluR2, GluR3, and GluR4. Using quantitative reverse
transcription-PCR analysis, we have found that light-induced degeneration of rat
retina dramatically suppresses developmental progression of the flip-to-flop
alternative splicing switch of retinal GluR1 mRNA. When animals were raised under
standard conditions of a 12 hr light/dark cycle (LD 12:12), the flop-to-flip
ratio in GluR1 and GluR2 dramatically increased between postnatal day 10 (P10)
and P28, and the ratios continued to increase gradually up to P84. When animals
were raised in complete darkness, this increase was delayed in GluR1 between P21
and P42. In addition, the increase of the flop-to-flip ratio in GluR1 was
strongly suppressed after P21 under conditions of continuous illumination from
P2. This is significant because P21 is just after the eye opening and is the
timing of the onset of light-induced retinal degeneration. This suppression of
the increase of the flop-to-flip ratio was specific to GluR1 and was not observed
in GluR2-4. Immunocytochemistry and immunoblot analysis suggested no changes in
either the distribution or expression of GluR1 protein in the light-damaged
retina measured at P84. When rats were raised under continuous illumination from
P2 to P21 followed by LD 12:12 from P22 to P84, retinal degeneration did not
progress after P22. In such animals the flop-to-flip ratio, once decreased to
approximately 50% of the control (LD 12:12) at P21, was restored to the control
level at P84. These findings demonstrate that developmental progression of the
flip-to-flop exon switch in retinal GluR1 is affected by lighting conditions, and
that light-induced retinal degeneration contributes to the mechanism of
suppression of this splicing switch.
PMID- 9547242
TI - Bcl-2 accelerates the maturation of early sensory neurons.
AB - Bcl-2 is a cytoplasmic protein that blocks apoptosis in a wide variety of cell
types. Here we report a novel role for Bcl-2 in the early stages of neuronal
development. Shortly after differentiating from progenitor cells, sensory neurons
undergo a distinct morphological change; initially they have small, spindle
shaped, phase-dark cell bodies that become large, spherical, and phase-bright.
Early sensory neurons cultured from the trigeminal ganglia of bcl-2-/- embryos at
embryonic day 11 (E11) and E12 underwent this change more slowly than trigeminal
neurons of wild-type embryos of the same ages. The delay was not attributable to
the well documented role of Bcl-2 in preventing apoptosis, because Bcl-2
deficient early sensory neurons survived as well as wild-type neurons.
Accordingly, there was a significantly smaller number of the more mature type of
neuron in the early trigeminal ganglia of bcl-2-/- embryos, yet the number of
neurons in the trigeminal ganglia of bcl-2-/- and wild-type embryos was similar.
The absence of Bcl-2 did not cause a uniform delay in the developmental program
of sensory neurons, because the time course of nerve growth factor receptor
expression (both trkA and p75) was unaffected in the trigeminal neurons of bcl-2
/- embryos. These findings indicate that Bcl-2 expression is required for the
normal progression of a particular early maturational change in embryonic sensory
neurons.
PMID- 9547243
TI - Brain-derived neurotrophic factor modulates the development of the dopaminergic
network in the rodent retina.
AB - Dopaminergic cells in the retina express the receptor for brain-derived
neurotrophic factor (BDNF) (). To investigate whether BDNF can influence the
development of the retinal dopaminergic pathway, we performed intraocular
injections of BDNF during the second or third postnatal week and visualized the
dopaminergic system with tyrosine hydroxylase (TH) immunohistochemistry. Both
regimens of BDNF treatment caused an increase in TH immunoreactivity in stratum 1
and stratum 3 of the inner plexiform layer (IPL). D2 dopamine receptor
immunoreactivity, a presynaptic marker of dopaminergic cells (), was also
increased in stratum 1 and stratum 3 of the inner plexiform layer. These data
suggest that BDNF causes sprouting of dopaminergic fibers in the inner plexiform
layer. Other neurochemical systems, for example, the cholinergic amacrine cells,
remained unaffected. Similar effects were observed after injections of
neurotrophin-3 and neurotrophin-4, but not nerve growth factor. Analysis of whole
mounted TH-immunolabeled retinae revealed hypertrophy of dopaminergic cells (+41%
in soma areas; p < 0.01) and an increase of labeled dopaminergic varicosities in
stratum 1 of the IPL (+51%; p < 0.01) after BDNF treatment. The opposite was
observed in mice homozygous for a null mutation of the bdnf gene: dopaminergic
cells were atrophic (-22.5% in soma areas; p < 0.05), and the density of TH
positive varicosities in stratum 1 was reduced (57%; p < 0.01). We conclude that
BDNF controls the development of the retinal dopaminergic network and may be
particularly important in determining the density of dopaminergic innervation in
the retina.
PMID- 9547244
TI - Neurolin, the goldfish homolog of DM-GRASP, is involved in retinal axon
pathfinding to the optic disk.
AB - Young axons of new retinal ganglion cells (RGCs) in the continuously growing
goldfish retina fasciculate with one another and their immediate forerunners on
their path toward the optic disk and along the optic nerve. They express the
immunoglobulin superfamily cell adhesion molecules (CAMs) neurolin (DM-GRASP) and
the L1-like E587 antigen. Repeated injections of Fab fragments from polyclonal
antisera against neurolin (neurolin Fabs) into the eye of 3. 4-cm-long and
rapidly growing goldfish caused highly aberrant pathways of young RGC axon
subfascicles in the dorsal retina. Many axons grew in circles and failed to reach
the optic disk. In contrast, E587 Fabs, used in parallel experiments, disrupted
the fascicles but did not interfere with the disk-directed growth. Neurolin Fabs
also disturbed axonal fasciculation in vivo as well as in vitro but less severely
than E587 Fabs. Coinjections of both Fabs increased defasciculation of the dorsal
axons in both aberrant and disk-directed routes. They also disrupted the order of
young RGC axons in the optic nerve more severely than E587 Fabs alone. This
demonstrates that the development of tight and orderly fascicles in the dorsal
retina and in the optic nerve requires both E587 antigen and neurolin. More
importantly, our results suggest an involvement of neurolin in RGC axonal
guidance from the retinal periphery to the optic disk. Because disrupted
fascicles and errant axon routes were found only in the dorsal retinal half, a
cooperation with so-called positional markers may be conceived.
PMID- 9547245
TI - Microcircuitry and mosaic of a blue-yellow ganglion cell in the primate retina.
AB - Perception of hue is opponent, involving the antagonistic comparison of signals
from different cone types. For blue versus yellow opponency, the antagonism is
first evident at a ganglion cell with firing that increases to stimulation of
short wavelength-sensitive (S) cones and decreases to stimulation of middle
wavelength-sensitive (M) and long wavelength-sensitive (L) cones. This ganglion
cell, termed blue-yellow (B-Y), has a distinctive morphology with dendrites in
both ON and OFF strata of the inner plexiform layer (Dacey and Lee, 1994). Here
we report the synaptic circuitry of the cell and its spatial density.
Reconstructing neurons in macaque fovea from electron micrographs of serial
sections, we identified six ganglion cells that branch in both strata and have
similar circuitry. In the ON stratum each cell collects approximately 33 synapses
from bipolar cells traced back exclusively to invaginating contacts from S cones,
and in the OFF stratum each cell collects approximately 14 synapses from bipolar
cells (types DB2 and DB3) traced to basal synapses from approximately 20 M and L
cones. This circuitry predicts that spatially coincident blue-yellow opponency
arises at the level of the cone output via expression of different glutamate
receptors. S cone stimuli suppress glutamate release onto metabotropic receptors
of the S cone bipolar cell dendrite, thereby opening cation channels, whereas M
and L cone stimuli suppress glutamate release onto ionotropic glutamate receptors
of DB2 and DB3 cell dendrites, thereby closing cation channels. Although the B-Y
cell is relatively rare (3% of foveal ganglion cells), its spatial density equals
that of the S cone; thus it could support psychophysical discrimination of a blue
yellow grating down to the spatial cutoff of the S cone mosaic.
PMID- 9547246
TI - GABAergic cells are the major postsynaptic targets of mossy fibers in the rat
hippocampus.
AB - Dentate granule cells communicate with their postsynaptic targets by three
distinct terminal types. These include the large mossy terminals, filopodial
extensions of the mossy terminals, and smaller en passant synaptic varicosities.
We examined the postsynaptic targets of mossy fibers by combining in vivo
intracellular labeling of granule cells, immunocytochemistry, and electron
microscopy. Single granule cells formed large, complex "mossy" synapses on 11-15
CA3 pyramidal cells and 7-12 hilar mossy cells. In contrast, GABAergic
interneurons, identified with immunostaining for substance P-receptor,
parvalbumin, and mGluR1a-receptor, were selectively innervated by very thin
(filopodial) extensions of the mossy terminals and by small en passant boutons in
both the hilar and CA3 regions. These terminals formed single, often perforated,
asymmetric synapses on the cell bodies, dendrites, and spines of GABAergic
interneurons. The number of filopodial extensions and small terminals was 10
times larger than the number of mossy terminals. These findings show that in
contrast to cortical pyramidal neurons, (1) granule cells developed distinct
types of terminals to affect interneurons and pyramidal cells and (2) they
innervated more inhibitory than excitatory cells. These findings may explain the
physiological observations that increased activity of granule cells suppresses
the overall excitability of the CA3 recurrent system and may form the structural
basis of the target-dependent regulation of glutamate release in the mossy fiber
system.
PMID- 9547247
TI - Patchy distribution of NMDAR1 subunit immunoreactivity in developing visual
cortex.
AB - Development of ocular dominance columns is dependent on patterned retinal
activity, and yet patterned activity alone cannot explain all aspects of cortical
column development. Features intrinsic to the cortex have been proposed to
interact with activity to guide the patterning of cortical columns (), and the
NMDA receptor, because of its role in experience-dependent plasticity, is an
obvious candidate. Using immunohistochemical techniques, we found a transiently
patchy distribution of the NMDA receptor 1 (NMDAR1) subunit in kitten visual
cortex. Regularly spaced patches of NMDAR1-immunoreactive neurons were found at
the top of the cortical plate in the developing visual cortex at 2 weeks of age.
At 4-5 weeks of age, the radial extent of the NMDAR1 patches spanned the
supragranular layers, and by 12 weeks of age, this nonuniform pattern of NMDAR1
immunostaining was no longer apparent. Monocular visual experience prevented the
expression of the NMDAR1 patches, but just 4 d of subsequent binocular visual
experience was sufficient to promote expression of the patches. Furthermore, the
NMDAR1 patches tended to be associated with the borders of ocular dominance
columns. These results suggest that the degree of plasticity associated with NMDA
mediated mechanisms is elevated in local regions across the tangential extent of
the visual cortex and that the NMDAR1 patches may participate in sculpting the
overall arrangement of visual cortical columns.
PMID- 9547248
TI - Calcium waves precede electrophysiological changes of spreading depression in
hippocampal organ cultures.
AB - Although intercellular Ca2+ waves resemble spreading depression (SD) and occur in
hippocampal organ cultures (HOTCs), SD has not been reported in these cultures.
Accordingly, electrophysiological and Ca2+ imaging techniques were used to
examine potential interrelations between Ca2+ waves and electrophysiological
changes of SD. Our results show, for the first time, that HOTCs can support SD.
Furthermore, two distinct Ca2+ waves were found to precede SD. The first traveled
>100 micron/sec along the pyramidal cell dendritic layer. The second subsequently
traveled mostly perpendicular to the pyramidal cell layer from CA3 (or CA1) but
also in all directions from its area of initiation. This second, slower wave
spread with the interstitial DC change of SD at millimeters per minute but always
ahead of it by 6-16 sec. Heptanol, which uncouples gap junctions, blocked both of
these Ca2+ waves and SD. Thus, two types of Ca2+ waves occur with the initiation
and propagation of SD. The first might reflect interneuronal changes linked by
gap junctions, whereas the second might stem from interastrocyte changes linked
via similar connections. Because individual cells can be followed in space and
time for protracted periods in HOTCs, this preparation may be ideal for studies
designed to explore not only the mechanisms of SD but also the long-term
consequences of SD, such as ischemic tolerance.
PMID- 9547249
TI - Distinct regions of the periaqueductal gray are involved in the acquisition and
expression of defensive responses.
AB - In fear conditioning, a rat is placed in a distinct environment and delivered
footshock. The response to the footshock itself is called an activity burst and
includes running, jumping, and vocalization. The fear conditioned to the distinct
environment by the footshock elicits complete immobility termed freezing. Lesions
of the ventral periaqueductal gray (vPAG) strongly attenuate freezing. However,
lesions of the dorsolateral periaqueductal gray (dlPAG) increase the amount of
freezing seen to conditional fear cues acquired under conditions in which intact
rats do not demonstrate much fear conditioning. To examine the necessity of these
regions in the acquisition and expression of fear, we performed five experiments
that examined the effects of electrolytic lesions of the dlPAG and the vPAG in
learned and unlearned fear. In experiment 1, lesions of the vPAG strongly
attenuated, whereas lesions of the dlPAG enhanced, unconditional freezing to a
cat. In experiment 2, lesions of the dlPAG made before but not after training
enhanced the amount of freezing shown to conditional fear cues acquired via
immediate footshock delivery. In experiment 3, vPAG lesions made either before or
after training with footshock decreased the level of freezing to conditional fear
cues. Neither dlPAG lesions nor vPAG lesions affected footshock sensitivity
(experiment 4) or consumption on a conditioned taste aversion test that does not
elicit antipredator responses (experiment 5). On the basis of these results, it
is proposed that activation of the dlPAG produces inhibition of the vPAG and
forebrain structures involved with defense. In contrast, the vPAG seems to be
necessary for postencounter freezing defensive behavior.
PMID- 9547250
TI - Muscle response to changing neuronal input in the lobster (Panulirus interruptus)
stomatogastric system: slow muscle properties can transform rhythmic input into
tonic output.
AB - Slow, non-twitch muscles are widespread in lower vertebrates and invertebrates
and are often assumed to be primarily involved in posture or slow motor patterns.
However, in several preparations, including some well known invertebrate "model"
preparations, slow muscles are driven by rapid, rhythmic inputs. The response of
slow muscles to such inputs is little understood. We are investigating this issue
with a slow stomatogastric muscle (cpv1b) driven by a relatively rapid, rhythmic
neural pattern. A simple model suggests that as cycle period decreases, slow
muscle contractions show increasing intercontraction temporal summation and at
steady state consist of phasic contractions overlying a tonic contracture. We
identify five components of these contractions: total, average, tonic, and phasic
amplitudes, and percent phasic (phasic amplitude divided by total amplitude).
cpv1b muscle contractions induced by spontaneous rhythmic neural input in vitro
consist of phasic and tonic components. Nerve stimulation at varying cycle
periods and constant duty cycle shows that a tonic component is always present,
and at short periods the muscle transforms rhythmic input into almost completely
tonic output. Varying spike frequency, spike number, and cycle period show that
frequency codes total, average, and tonic amplitudes, number codes phasic
amplitude, and period codes percent phasic. These data suggest that tonic
contraction may be a property of slow muscles driven by rapid, rhythmic input,
and in these cases it is necessary to identify the various contraction components
and their neural coding. Furthermore, the parameters that code these components
are interdependent, and control of slow muscle contraction is thus likely
complex.
PMID- 9547251
TI - Mechanisms of cortical reorganization in lower-limb amputees.
AB - The human motor system undergoes reorganization after amputation, but the site of
motor reorganization and the mechanisms involved are unknown. We studied the site
and mechanisms of motor reorganization in 16 subjects with traumatic lower-limb
amputation. Stimulation at different levels in the CNS was used to determine the
site of reorganization. The mechanisms involved were evaluated by measuring the
thresholds for transcranial magnetic stimulation (TMS) and by testing
intracortical inhibition and facilitation. With TMS, the threshold for muscle
activation on the amputated side was lower than that of the intact side, but with
transcranial electrical stimulation there was no difference in motor threshold
between the two sides. TMS at the maximal output of the stimulator activated a
higher percentage of the motor neuron pool (%MNP) on the amputated side than on
the intact side. The %MNP activated by spinal electrical stimulation was similar
on the two sides. Paired TMS study showed significantly less intracortical
inhibition on the amputated side. Our findings suggest that motor reorganization
after lower-limb amputation occurs predominately at the cortical level. The
mechanisms involved are likely to include reduction of GABAergic inhibition.
PMID- 9547252
TI - Response to change is facilitated by a three-neuron disinhibitory pathway in the
tiger salamander retina.
AB - Most retinal ganglion cells respond only transiently, for approximately 150 msec
at the onset and termination of a light flash. The responses are transient
because it has been shown that bipolar-to-ganglion cell transmission is truncated
after 150 msec by a feedback inhibition to bipolar cell terminals. The feedback
inhibition itself must be delayed by approximately 150 msec to allow the initial
bipolar-ganglion cell transmission. This study identifies a three-component
serial synaptic pathway from glycinergic amacrine cells to GABAergic amacrine
cells to bipolar cell terminals as one source of this delay. We used perforated
and whole-cell patch-clamp recordings to measure the timing of light responses in
amacrine, bipolar, and ganglion cells under control and glycine and GABA receptor
blocked conditions. Our results suggest that, after a light flash, a population
of glycinergic amacrine cells responds first, inhibiting a population of
GABAergic amacrine cells for approximately 150 msec. The GABAergic amacrine cells
feed back to bipolar terminals, but only after the 150 msec delay, allowing the
bipolar terminals to excite ganglion cells for the first 150 msec. Blocking the
glycinergic amacrine cell activity with strychnine allows the GABAergic system to
become active earlier. GABAergic amacrine cells then inhibit release from bipolar
cells earlier. Under these conditions, the ganglion cell response to change would
be decreased.
PMID- 9547253
TI - Time-dependent reversal of long-term potentiation by an integrin antagonist.
AB - The integrin antagonist Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP) was applied by local
ejection to one of two recording sites in hippocampal slices at various times
before and after long-term potentiation (LTP) was induced at both sites with
theta burst stimulation. Applications 10 min before, immediately after, and 10
min after induction caused LTP at the experimental site to decay steadily
relative to that at the within-slice control site. However, application at 25 min
or more after induction had no detectable effect on potentiation. Similar results
were obtained when the integrin antagonist was perfused into the slice rather
than applied locally. The time period after induction during which GRGDSP
interfered with LTP consolidation corresponds to that during which LTP is
susceptible to reversal by low-frequency afferent stimulation and newly formed
memories are vulnerable to various disruptive treatments. Comparable experiments
using a peptide that blocks an extracellular binding site of neural cell adhesion
molecules (NCAMs) did not yield time-dependent reversal of LTP; i.e., an
antagonist that interacts with the fourth immunoglobulin-like domain reduced LTP
when applied before induction but not afterward. Moreover, LTP formation occurred
normally in the presence of an antibody against the fibronectin repeat domain of
NCAM. These results suggest that integrin activation and signaling occurring over
several minutes after LTP induction are necessary for stabilizing synaptic
potentiation and by inference may be required for the conversion of new memories
into a not readily disrupted state.
PMID- 9547254
TI - Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene
dosage, genetic background, and developmental adaptations.
AB - Locomotor activity is a polygenic trait that varies widely among inbred strains
of mice (). To characterize the role of D2 dopamine receptors in locomotion, we
generated F2 hybrid (129/Sv x C57BL/6) D2 dopamine receptor (D2R)-deficient mice
by gene targeting and investigated the contribution of genetic background to open
field activity and rotarod performance. Horizontal activity of D2R-/- mice was
approximately half that of drug-naive, strain-matched controls but was
significantly greater than haloperidol-treated controls, which were markedly
hypokinetic. Wild-type 129/SvEv and C57BL/6 mice with functional D2 receptors had
greater interstrain differences in spontaneous activity than those among the F2
hybrid mutants. Incipient congenic strains of D2R-deficient mice demonstrated an
orderly gene dosage reduction in locomotion superimposed on both extremes of
parental background locomotor activity. In contrast, F2 hybrid D2R-/- mice had
impaired motor coordination on the rotarod that was corrected in the congenic
C57BL/6 background. Wild-type 129/SvEv mice had the poorest rotarod ability of
all groups tested, suggesting that linked substrain 129 alleles, not the absence
of D2 receptors per se, were largely responsible for the reduced function of the
F2 hybrid D2R-/- and D2R+/- mice. Neurochemical and pharmacological studies
revealed unexpectedly normal tissue striatal monoamine levels and no evidence for
supersensitive D1, D3, or D4 dopamine receptors in the D2R-/- mice. However,
after acute monoamine depletion, akinetic D2R+/- mice had a significantly greater
synergistic restoration of locomotion in response to SKF38393 and quinpirole
compared with any group of D2R+/+ controls. We conclude that D2R-deficient mice
are not a model of Parkinson's disease. Our studies highlight the interaction of
multiple genetic factors in the analysis of complex behaviors in gene knock-out
mice.
PMID- 9547255
TI - Phosphorylation of mitogen-activated protein kinase by one-trial and multi-trial
classical conditioning.
AB - The pathway supporting the conditioned stimulus (CS) is one site of plasticity
that has been studied extensively in conditioned Hermissenda. Several signal
transduction pathways have been implicated in classical conditioning of this
preparation, although the major emphasis has been on protein kinase C. Here we
provide evidence for the activation and phosphorylation of a mitogen-activated
protein kinase (MAPK) pathway by one-trial and multi-trial conditioning. A one
trial in vitro conditioning procedure consisting of light (CS) paired with the
application of 5-HT results in the increased incorporation of 32PO4 into proteins
detected with two-dimensional gel electrophoresis. Two of the phosphoproteins
have molecular weights of 44 and 42 kDa, consistent with extracellular signal
regulated protein kinases (ERK1 and ERK2). Phosphorylation of the 44 and 42 kDa
proteins by one-trial conditioning was inhibited by pretreatment with PD098059, A
MEK1 (ERK-Activating kinase) inhibitor. Assays of ERK activity with brain myelin
basic protein as a substrate revealed greater ERK activity for the group that
received one-trial conditioning compared with an unpaired control group. Western
blot analysis of phosphorylated ERK using antibodies recognizing the dually
phosphorylated forms of ERK1 and ERK2 showed an increase in phosphorylation after
one-trial conditioning compared with unpaired controls. The increased
phosphorylation of ERK after one-trial conditioning was blocked by pretreatment
with PD098059. Hermissenda that received 10 or 15 conditioning trials showed
significant behavioral suppression compared with pseudo-random controls. After
conditioning and behavioral testing, the conditioned animals showed significantly
greater phosphorylation of ERK compared with the pseudo-random controls. These
results show that the ERK-MAPK signaling pathway is activated in Pavlovian
conditioning of Hermissenda.
PMID- 9547256
TI - The D arm of tRNATyr is necessary and sufficient for import into Leishmania
mitochondria in vitro.
AB - Transfer RNAs are selectively imported from the cytoplasm into mitochondria of
kinetoplastid protozoa such as Leishmania . The specific structural features of
tRNA which determine selectivity are largely unknown. Using an in organello
system from Leishmania , the import signals on tRNATyrand on a synthetic
transcript which binds to the same receptor, were studied by deletion and
reconstruction analyses. In both cases, short oligoribonucleotides (minihelices)
containing the sequence UGGYAGAG were imported with high efficiency in the
presence of ATP. This motif is present in the D arm of tRNATyr, as well as in the
majority of imported Leishmania tRNAs. Deletion of the D arm, or a point mutation
in the conserved motif, reduces importability. The import signal coincides with
the binding site for the mitochondrial receptor TAB. tRNAGln, which is not
imported, forms non-productive, TAB-independent complexes with the mitochondrial
surface. However, the observation that the imported:bound ratio of the D arm
minihelix is higher than that of the entire molecule suggests that the post
binding translocation step is constrained in terms of size or structural
flexibility. Kinetic studies of minihelix import indicate stepwise insertion of
the molecule into import channels.
PMID- 9547257
TI - DNA topoisomerase II sites in the histone H4 gene during the highly synchronous
cell cycle of Physarum polycephalum.
AB - The nearly perfect synchrony of nuclear division in a plasmodium of Physarum
polycephalum provides a powerful system to analyze topoisomerase II cleavage
sites in the course of the cell cycle. The histone H4 locus, whose schedule of
replication and transcription is precisely known, was chosen for this analysis.
Drug-induced topoisomerase II sites are clustered downstream of the histone H4
gene and appear highly dependent on cell cycle stage. They were only detected in
mitosis and at the very beginning of S phase, precisely at the time of
replication of the histone H4 region. The sites, which were absent in G2 phase,
reappeared at the next mitosis. Remarkably, DNase I hypersensitive sites occurred
in nearly the same location, but their schedule was totally different: they were
absent in mitosis and present in G2. This schedule follows H4 transcription,
which peaks in mid-S phase and in the second part of G2 phase and is off during
mitosis. These results suggest that topoisomerase II may not be involved in
transcription, but plays a role in remodeling chromatin structure, both during
chromosome condensation in prophase/metaphase to allow their decatenation and
during chromosome decondensation after metaphase to allow replication fork
passage throughout the region.
PMID- 9547258
TI - Accelerated mRNA decay in conditional mutants of yeast mRNA capping enzyme.
AB - Current models of mRNA decay in yeast posit that 3' deadenylation precedes
enzymatic removal of the 5' cap, which then exposes the naked end to 5'
exonuclease action. Here, we analyzed gene expression in Saccharomyces cerevisiae
cells bearing conditional mutations of Ceg1 (capping enzyme), a 52 kDa protein
that transfers GMP from GTP to the 5' end of mRNA to form the GpppN cap
structure. Shift of ceg1 mutants to restrictive temperature elicited a rapid
decline in the rate of protein synthesis, which correlated with a sharp reduction
in the steady-state levels of multiple individual mRNAs. ceg1 mutations prevented
the accumulation of SSA1 and SSA4 mRNAs that were newly synthesized at the
restrictive temperature. Uncapped poly(A)+ SSA4 mRNA accumulated in cells lacking
the 5' exoribonuclease Xrn1. These findings provide genetic evidence for the long
held idea that the cap guanylate is critical for mRNA stability. The
deadenylation-decapping-degradation pathway appears to be short-circuited when
Ceg1 is inactivated.
PMID- 9547259
TI - Phosphorylation of tobacco eukaryotic translation initiation factor 4A upon
pollen tube germination.
AB - Eukaryotic translation initiation factor eIF-4A is a member of the DEAD box
family of RNA helicases and RNA-dependent ATPases. In tobacco, eIF-4A is encoded
by a gene family with one isoform, eIF-4A8, being exclusively expressed in
pollen. This pollen-specific isoform is a candidate for mediating translational
control in the developing gametophyte. Here we show that eIF-4A is barely
phosphorylated in mature pollen, but during pollen tube germination, two isoforms
of eIF-4A become phosphorylated. Phosphoamino acid analysis indicated
phosphorylation of threonine. In order to determine whether pollen-specific eIF
4A8 is among the phosphorylated isoforms, we raised transgenic tobacco plants
overexpressing eIF-4A8 containing a histidine tag. Hereby, we could show that
indeed eIF-4A8 is modified through phosphorylation. The biological relevance of
the phosphorylation of eIF-4A is discussed.
PMID- 9547260
TI - Cloning and characterization of a human DEAH-box RNA helicase, a functional
homolog of fission yeast Cdc28/Prp8.
AB - During the splicing process, spliceosomal snRNAs undergo numerous conformational
rearrangements that appear to be catalyzed by proteins belonging to the DEAD/H
box superfamily of RNA helicases. We have cloned a new RNA helicase gene,
designated DBP2 (DEAH-boxprotein), homologous to the Schizosaccaromyces pombe
cdc28(+)/prp8(+) gene involved in pre-mRNA splicing and cell cycle progression.
The full-length DBP2 contains 3400 nucleotides and codes for a protein of 1041
amino acids with a calculated mol. wt of 119 037 Da. Transfection experiments
demonstrated that the GFP-DBP2 gene product, transiently expressed in HeLa cells,
was localized in the nucleus. The DBP2 gene was mapped by FISH to the MHC region
on human chromosome 6p21.3, a region where many malignant, genetic and autoimmune
disease genes are linked. Because the expression of DBP2 gene in S.pombe prp8
mutant cells partially rescued the temperature-sensitive phenotype, we conclude
that DBP2 is a functional human homolog of the fission yeast Cdc28/Prp8 protein.
PMID- 9547261
TI - The pro-oligonucleotide approach: solid phase synthesis and preliminary
evaluation of model pro-dodecathymidylates.
AB - A modified phosphoramidite method has been designed for the solid-phase synthesis
of two dodecathymidine phosphotriesters and two dodecathymidine
thionophosphotriesters. In these analogs, each internucleoside link bears an S
acyl-2-thioethyl (Me-SATE or tBu-SATE) group removable upon esterase activation.
Efficient synthesis of these lipophilic analogs was achieved thanks to the use of
a photolabile linker anchored to the solid support in combination with thymidine
3'- O -phosphoramidites having a SATE group in place of the regular 2-cyanoethyl
one. Both dodecathymidine phosphotriester and thionophosphotriester having S
acetyl-2-thioethyl groups were found to be stable in the presence of snake venom
and calf spleen phosphodiesterases whereas, upon incubation in CEM cell extracts,
they were selectively hydrolyzed to the anionic parent dodecathymidylate and
dodecathymidine phosphorothioate, respectively. In addition, Me-SATE-protected
dodecathymidine thionophosphotriester was stable in mouse and human sera as well
as in human gastric juice. These results depict the potential of SATE-protected
oligonucleotides as prodrugs of antisense oligonucleotides.
PMID- 9547262
TI - Transcription activation by Escherichia coli FNR protein: similarities to, and
differences from, the CRP paradigm.
AB - During transcription activation at FNR-dependent promoters where the DNA site for
FNR overlaps the -35 element, a surface-exposed activating region in the upstream
subunit of the FNR dimer interacts with the C-terminal domain of the RNA
polymerase alpha subunit. Starting with a cloned fnr gene encoding a defective
FNR derivative carrying substitutions in this activating region, we screened a
library of random mutations to identify substitutions that restored FNR activity.
Activity can be restored by substitutions at residues T118, E47 and K60. The
locations of these residues identify three separate surface-exposed regions of
FNR that can play a role in transcription activation. These three regions appear
to be analogues of Activating Region 1, Activating Region 2 and Activating Region
3 of the cyclic AMP receptor protein, CRP: our results underscore the
similarities between FNR and CRP.
PMID- 9547263
TI - Improving stable transfection efficiency: antioxidants dramatically improve the
outgrowth of clones under dominant marker selection.
AB - Many cell lines are sensitive to growth at low cell density and undergo apoptosis
induced by oxidative stress if the cell density is decreased below a critical
threshold. In stable transfection experiments this cell density-dependent growth
may be the limiting factor, since during drug selection the cell density falls
below the critical threshold, precluding outgrowth of transfected clones. We
describe here a simple protocol for the establishment of stably transfected human
B cell lines making use of the protective action of antioxidants. The protocol
includes: (i) seeding the cells in medium supplemented with sodium pyruvate,
alpha-thioglycerol and bathocuproine disulfonate; (ii) delaying the onset of
dominant marker selection to improve recovery of the cells after electroporation.
Stably transfected clones have thus been obtained from Burkitt's lymphoma lines,
which have been regarded as untransfectable. Using this protocol the stable
transfection efficiency with episomal plasmids approaches the transient
transfection efficiency, indicating that virtually every transfected cell can be
established as a stably transfected clone. This protocol should also prove useful
for other cell lines, e.g. neuronal cells, having similar sensitivities to
oxidative stress.
PMID- 9547264
TI - (1,4,7-trimethyl-1,4,7-triazacyclononane)iron (III)-mediated cleavage of DNA:
detection of selected protein-DNA interactions.
AB - A new reagent for the oxidative cleavage of DNA, (1,4,7-trimethyl-1, 4,7
triazacyclononane)iron(III) chloride was recently introduced. We have determined
the utility of this reagent for detecting protein-DNA interactions within two
types of complexes. Interestingly, we find that the rates of DNA cleavage by this
reagent are differentially affected by the two classes of protein-DNA interactons
studied. We find that the rate of DNA cleavage by this reagent is relatively
unaffected by the non-sequence-specific histone-DNA interactions within a
nucleosome complex. Conversely, a clear footprint pattern is obtained with two
different DNA sequence-specific protein-DNA complexes. The results suggest that
(1,4,7-trimethyl-1,4,7-triazacyclononane)iron(III) chloride will be a useful
reagent to probe trans -acting-factor-DNA interactions within a chromatin
environment. Differences between these two types of protein-DNA interactions,
which might account for this observation, are discussed.
PMID- 9547265
TI - Short unligated sticky ends enable the observation of circularised DNA by atomic
force and electron microscopies.
AB - A comparative study of the stabilisation of DNA sticky ends by divalent cations
was carried out by atomic force microscopy (AFM), electron microscopy and agarose
gel electrophoresis. At room temperature, molecules bearing such extremities are
immediately oligomerised or circularised by addition of Mg2+or Ca2+. This
phenomenon, more clearly detected by AFM, requires the presence of uranyl salt,
which stabilises the structures induced by Mg2+or Ca2+. DNA fragments were
obtained by restriction enzymes producing sticky ends of 2 or 4 nucleotides (nt)
in length with different guanine plus cytosine (GC) contents. The stability of
the pairing is high when ends of 4 nt display a 100% GC-content. In that case,
95% of DNA fragments are maintained circular by the divalent cations, although 2
nt GC-sticky ends are sufficient for a stable pairing. DNA fragments with one
blunt end and the other sticky appear as dimers in the presence of Mg2+.
Dimerisation was analysed by varying the lengths and concentrations of DNA
fragments, the base composition of the sticky ends, and also the temperature. Our
observation provides a new powerful tool for construction of inverted dimers, and
circularisation, ligation analysis or short bases sequence interaction studies.
PMID- 9547266
TI - The activation function 2 domain of hepatic nuclear factor 4 is regulated by a
short C-terminal proline-rich repressor domain.
AB - Hepatic nuclear factor 4 (HNF4) is a transcription factor whose expression is
crucial for mouse embryonic development, for liver-specific gene expression and
for the prevention of one form of maturity-onset diabetes of the young. Its
domain structure has been defined previously and is similar to other members of
the nuclear receptor superfamily. A repressor domain has now been localised to a
region of 14 amino acids (residues 428-441) near the C-terminus of HNF4 and is
sufficient by itself to repress the activity of the activation function 2 (AF2)
domain. Multiple mutations within this repressor domain enhance activity.
Interestingly, this repressor domain shares homology with a repressor domain in
the progesterone receptor. In a detailed mutagenesis study of the AF2 core, we
demonstrate that L 366, which is conserved in the AF2 core between HNF4 and a
number of orphan nuclear receptors, is essential for the full activity of the AF2
domain. Furthermore, a double mutation of E 363 and L 366 suggests that these
residues might act in a cooperative manner.
PMID- 9547267
TI - Synthesis and RNA polymerase incorporation of the degenerate ribonucleotide
analogue rPTP.
AB - The synthesis and enzymatic incorporation into RNA of the hydrogen bond
degenerate nucleoside analogue 6-(beta-d-ribofuranosyl)-3, 4-dihydro-8H
pyrimido[4,5-c]-[1,2]oxazin-7-one (P) is described. The 5'-triphosphate of this
analogue is readily incorporated by T3, T7 and SP6 RNA polymerases into RNA
transcripts, being best incorporated in place of UTP, but also in place of CTP.
When all the uridine residues in an HIV-1 TAR RNA transcript are replaced by P
the transcript has similar characteristics to the wild-type TAR RNA, as
demonstrated by similar melting temperatures and CD spectra. The P-substituted
TAR transcript binds to the Tat peptide ADP-1 with only 4-fold lowered efficiency
compared with wild-type TAR.
PMID- 9547269
TI - Repressor titration: a novel system for selection and stable maintenance of
recombinant plasmids.
AB - The propagation of recombinant plasmids in bacterial hosts, particularly in
Escherichia coli, is essential for the amplification and manipulation of cloned
DNA and the production of recombinant proteins. The isolation of bacterial
transformants and subsequent stable plasmid maintenance have traditionally been
accomplished using plasmid-borne selectable marker genes. Here we describe a
novel system that employs plasmid-mediated repressor titration to activate a
chromosomal selectable marker, removing the requirement for a plasmid-borne
marker gene. A modified E.coli host strain containing a conditionally essential
chromosomal gene (kan) under the control of the lac operator/promoter, lac O/P,
has been constructed. In the absence of an inducer (allolactose or IPTG) this
strain, DH1 lackan , cannot grow on kanamycin-containing media due to the
repression of kan expression by LacI protein binding to lac O/P. Transformation
with a high copy-number plasmid containing the lac operator, lac O, effectively
induces kan expression by titrating LacI from the operator. This strain thus
allows the selection of plasmids without antibiotic resistance genes (they need
only contain lac O and an origin of replication) which have clear advantages for
use as gene therapy vectors. Regulation in the same way of an essential,
endogenous bacterial gene will allow the production of recombinant therapeutics
devoid of residual antibiotic contamination.
PMID- 9547268
TI - TFIID (TBP) stabilizes the binding of MyoD to its DNA site at the promoter and
MyoD facilitates the association of TFIIB with the preinitiation complex.
AB - The myogenic determination factor MyoD activates the transcription of muscle
specific genes by binding to consensus DNA sites found in the regulatory
sequences of these genes. The interaction of MyoD with the basal transcription
machinery is not known. Several activators induce transcription by recruiting
TFIID and/or TFIIB to the promoter. We asked whether MyoD interacted functionally
with TFIID and TFIIB in transcription. We reconstituted in vitro DNA binding and
transcription systems of MyoD and basal transcription factors, and found that
MyoD function in transcription occurred during the assembly of the preinitiation
complex. Interestingly, MyoD activated transcription without affecting the
binding of TFIID to the promoter. However, TFIID or TBP dramatically stabilized
the binding of MyoD to its recognition site. MyoD and TBP interacted in solution.
Deletion analysis of MyoD suggested that interaction of MyoD with TBP is needed
for its activity in transcription. At a later stage of assembly, MyoD stabilized
the binding of TFIIB to the preinitiation complex. These findings suggest that
MyoD is involved in two steps of preinitiation; first, TFIID stabilizes MyoD
binding to its DNA recognition site and at a later stage MyoD facilitates the
association of TFIIB with the preinitiation complex.
PMID- 9547270
TI - A stimulatory RNA associated with RecBCD enzyme.
AB - RecBCD enzyme acts in the major pathway of homologous recombination of linear DNA
in Escherichia coli. The enzyme unwinds DNA and is an ATP-dependent double-strand
and single-strand exonuclease and a single-strand endonuclease; it acts at Chi
recombination hotspots (5'-GCTGGTGG-3') to produce a recombinogenic single
stranded DNA 3'-end. We found that a small RNA with a unique sequence of
approximately 24 nt was tightly bound to RecBCD enzyme and co-purified with it.
When added to native enzyme this RNA, but not four others, increased DNA
unwinding and Chi nicking activities of the enzyme. In seven similarly active
enzyme preparations the molar ratio of RNA molecules to RecBCD enzyme molecules
ranged from 0.2 to <0.008. These results suggest that, although this unique RNA
is not an essential enzyme subunit, it has a biological role in stimulating
RecBCD enzyme activity.
PMID- 9547271
TI - Structure and regulation of a polymorphic gene encoding folate receptor type
gamma/gamma'.
AB - The human folate receptor (hFR) type gamma and gamma' are constitutively secreted
proteins that are expressed primarily in hematopoietic tissues and are potential
serum markers for certain hematopoietic malignancies. hFR-gamma' is a variant of
hFR-gamma with a two base deletion in its cDNA resulting in a truncated
polypeptide. The gene encoding hFR-gamma' was isolated from a placental genomic
library. The gene has five exons, four introns and a 5' flanking sequence which
contains multiple putative regulatory elements. From RNase protection assay and
RACE analysis, the major site of transcriptional initiation was identified at -56
nt. Systematically deleted fragments in the 5' region of the genomic DNA of FR
gamma' were ligated into the PGL3Basic plasmid and the reporter luciferase
activity was assayed in cell lysates from transiently transfected NIH3T3 cells.
From those results, putative positive and negative regulatory regions in the 5'
flanking sequences were noted, and a TATA-less proximal promoter was located
between -206 and -22 nt. Gel mobility shift and supershift analyses as well as
mutagenesis experiments revealed that Sp1 and ets binding elements in the
proximal promoter region confer transcriptional activity. From partial sequencing
of genomic DNA, genomic Southern blots, RACE analysis and RNase protection
assays, it appears that hFR-gamma shares the gene organization of hFR-gamma'. The
results of the analysis of genomic DNA in spleen tissues from several
individuals, were consistent with the interpretation that hFR-gamma and hFR
gamma' are encoded by a polymorphic gene.
PMID- 9547272
TI - DNA binding properties of a chemically synthesized DNA binding domain of hRFX1.
AB - The RFX DNA binding domain (DBD) is a novel highly conserved motif belonging to a
large number of dimeric DNA binding proteins which have diverse regulatory
functions in eukaryotic organisms, ranging from yeasts to human. To characterize
this novel motif, solid phase synthesis of a 76mer polypeptide corresponding to
the DBD of human hRFX1 (hRFX1/DBD), a prototypical member of the RFX family, has
been optimized to yield large quantities (approximately 90 mg) of pure compound.
Preliminary two-dimensional1H NMR experiments suggested the presence of helical
regions in this sequence in agreement with previously reported secondary
structure predictions. In gel mobility shift assays, this synthetic peptide was
shown to bind in a cooperative manner the 23mer duplex oligodeoxynucleotide
corresponding to the binding site of hRFX1, with a 2:1 stoichoimetry due to an
inverse repeat present in the 23mer. The stoichiometry of this complex was
reduced to 1:1 by decreasing the length of the DNA sequence to a 13mer
oligonucleotide containing a single half-site. Surface plasmon resonance
measurements were achieved using this 5'-biotylinated 13mer oligonucleotide
immobilized on an avidin-coated sensor chip. Using this method an association
constant (K a = 4 x 10(5)/M/s), a dissociation constant (K d = 6 x 10(-2)/s) and
an equilibrium dissociation constant (K D = 153 nM) were determined for binding
of hRFX1/DBD to the double-stranded 13mer oligonucleotide. In the presence of
hRFX1/DBD the melting temperature of the 13mer DNA was increased by 16 degreesC,
illustrating stabilization of the double-stranded conformation induced by the
peptide.
PMID- 9547273
TI - Molecular beacon probes combined with amplification by NASBA enable homogeneous,
real-time detection of RNA.
AB - Molecular beacon probes can be employed in a NASBA amplicon detection system to
generate a specific fluorescent signal concomitantly with amplification. A
molecular beacon, designed to hybridize within the target sequence, was
introduced into NASBA reactions that amplify the genomic RNA of potato leafroll
virus (PLRV). During amplification, the probe anneals to the antisense RNA
amplicon generated by NASBA, producing a specific fluorescent signal that can be
monitored in real-time. The assay is rapid, sensitive and specific. As RNA
amplification and detection can be carried out in unopened vessels, it minimizes
the risk of carry-over contaminations. Robustness has been verified on real-world
samples. This homogeneous assay, called AmpliDet RNA, is a significant
improvement over current detection methods for NASBA amplicons and is suitable
for one-tube applications ranging from high-throughput diagnostics to in vivo
studies of biological activities.
PMID- 9547274
TI - The importance of base pairing in the penultimate stem of Escherichia coli 16S
rRNA for ribosomal subunit association.
AB - The influence of base pairing in the penultimate stem of Escherichia coli 16S
rRNA (defined as nt 1409-1491) on ribosome function has been addressed by the
construction of mutations in this region of rRNA. Two sets of mutations were made
on either side of a structurally conserved region in the penultimate stem that
disrupted base pairing, while a third set of mutations replaced the wild-type
sequence with other base pair combinations. The effects of these mutations were
analyzed in vivo and in vitro . The mutations that disrupted base pairing caused
significant increases in cell doubling times as well as a severe subunit
association defect and a modest increase in frame shifting and stop codon read
through. Restoration of base pairing restored wild-type growth rates, decoding
and subunit association, indicating that base pairing in this region is essential
for proper ribosome function.
PMID- 9547275
TI - Characterisation of Leishmania telomeres reveals unusual telomeric repeats and
conserved telomere-associated sequence.
AB - Characterisation of the telomeres of Leishmania is important for understanding
many aspects of the parasitic life of this primitive protozoan and for the
completion of the physical map and sequencing of the genome. After sequencing
more than 300 telomere-derived clones from Leishmania braziliensis and Leishmania
major, a conserved 100 bp sequence was identified immediately adjacent to the
telomere at the chromosome end and was named LCTAS (Leishmania conserved telomere
associated sequence). The LCTAS contains two conserved sequence boxes, and is
present in all Leishmania species studied. The organisation of the LCTAS in the
telomeric region differs between L. braziliensis and L. major: in L. major the
LCTASs are tandemly repeated, while in L. braziliensis the LCTAS is present as a
single copy per end. Two additional TASs with 1.6 kb and 274 bp repeat
structures, which are apparently different to LCTAS, were isolated and mapped
onto a L. braziliensis 250 kb multicopy minichromosome and the L. major
chromosome 1, respectively. An unusual feature in L. braziliensis is that the
telomeric repeats are often comprised of a novel tandem repeat CCCTAACCCGTGGA. A
'slippage' mechanism for LCTAS formation is proposed in this study as an
alternative way for the synthesis and maintenance of telomeres and subtelomere
regions.
PMID- 9547276
TI - Coexistence of nuclear DNA-encoded tRNAVal(AAC) and mitochondrial DNA-encoded
tRNAVal(UAC) in mitochondria of a liverwort Marchantia polymorpha.
AB - The liverwort Marchantia polymorpha mitochondrial DNA encodes almost all tRNAs
required for mitochondrial translation except for the isoleucine (AUU, AUC) and
threonine (ACA, ACG) codons, while the missing tRNAs are supplied in part by the
nucleus and imported in mitochondria. In this paper, we report a finding of two
radically different nuclear tRNAVal(AAC) genes and import of the corresponding
tRNA isoacceptors in M.polymorpha mitochondria. This finding is surprising since
the mtDNA encodes the gene for tRNAVal(UAC), which alone was considered
sufficient for translating all four valine codons GUN by the U/N wobble
mechanism. The present results suggest for the first time that the import of
ncDNA-encoded tRNAs may result in decoding overlaps in plant mitochondria. The
coexistence of nuclear DNA-encoded tRNAVal(AAC) and mitochondrial DNA-encoded
tRNAVal(UAC) in liverwort mitochondria and the significance for the decoding
mechanism as well as evolution of tRNA import are discussed.
PMID- 9547277
TI - STAT 5 and NF-Y are involved in expression and growth hormone-mediated sexually
dimorphic regulation of cytochrome P450 3A10/lithocholic acid 6beta-hydroxylase.
AB - The level of expression of a number of sexually differentiated liver proteins is
primarily determined by plasma growth hormone (GH). Adult males have a pulsatile
profile of GH release, while females have a relatively steady-state pattern of GH
release. An important subset of these sexually differentiated hepatic proteins is
certain cytochrome P450s (P450s). CYP3A10/6beta-hydroxylase is a male-specific
P450 that catalyzes 6beta-hydroxylation of lithocholic acid, and the pattern of
GH secretion is directly responsible for male-specific expression of this gene.
The DNA element involved in GH-mediated regulation of CYP3A10/6beta-hydroxylase
promoter activity binds a member of the STAT (signal transducers and activators
of transcription) family of proteins. In this study we functionally demonstrate
that two members of the STAT family, STAT 5a and STAT 5b, mediate GH-dependent
regulation of CYP3A10/6beta-hydroxylase promoter activity. Furthermore, a
neighboring DNA element binds NF-Y, a transcription factor involved in
maintaining high levels of transcription of many genes and known to functionally
interact with other factors. In the CYP3A10/6beta-hydroxylase gene, NF-Y also
modulates binding of STAT 5, thereby modulating GH-mediated activation of its
transcription.
PMID- 9547278
TI - Triple helices formed at oligopyrimidine*oligopurine sequences with base pair
inversions: effect of a triplex-specific ligand on stability and selectivity.
AB - Oligonucleotide-directed triple helix formation is mostly restricted to
oligopyrimidine*oligopurine sequences of double helical DNA. An interruption of
one or two pyrimidines in the oligopurine target strand leads to a strong triplex
destabilisation. We have investigated the effect of nucleotide analogues
introduced in the third strand at the site opposite the base pair inversion(s).
We show that a 3-nitropyrrole derivative (M) discriminates G*C from C*G, A*T and
T*A in the presence of a triplex-specific ligand (a benzo[e]pyridoindole
derivative, BePI). N6-methoxy-2,6-diaminopurine (K) binds to an A*T base pair
better than a T*A, G*C or C*G base pair. Some discrimination is still observed in
the presence of BePI and triplex stability is markedly increased. These findings
should help in designing BePI-oligonucleotide conjugates to extend the range of
DNA sequences available for triplex formation.
PMID- 9547280
TI - Involvement of the 5'-untranslated region in cold-regulated expression of the
rbpA1 gene in the cyanobacterium Anabaena variabilis M3.
AB - Transcript of the rbpA1 gene in Anabaena variabilis accumulates significantly at
low growth temperatures below 28 degreesC. This accumulation was maximal at 16
degreesC. Accumulation of the rbpA1 transcript was completely abolished by
rifampicin, but not by chloramphenicol. Photosynthesis was not required for this
cold-induced accumulation. This accumulation of transcript was partly accounted
for by increased stability of the rbpA1 transcript at low temperature. Expression
of chimeric genes containing 3'-deleted rbpA1 sequences fused to the lacZ gene
was regulated by low temperature when almost the entire 5'-untranslated region
(5'-UTR) remained undeleted. Further deletion resulted in constitutive expression
of the chimeric gene. The 5'-UTR sequence formed two types of complexes in vitro
with protein extract from cells grown at 38 degreesC, but not with extract from
the 22 degreesC grown cells. Affinity purification identified polypeptides of 75
and 32 kDa in Complex 1 and a 72 kDa polypeptide in Complex 2. These results are
compatible with a model in which expression of the rbpA1 gene is regulated by
transcriptional derepression at low temperature, although additional mechanisms,
such as regulation of mRNA stability, might also contribute to temperature
dependent regulation.
PMID- 9547279
TI - Efficient in vitro repair of 7-hydro-8-oxodeoxyguanosine by human cell extracts:
involvement of multiple pathways.
AB - To investigate the repair of oxidative damage in DNA, we have established an in
vitro assay utilizing human lymphoblastoid whole cell extracts and plasmid DNA
damaged by exposure to methylene blue and visible light. This treatment has been
shown to produce predominantly 7-hydro-8-oxodeoxyguanosine (8-oxodG) in double
stranded DNA at low levels of modification. DNA containing 1. 6 lesions per
plasmid is substrate for efficient repair synthesis by cell extracts. The
incorporation of dGMP is 2.7 +/- 0.5 times greater than the incorporation of
dCMP, indicating an average repair patch of 3-4 nucleotides. Damage-specific
nicking occurs within 15 min, while resynthesis is slower. The incorporation of
dGMP increases linearly, while the incorporation of dCMP exhibits a distinct lag.
Extracts from xeroderma pigmentosum (XP) complementation groups A and B exhibit
25 and 40%, respectively, of the incorporation of dCMP compared with normal
extracts, but extracts from an XP-D cell line exhibit twice the activity. These
data suggest that the efficient repair of 8-oxodG lesions observed in human cell
extracts involves more than one pathway of base excision repair.
PMID- 9547281
TI - Structure-function analysis of the trypanosomatid spliced leader RNA.
AB - In trypanosomes, all mRNAs possess a spliced leader (SL) at their 5' end. SL is
added to pre-mRNA via trans -splicing from a small RNA, the SL RNA. To examine
structure-function aspects of the trypanosomatid SL RNA, an in vivo system was
developed in the monogenetic trypanosomatid Leptomonas collosoma to analyze the
function of chimeric and site-directed SL RNA mutants in trans -splicing. Stable
cell lines expressing chimeric and mutated SL RNA from the authentic SL RNA
regulatory unit were obtained. The chimeric RNA was expressed and assembled into
an SL RNP particle, but could not serve as a substrate in splicing. Mutations in
loop II and III of L.collosoma SL RNA formed the Y structure intermediate. In
addition, a double SL RNA mutant in loop II, and positions 7 and 8 of the intron,
also formed the Y structure intermediate, suggesting that these intron positions,
although proposed to participate in the interaction of SL RNA with U5, may not be
crucial for the first step of the trans -splicing reaction. A mutation in the
exon located in loop I was not utilized in splicing, suggesting the importance of
exon sequences for trans -splicing in trypanosomes. However, a double SL RNA
mutant in loop II and exon position 31 was utilized in both steps of splicing;
the mutant thus provides a model molecule for further analysis of positions
essential for the function of the SL RNA.
PMID- 9547282
TI - Exploratory studies on azole carboxamides as nucleobase analogs: thermal
denaturation studies on oligodeoxyribonucleotide duplexes containing pyrrole-3
carboxamide.
AB - In order to study base pairing properties of the amide group in DNA duplexes, a
nucleoside analog, 1-(2'-deoxy-beta-D-ribofuranosyl)pyrrole-3-carboxamide, was
synthesized by a new route from the ester, methyl 1-(2'-deoxy-3',5'-di-O-p
toluoyl-beta-D-erythro-pentofuranosyl)pyrrole-3-carboxylate, obtained from the
coupling reaction between 1-chloro-2-deoxy-3,5-di-O -toluoyl-d
erythropentofuranose and methyl pyrrole-3-carboxylate by treatment with
dimethylaluminum amide. 1-(2'-Deoxy-beta-D-ribofuranosyl)pyrrole-3-carboxamide
was incorporated into a series of oligodeoxyribonucleotides by solid-phase
phosphoramidite technology. The corresponding oligodeoxyribonucleotides with 3
nitropyrrole in the same position in the sequence were synthesized for UV
comparison of helix-coil transitions. The thermal melting studies indicate that
pyrrole-3-carboxamide, which could conceptually adopt either a dA-like or a dI
like hydrogen bond conformation, pairs with significantly higher affinity to T
than to dC. Pyrrole-3-carboxamide further resembles dA in the relative order of
its base pairing preferences (T >dG >dA >dC). Theoretical calculations on the
model compound N-methylpyrrole-3-carboxamide using density functional theory show
little difference in the preference for a syntau versus anti conformation about
the bond from pyrrole C3 to the amide carbonyl. The amide groups in both the
minimized antitau and syntau conformations are twisted out of the plane of the
pyrrole ring by 6-14 degrees. This twist may be one source of destabilization
when the amide group is placed in the helix. Another contribution to the
difference in stability between the base pairs of pyrrole-3-carboxamide with T
and pyrrole-3-carboxamide with C may be the presence of a hydrogen bond in the
former involving an acidic proton (N3-H of T).
PMID- 9547283
TI - Comparative gene expression profiling by oligonucleotide fingerprinting.
AB - The use of hybridisation of synthetic oligonucleotides to cDNAs under high
stringency to characterise gene sequences has been demonstrated by a number of
groups. We have used two cDNA libraries of 9 and 12 day mouse embryos (24 133 and
34 783 clones respectively) in a pilot study to characterise expressed genes by
hybridisation with 110 hybridisation probes. We have identified 33 369 clusters
of cDNA clones, that ranged in representation from 1 to 487 copies (0.7%). 737
were assigned to known rodent genes, and a further 13 845 showed significant
homologies. A total of 404 clusters were identified as significantly
differentially represented (P < 0.01) between the two cDNA libraries. This study
demonstrates the utility of the fingerprinting approach for the generation of
comparative gene expression profiles through the analysis of cDNAs derived from
different biological materials.
PMID- 9547284
TI - Advantages of 2'-O-methyl oligoribonucleotide probes for detecting RNA targets.
AB - We have compared various kinetic and melting properties of oligoribonucleotide
probes containing 2'-O-methylnucleotides or 2'-deoxynucleotides with regard to
their use in assays for the detection of nucleic acid targets. 2'-O-Methyl
oligoribonucleotide probes bound to RNA targets faster and with much higher
melting temperatures (Tm values) than corresponding 2'-deoxy oligoribonucleotide
probes at all lengths tested (8-26 bases). Tm values of both probes increased
with length up to approximately 19 bases, with maximal differences in Tm between
2'-O-methyl and 2'-deoxy oligoribonucleotide probes observed at lengths of 16
bases or less. In contrast to RNA targets, 2'-O-methyl oligoribonucleotide probes
bound more slowly and with the same Tm to DNA targets as corresponding 2'-deoxy
oligoribonucleotide probes. Because of their greatly enhanced Tm when bound to
RNA, 2'-O-methyl oligoribonucleotide probes can efficiently bind to double
stranded regions of structured RNA molecules. A 17 base 2'-O-methyl
oligoribonucleotide probe was able to bind a double-stranded region of rRNA
whereas the same 17 base 2'- deoxy oligoribonucleotide probe did not. Due to
their enhanced Tm when bound to RNA targets, shorter 2'-O-methyl
oligoribonucleotide probes can be used in assays in place of longer 2'-deoxy
oligoribonucleotide probes, resulting in enhanced discrimination between matched
and mismatched RNA targets. A 12 base 2'-O-methyl oligoribonucleotide probe had
the same Tm as a 19 base 2'-deoxy oligoribonucleotide probe when bound to a
matched RNA target but exhibited a much larger decrease in Tm than the 2'-deoxy
oligoribonucleotide probe when bound to an RNA target containing either 1 or 2
mismatched bases. The increased Tm, faster kinetics of hybridization, ability to
bind to structured targets and increased specificity of 2'-O-methyl
oligoribonucleotide probes render them superior to corresponding 2'-deoxy
oligoribonucleotides for use in assays that detect RNA targets.
PMID- 9547285
TI - Using neural networks for prediction of the subcellular location of proteins.
AB - Neural networks have been trained to predict the subcellular location of proteins
in prokaryotic or eukaryotic cells from their amino acid composition. For three
possible subcellular locations in prokaryotic organisms a prediction accuracy of
81% can be achieved. Assigning a reliability index, 33% of the predictions can be
made with an accuracy of 91%. For eukaryotic proteins (excluding plant sequences)
an overall prediction accuracy of 66% for four locations was achieved, with 33%
of the sequences being predicted with an accuracy of 82% or better. With the
subcellular location restricting a protein's possible function, this method
should be a useful tool for the systematic analysis of genome data and is
available via a server on the world wide web.
PMID- 9547286
TI - The effect of two antipodal fluorine-induced sugar puckers on the conformation
and stability of the Dickerson-Drew dodecamer duplex [d(CGCGAATTCGCG)]2.
AB - UV thermal melting studies, CD and NMR spectroscopies were employed to assess the
contribution of antipodal sugar conformations on the stability of the canonical B
DNA conformation of the Dickerson-Drew dodecamer duplex [[d(CGCGAATTCGCG)]2, (ODN
1)]. Different oligodeoxynucleotide versions of ODN 1 were synthesized with
modified thymidine units favoring distinct sugar conformations by using a 3'-
endo (north) 2'-fluoro-2'-deoxyribofuranosyl thymine (1) or a 2'- endo (south) 2'
fluoro-2'-deoxyarabinofuranosyl thymine (2). The results showed that two south
thymidines greatly stabilized the double helix, whereas two north thymidines
destabilized it by inducing a more A-like conformation in the middle of the
duplex. Use of combinations of north and south thymidine conformers in the same
oligo destabilized the double helix even further, but without inducing a
conformational change. The critical length for establishing a detectable A-like
conformation in the middle of a B-DNA ODN appears to be 4 bp. Our results suggest
that manipulation of the conformation of DNA in a sequence-independent manner is
possible.
PMID- 9547287
TI - Transverse formamide gradients as a simple and easy way to optimise DNA single
strand conformation polymorphism analysis.
AB - Although widely used, the detection of DNA mutations by the single-strand
conformation polymorphism (SSCP) method is often hampered by the need to examine
a large set of electrophoretic conditions in order to select the one suited to
the DNA sequence under study. We show here that the use of transverse chemical
gradient gels allows for a quick and easy optimisation of SSCP analysis, as
exemplified on two mutations in exon 2 of the alpha-1-antitrypsin gene.
PMID- 9547288
TI - Gel electrophoretic detection of 7,8-dihydro-8-oxoguanine and 7, 8-dihydro-8
oxoadenine via oxidation by Ir (IV).
AB - Two gel electrophoretic methods are described for detection of 7, 8-dihydro-8
oxoguanine and 7,8-dihydro-8-oxoadenine based on their further oxidation with one
electron oxidants including IrCl62-and IrBr62-. The products of nucleobase
oxidation lead to enhanced piperidine-sensitive cleavage and to highly visible
stop points in a primer extension assay. 8-oxoG and 8-oxoA lesions may be
distinguished by the latter's inability to be oxidized by IrBr62-compared to
IrCl62-Comparison is also made to oxidation by MnO4-.
PMID- 9547289
TI - Highly sensitive detection of gene expression of an intronless gene:
amplification of mRNA, but not genomic DNA by nucleic acid sequence based
amplification (NASBA).
AB - NASBA is an isothermal nucleic acid amplification reaction that amplifies mRNA in
a dsDNA background. Although similar to the sensitive reverse
transcription/polymerase chain reaction (RT-PCR) in mRNA detection, NASBA is not
prone to give false positive results caused by genomic dsDNA. Therefore, NASBA is
unique for sensitive detection of transcription of intronless genes, which
preclude strategies such as intron spanning primer pairs to control false
positive results in RT-PCR. Using NASBA, mRNA of the intronless human interferon
beta gene was demonstrated with a sensitivity of 10 copies, whereas 100 ng
genomic DNA gave a negative result.
PMID- 9547290
TI - A recombination based method to rapidly assess specificity of two-hybrid clones
in yeast.
AB - The yeast two-hybrid system is frequently used to identify protein-protein
interactions. Confirming the specificity of candidate clones requires separation
and isolation of yeast plasmids, propagation in bacteria and testing combinations
of DNA-binding and activation domain hybrids in yeast. In order to simplify this
procedure, we developed a rapid method based on PCR amplification of library
insert DNAs and in vivo cloning into the activation domain hybrid vector.
Reporter gene activity is assayed in parallel for combinations with different DNA
binding domain hybrids. Further characterization of inserts does not require
plasmid isolation and intermediate hosts.
PMID- 9547292
TI - Translocation of microtubules caused by the alphabeta, beta and gamma outer arm
dynein subparticles of Chlamydomonas.
AB - Three kinds of subparticles of Chlamydomonas outer-arm dynein containing the
alphabeta, beta and gamma heavy chains were isolated and assayed for their
activities to translocate microtubules in vitro. All of them had activities to
form bundles of microtubules in solution in an ATP-dependent manner and, when
adsorbed on an appropriate glass surface, translocated microtubules. The
alphabeta subparticle readily translocated microtubules on a silicone-coated
glass surface with a velocity of 4.6 micron/second at 1 mM ATP. The beta
subparticle translocated microtubules after it had been preincubated with tubulin
dimer and when the Brownian movement of microtubules was suppressed by addition
of methylcellulose. The velocity was on average 0.7 micron/second. The gamma
subparticle translocated microtubules after being preincubated with tubulin dimer
and adsorbed onto a silicone-coated glass surface. The velocity was about 3.8
micron/second. The tubulin dimer appeared to facilitate in vitro motility by
blocking the ATP-insensitive binding of dynein subparticles to microtubule. The
alphabeta, beta and gamma subparticles were thus found to have different
properties as motor proteins. In addition, these subparticles showed different
dependencies upon the potassium acetate concentration. Hence the outer-arm dynein
of Chlamydomonas is a complex of motor proteins with different properties.
PMID- 9547291
TI - Cell cycle-associated accumulation of tissue inhibitor of metalloproteinases-1
(TIMP-1) in the nuclei of human gingival fibroblasts.
AB - We first confirmed an earlier immunohistochemical study showing that
immunoreactive TIMP-1-like protein accumulated in the nuclei of human gingival
fibroblasts (Gin-1 cells), reaching a maximum in the S phase of the cell cycle
(Li, H., Nishio, K., Yamashita, K., Hayakawa, T. and Hoshino, T. (1995). Nagoya
J. Med. Sci. 58, 133-142). Then we isolated this protein from a nuclear extract
of Gin-1 cells and demonstrated it to be identical to human recombinant TIMP-1 by
western blotting, by a sandwich enzyme immunoassay for TIMP-1 and by an assay for
matrix metalloproteinase inhibition. The amount of TIMP-1 in the cytosolic
fraction of quiescent Gin-1 cells after stimulation by fetal calf serum increased
continuously for 48 hours, whereas that in the nuclear extract showed a maximum
at 24 hours (S phase) and significantly decreased thereafter. Gin-1 cells
expressed mRNAs for both TIMP-2 and TIMP-3 together with mRNA for TIMP-1.
However, neither TIMP-2 nor TIMP-3 proteins seemed to accumulate in the nuclei of
Gin-1 cells. These facts strongly suggest that TIMP-1 accumulates specifically in
the nuclei of Gin-1 cells in a cell cycle-dependent manner.
PMID- 9547293
TI - Osteopontin is a ligand for the alpha4beta1 integrin.
AB - Recent work has shown that osteopontin expression is upregulated at sites of
cardiovascular injury. It has been hypothesized that osteopontin provides an
adhesive matrix for endothelial and smooth muscle cells during remodeling of the
vascular wall following injury. Osteopontin has also been found to be synthesized
by monocytes and macrophages within injury sites. Here, we present data showing
that osteopontin can promote leukocyte adhesion through the alpha4beta1 integrin.
In the presence of physiologic concentrations of Mg2+ and Ca2+, osteopontin
purified from bovine milk promoted cell-substrate adhesion of HL-60 and Ramos
cells, two model leukocyte cell lines. As with other adhesive ligands, adhesion
to osteopontin required leukocyte activation. Under these conditions, no adhesion
to control substrates such as bovine serum albumin was observed. Leukocyte
adhesion was inhibited by anti-integrin antibodies directed at either the alpha4
or beta1 integrin subunits but not by control antibodies directed to other
integrins. Further adhesion experiments revealed that leukocyte binding to
osteopontin was completely inhibited by an alpha4beta1-binding peptide containing
the leucine-aspartate-valine (LDV) sequence, while a control, non-binding peptide
containing leucine-glutamate-valine (LEV) had minimal effects. Affinity
chromatography using either surface labeled HL-60 or Ramos cell extracts revealed
that the alpha4beta1 integrin specifically bound to osteopontin.
Immunoprecipitation of eluted fractions from these columns positively identified
the alpha4beta1 integrin. In order to localize potential alpha4beta1-binding
sites within osteopontin, the protein was proteolytically cleaved with thrombin.
A 30 kDa N-terminal osteopontin fragment purified using fast protein liquid
chromatography promoted alpha4beta1 dependent leukocyte adhesion in a manner
similar to that of the intact protein. These data collectively demonstrate that
the alpha4beta1 integrin is a new adhesion receptor for osteopontin and that an
alpha4beta1 binding site exists in the NH2-terminal thrombin fragment of
osteopontin.
PMID- 9547294
TI - Vitronectin regulates smooth muscle contractility via alphav and beta1 integrin.
AB - Previous work from this laboratory has established a method for maintaining
physiological contractility of dissociated avian smooth muscle in a defined
medium at low density. The present report emphasizes the dramatic potency of
serum to alter smooth muscle phenotype and induce a loss of contractility.
Vitronectin, a molecule purified from plasma, mimicked these effects of serum via
an integrin that is RGD-sensitive. Studies utilizing blocking antibodies against
vitronectin demonstrated that the presence of this specific adhesion molecule was
necessary for the serum-induced loss of contractility. Based on the actions of
function-blocking antibodies and RGD-containing peptides, the integrin
alphavbeta1 appears to be the primary receptor involved in vitronectin's ability
to induce phenotypic transformation in amniotic smooth muscle. The influence of
vitronectin on smooth muscle contractility is particularly relevant, because this
molecule is abundant in whole blood and plasma (approx. 400 microg/ml). The
results suggest that smooth muscle needs to be continually protected from normal
blood constituents in vivo. The implications of these results for smooth muscle
related diseases like atherosclerosis, restenosis and Kaposi's sarcoma are
discussed.
PMID- 9547295
TI - Up-regulation of p27Kip1, p21WAF1/Cip1 and p16Ink4a is associated with, but not
sufficient for, induction of squamous differentiation.
AB - Irreversible growth arrest is an early and integral part of squamous cell
differentiation in normal human epidermal keratinocytes (NHEKs) and is assumed to
be linked to the control of expression of differentiation-specific genes. In this
study, we examine the link between the molecular events associated with growth
arrest and the expression of differentiation genes. NHEKs that have been induced
to undergo growth arrest and differentiation by suspension culture contain
populations in both G1 and G2/M of the cell cycle. The irreversible growth arrest
state in NHEKs is characterized by an accumulation of the hypophosphorylated
forms of Rb and p130, with subsequent down-regulation of levels of Rb, up
regulation of p130 and associated down-regulation of E2F-regulated genes such as
cyclin A. These events correlate with an inhibition of G1 cdk activity, mediated
in part by an increase in the cdk inhibitors p21(WAF1/Cip1), p27(Kip1) and
p16(Ink4a). Flow cytometric and immunoblot analysis demonstrated that the timing
of the up-regulation of p27, p16 and p130 corresponds closely with the induction
of the squamous-specific genes cornifin alpha (SPRR-1) and transglutaminase type
I, suggesting a close link between control of growth arrest and differentiation.
However, growth arrest induced by over-expression of p27, p21 or p16 by
recombinant adenovirus is not sufficient to induce expression of the
differentiation genes, or to invoke the pattern of cell cycle regulatory protein
expression characteristic of the differentiation-specific irreversible growth
arrest. We conclude that growth arrest mediated by activation of the Rb pathway
is not sufficient to trigger terminal squamous differentiation and additional
signals which can be generated during suspension culture are required to promote
the complete differentiation program.
PMID- 9547296
TI - Opposite sorting and transcytosis of the polymeric immunoglobulin receptor in
transfected endothelial and epithelial cells.
AB - We have transfected a polarised endothelial cell line, ECV 304, and an epithelial
cell line, MDCK, with a well characterised epithelial protein, the rat polymeric
immunoglobulin receptor (pIgR), in order to study the protein sorting and
transcytosis in endothelial cells. The expressed protein was normally processed
and the steady state distribution between apical and basolateral surfaces was
similar in both cell types. MDCK cells, however, showed a marked polarity in the
delivery of newly synthesised pIgR to the cell surface, and in the release of
secretory component. 88% of newly synthesised pIgR in MDCK cells was first
delivered to the basolateral surface and 99% of secretory component was released
from the apical surface. In contrast the basolateral targeting signal of pIgR was
only partially recognised in endothelial cells, with 63% of the newly synthesised
pIgR being first delivered to the basolateral surface. At steady state only 43%
of the pIgR was found on the basolateral membrane. The direction of dimeric IgA
transcytosis in endothelial cells was from apical to basolateral surfaces,
opposite to that in MDCK cells. These data suggest that endothelial cells poorly
recognise the targeting signals of proteins from epithelial cells, and that the
direction of transcytosis is linked to the biological role of the cells.
PMID- 9547297
TI - Myofibrillar interaction of cytosolic creatine kinase (CK) isoenzymes: allocation
of N-terminal binding epitope in MM-CK and BB-CK.
AB - The molecular origin of the isoenzyme-specific interaction of cytosolic creatine
kinase isoenzymes, muscle-type creatine kinase and brain-type creatine kinase,
with myofibrillar structures has been studied by confocal microscopy in an
functional in situ binding assay with chemically skinned, unfixed skeletal muscle
fibers using wild-type and chimeric creatine kinase isoproteins. The specific
interaction of both wild-type isoforms with the sarcomeric structure resulted in
a stable, isoform-characteristic labeling pattern with muscle-type creatine
kinase bound exclusively and tightly to the sarcomeric M-band while brain-type
creatine kinase was confined to the I-band region. Chimeric proteins of both
muscle-type and brain-type creatine kinases were constructed to localize the
corresponding binding domain(s). Exchanged domains included the N-terminal part
(residues 1-234), the region containing an isoenzyme 'diagnostic box' (residues
235-285) and the C-terminal part (residues 286-380). The purified recombinant
proteins were all fully intact and enzymatically active. All chimeric proteins
containing the N-terminal region (amino acid 1-234) of muscle-type or brain-type
creatine kinase were always specifically targeted to the sarcomeric M-band or I
band, respectively. We therefore propose that the relevant epitope(s),
determining the isoenzyme-specific targeting in skeletal muscle, are entirely
located within the N-terminal regions of both cytosolic creatine kinase isoforms.
PMID- 9547298
TI - Roles of Ca2+, inositol trisphosphate and cyclic ADP-ribose in mediating
intercellular Ca2+ signaling in sheep lens cells.
AB - To further characterize how gap junction-dependent Ca2+ waves propagate between
sheep lens cells, we examined the possible roles of inositol 1,4,5-trisphosphate
(IP3), Ca2+ and cyclic ADP-ribose (cADPR) in mediating intercellular Ca2+ waves.
Second messengers were microinjected into a single cell in a monolayer of sheep
lens cells while monitoring cytosolic Ca2+ with fura-2 and fluorescence
microscopy. All three compounds initiated intercellular Ca2+ waves, but more
cells responded following the injection of either IP3 or cADPR than responded
following the injection of Ca2+. When either IP3 or cADPR was co-injected with
the Ca2+ chelator EGTA, cytosolic Ca2+ in the injected cell decreased but
cytosolic Ca2+ in the adjacent cells increased, indicating that the intercellular
messenger was IP3 or cADPR, rather than Ca2+. The phospholipase C inhibitor
U73122 eliminated mechanically initiated intercellular Ca2+ waves, indicating
that mechanical initiation probably requires IP3 production. In U73122-treated
cells, injected IP3 initiated an intercellular Ca2+ wave in which the number of
cells responding increased as the amount of IP3 injected increased, indicating
that the distance traveled by the Ca2+ wave was dependent on cell-to-cell
diffusion of IP3. In contrast, the ability of cADPR both to increase cytosolic
Ca2+ in the injected cell and to initiate intercellular Ca2+ waves was greatly
attenuated by U73122. In conclusion, Ca2+, IP3 and cADPR can all mediate
intercellular Ca2+ waves by passing through gap junction channels, but both IP3
and cADPR are more effective intercellular messengers than Ca2+.
PMID- 9547299
TI - Microtubule-mediated centrosome motility and the positioning of cleavage furrows
in multinucleate myosin II-null cells.
AB - To study centrosome motility and the interaction of microtubules with the cell
cortex in mitotic, post-mitotic and interphase cells, (alpha)-tubulin was tagged
in Dictyostelium discoideum with green fluorescent protein. Multinucleate cells
formed by myosin II-null mutants proved to be especially suited for the analysis
of the control of cleavage furrow formation by the microtubule system. After
docking of the mitotic apparatus onto the cell cortex during anaphase, the cell
surface is activated to form ruffles on top of the asters of microtubules that
emanate from the centrosomes. Cleavage furrows are initiated at spaces between
the asters independently of the positions of spindles. Once initiated, the
furrows expand as deep folds without a continued connection to the microtubule
system. Occurrence of unilateral furrows indicates that a closed contractile ring
is dispensable for cytokinesis in Dictyostelium. The progression of cytokinesis
in the multinucleate cells underlines the importance of proteins other than
myosin II in specifying a cleavage furrow. The analysis of centrosome motility
suggests a major role for a minus-end directed motor protein, probably
cytoplasmic dynein, in applying traction forces on guiding microtubules that
connect the centrosome with the cell cortex.
PMID- 9547300
TI - Identification of an interchromosomal compartment by polymerization of nuclear
targeted vimentin.
AB - A number of structural and functional subnuclear compartments have been
described, including regions exclusive of chromosomes previously hypothesized to
form a reactive nuclear space. We have now explored this accessible nuclear space
and interchromosomal nucleoplasmic domains experimentally using Xenopus vimentin
engineered to contain a nuclear localization signal (NLS-vimentin). In stably
transfected human cells incubated at 37 degrees C, the NLS-vimentin formed a
restricted number of intranuclear speckles. At 28 degrees C, the optimal
temperature for assembly of the amphibian protein, NLS-vimentin progressively
extended with time out from the speckles into strictly orientated intranuclear
filamentous arrays. This enabled us to observe the development of a system of
interconnecting channel-like areas. Quantitative analysis based on 3-D imaging
microscopy revealed that these arrays were localized almost exclusively outside
of chromosome territories. During mitosis the filaments disassembled and
dispersed throughout the cytoplasm, while in anaphase-telophase the vimentin was
recruited back into the nucleus and reassembled into filaments at the chromosome
surfaces, in distributions virtually identical to those observed in the previous
interphase. The filaments also colocalized with specific nuclear RNAs, coiled
bodies and PML bodies, all situated outside of chromosome territories, thereby
interlinking these structures. This strongly implies that these nuclear entities
coexist in the same interconnected nuclear compartment. The assembling NLS
vimentin is restricted to and can be used to delineate, at least in part, the
formerly proposed reticular interchromosomal domain compartment (ICD). The
properties of NLS-vimentin make it an excellent tool for performing structural
and functional studies on this compartment.
PMID- 9547302
TI - Two visual pigments in a single photoreceptor cell: identification and
histological localization of three mRNAs encoding visual pigment opsins in the
retina of the butterfly Papilio xuthus.
AB - This paper describes the localization of newly identified visual pigment opsins
in the tiered retina of the Japanese yellow swallowtail Papilio xuthus. We first
cloned three cDNAs encoding visual pigment opsins, PxRh1, PxRh2 and PxRh3, and
then carried out histological in situ hybridization to localize their mRNAs in
the retina. By combining the present data with our previous electrophysiological
results, we concluded that both PxRh1 and PxRh2 correspond to visual pigments
expressed in photoreceptor cells sensitive in the green wavelength region (green
receptors), whereas PxRh3 corresponds to a pigment in red receptors. The in situ
hybridization studies showed that some photoreceptor cells express two opsin
mRNAs. In the ventral half of the eye, all green receptors in the distal tier
were labelled by both PxRh1 and PxRh2 probes. The labelling by the PxRh2 and
PxRh3 probes was detected throughout the eye in the proximal tier; in 18 % of
ommatidia, the probes labelled the same photoreceptor cell. These results suggest
that the possible co-localization of two different visual pigments will broaden
the sensitivity spectrum of the photoreceptor cells.
PMID- 9547301
TI - Dynamic changes in the subnuclear organisation of pre-mRNA splicing proteins and
RBM during human germ cell development.
AB - RBM is a germ-cell-specific RNA-binding protein encoded by the Y chromosome in
all mammals, implying an important and evolutionarily conserved (but as yet
unidentified) function during male germ cell development. In order to address
this function, we have developed new antibody reagents to immunolocalise RBM in
the different cell types in the human testis. We find that RBM has a different
expression profile from its closest homologue hnRNPG. Despite its ubiquitous
expression in all transcriptionally active germ cell types, RBM has a complex and
dynamic cell biology in human germ cells. The ratio of RBM distributed between
punctate nuclear structures and the remainder of the nucleoplasm is dynamically
modulated over the course of germ cell development. Moreover, pre-mRNA splicing
components are targeted to the same punctate nuclear regions as RBM during the
early stages of germ cell development but late in meiosis this spatial
association breaks down. After meiosis, pre-mRNA splicing components are
differentially targeted to a specific region of the nucleus. While pre-mRNA
splicing components undergo profound spatial reorganisations during
spermatogenesis, neither heterogeneous ribonucleoproteins nor the transcription
factor Sp1 show either developmental spatial reorganisations or any specific co
localisation with RBM. These results suggest dynamic and possibly multiple
functions for RBM in germ cell development.
PMID- 9547303
TI - Rhodopsin-like proteins in planarian eye and auricle: detection and functional
analysis
AB - The presence of rhodopsin-like proteins in the eyes and auricles of the
freshwater planarian Dugesia japonica was confirmed using anti-frog-rhodopsin
rabbit IgG. The apparent relative molecular masses of these proteins were
65x10(3) and 62x10(3), and positive reactions to IgG were localized to the
microvilli of the photoreceptor cells in the eyes and to the sensory cilia,
rootlets and microvilli in the auricles. Eye- or head-excised planarians showed
no negative phototaxis, whereas intact or auricle-excised planarians did. During
regeneration in head-excised planarians, the appearance of rhodopsin-like
proteins in the regenerating eyes corresponded to the recovery of negative
phototaxis behaviour. Head or auricle excision enhanced asexual fission under
continuous illumination. However, eye excision had no such effect. These results
suggest that the rhodopsin-like proteins in the eyes work as photoreceptors for
negative phototaxis behaviour and that, in the auricles, they are involved in
asexual fission originating from the circadian rhythm.
PMID- 9547305
TI - Intracellular electrolyte levels and transport of secretory granules in exocrine
gland cells
AB - We demonstrate the intracellular transport of secretory granules of a silk
protein, fibroin, from the Golgi region to the apical cytoplasm with special
reference to microtubule organization, electrolyte concentrations and the acidic
intragranular pH of normal and mutant posterior silk gland cells, using the
techniques of electrophysiological microelectrode and microprobe analysis and of
light and electron microscopic autoradiography. The silk gland cells of a
recessive mutant making only flimsy cocoons were defective in the microtubule
systems, did not stain with an anti-tubulin antibody in immunofluorescent
microscopy, and accumulated intracellular granules in the apical and basal
cytoplasm. The increase in intracellular calcium concentration and levels of
chloride secretion were also reduced in the mutant cells. A carboxylic ionophore,
monensin, which collapsed the granular H+ gradient, induced the transport of
chloride and an increase in the intracellular calcium concentration, while it
blocked the intracellular transport of granules from the Golgi region to the
apical cytoplasm in normal cells. Thus, we conclude that the H+ gradient across
the membrane of secretory granules is responsible for the intracellular transport
of the secretory granules along the microtubule systems in silk gland cells,
while Ca2+ is thought to be required for the exocytosis of the granules.
PMID- 9547304
TI - Microtubules facilitate the stimulated secretion of beta-hexosaminidase in
lacrimal acinar cells.
AB - Stimulation of lacrimal acini with secretagogues such as carbachol initiates
movement and fusion of acinar secretory vesicles with the apical plasma membrane,
resulting in release of protein into the nascent tear fluid. Using rabbit
lacrimal acini reconstituted in vitro from isolated cells, we have investigated
the organization of the apical cytoskeleton and its role in stimulated secretion.
Confocal microscopy revealed a microtubule array emanating from the apical region
of the acini; the apical region was also enriched in microfilaments and (gamma)
tubulin. Cytokeratin-based intermediate filaments were apically concentrated, and
also detected at the cell periphery. Neither confocal microscopy nor biochemical
analysis revealed any reorganization of lumenal microfilaments or microtubules
which might accompany carbachol-stimulated release of secretory proteins.
However, major changes in the acinar microtubule array induced by taxol or
nocodazole were correlated with inhibition of carbachol-dependent release of the
secreted protein, beta-hexosaminidase. Major changes in lumenal microfilaments
induced by jasplakinolide or cytochalasin D did not inhibit the carbachol
dependent release of beta-hexosaminidase; rather, release of beta-hexosaminidase
from jasplakinolide- or cytochalasin D-treated carbachol-stimulated acini was
markedly increased relative to the release from untreated stimulated acini. Our
findings demonstrate that microtubules play a major role in stimulated lacrimal
secretion, and suggest a contributory role for microfilaments.
PMID- 9547307
TI - Neuronal mechanisms underlying the facilitatory control of uropod steering
behaviour during treadmill walking in crayfish. I. Antagonistically regulated
background excitability of uropod motoneurones
AB - One of the postural reflexes of crayfish, the uropod steering response, is
elicited by specific sensory inputs while the animal is walking. It is not
elicited, however, by the same inputs when the animal is at rest. To clarify the
neuronal mechanisms underlying this facilitatory control of body posture in the
active animals, we used intracellular recordings to analyse the synaptic
activities of uropod motor system neurones in an unanaesthetized whole-animal
preparation. Several uropod motoneurones were found to receive sustained
depolarizing inputs during walking, whereas the walking leg motoneurones sampled
always showed rhythmic activity. The membrane conductance of the uropod
motoneurones increased during the sustained synaptic activity. Premotor
nonspiking interneurones showed depolarizing or hyperpolarizing membrane
potential changes during walking that were also accompanied by increases in
membrane conductance. Some of these interneurones enhanced uropod motoneurone
activity, whereas others suppressed it during walking. These results suggest that
the background excitability of uropod motoneurones is kept at an intermediate
level during walking by the antagonistic inputs from premotor nonspiking
interneurones so that the uropod motor system can be responsive to both further
excitatory and inhibitory inputs resulting from postural changes.
PMID- 9547306
TI - The distribution and translocation of the G protein ADP-ribosylation factor 1 in
live cells is determined by its GTPase activity.
AB - ADP-ribosylation factors (ARF) are small G proteins that play key roles in
vesicular transport processes. We have studied the distribution of ARF1 in live
cells using chimeras of ARF1 mutants (wild type (wt) ARF1; Q71L-ARF1 (reduced
GTPase); T31N (low affinity for GTP); and (Delta)Nwt (deletion of amino acids 2
18)) with green fluorescent protein (GFP). Confocal microscopy studies showed
that the wt and Q71L proteins were localized in the Golgi and cytoplasm. The
(Delta)Nwt and the T31N mutants were exclusively cytoplasmic. The behavior of the
wt and Q71L proteins was studied in detail. About 15% of wt-ARF1-GFP was bound to
the Golgi. Bound wt-ARF1-GFP dissociated rapidly after addition of Brefeldin A
(BFA). This process did not appear to be a consequence of BFA-induced
disappearance of the Golgi. Photobleaching recovery showed that essentially all
the ARF-GFP was mobile, although it diffused very slowly. In contrast, about 40
50% of the Q71L mutant was found in the Golgi, and its rate of dissociation in
the presence of BFA was slow and biphasic. Q71L-ARF1-GFP diffused more slowly
than the wt. We conclude that ARF1 proteins exist in a dynamic equilibrium
between Golgi-bound and cytosolic pools, and that the translocation of ARF in
live cells requires the hydrolysis of GTP by the Golgi-bound protein.
PMID- 9547308
TI - Actin mRNA isoforms are differentially sorted in normal osteoblasts and sorting
is altered in osteoblasts from a skeletal mutation in the rat.
AB - Actin isoform sorting has been shown to occur in a variety of cell types in
culture. To this list we add osteoblasts, in which we show by in situ
hybridization that beta-actin is distributed primarily in cell processes and on
one side of the nucleus and gamma-actin has a perinuclear distribution.
Osteoblasts from the skeletal mutation toothless (tl), evaluated under identical
conditions, fail to sort these actin isoforms differentially and exhibit diffuse
labeling as their major manifestation. Northern analyses of actin mRNAs showed no
differences between normal and mutant cultures. Shortened osteoblast life span
and an inability to direct osteoclast-mediated bone resorption have recently been
demonstrated in tl mutants. The present results suggest that a failure of
osteoblasts to sort actin mRNAs may be related to one or both of these
pathological manifestations in this mutation and represent, to our knowledge, the
first correlation of an actin mRNA-sorting abnormality with a mammalian disease.
PMID- 9547309
TI - Nuclear envelope disassembly in mitotic extract requires functional nuclear pores
and a nuclear lamina.
AB - Using sea urchin embryonic and in-vitro-assembled nuclei incubated in sea urchin
mitotic extract, I provide evidence for a requirement for functional nuclear
pores and a nuclear lamina for nuclear envelope disassembly in vitro. In
interphase gastrula nuclei, lamin B interacts with p56, an integral protein of
inner nuclear membrane cross-reacting with antibodies to human lamin B receptor.
Incubation of gastrula nuclei in mitotic cytosol containing an ATP-generating
system rapidly induces hyperphosphorylation of p56 and lamin B. Subsequently, p56
lamin B interactions are weakened and the two proteins segregate into distinct
nuclear envelope-derived vesicles upon disassembly of nuclear membranes and of
the lamina. Nuclear disassembly is accompanied by chromatin condensation.
Blocking nuclear pore function with wheat germ agglutinin or antibodies to
nucleoporins prevents p56 and lamin B hyperphosphorylation, nuclear membrane
breakdown and lamina solubilization. These events are not rescued by
permeabilization of nuclear membranes to molecules of 150, 000 Mr with
lysolecithin. In-vitro-assembled nuclei containing nuclear membranes with
functional pores but no lamina do not disassemble in mitotic cytosol in spite of
p56 hyperphosphorylation. Nuclear import of soluble lamin B and reformation of a
lamina in interphase extract restores nuclear disassembly in mitotic cytosol. The
data indicate a role for functional nuclear pores in nuclear disassembly in
vitro. They show that p56 hyperphosphorylation is not sufficient for nuclear
membrane disassembly in mitotic cytosol and argue that the nuclear lamina plays a
critical role in nuclear disassembly at mitosis.
PMID- 9547310
TI - Neuronal mechanisms underlying the facilitatory control of uropod steering
behaviour during treadmill walking in crayfish. II. Modulation Of uropod
motoneurone excitation by leg proprioception
AB - The synaptic activities underlying the uropod steering behaviour of crayfish
evoked by tilting the substratum beneath the legs have been studied
intracellularly in unanaesthetized animals standing or walking on a treadmill.
The uropod motoneurones showed little or no synaptic response when the treadmill
was tilted while the animal was in a quiescent state and the membrane potential
was at its resting value. When the same stimulus was given while the animal was
walking or in an active stance on the treadmill, the motoneurones showed
transient much-enhanced excitatory or inhibitory responses to tilt, depending on
the tilt direction. These responses were superimposed on a sustained level of
background excitation so that the spike activity of the motoneurones either
increased or decreased. Premotor nonspiking interneurones also showed little or
no synaptic response to the tilt stimulus while the animal was resting, but
greatly enhanced responses, in either a depolarizing or a hyperpolarizing
direction, while the animal was walking or in the active-standing state. The
results indicate that the proprioceptor inputs converging onto the uropod
motoneurones, either directly or through premotor nonspiking interneurones, are
gated not only in the uropod motor system in the terminal abdominal ganglion but
also at as yet unidentified sites upstream in anterior ganglia, thus suggesting
multiple gate control of the descending proprioceptor pathway.
PMID- 9547312
TI - Multilayer reflectors in animals using green and gold beetles as contrasting
examples
AB - The light reflectors in the beetles Calloodes grayanus and Anoplognathus parvulus
are examined. Contrasting multilayer reflectors are revealed. Calloodes grayanus
appears a weak green colour, matching its background leaves, while A. parvulus is
strongly metallic-gold coloured. The former reflection is diffuse, as the result
of a structure causing scattering that overlies the multilayer reflector, whereas
the latter reflection is strongly directional. The green colour of C. grayanus is
achieved by a multilayer reflector with a fixed spatial periodicity, here termed
'regular', which is far removed from the quarterwave, or physically 'ideal',
condition. The gold colour of A. parvulus is achieved by a type of reflector
which involves systematically changing optical thicknesses of the component
layers with depth in the structure. A layer of melanin underlies the reflector of
C. grayanus to absorb the transmitted portion of light and prevent its back
reflectance, which would otherwise alter the green colour. The resultant
structural reflectance from C. grayanus effectively matches green pigments, which
are rare in beetles.
PMID- 9547311
TI - Contributions of extracellular and intracellular domains of full length and
chimeric cadherin molecules to junction assembly in epithelial cells.
AB - The integrity of cell-cell junctions in epithelial cells depends on functional
interactions of both extracellular and intracellular domains of cadherins with
other junction proteins. To examine the roles of the different domains of E
cadherin and desmoglein in epithelial junctions, we stably expressed full length
desmoglein 1 and chimeras of E-cadherin and desmoglein 1 in A431 epithelial
cells. Full length desmoglein 1 was able to incorporate into or disrupt
endogenous desmosomes depending on expression level. Each of the chimeric
cadherin molecules exhibited distinct localization patterns at the cell surface.
A chimera of the desmoglein 1 extracellular domain and the E-cadherin
intracellular domain was distributed diffusely at the cell surface while the
reverse chimera, comprising the E-cadherin extracellular domain and the
desmoglein 1 intracellular domain, localized in large, sometimes contiguous
patches at cell-cell interfaces. Nevertheless, both constructs disrupted
desmosome assembly. Expression of constructs containing the desmoglein 1
cytoplasmic domain resulted in approximately a 3-fold decrease in E-cadherin
bound to plakoglobin and a 5- to 10-fold reduction in the steady-state levels of
the endogenous desmosomal cadherins, desmoglein 2 and desmocollin 2, possibly
contributing to the dominant negative effect of the desmoglein 1 tail. In
addition, biochemical analysis of protein complexes in the stable lines revealed
novel in vivo protein interactions. Complexes containing beta-catenin and
desmoglein 1 were identified in cells expressing constructs containing the
desmoglein 1 tail. Furthermore, interactions were identified between endogenous E
cadherin and the chimera containing the E-cadherin extracellular domain and the
desmoglein 1 intracellular domain providing in vivo evidence for previously
predicted lateral interactions of E-cadherin extracellular domains.
PMID- 9547313
TI - Curve walking in freely moving crayfish (Procambarus clarkii)
AB - The curve walking of freely moving crayfish trained to walk along a curved path
during homing behaviour was investigated using a video-analysis system. The leg
kinematics and leg phase relationships, as well as the relationship between
stepping patterns and body axis rotation measured relative to external
references, were studied.
The anterior and posterior extreme positions of the
power stroke (AEP and PEP, respectively) and step amplitudes were analysed. As in
a previous study on crayfish curve walking on a treadmill, PEPs were more
posterior in outer legs (the legs on the outside of the turn) than in the inner
legs. As a result, outer legs showed larger step amplitudes than inner legs. Leg
kinematics varied within each walking sequence. AEP leg angles (the angles
between the body and leg axes at the AEP) tended to decrease over time for inner
legs and increase for outer legs. This leg angle drift was present mainly in the
anterior legs and it suggests that these legs did not completely compensate for
the body rotation after each step. In addition, leg angle asymmetries in a
direction opposite to that of leg angle drift were observed at the start of each
curve-walking sequence, suggesting that the extensive training (3 weeks) may have
allowed crayfish to anticipate the leg angle drift.
The rotational component
of curve walking showed a discontinuous pattern, with the animal's body axis
turning towards the inside of the curve only periodically. Analysis of cross
correlation functions showed that the angular acceleration of the body axis in
the direction of the turn occurred during the power strokes of inner legs 2 and 5
and outer leg 4. While the tripod formed by these three legs showed in-phase
relationships, the legs of the corresponding contralateral tripod (outer legs 2
and 5 and inner leg 4) were not in phase. We hypothesize that inner legs 2 and 5
and outer leg 4 act synergically causing the inward body rotation observed in
curve-walking crayfish and that some of the asymmetries found in step geometry
may be a passive phenomenon due to the body rotation.
PMID- 9547314
TI - Orthodromically and antidromically evoked local field potentials in the crayfish
olfactory lobe
AB - A local field potential, consistent in form and duration, can be recorded from
the olfactory lobe of crayfish following electrical stimulation of the outer
flagellum of the antennule. The field potential is reversibly blocked by
perfusion of the brain with low-[Ca2+] saline or
-aminobutyric acid and, to a lesser extent, histamine. Paired
shocks to the antennule and antidromic electrical stimulation of olfactory lobe
output neurones also partially block the field potential. Comparing the field
potential with simultaneously recorded intracellular responses of olfactory
interneurones reveals a coincidence between excitatory and inhibitory effects in
the interneurones and the appearance of identifiable components of the field
potential. We interpret the field potential to reflect the response of neural
elements in the olfactory lobe to orthodromic activity in the axons of the
olfactory receptor neurones on the antennule. We conclude from the blocking
experiments that the greater part of the field potential stems from neurones in
the olfactory lobe that are postsynaptic to olfactory receptor neurones. As such,
it provides a robust indication of olfactory neurone activity.
PMID- 9547315
TI - Conservation and variation in the feeding mechanism of the spiny dogfish squalus
acanthias
AB - Changes in the feeding mechanism with feeding behavior were investigated using
high-speed video and electromyography to examine the kinematics and motor pattern
of prey capture, manipulation and transport in the spiny dogfish Squalus
acanthias (Squalidae: Squaliformes). In this study, Squalus acanthias used both
suction and ram behaviors to capture and manipulate prey, while only suction was
used to transport prey. The basic kinematic feeding sequence observed in other
aquatic-feeding lower vertebrates is conserved in the spiny dogfish. Prey
capture, bite manipulation and suction transport events are characterized by a
common pattern of head movements and motor activity, but are distinguishable by
differences in duration and relative timing. In general, capture events are
longer in duration than manipulation and transport events, as found in other
aquatic-feeding lower vertebrates. Numerous individual effects were found,
indicating that individual sharks are capable of varying head movements and motor
activity among successful feeding events. Upper jaw protrusion in the spiny
dogfish is not restricted by its orbitostylic jaw suspension; rather, the upper
jaw is protruded by 30 % of its head length, considerably more than in the lemon
shark Negaprion brevirostris (Carcharhinidae: Carcharhiniformes) (18 %) with its
hyostylic jaw suspension. One function of upper jaw protrusion is to assist in
jaw closure by protruding the upper jaw as well as elevating the lower jaw to
close the gape, thus decreasing the time to jaw closure. The mechanism of upper
jaw protrusion was found to differ between squaliform and carcharhiniform sharks.
Whereas the levator palatoquadrati muscle assists in retracting the upper jaw in
the spiny dogfish, it assists in protruding the upper jaw in the lemon shark.
This study represents the first comprehensive electromyographic and kinematic
analysis of the feeding mechanism in a squaliform shark.
PMID- 9547316
TI - Ventilation and acid-base recovery following exhausting activity in an air
breathing fish
AB - The effects of exhausting activity in normoxic (PO2=20.7 kPa) and hypoxic
(PO2<2.7 kPa) water on ventilatory, metabolic and acid-base variables were
examined in spotted gar (Lepisosteus oculatus) to determine the role of the air
breathing organ in supporting active metabolism and recovery. The level of
aquatic hypoxia used effectively eliminated the gills as a site of O2 uptake,
forcing the fish to respire as a unimodal air-breather. Swimming duration (until
exhaustion) was not significantly different in normoxic and hypoxic water. Blood
gas, acid-base, cardiovascular and ventilatory variables were monitored at
intervals from 15 min to 24 h post-exercise. Fish survived exhaustive exercise
using a combination of anaerobic metabolism and increased ventilation (aerial and
aquatic), despite respiratory and metabolic acidoses. The cardiovascular effects
of exercise (heart rate and dorsal aortic blood pressure) were minor. The
metabolic effects of exercise were similar to those in unimodal water-breathing
fish; however, even hypoxic animals recovered from exhaustive exercise by 24 h.
Thus, the results of this study show that air breathing in L. oculatus allows gar
to exercise to the same extent in normoxic and hypoxic water and enables them to
re-establish blood gas and acid-base balance after exhaustive activity even in
hypoxic water.
PMID- 9547317
TI - A note on interactions between temperature, viscosity, body size and swimming
energetics in fish larvae
AB - In a previous study, it was shown that at a given speed the larvae of a species
of freshwater fish, the Danube bleak Chalcalburnus chalcoides, expended
considerably more metabolic energy at 15 degreesC than at 20 degreesC. We applied
hydromechanical arguments to our previous data in order to determine whether the
higher cost of swimming at the lower temperature might be due to the effects of
viscous forces. However, even under the unrealistic assumption of the larvae
swimming in the viscous regime at Reynolds numbers as high as 2000, we show here
that hydromechanical forces cannot explain the high energy cost of swimming at 15
degreesC. Instead, we offer a new hypothesis that the 'two-gear system' of the
swimming muscles operating in juvenile and adult fish is not yet functional in
the larvae, with the consequence that, when these fish are swimming at high
speeds in cold water, the muscle fibres have to operate over an increasingly
inefficient range of shortening velocities.
PMID- 9547318
TI - The impact of endurance training on arterial plasma K+ levels and swimming
performance of rainbow trout
AB - Arterial plasma K+ and lactate concentrations ([K+]a and [lactate]a), as well as
blood oxygenation status, were measured in relation to increasing swimming speeds
in rainbow trout Oncorhynchus mykiss. Neither [K+]a nor [lactate]a changed at
swimming speeds below 1.5 BL s-1, where BL is total body length. Between 1.5 and
2.0 BL s-1, [K+]a started to increase, and above 2.0 BL s-1 both [K+]a and
[lactate]a increased with swimming speed. Training shifted the onset of these
increases to higher swimming speeds and increased the critical swimming speed
(Ucrit) from 2.4 to 3.0 BL s-1. Blood oxygen content showed no changes in control
fish, whereas in trained fish it increased by 22 % at the final swimming speed.
From the [K+]a data, we suggest that no loss of K+ occurred from the working
muscle at low swimming speeds, allowing an unlimited endurance, whereas moderate
and higher speeds were probably associated with a loss of K+ from the working
muscles, indicating a limited endurance.
PMID- 9547319
TI - Tissue and whole-body extracellular, red blood cell and albumin spaces in the
rainbow trout as a function of time: a reappraisal of the volume of the secondary
circulation
AB - [58Co]EDTA, [51Cr]RBC and [125I]albumin spaces in the whole body and 28 tissue
samples were examined at timed intervals over 16 h in rainbow trout Oncorhynchus
mykiss. [58Co]EDTA space (which approximates extracellular fluid volume; ECF) in
fins, skin, gallbladder and eye are reported for the first time. After a 16 h
equilibration, ECF volume was large (376-726 microl g-1 wet tissue mass) in
kidney, swimbladder, skin and fins, moderate (219-313 microl g-1 wet tissue mass)
in stomach, skull, spleen, liver, intestine, gills, eye and cecum, and small (53
181 microl g-1 wet tissue mass) in red muscle, fat, brain, gallbladder and white
muscle. Whole-body ECF was 387+/-10.6 microl g-1 (mean +/- s.e.m.; N=11).
[51Cr]RBC space relative to [58Co]EDTA space was large in spleen, liver,
intestine and gill, and low in skin, fins, stomach and skull. Whole-body
[51Cr]RBC space was 9.9+/-0.6 microl g-1 body mass (N=17). Blood volume
calculated from [51Cr]RBC space at 16 h and a dorsal aortic hematocrit of 24.5 %
was 40.4 microl g-1 body mass. Whole-body [125I]albumin space at 16 h was 118.0+/
7.4 microl g-1 body mass (N=6), which resulted in an estimated blood volume of
156. 6 microl g-1 body mass, nearly four times that estimated from the [51Cr]RBC
space. Tissue hematocrits, calculated from [125I]albumin and [51Cr]RBC spaces,
were significantly lower than dorsal aortic hematocrit in all tissues except
spleen, kidney and liver. [58Co]EDTA and [51Cr]RBC spaces reached equilibrium in
nearly all tissues within 1 h, whereas [125I]albumin continued to accumulate in
many tissues up 24 h. The disparity between [125I]albumin distribution kinetics
compared with the kinetics of [58Co]EDTA and [51Cr]RBC distribution, as well as
the accumulation of [125I]albumin in tissues not known to have a secondary
circulation, indicates that [125I]albumin is a poor marker of plasma volume in
trout and that previous studies based on [125I]albumin clearance from the plasma
have overestimated both the volume and the turnover rate of the secondary system.
Revised estimates of secondary circulation volume, based on [58Co]EDTA
distribution rate, indicate that it is no more than 10-20 % of the volume of the
primary circulation.
PMID- 9547320
TI - Neuromuscular sensitivity to hydrogen sulfide in the marine invertebrate Urechis
caupo.
AB - Hydrogen sulfide (HS) is a well-known inhibitor of aerobic respiration via its
reversible binding of mitochondrial cytochrome c oxidase, but recent studies have
suggested that HS may have other non-respiratory actions. We have studied the
effects of HS on spontaneous and evoked contractions in vitro under hypoxic and
anoxic conditions in nerve-muscle preparations from the echiuran worm Urechis
caupo. Contraction amplitude in response to electric field stimulation under
anoxic conditions was completely abolished by HS within minutes in a classic dose
response relationship (Kd=31 mmol l-1, r2=0.86). Exposure of body wall and
esophagus to HS in vitro for up to 6 h demonstrated that the contraction
amplitude and frequency of spontaneous activity were relatively insensitive to
anoxia, but that the sensitivity to HS was similar to that seen in field
stimulated muscle (Kd=2.7-32 mmol l-1). The toxic effects of HS were reversible,
with almost complete recovery under anoxic conditions within the first hour.
These data indicate that HS at millimolar concentrations can directly inhibit
muscle contraction. Although the mechanism of this action is unknown, it does not
appear to involve metabolic pathways or oxygen transport.
PMID- 9547322
TI - Effect of cyclical salinity changes on cell volume and function in geukensia
demissa gills
AB - We acclimated the estuarine mussel Geukensia demissa to a regime of sinusoidal
salinity cycling (12 h cycle between 100 % and 60 % seawater) and correlated
changes in the volume of gill cells with changes in several indicators of the
functional status of gill cells (rate of O2 consumption, ATP content and amino
acid transport). There was no indication of short-term volume regulation in the
gill cells of mussels acclimated to salinity cycling. When exposed to cycling
salinity, cell water space consistently increased to approximately 3 ml g-1 dry
mass during the cycle troughs (60 % seawater) and returned to approximately 2 ml
g-1 dry mass at the cycle peaks (100 % seawater). In mussels acclimated for 2
weeks to cycling salinity, the gill contents of betaine, taurine and K+ were
unchanged (approximately 240, 230 and 160 micromol g-1 dry mass, respectively)
between the 60 % and 100 % seawater portions of the salinity cycle. The changes
in cell volume did not appear to be associated with large perturbations in the
functional status of cells. The rate of O2 consumption was approximately 100
microl O2 g-1 dry mass min-1, and ATP content was approximately 30 micromol g-1
protein, in all salinities to which mussels were exposed. Rates of uptake of
taurine, leucine and phenylalanine decreased by approximately 50 % during the
first sinusoidal decrease to 60 % seawater, but recovered following re-exposure
to 100 % seawater. Uptake rates of all three amino acids were unaffected by any
subsequent salinity cycles. These results suggest (1) that the regulation of gill
cell volume is normally absent from mussels exposed to repeated, gradual salinity
changes, and (2) that any effects of changes in cell volume are not severe enough
to justify the energetic expenditure that would be associated with repeated
regulation of cell volume. Unlike the response of gill cells to cycling salinity,
there was a decrease in the solute contents of ventricles during the salinity
troughs compared with the salinity peaks, suggesting that the presence of short
term volume regulation may be more critical in the ventricle.
PMID- 9547321
TI - Cell volume regulation in proximal renal tubules from trout (Salmo trutta).
AB - Regulatory volume decrease (RVD) following hypo-osmotic stimulation was studied
using videometric methods in isolated proximal renal tubules from trout (Salmo
trutta). The relative tubule diameter increased by 132.0+/-4.8 % (maximum
swelling within 1 min at 15 and 25 degrees C and within 4 min at 10 degrees C)
following a change from iso-osmotic (290 mosmol kg-1) to hypo-osmotic (160 mosmol
kg-1) Ringer's solution. The tubule diameter subsequently decreased to
approximately one-quarter of the maximal value. Ouabain (1 mmol l-1) reduced cell
swelling and inhibited the RVD response by 28.0+/-10.5 %. Furthermore, increasing
the bath K+ concentration by 30 mmol l-1 inhibited RVD by 76.5+/-3.6 %. The K+
channel blocker quinine, but not Ba2+ (1 and 2 mmol l-1), significantly decreased
the RVD response (by 25.0+/-5.4 and 72.3+/-5.1 % at 0.1 and 0.5 mmol l-1,
respectively). Similarly, increasing the Cl- concentration in the bath from 47 to
102 mmol l-1 induced a significant reduction (45. 2+/-7.9 %) in RVD. The RVD
response was also markedly reduced (by 54. 7+/-5.3 %) by the Cl- channel blocker
indacrinone (MK-196; 0.5 mmol l-1), but only marginally by 5-nitro-2-(3
phenylpropylamino)benzoic acid (NPPB; 1, 5, 8 and 10 micromol l-1). Addition of
the K+/Cl- symport inhibitor furosemide (0.1 mmol l-1) resulted in a 39.8+/-3.9 %
inhibition of RVD. This inhibition could be completely overcome by simultaneous
administration of 1 micromol l-1 tributyltin (anion exchanger) and furosemide.
Chelation of either extracellular (1 mmol l-1 EGTA) or both extra- and
intracellular Ca2+ (1 mmol l-1 EGTA, 10 micromol l-1 A23187) had no effect on
this RVD process. Furthermore, as measured using the fluorescent dye Fura-2/AM,
there was no increase in the intracellular free Ca2+ concentration upon hypo
osmotic stimulation. Administration of the 5-lipoxygenase antagonist ETH 615-139
(20 micromol l-1), however, induced a 60 % inhibition of RVD. Simultaneous
addition of ETH-615 and either the K+ ionophore gramicidin (0.5 mmol l-1) or the
anion exchanger tributyltin (1 micromol l-1) could not reverse the ETH 615-139
inhibition. Finally, administration of the cycloxygenase inhibitor indomethacin
had only a small, but significant, effect on RVD. We conclude that RVD following
hypo-osmotic swelling is in these cells a temperature- and ouabain-sensitive
process that appears to be the result of K+ efflux through quinine-sensitive,
Ba2+-insensitive K+ channels and Cl- efflux through an MK-196- and furosemide
sensitive Cl- conductance that is relatively unaffected by NPPB. This KCl efflux
seems to be regulated by eicosanoids produced by the 5-lipoxygenase. Arachidonic
acid metabolites from the cycloxygenase pathway are not involved in this process.
Similarly, neither extra- nor intracellular Ca2+ appears to be important for the
signalling of RVD.
PMID- 9547323
TI - Visual pigments, oil droplets and cone photoreceptor distribution in the european
starling (Sturnus vulgaris)
AB - Microspectrophotometric measurements of retinal photoreceptors from the European
starling (Sturnus vulgaris) revealed four classes of single cone, containing
visual pigments with wavelengths of maximum absorbance (
max) at 563, 504, 449 and close to 362 nm. The two longer
wave-sensitive single cones contained brightly coloured oil droplets which cut
off light below 572 and 514 nm, respectively. The 449 nm
max pigment was associated with a 'colourless' oil droplet
with peak measured absorptance below 400 nm. The ultraviolet-sensitive visual
pigment was paired with a transparent oil droplet which showed no significant
absorption above 350 nm. A single class of double cone was identified, both
members of which contained the longwave-sensitive (
max 563 nm) visual pigment. The principal member of the
double cone contained an oil droplet with a topographically variable cut-off
wavelength below 471 nm; the oil droplet found in the accessory member was only
measured in the ventral retina and displayed three distinct peaks of absorption
at approximately 430, 450 and 480 nm. Rod photoreceptors had a
max at 503 nm. A new polynomial for fitting visual pigment
templates to ultraviolet-sensitive visual pigment data is given. Topographic
density measurements of the different cone classes were made using Nitroblue
tetrazolium chloride to label selectively bleached photoreceptors. The two
classes of shortwave-sensitive single cone were more abundant in the dorsal
retina, and longwave-sensitive single cones were notably less abundant in the
dorso-temporal region of the retina, which subserves binocular vision.
PMID- 9547324
TI - Experimental approaches towards interpreting dolphin-stimulated bioluminescence.
AB - Flow-induced bioluminescence provides a unique opportunity for visualizing the
flow field around a swimming dolphin. Unfortunately, previous descriptions of
dolphin-stimulated bioluminescence have been largely anecdotal and often
conflicting. Most references in the scientific literature report an absence of
bioluminescence on the dolphin body, which has been invariably assumed to be
indicative of laminar flow. However, hydrodynamicists have yet to find compelling
evidence that the flow remains laminar over most of the body. The present study
integrates laboratory, computational and field approaches to begin to assess the
utility of using bioluminescence as a method for flow visualization by relating
fundamental characteristics of the flow to the stimulation of naturally occurring
luminescent plankton. Laboratory experiments using fully developed pipe flow
revealed that the bioluminescent organisms identified in the field studies can be
stimulated in both laminar and turbulent flow when shear stress values exceed
approximately 0.1 N m-2. Computational studies of an idealized hydrodynamic
representation of a dolphin (modeled as a 6:1 ellipsoid), gliding at a speed of 2
m s-1, predicted suprathreshold surface shear stress values everywhere on the
model, regardless of whether the boundary layer flow was laminar or turbulent.
Laboratory flow visualization of a sphere demonstrated that the intensity of
bioluminescence decreased with increasing flow speed due to the thinning of the
boundary layer, while flow separation caused a dramatic increase in intensity due
to the significantly greater volume of stimulating flow in the wake. Intensified
video recordings of dolphins gliding at speeds of approximately 2 m s-1 confirmed
that brilliant displays of bioluminescence occurred on the body of the dolphin.
The distribution and intensity of bioluminescence suggest that the flow remained
attached over most of the body. A conspicuous lack of bioluminescence was often
observed on the dolphin rostrum and melon and on the leading edge of the dorsal
and pectoral fins, where the boundary layer is thought to be thinnest. To
differentiate between effects related to the thickness of the stimulatory
boundary layer and those due to the latency of the bioluminescence response and
the upstream depletion of bioluminescence, laboratory and dolphin studies of
forced separation and laminar-to-turbulent transition were conducted. The
observed pattern of stimulated bioluminescence is consistent with the hypothesis
that bioluminescent intensity is directly related to the thickness of the
boundary layer.
PMID- 9547325
TI - Cardio-respiratory ontogeny during chronic carbon monoxide exposure in the clawed
frog Xenopus laevis.
AB - The present study investigates the ontogeny of cardio-respiratory physiology in
Xenopus laevis where O2 transport is obstructed. Animals were raised from eggs
(NF stage 1) to metamorphic climax (NF stage 63), while maintained either in air
or in chronic 2 kPa CO, which functionally ablates O2 transport by hemoglobin
(Hb). Whole-animal rate of oxygen consumption (.MO2), whole-body lactate
concentration, individual mass, heart rate (fh) and stroke volume (Vs) were
measured. Additionally, cardiac output (.Q) and the ratio of the rate of oxygen
consumption to the total rate at which oxygen is transported in the blood
(.MO2/.QO2) were calculated to determine limitations imparted when O2 transport
is impaired. Our data on early development suggest that the onset of convective
blood flow occurs prior to the absolute need for convection to supplement
diffusive transport. Values for .MO2, whole-body lactate concentration, mass and
fh did not differ significantly between controls and CO-exposed animals. However,
CO-exposed animals showed a significant (P<0.05) increase in Vs, .MO2/.QO2 and .Q
compared with controls. These results indicate that limiting blood O2 transport
is not deleterious to metabolism and development as a whole and that convective
oxygen transport via Hb is not essential for normal cardiovascular or respiratory
function during larval development.
PMID- 9547326
TI - Mechanisms of acid-base regulation in migrant sea lampreys (Petromyzon marinus)
following exhaustive exercise
AB - The life cycle of the sea lamprey (Petromyzon marinus) is characterized by a
terminal upstream spawning migration that may be associated with brief bursts of
high-intensity swimming. Such activity usually leads to pronounced blood acid
base disturbances in fishes, but lampreys rapidly correct these perturbations
within 1 h. In the present study, patterns of post-exercise H+ excretion (JHnet)
and ion movements were followed in sea lampreys to test the hypothesis that
dynamic manipulation of Na+ versus Cl- movements across the animal's body
surface, presumably at the gills, accounted for the rapid restoration of blood pH
following exercise. The first hour of post-exercise recovery in sea lampreys was
associated with marked stimulation of JHnet (equivalent to base uptake), which
approached -500 micromol kg-1 h-1. After 1 h, JHnet patterns had returned to
resting rates. Analyses of net Na+ and Cl- movements (JNanet, JClnet) suggested
that elevated net Cl- losses, which greatly exceeded net Na+ losses, accounted
for most of the JHnet. Subsequent experiments, using radiotracers (22Na+, 36Cl-),
indicated that differential increases in Cl- versus Na+ permeability accounted
for the greater post-exercise Cl- losses and the corresponding stimulation of net
proton excretion. Finally, metabolic acid budget analyses confirmed our
hypothesis that rapid excretion of metabolic protons was the primary means used
by sea lampreys to correct post-exercise extracellular acidosis.
PMID- 9547327
TI - Proprioceptive contribution to distance estimation by motion parallax in a
praying mantid
AB - The behavioural experiments described here examined, in the praying mantis
Tenodera sinensis, the manner in which the proprioceptive cervical hair plate
sensilla are involved in the measurement of the distance to a jump target with
the aid of motion parallax actively produced by translatory head motion. Various
combinations of surgical deafferentation of the cervical hair plate sensilla had
no influence on the linearisation of head motion. However, the measurement of
relative and absolute distance and the jump frequency were impaired by these
interventions. From the results, it is concluded that the cervical hair plate
sensilla are involved in the distance measurement mechanism, probably by allowing
the nervous system to compare retinal image motion with head motion.
PMID- 9547328
TI - New paths in human cancer serology.
PMID- 9547329
TI - The normal counterpart of IgD myeloma cells in germinal center displays
extensively mutated IgVH gene, Cmu-Cdelta switch, and lambda light chain
expression.
AB - Human myeloma are incurable hematologic cancers of immunoglobulin-secreting
plasma cells in bone marrow. Although malignant plasma cells can be almost
eradicated from the patient's bone marrow by chemotherapy, drug-resistant myeloma
precursor cells persist in an apparently cryptic compartment. Controversy exists
as to whether myeloma precursor cells are hematopoietic stem cells, pre-B cells,
germinal center (GC) B cells, circulating memory cells, or plasma blasts. This
situation reflects what has been a general problem in cancer research for years:
how to compare a tumor with its normal counterpart. Although several studies have
demonstrated somatically mutated immunoglobulin variable region genes in multiple
myeloma, it is unclear if myeloma cells are derived from GCs or post-GC memory B
cells. Immunoglobulin (Ig)D-secreting myeloma have two unique immunoglobulin
features, including a biased lambda light chain expression and a Cmu-Cdelta
isotype switch. Using surface markers, we have previously isolated a population
of surface IgM-IgD+CD38+ GC B cells that carry the most impressive somatic
mutation in their IgV genes. Here we show that this population of GC B cells
displays the two molecular features of IgD-secreting myeloma cells: a biased
lambda light chain expression and a C&mu-Cdelta isotype switch. The demonstration
of these peculiar GC B cells to differentiate into IgD-secreting plasma cells but
not memory B cells both in vivo and in vitro suggests that IgD-secreting plasma
and myeloma cells are derived from GCs.
PMID- 9547330
TI - T cell receptor (TCR) engagement in apoptosis-defective, but interleukin 2 (IL-2)
producing, T cells results in impaired ZAP70/CD3-zeta association.
AB - We have previously shown that a tyrosine to leucine replacement in the
transmembrane region of T cell receptor (TCR)-beta results in a deficient
induction of CD95-L and apoptosis upon TCR triggering in a transfected T cell
line. By contrast, interleukin (IL)-2 production and the expression of CD25 and
CD69 were normally induced. Since the mutation in TCR-beta also resulted in
impaired association of CD3-zeta, it was proposed that this chain is specifically
required for the induction of apoptosis. We now show that the deficient induction
of CD95-L and apoptosis does not derive from a general lower production of second
messengers, since intracellular Ca2+ fluxes and tyrosine phosphorylation of total
proteins were elicited at wild-type levels. Unlike in T cell clones stimulated
with partial agonists, both p21 and p18 forms of tyrosine-phosphorylated CD3-zeta
were detected, although the overall level of tyrosine-phosphorylated CD3-zeta was
low. More strikingly, inducible association of ZAP70 to CD3-zeta was strongly
inhibited, despite a normal induction of ZAP70 tyrosine phosphorylation. Finally,
ZAP70 was not concentrated near the plasma membrane in the apoptosis-deficient
cells. These results suggest that CD3-zeta is necessary for engagement of a
specific signaling pathway leading to CD95-L expression that also needs the
recruitment of ZAP70.
PMID- 9547331
TI - T helper 1 (Th1) and Th2 characteristics start to develop during T cell priming
and are associated with an immediate ability to induce immunoglobulin class
switching.
AB - The respective production of specific immunoglobulin (Ig)G2a or IgG1 within 5 d
of primary immunization with Swiss type mouse mammary tumor virus [MMTV(SW)] or
haptenated protein provides a model for the development of T helper 1 (Th1) and
Th2 responses. The antibody-producing cells arise from cognate T cell B cell
interaction, revealed by the respective induction of Cgamma2a and Cgamma1 switch
transcript production, on the third day after immunization. T cell proliferation
and upregulation of mRNA for interferon gamma in response to MMTV(SW) and
interleukin 4 in response to haptenated protein also starts during this day. It
follows that there is minimal delay in these responses between T cell priming and
the onset of cognate interaction between T and B cells leading to class switching
and exponential growth. The Th1 or Th2 profile is at least partially established
at the time of the first cognate T cell interaction with B cells in the T zone.
The addition of killed Bordetella pertussis to the hapten-protein induces
nonhapten-specific IgG2a and IgG1 plasma cells, whereas the anti-hapten response
continues to be IgG1 dominated. This indicates that a Th2 response to hapten
protein can proceed in a node where there is substantial Th1 activity.
PMID- 9547332
TI - Conversion of membrane-bound Fas(CD95) ligand to its soluble form is associated
with downregulation of its proapoptotic activity and loss of liver toxicity.
AB - Human Fas ligand (L) (CD95L) and tumor necrosis factor (TNF)-alpha undergo
metalloproteinase-mediated proteolytic processing in their extracellular domains
resulting in the release of soluble trimeric ligands (soluble [s]FasL, sTNF
alpha) which, in the case of sFasL, is thought to be implicated in diseases such
as hepatitis and AIDS. Here we show that the processing of sFasL occurs between
Ser126 and Leu127. The apoptotic-inducing capacity of naturally processed sFasL
was reduced by >1,000-fold compared with membrane-bound FasL, and injection of
high doses of recombinant sFasL in mice did not induce liver failure. However,
soluble FasL retained its capacity to interact with Fas, and restoration of its
cytotoxic activity was achieved both in vitro and in vivo with the addition of
cross-linking antibodies. Similarly, the marginal apoptotic activity of
recombinant soluble TNF-related apoptosis-inducing ligand (sTRAIL), another
member of the TNF ligand family, was greatly increased upon cross-linking. These
results indicate that the mere trimerization of the Fas and TRAIL receptors may
not be sufficient to trigger death signals. Thus, the observation that sFasL is
less cytotoxic than membrane-bound FasL may explain why in certain types of
cancer, systemic tissue damage is not detected, even though the levels of
circulating sFasL are high.
PMID- 9547333
TI - Aminooxypentane-RANTES induces CCR5 internalization but inhibits recycling: a
novel inhibitory mechanism of HIV infectivity.
AB - CCR5, a chemokine receptor expressed on T cells and macrophages, is the principal
coreceptor for M-tropic HIV-1 strains. Recently, we described an NH2-terminal
modification of the CCR5 ligand regulated on activation, normal T cell expressed
and secreted (RANTES), aminooxypentane-RANTES (AOP-RANTES), that showed potent
inhibition of macrophage infection by HIV-1 under conditions where RANTES was
barely effective. To investigate the mechanism of AOP-RANTES inhibition of HIV
infectivity we examined the surface expression of CCR5 using a monoclonal anti
CCR5 antibody, MC-1. We demonstrate that AOP-RANTES rapidly caused >90% decrease
in cell surface expression of CCR5 on lymphocytes, monocytes/ macrophages, and
CCR5 transfected Chinese hamster ovary (CHO) cells. RANTES also caused a loss of
cell surface CCR5, although its effect was less than with AOP-RANTES.
Significantly, AOP-RANTES inhibited recycling of internalized CCR5 to the cell
surface, whereas RANTES did not. When peripheral blood mononuclear cells are
cultured for prolonged periods of time in the presence of RANTES, CCR5 expression
is comparable to that seen on cells treated with control medium, whereas there is
no CCR5 surface expression on cells cultured in the presence of AOP-RANTES.
Immunofluorescence indicated that both AOP-RANTES and RANTES induced
downmodulation of cell surface CCR5, and that the receptor was redistributed into
endocytic organelles containing the transferrin receptor. When RANTES was
removed, the internalized receptor was recycled to the cell surface; however, the
receptor internalized in the presence of AOP-RANTES was retained in endosomes.
Using human osteosarcoma (GHOST) 34/CCR5 cells, the potency of AOP-RANTES and
RANTES to inhibit infection by the M-tropic HIV-1 strain, SF 162, correlated with
the degree of downregulation of CCR5 induced by the two chemokines. These
differences between AOP-RANTES and RANTES in their effect on receptor
downregulation and recycling suggest a mechanism for the potent inhibition of HIV
infection by AOP-RANTES. Moreover, these results support the notion that receptor
internalization and inhibition of receptor recycling present new targets for
therapeutic agents to prevent HIV infection.
PMID- 9547334
TI - T cell-mediated pathology in two models of experimental colitis depends
predominantly on the interleukin 12/Signal transducer and activator of
transcription (Stat)-4 pathway, but is not conditional on interferon gamma
expression by T cells.
AB - The requirements for interleukin (IL)-12/signal transducer and activator of
transcription (Stat)-4 signaling and induction of T cell-specific interferon
(IFN)-gamma expression in the development of T helper cell (Th)1-type pathology
were examined in two different models of experimental colitis. In each model,
abnormal reconstitution of the T cell compartment in immunodeficient mice by
adoptive cell transfer leads to a wasting syndrome and inflammation of the colon,
induced by IFN-gamma and tumor necrosis factor (TNF)-alpha-producing T cells. We
show here that treatment with anti-IL-12 antibodies in one of the models, or
reconstitution with T cells from Stat-4-deficient (Stat-4(null)) mice in both
models resulted in a milder disease in the majority of recipient animals,
compared with those that were left untreated or that had been reconstituted with
wt cells. Protected mice in each group also harbored lower frequencies of IFN
gamma-producing T cells than did diseased mice, suggesting that effects on
wasting and colitis resulted from the attenuation of IFN-gamma expression by T
cells. To test whether the development of pathogenic T cells in the two colitis
models was directly dependent on T cell-specific IFN-gamma expression, IFN
gammanull donors were used for T cell reconstitution in each system.
Surprisingly, large numbers of IFN-gammanull-reconstituted mice developed wasting
and colitis, which in many cases was of comparable severity to that seen in
animals reconstituted with wt cells. Furthermore, T cells from these animals
expressed TNF-alpha, demonstrating that they had retained the ability to produce
another proinflammatory cytokine. Taken together, these results demonstrate that
in some forms of chronic experimental colitis the development of pathogenic T
cells is influenced predominantly, though not exclusively, by IL-12 via the
actions of Stat-4 proteins. Furthermore, our data suggest that in the models of
colitis studied here the effects of IL-12/Stat-4 or other Th1 promoting pathways
are not limited to the induction of IFN-gamma gene expression in T lymphocytes.
PMID- 9547336
TI - CD3 ligation on immature thymocytes generates antagonist-like signals appropriate
for CD8 lineage commitment, independently of T cell receptor specificity.
AB - The signals that direct differentiation of T cells to the CD4 or CD8 lineages in
the thymus remain poorly understood. Although it has been relatively easy to
direct differentiation of CD4 single positive (CD4+) cells using combinations of
antibodies and pharmacological agents that mimic receptor engagements, equivalent
stimuli do not induce efficient maturation of CD8+ cells. Here we report that,
irrespective of the MHC-restriction specificity of the TCR, differentiation of
mature CD8+ thymocytes can be induced by ligation of CD3 polypeptides on immature
thymocytes with a F(ab')2 reagent (CD3fos-F(ab')2). The tyrosine phosphorylation
patterns stimulated by CD3fos-F(ab')2 have been shown to resemble those delivered
to mature T cells by antagonist peptides, which are known to direct positive
selection of CD8+ cells, and we can show that this reagent exhibits potent
antagonistic-like activity for primary T cell responses. Our results suggest a
distinction in the signals that specify lineage commitment in the thymus. We
present a model of thymocyte differentiation that proposes that the relative
balance of signals delivered by TCR engagement and by p56lck activation is
responsible for directing commitment to the CD8 or CD4 lineages.
PMID- 9547335
TI - Involvement of Bruton's tyrosine kinase in FcepsilonRI-dependent mast cell
degranulation and cytokine production.
AB - We investigated the role of Bruton's tyrosine kinase (Btk) in FcepsilonRI
dependent activation of mouse mast cells, using xid and btk null mutant mice.
Unlike B cell development, mast cell development is apparently normal in these
btk mutant mice. However, mast cells derived from these mice exhibited
significant abnormalities in FcepsilonRI-dependent function. xid mice primed with
anti-dinitrophenyl monoclonal IgE antibody exhibited mildly diminished early
phase and severely blunted late-phase anaphylactic reactions in response to
antigen challenge in vivo. Consistent with this finding, cultured mast cells
derived from the bone marrow cells of xid or btk null mice exhibited mild
impairments in degranulation, and more profound defects in the production of
several cytokines, upon FcepsilonRI cross-linking. Moreover, the transcriptional
activities of these cytokine genes were severely reduced in FcepsilonRI
stimulated btk mutant mast cells. The specificity of these effects of btk
mutations was confirmed by the improvement in the ability of btk mutant mast
cells to degranulate and to secrete cytokines after the retroviral transfer of
wild-type btk cDNA, but not of vector or kinase-dead btk cDNA. Retroviral
transfer of Emt (= Itk/Tsk), Btk's closest relative, also partially improved the
ability of btk mutant mast cells to secrete mediators. Taken together, these
results demonstrate an important role for Btk in the full expression of
FcepsilonRI signal transduction in mast cells.
PMID- 9547337
TI - The permeability transition pore complex: a target for apoptosis regulation by
caspases and bcl-2-related proteins.
AB - Early in programmed cell death (apoptosis), mitochondrial membrane permeability
increases. This is at least in part due to opening of the permeability transition
(PT) pore, a multiprotein complex built up at the contact site between the inner
and the outer mitochondrial membranes. The PT pore has been previously implicated
in clinically relevant massive cell death induced by toxins, anoxia, reactive
oxygen species, and calcium overload. Here we show that PT pore complexes
reconstituted in liposomes exhibit a functional behavior comparable with that of
the natural PT pore present in intact mitochondria. The PT pore complex is
regulated by thiol-reactive agents, calcium, cyclophilin D ligands (cyclosporin A
and a nonimmunosuppressive cyclosporin A derivative), ligands of the adenine
nucleotide translocator, apoptosis-related endoproteases (caspases), and Bcl-2
like proteins. Although calcium, prooxidants, and several recombinant caspases
(caspases 1, 2, 3, 4, and 6) enhance the permeability of PT pore-containing
liposomes, recombinant Bcl-2 or Bcl-XL augment the resistance of the
reconstituted PT pore complex to pore opening. Mutated Bcl-2 proteins that have
lost their cytoprotective potential also lose their PT modulatory capacity. In
conclusion, the PT pore complex may constitute a crossroad of apoptosis
regulation by caspases and members of the Bcl-2 family.
PMID- 9547338
TI - Extent of laminin-5 assembly and secretion effect junctional epidermolysis
bullosa phenotype.
AB - Junctional epidermolysis bullosa (JEB) is an autosomal recessive skin blistering
disease with both lethal and nonlethal forms, with most patients shown to have
defects in laminin-5. We analyzed the location of mutations, gene expression
levels, and protein chain assembly of the laminin-5 heterotrimer in six JEB
patients to determine how the type of genetic lesion influences the
pathophysiology of JEB. Mutations within laminin-5 genes were diversely located,
with the most severe forms of JEB correlating best with premature termination
codons, rather than mapping to any particular protein domain. In all six JEB
patients, the laminin-5 assembly intermediates we observed were as predicted by
our previous work indicating that the alpha3beta3gamma2 heterotrimer assembles
intracellularly via a beta3gamma2 heterodimer intermediate. Since assembly
precedes secretion, mutations that disrupt protein-protein interactions needed
for assembly are predicted to limit the secretion of laminin-5, and likely to
interfere with function. However, our data indicate that typically the most
severe mutations diminish mRNA stability, and serve as functional null alleles
that block chain assembly by resulting in either a deficiency (in the nonlethal
mitis variety) or a complete absence (in lethal Herlitz-JEB) of one of the chains
needed for laminin-5 heterotrimer assembly.
PMID- 9547339
TI - Identification of a human enterocyte lipoxin A4 receptor that is regulated by
interleukin (IL)-13 and interferon gamma and inhibits tumor necrosis factor alpha
induced IL-8 release.
AB - Epithelial cells of the alimentary tract play a central role in mucosal
immunophysiology. Pathogens and/or agonists that interact with mucosal surfaces
often elicit epithelial responses that upregulate inflammation. Therefore, it was
of interest to explore potential epithelial targeted antiinflammatory signals.
Here we identified and sequenced a human enterocyte lipoxin (LX) A4 [5(S),
6(R),15(S)-trihydroxy-7,9,13-trans-11-cis eicosatetraenoic acid] receptor, and
demonstrate that transcription of this receptor was controlled by cytokines, of
which lymphocyte-derived interleukin (IL)-13 and interferon gamma were the most
potent. When lipoxins and LXA4 stable analogs were evaluated for enterocyte
functional as well as immune responses, lipoxins sharply inhibited TNF-alpha
induced IL-8 release but did not alter either barrier function or agonist
stimulated chloride secretion. 15R/S-methyl-LXA4 and 16-phenoxy-LXA4 each
attenuated (IC50 approximately 10 nM) IL-8 release. Cyclooxygenase (COX) II is
emerging as an important component in wound healing and proliferation in
intestinal epithelia and when acetylated by acetylsalicylic acid (aspirin)
initiates the biosynthesis of a LXA4 receptor ligand. We therefore determined
whether colonic cell lines (HT-29 Cl.19A, Caco-2, or T84) express the COX II
isozyme. Results for RT-PCR and Western blot analysis showed that COX I as well
as an IL-1beta- and TNF-alpha-inducible COX II are expressed in HT-29 Cl.19A. In
addition, aspirin-treated enterocytes generated 15R-HETE, a precursor of 15-epi
LXA4 biosynthesis, whose potent bioactions were mimicked by the stable analog
15R/S-methyl-LXA4. Taken together, these results identify an endogenous pathway
for downregulating mucosal inflammatory events and suggest a potential
therapeutic benefit for LXA4 stable analogs.
PMID- 9547340
TI - Turnover of CD4+ and CD8+ T lymphocytes in HIV-1 infection as measured by Ki-67
antigen.
AB - We investigated CD4+ and CD8+ T cell turnover in both healthy and HIV-1-infected
adults by measuring the nuclear antigen Ki-67 specific for cell proliferation.
The mean growth fraction, corresponding to the expression of Ki-67, was 1.1% for
CD4(+) T cells and 1.0% in CD8(+) T cells in healthy adults, and 6.5 and 4.3% in
HIV-1-infected individuals, respectively. Analysis of CD45RA+ and CD45RO+ T cell
subsets revealed a selective expansion of the CD8+ CD45RO+ subset in HIV-1
positive individuals. On the basis of the growth fraction, we derived the
potential doubling time and the daily turnover of CD4+ and CD8+ T cells. In HIV-1
infected individuals, the mean potential doubling time of T cells was five times
shorter than that of healthy adults. The mean daily turnover of CD4+ and CD8+ T
cells in HIV-1-infected individuals was increased 2- and 6-fold, respectively,
with more than 40-fold interindividual variation. In patients with <200 CD4+
counts, CD4+ turnover dropped markedly, whereas CD8+ turnover remained elevated.
The large variations in CD4+ T cell turnover might be relevant to individual
differences in disease progression.
PMID- 9547341
TI - Impaired interleukin 4 signaling in T helper type 1 cells.
AB - Cluster of differentation (CD)4+ T helper cells (Th)1s fail to produce
interleukin (IL)-4. Even if restimulated in the presence of IL-4, a condition
that induces IL-4-producing capacity in naive CD4+ T cells, Th1s fail to become
IL-4 producers. We report that Th1 cells have a major impairment in IL-4
signaling. When compared to both Th2s and naive T cells, they display a striking
diminution in phosphorylation of Stat6. They also show reduced phosphorylation of
Janus kinase (JAK)-3 and insulin receptor substrate (IRS)-2 when compared to
Th2s. Stat6 and JAK-3 are present in equivalent amounts in Th1s and Th2s, but IRS
2 protein levels are much lower in Th1s than in Th2s. Altered sensitivity to IL
4, the major inducer of the Th2 phenotype, may explain the stability of the Th1
state.
PMID- 9547342
TI - CD40 ligand is not essential for induction of type 1 cytokine responses or
protective immunity after primary or secondary infection with histoplasma
capsulatum.
AB - The induction of type 1 immune responses (interleukin [IL]-12, interferon [IFN]
gamma) has been shown to be important in mediating protection against many
intracellular infections including Histoplasma capsulatum. Costimulatory
molecules such as CD40 ligand (CD40L) have been shown to be a central regulator
of type 1 responses in vivo. To study the role of CD40L in mediating protection
against infection with H. capsulatum, CD40L-deficient (CD40L-/-) and CD40L+/+
mice were infected with H. capsulatum and assessed for various parameters. After
a lethal challenge of H. capsulatum, CD40L-/- mice were not substantially
different from CD40L+/+ mice in terms of mortality, fungal burden, or production
of IFN-gamma, IL-12, nitric oxide, or tumor necrosis factor alpha. Moreover,
CD40L-/- mice treated with anti-IFN-gamma or anti-IL-12 at the time of infection
had accelerated mortality, providing further evidence that IL-12 and IFN-gamma
are produced in vivo in the absence of CD40L. In addition, CD40L-/- mice infected
with a sublethal dose of H. capsulatum survived infection, whereas all mice
infected with the same dose and treated with anti-IFN-gamma had accelerated
mortality, demonstrating that IFN-gamma but not CD40L was essential for primary
immunity to H. capsulatum infection. Interestingly, depletion of either CD4+ or
CD8+ T cells resulted in accelerated mortality in CD40L-/- mice, suggesting a
critical role for these cells in response to infection. Finally, CD40L-/- mice
initially infected with a sublethal dose of H. capsulatum were protected from
secondary infection with a lethal dose of H. capsulatum, demonstrating that CD40L
is not required for the maintenance of memory immunity.
PMID- 9547343
TI - B-1 cell development: evidence for an uncommitted immunoglobulin (Ig)M+ B cell
precursor in B-1 cell differentiation.
AB - Murine phosphatidyl choline (PtC)-specific B cells in normal mice belong
exclusively to the B-1 subset. Analysis of anti-PtC (VH12 and VH12/Vkappa4)
transgenic (Tg) mice indicates that exclusion from B-0 (also known as B-2) occurs
after immunoglobulin gene rearrangement. This predicts that PtC-specific B-0
cells are generated, but subsequently eliminated by either apoptosis or
differentiation to B-1. To investigate the mechanism of exclusion, PtC-specific B
cell differentiation was examined in mice expressing the X-linked
immunodeficiency (xid) mutation. xid mice lack functional Bruton's tyrosine
kinase (Btk), a component of the B cell receptor signal transduction pathway, and
are deficient in B-1 cell development. We find in C57BL/ 6.xid mice that VH12 pre
BII cell selection is normal and that PtC-specific B cells undergo modest clonal
expansion. However, the majority of splenic PtC-specific B cells in anti-PtC
Tg/xid mice are B-0, rather than B-1 as in their non-xid counterparts. These data
indicate that PtC-specific B-0 cell generation precedes segregation as predicted,
and that Btk function is required for efficient segregation to B-1. Since xid
mice exhibit defective B cell differentiation, not programmed cell death, these
data are most consistent with an inability of PtC-specific B-0 cells to convert
to B-1 and a single B cell lineage.
PMID- 9547344
TI - Tolerization of anti-Galalpha1-3Gal natural antibody-forming B cells by induction
of mixed chimerism.
AB - Xenotransplantation could overcome the severe shortage of allogeneic organs, a
major factor limiting organ transplantation. Unfortunately, transplantation of
organs from pigs, the most suitable potential donor species, results in
hyperacute rejection in primate recipients, due to the presence of anti-Galalpha1
3Gal (Gal) natural antibodies (NAbs) in their sera. We evaluated the ability to
tolerize anti-Gal NAb-producing B cells in alpha1,3-galactosyltransferase
knockout (GalT KO) mice using bone marrow transplantation (BMT) from GalT+/+ wild
type (WT) mice. Lasting mixed chimerism was achieved in KO mice by
cotransplantation of GalT KO and WT marrow after lethal irradiation. The levels
of anti-Gal NAb in sera of mixed chimeras were reduced markedly 2 wk after BMT,
and became undetectable at later time points. Immunization with Gal+/+ xenogeneic
cells failed to stimulate anti-Gal antibody production in mixed chimeras, whereas
the production of non-Gal-specific antixenoantigen antibodies was stimulated. An
absence of anti-Gal-producing B cells was demonstrated by enzyme-linked
immunospot assays in mixed KO + WT --> KO chimeras. Thus, mixed chimerism
efficiently induces anti-Gal-specific B cell tolerance in addition to T cell
tolerance, providing a single approach to overcoming both the humoral and the
cellular immune barriers to discordant xenotransplantation.
PMID- 9547345
TI - A double-edged kinase Lyn: a positive and negative regulator for antigen receptor
mediated signals.
AB - B cells from young lyn-/- mice are hyperresponsive to anti-IgM-induced
proliferation, suggesting involvement of Lyn in negative regulation of B cell
antigen receptor (BCR)-mediated signaling. Here we show that tyrosine
phosphorylation of FcgammaRIIB and CD22 coreceptors, which are important for
feedback suppression of BCR-induced signaling, was severely impaired in lyn-/- B
cells upon their coligation with the BCR. Hypophosphorylation on tyrosine
residues of these molecules resulted in failure of recruiting the tyrosine
phosphatase SHP-1 and inositol phosphatase SHIP, SH2-containing potent inhibitors
of BCR-induced B cell activation, to the coreceptors. Consequently, lyn-/- B
cells exhibited defects in suppressing BCR-induced Ca2+ influx and proliferation.
Thus, Lyn is critically important in tyrosine phosphorylation of the coreceptors,
which is required for feedback suppression of B cell activation.
PMID- 9547346
TI - A survey of the humoral immune response of cancer patients to a panel of human
tumor antigens.
AB - Evidence is growing for both humoral and cellular immune recognition of human
tumor antigens. Antibodies with specificity for antigens initially recognized by
cytotoxic T lymphocytes (CTLs), e.g., MAGE and tyrosinase, have been detected in
melanoma patient sera, and CTLs with specificity for NY-ESO-1, a cancer-testis
(CT) antigen initially identified by autologous antibody, have recently been
identified. To establish a screening system for the humoral response to
autoimmunogenic tumor antigens, an enzyme-linked immunosorbent assay (ELISA) was
developed using recombinant NY-ESO-1, MAGE-1, MAGE-3, SSX2, Melan-A, and
tyrosinase proteins. A survey of sera from 234 cancer patients showed antibodies
to NY-ESO-1 in 19 patients, to MAGE-1 in 3, to MAGE-3 in 2, and to SSX2 in 1
patient. No reactivity to these antigens was found in sera from 70 normal
individuals. The frequency of NY-ESO-1 antibody was 9.4% in melanoma patients and
12.5% in ovarian cancer patients. Comparison of tumor NY-ESO-1 phenotype and NY
ESO-1 antibody response in 62 stage IV melanoma patients showed that all patients
with NY-ESO-1(+) antibody had NY-ESO-1(+) tumors, and no patients with NY-ESO-1(
) tumors had NY-ESO-1 antibody. As the proportion of melanomas expressing NY-ESO
1 is 20-40% and only patients with NY-ESO-1(+) tumors have antibody, this would
suggest that a high percentage of patients with NY-ESO-1(+) tumors develop an
antibody response to NY-ESO-1.
PMID- 9547348
TI - Activation by diverse xenochemicals of the 51-base pair phenobarbital-responsive
enhancer module in the CYP2B10 gene.
AB - By extending previous studies of the phenobarbital (PB)-responsive 132-base pair
(bp) enhancer sequence in the CYP2B10 gene, we have delimited a 51-bp enhancer
element that is fully inducible by PB in mouse primary hepatocytes. Sixteen
structurally unrelated phenobarbital-type inducers activated the 51-bp enhancer
element in transient transfection assays. The results thus indicate that most PB
type inducers, if not all inducers, increase the transcription of the CYP2B10
gene by activating this 51-bp element, now designated PB-responsive enhancer
module or PBREM.
PMID- 9547347
TI - Requirement of SH2-containing protein tyrosine phosphatases SHP-1 and SHP-2 for
paired immunoglobulin-like receptor B (PIR-B)-mediated inhibitory signal.
AB - Paired immunoglobulin-like receptor B (PIR-B) (p91) molecule has been proposed to
function as an inhibitory receptor in B cells and myeloid lineage cells. We
demonstrate here that the cytoplasmic region of PIR-B is capable of inhibiting B
cell activation. Mutational analysis of five cytoplasmic tyrosines indicate that
tyrosine 771 in the motif VxYxxL plays the most crucial role in mediating the
inhibitory signal. PIR-B-mediated inhibition was markedly reduced in the SH2
containing protein tyrosine phosphatases SHP-1 and SHP-2 double-deficient DT40 B
cells, whereas this inhibition was unaffected in the inositol polyphosphate 5'
phosphatase SHIP-deficient cells. These data demonstrate that PIR-B can
negatively regulate B cell receptor activation and that this PIR-B-mediated
inhibition requires redundant functions of SHP-1 and SHP-2.
PMID- 9547349
TI - Involvement of c-Jun NH2-terminal kinase activation and c-Jun in the induction of
apoptosis by the ether phospholipid 1-O-octadecyl-2-O-methyl-rac-glycero-3
phosphocholine.
AB - The ether phospholipid 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET
18-OCH3; edelfosine) is a potent inducer of apoptosis in human tumor cells. We
show that ET-18-OCH3-induced apoptosis is associated with activation of the c-Jun
NH2-terminal kinase (JNK) signaling. The addition of ET-18-OCH3 to distinct human
leukemic cells (HL-60, U937, and Jurkat), which undergo rapid apoptosis on
treatment with ET-18-OCH3, induced a dramatic and sustained increase in the of c
jun mRNA level that was associated with activation of activator protein-1
transcription factor. We found that ET-18-OCH3 induced a persistent activation of
JNK in HL-60 cells that was detected before the onset of apoptosis, the latter
being assessed by DNA fragmentation and by the appearance of phosphatidylserine
on the external leaflet of the plasma membrane. The inductions of JNK after HL-60
monocyte/macrophage differentiation and ET-18-OCH3-mediated apoptosis were
distinguished by the different activation patterns, transient versus persistent,
respectively. ET-18-OCH3 analogues unable to induce apoptosis failed to activate
JNK. ET-18-OCH3-dependent JNK activation was not detected in K562 cells, which
did not undergo apoptosis on treatment with ET-18-OCH3. Phorbol myristate acetate
inhibited both ET-18-OCH3-induced apoptosis and sustained JNK activation; thus,
persistent JNK activation by ET-18-OCH3 is associated with the capacity of this
ether phospholipid to induce apoptosis. Furthermore, antisense oligonucleotides
directed against c-jun blocked ET-18-OCH3-induced apoptosis, indicating a role
for c-Jun in this apoptotic response. These data indicate that JNK activation and
c-Jun are involved in the induction of apoptosis by ET-18-OCH3.
PMID- 9547350
TI - A G protein beta gamma dimer-mediated pathway contributes to mitogen-activated
protein kinase activation by thyrotropin-releasing hormone receptors in
transfected COS-7 cells.
AB - Activation of mitogen-activated protein kinase (MAPK) is induced by adding
thyrotropin-releasing hormone (TRH) to COS-7 cells cotransfected with TRH
receptors and an epitope-tagged MAPK. Long term treatment of the cells with
pertussis toxin has no effect on TRH-induced MAPK activation. Incubation of the
cells with the protein kinase C (PKC) inhibitor GF109203X causes an almost
complete inhibition of MAPK activation by the PKC activator phorbol-12-myristate
13-acetate. In contrast, only approximately 50% of the TRH-induced MAPK activity
is inhibited by GF109203X, indicating that activation of MAPK by TRH is only
partially dependent on PKC. The inhibitory effect of GF109203X is additive with
that of p21(N17ras), a dominant negative mutant of p21(ras) that exerts little
effect on PKC-dependent MAPK activation by phorbol-12-myristate-13-acetate. The
TRH-induced activation of MAPK also is inhibited partially by overexpression of
transducin alpha subunits (alpha t), an agent known to sequester free G protein
beta gamma dimers. However, the inhibitory potency of alpha t on TRH-induced
activation is about half of that obtained in cells transfected with m2 muscarinic
receptors, which activate MAPK exclusively through beta gamma dimers. The effect
of alpha t is also additive with that of GF109203X but not with that of
p21(N17ras). MAPK activation is not induced by the constitutively active form of
G alpha q due to an inhibitory effect of its expression at a step downstream of
that at which PKC-dependent and -independent routes to MAPK converge. Our results
demonstrate that TRH receptors activate MAPK by a pathway only partially
dependent on PKC activity. Furthermore, they indicate that beta gamma dimers of a
pertussis and cholera toxin-insensitive G protein are involved in the PKC
independent fraction of the dual signaling route to MAPK initiated in the TRH
receptor.
PMID- 9547351
TI - Aryl hydrocarbon receptor-dependent suppression by 2,3,7, 8-tetrachlorodibenzo-p
dioxin of IgM secretion in activated B cells.
AB - The immune system has been identified as a sensitive target for the toxic effects
produced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Furthermore, the B cell
has been identified as a sensitive cellular target of TCDD by previous cell-type
fractionation studies from this laboratory. The mechanism responsible for the
immunotoxic effects produced by TCDD is unclear; however, many of the biological
effects of TCDD are thought to be mediated by the aryl hydrocarbon receptor
(AhR). Here, we describe two B cell lines that differ considerably in their
expression of the AhR and in their sensitivity to TCDD. Our results demonstrated
a marked expression of the AhR protein in the CH12.LX B cell line but not in the
BCL-1 B cell line. Transcripts for the AhR were not detected by reverse
transcriptase-polymerase chain reaction in the BCL-1 cells. The AhR nuclear
translocator (ARNT) protein was highly expressed in both cell lines. In addition,
the AhR and ARNT are functional in CH12.LX cells as demonstrated by TCDD-induced
CYP1A1 induction. TCDD did not induce CYP1A1 in BCL-1 cells. Furthermore, TCDD
treatment resulted in suppression of lipopolysaccharide (LPS)-induced IgM
secretion in CH12.LX cells. Conversely, TCDD-induced inhibition of IgM secretion
was not demonstrated in LPS-stimulated BCL-1 cells, implicating a role for the
AhR in the inhibition of B cell effector function. LPS-induced differentiation of
the CH12.LX cells also resulted in a marked induction of Ahr expression which was
not induced in LPS-stimulated BCL-1 cells. These studies have implicated the AhR
as a critical factor in TCDD-induced inhibition of IgM secretion and have
demonstrated an induction of AhR gene and protein expression after B cell
activation.
PMID- 9547352
TI - Activation of protein kinase C alpha and/or epsilon enhances transcription of the
human endothelial nitric oxide synthase gene.
AB - In primary human umbilical vein endothelial cells (HUVECs), incubation with
phorbol-12-myristate-13-acetate (PMA) enhanced basal and bradykinin-stimulated
nitric oxide production. In the HUVEC-derived cell line EA.hy 926, PMA and
phorbol-12,13-dibutyrate stimulated endothelial nitric oxide synthase (NOS III)
mRNA expression in a concentration- and time-dependent manner. Maximal mRNA
expression (3.3-fold increase) was observed after 18 hr. NOS III protein and
activity were increased to a similar extent. The specific protein kinase C (PKC)
inhibitors bisindolylmaleimide I (1 microM), Go 6976 [12-(2 cyanoethyl)-6,7,12,
13-tetrahydro-13-methyl-5-oxo-5H-indolo[2,3-a]pyrrolo-[3, 4-c]carbazole] (1
microM), Ro-31-8220 [3-[1-[3(amidinothio)propyl-1H-inoyl-3-yl]3-(1-methyl-1H-
indoyl-3-yl) maleimide methane sulfonate] (1 microM), and chelerythrine (3
microM) did not change NOS III expression when applied alone, but they all
prevented the up-regulation of NOS III mRNA produced by PMA. Of the PKC isoforms
expressed in EA.hy 926 cells (alpha, beta I, delta, epsilon, eta, zeta, lambda,
and mu), only PKC alpha and PKC epsilon showed changes in protein expression
after PMA treatment. Incubation of EA.hy 926 cells with PMA for 2-6 hr resulted
in a translocation of PKC alpha and PKC epsilon from the cytosol to the cell
membrane, indicating activation of these isoforms. After 24 hr of PMA incubation,
both isoforms were down-regulated. The time course of activation and down
regulation of these two PKC isoforms correlated well with the PMA-stimulated
increase in NOS III expression. When human endothelial cells (ECV 304 or EA.hy
926) were transiently or stably transfected with a 3.5-kb fragment of the human
NOS III promoter driving a luciferase reporter gene, PMA stimulated promoter
activity up to 2.5-fold. On the other hand, PMA did not change the stability of
the NOS III mRNA. These data indicate that stimulation of PKC alpha, PKC epsilon,
or both by active phorbol esters represents an efficacious pathway activating the
human NOS III promoter in human endothelium.
PMID- 9547353
TI - Cytotoxicity and apoptosis produced by cytochrome P450 2E1 in Hep G2 cells.
AB - Two Hep G2 subclones overexpressing CYP2E1 were established with the use of
transfection and limited dilution screening techniques. The Hep G2-CI2E1-43 and
47 (E47) cells (transduced Hep G2 subclones that overexpress CYP2E1) grew at a
slower rate than parental Hep G2 cells or control subclones that do not express
CYP2E1, but remained fully viable. When GSH synthesis was inhibited by treatment
with buthionine sulfoximine, GSH levels rapidly declined in E47 cells but not
control cells, which is most likely a reflection of CYP2E1-catalyzed formation of
reactive oxygen species. Under these conditions of GSH depletion, cytotoxicity
and apoptosis were found only with the E47 cells. Low levels of lipid
peroxidation were found in the E47 cells, which became more pronounced after GSH
depletion. The antioxidants vitamin E, vitamin C, or trolox prevented the lipid
peroxidation as well as the cytotoxicity and apoptosis, as did transfection with
plasmid containing antisense CYP2E1 or overexpression of Bcl-2. Levels of ATP
were lower in E47 cells because of damage to mitochondrial complex I. When GSH
was depleted, oxygen uptake was markedly decreased with all substrates in the E47
extracts. Vitamin E completely prevented the decrease in oxygen uptake. Under
conditions of CYP2E1 overexpression, two modes of CYP2E1-dependent toxicity can
be observed in Hep G2 cells: a slower growth rate when cellular GSH levels are
maintained and a loss of cellular viability when cellular GSH levels are
depleted. Elevated lipid peroxidation plays an important role in the CYP2E1
dependent toxicity and apoptosis. This direct toxicity of overexpressed CYP2E1
may reflect the ability of this enzyme to generate reactive oxygen species even
in the absence of added metabolic substrate.
PMID- 9547354
TI - Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4
methylenedioxymethamphetamine ("Ecstasy") in serotonin transporter-deficient
mice.
AB - The sodium-dependent, high affinity serotonin [5-hydroxytryptamine (5-HT)]
transporter (5-HTT) provides the primary mechanism for inactivation of 5-HT after
its release into the synaptic cleft. To further evaluate the function of the 5
HTT, the murine gene was disrupted by homologous recombination. Despite evidence
that excess extracellular 5-HT during embryonic development, including that
produced by drugs that inhibit the 5-HTT, may lead to severe craniofacial and
cardiac malformations, no obvious developmental phenotype was observed in the 5
HTT-/- mice. High affinity [3H]5-HT uptake was completely absent in 5-HTT-/-
mice, confirming a physiologically effective knockout of the 5-HTT gene. 5-HTT
binding sites labeled with [125I] 3 beta-(4'-iodophenyl)tropan-2 beta-carboxylic
acid methyl ester were reduced in a gene dose-dependent manner, with no
demonstrable binding in 5-HTT-/- mutants. In adult 5-HTT-/- mice, marked
reductions (60-80%) in 5-HT concentrations were measured in several brain
regions. While (+)-amphetamine-induced hyperactivity did not differ across
genotypes, the locomotor enhancing effects of (+)-3, 4
methylenedioxymethamphetamine, a substituted amphetamine that releases 5-HT via a
transporter-dependent mechanism, was completely absent in 5-HTT-/- mutants.
Together, these data suggest that the presence of a functional 5-HTT is essential
for brain 5-HT homeostasis and for 3,4-methylenedioxymethamphetamine-induced
hyperactivity.
PMID- 9547355
TI - Differences among type I, II, and III inositol-1,4,5-trisphosphate receptors in
ligand-binding affinity influence the sensitivity of calcium stores to inositol
1,4,5-trisphosphate.
AB - Type I, II, and III inositol-1,4,5-trisphosphate (InsP3) receptors are expressed
selectively in different cell lines and tissues. We examined whether type I, II,
and III InsP3 receptors differ in ligand-binding affinity and whether such
differences influence the sensitivity of Ca2+ stores to InsP3. Initially, SH-SY5Y
human neuroblastoma cells, AR4-2J rat pancreatoma cells, and RINm5F rat
insulinoma cells were studied because these cells express predominantly (>85%)
type I, II, and III receptors, respectively. Immunopurification of receptors from
these cell lines and measurement of InsP3 binding revealed that the rank order of
affinity for InsP3 was type I > type II > type III (binding sites were half
maximally saturated at 1.5, 2.5, and 22.4 nM InsP3, respectively). Examination of
Ca2+ store mobilization in permeabilized cells showed that InsP3 was equipotent
in SH-SY5Y and AR4-2J cells but was approximately 5-fold less potent in RINm5F
cells. In contrast, Ca2+ uptake and InsP3-independent Ca2+ release were very
similar in the three cell types. The binding affinity of InsP3 in permeabilized
SH-SY5Y, AR4-2J, and RINm5F cells correlated well with its potency as a Ca2+
mobilizing agent and with binding affinity to immunopurified type I, II, and III
receptors. Thus, InsP3 receptor binding affinity seems to influence the potency
of InsP3 as a Ca2+-mobilizing agent. Finally, immunopurification of type I, II,
and III receptors from rat tissues revealed that the affinity differences seen in
receptors purified from cultured cells are paralleled in vivo. In combination,
the data from cell lines and rat tissues reveal that type I, II, and III
receptors bind InsP3 with Kd values of approximately 1, approximately 2, and
approximately 40 nM, respectively, and that the selective expression of a
particular receptor type will influence the sensitivity of cellular Ca2+ stores
to InsP3.
PMID- 9547356
TI - Oxidative stress increases A1 adenosine receptor expression by activating nuclear
factor kappa B.
AB - The A1 adenosine receptor (A1AR) contributes to the cytoprotective action of
adenosine under conditions known to generate reactive oxygen species (ROS).
Pharmacological manipulation of A1AR expression has been shown to modulate this
cytoprotective role. In this study, we provide evidence that ROS generated could
increase the expression of the A1AR and thereby offset the detrimental effects of
ROS. Incubation of DDT1MF-2 smooth muscle cells with ROS-generating
chemotherapeutic agents, such as cisplatin (2.5 microM) or H2O2 (10 microM),
elicited an increase in A1AR expression within 24 hr. The induction by H2O2 was
reduced by the ROS scavenger catalase but not superoxide dismutase. Inhibition of
nuclear factor kappa B (NF kappa B) by pyrrolidine dithiocarbamate (200 microM),
dexamethasone (100 nM), or genistein (1 microM) abrogated the cisplatin-mediated
increase in A1AR. Cisplatin promoted rapid translocation of NF kappa B (but not
AP-1) to the nucleus, as detected by electrophoretic mobility shift assays and by
Western blotting. A putative NF kappa B sequence in the A1AR promoter effectively
competed with labeled kappa B probe for binding in nuclear preparations derived
from DDT1MF-2 cells. Transient transfection of DDT1MF-2 cells with the A1AR
promoter coupled to firefly luciferase reporter gene led to cisplatin-inducible
and pyrrolidine dithiocarbamate-sensitive luciferase activity, suggesting the
presence of functional NF kappa B binding site(s) in the A1AR promoter sequence.
Treatment of cells with (R)-phenylisopropyladenosine (1 microM), an agonist of
the A1AR, reduced cisplatin-mediated lipid peroxidation, which was reversed after
blockade of the A1AR. These data suggest that ROS can increase the expression of
the A1AR by activating NF kappa B regulatory site(s) on this gene and thereby
enhance the cytoprotective role of adenosine.
PMID- 9547357
TI - (-)-CGP 12177 causes cardiostimulation and binds to cardiac putative beta 4
adrenoceptors in both wild-type and beta 3-adrenoceptor knockout mice.
AB - Some blockers of beta1- and beta2-adrenoceptors cause cardiostimulant effects
through an atypical beta-adrenoceptor (putative beta4-adrenoceptor) that
resembles the beta3-adrenoceptor. It is likely but not proven that the putative
beta4-adrenoceptor is genetically distinct from the beta3-adrenoceptor. We
therefore investigated whether or not the cardiac atypical beta-adrenoceptor
could mediate agonist effects in mice lacking a functional beta3-adrenoceptor
gene (beta3 KO). (-)-CGP 12177, a beta1- and beta2-adrenoceptor blocker that
causes agonist effects through both beta3-adrenoceptors and cardiac putative
beta4-adrenoceptors, caused cardiostimulant effects that were not different in
atria from wild-type (WT) mice and beta3 KO mice. The effects of (-)-CGP 12177
were resistant to blockade by (-)-propranolol (200 nM) but were blocked by (-)
bupranolol (1 microM) with an equilibrium dissociation constant of 15 nM in WT
and 17 nM in beta3 KO. (-)-[3H]CGP 12177 labeled a similar density of the
putative beta4-adrenoceptor in ventricular membranes from the hearts of both WT
(Bmax = 52 fmol/mg protein) and beta3 KO (Bmax = 53 fmol/mg protein) mice. The
affinity of (-)-[3H]CGP 12177 for the cardiac putative beta4-adrenoceptor was not
different between WT (Kd = 46 nM) and beta3 KO (Kd= 40 nM). These results provide
definitive evidence that the cardiac putative beta4-adrenoceptor is distinct from
the beta3-adrenoceptor.
PMID- 9547358
TI - Suppression of interleukin-2 by the putative endogenous cannabinoid 2-arachidonyl
glycerol is mediated through down-regulation of the nuclear factor of activated T
cells.
AB - 2-Arachidonyl-glycerol (2-Ara-Gl) recently was identified as a putative
endogenous ligand for cannabinoid receptor types CB1 and CB2 by competitive
binding. More recent immune function assays demonstrated that 2-Ara-Gl possessed
immunomodulatory activity. Because several plant-derived cannabinoids inhibit
interleukin-2 (IL-2) expression, 2-Ara-Gl was investigated for its ability to
modulate this cytokine. The direct addition of 2-Ara-Gl to mouse splenocyte
cultures suppressed phorbol-12-myristate-13-acetate plus ionomycin-induced IL-2
secretion and steady state mRNA expression in a dose-dependent manner. 2-Ara-Gl
also produced a marked inhibition of IL-2 promotor activity as determined by
transient transfection of EL4.IL-2 cells with a pIL-2-CAT construct. 2-Ara-Gl at
5, 10, 20, and 50 microM suppressed phorbol-12-myristate-13-acetate plus
ionomycin-induced IL-2 promotor activity by 18%, 28%, 39%, and 54%, respectively.
To further characterize the mechanism for the transcriptional regulation of IL-2
by 2-Ara-Gl, the DNA-binding activity of transcription factors, nuclear factor of
activated T cells (NF-AT), nuclear factor for immunoglobulin kappa chain in B
cells (NF-kappa B/Rel), activator protein-1(AP-1), octamer, and cAMP-response
element binding protein was evaluated by electrophoretic mobility shift assay in
mouse splenocytes. In addition, a reporter gene expression system for p(NF-kappa
B)3-CAT, p(NF-AT)3-CAT, and p(AP-1)3-CAT was used in transiently transfected
EL4.IL-2 cells to determine the effect of 2-Ara-Gl on promoter activity for each
of the specific transcription factors. 2-Ara-Gl reduced both the NF-AT-binding
and promoter activity in a dose-dependent manner and, to a lesser degree, NF
kappa B/Rel-binding and promoter activity. No significant effect was observed on
octamer- and cAMP-response element-binding activity. AP-1 DNA-binding activity
was not inhibited by 2-Ara-Gl, but a modest inhibition of promoter activity was
observed.
PMID- 9547359
TI - N-Methyl-D-aspartate attenuates opioid receptor-mediated G protein activation and
this process involves protein kinase C.
AB - The effects of N-methyl-D-aspartate (NMDA) on opioid receptor-mediated G protein
activation were explored in neuroblastoma X glioma hybrid (NG108-15) cells.
Treatment of the cells with NMDA resulted in a remarkable attenuation of
[35S]guanosine-5'-O-(3-thio)triphosphate binding stimulated by [D-Pen2,D-Pen5]
enkephalin (DPDPE), a delta-opioid receptor agonist. The effects of NMDA were
dose and time dependent with an IC50 value of 5 nM and could be blocked by NMDA
receptor antagonists. After NMDA treatment, the DPDPE dose-response curve shifted
to the right (EC50 value increased approximately 7-fold, from 6 to 40 nM), and
the maximal response induced by DPDPE was reduced by approximately 60%. The
effects of NMDA were reversible, and the DPDPE response could recover within 60
min. The functional responses of delta-, mu-, and kappa-opioid receptors in
primarily cultured neurons also were attenuated significantly by NMDA treatment.
The inhibitory effects of NMDA on opioid receptor-mediated G protein activation
could be blocked by coadministration of the protein kinase C (PKC) inhibitors or
by elimination of the extracellular Ca2+. Correspondingly, NMDA treatment of
NG108 cells significantly elevated cellular PKC activity and stimulated Gialpha2
phosphorylation. Transient transfection into NG108-15 cells of the wild-type
Gialpha2 and a mutated Gialpha2 (Ser144Ala) resulted in a 2-fold increase in
DPDPE-stimulated G protein activation. The DPDPE responses were greatly inhibited
by NMDA treatment in the wild-type Gialpha2-transfected cells but much less
affected in the mutant Gialpha2-transfected cells. In summary, NMDA attenuates
opioid receptor/G protein coupling, and this process requires activation of PKC.
PMID- 9547360
TI - Protein kinase C activity is required for aryl hydrocarbon receptor pathway
mediated signal transduction.
AB - The role of protein kinase C (PKC) in the human aryl hydrocarbon receptor (hAhR)
signal transduction pathway was examined in cell lines stably transfected with
pGUDLUC6.1, in which luc+ is solely controlled by four dioxin-responsive elements
(DREs). These cell lines, P5A11 and HG40/6, were derived from HeLa and HepG2
cells respectively. Simultaneous treatment of these cells with 2,3,7,8,
tetrachlorodibenzo-p-dioxin (TCDD) and phorbol-12-myristate-13-acetate (PMA)
enhanced trans-activation of the reporter construct several-fold relative to
cells treated with TCDD alone. PKC inhibitors block the PMA effect and hAhR
mediated signal transduction, demonstrating these processes require PKC activity.
Examination of other independently generated, HeLa-derived cell lines stably
transfected with pGUDLUC6.1 demonstrates the PMA effect in P5A11 cells is not a
clonal artifact. Transient transfections indicate the PMA effect is not due to a
luciferase message/gene product stabilization mechanism or stimulation of the
basal transcription machinery. Examination of cytosolic preparations demonstrates
PKC stimulation or inhibition does not alter hAhR and hAhR nuclear translocator
protein levels or TCDD-induced down-regulation of hAhR levels. Similarly,
examination of nuclear extracts indicated PKC stimulation or inhibition does not
alter nuclear AhR levels or hAhR/hAhR nuclear translocator protein heterodimer
DRE-binding activity as assessed by electrophoretic mobility shift assay. These
results demonstrate a PKC-mediated event is required for the hAhR to form a
functional transcriptional complex that leads to trans-activation and that the
DRE is the minimal DNA element required for PMA to enhance AhR-mediated trans
activation.
PMID- 9547361
TI - Nuclear localization of overexpressed glyceraldehyde-3-phosphate dehydrogenase in
cultured cerebellar neurons undergoing apoptosis.
AB - We recently reported that overexpression of glyceraldehyde-3-phosphate
dehydrogenase (GAPDH; EC 1.2.1.12) is directly involved in cytosine
arabinonucleoside (ara-C)- and low K+-induced neuronal death of cultured
cerebellar granule cells. The former is entirely due to apoptosis, whereas the
latter involves both apoptosis and necrosis. We examined the subcellular
distribution of the overexpressed GAPDH occurring during apoptosis by using both
subcellular fractionation and immunocytochemistry with a monoclonal antibody
directed against this overexpressed protein. When immature cerebellar neurons
were exposed to ara-C, an overexpression of GAPDH was observed, primarily in the
nuclear fraction. In contrast, low K+ exposure of mature cerebellar neurons
induced the overexpression of GAPDH not only in the nuclear fraction but also in
the mitochondrial fraction. In both paradigms, no significant change of GAPDH
levels occurred in the microsomal and cytosolic fractions. Moreover, pretreatment
with GAPDH antisense oligonucleotide or classic apoptotic inhibitors clearly
suppressed the accumulation of GAPDH protein in these subcellular loci. This
discrete nuclear localization of GAPDH during apoptosis was supported further by
immunoelectron microscopy. Quantitative assessment of GAPDH immunogold labeling
revealed that a approximately 5-fold increase in the intensity of gold particles
was observed within the nucleus of apoptotic cells. Thus, the current results
raise the possibility that neuronal apoptosis may be triggered by GAPDH
accumulation in the nucleus, resulting in perturbation of nuclear function and
ultimate cell death.
PMID- 9547362
TI - Human histamine N-methyltransferase pharmacogenetics: common genetic
polymorphisms that alter activity.
AB - Histamine N-methyltransferase (HNMT) catalyzes a major pathway in histamine
metabolism. Levels of HNMT activity in humans are regulated by inheritance. We
set out to study the molecular basis for this genetic regulation. Northern blot
analysis showed that HNMT is highly expressed in the kidney, so we determined
levels of enzyme activity and thermal stability in 127 human renal biopsy
samples. DNA was isolated from 12 kidney samples with widely different HNMT
phenotypes, and exons of the HNMT gene were amplified with the polymerase chain
reaction. In these 12 samples, we observed a C314T transition that resulted in a
Thr105Ile change in encoded amino acid, as well as an A939G transition within the
3'-untranslated region. All remaining renal biopsy samples then were genotyped
for these two variant sequences. Frequencies of the alleles encoding Thr105 and
Ile105 in the 114 samples studied were 0.90 and 0.10, respectively, whereas
frequencies for the nucleotide A939 and G alleles were 0.79 and 0.21,
respectively. Kidney samples with the allele encoding Ile105 had significantly
lower levels of HNMT activity and thermal stability than did those with the
allele that encoded Thr105. These observations were confirmed by transient
expression in COS-1 cells of constructs that contained all four alleles for these
two polymorphisms. COS-1 cells transfected with the Ile105 allele had
significantly lower HNMT activity and immunoreactive HNMT protein than did those
transfected with the Thr105 allele. These observations will make it possible to
test the hypothesis that genetic polymorphisms for HNMT may play a role in the
pathophysiology of human disease.
PMID- 9547363
TI - Acceleration of oxime-induced reactivation of organophosphate-inhibited fetal
bovine serum acetylcholinesterase by monoquaternary and bisquaternary ligands.
AB - Reactivation of organophosphate (OP)-inhibited acetylcholinesterase (AChE) by
oximes is the primary reason for their effectiveness in the treatment of OP
poisoning. Reactivation is reported to accelerate by quaternary ligands such as
decamethonium, which is devoid of nucleophilicity. The mechanism of this
enhancement is not known. To better understand the acceleration phenomenon, we
examined ligand modulations of oxime-induced reactivation of methylphosphonylated
AChE using 7-(methylethoxyphosphinyloxy)-1-methylquinolinium iodide and fetal
bovine serum AChE. Edrophonium, decamethonium, and propidium, three quaternary
AChE ligands of different types, were tested as potential accelerators.
Experiments were carried out with both soluble enzyme preparation and AChE
conjugated to polyurethane. Kinetic measurements with oximes 2
[hydroxyiminomethyl]-1-methylpyridinium chloride, 1,1'-trimethylene bis-(4
hydroxyimino methyl)-pyridinium dibromide, and 1, 1'-[oxybis-methylene)bis[4
(hydroxyimino)methyl]pyridiniu um dichloride showed that in the presence of 50
microM edrophonium, the reactivation rate constants increased 3.3-12.0-fold; 200
microM decamethonium produced a 1.6-3.0-fold enhancement of reactivation rate
constants by the same oximes. Reactivation of the inhibited enzyme by 1-(2
hydroxyiminomethyl-1-pyridinium)-1-(4-carboxy-aminopyridinium )-d imethyl ether
hydrochloride, 1-(2-hydroxyiminomethyl-1-pyridinium)-1-(3-carboxy-aminopyridinium
)-d imethyl ether hydrochloride, and 1-[[[4
(aminocarbonyl)pyridino]methoxy]methyl]-2, 4, -bis(hydroxyimino)methyl pyridinium
dichloride was not affected by either ligand. Propidium slowed the reactivation
of 7-(methylethoxyphosphinyloxy)-1- methylquinolinium iodide-inhibited AChE by
all oximes. Results suggest that the accelerator site may reside inside the
catalytic gorge rather than at its entrance and acceleration may be due to the
prevention of reinhibition of the regenerated enzyme by the putative product, the
phosphonylated oxime. In addition to the nucleophilic property of the oximate
anion, some of the reactivators may carry an accelerating determinant, as
characterized with respect to edrophonium and decamethonium. Results offer
possible explanations for the superiority of 1-(2-hydroxyiminomethyl-1
pyridinium)-1-(4-carboxy-aminopyridinium )-d imethyl ether hydrochloride over
other oximes in the reactivation of specific AChE-OP conjugates.
PMID- 9547364
TI - ATP derivatives are antagonists of the P2Y1 receptor: similarities to the
platelet ADP receptor.
AB - Pharmacological properties of the human P2Y1 receptor transfected in Jurkat cells
and of the endogenous receptor in rat brain capillary endothelial cells were
analyzed under conditions in which the purity of adenine triphosphate nucleotides
was controlled by creatine phosphate/creatine phosphokinase (CP/CPK). ATP, a
partial agonist of the receptor, was inactive in the presence of CP/CPK. Results
further indicated that ATP was a competitive antagonist of ADP actions. Ki values
were 23.0 +/- 1.5 microM in endothelial cells and 14.3 +/- 0.3 microM in Jurkat
cells. Solutions prepared from commercially available 2-methylthio-ATP (2-MeSATP)
or 2-chloro-ATP (2-ClATP) contained approximately 10% of ADP derivatives. ADP
derivatives were removed from the solution by treatment with CP/CPK. Purified 2
MeSATP and 2-ClATP antagonized platelet aggregation induced by ADP. They did not
activate P2Y1 receptors but prevented ADP actions in a competitive manner. Ki
values for 2-MeSATP were 36. 5 microM in endothelial cells and 5.7 +/- 0.4 microM
in Jurkat cells, and Ki values for 2-ClATP were 27.5 microM in endothelial cells
and 2.3 +/- 0.3 microM in Jurkat cells. EDTA potentiated actions of ADP and ATP
on endothelial cells by 2.4- and 3.6-fold, respectively. In conclusion, the rat
and human P2Y1 receptors are ADP-specific receptors that recognize ADP and 2
methylthio-ADP, whereas ATP, 2-MeSATP, and 2-ClATP are competitive antagonists.
The results further point to the close pharmacological similarity of the P2Y1
receptor and the platelet ADP receptor.
PMID- 9547365
TI - Plasma membrane depolarization and disturbed Na+ homeostasis induced by the
protonophore carbonyl cyanide-p-trifluoromethoxyphenyl-hydrazon in isolated nerve
terminals.
AB - The effect of the protonophore carbonyl cyanide-p-trifluoromethoxyphenyl-hydrazon
(FCCP) was studied on the intracellular [Na+], pH, and plasma membrane potential
in isolated nerve terminals. FCCP induced a rise of [Na+]i at, and even below,
the concentrations (0.025-1 microM) in which it is usually used in intact cells
to eliminate Ca2+ uptake by mitochondria. The FCCP-induced increase of [Na+]i
correlates with a fall in both the ATP level and the ATP/ADP ratio. In addition,
a sudden rise of the intracellular proton concentration ([H+]i) from 83 +/- 0.4
to 124 +/- 0.7 nM was observed on the addition of FCCP (1 microM). Parallel with
the rise in [H+]i, an abrupt depolarization was detected, followed by a slower
decrease in the plasma membrane potential. Both the extent of the pHi change and
the fast depolarization of the plasma membrane were proportional to the proton
electrochemical gradient across the plasma membrane; when this gradient was
increased, greater depolarization was detected. The slower decrease of the
membrane potential after the fast initial depolarization was abolished when the
medium contained no Na+. It is concluded that FCCP (1) gives rise to a
depolarization by setting the plasma membrane potential close to the proton
equilibrium potential and (2) enhances the intracellular [Na+] as a consequence
of an insufficient ATP level and ATP/ADP ratio to fuel the Na+,K+/ATPase. Because
both disturbed Na+ homeostasis and plasma membrane depolarization could
profoundly interfere with Ca2+ homeostasis in the presence of protonophores,
consideration given to these alterations may help to clarify the cellular Ca2+
sequestration processes.
PMID- 9547366
TI - Reverse Na+/Ca2+ exchange contributes to glutamate-induced intracellular Ca2+
concentration increases in cultured rat forebrain neurons.
AB - Activation of ionotropic glutamate receptors causes increases in intracellular
Ca2+ concentration ([Ca2+]i) and intracellular Na+ concentration in neurons. It
has been suggested that reversal of the plasma membrane Na+/Ca2+ exchanger (NCE)
may account in part for the rise in [Ca2+]i. Recently, KB-R7943 (2-[2-[4-(4
nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate) was reported to
selectively inhibit the reverse mode of the NCE in non-neuronal cells. We
investigated the effects of KB-R7943 on glutamate-stimulated increases in
[Ca2+]i. In cultured rat forebrain neurons loaded with indo-1 acetoxymethyl
ester, KB-R7943 inhibited the reverse mode of NCE (IC50 = 0.7 microM). When
tested against kainate- (100 microM), N-methyl-D-aspartate- (30 microM),
glutamate- (3 microM), or KCl- (50 mM) induced [Ca2+]i transients (15 sec, in the
presence of Na+ and Ca2+), KB-R7943 inhibited these transients with IC50 values
of 6. 6, 8.2, 5.2, and 2.9 microM, respectively. [Ca2+]i increases caused by a
higher concentration of glutamate (100 microM) also were inhibited by KB-R7943
(10 microM). However, KB-R7943 had no effect on peak [Ca2+]i changes caused by
prolonged application of glutamate and did not inhibit glutamate-induced neuronal
injury. KB-R7943 did not inhibit N-methyl-D-aspartate- or kainate-induced whole
cell currents, nor did it substantially inhibit voltage-sensitive Ca2+ currents,
excluding a direct inhibition of these ion channels. These results suggest that
reverse NCE contributes to the immediate rise in [Ca2+]i resulting from glutamate
receptor activation. However, reverse NCE becomes less important as the stimulus
time is increased, and Ca2+ entry by this route is not critical for the
expression of excitotoxic injury.
PMID- 9547367
TI - Identification and characterization of two cysteinyl-leukotriene high affinity
binding sites with receptor characteristics in human lung parenchyma.
AB - We report the characterization of two distinct binding sites with receptor
characteristics for leukotriene (LT)D4 and LTC4 in membranes from human lung
parenchyma. The use of S-decyl-glutathione allowed us to characterize a
previously unidentified high affinity binding site for LTC4. Computerized
analysis of binding data revealed that each leukotriene interacts with two
distinct classes of binding sites (Kd = 0.015 and 105 nM for LTC4 and 0.023 and
230 nM for LTD4) and that despite cross-reactivity, the two high affinity sites
are different entities. LTD4 binding sites displayed features of G protein
coupled receptors, whereas LTC4 binding sites did not show any significant
modulation by guanosine-5'-(beta, gamma-imido)triphosphate or stimulation of
GTPase activity. The antagonists ICI 198,615 and SKF 104353 were unselective for
the high and low affinity states of LTD4 receptor, whereas only SKF 104353 was
able to recognize the two [3H]LTC4 binding sites although with different
affinities. These data indicate that in human lung parenchyma, LTD4 and LTC4
recognize two different binding sites; these binding sites are different
entities; and for LTD4, the two binding sites represent the interconvertible
affinity states of a G protein-coupled receptor, whereas for LTC4, the high
affinity site is likely to be a specific LTC4 receptor.
PMID- 9547368
TI - The relationship between agonist intrinsic activity and the rate of endocytosis
of muscarinic receptors in a human neuroblastoma cell line.
AB - The molecular mechanisms underlying the internalization of G protein-coupled
receptors are still poorly understood. Normally agonists but not antagonists
cause internalization (defined here as a reduction in the number of receptors at
the cell surface), suggesting a functional relationship between agonist activity
and internalization. In this study we investigated the effects of eight
muscarinic ligands on the rate constants for endocytosis and recycling of m3
muscarinic acetylcholine receptors in human SH-SY5Y neuroblastoma cells. We found
that there was a linear correlation between the intrinsic activity of the ligand
and its ability to increase the rate constant for endocytosis, suggesting that
the same active conformation of the receptor is responsible for stimulating both
second messenger generation and receptor endocytosis. In contrast, the rate
constant for recycling did not depend on which agonist had triggered receptor
endocytosis, suggesting that recycling is a purely constitutive process. Because
receptor internalization depends on the rate constants for both endocytosis and
recycling, the relationship between internalization and intrinsic activity is
nonlinear. In particular, mathematical modeling of receptor trafficking revealed
that under certain conditions very small (3% or less) increases in the rate
constant for endocytosis are sufficient to cause substantial receptor
internalization. An important implication of this analysis is that extremely weak
partial agonists (which may in practice be indistinguishable from antagonists)
may produce significant receptor internalization.
PMID- 9547369
TI - The agonism and synergistic potentiation of weak partial agonists by
triethylamine in alpha 1-adrenergic receptor activation: evidence for a salt
bridge as the initiating process.
AB - Alpha 1-adrenergic receptor (AR) activation is thought to be initiated by
disruption of a constraining interhelical salt bridge (). Disruption of this salt
bridge is achieved through a competition for the aspartic acid residue in
transmembrane domain three by the protonated amine of the endogenous ligand
norepinephrine and a lysine residue in transmembrane domain seven. To further
test this hypothesis, we investigated the possibility that a simple amine could
mimic an important functional group of the endogenous ligand and break this alpha
1-AR ionic constraint leading to agonism. Triethylamine (TEA) was able to
generate concentration-dependent increases of soluble inositol phosphates in COS
1 cells transiently transfected with the hamster alpha 1b-AR and in Rat-1
fibroblasts stably transfected with the human alpha 1a-AR subtype. TEA was also
able to synergistically potentiate the second messenger production by weak
partial alpha 1-AR agonists and this effect was fully inhibited by the alpha 1-AR
antagonist prazosin. However, this synergistic potentiation was not observed for
full alpha 1-AR agonists. Instead, TEA caused a parallel rightward shift of the
dose-response curve, consistent with the properties of competitive antagonism.
TEA specifically bound to a single population of alpha 1-ARs with a Ki of 28.7 +/
4.7 mM. In addition, the site of binding by TEA to the alpha 1-AR is at the
conserved aspartic acid residue in transmembrane domain three, which is part of
the constraining salt bridge. These results indicate a direct interaction of TEA
in the receptor agonist binding pocket that leads to a disruption of the
constraining salt bridge, thereby initiating alpha 1-AR activation.
PMID- 9547370
TI - Creating a functional opioid alkaloid binding site in the orphanin FQ receptor
through site-directed mutagenesis.
AB - Although much has been learned about the mechanisms of ligand selectivity between
different opioid receptor subtypes, little is known about the common opioid
binding pocket shared by all opioid receptors. The recently discovered orphanin
system offers a good opportunity to study the mechanisms involved in the binding
of opioid versus nonopioid ligands. In the current study, we adopt a "gain of
function" approach aimed at shifting the binding profile of the orphanin FQ
receptor toward that of the opioid receptors. After two rounds of mutagenesis,
several orphanin FQ receptor mutants can be labeled with the opiate alkaloid
[3H]naltrindole and show greatly increased affinities toward the opiate
antagonists naltrexone, nor-binaltrophine HCl, and (-)-bremazocine. These
orphanin FQ receptor mutants also display stereospecificity similar to that of
opioid receptors. Furthermore, the orphanin FQ receptor mutant that has the best
affinities toward the opioid alkaloids shows, in the presence of GTP and high
salt concentration, an affinity-shift profile similar to that of the delta
receptor. Most strikingly, the same mutant exhibits naltrindole-sensitive
etorphine-stimulated [35S]guanosine-5'-O-(3-thio)triphosphate binding, whereas
the effect of etorphine on GTP binding cannot be inhibited by naltrindole in the
wild-type receptor. Our results indicate that 1) several residues in the orphanin
FQ receptor are critical to its selectivity against the opiate alkaloids,
particularly antagonists; and 2) mutating these residues to those of the opioid
receptor at the corresponding position preserves the agonist/antagonist nature of
opiate alkaloids as they interact with the mutant receptor. It is reasonable to
hypothesize that the corresponding residues in the opioid receptors may form a
functional common binding pocket for opiate alkaloids. These findings may be
helpful to medicinal chemists in designing ligands for the orphanin FQ receptor
based on the structure of the opiate alkaloids.
PMID- 9547371
TI - The G protein-coupling profile of metabotropic glutamate receptors, as determined
with exogenous G proteins, is independent of their ligand recognition domain.
AB - Metabotropic glutamate (mGlu), Ca2+-sensing, gamma-aminobutyric acidB, and a
large number of pheromone receptors constitute a peculiar family of G protein
coupled receptors. They possess a large extracellular domain that has been
proposed to constitute their ligand binding domain. The aim of the current study
was to examine whether this large ligand binding domain had any influence on the
G protein-coupling selectivity of the receptor, and vice versa. We chose mGlu
receptors, which are classified into three groups according to their sequence
homology and pharmacology, as representatives of this receptor family. To define
a G protein-coupling profile for these receptors, we used a set of exogenous
phospholipase C-activating G proteins in the same way that synthetic ligands are
used to define agonist and antagonist pharmacological profiles. This set includes
Galpha15, Galpha16, Galphaq, and chimeric Galphaq proteins with the last few
amino acids of either Galphai2 (Galphaqi), Galphao (Galphaqo), or Galphaz
(Galphaqz). Cotransfection of mGlu receptors with these G proteins and
examination of their coupling to phospholipase C revealed that group I, II, and
III receptors have distinct G protein-coupling profiles. By swapping the
extracellular domains of the most distantly related mGlu receptors (the rat group
I mGlu1a and the Drosophila melanogaster group II DmGluA receptors), we show that
the extracellular domain determines the agonist pharmacological profile and that
this domain does not modify the G protein-coupling profile determined by the
seven-transmembrane-domain region of mGlu receptors.
PMID- 9547372
TI - Residues at the subunit interfaces of the nicotinic acetylcholine receptor that
contribute to alpha-conotoxin M1 binding.
AB - The two binding sites in the pentameric nicotinic acetylcholine receptor of
subunit composition alpha2 beta gamma delta are formed by nonequivalent alpha
gamma and alpha-delta subunit interfaces, which produce site selectivity in the
binding of agonists and antagonists. We show by sedimentation analysis that 125I
alpha-conotoxin M1 binds with high affinity to the alpha-delta subunit dimers,
but not to alpha-gamma dimers, nor to alpha, gamma, and delta monomers, a finding
consistent with alpha-conotoxin M1 selectivity for the alpha delta interface in
the intact receptor measured by competition against alpha-bungarotoxin binding.
We also extend previous identification of alpha-conotoxin M1 determinants in the
gamma and delta subunits to the alpha subunit interface by mutagenesis of
conserved residues in the alpha subunit. Most mutations of the alpha subunit
affect affinity similarly at the two sites, but Tyr93Phe, Val188Lys, Tyr190Thr,
Tyr198Thr, and Asp152Asn affect affinity in a site-selective manner. Mutant cycle
analysis reveals only weak or no interactions between mutant alpha and non-alpha
subunits, indicating that side chains of the alpha subunit do not interact with
those of the gamma or delta subunits in stabilizing alpha-conotoxin M1. The
overall findings suggest different binding configurations of alpha-conotoxin M1
at the alpha-delta and alpha-gamma binding interfaces.
PMID- 9547373
TI - Molecular actions of a Mn(III)Porphyrin superoxide dismutase mimetic and
peroxynitrite scavenger: reaction with nitric oxide and direct inhibition of NO
synthase and soluble guanylyl cyclase.
AB - Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP), described as a superoxide
dismutase mimetic and peroxynitrite scavenger, has been used previously to
investigate the cytotoxic potential of superoxide and peroxynitrite in several
pathological models. Here we report on the interference of MnTMPyP with NO/cGMP
signaling using cultured endothelial cells as well as purified soluble guanylyl
cyclase (sGC) either activated by the NO donor 2,2-diethyl-1-nitroso-oxyhydrazine
sodium salt (DEA/NO) or reconstituted with nitric oxide synthase (NOS). MnTMPyP
inhibited endothelial cGMP accumulation induced by A23187 (0.3 microM) with an
IC50 of 75.0 +/- 10.4 microM but had no significant effect on the potency of the
Ca2+ ionophore. Purified NOS was inhibited by MnTMPyP (IC50 = 5.5 +/- 0.8 microM)
because of an interference of the Mn-porphyrin with the reductase domain of the
enzyme. The most pronounced actions of MnTMPyP were direct inhibition of sGC and
scavenging of NO. Purified sGC stimulated with either Ca2+/calmodulin-activated
NOS (in the presence of GSH) or DEA/NO (in the absence of GSH) was inhibited with
IC50 values of 0.8 +/- 0.09 microM and 0.6 +/- 0.2 microM, respectively. In the
presence of GSH, MnTMPyP was reduced to the Mn(II) complex, resulting in
efficient scavenging of NO under these conditions. Our data demonstrate that
MnTMPyP (i) interferes with the reductase domain of NOS, (ii) scavenges NO in the
presence of GSH, and (iii) is a potent direct inhibitor of sGC. These results
cast doubt on the usefulness of MnTMPyP and related Mn-porphyrin complexes as
probes to study the involvement of peroxynitrite/superoxide in biological
systems.
PMID- 9547374
TI - Direct and indirect regulation of a single ion channel.
PMID- 9547375
TI - The revival of the role of the mitochondrion in regulation of transmitter
release.
PMID- 9547376
TI - Rhythmicity, synchronization and binding in human and primate motor systems.
AB - This review focuses on recent advances in our understanding of temporal pattern
coding in the motor systems of animals and man. Examples of millisecond time
scale rhythmic synchronization in the visual system are considered. Results of
experiments that demonstrate similar phenomena in the motor system are discussed.
Finally problems concerning the nature of the correlation between
neurophysiological signals and the relationship of correlation to motor behaviour
are explored.
PMID- 9547377
TI - Facilitation of rabbit alpha1B calcium channels: involvement of endogenous
Gbetagamma subunits.
AB - 1. The alpha1B (N-type) calcium channel shows strong G protein modulation in the
presence of G protein activators or Gbetagamma subunits. Using transient
expression in COS-7 cells of alpha1B together with the accessory subunits alpha2
delta and beta2a, we have examined the role of endogenous Gbetagamma subunits in
the tonic modulation of alpha1B, and compared this with modulation by exogenously
expressed Gbetagamma subunits. 2. Prepulse facilitation of control alpha1B/alpha2
delta/beta2a currents was always observed. This suggests the existence of tonic
modulation of alpha1B subunits. To determine whether endogenous Gbetagamma is
involved in the facilitation observed in control conditions, the betaARK1
Gbetagamma-binding domain (amino acids 495-689) was overexpressed, in order to
bind free Gbetagamma subunits. The extent of control prepulse-induced
facilitation was significantly reduced, both in terms of current amplitude and
the rate of current activation. In agreement with this, GDPbetaS also reduced the
control facilitation. 3. Co-expression of the Gbeta1gamma2 subunit, together with
the alpha1B/alpha2-delta/beta2a calcium channel combination, resulted in a marked
degree of depolarizing prepulse-reversible inhibition of the whole-cell ICa or
IBa. Both slowing of current activation and inhibition of the maximum current
amplitude were observed, accompanied by a depolarizing shift in the mid-point of
the voltage dependence of activation. Activation of endogenous Gbetagamma
subunits by dialysis with GTPgammaS produced a smaller degree of prepulse
reversible inhibition. 4. The rate of reinhibition of alpha1B currents by
activated G protein, following a depolarizing prepulse, was much faster with
Gbeta1gamma2 than for the decay of facilitation in control cells. Furthermore,
betaARK1 (495-689) co-expression markedly slowed the control rate of
reinhibition, suggesting that the kinetics of reinhibition depend on the
concentration of free endogenous or exogenously expressed Gbetagamma in the
cells. In contrast, the rate of loss of inhibition during a depolarizing prepulse
did not vary significantly between the different conditions examined. 5. These
findings indicate that, in this system, the voltage-dependent facilitation of
alpha1B that is observed under control conditions occurs as a result of
endogenous free Gbetagamma binding to alpha1B.
PMID- 9547378
TI - Voltage change-induced gating transitions of the rabbit skeletal muscle Ca2+
release channel.
AB - 1. We used the planar lipid bilayer method to study single ryanodine receptor
Ca2+ release channels (RyRCs) from fast skeletal muscle of the rabbit. We found
that changes in membrane voltage directly induced gating transitions of the RyRC:
(i) in the steady state, even at activating Ca2+ concentrations (20 microM), at a
constant membrane potential the channels resided in a low open probability (Po)
state (inactivated-, I-mode), and (ii) upon abrupt changes of voltage, the
apparent inactivation of the RyRCs was relieved, resulting in a rapid and
transient increase in Po. 2. The magnitude of the Po increase was a function of
both the duration and the amplitude of the applied prepulse, but was independent
of the channel activity during the prepulse. 3. The voltage-induced Po increase
probably involved major conformational changes of the channel, as it resulted in
substantial alterations in the gating pattern of the channels: the voltage change
induced increase in Po was accompanied by the rapid appearance of two types of
channel activity (high (H) and low (L) open probability modes). 4. The response
of the RyRC to voltage changes raises the interesting possibility that the
activation of RyRC in situ might involve electrical events, i.e. a possible
dipole-dipole coupling between the release channel and the voltage sensor.
PMID- 9547379
TI - Calcium-dependent inactivation of high-threshold calcium currents in human
dentate gyrus granule cells.
AB - 1. Dentate gyrus granule cells acutely dissociated from hippocampal slices
obtained from chronic temporal lobe epilepsy (TLE) patients displayed a high
voltage activated (HVA) Ca2+ conductance with a pronounced Ca2+-dependent
inactivation. 2. Inactivation time constants and peak HVA Ca2+ current (ICa)
amplitudes did not differ between perforated patch and whole-cell recordings
without added exogenous Ca2+ buffers, indicating that the Ca2+-dependent
characteristics of ICa inactivation were well preserved in whole-cell recordings.
3. Inactivation time constants correlated with whole-cell ICa, and were increased
when Ca2+ was replaced with Ba2+ in the external solution or 5 mM BAPTA was added
to the pipette solution. 4. In recordings without added exogenous Ca2+ buffers,
the time course of ICa inactivation was comparable between human TLE and kindled
rat granule cells. Conversely, the time course of ICa in human TLE granule cells
loaded with 5 mM intracellular BAPTA resembled that observed in buffer-free
recordings from control rat neurones. 5. The loss of a putative intraneuronal
Ca2+ buffer, the Ca2+-binding protein calbindin (CB), from human granule cells
during TLE may result in the pronounced Ca2+-dependent ICa inactivation. This
process could serve a neuroprotective role by significantly decreasing Ca2+ entry
during prolonged trains of action potentials known to occur during seizures.
PMID- 9547380
TI - Modulation of Ca2+ channel currents of acutely dissociated rat periaqueductal
grey neurons.
AB - 1. The actions of the neuropeptide nociceptin on the calcium channel currents
(IBa) of acutely dissociated rat periaqueductal grey (PAG) neurons were examined
using whole-cell patch clamp techniques. These effects were compared with those
of opioid receptor agonists and the GABAB receptor agonist baclofen. 2. Neurons
from young adult rats (23 to 56 days old) expressed predominantly omega-conotoxin
GVIA (N-type)- and omega-agatoxin IVA (P/Q-type)-sensitive IBa, together with
smaller amounts of nimodipine-sensitive current and current resistant to all
three blockers. There was proportionately more N-type IBa in neurons from female
rats and proportionately more resistant current in neurons from male rats. 3.
Nociceptin (EC50, 5 nM) and baclofen (EC50, 0.8 microM) inhibited IBa in all PAG
neurons, while the opioid agonist methionine enkephalin (met-enkephalin; 300 nM
10 microM) inhibited IBa in 40 % of neurons. The effects of met-enkephalin were
reversed by the mu-opioid antagonist CTAP, and mimicked by the mu-opioid agonist
DAMGO (300 nM-3 microM). The delta-opioid agonists DPDPE and deltorphin II, and
the kappa-opioid agonist U69593, did not affect IBa in any neuron. The actions of
nociceptin were not mimicked or blocked by the opioid antagonist naloxone or the
nociceptin analogue [desPhe1]-nociceptin. 4. The effects of nociceptin and
baclofen on IBa were blocked by pretreatment of the neurons with pertussis toxin
(500 ng ml-1, 8 h). 5. Nociceptin predominantly inhibited the N-type (EC50, 2 nM;
maximum inhibition, 50 %) and P/Q-type (EC50, 7 nM; maximum inhibition, 33 %) IBa
while having little effect on the L-type and R-type IBa. 6. These results are
consistent with the previously described actions of nociceptin, baclofen and
micro-opioids in PAG slices, whereby they couple to increases in an inwardly
rectifying K+ conductance. These agonists thus have the potential to modulate the
function of PAG neurons via a number of different cellular effectors.
PMID- 9547381
TI - Evidence that mitochondria buffer physiological Ca2+ loads in lizard motor nerve
terminals.
AB - 1. Changes in cytosolic and mitochondrial [Ca2+] produced by brief trains of
action potentials were measured in motor nerve terminals using a rapidly scanning
confocal microscope. Cytosolic [Ca2+] was measured using ionophoretically
injected Oregon Green BAPTA 5N (OG-5N). Mitochondrial [Ca2+] was measured using
rhod-2, bath loaded as dihydrorhod-2. 2. In response to 100-250 stimuli at 25-100
Hz the average cytosolic [Ca2+] showed an initial rapid increase followed by a
much slower rate of increase. Mitochondrial [Ca2+] showed no detectable increase
during the first fifteen to twenty stimuli, but after this initial delay also
showed an initially rapid rise followed by a slower rate of increase. The onset
of the increase in mitochondrial [Ca2+] coincided with the slowing of the rate of
rise of cytosolic [Ca2+]. The peak levels of cytosolic and mitochondrial [Ca2+]
both increased with increasing frequencies of stimulation. 3. When stimulation
terminated, the initial rate of decay of cytosolic [Ca2+] was much more rapid
than that of mitochondrial [Ca2+]. 4. After addition of carbonyl cyanide m
chlorophenyl hydrazone (CCCP, 1-2 microM) to dissipate the proton electrochemical
gradient across the mitochondrial membrane, cytosolic [Ca2+] rose rapidly
throughout the stimulus train, reaching levels much higher than normal. CCCP
inhibited the increase in mitochondrial [Ca2+]. 5. These results suggest that
mitochondrial uptake of Ca2+ contributes importantly to buffering presynaptic
cytosolic [Ca2+] during normal neuromuscular transmission.
PMID- 9547382
TI - A continuum of InsP3-mediated elementary Ca2+ signalling events in Xenopus
oocytes.
AB - 1. The elementary release events underlying inositol 1,4, 5-trisphosphate (InsP3)
mediated calcium signalling were investigated in Xenopus oocytes by means of high
resolution confocal linescan imaging together with flash photolysis of caged
InsP3. 2. Weak photolysis flashes evoked localized, transient calcium signals
that arose at specific sites following random latencies of up to several seconds.
The duration, spatial spread and amplitude of these elementary events varied
widely. Event durations (at half-maximal amplitude) were distributed
exponentially between about 100 and 600 ms. Fluorescence magnitudes (F/F0 of
Oregon Green 488 BAPTA-1) showed a skewed distribution with a peak at about 1.5
and a tail extending as high as 3.5. 3. Individual release sites exhibited both
small events (blips) and large events (puffs). The spatiotemporal distribution of
calcium signals during puffs was consistent with calcium diffusion from a point
source (< a few hundred nanometres), rather than with propagation of a
microscopic calcium wave. 4. Estimates of the calcium flux associated with
individual events were made by integrating fluorescence profiles along the scan
line in three dimensions to derive the 'signal mass' at each time point. The
smallest resolved events corresponded to liberation of < 2 x 10-20 mol Ca2+, and
large events to about 2 x 10-18 mol Ca2+. The rise of signal mass was more
prolonged than that of the fluorescence intensity, suggesting that calcium
liberation persists even while the fluorescence begins to decline. Rates of rise
of signal mass corresponded to Ca2+ currents of 0.4-2.5 pA. 5. Measurements of
signal mass from different events showed a continuous, exponential distribution,
arising through variability in magnitude and duration of calcium flux. 6. We
conclude that localized calcium transients in the oocyte represent a continuum of
events involving widely varying amounts of calcium liberation, rather than
falling into separate populations of 'fundamental' and 'elementary' events (blips
and puffs) involving, respectively, single and multiple InsP3 receptor channels.
This variability probably arises through stochastic variation in both the number
of channels recruited and the duration of channel opening.
PMID- 9547384
TI - Activation of Ca2+-activated K+ channels by an increase in intracellular Ca2+
induced by depolarization of mouse skeletal muscle fibres.
AB - 1. Ionic currents were simultaneously recorded at macroscopic and unitary level
using the whole-cell and cell-attached patch-clamp procedures together on the
same portion of isolated mouse skeletal muscle fibres. 2. In the presence of
Tyrode solution in the patch pipette and Tyrode-TTX solution in the bath,
macroscopic and unitary currents through delayed rectifier K+ channels were
simultaneously recorded in response to depolarizing pulses of 1 s duration. 3. In
five fibres, successive long-lasting incremental depolarizing levels induced, at
40 mV or -30 mV, the opening of a high conductance channel carrying an outward
current superimposed on delayed rectifier K+ channel activity. Opening of this
high conductance channel was not observed when the depolarization steps were
applied in the patch pipette. 4. Using the same depolarizing protocol, activation
of a high conductance channel was also observed in two fibres in the presence of
a K+-rich solution in the pipette (145 mM K+) . 5. With either Tyrode or K+-rich
solution in the pipette, unitary current amplitudes of the high conductance
channel matched well with the values obtained for Ca2+-activated K+ (KCa)
channels in inside-out patches under similar ionic conditions. 6. Indo-1
fluorescence measurements showed that the stimulation protocol that led to KCa
channel opening induced stepwise increases in intracellular [Ca2+] in the
submicromolar range. 7. Our results provide evidence that activation of
sarcolemmal KCa channels can be induced by a rise in intracellular [Ca2+]
following voltage-activated sarcoplasmic reticulum Ca2+ release.
PMID- 9547383
TI - Activation and co-ordination of InsP3-mediated elementary Ca2+ events during
global Ca2+ signals in Xenopus oocytes.
AB - 1. The activation of elementary calcium release events ('puffs') and their co
ordination to generate calcium waves was studied in Xenopus oocytes by confocal
linescan imaging together with photorelease of inositol 1,4,5-trisphosphate
(InsP3) from a caged precursor. 2. Weak photolysis flashes evoked no responses or
isolated calcium puffs, whereas flashes of increasing strength evoked more
frequent puffs, often occurring in flurries as abortive waves, and then a near
simultaneous calcium liberation originating at multiple sites. The numbers of
sites activated increased initially as about the fourth power of photoreleased
[InsP3]. 3. Following repeated, identical photolysis flashes, puffs arose after
stochastically varying latencies of a few hundred milliseconds to several
seconds. The cumulative number of events initially increased as about the third
power of time. No rise in free [Ca2+] was detected preceding the puffs,
suggesting that this co-operativity arises through binding of multiple InsP3
molecules, rather than through calcium feedback. 4. The mean latency to onset of
calcium liberation shortened as about the square of the flash strength, and the
dispersion in latencies between events reduced correspondingly. 5. Weak stimuli
often evoked coupled puffs involving adjacent sites, and stronger flashes evoked
saltatory calcium waves, propagating with non-constant velocity. During waves,
[Ca2+] rose slowly between puff sites, but more abruptly at active sites
following an initial diffusive rise in calcium. 6. Initial rates of rise of local
[Ca2+] at release sites were similar during puffs and release induced by much (>
10-fold) greater [InsP3]. In contrast, macroscopic calcium measurements averaged
over the scan line showed a graded dependence of rate of calcium liberation upon
[InsP3], due to recruitment of additional sites and decreasing dispersion in
activation latencies. 7. We conclude that the initiation of calcium liberation
depends co-operatively upon [InsP3] whereas the subsequent regenerative increase
in calcium flux depends upon local calcium feedback and is largely independent of
[InsP3]. Wave propagation is consistent with the diffusive spread of calcium
evoking regenerative liberation at heterogeneous discrete sites, the sensitivity
of which is primed by InsP3.
PMID- 9547385
TI - The role of intracellular Na+ and mitochondria in buffering of kainate-induced
intracellular free Ca2+ changes in rat forebrain neurones.
AB - 1. We have examined the mechanisms by which cultured central neurones from
embryonic rat brain buffer intracellular Ca2+ loads following kainate receptor
activation using fluorescent indicators of [Ca2+]i and [Na+]i. 2. Stimulation of
cultured forebrain neurones with 100 microM kainate produced a rapid increase in
[Ca2+]i that displayed a variable rate of recovery. Kainate also increased [Na+]i
with a response that was slightly slower in onset and markedly slower in
recovery. 3. The recovery of [Ca2+]i to baseline was not very sensitive to the
[Na+]i. The magnitude of the increase in [Na+]i in response to kainate did not
correlate well with the [Ca2+]i recovery time, and experimental manipulations
that altered [Na+]i did not have a large impact on the rate of recovery of
[Ca2+]i. 4. The recovery of [Ca2+]i to baseline was accelerated by the
mitochondrial Na+-Ca2+ exchange inhibitor CGP-37157, suggesting that the recovery
rate is influenced by release of Ca2+ from a mitochondrial pool and also that
variation in the recovery rate is related to the extent of mitochondrial Ca2+
loading. Kainate did not alter the mitochondrial membrane potential. 5. These
studies reveal that mitochondria have a central role in buffering neuronal
[Ca2+]i changes mediated by non-N-methyl-D-aspartate (NMDA) glutamate receptors,
and that the variation in recovery times following kainate receptor activation
reflects a variable degree of mitochondrial Ca2+ loading. However, unlike NMDA
receptor-mediated Ca2+ loads, kainate receptor activation has minimal effects on
mitochondrial function.
PMID- 9547387
TI - A mutation in the pore region of HERG K+ channels expressed in Xenopus oocytes
reduces rectification by shifting the voltage dependence of inactivation.
AB - 1. The effects of a mutation in the human ether-a-go-go-related gene (HERG)
(Ser631 to Ala, S631A) on the voltage- and extracellular [K+] dependence of
inactivation were studied in Xenopus oocytes using two microelectrode and single
channel voltage-clamp techniques. 2. The voltage required for half-inactivation
of S631A HERG was 102 mV more positive than for wild-type (WT)-HERG, resulting in
reduced rectification of the steady-state current-voltage relationship. In
contrast, the voltage dependence of channel activation was not altered by the
S631A mutation. These findings indicate that inactivation of HERG channels is not
linked to activation. 3. Rectification of whole-cell S631A HERG current was
caused by a voltage-dependent reduction in open probability, and inward
rectification of the current-voltage relationship of single channels. 4.
Elevation of extracellular [K+] from 2 to 20 mM shifted the half-point for
inactivation by +20 mV for WT-HERG, and +25 mV for S631A HERG. Thus, elevated
[K+]o and the S631A mutation affect HERG inactivation by different mechanisms. 5.
The S631A mutation altered the ion translocation rate of HERG channels. The
single channel conductance (gamma) of S631A HERG was 20 pS between -40 and-100
mV, and 6.0 pS between +40 and +100 mV (120 mM extracellular K+). This compares
to a gamma of 12.1 and 5.1 pS for WT-HERG channels under the same conditions.
PMID- 9547386
TI - alpha-Adrenergic effects on Na+-K+ pump current in guinea-pig ventricular
myocytes.
AB - 1. The whole-cell patch clamp was employed to study Na+-K+ pump current (Ip) in
acutely isolated myocytes. alpha-Adrenergic receptors were activated with
noradrenaline (NA) after blocking beta-adrenergic receptors with propranolol. Ip
was measured as the current blocked by strophanthidin (Str). 2. Activation of
alpha-receptors by NA increased Ip in a concentration-dependent manner. The K0.5
depended on intracellular calcium ([Ca2+]i), however maximal stimulation did not.
At 15 nM [Ca2+]i the K0.5 was 219 nM NA whereas at 1.4 microM [Ca2+]i it was 3
nM. 3. The voltage dependence of Ip was not shifted by NA at either high or low
[Ca2+]i. At each voltage, maximal stimulation of Ip was 14-15 %. 4. Staurosporine
(St), an inhibitor of protein kinase C (PKC), eliminated the alpha-receptor
mediated stimulation of Ip at either high or low[Ca2+]i. 5. The stimulation of Ip
was independent of changes in intracellular sodium or external potassium
concentrations, and did not reflect a change in affinity for Str. 6.
Phenylephrine, methoxamine and metaraminol, three selective alpha1-adrenergic
agonists, stimulate Ip in a similar manner to NA. Stimulation of Ip by NA was
eliminated by prazosin, an alpha1-antagonist, but was unaffected by yohimbine, an
alpha2-antagonist. 7. We conclude noradrenaline activates ventricular alpha1
receptors, which are specifically coupled via PKC to increase Na+-K+ pump
current. The sensitivity of the coupling is [Ca2+]i dependent, however the
maximal increase in pump current is [Ca2+]i and voltage independent.
PMID- 9547388
TI - Electrophysiological characterization of Na+ currents in acutely isolated human
hippocampal dentate granule cells.
AB - 1. Properties of voltage-dependent Na+ currents were investigated in forty-two
dentate granule cells (DGCs) acutely isolated from the resected hippocampus of
twenty patients with therapy-refractory temporal lobe epilepsy (TLE) using the
whole-cell patch-clamp technique. 2. Depolarizing voltage commands elicited
large, rapidly activating and inactivating Na+ currents (140 pS microm-2; 163 mM
extracellular Na+) that were reduced in amplitude by lowering the Na+ gradient
(43 mM extracellular Na+). At low temperatures (8-12 C), the time course of Na+
currents slowed and could be well described by the model of Hodgkin & Huxley. 3.
Na+ currents were reversibly blocked by tetrodotoxin (TTX) and saxitoxin (STX)
with a half-maximal block of 4.7 and 2.6 nM, respectively. In order to reduce
series resistance errors, the Na+ current was partially blocked by low toxin
concentrations (10-15 nM) in the experiments described below. Under these
conditions, Na+ currents showed a threshold of activation of about -50 mV, and
the voltages of half-maximal activation and inactivation were -29 and -55 mV,
respectively. 4. The time course of recovery from inactivation could be described
with a double-exponential function (time constants, 3-20 and 60-200 ms). The
rapid and slow time constants showed a distinct voltage dependence with maximal
values around -55 and -80 mV, respectively. These properties contributed to a
reduction of the Na+ currents during repetitive stimulation that was more
pronounced with higher stimulation frequencies and also showed a dependence on
the holding potential. 5. In summary, the most striking features of DGC Na+
currents were the large current density and the presence of a current component
showing a slow recovery from inactivation. Our data provide a basis for
comparison with properties of Na+ currents in animal models of epilepsy, and for
the study of drug actions in therapy-refractory epilepsy.
PMID- 9547389
TI - Regulation of Na+ channels by luminal Na+ in rat cortical collecting tubule.
AB - 1. The idea that luminal Na+ can regulate epithelial Na+ channels was tested in
the cortical collecting tubule of the rat using whole-cell and single-channel
recordings. Here we report results consistent with the idea of Na+ self
inhibition. 2. Macroscopic amiloride-sensitive currents (INa) were measured by
conventional whole-cell clamp. INa was a saturable function of external Na+
concentration ([Na+]o) with an apparent Km of 9 mM. Single channel currents (iNa)
were measured in cell-attached patches. iNa increased with pipette Na+
concentration with an apparent Km of 48 mM. Since INa = (iNa)NPo, the different
Km values imply that the channel density (N) and/or open probability (Po)
increase as [Na+]o decreases. Reduction of [Na+]o after increasing intracellular
Na+ concentration also increased the outward amiloride-sensitive conductance,
consistent with activation of the Na+ channels. 3. The underlying mechanism was
studied by changing pipette Na+ concentration while recording from cell-attached
patches. No increase in NPo was observed, suggesting that the effect is not a
direct interaction between [Na+]o and the channel. 4. [Na+]o was varied outside
the patch-clamp pipette while recording from cell-attached patches. When
amiloride was in the bath to prevent Na+ entry, no change in NPo was observed. 5.
Activation of the channels by hyperpolarization was observed with 140 mM Na+o but
not with 14 mM Na+o. 6. The results are consistent with the concept of self
inhibition of Na+ channels by luminal Na+. Activation of the channels by lowering
[Na+]o is not additive with that achieved by hyperpolarization.
PMID- 9547390
TI - Role of domain I of neuronal Ca2+ channel alpha1 subunits in G protein
modulation.
AB - 1. We studied the G protein inhibition of heteromultimeric neuronal Ca2+ channels
by constructing a series of chimeric channels between the strongly modulated
alpha1B subunit and the alpha1E(rbEII) subunit, which showed no modulation. 2. In
parallel studies, alpha1 subunit constructs were co-expressed together with the
accessory Ca2+ channel alpha2-delta and beta2a subunits in mammalian (COS-7)
cells and Xenopus oocytes. G protein inhibition of expressed Ca2+ channel
currents was induced by co-transfection of Gbeta1 and Ggamma2 subunits in COS-7
cells or activation of co-expressed dopamine (D2) receptors by quinpirole (100
nM) in oocytes. 3. The data indicate that transfer of the alpha1B region
containing the N-terminal, domain I and the I-II loop (i.e. the alpha1B1-483
sequence), conferred G protein modulation on alpha1E(rbEII), both in terms of a
slowing of activation kinetics and a reduction in current amplitude. 4. In
contrast, the data are not consistent with the I-II loop and/or the C-terminal
forming a unique site for G protein modulation.
PMID- 9547391
TI - The transient outward current in mice lacking the potassium channel gene Kv1.4.
AB - 1. The transient outward current (Ito) plays a prominent role in the
repolarization phase of the cardiac action potential. Several K+ channel genes,
including Kv1.4, are expressed in the heart, produce rapidly inactivating
currents when heterologously expressed, and may be the molecular basis of Ito. 2.
We engineered mice homozygous for a targeted disruption of the K+ channel gene
Kv1.4 and compared Ito in wild-type (Kv1.4+/+), heterozygous (Kv1.4+/-) and
homozygous 'knockout' (Kv1.4-/-) mice. Kv1.4 RNA was truncated in Kv1.4-/- mice
and protein expression was absent. 3. Adult myocytes isolated from Kv1.4+/+,
Kv1.4+/- and Kv1.4-/- mice had large rapidly inactivating outward currents. The
peak current densities at 60 mV (normalized by cellular capacitance, in pA pF-1;
means +/- s.e.m.) were 53.8 +/- 5. 3, 45.3 +/- 2.2 and 44.4 +/- 2.8 in cells from
Kv1.4+/+, Kv1.4+/- and Kv1.4-/- mice, respectively (P < 0.02 for Kv1.4+/+ vs.
Kv1.4-/-). The steady-state values (800 ms after the voltage clamp step) were
30.9 +/- 2.9, 26.9 +/- 3.8 and 23.5 +/- 2.2, respectively (P < 0.02 for Kv1.4+/+
vs. Kv1.4-/-). The inactivating portion of the current was unchanged in the
targeted mice. 4. The voltage dependence and time course of inactivation were not
changed by targeted disruption of Kv1.4. The mean best-fitting V (membrane
potential at 50 % inactivation) values for myocytes from Kv1.4 +/+, Kv1.4+/- and
Kv1. 4-/- mice were -53.5 +/- 3.7, -51.1 +/- 2.6 and -54.2 +/- 2.4 mV,
respectively. The slope factors (k) were -10.1 +/- 1.4, -8.8 +/- 1.4 and -9.5 +/-
1.2 mV, respectively. The fast time constants for development of inactivation at
30 mV were 27.8 +/- 2.2, 26.2 +/- 5. 1 and 19.6 +/- 2.1 ms in Kv1.4+/+, Kv1.4+/-
and Kv1.4-/- myocytes, respectively. At +30 mV, they were 35.5 +/- 2.6, 30.0 +/-
2.1 and 28. 7 +/- 1.6 ms, respectively. The time constants for the rapid phase of
recovery from inactivation at -80 mV were 32.5 +/- 8.2, 23.3 +/- 1.8 and 39.0 +/-
3.7 ms, respectively. 5. Nearly the entire inactivating component as well as more
than 60 % of the steady-state outward current was eliminated by 1 mM 4
aminopyridine in Kv1.4+/+, Kv1.4+/- and Kv1.4-/- myocytes. 6. Western blot
analysis of heart membrane extracts showed no significant upregulation of the Kv4
subfamily of channels in the targeted mice. 7. Thus, Kv1.4 is not the molecular
basis of Ito in adult murine ventricular myocytes.
PMID- 9547392
TI - Contribution of the Kv3.1 potassium channel to high-frequency firing in mouse
auditory neurones.
AB - 1. Using a combination of patch-clamp, in situ hybridization and computer
simulation techniques, we have analysed the contribution of potassium channels to
the ability of a subset of mouse auditory neurones to fire at high frequencies.
2. Voltage-clamp recordings from the principal neurones of the medial nucleus of
the trapezoid body (MNTB) revealed a low-threshold dendrotoxin (DTX)-sensitive
current (ILT) and a high-threshold DTX-insensitive current (IHT). 3. IHT
displayed rapid activation and deactivation kinetics, and was selectively blocked
by a low concentration of tetraethylammonium (TEA; 1 mM). 4. The physiological
and pharmacological properties of IHT very closely matched those of the Shaw
family potassium channel Kv3.1 stably expressed in a CHO cell line. 5. An mRNA
probe corresponding to the C-terminus of the Kv3.1 channel strongly labelled MNTB
neurones, suggesting that this channel is expressed in these neurones. 6. TEA did
not alter the ability of MNTB neurones to follow stimulation up to 200 Hz, but
specifically reduced their ability to follow higher frequency impulses. 7. A
computer simulation, using a model cell in which an outward current with the
kinetics and voltage dependence of the Kv3.1 channel was incorporated, also
confirmed that the Kv3.1- like current is essential for cells to respond to a
sustained train of high-frequency stimuli. 8. We conclude that in mouse MNTB
neurones the Kv3.1 channel contributes to the ability of these cells to lock
their firing to high-frequency inputs.
PMID- 9547393
TI - Bilaterally evoked monosynaptic EPSPs, NMDA receptors and potentiation in rat
sympathetic preganglionic neurones in vitro.
AB - 1. Whole-cell patch clamp and intracellular recordings were obtained from 190
sympathetic preganglionic neurones (SPNs) in spinal cord slices of neonatal rats.
Fifty-two of these SPNs were identified histologically as innervating the
superior cervical ganglion (SCG) by the presence of Lucifer Yellow introduced
from the patch pipette and the appearance of retrograde labelling following the
injection of rhodamine-dextran-lysine into the SCG. 2. Electrical stimulation of
the ipsilateral (n = 71) or contralateral (n = 32) lateral funiculi (iLF and cLF,
respectively), contralateral intermediolateral nucleus (cIML, n = 41) or
ipsilateral dorsal horn (DH, n = 34) evoked EPSPs or EPSCs that showed a constant
latency and rise time, graded response to increased stimulus intensity, and no
failures, suggesting a monosynaptic origin. 3. In all neurones tested (n = 60),
fast rising and decaying components of EPSPs or EPSCs evoked from the iLF, cLF,
cIML and DH in response to low-frequency stimulation (0.03-0.1 Hz) were sensitive
to non-NMDA receptor antagonists. 4. In approximately 50 % of neurones tested (n
= 29 of 60), EPSPs and EPSCs evoked from the iLF, cLF, cIML and DH during low
frequency stimulation were reduced by NMDA receptor antagonists. In the remaining
neurones, an NMDA receptor antagonist-sensitive EPSP or EPSC was revealed only in
magnesium-free bathing medium, or following high-frequency stimulation. 5. EPSPs
evoked by stimulation of the iLF exhibited a sustained potentiation of the peak
amplitude (25.3 +/- 11.4 %) in six of fourteen SPNs tested following a brief high
frequency stimulus (10-20 Hz, 0.1-2 s). 6. These results indicate that SPNs,
including SPNs innervating the SCG, receive monosynaptic connections from both
sides of the spinal cord. The neurotransmitter mediating transmission in some of
the pathways activated by stimulation of iLF, cLF, cIML and DH is glutamate
acting via both NMDA and non-NMDA receptors. Synaptic plasticity is a feature of
glutamatergic transmission in some SPNs where EPSPs are potentiated following a
brief high-frequency stimulus. Our data also suggest a differential expression of
NMDA receptors by these neurones.
PMID- 9547395
TI - Synaptic currents at individual connections among stellate cells in rat
cerebellar slices.
AB - 1. Unitary inhibitory synaptic connections among stellate cells were studied in
rat cerebellar slices. Presynaptic action potentials and inhibitory postsynaptic
currents (IPSCs) were simultaneously recorded by loose cell-attached and tight
seal whole-cell recording, respectively. 2. Several types of synaptic connections
were distinguished on the basis of the shape of the amplitude distribution of
successfully evoked currents. For simple synapses, which presumably arise at
single release sites, these histograms could be fitted to a single Gaussian (5
cases). In four additional cases a small amplitude component (< 50 pA) was
superimposed to a single Gaussian peak. The small events had slow rise times and
widely distributed amplitudes. Finally eleven histograms showed two or more
Gaussian components and were classified as complex connections. 3. Failure rates
ranged from 0.06 to 0.85 for unitary connections (n = 20) and from 0.59 to 0.78
for simple synapses (n = 5). 4. Coefficient of variation values derived from
Gaussian fits to simple synapse histograms ranged between 0.20 and 0.38 (n = 5).
5. In simple synapses peak current amplitudes were positively correlated to both
current rise time and decay half-width. 6. Intervals between presynaptic action
potentials were widely distributed. During stationary periods there was no
correlation between interspike interval and amplitude size, success rate or
latency. In some experiments, episodes with shorter interspike intervals were
observed. During these periods, amplitude and success rate decreased, and the
latency increased. Thus, IPSC characteristics depend on the mean frequency of
presynaptic spikes, but not on random fluctuations of interspike intervals during
stationary periods.
PMID- 9547394
TI - Ionotropic and metabotropic activation of a neuronal chloride channel by
serotonin and dopamine in the leech Hirudo medicinalis.
AB - 1. Cl- channels on the pressure-sensitive (P) neuron in the leech are directly
activated by synaptic release of serotonin (5-HT) and are indirectly stimulated
by the cAMP second messenger pathway, suggesting an unusual dual regulation of
the channels. We have investigated the mode of action of 5-HT and dopamine (DA)
on a Cl- channel in adult P cells in culture by recording from cell-attached
patches. 2. 5-HT increased Cl- channel activity only when included in the
recording pipette and not when applied in the bath. 3. Pipette or, more
effectively, bath application of DA led to an increase in Cl- channel activity.
This effect was blocked by the potent and specific dopaminergic (DA1) receptor
blocker, SCH-23390. 4. The stimulation by DA, but not by 5-HT, was also blocked
by the cAMP-dependent protein kinase A (PKA) inhibitor Rp-cAMP and was mimicked
by the membrane-permeant cAMP analogue dibutyryl cAMP (db-cAMP). 5. Our results
show that 5-HT directly gates a Cl- channel that is also activated by DA via the
cAMP pathway. This study demonstrates that a ligand-gated channel can be
independently operated by another transmitter acting via a second messenger
pathway.
PMID- 9547396
TI - Differential effects of noradrenaline on evoked, spontaneous and miniature IPSCs
in rat cerebellar stellate cells.
AB - 1. The modulation by noradrenaline (NA) of synapses among stellate cells was
investigated in rat cerebellar slices by using presynaptic loose cell-attached
recording and postsynaptic whole-cell recording. 2. NA increased the frequency of
spontaneous IPSCs recorded from stellate cells without changing their mean
amplitude. 3. NA increased the firing rate of stellate cells. This effect
persisted after blocking ionotropic glutamate receptors and GABA receptors,
indicating that it was independent of synaptic input. 4. The effects of NA on
action potential frequency were mimicked by the beta-receptor agonist
isoprenaline but not by the alpha-receptor agonist 6-fluoro noradrenaline, and
they were not blocked by the alpha-receptor antagonist phentolamine, indicating
that they were mediated by beta-receptors. 5. In paired recordings of connected
stellate cells, NA slightly decreased the success rate of synaptic transmission.
A small decrease in mean IPSC amplitude (excluding failures) and a slight
increase in latency were also observed in NA. 6. These results show that, while
NA increases the number of action potential-dependent IPSCs by increasing the
firing rate of stellate cells, it actually reduces the probability of evoked
release. Since previous studies showed that NA increases the rate of miniature
IPSCs in this preparation, we conclude that different mechanisms underly the
modulation by NA of action potential-dependent and action potential-independent
transmitter release.
PMID- 9547397
TI - Blockade of synaptic inhibition within the pre-Botzinger complex in the cat
suppresses respiratory rhythm generation in vivo.
AB - 1. The role of synaptic inhibition in respiratory rhythm generation was analysed
by microinjections of GABAA and glycine receptor antagonists into the bilateral
pre-Botzinger complex (PBC) of anaesthetized cats. Central respiratory activity
was monitored by phrenic nerve recordings. 2. Bilateral injections of bicuculline
(50 or 100 microM) irreversibly slowed respiratory frequency and induced
apneustic patterns. 3. Bilateral injections of strychnine (50 or 100 microM)
greatly reduced phrenic burst amplitudes leading to increased burst frequency or
irreversibly blocked rhythmic phrenic discharges. After unilateral tetrodotoxin
(TTX) blockade in the PBC, strychnine injection into the contralateral PBC
blocked rhythmic phrenic discharges. 4. Bilateral blockade of both GABAergic and
glycinergic inhibition abolished rhythmic burst discharges and only tonic phrenic
activity remained. Such tonic activity was blocked only by TTX (1 microM). 5.
Potentiation of synaptic inhibition by the serotonin 1A receptor agonist 8
hydroxydipropylaminotetralin (8-OH-DPAT; 50 microM) restored rhythmic activity
only when given shortly after strychnine and bicuculline applications. It was,
however, ineffective after blockade of synaptic inhibition was complete. 6. The
study demonstrates the significance of synaptic inhibition in the process of
respiratory generation in the adult cat in vivo.
PMID- 9547398
TI - AMPA receptor activation and phosphatase inhibition affect neonatal rat
respiratory rhythm generation.
AB - 1. We investigated the role of alpha-amino-3-hydroxy-5-methylisoxazole-4
propionate (AMPA) receptors and their regulation in affecting respiratory-related
neurones in a neonatal rat medullary slice that spontaneously generates
respiratory-related rhythm and motor output in the hypoglossal (XII) nerve. 2.
Bath application of the AMPA receptor antagonist 1-(4-aminophenyl)-4-methyl-7,8
methylenedioxy-5H-2, 3-benzodiazepine (GYKI) completely blocked XII nerve
activity, as well as respiratory-related synaptic drives in neurones within the
preBotzinger Complex (preBotC), site of rhythm generation in the slice. 3. Local
application of GYKI to the preBotC blocked respiratory rhythm. Local application
of AMPA to the preBotC increased rhythm frequency and depolarized respiratory
related neurones. 4. In the presence of tetrodotoxin (TTX), GYKI completely
blocked the inward current induced by local application of AMPA, but not that
induced by kainate. 5. Local application of okadaic acid, a membrane-permeable
inhibitor of phosphatase 1 and 2A, to the preBotC increased the frequency of
respiratory motor discharge. 6. Intracellular application of microcystin, a
membrane-impermeable inhibitor of phosphatase 1 and 2A, enhanced endogenous
inspiratory drive and exogenous AMPA-induced current (in the presence of TTX) in
preBotC inspiratory neurones. Both the enhanced inspiratory drive and the
increased AMPA-induced current were completely blocked by GYKI. 7. We suggest
that AMPA receptor activation and AMPA receptor modulation by phosphorylation are
crucial for the rhythm generation within the preBotC.
PMID- 9547399
TI - Neutralization of pyrogen-induced tumour necrosis factor by its type 1 soluble
receptor in guinea-pigs: effects on fever and interleukin-6 release.
AB - 1. A soluble form of the tumour necrosis factor (TNF) type 1 receptor (referred
to as TNF binding protein, TNF-bp) at a dose of 1 mg per animal, or an equivalent
volume of solvent, was injected together with 10 microg kg-1 lipopolysaccharide
(LPS) or 50 microg kg-1 muramyl-dipeptide (MDP) directly into the arterial
circulation of guinea-pigs and the effects on circulating TNF or interleukin-6
(IL-6) and on abdominal temperature were studied. 2. At 15 or 60 min after
injection, LPS-induced and MDP-induced circulating TNF was below the detection
limit of the assay and thus completely neutralized in animals treated with TNF
bp. In the control group, TNF was still below the limit of detection in most
animals 15 min after LPS was injected; in some animals small traces of TNF could
already be detected at that time. However, 60 min after administration of LPS,
large amounts of TNF (19508 +/- 4682 pg ml-1) were measured in the control group.
MDP-induced TNF in plasma was below the limit of detection 15 min after MDP was
injected, and rose to 10862 +/- 3029 pg ml-1 60 min after injection. 3. Low
levels of circulating IL-6 (20-40 international units (IU) ml-1) were measured in
all groups of animals 15 min after injection of LPS or MDP. This value
corresponds to the baseline activity of IL-6 in plasma of guinea-pigs. One hour
after administration of LPS, IL-6 rose to 5442 +/- 1662 IU ml-1 in the control
group and to a significantly lower value of 1485 +/- 179 IU ml-1 in guinea-pigs
treated with TNF-bp. One hour after injection of MDP, circulating IL-6 was 2614
+/- 506 IU ml-1 in the control group, while the corresponding value in animals
treated with TNF-bp again was significantly lower (873 +/- 312 IU ml-1). 4. The
second phase of the characteristic biphasic LPS fever in guinea-pigs was
significantly attenuated in animals treated with TNF-bp. The shorter first phase
of the febrile response to LPS was identical in both groups of animals. 5. The
late phase of MDP-induced fever (7-22 h after injection) was depressed by
treatment with TNF-bp, while the first phase of MDP-induced fever (0-7 h after
injection) was significantly enhanced by the neutralization of TNF by TNF-bp.
PMID- 9547400
TI - Harmonic distortion on the basilar membrane in the basal turn of the guinea-pig
cochlea.
AB - 1. Mechanical responses to pure-tone stimuli were recorded from the basilar
membrane in the basal turn of the guinea-pig cochlea using a displacement
sensitive laser interferometer. The harmonic content of the responses was
evaluated using Fourier analysis. 2. Harmonic distortion products were observed
in many of the basilar membrane responses. Response components locked to twice
the frequency of the stimulus (i.e. 2F0) were the largest of the distortion
products. 3. The second harmonic responses showed a bimodal frequency
distribution at low to moderate sound pressure levels: one peak occurred around
the preparation's best or most sensitive frequency (i.e. when F0 approximately 17
kHz), and another occurred around one-half of the best frequency (when F0
approximately 8.5 kHz). 4. The absolute levels of most distortion products
increased progressively with increasing stimulus strength. When expressed with
respect to the levels of the fundamental responses, however, the distortion
levels usually decreased with increasing stimulus strength. 5. The levels of the
distortion decreased (in both absolute and relative terms) with deterioration in
the physiological condition of the cochlea. 6. Maximum second harmonic distortion
levels amounted to approximately 3.5 and approximately 28 % of the fundamental
responses to tones near and below the best frequency, respectively. 7. The above
findings are shown to be consistent with a highly simplified model of cochlear
mechanics which incorporates an asymmetric, saturating non-linearity in a
positive feedback loop.
PMID- 9547401
TI - Induction of antioxidant enzyme activity by hyperoxia (60 % O2) in the developing
chick embryo.
AB - 1. At premature birth, man and animals are exposed to relatively high oxygen
levels, compared with intra-uterine conditions, at a time when their antioxidant
enzyme (AOE) system is still immature. Using the chick embryo as a study model,
we investigated changes in the AOE system in response to hyperoxia applied at
different time points during the incubation period. Relations between hyperoxia
and AOE activity were studied in selected organs (brain, heart, liver, intestine
and lungs) of developing chick embryos (during the second half of the incubation
period). 2. Incubated White Leghorn eggs were divided into four groups: control
(n = 100) and three test groups exposed for 48 h to 60 % O2 on day 10 (test group
1, n = 80), day 14 (test group 2, n = 60) and day 18 (test group 3, n = 30).
Superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) enzyme
activities were measured in homogenates of the brain, heart, liver, intestine and
lungs. 3. Exposure to hyperoxia at different time points during incubation
resulted in a 2- to 10-fold increase in SOD activity in all organs except the
brain. Catalase and GPx enzyme activities were only induced in test group 1, 48 h
after initiation of hyperoxia. 4. In the developing chick embryo, hyperoxia can
produce a temporary induction of AOE activity, which is dependent on the AOE,
organ, incubation time and time point of exposure.
PMID- 9547402
TI - The role of endothelin-A receptors in cardiovascular responses to acute
hypoxaemia in the late gestation sheep fetus.
AB - 1. In unanaesthetized chronically instumented fetal sheep (118-121 days
gestation) we investigated the effect of acute isocapnic hypoxaemia (arterial
Po2, 12.5 +/- 0.6 mmHg) on heart rate (FHR), mean systemic arterial blood
pressure (MABP), carotid and femoral blood flows (CBF and FBF, respectively), and
carotid and femoral vascular resistances (CVR and FVR, respectively) with the
infusion of either the endothelin-A (ETA) receptor antagonist FR139317, or saline
vehicle. 2. During normoxaemia FHR (P < 0.05) and CBF (P < 0. 01) were greater,
and CVR (P < 0.01) was lower with FR139317 than with vehicle infusion. CVR
remained lower with FR139317 than with vehicle infusion during hypoxaemia (P <
0.01) and recovery (P < 0. 05). During hypoxaemia the rapid initial bradycardia,
the increase in MABP and FVR and the decrease in FBF were similar with vehicle
and FR139317 infusion. In both groups plasma endothelin-1 concentration ([ET-1])
was unaltered by hypoxaemia. The increase in CBF during hypoxaemia with vehicle
(P < 0.01) was absent with FR139317 infusion. 3. Thus in the late gestation ovine
fetus endogenous ET-1 modulates basal FHR, CBF and CVR via ETA receptors.
Modulation of CBF and CVR persists during hypoxaemia but ETA receptors do not
appear to contribute to the decrease in femoral blood flow measured during acute
hypoxaemia.
PMID- 9547404
TI - Nitrite adulteration of workplace urine drug-testing specimens. I. Sources and
associated concentrations of nitrite in urine and distinction between natural
sources and adulteration.
AB - The active ingredient in the commercial workplace urine drug-testing adulterant,
Klear, was previously determined to be nitrite ion. Nitrite adulteration
compromises the confirmation of some drugs, notably the marijuana metabolite. A
previously reported bisulfite step overcomes some nitrite adulteration, but it
cannot do so in every case, which leaves the laboratory to report the specimen as
not suitable for testing. Unlike many other adulterants, nitrite is found in
normal urine at low concentrations. In order to defend a report of nitrite
adulteration, it is necessary to provide evidence that the amount of nitrite in a
workplace urine specimen could not arise by normal means. The objectives of this
study were to identify all sources of nitrite in urine and the range of
concentrations associated with these sources and to determine if nitrite
adulteration can be supported based upon a quantitative result. The scientific
literature was reviewed for internal and external sources of nitrite and their
concentration ranges and are reported. The following specimens were obtained and
nitrite concentrations measured by a spectrophotometric method: clinical
specimens nitrite positive by test strip (< 15 micrograms/mL); specimens culture
positive for nitrate-reducing microorganisms (< 36 micrograms/mL); specimens from
patients on medications that may metabolize to nitrite (< 6 micrograms/mL); and
drug-test specimens, both negative (< 130 micrograms/mL) and others that appeared
to be adulterated with nitrite (range 1910-12,200 micrograms/mL, mean 5910). The
literature and the nitrite measurements of this study indicate a substantial
difference between concentrations from natural sources compared with
adulteration. A quantitative measurement of nitrite by a well-structured assay
can provide scientifically valid and forensically defensible proof of
adulteration with a nitrite-containing substance.
PMID- 9547403
TI - Exercise metabolism in human skeletal muscle exposed to prior eccentric exercise.
AB - 1. The effects of unaccustomed eccentric exercise on exercise metabolism during a
subsequent bout of graded concentric exercise were investigated in seven healthy
male subjects. Arterial and bilateral femoral venous catheters were inserted 2
days after eccentric exercise of one thigh (eccentric thigh) and blood samples
were taken before and during graded two-legged concentric knee-extensor exercise.
Muscle biopsies were obtained from the eccentric and control vastus lateralis
before (rest) and after (post) the concentric exercise bout. 2. Maximal knee
extensor concentric exercise capacity was decreased by an average of 23 % (P <
0.05) in the eccentric compared with the control thigh. 3. The resting muscle
glycogen content was lower in the eccentric thigh than in the control thigh (402
+/- 30 mmol (kg dry wt)-1 vs. 515 +/- 26 mmol (kg dry wt)-1, means +/- s.e.m., P
< 0.05), and following the two-legged concentric exercise this difference
substantially increased (190 +/- 46 mmol (kg dry wt)-1 vs. 379 +/- 58 mmol (kg
dry wt)-1, P < 0.05) despite identical power and duration of exercise with the
two thighs. 4. There was no measurable difference in glucose uptake between the
eccentric and control thigh before or during the graded two-legged concentric
exercise. Lactate release was higher from the eccentric thigh at rest and, just
before termination of the exercise bout, release of lactate decreased from this
thigh (suggesting decreased glycogenolysis), whereas no decrease was found from
the contralateral control thigh. Lower glycerol release from the eccentric thigh
during the first, lighter part of the exercise (P < 0.05) suggested impaired
triacylglycerol breakdown. 5. At rest, sarcolemmal GLUT4 glucose transporter
content and glucose transport were similar in the two thighs, and concentric
exercise increased sarcolemmal GLUT4 content and glucose transport capacity
similarly in the two thighs. 6. It is concluded that in muscle exposed to prior
eccentric contractions, exercise at a given power output requires a higher
relative workload than in undamaged muscle. This increases utilization of the
decreased muscle glycogen stores, contributing to decreased endurance.
PMID- 9547405
TI - A rapid, sensitive method for the quantitation of N-acetyl-S-(2-hydroxyethyl)-L
cysteine in human urine using isotope-dilution HPLC-MS-MS.
AB - Because of increasing concern about exposure to carcinogens and other toxicants,
reliable methods for biological monitoring of potentially exposed populations
must be developed. For biological monitoring to be useful, appropriate biomarkers
of exposures to xenobiotics must be identified, and sensitive, specific methods
for quantifying the targeted biomarker must be developed. We have developed a
sensitive and selective method for the analysis of N-acetyl-S-(2-hydroxyethyl)-L
cysteine (HEMA), urinary metabolite of at least three different known human
carcinogens (vinyl chloride, ethylene oxide, and ethylene dibromide). The method
uses strong anion-exchange solid-phase extraction and isotope-dilution high
performance liquid chromatography-tandem mass spectrometry. Our method is simple
and is not labor intensive; the preparation time per sample is less than 10 min.
Because urine samples vary in both their concentration and ion strength,
intersample variability in HEMA recovery during the extraction is large. To
overcome this inherent limitation, we use the isotope-dilution technique, which
allows a complete correction for the extraction recovery for each sample. The
limit of detection of the method is 0.68 microgram/L in a 1-mL urine sample with
a coefficient of variation of 22% (determined by replicate analyses at both 4 and
11 micrograms/L) and an accuracy indistinguishable from 100%. Preliminary
analyses of urine from a population with no known overt exposure to the parent
toxicants show a frequency of detection of approximately 75%, which indicates
that this method has the sensitivity to detect urinary HEMA derived from
environmental exposure. We are currently using this method to establish a
reference range of background exposure to these toxicants in the U.S. population.
PMID- 9547406
TI - A barbiturate screening assay for the Abbott AxSYM analyzer.
AB - A fluorescence polarization immunoassay for barbiturates on the Abbott AxSYM
analyzer is described. The assay displayed dilution linearity up to 1200 ng/mL;
coefficients of variation varied from 5.96 to 8.61%; recovery varied from 94.9 to
105.3%; and sensitivity was less than 40 ng/mL. Good correlation between the
standard six- and factory two-point calibration methods was observed. The
Immunoassay demonstrated good cross-reactivity to several commonly prescribed
barbiturates; low cross-reactivity with structurally similar compounds; low
interference from endogenous substances, dyes, preservatives, and several
commonly available adulterants; and good correlation with the TDx Barbiturate
Urine assay.
PMID- 9547407
TI - Detection and determination of theobromine and caffeine in urine after
administration of chocolate-coated peanuts to horses.
AB - The objective of this study was to determine the urinary excretion of
methylxanthines in horses following ingestion of chocolate over eight days. The
study was performed in response to gas chromatography-mass spectrometry (GC-MS)
confirmation of the presence of caffeine in a positive urine test in a racehorse.
The trainer of the horse alleged that he often administered chocolate-coated
peanuts as treats to his horses, and he believed that the ingestion of chocolate
was responsible for the positive urine test. The urinary excretion of theobromine
and caffeine after the ingestion of chocolate-coated peanuts was investigated in
three horses. Enzyme-linked immunoassay (ELISA), high-performance liquid
chromatography (HPLC), and GC-MS assays were performed on all urine specimens.
Theobromine (HPLC) was detected for 72 h and caffeine (GC-MS) for 48 h after
chronic ingestion of chocolate-coated peanuts. Methylxanthines were detected by
ELISA for 120 h after administration of chocolate.
PMID- 9547408
TI - Survey on drugs-of-abuse testing in the European Union.
AB - A survey on the quality of drugs-of-abuse testing in European laboratories was
performed in 1993 (Part I) and 1994 (Part II). A total of 195 laboratories
participated in Part I and 228 in Part II. There were 154 repeater laboratories.
In each part of the survey, six urine samples were sent for analysis under
routine conditions. A set of reference materials, including deuterated drug
standard solutions, was provided in Part II of the survey for optimization of
analytical procedures. Screening for groups of substances was mainly performed by
immunological techniques. Rates of false-positive (FP) results were 0 and 0.5%,
respectively, in Parts I and II, and rates of false-negative (FN) results were
7.7% in Part I and 3.4% in Part II. Identification and quantitation of specific
substances was mainly carried out by chromatographic methods, particularly gas
chromatography coupled to mass spectrometry. Application of chromatographic
methods showed a lack of sensitivity (14.9% and 16.7% FN in Parts I and II,
respectively) and a lack of specificity (0.8% FP in Part I versus 1.1% in Part
II). Repeater laboratories improved their results (17.4% FN in Part I versus
14.2% Part II). The improvement of repeater laboratories emphasizes the need of
external quality control programs. The experience is being used as a basis for a
recommendation on drug-testing guidelines by a group of European toxicologists.
PMID- 9547410
TI - The feasibility of the detection and quantitation of beta-adrenergic blockers by
solid-phase extraction and subsequent derivatization with methaneboronic acid.
AB - Urine specimens containing 11 common beta blockers were processed using solid
phase extraction technology to extract the drugs from the urine matrix, then
converted to their cyclic methaneboronates by treatment with methaneboronic acid
in ethyl acetate. The compounds tested included acebutolol, atenolol, alprenolol,
bisoprolol, betaxolol, carteolol, penbutolol, propranolol, pindolol, timolol,
nadolol, sotalol, labetolol, metoprolol, and oxprenolol. The extraction
efficiencies were greater than 90% for all drugs tested. The cyclic
methaneboronates formed by this procedure generally possessed good
chromatographic properties. The mass spectral behavior of the methaneboronates
was excellent, with all compounds containing several high mass fragments and
every tested compound possessing a unique mass spectrum.
PMID- 9547409
TI - Screening procedure for beta-adrenergic drugs in sports drug testing by
immunological methods.
AB - A systematic study of the cross-reactivities of beta-adrenergic agonists and
antagonists and their metabolites with an ELISA test designed to detect
terbutaline and other beta 2-agonists has been performed in order to evaluate the
applicability of this immunological test as screening method in routine human
sports drug testing. Concentration response curves were calculated. IC50 values
from 1.7 to 21.5 ng/mL were obtained for beta 2-agonists, and values from 3.1 to
520.8 ng/mL were obtained for most of the beta-blockers. The highest cross
reactivity was mainly depending on the amino substituent of the molecules
although the structure of the aromatic ring was also important. Minor changes in
the aromatic ring, such as 4-hydroxylation for propranolol, did not largely
influence the IC50 value. Distribution of control activities (percentage of
optical density as compared with a blank sample) of urines obtained in controlled
excretion studies (70 samples) and urines collected after competition in sports
in which beta-blockers are recommended to be tested (147 samples) showed a very
small overlapping between the subpopulations of positive and negative samples.
Cutoff values of 45 or 60% control activity were proposed for routine analysis.
Sensitivity and specificity values of 92.8 and 98.8%, respectively (cutoff 45%),
or 98.2 and 95.0%, respectively (cutoff 60%), were obtained. Because the known
prevalence of positive results of beta-blockers and beta 2-agonists in the target
population was very low, the predicted percentage of presumptive positive cases
that would need further confirmation by gas chromatography-mass spectrometry was
also low, accounting for a 1.48 and 5.28% (for the cutoffs of 45 and 60%,
respectively) of the total number of samples to be screened by the presented
ELISA test. Thus, in terms of time and cost savings, the ELISA test is a powerful
tool for the purpose of screening for beta-adrenergic drugs in human urine.
PMID- 9547411
TI - Morphine formation from ethylmorphine: implications for drugs-of-abuse testing in
urine.
AB - In drugs-of-abuse testing, opiates constitute a delicate and controversial task
because morphine may occur in urine for several reasons. Ethylmorphine (EtM),
which is used as an antitussive drug in many countries, is metabolically
converted to morphine. The present study was performed in order to document intra
and interindividual differences in morphine formation after single-dose intake
of EtM at two different doses (25 and 50 mg). The urinary excretion of opiates
was measured during 48 h with EMIT and gas chromatography-mass spectrometry in 10
healthy volunteers. The mean values of totally recovered EtM and morphine in
hydrolyzed urine during 48 h were 42 and 47% of the given dose at high and low
dose level, respectively. The ratio between total recovered morphine and EtM
ranged from 19 to 131% with a mean value of 48%. The rate of positive outcome in
the EMIT opiate-screening assay was 100% during the first 24 h for both doses,
and it was still high (> or = 67%) in the 24-48 h time interval. It was found
that the decline in urinary EtM is more rapid than for morphine, which leads to
an increasing morphine/EtM ratio in urine over time. THe mean value of the
morphine/EtM ratio was found to be greater than 1 during the 12-24 h interval and
finally increased to greater than 10. There was an intra-individual concordance
in morphine/EtM ratio between doses, but there was marked interindividual
variation. Morphine/EtM ratios that were greater than 1 were only seen when the
concentration of morphine was below 300 micrograms/mmol creatinine. Our results
demonstrate that morphine is formed from EtM at a high and variable rate and may
be present in urine in concentrations greater than those of EtM even shortly
after drug intake.
PMID- 9547412
TI - Development and evaluation of immunochromatographic rapid tests for screening of
cannabinoids, cocaine, and opiates in urine.
AB - The test principle and the optimization of the reactive ingredients are described
for the one-step dip and-read immunochromatographic FRONTLINE rapid tests for
drugs-of-abuse testing in urine samples. In a multicenter evaluation the rapid
tests were compared with FPIA and EMIT immunoassays. Discrepant results were
further analyzed by gas chromatography-mass spectrometry methods. In the
comparison of the cannabinoids rapid tests versus both immunoassays using
clinical and forensic urine samples (399 versus FPIA and 755 versus EMIT),
sensitivities and specificities were 97% or better for both comparisons. For
cocaine, a sensitivity of 100% versus both routine technologies was obtained,
whereas the specificity was reduced somewhat to 91% because of some cross
reactivity with metabolites of methadone and of clozapine. Specificity was very
high for the cocaine rapid tests (98-100%) when applied to urine samples of
persons not in a methadone maintenance program. Sensitivities and specificities
for the opiates rapid tests were 99% or better at all sites when compared with
the routine methods. In the screening of about 1200 clinical urine samples for
cannabinoids, cocaine or opiates misuse only six samples would have stayed
undetected by rapid test analyzes. These results show the FRONTLINE assays allow
a reliable and immediate screening for drugs of abuse.
PMID- 9547413
TI - Incorporation of isotopically labeled cocaine into human hair: race as a factor.
AB - In order to evaluate race as a possible factor affecting the incorporation of
drugs into human hair, 2 mg/kg deuterium-labeled cocaine (cocaine-d5) was
administered intranasally to nine male non-Caucasian volunteers under controlled
laboratory conditions. Sequential blood samples were collected for up to three
days, and scalp hair samples were collected at 24 and 72 h after dosing and at
monthly intervals for up to 12 months. The samples were then analyzed by gas
chromatography-mass spectrometry for cocaine-d5 and benzoylegonine-d5 (BZE-d5).
The amounts of cocaine-d5 found in the hair of these non-Caucasian subjects were
compared with the amounts of cocaine-d5 found in the hair of Caucasian subjects
who received the same cocaine dose under identical conditions as part of a study
we reported previously. The non-Caucasians in the present study had approximately
2.7 times more cocaine-d5 in their hair than the Caucasian subjects in the
earlier study. In five of the non-Caucasian subjects, cocaine-d5 could be
detected in hair within 24 h after dosing. Curiously, we were unable to detect
any cocaine-d5 in one of the non-Caucasian subject's hair at any time after
dosing even though cocaine-d5 was in plasma at the expected levels. The results
from these studies suggest there may be a racial bias in the incorporation of
cocaine into human hair; however, the data are not conclusive because of the
relatively small sample size.
PMID- 9547414
TI - Suicide with the veterinary drug acepromazine.
AB - A suicide case involving the veterinary drug acepromazine is described. After a
single-step liquid alkaline extraction, acepromazine was identified in a chest
cavity blood sample using gas chromatography (GC) with nitrogen-phosphorus (NPD)
and mass selective detectors. Acepromazine was then quantitated in the blood and
other postmortem tissues by GC with NPD using chlorpromazine as the internal
standard. Acepromazine concentrations in the chest-cavity blood, liver, brain,
and bile were 0.6, 3.0, 0.4, and 6.5 micrograms/mL, respectively. The stomach
contents contained a total of 2.5 mg acepromazine.
PMID- 9547415
TI - Recent paramethoxyamphetamine deaths.
AB - Paramethoxyamphetamine (PMA) is a methoxylated phenethylamine derivative that has
been used illicitly in Australia since late 1994. It is purportedly sold under
the guise of "ecstasy", which is the colloquial name for
methylenedioxymethamphetamine (MDMA). Methods for extraction, identification, and
quantitation are presented. Toxicology findings in six fatalities involving the
drug are discussed. Femoral blood PMA levels ranged from 0.24 to 4.9 mg/L (mean,
2.3 mg/L). Liver PMA levels ranged from 1.4 to 21 mg/kg (mean, 8.9 mg/kg). Other
amphetamines were found in five of the six cases. Blood PMA levels in three
nonfatal cases are also presented. PMA appeared to be more toxic than MDMA, and
blood levels greater than 0.5 mg/L seemed likely to be associated with toxic
effects.
PMID- 9547417
TI - Stabilization of blood cyanide.
PMID- 9547416
TI - 6-acetylmorphine detection in postmortem cerebrospinal fluid.
PMID- 9547418
TI - Analysis of Hempen Ale for cannabinoids.
PMID- 9547420
TI - Coping with chronic pain: sources of intrinsic and contextual variability.
AB - Univariate and multivariate analyses were used to investigate intrinsic and
contextual sources of coping variability among 90 patients with chronic pain.
Pain coping strategies were assessed by the subscales of the Coping Strategies
Questionnaire. Intrinsic variables included demographic characteristics and
dispositional optimism. Contextual variables included pain-related variables and
pain control appraisals. In univariate analyses, ethnicity was a statistically
significant intrinsic source of variability for the praying and hoping coping
subscale; however, comparisons between pairs of ethnic groups were not
statistically significant. A multivariate perspective of the data found three
independent and salient patterns of correlation between the intrinsic and
contextual variables and coping subscales. These patterns of correlation
accounted for 96% of the total variance and were conceptualized as optimistic
active coping, educated rational coping, and optimistic restricted coping. The
findings raise the prospect that there are intrinsic and contextual explanations
of coping variability for patients with chronic pain.
PMID- 9547419
TI - Off-treatment fatigue in breast cancer survivors: a controlled comparison.
AB - Fatigue is a common and distressing symptom following cancer treatment. Research
examining "off-treatment" fatigue has been weakened by limited assessments of
fatigue and lack of suitable comparison groups. The extent of off-treatment
fatigue following treatment for breast cancer (BC) was examined. Women with BC (n
= 88; mean, 28 months posttreatment) and age-matched women (n = 88) with benign
breast problems (BBP), completed a set of fatigue questionnaires at an Initial
assessment and a 4-month Follow-up assessment. The BC group reported more
fatigue, more weakness, and less vitality relative to the BBP group at both
assessments. No relationship was found in the BC group between fatigue and extent
of treatment or time since treatment completion. While the results document the
existence of off-treatment fatigue following BC, elucidation of the
psychobiological processes underlying this symptom and development of clinical
management strategies remain as challenges for future research.
PMID- 9547421
TI - Health status in sickle cell disease: examining the roles of pain coping
strategies, somatic awareness, and negative affectivity.
AB - People with sickle cell disease (SCD) vary in their pain, activity levels, and
medical care. We examined how coping (Coping Strategies Questionnaire), somatic
awareness, and illness worry were related to these health indices in 70 African
American adults with SCD. Negative Thinking/Passive Adherence and/or somatic
awareness was positively correlated with pain episode frequency, duration, or
severity, after controlling for demographics and disease severity and positively
correlated with activity reduction or hospitalization frequency after also
controlling for pain. Self-reported negative affectivity was correlated with both
psychological and SCD measures; and controlling for negative affectivity
eliminated several, but not all, relationships. Examination of the Negative
Thinking/Passive Adherence factor suggested a distinction between Negative
Thinking and Passive Adherence, which was partially supported by their different
relationships. We conclude that negative thinking, passive coping, and somatic
awareness are related to several measures of poor health in SCD but that some
relationships are better accounted for by general measures of negative
affectivity.
PMID- 9547422
TI - The evaluation of medical symptoms by patients and doctors.
AB - This study investigates discrepancy and congruence between doctors and patients
in their beliefs about the need for medical treatment. One hundred seventy-six
outpatients and 337 university students rated each of a set of 35 symptoms on the
urgency with which they would seek medical advice were they experiencing that
symptom. Sixty-six general practitioners rated the urgency with which a person
experiencing that symptom should seek medical advice. These symptoms were
classified as relatively serious or nonserious on the basis of ratings by a
separate set of doctors. General practitioners perceived a greater overall need
for treatment than did patients, but this difference was greater for nonserious
than for serious symptoms. In fact patients perceived treatment to be more urgent
for three serious symptoms, each potentially indicative of cancer. The observed
pattern of doctor-patient discrepancies can be explained in terms of the
availability heuristic. The role of this heuristic in the cognitive dynamics of
doctor-patient relationships merits future attention.
PMID- 9547424
TI - The effects of evening light exposure on the sleep of elderly women expressing
sleep complaints.
AB - In order to address the typical phase advanced, disturbed sleep of the elderly,
additional evening light was provided to elderly women by means of a "visor"
which provides 2000 lux to each eye. The subjects wore the light visor for 30 min
in the evening. The subjects were 10 community-residing women over the age of 65
(mean = 79.4 years; range, 67-87 years). Sleep was recorded in the home for 28
successive 24-hr periods: 7 days pretreatment, 14 days while using the light
visor, and 7 days posttreatment. Thus, each subject served as her own control.
Sleep was recorded using the Home Monitoring System (HMS), a nonintrusive
procedure which does not require instrumentation of the subject. The subjects
showed significant changes during and even after the intervention: there was a
significant decrease in sleep latency over weeks, and a significant increase in
sleep time and sleep efficiency. The subjects also reported less fatigue during
treatment. The results suggest that additional light, provided for as little as
0.5 hr in the evening and at only 2000 lux, increases the amount of nighttime
sleep and improves the quality of sleep in older women.
PMID- 9547423
TI - Assessment of self-reward strategies for maintenance of breast self-examination.
AB - This study examined the relative impact of different self-reward strategies on
maintenance of breast self-examination (BSE) practice among 1649 women trained to
do BSE. Training groups were randomized into four conditions: (a) self-reward
instructions and materials delivered at the end of the BSE training session; (b)
self-reward suggestions delivered through the mail each month, contingent upon
the BSE performance; (c) external monetary rewards and self-reward suggestions
delivered through the mail each month on an intermittent schedule, contingent
upon BSE practice; and (d) a no-reward control condition. Follow-up assessments
12 months following training revealed a pattern of evidence in support of the
benefits of external monetary rewards and self-reward prompts on BSE frequency
and quality; however, it is likely that the value of that condition lies in the
external reward component.
PMID- 9547425
TI - Overall false positive rates in tests for linear trend in tumor incidence in
animal carcinogenicity studies of new drugs.
AB - Based on results of simulation and empirical studies conducted within the
Divisions of Biometrics, Center for Drug Evaluation and Research, Food and Drug
Administration, and in collaboration with the National Toxicology Program, the
Center has recently changed the significance levels for testing positive linear
trend in incidence rate for common and rare tumors, respectively, from 0.01 and
0.05 to 0.005 and 0.025. The overall false positive rate resulting from the use
of this new rule in the tests for linear trend in a two-species-two-sex study is
about 10%, the rate that is judged as the most appropriate in a regulatory
setting by the Center. This paper describes two of the studies.
PMID- 9547426
TI - Weighted multiplicity adjustments for animal carcinogenicity tests.
AB - Sparse data is a difficulty in the analysis of animal carcinogenicity data: it is
difficult to detect effects when the background tumor rates are low. The widely
used "Haseman rule" and its variants provide more power to tests with low
background rates, while maintaining a degree of control over the global false
positive rate. In this article we explore the use of these rules, finding global
error rates that are unacceptably high for many animal carcinogenicity studies.
We provide alternative weighting methods that correct the deficiencies of the
Haseman rule, and apply them to carcinogenicity data from a pharmaceutical
company.
PMID- 9547427
TI - Analysis of homogeneity of treatment effect in adaptive multicenter clinical
trials.
AB - In this paper, an exact test for analyzing the homogeneity of treatment effect in
adaptive multicenter clinical trials is proposed. Extensive simulation studies
are performed to investigate the large sample behavior of a commonly used test
statistic for testing homogeneity of treatment effect. When the sample size in
each center is large relative to the number of centers, the asymptotic null
distribution of the test statistic is reasonable. On the other hand, when the
data are relatively sparse, the proposed exact test should be used to incorporate
the adaptive nature of the design.
PMID- 9547428
TI - Statistical methodology for screening studies with qualitative/quantitative
mixtures.
AB - A statistical method for designing screening studies involving several
experimental treatments compared to a standard treatment is developed. The
screening study identifies the most promising experimental treatments, which then
undergo more rigorous evaluation in a future, larger study. The technique is
especially relevant for biopharmaceutical research and development in which phase
II clinical trials are conducted to identify the most promising drug regimens,
which then move on to phase III of clinical development. It is assumed that the
underlying distribution of the primary efficacy random variable is a
qualitative/quantitative mixture. The proposed methodology involves calculating
the probability of accepting each experimental treatment compared to the standard
treatment, where the criterion for acceptance is based on the proportion of
qualitative observations and a measure of their location. The probability of
acceptance is displayed in two dimensions using operating characteristic contour
plots. The techniques are illustrated with some practical examples and some
extensions are indicated.
PMID- 9547430
TI - Simple methods for determination of the release limits for drug products.
AB - The potency of a batch of drug product needs to meet a release limits at the time
of release so that the potency at the end of shelf life remains above the lower
registration limit (LRL). This article discusses two methods which determine the
release limits such that the chance to fail LRL at the end of shelf life of the
product will be controlled under a desirable level. In additional to controlling
failure rate, a method which determines the release limits such that the expected
total cost due to rejecting a batch at time zero and at the end of shelf life is
minimized. All the methods assume a very flexible sampling schedule, and are
simple to implement. Each method is illustrated in an example.
PMID- 9547429
TI - An application of methods for clustered binary responses to a cardiovascular
study with small sample size.
AB - This paper discusses statistical methods for a cardiovascular study in which each
of eight animals had a dichotomous outcome observed for each of several
treatments. There were five treatments in all: shunt, control, two doses of a
test drug for potentially causing an unfavorable cardiovascular event, and a
combination of the test drug and a counteracting agent. Exact conditional methods
were used through LogXact, a statistical software for exact logistic regression
and an alternative framework for performing a large class of nonparametric tests
performed by StatXact. The results agreed reasonably with asymptotic methods even
though the sample size was small.
PMID- 9547431
TI - Hypothesis testing and confidence interval construction in 2 x 2 tables of
correlated proportions.
AB - The 2 x 2 table is an invaluable tool for displaying bivariate binary data. It is
easy to find examples of correlated binary response in biopharmaceutical
experiments and clinical research and analysis of these data is a current
research topic. The most common hypothesis tested for 2 x 2 tables of correlated
proportions is that of homogeneity of the marginal proportions or, equivalently,
the hypothesis of table symmetry. The 2 x 2 table of correlated proportions is
rich with information and we present a survey of some of the analyses relevant
for these data. Using asymptotic theory, we develop estimators of relevant
parameters and associated test statistics that are of interest. We discuss
interval estimation using arguments proposed by Quesenberry and Hurst (1) and
Goodman (2). These interval estimators do not rely on estimation of the
covariance matrix and are not necessarily equivalent to those obtained using
modified chi-square statistics.
PMID- 9547432
TI - Accommodating negative intracluster correlation with a mixed effects logistic
model for bivariate binary data.
AB - We extend the random intercept logistic model to accommodate negative
intracluster correlations for bivariate binary response data. This approach
assumes a single random effect per cluster, but entails separate affine
transformations of this random effect for the two responses of the pair. We show
this approach works for two data sets and a simulation, whereas other mixed
effects approaches fail. The two data sets are from a crossover trial and a
developmental toxicity study of the effects of chemical exposure on malformation
risk among rat pups. Comparisons are made with the conditional likelihood
approach and with generalized estimating equations estimation of the population
averaged logit model. Simulations show the conditional likelihood approach does
not perform well for moderate to strong negative correlations, as a positive
intracluster correlation is assumed. The proposed mixed effects approach appears
to be slightly more conservative than the population-averaged approach with
respect to coverage of confidence intervals. Nonetheless, the statistical
literature suggests that mixed effects models provide information in addition to
that provided by population-averaged models under scientific contexts such as
crossover trials. Extensions to trivariate and higher-dimensional responses also
are addressed. However, such extensions require certain constraints on the
correlation structure.
PMID- 9547433
TI - Step-down trend tests for identifying the minimum effective dose.
AB - Many authors, most recently Tamhane, Hochberg, and Dunnett (18), have studied the
problem of determining the minimum effective dose in dose-response studies. Based
on past research and on findings from their own extensive simulation study, which
covered a wide range of balanced normal homoscedastic situations, Tamhane et al.
recommended a procedure they called SD2L, since it exhibited good performance in
almost all the situations they studied. This method is a step-down procedure with
a simple linear contrast-based trend test at each step. In this paper, we
demonstrate that replacing the linear contrast trend test by Bartholomew's test
leads to a procedure, SD2B, that consistently outperforms SD2L. In addition to
the balanced normal homoscedastic framework, the finite sample performance of
these procedures is also explored under unbalanced and/or heteroscedastic
conditions. A third procedure, SD2W, which replaces the linear contrast test by
Welch's test, offers some improvement over SD2B in a few heteroscedastic
situations. In many cases, the increase in efficiency of SD2B and SD2W over SD2L
exceeds 10%.
PMID- 9547434
TI - The analysis of small-sample multivariate data.
AB - Clinical pharmacology studies typically consist of few subjects per treatment
group, but with many, possibly highly correlated, measurements taken per subject.
Permutational methods for testing equality of the multivariate treatment means
when the number of variables exceeds the number of independent subjects have been
developed, but are highly computationally intensive. In this paper, a parametric
test was derived, using Edgeworth expansions, for the case of two groups, and
compared with competing test statistics proposed by Mercante and Johnson (7),
Dempster (5), Chung and Fraser (3), Mantel and Valand (6). The proposed test
compares favorably with the others in terms of type I error rate, as well as
power, and has the advantages of not requiring computationally intensive
resources and being easily extendable to more than two groups.
PMID- 9547435
TI - Unclear points from Bristol's equivalence tests.
PMID- 9547436
TI - Industry, academia, and postgraduate education.
PMID- 9547437
TI - The effects of simvastatin on the incidence of heart failure in patients with
coronary heart disease.
AB - BACKGROUND: Although treatment of myocardial overload effectively reduces death
from progression of heart failure, it is not known whether the retardation of
progressive coronary artery disease obtained with lipid lowering treatment will
prevent the onset and consequences of heart failure in patients without previous
symptoms of heart failure. METHODS AND RESULTS: In the Scandinavian Simvastatin
Survival Study, 4444 patients with coronary heart disease without evidence of
heart failure were randomized to placebo (n = 2223) or simvastatin 20-40 mg (n =
2221) and followed for more than 5 years. Among the patients who received
placebo, 228 (10.3%) were diagnosed with heart failure during follow-up
evaluation compared with 184 (8.3%) of patients who received simvastatin (P <
.015). Mortality was 31.9% in the placebo group and 25.5% in the simvastatin
group among patients who developed heart failure. These compare with 9.2 and
6.6%, respectively, among non-heart failure patients. There were 45
hospitalizations because of acute heart failure in the placebo group and 23 in
the simvastatin group (NS). Patients who developed heart failure were more likely
to have suffered a recurrent myocardial infarction and have a history of
diabetes, peripheral artery disease, and hypertension than patients who did not
develop congestive heart failure. CONCLUSION: Long-term prevention with
simvastatin reduces the occurrence of heart failure in a cohort of patients with
coronary heart disease without previous evidence of congestive heart failure.
PMID- 9547438
TI - Clinical trials for prevention of congestive heart failure: from retrospective
analysis to prospective hope.
PMID- 9547439
TI - Ventilatory drive during exercise in congestive heart failure.
AB - BACKGROUND: Continuous increases in the ventilatory equivalent for carbon dioxide
(the ratio of minute ventilation to carbon dioxide production, an index of
ventilatory drive) during exercise in patients with congestive heart failure
would suggest that factors other than carbon dioxide excessively stimulate
ventilation during exercise, and may be an important factor in exercise-related
dyspnea and fatigue in these patients. METHODS AND RESULTS: Eighty-five patients
with congestive heart failure and 17 normal control subjects underwent symptom
limited exercise testing with gas-exchange analysis. Patients were divided into
four functional classes (A-D, Weber's classification) based on peak exercise
oxygen consumption. In all heart failure patient groups and in control subjects
the ventilatory equivalent for carbon dioxide decreased (P < .005, class D; P <
.0001, all other groups) from rest to anaerobic threshold. Three isolated
patients showed a continuous increase in ventilatory drive during exercise (mean
peak oxygen consumption 13.7 mL/kg/min). In the lowest functional class (D) the
ventilatory equivalent for carbon dioxide was greater than in all other groups at
rest, at anaerobic threshold, and at peak exercise (P < .01). CONCLUSIONS: In all
heart failure groups and in normal control subjects ventilatory drive, as
determined by the ventilatory equivalent for carbon dioxide, decreases during
exercise, Continuous increases in ventilatory drive during exercise are
infrequently seen, suggesting that factors other than carbon dioxide production
do not excessively stimulate ventilation in heart failure patients during
exercise.
PMID- 9547440
TI - Pulmonary hemodynamics and endothelin levels in pacing-induced heart failure:
during rest and exercise.
AB - Elevated plasma levels of endothelin (ET) have been reported to accompany the
development of heart failure (HF), and therefore, this potent vasoconstrictive
peptide has been postulated to contribute to the altered pulmonary hemodynamics
that occur in this disease process. The overall goal of this study was to examine
more carefully the relationship between ET levels in the pulmonary system and
pulmonary hemodynamics in the normal and HF states, during both rest and
exercise. This study used a porcine model of chronic rapid pacing that has been
shown in previous studies to produce left ventricular dysfunction and
neurohormonal system activation consistent with the syndrome of HF. Pigs (n = 10)
were chronically instrumented to measure pulmonary and systemic hemodynamics,
parenchymal flow, and ET content and to obtain blood samples from the pulmonary
circuit in the conscious state. Measurements were performed in the normal control
state and again following the development of pacing-induced HF (240 beats/min per
21 days), both at rest and during treadmill exercise (3 mph, 15 degrees incline,
12 minutes). With HF, under ambient resting conditions, a threefold increase in
pulmonary plasma ET occurred and was accompanied by a fivefold increase in
pulmonary vascular resistance. During treadmill exercise, pulmonary plasma ET and
pulmonary vascular resistance remained elevated in the HF group when compared
with the normal state and were associated with a sixfold decrease in pulmonary
parenchymal flow. Pulmonary parenchymal ET content was increased with HF when
compared with values for normal control subjects (8.5 +/- 0.6 vs 5.6 +/- 0.8 fmol
ET/mg protein, P < .05). Thus, the findings of this study suggest that in this
model of HF, increased ET within the pulmonary circuit contributed to
abnormalities in resistive properties and parenchymal flow.
PMID- 9547441
TI - Nebivolol in the treatment of cardiac failure: a double-blind controlled clinical
trial.
AB - BACKGROUND: Nebivolol is a highly cardioselective long-acting beta-blocker with
vasodilating properties, which acts in part via the endothelial L-arginine/nitric
oxide pathway. As an antihypertensive drug it is effective in once-daily dosage.
Nebivolol has previously been shown to improve left ventricular function in
patients with cardiac impairment. METHODS AND RESULTS: This paper reports a
double-blind randomized trial comparing, in patients with heart failure, once
daily nebivolol 2.5 or 5.0 mg (initiated in all at 2.5 mg) with placebo on a
constant background of digitalis plus diuretic. There was with nebivolol no
overall deterioration of cardiac function or cardiac symptoms, and especially not
of exercise capacity, in comparison with placebo. One patient on nebivolol 2.5 mg
developed hypotension and pulmonary edema, and one patient on nebivolol 5 mg,
bradycardia. All the remaining patients continued with unchanged diuretic and
digitalis dosage. Nebivolol was accompanied by a trend toward clinical and
functional improvement; rather better results were obtained with 2.5 than 5.0 mg.
CONCLUSIONS: In view of increasing interest in beta-blockade in heart failure,
nebivolol merits further study in this context. The capacity of nebivolol to
enhance endothelial nitric oxide production appears potentially attractive.
PMID- 9547442
TI - Contrasting preload-dependent hemodynamic and neurohumoral effects of isomazole,
a partial phosphodiesterase inhibitor and calcium sensitizer.
AB - BACKGROUND: Currently evaluated positive inotropic agents that act predominantly
through phosphodiesterase III-inhibiting properties, have been disappointing in
the treatment of heart failure. Lack of efficacy as a result of diminished
cellular cyclic adenosine monophosphate and vasodilating tolerance and side
effects are prevalent. In contrast, calcium sensitization is preserved in heart
failure and agents that combine phosphodiesterase-inhibiting and calcium
sensitizing properties may be more efficacious. Isomazole is such a novel agent
with combined properties. This study investigated the acute hemodynamic and
neurohormonal effects of intravenous isomazole (3 micrograms/kg/min for 30
minutes). METHODS AND RESULTS: The effects of preexisting preload were evaluated
in 18 patients with heart failure, New York Heart Association class II/III, and
elevated (> 15 mmHg, n = 11, group I) and normal; (n = 7, group II) pulmonary
wedge pressure at baseline. In the overall group, isomazole increased myocardial
contractility and relaxation and decreased systemic resistance by 20%. Left and
right filling pressures fell by 35-45%, accompanied by a 69% reduction in cardiac
atrial natriuretic peptide release. In contrast, levels of arterial
norepinephrine and renin both increased by 27%. Cardiac output increased in group
I (23%), but fell in group II (18%), accompanied by a 51% increase in arterial
norepinephrine. Cardiac atrial natriuretic peptide decreased in group I, but not
in group II. CONCLUSIONS: Isomazole induced positive inotropic and lusitropic
effects and arterial vasodilation in all patients. Cardiac pump function improved
only in group I, accompanied by a reduction in sympathetic activity and renin
angiotensin and aldosterone levels and a more pronounced decrease in cardiac
atrial natriuretic peptide release. In contrast, in patients with normal to low
preload, the further reduction in preload led to a deterioration of pump function
and increased sympathetic tone.
PMID- 9547443
TI - Effects of angiotensin-converting enzyme inhibitor on plasma B-type natriuretic
peptide levels in patients with acute myocardial infarction.
AB - BACKGROUND: Plasma levels of B-type natriuretic peptide (BNP) are markedly
increased in patients with heart failure and acute myocardial infarction. The
changes in plasma BNP levels in the treatment of acute myocardial infarction with
angiotensin-converting enzyme inhibitors have not been examined well. This study
was designed to examine the effects of early angiotensin-converting enzyme
inhibitor therapy on plasma BNP levels in patients with acute myocardial
infarction. METHODS AND RESULTS: We measured the plasma levels of B-type
natriuretic peptide over the time course for 2 weeks in 30 patients with acute
myocardial infarction in whom either imidapril (n = 15) or placebo (n = 15) was
given at random immediately after admission. Plasma BNP levels increased and
reached a peak of 192 +/- 28 pg/ML 16 hours after administration; thereafter, the
levels decreased and then again increased, forming the second peak of 217 +/- 38
pg/ML on the fifth day (biphasic pattern). On the other hand, plasma BNP levels
increased and reached a peak level of 190 +/- 22 pg/ML 16 hours after admission
and then decreased from 2 days after admission until the second week in the
imidapril group (monophasic pattern). Left ventricular ejection fraction measured
in the second week was significantly higher in the imidapril group than in the
control group (62.2 +/- 1.1% vs 51.2 +/- 3.6%, P < .01). CONCLUSION: It is
concluded that plasma BNP levels followed a monophasic pattern after imidapril
treatment, whereas a biphasic pattern was followed after placebo, and that plasma
BNP levels constitute a marker of ventricular dysfunction in the treatment of
acute myocardial infarction with angiotensin-converting enzyme inhibitors.
PMID- 9547444
TI - Angiotensin-converting enzyme inhibitors in heart failure: physicians'
prescribing behavior.
AB - BACKGROUND: Several studies document an underuse of angiotensin-converting enzyme
inhibitors (ACEIs) in heart failure (HF) patients, despite their proven efficacy
and good tolerability. Also, there is some evidence that the doses used in
clinical practice are far lower than those used in clinical trials. METHODS AND
RESULTS: To identify patterns of ACEI use in HF patients this study examined data
collected on admission day regarding demographic, clinical, and medical care
characteristics of 355 patients hospitalized because of decompensated HF who were
treated with and without ACEIs. Additionally, measures of in-hospital outcome
were compared among the two groups. Fifty-eight point six percent of patients
were receiving ACEIs at admission and 80.6% were treated with ACEIs during
hospitalization. The average ACEI does was low. No differences were observed in
age and measures of severity of HF between ACEI-prescribed and nonprescribed
patients. Patterns that could explain ACEI underuse included female sex, lower
systolic blood pressure, worse renal function, left ventricular diastolic
dysfunction, use of alternate drugs (eg, spironolactone), and overall less
intense medical management. Patterns associated with the use of lower doses of
ACEIs included older age, higher New York Heart Association functional class, and
lower systolic blood pressure. In-hospital death rates were significantly higher
for patients not treated with ACEIs. CONCLUSIONS: This study suggests that many
patients eligible for ACEI treatment were deprived of the advantages of these
drugs because of erroneous clinical strategies. Nevertheless, the patterns of
ACEI use were similar to those reported by other studies. Clinical trials
conducted to determine the risk/benefit ratio of ACEI use in patients with renal
dysfunction and the utility of ACEIs in diastolic HF, as well as programs to
educate care providers on proper use of ACEIs in HF patients, are strongly
recommended.
PMID- 9547446
TI - Altered vascular function in early stages of heart failure in hamsters.
AB - BACKGROUND: Congestive heart failure is a clinical condition associated with
alterations in the normal balance of neurohumoral agents and factors acting on
the vascular wall. The etiology of this condition, however, remains largely
undefined. To help elucidate the pathophysiology of this disease, vascular
function and angiotensin-converting enzyme activity were evaluated in 2-month-old
Syrian cardiomyopathic hamsters (SCHs) that had not yet developed heart failure.
Age-matched normal hamsters were used as control hamsters. METHODS AND RESULTS:
Vascular function studies included determinations of contractile responses of
aortic rings to 0.1 microM angiotensin II and 0.1 microM norepinephrine. In
addition, endothelial function was evaluated by the vasorelaxant action of
acetylcholine on norepinephrine-precontracted aortic rings. The results indicate
that the pressor effect of angiotensin II (0.1 microM) was 35% greater in aortic
rings from SCRs than that observed in control animals. This effect is specific
for angiotensin II because the contraction induced by NE (0.1 microM) was similar
in both of these strains. Angiotensin-converting enzyme activity was three-fold
higher in aorta homogenates from SCHs but normal in plasma and heart tissue when
compared with control hamsters. Aortic ring preparations from SCHs also exhibited
endothelial dysfunction because the maximal relaxation elicited by 10 microM
acetylcholine was reduced 53%. Concentration-response curves with acetylcholine
yielded EC50 values that were threefold lower in SCHs (97.2 +/- 0.1 nM) than in
control animals (286 +/- 7 nM). Indomethacin (1 microM) increased the
vasorelaxant effect of acetylcholine 28% in SCHs and shifted to the left the
concentration-response curve of this agonist, suggesting an increased relaxation
with the cyclooxygenase inhibitor. No effect of indomethacin on acetylcholine
induced relaxation was observed in control animals. Sodium nitroprusside induced
similar relaxations in both control animals and SCHs, suggesting that the
vascular smooth muscle response is normal in SCR. CONCLUSIONS: Altogether these
results point to a state of enhanced vascular contractility in young SCHs that
could predispose these animals to develop heart failure, the enhanced vascular
contractility could result from increased activity of the local renin-angiotensin
system, augmented vascular response to angiotensin II, reduced nitric oxide
synthesis, and enhanced production of prostaglandins.
PMID- 9547445
TI - Up-regulated expression of angiotensin II type 1 receptor gene in human
pathologic hearts.
AB - BACKGROUND: An accumulation of evidence suggests that the local renin-angiotensin
system plays a role in the development of cardiac hypertrophy in vivo; however,
it remains unknown how the expression of angiotensin II type 1 receptor (AT1),
which mediates most of the cardiovascular effects of angiotensin II, is regulated
in the left ventricles of human pathologic hearts. METHODS AND RESULTS:
Expression of AT1 gene in the left ventricle wall of 14 autopsied human hearts
was examined by reverse transcription polymerase chain reaction. The levels of
AT1 messenger RNA relative to those of beta-actin messenger RNA in the left
ventricle wall were increased 3.8-fold in the hearts with dilated cardiomyopathy
(n = 4, P < .05) and 6.2-fold in the noninfarcted areas of hearts with old
myocardial infarction (n = 4, P < .05), compared with the control hearts without
any cardiac disease (n = 6). The increases in the relative AT1 messenger RNA
level showed a positive correlation with myocyte diameter in the adjacent tissue
(r = .927, P < .001 for dilated cardiomyopathy and r = .934, P < .005 for old
myocardial infarctions) and with the extent of fibrosis (r = .880, P < .005 for
dilated cardiomyopathy and r = .690, P < .05 for old myocardial infarction).
CONCLUSIONS: Expression of AT1 in these human pathologic hearts was associated
with myocardial cell hypertrophy and extent of fibrosis, a finding that further
emphasizes the importance of the local renin-angiotensin system in the remodeling
of human hearts with dilated cardiomyopathy and old myocardial infarction.
PMID- 9547447
TI - Evolving concepts of heart failure: cooling furnace, malfunctioning pump,
enlarging muscle--Part I.
AB - Understanding of the causes of dyspnea and anasarca, the cardinal features of
heart failure, has changed dramatically since Greco-Roman times, when sputum and
pleural effusions were thought to originate in the brain, and the heart was
believed to heat and distribute the vital spirit. It was not until the
seventeenth century, when Harvey demonstrated that the heart was a pump and
autopsy descriptions revealed valve abnormalities that interfered with the
circulation, that it became possible to identify the role of heart disease in
causing shortness of breath and edema. Morgagni's recognition, toward the end of
the eighteenth century, that overload caused the heart to enlarge was followed
less than 50 years later by Corvisart's distinction between hypertrophy and
dilation. Differences in the architecture of failing hearts focused attention of
nineteenth-century clinical scientists on the myocardial response to overload,
and by the end of this century overload-induced hypertrophy was recognized not
only to have immediate adaptive effects, but also to cause progressive
degeneration of the heart muscle. This focus on the failing myocardium ended in
the early years of the twentieth century, when new discoveries in hemodynamic
physiology shifted attention to pressure and flow abnormalities caused by the
then prevalent rheumatic valvular heart disease. During the past decade, new
emphasis on prognosis, along with realization that drugs intended to correct
hemodynamic abnormalities often had adverse effects on survival, has led to a
reexamination of the biology of the failing heart. As a result, the focus in
heart failure research has returned to the myocardium. This article reviews some
of the misconceptions and errors of early physicians, who, while often careful
and intelligent observers, lacked the means to explain and treat heart failure.
It is hoped an appreciation of the evolving concepts of heart failure will help
the reader meet today's challenge of incorporating new information from molecular
biology that holds the key to further progress in understanding the causes and
therapy of this syndrome.
PMID- 9547448
TI - On the horizon: minimally invasive cardiac surgery.
AB - The landscape of cardiac surgery is changing. Advances in endoscopic and other
instrumentation procedures such as port access, video instrumentation, and
computer-assisted technology are opening new vistas for cardiac surgery. On the
immediate horizon is minimally invasive cardiac surgery, also known as keyhole
surgery. Imagine a patient not needing a median sternotomy incision or
cardiopulmonary bypass. This new type of cardiac surgery is currently being
explored at some cardiac surgical centers internationally. This article explores
the current state-of-the-art related to minimally invasive direct coronary artery
bypass surgery. The operative procedure, implications for perioperative nursing
care, likely future technologies, and the research literature on outcomes are
also discussed.
PMID- 9547449
TI - Transmyocardial laser revascularization.
AB - Transmyocardial laser revascularization is a new treatment modality for patients
with chronic angina that is refractory to traditional management. A laser is used
to create full-thickness channels through areas of ischemic myocardium.
Transmyocardial laser revascularization is performed in an effort to improve
myocardial oxygenation, eliminate or reduce angina, and improve functional
status. Transmyocardial laser revascularization currently is undergoing clinical
trials. Early results have demonstrated significant reduction in anginal
symptoms. Long-term efficacy of transmyocardial laser revascularization remains
to be determined.
PMID- 9547450
TI - Advances in myocardial protection.
AB - The success of cardiac surgery is due in large part to the myocardial protection
techniques employed to maintain cardiac viability during the period of induced
ischemic arrest. As the number of older, high-risk cardiac surgical patients
increases, advances in myocardial protection have become necessary to achieve a
quiet, bloodless operative field without the production of irreversible
intraoperative myocardial damage. Current efforts to provide optimal myocardial
protection have focused on the effects of cardioplegic perfusate temperature,
distribution of cardioplegia flow, and components of the arresting solution.
Minimally invasive techniques have expanded surgical options and have led to the
development of new methods to protect the myocardium.
PMID- 9547451
TI - Managing pain after coronary artery bypass surgery.
AB - Nurses are responsible for assessing patients' pain and intervening with
modalities such as opioids. However, after coronary artery bypass surgery,
patients experience moderate to severe pain and receive inadequate analgesia.
These practices are problematic as unrelieved acute pain is harmful and may
result in negative consequences that influence recovery. Consistent with the
subjectivity and multidimensionality of pain, as described in Gate Control
Theory, patients need to be involved as participants in their care where
possible. Pain policies and education programs need to reflect current
professional guidelines and be proactive in addressing staff and patient gaps in
pain knowledge and misbeliefs.
PMID- 9547452
TI - Pharmacology.
AB - Inadequate pain relief has been identified as a common problem after coronary
artery bypass surgery, Understanding the pharmacology of analgesics commonly used
after cardiovascular surgery is a fundamental part of effective pain management.
The pharmacologic properties for two analgesic drug classes, opioid and
nonopioid, are reviewed. Major drugs in each class are discussed in terms of
their pharmacodynamic and pharmacokinetic properties.
PMID- 9547453
TI - Management of postoperative atrial fibrillation.
AB - Atrial fibrillation is a common complication of heart surgery. Consequences for
the patient who develops this dysrhythmia are many. It prolongs hospitalization,
may induce hemodynamic compromise, and carries the risks of thromboembolism and
stroke. Ongoing research for the past 30 years has identified several potential
etiologies; therefore, management must be highly individualized. This article
reviews current and past research on postoperative atrial fibrillation with a
focus on individualized prevention and treatment of this problematic heart
surgery complication.
PMID- 9547455
TI - A comprehensive approach to facilitating the recovery of cardiac surgery
patients.
AB - This article describes the cardiac surgery program at Baystate Medical Center. It
emphasizes the importance of planning for the discharge process, early
extubation, and structured activity guidelines and their effect on patient
outcomes. The unique roles of the staff nurse, mid-level practitioner, and the
clinical resource coordinator in facilitating the case management process are
addressed.
PMID- 9547454
TI - Dysrhythmia update: The effect of intermittent heart block on the central venous
pressure trace.
AB - A 75-year-old man developed heart block with intermittent conduction following
mitral valve replacement. A simultaneously recorded central venous pressure (CVP)
trace revealed evidence of the normal sequence of atrial and ventricular
contraction, as well as episodes of ventricular contraction that preceded atrial
contraction and episodes of simultaneous atrial and ventricular contraction. The
dysrhythmia and CVP trace are analyzed and clinical implications relevant to this
case history are discussed.
PMID- 9547456
TI - The Middle/Upper Paleolithic interface and the relationship of Neanderthals and
early modern humans in the Hrvatsko Zagorje, Croatia.
AB - This paper presents the first detailed analysis of the artefacts from the
Mousterian level G3 at Vindija Cave and a revision of the artefact analysis for
the early Upper Paleolithic levels (j, i) at Velika Pecina, both in Croatia.
Combined with an assessment of the artefacts from the crucial G1 level at
Vindija, results of these analyses are used to argue that the combination of
Middle and Upper Paleolithic elements in the upper G complex at Vindija is not
necessarily the result of geological mixing but may well represent a natural
cultural assemblage. Some Upper Paleolithic elements are possibly derived from
the local Mousterian, while others result from extraneous cultural influences
into this region. Interestingly, currently available radiocarbon dates indicate
that Neanderthals (Vindija level G1) and early modern humans (Velika Pecina) were
penecontemporaneous in this region at ca. 33 ka, or perhaps somewhat earlier if
the radiocarbon dates are taken as minimum age estimates. Therefore some Upper
Paleolithic tools associated with the Vindija G1 Neanderthals, such as bone
points, may result from imitation of or trade with early modern people. While
there is external influence on the development of the early Upper Paleolithic in
this region, it exhibits a unique character which does not conform to that of
classic Western or Central European Aurignacian.
PMID- 9547457
TI - Comparative morphometric study of the australopithecine vertebral series Stw
H8/H41.
AB - Lower spinal structure correlates well with positional behavior among mammals.
Nonetheless, the functional morphology of the axial post-crania of
australopithecines has received less attention than their appendicular skeletons.
This paper presents a detailed description and comparative morphometric analysis
of the australopithecine thoracolumbar vertebral series Stw-H8/H41, and examines
spinal mechanics in early hominids. Stw-H8/H41 is an important specimen, as the
australopithecine vertebral sample is small, and vertebral series are more useful
than isolated elements for the interpretation of spinal function. Results of the
study support the interpretation that australopithecine species are highly
sexually dimorphic. The study also reveals a considerable amount of morphometric
variation other than size among australopithecine vertebrae, though the sample is
too small and incomplete to ascertain whether this indicates significant
interspecific differences in spinal function. Most importantly, structural and
metric observations confirm that the morphology of the lower spine in
australopithecines has no modern analogue in its entirety. Aspects of
zygapophyseal structure, numerical composition of the lumbar region, and centrum
wedging suggest that the australopithecine vertebral column was adapted to human
like intrinsic lumbar lordosis and stable balance of the trunk over the pelvis in
sustained bipedal locomotion. However, relative centrum size in
australopithecines indicates that either they had a different mechanism for
channeling vertical forces through the vertebral column than humans, or differed
behaviorally from humans in ways that produced smaller increments of compression
across their centra. These findings have important implications for hypotheses of
australopithecine positional behavior, and demonstrate that larger samples and
more complete vertebral series are needed to improve our understanding of
australopithecine spinal function.
PMID- 9547459
TI - A metrical study of the WLH-50 calvaria.
PMID- 9547458
TI - Mortality analysis of Pleistocene bears and its paleoanthropological relevance.
AB - Bear bones and Paleolithic stone artefacts often co-occur in Pleistocene cave
deposits of Eurasia, raising the question of how these associations come about
and the need for effective methods with which to obtain a clear answer. Building
upon knowledge of modern bears, I present a method for testing two competing
hypotheses about the causes of bear mortality in hibernation contexts. The first
hypothesis proposes that age-dependent deaths resulted from non-violent causes
(principally starvation), implying that bears' presence in a cave was not linked
in time to human activities there. The second hypothesis proposes that random
bear deaths in caves resulted from hunting by humans or other large predators,
implying a temporal link between them; the expectation of a nonselective age
pattern in this circumstance arises from the fact that the individual characters
of hibernating bears are hidden from predators. Three elements of the method and
its development are presented: (1) a brief review of the biological bases of
hibernation-related mortality in modern Ursus, its paleontological consequences,
and test expectations drawn therefrom; (2) a detailed, illustrated technique for
age-scoring isolated bear cheek teeth based on tooth eruption-wear sequences,
developed primarily for cave and brown bears; and, (3) a simple, accurate way to
evaluate real cases in terms of contrasting mortality models. The final step is
demonstrated by application to a Middle Pleistocene cave bear assemblage (Ursus
deningeri) from Yarimburgaz Cave in Turkey, a large collection found in general
stratigraphic association with Paleolithic artefacts. The advantages of the
method include its ability to (a) handle small samples, (b) use isolated tooth
specimens, and (c) evaluate cases simultaneously in terms of idealized age
structure models and the variation that normally is associated with each under
natural conditions. While the more obvious benefit of bear mortality analysis may
be to research on ancient bear demography, the principles and procedures offered
here are equally pertinent to archaeological studies of carnivore-mediated
formation processes in cave sites. As is generally true in taphonomic research,
however, bear mortality patterns are most effective when used in combination with
independent lines of evidence to address questions about assemblage formation.
PMID- 9547460
TI - The clinician-scientist in neuropsychiatry: a position statement from the
Committee on Research of the American Neuropsychiatric Association.
AB - Neuropsychiatric research seeks to improve the lives of patients with brain-based
behavioral disturbances. There has been dramatic progress in diagnosis and
treatment of neuropsychiatric disorders, and progress in neuroscience and
biotechnology promises further success. Paradoxically, recent trends threaten to
erode this progress. In this environment, neuropsychiatric clinician-scientists
must advocate for the importance of research. This position statement defines
neuropsychiatric research, describes current challenges to the neuropsychiatric
clinician-scientist, summarizes research opportunities, describes how future
neuropsychiatric clinician-investigators should be trained, and makes
recommendations for promoting neuropsychiatric research.
PMID- 9547461
TI - Neuropsychiatric aspects of the adult variant of Tay-Sachs disease.
AB - Tay-Sachs disease (a GM2 gangliosidosis) is an inherited neuronal storage disease
that can affect individuals across the age spectrum. Psychosis is reported in 30%
to 50% of adult-onset patients, and many are misdiagnosed with schizophrenia.
Mood disorders are present in more than 25% and cognitive impairment in more than
20%. Treatment of psychosis with neuroleptics may not have a favorable
risk/benefit ratio, but treatment with benzodiazepines or electroconvulsive
therapy may be efficacious. Metabolic diseases such as gangliosidosis are
probably under-recognized as causes of neuropsychiatric illness. Increased
awareness of these disorders will lead to accurate diagnosis, appropriate
treatment selection, and genetic counseling.
PMID- 9547462
TI - The use of rapid-rate transcranial magnetic stimulation (rTMS) in refractory
depressed patients.
AB - Rapid-rate transcranial magnetic stimulation (rTMS) allows for the noninvasive
examination of the cerebral cortex. Recent studies have begun to investigate
whether rTMS may be therapeutic for the treatment of depression. In the present
study, the authors report on the safety and efficacy of rTMS in treating 50
patients with refractory depression. Overall, there were 21 responders (42%).
Interestingly, 56% of the young patients responded, but only 23% of the elderly
patients responded to rTMS. Overall, rTMS was well tolerated in all patients.
Specifically, no patient developed a new onset of seizures during rTMS. The
authors discuss the extant literature on rTMS for the treatment of depression
along with future areas of research.
PMID- 9547463
TI - Functional impairment associated with acute poststroke depression: the Stroke
Data Bank Study.
AB - To examine the independent association of depression following acute stroke with
impairment in activities of daily living (ADL), the authors conducted a cross
sectional analysis of stroke patients enrolled in the Stroke Data Bank (U.S.A.)
who had completed the Center for Epidemiological Studies Depression Scale (CES
D). Scores on the Barthel Index, a measure of ADL, were compared between
depressed (CES-D > or = 16) and nondepressed patients (CES-D < or = 15) at 7-10
days after stroke. Of the 626 who completed CES-D, 160 were depressed. Depressed
stroke patients evidenced greater impairment in ADL than nondepressed patients,
independently of all other factors that influenced poststroke physical
disabilities. CES-D scores were negatively correlated with Barthel scores in the
entire stroke population. Neurological factors, greater age, poor prestroke
physical activity, and prestroke disturbances in sexual functioning were also
independently associated with limitations in functional status of stroke
patients.
PMID- 9547464
TI - Effects of anxiety disorder on impairment and recovery from stroke.
AB - The effect of anxiety disorder on recovery from impairment following stroke was
examined in 142 patients with acute stroke who had follow-up evaluations. Anxiety
disorder significantly interacted with depression to influence the severity and
course of depression, outcome of activities of daily living, and social
functioning. Anxiety disorder, however, did not affect cognitive impairment,
which was influenced only by major depression. These data suggest that the
existence of anxiety disorders plays an important role in the prognosis of
patients with poststroke depression. These data also suggest that depression and
anxiety disorder may have different mechanisms.
PMID- 9547465
TI - Gender differences in poststroke depression.
AB - In stroke and other medical illnesses, secondary depression may be associated
with different factors in women than in men. The authors examined 301 consecutive
admissions for acute treatment of cerebrovascular accident for gender differences
in depression, psychosocial factors, physical impairment, and lesion location.
Women were twice as frequently diagnosed with major depression as men. Women with
major depression had a greater frequency of left hemisphere lesions than men. In
men, major depression was associated with greater impairment in activities of
daily living, and greater severity of depression was associated with greater
impairment in daily activities and social functioning. In women, greater severity
of depression was associated with prior diagnosis of psychiatric disorder and
cognitive impairment. These findings suggest a different nature of poststroke
depression in men and women and may have implications for its treatment.
PMID- 9547466
TI - Chronological association between increases in drug abuse and psychosis in
Connecticut state hospitals.
AB - Disagreement remains as to whether drug use can result in an autonomous psychotic
disorder. If drug use can create new psychosis cases, an increase in the number
of psychosis patients ought to be observable following periods of increased drug
use by the general population. First admissions data for the categories of drug
abuse and schizophrenia/paranoid disorders from all Connecticut state hospitals
from 1965 to 1983 were examined to determine the prevalence of psychotic
disorders before, during, and after a period of increased drug use by the general
population. Affective disorders first admissions were examined for comparison. A
rapid increase in new schizophrenia admissions coincided with a peak period for
drug-related admissions. The data suggest that increased drug use of the late
1960s may have contributed to the increase noted 3 to 5 years later in first
admissions of patients diagnosed with psychotic disorders.
PMID- 9547467
TI - Differential neuropsychiatric symptom responses to tacrine in Alzheimer's
disease: relationship to dementia severity.
AB - Neuropsychiatric symptom responses to tacrine were investigated in an open-label
study of Alzheimer's outpatients. Forty subjects were stratified into three
groups (Mild, Moderate, and Severe) based on Mini-Mental State Examination
scores. A significant reduction in total Neuropsychiatric Inventory score across
all subjects was principally attributable to changes in the Moderate group.
Apathy and disinhibition symptoms were significantly reduced overall. Whereas
other symptoms showed differential responses in Mild and Severe subjects, all
symptoms improved in Moderate subjects. These findings suggest that disease
severity may significantly influence neuropsychiatric symptom responses to
tacrine. Putative mechanisms underlying the observed pattern of responses are
explored.
PMID- 9547468
TI - Olfactory dysfunction discriminates Alzheimer's dementia from major depression.
AB - This study tested the hypothesis that olfactory dysfunction could discriminate
between groups of patients with Alzheimer's disease and major depression. Forty
patients meeting DSM-IV criteria for Alzheimer's disease and for major depression
(20 per group) underwent assessment with the Pocket Smell Test (PST), a three
item screening measure of cranial nerve I function. A PST score of < or = 1 (1 or
0 correct) discriminated between the groups with a hit rate of 90% (sensitivity =
80%, specificity = 100%). Olfactory assessment may be a useful adjunctive
screening measure in differentiating Alzheimer's disease from depression in
elderly patients.
PMID- 9547469
TI - Determinants of spontaneous extrapyramidal symptoms in elderly psychiatric
inpatients diagnosed with Alzheimer's disease, major depressive disorder, or
psychotic disorders.
AB - Extrapyramidal symptoms (EPS) occur more frequently in dementia of the
Alzheimer's type (DAT) than in normal aging. Other late-life mental disorders,
however, have also been associated with EPS. To examine whether EPS are increased
in DAT patients relative to neuropsychiatric control subjects, the authors
compared EPS in 127 neuroleptic-free elderly patients diagnosed with either DAT,
major depressive disorder (MDD), or a psychotic disorder (SCHIZ/DELUS). They also
examined whether depressive or psychotic symptoms were associated with EPS
independently of diagnosis. Severity of parkinsonian rigidity was found to be
independently associated with DAT. Rank order of rigidity was DAT > MDD >
SCHIZ/DELUS. Bradykinesia, although not associated with diagnostic group, was
positively correlated with withdrawn depression. These findings suggest that
rigidity is associated with DAT independently of any concurrent psychotic or
depressive process, whereas bradykinesia does not appear to be specific to DAT
among late-life neuropsychiatric illnesses.
PMID- 9547471
TI - The motor agitation and retardation scale: a scale for the assessment of motor
abnormalities in depressed patients.
AB - Increasing recognition of the neurologic aspects of depressive disorder has
aroused new interest in the potential neuropathologic significance of
"psychomotor" symptoms in depression. Psychomotor symptoms have yet to be clearly
defined, however. The Motor Agitation and Retardation Scale (MARS) was developed
to provide a comprehensive and nonredundant measure of the motor abnormalities
associated with agitation and retardation in depression. Forty-one depressed in
patients and 20 normal control subjects were assessed. In this sample, the MARS
provided a reliable and valid scale for the clinical assessment of 19 abnormal
motor behaviors associated with agitation and retardation in depression. The MARS
may be useful for investigation of the pathophysiologic significance of various
manifestations of motor abnormalities in depression and, as part of a larger
battery, for the investigation of the relative contribution of motor
abnormalities to psychomotor impairment in depression.
PMID- 9547470
TI - Blood-brain barrier integrity in Alzheimer's disease patients and elderly control
subjects.
AB - A defective blood-brain barrier (BBB) has been postulated to be present in
Alzheimer's disease (AD), which would allow circulating beta-amyloid peptide to
enter the brain. The authors tested this hypothesis by studying BBB function in
14 individuals with probable AD and 9 elderly control subjects. A computed
tomographic method was used to measure blood-to-brain transport (K1), tissue-to
blood efflux (k2), tissue plasma space (Vp), and tissue extracellular space (Ve)
of meglumine iothalamate. Repeated-measures analysis of variance indicated no
significant differences between the groups for any of the measures. The authors
conclude that there is no generalized abnormality of the blood-brain barrier in
AD.
PMID- 9547472
TI - Use of clozapine in 10 mentally retarded adults.
AB - The cost, side effect profile, and required weekly blood draws associated with
clozapine may dissuade some clinicians from prescribing this atypical neuroleptic
to mentally retarded patients. All publications on clozapine use in mentally
retarded patients are reviewed and the treatment of 10 such patients is
described, bringing the total number of published cases to 84. Clozapine is
efficacious and well tolerated in this population and should be considered for
those patients with psychosis or bipolar illness who are intolerant of or
unresponsive to other agents.
PMID- 9547473
TI - Is olfactory reference syndrome an obsessive-compulsive spectrum disorder?: two
cases and a discussion.
AB - A number of disorders characterized by intrusive repetitive symptoms and varying
degrees of insight may overlap phenomenologically and neurobiologically with
obsessive-compulsive disorder (OCD). There is a question as to whether olfactory
reference syndrome, a disorder characterized by persistent preoccupations about
body odor accompanied by shame and embarrassment, is also an OCD spectrum
disorder. Two cases of olfactory reference syndrome, with accompanying
phenomenological and neurobiological data, are presented in order to discuss the
possible overlap with OCD. A number of phenomenological and neurobiological
features in these patients were at least partially reminiscent of OCD. In
particular, despite having poor insight, both patients demonstrated significant
improvement upon treatment with a serotonin reuptake inhibitor.
PMID- 9547474
TI - Prevalence of Alzheimer's disease and apolipoprotein E allele frequencies in the
Old Order Amish.
AB - The authors examined the prevalence of Alzheimer's disease and apolipoprotein E
allele frequencies in the Old Order Amish. A lower frequency of dementia in the
Amish does not appear to be due to a reduced E4 frequency.
PMID- 9547475
TI - Does stroke cause depression?
PMID- 9547476
TI - Risperidone for the treatment of delusional disorder due to HIV disease.
PMID- 9547477
TI - When fluvoxamine treats only depression and clomipramine treats only obsessive
compulsive disorder--combine them?
PMID- 9547478
TI - Buspirone and brain injury.
PMID- 9547479
TI - Affect and the limbic system: some hard problems.
PMID- 9547480
TI - Obsessive-compulsive disorder, Tourette's syndrome, and basal ganglia pathology
on MRI.
PMID- 9547481
TI - Palicoprolalia: an unusual variant of palilalia in Gilles de la Tourette's
syndrome.
PMID- 9547482
TI - Greatest suicide success rate found in depressed elderly.
PMID- 9547483
TI - The impact of child sexual abuse on addiction severity: an analysis of trauma
processing.
AB - The Information of Processing Trauma Model provides a framework for understanding
the dynamics and responses of childhood sexual abuse. Chemical dependency plays a
role in both the cause and effect of childhood sexual abuse. Survivors of
childhood sexual abuse with chemical dependency require treatment of both
disorders. This treatment should emphasize the key role of the encapsulation
phase in symptom formation and recovery.
PMID- 9547485
TI - Preparing feminist facilitators. Assisting abused women in transitional or
support-group settings.
AB - This article has reviewed one approach to the preparation of support group
facilitators to enable them to better meet the needs of abused women. Those women
may still be in abusive relationships or they may have left one; they may be
unsure whether they are abused; or they may be seeking practical suggestions
about ways to tackle a particular problem. Whatever their specific situations,
they can benefit from a supportive, accepting, and safe environment in which to
explore their options.
PMID- 9547484
TI - Implementation of groups for creative expression on a psychiatric inpatient unit.
AB - Patients benefited from creativity group participation through expression of both
positive and negative feelings, group acceptance, and acceptance of self in a non
competitive activity. Psychiatric nurses can lead creativity groups with a focus
on creative expression, rather than psychotherapy. No specific training in the
arts is required for these simple creative formats. It was found from using a
variety of creative formats that, overall, patients received group projects
better than individual projects done in a group setting.
PMID- 9547486
TI - Adolescents from families of divorce: vulnerability to physiological and
psychological disturbances.
AB - Multiple factors contribute to the vulnerability of adolescents to physiological
and psychological disturbances following parental divorce. These include father
absence, interparental conflict, economic distress, multiple life stressors,
parent adjustment, and short-term crisis. Clinical and societal problems
manifested in these vulnerable adolescents are discussed. Systems theory is used
to explain this vulnerability of adolescents and to identify appropriate
interventions and policies to promote health in this population. Policies
recommended include required divorce mediation, early referrals for family and
sibling therapy, and school programs to identify and support those most
vulnerable.
PMID- 9547487
TI - Classical conditioning using vestibular reflexes.
AB - Adaptation of the vestibulo-ocular reflex (VOR) is one of the principal models
for studying motor learning in the mammalian CNS. However, there has been no
previous comprehensive attempt to understand the behavioral characteristics of
VOR adaptation in terms of traditional psychological learning theory. To
accomplish this objective, the effectiveness of vestibular-evoked responses in
serving as the conditioned or unconditioned stimulus in classical conditioning
paradigms is first reviewed. Then, the various procedures for eliciting VOR
adaptation are reviewed from the perspective of their similarity to standard
classical conditioning protocols. A systematic analysis of Western and Russian
literature yielded a relatively small number of studies that explicitly used
vestibular reflexes in classical conditioning paradigms, and they report a wide
range in success. Potential explanations for these diverse findings are
discussed. A comprehensive categorization of the behavioral parallels between VOR
adaptation and classical conditioning is then presented. Viewing VOR adaptation
as a form of classical conditioning is a useful heuristic device and leads
directly to the description of further behavioral experiments that could throw
additional light on general mechanisms for inducing neural plasticity. Such an
exercise is of benefit in order to further understand the common framework which
might exist between VOR adaptation and other models of motor learning (for
example, rabbit eye blink conditioning).
PMID- 9547488
TI - Immersed false vertical room. A new motion sickness model.
AB - We evaluated a new model of motion sickness--an enclosure decorated with visual
cues to upright which was immersed either inverted or "front"-wall down, in
Johnson Space Center's Weightless Environment Training Facility (WETF) pool. This
"WETF False Vertical Room" (WFVR) was tested with 19 male and 3 female SCUBA
diver subjects, aged 23 to 57, who alternately set clocks mounted near the room's
8 corners and made exaggerated pitch head movements. We found that (1) the WFVR
test runs produced motion sickness symptoms in 56% and 36% of subjects in the
room-inverted and room-front-down positions, respectively. (2) Pitch head
movements were the most provocative acts, followed closely by setting the clocks-
particularly when a clock face filled the visual field. (3) When measured with a
self-ranking questionnaire, terrestrial motion sickness susceptibility correlated
strongly (P < 0.005) with WFVR sickness susceptibility. (4) Standing instability,
measured with a modified Fregly-Graybiel floor battery, also correlated strongly
(P < 0.005) with WFVR sickness susceptibility. This result may reflect a
relationship between visual dominance and WFVR sickness. (5) A control study
demonstrated that the inverted and front-down positions produced WFVR sickness,
but the upright position did not, and that adaptation may have occurred in some
subjects with repeated exposure. The WFVR could become a useful terrestrial model
of space motion sickness (SMS) because it duplicates the nature of the gravity
dependent sensory conflicts created by microgravity (visual and otolith inputs
conflict while somatosensory gravity cues are minimized), and it also duplicates
the nature of the provocative stimulus (sensory environment "rule change" versus
application of motion to passive subject) more closely than any other proposed
terrestrial SMS model. Also, unlike any other proposed terrestrial SMS model, the
WFVR incorporates whole-body movement in all three spatial dimensions. However,
the WFVR's sensory environment differs from that created by spaceflight in
several respects, including the presence of frictional drag on limb movement,
magnification at the face-mask-water interface, greater otolith conflict, exhaled
bubbles, and the presence of some gravity-dependent somatosensory inputs.
PMID- 9547489
TI - Further evidence for gender differences in circularvection.
AB - This paper reports further evidence that gender is a significant factor in the
experience of circularvection (CV), the illusion of self-rotation. Using
optokinetic drum velocities between 24 degrees and 92 degrees/s, latency to
experience Stage 2 or Stage 3 CV was measured. Males exhibited significantly
longer CV latencies than females (P < 0.0001), although the difference was
greater for Stage 3 CV than for Stage 2 CV. This result suggests that the
potential influence of gender must be carefully controlled in visual-vestibular
interaction experiments.
PMID- 9547490
TI - Cogan's Syndrome. High resolution MRI indicators of activity.
AB - In the chronic-relapsing form of Cogan's syndrome, it can be difficult to
evaluate the activity of the disease. In contrast to the initial stage, routine
diagnostic techniques sometimes fail to indicate progression in the chronic
stage. To determine whether high-resolution magnetic resonance imaging (HR-MRI)
can be used to differentiate between active and inactive stages, we examined
three patients with Cogan's syndrome (one during an acute relapse, two with
chronic audiovestibular deficits), all of whom had antibodies to inner ear tissue
(cochlea, vestibular labyrinth). Unenhanced T1-, T2, gadolinium-enhanced T1
weighted, and three-dimensional constructive interference in steady stage (CISS)
images were used. Abnormal MRI signals of the inner ear were related to the
activity of the disease. The patient studied during an acute exacerbation showed
abnormal MRI signals in the vestibule, semicircular canals, vestibular nerve, and
cochlea, which disappeared after the relapse. These abnormalities included high
signal in the membranous labyrinth, the vestibule, and cochlea, with enhancement
on T1-weighted images, indicating gadolinium leakage through the abnormal
labyrinthine membrane into the perilymphatic spaces. In contrast, the other two
patients with chronic audiovestibular deficits but no clinical signs of an acute
relapse, had narrowing or occlusion of semicircular canals of the cochlea on the
3D-CISS images, but no high signal lesions (T1) and no enhancement. We conclude
that sequential gadolinium-enhanced MRI can identify the active stage of Cogan's
syndrome. The combination of HR-MRI and antibodies to inner ear antigens are
helpful in the diagnosis of acute, sequential, bilateral audiovestibular
impairment of autoimmune origin.
PMID- 9547491
TI - Direct influence of temperature on the semicircular canal receptor.
AB - Effect of thermal stimulus on the vestibular receptor was studied using the
isolated frog semicircular canal. The posterior (PSC) and lateral semicircular
canals (LSC) were placed in the horizontal plane in frog Ringer's solution. The
ampullary nerve was sucked into a glass suction electrode to record compound
potentials. The steel thermal probe was positioned next to the ampullary surface
to give thermal stimuli. When the PSC ampulla was cooled, the spontaneous
discharge markedly increased. When the PSC ampulla was warmed, the discharge
decreased. When the LSC ampulla was cooled, the discharge increased in the same
manner as in the PSC. Also, warming of the LSC decreased the discharge in the
same manner as in the PSC. The cupula was removed from the crista in order to
eliminate the effect of volume change of the endolymph. The results were
comparable to those with intact cupula in both the PSC and LSC. Cooling
increased, while warming decreased the discharge. These responses are possibly
due to a mechanism other than mechanical volume change, because the PSC and LSC
yielded the same type of responses. Direct temperature reaction of the vestibular
hair cell was suggested.
PMID- 9547492
TI - Viewing distance related sensory processing in the ascending tract of deiters
vestibulo-ocular reflex pathway.
AB - The firing behavior of seven antidromically identified ascending tract of Deiters
(ATD) neurons was recorded in one alert squirrel monkey trained to pursue moving
targets and to fixate visual targets at different distances from the head during
whole body rotation. 2. ATD cells generated signals related to contralateral
horizontal smooth pursuit eye movements and to ipsilateral angular and linear
head velocity. Most ATD neurons reversed the direction of their response to head
rotation when the vestibulo-ocular reflex was canceled by fixation of a head
stationary target. 3. ATD unit gains in respect to linear head velocity increased
dramatically (> 4x) when a near, earth stationary target (10 cm from the eyes)
was fixated, compared to the response recorded during fixation of a far target
(130 to 170 cm from the eyes). Since the viewing distance related changes in the
responses of ATD neurons closely parallel the changes in the responses of the
eyes, the ATD appears to be an important premotor pathway for producing viewing
distance related changes in the gain of the vestibulo-ocular reflex.
PMID- 9547493
TI - The LNT model is appropriate for the estimation of risk from low-level (less than
100 mSv/year) radiation, and low levels of radon in homes should be considered
harmful to health.
PMID- 9547494
TI - The linear no-threshold debate: where do we go from here?
AB - For the past several years, the LNT (linear no-threshold) theory has come under
attack within the scientific community. Analysis of a number of epidemiological
studies of the Japanese survivors of the atomic bombings and workers exposed to
low level radiation suggest that the LNT philosophy is overly conservative, and
low-level radiation may be less dangerous than commonly believed. Proponents of
current standards argue that risk conservatism is justified because low level
risks remain uncertain and it is prudent public health policy; LNT opponents
maintain that regulatory compliance costs are excessive, and there is now
substantial scientific information arguing against the LNT model. Regulators use
the LNT theory in the standards setting process to predict numbers of cancers due
to exposure to low level radiation because direct observations of radiation
induced cancers in populations exposed to low level radiation are difficult. The
LNT model is simplistic and provides a conservative estimate of risk. Abandoning
the LNT philosophy and relaxing regulations would have enormous economic
implications. However, alternative models to predict risk at low dose are as
difficult to justify as the LNT model. Perhaps exposure limits should be based on
model-independent approaches. There is no requirement that exposure limits be
based on any predictive model. It is prudent to base exposure limits on what is
known directly about health effects of radiation exposure of human populations.
PMID- 9547495
TI - The linear no-threshold response: why not linearity?
AB - ICRP and NCRP recommend risk coefficients for use in radiation protection that
are based on a linear quadratic response in the low dose region. This is a
derivative of the linear no threshold (LNT) hypothesis with allowance for low
dose and dose rate effects. The risk coefficients are derived from the Lifespan
Study of the A-bomb survivors but are supported by many other epidemiological
studies some, such as occupational, at low doses. Nevertheless, the risk
coefficients are uncertain and range (90% confidence intervals) over a factor of
2-3 above and below the nominal values. Various possible dose responses in the
low dose region are considered including those that may result from adaptive
responses. Laboratory studies show linearity in some systems to doses as low as
2.5 mGy. Epidemiological studies include several with significant excess risks at
100 mGy or less with at least one at 10 mGy. The linear quadratic response seems,
therefore, the most likely response in the very low dose region. Adopting the
linear quadratic response in the low dose region does not prevent common sense
judgements about dismissing small radiation risks. NCRP defined first a
negligible individual risk (1987) and then an individual dose (1993) to encourage
common sense judgements in the low dose region. More consideration might be given
to dismissing minor risks in common sense applications in radiation protection.
PMID- 9547496
TI - The linear no-threshold dose-effect relation: is it relevant to radiation
protection regulation?
AB - Official radiogenic cancer risk estimates for low-dose, protracted exposure
conditions have been based on linear, no-threshold downward extrapolation from
medium and high-dose effects among a population of A-bomb survivors, with the
application of a downward correction for an assumed reduced biological
effectiveness at low doses and low dose rates (DDREF correction). Neither in the
follow-up of populations exposed to the high-dose A-bomb flash, nor from
epidemiological data after low-dose occupational or medical irradiation is there
any convincing evidence for this DDREF hypothesis--even less for a zero-effect
threshold dose. To the contrary, for external low-dose exposures of nuclear
workers or general populations, cancer risks per unit dose have been found to be
about 1 order of magnitude larger than those derived from the Japanese survivors,
with larger discrepancies for persons above 50 years of age, and for x-rayed
fetuses. This may be due to a dose and dose-rate effect exactly opposite from
that postulated by the DDREF assumption, and a dose-dependent bias due to
selection for exceptionally high immune competence among the > 5 years A-bomb
survivor cohort. Excess cancer mortality following occupational exposures to
ingested fission products and radiation-associated teratogenic, genetic, and
cancer detriment among diverse populations who had ingested small amounts of
radioactivity after the precipitation of fallout at great distances from the
Chernobyl nuclear explosion, suggest discrepancies of as much as 2 orders of
magnitude with official risk estimates. Contrary to widely publicized statements,
claiming that current regulations of population exposures are far too
restrictive, thus unnecessarily costly for the radiation industries, the
aggregate of radiation epidemiological evidence suggests that current standards
are inadequate to protect public health.
PMID- 9547497
TI - Writing software for the clinic.
AB - Medical physicists often write computer programs to support scientific,
educational, and clinical endeavors. Errors in scientific and educational
software can waste time and effort by producing meaningless results, but errors
in clinical software can contribute to patient injuries. Although the ultimate
goal of error-free software is impossible to achieve except in very small
programs, there are many good design, implementation, and testing practices that
can be used by small development groups to significantly reduce errors, improve
quality, and reduce maintenance. The software development process should include
four basic steps: specifications, design, implementation, and testing. A
specifications document defining what the software is intended to do is valuable
for clearly delimiting the scope of the project and providing a benchmark for
evaluating the final product. Keep the software design simple and
straightforward. Document assumptions, and check them. Emphasize maintainability,
portability, and reliability rather than speed. Use layers to isolate the
application from hardware and the operating system. Plan for upgrades. Expect the
software to be used in unplanned ways. Whenever possible, be generous with RAM
and disk storage; hardware is cheaper than development and maintenance. During
implementation, use well-known algorithms whenever possible. Use prototypes to
try out ideas. Use generic modules, version numbering, unique file names,
defensive programming, and operating system and language/compiler defaults. Avoid
binary data files and clever tricks. Remember that real numbers are not exact in
a computer. Get it right before making it faster. Document the software
extensively. Test continuously during development; the later a problem is found,
the more it costs to fix. Use a written procedure to test the final product
exactly as a typical user would run it. Allow no changes after clinical release.
Expect to spend at least an additional 50% of the initial development effort on
testing, fixing errors, and getting the software into routine operation.
PMID- 9547498
TI - A new approach to electron-beam reference dosimetry.
AB - A new approach is proposed for electron-beam dosimetry under reference conditions
and data necessary to use this approach are presented. The approach has the
following features; it uses ion chambers and starts from an absorbed-dose
calibration factor for 60Co to be consistent with the present proposal for the
new AAPM photon-beam protocol; it uses R50 to specify the beam quality and the
reference depth, dref = 0.6R50 - 0.1 (all quantities in cm), recommended by Burns
et al. [Med. Phys. 23, 383-388 (1996)]; it has a formalism which is parallel to
the kQ formalism for photon-beam dosimetry; it fully accounts for the impact on
stopping-power ratios of realistic electron beams; it allows an easy transition
to using primary standards for absorbed dose to water in electron beams when
these are available. The equation for dose to water under reference conditions
is; DWQ = MPionPgrQk'R50kecalND,w60Co. The term PgrQ is not needed with plane
parallel chambers but corrects for gradient effects with cylindrical chambers and
is measured in the user's beam. The parameter kecal is associated with converting
the 60Co absorbed-dose calibration factor into one for an electron beam of
quality Qe and contains most of the chamber to chamber variation. Calculated
values of kecal are presented as well as Monte Carlo calculated Pwall values for
plane-parallel chambers in a water phantom irradiated by a 60Co beam since these
are needed to calculate kecal. The factor k'R50 is a function of R50 and converts
the absorbed-dose calibration factor to that for the electron-beam quality of
interest. Two analytical expressions are presented which are close to universal
expressions for all cylindrical Farmer-like chambers and for well-guarded plane
parallel chambers respectively. Calculated values are presented graphically for
electron beams with energies between 5 and 50 MeV.
PMID- 9547499
TI - A gradient inverse planning algorithm with dose-volume constraints.
AB - An inverse planning algorithm for determining the intensity-modulated beams that
will most closely generate a desired dose distribution is presented. The
algorithm is three-dimensional and does not explicitly depend on beam energies
and modalities. It allows a single prescription dose or a window of acceptable
doses to be specified for the target, with additional constraints to account for
under- or over-dosing. For the protection of organs at risk, it provides maximum
dose and dose-volume constraints. The latter apply to the entire volume of the
organ exposed to the corresponding dose levels. Several levels of each type of
constraint, with varying penalty weights, may be specified for each organ. The
objective function that serves as the measure of the goodness of the solution is
of the least-squares type and is minimized using conjugate gradient methods.
Typical clinical cases involving 40,000 points and 4000 rays to be determined
require about 10 min of CPU time on a DEC AlphaStation. Results are presented for
two clinical sites, prostate and lung. The optimization algorithm yielded plans
that featured higher target dose homogeneity, compared with the human planner's
plan, while selectively sparing more of the normal organs at the desired dose
regions.
PMID- 9547500
TI - Measurement of backscatter to the monitor chamber of medical accelerators using
target charge.
AB - A simple noninvasive method is described for determining the backscatter to a
monitor chamber of a medical accelerator based on the measurement of charge
deposited in the target. This method is compared quantitatively to the more
elaborate telescopic method for photon beams of 6 MV and 15 MV on linear
accelerators having mica and Kapton monitor chambers. The new target charge
method gives results consistent with the telescopic method to within 0.3%.
PMID- 9547501
TI - Calibration and characterization of beta-particle sources for intravascular
brachytherapy.
AB - The calibration of a catheter-based system to be used for therapeutic radiation
treatment to prevent restenosis following interventional coronary procedures is
described. The primary dosimetry was performed ionometrically using an
extrapolation chamber equipped with a 1-mm diameter collecting electrode to
measure absorbed dose in tissue equivalent plastic at a depth of 2 mm. These
results are compared with measurements with radiochromic dye film, which is also
used to characterize sources for axial and trans-axial uniformity, and to
determine dose distributions at various depths. A protocol for dose calculation
based on that of AAPM TG43 is suggested for these sources, and examples of its
use are given for the calculation of the enhancement effect on dose rate from a
single seed source due to neighboring seeds. Monte Carlo calculations were also
performed to validate the measured results.
PMID- 9547502
TI - Lithium borate TLD for determining the backscatter factors for low-energy x rays:
comparison with chamber-based and Monte Carlo derived values.
AB - Recently, new backscatter factors for low-energy x rays derived from Monte Carlo
calculations have been recommended in the UK code of practice for kilovoltage
dosimetry published by (IPEMB). As these data, presented as a function of half
value layer, do not take account of the variation of the x-ray spectra for a
given HVL, we have undertaken an experimental study in order to determine BSG for
the beam qualities provided by a Darpac 2000 therapy unit. A RTL detector such as
Li2B4O7:Cu and parallel-plate ion chambers specially designed for low-energy x
ray dosimetry have been used. The results obtained show very good agreement
between the TLD and the Monte Carlo calculations, confirming values obtained by
other authors with lithium borate TLD. On the contrary, the results obtained with
plane-parallel ion chambers show discrepancies up to 9% that are discussed.
PMID- 9547503
TI - Physical imaging performance of a compact computed radiography acquisition
device.
AB - A comprehensive investigation of the physical imaging performance of a Philips
AC3 computed radiography system using fifth-generation image plate technology has
been undertaken. Measurements include characteristic response, modulation
transfer function (MTF) and Wiener spectra (WS) for standard and high resolution
image plates sampled at 10 pixels/mm. These results were used to calculate noise
equivalent quanta (NEQ) and detective quantum efficiency (DQE) spectral
descriptions of system performance. Luminescence noise and x-ray quantum noise
components were separated. From an estimate of the luminescence noise power, the
average system gain was calculated and results show a substantial improvement
over earlier generations of computed radiography systems for standard image
plates.
PMID- 9547504
TI - Isolation and characterization of all-trans-retinoic acid-responsive genes in the
rat testis.
AB - By way of differential screening of testis cDNA libraries from vitamin A
deficient (VAD) rats before and after administration of all-trans retinoic acid
(ATRA), genes, the transcription of which was influenced by ATRA, were isolated.
Most clones with an increased transcription encoded different subunits of the
same mitochondrial protein complex, cytochrome c oxidase (COX). The mRNA
expression of COX increased by a factor 3.9 +/- 1.5 (mean +/- SD, n = 4). This
increased expression seems to reflect an increased energy demand in the ATRA
supplemented VAD testis. Also, one gene was isolated, the transcription of which
was reduced to about 70% by ATRA. This gene, sulfated glycoprotein 2 (Sgp-2), is
a major secretion product of Sertoli cells, the function of which is still
unknown. The effect of ATRA on Sgp-2 expression may be direct, since the promoter
of Sgp-2 contains a putative ATRA-responsive element (RARE).
PMID- 9547505
TI - Sequences and expression patterns of alkaline phosphatase isozymes in
preattachment bovine embryos and the adult bovine.
AB - We report the cloning and partial sequences of two novel bovine tissue-specific
alkaline phosphatase (AP) isozymes (TSAP2 and TSAP3) from in vitro-produced
bovine blastocysts. Using a reverse-transcribed polymerase chain reaction (RT
PCR)-based assay for mRNA expression and in vitro-produced preattachment bovine
embryos, TSAP2 mRNA was detected first at the four-cell stage prior to the major
burst of embryonic transcription in cattle and TSAP3 at the eight-cell stage with
the major burst in transcription. Furthermore, the transcription of TSAP2 and
TSAP3 displays a curious "on-off" pattern during early cleavages between 40 and
120 hr after insemination. Activity of bovine AP, measured by an azo-dye coupling
technique, indicates that at least one AP isozyme is functional in oocytes and
embryos throughout bovine preattachment development. However, maternal and
embryonic-derived AP activity may have different cell-surface distributions. This
novel expression pattern of the bovine AP isozymes could provide a useful tool
for identifying and clarifying the events controlling transcription and gene
expression during early embryo development.
PMID- 9547507
TI - DNA ploidy abnormalities in rabbit preimplantation embryos are not increased by
conditions associated with in vitro culture.
AB - Possible adverse effects of in vitro culture-associated physical factors were
studied in 3- and 4-day-old rabbit embryos. Laboratory conditions were mimicked
by exposure to visible light (320-740 nm, 1600 lx) or decreased temperature (22
+/- 1 degree C). Embryos were exposed for a 24-hr period followed by either
immediate evaluation or an additional 24 hr of standard in vitro culture
(darkness, 37 degrees C) and evaluation thereafter. Effects were assayed by
cytophotometric measurement of the DNA content in Feulgen-stained cell nuclei and
by cell number. The incidence of DNA aneuploid embryos and DNA aneuploid cell
nuclei per embryo, as well as the average nuclear DNA content, was not
significantly different between exposed embryos and controls. Both in vitro
culture and reduced temperature caused a decrease in cell number. The temperature
induced cell number decrease was reversible within 24 hr after return to 37
degrees C. These results demonstrate that physical factors associated with in
vitro culture do not increase DNA ploidy abnormalities in cultured
preimplantation embryos.
PMID- 9547506
TI - The identification and characterization of expression of Pftaire-1, a novel Cdk
family member, suggest its function in the mouse testis and nervous system.
AB - We have isolated a murine cDNA encoding for a novel putative Cdk-related protein
kinase, which has been named Pftaire-1, by screening a testis cDNA library for
new serine/threonine kinases. Pftaire-1 showed 50% and 49% amino acid identity
with Cdk5 and Pctaire-3, respectively, and contains the eleven subdomains
characteristic of the protein kinases. By northern blot analysis we detected two
transcripts of approximately 5.5 and 4.9 kb in size. These transcripts were
expressed at low level in all murine tissues tested, except in the brain, testis
and embryo, where high expression was detected. Cellular localization of the
mRNAs by in situ hybridization analysis shows that Pftaire-1 is expressed in late
pachytene spermatocytes in the testis and in post mitotic neuronal cells both in
the brain and the embryo, suggesting a role of Pftaire-1 both in the process of
meiosis as well as neuron differentiation and/or function.
PMID- 9547508
TI - Selective loss of mouse embryos due to the expression of transgenic major
histocompatibility class I molecules early in embryogenesis.
AB - Among the numerous hypotheses proposed to explain the absence of fetal rejection
by the mother in mammals, it has been suggested that regulation of expression of
the polymorphic major histocompatibility complex (MHC) at the fetal-maternal
interface plays a major role. In addition to a lack of MHC gene expression in the
placenta throughout gestation, the absence of polymorphic MHC molecules on the
early embryo, as well as their low level of expression after midgestation, could
contribute to this important biologic phenomenon. In order to test this
hypothesis, we have produced transgenic mice able to express polymorphic MHC
class I molecules early in embryogenesis. We have placed the MHC class la gene H
2Kb under the control of a housekeeping gene promoter, the hydroxy-methyl
glutaryl coenzyme A reductase (HMG) gene minimal promoter. This construct has
been tested for functionality after transfection into mouse fibroblast L cells.
The analysis of three founder transgenic mice and their progeny suggested that
fetoplacental units that could express the H-2Kb heavy chains are unable to
survive in utero beyond midgestation. We have shown further that a much higher
resorption rate, on days 11 to 13 of embryonic development, is observed among
transgenic embryos developing from eggs microinjected at the one-cell stage with
the pHMG-Kb construct than in control embryos. This lethality is not due to
immune phenomena, since it is observed in histocompatible combinations between
mother and fetus. These results are discussed in the context of what is currently
known about the regulation of MHC expression at the fetal-maternal interface and
in various transgenic mouse models.
PMID- 9547509
TI - Improved development of in vitro-derived bovine embryos by use of a nitric oxide
scavenger in a cumulus-granulosa cell coculture system.
AB - This study was conducted to examine the hypothesis that nitric oxide (NO) affects
prehatching development of bovine oocytes fertilized in vitro. In experiment 1,
inseminated oocytes were cultured in a cumulus-granulosa cell (CG) coculture
system to which 0.008 or 0.04 mM of sodium nitroprusside (SNP), a spontaneous NO
releaser, was added at 18 or 60 hr postinsemination. Embryo development was
greatly (P < 0.001) inhibited by the addition of SNP, regardless of time of
addition or SNP concentration. In experiment 2, eight-cell embryos were cultured
singly in a defined medium, to which 0.0016, 0.008, or 0.04 mM of SNP was added.
Development to the blastocyst stage was greatly (P < 0.001) decreased after
addition of SNP compared with no addition. Higher (P < 0.02) concentration of NO
metabolites was found in developmentally arrested embryos than in developing
embryos at 144 hr postinsemination (experiment 3). In experiment 4, blastocyst
formation of oocytes cocultured with CGs was significantly (P < 0.02) increased
after addition of hemoglobin (Hb, 1 microgram/ml), an NO scavenger. Prehatching
development of oocytes was significantly (P < 0.05) increased after addition of
Hb at different time intervals (18, 60, or 144 hr postinsemination) in experiment
5. Embryo development was not enhanced by Hb addition to the culture medium in
the absence of CGs (experiment 6). Prehatching development of eight-cell embryos
derived from a Hb-containing culture system was not promoted by the further
addition of Hb after transfer of the embryos to a defined and CG-free single
embryo culture system (experiment 7). In conclusion, NO, which may be secreted
from CGs, has an inhibitory role in prehatching development of bovine oocytes
fertilized in vitro, and use of an NO scavenger, Hb, in a coculture system
enhances blastocyst formation.
PMID- 9547510
TI - Paracrine effects of bFGF and KGF on the process of mouse blastocyst
implantation.
AB - Implantation is a complex process that requires the interaction of the
blastocyst, and subsequently, that of the developing embryos with the
endometrium. Several growth factors and cytokines are involved in implantation,
but the details of their actions as related to the regulation of blastocyst
implantation remain unclear. In the present study, the RT-PCR method was used to
determine the gene expression of basic fibroblast growth factor (bFGF),
keratinocyte growth factor (KGF), FGF receptor 1 (FGFR1), FGF receptor 2 (FGFR2),
and KGF receptor (KGFR) in mouse embryos and in the stromal and epithelial cells
of the uterine endometrium. Basic FGF and KGF mRNA were expressed in the
endometrial cells, but were not expressed in the embryos. The mRNAs of receptors
for bFGF and KGF were expressed in the blastocysts and in the in vitro implanting
embryos, suggesting that bFGF and KGF may exert paracrine effects on blastocyst
implantation. In this mouse model of blastocyst implantation, it was found that
transforming growth factor alpha (TGF-alpha) at the concentrations of 1 ng/ml and
10 ng/ml significantly enhanced the blastocyst attachment and trophoblast
spreading and increased trophoblast surface area. Relatively high concentrations
of bFGF (100-500 ng/ml) significantly enhanced the rates of blastocyst attachment
and of trophoblast spreading and promoted the expansion of the surface area of
the implanting embryos. Unlike the rates of blastocyst attachment and trophoblast
spreading, the surface area of the spreading embryos was significantly increased
by addition of KGF (1-100 ng/ml). These results suggest that the bFGF and KGF
derived from the endometrial cells exert paracrine effects on the process of
implantation by stimulating trophoblast outgrowth through their cognate
receptors.
PMID- 9547511
TI - Regulation of plasminogen activator in rat endometrial stromal cells: the role of
epidermal growth factor.
AB - The effect of epidermal growth factor (EGF) on the accumulation of plasminogen
activator (PA) activity in the medium of cultured rat endometrial stromal cells
isolated from uteri sensitized for the decidual cell reaction was examined.
Treatment with EGF increased, in a concentration-dependent manner, PA activity in
the medium. This effect was inhibited or greatly reduced by inhibitors of
transcription and translation. Incubation of the cells with prostaglandin E2
increased PA activity in the medium. Indomethacin, which inhibited prostaglandin
accumulation in the medium, slightly but significantly decreased the EGF-induced
increase in PA activity in the medium. As indicated by zymography and the use of
amiloride in the PA assay, the activity in the medium was primarily urokinase
type plasminogen activator (uPA). Finally, EGF caused an increase in the steady
state uPA mRNA levels in the cells. These results provide evidence that EGF
causes an increase in the secretion of uPA by rat endometrial stromal cells from
uteri sensitized for the decidual cell reaction through a mechanism that involves
an increase in steady-state uPA mRNA levels.
PMID- 9547512
TI - Four isoforms of the signal-transduction and RNA-binding protein QKI expressed
during chicken spermatogenesis.
AB - Genes expressed during spermatogenesis undergo alternative initiation and
alternative splicing and may be under the control of a coordinated mechanism of
RNA processing. A family of proteins that combine features of signal-transduction
and RNA-binding molecules could be instrumental in this process. We have
characterized a cDNA from adult chicken testis that codifies a highly conserved
member of the STAR protein family, the orthologue of the mouse quaking gene qki.
The predicted chicken protein differs only in four amino acids from the
corresponding mouse protein. Messages of 7, 6, and 5 kb are expressed
differentially during chicken spermatogenesis. The 5-kb message, the predominant
form in adult testis, presents heterogeneity in the coding region, showing
insertions of 51 and 75 bp and a deletion of 24 bp, which gives rise to four
possible isoforms of the protein.
PMID- 9547513
TI - Association of protein kinase A type I with detergent-resistant structures of
mammalian sperm cells.
AB - The finding that flagellar movement in detergent-permeabilized sperm cells is
restored when Mg ATP and cAMP are added implicated detergent-resistant protein
kinase A (PKA) in the regulation of sperm motility. It is widely believed that
only the PKA regulatory subunit RII can associate with the cytoskeleton and/or
organelles. In this paper we used monoclonal antibodies against the PKA catalytic
subunit and RI subunit and demonstrated that PKA type I is also associated with
the sperm cytoskeleton. To our knowledge, this is the first report showing
anchored PKA type I. This association was found in sperm of nonrodent mammalian
species and, to a lesser extent, also in mouse sperm. The PKA catalytic subunit
is bound to the cytoskeleton secondarily via its complex with the regulatory
subunit. The detergent-resistant complexes of RI and catalytic subunits localize
predominantly to the flagellum. Ultrastructural immunogold labeling revealed the
association of detergent-resistant PKA type I with outer dense fibers (ODF) and
the fibrous sheath (FS) but not with microtubules. This location is consistent
with a proposed role of PKA in regulation of FS sliding on underlying ODF.
PMID- 9547514
TI - Changes in lipid diffusibility in the hamster sperm head plasma membrane during
capacitation in vivo and in vitro.
AB - The technique of fluorescence recovery after photobleaching (FRAP) was employed
on spermatozoa labeled with the fluorescent lipid analogue C14dil to provide two
measures of lateral diffusion in the plane of the sperm plasma membrane during
capacitation in vivo and in vitro: the diffusion coefficient (D) for C14dil and
the fraction of C14dil that is free to diffuse (%R) within the domain. To
evaluate changes in lipid diffusibility during capacitation in vivo, spermatozoa
were recovered from the uterus within 30 min after ejaculation or from the
oviduct at 2, 4, 6 and 8 hr after mating. To compare the changes which occur in
vivo with those which occur during capacitation in vitro, caudal epididymal
spermatozoa were incubated under capacitating or non-capacitating (control)
conditions for 4 hr. Although transient changes in D occurred during the course
of capacitation, there was no net change in D for either anterior (AH) or
posterior head (PH) domains following capacitation in vitro or in vivo.
Significant differences in the lipid diffusion coefficient between the two head
domains were observed during the course of capacitation. A transient decrease in
%R was observed for the AH domain during capacitation in vitro and incubation
under control conditions, but no significant change in %R was observed in the AH
domain during capacitation in vivo. A significant decline in %R of the PH domain
was observed for spermatozoa during capacitation in vivo, in vitro and following
incubation under non-capacitating conditions. These data indicate that the
changes in the lipid diffusibility of the AH and PH domains which occur during
capacitation in vivo exhibit both similarities and differences to those which
occur during capacitation in vitro.
PMID- 9547515
TI - Expression of germ cell nuclear factor (GCNF/RTR) during spermatogenesis.
AB - Germ cell nuclear factor (GCNF/RTR), a novel orphan receptor in the nuclear
receptor superfamily of ligand-activated transcription factors, is expressed
predominantly in developing germ cells. In several mammalian species two GCNF/RTR
mRNAs are present in the testis, with the smaller 2.3-kb transcript generally
expressed at higher levels than the larger 7.4- or 8.0-kb transcript. In both the
mouse and rat, the 2.3- and 7.4-kb GCNF/RTR transcripts were detected in isolated
spermatogenic cells, but not in Sertoli cells. Expression of these transcripts is
differentially regulated, with the larger 7.4-kb mRNA appearing earlier during
testicular development. The major 2.3-kb transcript is expressed predominantly in
round spermatids in the mouse and rat. In situ hybridization studies in the rat
demonstrated that GCNF/RTR transcripts reach maximal steady-state levels in round
spermatids at stages VII and VIII of the spermatogenic cycle, and then decline
abruptly as spermatids begin to elongate. RNase protection assays were used to
predict the 3' termination site of the 2.3-kb transcript. An alternative
polyadenylation signal (AGUAAA) was identified just upstream of this termination
site. These studies suggest that GCNF/RTR may regulate transcription during
spermatogenesis, particularly in round spermatids just prior to the initiation of
nuclear elongation and condensation.
PMID- 9547516
TI - Targeting of the domain-specific integral membrane protein PM52 to the
periacrosomal plasma membrane during guinea pig spermiogenesis.
AB - The sperm plasma membrane is segregated into functionally, biochemically, and
structurally distinct domains yet the protein sorting pathways and assembly
mechanisms that assemble these domains during spermiogenesis are incompletely
understood. We previously characterized two structurally related size-variant,
integral membrane proteins of 52 kDa (PM52) and 35 kDa localized to the
periacrosomal plasma membrane of guinea pig cauda epididymal spermatozoa
(Westbrook-Case et al., 1994). In this study we used light and electron
microscopic immunocytochemistry to define the expression pattern and sorting
pathway that establishes the domain-specific distribution of PM52 during
spermiogenesis. The PM52 is first expressed in acrosome-phase spermatids and it
localizes exclusively to the cytoplasmic lobe. Immunoelectron microscopy revealed
that both cytoplasmic vesicles and the plasma membrane of the cytoplasmic lobe
labeled with anti-PM52. During early stages of expression, PM52 appeared to be
absent from the head region, but significant PM52 accumulation over the spermatid
head was noted in late acrosomal phase spermatids. Throughout spermiogenesis PM52
extended posteriorly to the annulus, which represents a barrier preventing PM52
diffusion into the posterior tail. Following the migration of the annulus to the
midpiece-principal piece junction, PM52 began to disappear from the flagellar
region and at the completion of spermiogenesis most of the PM52 was restricted to
the acrosomal segment. Spermatids and epididymal sperm PM52 exhibited identical
sizes by SDS-PAGE and immunoblotting, indicating that they are not
proteolytically modified during epididymal maturation. The PM52 antibodies were
also used to screen a guinea pig testis cDNA library, and sequence determination
of full-length PM52 clones demonstrated identity of a sperm membrane protein
recently termed "sperad" (Quill and Garbers, 1996). Membrane barriers and
potential mechanisms establishing the domain-specific residence of PM52 are
discussed.
PMID- 9547517
TI - Phosphorylation of Shc proteins in human sperm in response to capacitation and
progesterone treatment.
AB - Several authors have demonstrated the involvement of tyrosine kinases during
sperm capacitation and acrosome reaction. Shc proteins (p46Shc, p52Shc, and
p66Shc) are cytoplasmic substrates of activated tyrosine kinases and are widely
expressed in mammalian somatic tissues. Experiments were designed to demonstrate
the presence of Shc in spermatozoa and to study its involvement in the signal
transduction events leading to acrosome reaction. Anti-Shc antibodies strongly
reacted with the acrosomal region of methanol-fixed human sperm. Only one Shc
isoform (p52Shc) was detected on Western blot. To study the degree of
phosphorylation of Shc during capacitation and acrosome reaction, sperm samples
were divided into two groups: noncapacitated and capacitated/progesterone
treated. Lysates from both groups were immunoprecipitated with anti
phosphotyrosine antibodies and the precipitated (i.e., phosphorylated) proteins
were tested with anti-Shc antibodies. The intensity of p52Shc was clearly
increased in capacitated/progesterone-stimulated cells.
PMID- 9547518
TI - Synthesis and biological activity of some 4-amino-3-cinnoline carboxylic acid
derivatives. Part 4: 2,4-Dioxo-1,2,3,4-tetrahydropyrimido[5,4-c]cinnolines.
AB - A series of new 2,4-dioxo-1,2,3,4-tetrahydropyrimido[5,4-c]cinnolines and their 3
substituted derivatives were prepared. These compounds were obtained by
cyclocondensation of the appropriate substituted 4-amino-3-cinnolinecarboxylic
acid with urea or 4-amino-3-cinnolinecarboxamides with N,N'-carbonyldiimidazole
(DCl), oxalyl chloride or diethyl carbonate. Most of these compounds showed a
high sedative action in low doses.
PMID- 9547519
TI - [Solid phase microextraction (SPME) of sample preparation during of a complex
biological matrix in biotransformation studies].
AB - Within the scope of the investigation of drug metabolism in keratinocytes solid
phase microextraction (SPME) was investigated as a suitable method for sample
preparation. The application of SPME is based on the fact, that a amount of
analyte is absorbed by the polymer fiber at equilibrium, and the fiber is
localized on a tip of a GC-syringe. The stable nitroxyl radical TEMPO (2,2,6,6
tetramthylpiperidine-1-oxyl) and its apolar metabolite 2,2,6,6
tetramethylpiperidine were analyzed by SPME and subsequent GC using thymol as
internal standard. By means of the headspace-technique and an apolar fiber the
recovery rate of TEMPO and the metabolite was nearly 100% and the precision was
high. However, the results of the direct SPME were unsatisfactory. In comparison
with conventional liquid/liquid extraction and solid phase extraction SPE the
SPME proved the best results with regard to recovery rate and precision.
Furthermore, the main advantages of SPME are the renunciation of organic
solvents, the saving of time, the possibility to reuse the fiber about 100-150
times and the option for a complete automatisation of the extraction procedure.
PMID- 9547520
TI - Antimicrobial activity of organic thiosulfates (Bunte salts).
AB - A number of organic thiosulfates (Bunte salts) were prepared from appropriate
primary bromides or iodides. In the case of substrates with long aliphatic
chains, an addition of benzyltrimethylammonium chloride as phase transfer
catalyst was very successful. The Bunte salts obtained were tested for
antibacterial and fungicidal activity by means of the agar disc-diffusion method
and by assignation of the minimum inhibitory concentrations (MIC). It was found
that the microorganisms Proteus vulgaris, Candida albicans and Staphylococcus
aureus showed the highest sensitivity. Biological activity of the compounds
studied was dependent on the length of the aliphatic chain. Among the
investigated compounds, aliphatic thiosulfates with 10-13 carbon atom chain were
the most potent.
PMID- 9547521
TI - Antimycobacterial activity of 3'- and 4'-fluorothiobenzanilides.
AB - On the basis of a preliminary study of the antimycobacterial activity of
thiobenzanilides, a group of 3'-fluoro- and 4'-fluorothiobenzanilides has been
synthesized and tested against Mycobacterium tuberculosis, M. kansasii, M. avium
and M. fortuitum. The results of this study demonstrate that electron withdrawing
groups increase the activity of thiobenzanilides and fluoro benzothioanilides
against atypical strains which is higher then that of INH.
PMID- 9547522
TI - Mannich bases of arylalicyclic ketones and related quaternary ammonium compounds
with antileukemic properties.
PMID- 9547523
TI - Comparison of reinforcement schedules in the reduction of stereotypy with
supported routines.
AB - The rates and durations of stereotypic behaviors in four adolescents with severe
mental retardation were measured during two daily vocational training sessions
and during contiguous periods of leisure in their special education classrooms.
Vocational training was conducted in two different tasks, alternating across
days. The task requirements for each participant were matched to each
participant's learning and performance characteristics. The participants were
exposed to a fixed ratio schedule of tokens exchangeable for food items on one
task and to a variable interval schedule for the same consequences on the second
task. The schedules were chosen as an initial test of a matching-law based
prediction by Myerson and Hale (1984): Variable interval reinforcement for
adaptive behavior will produce less allocation of responding to maladaptive
behavior than will a ratio-based intervention. When work performances stabilized,
the schedules of token delivery were reversed across the tasks and performances
again stabilized. Results are reported for periods when work performances met
stability criteria. Stereotypy occurred more during leisure than during
vocational training under either schedule. The major differences in stereotypy
between leisure and vocational training were differences in episode length rather
than rate of onset. Onset of stereotypy in vocational training, however, occurred
at higher rates under the interval schedule than under the ratio schedule in both
tasks. The results are discussed in terms of Myerson and Hale's prediction and
implications for further research and application.
PMID- 9547524
TI - Behavior disorders in persons with mental retardation receiving antipsychotic
medication.
AB - The behavior disorders of mentally retarded individuals receiving antipsychotic
medication and the relationship between behavior disorders and the daily dose of
drug were investigated. Of 355 residents of residential facilities in Wakayama
Prefecture, Japan (age range, 7-64 years), the problem behaviors of 54 subjects
receiving antipsychotic drugs were compared to those of 52 subjects receiving
anticonvulsants and of 202 subjects without any medication at all, using the
Japanese version of the Aberrant Behavior Checklist (ABC-J). All five subscale
scores of the ABC-J were significantly higher for the antipsychotic group than
for those of the other groups, whereas only the Irritability subscale was
prominent in the subjects receiving anticonvulsants. The mean chlorpromazine
equivalent dose was higher in the subjects with severe/profound disability than
in those with mild/moderate disability and correlated with the Hyperactivity
subscale scores. The problem behaviors of individuals with mental retardation
prescribed antipsychotic drugs were more severe than those without medication;
more severe disability and higher Hyperactivity scores were associated with dose
of antipsychotic drugs.
PMID- 9547525
TI - The Motivation Assessment Scale: reliability and construct validity across three
topographies of behavior.
AB - The psychometric properties of the Motivation Assessment Scale (MAS) were
examined. Specifically, reliability, internal consistency, and construct validity
were estimated using 90 ratings of different problem behaviors among 86
individuals with mental retardation. Data were analyzed under conditions of (a)
three topographies of problem behavior and (b) two methods of calculation.
Although reliability and internal consistency were generally poor, the results
depended upon the above conditions. Factor analysis revealed that the four
factors of the MAS differed from the subscale structure obtained in this study,
proposed by the authors of the MAS. Thus, the construct validity of this scale
was ambiguous. It is concluded that the MAS should be employed in conjunction
with other instruments to assess the functional characteristics of problem
behavior with individuals who have mental retardation.
PMID- 9547526
TI - The treatment of severe self-injurious behavior by the systematic fading of
restraints: effects on self-injury, self-restraint, adaptive behavior, and
behavioral correlates of affect.
AB - Severe self-injurious behavior (SIB) in people with mental retardation is
difficult to treat when dangerously frequent or intense responding rules out
functional analysis and interventions that permit free responding. This situation
is common when restrictive devices, such as straight arm splints, are used. In
this study, the effects of introducing flexion into a straight-arm splint, on
SIB, self-restraint, adaptive behavior, and behavioral correlates of affect were
examined for three individuals with severe mental retardation. Using single-case
design methodology, for two individuals self-injury was reduced to zero, while
the overall level of restriction was also significantly reduced. From the
observed behavioral correlates of affect, there was no evidence of an increase in
negative affect with the introduction of the new splint and the fading procedure,
but there was evidence of an increase in positive vocalizations. Engagement in
activities and social contact were not affected by the introduction of the new
splint. The reasons for a decrease in SIB with a corresponding decrease in
restriction in the absence of any manipulation of contingencies for SIB are
discussed, with particular reference to stimulus control.
PMID- 9547527
TI - Social-emotional characteristics of preschool-aged children referred for Child
Find screening and assessment: a comparative study.
AB - Differences in parent ratings of social-emotional behavior among young children
referred for Child Find screening and assessment and nonreferred children were
examined. Participants included 64 preschool-aged children referred for Child
Find screening and assessment (CF group) and 64 preschool-aged children without
such referrals or identified disabilities (Comparison group). The Comparison
group was matched to the CF group by gender and age, using a randomized block
procedure. Social-emotional behavior of the participants was assessed using
parent ratings on the Preschool and Kindergarten Behavior Scale (PKBS), a social
skills and problem-behavior rating scale for use with children aged 3-6. PKBS
scores were found to classify the participants into their respective groups with
a substantial degree of accuracy. Significant differences were found between the
two groups in social skills and problem behavior scores, with the CF participants
evidencing greater social skills deficits and problem behavior excesses than the
participants in the Comparison group. An inspection of frequency distributions of
the two groups revealed that children referred for Child Find screening were
approximately four times as likely to have significant social deficits, and
approximately six times as likely to have significant problem-behavior excesses
than their nonreferred comparison peers. New validity evidence for the PKBS is
provided, along with recommendations for future research and clinical practice
with the Child Find population.
PMID- 9547528
TI - Evaluating the reinforcing effects of choice in comparison to reinforcement rate.
AB - A concurrent-operants arrangement was used to evaluate a boy's preference for a
choice condition (in which he chose the reinforcement) over a no-choice condition
(in which the therapist selected the reinforcement for him) when (a) these
conditions produced equal rates of reinforcement and (b) lower rates of
reinforcement were associated with the choice condition. The boy preferred the
choice condition even when it resulted in a much less favorable rate of
reinforcement than the no-choice condition (up to 4000% less).
PMID- 9547529
TI - Task variation versus task repetition for people with profound developmental
disabilities: an assessment of preferences.
AB - An assessment of preferences between task variation and task repetition with four
adults with profound developmental disabilities was implemented. After
participants were exposed to both task variation and task repetition conditions,
they were allowed to choose between them. Results showed that all participants
had strong preferences; three preferred task variation and one task repetition.
Aspects of the assessment and use of assessment data for planning daily work
conditions were discussed.
PMID- 9547530
TI - Regulation of phosphoinositide phospholipases by G-proteins.
PMID- 9547531
TI - The effects of group II phospholipase A2 on ras-induced metastasis.
PMID- 9547532
TI - Activation of Ca(2+)-sensitive cytosolic phospholipase A2 (cPLA2) in human
platelets.
PMID- 9547533
TI - Involvement of reactive oxygen species in phospholipase A2 activation: inhibition
of protein tyrosine phosphatases and activation of protein kinases.
AB - Activators of PKC in combination with vanadate induce massive formation of
reactive oxygen species. The formation of ROS leads to suppression of protein
tyrosine phosphatase activity and consequently to enhanced protein tyrosine
phosphorylation. This culminates in the activation of the MAP-K cascade and of
PLA2 (Scheme 1).
PMID- 9547534
TI - High molecular weight phospholipase A2: its occurrence and quantification in
human colon cancer and normal mucosa.
PMID- 9547535
TI - (S)-type lipoxygenase and cyclooxygenase reaction box models characterizing the
stereochemistry of the dioxygenation reaction.
AB - In summary, these models provide a unifying stereochemical summary of the
dioxygenation reactions catalyzed by (S)-type lipoxygenases or for the first
dioxygenation step of prostaglandin H synthases.
PMID- 9547536
TI - Activation of 5-lipoxygenase in whole polymorphonuclear leukocytes by arachidonic
acid: evidence of cytosolic active enzyme.
PMID- 9547537
TI - Intracellular distribution, activity, and Ca(2+)-dependent translocation of 12
lipoxygenase in Lewis lung tumor cells.
PMID- 9547538
TI - Cloning and sequencing of prostaglandin H synthetase from rat tracheal epithelial
cells: structural evidence that a TPA regulated mRNA codes for the rat ortholog
of murine PHS-1.
PMID- 9547539
TI - Non-enzymatic rearrangement of leukotriene A4 to 5-keto-(7E,9E,11Z,14Z)
eicosatetraenoic acid in aqueous media.
PMID- 9547540
TI - Bromoacetamido-analogs of indomethacin and mefenamic acid affinity-label
prostaglandin H2 synthase at two sites.
PMID- 9547541
TI - Regulation of eicosanoid synthesis in liver macrophages.
PMID- 9547542
TI - Comparison of arachidonic acid metabolism by normal, precancerous and neoplastic
epithelial cell lines of the upper aerodigestive tract.
PMID- 9547543
TI - Induction of prostaglandin endoperoxide synthase-1 (COX-1) in a human
promonocytic cell line by treatment with the differentiating agent TPA.
AB - Prostaglandin endoperoxide synthase (PGH synthase) is responsible for converting
arachdonic acid to PGH2, the common precursor of prostaglandins. It has been
shown previously that phorbol ester-induced differentiation of human promonocytic
leukemia cell lines is accompanied by induction of PGH synthase enzyme and
enhanced capacity to produce prostaglandins. However, the identity of the isoform
of PGH synthase, i.e., PGH synthase-1 or -2, that is induced under these
conditions has not been established. Northern and Western analyses revealed a
dramatic increase in levels of PGH synthase-1 mRNA and protein levels within 24
hr after treatment of THP-1 cells with phorbol ester. No significant increase in
PGH synthase-2 mRNA or protein was observed. The increases in PGH synthase-1 were
accompanied by an enhanced capacity of the cells to produce PGE2. The current
findings indicate that expression of PGH synthase-1 is greatly enhanced in a
promonocytic cell line by treatment with an agent that induces differentiation.
PMID- 9547544
TI - X-ray crystallographic study of the structure of prostaglandin H synthase.
PMID- 9547545
TI - Properties of prostacyclin synthase.
AB - Prostacyclin synthase (PGIS) was isolated from bovine aortic microsomes after
detergent solubilisation following purification by DEAE-Sephacel, immobilized
metal affinity, and hydroxy apatite chromatography. The homogenous protein
exhibited spectral characteristics of a heme-thiolate protein (P450) like the
enzyme purified earlier from porcine microsomes and had an apparent mass of 52
kDa on SDS/PAGE. Three peptides from an endoproteinase Lys-C digest were isolated
and sequenced. An antiserum was prepared from rabbits and purified by affinity
chromatography. This allowed Western blots of microsomes from cultured
endothelial cells. After treatment with IL-1 the activity of the cells in
producing 6-keto-PGF1 alpha increased about threefold over 27 h which was
accompanied by an increase in PGIS mass. A monoclonal antibody was used to set up
an ELISA which served for the quantitation of PGIS in bovine tissues.
PMID- 9547546
TI - Regulation of prostaglandin H synthase-1 gene expression.
PMID- 9547547
TI - Mammalian arachidonate 12-lipoxygenases.
PMID- 9547548
TI - The three-dimensional structure of soybean lipoxygenase-1: an arachidonic acid 15
lipoxygenase.
PMID- 9547549
TI - Purification and characterization of the epidermal 8(S)lipoxygenase.
PMID- 9547550
TI - The effect of 5-lipoxygenase-activating protein (FLAP) on substrate utilization
by 5-lipoxygenase.
PMID- 9547551
TI - Leukotriene A4 hydrolase: differential inhibition of the catalytic activities by
divalent cations.
PMID- 9547552
TI - Regulation of 12(S)-HETE production in tumor cells.
PMID- 9547553
TI - Distribution of COX-1 and COX-2 in normal and inflamed tissues.
AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment
of a number of inflammatory diseases and are believed to act via inhibition of
the enzyme cyclooxygenase (COX). This enzyme catalyzes the conversion of
arachidonic acid to the prostaglandins (PGs). Although commercially available
NSAIDs are efficacious anti-inflammatory agents, significant side effects limit
their use. Recently two forms of COX were identified-a constitutively expressed
COX-1 and a cytokine-inducible COX-2. Potent anti-inflammatory agents like the
glucocorticoids are known to inhibit specifically the expression of COX-2 while
commercially available NSAIDs like indomethacin inhibit both COX-1 and COX-2.
These findings have led to the hypothesis that toxicities associated with NSAID
therapy are due to inhibition of the non-regulated or constitutive form of COX
(COX-1), whereas therapeutic benefit derives from inhibition of the inducible
enzyme, COX-2. We have examined the relative distribution of COX-1 and COX-2 in
both normal and inflamed tissues and report that COX-1 expression dominates
normal tissues while COX-2 mRNA is induced at the inflammatory site. Furthermore,
compounds that selectively inhibit COX-2 are anti-inflammatory without gastric
toxicity.
PMID- 9547554
TI - Examination of prostaglandin H synthase-1 topology in the endoplasmic reticulum
membrane.
PMID- 9547555
TI - Coordinate regulation of the inducible forms of prostaglandin synthase and nitric
oxide synthase in fibroblasts and macrophages.
PMID- 9547556
TI - Molecular cloning of prostacyclin synthase from bovine endothelial cells.
PMID- 9547557
TI - Interaction of PGH synthase isozymes-1 and -2 with nonsteroidal anti-inflammatory
drugs.
PMID- 9547558
TI - Dual effect of propranolol on the human platelet activation by thrombin:
potentiation of free intracellular Ca2+ mobilization and inhibition of
phospholipase D activity.
PMID- 9547559
TI - Molecular diversity of prostanoid receptors; subtypes and isoforms of
prostaglandin E receptor.
AB - cDNA cloning of PGE receptors revealed that there are at least three distinct
subtypes of the receptor derived from different genes, which are different in
ligand binding character and signal transduction. They also distribute
differently in the body and localize in different cells of the organ. The cloning
study also revealed that multiple isoforms of EP3 are produced by alternative
splicing of its mRNA, and that these isoforms show identical ligand binding
properties but couple to different signal transduction pathways. Thus, our study
has shown that the diversity of PGE actions in the body is elicited by the
molecular diversity of its receptor mediating these responses.
PMID- 9547560
TI - Molecular characterization and physiological functions of PAF receptors.
PMID- 9547561
TI - Identification of the FP-receptor as a discrete entity by radioligand binding in
biosystems that exhibit different functional rank orders of potency in response
to prostanoids.
AB - The definition of the FP-receptor is currently based on the functional potency of
agonists. Functional studies suggest that the FP-receptor has particular
sensitivity to PGF2 alpha and certain PGF2 alpha analogs but is also stimulated
by PGD2 and PGE2. In order to examine the concept that these responses involve a
single (FP) receptor, we compared functional responses with radioligand binding
competition studies. In Swiss 3T3 cells, an identical potency rank order was
obtained for Ca2+ transient signals and competition at binding sites for 3H-PGF2
alpha and 3H-17-phenyl PGF2 alpha (i.e., 17-phenyl PGF2 alpha > PGF2 alpha > PGD2
> PGE2), suggesting interaction at a single receptor. This conclusion was further
supported by successive addition studies where cells pretreated with a maximally
effective dose of PGF2 alpha were refractory to subsequent addition of PGF2
alpha, PGD2, or PGE2 but not PDGF. We also performed competition binding studies
in the rat colon and uterus as representative tissues where the functional
potency rank order is inconsistent with an FP receptor or any other prostanoid
receptor subtype. Radioligand binding studies involving 3H-17-phenyl PGF2 alpha
and 3H-PGE2 in the rat colon and uterus indicated the co-existence of both FP and
EP3 receptors according to the competition afforded by natural PGs and selective
analogs for FP and EP3 receptors. Thus, the FP-receptor can be identified in a
mixed population of prostanoid receptors and this lends further support to the FP
receptor as a discrete entity.
PMID- 9547562
TI - Cellular activation by thromboxane A2 and 8-EPI-PGF2 alpha.
PMID- 9547564
TI - Prostaglandin receptors involved in inflammatory events.
PMID- 9547563
TI - Modification on ligand binding to TXA2/PGH2 receptors by diethylpyrocarbonate.
PMID- 9547565
TI - LTB4 receptor antagonists exacerbate T lymphocyte-mediated delayed
hypersensitivity in guinea pigs.
PMID- 9547566
TI - Isolation and cloning of human peroxisome proliferator activated receptor gamma
cDNA.
PMID- 9547567
TI - Structure and localization of the rabbit prostaglandin EP3 receptor.
PMID- 9547568
TI - Prostaglandin regulation of gene expression and growth in normal and malignant
tissues.
PMID- 9547569
TI - Distinct signaling pathways mediate induction of c-fos by PGE2 in glomerular
mesangial cells.
AB - Prostanoids induce expression of several immediate-early genes but the molecular
mechanisms underlying these responses remain poorly characterized. We have
studied induction of the proto-oncogenc c-fos by PGE2 in mesangial cells as a
model of gene regulation by prostanoids. PGE2 induced marked and transient
accumulation of c-fos mRNA. Induction of c-fos by PGE2 and TxA2 did not correlate
with induction of phospholipase C. Addition of exogenous cAMP failed to induce c
fos mRNA, suggesting that activation of an EP2 receptor linked to adenylate
cyclase did not account for induction of c-fos by PGE2. These data contrast with
previous experiments in NIH 3T3 cells where PGE2 induced c-fos by a cAMP
dependent mechanism. We further showed that PGE2 induces the c-fos gene by direct
activation of the serum response element. Taken together these experiments
provide evidence for a pathway linking a PGE2 receptor on the plasma membrane to
transcriptional activation in the nucleus.
PMID- 9547570
TI - Cytosolic 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid binding sites in
carcinoma cells.
AB - 12(S)-HETE stimulates gene and cell surface expression of the integrin GPIIb/IIIa
in carcinoma cells. The cells have high affinity binding sites for 12(S)-HETE.
Analyses of the subcellular distribution and size of these sites showed that
cytosol was the predominant location and that the apparent molecular weight was
close to 670,000. Besides cytosol, mitochondria, nuclei, and plasma membranes
also contained 12(S)-HETE binding sites. The mainly cytosolic location of the
binding sites is different from that of other eicosanoid receptors which are G
protein coupled plasma membrane proteins of the rhodopsin gene family.
PMID- 9547571
TI - DAG second messengers: molecular switches and growth control.
PMID- 9547572
TI - Sphingolipid second messengers: tumor suppressor lipids.
PMID- 9547573
TI - The role of protein kinase C in signal transduction, growth control and lipid
metabolism.
PMID- 9547574
TI - Tumor responsiveness to the metastasis-stimulatory effects of prostaglandin E2 is
restricted by protein phosphatases.
PMID- 9547576
TI - The role of lipid peroxidation products in the regulation of protein kinase C
activity in vitro.
PMID- 9547575
TI - Interactions between specific phosphoproteins during modulation of prostacyclin
secretion in cultured bovine aortic endothelial cells.
PMID- 9547577
TI - Role of protein kinase C and phosphatases in 12(S)-HETE-induced tumor cell
cytoskeletal reorganization.
AB - Adherent B16 amelanotic melanoma (B16a) cells exposed to fatty acid 12(S)-HETE, a
lipoxygenase metabolite of arachidonic acid, demonstrated a gradual dissolution
of stress fibers and bundling-together of vimentin. The 12(S)-HETE effects on
tumor cell cytoskeleton appeared 5 min after treatment, became prominent
approximately 15 min following stimulation, and generally disappeared by 30 min.
Simultaneous treatment of cells with 12(S)-HETE and okadaic acid (OA) prevented
disappearance of the 12(S)-HETE effects by 30 min. Quantitative double
immunoblotting of actin and vimentin indicated that actin, but not vimentin,
underwent a time-related depolymerization. On the other hand, enhanced
phosphorylation of vimentin but not of actin was observed after 12(S)-HETE
treatment. 12(S)-HETE-enhanced vimentin phosphorylation was abolished by protein
kinase C (PKC) inhibitor calphostin C, thus suggesting the involvement of PKC.
PMID- 9547578
TI - PX-52, A novel inhibitor of 14 kDa secretory and 85 kDa cytosolic phospholipases
A2.
AB - Previously we reported that PGBx, a prostaglandin oligomer with anti-inflammatory
activity, inhibited 14 kDa phospholipase A2 (PLA2) activity and blocked
arachidonic acid mobilization in prelabeled human neutrophils (Biochim. Biophys.
Acta 1006:272-277, 278-286, 1989) This study describes a new inhibitor of
phospholipase A2, PX-52, that also blocks agonist induced arachidonic acid
mobilization in prelabeled cells. PX-52, a fatty acid polymer, inhibited
hydrolysis of 14C-oleate labeled E.coli by a variety of 14 kDa PLA2s including
human PMN, sperm, synovial fluid and disc, as well as porcine pancreas, N. naja,
and bee venom in a dose-dependent manner with IC50s ranging from 1.0-3.7 uM.
Inhibition of activity was comparable at different Ca2+ concentrations, but was
relieved by increasing substrate concentration or by methylation of PX-52.
Hydrolysis of [14C]-arachidonyl phosphatidylcholine by 85 kDa, cytosolic PLA2
from U937 cells was similarly inhibited by PX-52, the IC50 = 5 uM. Arachidonic
acid mobilization induced by A23187 in prelabeled human PMNs was blocked by PX
52; IC50 = 10-15 uM while concentrations of up to 80 uM oleate had no effect.
These results demonstrate that PX-52 inhibits the in vitro activity of secretory
and cytosolic PLA2s and agonist-induced arachidonic acid release from human
cells. Given its ability to block the arachidonic acid cascade, PX-52 may be
useful in the control of inflammation.
PMID- 9547579
TI - Hepoxilin A3 inhibits agonist-evoked rise in free intracellular calcium in human
neutrophils.
PMID- 9547580
TI - The discovery of LY293111, a novel, potent and orally active leukotriene B4
receptor antagonist of the biphenylphenol class.
PMID- 9547581
TI - Inhibition of leukotriene B4 (LTB4) in human neutrophils by L-threo
dihydrosphingosine.
AB - The sphingosine analog L-threo-dihydrosphingosine has been shown to inhibit
protein kinase C (PKC) isoenzymes in mixed micelle and vesicle assays. This
compound also inhibited the reactive oxygen intermediates (ROI) released from
isolated neutrophils (IC50 approximately 2 microM) and phorbol ester-induced
edema and neutrophil influx in the mouse ear model (ED50 approximately 11 mg/kg).
Based on the anti-inflammatory activity of this compound, studies were done to
determine its effect on arachidonate metabolism by the lipoxygenase pathway.
Neutrophils were preincubated with test agents or vehicle for one minute and then
incubated with 1 microM calcium ionophore A23187 for two minutes. Supernatants
were assayed for LTB4 using a radioimmunoassay. The reference lipoxygenase
inhibitor nordihydroguaiaretic acid exhibited 98.3% inhibition at 1 microM (n =
2) and prevented ROI production (IC50 approximately 6 microM). In contrast, the
potent PKC inhibitor staurosporine was inactive against LTB4 in these studies (<
23% inhibition at 10 microM, n = 2), but inhibited ROI formation (IC50
approximately 3nM). L-threo-dihydrosphingosine inhibited LTB4 production 96.9 +/-
1.3%, at 10 microM (IC50 = 6 microM, n = 2). These data suggest that L-threo
dihydrosphingosine blocks the release of LTB4 from human neutrophils via a
mechanism independent of PKC.
PMID- 9547582
TI - Aspirin and gastrointestinal cancer.
AB - In rodents, nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin
inhibit chemically induced adenomas and early carcinomas of the colon. The NSAID
Sulindac inhibits the growth of polyps of the colon and rectum in two randomized
trials of patients with familial adenomatous polyposis (FAP), although the
inhibition is not complete. Eight epidemiologic studies have found a 40-50%
reduction in polyps or colorectal cancer among persons who regularly use aspirin
or other NSAIDs compared to those who do not. Two epidemiologic studies show a
slight increase in risk. Interpretation of the epidemiologic studies is
complicated, because bleeding induced by aspirin may enhance the diagnosis and
early treatment of cancer, and at least in theory, the symptoms of cancer could
cause patients to avoid aspirin. Clinical trials designed specifically to
investigate the aspirin hypothesis in humans at high risk of colorectal polyps or
cancer are needed to establish causality, and to define the optimal dose and
drug. Experimental studies should further define the mechanism of tumor
inhibition in animals.
PMID- 9547583
TI - Monohydroxylated fatty acids in mouse epidermis papilloma quantification and
stereochemical characterization.
PMID- 9547584
TI - Negative growth regulation of oncogene-transformed mammary epithelial cells by
tumor inhibitors.
AB - Deregulated expression of Ras and myc oncogenes confers neoplastic transformation
in non-tumorigenic mammary epithelial cells. Down-regulation of perturbed
biomarkers prior to tumorigenesis may provide a means of effective
chemoprevention. In vitro experiments were designed to i) identify specific
molecular, endocrine and cellular biomarkers as quantitative end points for
preneoplastic transformation, and ii) utilize these end points to evaluate
chemopreventive efficacy of selected naturally-occurring and synthetic tumor
inhibitors. Stable Ras and myc transfectants exhibited persistent expression of
oncogene specific mRNA transcripts, altered estradiol biotransformation and
enhanced anchorage-independent growth in vitro prior to tumorigenesis in vivo.
Treatment of the transfectants with omega-3-fatty acid, indole-3-carbinol and
tamoxifen individually suppressed the perturbed molecular, endocrine and cellular
biomarkers in vitro. Thus, suppressed oncogene expression and altered estrogen
metabolism may be important determinants for antiproliferative mechanisms in
mammary tumor inhibition, providing useful end points for chemopreventive
intervention of preneoplasia.
PMID- 9547585
TI - Different expression of prostaglandin-H synthase isozymes and lipoxygenases
during multistage carcinogenesis in mouse skin.
PMID- 9547586
TI - Expression of two cPLA2 isoforms in mouse epidermis in vivo.
PMID- 9547587
TI - Regulation of arachidonic acid release and metabolism by tumor promoters.
PMID- 9547588
TI - Effect of the peroxisome proliferators ciprofibrate and perfluorodecanoic acid on
eicosanoid concentrations in rat liver.
PMID- 9547589
TI - A mitogenic and hormonal signalling network regulate mammalian cell division
commitment time.
AB - A basic property of mammalian cells is to retain the mitogenically induced
"commitment" to undergo DNA replication even in the absence of stimuli. Recent
findings on PGF2 alpha and hormone-induced Swiss 3T3 cell multiplication, reveal
that this crucial cell cycle event can be regulated by several signalling
mechanisms.
PMID- 9547590
TI - Growth inhibitory effects of thromboxane antagonists on breast cancer cell lines:
a preliminary study.
PMID- 9547591
TI - The rise and fall of ceramide and 1,2-diacylglycerol (DAG): modulation by
transforming growth factor-beta 1 (TGF beta 1) and by epidermal growth factor
(EGF).
AB - Transforming growth factor beta 1 (TGF beta 1) increases the phosphorylation of
the epidermal growth factor (EGF) receptor and inhibits the growth of A431 cells,
but the mechanism of TGF beta 1 signaling is unknown. Recent studies from this
and other laboratories suggest a novel sphingomyelin signal transduction pathway
(1-4). Ceramide, which is generated by sphingomyelinase action, can be deacylated
to sphingoid bases, which are potential inhibitors of protein kinase C (PKC).
Ceramide appears to have bioeffector properties. Cell-permeable ceramide analogs
stimulate monocytic differentiation of human leukemia (HL60) cells (1), as well
as the phosphorylation of the EGF receptor at Thr669 in A431 human epidermoid
carcinoma cells (2). Further studies (3,4) demonstrate the existence of a
ceramide-activated protein kinase (CAPK) that may mediate some of these aspects.
The present studies aim to investigate the mechanism of TGF beta 1 signaling and
to explore whether TGF beta 1's pathway involves activation of PKC by 1,2
Diacylglycerol (DAG) and/or stimulation of a CAPK by ceramide. Ceramide and DAG
levels of A431 cells are determined by thin layer chromatography (TLC) after
treatment with either TGF beta 1 or with EGF. 100 pM TGF beta 1 treatment for 1
hr increases the cellular contents of DAG 2-fold. 20 nM EGF treatment for 15 min
decreases it 0.5-fold. Ceramide levels are reduced 2-fold by TGF beta 1 and
almost unaffected by EGF. To evaluate the involvement of other components of
signal transduction, the effects of TGF beta 1 and EGF on PKC activity are
studied. 20 nM EGF decreases membrane PKC activity to 0.5-fold of controls,
whereas 100 pM TGF beta 1 treatment of A431 cells increases this activity 4-fold.
Modulation of PKC activity is paralled by translocation of the enzyme between the
cytosol and the membrane as determined by Western immunoblot analysis. These
studies suggest that TGF beta 1 and EGF may have regulatory effects on both
sphingolipid and phospholipid metabolisms which could transmodulate both the CAPK
and the PKC mediated signal tranduction pathways.
PMID- 9547592
TI - Antioxidant defence mechanisms and PGE secretion by different types of
transformed and tumor cells: in vivo selective advantages.
PMID- 9547593
TI - The relationship between farnesylation and carcinogenesis: the effect of
lovastatin on fibroblast proliferation.
PMID- 9547594
TI - Eicosanoid production and growth regulation in rat intestinal epithelial cells.
PMID- 9547595
TI - Role of arachidonic acid and linoleic acid metabolism in epidermal growth factor
initiated proliferation of Syrian hamster embryo fibroblasts.
PMID- 9547597
TI - Structural requirements for enhancement of EGF-dependent DNA synthesis by
oxygenated metabolites of linoleic acid.
PMID- 9547596
TI - Phenylacetate and phenylbutyrate as novel, nontoxic differentiation inducers.
AB - Phenylacetate and analogs represent a new class of pleiotropic growth regulators
that alter tumor cell biology by affecting gene expression at both the
transcriptional and post transcriptional levels. Based on these findings, NaPA
and NaPB entered clinical trials at the National Cancer Institute. Ongoing phase
I studies with NaPA, involving adults with prostate and brain cancer, have
confirmed that therapeutic levels can be achieved with no significant toxicities,
and provide preliminary evidence for benefit to patients with advanced disease
(Thibault et al., submitted).
PMID- 9547598
TI - Decreased DNA synthesis in SCC-25 cells with ETYA and SC41661.
PMID- 9547600
TI - Induction of 12-lipoxygenase expression by epidermal growth factor is mediated by
protein kinase C in A431 cells.
PMID- 9547601
TI - Prostaglandin F2 alpha (PGF2 alpha) triggers protein kinase C (PKC) and tyrosine
kinase activity in cultured mammalian cells.
AB - Prostaglandin F2 alpha (PGF2 alpha) added to confluent resting Swiss 3T3 cells
triggers tyrosine kinase (PTK) activation characterized by the phosphorylation of
a set of 75, 86, 110 and 140 kD proteins. PGF2 alpha induces this event
independently of PKC activation. However, both PKC and PTK activities appear to
act concertedly to cause mitogenesis. Here we discuss their relevance in the
control of mammalian cell division.
PMID- 9547599
TI - Liver fatty acid binding protein and mitogenesis in transfected hepatoma cells.
PMID- 9547602
TI - Mechanisms of the selective cytotoxic actions of certain essential fatty acids.
AB - Polyunsaturated fatty acids (PUFA) have a selective cytotoxic/cytostatic effect
on a number of tumor cell lines in culture. Although this process may be enhanced
by the addition of iron there is a minimum level of PUFA necessary for
potentiation of cell death. Vitamin E blocks PUFA cytotoxicity when added up to 5
days after fatty acid administration. Levels of thio-barbiturate reactive
material (TBARM) in the medium rise in parallel with cell death. However, they
are not affected by small alterations in temperature or oxygen tension.
Incubating cells with PUFA causes marked alterations in the fatty acid patterns
of both neutral and phospholipid fractions. Membrane fluidity is increased and
the activity of membrane-bound receptors may be influenced directly or through
the actions of eicosanoids derived from the exogenous fatty acid. PUFA may be an
effective way of influencing tumor growth and a safe approach for the management
of human cancer.
PMID- 9547603
TI - Eicosanoids, cancer metastasis, and gene regulation: an overview.
PMID- 9547604
TI - Radiation-induced apoptosis in tumors: effect of radiation modulating agents.
PMID- 9547605
TI - Prostaglandin E2 mediated apoptosis in subsets of malignant B lymphoma cells.
PMID- 9547606
TI - 13-HODE dehydrogenase activity as a modulator of intestinal cell differentiation.
PMID- 9547607
TI - Effect of GM-CSF on leukotriene B4 synthesis in human neutrophils: facilitation
of the priming effect by autologous plasma.
PMID- 9547609
TI - Regulation of 15-lipoxygenase expression by cytokines.
AB - The arachidonate 15-lipoxygenase is induced in peripheral human monocytes by
culturing the cells for 3 days in the presence of interleukin 4 (IL-4) in
concentrations as low as 40 pM. Linoleic acid is oxygenated by IL-4 treated
monocytes to 13(S)-hydroxy-9Z, 11E-octadecadienoic acid [13(S)-HODE] with a
specific activity of about 2 nmoles 13(S)-HODE/10(6) cells min. A screening of
various permanent cell lines expressing the IL-4 receptor indicated that all
monocyte/macrophage lines tested did not exhibit the effect of LOX induction.
However, IL-4 treatment of the lung carcinoma cell line CCC 185 and of the colon
carcinoma cell line HTB 38 induces the 15-LOX as shown by activity assay and
immunohistochemistry. The IL-4 mutant Y124D which has been characterized as
specific IL-4 receptor antagonist in human T-cells does not induce the 15-LOX but
appears to act as competitive inhibitor for the induction. Subcellular
fractionation of IL-4 treated monocytes indicated a cytosolic and a membrane
bound enzyme pool. The intracellular action of the LOX leads to a specific
oxygenation of the membrane phospholipids which is drastically increased after
damage to the cells. The possible biological role of the 15-LOX for monocyte
metabolism is discussed.
PMID- 9547608
TI - Docosahexaenoic and eicosapentaenoic acids inhibit in vitro human endothelial
cell production of interleukin-6.
AB - The interaction between lymphocytes, cytokines, and endothelial cells (EC) is a
key step in the inflammatory process. Interleukin-6 (IL-6) a pleiotropic cytokine
in its effects, seems to be an early indicator of acute systemic inflammation. In
this study, we have examined the effects of polyunsaturated fatty acids (PUFAs)
on the production of IL-6 by human unstimulated EC or EC stimulated with TNF
alpha (100 U/ml); IL-4 (100 U/ml); LPS (1 ug/ml); or allogeneic peripheral blood
lymphocytes (PBL). Twenty-four hour culture supernatants of immunoreactive IL-6
were measured by Sandwich ELISA. We have shown that the production of IL-6 was
potentiated when EC were stimulated with TNF-alpha; IL-4; LPS; or monocyte
depleted PBL in comparison to unstimulated EC. The addition of n-3 PUFAs in
culture medium (100 ug/ml DHA or EPA) significantly reduces the production of IL
6 by unstimulated EC; or stimulated with TNF-alpha; IL-4 pg/ml); LPS or depleted
PBL respectively for DHA and EPA, whereas the n-6 PUFAs (Arachidonic acid), even
used at the highest concentration, was ineffective. This inhibitory effect is
PUFA dose dependent but is more potent with EPA than DHA. Regardless of the mode
of action, since IL-6 is known to be involved in hematopoiesis, in the regulation
of the immune response and in the inflammatory reaction, these results suggest
that n-3 PUFAs may play a role in suppressing inflammation. Further studies are
needed to elucidate the mechanism involved and the choice between the two fatty
acids for clinical and therapeutic purposes.
PMID- 9547610
TI - Modulating effect of omega-3 fatty acids on the proliferative pattern of human
colorectal mucosa.
PMID- 9547611
TI - Agonist-induced lipoxin A4 generation in vitro and in aspirin-sensitive
asthmatics: detection by a novel lipoxin A4-ELISA.
PMID- 9547612
TI - Regulation of inducible prostaglandin G/H synthase by interleukin-1, transforming
growth factors-alpha and -beta, and prostaglandins in bone cells.
PMID- 9547613
TI - Potential role of heat shock transcription factor in the expression of
inflammatory cytokines.
PMID- 9547614
TI - Transcellular pathways and cell adhesion as potential contributors to leukotriene
and lipoxin biosynthesis in acute glomerulonephritis.
PMID- 9547615
TI - Lipoxin metabolism by human promyelocytic leukemia (HL-60) cells.
PMID- 9547616
TI - IL-1 increases the ability of human endothelial cells to transform linoleic acid
into monohydroxy-isomers and their incorporation into cell lipids.
PMID- 9547617
TI - Apoptosis in tumor biology and therapy.
PMID- 9547618
TI - Integrin functions and signal transduction.
PMID- 9547619
TI - Regulation of tumor cell motility by 12(S)-HETE.
PMID- 9547620
TI - Inhibition of mouse B16 melanoma cell motility by sphingosine-1-phosphate.
PMID- 9547621
TI - Effects of leukotrienes B4 (LTB4) and D4 (LTD4) on motility of isolated
normodense human eosinophils and neutrophils.
AB - The effects of exogenous leukotrienes B4 and E4 (LTB4, LTD4) on the under-agarose
motility of isolated normodense human eosinophils and neutrophils were examined
using a novel sampling strategy for quantitation of leukocyte migration distance
and vectorial orientation. Eosinophil chemotaxis to LTD4 was evident at a 10(
10)M threshold. The selective peptide-LT antagonist, SK&F 104353, abolished LTD4
induced eosinophil migration, indicating pharmacological specificity of the
response. Neutrophil chemotaxis was apparent only with a very high (10(-5)M LTD4
concentration. LTB4 was a potent eosinophil and neutrophil chemoattractant over a
10(-9)M to 10(-4)M dose range. Analysis of leukocyte orientations provided
evidence that chemokinetic responses were not being interpreted as indications of
chemotactic behavior. LTB4 and LTD4 significantly altered neutrophil vectorial
orientation. Comparison of migration distance and orientation at the leading edge
and at the periphery of the well seeded with cells suggested that cell
polarization appeared to be the earliest response to chemoattractive LTs. These
results indicate that chemoattractant responses to LTs may be identified by
utilizing the under-agarose technique and computer assisted analysis of cell
orientation.
PMID- 9547622
TI - 12(S)-HETE increases the motility of prostate tumor cells through selective
activation of PKC alpha.
AB - Prostate carcinoma has become the second most fatal cancer in American men. In
rat Dunning prostate adenocarcinoma cells, increased cellular motility has been
associated positively with their increased metastatic potential. However, the
mechanism(s) responsible for regulation of tumor cell motility is poorly
understood. We have reported that a lipoxygenase metabolite of arachidonic acid
12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] augments tumor cell metastatic
potential through activation of protein kinase C (PKC). We report here that 12(S)
HETE increased the motility of AT2.1 cells and this 12(S)-HETE increased motility
was inhibited by PKC inhibitor calphostin C. Western blot analysis revealed that
AT2.1 cells expressed the Ca(2+)-dependent PKC isoform alpha and Ca(2+)
independent PKC isoform delta. Pretreatment of cells with a Ca2+ chelator BAPTA
blocked the 12(S)-HETE increased motility. Further, the motility of AT2.1 cells
was increased in a dose dependent manner by thymelea toxin, a selective PKC alpha
activator. Our data demonstrate that 12(S)-HETE augments the motility of AT2.1
cells via its selective activation of PKC alpha which may serve as a key target
for the development of antimetastatic drugs useful for combating prostate
cancers.
PMID- 9547624
TI - Enhancement of metastatic potential in a murine fibrosarcoma line by exposure to
Corynebacterium parvum-elicited macrophages; effect of eicosanoid biosynthesis
inhibition.
PMID- 9547623
TI - Role of complex gangliosides in the integrin-dependent adhesion of cells in
culture.
PMID- 9547625
TI - A regulatory role of prostaglandin E2-activated adhesion molecules in
myelopoiesis.
PMID- 9547626
TI - Efficacy of Cicaprost on metastasis in advanced tumor disease.
PMID- 9547627
TI - Post-translational regulation of surface integrin expression in tumor cells by
12(S)-HETE.
PMID- 9547628
TI - Eicosanoid 12(S)-HETE upregulates endothelial cell alpha V beta 3 integrin
expression and promotes tumor cell adhesion to vascular endothelium.
PMID- 9547630
TI - Radioprotection by misoprostol (PGE1 methyl analog) in combination with vitamin
E, selenomethionine and WR-3689794.
PMID- 9547629
TI - Dietary fatty acids alter the adhesion properties of lymphocytes to extracellular
matrix proteins.
AB - Dietary fats have been shown by many investigators to affect immune responses in
vitro and in vivo. However, the exact mechanism(s) by which fats or their
metabolic derivatives affect immune function is still unknown. In this report we
have investigated whether short-term in vitro exposure to fatty acids alters the
adhesion of lymphocytes to extracellular matrix proteins. We found remarkably
heterogeneous effects with these agents on lymphocyte adhesion; increases and
decreases in adhesion were observed depending upon the fatty acid, cell type and
extracellular matrix protein used. Alterations in the adhesion potential of
lymphocytes could serve as a mechanism for the reported effects of fatty acids on
immune function since lymphocytes are dependent upon rapid and reversible
adherence events for most of their effector activities.
PMID- 9547631
TI - Behavioral and radioprotective effects of misoprostol in adrenalectomized mice.
PMID- 9547632
TI - Effects of eicosanoid radioprotectors on rat motor performance.
PMID- 9547633
TI - Protection from radiation-induced oral mucositis by a mouth rinse containing the
prostaglandin E1 analog, misoprostol: a placebo controlled double blind clinical
trial.
PMID- 9547634
TI - Interleukin, radiation, and thermoregulation.
PMID- 9547635
TI - Tumor radiosensitization based on the use of inhibitors of the mevalonate pathway
of cholesterol synthesis.
PMID- 9547636
TI - Synergistic protection of irradiated mice by a combination of iloprost and
misoprostol.
PMID- 9547637
TI - Regulation of the biosynthesis of the sulphido-leukotrienes.
PMID- 9547638
TI - The role of lipid peroxidation in growth suppression of human breast carcinoma by
dietary fish oil.
PMID- 9547639
TI - Misoprostol: a potent cytotoxic and oncogenic radioprotector.
PMID- 9547640
TI - Modification of radiation-induced gastrointestinal and hematopoietic injury in
mice by combinations of agents: effects of indomethacin and caffeine.
PMID- 9547641
TI - Anti-inflammatory drug treatment of radiation injuries.
PMID- 9547642
TI - Low dose radiation induces endothelial cell eicosanoid metabolism and
cytoskeletal rearrangement.
PMID- 9547643
TI - Nonlethal gamma radiation displays similar cytoplasmic rearrangements as 12(S)
HETE.
AB - Timar et al. (Int. J. Canc., 52:594-603, 1992) and Onoda et al. (Rad. Res.,
130:281-288, 1992) implicated 12(S)-HETE and nonlethal gamma radiation
respectively, in enhanced expression of the alpha IIb beta 3 integrin receptor in
B16a tumor cells. 12(S)-HETE has been reported to induce rearrangement of
cytoplasmic elements and movement of cytoplasm (Haddad and Taylor, Proc. Amer.
Cancer Res., 34:51, 1993); Timar et al., Cell Motil. Cytoskel., 26:49-65, 1993).
Here, we report similar results in B16a tumor cells by post 90 cGy gamma
radiation. Control cells were circular without cytoplasmic processes with the
majority of their organelles and elements in perinuclear regions both surrounded
by a ring of actin microfilaments. The cell's extensive leading edge was
organelle free with the exception of occasional endoplasmic reticular cisternae
parallel to one or two microtubules, and short bundles of actin microfilaments
perpendicular to the plasma membrane. As early as 5 sec, but better defined by 60
90 sec, one end of elongated microfilaments bundles became associated with the
plasma membrane while the other end of the bundles became associated with
perinuclear mass protrusions. By 5 min, prominent by 15 min, protrusions, now
separated from the leading edge by mixture of bundle and ring microfilaments,
reached the plasma membrane to form cellular processes. By 30 min, some
cytoplasmic masses showed signs of retraction along with the disappearance of
their associated mixed microfilaments. As well as numerous vesicles of unknown
origin, primarily associated with microtubules perpendicular to the plasma
membrane, mitochondria and endoplasmic reticular cisternae were found in the
cytoplasmic masses.
PMID- 9547645
TI - Impairment in the fatty acid composition of keloids.
PMID- 9547644
TI - Dietary arachidonic acid increases eicosanoid production in the presence of equal
amounts of dietary eicosapentaenoic acid.
AB - Previously, we demonstrated that dietary n-3 PUFA (1.5%, w/w) effectively
inhibited the production of eicosanoids derived from tissue arachidonic acid (AA)
(Whelan et al., 1991). More recently, we also reported that dietary AA (1.0%,
w/w) significantly augmented platelet and macrophage eicosanoid production in
vitro (Whelan et al., 1993). This present study was designed to investigate the
antithetic relationship of dietary AA and EPA on eicosanoid production in vivo.
Forty-nine CD-1 male mice were randomly divided into four dietary groups.
Identical diets were supplemented with ethyl esters (1.5%, w/w) of the following
fatty acids: oleic acid (OA), AA, EPA or AA + EPA (A + E). After four weeks on
diet, peritoneal cells were stimulated in vivo with opsonized zymosan and
analyzed for eicosanoid production (PGE2, 6-keto-PGF1a, TXB2, LTE4, LTB4, LTE5
and LTB5). The pooled eicosanoid production in the AA group was 41% and 300%
higher compared to the OA (control) and EPA groups, respectively. Pooled
eicosanoid production in the EPA group was 47% that of the OA group. When
equivalent amounts of AA and EPA (AA + EPA) were included in the diet, the pooled
eicosanoid production was 29% and 274% higher compared to the OA and EPA groups,
respectively. These data demonstrate that dietary AA (1) enhances eicosanoid
production in vivo and (2) abrogates virtually all of the effects observed with
dietary EPA when both are included in the diet. The clinical implications of
dietary AA as modulated by increased eicosanoid production could be significant,
particularly when n-3 PUFA are used to reduce eicosanoid-mediated events.
PMID- 9547646
TI - Linoleic acid levels in cutaneous tumors with different growth patterns as an
additional sensitive diagnostic feature.
PMID- 9547647
TI - The importance of linoleic acid in the total fatty acid compositions of benign
and malignant neuroglial tumors.
PMID- 9547648
TI - Dietary fat and energy modulation of biochemical events in tumor promotion.
PMID- 9547649
TI - Chemoprevention of colon cancer by dietary administration of naturally-occurring
and related synthetic agents.
PMID- 9547650
TI - Diradylglycerol formation is altered by n-3 highly unsaturated fatty acids, with
differences between eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids.
PMID- 9547651
TI - Arachidonic acid metabolites in saliva of patients with squamous cell carcinoma
of the head and neck.
PMID- 9547652
TI - Preparation of two dosage forms containing antitumor prostaglandin and their
antitumor effect in vitro and in vivo: Lipiodol solution for i.a. administration
and lipid microspheres for i.p. or i.v. administration.
PMID- 9547653
TI - Urinary excretion of prostanoids in children with chronic pyelonephritis.
PMID- 9547654
TI - Interaction of phospholipase C-gamma with activated growth factor receptor
tyrosine kinases.
PMID- 9547655
TI - Prostanoid and anti-thrombin III levels in premature infants.
PMID- 9547656
TI - Molecular biology of prostanoid biosynthetic enzymes and receptors.
PMID- 9547657
TI - Tumor infiltrating lymphocytes in squamous cell carcinoma of the head and neck:
mechanisms of enhancement using prostaglandin synthetase inhibitors.
AB - Indomethacin has been shown clinically to inhibit growth of SCCHN (Panje, 1981).
This inhibition appears to be due to augmentation of cellular immunity. The
inhibitory effect of indomethacin may act by limiting tumor associated
prostaglandin E2 production, thereby allowing return of costimulatory cytokines
by antigen presenting cells. This would have the net result of relief from host
unresponsiveness and promotion of B-cell and CTL differentiation, allowing the
individual to mount an effective response. The enhancement of tumor infiltrating
lymphocytes in SCCHN seen with indomethacin administration could presumably be
further augmented when given in combination with cytokine therapy. Future
investigation may allow the biochemical staging of an individuals' tumor to
determine the optimal combination of cytokine therapy and prostaglandin
inhibition through selective use of NSAID's. The effect of NSAID manipulation of
prostaglandin and leukotriene metabolism on prevention of metastatic disease in
SCCHN has yet to be studied. Given that a preselected, potentially responsive
subset of immunocytes exists within the tumor tissue and lymph nodes, the
development of the LAK phenomenon in TIL's and tumor draining lymph nodes from
surgical specimens is a viable and exceedingly interesting area for future
investigations in autologous LAK immunotherapy. The potential exists to harvest a
preselected population of tumor infiltrating (Boscia, 1988) or tumor draining
immunocytes (McKinnon, 1990). These can then potentially be returned to a state
of antigen responsiveness with a combination of cytokine exposure (e.g. rIL-2)
and systemic cytokine therapy. With subsequent inhibition of tumor associated
prostaglandin synthesis by the systemic administration of prostaglandin synthesis
inhibitors, it may be possible to successfully alter the host response to tumor.
PMID- 9547658
TI - An empirical analysis of eating disorder, not otherwise specified: preliminary
support for a distinct subgroup.
AB - OBJECTIVE: In recent years, there has been debate concerning whether distinct
subgroups exist within the eating disorder, not otherwise specified (EDNOS)
diagnostic category. One subgroup that has been suggested is binge-eating
disorder (BED). While BED has received some research attention, relatively little
is known about other possible subgroups within the EDNOS category. The purpose of
the present study is to empirically investigate whether distinct subgroups exist
within the diagnostic category of EDNOS. METHOD: Participants were 53 EDNOS
patients who presented to psychotherapy clinics for treatment of an eating
disorder. Information gathered from a clinical assessment, which included a
clinical interview and self-report questionnaires, was used in the analyses of
the study. RESULTS: Using cluster analytic procedures, two subgroups of patients
diagnosed with EDNOS were identified. The two subgroups differed from each other
in terms of weight, binging, and body image variables. Specifically, the second
subgroup (of 11 patients) appeared to be a distinct subgroup of overweight binge
eating patients, while the first subgroup appeared to be a heterogenous group of
EDNOS patients. The overweight binge-eating subgroup was significantly higher in
current weight, in reported highest adult weight, in reported higher lowest adult
weight, and had more binges per week than the heterogenous EDNOS subgroup.
Interestingly, the two subgroups did not differ in terms of self-reported purging
and/or compensatory behaviors (e.g., vomiting and laxative use). DISCUSSION: The
results of the present study provide preliminary support for a distinct subgroup
within the EDNOS diagnostic category. This subgroup resembles BED, with the
exception of the presence of purging behaviors. The findings of the present study
suggest the need to further investigate the exclusionary criteria of
purging/compensatory behaviors for the BED diagnosis.
PMID- 9547659
TI - Relations of restraint and negative affect to bulimic pathology: a longitudinal
test of three competing models.
AB - OBJECTIVE: Although theorists have proposed that restraint and negative affect
cause bulimia nervosa, it is possible that bulimic pathology promotes restraint
and negative affect, or that bulimic symptoms are reciprocally related to these
two factors. The present study tested these competing models. METHOD:
Longitudinal data from a community sample of adolescent females (N = 218) was
used to test these alternative models. RESULTS: Prospective correlations
suggested that bulimic pathology was reciprocally related to both restraint and
negative affect. However, in more stringent tests controlling for the temporal
stability of these factors, restraint was not related to subsequent bulimic
symptoms, but bulimic pathology predicted future restraint. Negative affect and
bulimic symptoms were not related over time when the stability of these factors
was controlled, but they did show contemporaneous reciprocal relations.
DISCUSSION: Results provide some support for the negative affect model of
bulimia, but raise questions about the restraint model.
PMID- 9547660
TI - A comparison of purging and nonpurging eating-disordered outpatients: mediating
effects of weight and general psychopathology.
AB - OBJECTIVES: The present study compared purging and nonpurging eating-disordered
outpatients on key behavioral and psychological features of their disorder. It
also investigated the possible mediating effects of current level of depression,
anxiety or general psychopathology, and current weight on differences between
purgers and nonpurgers. METHOD: Seventy-seven patients from an outpatient eating
disorder clinic who purged were compared to 48 clinic patients who did not purge
on measures of eating behavior disturbances and specific psychopathology while
controlling for weight, level of depression, anxiety, and general distress.
RESULTS: Purgers reported significantly more eating behavior disturbance and
higher scores on measures of specific psychopathology than the nonpurgers. These
differences were unrelated to current weight, level of anxiety, or general
distress. However, severity of depression did moderate some of the difference
between the groups. CONCLUSION: These data provide further support for the
proposition that purging is a distinctive clinical marker in all types of eating
disordered patients.
PMID- 9547661
TI - Motivations for running and eating attitudes in obligatory versus nonobligatory
runners.
AB - OBJECTIVE: This study examined the association between motivations to run and
eating disturbances in a sample of obligatory and nonobligatory runners. METHOD:
240 males and 84 females were evaluated for running habits, motivations for
running, and eating and weight concerns. 26.2% of the men and 25% of the women
were classified as obligatory runners. RESULTS: Obligatory runners were more
motivated to run by negative factors such as guilt for stopping, scored
significantly higher on the Eating Attitudes Test (EAT), and had lower weights.
These effects were strongest in women. DISCUSSION: The results suggest that
female obligatory runners may be at increased risk for eating disorders.
PMID- 9547662
TI - The relationship between alexithymia, depression, and axis II psychopathology in
eating disorder inpatients.
AB - OBJECTIVE: The major purpose of this study was to examine alexithymia in
relationship to depression and Axis II psychopathology in eating disorder
patients. METHOD: Fifty-three female inpatients representing three DSM-IV eating
disorder diagnostic groups and 14 control subjects completed the Toronto
Alexithymia Scale (TAS), the Eating Disorder Inventory-2, and the Beck Depression
Inventory within the first week of their hospital admission and shortly before
discharge. Structured Clinical Interviews for DSM-III-R (SCID) I and II were also
conducted. Multiple regression analyses were used to determine the contribution
of mood, diagnostic, and personality variables in predicting the alexithymia
score. RESULTS AND DISCUSSION: After controlling for depression, only the TAS
factor, "difficulty expressing feelings," remained significantly different
between groups, with the anorexia nervosa-restrictors (AN-R) having significantly
higher scores than controls and bulimia nervosa patients. This factor appears to
be a relatively stable personality characteristic in AN-R. The level of
depression and the presence of avoidant personality disorder were the most
predictable variables for the alexithymia total score.
PMID- 9547663
TI - Body weight preoccupation in middle-age and ageing women: a general population
survey.
AB - OBJECTIVE AND METHODS: The desired weights and dieting behavior of a sample of
1,053 women aged 30-74 years in the general population of Geneva, Switzerland,
were explored by means of a questionnaire. Multivariate analyses of variance were
performed. RESULTS: Twenty-five percent of the women were satisfied with their
weight, whereas 71% wanted to be thinner, although 73% of them were at normal
weight. Among women older than 65 years, 62% wanted to lose weight, 65% of them
being at normal weight. For women wanting to lose weight, mean desired weight
loss amounted to 9% of their current weight. Weight dissatisfaction increased
with higher education (p < .001), and with increasing current weight (p < .001).
Within the last 5 years, 42% of the women had dieted for weight control,
including 67% at normal weight. Thirty-one percent of the women older than 65
years had also dieted, 62% of them being at normal weight. DISCUSSION: A majority
of middle-age and ageing women in this general population sample expressed
dissatisfaction about their weight. Many attempted dieting, even when they were
at normal weight. Considering the vulnerability of the elderly to nutritional
deficiencies, dieting to lose weight in normal weight ageing women should be
discouraged or closely monitored.
PMID- 9547664
TI - The slender ideal and eating disorders: an interdisciplinary "telescope" model.
AB - OBJECTIVE: This paper interprets eating disorders (including anorexia and
bulimia) as one (nonfunctional) manifestation, in modern environments, of evolved
psychological mechanisms which modulate the standard of feminine bodily
attractiveness as a response to economic conditions. METHOD: Published evidence
from anthropology, sociology, and psychology was used to evaluate predictions
that (1) where economic independence is possible, women favor a slender standard
and (2) where women lack economic power, marriage tends to be favored and the
standard becomes more curvaceous. These patterns were tested by correlating U.S.
economic data with changing standards of bodily curvaceousness in Vogue and
Playboy. Psychological and biological mechanisms by which the slender standard
produces anorexia and bulimia were examined. RESULTS: Published evidence and the
empirical data suggest that the standard of bodily curvaceousness is determined
by the economics of reproduction. DISCUSSION: These ideas permit integration of
the research on eating disorders in several disciplines and suggest many avenues
for future enquiry.
PMID- 9547665
TI - The role of family status and ethnic group on body image and eating behavior.
AB - OBJECTIVE: To examine the role of ethnic group and family status on body
dissatisfaction and eating behavior. METHOD: One hundred women (Asian mothers and
daughters, n = 50; white mothers and daughters, n = 50) completed a questionnaire
about their perceived ethnic identity (acculturation), body image, and eating
behavior. RESULTS: The results showed no matching between mothers and daughters
and no effect of acculturation on body image and eating behavior. However,
mothers reported greater body dissatisfaction and white subjects reported higher
levels of restrained eating. In addition, the results showed a significant Ethnic
Group x Family Status interaction for both body image and eating behavior
irrespective of body mass index (BMI). Accordingly, white daughters were found to
be the most dissatisfied with their bodies and most concerned with the calorie
content of their food, followed by the Asian mothers. White mothers were found to
be the most satisfied with their body and Asian daughters were the least
concerned with calories. DISCUSSION: The results are discussed in terms of the
changing nature of media images in both Asian and white cultures and the impact
of the transition between these two cultures.
PMID- 9547666
TI - An ethnic comparison of eating attitudes and associated psychological problems in
young British women.
AB - OBJECTIVE: The study aimed to investigate possible differences in eating
attitudes/problems and associated psychological problems in young women of
differing ethnic origin. METHOD: In a city with a relatively high Asian
population (with a background in the Indian subcontinent), 235 young women aged
18-27 registered with a general practice responded to a postal questionnaire. The
questionnaire examined eating and weight problems (including the 26-item Eating
Attitudes Test), self-esteem (measured by the Rosenberg Self-Esteem Scale), and
general psychological well-being (measured by The Hospital Anxiety and Depression
Scale). We also included three short vignettes designed to assess illness
perception and health seeking-behavior. RESULTS: We found relatively little
difference in eating attitudes and problems according to ethnicity, although self
induced vomiting for weight control was more common among Caucasian women.
Neither was there any difference in self-esteem, anxiety, depression, and illness
perception. DISCUSSION: The results suggest that one cannot generalize about
eating problems across the Asian population and a more sophisticated approach to
the examination of sociocultural factors is recommended.
PMID- 9547667
TI - Well-being and morbid obesity in women: a controlled therapy evaluation.
AB - OBJECTIVE: Morbidly obese individuals are unlikely to reach and maintain
normative weights. Thus, interventions aimed at alleviating corollary problems,
independent of attempts at weight loss, are appropriate. A cognitive group
treatment program (CT) was developed which incorporated a nondieting approach,
regular exercise, and use of alternative coping skills. Weight loss per se was
not a focus of the intervention. The purpose of the current work was to evaluate
this program in a controlled, comparative treatment outcome study. METHOD: Sixty
two obese women with a history of treatment failures were randomly assigned to
the CT program, a behavior therapy weight loss program (BT), or a wait-list
control group. RESULTS: For CT participants, depression, anxiety, and eating
related psychopathology decreased significantly over the course of treatment
while perceptions of self-control increased; BT and control subjects showed no
significant changes in these variables. Women in both active treatment groups
lost significant amounts of weight, while members of the control group showed a
nonsignificant increase in weight. At 6-month follow-up, treatment benefits were
maintained. DISCUSSION: Findings suggest that interventions not directly aimed at
weight loss can enhance psychological well-being and thus may be appropriate for
some obese women.
PMID- 9547668
TI - Does the Composite International Diagnostic Interview underdiagnose the eating
disorders?
AB - OBJECTIVE: A study was undertaken to assess the procedural validity of the
Composite International Diagnostic Interview (CIDI) for the diagnosis of eating
disorders. METHOD: The CIDI was administered to 44 patients consecutively
admitted to an eating disorders unit. CIDI-generated diagnoses were compared with
clinical diagnoses documented in patient files. Discrepancies between diagnoses
were examined in detail. RESULTS: A significant level of disagreement was
apparent, particularly for anorexia nervosa patients. A large number of patients
with symptoms requiring inpatient treatment did not reach criteria using CIDI's
diagnostic algorithm. CONCLUSION: Considerable difficulties remain in the use of
standardized assessments, such as the CIDI, to diagnose eating disorders. While
presenting features of the illness, for example, ego syntonic nature of the
illness, secrecy, and denial, may be part of the reason, the questions used by
the CIDI appear to be in need of some refinement.
PMID- 9547669
TI - Multiple resistance modulators combined with carboplatin for resistant
malignancies: a pilot study.
AB - BACKGROUND: Chemotherapy resistance is probably multifactorial; hence, we
assessed the feasibility of adding to carboplatin 6 concurrent resistance
modulators in 53 patients with resistant cancers. METHODS: Pentoxifylline and
dipyridamole were added to carboplatin 400 mg/m2 in cohort 1, and metronidazole
was also given in cohort 2. Mannitol and saline were administered in each cohort
with the theoretical objective of improving carboplatin delivery to tumors by
reducing blood viscosity. Because of excessive toxicity in cohort 2, cohort 3
received the same modulators as in cohort 2 but with a reduced dose of
carboplatin (200 mg/m2). Subsequent patients had the following drugs added to
those in the previous cohort: novobiocin (cohort 4), tamoxifen (cohort 5),
ketoconazole (cohort 6). Cohort 7 patients received the 6 cohort 6 modulators
along with carboplatin 300 mg/m2. RESULTS: Thrombocytopenia was excessive in
early cohorts with a carboplatin dose of 400 mg/m2, but was minimal at lower
doses. Other toxicity was generally tolerable and reversible, particularly at
carboplatin doses < or = 300 mg/m2, although gastrointestinal and neurological
toxicity tended to worsen as additional modulators were added. No major responses
(but 4 minor responses) were seen in this patient population with heavily
pretreated or primarily resistant cancers. CONCLUSIONS: Acceptable doses for
phase II studies are carboplatin 300 mg/m2, 20% mannitol 250 ml plus normal
saline 500 ml over 1 hr prior to carboplatin, pentoxifylline 700 mg/m2/day p.o.
from 3 days before carboplatin to cessation of therapy, dipyridamole 100 mg/m2
p.o. q6h x 6 days starting 24 hr before carboplatin, metronidazole (750 mg/m2
p.o. 12 hr and immediately before, and 24 hr after carboplatin; 250 mg/m2
suppository p.r. 12 hr and immediately before, and 6 and 24 hr after carboplatin;
and 500 mg/m2 i.v. right after carboplatin), novobiocin 600 mg/m2 p.o. q12h x 6
days starting 24 hr before carboplatin, and tamoxifen 100 mg/m2/day plus
ketoconazole 700 mg/m2/day x 3 days starting the day before carboplatin, with
oral dexamethasone and ondansetron as antimetics.
PMID- 9547671
TI - An in vitro assessment of the antineoplastic potential of 2H-1,3-oxazine-2,6(3H)
dione (3-oxauracil), a novel pyrimidine.
AB - The pyrimidine (uracil) analogue 3-oxauracil (OU) previously had been shown to
completely inhibit the growth of E. coli B and decrease by 96% the replication of
herpes simplex virus type 2 when present in the culture fluid at a concentration
of 10(2) microM. Limited in vivo studies in mice demonstrated antiviral effects
without significant toxicity when given i.p. daily for two weeks at a
concentration of 3.23 mg/kg. However, the antineoplastic properties of OU were
unknown. We assessed the ability of OU to inhibit the proliferation of various
human tumor cell lines (3 pancreatic, 1 colon, 1 neuroendocrine, and 1 lung) in
an in vitro radiometric (Bactec) system. In the pancreatic lines (RWP-2, MiaPaCa
2, and PANC-1), the colon line (HT-29), the neuroendocrine line (COLO 320DM), and
the lung cancer cell line (SK-MES-1), OU at a concentration of 10(3) microM,
produced a dramatic decrease in percent cell survival. When compared with
cytotoxic drugs of choice for these tumor cells (gemcitabine, 5-fluorouracil, and
adriamycin, respectively) a significantly higher concentration of OU was required
usually to achieve comparable results with two exceptions. These were the HT-29
and the COLO 320DM cell lines. These results indicate OU has significant (p <
0.05) cytotoxic activity against pancreatic, colon, neuroendocrine, and nonsmall
cell lung cancer lines, when compared to untreated control cultures. Additional
in vivo testing of this potential antineoplastic agent is warranted.
PMID- 9547670
TI - IL-4R expression in AIDS-KS cells and response to rhIL-4 and IL-4 toxin (DAB389
IL-4).
AB - Interleukin-4 (IL-4) is a pleiotropic cytokine affecting growth and
differentiation of various cell types as well as regulating other cytokines. To
study the effect of IL-4 on AIDS-related Kaposi's sarcoma (AIDS-KS) cells, we
first examined the tumor cells for IL-4 receptor (IL-4R) expression. KS cells
express a single 4 kB IL-4R-specific mRNA and 1828 +/- 408 high affinity IL-4
binding sites per cell with a dissociation constant (Kd) of 154 +/- 37 pM.
Addition of recombinant human IL-4 (rIL-4) minimally inhibited AIDS-KS cell
growth and expression of IL-6. We then studied the effects of a chimeric fusion
toxin DAB389-IL-4 which exerts cellular toxicity only on cells expressing IL-4R.
DAB389-IL-4 inhibited protein synthesis in AIDS-KS cells at low concentrations
(IC50 of 5 x 10(-11) M). This effect was abrogated by neutralizing antibody to IL
4 (25D2). We conclude that KS cells express a functional IL-4R and this receptor
could serve as a target for novel therapy with agents such as DAB389-IL-4.
PMID- 9547672
TI - Preclinical toxicity of a new oral anticancer drug, CI-994 (acetyldinaline), in
rats and dogs.
AB - CI-994 (acetyldinaline) is an orally active anticancer drug currently in Phase 1
clinical trials. To assess its preclinical toxicity, CI-994 was administered
orally as suspensions to Wistar rats (10/sex/dose) and in capsules to beagle dogs
(3/sex/dose) once daily for two weeks. Doses were 1.5, 5, and 15 mg/kg for rats
(9, 30, and 90 mg/m2, respectively), and 0.5, 2, and 5 mg/kg for dogs (10, 40,
and 100 mg/m2, respectively). Systemic exposure was dose-proportional based on
toxicokinetic analysis in dogs. Severe clinical signs and mortality occurred at
the highest dose in both species beginning on Day 10. Neutropenia,
lymphocytopenia, thrombocytopenia, lymphoid depletion, bone marrow
hypocellularity, and testicular degeneration were observed in both species,
primarily at the mid- and high-doses. Despite continued treatment, neutrophil
counts in dogs returned to control levels in Week 2. Other microscopic findings
in rats included splenic hematopoietic depletion at all doses and epithelial cell
necrosis in various tissues at 15 mg/kg. Additional bone marrow changes in dogs
involved myeloid and megakaryocyte hyperplasia at 2 mg/kg and abnormal myeloid
and megakaryocyte maturation at 2 and 5 mg/kg. Except for the testicular effects
in both species, all changes were reversible within a 4-week (rat) or 9-week
(dog) recovery period. The results of these studies show that target organ
effects of CI-994 principally involve tissues with rapidly dividing cell
populations and that bone marrow suppression is the dose-limiting toxicity. CI
994 also seems to interfere with the release and/or maturation of cells in the
bone marrow.
PMID- 9547673
TI - Potent induction of human colon cancer cell uptake of chemotherapeutic drugs by N
myristoylated protein kinase C-alpha (PKC-alpha) pseudosubstrate peptides through
a P-glycoprotein-independent mechanism.
AB - Phorbol ester protein kinase C (PKC) activators and PKC isozyme over-expression
have been shown to significantly reduce intracellular accumulation of
chemotherapeutic drugs, in association with the induction of multidrug resistance
(MDR) in drug-sensitive cancer cells and enhancement of drug resistance in MDR
cancer cells. These observations constitute solid evidence that PKC plays a
significant role in the MDR phenotype of cancer cells. PKC-catalyzed
phosphorylation of the drug-efflux pump P-glycoprotein was recently ruled out as
a contributing factor in MDR. At present, the sole drug transport-related event
that has been identified as a component of the role of PKC in MDR is PKC-induced
expression of the P-glycoprotein-encoding gene mdr1. The objective of this study
was to test the hypothesis that PKC can modulate the uptake of chemotherapeutic
drugs in cancer cells independently of P-glycoprotein. We analyzed the effects of
selective PKC activators/inhibitors on the uptake of radiolabelled cytotoxic
drugs by cultured human colon cancer cells that lacked P-glycoprotein activity
and did not express the drug efflux pump at the level of message (mdr1) or
protein. We found that the selective PKC activator 12-O-tetradecanoylphorbol-13
acetate (TPA) significantly reduced uptake of [14C] Adriamycin and [3H]
vincristine in human colon cancer cells devoid of P-glycoprotein activity, and
that PKC-inhibitory N-myristoylated PKC-alpha pseudosubstrate synthetic peptides
potently and selectively induced uptake of the cytotoxic drugs in the phorbol
ester-treated and non-treated colon cancer cells. TPA treatment of the cells did
not induce expression of either P-glycoprotein or its message mdr1. In contrast
with [14C]Adriamycin and [3H] vincristine uptake, [3H] 5-fluorouracil uptake by
the cells was unaffected by TPA and reduced by the PKC-inhibitory peptides. These
results indicate that PKC activation can significantly reduce the uptake of
multiple cytotoxic drugs by cancer cells independently of P-glycoprotein, and
that N-myristoylated PKC-alpha pseudosubstrate peptides potently and selectively
induce uptake of multiple cytotoxic drugs in cultured human colon cancer cells by
a novel mechanism that does not involve P-glycoprotein and may involve PKC
isozyme inhibition. Thus, N-myristoylated PKC-alpha pseudosubstrate peptides may
offer a basis for the development of agents that reverse intrinsic drug
resistance in human colon cancer.
PMID- 9547674
TI - An Eastern Cooperative Oncology Group phase I trial of all-trans-retinoic acid
and interferon-alpha: E2Y92.
AB - The Eastern Cooperative Oncology Group conducted a Phase I trial to determine the
maximally tolerated doses of combination therapy with alpha interferon (IFN
alpha) and all-trans-retinoic acid (tRA). Fifty patients with incurable
malignancies received IFN-alpha administered subcutaneously three times weekly,
and tRA administered by mouth at bedtime. Doses were escalated between patient
groups, starting at tRA dose level of 45 mg/m2 and 3 million units of IFN-alpha.
Major, dose-limiting toxicities were attributable to either the tRA (rash,
chelitis) or IFN (constitutional symptoms), and were observed only at tRA dose
levels of 224 mg/m2 and 291 mg/m2, or 6 million units of IFN-alpha. The maximally
tolerated dose level of 172.5 mg/m2 of tRA and 3 million units of IFN-alpha was
well-tolerated, with no grade 3 or 4 toxicities attributable to therapy. One
patient at the third dose level (75 mg/m2 of tRA and 3 million units of IFN
alpha) developed acute hepatic and renal failure and a metabolic encephalopathy
of unclear etiology. We conclude that tRA and IFN-alpha may be safely
administered together at the maximally tolerated dose of tRA as a single agent
without unexpected side effects. The recommended doses of IFN-alpha and tRA for
Phase II trials are 3 million units of IFN-alpha and 172.5 mg/m2 of tRA.
PMID- 9547675
TI - Phase I study of high dose etoposide phosphatase with filgrastim (G-CSF) in the
treatment of advanced refractory malignancies.
AB - PURPOSE: To define the maximum tolerated dose of etoposide phosphate when used
with G-CSF in the treatment of patients with refractory malignancies. PATIENTS
AND METHODS: Eleven patients with advanced cancer refractory to standard therapy
were treated with etoposide phosphate given over 1-2 hours on three consecutive
days. The first cohort of patients received a total dose of 1596 mg/m2
(equivalent to etoposide 1400 mg/m2); doses were escalated in subsequent patient
cohorts. G-CSF 5 micrograms/kg was administered subcutaneously from day 4 until
the total leukocyte count rose to > 10,000/microL. Two courses were given at 28
day intervals. RESULTS: Toxicity produced by high dose etoposide phosphate
included myelosuppression and mucositis. Three of five patients treated at the
2280 mg/m2 dose level (equivalent to etoposide 2000 mg/m2) had dose limiting
toxicities (grade 4 leukopenia for 7 days, 2 patients; grade 4 mucositis +
leukopenia, 1 patient). In addition, median days with severe thrombocytopenia (<
50,000/microL) rose to six days at this dose. Other toxicity was uncommon.
CONCLUSIONS: In pretreated patients, the maximum tolerated dose of etoposide
phosphate with G-CSF is 1938 mg/m2 (equivalent to etoposide 1700 mg/m2). Dose
limiting toxicities were myelosuppression and mucositis, as with high dose
etoposide. Etoposide phosphate can be substituted for etoposide in high dose
regimens; due to its greater solubility, administration can be more rapid,
requires less fluid volume, and is not associated with acidosis.
PMID- 9547676
TI - A phase I trial of weekly gemcitabine administered as a prolonged infusion in
patients with pancreatic cancer and other solid tumors.
AB - PURPOSE: Pharmacological studies of gemcitabine (2',2'-difluorodeoxycytidine)
have shown that increased levels of the active triphosphate metabolite are
achieved by prolonging infusion time while holding the dose rate constant. The
primary aim of this study was to determine the maximum tolerated dose (MTD) of
gemcitabine administered as a fixed rate infusion (10 mg/m2/min) on a weekly
schedule in patients with untreated non-hematologic malignancies. PATIENTS AND
METHODS: Twenty-seven patients (21 pancreatic adenocarcinoma, 3 hepatoma, 1
neuroendocrine tumor, and 2 adenocarcinoma of unknown primary) were enrolled in
this open-label, non-randomized study. Three different entry dose levels (1200
mg/m2, 1500 mg/m2 and 1800 mg/m2) were evaluated for gemcitabine administered on
days 1, 8, and 15 of a 28-day cycle. RESULTS: The MTD was defined as 1500 mg/m2
with granulocytopenia and thrombocytopenia being dose-limiting. There were no non
hematological dose limiting toxicities. The maximum WHO grade 3 or 4 toxicities
for hemoglobin, leukocytes, neutrophils, and platelets for all doses of
gemcitabine administered were 11.5%, 30.8%, 57.7%, and 26.9%, respectively. Non
hematologic toxicities included nausea, vomiting and fever. Four patients were
withdrawn from the study for non-hematological toxicities: pneumonitis, ascites,
disabling fatigue, and an acute myocardial infarction. Two of these events were
severe (pneumonitis and myocardial infarction) but these may not be related to
drug administration. CONCLUSION: Gemcitabine administered at a rate of 10
mg/m2/min was tolerated up to 1500 mg/m2 in patients with previously untreated
non-hematologic malignancies. Myelosuppression seen in this study is more severe
than anticipated based on previous reports of bolus administration of similar
doses of gemcitabine. This supports earlier studies suggesting that prolonged
duration of infusion increases the intracellular accumulation of active
metabolites of gemcitabine.
PMID- 9547677
TI - Long-term response to crisnatol mesylate in patients with glioma.
AB - A total of 26 patients (6 with anaplastic astrocytoma; 20 with glioblastoma) were
treated with crisnatol mesylate. All patients had residual or progressive disease
following surgery and standard radiotherapy; nine patients had prior
chemotherapy. Crisnatol was administered as a 72-hour infusion every 21 days at a
starting dose of 2250 mg/m2. Two patients who had not received prior chemotherapy
achieved a complete response and remain in continuous complete remission over
seven and six years, respectively, post-diagnosis. Two other patients remained
stable on crisnatol for 10 months before disease progression. One patient with
mixed oligodendroglioma/glioblastoma progressed after 12 months on crisnatol. He
survives at 7 years post-diagnosis, with Karnofsky Performance Status of 60
following other therapies. One patient with anaplastic astrocytoma stopped
treatment by request after 10 months and remains stable 64 months post diagnosis.
Seventeen evaluable patients, including nine patients with prior chemotherapy,
progressed after 2-9 courses of therapy. Median survival is 9.25 months, with a
one year survival rate of 30% and 2 years survival rate of 17%. Neurotoxicity was
acute and dose-limiting. Side effects were tolerable and limited to duration of
infusion. Two complete, long-lasting responses to crisnatol mesylate in patients
with progressive malignant glioma are encouraging results and warrant further
investigation.
PMID- 9547678
TI - A phase II study of 13-cis-retinoic acid in patients with advanced renal cell
carcinoma.
AB - The aim of this study was to determine the antitumor activity of 13-cis-retinoic
acid as a single agent in patients with advanced renal cell carcinoma. Eligible
patients had advanced renal cell carcinoma with bi-dimensionally measurable
disease, a Karnofsky performance status of at least 70, life expectancy of
greater than three months, no evidence of brain metastases, and treatment with no
more than one chemotherapy regimen. Patients were treated with one mg/kg/day of
13-cis-retinoic acid orally. Twenty-six patients were enrolled in this study and
25 were evaluable for response and toxicity. Of the twenty-five evaluable
patients, no major responses were achieved. Toxicity was mild, with no patient
requiring a dose reduction. At the dose administered in this trial, 13-cis
retinoic acid is inactive as a single agent in renal cell carcinoma.
PMID- 9547679
TI - Phase II evaluation of topotecan in patients with advanced colorectal cancer. A
Southwest Oncology Group trial (SWOG 9241).
AB - The topoisomerase-1 inhibitor, topotecan, was tested in 48 eligible patients with
advanced colorectal cancer. The patients had no prior chemotherapy and a
Southwest Oncology Group performance status of 0-2. Topotecan was administered
intravenously at 1.5 mg/m2/day for five days and repeated every 21 days. The
major toxicity was hematologic with 19 out of 48 (40%) patients having grade IV
granulocytopenia and 4 out of 48 (8%) patients demonstrating grade IV
thrombocytopenia. Two patients (4%) demonstrated partial response. Thirty
patients have died and the Kaplan-Meier estimate of median survival is 9 months
(95% confidence interval; 7-16 months). Topotecan in this dose and schedule does
not appear active in patients with advanced colorectal cancer.
PMID- 9547680
TI - Phase II study of flutamide as second line chemotherapy in patients with advanced
pancreatic cancer.
AB - Androgen receptors are present in both pancreatic cancer tissue and cell lines.
Flutamide is a potent antiandrogen widely used in clinical practice for patients
with metastatic prostate cancer. This Phase II trial was undertaken to evaluate
the impact of flutamide in patients with advanced pancreatic adenocarcinoma who
had developed progressive disease following therapy with one 5-FU-based regimen.
Fourteen patients were treated with flutamide, 250 mg orally three times per day.
Therapy was generally well tolerated. No patients achieved objective tumor
response. No patient had improvement in tumor-related symptoms as measured by
improvement in pain intensity, analgesic requirement, performance status, or
nutritional status. Median survival was 4.7 months. We conclude that flutamide is
ineffective second line therapy for patients with advanced pancreatic
adenocarcinoma.
PMID- 9547681
TI - Improving functional outcomes in older patients: lessons from an acute care for
elders unit.
AB - BACKGROUND: Hospitalization often marks the beginning, and may be partially
responsible for, a downward trajectory characterized by declining function,
worsening quality of life, placement in a long term care facility, and death. At
the University Hospitals of Cleveland, an Acute Care for Elders (ACE) unit that
reengineered the process of caring for older patients (> or = 70 years of age) to
improve functional outcomes was established in September 1990. DESCRIPTION OF
INTERVENTION: The general principles of ACE included an approach to care guided
by the biopsychosocial model and recognition of the importance of fitting the
hospital environment to the patient's needs. The design of the intervention was
consistent with principles of comprehensive geriatric assessment and continuous
quality improvement. Care, which focused on maintaining function, was directed by
an interdisciplinary team that considered the patient's needs both at home and in
the hospital. The major components of the ACE Unit intervention included patient
centered nursing care (daily assessment of functional needs by nursing, nursing
based protocols to improve outcomes, daily rounds by a multidisciplinary team), a
prepared environment, planning for discharge, and medical care review. RESULTS:
In a randomized trial comparing ACE with usual care, patients receiving ACE had
improved functional outcomes at discharge. The costs to the hospital for ACE unit
care were less than for usual care. The functional status of ACE and usual care
patients was similar 90 days after discharge. FUTURE DIRECTIONS: The ACE unit
intervention is being expanded to preserve the improvements observed during the
hospitalization in the outpatient setting. In addition, needs other than function
which are critical to patients' long-term quality of life are being considered.
PMID- 9547682
TI - Using a computerized sign-out program to improve continuity of inpatient care and
prevent adverse events.
AB - BACKGROUND: Many medical injuries are preventable, but there are few reported
successful strategies to prevent such injuries. Previous work identified coverage
by house staff not primarily responsible for the patient (cross-coverage) as a
significant correlate of risk for preventable adverse events. A four-month
intervention--computerized sign-outs--was introduced in 1993 in an urban teaching
hospital to improve continuity of care during cross-coverage and thereby reduce
risk for preventable adverse events. MEASUREMENTS: A previously tested
confidential self-report system was used to identify adverse events, which were
defined as unexpected complications of medical therapy that resulted in increased
length of stay or disability at discharge. A panel of three board-certified
internists confirmed events and evaluated preventability based on case summaries.
RESULTS: After the intervention, the rate of preventable adverse events among the
3,747 patients admitted to the medical service decreased from 1.7% to 1.2% (p <
0.10). Both univariate and multivariate analysis revealed no association between
cross coverage and preventable adverse events after the intervention. In the
baseline period, the odds ratio (OR) for a patient suffering a preventable
adverse event during cross coverage was 5.2 (95% confidence interval [CI], 1.5
18.2; p = 0.01), but was no longer significant after the intervention (OR, 1.5;
95% CI, 0.2-9.0). CONCLUSION: House staff are willing participants in efforts to
measure and improve the quality of health care systems. The intervention may have
reduced the risk for medical injury associated with discontinuity of inpatients
care. Four years after the end of the study, the computerized sign-out program
remained an integral part of the computing support system for house staff and was
widely used.
PMID- 9547683
TI - Quality indicators using hospital discharge data: state and national
applications.
AB - BACKGROUND: Demand for information about the quality of health care has
escalated. Yet many organizations lack well-specified quality measures,
statistical expertise, or the requisite data to produce such information. The
Healthcare Cost and Utilization Project Quality Indicators (HCUP QIs) represent
one approach to measuring health care quality using readily available data on
hospital inpatients. METHODS: The HCUP QIs, developed in 1994, address clinical
performance rather than other dimensions of quality such as satisfaction or
efficiency. The 33 indicators produce rates that represent measures of outcomes
(mortality and complications), utilization, and access. In lieu of complex
multivariate techniques, two methods were used: (1) restrictions in defining
patient subgroups to isolate homogeneous at-risk populations and (2)
standardization when populations are diverse. Stratified analyses are recommended
when patient or hospital factors are believed to influence the outcome. A simple
method for making statistical comparisons to national rates was developed. The
HCUP QI software, available in both mainframe and microcomputer applications,
have enabled organizations to use their own data to produce comparative
statistics and examine trends over time. Results summarized at the individual
hospital or aggregate level are being used to stimulate continuous quality
improvement initiatives. CONCLUSIONS: The HCUP QIs offer a low-cost alternative
for organizations that have access to administrative data. Current users include
hospital associations, state health departments, statewide data organizations,
and individual hospitals. Although the HCUP QIs are intended to serve as
indicators, not definitive measures, of quality, they were designed to highlight
quality concerns and to target areas for more intensive study.
PMID- 9547684
TI - Demanding medical excellence: an interview with Michael Millenson. Interview by
Louise Kaegi.
PMID- 9547685
TI - Chromosome 21 detection in human oocyte fluorescence in situ hybridization:
possible effect of maternal age.
AB - PURPOSE: The purpose of this study was to evaluate, among 100 uncleaved oocytes,
the incidence of numerical and structural chromosome 21 and X abnormalities and
to analyze the influence of various factors, such as in vitro (IVF) indications,
follicle stimulation protocols, and women's age. METHODS: We investigated 150
uncleaved oocytes from 128 patients after an IVF attempt. After cytogenetic
analysis (Giemsa) 100 oocytes (66%) were selected for fluorescence in situ
hybridization (FISH). Fluorescent probes for human chromosomes X and 21 were used
simultaneously according to standard procedures for their hybridization and
detection. RESULTS AND CONCLUSIONS: We analyzed by the FISH protocol 100
metaphase II oocytes with 22 to 25 chromosomes. Our results demonstrate a high
rate of disomy for chromosome 21 in human oocytes. Among them, eight were disomic
(8%) and three were nullosomic (3%) for chromosome 21. Only one disomy of
chromosome X was noted. The various indications of IVF and the different
folliculogenesis stimulating protocols did not seem to influence the results but
suggested a correlation between the maternal age and the aneuploidy rate of
chromosome 21.
PMID- 9547686
TI - Low multiple pregnancy rates and reduced frequency of cancellation after
ovulation induction with gonadotropins, if eventual supernumerary follicles are
aspirated to prevent polyovulation.
AB - PURPOSE: Our purpose was to demonstrate the feasibility of the routine aspiration
of supernumerary follicles in infertile patients with imminent polyovulation
after ovulation induction with gonadotropins and to examine its effect on the
frequency of cycle cancellation and on the (multiple) pregnancy rate. METHODS:
The data on 796 treatment cycles, performed between 1989 and 1996 on 410
infertile couples, were analyzed retrospectively. From October 1992, whenever
necessary, supernumerary ovarian follicles were selectively aspirated
transvaginally under ultrasound guidance to prevent the ovulation of more than
three follicles. Thereafter, intrauterine insemination was performed. RESULTS:
After the adoption of transvaginal ultrasound-guided aspiration of supernumerary
follicles into the treatment protocol in October 1992, the number of canceled
cycles (P < 0.0001) and the multiple pregnancy rate (P < 0.01) were significantly
reduced compared to those previously. The overall pregnancy rate remained stable.
No ovarian hyperstimulation syndrome requiring hospitalization was noted, and no
complications resulting from the follicle aspiration were registered.
CONCLUSIONS: Transvaginal ultrasound-guided aspiration of supernumerary ovarian
follicles increases both the efficacy and the safety of ovulation induction with
gonadotropins. Because of the limited equipment required, this method represents
an alternative for conversion of overstimulated cycles to more costly
alternatives such as in vitro fertilization.
PMID- 9547687
TI - Isolation and purification of an early pregnancy factor-like molecule from
culture supernatants obtained from lymphocytes of pregnant women.
AB - PURPOSE: Our purpose was to determine whether lymphocytes synthesize proteins
during pregnancy, to observe whether one of the proteins synthesized has early
pregnancy factor (EPF)-like activity and to isolate and purify this molecule from
culture supernatants obtained from stimulated lymphocytes of pregnant women.
METHODS: Lymphocyte proliferation assay and 35S-methionine labeling were done to
study de novo synthesis of proteins followed by autoradiography to confirm
synthesis of proteins. The rosette inhibition assay was used for detection of the
EPF-like molecule. Gel filtration on Sephadex G-100 and RPHPLC were used for
purification of the EPF-like molecule. RESULTS: The rate of incorporation of 35S
methionine was significantly higher in the lymphocytes of pregnant women compared
to those of the control, and autoradiography confirmed the synthesis of proteins
during pregnancy. There is a total protein enhancement trend observed during the
first trimester that declines toward term. The EPF-like molecule is observed to
be synthesized during all the trimesters of pregnancy. This molecule, when
purified, showed a single homogeneous biologically active peak. CONCLUSIONS: The
results indicated that there is an enhancement of existing protein or synthesis
of new proteins during pregnancy. The EPF-like molecule is one of the many
proteins synthesized and secreted by lymphocytes during pregnancy that, when
purified, is biologically active.
PMID- 9547688
TI - Performing testicular or epididymal sperm retrieval prior to the injection of
hCG.
AB - PURPOSE: Our purpose was to determine the feasibility and efficacy of performing
testicular or epididymal sperm retrieval prior to the injection of human
chorionic gonadotropin (hCG). METHODS: This report deals with 87 sperm-positive
percutaneous epididymal sperm aspiration (PESA), percutaneous testicular sperm
aspiration (PTSA), or testicular sperm extraction (TESE) cycles. All sperm
retrieval procedures were performed prior to administration of hCG to the women.
Retrieved spermatozoa were cultured in vitro in simple medium for approximately
40 hr prior to intracytoplasmic sperm injection. RESULTS: In all but one cycle in
which TESE was performed for nonobstructive azoospermia, motile sperm were
available for ICSI. The overall fertilization rate was 53%. Pregnancy rate per
transfer and implantation rate per embryo were 41.2 and 15.7%, respectively.
CONCLUSIONS: Satisfactory fertilization and pregnancy rates can be achieved when
PESA, PTSA, or TESE is performed prior to the injection of hCG followed by in
vitro culture of spermatozoa approximately 40 hr before ICSI. Scheduling of
testicular or epididymal sperm retrieval cases in this way appears to ease the
workload on laboratory and operating room personnel. Furthermore, withholding hCG
when sperm is absent may obviate the unnecessary risk of ovarian hyperstimulation
when spermatozoa cannot be retrieved.
PMID- 9547689
TI - Paternal centrosomal dynamics in early human development and infertility.
AB - PURPOSE: Our purpose was to demonstrate the dynamics of the human sperm
centrosome during fertilization and cleavage. METHODS: Human gametes, fertilized
oocytes, and preimplantation embryos were examined by transmission electron
microscopy. RESULTS: The functional sperm centrosome containing a typical
centriole (proximal) is inherited at fertilization and forms a sperm monoaster.
It then replicates and is perpetuated during cleavage. It organizes the mitotic
apparatus at each stage of cleavage up to the hatching blastocyst stage. Bipolar
spindles are formed in all monospermic and most dispermic embryos. Occasionally,
two sperm asters and tripolar spindles are formed in dispermic embryos.
Centrioles are associated with pronuclei and nuclei at interphases when they
duplicate and occupy pivotal positions at spindle poles during mitoses. The
maternal centrosome is not functional. CONCLUSIONS: The human embryo shows
paternal centrosome inheritance and perpetuation like most other animals.
Inheritance of defective centrosomes may lead to abnormal cleavage and contribute
to infertility.
PMID- 9547690
TI - Preimplantation genetic diagnosis of inherited cancer: familial adenomatous
polyposis coli.
AB - PURPOSE: Our purpose was to achieve preimplantation genetic diagnosis (PGD) of
the dominant cancer predisposition syndrome, familial adenomatous polyposis coli
(FAPC), as an alternative to prenatal diagnosis. METHODS: The affected patient
was superovulated and oocytes were retrieved and fertilized by intracytoplasmic
sperm injection (ICSI). Two cells were biopsied from each embryo and the whole
genome was amplified by primer extension preamplification (PEP). Nested PCR was
then used to amplify two APC fragments: one including the APC mutation site and
the other an informative intragenic polymorphism. Both were detected by
simultaneous single-strand conformation polymorphism and heteroduplex analysis.
RESULTS: Four normally fertilized embryos were biopsied on day 3 post ICSI, and
two cells were successfully removed from each embryo. Following PEP the APC
mutation was successfully amplified in 7 of 8 cells, and the polymorphism in 6 of
8 cells. The APC mutation was detected in three embryos. This result was
confirmed by identification of the mutation associated polymorphism in two cases.
A single embryo was diagnosed as homozygous normal for the mutation and the
polymorphism in both cells sampled. This unaffected embryo was transferred to the
mother, but no pregnancy resulted. CONCLUSIONS: We report here the first
diagnosis of a cancer predisposition syndrome in human preimplantation embryos.
Our results indicate that difficulties associated with single-cell PCR, allele
specific amplification failure in particular, need not prevent preimplantation
diagnosis of diseases with a dominant mode of inheritance, provided appropriate
strategies are applied.
PMID- 9547692
TI - Comparison of the media for isolation and storage of round spermatid nuclei
before intracytoplasmic injection.
AB - PURPOSE: This study investigated whether K(+)-rich medium is better than pure
NaCl solution or Na(+)-rich cell culture medium for handling round spermatid
nuclei prior to injection into oocytes (ROSNI). METHODS: Round spermatids of the
mouse were isolated and stored in isotonic NaCl, a cell culture medium (CZB), or
a nucleus isolation medium (NIM) before injection into oocytes. The rates of
normal fertilization, embryonic development in vitro, and birth of normal
offspring after transfer of embryos to foster mothers were determined. RESULTS:
In vitro development of ROSNI-produced zygotes to blastocysts was the same when
"naked" spermatid nuclei were exposed briefly to three media. However, a long (60
min) exposure of the nuclei to Na(+)-rich medium was detrimental. In K(+)-rich
NIM "naked" spermatid nuclei best retained their ability to participate in normal
embryonic development. CONCLUSION: NIM was better than Na(+)-rich medium for
retaining isolated spermatids competent to participate in normal embryonic
development.
PMID- 9547691
TI - In vitro stimulation of cumulus-cell expansion by human cord serum in mouse
oocyte-cumulus complexes.
AB - PURPOSE: The aim of this study was to test whether human cord serum (HCS)
containing gonadotropins has an effect on the expansion of oocyte-cumulus
complexes (OCCs). METHODS: The concentration of follicle stimulating hormone
(FSH) and luteinizing hormone (LH) was measured in HCS by radioimmunoassay (RIA).
After short-term culture (4 hr) with or without OCCs, medium containing 0.4%
bovine serum albumin (BSA) as control or 10% HCS was collected and analyzed for
its concentration of estradiol, progesterone, and testosterone. RESULTS: The FSH
concentration was at the basal level, but the LH level was as high as 142.4
mIU/ml in both natured and denatured serum. Undetectable levels of steroids were
observed in control media with or without OCCs. In contrast, a moderate amount of
steroid hormones was detected in culture medium containing HCS. OCCs secreted a
minute amount of steroid hormones in response to HCS. Similar patterns of cumulus
expansion were observable by treatment with HCS, human chorionic gonadotropin
(hCG), or HCS plus hCG after 4, 8, or 22 hr of culture. However, no cumulus
expansion was observed in controls. CONCLUSION: These results suggest that LH in
HCS induces cumulus expansion but does not affect the secretion of steroid
hormones by OCCs during culture.
PMID- 9547693
TI - Progesterone-activated spermatozoa used for in vitro fertilization.
PMID- 9547694
TI - An ectopic pregnancy masked by follicular initiation of gonadotropin-releasing
hormone agonist for pituitary desensitization prior to in vitro fertilization.
PMID- 9547695
TI - Utilization of Fourier transform-Raman spectroscopy for the study of
pharmaceutical crystal forms.
AB - It is well understood that the solid state physical characterization of a drug
substance is necessary for successful development and approval of a
pharmaceutical product AAPS [1]. Physical analytical techniques used include:
XRD, IR, DSC, TG, and NMR. Recently, Fourier transform (FT) Raman spectroscopy
has become a more common technique. Complimentary to IR, FT-Raman can be used to
differentiate between different crystal forms of a drug substance. FT-Raman
exhibits several advantages over IR and the other physical analytical techniques.
Very little sample is required with no preparation (dilution), analysis time is
quick, and since water is a weak scatter (Raman spectrum of water contains three
low intensity peaks), crystallization studies of drug substances from aqueous
solutions can be performed. Additionally, through the use of a variable
temperature accessory, phase diagrams can be determined for crystal systems,
leading to further characterization of those systems. This paper introduces the
use of FT-Raman spectroscopy for pharmaceutical development activities. Specific
examples will be shown for investigations of crystal forms (qualitative and
quantitative) and crystallization studies.
PMID- 9547696
TI - Development of a simple spectrophotometric method for propylene glycol detection
in tablets.
AB - A simple spectrophotometric procedure was developed and validated to indirectly
assess the quantities of propylene glycol (PG) remaining in compressed
liquid/powder admixtures. Such simplified quantitation may facilitate several
testing procedures related to various aspects of formulation development and
material testing of pharmaceutical powder excipients using various nonvolatile
liquids as the diluents. In the present study, this new and simple approach for
PG quantitation was developed as an integral part of a new method termed the
liquisolid compressibility (LSC) test, used to characterize the compaction
behavior of powder excipients. According to LSC testing, several admixtures of a
nonvolatile liquid (in this case PG) and a powder, differing in their PG/powder
weight ratio, are compressed in order to assess their compactabilities. The PG
content of such compacts may then be directly quantitated by the USP gas
chromatographic method or, indirectly, by this new simple spectrophotometric
procedure. The new approach involves the addition of a dye marker to the PG prior
to its incorporation into the powder. After compression, the PG amount remaining
in the compacts may be determined by simply extracting the dye from the tablets
and analyzing the extracts spectrophotometrically. In this manner, the dye
content thus obtained may be extrapolated to the respective net amount of PG
originally added as a dye/PG solution to the powder. Statistical comparison of
the results obtained from both methods revealed almost absolute correlation.
PMID- 9547697
TI - Capillary gas chromatographic assay of residual methenamine hippurate in
equipment cleaning validation swabs.
AB - A capillary gas chromatographic method is described for the determination of
methenamine hippurate residue in swabs collected from manufacturing equipment
surfaces. Any residual methenamine hippurate remaining on process equipment after
cleaning is removed by swabbing with one wet polyester Absorbond swab (4" x 4")
pre-moistened with water followed by a dry Absorbond swab. The residual
methenamine hippurate is chromatographed on a 30 x 0.32 mm (i.d.) Supelcowax-10
capillary column of 0.25-micron film thickness. The amount of residual
methenamine hippurate is determined by comparing the ratio of methenamine
hippurate peak area response to that of p-cresol (internal standard) obtained for
the sample to a linear calibration curve obtained for a series of standard
solutions. The method is demonstrated to be sufficiently linear, accurate,
precise, sensitive and rugged for the determination of low levels of methenamine
hippurate on equipment surfaces. Using this method, the mean recovery of
methenamine hippurate from spiked Absorbond swab samples contained in high
density polyethylene bottles was 105.2%, with a relative standard deviation (RSD)
of +/- 7.1% (n = 25). The mean recoveries of methenamine hippurate from spiked
test plates for '180 Grit' Stainless Steel, Teflon and WARCO White (neoprene and
PVC) gasket material were 77.2, 96.1 and 50.6%, with RSDs of +/- 9.4 (n = 25), +/
4.3 (n = 25) and +/- 36% (n = 20), respectively. Recovery correction factors
have been incorporated into the method. The method was successfully applied to
the assay of actual equipment cleaning validation swab samples. Stability studies
demonstrate that methenamine hippurate is not very stable on the equipment
surfaces or in the swabs. It is recommended that the surfaces be swabbed
immediately after cleaning and the swabs analyzed within 24 h after sample
collection. The results demonstrate that in order to fully validate the cleaning
procedures, it is not only necessary to investigate the recovery of the drug from
equipment surfaces and swabs but also that the stability of the drug on the
surfaces and swabs be determined.
PMID- 9547698
TI - Evaluation of microdialysis sampling of aqueous humor for in vivo models of
ocular absorption and disposition.
AB - The dynamics of beta-adrenergic-associated reductions in aqueous humor production
for treatment of elevated intraocular pressure are not well understood. In
particular, the relationship between ocular pharmacokinetics and pharmacodynamics
has yet to be established. This study was undertaken to develop a procedure for
examining the ocular absorption and disposition of topically administered
ophthalmic beta-adrenergic antagonists in individual animals. Dogs were
anesthetized with isoflurane and a microdialysis probe was implanted in the
anterior chamber of one eye and perfused with 0.9% saline at a rate of 2
microliters min-1. 3H-propranolol was administered by intracameral injection or
topically. Each dog received intracameral and topical propranolol, in alternate
eyes on separate days, in a randomized cross-over fashion. Microdialysis probe
effluent was collected every 5 min for > or = 2.5 h; concentrations of
propranolol were determined by liquid scintillation spectroscopy and were
corrected for probe recovery of the substrate as determined by in vivo
retrodialysis (approximately 46%) to estimate aqueous humor concentrations. In
separate experiments in rabbits, microdialysis probes were implanted in each eye.
3H-propranolol was administered topically to one eye; the contralateral eye
received intracameral 3H-propranolol. Model-independent pharmacokinetic
parameters for each treatment phase were calculated. The mean +/- S.D. times to
peak concentration of propranolol in aqueous humor were 86.6 +/- 47.6 min in the
dog and 54.1 +/- 20.4 min in the rabbit. The terminal rate constant was 0.0189 +/
0.00429 min-1 in the dog vs. 0.00983 +/- 0.00546 min-1 in the rabbit.
Intraocular tissue availability of propranolol differed markedly between the dog
(n = 3) and rabbit (n = 3) (approximately 0.056 in the dog vs. approximately 0.55
in the rabbit). These results demonstrate the utility of microdialysis sampling
for examination of ocular pharmacokinetics.
PMID- 9547699
TI - Sensitive determination of erythromycin in human plasma by LC-MS/MS.
AB - A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the
analysis of erythromycin in human plasma (EDTA as anticoagulant) was developed
and validated. The concentration ranges were 0.5-50 and 50-5000 ng ml-1. The
procedure involved alkalization of 0.5 ml of plasma, one step liquid-liquid
extraction, dryness of the extract and reconstitution in 80:20
water:acetonitrile. An Inertsil ODS-2 5 microns, 3.0 x 50 mm column (Metachem)
with a C8 guard column and isocratic mobile phase were used for liquid
chromatography. The mobile phase consisted of 1:1 acetonitrile:water with 2 mM
NH4OAc and 0.1% HOAc. A flow rate of 0.7 ml min-1 was used. The analysis time on
LC-MS/MS for one sample was approximately 2 min. A Turbo-Ionspray source was
interfaced between the HPLC and triple quadrupole mass spectrometer (Sciex API
III Plus). MS/MS analysis used Multi-Reaction Monitoring (MRM) mode. The lowest
limit of quantitation (LOQ) was 0.5 ng ml-1 with all Quality Control (QC) sample
recoveries varying between 88 and 105%. Nine intraday and interday calibration
curves were generated yielding correlation coefficients ranging from 0.995 to
1.000. Average recovery for erythromycin at 1 ng ml-1 was 105% (+/- 4.5%).
Average recovery for the internal standard was 83-103%. Short-term and long-term
stability in the freezer (-20 degrees C), bench stability, and stability after 3
freeze/thaw cycles at -20 and -80 degrees C were conducted. The samples were
found to be stable under all conditions. The method developed and validated
proved useful for clinical pharmacokinetic study sample analysis with high
throughput due to its high sensitivity and very short analysis time.
PMID- 9547701
TI - Validation of an LC-MS assay for the quantification of the enantiomers of Org
4428 in human plasma.
AB - A sensitive and selective liquid chromatographic mass spectrometric assay has
been validated for the quantification of Org 4428 enantiomers in human plasma.
The assay employs n-hexane extraction from alkalinized plasma, separation on a
narrow-bore enantioselective normal phase Chiralpak AD column and APCI MS-MS
detection. The lower limit of quantification is 0.5 ng ml-1 plasma for the
individual enantiomers.
PMID- 9547700
TI - High-performance liquid chromatography-mass spectrometry-mass spectrometry
analysis of morphine and morphine metabolites and its application to a
pharmacokinetic study in male Sprague-Dawley rats.
AB - A high-performance liquid chromatography tandem mass spectrometry-mass
spectrometry (LC-MS-MS) assay was developed for the analyses of morphine,
morphine glucuronides and normorphine in plasma samples from rats. The analytes
were extracted by using C2 solid-phase extraction cartridges. The extraction
recoveries were 100% for morphine, 84% for morphine-3-glucuronide, 64% for
morphine-6-glucuronide and 88% for normorphine. Both intra- and inter-assay
variabilities were below 11%. Using a plasma sample size of 100 microliters, the
limits of detection were 13 nmol l-1 (3.8 ng ml-1) for morphine, 12 nmol l-1 (5.5
ng ml-1) for morphine-3-glucuronide, 26 nmol l-1 (12 ng ml-1) for morphine-6
glucuronide and 18 nmol l-1 (5.0 ng ml-1) for normorphine, at a signal-to-noise
ratio of 3. The present assay was applied to a pharmacokinetic study in rats
after intraperitoneal administration of morphine.
PMID- 9547702
TI - Identification and determination of phase I metabolites of propafenone in rat
liver perfusate.
AB - Propafenone (PF) is a class 1C antiarrhythmic agent. To study the mechanisms of
PF interactions with dietary nutrients in isolated, perfused rat livers,
metabolites of PF in liver perfusate were identified and an analytical method was
developed for these metabolites plus parent drug. Identification of phase I
metabolites was performed using HPLC/MS equipped with a Lichrospher RP-18 column
and tandem mass spectrometry (MS/MS) with electrospray and atmospheric pressure
chemical ionizations. Three major metabolite peaks, whose protonated molecular
ions were m/z 358, 358 and 300, were identified as a propafenone derivative
hydroxylated in the omega-phenyl ring (omega-OH-PF), 5-hydroxypropafenone (5-OH
PF), and N-despropylpropafenone (N-des-PF). The levels of omega-OH-PF, 5-OH-PF, N
des-PF and PF were determined simultaneously by HPLC with UV detection at 210 nm
and a mobile phase of 0.03% triethylamine and 0.05% phosphoric acid in water
acetonitrile-methanol (45:20:35, v/v/v) after extraction with 5 ml diethyl ether
at pH 10.0 and evaporation of solvent under nitrogen. The results revealed that
omega-OH-PF, which was not found in humans, was the major metabolite of PF in rat
liver perfusate, not 5-OH-PF which is the major metabolite in human plasma.
PMID- 9547703
TI - Rapid and sensitive high performance liquid chromatographic method for the
determination of itraconazole and its hydroxy-metabolite in human serum.
AB - Published high performance liquid chromatographic (HPLC) methods for the
determination of itraconazole (ITZ) in biological matrices are labor intensive,
extraction-based procedures which operate at a pH approaching the limit of column
tolerance, and unless modified, cannot measure its hydroxy-metabolite (OH-ITZ). A
protein precipitation-based method requiring no solvent extraction and utilizing
a base-deactivated C18 analytical column to minimize peak tailing is described
herein. Calibration curves for OH-ITZ and ITZ were linear from 25-1500 ng ml-1
(r2 > or = 0.999). Intra-assay relative standard deviations (R.S.D.) were below
12%. Inter-assay R.S.D. were below 14%. This method provides a rapid means for
the accurate and precise determination of both OH-ITZ and ITZ concentrations in
human serum.
PMID- 9547704
TI - A HPLC method for the determination of 9-cis retinoic acid (ALRT1057) and its 4
oxo metabolite in human plasma.
AB - A HPLC method was developed and validated for the quantitation of 9-cis-retinoic
acid (ALRT1057) and its major metabolite, 4-oxo-9-cis-retinoic acid (LG100182) in
human plasma. Samples were buffered and extracted with methyl-tert-butyl-ether.
The analytes and an I.S. were separated on a C18 HPLC column using a shallow
gradient of 70-89% organic solvent. The analytes were quantitated by UV detection
at 348 nm. Selectivity against endogenous compounds and potential metabolites
(retinol, all trans-, 13-cis-, and 4-hydroxy-9-cis-retinoic acid) was
demonstrated. The run time was 29 min. The standard curve was linear from 2.5 to
450 ng ml-1. Interassay precision for both analytes in quality control samples
was less than 5.0% RSD. Accuracy was within 11.0% RE for both compounds. Analyte
stability during sample storage, extraction processing, and chromatography was
established. Method ruggedness was tested by two analysts and on two HPLC
systems. This method has been applied to the quantitation of clinical samples.
PMID- 9547705
TI - Determination of methazolamide concentrations in human biological fluids using
high performance liquid chromatography.
AB - Methazolamide is a carbonic anhydrase inhibitor used to treat glaucoma. In vivo,
methazolamide readily distributes into red blood cells. Therefore, both blood and
plasma concentration data are needed in order to characterize the
pharmacokinetics of methazolamide. In the present study, an analytical method
using high performance liquid chromatography was validated for determination of
methazolamide concentrations in several biological fluids. Through slight
modification of a previously reported method for acetazolamide, another carbonic
anhydrase inhibitor, methazolamide was readily quantitated in whole blood, plasma
and urine. Sample preparation involved liquid-liquid extraction with ethyl
acetate followed by a washing step using phosphate buffer (pH 8.0). After back
extraction into glycine buffer (pH 10.0), samples were then washed with ether and
injected onto the chromatograph. Chromatography was performed using a C-18, 5
microns reverse-phase column with UV detection at a wavelength of 285 nm. Mobile
phase consisted of 0.05 M sodium acetate (pH 4.0) and acetonitrile (20%). The
assay was validated over two standard concentration ranges from 1 to 100
micrograms ml-1, concentrations reflective of those expected in vivo, Calibration
curves were linear for all biological fluids and coefficients of variation for
interday and intraday reproducibility studies were less than 8% (range 3.1-7.9%).
The method was used to measure methazolamide concentrations in blood, plasma and
urine following oral administration to five human subjects.
PMID- 9547706
TI - Simplified reversed-phase HPLC method with spectrophotometric detection for the
assay of verapamil in rat plasma.
AB - A high-performance liquid chromatographic (HPLC) method was developed for the
assay of verapamil in rat plasma. After deproteinization of the plasma sample
with an acetonitrile-perchloric acid (8:2) mixture containing dextromethorphan,
the internal standard, an aliquot of the supernatant was directly analyzed on a
cyanopropylsilane column with methanol-acetonitrile-triethylamine acetate buffer
(10:30:60) as the mobile phase and detection at 235 mm. At a flow rate of 1.5 ml
min-1, a complete analysis was completed in less than 6 min. The method was
linear for verapamil concentrations in the range 0.5-10 micrograms ml-1 (r =
0.9999). Recoveries for the same drug concentrations from spiked rat plasma
ranged from 85.6-93.0% (n = 8). The mean RSD values for intraday and interday
assay reproducibility (n = 3) were, in both cases, less than 0.9%. The limit of
detectability was about 0.1 microgram ml-1. The method was found useful to
monitor the plasma levels of verapamil in rats that had received this drug by the
nasal, oral and intravenous routes of administration.
PMID- 9547707
TI - A simplified chromatographic method for quantitative determination of coenzyme
Q10 in dog plasma.
PMID- 9547708
TI - A sensitive assay of metoprolol and its major metabolite alpha-hydroxy metoprolol
in human plasma and determination of dextromethorphan and its metabolite
dextrorphan in urine with high performance liquid chromatography and fluorometric
detection.
AB - A reverse-phase High Performance Liquid Chromatographic (HPLC) method was
developed for the analysis of metoprolol in the large number of human plasma
samples obtained in in vitro-in vivo correlations (IVIVC) and bioavailability
studies of extended release formulations of metoprolol tartrate. The metabolite,
alpha-hydroxy metoprolol (OH-met), could also be quantified. The analytes were
extracted from the plasma using solid phase columns, separated on a C-4
analytical column followed by fluorimetric detection. The linearity, precision,
accuracy, stability, selectivity and ruggedness were validated for the
concentration ranges of 1-400 ng ml-1 for metoprolol and 0.5-200 ng ml-1 for OH
met. The same chromatographic conditions were slightly modified to quantify
dextromethorphan and its metabolite dextrorphan in urine in the concentration
range 0.052-0.05 microgram ml-1 as a method for screening for fast metabolizers.
PMID- 9547709
TI - Determination of famotidine in human plasma by high performance liquid
chromatography with column switching.
AB - A rapid, sensitive and robust reverse-phase high performance liquid
chromatographic (HPLC) method with column switching and an internal standard for
the quantitative determination of famotidine in human plasma is described.
Famotidine and the internal standard were isolated from plasma samples by cation
exchange solid phase extraction with SCX cartridges. The chromatographic
separation was accomplished by an Inertsil C4 column with a mobile phase of
acetonitrile/phosphate aqueous solution, connected by a switching valve to a BDS
Hypersil C8 column with a mobile phase of acetonitrile/sodium dodecyl sulfate and
phosphate aqueous solution. UV detection was set at 267 nm. The standard curve
was linear in the concentration range of 1-100 ng ml-1. The intraday coefficients
of variation at all concentration levels were less than 10%. The interday
consistency was assessed by running QC samples during each daily run. The limit
of quantification for famotidine in human plasma was 1 ng ml-1. The method has
been utilized to support clinical pharmacokinetic studies in healthy volunteers
who received famotidine 10 mg orally.
PMID- 9547710
TI - Determination of blood sugars by high pressure liquid chromatography with
fluorescent detection.
AB - In this study, a high pressure liquid chromatography method with fluorescent
detector was developed to analyze blood galactose, lactose and glucose
simultaneously. Plasma sugars were prepared as fluorescent derivatives to react
with FMOC-hydrazine (9-fluorenyl methyl chloroformate). A C18 reversed phase
column and a fluorescent detector were used and run in ambient. The resolution
index of galactose and glucose derivatives in the analytical method was 1.15. The
coefficients of variation of the analysis were less than 7.5%. The concentration
of FMOC-hydrazine did not significantly influence the analytical results for
determination of the concentration of galactose. However, the ratios of
acetonitrile in the mobile phase significantly affected the analysis of the
fluorescent derivatives of sugars. The sensitivity of this method for galactose
detection was 5 micrograms ml-1, and the required plasma volume for testing was
only 25 microliters each. This analytical method was successfully applied to
study the pharmacokinetics of galactose in vivo in a rabbit model.
PMID- 9547711
TI - A rapid and simple assay to determine the blood and urine concentrations of 1-(5
[123/125I]iodo-5-deoxyarabinofuranosyl)-2-nitroimidazole, a hypoxic cell marker.
AB - Pharmacokinetic and dosimetric parameters of the hypoxic tissue imaging agent
iodoazomycin arabinoside (123I-IAZA) have been investigated in human volunteers.
In conjunction with this study it was necessary to develop an assay for low
levels of the radiolabelled compound in blood and urine. A combination of high
performance liquid chromatography (HPLC) and gamma counting produced a highly
selective, sensitive and rapid assay for the analysis of 123/125I-IAZA in human
and animal blood and urine samples. Conventional HPLC assays for the tracer
quantities of this radioactive agent in blood have not been reported previously.
The addition of non-radiolabelled IAZA to the blood and urine samples containing
radiolabelled IAZA allowed the pharmaceutical to serve as its own internal
standard. This reverse isotope dilution approach permitted identification of the
appropriate HPLC peak by UV detection, followed by highly sensitive
quantification of the radiolabelled species by gamma counting. Blood samples were
prepared for HPLC by a solid-phase extraction without the loss of IAZA from
serum, with an extraction efficiency of 99.7 +/- 7.1% from human serum. Urine
samples could be analyzed directly by HPLC, without the solid-phase extraction
step. The detection limit in biological fluids depends on the specific activity
of radiolabelled 123/125I-IAZA. In this study it was possible to detect serum
concentrations of 123I-IAZA as low as 7.46 pg (21 fmol) per ml. The radiometric
detection limit for 123I-IAZA in this assay was 10.8 Bq ml-1 of serum.
PMID- 9547712
TI - Validation of an HPLC method for the determination of CP-93,393 in CP-93,393-1
tablets.
AB - A reversed-phase high performance liquid chromatographic (HPLC) assay developed
for the CP-93,393-1 drug substance was adapted for use with CP-93,393-1 tablets.
Using a novel experimental matrix, validation was performed to obtain linearity,
reproducibility and recovery and to meet current regulatory requirements.
Deviations in the sample preparation procedure were performed to demonstrate the
ruggedness of the assay.
PMID- 9547713
TI - Determination of trace levels of hydrazine in the penultimate intermediate of a
novel anti-infective agent.
PMID- 9547714
TI - Determination of aspartame and its degradation and epimerization products by
capillary electrophoresis.
AB - Two capillary zone electrophoretic assays using run buffers of pH 9.35 and pH
2.70 have been developed for the determination of aspartame (alpha-L-Asp-L
PheOMe) and its potential degradation products including Phe, PheOMe, 5-benzyl
3,6-dioxo-2-piperazineacetic acid (DKP), the dipeptides Asp-Phe and Phe-Asp, as
well as the isomeric beta-aspartame (beta-L-Asp-L-PheOMe). As an uncharged
species at pH 2.7 DKP could not be determined. Between pH 2.0 and 3.5 the
resolution of the diastereomers of aspartame and beta-aspartame was investigated.
While the resolution of the epimeric beta-isomers exhibited a plateau between pH
2.3 and 2.7, resolution of the aspartame diastereomers peaked at pH 3.0. Using
salicylic acid and Phe-Gly as internal standards at pH 9.35 and 2.70,
respectively, linear calibration curves were obtained for a concentration range
between 5 micrograms ml-1 and 1 mg ml-1. The R.S.D. for intraday and interday
analysis ranged from 1.0 to 3.6% and 1.5% to 9.1%, respectively. The capillary
electrophoresis assays were applied to analyze aspartame solutions heated to 70
degrees C. In agreement with the literature data aspartame was found to be less
stable at pH 7 compared to pH 3. In contrast to aspartame itself, an approximate
20% epimerization of beta-aspartame was observed in the incubation mixtures.
PMID- 9547715
TI - The application of capillary electrophoresis for monitoring effects of excipients
on protein conformation.
AB - Studies were conducted to assess the utility of free solution capillary
electrophoresis (CE) for monitoring the effects of selected excipients on the
thermal denaturation of a model protein (Ribonuclease A, RNase A) at low pH.
Thermal denaturation/unfolding experiments were conducted via temperature
controlled CE using a run buffer of 20 mM citric acid in the pH range of 2.3-3.1,
with a marker peptide incorporated to correct for temperature-induced changes in
endoosmotic flow. The effects of selected excipients on the thermal unfolding of
RNase A were then evaluated by adding either sorbitol, sucrose, polyethylene
glycol 400 (PEG 400) or 2-methyl-2,4-pentanediol (MPD) to the electrophoretic run
buffer (pH 2.3). Confirmatory denaturation experiments were conducted under the
same solution conditions using circular dichroism (CD) spectropolarimetry. Using
temperature-controlled CE, an increase in solution pH from 2.3 to 2.7 and 3.1
resulted in an increase in transition temperatures of RNase A by approximately 8
and 13 degrees C, respectively. Similar shifts in transition temperatures were
observed when thermal denaturation transitions were monitored by far-UV CD.
Sorbitol (0.55-1.1 M) and sucrose (0.55 M) each shifted the denaturation
transition temperatures of RNase A to higher values, whereas PEG 400 and MPD had
minimal effect on the unfolding transition midpoint at the concentrations
evaluated (0.55 M for each). The observed changes in the transition temperatures
for RNase A as a function of pH and selected excipients were similar when
measured by either CE or far-UV CD. These results support the utility of CE for
monitoring the effects of neutral excipients on the thermal denaturation of a
model protein under selected conditions. The widespread utility of the technique
may be limited by the narrow temperature range of most commercial CE instruments
and the need to use extreme pH conditions to monitor the complete denaturation
transition.
PMID- 9547716
TI - Bioanalytical calibration curves: variability of optimal powers between and
within analytical methods.
AB - The objective of this study was to investigate the variability of optimal power
models in contrast to common regression models within and between analytical
methods, as well as the frequency of outlier rejection. This was done by fitting
the power model to calibration curve data using the minimum sum of squared
residuals as a curve selection criterion. The jackknife percent deviation was
used for detecting outliers. The data were obtained from 2087 analytical batches
for 91 projects using various analytical techniques. The most frequent regression
model varied between analytical techniques while the median and interquartile
range of the optimal powers were stable. Outlier rejection is highest in GC and
LCMS in which the Wagner (Quadratic, log-log) is the most frequent model. These
results suggest that the greatest source of variability in the ideal
transformation may not be the analytical technique but other within-lab sources.
Outlying values may be due to these other sources of variability as suggested by
the outlier rejection profile.
PMID- 9547717
TI - Bioanalytical calibration curves: proposal for statistical criteria.
AB - Curve fitting procedures for bioanalytical assays are based on classical linear
least squares (LSE) theory. A common procedure is to select among various models
and weighting factors using the R2 as a goodness-of-fit criterion. It is
questionable whether R2 is the most appropriate criterion for model selection.
This is compounded by an often subjective removal of outliers. In this article,
statistical curve fitting and diagnostic criteria are proposed. The fitting
procedure is a Box-Cox-type power transformation of the data. The optimal
transformation is obtained as the one that minimises the sum of squared
deviations. Potential outlying standards are screened during the diagnostics
stage as those whose jackknife percent deviations exceed 20%. The main advantage
of this method is that it is objective and uniformly applicable across analytical
techniques. Furthermore, the optimal transformation obtained in this way is
unique. The results are demonstrated by comparing the power model to the R2
approach through the statistical analysis of 2094 analytical batches for 91
projects using various analytical techniques, namely GC, HPLC, LCMS and GCMS. The
results indicate that the power model is robust and that QC batch acceptance
using the power model is at least as good as the current method. These results
hold true across all analytical techniques. It is thus strongly suggested that
curve fitting and standard outlier detection for bioanalytical assays should be
based on a power model and on jackknife percent deviations method with acceptable
cut-off values.
PMID- 9547718
TI - [Mortality inequalities according to education in the city of Barcelona].
AB - BACKGROUND: In Spain, individual-based studies on inequalities in mortality are
scarce by the fact that death certificate often do not complete information on
occupation. This study describes socio-economic inequalities in mortality using
as social indicator the level of education, because in Barcelona the mortality
registry is linked with the municipal census. MATERIAL AND METHODS: 28,046
residents in Barcelona, Spain, 24 years and older who died in 1992 and 1993 were
studied. The level of education of the deceased people was obtained from the
municipal census. Age standardized mortality rates were calculated by each
educational level by sex. The most important causes of death were studied.
Poisson regression models were adjusted to obtain the mortality ratio among the
educational levels (being the more educated the reference group). RESULTS: The
mortality ratio by all causes in illiterate was 2.05 times higher in males (p <
0.001) and 1.62 in females (p < 0.001). The higher was the education level, the
lower were the rates. This mortality pattern was observed in the majority of
causes of death studied and mainly in AIDS, cirrhosis and drug overdose, also in
lung cancer in males and coronary disease in females. Breast and lung cancer in
females were higher in the more educated. Educational inequalities by age group
were more important in the youngest people and diminished with increasing age.
CONCLUSION: This results show the existence in Barcelona, Spain, of inequalities
in mortality by education level in the main causes of death in males and females
and in the majority of age groups.
PMID- 9547721
TI - [Mortality and little education].
PMID- 9547719
TI - [Prevalence of human immunodeficiency virus type 1 and Mycobacterium tuberculosis
infections in a prison population in the years 1989 to 1995].
AB - BACKGROUND: This study was carried out to know the prevalence of human
immunodeficiency virus type 1 (HIV-1) and Mycobacterium tuberculosis infection in
a penitentiary center, the risk factors and the prevention measures to reduce
this infection. SUBJECTS AND METHODS: 1,173 men from a penitentiary center
between 1989-1995 were included. Demographic data, risk factors and penitentiary
variables were studied. Antibodies against HIV were found and confirmed using
Western blot; tuberculin skin reaction (PPD) and CD4 lymphocyte cant were
studied. RESULTS: The mean age was 31.8 (SD 8.8 years). They were 61.5% Spanish
people and 48.1% were in prison for second time. The 49.7% used illegal drugs.
Overall prevalence of HIV-1 infection was 24.3%. The differences of percentages
for HIV-1 infection in intravenous drug users (IVDU) were 67.7% and in non IVDU
were 3.8% with a significant statistical difference (chi 2 = 557.5; p < 0.0001).
Using a multivariate test (stepwise method) we found that the probability to be
HIV-1 positive in a penitentiary center was 21.9 times higher in IVDU, 5.6 times
in Spanish prisoners, 2.6 times in subjects with more than one prison stay and
1.7 times if they had tatoos. The global prevalence of tuberculosis infection
(PPD positive) was a 43.8%, and was associated to the second time inmates in this
penitentiary center (chi 2 = 22.1; p < 0.001). A 54.4% of HIV-1 positive people
showed a CD4 T lymphocyte count > or = 500 x 10(6)/l. CONCLUSIONS: We found a
high prevalence of HIV-1 and tuberculosis infection and drug use in this
penitentiary center. HIV-1 was transmitted and related by sharing syringes
between IVDU independent of the stay in prison. The diagnosis of HIV-1 infection
was made soon. The treatments of drug users in penitentiary centers and programs
for lowering the risk are very important.
PMID- 9547720
TI - [Defects of adrenal steroidogenesis in patients with hirsutism].
AB - BACKGROUND: To determine the frequency and the type of adrenal steroidogenic
abnormalities in hirsute women. SUBJECTS AND METHODS: ACTH test was performed
during follicular phase in 127 hirsute and 40 normal (control) women. Before ACTH
injection we measured in serum by RIA: 17-OH-pregnenolone (17-OH-P5), 17-OH
progesterone (17-OH-P4), androstenedione (AN), cortisol (CT), 11-deoxycortisol
(DCT), dehydroepiandrosterone (DHEA) and its sulphate (DHEAS), total (TT) and
free (FT) testosterone, oestradiol (E2), progesterone (PR), androstenediol
glucuronide (AG), LH, FSH and prolactin. After 60 min of ACTH injection 17-OH-P5,
17-OH-P4, AN, DHEA, CT and DCT were measured. Net increment of stimulated
steroids and the ratios 17-OH-P5/17-OH-P4, DHEA/AN, 17-OH-P4/CT, 17-OH-P5/CT and
DCT/CT were calculated. Pelvic ultrasonographic exploration was done when
irregular menses were reported. RESULTS: Up to 31% of the patients presented
enzymatic defects in adrenal steroidogenesis. Diagnostic criteria for enzyme
defects were established. Late-onset 21-hydroxylase deficiency was diagnosed in 6
(4.5%) patients, HLA typing of these patients demonstrated that 4 out of 6 had
B14-DR1. Sixteen women (12.6%) displayed a 17-OH-P4 response and the net
increment 2 SD above the normal mean concentration, which are diagnostic criteria
for late-onset 21-hydroxylase deficiency carriers. We diagnosed a 3 beta
hydroxysteroid dehydrogenase defect when 17-OH-P5 and DHEA responses, their net
increment and the 17-OH-P5/17-OH-P4 and 17-OH-P5/CT ratios were 2 SD above the
normal mean after ACTH: 14 women were diagnosed. 11 beta-hydroxylase deficiency
diagnosis was made when DCT response, its net increment and the DCT/CT ratio
after ACTH were 2 SD above the normal mean: 7 women were detected. Associated
biosynthetic defects were described. CONCLUSIONS: One third of our patients with
hirsutism presented anomalous response to ACTH, consistent with enzymatic
abnormalities in adrenal steroidogenesis.
PMID- 9547722
TI - [Glucose intolerance: the fragile threshold of diabetes mellitus].
PMID- 9547723
TI - [Atypical familial microcytosis: a familial and genetic study].
AB - The characteristics of familiar atypical microcytosis studied during one year
were evaluated. Out of 149 patients with microcytosis in whom iron deficiency was
ruled out, a heterogenous beta-thalassemia was diagnosed in 72 cases, a
heterozygous delta beta-thalassemia in 16 cases and a hemoglobinopathy in 3
cases. The microcytosis was related to an inflammatory anemia in 12 cases and to
an hemopathy in 9 cases. An atypical microcytosis was detected in 37 patients. A
familiar and molecular analysis was carried out to detect alpha-thalassemia in
cases with atypical microcytosis. It was possible to complete the familiar and
molecular analysis in 35 out of 37 cases, and an alpha-thalassemia was observed
in 31 patients. Most cases proved to be heterozygous or homozygous-alpha 3.7
thalassemia. No patient with heterozygous alpha zero-thalassemia was found. Most
cases of familiar atypical microcytosis in our country are due to -alpha 3.7
thalassemia. Bearing these findings in mind, this analysis should only be used in
situations where a problem of prenatal diagnosis is present. Moreover, systematic
molecular analysis of familiar atypical microcytosis could be justified if the
MCV is lower than 75 fl.
PMID- 9547724
TI - [AIDS: ethical and legal problems of physician-patient relations in the light of
the new penal code].
PMID- 9547725
TI - [Value of differences among patients in comparative trials].
PMID- 9547726
TI - [Who wants to be the chief?].
PMID- 9547727
TI - [Actol and acfol: drugs that won't be confused anymore].
PMID- 9547728
TI - [Hereditary cancer of the breast and ovary].
PMID- 9547729
TI - [Computer technology applied to hospitalized patients].
PMID- 9547730
TI - [Prevalence of bacterial vaginosis in an obstetric population of Barcelona].
AB - OBJECTIVES: To investigate the prevalence and risk factors of bacterial vaginosis
(BV) in a pregnant population of Barcelona (Spain). MATERIAL AND METHODS: 301
pregnant women controlled in the Hospital Clinic i Provincial (HCP) of Barcelona
were enrolled in the study. Complete epidemiological information, and vaginal
samples were available in 293 women. BV was diagnosed by Gram stain of vaginal
smear (Nugent's criteria). RESULTS: BV was detected in 22 pregnant women (7.5%;
95% CI: 4.6-10.5%). There was no association between race, parity, education,
marital status, smoking and drug use, and the presence of BV. Non-use of birth
control method (72.3% vs 34.4%; p < 0.0001), presence of sexually transmitted
diseases (STD) during pregnancy (22.7% vs 3.7%; p < 0.0001), HIV seropositivity
(13.6% vs 2.9%; p = 0.041) and presence of symptoms of vaginitis (40.9% vs 13.3%;
p = 0.009) were significantly associated with the presence of BV. CONCLUSIONS:
The prevalence of BV in a pregnant population of Barcelona (Spain) is 7.5%.
Further work is needed to evaluate the usefulness of BV as a prescreening marker
for STD and HIV infection. The Gram stain provides an inexpensive, fast and easy
method to diagnose BV, and may allow us to screen, treat and prevent the
morbidity and mortality associated with it.
PMID- 9547731
TI - [Incidence and risk factors of the association of AIDS and tuberculosis in
Spain].
AB - BACKGROUND: Incidence of tuberculosis in persons coinfected with HIV is very
high. The aim of this study was to determine the risk factors for tuberculosis in
AIDS patients in Spain. PATIENTS AND METHODS: A study was carried into AIDS cases
(1993 European AIDS case definition) over 12 years old, diagnosed in Spain in
1994. A comparison was run between cases with tuberculosis and the remaining
reported AIDS cases on the register, by sex, age, transmission category and
prison record. Multiple logistic regression was used to assess the independent
effect of each variable, with the adjusted odds ratio (ORa) and their 95%
confidence intervals. RESULTS: Annual incidence of AIDS and tuberculosis
comorbidity was 8.9 per 100,000 inhabitants. Multivariate analysis revealed that
tuberculosis in AIDS patients appeared with higher frequency in: males (ORa =
1.4; CI 95%, 1.3-1.6); the 13-29 age group (ORa = 1.3; CI 95%, 1.1-1.5) and the
30-39 year old group (ORa = 1.1; CI 95%, 1.0-1.3), injecting drug users (IDU)
(ORa = 1.4; CI 95%, 1.2-1.6), and those patients with a prison record (ORa = 2.1;
CI 95%, 1.9-2.4). CONCLUSIONS: In Spain, male AIDS patients, under age 40 years
with a prison record and IDU have a higher risk of tuberculosis. Control measures
for tuberculosis should therefore be intensified among these patients.
PMID- 9547732
TI - [Trends in human immunodeficiency virus infection prevalence in
homosexual/bisexual men in Madrid (1986-1995)].
AB - BACKGROUND: We analysed the trend in seroprevalence for human immunodeficiency
virus (HIV) in homosexual or bisexual men who voluntary requested the test in a
sexually transmitted disease/HIV clinic in Madrid. PATIENTS AND METHODS: We
studied 5,424 homo/bisexual non-injecting drug user (non-IDU) men, who came for
the first time since 1986 to 1995. We analysed the HIV seroprevalence taken into
account the year, age and exchange of sex by money. A hundred and thirty-six IDU
homo/bisexual men were also attended during the same period and they were
compared with non-IDU. RESULTS: HIV seroprevalence among the 5,424 non-IDU
homo/bisexual men were 20.2%, rising from 19.6% in 1986 to 29.6% in 1990. After
then, the trend decreased to 15.3% in 1995 (chi 2 for trend, 66.8; p < 0.0001).
Average age was three years higher among seropositives (p < 0.0001), and showed
an upward trend from 29.9 in 1986 to 34.6 in 1995 (p = 0.0059). Seroprevalence
among homosexuals younger than 25 fell in the last years. One percent of
individuals had ever practiced the prostitution. They were younger (average age,
27.6), and their HIV seroprevalence were 25.9%. A hundred and thirty-six IDU
homo/bisexual men were also attended for the first time, being 2.4% of overall
homo/bisexual men. They had a higher seroprevalence (48.5%) than non-IDU (p <
0.0001), and did not show any significative time-trend. CONCLUSIONS: A favourable
evolution can be observed in HIV seroprevalence among homo/bisexual from Madrid,
Spain, men who came to be tested, especially among the youngest. Prevention
programs should make an effort to maintain this trend.
PMID- 9547734
TI - [Master formulas for the treatment of obesity: an interminable history?].
PMID- 9547733
TI - [Bacterial vaginosis: where are we?].
PMID- 9547735
TI - [The 1st case in Spain of detection of occult squamous carcinoma using LIFE
system].
AB - LIFE system (lung imaging fluorescence endoscope) is a new system of detection
for early lung cancer using a He-Cd laser through a conventional fiberoptic
bronchoscope. This system is able to capture and processing the autofluorescence
from the bronchial mucosa and to show it in a video screen in real time. In the
screen the normal tissue appears in green colour and the neoplastic tissue in
brown colour. The first studies performed with LIFE system show the same
specificity of the conventional bronchoscopy but the sensibility is 50% higher.
In this paper we present the first case of detection of a occult squamous cell
carcinoma with sputum and bronchial aspiration cytology positive for carcinoma
but chest X ray, CT scanner and bronchoscopy negative for lung cancer. The LIFE
system was able to detect carcinoma in the carina.
PMID- 9547736
TI - [Abdominal pain and weight loss in a 70-year-old man].
PMID- 9547737
TI - [Calcium antagonists and their impact on coronary risk].
PMID- 9547738
TI - [Publishing of clinical trials: methods and ethics].
PMID- 9547739
TI - [Malignant neuroleptic syndrome associated to risperidone].
PMID- 9547740
TI - [Pathophysiologic changes in patients with severe burns: role of hormones and
chemical mediators].
AB - The body's general response to serious thermal injury is characterized by
increased vascular permeability immediately after injury and subsequent
hypovolemic shock. Skeleto-muscular proteolysis, lipolysis, gluconeogenesis,
increased metabolic rate, and a severe systemic inflammatory response induced by
local infections or surgical procedures. The increased vascular permeability is
mediated by histamine and numerous vasoactive substances, including serotonin,
bradykinin, prostaglandins, leukotrienes, and platelet activating factor. Hyper
metabolism is mediated by hormones such as catecholamines, glucagon, and
particularly cortisol. In addition, among the putative mediators of the metabolic
response to injury, attention has recently been focused on cytokines and lipid
mediators which are mainly produced by activated reticuloendothelial cells.
Cytokines such as interleukin-1, interleukin-6 and tumor necrosis factor and
cortisol responses are interrelated, since cytokines activate the hypothalamo
adrenal axis. The cytokine storm seen in burn patients may be associated with
depression of the immune system and with susceptibility to infection. Thermal
injury can also lead to activation of the renin-angiotensin-aldosterone system,
increased ADH production, and production of atrial natriuretic polypeptide to
maintain the circulatory volume. Burn wound infections or surgical procedures can
produce and perpetuate a mediator-induced systemic inflammatory response that may
lead to multiple organ failure. Serum levels of interleukin-6 are very sensitive
to surgical stress, and may be a useful indicator of the general condition of
severely burned patients.
PMID- 9547741
TI - [Early treatment for body fluid shifts and circulatory derangement in patients
with extensive burns].
AB - The initial postburn period is characterized by body fluid shifts and circulatory
derangement, or so-called burn shock. The fluid shifts are mainly due to a marked
increase in capillary permeability. This loss of capillary integrity is so great
that colloid including albumin, readily disperse into the extravascular space.
This is limited to the burned area when of 30% or less of the body surface area
(BSA) is involved, but is found throughout the entire body when more than 30% of
the BSA is involved. The tremendous fluid shifts from the intravascular to the
extravascular space result in edema formation and hemoconcentration. Along with
the reduction in intravascular volume, there is a rapid reduction in cardiac
output which gradually returns to the normal level 24 to 48 hours after burn
injury. Therefore fluid resuscitation should be initiated immediately after
injury. Currently a number of methods for achieving adequate volume replacement
are available. In this paper we review fluid resuscitation methods for patients
with extensive burns and also introduce recent topics on new regimens for
resuscitation.
PMID- 9547742
TI - [Current treatment burn wounds: alternative wound coverage methods].
AB - In patients with massive burn injuries and very limited skin donor sites, both
acute-phase and long-term problems of skin loss must be solved by the use of
alternative wound closure materials. Alternative materials can be used for either
temporary wound coverage or for permanent wound closure. Recently, allogenic skin
grafts have most commonly been used as alternative wound closure material.
However, research is ongoing on many new materials to provide a readily available
substitute for skin allografts for permanent wound closure. The best approach to
the development of alternative permanent wound closure materials is to
incorporate the host's own cellular and structural components. Four general
strategies have been devised so far based on the type of matrix structure and
cellular content: allografts; cultured epidermal grafts; dermal matrix grafts;
and cultured-dermal matrix composite grafts. Several approaches using combined
alternative wound closure materials have been used, including transplantation of
artificial dermal matrix with thin epidermal autografts, and transplantation of
artificial dermal matrix containing human fibroblasts. Ultimately, the best
candidate materials for permanent wound closure after extensive burn injury must
be determined in prospective, randomized, controlled clinical trials.
PMID- 9547743
TI - [Metabolism and nutritional support after burn injury].
AB - The nutritional status of the burn patient plays a major role in the ability to
ward off an infectious challenge. The immune and inflammatory systems can be
modulated by nutritional support, and therefore this article focuses on the
nutritional support after burn injury. The hypermetabolic response that occurs
after burn injury is characterized by a greater magnitude than that observed
after any other form of trauma. The hypothesis that gut-or wound-derived
bacterial translocation is one of the major triggers of the hypermetabolic
response has attracted attention recently. The first set of goals of nutritional
support is to prevent starvation and nutrient deficiencies, and the second is to
provide the correct amount of nutrients prevent injury-related adverse
physiologic complications. The route and timing of nutritional support are most
important. Enteral alimentation appears to preserve the host immune function and
to attenuate the hypermetabolic response by preserving the intestinal mucosal
barrier. Immediate enteral feeding is superior to delayed enteral feeding, even
though only limited amounts of enterally administered nutrients are absorbed
during the early days postburn.
PMID- 9547744
TI - [Immunological alterations after extensive burn injury].
AB - It is recognized that extensively burned patients have an increased
susceptibility to infection and often succumb to multiple organ failure related
to sepsis. Numerous investigations performed over more than 30 years have
demonstrated immunologic abnormalities in burn patients, including changes in
serum immunoglobulin and opsonin levels, alterations in the complement system,
impairment of phagocyte and neutrophil function, suppression of delayed
hypersensitive reactions, and prolongation of allograft survival. Recent progress
in immunology has shown that inadequate production of both cytokines and
arachidonic acid derivatives is profoundly involved in immunosuppression after
severe burn injury. A better understanding of immunologic status is necessary to
reduce the mortality rate from infection in extensively burned patients. This may
also lead to discovering the therapeutic control mechanisms for their immunity.
PMID- 9547745
TI - [Sepsis in extensive burned patients].
AB - The prognosis of extensively burned patients is dependent upon the presence of
sepsis. The more extensive the burns, the more likely patients are to become
septic. Although recently the frequency of burn wound sepsis has been decreased
due to the early excision of necrotic tissue, that of sepsis resulting from
respiratory tract infection has increased. Staphylococcus aureus (methicillin
resistant S. aureus) and Pseudomonas aeruginosav are the agents most likely to
cause infections. Sepsis syndrome also results from bacterial translocation (BT),
in which gut bacteria and/or endotoxins are thought to enter the portal
bloodstream and/or lymphosystem. The pathophysiological mechanism of sepsis is
the increased release of inflammatory mediators and resulting imbalances between
these substances and their antagonists. In cases of severe sepsis, the sequelae
of the imbalance between inflammatory mediators and their antagonists can lead to
endothelial injury, DIC, and finally MODS. Strategies against the occurrence of
sepsis include hospital-wide infection control measures, blockage of infection
routes, and administration of antibiotics. The early initiation of nutritional
management, preferably by the enteral route, to enhance immune system function
and minimize the occurrence of BT is recommended. Several drugs to control
inflammatory mediator release are currently under development and are expected to
be used clinically in future.
PMID- 9547746
TI - [Immediate burn wound excision and grafting decreases the mortality rate and
hospital stay duration in extensive burn patients].
AB - The treatment of patients with extensive burn injuries has begun to changed in
recent years. Traditional methods have consisted of dressing the burn wound with
topical antimicrobials, tubbing the patient daily, encouraging the shoughing off
of eschar using surgical debridement as necessary, and finally, closing the
granulating wound with split-thickness skin grafts after 2 to 4 weeks. An
alternative and more radical procedure is now being used with increasing
frequency: complete surgical excision of the eschar is performed as soon as the
patient is hemodynamically stable after resuscitation from burn shock. From 1991
to 1997, we performed immediate burn wound excision and grafting in 15 extensive
burn patients within 24 hours after injuries. The mean burn surface area (BSA)
was 48 +/- 20%, and the mean burn index was 44 +/- 19. The mean prognostic burn
index (PBI = burn index + age) was 94 +/- 23. There were 5 deaths, for an overall
mortality rare of 33%, which is less than that experienced by 11 other burn units
in Tokyo (51.4%). The duration of hospital stay of survivors was approximately 1
day/%BSA.
PMID- 9547747
TI - [Clinical and pathophysiologic problems associated with smoke inhalation injury].
AB - Smoke inhalation injury is one of the primary determinants of survival following
major burn injury. The primary site of injury in smoke inhalation appears to be
the small airway rather than the alveoli, and thus small airway occlusion caused
by edema and pseudomembrane formation are the primary mechanisms of progressive
hypoxia. Ventilation-perfusion (VA/Q) alterations after smoke inhalation are
characterized by increased blood flow to low VA/Q compartments, although an
increase in true shunt (VA/Q = 0) was not a consistent finding. This differs
considerably from most adult respiratory distress syndrome (ARDS) patients or
oleic acid-induced lung edema models, in which an increase in true shunt is the
major mechanism of hypoxia. Such differences lead to different responses to
nitric oxide (NO) inhalation therapy, and NO does not improve oxygenation and
outcome in patients with smoke inhalation injury. In the treatment of inhalation
injury, meticulous removal of pseudomembrane by fiberoptic bronchoscopy is
essential, the use of high concentrations of oxygen should be avoided since it
can cause absorption atelectasis. High-frequency percussive ventilation is a
suitable treatment for inhalation injury, as it improves oxygenation and
facilitates removal of pseudomembrane.
PMID- 9547748
TI - [Electrical injury].
AB - Electrical injury can be classified into true electrical injury, are burn. In
true electrical injury, large or small, dry, dark brown necrotic wounds (electric
current spots) are observed on the skin at the entrance and exit sites of the
electric current, and progressive necrosis develops in surrounding tissues. As
generalized symptoms, ventricular fibrillation, respiratory arrest, and loss of
consciousness may be observed temporarily immediately after the injury. Necrosis
also occurs in deep tissues including muscles, and pathology resembling crush
injury is seen. Myoglobin released into the circulation due to muscle necrosis
tissue causes myoglobinuria and increases the risk of acute renal failure.
Treatment consists of emergency resuscitation and fluid supplementation with
lactated Ringer's solution. However, more fluid should be administered than in
cases of common burns to accelerate urinary excretion of myoglobin in the
circulation. For local treatment, debridement should be performed in areas with
clear third-degree burns, but in the presence of progressive necrosis, repair and
reconstruction after debridement should be postponed for 2-3 weeks.
PMID- 9547749
TI - Measurement of temporal asymmetries of glucose consumption using linear profiles:
reproducibility and comparison with visual analysis.
AB - AIM: One approach to regionally analyze temporal glucose consumption consists in
drawing linear profiles over the maximal values measured in the temporal cortical
ribbon. The aim of our study was to test the reproducibility of this method and
to compare its diagnostic performance to that of visual analysis in patients with
complex partial seizures (CPS). METHODS: Regional cerebral glucose consumption
(rCMRGIc) was measured interictally in 25 CPS patients and 10 controls using F-18
deoxyglucose and the positron emission tomography (PET) camera ECAT EXACT 47. The
PET scans were visually analyzed for the occurrence of unilateral temporal
hypometabolism. Furthermore, rCMRGIc was quantified on six contiguous coronal
planes by manually tracing maximal values of temporal glucose consumption, thus
creating line profiles of temporal glucose consumption for each side. Indices of
asymmetry (ASY) were then calculated from these line profiles in four temporal
regions and compared to the corresponding 95% confidence intervals of the control
data. All analyses were performed by two observers independently from each other
and without knowledge of the clinical findings. RESULTS: The agreement between
the two observers with regard to focus lateralization was 96% (kappa = 0.93) on
visual analysis and 100% (kappa = 1) on quantitative analysis. There was an
excellent agreement with regard to focus lateralization between visual and
quantitative evaluation (kappa = 0.8). CONCLUSION: Quantitation of local temporal
rCMRGIc by using linear profile analysis is highly reproducible; for the
lateralization of epileptogenic foci, however, this method does not possess
significant advantages over the visual evaluation of the scans.
PMID- 9547750
TI - Quantitative estimation of I-123-Iomazenil receptor binding in temporal lobe
epilepsies using two SPECT acquisitions--comparison with the regional cerebral
blood flow and a compartment model.
AB - AIM: To compare published fractional rate constants of I-123-Iomazenil (IMZ) and
C-11-Flumazenil (three-compartment/four-parameter model) with a I-123-Iomazenil
receptor index calculated from two SPECT acquisitions and to compare the receptor
index of the epileptogenic area with the contralateral side in patients with
unilateral temporal lobe epilepsies. METHODS: 28 patients were studied. 13/28
patients had a drug-resistant unilateral temporal lobe epilepsy with a successful
focus localisation performed by an extensive video/EEG monitoring. 15 other
patients with clinically suspected focal epilepsy and a normal MRI and IMZ SPECT
scanning were used as controls. SPECT scanning was performed in all patients 15
and 100 min after intravenous injection of 111 MBq IMZ and 10 min after
application of 740 MBq Tc-99m-HMPAO. Quantification of the regional uptake was
performed using ROI-technique and the specific and non-specific binding of IMZ
was calculated. The receptor index was calculated by the difference of the
specific binding from 15 to 100 min p.i. divided by the time interval. RESULTS:
The receptor index showed a linear correlation with recently published fractional
rate constants k3 (r = 0.69 and 0.67; p = 0.15) and a moderate correlation with
the k4 constant (-0.53 and -0.43; p = 0.28) by the means of C-11-Flumazenil PET
and I-123-Iomazenil SPECT studies, respectively. However, statistical
significance was not reached due to the few data points available from the
published reports. Furthermore, the IMZ receptor index was lower in the
epileptogenic area of patients with unilateral temporal lobe epilepsies compared
with their contralateral side (p = 0.02; Wilcoxon-test). The IMZ receptor index
showed a weak correlation with the regional cerebral blood flow independent of
the evaluated region (r < 0.4; p < 0.05). CONCLUSION: The IMZ receptor index
indicated to be a simple routine approach to estimate the fractional rate
constant k3 (r = 0.67). The lower value of the receptor index within the
epileptogenic area might be due to a lower receptor density. However in further
studies, IMZ might be a helpful tool to find out subtle changes of the receptor
affinity due to its approximately 30-fold higher ligand-receptor affinity
compared to C-11-Flumazenil.
PMID- 9547751
TI - [Esophageal scintigraphy of Zenker's diverticula before and after
diverticulotomy].
AB - AIM: The filling and evacuation of Zenker's diverticula were scintigraphically
examined before and after operation to quantify their functional relevance. These
results were correlated with the symptoms of the patients and the findings of the
barium swallow x-ray examination using cineradiography. METHODS: Sequential and
static esophageal scintigraphies were performed in 17 patients with Zenker's
diverticulum before and after laser surgical diverticulotomy. We used a gamma
camera system in 45 degrees LAO-position after application of 15 ml of tea which
was marked with 99mTc-DTPA. Filling and evacuation of the diverticulum were
expressed in proportion to the administered activity. Relative volumes of the
diverticula were obtained from cineradiography by using the height of the
neighbouring cervical vertebra, and the clinical symptoms were divided into 4
groups. RESULTS: Zenker's diverticula could be verified visually and
quantitatively by scintigraphy. The precise temporal course of the reduction of
activity in the diverticulum was exactly determined. The scintigraphic retentions
correlated with the x-ray volumes with a coefficient ranging from 0.55 to 0.85.
Clinical symptoms also were not very closely related to scintigraphic and x-ray
findings, respectively. CONCLUSION: The esophageal scintigraphy allows
quantification of the filling and evacuation of Zenker's diverticula, thus it is
suitable for objectivization of the functional relevance of the diverticula.
That's why the esophageal scintigraphy should be taken to the diagnosis of
diverticula in addition to the clinic and the x-ray examinations. The method is
especially useful to evaluate the results after diverticulotomy.
PMID- 9547752
TI - [Optimization of PET image quality by means of 3D data acquisition and iterative
image reconstruction].
AB - PURPOSE: In the recent past, several algorithms have been developed in order to
transform 3D sinograms acquired at volume PET systems into 2D data sets. These
methods offer the possibility to combine the high sensitivity of the 3D
measurement with the advantages of iterative 2D image reconstruction. The purpose
of our study was the assessment of this approach by using phantom measurements
and patient examinations. METHODS: The experiments were performed at the latest
generation whole-body PET system ECAT EXACT HR+. For 2D data acquisition, a
collimator of thin tungsten septa was positioned in the field-of-view. Prior to
image reconstruction, the measured 3D data were sorted into 2D sinograms by suing
the Fourier rebinning (FORE) algorithm developed by M. Defrise. The standard
filtered backprojection (FBP) method and an optimized ML/EM algorithm with
overrelaxation for accelerated convergence were employed for image
reconstruction. The spatial resolution of both methods as well as the convergence
and noise properties of the ML/EM algorithm were studied in phantom measurements.
Furthermore, patient data were acquired in the 2D mode as well as in the 3D mode
and reconstructed with both techniques. RESULTS: At the same spatial resolution,
the ML/EM-reconstructed images showed fewer and less prominent artefacts than the
FBP-reconstructed images. The resulting improved detail conspicuously was
achieved for the data acquired in the 2D mode as well as in the 3D mode. The best
image quality was obtained by iterative 2D reconstruction of 3D data sets which
were previously rebinned into 2D sinograms with help of the FORE algorithm. The
phantom measurements revealed that 50 iteration steps with the optimized ML/EM
algorithm were sufficient to keep the relative quantitation error below 5%.
CONCLUSION: Our measurements show that the image quality in 3D PET can be
improved by using iterative reconstruction techniques. The concept of 3D data
acquisition and combining the FORE algorithm with 2D ML/EM reconstruction can
readily be employed in clinical practice since the computation time is not
considerably longer than that in iterative reconstruction of true 2D data.
PMID- 9547753
TI - [Dosimetry fundamentals of endovascular therapy using Re-188 for the prevention
of restenosis after angioplasty].
AB - AIM: Various radionuclides can be used for endovascular brachytherapy. A new
concept is to inflate the balloon of a dilatation catheter with a radioactive
solution. Re-188 can be eluted from a generator system and is available daily.
The aim of this study was to obtain dosimetric data for this radionuclide.
METHODS: The dose decrease of Re-188 was calculated and measured with a TLD
system radial to a balloon catheter typically used in cardiology (diameter: 3 mm,
length: 20 mm). RESULTS: Using a specific activity of 370 MBq/ml a dose of 0.3 Gy
could be achieved within 1 min in a TLD in contact with the balloon. Paired TLDs
differed about 3%. A fast dose reduction of 50% and 10% were stated within 0.5 mm
and 2.5 mm, respectively. Calculated and measured values were in good agreement.
The data are comparable to those known for Y-90. CONCLUSION: Calculations of dose
distribution are consistent with TLD measurements of Re-188. Using a specific
activity of 1.85 GBq/ml, a dose of 10-15 Gy at the coronary artery wall can be
achieved within 2-3 min. Compared to radioactive stents or wires the use of this
liquid beta-emitter is a simple alternative for prevention of the restenosis
following the angioplasty.
PMID- 9547754
TI - Positive I-123-MIBG-scintigraphy in osteosarcoma.
AB - I-123-MIBG scintigraphy has become a standard imaging technique in the detection
of neuroendocrine or neurocrest derived tumors, especially neuroblastoma and
pheochromocytoma. We report on a positive I-123-MIBG uptake in a pediatric
osteosarcoma patient and demonstrate, that unusual results still occur with this
established imaging method.
PMID- 9547755
TI - [18F]fluoride PET indicates reduced bone formation in severe glucocorticoid
induced osteoporosis.
AB - A 61-year-old female patient presenting with mixed connective tissue disease
(Sharp syndrome), underwent a long-term high dose glucocorticoid treatment
because of multiple organ manifestations. Under steroid therapy she developed
severe osteoporosis resulting in multiple fractures. A dynamic [18F]fluoride PET
study in this patient revealed reduced fluoride influx in non-fractured
vertebrae. This finding corresponds to pathogenetic concepts which propose an
inhibition of bone formation as major cause of glucocorticoid-induced
osteoporosis. In the light of the presented case it seems to be promising to
evaluate the diagnostic benefit of [18F]fluoride PET in osteoporosis.
PMID- 9547756
TI - [Occult fracture of the femoral neck fractures of the proximal femur].
AB - Bone scintigraphy is a highly sensitive method for the detection of fractures. In
case a trauma and clear clinical signs are evident, but the radiography is
inconspicuous, bone scintigraphy may lead to the final diagnosis. In the present
case of an occult fracture in the proximal femur only scintigraphy indicated the
fracture, which then was proved topographically by magnetic resonance imaging.
PMID- 9547757
TI - Biology of addiction.
AB - It is unknown why an individual becomes addicted to drugs. Substance abuse is
typified by a wide variety of use patterns and variation in individual responses.
Behavioral psychology teaches that if something either increases the individual's
sense of pleasure or decreases his or her discomfort, then the individual is
likely to repeat the behavior. Evidence has suggested that abusers report a sense
of pleasure when they use substances because of the ability of the substance to
stimulate the release of neurotransmitters known to be used by the brain's
pleasure system. This article provides an overview of the substance-related
disorders, including their definition in the Diagnostic and Statistical Manual of
Mental Disorders (DSM-IV).
PMID- 9547758
TI - Pharmacology of drug transfer across the placenta.
AB - The effect of drugs in the fetus can be thought of in terms of the dose-response
based on a knowledge of the general principles by which drug is transferred from
the mother to the fetus. Fetal drug concentration, which determines the fetal
response, is a function of the maternal concentration, the placental
permeability, the fetal drug clearance, and differences in protein binding and
ionization between the maternal and fetal plasma.
PMID- 9547759
TI - Detection of drug use during pregnancy.
AB - Several methods of drug testing are efficacious in identifying and monitoring
drug use during pregnancy. Urine screening remains the most commonly used method
despite the limited period during which drugs can be detected. Hair has been
recognized as a possible alternate test specimen, but wider acceptance of hair
testing must await better understanding of drug disposition in hair, answers to
the issues relating to interpretation, and the development of less demanding
laboratory techniques. Regardless of the matrix used, proper interpretation of
the results of drug testing requires familiarity with the sensitivity,
specificity, and limitations of the laboratory methodologies employed. Moreover,
unconfirmed positive results may actually be false-positives and must be
interpreted with caution, particularly if they are the basis for major clinical
decisions.
PMID- 9547760
TI - Marihuana and tobacco use in pregnancy.
AB - Marihuana and tobacco smoking are two of the most commonly abused substances in
pregnancy. Smoke from both agents contain a multitude of potentially active
components, which make them difficult to study. Both have been associated with
adverse effects in pregnancy in animal and human studies. Data on marihuana use
during pregnancy have been conflicting. There is much evidence, however,
demonstrating adverse pregnancy outcomes associated with cigarette smoking which,
fortunately, can be reversed with smoking cessation.
PMID- 9547761
TI - Fetal alcohol syndrome. Hearing, speech, language, and vestibular disorders.
AB - Fetal alcohol syndrome (FAS) refers to a pattern of anomalies that include
craniofacial, CNS, growth, and various sensory anomalies. We have observed that
FAS is associated with four kinds of hearing disorders: (1) developmentally
delayed auditory function, (2) sensorineural hearing loss, (3) intermittent
conductive hearing loss owing to recurrent serous otitis media, and (4) central
hearing loss. As is the case with other syndromes associated with craniofacial
anomalies and hearing impairments, speech and language pathologies also are
common in FAS patients. Although auditory and vestibular systems arise from
similar embryological tissue, vestibular dysfunction is variable in FAS. Early
identification and intervention to treat hearing, language, and speech problems
should improve the functional level of FAS in children.
PMID- 9547762
TI - Cocaine in pregnancy. Recent data on maternal and fetal risks.
AB - Cocaine continues to be abused during pregnancy, creating increased demands on
the health care system. Epidemiology and basic science research have identified
and confirmed risks of adverse maternal and fetal effects when cocaine is used
during pregnancy. These effects of cocaine in pregnant women often are influenced
by a number of confounding variables. This article reviews those cocaine effects
as well as recent data, which examine in greater detail the risks of adverse
outcomes of prenatal cocaine exposure during pregnancy.
PMID- 9547763
TI - Prenatal exposure to amphetamines. Risks and adverse outcomes in pregnancy.
AB - Based on findings in humans and the confirmation of prenatal exposures in
animals, amphetamines and methamphetamines increase the risk of an adverse
outcome when abused during pregnancy. Clefting, cardiac anomalies, and fetal
growth reduction deficits that have been seen in infants exposed to amphetamines
during pregnancy have all been reproduced in animal studies involving prenatal
exposures to amphetamines. The differential effects of amphetamines between
genetic strains of mice and between species demonstrate that pharmacokinetics and
the genetic disposition of the mother and developing embryo can have an enormous
influence on enhancing or reducing these potential risks. The effects of prenatal
exposure to amphetamines in producing altered behavior in humans appear less
compelling when one considers other confounding variables of human environment,
genetics, and polydrug abuse. In view of the animal data concerning altered
behavior and learning tasks in comparison with learning deficits observed in
humans, the influence of the confounding variables in humans may serve to
increase the sensitivity of the developing embryo/fetus to prenatal exposure to
amphetamines. These factors and others may predispose the developing conceptus to
the damaging effects of amphetamines by actually lowering the threshold of
susceptibility at the sites where damage occurs. Knowledge of the effects of
prenatal exposure of the fetus and the mother to designer amphetamines is
lacking. Based on the few studies in which designer drugs have been examined in
animal models, more questions are raised than answered. Possible reasons why no
malformations or significant fetal effects were found in the study by St. Omer
include the genetic strain of rat used, the conservative exposure profile, or the
fact that the placenta metabolized MDMA before reaching the embryo. These
questions underscore the need for further investigations concerning the prenatal
exposure effects of designer compounds and the effects of amphetamine and
methamphetamine in general.
PMID- 9547764
TI - Opioid dependence during pregnancy. Effects and management.
AB - This article describes the complex problems associated with opioid dependence
during pregnancy. Medical, obstetric, and psychosocial problems are presented.
Methadone maintenance for the treatment of opioid dependence is described in this
article. Specific issues of appropriate methadone dose during pregnancy, medical
withdrawal, and the relationship of methadone dose and the severity of neonatal
abstinence also are discussed.
PMID- 9547765
TI - Inhalant abuse in pregnancy.
AB - Information from a variety of sources suggests the possibility of adverse effects
of maternal inhalant abuse, although a well-controlled, prospective study in this
area has not been conducted. One source of this concern is the data from
occupational exposure to some of the abused solvents, specifically toluene and
TCE, with numerous reports suggesting increased spontaneous abortion and fetal
malformations. There are also data suggesting decreased fertility and an
increased risk for spontaneous abortion in health care workers exposed to nitrous
oxide. The relevance of these studies to problems of inhalant abuse is not clear.
Although the chemicals involved are the same, there are many differences in the
exposure parameters, the populations exposed, and the types of associated risk
factors. Nonetheless, there are more than 100 cases reported in the literature of
children born to solvent-abusing mothers. Many of these children were small at
birth, and some have craniofacial abnormalities not unlike that seen in children
with FAS. In the few studies reporting the findings of follow-up in these
children, some evidence has been obtained for retardation in growth and
development and for residual deficits in cognitive, speech, and motor skills.
Clearly, more research is needed to rule out the concomitant risk factors and to
identify specific chemicals and patterns of use associated with adverse effects.
Animal studies provide more direct evidence that prenatal exposure to toluene or
TCE can produce reduced birth weights, occasional skeletal abnormalities, and
delayed neurobehavioral development, even under conditions designed to mimic
inhalant abuse patterns. Additional research is needed to identify other
chemicals with adverse effects, critical periods of exposure, effects of
combinations of inhalants, or interactions with drugs of abuse. The research
literature seems sufficient to alert clinicians to possible problems in patients
who abuse inhalants while pregnant. Diagnosis and good prenatal care for these
women are important. The evidence for neonatal withdrawal is limited at this
time; however, infants born to women who have recently used inhalants should be
observed carefully for an alcohol-like withdrawal syndrome. Although it is not
possible to link a specific birth defect or developmental problem in the child of
an inhalant abuser to prenatal exposure to a specific chemical, it is clear that
inhalant abuse and its associated lifestyle place children at increased risk. A
wider appreciation of this is needed among health care professionals and the
general public.
PMID- 9547766
TI - The impact of prenatal drug exposure on the neonate.
AB - Several social or recreational drugs singly or together have demonstrated effects
on the fetus and neonate, with those effects extending into adulthood. The use of
recreational drugs during pregnancy remains a major health problem, with adverse
effects including higher rates of fetal distress and demise, lower Apgar scores,
growth retardation, and adverse neurodevelopmental outcome. Ethanol has the most
profound effects, with physical stigmata of the drug seen in one third of exposed
infants. In children without the affected physical appearance, profound
neurodevelopmental sequelae have been demonstrated. Other drugs, such as cocaine,
heroin, amphetamines, and nicotine, have been associated with impaired fetal
growth and acute withdrawal during the neonatal period. Subsequently, these
infants and children have an increased risk for altered neurodevelopment and long
term health status. Long-term follow-up and assessment are essential. The risk of
neonatal withdrawal or abstinence syndrome is greatest with narcotic drugs but
has been found to occur in neonates following exposure to cocaine, nicotine, and
amphetamines. Early treatment with tincture of opium, paregoric, or phenobarbital
is crucial. Assessment of the overall health status of the infant should include
growth parameters, signs and symptoms of infection (especially hepatitis,
syphilis, and immunodeficiency viruses), and neurobehavioral function. Such
assessments should not be limited to the newborn period, as neurodevelopmental
sequelae may not be manifest until later in infancy and childhood. In addition,
evaluation of the social milieu is warranted because of the increased risk for
neglect and abuse of drug-exposed infants and children. Early intervention,
maternal drug rehabilitation treatment, and parenting classes are frequently
prescribed, but their efficacy is variable. Further investigations should study
the potential benefits of these recommendations.
PMID- 9547767
TI - Breast-feeding and drug exposure.
AB - Breast-feeding provides important benefits to mother and infant and should be
strongly encouraged as the optimal feeding choice for most infants. In the mother
with an ongoing illicit drug abuse problem, the risks posed to the infant are
substantial and outweigh the benefits of breast-feeding in most cases. Moderate
use of alcohol, cigarettes, or caffeine is compatible with breast-feeding.
PMID- 9547768
TI - An introduction to reactive oxygen species and their possible roles in substance
abuse.
AB - There is a growing body of information relating diverse diseases and the
consequences of injury to generation and toxicity of reactive oxygen species
(ROS). Recently, it has been shown that the fetus and its membranes are also
vulnerable to this toxicity, suggesting that a number of obstetric diseases may
result from exposure to ROS, which are ubiquitous in aerobic organisms.
Endogenous antioxidants, including superoxide dismutase, catalase, and
glutathione peroxidase are essential for defense against ROS. It is significant
that all antioxidants appear to be down-regulated in the fetus and membranes,
suggesting the possibility that any process that further depresses their
activities or increases the burden of ROS may compromise fetal development or
maternal health. When permitted to accumulate, ROS can damage all classes of
macromolecules, including lipids, proteins, and nucleic acids. Toxicity includes
mutation, protein degradation, and lipid peroxidation, which can severely disturb
membrane permeability and alter intracellular calcium and pH. An understanding of
the generation and toxicity of ROS should help to define their potential roles in
obstetric disease and lead to innovative preventive and therapeutic approaches.
PMID- 9547769
TI - Moral and social issues regarding pregnant women who use and abuse drugs.
AB - Pregnant women who abuse drugs, such as alcohol, cocaine, and marihuana may face
a variety of legal and social responses, including involuntary commitment, forced
treatment, and criminal sanctions. These programs are intended to remedy apparent
maternal-fetal conflicts but paradoxically may encourage some women to avoid
beneficial medical and social services or to seek abortion. Although pregnant
women have ethical duties to give due consideration to their offspring, these
moral obligations fail to justify coercive and punitive programs regarding
substance abuse. Coercive fetal protection policies may undermine pregnant
women's trust and cooperation, violate their autonomy, weaken our civil
liberties, and raise a host of ethical problems relating to race, gender, and
class prejudice. Education and drug treatment programs, rather than punitive and
coercive measures, may better help pregnant women fulfill their moral duties to
refrain from abusing substances.
PMID- 9547770
TI - The drug court. A new strategy for drug use prevention.
AB - The concept of Drug Treatment Court is relatively new and is an innovative
response by local communities to deal with the escalation of criminal activity
associated with substance abuse. The frequency of repeated offenses by drug
users, the overcrowding of jail space, and a diminished sense of community well
being contributed to the motivation to look for a new approach by the criminal
justice system--the creation of Drug Treatment Courts. This article reviews the
strategy behind this creation.
PMID- 9547771
TI - Erbium:YAG laser-assisted cataract surgery.
AB - BACKGROUND AND OBJECTIVE: To assess the safety and efficacy of erbium:YAG laser
assisted cataract removal. PATIENTS AND METHODS: A total of 15 patients underwent
cataractous lens removal. All the patients had a visual acuity of 20/50 or worse
secondary to senile cataract. The endothelial cell count was calculated
preoperatively and at 6 weeks postoperatively. A 2.94-micron-wavelength erbium:
YAG laser with a zirconium-fluoride fiber optic and silica tip was used to
fracture and emulsify the nucleus. The erbium:YAG laser was chosen due to its
high absorption in water, a primary component of a cataractous lens. RESULTS: The
postoperative visual acuity was 20/30 or better in all the eyes that were treated
with surgery. The endothelial cell loss at 3 months was 0% to 10%. No laser
related complications were noted. A conversion to an ultrasound surgical
technique was utilized in six cases. Vitreous loss occurred in one case due to
the posterior extension of an anterior capsulotomy tear. CONCLUSION: This study
demonstrated the ability of an erbium:YAG laser system to safely and effectively
emulsify the lens nucleus. Laser-assisted cataract surgery is a promising new
clinical procedure.
PMID- 9547772
TI - Outcomes of vitreoretinal surgery in patients with X-linked retinoschisis.
AB - BACKGROUND AND OBJECTIVE: To assess the outcomes of vitreoretinal surgery in the
treatment of vision-threatening posterior segment complications of X-linked
retinoschisis. PATIENTS AND METHODS: The authors performed a retrospective
analysis of 16 eyes from 11 patients who underwent vitreoretinal surgery. All the
patients had a documented positive family history of X-linked retinoschisis, and
all patients had bilateral macular disease. RESULTS: The ages of the patients
ranged from 14 months to 37 years (mean age 15.1 years; median age 11.5 years),
and postoperative follow-up ranged from 3 months to 10 years (mean 2.8 years;
median 1 year). The indications for surgical intervention included rhegmatogenous
retinal detachment (12 eyes), vitreous hemorrhage (2 eyes), progression of the
schisis cavity through the fovea (2 eyes), cataract associated with a persistent
hyperplastic primary vitreous-like condition (2 eyes), and exudative maculopathy
(1 eye). The primary surgical intervention included pars plana vitrectomy alone
(7 eyes), pars plana vitrectomy and pars plana lensectomy (4 eyes), and a scleral
buckle procedure alone (5 eyes). Surgical success (defined as reattachment of the
retina, removal of media opacities, or arrest of schisis progression) was
achieved in 14 of 16 eyes, after an average of 1.2 procedures per eye. The major
reason for reoperations was recurrent retinal detachment due to proliferative
vitreoretinopathy. Two eyes were eventually enucleated due to pain associated
with neovascular glaucoma resulting from recurrent retinal detachment. Of the
remaining 14 eyes, visual acuity improved in 8 eyes and remained unchanged in 6
eyes. CONCLUSION: Vitreoretinal surgery is often helpful in stabilizing or
improving visual function in patients with posterior segment complications from X
linked retinoschisis.
PMID- 9547773
TI - The progressive outer retinal necrosis syndrome: successful treatment with
combination antiviral therapy.
AB - BACKGROUND AND OBJECTIVE: To assess a two-drug combination of antiviral therapy
for the progressive outer retinal necrosis syndrome (PORN), given the current
poor outcome with acyclovir alone. PATIENTS AND METHODS: A retrospective review
was performed on six consecutive patients who were diagnosed with PORN and were
treated with various combinations of intravenous or oral plus intravenous
antiviral therapy. The relative efficacies of these modalities were compared.
RESULTS: Six eyes of six patients showed active retinitis at the time of
presentation. Three patients had unilateral retinitis, and the remaining patients
had necrotic, end-stage disease in their fellow eye. All the patients were
treated with combination therapy, consisting of either ganciclovir and acyclovir
(three patients), foscarnet and ganciclovir (two patients), or foscarnet and
acyclovir (one patient). Standard induction doses were employed. During the
combination therapy, all six eyes showed resolution of the retinitis, manifested
by complete fading of the original retinal lesions and an absence of new lesion
formation. At the final follow-up, the areas of prior active retinitis had
resolved and remained quiescent. A mild recurrence developed in one eye when
ganciclovir and foscarnet were both tapered to a single daily dose. This
recurrence promptly resolved with reinduction (twice daily) dosing. Two patients
maintained a visual acuity of 20/50 or better in their involved eye for the
duration of follow-up (38 and 27 weeks, respectively). One patient maintained a
visual acuity of 20/40 for 14 weeks. The remaining three patients had macula-off
retinal detachments despite resolution of active retinitis. In addition, for the
duration of follow-up, one of the three patients with unilateral disease had
retinitis in the uninvolved eye; all three uninvolved fellow eyes maintained a
visual acuity of 20/20. One patient had progressive optic atrophy. CONCLUSIONS:
Prolonged combination antiviral therapy for PORN may successfully arrest the
progression of retinitis, maintain remission, and prevent involvement of the
fellow eye. Furthermore, if aggressive therapy is begun early, good vision may be
preserved.
PMID- 9547774
TI - Oculocardiac reflex during retinal surgery using peribulbar block and nitrous
narcotic anesthesia.
AB - BACKGROUND AND OBJECTIVES: This study was designed to examine the effects of
local and general anesthesia on the oculocardiac reflex (OCR) in adults during
retinal detachment surgery, with an aim of determining the safest type of
anesthesia and on which extraocular muscle traction causes a higher incidence of
OCR. PATIENTS AND METHODS: The study was performed on 30 American Society of
Anesthesiologists-I patients (age range 40-60 years) who were undergoing retinal
detachment surgery. Fifteen patients underwent surgery with general anesthesia
and 15 were given a local peribulbar block. A fixed traction of 400 g was applied
to all the extraocular muscles, and the heart rate, rhythm, and electrocardiogram
of each patient was monitored. RESULTS: The overall incidence of OCR was higher
with general anesthesia (63.3%) than with local anesthesia (14.4%). There was a
significant decrease in heart rate for the rectus muscles (P < .0005) as well as
the oblique muscles (P < .005) during traction with general anesthesia. All four
rectus muscles were equally sensitive in eliciting the reflex. The incidence of
dysrhythmias was 20% with general anesthesia and 6.67% with local anesthesia.
CONCLUSION: This study showed that local anesthesia produces less bradycardia and
ectopic arrhythmias and, therefore, may be safer and better than general
anesthesia for surgeries in which traction of extraocular muscles is required.
PMID- 9547775
TI - The accuracy of finger tension for estimating intraocular pressure after
penetrating keratoplasty.
AB - BACKGROUND AND OBJECTIVE: Intraocular pressure (IOP) estimation by Goldmann
tonometry is inaccurate in the immediate postoperative period after penetrating
keratoplasty. For this reason, many corneal surgeons use a finger tension (FT)
IOP estimation technique in the early post-keratoplasty period. The authors
performed a prospective clinical study to evaluate the accuracy of this
traditional technique. PATIENTS AND METHODS: FT estimates were performed by three
experienced corneal surgeons on 68 patients on the first and second days after
penetrating keratoplasty. These estimates were compared with MacKay-Marg (MM)
tonometry readings for these patients. RESULTS: The mean confident FT from the
pooled data of the three surgeons exceeded the MM reading by 5.0 mm Hg (22.6 vs.
17.6). The mean FT exceeded the MM reading by only 3.9 mm Hg for the most
accurate surgeon. Some observers were significantly more accurate than others,
however, lid edema and tenderness of the globe markedly diminished the FT
accuracy of all of the observers at significance levels of P < .001 and P < .01,
respectively. Among all of the FT estimates, in only one patient (2%) did the FT
underestimate the MM reading by more than 10 mm Hg. CONCLUSION: The authors'
results suggest that for some patients, and for some surgeons, the FT or digital
method of IOP estimation remains useful for detecting elevated IOP early after
corneal transplantation if the proper technique is used and substantial lid edema
and patient discomfort are absent.
PMID- 9547776
TI - The "deroofing" of Schlemm's canal in patients with open-angle glaucoma through
placement of a collagen drainage device.
AB - BACKGROUND AND OBJECTIVES: A preliminary study was conducted to examine a new
surgical approach for the management of patients with open-angle glaucoma in
which Schlemm's canal is opened to restore drainage in a nonpenetrating fashion.
The authors compared the results of the surgical procedure including the new
glaucoma drainage device with the results of standard trabeculectomy. PATIENTS
AND METHODS: The authors performed a new type of surgical procedure on 58
consecutive patients with open-angle glaucoma. The procedure entails "deroofing"
Schlemm's canal to facilitate the drainage of aqueous without penetrating the
eye. This is done by exposing the canal after a partial-thickness sclerectomy and
keratectomy along a 5-mm arc. After the canal was deroofed, a new type of
collagen glaucoma drainage device was placed in the surgical site to maintain
drainage postoperatively. Patient data, including intraocular pressure (IOP),
complications, and the number of medications required to maintain adequate
pressures, were analyzed for 1 year postoperatively. RESULTS: Within 1 to 2
months postoperatively, 80.9% of the patients achieved an IOP lower than 21 mm
Hg. This improved to 88.9% at 3 to 6 months postoperatively and 87.5% at 6 to 12
months postoperatively. The only major complications were microperforations
(8.6%) related to surgical technique and a few cases of high IOP that required
repeat operations (10.3%). CONCLUSIONS: The nonpenetrating technique for
deroofing the canal effectively allows the drainage of aqueous to acceptable
levels (in the range of 15 to 17 mm Hg) without the complications associated with
penetrating trabeculectomy. Complications are rare, and the collagen drainage
device appears to be effective for allowing the drainage site to remain patent
after its dissolution.
PMID- 9547777
TI - Phacotrabeculectomy: comparison of results from 3.5- and 5.2-mm incisions.
AB - BACKGROUND AND OBJECTIVE: To compare the intraocular pressure control, visual
results, and astigmatic results of 3.5-mm and 5.2-mm incisions following
phacotrabeculectomy with 12 months of follow-up. PATIENTS AND METHODS: Fifty eyes
underwent clear cornea punch trabeculectomy under a 5.0 x 2.5-mm scleral flap,
closed with two 10-0 polyglactin sutures. The first 25 eyes underwent wound
extension to 5.2 mm for insertion of a single-piece polymethylmethacrylate (PMMA)
lens. The next 25 eyes underwent wound extension to 3.5 mm for insertion of a
folded silicone lens. RESULTS: The mean intraocular pressure decrease from the
preoperative level was 7.6 mm Hg in the 3.5-mm incision group and 7.8 mm Hg in
the 5.2-mm incision group. One patient required continued medication. The best
corrected visual acuity was 20/40 or better in 86% of the patients, with no
significant difference between the groups. The mean "with the wound" induced
astigmatism showed no statistical difference between the two groups. CONCLUSIONS:
The use of 10-0 polyglactin appears to aid filtration, yet minimizes hypotony or
the need for antimetabolites. For surgeons who wish to reduce costs without
compromising results during phacotrabeculectomy, there is merit in considering a
5.2-mm incision; moreover, the more rigid single-piece PMMA lens appears to be
associated with fewer complications in the immediate postoperative period.
PMID- 9547778
TI - Subretinal semiconductor microphotodiode array.
AB - BACKGROUND AND OBJECTIVE: To examine the function of a semiconductor
microphotodiode array (SMA) surgically implanted in the subretinal space.
MATERIALS AND METHODS: Positive-intrinsic layer-negative (PiN) or negative
intrinsic layer-positive (NiP) SMAs were surgically placed into the subretinal
space of rabbits through a pars plana incision and a posterior retinotomy. The
implants required no external connections for power and were sensitive to light
over the visible and infrared (IR) spectrum; IR stimuli were used to isolate
implant-mediated responses from the activity of native photoreceptors. A
stimulator ophthalmoscope was used to superimpose IR stimuli on the implant and
adjacent retinal areas, and responses were recorded during the postoperative
recovery period. SMA responses were also evaluated in vitro. The animals were
given lethal anesthetic overdoses, and the retinas were examined histologically.
RESULTS: The in vitro implant response consisted of an electrical spike, followed
by a small-amplitude DC offset that followed the time course of the IR
stimulation, and an overshoot at the stimulus offset. The SMAs placed in the
subretinal space retained a stable position and continued to function throughout
the postoperative period. The SMA responses recorded in vivo included additional
slow-wave components that were absent from the in vitro recordings. These
responses reverted to the in vitro configuration following the death of the
animal. There was a significant loss of retinal cells in areas overlying the
implant, and the retina appeared normal away from the implant and surgical site.
CONCLUSION: SMAs can be successfully implanted into the subretinal space and will
generate current in response to light stimulation during an extended period of
time.
PMID- 9547779
TI - Chorioretinal folds following glaucoma valve implantation.
AB - Glaucoma valve implants have been observed to cause scleral indentation and
flattening. The authors report the case of a 79-year-old woman who had previously
undergone glaucoma valve implantation, and who subsequently developed
chorioretinal folds that corresponded to the implant in location and
configuration. Accumulation of fluid behind the implant, as documented by B-scan
ultrasonography, appeared to result in the observed scleral and chorioretinal
changes. The authors conclude that chorioretinal folds can result following
glaucoma valve implantation.
PMID- 9547781
TI - Delayed-onset expulsive choroidal hemorrhage following traumatic globe rupture.
AB - The authors describe a 59-year-old woman who had a traumatic wound rupture 6
months following penetrating keratoplasty. While she was in the pre-operative
holding area awaiting surgical repair, hemorrhagic choroidal detachments
developed. Digital pressure was initiated on diagnosis of imminent expulsion of
intraocular contents and maintained until repair of the wound rupture could be
performed. Four months postoperatively, the patient's vision was 20/80 and her
central pachymetry was 585 microns. This case demonstrates that a delayed-onset
expulsive choroidal hemorrhage may be successfully managed with simple and rapid
intervention based on knowledge of the disease process.
PMID- 9547780
TI - The use of pneumatic retinopexy to delay surgical repair of a retinal detachment
associated with the ganciclovir intraocular device.
AB - Rhegmatogenous retinal detachments are associated with cytomegalovirus (CMV)
retinitis and the use of the ganciclovir intraocular device. Pars plana
vitrectomy with silicone oil tamponade is the preferred technique to repair such
detachments. The authors describe the use of pneumatic retinopexy as part of a
treatment strategy in the management of multiple retinal detachments in a patient
with CMV retinitis treated with ganciclovir implants. Pneumatic retinopexy may
benefit patients when the causative retinal break is superior and is located in
an area of retina uninvolved with CMV infection, because it can be used to delay
surgical intervention.
PMID- 9547783
TI - Dislocation of the mandible during the course of cataract surgery.
AB - Spontaneous dislocation of the mandible is a well-described clinical entity with
which the ophthalmologist may not be familiar. However, the widespread use of
intravenous sedation places susceptible individuals at risk for the development
of dislocation of the mandible. The authors describe a patient who underwent
routine cataract surgery and suffered a dislocation of the mandible that
initially went unrecognized. Ophthalmic surgeons who use intravenous sedation
need to be aware of this complication and need to recognize the symptoms so that
patients may receive timely attention.
PMID- 9547782
TI - Monopolar electrosurgical flash fire.
AB - A 78-year-old man underwent ectropion repair with a monopolar electrosurgical
unit. A flash fire occurred, resulting in a loss of eyelashes of the left upper
and lower eyelids. A retrospective analysis of the case was conducted, including
a review of the relevant literature. Although rare, the possibility of a flash
fire should be considered when performing surgery with an electrosurgical unit.
Minimizing supplemental oxygen and electrosurgical power settings may help to
avoid such an incident.
PMID- 9547784
TI - A simple, cost-effective method for practicing phacoemulsification in the
cadaveric eye.
AB - The authors describe an inexpensive, reliable method for practicing intraocular
surgery using a rigid contact lens as a temporary keratoprosthesis. This method
allows clear visualization of the anterior chamber and lenticular structures for
practicing modern cataract surgery, including capsulorhexis, hydrodissection,
phacoemulsification, cortical aspiration, and intraocular lens insertion.
PMID- 9547785
TI - Localized delivery of anti-cancer drugs by electroporation.
PMID- 9547786
TI - Yeast arrays join the search for specific drugs.
PMID- 9547787
TI - A molecular basis for sudden infant death syndrome.
PMID- 9547788
TI - New strategies to combat fungal infections.
PMID- 9547789
TI - Animal cell technology for new healthcare products. 15th European Society for
Animal Cell Technology (ESACT) meeting. Tours France 7-11 September 1997.
PMID- 9547790
TI - Transplantation biology: recent advances. 5th basic sciences symposium of the
Transplantation Society. Chautauqua, NY, USA, 6-11 September 1997.
PMID- 9547791
TI - The Human Genome Diversity Project: medical benefits versus ethical concerns.
AB - By the year 2005 the entire human genome should have been sequenced and the genes
identified. But the resulting genomic sequence, although a marvelous
accomplishment, will be a composite of just a handful of individuals selected at
random. The Human Genome Diversity Project was proposed as a means to overcome
these limitations by obtaining genetic information from many diverse populations
of the world. This would give medical geneticists a handle on the variations in
susceptibility to disease among different populations, as well as being of
anthropological value. But would such a project risk exploiting the indigenous
populations involved?
PMID- 9547792
TI - Immune evasion by tumours: involvement of the CD95 (APO-1/Fas) system and its
clinical implications.
AB - T cells can cause the death of tumour cells by two mechanisms, one involving CD95
and the other involving perforin. T-cell activity or reduced tumour-cell
responsiveness towards CD95 stimulation might result in an impaired anti-tumour
immune response and tumour cell outgrowth. Recent data suggest that de novo
expression of the CD95 ligand (CD95L) in tumours might result in elimination of
CD95+ anti-tumour lymphocytes, and that tumours might therefore be privileged
sites. However, conflicting data on the role of CD95L in transplantation
experiments indicate that CD95L expression alone might not be sufficient to
confer the status of immune privilege.
PMID- 9547793
TI - Regulation of cardiovascular collagen deposition by mechanical forces.
AB - Collagen is a vital component of the extracellular matrix of both the heart and
blood vessel walls. It acts as a scaffold to maintain myocardial shape and permit
an even distribution of force, and plays a crucial role in the mechanical
properties of the blood vessels. Under normal circumstances, collagen is
continually being synthesized and degraded throughout life. Increased mechanical
stress, which causes myocardial hypertrophy and vessel wall thickening,
stimulates collagen turnover. If collagen is deposited in excess (fibrosis),
tissue function can be compromised. An understanding of the mechanisms of
'mechanosignal transduction' involved in this process will enable therapeutic
approaches to be devised that will prevent inappropriate collagen deposition and
thereby help to preserve function.
PMID- 9547794
TI - Antibodies to OX-40 (CD134) can identify and eliminate autoreactive T cells:
implications for human autoimmune disease.
AB - Autoantigen-specific CD4+ T cells have been implicated as the causative cell type
in: multiple sclerosis, rheumatoid arthritis, autoimmune uveitis, diabetes
mellitus, inflammatory bowel disease and graft-versus-host disease. The pathology
of a number of experimentally induced autoimmune diseases is also mediated by
autoantigen-specific CD4+ T cells. Ideally, treatment of CD4+ T-cell-mediated
diseases would eliminate the autoantigen-specific cells, while sparing the
remainder of the T-cell repertoire. We have developed an effective therapy that
deletes the autoreactive T cells at the site of autoimmune tissue destruction.
This approach uses an antibody directed against a cell-surface protein (OX-40,
also known as CD134) that is selectively upregulated on activated autoantigen
specific T cells within the inflamed tissue.
PMID- 9547796
TI - Is routine dilation a waste of time?
PMID- 9547795
TI - Strategies for achieving multiple layers of selectivity in gene therapy.
AB - Here we review the progress towards the development of targeted vectors for
direct in vivo delivery in gene therapy. Currently, there are many separate
approaches. These include: simple physical/anatomical localization of
administration of the vector at the site where gene transfer is required;
exploitation of natural tropisms of plasmid, viral and cellular vectors; and the
use of molecular engineering to change the specificity of proteins and nucleic
acids so that they specifically recognize target ligands expressed on/in the
target cells. Unfortunately, each of these approaches is usually imperfect by
itself. However, combinations of these strategies might produce vectors in which
several layers of imperfect targeting give an overall level of specificity that
can justify systemic delivery of vectors to treat human disease.
PMID- 9547797
TI - Free-floating vitreous cyst.
AB - Cysts of the vitreous are an unusual clinical finding, with only about 50 such
cases reported in the literature. The sizes of the cyst may vary from 0.15 to 12
mm, and they have been found in the anterior and posterior vitreous. The etiology
has been theorized to be both congenital and acquired. Acquired cysts may be due
to trauma or other forms of intraocular inflammation. Pigmented cysts are
believed to originate from the pars ciliaris and nonpigmented cysts are likely to
be derived from the remnants of the hyaloidal artery system. The appearances of
the cysts are striking and are often seen as clear spherical bodies in the
vitreous with interesting interlacing surface patterns. The cysts are benign and
are of little significance, except when they encroach on the visual axis and
produce visual disturbances (usually floater symptoms).
PMID- 9547798
TI - Visual correlates of obstacle avoidance in adults with low vision.
AB - This study examined how mobility performance in a heterogeneous sample of
visually impaired adults relates to measures of visual sensory and perceptual
function. We found that the best predictors of mobility performance under
photopic and scotopic lighting conditions were models that incorporated visual
field extent (VFE) and scanning ability. Together with measures of contrast
sensitivity and spatial resolution, these models accounted for approximately 50%
of the variance in mobility performance. We also found that VFE and scanning
ability were the dominant predictor variables when the sample was broken down by
subjects' type of vision loss into an acuity loss, a visual field restriction,
and a combination loss group.
PMID- 9547799
TI - Psychophysics of reading. XVII. Low-vision performance with four types of
electronically magnified text.
AB - Most people with low vision need magnification to read. Page navigation is the
process of moving a magnifier during reading. Modern electronic technology can
provide many alternatives for navigating through text. This study compared
reading speeds for four methods of displaying text. The four methods varied in
their page-navigation demands. The closed-circuit television (CCTV) and MOUSE
methods involved manual navigation. The DRIFT method (horizontally drifting text)
involved no manual navigation, but did involve both smooth-pursuit and saccadic
eye movements. The rapid serial visual presentation (RSVP) method involved no
manual navigation, and relatively few eye movements. There were 7 normal subjects
and 12 low-vision subjects (7 with central-field loss, CFL group, and 5 with
central fields intact, CFI group). The subjects read 70-word passages at speeds
that yielded good comprehension. Taking the CCTV reading speed as a benchmark,
neither the normal nor low-vision subjects had significantly different speeds
with the MOUSE method. As expected from the reduced navigational demands, normal
subjects read faster with the DRIFT method (85% faster) and the RSVP method
(169%). The CFI group read significantly faster with DRIFT (43%) and RSVP (38%).
The CFL group showed no significant differences in reading speed for the four
methods.
PMID- 9547800
TI - Benefits of rapid serial visual presentation (RSVP) over scrolled text vary with
letter size.
AB - We previously reported that low vision readers do not benefit from a rapid serial
visual presentation (RSVP) display relative to a scroll display. Each reader in
those studies was presented with only one letter size, and it was the same for
both displays. In the current study, we systematically varied the size of the
letters and compared reading rates from the 2 displays for letters that were 2,
4, 6, 8, and 10 times each reader's acuity threshold. Using this paradigm, we
found that subjects with normal vision (n = 12) read faster with RSVP for all
text sizes. Low vision subjects (N = 20) showed no benefit of RSVP until the text
was at least 8x their acuity threshold. As in our prior studies, there was a
great deal of variability within the low vision group, and for a small number of
subjects (25%), reading was faster from the scroll than from the RSVP display.
PMID- 9547801
TI - Corneal aberrations, monocular diplopia, and ghost images: analysis using corneal
topographical data.
AB - Corneal irregularities can create conditions in which monocular diplopia, "ghost
images," and multiple images of various types occur, thus degrading vision. For
these secondary images to occur, corneal irregularities must create areas which
form: (1) images which are displaced from the primary image; (2) sufficiently
focused images; and (3) images which have sufficient contrast to be noticed in
the presence of the primary image. Criteria necessary to satisfy these three
conditions using measurable data are developed. The concept of a differential
deflection field is introduced, and a method to create this field using corneal
topography data is developed. It is shown how to use differential deflection
field data to assess if conditions necessary for creating secondary images will
occur in cases of corneal distortion.
PMID- 9547802
TI - Validating a "pillar and collar" technique for measuring the edge lift of rigid
contact lenses.
AB - PURPOSE: The clinical importance of the edge lift of rigid contact lenses is
often neglected, possibly due to previous difficulties in its measurement. A new
method of measuring axial edge lift (AEL) and radial edge lift (REL) using
standard contact lens verification equipment, such as an optical spherometer, a
thickness gauge, and contact lens V gauge, is described. METHODS: The technique
was validated for trueness (accuracy) and precision (repeatability) by measuring
the edge lift of a number of monocurve lenses, manufactured both with and without
a normal edge finish. RESULTS: Edge lift was measured to an accuracy of 0.01 mm.
CONCLUSIONS: As long as a mean of eight independent measurements of back optic
zone radius (BOZR), sagitta, and one measurement of center thickness are taken,
the pillar and collar technique is capable of producing accurate and repeatable
measurements of the edge lift of a rigid contact lens.
PMID- 9547803
TI - "Pillar and collar" technique for measuring the axial edge lift of multicurve
rigid lenses.
AB - BACKGROUND: The method of using an optical spherometer and a lens thickness
gauge, in combination with a pillar and collar, has previously been shown to be
repeatable and accurate (to 0.01 mm) in measuring the edge lift of rigid
monocurve lenses. PURPOSE: This paper goes on to validate the technique for
measurements taken on edge-finished multicurve rigid lenses. METHODS: The axial
edge lift (AEL) of a series of multicurve rigid lenses having known values of AEL
was measured using an optical spherometer, a thickness gauge, and contact lens V
gauge in a similar way as was described in the companion paper. RESULTS: The
results show that as long as a correction factor of 0.01 mm is applied, as found
in the previous paper, the technique will allow satisfactory verification of the
edge lift. CONCLUSIONS: The technique is accurate and reproducible, even in
multicurve lens designs, provided that a calibrating correction factor of 0.01 mm
is applied to account for methodological error. It will also indirectly allow the
accuracy of manufacture of the peripheral curves and diameters of any rigid
contact lens to be verified.
PMID- 9547804
TI - Influences of the accommodative stimulus and aging on the accommodative
microfluctuations.
AB - The effects of the accommodative stimulus and age on the accommodative
microfluctuations were investigated in human subjects. Accommodative responses
were measured by using an infrared (IR) optometer, and accommodative
microfluctuations were quantified by power spectrum analysis. Two frequency bands
were determined: low frequency components (< 0.5 Hz, LFC) and high frequency
components (1.3 to 2.2 Hz, HFC). Among younger subjects, the changes in the HFC
in response to the accommodative stimuli differed between subjects. The activity
of the HFC reached a peak in the center of the accommodation range, whereas the
activity of the LFC was its maximum in the presence of darkness or blur in the
over-accommodation range. Smaller changes in the magnitude of the HFC were
observed in older subjects. Although the LFC may be controlled neurologically,
the HFC seems to arise from mechanical and elastic properties of the lens, and
may be modulated by other physiological rhythmic variations.
PMID- 9547805
TI - Influence of spatial distribution with blur on fluctuations in accommodation.
AB - PURPOSE: We investigated the influence of spatial distribution of retinal image
with blur on the waveform of microfluctuations in accommodation. METHODS: We
studied changes in accommodation in 8 young emmetropic subjects (21.88 +/- 2.36
years old), who viewed monocularly a target with the natural pupil. The spatial
frequency of the target was varied from 0.85 to 15 cpd in 7 steps, and the blur
intensity was increased in 7 steps to obtain a Gaussian distribution of retinal
image. Continuous accommodation signals were recorded using an eye-tracking
infrared optometer with a sampling frequency of 40.98 Hz, and analyzed with a
fast Fourier transform (FFT) analyzer. The power spectra of the low frequency
component (LFC, < 0.6 Hz) and the high frequency component (HFC) at approximately
1.9 Hz were calculated for each target with a frequency resolution of 0.02 Hz.
RESULTS: Microfluctuations in accommodation increased as the blur was increased
and decreased at further increases in blur intensity level. Microfluctuations
peaked at a lower blur level as the spatial frequency was increased. Power
spectral analysis revealed that these changes in the microfluctuations could be
attributed mainly to increases of power in the LFC. CONCLUSIONS: Blurring of the
edge and reduction in contrast provided accommodative cues, inducing
microfluctuations in accommodation, and the LFC increased as the target sharpness
was reduced, possibly in an attempt by the accommodation system to maintain the
sharpness of the retinal image under poor stimulus conditions. However, when the
blur level was increased, the amount of blur was indistinguishable and
microfluctuations in accommodation decreased.
PMID- 9547807
TI - Freeze-dried cortical allografts.
PMID- 9547806
TI - Broken intramedullary femoral nail.
PMID- 9547808
TI - Consumers losing confidence in managed care.
PMID- 9547809
TI - The effect of partial lateral meniscectomy in patients > or = 60 years.
AB - To determine the benefit, if any, of meniscectomy in an older population, all
patients > or = 60 years who underwent partial lateral meniscectomy were
evaluated. Thirty-five patients (36 knees) were available for follow-up. The
average patient age was 64.9 years. Patients were divided into two groups based
on the degree of articular cartilage damage. Patients in group 1 had no damage
worse than grade II and underwent arthroscopic partial meniscectomy only, while
patients in Group 2 had grade III or IV damage and underwent arthroscopic
debridement as well as partial meniscectomy. With an average follow-up of 36.8
months, the overall failure rate was 13.9%. Eighty-six percent of the patients
reported the overall assessment of their knee as improved (94% and 80% in groups
1 and 2, respectively). While patients in group 2 tended to have less favorable
results than patients in group 1, these results indicate that this procedure is
warranted and that both groups benefited significantly from partial meniscectomy.
PMID- 9547810
TI - Side effect of ibuprofen and valproic acid.
PMID- 9547811
TI - Post-traumatic heterotopic ossification about the elbow.
AB - To evaluate the effect of surgical timing on the formation of heterotopic
ossification about the elbow, 71 consecutive patients with elbow trauma requiring
operative management were evaluated. Fourteen patients were excluded because they
suffered from head injury, burns, or severe open injuries requiring surgery on
two or more occasions. Sixteen patients were lost to follow-up, leaving a group
of 41 patients. The average age of patients was 35 years. The fractures involved
the olecranon in 19, distal humerus in 12, and radial head/neck in 10 patients.
Six of these fractures were accompanied by a dislocation. Eleven were open
injuries; the remaining 30 were closed. Bone grafting was performed in nine
patients. The interval between injury and surgical intervention averaged 57
hours. None (0%) of 17 patients treated within 48 hours developed grade II, III,
or IV heterotopic ossification, whereas 8 (33%) of 24 patients treated after 48
hours developed grade II, III, or IV heterotopic ossification. There were no
significant differences in demographic or injury parameters between these two
groups. These findings suggest that fixation of unstable elbow fractures within
48 hours of injury may reduce the formation of ectopic bone.
PMID- 9547812
TI - The Richards Series 2 total hip prosthesis: a 13-year study and radiographic
evaluation.
AB - This retrospective long-term study analyzes the clinical function, failures, and
radiographic status of 131 Richards Series 2 prostheses in total hip
arthroplasties (THAs) performed during 1981 and 1982. After a minimum follow-up
period of 11 years, the results were evaluated. Sixty two (54%) patients with 71
THAs were available for follow-up; 44 (38%) patients with 49 THAs had died. Three
patients with three THAs were lost to follow-up, and seven patients with eight
THAs were unable to participate in the examination due to causes not related to
their present hip status. Ten patients underwent revision THA during the
observation period. The median hip functional index (HFI) was 8.6 preoperatively
and 15.8 at follow-up. Hip functional index correlated to radiographic signs of
loosening. With revision as endpoint, the Kaplan-Meier survivorship for all 131
hips was 93% after 10 years and 91% after 12 years. The radiographic examination
at follow-up revealed 5 (8%) definite loose cups and 12 (19%) definite loose
stems. Including the number of aseptic loosened cups and stems confirmed at
revision, aseptic loosening was found in 6% of all cups and 13% of all stems.
This radiographic evaluation confirmed that lack of containment of the cup and
varus position of the stem were factors influencing the long-term stability of
the prostheses, whereas etiology, type of arthritis, and ectopic ossification did
not. A fixation and stability score that was modified for cemented prostheses was
developed and was of value in detecting the prostheses at risk. The long-term
results of the Richards Series 2 THA are acceptable and comparable with other
long-term studies on conventional prosthetic designs. Ten percent to 20% revision
THAs due to aseptic loosening can be expected. In addition, patients younger than
age 60 at surgery and especially men were found to belong to a high-risk group
with regard to revision THA. These patients must be evaluated carefully so that
revision THA can be performed before the bone bed is destroyed.
PMID- 9547813
TI - Comparison of fixation methods for preventing pelvic ring expansion.
AB - Several methods of external and internal fixation are used in urgent situations
to lessen intrapelvic bleeding associated with unstable pelvic fractures. Pelvic
stabilization limits pelvic expansion and thereby restricts the space for
potential blood loss. This study compared several fixation methods using
cadaveric pelves to determine which method best prevents pelvic expansion. Three
methods of internal fixation and three methods of external fixation were
compared. Anteroposterior fixation provided the greatest control against pelvic
expansion; however, it is clinically impractical for emergency use. Therefore,
external fixation provided the most reliable control of pelvic expansion in the
emergency setting.
PMID- 9547814
TI - The effects of pulsed electromagnetism on fresh fracture healing: osteochondral
repair in the rat femoral groove.
AB - Some clinical studies have claimed significant reductions in the healing time of
fresh fractures with the use of pulsed electromagnetic fields (PEMFs). Animal
models, however, have produced more equivocal results. This investigation
examined the effects of PEMF treatment on an osteochondral defect placed in the
patellofemoral groove of the rat. The results indicated that PEMF enhances early
vascular reaction and suppresses initial pannus proliferation. Early
chondrogenesis and bone formation were consistently stimulated, and the
restoration of normal bone trabeculae advanced. Pulsed electromagnetic field
treatment therefore may be useful in advancing repair during the early
proliferative stage. Later results were variable and suggest that prolonged use
may have deleterious effects, enhancing chondrogenesis beyond a point observed in
normal repair and thus delaying normal subsurface trabeculation.
PMID- 9547815
TI - Functional distal interphalangeal joint splinting for trigger finger in laborers:
a review and cadaver investigation.
AB - This two-part study evaluates the efficacy of functional distal interphalangeal
joint (DIP) splinting for the treatment of trigger finger. Thirty-one fingers
from 21 meat packing plant workers were treated with DIP splinting. A single
corticosteroid injection was offered if triggering was stage 4 or greater. All
workers returned to work immediately. Eighty-one percent of the digits were
treated successfully (mean follow-up: 1 year). Treatment failure correlated with
duration of symptoms and stage of triggering but did not correlate with age,
race, sex, disease in multiple digits, or prior treatment. For the second part of
the study, the effect of DIP splinting on flexor digitorum profundus (FDP) tendon
excursion was studied in 16 fingers from 4 fresh cadavers. Excursion decreased
4.8 mm for the Stax splint and 4.2 mm for the dorsal Alumafoam splint. We
conclude that DIP splinting provides a reliable and functional means of treating
work-related trigger finger without lost time from work. Our cadaver
investigation supports our theory that DIP splinting significantly decreases FDP
excursion.
PMID- 9547816
TI - Newborn clavicle fractures.
AB - A prospective screening program of 9106 newborns identified 43 infants with
clavicle fractures for a prevalence of 1 fracture in every 213 live births
(0.5%). The fractures were equally distributed by right and left side
involvement, and male and female sex. All fractures occurred during vaginal
deliveries. None were breech presentation. Risk factors for fracture included
large birth-weight, shoulder dystocia, mechanically assisted delivery, and
prolonged gestational age. One in 11 newborns with a clavicle fracture also had a
brachial plexus palsy.
PMID- 9547817
TI - Revision arthroplasty of femoral cortex defect using a noncemented stem, Mennen
plate, and bone graft.
AB - Twelve patients who underwent total hip replacement complicated by aseptic
loosening with severe bone loss were included in this study. Two patients had
aseptic loosening of the second revision, six of the third revision, and the
remaining four patients of the fourth revision total hip replacement. In all
patients, the radiographs revealed an extremely thin cortex around the stem of
the prosthesis and almost complete disappearance of one cortex. All patients were
treated by revision total hip replacement in conjunction with Mennen plate
fixation and allograft bone support. The allograft bone support included three
cortical struts and nine massive bone grafts that used cement as a strew. The
results were satisfactory in 10 patients in respect to functional activity, pain
and radiographic evaluation. In two patients who underwent their fifth revision,
the results were unsatisfactory but better than before the operation. Mennen
plate fixation provides a sufficient and easy technique for aseptic loosening of
total hip replacement with severe bone loss. By preserving the periosteal blood
supply, the time required for bone graft incorporation is shortened, resulting in
an early final outcome.
PMID- 9547818
TI - The location of the spinal nerve root on plain radiographs of the cervical spine.
AB - Twelve cervical spines from C2 to T1 were harvested from embalmed cadavers to
study the location of the nerve root on plain radiographs. After removal of the
soft tissue, the spinal nerves just lateral to the transverse processes were
exposed and injected with lead oxide. Plain radiographs including anteroposterior
(AP) and left and right oblique views were taken. Angular and linear measurements
were performed directly on the radiographs. Results showed that the average
frontal angle of the nerve root for all levels was 155 degrees on the AP view,
108 degrees on the foraminal side of the oblique view, and 153 degrees on the
opposite side of the oblique view. The nerve root height for all levels averaged
4.7 +/- 0.5 mm. The interpedicular space height increased consistently from 7.8
+/- 0.7 mm at C3-C4 to 9.0 +/- 1.3 mm at C6-C7 except at C2-C3. The nerve root
height with respect to the interpedicular space height was 56.2% at C2-C3, 57.8%
at C4-C5, and 53.7% at C6-C7. A knowledge of the location of the cervical nerve
root related to plain radiographs may enhance the value of plain radiographs in
the diagnosis and treatment of cervical spinal disorders.
PMID- 9547819
TI - Limb salvage versus amputation for severe open fractures of the tibia.
PMID- 9547820
TI - Osteoblastoma of the acetabulum.
PMID- 9547822
TI - An unusual presentation of locked knee.
PMID- 9547821
TI - Recurrent osteochondromatosis of the shoulder in a child.
PMID- 9547823
TI - Nonunion of the radial neck following fracture of the radial head and neck: case
reports and a review of the literature.
PMID- 9547824
TI - Carpal tunnel syndrome associated with eosinophilic fasciitis.
PMID- 9547825
TI - Primary proximal row carpectomy.
PMID- 9547826
TI - Radiologic case study. Osteochondritis dissecans.
PMID- 9547827
TI - A possible defective estimation of antineutrophil cytoplasmic antibodies in
systemic lupus erythematosus due to the coexistence of periodontitis: preliminary
observations.
AB - The objectives of this study is to determine if periodontitis-related ANCA hinder
the accurate estimation of this kind of autoantibodies in systemic lupus
erythematosus (SLE), due to the frequent coexistence of SLE and periodontitis,
and the high incidence of antineutrophil cytoplasmic antibodies (ANCA) in this
periodontal condition. Thirty SLE, thirty periodontitis lacking systemic
involvement patients, and twenty healthy controls were utilized in this study.
The periodontal condition and the presence of ANCA in sera of all individuals was
carefully evaluated. For ANCA determination an EIA assay was utilized, directed
to a neutrophil granular extract and six neutrophil granule proteins. Sixty
percent of SLE patients had periodontitis, and sixty-five percent were ANCA
positive. Eighty three percent of all ANCA cases were coexisting with
periodontitis. A significant association (p > 0.005) between periodontitis and
ANCA was found (Chi Square Test). Fifty percent of the patients with
periodontitis lacking systemic involvement were ANCA positive. The results
obtained in this study suggest that the figures of ANCA previously reported for
SLE, might be overestimated due to the inadvertent presence of periodontitis.
PMID- 9547828
TI - Early detection of depression using the Zung Self-Rating Depression Scale.
AB - OBJECTIVE: Compare the findings of the application of the Zung self-rating
depression scale to spanish community during the NDSD on three consecutive years
(1993, 1994, 1995). METHOD: 630 adults in a spanish community filled out the Zung
Self Rating Depression Scale (spanish translation) during the NDSD in october
1993, 1994, 1995. The responders were oriented regarding the results and clinical
implications. Scale results were entered on epi-info 6.0 for statistical
analysis. RESULTS: The obtained data shows a female preponderance in all samples.
The groups found with SDS compatible with severe to extreme depression were 9.2%,
9.3 and 11.3% for the respective years. Symptoms more significantly reported by
the responders with a SDS of 50 or more were psychomotor retardation, confusion
and anhedonia. Suicidal ideations were reported in 17.8% (1993), 15.5% (1994) and
20.7% (1995) of the sample. CONCLUSION: Despite the limitations of this study the
results suggest that the Zung self-rating depression scale can be helpful in the
early detection of depression in patients seen in their initial evaluation by the
primary care physician. It's usefulness with spanish speaking communities at
other clinical settings should be assessed more extensively.
PMID- 9547829
TI - Dietary analysis of meals served in the breakfast and lunch programs of Puerto
Rican schools.
AB - BACKGROUND: Nutritional analysis of meals in the Federally-sponsored Breakfast
and Lunch Programs in Stateside Schools has recently been completed. However due
to ethnic and cultural differences, the findings may not be directly applicable
to similar nutrition programs in Puerto Rico. It is our aim to carry out an
analysis of meals served in Federal programs in Puerto Rico and to compare
results to the stateside study. METHODS: Twenty eight different breakfast meals
and 96 different lunch meals being cycled in elementary, middle and secondary
schools throughout the entire island of Puerto Rico were analyzed for content
using the Minnesota Nutrition Data System 32 and compared with: 1) compliance to
meal pattern requirements of federal programs, 2) dietary guidelines for
Americans (DG) and 3) recommended dietary allowances (RDA's). RESULTS: Breakfasts
and lunches served in Puerto Rican Schools satisfy federal meal pattern
requirements however most frequently offered foods different from programs in the
mainland, reflecting ethnic and cultural food preferences. In terms of DG's
adequate protein was present, cholesterol content was satisfactory but meals had
excess percent energy from fat as well as excess energy from saturated fat, high
sodium and a lower than recommended level of energy from carbohydrate. In terms
of RDA's meals had prescribed levels of vitamin A, vitamin B12, vitamin C,
calcium, folacin, magnesium, phosphorus and potassium. Below prescribed levels
included vitamin B6, copper, vitamin E, energy, fiber, iron, niacin and zinc.
CONCLUSIONS: While differences in food preferences exist between foods available
in the Breakfast and Lunch Programs in Puerto Rican and U.S., schools, they have
similar strengths and weaknesses when compared to compliance with U.S. Dietary
Guidelines and with recommended dietary allowances.
PMID- 9547830
TI - Folate supplementation and neural tube defects: a review of a public health
issue.
AB - Folate deficiency is one of today's most common vitamin deficiencies in women.
Women who consume a low level of folate during pregnancy are at risk for poor
pregnancy outcomes including neural tube defects (NTD). However, other factors
such as heredity, social class, maternal age, birth order, maternal diet, length
of time between pregnancies, maternal zinc deficiency, use of anticonvulsant
drugs, abnormal homocysteine metabolism and the use of oral contraceptives, have
also been implicated as causes of NTD. Animal studies have shown that fetuses are
highly dependent on the folate status of the mother. In addition, several
retrospective and prospective human studies have provided evidence that folate
lowers the incidence of NTD.
PMID- 9547831
TI - Cesarean childbirth in Puerto Rico: the facts.
AB - According to the last Island-wide survey carried out in 1982 in Puerto Rico, the
cesarean rate for the trienium of 1980-82 was estimated in 27 percent. Since
1989, an item about the type of delivery has been included in the live birth
certificate. These data indicate that the incidence of cesarean deliveries
continued to increase and by 1994 it amounted to 31 percent, undoubtedly the
highest rate of the world. However, its fluctuation since 1990 suggests that this
type of delivery has finally steadied in Puerto Rico. The high proportion of
repeated cesareans and the low percentage of vaginal birth after cesarean (VBAC)
deliveries were important factors contributing to the overall rate. Unexpectedly
high risk mothers such as, adolescents, unwed and those of the lower
socioeconomic status had highest cesarean rates than their encounterparts.
Similarly, mothers who had the most adequate prenatal care had the highest
percentages of surgical deliveries. In spite of dealing with a selected
clientele, the cesarean rate in private hospitals was more than twice that of
public institutions. In fact, a multiple correlation analysis demonstrate that
the type of hospital of delivery was the most important correlate of a cesarean.
PMID- 9547832
TI - [Women abandoned by Social and Health Agencies. Challenge in the prevention of
HIV/AIDS].
AB - The present study examined the role of an intervention directed to link a group
of sexual workers with social and health services. The subjects receptivity to
use these services was measured by the degree of acceptance that the selected
agencies provided to the participants of this study. The present investigation
included two groups of subjects consisting of sexual workers and other women that
were at high risk of prostitution because of their social circumstances. The
sample consisted of 92 women residents of either the San Juan area of other towns
from the eastern part of Puerto Rico. The method of focal group and a agencies
directory was utilized during the intervention. In addition, the attempt to
establish a helpful relationship between the subject and the agency was also
incorporated to the investigation. The present findings showed the presence of a
considerable social distance between the agencies and the subjects studies. The
use of the studied intervention failed to be an efficient strategy. The authors
recommend to explore different and new intervention modalities that elicit
significant social change. Moreover, these interventions should innovate the
current treatments aimed at the social problems related to sexual work.
PMID- 9547834
TI - Electrophysiology in the 19th century.
PMID- 9547833
TI - Static or frictional electricity and the discovery of direct current.
PMID- 9547835
TI - [Medical justice as a priority for Latin America].
PMID- 9547836
TI - Four-step CPR--improving skill retention.
AB - This study is an attempt to see if simplifying the teaching of basic life support
leads to better skill acquisition and retention. Forty-eight lay volunteers
received instruction in CPR; 24 were taught the standard 8-step sequence whereas
24 were taught a simplified 4-step sequence. Tests of performance were carried
out on a manikin before and after training. Those in the 4-step group were
significantly better than those in the 8-step group at remembering the sequence
of skills immediately after training (P = 0.04), 1 week later (P < 0.001) and at
6 weeks (P < 0.001). Twenty-three out of the 24 volunteers in the 4-step group
got the sequence completely correct each time they were tested, in contrast to
only 2 out of the 24 in the 8-step group. There was no difference, however, in
the quality of performance of the skills between the two groups. In addition, it
was shown that use of the 4-step sequence should result in a useful reduction in
the time taken before a rescuer calls for the emergency services and commences
CPR. Whether such a radical change in teaching should be introduced is a matter
for further discussion and research.
PMID- 9547838
TI - Fatal outcome after polytrauma: multiple organ failure or cerebral damage?
AB - To assess the relative importance of multiple organ failure (MOF) and cerebral
damage on the mortality rate following trauma we analyzed retrospectively the
records from 99 polytrauma patients admitted to a multidisciplinary European
intensive care unit in a 2 year period. In all, 93% of the trauma was non
penetrating and 73% was the result of road accidents. 28 patients died giving an
overall mortality of 28.3%. The cause of death was cerebral lesions in 19
patients, hemorrhagic shock in eight and multiple organ failure in one patient
who had an injury severity score (ISS) of 13. Most deaths (78%) occurred within
24 h of admission, 15 of these were due to extensive cerebral lesions and seven
due to hemorrhagic shock. A total of six deaths occurred after 24 h, four due to
extensive cerebral lesions, one due to hemorrhagic shock and one due to multiple
organ failure. In our experience, cerebral damage was a more common cause of
death than MOF following multiple non-penetrating trauma.
PMID- 9547837
TI - Efficacy of cardiopulmonary resuscitation in pulseless paediatric trauma
patients.
AB - BACKGROUND: A study was designed to determine which paediatric trauma patients
with no detectable vital signs are likely to benefit from cardiopulmonary
resuscitation (CPR). METHODS: A 10-year retrospective study of all pulseless
patients under 16 years of age with trauma in whom CPR was initiated in a
prehospital or in-hospital setting in Southern Finland. RESULTS: Forty-one
patients, 25 male and 16 female, were included in this study. The mean age was
7.8 years (range 0.1-15.9 years). Twenty three patients had blunt injuries and
three patients had penetrating injuries. The mean Injury Severity Score was 51
(range 25-75). In 15 patients, the arrest was secondary to smoke inhalation,
strangulation or electric shock. Resuscitation was initiated at the scene or en
route in 28 patients and in 13 patients at the hospital. Five patients received
open-chest CPR and 36 patients closed-chest CPR. Spontaneous circulation was
restored in four patients with open-chest CPR and in six patients with closed
chest CPR. Two patients had intact survival and one patient survived with
moderate disability. The mechanism of traumatic cardiac arrest, initial cardiac
rhythm or location of arrest did not seem to affect outcome of CPR. CONCLUSIONS:
The overall survival rate of paediatric patients with cardiac arrest secondary to
trauma is poor. Trauma patients in whom cardiac arrest is caused by respiratory
arrest or by thoracoabdominal trauma in the hospital setting may have a chance of
survival if a spontaneous circulation is rapidly restored with effective
resuscitative measures.
PMID- 9547839
TI - Tracheal intubation via the laryngeal mask airway: a viable alternative to direct
laryngoscopy for nursing staff during cardiopulmonary resuscitation.
AB - Eight nurses with no previous experience of advanced airway management were
randomly assigned to be taught tracheal intubation either by direct laryngoscopy
or via a laryngeal mask. Once competent in the technique using a manikin, they
attempted a maximum of ten intubations on anaesthetised patients. They were then
taught the alternative technique and the assessment repeated. Median times for
practice were the same for both techniques. Intubation in under 30 s was
successful via the laryngeal mask in 60% of patients (42/70) compared to 39%
(27/70) when using a laryngoscope (P = 0.11). It appears that non-medical
personnel can be successfully taught to intubate the trachea using the laryngeal
mask as a conduit, for those circumstances where a cuffed tracheal tube is
considered essential during resuscitation.
PMID- 9547840
TI - Effectiveness of mask ventilation in a training mannikin. A comparison between
the Oxylator EM100 and the bag-valve device.
AB - The demands for an optimal ventilation apparatus are that it can be easily
handled, achieves a sufficiently high ventilation volume, and minimizes gastric
inflation. Our aim was therefore to carry out a study in a training mannikin to
find out whether the Oxylator EM100, compared with the bag, obtains improved
ventilation and a decrease in gastric inflation. In a randomized crossover study,
72 subjects were selected (24 physicians, 44 nurses and 4 auxiliary nurses),
chosen from the operating theatre, emergency department and intensive care unit
of two hospitals. We used the Ambu-Bag Mark III with mask No. 4, the Oxylator
EM100 with a pressure setting of 35 cm H2O run in the manual setting, the Ambu
Man C mannikin as well as the Ambu-CPR computer program. The resuscitation cycles
of the standard two-rescuer's adult procedure lasted 3 min each, with a 3-min
pause between the crossover procedure. The participants could improve their
ventilatory volume with the Oxylator EM100 by 635 ml (95% confidence interval 578
692 ml) compared with the bag ventilation. The number of subjects who could
attain a mean ventilatory volume of 800 ml or more increased from 15% to 98.6% (P
< 0.001). Compared with the bag, the increase of adequate respirations (> or =
800 ml) obtained by the Oxylator EM100 for the individual participants amounted
to a median of 91% (P < 0.001). Moreover, conventional ventilation caused in 42%
one or several instances of gastric inflation, whereas no such reactions occurred
with the Oxylator EM100. The Oxylator EM100 showed significantly better results
in the mannikin than the bag. Of most importance is a significant lowering of
gastric inflation and less so a marked increase in ventilatory volume. Our trial
procedure with a relatively high lung compliance and a high oesophageal sphincter
opening simulated favorable conditions. Owing to a large in vivo variability of
these magnitudes, a direct testing in real patients with circulatory arrest is
indicated.
PMID- 9547841
TI - Survival after cardiac arrest outside hospital in Sweden. Swedish Cardiac Arrest
Registry.
AB - The voluntary Swedish Cardiac Arrest Registry has collected and analyzed 14,065
standardised reports on cardiac arrests up until May 1995. The reports have been
collected from approximately half of Sweden's ambulance districts, which cover
60% of the population. Resuscitation was attempted in 10,966 cases. The median
age was 70 years. In 70.0% the arrest was witnessed, and in 43.3% the first
recorded rhythm was VT/VF. Bystander-CPR was initiated in 32.3% of the cases.
Most cardiac arrests took place at home (65.8%) and 67.1% were judged to be of
cardiac origin. In 1692 cases (15.4%), the patient was admitted alive in hospital
and 544 patients (5.0%) were alive after 1 month. Survival to 1 month in the
subgroup which presented with VT/VF was 9.5%. We found no significant difference
between survival in large cities and smaller communities. The survivors were
analysed in relation to time to defibrillation and we found a strong correlation
between a short time and increased survival.
PMID- 9547842
TI - A rule for early outcome classification of out-of-hospital cardiac arrest
patients presenting with ventricular fibrillation.
AB - The aim of the study was to develop a scoring system for outcome classification
at the start of prehospital first tier resuscitation for patients with cardiac
arrest from ventricular fibrillation (VF). We studied a consecutive sample of 100
out-of-hospital cardiac arrest patients, presenting with VF of presumed cardiac
etiology on arrival of the first tier (in a two-tiered urban Emergency Medical
Services system). The number of patients discharged was 29 ('survivors') and 71
died ('non-survivors'). The electrocardiography (ECG) tracings recorded during
resuscitation using a semi-automatic defibrillator were retrospectively analysed.
For each patient, VF amplitude in mV (VF_a) and the number of base-line crossings
per second (VF_blc) were calculated. Fisher's linear discriminant analysis was
applied to discriminate between survivors and non-survivors using the variables
VF_a, VF_blc and age. Patients were classed as potential survivors or non
survivors using a survival index = 0.6*(VF_a) + 0.4*(VF_blc)-4.0. If for a given
patient the survival index is < 0, he is classified in the non-survivor group, if
the survival index is > 0, he is classified in the survivor group. Using this
index 79% of the survivors and 70% of the non-survivors could be classified
correctly. Adding age to the formula increased the correct classification of
survivors to 86 and 73% for the non-survivors. The survival index provides a
research tool for the discrimination between potential survivors and non
survivors, which opens the possibility for the development of alternative
treatment protocols in cardiac arrest.
PMID- 9547843
TI - Neurological and circulatory outcomes of cardiopulmonary resuscitation in
progress: influence of pre-arrest and arrest factors.
AB - Possible correlations between the circulatory and neurological responses to
cardiopulmonary resuscitation (CPR) and the influence of pre-arrest factors
(demographic data, medical history and aetiology of circulatory arrest) and
arrest factors (location of arrest, ECG configurations, and duration of
resuscitation) on the course of circulatory and neurological recovery were
investigated in 111 victims of circulatory arrest. At the start of resuscitation
57 patients (Group I) had some brain function and 54 (Group II) had no brain
function. Sixty nine patients (62%) had circulation restored but 54 (78%) were
left with heart failure. Forty one patients (39%) survived the first day, 26
(63%) with heart failure; only 34 (31%) were alive after 48 h, 17 (50%) with
heart failure. Half of the patients surviving 24 or 48 h had awakened.
Consciousness returned in 32 patients (29%) during the first 48 h, more
frequently in Group I than in Group II. Patients in Group I had a higher
incidence of in-hospital arrest and had their circulation restored more often
than those in Group II. Survival and post-resuscitation heart failure was alike
in the groups. The pre-arrest factors explored did not modify the circulatory or
neurological outcome whereas initial ventricular fibrillation was significantly
related to recovery of consciousness. The revivability of spontaneous circulation
and of neurological functions was found thus mainly to be determined by global
ischaemia sustained prior to and during CPR.
PMID- 9547844
TI - Evaluating CPR performance in basic life support: the VIDRAP protocol.
AB - This paper presents the second part of the validated Cardiff test for one rescuer
basic life support skills, based on observation of video recording combined with
the Recording Resusci Anne printout (VIDRAP). The authors believe that this is a
robust evaluation tool which is capable of assessing the potential value to a
casualty of a simulated resuscitation. The adoption of a widely accepted test
methodology would facilitate comparison of research in different centres, which
is not possible at present.
PMID- 9547845
TI - Impact of a child first aid wall calendar on lay people's skills and knowledge of
infant CPR.
AB - The aim of the study was to evaluate whether mass-mailing of a 12-month wall
calendar which focused on child and infant safety and first aid treatment had any
educational effect on lay people. The calendar included algorithms for removal of
a foreign body from the airways and infant and child CPR. The knowledge and
skills in these procedures were tested in two groups using a previously validated
check-list before and after the introduction of the calendar. One group received
the calendar by mass mailing, free-of-charge. Six months after calendar
distribution the mean result for 52 persons tested was 18% correct, not different
from the 19% correct for 65 persons tested before calendar distribution. The
other group received the calendar as part of an internal company campaign
focusing on infant and child safety with a possibility for borrowing a baby
manikin, but with no instruction involved. In this group the mean result improved
significantly from 27% precalendar (n = 57) to 47% (n = 125) (P < 0.001) 1 week
after calendar distribution with a significant reduction to 38% (n = 52) (P =
0.004) 6 months later, still significantly better than precalendar (P = 0.004).
Test persons younger than 50 years old scored better than those older than 50
years (39 vs. 22%, P < 0.001), and the test persons scored better if they had
been tested previously (44 vs. 35%, P = 0.04) or had practised with a baby
manikin (45 vs. 35%, P = 0.02). Whether the test persons had children 0-8 years
old or not, did not affect the results. In conclusion the calendar had no
educational effect when distributed by mail, but a safety campaign which included
distribution of the calendar and a possibility to borrow a manikin had a positive
influence on the first aid skills and knowledge of lay people. Mass mailing of
CPR or other first aid material free-of-charge does not seem to further the goal
of increasing the rate and proficiency of bystander interventions to save lives.
PMID- 9547847
TI - Severe ventilatory compromise due to gastric distention during pediatric
cardiopulmonary resuscitation.
AB - We describe a child in cardiac arrest with severe ventilatory compromise due to
gastric distention. During cardiopulmonary resuscitation (CPR), positive pressure
ventilation may lead to gastric insufflation because of decreased pulmonary
compliance and decreased lower esophageal sphincter tone. Essentially, gas
delivered will follow the path of least resistance, which may be to the stomach.
In our patient, gastric distention precluded effective ventilation and gastric
decompression relieved ventilatory compromise. The values and pitfalls of
clinical evaluation and capnography are presented.
PMID- 9547846
TI - Changes in brainstem auditory evoked response latency predict survival after CPR
in a rat model of cardiac arrest and resuscitation.
AB - Brainstem auditory evoked responses (BAER) are routinely used to monitor
brainstem function in hospitalized comatose patients. We used a rat model of
cardiac arrest and resuscitation to explore the possibility that the BAER,
monitored during and immediately after cardiopulmonary resuscitation (CPR), could
be used to determine whether the CPR was effective in restoring brainstem blood
flow. Long-Evans rats were subjected to 7 min of cardiac arrest, induced by chest
compression under Ketamine anesthesia sufficient to mechanically prevent the
heart from pumping blood and were then resuscitated using a standard CPR
protocol. During CPR, click stimuli were applied to one ear at 11/s and BAER
averages recorded every 15 s. In three rats the BAER did not return after CPR;
none of these rats respired spontaneously and all died. In 33 rats the BAER did
return; within 15 min after the start of CPR BAER peak latencies decreased
rapidly, increased again and then decreased. If the increase in the latency of
the N2 peak was less than 0.3 ms, then the rat survived. If it was greater than
0.35 ms the rat died. This signal was used as a cue for intervention in three
rats; two survived. Thus, in this preparation, the BAER provided a useful measure
of CPR effectiveness, in time to permit successful intervention.
PMID- 9547848
TI - A reappraisal of mouth-to-mouth ventilation during bystander-initiated
cardiopulmonary resuscitation.
PMID- 9547849
TI - A reappraisal of mouth-to-mouth ventilation during initiated cardiopulmonary
resuscitation.
PMID- 9547850
TI - Immunosuppressive drugs in the treatment of inflammatory bowel disease.
AB - Immunosuppressive (IS) drugs are an important option in the management of both
forms of inflammatory bowel disease (IBD): Crohn's disease and ulcerative
colitis. As the experience of using these agents in the treatment of IBD has
increased and more data have become available on their efficacy, these drugs are
being used more extensively. The principle drugs used in clinical practice at
this time include: azathioprine (AZA) and its metabolite 6-mercaptopurine (6-MP),
methotrexate, and cyclosporin A. AZA and 6-MP are generally considered the first
line immunosuppressive agents. These drugs are effective and generally well
tolerated by the majority of patients started on them, enabling many patients to
avoid the predictable side effects of steroid therapy. Because of their extensive
use, it is important that clinicians involved in the care of IBD patients are
familiar with the IS drugs used to treat IBD, especially AZA and 6-MP.
PMID- 9547851
TI - Medical management of perianal Crohn's disease.
AB - Perianal disease is a frequent complication necessitating both medical and
surgical management in Crohn's disease. Fissures, fistulae, or abscesses are
found in approximately 36% of patients; occur more often in the ileocolonic and
colonic disease; and may precede the onset of intestinal symptoms (Farmer et al,
Gastroenterology 68:627-635, 1975; Rankin et al, Gastroenterology 77:914-920,
1979; Gray et al, Gut 6:515-524, 1965; and Homan et al, Arch Surg 111:1333-1335,
1976). To approach perianal manifestations, the physician must identify the
anatomic location of the disease, treat the suppurative complications, and
consider a long-term approach to palliation of chronic inflammatory sequelae.
This article will review the medical management of perianal Crohn's disease and
indications for surgery.
PMID- 9547852
TI - Surgical options in the management of perianal Crohn's disease.
AB - Perianal complications of Crohn's disease are common, and surgical management has
been controversial. Over the last 10 years, improved outcomes have defined a more
prominent role for operative interventions, especially with respect to management
of focal perineal sepsis and fistulas. Liberal placement of drainage catheters
and noncutting setons, advancement flap closure of perineal fistulas, and
selective construction of diverting stomas have good results when combined with
optimal medical therapy to induce remission of inflammation. Proctectomy, which
is infrequently required, can often be postponed for several years when
complementary surgical and medical treatments are provided.
PMID- 9547853
TI - Nutritional issues and therapy in inflammatory bowel disease.
AB - Nutritional issues in inflammatory bowel disease (IBD) often receive inadequate
attention both in regard to therapy and nutritionally related complications of
IBD. This article reviews much of the research that has evaluated the role of
diet in the causation, primary treatment, and adjunctive therapy of both
ulcerative colitis (UC) and Crohn's disease (CD). Benefits have been demonstrated
in the use of elemental diets or polymeric diets in CD in both acute flare up or
maintenance of IBD. A careful team approach can overcome problems in implementing
nutritional therapy. Nutrition also has a critical benefit in postoperative CD
and perioperative UC. Numerous easily corrected, nutritional abnormalities are
often overlooked in patients with IBD, which may have significant consequences.
Nutritional therapy may have a central place in the hierarchy of treatment in IBD
and further research is critical in this area to better define the benefits of
nutrition in IBD.
PMID- 9547854
TI - The medical management of acute fulminant ulcerative colitis.
PMID- 9547855
TI - Pharmacological and toxicological effects of chronic porcine growth hormone
administration in dogs.
AB - The purpose of this study was to evaluate the pharmacological and toxicological
effects of exogenous GH administration in normal adult dogs. Because porcine GH
(pGH) is structurally identical to canine GH, pGH was selected for a 14-wk study
in dogs. Thirty-two dogs (< 2 yr) were randomized to 4 groups (4 dogs/sex/group);
1 group was treated with the vehicle and 3 groups received pGH at 0.025, 0.1, or
1.0 IU/kg/day subcutaneously. Daily clinical signs and weekly body weights were
recorded. Hematology, serum biochemistry, urinalyses, electrocardiograms, and
ophthalmoscopic examinations were done. Serum GH, insulin-like growth factor-1
(IGF-1), insulin, thyroxine (T4), triiodothyronine (T3), and cortisol levels were
determined. Necropsies were performed, organs weighed, and tissues were fixed and
processed for light microscopic examination. Porcine GH caused increased body
weight gain (p < or = 0.05) through the mid dose; the mean weight gains at study
termination in mid- and high-dose groups were 2.8 kg and 4.7 kg, respectively,
compared to 0.4 kg and 0.8 kg in control and low-dose groups, respectively. Dose
related increased weights of liver, kidney, thyroid, pituitary gland, skeletal
muscle, and adrenal gland were noted. In pGH-treated dogs, increased skin
thickness seen grossly correlated histologically with increased dermal collagen.
There was no gross or histomorphological evidence of edema. There were dose
related increased serum IGF-1 levels (approximately 2-10-fold; p < or = 0.05)
that correlated with the elevated serum GH levels in pGH-treated dogs. Also,
increased serum insulin levels (p < or = 0.05) through the mid dose were seen
throughout the study. In high-dose dogs, the insulin levels remained elevated
over 24 hr postdose. The serum glucose levels in fasted dogs remained within the
control range and there was no chronic hyperglycemia based on glycosylated
hemoglobin levels. Renal glomerular changes, significant polyuria with decreased
urine specific gravity, and increased serum insulin levels suggested that the
dogs had early insulin-resistant diabetes. There was minimal or no biologically
significant effect of pGH on serum T3, T4, and cortisol levels in dogs. Other
serum biochemical changes in pGH-treated dogs included decreased urea nitrogen
and creatinine, and increased potassium, cholesterol, and triglycerides.
Significant increases in serum calcium and phosphorous levels and alkaline
phosphatase activity (bone isozyme) correlated with the histological changes in
bone. In pGH-treated dogs, there was a dose-related normochromic, normocytic,
nonregenerative anemia. The changes described above, except for the anemia, are
related to either anabolic or catabolic effects of high doses of GH. Based on
this study, it is concluded that the dog is a good model in which to evaluate the
safety of GH secretagogues as well as compounds with GH-like activity.
PMID- 9547856
TI - Morphological changes in the pituitary gland of dogs chronically exposed to
exogenous growth hormone.
AB - Growth hormone (GH) synthesis and release from the pituitary is regulated by
hypothalamic releasing hormone, insulin-like growth factor-1 (IGF-1), and
somatostatin. However, the potential effects of pharmacological doses of
exogenous GH on the pituitary are not well studied. To determine the potential
chronic effects of exogenous GH on pituitary morphology in dogs, porcine GH (pGH)
was administered subcutaneously to 3 groups of dogs (4 animals/sex/group) at
doses of 0.025, 0.1, and 1.0 IU/kg/day for 14 wk. A group (4/sex) of dogs served
as the vehicle control. The pituitaries from all dogs were weighed and fixed in
appropriate fixatives for light and electron microscopic examination; in
addition, cells of the pars distalis were quantitated by a point counting method
following immunostaining to identify cells containing GH, prolactin (PRL), and
adrenocorticotrophic (ACTH) hormones. Administration of pGH resulted in a
statistically significant (p < or = 0.05) increased pituitary weight through the
high dose. By light microscopy (LM), hypertrophy of pars distalis cells was
evident in mid- and high-dose female dogs. The pituitaries of dogs given the
lowest dose (0.025 IU/kg/day) of pGH were not remarkable based on weight and LM
findings. In addition, transmission electron microscopic (TEM) examination of the
pituitary gland of high-dose demonstrated, in both sexes, pituitary cells with
variably dilated rough endoplasmic reticulum and decreased numbers of secretory
granules; some of these cells reacted positively to GH immunostaining.
Quantitative analysis of the pituitary gland of high-dose males and females
showed an increase in the absolute volume of all cell populations studied: GH-,
PRL-, and ACTH-positive cells. Based on the LM and TEM findings, the increased
volume of the cell populations studied is likely related to cellular hypertrophy.
The expected elevation in serum GH levels following repeated administration of
pGH and an associated elevation in serum IGF-1 levels resulted in morphologic
changes in the pituitary gland of dogs given high doses (> or = 0.1 IU/kg/day) of
pGH; these observations differed from the reported findings in pituitaries of
transgenic mice secreting large quantities of bovine GH.
PMID- 9547857
TI - Effect of chronic growth hormone administration on skeletal muscle in dogs.
AB - Administration of growth hormone (GH) results in increased body weight gain in
dogs. Increased body weight gain is believed to be a result of the trophic effect
of GH on the musculoskeletal system. However, edema is one of the side effects
described in man following exogenous GH administration. Thus, the objective of
this study was to determine if the expected increased weight gain in GH-treated
dogs is a result of increased muscle mass. Porcine growth hormone (pGH),
administered subcutaneously to beagle dogs at doses of 0.025, 0.1, and 1
IU/kg/day for 14 wk, resulted in elevated serum GH and insulin-like growth factor
1 (IGF-1) levels (see accompanying paper, Prahalada et al). This was associated
with a significant increase in body weight gain and weights of the cranial
tibialis muscle in both male and female dogs. The increased muscle mass likely
contributed to the significant increase in body weight gain seen in both sexes.
Quantitative analysis of skeletal muscle sections stained for ATPase activity
showed increases in type I (slow twitch) and type II (fast twitch) myofiber sizes
in mid- and high-dose males and in high-dose females. The ratio of type I and
type II muscle fibers remained unchanged. Hypertrophic myofibers were enlarged
but had a normal histologic and ultrastructural organization when observed by
light and transmission electron microscopy. The results of this study have
demonstrated that increased muscle mass in pGH-treated dogs is related to
hypertrophy of muscle fibers and not due to edema. Exogenous GH administration
has an anabolic effect on skeletal muscle in dogs.
PMID- 9547858
TI - Growth hormone augmentation--a new era?
PMID- 9547859
TI - Ocular irritation: microscopic changes occurring over time in the rat with
surfactants of known irritancy.
AB - The pathology of surfactant-induced ocular irritation, especially in the context
of accidental human exposures and animal tests used to assess a surfactant's
potential ocular irritation, is not well understood. The purpose of this study
was to characterize the microscopic changes in rats at 3 hr and on days 1, 2, 3,
4, 7, 14, and 35 following treatment with anionic, cationic, and nonionic
surfactants of differing irritancy. The right eye of each rat was treated by
placing 10 microliters of a surfactant directly on the cornea. Untreated left
eyes served as the controls. At each time point, eyes and eyelids were
macroscopically examined and collected for microscopic examination.
Macroscopically, the differing levels of irritation were characterized by
differences in incidence and magnitude of scores, reflecting involvement of the
cornea, conjunctiva, and iris, as well as by the incidence of neovascularization
and time to recovery. Microscopically, differences in the area and depth of
injury paralleled the differences seen grossly and the relative irritancy of the
various surfactants. All surfactants affected the corneal and conjunctival
epithelium. All surfactants, except the slightly irritating anionic surfactant,
caused corneal stromal changes, with this involvement being proportional to their
overall level of irritation. Corneal endothelial cell effects principally
occurred with only the severely irritating cationic surfactant. Over time,
responses to surfactants of differing irritancy were qualitatively and
quantitatively different, and these differences correlated with the extent of
initial injury. Qualitative differences in response included presence of
keratocyte regeneration, corneal neovascularization, and conjunctivalization of
the corneal epithelium with all of the surfactants except the slight irritant.
Quantitative differences in response occurred in the extent of epithelial
regeneration, edema, and inflammation for surfactants of slight to severe
irritancy, and with neovascularization, keratocyte regeneration, and
conjunctivalization for surfactants of mild to severe irritancy. These results
suggest that by defining initial area and depth of injury associated with an
ocular irritant, it may be possible to predict the subsequent response and final
outcome. Such an approach would be applicable to the development of
mechanistically based in vitro assays.
PMID- 9547860
TI - Ocular irritation: pathological changes occurring in the rat with surfactants of
unknown irritancy.
AB - We believe the development and validation of in vitro alternatives to eliminate
the need to use animals in ocular irritation testing must be based on a thorough
understanding of the mechanisms of ocular irritation. We have recently undertaken
the task of developing such an understanding for a panel of surfactants. The
purpose of this study was to expand our current panel of surfactants for which
the microscopic changes occurring over time have been characterized. Macroscopic
and microscopic findings regarding the ocular irritation of 6 surfactants of
relatively unknown irritancy were compared to those of 6 surfactants of known
irritancy. The right eye of each rat was treated by placing 10 microliters of a
surfactant directly on the cornea. Untreated left eyes served as the controls. At
3 hr and on days 1, 3, and 35, eyes and eyelids were collected for microscopic
examination. Collectively, the macroscopic and microscopic findings revealed 3
surfactants to be similar to the mildly irritating surfactants previously
studied, and 3 surfactants to be similar to the moderately irritating surfactant
previously studied. Information such as this will be important to develop
mechanistically based in vitro alternatives to replace the use of animals for
ocular irritation testing.
PMID- 9547861
TI - Retinal degeneration in rats induced by CI-1010, a 2-nitroimidazole
radiosensitizer.
AB - The anti-cancer compound CI-1010, designated as (R)-alpha-([(2
bromoethyl)amino]methyl)-2-nitro-1H-imidazole-1-ethanol monohydrobromide, has a
proposed dual mechanism of action due to alkylating and radiosensitizing
activities. To assess potential toxicity, adult Wistar rats were treated with a
single intravenous injection (0, 50, 100, 150, 225, or 350 mg/kg) and necropsied
at 4 or 29 days following treatment. In a repeated dose experiment, rats were
injected daily (0, 10, 40, or 80 mg/kg; 5 doses/wk) for 3 wk and necropsied at
the end of week 3 or 7. CI-1010 induced retinal degeneration by 4 days after a
single injection of > or = 225 mg/kg or by 3 wk of repeated injections of > or =
40 mg/kg. The locally extensive to diffuse retinal degeneration involved the
photoreceptor and outer nuclear layer. The photoreceptor layer was vacuolated and
compressed corresponding to ultrastructural evidence of inner segment swelling
and outer segment fragmentation. The outer nuclear layer was thinned due to loss
of nuclei and contained numerous pyknotic or karyorrhectic nuclei. These nuclear
changes were morphologically consistent with apoptosis and many outer nuclear
layer nuclei labeled with in situ TdT-mediated dUTP-digoxigenin nick end labeling
(Apoptag). The retinal degeneration was nonreversible, evidenced by increased
lesion severity and incidence after CI-1010 was withdrawn for either 25 or 28
days.
PMID- 9547862
TI - Receptor and nonreceptor-mediated organ-specific toxicity of di(2
ethylhexyl)phthalate (DEHP) in peroxisome proliferator-activated receptor alpha
null mice.
AB - The peroxisome proliferator-activated receptor alpha (PPAR alpha) is the mediator
of the biological effects of peroxisome proliferators through control of gene
transcription. To determine if the toxic effects of di(2-ethylhexyl)phthalate
(DEHP) are mediated by PPAR alpha, we examined its effect in PPAR alpha-null
mice. Male Sv/129 mice, PPAR alpha-null (-/-) or wild-type (+/+) were fed ad
libitum either a control diet or one containing 12,000 ppm DEHP for up to 24 wk.
Significant body weight loss and high mortality was observed in (+/+) mice fed
DEHP. By 16 wk, all DEHP-fed (+/+) mice had died of cystic renal tubular disease.
In contrast, the (-/-) mice fed DEHP had no changes in body weight until later in
the study nor increased mortality. Histologically, (+/+) mice fed DEHP had
typical toxic lesions in liver, kidney, and testis while (-/-) mice fed DEHP had
no toxic liver lesions but did show evidence of toxicity in kidney and testis
after 4-8 wk of feeding, which progressed into moderate lesions by 24 wk.
Analysis of hepatic and renal mRNAs showed a typical pleiotropic response in gene
expression in the DEHP-fed (+/+) mice that was absent in the DEHP-fed (-/-) mice.
These results provide evidence that PPAR alpha mediates the subacute-chronic
toxicity of DEHP in liver, kidney, and testis. However, because (-/-) mice did
develop toxic lesions in kidney and testis, DEHP can also act through PPAR alpha
independent pathways in mediating renal and testicular toxicity.
PMID- 9547863
TI - Immunohistochemical detection of 8-hydroxy-2'-deoxyguanosine in paraffin-embedded
sections of rat liver after carbon tetrachloride treatment.
AB - To test the applicability of an anti-8-hydroxy-2'-deoxyguanosine (8-OH-dG)
antibody for immunohistochemistry using paraffin-embedded sections, carbon
tetrachloride (CCl4)-induced rat liver injury was evaluated. Male rats were given
a single dose of CCl4 and killed at 6 hr, 12 hr, 1, 2, 3, and 7 days thereafter.
Severe centrilobular necrosis was evident at 1 day. At 2 days, moderate
mononuclear cell infiltration was present in centrilobular necrotic regions.
Infiltrating mononuclear cells, surrounding sinusoidal endothelial cells and
hepatocytes were stained with anti-8-OH-dG antibody at 2 and 3 days. Formation of
8-OH-dG in DNA and 8-oxo-dGTPase mRNA expression were also increased at these
time points, the amounts of malondialdehyde and 4-hydroxy-2-nonenal showed 2
peaks at 6 hr and 3 days. The findings suggest that the main contributory factor
in the massive hepatic necrosis was increased lipid peroxidation, rather than
excessive formation of 8-OH-dG, and that the observed increase in the latter was
largely due to infiltrating mononuclear cells. The agreement between biochemical
data and the results for immunohistochemical analysis confirms that the anti-8-OH
dG antibody is applicable for detection of cells targeted by free radicals in
paraffin-embedded sections and also for investigation of the mechanisms of
oxidative damage-related disease, including carcinogenesis.
PMID- 9547864
TI - Effect of phenobarbital on hepatic gap junctional intercellular communication in
rats.
AB - The effects of in vivo exposure to phenobarbital (PB) on hepatic gap junctional
intercellular communication (GJIC) and connexin protein expression in Sprague
Dawley rats were examined by in vivolin vitro dye-transfer assay,
immunohistochemical staining, and by Western blot analysis. PB (50 mg/kg) was
administered orally once a day for up to 6 wk. The average size of the dye spread
after injection of Lucifer Yellow decreased at week 1 and remained at the same
level until week 6. The area and number of connexin 32 (Cx32) spots per
hepatocyte in the central zone of liver lobules decreased from week 1 to week 6,
but no change of Cx32 spots in the peripheral zone was observed. The average area
and number of connexin 26 (Cx26) spots per hepatocytes showed no clear change
through the experimental periods. The decreased level of Cx32 protein in plasma
membranes was observed in the PB group. These results suggest that PB, a liver
tumor-promoting agent, inhibits hepatic GJIC in vivo in rats and that aberrant
Cx32 protein expression and/or localization may be responsible for this effect.
PMID- 9547865
TI - Gap junction intercellular communication should be altered in mitosis.
PMID- 9547866
TI - Systemic histopathology of rats treated with 6-sulfanilamidoindazole, a novel
arthritogenic sulfonamide.
AB - 6-Sulfanilamidoindazole (6SAI) is a sulfonamide that induces acute, self-limiting
arthritis in rats, and 6SAI-induced arthritis is thought to be a model for
testing anti-inflammatory agents. In this study, in order to clarify the location
of arthritis and relationships between arthritis and other changes in this model,
we have investigated the detailed pathologic changes in rats administered orally
with 6SAI (125, 250, 500 mg/kg) daily for 4 wk in a time-course experiment.
Moderate to severe arthritis was observed in rats of middle- and high-dose
groups. Histologically, in the affected ankle, exudative synovitis and
periarthritis were observed at 1 wk, granulation tissue formation with
angiogenesis and periosteal new bone formation at 2 wk, and marked fibrosis of
affected area at 4 wk, respectively. In addition to these changes, in
periarticular and periosteal tissues of affected ankles, subendothelial
insudation of small-sized arteries and medial fibrinoid degeneration of medium
sized arteries were observed at 1 and 2 wk and intimal thickening and medial
hypertrophy at 4 wk, respectively. No arterial changes were observed in the
unaffected ankles. Similar arterial changes were often observed in the liver,
thyroid glands, and lungs and rarely in various organs and tissues. Acute
inflammation of serous tissues such as mesentery, mediastinum, and capsule of
spleen or thymus were also present in 6SAI-treated groups, and it was sometimes
accompanied by arteritis. In addition, in 6SAI-treated rats, follicular
hyperplasia of thyroid glands and pituitary changes, which are thought to be
related to depression of thyroid hormone production by 6SAI, were observed. These
results show that 6SAI induces not only arthritis but also arteritis, serositis,
and thyroid change, and it is necessary to take the interaction between these
changes into consideration when anti-inflammatory agents are tested in this
model.
PMID- 9547867
TI - Effects of cholestyramine and diet on small intestinal histomorphometry in rats.
AB - Reports on the effects of cholestyramine on small intestinal structure of rats
have produced contradictory data about changes in mucosal histomorphometry,
perhaps due to interacting effects of dietary composition. In order to identify
effects of cholestyramine and diet on structure of the small intestines, 40 male
rats were divided into 4 groups of 10 and fed 1 of each of the following diets
for 1 month: standard diet, purified fiber-free diet, standard diet + 2%
cholestyramine, or purified fiber-free diet + 2% cholestyramine. Serum
concentrations of cholesterol and triglycerides were moderately increased in rats
fed the purified fiber-free diet versus the standard diet. Neither total length
nor weight of small intestine were affected by either diet or cholestyramine.
Mucosal weight was affected by interactions between cholestyramine and diet,
indicating that outcome depended upon modulating effects of both variables.
Significant interactions were similarly detected among the variables of anatomic
site, diet, and cholestyramine for many histomorphometric parameters of
intestinal mucosa. Cholestyramine reduced total mucosal thickness in both jejunum
and ileum and reduced villus height and villus:crypt ratio in the ileum.
PMID- 9547868
TI - Brevetoxicosis in manatees (Trichechus manatus latirostris) from the 1996
epizootic: gross, histologic, and immunohistochemical features.
AB - In 1996, at least 149 manatees (Trichechus manatus latirostris) died in an
unprecedented epizootic along the southwest coast of Florida. At about the same
time, a bloom of the brevetoxin-producing dinoflagellates, Gymnodinium breve, was
present in the same area. Grossly, severe nasopharyngeal, pulmonary, hepatic,
renal, and cerebral congestion was present in all cases. Nasopharyngeal and
pulmonary edema and hemorrhage were also seen. Consistent microscopic lesions
consisted of catarrhal rhinitis, pulmonary hemorrhage and edema, multiorgan
hemosiderosis, and nonsuppurative leptomeningitis. Immunohistochemical staining
using a polyclonal primary antibody to brevetoxin (GAB) showed intense positive
staining of lymphocytes and macrophages in the lung, liver, and secondary
lymphoid tissues. Additionally, lymphocytes and macrophages associated with the
inflammatory lesions of the nasal mucosa and meninges were also positive for
brevetoxin. These findings implicate brevetoxicosis as a component of and the
likely primary etiology for the epizootic. The data suggest that mortality
resulting from brevetoxicosis may not necessarily be acute but may occur after
chronic inhalation and/or ingestion. Immunohistochemical staining with
interleukin-1-beta-converting enzyme showed positive staining with a cellular
tropism similar to GAB. This suggests that brevetoxicosis may initiate apoptosis
and/or the release of inflammatory mediators that culminate in fatal toxic shock.
PMID- 9547870
TI - A communicating intestinal duplication in a Sprague-Dawley rat.
AB - Duplications of the gastrointestinal tract are exceedingly rare in laboratory
animals. We report a case of a communicating intestinal duplication in a 17-wk
old Sprague-Dawley (SD) rat. The duplication was present in the mesenteric border
of the ileum, and both proximal and distal ends were communicated with the lumen
of ileum. Histologically, the duplicated portion had a thick muscle wall and a
mucosa similar to that of the small intestine. This is the first reported case of
intestinal duplication in an SD rat.
PMID- 9547869
TI - Pathology of the oropharyngeal cavity in six strains of rats: predisposition of
Fischer 344 rats for inflammatory and degenerative changes.
AB - The sagittolongitudinal histopathological evaluation of the oropharyngeal cavity
in 6 strains of rats revealed a clear predisposition of the Fischer 344 strain
for degenerative and inflammatory lesions in this region. A degeneration and
calcification predominantly of the laryngeal cartilage is evident in 72%,
granulomas of the seromucinous glands in 38%, and an inflammation with bacterial
colonies or plant material in the basal part of the laryngotracheal junction in
26% of the Fischer 344 rats. The incidences of these types of lesions were
negligible in the other rat strains evaluated. The comparison of control Fischer
344 rats from 2 carcinogenicity studies (untreated group; gavaged group with
water, pH 10; gavaged group with propylene glycol/methocel) showed an influence
of the gavage technique with the solvent on the survival rate in the female
Fischer 344 rats. The lower survival rate was accompanied by the occurrence of
food impaction in the oropharyngeal cavity. This increased mortality in female
Fischer 344 rats was also associated with a degeneration of the laryngeal
cartilages, whereas the formation of granulomas and inflammation seemed to have
no direct relationship to the mortality. The gavage technique with the applied
solvent was an enhancing factor in the female Fischer 344 rats on mortality, on
cartilage degeneration, but not on inflammatory changes. In contrast to the
females, male Fischer 344 rats had a higher incidence of granulomas and
inflammation, which, however, did not influence the survival rate. In conclusion,
Fischer 344 rats, especially the female sex, exposed to chronic daily irritation
by gavage, are predisposed to have a high mortality rate in chronic toxicologic
tests. An explanation lies in the disposition of the Fischer 344 rat to a high
incidence of cartilage degeneration, which presumably leads to a dysfunction of
the larynx.
PMID- 9547871
TI - Case report: pineocytoma in a male Fischer 344 rat.
AB - An enlarged pineal gland was observed in a 112-wk-old male Fischer 344 rat from
the low-dose treatment group in a 2-yr bioassay. Formalin-fixed, paraffin
embedded sections of the gland were stained with hematoxylin and eosin along with
the immunohistochemical biomarkers synaptophysin, placental alkaline phosphatase,
glial fibrillary acidic protein, and vimentin. Based on its histomorphological
features and on positive staining with synaptophysin, the lesion was diagnosed as
a malignant pineal gland parenchymal cell tumor or pineocytoma of incidental
origin.
PMID- 9547872
TI - Spontaneous cystic keratinizing epithelioma in the lung of a Sprague-Dawley rat.
AB - A spontaneous cystic keratinizing epithelioma in the lung of a 704-day-old female
Hsd:Sprague-Dawley rat is described. The rat had a white subpleural discoloration
on 1 diaphragmatic lobe at necropsy. Microscopically, a central keratin mass,
surrounded by a multilayered squamous epithelium of varying thickness, was found.
In the periphery of the tumor, epithelial nests projected multifocally into the
adjacent alveolar spaces. Immunohistochemical labeling of nuclei by PCNA
(proliferating cell nuclear antigen) revealed proliferative activity in 1 or 2
peripheral cell layers in most locations. To the best of the authors' knowledge,
this is the first report dealing with the morphological and immunohistochemical
features of a spontaneous cystic keratinizing epithelioma in a rat.
PMID- 9547873
TI - Mouse liver nodules induced by piperonyl butoxide, a mixed-function oxidase
inducer.
PMID- 9547874
TI - New indications for hyperbaric oxygen therapy and its complication.
PMID- 9547876
TI - Hyperbaric oxygen therapy as a stimulator of osseointegration.
PMID- 9547875
TI - Hyperbaric oxygen therapy in the management of osteoradionecrosis of the
mandible.
PMID- 9547877
TI - Hyperbaric oxygen therapy for necrotizing cervical infections.
PMID- 9547878
TI - Effect of isobaric oxygen versus hyperbaric oxygen on the normal and noise
damaged hypoxic and ischemic guinea pig inner ear.
PMID- 9547879
TI - Effect of hyperbaric oxygen therapy in comparison to conventional or placebo
therapy or no treatment in idiopathic sudden hearing loss, acoustic trauma, noise
induced hearing loss and tinnitus. A literature survey.
AB - With the published clinical data to hand on the therapeutic results of patients
with idiopathic sudden hearing loss, acoustic trauma or noise-induced hearing
loss, it may be confirmed that 65% of those polypragmatically treated patients
demonstrated a hearing improvement of 19 +/- 4 dB. In 35% of the cases, no
hearing improvement was detected independent of the drugs administered. This
corresponds to the results obtained from placebo-treated patients who
demonstrated a hearing improvement of 20 +/- 2 dB in 61% of cases and no hearing
gain in 39% of cases (fig. 1). A different set of results was obtained from
patients with a hearing loss who were treated either with prednisolone or
placebo. The percentage of patients who achieved normal hearing again in the
placebo-treated group amounted to 31% and 38% and in the verum-treated group 50%
and 78%. It may be concluded that a placebo therapy is equally effective to that
of all nonsteroidal drugs. Problems arise when comparing non-treated patients
since information on spontaneous remission rates differs greatly in the
references, i.e. between 25-68% for spontaneous full remissions and 47-89% for
spontaneous partial remissions. From a statistical view, 35% and 39% of patients
experienced no success with nonsteroidal drugs or placebo, respectively. These
patients can still be helped with HBO therapy. 18 patients only underwent primary
HBO therapy. In all other 50 studies evaluated here with a total of 4, 109
patients suffering from idiopathic sudden hearing loss, acoustic trauma or noise
induced hearing loss and/or tinnitus, HBO therapy was administered as a secondary
therapy, i.e. following unsuccessful conventional therapy. If the onset of
affliction was more than 2 weeks but no longer than 6 weeks, one half of the
cases showed a marked hearing gain (in at least 3 frequencies of more than 20
dB), one-third showed a moderate improvement (10-20 dB) and 13% showed no hearing
improvement at all (fig. 2). 4% no longer experienced tinnitus, 81.3% observed an
intensity decrease and 1.2% an intensity increase of their tinnitus condition.
13.5% remained unchanged (fig. 2). If HBO therapy was administered at a later
stage, but still within 3 months following onset of affliction, 13% showed a
definite improvement in hearing, 25% a moderate improvement and 62% no
improvement at all. 7% no longer suffered from tinnitus, 44% reported an
intensity decrease, a similar percentage noticed no change and 5% a temporary
deterioration of their tinnitus condition. If the onset of affliction was longer
than 3 months up to several years, no hearing improvement can be expected in the
majority of patients (fig. 3); however, one third of the cases reported an
intensity decrease of tinnitus, 60-62% reported no change and 4-7% noticed a
temporary intensity increase (fig. 4). In conclusion, it may be deduced that HBO
therapy is recommended and warranted in those patients with idiopathic sudden
deafness, acoustic trauma or noise-induced hearing loss within 3 months after
onset of disorder.
PMID- 9547880
TI - Hyperbaric oxygen therapy for sudden deafness.
PMID- 9547881
TI - Hyperbaric oxygenation as a treatment for facial palsy.
PMID- 9547882
TI - Otological complications of hyperbaric oxygen therapy.
PMID- 9547883
TI - Drug therapy: the impact of managed care.
PMID- 9547884
TI - The role of phosphodiesterase enzymes in allergy and asthma.
PMID- 9547885
TI - Modulating protein kinase C signal transduction.
PMID- 9547886
TI - Preventive role of renal kallikrein-kinin system in the early phase of
hypertension and development of new antihypertensive drugs.
PMID- 9547887
TI - The multienzyme PDE4 cyclic adenosine monophosphate-specific phosphodiesterase
family: intracellular targeting, regulation, and selective inhibition by
compounds exerting anti-inflammatory and antidepressant actions.
PMID- 9547888
TI - Clinical pharmacology of systemic antifungal agents: a comprehensive review of
agents in clinical use, current investigational compounds, and putative targets
for antifungal drug development.
PMID- 9547889
TI - Therapeutic monitoring of tacrolimus.
PMID- 9547890
TI - Analytical aspects of antioxidants and free radical activity in clinical
biochemistry.
PMID- 9547891
TI - Renal tubular reabsorption of phosphate (TmP/GFR): indications and
interpretation.
PMID- 9547892
TI - Urine analysis in the diagnosis of mucopolysaccharide disorders.
PMID- 9547893
TI - Simplified detection of a mutation causing familial hypercholesterolaemia
throughout Britain: evidence for an origin in a common distant ancestor.
AB - Familial hypercholesterolaemia (FH) is an inherited autosomal codominant disorder
caused by many different mutations in the low-density lipoprotein receptor (LDLR)
gene. The one described most frequently in patients with FH from England, arises
from a G-->A transition at the first nucleotide of codon 80, resulting in the
substitution of lysine for glutamic acid at residue 80 of the mature protein, FH
E80K. We describe a simple method to detect this mutation in genomic DNA using
the polymerase chain reaction (PCR). A 69 base pair (bp) fragment of exon 3 of
the LDLR gene is amplified using a mutagenic upstream PCR primer. This
substitutes a T for an A residue in the amplified product, 2 bp upstream from the
mutant site, generating a restriction site for the endonuclease Taq I, in normal,
but not in mutant DNA. Following digestion of amplified DNA with Taq I, normal
but not mutant DNA is cut into two fragments of 29 and 40 bp, which are readily
identified by polyacrylamide gel electrophoresis. Using this method, 410 patients
with clinically diagnosed FH, attending lipid clinics in Edinburgh (72), Newport
(158), Walsall (30) and Southampton (150), were screened for the mutation. Five
individuals tested positive as heterozygotes, one from Edinburgh, three from
Newport and one from Southampton. This finding was confirmed by DNA sequence
analysis. We conclude that FH due to this mutation occurs in individuals
throughout Great Britain and that it can be detected accurately using this simple
technique. DNA from these and other individuals previously identified to be
heterozygous for FH E80K, was then studied using PCR of highly informative
microsatellite markers flanking the LDLR gene. Sixteen of 17 apparently unrelated
individuals heterozygous for FH E80K also were heterozygous for an identical size
(239 nucleotide) allele, of polymorphic microsatellite D19S394, located
approximately 250 kb away from the LDLR gene. This supports the hypothesis that
FH E80K in these 16 individuals arose from a single ancestor less than 1000 years
ago.
PMID- 9547894
TI - The assessment of platelet derived growth factor concentration in post myocardial
infarction and stable angina patients.
AB - Platelet derived growth factor (PDGF) has been implicated in the pathogenesis of
atherosclerosis. PDGF is released by aggregating platelets and monocytes which
gather around sites of arterial injury. In the study reported here the
concentration of plasma PDGF was measured in post myocardial infarction (MI)
patients (n = 28), angina patients (n = 25), and control subjects (n = 27).
Venous blood samples were taken and the concentration of PDGF determined by an
enzyme linked immunosorbent assay (ELISA). Plasma PDGF concentrations were
significantly higher in the post MI group compared to both the control and angina
groups (P < or = 0.05). The increase in PDGF concentration may be due to
increased activation of platelets or monocytes since these two cells are major
sources of plasma PDGF. High concentrations of PDGF in the circulation could
further accelerate the progression of the disease.
PMID- 9547895
TI - Serum sialic acid, a reputed cardiovascular risk factor, is elevated in South
Asian men compared to European men.
AB - Serum total sialic acid (TSA) has recently been reported as a cardiovascular risk
factor, but whether there are racial differences is not known. One hundred and
twenty-four healthy young subjects (62 women and 62 men) were studied. Their age
was 20.7 [0.9] years and they were matched for body mass index (BMI). Sixty-eight
were of South Asian origin (37 women and 31 men) and 56 (25 women and 31 men)
were European. Mean (SD) serum TSA was significantly higher in the South Asian
men than the age-matched European men (74.3 [12.3] mg/dL versus 68.2 [13.0]
mg/dL, P = 0.0198). In addition, serum TSA was significantly higher in South
Asian women compared with European men (71.6 [8.9] mg/dL versus 68.2 [13.0]
mg/dL, P = 0.0352). Finally, serum TSA was significantly higher in European women
compared with European men (76.0 [13.1] mg/dL versus 69.2 [13.0] mg/dL, P =
0.008). We conclude that serum TSA may be worth measuring in different racial
groups and also may be useful to assess individuals at risk of cardiovascular
disease. Large prospective studies may help to explain why serum TSA is a reputed
cardiovascular risk factor and shows racial differences.
PMID- 9547896
TI - Preparation of urine samples for trace metal determination: a study with
aluminium analysis by inductively coupled plasma optical emission spectrometry.
AB - Urinary analysis of trace metals forms a significant role in clinical chemistry,
but the optimal preparation and analysis of urine samples has not been
investigated. Human urine is generally supersaturated with dissolved solids.
Therefore, samples often precipitate following collection. X-ray microanalysis
showed that this precipitate was predominantly rich in calcium and phosphorus but
could include some trace metals from urine, potentially lowering their
concentrations in solution. Hence, the precipitate must be fully redissolved for
accurate analysis of trace metals in urine. Methods are emphasized for the best
collection and preparation of urine samples for subsequent trace metal analysis;
in this work inductively coupled plasma optical emission spectrometry (ICPOES)
was used for the analysis of aluminium. For optimal accuracy, peak profiles were
collected over 396.147 nm-396.157 nm. Urinary aluminium levels were investigated
from 10 healthy volunteers and concentrations were obtained using either aqueous,
pooled or individual urine-based standard curves. Since urine has a highly
variable matrix, individual sample-based standards, which are unique to that
particular sample, gave the most accurate results. However, where sample size is
small or sample numbers are unfeasibly large, pooled sample-based standards give
good approximations to within 15% and, with appropriate validation, other
elements as internal standards could also be used for approximations. Aqueous
standards should be avoided. Spike-recovery experiments confirmed these data
since individual sample based standards showed optimal recovery [99.3 (4.4)%],
while pooled sample-based standards were a close proxy [101.6 (9.2)%] but aqueous
standards were inappropriate [137.4 (12.8)%]. Postprandial urinary aluminium
levels of the 10 volunteers were [7.2 (3.7)micrograms/L] after analysis using
individual sample-based standard curves.
PMID- 9547897
TI - Oxidative stress of vanadium-mediated oxygen free radical generation stimulated
by aluminium on human erythrocytes.
AB - It has been suggested that aluminium stimulates vanadium-mediated superoxide
radical generation. The oxidative stress of generated superoxide radicals on
antioxidant enzyme activity, oxidation of NADH and NADPH, membrane lipid
peroxidation and osmotic fragility in human red blood cells (RBC) was
investigated. RBC were incubated with varying concentrations of vanadium and
aluminium ions at 37 degrees C for 2 h. RBC incubated with vanadium ions showed
significantly increased superoxide dismutase and catalase activities, and
oxidized NADH and NADPH concentrations compared with control RBC preparations.
Erythrocyte lipid peroxidation was assessed by measuring thiobarbituric acid
reactivity. RBC incubated with elevated levels of vanadium showed significantly
increased membrane lipid peroxidation when compared with control RBC; it
increased further on addition of aluminium. A significant positive correlation
was observed between the extent of vanadium induced membrane lipid peroxidation
and the osmotic fragility of treated RBC. In the presence of vanadium, aluminium
stimulates superoxide dismutase and catalase activities. NADH and NADPH oxidation
and membrane lipid peroxidation, as well as increasing osmotic fragility of human
erythrocytes. The stimulatory effect of aluminium was dependent on concentration.
These results may have implications for the mechanism of toxicity of aluminium
and vanadium in haemodialysis patients.
PMID- 9547898
TI - Guidelines for the interpretation of analytical toxicology results and unit of
measurement conversion factors.
AB - A data compilation has been published on the World Wide Web [http://
www.leeds.ac.uk/acb/annals] which aims to assist in the interpretation of
analytical toxicology results in individual patients. 'Therapeutic' or 'normal'
plasma/whole blood/urine concentrations, as well as the concentrations associated
with serious toxicity (if known), for some 700 analytes of toxicological interest
are given together with (when possible) relative atomic or formula masses, and
mass/amount and amount/mass concentration conversion factors. This paper gives
background and supplementary information which should be borne in mind when
providing interpretation or using the Web table. Supplementary tables listing (i)
common therapeutic drug monitoring assays and guidelines for interpretation of
results, (ii) emergency toxicology analyses which may influence active treatment,
(iii) blood carboxyhaemoglobin saturation and clinical features of toxicity, (iv)
information important when interpreting the results of toxicology investigations,
(v) factors which may affect interpretation of analytical toxicology results, and
(vi) conversion factors for volatile compounds are included.
PMID- 9547899
TI - A simple method for carbohydrate-deficient transferrin measurements in patients
with alcohol abuse and hepato-gastrointestinal diseases.
AB - Carbohydrate-deficient transferrin (CDT) is known to be increased in alcohol
abuse. Several methods were developed for its measurement (e.g. isoelectric
focusing with Western blotting or immunofixation, anion-exchange chromatography
followed by immunoassays). We describe a greatly simplified isoelectric focusing
technique which does not require immunofixation. CDT results obtained with this
method were compared to other biological markers of alcohol abuse, i.e. mean
corpuscular volume (MCV), aspartate aminotransferase (ASAT) and gamma-glutamyl
transferase (GGT), in 55 patients distributed in three groups (i.e. healthy
control subjects, control patients suffering from various hepato-gastrointestinal
diseases and alcohol abusing patients). Sensitivity and specificity were 33-89%,
61-57%, 89-49% and 83-100% for MCV, ASAT, GGT and CDT, respectively. We conclude
that our method is highly suitable for routine clinical use.
PMID- 9547900
TI - Glucose interference in the pancreolauryl test.
AB - The influence of the glucose concentration in urines being assayed as part of a
pancreolauryl test was investigated. Paired patient urines (n = 5) were assayed
at 60 degrees and 70 degrees C, before and after spiking to 5% glucose. The
influence of assay temperature alone was assessed using glucose-free paired
patient urines (n = 10). Aqueous glucose solutions and spiked (5% glucose) normal
random urines (n = 5) were assayed to assess the effect of glucose concentration
alone. There was no difference in T/K ratios for glucose-free patient samples at
60 degrees, 70 degrees and 80 degrees C. After spiking with glucose T/K ratios
were significantly different when assayed at 70 degrees C, but not when assayed
at 60 degrees C. Aqueous glucose solutions > or = 0.6% produced a pigment at
temperatures > or = 65 degrees C which absorbed at the lambda max of fluorescein.
Glucose was found to interfere in the pancreolauryl test. Caution should be
exercised when interpreting results from glucosuric samples.
PMID- 9547901
TI - Determination of free fatty acids in human bile by high-performance liquid
chromatography.
AB - We developed a high-performance liquid chromatography (HPLC) method for free
fatty acids (FFAs) analysis in bile. In this method, FFAs were extracted from
bile in a single step using an Isolute ODS cartridge, derivatized with 9
anthryldiazomethane (ADAM). ADAM was chosen because of its high reactivity with
carboxylic acid at room temperature. Then, HPLC was used for separating and
quantifying FFAs. This method proved to be simple and time-saving. The mean
recovery of FFA added to human gallbladder bile was 97.6%, and the detection
limit was 100-250 pg. Using this method, we determined FFA concentrations in the
gallbladder bile of 11 gallstone patients. The mean concentration of total FFA
was 0.61 (SD = 0.41) mmol/L, and there was wide variation in the individual FFAs.
PMID- 9547902
TI - A comparison of automated fructosamine and HbA1c methods for monitoring diabetes
in pregnancy.
AB - Two automated methods for measuring fructosamine (Test Plus and the original
fructosamine assay) and glycated haemoglobin (Tina-quant immunoassay) were
compared to determine which is the best index of blood glucose control during
pregnancy. Thirteen women with type 1 diabetes were studied, with four-weekly
measurements of HbA1c and fructosamine Test Plus using a Hitachi 911 analyser and
fructosamine measured using an Olympus AU800 analyser. HbA1c correlated better (r
= 0.573) with mean blood glucose (MBG) concentration than did fructosamine Test
Plus (r = 0.347), even after correction for total protein concentration (r =
0.463), while there was no significant correlation with the original fructosamine
method (r = 0.201). HbA1c correlated better with fasting/pre-prandial MBG
concentrations, whereas fructosamine Test Plus correlated better with post
prandial MBG concentrations. Fructosamine Test Plus decreased with gestational
age, and correlated with albumin and total protein concentrations, whereas HbA1c
did not change with gestational age. Thus, HbA1c and fructosamine Test Plus were
found to be useful in verifying home blood glucose measurements in diabetic
pregnancy, with HbA1c being the best predictor of MBG concentration.
PMID- 9547903
TI - Endothelin-1 production by human synoviocytes.
AB - Immunoreactive (ir)-endothelin (ET)-1 concentrations in serum samples and
synovial fluids from patients with rheumatoid arthritis were higher than
concentrations in sera obtained from healthy volunteers. No significant
difference in ir-ET-1 concentrations in synovial fluid was observed between
rheumatoid arthritis patients and osteoarthritis patients. Cultured fluids of
synovial cells collected from synovial tissues and leucocytes from synovial
fluids of rheumatoid arthritis patients were studied to determine the origin of
ir-ET-1 in synovial fluids. Ir-ET-1 was detected in the cultured fluids of
synovial macrophage-like type A cells, but not in those of fibroblast-like type B
cells from the synovial tissues or leucocytes from the synovial fluids.
Longitudinal studies showed that the ir-ET-1 concentration in the cultured fluid
reached a peak around 24 h after starting the culture. ET-1 secreted from
macrophage-like synoviocytes may be involved in the pathogenesis of inflammatory
arthritis.
PMID- 9547904
TI - Isolation and properties of a novel phospholipase A from rat brain that
hydrolyses fatty acids at sn-1 and sn-2 positions.
AB - A Ca(2+)-independent phospholipase A that releases various fatty acids from sn-1
and sn-2 positions was partially purified from rat brain soluble fraction. The
enzyme showed an approximate molecular mass of 300 kDa on gel filtration column
chromatography. Its enzymatic properties are distinct from those of well
characterized phospholipase A2 enzymes; by using a series of synthetic
phosphatidylcholines, the enzyme cleaved oleic, linoleic, and arachidonic acids
like phospholipase A2, and released palmitic and stearic acids like phospholipase
A1. Phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and
phosphatidic acid were hydrolysed with almost equal efficiencies by this enzyme.
These results indicate that the enzyme isolated is a novel Ca(2+)-independent
intracellular phospholipase A that might be responsible for production of various
fatty acids from membrane phospholipids.
PMID- 9547905
TI - Butyrylcholinesterase genes in individuals with abnormal inhibition numbers and
with trace activity: one common mutation and two novel silent genes.
AB - A random population was screened for abnormal dibucaine and fluoride numbers (DN
& FN) to find some common mutations in butyrylcholinesterase (BCHE) gene. Of 2375
unrelated individuals, 10 were found to have low DN and FN and were selected for
further studies. DNA analysis of these hypocholinesterasemics revealed that seven
patients were heterozygous for missense mutation at codon 330 (TTA to ATA;
BCHE*330I). The frequency of BCHE*330I mutation was calculated to be at least
0.29% among the Japanese. On the other hand, two novel mutations were found in
three families and two individuals including probands whose enzyme activity was
very low (silent gene). Polymerase chain reaction and single stranded
conformation polymorphism (PCR-SSCP) and restriction fragment length polymorphism
(PCR-RFLP) were used for identification of the common and known mutation types
such as BCHE*250P (ACT to CCT), BCHE*365R (GGA to CGA), and BCHE*539T (GCA to
ACA; K-polymorphism), whereas PCR-SSCP was used in combination with direct DNA
sequencing for new mutations like BCHE*446V (TTT to GTT) and BCHE*451X (GAA to
TAA).
PMID- 9547906
TI - Conversion of apolipoproteins A-1 and B reference limits obtained by a
turbidimetric procedure to other methods.
PMID- 9547907
TI - Falsely lowered FT4 and raised TSH concentrations in a patient with
hyperthyroidism and human anti-mouse monoclonal antibodies.
PMID- 9547908
TI - The effect of an unusual haemoglobin variant (beta 51Pro-->His) on haemoglobin
A1c measurement.
PMID- 9547909
TI - Osteocalcin following tibial shaft fracture.
PMID- 9547910
TI - Diagnosing Cushing's syndrome.
PMID- 9547911
TI - Haematocrit and the Boehringer advantage blood glucose meter.
PMID- 9547912
TI - Air tube systems and safety.
PMID- 9547913
TI - Lipoprotein (a) and ischaemic cerebrovascular disease.
PMID- 9547914
TI - The Hemocue B glucose analyser and neonatal blood glucose monitoring.
PMID- 9547915
TI - The Hemocue B glucose analyser and neonatal blood glucose monitoring.
PMID- 9547916
TI - The Hemocue B glucose analyser and neonatal blood glucose monitoring.
PMID- 9547917
TI - The Hemocue B glucose analyser and neonatal blood glucose monitoring.
PMID- 9547918
TI - Serum antioxidant activity after myocardial infarction.
PMID- 9547919
TI - Microalbuminuria in type 2 diabetic patients.
PMID- 9547920
TI - Screening for prostatic carcinoma.
PMID- 9547921
TI - Multiple auditory steady-state responses (MASTER): stimulus and recording
parameters.
AB - Steady-state responses evoked by simultaneously presented amplitude-modulated
tones were measured by examining the spectral components in the recording that
corresponded to the different modulation frequencies. When using modulation
frequencies between 70 and 110 Hz and an intensity of 60 dB SPL, there were
significant interactions between two stimuli when the carrier frequencies were
closer than one half of an octave apart, with attenuation of the response to the
lower carrier frequency. However, there were no significant decreases in response
amplitude with four simultaneous stimuli provided the carrier frequencies
differed by one octave or more. Higher intensities (70 dB SPL) resulted in
greater interactions between the stimuli than when low intensities (35 dB SPL)
were used. Modulation frequencies could be as closely spaced as 1.3 Hz without
affecting the responses. Using broad-band noise as a carrier instead of a pure
tone resulted in a significantly larger response when the stimuli were presented
at the same sound pressure level. At modulation frequencies between 30 and 50 Hz,
there were greater interactions between stimuli than at faster modulation
frequencies. These results support the following recommendations for using
multiple stimuli in evoked potential audiometry: (1) The multiple stimulus
technique works well for steady state responses at frequencies between 70 and 110
Hz. (2) Up to four stimuli can be simultaneously presented to an ear without
significant loss in amplitude of the response, provided the carrier frequencies
are separated by an octave and the intensities are 60 dB SPL or less. (3)
Bandpass noise might serve as a better carrier signal than pure tones.
PMID- 9547922
TI - Distortion-product otoacoustic emissions in middle-aged subjects with normal
versus potentially presbyacusic high-frequency hearing loss.
AB - Distortion-product otoacoustic emissions (DPOAEs) are still undergoing evaluation
for clinical use. Although the effects of ageing on otoacoustic emissions have
been studied quite extensively in the past, DPOAE response-growth or input-output
(I-O) measures, which are well suited as an objective method for monitoring
cochlear function at specific frequencies, have been less thoroughly examined.
The aim of the present study was to assess the 2f1-f2 DPOAEs in a clinical
setting in order to examine the response of 20 normally hearing middle-aged
adults and to compare the results with those of 20 people of the same age with
ears of sensorineural high-frequency hearing loss (HL). The experiment consisted
of two stages. First, the DPOAE-gram was recorded in 1-4-octave steps at a
stimulus level of 70 dB SPL over a frequency range of the f2 primary tone which
extended from 1.001 to 6.299 kHz. Secondly, in order to elicit DPOAE I-O
functions, the two primary stimuli were presented at equilevel intensities
ranging from 20 to 71 dB SPL. The stimulus-level step size was 3 dB. The I-O
functions were recorded at five separate DPOAE frequencies, with the f2 frequency
most closely related to the clinical audiogram (f2 = 1.0, 1.5, 2.0, 4.0 and 6.0
kHz). Two clearly separated portions in the form of the I-O function for normally
hearing ears were found. The first portion, in response to primary levels of 60
dB SPL and below, showed a plateau (saturating) behaviour. If primary levels
exceeded 60 dB SPL, I-O functions became more linear. The attenuation of the
saturation portion of the I-O function in ears with high-frequency HL across the
frequency-test range is difficult to explain because elevated behavioural
thresholds were observed only for frequencies > 1.5 kHz. Thus, the more linear I
Os associated with the hearing-loss frequencies may indicate deficiencies in the
active properties of outer hair cells (OHCs), whereas those for I-Os < 1.5 kHz,
where hearing was normal, may indicate a beginning of damage to active OHC
micromechanical processes prior to their clinical manifestation. DPOAE recordings
from people with high-frequency HL, possibly age-related, supplement recordings
of TEOAEs and give complementary information on degenerative changes in the outer
hair-cells. DPOAE I-O functions may reveal discrete pathological alterations both
in the active cochlear signal processing and in the passive mechanisms of the
cochlea prior to their detection by clinical audiometric tests.
PMID- 9547923
TI - Effects of click polarity on the auditory brainstem responses of older men.
AB - This study was designed to evaluate the effects of stimulus polarity on the
auditory brainstem responses (ABRs) in the older population. Nine men between the
ages of 40 and 69 years participated in the study. Rarefaction and condensation
clicks were delivered at 70 and 80 dB nHL to elicit the ABRs. The latencies were
significantly earlier for rarefaction clicks for components II and V. The inter
peak interval I-II was significantly shorter for rarefaction clicks than for
condensation clicks. The amplitudes of the IV-V complex did not change with
stimulus polarity at 80 dB nHL, but at 70 dB nHL larger amplitudes were observed
with rarefaction clicks yielding a significant polarity-intensity interaction.
The IV-V/I ratio elicited by rarefaction clicks was larger than that produced by
condensation clicks at 80 dB nHL, but it was much larger for rarefaction clicks
at 70 dB nHL resulting in a significant polarity-intensity interaction. The
waveform morphology also changed with click polarity, with the most prominent
effects apparent on components II and IV. A new hypothesis suggesting separate
generators for ABRs recorded in response to the two click polarities is proposed.
Use of both condensation and rarefaction clicks is recommended in recording ABRs
for clinical use.
PMID- 9547924
TI - Modulation detection by normal and hearing-impaired listeners.
AB - In five normally hearing subjects and seven subjects with damaged cochleas,
detection thresholds for sinusoidal frequency modulation (FM) and amplitude
modulation (AM) were measured using 1 s stimuli with a 500 Hz carrier frequency
(Fc) at a 'comfortable' loudness (given by subject-dependent SPLs and SLs). The
modulation frequency (Fmod) was 2 Hz or 10 Hz. FM (but not AM) detection was
poorer in the hearing-impaired group, especially when the hearing loss at Fc
exceeded 50 dB. Fmod had a different effect on FM and AM detection. The
corresponding interaction was essentially identical for the two groups of
subjects. Previous studies strongly suggested that normal listeners use mainly
neural phase-locking cues for the detection of FM when Fmod = 2 Hz, but mainly
tonotopic cues when Fmod = 10 Hz. The present results suggest that cochlear
damages reduce the usefulness of these two types of cues to an approximately
equal degree.
PMID- 9547925
TI - Neural networks as models of psychopathology.
AB - Neural network modeling is situated between neurobiology, cognitive science, and
neuropsychology. The structural and functional resemblance with biological
computation has made artificial neural networks (ANN) useful for exploring the
relationship between neurobiology and computational performance, i.e., cognition
and behavior. This review provides an introduction to the theory of ANN and how
they have linked theories from neurobiology and psychopathology in schizophrenia,
affective disorders, and dementia.
PMID- 9547926
TI - Hippocampal neuronal dysfunction in schizophrenia as measured by proton magnetic
resonance spectroscopy.
AB - BACKGROUND: Previous neuropathological and neuroimaging studies have documented
neuronal loss in the hippocampal region in schizophrenia. N-acetylaspartate (NAA)
is a neuronal/axonal marker that may be utilized to assess neuronal loss or
dysfunction by proton magnetic resonance spectroscopy (1H MRS). This study
measured NAA, choline, and creatine in the hippocampal region of patients with
schizophrenia using in vivo proton magnetic resonance spectroscopic imaging (1H
MRSI). METHODS: 1H MRSI was performed on the right and left hippocampal regions
in 30 chronic schizophrenic patients and 18 control subjects. Concentration
estimates of NAA, creatine, and choline were determined. RESULTS: Relative to the
control group, the patients with schizophrenia demonstrated significantly lower
NAA in both the right and left hippocampal regions. No group differences in
choline were noted; however, there was a trend for creatine to be higher on the
left than the right hippocampus in the schizophrenic group. There was also no
association between NAA and duration of illness or medication dosage.
CONCLUSIONS: This preliminary study provides support for neuronal dysfunction
and/or decreased neuronal density in the hippocampal region. The absence of
choline signal elevation does not support accelerated turnover of membrane
phospholipids, which might be expected if there were ongoing neuronal atrophy or
neuronal necrosis.
PMID- 9547927
TI - Psychobiological heterogeneity of familial and sporadic schizophrenia.
AB - BACKGROUND: Although schizophrenia is presumed to be heterogeneous, there has
been limited success distinguishing familial from sporadic cases. We used
psychobiological measures to examine heterogeneity, as they may be closer to
neurobiology than symptoms. Smooth pursuit eye movement quality (SPEM) and
dichotic listening (DL) tests to tones and words were used to assess hemispheric
laterality asymmetry. METHODS: Forty-six research unit patients participated in
assessments of family history (FH) and physiological measures. FH was categorized
by three exclusive groups: FH-1 patients had a chronic schizophrenia-related
psychosis in a first-degree relative, FH-2 had it in second-degree relative, and
FH-3 had no family member with a reoccurrence. RESULTS: Analysis of variance
showed a significant group difference for SPEM and DL tones. SPEM was
significantly worse in all three schizophrenia groups than for the normal
comparison subjects. Among the schizophrenia groups, the nonfamilial group (FH-3)
had the worst SPEM quality, FH-2 had intermediate quality, and FH-1 had the best
quality. Conversely, only the nonfamilials (FH-3) had normal right hemispheric
lateralization for tones, whereas familials did not, and FH-2 again had
intermediate values. The lateralization quotient for DL words did not
significantly differ among the groups. CONCLUSIONS: SPEM was affected most in
sporadic, not familial schizophrenia, whereas dichotic listening was most
affected in familial schizophrenia. This double dissociation supports the utility
of the familial/sporadic distinction and suggests that etiological factors in
different forms of schizophrenia may impact principally on distinct
neurobiological substrates, despite similar patient phenomenology.
PMID- 9547928
TI - Olfactory deficits in patients with schizophrenia and severe polydipsia.
AB - BACKGROUND: The present study was designed to assess olfactory function in
severely polydipsic/hyponatremic patients with schizophrenia who also had
intermittent water intoxication. METHODS: The University of Pennsylvania Smell
Identification Test and an olfactory acuity battery were administered to three
groups of male subjects: 9 patients with schizophrenia and severe
polydipsia/hyponatremia, 9 control nonpolydipsic/normonatremic patients with
schizophrenia, and 9 normal controls. RESULTS: Male patients with severe
polydipsia/hyponatremia and intermittent water intoxication had marked olfactory
acuity and identification deficits when compared to the patient control group of
similar age and age at illness onset, and to normal controls. CONCLUSIONS: The
finding of deficient acuity (detection threshold) in the polydipsic/hyponatremic
group but not the nonpolydipsic, normonatremic group suggests that for this
subgroup, abnormalities of olfactory sensory function may occur in a pattern
previously reported for other brain disorders such as Alzheimer's disease.
PMID- 9547929
TI - An analysis of the brain's transfer properties in schizophrenia: amplitude
frequency characteristics and evoked potentials during sleep.
AB - BACKGROUND: Classical analysis of spontaneous sleep electroencephalogram (EEG) in
schizophrenia commonly reveals alterations of sleep continuity, number of
awakenings, slow-wave sleep (SWS), and REM sleep compared to healthy controls;
however, conventional analysis cannot help understand dynamic differences of the
sleep EEG during different sleep stages. METHODS: We measured late components of
auditory evoked potentials (AEPs) and visual evoked potentials (VEPs) during
different sleep stages of 11 schizophrenic inpatients and in a sex- and age
matched control group from scalp positions FZ, CZ, and PZ. According to linear
system theory, we then computed the amplitude-frequency characteristic (AFC) from
averaged AEPs and VEPs in different sleep stages. These AFCs describe the input
output relation of the system under study, leading to a characterization of the
transfer properties of the schizophrenic brain during sleep. RESULTS: Significant
differences could be found for the transfer properties during stage II and SWS
between schizophrenics and controls. During REM a marked enhancement of theta
resonance was seen in schizophrenics. CONCLUSIONS: The results of the present
study point to highly different central nervous system transfer properties in
schizophrenics and controls. Compared to previous investigations in depression,
the results provide additional information for distinguishing schizophrenia and
depression in EEG studies.
PMID- 9547931
TI - Clozapine and body mass change.
AB - BACKGROUND: Patients treated with clozapine have been reported to gain weight. We
hypothesized that patients would also experience an increase in body mass, which
can be more directly related to cardiovascular morbidity. METHODS: Forty-two
patients who had been treated with clozapine for at least 1 year were weighed and
measured, and waist-hip ratios (WHR) and body mass index (BMI), measured as
kg/m2, were calculated. Patients were also asked about a series of factors
potentially related to change in body mass. RESULTS: Female patients gained both
weight and body mass. Their WHR after 37 months of clozapine therapy was .83,
with a significant increase in BMI from 23.2 to 29.1 kg/m2 (p = .001). Male
subjects also gained weight and body mass. Their WHR after 39 months of clozapine
therapy was .93, with a significant increase in BMI from 26.4 to 29.7 kg/m2 (p <
.001). Stepwise multiple-regression analysis showed that factors related to final
body mass were initial body mass, dose of clozapine, and decrease in smoking.
Baseline BMI contributed most to the final BMI, but the addition of dose and
decrease in smoking made significant contributions to the model. CONCLUSIONS:
Both female and male patients treated with clozapine gain body mass. This may
place them at greater risk for cardiovascular morbidity.
PMID- 9547930
TI - A novel pentadecapeptide, BPC 157, blocks the stereotypy produced acutely by
amphetamine and the development of haloperidol-induced supersensitivity to
amphetamine.
AB - BACKGROUND: A novel gastric pentadecapeptide, BPC 157, has been shown to
attenuate different lesions (i.e., gastrointestinal tract, liver, pancreas,
somatosensory neurons). This suggests an interaction with the dopamine system.
When used alone, BPC 157 does not affect gross behavior or induce stereotypy.
METHODS: We first investigated the effect of pentadecapeptide BPC 157 on
stereotypy and acoustic startle response in rats, given as either a prophylactic
(10 micrograms/kg i.p.) or therapeutic (10 ng/kg i.p.) regimen, with the dopamine
indirect agonist amphetamine (10 mg/kg i.p.). RESULTS: There was a marked
attenuation of stereotypic behavior and acoustic startle response. When the
medication was given at the time of maximum amphetamine-induced excitability,
there was a reversal of this behavior. A further focus was on the effect of this
pentadecapeptide on increased climbing behavior in mice pretreated with the
dopamine antagonist haloperidol (5.0 mg/kg i.p.), and subsequently treated with
amphetamine (20 mg/kg i.p. challenge 1, 2, 4, and 10 days after haloperidol
pretreatment). This protocol is usually used for the study of behavioral
supersensitivity to the amphetamine stimulating effect. CONCLUSIONS: An almost
complete reversal was noted when pentadecapeptide was coadministered with
haloperidol. Together, these data provide compelling evidence for the interaction
of pentadecapeptide BPC 157 with the dopamine system.
PMID- 9547932
TI - Cortisol and response to dexamethasone as predictors of withdrawal distress and
abstinence success in smokers.
AB - BACKGROUND: Glucocorticoids have been linked to self-administration of a wide
range of drugs in animals and are increased endogenously by chronic nicotine
intake. Corticosteroids have also been shown to regulate nicotine receptor
sensitivity and to be involved in behavioral sensitization to nicotine. METHODS:
Cortisol levels and cortisol suppression in response to dexamethasone were
measured in a sample of smokers participating in a smoking cessation treatment
trial. RESULTS: Cortisol levels dropped significantly during the early quitting
process (2 weeks post-quit) and returned to a level below baseline 1 month post
quit. The magnitude of the initial drop in cortisol was strongly related to post
quit distress and marginally predictive of abstinence. Neither baseline nor post
quit changes in percent cortisol suppression after dexamethasone were related to
abstinence success or withdrawal distress. CONCLUSIONS: Withdrawal from cigarette
smoking is marked by a reduction in cortisol levels that appears to be related to
the degree of distress experienced during the early quitting period. Further work
is needed to determine whether withdrawal-related cortisol changes or distress
are predictive of abstinence success.
PMID- 9547933
TI - Salivary cortisol and cardiovascular activity during stress in oppositional
defiant disorder boys and normal controls.
AB - BACKGROUND: Arousal-regulating mechanisms are important in explaining individual
differences in antisocial behavior. METHODS: Alterations in salivary cortisol
concentration and cardiovascular activity were studied in 21 boys with
oppositional defiant disorder (ODD) and 31 normal controls (NC) during a 2-hour
stressful procedure involving frustration and provocation. RESULTS: Baseline
levels of heart rate (HR) were significantly lower in the ODD group, but their HR
levels were higher during provocation and frustration. Cortisol levels in the ODD
group were overall lower than those of the NC group, and the effect of stress
seemed to be minimal and similar for both groups; however, individual differences
were large. Since anxiety plays an important mediating role in cortisol response,
subjects were divided into one of four groups based on the intensity of their
externalizing behavior and anxiousness. Cortisol increase due to stress exposure
was strongest in highly externalizing and highly anxious subjects; cortisol
decrease was strongest in those subjects who were high in externalizing behavior
and low in anxiousness. CONCLUSIONS: The results of the study support an
important role for hypothalamic-pituitary-adrenal axis sympathetic autonomic
functioning in persistent antisocial behavior in young boys.
PMID- 9547934
TI - Chronic disulfiram treatment effects on intranasal cocaine administration:
initial results.
AB - BACKGROUND: Simultaneous abuse of cocaine and alcohol is common. Alcohol
decreases negative stimulant effects and potentiates "high." Disulfiram
(Antabuse) is being studied in outpatient trials as a cocaine pharmacotherapy
with the rationale that inability to modulate cocaine effects with alcohol may
decrease cocaine use. METHODS: We examined the interaction of disulfiram and
cocaine in a randomized, double-blind, placebo-controlled study where subjects
were chronically treated with disulfiram and then participated in intranasal
cocaine administration studies. RESULTS: Disulfiram 250 mg/day treatment
significantly increased plasma cocaine concentrations (p = .013), heart rate
(cocaine 1 mg/kg, p = .046), and systolic (cocaine 2 mg/kg p = .003) and
diastolic (cocaine 2 mg/kg, p = .022) blood pressure. "High" and "nervous"
ratings were nonsignificantly increased. CONCLUSIONS: The combination of "high"
with increased anxiety in the context of inability to lessen negative effects
with alcohol may be an effective treatment in selected patients. The significant
pharmacokinetic interaction must be considered in the decision regarding use of
disulfiram.
PMID- 9547935
TI - Heart rate variability as an index of cue reactivity in alcoholics.
AB - BACKGROUND: Autonomic responses follow exposure to conditioned stimuli such as
contextual factors associated with alcohol ingestion. Heart rate variability is
under autonomic control and may be a measure of such response. METHODS: Twenty
alcoholics and 23 matched social drinkers (all male) were exposed to a neutral
cue and then an alcohol cue in identical settings, during which the
electrocardiogram of these subjects was recorded. Time and frequency domain
parameters of heart rate variability (HRV) were computed by a blind rater.
RESULTS: Coefficient of variation of R-R intervals and absolute powers of HRV
spectrum (in frequency bands 0.05-0.15 Hz and 0.01-0.05 Hz) following alcohol cue
were significantly higher in alcoholics than social drinkers. The mean heart rate
(MHR) failed to reflect this difference. CONCLUSIONS: HRV paradigm appears more
sensitive than MHR to measure cue reactivity.
PMID- 9547936
TI - Substituted pyrido[3,2-b]oxazin-3(4H)-ones: synthesis and evaluation of
antinociceptive activity.
AB - A new series of N-substituted pyrido[3,2-b]oxazinones has been synthesized,
pharmacologically evaluated, and compared with acetyl salicylic acid. The
compound with the maximal combination of safety and analgesic efficacy was 4-?3
[4-(4-fluorophenyl-1-piperazinyl)propyl]?-2H-pyrido[3,2-b]-1, 4-oxazin-3(4H)-one
(6c) with ED50 values of 12.5 mg/kg po (mouse: phenylquinone writhing test) and
27.8 mg/kg po (rat: acetic acid writhing test), respectively. Compound 6c proved
to be more active than aspirin with a safety index of 5.1.
PMID- 9547938
TI - Probing the conformation of bilirubins with monopropionic analogs: a biological,
spectroscopic, and molecular modeling study.
AB - The in vivo metabolism of a bilirubin analog substituted with a propionic acid
chain in C8 (5) showed that it is excreted in bile conjugated with glucuronic
acid, while a positional isomer substituted with a propionate in C7 (6) is
excreted in bile without conjugation. A conformational analysis employing an
optimized Monte Carlo method and a mixed Monte Carlo/stochastic dynamics reveals
that isomer 5 adopts a 'ridge tile' conformation, stabilized by the presence of
three intramolecular hydrogen bonds. On the contrary, isomer 6 exhibits a more
closed structure, where impairment in the formation of at least one of the
hydrogen bonds occurs. These theoretical predictions agree well with 1H NMR, UV
vis, and TLC data.
PMID- 9547937
TI - 1-Methyl-3-pyrrolines and 2-methylisoindolines: new classes of cyclic tertiary
amine monoamine oxidase B substrates.
AB - Both 1-methyl-3-pyrrolines and 2-methylisoindolines are substrates for MAO-B with
Vmax/Km values ranging from 200 to 2000 min-1 mM-1 at 37 degrees C. These
compounds represent new classes of cyclic tertiary amine substrates for this
flavoenzyme. The only other known cyclic amines that are MAO-B substrates are 1,4
disubstituted 1,2,3,6-tetrahydropyridinyl derivatives. The presence of an allylic
(benzylic) amino functionality in all of these compounds may be linked to their
substrate properties since related piperidinyl and pyrrolidinyl analogs are
stable in the presence of MAO-B. This paper discusses energetic and geometric
features of these compounds in relationship to their substrate properties and in
anticipation of their utility to probe the active site of this flavoenzyme.
PMID- 9547939
TI - Quantitative structure-activity relationships on 5-substituted terbenzimidazoles
as topoisomerase I poisons and antitumor agents.
AB - Several 5-substituted terbenzimidazoles were synthesized and evaluated as
mammalian topoisomerase I poisons and for cytotoxicity against a human
lymphoblastoma cell line, RPMI-8402. No correlation was observed between
topoisomerase I poisoning activity and the Hansch pi value or the sigma meta and
sigma para values associated with each substituent. These data suggest that
electronic effects and relative lipophilicity of substituents at the 5-position
of these terbenzimidazoles do not have a significant effect upon intrinsic
topoisomerase I poisoning activity. There was, however, a good correlation
between the relative pi values for the various substituents evaluated and
cytotoxic activity. Experimentally determined log P values did not correlate well
with either cytotoxicity or pi values. Capacity factors (log k') as determined by
high pressure liquid chromatography did correlate well with the pi values of
varied substituents and cytotoxicity. These data indicate that the relative
lipophilic activity of substituents at the 5-position of these terbenzimidazoles
can strongly influence relative cytotoxic activity.
PMID- 9547940
TI - Synthesis and biological evaluation of 2,6-di-tert-butylphenol hydrazones as 5
lipoxygenase inhibitors.
PMID- 9547941
TI - Potential inhibitors of plasmodial heme oxygenase; an innovative approach for
combating chloroquine resistant malaria.
AB - Syntheses of imidazo-pyridines and substituted prolines and their effect on heme
oxygenase activity of Plasmodium yoelii and corresponding infected host have been
studied. Six compounds in vitro and one in vivo showed selective inhibition of
parasite enzyme which may be further exploited in the development of resistant
reversal agents.
PMID- 9547942
TI - Two related neurokinin-1 receptor antagonists have overlapping but different
binding sites.
AB - The neuropeptide substance P binds to the G protein-coupled neurokinin-1 (NK-1)
receptor and elicits cellular responses thought to be involved in pain,
neurogenic inflammation, vasodilatation, and plasma exudation. Several small
molecule nonpeptide antagonists of the substance P/NK-1 receptor interaction have
been developed. Mutational analysis of the receptor protein sequence has led to
the conclusion that the binding site for these nonpeptide antagonists lies within
the bundle created by transmembrane domains IV-VII of the receptor. This current
investigation employs site directed mutagenesis of the NK-1 receptor to compare
the binding site of CP-96,345 with that of a related compound CP-99,994. The data
demonstrate that while both compounds appear to bind within the transmembrane
domain bundle, the contribution of individual amino acid residues to the binding
of each compound differs.
PMID- 9547943
TI - Aminobicyclo[2.2.1.]heptane dicarboxylic acids (ABHD), rigid analogs of ACPD and
glutamic acid: synthesis and pharmacological activity on metabotropic receptors
mGluR1 and mGluR2.
AB - Isomeric norbornane-derived rigid analogs mimicking different potential
conformations of ACPD (1-aminocyclopentane-1,3-dicarboxylic acid) and glutamic
acid have been synthesized, via the hydantoin route, to be used as conformational
probes for bioactive conformations at the glutamatergic receptors of the central
nervous system. Activities on metabotropic receptors mGluR1 and mGluR2 are
reported and discussed.
PMID- 9547944
TI - Transferred nuclear Overhauser effect study of macrolide-ribosome interactions:
correlation between antibiotic activities and bound conformations.
AB - The study of macrolide-ribosome interactions has been investigated using two
dimensional transferred nuclear Overhauser effect spectroscopy (TRNOESY). A new
medically important macrolide antibiotic, roxithromycin, with the replacement of
the 9-keto group in erythromycin by a 9-oxime chain, was studied in the complex
state with the bacterial ribosome. Analysis of transferred nuclear Overhauser
effect (TRNOE) experiment resulted in a set of constraints for all protons pairs.
These constraints were used in structure determination procedures based on
molecular modelling to obtain a bound structure compatible with the experimental
NMR data. The results compared with the conformational analysis of the substrate
in solution indicate that only one specific conformation is preferred in the
bound state while in the free state the sugar ring moities were relatively
disordered. The bioactive macrolide antibiotics studied roxithromycin and
erythromycin which displayed a strong NMR response, are metabolized in RU39001
and erythralosamine respectively which do not retain antimicrobial activity. The
inactive major metabolites were used to define if TRNOEs observation may be
characteristic of a biological activity. These control experiments gave
essentially blank TRNOESY spectra. This study shows that Mg2+ does not play a
direct role for the low affinity binding site studied by TRNOE what is in
agreement with an hypothesis of two distinct binding levels, with a low affinity
binding level necessary for the tight binding one.
PMID- 9547945
TI - Conformational studies on resiniferatoxin (RTX), an ultrapotent vanilloid
agonist.
AB - In polar solution, NOE studies show a pronounced clustering of the aromatic
moieties (9,13,14-phenylacetate orthoester and 20-homovanillate) of the
ultrapotent vanilloid agonist resiniferatoxin (RTX). This clustering is absent in
nonpolar solution. Low energy clustered structures from molecular dynamics
simulations account for the observed NOEs. These results suggest that the
phenylorthoacetate moiety can assist the attainment of specific alignments
between the terpenoid core and the vanillyl moiety, possibly preorganizing them
for ideal receptor binding.
PMID- 9547947
TI - A novel type of structurally simple nonpeptide inhibitors for alpha-chymotrypsin.
Induced-fit binding of methyl 2-allyl-3-benzenepropanoate to the S2 subsite
pocket.
AB - Unexpectedly, methyl and benzyl esters of 2-allyl-3-benzenepropanoic acid were
found to be not substrates but potent competitive inhibitors for alpha
chymotrypsin. The inhibitory property of the structurally simple nonpeptidic
compounds is ascribed to their high binding affinity to the enzyme at the S2
rather than S1 subsite pocket. These inhibitors exist in a flexible form in
solution, but as they bind to the enzyme bulky contrained conformers present in a
minute concentration play an important role, forming tighter enzyme.inhibitor
complexes by binding to the large hydrophobic S2 pocket. The contrained
conformers are thought to be resulted from intramolecular CH/pi interactions
between a vinylic proton and the aromatic pi-electron cloud in the inhibitor
molecules. These compounds constitute novel examples of the induced-fit binding
inhibitor of possibly simplest structure.
PMID- 9547946
TI - Effective lowly cytotoxic analogs of an HIV-cell fusion inhibitor, T22 ([Tyr5,12,
Lys7]-polyphemusin II).
AB - A tachyplesin peptide analog, T22 ([Tyr5,12, Lys7]-polyphemusin II), and its
shortened congener, TW70 (des-[Cys8,13, Tyr9,12]-[D-Lys10, Pro11]-T22) have
strong anti-human immunodeficiency virus (HIV) activity, comparable to that of 3'
azido-2', 3'-dideoxythymidine (AZT). T22 and TW70 are extremely basic peptides,
containing 5 Arg residues and 3 Lys residues. The number of positive charges
might be related in part to high collateral cytotoxicities of T22 and TW70. Here
we have synthesized several analogs, in which the number of positive charges has
been reduced through amino acid substitutions using Glu or L-citrulline. As a
result, several effective compounds have been found which possess higher
selectivity indexes (SIs, 50% cytotoxic concentration/50% effective
concentration) than those of T22 and TW70. Higher SIs were attributed mainly to a
decrease in cytotoxicity.
PMID- 9547948
TI - Mood disorders following traumatic brain injury: identifying the extent of the
problem and the people at risk.
AB - The extent of mood disorders following traumatic brain injury (TBI), and the
possible risk factors, are investigated. New data are presented from a
prospective study of consecutive hospital admissions. Six months post-TBI, 99
adults completed a standardized assessment of emotional state, the Wimbledon Self
Report Scale. Cognitive performance and the impact of the injury on everyday
functioning were also assessed. The rate of clinically significant mood disorders
(caseness) was 38%. Of the demographic or injury characteristics, only pre-injury
occupational status predicted post-injury caseness. Those unoccupied pre-injury
were more likely to report mood disturbance post-injury. In contrast, post-injury
occupational status was not related to caseness either for the whole group or the
subgroup of those previously occupied, despite the adverse effects on
occupational functioning for a significant proportion of subjects. Associations
were found between emotional state and cognitive and everyday functioning 6
months post-injury. Psychosocial disabilities appeared more strongly associated
to mood disorders than did physical disabilities. A significant level of unmet
need has been highlighted, and possible risk factors identified, which may inform
the purchase and provision of TBI rehabilitation services. Follow-up data on
these subjects are available and will be reported separately.
PMID- 9547949
TI - Clinical evaluation of the InnerSpace fibreoptic intracranial pressure monitoring
device.
AB - OBJECTIVE: The aim of this study is the clinical evaluation of the
intraparenchymal ICP monitor InnerSpace OPX 100. METHODS: Sixty-four Inner Space
OPX 100 transducers in 51 patients with severe head injury (42), intracranial
spontaneous bleeding (6) or hypoxia (3) were studied. The transducer was placed
in the frontal white matter. Thirty-nine patients received one catheter, eleven
patients two catheters and one patient three catheters. The study period ranged
from 10 hours-25 days; total study time was 421.5 days (mean duration 6.6 days).
RESULTS: In nine cases (14.1%) an inadequate location of the ICP transducer was
found, but the accuracy of the measurement was not influenced. Dislocation of the
transducer occurred in eight cases (12.5%) due to inadequate handling. A failed
transducer was observed in four cases (6.3%) because of a damaged optical fibre
(1) or inadequate handling (3). In one patient (1.9%) a minor local infection
developed. In eleven cases (17%) a haematoma around the ICP sensor was observed.
Six haematomas were small; five haematomas were larger than 1 cm in diameter. In
two patients a large frontal haematoma developed after exchange of the
transducer. Operative evacuation was necessary in both cases. Zero shift was
below 2 mmHg in all catheters. CONCLUSION: It is concluded that the InnerSpace
intraparenchymal ICP monitor is a reliable device: the rate of catheter related
intracerebral haematomas, however, is not acceptable. This could be improved by a
better fixation of the catheter in the burr hole in order to avoid micromovements
of the transducer.
PMID- 9547951
TI - Prevalence of traumatic brain injury in psychiatric and non-psychiatric subjects.
AB - Traumatic brain injury (TBI) and its sequelae may impact the expression and
treatment of psychiatric disorders. The prevalence of TBI in psychiatric patients
is unknown and investigations in the general population are limited. This study
examined the prevalence of TBI with loss of consciousness in mental health
setting patients (n = 231), general hospital and university staff and students (n
= 534) and non-psychiatric medical clinical patients (n = 59). The Traumatic
Brain Injury Questionnaire was used to assess TBI. A greater percentage of
psychiatric patients reported TBI than medical patients or staff and students.
Traumatic brain injuries were typically mild--moderate, medical assistance was
frequently sought and use of alcohol and drugs was reported in a minority of TBI
incidents. Multiple injuries were most common in psychiatric patients. The
percentage of medical patients and staff and students reporting TBI was similar
to previous research. The greater percentage of psychiatric patients reporting
TBI indicates the need to assess TBI in this population. The role of TBI in the
emergence, expression and treatment outcome of psychiatric disorders and the risk
factors that leave psychiatric patients vulnerable to TBI should be further
examined.
PMID- 9547950
TI - Interpretive risks: the use of the Hopkins Symptom Checklist 90-Revised (SCL 90
R) with brain tumour patients.
AB - Patients with brain tumours often report distress. Interpretive problems ensue
when measures normed on healthy persons are utilized to quantify distress. This
study investigated potentially spurious elevations on the Hopkins Symptom
Checklist 90 Revised (SCL 90-R). Responses of 17 patients were obtained prior to
aggressive chemotherapy. Traditional interpretation indicated that 47% of the
patients endorsed clinical levels of somatization, 53% obsessive-compulsive and
59% psychotic disorders. Elevations were attributable to common consequences of
brain tumours, medication and the emotional reaction to prognosis. Conventional
interpretation would lead to inappropriate classifications. The majority of SCL
90-R item endorsements were significantly different than those of the norm group.
Appropriate interpretation of scores is discussed.
PMID- 9547952
TI - Community-based training after acquired brain injury: preliminary findings.
AB - Persons entering or returning to the workforce after brain injury often require
assistance to identify, locate, secure and maintain employment. This is
especially true for workers from economically disadvantaged environments who may
have limited pre-injury work experience. Supported employment, the use of natural
supports, and community-based approaches are helpful for the process of
identifying, securing and maintaining work. However, reports are limited as to
how these approaches are helpful for economically disadvantaged persons,
especially in identifying meaningful work. An approach is described here which
combines work adjustment training and supported employment; which is helpful in
identifying consumer interest, and in improving position attainment, job
retention and work satisfaction. A sample of persons (n = 38) with brain injury
were contacted after completing the programme. A total of 59% of these persons
remained employed at follow-up, compared to 32% at time of injury. Additional
outcome data are presented to describe the usefulness of this approach.
PMID- 9547953
TI - Caregiver burden at 6 months following severe traumatic brain injury.
AB - Sixty-nine primary caregivers of people with a severe traumatic brain injury
(TBI) were assessed at 6 months post injury. Caregivers completed questionnaires
on the physical, cognitive, emotional, behavioural, and social functioning of the
persons with the TBI. Caregiver psychosocial functioning and levels of subjective
and objective burden were also assessed. Clinically significant levels of
anxiety, depression, and impairment in social adjustment were evident in over a
third of the caregivers. The frequency with which various changes in the person
with the TBI and types of objective burden were reported had little relationship
to the degree of distress caused by these changes. The person with TBI's social
isolation and negative emotional behaviours caused the greatest degree of stress
for caregivers. Caregivers were also most distressed by the impact that
caregiving had on their personal health and free time. The results from a
multiple regression analysis suggest that it is the presence of behavioural
problems in the person with the TBI that has the most severe and pervasive impact
on all aspects of caregiver functioning. It is suggested that these findings be
taken into account when providing rehabilitation services to people with TBI and
their families.
PMID- 9547954
TI - Hypoxic brain injury with motor apraxia following an anaphylactic reaction to
hymenoptera venom.
AB - Hypoxic brain injury can be a complication following several well known
situations or disorders. The neurological and neuropsychological characteristics
of patients who suffer hypoxic brain injury depend on the mechanism of injury and
the structures of the brain that are particularly vulnerable to hypoxia. Injury
to the hippocampus with resultant memory impairment is a well described clinical
feature. Motor apraxia has not been described as a common feature following
hypoxic injury. This paper describes an unusual case of hypoxic brain injury that
resulted from an anaphylactic reaction to hymenoptera venom. The patient
presented with severe ideomotor apraxia as he emerged from coma after
cardiorespiratory arrest. Surprisingly, the patients memory was relatively
preserved in relation to other cognitive impairments. A brief discussion of the
pathophysiology of hypoxic brain injury and the patient's rehabilitation outcome
is presented.
PMID- 9547955
TI - The empowering of Hong Kong Chinese families with a brain damaged member: its
investigation and measurement.
AB - This is an increasing recognition of the influential roles played by the families
of brain damaged persons in rehabilitation. Although these families are expected
to take up the burden of care, they are usually ill-prepared to face this long
term process. This preliminary study of empowerment is aimed at helping Hong Kong
Chinese families with a brain damaged member to regain a sense of mastery over
the brain damage, their environment and their lives. The impact of brain damage
on families was explored in order to propose a model to guide the development of
assessment and intervention, as well as for the justification of practice by
health care professionals. A 52-item instrument, the empowerment questionnaire,
was developed through explorative factor analysis of responses of 211 families
that included a brain damaged member. This analysis yielded four interpretable
factors: efficacy: knowledge: support and aspiration and they demonstrated high
validity reliability.
PMID- 9547956
TI - Mothers, daughters and dieting: investigating the transmission of weight control.
AB - OBJECTIVES: Research by Pike & Rodin (1991) found higher levels of weight concern
and dissatisfaction with family functioning in mothers of eating disordered
adolescent girls. The present study sought to extend this research by examining
the maternal influences on weight and dieting concerns at a younger age. DESIGN:
A cross-sectional comparison of high and low dietary restraint girls and their
mothers was used. METHODS: Two groups of 20 11-year-old girls and their mothers
completed assessments of dietary restraint, body shape preference, self
perception, family functioning and body weight and height. RESULTS: Mothers of
high restraint girls did not differ from comparison mothers in their current
level of dieting, but did report more between-meal snacking and fasting. In
addition, they rated their daughters' attractiveness significantly lower than the
other mothers. Furthermore, families with a highly restrained daughter scored
significantly lower on perceived family cohesion, organization and moral
religious emphasis. CONCLUSIONS: The parallel with the findings of Pike & Rodin
supports the role that mothers may play in the transmission of cultural values
regarding weight, shape and appearance. Importantly, it also places early dieting
within a wider context of dissatisfaction with family functioning.
PMID- 9547957
TI - The value of the Rivermead Behavioural Memory Test (Children's Version) in an
epidemiological study of older adults with Down syndrome.
AB - The Rivermead Behavioural Memory Test for Children (RBMT-C) was used to assess a
population-based sample of 74 people with Down syndrome (DS) aged 30 years and
over (range 30-65 years) living in the Cambridge health district. Given the high
age-specific risk of Alzheimer-like neuropathology in people with DS, the aim of
this study was to determine whether this test provided a suitable measure of
memory function in an older population of adults with DS who were at the age of
risk for Alzheimer's disease. We also investigated whether there was a
significant difference in everyday memory performance between different age,
gender and day-centre groups. The level of learning disability in our sample
ranged from mild, through severe to profound. Individuals with severe or profound
learning disability were virtually untestable on this and other cognitive tests,
but for the remaining two-thirds of the group, the RBMT-C could be used to assess
memory function. Significant differences in memory function were found between
younger (30-44 years) and older (45+ years) participants. Performance also varied
between groups (e.g. from different day centres), illustrating the importance of
population-based samples when determining the value of such tests. Ongoing
longitudinal studies are required to establish the extent to which the RBMT-C is
useful in assessing change in retrospective and prospective memory.
PMID- 9547958
TI - Simulating a memory impairment: can amnesics implicitly outperform simulators?
AB - OBJECTIVES: The purpose of this study was to examine the effectiveness of a
variety of tests in differentiating simulating test performances from genuine
memory-impaired and normal (control) test performances. DESIGN: A simulation
design was implemented, based on an analogue design in which normal participants
were given experimental instructions to feign a mental impairment and are
compared to (a) other normal participants with instructions to perform honestly,
and (b) a comparison group, for example, acquired brain-injured persons, with
similar instructions. METHOD: Forty individuals comprised the simulating and
control group and all participants were randomly assigned to the simulating and
control groups. Twenty memory-impaired patients, all of whom had been diagnosed
as suffering from a memory impairment following acquired brain damage,
participated as the memory-impaired control group. The simulation group was
directed to imitate a person with a memory impairment. The primary outcome
measure involved identifying those tests, if any, where simulators were
significantly different from normal and memory-impaired participants. RESULTS: On
5 of the 15 tasks administered, simulators performed significantly differently
from normal and memory-impaired participants. Of these 5 tasks, the coin-in-the
hand, when administered in conjunction with the autobiographical interview,
identified 95 per cent of the simulators without misclassifying any of the memory
impaired or normal participants. CONCLUSION: It is suggested that these two
tests, when administered jointly, might be of use in clinical settings to assist
in the detection of malingerers.
PMID- 9547959
TI - Do chronic pain patients 'Stroop' on pain stimuli?
AB - OBJECTIVES: Two experiments investigating the presence of information-processing
biases on tasks of attention (Stroop task) and memory (free recall) in relation
to mood states in chronic pain patients are reported. The first investigates
whether previously reported attentional bias is a function of pain status or mood
state. The second describes a more detailed examination of the roles of anxiety
and depression in processing biases in chronic pain patients. DESIGN AND METHOD:
Both studies compared interference time on an emotional Stroop task between
chronic pain patients and controls. Other measures included self-report of pain,
depression and anxiety. RESULTS: Neither study found evidence for an attentional
bias, although a memory recall bias was demonstrated. CONCLUSIONS: Interference
in attending to emotionally salient stimuli appears to be related to measures of
anxiety and depression rather than pain per se. When added to the findings of
other investigators, these results suggest that the presence of attentional
biases in chronic pain patients can best be accounted for as arising from mood
state rather than pain-patient status.
PMID- 9547960
TI - Care staff responses to people with learning disabilities and challenging
behaviour: a cognitive-emotional analysis.
AB - This study explores the application of Weiner's cognitive-emotional model of
helping behaviour to care staff responses to challenging behaviour of people with
learning disabilities. Participants were 20 residential care staff who worked
with people with challenging behaviour and 20 who did not. Six examples of
challenging behaviour were presented, and for each behaviour participants were
asked to give a probable cause, rate attributions of stability, internality,
globality and controllability for their cause, their optimism for change of the
behaviour, their evaluation of the behaviour and a person showing the behaviour,
their emotional response to the behaviour and their willingness to put extra
effort in to helping change the behaviour. Data were analysed using correlation
and regression methods. Carers working with people with challenging behaviour
were more likely to evaluate the person more positively and report they would be
more likely to offer extra effort in helping. A path analysis showed that helping
behaviour was best predicted by optimism, which was best predicted by negative
emotion which was best predicted by the attribution of controllability. We
conclude that attributions and emotions reported by carers in response to
challenging behaviour are consistent with Weiner's cognitive-emotional model of
helping behaviour. Formulating carer behaviour using such models offers the
possibility of using cognitive-behavioural methods in working with staff beliefs,
emotions and behaviour in response to challenging behaviour.
PMID- 9547961
TI - Behavioural effects of long-term multi-sensory stimulation.
AB - OBJECTIVES: Regular access to a multi-sensory environment (MSE or Snoezelen room)
was compared with a non-complex sensory environment for individuals with learning
disabilities. We also tested the prediction that those individuals whose
challenging behaviour was maintained by sensory consequences would benefit most
from exposure to the MSE. DESIGN: The conditions were compared over 16-week
periods using a double crossover design, and were matched for social contact and
attention from the enabler. Participants were randomly assigned to orders of
treatments. METHODS: Participants were 27 adults with severe/profound learning
disabilities who exhibited challenging behaviour. Behaviour was assessed before
and after each treatment phase using both direct observation and standardized
assessments (the Functional Performance Record and the Problem Behaviour
Inventory). The behavioural observations formed the basis of a functional
analysis of each individual's challenging behaviour. RESULTS: Some participants
became more calm and relaxed while in the MSE, however, the objective measures of
behaviour outside the treatment settings revealed no difference between the MSE
and control conditions. Challenging behaviour maintained by sensory consequences
showed no greater responsivity to the MSE than to the control condition.
CONCLUSIONS: The multi-sensory environment had no effects beyond those that could
be ascribed to the social interaction between participant and enabler. Anecdotal
evidence of favourable responses within the MSE itself could not be confirmed
outside the environment.
PMID- 9547962
TI - The treatment of six men with a learning disability convicted of sex offences
with children.
AB - This paper describes a cognitive therapy for men with a learning disability
convicted of sex offences against children. Methods are described which focus the
session, emphasize confidentiality, ensure that the patient accepts
responsibility for the offence, and deal with issues of intent, harm done to the
victim and sequences of offending behaviour. Methods for producing cognitive
change are described. Patients were assessed regularly and data are presented in
detail. While all six men showed improvement, there were several variables which
interfered with the course of treatment. The study attempts to address two major
problems in work with sex offenders: the difficulty of employing a controlled
treatment design and the importance of a long follow-up period.
PMID- 9547963
TI - Malingering of memory impairment on the Colorado Priming Test.
AB - OBJECTIVES: We hypothesized that simulated malingerers would show a weaker
priming effect and a longer response latency than control patients and patients
with a brain injury on a priming test. DESIGN: Participants were compared on
their performance on the Colorado Priming Test to replicate and extend the
original validation study. METHODS: Of 33 participants, 16 were people with a
brain injury and 17 were non-head injured control patients who were also
instructed to feign cognitive impairment (simulators N = 17). RESULTS: Up to 88
per cent of simulating malingerers and 75 per cent of head-injured participants
were correctly classified. CONCLUSIONS: The Colorado Priming Test may be useful
in identifying patients feigning memory impairment.
PMID- 9547964
TI - Cognitive inhibition in phobia.
AB - OBJECTIVES: The purpose of this study was to investigate whether cognitive bias
for threat in anxious individuals may be attributed to a defective inhibition.
DESIGN: It was investigated whether phobics and not non-phobics would show a
defective inhibition of threat words as compared to neutral words. METHOD:
Inhibition was measured by a negative priming task, which was administered to
spider phobic participants (N = 29) and non-phobic controls (N = 31). RESULTS:
The phobics did not show less negative priming of threatening information.
Instead, they showed a general delay on all probe displays that were presented
after threatening primes. CONCLUSION: Anxiety is related to defective inhibition
of threat, in the sense that this inhibition consumes extra cognitive resources.
PMID- 9547965
TI - Oxford-Liverpool Inventory of Feelings and Experiences: reliability in an
experimental population.
AB - Further to the recent development of the Oxford-Liverpool Inventory of Feelings
and Experiences (O-LIFE), a short multidimensional schizotypy questionnaire, the
present study set out to identify the reliability of all scales of this
questionnaire within the same population. Participants were required to complete
the O-LIFE on two separate occasions, whilst taking part in latent inhibition and
negative priming experiments. All scales correlated highly, thus lending further
support to the reliability of this time efficient questionnaire.
PMID- 9547966
TI - Changes following community living skills training: a controlled study.
AB - Fifty-seven adults with mild to moderate learning disability served as
participants in a community living skills training programme. Twenty-nine were
trained using in vivo techniques, 13 were taught using classroom techniques and
15 acted as a no treatment control group. Assessments of community living skills
and adaptive behaviour found those receiving in vivo training performed
significantly better than the other groups. Eventual placement in the community
reflected this superiority.
PMID- 9547967
TI - A long-term follow-up study of a cohort of referrals to an adult mental health
clinical psychology department.
AB - The study, using the SCL-90-R, investigated the long-term outcome of clinical
psychology interventions with adults by contacting 95 clients between five and
eight years after initial contact. Post-treatment improvements in global
psychological well-being were generally maintained at long-term follow-up. About
a quarter of clients, however, did not report any improvement in the initial
problem and about a half had received help from other services since ending
contact with the department. The study provides encouraging evidence of long-term
benefits for many clients, but we suggest a reconsideration of the optimal
provision of psychological help for people whose problems may be enduring and/or
recurrent.
PMID- 9547968
TI - Early experiences with the Tip-Edge appliance.
PMID- 9547969
TI - Orthodontic reconstruction in a victim of murder.
AB - Accurate comparison of ante-mortem photographs and the skull of a deceased person
is dependent upon suitable superimposition techniques and a post-mortem dentition
which is comparable to the situation obtaining in the individual at the time of
death. The skull featuring in this case presented with a missing upper lateral
incisor, lost after death, and the occlusion was studied enabling a replacement
tooth to be provided and positioned as in life. Although no dental records were
available, good quality photographs of a putative identity were compared by
electronic superimposition and the restored occlusal characteristics of the skull
were shown to accurately match the photographs of one possible victim. This
evidence resulted in positive identification by a Coroner. This case illustrates
the importance of seeking specialist clinical advice in forensic dental cases.
PMID- 9547970
TI - Applications of Scanora multimodal maxillofacial imaging in orthodontics.
AB - The principles of the Scanora multimodal radiography system are described. This
self-contained unit of X-ray generator, patient chair, and imaging elements
incorporates the two basic principles of narrow beam radiography and spiral
tomography. Conventional panoramic images or magnified images of the dentition
can be produced. In orthodontics, the application of spiral tomography in order
to obtain cross sectional images has proved helpful in the assessment of a number
of patients. Four cases are reported in which the images obtained using this
system has substantially contributed to their management.
PMID- 9547971
TI - The Clinical Standards Advisory Group (CSAG) Cleft Lip and Palate Study.
AB - A national study of care and outcomes in children born with a unilateral cleft
lip and palate (UCLP) was performed over a 15-month period. Two cohorts of
children ('5-year-olds' and '12-year-olds') were examined. There were 57 active
cleft teams in the U.K. with 105 consultant orthodontists involved in the care of
these children. Only 36 teams could provide basic data such as patients names. Of
the patients, 47-51 per cent had neonatal appliances. The dental arch
relationships were measured with the Goslon Index and a Five-Year-Old Index, 37
39 per cent of both age groups were either 'poor' or 'very poor'. Seventy per
cent of the 12-year-old patients had a Skeletal III relation and 42 per cent of
bone grafts were seriously deficient or failed. Dental treatment for active
caries was needed by 40 per cent of 5-year-olds and 20 per cent of 12-year-olds.
In addition, the training of recently appointed consultant orthodontists involved
in the care of these children was scrutinized. As a whole, the results were
disappointing with standards of care not significantly raised in the last decade.
Recommendations have been made to the Department of Health and the implications
for the orthodontic profession are explored. Overall, it seems that fewer
orthodontists will need to be involved in a centralized care model for these
children.
PMID- 9547972
TI - Assessing malocclusion--the time factor.
AB - Assessment of occlusal status for orthodontic purposes may be undertaken by
subjective assessment or by means of an index of occlusion. The assessment method
should be reproducible and should achieve the intended outcomes. This study
investigated another possible modifying factor--performance over time.
Photographs and dental casts of 45 subjects at 12 years of age were compared with
follow-up records at 16 years of age. No orthodontic intervention had occurred
during the 4 years. Subjective severity assessments and Aesthetic Component (AC)
scores of the Index of Treatment Need (IOTN) for first and second series records
were made by four orthodontists. Scores of the Dental Aesthetic Index (DAI) and
Dental Health Component (DHC) of the IOTN were made by one of the authors.
Implications for hypothetical decisions to treat were considered. There was a
significant reduction in the subjective severity and DAI scores across the whole
sample and in the mixed dentition subgroup. There was a non-significant reduction
in the AC (IOTN) scores across the whole samples, but there was a significant
reduction in the AC (IOTN) scores in the mixed dentition subgroup. The DHC (IOTN)
categorisations proved to be more stable over the period of study.
PMID- 9547973
TI - An ex vivo investigation into the effects of chemical solvents on the debond
behaviour of ceramic orthodontic brackets.
AB - The problems of ceramic bracket debond have been well documented. A peppermint
oil material has been marketed previously as a debonding agent. This study
assessed ex vivo the effects of peppermint oil application on the debond
behaviour of ceramic brackets compared with ethanol and acetone which are
recognized softening agents. Intrigue brackets were bonded to 100 extracted
premolar teeth. Groups of 20 bonded teeth were then placed in a test solution,
control (distilled water), peppermint oil (5 minutes and 1 hour), acetone (1
hour), and ethanol (1 hour). The teeth were debonded using an Instron. Universal
Testing Machine and debond forces recorded. The site of bond failure along with
the adhesive remnant index was recorded for each tooth. One hour placement in
peppermint oil produced the lowest mean and maximal debond forces (77 and 114 N,
respectively). Weibull analysis showed that the probability of failure at 100 N
was increased for the 1-hour peppermint group at 88 per cent compared with 52 per
cent for the control. Placement in peppermint oil produced the lowest levels of
retained resin. There was no evidence of enamel fracture with any of the groups,
but bracket fracture remained a problem.
PMID- 9547974
TI - Parental perceptions and attitudes on orthodontic care.
AB - The objective of this paper is to determine whether an association existed
between parents' attitudes to orthodontic issues affecting themselves and their
attitudes to possible orthodontic treatment for their child. It consisted of an
analytical survey using a self-administered questionnaire, taken in South East
England of six-hundred parents of children aged 9 years. The questionnaires were
delivered to the parent with the help of their child's school. Four-hundred-and
thirty-seven questionnaires were returned (73 per cent). Significant associations
were found between desire by the parents for orthodontic treatment for themselves
and perception of need in their child, parental satisfaction with own dental
appearance and perception of need in their child, a parental history of
orthodontic treatment and a determination to insist on their child's co-operation
with orthodontic treatment. Logistic regression models show the odds of parents
who desire orthodontic treatment themselves, perceiving need in their children
are three times greater than for other parents. 1. There is some evidence that
parents who desire orthodontic treatment for themselves, or who are former
orthodontic patients are more likely to approve of orthodontic care in principle
and to perceive a need for it in their child. 2. Further research is required to
establish to what extent genetic factors are involved.
PMID- 9547976
TI - Toothbrushes.
PMID- 9547977
TI - How UK orthodontists advise patients on oral hygiene.
AB - In 1993, 1038 UK orthodontists (all the members of the British Association of
Orthodontists and the British Society for the Study of Orthodontics) were asked
by questionnaire about the oral hygiene advice they gave to patients undergoing
routine orthodontic treatment. All the orthodontists gave advice on tooth
brushing. Most (89.5 per cent) gave dietary advice and (84 per cent) used
disclosing tablets. A fluoride rinse was recommended by 73 per cent and a
chlorhexidine mouthwash by 41.9 per cent. Many orthodontists advocate appropriate
oral hygiene measures, but the efficacy of such methods is determined by the
patient's motivation. The orthodontist therefore requires skills in behavioural
management. Oral hygiene measures may be more cost-effective when undertaken by
trained auxiliaries.
PMID- 9547975
TI - A critical assessment of high-earning orthodontists in the General Dental
Services of England and Wales (1990-1991)
AB - Cases from the Dental Practice Board's 2 per cent random sample of completed
cases which had been treated by orthodontic practitioners with high gross
earnings, were compared to all the cases within the sample from other
practitioners. They were assessed using the PAR index and IOTN. High earning
orthodontists treated slightly more cases with lower objective need for
treatment, but treated no more cases 'Unnecessarily' than other practitioners.
They used more fixed appliances, and had marginally better levels of residual
need for treatment at finish, although this was at least partially explained by
lower levels at start. Generally, their standards were not substantially
different to other practitioners. Appliance type had a marked effect on outcome,
as did levels of malocclusion and need for treatment at start. Both groups of
practitioners performed similarly (better) with dual arch fixed appliances:
however, overall standards could only be described as mediocre. There is no
justification to single out high earning orthodontists for special scrutiny.
However, it may be beneficial if the system of remuneration in the General Dental
Services could be modified to give more positive incentive to quality, rather
than simply quantity of treatments.
PMID- 9547978
TI - Re: A life threatening complication of removable appliance therapy?
PMID- 9547979
TI - Re: Risk assessment.
PMID- 9547980
TI - Orthodontics in Spain--at the crossroads.
PMID- 9547981
TI - Orthodontic postgraduate training in Germany--have we anything to learn?
AB - In 1996, the authors were able to visit the University Orthodontic Unit in
Marburg, Germany. Author FL was able to undertake the visit as part of a
discretionary secondment for specialist training and this article describes the
author's (FL) experience of orthodontic, postgraduate training there, and
highlights differences between training in the U.K. and Germany. In the current
climate of change with regard to specialist training, it seemed timely to
investigate how training occurs elsewhere in Europe.
PMID- 9547982
TI - Lymphoma. Introduction.
PMID- 9547983
TI - FISH and related techniques in the diagnosis of lymphoma.
AB - Many malignant lymphomas are characterized by recurrent genetic abnormalities.
These include numerical abnormalities, deletions and reciprocal translocations.
In this chapter, we have focused on the detection of chromosomal translocations
in B cell lymphomas and discussed some trisomies in lymphomas and CLL. FISH is a
well developed molecular method by which it is possible to detect numerical and
structural chromosomal abnormalities. We addressed various aspects of metaphase,
and especially interphase, FISH and also described the recently developed DNA
fibre FISH technology. Using this method, it is possible simultaneously to detect
and map chromosomal breakpoints. FISH is also compared with more conventional
detection methods such as banding analysis, Southern blot analysis and PCR for
the translocations t(8;14) and variant translocations in Burkitt's lymphoma,
t(14;18) in follicular lymphoma and t(11;14) in MCL. Other breakpoints in B cell
lymphoma are also discussed. It might be concluded that the rapid development in
interphase and DNA fibre FISH will provide us with quick, easy and cheap tools to
identify specific chromosomal translocations and other genomic abnormalities in
human tumours.
PMID- 9547984
TI - Polymerase chain reaction in the assessment of lymphomas.
AB - The polymerase chain reaction (PCR) offers a practical means of studying the
molecular genetic features of lymphomas. The method is rapid and, as formalin
fixed, paraffin processed samples can be used, does not require special tissue
handling procedures. PCR amplified immunoglobulin and T cell receptor gene
rearrangements can be exploited as markers of clonality and lineage and genetic
abnormalities such as chromosome translocations and mutations of oncogenes and
tumour suppressor genes can be used to identify specific lymphoma types.
Polymorphic X linked loci may also be used as markers of clonality in females.
Direct sequencing of PCR amplified IGH variable regions has provided insights
into the developmental stages, susceptibility to antigen drive and dissemination
patterns of lymphomas. The role of oncogenes and tumour suppressor genes such as
MYC and TP53 in lymphomas can be studied by PCR amplification of mutation
hotspots and direct sequencing of products. Known viral and bacterial DNA can
readily be identified using PCR and unknown organisms sought using conserved
primers to amplify polymorphic sequences. PCR analysis of the lymphomas and
related disorders has accelerated our understanding of their molecular biology
and provides a practical tool with diagnostic and prognostic applications. Future
development of in situ PCR methods will provide cellular localization of genetic
defects and infectious agents.
PMID- 9547985
TI - Molecular single cell studies of normal and transformed lymphocytes.
AB - The polymerase chain reaction allows the characterization of RNA and DNA
sequences from single cells. Methods were established to analyse single cells
isolated from suspension or by multicolour flow cytometry. We established a
method to isolate single immunostained cells from frozen tissue sections and to
analyse those cells for immunoglobulin gene rearrangements. This method was first
used to study B cell differentiation within human germinal centres. In another
series of experiments, Hodgkin and Reed-Sternberg (HRS) cells from a total of 14
cases of HD were analysed for B lineage derivation and clonality. In 13 of the 14
cases, clonal V gene rearrangements were identified. This shows that HRS cells
generally represent the outgrowth of a clonal population of B cells. The
detection of somatic mutations in all VH gene rearrangements amplified from HRS
cells and the nature of those mutations identifies a GC B cell as the HRS
precursor.
PMID- 9547986
TI - The NPM/ALK gene fusion in the pathogenesis of anaplastic large cell lymphoma.
AB - The cloning of the t(2;5) translocation breakpoints and the identification of the
NPM/ALK fusion in Ki-1 ALCL have brought forth from this heterogeneous
morphological grouping a subset of cases defined by an aetiological genetic
alteration. The analysis of NPM/ALK positive lymphomas as a single
clinicopathological entity has already begun to clarify and explain some previous
clinical observations in Ki-1 ALCL. It has also confirmed that HD is
pathogenetically unrelated to NPM/ALK positive Ki-1 ALCL. This is yet another
example of the overall nosological evolution from morphological entities to
pathogenetic entities among lymphomas, leukaemias and, more recently, sarcomas.
Although much work remains to be done on the mechanism of NPM/ALK
lymphomagenesis, rational treatment approaches are now within reach. Such novel
approaches could target NPM/ALK at the level of the genomic sequence, transcript,
protein or its downstream targets, when the latter are further elucidated.
Systems developed to inhibit other fusion transcripts and oncogenic tyrosine
kinases can now be applied to NPM/ALK positive lymphomas. Furthermore, the strong
and highly selective surface expression of CD30 in Ki-1 ALCL may provide a basis
for the targeted delivery of these novel therapeutic agents.
PMID- 9547987
TI - Anaplastic large cell lymphoma and its morphological variants.
AB - Clinicopathological studies have identified CD30+ ALCL as a clinicopathological
entity with heterogeneous morphology and a frequent translocation involving
t(2;5), with a better prognosis than most other T cell neoplasms and a different
natural history and prognosis than Hodgkin's disease. Because of the different
natural history and prognosis of CD30+ ALCL, it is important to recognize this
entity and its morphological variants. Further studies are indicated to determine
whether specific clinical management(s) and therapies are necessary for variants
of ALCL such as HD like ALCL and the small cell predominant type.
PMID- 9547988
TI - The interface of Hodgkin's disease and anaplastic large cell lymphoma.
AB - We reviewed 18 cases in which morphology was intermediate between Hodgkin's
disease (HD) and anaplastic large cell lymphoma (ALCL). Eight cases exhibited the
usual CD30+, CD15+/-, null cell phenotype of classic HD but were rich in
neoplastic cells with sinusoidal infiltrating pattern. In this group, there was
no expression of antigens (EMA, BNH9, CBF78) associated with ALCL, and only two
were positive for Epstein-Barr virus (EBV). Ten EBV negative cases fit the
description of HD like ALCL by variable expression of antigens unassociated with
HD. EMA was clearly and strongly expressed in all ten, whereas antigens
recognized by BNH9 and CBF78 were expressed in four and three cases,
respectively. Focal expression of CD45 and CD43 was observed in half of these
cases. In only one case was the t(2.5) translocation detected with the new
monoclonal antibody, ALK1. Therefore, the expression of EMA, BNH9 and CBF78,
often in concert without CD15 and without the specific translocation, appears
currently to be the most probable phenotype and genotype of HD like ALCL. There
was a tendency for aggressive behaviour of the disease considered HD like ALCL.
Whether such patients will benefit from a therapeutic strategy that takes into
account both phenotype and genotype remains to be discovered.
PMID- 9547990
TI - Clonality in lymphocyte predominance Hodgkin's disease.
AB - Abundant evidence has led to the clinical and biological separation of lymphocyte
predominance from other types of Hodgkin's disease. However, it is still not
clear whether lymphocyte predominance represents a polyclonal reactive lesion
(possibly representing an abnormal immune disorder), a polyclonal or oligoclonal
preneoplastic disorder or a monoclonal neoplastic disorder. The clinical and
histological features are distinctive, but they do not provide clear indications
of the nature of lymphocyte predominance. Some immunohistochemical and in situ
hybridization studies have shown monotypic light chain restriction in the L&H
cells, almost always of kappa type, implying a monoclonal process. Southern
blotting studies are of limited utility, given their relatively low sensitivity
and the rarity of L&H cells within involved tissues. Polymerase chain reaction
studies have yielded conflicting results. Some, but not all, have demonstrated
monoclonal populations in tissue extracts. Single cell PCR studies have generally
not found monoclonal populations, although one case stands as an exception. Cases
of large cell lymphoma complicating lymphocyte predominance have been monoclonal
by polymerase chain reaction and clonospecific primers derived from these clones
have demonstrated similar populations in the corresponding lymphocyte
predominance tissues in some, but not all, studies.
PMID- 9547989
TI - Molecular biology of Hodgkin's disease.
AB - The mist surrounding the origin and genesis of HRS cells of classical HD is
beginning to dissipate. Molecular biological studies of classical HD at the
single cell level strongly suggest that the HRS cells in the majority of cases
represent a monoclonal outgrowth of late germinal centre B cells that have lost
their capacity to express IG through crippling mutations introduced during the
germinal centre reaction. Because of the expression of T cell antigens and/or
cytotoxic molecules, the HRS cells of a minority of classical HD cases appear to
originate from T cells. Under physiological conditions, B cells that are unable
to express IG are eliminated by apoptosis. In most B cell derived classical HD
cases, the HRS cells have lost their IG gene coding capacity through mutation and
should therefore die of apoptosis. Since this usually does not happen, blockade
of the apoptotic pathway may be a major event in the pathogenesis of B cell
related classical HD. It is tempting to assume that viruses such as EBV, as well
as regulator genes that normally monitor the human genome for damaged DNA, such
as TP53, might be involved in the postulated hindrance of the apoptotic pathway,
leading to the genesis of classical HRS cells.
PMID- 9547991
TI - Epstein-Barr virus infection and the pathogenesis of malignant lymphomas.
AB - EBV is associated with an ever increasing number of human malignancies, which
illustrates the importance of understanding how the virus contributes to
tumorigenesis. Recent work has identified as set of EBV latent proteins that are
indispensable for B cell transformation in vitro, and possible mechanisms of
action are beginning to emerge for some of these proteins. In addition to viral
gene expression, host factors appear to be involved in the development of virus
associated tumours. Firstly, virus specific immunity is important for preventing
the outgrowth of EBV associated tumours. Disturbances of EBV specific
immunosurveillance can occur as a consequence of systemic immunosuppression or
due to local factors, some of which may directly or indirectly result from the
expression of EBV genes. Secondly, the phenotype of virus infected cells seems to
be important. Thus, many EBV associated tumours appear to arise from cell types
that do not represent a "physiological" target for the virus and thus may not be
adapted to establishing asymptomatic persistent EBV infection. Furthermore, the
function of transformation associated viral gene products may vary according to
the cellular phenotype.
PMID- 9547992
TI - Cytogenetic mechanisms in the pathogenesis and progression of follicular
lymphoma.
AB - A summary of the clinically significant cytogenetic markers in follicular
lymphoma is presented in Table 3. It is clear that the use of cytogenetic
analysis to evaluate progression and transformation in follicular lymphoma is
complicated by the variety and complexity of the chromosomal aberrations present
in this disease. Cytogenetic and molecular studies have indicated that the
t(14;18) translocation is the prerequisite of a multistep process in the
lymphomagenesis of follicular lymphoma; it is usually followed by a long
quiescent period during which the B cell population expands and additional
oncogenic mutations occur leading to eventual progression and transformation to a
highly malignant form. This process can be accomplished by a variety of pathways:
Activation of other oncogenes by additional chromosomal rearrangements (e.g. MYC,
LAZ3) Deletion and mutation of tumour suppressive genes (e.g. TP53, proposed
genes on 6q) Gain of whole or parts of chromosomes, leading to increased
expression of important regulating factors (e.g. MDR and T cell receptor genes on
chromosome 7) More studies are required to determine which of these pathways, if
any, is most important for neoplastic transformation.
PMID- 9547993
TI - Primary splenic lymphoma.
AB - Although a number of lymphomas and leukaemias can involve the spleen and may
present clinically with splenomegaly, only the B cell disorders SMZL and
hepatosplenic gamma/delta T cell lymphoma can be considered true primary splenic
lymphomas. The former is not uncommon and has histological features which may be
to a certain extent recapitulated by other B cell lymphomas when they involve the
spleen. In view of the characteristic clinically indolent behaviour of SMZL and
its favourable response to splenectomy, rather than chemotherapy, the
differential diagnosis from other B cell lymphomas is important. Hepatosplenic
gamma/delta T cell lymphoma is rare; for the purpose of precise classification,
it needs to be distinguished from other NK like T cell lymphomas and NK cells
lymphomas that sometimes involve the spleen.
PMID- 9547994
TI - Gastric MALT lymphoma and Helicobacter pylori.
AB - The majority of low grade gastric lymphomas arise within acquired organized
lymphoid tissue, which has all the features of MALT. This MALT is specifically
acquired most commonly in response to infection of the gastric mucosa by H
pylori. The lymphocytes within this MALT are therefore programmed to respond to
this organism and the neoplastic cells of the lymphoma that may develop within
this acquired MALT retain the ability to respond to the immunological
proliferative drive associated with the continued presence of the organism.
Following the removal of this immunological drive by eradication of the organism
in vivo, the lymphoma shows clinical and histological regression. The time
required to see this response is unknown and there are some lymphomas that fail
to respond to simple Helicobacter eradication. In some cases, there is continued
molecular evidence of the presence of the lymphoma clone in low levels and the
significance of this remains unknown. These factors are presently under detailed
examination, and several clinical trials to assess the response of a large series
of low grade gastric MALT lymphomas to anti-Helicobacter therapy and the
requirement for additional chemotherapy are at present in progress.
PMID- 9547996
TI - Enteropathy associated T cell lymphoma.
AB - Enteropathy associated T cell lymphoma (EATCL) is the most serious complication
of coeliac disease. HLA genotyping shows that patients with EATCL have the
coeliac disease associated DQA1*0501, DQB1*0201 phenotype. Other HLA-DR/DQ
alleles that may be associated with adult onset coeliac disease appear to
represent additional risk factors for lymphoma development. Increased numbers of
small intestinal intraepithelial cytotoxic T cells are found in the small
intestinal mucosa of patients with coeliac disease and in the enteropathic bowel
of patients with EATCL. The neoplastic cells of EATCL have the immunophenotype of
intraepithelial cytotoxic T cells and may exhibit epitheliotropism. Analysis of T
cell receptor genes and immunohistochemistry have shown that the intestinal
mucosa distant from the tumour contains clonal populations of small T cells,
often of the same clone as the high grade T cell lymphoma. Most cases of chronic
ulcerative enteritis are probably part of the same disease process. The
ulceration seen in chronic ulcerative enteritis and in enteropathy associated T
cell lymphoma may be due to the release of cytolytic enzymes by cytotoxic T cells
and tumour cells. These findings suggest that EATCL arises in the setting of
coeliac disease and evolves from intraepithelial lymphocytosis through low grade
lymphoma to a high grade tumour, possibly under antigen drive from gliadin
peptides. These peptides may be presented to the intraepithelial cytotoxic T
cells directly by epithelial cells bearing the coeliac disease associated HLA-DQ
alleles.
PMID- 9547995
TI - Lymphomatoid granulomatosis: pathogenesis, pathology and clinical implications.
AB - Lymphomatoid granulomatosis (LG) exhibits many similarities both clinically and
pathologically to angiocentric T/NK cell lymphoma and was until recently
considered to be part of the same disease spectrum. However, recent data indicate
that LG is an EBV positive B cell proliferation associated with an exuberant T
cell reaction. LG presents in extranodal sites, most commonly the lung
(Katzenstein and Peiper, 1990). Other frequent sites of involvement include
kidney, skin, central nervous system and liver. The pattern of necrosis in both
LG and T/NK cell lymphoma is very similar, emphasizing the probable importance of
EBV in mediating the vascular damage. Recent studies implicate the chemokines IP
10 and Mig in the pathogenesis of the vascular damage. Although the predominant
infiltrating cells are T cells, the T cell receptor genes are not clonally
rearranged. However, by VDJ polymerase chain reaction, approximately 60% of cases
contain clonal rearrangements. EBV sequences can be localized to B cells and are
clonal in most cases. Most patients with LG when carefully evaluated clinically
have defects in cytotoxic T cell function and reduced levels of CD8+ T cells. LG
is also common in many immunodeficiency states, such as AIDS, Wiskott-Aldrich
syndrome and post-transplantation immunodeficiency. Thus, in many respects, LG
resembles an EBV driven lymphoproliferative disorder. Some cases of LG regress
spontaneously, but most patients require therapy. Treatment approaches have
included cyclophosphamide and prednisone, aggressive combination chemotherapy and
interferon alpha 2b, because of its antiviral, antiproliferative and
immunomodulatory effects.
PMID- 9547997
TI - Lymphomas associated with HIV infection.
AB - Lymphomagenesis in HIV positive patients is a complex phenomenon not yet
completely understood (Karp and Broder, 1992). The great majority of NHL are of
the B cell type. Burkitt lymphoma seems to develop early during the evolution of
HIV infection in patients with a CD4 count above 200/microliter. MYC is
rearranged in the majority of the cases. EBV latent infection is observed in 30
45%. EBV status is characterized by a negativity for EBNA2 and LMP1 The main
sites of the tumour are the lymph node and the bone marrow. Diffuse large cell
lymphomas, mostly represented by immunoblastic lymphomas with plasmacytoid
differentiation and by centroblastic lymphomas rich in immunoblasts, are a late
event in HIV infection, in patients with a low CD4 count (often below
50/microliter). The prognosis is worse than in Burkitt and Burkitt like lymphoma.
MYC is rearranged in about 30-40% of the cases, whereas more than 70% are EBV
positive. EBV status is characterized by a positivity for both EBNA2 and LMP1. B
type ALC lymphomas are more frequently associated with EBV than in the general
population and exhibit the same EBV status as diffuse large cell lymphomas. HD
occurs at any stage of HIV infection. The majority of patients are in clinical
stage III or IV at the time of diagnosis, and HIV associated HD shows a more
aggressive course than non-HIV HD. Many cases remain difficult to classify;
instead, the immunophenotype of neoplastic cells is similar to that in HD
occurring in the general population. Histiocytes and epithelioid cells are even
more numerous than T lymphocytes, and the CD4:CD8 ratio is low. Neoplastic cells
are EBV positive in most or all cases, although they are consistently HIV
negative by in situ hybridization. Lymphomagenesis seems to be very complex, with
multiple agents acting together or successively. EBV, other viruses,
rearrangement of various genes and production of cytokines all seem to have major
roles in addition to immune deficiency.
PMID- 9547998
TI - Targeted antibodies in the treatment of lymphomas.
AB - Monoclonal antibodies coupled to drugs and toxic agents (immunotoxins) or
radionuclides (radioimmunoconjugates) represent new tools for immunotherapy of
haematological malignancies. Immunotoxins constructed with toxins of either plant
or bacterial origin have shown a powerful antitumor activity both in vitro and in
mice with severe combined immunodeficiency bearing various kinds of leukaemias
and lymphomas. Preliminary clinical trials have shown an activity of these
compounds at least in a proportion of patients. However, tumour responses have
generally been partial and transient. The main problems with immunotoxin therapy
remain the inability of immunotoxins to target tumour cells in the presence of a
high burden of disease, the host immune response against both the antibody and
the toxin moieties, which precludes repeated administration of immunotoxins, and
the vascular leak syndrome. Targeting of tumour cells with specific antibodies
armed with radionuclides (usually iodine-131 or yttrium-90) appears to be an even
more attractive approach. Preliminary clinical studies have clearly demonstrated
the ability of radioimmunoconjugates, especially when administered at high dose
followed by bone marrow rescue, to induce durable complete remission in patients
with non-Hodgkin's lymphomas refractory to conventional therapies.
Radioimmunotherapy also overcomes the antigenic heterogeneity of the tumour cell
population, since antigen negative tumour cells will be irradiated by the nearby
targeted antigen-positive cells. Efforts should now be focused on defining more
precisely the optimal clinical setting for administration of immunotoxin and
radioimmunoconjugates (e.g. minimal residual disease), to reduce the
immunogenicity of these compounds and solve the problem of vascular leak
syndrome.
PMID- 9547999
TI - Antisense therapy for B cell lymphomas.
PMID- 9548000
TI - Gene therapy for B cell lymphomas.
AB - The use of genes or genetically modified cells for therapeutic benefit is likely
to have a significant therapeutic role for patients with B cell lymphomas in the
future. To date, most gene therapy strategies applicable to the therapy of these
diseases have not reached the point of clinical study. Adoptive immunotherapy
using donor leucocyte infusion to treat aggressive B cell neoplasms in
immunosuppressed patients has, however, shown great promise clinically, and
studies of idiotypic vaccination in patients with low grade B cell neoplasms are
also under way. Results from in vitro and animal studies continue to suggest that
it may become possible to use the immune system for therapeutic benefit, and many
current basic research strategies in the gene therapy of B cell non-Hodgkin's
lymphoma are based on immune modulation of T cells or tumour cells themselves.
Other major approaches to gene therapy for B cell malignancies include the
introduction of directly toxic or "suicide genes" into B cells or the
chemoprotection of haemopoietic stem cells by the introduction of drug resistance
genes. All of these approaches require efficient and accurate gene transfer as
well as correct expression of the gene product within the target cell. Although
some way from therapeutic use, specific targeting of gene delivery is an area of
active investigation and will be of value in many of the gene therapy strategies
applicable to B cell lymphomas.
PMID- 9548002
TI - Secondary prevention for stroke after CAPRIE and ESPS-2. Opinion 2.
PMID- 9548001
TI - Secondary prevention for stroke after CAPRIE and ESPS-2. Opinion 1.
PMID- 9548003
TI - Magnetic resonance angiography detection of four asymptomatic intracranial
aneurysms.
PMID- 9548004
TI - Comparison of the three strategies of verbal scoring of the Glasgow Coma Scale in
patients with stroke.
AB - Presence of aphasia in patients with stroke poses a problem in the use of the
full form (eye-motor-verbal) Glasgow Coma Scale (GCS). Stroke investigators and
clinicians have used three different strategies to deal with the untestable
verbal subscale, i.e. eliminating the verbal subscale; pseudoscoring with 'one',
and median value substitution; but the predictive accuracy of the strategies has
not been compared. To compare the predictive accuracy of the three strategies for
acute mortality in stroke, we prospectively applied the GCS to 275 consecutive
patients with acute stroke and recorded their survival status before discharge
from hospital. 95 (33.8%) patients died. 32 (12%) patients had untestable verbal
score. Receiver-Operator-Characteristic curves for predicting mortality were
constructed with the GCS sum score and with the multivariate logistic models, and
areas under the curves were measured to compare the predictive accuracy. They
were all found to be similar (0.87-0.88 sq unit). Specifically, the GCS with eye
and motor subscale had 87% accuracy compared to 88% for the model with eye, motor
and verbal scale. We conclude that the short-form (eye-motor) GCS is as good a
predictor of early mortality (within 2 weeks) as the full form (eye-motor-verbal)
GCS in patients with stroke.
PMID- 9548005
TI - Stroke register: experience from the eastern province of Saudi Arabia.
AB - A stroke registry was established in the Eastern Province of Saudi Arabia with an
estimated population of 750,000 inhabitants of whom 545,000 are Saudi citizens.
The register started in July 1989 and ended in July 1993. The Gulf war led to its
interruption from August 1990 to August 1991. Four hundred eighty-eight cases
(314 males, 174 females) of first-ever strokes affecting Saudi nationals were
registered over the 3-year period. The crude incidence rate for first-ever
strokes was 29.8/100,000/year (95% CI: 25.2-34.3/100,000 year). When standardized
to the 1976 US population, it rose up to 125.8/100,000/year. Ischemic strokes
(69%) predominated as in other studies but subarachnoid hemorrhage (SAH) was
extremely rare (1.4%). The important risk factors were: systemic hypertension
(38%), diabetes mellitus (37%), heart disease (27%), smoking (19%) and family
history of stroke (14%). Previous transient ischemic attacks (3%) and carotid
bruits (1%) were uncommon. The 30-day case fatality rate was 15%. The study
showed that the age-adjusted stroke incidence rate for Saudis in this region is
lower than the rates reported in developed countries but within the range
reported worldwide. The pattern of stroke in Saudi Arabia is not different from
that reported in other communities with the exception of the low incidence of
SAH. The risk factors are similar to findings in other studies except for the
high frequency of diabetes mellitus in our cases. The lower mortality rate was
probably due to the younger age of the population and the availability of free
medical services for management of cases.
PMID- 9548006
TI - Impaired orientation in acute stroke: frequency, determinants, and time-course of
recovery. The Copenhagen Stroke Study.
AB - Orientation is an indicator of general intellectual function and is defined as
the ability to report time, place, and personal data. Our knowledge of
orientation in acute stroke is sparse. We examined the frequency of impaired
orientation in acute stroke, its determinants, and recovery in 653 consecutive
patients with acute stroke who were not unconscious and who were without severe
aphasia. Prospective assessments of orientation and stroke severity were done by
the Scandinavian Neurologic Stroke Scale at the time of acute admission and
hereafter weekly until the end of rehabilitation. Impaired orientation was found
in 23% of the patients on acute admission and in 12% of the survivors after
completed rehabilitation. A stationary level of orientation was achieved by 80%
of the patients within 2 weeks and by 95% within 6 weeks. A multiple linear
regression analysis found neurological score (B = 0.027, SE(B) = 0.003), age (B =
-0.013, SE(B) = 0.003), and comorbidity (B = -0.023, SE(B) = 0.078), but not sex,
prior stroke, handedness, or side of stroke lesion to be significant independent
determinants of orientation score on acute admission. Lesions involving the
anterior and medial thalamus and/or any of the cerebral lobes were associated
with impaired orientation. In conclusion, impaired orientation is frequent in
acute stroke and the time-course of recovery is similar to what has been found in
other neuropsychological impairments with the major part of recovery early after
stroke onset.
PMID- 9548007
TI - Cognitive alterations in non-demented CADASIL patients.
AB - CADASIL is an inherited small-artery disease of the brain due to mutations of the
Notch3 gene on chromosome 19. It is characterized by strokes, migraine with aura,
and severe mood disturbances during mid adulthood and leads progressively to
subcortical dementia. The precise onset of the cognitive decline in CADASIL
remains unknown. We report here the cognitive evaluation of 8 non-demented
symptomatic patients with CADASIL from 35 to 66 years of age. Altered
performances were found in all subjects with the Wisconsin Card-Sorting Test
(WCST), in 5/8 with the Trail-Making Test, and in 3/8 with copying of Rey's
figure. Altered performances with codes and similarities of the WAIS-R, the
Wechsler Memory Scale, Raven's Progressive Matrices, and the category and letter
fluency task were observed less frequently (n < or = 2). The score obtained with
the WCST was not significantly correlated with the severity of the white-matter
or basal ganglia signal abnormalities at MRI examination. Our data show that: (1)
symptomatic CADASIL patients, although non-demented, can present with a subtle
cognitive impairment; (2) tasks involving the frontal lobes are found most
frequently altered, and (3) this subtle cognitive deficit can develop in the
absence of major vascular events and does not appear to be correlated with the
severity of brain lesions as seen at MRI examination.
PMID- 9548008
TI - Mitochondrial DNA in stroke and migraine with aura.
AB - Patients presenting with thrombotic stroke of unexplained etiology and or
migraine with aura were screened for mitochondrial (mt) DNA mutations associated
with cytopathies given that both migraine and stroke-like episodes are recognised
with certain mt DNA mutations. Mutations usually associated with either
mitochondrial encephalopathy, lactic acidosis and stroke-like episode, myoclonic
epilepsy with ragged red fibres, or those strongly linked to Leber's hereditary
optic neuropathy (LHON) were not detected in patients or controls. However,
increased levels of two of the secondary LHON mutations were found. The T-->C
mutation at nucleotide 4216 was more common than expected in patients aged 35
years or less, as was the 13708 G-->A mutation in young stroke patients. This
data lends support to the possibility that an accumulation of minor mt DNA
mutations may contribute to the pathoaetiology of stroke and migraine with aura
in some young patients.
PMID- 9548009
TI - Frequency and determinants of microembolic signals on transcranial Doppler in
unselected patients with acute carotid territory ischemia. A prospective study.
AB - BACKGROUND AND PURPOSE: Few data exist regarding to the occurrence of
microembolic high-intensity transient signals (HITS) on transcranial Doppler
ultrasound (TCD) in unselected acute stroke patients. The aim of this study was
to investigate prospectively the frequency and determinants of HITS in acute
carotid territory ischemia. We hypothesized that carotid artery disease, cardiac
abnormalities, and nonlacunar infarcts were independent predictors of HITS in
acute stroke. METHODS: We investigated 145 consecutive patients with acute
internal carotid artery territory ischemia. The median time interval between
stroke and TCD examination was 2 days. TCD monitoring was performed for 30 min on
each middle cerebral artery. The frequency of HITS was cross-classified with
carotid artery status, potential cardiac sources of embolism, and nonlacunar
infarct subtype. Multivariate logistic regression models determined the
independent relationship of these variables to HITS. RESULTS: Microembolic
signals were detected in 35 patients (24.1%), Ipsilateral carotid artery disease
was significantly and independently associated with HITS (odds ratio 3.3, 95%
confidence interval 1.4-7.8, p = 0.007), whereas potential cardiac sources (OR
1.07, 95% CI 0.48-2.4, p = 0.84) and infarct subtype (OR 0.84, 95% CI 0.29-2.4, p
= 0.75) were not. CONCLUSIONS: High-intensity transient signals can be found in
almost 25% of patients with acute anterior cerebral circulation ischemia and are
significantly more prevalent among those with symptomatic carotid artery disease.
Future clinical studies are required to determine whether HITS are a marker of
increased stroke recurrence and can help to clarify stroke etiology in patients
with competing stroke mechanisms.
PMID- 9548010
TI - Venous Doppler ultrasound assessment of the parasellar region.
AB - The purpose of this report is to present normal values for venous blood flow
velocities from the parasellar region using transcranial Doppler ultrasound (2
MHz transducer) with both transtemporal and transorbital approaches and to
examine the nature of previously reported low-pulsatility signals with velocities
in the arterial range from this area. Forty-three subjects ranging in age from 18
to 56 years (mean +/- SD, 31.9 +/- 10.1 years) were examined. In all subjects, a
venous signal directed away from the probe with the source lateral to the
internal carotid artery siphon was detected on at least one side. A total of 72
parasellar venous signals were insonated. Signals were considered to belong to
the main inflow and outflow vessels of the cavernous sinus. The mean blood flow
velocity ranged from 6 to 81 cm/s (mean +/- SD, 27.3 +/- 17.4 cm/s). Typical
transients in the Valsalva test confirmed the venous character of the signals. No
significant gender, side-to-side or age dependency was observed. A separate
analysis was done for venous high-velocity signals defined by a mean blood flow
velocity greater than 30 cm/s. They were detected in 21 out of 43 subjects
(48.9%) via a transtemporal approach and in 6 of them (14%) via the transorbital
route, too. Again, no significant gender, side-to-side or age dependency was
noted. In summary, we found a greater variability of venous blood flow velocities
in the parasellar region compared to other basal cerebral veins, e.g. the basal
vein of Rosenthal. The previously reported low-pulsatility signals with
velocities in the arterial range proved to be of venous origin.
PMID- 9548012
TI - Complications of acute ischaemic stroke.
AB - Neurological, cardiac, and systemic complications during the first days to weeks
after ischaemic stroke can cause substantial morbidity and mortality. The
reported 30-day case fatality rate for cerebral infarction varies between 10 and
17%. The incidence and effects of the various complications vary with time after
stroke: transtentorial herniation and other cerebral complications prevail during
the 1st week, whereas medical complications are more prominent in the weeks
thereafter. Many complications are treatable, and some are preventable. The goal
of this report is to provide information on their incidence, consequences, and
management.
PMID- 9548011
TI - Autonomic nervous activity during sleep in middle cerebral artery infarction.
AB - No data are available on the autonomic system during sleep in patients with
stroke. The purpose of this study was to determine the influence of acute
ischemic stroke on the autonomic cardiovascular system during sleep, and to
correlate autonomic activity with the clinical status of patients. Ten patients
with ischemic stroke in the middle cerebral artery were studied by means of an
all-night polysomnographic recording within the 1st week of the onset of symptoms
and at the 3-week follow-up examination. Power spectrum analysis of the heart
rate variability was performed using an autoregressive algorithm in 180
consecutive electrocardiographic RR intervals. Spectral power was calculated in 3
main frequency bands: high frequency (HF), 0.15-0.4 Hz; low frequency (LF), 0.04
0.15 Hz; very low frequency (VLF), < 0.04 Hz. The data were compared with those
of 10 age-matched controls. A significant increase in VLF (p < 0.0005) and a
decrease in HF (p < 0.0002) components were found in ischemic stroke patients.
The sympathetic-parasympathetic balance (VLF + LF/HF) was higher in patients than
controls (p < 0.005). However, these components changed significantly during
sleep, revealing a physiological pattern. These power spectral data were still
present at the 3-week follow-up. The 4 patients who developed cardiac arrhythmias
showed higher sympathetic-parasympathetic balance than patients without
arrhythmias (p < 0.05). These data suggest a sympathetic predominance in patients
with acute ischemic stroke during sleep. However, the flexible and dynamic
properties of the autonomic nervous system are preserved. Cardiac arrhythmias
following stroke may be related to the degree of sympathetic predominance.
PMID- 9548013
TI - Detection of intraluminal thrombus in acute stroke by proton density MR imaging.
PMID- 9548014
TI - Hormone replacement therapy in gynecological cancer survivors.
PMID- 9548015
TI - Surgery or radiation: is there really a choice for early prostate cancer.
AB - One of the most difficult tasks for the practicing urologist is to counsel the
patient in a decision for the optimal treatment for his localized prostate
cancer. After providing the patient with contemporary and unbiased information
and data, it is important to find the preferred treatment based on his age, the
medical realities and, last but not least, the patient's personal preference.
Radical prostatectomy, radiotherapy and observation are standard treatment
options. TRUS-guided brachytherapy and cryosurgery are considered investigational
treatment options since follow-up is inadequate to provide sufficiently precise
outcome estimates. The literature does not provide clear-cut evidence for the
superiority of any one treatment. The patient most likely to benefit from radical
prostatectomy would have a relatively long life expectancy, no significant
surgical risk factors and a preference to undergo surgery. The major advantage of
radical prostatectomy is its potential for total removal of the cancer and cure
in properly selected patients. Potential harm includes urinary incontinence and
impotence. The patient most likely to benefit from radiation therapy would have a
relatively long life expectancy, no significant risk factors for radiation
toxicity and a preference for radiotherapy. The advantages of radiotherapy are
that it has a potential for cure and it is well tolerated in the majority of men
when the modern techniques are used. Potential harm includes radiation cystitis,
proctitis and impotence, persisting severe complications are only seen in 1% of
patients. The patient most likely to benefit from surveillance are those with a
shorter life expectancy and/or a low grade tumour. Benefits are lack of treatment
related morbidity with only marginal compromise of disease-specific survival at 5
10 years follow-up.
PMID- 9548016
TI - The cellular biology of B-cell chronic lymphocytic leukemia.
AB - In conclusion, B-CLL cells through their immunophenotype have the functional
potential required to interact with cells in what has been called the
immunological synapse, i.e. the cognate interactions between T-cells, antigen
presenting cells and B-cells during immunopoiesis. The data reviewed herein
provides substantial evidence to suggest that B-CLL cells in fact can interact,
not only with T-cells but also with endothelial cells and stromal cells in the
bone marrow. These interactions, in particular signaling through CD40, contribute
to extended survival and proliferation of B-CLL cells and, thereby, the risk of
complete malignant transformation of the clone. Therefore, this review would
suggest that the answers to how B-CLL is initiated may be found in molecules
responsible for the normal regulation of immunopoiesis. Transformation to
malignancy, by contrast, is likely to be caused by loss of control over the G1
restriction in the cell cycle in B-CLL cells.
PMID- 9548018
TI - Cytoskeletal and adhesion protein changes during neoplastic progression of human
prostate epithelial cells.
PMID- 9548017
TI - Anthracycline-induced cardiotoxicity in children and young adults.
PMID- 9548019
TI - Violence faced by staff in a learning disability service.
AB - This study explores the issue of violence experienced by staff in the learning
disability service of an NHS Trust. Based on the literature review a
questionnaire survey was sent to all staff employed in the Trust's learning
disability service (n = 295). The questionnaire sought: background details of
respondents; numerical incidences and types of violence experienced over the
previous 12 months; reporting mechanisms; reactions to and impact of violence on
individuals and their work; support received. Vignettes provide a rich picture of
the types of violent incidences and their impact. The findings show that 81% of
staff in the learning disability service had experienced violence in the previous
12 months. Many had numerous experiences of violence. New and inexperienced staff
are particularly vulnerable. Training and support systems are, on the whole,
limited. Support received from colleagues is generally regarded as more helpful
than that of line management. To explore good practice elsewhere, semi-structured
interviews were held with individuals working with potentially violent clients in
organizations other than the learning disability service. Suggestions are offered
for putting in place human resource strategies to reduce the incidences of
violence and provide appropriate post-incident support for staff on a continuing
basis.
PMID- 9548020
TI - Knowledge of stroke in rehabilitation and community samples.
AB - This study examined the stroke knowledge of 60 stroke rehabilitation patients, 46
spouses, 25 family members, and 103 people in the general community. Changes in
stroke knowledge with time, and determinants of stroke knowledge, were also
examined. Clinical participants were assessed on acute admission, admission to
and discharge from rehabilitation, and 6 and 12 months after discharge. Community
participants were assessed once. Instruments used were the Stroke Care
Information Test, Australian ADL Index, Frenchay Activities Index, Illness
Behaviour Questionnaire and Zung Self-rating Depression Scale. The stroke
knowledge of all participants, particularly patients, was poor, but improved with
time. Better-informed patients were younger, had milder strokes, were less
depressed, were less likely to develop abnormal illness behaviour, and made a
better functional recovery than patients with poorer knowledge. Structured
information programmes are needed for stroke patients and their families.
Improved community awareness of stroke may help the prospects for recovery and
quality of life for people who have strokes.
PMID- 9548021
TI - Is neurological rehabilitation ready for 'immersion' in the world of virtual
reality?
PMID- 9548022
TI - Does virtual reality have a place in the rehabilitation world?
PMID- 9548023
TI - Virtual reality: a fascinating tool for motor rehabilitation (to be used with
caution)
PMID- 9548024
TI - Virtual reality: opening the way.
PMID- 9548025
TI - Virtual reality: consumer perspectives.
AB - This commentary extends the discussion of the applications of virtual reality to
persons with disabilities by focusing on: (a) the use of virtual reality for
stimulating residential features for persons being deinstitutionalized into four
person community residences; and (b) the involvement of consumers in key
decisions regarding their residence and personal assistive technologies.
PMID- 9548026
TI - Virtual reality in rehabilitation.
PMID- 9548027
TI - A rejoinder.
PMID- 9548028
TI - Sports-medical assessment for athletes with a disability.
AB - The purpose of this article is to describe a Sports-Medical Assessment Protocol
(SMAP) for athletes with a disability. The purposes of the SMAP are to identify
medical problems and therapeutic goals for supplementary training programmes for
athletes with a disability, and to provide baseline data for future follow up.
The SMAP includes an interview, cardiorespiratory assessment and physical and
functional examination. Data were collected from assessment protocols of 14 male
athletes with various neurological disorders who qualified to participate in the
Atlanta Paralympic Games in 1996. Nine of the athletes had some range of motion
(ROM) limitations, one had shoulder pain and one low back pain following physical
stress. Two athletes with postpolio presented muscle fasciculation and one of
them also presented bilateral Carpal Tunnel Syndrome. Based on the results we
concluded that utilizing the SMAP may contribute to trainers' and athletes' (with
a disability) awareness of the physical needs of elite athletes as well as
participants in leisure sport activities.
PMID- 9548029
TI - Developmental patterns of heart rate and variability in infants with persistent
apnea of infancy.
AB - During periods of regular breathing, heart rate is slower and more variable in
healthy (no history of respiratory distress syndrome) prematurely born infants
with persistent apnea, relative to full-term control infants of comparable post
conceptional ages. We tested the hypothesis that the cardiovascular differences
may be linked to the persistent apnea, rather than premature birth, by assessing
heart rate and variability in full-term infants with persistent apnea. Thus,
resting heart rate and variability were compared in full-term infants with apnea
of infancy, prematurely born infants with persistent apnea, and full-term control
infants. Full-term infants with persisting apnea showed slower heart rates than
control infants, beginning at 4 months after birth, and enhanced heart rate
variability beginning at 6 months. Healthy prematurely born infants with
persistent apnea showed cardiovascular alterations similar to those of full-term
infants with apnea; these alterations differed from those observed in very
premature infants with histories of respiratory distress. The postnatal
development of cardiovascular aberrations in infants with persistent apnea
suggests that mechanisms accompanying apneic events may contribute to long-term
alterations in autonomic control.
PMID- 9548030
TI - Hourly fetal urine production rate in the near-term fetus: is it really increased
during fetal quiet sleep?
AB - Fetal bladder volume and hourly fetal urine production (HFUPR) is calculated on
the assumption that the fetal bladder is ellipsoid in shape. A recent validation
study demonstrated a progressive overestimation at increasing bladder volumes.
This may be due to changes in shape of the fetal bladder at increasing volumes.
Two independent papers have shown increased HFUPR during fetal behavioural state
1F (S1F) when compared with S2F. The aim of the present study was to assess
whether this increase of HFUPR during S1F, previously observed by others, could
be the result of an error introduced by the method of volume calculation. A
retrospective evaluation was performed in a series of 208 HFUPR measurements in
123 normal near term pregnant women attending a low-risk atenatal clinic.
Adequate bladder filling in both states was identified in 43 recordings. Maximum
fetal bladder volumes were greater (> 10 ml) during S1F in comparison to S2F in
56% of these recordings and HFUPR was significantly greater during S1F only in
these cases. Bladder volumes are usually lower during S2F as a result of fetal
voiding, which occurred in association with 22 of 36 transitions from S1F to S2F,
and only 1 of 13 transitions from S2F to S1F (P < 0.001). When disregarding
calculated bladder volumes in excess of 20 ml for the purpose of calculating
HFUPR, eleven recordings remained. HFUPR calculated in this way was significantly
lower in comparison to measurements where larger bladder volumes were included
and no difference was observed between states. This implies that the differences
observed are the result of the greater error in calculating bladder volumes and
HFUPR during S1F, where volumes are usually greater and that calculation of fetal
bladder volume should not be performed on the assumption that the bladder is
ellipsoid in shape. Alternative techniques include limiting measurements to a
maximum volume of approximately 20 ml, when the bladder is usually ellipsoid in
shape or basing volume calculation on the surface area of a series of sagittal
views as suggested by Hedriana and Moore [Hedriana HL, Moore TR. Ultrasonographic
evaluation of human fetal urinary flow rate: accuracy of bladder volume
estimations. Am J Obstet Gynecol 1994;170:1250-1254; Hedriana HL, Moore TR.
Accuracy limits of ultrasonographic estimation of fetal urinary flow rate.
PMID- 9548031
TI - Cardiovascular responses to feeding in the neonate during the first four days of
life.
AB - Prior work has demonstrated acute cardiovascular responses associated with breast
and bottle feeding of newborn infants that consist of increases in both blood
pressure and heart rate. This current study sought to determine if the amplitude
of these responses is related to the age of the infant and/or the amount of
nutrient ingested during the study period. Results show that the magnitude of the
feeding responses does not change over the first four days of life. In a second
study it was found that changes in systolic blood pressure during feeding are
positively correlated with volume of nutrient intake during the initial phase of
feeding (r = +0.75, p < 0.01). These results suggest that some of the individual
variability in the increase in blood pressure during feeding is related to the
amount of nutrient ingested. It is not known whether these differences are due to
differences in sucking effort or other aspects of feeding efficiency.
PMID- 9548032
TI - Neurological condition in 42-month-old children in relation to pre- and postnatal
exposure to polychlorinated biphenyls and dioxins.
AB - Adverse neurological effects of exposure to PCBs have been found up to 18 months
of age. Now we report on the effect of pre- and postnatal exposure to PCBs and
dioxins on the neurological condition at 42 months of age. For this purpose, PCB
levels were determined in cord and maternal plasma, and used as a measure of
prenatal exposure. Breast milk was analyzed for PCBs and dioxins. In addition,
PCBs were determined in plasma sampled from the child at 42 months of age. We
evaluated the neurological condition of 394 children using the Touwen/Hempel
method. After adjustment for covariates, neither prenatal PCB exposure nor
postnatal exposure to PCBs and dioxins was found to be related to the
neurological condition at 42 months of age.
PMID- 9548033
TI - Maternal nutritional status, diabetes and risk of macrosomia among Native
Canadian women.
AB - Multivariate methods were used to identify risk factors for macrosomia (birth
weight > 4000 g) among 741 singleton births to Native Canadian women from Sioux
Lookout Zone, Ontario, Canada, in 1990-1993. The average birth weight was 3691 +/
577 g, and 29.2% of infants weighed more than 4000 g at birth. Macrosomic
infants were born at later gestational ages and were more likely to be male.
Women delivering macrosomic infants were taller, entered pregnancy with higher
body mass indexes (BMI) and gained more weight during pregnancy, but were less
likely to smoke cigarettes. They were more likely to have previously delivered a
macrosomic infant and to have had gestational diabetes mellitus (GDM). Risk of
macrosomia was associated with maternal glycemic status; women with pre-existing
diabetes were at greatest risk, followed by those with GDM A2 (fasting glucose >
or = 6 mmol/l). Women with GDM A1 (fasting glucose < 6 mmol/l) were not at
increased risk for delivering a macrosomic infant, but glucose-tolerant women
with high glucose concentrations 1 h after the 50 g challenge were at somewhat
increased risk. Maternal glycemic status and maternal nutritional status before
and during pregnancy are important determinants of macrosomia in this native
population.
PMID- 9548034
TI - Screening for inborn errors of metabolism in high-risk children from Rio de
Janeiro, Brazil.
AB - From 1988 to 1995, our laboratory at the Institute of Chemistry of the Federal
University of Rio de Janeiro, in Rio de Janeiro, screened 2650 samples from 2000
high-risk patients (mostly children) for Inborn Errors of Metabolism (IEM).
Chemical tests, various chromatographic techniques and enzyme assays were
performed on urine, plasma and in some cases, cerebrospinal fluid (CSF). A total
of 145 cases of IEM (7.2%) was identified. These were related to: the metabolism
of amino acids (41) and carbohydrates (17), organic acids (7), lysosomal enzymes
(61), membrane transport system (16), metals (2), intestinal disaccharidases (1)
and porphyrin metabolism (3). Furthermore, a relevant number of patients with
abnormal findings is still under investigation. Biochemical results and clinical
symptoms are presented and the importance of reference laboratories for the
detection of IEM is stressed.
PMID- 9548035
TI - Laparoscopy as a day-case procedure in patients with liver disease.
AB - BACKGROUND AND STUDY AIMS: The present study was aimed at exploring the
feasibility of diagnostic laparoscopy on a day-case basis in patients with liver
disease. PATIENTS AND METHODS: Retrospective analysis was carried out of 85
consecutive day-case laparoscopies performed between January 1990 and January
1994. During this period, patients were observed in day-care facilities for a
period of three hours. Patients' perception and acceptance of the procedure were
assessed using a postal questionnaire. RESULTS: Laparoscopy was successful in 84
of the 85 patients; adequate liver biopsies were obtained in 83 patients. In
three cases, the procedure was converted to a one-night hospital admission
because of pain (1), persistent sedation (1) and collapse (1). Abdominal skin
hematomas were reported by eight patients, and fever by two. Serious
complications were not observed. The majority of patients experienced no
complaints, or minor ones, after the procedure, and they expressed a preference
for an outpatient procedure in case a renewed investigation might be indicated.
Compared with in-hospital procedures, day-case laparoscopy was associated with a
33% reduction in cost. CONCLUSIONS: Diagnostic laparoscopy, with the hospital
stay reduced to three hours, can be performed safely as a day-case procedure in
selected patients.
PMID- 9548036
TI - Does laparoscopic cardiomyotomy require an antireflux procedure?
AB - BACKGROUND AND STUDY AIMS: There is controversy concerning the need for an
antireflux procedure in patients undergoing open or endoscopic cardiomyotomy for
achalasia. The addition of an antireflux wrap (partial or total), while
preventing reflux, may result in persistence or incomplete relief of dysphagia in
patients with total oesophageal aperistalsis. The technique of laparoscopic
cardiomyotomy used in Dundee preserves the lateral and posterior attachments of
the gastro-oesophageal junction, and was designed to minimize the risk of gastro
oesophageal reflux. PATIENTS AND METHODS: A consecutive series of patients with
achalasia (n = 19) were treated by laparoscopic cardiomyotomy using the Dundee
technique, which limits the mobilization to the anterior wall of the abdominal
and thoracic oesophagus. The patients were followed up prospectively to assess
the long-term relief of dysphagia and the postoperative incidence of reflux
symptoms, with or without oesophagitis. RESULTS: The follow-up symptoms and
assessment of the patients (15-53 months, median 27 months) showed total relief
(n = 12) or substantial relief (n = 5) of dysphagia in 89%. On assessment at a
median follow-up of 27 months, the number of patients experiencing heartburn
after this operation increased from four of 15 to five of 15, and one patient
(6.6%) developed endoscopically proved oesophagitis, with a positive oesophageal
pH monitoring test. CONCLUSIONS: The routine addition of an antireflux operation
is not justified in patients undergoing laparoscopic cardiomyotomy, provided that
the lateral and posterior attachment of the oesophagus are kept intact.
PMID- 9548038
TI - The role of surveillance endoscopic retrograde cholangiopancreatography in
preventing episodic cholangitis in patients with recurrent common bile duct
stones.
AB - BACKGROUND AND STUDY AIMS: Approximately 2-7% of patients who have undergone
previous removal of bile duct stones have recurrence often presenting as
ascending cholangitis. The aim of this study was to identify the incidence,
clinical presentation, and objective findings in this group of patients.
Additionally, the effect of surveillance endoscopic retrograde
cholangiopancreatography (ERCP) in preventing cholangitis, was studied. PATIENTS
AND METHODS: Two thousand and ninety-six patients who underwent ERCP for
cholelithiasis were studied with 45 of these patients being identified as having
recurrent common bile duct stones. Of the 45, 13 had two or more recurrences
without having any obvious predisposing factors. The mean age of the 13 patients
was 57 years. The characteristics of 13 patients were reviewed, including
sphincterotomy size, liver function tests, and contrast drainage time. RESULTS:
All 13 patients with recurrent stones presented with ascending cholangitis.
Stones were found to be soft, brown and accompanied by a large amount of sludge.
The common bile duct in all 13 patients was noted to be dilated and had notable,
widely patent sphincterotomes. There was significant delayed drainage in 77% of
these patients. Yearly surveillance ERCPs were performed in the 13 patients, the
incidence of acute cholangitis episodes per patient decreased from 2 to 0.6 with
a four-year follow-up. CONCLUSION: In a subgroup of patients with multiple common
bile duct stone recurrences, annual surveillance ERCP with stone removal
decreases the incidence of recurrent episodes of ascending cholangitis as well as
its associated morbidity and mortality.
PMID- 9548037
TI - Endoscopic papillary balloon dilation for the management of common bile duct
stones: experience of 226 cases.
AB - BACKGROUND AND STUDY AIMS: Endoscopic sphincterotomy is a widely accepted
technique for the treatment of patients with common bile duct stones. However, it
is still associated with occasional complications. The recently developed
technique of endoscopic papillary balloon dilation seems to be a safe and
effective procedure, and to have great potential for replacing endoscopic
sphincterotomy. However, few reports have been published on the use of this
technique for bile duct stones. The present study was undertaken to evaluate its
safety and efficacy. PATIENTS AND METHODS: Endoscopic papillary balloon dilation
was used to remove common bile duct stones in 226 consecutive patients including
41 patients of ASA classification III/IV, 41 elderly patients (> 80 years) 24
with liver cirrhosis, and 86 with periampullary diverticulum. After dilation of
the papilla with a balloon diameter of 8 mm, the stones were retrieved. RESULTS:
In conjunction with the use of a mechanical or/and electrohydraulic lithotriptor
in 79 patients (35%) with large stones (> 10 mm in diameter), clearance of the
common bile duct was achieved in 225 of 226 patients (99%) without serious
complications, such as hemorrhage or severe pancreatitis; mild (n = 13) or
moderate (n = 2) pancreatitis occurred in 7% of cases. CONCLUSIONS: Endoscopic
papillary balloon dilation is a safe and effective technique for the treatment of
common bile duct stones, even in high-risk patients.
PMID- 9548039
TI - A prospective, randomized controlled trial of sedation vs. no sedation in
outpatient diagnostic upper gastrointestinal endoscopy.
AB - BACKGROUND AND STUDY AIMS: The majority of gastrointestinal endoscopists in the
United Kingdom routinely use intravenous sedation prior to diagnostic upper
gastrointestinal endoscopy. We conducted a prospective, randomized controlled
clinical trial to help determine whether the use of sedation influences the
duration, safety, and tolerance of diagnostic upper gastrointestinal endoscopy.
PATIENTS AND METHODS: Adults referred for outpatient diagnostic upper
gastrointestinal endoscopy were invited to participate in the study. Patients
with a history of previous upper gastrointestinal endoscopy or dysphagia were
excluded. Patients were prospectively randomized to sedation with intravenous
midazolam (5 mg for those under 65 years or 3 mg for those aged 65 or more), or
no sedation. All patients were given topical oropharyngeal anaesthesia with 100
mg lignocaine spray. Outcome measures included duration of procedure, ease of
procedure (as assessed by medical and nursing staff), tolerance of procedure (as
assessed by patients), and incidence of complications. RESULTS: 100 patients were
randomized to receive sedation or no sedation. The two groups were well matched
for age, sex, and number of biopsies taken during the procedure. In the non
sedated group, the duration of endoscopy tended to be reduced and the procedure
tended to be easier according to the endoscopists' assessment (neither of these
observations was significant). The sedated group reported greater comfort for the
procedure (P < 0.001), although both groups tolerated the procedure well, and the
majority in both groups preferred to have any future procedure repeated in the
same manner. There were no serious adverse events in either group. CONCLUSIONS:
In patients who are willing to contemplate upper gastrointestinal endoscopy
without sedation, the avoidance of sedation may lead to faster and easier
endoscopies, without any increased risk of procedural difficulties or adverse
events.
PMID- 9548040
TI - Effect of large fundal varices on changes in gastric mucosal hemodynamics after
endoscopic variceal ligation.
AB - BACKGROUNDS AND STUDY AIMS: Effect of endoscopic variceal ligation (EVL) on
gastric mucosal hemodynamics would differ in patients with and without large
fundal varices. The aim of this study was to test this hypothesis. PATIENTS AND
METHODS: Twenty-seven patients with cirrhosis and large sized esophageal varices
were prospectively studied. There were eight patients with large fundal varices
and 19 patients without large fundal varices. Before EVL, gastric mucosal
hemodynamics were endoscopically assessed by laser-Doppler velocimetry and
reflectance spectrophotometry in the antrum and the corpus. In the reflectance
spectrophotometric measurements, gastric mucosal hemoglobin content (IHb) and
gastric mucosal oxygen saturation (ISO2) were determined. The severity of portal
hypertensive gastropathy (PHG) was also recorded at the antrum and the corpus.
For data analysis, PHG was scored (absent, 0; mild, 1; severe, 2; bleeding, 3).
These measurements were repeated after initial (three days after initial session)
and repeated (seven days after last session) EVL. RESULTS: At the antrum, neither
PHG score nor gastric mucosal hemodynamic parameters were modified after initial
and repeated EVL in patients with and without large fundal varices. In addition,
no significant differences of the integrated changes in PHG score and gastric
mucosal hemodynamic parameters were observed in the two groups. At the corpus,
PHG score significantly increased after initial and repeated EVL in patients
without large fundal varices. In these patients, laser-Doppler signal and ISO2
significantly decreased and IHb significantly increased after initial and
repeated EVL. In contrast, PHG score, laser-Doppler signal, and ISO2 did not
change significantly in patients with large fundal varices, although IHb
transiently increased after initial EVL. Furthermore, the integrated changes in
PHG score and gastric mucosal hemodynamic parameters were significantly lower in
patients with large fundal varices than in those without. CONCLUSION: The
aggravation of PHG after EVL is due to congestion of the gastric mucosal
circulation. The presence of large fundal varices plays a protective role in the
development of EVL-induced gastric mucosal hemodynamic derangement.
PMID- 9548041
TI - Endosonography-guided biopsy of mediastinal and pancreatic tumors.
AB - BACKGROUND: Although endoscopic ultrasound (EUS) allows sensitive imaging of the
upper gastrointestinal (GI) tract, it remains difficult to differentiate between
benign and malignant lesions on the basis of ultrasound morphology. The purpose
of this study was to determine the value of EUS-guided biopsy for the diagnosis
of submucosal and extraluminal tumors. METHODS: EUS-guided biopsy was carried out
in 50 patients with upper GI-tract lesions. All patients were examined using a
flexible echoendoscope with a 5/7.5 MHz curved array transducer. A specially
designed biopsy device (type Vilmann) with a fine needle (diameter 0.8 mm) was
used for EUS-guided biopsy. RESULTS: EUS-guided biopsy was performed for
evaluation of mediastinal lesions (n = 15), pancreatic tumors (n = 26) and
submucosal (n = 5) or stenotic tumors of the esophagus (n = 4). Fine-needle
aspiration yielded diagnostic tissue samples in 44 of 50 patients (88%).
Histology demonstrated benign lesions in 20 of 44 patients and malignant tumors
in the other 24 patients. EUS-guided biopsy failed in only six patients (12%): in
four patients it was impossible to advance the needle into very hard pancreatic
tumors; non-representative biopsy material was obtained in two further cases. The
results of EUS-guided biopsy were validated by surgery (n = 21), autopsy (n = 3)
or clinical follow-up (n = 20). After a mean follow-up of 16 months there is no
evidence of malignancy in any of the patients with benign histology. The
sensitivity and specificity of EUS-guided biopsy in the diagnosis of malignancy
were 88% and 100%, respectively. None of the patients experienced complications
related to endosonographic biopsy. CONCLUSIONS: EUS-guided biopsy with the
Vilmann needle device is a safe and accurate method for tissue sampling of
extraluminal lesions. This technique considerably improves the diagnostic value
of endosonography.
PMID- 9548042
TI - Injection treatment of hemorrhage induced by endoscopic sphincterotomy.
AB - BACKGROUND AND STUDY AIMS: Hemorrhage is one of the most common severe
complications after endoscopic sphincterotomy (ES) and the mortality after
surgical treatment can be as high as 50%. We prospectively evaluated the effect
of injection treatment in nine patients with appreciable hemorrhage after ES.
PATIENTS AND METHODS: Bleeding was detected immediately after ES in five patients
and 48, 72, 120 and 216 hours after the procedure in the remaining four. Patients
were treated with a combined injection of epinephrine and polidocanol (1-3 and 3
6 ml, respectively) into the bleeding site. RESULTS: Treatment was effective in
arresting hemorrhage in all cases. Two patients had abnormal clotting tests,
which emphasizes the importance of identifying risk factors for hemorrhage before
ES. No patient required operation and there were no late complications related to
the injection during a mean follow-up period of six months. CONCLUSIONS: Our
results suggest that bleeding after sphincterotomy can be safely and effectively
controlled by a combined epinephrine and polidocanol injection, thereby avoiding
operation.
PMID- 9548043
TI - What to do when the papilla bleeds after endoscopic sphincterotomy.
PMID- 9548044
TI - What is the current status of endoscopic balloon dilation for stone removal?
PMID- 9548045
TI - The treatment of cricopharyngeal dysmotility with a transmucosal cricopharyngeal
myotomy using the potassium-titanyl-phosphate (KTP) laser.
AB - Cricopharyngeal dysfunction is a relatively uncommon disorder that is
misunderstood by many physicians. Cricopharyngeal dysmotility is thought to
indicate abnormal function in the upper esophageal or cricopharyngeal sphincter,
the etiology of which is related to uncoordinated pharyngeal swallowing,
achalasia, or a combination of these factors. Unfortunately, standard diagnostic
tests do not consistently show that the cricopharyngeal sphincter malfunctions;
so cricopharyngeal myotomy has been suggested as a diagnostic and therapeutic
tool in the treatment of dysmotility. The current report reviews trends in the
diagnosis and treatment of cricopharyngeal myotomy, including the results of
cricopharyngeal myotomy using the potassium-titanyl-phosphate (KTP) laser. A
transmucosal cricopharyngeal myotomy with the KTP laser may be a viable
alternative for patients with cricopharyngeal dysmotility compared with
conventional techniques.
PMID- 9548046
TI - Forward-viewing endoscope or side-viewing duodenoscope for ERCP in patients after
Billroth II gastrectomy?
PMID- 9548048
TI - Early gastric cancer in a fundic diverticulum.
PMID- 9548047
TI - Percutaneous endoscopic gastrostomy/jejunostomy in the early postoperative
period.
PMID- 9548049
TI - Esophageal perforation due to endoscopic retrograde cholangiopancreatography.
PMID- 9548050
TI - Use of a new mouthpiece in placing a nasobiliary drainage tube.
PMID- 9548051
TI - Biliary opening anomalies: ectopic drainage of pancreaticobiliary ducts.
PMID- 9548052
TI - Application of clips during ERCP: a new anchoring method for redundant
Kerckring's fold covering the duodenal papilla.
PMID- 9548053
TI - Removal of Ascaris lumbricoides from the bile duct using balloon
sphincteroplasty.
PMID- 9548054
TI - Diagnostic endoscopic ultrasound of the pancreas may cause acute pancreatitis.
PMID- 9548055
TI - Cocaine-induced ischemic colitis.
PMID- 9548056
TI - Gastrointestinal involvement in infections caused by varicella virus.
PMID- 9548057
TI - The Healthy Neighborhoods Project: a local health department's role in catalyzing
community development.
AB - Studies show that community development approaches to health education may lead
not only to improved social, economic, and health status but also to increased
individual participation in health education and preventive health care
activities. However, because of categorical funding restraints and philosophical
issues, local health departments have rarely given control of defining project
outcomes to the community. One such project was in a low-income urban
neighborhood in the San Francisco Bay Area. In this Healthy Neighborhoods
Project, the health department catalyzed community development and organization
in a multiethnic public housing complex. As a result, an empowered community
successfully advocated to improve public safety by installing street speed humps
and increased street lighting. After project completion, residents initiated
several additional health actions, including the removal of a neighborhood
tobacco billboard. This article describes the project, which may serve as a model
for other urban public health programs to explore their role in community
empowerment.
PMID- 9548059
TI - Youth violence in the city: the role of educational interventions.
AB - Interpersonal violence is a major cause of ill health in urban communities and a
significant social and political problem. The epidemiology of interpersonal
violence is summarized, highlighting the fact the youth are overrepresented as
victims and perpetrators of violence. General areas of agreement and disagreement
about programmatic approaches to reducing youth violence are summarized,
emphasizing that the most effective programs are comprehensive and integrated and
incorporate multiple strategies at multiple levels in multiple settings. Four
types of educational strategies to reduce youth violence are summarized: conflict
management skills training, youth-operated programs, psychoeducational
strategies, and family-based educational strategies. Exemplars of each are
presented, and their strengths and weaknesses are discussed. Strategies to
implement effective programs are summarized, and the policy and program planning
implications of what is known are discussed.
PMID- 9548058
TI - Breaking the cycle of violence among youth living in metropolitan Atlanta: a case
history of kids alive and loved.
AB - More teenagers in the United States die from gunshot wounds than from all natural
causes of disease combined. Firearm-related mortality accounts for almost half of
all deaths among African American teens. Residents of central cities have the
highest probability of experiencing violent crimes. This article describes an
innovative community-based intervention designed to break the cycle of violence
among youth in metropolitan Atlanta. The intervention, Kids Alive and Loved
(KAL), emerged from the African American community as one mother's response to
the violent death of her 17-year-old son. The authors describe how her response
to tragedy gave birth to a culturally appropriate intervention for youth exposed
to violence. This article delineates the evolution of KAL, the role of community
partners in the design of the intervention, and how diffusion of innovation
theory has implications for understanding the KAL approach to breaking the cycle
of violence.
PMID- 9548060
TI - Preventing Halloween arson in an urban setting: a model for multisectoral
planning and community participation.
AB - Arson is a violent crime and a public health problem that causes injuries and
deaths, destroys homes, and destabilizes neighborhoods. During the late 1970s,
pre-Halloween pranks in Detroit, Michigan, turned destructive when hundreds of
fires were set deliberately throughout the city; in 1984, a record of 810 fires
were set during the Halloween period. In 1985, a city wide anti-arson campaign
that involved the mobilization and training of thousands of community volunteers
was begun in Detroit. This report describes the multiple components of the anti
arson intervention from 1985 through 1996 and changes in the incidence of
Halloween fires. Both the decrease in annual Halloween arson fires after the
intervention began and the inverse relationship between the number of volunteers
and the number of fires suggest a causal effect. This study illustrates the
capacity of an urban community to mobilize its residents and stakeholders, the
importance of community participation and multisectoral partnerships in program
planning and implementation, and the challenges faced in retrospectively
evaluating an apparently successful, complex, community-based intervention.
PMID- 9548061
TI - CINCH: an urban coalition for empowerment and action. Consortium for the
Immunization of Norfolk's Children.
AB - CINCH (Consortium for the Immunization of Norfolk's Children) is an urban
coalition that was developed in 1993 to improve childhood immunization rates in
Norfolk, Virginia. CINCH involves diverse citizens and institutions in effective
community-based assessment, planning, and action. A needs assessment from 1993
found that only 49% of Norfolk 2-year-olds were adequately immunized. Using this
data, CINCH developed a plan focused on education and communication, support for
at-risk families, increased access to immunizations, and improved immunization
delivery. After federal funding ended in 1995, members voted to expand the scope
of the coalition to address additional child health needs and to broaden the
membership. CINCH is a model for a sustainable city-citizen learning environment
that intervenes to "help families help themselves to better health." The
coalition is presented as an organization that focuses on community empowerment
and development. The stages of coalition development and implications for
coalition implementation in other sites are discussed.
PMID- 9548062
TI - Disease prevention and health promotion in urban areas: CDC's perspective.
AB - The mission of the Centers for Disease Control and Prevention (CDC) is to prevent
disease, injury, and premature death and to promote quality of life. This mission
applies to all Americans, especially to the poor and underserved. As so many
people who are impoverished live in America's urban areas, the CDC has a unique
and specific interest in the health problems of our urban population. The CDC has
established five priorities: (1) strengthen essential public health services, (2)
enrich capacity to respond to urgent threats to health, (3) develop a nationwide
prevention network and program, (4) promote women's health, and (5) invest in our
nation's youth. Each of these priorities will contribute to improving the health
of people living in urban areas. The CDC has recently undertaken numerous
initiatives to address health promotion and disease prevention issues in the
urban setting. Future directions for the CDC lie in better understanding the role
of socioeconomic and cultural factors in promoting health and how resources
within urban areas can be used to promote health. The CDC needs to explore
potential relationships with various types of partners. Solving urban health
problems requires actions from many federal agencies as well as from state and
local organizations.
PMID- 9548063
TI - Symptoms of acute myocardial infarction: expectations of a community sample.
AB - OBJECTIVE: To identify the lay public's expectations of the symptoms of acute
myocardial infarction (AMI). DESIGN: Street-intercept survey method. SETTING:
Four neighborhoods in a large metropolitan area. SAMPLE: One hundred ninety-seven
women and 217 men. INSTRUMENT: The Representation of Heart Attack Symptoms
questionnaire (RHAS), a 48-item instrument that identifies subjects' expectations
concerning the associated symptoms of AMI and the location, quality, and
intensity of the discomfort of AMI. RESULTS: The symptoms most individuals
expected during AMI included: chest pain, irregular heart beats, inability to
move, and shortness of breath. The locations selected as most likely included:
middle, left, and right side of the chest, upper and lower back. The most common
descriptors of the expected discomfort were "tight," "pressure," and "heaviness."
More than 88% of subjects expected the intensity of a heart attack to be at least
a 9 on a scale of 0 (No discomfort) to 10 (The most discomfort imagined).
CONCLUSIONS: The lay public have both accurate and inaccurate expectations about
the symptoms of AMI.
PMID- 9548064
TI - Taiwanese patients' concerns and coping strategies: transition to cardiac
surgery.
AB - OBJECTIVE: To explore patients' concerns during the admission transition to
cardiac surgery. DESIGN: A descriptive qualitative design. SETTING: Four
hospitals in northern Taiwan, Republic of China. PATIENTS: A purposive sample
consisting of 40 adult patients (20 men and 20 women) who planned to have cardiac
surgery. Age range was 20 to 70 years (mean 50.1 years). OUTCOME MEASURES: The
types, levels, components, coping strategies, context, and conceptual framework
of patients' concerns. INTERVENTION: Data were collected through semistructured
interviews, and then analyzed using qualitative content analysis. RESULTS: Ninety
percent of subjects (N = 36) reported two types of concerns: certain (80%) and
uncertain (10%). Their certain concerns reflected three levels of concerns:
"Caring about" or "Thinking about" (52%); "Worrying about" or "Being afraid of"
(43%); and "Experiencing a mortal fear of" (30%), ordered from the weakest to the
strongest. The components of patients' concerns were the process of recovery;
hospital experiences, including maintaining daily activities, pain at admission,
and expectant discomforts and disabilities in the intensive care unit; death;
unfinished responsibilities and life goals, significant persons, and places;
financial needs; and poor quality of care. Strategies developed to manage their
concerns included (1) The use of person-focused effort (both cognitive and
psychomotor), (2) Seeking help from others, including family members, friends,
other patients, and health professionals, and (3) Turning to metaphysical power.
The context for the phenomenon of Taiwanese subjects' concerns concerning cardiac
surgery during the admission transition were "Being a person," resuming
normality, and empowerment of self. CONCLUSION: The types, levels, components,
and coping strategies of patients' concerns during the admission transition to
cardiac surgery were discovered and delineated. The background context and
conceptual framework for the phenomenon also were developed from the data
analysis to describe and depict this phenomenon.
PMID- 9548065
TI - Continuous positive airway pressure: patients' and caregivers' learning needs and
barriers to use.
AB - OBJECTIVE: To identify learning needs and factors related to postdischarge use of
continuous positive airway pressure (CPAP) ventilation. DESIGN: Exploratory
descriptive correlational. SETTING: Metropolitan and rural clinics. SUBJECTS:
Adult patients (N = 21) and family caregivers, one half 60 years or older.
INSTRUMENTS: Family interviews, life satisfaction and quality, family function
and relationship, depression and learning preparedness. RESULTS: There were
numerous learning needs related to CPAP machine management, monitoring illness
severity, and recognizing depressive symptomology, oxygen deficits, and
cardiovascular sequelae. Family members are involved in overcoming barriers
interfering with nightly CPAP use. Interview and questionnaire data clearly
indicate life satisfaction improves after CPAP treatment. CONCLUSION:
Predischarge and teaching programs coordinated by expert nurses are needed to
address families' learning needs and support habitual long-term CPAP use. Family
problem solving and depression interventions, instruction on recognizing symptoms
of cardiovascular complications, and long-term follow-up programs are currently
being studied.
PMID- 9548066
TI - Effects of specialized community nursing care in patients with chronic
obstructive pulmonary disease.
AB - OBJECTIVE: To investigate the effects of specialized respiratory home nursing
care after discharge from a pulmonary rehabilitation center. DESIGN: Pretest
posttest control group design. Patients in the experimental group were visited by
a nurse who specializes in respiratory care, whereas the control group received
care from nurses who did not specialize in respiratory care. SETTING: Data were
collected on admission, at program discharge, and 4 months and 9 months after
discharge from a pulmonary rehabilitation center. PATIENTS: One hundred fifteen
patients were included in the study and observed for 1 year. OUTCOME MEASURES:
Health-related quality of life (HRQL), coping strategies, compliance,
hospitalization, and satisfaction with the care provided. RESULTS: Complete data
sets were obtained from 78 patients with severe airflow obstruction (FEV1 = 41%;
predicted +/- SD = 15). Corrections were made for the selective nonresponse, but
did not lead to adjustments in outcome scores. In both groups, HRQL scores
improved between admission and discharge, but deteriorated 4 months and 9 months
after discharge. The only statistically significant short-term effect was found
on the "activities" component of HRQL in favor of the control group. No
differences were found between groups regarding coping, compliance, and
hospitalization. Patients in the experimental group, however, were more satisfied
with the care provided by the specialized community nurses. CONCLUSIONS: The
treatment intervention of specialized respiratory home nursing might not have
been specific or intensive enough to result in outcome benefits. Secondly, the
initial benefits from baseline pulmonary rehabilitation alone may have led to
positive outcomes in both patient groups.
PMID- 9548067
TI - Bilioptysis: a sign of pulmonary capillary permeability injury.
PMID- 9548068
TI - Pain and distress among elderly intensive care unit patients: comparison of
patients' experiences and nurses' assessments.
AB - OBJECTIVE: To investigate elderly intensive care unit (ICU) patients' experiences
of pain and distress, as well as interventions aimed at reducing these
conditions, and to compare these experiences with the way nurses and assistant
nurses, respectively, assess their patients' responses related to these issues.
DESIGN: Descriptive, correlational, comparative. SETTING: Two medical-surgical
ICUs at county hospitals in two medium-sized cities in Sweden. SUBJECTS: Fifty
one elderly patients, 44 nurses, and 37 assistant nurses in two Swedish ICUs.
METHODS: Data were collected through personal interviews with patients and
questionnaires completed by each nurse and assistant nurse responsible for the
patients. RESULTS: Patients' experiences of pain and distress do not fully agree
with nurses' and assistant nurses' assessments; nor is there consistency between
the views of nurses and those of assistant nurses. Nurses overestimated patients'
breathing and intellectual problems. Assistant nurses assessed that patients
received more assistance to relieve physical pain, physical discomfort, fatigue,
and fear than patients reported. Compared with nurses' assessments, assistant
nurses also perceived patients to suffer less from physical discomfort, breathing
problems, and fatigue. CONCLUSIONS: Nurses need more systematic procedures to
assess patients' distress and pain experiences. To reduce the discrepancies
observed between nurses and assistant nurses, organization of care should
optimize the possibilities for the caregivers to carry out the desired
assessments and interventions with a high degree of continuity and communication
among staff.
PMID- 9548069
TI - Decision making of nurses practicing in intensive care in Canada, Finland,
Northern Ireland, Switzerland, and the United States.
AB - In this study, our intention was to describe the decision making of nurses
practicing in intensive care, and the differences of nurses' decision making in
Canada, Finland, Northern Ireland, Switzerland, and the United States. The
instrument used in the study was a 56-item Likert-type questionnaire that has
been used in previous studies and has proved to be a reliable tool. The target
group comprised a nonrandom sample of nurses (N = 314) from five countries. The
samples are not representative; therefore, the results in these cases cannot be
generalized. The results showed that the decision making of nurses practicing in
intensive care was broadly based, and that there were some country differences in
data collection, problem definition, and planning. In contrast, decision making
related to the implementation and evaluation of nursing is quite similar in the
different countries. Canada and the United States on the one hand, and Finland,
Northern Ireland, and Switzerland on the other, showed more similarities with
each other in data collection, problem definition, and nursing planning related
to decision making. Neither experience nor nurse's knowledge structure was
associated with different decision-making approaches.
PMID- 9548070
TI - Tuberculous bronchoesophageal fistulae in patients infected with the human
immunodeficiency virus: a case report and review.
PMID- 9548071
TI - Proteus penneri urosepsis in a patient with diabetes mellitus.
AB - Proteus penneri has been isolated from many different clinical sources, including
surgical wound infections, urine, and blood. We describe the first reported case
of P. penneri nosocomial urosepsis in a patient with diabetes. P. penneri was
subsequently isolated from bronchoalveolar lavage fluid and a pulmonary artery
catheter tip.
PMID- 9548072
TI - Bidirectional tachycardia.
PMID- 9548073
TI - Repertoire breadth of human CD4+ T cells specific for HIV gp120 and p66 (primary
antigens) or for PPD and tetanus toxoid (secondary antigens)
AB - Antigen derived peptides bound on MHC class II molecules on presenting cells
stimulate specific CD4 lymphocytes that are in a naive state if antigen is given
for the first time, or in a memory state if antigen has been previously
encountered. In order to compare clonal heterogeneity of the human CD4+ T helper
repertoire in primary vs. recall responses, we have generated T cell lines in
vitro by repeated stimulation of peripheral lymphocytes with primary or with
recall antigens. Clonal heterogeneity was broad in the case of recall response to
tetanus toxoid or PPD, with a high frequency of specific precursors (> 100
cells/10(6) lymphocytes). In contrast, T cell lines responsive to primary
antigens (HIV gp120 or HIV p66) were oligoclonal as defined by TCR V beta gene
usage and by spectratyping, and the precursor frequency was low (< 2 cells/10(6)
lymphocytes). Primary T cell lines generated from blood samples drawn at
different times from the same donor showed that clones with identical TCR CDR3
region coding sequences were expanded, suggesting that in these individuals a
large progeny derived from one single precursor is present, even though a
previous encounter with the antigen was not documented. Assuming an even in vivo
distribution of such cells, the presence of one precursor every 10(6) CD4
lymphocytes (within the CD4 T repertoire that comprises roughly 10(11) CD4 T
cells) indicates that approximately 10(5) identical T cells from the same clonal
precursor account for the primary response against the model antigens we have
studied.
PMID- 9548074
TI - Promiscuous T-cell recognition of a rubella capsid protein epitope restricted by
DRB1*0403 and DRB1*0901 molecules sharing an HLA DR supertype.
AB - Two T cell clones derived from different donors with HLA-DRB1*0403 or DRB1*0901
phenotype recognize a rubella capsid peptide, C(265-273) in the context of
several different HLA-DR molecules in addition to DRB1*0403 and DRB1*0901. All DR
molecules restricting the T-cell clones have in common residues, R or Q at
position beta 70, R at position beta 71, and E at position beta 74 in pocket '4'
of the DR peptide binding groove, suggesting that a DR subregion structure or
supertype, "Q/RRE" underlies the promiscuous T-cell recognition of this peptide.
Single amino acid substituted analogs of peptide C(263-275) at anchor position 4
for natural residue R were tested for their ability to induce clonal T-cell
cytotoxic responses. The results indicated that a positively charged residue, R
or K, was required for T-cell recognition, suggesting a possible mechanism of
electrostatic interactions between the negatively charged residue E at position
beta 74 of these DR molecules and the positively charged residue at anchor
position 4 of the peptide in T-cell recognition.
PMID- 9548075
TI - Genetic and immunologic studies of patients on procainamide.
AB - Forty (40) patients with cardiac arrhythmias receiving procainamide (PA) therapy
and 24 patients who were receiving other drugs for their cardiac disorders were
investigated for class II HLA phenotypes and their DRB1*04 and DQB1*03 subtypes.
Other genetic marker evaluations in the PA patients included: 1) class III MHC
C4A and C4B null alleles of complement; and, 2) acetylation phenotype. Twenty
(20) of the PA patients were also tested for the ability of their stimulated
cells to secrete Interleukin-1 (IL-1 beta) and tumor necrosis factor (TNF alpha).
We also examined the spontaneous production of these cytokines by peripheral
blood leukocytes (PBL) from patients who were receiving chronic PA treatment. The
results revealed no association of acetylation phenotypes with the class II HLA
phenotypes nor class III MHC C4 allotypes in these patients. The results did show
a significant increase in class III C4 complement allotypes in the PA patients
when compared to the controls. The results also showed a significant increase in
autoantibodies and DQw3 phenotypes in the PA patient group when compared to
control populations. Results of spontaneous IL-1 and TNF production suggested
there may be an association of select class II HLA phenotypes in some patients
and this may be relevant to host responsiveness to PA treatment.
PMID- 9548076
TI - HLA-DQ2-negative celiac disease in Finland and Spain.
AB - Genetic susceptibility to celiac disease (CD) is strongly associated with
DQA1*0501 and DQB1*02 (= DQ2). To study whether CD patients without DQ2 share
other MHC class II or TNF alleles, we screened DQ2-negative patients in Finland
and Spain. Twelve of 84 (14%) Finnish patients and 13 of 189 (6%) Spanish
patients were negative for DQ2. We observed that all but two of altogether 25 DQ2
negative patients had the DR4 DQ8 haplotype, or either DQA1*0501 or DQB1*02
alone. Also, all but three were positive for DRB4*01. The only patients without
any of these alleles were both positive for DR 13. There was a clear difference
between Finland and Spain: Ten (83%) of the 12 Finnish DQ2-negative patients but
only five (38%) of the 13 Spanish patients had DRB1*03, DQA1*03, DQB1*0302 (=
DQ8) alleles. Of the Spanish patients, eight (62%) had DQB1*02 without DQA1*0501
and three (23%) had DQA1*0501 without DQB1*02. None of the TNF, TAP, or DPB1
alleles was found to be significantly associated with CD. Our results indicate
that in addition to the DQ2 heterodimer, the other major risk alleles for CD are
DR4 DQ8, and either DQA1*0501 or DQB1*02 alone. Patients without these alleles
appear to be very rare, only two (0.7%) were identified in altogether 253
patients tested.
PMID- 9548078
TI - HLA-DRB1*0405 is the predominant allele in Brazilian patients with Vogt-Koyanagi
Harada disease.
AB - Vogt-Koyanagi-Harada (VKH) disease is a rare disorder affecting pigmented
structures especially the eye and is the main cause of autoimmune non-infectious
uveitis in the Brazilian population. The autoimmune target is believed to be the
melanocyte. A strong association of VKH disease with HLA-DR4 in the Japanese
population is well known. The same association, albeit with lower relative risks
has been found in other populations. A secondary association to HLA-DR1 involving
a sequence linked with susceptibility to Rheumatoid Arthritis has also been
described. VKH disease is more common in non-Caucasian populations. Brazilian
patients of varying ethnic origins have been typed for HLA class II antigens.
Several of the features found in other population samples are present. Over half
of the patients typed HLA-DR4 (20/37) and typing with sequence-specific
oligonucleotides disclosed predominance of the DRB1*0405 allele with a relative
risk of 11.76 over the general population. In addition, HLA-DR1 and DQ4 were also
present, in patients both positive and negative for HLA-DR4. These results
suggest that, as in other autoimmune diseases, multiple overlapping
susceptibility factors encoded by the MHC complex contribute to the overall
susceptibility for the disease, the major factor however, being the presence of
the DRB1*0405 allele.
PMID- 9548077
TI - Major histocompatibility class II genes polymorphism in insulin dependent
diabetes mellitus with or without associated thyroid autoimmunity.
AB - Insulin dependent diabetes mellitus (IDDM) is sometimes associated with
extrapancreatic organ-specific autoimmune diseases, but whether this phenotype
results from a peculiar genetic profile is still unclear. The allelic
distribution of the major histocompatibility complex (MHC) class II genes (HLA
DRB1, DQA1, DQB1 and TAP) was analysed in 143 patients with IDDM alone by
comparison with 82 IDDM patients with autoimmune thyroid disease (IDDM/AITD). The
frequency of the DQB1*0301 IDDM-protective phenotype seemed to be lower in IDDM
than in IDDM/AITD patients (16.8% vs 30.5% respectively, p = 0.02). By contrast,
the frequency of the DRB1*04-DQB1*0302 IDDM-predisposing phenotype was higher in
IDDM than in IDDM/AITD patients (91.3% vs 76.1% of DR4-positive patients
respectively, p = 0.007), but these differences were not significant after
correcting the p values, except in the case of the DRB1*0405-DQB1*0302
combination (21.3% vs 2.4% of DR4-positive patients, Pc = 0.05). Furthermore, all
differences disappeared when patients were matched for age at IDDM-onset. Our
data do not long give support for a particular role of MHC class II genes in
favouring the occurrence of thyroid autoimmunity in IDDM patients, but rather
suggest that some class II alleles or residues might determine the rapidity of
progression to IDDM in genetically susceptible individuals. The involvement of
non-MHC genes and/or environmental factors remains to be determined.
PMID- 9548079
TI - HLA-DP epitope typing using monoclonal antibodies.
AB - We have made a panel of murine anti-DP monoclonal antibodies for serological
typing of HLA-DP polymorphisms; they can be used in microcytotoxicity (for 7
epitopes) and binding assays (for 8 epitopes). The antibodies detect polymorphic
differences in both alpha and beta chains. As immunogens we sometimes used B
lymphoblastoid lines or purified DP molecules but mostly used mouse fibroblast
transfectants expressing DP molecules. The DP beta genes were made from a cloned
DPB1*0201 gene by replacing its major area of polymorphism with matching
stretches of DNA amplified from other alleles; cloned DPA1*01 and DPA1*02 genes
were used for transfection along with the beta chain genes. The monoclonal
antibodies showed reaction patterns that correlated with the presence of
particular amino-acid sequence motifs; thus none of the antibodies is allele
specific. They bind instead to epitopes which are found on a number of different
HLA-DP types. We have constructed frequency tables so that the epitope (motif)
data can be interpreted as the most likely genotype in each case. The basic
assumption to justify this work is that HLA-DP matching or mismatching will
likely influence transplant outcome, particularly in bone marrow transplantation.
The present challenge is to define permissive and nonpermissive combinations of
HLA-DP; it may be that matching for epitopes, rather than for full alleles, will
help to resolve this issue.
PMID- 9548080
TI - Optical tomography for biomedical applications.
PMID- 9548081
TI - Developments in ECG acquisition, preprocessing, parameter measurement, and
recording.
PMID- 9548082
TI - Improving instrumentation for hospital care of neonates in Hungary. A system to
help reduce the rate of perinatal mortality.
PMID- 9548083
TI - PC-based noninvasive measurement of the autonomic nervous system. Detecting the
onset of diabetic autonomic neuropathy.
PMID- 9548084
TI - Nonlinear filtering and fast ray tracing of 3-D Image data. Improving
visualization in medical imaging.
PMID- 9548085
TI - Early detection of Parkinson's disease through automatic movement evaluation.
PMID- 9548087
TI - Applying nonlinear dynamics to ECG signal processing. Two approaches to
describing ECG and HRV signals.
PMID- 9548086
TI - Tracking EEG signal dynamics during mental tasks. A combined linear/nonlinear
approach.
PMID- 9548088
TI - Specific processing of the spontaneous EMG. Detection and classification of
multiplets using self-organizing neural networks.
PMID- 9548089
TI - Advantages of stereological methods in biomedicine. Efficiently obtaining
unbiased estimates of geometrical characteristics for 3-D structures.
PMID- 9548090
TI - Gene Alert--a sequence search results keyword parser.
PMID- 9548091
TI - Science in the Supreme Court: round two.
PMID- 9548092
TI - Symptomatic colonic lipoma: differential diagnosis of large bowel tumors.
AB - Symptomatic colonic lipomas, although unusual, continue to present difficulties
in the preoperative differential diagnosis between malignant and benign colonic
neoplasm. Although new imaging techniques are available, they are frequently
diagnosed at laparotomy, and definitive histology is required. Local excision is
adequate treatment, but segmental excision may be necessary when there is doubt
about the diagnosis, or when a complication occurs.
PMID- 9548093
TI - Hereditary non-polyposis colorectal cancer.
AB - Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant
condition in which affected individuals develop colorectal cancer or extracolonic
cancers, most commonly endometrial, at an early age. Recent advances in molecular
genetics have led to the identification and sequencing of four genes thought to
be responsible for the majority of cases of hereditary non-polyposis colorectal
cancer. A description of the disease along with details of the underlying
genetics and pathological features are presented. Current management and
screening policies in these pedigrees are not clearly established. This article
discusses some of the controversies in the light of predictive testing.
PMID- 9548094
TI - Rectocele is associated with paradoxical anal sphincter reaction.
AB - Rectocele is a frequent finding in constipated patients. However, constipation is
not always relieved by rectocele repair, which may be due to other overlooked
reasons for constipation. The study was designed to investigate patients with
rectocele, in order to elucidate concomitant colorectal disorders and their
association with rectocele. One hundred and twelve female patients suffering from
severe constipation and rectal emptying difficulties were investigated using
defecography, electrophysiology, anorectal manometry and colon transit time.
Fifty-six patients with rectocele demonstrated by defecography were compared with
56 patients without rectocele, but with other abnormal findings at defecography.
The frequency of paradoxical anal sphincter reaction (PSR) was higher in patients
with rectocele (60%) than in patients without rectocele (24%). The present study
supports an association between rectocele and PSR. We suggest that constipated
patients with a rectocele should be investigated thoroughly before rectocele
repair is considered. Further studies on the effect of biofeedback training in
patients with rectocele and PSR are indicated.
PMID- 9548095
TI - Terminal ileal transposition procedure in ileoanal anastomosis following
proctocolectomy.
AB - We introduced a terminal ileal transposition procedure (TITP) in ileal pouch-anal
anastomosis, in which a 50 to 70 cm isolated ileal segment 20 to 40 cm from the
ileocecal valve was interposed between the terminal ileum and the anus. Twelve
patients underwent this procedure in two or three-staged operations. Mean stool
frequency per 24 hours was 4.4 +/- 1.7, and stool consistency was formed and soft
in all patients at the mean of 13 months after TITP. We observed neither surgical
technique-related complications nor metabolic disorders, except for iron
deficiency anemia, during and after the operations. The serum level of vitamin
B12 significantly increased after the operation in eight patients (P < 0.05).
TITP has advantages such as preventing the terminal ileum from metabolic
dysfunction due to pouchitis, avoiding sacrifice of the terminal ileum in the two
staged operation, and obviating the need for reconstruction of ileostomy in the
three-staged operation. It may also promote intestinal absorption and reduce late
metabolic complications.
PMID- 9548096
TI - Relationship between anal canal diameter and pressure evaluated simultaneously by
endosonography and manometry in normal human subjects.
AB - The study investigated the relationship between anal canal size and anal canal
pressure measured simultaneously by anal endosonography and an electronic
pressure probe. Twelve normal subjects were studied. Anal endosonography was
performed using a 7.5-Mhz rotating transducer of 2-5 cm focal length covered with
a sylastic balloon filled with degassed water (25 ml). During anal endosonography
an electronic manometric probe was passed along the side of the probe and
positioned in the anal canal. The ultrasonic image was frozen when maximal anal
pressure was seen at basal, squeeze, and minimal pressure during straining. An
image was also obtained at maximal anal relaxation after rectal distension with a
balloon filled with 150 ml air. The results showed that anal canal pressure was
significantly and linearly correlated with anal canal diameter (P < 0.001).
PMID- 9548097
TI - Delay in the presentation of colorectal carcinoma: a review of causation.
AB - This review paper studies the reasons behind the delay in presentation of
colorectal carcinoma. Such delay can occur at three different levels: delay on
the part of the patient, delay by the general practitioner prior to patient
referral and delay incurred at the hospital after patient referral. There is some
evidence that patient delay has decreased in recent years; general practitioner
delay is disputed by some authors, but there is considerable evidence that it
exists. Hospital delay can be influenced by the general practitioner; there is
evidence that it has increased in recent years and is likely to increase further
with the current pressure on in-patient beds.
PMID- 9548098
TI - Surgery for local pelvic recurrence after resection of rectal cancer.
AB - This retrospective study evaluated outcome with regard to procedure, local
control, and survival after curative surgical resection with and without
preoperative radiotherapy for local pelvic recurrence. A total of 58 consecutive
patients with local pelvic recurrence of rectal cancer after previous curative
resection for primary tumors were reviewed. Of these, 36 underwent both initial
resection and follow-up in our department; the remaining 22 had initial surgery
and follow-up elsewhere. Of the 58 patients 27 underwent curative re-resection, 9
had palliative resection, and 22 were treated by conservative therapy. Among the
27 patients with curative resection 17 received preoperative radiotherapy (40 Gy)
plus surgery and 10 surgery only. No patients were lost to follow-up; median
follow-up time was 36.3 months. The overall rate of curative resection was 46.6%:
55.6% in our own follow-up group and 31.8% in the others. With regard to surgical
procedure, abdominoperineal resection (APR) with or without sacral resection was
standard following previous low anterior resection, and total pelvic exenteration
(TPE) with or without sacral resection was common following APR. There was a high
incidence of morbidity (71.4%) after TPE. Re-recurrence was observed in 12
(44.4%) after curative re-resection. There was local re-recurrence in 6 (22.2%).
The local re-recurrence rate was 11.8% (n = 2) with radiotherapy plus surgery,
and 40.0% (n = 4) with surgery alone. The estimated 5-year survival following
curative re-resection was 45.6% (61.2% with radiotherapy plus surgery, 29.6% with
surgery alone). Both survival and local control with radiotherapy plus surgery
tended to be better than with surgery alone. Thus, in selected patients pelvic
local recurrence of rectal cancer can be re-resected curably by APR or TPE (with
or without sacral resection) combined with preoperative radiotherapy.
PMID- 9548099
TI - Prophylactic pancreaticoduodenectomy for premalignant duodenal polyposis in
familial adenomatous polyposis.
AB - The frequency of duodenal adenomas in patients with, familial adenomatous
polyposis is high. Duodenal adenoma has malignant potential, and duodenal
adenocarcinoma is one of the main causes of death in patients who have had
previous proctocolectomy. A conservative approach to the treatment of duodenal
adenomas (nonsteroidal anti-inflammatory drugs, endoscopy, polypectomy through
duodenotomy) is inefficient and unsafe. When invasive cancer occurs in duodenal
adenomas, the result of surgery is poor. We have performed prophylactic
pancreaticoduodenal resection (PDR) for nonmalignant severe duodenal polyposis in
five patients since 1991. No operative mortality was observed. One patient
developed a pancreatic fistula which was successfully managed by medical
treatment. The mean follow-up was 35 months. All five patients are still alive
and have a good functional outcome. Prophylactic PDR may be indicated in familial
adenomatous polyposis when duodenal polyposis is severe. Stages III and IV of
Spigelman's classification, periampullary adenoma, age above 40, and family
history of duodenal cancer are factors that may lead to the decision to perform
prophylactic PDR.
PMID- 9548100
TI - Laparoscopic colorectal resection for diverticulitis.
AB - This study evaluated outcome in patients undergoing laparoscopically assisted
sigmoid resection for diverticular disease. A total of 29 consecutive patients
were treated surgically for colonic diverticulitis; in 27 of these laparoscopy
was performed. The review of medical records from a control group of 34 patients
undergoing open resection were used for comparison. The conversion rate was 7.5%.
Using the laparoscopic technique the duration of surgery was longer (165 vs. 121
min, P < 0.05), blood loss less (182 vs. 352 ml, P < 0.05), and subsequent blood
transfusion less (0 vs. 61%). The incidence of complications following
laparoscopic resection was lower (two anastomotic leakages, two wound infections)
than in the conventional group. Convalescence in the laparoscopic group was more
rapid and hospital stay shorter (7.9 vs. 14.3 days, P < 0.05). In the
laparoscopic group patients expressed less pain at rest and in motion. The cost
of the laparoscopically assisted procedure was less than that of conventional
resection (7185 vs. 8975 DM). In this series laparoscopically assisted sigmoid
resection for diverticulitis proved safe. Recovery was faster, hospital stay was
shorter, and patients expressed less pain than in conventional open surgery.
PMID- 9548101
TI - Necrotizing perineal infections (Fournier's disease): old remedies for an old
disease.
AB - Perineoscrotal gangrene (Fournier's disease, a specific type of necrotizing
fasciitis) is a rare and potentially fatal clinical entity characterized by
progressive spread of necrosis in the skin and subcutaneous tissues combined with
severe systemic sepsis. We analyzed retrospectively seven patients with
perineoscrotal gangrene, illustrating the various clinical presentations,
problems in management, and specific approaches to therapy. On admission all
patients were evaluated as being in critical condition, having severe systemic
disease and rapidly advancing gangrene. After hemodynamic stability was achieved
broad spectrum antibiotics were started, and aggressive surgical treatment
initiated. In all the patients the infection originated from the anorectal area
and proved to be polymicrobial in nature. Six patients survived and were able to
be discharged from hospital there was one death on the fifth postoperative day
due to pulmonary embolism. The crucial points in the management of this infection
remains early diagnosis, wide and repeated surgical debridements, and appropriate
antibiotic therapy.
PMID- 9548102
TI - Improved determination of terminal pudendal latency by modification of the
standard electrode.
PMID- 9548103
TI - Internal anal sphincter repair.
PMID- 9548104
TI - Pathological features of rectal cancer after preoperative radiochemotherapy.
PMID- 9548105
TI - What price glory?
PMID- 9548106
TI - Prospective evaluation of the Ottawa Ankle Rules in a university sports medicine
center. With a modification to increase specificity for identifying malleolar
fractures.
AB - In a sports medicine center, we prospectively evaluated the Ottawa Ankle Rules
over 1 year for their ability to identify clinically significant ankle and
midfoot fractures and to reduce the need for radiography. We also developed a
modification to improve specificity for malleolar fracture identification.
Patients with acute ankle injuries (< or = 10 days old) had the rules applied and
then had radiographs taken. Sensitivity, specificity, and the potential reduction
in the use of radiography were calculated for the Ottawa Ankle Rules in 132
patients and for the new "Buffalo" rule in 78 of these patients. There were 11
clinically significant fractures (fracture rate, 8.3% per year). In these 132
patients, the Ottawa Ankle Rules would have reduced the need for radiography by
34%, without any fractures being missed (sensitivity 100%, specificity 37%). In
78 patients, the specificity for malleolar fracture for the new rule was
significantly greater than that of the Ottawa Ankle Rules malleolar rule (59%
versus 42%), sensitivity remained 100%, and the potential reduction in the need
for radiography (54%) was significantly greater. The Ottawa Ankle Rules could
significantly reduce the need for radiography in patients with acute ankle and
midfoot injuries in this setting without missing clinically significant
fractures. The Buffalo modification could improve specificity for malleolar
fractures without sacrificing sensitivity and could significantly reduce the need
for radiography.
PMID- 9548107
TI - Achilles tendinosis and calf muscle strength. The effect of short-term
immobilization after surgical treatment.
AB - We prospectively studied calf muscle strength in 7 men and 4 women (mean age,
40.9 +/- 10.1 years) who had surgical treatment for chronic Achilles tendinosis.
Surgery was followed by immobilization in a weightbearing below-the-knee plaster
cast for 2 weeks followed by a stepwise increasing strength training program.
Strength measurements (peak torque and total work) were done preoperatively (Week
0) and at 16, 26, and 52 weeks postoperatively. We measured isokinetic concentric
plantar flexion strength at 90 and 225 deg/sec and eccentric flexion strength at
90 deg/sec on both the injured and noninjured sides. Preoperatively, concentric
and eccentric strength were significantly lower on the injured side at 90 and 225
deg/sec. Postoperatively, concentric peak torque on the injured side decreased
significantly between Weeks 0 and 16 and increased significantly between Weeks 26
and 52 at 90 deg/sec but was significantly lower than that on the noninjured side
at all periods and at both velocities. The eccentric strength was significantly
lower on the injured side at Week 26 but increased significantly until at Week 52
no significant differences between the sides could be demonstrated. It seems,
therefore, that the recovery in concentric and eccentric calf muscle strength
after surgery for Achilles tendinosis is slow. We saw no obvious advantages in
recovery of muscle strength with a short immobilization time (2 weeks) versus a
longer (6 weeks) period used in a previous study.
PMID- 9548108
TI - Effects of nonsteroidal antiinflammatory medication on satellite cell
proliferation during muscle regeneration.
AB - Previous experimental studies have indicated delayed muscle regeneration after
nonsteroidal antiinflammatory drug therapy. Successful regeneration of muscle
after injury requires activation of normally dormant satellite cells that share
the basal laminae with adjacent muscle cells. In the presence of adequate
capillary ingrowth, satellite cells proliferate into myotubes and eventually form
new muscle cells. In this study, the onset and extent of satellite cell and
fibroblast proliferation as well as the production of myotubes and capillaries
were analyzed with immunohistochemical methods after contusion injuries to rats'
gastrocnemius muscles. Two groups of animals received daily doses of an
intramuscular nonsteroidal antiinflammatory drug (naproxen) starting 6 hours and
3 days after injury, respectively. Treated animals were compared with similarly
injured untreated animals. Satellite cell and fibroblast proliferation were
unaffected by the treatment, and there were no significant differences in myotube
or capillary production between treated and control animals. We conclude that
naproxen treatment does not compromise the basic process of myofiber regeneration
after injury.
PMID- 9548109
TI - Occurrence of cervical spine injuries during the rugby scrum.
AB - A retrospective study of cervical spine injuries that occurred during the rugby
scrum in the United States was undertaken. In the U.S., from 1970 to 1996, 36
(58%) of the 62 documented injured players injured their cervical spines during
the scrum. Thirty-five men (97%) and one woman (3%) were injured. Twenty-three of
the injuries (64%) occurred when the opposing packs came together (engagement),
and 13 (36%) occurred when the scrum collapsed. Twenty-eight (78%) hookers, seven
(19%) props, and one (3%) second-row player were injured. Twenty (56%) hookers
and three (8%) props were hurt during engagement. Eight hookers (22%), four props
(11%), and one second-row player (3%) were injured when the scrum collapsed.
Significantly more injuries occurred during engagement than during collapse, and
hookers were injured significantly more than props. We conclude that in the rugby
scrum in the U.S., the hooker suffers most of the cervical spine injuries (78% in
this study) and this position is by far the most vulnerable. This study should be
used to develop rugby law (rule) changes and educate players, coaches, and
referees in United States rugby.
PMID- 9548110
TI - Five-year results of single-incision arthroscopic anterior cruciate ligament
reconstruction with patellar tendon autograft.
AB - We performed a retrospective study on 80 patients who underwent single-incision
arthroscopic anterior cruciate ligament reconstruction with patellar tendon
autograft and interference fit screw fixation in 1989. Twelve patients were lost
to followup, allowing a clinical assessment of 68 patients to be conducted by
independent examiners at 1 and 5 years after surgery, with radiographic
assessment at 5 years. Thirty-three patients had chronic anterior cruciate
ligament-deficient knees. Three patients reruptured their grafts during sports at
29, 48, and 56 months. At 5 years, 64 patients (98%) had grade 0 or 1 Lachman and
pivot shift tests with manual stability testing. Fifty patients (77%) were
participating in level I or II activities according to the International Knee
Documentation Committee scale. Twenty-nine patients (45%) experienced low levels
of pain when performing at their highest activity level. Five (8%) had thigh
atrophy greater than 1 cm, and three (5%) had an extension loss of more than 3
degrees. Eleven patients (17%) had tenderness over the graft site when kneeling.
Fifteen of 62 patients (24%) had degenerative changes on radiographs, and this
was more common in patients with chronic anterior cruciate ligament-deficient
knees. Fifty-two patients (80%) had normal or nearly normal knees according to
the overall International Knee Documentation Committee score.
PMID- 9548111
TI - Arthroscopic distal clavicle resection for isolated atraumatic osteolysis in
weight lifters.
AB - Ten consecutive patients with isolated atraumatic osteolysis of the distal
clavicle who had failed results with conservative treatment were treated with
arthroscopic resection of the involved distal clavicle (average, 4.5 mm). All
patients were men with an average age of 30.4 years, had unilateral involvement,
and were considered aggressive amateur to elite weight lifters or bodybuilders.
Postoperative symptoms consisted of pain at the incision and discomfort from
extravasation of the irrigation fluid. At an average followup of 18.7 months, all
patients had returned to their sport (average, 3.2 days) and to their
preoperative weight training program (average, 9.1 days). They continued to be
asymptomatic throughout the follow-up period and were able to increase both their
training volume and strength from preoperative levels. Limited arthroscopic
resection of the distal clavicle for isolated atraumatic osteolysis is a viable
alternative for the weight lifter or bodybuilder. The ability to continue
training without significant interruption as well as a more acceptable cosmetic
appearance are benefits for these patients. Limited arthroscopic resection of the
distal clavicle may be sufficient for this entity in this patient population,
rather than the 1 to 2 cm previously reported. A sport-specific functional
outcome questionnaire has been developed for this patient population.
PMID- 9548112
TI - Winner of the AlbertTrillat Young Investigator Award. The effects of aggressive
notchplasty on the normal knee in dogs.
AB - We assessed the possible association between an aggressive intercondylar
notchplasty and histopathologic, radiographic, and gait changes to the knee.
Three groups of six adult greyhounds were observed for 6 months. Group I dogs had
a sham operation. Group II dogs had a 4-mm notchplasty of the lateral femoral
condyle where it articulates with the lateral tibial spine. Group III dogs had a
7- to 8-mm notchplasty of the lateral femoral condyle to simulate the long-term
effects of an overly aggressive notchplasty. Force plate gait analyses were not
significantly different for any dogs at 3 and 6 months. Histopathologic studies
(hematoxylin and eosin and safranin O stains) revealed notchplasty area
remodeling with a thin layer of lamellar bone covered by fibrous connective
tissue. Both Group II and III dogs had significant loss of lateral femoral
condyle and trochlear groove articular surface proteoglycans. The radiographic
notch width index remained unchanged throughout the study for Group I; the
indexes increased immediately after surgery in Groups II and III because of the
notchplasty, but after 6 months these values returned to near-preoperative
measurements. An aggressive intercondylar notchplasty caused articular cartilage
histopathologic changes at 6 months consistent with those found in knees with
early degenerative arthritis. Significant refilling of a non-impinged notchplasty
occurred by 6 months after surgery. Our results raise concern about the effects
of aggressive intercondylar notch widening in humans.
PMID- 9548113
TI - The effects of removal and reconstruction of the anterior cruciate ligament on
patellofemoral kinematics.
AB - Patellofemoral pain may be associated with anterior cruciate ligament deficiency
or may occur after anterior cruciate ligament reconstruction. We investigated the
effects of the removal and reconstruction of the anterior cruciate ligament on
the kinematics of the tibiofemoral and patellofemoral joints during physiologic
levels of quadriceps muscle loads in seven cadaveric knees. A bone-patellar
tendon-bone graft was used for intraarticular reconstruction of the anterior
cruciate ligament. The spatial positions of the tibiofemoral and patellofemoral
joints were measured between 0 degrees and 90 degrees of knee flexion in 15
degrees increments with a six degree-of-freedom digitizing system. Excision of
the anterior cruciate ligament resulted in statistically significant increases in
anterior tibial translation between 0 degrees and 90 degrees and valgus tibial
rotation between 30 degrees and 90 degrees; intraarticular reconstruction
returned these to levels not significantly different from those of the intact
knee. Excision of the anterior cruciate ligament resulted in significant
increases in lateral patellar tilt, ranging from 6.3 degrees to 9.0 degrees
between full extension and 90 degrees of knee flexion, and in lateral patellar
shift, ranging from 2.9 mm at 15 degrees of knee flexion to 5.9 mm at 90 degrees;
intraarticular reconstruction returned these to levels not significantly
different from those of the intact knee. Neither removal nor reconstruction of
the anterior cruciate ligament significantly affected tibial internal-external
rotation, patellar flexion, patellar mediolateral rotation, patellar
anteroposterior translation, or patellar proximodistal translation.
PMID- 9548114
TI - Electromyographic activity and applied load during shoulder rehabilitation
exercises using elastic resistance.
AB - Muscle activity (measured by electromyography) and applied load were measured
during seven shoulder rehabilitation exercises done with an elastic resistance
device. Nineteen men with no shoulder abnormalities performed seven exercises:
external and internal rotation, forward punch, shoulder shrug, and seated rowing
with a narrow, middle, and wide grip. Qualitative video (60 Hz) was synchronized
with the electromyography data from eight muscles (2000 Hz). Fine-wire
intramuscular electrodes were inserted into the supraspinatus and subscapularis
muscles, and surface electrodes were placed over the anterior deltoid,
infraspinatus, pectoralis major, latissimus dorsi, serratus anterior, and
trapezius muscles. Ten trials per subject were analyzed for average and peak
amplitude, and the results were expressed as a percentage of maximum voluntary
contractions. The peak loads for all exercises ranged from 21 to 54 N. The muscle
activity patterns suggest that these shoulder rehabilitation exercises
incorporating elastic resistance, controlled movements, and low initial loading
effectively target the rotator cuff and supporting musculature and are
appropriate for postinjury and postoperative patients.
PMID- 9548115
TI - Early phase differential effects of slow and fast barbell squat training.
AB - To examine the importance of resistance training movement speed, two groups of
women (24 +/- 4 years, 162 +/- 5 cm, 59 +/- 7 kg) squatted repeatedly at 1) 2
seconds up, 2 seconds down (slow, N = 11); or 2) 1 second up, 1 second down
(fast, N = 10), doing three warm-up sets and three eight-repetition maximum sets,
three times per week for 7 weeks. Tests included force platform and video
analysis of the vertical jump, long jump, and maximum squat, and isometric and
isokinetic knee extensor testing at speeds from 25 to 125 deg/sec. The groups
improved similarly in many variables with training but also showed some
differences. In the long jump, the fast group was superior in numerous variables
including knee peak velocity and total-body vertical and absolute power. In the
vertical jump, fast training affected the ankle and hip more (e.g., average
power), and slow training mostly affected the knee (average torque). In
isokinetic testing, the fast group improved strength most at the faster
velocities, while the slow group strength changes were consistent across the
velocities tested. Although both slow and fast training improved performance,
faster training showed some advantages in quantity and magnitude of training
effects.
PMID- 9548116
TI - A new concept for isokinetic hamstring: quadriceps muscle strength ratio.
AB - Conventionally, the hamstring:quadriceps strength ratio is calculated by dividing
the maximal knee flexor (hamstring) moment by the maximal knee extensor
(quadriceps) moment measured at identical angular velocity and contraction mode.
The agonist-antagonist strength relationship for knee extension and flexion may,
however, be better described by the more functional ratios of eccentric hamstring
to concentric quadriceps moments (extension), and concentric hamstring to
eccentric quadriceps moments (flexion). We compared functional and conventional
isokinetic hamstring: quadriceps strength ratios and examined their relation to
knee joint angle and joint angular velocity. Peak and angle-specific (50 degrees,
40 degrees, and 30 degrees of knee flexion) moments were determined during
maximal concentric and eccentric muscle contractions (10 degrees to 90 degrees of
motion; 30 and 240 deg/sec). Across movement speeds and contraction modes the
functional ratios for different moments varied between 0.3 and 1.0 (peak and 50
degrees), 0.4 and 1.1 (40 degrees), and 0.4 and 1.4 (30 degrees). In contrast,
conventional hamstring:quadriceps ratios were 0.5 to 0.6 based on peak and 50
degrees moments, 0.6 to 0.7 based on 40 degrees moment, and 0.6 to 0.8 based on
30 degrees moment. The functional hamstring:quadriceps ratio for fast knee
extension yielded a 1:1 relationship, which increased with extended knee joint
position, indicating a significant capacity of the hamstring muscles to provide
dynamic knee joint stability in these conditions. The evaluation of knee joint
function by use of isokinetic dynamometry should comprise data on functional and
conventional hamstring:quadriceps ratios as well as data on absolute muscle
strength.
PMID- 9548117
TI - Concussion incidence in elite college soccer players.
AB - A unique aspect of soccer is the use of the head for directing the ball. The
potential for resultant head injuries has been the focus of discussions
worldwide. Prior work has attributed neuropsychologic deficits to the cumulative
effects of heading, without evaluating concussion rates in soccer players. We
prospectively studied the seven men's and eight women's varsity soccer teams in
the Atlantic Coast Conference during two seasons to document concussion
incidence. The 29 concussions diagnosed over the 2 years in 26 athletes, 17 (59%)
concussions in men and 12 (41%) in women, resulted from contact with an
opponent's head (8, 28%), elbow (4, 14%), knee (1, 3%), or foot (1, 3%); the ball
(7, 24%); the ground (3, 10%); concrete sidelines (1, 3%); goalpost (1, 3%); or a
combination of objects (3, 10%). Twenty concussions (69%) occurred in games; none
resulted from intentional heading of the ball. The basic incidence was 0.96
concussions per team per season. The overall incidence was 0.6 per 1000 athlete
exposures for men, and 0.4 per 1000 athlete-exposures for women. By concussion
grade, there were 21 (72%) grade 1, 8 (28%) grade 2, and no grade 3 concussions.
These findings suggest that concussions are more common in soccer than
anticipated and that acute head injuries may have potential for long-term
neuropsychologic changes.
PMID- 9548118
TI - Throwing fracture of the humeral shaft. An analysis of 90 patients.
AB - Ninety patients with humeral shaft fractures sustained during throwing were
analyzed to determine what caused their injuries. All patients were recreational
baseball players: 89 were men and 1 was a woman. The average age was 25 years
(range, 12 to 43). The throwing style, type of pitch, fielding position, and type
of ball used varied; however, the patients sustained their fractures while
performing a hard throw in 87 (97%) of the occurrences. The actual courses of the
balls thrown ranged from sideways to straight forward. All fractures were
external rotation spiral fractures; 25 patients (28%) had a medial butterfly
fragment, and 14 patients (16%) had radial nerve palsy. Fractures were most
likely to have occurred in the distal half of the humerus, although they occurred
frequently in the proximal half in patients in their early teens. We conclude
that 1) the fracture can occur at any time during the acceleration phase before
ball release, 2) this type of fracture can occur in any recreational baseball
player attempting to perform a hard throw, and 3) the cause of this fracture is
the throwing action itself.
PMID- 9548119
TI - Humeral torsion in the throwing arm of handball players.
AB - Sport-specific upper extremity strain, mostly unilateral, during growth may lead
to adaptations in soft tissue and bone. We investigated 51 male professional
handball players between 18 and 39 years of age (average, 27 years), 39 right
handed and 12 left-handed. Thirty-eight players had no shoulder problems, and 13
had chronic shoulder pain. Humeral retrotorsion was determined by radiograph. The
differences between the throwing and contralateral arms were compared with those
of 37 controls who had no history of unilateral strain either through sports or
profession. Standard statistical analysis was performed using the t-test. The
retrotorsional angle of the humerus in the handball professionals' throwing arm
was an average of 9.4 degrees larger in the dominant side than in the
nondominant, with a side-to-side difference up to 29 degrees. In the control
group, no statistically significant difference was found. In the group without
chronic shoulder pain, the side-to-side difference was an average of 14.4 degrees
more in the throwing arm than the other side. Players with chronic shoulder pain
did not exhibit this increase, even showing an average decrease of humeral
retrotorsion of 5.2 degrees in the throwing arm. The humeral retrotorsion
increase can be explained as an adaptation to extensive external rotation in
throwing practice during growth. Athletes who do not adapt this way seem to have
more strain on their anterior capsules at less external rotation and develop
chronic shoulder pain because of anterior instability.
PMID- 9548120
TI - Clinical, functional, and radiographic assessments of the conventional and
modified Boyd-Anderson surgical procedures for repair of distal biceps tendon
ruptures.
AB - The purpose of this study was to evaluate the clinical, functional, and
radiographic outcomes of the conventional and modified Boyd-Anderson procedures
for repair of distal biceps tendon ruptures. Thirteen of 18 men who underwent
surgical repair for unilateral distal biceps tendon ruptures at one university
center participated in the study. In general, follow-up outcomes were favorable
with respect to return to premorbid activity levels, patient satisfaction with
surgical outcome, and overall clinical results. Elbow flexion, forearm
supination, and upper extremity functional concentric peak torque and range of
motion results were not significantly different between the surgical and
nonsurgical arms when dominance was controlled as a confounding factor.
Radiographic findings revealed no clinically remarkable signs of heterotopic
ossification or proximal radioulnar synostosis. Results of the study reveal that
the conventional and modified Boyd-Anderson procedures are clinically,
functionally, and radiographically efficacious for repair of distal biceps tendon
ruptures.
PMID- 9548121
TI - The effects of muscle fatigue on shoulder joint position sense.
AB - Proprioception, or joint position sense, probably plays an important role in
shoulder joint function. In this study, we assessed the effect of muscle fatigue
on shoulder proprioception in 20 volunteers with no shoulder abnormalities.
Shoulder proprioception was measured as the threshold to first detection of
humeral rotation with the joint at 90 degrees of abduction and 90 degrees of
external rotation. Subjects were tested while rested, exercised on a isokinetic
testing machine until fatigued, and then retested in an identical fashion. Both
shoulders were tested, and the order of dominant and nondominant shoulder was
randomized. Shoulder proprioception was analyzed for its dependence on arm
dominance, direction of rotation, and muscle fatigue. Subjects detected external
rotation after significantly less movement than they did internal rotation.
Overall, before exercise, motion was detected after a mean of 0.92 degrees of
rotation. After exercise, this threshold to detection of movement increased to
1.59 degrees, an increase of 73%. This significant increase occurred with both
internal and external rotation. The decrease in proprioceptive sense with muscle
fatigue may play a role in decreasing athletic performance and in fatigue-related
shoulder dysfunction. It remains to be determined if training can lessen this
loss in position sense.
PMID- 9548122
TI - The clinical diagnosis of subcutaneous tear of the Achilles tendon. A prospective
study in 174 patients.
AB - A study to determine the sensitivity, specificity, and positive and negative
predictive values of several clinical diagnostic tests of subcutaneous Achilles
tendon rupture was performed during a 13-year period. There were 174 patients
with clinical diagnosis of unilateral complete subcutaneous Achilles tendon tear
and 28 patients with unilateral suspected but no actual Achilles tendon tear. The
following tests were used: palpation, calf squeeze, Matles, Copeland, and
O'Brien. Palpation of the gap was the least sensitive clinical test with the
patient awake (0.73), increasing to 0.81 when the test was performed under
anesthesia; the Copeland and O'Brien tests showed a sensitivity of 0.8. Both the
calf squeeze and Matles tests were significantly more sensitive than the other
tests (0.96 and 0.88, respectively; 0.022 < P < 0.05). All tests showed a high
positive predictive value, with no statistically significant difference between
the various tests. In the 28 patients with no evidence of a subcutaneous Achilles
tendon tear on imaging, the tests showed a high capability to detect that the
Achilles tendon was intact (gap palpation specificity, 0.89; calf squeeze test
specificity, 0.93; Matles test specificity, 0.85). Whichever tests were
performed, at least two of them were positive for a subcutaneous tear of the
Achilles tendon in all patients in this study.
PMID- 9548123
TI - The snowboarder's foot and ankle.
AB - We undertook a prospective study to determine the type and distribution of foot
and ankle snowboarding injuries. Reports of 3213 snowboarding injuries were
collected from 12 Colorado ski resorts between 1988 and 1995. Of these, 491
(15.3%) were ankle injuries and 58 (1.8%) were foot injuries. Ankle injuries
included 216 (44%) fractures and 255 (52%) sprains. Thirty-three (57%) of the
foot injuries were fractures and 16 (28%) were sprains. The remaining injuries
were soft tissue injuries, contusions, or abrasions. There was no significant
correlation between boot type (soft, hybrid, or hard) and overall foot or ankle
injury rate. There were significantly fewer ankle sprains in patients wearing
hybrid boots and fewer fractures of the lateral process of the talus in patients
wearing soft boots. An unexpectedly high number of fractures of the lateral
process of the talus were noted. These 74 fractures represented 2.3% of all
snowboarding injuries, 15% of all ankle injuries, and 34% of the ankle fractures.
Many of these fractures are not visible on plain radiographs and require computed
tomography imaging to be diagnosed. Diagnosis of this fracture pattern is
paramount; the physician should be very suspicious of anterolateral ankle pain in
the snowboarder, where subtle fractures that may require surgical intervention
can be confused with anterior talofibular ligament sprains.
PMID- 9548124
TI - Meniscal repair in the goat model. The use of healing adjuncts on central tears
and the role of magnetic resonance arthrography in repair evaluation.
AB - We evaluated the effect of adjunctive healing measures on central tears of the
adult goat medial meniscus and the role of magnetic resonance arthrography in the
assessment of menisci that have undergone a repair. Peripheral tears were made
unilaterally in the medial menisci of seven goats in Group I and repaired with
nonabsorbable suture. Six Group II goats had central medial meniscal tears
repaired as in Group I plus an exogenous fibrin clot. Eight Group III goats had
central tears plus abrasion of the parameniscal synovium and tear edges. Six
months after surgery, a magnetic resonance imaging scan and a magnetic resonance
arthrogram were obtained and the menisci were examined grossly. Group I goats
showed healing in all seven knees. Central tears repaired with a fibrin clot
(Group II) showed healing in one of six knees (17%). Central tears repaired with
abrasion (Group III) showed healing in seven of eight knees (87.5%). Magnetic
resonance arthrography was 100% accurate in detecting the presence or absence of
complete residual tears. This study supports the current trend of using
adjunctive measures for repair of central tears. Furthermore, abrasion of the
parameniscal synovium and the tear edges appears to be more effective than the
use of an exogenous fibrin clot. Magnetic resonance arthrography is useful in the
evaluation of menisci that have undergone repair.
PMID- 9548125
TI - Three-dimensional knee joint kinetics during a golf swing. Influences of skill
level and footwear.
AB - This study characterized knee joint kinetics during a golf swing and determined
the influence of shoe type and golfer skill on the peak knee joint loads.
Thirteen golfers each hit a golf ball using a five iron under two footware
conditions: spiked and spikeless golf shoes. Data from a video-based motion
capture system and force plates were used to compute the knee joint kinetics.
Mean peak forces and moments differed significantly between the lead and trail
knees, but these peak loads were not significantly affected by shoe type. Only
the lead knee flexion and internal rotation moments were significantly correlated
to skill level. The magnitude of some of the peak loads at the knee during the
golf swing approached those reached during activities prohibited until late-stage
knee rehabilitation. We concluded the following: The type of shoe worn and the
skill level of the golfer need not be considered in deciding time to return to
golfing; however, the leg that is recovering from surgery or injury should be
considered. The most stressful phase of the golf swing, relative to the knee, is
the downswing. There is probably no "normal" swing; each golfer seems to possess
consistent, characteristic, patterns of knee loading.
PMID- 9548126
TI - Strength deficits related to distal biceps tendon rupture and repair. A case
report.
PMID- 9548127
TI - Radial artery thrombosis in a young athlete. A case report.
PMID- 9548128
TI - Fracture of the proximal tibia after Fulkerson anteromedial tibial tubercle
transfer. A report of four cases.
PMID- 9548129
TI - Pitcher's periostitis. A case report.
PMID- 9548131
TI - The role of the scapula in athletic shoulder function.
AB - The exact role and the function of the scapula are misunderstood in many clinical
situations. This lack of awareness often translates into incomplete evaluation
and diagnosis of shoulder problems. In addition, scapular rehabilitation is often
ignored. Recent research, however, has demonstrated a pivotal role for the
scapula in shoulder function, shoulder injury, and shoulder rehabilitation. This
knowledge will help the physician to provide more comprehensive care for the
athlete. This "Current Concepts" review will address the anatomy of the scapula,
the roles that the scapula plays in overhead throwing and serving activities, the
normal biomechanics of the scapula, abnormal biomechanics and physiology of the
scapula, how the scapula may function in injuries that occur around the shoulder,
and treatment and rehabilitation of scapular problems.
PMID- 9548130
TI - Articular cartilage repair.
AB - Articular cartilage can tolerate a tremendous amount of intensive and repetitive
physical stress. However, it manifests a striking inability to heal even the most
minor injury. Both the remarkable functional characteristics and the healing
limitations reflect the intricacies of its structure and biology. Cartilage is
composed of chondrocytes embedded within an extracellular matrix of collagens,
proteoglycans, and noncollagenous proteins. Together, these substances maintain
the proper amount of water within the matrix, which confers its unique mechanical
properties. The structure and composition of articular cartilage varies three
dimensionally, according to its distance from the surface and in relation to the
distance from the cells. The stringent structural and biological requirements
imply that any tissue capable of successful repair or replacement of damaged
articular cartilage should be similarly constituted. The response of cartilage to
injury differs from that of other tissues because of its avascularity, the
immobility of chondrocytes, and the limited ability of mature chondrocytes to
proliferate and alter their synthetic patterns. Therapeutic efforts have focused
on bringing in new cells capable of chondrogenesis, and facilitating access to
the vascular system. This review presents the basic science background and
clinical experience with many of these methods and information on synthetic
implants and biological adhesives. Although there are many exciting avenues of
study that warrant enthusiasm, many questions remain. These issues need to be
addressed by careful basic science investigations and both short- and long-term
clinical trials using controlled, prospective, randomized study design.
PMID- 9548133
TI - Distal femoral shaft fracture: a complication of endoscopic anterior cruciate
ligament reconstruction--a case report.
PMID- 9548132
TI - A statistics primer. Correlation and regression analysis.
PMID- 9548134
TI - Low-field magnetic resonance imaging of the canine stifle joint: normal anatomy.
AB - Low-field magnetic resonance imaging (MRI) was performed on the stifle joints of
four normal adult mongrel dogs using a 0.064 Tesla scanner. Markers were placed
on each stifle joint to serve as reference points for comparing gross sections
with the images. A T1-weighted sequence was used to image one stifle joint on
each dog in the sagittal plane and the other stifle joint in the dorsal plane.
The dogs were euthanized immediately following MRI and the stifle joints frozen
intact. Each stifle joint was then embedded in paraffin, again frozen, and
sectioned using the markers as reference points. On T1-weighted images, synovial
fluid had low signal intensity (dark) compared to the infrapatellar fat pad which
had a high signal intensity (bright). Articular cartilage was visualized as an
intermediate bright signal and was separated from trabecular bone by a dark line
representing subchondral bone. Menisci, fibrous joint capsule, and ligamentous
structures appeared dark. In the true sagittal plane, the entire caudal cruciate
ligament was often seen within one image slice. The patella was visualized as an
intermediate bright signal (trabecular bone) surrounded by a low intensity signal
(cortical bone). The trochlea and the intercondylar notch were difficult areas to
analyze due to signal volume averaging of the curved surface of these areas and
the presence of several types of tissues.
PMID- 9548137
TI - Quantitative methods for indirect CT lymphography.
AB - In this investigation, we applied quantitative CT methods to characterize
contrast enhanced lymph nodes opacified using iodinated contrast media for
indirect CT lymphography. Iodinated nanoparticles were injected into the buccal
submucosa and SQ into the metatarsus and metacarpus of four normal swine (1.0-4.0
ml/site, 76 mg I/ml). Attenuation (HU), volume (cm3), iodine concentration (mg
I/cm3), total iodine uptake (mg I), contrast-to-noise ratio (CNR), and percent
injected dose (%ID) were estimated in opacified inguinal, cervical and
parotid/mandibular lymph nodes using manual image segmentation techniques on 24
hour post-contrast CT images. Lymph node volumes estimated by multiple slice ROI
analysis were compared with estimates obtained by post-excisional weight
measurements. HU and iodine concentration increased 5-20 fold in opacified nodes
(p < 0.01) and CNR increased more than four-fold (p < 0.001). %ID ranged between
3.5 and 11.9% and did not appear dose related. ROI estimated lymph node volumes
approximated volumes calculated from weight measurements. (R2 = 0.94, p <
0.0001). We conclude that interstitially injected iodinated nanoparticles
increase attenuation and conspicuity of targeted nodes on CT images. Quantitative
methods could play an important clinical role in more accurate metastasis
detection.
PMID- 9548135
TI - Development of interactive patient-based multimedia computer programs in
veterinary orthopedic radiology.
AB - Three computerized multimedia programs on large and small animal veterinary
orthopedic radiology were developed and implemented for the radiology curriculum
as an alternative to traditional film-based laboratory learning. Programs
utilized "hot words" (colored text words that displayed an overlaid image label
that highlighted lesions) and interactive quizzes which responded appropriately
to selected answers. "Hot words" helped students develop confidence in accurate
lesion detection and the interactive quizzes transformed learning from a passive
to an active process. Multiple examples were provided for reinforcement and
concepts were incorporated from other clinical disciplines for curriculum
integration. Programs were written using a presentation software program,
Toolbook for DOS based platform, and contained radiographic images made by laser
scanning digitization. Multiple students could simultaneously access the programs
through a network server. These pilot programs were implemented successfully and
computerized multimedia presentation proved to be well suited to teaching
radiology. Development of the programs required attention to a number of
hardware, software, time and cost factors.
PMID- 9548136
TI - A prospective clinical trial comparing metrizamide and iohexol for equine
myelography.
AB - A prospective clinical trial comparing adverse postmyelographic effects and
myelographic quality of metrizamide and iohexol was conducted. Using a
predetermined, randomized assignment, 24 horses exhibiting neurologic signs were
administered either metrizamide (180 mgl/ml) or iohexol (180 mgl/ml) via
cerebellomedullary puncture. Each horse was evaluated postmyelographically for
adverse effects. Myelographic quality was assessed by a numerical scoring method.
Adverse effects were observed more frequently with metrizamide (21) compared with
iohexol (6) myelography (p < 0.05). Seizures, intensification of preexisting
neurologic signs and prolonged anesthetic recovery were the most common
complications after myelography. There was no difference in myelographic quality
(p > 0.05). We conclude that iohexol is safer than metrizamide for equine
myelography and that quality myelograms can be obtained with either contrast
medium.
PMID- 9548138
TI - Use of computed tomography to evaluate the intestinal tract of adult llamas.
AB - In the llama, signs of colic are obscure and may be exhibited as persistent
sternal recumbency and anorexia even in the presence of a surgical lesion.
Diagnostic methods for evaluation of abdominal disorders are limited. As a
result, surgical intervention may be prolonged and increase the risk of mortality
and postoperative complications. The objective of this study was to determine the
feasibility of computed tomography to evaluate the llama intestinal tract.
Eighteen hours prior to the computed tomography scan, six llamas were given
barium sulfate (15%) via an orogastric tube. Following induction of general
anesthesia, the llamas were positioned in sternal recumbency, and 10 mm
contiguous slices were obtained from the diaphragm to the tuber ischiadicum.
Structures that were consistently identified included the first, second, and
third compartments (C1, 2, and 3), small intestine, spiral colon, and ascending
colon. C1 was easily identified in the cranial aspect of the abdomen due to its
large size relative to the other compartments and characteristic saccules. C2 was
located cranial, ventral, and to the right of C1, while C3 was visualized as a
tubular structure to the right and ventral to C1 and C2, C3 was traced caudally
until it turned dorsally and continued cranially to a dilated ampulla in the
right cranial abdomen delineating the entrance to the small intestine. The spiral
colon was identified consistently in the left ventral caudal abdomen. Structures
that could not be conclusively identified included the cecum and mesenteric lymph
nodes. Computed tomography allowed a consistent evaluation of the major
intestinal structures associated with colic in the llama. Thus, computed
tomography is a potentially valuable noninvasive diagnostic tool to effectively
evaluate the abdominal cavity and differentiate medical from surgical lesions in
the llama.
PMID- 9548139
TI - Radiographic diagnosis: liver lobe entrapment and associated emphysematous
hepatitis.
PMID- 9548140
TI - Radiographic appearance of the navicular bone and distal interphalangeal joint
and their relationship with ossification of the collateral cartilages of the
distal phalanx in Finnhorse cadaver forefeet.
AB - Radiographic findings in the navicular bone and distal interphalangeal joint as
well as the ossification status of the collateral cartilages of the distal
phalanx were evaluated in 100 Finnhorse cadaver forefeet. The most common shapes
of the proximal articular margin of the navicular bone were convex and straight.
Remodeling of the navicular bone was common, especially on the lateral extremity.
No bony fragments were identified at the distal flexor margin even though this
area appeared irregular in several feet. Several large, rounded or lollipop
shaped synovial invaginations were identified in only six feet. The thickness of
the flexor cortex varied considerably, and the corticomedullary junction was uni-
or bilaterally indistinct in nine feet. The shape of the sagittal ridge of the
flexor cortex was commonly flat but varied. It appeared locally irregular or
indistinct in 17 feet, but changes elsewhere along the flexor cortex were rare.
Osteophytosis on the dorsal and palmar margins of the distal interphalangeal
joint and entheseophytosis on the dorsal aspect of the middle phalanx and on the
extensor process of the distal phalanx were common. "Possibly significant"
ossification of the collateral cartilages (high sidebones or separate centers of
ossification) was present in 36 feet; all grades of ossification in the
proximal/palmaroproximal direction as well as palmar ossification were seen. A
statistically significant relationship was found between entheseophytosis on the
proximal flexor margin of the navicular bone and "possibly significant"
ossification. Osteophytosis on the palmarodistal margin of the middle phalanx was
more common in feet with a relatively long distal phalanx, suggestive of palmar
ossification. Radiographic changes in the navicular bone or in the distal
interphalangeal joint did not otherwise appear to be associated with ossification
of the collateral cartilages of the distal phalanx in Finnhorses.
PMID- 9548141
TI - Computed tomographic evaluation of dinosaur egg shell integrity.
AB - The purpose of this study was to determine whether computed tomography (CT) could
be used to identify hatching holes in partially embedded dinosaur eggs. One
Faveololithus and two Dendroolithus eggs were examined using a fourth generation
CT scanner. The eggs were partially embedded in a fossilized sediment matrix,
with the exposed portion of the shell appearing intact. In CT images of all three
eggs, the shells appeared hyperdense relative to the matrix. Hatching holes were
visible as large gaps in the embedded portion of the shell, with inwardly
displaced shell fragments. It was concluded that CT is an effective technique for
nondestructively assessing dinosaur egg shell integrity.
PMID- 9548142
TI - Ultrasonography of the femoral artery in six normal horses and three horses with
thrombosis.
AB - Ultrasonography of the femoral artery in the horse, including color, power and
spectral Doppler, provides morphologic and dynamic information. This paper
describes the use of the techniques in six clinically normal horses and three
with femoral artery thrombosis. Useful landmarks for orientation are the
saphenous artery and the medial saphenous vein. The lateral circumflex femoral
artery can not be visualized. Recognition of the genus descendens artery is
complicated due to the presence of multiple distal caudal femoral arteries. The
femoral artery feeds a high resistance bed. In normal horses the peak systolic
velocity varies between 50-90 cm/sec. Echoic tissue in the femoral artery lumen
with stenosis, occlusion and collateral blood flow formation are features
encountered in the patients.
PMID- 9548144
TI - Ultrasound corner: "pseudo-catheter-sleeve" sign in the jugular vein of a horse.
PMID- 9548143
TI - Ultrasound-assisted diagnosis of renal dysplasia in a 3-month-old Quarter Horse
colt.
AB - A 3-month-old foal was presented for correction of bilateral angular limb
deformities. Azotemia was detected as an incidental finding. Small, misshapened,
hyperechoic kidneys with decreased corticomedullary demarcation were noted with
ultrasonography. Additionally, the internal renal architecture was abnormal in
that the intrarenal vessels and distant collecting system were not clearly seen
in either kidney. Ultrasound-guided renal biopsy was suggestive of congenital
renal dysplasia, which was later confirmed at necropsy. Clinical, sonographic,
and pathologic features of equine renal dysplasia are discussed.
PMID- 9548145
TI - Ultrasonographic diagnosis--radiolucent pulmonary foreign body.
PMID- 9548146
TI - MRI case presented as part of the 1997 A.C.V.R. oral certification examination:
computed tomography/magnetic resonance imaging elective.
PMID- 9548147
TI - CT case presented as part of the 1997 A.C.V.R. oral certification examination:
computed tomography/magnetic resonance imaging elective.
PMID- 9548148
TI - Profiling assisted reproductive technology: outcomes and quality of infertility
management.
AB - OBJECTIVE: To critically appraise the content of the American Society for
Reproductive Medicine (ASRM)/Society for Reproductive Technology (SART) Registry.
DESIGN: English-language literature review. PATIENT(S): Women undergoing
treatment with assisted reproductive technology (ART). INTERVENTION(S): Current
ART treatments, including IVF, GIFT, zygote intrafollopian transfer (ZIFT),
oocyte micromanipulation, and cryopreserved embryo transfers. MAIN OUTCOME
MEASURE(S): Compliance with clinical practice guidelines, and casemix-adjusted
rates of live delivery, clinical pregnancy, ectopic pregnancy, miscarriage, birth
defects, implantation, fertilization, and retrieval. RESULT(S): Outcomes should
be adjusted for variation in patient characteristics known to affect prognosis,
including maternal age, the duration of infertility, the presumed cause(s) of
infertility, the patient's prior history of treatment for infertility, and
diethylstilbestrol exposure. Outcome rates should be reported using the patient
as the denominator, as well as cycle, retrieval, and transfer. The statistical
significance of observed differences in events rates should be indicated. Because
widely accepted clinical practice guidelines related to performance of ART
procedures are not available, compliance with practice guidelines cannot
currently be assessed. CONCLUSION(S): Reports based on ASRM/SART Registry data
can be enhanced by refined casemix adjustment, assessing outcome rates per
patient, as well as per component of ART procedure, and by providing an
indication of the statistical significance of observed differences in event
rates. In addition, a critical appraisal of available evidence related to
particular aspects of infertility management would help clarify the areas in
which there is an evidentiary basis for formulation of practice guidelines, as
well as topics requiring additional clinical research.
PMID- 9548149
TI - Profiling assisted reproductive technology: the Society for Assisted Reproductive
Technology registry and the rising costs of assisted reproductive technology.
PMID- 9548150
TI - Impairment of the developmental potential of frozen-thawed human zygotes obtained
after intracytoplasmic sperm injection.
AB - OBJECTIVE: To evaluate the effects of cryopreservation on the survival, cleavage,
and morphology of embryos and on the implantation and embryonic loss rates of
human zygotes obtained after ICSI compared with frozen-thawed zygotes obtained
after traditional IVF. A further objective was to evaluate the same parameters in
nonfrozen sibling ICSI and IVF zygotes and to compare them with corresponding
frozen-thawed zygotes. DESIGN: Open, retrospective, comparative study. SETTING:
University-associated assisted reproductive program. PATIENT(S): Couples with
severe male factor infertility and couples undergoing IVF during the same period.
INTERVENTION(S): A cohort of 408 ICSI zygotes and 299 IVF zygotes was frozen in
1,2 propanediol and sucrose using a slow-freezing protocol. Both groups of
zygotes were frozen at approximately the same time after microassisted or
conventional insemination. One hundred and eighty-seven ICSI and 110 IVF frozen
zygotes were rapidly thawed during 44 ICSI cycles and 24 IVF cycles. Zygotes that
appeared to have survived were cultured for 24 hours, and most of these embryos
that were morphologically normal were transferred into patients. MAIN OUTCOME
MEASURE(S): Survival rate (morphologically intact after thawing), cleavage rate
and morphology of embryos, implantation rate, and the incidence of embryonic
losses. RESULT(S): Except for survival rates, for which both ICSI and IVF frozen
thawed zygotes showed similar and relatively high values (87.7% and 89.1%), the
outcomes of other parameters evaluated were significantly different. Thus, from a
total of 128 ICSI and 68 IVF embryos transferred, 14 (10.9%) and 17 (25.0%)
implanted in 44 ICSI and 24 IVF frozen-thawed cycles, respectively. This
difference in implantation corresponded with the rate of cleavage and morphology
of the replaced embryos; the embryos that developed from frozen-thawed IVF
zygotes cleaved faster and were more regular compared to the frozen-thawed ICSI
zygotes. The embryonic loss rate was 57.1% for cryopreserved ICSI zygotes and
11.8% for IVF zygotes. On the other hand, no difference in cleavage pattern,
embryo morphology, implantation, and embryonic loss rates was found between
nonfrozen sibling ICSI and IVF zygotes. CONCLUSION(S): The zygotes arising from
ICSI cycles survived cryopreservation at a rate similar to IVF zygotes, but their
ability to implant and develop further was probably affected by the
cryopreservation procedure. The timing of zygote freezing was considered to be
the principal reason for the lower developmental potential of frozen-thawed ICSI
zygotes in the present study.
PMID- 9548151
TI - Evidence for a stimulatory role of follicle-stimulating hormone on the
spermatogonial population in adult males.
AB - OBJECTIVE: To evaluate the effects of treatment with FSH on seminal indices and
on the seminiferous epithelium of oligozoospermic subjects with normal FSH plasma
levels. DESIGN: Placebo-controlled, double-blind randomized study. SETTING:
Academic setting. PATIENT(S): Ninety subjects with idiopathic oligozoospermia
(sperm count of < 10 x 10(6)/mL) and normal plasma levels of FSH.
INTERVENTION(S): Three months of treatment with FSH (60 patients) or placebo (30
patients); bilateral testicular fine-needle aspiration. MAIN OUTCOME MEASURE(S):
Seminal indices; testicular cytologic features; plasma levels of FSH, LH, and
testosterone; and ultrasonographic testicular examination. RESULT(S): According
to seminal indices, patients treated with FSH and placebo were classified as
nonresponders or as responders (as determined by at least a doubling of sperm
count). No placebo-treated patients responded to treatment. Among FSH-treated
patients, 20 responded to hormonal treatment and 40 did not. The results of
pretreatment cytologic examination of testicular specimens from patients who did
not respond to FSH treatment were consistent with hypospermatogenesis associated
with maturational disturbances at the spermatid level. In contrast, patients who
responded to treatment with FSH had isolated hypospermatogenesis without
maturational disturbances. After FSH therapy, we detected an increase of
spermatogonia and spermatocyte population in both the responder and nonresponder
subjects. This increase was associated with an activation of spermatogenic and
spermiogenic processes and with a rise in ejaculated sperm concentration only
when isolated hypospermatogenesis was present (responder patients).
CONCLUSION(S): The findings of this study demonstrate that FSH treatment
increases the spermatogonial population in men. This treatment may be appropriate
for oligozoospermic subjects who have normal FSH plasma levels and a testicular
evaluation characterized by hypospermatogenesis without maturational
disturbances.
PMID- 9548152
TI - Coculture of human sperm with bovine oviduct epithelial cells decreases sperm
chromatin structural changes seen during culture in media alone.
AB - OBJECTIVE: To compare sperm chromatin structural changes seen in media only
culture or in coculture with bovine oviduct epithelial cells. DESIGN: Three
freshly ejaculated and three cryopreserved sperm samples in media culture or in
oviduct epithelial cell coculture. Sperm in each treatment were evaluated by the
sperm chromatin structure assay during a 72-hour time course. SETTING: An
academic research laboratory. PATIENT(S): Normospermic donors with children.
INTERVENTION(S): Semen collection through masturbation after 48 hours of
abstinence. MAIN OUTCOME MEASURE(S): The sperm chromatin structure assay using
flow cytometry to detect the susceptibility of sperm in either treatment to
denaturation of DNA in situ. RESULT(S): The sperm chromatin structure assay data
differed for sperm type (fresh or cryopreserved), over time, and between
treatments within 6 hours of culture. In oviduct epithelial cell coculture, fresh
sperm chromatin structure assay values for fresh sperm were stable, whereas in
control medium higher chromatin degeneration levels were seen by 10 hours. For
cryopreserved sperm, chromatin degeneration had increased by 1 hour postthaw in
both treatments, although levels were higher in the control treatment thereafter.
CONCLUSION(S): Sperm chromatin structural changes occur over time in culture.
Such changes were observed within 2 hours for cryopreserved sperm. Coculture of
sperm with oviduct epithelial cells results in a stabilizing effect for sperm
against chromatin changes.
PMID- 9548153
TI - Maximizing pregnancy rates and limiting higher-order multiple conceptions by
determining the optimal number of embryos to transfer based on quality.
AB - OBJECTIVE: To define statistical thresholds for the number of embryos to be
transferred to achieve an optimal pregnancy rate and keep higher-order multiple
conceptions (pregnancy with more than two fetal sacs with cardiac activity)
within an acceptable limit. DESIGN: A retrospective review of patient records.
SETTING: Private practice assisted reproductive technology (ART) facility.
PATIENT(S): Seven hundred fifty-four consecutive patients who underwent IVF-ET
from 1994-1996. INTERVENTION(S): Embryo grading and score system used on day 3 of
embryo transfer. MAIN OUTCOME MEASURE(S): Implantation, pregnancy, and multiple
conception rates. RESULT(S): For women < or =35 years old, transfer of up to four
poor-quality, two fair-quality, or two good-quality embryos is optimal to
eliminate any risk of higher-order multiple pregnancies. Transfer of four poor
quality, three fair-quality, or two good-quality embryos is recommended for women
36 to 39 years old. In women who are > or =40 years old, five embryos need to be
transferred regardless of embryo quality. CONCLUSION(S): The mean cumulative
embryo score can be used as a reference to determine an optimal number of embryos
to transfer and to predict pregnancy outcome.
PMID- 9548154
TI - The performance of subcutaneously injected Fertinex when used as the sole
gonadotropin for in vitro fertilization stimulation.
AB - OBJECTIVE: To assess the performance of Fertinex (urofollitropin; Serono
Laboratories, Norwell, MA) in stimulating the development of multiple follicles
and initiating subsequent pregnancy in patients undergoing controlled ovarian
hyperstimulation (COH) for IVF. DESIGN: Prospective observational study. SETTING:
Private assisted reproductive technology (ART) center. PATIENT(S): Ninety-three
women who underwent an IVF cycle of COH in which Fertinex was used as the sole
gonadotropin. INTERVENTION(S): The COH protocol included Fertinex with leuprolide
acetate down-regulation in the late luteal phase or the early follicular phase.
Embryo transfer was performed after 3 days of culture. MAIN OUTCOME MEASURE(S):
Stimulation parameters, embryologic data, and pregnancy rates (PRs). RESULT(S):
Ninety-three patients underwent 97 cycles of COH, with a cancellation rate of
13.4%. The clinical PR was 42% per initiation, 49% per retrieval, and 51% per
transfer. Shorter stimulation periods, lower estradiol levels either per follicle
punctured or per oocyte retrieved, and slower embryo development were observed.
Patients responded to Fertinex in three distinct stimulation patterns: escalating
response with a peak estradiol level of < or =3,000 pg/mL, escalating response
with a peak estradiol level of >3,000 pg/mL, or escalating response characterized
by a drop in the estradiol level or a plateau before hCG administration. All
three responses had similar PRs. CONCLUSION(S): Fertinex can be used successfully
as the sole gonadotropin for COH in ART without compromising high PRs.
Traditional estradiol response curves or cancellation criteria may not apply when
Fertinex is used as the sole gonadotropin for COH in ART.
PMID- 9548155
TI - Recruitment of follicles by recombinant human follicle-stimulating hormone
commencing in the luteal phase of the ovarian cycle.
AB - OBJECTIVE: To investigate, in patients who previously had a suboptimal ovarian
stimulation cycle, the benefit of starting ovarian stimulation before the onset
of menses. DESIGN: Prospective, randomized, controlled study. SETTING: A tertiary
referral center for infertility treatment. PATIENT(S): Forty patients undergoing
IVF or GIFT from whom only 3-6 oocytes were retrieved in their last cycle.
INTERVENTION(S): Recombinant human FSH was administered before the onset of the
menstrual period (experimental group) or in the early follicular phase after the
onset of menses (control group). MAIN OUTCOME MEASURE(S): The number of oocytes
retrieved. RESULT(S): Patients in the experimental group were ready for oocyte
retrieval on menstrual cycle day 11 instead of cycle day 14. The number of
oocytes retrieved was not significantly different between the two groups.
CONCLUSION(S): Poor responders do not benefit from commencing recombinant human
FSH therapy in the luteal phase.
PMID- 9548156
TI - Gestational carrier pregnancy.
AB - OBJECTIVE: To evaluate the results of a gestational carrier program in terms of
pregnancy rates in fresh and cryopreserved cycles. DESIGN: Retrospective
analysis. SETTING: Private IVF program. PATIENT(S): Women with uterine or medical
reasons for unsuccessful gestation. INTERVENTION(S): In vitro fertilization of
oocytes with fresh or cryopreserved ET to gestational carriers. MAIN OUTCOME
MEASURE(S): Pregnancy rates and deliveries. RESULT(S): A PR of 56.3% and a cycle
rate of 30.8% was achieved in each patient <40 years of age in 117 cycles of
fresh or cryopreserved ET. There were no pregnancies for nine patients >40 years
of age in 27 cycles. CONCLUSION(S): Carrier gestation offers a satisfactory
solution to childlessness caused by uterine or major medical factors.
PMID- 9548157
TI - First pregnancies after preconception diagnosis of translocations of maternal
origin.
AB - OBJECTIVE: To develop an approach to preimplantation diagnosis of translocations
that would not require the use of specific DNA probes for each translocation
type. DESIGN: Retrospective analysis. SETTING: Clinic. PATIENT(S): Two patients
with 45XX,der(13;14)(q10;q10) karyotypes and one patient with a
46XX,t(4;14)(p15;q24) karyotype. INTERVENTION(S): Based on the observation that
first polar body chromosomes remain at the metaphase stage for a few hours after
oocyte retrieval, fluorescence in situ hybridization with chromosome-painting
probes was used to perform preconception genetic diagnosis of translocation of
maternal origin. MAIN OUTCOME MEASURE(S): Oocyte FISH analysis. RESULT(S): A
total of 31 mature oocytes were produced, and results were obtained in 23 first
polar bodies. After IVF-ET, all three patients became pregnant, preconception
diagnoses being confirmed by prenatal diagnosis or birth. CONCLUSION(S):
Preconception diagnosis of translocations may reduce significantly the risk of
chromosomally unbalanced offspring and pregnancy loss. This method is simpler
than previous approaches because the need to develop specific DNA probes for each
translocation type is avoided.
PMID- 9548159
TI - Metformin therapy improves the menstrual pattern with minimal endocrine and
metabolic effects in women with polycystic ovary syndrome.
AB - OBJECTIVE: To determine the clinical, hormonal, and biochemical effects of 4-6
months of metformin therapy in obese patients with polycystic ovary syndrome
(PCOS). DESIGN: Prospective study. SETTING: The Gynecological Endocrine Unit of
University Central Hospital, Oulu, Finland. PATIENT(S): Twenty obese patients
with PCOS. INTERVENTION(S): Patients were treated with 0.5 g of metformin three
times daily for 4-6 months. MAIN OUTCOME MEASURE(S): Clinical symptoms, menstrual
pattern, and hirsutism, as well as serum concentrations of sex steroids, sex
hormone-binding globulin (SHBG), gonadotropins, and lipids were assessed during
the treatment. RESULT(S): Eleven women (68.8% of the women with menstrual
disturbances) experienced more regular cycles during therapy. No changes in
hirsutism, body mass index, or blood pressure occurred. The mean testosterone
level was decreased significantly after 2 months of treatment but returned to the
starting level by 4-6 months. Free testosterone levels decreased significantly
during the treatment. There was no significant change in the levels of other sex
steroids or lipids measured at 4-6 months of treatment. CONCLUSION(S): Metformin
therapy is well tolerated by the majority of patients and may be clinically
useful, especially in obese patients with PCOS and menstrual disturbances.
PMID- 9548158
TI - Serum androgen levels in women who have recurrent miscarriages and their
correlation with markers of endometrial function.
AB - OBJECTIVE: To compare plasma androgen concentrations in women who have recurrent
miscarriages and in fertile women, and to correlate the results with
concentrations of the endometrial protein PP14 in uterine flushings and plasma
from women who have recurrent miscarriages. DESIGN: Retrospective study. SETTING:
Hospital research unit. PATIENT(S): Women attending a recurrent miscarriage
clinic and normal fertile volunteers. Ten of the women with recurrent
miscarriages had polycystic ovary disease (PCOD) as assessed by ultrasonography
or increased follicular LH levels. INTERVENTION(S): Plasma samples were obtained
from the women on days LH-7, LH-4, LH+0, and LH+7 or LH+10 of a cycle. An
endometrial flushing sample and a biopsy specimen were taken from women with
recurrent miscarriages on day LH+7 or LH+10. MAIN OUTCOME MEASURE(S):
Androstenedione, testosterone, and sex hormone-binding globulin (SHBG) were
measured in the plasma samples. The endometrial protein PP14 was measured in the
uterine flushings and in the LH+7 or LH+10 plasma samples from the women with
recurrent miscarriages. RESULT(S): Testosterone concentrations were higher in the
women with recurrent miscarriages both with and without PCOD on days LH-7 and LH
4 of the cycle. Concentrations of androstenedione also were higher in the women
with recurrent miscarriages, but without PCOD on day LH-7. Testosterone SHBG
ratios were higher in the women with recurrent miscarriages, without PCOD
compared with the controls on days LH-7, LH+0, and LH+7. Mean follicular
testosterone concentrations were correlated negatively with both uterine (r =
0.47) and plasma (r = -0.49) PP14 levels on day LH+10. Mean luteal phase
testosterone SHBG ratios were correlated negatively with uterine PP14
concentrations on day LH+7 of the cycle (r = -0.674). CONCLUSION(S): Androgen
levels are higher in women who have recurrent miscarriages than in normal fertile
controls. These high levels of androgens may have a detrimental effect on
endometrial function.
PMID- 9548160
TI - Late endocrine effects of ovarian electrocautery in women with polycystic ovary
syndrome.
AB - OBJECTIVE: To examine the duration of the changes in endocrine indices produced
by ovarian electrocautery in women with polycystic ovary syndrome (PCOS). DESIGN:
Long-term observational study. SETTING: University hospital. PATIENT(S):
Infertile women with PCOS. INTERVENTION(S): Ovarian electrocautery was performed
through the laparoscope. Blood was sampled before the operation and at defined
intervals thereafter. After the establishment of regular cycles, sampling was
performed 1 week before the menstrual period. MAIN OUTCOME MEASURE(S): The
patients were observed before and at defined intervals for up to 20 years after
ovarian electrocautery. Serum concentrations of hypophyseal and ovarian hormones
were determined, including sex hormone-binding globulin (SHBG). RESULT(S): There
was a clear shift from anovulation to ovulatory cycles and a significant decrease
in androgens and gonadotropins. The concentration of SHBG increased. These
effects lasted for many years; after 18-20 years, two thirds of the women were
still ovulating. CONCLUSION(S): Ovarian electrocautery for PCOS normalizes
ovarian function, including androgen production, and the results seem to be
stable for 18-20 years.
PMID- 9548161
TI - Effects of triptorelin versus placebo on the symptoms of endometriosis.
AB - OBJECTIVE: To compare the effect of a GnRH-agonist, triptorelin, versus placebo
on the symptoms of endometriosis. DESIGN: A prospective, randomized, double-blind
study of 6 months of treatment followed by 12 months of follow-up. SETTING:
Departments of Obstetrics and Gynecology at two universities and one general
hospital. PATIENT(S): Forty-nine women with symptoms of laparoscopically verified
endometriosis. INTERVENTION(S): Triptorelin depot or placebo was given every 4
weeks. Clinical evaluation, including the Duration Intensity Behavior Scale and
Visual Analogue Scale for pain, was performed before the injections and up to 12
months after treatment. A control laparoscopy was performed 4-6 weeks after the
last injection. MAIN OUTCOME MEASURE(S): Quantitation of pain. RESULT(S): Twenty
four patients had active treatment and 25 received placebo. Pain symptoms
according to both scales were significantly more reduced after 2 months of
triptorelin treatment compared to placebo. The extent of endometriotic lesions
was reduced 50% during triptorelin treatment and increased 17% during placebo.
The average area of endometriotic lesions was reduced 45% during triptorelin
treatment but was unchanged during placebo. Side effects, mainly hot flushes,
were experienced by 80% of the actively treated group but also by 33% of patients
in the placebo group. Because of recurrent symptoms, only five patients could be
observed for 12 months after completion of treatment. CONCLUSION(S): Triptorelin
reduces endometriotic lesions and pain to a significantly higher degree than
placebo.
PMID- 9548162
TI - Treatment of severe postmenopausal endometriosis with an aromatase inhibitor.
AB - OBJECTIVE: To treat an unusually aggressive case of recurrent postmenopausal
endometriosis. DESIGN: Case report. SETTING: University of Texas Southwestern
Medical Center (Dallas, Texas). PATIENT(S): A 57-year-old woman who presented
with recurrent severe endometriosis after hysterectomy and bilateral salpingo
oophorectomy. INTERVENTION(S): Oral administration of anastrozole (an aromatase
inhibitor) (1 mg/d) and elemental calcium (1.5 g/d) for 9 months. Alendronate (a
nonestrogenic inhibitor of bone resorption), 10 mg/d, was added to this regimen.
MAIN OUTCOME MEASURE(S): Reduction in size of endometriotic lesion, pain relief,
tissue levels of aromatase P450 messenger RNA, bone density. RESULT(S):
Circulating levels of estradiol-17beta were reduced to approximately 50% of the
baseline value after the onset of treatment with anastrozole. Pain rapidly
decreased and completely disappeared after the 2nd month of treatment. The 30 x
30 x 20-mm bright red polypoid vaginal lesion was reduced to a 3-mm gray tissue
by the end of 9 months of treatment. Markedly high pretreatment levels of
aromatase P450 messenger RNA in the endometriotic tissue became undetectable in a
specimen obtained from a repeated biopsy after 6 months of treatment. Bone
density of lumbar spine decreased by 6.2% after 9 months of treatment.
CONCLUSION(S): This is the first description of the use of an aromatase inhibitor
in the treatment of endometriosis. The short-term results were extraordinarily
successful in elimination of pain and near-complete eradication of implants
associated with severe endometriosis not responsive to other therapy. We conclude
that the recently developed potent aromatase inhibitors are candidate drugs in
the treatment of endometriosis that is resistant to standard regimens.
PMID- 9548163
TI - Ovarian function during the use of a single contraceptive implant: Implanon
compared with Norplant.
AB - OBJECTIVE: To study the mechanism of action of Implanon, a single-rod
contraceptive implant containing etonogestrel, in healthy women during 3 years.
DESIGN: Prospective, randomized comparison with Norplant. The study was conducted
for 2 years in Sweden but was extended to 3 years in Finland. SETTING: Two
outpatient clinics. PATIENT(S): Thirty-two healthy women who were between 18 and
40 years of age with normal ovulatory cycles. Seven women receiving Implanon and
three receiving Norplant participated in the third year. INTERVENTION(S): On or
between days 1 and 5 of a spontaneous menstrual cycle, the subjects received
either the etonogestrel-containing implant (Implanon) or the levonorgestrel
containing implant (Norplant). MAIN OUTCOME MEASURE(S): Ultrasonography was
performed and/or progesterone concentrations were determined to confirm ovulation
in a control cycle. Follicular development, endometrial thickness, and serum
concentrations of 17beta-estradiol and progesterone were assessed twice per week
during 4-week periods at regular intervals and after implant removal for 6 weeks
to monitor return of ovulation. Times required to remove the respective implants
were evaluated, as were possible complications. RESULT(S): Seven women who
received Implanon and three who received Norplant completed 3 years of study.
There were no pregnancies. Ovulation was observed for the first time with
Norplant after 18 months. The first ovulation with Implanon was observed after 30
months. Mean endometrial thickness was <4 mm during treatment with Implanon from
month 12 onward. The mean (+/-SD) time to remove Implanon was 5.9 +/- 3.4
minutes. The mean (+/-SD) time to remove Norplant was 17.9 +/- 9.9 minutes.
Ovulation resumed promptly after the use of either implant. CONCLUSION(S):
Results from this study provide convincing evidence of 3-year contraceptive
efficacy with Implanon, mainly by ovulation inhibition.
PMID- 9548164
TI - Preparation by differential gradient centrifugation is better than swim-up in
selecting sperm with normal morphology (strict criteria).
AB - OBJECTIVE: To evaluate two commonly used methods of sperm preparation with
respect to their effects on sperm morphology (strict criteria). DESIGN: Auto
controlled, split sample study performed on the semen of 74 male partners of
couples enrolled for IVF. SETTING: In vitro fertilization and andrology
laboratories at a tertiary care, major teaching hospital. PATIENT(S): Seventy
four male partners of couples who were scheduled to undergo IVF. INTERVENTION(S):
Equal halves of the same semen sample were evaluated for strict criteria sperm
morphology before and after preparation by differential gradient centrifugation
using Percoll (Pacific Andrology, Montrose, CA) and by the standard swim-up
method. MAIN OUTCOME MEASURE(S): The percentage of morphologically normal sperm
was assessed using strict criteria before and after the two methods of sperm
preparation. Specific parameters studied were individual abnormalities of the
head, midpiece, and tail. RESULT(S): Sperm preparation using differential
gradient centrifugation with Percoll produced a significantly greater number of
specimens with normal sperm morphology and also showed higher absolute
quantitative improvement over the swim-up method. The two methods were comparable
in regard to their effects on specific sperm abnormalities (i.e., head, midpiece,
and tail defects). CONCLUSION(S): The differential gradient sperm separation
method using Percoll is superior to the swim-up method for selecting sperm with
normal morphology as assessed by strict criteria. Because sperm morphology as
assessed by strict criteria is a good predictor of oocyte fertilization, this
method can be recommended as the method of choice for assisted reproductive
technology laboratories. Use of this method may help improve outcome by
increasing fertilization rates.
PMID- 9548165
TI - Creatine kinase activity in human spermatozoa and seminal plasma lacks predictive
value for male fertility in in vitro fertilization.
AB - OBJECTIVE: To examine the predictive value of creatine kinase in human
spermatozoa and seminal plasma from patients treated in an IVF program. DESIGN:
Prospective, blind clinical study. SETTING: Male infertility clinic. PATIENT(S):
Seventy-three patients and 32 fathers (age, <45 years). INTERVENTION(S):
Determination of creatine kinase activity in seminal plasma, washed spermatozoa,
and swim-up purified spermatozoa from patients treated in an IVF program. MAIN
OUTCOME MEASURE(S): Creatine kinase activity in seminal plasma, washed
spermatozoa, and swim-up purified spermatozoa. RESULT(S): Creatine kinase
activity in washed spermatozoa correlated significantly with normal sperm
morphology. No significant correlations were found between creatine kinase
activity or creatine kinase isoenzyme ratio in seminal plasma, washed
spermatozoa, or swim-up purified spermatozoa and success in the IVF program. The
percentage of spermatozoa with normal morphology was significantly lower in
patients whose sperm did not fertilize than in patients whose sperm did fertilize
oocytes and in the control group of proven fathers. CONCLUSION(S): Total creatine
kinase activity and creatine kinase isoenzyme distribution are not sperm function
markers for prediction of male fertility in IVF treatment.
PMID- 9548166
TI - Alpha-glycosidase activity in seminal plasma: predictive value for outcome in
intrauterine insemination and in vitro fertilization.
AB - OBJECTIVE: To test the hypothesis that alpha-glycosidase activity in seminal
plasma can predict the outcome of both IUI and IVF. DESIGN: A retrospective
cohort study. SETTING: Tertiary fertility center in a university hospital.
PATIENT(S): Eighty-three subfertile couples who underwent IUI and 125 subfertile
couples who underwent IVF. INTERVENTION: None. MAIN OUTCOME MEASURE(S):
Determination of the alpha-glycosidase activity in seminal plasma before an IUI
or IVF attempt, correlation of alpha-glycosidase activity and other semen
parameters, and prediction of pregnancy using alpha-glycosidase activity in
seminal plasma. RESULT(S): Alpha-glycosidase activity correlated with sperm
count. In the IUI group, alpha-glycosidase activity of >23.9 mU/mL predicted
pregnancy with a sensitivity of 100% and a specificity of 55.2%. In the IVF
group, the outcome could not be predicted with use of any of the semen
parameters. CONCLUSION(S): Alpha-glycosidase activity measured in mU/mL probably
can be used as a predictor for IVF and pregnancy in an IUI program but has no
predictive value with regard to pregnancy rate in an IVF program.
PMID- 9548167
TI - Simultaneous assessment of sperm chromatin condensation and morphology before and
after separation procedures: effect on the clinical outcome after in vitro
fertilization.
AB - OBJECTIVE: To look for correlations between acridine orange (AO) staining and
semen parameters before and after sperm separation procedures and to assess
whether the AO test predicts fertilization or pregnancy outcomes after standard
IVF and intracytoplasmic sperm injection. DESIGN: Prospective study that
simultaneously assesses sperm morphology and nuclear protein maturity on a cell
by-cell basis before and after preparative procedures. SETTING: University
teaching hospital. PATIENT(S): Men (n = 140) undergoing diagnostic semen
analysis. MAIN OUTCOME MEASURE(S): Acridine orange fluorescence of sperm nuclei,
semen parameters, IVF outcome. RESULT(S): In unprocessed samples, 90% of sperm
with normal heads displayed green fluorescence (mature nuclear protein);
significantly lower percentages of green fluorescence were observed in sperm with
abnormal heads. The percentage of mature normal sperm in the specimen correlated
with motility. Sperm maturity after swim-up or Percoll gradient was significantly
improved for sperm with normal or abnormal heads. The percentage of mature normal
sperm correlated with motility after either Percoll or swim-up. Neither the
percentages of mature nuclei nor mature normal nuclei correlated with
fertilization or pregnancy outcome. CONCLUSION(S): Nuclear protein maturation
correlates with sperm motility and morphology. Because morphologically normal and
motile sperm are more mature, separation procedures should generate a population
of sperm with the highest fertilization capacity. Acridine orange staining,
however, did not predict fertilization efficiency or pregnancy outcome in IVF
cycles.
PMID- 9548169
TI - Detection of P2 precursors in the sperm cells of infertile patients who have
reduced protamine P2 levels.
AB - OBJECTIVE: To determine whether the reduction in the protamine P2 content
(increased P1/P2 ratio) reported in some infertile patients could result from
incomplete processing of protamine P2 precursors. DESIGN: Analysis of samples
with a marked reduction in the protamine P2 content using polyacrylamide gel
electrophoresis and subsequent detection of protamine P2 precursors through
Western blot analysis. SETTING: University departments and laboratories.
PATIENT(S): One hundred eighty-four men undergoing an evaluation for infertility.
MAIN OUTCOME MEASURE(S): Comparative Western blot analysis of nuclear sperm
proteins using specific antibodies to protamine P1 and protamine P2. RESULT(S):
After selection of the samples with a marked reduction of the protamine P2
content and subsequent analysis by Western blot, a small proportion of putative
P2 precursors was detected in most samples, whereas a significant increase was
detected in two of them. CONCLUSION(S): In some infertile men, a reduction in the
protamine P2 content relative to protamine P1 (increased P1/P2 ratio) is detected
concomitant with an increase in the amount of putative P2 precursors. This could
represent the first report of incomplete processing of a nuclear sperm protein in
humans.
PMID- 9548168
TI - Increase of intracellular calcium is not a cause of pentoxifylline-induced
hyperactivated motility or acrosome reaction in human sperm.
AB - OBJECTIVE: To investigate the effects of the phosphodiesterase inhibitor
pentoxifylline on hyperactivated motility and acrosome reaction in human sperm
and to determine whether its stimulatory effects occur via increased
intracellular calcium levels. DESIGN: Prospective study. SETTING: Academic
tertiary care facility. PARTICIPANT(S): Healthy male donors. INTERVENTION(S): The
effects of pentoxifylline on hyperactivated motility, acrosome reaction, and
intracellular calcium were studied and compared with the effects of progesterone.
Thapsigargin, a known mobilizer of intracellular calcium, also was used as
positive control. MAIN OUTCOME MEASURE(S): Hyperactivated motility was assessed
by computer-assisted sperm motion analysis using the HTM-IVOS, acrosome reaction
was evaluated with the fluorescent probe fluorescein isothiocyanate-labeled Pisum
sativum agglutinin, and intracellular calcium was determined by fura-2 using
spectrofluorometry. RESULT(S): Pentoxifylline significantly increased both
hyperactivated motility and acrosome reaction. Enhancement of hyperactivated
motility by pentoxifylline in the capacitation medium persisted for up to 5 hours
after pentoxifylline was washed from the medium. It also enhanced the percentage
of acrosome-reacted spermatozoa after 4 hours of incubation. These effects
occurred in the presence of a marginally significant decrease in intracellular
calcium. CONCLUSION(S): Pentoxifylline stimulates hyperactivated motility and
acrosome reaction in spermatozoa from fertile men. Its stimulatory effects occur
through mechanism(s) other than increase in intracellular calcium.
PMID- 9548170
TI - Characterization of tubal and decidual leukocyte populations in ectopic
pregnancy: evidence that endometrial granulated lymphocytes are absent from the
tubal implantation site.
AB - OBJECTIVE: To compare and quantify leukocyte populations at the tubal
implantation site, in the tubal mucosa away from the implantation site and in the
intrauterine decidua in women who have had an ectopic tubal pregnancy with
leukocyte populations in the decidualized endometrium in women who have had a
normal intrauterine pregnancy. DESIGN: Retrospective immunohistochemical study.
SETTING: Department of Pathology, University of Newcastle, Royal Victoria
Infirmary, Newcastle upon Tyne, Tyne and Wear, United Kingdom. PATIENT(S):
Paraffin-embedded tissue blocks from 30 women who had had an ectopic pregnancy
(EP) and control tissue blocks from 19 women who had undergone elective first
trimester pregnancy termination. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S):
Quantitative analysis of defined leukocyte subpopulations in the fallopian tube
(at the implantation site and in the tubal mucosa away from the implantation
site) and intrauterine decidua. RESULT(S): Endometrial granulated lymphocytes
were absent from both the tubal mucosa away from the implantation site and the
tubal implantation site. T lymphocytes and macrophages formed the predominant
leukocyte subpopulations in both tubal areas. In the intrauterine decidua from
women who had had an EP, endometrial granulated lymphocytes were the most
abundant leukocyte population and macrophages and T cells formed the second and
third major leukocyte subpopulations, respectively. No differences were detected
in the number or proportion of these decidual leukocytes in women who had had a
normal pregnancy vs. in those who had had an EP. CONCLUSION(S): The absence of
endometrial granulated lymphocytes from the tubal implantation site suggests that
the local presence of the cells is not essential for implantation and early
placental development events.
PMID- 9548171
TI - Assessment of a tablet drug delivery system incorporating nonoxynol-9
coprecipitated with polyvinylpyrrolidone in preventing the onset of pregnancy in
rabbits.
AB - OBJECTIVE: To assess the in vivo efficacy of the tablet drug delivery system
containing nonoxynol-9 coprecipitated with polyvinylpyrrolidone by delivering the
spermicidal agents vaginally and evaluating their ability to prevent the onset of
pregnancy in rabbits. DESIGN: Controlled clinical study. SETTING: Division of
Laboratory and Animal Resources, College of Pharmacy, University of Kentucky.
ANIMAL(S): Forty-two New Zealand White female rabbits. INTERVENTION(S): The
rabbits were artificially inseminated at various intervals after vaginal
insertion of the tablet drug delivery system containing either
polyvinylpyrrolidone only (0 minutes) or nonoxynol-9 coprecipitated with
polyvinylpyrrolidone (polyvinylpyrrolidone/nonoxynol-9; 0, 3, 30, 180, and 360
minutes). The rabbits were induced to ovulate 6 hours before insemination by i.m.
injection of hCG (200 IU). MAIN OUTCOME MEASURE(S): The onset of pregnancy in the
rabbits was evaluated after insertion of the tablet drug delivery system
containing polyvinylpyrrolidone only or polyvinylpyrrolidone/nonoxynol-9 at
various intervals, followed by artificial insemination. RESULT(S): The onset of
pregnancy was not reduced significantly when the tablet drug delivery system
containing polyvinylpyrrolidone or polyvinylpyrrolidone/nonoxynol-9 was used and
insemination was performed immediately after tablet insertion (time 0). However,
pregnancy rates (PRs) were reduced significantly in the rabbits that received the
tablet drug delivery system containing polyvinylpyrrolidone/nonoxynol-9 and were
inseminated at 3, 30, 180, and 360 minutes after tablet insertion. The highest PR
reduction occurred between 30 and 180 minutes after insertion of the tablet drug
delivery system containing polyvinylpyrrolidone/nonoxynol-9. CONCLUSION(S): The
tablet drug delivery system is an efficient method of delivering the tested
spermicidal agents vaginally. The design and dosage used in preparing the tablet
drug delivery system provide short- and long-term release of the spermicidal
agents, which results in almost immediate and extended enhancement of their
contraceptive properties.
PMID- 9548172
TI - Soluble intercellular adhesion molecule-1 in ovarian follicles: production by
granulosa luteal cells and levels in follicular fluid.
AB - OBJECTIVE: To determine the concentration of the soluble form of intercellular
adhesion molecule (ICAM)-1 in granulosa luteal cell-conditioned media and in
follicular fluid (FF). DESIGN: Granulosa cells and FF samples were obtained at
the time of oocyte retrieval for IVF. In 10 women, a total of 33 fluids were
obtained from individual follicles, whereas in 70 women, the follicular aspirates
were pooled. SETTING: Clinica "L. Mangiagalli" and Reproductive Center, San
Raffaele Hospital, Milan, Italy. PATIENT(S): Eighty women referred for IVF for
tubal factor or male factor infertility. INTERVENTION(S): Women underwent ovarian
hyperstimulation. MAIN OUTCOME MEASURE(S): Soluble ICAM-1 was measured by an
ELISA, and its levels were correlated with follicular size, the number of
retrieved oocytes, and the number of follicles with a diameter of >15 mm.
RESULT(S): The concentration of soluble ICAM-1 in granulosa luteal cell
conditioned media was 17.8 +/- 1.8 ng/5 x 10(5) cells. Interleukin-1beta can
stimulate soluble ICAM-1 release in a dose-dependent manner. A significant
positive correlation was demonstrated between levels of soluble ICAM-1 in pooled
FF and the number of retrieved oocytes or the number of follicles with a diameter
of >15 mm. CONCLUSION(S): Soluble ICAM-1 can be released by granulosa luteal
cells and can be detected in FF after ovarian hyperstimulation. Levels of soluble
ICAM-1 in FF correlate directly with some indices of ovarian function.
PMID- 9548173
TI - Transvaginal drainage of ascites as an alternative to abdominal paracentesis in
patients with severe ovarian hyperstimulation syndrome, obesity, and generalized
edema.
AB - OBJECTIVE: To describe an alternative technique for transvaginal drainage of
ascites in a case of severe ovarian hyperstimulation syndrome (OHSS), generalized
edema, and obesity. DESIGN: Case report. SETTING: A university-based hospital IVF
and Reproductive Medicine Unit. PATIENT(S): A patient hospitalized with severe
OHSS after IVF-ET in whom drainage of large amounts of ascitic fluid was
necessary. INTERVENTION(S): Ultrasonographic transvaginal insertion of a wire
guide through a standard IVF needle into the Douglas pouch. Placement of a "peel
away" set on the wire, which was replaced with a "pigtail" indwelling catheter.
MAIN OUTCOME MEASURE(S): Amount of drained ascitic fluid. RESULT(S): Ascitic
fluid was drained efficiently, leading to improvement of the patient's condition.
CONCLUSION(S): Transvaginal ultrasonography-guided insertion of a pigtail
catheter through the Douglas pouch is an efficacious procedure when the abdominal
approach for decompression of ascites is difficult.
PMID- 9548174
TI - A new assisted hatching technique using a piezo-micromanipulator.
AB - OBJECTIVE: To estimate the efficacy of a new assisted hatching technique using a
piezo-micromanipulator to support embryonic implantation. DESIGN: Sibling spare
embryos from human cycles of IVF were allocated to either a treated group for
assisted hatching by a piezo-micromanipulator or a nontreated control group.
SETTING: The Infertility and IVF unit of the Kyoto University Hospital.
PATIENT(S): Sixty-eight women undergoing conventional IVF treatment.
INTERVENTION(S): One hundred ten spare 4- or 8-cell embryos from 68 patients
undergoing IVF were treated with the new assisted hatching technique, and the
results were compared with those obtained for 112 sibling embryos without the
treatment. In the assisted hatching procedure, zona thinning combined with
drilling was performed by the vibration of a microneedle produced by the piezo
micromanipulator unit. MAIN OUTCOME MEASURE(S): The rates of partial hatching and
completely hatched blastocysts. RESULT(S): The rates of hatching and of hatched
blastocysts per total developing blastocysts were significantly higher in the
treated group (86.7% and 33.3%, respectively) than in the control group (15.3%
and 2.8%, respectively). CONCLUSION(S): These results demonstrate that the newly
devised zona thinning and drilling technique using a piezo-micromanipulator is
useful for assisted hatching.
PMID- 9548175
TI - Carrot juice junkies and big bangs.
PMID- 9548176
TI - Clarification of fertility after tubal surgery for ectopic pregnancy.
PMID- 9548177
TI - Clarification of fertility after tubal surgery for ectopic pregnancy.
PMID- 9548179
TI - Fibroblast growth factor-2 and fibroblast growth factor receptor-1 mRNA
expression and peptide localization in placentae from normal and diabetic
pregnancies.
AB - Fibroblast growth factor-2 (FGF-2) is a potent mitogen expressed widely during
embryogenesis and in tissues of the human fetus. It is recognized as an
endothelial cell mitogen and is angiogenic in vivo. Expression of FGF-2 mRNA has
also been shown within the human term placenta, and FGF-2 isolated from placental
tissue, suggesting a role in placental growth including angiogenesis. The purpose
of this study was to quantify and localize the sites of expression of FGF-2 and
its high-affinity receptor, FGFR1, within placentae from normal term human
pregnancies (n=8, 39-42 weeks), and pregnancies complicated by pregestational,
type 1 diabetes (n=8, 36-40 weeks). Tissues were collected immediately following
delivery and were either snap-frozen for RNA isolation, or fixed for either in
situ hybridization using a 35S-labelled cRNAs encoding human FGF-2 or FGFR1, or
immunocytochemistry using antibodies against human FGF-2 or FGFR1. Northern blot
hybridization showed a significantly increased abundance of mRNAs for both FGF-2
and FGFR1 in placentae from diabetic women compared to those from normal women.
In normal term placenta FGF-2 mRNA was present at low abundance in fetal villous
tissue, in the vascular endothelium of blood vessels, and in the
syncytiotrophoblast. FGF-2 mRNA was considerably more abundant in the
syncytiotrophoblast and villous tissue of placentae from diabetic patients.
Messenger RNA for FGFR1 was similarly distributed to that encoding FGF-2.
Immunocytochemistry revealed abundant FGF-2 and FGFR1 peptides in villous
vascular endothelial cells, and associated with the cell membranes of stromal
tissues in placentae from control pregnancies. Little immunoreactive FGF-2 was
present in the syncytiotrophoblast at term. In pregnancies complicated by
diabetes intense staining for immunoreactive FGF-2 and for FGFR1 additionally
existed in syncytiotrophoblast. The results suggest that FGF-2 acting as an
autocrine agent contributes to placental angiogenesis, but may be released from
the syncytium into the maternal circulation. Expression is elevated in placentae
from diabetic pregnancies, and is particularly associated with the
syncytiotrophoblast. This suggests a placental source for the elevated
circulating maternal FGF-2 previously described in diabetic pregnancy.
PMID- 9548178
TI - HLA-G1 protein expression is not essential for fetal survival.
AB - HLA-G is a nonclassical, class I HLA gene that is primarily expressed by fetal
cells at the maternal-fetal interface and is thought to play a key role in the
induction of tolerance in pregnancy. This paper reports the identification of a
single base pair deletion at position 1597 (1597delC) in exon 3 (encoding the
alpha2-domain) of HLA-G on 20 of 272 (7.4 per cent) African American chromosomes,
three of 102 (2.9 per cent) Hispanic chromosomes, and none of 134 Caucasian
chromosomes. This relatively common frameshift mutation results in amino acid
substitutions in all of the residues in the second half of exon 3 including the
conserved cysteine at codon 164. An adult individual was identified who was
homozygous for this 'null' allele, and a first trimester placenta that was
homozygous for 1597delC had no detectable HLA-G1 protein. These data indicate
that expression of HLA-G1 protein is not essential for fetal survival.
PMID- 9548180
TI - Fetal growth retardation and second trimester maternal serum human chorionic
gonadotrophin levels.
AB - Second trimester maternal serum human chorionic gonadotrophin (hCG) levels in
women who remained normotensive but delivered an unexplained growth retarded
infant were compared with those from a control group and a group of women who
developed pre-eclampsia in a retrospective observational study. Our hypothesis
was that the similar placental pathological changes shared by unexplained
normotensive IUGR and pre-eclampsia would be reflected by elevated maternal serum
hCG levels in the second trimester. Normotensive women delivering unexplained
singleton growth retarded infants were identified (n=43) and their second
trimester hCG levels, taken as part of antenatal screening for Down's syndrome,
were obtained. These were compared with a control group of 625 women, and a group
of 48 women who subsequently developed pre-eclampsia. There was no significant
difference in the hCG levels expressed as multiples of the median (MOM) between
the women who delivered growth retarded fetuses (median MOM 0.96) and the control
group (median MOM 0.97). The levels of hCG in the women who subsequently
developed pre-eclampsia were significantly higher (median MOM 1.3, P=0.008).
There were no significant differences in AFP levels in the three groups; however,
the trend was towards a higher level of AFP in the fetal growth retardation
group. Maternal serum hCG in the second trimester does not appear to be elevated
in normotensive women who later produce a growth retarded fetus, although human
chorionic gonadotrophin levels are significantly higher in women who subsequently
develop pre-eclampsia.
PMID- 9548181
TI - Evidence for basic fibroblast growth factor as a crucial angiogenic growth
factor, released from human trophoblasts during early gestation.
AB - The objective of this study was to clarify the possible angiogenesis-promoting
factors from human trophoblasts in early stage gestation. The existence of
angiogenic growth factors such as basic fibroblast growth factor (bFGF) and
vascular endothelial growth factor (VEGF) in the condition medium from human
villous trophoblasts was determined. Biological activity of angiogenic growth
factors released by trophoblasts was examined using vascular endothelial cell
lines. The condition medium from trophoblasts enhanced the growth of endothelial
cells. Although cultured trophoblasts exhibited immunoreactive products for both
bFGF and VEGF in the cytoplasm, only bFGF was detected in the condition medium by
ELISA. The growth-enhancing activity of the condition medium was eliminated
completely by the addition of anti-bFGF antibody but not with anti-VEGF antibody.
Thus, trophoblastic cells seem to play an important role in extensive
angiogenesis occurring in early gestation, mainly by releasing bFGF but not VEGF.
PMID- 9548183
TI - Expression of cytokine receptors in the placenta in term and preterm labour.
AB - Elevated uterine concentrations of interleukin-1beta (IL-1beta), interleukin-6
(IL-6) and tumour-necrosis factor-alpha (TNF-alpha) are suspected to cause
increased prostaglandin release from gestational tissues, but little information
is available about the expression pattern of cytokine receptors in these tissues.
In this study, cytokine receptor positive cells in frozen tissue sections of
placentae (n=70) and fetal membranes (n=50) were identified by immunohistological
staining with monoclonal antibodies specific for IL-6 receptor, TNF receptors I
and II, and IL-1 receptor I. Both subunits of the IL-6 receptor (gp130 and gp80)
as well as TNF receptors I and II were expressed by fetal endothelial cells
within placental villi, while IL-1-receptor I was detected exclusively in stromal
cells of the maternal decidua. The IL-1 receptor I and TNF receptors I and II
were expressed in both uterine quiescence and labour, irrespective of gestational
age. Immunoreactivity of the gp130 subunit of the IL-6 receptor was found also
throughout pregnancy, while the appearance of the gp80 subunit correlated with
the presence of term and preterm labour. In case of preterm labour, expression of
the gp80 subunit was predominantly detected in the absence of intrauterine
infection. Therefore, it is concluded that the de novo expression of the gp80
subunit and consequently the appearance of entire IL-6 receptors in the placenta
is associated with spontaneously occurring labour at term and also with preterm
occurring labour in the absence of inrauterine infection.
PMID- 9548182
TI - Expression of syndecan-1 in human placenta and decidua.
AB - Syndecan-1 is a cell surface heparan sulphate proteoglycan, which binds to the
extracellular matrix (ECM), growth factors and antithrombin III. The early
expression of syndecan-1 during mouse embryonic development suggests a potential
role in the communication between the embryo and the ECM of decidua. Using
immunohistochemical methods, the present study showed that the expression of
syndecan-1 in the trophoblast cells changes along trophoblast differentiation.
The syncytiotrophoblasts in the chorionic villi exhibited an apical expression of
syndecan-1. This suggests that the expression is restricted to non-migrating, non
proliferating trophoblasts. The mode of syndecan-1 expression by human placental
trophoblasts is independent of gestational age. The expression is not changed in
miscarriages. In pre-eclampsia, the staining for syndecan-1 on the villous
syncytiotrophoblast is weaker compared to normal pregnancy, but in placental bed
the expression is similar. The unique apical localization of syndecan-1 in
chorionic villi, not detected in any other tissues, suggests a potential role in
fetomaternal communication probably via growth factor binding and in
anticoagulation of intervillous circulation.
PMID- 9548184
TI - Localization and distribution of tissue type and urokinase type plasminogen
activators and their inhibitors Type 1 and 2 in human and rhesus monkey fetal
membranes.
AB - Fetal membranes consist of 10 distinct layers including components of amnion,
chorion and decidua, the latter being of maternal origin. They form mechanically
integrated sheets capable of retaining amniotic fluid and play an essential role
in protecting fetal growth and development in the pregnant uterus. The
extracellular matrix, substrate for plasminogen activators (PAs), is an important
supportive framework of the fetal membranes. Fetal membranes from women with
preterm premature rupture of membranes may differ in their protease activity
compared with normal membranes. To identify the presence of PAs and their
inhibitors (PAI) and their possible role in the process of fetal membrane
rupture, this study investigated the distribution and localization of both
protein and mRNA for tissue (t) and urokinase (u) PA and their inhibitors type 1
(PAI-1) and type 2 (PAI-2) in amniochorion of human and rhesus monkey using
conventional and confocal immunofluorescence microscopy. In situ hybridization
analysis showed that the distribution and localization of mRNAs for tPA, uPA, PAI
1 and PAI-2 were similar in the fetal membranes of human and rhesus monkey; no
obvious species difference was observed. Evidence of tPA mRNA was detected in
amniotic epithelium, trophoblast cells and nearly all cells of the decidual
layer. Strong expression of uPA mRNA was noted in the decidual cells which
increased in intensity as the abscission point was approached. Weak staining in
chorion laeve trophoblast was also detected. In situ hybridization experiments
showed PAI-1 mRNA to be concentrated mainly in the decidual cells, some of which
were interposed into the maternal-facing edge of the chorion laeve. Maximal
labelling of the decidua occurred towards the zone of abscission. Weak expression
of PAI-1 mRNA was also noted in some cells of the chorion laeve. The distribution
of PAI-2 mRNA in amniochorion was also concentrated in the cells of the decidual
layer, maximum expression of the mRNA was in the level of abscission. No
detectable amount of mRNAs for tPA, uPA, PAI-1 and PAI-2 was found in the
fibroblast, reticular and spongy layers. Distribution of the proteins of tPA, uPA
and PAI-1 in the fetal membranes of these two species was consistent with the
distribution of their mRNA. Anti-PAI-2 immunofluorescence was found to be
strongly concentrated in the amniotic epithelium, but PAI-2 mRNA was negative in
this layer, suggesting that the epithelium-associated PAI-2 is not of epithelial
origin. These findings suggest that a local fibrinolysis in fetal membranes
generated by precisely balanced expression of PAs and their inhibitors via
paracrine or autocrine mechanisms may play an essential role in fetal membrane
development, maturation and in membrane rupture. Following an analysis of the
distribution and synthesis of activators and inhibitors it was found that they
may play a role in abscission during the third stage of labour.
PMID- 9548185
TI - Eosinophil cationic protein and eosinophil protein X: human amniotic fluid
concentrations and gestational tissue content at term.
AB - The aim of this study was to determine the presence and concentration of
immunoreactive eosinophil cationic protein (ECP) and eosinophil protein X (EPX)
in human amniotic fluid at term and assess labour-associated changes in their
mean concentrations. In addition, ECP and EPX content in term amnion,
choriodecidua and placenta obtained before and after labour and delivery was
established. Immunoreactive ECP and EPX were identified in all samples of
amniotic fluid (n=47) and gestational tissue (n=60) assayed. EPX was
quantitatively more abundant than ECP in both amniotic fluid and gestational
tissues. In amniotic fluid, ECP and EPX concentrations increased 8-fold (P<0.02)
and 1.5-fold (P<0.02), respectively, with labour onset. In gestational tissues, a
labour-associated change in tissue content was only identified for ECP in
choriodecidua, which increased 1.9-fold with labour and delivery (P<0.01). The
labour-associated increase in amniotic fluid concentrations of ECP and EPX
demonstrated in this study is consistent with the well-characterized role of
these proteins in inflammatory reactions. It remains to be established whether
the observed increase in ECP and EPX amniotic fluid concentrations is an
epiphenomenon of labour onset or is involved causally in this process.
PMID- 9548186
TI - Ovine placentome morphology: effect of high altitude, long-term hypoxia.
AB - The effect of high altitude, long-term hypoxaemia on placentome morphology in the
sheep was examined using singleton and twin pregnant ewes. Normoxic twins had
lower fetal and placental weights (3.7+/-0.2 kg and 215+/-26 g, respectively)
than normoxic singleton fetuses (4.3+/-0.2 kg and 336+/-17 g, respectively).
Fetal and placental weights were similar in normoxic singleton and high altitude
(3820 m) hypoxic singleton fetuses (4.3+/-0.2 and 4.4+/-0.4 kg, 336+/-17 and
342+/-62 g, respectively). The distribution of placentome types was classified
into four major categories (A-D) and for normoxic singletons was as follows:
A=76+/-4, B=22+/-3, C=1+/-2, and D=1+/-1. Normoxic twins tended to have more type
B (type A=63+/-10, B=33+/-8, C=2+/-1, and D=2+/-1). High altitude hypoxic
singletons had significantly fewer type A (33+/-4) and more type B (50+/-3), C
(10+/-7), D (7+/-1) placentomes than normoxic singletons. In addition, in the sea
level control group, five animals were found to be spontaneously hypoxic with a
placentome distribution similar to that of the high altitude hypoxic fetuses. In
conclusion, both high altitude, long-term hypoxia and low altitude spontaneous
hypoxia lead to a significant change in placentome distribution with less type A
and increases in types B, C and D. Physiologically, the change in the several
placentome types with high altitude hypoxia suggests an acclimatization response
to optimize transplacental exchange efficiency.
PMID- 9548187
TI - Haemodynamic model of twin-twin transfusion syndrome in monochorionic twin
pregnancies.
AB - Twin-twin transfusion syndrome in monochorionic twin pregnancies is not
understood completely and is controversial which hampers development of
acceptable diagnostic and rational treatment strategies. A haemodynamic model was
developed that relates fetal growth with (1) fetoplacental blood flow and
fetomaternal effects, and (2) net twin-twin transfusion from donor to recipient
twin. Fluid balance mechanisms were neglected. Placental vascular anastomoses
(arteriovenous, venoarterial, arterioarterial, venovenous) were modelled as
straight blood vessels connecting the placental cord insertions that grow during
pregnancy. Poiseuille's law predicts significantly decreasing anastomosing
resistances, and when placental sharing is unequal it is assumed that smaller
placental fractions cause smaller blood volumes and pressures. Two coupled first
order differential equations describing each twin's blood volume were determined
and analysis showed that placental and anastomotic development cause anastomotic
blood flow to increase faster than fetal growth. Hence, it is proposed as the
syndrome's underlying pathophysiology that fetal discordance increases
progressively, beyond fetal compensatory capacity. Fewer anastomoses cause larger
discordance, but its onset can vary widely during pregnancy. Arteriovenous plus
compensating anastomoses produce dynamic steady-state growth patterns with large,
opposite, measurable anastomotic blood flows. Clinical study of fetal growth
patterns may identify the syndrome's underlying placental anatomy. Predicted
trends depend only weakly on implemented fetal physiology and are most likely
realistic. This knowledge could improve future management of the syndrome.
PMID- 9548188
TI - Overlay blot identification of GTP-binding proteins in mitochondria from human
placenta.
AB - In this study, an overlay blot method was used to identify GTP-binding proteins
in fractions of human placenta. Human placenta were fractionated by
centrifugation into preparations containing (1) mitochondria, (2) nucleoli and
(3) microsomes, plasma membrane and cytosol. GTP-binding proteins were detected
by overlay blot using alpha32P-GTP. Proteins of 23 and 25 kDa were identified in
all fractions and GTP binding was higher in the presence of 1.0, 2.5, 5.0 and
10.0 mM MgCl2 as compared to equivalent concentrations of CaCl2. In mitochondrial
preparations binding of alpha32P-GTP to 23 and 25 kDa was displaced significantly
by GDP and GTP but not ADP or ATP. Fractions containing microsomes, plasma
membrane and cytosol displayed two labelled bands of 14 and 18 kDa that were not
present in other fractions. These data indicate that the placenta contains
specific GTP-binding proteins of molecular weights that are consistent with the
small monomeric GTP binding protein family (18-36 kDa). Two of these are located
in the mitochondria and may regulate the function of these organelles in the
placenta.
PMID- 9548189
TI - Specific expression of PP5/TFPI2 mRNA by syncytiotrophoblasts in human placenta
as revealed by in situ hybridization.
AB - Placental protein 5 (PP5) is a placenta-derived glycoprotein with serine
proteinase-inhibiting activity. To date its physiological functions have not been
well elucidated. Recently, cDNA sequence analysis revealed that PP5 belongs to
the Kunitz-type proteinase inhibitor family and it is identical to tissue factor
pathway inhibitor-2 (TFPI-2), homologous to TFPI. Northern blot analysis
demonstrated that placental tissue is extremely rich in the transcripts. This
study localized PP5/TFPI-2 mRNA in placental tissues at three different
gestational periods using in situ hybridization. PP5/TFPI-2 mRNA was specifically
detected in syncytiotrophoblast at any gestational period examined, suggesting
that syncytiotrophoblast is the principal production site of PP5/TFPI-2 in
developing placental tissues. This mRNA expression pattern of PP5/TFPI-2 is quite
different from that of TFPI, which is mainly found in vascular endothelial cells.
The results indicated possible roles of PP5/TFPI-2 in the trophoblast
differentiation and in the maintenance of intervillous blood flow. Also, Northern
analysis demonstrated no or little expression of PP5/TFPI-2 in four
choriocarcinoma cell lines, in contrast to its abundant expression in
syncytiotrophoblast.
PMID- 9548190
TI - Determinants of species- and placenta-specific expression of p100 GAP.
AB - This study was based on the hypothesis that both primary sequence and methylation
status of the GTPase activating protein (GAP) gene limits expression of p100 GAP
to primate placenta. Due to alternate splicing, a 65-bp insert appears between
the first and second coding exons of p100 GAP mRNA, and translation of p100 GAP
initiates within this insert. Examination of the sequence surrounding the 65-bp
insert revealed that the monkey GAP gene contained both the 3' splice donor site
and the internal start codon, whereas the mouse GAP gene contained neither. To
address p100 GAP tissue specificity, the methylation status of the GAP gene was
examined. Site-specific demethylation was found to correlate with synthesis of
p100 GAP, suggesting that methylation regulates the expression of different GAP
isoforms. The results of this study provide a mechanistic basis for the
observation that p100 GAP is synthesized only in primate placenta and suggest
that its expression is regulated, in part, by gene methylation.
PMID- 9548191
TI - Progress with nuclear medicine audit in the UK.
PMID- 9548192
TI - FDG uptake, tumour characteristics and response to therapy: a review.
AB - The use of FDG-PET imaging in tumour detection is now well established. Many
studies have suggested that changes in the uptake of FDG predict tumour response
to therapy and that further clinical information regarding tumour grade and
proliferative status may also be derived from FDG-uptake scans. More studies are
required to verify the role of FDG-PET in patient management. Upregulation of
hexokinase and glucose transporters, especially Glut-1, and downregulation of
glucose-6-phosphatase are frequently associated with transformation. The extent
of these changes has been related to both differentiation and proliferation
largely corresponding with FDG-uptake studies.
PMID- 9548193
TI - A structured approach to the interpretation and reporting of
ventilation/perfusion scans.
AB - The aim of this study was to develop a structured approach to the reporting and
in particular the clinical interpretation of ventilation/perfusion (V/Q) scan
results. An initial audit indicated that there were significant variations in the
clinical management of patients particularly after a non-diagnostic V/Q scan
report. There were also differences in the approaches used to interpret the scan
itself. In an attempt to improve this, a set of interpretation guidelines was
produced based on the revised PIOPED data. To combat the problems with clinical
interpretation, a standard method for assessing the pre-test clinical probability
of pulmonary embolism was established. This clinical risk was then combined with
the V/Q scan result to give an overall probability for the presence of pulmonary
embolism. The more precise risk stratification which resulted allowed explicit
clinical advice on patient management to be incorporated into the final report. A
second audit was performed with the revised methodology in place. The level of
inter-observer variability for scan reporting decreased from 30% to 12%. The
prior assessment of clinical risk and the standardized method of combining this
with the scan result led to an improvement in patient management. This was
particularly true for the non-diagnostic group, in whom additional investigations
were more appropriately used. A structured approach which allows the pre-test
probability of pulmonary embolism to be combined in an explicit fashion with the
V/Q scan result can provide a more precise risk stratification allowing
appropriate recommendations to be made. Such an approach can result in improved
patient management.
PMID- 9548194
TI - A preliminary evaluation of diagnostic odds in lung scan reporting.
AB - Reporting of lung scans for pulmonary embolism (PE) using a descriptive
probability notation is tried and tested. Subjectivity in interpretation of this
jargon can be a problem for internists. Parallel descriptive and numerical
probability reporting has been recommended, but the numerical probability scale
is less precise than likelihood ratios expressed as odds. We therefore assessed
internists' intuitive understanding of lung scan reports in the odds format
compared to the descriptive probability notation. A questionnaire was sent to
Scotland's 217 internists to assess their intuitive understanding of odds
reporting and to compare their management strategies when confronted by lung scan
reports in both an odds and a descriptive probability notation. There was a broad
understanding of numerical odds. Internists used 'normal' and '100:1 against PE'
identically; similarly, 'low probability' and '10:1 against PE'. There was a
statistically significant preference for the diagnosis of PE when internists were
given the '1:1 evens' report compared with the 'indeterminate' report. There does
appear to be a greater awareness of the risk of PE when non-diagnostic lung scans
are reported in numerical odds as compared with the descriptive probability
format.
PMID- 9548195
TI - Comparison of dual-isotope acquisition of 201Tl and 99Tcm-tetrofosmin for the
detection of ischaemic heart disease and determination of the optimal imaging
time of 99Tcm-tetrofosmin.
AB - Comparative studies of thallium-201 (201Tl) and 99Tcm-tetrofosmin for the
detection of ischaemic heart disease (IHD) have previously been reported. These
201Tl and 99Tcm-tetrofosmin studies were usually performed separately with
different exercise loads at an interval of several days. Here, we used a dual
isotope technique with exercise myocardial SPET (single photon emission
tomography) in 17 patients with IHD and 10 patients with normal coronary
arteries. The triple-energy window (TEW) method was applied for cross-talk
correction. SPET imaging was performed at 10 and 70 min (S1 and S2) after the
injection of 99Tcm-tetrofosmin (222 MBq) and 201Tl (74 MBq) at peak exercise to
determine the optimal imaging time of 99Tcm-tetrofosmin. The S2 value was
obtained 35 min after the subject drank a glass of milk to accelerate
hepatobiliary clearance. Twenty-five minutes after S2, 37 MBq of 201Tl were
reinjected at rest and SPET imaging (S3) was performed. Immediately after S3, 666
MBq of 99Tcm-tetrofosmin were reinjected and SPET imaging (S4) was performed 50
min later. Representative short and vertical long axis tomograms were divided
into 17 segments. Each segment was assessed using a 4-point scoring system. The
defect score was defined as the sum of each segmental score. The defect scores
for imaging at exercise were 14.3 +/- 11.4 for 201Tl at S1, 11.4 +/- 8 for 99Tcm
tetrofosmin at S1 and 9.7 +/-9.8 for 99Tcm-tetrofosmin at S2 (P < 0.01),
respectively. The washout rate of 99Tcm-tetrofosmin for the first hour was 15.5
+/- 7.3% and 11.8 +/- 7.7% (P < 0.01), respectively, for the normal and ischaemic
segments. The image quality of 201Tl at S1 was almost equivalent to that of 99Tcm
tetrofosmin at S1/S2. The overall sensitivity and specificity for the detection
of ischaemia was 94% and 82% for 201Tl at S1, 89% and 86% for 99Tcm-tetrofosmin
at S1, and 88% and 95% for 99Tcm-tetrofosmin at S2, respectively. The overall
accuracy was 86%, 88% and 92%, respectively. The myocardial viability score was
7.4 +/- 7.1 for 201Tl at S3 and 5.8 +/- 7.0 for 99Tcm-tetrofosmin at S4 (P <
0.01). The results indicate that the diagnostic accuracy of 99Tcm-tetrofosmin for
myocardial ischaemia is almost equivalent to that of 201Tl as assessed by dual
SPET imaging, and that the optimal imaging time for 99Tcm-tetrofosmin is within
10-35 min (S1) after exercise.
PMID- 9548196
TI - The role of 99Tcm-tetrofosmin myocardial perfusion scintigraphy in the assessment
of patients with previous myocardial infarction: a comparative study with 201Tl.
AB - The aim of this study was to determine the utility of 99Tcm-tetrofosmin cardiac
imaging in patients with previous myocardial infarction and with significant
coronary artery disease (CAD) compared with that of 201Tl cardiac imaging.
Sixteen patients (14 males, 2 females) were studied by same-day exercise-rest
99Tcm-tetrofosmin imaging and exercise, rest and reinjection 201Tl cardiac
imaging. For each study, semi-quantitative visual analysis was performed in 20
segments using a 4-point scale. The regional distribution and defect
reversibility with the two tracers were compared with the results of coronary
angiography. A total of 320 segments were analysed. There was a statistically
significant concordance between the numbers of fixed and reversible segments in
both studies in myocardial segments supplied by totally occluded coronary
arteries (Group 1), as well as in segments supplied by significantly stenosed
coronary vessels (Group 2). The exercise and rest uptake of both 99Tcm
tetrofosmin and 201Tl in myocardial segments supplied by totally occluded
coronary arteries with poor collateral flow was significantly lower compared with
segments supplied by totally occluded coronary arteries with efficient collateral
flow (P < or = 0.05). When the uptake of both tracers was analysed according to
each major vascular territory, the mean exercise and rest uptake grades of 99Tcm
tetrofosmin and 201Tl were similar. There was also no significant difference in
defect reversibility between the two tracers. Discordant results were observed in
the territory of the right coronary artery in Group 1 (mean exercise grade of
99Tcm-tetrofosmin = 2.26 +/- 0.7 and of 201Tl = 1.92 +/- 0.8; P < or = 0.001) and
in Group 2 (mean grade of 99Tcm-tetrofosmin = 0.79 +/- 0.65 and of 201Tl = 0.95
+/- 0.65; P < or = 0.05). The results of the present study indicate that the
overall diagnostic utility of 99Tcm-tetrofosmin in the identification of
individual stenosed vessels is comparable with 201Tl in both patients with
totally occluded coronary arteries and those with significantly stenosed vessels.
The regional distribution of both tracers was lower in myocardial segments
supplied by totally occluded coronary arteries with poor collateral flow.
PMID- 9548197
TI - Decreased myocardial accumulation of 123I-meta-iodobenzyl guanidine in
Parkinson's disease.
AB - The aim of this study was to evaluate 123I-meta-iodobenzyl guanidine (123I-MIBG)
myocardial scintigraphy in patients with Parkinson's disease as a way of
detecting cardiac sympathetic dysfunction, and comparing the stage of disease and
intensity of drug treatment with accumulation of 123I-MIBG. 123I-MIBG myocardial
scintigraphy was performed in 48 patients with Parkinson's disease and 25 control
subjects. In the planar imaging studies, the data acquisition matrix was 256 x
256 and the preset time was 5 min. The heart-to-mediastinum (H/M) average count
ratio was calculated for both early (15 min) and delayed (3-4 h) images after
123I-MIBG injection (111 MBq). The mean H/M ratio in patients with Parkinson's
disease was significantly lower than that in the controls (P < 0.0001).
Regardless of disease severity, intensity of anti-Parkinson treatment and the
presence or absence of orthostatic hypotension, the mean H/M ratios were always
low in the Parkinsonian patients. Parkinson's disease may result in a severe
abnormality of cardiac sympathetic function which has not been detected by
previous cardiovascular autonomic studies.
PMID- 9548198
TI - A dual-tracer method for studying intragastric distribution and gastric emptying
of solids and liquids in functional dyspepsia.
AB - Twenty-five patients with functional dyspepsia and 11 healthy controls matched
for age and sex were examined. The patients were divided into two groups:
patients with dysmotility-like symptoms and those with ulcer-like symptoms. In a
dual-tracer gastric emptying study, dysmotility-like and ulcer-like symptoms
could not be distinguished from each other on the basis of gastric emptying
times. The intragastric distribution and the solid lag time in dysmotility-like
dyspepsia differed significantly from those of the controls.
PMID- 9548199
TI - Age- and sex-related 99Tcm-DMSA renal uptake at 24 h in children with a normal
scintigram.
AB - We performed a retrospective study to determine the age- and sex-related normal
values of absolute 99Tcm-DMSA uptake at 24 h in children with normal kidneys. Of
the 576 scintigrams performed between 1993 and 1996, 136 (272 kidneys) were
classified as 'normal' by two independent observers on the basis of the presence
of a smooth cortical outline, the absence of cortical loss, relative uptake in
the range 45-55% and normal echographic parenchymal findings. The 136 scintigrams
were divided into eight groups based on the children's age: Group I, < 1 month (2
boys); Group II, 1-3 months (6 boys, 8 girls); Group III, 4-7 months (7 boys, 6
girls); Group IV, 8-12 months (8 boys, 8 girls); Group V, 13-24 months (14 boys,
4 girls); Group VI, 25-36 months (6 boys, 13 girls); Group VII, 37-120 months (13
boys, 19 girls); Group VIII, 121-180 months (8 boys, 10 girls). In contrast to
the results of Morris et al. using absolute 99Tcm-DMSA uptake at 4-6 h, we found
that combined left and right kidney uptake increased until age 8 months (Group I,
22.0 +/- 6.7%; Group II, 45.9 +/- 5.0%; Group III, 50.8 +/- 5.0%; Group IV, 56.9
+/- 8.5%; P = 0.019), after which it reached a plateau (Group V, 55.4 +/- 7.3%;
Group VI, 60.1 +/- 7.8%; Group VII, 62.0 +/- 5.0%; Group VIII, 62.4 +/- 6.3%).
Uptake at 24 h tended to be lower in the girls than in the boys, but this
difference was not significant.
PMID- 9548200
TI - Evaluation of renal function following treatment with extracorporeal shock wave
lithotripsy (ESWL): the use of whole-kidney, parenchymal and pelvic transit
times.
AB - The aim of this prospective study was to assess the efficacy of using whole
kidney, mean parenchymal and pelvic transit times to evaluate renal function
following treatment with extracorporeal shock wave lithotripsy (ESWL). Fifteen
patients were evaluated 24-48 h before and after ESWL therapy using 99Tcm-DTPA
renal scintigraphy. Using deconvolution analysis, whole-kidney, mean parenchymal
and pelvic transit times were calculated and the pre-ESWL values were compared
with the post-ESWL values. In both kidneys, there were no significant changes in
the glomerular filtration rate or relative renal uptake when compared with the
pre-ESWL values. The mean whole-kidney transit time of the tracer did not change
significantly during the post-ESWL period. In the treated kidney, the mean post
ESWL parenchymal transit time was significantly increased (P < 0.05), while the
mean pelvic transit time was significantly decreased (P < 0.05). In the untreated
kidney, there were no significant changes in any of these parameters. We conclude
that the dual use of parenchymal and pelvic transit times is more sensitive than
the mean whole-kidney transit time and other measures, such as glomerular
filtration rate and relative renal uptake, for the assessment of outcome of
therapy and other related post-ESWL changes.
PMID- 9548201
TI - Hybrid phantoms for testing the measurement of regional dynamics in dynamic renal
scintigraphy.
AB - A hybrid phantom is a synthetic dynamic scintigraphic study reconstructed from
dynamic components of real clinical data. The aim of a hybrid simulation is to
provide realistic reference studies with systematically varying quantitative
diagnostic parameters for testing the quality of measurement of regional
dynamics. The components of the phantom are extracted from a representative
patient study using factor analysis. Prior to the construction of the phantom,
selected components are modified in a known way or substituted with heterologous
data. The phantom study is constituted from the altered components using a
procedure inverse to factor analysis, and completed by the addition of residual
noise. The hybrid phantom is a compromise between simulated and software
phantoms. Unlike simulated phantoms, it preserves a significant part of data
variability and the natural complex structure of scintigraphic images. Unlike
software phantoms, it provides values for selected diagnostic parameters or
magnitudes of their relative changes. A set of hybrid phantoms from a dynamic
renal study and the results of a pilot clinical evaluation are presented.
PMID- 9548202
TI - 188Re(V)-DMSA revisited: preparation and biodistribution of a potential
radiotherapeutic agent with low kidney uptake.
AB - Methods of preparation and biodistribution in mice of tin-free 99Tcm(V)-DMSA and
188Re(V)-DMSA, a potential matching pair of radiopharmaceuticals for diagnosis
and therapy of certain cancers, are described. Preparation of tin-free 188Re(V)
DMSA (I) is based on reduction with either SO2-releasing compounds like Na2S2O4
(30 mg Na2S2O4, 10 mg DMSA, 1 mg L-ascorbic acid, 37 degrees C, 60 min
incubation), Na2S2O5 (as before, 70 degrees C, 15 min incubation), or HBr (0.2 ml
48% HBr, 0.2 ml 7 M HCl, 10 mg DMSA, 1 mg L-ascorbic acid, 70 degrees C, 60 min
incubation). I exhibits significantly lower kidney uptake than tin-containing
188Re(V)-DMSA (II) (2-3% and 49% injected dose per gram organ, 1 h post
injection, respectively). HPLC profiles of I and II are similar. DMSA excess in
tin-free 188Re(V)-DMSA is not responsible for the low kidney uptake of I. High
kidney uptake of II is explained by formation of a mixed 188Re(V)-Sn-DMSA complex
in vivo. Age-linked bone uptake in mice dependent on the maturation of the bone
is demonstrated for both I and II.
PMID- 9548203
TI - Salivary gland scintigraphy after radioiodine therapy.
PMID- 9548204
TI - In vivo function tests of hepatic drug-oxidizing capacity in patients with liver
disease.
AB - Aminopyrine, antipyrine and trimethadione have been widely used for some time as
probe drugs to assess non-selective P450 liver function. They have proved useful
in evaluating pre- and post-operative liver function when performing surgery,
transplantations, etc., in addition to a general evaluation of liver function and
drug interactions. Progress has recently been made both in these non-selective
P450 function tests and in the analysis of drug-metabolizing enzymes at a
molecular level, which has resulted in more selective P450 function tests. The
caffeine (CYP1 A2), chlorzoxazone (CYP2E1), lidocaine (CYP3 A) and midazolam
(CYP3 A) function tests and the erythromycin breath test (CYP3 A) are currently
being used as specific probes. The future use of these tests needs to be
discussed in terms of potential clinical implications.
PMID- 9548205
TI - Therapeutic advances: donepezil for the treatment of Alzheimer's disease.
AB - Until recently, few drugs have been available for the treatment of Alzheimer's
disease. The first such drug to be launched in the U.K. was the
acetylcholinesterase inhibitor, donepezil. The limited published data on
donepezil shows only modest cognitive benefit in patients with Alzheimer's
disease. The cost of diagnosis and drug treatment, the distressing nature of the
disease and the limited evidence available, pose difficult decisions for the
introduction of new drugs and the management of this condition.
PMID- 9548206
TI - Stability of refrigerated and frozen solutions of tropisetron in either
polyvinylchloride or polyolefin infusion bags.
AB - OBJECTIVE: To investigate the stability of 50 microg/ml tropisetron in 0.9%
sodium chloride or 5% dextrose injections on storage in either 100 ml
polyvinylchloride (Tuliflex) or polyolefin (Clear-flex) infusion bags, at +4
degrees C and -20 degrees C. METHOD: A stability-indicating high-performance
liquid chromatography (HPLC) assay was used to measure residual drug at day 0
(D0), D8, D15, D30, D60 and D90 for each bag. Samples were tested for pH at D0,
D60 and D90. Frozen samples were thawed in a microwave oven according to a
validated procedure before analysis. RESULTS: In 0.9% sodium chloride and 5%
dextrose, no degradation products were observed in any of the chromatograms. No
admixtures, at any time, contained less than 98.2% of the initial concentration.
Only minor changes (-0.12 unit) in pH occurred over the storage period. No colour
or other visual changes were seen in any sample. CONCLUSION: Tropisetron (50
microg/ml) in either 0.9% sodium chloride or 5% dextrose is chemically stable in
polyvinylchloride or polyolefin bags for at least 3 months when stored in a
refrigerator or in a frozen state.
PMID- 9548207
TI - Appropriateness of self-medication: method development and testing in urban
Indonesia.
AB - BACKGROUND: Most illness episodes are treated by self-medication, however, little
is known about the appropriateness of this self-medication. Moreover, tools to
evaluate the appropriateness of self-medication still need to be developed. In
order to monitor the use of drugs by the general public, we developed methodology
(for evaluation of the appropriateness of self-medication) that would be
reproducible and would therefore allow comparison over time and between regions.
METHOD: For each complaint, criteria for appropriate treatment were set, based on
evaluation of both the efficacy and the risks of the medications used. To keep
cost at a minimum and to ensure reproducibility, no use was made of expert
panels. Instead, only internationally recognized printed sources were used.
RESULTS: This study used data on self-medication collected in urban Indonesia in
1993. After excluding illness episodes first treated only with traditional drugs,
non-drug treatments or treated by a health worker, we found that self-medication
used as a first action was appropriate in 16% of the cases. Fifty-six per cent
combined appropriate and unnecessary components and 8% included unnecessary
components only. Sixteen per cent of treatments were considered potentially
harmful. Only 4.5% of the illness episodes were not treated. Analysis of these
potentially harmful treatments showed that over use of antihistamine in children
under 5 years of age, use of prescription drugs and multiple intake of
paracetamol or antihistamines in different medicines were the main problems. The
results of this analysis enabled us to set priorities and formulate
recommendations to rationalize the use of drugs in self-medication. CONCLUSION:
The proposed methodology should allow international comparisons and the
evaluation of the impact of future interventions.
PMID- 9548208
TI - A long-term comparison between enalapril and captopril on insulin sensitivity in
normotensive non-insulin dependent diabetic volunteers.
AB - BACKGROUND: There are conflicting reports about the effects of angiotensin
converting enzyme inhibitors on insulin sensitivity and glycaemic control. In
addition, the chronic effects of ACEI on insulin sensitivity in normotensive but
insulin resistant individuals have been controversial. AIM: To determine the long
term effects of low-dose captopril or enalapril on insulin sensitivity and lipid
parameters in normotensive non-insulin dependent diabetic volunteers. METHODS:
Twenty-eight normotensive non-insulin dependent diabetes mellitus subjects on
diet alone or diet plus oral hypoglycaemic agents were randomized in a single
blind cross-over study to receive either captopril (12.5 mg daily) or enalapril
(5 mg daily). Initially, captopril was compared with enalapril for 28 days with a
28-day washout period between drug regimens. For the long-term study, the
subjects then remained on the second ACEI for a further 11 months. Insulin
sensitivity was measured using the isoglycaemic hyperinsulinaemic clamp (insulin
infusion rate 20 mIU/kg/min) at the start and completion of each part of the
cross-over study and then at 3, 6 and 12 months of drug therapy. Fasting glucose,
insulin, HbA1, lipids and lipoproteins were measured at the start of each clamp.
RESULTS: No first or second order carry-over effects were demonstrated between
the ACEIs. No differences were detected between enalapril and captopril on
insulin sensitivity at any of the time points. Statistically significant
hypotension was avoided, and at doses used the ACEIs did not modify any
parameters of glycaemic control over the 12-month study period. There were no
significant alterations in plasma cholesterol, triglycerides, HDL cholesterol or
Apo A1 levels during the study. CONCLUSIONS: Long-term low-dose ACEIs
(captopril/enalapril) do not modify insulin sensitivity, glycaemic control or
lipids in normotensive non-insulin dependent diabetic subjects.
PMID- 9548209
TI - Improvements are needed in the existing packaging of medicated oils containing
methyl salicylate.
AB - In view of the toxic potential of medicated oils containing methyl salicylate, we
have studied the existing packaging of 10 commonly used preparations from Hong
Kong and Singapore and identified areas for improvement with respect to the
prevention of poisonings. They were all packed in translucent bottles without
child-resistant closures. The methyl salicylate content ranged from 15 to 67%.
Many preparations also contained other potentially toxic ingredients in
significant amounts, such as turpentine oil and camphor. The contents of the
larger bottles could generally be emptied more easily because of the greater size
of their openings. The product with the highest methyl salicylate content also
had the biggest opening of all. The threat from ingestion of medicated oils
containing methyl salicylate can probably be 'reduced' by: (i) using child
restraint closures; (ii) restricting the size of both the openings and the
bottles; and (iii) reducing the methyl salicylate content.
PMID- 9548210
TI - Study protocol: stability of morphine injected without preservative, delivered
with a disposable infusion device.
AB - BACKGROUND AND OBJECTIVE: Morphine hydrochloride, a major analgesic drug, is
being increasingly administered using portable disposable infusion devices. The
objective of this study was to investigate the stability of morphine in such a
system at two concentrations (2.50 and 5.00 mg/ ml) over a 30-day period. METHOD:
High-performance liquid chromatography of stored morphine solutions. RESULTS: The
best stability was observed with disposable infusion devices filled with a
morphine solution containing sodium metabisulphite as a preservative. No
breakdown products were detected after 1 month of storage at room temperature, in
light or darkness. On the other hand, 2.50 and 5.00 mg/ml morphine solutions
without sodium metabisulphite, stored in the infusion device led to the formation
of 0.205% and 0.235% of pseudomorphine, respectively, after 6 days of storage in
the light, and 1.50% and 0.94% after 30 days storage. CONCLUSION: Morphine
hydrochloride solutions stored in disposable infusion devices degraded very
slowly, particularly when preserved with sodium metabisulphite. The solutions are
stable over 5 days, the maximum period of storage normally required when using
disposable infusers.
PMID- 9548211
TI - A retrospective drug utilization evaluation of antihyperlipidaemic agents in a
medical centre in Taiwan.
AB - OBJECTIVE: The purpose of this study was to retrospectively evaluate the
prescribing of antihyperlipidaemic agents in an 800-bed medical centre in
southern Taiwan. METHODS: A retrospective study based on reviewing medical
records was conducted using a computerized database. We randomly selected 344
patients (age range 5-85 years) who received an antihyperlipidaemic agent between
1 April 1994 and 30 September 1994 and reviewed their medical records. All the
related data from the date when the antihyperlipidaemic agent was first
prescribed to 31 December 1994 was assessed. Usage guidelines for
antihyperlipidaemic agents were defined by referring to the literature and
specialist opinion. RESULTS: Two hundred and twenty-two patients (64.5%) were
treated with antihyperlipidaemic agents in accordance with the usage guidelines.
In addition, most of the treatments complied with the regulations laid down by
related health insurance programmes. The other 122 cases (35.5%) failed to meet
any of the indications of the usage guidelines. Only 102 patients (29.7%) had
their baseline lipid profiles examined and 117 patients (34%) had their baseline
liver function tested. Over all, very few cases had lipid profiles and liver
function tests every 3 months while taking antihyperlipidaemic agents. Patients
who had been prescribed antihyperlipidaemic agents for more than 1 year were
evaluated to assess the effectiveness of their pharmacological therapy. The
prescribed doses were found to be lower than recommended in the general
literature except for patients who received lovastatin and pravastatin.
CONCLUSIONS: There are many treatment guidelines for hypercholesterolaemia in
north America and Europe. This study revealed that a large proportion of
antihyperlipidaemic agents used in our patient population did not comply with
these general recommendations. Although the reasons for not complying with usage
guidelines need to be further investigated, our study findings may well serve as
the basis for further quality management and pharmacoeconomic analysis.
PMID- 9548212
TI - Topical sodium sulfacetamide/sulfur lotion.
PMID- 9548213
TI - Vesicular osmometers, vasopression secretion and aquaporin-4: a new mechanism for
osmoreception?
AB - This review cites new evidence suggesting a link between the recently discovered
membrane bound water-selective channel, aquaporin-4 (AQP4), and the mechanism of
central osmoreception. AQP4 is found in a number of brain regions associated with
the osmoregulation of vasopressin secretion and thirst, including the supraoptic
nucleus (SON) and subfornical organ (SFO). AQP4 expression is restricted to
ependymal cell membranes in the SFO and astrocyte membranes in the SON,
especially perivascular end foot processes, suggesting that glial cells may
correspond to Verney's hypothalamic 'vesicular osmometers'. Information on
osmotic status may thus be conveyed to the neuronal elements of the 'osmoreceptor
complex' by a neurone-glial interaction.
PMID- 9548214
TI - Ligand-inducible retinoid X receptor-mediated protein: DNA interactions in the
retinoic acid receptor beta2 gene promoter in vivo.
AB - Retinoid X receptors (RXRs) are recently characterized transcription factors that
are members of the nuclear hormone receptor superfamily. However, it is not known
whether the endogenous RXR complex requires its ligand for access to its hormone
response element (HRE) of a target gene in vivo. Hence, dimethyl sulfate-based
genomic footprinting was carried out to examine occupancy of HREs in the retinoic
acid (RA) receptor beta2 (RARbeta2) gene promoter in the murine melanoma cell
line S91 cultured in the absence or presence of T3, all-trans-RA (atRA), or
CD2624, an RXR-selective retinoid. No footprint was observed at the RA-response
element (betaRARE) in the absence of ligands. However, a footprint was detected
at the betaRARE and other cis-acting elements after a 6 h incubation with CD2624
and atRA. Interestingly, only the betaRARE was footprinted after 60 min
incubation with CD2624. These results suggest that the endogenous RXR complex can
interact with an HRE of a target gene in the presence of ligand, and subsequently
may initiate additional interactions between DNA and other transcription factors.
PMID- 9548215
TI - Ultrastructural and secretory heterogeneity of fa/fa (Zucker) rat islets.
AB - Many previous studies of obese rodents documented biochemical changes in
pancreatic islets that contribute to hyperinsulinemia in vivo. Those studies used
heterogeneous populations of islets, although the size of islets from obese rats
ranges from < 100 to > 500 microm. Here, functional and morphological changes in
size-sorted (< 125 and > 250 microm diameter) islets from obese Zucker (fa/fa)
rats were correlated. Ultrastructural examination revealed that > 250 microm
cultured islets had an increased number of immature secretory granules in the
beta cells. The number of degranulated beta cells in > 250 and < 125 microm
cultured islets from fa/fa rats was higher than in lean rat islets (33 vs 25%).
The glucose EC50 values for cultured islets were 4.64 +/- 0.43, 7.9 +/- 0.70 and
7.29 +/- 1.64 mmol.l(-1) for > 250 microm, < 125 microm, and lean groups,
respectively. Inhibition of insulin secretion by 10 mmol.l(-1) mannoheptulose was
reduced by 50% in > 250 microm islets compared with small islets. Studies of
individual beta cells by reverse hemolytic plaque assay revealed 3-fold more
cells from > 250 microm islets were stimulated by 1.4 mmol.l(-1) glucose than
cells from < 125 microm islets. We conclude that functional defects in mixed size
populations of islets from fa/fa rats are mainly due to alterations in the large
islets, whereas smaller islets have relatively normal function. Exposure to high
glucose exacerbates morphological and functional differences of large islets,
which could have important implications in the transition to noninsulin-dependent
diabetes when beta cell insulin production is unable to compensate for
hyperglycemia.
PMID- 9548216
TI - Age-related loss of calcitriol stimulation of phosphoinositide hydrolysis in rat
skeletal muscle.
AB - We have examined the effects in vitro of calcitriol [1,25(OH)2D3], the hormonal
form of vitamin D3, on the breakdown of membrane phosphoinositides in skeletal
muscle from young (3 months) and aged (24 months) rats. Calcitriol (10(-9) M)
induced a rapid and transient release of IP3/inositol phosphates and
diacylglycerol (DAG) from muscle slices/membranes prelabeled with [3H]myo
inositol and [3H]arachidonate, respectively. Inositol phosphate release was
maximal at 15 s and then declined. The effects of hormone specificity exhibited
as the closely related derivatives of vitamin D3, 25OHD3, 1alphaOHD3 and
24,25(OH)2D3 did not alter muscle inositol phosphate levels. The stimulation of
DAG was biphasic, the early phase (15 s) being abolished by neomycin (0.5 mM), an
inhibitor of phosphoinositide hydrolysis, similar to IP3 formation and consistent
with a role of phospholipase C (PLC) in intracellular signal generation. Neomycin
had no effect on the second DAG peak (2 min) induced by calcitriol, suggesting
that the late phase of DAG formation is independent from the hydrolysis of
phosphoinositides. Higher basal inositol phosphate and DAG levels were detected
in muscle from aged rats thereby reducing the effects of the hormone on second
messenger generation ( -80 and -60% for IP3 and DAG, respectively). Calcitriol
stimulation of PLC was mimicked, in both young and old rats, by GTPgammaS, a non
hydrolyzable analogue of GTP, while GDPbetaS, a G protein inhibitor, suppressed
the effect of the hormone. The early effects of calcitriol and GTPgammaS were not
additive. Bordetella pertussis toxin abolished by 85% the effects of calcitriol
on inositol phosphate release in young rats but was without effect in aged
animals. These results demonstrate that calcitriol activates phosphoinositide-PLC
in rat skeletal muscle by a mechanism which involves a pertussis-sensitive G
protein and that the effects of the hormone are altered with ageing.
PMID- 9548218
TI - Molecular cloning of a cDNA encoding molt-inhibiting hormone of the crab, Cancer
magister.
AB - A neuropeptide molt-inhibiting hormone (MIH) negatively regulates crustacean
molting glands (Y-organs). We report here the molecular cloning of a cDNA
encoding putative MIH of the Dungeness crab, Cancer magister. A cDNA library was
commercially prepared using poly (A+) RNA isolated from C. magister eyestalk
neural ganglia. The library was screened using as probe a previously cloned
portion of a cDNA encoding MIH of the blue crab, Callinectes sapidus. DNA
sequence analysis of one positive clone revealed a 339 base pair open reading
frame encoding a 78 amino acid putative MIH and a 35 amino acid signal peptide.
The deduced amino acid sequence of C. magister MIH shows high sequence identity
(80-98%) with MIH of three other brachyuran crabs, but lower identity (26-45%)
with MIH and MIH-like peptides from astacurans and shrimp. Studies using reverse
transcription-polymerase chain reaction (RT-PCR) indicate the MIH gene is
expressed in eyestalk but not control (muscle, gill, gonad, hepatopancreas)
tissue.
PMID- 9548217
TI - Ontogeny and epithelial-stromal interactions regulate IGF expression in the ovine
mammary gland.
AB - Although the insulin-like growth factors (IGF-I and -II) have been implicated in
the stimulation of mammogenesis, little is known of their regulation in the
mammary gland. In this study we removed epithelial tissue from one of the two
mammary glands of 1-week-old ewe lambs and examined IGF-I and -II mRNA expression
during postnatal development in both the intact mammary gland and in the gland
cleared of epithelial tissue. Expression of IGF-I mRNA was highest at 6 and 10
weeks of age, coincident with the prepubertal phase of rapid mammary growth, then
declined and remained low until expression increased during late pregnancy. IGF-I
mRNA was more abundant in the mammary fat pad adjacent to parenchyma (MFP) than
in the contralateral fat pad that had been surgically cleared of epithelium
(CFP). The level of IGF-II mRNA in parenchyma was highest at 1-23 weeks of age
due to an increase in the abundance of specific mRNAs. Expression was lower in
the fat pads, with generally higher levels in the intact MFP than the CFP, and in
these tissues IGF-II expression was shown to increase with age between 6 and 23
weeks. We also investigated the influence of the ovary and estrogen on the
expression of IGFs. While IGF-I mRNA abundance was unaffected by ovariectomy,
exogenous estrogen resulted in higher levels of expression in the MFP of
ovariectomized ewes and tended to increase its level in the parenchyma of intact
ewes. Ovariectomy increased IGF-II mRNA within mammary parenchyma whereas
estrogen suppressed levels in both the parenchyma and MFP. These findings
demonstrate that IGF-I and -II mRNAs are expressed locally within the developing
ovine mammary gland and are regulated by stage of ontogeny, ovarian hormones, and
epithelial stromal interaction.
PMID- 9548219
TI - Zinc chelation enhances thyroid hormone induction of growth hormone mRNA in GH3
cells.
AB - The effects of restriction and addition of zinc on thyroid hormone responsiveness
of the growth hormone gene were investigated in GH3, rat pituitary tumor cells.
Addition of diethylenetriaminepenta-acetic acid (DTPA), a membrane-impermeable
chelator, resulted in up to 10-fold increases in GH mRNA in the presence of 10 nM
T3, with half-maximal induction at 50 microM DTPA. Only minor effects were seen
in the absence of T3. Addition of zinc inhibited the stimulatory effect of DTPA
in a dose-dependent manner. Equimolar concentrations of other divalent cations
could not substitute for zinc, though inhibitions of the DTPA effect were
observed at higher concentrations. In the absence of DTPA, exogenous zinc (100
microM) inhibited T3-induced GH mRNA by approximately 33%. Addition of DTPA or
zinc did not affect T3 binding to its nuclear receptor. DTPA also enhanced the
stimulatory effect of dexamethasone on GH mRNA. The results demonstrate that
restricted zinc availability positively affects T3 induction of the GH gene in
GH3 cells.
PMID- 9548220
TI - Epilepsy and learning disabilities--a challenge for the next millennium?
AB - People with learning disabilities often have seizures in addition to other
disorders. Precise diagnosis may be difficult, but accuracy can be improved using
electroencephalographic and video investigations. Following the establishment of
a diagnosis of epilepsy, individually tailored care is necessary taking into
account other health, behavioural and therapeutic issues. Neuroimaging may
indicate a need for surgery which should not be automatically excluded as a
treatment option. Rational antiepileptic drug use is advised, with emphasis upon
the newer agents due to their better tolerance and ease of use. A programme of
regular review will prevent over-medicating. Drug therapy may be withdrawn in a
seizure-free patient. Realistic goals should be established for each individual
coupled with an optimistic approach to care. However, future developments require
a solid evidence base combined with rationality in all aspects of management. The
community learning disability epilepsy nurse specialist is the key health-care
professional who can ensure that a learning disabled individual with epilepsy is
able to take full advantage of all available services. Education, closer
collaboration and the mutual recognition of skills will ensure more cohesive and
comprehensive care for this disadvantaged patient population.
PMID- 9548221
TI - Amnesia in temporal lobectomy patients: historical perspective and review.
AB - Profound memory loss is a rare but serious complication of temporal-lobe surgery
for the relief of medically intractable epilepsy. This paper examines the
characteristics of the patients who have been reported to become amnesic
following temporal-lobe surgery over the last four decades. The critical role of
the hippocampi in memory function are implicated in autopsy studies and MRI
investigations, but these cases suggest that a range of memory impairments result
from bilateral hippocampal damage, rather than a pure amnesic syndrome in every
case. There is some evidence that bilateral structural hippocampal abnormalities
may not necessarily be associated with significant memory problems, if these
abnormalities have a developmental basis. However, whilst not necessarily
profound, any post-operative deterioration in memory function remains a
significant consideration in the presurgical evaluation of temporal-lobe epilepsy
patients.
PMID- 9548222
TI - Treatment of epilepsy following rejection of epilepsy surgery.
AB - Important progress has been made with the development of both surgical and
medicinal treatment of epilepsy but these two developments are rarely seen in a
common perspective. Today epilepsy surgery should be discussed with the patient
when a reasonable degree of pharmacoresistance has been established, and the
chances of an operation clearly outweigh its risks. At that time, there will
still be a number of pharmacological options. A study of 15 patients who were
evaluated for at least four years after surgery had been considered but rejected
after intensive monitoring, pharmacological pursuit was successful in eight, and
failed in seven. The successfully treated patients comprise three who became
seizure free, and one with isolated auras as the only persisting seizure type.
The successful regimens were highly individual, stretching from monotherapies to
one four-drug combination. The idea of presenting this small series is not to
promote or establish any therapeutic strategies and guidelines but, rather, to
draw attention to a neglected interface between surgical and medicinal
procedures, and to increase awareness that epilepsy therapy will still be most
successful when it is seen as a whole, and must not be split up into competing
ideologies. Concerns are not well founded that epilepsy surgery may be seen as
the last hope for pharmacoresistant patients, and that, if surgery is declined, a
loss of this hope may be intolerable to the patient.
PMID- 9548223
TI - Juvenile myoclonic epilepsy: clinical characteristics, treatment and prognosis in
a Norwegian population of patients.
AB - Forty-three patients with juvenile myoclonic epilepsy (JME) is presented. The
female to male ratio was 2.9:1. The patients answered a standardized
questionnaire pertaining to social situation, medical history, onset of epilepsy,
types and frequency of seizures, treatment, experienced control over seizures and
consequences of having epilepsy. Myoclonic jerks, which are the hallmark of the
condition, are often forgotten by the patients or not considered as epileptic
seizures. This could be one reason why JME still seems underdiagnosed. JME may
comprise absence, myoclonic and generalized tonic-clonic seizures (GTCS),
proposed to occur in age-related sequence. We found that absence seizures may
start after onset of other seizures. Our results confirm the need for medication
since, during the last year, only 7% were seizure free without medication. Of
patients on antiepileptic drugs (AEDs), 79.5% had no GTCS and 41% were seizure
free during the last year, which confirms a relatively good response to
appropriate treatment. Although most patients used AED daily and many still had
one or more types of epileptic seizure, the epilepsy in general had very little
impact on their lives.
PMID- 9548224
TI - Interictal quantitative EEG in epilepsy.
AB - The interictal EEG is often normal in epilepsy patients, particularly with
partial seizures of extratemporal origin. Quantitative techniques of EEG analysis
may increase the yield of diagnostic abnormality in such patients. Thirty
patients with partial seizures of frontal or temporal origin had EEG recorded
from left frontal (F7-C3), right frontal (F8-C4), left posterior (T5-O1), and
right posterior (T6-O2) derivations. Four-second epochs were used to compute
power in the delta (0.25-4.0 Hz), theta (4.25-8.0 Hz), alpha (8.25-13 Hz), and
beta (13.25-30 Hz) bands. The ratio of high (8.25-30 Hz) to low (0.25-8 Hz) power
on the left and the right was measured, as was the ratio between the left and the
right hemisphere total power. The mean frequency deviation in the alpha band
between the left and the right hemispheres was also measured, and spectral
mobility was determined in the right and the left frontal regions. These values
were also calculated in normal subjects and tension headache patients with normal
EEGs. Seizure patients with abnormal interictal EEGs had decreased ratios of high
to low power, greater asymmetry of total power and alpha frequency, and reduced
spectral mobility on the side of their EEG foci. Epileptics with normal
interictal EEGs had lower ratios of high to low power, greater alpha frequency
asymmetry, and lower spectral mobility than did headache patients or normal
controls. Power and frequency measurements, and determination of spectral
measures such as mobility, can be done with commercially available digital EEG
equipment. They may demonstrate otherwise obscure asymmetries in the interictal
EEG and thereby aid in epilepsy diagnosis and classification.
PMID- 9548225
TI - Clinical observations of juvenile myoclonic epilepsy in 131 patients: a study in
South India.
AB - We studied clinical features of 131 patients with juvenile myoclonic epilepsy
(JME). The prevalence was 7.7% among the epileptic patients registered. The mean
age at onset was 13.37+/-4.93 years and the diagnosis was established at a mean
age of 19.53+/-7.85 years. Absence seizures were reported by 27 (20.6%) patients,
myoclonic jerks by 131 (100%) and generalized tonic-clonic seizures (GTCS) by 111
(84.7%). The triad of absence seizures, myoclonic jerks and GTCS was noted in 23
(17.5%) patients, 88 (67.2%) had myoclonic jerks and GTCS, 4 (3%) had absence
seizures and myoclonic jerks and 16 (12.2%) had only myoclonic jerks. Early onset
absences were seen in 21 (16%) patients and the onset was late in 6 (4.6%).
Absences antedated other types of seizures in all the patients. Myoclonic jerks
were predominantly unilateral or had unilateral onset in 22 (16.8%). In 17 (13%)
patients GTCS antedated myoclonic jerks. Myoclonic jerks had characteristic
circadian distribution in 112 (85.5%) patients. On awakening GTCS occurred in 87
(78.4%) patients and in 4 (3.6%) patients they were purely nocturnal. Sleep
deprivation was the most important precipitating factor (54.2%). Initial
electroencephalogram (EEG) showed classical generalized spike or multiple-spike
slow-wave paroxysms in 81% of records. Focal EEG abnormalities were noted in
20.6% of records. The most common focal abnormality was voltage asymmetry. A
family history of epilepsy was noted in 31 (23.6%) probands. Diagnosis of JME was
made in all the cases in the clinic. The factors responsible for delay in
diagnosis of the 36 patients seen by neurologists included failure to ask or
interpret the history which was otherwise suggestive of myoclonic jerks in all 36
(100%) cases, the type of seizure for which the patients sought medical
attention, and misinterpretation of EEGs in 28 patients. Diagnosis of partial
epilepsy was made in seven patients. The factors responsible for such diagnoses
were, unilateral jerks in one patient, unilateral jerks and absence seizures in
three patients and focal EEG abnormalities in three patients.
PMID- 9548226
TI - Epilepsy, cerebral calcifications and clinical or subclinical coeliac disease.
Course and follow up with gluten-free diet.
AB - We have studied four patients (three male, one female, age range 15-25 years)
with epilepsy, bilateral occipital calcifications and latent coeliac disease
(CD). The epilepsy started at mean age 7 years, in three cases there were partial
seizures and in one case generalized seizure. Three cases had symptoms suggesting
malabsorptive syndrome during infancy and one case was diagnosed CD before the
onset of seizures. In all cases serologic markers of CD were found, especially
antiendomisium antibody, and intestinal biopsy indicated several grades of
atrophy. The electroencephalograph (EEG) findings pointed to focal abnormalities
in three patients and generalized abnormalities in one patient. In all cases
computer tomography (CT) showed bilateral, almost symmetrical occipital
calcifications in the cortical subcortical layers. The enhanced CT were
unremarkable and magnetic resonance images (MRI) were normal. After diagnosis of
CD, all patients followed a gluten-free diet and in three patients a significant
reduction in seizure frequency was observed. CD should be ruled out in all cases
of epilepsy, cerebral calcifications of unexplained origin and malabsorption
syndrome in infancy.
PMID- 9548227
TI - Gabapentin add-on therapy with adaptable dosages in 610 patients with partial
epilepsy: an open, observational study. The French Gabapentin Collaborative
Group.
AB - The objectives were to evaluate gabapentin add-on therapy in a large population
under conditions close to real practice and to determine the therapeutic doses as
reached with adaptable dosages. A 6-month multicentre, open-label study, involved
addition of gabapentin to pre-existing treatment at the initial dosage of 1200 mg
and subsequent adjustment between 900 and 2400 mg/day according to efficacy and
tolerability. A study group of 610 adult patients, with partial epilepsy,
persistent seizures and a median seizure frequency with a baseline of 7.2 per
month were recruited; one-third had less than four seizures per month.
Polypharmacy was frequent, with a mean of 2.3 concomitant drugs. After 6 months,
368 patients (62%) continued on gabapentin, at a mean dosage of 1739 mg/day with
44% of responders. On an intention-to-treat basis, median reduction in frequency
was 21.2%, and the responder rate was 33.9%. The responder rate increased to
40.7% in the less severe subgroup receiving only one concomitant drug. Seventy
nine patients (13.4%) remained without seizures during the last evaluation
period, versus nine (1.5%) during the baseline. Most of them had initially less
than four seizures per month. The most frequent adverse effects, somnolence
(29.3%), asthenia (14.6%), nausea (7.9%), ataxia (7.7%) and vertigo (7.2%),
occurred rapidly after initial titration to 1200 mg/day, and were usually
transitory. Weight gain (8.8%) seemed to be related to gabapentin dose. The
combination of two recent drugs, vigabatrin and gabapentin, in 190 patients led
to similar efficacy levels, with a tendency for more frequent somnolence and
asthenia.
PMID- 9548228
TI - Misdiagnosis and treatment in juvenile myoclonic epilepsy.
AB - Of 1300 epileptic patients 76 (5.8%) were found to have juvenile myoclonic
epilepsy (JME). These 76 patients were examined at the epilepsy outpatient clinic
of Bakirkoy State Hospital for Neurological and Psychiatric Diseases between 1991
and 1996 and data obtained were analysed retrospectively. Clinically typical
absence seizures were reported in 40.8%, myoclonic jerks in 100%, and generalized
tonic-clonic seizures in 82.9% of the patients. Neurological and mental
examination was normal for all patients with the exception of three cases; two
with essential tremor and one with minimal dysarthria. Precipitating factors were
noted in 85.5% of cases. Abnormal EEG was recorded in 73 (6.1%) patients.
Abnormalities mainly consisted of generalized discharges of spike/polyspike and
slow-wave (86.6%) and generalized paroxysmal theta or delta (9.2%). Fifteen
(19.7%) had focal abnormalities and 20 (26.4%) had photoconvulsive discharges. Of
the 76 patients, 40 (52.6%) were not diagnosed at the initial interview; definite
diagnosis was delayed by a mean of 5.9 years. As a result of misdiagnosis at the
initial interview 40 patients had been administered AED except for valproate.
After reassessment of clinical and EEG findings, the medication was changed to
valproate therapy. As a result, 65 of our JME patients (85.5%) were seizure free
after a one-year follow-up period.
PMID- 9548229
TI - Episodic nocturnal wandering and complex visual hallucination. A case with long
term follow-up.
AB - Episodic nocturnal wandering is rare and thought to be an atypical form of
nocturnal epilepsy which is responsive to anticonvulsant therapy. We report a
case of adult-onset episodic sleep-walking and daytime complex visual
hallucination. Ambulatory EEG recordings suggested that both events were ictal
phenomenon. Interictal sphenoidal EEG and SPECT studies revealed an epileptogenic
focus in the left anterior temporal lobe. During the nocturnal wanderings, the
patient had bizarre but non-violent behaviour, and was at risk of minor or severe
injury to himself. Both events were completely controlled by carbamazepine for a
follow-up period of 8 years. The present case further supports the notion that
episodic nocturnal wandering represents an unusual type of nocturnal complex
partial seizures.
PMID- 9548230
TI - Injury-induced physiological events that may modulate gene expression in neurons
and glia.
AB - Damage to the brain triggers a host of reactive responses in neurons and glia
which are seen at sites of focal injury as well as at sites that are at a
distance from the injury. Although many of these responses have been studied
extensively, the signals that initiate the different responses have not been
fully characterized, and it is still not understood how focal injury affects
neurons and glia in distant sites. The present review summarizes recent findings
that suggest that physiological events that occur at the time of the injury or
during the early postlesion period can play an important and variable role in
modulating neuronal and glial responses to injury. We focus on the events that
occur in the hippocampal formation following unilateral lesions of the entorhinal
cortex - a model system that has been used extensively for studies of cellular
responses following focal brain injury. This lesion destroys the cells of origin
of a massive excitatory projection to the dentate gyrus and hippocampus proper.
Over time, the denervated neurons in the hippocampal formation are almost
completely reinnervated as a result of local sprouting of systems that survive
the lesion. Thus, this model system has been useful for studying cellular
responses to both denervation and reinnervation. We summarize the information
that this injury triggers physiological events that can strongly modulate gene
expression in neurons and glia, including episodes of spreading depression that
occur at the time of the injury, seizures that occur during the early postlesion
period, the loss of afferent drive which leads to decreases in postsynaptic
activity, and the restoration of activity that occurs in conjunction with
reinnervation. We describe recent studies which suggest that some of these
physiological events occur to a variable extent in different animals, especially
the episodes of spreading depression and the recurrent seizures. Thus, the
spatial pattern and temporal dynamics of altered gene expression following this
"model" experimental injury may vary from animal to animal. The fact that
physiological events strongly modulate the reactive changes in gene expression
that occur following injury has important implications for understanding the
sequelae of injury, and offers new opportunities for experimental and therapeutic
interventions that may improve cellular repair, regeneration, and recovery of
function.
PMID- 9548231
TI - Two forms of hippocampal long-term depression, the counterpart of long-term
potentiation.
AB - In the hippocampus there are two distinct forms of long-term depression (LTD) of
excitatory synaptic transmission. In the CA1 region, prolonged low-frequency
stimulation induces LTD by activating postsynaptic NMDA receptors, which causes a
moderate rise in Ca2+ concentrations. In mossy fiber synapses of the CA3 region,
similar low-frequency stimulation also gives rise to LTD. However, this form of
LTD (mossy fiber LTD) does not require activation of NMDA receptors, but is
mediated by activation of presynaptic metabotropic glutamate receptors. Induction
of mossy fiber LTD is not dependent on postsynaptic depolarization or activation
of postsynaptic ionotropic glutamate receptors, thus it is likely to be mediated
by purely presynaptic mechanisms. This conclusion is confirmed by the analysis of
mutant mice lacking presynaptic mGluR2, in which mossy fiber LTD is almost
absent. Since long-term potentiation at mossy fiber synapses is also induced
presynaptically, the synaptic efficacy may be regulated through common mechanisms
bidirectionally, which may contribute to neural information processing in the
hippocampus.
PMID- 9548232
TI - The neuroregulatory properties of L-DOPA. A review of the evidence and potential
role in the treatment of Parkinson's disease.
AB - Accumulating evidence suggests that L-dihydroxyphenylalanine (L-DOPA) has
neurotransmitter-like and/or neuromodulatory properties in the CNS. Such evidence
is based on a wide range of findings including the existence of specific L
DOPAergic neurons in several regions of the CNS, neurotransmitter-like
characteristics and specific pharmacological effects. This review attempts to
outline the main evidence for this conception and to relate such findings to L
DOPA treatment effects in Parkinson's disease. In this context L-DOPA in itself
has been shown to potentiate D2 receptor-mediated effects, inhibit acetylcholine
release and increase the release of L-glutamate, neuropharmacological effects
which can be linked to treatment side-effects in advanced Parkinson's disease. It
is suggested that supersensitive L-DOPA-mediated effects contribute to the
pathogenesis underlying L-DOPA-induced motor complications in advanced
Parkinson's disease. However, since specific L-DOPA receptors have yet to be
identified, the assessment of the relative importance of L-DOPA-mediated effects
in this clinical context must be regarded as incomplete.
PMID- 9548233
TI - The basis of the neural organization for language: evidence from sign language
aphasia.
PMID- 9548234
TI - Apoptosis, neurotrophic factors and neurodegeneration.
AB - Apoptosis is an active process of cell death characterized by distinct
morphological features, and is often the end result of a genetic programme of
events, i.e. programmed cell death (PCD). There is growing evidence supporting a
role for apoptosis in some neurodegenerative diseases. This conclusion is based
on DNA fragmentation studies and findings of increased levels of pro-apoptotic
genes in human brain and in in vivo and in vitro model systems. Additionally,
there is some evidence for a loss of neurotrophin support in neurodegenerative
diseases. In Alzheimer's disease, in particular, there is strong evidence from
human brain studies, transgenic models and in vitro models to suggest that the
mode of nerve cell death is apoptotic. In this review we describe the evidence
implicating apoptosis in neurodegenerative diseases with a particular emphasis on
Alzheimer's disease.
PMID- 9548235
TI - Support for a pragmatic health minister.
PMID- 9548237
TI - Africa defends rights to indigenous knowledge.
PMID- 9548236
TI - Legal fight looms over patent bid on human/animal chimaeras.
PMID- 9548238
TI - Neuroscientist accused of misconduct turns on his accusers.
PMID- 9548239
TI - Scientists defy their ethics codes and take gifts from industry.
PMID- 9548240
TI - Ageing population of voters backs Alzheimer's funding.
PMID- 9548241
TI - Coalition to pursue ethnic concerns over gene research.
PMID- 9548242
TI - Scapegoat for fraud in Germany?
PMID- 9548243
TI - AIDS therapy in Brazil.
PMID- 9548244
TI - A sense of direction.
PMID- 9548245
TI - Molecular endocrinology. Steroids tickle cells inside and out.
PMID- 9548246
TI - Biomathematics. Merging lines and emerging levels.
PMID- 9548247
TI - Apoptosis. Phagocytic docking without shocking.
PMID- 9548248
TI - Domains of rasGAP and rhoGAP are related.
PMID- 9548249
TI - Support for shared ancestry of GAPs.
PMID- 9548250
TI - Meningitis bacterium is viable without endotoxin.
PMID- 9548251
TI - Speed perception fogs up as visibility drops.
PMID- 9548253
TI - Cerebellar complex spikes encode both destinations and errors in arm movements.
AB - Purkinje cells of the cerebellum discharge complex spikes, named after the
complexity of their waveforms, with a frequency of approximately 1 Hz during arm
movements. Despite the low frequency of firing, complex spikes have been proposed
to contribute to the initiation of arm movements or to the gradual improvement of
motor skills. Here we recorded the activity of Purkinje cells from the hemisphere
of cerebellar lobules IV-VI while trained monkeys made short-lasting reaching
movements (of approximately 200 milliseconds in duration) to touch a visual
target that appeared at a random location on a tangent screen. We examined the
relationship between complex-spike discharges and the absolute touch position,
and between complex-spike discharges and relative errors in touching the screen.
We used information theory to show that the complex spikes occurring at the
beginning of the reach movement encode the absolute destination of the reach, and
the complex spikes occurring at the end of the short-lasting movements encode the
relative errors. Thus, complex spikes convey multiple types of information,
consistent with the idea that they contribute both to the generation of movements
and to the gradual, long-term improvement of these movements.
PMID- 9548252
TI - Light-driven production of ATP catalysed by F0F1-ATP synthase in an artificial
photosynthetic membrane.
AB - Energy-transducing membranes of living organisms couple spontaneous to non
spontaneous processes through the intermediacy of protonmotive force (p.m.f.)--an
imbalance in electrochemical potential of protons across the membrane. In most
organisms, p.m.f. is generated by redox reactions that are either photochemically
driven, such as those in photosynthetic reaction centres, or intrinsically
spontaneous, such as those of oxidative phosphorylation in mitochondria.
Transmembrane proteins (such as the cytochromes and complexes I, III and IV in
the electron-transport chain in the inner mitochondrial membrane) couple the
redox reactions to proton translocation, thereby conserving a fraction of the
redox chemical potential as p.m.f. Many transducer proteins couple p.m.f. to the
performance of biochemical work, such as biochemical synthesis and mechanical and
transport processes. Recently, an artificial photosynthetic membrane was reported
in which a photocyclic process was used to transport protons across a liposomal
membrane, resulting in acidification of the liposome's internal volume. If
significant p.m.f. is generated in this system, then incorporating an appropriate
transducer into the liposomal bilayer should make it possible to drive a non
spontaneous chemical process. Here we report the incorporation of F0F1-ATP
synthase into liposomes containing the components of the proton-pumping
photocycle. Irradiation of this artificial membrane with visible light results in
the uncoupler- and inhibitor-sensitive synthesis of adenosine triphosphate (ATP)
against an ATP chemical potential of approximately 12 kcal mol(-1), with a
quantum yield of more than 7%. This system mimics the process by which
photosynthetic bacteria convert light energy into ATP chemical potential.
PMID- 9548254
TI - Synaptic vesicles retain their identity through the endocytic cycle.
AB - After fusion of synaptic vesicles with presynaptic membrane and secretion of the
contents of the vesicles into the synaptic cleft (a process known as exocytosis),
the vesicular membrane is retrieved by endocytosis (internalization) for re-use.
Several issues regarding endocytosis at central synapses are unresolved,
including the location of membrane retrieval (relative to the active zone, where
exocytosis occurs), the time course of various endocytic steps, and the recycling
path taken by newly endocytosed membranes. The classical model of synaptic
vesicle recycling, proposed by analogy to other cellular endocytic pathways,
involves retrieval of the membrane, fusion of the membrane with endosome-like
compartments and, finally, budding of new synaptic vesicles from endosomes,
although the endosomal station may not be obligatory. Here we test the classical
model by using the fluorescent membrane dye FM1-43 with quantitative fluorescence
microscopy. We find that the amount of dye per vesicle taken up by endocytosis
equals the amount of dye a vesicle releases on exocytosis; therefore, we conclude
that the internalized vesicles do not, as the classical picture suggests,
communicate with intermediate endosome-like compartments during the recycling
process.
PMID- 9548255
TI - C. elegans phagocytosis and cell-migration protein CED-5 is similar to human
DOCK180.
AB - During programmed cell death, cell corpses are rapidly engulfed. This engulfment
process involves the recognition and subsequent phagocytosis of cell corpses by
engulfing cells. How cell corpses are engulfed is largely unknown. Here we report
that ced-5, a gene that is required for cell-corpse engulfment in the nematode
Caenorhabditis elegans, encodes a protein that is similar to the human protein
DOCK180 and the Drosophila melanogaster protein Myoblast City (MBC), both of
which have been implicated in the extension of cell surfaces. ced-5 mutants are
defective not only in the engulfment of cell corpses but also in the migrations
of two specific gonadal cells, the distal tip cells. The expression of human
DOCK180 in C. elegans rescued the cell-migration defect of a ced-5 mutant. We
present evidence that ced-5 functions in engulfing cells during the engulfment of
cell corpses. We suggest that ced-5 acts in the extension of the surface of an
engulfing cell around a dying cell during programmed cell death. We name this new
family of proteins that function in the extension of cell surfaces the CDM (for
CED-5, DOCK180 and MBC) family.
PMID- 9548256
TI - Human CD14 mediates recognition and phagocytosis of apoptotic cells.
AB - Cells undergoing programmed cell death (apoptosis) are cleared rapidly in vivo by
phagocytes without inducing inflammation. Here we show that the
glycosylphosphatidylinositol-linked plasma-membrane glycoprotein CD14 on the
surface of human macrophages is important for the recognition and clearance of
apoptotic cells. CD14 can also act as a receptor that binds bacterial
lipopolysaccharide (LPS), triggering inflammatory responses. Overstimulation of
CD14 by LPS can cause the often fatal toxic-shock syndrome. Here we show that
apoptotic cells interact with CD14, triggering phagocytosis of the apoptotic
cells. This interaction depends on a region of CD14 that is identical to, or at
least closely associated with, a region known to bind LPS. However, apoptotic
cells, unlike LPS, do not provoke the release of pro-inflammatory cytokines from
macrophages. These results indicate that clearance of apoptotic cells is mediated
by a receptor whose interactions with 'non-self' components (LPS) and 'self'
components (apoptotic cells) produce distinct macrophage responses.
PMID- 9548257
TI - Inhibition of oxytocin receptor function by direct binding of progesterone.
AB - The steroid hormone progesterone (P4) is essential for establishing and
maintaining pregnancy in mammals. One of its functions includes maintenance of
uterine quiescence by decreasing uterine sensitivity to the uterotonic peptide
hormone oxytocin. Although it is generally held that steroid hormones such as P4
act at a genomic level by binding to nuclear receptors and modulating the
expression of specific target genes, we show here that the effect of P4 on
uterine sensitivity to oxytocin involves direct, non-genomic action of P4 on the
uterine oxytocin receptor (OTR), a member of the G-protein-coupled receptor
family. P4 inhibits oxytocin binding to OTR-containing membranes in vitro, binds
with high affinity to recombinant rat OTR expressed in CHO cells, and suppresses
oxytocin-induced inositol phosphate production and calcium mobilization. These
effects are highly steroid- and receptor-specific, because binding and signalling
functions of the closely related human OTR are not affected by P4 itself but by
the P4 metabolite 5beta-dihydroprogesterone. Our findings provide the first
evidence for a direct interaction between a steroid hormone and a G-protein
coupled receptor and define a new level of crosstalk between the peptide- and
steroid-hormone signalling pathways.
PMID- 9548258
TI - Fatty acyl-CoA thioesters are ligands of hepatic nuclear factor-4alpha.
AB - Dietary fatty acids specifically modulate the onset and progression of various
diseases, including cancer, atherogenesis, hyperlipidaemia, insulin resistances
and hypertension, as well as blood coagulability and fibrinolytic defects; their
effects depend on their chain length and degree of saturation. Hepatocyte nuclear
factor-4alpha (HNF-4alpha) is an orphan transcription factor of the superfamily
of nuclear receptors and controls the expression of genes that govern the
pathogenesis and course of some of these diseases. Here we show that long-chain
fatty acids directly modulate the transcriptional activity of HNF-4alpha by
binding as their acyl-CoA thioesters to the ligand-binding domain of HNF-4alpha.
This binding may shift the oligomeric-dimeric equilibrium of HNF-4alpha or may
modulate the affinity of HNF-4alpha for its cognate promoter element, resulting
in either activation or inhibition of HNF-4alpha transcriptional activity as a
function of chain length and the degree of saturation of the fatty acyl-CoA
ligands. In addition to their roles as substrates to yield energy, as an energy
store, or as constituents of membrane phospholipids, dietary fatty acids may
affect the course of a disease by modulating the expression of HNF-4alpha
controlled genes.
PMID- 9548259
TI - Dual function of the messenger RNA cap structure in poly(A)-tail-promoted
translation in yeast.
AB - The messenger RNA 3' poly(A) tail critically affects the initiation and control
of translation in eukaryotes. By analogy to elements involved in transcription
initiation, the poly(A) tail has been described as a 'translational enhancer'
that enhances the 'translational promoter' activity of the mRNA 5'-cap structure.
Elongation or shortening of the poly(A) tail regulates translation during
development. Here we show, using cell-free and in vivo translation analyses in
Saccharomyces cerevisiae, that the poly(A) tail can act as an independent
'translational promoter', delivering ribosomes to uncapped mRNAs even if their 5'
end is blocked. When mRNAs compete for ribosome binding, neither the cap
structure nor the poly(A) tail alone is enough to drive efficient translation,
but together they synergize and direct ribosome entry to the 5' end. The cap
structure both promotes ribosome recruitment, together with the poly(A) tail, and
tethers recruited ribosomes to the 5' end. Correct choice of translation
initiation codons and the function of translational regulators acting on the 5'
untranslated region are thus ensured by the functional interaction of the poly(A)
tail with the cap structure.
PMID- 9548260
TI - Interaction of polyadenylate-binding protein with the eIF4G homologue PAIP
enhances translation.
AB - In the initiation of translation in eukaryotes, binding of the small ribosomal
subunit to the messenger RNA results from recognition of the 5' cap structure
(m7GpppX) of the mRNA by the cap-binding complex eIF4F. eIF4F is itself a three
subunit complex comprising the cap-binding protein eIF4E, eIF4A, an ATP-dependent
RNA helicase, and eIF4G, which interacts with both eIF4A and eIF4E and enhances
cap binding by eIF4E. The mRNA 3' polyadenylate tail and the associated poly(A)
binding protein (PABP) also regulate translational initiation, probably by
interacting with the 5' end of the mRNA. In yeast and plants, PABP interacts with
eIF4G but no such interaction has been reported in mammalian cells. Here, we
describe a new human PABP-interacting protein, PAIP-I, whose sequence is similar
to the central portion of eIF4G and which interacts with eIF4A. Overexpression of
PAIP-1 in COS-7 cells stimulates translation, perhaps by providing a physical
link between the mRNA termini.
PMID- 9548261
TI - Signal transduction in hepatic stellate cells.
AB - Hepatic stellate cells (HSC) are presently regarded as one of the key cell types
involved in the progression of liver fibrosis and in the related
pathophysiological and clinical complications. Following acute or chronic liver
tissue damage, HSC undergo a process of activation towards a phenotype
characterised by increased proliferation, motility, contractility and synthesis
of extracellular matrix (ECM) components. Several factors have been shown to play
a key role in the promotion of the full-blown picture of activated HSC. These
include extensive changes in the composition and organisation of the ECM, the
secretion of several growth factors, cytokines, chemokines, products of oxidative
stress and other soluble factors. It is evident that each cellular response to
extracellular stimuli must be framed in a scenario where different forces
modulate one another and result in a prevalent biological effect. Along these
lines, the identification and characterisation of intracellular signalling
pathways activated by different stimuli in HSC represent a mandatory step. In
this review article we have made an attempt to summarise recent acquisitions to
our knowledge of the involvement of different intracellular signalling pathways
in key aspects of HSC biology.
PMID- 9548262
TI - Angiogenesis in hepatocellular carcinoma as evaluated by CD34
immunohistochemistry.
AB - To clarify the relationship between angiogenesis and hepatocarcinogenesis on
progression of hepatocellular carcinoma (HCC), we quantitatively evaluated
angiogenesis by CD34 immunohistochemistry in liver cirrhosis (LC), adenomatous
hyperplasia (AH), and HCC, and proliferative activity estimated by Ki-67
immunohistochemistry. Angiogenesis was evaluated by CD34 immunohistochemistry
using monoclonal antibody HPCA-2, and tumor proliferative activity was evaluated
using monoclonal antibody MIB-1. We used an image analysis system to assess the
microvessel density as the area percentage of the endothelial area. Angiogenesis
was generally observed in HCC and there was no significant difference among all
clinical stages and histological grades of HCC. On the other hand, the staining
of CD34 was partly observed in sinusoids of AH, although no positive staining was
seen in any sinusoids of LC. The proliferative activity was significantly
correlated with the clinical stage and histological grade of HCC. Our results
indicate that the quantitation of angiogenesis does not provide significant
prognostic information in HCC, but that it may have diagnostic value in
distinguishing HCC from non-HCC. Meanwhile, AH, which is not morphologically
diagnosed as cancer, shows positive staining for CD34, suggesting that some
portion of AH contains cancerous characteristics.
PMID- 9548263
TI - Regeneration of the hepatic nerves following surgical denervation of the liver in
dogs.
AB - This study was conducted to examine the regeneration process of hepatic nerves
following surgical hepatic denervation in dogs. A denervation model was
surgically created by removing all visible nerves around the hepatoduodenal
ligament along with the peri-hepatic tissues. The hepatic nerves were examined on
the hepatic specimens taken at 1 week, 1 month and 3 months post-denervation by
means of immunohistochemical staining, and also electron microscopy. At 1 week
post-denervation, the extrinsic hepatic nerves were observed not to have
regenerated. However, at 1 month post-denervation, GAP-43-positive nerves were
identified and regenerating axons were shown to be present on electron
microscopic observation. The immunoreactivity for anti-GAP-43 antibody was not
shown any longer at 3 months post-denervation, and the regenerated nerve axons
were shown to be similar to those at pre-denervation on ultrastructural study.
Results of the present study suggested that regeneration of the extrinsic hepatic
nerves began to appear about 1 month after the hepatic denervation, and was
completed by 3 months post-denervation.
PMID- 9548264
TI - Autonomic nervous system activity during infusion of L-arginine in patients with
liver cirrhosis.
AB - Patients with liver cirrhosis exhibit a hyperdynamic circulatory state as
evidenced by tachycardia and an increase in cardiac output accompanied by an
elevation of sympathetic tone. This condition is due to the excessive release of
nitric oxide (NO), an endogenous vasodilator, which is in turn related to the
abnormal induction of NO synthase. The present study investigated whether the
intravenous infusion of L-arginine, the precursor of NO, may cause a similar
hyperdynamic circulatory state. A new method, the analysis of power spectrum
heart rate variability, was used to evaluate autonomic nervous activity. Twenty
patients with liver cirrhosis underwent continuous Holter monitoring of the ECG
during the intravenous administration of L-arginine (10 g) (Fisher's solution)
infused over 60 min. Power spectral analysis was computed from 512 beats of the
Holter ECG data. Low frequency (LF; 0.04-0.15 Hz) and high frequency (HF; 0.15
0.40 Hz) spectral powers and the ratio of LF to HF (LF/HF) were calculated every
10 min before and after the infusion of L-arginine. The LF power, which reflects
sympathetic tone modified by vagal tone, and the LF/HF, an indicator of
sympathetic tone, were both significantly increased during the infusion (p<0.05).
HF power, an indicator of parasympathetic tone, showed no significant change in
the early stage of the infusion but was significantly increased in the late stage
(p<0.05). The administration of L-arginine thus led to an elevation of
sympathetic tone. Fisher's solution, which is administered to patients with
hepatic insufficiency, contains L-arginine, and may also produce a hyperdynamic
circulatory state as an adverse effect related to an elevation of the plasma
level of NO by L-arginine. The monitoring of such patients is thus indicated.
PMID- 9548265
TI - Hepatitis C virus genotypes: epidemiological and clinical associations. Benelux
Study Group on Treatment of Chronic Hepatitis C.
AB - In a cohort of 292 chronic hepatitis C patients living in the Benelux countries
the relationship between viral genotype and geographical origin, route of
transmission, clinical characteristics and severity of liver disease was
analyzed. HCV-RNA isolates could be classified by the Line Probe Assay (LiPA) as
1a, 1b, 2, 3, 4 or 5 in 286 (98%) cases. Patients of European origin were
predominantly infected with HCV subtype 1b (164/254, 65%, CI 58-70%), as were
patients of Asian origin (7/13, 54%). Patients originating from Surinam (South
America) had predominantly type 2 (9/10, 90%), whereas Africans were mainly
infected with type 4 (7/9, 77%). Blood transfusion was the mode of transmission
in 142 (50%) patients, intravenous drug abuse (IVDA) in 40 (14%), occupational
needle accident or tattoo in 11 (4%); no obvious source of infection was found in
93 (33%). In patients infected by blood transfusion, subtype 1b was predominant
(70%, CI 61-77%), whereas subtypes la and 3 were predominant in those infected by
IVDA (25% and 45%, respectively, p<0.001). Cirrhosis was observed in 68 (24%)
patients; in multivariate analysis, factors independently related to cirrhosis
were: the duration of infection, age and prior hepatitis B. No significant
relationship was found between the severity of fibrosis or liver inflammation and
the HCV (sub)types. In summary, in this large cohort of patients in the Benelux
countries the hepatitis C virus (sub)type present was clearly related to the
country of origin and the route of transmission, but not to the severity of liver
disease.
PMID- 9548266
TI - An endothelin receptor antagonist TAK-044 ameliorates carbon tetrachloride
induced acute liver injury and portal hypertension in rats.
AB - Hepatic levels of a powerful vasoconstrictor endothelin-1 (ET-1) and its
receptors increase in human and carbon tetrachloride (CCl4)-induced liver
cirrhosis. The aim of this study was to determine whether antagonism of hepatic
ET-1 receptors ameliorates CCl4-induced hepatic injury and portal hypertension in
rats. Acute liver injury was induced by a single intraperitoneal injection of
CCl4 (0.3 ml/kg), whereas cirrhosis and portal hypertension were induced by CCl4
treatment (0.15 ml/kg twice a week) for 8 weeks. Hepatic morphology, ET-1 and its
receptors, and portal venous pressures were determined. Increases in ET-1 and its
receptors occurred within 24 h of CCl4 administration, and progressively
thereafter during the development of cirrhosis. The acute CCl4-induced hepatic
injury was characterized by significant increases in portal pressure (from 8.7+/
1.8 to 17.6+/-3.3 mmHg; p<0.01) and serum levels of liver enzymes, as well as
massive hepatocellular necrosis (62+/-8%). Intravenous administration of an ET-1
receptor antagonist TAK-044 reduced portal pressure to 13.6+/-2.8 mmHg (p<0.05),
and ameliorated hepatocellular necrosis by about 35% (p<0.001). TAK-044 treatment
also produced significant reduction in serum levels of liver enzymes. In
cirrhotic rats, portal venous infusion of TAK-044 reduced portal hypertension by
about 40% (p<0.05). In conclusion, these results indicate involvement of ET-1 in
acute liver injury as well as portal hypertension associated with hepatic
cirrhosis, and a potential for ET-1 receptor antagonists in the treatment of
these pathologic conditions.
PMID- 9548267
TI - Hepatitis C associated with Guillain-Barre syndrome.
AB - Hepatitis C is frequently associated with immune-mediated diseases, such as
cryoglobulinemia. Guillain-Barre syndrome is an acute demyelinating neuropathy of
probable immune pathogenesis. We describe two patients with Guillain-Barre
syndrome, and associated chronic hepatitis C, the second one previously treated
with interferon. The link between both conditions may be hepatitis C being the
trigger of this immune polyneuropathy. Guillain-Barre syndrome should be added to
the list of conditions associated with hepatitis C.
PMID- 9548268
TI - Enhancement of albumin production by hepatocyte growth factor in rat hepatocytes:
distinction in mode of action from stimulation of DNA synthesis.
AB - Hepatocyte growth factor (HGF) has been shown to enhance albumin production as
well as stimulate DNA synthesis in hepatocytes. The mode of action of HGF in
exerting both effects is to be elucidated. We previously observed that hepatocyte
proliferation occurred in normal rats given recombinant human HGF (rhHGF)
intravenously. When rats received rhHGF similarly, serum albumin levels were
significantly increased compared to controls. In primary culture of rat
hepatocytes, albumin concentration in culture medium was significantly increased
by rhHGF added at 24 h of culture compared to controls, increasing with time of
culture. This effect of rhHGF was dose-related. When actinomycin D was added to
the medium, the albumin concentration was reduced in a dose-related manner, but
its enhancement by rhHGF was maintained. Albumin mRNA levels were not increased
by rhHGF. When rhHGF was added similarly to the medium, immunocytochemically
positive hepatocytes for 5-bromo-2'-deoxyuridine (BrdU) incorporation appeared 30
h later. Of these labeled hepatocytes, 12.5% were concomitantly stained for
albumin. In contrast, albumin-positive hepatocytes were seen in 77% of BrdU-non
labeled hepatocytes (p<0.01). We conclude that HGF may enhance albumin production
through post-transcriptional regulation in non-proliferating hepatocytes, but not
in proliferating hepatocytes.
PMID- 9548269
TI - Deferoxamine arrests in vitro the proliferation of porcine hepatocyte in G1 phase
of the cell cycle.
AB - Iron is required for cell proliferation of all living species. Moreover, iron
excess may be involved in the development of hepatocellular carcinoma. In this
study we analyzed the effects of deferoxamine, an iron chelator, on normal
porcine hepatocyte proliferation. We confirmed that hepatocytes isolated from
young pigs proliferate in the presence of insulin and fetal calf serum as shown
by [3H] methyl-thymidine incorporation, presence of mitotic figures and increase
in cell number. This was paralleled by nuclear expression of p34cdc2 and its
associated histone H1 kinase activity. In the presence of deferoxamine, [3H]
methyl-thymidine incorporation, expression of nuclear proteins (p34cdc2 and PCNA)
and H1 kinase activity were drastically reduced. In addition, in contrast with
control cultures, cells in S-phase were not detected by flow cytometry. These
data suggest that iron chelation by deferoxamine can arrest the progression of
porcine hepatocytes in the G1 phase of the cell cycle.
PMID- 9548270
TI - Fulminant hepatic failure associated with dicoumarol therapy.
AB - Coumarins have been associated with non-predictable hepatic injury. In the case
of dicoumarol, there is no hard evidence in the literature of a causal connection
with liver damage. We report the case of a 73-year-old woman who developed a
fatal liver disease of a mixed hepatocellular-cholestatic type after 3 months of
treatment with dicoumarol. A thorough diagnostic work-up did not reveal any other
possible cause of the liver disease.
PMID- 9548271
TI - Theoretical studies on the mobility-shift assay of protein-DNA complexes.
AB - The theory of mass transport coupled to reversible macromolecular interactions
under chemical kinetic control forms the basis for computer simulation of the
electrophoretic mobility-shift behavior of protein-DNA complexes. Model systems
include (i) specific binding of a univalent protein molecule to a single site on
the DNA molecule; (ii) the putative cage effect; (iii) cooperative binding to
multiple sites; (iv) formation of looped complexes of 1:1 and 2:1 stoichiometry;
(v) noncooperative and cooperative, nonspecific binding modes; and (vi) binding
of dimerizing transcriptional factors to response elements of target genes.
Favorable comparison of simulated with experimental mobility-shift behavior
indicates that the phenomenological mechanisms, whereby observed mobility-shift
patterns are generated during electrophoresis, are embodied in the theory. These
studies have provided guidelines for definitive interpretation of mobility-shift
assays and for the design of experiments to develop a detailed understanding of
the particular system under investigation.
PMID- 9548272
TI - Myoglobin intron variation in the Gouldian Finch Erythrura gouldiae assessed by
temperature gradient gel electrophoresis.
AB - In this study we show how the use of exon-primed, intron-crossing (EPIC)
polymerase chain reaction (PCR) of a diploid intronic region, in conjunction with
temperature gradient gel electrophoresis (TGGE), can be used to detect and
rapidly assess allelic variation at the nucleotide level. We developed passerine
specific primers to amplify and sequence a 762 bp region including the second
intron of the myoglobin gene in the Gouldian Finch, Erythrura gouldiae. A POLAND
plot based on this sequence indicated that TGGE in combination with heteroduplex
analysis (TGGE/HA) should reveal nucleotide variation in the 160 bp low-melting
domain. Sequencing of the entire fragment from 19 Er. gouldiae revealed five
nucleotide substitution differences within the low-melt domain, all of which
could be detected and differentiated by TGGE/HA, and an additional substitution
in a section of the high-melt domain which characterised another allele. A total
of 181 individuals from four populations were screened for these six alleles.
PMID- 9548273
TI - Nonradioactive sequence-tagged microsatellite site analyses: a method
transferable to the tropics.
AB - Utilization of existing isozyme analysis facilities to detect sequence-tagged
microsatellite site (STMS) polymorphism or any simple sequence repeat (SSR)
variation is described. Different parameters concerning the difficulties in
transferring molecular techniques to less sophisticated laboratory
infrastructures (i.e. tropical outstations) are discussed (e.g. reproducibility,
efficacy, precision). Nonradioactive STMS analysis is bound to foster
collaborative research between "biodiversity" and "biotechnology" centers.
PMID- 9548274
TI - Oligonucleotide DNA fingerprinting optimized to determine parentage in three
beetle species.
AB - Oligonucleotide fingerprinting was performed on three beetle species from
different families (Coleoptera: Staphylinidae: Aleochara curtula; Silphidae:
Nicrophorus vespilloides; Tenebrionidae: Blaps lethifera) to obtain detailed
information on parentage in mating systems. We report variations in the number of
hybridizing fragments for the different species depending on the combinations of
probes and restriction enzymes used. In addition to conventional multilocus
fingerprint patterns, we established a single locus system for A. curtula (GTG5;
HinfI) and described an oligolocus system in N. vespilloides (GATA4; HaeIII).
PMID- 9548275
TI - Development of standard reference materials for diagnosis of p53 mutations:
analysis by slab gel single strand conformation polymorphism.
AB - We have amplified by polymerase chain reaction (PCR) a 2.0 kbp region of the p53
gene containing exons 5--9 from seven cell lines reported in the literature to
contain the majority of mutations reported for this gene. Sequence analysis of
these products show that all seven cell lines contain mutations within the
mutational hot spots of the p53 gene. Six of the seven clones have single base
substitutions and the seventh has a single base deletion. We have analyzed the
seven p53 single point mutations by single strand conformation polymorphism
(SSCP) analysis using fluorescence slab gel electrophoresis (SG-SSCP).
Fluorescent-labeled PCR primers were used for amplification of specific exons for
mutation detection. SG-SSCP was conducted using Model 373 and Model 377 DNA
sequencers with GeneScan Software (Perkin Elmer, Applied Biosystem Division).
Nine different gel systems were first tested for their ability to resolve the p53
mutations using the Model 373 instrument. Two gel systems were capable of
resolving all of the mutations that were screened. Optimal results were obtained
with 12% w/v acrylamide 50:1 plus 10% v/v glycerol. This gel system was used to
evaluate the effect of temperature on the ability to resolve the mutations. The
separation with respect to wild type varied for each mutation examined.
Subambient temperature (20 degrees C) was preferable overall for discrimination
of these mutations as a group. We intend to use this system to examine a much
larger panel of p53 mutation standards that are now under development.
PMID- 9548276
TI - Detection of p53 point mutations by single strand conformation polymorphism:
analysis by capillary electrophoresis.
AB - We have analyzed five p53 single point mutations by single strand conformation
polymorphism using capillary electrophoresis (CE-SSCP) and have compared these
measurements to measurements obtained by slab gel electrophoresis (SG-SSCP). PCR
primers were used for amplification of specific exons for mutation detection. 5'
Primers were labeled with FAM (5-carboxyfluorescein) and 3' primers were labeled
with JOE (2',7'-dimethoxy-4',5'-dichloro-6-carboxyfluorescein). CE-SSCP was
performed using the Perkin Elmer ABI PRISM 310 Genetic Analyzer with GeneScan
Software and the Beckman P/ACE 5510 CE equipped for laser-induced fluorescence
detection. Although the shifts in migration times for the p53 mutations relative
to the corresponding wild-type strands could be successfully detected by either
SG or CE analysis, the individual electrophoresis run times were about tenfold
faster and more automated with capillary electrophoresis. The CE-SSCP
measurements were performed at temperatures ranging from 10 to 60 degrees C on a
prototype instrument. For mutations measured at ambient temperature (25 degrees
C), characteristic shifts in direction and magnitude were observed in the
migration times of both strands of all mutations relative to the wild type. This
demonstrated the ability of CE at ambient temperature to resolve these mutations.
However, the magnitude and direction of shifts in migration time varied with
temperature in a discrete pattern for each mutation and resulted in a temperature
specific profile for each mutation. This demonstrated that extended temperature
control will be an important advantage in resolving single point mutations by CE
SSCP. In addition, by using CE, discrete intra-strand isoforms could be easily
observed at different temperatures. The combination of mutation-specific
temperature profiling and analysis of isoforms by CE-SSCP should be of help to
the diagnostic community in the detection of genetic mutations.
PMID- 9548277
TI - Amperometric pH regulation--a flexible tool for rapid and precise temporal
control over the pH of an electrolyte solution.
AB - Temporal control over both pH and ionic strength of an electrolyte solution with
high accuracy was achieved with a dynamic, computer feedback-controlled
amperometric pH-stat device consisting of four pH-regulating electrodes placed in
electrolyte reservoirs that are separated by dialysis membranes from a central
compartment. Theoretical predictions of the behavior of this arrangement,
obtained by computer simulation, were validated by running temporal pH programs
such as step functions, oscillations, and linear pH gradients. Deviations from
nominal values given by the computer program are within the limits of accuracy of
the pH-measuring electrodes. No volume changes accompany a change of pH or
conductivity since ions are forced to leave or enter the central compartment
through the membranes by the electrical force applied between the pH-regulating
electrodes. The device is flexible, easy to use and easily miniaturized. We
discuss a wide range of possible applications in biochemistry and cell science.
These include automated pH adjustment, isoelectric protein separation,
amperometric measurement of enzyme kinetics and the response of cell cultures to
well-defined pH changes.
PMID- 9548278
TI - Can amphoteric substances with very small (or negative) deltapK difference exist
and what properties would their water solutions exhibit?
AB - For calculating the buffer capacity of ampholytes an application of the stepwise
and parallel dissociation models is considered. It is demonstrated that the
scheme with stepwise dissociation possesses a "nonadditive" sum, i.e., the
resulting buffer capacity of the system exceeds the sum of the separate
contributions of the two ionogenic groups. On the other hand, the scheme of
parallel dissociation is free from this disadvantage, and thus does not impose
any restriction on the deltapK parameter.
PMID- 9548279
TI - Isotachophoresis at pH extremes: theory and experimental validation.
AB - The evolution of an isotachophoresis (ITP) system in acidic or basic pH ranges
can be quite different from that predicted by the existing theory. It was found
theoretically and proved experimentally that the contribution of hydrogen or
hydroxyl ion to conductivity of solution and/or its net charge changes the
behavior of the ITP system, creating in the terminating electrolyte an additional
zone close to the initial interfaces between electrolytes (leader and
terminator). One boundary of the zone, being either sharp or dispersed, moves
toward the leader; the other is always sharp and stationary and coincides with
initial electrolytes' discontinuity. The latter can be registered in the presence
of electroosmotic flow which delivers it to the detection point. In order to
describe the dynamics of the ITP system at pH extremes an algorithm of analytical
solution was developed, based on the revised Kohlrausch theory. Its predictions
coincide well with computer simulations and experimental data. The results
presented can help in a correct analysis of ITP data and explain some confusing
phenomena which were considered to be artifacts.
PMID- 9548280
TI - Enhanced detection sensitivity of "fluorescence reduction" by shifting the
analyte absorbance spectrum and use of a fluorescent paper with higher
signal/noise ratio.
AB - Nonfluorescing protein bands can be detected by the fluorescence optics of the
commercial gel electrophoresis apparatus with automated scanning of the migration
path (HPGE-1000, LabIntelligence, Belmont CA), taking advantage of the decrease
of emission from a fluorescent paper placed below the gel by the absorbance of
proteins ("fluorescence reduction"). That decrease of fluorescence gives rise to
an inverted protein peak. Nonfluorescent colorless proteins appear to reduce the
intensity of light emitted from the fluorescent paper due to absorbance of
incident and emitted light. When the absorbance spectrum only slightly overlaps
with the excitation and emission spectra of the fluorescent paper, that reduction
is weak, and detection sensitivity in that application is consequently only 1/30
of that of fluorescent proteins. By contrast, when the protein is colored so that
its absorbance spectrum overlaps widely with the excitation and emission spectra
of the fluorescent paper, the sensitivity of "fluorescence reduction" equals 1/4
to 1/5 of that obtained for fluorescent proteins. Bands detected by "fluorescence
reduction" provide a quantitative measure of protein load and mobility. The area
of the inverted bands is proportional to protein loads up to 16 microg/lane of
the gel tray. A theory of "fluorescence reduction" is presented which accounts
for the existence of a linear relationship between band area and load.
PMID- 9548281
TI - Activity staining on polyacrylamide gels of trypsin inhibitors from leaves of
sweet potato (Ipomoea batatas L. Lam) varieties.
AB - The failure of activity staining of trypsin inhibitors in crude leaf extracts of
sweet potato varieties including Tainong 27, Tainong 34, and Tainong 57 on a 15%
sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gel was
prevented by dipping the gels in solutions containing 10-40 mM hydrogen peroxide,
10 mM Tris buffer (pH 7.9) for 30 min before staining.
PMID- 9548282
TI - Electrophoretic applications of phycobiliproteins.
AB - Phycobiliproteins are homologous chromoproteins which constitute the
phycobilisomes, the light harvesting complexes of the photosynthetic apparatus in
cyanobacteria, rhodophyta and cryptophyta. In the present work, phycocyanin (PC)
and phycoerythrin (PE) from a Nostoc species are proposed as protein markers for
electrophoretic techniques. Phycocyanin is a blue-colored phycobiliprotein; it
carries phycocyanobilin as chromophoric group and is composed of two subunits,
alpha and beta, with Mr of 14000 and 17000, respectively. In contrast, the PE
subunits, having a similar Mr of 21000, are deep rose chromoproteins and carry
phycoerythrobilin residues. Both low molecular weight phycobiliproteins are also
suitable for monitoring protein blotting and the focusing time of protein samples
during isoelectric focusing as internal markers. The PE subunits which form a
single broad band after sodium dodecyl sulfate-polyacrylamide gel electrophoresis
have different isoelectric points, and they form two visible bands when they
reach their isoelectric point. The phycobilisomes constitute up to 50% of the
total protein in cyanobacteria and their content in PC or PE can be up- or down
regulated by using different light conditions (chromatic adaptation).
PMID- 9548283
TI - Elution of glycoproteins from replicas of sodium dodecyl sulfate-polyacrylamide
gel electrophoresis gels.
AB - A method for the elution of glycoproteins from sodium dodecyl sulfate
polyacrylamide gel electrophoresis (SDS-PAGE) replicas of gels on polyvinylidene
difluoride (PVDF) membranes is described. Ten model glycoproteins were resolved
by SDS-PAGE and then electrotransferred onto PVDF membranes. After reversible
staining, glycoprotein bands were eluted with a mixture of SDS/Triton X-100 at pH
9 or with a mixture of guanidinium hydrochloride/lysophosphatidylcholine at
neutral pH. For both types of eluents, the final recoveries ranged from over 30%
to about 80%. Good recoveries and mild conditions of elution render the method
applicable for the structural elucidation of glycan chains.
PMID- 9548284
TI - Separation of 4-color DNA sequencing extension products in noncovalently coated
capillaries using low viscosity polymer solutions.
AB - A low viscosity (ca. 75cP) solution using polydimethylacrylamide (PDMA) was
developed for separating DNA sequencing extension products by capillary
electrophoresis (CE). This medium gave a length-of-read (LOR) value of
approximately 600 bases in about 2 h using four-color sequencing in 50 microm
capillary at 42 degrees C under a field of 160 V/cm. This medium also works in
bare capillaries by noncovalently coating the surface to suppress both
electroosmotic flow (EOF) and DNA-capillary wall interactions, and eliminates the
need for complicated covalent coatings. At least 100 successive sequencing runs
were performed in the same capillary by simply pumping fresh medium after every
run, without requiring any reconditioning of the capillary surface between runs.
The thermal stability of the noncovalent coating can be improved by adding small
amounts of high molecular weight PDMA to the separation medium. The advantages of
low viscosity separation media and uncoated capillaries are of paramount
importance to develop high-throughput instruments for DNA sequencing.
PMID- 9548285
TI - Viscosity-adjustable block copolymer for DNA separation by capillary
electrophoresis.
AB - The viscosity-adjustable property of F127 block copolymer PEO99PPO69PEO99, PEO
and PPO being poly(ethylene oxide) and poly(propylene oxide), respectively, was
found to be useful for the development of automated capillary electrophoresis
(CE). The polymer solution can form a gel-like structure with sieving ability and
can also serve as a dynamic coating material, thereby effectively suppressing the
electroosmotic flow induced by the ionization of the silanol group on the quartz
capillary inner wall. When applied to CE as a separation medium, F127 block
copolymer can provide the advantages of high separation resolution, easy
injection and replacement of the triblock copolymer solution and convenient
capillary column treatment. High reproducibility of DNA electrophoretic migration
time in CE by replenishing F127 solution in acid-washed capillary tubings can be
achieved. The relative standard deviation of the DNA migration time is less than
2%. In the investigation of F127 concentration and temperature effects on the
performance of DNA separation in CE, we have found that the DNA electrophoretic
migration behavior in the F127 gel-like solution cannot be described by any one
of the existing models.
PMID- 9548286
TI - Characterization of high molecular mass linear polyacrylamide powder prepared by
emulsion polymerization as a replaceable polymer matrix for DNA sequencing by
capillary electrophoresis.
AB - In a previous paper, a 2% w/w replaceable high molecular mass linear
polyacrylamide solution (high molecular mass LPA) was used to achieve long read
lengths for DNA sequencing by capillary electrophoresis (E. Carrilho et al.,
Anal. Chem. 1996, 68, 3305-3313). In that work, the polymer was prepared by
polymerization in water at 6% w/w, followed by dilution to 2% w/w. In this study,
an improved method for preparation of high molecular mass LPA was developed,
based on inverse emulsion polymerization. With this polymerization procedure, the
LPA results in a molecular mass of approximately 9 MDa, with characteristics of a
fine powder of high purity and practically unlimited shelf life. Using size
exclusion chromatography (SEC) and viscosity measurements to characterize the
polymer, good batch-to-batch reproducibility was found. It was observed that the
viscous polymer solutions made from these high molecular mass polymers require
careful preparation and handling because the method of dissolution could affect
the molecular mass distribution and the resultant separation of DNA components.
Solutions containing 2% w/w of LPA made by emulsion polymerization were simple to
prepare, resulting in excellent performance as a replaceable matrix for DNA
sequencing by capillary electrophoresis. The viscosity of the polymer decreased
exponentially when pressure was applied, allowing easy replacement from a
capillary using a syringe. With a properly prepared matrix, a read-length of more
than 1000 bases in 80 min with an accuracy better than 97%, and better than 99%
for the first 800 bases, could be achieved.
PMID- 9548287
TI - Fast detection of a (CA)18 microsatellite repeat in the IgE receptor gene by
capillary electrophoresis with laser-induced fluorescence detection.
AB - The optimum separation conditions of polymerase chain reaction (PCR) products
have been found for high-speed capillary electrophoresis (CE) with laser-induced
fluorescence (LIF) detection. DNA fragments obtained after PCR amplification of
the region covering the (CA)18 microsatellite repeat in nitron 5 of the gene for
FcERIbeta, a high affinity glycoprotein receptor for IgE, located on chromosome
11 (11q13), were analyzed with the aim of investigating the repeat polymorphism.
The results of polyacrylamide slab gel electrophoresis (PAGE), agarose gel
electrophoresis, CE with absorbance detector and CE with LIF are compared. The CE
with LIF proved to shorten analysis time by a factor of 100 when compared to slab
gel electrophoresis. CE-LIF utilizes a short capillary with an effective length
of 6.3 cm and electric field strength from 100 to 550 V/cm. The respective PCR
products of sizes from 116 to 210 base pairs (bp) were analyzed in 3 min.
PMID- 9548288
TI - Forensic validation of the short tandem repeat HUMACTBP2 using capillary
electrophoresis.
AB - Experiments were performed to evaluate the forensic identification of the short
tandem repeat (STR) HUMACTBP2 (human beta-actin-related pseudogene) using
automated fluorescence-based capillary electrophoresis. The HUMACTBP2 is a
complex tetranucleotide STR locus with more than 32 alleles in the range of 202
323 bp. The reproducibility of genetic typing using a fluorescent labeled allelic
ladder was determined by comparison of the calculated fragment size after
consecutive (within-day) and nonconsecutive (day to day) injection. The maximum
variation in size (window) observed for any allele was 0.23 bp for the within-day
and 0.8 bp for the day-to-day precision. Furthermore, it is possible to achieve a
1 bp resolution, the precision of the reproducibility assays being about 99.95%.
Sixty blood samples and twenty stains were typed with both automated fluorescent
sequencer ABI 373A and ABI 310. Identical genotypes were obtained with both
techniques and the ABI 310 seemed to be more sensitive than the ABI 373A. A
population sample of 197 unrelated individuals from southwest Switzerland was
analyzed and the genotype frequencies observed were similar to those reported by
others. Thirty-one alleles and 126 genotypes were found. The observed
heterozygosity was 0.934. Mixtures from two different blood samples varying in
their ratio were typed and the minor fraction was detectable to about 1:10. The
practical usefulness of the HUMACTBP2 is illustrated by analyzing casework
samples. This validation study proves the usefulness of the HUMACTBP2 locus in
forensics and the detection efficiency using fluorescent capillary
electrophoresis.
PMID- 9548289
TI - Capillary electrophoresis of peptides and proteins in fused-silica capillaries
coated with derivatized polystyrene nanoparticles.
AB - High-resolution capillary electrophoretic separation of proteins and peptides was
achieved by coating the inner wall of 75 microm ID fused-silica capillaries with
40-140 nm polystyrene particles which have been derivatized with alpha-omega
diamines such as ethylenediamine or 1,10-diaminodecane. A stable and irreversibly
adsorbed coating was obtained upon deprotonation of the capillary surface with
aqueous sodium hydroxide and subsequent flushing with a suspension of the
positively charged particles. At pH 3.1, the detrimental adsorption of proteins
to the capillary inner wall was suppressed efficiently because of electrostatic
repulsion of the positively charged proteins from the positively charged coating
which enabled protein separations with maximum efficiencies of 400000 plates per
meter. A substantial improvement of separation efficiency in particle-coated
capillaries was observed after in-column derivatization of amino functionalities
with 2,3-epoxy-l-propanol, resulting in a more hydrophilic coating. Five basic
and four acidic proteins could be separated in less than 7 min with efficiencies
up to 1900000 theoretical plates per meter. Finally, coated capillaries were
applied to the high-resolution analysis of protein glycoforms and bioactive
peptides.
PMID- 9548290
TI - Selenium speciation by interfacing capillary electrophoresis with inductively
coupled plasma-mass spectrometry.
AB - The high resolution potential of capillary electrophoresis (CE) makes CE
techniques valuable for separations of selenium species. Further, inductively
coupled plasma-mass spectrometry (ICP-MS) affords element-specific multi-element
detection, providing extremely low detection limits. The combination of CE with
ICP-MS promises to become a powerful tool for metal speciation. Therefore, an on
line hyphenation of CE with ICP-MS, which was developed earlier (Michalke, B.,
Schramel, P., Fresenius' J. Anal. Chem. 1997, 257, 594-599), was modified and
applied to selenium speciation. For this reason, capillary zone electrophoresis
(CZE) methods were developed, providing the possibility to analyze six Se species
of interest in one run: Se (IV), Se (VI), selenium carrying glutathione (GSSeSG),
selenomethionine (SeM), selenocystine (SeC), and selenocystamine (SeCM). The
final CE method used an alkaline background electrolyte (Na2CO3/NaOH) with
separation differentiated from the detection step during hyphenation. This
resulted in short separation times (10 min) and a subsequent detection step of
100s. The Se species were sufficiently separated from each other and appeared at
7s (SeCM), 16s (Se [VI]), 22s [SeC], 27s (Se [IV]), 35s [SeM] and 56s (GSSeSG)
during the detection step. Detection limits were calculated as 10 or 20 microg
Se/L for inorganic Se species and 35-50 microg Se/L for organic Se species.
PMID- 9548291
TI - Methods for determination of electrophoretic mobility and stability of complexes
originating in solutions during the chiral discrimination process.
AB - An equation for the calculation of electrophoretic mobility of kinetically labile
complexes originating in solutions during the chiral discrimination process is
derived. The mobility of the complex is calculated from that of a fully ionized
racemic compound, measured in absence of the chiral selector, and from the
effective mobilities of its enantiomers, corresponding to the concentration of
the chiral selector causing their maximum difference. Correct values of
stoichiometric stability constants of both enantiomers may be calculated from the
mobility of the complex obtained in this way. Both the mobility and the stability
values hold only for the experimental conditions used and the selected background
electrolyte. The proposed method is demonstrated for the separation of the fully
ionized N-t-BOC-DL-tryptophan with beta-cyclodextrin in 20 mM aqueous solution of
alpha-hydroxyisobutyric acid, adjusted with NaOH to pH 4.5. Mobility of the
complex is 8.4 X 10(-9) m2V[-1]s(-1) at 25 degrees C. The stability constants of
D- and L-enantiomers of N-t-BOC-DL-tryptophan with beta-cyclodextrin, KD and KL
obtained from migration data using this mobility of the complex, are 374+/-37 M(
1) and 336+/-31 M(-1), respectively. The geometrical mean value of calculated
stability constants, 355 M(-1), agrees perfectly with the value of 350 M(-1),
calculated from the same experimental data by another procedure recently.
PMID- 9548292
TI - Stereoselective interaction of drug enantiomers with human serum transferrin in
capillary zone electrophoresis (II).
AB - Further studies on chiral resolution of drugs with different chemical structures
by capillary zone electrophoresis using iron-free human serum transferrin are
described. The substances passed a highly concentrated pseudo-stationary protein
zone applied in a coated capillary and the possible chiral separation of the
optical isomers was followed. Eighteen drugs with different structures were
screened, and the enantiomers of clofedanol, buphenine, acebutolol and
chlorphenamine were resolved. Several, but not all drugs, showed longer migration
times while passing the protein zone, indicating an interaction with transferrin,
although chiral resolution was not observed in all cases. The observations
provided further information about the properties of the surface interaction
sites of transferrin.
PMID- 9548293
TI - Separation of cis/trans conformers of human and salmon calcitonin by low
temperature capillary electrophoresis.
AB - Conformer-specific recognition of peptides and proteins has often been proved
with the aid of indirect methods. Here we provide an analytical approach for a
direct investigation of separated isomers. Cis/trans conformers of the peptide
hormones human (hCT) and salmon (sCT) calcitonin exhibit different migration
properties in capillary zone electrophoresis at subambient temperatures.
Calcitonin consists of 32 amino acids with two proline residues incorporated. It
is the longest unstructured peptide for which a conformer separation by capillary
electrophoresis has yet been achieved. Lowering the temperature yielded a
splitting into two and three peaks for sCT and hCT, respectively, in acidic
buffer. The peak ratios of 66:34 for sCT and 71:23 for hCT are in good agreement
with the conformer distribution previously reported from nuclear magnetic
resonance (NMR) studies. The addition of different organic modifiers (5-20% v/v)
to the running buffer does not improve the separation. The observed merging of
conformer peaks in buffer containing 20% v/v 2,2,2-trifluoroethanol (TFE) is
attributed to structure formation.
PMID- 9548294
TI - Analysis of polyanionic macromolecular carrier poly-(N-vinylpyrrolidone-co-maleic
acid) and its bioconjugats by capillary electrophoresis.
AB - Anionic carrier poly(N-vinylpyrrolidone-co-maleic acid) and its conjugates,
prepared with coupling of 2-cyano-3-hydroxy-5-amino-2-pentenoyc(4-trifluoromethyl
anilide) or (6', 7'-dimethyl-l'-quinoxalinyl)-4-(2' amino) acetanilide to the
carrier, were analyzed by capillary zone electrophoresis (CZE) and micellar
electrokinetic chromatography (MEKC) in the following buffers: 0.25 N
triethylammonium phosphate (TEAP); sodium dodecyl sulfate (SDS; 25-150 mM) in
TEAP (pH 2.25-6.30); 0.1 N Na-borate buffer (pH range 7-11) and SDS (25-150 mM)
in Na-borate buffer (pH range 7-11). The presence of strong carboxyl groups
(dissociated even at pH 2.25) on the polymer chain was proved by the CZE method.
It was also proved by potentiometric titration that carboxyls with a wide range
of acidity were on the polymer chain. CZE was able to differentiate among the
analytes possessing carboxyl groups of different acidic strengths at pH 2.25.
These components were not distinguished by CZE at high pH values (11.0).
Interaction between the analyte and SDS affected the separation at this pH, and
hence good resolution was obtained by MEKC. Informative separations were achieved
both for the carrier and the conjugates in TEAP buffer at pH 2.25 by the CZE
method. Optimal separation was achieved in borate buffer containing 75 mM SDS at
pH 11.0 for the carrier and at pH 7.7 for the conjugates in MEKC.
PMID- 9548296
TI - Quantitative trace analysis of interleukin-3, interleukin-6, and basic model
proteins using isotachophoresis-capillary zone electrophoresis with hydrodynamic
counterflow.
AB - A quantitative analytical technique to determine trace concentrations of
recombinant human interleukin-3 (rhIL-3), recombinant human IL-6 (rhIL-6), and
various basic model proteins is described using isotachophoresis-capillary zone
electrophoresis (ITP-CZE). Proteins were separated on coated fused-silica
capillaries using a commercial capillary electrophoretic system modified for the
application of isotachophoretic preconcentration with hydrodynamic counterflow.
The effect of injection time and isotachophoretic focusing time was investigated
and compared with predictions from existing mathematical models. Good linearity
of the calibration graphs (r > 0.995) was observed for all investigated proteins.
The limit of quantification was in the 10(-8) M range using UV detection at 200
nm. Within-day and between-day precision of peak area ranged between 1 and 6%.
Precision was unaffected by isotachophoretic preconcentration. In conclusion, the
described method is feasible to quantify trace concentrations of rhIL-3, rhIL-6,
and basic proteins. Potential applications comprise issues of pharmaceutical
quality control.
PMID- 9548295
TI - Quantitative trace analysis of L-ascorbic acid in human body fluids by on-line
combination of capillary isotachophoresis and zone electrophoresis.
AB - On-line combination of capillary isotachophoresis and zone electrophoresis
performed in two coupled capillaries (ITP-CZE) is used for the trace analysis of
L-ascorbic acid in human serum, urine and stomach fluid. At the ITP stage,
anionic sample components are separated into individual zones and macrocomponents
are detected and driven out of the migration path. In the CZE stage, only a small
segment of the sample zones containing L-ascorbic acid is analyzed. High
sensitivity of this hyphenated method (limit of detection, 0.09-0.15 mg/L), low
sample volume consumption (2 microL), and acceptable reproducibility of the
results (relative standard deviation, 8%) in the concentration range 0.1-15 mg/L
demonstrate that the method is applicable for the study of the relation between
the content of L-ascorbic acid in body fluids and the state of health of a
person, in which lower amounts of L-ascorbic acid than the normal levels (i.e.,
5.1-15.1 mg/L in human serum and 12.5-26.8 mg/L in urine) are expected. Possible
interferences of other components of the body fluids are excluded by good
correlation of the results obtained by the ITP-CZE method and a routine
colorimetric method.
PMID- 9548297
TI - Wheat cultivar discrimination by capillary electrophoresis of gliadins in
isoelectric buffers.
AB - A modified method is reported for screening of wheat cultivars: capillary zone
electrophoresis of gliadins in isoelectric buffers. Previously published
procedures recommended a 100 mM phosphate buffer, supplemented with 0.05%
hydroxypropylmethylcellulose and 20% acetonitrile, in uncoated capillaries. Due
to the very high conductivity of such a buffer (4.7 mmhos at 25 degrees C) high
speed separations (10-12 min analysis time at 800 V/cm) could only be elicited in
20 microm internal diameter (ID) capillaries, at the expense of sensitivity. In
the present report, we optimized the background electrolyte as follows: 40 mM
aspartic acid (pH=pI=2.77) in the presence of 7 M urea and 0.5% short-chain
hydroxyethylcellulose (Mn 27000 Da; apparent pH 3.9 in 7 M urea). As an
alternative recipe, the same isoelectric buffer can be supplemented with a mixed
organic solvent composed of 4 M urea and 20% acetonitrile (apparent pH 3.66). Due
to the much lower conductivity (0.7 mmhos), separations can be carried out at
1000 V/cm in only 10 min, but in larger bore capillaries (50 microm ID), ensuring
a five-times higher sensitivity. The gliadin patterns thus obtained are species
specific and allow easy identification of all cultivars tested of both durum and
bread wheat. No adsorption of proteins to the silica wall seems to occur and high
reproducibility in peak areas and transit times is obtained.
PMID- 9548298
TI - Sodium alkyl ether sulfate preparative electrophoresis for the preparation of
reaction centers without H-subunit from Rhodopseudomonas viridis.
AB - Sodium alkyl ether sulfate (AES), an analog of sodium dodecyl sulfate (SDS) was
used in polyacrylamide gel electrophoresis (PAGE) for the partial decomposition
of the photosynthetic reaction center (RC) of Rhodopseudomonas viridis. Unlike
SDS, AES did not completely dissociate RC into its subunits but selectively
detached H-subunit from RC to give RC(-H) without losing the spectroscopic nature
of RC. For the denaturation of RC(-H), AES was found to be as mild as 3-[3
cholamidopropyl)dimethylammonio]-l-propanesulfonate (CHAPS).
PMID- 9548299
TI - Expression and subcellular distribution of filamin isotypes in endothelial cells
and pericytes.
AB - Two principal forms of the actin binding protein, filamin, are expressed in
mammalian cells: nonmuscle and muscle isotypes (FLN-1 and FLN-2). A protein that
copurifies with an alpha-naphthyl acetate hydrolyzing esterase from human omentum
microvessel endothelial cells (EC) is isolated by nondenaturing electrophoresis,
sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis and
electroblotting. The purified protein is subjected to in situ trypsin cleavage,
reversed-phase high performance liquid chromatography (HPLC) and automated Edman
degradation. Six peptide fragments from the protein are identified to have 60-66%
identity with nonmuscle filamin (ABP-280). Two of these peptides are 100%
identical to a previously sequenced human muscle filamin fragment. Polyclonal
antibody is produced using a 16-residue synthetic peptide corresponding to a
structural beta-sheet region of muscle filamin. Compared with a variety of
vascular cells evaluated, retinal pericytes express an abundance of both muscle
and non-muscle filamin isotypes. Pericytes contain at least 10 times more muscle
filamin than human umbilical vein EC and at least three times the amount
expressed in human omentum microvessel and bovine pulmonary artery EC.
Differential detergent fractionation indicates that both filamin isotypes are
primarily localized in the cytosol and membrane/organelle fractions of pericytes.
Another actin crosslinking protein, alpha-actinin, is primarily found in the
cytosol and cytoskeletal fractions. The dynamic regulation of actin microfilament
organization in pericytes may be controlled in part by the two filamin isotypes,
which in turn may contribute to pericyte contractility.
PMID- 9548300
TI - Analysis of differential protein expression in normal and neoplastic human breast
epithelial cell lines.
AB - High-resolution two-dimensional gel electrophoresis (2-DE) and database analysis
was used to establish protein expression patterns for cultured normal human
mammary epithelial cells and thirteen breast cancer cell lines. The Human Breast
Epithelial Cell database contains the 2-DE protein patterns, including relative
protein abundances, for each cell line, plus a composite pattern that contains
all the common and specifically expressed proteins from all the cell lines.
Significant differences in protein expression, both qualitative and quantitative,
were observed not only between normal cells and tumor cells, but also among the
tumor cell lines. Eight percent (56/727) of the consistently detected proteins
were found in significantly (P< 0.001) variable levels among the cell lines.
Eight proteins present in normal cultured breast epithelial cells were not
detected in any of the tumor cell lines. We identified a subset of the
differentially expressed proteins using a combination of immunostaining, protein
sequencing, comigration, and subcellular fractionation. These identified proteins
include the intermediate filament components vimentin and cytokeratins. The cell
lines can be classified into four distinct groups based on their intermediate
filament protein profile. We also identified heat shock proteins; hsp27 and hsp60
varied in abundance and in some cases in the relative phosphorylation levels
among the cell lines. Many of the differentially expressed proteins we identified
have roles in cellular proliferation and differentiation, including annexin V,
elongation initiation factor 5A, Rho GDP dissociation inhibitor, and prohibitin.
We identified inosine-5-monophosphate dehydrogenase in each of the cell lines,
and found the levels of this enzyme in the tumor cell lines elevated 2- to 20
fold relative to the levels in normal cells. These results expand the human
breast epithelial cell protein database (http:// www.anl.gov/CMB/PMG) which is
being built to assist researchers with the identification of abnormal patterns of
expression and pathways associated with malignancy.
PMID- 9548301
TI - TMIG-2DPAGE: a new concept of two-dimensional gel protein database for research
on aging.
AB - Cellular proteins of a normal human diploid fibroblast line (TIG-3) at various
stages of replicative aging were resolved by horizontal isoelectric focusing on
an immobilized pH gradient, followed by vertical sodium dodecyl sulfate (SDS)
polyacrylamide gel electrophoresis (PAGE). Spot proteins were visualized by
silver staining and quantitated by image processing. All corresponding spots were
matched among two-dimensional gel images, and variation profiles in relative
abundance of individual proteins during in vitro aging were classified into five
categories, i.e., (i) increase, (ii) decrease, (iii) increase followed by
decrease, (iv) decrease followed by increase, and (v) irregular or nonsignificant
variation. The new concept of the Tokyo Metropolitan Institute of Gerontology two
dimensional gel protein database (TMIG-2DPAGE) was prepared from the above data
to support research on cellular aging. The database was put on our World Wide Web
home page at the URL of http://www.tmig.or.jp/2D/ to allow free access through
the Internet. The individual protein data entries were linked to the standard
spot protein map of the two-dimensional gel image in order to be accessible by
clicking the mouse on it.
PMID- 9548302
TI - Plasma protein adsorption patterns on emulsions for parenteral administration:
establishment of a protocol for two-dimensional polyacrylamide electrophoresis.
AB - The two-dimensional polyacrylamide electrophoresis (2-D PAGE) of the plasma
protein adsorption pattern previously established for polymeric nanoparticles was
modified and transferred to oil in water emulsions for intravenous
administration. The emulsions were incubated with citrated plasma, and separation
from excess plasma was performed by centrifugation under optimized conditions:
15000 g and three washing steps with 0.05 M phosphate buffer, pH 7.4. With this
sample preparation, coalescence of droplets could be avoided and an unchanged
surface area maintained, in addition the phosphate buffer minimized artificial
IgG adsorption. Critical factors affecting sensitivity were contamination of the
sample by oil residues and the use of thiourea in the immobilized pH gradients.
Changes in the protein adsorption pattern caused by altered surface properties of
the emulsion (i.e. adsorbed Poloxamer 407) were detectable when applying the
optimized protocol. Knowledge of the protein adsorption patterns and their
correlation to in vivo behavior opens the perspective for the development of
intravenous emulsions for controlled drug delivery.
PMID- 9548303
TI - Analysis of changes in acute-phase plasma proteins in an acute inflammatory
response and in rheumatoid arthritis using two-dimensional gel electrophoresis.
AB - Two-dimensional (2-D) gel analysis was used to examine differences in the levels
of 19 plasma proteins: before and after an acute inflammatory reaction
(parenteral typhoid vaccination) in normal subjects, between rheumatoid arthritis
(RA) patients and normals and in RA patients treated with tenidap (120 mg) and
piroxicam (20 mg). Typhoid vaccination increased levels of SAA, haptoglobin
alpha1, haptoglobin alpha2, haptoglobin beta and alpha1-anti-chymotrypsin but
decreased transthyretin and apolipoprotein E. In RA patients, serum amyloid A
(SAA), haptoglobin alpha2, haptoglobin beta, alpha1-antichymotrypsin and C3
proactivator levels were elevated while apolipoprotein A-I, apolipoprotein A-IV,
transthyretin, Gc-globulin, alpha2-HS glycoprotein, alpha2-macroglobulin and
alpha1-B glycoprotein levels were decreased, compared to normals. Compared to
piroxicam, tenidap lowered levels of alpha1-antiprotease and SAA but raised the
levels of transthyretin, Gc-globulin, alpha2-HS-glycoprotein and alpha2
macroglobulin in RA patients. C-reactive protein (CRP) could not be quantified on
2-D gels but, when measured by rate nephelometry, levels were reduced after
treatment with tenidap compared to piroxicam. The general pattern of the acute
phase protein response to an acute inflammatory response to typhoid vaccination
is similar to that in the chronic inflammatory condition, RA. The impact of
tenidap on both positive and negative acute-phase proteins in RA patients could
clearly be distinguished from that of piroxicam.
PMID- 9548305
TI - Endoscopic manometry of the sphincter of Oddi in patients with Lemmel's syndrome.
AB - Endoscopic manometry was performed to evaluate the motor activity of the
sphincter of Oddi (OS) in six patients with Lemmel's syndrome, four of whom had
acute cholangitis and two of whom had acute pancreatitis. As controls, 24
patients undergoing cholecystectomy without juxtapapillary duodenal diverticula
(JPD) for cholelithiasis or cholesterol polyps in the gallbladder were also
studied. The OS basal pressure and contraction pressure values were 12.4 +/- 5.1
mmHg and 103.4 +/- 24.3 mmHg, respectively, in the patients with Lemmel's
syndrome, and 19.5 +/- 5.1 mmHg and 136.8 +/- 28.2 mmHg, respectively, in the
control patients. These differences between the groups were statistically
significant; however, the wave frequency was not significantly different between
the groups. The mean percentages of antegrade, simultaneous, and retrograde
sequences were 37.5% +/- 11.3%, 19.9% +/- 8.7%, and 43.4% +/- 11.7%,
respectively, in the patients with Lemmel's syndrome, and 66.5% +/- 11.0%, 20.2%
+/- 4.7%, and 14.3% +/- 9.2%, respectively, in the controls. The differences
between the groups were significant (P < 0.01) for the antegrade and retrograde
sequences. These findings indicate that dysfunction of the OS in patients with
Lemmel's syndrome could be important in the development of
hepatocholangiopancreatic disease caused by duodenobiliary and duodenopancreatic
reflux.
PMID- 9548306
TI - Serum cell adhesion molecules in patients with colorectal cancer.
AB - The serum levels of intercellular adhesion molecule-1 (sICAM-1) and endothelial
leukocyte adhesion molecule-1 (sELAM-1) were determined in 40 patients with
colorectal cancer. The sICAM-1 and sELAM-1 levels in the drainage venous blood
adjacent to a tumor were significantly correlated with those in the peripheral
venous blood in patients without evident hematogenous dissemination of tumor
cells. The sICAM-1 levels in peripheral venous blood were significantly higher in
patients with hepatic metastases, while the sELAM-1 levels were significantly
higher in those with pulmonary metastases. An immunohistochemical study of
metastatic sites in the liver revealed that ICAM-1 was expressed in cancer
stroma, but not in the cancer cells. In conclusion, the sICAM-1 and sELAM-1
levels in the peripheral venous blood in colorectal cancer patients without any
distant metastasis are likely to reflect the topical production of these cell
adhesion molecules, and appear to be instructive in predicting hematogenous
dissemination in patients with colorectal cancer.
PMID- 9548304
TI - Metabolic alteration in patients with cancer: nutritional implications.
AB - During the past 20 years, efforts have been made to elucidate the metabolic
changes observed in patients with cancer by using stable and radioactive isotopic
tracers. These metabolic changes in patients with cancer may be similar to those
in other stress conditions, in which glucose production and utilization,
lipolysis and free fatty acid flux, and net protein catabolism are increased.
Stress hormones, such as glucagon and catecholamines, and certain cytokines may
be responsible for these metabolic changes. Although it has been shown that
cachexia in patients with cancer signals a poor prognosis, efforts to improve the
clinical outcomes with nutritional support have been disappointing. The failure
of cancer patients to respond to nutritional support may be related to an
alteration in the intermediate metabolism. Therefore, further research evaluating
the metabolic abnormalities associated with cancer may lead to more effective
nutritional therapies.
PMID- 9548307
TI - Abdominal surgery for patients on maintenance hemodialysis.
AB - Despite the growing number of major surgical procedures being performed for
patients on maintenance hemodialysis, few reports focus on the management and
outcome of such patients, especially those undergoing major abdominal surgery. We
conducted a retrospective review of 30 patients on maintenance hemodialysis who
underwent abdominal surgery, 20 of whom underwent an elective operation and 10,
an emergency operation. The indications of elective surgery included
gastrointestinal cancer, biliary tract disease, and abdominal aortic aneurysm,
while those for emergency surgery mainly involved gastrointestinal perforation or
bleeding. There were no statistically significant differences between the
elective group and the emergency group regarding either the mean time on
hemodialysis or the preoperative clinical data. The morbidity and mortality rates
were 15% and 10%, respectively, for the patients who underwent elective surgery
and 50% and 70%, respectively, for those who underwent emergency surgery (P <
0.01 and P < 0.05, respectively). Those patients with more than a 2-year history
of hemodialysis had a significantly higher mortality rate following abdominal
surgery than those with less than a 2-year history (P < 0.01). Thus, the
morbidity and mortality rates of patients on maintenance hemodialysis who require
major abdominal surgery are significantly high, which reinforces the need to
further improve the intensive perioperative management of such patients.
PMID- 9548308
TI - The suppression of postoperative liver metastasis caused by the continuous
intraportal infusion of angiogenesis inhibitor FR-118487 in a rabbit colon cancer
model.
AB - The inhibitory effect of FR-118487, a potent angiogenesis inhibitor, on
neovascularization induced by the VX2 tumor was confirmed in a rabbit corneal
assay. The antimetastatic effect of FR-118487 was also investigated in 21
rabbits. Spontaneous liver metastases were induced by VX2 tumor cell implantation
into the ascending colonic wall. FR-118487 was then infused continuously into the
portal vein for 7 days after resection of the primary lesion at a dose of 1
mg/kg/day (FR-1 group) or 3 mg/kg/day (FR-3 group). The incidence of liver
metastases was 71.4%, occurring in 5 of 7 rabbits, in each of the FR-1 and FR-3
groups, compared with 100%, being all of 7 rabbits, in the control group. The
number of metastatic foci tended to be less in the FR-1 (31.0 +/- 36.0) and FR-3
(24.6 +/- 45.1) groups than in the control group (83.7 +/- 73.9) and the weight
of metastatic foci was significantly less in the FR-1 (1.4 +/- 1.8 g) and FR-3
(1.3 +/- 2.0 g) groups than in the control group (6.5 +/- 4.9 g) (P < 0.05).
However, leakage of the colonic anastomosis and body weight loss were limited to
the FR-3 group. These results suggest that the continuous intraportal infusion of
FR-118487 at 1 mg/kg/day suppressed liver metastases by inhibiting angiogenesis,
without producing any adverse effects.
PMID- 9548310
TI - Changes in lung lobar volume and bronchial deformity after right upper lobectomy.
AB - To explore the anatomical repositioning of the middle lobe following right upper
(RU) lobectomy, we measured the lobar volumes of the lung and the branching
angles of the airway, and defined their changes after RU lobectomy in a rabbit
model. Groups A1 (n = 10) and A2 (n = 10) were control groups and groups B1 (n =
10) and B2 (n = 10) underwent RU lobectomy. Casting material was introduced into
the airway and a heart-lung bloc was removed form the thoracic cavity in all
groups. In groups A1 and B1, the volume of each lobe of the bilateral lungs was
measured, while in groups A2 and B2, bronchial casts were made and the branching
angles of the airway were measured. The volume ratio of the right upper lobe
(RUL) to the total lung was 12.0 +/- 0.4% in group A1; however, after RU
lobectomy, the volume ratio of the right middle lobe (RML) to the total lung
increased from 8.7 +/- 0.6% in group A1 to 13.5 +/- 0.8% in group B1. The volume
of the left lung also increased from 43.0 +/- 0.5% in group A1 to 48.8 +/- 1.1%
in group B1. The angle between the truncus intermedius and the RML bronchus was
significantly smaller in group B2, at 109.0 +/- 3.5 degrees, than in group A2, in
which it was 138.5 +/- 1.7 degrees. The angle between the RML bronchus and the
coronal plane was 57.5 +/- 2.5 degrees in group A2 and 33.5 +/- 3.3 degrees in
group B2. Our method of measuring the bronchial branching angle subsequent to RU
lobectomy proved useful to illustrate postoperative positional changes and
expansion of the remaining lobes.
PMID- 9548309
TI - The adverse effects of octreotide on the healing of colonic anastomoses in rats.
AB - Octreotide, a long-acting somatostatin analogue, is widely used in
gastrointestinal hypersecretory states and also for endocrine tumors in an
attempt to inhibit the paracrine hormones. Although it is well known that
octreotide inhibits trophic and anabolic hormones, no research has been conducted
on its adverse effects on wound healing. In the present study, groups of rats
were given 20 mcg/kg/day octreotide and 100 mg/kg/day hydrocortisone, the latter
being the negative control group, starting 5 days preoperatively. The colonic
anastomoses were assessed for healing on postoperative days (PODs) 5 and 8 by
determining the bursting pressure of the anastomoses, performing
histopathological analysis, and measuring the hydroxyproline content of the
anastomotic tissues. Octreotide was found to affect anastomotic healing
negatively on both PODs 5 and 8, but the negative effect of hydrocortisone was
significant only on POD 8. No significant difference was found between the
adverse effects of the two agents on POD 8. These findings indicated that
octreotide has an adverse effect on the healing of colonic anastomoses in rats.
PMID- 9548311
TI - Constant infusion rates of lipid emulsions to stabilize plasma triglyceride
concentrations: medium-chain triglyceride/long-chain triglyceride emulsions
(MCT/LCT) versus LCT.
AB - As medium-chain triglyceride emulsions (MCT) are more rapidly hydrolyzed than
long-chain triglyceride emulsions (LCT), MCT/LCT tends to be infused faster than
LCT. The purpose of the present study was to determine the most appropriate
infusion rate for MCT/LCT to stabilize plasma concentrations of triglyceride
(TG), being equivalent to the optimal infusion rate of the emulsion. A TG clamp
was set up by raising the mean +/- SD concentrations of TG in plasma, being 1.08
+/- 0.18 delta mmol l(-1) for LCT, and 1.65 +/- 0.31 delta mmol l(-1) for MCT/LCT
after a 50-min priming infusion of each emulsion. Thereafter, the infusion rate
of lipid was controlled every 10 min to maintain a steady concentration of TG for
a period of 150 min. A constant infusion of glucose at 0.32 g/kg body weight (BW)
per h was administered for the test period. The weight-based rate of the infusion
to maintain a steady state of plasma TG concentrations did not differ between
MCT/LCT and LCT, being 0.125 +/- 0.013 vs 0.117 +/- 0.021 g/kg BW per h, while
the molar-based infusion rate was 0.203 +/- 0.021 mmol/kg BW per h for MCT/LCT
and 0.132 +/- 0.023 mmol/kg BW per h for LCT (P < 0.05). These results suggest
that although 54% more molar MCT/LCT-TG can be hydrolyzed during a constant
infusion, MCT/LCT should not be infused at a rate faster than 0.1 g/kg BW per h
under a steady state.
PMID- 9548312
TI - Massive intraperitoneal hemorrhage caused by a giant exogastric leiomyoblastoma.
AB - Leiomyoblastomas account for a small percentage of smooth muscle tumors of the
stomach. Intraperitoneal bleeding is an unusual and unexpected presenting sign.
We herein present a 43-year-old woman who was urgently operated on due to signs
of collapse. A large hemorrhagic mass measuring 25 x 18 x 15 cm was found arising
from the greater curvature of the stomach. A histologic examination demonstrated
rounded and spindle cells, and rare mitoses were also seen. Although the number
of mitoses was small, the lesion was nevertheless felt to be consistent with
malignant leiomyoblastoma because of its large size. Three years later the
patient is doing well with no evidence of tumor recurrence. We conclude that
intraperitoneal bleeding due to leiomyoblastoma of the gastrointestinal tract is
an extremely rare phenomenon and has been described only in a few reports, and
only one other previous case presented with signs of collapse.
PMID- 9548313
TI - Malignant fibrous histiocytoma of the stomach: report of two cases.
AB - Malignant fibrous histiocytoma (MFH) in the stomach is very rare, and only four
cases have been reported. As a result, there is still little understanding of its
clinical and pathological features. We recently experienced two cases of gastric
MFH. The first case was a 78-year-old man with epigastralgia and a loss of body
weight. Endoscopy revealed an ulcerated submucosal tumor. A gastrectomy was
performed and the diagnosis of MFH was made histopathologically. The second case
was a 77-year-old man with pulmonary symptoms. An image diagnosis indicated a
strong suspicion of lung cancer, and a right middle and lower lobectomy was thus
performed. One month after the operation, a bleeding gastric tumor was found and
therefore a gastrectomy was performed. Both tumors were diagnosed as MFH. From
the analysis of six reported cases including ours, a preoperative correct
diagnosis is found to be difficult although the lesion has grown to a
considerable size at the time of operation. Since a metastatic lung lesion was
first detected in two out of six cases, it is thus recommended that the stomach
should be examined when lung MFH is found. Considering the high mortality and the
short survival in the six cases, the prognosis for gastric MFH seems to be poorer
than that in the extremities. However, lymph node metastasis is uncommon, and a
curative resection is possible in some cases such as in our second case.
PMID- 9548315
TI - Amebic liver abscess with jaundice.
AB - A case of an amebic liver abscess with unusual clinical manifestations is
presented. A middle-aged male with an abscess in both lobes of the liver
presented with obstructive jaundice due to pressure on the porta hepatis with
stasis of the bile in the intrahepatic biliary radicals. The patient did not
respond to repeated needle aspirations and thus required open drainage.
Subsequently, the patient developed a biliary leak through the drainage sites,
and an injection of contrast dye into the cavity revealed a communication between
the abscess cavities and the biliary tree. The biliary leak stopped
spontaneously, and the large cavities also closed completely during the followup
period.
PMID- 9548314
TI - Colonoscopic diagnosis of lymphoid hyperplasia causing recurrent intussusception:
report of a case.
AB - This paper describes a 6-year-old boy with recurrent ileocecal intussusception
due to lymphoid hyperplasia in the terminal ileum, which was diagnosed
preoperatively by colonoscopy. At the age of 3 years, he developed diarrhea and a
tender abdominal mass. He was diagnosed as having intussusception by ultrasound
and was treated by hydrostatic barium enema. After resolution, he had three
recurrent episodes of intussusception. A contrast barium enema revealed a small
mass in the ileocecal region. Colonoscopy showed several exaggerated folds of the
terminal ileum and a biopsy showed lymphoid hyperplasia. Because the repeated
intussusception seemed to have been caused by the lymphoid hyperplasia in the
terminal ileum, he underwent an ileocecal resection without any subsequent
recurrence. Based on the above findings, we conclude that a colonoscopy may thus
be useful both for diagnosing lymphoid hyperplasia in the terminal ileum as a
cause of recurrent intussusception and for deciding how to manage it.
PMID- 9548316
TI - Laparoscopic cholecystectomy in patients undergoing anticoagulant therapy.
AB - We recently performed a laparoscopic cholecystectomy on three patients receiving
preoperative oral anticoagulant therapy. The patients requiring anticoagulants
for pre-existing cardiac conditions have the following risks at surgery:
thromboembolism, hemorrhage, endocarditis, and cardiopulmonary dysfunction. In
patients receiving anticoagulant therapy, one must thus maintain a balanced
international normalized ratio of the prothrombin time to prevent thromboembolism
or hemorrhage. Warfarin sodium was discontinued preoperatively in all patients.
Heparin sodium was individualized according to each patient's risk of
thromboembolism. As a result, these patients all underwent a laparoscopic
cholecystectomy without complications. Attention was paid to achieve hemostasis
in the operative field and the trocar inserted sites during the procedure. The
administration of warfarin sodium was resumed on the first postoperative day in
all patients. Restarting warfarin sodium early also helps to simplify
postoperative management. A broad spectrum of antibiotic therapy was also used to
reduce the risk of endocarditis. Each patient's cardiopulmonary function was
carefully monitored. The minimal invasion experienced during a laparoscopic
cholecystectomy may thus facilitate the management of gallstones in patients
receiving systemic anticoagulation treatment based on the findings of this
limited series.
PMID- 9548317
TI - Anomalous duplicated cystic duct as a surgical hazard: report of a case.
AB - Anomalies of the biliary ductal system are not uncommon, and their clinical
significance is variable. We present herein the case of a 70-year-old Japanese
woman found to have an anomalous duplicated cystic duct, which is an extremely
rare congenital anomaly. Intraoperative delineation of the anomaly by real-time
cholangiograms assisted us in being able to subsequently perform a safe
cholecystectomy. This case serves to demonstrate the importance of being aware of
the possibility of potential biliary variations in order to avoid ductal injuries
during biliary surgery.
PMID- 9548318
TI - Urgent total arch graft replacement in an elderly patient with acute type A
dissection: report of a case.
AB - There are many controversies regarding the treatment of acute aortic dissections.
We herein present the case of an elderly patient over 80 years of age who
underwent an urgent total arch graft replacement for a Stanford type A acute
thrombosed aortic dissection complicating cardiac tamponade. An 81-year-old woman
with chest discomfort and shock that developed 1 day earlier was transferred to
our hospital by ambulance. A plain chest computed tomogram, aortogram, and an
echocardiography revealed mild pericardial effusion and an ascending aortic
aneurysm measuring 5 cm in diameter, but no evidence of an intimal tear in the
ascending aorta and aortic arch. At operation, after the bloody pericardial
effusion had been decompressed, her blood pressure was elevated and a type A
acute thrombosed aortic dissection with the intimal tear in the aortic arch was
confirmed, with a false channel filled with clotted blood. She underwent a
successful emergency total arch graft replacement using selective cerebral
perfusion and open distal anastomosis. The postoperative course was uneventful
and the false lumen was closed. We thus conclude that early graft replacement
should be performed on patients with Stanford type A acute thrombosed aortic
dissection complicating cardiac tamponade, even in elderly patients over 80 years
old.
PMID- 9548319
TI - Aortocoronary saphenous vein graft aneurysm in redo coronary artery bypass
grafting: report of a case.
AB - We report herein the case of an 80-year-old woman who underwent successful redo
coronary artery bypass grafting (CABG) for a saphenous vein graft aneurysm found
10 years after her initial operation. On presentation, coronary angiography (CAG)
revealed aneurysmal dilatation of the saphenous vein graft and severe stenosis of
the left main trunk (LMT). A percutaneous transluminal coronary angioplasty
(PTCA) of the LMT lesion was performed; however, a CAG after the PTCA revealed
restenosis and the patient developed anginal chest pain at rest. Thus, repeat
CABG was urgently carried out, which was followed by a good outcome. Histological
examination of the aneurysmal dilatation showed a true aneurysm. Only 15 other
cases of redo CABG for this indication have been reported, the features of which
are also discussed.
PMID- 9548320
TI - Infected atherosclerotic ulcer of the abdominal aorta as a cause of mycotic
aneurysm treated by in-situ prosthetic graft reconstruction: report of a case.
AB - A 68-year-old man with an infrarenal mycotic aneurysm underwent successful in
situ graft reconstruction using a woven Dacron graft. A tissue culture taken from
the excised aortic wall revealed Staphylococcus epidermidis, and histological
study subsequently showed penetrating atherosclerotic ulcers (PAU) involving all
layers of the aortic wall and marked neutrophilic infiltration with abscess
formation inside the ulcer. Atherosclerotic aortic lesions such as PAU are
considered susceptible to bacterial infection, which may lead to the formation of
an aneurysm after destruction of the vessel wall. Hence, elderly hypertensive
patients, being at high risk for such aortic pathology, require careful studies
performed to assess the aorta. The usefulness of computed tomographic (CT) scans
to determine the presence of PAU or surrounding inflammation should be borne in
mind even when a small mycotic aneurysm exists.
PMID- 9548321
TI - Y-shaped tracheobronchial stent for carinal and distal tracheal stenosis.
AB - A Y-shaped tracheo-bronchial tube was designed and used for two patients with
carinal stenosis following a lower tracheal resection in one case and a malignant
tracheal fistula in the other. The tube consisted of three parts including a Y
shaped, thin-walled, soft silicone stent; a spiral-wire-reinforced main tube; and
a curved tracheostomy tube. The stent was inserted easily and comfortably through
the tracheostomy under fiberoptic bronchoscopic guidance with minimal local
anesthesia. The positioning stability of the tube was excellent because of the
carina-shaped structure of the tube end. Resistance to compression was
satisfactory due to the embedded spiral wire. The insertion procedure through the
tracheostomy was smooth, even in patients whose respiratory condition was severe
or critical. Satisfactory phonational activity was also provided by breathing
through the hole on the tube back up to the vocal cord. Bronchoscopic inspection
was uncomplicated, and the patients themselves could easily clean the stent.
Since palliation of the airway obstruction is the main purpose of such a stent
for patients with either severe lower tracheal or carinal stenosis, and because
of the difficulty of ordinary stent insertion in this part of the airway, this
device appears to offer excellent stability and easy insertion of the stent. In
addition, the ease of maintenance and suctioning through the tracheostomal end
allows for an excellent quality of life in which the patients are able to return
to their homes.
PMID- 9548322
TI - Successful resection of a glomus tumor arising from the lower trachea: report of
a case.
AB - Tracheal glomus tumors are extremely rare. We present herein the case of a 43
year-old man with hoarseness who was found to have a glomus tumor arising from
the lower trachea. Bronchoscopy and chest computed tomography revealed a polypoid
mass in the membranous portion of the trachea just above the carina. The patient
underwent successful tracheal sleeve resection and reconstruction. A pathologic
diagnosis of a glomus tumor with clear surgical margins was subsequently
confirmed, and the patient is well 20 months postoperatively with an intact
anastomosis.
PMID- 9548323
TI - Idiopathic mediastinal fibrosis: report of a case.
AB - We report herein the case of a 28-year-old woman who presented with a mediastinal
mass, subsequently confirmed to be idiopathic mediastinal fibrosis. Preoperative
chest computed tomography (CT) showed a noncalcified mediastinal mass and surgery
was performed to exclude malignancy. The mass was hard and dense, involved the
left phrenic nerve, vagus nerve, and left upper lobe, and surrounded the
subclavian artery, subclavian vein, superior vena cava, and left pulmonary
artery. Pathologic examination showed the findings of mediastinal fibrosis and
the mass was partially excised. Postoperative medical treatment was performed
with prednisolone and tranilast, and a 3-year follow-up has not demonstrated any
complications.
PMID- 9548324
TI - Retroperitoneal and scrotal giant liposarcoma: report of a case.
AB - The case of a 63 year-old man with a giant scrotal and retroperitoneal tumor is
herein reported. The initial symptoms began in the scrotum and subsequent
abdominal distention resulted in discomfort 2 years later. The intraabdominal
organs were under pressure because of the bulky mass, and the patient had
dyspnea. Ultrasonograpy, computed tomography, and fine needle aspiration biopsy
investigations all revealed a retroperitoneal tumor suspected to be liposarcoma.
At operation, a tumor weighing 42 kg was excised. Respiratory support was
provided in the early postoperative period. The histopathological diagnosis was
myxoid liposarcoma. The patient was discharged from the hospital 14 days after
the operation and was scheduled to undergo radiotherapy.
PMID- 9548325
TI - Laparoscopic resection of a primary retroperitoneal mucinous cystadenoma: report
of a case.
AB - Primary retroperitoneal mucinous cystic tumors are extremely rare, and although
their histogenesis is still uncertain, several theories have been proposed.
Traditionally, transabdominal laparotomy and enucleation of the cyst is the
treatment of choice and laparoscopic resection has not previously been reported.
This paper presents the case of a 48-year-old woman in whom a primary
retroperitoneal cystic mass, 15 x 13 x 9 cm in size, was successfully resected
through the laparoscope. Pathological examination revealed a mucinous cystadenoma
with borderline malignancy. The patient had a prompt recovery and there was no
evidence of recurrence at her 8-month follow-up. However, the prevention of
cystic fluid spillage during laparoscopic manipulation is important, especially
when the pathology of the retroperitoneal cyst is unclear.
PMID- 9548326
TI - Vertical stab wound to the lumbo-sacral spinal canal: report of a case.
AB - A 63-year-old man was stabbed by an iron bar in the perineum. On admission, the
external aspect of this wound appeared to be only a tiny hole. However, the bar
had penetrated the rectum, sacrum, and lumbar spinal canal up to the third lumbar
vertebral body. This patient was eventually treated with sacral wound drainage, a
closure of the rectal wound, and pelvic drainage. Lumbar surgery was not
performed because computed tomography (CT) and magnetic resonance imaging (MRI)
did not show a progression of inflammatory changes in either the lumbar canal or
perispinal hollow caused by the iron bar during the hospital stay. The clinical,
CT, and MRI findings thus provided important information in the diagnosis and
treatment of stab wounds.
PMID- 9548327
TI - Neuroblastoma in an adult with a high serum level of carbohydrate antigen, CA125:
report of a case.
AB - We report herein the case of a 56-year-old woman with a neuroblastoma associated
with a high serum level of carbohydrate antigen, CA125. The patient presented
with massive ascites and a firm mass in her upper abdomen for which a laparotomy
was performed. However, a recurrent tumor was found 6 months later and she died
of the disease within 1 year of surgery despite several courses of adjuvant
chemotherapy. Neuroblastoma rarely occurs in adults, and the features of 58 adult
cases described in the world literature is summarized following the presentation
of the clinical data on this case. The distribution of primary sites in adults is
dispersed compared to that seen in pediatric cases, while the natural history of
the disease in adults may be longer and less sensitive to chemotherapy than in
children. The survival rate of adults with this disease is poor. We conclude that
aggressive surgical intervention combined with appropriate chemotherapy protocols
as applied in children should be performed in an attempt to achieve complete
remission and improve the survival rate of adults with neuroblastoma.
PMID- 9548328
TI - The development of extrahepatic portal obstruction after undergoing multiple
operations for a congenital dilatation of the bile duct: report of a case.
AB - As a long-term complication after undergoing a cystenterostomy for a congenital
dilatation of the bile duct, liver cirrhosis due to stenosis of the anastomosis
or reflux cholangitis has been reported in conjunction with subsequent portal
hypertension. We treated a 48-year-old Japanese woman who developed both portal
hypertension and pancytopenia after undergoing multiple operations for a
congenital dilatation of the bile duct. She underwent a Hassab's operation in
July 1994, when an occlusion of the extrahepatic portal vein, which resulted in
portal hypertension, was first noted; the liver was microscopically normal. The
etiology of the extrahepatic portal obstruction in our patient was most likely
due to either repeated inflammation or adhesion at the hepatic hilus. Based on
these findings, the differential diagnosis of portal hypertension after an
operation for a congenital dilatation of the bile duct should therefore include
an extrahepatic portal obstruction in addition to liver cirrhosis.
PMID- 9548329
TI - Leiomyosarcoma of the inferior vena cava. Resection and reconstruction of the
renal vein using the gonadal vein.
AB - We succeeded in surgically resecting a leiomyosarcoma of the inferior vena cava
(IVC), which originated at the confluent portion of the right renal vein (RRV),
together with the IVC and RRV, and also were able to preserve the right kidney by
reconstructing the RRV with end-to-end anastomosis using the right gonadal vein.
A good blood flow of the reconstructed RRV was thereafter confirmed by color
Doppler ultrasonography, and the renal function was also satisfactory. This new
procedure, a reconstruction of the RRV using the gonadal vein, has not been
previously reported, but is considered to be an easy and effective method which
enables the surgeon to preserve the normal right kidney.
PMID- 9548330
TI - Spinal cord astrocytomas: long-term results comparing treatments in children.
PMID- 9548331
TI - Modern treatment strategies in medulloblastoma.
AB - Chemotherapy has an important role in the modern treatment of children with
medulloblastoma (MB). In patients at high risk, intense chemotherapy should
improve the survival rate. In low-risk patients chemotherapy should allow the
dose of craniospinal irradiation to be reduced, which in turn should improve the
quality of life. In infants under 3 years of age radiotherapy should be delayed,
or even replaced by postoperative chemotherapy. Chemotherapy is also necessary to
prevent or treat systemic dissemination. The optimal timing of chemotherapy is a
focus of contemporary research.
PMID- 9548332
TI - Chemotherapy in low-grade astrocytoma management.
AB - The role of chemotherapy (CHT) in the management of low-grade astrocytoma (LGA)
is still unclear. Nineteen children with nonresectable symptomatic LGA were
treated with carboplatin (CBDCA) and etoposide (E). There were 15 newly diagnosed
cases and 4 were relapses; 6 of the children were under 5 years old. In all
children radiological evaluation by CT scan and/or MRI was performed after four
courses of CHT. We observed complete response (CR)+ minor response (MR) in 37% of
these cases and an improvement in neurological symptoms in 63%. Radiological
evaluation performed in 6 patients who received CHT for longer periods (8-12
courses) showed major responses (CR+PR) in 67%. Local radiotherapy (40 Gy) was
administered after CHT in 14 cases, but in 3 of these radiotherapy was delayed
for 2 years. Five patients did not receive radiotherapy. The overall survival was
58% after an average follow-up of 60 months. All patients with brain stem tumors
died of progressive disease even though 3 of these had shown clinical improvement
after chemotherapy. In conclusion, in the treatment of nonresectable symptomatic
LGA, CHT with CBDCA associated with E can be used to postpone radiotherapy in
young children and even to avoid radiotherapy in some cases.
PMID- 9548333
TI - Abdominal metastases of pediatric brain tumors via ventriculo-peritoneal shunts.
AB - Internal drainage of cerebrospinal fluid (CSF) to the abdominal cavity via a
ventriculo-peritoneal shunt (VPS) is a procedure that is commonly used for the
treatment of obstructive hydrocephalus. As this condition is often caused by
brain tumors blocking the natural CSF pathways, a VPS, as an artificial
anastomosis, can provide the means for tumor cells to be spread with the CSF. A
review of the literature reveals 35 VPS-related abdominal metastases from
pediatric brain tumors; 17 in patients aged 0-9 (group A) and 18 in patients aged
10-18 years (group B); the mean age of male patients was 10.5, and that of female
patients, 7 years. The male-to-female ratio was 1.9 (group A 1.1, group B 3.5),
and the mean interval between shunt operation and diagnosis of metastases, 16.7
months (group A 11.6, group B 22.6 months; boys 21.6, girls 7.5 months). During
the observation period, 22/30=73.3% of the patients died (group A 13/15=86.7%,
group B 9/15=60%; boys 13/21=61.9%, girls 9/9=100%); their mean survival time
after shunting was 18.7 months (group A 15.7, group B 23.1 months; boys 25.5,
girls 9 months). The four most common sources of metastases were germinomas (9
cases=25.7%; group A none, group B 9), medulloblastomas (8 cases=22.9%, group A
7, group B 1), endodermal sinus tumors (5 cases=14.3%, group A 1, group B 4), and
astrocytomas (4 cases=11.4%, group A 4, group B none). Metastases via VPS are
rare, but should be considered as a possible complication and mode of systemic
spread in children with primary intracranial malignancy. They have a more
favorable prognosis in boys and in the second decade of life.
PMID- 9548334
TI - Intractable seizure disorder associated with chronic herpes infection. HSV1
detection in tissue by the polymerase chain reaction.
AB - We describe the pathological findings and report the detection of herpes simplex
virus 1 (HSV1) in the brain in three patients who presented with intractable
seizures. All three patients had a previous history of HSV1 encephalitis and went
on to develop a medically refractory seizure disorder necessitating surgical
intervention. HSV1 encephalitis was clinically diagnosed and treated at 6 months,
3 years, and 7 months and surgical resection was done at 8.5 years, 6 years, and
3 years, in cases 1, 2 and 3, respectively. Pathological examination revealed
chronic encephalitis in all three cases, with microglial nodules,
intraparenchymal, perivascular and meningeal lymphocytic infiltrates, and
gliosis. While immunohistochemical and ultrastructural studies were negative for
viral pathogens, polymerase chain reaction (PCR) analysis revealed HSV1 genome.
These cases represent examples of chronic herpes encephalitis and seizure
disorder with presence of viral genome in the brain long after the initial
episode of treated herpes encephalitis.
PMID- 9548336
TI - The Surgical Isolation Bubble System and patient temperature during
ventriculoperitoneal shunt insertion in preterm and term newborn infants.
AB - The ultraclean air environment in a plastic isolator has been used in
cerebrospinal fluid shunt interventions in an attempt to reduce the incidence of
infections. The blower that maintains a continuous flow of filtered air in the
operative field may create body temperature changes. In this study we assessed
the temperature before, during and at the end of the operation in preterm and
term infants in whom ventriculoperitoneal shunts were being placed. There were 12
preterm and 9 term infants. The duration of the operative intervention ranged
from 25 to 50 min. In the preterm infants the mean initial temperature was 36.2+/
0.2 degrees C, and the final temperature was 35.7+/-0.2 degrees C. This
difference was not significant. The initial temperature in the term infants was
36.26+/-0.2 degrees C, and the final temperature was 35.9+/-0.3 degrees C, also
not significantly different. The surgical isolation bubble system does not alter
the temperature of preterm and term infants significantly during
ventriculoperitoneal shunt procedures performed within the operative times seen
in this study.
PMID- 9548335
TI - Ornithine decarboxylase in developing brain of hydrocephalic rats. Effects of
shunt operation.
AB - We examined the changes in ornithine decarboxylase (ODC) immunoreactivity in the
hydrocephalic cerebral cortex of HTX rats after decompression by shunt operation.
The ODC immunoreactivity reached a very low level after the completion of
cortical layer formation, and only faint staining was found on postnatal day (Pd)
11. The ODC immunoreactivity re-appeared after the shunt operation when the
operation was done in the early days of life: the ODC immunoreactivity was first
found on day 2 after shunting and persisted until day 8 after shunting. However,
this was not apparent when the operation was not performed until Pd 14. The re
expression of ODC in hydrocephalic brain after shunting appears to cause
resumption of the developmental process by relieving neurons from increased
hydrostatic pressure. The dependence of ODC re-expression on the timing of the
operation indicates that there may be a period of neocortical decompression that
is critical for effective compensatory development, so that when delayed,
decompression fails to re-activate the ODC-dependent development.
PMID- 9548337
TI - Patient satisfaction with surgical treatment of refractory epilepsy done in
childhood and early adolescence.
AB - The results of a retrospective self-controlled telephone satisfaction survey of
63 patients who had undergone an earlier resection for the treatment of medically
refractory epilepsy before the age of 18 years was reported. The survey items
consisted of a global rating scale and a series of open-ended questions about
positive and negative outcomes as a result of the surgery. Most (80%) of the
patients felt the surgery had had a positive effect on their lives. The mean
global score was 6.24+2.4 (scale 0-9). Strong positive correlations were found
between seizure control and degree of satisfaction and between perceived
postsurgical neurological deficits and dissatisfaction.
PMID- 9548338
TI - Recent advances and racial differences in therapeutic strategy to the pineal
region tumor.
AB - The therapeutic modalities for pineal region tumors in Western countries differ
from those in Japan, mainly because of the different patient populations. The
majority of pineal region tumors in Japan are radio- and/or chemosensitive, and
adjuvant therapy rather than extensive surgery plays the main part in the
treatment of these tumors. The specific clinical features of and therapeutic
modalities for pineal region tumors, together with racial differences, were
analyzed at the joint symposium of the Japanese Society for Pediatric
Neurosurgery and the Korean Society for Pediatric Neurosurgery. The results of a
cooperative study, together with the collective experience in Korea, confirmed
that this specific patient population is nearly identical to the Japanese one.
The new therapeutic approaches to pineal region tumors recommended included
neuroendoscopic or stereotactic biopsy as a "minimally invasive" initial
procedure. The adjuvant therapeutic modalities were further analyzed and
neoadjuvant chemotherapy, mainly with cisplatin or carboplatin with or without
etoposide (VP-16), was recommended for the treatment of germinoma and
nongerminomatous malignant germ cell tumors. "Target radiation therapy" with
extensive chemotherapy is a hopeful regimen and a future subject of research.
PMID- 9548340
TI - Treatment of germ cell tumors in the pineal region.
AB - The authors retrospectively analyzed 107 patients with primary intracranial germ
cell tumor (GCT), who were treated at the Department of Neurosurgery, Yonsei
Medical Center between January 1986 and January 1996. The incidence of GCT was
2.8% in pediatric patients with intracranial tumor. Of the 107 tumors, 60 were
located in the pineal region, 30 in the suprasellar region, 16 in basal ganglia
or the thalamic region, and 1 in the posterior fossa. The 60 pineal GCT consisted
of 39 germinomas (29 pure germinomas, 6 germinomas with STGC, 4 germinomas mixed
with teratoma), 5 mature teratomas, and 16 nongerminomatous GCT. Thirty patients
underwent surgery: their operations took the form of total resection in 14 cases,
subtotal resection in 10, and biopsy in 6. Thirty patients (27 with germinomas, 3
with endodermal sinus tumors) were managed without surgery on the basis of
radiological findings and tumor markers. The 5-year survival was 91% for 39
patients with germinomas, 80% for 5 with mature teratomas, and 49% for 16 with
nongerminomatous GCT. Univariate analysis of prognostic factors with the Kaplan
Meier survival curve showed that histological tumor type, radiological findings,
results of tumor marker studies, and response to trial radiation or chemotherapy
were highly correlated with outcome. Chemotherapy was beneficial as the method of
trial treatment in pineal GCT and treatment in recurrent tumors. The
administration of trial chemotherapy or radiotherapy without tissue biopsy is
well justified as a treatment modality in pineal GCT suspected on the basis of
radiological findings and tumor marker studies. Aggressive multimodality
approaches with surgery, radiotherapy, and chemotherapy are necessary to improve
the outcome in these tumors. We propose new protocol for treatment of germ cell
tumors in the pineal region, which is based on a minimally invasive approach.
PMID- 9548339
TI - Identical characteristics of the patient populations with pineal region tumors in
Japan and in Korea and therapeutic modalities.
AB - The therapeutic modalities used for tumors of the pineal region in Western
countries differ from those in Japan, mainly because of the different patient
populations. An extensive survey was conducted to delineate the racial
differences in Japan and in Korea in the epidemiology and recent therapeutic
modalities for this tumor group. Among the members of International Society for
Pediatric Neurosurgery (ISPN), 15 from Japan and 5 from Korea reported their
recent findings in 118 (1-25 years of age, mean 7.38-year period) and 125 (1-12
years of age, mean 6.69-year period) histologically verified cases, respectively.
The patient populations in the two countries were found to be almost identical,
with an extremely high incidence of germ cell tumors representing 71.2% (in
Japan) and 80.0% (in Korea) of all pineal region tumors and neuroectodermal
tumors representing only 15.2% and 16.8%, respectively. The most common type of
pineal region tumor was germinoma (46.6% in Japan and 47.2% in Korea). The
majority of tumors were radio- and/or chemosensitive, and adjuvant therapy rather
than extensive surgery played the major role in the treatment in both countries.
Radical resection of the tumor was recommended as the initial procedure by only
22.2% of neurosurgeons in Japan and 16.6% in Korea. Biopsy was recommended by
38.9% and 50.0%, and radiation therapy by 38.9% and 37.5%, respectively. A
minimally invasive procedure, by either a neuroendoscopic (33.3% of biopsies in
Japan) or a stereotactic approach (33.3% of biopsies in Korea), was considered to
be appropriate as the initial procedure. The study disclosed the almost identical
epidemiology of this brain tumor in Japan and in Korea and clarified the
consequent therapeutic modalities. The authors emphasize that minimally invasive
tissue diagnosis with or without tumor debulking should be considered as the
initial step for the treatment planning of the pineal region tumor, followed by
the most commonly indicated major procedures, including radiation therapy,
chemotherapy and/or radical resection with various methodologies.
PMID- 9548341
TI - Operative approaches to the pineal region tumors.
AB - Until the introduction of microsurgery, the surgical treatment of pineal region
tumors had very poor results with high mortality and morbidity. However, there
have been remarkable improvements with modern surgical technology and advanced
knowledge. Now the main surgical approaches to pineal region tumors are the
occipital transtentorial approach and the infratentorial supracerebellar
approach. Recently the neuroendoscopic approach has been added. The surgical
approach and any supplementary treatment should be selected in each case
according to the nature of the individual tumor. The forms of treatment practiced
by ourselves, including neuroendoscopic surgery, are presented, and the surgical
treatments now applied are discussed.
PMID- 9548342
TI - Pineal tumors: experience with 48 cases over 10 years.
AB - The authors retrospectively reviewed 48 patients treated at Seoul National
University Hospital (SNUH) between 1986 and 1995. There were 35 children and 13
adults, accounting for 10.1% of 345 pediatric and 0.68% of 1914 adult brain
tumors in SNUH during the same period. The 48 cases consisted of 33 cases of germ
cell tumor (69%, GCT); 6 of pineoblastoma (PB, 12.5%); 3 of pineocytoma (PC,
6.3%); 3 of anaplastic astrocytoma (6.3%); 1 of astrocytoma; 1 of glioblastoma;
and 1 of ependymoma. The median age was 13 years (range 1-59) and the male-to
female ratio was 3.36:1. The most frequent presenting symptom was due to
increased intracranial pressure (90%), followed by Parinaud syndrome or diplopia
(50%). Patients with a benign tumor, such as teratoma (TE), astrocytoma, or
ependymoma, underwent surgery by the occipital transtentorial approach (OTT) for
attempted radical resection without adjuvant therapy, while patients with
immature teratoma (imTE), PC, and anaplastic astrocytoma underwent regional
radiotherapy (RT) after debulking via OTT. Seven patients with nongerminomatous
malignant GCT (NG-MGCT) and 3 with germinoma (GE) underwent craniospinal
radiation only, 6 with GE, a NG-MGCT, and 2 with GE+TE received craniospinal
radiotherapy (CSRT) after debulking via OTT. Three patients with GE, 4 with NG
MGCT, and 3 with PB underwent radiochemotherapy after debulking via OTT. Forty
four patients were followed up after treatment. The median follow-up period was
36 months. All patients with GE were alive after RT at 36 months (median) of
follow-up (range 7-70 months). All with GE+TE and TE were alive. Three patients
with PC or astrocytoma were also alive with stable or no evidence of disease. In
1 of the 3 cases of imTE there was a recurrence. However, 4 patients with NG-MGCT
died, all of whom had undergone CSRT only; 2 PB patients were alive (12, 19
months), 1 in a moribund status (36 months), and 2 were dead (6, 60 months). The
overall mean survival time with pineal tumors was 66 months and the 3-year
survival rate was 84% with minimal posttreatment complications. It is concluded
that pineal region tumors have male and childhood predominances, and the most
common tumor is GCT. The majority of pineal region tumors are malignant. Pineal
region tumors can be approached safely and effectively and the surgical
complications are mostly transient. Their prognosis is dependent on the
pathologies and treatment modalities.
PMID- 9548343
TI - Combined treatment with chemotherapy and radiation therapy for intracranial germ
cell tumors.
AB - We analyzed our treatment results in 153 patients with histologically verified
intracranial germ cell tumors and proposed classifying them into three
therapeutic groups with good prognosis, intermediate prognosis, and poor
prognosis. In this work, we selected patients treated with chemotherapy
(cisplatin or carboplatin combinations) in each subgroup, and we discuss the role
of chemotherapy in their treatment. Our combination chemotherapy regimens are:
cisplatin-vinblastine-bleomycin, cisplatin-etoposide, and carboplatin-etoposide.
We delivered these chemotherapies to the last 33 patients and compared their
treatment results with those obtained in the previous 31 patients, who were
treated with conventional radiation therapy alone. A combination with
chemotherapy and a reduced dose of irradiation with local field was given to 7
patients with germinoma to increase the cure rate and reduce radiation-induced
side effects, including anterior pituitary dysfunction. We obtained an excellent
initial response to chemotherapy. The chemotherapy we delivered had significantly
better effects in the group with intermediate prognosis, but not in the group
with poor prognosis. More aggressive chemotherapy and radiation therapy should be
given as the initial treatment.
PMID- 9548344
TI - Experience with pineal region tumors.
AB - The results are reported of a retrospective review of the presentation and
outcome of 43 pineal region tumors treated from 1982 to 1996, including 20
identified tumors: 5 germinomas, 8 teratomas, 2 embryonal carcinomas, 1
endodermal sinus tumor, 2 pineocytomas and 2 pineoblastomas. Of the 43 tumors
reviewed, 36 were located in the pineal region, 5 in the suprasellar, and 2 in
both the pineal and suprasellar regions. Twenty patients underwent surgical
resection: total in 6 and partial in 10, while only a biopsy was taken in 4
cases. Fifteen patients were managed on the basis of serum CSF tumor markers and
radiation response. Twenty-three patients with germinomas received radiotherapy
(RT) and had a 5-year survival rate of 87%. Fifteen patients with non
germinomatous germ cell tumors received RT and chemotherapy following direct
surgery, and 5 died (mortality rate of 33.3%). The overall survival rate of the
43 patients with pineal tumors was 79.1% (34/43) and the death rate was 20.9%
(9/43). It is now recognized that the wide variety of tumor types found in the
pineal region necessitates different modes of treatment, and improved
microsurgical and stereotactic surgical techniques have made mortality and
morbidity rates acceptably low. Because the radiation response and CSF cytology
are not enough to determine optimum treatment, a tissue diagnosis should be
obtained in all patients.
PMID- 9548346
TI - Pigmented medulloepithelioma: report of a case and review of the literature.
AB - A 9-year-old male child had a IV ventricular medulloepithelioma of classical
histology, showing tubulopapillary and undifferentiated areas. The unusual
feature, however, was the presence of melanin pigmentation in the cells, which
was further confirmed by electron microscopy. So far 28 cases of
medulloepithelioma have been reported in the English literature. However, none of
them showed melanin pigmentation. To the best of our knowledge this is the first
case of pigmented medulloepithelioma in the English literature.
PMID- 9548345
TI - Intracranial dural cyst.
AB - Intracranial dural cyst is a very rare congenital malformation. The presence of
such a cyst was confirmed by means of computed tomography and magnetic resonance
findings in a child with an enlargement of the head and developmental retardation
and confirmed histologically in surgically obtained specimens of cyst wall.
PMID- 9548347
TI - Primary giant granulomatous basal meningitis: an unusual presentation of
tuberculosis.
AB - A case of granulomatous tuberculous meningitis in a 3-year-old child without any
known primary disease in any other organ is presented. Tuberculous meningitis is
an uncommon presentation of tuberculosis and is characterized by diffuse or
circumscribed granulomatous involvement of the meninges, particularly at the base
of the brain. Early diagnosis and treatment are essential to prevent the worst
events it can bring and to improve the chances of survival. Diagnosis remains
difficult because of the lack of reliable clinical diagnostic criteria.
PMID- 9548348
TI - Multiple intracranial aneurysms in a patient with Seckel syndrome.
AB - A 17-year-old girl affected by Seckel syndrome and multiple intracranial
aneurysms is reported. Cerebral hemorrhage was the reason for the diagnostic work
up. The aneurysms were surgically treated. The main features of the syndrome,
technical problems encountered during surgery and the prognosis of this condition
are discussed.
PMID- 9548349
TI - Surgically treated traumatic synchondrotic disruption of the odontoid process in
a 15-month-old girl.
AB - A case of traumatic synchondrotic disruption in a 15-month-old girl is reported;
she was treated with interlaminar wiring of C1-C2 without grafting. Reduction of
the dislocation and angulation and stability were achieved without evidence of
growth disturbance. However, the child's initial poor neurological status with
tetraplegia below the level of C7 remained unchanged. Besides our case, there are
only three other cases in the literature of young children primarily operated on
for a traumatic odontoid synchondrotic disruption. Even though the dorsal
interlaminar wiring of C1-C2 without grafting is an easy and safe procedure even
in the very young, the optimal form of treatment for this rare injury is still
unsettled.
PMID- 9548350
TI - Crisis: what crisis?
AB - There is a large economic cost associated with low back pain. In 1994 its cost to
the United Kingdom (UK) was estimated by the UK Clinical Standards Advisory Group
report to be nearly pound sterling 6,000 million (ECU 8,350 million) annually.
This principally consists of the indirect costs of lost production and disability
payments rather than direct health service costs. A re-examination of the
assumptions in the report shows that these costs appear to overestimate the
economic cost of back pain by an unquantified, but possibly large, amount. This
may restrict the benefit of introducing more effective treatments for back pain.
PMID- 9548351
TI - Gait analysis in idiopathic scoliosis before and after surgery: a comparison of
the pre- and postoperative muscle activation pattern.
AB - In a prospective experimental study the level gait activity scores of the
iliocostalis lumborum, glutaeus medius, tensor fasciae latae, vastus lateralis
and peronaeus longus muscles of both body sides were examined by computerized
electromyography in 23 patients with idiopathic scoliosis before and after CD
instrumentation. The pre- and postoperative findings were examined as to
asymmetric patterns in muscle requisition during gait and the respective changes
induced by the spinal correction. These results were compared with the
corresponding results obtained in healthy subjects in two independent sessions
with identical experimental conditions. A muscle activity asymmetry coefficient
was defined to quantify the degree of left/right muscle activation asymmetry
observed. Postoperatively a statistically significant reduction (P < 0.05) of a
preoperatively strongly increased activity was found in the lumbar muscles of the
convex side of double major scolioses as well as in the glutaeus medius and
tensor fascia lata muscles of the concave side of thoracic curvatures. Both the
casuistic and statistical analysis of the results of our study support the
hypothesis that activity asymmetries observed in the paravertebral musculature in
idiopathic scoliosis patients are the result of the scoliotic body deformities,
with consequent asymmetries in the biomechanical force patterns of body postures
and body motions, rather than an aetiological factor of scoliotic curvatures.
PMID- 9548353
TI - Characterization of the mechanical behaviour parameters of the costo-vertebral
joint.
AB - This in vitro study introduces a new method to determine quantitative parameters
characterizing the mechanical behaviour of the costo-vertebral joint. These
parameters are useful in building numerical models of the thoracic spine, taking
into account the thoracic cage. Nine thoracic cages were isolated from fresh
human cadavers. From each cage, three functional units were tested: T1-T2, T5-T6,
T9-T10. Loads were applied according to the joint local coordinate system. Every
functional unit was tested first intact and again after section of successive
costo-transverse ligaments. We used an opto-electronic system to follow the three
dimensional motion of the joint, and obtained non-linear load/displacement curves
according to the primary rotation axis. A statistical analysis of these curves
allowed the calculation of parameters describing the joint mechanical behaviour:
total range of motion, motion in the low-stiffness zone, and flexibilities in the
positive and negative quasi-linear zones. These values can be used as a database
for mechanical modeling of the spine.
PMID- 9548352
TI - Quantification of cosmesis for patients affected by adolescent idiopathic
scoliosis.
AB - The aim of this study was to quantify cosmesis for patients affected by
adolescent idiopathic scoliosis. Eight nonmedical judges were asked to examine
photographs of 40 patients with adolescent idiopathic scoliosis, and to score the
cosmesis of their backs without any information. Various parameters were measured
from radiographs, Moire topographies, and physical measurements of patients, and
these were compared with the cosmetic scores of the judges. The judges' scoring
proved to be reliable. The cosmetic scores showed a significant correlation with
the Cobb angle, hump severity, asymmetry of the waist line, circumference of the
chest, and obesity. Multivariate analysis produced equations to calculate the
cosmetic score for the back. This equation is thought to have a useful clinical
application.
PMID- 9548354
TI - Lumbar disc herniation: favourable outcome associated with intake of wine.
AB - Recent research indicates that non-smoking and intake of alcoholic beverages, in
particular wine, are associated with beneficial effects on several diseases,
especially atherosclerosis. The aim of the study was to investigate whether
smoking or the intake of different alcoholic beverages are associated with the
outcome 2 1/2 years after first-time lumbar disc surgery. The design was a follow
up study, using a questionnaire including a rating scale. All 170 patients
consecutively operated upon for a lumbar disc herniation over a 1-year period
were clinically examined at the time of the operation and classified according to
various social and demographic variables. The main outcome measure, 2 1/2 years
after, was the total rating score, i.e. the sum of three equally weighted outcome
measures: pain, impairment and self-assessment of the operation result. The
questionnaires were completed by 148 patients (87%). The median age of patients
was 41 years; 60 of them were women. Fifty-four per cent were smokers and 42%
wine drinkers. Logistic regression analysis calculated a fourfold increase in the
success rate for wine drinkers. This fourfold odds ratio was not significantly
reduced by the following variables: age, sex, social class, household income,
smoking habits, employment status or marital status. Smoking could not be shown
to be an independent risk factor for the outcome. Intake of wine was found to be
associated with a good prognosis after first-time lumbar disc surgery, and this
association could not be attributed to the lifestyle characteristics studied.
PMID- 9548355
TI - Fitness for work after surgery for lumbar disc herniation: a retrospective study.
AB - This report retrospectively evaluates fitness for work in 3956 cases of surgery
for lumbar disc herniation between 1992 and 1994. Patient records were derived
from a database including all interventions of the insured population of the
largest Belgian sickness fund. The datafile consisted of 126 cases of
percutaneous nucleotomy (nucleotomy group), 286 cases of lumbar disc surgery with
fusion (fusion group) and 3544 cases of standard lumbar disc surgery (standard
group). Fitness to resume work within 12 months after intervention was obtained
in about 70% of the patients in the standard and nucleotomy groups but in only
45% of the patients in the fusion group. Ten medicosocial factors were related to
fitness for work as outcome measure. Incapacity for work more than 12 months
after intervention was defined as a bad outcome. Logistic regression was used to
test the combined relative significance of the different variables. For the
standard group a long duration of work incapacity before intervention, older age,
lower benefit, employment as a blue-collar worker, a long duration of hospital
stay and unemployment were significantly associated with a poor outcome. Related
factors for the fusion group were a long duration of work incapacity before
operation, a long duration of hospital stay and unemployment. For the nucleotomy
group, no factor was significantly associated with a poor outcome. For the total
group, discectomy combined with fusion was significantly related to a poor
outcome whereas a standard discectomy and a percutaneous nucleotomy did not
differ in their impact on fitness for work.
PMID- 9548356
TI - Effects on the vertebral end-plate of uncomplicated lumbar discography: an MRI
study.
AB - The study aimed to identify and characterise changes occurring in the vertebral
end-plate on MRI following uncomplicated lumbar discography. MRI was performed
immediately before and within 2 h after uncomplicated lumbar discography in 20
consecutive patients undergoing the study as a precursor to possible spinal
fusion. Of these, seven patients underwent a further MRI study at a mean of 72
days after discography (range 19-183 days). The MRI scans were assessed for the
presence of any changes in the end-plates prior to and following discography. End
plate changes were identified in eight patients (40%) prior to discography. No
new changes in end-plate signal intensity (SI) were identified in either the
immediate or delayed MRI studies. The study suggests that any changes occurring
in the vertebral end-plate following discography should be considered due to
infectious discitis. There is no support for the concept of chemical discitis,
chemical irritation of bone or microfracture of subchondral trabeculae as a cause
of pain at discography.
PMID- 9548357
TI - The relationship between vertebral body deformity and disc degeneration in lumbar
spine of the senile.
AB - This study provides an investigation of the relationship between vertebral
deformities and disc degeneration in patients with senile osteoporosis using
biomechanical and medical imaging methods. The finite element analysis showed
that stress concentration in the central area of the vertebral body is much
decreased with disc degeneration, indicating that load transmission has been
altered. Radiography and MRI suggested that vertebral deformities are related to
the height and degeneration of the disc just below this vertebral body. When a
disc has decreased height or degeneration, the vertebral body just above it is
less likely to be deformed for patients with spinal osteoporosis.
PMID- 9548358
TI - Calcium pyrophosphate dihydrate deposition in degenerate lumbar discs.
AB - Calcium pyrophosphate dihydrate (CPPD) crystal deposition in lumbar
intervertebral discs has been described, but its clinical significance remains
unclear. The present study analyzed histological sections of lumbar discs that
were obtained from patients undergoing anterior lumbar interbody fusion.
Immunohistological staining was undertaken to identify neural elements and blood
vessels. Patients with CPPD deposition were compared with a group without CPPD
deposition undergoing the same operation. CPPD was found in 15.7% of investigated
patients (12.6% of analyzed discs). Deposits were found in areas of the annulus
and nucleus showing advanced degeneration. Two patterns were identified: one
comprised sharply demarcated rounded deposits, while the other showed diffuse
deposition of crystals. There was no association with ingrowth of vascular or
neural tissue. Clinical data did not differ significantly in the two groups of
patients. However, in all patients with CPPD deposition there was a history of
trauma, previous surgery, or both. Isolated CPPD deposition in lumbar
intervertebral discs appears to be an incidental finding that is not related to
systemic diseases or general arthropathies.
PMID- 9548359
TI - Vertebral osteomyelitis: an analysis of 38 surgically treated cases.
AB - The purpose of the study was to evaluate the characteristics of patients with
vertebral osteomyelitis who were treated by anterior debridement and interbody
fusion. Thirty-eight patients with vertebral osteomyelitis, who were treated
between 1980 and 1993, were analyzed in terms of age at the occurrence of
disease, duration of disease, type of onset symptoms, radiological type of
vertebral destruction, species of pathogen, and surgical result. Thirty-one out
of 38 patients (82%) were more than 40 years of age. The patients with severe
vertebral destruction were significantly older than those with mild vertebral
destruction. Vertebral destruction in the thoracic spine was significantly more
severe than that in the lumbar spine. Staphylococcus aureus was identified in
only six patients (32% of organism-determined cases). In the present patients who
required anterior debridement and bone grafting for this disease, the prognosis
was quite good after anterior interbody fusion in conjunction with antibiotics
therapy.
PMID- 9548360
TI - Vertigo in patients with cervical spine dysfunction.
AB - To our knowledge, quantitative studies on the significance of disorders of the
upper cervical spine as a cause of vertigo or impaired hearing do not exist. We
examined the cervical spines of 67 patients who presented with symptoms of
dizziness. Prior to the orthopaedic examination, causes of vertigo relating to
the field of ENT and neurology had been ruled out. Fifty patients of the above
mentioned group were studied. They followed the outlined treatment protocol with
physical therapy and were available for 3 months of follow-up. Thirty-one
patients, hereinafter referred to as group A, were diagnosed with dysfunctions of
the upper cervical spine. Nineteen patients, hereinafter referred to as group B,
did not show signs of dysfunction. Cervical spine dysfunctions were documented as
published by Bischoff. In group A dysfunctions were found at level C1 in 14
cases, at level C2 in 6 cases and at level C3 in 4 cases. In seven cases more
than one upper cervical spine motion segment was affected. Dysfunctions were
treated and resolved with mobilising and manipulative techniques of manual
medicine. Regardless of cervical spine findings seen at the initial visit, group
A and B patients received intensive outpatient physical therapy. At the final 3
month follow-up, 24 patients of group A (77.4%) reported an improvement of their
chief symptom and 5 patients were completely free of vertigo. Improvement of
vertigo was recorded in 5 group B patients (26.3%); however, nobody in group B
was free of symptoms. We concluded that a functional examination of motion
segments of the upper cervical spine is important in diagnosing and treating
vertigo, because a non-resolved dysfunction of the upper cervical spine was a
common cause of long-lasting dizziness in our population.
PMID- 9548361
TI - Three-dimensional measurement of wedged scoliotic vertebrae and intervertebral
disks.
AB - Idiopathic scoliosis involves complex spinal intrinsic deformations such as the
wedging of vertebral bodies (VB) and intervertebral disks (ID), and it is obvious
that the clinical evaluation obtained by the spinal projections on the two
dimensional (2D) radiographic planes do not give a full and accurate
interpretation of scoliotic deformities. This paper presents a method that allows
reconstruction in 3D of the vertebral body endplates and measurement of the 3D
wedging angles. This approach was also used to verify whether 2D radiographic
measurements could lead to a biased evaluation of scoliotic spine wedging. The 3D
reconstruction of VB contours was done using calibrated biplanar X-rays and an
iterative projection computer procedure that fits 3D oriented ellipses of
adequate diameters onto the 3D endplate contours. "3D wedging angles" of the VB
and ID (representing the maximum angle between adjacent vertebrae) as well as
their angular locations with respect to the vertebral frontal planes were
computed by finding the positions of the shortest and longest distances between
consecutive endplates along their contour. This method was extensively validated
using several approaches: (1) by comparing the 3D reconstructed endplates of a
cadaveric functional unit (T8-T9) with precise 3D measurements obtained using a
coordinate measuring machine for 11 different combinations of vertebral angular
positions; (2) by a sensitivity study on 400 different vertebral segments
mathematically generated, with errors randomly introduced on the digitized points
(standard deviations of 0.5, 1, 2, and 3 mm); (3) by comparing the clinical
wedging measurements (on postero-anterior and lateral radiographs) at the
thoracic apical level of 34 scoliotic patients (15 degrees < Cobb < 45 degrees)
to the computed values. Mean errors for the 11 vertebral positions were 0.5 +/-
0.4 mm for VB thickness, less than 2.2 degrees for endplate orientation, and
about 11 degrees (3 mm) for the location of the maximum 3D wedging angle along
the endplate contour. The errors below 2 mm (introduced on the digitized points)
slightly affected the 3D wedging angle (< 2 degrees) and its location (< 4
degrees) for the ID. As for the clinical evaluation, average angular errors were
less than 0.4 degrees in the radiographic frontal and lateral planes. The mean 3D
wedged angles were about 4.9 degrees +/- 1.9 degrees for the VB and 6.0 degrees
+/- 1.7 degrees for the ID. Linear relations were found between the 2D and the 3D
angles, but the 3D angles were located on diagonal planes statistically different
than the radiographic ones (between 100 degrees and 221 degrees). There was no
statistical relation between the 2D radiographic angles and the locations of the
3D intervertebral wedging angles. These results clearly indicate that VB and ID
endplates are wedged in 3D, and that measurements on plain radiographs allow
incomplete evaluation of spinal wedging. Clinicians should be aware of these
limitations while using wedging measurements from plain radiographs for diagnosis
and/or research on scoliotic deformities.
PMID- 9548362
TI - Harvesting and preparation of cadaveric osseoligamentous lower cervical spine (C2
C7) for biomechanical testing.
AB - Cadaveric osseoligamentous lower cervical spines (C2-C7) are often used in the
investigation of spinal biomechanics in vitro. Surprisingly, however, the
techniques of harvesting at postmortem and preparation of cadaveric
osseoligamentous lower cervical spine for biomechanical testing have not been
described in detail. We describe a simple and effective method that can be
readily integrated into the routine autopsy procedure. Points on the avoidance of
disfiguring the cadaver and damaging the spinal osseoligamentous structures are
highlighted.
PMID- 9548364
TI - Unrecognized laceration of main bronchus caused by fracture of the T6 vertebra.
AB - We report on an extremely rare case of a 58-year-old male polytraumatized patient
who sustained a bursting fracture of the T6 vertebral body associated with
laceration of the posterior wall of the right main bronchus from the spiculae of
the vertebral body fragments. The patient was on admission asymptomatic until he
underwent an endotracheal anesthesia for stabilization of associated fractures of
the extremities, when he developed acute respiratory disturbances. The opening of
the bronchus was repaired via a thoracotomy, while the spine was successfully
supported with a custom-made brace for 3 months. In the 3-year follow-up
evaluation, the patient did well and suffered no complaints of the spine or
lungs. Spine surgeons should be aware of this rare complication, which may
accompany bursting fractures in the midthoracic spine. Laceration of the bronchus
should be suspected when fragments of the vertebral body are dislocated far
anteriorly.
PMID- 9548365
TI - Occipitoatlantal instability associated with articular tropism.
AB - The authors report the case of a patient with rotatory posterior subluxation of
the occiput on the atlas associated with tropism of the O-C1 articulations.
Lateral flexion-extension plain films demonstrated 5 mm of posterior translation
of the occiput on the atlas. Tomographs revealed tropism of the O-C1
articulations, and CT scans on extension demonstrated posterior rotatory
subluxation of the occiput on the atlas. The patient had no osseous abnormality
caudally below the atlantoaxial joint, and underwent posterior occipitoatlantal
fusion by wiring. At the 4-year follow-up, the grafted bone had been
incorporated, and the patient was completely free from preoperative symptoms. In
the present patient, occipitoatlantal instability is presumed to have derived
from articular tropism.
PMID- 9548363
TI - Increased kyphosis by a combination of fractures of the sternum and thoracic
spine.
AB - A 67-year-old patient suffered a fall and sustained injuries to the thorax,
combined with fractures of the ribs, sternum and thoracic spine. Her pre-existing
kyphosis (caused by osteoporotic vertebral collapse) increased in severity. There
was a clear relationship between a sternal fracture, deterioration of thoracic
kyphosis and a fracture of the thoracic spine.
PMID- 9548366
TI - Tubular peroxisomes in HepG2 cells: selective induction by growth factors and
arachidonic acid.
AB - We showed recently the plasticity of the peroxisomal compartment in the human
hepatoblastoma cell line HepG2 as evidenced by the presence of elongated tubular
peroxisomes measuring up to 5 microm next to much smaller spherical or rod-shaped
ones (0.1-0.3 microm). Since the occurrence of tubular peroxisomes in a given
cell in culture is synchronized, with neighboring cells containing either small
spherical or elongated tubular peroxisomes, cell counting of immunofluorescence
preparations stained for catalase was used for the quantitative assessment of the
dynamics of the peroxisomal compartment and the factors regulating this process.
Initial studies revealed that the formation of tubular peroxisomes is primarily
influenced by the cell density as well as by lipid- and protein-factors in fetal
calf serum, being independent of an intact microtubular network. Biochemical
studies showed that the occurrence of tubular peroxisomes correlated with the
expression of the mRNA for 70 kDa peroxisomal membrane protein (PMP70), but not
with that of matrix proteins. By cultivation of cells in serum- and protein-free
media specific factors were identified which influenced the formation of tubular
peroxisomes. Among several growth factors tested, nerve growth factor (NGF) was
the most potent one inducing tubular peroxisomes and its effect was blocked by
K252b, a specific inhibitor of neurotrophin receptor pathway, suggesting the
involvement of signal transduction in this process. Furthermore, from several
polyunsaturated fatty acids (PUFA) which all induced tubular peroxisomes, the
arachidonic acid (AA) was the most potent one. Our observations suggest that
tubular peroxisomes are transient structures in the process of rapid expansion of
the peroxisomal compartment which are induced either by specific growth factors
or by polyunsaturated fatty acids both of which are involved in intracellular
signaling.
PMID- 9548367
TI - Tyrosine and serine phosphorylation of the neural cell adhesion molecule L1 is
implicated in its oligomannosidic glycan dependent association with NCAM and
neurite outgrowth.
AB - We have previously shown that a cis interaction between the cell adhesion
molecules L1 and NCAM is mediated by N-linked oligomannosidic glycans carried by
L1 and that this L1/NCAM association is involved in basal neurite outgrowth from
early postnatal cerebellar neurons of mouse brain [R. Horstkorte et al., J. Cell
Biol. 121, 1409-1421 (1993)]. Extending these earlier studies we investigated
signal transduction mechanisms elicited by this molecular interaction. We show
here that phosphorylation of L1 is reduced concomitant with reduced neurite
outgrowth when the L1/NCAM interaction is inhibited by oligomannosidic
glycopeptides. Similarly, when a peptide of the 4th immunoglobulin (Ig)-like
domain of NCAM - representing part of NCAM's carbohydrate-binding site - was
added to the culture medium of the cells, neurite outgrowth and phosphorylation
of L1 was strongly reduced. No effect on neurite outgrowth and phosphorylation of
L1 was observed when cells were maintained in the presence of a peptide
comprising part of the 1st Ig-like domain of NCAM or in the presence of the
peptide encoded by the variable alternative spliced exon (VASE), which is also
located in the 4th Ig-like domain of NCAM. Furthermore, phosphorylation of
tyrosine and serine residues of L1 is reduced when the L1/NCAM interaction at the
cell surface of cerebellar neurons is perturbed. Our observations suggest that a
signal transduction mechanism is implicated in basal neurite outgrowth in which
both tyrosine and serine phosphorylation of L1 represent a possible proximal
step. Some of these results were presented at the International Glycoconjugate
Symposium in Seattle, USA [P. C. Heiland et al., Glycoconj. J. 12, 521(1995)].
PMID- 9548369
TI - Characterization of monoclonal antibodies against cell wall epitopes of the
insect pathogenic fungus, Nomuraea rileyi: differential binding to fungal
surfaces and cross-reactivity with host hemocytes and basement membrane
components.
AB - Monoclonal antibodies (MAbs) were generated against epitopes on yeast-like hyphal
bodies and hyphae of the entomopathogenic hyphomycete, Nomuraea rileyi. Two MAbs
(4C10, 2H4) bind to epitopes common to both hyphal bodies and hyphae, whereas MAb
4E9 binds only to hyphal surfaces. 4C10 and 2H4 appear to be directed towards
carbohydrate portions of cell surface mannoproteins, as evidenced by similarities
in staining patterns between these MAbs and Concanavalin A on Western blots of N.
rileyi cell wall extracts. These MAbs cross-react with antigens on blastospore
and hyphal surfaces of two other entomopathogenic fungi, Beauveria bassiana and
Paecilomyces farinosus in fluorescence microscopy assays, but do not cross-react
with a non-entomopathogenic strain of Candida albicans or with Saccharomyces
cerevisiae yeasts. MAb 4C10 also cross-reacts with immunocompetent granular
hemocytes from Spodoptera exigua (beet armyworm) and Trichoplusia ni (cabbage
looper) larvae and with S. exigua plasmatocytes. Electron microscopy revealed
that this MAb binds to a component in cytoplasmic granules in the hemocytes, and
that surface labeling may be due to the release of this MAb-positive component
upon degranulation. MAb 2H4 does not cross-react with granular hemocytes, but
does bind to plasmatocytes and hemocytes that tightly adhere to the substrate in
monolayer assays. Additionally, MAb 4C10 specifically labels a basement membrane
epitope on S. exigua fat body, suggesting that this antibody binds to mannose
residues on extracellular matrix glycoproteins. Cross-reactivity of these N.
rileyi MAbs with insect hemocyte and tissue components indicates that fungal
surface epitopes can mimic host surface molecules, which could explain why N.
rileyi hyphal bodies are not recognized by granulocytes and are able to circulate
freely in the hemolymph without binding to basement membranes lining the
hemocoel.
PMID- 9548368
TI - Beta1B integrin interferes with matrix assembly but not with confluent monolayer
polarity, and alters some morphogenetic properties of FRT epithelial cells.
AB - Beta1B is a beta1 integrin splice variant that differs from the ubiquitous beta1A
in the terminal portion of the cytosolic tail. The expression of this variant in
CHO cells results in reduced fibroblast adhesion and motility (Balzac, E et al.,
J. Cell Biol. 127, 557-565 (1994)). We have evaluated the phenotypic changes
induced by the expression of beta1B in the FRT epithelial cell line. Stable
transfectants of FRT cells expressing beta1B or beta1A human integrins were
obtained. The transfected integrins associated with the endogenous alpha subunits
and were delivered to the plasma membrane. Beta1B expressing cells attached less
efficiently and spread less on fibronectin, laminin or type IV collagen coated
dishes. A great reduction of fibronectin fibrils associated to the basal membrane
of non-confluent beta1B transfected cells was observed. This was paralleled by
the disappearance of microfilament bundles and loss of basally located focal
adhesions. On the contrary, upon beta1A transfection, a higher amount of
fibronectin fibrils, together with microfilament bundles and focal adhesions, was
observed. Expression of beta1B did not significantly modify the ability to
manifest the polarized phenotype when cells were grown to confluence on filters
in two-chamber-systems. Beta1B-transfected cells showed reduced motile properties
when embedded as aggregates in type I collagen gels. Moreover, formation of
polarized cysts in suspension culture was impaired. The results show that beta1B,
by interfering with focal adhesion organization, microfilament and fibronectin
assembly, cell spreading and migration, affects some morphogenetic properties of
FRT epithelial cells.
PMID- 9548370
TI - Adenosine inhibits actin dynamics in human neutrophils: evidence for the
involvement of cAMP.
AB - The mechanisms by which adenosine regulates the inflammatory reaction are poorly
characterized. In this study, we investigated the effects of adenosine on
neutrophil actin polymerization elicited by the chemotactic peptide N-formyl
methionyl-leucyl-phenylalanine (fMLP) or IgG-opsonized yeast particles. We used
bodipy-phallacidin staining in combination with flow cytometry and found that
adenosine markedly reduced actin polymerization triggered by IgG-yeast, whereas
the effect on the fMLP-response was less pronounced. Similar or even more
pronounced effects were obtained with the adenosine A2 receptor agonist 5'-N
ethylcarboxamidoadenosine (NECA), suggesting an A2 receptor-mediated mechanism.
The following observations indicate that the A2 receptor-induced effects involve
the cAMP-protein kinase A (PKA) signaling pathway: (1) a combination of NECA and
the cAMP-specific phosphodiesterase (PDE) inhibitor Ro 20-1724 raised the cAMP
content in both unstimulated and stimulated neutrophils and also further
inhibited the actin dynamics; (2) the PKA inhibitor H89 reversed the inhibitory
effects of NECA on the actin dynamics; (3) Ro 20-1724, isoproterenol and
dibutyryl cAMP (DBcAMP) reduced actin polymerization in almost the same way as
NECA did. NECA together with Ro 20-1724 impaired the fMLP-induced shape changes
and cortical accumulation of actin filaments. In contrast, H89 potentiated the
fMLP-induced formation of a submembranous ring of actin filaments. Neutrophils
phagocytosing yeast particles in the presence of NECA and Ro 20-1724 were
predominantly round in shape, and their ability to extend actin-rich pseudopods
around the prey was reduced. These effects were partly antagonized by H89. In
correlation with the effects on actin polymerization, NECA more effectively
diminished IgG-induced upregulation of the beta2 integrin CD11b/CD18 than such
upregulation induced by fMLP. The inhibitory effects of A2-receptor activation on
actin dynamics and beta2 integrin expression in neutrophils exposed to IgG-yeast
were also associated with a cAMP-dependent reduction of the phagocytic capacity.
In conclusion, we show that adenosine inhibits actin dynamics and shape changes
in neutrophils via a cAMP-dependent pathway. This finding further characterizes
the mechanisms by which adenosine functions as an important modulator of the
inflammatory response.
PMID- 9548371
TI - Changes in kinesin distribution and phosphorylation occur during regulated
secretion in pancreatic acinar cells.
AB - In secretory cells, microtubule- (Mt-) based motor enzymes are thought to support
transport of secretory vesicles to the cell surface for subsequent release. At
present, the role of Mts and kinesin in secretory vesicle transport in exocrine
epithelial cells has not been defined. Furthermore, it is unclear whether an
agonist-induced secretory event modifies kinesin function and distribution, thus
altering vesicle transport. To this end, we utilized isolated rat pancreatic
acini and cultured rat pancreatic acinar cells to examine the role of Mts and
kinesin in regulated secretion. Exposure of cells to cytoskeletal antagonistic
drugs demonstrated that the observed movements of apically clustered zymogen
granules (ZGs) are supported by Mts, but not actin. Morphological studies of Mt
organization in polarized acini show that Mt plus ends extend outward from the
apical membrane toward the cell center. Immunofluorescence microscopy in both
cell models revealed a clear association of kinesin with apical ZGs, while
quantitative immunoblot analysis of pancreatic subcellular fractions confirmed
kinesin enrichment on ZG membranes. In addition, microinjection of kinesin
antibodies into cultured acinar cells inhibited ZG movements. Indirect
immunofluorescence staining of isolated cells and quantitative Western blotting
of isolated ZGs revealed that kinesin association with granule membranes
increased up to 3-fold in response to a secretory stimulus. Autoradiographic
studies of 32P-labeled acini showed up to a 6-fold increase in kinesin heavy
chain (KHC) phosphorylation during stimulated secretion. These studies provide
the first direct evidence that Mts and kinesin support ZG movements and that
physiological agonists induce a marked phosphorylation of KHC while increasing
the association of kinesin with ZG membranes. These changes during agonist
stimulation suggest that the participation of kinesin in zymogen secretion is
regulated.
PMID- 9548372
TI - Acinar lumen pH regulates endocytosis, but not exocytosis, at the apical plasma
membrane of pancreatic acinar cells.
AB - A two-step exocytosis/endocytosis protocol was used in rat pancreatic acini to
study membrane trafficking events at the apical plasma membrane (APM) as a
function of extracellular pH. Exocytosis, as measured by cholecystokinin (CCK)-8
induced release of amylase into the incubation medium, was relatively insensitive
to changes in extracellular pH from 5.5 to 9.0. In contrast, endocytosis, as
measured by temperature-dependent uptake of horseradish peroxidase (HRP), was
robust at pH values between 6.5 and 8.3 but abolished at acidic pH values of 5.5
to 6.0. Energy metabolism and cell viability were maintained during pH 6-induced
cessation of HRP uptake, and the vesicular block could be reversed upon raising
the luminal pH to 7.4. Histochemical and morphometric studies of HRP uptake
examined by electron microscopy indicated that extracellular pH regulates
endocytosis at the apical plasma membrane. At pH 6.0 in prestimulated cells, HRP
uptake at the APM was abolished, and acinar lumen membranes remained markedly
dilated with decreased density of microvilli and "arrested" exocytic images. At
pH 7.4, HRP was taken up into endolysosomal structures within the Golgi complex,
and acinar lumen membranes were contracted. Cleavage of GP2, a glycosyl
phosphatidylinositol-anchored protein, was associated with the pH-dependent
activation of HRP uptake. These studies demonstrate that acinar lumen pH
regulates endocytic but not exocytic activity at the APM and suggest that
alkalinization of the acinar lumen by duct cells is required for retrieval of
exocytic membranes into the acinar cell via vesicular uptake mechanisms. The role
of acid-base interactions within the acinar lumen provides a novel basis for
understanding the cellular and luminal defects observed within the exocrine
pancreas in cystic fibrosis.
PMID- 9548373
TI - Cleavage of GPI-anchored proteins from the plasma membrane activates apical
endocytosis in pancreatic acinar cells.
AB - Using rat pancreatic acini, we have recently shown that apical endocytosis is
inhibited at pH 6.0 and progressively activated as the pH is increased to 8.3.
Endocytotic activity correlated with the release of GP2, a GPI-linked protein,
from the apical plasma membrane. To determine whether the cleavage of GPI
anchored proteins from the membrane of rat acinar cells was responsible for
activation of endocytosis, cells at pH 6.0 were incubated with PI-specific
phospholipase C (PI-PLC). PI-PLC treatment reversed the inhibition of endocytosis
observed at pH 6.0. Reactivation of endocytosis correlated with PI-PLC-induced
release of GP2 but not cleavage of phospholipids in cellular membranes.
Furthermore, administration of diacylglycerol or phorbol esters had no effect on
reactivation of endocytosis. PI-PLC did not alter intracellular pH or calcium
levels. Two proteins were identified as GPI-linked proteins on the cell surface.
One was GP2, whose release from the apical plasma membrane correlated with apical
endocytosis of horseradish peroxidase (HRP). The other protein, identified by
Western blotting using an antibody directed against a cryptic determinant exposed
on GPI-linked proteins after cleavage with PI-PLC, has a molecular weight of
98000 in nonreducing SDS gels and 54000 in reducing SDS gels. By nondenaturing
gel electrophoresis and staining with naphthylphosphate, this protein was found
to be alkaline phosphatase. In contrast to GP2, alkaline phosphatase was not
endogenously released at pH values of 7.4 or 8.3, conditions that activate
endocytosis of HRP under physiological conditions. By electron microscopic
evaluation, incubation of cells at pH 6.0 with PI-PLC led to induction of HRP
uptake into vesicles at the apical pole of the cell, a reduction in apical plasma
membranes, and a concomitant contraction of the acinar lumen space. Internalized
HRP accumulated in the Golgi region of the cell. These results suggest that the
cleavage of GPI-anchored proteins from the apical plasma membrane activates
apical endocytosis.
PMID- 9548374
TI - The SURF-6 protein is a component of the nucleolar matrix and has a high binding
capacity for nucleic acids in vitro.
AB - The recently identified novel protein SURF-6 is shown to be a component of the
nucleolar matrix. Immunofluorescence analysis demonstrated that SURF-6 was
localized in residual nucleoli of in situ nuclear matrix preparations of mouse
fibroblast cells (NIH 3T3), which were depleted of soluble and chromatin related
proteins. Immunoblot analysis of biochemical nucleolar subfractions confirmed
that SURF-6 was present in the nucleolar matrix fraction, and was absent from the
fractions of soluble proteins released by DNase or RNase. The capacity of SURF-6
to bind nucleic acids was investigated in vitro. Both endogenous SURF-6 from
nuclear extracts and recombinant SURF-6 exhibited a strong binding capacity for
nucleic acids. It was shown that SURF-6 bound to both DNA and RNA, however, it
showed stronger binding to RNA. The presence and nuclear distribution of SURF-6
during the cell cycle was explored by immunofluorescence analysis. It was shown
that SURF-6 was always found in the nucleolus regardless of the phase of the cell
cycle suggesting that it is a structural protein constitutively present in
nucleolar substructures. The colocalization of SURF-6 with the major nucleolar
proteins B23 and fibrillarin, which are known to be involved in the processing of
ribosomal RNA (rRNA), was examined both in interphase and mitosis by double
immunolabeling of cells. SURF-6 was found to be largely coincident with both
proteins in interphase and it was distributed in the same cellular locations,
namely the perichromosomal layer, the cytoplasm and prenucleolar bodies, in
mitosis. However, colocalization of SURF-6 with fibrillarin and B23 was only
partial in interphase, and the dynamics of its localization was not completely
the same as those of either fibrillarin or B23 during mitosis. Taken together,
these results indicate that SURF-6 is a novel nucleolar matrix component and
imply that SURF-6 might support nucleolar matrix structure and function(s) via
its association with nucleic acids. We propose that SURF-6 may be involved in
processing of rRNA, based on its cytological characteristics, but at stages in
ribosomal biogenesis which are different from those for fibrillarin and B23.
PMID- 9548375
TI - Effects of genic substitution at the agouti, brown, albino, dilute, and pink-eyed
dilution loci on the proliferation and differentiation of mouse epidermal
melanocytes in serum-free culture.
AB - To examine the effects of coat-color genes on the proliferation and
differentiation of mouse epidermal melanocytes, we cultured epidermal, cell
suspensions derived from neonatal skins of C57BL/10JHir (black) and its congenic
mice carrying agouti, brown, albino, dilute, and pink-eyed dilution genes in a
serum-free medium supplemented with dibutyryl adenosine 3',5'-cyclic
monophosphate. The proliferative rates of agouti, brown and dilute black
melanocytes were similar to that of black melanocytes, while those of albino and
pink-eyed black melanocytes were about one-half of that of black melanocytes. The
morphology of albino and pink-eyed black melanocytes, though nonpigmented, was
similar to black melanocytes; namely, dendritic, polygonal or epithelioid. Dilute
black melanocytes also possessed the similar morphology, whereas their
melanosomes were accumulated in the perinuclear region. Dopa-melanin depositions
after dopa reaction in brown and dilute black melanocytes were greater than in
black and agouti melanocytes. Although dopa-melanin depositions were not observed
in albino melanocytes, about 8% of pink-eyed black melanocytes were positive to
dopa reaction. Silver depositions after combined dopa-premelanin reaction in
agouti, brown and dilute black melanocytes were similar to that in black
melanocytes. Although albino melanocytes were devoid of silver depositions, about
25% of pink-eyed black melanocytes were positive to the reaction. Pyrrole-2,3,5
tricarboxylic acid (PTCA, degradation product of eumelanin) contents in agouti
and dilute black melanocytes were slightly lower than in black melanocytes, while
that in brown melanocytes was reduced to one-third. In contrast, PTCA contents in
albino and pink-eyed black melanocytes were reduced to less than 0.5%.
Aminohydroxyphenylalanine (AHP, degradation product of pheomelanin) contents did
not differ among these melanocytes. These results suggest that the coat-color
genes exert their influences on the proliferation and differentiation of mouse
epidermal melanocytes by affecting tyrosinase activity, melanosome maturation and
transport, and eumelanin synthesis.
PMID- 9548376
TI - A novel methodology for the investigation of intracellular proteolytic processing
in intact cells.
AB - Taking advantage of the unique spectral properties of the fluorescent probe FL
Bodipy, we have developed a new methodology to study processing of exogenous
proteins in intact cells. FL-Bodipy was conjugated to bovine serum albumin (BSA)
at a molar ratio of 29 probe molecules to 1 albumin equivalent. The resulting
conjugate was 98% self-quenched due to fluorescence resonance energy transfer
(homotransfer) between neighboring Bodipy molecules. In vitro proteolytic
cleavage of the conjugate led to relaxation of self-quenching and to a
significant increase in fluorescence. Flow cytometry and fluorescence microscopy
indicated that Bodipy-labeled BSA was readily internalized by J774 macrophages
and accumulated in intracellular compartments. The kinetics of intracellular
degradation of Bodipy-BSA was linear for up to 2 hours and was completely
inhibited by a combination of protease inhibitors. Future applications of the
methodology reported here may comprise studies of antigen processing and
presentation, as well as the investigation of cellular events related to
processing and disassembly of intracellular pathogens such as parasites, bacteria
and viruses.
PMID- 9548377
TI - Population heterogeneity of higher-plant mitochondria in structure and function.
AB - Mitochondria of rapidly developing mungbean seedlings were fractionated into four
populations: two density classes, each from a 1500S and a 150S pellet. Each of
the four populations exhibited cytochrome c oxidase (COX) activity and contained
mitochondrial DNA and cardiolipin; plastid and glyoxysome content were found to
be relatively low. Five mitochondrial membrane proteins, COXII/III, ATPase
alpha/beta and porin, and a matrix enzyme, manganese superoxide dismutase
(MnSOD), were detected by immunoblots in all four populations. Another matrix
enzyme, pyruvate dehydrogenase was detected only in the two respiratory-competent
1500S populations. The two 150S populations contained a previously unidentified
organelle that lacked demonstrable respiratory capability. This organelle, which
we have tentatively referred to as "slow-sedimenting (ss-) mitochondrion", was
small in size (below light-optics resolution, 70-300nm, majority < or =200nm) and
possessed a peculiar looking boundary membrane, ribosomes, and an occasional
prominent electron-dense spot. Characteristically, ss-mitochondria were almost
always in contact with a filament-aligned membrane-like structure of varying
length. Cristae structure, while undetected in small ss-mitochondria, appeared in
larger individuals. Typical mitochondria were found in the denser 1500S
population, while the lighter 1500S population consisted of 300-800 nm
mitochondria exhibiting a varying degree of size-dependent inner membrane
folding. Using electron microscopy (EM) immunolocalization and serial sectioning,
we have identified in situ organelles resembling in size and in fine structure
the ss-mitochondria, which also exhibit a size-dependent folding of the inner
membrane. These results suggest that small ss-mitochondria may undergo a
progressive development in situ. Taken together, our findings demonstrate the
existence of a pattern of structure-function-coordinated gross heterogeneity
among mitochondria. This pattern of mitochondrial heterogeneity, characterized
both in isolated mitochondria and in situ, implies that small ss-mitochondria may
represent a type of "nascent mitochondria" derived from a yet unidentified
mitochondria-propagation mode operating during rapid seedling growth.
Mitochondrial division by binary fission, characterized by the appearance of
dumbbell-shaped intermediates, was also detected.
PMID- 9548378
TI - Apomorphine-induced hypoattention in rats and reversal of the choice performance
impairment by aniracetam.
AB - Aging-, disease- and medication-related imbalance of central dopaminergic neurons
causes functional impairment of cognition and neuropsychological delirium in
humans. We attempted to develop a new delirium model using the direct dopamine
agonist, apomorphine, and a choice reaction performance task performed by middle
aged rats. The psychological properties of the model were assessed by determining
behavioral measures such as choice reaction time, % correct and % omission.
Apomorphine (0.03-0.3 mg/kg s.c.) produced a dose-dependent impairment of task
performance. The dose of 0.1 mg/kg prolonged choice reaction time, decreased %
correct and increased % omission, indicating that rats had attentional deficits
and a reduced arousal or vigilance but no motor deficits or reduced food
motivation. This psychological and behavioral impairment of performance resembled
that of clinically defined delirium. In this model, the cholinomimetic,
aniracetam (10 mg/kg p.o.), reversed the performance impairment induced by
apomorphine. Its two metabolites, 2-pyrrolidinone (10 and 30 mg/kg p.o.) and N
anisoyl-gamma-aminobutyric acid (GABA, 10 mg/kg p.o.), effectively reversed the
performance impairment as the intact drug did. Another pyrrolidinone derivative,
nefiracetam (10 and 30 mg/kg p.o.), tended to worsen the apomorphine effect. The
cholinesterase inhibitor, tacrine (10 mg/kg p.o.), markedly worsened all of the
behavioral measures. Neuroleptics, haloperidol (0.025 mg/kg s.c.), tiapride (30
mg/kg p.o.) and sulpiride (10 and 30 mg/kg p.o.), antagonized the apomorphine
effect. The present results suggest that apomorphine-induced behavioral
disturbances in the choice reaction performance task seems to be a useful
delirium model and aniracetam may improve delirium through the action of 2
pyrrolidinone and N-anisoyl-GABA, presumably by facilitating dopamine release in
the striatum by acting as an AMPA or metabotropic glutamate receptor agonist.
PMID- 9548379
TI - Benzodiazepine receptor antagonists modulate the actions of ethanol in alcohol
preferring and -nonpreferring rats.
AB - The pyrazoloquinoline CGS 8216 (2-phenylpyrazolo-[4,3-c]-quinolin-3 (5H)-one,
0.05-2 mg/kg) and the beta-carboline ZK 93426 (ethyl-5-isopropyl-4-methyl-beta
carboline-3-carboxylate, 1-10 mg/kg) benzodiazepine receptor antagonists were
evaluated for their capacity to modulate the behavioral actions of ethanol in
alcohol preferring and -nonpreferring rats. When alcohol-preferring rats were
presented with a two-bottle choice test between ethanol (10% v/v) and a saccharin
(0.0125% g/v) solution, both antagonists dose-dependently reduced intake of
ethanol by 35-92% of control levels on day 1 at the initial 15 min interval of
the 4 h limited access. Saccharin drinking was suppressed only with the highest
doses. CGS 8216 (0.25 mg/kg) and ZK 93426 (4 mg/kg) unmasked the anxiolytic
effects of a hypnotic ethanol dose (1.5 g/kg ethanol) on the plus maze test in
alcohol-preferring rats, but potentiated the ethanol-induced suppression in
alcohol-nonpreferring rats. CGS 8216 (0.25 mg/kg) and ZK 93426 (4 mg/kg)
attenuated the ethanol (0.5 and 1.5 g/kg)-induced suppression in the open field
in alcohol-nonpreferring rats; however, CGS 8216 potentiated the depressant
effects of the lower ethanol dose (0.5 g/kg) in alcohol-preferring rats. These
findings provide evidence that benzodiazepine receptor antagonists may
differentially modulate the behavioral actions of ethanol in alcohol-preferring
and-nonpreferring rats. It is possible that the qualitative pharmacodynamic
differences seen in the present study may be related to selective breeding for
alcohol preference. The findings indicate the potential for development of
receptor specific ligands devoid of toxic effects which may be useful in the
treatment of alcohol abuse and alcoholism.
PMID- 9548381
TI - The antidepressant, nefazodone, attenuates corticosterone-induced increases in 5
HT2A receptor-mediated behaviors in the female rat.
AB - The effects of chronic corticosterone administration on sexual behavior and on
wet-dog shakes, a 5-HT2A mediated behavior, were investigated in the female rat.
In addition, effects of the antidepressant nefazodone, a selective 5-HT2A
receptor antagonist, both alone and in combination with corticosterone were
examined. Testing was conducted in ovariectomized animals primed with estrogen
and progesterone. Corticosterone was found to significantly increase sexual
receptivity, sexual proceptivity and wet dog shakes. While nefazodone alone had
no significant effects, it completely attenuated the corticosterone-induced
increases in both sexual behavior and wet dog shakes. This suggests that
corticosterone influences sexual behavior and wet dog shakes via a 5-HT2A
receptor mechanism.
PMID- 9548380
TI - Behavioral and neurochemical effects of the preferential dopamine D3 receptor
agonist cis-8-OH-PBZI.
AB - In the present study we investigated the in vivo pharmacological profile of the
benz[e]indole cis-8-hydroxy-3-(n-propyl)],2,3a,4,5,9b-hexahydro-1H-benz[e]indole
(cis-8-OH-PBZI), which has been described as a preferential dopamine D3 receptor
agonist in vitro. The compound inhibited spontaneous locomotor activity in mice,
an effect which was antagonized by the dopamine D3 receptor antagonist 5,6
dimethoxy-2-(di-u-propylamino) indan (U99194A). Moreover, cis-8-OH-PBZI inhibited
conditioned avoidance responding in rats, a preclinical test indicative of
antipsychotic efficacy, at doses which did not induce catalepsy. Doses of cis-8
OH-PBZI (6 and 12 mg/kg) that inhibited spontaneous locomotor activity in rats
did not affect interstitial levels of dopamine and dihydroxyphenylacetic acid
(DOPAC) in the nucleus accumbens or dorsolateral striatum. In contrast to the
effect of the dopamine receptor agonist (+/-)-2-dipropylamino-7-hydroxy-1,2,3,4
tetrahydronaphythalene (7-OH-DPAT), cis-8-OH-PBZI did not induce locomotor
activity in reserpinized mice. In conclusion, cis-8-OH-PBZI exhibits a
pharmacological profile that suggests it has antipsychotic activity but lacks the
motoric side effects often associated with antipsychotic medication. The data
suggest a mechanism requiring the activation of postsynaptic dopamine D3
receptors and support the hypothesis that these receptors mediate inhibitory
behavioral effects.
PMID- 9548382
TI - Concentration-dependent actions of a new indene derivative, TN-871, in the
enteric nervous system.
AB - Intracellular electrical recordings and fluorimetric measurement of intracellular
Ca2+ concentration ([Ca2+]i) were made from enteric neurons of the guinea-pig
myenteric and submucosal plexuses to examine the actions of 2-n-butyl-1-(4
methylpiperazinyl)5,6-ethylendioxyindene x 2HCl (TN-871) on neural activity in
the single cell. TN-871 affected neuronal electrophysiological properties and
synaptic transmission in the enteric nervous system in a concentration-dependent
manner; TN-871 at lower concentrations hyperpolarized enteric neurons and/or
facilitated synaptic transmission, whereas at higher concentrations it
depolarized enteric neurons and/or inhibited synaptic transmission. Experiments
with fura-2 showed that TN-871 modulated both resting [Ca2+]i and [Ca2+]i
transient associated with action potentials. Thus, the present results
demonstrated that TN-871 at lower concentrations facilitates but at higher
concentrations depresses Ca2+-dependent or Ca2+-involving processes, suggesting
that TN-871 may affect the Ca2+ dynamics in enteric neurons either directly,
indirectly or both.
PMID- 9548383
TI - Anxiolytic effects of flesinoxan in the stress-induced hyperthermia paradigm in
singly-housed mice are 5-HT1A receptor mediated.
AB - In the stress-induced hyperthermia paradigm in singly-housed male mice, two
sequential rectal temperature measurements reveal the basal temperature (T1) and,
10 min later, an enhanced body temperature (T2), due to the stress of the first
rectal measurement. The difference T2 - T1 (deltaT) is the stress-induced
hyperthermia and putatively reflects a stress-induced anxiogenic response. The
full 5-HT1A receptor agonist flesinoxan ((+)-enantiomer), its (-)-enantiomer and
the racemic mixture reduced stress-induced hyperthermia effects, indicating
putative anxiolytic properties. The ratio of their potencies to reduce stress
induced hyperthermia was similar to their potency in receptor binding affinities
for 5-HT1A receptors, supporting that the anti-hyperthermia effects are mediated
by the 5-HT1A receptor. This was further substantiated when the 5-HT1A receptor
antagonists WAY 100635 ((N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2
pyridinyl) cyclo-hexane carboxamine trihydrochloride) and DU 125530 (2-[4-[4-(7
chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl ]butyl]-1,2-benzisothiazol
3(2H)-one-1,1-dioxide, monomesylate) both were able to antagonize the anti-stress
induced hyperthermia effects of flesinoxan. The stress-induced hyperthermia
paradigm in singly-housed mice represents a simple and robust paradigm to measure
putative anxiolytic effects of drugs.
PMID- 9548384
TI - Inhibition of stimulus-triggered and spontaneous epileptiform activity in rat
hippocampal slices by the Aconitum alkaloid mesaconitine.
AB - The aim of the present study was to investigate if the plant alkaloid,
mesaconitine, which has been reported to have antinociceptive effects via
stimulation of the noradrenergic system, inhibits epileptiform field potentials.
The experiments were performed as extracellular recordings on rat hippocampal
slices. Epileptiform activity was induced by omission of Mg2+ from the bathing
medium or by addition of bicuculline and stimulus-evoked population bursts were
recorded in the CA1 region. Spontaneous epileptiform activity was elicited by
perfusing a nominally Mg2+-free bathing medium with high K+ concentration (5 mM).
Both stimulus-triggered and spontaneous epileptiform activity was attenuated in a
concentration-dependent manner by mesaconitine (30 nM-1 microM). The inhibitory
effect was rather variable in appearance when lower concentrations (30 and 100
nM) of mesaconitine were applied. Pretreatment of the slices with the alpha
adrenoceptor antagonist yohimbine (1 microM) prevented the effect of
mesaconitine. It is concluded that the inhibitory action of mesaconitine at low
concentration is mediated via alpha-adrenoceptors.
PMID- 9548385
TI - Lubeluzole protects hippocampal neurons from excitotoxicity in vitro and reduces
brain damage caused by ischemia.
AB - Previously reported effects of lubeluzole, such as inhibition of glutamate
release, inhibition of nitric oxide (NO) synthesis and blockage of voltage-gated
Na+- and Ca2+-ion channels, suggest a neuroprotective action of this drug. Here
we report about the effects of lubeluzole and its R-isomer on glutamate-induced
neuronal cell death in mixed hippocampal cultures. In addition, we studied the
effect of lubeluzole in focal cerebral ischemia models in mice and rats. In
hippocampal cultures exposed to 500 nM glutamate for 1 h, lubeluzole (0.1-100
nM), but not the R-isomer (1-100 nM), reduced the percentage of damaged neurons
from 42 +/- 8% to 18 +/- 7% (P < 0.01). In mice and rats, lubeluzole reduced
ischemic brain damage, when administered immediately after middle cerebral artery
occlusion. Interestingly, the protective effect (reduction of the infarct volume
in rats to 77% of control; P < 0.01) was also found when the lubeluzole treatment
(2.5 mg/kg) was started 3 h after ischemia. Especially this latter effect
suggests that lubeluzole will be a useful drug for stroke therapy.
PMID- 9548386
TI - The potency of the novel tachykinin receptor antagonist CGP49823 at rat and
gerbil motoneurones in vitro.
AB - The novel tachykinin receptor antagonist CGP49823 ((2R,4S)-2-benzyl-1-(3,5
dimethylbenzoyl)-4-(quinolin-4-y lmethylamino)piperidine) has been compared with
three other selective non-peptide tachykinin NK1 receptor antagonists. The drugs
were tested as antagonists of the depolarization of spinal motoneurones induced
by bath application of the selective tachykinin NK1 receptor agonist septide-(6
11) (300 nM) for 120 s at 15 min intervals. The antagonists were bath applied and
the depolarizations were recorded from lumbar ventral roots of 7 to 12 day old
rat and gerbil hemisected spinal cords in vitro. The gerbil preparation is
considered to model the human species variant of the tachykinin NK1 receptor.
With the exception of SR140333 ((S)-1-[2-[3-(3,4-dichlorophenyl)-1-[[3-(1
methylethoxy)phenyl]ace tyl]-3-piperidinyl]ethyl]-4-phenyl-1
azoniabicyclo[2.2.2]octane chloride), the antagonists were approximately thirty
fold more potent on gerbil preparations. The respective mean IC50 values from
gerbil preparations produced by CP96345 ((2S-cis)-2-(diphenylmethyl)-N-[(2
methoxyphenyl)methyl]-1-azabicy clo[2.2.2]octan-3-amine), CGP49823, SR140333 and
CP99994 ((2S-cis)-N-[(2-methoxyphenyl)methyl]-2-phenyl-3-piperidinamine) were, in
microM +/- S.E. (n) 0.10 +/- 0.02 (6), 0.22 +/- 0.03 (6), 0.30 +/- 0.10 (5) and
0.38 +/- 0.02 (5) and the corresponding values from the rat preparations were 3.7
+/- 0.4 (5), 7.8 + 1.3 (5), 1.06 +/- 0.16 (6) and 10.5 +/- 2.2 (7). Dominance of
tachykinin NK1 receptor activity in the measured responses was confirmed by low
potency of the tachykinin NK2-selective antagonist SR48968 ((S)-N-methyl-N[4-(4
acetylamino-4-phenyl piperidino)-2-(3,4-dichlorophenyl)butyl] benzamide) which
yielded an IC50 value of 12.0 +/- 2.8 (5) on gerbil preparations and produced
less than 50% depression of septide-induced depolarization of rat motoneurones at
the highest concentration (100 microM) tested.
PMID- 9548388
TI - Arachidonic acid metabolites and the synaptic potentiation evoked by activation
of metabotropic glutamate receptors.
AB - We have previously shown that coapplication of arachidonic acid (10 microM) and
(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD, 50 microM) evokes an
enhancement of synaptic transmission in the CA1 region of the rat hippocampal
slice. Here we have investigated whether the metabolites of arachidonic acid are
implicated in this potentiation. Inclusion of the cyclo-oxygenase inhibitor
indomethacin (10 microM) did not block the potentiation induced by coapplication
of arachidonic acid and ACPD. However, the presence of either the cyclo-, lipo-
and epoxygenase inhibitor 5,8,11,14-eicosatetraynoic acid (ETYA, 20 microM), or
the lipoxygenase inhibitor nordihydroguaiaretic acid (10 microM), prevented the
long-lasting enhancement. The results suggest that the lipoxygenase and
epoxygenase metabolites of arachidonic acid may be involved in the induction of
this form of synaptic potentiation.
PMID- 9548387
TI - MK-801 reverses Fos expression induced by the full dopamine D1 receptor agonist
SKF-82958 in the rat striatum.
AB - Administration of the selective and full dopamine D1 receptor agonist SKF-82958
((+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-b
enzazepine) (1 and 3 mg/kg i.p.) led to a dose-dependent induction of Fos protein
in the rat striatum. The 3 mg/kg SKF-82958-induced expression of striatal Fos
protein was blocked by the dopamine D1 receptor antagonist SCH-23390 (R(+)-7
chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benza zepine) (0.3
mg/kg i.p.). The noncompetitive NMDA receptor antagonist MK-801 ((5R,10S)-(+)-5
methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5 ,10-imine) (1 mg/kg i.p.) also
completely prevented striatal Fos induction by an injection of 3 mg/kg SKF-82958.
These results suggest that dopamine D1 receptor activation by the full agonist
SKF-82958 is sufficient to trigger Fos expression in the striatum, but that
concomitant stimulation of NMDA receptors is required for the striatal Fos
induction in response to dopamine D1 receptor activation.
PMID- 9548389
TI - Halothane attenuates nitric oxide relaxation of rat aortas by competition for the
nitric oxide receptor site on soluble guanylyl cyclase.
AB - Endothelial cells play an important role in the regulation of vascular activity
through the release of endothelium derived relaxing factor (EDRF) now believed to
be nitric oxide (NO). NO and the NO donor drug nitroglycerin relax vascular
smooth muscle by stimulating soluble guanylyl cyclase leading to elevation of
intracellular levels of cyclic guanosine 3',5'-monophosphate (cGMP). Halothane
has been shown to inhibit the action of NO on blood vessels. This study was
designed to further investigate the mechanisms by which halothane attenuates NO
induced vascular relaxations. This was done by examining the effects of halothane
on nitroglycerin and NO-induced relaxations in the presence and absence of the
inhibitors of soluble guanylyl cyclase, methylene blue and 6-anilino-5,8
quinolinedione (LY 83583). Thoracic aortas from anesthetized male Sprague-Dawley
rats were excised and cut into rings and the endothelium was removed. The aortic
rings were suspended in organ baths containing Krebs solution and equilibrated at
their optimal passive tension. When a stable plateau of contraction was produced
by EC60 concentrations of norepinephrine, increasing concentrations of
nitroglycerin or NO were added to the baths to relax the rings. This contraction
relaxation procedure was repeated three or four times. In some baths halothane
was administered by a calibrated vaporizer 10 min before beginning the second
procedure. Either methylene blue or LY 83583 was added to the baths 20 min before
the third procedure. The combination of halothane, methylene blue or LY 83583 was
added before the fourth procedure. Halothane, methylene blue or LY 83583
significantly inhibited nitroglycerin-induced relaxation individually. Halothane
and LY 83583 also significantly inhibited NO-induced relaxations (5 x 10(-9)-3 x
10(-8) M and 5 x 10(-9)-3 x 10(-5) M, respectively) individually. The combination
of halothane and methylene blue or halothane and LY 83583 significantly inhibited
nitroglycerin-induced relaxation, also, the combination of halothane and LY 83583
significantly inhibited NO-induced relaxations. Halothane, methylene blue and LY
83583 treatment led to rightward shift in the concentration-effect curves.
Halothane, in combination with methylene blue or LY 83583, produced inhibition
equivalent to the sum of their individual effects. The present study demonstrates
that the halothane, methylene blue and LY 83583 attenuate nitroglycerin and NO
induced relaxations of endothelium-denuded rat aortic rings. This suggests that
halothane, methylene blue and LY 83583 may act through competitive antagonism at
a common site of action on soluble guanylyl cyclase in the EDRF/NO relaxation
pathway.
PMID- 9548390
TI - Coronary vasoconstriction produced by vasopressin in anesthetized goats. Role of
vasopressin V1 and V2 receptors and nitric oxide.
AB - To examine the role of vasopressin V1 and V2 receptors, nitric oxide and
prostanoids in the coronary vascular effects of [Arg8]vasopressin, coronary blood
flow was measured with an electromagnetic flow transducer placed around the left
circumflex (23 goats) or anterior descending (11 goats) coronary artery and
vasopressin (0.03-1 microg) was intracoronarily injected in 34 anesthetized, open
chest goats. Basal mean values for coronary blood flow, mean systemic arterial
pressure and heart rate, were 34 +/- 2.38 ml/min, 89 +/- 3.34 mmHg and 80 +/-
3.06 beats/min, respectively. Vasopressin produced dose-dependent decreases in
coronary blood flow and the maximal reduction of this flow, attained with 1
microg of vasopressin, was 14 +/- 1.49 ml/min (42 +/- 2.64% of basal flow) (P <
0.01). Desmopressin (0.03-1 microg; 8 goats) did not affect significantly
coronary blood flow. The intracoronary infusion of the antagonist for vasopressin
V1 receptors d(CH2)5Tyr (Me) arginine vasopressin (2 microg/min per kg, 6
animals) significantly diminished the effects of vasopressin on coronary blood
flow (the effects of 1 microg of vasopressin were reduced by 28%, P < 0.05). The
mixed antagonist for vasopressin V1 and V2 receptors desGly-d(CH2)5-D-Tyr(Et)Val
arginine vasopressin (0.2, 0.7 and 2 microg/min per kg, 9 animals) decreased in a
dose-dependent manner the effects of vasopressin on coronary blood flow (the
effects of 1 microg of vasopressin were decreased by 61% with 2 microg/min per
kg, P < 0.01). Intracoronary infusion of saline (vehicle, 3 goats) did not change
the effects of vasopressin on coronary blood flow. Intravenous administration of
the inhibitor of nitric oxide synthesis N-omega-nitro-L-arginine methyl ester (L
NAME, 47 mg/kg, 9 animals) decreased resting coronary blood flow by 10% (P <
0.01) and augmented mean systemic arterial pressure by 20% (P < 0.01), without
changing heart rate. During this treatment the reduction in coronary blood flow
produced by vasopressin was higher than under control (the effects of 1 microg of
vasopressin were increased by 28%, P < 0.01). Intravenous administration of the
inhibitor of cyclooxygenase, meclofenamate (5 mg/kg, 7 animals), neither modified
resting coronary blood flow, arterial pressure and heart rate nor the effects of
vasopressin on this flow. These data indicate that vasopressin produces marked
coronary vasoconstriction and suggest that: (a) it may be mediated by vasopressin
V1 receptors, without involvement of vasopressin V2 receptors, (b) it is probably
inhibited by nitric oxide under normal conditions and (c) it may be not modulated
by prostanoids.
PMID- 9548391
TI - The effect of chronic L-carnitine treatment on blood pressure and plasma lipids
in spontaneously hypertensive rats.
AB - The effect of chronic L-carnitine treatment on blood pressure and plasma lipids
was studied in spontaneously hypertensive rats (SHR). L-Carnitine treatment for 6
weeks lowered significantly both the systolic and mean arterial pressure of SHR
but its influence on diastolic and pulse pressure was only modest. L-Carnitine
did not influence the relative heart and kidney weight of SHR. However, L
carnitine completely abolished the age-dependent rise of plasma total
cholesterol, triglycerides and uric acid seen in untreated SHR. On the other
hand, L-carnitine treatment had no significant effects on blood pressure,
relative organ weight and plasma lipids in normotensive Wistar-Kyoto rats. Our
results suggest that L-carnitine might prevent some cardiovascular alterations by
its influence on lipid metabolism.
PMID- 9548393
TI - Central effect of SNC 80, a selective and systemically active delta-opioid
receptor agonist, on gastrointestinal propulsion in the mouse.
AB - We investigated the effects of SNC 80 ((+)-4-[alphaR)-alpha-((2S,5R)-4-ally1-2,5
dimethyl-1-pipera zinyl)-3-methoxybenzyl]-N,N-diethylbenzamide), a new highly
selective, non-peptidic and systemically active delta-opioid receptor agonist, on
gastrointestinal and colonic propulsion in mice. Intraperitoneally (i.p.) SNC 80
(1, 10 and 30 mg/kg) significantly decreased gastrointestinal propulsion measured
as transit of an orally administered charcoal meal. Pretreatment with the delta
opioid receptor antagonist, naltrindole (1 mg/kg) subcutaneously (s.c.), with the
non-selective opioid antagonist, naloxone (5 mg/kg, s.c.) or the mu1-opioid
receptor antagonist, naloxonazine (10 mg/kg, i.p.), significantly decreased the
antitransit effect of SNC 80 but pretreatment with the non-selective opioid
antagonist, naloxone methiodide (5 mg/kg, s.c.), a quaternary salt of naloxone
that does not cross the blood-brain barrier, did not. SNC 80 (1, 5 and 10 mg/kg,
i.p.), produced dose-related inhibition of colonic propulsion measured as the
increase in mean expulsion time of a 3 mm glass bead placed in the distal colon.
Naloxone (5 mg/kg, s.c.) and naltrindole (1 mg/kg, s.c.), completely antagonized
the colonic antipropulsive effect of SNC 80. In contrast, naloxone methiodide (5
mg/kg, s.c.), left the inhibitory effect of i.p. SNC 80 on colonic function
unchanged. These results suggest that peripherally injected SNC 80 inhibits
gastrointestinal transit and colonic propulsion. It does so mainly through a
central mechanism. Although the gastrointestinal antitransit effect of SNC 80 is
naltrindole- and naloxonazine-sensitive, we cannot exclude an opioid-independent
mechanism. The colonic antipropulsive effect of SNC 80 confirms the inhibitory
role of the central delta-opioid receptor system on colonic motility.
PMID- 9548392
TI - Platelet-activating factor receptor antagonist attenuates endotoxin-induced
vascular hyporeactivity in the pithed rat.
AB - The role of platelet activating factor (PAF) and nitric oxide (NO) in the
endotoxin-induced hyporeactivity to noradrenaline was studied in the pithed rat.
Pressor dose-response curves to noradrenaline (0.01-10 microg/kg, i.v.) were made
starting 1 h after the administration of endotoxin (0.5 mg/kg, i.v.) to the rats.
Saline was administered to the control rats. The PAF receptor antagonist, TCV-309
(3-bromo-5-[N-phenyl-N-[2-[[2-(1,2,3,4-tetrahydro-2-isoquinolylcarbon
yloxy)ethyl]carbamoyl]ethy]carbamoyl]-1-propylpyridinium nitrate, 100 microg/kg,
i.v.), or the NO synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA, 30
mg/kg, i.v.), was administered to the endotoxin-treated rats 20 or 10 min before
the noradrenaline challenge. L-NMMA reversed endotoxin-induced hyporeactivity
completely. TCV-309 produced a significant, but partial attenuation of the
hyporeactivity to noradrenaline (P < 0.01). There was still significant
hyporeactivity when compared with the control rats (P < 0.01) and the L-NMMA
treated endotoxin-administered rats (P < 0.05). These data suggest that
endogenous PAF contributes to the vascular hyporeactivity to noradrenaline
induced by endotoxin and that NO plays a major role in the endotoxin-induced
hyporeactivity.
PMID- 9548395
TI - Respiratory effects of halothane and AMPA receptor antagonist synergy in rats.
AB - The influence of N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5
methylisoxazole-4-propionate (AMPA) receptor antagonists in combination with
halothane anaesthesia on the respiratory system was investigated. Under 1.5%
halothane anaesthesia, respiratory parameters including respiratory rate, minute
volume, tidal volume, inspiratory and expiratory duration were measured before
and after drug administration in rats. The AMPA receptor antagonists, 6-(1H
imidazol-1-yl)-7-nitro-2,3-(1H,4H)-quinoxalinedione hydrochloride, YM90K (5 and
10 mg/kg) and 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX, 15
mg/kg), which were administered intravenously for 30 min, significantly reduced
the respiratory rate (P < 0.01) and minute volume (P < 0.01) and increased the
tidal volume (P < 0.05) compared with values obtained before drug administration.
None of these drugs affected respiratory parameters in the absence of
anaesthesia. A NMDA receptor antagonist, MK-801 (0.5 mg/kg), which was
administered intravenously for 30 min, also significantly reduced respiratory
rate (P < 0.01), minute volume (P < 0.01) and tidal volume (P < 0.01) and
prolonged inspiratory duration (P < 0.05). These results suggest that both AMPA
and NMDA receptor antagonists cause respiratory depression under halothane
anaesthesia in rats, although the mechanisms may be different for the two types
of antagonists.
PMID- 9548394
TI - Effect of cigarette smoke on ethanol-induced gastric mucosal lesions: the role of
nitric oxide and neutrophils.
AB - The roles of neutrophil aggregation, inducible nitric oxide synthase activation
and chemoattractant, leukotriene B4, in potentiation of the cigarette smoke
effect on ethanol-induced gastric mucosal damage were studied. Smoke exposure
markedly increased gastric lesion formation following ethanol administration and
this was accompanied by substantial increase in gastric mucosal leukotriene B4
concentration, myeloperoxidase and inducible nitric oxide synthase activities.
Antineutrophil serum or aminoguanidine pretreatment significantly attenuated both
gastric mucosal lesion formation and inducible nitric oxide synthase activity.
The increased myeloperoxidase activity was abolished by antineutrophil serum but
not by aminoguanidine. These data indicated that both neutrophil mobilization and
inducible nitric oxide synthase activation in the gastric mucosa play an
important role in the potentiating action of cigarette smoke on ethanol-induced
gastric mucosal lesion formation. Increased synthesis of nitric oxide from
inducible nitric oxide synthase during gastric damage may be secondary to
neutrophil infiltration in the gastric mucosa. Chemoattractant leukotriene B4
could also contribute to neutrophil recruitment in the tissue.
PMID- 9548396
TI - Preventive effects of the deleted form of hepatocyte growth factor against
various liver injuries.
AB - The effects of a naturally occurring deleted form of hepatocyte growth factor
(HGF) on hepatic disorder were studied in various models of hepatic failure. The
pretreatment of rats and mice with the deleted form of HGF prevented the liver
injuries and coagulopathy induced by endotoxin, dimethylnitrosamine and
acetaminophen and reduced the mortality due to hepatic dysfunction induced by
these hepatotoxins. The concurrent administration of the deleted form of HGF also
prevented the liver injury and hepatic fibrosis in mice treated with alpha
naphthylisothiocyanate and in rats treated with dimethylnitrosamine. Moreover,
the deleted form of HGF normalized the results of the bromosulphalein-clearance
test and ameliorated jaundice in rats with periportal cholangiolitic hepatopathy
induced by alpha-naphthylisothiocyanate. The deleted form of HGF also reversed
the coagulopathy in rats with hepatic disorder induced by dimethylnitrosamine or
by 70% resection of cirrhotic liver (induced by carbon tetrachloride). In Long
Evans cinnamon rats receiving vehicle, 20 out of 21 animals died within 4 days
after the onset of jaundice. After infusion of the deleted form of HGF for 4
days, 7 out of 20 Long-Evans cinnamon rats survived. These results indicate that
the deleted form of HGF could have therapeutic potency in patients with severe
hepatic failure.
PMID- 9548398
TI - A nitric oxide donor NOC 7 suppresses renal responses induced by norepinephrine
and angiotensin II in the NO-depleted denevated rabbit kidney.
AB - Intrarenal arterial infusion of norepinephrine (30 ng/kg per min) or of
angiotensin II (4 ng/kg per min) reduced the glomerular filtration rate and
urinary Na+ excretion in denervated kidneys of anesthetized rabbits pretreated
intrarenally with a nitric oxide (NO) synthase inhibitor N(omega)-nitro-L
arginine methyl ester (50 microg/kg per min). Angiotensin II but not
norepinephrine reduced fractional Na+ excretion. Intrarenal administration of a
spontaneous NO donor 1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1
triazene (NOC 7, 30 ng/kg per min) in L-NAME pretreated kidneys did not affect
basal values, but attenuated the reduction in urinary Na+ excretion induced by
these agonists without affecting the angiotensin II-induced reduction in
glomerular filtration rate. The results suggest that NOC 7 can suppress the
norepinephrine-induced hypofiltration and the angiotensin II-evoked tubular
reabsorption and thereby attenuates the agonist-induced antinatriuresis in the
denervated and endogenous NO-depleted rabbit kidney.
PMID- 9548397
TI - Effect of dopamine on NaCl transport in the medullary thick ascending limb of the
rat.
AB - The aim of the present study was to determine whether dopamine affects NaCl
reabsorption in the medullary thick ascending limb of the loop of Henle.
Basolateral dopamine (10(-6) M) significantly inhibited Cl- reabsorption in the
in vitro microperfused rat medullary thick ascending limb by 21 +/- 2% (P <
0.01). The response to 10(-6) M dopamine was completely blocked by pretreatment
with the dopamine D1 receptor antagonist R(+)-SCH-23390 (5 x 10(-5) M), and was
mimicked by the dopamine D1 receptor agonist A-77636 (10(-6) M; delta - 36 +/-
2%; P < 0.05). In contrast, basolateral administration of the dopamine D2
receptor agonist (+)-bromocriptine (10(-6) M) transiently increased Cl-
reabsorption by 49 +/- 18% (P < 0.05). Neither the D1 nor the D2 agonist affected
Cl- reabsorption when selectively administered to the luminal membrane. These
data suggest that the predominant effect of dopamine on the medullary thick
ascending limb of the rat is to inhibit the reabsorption of NaCl, a response
which is mediated by dopamine D1 receptors.
PMID- 9548399
TI - Insulin and glucagon secretion by ganglionic nicotinic activation in
adrenalectomized mice.
AB - The pancreatic islets are innervated by nerves emanating from intra- and
extrapancreatic ganglia. However, the effects of ganglionic activation on insulin
and glucagon release in vivo have not been established. We therefore investigated
the effects of pharmacological ganglionic activation by the nicotinic agonists
DMPP (1,1-dimethyl-4-phenylpiperazinium iodide) and nicotine on insulin and
glucagon release in sham-operated and adrenalectomized mice. In sham-operated
animals, DMPP (0.5 or 1.6 micromol/kg, i.v.) or nicotine (0.075 or 0.75
micromol/kg, i.v.), did not affect plasma insulin levels, but markedly increased
plasma glucagon levels (P < 0.05). In contrast, after adrenalectomy or alpha2
adrenoceptor blockade by yohimbine (3.6 micromol/kg), nicotinic activation
markedly increased plasma insulin levels (P < 0.05), whereas the glucagon
response to nicotinic activation was inhibited under these conditions (P < 0.05).
We conclude that pharmacological ganglionic nicotinic activation in mice
stimulates insulin and glucagon secretion. The insulinotropic effect is, however,
counteracted by a concomitant adrenal activation through an alpha2-adrenoceptor
mediated mechanism.
PMID- 9548400
TI - Combination of OK432 and human interferon-alpha for treating viral-induced
diabetes mellitus in mice.
AB - We investigated the therapeutic effects of OK432 (picibanil; CAS39325-1-4), an
immunomodulator that is derived from the Su strain of Streptococcus pyogenes.
This agent was administered alone or combined with human interferon-alpha in a
murine model of insulin-dependent diabetes mellitus. Interferon-alpha inhibits
viral replication, reducing the incidence of virus-induced IDDM. Groups of DBA/2
mice (N = 25 per group) received an intraperitoneal injection of OK432 and
interferon-alpha daily for 16 d beginning 1 d after inoculation with 500 plaque
forming units of encephalomyocarditis virus (EMCV). The dose of OK432 was one
clinical unit (corresponding to 0.1 mg dried cells) per mouse, and that of
interferon-alpha was 1 x 10(4) u/g. The animals were killed at random at 3 or 7 d
after inoculation with EMCV. The survival rate of mice treated with the
combination of OK432 and with interferon-alpha was significantly greater than
that of the non-treated infected control animals (P < 0.01). Fasting levels of
blood glucose were significantly lower in the mice administered the combination,
than in the controls, both on day 3 (68 +/- 21 mg/dl vs. 270 +/- 135 mg/dl, P <
0.01) and on day 7 (101 +/- 29 mg/dl vs. 219 +/- 112 mg/dl, P < 0.01). Serum
levels of insulin were significantly higher in the treated mice than in the
controls (65 +/- 5 vs. 55 +/- 1 microU/ml, P < 0.05). However, in the mice
treated with OK432 or interferon-alpha alone, the survival rate and the blood
level of glucose and insulin did not differ from those of infected controls.
Natural killer (NK) cell activity was significantly higher in the mice treated
with the drug combination than in the controls on both days evaluated: day 3, 65
+/- 5 vs. 55 +/- 1%, n = 3, P < 0.05; day 7, 44 +/- 3 vs. 22 +/- 8%, n = 3, P <
0.05). Serum levels of murine interferon in the treated mice exceeded those in
controls on both days evaluated (day 3, 671 U/ml vs. 442 U/ml; day 7, 57 U/ml vs.
43 U/ml). There were no significant differences in NK cell activity or in the
interferon level in mice treated with either OK432 or interferon-alpha alone as
compared with the infected, non-treated controls. Results suggest that the
combination of OK432 and interferon-alpha protects against virally induced IDDM
by increasing the activity of NK cells as well as the plasma level of interferon.
PMID- 9548402
TI - Alpha1-adrenoceptor subtype activation increases proto-oncogene mRNA levels. Role
of protein kinase C.
AB - Noradrenaline increased the mRNA levels of c-fos and c-jun in rat-1 fibroblast
lines stably expressing the cloned alpha1-adrenoceptor subtypes. The efficacy to
induce the expression of c-fos mRNA was similar for the three cell lines (alpha1d
= alpha1b = alpha1a) but different for c-jun (alpha1a > or = alpha1b > alpha1d).
The EC50 values were also different: approximately 5 nM (c-fos) and approximately
300 nM (c-jun) for cells transfected with the alpha1a subtype, approximately 30
nM (c-fos) and approximately 300 nM (c-jun) for cells transfected with the
alpha1b subtype and approximately 300 nM (c-fos and c-jun) for those transfected
with the alpha1d subtype. Staurosporine and protein kinase C down-regulation
blocked such effects, indicating a role of this protein kinase. Endothelin-1 (10
nM) also increased the levels of c-fos and c-jun mRNAs. These actions of
endothelin-1 were unaffected by staurosporine and protein kinase C down
regulation. It is concluded that activation of any of the three cloned subtypes
can increase the levels of c-fos and c-jun mRNAs and that protein kinase C plays
a major role in mediating such effects.
PMID- 9548401
TI - Glatiramer acetate blocks the activation of THP-1 cells by interferon-gamma.
AB - Glatiramer acetate (previously known as copolymer 1) is a synthetic copolymer of
four amino acids that has been approved for use in the treatment of multiple
sclerosis. It has been shown to suppress myelin antigen specific T cell
activation by competing with these antigens at the major histocompatibility
complex class II binding site and by inducing antigen specific suppressor T
cells. In this study we investigated the effects of glatiramer acetate on the
human monocytic cell line, THP-1, activated by lipopolysaccharide and interferon
gamma as a model for macrophages. At non-toxic concentrations of glatiramer
acetate there were dose dependent reductions in the percentage of cells
expressing human leukocyte DR and DQ antigen as well as in mean fluorescence
intensity by flow cytometry. Production of tumor necrosis factor-alpha and the
lysosomal cysteine proteinase cathepsin B were markedly inhibited, but production
of interleukin-1 increased. These results suggest that glatiramer acetate might
alter macrophage effector function and suggest that further studies in human
monocytes and macrophages are warranted.
PMID- 9548403
TI - Binding characterization of [3H]S-0139, an antagonist of the endothelin ET(A)
receptor subtype.
AB - S-0139 (27-O-3-[2-(3-carboxy-acryloylamino)-5-hydroxyphenyl]-acryloylo xy
myricerone, sodium salt) is a highly specific nonpeptide endothelin ET(A)
receptor antagonist. The binding of [3H]S-0139 was compared to that of
[125I]endothelin-1 to characterize the binding of the antagonist in porcine
aortic smooth muscle membranes. Scatchard analysis revealed a single class of
[3H]S-0139 binding sites with a Kd value of 0.61 +/- 0.10 nM and a Bmax of 0.72
+/- 0.16 pmol/mg protein. These sites were saturable and reversible.
[125I]Endothelin-1 also showed binding with high affinity (Kd = 0.12 +/- 0.02 nM)
to a homogeneous population of binding sites, whose Bmax (0.71 +/- 0.20 pmol/mg
protein) was almost the same as that for [3H]S-0139. In both cases, the binding
could be displaced by known endothelin receptor ligands and their IC50 values in
each case showed a very close correlation (r = 0.986). The potency of seven
endothelin receptor antagonists to displace [3H]S-0139 binding also correlated
highly to the potency for inhibiting the endothelin-1-induced increase in
cytosolic Ca2+ concentration (r = 0.949). Myriceric acid A showed a more potent
functional activity than expected from its binding affinity, but this seemed to
result from the different assay conditions, such as incubation time. Together,
the results suggest that S-0139 labels only endothelin ET(A) receptor binding
sites in porcine aortic smooth muscle.
PMID- 9548404
TI - Mechanism of the dynorphin-induced dualistic effect on free intracellular Ca2+
concentration in cultured rat spinal neurons.
AB - In order to study the different mechanisms of dynorphin spinal analgesia and
neurotoxicity at low and high doses, the effects of various concentrations of
dynorphin A-(1-17) on the free intracellular Ca2+ concentration ([Ca2+]i) in the
cultured rat spinal neurons were studied using single cell
microspectrofluorimetry. While dynorphin A-(1-17) 0.1-100 microM had no
significant effect on basal [Ca2+]i, dynorphin A-(1-17) 0.1 and 1 microM
significantly decreased the high KCl-evoked peak [Ca2+]i by 94% and 83%
respectively. Dynorphin A-(1-17) 10 and 100 microM did not affect the peak
[Ca2+]i following K+ depolarization, but in all these neurons there was a
sustained and irreversible rise in [Ca2+]i following high-K+ challenge.
Pretreatment with the specific kappa-opioid receptor antagonist nor
binaltorphimine 10 microM, but not the competitive NMDA receptor antagonist, DL-2
amino-5-phosphonovalerate (APV) 10 microM, significantly blocked the inhibitory
effect of dynorphin A-(1-17) 0.1 microM on peak [Ca2+]i. However, APV 10 microM
and nor-binaltorphimine 10 microM significantly antagonized the sustained rise in
[Ca2+]i induced by a high concentration of dynorphin A-(1-17) 10 microM.
Furthermore, in the presence, and following the addition, of increasing
concentrations of dynorphin A-(1-17) (0.1, 1, 10 and 100 microM), the high
concentrations of dynorphin A-(1-17) failed to produce a sustained rise in peak
[Ca2+]i. These results suggested that dynorphin exerted a dualistic modulatory
effect on [Ca2+]i in cultured rat spinal neurons, inducing a sustained and
irreversible intracellular Ca2+ overload via activation of both NMDA and kappa
opioid receptors at higher concentrations, but inhibiting depolarization-evoked
Ca2+ influx via kappa-opioid but not NMDA receptors at lower concentrations.
Serial addition of graded concentrations of dynorphin A-(1-17) prevented the
effect of high concentrations of dynorphin A-(1-17) on [Ca2+]i.
PMID- 9548405
TI - Chloroquine inhibits alpha1B-adrenergic action in hepatocytes.
AB - Noradrenaline increased phosphorylase a activity through activation of alpha1B
adrenoceptors in rat hepatocytes. Such effect was inhibited by chloroquine (Ki
approximately 55 nM) and only slightly reduced by high concentrations of
primaquine. Chloroquine did not inhibit the activation of phosphorylase a induced
by vasopressin or angiotensin II. Binding competition experiments using
[3H]prazosin showed that both chloroquine and primaquine interact with alpha1B
adrenoceptors, but only at very high concentrations. This indicates that the
ability of chloroquine to block the alpha1B-adrenergic action was not due to
antagonism at the receptor level. Noradrenaline increased phosphatidylinositol
resynthesis and inositol trisphosphate production; these effects were inhibited
by chloroquine and phorbol 12-myristate 13-acetate. Staurosporine and Ro 31-8220
(3-[1-[3-(amidinothio)propyl-1H-indol-3-yl]-3-(1-methyl-1H-indol-3
yl)maleimide), reduced the inhibitions induced by the active phorbol ester and
the antimalarial drug on adrenergic-stimulated phosphatidylinositol resynthesis.
Similarly, staurosporine blocked the inhibitory actions of chloroquine and
phorbol 12-myristate 13-acetate on noradrenaline-stimulated inositol
trisphosphate production. These data suggest the possibility that protein
kinases, such as protein kinase C, could be involved in the actions of
chloroquine.
PMID- 9548406
TI - Different potencies of dihydropyridine derivatives in blocking T-type but not L
type Ca2+ channels in neuroblastoma-glioma hybrid cells.
AB - Evidence has accumulated that classic L-type Ca2+ channel blockers with a
dihydropyridine structure also inhibit T-type Ca2+ channels in certain types of
central and peripheral neurons and in smooth muscle cells, albeit with a lower
potency. Thus beneficial therapeutic effects of dihydropyridines in
cardiovascular and neurological diseases may not only be associated with L-type
but also with T-type Ca2+ channel blockade. Little is known about the exact order
of potency of dihydropyridine derivatives at T-type Ca2+ channels. Here we
investigate the efficacy and potency of four therapeutically used compounds, i.e.
nifedipine, nimodipine, nicardipine, niguldipine, in the neuroblastoma-glioma
cell line NG108-15. For comparative purposes the Ca2+ channel agonist Bay K 8644
was included. Ca2+ channel currents were measured with the whole-cell voltage
clamp technique. Subtype Ca2+ channel currents were separated by clamp protocol
and selective blockers. T-type Ca2+ channel currents were inhibited with
decreasing potency in the order niguldipine > nicardipine > nimodipine >
nifedipine (IC50-values 244 nM, 2.5 microM, 9.8 microM, 39 microM), whereas L
type Ca2+ channel currents were blocked with similar potency (IC50 for
nicardipine 75 nM). Bay K 8644 increased T-type Ca2+ channel current at nanomolar
concentrations (i.e. 95 +/- 16% increase by 300 nM). T-type Ca2+ channel block
was completely reversible with exception of the block by niguldipine. Our results
indicate a variability of two orders of magnitude in potency of T-type Ca2+
channel block by the dihydropyridine derivatives investigated. It is speculated
that the relation between the L- and T-type Ca2+ channel block may determine the
therapeutic profile of a dihydropyridine derivative.
PMID- 9548407
TI - CP-060S interacts with three principal binding sites on the L-type Ca2+ channel.
AB - CP-060S, (-)-(S)-2-[3,5-bis(1,1-dimethylethyl)-4-hydroxypheny1]-3-[3-[N-met hyl-N
[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]-1,3-thi azolidin-4-one hydrogen
fumarate is a novel cardioprotective drug, which is able to prevent Na+-, Ca2+
overload and also has Ca2+ channel blocking activity. The latter action of CP
060S was characterized by radioligand binding experiments with rat cardiac
membranes in terms of the interaction with the three principal binding sites on
the L-type Ca2+ channel, which bind such drugs as the 1,4-dihydropyridines,
phenylalkylamines and benzothiazepines. CP-060S exhibited complete and
concentration-dependent inhibition of [3H](+)-PN200-110, [3H](-)
desmethoxyverapamil and [3H]cis-(+)-diltiazem binding to their specific binding
sites. Saturation studies showed that CP-060S increased the Kd of [3H](+)-PN200
110 and [3H](-)-desmethoxyverapamil without causing a significant change in the
maximum binding density. The dissociation kinetics of the three radioligands were
accelerated by CP-060S. These results suggest that CP-060S interacts with a novel
binding site on the L-type Ca2+ channel and has a negative allosteric interaction
with the three principal binding sites for the 1,4-dihydropyridines,
phenylalkylamines and benzothiazepines.
PMID- 9548409
TI - The tachykinin NK1 receptor antagonist, RP67580, inhibits the bradykinin-induced
rise in intracellular Ca2+ concentration in bovine pulmonary artery endothelial
cells.
AB - The bradykinin-induced rise in intracellular Ca2+ concentration ([Ca2+]i) and the
bradykinin receptor involved in this response were characterized in bovine
pulmonary artery endothelial cells. It was found that bradykinin induces an
intracellular biphasic Ca2+ response, consisting of a transient peak followed by
an elevated plateau phase. Both bradykinin and the bradykinin B1 receptor
agonist, des-Arg9-bradykinin, induced a concentration-dependent increase in
[Ca2+]i, but the bradykinin-induced rise was much greater. Moreover, the
bradykinin-induced [Ca2+]i rise could be inhibited by the bradykinin B2 receptor
antagonists, D-Arg0[Hyp3, Thi(5,8), D-Phe7]bradykinin and Hoe 140 (D-Arg[Hyp3,
Thi5, D-Tic7, Oic8]bradykinin), but not by the bradykinin B1 receptor antagonist,
des-Arg9-[Leu8]bradykinin. From these results it can be concluded that a
bradykinin B2 receptor is involved in this response. Furthermore, we found that
the tachykinin NK1 receptor antagonist, RP67580 ([imino 1 (methoxy-2-phenyl)-2
ethyl]-2 diphenyl 7,7 perhydroisoindolone-4 (3aR, 7aR)), and its negative
enantiomer, RP68651 (2-[1-imino 2-(2 methoxy phenyl) ethyl] 7,7 diphenyl 4
perhydroisoindolone (3aS-7aS)), could inhibit the bradykinin-induced [Ca2+]i
response, although no functional tachykinin NK1 receptors were found. Binding
studies evidenced no binding of RP67580 or RP68651 to the bradykinin receptor. We
conclude that RP67580 inhibits the bradykinin-induced rise in [Ca2+]i via a
bradykinin B2 receptor-independent mechanism.
PMID- 9548408
TI - Inhibition of recombinant human cardiac L-type Ca2+ channel alpha1C subunits by 3
isobutyl-1-methylxanthine.
AB - Inhibition of ion channels by the phosphodiesterase inhibitor 3-isobutyl-1
methylxanthine (IBMX) and related compounds has been demonstrated in various cell
types, including the neuromuscular junction, GH3 cells and vascular smooth muscle
cells. These effects may be unrelated to the actions of these compounds on
cellular metabolism, intracellular Ca2+ stores and phosphodiesterase inhibition.
In this study, the inhibition of recombinant human cardiac L-type Ca2+ channel
alpha1C subunits by IBMX was examined using the whole-cell configuration of the
patch clamp technique. Inhibition was repeatable, voltage-independent and
associated with increased apparent channel inactivation. The actions of IBMX were
unaffected in the presence of inhibitors of protein kinases A and G. The non
xanthine phosphodiesterase inhibitor rolipram had a small inhibitory effect on
currents, but this was also unaffected by a protein kinase A inhibitor. These
effects of IBMX could not be attributed to release of Ca2+ from intracellular
stores. Our findings indicate that methylxanthines can inhibit the cardiac L-type
Ca2+ channel alpha1C subunit in the absence of auxiliary subunits by an
undetermined, possibly direct mechanism.
PMID- 9548410
TI - Adaptation of cortical NMDA receptors by chronic treatment with specific
serotonin reuptake inhibitors.
AB - Glycine displaces [3H]CGP-39653 ([3H]D,L-(E)-2-amino-4-propyl-5-phosphono-3
pentenoic acid) binding to the glutamate recognition site with both high and low
affinity. We reported previously that chronic treatment with antidepressants
reduced the proportion of high to low affinity sites, or, even eliminated the
high affinity sites in case of citalopram. Here, we compared the effects of
citalopram with another serotonin specific reuptake inhibitor, fluoxetine on this
measure. Chronic administration of citalopram or fluoxetine eliminated high
affinity glycine-displaceable [3H]CGP-39653 binding to the mouse cortex in 78 and
56% of animals, respectively, indicating that selective serotonin reuptake
inhibitors produce qualitatively similar adaptive changes at NMDA receptors, that
differ from other antidepressants in this neurochemical measure.
PMID- 9548411
TI - Inhibition of ornithine decarboxylase by ifenprodil.
AB - Ifenprodil (NMDA receptor antagonist) was tested as an inhibitor of ornithine
decarboxylase. It was found that ifenprodil inhibited ornithine decarboxylase
activity with the same potency as alpha-difluoromethylornithine, a major
inhibitor of ornithine decarboxylase. This result suggests that ifenprodil could
target either the polyamine site on the NMDA receptor complex or/and polyamine
biosynthesis.
PMID- 9548412
TI - Expression of dipeptidylaminopeptidase IV/CD26 in peripheral blood lymphocytes of
hemophilic subjects.
AB - CD26 antigen, a 110 kDa membrane glycoprotein with exopeptidase activity (DAP
IV), is an activation marker of T lymphocytes preferentially expressed on CD4+
memory cells and involved in T cell proliferation and IL-2 production after
antigenic stimulation. We employed cytochemical and immunocytochemical techniques
to study DAP IV/CD26 expression in circulating lymphocytes from 40 hemophilic
patients, chronically treated with coagulation factors, in order to verify the
possible involvement of this molecule in the immunological alterations of
hemophilia. In all the hemophiliacs DAP IV activity was significantly lower than
in the controls, independently of the quantity of blood transfused and previous
exposure to viruses. This reduction may be responsible for the impaired
proliferative response of lymphocytes to antigens and mitogens, notoriously
observed in hemophilia. Whereas in the group of HIV- patients CD26 expression was
similar to that of normal controls, in the 8 HIV+ hemophilic patients both
percentages of positive lymphocytes and intensity of staining were significantly
lower. In only 4 of the 8 cases was this deficit associated with CD4+ cell
depletion. The significant selective loss of CD26 expression observed in HIV+
patients is probably an early event after HIV infection and seems to occur even
before CD4 cell depletion. In conclusion, evaluation of DAP IV/CD26 might be a
useful option for monitoring the immunological alterations of all hemophilic
patients, HIV positive or not, chronically treated with coagulation factors.
PMID- 9548413
TI - Circulating CD34+ cells in cord blood and mobilized blood have a different
profile of adhesion molecules than bone marrow CD34+ cells.
AB - The expression of adhesion molecules was studied on CD34+ hematopoietic
precursors in cord blood, bone marrow and mobilized blood. The samples were
labeled in a double immunofluorescence procedure with a CD34 monoclonal antibody
and with antibodies against maturation and differentiation antigens and adhesion
molecules. Myeloid precursors formed the majority of the CD34+ cells in all
samples. In bone marrow a separate cluster of B-cell precursors with low forward
scatter was present. Nearly all CD34+ cells in normal bone marrow expressed VLA-4
and VLA-5, PECAM-1, LFA-3 and HCAM. The majority of the CD34+ cells also had LFA
1 and L-selectin on the surface membrane. A small subset was VLA-2, VLA-3, ICAM-1
or Mac-1 positive. CD34+ cells expressing the vitronectin receptor or the CD11c
antigen were rare. Cord blood and mobilized blood CD34+ cells had a lower
expression of VLA-2, VLA-3 and VLA-5 and a higher expression of LFA-1, ICAM-1 and
L-selectin than bone marrow CD34+ cells. Except for LFA-1, this was not due to
the presence of more myeloid precursors in these samples. Low beta1 integrin
expression may lead to less adhesion to the extracellular matrix. High expression
of L-selectin may facilitate interaction with endothelial cells. Therefore, this
phenotype may favour mobilization.
PMID- 9548414
TI - Inv(16) acute myeloid leukemia cells show an increased sensitivity to cytosine
arabinoside in vitro.
AB - Karyotype represents the major independent prognostic factor for response and
remission duration in acute leukemia. In particular, it has been reported that
acute myeloid leukemia (AML) patients with inv(16) abnormality show a better
prognosis, especially in case of treatment with high-dose Ara-C (HD Ara-C)
containing regimens. In this study we aimed at testing whether leukemic cells
from patients showing the inv(16) were more sensitive to Ara-C in vitro, compared
to AML blasts from patients with normal karyotype or chromosomal abnormalities
other than t(15;17) or t(8;21). We analyzed blast cells from 30 patients who were
diagnosed and treated in our institution. The IC50 of Ara-C, as tested by the XTT
colorimetric assay, was significantly lower in cases with inv(16) (18.5+/-15.88
micromol/l vs. 38+/-14.6 micromol/l,in cases with other abnormalities, p=0.01).
This result was confirmed by a higher incorporation of [3H]-Ara-C into DNA
(p=0.02 and p=0.001 compared to samples with normal and abnormal karyotype,
respectively). All the same, Ara-C induced apoptosis was significantly increased
in cells from patients with inv(16). Our data suggest a possible interaction
between the molecular background of inv(16) and a modification of intracellular
metabolism of Ara-C, and could thus provide a rationale for HD-Ara-C-based
schedules for patients with inv(16) AML.
PMID- 9548415
TI - Methyl-GAG, ifosfamide, methotrexate and etoposide (MIME) as salvage therapy for
Hodgkin's disease: a prospective study.
AB - This study presents the results of a prospective study of methyl-gag, ifosfamide,
methotrexate and etoposide (MIME) as salvage regimen for Hodgkin's disease (HD)
in Sweden. Sixty-four patients with recurrent or refractory HD were treated with
MIME between July 1988 and December 1993. All patients except one had, earlier,
been treated with and failed consecutive or alternating MOPP and ABVD. Median age
was 37 yr (range 14-73). Twenty patients (31%) achieved a complete remission (CR)
and 17 (27%) a partial remission (PR), giving an overall response rate of 58%.
The 5-yr survival for all patients was 43%. In a multivariate analysis, the most
important factors predicting a poor survival were the presence of extranodal
disease at relapse, male gender and high age. Twenty-nine patients were treated
with high-dose chemotherapy with stem-cell rescue after MIME. Those patients had
a similar survival compared to the patients responding to MIME but not treated
with high-dose chemotherapy. We conclude that MIME induces remissions in a high
proportion of patients with recurrent and refractory HD with acceptable toxicity.
The remissions probably need consolidation, but the nature of this consolidation
is still controversial.
PMID- 9548416
TI - Granulocyte colony-stimulating factor and drugs elevating extracellular adenosine
synergize to enhance haematopoietic reconstitution in irradiated mice.
AB - The activation of adenosine receptors has recently been demonstrated to stimulate
haematopoiesis. In the present study, we investigated the ability of drugs
elevating extracellular adenosine to influence curative effects of granulocyte
colony-stimulating factor (G-CSF) in mice exposed to a sublethal dose of 4 Gy of
60Co radiation. Elevation of extracellular adenosine in mice was induced by the
combined administration of dipyridamole, a drug inhibiting the cellular uptake of
adenosine, and adenosine monophosphate (AMP), an adenosine prodrug. The effects
of dipyridamole plus AMP, and G-CSF, administered either alone or in combination,
were evaluated. The drugs were injected to mice in a 4-d treatment regimen
starting on d 3 after irradiation and the haematopoietic response was evaluated
on d 7, 10, 14, 18 and 24 after irradiation. While the effects of G-CSF on the
late maturation stages of blood cells, appearing shortly after the completion of
the treatment, were not influenced by dipyridamole plus AMP, positive effects of
the combination therapy occurred in the post-irradiation recovery phase which is
dependent on the repopulation of haematopoietic stem cells. This was indicated by
the significant elevation of counts of granulocyte-macrophage progenitor cells
(GM-CFC) and granulocytic cells in the bone marrow (d 14), of GM-CFC (d 14),
granulocytic and erythroid cells (d 14 and 18) in the spleen, and of neutrophils
(d 18), monocytes (d 14 and 18) and platelets (d 18) in the peripheral blood.
These effects suggest that the repopulation potential of the combination therapy
lies in a common multilineage cell population. The results of this study
implicate the promising possibility to enhance the curative effects of G-CSF
under conditions of myelosuppressive states induced by radiation exposure.
PMID- 9548417
TI - Circadian-based effects of AcSDKP, with or without rhG-CSF on hematologic
toxicity of chemotherapy in mice.
AB - The hematologic toxicity of arabinosylcytosine (Ara-C) and carboplatin (CBDCA) as
well as the stimulating effect of recombinant human granulocyte colony
stimulating factor (rhG-CSF) on murine bone marrow vary according to their dosing
time along the 24-h time scale. In the present study, we investigated whether the
tolerability of Ara-C or CBDCA, given at their least toxic circadian time, could
be improved further with AcSDKP, a negative regulator of hemopoiesis, rhG-CSF or
both. A total of 228 B6D2F1 mice received once-daily injection of either Ara-C
(42 mg/kg/d s.c.) for 7 d (d 0-6) at 8 hours after light onset - HALO) or CBDCA
(40 mg/kg/d i.p.) for 5 d (d 2-6) at 16 HALO. AcSDKP (24 microg/d) was
continuously infused for 7 d (d 0-6), using an osmotic minipump. rhG-CSF (400
microg/kg/d s.c.) was injected for 4 d (d 9-12) at 9 HALO. Subgroups of mice were
sacrificed at 3 HALO on various days following treatment. AcSDKP significantly
increased CFU-GM count on d 7 and leukocyte, neutrophil and monocyte counts on d
13 and d 16 compared to Ara-C alone. Also, rhG-CSF produced similar protective
effects to those of AcSDKP with regard to leukocyte and CFU-GM counts. The
combination of AcSDKP with rhG-CSF induced a further increase in total leukocytes
and their subsets as compared to either agent alone, but did not alter the CFU-GM
counts. Neither AcSDKP nor rhG-CSF nor their combination reduced CBD CA-induced
hematological toxicity. In conclusion, AcSDKP or rhG-CSF administration further
improved the tolerability of Ara-C beyond that already achieved with optimal
circadian timing, while no such effect was observed in mice receiving CBDCA at
the dose used. The results warrant further exploration of chronopharmacologic
delivery schedules combining Ara-C with AcSDKP.
PMID- 9548418
TI - Modulatory function on autologous myeloid progenitor cells of clonal T
lymphocytes following autologous bone marrow transplantation.
AB - We have studied the regulatory capacity of clonal T-lymphocytes from patients
undergoing autologous bone marrow transplantation (ABMT) on the generation of CFU
GM from their harvest marrow preparations. To this end, T-lymphocytes from
peripheral blood from 5 patients undergoing ABMT isolated 10 d before and 7, 14
and 28 d post-ABMT were placed in limiting dilution conditions (384 wells for
each patient at each time point) and polyclonally stimulated. From more than 1600
wells with growth from the 5 patients, preparations from more than 900 wells
could be expanded (range between patients 33-452) and identified by
immunophenotyping (IP) and flow cytometry (FCM) by their exclusive expression of
CD4 or CD8. This was significantly fewer than seen in normal donors, especially
so at d 7 and 14 post-ABMT The ratio between CD4+ and CD8+ clones varied between
0.6 and 2.8 (median 1.3) and was significantly lower in the patients compared to
normal donors (median 3.1; range 3.0-6.5). When the clonal T-cell preparations
were co-cultured with autologous bone marrow cells obtained at the time of
harvest and depleted for T-lymphocytes, the vast majority of both CD4+ and CD8+
clones exerted a clear enhancement on the CFU-GM growth with no relation to time
of blood sampling in its the magnitude. Moreover, a trend seen in the normal
donors towards CD4+ clones being more effective in this enhancement was not
observed in ABMT patients. We conclude that clonal T-cells from ABMT patients,
irrespective of their phenotype and time of isolation, exert an enhancement on
the growth of autologous CFU-GM, which is equal to that seen in normal donors.
PMID- 9548419
TI - Analysis of the granulocyte colony-stimulating factor receptor gene structure
using PCR-SSCP in myeloid leukemia and myelodysplastic syndrome.
AB - The membrane-proximal cytoplasmic region of the granulocyte colony-stimulating
factor receptor (G-CSFR) is known to be essential for the proliferation signal,
with a more distal region being required for the differentiation signal. Such a
separation of functional domains raises the possibility that mutations occurring
at these regions may contribute to cell proliferation in the absence of
differentiation, this being the most important characteristic in acute leukemia
cells. Therefore, we analysed the structural abnormalities at the transmembrane
and cytoplasmic region of G-CSFR in a significant number of patients with various
myeloid malignancies. When we examined the genomic DNA of G-CSFR obtained from 41
patients with acute myelogenous leukemia (AML), 18 with chronic myelogenous
leukemia (CML), 7 with myelodysplastic syndrome (MDS), 2 with chronic
myelomonocytic leukemia and 1 with chronic neutrophilic leukemia, we found a
polymorphism in 3 patients, but no significant pathogenic mutations in any
patients. The screening for this polymorphism in 100 hematologically normal
controls revealed that it may be useful as a linkage marker for population and
family studies, because the heterozygosity index is at a high level (0.055).
While there have been several reports discussing the leukemogenic potential of
mutations in the cytokine/hematopoietin receptor superfamily, genetic alterations
in the transmembrane and cytoplasmic region of G-CSFR do not seem to play a
pathogenic role in leukemia.
PMID- 9548420
TI - An unusual case of familial aplastic anaemia: in vitro and in vivo evidence for a
multipotent progenitor responsive to G-CSF.
PMID- 9548421
TI - Pancytopenia in infants of aplastic anaemic mothers: case report.
PMID- 9548422
TI - Veto cell suppression mechanisms in the prevention of allograft rejection.
AB - Substantial evidence has accumulated to suggest that in the near future
implementation of the veto-cell-suppressor concept in the treatment of kidney
allograft recipients might lead to the establishment of life-long specific
allograft tolerance in the absence of further immunosuppressive therapy. Veto
suppression prevents the generation of antigen-specific T-helper and cytotoxic T
lymphocytes in vitro provided that the T-lymphocyte precursors specifically
recognize antigenic peptides associated with the major histocompatibility complex
molecules class II and class I, respectively, expressed on the surface of the
veto-active cell. Data from a large number of experimental and clinical studies
strongly indicate that veto-active cells function in vivo and are capable of
preventing allograft rejection. Thus, donor-cell-mediated veto activity is the
most likely explanation for the well-known graft tolerizing effect of
pretransplant donor blood transfusions in kidney graft recipients. A prerequisite
for a veto-active environment in vivo is the establishment of lymphoid
microchimerism, in which veto-active donor and recipient cells mutually
downregulate potential alloaggression.
PMID- 9548424
TI - Renal structural changes in insulin-dependent diabetic patients with albuminuria.
Comparison of cases with onset of albuminuria after short or long duration.
AB - The large interindividual variation in diabetes duration until the onset of
nephropathy is partly unexplained. This study was performed to compare renal
structure in insulin-dependent (IDDM) patients who had developed signs of
nephropathy after a short or long duration of diabetes. Renal biopsies were
obtained from 17 IDDM patients, with albumin excretion rate 20-300 microg/min and
normal blood pressure. Six patients had <25 years duration ("short-term", early
onset of microalbuminuria) and eight patients had duration >30 years ("long
term", late onset of microalbuminuria). Biopsies were obtained 18 months after
entry into a study testing the effect of low-dose antihypertensives. Parameters
characterizing diabetic glomerulopathy were significantly increased in IDDM
patients compared with those in 17 living donors: Basement membrane thickness,
mean and (CV): 591 nm (0.17) vs 320 nm (0.12), mesangial volume fraction per
glomerulus 0.27 (0.19) vs 0.19 (0.10), matrix volume fraction per glomerulus 0.16
(0.20) vs 0.097 (0.22), matrix star volume 38.5 microm3 (0.43) vs 13.9 microm3
(0.31), (p<10(-4) for each). Comparison of short vs long-term patients showed no
significant differences in glomerulopathy parameters, glomerular volume or
extracellular material per glomerulus, whereas the fraction of occluded glomeruli
was significantly increased in long-term patients. A close correlation obtained
between fraction of occluded glomeruli and glomerular filtration rate (r=0.72, p=
0.001). Glomerular occlusion occurred unrelated to the severity of diabetic
glomerulopathy. It is suggested that diabetic macroangiopathy and arteriolar
hyalinization may play an important role in the renal function of patients with
slow development of nephropathy.
PMID- 9548423
TI - T-cell subsets in adenoids and peripheral blood related to age, otitis media with
effusion and allergy.
AB - Adenoids and peripheral blood samples from 29 children (20-120 months of age)
undergoing adenoidectomy for long-standing otitis media with effusion (OME)
(n=16) or obstructive adenoid hyperplasia (n=13) were investigated by flow
cytometry for their T-lymphocyte profile. Eleven of the enrolled children were
allergic to inhalant and/or food allergens. For the whole group, the percentage
of helper T cells belonging to the memory phenotype (CD4+/CD45RO+ cells) was
significantly higher in adenoids than in blood (p<0.0001), while the same cell
category increased with age in peripheral blood (p<0.01). A highly significant
negative regression (p<0.001) was found between age and the percentage ratio of
CD4+ cells that were CD45RO+ in adenoids and blood. Allergic children had a
higher CD4+/CD8+ ratio for cells expressing CD45RO+ (p<0.05) in adenoids. The
results of this study indicate that adenoids participate in the development of an
immunological memory. Our findings support a relationship between allergy and
memory cells in adenoids.
PMID- 9548425
TI - Molecular genetic analysis of easily accessible breast tumour DNA, purified from
tissue left over from hormone receptor measurement.
AB - In order to establish a large panel of normal and tumour DNA from primary breast
cancer patients, we looked for a source of easily accessible, good quality breast
tumour DNA. Following routine hormone receptor analysis at the hospital the
leftover pellets contained the nuclei from the tumour tissue. We collected 670
pellets over a period of 2 1/4 years and isolated a large amount of DNA (on
average 400 microg per pellet). To control the quality of this tumour DNA, we
analysed 41 pellets and matching normal DNA for loss of heterozygosity (LOH),
with 11 microsatellite markers along chromosome 17. This chromosome is well
described for breast cancer. LOH is a sensitive method, requiring good quality
and pure tumour DNA. Contamination with normal DNA will blur the results. We
found a high rate of LOH, ranging from 33 to 74%, which is in agreement with
other reports, and therefore recommend this rich source of breast tumour DNA for
molecular biological analysis.
PMID- 9548426
TI - Autopsy-verified venous thromboembolism within a defined urban population--the
city of Malmo, Sweden.
AB - OBJECTIVE: To analyse the frequency of autopsy-proven venous thromboembolism
within a defined region and evaluate if certain risk groups not earlier
recognized could be found. The incidence of objectively diagnosed venous
thromboembolism was also calculated. SETTING: The city of Malmo, Sweden, with
230,000 inhabitants. MAIN OUTCOME MEASURE: Analysis of 2,356 autopsies for the
year 1987 of deceased inhabitants from the city of Malmo (2,981 deceased, autopsy
frequency 79.0%) regarding venous thromboembolism. RESULTS: 25% of autopsies
revealed venous thromboembolism. At the acute-care hospital 31%, at the chronic
hospital 37%, but in forensic autopsies of non-hospital deaths only 5% (p<0.001)
revealed venous thromboembolism. Major pulmonary embolism was seen in 13% and was
more frequent in in-hospital deaths (p<0.001). Two in-hospital and two non
hospital deaths due to pulmonary embolism and fractures were found: two patients
with knee fractures, one hip fracture and one ankle fracture patient. The
incidence of objectively diagnosed venous thromboembolism (autopsy, phlebography,
perfusion scintigraphy) was calculated and an incidence of 42.5/10,000
inhabitants/year was found, (strongly age-dependent). CONCLUSION: Venous
thromboembolism is a common finding in autopsies of hospitalized patients.
Patients with fractures other than hip fractures are less well studied as regards
venous thromboembolic complications. Further studies on these fracture patients
are warranted.
PMID- 9548427
TI - Evaluation of an immunohistochemical test with polyclonal antibodies raised
against mycobacteria used in formalin-fixed tissue compared with mycobacterial
specific culture.
AB - An immunohistochemical (IH) test (commercially available polyclonal antiserum
rabbit anti-Myco-bacterium bovis; DAKO A/S) was used to detect the presence of
mycobacteria in 65 formalin-fixed, paraffin-embedded tissue blocks from different
organs, showing necrotizing caseous granuloma lesions on hematoxylin and eosin
sections from 65 patients. These 65 samples were dyed using an acid-fast
fluorescent technique and compared using the immunohistochemical method. Both
results were also compared with the mycobacterial cultures. The IH test, compared
with the culture, showed a sensitivity (S) of 52%, a specificity (Sp) of 76%, a
positive predictive value (PV pos) of 61% and a negative predictive value (PV
neg) of 69%. We analyze these data and discuss the possible causes of false
positive and -negative results of the IH test. This rapid test on paraffin
embedded tissue seems valuable in the period when waiting for the culture
results.
PMID- 9548428
TI - Association between in vivo iododeoxyuridine labeling, MIB-1 expression,
malignancy grade and clinical stage in human prostate cancer.
AB - Large variability in the biological behavior of prostate cancer makes prognostic
markers important. The extent of tumor cell proliferation has been suggested as
an important predictor of clinical outcome. Fifty-five patients suspected of
having or with previously diagnosed prostate cancer were labeled in vivo with
IdUrd (a thymidine analogue incorporated into DNA in S-phase cells) by
intravenous infusion before transurethral resection. IdUrd-labeled cells and MIB
1-positive cells were detected by immunohistochemistry. We found statistically
significant associations between the tumor cell proliferation rates measured by
in vivo IdUrd labeling and MIB-1 expression in formalin-fixed paraffin-embedded
tumors. Good correlations were also found between S-phase fraction, MIB-1
expression, clinical stage and malignancy grade. These results make larger
retrospective studies on archival tissue meaningful.
PMID- 9548429
TI - Pyogenic hepatic abscess. A 10-year population-based retrospective study.
AB - A 10-year retrospective survey was undertaken of patients with pyogenic hepatic
abscesses (PHA). Fifty-two patients fulfilled the criteria of PHA, equivalent to
a mean annual incidence of 11/1,000,000. The main symptom was fever. Laboratory
tests were compatible with infection, slightly elevated alkaline phosphatase
being the only test pointing towards the liver as the focus of infection. Forty
one patients (79%, 95% CL, 68-90%) had positive cultures from aspirated pus, with
a total of 79 isolates. Enteric Gram-negative rods accounted for 45% and
anaerobic bacteria for 31% of PHA isolates. Gram-positive cocci, predominantly
non-haemolytic streptococci, were the third largest group (19%), but were rare
among blood isolates. Positive blood cultures were found in 21 patients (40%, 95%
CL, 27-54%), with a total of 28 isolates. Percutaneous drainage was performed in
26, percutaneous needle aspiration in 10, combinations thereof in 5, and
abdominal surgery in 5. Forty-nine patients received systemic antibiotic therapy,
four of whom were treated with antibiotics only. Seven recurrences occurred and
the overall case fatality rate was 6% (95%, CL 0-12%), which might reflect a low
rate of underlying malignant diseases in our study material.
PMID- 9548430
TI - Primary mucosal melanomas of the nasal cavity and paranasal sinuses. A
clinicopathological analysis of 14 cases.
AB - We present 14 patients with primary sinonasal melanomas (SM) identified from 1984
1997 in our archives (11/14 lateral nose, 1/14 nasal septum, 2/14 paranasal
sinuses; 8M/6F, mean age 67.7 years, range 39-88 years). Survival was poor
(median 9 months) with death related to extensive local disease and/or widespread
hematogenous metastases. The following histological subtypes were identified in
descending order: amelanotic small blue cell, pleomorphic, epithelioid, spindle
cell and myxoid. High mitotic rate and vascular invasion, absence of tumor
infiltrating lymphocytes and regression were features shared by all SM. Negative
staining of B- and T-cell markers, LCA, neuroendocrine markers such as NSE,
chromogranin and synaptophysin, and CK-negativity excluded olfactory
neuroblastoma, small cell undifferentiated carcinoma, and lymphoma. S-100 protein
was expressed in all SM, but demonstrated variable staining intensity with areas
of complete negativity. HMB45 was strongly and uniformly (>80%) expressed in all
undifferentiated small blue cell SM. The pigmented SM were predominantly HMB45
negative. The strong HMB45 staining in amelanotic small blue cell SM is explained
by the reaction of HMB45 antibody with an oncofetal antigen found in immature
melanosomes. In these poorly differentiated amelanotic malignant melanomas,
antibody to HMB45 proved to be a superb diagnostic marker. We therefore strongly
advocate the inclusion of HMB45 antibody in the panel of antibodies for initial
work-up of undifferentiated mucosal neoplasms, since a negative S-100 stain in
small biopsy material may result in incorrect classification of these neoplasms.
PMID- 9548431
TI - Coagulase-negative staphylococci in a major Danish university hospital: diversity
in antibiotic susceptibility between wards.
AB - Over a one-year period, all coagulase-negative staphylococci (CoNS) from blood
cultures, cerebrospinal fluids and peritoneal effluents from patients in a major
Danish university hospital were investigated for susceptibility to penicillin G;
methicillin; gentamicin; netilmicin; amikacin; erythromycin; clindamycin; fusidic
acid; rifampicin; tetracycline; chloramphenicol; ciprofloxacin; teicoplanin; and
vancomycin. Among the CoNS-isolates, 56% were resistant to methicillin, 51% to
gentamicin, 28% to ciprofloxacin, and 5% to teicoplanin. Blood culture CoNS
isolates from patients with a central venous catheter (CVC) were more often
resistant to various antibiotics compared to CoNS-isolates from patients without
a CVC, e.g. methicillin (72% vs 21%), gentamicin (65% vs 22%) (p<0.00000001).
Great diversity in antibiotic resistance between the wards was found; methicillin
resistance (in most cases multiple antibiotic resistance) was in particular
associated with consumption of broad-spectrum beta-lactams, quinolones, and total
antibiotic consumption in a ward. Thus, the antibiotic policy of a ward is an
important factor for antibiotic resistance among CoNS.
PMID- 9548432
TI - Herpes simplex virus and human papillomavirus in a population-based case-control
study of cervical intraepithelial neoplasia grade II-III.
AB - In order to evaluate the association between seropositivity for herpes simplex
virus (type 1 and type 2) and cervical intraepithelial neoplacia (CIN), we
analysed data from a population-based case-control study of CIN grade II-III
which included Norwegian women aged 20 to 44 years, 94 cases and 228 controls.
Our objectives were to determine if HSV-1 and/or HSV-2 seropositivity were
independent risk factors for CIN, taking human papillomavirus exposure into
account, and to elucidate the combined effect of HPV positivity and
seropositivity for HSV In logistic regression analyses, the association between
HSV-2 or HSV-1 seropositivity and CIN II-III was not explained by HPV (adjusted
OR 3.0; 95%, CI 1.3-7.2 and adjusted OR 3.3; 95% CI 1.3-8.4, respectively). In
analyses restricted to HPV-16 DNA-positive individuals, seropositivity for HSV-2
increased the risk of CIN (OR 11.1; 95% CI 1.2-105.7), whereas HSV-1
seropositivity was not significantly associated with CIN. In women positive for
other HPV types, only HSV-1 seropositivity was associated with CIN (OR 8.5; 95%
CI 1.3-55.8). In analyses of the HPV-16-seropositive individuals, neither HSV-1
nor HSV-2 seropositivity was associated with CIN. Compared to the reference group
of jointly unexposed subjects, the HPV-16 DNA-positive women who were anti-HSV-2
negative had an increased risk of CIN (OR 29; 95% CI 12-67), whereas the risk in
women who were both HPV-16 DNA-positive and HSV-2 was OR=247 (95% CI 31-1996).
The estimate of interaction was strong, but did not reach significance, and our
findings may suggest that the combined effect of the two viruses is of
aetiological importance in cervical carcinogenesis. Furthermore, the results
indicate that HPV DNA positivity is not sufficient to explain the sexual
behaviour-associated risk of cervical neoplasia and that further studies on the
role of genital HSV (type 1 as well as type 2) and other STDs are warranted.
PMID- 9548433
TI - Role of tenascin in cancer development.
PMID- 9548434
TI - Induction of glandular stomach cancers in Helicobacter pylori-sensitive Mongolian
gerbils treated with N-methyl-N-nitrosourea and N-methyl-N'-nitro-N
nitrosoguanidine in drinking water.
AB - An animal model of stomach carcinogenesis was established using Mongolian gerbils
with N-methyl-N-nitrosourea (MNU) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)
as the carcinogens. In addition, the sensitivity of these gerbils to Helicobacter
pylori (H. pylori) was confirmed. One hundred and sixty specific pathogen-free
male MGS/Sea animals, 7 weeks old, were treated with MNU in the drinking water
(30 ppm for alternate weeks to give 10 weeks exposure, or 10 ppm or 3 ppm for 20
weeks continuous exposure), or given MNNG in the drinking water at 400 ppm or 200
ppm for 20 weeks, or orally inoculated with ATCC43504 H. pylori (1.7 x 10(8)
CFUs/animal). Adenocarcinomas in the glandular stomach were found in 2 out of 12
effective animals (2/ 12) treated with 30 ppm MNU at week 20, although all were
dead or moribund by week 30 due to MNU toxicity. At week 50, the incidences of
gastric adenocarcinomas in groups treated with 10 ppm MNU, 3 ppm MNU, 400 ppm
MNNG, and 200 ppm MNNG were 2/21 (9.5%), 1/23 (4.3%), 7/ 11 (63.6%), and 1/10
(10.0%). The lesions were generally well differentiated, although poorly
differentiated adenocarcinoma was also found in a single gerbil in each of the 10
ppm MNU and 400 ppm MNNG groups. In control animals no tumors were found. In the
infection study, the animals were killed at week 20, and H. pylori was detected
in all cases, causing multiple erosions with marked inflammatory cell
infiltration in the lamina propria and submucosa, and frequent formation of
lymphoid follicles. Thus, MNU and MNNG in the drinking water induced neoplastic
lesions in the glandular stomach epithelium of H. pylori-sensitive gerbils.
PMID- 9548435
TI - Induction of squamous cell carcinomas in the salivary glands of rats by potassium
iodide.
AB - In a 2-year carcinogenicity study of potassium iodide (KI) in F344/DuCrj rats,
squamous cell carcinomas (SCCs) were observed in the salivary glands of 4/40
males and 3/40 females receiving 1000 ppm KI in the drinking water. Ductular
proliferation with lobular atrophy was observed at high incidence in the
submandibular glands of the high-dose animals, and squamous metaplasia was
frequently evident within the proliferative ductules and the larger interlobular
ducts. A transition from metaplasia to SCC was apparent. The results suggest that
squamous metaplasia in proliferative ductules, occurring secondarily to lobular
impairment induced by KI, may develop into SCCs via a non-genotoxic,
proliferation-dependent mechanism.
PMID- 9548436
TI - Up-regulation of p27Kip1 correlates inversely with anchorage-independent growth
of human cancer cell lines.
AB - We examined the correlation between anchorage-independent growth and cell cycle
related molecules using 39 human cancer cell lines. They consisted of lung-,
colon-, stomach-, breast-, ovarian-, brain-, renal- and melanoma-derived cell
lines. Their anchorage-independent growth ability varied, but was not clearly
related to the tissue of origin. There was a tendency for the levels of cyclin
D1, cyclin E, cyclin A, p27, and p21 to show a tissue-dependent expression
pattern. Statistical analysis revealed an inverse correlation of the p27 level
with anchorage-independent growth (r=-0.456, P<0.01). Thus, the regulation of p27
is suggested to be linked to the anchorage independence of human cancer cells.
PMID- 9548437
TI - Risk factors for benign breast disease according to histopathological type:
comparisons with risk factors for breast cancer.
AB - We evaluated risk factors for benign breast disease by using a case-control study
method. The series was taken from participants in breast cancer screening
programs during 1978-1986 in Miyagi Prefecture, Japan. All benign breast lesions
diagnosed during this period were reviewed and reclassified into proliferative
and non-proliferative types based on the Dupont and Page classification. Data on
382 benign breast disease cases (130 proliferative-type cases and 252 non
proliferative-type cases) and 1,489 screening year-, age- and screening area
matched normal controls were used for analysis. Nulliparity or low parity and
family history of breast cancer in mother or sisters were significantly
associated with an increased risk of proliferative type. Premenopausal status was
significantly associated with an increased risk of non-proliferative type. No
significant association with history of lactation for the last child was observed
in either type, but the risk of proliferative type increased with increasing
duration of lactation (P=0.08). A comparison between the present findings and the
risk factors for breast cancer indicated epidemiologic similarities between
proliferative benign and malignant breast lesions in general. The associations of
these two lesions with lactation patterns were, however, dissimilar.
PMID- 9548438
TI - Calcium, magnesium, and nitrate in drinking water and gastric cancer mortality.
AB - The possible association between the risk of gastric cancer and the levels of
calcium, magnesium, and nitrate in drinking water from municipal supplies was
investigated in a matched case-control study in Taiwan. Records of gastric cancer
deaths among eligible residents in Taiwan from 1987 through 1991 were obtained
from the Bureau of Vital Statistics of the Taiwan Provincial Department of
Health. Controls were deaths from other causes and were pair-matched to the cases
by sex, year-of-birth, and year-of-death. Each matched control was selected
randomly from the set of possible controls for each case. Data on calcium,
magnesium, and nitrate levels in drinking water throughout Taiwan were obtained
from the Taiwan Water Supply Corporation. The municipality of residence of the
cases and controls was assumed to be the source of the subject's calcium,
magnesium, and nitrate exposure via drinking water. The subjects were divided
into tertiles according to the levels of calcium, magnesium, and nitrate in their
drinking water. The results of the present study show that there is a significant
positive association between drinking water nitrate exposure and gastric cancer
mortality. The present study also suggests that there was a significant
protective effect of calcium intake from drinking water on the risk of gastric
cancer. Magnesium also exerts a protective effect against gastric cancer, but
only for the group with the highest levels.
PMID- 9548439
TI - Enhancing effects of quinacrine on development of hepatopancreatic lesions in N
nitrosobis(2-oxopropyl)amine-initiated hamsters.
AB - The modifying effects of quinacrine administration during the post-initiation
phase of carcinogenesis were investigated in hamsters treated with N-nitrosobis(2
oxopropyl)amine (BOP). Female Syrian hamsters were given three weekly s.c.
injections of BOP at a dose of 10 mg/kg and then 300 or 100 ppm quinacrine in
their diet for 37 weeks. Additional groups of animals received the BOP injection
alone, or only the 300 ppm quinacrine treatment as BOP-negative controls. At week
40 of the experiment, all surviving animals were killed and development of
proliferative lesions was assessed histopathologically. The multiplicity of
pancreatic adenocarcinomas and dysplastic lesions per hamster was significantly
higher (P<0.01 and P<0.05) in the BOP/Q100 group (1.92 and 1.78) than in the BOP
alone group (1.07 and 0.79). The incidence of hepatocellular adenomas plus
carcinomas was also significantly elevated (P<0.05) in the BOP/Q300 and BOP/Q100
groups. In contrast, the multiplicity of lung adenomas plus adenocarcinomas was
significantly decreased (P<0.05) by the Q300 treatment. Neither the incidence nor
the multiplicity of renal cell tumors (adenomas and carcinomas) or
nephroblastomas significantly differed between the BOP-treated groups. Electron
microscopic examination revealed an abundance of myeloid lamellar bodies filling
the cytoplasm of hepatocytes and pancreatic ductular and acinar cells, and
epithelial cells of the gallbladder in the quinacrine-treated animals, the degree
being dose-dependent. Our results indicate that quinacrine enhances pancreatic
and hepatic carcinogenesis in hamsters induced by BOP.
PMID- 9548440
TI - Chemoprevention of N-nitroso-N-methylurea-induced rat mammary carcinogenesis by
soy foods or biochanin A.
AB - We examined the effects of soybeans, a soy product (miso) and biochanin A, an
isoflavone derivative, on N-nitroso-N-methylurea (MNU)-induced rat mammary
carcinogenesis. Seven-week-old female CD/Crj rats received a single i.v. dose (40
mg/kg body weight) of MNU. After administration of MNU, rats were fed diet
containing 0% (control), 2% or 10% soybeans, or 10% miso as a soy-supplemented
diet, or 10 or 50 mg/kg biochanin A. All rats were observed for 18 weeks after
MNU administration. At 18 weeks, the multiplicity (mean tumors/rat) of palpable
mammary tumors was significantly decreased in the 10% soybean (1.1) and 10% miso
(1.2) diet groups compared to the control (2.2) (P<0.05, respectively). In the
biochanin A-supplemented diet groups, the incidence (percentage of rats with
tumors) was significantly decreased in the 50 mg/kg (32%) diet group compared to
the control (80%) (P<0.01), and the multiplicity was significantly decreased in
both the 10 mg/kg (0.7) and 50 mg/kg (0.5) diet groups compared to the control
(2.2) (P<0.01 and P<0.001, respectively). The proliferative cell nuclear antigen
labeling index of mammary tumors was significantly decreased in both biochanin A
supplemented diet groups compared to the control. The present results indicate
that soybeans, miso, and biochanin A are useful for the prevention of mammary
cancer.
PMID- 9548441
TI - Suppressive effect of the angiogenesis inhibitor TNP-470 on the development of
carcinogen-induced hepatic nodules in rats.
AB - Tumor metastasis can be prevented by inhibiting angiogenesis. In the present
study, we have demonstrated that the angiogenesis inhibitor TNP-470 also
suppresses the development of primary hepatic nodules. Hepatocarcinogenesis was
performed by the feeding of 2-acetylaminofluorene to hepatectomized rats during 8
14 weeks of age. Predominantly arterial-to-portal circulation and sinusoidal
capillarization were determined by the staining of nodules with arterially
infused ink and immunostaining for factor VIII-related antigen, respectively.
Intraperitoneal administration of 30 mg/kg b.w. of TNP-470 twice a week
significantly reduced the number of hepatic nodules. Among the nodules,
hyperplastic nodules stained with ink, atypical hyperplastic nodules and
hepatocellular carcinoma, all of which possess structurally altered sinusoidal
endothelial cells or capillary-type endothelial cells, were dramatically
decreased in number. Suppression was observed equally in nodules of all sizes.
TNP-470 was more effective when administered during 8-20 weeks than during 14-26
weeks. In contrast, ink-non-stained hyperplastic nodules, which have normal
sinusoidal endothelial cells, were not affected at all. The present results
indicate that TNP-470 suppresses the development of primary hepatic nodules whose
microvessels are capillaries or transitional forms from sinusoids to capillaries.
PMID- 9548442
TI - Transgenic mouse expressing a full-length hepatitis C virus cDNA.
AB - Hepatitis C virus (HCV), a major causative agent of post transfusion non-A, non-B
hepatitis (NANBH), can only infect humans and chimpanzees. We produced nine
transgenic mouse lines carrying a full-length HCV cDNA with the human serum
amyloid P component (hSAP) promoter that can direct liver-specific expression. In
one of these lines HCV mRNA and HCV core protein were detected in the liver of
the transgenic mouse, although the levels of expression were very low. In
addition, HCV-related antibody was detected in the serum.
PMID- 9548444
TI - Globotriaosyl ceramide and globoside as major glycolipid components of
fibroblasts in scirrhous gastric carcinoma tissues.
AB - Scirrhous gastric cancer is characteristic in that cancer cells proliferate and
invade with prominent fibrosis. To search for the expression of specific
carbohydrate chains in scirrhous gastric cancer, we have examined the
glycosphingolipid composition of scirrhous cancer tissues (n=10) in comparison
with that of non-scirrhous cancer tissues (n=10) by means of two-dimensional thin
layer chromatography, followed by fast atom bombardment mass spectrometry of the
individual glycolipids and immunostaining analysis. The major neutral
glycosphingolipids from scirrhous gastric cancer tissues were identified as
ceramide monohexoside, ceramide dihexoside, globotriaosyl ceramide (Gb3) and
globoside (Gb4), while the major acidic glycosphingolipids were II3 NeuAcalpha
LacCer, II3 NeuAcalpha2-LacCer and sulfatide. Relative concentrations of Gb3 and
Gb4 in scirrhous gastric cancer tissues (Gb3 + Gb4 = 58%) were two times higher
than those in non-scirrhous gastric cancer tissues (29%). Orthotopic fibroblasts
cloned from scirrhous gastric cancer tissues showed similar high concentrations
of Gb3 and Gb4 to scirrhous gastric cancer tissues. Furthermore,
immunohistochemical study revealed that Gb3 and Gb4 were expressed intensely on
the fibroblasts. On the other hand, analysis of glycosphingolipids in four
scirrhous gastric cancer cell lines yielded the following results. i) The
contents of Gb3 and Gb4 were low (6%), compared with orthotopic fibroblasts
(62%). ii) Significant amounts of Le(a) (pentaglycosylceramide) and Le(b) (hexa-
and heptaglycosylceramides), which could not be detected in scirrhous cancer
tissues, were observed. The results show that the major neutral
glycosphingolipids such as Gb3 and Gb4 of scirrhous gastric cancer tissues were
derived from orthotopic fibroblasts and not from the cancer cells.
PMID- 9548443
TI - Cyclin D1 overexpression detected by a simple competitive reverse transcription
polymerase chain reaction assay for lymphoid malignancies.
AB - t(11;14)(q13;q32) observed in B-cell malignancies is associated with cyclin D1
(bcl-1, PRAD1, CCND1) overexpression. We devised a simple competitive reverse
transcription-polymerase chain reaction (RT-PCR) assay for rapid detection of
cyclin D1 overexpression. Sharing a single upstream primer derived from a
homologous sequence in cyclins D1, D2 and D3, each PCR product serves as a
competitor and cyclin D1 overexpression is determined by comparing the
intensities of the three amplified products. We analyzed cyclin D1 in clinical
specimens from 104 patients with lymphoid malignancies. Cyclin D1 overexpression
was evident in 13 of 104 (7/72 non-Hodgkin's lymphomas, 0/6 adult T-cell
lymphoma/leukemias, 0/4 Hodgkin's diseases, 0/11 acute lymphoblastic leukemias,
3/4 multiple myelomas, 1/2 Waldenstrom's macroglobulinemias, 1/2 prolymphocytic
leukemias and 1/3 chronic lymphocytic leukemias). Among 72 patients for whom
cytogenetic studies had been done, all 7 patients with t(11;14) were positive.
The relative expression levels of D-type cyclins altered dramatically in the
presence of t(11;14). Thus, this RT-PCR assay can identify tumors with cyclin D1
overexpression. Cyclin D1 overexpression was frequent in extranodal specimens (11
out of 32 vs. 2 of 72 lymph nodes) and was restricted to specific types of
lymphoid malignancies, as observed using other methods. This reliable assay
should be suitable to provide clinical guidance for the diagnosis and management
of lymphoid malignancies, especially in the case of extranodal involvement.
PMID- 9548445
TI - Homotypic adhesion through carcinoembryonic antigen plays a role in hepatic
metastasis development.
AB - We established a cell line with high metastatic potential to the liver (LS-LM4)
after four successive repetitions of splenic injection of liver-metastatic cells
in SCID mice. This cell line strongly expressed CEA and showed increased
homotypic adhesion as compared with the parent cell line (LS174T). To examine the
role of CEA in the increased homotypic adhesion, LS-LM4 cells were treated with
anti-CEA antibody and subjected to an in vitro adhesion and aggregation assay.
Further, to study the role of CEA in the hepatic metastasis of cells with high
metastatic potential, LS-LM4 cells were treated with anti-CEA antibody, and the
inhibition of hepatic metastasis after splenic injection in vivo was examined.
There was a 62% decrease in the homotypic adhesion of anti-CEA antibody-treated
(100 microg/ml) LS-LM4 cells under a Ca2+-free condition as compared with the
control (P<0.01). Anti-CEA antibody (100 microg/ml) inhibited cell aggregation
under a Ca2+-free condition (P<0.05). Treatment with anti-E-cadherin antibody (60
microg/ml) plus anti-CEA antibody (100 microg/ml) inhibited cell aggregation more
potently than anti-E-cadherin antibody treatment alone in the presence of Ca2+.
In vivo, there was a 75% decrease in the number of hepatic metastatic nodules in
the G125 anti-CEA antibody-treated group as compared with the control group
(P<0.01). Similarly, there was a 40% decrease in the diameter of metastatic
nodules and there was a 90% decrease in total tumor volume of hepatic metastasis
in the G125 anti-CEA antibody-treated group as compared with the control
(P<0.01). These results suggest that increased metastatic potential to the liver
is at least partly due to increased homotypic binding mediated by CEA.
PMID- 9548447
TI - Effects of interleukin-12 on the induction of cytotoxic T lymphocytes from the
regional lymph node lymphocytes of patients with lung adenocarcinoma.
AB - Lung cancer-specific cytotoxic T lymphocytes (CTL) were induced by repeated
stimulations of regional lymph node lymphocytes (RLNL) in lung cancer patients
with either autologous or HLA-A-locus-matched tumor cells. To investigate the
effect of interleukin-12 (IL-12), IL-12 was added during the stimulation of RLNL
from HLA A24/adenocarcinoma patients with either autologous tumor cells or HLA
A24-positive adenocarcinoma cells (PC-9) in combination with, or instead of
interleukin-2 (IL-2), and then the cytotoxic activity, cytokine production and
populations of the lymphocyte subsets were examined. The addition of IL-12, or
the substitution of IL-2 by IL-12 was found to enhance the cytotoxic activity and
the cytokine production (IFN-gamma, GM-CSF) of the CTL as compared with IL-2
alone. The cytotoxic activity and cytokine production were both partially
inhibited by anti-MHC-class I monoclonal antibody. The CTL thus induced by IL-12
had a higher proportion of CD3+/CD56+ cells than the CTL induced with IL-2 alone.
The positively selected CD8+/CD56- lymphocytes showed PC-9-specific cytotoxic
activity, because the population did not show any cytotoxicity to K562 or A549
(HLA-A26/A30). However, the CD3+/CD56+ lymphocytes were cytotoxic to both PC-9
and K562. In conclusion, IL-12 is considered to be a useful cytokine for both the
induction of lung-cancer specific CTL and the augmentation of non-MHC-restricted
cytotoxicity against tumor cells, and may be applicable for adoptive
immunotherapy using CTL.
PMID- 9548446
TI - Increased expression of sucrase and intestinal-type alkaline phosphatase in human
gastric carcinomas with progression.
AB - The activities of sucrase, total alkaline phosphatase (total ALP) and intestinal
type alkaline phosphatase (I-ALP) were assayed in gastric carcinomas and in their
surrounding mucosae from 57 patients with advanced cancers, and the localization
of sucrase in 203 carcinomas, including 86 early cancers, was examined
immunohistochemically using polyclonal anti-sucrase antibody. All three enzymes
were active in the 57 carcinomas as well as in their surrounding mucosae, but the
levels were fairly low as compared to those in normal jejunum mucosa. A
considerable part of the total ALP activity in tumor specimens was assumed to be
due to I-ALP itself. Increased sucrase and I-ALP were found with greater depth of
invasion by undifferentiated-type carcinomas. The pattern of immunohistochemical
localization of sucrase in the 203 carcinomas also clearly indicated increased
expression with greater depth of invasion even in differentiated-type carcinomas.
PMID- 9548448
TI - Suppression of anti-microtubule agent-induced apoptosis by nitric oxide: possible
mechanism of a new drug resistance.
AB - The propensity of a cell to undergo apoptosis has been proposed to be a
determinant of sensitivity to anti-microtubule agents. The anti-microtubule
agents vincristine and paclitaxel induce key features of apoptosis, such as
intranucleosomal DNA fragmentation and changes in nuclear morphology in the human
neuroblastoma cell line, NB-39-nu. Nitric oxide (NO) generated from NO-releasing
drugs prevented anti-microtubule agent-induced apoptosis in this cell line. The
mechanism of suppression of apoptosis by NO appears to be via the inhibition of
an interleukin-1beta converting enzyme-like protease cascade. This finding
reveals a new biological function of NO, as well as a new molecular insight into
resistance to chemotherapy with anti-microtubule agents.
PMID- 9548449
TI - Oral administration of a Kampo (Japanese herbal) medicine Juzen-taiho-to inhibits
liver metastasis of colon 26-L5 carcinoma cells.
AB - We have investigated the inhibitory effect of oral administration of Juzen-taiho
to, a Kampo Japanese herbal medicine, on liver metastasis by the inoculation of a
liver-metastatic variant (L5) of murine colon 26 carcinoma cells into the portal
vein. Oral administration of Juzen-taiho-to for 7 days before tumor inoculation
resulted in dose-dependent inhibition of liver tumor colonies and significant
enhancement of survival rate as compared with the untreated control, without side
effects. We also found that liver metastasis of L5 cells was enhanced in BALB/c
mice pretreated with anti-asialo GM1 serum or 2-chloroadenosine, and in BALB/c
nu/nu mice, compared to normal mice. This indicates that NK cells, macrophages,
and T-cells play important roles in the prevention of metastasis of tumor cells.
Juzen-taiho-to significantly inhibited the experimental liver metastasis of colon
26-L5 cells in mice pretreated with anti-asialo GM1 serum and untreated normal
mice, whereas it did not inhibit metastasis in 2-chloroadenosine-pretreated mice
or T-cell-deficient nude mice. Oral administration of Juzen-taiho-to activated
peritoneal exudate macrophages (PEM) to become cytostatic against the tumor
cells. These results show that oral administration of Juzen-taiho-to inhibited
liver metastasis of colon 26-L5 cells, possibly through a mechanism mediated by
the activation of macrophages and/or T-cells in the host immune system. Thus,
Juzen-taiho-to may be efficacious for the prevention of cancer metastasis.
PMID- 9548450
TI - Absence of p53 overexpression and favorable response to cisplatin-based
neoadjuvant chemotherapy in urothelial carcinomas.
AB - It has been controversial whether cancer cells harboring loss or inactivation of
the tumor suppressor p53 are resistant or sensitive to DNA-damaging agents
including cisplatin and doxorubicin. Overexpression of mdm2 oncoprotein, a
negative regulator of p53, is assumed to be an alternative to p53 dysfunction.
Archival urothelial carcinoma specimens obtained from 60 patients prior to
cisplatin-based chemotherapy were immunohistochemically studied for
overexpression of p53 and mdm2. Thirty-two patients (group I) were treated with
chemotherapy in the neoadjuvant setting, while 28 patients (group II) underwent
chemotherapy for distant metastases or inoperable locoregional tumors. In group
I, the responsiveness was correlated with staining status of p53 (P=0.0225) and
the combination of p53 and mdm2 (P=0.0497). Negative staining of p53 and negative
for both p53 and mdm2 could have predicted favorable response to chemotherapy in
16 of 18 (88.9%) and in 12 of 13 (92.3%) tumors, respectively. On the other hand,
p53-positive and p53 and/or mdm2-positive staining could have predicted poor
response only in 7 of 14 (50.0%) and 8 of 19 (42.1%) tumors, respectively.
Disease-specific survival of the p53-negative group was significantly superior to
that of the p53-positive group (P=0.0086). Difference in survival did not become
more significant when overexpression of mdm2 was taken into consideration
(P=0.0456). In contrast, in group II, there was no correlation of responsiveness
to chemotherapy or survival with p53- or p53/mdm2-staining status. The patients
with urothelial carcinomas negative for overexpression of p53 will benefit from
neoadjuvant chemotherapy. From clinical viewpoint, however, p53 status alone or
the combination of p53 and mdm2 status is not enough to identify those patients
who will not benefit from the treatment.
PMID- 9548452
TI - 1-Methyl-3-propyl-7-butylxanthine, a novel biochemical modulator, enhances
therapeutic efficacy of adriamycin.
AB - We have screened xanthine derivatives for activity as novel biochemical
modulators by assay of their inhibitory effect on adriamycin efflux from tumor
cells. Strong inhibition of adriamycin efflux was shown by some xanthine
derivatives with various alkyl or oxoalkyl substituents at the 1-, 3- and 7
positions. 1-Methyl-3-propyl-7-butylxanthine (XT-77), which had the greatest
inhibitory effect on adriamycin efflux in vitro among the compounds tested,
potentiated adriamycin-induced antitumor activity by causing an increase of
adriamycin concentration in the tumor in vitro. Furthermore, XT-77 reduced the
adverse drug reactions of adriamycin by decreasing the adriamycin concentrations
in the heart and the liver. Thus, the combination of XT-77 with adriamycin not
only increased the antitumor activity of adriamycin, but also decreased the
adverse drug reactions.
PMID- 9548451
TI - Role of MDM2 overexpression in doxorubicin resistance of breast carcinoma.
AB - Several oncoproteins or tumor suppressor gene products have been indicated to be
of value as predictors of the de novo resistance to cytotoxic agents. In this
study, we have investigated the role of MDM2 (murine double minutes)
overexpression in doxorubicin resistance of breast cancer. Immunocytochemical
analysis demonstrated that MDM2-positive tumors, even with p53-negative
phenotype, were significantly more resistant to doxorubicin treatment compared to
MDM2-negative tumors. An in vitro experimental model using stable mdm2
transfected MCF-7 cells carrying wild-type p53 confirmed that the cells become
approximately 3-fold more resistant to doxorubicin as a result of MDM2
overexpression, and the wild-type p53 function, such as the induction of p21Waf1
following DNA damage, was significantly suppressed. MDM2 overexpression is
suggested to be a novel marker for predicting lack of response to doxorubicin
treatment in breast cancer patients.
PMID- 9548453
TI - Calcitonin gene-related peptide is necessary for ultraviolet B-impaired induction
of contact hypersensitivity.
AB - Since nerve termini on Langerhans cells (LC) contain calcitonin gene-related
peptide (CGRP), and since ultraviolet B radiation (UVR) causes CGRP to be
released from cutaneous nerve endings, we examined whether CGRP participates in
the immune aberrations caused in skin by UVR. First, intradermally injected CGRP,
in a dose-dependent manner, reduced LC density and impaired CH induction when
hapten was painted on the injected site. Second, CGRP antagonist restored CH
induction after UVR. Third, anti-TNF-alpha Abs injected before CGRP prevented the
loss of LC density and restored CH induction. Fourth, CGRP failed to impair CH
induction in mast cell-deficient mice. Fifth, CGRP induced mast cells to release
TNF-alpha. We conclude that CGRP plays an essential role in the loss of CH
induction after UVR. These data indicate that UVR, by causing the release of CGRP
from cutaneous nerve endings, triggers mast cell release of TNF-alpha, which
impairs CH induction.
PMID- 9548454
TI - Immunosuppressive effects of human CTLA4Ig in a non-human primate model of
allogeneic pancreatic islet transplantation.
AB - Ag-specific T cell activation requires a CD28-mediated costimulatory interaction.
This observation has suggested novel approaches to suppress donor-specific
immunity, including the use of soluble CD28 antagonists, such as CTLA4Ig, which
suppresses transplant rejection in small animal models. In this study, CTLA4Ig
therapy was examined in a non-human primate model of allogeneic pancreatic islet
transplantation. Two of five CTLA4Ig-treated monkeys showed prolonged graft
survival, which correlated with donor-specific hyporesponsiveness in vitro.
Humoral responses to the transplanted tissue were suppressed in all treated
animals. These results suggest that CTLA4Ig is effective in suppressing both
humoral and cellular immune responses in a non-human primate model of allogeneic
transplantation.
PMID- 9548455
TI - A family of human lymphoid and myeloid Ig-like receptors, some of which bind to
MHC class I molecules.
AB - Leukocyte Ig-like receptors (LIRs) are a newly discovered family of
immunoreceptors expressed on monocytes and B cells and at lower levels on
dendritic cells and NK cells. The amino acid sequences in the extracellular
regions of eight of these receptors show between 63 and 84% identity to the
prototypic LIR-1 sequence. LIRs contain either two or four Ig domains and fall
into three classes: those with cytoplasmic domains containing two, three, or four
immunoreceptor tyrosine-based inhibitory motif-like motifs; those with a short
cytoplasmic domain and no immunoreceptor tyrosine-based inhibitory motif-like
motifs; and those with no transmembrane domain represented by a single LIR
molecule that is presumably secreted. The LIRs are structurally related to the
human Fc(alpha)R and the killer inhibitory receptors and map to the same region
of chromosome 19 as these genes. Like killer inhibitory receptors, at least two
LIRs bind to MHC class I Ags, but their different cellular distribution suggests
a distinct role in immune system modulation.
PMID- 9548456
TI - CD8+ T cells clear influenza virus by perforin or Fas-dependent processes.
AB - Influenza virus infection is controlled in CD4-depleted mice that are also
defective for the expression of either Fas (Fas-/-) or perforin (P-/-). Virus
immune P+/+ and P-/- CD8+ T cells can thus function in, respectively, a Fas-/- or
Fas+/+ lung environment. The obvious question is whether the P-/- CD8+ set is
effective in Fas-/- mice, a conclusion that would tend to favor cytokine
secretion as the mode of virus clearance. Short term chimeras were made with P-/-
bone marrow, P+/+ or P-/- T cells, and Fas+/+ or Fas-/- irradiated recipients.
While the P+/+ CD8+ population cleared the virus from Fas+/+ and Fas-/-
respiratory epithelium, the P-/- effectors were operational only if there was the
potential for Fas to be expressed on radiation-resistant lung cells. Target cell
destruction mediated via the Fas or perforin pathways is clearly the primary
mechanism used by CD8+ T cells to terminate this viral pneumonia.
PMID- 9548457
TI - Molecular cloning of leukotactin-1: a novel human beta-chemokine, a
chemoattractant for neutrophils, monocytes, and lymphocytes, and a potent agonist
at CC chemokine receptors 1 and 3.
AB - A new member of human beta-chemokine cDNA was isolated and named leukotactin-1
(Lkn-1). Lkn-1, along with murine macrophage inflammatory protein-related protein
1 and -2, defines a subgroup of beta-chemokines based on two conserved cysteines
in addition to the four others conserved in all beta-chemokines. The putative
mature Lkn-1 is composed of 92 amino acids with a calculated m.w. of 10,162. The
Lkn-1 gene was mapped to human chromosome 17, region q12. Recombinant Lkn-1 was a
potent chemoattractant for neutrophils, monocytes, and lymphocytes and induced
calcium flux in these cells. Lkn-1 specifically induced calcium flux in CCR1- and
CCR3-expressing HOS cell lines. Lkn-1 suppressed colony formation by human
granulocyte-macrophage, erythroid, and multipotential progenitor cells stimulated
by combinations of growth factors. Hence, we have isolated and characterized a
human C6 beta-chemokine that is a potent agonist at CCR1 and CCR3 and shows broad
biologic activities, including leukocyte chemoattraction.
PMID- 9548458
TI - Constitutive activation of the Janus kinase-STAT pathway in T lymphoma
overexpressing the Lck protein tyrosine kinase.
AB - The Lck protein, a Src family tyrosine kinase, plays a critical role in T cell
maturation and activation. Dysregulation of Lck expression or Lck kinase activity
has been implicated in T cell leukemias from mice to humans, although the
mechanism underlying Lck-mediated oncogenesis is still largely unclear. We report
here that both DNA binding activities and tyrosine phosphorylation of STAT3 and
STAT5, but not STAT1, are constitutively enhanced in the mouse T cell lymphoma
LSTRA, which is a well-characterized cell line that overexpresses Lck protein and
exhibits high levels of Lck kinase activity. Furthermore, Janus kinase 1 (jak1)
and Jak2 protein tyrosine kinases are constantly activated in these cells, as
determined by their autophosphorylation in an in vitro kinase assay and increased
levels of tyrosine phosphorylation on immunoblots. Therefore, like Src
transformed cells, Lck-overexpressing LSTRA cells also exhibit constitutive
activation of distinct Jak and STAT proteins.
PMID- 9548459
TI - Induction of HLA-A2-restricted CTLs to the mucin 1 human breast cancer antigen.
AB - HLA-A*0201/Kb transgenic mice were immunized with oxidized mannan-mucin 1 (MUC1)
as a fusion protein (containing five repeats of the 20-amino-acid MUC1 VNTR
(variable number of tandem repeats) that generated highly active CD8+ CTLs to
MUC1 peptides. In a direct CTL assay, the MUC1 peptides could be presented
specifically by both the transgenic murine HLA-A*0201/Kb and human HLA-A*0201
molecules. The 9-mer MUC1 peptide sequences (APDTRPA and STAPPAHGV) were
presented by HLA-A*0201, although they did not contain L at P2 and L/V at P9, the
preferred motifs; as a consequence, the binding was of relatively low affinity
when compared with a high affinity-binding HIV peptide (ILKEPVHGV). In addition,
when mice were immunized separately with the HLA-A*0201-binding peptides
(STAPPAHGV or APDTRPAP-containing peptides-keyhole limpet hemocyanin-mannan),
direct lysis of MCF-7 (HLA-A*0201+, MUC1+) also occurred. The findings are of
interest for tumor immunotherapy, particularly as the CTLs generated to low
affinity-binding peptides were highly active and could specifically lyse an HLA
A*0201+ human breast cancer cell line without further in vitro stimulation. The
findings demonstrate that the range of peptides that can generate CTLs is broader
than formerly considered.
PMID- 9548460
TI - The basis for self-tolerance of natural killer cells in beta2-microglobulin- and
TAP-1- mice.
AB - Cells from mice with mutations in the genes for beta2-microglobulin (beta2m) or
for TAP-1 express only low levels of MHC class I proteins on their surfaces, and
are thus sensitive to attack by normal NK cells. Although NK cells are present in
beta2m- mice and TAP-1(-) mice, they are completely self-tolerant. The underlying
mechanism for this tolerance is unknown. It has been proposed that education
processes render NK cells from these mice hypersensitive to class I-mediated
inhibition, so that they can be inhibited even by the low levels of class I
expressed on autologous cells. In this study, we present evidence against this
hypothesis, by demonstrating that NK cells from beta2m- mice and TAP-1(-) mice
fail to attack beta2m(-)TAP-1(-) double-mutant cells in both in vitro and in vivo
assays. The latter cells express substantially lower levels of class I than
single-mutant cells, based on serologic tests, as well as a significantly
diminished sensitivity to attack by class I-specific CTL. Furthermore, the Ly-49
repertoire on NK cells derived from beta2m(-)TAP-1(-) mice is highly similar to
that of either single mutant, indicating that the developmental processes that
shape the Ly-49 repertoire cannot respond to the differences in class I levels
among these mice. We propose that self-tolerance of NK cells in beta2m- mice and
TAP-1(-) mice is likely to result from hyporesponsiveness of the cells to
activating signals, or alternatively, to induction of inhibitory signaling
through receptors specific for non-class I MHC ligands.
PMID- 9548461
TI - Protein-tyrosine phosphorylation by IgG1 subclass CD38 monoclonal antibodies is
mediated through stimulation of the FcgammaII receptors in human myeloid cell
lines.
AB - The human surface Ag CD38 is a 46-kDa type II transmembrane glycoprotein, and its
expression is dependent on the cell differentiation and activation of
lymphocytes. Our previous work in human myeloid cells showed that ligation of
CD38 with mAbs (HB-7 and T-16; IgG1 subclass) not only induced protein-tyrosine
phosphorylation but also potentiated superoxide generation stimulated by G
protein-coupled receptors. In the present study we analyzed the mechanisms of
action of the agonistic mAbs. HB-7-induced tyrosine phosphorylation could be
still observed in human myeloid cells expressing CD38 mutants, of which
cytoplasmic and transmembrane domains had been deleted or replaced by those of
another type II glycoprotein (PC-1). Moreover, N-linked glycosylation on the cell
surface CD38 was not required for the HB-7-induced cell signaling. The profile of
tyrosine-phosphorylated proteins by HB-7 was exactly the same as that induced by
cross-linking of FcgammaII receptors (FcgammaRII/CD32), and FcgammaRII itself was
tyrosine phosphorylated in the two stimulated cells. The HB-7-induced tyrosine
phosphorylation was completely abolished after masking of FcgammaRII with its
mAb. Finally, F(ab')2 of HB-7 failed to mimic the actions of the whole form of
mAb. These results indicate that anti-CD38 mAb-induced tyrosine phosphorylation
and its associated cell response are entirely mediated through the FcgammaRII
induced signaling pathway, possibly resulting from stimulation of the cell
surface human FcgammaRII with the mouse Fc region (IgG1 subclass) of CD38-ligated
mAbs.
PMID- 9548462
TI - Spectratyping of TCRs expressed by CTL-infiltrating minor histocompatibility
antigen-disparate allografts.
AB - Minor histocompatibility Ags (HA) play prominent roles in stimulating allograft
rejection and are recognized by CTLs that mediate this process. However, there is
no information on the diversity of TCRs that are specific for single minor
histocompatibility Ag peptides and expressed by CTLs in vivo. We have used the
technique of spectratyping to study the diversity of Vbeta usage and beta
complementarity-determining region 3 (CDR3) length of TCRs expressed by CTL
infiltrating skin allografts expressing the immunogenic H4 peptide during the
process of rejection. Spectratyping revealed overall reduction in diversity of
both Vbeta usage and CDR3 length, with sequential application of primary, second
set, and third-set H4-incompatible grafts. This dissection of the array of beta
chains expressed by graft-infiltrating CTLs allowed the direct sequencing of
individual beta-chain PCR products. Beta CDR3s were characterized by a net
negative charge, as we have observed previously with CDR3s expressed by H4
specific CTL clones selected in vitro. Identical and closely related CDR3 amino
acid sequences could be identified that were shared by TCRs that 1) utilized
different Vbeta genes, 2) derived from different mice, or 3) derived from
different sequential sets of allografts on individual mice. Furthermore, a number
of CDR3 sequences expressed by graft-infiltrating CTLs were identical or closely
related to sequences we have identified previously in in vitro selected CTL
clones that were specific for the H4 peptide.
PMID- 9548463
TI - Apoptotic cell death upon contact of CD4+ T lymphocytes with HIV glycoprotein
expressing cells is mediated by caspases but bypasses CD95 (Fas/Apo-1) and TNF
receptor 1.
AB - Loss of CD4+ T helper lymphocytes is central to the development of
immunodeficiency after infection with HIV. In this study, we demonstrate that
contact of primary uninfected CD4+ T lymphocytes with HIV-infected or HIV
envelope glycoprotein-expressing cells results in apoptotic cell death of both
uninfected and infected cells. Apoptosis was blocked by inhibitors of caspases/IL
1beta-converting enzyme-like proteases. This finding provides conclusive evidence
that cytotoxicity upon contact of HIV-infected and uninfected primary cells is an
active process and represents another example for the role of caspases in the
induction of apoptosis. Prevention of apoptosis by inhibition of caspases did not
block the formation of syncytia, indicating that apoptosis occurs either in a
subpopulation of cells or in syncytia. Cell death was not mediated by the CD95
(Fas/Apo-1) or TNF receptor 1 molecules, which indicates a different pathway of
apoptosis induction. The data indicate that initiation of apoptosis significantly
shortens the life span of uninfected CD4+ T cells upon contact with HIV-infected
cells and may represent a factor that contributes to the destruction of CD4+ T
lymphocytes in vitro. Elucidation of the mechanism that initiates apoptosis in
this situation will add to our understanding of both HIV pathogenesis and
apoptotic signaling.
PMID- 9548464
TI - A dominant-negative mutant of the Rab5 GTPase enhances T cell signaling by
interfering with TCR down-modulation in transgenic mice.
AB - TCR triggering results in the down-modulation of engaged receptors by
endocytosis. As a result of this process, Ag-binding sites are depleted from the
surface and signaling responses should be attenuated. To test the importance of
TCR down-regulation on T cell signaling, we generated mice expressing a dominant
negative form of Rab5 (Rab5N133I) in T cells. Rab5, a monomeric GTPase of the Ras
superfamily, has been implicated in the regulation of early steps in the
endocytic pathway. In Rab5N133I mice, mature thymocytes developed, but the
absolute number of CD4+CD8+ double positive thymocytes was reduced. Fluid phase
endocytosis was severely impaired in the transgenic thymocytes. In peripheral T
cells, the kinetics and rate of ligand-induced TCR down-modulation were delayed
and reduced. These effects were correlated with enhanced early and late signaling
responses. Analysis of thymocyte development in doubly transgenic mice for
Rab5N133I and a lymphocytic choriomeningitis virus (LCMV) peptide-specific TCR
demonstrated that TCR signaling was enhanced by dominant inhibition of Rab5
function, resulting in altered thymic selection. These findings suggest that TCR
endocytosis is an important regulatory component of TCR signaling and that
defects in this regulation can result in prolonged signaling and alter thymic
development.
PMID- 9548465
TI - Distinct signal transduction pathways mediate nuclear factor-kappaB induction by
IL-1beta in epithelial and lymphoid cells.
AB - We previously demonstrated that IL-1beta-mediated induction of the nuclear factor
kappaB (NF-kappaB) transcription factor proceeds through the production of
reactive oxygen intermediates in lymphoid cells, while it occurs independently of
any oxidative stress in epithelial transformed cells. Indeed, inhibition of
receptor internalization as well as NH4Cl and chloroquine blocked IL-1beta
mediated induction of NF-kappaB in OVCAR-3 and in other epithelial cell lines but
not in lymphoid cells, indicating that distinct pathways are involved.
Conversely, while we observed phospholipase A2 activity in both cell types
following IL-1beta stimulation, specific inhibitors of this enzyme inhibited NF
kappaB induction only in lymphoid cells. Moreover, expression of the 5
lipoxygenase (5-LOX) enzyme was not detected in epithelial cells, and inhibition
of this enzyme blocked NF-kappaB induction by IL-1beta only in lymphoid cells.
This study thus indicates that the activation of NF-kappaB following IL-1beta
treatment involves the activation of phospholipase A2 and 5-LOX and the
production of reactive oxygen intermediates (ROIs) in lymphoid cells, while in
epithelial cells, another pathway predominates and could involve the acid
sphingomyelinase. Moreover, arachidonic acid could induce NF-kappaB in epithelial
and lymphoid cells, but this activation involved the 5-LOX enzyme and the
production of ROIs only in lymphoid cells. The inefficiency of the ROI pathway in
epithelial cells is probably the consequence of both low ROI production due to
undetectable expression of 5-LOX and rapid degradation of hydrogen peroxide due
to high catalase activity.
PMID- 9548466
TI - oct-2 gene disruption eliminates the peritoneal B-1 lymphocyte lineage and
attenuates B-2 cell maturation and function.
AB - Targeted mutation of the gene for the Oct-2 transcription factor in mice caused
neonatal lethality and abrogated mitogen-induced proliferation and
differentiation of mature B lymphocytes in vitro. Here we show that Oct-2 is
required for normal humoral responses upon immunization with T cell-dependent as
well as T-independent Ags. oct-2-null T cell behavior was normal, implying a B
cell-restricted lesion. oct-2-/- B cells displayed aberrant behavior during
activation in vitro: both acquisition of markers of cellular activation and cell
survival were diminished. Production of early B lineage cells in the bone marrow
was normal, yet mature B cells were under-represented in blood and lymphoid
organs. Furthermore, peritoneal B-1 lymphocytes were not detected in animals with
a reconstituted oct-2-/- lymphoid system. We conclude that Oct-2 is required for
B-1 cell maintenance and for normal Ag-driven maturation of conventional B cells
in vivo.
PMID- 9548467
TI - Role of Thy-1 in T cell development.
AB - Tolerance to self proteins is accomplished in part by elimination of autoreactive
immature T cells as they develop in the thymus. Although many investigators have
studied the cellular interactions that regulate this important process, the
specific molecules involved in negative selection are still not well understood.
Thy-1 is a glycosyl-phosphatidylinositol-linked protein that is expressed at high
levels on immature thymocytes, and recent evidence suggests that it is involved
in thymocyte apoptosis. Correspondingly, we have found that Abs to Thy-1 block Ag
dependent thymocyte deletion in an in vitro culture system. Thus, we investigated
the role of Thy-1 in T cell development by using Thy-1 -deficient mice containing
a TCR transgene specific for a class II MHC-restricted Ag. With this system, the
role of Thy-1 in Ag-specific self-restriction and self-tolerance could be
analyzed. Thy-1-null mice were found to undergo normal negative selection in
three different models: the in vitro culture system, anti-CD3-induced thymocyte
deletion in vivo, and Ag-induced thymocyte deletion in vivo. Self-restriction to
MHC class II also appeared to occur normally in Thy-1-null mice. These results
therefore suggest that Thy-1 is not essential for either self-restriction or self
tolerance to MHC class II-restricted Ags. This finding is discussed in light of
recent data regarding the role of other glycosyl-phosphatidylinositol-linked
proteins in thymocyte development.
PMID- 9548468
TI - Acquisition of granzyme B and Fas ligand proteins by human keratinocytes
contributes to epidermal cell defense.
AB - In vertebrate tissues, cell integrity is maintained by at least three mechanisms.
During an immune response, injured cells are eliminated by cytotoxic lymphoid
cells that produce perforin, granzyme B, and Fas ligand (FasL). Second,
epithelial cells can produce FasL as an immunosuppressive protein, probably to
protect the tissue against immune-mediated damage. Third, locally secreted
antimicrobial peptides can be operative in the protection of animal and human
epithelia. In this work, as another contribution to local mechanisms of host
defense, the ability of human epidermal keratinocytes to produce cytotoxic
proteins was investigated. To address this question, freshly isolated human
epidermal cells and keratinocytes grown in vitro were studied. Freshly isolated
epidermal cells did not express the cytolytic proteins. In contrast, keratinocyte
growth to confluence was associated with granzyme B, perforin, and FasL mRNA and
protein synthesis. These proteins were secreted in the culture medium. Further
analysis showed that they were identical with the ones used by cytotoxic
lymphocytes. Their function was then investigated with a view to a potential role
in epidermal cell integrity. The data showed that activated human keratinocytes
were able to protect against invading pathogens through granzyme B expression.
This was demonstrated by the ability of granzyme B to greatly decrease the
bacterial growth of Staphylococcus epidermidis. In addition, keratinocytes
expressing FasL were found to prevent immune epidermal cell damage. Apoptosis of
Fas-sensitive T cells occurred during coculture with confluent epidermal
keratinocytes and was largely reduced by the addition of a FasL inhibitor. The
data favor keratinocyte involvement in the regulation of dermal inflammatory
responses.
PMID- 9548469
TI - The mucosal adjuvanticity of cholera toxin involves enhancement of costimulatory
activity by selective up-regulation of B7.2 expression.
AB - Cholera toxin (CT) is a potent mucosal immunogen and adjuvant that can strongly
prime mucosal T cells. The present study was undertaken to investigate the
effects of CT on the expression and functional activity of the costimulatory
molecules B7.1 and B7.2 on macrophages and the relationship of these effects to
the mucosal adjuvanticity of CT. Bone marrow macrophages (BMM) were generated by
culturing bone marrow with macrophage CSF or granulocyte-macrophage CSF. After
treatment with either CT alone or IFN-gamma alone, B7.2 expression on BMM was
moderately up-regulated and was further increased when BMM were treated with both
CT and IFN-gamma together. Interestingly, CT had no effect on B7.1 expression
despite the close relationship between these two molecules. Up-regulation of B7.2
expression by CT was mediated by intracellular cAMP production, in that CT-B
subunit had no effect and dibutyryl cAMP could mimic the effect. CT increased
functional costimulatory activity of macrophages for both anti-CD3-stimulated and
allostimulated T cells, an increase that was blocked by anti-B7.2, but not anti
B7.1, Ab. B7.2 expression by Mac1+ Peyer's patch cells was increased after
intraluminal exposure to CT in vivo. Treatment of mice with anti-B7.2 Ab in vivo
inhibited both the mucosal adjuvanticity and the immunogenicity of CT. We
conclude that CT enhances the costimulatory activity of mucosal APC by
differentially up-regulating B7.2 expression, an effect that appears to be
important for its mucosal adjuvanticity and immunogenicity.
PMID- 9548470
TI - The p38 mitogen-activated protein kinase is activated by ligation of the T or B
lymphocyte antigen receptors, Fas or CD40, but suppression of kinase activity
does not inhibit apoptosis induced by antigen receptors.
AB - We have investigated the activation of the p38 mitogen-activated protein kinase
(MAPK) in normal mouse T and B cells and its role in apoptosis. Cross-linking of
the CD3 chains of the TCR complex on proliferating T cells resulted in activation
of p38 MAPK and MAPKAP kinase-2. Cross-linking of CD28 failed to activate p38
MAPK or MAPKAP kinase-2, but synergized strongly with low doses of anti-CD3.
Cross-linking of Fas on T cells also induced rapid activation of p38 MAPK and
MAPKAP kinase-2. The in vivo activation of MAPKAP kinase-2 in response to cross
linking of CD3, Fas, or CD3 and CD28 was shown to be dependent on p38 MAPK
activity using a specific inhibitor, SB 203580. SB 203580 did not inhibit
activation-induced cell death in T cells when used at concentrations that
suppressed activation of MAPKAP kinase-2 in vivo. Cross-linking of the B cell Ag
receptor (BCR) or CD40 on freshly isolated or LPS-activated splenic B cells or
the immature B lymphoma, WEHI 231, resulted in activation of p38 MAPK and MAPKAP
kinase-2. In vivo inhibition of p38 MAPK activity in WEHI 231 cells by SB 203580
had no effect on either BCR-induced apoptosis or anti-CD40-mediated suppression
of apoptosis. We conclude that the activation of p38 MAPK and MAPKAP kinase-2 by
cross-linking of the TCR, BCR, Fas, or CD40 was not correlated with their roles
in regulating lymphocyte survival, and that suppression of kinase activity did
not inhibit the induction of apoptosis.
PMID- 9548471
TI - Dissociation of cytokine signals for proliferation and apoptosis.
AB - Cytokines such as IL-2 or IL-3 prevent cell death through apoptosis, either by
preventing apoptosis directly or by sensitizing cells to survival factors present
in serum. We demonstrate herein that BAF-B03 cells transfected with the wild-type
IL-2R beta-chain undergo apoptosis when stimulated with IL-2 or IL-3 in the
absence of serum. IL-2 also induced apoptosis in normal IL-2-responsive human T
cell blasts in the absence of serum, and furthermore, epidermal growth factor and
fibroblast growth factor induced increased rates of apoptosis in fibroblasts in
the absence of serum, suggesting that cytokine-induced apoptosis in the absence
of serum survival factors might represent an important biologic phenomenon. In
the presence or the absence of serum, IL-2 and IL-3 induced expression of both c
Myc and Bax. In contrast, optimal cytokine-induced expression of Bcl-2 requires
serum. Constitutive expression of Bcl-2 prevented cytokine-induced apoptosis.
Transferrin mimicked serum by inducing an increase in Bcl-2 expression levels and
concurrently prevented apoptosis. These results suggest that the balance between
cytokine- and serum-induced Bcl-2 expression and cytokine-induced Bax expression
may determine whether a cell undergoes cytokine-induced apoptosis. In BAF/BO3
cells expressing a mutant IL-2Rbeta with a deletion of the acidic domain, IL-2
did not induce either Bax expression or apoptosis. This suggests that the acidic
domain of the IL-2R beta-chain plays an essential role in regulating IL-2
mediated Bax expression and apoptosis. Cytokine-induced apoptosis and its
counterbalance by survival factors present in serum may play an important role in
the regulation of cellular homeostasis during pathophysiologic processes.
PMID- 9548472
TI - Insulin down-regulates the inducible nitric oxide synthase pathway: nitric oxide
as cause and effect of diabetes?
AB - Evidence in this paper indicates that insulin can down-regulate the inducible
nitric oxide synthase (iNOS) pathway in vivo. The iNOS pathway is up-regulated in
diabetes-prone rats and mice and is associated with an autoimmune process.
However, the results presented here indicate that macrophage nitric oxide (NO)
production and iNOS mRNA expression are also elevated in rats or mice made
diabetic by streptozotocin injection in which there is no primary autoimmune
component. Insulin administration reduces NO production in autoimmune-prone and
streptozotocin-induced diabetic rodents. Finally, insulin decreases macrophage NO
production in normal hosts. These results indicate that the autoimmune paradigm
is inadequate to explain increased NO in diabetes. As a potential mechanism to
explain insulin-mediated regulation of NO production, TGF-1 may be involved
because 1) macrophages from diabetic mice produce less TGF-beta1 than macrophages
from normal hosts; 2) the circulating TGF-beta1 level is lower in diabetic mice;
and 3) insulin administration increases circulating TGF-beta1 in normal mice.
Together, these results provide evidence that increased NO in diabetes is not
only a cause but also an effect of beta-cell destruction and results in part from
a heretofore unrecognized immunomodulatory activity of insulin.
PMID- 9548473
TI - Functional consequences of dysregulated B7-1 (CD80) and B7-2 (CD86) expression in
B or T lymphocytes of transgenic mice.
AB - T cell activation and tolerance are regulated by interactions between CD28 or
CTLA-4 on T cells and B7 costimulatory molecules on APCs. We have generated
transgenic mouse strains that constitutively express B7-1 (CD80) at high levels
on B cells or T cells or express B7-2 (CD86) on T lymphocytes to examine the
consequences of dysregulated B7 expression on T cell responses. The transgene
derived B7 molecules are functional, because B7-1 transgenic B cells are more
efficient APCs than are wild-type B cells, and the activation of B7 transgenic T
cells is less dependent on exogenous costimulation than that of wild-type T
cells. In vivo, constitutive expression of B7 molecules leads to the elimination
of immature B cells. The expression of B7 molecules on thymocytes results in the
down-regulation of CD28 expression. However, B7 transgenic mice have normal
numbers of mature lymphocytes and mount normal T cell responses following
immunization with protein Ag. Neither anergy induction nor superantigen-mediated
deletion of T cells is altered by the dysregulated expression of B7-1 or B7-2 on
B or T lymphocytes in these transgenic strains. Therefore, functionally
significant levels of B7 expressed constitutively on mature lymphocytes are not,
by themselves, sufficient to abrogate T cell tolerance or induce autoimmune
disease.
PMID- 9548474
TI - T cell stimulation via CD47: agonistic and antagonistic effects of CD47
monoclonal antibody 1/1A4.
AB - CD47/integrin-associated protein has been extensively studied on various cell
types. The function of CD47 on T cells, however, remained poorly understood. We
demonstrate here that our CD47 mAb 1/1A4 has both inhibitory as well as
costimulatory effects in terms of T cell activation. Soluble, not cross-linked,
CD47 mAb 1/1A4 blocks allogeneic MLRs. This effect is predominantly observed with
suboptimal numbers of stimulator cells. In contrast, cross-linking of CD47 in the
presence of CD28 mAb or phorbol ester induces vigorous T cell proliferation that
is sensitive to cyclosporin A. Cross-linking, but not immobilization, of the CD47
mAb 1/1A4 is an essential requirement for the CD28- or phorbol ester-dependent
induction of T cell mitogenesis. Furthermore, CD47 mAb 1/1A4 induces T cell
proliferation when coimmobilized with a CD3 mAb to the same surface. Ligation
with cross-linked 1/1A4 mAb induces an increase in intracellular free calcium
levels and leads to tyrosine phosphorylation of various cellular proteins and, in
the presence of suboptimal concentrations of plate-bound CD3 mAb, to enhanced IL
2 promotor activity in T cells. Furthermore, we present evidence that upon cross
linking of CD47 with mAb 1/1A4, purified T cells acquire responsiveness for
several T cell growth factors. IL-1beta and/or IL-6 dramatically augment this
CD47-induced cytokine responsiveness. Our results suggest that the novel
activation pathway via CD47 might be critically involved in Ag-dependent and Ag
independent T cell functions.
PMID- 9548475
TI - Structural requirements for beta1 integrin-mediated tyrosine phosphorylation in
human T cells.
AB - The beta1 integrin adhesion receptors activate signal transduction pathways that
induce tyrosine phosphorylation of a variety of substrates. Increased tyrosine
phosphorylation is mediated by the beta1 subunit cytoplasmic domain, which
consists of 46 amino acids and contains no intrinsic kinase activity. In the H9 T
cell line, beta1 integrin engagement leads to the increased tyrosine
phosphorylation of three 105 to 115-kDa substrates that are distinct from focal
adhesion kinase (FAK): HEF1 (human enhancer of filamentation 1), a protein with
structural homology to p130Cas, and two novel substrates, pp105 and pp115. DNA
mediated gene transfer was used to explore the role of the beta1 cytoplasmic
domain in integrin-mediated tyrosine phosphorylation of HEF1, pp105, and pp115 in
human T cells. Using a chimeric receptor composed of the cytoplasmic domain of
the beta1 integrin subunit and the extracellular and transmembrane domains of the
CD2 Ag, we demonstrate that the beta1 cytoplasmic domain is necessary and
sufficient for inducing tyrosine phosphorylation of each of these three
substrates in H9 T cells. Analysis of a series of beta1 cytoplasmic domain
truncations reveals that a truncation of only five amino acids from the carboxyl
terminal end of the beta1 cytoplasmic domain abrogates the ability of the
CD2/beta1 chimera to activate tyrosine phosphorylation of HEF1, pp105, or pp115.
Thus, the carboxyl-terminal five amino acids, Lys-Tyr-Glu-Gly-Lys (KYEGK), of the
beta1 integrin cytoplasmic domain are critical for the coordinate tyrosine
phosphorylation of three non-FAK substrates in human T cells.
PMID- 9548476
TI - TAP peptide transporter-independent presentation of heat-killed Sendai virus
antigen on MHC class I molecules by splenic antigen-presenting cells.
AB - Immunization of C57BL/6 (B6) mice with heat-killed Sendai virus generates a
Sendai virus-specific CD8+ T cell response. This suggests that APC have the
capacity to take up and present exogenous (nonreplicative) Sendai virus Ag on MHC
class I molecules. Little is known about the intracellular requirements for
processing of this form of Ag and its presentation on MHC class I. Therefore, we
have studied the processing and presentation of heat-killed Sendai virus Ag on
MHC class I molecules in splenic APC. Heat-killed Sendai virus Ags were
efficiently processed by normal B6 as well as by TAP-1(-/-) splenic APC.
Presentation was MHC class I restricted, since no presentation was seen by APC
from TAP-1/beta2m-/- mice that lack expression of MHC class I. Presentation
occurred even in the presence of brefeldin A, but was blocked by cytochalasin D
as well as chloroquine. Finally, B6 as well as TAP-1(-/-) splenic APC, loaded
with heat-killed Sendai virus Ag in vitro, primed naive CD8+ T cells in vivo.
These studies suggest the existence of a TAP-independent pathway for Ag
presentation on MHC class I in normal splenic APC, bearing many similarities with
the MHC class II pathway for Ag presentation. The present results are discussed
in relation to the events underlying the processing and presentation of exogenous
Ag on MHC class I, the molecular basis for CD8+ T cell priming during viral
infections, and prospects for vaccine development.
PMID- 9548477
TI - Identification of two distinct populations of dendritic cells in afferent lymph
that vary in their ability to stimulate T cells.
AB - Immunofluorescent staining and flow cytometric analysis of dendritic cells from
cattle afferent lymph has established that within the afferent lymph veiled cells
(ALVC) there are two phenotypically distinct, major populations. One is CD11a+,
CD5+, CD21- and expresses the bovine WC10 (workshop cluster 10) molecule and the
Ag recognized by mAb CC81 but is not recognized by mAbs CC149 and IL-A24. The
second ALVC subpopulation is CD11a-, CD5-, CD21+/-, workshop cluster 10- and is
not recognized by mAb CC81 but is recognized by mAb CC149. Thus, the two
populations, which can be identified by staining for CD11a, are defined by the
differential expression of a number of Ag. The ALVC populations had differing
capacities to stimulate T cells. CD11a- ALVC were more effective at stimulating
proliferative responses in allogeneic CD4+ T cells and CD8+ T cells. This was not
related to binding of CTLA4Ig or CD40L fusion proteins, implying similar levels
of expression of their ligands, CD80 and CD86 or CD40. Both subsets were able to
present OVA to resting memory CD4+ T cells, indicating that both were able to
take up and process soluble native protein. In contrast, the CD11a- ALVC were
more effective in presenting respiratory syncytial virus Ag to resting CD4+ T
cells. Considering the central role of dendritic cells in the initiation of
immune responses in naive animals, the two cell types may have different roles in
the induction of primary responses induced following infection or immunization.
PMID- 9548478
TI - Natural variants of the immunodominant HLA A11-restricted CTL epitope of the EBV
nuclear antigen-4 are nonimmunogenic due to intracellular dissociation from MHC
class I:peptide complexes.
AB - EBV isolates from human populations with a high frequency of HLA A11 evade
recognition by CTLs specific for an immunodominant A11-restricted epitope derived
from the EBV nuclear antigen 4 (EBNA-4). We have previously described four
nonimmunogenic variants of this epitope carrying single amino acid substitutions
in the anchor residues of the peptide. We have now investigated the antigenicity,
A11 binding capacity, endoplasmic reticulum translocation, endogenous processing,
and presentation of these variants. The nonimmunogenic peptides were either
unable to bind to HLA A11 or formed complexes of significantly lower stability
compared with the immunogenic epitope. The latter peptides were produced in
relatively large amounts by endogenous processing of EBNA-4 and associated with
A11 molecules almost as efficiently as the immunogenic epitope, but the complexes
failed to accumulate at the cell surface. The defect was not reversed by
incubation of lymphoblastoid cell lines carrying the variant EBV strains at 26
degrees C. CTL lysis of HLA A11 positive targets was achieved by expressing one
of the nonimmunogenic peptides through a vaccinia recombinant. However, the
amount of peptide required for CTL sensitization exceeded, by at least 30-fold,
that required for recognition of the immunogenic epitope. Collectively, these
results suggest that complexes containing the nonimmunogenic peptides are formed
but are then destroyed intracellularly. Thus, a specialized sorting mechanism
seems to contribute in shaping the repertoire of peptides presented to T
lymphocytes.
PMID- 9548479
TI - Processing of engulfed apoptotic bodies yields T cell epitopes.
AB - Programmed death via apoptosis is the metazoan physiologic mode of cell death.
Apoptotic cells are recognized by scavenger phagocytes via a number of membrane
receptors and engulfed. Thereafter, little is known of their fate, or that of
phagocytes. Here, we have traced apoptotic cells upon their engulfment by
macrophages. After 3 h, apoptotic cells were contained in discrete well-defined
vacuoles. Upon overnight chase, several small vesicles, possibly originating from
the fragmentation of original vacuoles, were evident all over the macrophage
body. Furthermore, Ags were diffused in the cytosol of some cells, which raises
the possibility that epitopes from engulfed apoptotic cells may associate with
macrophage MHC class I molecules and be recognized by T lymphocytes. Indeed, Ag
specific CTLs recognize and specifically lyse syngeneic macrophages upon
phagocytosis of MHC class I-positive or -negative apoptotic cells, provided that
they contain the relevant Ags. Synthesis and membrane expression of class I
molecules by macrophages, together with functional transporters associated with
Ag presentation, were necessary for recognition and lysis. The indirect
presentation of epitopes from engulfed apoptotic cells by scavenger Ag-presenting
phagocytes may, in the absence of "danger" signals, have implications for the
establishment of central and peripheral self-tolerance.
PMID- 9548480
TI - Leech immunocytes contain proopiomelanocortin: nitric oxide mediates hemolymph
proopiomelanocortin processing.
AB - This report establishes the presence of mammalian-like proopiomelanocotropic
hormone (POMC), and six of its peptides, including adrenocorticotropic hormone
(ACTH) and melanocyte-stimulating hormone (MSH), in the immune tissues of the
leech Theromyzon tessulatum. The 25.4-kDa protein was purified by high pressure
gel permeation chromatography, anti-ACTH-affinity column, and reverse-phase HPLC.
Its characterization was performed by Edman degradation, enzymatic treatments,
and electrospray mass spectrometry. Leech POMC exhibits considerable amino acid
sequence similarity to mammalian POMC. Of the six peptides, three showed high
sequence similarity to their vertebrate counterparts met-enkephalin, alpha-MSH,
and ACTH: 100, 84.6, and 70%, respectively; whereas gamma-MSH, beta-endorphin,
and gamma-lipotropin hormone exhibited only 45, 20, and 10% sequence identity,
respectively. No dibasic amino acid residues were found at the C terminus of the
gamma- and beta-MSH peptides. In contrast, the leech alpha-MSH was flanked at its
C-terminal by the Gly-Arg-Lys amidation signal. ACTH and corticotropin-like
intermediary pituitary peptide were also C-terminally flanked by dibasic amino
acid residues. The coding region of leech POMC was obtained by reverse
transcription-PCR using degenerated oligonucleotide primers. Circulating levels
of ACTH and MSH were 10 and 1 fmol/microl hemolymph, respectively. Morphine, in a
dose-dependent manner, increased the levels of both peptides threefold; this
effect was blocked by naloxone treatment. Similar results were found with the
anandamide. Leech ACTH was processed to MSH by the enzymes neutral endopeptidase
(24.11) and angiotensin-converting enzyme. Leech alpha-MSH had the same activity
as authentic alpha-MSH in two bioasssay systems. Taken together, the study
demonstrates that POMC is present in invertebrates and its immunoregulatory
actions have been conserved during evolution.
PMID- 9548481
TI - Evidence for multiple promoters of the human IL-5 receptor alpha subunit gene: a
novel 6-base pair element determines cell-specific promoter function.
AB - In addition to a previously characterized promoter (P1), we now show the
existence of a second promoter for the human IL-5Ralpha gene. Initially, a
genomic region (P2) 5' upstream of human IL-5Ralpha exon 2 was cloned by an
inverted PCR. The transcriptional start site was then mapped to a deoxycytidine
(C) residue within P2 by analyzing cellular mRNA with both the 5' rapid
amplification of cDNA end-PCR and S1 nuclease protection assays. Transfection of
eosinophilic HL-60 cells with reporter gene constructs in which either P1 or P2
was linked to the bacterial chloramphenicol acetyltransferase (CAT) gene resulted
in CAT expression; little or no CAT expression occurred in other myeloid and
nonmyeloid cell lines. Deletion studies showed that a 66-bp region, ranging from
31 to +35, was sufficient to promote CAT expression in eosinophilic HL-60 cells.
Analysis of linker-scanning mutants identified a novel 6-bp element (5' CTAATT
3') spanning -19 to -14 that was essential for P2 promoter activity. In
electrophoretic mobility shift assays, a P2 region from -31 to +1 containing the
unique 6-bp element, when used as a probe, formed a complex with a protein(s)
that was found only in the eosinophilic cell line. This binding activity was lost
upon replacement of the 6-bp element with a 6-bp linker, suggesting that this
element likely serves as the binding site for an eosinophilic HL-60 cell-specific
transcription factor(s). Together, these data suggest an important role for P2
promoter in the regulation of eosinophil-specific expression of the human IL-5
receptor alpha gene.
PMID- 9548482
TI - Molecular analysis of V gene sequences encoding cytotoxic anti-streptococcal/anti
myosin monoclonal antibody 36.2.2 that recognizes the heart cell surface protein
laminin.
AB - Anti-streptococcal/anti-myosin mAb 36.2.2 is unique among the cross-reactive anti
streptococcal mAbs due to its cytotoxicity for rat heart cells and its ability to
strongly label the surface of heart cells in indirect immunofluorescence assays.
In this study, cytotoxic mAb 36.2.2 was found to react strongly with the
extracellular matrix protein laminin in immunoblots and inhibition assays, while
11 other cross-reactive anti-streptococcal mAbs did not react with laminin and
were not cytotoxic. Cytotoxicity appeared to correlate with the presence of
laminin on the surface of cells. Heavy and light chain variable region genes
encoding mAb 36.2.2 were highly homologous to other V genes encoding anti
carbohydrate and/or autoantibodies. VH, JH, and Jkappa segments of mAb 36.2.2 may
be encoded by germline gene segments. The VH segment may be identical with an as
yet unidentified VH7183 family germline sequence, and the 36.2.2 Vkappa region
gene is encoded by a Vkappa8 family member.
PMID- 9548483
TI - Delta-opioid receptors expressed by Jurkat T cells enhance IL-2 secretion by
increasing AP-1 complexes and activity of the NF-AT/AP-1-binding promoter
element.
AB - Recent molecular evidence points to transient and/or stage-specific expression of
delta- and kappa-opioid receptors by thymic and peripheral T lymphocytes. Since
medical treatments or stress commonly increase opioid levels, it is important to
understand the mechanisms by which opioids affect T lymphocyte functions. We
therefore created and studied a T cell line expressing the cloned delta-opioid
receptor (DOR1). DOR1 ligation by a specific DOR1 agonist, deltorphin, augmented
IL-2 secretion by synergizing with signals from TCR-CD3 and CD28. Reporter gene
constructs were used to map this effect of deltorphin to the AP-1- and NF-AT/AP-1
binding sites of the IL-2 promoter. Although DOR1 signaling increased [Ca2+]i,
deltorphin enhanced transcriptional activity of the NF-AT/AP-1-binding site via a
mechanism independent of calcineurin and distinct from the effects of elevated
[Ca2+]i. Deltorphin also increased accumulation of AP-1 transcription factor
complexes, suggesting that DOR1 augments IL-2 secretion by increasing the AP-1
component of the NF-AT/AP-1 transcription factor. These results advance the
molecular understanding of opioid effects on lymphocytes, and in addition,
demonstrate regulation of IL-2 synthesis and secretion by the novel mechanism of
receptor-mediated AP-1 induction.
PMID- 9548484
TI - Cloning and analysis of the promoter region of CCR5, a coreceptor for HIV-1
entry.
AB - The chemokine receptor CCR5 is a cofactor for cellular entry of macrophage-tropic
strains of HIV-1. Expression of CCR5 is restricted to T cells, macrophages, and
certain cell lines; however, the mechanisms controlling its expression remain
largely unknown. To delineate these mechanisms, approximately 1.0 kb of DNA from
the immediate 5' upstream region of CCR5 was cloned and characterized. CCR5
promoter activity was up-regulated by PMA, and a region spanning -417 to +61
relative to the transcription start site was sufficient for the basal and induced
activity. DNase I footprinting assays demonstrated several protected areas within
this region, and gel shift assays determined binding sites for transcriptional
factors Oct-1, Oct-2, T cell factor 1alpha, and GATA1. CCR5 promoter activity was
also induced by IL-2 or anti-CD3 Ab, while stimulation with anti-CD28 Ab markedly
reduced CD3-mediated up-regulation of the CCR5 promoter. Flow cytometry confirmed
the findings at the level of cell surface expression. Further delineation of the
regulation of the CCR5 promoter will be important for a more comprehensive
understanding of the pathogenesis of HIV disease.
PMID- 9548485
TI - Role of cyclic AMP response element-binding protein in cyclic AMP inhibition of
NF-kappaB-mediated transcription.
AB - The NF-kappaB family of transcription factors regulates the inducible expression
of a variety of genes. Recently, we showed that elevation of intracellular cyclic
AMP inhibits NF-kappaB-mediated transcription in human monocytes and endothelial
cells without preventing nuclear translocation of NF-kappaB complexes. The
present study examined the molecular mechanism of this inhibition. We
hypothesized that activation of the protein kinase A signaling pathway may
inhibit NF-kappaB-mediated transcription by phosphorylating proteins, such as
cAMP response element-binding protein (CREB), which compete for limiting amounts
of the coactivator CBP. Here, we show that the amino-terminal region (amino acids
1-450) of CBP specifically interacts with the carboxyl-terminal region (amino
acids 286-551) of NF-kappaB p65 (RelA) both in vitro and in vivo. Functional
studies using human endothelial cells demonstrated that overexpression of CBP
rescued cAMP inhibition of NF-kappaB-mediated transcription and transcription
mediated by a chimeric protein, GAL4-p65(286-551), which contained the GAL4 DNA
binding domain fused to the carboxyl-terminal region of p65 (amino acids 286
551). In contrast, overexpression of CREB inhibited GAL4-p65(286-551)-mediated
transcription. These results suggest that activation of the protein kinase A
pathway inhibits NF-kappaB transcription by phosphorylating CREB, which competes
with p65 for limiting amounts of CBP.
PMID- 9548486
TI - The DMB promoter: delineation, in vivo footprint, trans-activation, and trans
dominant suppression.
AB - The HLA-DM loci encode the heterodimeric unconventional class II MHC molecules
that are coexpressed with conventional class II MHC molecules. DM molecules are
essential for the proper formation and function of conventional class II MHC
molecules. This report characterizes the DMB promoter both by in vivo footprint
and by in vitro functional analysis and reveals a promoter structure similar to
that of conventional class II MHC genes. DR-negative mutant cell lines
selectively defective in the transcription factor or class II trans-activator
(CIITA) were used to reveal a requirement for both these factors in DMB promoter
activation. Complementation of defective cell lines with the appropriate
transcription factor reconstituted DMB promoter activation. Further analysis with
CIITA identified several mutant forms of CIITA that are trans-dominant-negative
mutants, i.e., they suppressed DMB promoter activation by transfected and
endogenous CIITA. These mutants may be used in abiological setting to down
regulate the function of DM in Ag processing.
PMID- 9548487
TI - IL-4-induced STAT6 suppresses IFN-gamma-stimulated STAT1-dependent transcription
in mouse macrophages.
AB - IL-4 suppresses the IFN-gamma-induced expression of the IFN regulatory factor-1
(IRF-1) gene, and this suppression is attenuated by increasing the amount of IFN
gamma. The effects of IFN-gamma and IL-4 on transcription of a reporter gene
under control of a 1.3-kb fragment from the IRF-1 gene promoter or the STAT
binding element (SBE) from this gene in the context of a heterologous promoter
are similar to their effects on the endogenous IRF-1 gene. IFN-gamma-dependent
transcription of reporter gene is suppressed by IL-4, but IL-4 alone has no trans
activating function. IL-4 treatment does not inhibit the tyrosine phosphorylation
or nuclear translocation of IFN-gamma-activated STAT1. Rather, IFN-gamma and IL-4
independently activate STAT1 and STAT6, respectively, and both proteins bind to
the IRF-1 SBE in homodimeric form. The affinity of STAT1 for the IRF-1 SBE is
higher than the affinity of STAT6, as measured by competition with unlabeled
oligonucleotide. These observations suggest that IL-4 may suppress IFN-gamma
stimulated transcription of the IRF-1 gene by activation of STAT6, which can
compete with STAT1 for occupancy of the IRF-1 SBE when STAT1 levels are low.
Suppression may be attenuated as the quantity of STAT1 relative to that of STAT6
increases in cells treated with increasing amounts of IFN-gamma and displaces
STAT6.
PMID- 9548488
TI - Augmentation of dendritic cells in murine organ donors by Flt3 ligand alters the
balance between transplant tolerance and immunity.
AB - Treatment of mice with the recently cloned hemopoietic growth factor Flt3 ligand
(FL; 10 microg/day for 10 days) resulted in a large increase in myeloid lineage
cells within the liver. While the number of nonparenchymal cells (NPC) harvested
from liver increased about 9-fold, a 90-fold increase was observed in the
proportion of CD11c+ dendritic cells (DC) recovered from NPC following overnight
(18-h) culture in granulocyte-macrophage CSF. In contrast, only a 50% increase
was seen in CD11c+ cells within heart single cell suspensions and in the number
of DC obtained from hearts after 18-h culture. Liver NPC and heart cell
suspensions freshly isolated from 10-day FL-treated animals exhibited increased T
cell allostimulatory capacity compared with controls. Overnight cultured DC from
livers of FL-treated animals expressed both higher levels of costimulatory
molecules (CD80 and CD86) and allostimulatory activity than those from controls.
Heart-derived DC also displayed enhanced stimulatory capacity. Pretreatment of
organ donors with FL for either 5 or 10 days before transplant of organs to
normal recipients abrogated the spontaneous liver allograft acceptance normally
observed and resulted in delayed or acute graft rejection (median survival times,
40 and 12 days, respectively). Heart rejection was significantly accelerated by
pretreatment of donors with FL for 5 or 10 days (median survival times, 8 and 7
days, respectively, vs 12 days in controls). These novel findings reveal the
potent immunologic adjuvant properties of FL in vivo. They also show that
substantial augmentation of the number of potential allostimulatory cells in
donor organs before transplantation favors rejection rather than tolerance
induction.
PMID- 9548489
TI - Transcriptional regulation of the complement receptor 2 gene: role of a
heterogeneous nuclear ribonucleoprotein.
AB - Complement receptor 2 (CR2) has been implicated as a regulator of B cell
function. In this study, we sought to identify mechanisms that control the
expression of the CR2 gene in human B cells. Dibutyryl cAMP increased the DNA
binding activity of a nuclear protein that recognized specifically a CR2 promoter
defined oligonucleotide in human B cell lines. The nuclear protein was
subsequently purified from B cell nuclear extracts using a biotinylated CR2
promoter-defined oligonucleotide. Partial amino acid sequence analysis of
internal peptides revealed that the 42-kDa protein belongs to a family of
heterogeneous nuclear ribonucleoproteins (hnRNP). Using a set of mutated double
stranded oligonucleotides, we demonstrated that the purified protein displayed
sequence specificity for the CR2 promoter-defined oligonucleotide. Like some
hnRNP, this protein was found to bind to single-stranded DNA. The DNA-binding
activity of the purified protein increased after in vitro phosphorylation with
protein kinase A. Using a CAT reporter gene driven by a single recognition site
in B cell lines, dibutyryl cAMP caused a 3-fold induction of reporter gene
expression. The highest induction (6.7-fold) was achieved with a combination of
dibutyryl cAMP and PMA. The involvement of the nuclear protein in regulating the
expression of the CR2 gene is supported by our finding that dibutyryl cAMP
increased the levels of the CR2 mRNA and CR2 surface membrane protein in human B
cell lines. These data strongly suggest that a cAMP-inducible hnRNP, which can
recognize a novel DNA-motif, controls the expression of the CR2 gene.
PMID- 9548490
TI - Differential induction of DNA-binding activities following CD19 cross-linking in
human B lineage cells.
AB - The B cell-specific cell surface molecule CD19 is expressed at all stages of B
cell development, including normal plasma cells, and mediates signal transduction
via interaction with cytoplasmic effector proteins. Cross-linking CD19 on early
human B lineage cells induces the formation of a CD19/Vav/phosphatidylinositol-3
kinase complex, tyrosine phosphorylation of CD19 and Vav, and activation of the
Ras pathway. To further explore the ramifications of CD19 signaling, the current
study examined whether phosphorylation of Elk-1, activation of activator protein
1 (AP-1), or activation of nuclear factor-kappaB (NF-kappaB) transcription
factors occurred following CD19 cross-linking. The cells used were the BLIN-1 pre
B cell line expressing low levels of cell surface mu heavy chain associated with
surrogate light chain and the 1E8 immature B cell line expressing cell surface
mu/kappa. Lysates from CD19 cross-linked 1E8 cells induced robust phosphorylation
of an Elk-1 fusion protein in vitro, whereas no phosphorylation of Elk-1 fusion
protein occurred using lysates from CD19 cross-linked BLIN-1 cells. An
electrophoretic mobility shift assay employing AP-1 and NF-kappaB consensus
oligonucleotides was used to demonstrate that AP-1 -binding activity increased,
while constitutive NF-kappaB-binding activity was not enhanced, following 2 h of
CD19 cross-linking in 1E8 cells. Supershift experiments revealed that JunD and c
Fos proteins mediated anti-CD19 induced AP-1-binding activity in 1E8 cells. In
contrast, CD19 cross-linking in BLIN-1 cells resulted in the induction of NF
kappaB, but had no apparent effect on AP-1-binding activity. These data suggest
that CD19-mediated signal transduction activates different transcription factors
at juxtaposed stages of B cell development that may culminate in the activation
or suppression of distinct sets of genes.
PMID- 9548491
TI - Adoptive transfer of in vitro-targeted, activated T lymphocytes results in total
tumor regression.
AB - Adoptive immunotherapy of cancer uses the transfer of tumor-reactive immune
cells. The success of this procedure is dependent upon the specificity of the
transferred immune cells, their number, and their ability to reach their target
cells. We genetically modified T lymphocytes and equipped them with the ability
to specifically recognize tumor cells. Tumor cells overexpressing the ErbB-2
receptor served as a model. The target cell recognition specificity is conferred
to T lymphocytes by transduction of a chimeric gene encoding the zeta-chain of
the TCR and a single chain antibody (scFv(FRP5)) directed against the human ErbB
2 receptor. The chimeric scFv(FRP5)-zeta gene was introduced into primary mouse T
lymphocytes via retroviral gene transfer. Naive T lymphocytes were activated and
infected by cocultivation with a retrovirus-producing packaging cell line. The
scFv(FRP5)-zeta fusion gene was expressed in >75% of the T cells. These T cells
lysed ErbB-2-expressing target cells in vitro with high specificity. We tested
the antitumor efficacy of scFv(FRP5)-zeta-expressing T cells in a syngeneic
BALB/c model. The mice were treated with autologous, transduced T cells. The
adoptively transferred scFv(FRP5)-zeta-expressing T cells caused total regression
of ErbB-2-expressing tumors. The presence of the transduced T lymphocytes in the
tumor tissue was monitored. No humoral response directed against the transduced T
cells was observed. Abs directed against the ErbB-2 receptor were detected upon
tumor lysis.
PMID- 9548492
TI - TCR vaccines for active immunotherapy of T cell malignancies.
AB - We have developed a TCR-based vaccine approach for the treatment of T cell
malignancies. TCR genes were isolated from C6VL, a T cell tumor of C57BL/Ka
origin. The transmembrane encoding domains of the TCR genes were replaced by
sequences encoding for phosphatidylinositol-linked cell surface expression. A
high expressing cell line was produced by transfection and amplification of the
TCR genes. Large quantities of soluble native C6VL TCR-alphabeta protein was
obtained by treating the high-expressing cells with a specific phospholipase and
purifying the released TCR by affinity chromatography. Following vaccination with
the TCR linked to keyhole limpet hemocyanin, specific anti-TCR humoral responses
were induced. Both the carrier protein and an adjuvant were required for optimal
responses. Hyperimmune serum from vaccinated mice reacted specifically with C6VL
cells, and the immunizations did not affect the TCR repertoire, which suggested
that the immune response was Id specific. The TCR-vaccinated mice were
specifically protected from a lethal number of C6VL tumor cells. B cell-deficient
mice were not protected by TCR vaccinations. Similarly, TCR-immunized mice
depleted of CD8+ cells prior to tumor challenge were not protected. Thus, C6VL
TCR vaccine effectively stimulated tumor protection, which depends on the
presence of both B cells and CD8+ T cells.
PMID- 9548493
TI - IL-18 protects mice against pulmonary and disseminated infection with
Cryptococcus neoformans by inducing IFN-gamma production.
AB - We examined the effects of a newly identified cytokine, IL-18, originally
designated as IFN-gamma-inducing factor, in a mouse model of pulmonary and
disseminated infection with a highly virulent strain of Cryptococcus neoformans.
Administration of murine rIL-18 enhanced elimination of live micro-organisms from
the lungs, prevented fungal dissemination to the brain, reduced the level of
serum cryptococcal capsular polysaccharide Ags, and increased the survival rate
of infected mice. Histologic examination of lung sections of infected and PBS
treated mice showed a poor cellular inflammatory reaction and a large number of
multiplying C. neoformans yeast cells in alveolar spaces. In contrast, massive
infiltration of inflammatory cells, consisting mainly of mononuclear cells,
characterized sections of lungs of infected animals treated with IL-18. Treatment
with IL-18 also increased the level of serum IFN-gamma. In addition, the
protective effect of IL-18 on cryptococcal infection was abrogated by
administration of neutralizing anti-IFN-gamma mAb. Finally, we examined the
effect of neutralizing anti-IL-18 Ab on cryptococcal infection to define the
physiologic role of this cytokine in host defense using another weakly virulent
strain of C. neoformans, which induced the expression of IL-18 mRNA in the
infected lungs. Administration of this Ab exacerbated the infection, as shown by
the increased lung burden. Our results indicate that IL-18 plays an important
role in host defense against infection with C. neoformans.
PMID- 9548494
TI - A cryptic T cell epitope on the apical membrane antigen 1 of Plasmodium chabaudi
adami can prime for an anamnestic antibody response: implications for malaria
vaccine design.
AB - We have investigated the proliferative and Th cell responses to the Plasmodium
chabaudi adami DS homologue of the Plasmodium falciparum apical membrane Ag 1
(AMA-1), a leading malaria vaccine candidate. Immunodominant T cell epitopes were
defined following immunization of BALB/c mice with Escherichia coli-expressed,
refolded P. c. adami DS AMA-1 recombinant protein and testing cells from the
draining lymph nodes for responses against a series of overlapping peptides
spanning P. c. adami AMA-1. A limited number of major T cell sites were
identified in both conserved and variable regions of the protein. Several cryptic
epitopes that evoked T cell responses following immunization with peptides, but
not after protein immunization, were also identified. Adoptive transfer of a T
cell line specific for a conserved cryptic epitope (corresponding to residues 31
50) provided help for an anti-AMA-1 protein-specific Ab response following in
vivo challenge with P. c. adami parasitized RBC, such that AMA-1-specific Abs
appeared more rapidly in recipient mice than in controls. Furthermore, T cells
specific for cryptic epitopes afforded partial protection against P. c. adami
infection in nude mice. The identification of conserved cryptic Th cell epitopes
has important implications for malaria vaccine design.
PMID- 9548495
TI - Targeting of cytotoxic T cells against leukemic B cells by bispecific antibody
(aCD3 x aCD19) does not distract the T cell from its primary target.
AB - Bispecific Abs (BsAb) represent a novel format of immunotherapy, recognizing
immune effector cells (e.g., T cells), on the one hand, and target cells (e.g.,
tumor cells), on the other hand. To be successful, cross-linking of the two cell
types is necessary for effector cell activation and subsequent killing of the
malignant target cells. We asked the question, whether CTL that were incubated
with the BsAb aCD3 x aCD19 and malignant B cells and activated to kill the
malignant B cells were still able to eliminate their natural target cells (e.g.,
virus-infected autologous body cells). To test this, HLA-A*0201-restricted,
influenza-specific CTL were incubated with BsAb- and HLA-A*0201-positive B
lymphoid tumor cells in combination with HLA-A*0201-positive, virus-infected non
B lymphoid cells as natural target cells. The results showed that even in the
presence of BsAb and high amounts of tumor B cells, CTL were still capable of
eliminating the virus-infected non-B lymphoid target cells; actually, CTL
recognized and eliminated the homologous original target cells preferentially.
PMID- 9548496
TI - Involvement of mitogen-activated protein kinase pathways in the nuclear responses
and cytokine production induced by Salmonella typhimurium in cultured intestinal
epithelial cells.
AB - Central to the pathogenesis of Salmonella typhimurium is its ability to engage
the host cell in a two-way biochemical interaction. As a consequence of this
interaction, a dedicated protein secretion system, termed type III, is activated
in these bacteria and directs the translocation of signaling proteins into the
host cell. Secretion of these proteins stimulates host cell signal transduction
pathways that lead to a variety of cellular responses. An important feature of S.
typhimurium pathogenesis is the induction of a profound inflammatory response in
the intestinal epithelium. In this report, we show that S. typhimurium induces
host cell signal transduction pathways that lead to the activation of the
transcription factors NF-kappaB and AP-1, resulting in the production of
proinflammatory cytokines such as IL-8. We also show that S. typhimurium
infection of cultured intestinal epithelial cells results in the activation of
the mitogen-activated protein (MAP) kinases ERK, JNK, and p38. Induction of these
signaling pathways and the synthesis of IL-8 was strictly dependent on the
function of the invasion-associated type III protein secretion system encoded by
S. typhimurium. Pretreatment of cells with the highly specific p38 MAP kinase
inhibitor SB 203580 prevented S. typhimurium-induced IL-8 production. These
results indicate that the inflammatory response induced by S. typhimurium may be
due to the specific stimulation of MAP kinase signaling pathways leading to
nuclear responses.
PMID- 9548497
TI - Functional properties of human intestinal mast cells cultured in a new culture
system: enhancement of IgE receptor-dependent mediator release and response to
stem cell factor.
AB - Culture of human mast cells (MC) in vitro has only been possible to date in the
presence of 3T3 fibroblasts. The aim of the present study was to maintain freshly
isolated human MC in culture without addition of feeder cells and to study their
functional properties. We isolated cell suspensions containing 1 to 11% MC from
human intestinal tissue and cultured them in standard medium. MC survived in
culture for about 2 wk without cytokine supplementation and for several months
with supplementation of medium with stem cell factor (SCF). SCF selectively
supported MC survival, whereas the number of contaminating cells declined rapidly
during culture. Most interestingly, we found that histamine and leukotriene
release induced by IgE receptor cross-linking was substantially enhanced in
cultured MC compared with that in MC stimulated directly after cell isolation.
Cultured MC, but not freshly isolated MC, released mediators in response to SCF
in a concentration-dependent fashion provided that the cells were cultured in SCF
free medium. These findings demonstrate that human MC isolated from intestinal
tissue can be maintained in culture in vitro for several weeks. After culture
they have different functional properties, which might resemble more closely the
functional status of human intestinal MC in vivo than that of freshly isolated
cells.
PMID- 9548498
TI - Beta2 integrins are not required for tyrosine phosphorylation of paxillin in
human neutrophils.
AB - Although many of the receptors mediating neutrophil (polymorphonuclear leukocyte
(PMN)) adhesion to extracellular matrix (ECM) proteins have been identified, the
signal transduction pathways leading to cell spreading are not clearly defined.
Studies showing that protein tyrosine phosphorylation increases with PMN adhesion
suggest that phosphorylation is critical for adhesion-dependent processes. In
other cells, increased tyrosine phosphorylation of focal adhesion kinase (FAK)
and paxillin are thought to play pivotal roles in ECM-mediated signaling. In the
present study we compared the tyrosine phosphorylation of FAK and paxillin in
PMNs plated onto thrombospondin (TSP) or laminin (LN). Increased tyrosine
phosphorylation of paxillin correlated with adhesion and spreading of PMNs plated
onto LN or TSP. In PMNs adherent to LN, the kinetics of FAK phosphorylation
preceded the kinetics of paxillin phosphorylation, suggesting that paxillin may
be a downstream target of FAK. In contrast, FAK was not phosphorylated in PMNs
spread on TSP. These findings suggested activation of different signaling
pathways in TSP- vs LN-adherent PMNs. Others have proposed that paxillin
phosphorylation requires beta2 integrins. Therefore, we used PMNs from a patient
with leukocyte adhesion deficiency (LAD), lacking beta2 integrins, to determine
whether these receptors were necessary for paxillin phosphorylation. LAD PMNs did
not adhere to LN, and consequently, there was no tyrosine phosphorylation of FAK
or paxillin. In contrast, paxillin, but not FAK, was phosphorylated in LAD PMNs
adherent and spread on TSP. These results indicate that ECM-beta2 integrin
mediated signaling initiates the FAK/paxillin signaling pathway(s), while TSP
mediated signaling results in paxillin phosphorylation independent of FAK
phosphorylation.
PMID- 9548499
TI - Characterization of the CCR2 chemokine receptor: functional CCR2 receptor
expression in B cells.
AB - We have derived anti-human CCR2-specific mAbs by immunization with synthetic
peptides corresponding to CCR2 sequences presumably involved in the interaction
with its ligand(s). The characterization of these mAbs includes the ability to
recognize the CCR2 receptor specifically, as well as the function based on their
ability to promote Ca2+ influx or to block MCP-1-induced Ca2+ influx and
chemotaxis. One mAb (MCP-1 R02) that is directed to the NH2 terminal domain of
the CCR2 receptor has MCP-1 agonist activity, and two that recognize the third
extracellular domain (MCP-1R04 and MCP-1 R05) have MCP-1 antagonist activity. We
analyzed the presence of CCR2 in several PBL and tonsil-derived leukocyte
populations and found expression of this receptor in monocytes, activated T
cells, and, surprisingly, in B cells. CCR2 receptor expression in B cells was
further corroborated in Southern blot using CCR2-specific probes. Moreover, both
MCP-1 and the agonist mAb trigger specific B cell migration via a PTX-sensitive
mechanism, indicating the presence of a functional CCR2 receptor in these cells.
PMID- 9548500
TI - Alteration of the cytokine phenotype in an experimental lung granuloma model by
inhibiting nitric oxide.
AB - Pulmonary granulomatous inflammation modulated by IFN-gamma and IL-12 is also
associated with augmented inducible nitric oxide synthase (NOS II). To address
the role of increased nitric oxide synthesis in this model, mice received daily
i.p. injections of NG-nitro-L-arginine-methyl ester (L-NAME; 8 mg/kg) during both
the 2-wk immunization period with purified protein-derivative (PPD) and the
subsequent lung challenge with PPD-coated Sepharose beads. Other groups of
animals received saline, L-NAME or NG-nitro-D-arginine-methyl ester (D-NAME; 8
mg/kg) during the pulmonary embolization period and not the PPD sensitization
period. On day 4 post-PPD bead challenge, PCR analysis of the whole lung revealed
that NOS II expression appeared to be similar in both of the L-NAME treatment
protocols. L-NAME-treated mice in both dosing protocols had lung lesions that
were significantly larger than granuloma lesions measured in mice that received
saline or D-NAME. The enlarged lesions from L-NAME-treated mice contained
markedly greater numbers of neutrophils and eosinophils. Equivalent numbers of
PPD-activated dispersed cells from whole lungs of L-NAME-treated mice produced
significantly higher levels of IL-4 and IL-10 and smaller amounts of IL-12 and
IFN-gamma compared with similar lung cultures derived from control or D-NAME
treated mice. Levels of C-C chemokines such as monocyte chemoattractant protein-1
(MCP-1), C10, and macrophage inflammatory protein-1alpha (MIP-1alpha) were also
significantly elevated in lung cultures from L-NAME-treated mice compared with
controls. Thus, nitric oxide regulates the size and cellular composition of the
Th1-type lung granuloma, possibly through its effects on the cytokine and
chemokine profile associated with this lesion.
PMID- 9548501
TI - C1q augments platelet activation in response to aggregated Ig.
AB - Immune complexes and aggregated IgG (agg-IgG) induce platelet aggregation and the
release reaction. Immune complexes also activate the complement system and
interact with the complement component C1q. Since platelets possess both Fc and
C1q receptors capable of signal transduction, the present study focused on the
interaction between these binding sites and platelet activation. Subaggregating
doses of agg-IgG (20-400 microg/ml) were identified for washed platelets from
each of 11 healthy donors, and platelet aggregation was monitored in the presence
or the absence of increasing concentrations of C1q (5-100 microg/ml). C1q
produced a dose-dependent potentiation of platelet alphaIIb/beta3 integrin
activation, platelet aggregation, and granule secretion when combined with low
doses of agg-IgG. C1q alone was without effect. Maximal enhancement of agg-IgG
induced platelet activation was noted at C1q concentrations ranging from 50 to
100 microg/ml. The observed C1q-induced potentiation of platelet aggregation in
response to agg-IgG was blocked by polyclonal antibody F(ab')2 directed against
platelet binding sites recognizing the collagen-like domain of C1q (cC1qR) or by
mAb Fab (IV.3) directed against platelet FcgammaRII receptors. These data suggest
a cooperative interaction between platelet FcgammaRII and cC1q receptors and
support a potential role for platelet cC1q receptors in pathologic platelet
activation by circulating immune complexes often associated with in vivo
thrombosis and thrombocytopenia.
PMID- 9548502
TI - Interchangeable endotoxin-binding domains in proteins with opposite
lipopolysaccharide-dependent activities.
AB - Host defense against microorganisms involves proteins that bind specifically to
bacterial endotoxins (LPS), causing different cellular effects. Although LPS
binding protein (LBP) can enhance LPS activities, while bactericidal/permeability
increasing protein (BPI) and Limulus anti-LPS factor (LALF) neutralize LPS, it
has been proposed that their LPS-binding domains possess a similar structure.
Here, we provide evidence that the LBP/LPS-binding domain is, as in the LALF
structure, solvent exposed and therefore available for LPS binding. Our
investigations into the activity of LPS-binding domains of different LPS-binding
proteins, in the context of LBP, provide the first functional analysis of these
domains in a whole protein. We constructed domain exchange hybrid proteins by
substituting 12 amino acids of the LBP/LPS-binding domain with those of BPI and
LALF and expressed them in Chinese hamster ovary cells. Although discrete point
mutations within the LPS-binding domain of LBP disrupted its specific functions,
the hybrid proteins were still able to bind LPS and, in addition, retained the
wild-type LBP activity of enhancing LPS priming for FMLP-induced oxygen radical
production by neutrophils and transferring LPS aggregates to CD14. Although BPI
and LALF display opposite activities to LBP, and LALF does not share any sequence
homology with LBP, our data provide strong evidence that LBP, BPI, and LALF
possess a solvent-exposed, interchangeable LPS binding motif that is functionally
independent of LPS transport or neutralization.
PMID- 9548503
TI - Human alternative complement pathway-mediated lysis of rabbit erythrocytes is
enhanced by natural anti-Galalpha1-3Gal antibodies.
AB - Human serum is effective at lysing unsensitized rabbit erythrocytes due to
activation of the alternative complement pathway. Hemolysis is known to be
enhanced by the addition of human IgG. We demonstrate that the enhancement of
alternative pathway-mediated rabbit E lysis by human Ig is due to natural Abs
specific for galactosyl (Gal)alpha1-3Gal. Depletion of normal human serum (NHS)
of anti-Galalpha1-3Gal Abs removes almost all hemolytic activity from NHS, and
activity can be restored by repletion with anti-Galalpha1-3Gal affinity-purified
Abs. Factor B-depleted serum (inactive alternative pathway) did not lyse rabbit
erythrocytes. Although C2-depleted serum was fully hemolytic, activity was
removed by depletion of anti-Galalpha1-3Gal Abs. Of the total anti-Galalpha1-3Gal
Abs affinity isolated from NHS, about one-third were IgM and two-thirds were IgG.
Both anti-Galalpha1-3Gal IgG and IgM enhanced alternative pathway-mediated
erythrocyte lysis.
PMID- 9548504
TI - Aberrant cytokine expression and autocrine regulation characterize macrophages
from young MRL+/+ and NZB/W F1 lupus-prone mice.
AB - We investigated whether macrophages (Mphi) from young, lupus-prone MRL+/+ and
NZB/W F1 mice expressed common defects in immunoregulatory cytokine production.
Endotoxin-activated Mphi from both strains, obtained well before disease signs,
had a markedly reduced capacity to maintain IL-1 production compared with Mphi
from normal strains (BALB/c, A/J, and C57BL/6). Mphi from lupus-prone mice showed
similar defects in IL-6 and TNF-alpha production, which preceded the IL-1 defect.
In fact, defective TNF-alpha production appeared to be responsible for aberrant
expression of the other cytokines because this defect was the first to be
expressed, and treatment with exogenous TNF-alpha reduced the extent of defective
IL-1 and IL-6. These "proinflammatory" cytokine defects appeared to be selective
because the anti-inflammatory cytokine IL-10 was not expressed aberrantly in the
lupus-prone strains. For this reason, and because anti-IL-10 mAb treatment did
not correct defective proinflammatory cytokine production, IL-10 did not appear
to be responsible for these defects. IFN-gamma was able to normalize TNF-alpha
production in Mphi from lupus-prone mice, demonstrating a stimulus-specific
induction of the proinflammatory defects. These studies also revealed that Mphi
from the three normal strains studied here maintain a precise inverse
relationship between levels of TNF-alpha and IL-10, a relationship not seen in
Mphi from lupus-prone strains. These findings reveal shared elements of cytokine
dysregulation in the two principal animal models of multigenic lupus, and suggest
that the study of Mphi (and perhaps other cells of the innate immune system) may
provide valuable insights into intrinsic functional defects associated with
systemic autoimmunity.
PMID- 9548505
TI - Thrombin activates nuclear factor-kappaB and potentiates endothelial cell
activation by TNF.
AB - Thrombin is the central bioregulatory enzyme in hemostasis and is generated in
vascular beds in which inflammatory responses are ongoing. In this study, we
examined the effect of thrombin, both alone and in combination with TNF, on gene
expression in porcine aortic endothelial cells (EC). Thrombin (1-10 U/ml) induced
increased mRNA levels of E-selectin, monocyte chemoattractant protein-1, IL-8,
plasminogen activator inhibitor-1, and IkappaB-alpha. These effects were mimicked
by a thrombin receptor-activating peptide; preincubation of thrombin with hirudin
blocked the induction of mRNA, suggesting that the increased gene expression was
due to thrombin-specific activity. Because these genes are known to contain
nuclear-factor-kappaB (NF-kappaB)-binding elements in their promoter region, we
next examined the ability of thrombin to activate this transcription factor. As
detected by electrophoretic mobility shift assay, thrombin (10 U/ml) or thrombin
receptor-activating peptide (100 microM) stimulated increased NF-kappaB-binding
activity. Supershift analysis revealed that these complexes were comprised
principally of the RelA (p65) and NF-kappaB1 (p50) Rel family members. Thrombin
alone did not substantively increase protein levels of E-selectin despite the
increase in E-selectin mRNA levels. However, thrombin (3-10 U/ml) stimulated a 10
fold enhancement in the ability of TNF (0.3-1.0 ng/ml) to induce E-selectin
surface expression. Similar potentiation of TNF-induced NF-kappaB activity and E
selectin transcription by thrombin was observed in experiments utilizing
luciferase reporter constructs expressed in bovine aortic EC. The ability of
thrombin to potentiate TNF-induced EC activation thus provides an important
mechanism by which products of the coagulation cascade may enhance cytokine
mediated inflammatory responses.
PMID- 9548506
TI - Generation of HER-2/neu-specific cytotoxic neutrophils in vivo: efficient arming
of neutrophils by combined administration of granulocyte colony-stimulating
factor and Fcgamma receptor I bispecific antibodies.
AB - Abs are able to induce inflammatory antitumor responses by recruiting IgG Fc
receptor (FcgammaR)-bearing cytotoxic effector cells. We recently described the
capacity of the high affinity FcgammaRI (CD64) to trigger cytotoxic activity of
neutrophils (PMN) during granulocyte CSF (G-CSF) treatment. To take advantage of
FcgammaRI as a cytotoxic trigger molecule on PMN, two Ab constructs were
prepared. We show that a chimeric human IgG1 Ab (Ch520C9) and an anti-FcgammaRI
bispecific Ab (BsAb; 22x520C9), both directed to the proto-oncogene product HER
2/neu, interact with FcgammaRI. In addition, both Ab constructs mediate enhanced
lysis of HER-2/neu-expressing tumor cells by G-CSF-primed PMN. However,
engagement of FcgammaRI by Ch520C9 was inhibited by human serum IgG, thereby
abrogating the enhanced Ch520C9-mediated cytotoxicity. BsAb 22x520C9, which binds
FcgammaRI outside the ligand binding domain, effectively recruits the cytotoxic
potential of FcgammaRI on G-CSF-primed PMN regardless of the presence of human
serum. These results indicate that under physiologic conditions, serum IgG
impairs activation of FcgammaRI-mediated cytotoxicity by conventional antitumor
Abs. The IgG blockade can be circumvented with anti-FcgammaRI BsAbs. Using human
FcgammaRI transgenic mice we demonstrate that BsAb 22x520C9 is able to engage
FcgammaRI in vivo. BsAb 22x520C9 injected i.v. was readily detected on
circulating PMN of G-CSF-treated transgenic animals. In addition, we showed that
PMN remain "armed" with BsAb 22x520C9 during migration to inflammatory sites, and
that after isolation such PMN specifically lyse HER-2/neu-expressing tumor cells.
These results point to the possibility of targeting anti-FcgammaRI BsAbs to G-CSF
primed PMN in vivo, endowing them with specific anti-tumor activity.
PMID- 9548507
TI - CD40 ligand stimulates proinflammatory cytokine production by human endothelial
cells.
AB - Functional expression of CD40 has recently been described on the surface of
HUVEC, and activation of these cells with CD40 ligand (CD40-L) leads to increased
adhesion molecule expression. Here, we analyzed the effect of CD40 triggering on
cytokine production by HUVEC. CD40-L-transfected fibroblasts, in contrast to
their untransfected counterparts, as well as a soluble recombinant human CD40
L/murine CD8alpha chimeric molecule were able to importantly increase (by a mean
of fourfold) the production of leukemia inhibitory factor (LIF) by HUVEC. CD40-L
displayed an additive effect with IL-4, IL-1alpha, and TNF-alpha on the
enhancement of LIF secretion. Cyclosporin A did not affect LIF synthesis by
resting or CD40-L-activated HUVEC, whereas dexamethasone diminished the basal
level of LIF production and abrogated the CD40-L effect. The secretions of two
other proinflammatory cytokines, granulocyte-macrophage CSF and IL-6, were also
increased in the presence of CD40-L. However, CD40-L neither affected HUVEC
proliferation nor rescued them from IFN-gamma- and TNF-alpha induced apoptosis.
Together, these results indicate that endothelial cell activation by CD40-L may
play an important role not only in leukocyte recruitment through enhancement of
adhesion molecule expression, but also in the maintenance of an inflammatory loop
through the increase in proinflammatory cytokine secretion.
PMID- 9548508
TI - Oncostatin M stimulates the expression and release of the IL-6 receptor in human
hepatoma HepG2 cells.
AB - Soluble IL-6R (sIL-6R), which lacks the transmembrane domain, has been suggested
to be a potent immunomodulator of IL-6 biologic activity. In this study, the
ability of cells of hepatic origin to generate the sIL-6R was investigated. It
was found that oncostatin M alone or in combination with the glucocorticoid
analogue dexamethasone significantly up-regulated IL-6R release. Oncostatin M
appeared to generate the sIL-6R primarily through an alternative splicing
mechanism. Since sIL-6R is able to form biologically active complexes with IL-6,
the release of the sIL-6R from hepatocytes may be important to sensitize cells
lacking the membrane-bound receptor, particularly during an acute phase reaction.
PMID- 9548509
TI - Human monocytes and macrophages express substance P and neurokinin-1 receptor.
AB - We present data demonstrating the gene expression of substance P and its receptor
in human peripheral blood-isolated monocytes and macrophages. Using the RT-PCR
assay, preprotachykinin-A (substance P) mRNA is detected in human peripheral
blood-isolated monocytes and macrophages. Among the alpha, beta, and gamma
transcripts of the substance P gene, only the beta and gamma transcripts are
detectable in these cells. By Southern blot assay these RT-PCR-amplified
transcripts are recognized using a specific substance P probe. Sequence analysis
of the RT-PCR products from both monocytes and macrophages also confirmed the
structure of these transcripts, which are identical to those found in human
neuronal cells. At the protein level, both human monocytes and macrophages
produced endogenous substance P as determined by an enzyme immunoassay.
Capsaicin, a vanillyl fatty acid amide (ingredient of hot pepper), released
substance P from both human monocytes and macrophages. In addition, using nested
RT-PCR analysis, we identified the presence of mRNA for neurokinin-1 receptor
(the receptor for substance P) in human peripheral blood-isolated monocytes and
macrophages, which was confirmed by DNA sequencing analysis. The demonstration
that human monocytes and macrophages express substance P and its receptor support
the notion that substance P is biologically involved in regulating the functions
of these cells in an autocrine fashion.
PMID- 9548510
TI - IL-11 regulates macrophage effector function through the inhibition of nuclear
factor-kappaB.
AB - Recombinant human IL-11 (rhIL-11) is an anti-inflammatory cytokine that can
reduce the production of inflammatory mediators such as TNF-alpha, IL-1beta, IL
12, IL-6, and nitric oxide. Inhibition of proinflammatory cytokine production
from activated macrophages was associated with a reduction in the levels of LPS
induced TNF-alpha, IL-1beta, IL-6, and IL-12 p40 mRNA. Analysis of rhIL-11
effects on transcription factors that activate proinflammatory cytokines
demonstrated that the level of LPS-induced NF-kappaB binding activity in the
nucleus of rhIL-11-treated peritoneal macrophages was significantly reduced. The
block to NF-kappaB nuclear translocation correlated with the ability of rhIL-11
to maintain or increase protein levels of the inhibitors of NF-kappaB, IkappaB
alpha, and IkappaB-beta following LPS treatment. Furthermore, rhIL-11-treatment
of LPS macrophages resulted in significant elevation of IkappaB-alpha and IkappaB
beta mRNA levels. These results suggest that the anti-inflammatory activity of
rhIL-11 is mediated in part by inhibition of NF-kappaB-dependent transcriptional
activation. Furthermore, these studies demonstrate for the first time the
regulation of IkappaB-beta by an anti-inflammatory cytokine. Given the finding
that inappropriate activation of NF-kappaB contributes to multiple inflammatory
conditions, the ability of rhIL-11 to inhibit the binding activity of this
pleiotropic transcription factor indicates that rhIL-11 has therapeutic potential
in a wide range of diseases.
PMID- 9548511
TI - Identification of a new mouse beta-chemokine, thymus-derived chemotactic agent 4,
with activity on T lymphocytes and mesangial cells.
AB - Thymus-derived chemotactic agent 4 (TCA4), a new member of the beta-chemokine
family, was cloned from a mouse thymic cDNA library. High levels of TCA4 mRNA are
expressed in thymus; lower levels of message are found in spleen, heart, and
kidney. Anti-TCA4 antibodies were used to localize sites of TCA4 expression
within lymphoid tissues. In the thymus, UEA-1+ medullary epithelial cells, some
endothelial cells, and additional undefined stromal elements were stained with
anti-TCA4. TCA4 was also expressed as a meshlike network in splenic white pulp
and in the medullary region of the lymph nodes. In addition, some lymph node and
splenic blood vessels stained with anti-TCA4 antibodies. Rel B NFkappaB-deficient
mice lack a transcription factor required for the generation of dendritic cells
and the development of an organized thymic medulla. Rel B-deficient animals
express very low levels of TCA4 in the thymus and little or no TCA4 in the
periphery. At subnanomolar concentrations, TCA4 is a chemoattractant of mature T
cells; the potential role of this novel chemokine in facilitating normal
lymphocyte traffic is discussed. TCA4 is also a chemoattractant of cultured
mesangial cells. Neutralizing anti-TCA4 mAb was used to demonstrate the
specificity of TCA4-mediated cell migration. Finally, competitive binding studies
with a SV40-transformed mouse mesangial cell line demonstrated that other murine
beta-chemokines (monocyte chemotactic protein-1, macrophage inflammatory protein
1alpha, macrophage inflammatory protein-1beta, and thymus-derived chemotactic
agent 3) do not compete for TCA4 binding.
PMID- 9548512
TI - Protective antibodies develop, and murine Lyme arthritis regresses, in the
absence of MHC class II and CD4+ T cells.
AB - Murine Lyme borreliosis is characterized by arthritis and carditis that are most
severe at 2 to 3 wk, then regress during the course of persistent infection.
Borrelia burgdorferi-specific Abs and CD4+ T cells have been implicated in the
resolution phase of arthritis. Therefore, MHC class II transactivator (CIITA)
deficient mice that do not express conventional class II molecules and lack the
normal CD4 repertoire were used to investigate the role of MHC class II-mediated
responses in Lyme disease. The development of arthritis and carditis, and the
resolution of arthritis, were similar in CIITA-deficient and control C57/BL6
mice. In contrast, the resolution of carditis was delayed in CIITA-deficient
animals compared with controls. Moreover, CIITA-deficient mice developed B.
burgdorferi-specific IgG2b Abs, and sera from these animals passively protected
naive C3H/HeN mice from challenge inoculation and cleared B. burgdorferi from 2
day-infected C.B.17 SCID mice. These data suggest that CD4+ T cells and MHC class
II-mediated responses are not required for the generation of protective Abs or
the regression of arthritis, but may be important in the resolution of Lyme
carditis in mice.
PMID- 9548513
TI - Suppression of collagen-induced arthritis by continuous administration of IL-4.
AB - The onset of collagen-induced arthritis in DBA/1 mice is accompanied by a
predominantly Th1 response, characterized by production of the proinflammatory
cytokines IFN-gamma and TNF-alpha, and a predominance of IgG2a anti-collagen Abs.
This study has primarily addressed the effects of continuous administration of
exogenous IL-4, a Th2 cytokine, on collagen-induced arthritis in terms of time of
onset, clinical symptoms, and histologic changes compared with those in untreated
controls. The contributions of Th1 and Th2 cell responses were studied by
examining anti-CII IgG subclasses, serum IgE levels, and cytokine production by
synovial membrane and lymph node cell cultures. Continuous exposure to IL-4 for
28 days significantly delayed the onset of arthritis from 19 to 37 days and
suppressed clinical symptoms. Arthritis occurred approximately 13 to 24 days
after treatment ceased. Thereafter, the severity and duration of clinical
symptoms were similar to those in control animals, although both joint damage and
inflammation at the histologic and cellular levels were less severe than those in
untreated controls. During IL-4 treatment, anti-collagen Ab levels were reduced
(most significantly those of the IgG2a subclass), histology scores were lower,
and the most striking effect was a 1000-fold decrease in TNF-alpha secretion by
synovial cells. No significant differences in IgE levels were found between
controls and IL-4-treated mice. These data suggest that the anti-inflammatory
properties of IL-4 are mediated in part by down-regulation of Th1 responses
rather than up-regulation of Th2 responses.
PMID- 9548514
TI - Induction of high affinity fibroblast growth factor receptor expression and
proliferation in human endothelial cells by anti-HLA antibodies: a possible
mechanism for transplant atherosclerosis.
AB - The major limitation to long term survival of organ allografts is chronic
rejection, which is manifested as atherosclerosis of the vessels of the
transplanted organ. There is a significant association between transplant
atherosclerosis and the development of Abs to the disparate HLA Ags present on
the graft vasculature. We have investigated the effect of anti-HLA Abs on
endothelial cells (EC) and smooth muscle cells cultured in vitro. Ab ligation of
class I molecules on ECs results in increased high affinity fibroblast growth
factor receptor mRNA expression, and enhanced basic fibroblast growth factor
ligand binding. Ab binding to class I molecules on EC and smooth muscle cells is
also accompanied by augmented cell proliferation. These results suggest that the
intimal thickening observed in transplant atherosclerosis is the result of the
proliferative effects of anti-HLA Abs.
PMID- 9548515
TI - Priming with IL-4 and IL-13 during HIV-1 infection restores in vitro IL-12
production by mononuclear cells of HIV-infected patients.
AB - The production of proinflammatory cytokines can be regulated by several factors
that exert activating or inhibitory effects. IL-4, IL-10, IL-13, TGF-beta, and
PGE2 have demonstrated a very wide range of potent macrophage-deactivating
activities and, specifically, down-regulation of the production of many
proinflammatory monokines. IL-12 plays a key role during immune response by
providing a link between natural resistance and adaptive immunity. We and others
have previously shown an impairment in IL-12 production by PBMC from HIV-1
infected individuals in response to various stimuli, but defining the mechanism
responsible remains elusive. In this study, we observed that pretreatment of PBMC
from patients with IL-4 or IL-13 for 24 h primes the cells for enhanced
production of IL-12 in response to Staphylococcus aureus, and almost completely
restores their deficient IL-12 production when compared with healthy controls.
Although this priming effect was completely abrogated by IL-10 and PGE2, IL-10
was produced equivalently by untreated and IL-4- or IL-13-pretreated PBMC from
both patients and controls. Additionally, indomethacin, which shuts off PGE2
synthesis, and cAMP-blocking reagents failed to restore or enhance IL-12
production. The priming effect of IL-4 and IL-13 is at the transcription level
for both p40 and p35 genes. This complete restoration of IL-12 production by Th2
associated cytokines was unexpected in light of the mutually antagonistic roles
of IL-12 and IL-4 in promoting Th1 or Th2 immune responses.
PMID- 9548516
TI - A single nonamer from the Yersinia 60-kDa heat shock protein is the target of HLA
B27-restricted CTL response in Yersinia-induced reactive arthritis.
AB - The reason for the high association of HLA-B27 with diseases such as ankylosing
spondylitis and reactive arthritis is not clear. In reactive arthritis, the
triggering bacteria are known, thus allowing investigation of their interaction
with HLA-B27. CTL lines derived from five patients with Yersinia-induced reactive
arthritis were raised by repeated stimulation in vitro with either Yersinia
infected autologous macrophages (four patients) or pooled peptides (three
patients) having the HLA-B27-binding motif. The peptides were derived from five
Yersinia proteins and from the chlamydial 57-kDa heat shock protein (hsp).
Cytotoxicity of T cell lines was then tested against these peptides. Lytic
activity was obtained with T cells stimulated with viable Yersinia or pooled
peptides. Targets successfully used for lysis were cells pulsed with peptides
from the Yersinia 60-kDa hsp, but not cells pulsed with peptides from other
Yersinia proteins or the chlamydial hsp. T cell lines raised with 60-kDa peptides
also lysed targets infected with Yersinia. Most interestingly, all three CTL
lines tested (one raised with Yersinia; two with pool of peptides) recognized
only one single peptide (321-329) of seven tested from the Yersinia hsp60.
Cytotoxicity occurred only when target cells were matched for HLA-B27. This
identification of an immunogenic peptide derived from an arthritogenic bacterium
and presented by HLA-B27 opens the way for future investigation of the role of T
cells specific for this peptide or cross-reacting peptides, in the
immunopathology of HLA-B27-associated diseases.
PMID- 9548517
TI - IgE from latex-allergic patients binds to cloned and expressed B cell epitopes of
prohevein.
AB - Prohevein is one of the major allergens associated with latex allergy. In the
present study, we identified IgE binding regions of prohevein, and expressed
multiple IgE binding epitopes by selective cloning. These truncated polypeptides
were then used to demonstrate IgE in the sera of patients. Decapeptides of
prohevein were synthesized on derivatized cellulose membrane with an offset of
one amino acid. The IgE reactivity of these linear peptides was evaluated
separately using pooled sera from latex-allergic health care workers (HCW) and
spina bifida (SB) patients. A total of 10 IgE binding epitopes representing
unique as well as shared epitopes from both the N- and C-domains of the prohevein
were identified. Recombinant polypeptides were constructed based on the
identified epitopes, and clones carrying DNA fragments were overexpressed. These
recombinant peptides were evaluated for IgE binding with sera from HCW, SB, and
normal individuals. Recombinant prohevein, hevein, and the C-domain exhibited IgE
binding in 84, 88, and 40% of HCW sera, respectively, as against reactivity of
84% with crude latex allergens. However, only 48% of the sera from SB patients
showed IgE binding with recombinant prohevein, while 56 and 28% had reactivity
with recombinant N- and C-domains, respectively. Among the three remaining
recombinant peptides of the C-domain, only CA44-103 showed IgE binding with SB
patients. The results of the present study suggest that linear IgE epitope
analysis and construction of recombinant peptides increase the sensitivity and
specificity of the immunodiagnosis of latex allergy and provide more information
on the immunopathogenesis of hypersensitivity reaction mediated by type I
allergy.
PMID- 9548518
TI - Cell death during autoimmune demyelination: effector but not target cells are
eliminated by apoptosis.
AB - The Fas and FasL apoptotic pathway was investigated by protein
immunohistochemistry, flow cytometry, and reverse transcriptase-PCR analysis to
assess whether it is involved in the elimination of target and/or effector cells
from the central nervous system (CNS) during adoptively transferred chronic
relapsing experimental autoimmune encephalomyelitis (EAE), a model for multiple
sclerosis. In addition to Fas and FasL, we studied Bax, an intracellular protein
of the apoptotic cascade, the Bax antagonist and anti-apoptotic molecule Bcl-2,
and DNA fragmentation, the final step in the apoptotic pathway. Infiltrating CD4+
T cells and parenchymal microglia expressed Fas, FasL, and Bax, and about half of
these cells showed DNA fragmentation, a combination indicative of ongoing
apoptosis. Using flow cytometry and reverse transcriptase-PCR, a positive
correlation was seen between disease activity and up-regulation of the Fas
system; in fact, Fas and FasL were expressed at low levels at the onset of EAE
and increased at the height of disease to involve about one-third of all
infiltrating lymphocytes. In the normal CNS, Fas immunoreactivity was
constitutively present at low levels on oligodendrocytes and was up-regulated in
the CNS during the course of EAE. However, oligodendrocytes showed no Bax
reactivity or DNA fragmentation and expressed high levels of Bcl-2, as did the
majority of infiltrating CD3+ cells, a pattern inconsistent with apoptosis. Thus,
while molecules of the apoptotic cascade are well represented in the CNS during
EAE, their expression correlates with elimination of infiltrating cells and
microglia, not the myelinating cell, the oligodendrocyte.
PMID- 9548519
TI - Ligation of cell surface CD4 inhibits activation-induced death of human T
lymphocytes at the level of Fas ligand expression.
AB - Cross-linking of cell surface CD4 molecules by anti-CD4 mAb or HIV-1 gp120/anti
gp120 Ab primes resting T lymphocytes for activation-induced cell death (AICD)
triggered via the CD3/TCR complex. In striking contrast, we demonstrate here that
preincubation of activated human CD4+ T cells with anti-CD4 mAb consistently
inhibited AICD triggered via anti-CD3 mAb or Staphylococcus aureus enterotoxin A
superantigen. Inhibition of AICD of CD4+ T cell clones was also observed with
F(ab')2, but not with Fab, of anti-CD4 mAb. Moreover, soluble HIV-1 gp120, but
not rIL-16, inhibited AICD stimulated by S. aureus enterotoxin A. In susceptible
clones, CD4 ligation prevented the up-regulation of Fas ligand mRNA and cell
surface expression in response to anti-CD3 mAb or superantigen stimulation.
CD3/TCR-dependent protein tyrosine phosphorylation and cytokine production were
also prevented by preceding CD4 ligation. The inhibition of AICD due to the
prevention of Fas ligand upregulation reveals a novel immunoregulatory
consequence of CD4 ligation that might play a role in HIV infection and in the
therapeutic application of anti-CD4 mAb.
PMID- 9548520
TI - Notice of duplicate publication.
PMID- 9548521
TI - Molecular biology of axonal outgrowth. 1. Growth cones and GAP-43.
PMID- 9548522
TI - Optic chiasm astrocytomas of childhood. 1. Long-term follow-up.
AB - We reviewed 61 patients seen from 1975 to 1994 with a biopsy-confirmed optic
chiasm astrocytoma or a characteristic clinical and imaging presentation. The
mean age at diagnosis was 72 months, including 30 who were less than 5 years old.
The mean tumor diameter at presentation was 31 mm among 54 tumors measured.
Tumors involved the optic nerve in 41, hypothalamus in 38, optic tract in 15, and
optic radiations in 2. Four patients, all with neurofibromatosis, received no
treatment. Forty patients received conventional radiation therapy at a mean age
of 89 months. Chemotherapy was given to 19 children and 7 of these were followed
for greater than 1 year. Six of these 7 had progressive disease which required
subsequent surgery and/or radiation therapy. Thirty-six patients underwent
surgery. We restricted our analysis of outcome to those 38 patients followed for
longer than 60 months. Development was normal in 13%, mildly disabled in 53%,
severely disabled in 21% and dead in 13%. Children were severely disabled or dead
in 47% if younger than 5 years at diagnosis, and 21% if older. There was no
endocrine dysfunction in 18% and new endocrine failure was seen in 61%. More
posterior tumors did not portend a poorer prognosis. Children less than 5 years
old had a poorer prognosis. Neurofibromatosis did not have a marked effect on
outcome. Intracranial hypertension was an indicator of a poor prognosis. No
specific treatment modality was clearly superior in terms of long-term survival
or improvement in quality of life.
PMID- 9548523
TI - Optic chiasm astrocytomas of childhood. 2. Surgical management.
AB - We presented our experience from 1975 to 1994 with emphasis on the long term
follow-up of children with optic chiasm astrocytomas in part I. In part II we
describe the surgical management of 20 patients with the diagnosis of an
astrocytoma of the optic chiasm confirmed by biopsy. These patients underwent
surgery by the senior author between 1988 and 1994. The patients and the tumors
in this series are comparable in age, sex, and presentation and imaging
characteristics to other series. Surgery was undertaken with the intent to reduce
tumor volume and mass effect and in certain cases to confirm the diagnosis. The
patients' mean age at the time of surgery was 81 (range 18-216) months. The
surgical approaches used were pterional in 11 patients, transorbital/subfrontal
in 8, and subfrontal in 1 patient. Greater than 50% of the tumor was resected in
8 patients, less than 50% was resected in 9, and biopsy only was achieved in 3
patients. Larger tumors were more likely to have magnetic resonance imaging
documented debulking of tumor. Permanent morbidity included mild visual loss,
diabetes insipidus, mild hemiparesis, and panhypopituitarism in 1 patient each.
There was no surgical mortality. The likelihood of resecting greater than 50% of
the tumor was higher in those with a diameter greater than 25 mm. The indications
for craniotomy are (1) to debulk symptomatic tumors greater than 50 mm in
diameter which are exophytic or cystic; (2) to relieve obstruction at the foramen
of Monro, and (3) for diagnostic biopsy.
PMID- 9548524
TI - Surgical management of sagittal synostosis: a comparative analysis of strip
craniectomy and calvarial vault remodeling.
AB - Although surgical treatment of sagittal synostosis has become normative, the
procedure of choice is still debated. This retrospective analysis, during a 10
year period (1986-1995) at Children's Hospital Los Angeles, compares the more
conservative strip craniectomy (SC) procedure with a more extensive occipital
reduction-biparietal widening calvarial vault remodeling (CVR) technique for the
management of sagittal synostosis. SC was performed in 72 patients (61%) and CVR
in 46 (39%). Patients undergoing CVR were older (mean 5.3 vs. 3.0 months, p <
0.01), the procedure time longer (mean 126 min vs. 72 min, p < 0.01),
intraoperative blood loss greater (mean 243 vs. 54 cm3, p < 0.01), and the
frequency of intraoperative blood transfusion increased (100 vs. 38%, p < 0.01;
mean volume 357 vs. 51 cm3, p < 0.01) compared to patients undergoing SC. No
significant intraoperative complications occurred in either group. The total time
of hospitalization was similar (mean 4.4 vs. 3.8 days, p = 0.02). No
neurological, hematological, or transfusion-related complications or deaths were
encountered in either group. Cosmetic outcomes were significantly better in the
CVR group with 79% rated as excellent compared to 41% in the SC group (p < 0.01).
Fifty-nine percent of the SC patients manifested bony defects at last follow-up
visit. Two SC patients required reoperation for poor cosmetic outcomes; CVR was
successfully employed in both cases. These findings demonstrate that CVR is
superior to SC in providing immediate and lasting correction of calvarial
deformities secondary to sagittal synostosis. The optimal age at time of surgery
is <6 months; however, CVR can be utilized throughout infancy, while SC becomes
progressively less effective after 6 months of age. No significant complications
were observed in either group, despite the increased operative manipulation and
greater incidence of blood transfusion in the CVR patients.
PMID- 9548525
TI - Treatment of hydrocephalus with third ventriculocisternostomy: outcome and CSF
flow patterns.
AB - Third ventriculocisternostomy was performed in 23 patients for management of
hydrocephalus. The procedure was offered as the first treatment in 18 cases and
in lieu of a shunt revision in 4 cases. Median follow-up was 17 months (range 7
44 months). In 16 patients the operation was successful in treating their
symptoms (73%). Cine MRI was helpful in evaluating patients with persistent
ventriculomegaly. Resolution of symptoms in association with decreased
ventricular size correlated best with outcome following this procedure. Third
ventriculocisternostomy is technically safe and minimally invasive and should be
offered as the first procedure in the management of noncommunicating
hydrocephalus.
PMID- 9548526
TI - Diffuse infiltrating astrocytoma of the cervicomedullary region:
clinicopathologic entity.
AB - Recent imaging and neurosurgical techniques have led to an improvement in the
surgical management of children with brainstem tumors (BSTs). Many children with
tumors previously considered 'inoperable' can now benefit from surgery. Increased
experience has brought about new theories concerning the growth pattern, natural
history, classification and optimal management of these tumors. Cervicomedullary
(CM) tumors commonly have an indolent presentation reflecting either medullary or
cervical spinal cord dysfunction and tend to arise in the upper cervical cord
growing into the medulla in a posterior exophytic fashion. Intrinsic BSTs often
present acutely with cranial nerve dysfunction and generally arise in the pons
with a diffuse infiltrating growth pattern. A 21-month-old patient had developed
feeding difficulty and reactive airway disease at approximately 8 months of age.
MRI showed a diffuse, nonenhancing tumor in the CM region. Following radical
resection, and an unremarkable perioperative course, he aspirated, developed
pulmonary insufficiency and expired. Postmortem examination revealed a low-grade
diffuse fibrillary astrocytoma extending from C6 to the medulla. The medullary
portion arose in a paramedian location and infiltrated dorsally into the fourth
ventricle, the obex, the leptomeninges, and the adjacent cerebellum. This case
demonstrates the growth pattern of a distinct subset of CM tumors that behave in
a manner similar to intrinsic diffuse BST. Future identification of these subsets
by a careful analysis of the clinical presentation and MRI images will enable
better operative planning and optimal management.
PMID- 9548527
TI - Two-year-old boy with seizures.
PMID- 9548528
TI - Preparation and photoactivation of caged fluorophores and caged proteins using a
new class of heterobifunctional, photocleavable cross-linking reagents.
AB - The design, synthesis, and spectroscopic and chemical properties of four members
of a new class of heterobifunctional photocleavable (caged) cross-linking
reagents were described. One of the two reactive groups of the cross-linker
reacted with amino groups to form the corresponding photolabile carbamates. Amino
group containing compounds or proteins caged with these reagents can be coupled
through the thiol reactive oxirane group of the cross-linker to a different
biomolecule or to a thiol-derivatized surface. The 3,4-dimethoxy-6-nitrophenyl
photoisomerization group of the reagent was physically and chemically isolated
from the cross-linking functionality, and the high extinction coefficient and red
shifted action spectrum of this chromophore make it suitable for photoactivation
applications of caged compounds on surfaces or in living cells. The bifunctional,
photocleavable cross-linking reagents were used to prepare a thiol reactive caged
rhodamine 110. The new reagents and conjugation procedures described may be used
as part of a general procedure to cage the activity of proteins by physically
masking binding sites.
PMID- 9548529
TI - Cell targeting by glycosidic telomers. Specific recognition of the Kb CWL1 lectin
by galactosylated telomers.
AB - This work deals with the synthesis and lectinic recognition ability of
galactosylated telomers. To investigate if telomeric carriers could exhibit
cellular recognition properties, we have synthesized mono- and polygalactosylated
tris(hydroxymethyl)acrylamidomethane (THAM) telomers. The affinity of such
macromolecular drug carriers toward a receptor, the yeast Kb CWL1 lectin, was
defined, and the influence of mono- or polygalactosylation of THAM units on the
recognition phenomenon was assessed. The lectinic affinity of the compounds was
estimated by measuring the inhibition of yeast aggregation. The average degree of
polymerization as well as the hydrophilic-lipophilic balance of such
galactosylated telomers affects their recognition ability for the lectin.
PMID- 9548530
TI - A homobifunctional rhodamine for labeling proteins with defined orientations of a
fluorophore.
AB - The synthesis and characterization of a bifunctional rhodamine dye bearing 2
(iodoacetamido)ethyl substituents on the 3'- and 6'-nitrogen atoms is described.
Aspects of the conversion of chloroacetamides to iodoacetamides are discussed,
including a remarkably mild dehalogenation of an aromatic haloacetamide in the
presence of NaI and camphorsulfonic acid. The bifunctional rhodamine has been
designed for two-site, 1:1 labeling of proteins that contain two suitably
disposed cysteine residues and is intended to constrain the orientation of the
rhodamine absorption and emission dipoles in a predictable relationship to the
protein structure.
PMID- 9548531
TI - Hybridization characteristics of biomolecular adaptors, covalent DNA-
streptavidin conjugates.
AB - Semisynthetic, covalent streptavidin-DNA adducts are versatile molecular
connectors for the fabrication of both nano- and microstructured protein arrays
by use of DNA hybridization. In this study, the hybridization characteristics of
six adduct species, each containing a different DNA sequence of 21 or 24 bases,
have been compared. First, the adducts were conjugated to biotinylated alkaline
phosphatase, and their binding to immobilized oligomer complements of similar
lengths was quantified in a microplate assay. The binding efficiency observed
varied to a great extent with the specific sequence of the oligonucleotide
attached, and could not be predicted from affiliated thermodynamic data of duplex
stability. To further elucidate the hybridization properties, the hybridization
rate constants of association and dissociation (kassn and kdissn) have been
determined for both unconjugated oligonucleotides and protein adducts, using a
surface plasmon resonance biosensor. The kassn values observed for the
oligonucleotides are in the range of 9 x 10(3) to 2 x 10(5) M[-1] s(-1) and
correlate with structural properties of the probe strands. Up to 3-fold decreased
kassn values were obtained for the corresponding protein adducts. Likewise,
values were observed for kdissn ranging from 1.4 x 10(-4) to 1.9 x 10(-5) s[-1]
for the oligonucleotides. The dissociation of the analogous protein conjugates
was reduced by up to 5-fold. The extent of this decrease correlates with the
formation of homodimeric or intramolecular aggregation of probe strands. A
mechanistic model for explaining these data is based on attractive intramolecular
interaction between the nucleic acid and protein moiety.
PMID- 9548532
TI - Extending insulin action in vivo by conjugation to carboxymethyl dextran.
AB - The biochemical and pharmacological properties of bioactive peptides and proteins
can be altered by conjugation with polymers. This report describes site-specific
attachment of insulin to activated carboxyl groups of carboxymethyl dextran (CMD,
MW=51000) through the GlyA1 insulin amino group. On average, three or four
insulin molecules were grafted to a CMD linear chain. Coupled insulin molecules
were properly folded, and the bioactivity of conjugated insulin in the blood
glucose depression assay was 9.6 IU/mg, which was only 2.6 times less than that
for native insulin. The cell growth study indicated that the CMD-insulin
conjugate was as mitogenic as insulin on vascular smooth muscle cells, whereas
the starting CMD polymer was not. The insulin receptor binding constant of the
conjugate (3.6 x 10[9] M[-1]) compared well with that of native insulin (7.6 x
10[9] M[-1]), indicating that the CMD chain does not present any major
constraints to binding. Plasma clearance of CMD-insulin obeyed a two-compartment
pharmacokinetic (PK) model with a CMD-insulin conjugate plasma elimination half
life of 114.1 min, which was significantly longer than that of soluble Zn-insulin
(12.4 min). In contrast, pharmacodynamic (PD) profiles (blood glucose lowering
effects) after intravenous (iv) administration of the conjugate or insulin in
rats were not different. Subcutaneous (sc) administration of the conjugate
resulted in a significantly prolonged plasma profile with a noncompartmental PK
parameter mean residence time (MRT) of 103.5 min which was significantly longer
than that of soluble Zn-insulin (40.5 min). This was reflected in the protracted
PD effect of sc administered conjugate with time needed to reach minimum glucose
concentration Tnadir of 95.7 min, which was significantly longer than that of
insulin (62 min). We conclude that the conjugation of insulin to CMD leads to a
bioactive conjugate with a delayed sc PD profile showing prolonged response,
resembling intermediate acting insulin preparations.
PMID- 9548533
TI - Antibody-mediated versus nontargeted delivery in a human small cell lung
carcinoma model.
AB - The uptake of macromolecular agents in tumor cells (LX-1, human small cell lung
carcinoma) and in corresponding tumor xenografts was compared in a parallel study
utilizing a long-circulating biocompatible graft copolymer, MPEGs-PL-DTPA
[Bogdanov, A., Jr., et al. (1995) Adv. Drug Delivery Rev. 16, 335-348; Bogdanov,
A., Jr., et al. (1996) Bioconjugate Chem. 7, 144-149] and a tumor-specific
chimeric monoclonal antibody, BR96 [Hellstrom, I., et al. (1990) Cancer Res. 50,
2183-2190; Garrigues, J., et al. (1993) Am. J. Pathol. 142, 607-622]. Covalent
grafted conjugates of methoxy-(polyethylene glycol)succinate and polylysine and
BR96 were modified with DTPA, biotinyl, or rhodamine-X-residues. Using
radionuclide and fluorescent labeled derivatives of the copolymer and the
antibody, we established that (1) the copolymer does not associate with the
plasma membrane in N-ethylmaleimide-treated cells and is slowly internalized by
live cells at 37 degrees C; (2) the antibody binds rapidly to the surface of LX-1
cells and shows active internalization in vesicles with a subsequent slow
decrease in the cell-associated antibody concentration; (3) LX-1 cells bear more
than 1 million BR96 binding sites/cell (with an apparent Kd of 4.5 x 10[-7] M);
and (4) intravesicular fluorescence intensity in LX-1 cells was linearly
dependent on copolymer concentration, suggesting fluid phase endocytosis. Tumor
localization by nuclear imaging, biodistribution, microdistribution by histology,
and determination of tumor cell fraction uptake was performed in LX-1 tumor
xenografts. In vivo study showed that MPEGs-PL-DTPA progressively accumulates in
the tumor, yielding from 2.8+/-1.5% injected dose per gram of tissue (ID/g) at 24
h to 5.2+/-1.7% ID/g of tissue at 48 h. The antibody accumulation peaked at 24 h
(6.0+/-3.2% ID/g) and decreased thereafter. We determined that at 24 h 43.9+/
11.29% of the polymer accumulated in the tumor was associated with tumor cell
fraction with the remainder of the accumulated dose localized in the
interstitium. Accumulation of the biotinylated graft copolymer and the antibody
in LX-1 xenografts and their uptake in cells were confirmed by histology using
avidin-peroxidase staining. Our study demonstrates that, although BR96 is highly
specific in vitro, tumoral drug delivery in vivo can be equally high with long
circulating graft copolymers because of slow extravasation at the tumor site.
PMID- 9548534
TI - Identification of the soluble in vivo metabolites of indium-111
diethylenetriaminepentaacetic acid-D-Phe1-octreotide.
AB - Indium-111-diethylenetriaminepentaacetic Acid-D-phenylalanine-octreotide ([111]In
DTPA-octreotide) is a cyclic eight amino acid somatostatin analogue which is
approved for gamma scintigraphy of neuroendocrine tumors. To address the factors
that contribute to liver and kidney retention of this radiopharmaceutical, its
metabolism was evaluated in normal and tumor-bearing rats. The soluble fractions
from nontarget (liver and kidney) and target (tumor, pancreas, adrenals) organ
homogenates were analyzed out to 21 h postinjection, and urine was analyzed out
to 12 h postinjection. The blood was analyzed at shorter time intervals due to
the rapid clearance of (111)In-DTPA-octreotide. Radio-TLC and HPLC were used to
analyze organ homogenates, blood, and urine. By TLC, intact (111)In-DTPA
octreotide was resolved from the soluble metabolites, and a similar apparent rate
of metabolism was observed in the liver, kidney, tumor, and pancreas with
approximately 30% intact (111)In-DTPA-octreotide at 4 h postinjection. In the
adrenals, metabolism occurred more slowly with approximately 60% intact (111)In
DTPAoctreotide at 4 h postinjection. At 4 h postinjection, the activity excreted
in the urine consisted of 85% intact (111)In-DTPA-octreotide. HPLC provided
resolution of the individual extractable metabolites. In an attempt to identify
these metabolites, two DTPA-amino acid sequences were synthesized: DTPA-D-Phe-Cys
and DTPA-D-Phe. Under the conditions used for metabolite analysis, (111)In-DTPA-D
Phe-Cys-OH eluted at 14.6 min and (111)In-DTPA-D-Phe-OH eluted at 7.0 min. Each
of these standard sequences was combined with the soluble portion of the organ
homogenate and was shown by HPLC to coelute with the metabolites. These data
suggest that (111)In-DTPA-octreotide was initially degraded to (111)In-DTPA-D-Phe
Cys-OH and (111)In-DTPA-D-Phe-OH. The (111)In-DTPA-D-Phe-Cys-OH was further
degraded to (111)In-DTPA-D-Phe-OH, which appeared to be the final metabolite that
was extracted from the organs. From these results, it can be concluded that at
longer time points (> 2 h postinjection) a significant amount of (111)In was
retained in nontarget organs as (111)In-DTPA-D-Phe-OH and (111)In-DTPA-D-Phe-Cys
OH and not as intact (111)In-DTPA-octreotide.
PMID- 9548535
TI - Interleukin 7 (IL-7) receptor-specific cell killing by DAB389 IL-7: a novel agent
for the elimination of IL-7 receptor positive cells.
AB - Interleukin 7 (IL-7) induces the proliferation of B cell progenitors in long-term
bone marrow cultures, promotes the growth of resting fetal and adult thymocytes,
and costimulates mature human T cell proliferation. IL-7 also induces cell growth
in hematologic malignancies such as acute lymphoblastic leukemia, chronic
lymphocytic leukemia, acute myelogenous leukemia, and Sezary syndrome. We have
constructed a recombinant fusion protein, DAB389 IL-7, composed of the catalytic
and transmembrane domains of diphtheria toxin (DT), fused to IL-7. We demonstrate
that DAB389 IL-7 is selectively cytotoxic for only those cells bearing the IL-7
receptor and that entry into target cells is mediated through the receptor. The
nontoxic mutant, DA(E149S)B389 IL-7, was constructed and used to demonstrate that
the catalytic domain of DT is responsible for the ADP ribosylation of elongation
factor 2 that results in cytotoxicity. Finally, we demonstrate that DA(E149S)B389
IL-7 induces the growth of IL-7-dependent cells, verifying the bioactivity of the
IL-7 binding domain of DAB389 IL-7. We propose that DAB389 IL-7 may be an
important reagent in studying the IL-7--IL-7 receptor complex and may possess
potential as a therapeutic agent against IL-7 receptor-bearing hematologic
malignancies.
PMID- 9548536
TI - High-affinity no-carrier-added 99mTc-labeled chemotactic peptides for studies of
inflammation in vivo.
AB - Nalpha-for-Nle-Leu-Phe-Nle-Tyr-Lys, a chemotactic peptide that binds with high
affinity to the chemoattractant receptor on granulocytes and monocytes, was
labeled with 99mTc using the diaminedithiol (DADT) chelating system to coordinate
the Tc. 99mTc labeling of the DADT-coupled peptide was accomplished in 84%
overall yield (room temperature for 10 min) using [99mTc]glucoheptonate as the
donor of prereduced Tc. HPLC analysis showed two major 99mTc-labeled peptide
peaks, 99mTc-DADT-Pep-I and 99mTc-DADT-Pep-II, were obtained in a ratio of
1:0.85. Using an iodoacetamide-derivatized gel to remove unlabeled peptide from
the 99mTc labeling mixtures, essentially no-carrier-added (nca) high-specific
activity 99mTc-labeled chemotactic peptides were obtained. The 99Tc analogues of
the peptides were synthesized (72% yield) in a similar fashion and correlated
with 99mTc complexes I and II by HPLC. In vitro competitive receptor binding
assays of the isolated 99Tc analogues were performed against the tritiated
chemotactic peptide [3H]N-for-Met-Leu-Phe ([3H]fMLF) using isolated granulocytes.
The 99Tc-derivatized peptides showed similar binding affinities to the
chemoattractant receptor as the unlabeled Nalpha-for-Nle-Leu-Phe-Nle-Tyr-Lys. The
nca 99mTc-labeled peptides gave high contrast images of experimental inflammation
in rabbits without causing neutropenia. Thus, it is feasible to attach the Tc
DADT chelate to low-molecular weight receptor binding chemotactic peptides and
retain substantial binding to the receptor. Chemotactic peptides labeled with
99mTc via the DADT ligand system have the potential for imaging focal sites of
inflammation without toxic effects, an important consideration in the successful
utilization of chemotactic peptide agonists.
PMID- 9548537
TI - Design, synthesis, and initial evaluation of high-affinity technetium bombesin
analogues.
AB - Potent antagonists of bombesin-like peptides have shown great potential for
applications in cancer therapy. A 99mTc-labeled agent capable of identifying
patients who could benefit from these emerging therapies would have a great
impact on patient management. This study involves the synthesis and initial
evaluation of technetium diaminedithiolate analogues derived from the potent
bombesin analogue Pyr-Gln-Lys-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2
(Lys3-bombesin). We coupled two diaminedithiol (DADT) bifunctional chelating
agents (BCAs 1 and 2) to the Lys3 residue at the N-terminal region that is not
required for binding to the receptor. 99mTc labeling was performed by ligand
exchange on addition of [99mTc]glucoheptonate to a solution of the adduct at room
temperature. Two products were obtained from each adduct on analysis by HPLC. The
major to minor product ratios of the 99mTc-labeled analogues were 3:1 for
products from BCA 1 and 9:1 for the products from BCA 2. Macroscopic amounts of
the 99Tc analogues were similarly prepared using [99Tc]glucoheptonate. In this
case, the major to minor ratios were 2:1 for the products from both BCAs. For
initial evaluation of the binding of the Tc-labeled peptides to bombesin
receptors, the 99Tc analogues were used in vitro in competitive binding assays in
rat brain cortex membranes against [125I-Tyr4]bombesin. Results of the in vitro
assays showed that the inhibition constants (Ki) of the major and minor products
were 3.5+/-0.7 and 3.9+/-1.5 nM, respectively, for the products from BCA 1; and
7.4+/-2.0 and 5.2+/-1.5 nM for the products derived from BCA 2, respectively. The
high affinity exhibited by these technetium analogues is an indication of their
potential for use in non-invasive in vivo biochemical characterization of cancers
that possess receptors for bombesin.
PMID- 9548538
TI - Structure characterization of functional histidine residues and carbethoxylated
derivatives in peptides and proteins by mass spectrometry.
AB - We developed a mass spectrometric method to precisely characterize the structures
of the diethyl pyrocarbonate (DEP)-modified amino acid derivatives in intact
peptides and proteins. Using acetate-buffered solutions for modification
reactions improved the yields of DEP modification. UV quantification of
carbethoxylation of angiotensin II was consistent with the degree of mass
spectrometrically determined modification. Unequivocal identification of the
modification sites in carbethoxylated angiotensin II derivatives was achieved by
HPLC separation and mass spectrometric sequencing. With increasing concentrations
of DEP, a gradual increase of carbethoxy groups, comprising biscarbethoxylation
products, was detected in angiotensin II and in insulin. When using a high molar
excess of DEP, histidine carbethoxylation was found together with modifications
at alpha-amino groups and tyrosine residues. The sites of carbethoxylation in
insulin were identified by MALDI-MS-peptide mapping analyses of the tryptic
digestion mixtures from the nonreduced insulin derivatives and after reduction of
disulfide bonds, demonstrating that histidine carbethoxylation was sufficiently
stable during disulfide bond reduction and tryptic digestion at pH 7.5. The mass
spectrometric identification of mono- and biscarbethoxylated histidine residues
in insulin is in agreement with surface accessibilities of imidazolyl nitrogen
atoms and seems to reflect the microenvironment of the protein tertiary
structure. Thus, mass spectrometric peptide mapping analyses of carbethoxylated
protein derivatives allowed both the simultaneous identification of histidine
carbethoxylation in the presence of other modified groups and the detection of
different chemical behavior of histidine residues by the unambiguous
identification of mono- and bismodifications.
PMID- 9548539
TI - Molecular characterization of a conformational epitope of hen egg white lysozyme
by differential chemical modification of immune complexes and mass spectrometric
peptide mapping.
AB - A new approach for the characterization of conformationally dependent epitope
structures in protein antigens is described using differential chemical
modification of immune complexes in combination with mass spectrometric peptide
mapping analysis. Well-established methods for epitope characterization are
frequently not applicable to conformationally dependent epitopes, and direct
methods of structure analysis such as X-ray crystallography of immune complexes
have been successful only in a few cases. Our approach combines tertiary
structure-selective chemical modification of immune complexes with the molecular
characterization of reaction products by mass spectrometric peptide mapping. The
comparison of the modification pattern of free and antibody-bound antigen
provides the identification of residues protected from modification by the
antibody. These residues hence are characterized as part of the epitope
structure. The well-characterized hen egg white lysozyme and a corresponding
monoclonal IgM-type antibody were investigated as a model system. Specific
modification reactions for arginine, lysine, and tyrosine residues were
performed, and the modification sites in free and antibody-bound antigen were
determined by mass spectrometric peptide mapping. The R14 residue and residues
K13 and K96 in the antibody-bound lysozyme were found to be protected from
modification, comprising a surface of spatially adjacent residues by folding of
the native protein. In contrast, other K and R residues as well as Y20 and Y23
showed no significant shielding from modification in the immune complex. These
results provided an estimation of the molecular epitope surface area of native
lysozyme.
PMID- 9548540
TI - Fluorescently detectable magnetic resonance imaging agents.
AB - This report describes the synthesis, characterization, and in vivo testing of
several bifunctional contrast-enhancing agents for optical and magnetic resonance
imaging (MRI) of experimental animals. These new agents integrate the advantages
of both techniques since they can be visualized simultaneously by light and MRI
microscopy. Employing this strategy allows the same biological structures of a
specimen to be studied at dramatically different resolutions and depths. The
complexes possess a metal chelator for binding a paramagnetic ion, gadolinium
(Gd3+), and a covalently attached fluorescent dye. The first class of complexes
are low-molecular weight species that are composed of the macrocyclic tetraamine
1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA) as the metal
chelating ligand coupled to tetramethylrhodamine. The second class of MRI
enhancing agents are composed of high-molecular weight polymers that are membrane
impermeable and once injected into a cell or cells are trapped inside. These
complexes possess multiple copies of both the metal-chelator
diethylenetriaminepentaacetic acid (DTPA) and the tetramethylrhodamine attached
to a macromolecular framework of either poly(D-lysine) (pdl) or dextran. Images
acquired of single cells after injection with these bifunctional agents enabled
us to follow the relative motions and reorganizations of different cell layers
during amphibian gastrulation and neurulation in Xenopus laevis embryos.
PMID- 9548541
TI - Synthesis of disulfide-containing phospholipid analogs for the preparation of
head group-specific lipid antigens: generation of phosphatidylserine antibodies.
AB - In this report, we describe a new approach for the production of lipid antigens
that elicit specific immune responses against phosphatidylserine (PS). Because
phospholipids are small nonimmunogenic haptens, PS analogs containing activated
coupling groups were synthesized and covalently attached to carrier proteins.
Sulfhydryl-reactive PS was generated by acylation of 1-oleoyl-2-(aminocaproyl)
phosphatidylcholine with N-succinimidyl-3-(2-pyridyldithio) propionate, converted
to PS by phospholipase D-catalyzed base exchange with L-serine, and conjugated to
carrier proteins by thiol-disulfide exchange. Antisera to these lipid hapten
protein carrier conjugates were developed in rabbits. Antibodies bound PS but not
phosphatidylcholine (PC), phosphatidylglycerol, phosphatidic acid, or
phosphatidylethanolamine (PE) when presented together with PC. Inhibition studies
using water-soluble lipid analogs and sonicated vesicles indicated that antibody
specificity was directed toward the lipid's polar head group. These antibodies
also inhibited the PS-dependent prothrombinase activity assay by approximately
60%. These data show that the covalent coupling of phospholipid haptens to
protein carriers via the lipid's fatty acyl side chains preserves its primary
head group moiety for the production of specific lipid antibodies.
PMID- 9548542
TI - Development and activities of a new melphalan prodrug designed for tumor
selective activation.
AB - The synthesis of C-Mel, a cephalosporin carbamate derivative of the clinically
used alkylating agent melphalan, is described. C-Mel was designed as an
anticancer nitrogen mustard prodrug that releases melphalan upon tumor-specific
activation by targeted beta-lactamase (bL). The Km and kcat values for bL
hydrolysis of C-Mel were 218 microM and 980 s(-1), respectively. In vitro
cytotoxicity assays with 3677 human melanoma cells demonstrated that C-Mel was 40
fold less toxic than melphalan and was activated in an immunologically specific
manner by L49-sFv-bL, a recombinant fusion protein that binds to the
melanotransferrin antigen on melanomas and on some carcinomas. L49-sFv-bL in
combination with C-Mel led to regressions and cures of established subcutaneous
3677 tumors in nude mice. The effects were significantly greater than those of
melphalan, which did not result in any long-term regressions in this tumor model.
The therapeutic effects were comparable to those obtained in mice treated with
the previously described L49-sFv-bL/7-(4-carboxybutanamido)-cephalosporin mustard
(CCM) combination. However, C-Mel may be more attractive than CCM for clinical
development since the released drug is clinically approved.
PMID- 9548543
TI - Membrane permeabilization and efficient gene transfer by a peptide containing
several histidines.
AB - We designed a peptide, H5WYG (GLFHAIAHFIHGGWHGLIHGWYG), that permeabilizes cell
membrane at a slightly acidic pH but not at neutral pH. Absorbance, fluorescence,
and circular dichroism spectra showed that H5WYG undergoes a dramatic
conformational change between pH 7.0 and 6.0 that correlates with the protonation
of the histidyl residues. Cell permeabilization studies monitored by flow
cytometry on living cells showed that H5WYG permeabilizes the cell membrane with
a great efficiency at pH 6.4 but was not active at neutral pH; at pH 6.8, the
peptide permeabilized 50% of the cells at 20 degrees C within 10 min. H5WYG
increased the expression of genes transferred to cells as glycosylated polylysine
DNA complexes, and the transfection efficiency was not impaired in the presence
of serum. Therefore, this peptide containing several histidines that become
positively charged when the pH decreased to less than 7.0 is a suitable helper
for delivering molecules into the cytosol upon either permeabilization of the
plasma membrane induced by lowering the extracellular medium to pH 6.4 or
permeabilization of the endosomal membrane induced by acidification of endosomes.
PMID- 9548544
TI - Novel glycosynthons for glycoconjugate preparation:
oligosaccharylpyroglutamylanilide derivatives.
AB - The reducing sugar of an oligosaccharide reacting with the alpha-amino group of
an amino acid is converted to an N-oligosaccharylamino acid which can then be
stabilized by N-acylation. Oligosaccharides in solution in N,N-dimethylformamide
reacted with alpha-glutamyl-p-nitroanilide at 50 degrees C for a few hours,
leading to an N-oligosaccharylglutamyl-p-nitroanilide. Then, the gamma-carboxylic
group of the glutamyl moiety, activated by adding (benzotriazol-1
yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), reacted with the
substituted alpha-amino group of the glutamyl residue, leading to an N
oligosaccharylpyroglutamyl-p-nitroanilide within 0.5 h. Such a one-pot two-step
reaction was shown to be very efficient in the case of a disaccharide such as
lactose, or pentasaccharides such as lacto-N-fucopentaoses, Lewis(a) or Lewis(x).
The glycosynthons were characterized by chromatography (HPAEC and HPLC); their
molecular mass was determined by electrospray ionization mass spectrometry, and
the glycosylamides were shown to have a beta-anomeric configuration on the basis
of their proton NMR. The N-oligosaccharylpyroglutamyl-p-nitroanilides are quite
stable at room temperature over a large pH range. They are easily converted to N
oligosaccharylpyroglutamyl-p-isothiocyanatoanilides which can be used to prepare
glycoconjugates such as cationic glycosylated polylysines suitable for
specifically delivering genes or oligonucleotides in a sugar-dependent manner.
PMID- 9548545
TI - Micropatterned immobilization of epidermal growth factor to regulate cell
function.
AB - Photoreactive epidermal growth factor (EGF) was synthesized by conjugating mouse
EGF with photoreactive polyallylamine, which was synthesized by the coupling
reaction of polyallylamine with N-[4-(azidobenzoyl)oxy]succinimide. The EGF
derivative was pattern-immobilized onto a polystyrene plate by UV irradiation in
the presence of a photomask in a prescribed micropattern. The patterned
immobilization of EGF on the polystyrene plate was confirmed by immunostaining
with anti-EGF antibody. Chinese hamster ovary (CHO) cells overexpressing EGF
receptors were cultured on the micropatterned plate. The phosphorylated tyrosine
residues of signal proteins, including EGF receptors, were detected only in the
cells adhered in the EGF-immobilized area, and cell growth was observed only in
the EGF-immobilized area. The cells growing in the EGF-immobilized area were
partially stained by anti-phosphotyrosine antibody, when the area of EGF
immobilization was smaller than the cell. The partial staining of activated
proteins indicates that immobilization of EGF inhibited the free lateral
diffusion and internalization of the activated EGF-EGF receptor complex. The
enhanced cell growth is due to juxtacrine stimulation realized by immobilized
EGF.
PMID- 9548546
TI - A mild and efficient solid-support synthesis of novel oligonucleotide conjugates.
AB - Conjugates of oligodeoxyribonucleotide phosphorothioate (ODN-PS) with folic acid,
retinoic acid, arachidonic acid, and methoxypoly(ethylene glycol)propionic acid
have been synthesized. The procedure involved the initial solid-phase preparation
of 5'-amino-functionalized ODN-PS using N-pent-4-enoyl-derived (PNT) nucleoside
phosphoramidites followed by conjugation of the oligonucleotide either to the
ligand acids, using 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide as a coupling
reagent, or to their corresponding succinimidyl derivatives. Subsequent exposure
of the support to aqueous ammonium hydroxide (28%, 2 h, 55 degrees C) resulted in
the release of the fully deprotected ODN conjugates, which were purified by
reversed-phase HPLC or by preparative polyacrylamide gel electrophoresis. The
identity of the oligonucleotide conjugates was confirmed by MALDI-TOF mass
spectral analysis.
PMID- 9548547
TI - Characterization of interpolyelectrolyte complexes between double-stranded DNA
and polylysine comb-type copolymers having hydrophilic side chains.
AB - The polyionic interaction between DNA and polycations grafted with hydrophilic
dextran side chains was evaluated. The comb-type copolymers, poly(L-lysine)-graft
dextran, were successfully prepared by employing a reductive amination reaction
between epsilon-amino groups of poly(L-lysine) (PLL) and the reductive ends of
dextran (Dex). A coupling efficacy on the order of 70% was obtained regardless of
intrinsic philicities of the solvents used, either aqueous buffer or DMSO. The
resulting graft copolymers, which varied in the degree of grafting and the length
of hydrophilic side chains, formed a soluble complex with DNA. They also affected
the melting behavior of double-stranded DNA (dsDNA) in different ways. Copolymers
having a high degree of grafting thermally stabilized dsDNA without affecting its
reversible transition between single-stranded and double-stranded forms. However,
copolymers with a low degree of grafting or with a high degree of grafting of
short dextran chains impeded the reversibility of this transition. Furthermore,
highly grafted copolymers also accelerated the hybridization of DNA strands in a
low-ionic strength medium. It is of particular note that these copolymers
scarcely altered circular dichroismic signals of dsDNA even when the copolymers
were added in excess. This suggested that the copolymer interacted with dsDNA
without affecting its native structure or physicochemical properties. Finally,
the copolymer even formed a stable complex with a short oligonucleotide (20
bases). We, therefore, concluded that, by regulating the degree of grafting and
the molecular weight of grafted side chains, it would be possible to design novel
different graft copolymers capable of acting as carriers of functional genes to
target cells or tissue.
PMID- 9548548
TI - Synthesis of heterobifunctional poly(ethylene glycol) with a reducing
monosaccharide residue at one end.
AB - A new synthetic method for a heterobifunctional poly(ethylene glycol) (PEG)
having a monosaccharide moiety at one end was created. PEG with a reducing
monosaccharide residue at the alpha-end, which is linked to a defined position of
the sugar molecule, could be prepared via the anionic polymerization of ethylene
oxide (EO) initiated with a potassium alkolate of a protected monosaccharide such
as 1,2;5,6-di-O-isopropylidene-D-glucofuranose (DIGL), 1,2;3,4-di-O
isopropylidene-D-galactopyranose (DIGA), and 1,2-O-isopropylidene-3,5-O
benzylidene-D-glucofuranose (IBGL). The resulting PEGs possess the corresponding
sugar molecule at the alpha-chain end and a hydroxyl group at the omega-chain
end. The omega-chain end could be converted to several functional groups such as
allyl, amino, and hydroxycarbonyl groups in high yield. Such heterobifunctional
PEGs possessing a reducing monosaccharide residue at the alpha-end are one of the
promising tools for bioconjugate chemistries.
PMID- 9548550
TI - Subicular efferents are organized mostly as parallel projections: a double
labeling, retrograde-tracing study in the rat.
AB - To understand the functional relevance of the subiculum as a major distributor of
hippocampally processed information, detailed information about its neuronal
organization is necessary. A striking feature of the subiculum is that it can be
divided into four different areas, each characterized by a specific set of
efferent connections. To establish whether the different areas of the subiculum
are similar with respect to the organization of the origin of their respective
efferents, the double-fluorescence retrograde-tracing technique was used to study
the degree of collateralization. Because CA1 gives rise to a major input to the
subiculum but also projects to some of the targets reached by subicular
projections, we compared the subicular degree of collateralization with that of
CA1. Throughout CA1, the percentages of double-labeled cells were high, ranging
from 17% to 39%. In contrast, the percentages of double-labeled cells in the
subiculum were much lower, ranging from 0% to 12%, and no differences were noted
between the four areas of the subiculum. This indicates that the four regions of
the subiculum are organized in the same way with regard to the output
connectivity. Because all four different regions of the subiculum share this
paucity of collateralized projections, we conclude that subicular outputs
generally originate as parallel projections. This characteristic organization is
in line with a proposed function of the subiculum in information storage.
PMID- 9548549
TI - Morphology of basal optic tract terminals in the turtle, Pseudemys scripta
elegans.
AB - The morphologies of axon terminals of retinal ganglion cells projecting to the
basal optic nucleus (BON) via the basal optic tract (BOT) were studied in the red
eared turtle. The BOT was visualized on the ventral surface of the brainstem in
vitro, and either biotinylated dextran amine was injected extracellularly or
neurobiotin was injected into physiologically identified axons during
intracellular recordings. Up to 16 hours after tracer injection, the brains were
fixed, sectioned parasagittally, and stained for biotin and Nissl substance. The
diameters and depths of extracellularly filled axons were measured at three BON
sites. Fourteen axons were reconstructed from serial sections with the aid of
appropriate computer software. Analysis of extracellularly filled retinal axons
revealed that about three times more axons were present just inside the rostral
border of the BON compared with its caudal border. Thick (2-4 microm) axons were
located within 100 microm from the ventral border, whereas thin (<2 microm) axons
were found throughout the nucleus. Only the thinnest axons (<1 microm) extended
caudally from the nucleus, indicating that some extracellularly labelled fibers
passed through the BON. The intracellularly filled axons were more similar to the
thick axons filled extracellularly and arborized entirely within the BON. All of
the intracellularly filled axons had thick ventral trunks from which many thin
branches extended dorsally and obliquely within the BON. The thin branches
bifurcated repeatedly to form bead-like varicosities or boutons that often formed
clusters within regions of 150 microm3 or less. These clusters may reflect areas
of focused synaptic contact on BON cells with specific direction preferences.
PMID- 9548551
TI - Spatial distributions of retinoic acid receptor gene transcripts in the prenatal
mouse inner ear.
AB - The expression patterns of the three mouse retinoic acid (RA) receptor gene
isotypes (RARalpha, RARbeta, and RARgamma) and retinoid X receptor gene isotypes
(RXRalpha, RXRbeta, and RXRgamma) have been investigated by in situ hybridization
analysis of their RNA transcripts in the inner ear of mouse fetuses at 18.5 days
of gestation. Two RARs (RARalpha and RARgamma) and two RXRs (RXRalpha and
RXRbeta) presented an almost ubiquitous transcript distribution with overlapping
expression in several regions of the cochlea, such as Kolliker's organ, the organ
of Corti, the spiral limbus, and nervous structures. The organ of Corti showed an
enhanced in situ labeling with RARalpha and RXRbeta. By contrast, RARbeta and
RXRgamma displayed more restricted expression patterns. RXRgamma in particular
was strongly expressed in Kolliker's organ and in the spiral ganglion. This
expression pattern suggests that RA may be involved in the differentiation of
several cochlear cell types. Moreover, the colocalization of several RAR and RXR
gene transcripts suggests possible heterodimerization between these receptors in
several regions of the cochlea.
PMID- 9548552
TI - Gamma-aminobutyric acidA receptors on a bistratified amacrine cell type in the
rabbit retina.
AB - Gamma-Aminobutyric acid (GABA) is considered to be a major inhibitory
neurotransmitter in the inner plexiform layer of the retinas of all vertebrate
species. It is contained in and released from nearly 40% of the amacrine cells
and is known to play a major role in many aspects of visual processing. By using
well-characterized antibodies to several subunits of the GABA(A) receptor, we
have analyzed their localization on the cell bodies and dendritic trees of two
amacrine cell populations in the rabbit retina, which have been either filled
intracellularly with Lucifer yellow or stained immunohistochemically. Both
populations are selectively stained by intravitreal injection of the fluorescent
nuclear dye 4',6-diaminidin-2-phenylindoldihydrochloride (DAPI). We have found
that the most significant concentration of the alpha1 and beta2/3 GABA(A)
receptor subunits is localized to the DAPI-3 type amacrine cell. The perikarya of
the DAPI-3 cells are found in the proximal inner nuclear layer and send their
processes into two sublayers in sublaminae a and b of the inner plexiform layer.
These processes abut but do not directly overlap those of the two mirror
symmetric populations of starburst amacrine cells. Because the cell bodies of the
DAPI-3 cells are the only ones in the inner nuclear layer that stain strongly for
either the alpha1 or beta2/3 subunits, such staining is a diagnostic feature of
these cells. Their processes also constitute the most strongly staining ones
found within the inner plexiform layer. The dendritic trees of DAPI-3 cells,
which range from about 150 microm up to about 300 microm, exhibit recurvate
looping processes reminiscent of those described for directionally selective
ganglion cells. In contrast to the DAPI-3 cell, we have also shown that the
starburst amacrine cells exhibit no immunoreactivity for the alpha1 GABA(A)
receptor subunit and very little for the beta2/3 subunit. Thus, we have shown
that the DAPI-3 cells contain the highest concentrations of the alpha1 and
beta2/3 GABA(A) receptor subunits in the rabbit retina. These cells, which
costratify near the processes of both the starburst amacrine cells and the ON-OFF
directionally selective ganglion cells, thus, are situated both anatomically and
by virtue of their receptor content to potentially interact.
PMID- 9548553
TI - Developmental expression of alpha 9 acetylcholine receptor mRNA in the rat
cochlea and vestibular inner ear.
AB - Expression of alpha9 acetylcholine receptor (AChR) mRNA was studied by in situ
hybridization in the rat adult and developing cochlea and vestibular inner ear.
Alpha9 AChR mRNA was first observed in cochlear hair cells (HCs) at embryonic day
18 (E18), increased markedly after birth, stayed high until postnatal day 10
(P10), and decreased to substantially lower adult levels by P14. High levels of
alpha9 AChR mRNA expression were also noted in the developing nonneuronal
structures of the inner sulcus, chondrocytes, and/or osteoblasts in the cochlear
capsule and interscalar laminae. Both developing and adult bone marrow cells also
expressed intense alpha9 AChR mRNA. In the vestibular system, alpha9 AChR mRNA
was first observed in HCs at E16 in all sensory epithelia, increased to its
highest levels by P0-P4, then decreased slightly to reach adult levels by P10.
The results are consistent with the alpha9 AChR subserving efferent
neurotransmission to both cochlear and vestibular HCs. The observation of alpha9
AChR mRNA in cochlear HCs 2 weeks prior to functional onset in the cochlea
further suggests that expression of this gene is not related to HC activity. The
observation of substantial nonneuronal expression of alpha9 AChR mRNA suggests
that this receptor also has functions separate from its role in
neurotransmission.
PMID- 9548555
TI - Quantitative Golgi study of the rat cerebellar molecular layer interneurons using
principal component analysis.
AB - In this study, we applied for the first time a multivariate analysis to describe
the anatomy of cerebellar molecular layer interneurons. Forty variables extending
over a variety of morphological features (geometrical, topological, and metrical)
were obtained from a three-dimensional reconstruction of 26 rat rapid Golgi
stained neurons. The subsequent principal component analysis showed that the
first principal component was strongly correlated with variables related to the
depth of each cell's soma in the molecular layer. The second principal component
was strongly correlated with parameters describing axonal morphology. Finally, an
analysis of the distribution of these anatomical features suggested that these
cells cannot be classified into distinct groups but, instead, represent one
continuously varying population. Thus, the classical division of molecular layer
neurons into deep basket cells and superficial stellate cells is not supported by
our analysis. These results have important implications for the development of
the cerebellar cortex as well as for the expected patterns of Purkinje cell
activity following activation of the granule cell layer.
PMID- 9548554
TI - Immunohistochemical localization of metabotropic glutamate receptors, mGluR7a and
mGluR7b, in the central nervous system of the adult rat and mouse: a light and
electron microscopic study.
AB - The distributions of two alternative splicing variants of metabotropic glutamate
receptor mGluR7, mGluR7a and mGluR7b, were examined immunohistochemically in the
rat and mouse by using variant-specific antibodies raised against C-terminal
portions of rat mGluR7a and human mGluR7b. Many regions throughout the central
nervous system (CNS) showed mGluR7-like immunoreactivities (LI). The distribution
patterns of mGluR7-LI in the rat were substantially the same as those in the
mouse, although some species differences were observed in a few regions. Intense
mGluR7a-LI was seen in the main and accessory olfactory bulbs, anterior olfactory
nucleus, islands of Calleja, superficial layers of the olfactory tubercle,
piriform cortex and entorhinal cortex, periamygdaloid cortex, amygdalohippocampal
area, hippocampus, layer I of the neocortical regions, globus pallidus,
superficial layers of the superior colliculus, locus coeruleus, and superficial
layers of the medullary and spinal dorsal horns. The distribution of mGluR7b was
more restricted. It was intense in the islands of Calleja, substantia innominata,
hippocampus, ventral pallidum, and globus pallidus. The medial habenular nucleus
also showed intense mGluR7a-LI in the rat but not in the mouse. For both mGluR7a-
and mGluR7b-LI, localization in the active zones of presynaptic axon terminals
was confirmed electron microscopically at synapses of both the asymmetrical and
symmetrical types. It is noteworthy that mGluR7a-LI is seen preferentially in
relay nuclei of the sensory pathways and that both mGluR7a- and mGluR7b-LI are
observed not only in presumed glutamatergic axon terminals, but also in non
glutamatergic axon terminals including presumed inhibitory ones. Thus, mGluR7 may
play roles not only as an autoreceptor in glutamatergic axon terminals, but also
as a presynaptic heteroreceptor in non-glutamatergic axon terminals in various
CNS regions.
PMID- 9548556
TI - Distribution of butyrylcholinesterase in the human amygdala and hippocampal
formation.
AB - The distribution of the major cholinergic regulatory enzyme acetylcholinesterase
(AChE, EC 3.1.1.7) has been extensively studied in the human brain, but the
distribution of the closely related enzyme butyrylcholinesterase (BuChE, EC
3.1.1.8) is largely unknown. Because of the importance of BuChE and AChE in
Alzheimer's disease, we have studied the distribution of BuChE in the normal
human amygdala and hippocampal formation and compared it with that of AChE by
using histochemical techniques. In the amygdala, the distribution of BuChE
differed significantly from that of AChE in that BuChE was found primarily in
neurons and their dendritic processes, whereas AChE was found predominantly in
the neuropil. BuChE-positive neurons were present in up to 10% of the neuronal
profiles in lateral, basolateral (basal), basomedial (accessory basal), central,
cortical, and medial amygdaloid nuclei. AChE was found primarily in the neuropil
in these nuclei with only a few AChE-positive neurons. In the hippocampal
formation, BuChE was also found in neurons and not in the neuropil, whereas AChE
was found in both neurons and in the neuropil. BuChE and AChE neurons were
present in the polymorphic layer of the dentate gyrus, as well as the stratum
oriens and stratum pyramidale of the hippocampus proper. There was considerable
overlap in shapes, sizes, and numbers of BuChE- and AChE-positive neurons,
suggesting that the enzymes were colocalized in neurons of the hippocampal
formation. The distinct distribution of BuChE suggests that it may have specific
functions including coregulation of cholinergic and noncholinergic
neurotransmission in human amygdala and hippocampal formation.
PMID- 9548557
TI - Synaptology of the direct projections from the nucleus of the solitary tract to
pharyngeal motoneurons in the nucleus ambiguus of the rat.
AB - During the pharyngeal phase of the swallowing reflex, the nucleus of the solitary
tract (NTS) receives peripheral inputs from the pharynx by means of the
glossopharyngeal ganglion and is the location of premotor neurons for the
pharyngeal (PH) motoneurons. The semicompact formation of the nucleus ambiguus
(AmS) is composed of small and medium-sized neurons that do not project to the
pharynx, and large PH motoneurons. We investigated whether the neurons in the NTS
projected directly to the PH motoneurons or to the other kinds of neurons in the
AmS by using the electron microscope. When wheat germ agglutinin-conjugated
horseradish peroxidase (WGA-HRP) was injected into the NTS after cholera toxin
subunit B-conjugated HRP (CT-HRP) injections into the pharyngeal muscles of male
Sprague-Dawley rats, many nerve terminals anterogradely labeled with WGA-HRP were
found to contact PH motoneurons retrogradely labeled with CT-HRP. Most of the
labeled axodendritic terminals (63%) contained pleomorphic vesicles with
symmetric synaptic contacts (Gray's type II), and the remaining ones contained
round vesicles with asymmetric synaptic contacts (Gray's type I). About 14% of
the axosomatic terminals on PH motoneuron in a sectional plane were anterogradely
labeled, and about 70% of the labeled axosomatic terminals were Gray's type II.
Observations of serial ultrathin sections revealed that both the small and the
medium-sized neurons received only a few labeled axosomatic terminals that were
exclusively Gray's type I. These results indicate that the NTS neurons may send
mainly inhibitory as well as a few excitatory inputs directly to the PH
motoneurons in the AmS.
PMID- 9548558
TI - Induction of interleukin (IL)-1 alpha and beta gene expression in human
keratinocytes exposed to repetitive strain: their role in strain-induced
keratinocyte proliferation and morphological change.
AB - Recent studies in our laboratory have demonstrated that mechanical strain alters
many facets of keratinocyte biology including proliferation, protein synthesis,
and morphology. IL-1 is known to play an important role in the autocrine
regulation of these basic cellular properties under basal and stimulated
conditions. However, it is not known whether IL-1 plays a role in strain-induced
alteration of keratinocyte biology. Thus, the objective of this study was to test
the hypothesis that cyclic strain stimulates IL-1 expression and that strain
induced changes in keratinocyte function is regulated by IL-1. To test this
hypothesis, we examined the effect of cyclic strain (10% average deformation) on
keratinocyte IL-1 gene expression and the effect of neutralizing antibodies of IL
1 alpha and IL-1 beta on strain-induced changes in keratinocyte proliferation,
morphology, and orientation. Northern blot analyses demonstrated that steady
state levels of IL-1 alpha and beta mRNA were elevated by 4 h, peaked at 1 2 h of
cyclic strain (IL-1 alpha, 304+/-14.2%; IL-1 beta, 212+/-5.6% increase vs. static
controls) and decreased gradually by 24 h. IL-1 antibodies (IL-1 alpha, 0.01
microg/ml; IL-1 beta, 0.01 microg/ml) significantly blocked strain-induced
keratinocyte proliferation as well as the basal rate of proliferation. In
contrast, IL-1 antibodies (IL-1 alpha, 0.01 microg/ml; IL-1 beta, 0.1 microg/ml)
had no effect on strain-induced morphological changes such as elongation and
alignment. We conclude that mechanical strain induces IL-1 mRNA expression in
keratinocytes. The role of IL-1 in mediating strain-induced changes in
keratinocyte biology remains to be determined but appears to be independent of
morphological changes.
PMID- 9548559
TI - Pre-mRNA processing enhancer (PPE) element increases the expression of an
intronless thymidylate synthase gene but does not affect intron-dependent S phase
regulation.
AB - The pre-mRNA processing enhancer (PPE) element is an RNA sequence element derived
from the intronless HSV-TK gene. Insertion of the element into the highly intron
dependent human beta-globin gene leads to efficient expression in the absence of
splicing. We have analyzed the effect of the PPE element on the expression of
mouse thymidylate synthase (TS) minigenes. We have previously shown that the
expression of intronless TS minigenes is moderately (up to 20-fold) stimulated by
the inclusion of introns. Furthermore, S phase-specific expression of TS
minigenes in growth-stimulated cells depends on the presence of a spliceable
intron as well as the TS promoter. The goal of our study was to determine if the
PPE element would overcome the dependence on introns for efficient expression and
for S phase-specific expression of transfected TS minigenes. We found that
insertion of the PPE element into an intronless TS minigene partially overcame
intron dependence. However, the increase in expression was much less than that
observed for the intronless beta-globin gene. We also found that intronless TS or
HSV-TK genes that contained the PPE element and that were driven by the TS
promoter were expressed at a constant level in serum-stimulated cells. However,
when an intron was included in these genes, they were expressed in an S phase
specific manner. Thus the PPE element was not able to overcome the dependence on
introns for S phase-specific expression of TS minigenes.
PMID- 9548560
TI - The haemochromatosis candidate gene HFE (HLA-H) of man and mouse is located in
syntenic regions within the histone gene cluster.
AB - The HFE (HLA-H) gene is a strong candidate gene for hereditary haemochromatosis
and was localized on the short arm of chromosome 6 to 6p21.3-p22. In addition,
the sequence of the homologous mouse and rat cDNA and a partial sequence from the
mouse gene have been reported recently. In this report, we describe the location
of the human and the mouse HFE (HLA-H) gene within the histone gene clusters on
the human chromosome 6 and the mouse chromosome 13. Both the human and the murine
gene were located on syntenic regions within the histone gene clusters in the
vicinity of the histone H1t gene. The genomic sequence of the human HFE (HLA-H)
gene and the 3' portion of the homologous mouse gene were determined. Comparison
of the genomic sequences from man and mouse and the cDNA sequence from rat shows
significant similarities, also beyond the transcribed region of the mouse gene.
PMID- 9548561
TI - DNA topoisomerase II can drive changes in higher order chromosome architecture
without enzymatically modifying DNA.
AB - Topoisomerase II has been suggested to play a major role in chromosome
organization based on its DNA decatenating activity and its ability to mediate
direct binding interactions between DNA and nuclear matrix. However, this latter
point remains controversial. Here we address the question of whether the
chromatin binding activity of Topoisomerase II is sufficient to modify chromosome
form using whole mammalian chromosomes in vitro. Intact chromosomes were
microsurgically removed from living cells and disassembled by treatment with
protease or heparin. When these disassembled chromosomes were incubated with
recombinant human Topoisomerase II, the enzyme became incorporated into chromatin
and reassembly resulted, leading to almost complete restoration of pre-existing
chromosome shape and position within minutes. Chromosome reconstitution by
Topoisomerase II was dose-dependent, saturable, and appeared to be controlled
stoichiometrically, rather than enzymatically. Similar reassembly was observed in
the absence of ATP and when a catalytically inactive thermosensitive
Topoisomerase II mutant was used at the restrictive temperature. Chromosome
recondensation also could be induced after the strand-passing activity of
Topoisomerase II was blocked by treatment with an inhibitor of its catalytic
activity, amsacrine. When a non-hydrolyzable beta,gamma-imido analog of ATP (AMP
PNP) was used to physiologically fix bound Topoisomerase II enzyme in a closed
form around DNA, subsequent chromosome disassembly was prevented in the presence
of high salt. These data suggest that Topoisomerase II may control higher order
chromatin architecture through direct binding interactions, independently of its
well-known catalytic activity.
PMID- 9548562
TI - Extracellular calcium influx stimulates metalloproteinase cleavage and secretion
of heparin-binding EGF-like growth factor independently of protein kinase C.
AB - The phorbol ester, tetradecanoyl-phorbol 13-acetate (TPA), stimulates rapid
proteolytic processing of the transmembrane, pro- form of heparin-binding
epidermal growth factor-like growth factor (HB-EGF) at cell surfaces, suggesting
the involvement of protein kinase C (PKC) isoforms in the HB-EGF secretion
mechanism. To test this possibility, we expressed a chimeric protein, consisting
of proHB-EGF fused to placental alkaline phosphatase (AP) near the amino terminus
of processed HB-EGF, in NbMC-2 prostate epithelial cells. The proHB-EGF-AP
chimera localized to plasma membranes and functioned as a diphtheria toxin
receptor. Secreted HB-EGF-AP bound to heparin and exhibited potent growth factor
activity. The presence of the AP moiety allowed highly quantitative measurements
of cleavage-secretion responses of proHB-EGF to extracellular stimuli. As
expected, rapid secretion of HB-EGF-AP was induced in a time- and dose-dependent
manner by TPA. However, this was also observed with the Ca2+ ionophore,
ionomycin, suggesting the involvement of extracellular Ca2+ ions in the secretion
mechanism. Ionomycin-induced secretion was inhibited by extracellular calcium
chelation but not by the PKC inhibitors, GF109203X, staurosporine, or
chelerythrine. The TPA-mediated secretion effect was inhibited by staurosporine,
GF109203X, and by pretreatment with TPA, but not by calcium chelation. A small
secretion response was induced by thapsigargin, which releases Ca2+ from
intracellular stores, but this was completely eliminated by extracellular calcium
chelation. Ionomycin- and TPA-induced HB-EGF-AP secretion was not dependent on
the presence of the proHB-EGF cytoplasmic domain and was specifically inhibited
by the metalloproteinase inhibitors 1,10-phenanthroline and tissue inhibitor of
metalloproteinase-1 (TIMP-1). These data demonstrate that extracellular Ca2+
influx activates a membrane-associated metalloproteinase to process proHB-EGF by
a pathway that does not require PKC.
PMID- 9548563
TI - Multiple levels of steroid hormone-dependent control of osteocalcin during
osteoblast differentiation: glucocorticoid regulation of basal and vitamin D
stimulated gene expression.
AB - We have examined the contribution of transcriptional mechanisms to the
pleiotropic effects of glucocorticoids on basal and vitamin D stimulated
expression of the developmentally regulated bone-specific osteocalcin (OC) gene.
OC expression was systematically investigated at the level of protein, mRNA, and
newly synthesized transcripts during maturation of the bone cell phenotype in
cultures of fetal rat calvarial-derived osteoblasts. Our results indicate that
transcriptional control of basal and hormone-regulated OC expression predominates
in immature osteoblasts prior to matrix mineralization. However, in mature
osteoblasts OC expression is controlled primarily by posttranscriptional
mechanisms reflected by elevated mRNA levels with a decline in transcription.
Vitamin D, alone or in combination with Dex, is a significant factor contributing
to mRNA stabilization in mature osteoblasts with a mineralized extracellular
matrix. Transcriptional modifications in response to Dex are reflected by
quantitative differences between proliferating and mature osteoblasts in the
formation of glucocorticoid receptor binding complexes at the proximal OC
glucocorticoid response element. Vitamin D and glucocorticoid receptor mRNA
levels are significantly higher in mature osteoblasts than in early stage bone
cells. However, receptor complexes do not appear to be rate limiting in
proliferating osteoblasts when the OC gene is not transcribed. Our results
indicate (1) developmental stage-specific effects of steroid hormone on
transcriptional regulation of bone expressed genes, and (2) inverse relationships
between levels of transcription and cellular representation of mRNA with OC
message stabilized in mature osteoblasts.
PMID- 9548564
TI - Pulse application of platelet-derived growth factor enhances formation of a
mineralizing matrix while continuous application is inhibitory.
AB - Platelet-derived growth factor (PDGF) stimulates chemotaxis and proliferation of
osteoblasts, and induces bone formation in vivo. To determine how PDGF might
regulate these cells, the effect of PDGF on long-term mineralizing cultures of
fetal rat osteoblastic cells was examined. Although PDGF increased cell
proliferation in these cultures, continuous treatment with PDGF caused a dose
dependent decrease in mineralized nodule formation. When cells were treated with
multiple, brief (1 day) exposures to PDGF at the osteoblast differentiation
stage, there was a significant 50% increase in mineralized nodule area. Based on
modulation of alkaline phosphatase activity it appears that longer-term exposure
to PDGF reduces mineralized nodule formation largely by inhibiting differentiated
osteoblast function, while short-term exposure enhances proliferation without
inhibiting the differentiated phenotype. Thus, the ultimate affect of PDGF on
bone formation is likely to reflect two processes: a positive effect through
enhancing cell number or a negative effect by inhibiting differentiated function.
The inhibitory effect of PDGF on formation of a mineralized matrix is unlikely to
be simply a result of enhanced proliferation of "fibroblastic" cells since
cultures treated with PDGF for 3 days and then transferred to new plastic dishes
exhibited a 70% increase in mineralized nodule area compared to controls. These
results would predict that multiple, brief exposures to PDGF would enhance bone
formation in vivo, while prolonged exposure to PDGF, which is likely to occur in
chronic inflammation, would inhibit differentiated osteoblast function and limit
bone regeneration.
PMID- 9548565
TI - Myc-mediated transactivation of HSP70 expression following exposure to magnetic
fields.
AB - We investigated c-myc protein-binding sites on the HSP70 promoter as modulators
of the induction of HSP70 gene expression in response to magnetic field
stimulation (8microT at 60Hz) and whether the presence of c-myc protein
potentiates transactivation of HSP70 expression. A 320 base pair region in the
HSP70 promoter (+1 to -320) was analyzed. This region contains two c-myc-protein
binding sites with consensus sequences located at -230 and -160 nucleotide
positions (relative to the transcription initiation site) and overlapping with
the region reported for the regulation of HSP70 gene expression by c-myc protein.
This promoter region is upstream of other regulatory sequences, including the
heat shock element (HSE), AP-2, and serum response element (SRE). Transfectants
containing both c-myc protein-binding sites, HSP-MYC A and HSP-MYC B, and exposed
to magnetic fields showed a 3.0-fold increase in expression of CAT activity as
compared with sham-exposed control transfectants. Transfectants containing one c
myc binding site, HSP-MYC A, and exposed to magnetic fields showed a 2.3-fold
increase in CAT expression. Transfectants in which both HSP-MYC A and HSP-MYC B
binding sites were deleted showed no magnetic field sensitivity; values were
virtually identical with sham-exposed controls. If the c-myc expression vector
was not co-transfected with the constructs containing myc-binding sites, there
was no difference in the expression of CAT activity between magnetically
stimulated and sham-exposed controls, although both responded to heat shock.
These data suggest that endogenous elevated levels of myc protein contribute to
the induction of HSP70 in response to magnetic field stimulation.
PMID- 9548566
TI - Inhibition of PPAR alpha/RXR alpha-mediated direct hyperplasia pathways during
griseofulvin-induced hepatocarcinogenesis.
AB - Chronic griseofulvin (GF) feeding induces preneoplastic foci followed by
hepatocellular carcinoma in the mouse liver. Our previous study suggested that GF
induced hepatocellular proliferation had a different mechanism from that of
peroxisome proliferator (PP)-induced direct hyperplasia. The GF-induced
hepatocellular proliferation was mediated through activation of immediate early
genes such as Fos, Jun, Myc, and NFKB. In contrast, PP-induced direct hyperplasia
does not involve activation of any of these immediate early genes. It has been
shown that nuclear hormone receptors including peroxisome proliferator activated
receptors (PPARs) and retinoid x receptors (RXRs) play important roles in
mediating the pleiotropic effects of PPs. To examine the possible roles of PPARs
and RXRs during non-PP-induced hepatocellular proliferation and the interaction
between PP and non-PP-induced proliferation, we have studied the expression of
the PPAR and RXR genes in the GF model using northern blot hybridizations and gel
retardation assays. The data showed that the expression of PPARalpha and RXRalpha
genes was down-regulated in the livers containing preneoplastic nodules and in
the liver tumors induced by GF. The mRNA down-regulation was accompanied by a
decrease in the amount of nuclear protein-bound to peroxisome proliferator and
retinoic acid responsive elements. Down-regulation was also associated with the
suppressed expression of the PPARalpha/RXRalpha target genes (i.e., acyl-Co
oxidase and cytochrome P450 4A1) and the catalase gene. The RXR-gamma gene was
also down-regulated, but the RARalpha, beta, and gamma and PPARbeta and gamma
genes were up-regulated. These results indicated that the hepatocarcinogenesis
induced by GF is accompanied by suppression of the PPARalpha/RXRalpha-mediated
direct hyperplasia pathway. The differential expression of these nuclear hormone
receptors reveals a new aspect for understanding the individual roles and
intercommunication of PPAR, RXR, and RAR isoforms in the liver.
PMID- 9548567
TI - Effect of sodium butyrate on the expression of genes transduced by retroviral
vectors.
AB - We have studied the effects of sodium butyrate (NaBu) on the expression of genes
transduced by retroviral vectors and stably expressed in two salivary gland
derived cell lines, A5-DAP and A5-BAG, established earlier. These cell lines were
obtained by infecting A5 cells with the retroviral vectors DAP and BAG,
respectively, and by selecting neomycin-resistant transduced cells. A5-DAP cells
express human placental alkaline phosphatase (PLAP) and A5-BAG cells bacterial
beta-galactosidase, both under the control of the viral long terminal repeat
(LTR) enhancer-promoter. NaBu in the concentration of 2-8 mM inhibited the growth
of A5-DAP cells, and induced the expression of heat-stable PLAP. These effects of
NaBu were dose-dependent. Induction of PLAP in clones of A5-DAP cells that
express different basal levels of the enzyme was not correlated with the relative
inducibilty by NaBu. Exposure to 4 mM NaBu for 48 h increased the PLAP mRNA level
by 31%. A5-DAP cells released, in a time-dependent manner, PLAP into the culture
medium. Cells treated with NaBu released more PLAP than untreated cells in
proportion to their elevated level of the enzyme. The parent A5 cells also
express a low level of tissue non-specific type alkaline phosphatase, which was
also induced by NaBu. NaBu inhibited the growth of A5-BAG cells also, and
increased the beta-galactosidase level. These data indicate the genes transduced
by retroviral vectors can be induced by NaBu, which most likely interacts with
the viral LTR.
PMID- 9548568
TI - Mechanism of protein kinase CK2 association with nuclear matrix: role of
disulfide bond formation.
AB - Nuclear matrix (NM) appears to be an intranuclear locale for significant and
dynamic association of the ubiquitous multifunctional messenger-independent
serine/threonine protein kinase CK2 that has been implicated in growth control
[Tawfic et al. (1996): J Cell Biochem 61:165-171]. We have examined the nature of
the association of CK2 with the NM. Nuclei prepared in the presence of a
sulfhydryl-blocking reagent such as iodoacetamide demonstrate a reduction in the
amount of CK2 associated with the NM to less than 5% of the control. On the other
hand, when nuclei are treated with the sulfhydryl crosslinking reagent sodium
tetrathionate, NM-associated CK2 increases severalfold. Treatment of nuclei with
sodium tetrathionate followed by 2-mercaptoethanol blocks this increase. Nuclei
isolated from rat liver and prostate behaved similarly, suggesting an identical
mode of association of CK2 with the NM regardless of the organ. These results
indicate a role of sulfhydryl interactions such that NM anchoring of CK2 occurs
via its beta subunit, which contains several vicinal cysteine residues. Further,
various sulfhydryl-blocking reagents inhibited CK2 activity in a concentration
dependent manner, and the inhibitory effect was reversed by agents such as
dithiothreitol, implying that cysteine residues in the CK2 play a role in its
catalytic activity.
PMID- 9548569
TI - Induction of stress response and differential expression of 70 kDa stress
proteins by sodium fluoride in HeLa and rat brain tumor 9L cells.
AB - We herein demonstrate that sodium fluoride (NaF) acts as a stress response
inducer on HeLa and 9L rat brain tumor cells. NaF is only slightly cytotoxic, and
inhibitory to Ser/Thr-phosphatases but not to Tyr-phosphatases in both cell
lines. After treatment with 5 mM NaF for 2 h, the phosphorylation levels of
vimentin and an alkali-resistant 65-kDa phosphoprotein were enhanced, a common
phenomenon detected in cells under a variety of stress conditions. Under an
identical treatment protocol, in which the cells were treated with 5 mM NaF for 2
h and then allowed to recover under normal growing conditions for up to 12 h, NaF
differentially induced the cytoplasmic/nuclear heat-shock protein70s (including
both the inducible and the constitutively expressed members of this protein
family) in HeLa cells and the endoplasmic reticulum residing heat-shock protein70
(the glucose-regulated protein with an apparent molecular weight of 78 kDa) in 9L
cells. Electrophoretic mobility shift assays (EMSA) using probes containing well
characterized regulatory elements revealed the activation of the heat-shock
factor in HeLa but not in 9L cells; this is in good agreement with the stress
protein induction pattern. Additional differential induction of binding
activities toward EMSA probes individually containing NF-KB, AP-2, and CRE-like
elements were detected in NaF-treated cells. The possible involvement of these
binding sites as well as the corresponding factors in the stress response are
discussed.
PMID- 9548570
TI - Macular hole.
AB - A macular hole is a full-thickness defect of retinal tissue involving the
anatomic fovea, thereby affecting central visual acuity. Macular holes have been
associated with myriad ocular conditions and originally were described in the
setting of trauma. The pathogenesis of idiopathic, age-related macular holes
remains unclear despite a litany of theories. Recently, Gass has described an
updated biomicroscopic classification of macular holes and postulated that
tangential vitreous traction may play a role. Cellular components surrounding the
rim of macular holes may also contribute tangential traction forces and elevate
the rim. Pseudomacular holes may be mistaken for macular hole lesions, despite
careful clinical examination. Careful biomicroscopic examination with a contact
lens and use of the Watzke and laser aiming beam tests help to ensure accurate
diagnosis. Newer imaging technology, such as optical coherence tomography, helps
distinguish true macular holes from pseudoholes and may provide additional
insight into the pathogenesis of this condition. Surgical management with or
without pharmacosurgical adjuncts can improve vision in select cases. The most
common surgical complication is progressive lens opacification in phakic
patients.
PMID- 9548571
TI - Intraocular lens complications requiring removal or exchange.
AB - Intraocular lens (IOL)-related complications are caused primarily by mechanical
trauma, inflammatory or infectious complications, or optical problems.
Complications may occur at the time of surgery or be the result of an ongoing
postoperative process. Mechanical and inflammatory injury may produce corneal
decompensation, cystoid macular edema, hyphema, uveitis, and glaucoma, causing
reduced vision and in some cases chronic pain. Optical problems may be due to a
wrong power of the IOL or to postoperative decentration or dislocation of the
lens. Ophthalmologists should be aware of the indications for IOL removal or
exchange in those patients who have ongoing IOL-induced injury or impairment.
Removal or exchange of an IOL frequently involves a complex decision-making
process and is often associated with immense technical challenge. Various medical
and surgical treatments may be tried to correct IOL problems before the decision
is made to remove or exchange the lens.
PMID- 9548573
TI - The vanishing of the sun: a manifestation of cortical plasticity.
AB - In Monet's painting impression. Rising Sun, when one steadily fixates the image
of a sailor in the center of the picture for several seconds, the solar disk
progressively disappears, being replaced in both brightness and color by the
surrounding sky. This "filling-in" phenomenon reflects a process of cortical
remapping, similar to the one that occurs in the presence of visual field
defects. Filling-in is largely ignored by clinicians, despite its major
implications in ophthalmologic practice, especially the nonrecognition of visual
field deficits.
PMID- 9548572
TI - Double choroidal malignant melanoma in an eye with apparent clinical regression.
AB - Multicentric melanomas in the same eye are rare, with few cases substantiated by
histology and serial sectioning. We report a patient with two documented
choroidal malignant melanomas in one eye. The initial tumor spontaneously
decreased in size for over 2 years before a second tumor appeared in a
noncontiguous location in the same eye. After enucleation, serial sections showed
that the two lesions were independent choroidal melanomas. We review the
literature regarding multiple, independent intraocular choroidal malignant
melanomas.
PMID- 9548574
TI - Visual loss after coronary artery bypass surgery.
AB - A 70-year-old man underwent coronary artery bypass graft complicated
postoperatively by visual loss. The diagnosis was nonarteritic anterior ischemic
optic neuropathy. Possible predisposing factors in this patient were hypotension,
anemia, a "disk at risk," and internal carotid artery stenosis. In the
postoperative setting, the erythrocyte sedimentation rate may be elevated, as it
was in this case and does not by itself suggest a diagnosis of giant cell
arteritis.
PMID- 9548575
TI - Wegener's granulomatosis.
AB - Clinical manifestations of Wegener's granulomatosis are nonspecific and
indistinguishable from a variety of neoplastic, infectious, and inflammatory
diseases. Ophthalmic disease is the presenting feature in nearly one sixth of
patients with Wegener's granulomatosis and will ultimately develop in a majority.
The discovery of antineutrophil cytoplasmic antibodies, particularly
antiproteinase-3, has changed the clinical approach to evaluating patients
suspected of having Wegener's granulomatosis. These antibodies are distinguished
from other related autoantibodies because they produce a coarse granular pattern
of cytoplasmic staining on indirect immunofluorescence with ethanol-fixed
neutrophils. Treatment of Wegener's granulomatosis with oral cyclophosphamide and
corticosteroids has decreased morbidity and improved survival, but side effects
from long-term immunosuppressive therapy are common and sometimes serious. The
effectiveness of trimethoprim-sulfamethoxazole in decreasing the number and
severity of recurrences of Wegener's granulomatosis is being investigated. It
remains to be determined if wide use of trimethoprim-sulfamethoxazole in limited
Wegener's granulomatosis could further improve the quality of life for some
patients.
PMID- 9548576
TI - Was Dom Perignon really blind?
AB - Many sources perpetuate the tripartite myth that Dom Perignon was the blind
inventor of champagne, whose senses of taste and smell were enhanced by his loss
of vision. This myth, however, is seemingly contradicted by historical fact. Not
only do ancient references suggest that sparkling wine existed long before
Perignon's time, but the making of champagne was a scientific process that
required careful measuring, weighing, and record keeping, and it is unlikely that
Perignon was blind when he was perfecting champagne. While the truth regarding
Dom Perignon's blindness has disappeared during the more than two and a half
centuries since his death, it is interesting to speculate why he may have lost
vision at some stage of life. A brief history of Perignon's discovery of the
secret of champagne and the blindness myth is traced, and a differential
diagnosis is given, including cataracts, uncorrected refractive error, alcohol
toxicity, and champagne-related ocular/cerebral trauma.
PMID- 9548577
TI - Hypothesis: septo-optic dysplasia is a vascular disruption sequence.
PMID- 9548578
TI - Variations in cataract extraction rates in Medicare prepaid and fee-for-service
settings.
PMID- 9548579
TI - Visual symptoms after optic neuritis: results from the Optic Neuritis Treatment
Trial.
PMID- 9548580
TI - An additional article on Rosenbaum cards.
PMID- 9548581
TI - Fatty acid transport: difficult or easy?
AB - Transport of unesterified fatty acids (FA) into cells has been viewed either as a
simple diffusion process regulated mainly by lipid physical chemistry or as a
more complex process involving protein catalysis. In this review FA transport in
cell membranes is broken down into three essential steps: adsorption,
transmembrane movement, and desorption. The physical properties of FA in aqueous,
membrane, and protein environments relevant to transport mechanisms are
discussed, with emphasis on recent information derived from NMR and fluorescence
studies. Because of their low solubility in water and high hydrophobicity, FA
bind rapidly and avidly to model membranes (phospholipid bilayers); if albumin is
a donor, FA desorb rapidly to reach their equilibrium distribution between the
membrane and albumin. The ionization properties of FA in a phospholipid bilayer
result in a high population of the un-ionized form (approximately 50%) at pH 7.4,
which diffuses across the lipid bilayer (flip-flops) rapidly (t(1/2) < 1 sec).
Desorption of FA from a phospholipid surface is slower than transmembrane
movement and dependent on the FA chain length and unsaturation, but is rapid for
typical dietary FA. These physical properties of FA in model systems predict that
proteins are not essential for transport of FA through membranes. The only
putative FA transport protein to be purified and reconstituted into phospholipid
bilayers, the mitochondrial uncoupling protein (UCP1), was shown to transport the
FA anion in response to FA flip-flop. New experiments with cells have found that
FA movement into cells acidifies the cytosol, as predicted by the flip-flop
model.
PMID- 9548582
TI - Isolation of macrophage-like cell mutants resistant to the cytotoxic effect of
oxidized low density lipoprotein.
AB - A high concentration of oxidized low density lipoprotein (Ox-LDL) showed a
cytotoxic effect on mouse macrophage-derived J774 cells. Mutant cells were
selected from these cells that were resistant to the cytotoxic effect of Ox-LDL.
One mutant form, named JO21b cells, was characterized in the present study. In
spite of a marked resistance to the cytotoxic effect of Ox-LDL, JO21b cells were
apparently as sensitive as the parent cells not only to toxic moieties of Ox-LDL,
such as 7-ketocholesterol and lysophosphatidylcholine, but also to t-butyl
hydroperoxide, an artificial lipid hydroperoxide analog. However, the cellular
association of 125I-labeled Ox-LDL with, and subsequent endocytic degradation by
JO21b cells was reduced by 70-80% compared with J774 cells. Similarly,
accumulation of cholesteryl esters in JO21b cell by Ox-LDL was also reduced by
70%. Northern blot analyses of type I and type II macrophage scavenger receptors
(type I and type II MSR) demonstrated that the mRNA levels of JO21b cells were
lower than those of J774 cells. Moreover, peritoneal macrophages obtained from
MSR-knockout mice showed a higher resistance to the cytotoxic effect of Ox-LDL
than those from their wild-type littermates. Our results suggest, therefore, that
macrophage scavenger receptor-mediated endocytic uptake of oxidized low density
lipoproteins (Ox-LDL) may play an enhancing role in Ox-LDL cytotoxicity to
macrophages or macrophage-derived cells.
PMID- 9548583
TI - Temporal and spatial pattern of expression of the HDL receptor SR-BI during
murine embryogenesis.
AB - During rodent fetal development, maternal lipoproteins can be sources of
cholesterol for the membrane synthesis required for tissue growth in the
developing embryo and for steroid hormone production in the extraembryonic
tissues. Although the mechanisms underlying the maternal-fetal lipoprotein
cholesterol transport system are not well defined, the placenta and yolk sac seem
to play major roles in this process, serving as functionally active interfaces
between maternal circulation and the embryo. In rodents, the principal
cholesterol transporter in the plasma is HDL, and the HDL receptor SR-BI is a
physiologically important mediator of cholesterol uptake in adult liver and
steroidogenic tissues. To begin to investigate SR-BI's role in maternal
cholesterol uptake by the fetus, we used immunofluorescence microscopy to
determine the pattern of SR-BI expression during murine embryogenesis. At day
E7.5 in gestation, there was significant SR-BI expression in endothelial cells of
the decidua, but little in intraembryonic and extraembryonic tissues. By day
E8.5, there was a dramatic increase in SR-BI expression in the trophoblast cells
which surround the developing embryo. Beginning at day E10, SR-BI was expressed
in both the placenta and yolk sac. The expression in these extraembryonic tissues
was correlated with significant uptake of fluorescent dye by the yolk sac
visceral endodermal cells from DiI-labeled HDL injected into pregnant mice.
Within the embryo proper, SR-BI expression appeared by day E14.5 at high levels
in the adrenal gland. SR-BI expression was not detected in the embryonic liver
through day E17.5 of gestation; however, it could be observed in neonatal livers.
These findings suggest that SR-BI may play a role in the rodent maternal-fetal
lipoprotein cholesterol transport system, supplying HDL cholesterol for either
membrane or steroid hormone synthesis, or both.
PMID- 9548584
TI - Alternative pre-mRNA splicing of the sterol 27-hydroxylase gene (CYP 27) caused
by a G to A mutation at the last nucleotide of exon 6 in a patient with
cerebrotendinous xanthomatosis (CTX).
AB - A recently identified G to A mutation at the last nucleotide of exon 6 of the
sterol 27-hydroxylase gene (CYP 27) in a patient with cerebrotendinous
xanthomatosis (CTX) was shown here to cause alternative pre-mRNA splicing of the
gene. Northern blot analysis of the patient's RNA revealed a broadened band in
the human CYP 27 mRNA region compared to that of the normal sample, indicating
that there may exist differently spliced mRNA species in the patient. RT-PCR
produced three fragments in the patient, one was full-length size and the other
two were of smaller sizes. Sequence analysis confirmed that the nucleotide of the
full-length size was identical to that of the normal full-length cDNA, except for
the G to A mutation at codon 362, which corresponds to the last nucleotide of
exon 6. One of the smaller size species lacked exon 6 and the other was absent
from the 3' terminal 88 bp of exon 6 due to the use of an activated cryptic 5'
splice site in exon 6. The correctly spliced mRNA harbouring the G to A mutation
was responsible for the deficiency of the sterol 27-hydroxylase activity, as
confirmed by transfection experiment. Transfection of constructed minigenes, with
or without the mutation, showed that correctly spliced mRNA was observed in the
normal minigene while the mutant minigene was differently spliced. This is the
first report of a G to A substitution at the last nucleotide of an exon resulting
in both normal and abnormal pre-mRNA splicings, including exon skipping and
activating of a coding region cryptic 5' splice site. The results reveal a new
molecular basis for the CTX and provide information on aberrant splicing of pre
mRNA in multi-exon genes.
PMID- 9548585
TI - Transport of maternal LDL and HDL to the fetal membranes and placenta of the
Golden Syrian hamster is mediated by receptor-dependent and receptor-independent
processes.
AB - Maternal lipoproteins provide nutrients to the fetus via the placenta, yolk sac,
and uterine membrane plus decidua. To determine the transport processes that are
responsible for the removal of lipoproteins from the maternal circulation, we
measured the clearance rates of maternal LDL and HDL in vivo, as well as the
tissue distribution of expression of the LDL receptor, glycoprotein 330 (gp330)
and the newly described HDL receptor, SR-BI, in the placenta, yolk sac, and
uterine membrane plus decidua at mid- and late-gestation of the hamster. In mid
gestation (day 10.5), LDL clearance rates of the placenta and yolk sac were
similar to those in the liver (approximately 100 microl/h per g) and higher than
those in the decidua (18 +/- 3 microl/h per g). Clearance rates for HDL-apoA-I
and HDL-cholesteryl ether were similar to those of LDL in the placenta and
decidua whereas rates in the yolk sac were dramatically higher (>1700 microl/h
per g). Additionally, albumin was cleared in the placenta and decidua at
approximately 16 microl/h per g whereas the yolk sac cleared the protein at much
higher rates (196 +/- 22 microl/h per g). Low levels of LDL receptor were
detected by immunoblot analysis in the placenta with trace amounts in the yolk
sac. Gp330 and SR-BI were both barely detectable in the placenta but were
expressed at high levels in the yolk sac. As gestation progressed to day 14.5,
LDL and HDL clearance rates decreased in all three tissues; immunodetectable LDL
receptor decreased in the placenta whereas the expression of gp330 and SR-BI in
the placenta and yolk sac remained relatively constant. These data suggest that
the clearance of maternal lipoproteins by the placenta, yolk sac, and decidua are
mediated by receptor-mediated as well as receptor-independent processes.
PMID- 9548586
TI - A naturally occurring isoform of the human macrophage scavenger receptor (SR-A)
gene generated by alternative splicing blocks modified LDL uptake.
AB - The class A macrophage scavenger receptors (SR-A) are macrophage-specific
trimeric integral membrane glycoproteins that have been implicated in many
macrophage-associated physiological and pathological processes including
atherosclerosis, Alzheimer's disease, and host defense. There are two forms of
the receptor that have been previously cloned, and both are generated by
alternative splicing of a single gene. Here we report the cloning of a third,
alternatively spliced isoform of the human SR-A gene (type III hSR-A). The novel
isoform is expressed in the human monocytic leukemia cell line THP-1 and also in
primary human monocyte derived macrophages. When expressed in CHO-K1 cells, type
III hSR-A does not internalize AcLDL despite having the domain shown to mediate
this function in type I and II hSR-A. We show that type III protein has altered
intracellular processing and is trapped within the endoplasmic reticulum, making
it unable to perform endocytosis. Type III protein acts as a dominant negative
isoform by reducing modified LDL uptake in CHO cells stably expressing either
type I or type II SR-A. The demonstration that a naturally occurring splice
variant of SR-A mRNA can act as a dominant negative isoform suggests a novel
mechanism for regulation of scavenger receptor activity in macrophages.
PMID- 9548587
TI - Cholesterol transport between cells and high density lipoprotein subfractions
from obese and lean subjects.
AB - We studied the pathway of cholesterol efflux from fibroblasts by testing plasma
samples from obese and lean subjects. Plasma samples were incubated with
[3H]cholesterol-labeled human skin fibroblasts for 1 h to ensure uniform labeling
of all of the high density lipoprotein (HDL) subfractions. Supernatants were then
transferred to unlabeled cells and the displacement of labeled cholesterol within
HDL subfractions by unlabeled cellular cholesterol was analyzed in short-term
experiments. Plasma samples of obese subjects were characterized by a lower
content of total apolipoprotein A-I (apoA-I) and alpha1-HDL and a lower overall
capacity to take up labeled cholesterol. In plasma of lean subjects, pre beta2
HDL and alpha1-HDL appeared to be the most active particles in the initial uptake
of unlabeled cellular cholesterol. By contrast, in plasmas of obese subjects, the
pre beta1-HDL appeared to be most active in taking up unlabeled cellular
cholesterol and transferring [3H]cholesterol. There were negative correlations
between body mass index (BMI) and apoA-I and alpha1-HDL concentrations, and with
the apparent increments of cellular cholesterol uptake within pre beta2-HDL and
alpha1-HDL, as well as with the overall capacity to promote cholesterol efflux.
By contrast, BMI was positively correlated with the apparent increment in
cellular cholesterol within pre beta1-HDL. While cholesterol efflux was
correlated with total plasma apoA-1, there were no such correlations with the
concentration of any individual HDL subfraction. We conclude that the pattern of
cholesterol transfer between fibroblasts and high density lipoprotein particles
is influenced by body fatness and may be a factor in the abnormal metabolism of
HDL in obesity.
PMID- 9548588
TI - Interaction of pulmonary surfactant protein A with dipalmitoylphosphatidylcholine
and cholesterol at the air/water interface.
AB - Interaction of pulmonary surfactant protein A (SP-A) with pure and binary mixed
dipalmitoylphosphatidylcholine (DPPC) and cholesterol (3.5 wt%) at the
air/saline, 1.5 mM CaCl2 interface was investigated using a rhomboid surface
balance at 37 degrees C. Surface tension-area isotherms were measured to access
the surface active properties of the monolayers. The organization of DPPC and
cholesterol in DPPC and DPPC/cholesterol mixed monolayers with or without SP-A at
equilibrium surface tension (approximately 23 mN/N) was revealed by
autoradiographs of Langmuir-Blodgett (L-B) films deposited from [14C]DPPC or
[14C]cholesterol-labeled monolayers. The results showed that SP-A can interact
with the polar head groups of DPPC monolayers and aggregate DPPC molecules. SP-A
decreased the surface area reduction required for DPPC monolayers to achieve near
zero surface tension from 30 to 25% of the area at equilibrium. SP-A also reduced
the collapse surface tension of pure cholesterol from 27 to 23 mN/m. DPPC and
cholesterol formed homogeneous mixed monolayers when both were dissolved in the
spreading solvent prior to spreading, while separate cholesterol-rich domains
appeared when DPPC and cholesterol were spread successively. Cholesterol resisted
squeeze-out from either mixed monolayer through compression. Although SP-A could
not promote the squeeze-out of cholesterol from homogeneous mixed monolayers, it
facilitated that of cholesterol domains especially when SP-A had first interacted
with DPPC. These results indicate that pulmonary surfactant protein A facilitates
the squeeze-out of cholesterol domains from mixed monolayers by condensing DPPC
and limiting lateral interactions of DPPC with cholesterol domains.
PMID- 9548589
TI - Identification and characterization of several forms of phospholipase A2 in mouse
epidermal keratinocytes.
AB - The tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) stimulated the
release of arachidonic acid (AA) from mouse keratinocytes. A distinct difference
was observed between the fatty acid release profile elicited by TPA and other
stimuli. These findings led to the investigation of keratinocyte phospholipase A2
(PLA2), which catalyzes the release of sn-2 fatty acids from membrane
phospholipids and regulates the production of eicosanoids. We characterized and
identified several forms of PLA2 in mouse keratinocytes, a cytosolic or cPLA2 and
two secretory or sPLA2s in the membrane. The PLA2 in keratinocyte cytosol is
sensitive to heating and acid treatment, while resistant to reducing reagent. The
PLA2 in keratinocyte membrane is resistant to heating and acid treatment, while
sensitive to reducing reagent. These characteristics suggested the presence of a
cPLA2 and at least one type of sPLA2. Inhibitor data further confirmed the
identities of these PLA2s. The cPLA2 was activated by TPA, and appeared to be
responsible for the majority of the specific release of AA observed in mouse
keratinocytes treated with TPA. The calcium ionophore A23187, and 4alpha-TPA did
not elicit the selectivity towards AA observed with TPA. The release of linoleic
acid (LA) and oleic acid (OA) from A23187- and 4alpha-TPA-treated keratinocytes
suggests activation of sPLA2. These activities may be due to the existence of
both type I and type II sPLA2, as both were identified by polymerase chain
reactions. In conclusion, keratinocytes express several forms of phospholipase A2
that differ in their substrate specificities and mechanisms of activation,
resulting in distinct agonist-specific fatty acid release profiles.
PMID- 9548591
TI - Quantitation of cholesterol-carrying particles in human gallbladder bile.
AB - The inter-mixed micellar/vesicular (non-phospholipid-associated) bile salt
concentration (IMC) can be rapidly measured in model biles by centrifugal
ultrafiltration, thus allowing reliable separation of vesicular and micellar
cholesterol carriers by gel filtration with an elution buffer containing bile
salts at the correct IMC (Donovan, J. M., and A. A. Jackson. 1993. J. Lipid Res.
34: 1121-1129). We adapted this method to the more complex human gallbladder bile
and examined the relationship between cholesterol solubilization and
crystallization in gallbladder biles from 10 cholesterol gallstone patients. The
IMC (mean +/- SEM) was 9.67 +/- 1.97 (range 3.56-35.02) mM with significant
enrichment with hydrophilic bile salt species. Upon gel filtration of these biles
with an eluant buffer containing 10 major bile salts at concentrations according
to their IMC, cholesterol was found to be solubilized mainly in mixed micelles.
Vesicles were detected in all 10 biles after separation by KBr density gradient
ultracentrifugation but in only 5 of these biles with the IMC method. Biles
without vesicles had a lower CSI (1.15 +/- 0.12 vs. 1.90 +/- 0.28, P < 0.05), a
higher total lipid concentration (11.9 +/- 2.3 vs. 5.9 +/- 1.1, P < 0.05), and a
higher bile salt/ (bile salt + phospholipid) ratio (0.83 +/- 0.01 vs. 0.74 +/-
0.04, P = 0.07). For both IMC and ultracentrifugation methods, vesicular
cholesterol concentration showed a negative correlation with crystal observation
time and a positive correlation with cumulative crystal score during 21 days. Our
data indicate that methods such as density gradient ultracentrifugation
overestimate vesicular cholesterol solubilization in human biles.
PMID- 9548590
TI - Docosahexaenoic and eicosapentaenoic acids are differently metabolized in rat
liver during mitochondria and peroxisome proliferation.
AB - The 3-thia fatty acids, tetradecylthioacetic acid and 3,10-dithiadicarboxylic
acid are mitochondrion and peroxisome proliferators. Administration of these
promotes an increased transport of endogenous fatty acids to these organelles and
a higher capacity of beta-oxidation. Administration of 3-thia fatty acids to rats
resulted in a significant decrease of the hepatic level of docosahexaenoic acid
(DHA) (17-24%) and especially eicosapentaenoic acid (EPA) (40-80%) accompanied by
increased gene expression of mitochondrial 2,4-dienoyl-CoA reductase and enoyl
CoA isomerase. The mitochondrial oxidation of EPA was increased more than 4-fold
after administration of 3-thia fatty acids. EPA-CoA was a good substrate for
mitochondrial carnitine acyltransferase-I and treatment with 3-thia fatty acids
increased the activity 1.7-fold. DHA was a poor substrate for both mitochondrial
and peroxisomal beta-oxidation. DHA-CoA was a very poor substrate for
mitochondrial carnitine acyltransferase-I and -II, and the activity did not
increase after treatment. However, the peroxisomal DHA-CoA oxidase increased 10
fold after 3-thia fatty acid treatment, whereas the peroxisomal EPA-CoA oxidase
increased only 5-fold. In isolated hepatocytes, 16% of total metabolized EPA was
oxidized and 76% was incorporated into glycerolipids, whereas DHA was oxidized
very little. We conclude that under conditions of increased mitochondrial and
peroxisomal proliferation by 3-thia fatty acids, a relatively higher oxidation
rate of polyunsaturated n-3 fatty acids might result in a decreased hepatic level
of EPA and DHA. Under these conditions DHA seems to be oxidized by the
peroxisomes, whereas EPA, which can be oxidized in both organelles, is mainly
oxidized by mitochondria.
PMID- 9548592
TI - Substrate specificity of retinyl ester hydrolase activity in retinal pigment
epithelium.
AB - In the eye, hydrolysis of stored retinyl esters is catalyzed by retinyl ester
hydrolase (REH) activities in retinal pigment epithelium (RPE) membranes. In the
present study, biochemical analyses were conducted to determine the substrate
specificity of these activities. Specific activities determined for hydrolysis of
various retinol isomers of retinyl palmitate (9-cis-, 11-cis-, 13-cis-, and all
trans-retinyl palmitates) indicated that 11-cis-retinyl palmitate is
preferentially hydrolyzed (1.7 nmol/min/mg) compared to the other isomers (0.1
0.3 nmol/min/mg). Examination of the specificity of REH activity for 11-cis
retinyl esters of varied acyl chain length (-myristate, -palmitate, and
stearate) and degree of saturation (-oleate and -linoleate) further demonstrated
that palmitate is the preferred fatty acyl moiety. Notably, retinyl esters
possessing chain lengths which more closely approximate that of the palmitate
ester exhibited higher rates of hydrolysis. Similar results were obtained in
retinyl ester-plasma membrane fusion studies in which hydrolysis took place
within the membrane domain rather than at the lipid-water interface. REH
substrate specificity was further assessed in competition studies in which 11-cis
retinyl palmitate hydrolysis was monitored in the presence of 13-cis-, 9-cis-, or
all-trans-retinyl palmitate. Results show that addition of these retinyl
palmitate isomers does not affect the rate of hydrolysis of 11-cis-retinyl
palmitate. However, the hydrolytic rates associated with other retinyl palmitate
isomers were significantly reduced in the presence of 11-cis-retinyl palmitate.
Finally, cholesterol ester hydrolase activity was found to be distinct from the
observed 11-cis-REH activity and the presence of cholesterol oleate did not
affect the rate of 11-cis-retinyl palmitate hydrolysis. Collectively, these data
support the hypothesis that a distinct, membrane-associated, 11-cis-retinyl
palmitate-specific retinyl ester hydrolase activity exists in the retinal pigment
epithelium.
PMID- 9548593
TI - Triglyceride-enrichment of high density lipoproteins enhances their remodelling
by phospholipid transfer protein.
AB - Phospholipid transfer protein (PLTP) converts high density lipoproteins (HDL) to
larger and smaller particles during incubation in vitro. The present study shows
that these conversions are enhanced in triglyceride (TG)-enriched HDL. When pig
HDL were enriched with TG by incubation with cholesteryl ester transfer protein
(CETP) and very low density lipoproteins, the TG/apoA-I molar ratio increased
from 0.7/1 to 11.4/1 and the diameter increased from 9.0 to 9.5 nm. When
unmodified pig HDL were incubated with PLTP, the diameter increased from 9.0 to
9.5 nm. Incubation of the TG-enriched pig HDL with PLTP generated larger (13.0
nm) and smaller (7.5 nm) particles. The composition of the large particles was
comparable to the non-incubated, TG-enriched HDL. The small particles contained
only phospholipids and apolipoprotein (apo) A-I. Studies were also carried out
with spherical, reconstituted HDL (rHDL) containing only cholesteryl esters in
their core. When the rHDL were enriched with TG by incubation with Intralipid and
CETP, the diameter increased from 9.0 to 9.2 nm and the TG/apoA-I molar ratio
became 5.7/1. When unmodified rHDL were incubated with PLTP, the diameter of 15%
of the particles increased to 11.0 nm, 18% decreased to 7.6 nm, and 67% were
unchanged. When the TG-enriched rHDL were incubated with PLTP, the diameter of
62% of the particles increased to 11.4 nm, 26% decreased to 7.6 nm, and 12% did
not change. Preincubation with Intralipid alone or CETP alone did not enrich the
rHDL with TG or enhance the size changes. These results show that the TG content
of HDL has a major influence on PLTP-mediated size changes.
PMID- 9548594
TI - Modification of a phospholipid stabilized emulsion interface by bile salt: effect
on pancreatic lipase activity.
AB - Lipase is activated by binding to an insoluble emulsified or aggregated
substrate. The extent of binding is related to the physicochemical as well as the
compositional structure of the interface, the quality of the interface. 'Quality'
is as yet undefined but thought to contain contributions from electrostatic
interactions, orientation of substrate, and hydration forces. To investigate the
electrostatic and compositional factors we have used olive oil-in-water emulsions
prepared with phosphatidylcholine and four bile salts of varying
hydrophobicities. By measurement of the droplet zeta potential we have monitored
semi-quantitatively the incorporation of bile salts within the interface. No
correlation was found between droplet surface charge as monitored by the zeta
potential and lag phase. The duration of the observed lag phase was found to be
inversely related to the degree of incorporation of the bile salts.
Simultaneously there was evidence of lipase binding to monomeric bile salts,
reducing its availability for adsorption. Calcium ions reduced the surface charge
but there was no correlation with lag phase duration. The evidence presented here
agrees with a more specific role for calcium ions, i.e., the formation of a new
catalytically active enzyme complex, (enzyme)-(mixed micelle)-(calcium ion).
PMID- 9548595
TI - Identification of the epitope of a monoclonal antibody that inhibits heparin
binding of lipoprotein lipase: new evidence for a carboxyl-terminal heparin
binding domain.
AB - A panel of 13 monoclonal antibodies to avian lipoprotein lipase (LPL) was
screened for inhibition of LPL binding to primary avian adipocytes. One
monoclonal antibody, designated xCAL (monoclonal antibody to chicken adipose
lipoprotein lipase) 3-6a, was found to inhibit the binding of LPL to primary
avian adipocytes. In solid phase assays, xCAL 3-6a inhibited the binding of LPL
to both heparan sulfate and heparin. XCAL 3-6a did not inhibit the catalytic
activity of the avian enzyme. The monoclonal antibody was not found to cross
react significantly with bovine lipoprotein lipase. In order to determine the
location of the epitope of xCAL 3-6a on lipoprotein lipase, several avian
lipoprotein lipase deletion mutants were constructed and produced as glutathione
S-transferase (GST) fusion proteins in E. coli. These mutants were screened for
their ability to react with xCAL 3-6a using Western blotting. The minimum
continuous fragment of lipoprotein lipase that was required for reactivity
contained the amino acids 310 to 450. Site-directed mutagenesis of basic residues
321, 405, 407, 409, 415, and 416 revealed that Arg 405 is necessary for the
interaction of LPL with xCAL 3-6a. Additional deletions of either the amino- or
carboxyl-terminal portion of the fragment containing residues 310-450 resulted in
loss of antibody binding, suggesting that the epitope is a discontinuous one that
is formed when the termini are brought together through protein folding. Heparin
Sepharose chromatography of wild-type LPL and a mutant LPL in which the well
characterized heparin-binding sequence (Arg 281-Lys 282-Arg 284) has been mutated
was carried out in the presence and absence of xCAL 3-6a. These experiments
indicate that lipoprotein lipase contains a heparin-binding domain, in addition
to Arg 281-Arg 284, that can be blocked by xCAL 3-6a.
PMID- 9548596
TI - 7-Dehydrocholesterol down-regulates cholesterol biosynthesis in cultured Smith
Lemli-Opitz syndrome skin fibroblasts.
AB - The Smith-Lemli-Opitz syndrome (SLOS) is a common birth defect-mental retardation
syndrome caused by a defect in the enzyme that reduces 7-dehydrocholesterol to
cholesterol. Because of this block, patients' plasma cholesterol levels are
generally low while 7-dehydrocholesterol concentrations are markedly elevated. In
addition, plasma total sterols are abnormally low and correlate negatively with
the percent of 7-dehydrocholesterol (r = -0.65, P < 0.0001) suggesting that 7
dehydrocholesterol might inhibit the activity of HMG-CoA reductase. Cultured skin
fibroblasts from SLOS patients grown in fetal bovine serum or for 1 day in
delipidated medium contain little 7-dehydrocholesterol (3 +/- 1% of total
sterols) and HMG-CoA reductase activities are indistinguishable from that
measured in control cells. However, raising the 7-dehydrocholesterol
concentration to 20 +/- 3% of total sterols, equal to the mean proportion in
plasma of SLOS patients, by either growing cells for 1 week in delipidated medium
or adding 20 microg/ml 7-dehydrocholesterol directly to the cells reduced HMG-CoA
reductase activities from 74 +/- 7 to 9 +/- 2 pmol/min per mg protein, or from 92
+/- 22 to 16 +/- 4 pmol/min per mg protein, respectively (P < 0.01). In contrast,
adding 20 microg/ml cholesterol evoked a 2- to 4-fold lesser suppression of
activity (39 +/- 8 pmol/min per mg protein, P < 0.05, vs. 7-dehydrocholesterol).
HMG-CoA synthase and LDL binding were inhibited equally by 7-dehydrocholesterol
and cholesterol. Ketaconazole prevented the down-regulation of HMG-CoA reductase
by 7-dehydrocholesterol, suggesting that an hydroxylated derivative of 7
dehydrocholesterol may be especially important in suppressing cholesterol
synthesis. These results demonstrate that 7-dehydrocholesterol, perhaps as an
hydroxylated derivative(s), is a very effective feedback inhibitor of HMG-CoA
reductase.
PMID- 9548597
TI - Apolipoprotein E2 (Arg136 --> Cys) mutation in the receptor binding domain of
apoE is not associated with dominant type III hyperlipoproteinemia.
AB - Using apoE phenotyping by immunoblotting and apoE genotyping we identified four
heterozygous carriers of a rare apolipoprotein (apo) E2 variant, apoE2 (Arg136 -
> Cys). ApoE2 (Arg136 --> Cys) was not distinct from apoE2 (Arg158 --> Cys) by
phenotyping, but produced a unique pattern of bands on CfoI restriction typing of
a 244 bp apoE gene fragment. Two of the four apoE2 (Arg136 --> Cys)/3
heterozygotes had elevated triglycerides, two were normolipidemic. The
composition of very low density lipoproteins (VLDL) was normal in each of the
four apoE2 (Arg136 --> Cys) carriers, regardless of the triglyceride
concentrations. None of the apoE2 (Arg136 --> Cys) carriers displayed a broad
beta-band and none revealed beta-migrating particles in the VLDL. The two
hypertriglyceridemic carriers of apoE2 (Arg136 --> Cys) were, therefore,
classified as having type IV rather than type III hyperlipoproteinemia. LDL
receptor binding activities were studied using recombinant apoE loaded to
dimyristoylphosphatidylcholine (DMPC) vesicles and to VLDL and from an apoE
deficient individual. LDL receptor binding of apoE2 (Arg136 --> Cys) was 14% of
apoE3 and was thus higher than that of apoE2 (Arg158 --> Cys). Both apoE2 (Arg136
--> Cys) and apoE2 (Arg158 --> Cys) displayed substantial heparin binding (61 and
53% of apoE3, respectively). As the dominant apoE variants known so far are
characterized by more pronounced reductions of heparin binding, we suggest that
apoE2 (Arg136 --> Cys) is not associated with dominant expression of type III
hyperlipoproteinemia. These findings lend support to the concept that apoE
variants predisposing to dominant type III hyperlipoproteinemia differ from
recessive mutations by a more severe defect in heparin binding.
PMID- 9548598
TI - Prebeta-1 HDL in plasma of normolipidemic individuals: influences of plasma
lipoproteins, age, and gender.
AB - Prebeta-1 HDL is a molecular species of plasma HDL of approximately 67 kDa mass
that contains apolipoprotein A-I, phospholipids, and unesterified cholesterol. It
participates in a cyclic process involved in the retrieval of cholesterol from
peripheral tissues. In this cycle, unesterified cholesterol from cells is
incorporated into prebeta-1 HDL, providing a substrate for esterification of
cholesterol by lecithin:cholesterol acyltransferase. Prebeta-1 HDL then becomes
incorporated into larger HDL species of alpha mobility as esterification proceeds
and is regenerated during the transfer of cholesteryl esters from alpha HDL
particles to acceptor lipoproteins. Thus the steady state level of prebeta-1 HDL
in plasma reflects the relative efficiencies of the major metabolic processes
involved in its generation and removal. We have used an isotope dilution
technique to measure prebeta-1 HDL levels in the plasmas of 136 normolipidemic
individuals (46 M, 90 F). The mean absolute concentration of prebeta-1 HDL as
apolipoprotein A-I was 68 +/- 40 microg/ml for women, and 84 +/- 49 m/ml for men.
Prebeta-1 HDL represented 5.5 +/- 3.3% of total apolipoprotein A-I in women, and
7.2 +/- 4.0% in men. The distributions of both absolute and percent prebeta-1 HDL
are highly asymmetric, with skew toward higher values. However, the skew appears
not to be attributable to either plasma cholesterol or triglyceride levels which
are also skewed in population samples. The percent prebeta-1 HDL was negatively
correlated with HDL cholesterol levels (P < 0.0001), whereas absolute levels of
prebeta-1 HDL were positively correlated with apolipoprotein A-I and negatively
correlated with HDL cholesterol (P, for both, < 0.0001). Multiple linear
regression analysis revealed effects of age and gender, but no association with
lipoprotein fractions other than HDL. Lower levels of prebeta-1 HDL were
associated with female gender in all models.
PMID- 9548599
TI - An efficient chromatographic system for lipoprotein fractionation using whole
plasma.
AB - We have validated a semi-automatic procedure for the efficient isolation of
plasma lipoproteins from 300 microl of whole plasma (actual injection volume 200
microl) by Fast Phase Liquid Chromatography (FPLC). Modified enzymatic assays
were established to allow the determination of low concentrations (1-20 mg/dl) of
triglycerides and cholesterol using the Beckman CX-5 Autoanalyzer. The sum of the
cholesterol contents in the fractions corresponding to low density (LDL) and high
density lipoprotein (HDL) can be demonstrated to be highly correlated to values
obtained with dextran sulfate/MgCl2 precipitation for HDLc (slope = 0.98, r2 =
0.997) and ultracentrifugation (beta-quant) for LDLc (slope = 1.03, r2 = 0.988).
Using pure lipoprotein fractions isolated by ultracentrifugation, linear ranges
of detection for HDLc and HDL apoA-I were performed at 18-95 mg/dl and 59-262
mg/dl, respectively. The ranges for LDLc were 41-435 mg/dl and 21-280 mg/dl for
LDL apoB. The mean (range) fractional standard deviations for quadruplicate runs
for 15 individual plasma samples ranging widely in lipoprotein concentrations
were 0.97 (0.29-2.86%) for LDLc (range: 101.5-258.5 mg/dl), 3.67 (0.62-14.11%)
for HDLc (range: 27.1-85.1 mg/dl) and 2.19 (0.16-6.56%) for VLDL-TG (range: 6.1
515.0 mg/dl).
PMID- 9548600
TI - A 13CO2 breath test to assess the metabolism of triglyceride-rich lipoprotein
remnants in mice.
AB - Remnant-like emulsions were prepared with lipid compositions similar to remnants
derived from triacylglycerol-rich lipoproteins. When injected into the
bloodstream of conscious mice the remnant-like emulsions labeled with
cholesteryl[13C]oleate were metabolized in the liver and the appearance of 13CO2
in the breath was measured. In control mice injected with remnant-like emulsions
labeled with cholesteryl[13C]oleate, enrichment of 13CO2 in the breath peaked at
45 min and then decreased markedly by 3 h. In apoE-deficient (-/-) mice no
enrichment was found and in low density lipoprotein receptor (LDLr)-deficient (-/
) mice the appearance of 13CO2 in the breath was markedly decreased. These
findings were consistent with the ability of the breath test to detect defects in
remnant metabolism. The breath test was useful in detecting a defect in remnant
metabolism in LDLr heterozygote (+/-) mice, in which the appearance of 13CO2 in
the breath was less by 45 min but remained elevated for the duration of the
experiment when compared with control mice. In hepatic lipase-deficient (-/-)
mice no defect in remnant metabolism was found. Under fasting conditions, the
enrichment of 13CO2 in the breath after injection of emulsion was markedly
increased when compared with fed mice, indicating that the metabolism of the
injected remnant-like emulsion was probably competed for by post-prandial
particles under fed conditions. Our findings show that a 13C breath test can be
used to assess the metabolism of remnants. The test provides a useful and
sensitive method for non-invasive testing of remnant metabolism in experimental
animals.
PMID- 9548601
TI - In vitro concentration response studies and in vitro phase II tests as the
experimental basis for regional chemotherapeutic protocols.
AB - The theoretical pharmacologic benefit of regional vs. systemic chemotherapy is
defined and the concentration response behavior of cytostatic drugs and their
optimal exposure times are described with human cancer cell lines (HT29,
NMG64/84) and fresh human tumor cell suspensions in the human tumor colony assay
(HTCA). The theoretical pharmacological advantages are 5.8 to 6 for adriamycin
(ADM), 8 for cisplatinum (CDDP), 6.3 for epidoxorubicin (EPI), 22 to 58 for 5
fluorouracil (5FU), 4.6 for mitomycin C (MMC), and 6.3 for mitoxantrone (NOV).
The drugs differed in their cytotoxic potency in vitro and thus also potential
efficacy for regional chemotherapy; however, all but 5-fluorodeoxyuridine (5FUDR)
exerted cytotoxicity dependent on exposure time and concentration. On average,
elevation of the test concentrations by 1 lg doubled responses in fresh human
tumor cell suspensions. From these results and clinical considerations, optimal
times were defined for the regional chemotherapy strategies of hepatic artery
infusion, intraperitoneal instillation, and chemoembolisation as performed at our
institution.
PMID- 9548602
TI - Isolated limb perfusion in primary and recurrent melanoma: indications and
results.
AB - In advanced melanoma of the limbs with in-transit metastasis, melphalan with
isolated limb perfusion (M-ILP) produces around 50% complete remissions (CR). The
combination of melphalan with tumour necrosis factor-alpha (TNFalpha) and
interferon-gamma (IFNgamma) in isolated limb perfusion (TIM-ILP) gives around 80%
CR. A prospective randomised phase II study compared 32 patients who received TIM
ILP with 32 patients who received TM-ILP (without IFNgamma). The overall
remission rate (ORR) and the CR rate were superior with TIM-ILP as compared to TM
ILP, 100% vs. 91% and 78% vs. 69% respectively, but the differences are not
significant. Given the efficacy of M-ILP on in-transit metastasis, the procedure
was tested as an adjunct to surgery in high-risk (Breslow > or = 1.5 mm) primary
melanoma of the limbs. Through the combined effort of the melanoma groups of the
European Organization for Research and Treatment of Cancer (EORTC), the World
Health Organization (WHO), and the North American Perfusion Group, 832 evaluable
patients from 16 centres were entered in a phase III study. Median followup is
6.4 years. There was a trend for a longer disease-free interval after M-ILP. The
difference is significant if the patients without elective lymph node dissection
(ELND) are separately analysed, with a high significance in the 1.5 to 3 mm
thickness subgroup. The occurrence of in-transit metastases was reduced from 6.6%
to 3.3% by M-ILP. There was, however, no benefit of M-ILP in terms of survival.
Prophylactic M-ILP cannot be recommended as a standard adjunct to surgery in high
risk primary limb melanoma. TIM-ILP or TM-ILP is a regional therapy with a very
high regional response rate on melanoma in-transit metastasis.
PMID- 9548603
TI - Hyperthermic isolated limb perfusion for the treatment of soft tissue sarcomas.
AB - Hyperthermic isolated limb perfusion (HILP) with various chemotherapeutic agents
has been used for the local treatment of high-grade soft tissue sarcomas (STS) of
the extremities, but in most cases, with a disappointing result. Most such
regimens certainly should not be considered superior to surgery plus
radiotherapy. Although the majority of extremity STS can be resected locally,
some are very large and are in close proximity to bone, nerve or blood vessels.
In these cases, amputation is the only means of resecting the tumour. A new
combination of drugs used in the set-up of HILP with tumour necrosis factor-alpha
and melphalan has emerged as a very promising option for the limb-saving
management of locally advanced STS. In recent studies, complete response rates of
approximately 30% and partial remission rates of 50% have been achieved, while
the overall limb-salvage rate is more than 80%.
PMID- 9548605
TI - Toxicity and morbidity of isolated limb perfusion.
AB - Because a relationship between toxicity and treatment outcome has never been
demonstrated for isolated limb perfusion (ILP) with melphalan, it is important to
keep the side-effects of the procedure restricted to a minimum. Risk factors for
more severe acute regional toxicity have recently been identified with tissue
temperature above 40 degrees C and a high melphalan peak concentration being the
most important. Acute regional toxicity should be mild taking into account these
factors and maintaining the normal physiological conditions in the limb during
ILP. This should also decrease the incidence of long-term morbidity, especially
ankle stiffness and muscle atrophy, since a relation between the severity of the
acute regional tissue reactions and long-term morbidity has been demonstrated.
Lymphedema is strongly linked to a concomitant regional lymph node dissection and
this operation may be delayed until the acute regional tissue reactions have
faded. It is not yet clear whether the addition of tumor necrosis factor-alpha
(TNF-alpha) to melphalan increases regional toxicity. In the absence of melphalan
leakage to the systemic circulation, systemic toxicity is minimal; this is also
true with TNF-alpha. Compared to ILP with melphalan +/- TNF-alpha, ILP with other
drugs is less effective and often is associated with increased regional toxicity.
PMID- 9548604
TI - The application of hyperthermia in regional chemotherapy.
AB - To evaluate the role of hyperthermia combined with chemotherapy in the loco
regional treatment of tumors, a retrospective analysis was done with 228 limb
melanoma patients treated with hyperthermic antiblastic perfusion (HAP). A series
of treatment- and tumor-related prognostic factors was analyzed to establish
their influence on tumor response, loco-regional control, and survival.
Concerning tumor response, the logistic model showed that the number of lesions
and the minimal tumor temperature (min T) maintained their individual predictive
values (P < 0.000001 and P = 0.04, respectively). For loco-regional control, only
the number of lesions had a significant predictive value. No direct correlation
was found between the treatment-related variables and loco-regional control.
However, the 5-year survival rate was significantly higher for patients who
achieved a complete response (CR) (51.5%, P = 0.0033) as compared to those who
did not (33.3%), providing indirect evidence of the role of the treatment.
Multivariate analysis showed that both disease-free and overall survival are
strongly influenced by numerous clinical variables and the min T always
maintained its significance. When analyzing the subgroup of 119 patients
evaluable for tumor response, the Cox model selected the tumor response as the
dominant factor for both disease-free and overall survival. These data seem to
demonstrate that the optimization of treatment parameters is crucial in
determining the CR rate, which, in turn, positively affects the disease outcome.
HAP is the treatment of choice for recurrent limb melanoma, and hyperthermia
plays an important role in exploiting the efficacy of this technique.
PMID- 9548606
TI - Tumor necrosis factor-alpha in isolated perfusion systems in the treatment of
cancer: the Rotterdam preclinical-clinical program.
AB - The clinical success of the application of tumor necrosis factor-alpha (TNFalpha)
in isolated limb perfusions in patients with advanced sarcomas, melanomas and
other tumors has renewed the interest in this agent as an anticancer drug. At the
Rotterdam Cancer Center, we have developed an interactive preclinical-clinical
TNFalpha program that explores new methods to use TNFalpha in various settings.
Regional organ perfusion models were developed and the effectivity of targeting
of TNFalpha to the tumor by means of systemic administration of liposomes are
tested. Furthermore various drugs and mechanisms that may enhance the activity of
TNFalpha are under investigation. A summary of this comprehensive program is
presented here.
PMID- 9548607
TI - Isolated limb infusion with cytotoxic agents: a simple alternative to isolated
limb perfusion.
AB - Isolated limb perfusion (ILP) with cytotoxic agents is an effective but complex
procedure. Isolated limb infusion (ILI) has been developed as a simpler
alternative. Catheters are inserted percutaneously into the axial artery and vein
of the affected limb and a pneumatic tourniquet is inflated proximally. Cytotoxic
agents are then infused through the arterial catheter and circulated with a
syringe for 15 to 20 minutes. Progressive hypoxia occurs, but normothermia is
maintained. To date, 175 ILIs have been performed: 164 for melanoma and 11 for
other tumours. Results obtained are similar to those obtained by conventional
ILP. Morbidity is low and treatment of frail and elderly patients who would not
tolerate ILP is possible. An elective double ILI protocol can be used to obtain
the additional benefits of fractionated chemotherapy. The possibility of
increasing ILI response rates by using other drugs and drug combinations and by
multiple fractionated dosing is being investigated.
PMID- 9548608
TI - Intra-arterial infusion: overview and novel approaches.
AB - Intra-arterial infusion includes a variety of treatment modalities, adjusted
selectively to chemosensitivity and vascularization. For most drugs, response
behaviour of different tumors is concentration dependent and requires improved
modes of application of cytotoxics. In the treatment of liver metastases from
colorectal cancer and hepatocellular carcinoma, blood flow reduction by micro
embolization with starch microspheres has brought significant advantage in
response. Balloon stopflow infusion combined with micro-embolization induced 83%
complete remissions in a study including 100 patients with locally recurrent
breast cancer. Stepwise increased local exposure demonstrated concentration
dependent response. Stopflow infusion of the celiac axis combined with
microspheres for advanced Stage III and IV pancreatic cancer induced a 96%
remission rate (n = 24 patients) at a median survival of 10 months. This was
confirmed in a series of consecutive studies including 242 patients. Quality of
life was significantly improved in all responding patients. Overall pain response
was 80%. A prospective randomized trial in this patient group, comparing systemic
vs. regional chemotherapy in the form of intra-arterial infusion with tumor
adjusted concentrations, was stopped in an early phase because median survival
time was significantly prolonged (P = 0.001) in the arterial group.
PMID- 9548609
TI - Intraperitoneal chemotherapy and cytoreductive surgery for the prevention and
treatment of peritoneal carcinomatosis and sarcomatosis.
AB - Intraperitoneal chemotherapy and cytoreductive surgery have been combined to
reach treatment objectives in patients with peritoneal carcinomatosis or
sarcomatosis that neither modality by itself can achieve. These treatments must
be combined with the proper selection of patients in order to observe "high
value" results from therapy. There are three principles of management to support
treatments for peritoneal carcinomatosis and sarcomatosis. First, the clinician
must select patients who have isolated disease distributed on the surfaces of
abdominal and pelvic structures. Patients treated for peritoneal implants who
have persistent disease at other sites will profit little or not at all. Second,
this disease must be reduced to its lowest possible mass by peritonectomy
procedures and resections of viscera. Third, maximal intraperitoneal and systemic
chemotherapy are utilized to eradicate the disease on peritoneal surfaces as well
as control the primary or recurrent tumor. These principles of management and a
presentation of the results achieved to date are reviewed.
PMID- 9548611
TI - The Internet--friend or foe to scientific journals?
PMID- 9548610
TI - Delivery of anticancer drugs via isolated hepatic perfusion: a promising strategy
in the treatment of irresectable liver metastases?
AB - The prognosis of patients with irresectable liver metastases derived from
colorectal cancer is invariably poor; unfortunately, these tumours show only
minor responses to conventional anticancer agents. The best responses have been
obtained by fluoropyrimidines delivered as continuous infusion into the hepatic
artery (HAI): their rapid uptake and detoxification by liver cells results in
relatively low systemic drugs levels. This approach increases mean survival
duration from 17 to 26 months and, in few patients, causes "down-staging" that
may result in resectability. To improve opportunities for chemotherapy, the
technique of 1-hour recirculating perfusion of the vascularly isolated liver
(isolated hepatic perfusion, IHP) was developed. If leakage to the systemic
circulation is negligible-and the compounds used do not readily cause
hepatotoxicity-IHP allows usage of drug doses that would be fatal if delivered
systemically. Because alkylating agents generally have steep dose-response
curves, mitomycin C (MMC) and melphalan (L-PAM) entered phase I/II studies on
IHP. Using these drugs, IHP was performed in principle as a single procedure in
60 otherwise untreated patients at our institution. However, despite preliminary
data that indicate impressive clinical responses are obtained, improvement over
HAI will probably be minor. Because IHP is a complicated way of drug delivery,
one could argue that its use is justified only when it has the potential to kill
all tumour cells in the liver. We critically discuss the possibilities of IHP
and/or the use of gene therapy in an IHP setting.
PMID- 9548612
TI - The introduction of H2-receptor antagonists to Scandinavia: effects of experts'
opinions.
PMID- 9548613
TI - Lansoprazole, amoxicillin, and clarithromycin triple therapy in vagotomized
patients with dyspeptic complaints. A randomized, double-blind, placebo
controlled, clinical study without pretreatment diagnostic upper endoscopy.
AB - BACKGROUND: The Maastricht Consensus Report advises that, in Helicobacter pylori
positive patients after surgery for peptic ulcer disease, H. pylori should be
eradicated. The aim of the present study was to investigate the symptomatic
response of H. pylori eradication in previously vagotomized peptic ulcer patients
with persistent dyspeptic complaints. METHODS: The study was performed as a
randomized, double-blind, placebo-controlled study. Pretreatment diagnostic upper
endoscopy was omitted. All the results were submitted to intention-to-treat and
efficacy analyses. RESULTS: We could not find any differences between the two
groups with regard to intensity or frequency of upper abdominal pain, nausea,
heartburn, or other abdominal symptoms during the 12-month follow-up. The triple
therapy eradication rate was 88% at both 3- and 12-month controls. CONCLUSION:
Vagotomized peptic ulcer patients with persistent dyspeptic complaints should
undergo a diagnostic upper endoscopy to detect ulcer recurrence before H. pylori
eradication treatment is considered.
PMID- 9548614
TI - Gastric meal accommodation studied by ultrasound in diabetes. Relation to vagal
tone.
AB - BACKGROUND: Disturbed gastric meal accommodation may cause abdominal symptoms in
patients with functional dyspepsia and diabetes mellitus who have poor vagal
control of gastric motility. In the present study we aimed to explore the
relation between gastric meal accommodation and vagal tone in diabetic patients
with vagal neuropathy. METHODS: Twenty patients with diabetes (DM) (insulin
dependent type; 10 men and 10 women, aged 35.3 +/- 7.6 years) and 20 healthy
controls (HC) (10 men and 10 women; aged 34.7 +/- 10.7 years) were studied.
Proximal gastric size was assessed with ultrasound in a sagittal area and a
frontal diameter. Distal gastric (antrum) size was assessed in a sagittal area.
Vagal tone was assessed non-invasively by recording of respiratory sinus
arrhythmia (RSA) in beats per minute. RESULTS: Proximal sagittal area was
significantly (P = 0.03) smaller in DM (18.5 +/- 5.5 cm2) than in HC (22.2 +/-
4.6 cm2). Proximal frontal diameter did not differ significantly (P = 0.60)
between DM and HC (5.9 +/- 1.1 cm versus 5.7 +/- 0.8 cm). Antral area, too, did
not differ significantly (P = 0.59) between DM and HC (14.5 +/- 4.1 cm2 versus
13.6 +/- 5.8 cm2). Proximal/distal meal distribution ratio, defined as proximal
sagittal area/distal sagittal area, was significantly (P = 0.05) smaller in DM
(6.8 +/- 0.6) than in HC (9.9 +/- 5.5). Vagal tone was significantly (P = 0.03)
lower in DM (4.5 +/- 1.9 beats/min) than in HC (6.3 +/- 2.7 beats/min). Vagal
tone tended (r = 0.33, P = 0.06) to correlate with proximal sagittal area in DM
and HC pooled. Vagal tone correlated (r = 0.34, P = 0.05) with proximal frontal
diameter in DM and HC pooled. A significant negative correlation (r = -0.39, P =
0.03) was observed between vagal tone and antral area in DM and HC pooled.
CONCLUSIONS: Patients with diabetes and low vagal tone have an impaired
postprandial gastric meal distribution characterized by a small proximal stomach
and a small proximal/distal meal distribution ratio.
PMID- 9548615
TI - The ability of enteric diarrhoeal pathogens to ferment starch to short-chain
fatty acids in vitro.
AB - BACKGROUND: Short-chain fatty acids (SCFA), produced in the normal colon by
bacterial fermentation, are decreased in acute diarrhoea. This may have
deleterious effects on epithelial function in the colon. METHODS: The ability of
several diarrhoeal pathogens to produce SCFA when incubated with starch in vitro
was studied. Isolated pathogens were incubated for 24 h with either no added
substrate, glucose, or starch under anaerobic conditions, and SCFA were
quantitated by gas-liquid chromatography. RESULTS: Unlike the normal colonic
flora, the pathogens produced acetate but not propionate or butyrate. D-Lactate
was also produced by all the pathogens studied. When the pathogens were incubated
in anaerobic medium containing starch, significantly greater amounts of acetate
and significantly lesser amounts of lactate were produced. CONCLUSIONS: The
inability of enteric pathogens to produce butyrate may impair epithelial cell
function, whereas production of D-lactate may enhance mucosal damage in
diarrhoeal disease. The presence of luminal starch may be helpful in shifting the
fermentation profile to a more favourable pattern.
PMID- 9548616
TI - Depressive symptoms in adult coeliac disease.
AB - BACKGROUND: Psychic symptoms and depression have been reported in coeliac disease
(CD). The aim of this study was to explore depression in a large cohort of adult
CD patients. METHODS: Depressive symptoms were evaluated in 92 adult coeliacs,
100 normal controls (NC), and 48 chronic persistent hepatitis (CPH) patients by
means of a modified version of the Zung Self-Rating Depression Scale (M-SDS). CD
patients were evaluated for the level of knowledge about CD and the compliance
with diet. RESULTS: The M-SDS score differentiated CD patients from NC. Age at
diagnosis and duration of and compliance with diet did not correlate with
depression. Three main factors could be identified with the M-SDS:
'reactiveness', 'pessimism', and 'anhedonic-asthenic'. CONCLUSION: Depressive
symptoms are a feature of CD; they are present to a similar extent in patients
with childhood- and adulthood-diagnosed CD. The results underline the relevance
of personal psychologic resources, which play a fundamental role in determining
and sustaining depression.
PMID- 9548617
TI - IgA- and IgG-class antihuman umbilical cord antibody tests in adult coeliac
disease.
AB - BACKGROUND: An antiendomysium antibody test using human umbilical cord as antigen
has recently been introduced. METHODS: We determined IgA- and IgG-class antihuman
umbilical cord (HUC-ab), antireticulin (ARA), and antigliadin antibodies (AGA) in
92 untreated adult coeliac patients, in 95 non-coeliac subjects, and in 4 coeliac
patients with selective IgA deficiency. Tissue antibodies were measured with an
indirect immunofluorescence method and AGA with an enzyme-linked immunosorbent
assay. RESULTS: Of adult coeliac patients 85% were positive for IgA-class HUC-ab,
78% were positive for ARA, and 80% for AGA; the specificity for HUC-ab and ARA
was 100%, and for AGA 86%. Combination of HUC-ab, ARA, and high-titre AGA
increased the sensitivity to 96% without loss of specificity. IgG-class HUC-ab
was positive in 12% of coeliac patients, in all four coeliac patients with IgA
deficiency, and in none of the controls. CONCLUSIONS: The HUC-ab test is highly
specific but not 100% sensitive for detecting adult coeliac disease. A
combination of the IgA-class HUC-ab, ARA, and high-titre AGA tests is
recommended. In selective IgA deficiency the IgG-class HUC-ab test seems to work
well.
PMID- 9548618
TI - Fecal alpha-1-antitrypsin excretion in children with diarrhea.
AB - BACKGROUND: The aim of this study was to compare the concentration and
immunoelectrophoretic characterization of alpha-1-antitrypsin (AAT) excreted in
random fecal samples in children with acute and chronic diarrhea and in control
groups. METHODS: Thirty-two children with diarrhea and 23 healthy children were
evaluated. The concentration and characterization of AAT were determined by
radial immunodiffusion and crossed immunoelectrophoresis, respectively. RESULTS:
The increase in the concentration of fecal AAT was more than the upper limit for
the control group (1.25 mg/g of dry stool mass) in the patients with chronic
infectious diarrhea and in 52% of those with chronic non-infectious diarrhea but
not in those with acute diarrhea, infectious or non-infectious.
Immunoelectrophoretic analysis showed two forms of fecal AAT in both sick and
healthy children. The alterations in the concentration of fecal AAT did not
correlate with the immunoelectrophoretic pattern of AAT. CONCLUSION: Our results
suggest that the determination of fecal AAT could give clinically useful
information about the difference between infectious and non-infectious diarrhea
and the activity of characterizing disease with diarrhea.
PMID- 9548619
TI - Time trends for peptic ulcer disease in Denmark, 1981-1993. Analysis of
hospitalization register and mortality data.
AB - BACKGROUND: Since the mid-1980s there has been great improvement in the available
diagnostic tools and treatments for peptic ulcers. The aim of this study was to
determine whether these improvements have been paralleled by decreasing age- and
sex-specific hospitalization and death rates for peptic ulcers in Denmark.
METHODS: The study was based on all discharges from Danish somatic hospitals as
registered in the National Hospital Discharge Registry and all the death
certificates as registered in the Danish National Board of Health from 1981
through 1993, when a diagnosis of peptic ulcer was recorded. The age- and sex
specific and age-adjusted hospitalization and death rates were estimated.
RESULTS: In men the age-adjusted hospitalization rate for all types of peptic
ulcers decreased by 0.88, but the mortality increased by 1.19. In women the age
adjusted hospitalization and mortality increased for all types of peptic ulcers.
The increasing mortality was mainly due to bleeding and perforated duodenal
ulcers. The analysis of the age-specific hospitalization and mortality for peptic
ulcer complications showed that the increasing trends mainly occurred among the
elderly. CONCLUSION: The improved medical treatment of peptic ulcers has not been
paralleled by decreasing hospitalization or death from complicated peptic ulcers
in Denmark. On the contrary, we found an increasing hospitalization and mortality
from peptic ulcer complications, particularly in elderly Danish people.
PMID- 9548620
TI - The influence of Helicobacter pylori eradication on the gastric mucosal content
of epidermal growth factor, transforming growth factor-alpha, and their common
receptor.
AB - BACKGROUND: The relationship between the expression of epidermal growth factor
(EGF) and transforming growth factor-alpha (TGF-alpha) and that of their receptor
(EGF-R) in the Helicobacter pylori-infected gastric mucosa has not been
completely elucidated. The aim of this study was to examine the interplay between
H. pylori colonization and gastric mucosal growth factor content. METHODS: By
means of a solid-phase enzyme-linked immunosorbent assay EGF, TGF-alpha, and EGF
R levels and interleukin-1beta (IL-1beta) content, which is considered a marker
of chronic inflammation, were evaluated in the antral mucosa of 24 H. pylori
positive patients before and 8 weeks after eradication therapy. RESULTS: After
therapy H. pylori was eradicated in 19 patients. The eradication was accompanied
by a significant decrease in IL-1beta content and an increase in EGF and TGF
alpha levels. On the other hand, in the five patients in whom the bacterium was
not eradicated EGF, TGF-alpha, and EGF-R levels were quite similar to those
assayed before therapy, whereas IL-1beta content was still high. CONCLUSIONS:
These results suggest that H. pylori exerts an inhibitory effect on the mucosal
expression of EGF and TGF-alpha, which are likely involved in the gastric mucosa
repair process.
PMID- 9548621
TI - Antigastric autoantibodies and gastric secretory function in Helicobacter pylori
infected patients with duodenal ulcer and non-ulcer dyspepsia.
AB - BACKGROUND: Autoantibodies against epitopes located at the canaliculi of human
parietal cells occur in about 30% of Helicobacter pylori-infected patients. This
has led to the hypothesis that gastric secretory function could be inhibited by
anticanalicular autoantibodies in H. pylori gastritis. METHODS: Forty-four H.
pylori-infected patients with and without duodenal ulcers were screened for
anticanalicular autoantibodies by means of immunohistochemistry. Plasma gastrin
levels and basal and maximal gastric acid output were determined. RESULTS:
Fasting gastrin levels were significantly increased in the group with
anticanalicular autoantibodies. In the group of patients with non-ulcer dyspepsia
the presence of anticanalicular autoantibodies was significantly correlated with
an impaired basal acid secretion. CONCLUSIONS: Antigastric autoimmunity in H.
pylori gastritis seems to be relevant for gastric hyposecretion either directly
by inhibiting the proton pump or indirectly through the development of gastric
mucosa atrophy.
PMID- 9548622
TI - Evaluation and validation of a Crohn's disease inflammatory activity index
reflecting pattern of endoscopic severity.
AB - BACKGROUND: This study was designed to investigate objective variables assessing
the inflammatory activity of Crohn's disease accessible for routine management
and their suitability to act as surrogate indicators for endoscopic alterations.
METHODS: Thirty-six patients were included in a prospective study and underwent
endoscopic investigation, 18 with clinically exacerbated disease and 18 after
acute-phase conservative therapy. The endoscopic findings were classified to
define the dependent variable, yielding two categoric levels: acute active
disease and remission. The extent of affected mucosal area was not taken into
consideration. The serum variables alpha1-antitrypsin, acid alpha1-glycoprotein
(AGP), C-reactive protein (CRP), sialic acids, prealbumin (PAB), and albumin were
used as independent variables to predict the dependent variable. To compare the
results with common indices, the Crohn's Disease Activity Index (CDAI) and van
Hees Index were calculated. RESULTS: The following model was calculated by
stepwise logistic regression analysis: if AGP (mg/dl) -4.2 x PAB (mg/dl) > or
=0.8, then endoscopically active disease will be predicted with a sensitivity of
100% and a specificity of 95% (P < 0.001). The predictive values of the single
variables, CDAI, and van Hees Index were lower. For validation of results an
analogous study was performed including 44 patients, 29 with active disease and
15 controls. The existence of the model was confirmed, again showing high values
for sensitivity (86%) and specificity (100%). CONCLUSIONS: On a qualitative level
focusing on clinical relevance, the endoscopic and biologic findings of Crohn's
disease are highly associated. In addition to clinical assessment, usage of the
developed index as a rationale contributing to therapeutic decisions in the short
and long-term management might be reasonable.
PMID- 9548623
TI - Chronic inflammatory changes in the pouch mucosa are associated with cholangitis
found on peroperative liver biopsy specimens at restorative proctocolectomy for
ulcerative colitis.
AB - BACKGROUND: The clinical syndrome of primary sclerosing cholangitis (PSC),
diagnosed in about 5% of patients with ulcerative colitis (UC), has been shown to
be associated with pouchitis after ileal pouch-anal anastomosis. The aim of this
study was to ascertain whether UC patients with cholangitis on liver biopsy at
proctocolectomy, with or without the clinical syndrome of PSC, have an increased
risk of inflammatory changes in the ileal reservoir mucosa and clinical
pouchitis. METHODS: Of the consecutive 81 UC patients treated with restorative
proctocolectomy with ileal J reservoir at Tampere University Hospital between
1985 and 1991, 73 with peroperative liver biopsy were included. A peroperative
liver biopsy was obtained during proctocolectomy. After a median follow up of 64
months, pouch biopsy specimens were obtained. Periods of clinical pouchitis were
diagnosed by means of clinical criteria alone or by clinical criteria combined
with the results of previous pouch endoscopies in all patients. RESULTS: Ten
patients (14%) showed histologic features consistent with small-duct PSC on liver
biopsy. Endoscopic retrograde cholangiography had previously been performed on
four of these patients, and all four had large-duct PSC. Patients with
cholangitis had significantly more severe chronic, but not acute, inflammation in
the pouch mucosa than patients without cholangitis. At least one episode of
pouchitis occurred in 30% of the patients without cholangitis as compared with
90% of the patients with cholangitis. Chronic pouchitis was more frequent in the
group with cholangitis than in the group without it (70% versus 11%).
CONCLUSIONS: The only means of detecting all UC patients with cholangitis is a
liver biopsy. Cholangitis, either with the clinical syndrome of PSC or found on
liver biopsy, seems to be a risk factor for chronic-type inflammatory changes in
the pouch mucosa and for the development of pouchitis.
PMID- 9548625
TI - Expression of CD44 and variant proteins in human colorectal cancer and its
relevance for prognosis.
AB - BACKGROUND: CD44 is a cell adhesion molecule often expressed in the form of
various splice variants. The role of standard CD44 isoform (CD44s) and its
variants in colorectal carcinogenesis is partly conflicting. Therefore, we
compared the expression of CD44s (hermes-3) and its splice variants (v3 and v6)
with traditional prognostic factors in 194 colorectal cancer patients treated at
Kuopio University Hospital and followed up for a mean of 14 years. METHODS:
Formalin-fixed, paraffin-embedded tissue sections from 194 patients with
colorectal carcinoma were examined immunohistochemically to detect the expression
of different forms of CD44. The hypothesis that CD44s, CD44v3, and CD44v6
expression intensities and distribution in cancer cells correlated with survival
was tested with the log-rank test, hazard ratios, and their confidence intervals.
RESULTS: In high-grade tumours CD44s and CD44v6 expression intensities and CD44s
percentages were stronger than in low-grade tumours. CD44v6, CD44v3, and CD44s
expression intensities in tumour epithelium were also stronger in Dukes C and D
tumours than in A and B tumours. In the univariate survival analysis patients
with strong CD44s, CD44v3, and CD44v6 expression intensities in tumour epithelium
had lower cancer-related survival than the patients who had weak CD44s, CD44v3,
and CD44v6 expression intensities. Recurrence-free survival was also shorter in
patients with intense signals for CD44v3 and CD44v6 in tumour epithelium. In the
multivariate analysis the CD44v6 expression intensity in tumour epithelium
predicted independently both cancer-related and recurrence-free survival in T1
4N0-3M0 and T1-3N0M0 cases. In addition, the CD44v3 expression intensity in
tumour epithelium was a significant predictor of RFS in T1-3N0M0 cases.
CONCLUSIONS: These results strongly suggest that the CD44 splice variants v6 and
v3 have prognostic significance in colorectal cancer.
PMID- 9548624
TI - Gastric cancer and premalignant lesions in atrophic gastritis: a controlled trial
on the effect of supplementation with alpha-tocopherol and beta-carotene. The
Helsinki Gastritis Study Group.
AB - BACKGROUND: Vitamin E and beta-carotene are considered to decrease the risk of
gastric cancer both in humans and in laboratory animals. We studied the effect of
dietary supplementation with alpha-tocopherol and beta-carotene on the end-of
trial prevalence of premalignant and malignant lesions of the stomach in older
men with atrophic gastritis. METHODS: The study was carried out within the Alpha
Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC study) in Finland, in
which 29,133 male smokers aged 50-69 years were randomly assigned to receive
daily 50 mg alpha-tocopherol, 20 mg beta-carotene, both of these agents, or
placebo, for 5-8 years. Serum pepsinogen was determined at base line and after 3
years' supplementation to find men with atrophic gastritis. A low serum
pepsinogen I level, indicating atrophic gastritis of the corpus area of the
stomach, was found in 2132 men. These men were invited to have upper
gastrointestinal endoscopy (gastroscopy), which was performed on 1344 subjects
after a median supplementation time of 5.1 years. RESULTS: Neoplastic alterations
were found in 63 of the men (4.7%): 42 with definite dysplasias of low grade
(moderate dysplasia), 7 with definite dysplasias of high grade (severe
dysplasia), 11 with carcinomas (of which 7 were 'early' cancers), and 3 with
carcinoid tumors. Neither alpha-tocopherol (relative risk, 0.98; 95% confidence
interval, 0.57-1.69) nor beta-carotene (relative risk, 1.13; 95% confidence
interval, 0.65-1.95) supplementation had any association with end-of-trial
prevalence of gastric neoplasias after adjustment for other possible risk
factors. The effect was not modified by base-line serum level or dietary intake
of vitamins, prevalence of Helicobacter pylori infection, or other covariates.
CONCLUSIONS: We thus conclude that supplementation with alpha-tocopherol or beta
carotene for 5 years has no major impact on the occurrence of neoplastic changes
of the stomach in older male smokers with atrophic gastritis.
PMID- 9548626
TI - Benzodiazepine-like compounds in the plasma of patients with fulminant hepatic
failure.
AB - BACKGROUND: Benzodiazepine-like compounds have been implicated in the
pathogenesis of encephalopathy after fulminant hepatic failure. METHODS: The
levels and the nature of benzodiazepine-like compounds were determined in six
cases of fulminant hepatic failure during the course of the disease. Blood
samples were collected on admission and a few days later, when the neurologic
status had improved in five cases and immediately before death in one case. The
compounds were measured in sera with a binding technique after high-performance
liquid chromatography purification and analyzed with mass spectrometry. RESULTS:
Their levels were highly variable in those with severe encephalopathy and were
still increased on awakening in some cases. Diazepam and N-desmethyldiazepam were
inconsistently present. CONCLUSIONS: The inconsistent presence of benzodiazepine
like compounds in encephalopathy after fulminant hepatic failure and their
persistence, in some cases, at high levels on awakening from coma seem to
indicate that the encephalopathy is not strictly dependent on the levels of these
compounds.
PMID- 9548627
TI - Time course-dependent evolution of nitric oxide-mediated arterial hyporeactivity
to phenylephrine in rats with ligated bile duct.
AB - BACKGROUND: Nitric oxide (NO) may be heavily involved the phenomenon of arterial
vasodilation in cirrhosis. However, the subject is still controversial. AIM: This
study therefore characterizes the dynamic role of the NO system during
development of experimental cirrhosis. METHODS: The contractile response to
phenylephrine of thoracic rat aortic rings was studied in vitro before and after
nitric oxide blockade. Experiments were performed 1, 2, 3, and 4 weeks after
induction of cirrhosis via bile duct ligation with an appropriate control group.
RESULTS: In bile duct-ligated rats reduction of the maximum contractile response
to phenylephrine was 4.4 +/- 7.3% after 1 week, 22.7 +/- 8.7% after 2 weeks, 48.4
+/- 8.3% after 3 weeks, and 64.6 +/- 8.9% after 4 weeks, in comparison with the
control group. This reduction in contractility to phenylephrine was completely
reversed by blocking NO synthesis. CONCLUSION: The data presented indicate a
dynamic decrease in contractile response to phenylephrine even at an early stage
of secondary cirrhosis. Reversibility of the effect after NO synthesis blockade
suggests that increased NO synthesis is a major factor in vascular hyporeactivity
to vasoconstrictors in cirrhosis.
PMID- 9548628
TI - Increased plasma, biliary, and hepatic cholesterol precursors in pigs with ileal
autotransplantation-induced malabsorption of cholesterol and bile acids.
AB - BACKGROUND: Small-bowel transplantation impairs intestinal absorptive function
for unknown reasons. METHODS: The proportions of plasma, biliary, and hepatic
cholesterol precursors to cholesterol were determined by gas-liquid
chromatography after resection of the proximal 75% of the porcine jejunoileum (n
= 15) and autotransplantation of the remaining ileum (n = 15) and were related to
in vivo absorption and fecal excretion of cholesterol. RESULTS: Ileal
autotransplantation significantly decreased serum (18%; P < 0.05) and liver
(7.6%; P < 0.05) cholesterol content, the esterification percentage of serum
cholesterol (5.1%; P < 0.0001), and the total amount of cholesterol absorbed
(48%; P < 0.05) and increased fecal excretion of bile acids (108%; P < 0.0001),
net cholesterol elimination (53%; P < 0.001), and the proportions of plasma
(207%; P < 0.0001), biliary (183%; P < 0.0001), and hepatic (114%; P < 0.0001)
cholesterol precursors. The increases were most striking for the side-chain
saturated demethylated sterols, cholesterol and lathosterol, and monomethyl
sterols, whose bile/liver and plasma/liver ratios were increased in the
autotransplantation group. Plasma, biliary, and hepatic precursor proportions
were positively related to each other and similarly correlated with fecal bile
acids and the net elimination of cholesterol in feces. CONCLUSIONS: These
findings suggest that ileal autotransplantation in pigs with proximal gut
resection increased the levels of cholesterol precursor sterols in plasma, bile,
and liver mainly due to a bile-acid-malabsorption-induced increase in hepatic
synthesis of cholesterol. Enhanced secretion of cholesterol precursors from the
liver into the plasma and bile may have contributed to their increased values
during the increased rate of cholesterogenesis.
PMID- 9548629
TI - Comparative clinical evaluation of the 13C-mixed triglyceride breath test as an
indirect pancreatic function test.
AB - BACKGROUND: Breath tests using stable isotopes of carbon or hydrogen are
increasingly becoming established for the evaluation of various gastrointestinal
functions, including measurement of exocrine pancreatic insufficiency. We wanted
to evaluate the clinical relevance of the non-invasive, non-radioactive 13C-mixed
triglyceride breath test in comparison with the secretin-caerulein test as the
'gold standard' of pancreatic function testing and with faecal chymotrypsin and
elastase 1 in patients with mild and severe exocrine pancreatic insufficiency.
METHODS: The secretin-caerulein test, faecal fat analysis, 13C-mixed triglyceride
breath test, faecal elastase 1, and chymotrypsin and various morphologic
investigations were done in 26 patients with mild (n = 13) or severe (n = 13)
exocrine pancreatic insufficiency and 25 patients with gastrointestinal diseases
of non-pancreatic origin. Twenty-seven healthy volunteers served as normal
controls. After a 12-h fast 200 mg mixed triglyceride (1,3-distearyl,2(carboxyl
13C)octanoyl glycerol) were orally administered with a test meal, and breath
samples were taken before and at 30-min intervals for 5 h thereafter, and the
increase in 13C/12C isotopic ratio in breath was analysed by mass spectrometry.
Various modifications of the test procedure were investigated. RESULTS:
Specificity for impaired pancreatic function was higher for faecal elastase (90%)
and equal for faecal chymotrypsin (82%) as compared with the various variables of
the 13C-mixed triglyceride breath test (69-85%). The sensitivity of the 13C-mixed
triglyceride breath test for total and separately for mild and severe exocrine
pancreatic insufficiency was higher (total, 69-81%) than that of faecal
chymotrypsin (total, 56%) but lower than faecal elastase (total, 92%).
CONCLUSION: The 13C-mixed triglyceride breath test very sensitively reflects
severe exocrine pancreatic insufficiency (steatorrhoea) but has limited
sensitivity for the detection of mild cases. With regard to the higher
sensitivity and specificity, the higher practicability, and the much lower cost,
determination of faecal elastase 1 concentrations is superior to the 13C-mixed
triglyceride breath test and therefore remains the most reliable indirect
pancreatic function test available today.
PMID- 9548630
TI - Retention in an aftercare program for recovering women.
AB - Examining the correlates of aftercare participation is critical to program
development and successful relapse prevention. This study assesses retention in
an aftercare program of case management and peer support for formerly homeless
recovering mothers. Length of residential drug treatment, length of sobriety,
strong support networks, and concerns about housing and parenting predicted
completion of the case management component. Emotional instability and the
severity of problems were found to be correlated with participation in the peer
support group. Sociodemographic characteristics were not related to program
retention. The findings illustrate the need to tailor aftercare services to the
level of clients' recovery and the need for female-only aftercare groups where
women can safely discuss physical and sexual abuse issues related to their misuse
of drugs.
PMID- 9548631
TI - Computer-based smoking cessation interventions in adolescents: description,
feasibility, and six-month follow-up findings.
AB - The impact of adolescent smoking cessation clinics has been disappointing due to
low participation rates, high attrition, and low quit rates. This paper describes
two computerized self-help adolescent smoking cessation intervention programs: 1)
a program utilizing the expert system which is based on the transtheoretical
model of change and 2) a popular action-oriented smoking cessation clinic program
for teens which was modified for computer presentation. High participation rates
in the program among 132 smokers demonstrate the high feasibility and
acceptability of the programs. Quit rates of up to 20% were observed during the
intervention, and an additional 30% made unsuccessful quit attempt(s). The 6
month follow-up findings indicated that adolescents were poorly prepared to
maintain abstinence.
PMID- 9548632
TI - The role of intergenerational discrepancy of cultural orientation in drug use
among Latina adolescents.
AB - The role of intergenerational discrepancy for cultural orientation was examined
in the etiology of drug use among Latina adolescents and in the context of family
support. Intergenerational discrepancy occurs when a family member of one
generation differs from a family member of another generation in cultural
identity factors; this is usually manifested in conflict between a first
generation child and the immigrant generation parent. It was hypothesized that
the Latina adolescents experiencing intergenerational discrepancy might use drugs
more frequently than Latina adolescents who were not; and that family support
would be an important moderator of the relationship. A sample of 295 ninth and
tenth grade Latina students (approximately 80% Mexican-American) from four Los
Angeles area schools were surveyed as part of a larger study. In this secondary
analysis, a 2 (family support ) x 2 (discrepancy) ANOVA revealed that
intergenerational discrepancy was associated with more drug use in certain cases,
and that family support did not moderate this relationship. Results partially
validate and extend a theoretical model presented by Szapocznik and Kurtines
(1980), and indicate a need to focus on cultural variables when intervening in
drug use/misuse among Latina adolescents.
PMID- 9548633
TI - Primary socialization theory: the etiology of drug use and deviance. I.
AB - The fundamental theorem of primary socialization theory is that normative and
deviant behaviors are learned social behaviors, products of the interaction of
social, psychological, and cultural characteristics, and that norms for social
behaviors, including drug use, are learned predominantly in the context of
interactions with the primary socialization sources. During adolescence, learning
of social behaviors is frequently dominated by interactions with peer clusters.
There are a number of additional postulates: 1) The strength of the bonds between
the youth and the primary socialization sources is a major factor in determining
how effectively norms are transmitted. 2) Any socialization link can transmit
deviant norms, but healthy family and school systems are more likely to transmit
prosocial norms. 3) Peer clusters can transmit either prosocial or deviant norms,
but the major source of deviant norms is usually peer clusters. 4) Weak
family/child and/ or school/child bonds increase the chances that the youth will
bond with a deviant peer cluster and will engage in deviant behaviors. 5) Weak
peer bonds can also ultimately increase the changes of bonding with deviant
peers. Primary socialization theory is consistent with current research, has
strong implications for improving prevention and treatment, and suggests specific
hypotheses for further research.
PMID- 9548634
TI - Effectiveness of a drug-free detention treatment program in a Dutch prison.
AB - Several Dutch penitentiaries, which have relatively severe drug-use related
problems, experimented with drug-free detention treatment programs (DVA). These
programs aim at controlling drug use by offering a therapeutic atmosphere and
serve as linkage to detention posttreatment. In a Rotterdam jail (335 cells), ca.
10% were the DVA. Information was gathered from 86 male inmates who volunteered
to enter the program, and 42 from other wings. After 1 year the drug-free
detention group more actively searched and accepted treatment. No differences
were found in drug use, recidivism, or physical, social, and psychological
problems.
PMID- 9548635
TI - Classification of developmental delays.
AB - Developmental delay is frequently used to identify children with delay in meeting
developmental milestones in one or more streams of development. There is no
consensus on the specific definition. Developmental delay is best viewed
generically as a chief complaint rather than a diagnosis. A child suspected to
have delays should always be assessed in each of the major streams of
development: expressive and receptive language, including social communication;
visual problem solving (nonverbal cognition); motor development; neurobehavioral
development; and social-emotional development. A model developed by the National
Center for Medical Rehabilitation Research is used to compare existing
classifications of developmental delays. This model defines the five domains in
the disability process: pathophysiology, impairment, functional limitation,
disability, and societal limitation. An etiology domain is added. This model is
used to illustrate how existing classification systems of cerebral palsy, mental
retardation, autism, and language delay draw on information from one or more
domains. The model illustrates some of the conflicts between different systems.
For example, most classification systems for cerebral palsy emphasize only
impairment (spasticity, dyskinesias, and topography). The current definition and
classification system for mental retardation focuses on functional limitations
(IQ), disability, and societal limitations, ignoring pathophysiology and details
of impairment. Given the complexity of neurodevelopmental disabilities, it is
unlikely that a single classification system will fit all needs.
PMID- 9548636
TI - The etiology of developmental delay.
AB - Developmental delay includes mental retardation (IQ less than 70) and borderline
intellectual functioning (IQ 71 to 84). The overall frequency is between 1% and
2% of the child population with most cases in the mild range (IQ 50 to 70).
Severe mental retardation is mostly due to genetic or acquired biological causes.
Mild retardation is more commonly of acquired causes, and in borderline
intellectual functioning, sociocultural factors play a role in addition to
biological factors. The main prenatal causes include chromosomal and
nonchromosomal genetic conditions, metabolic disorders, and adverse events during
gestation, whereas environmental factors (eg, alcohol) more commonly cause mild
retardation.
PMID- 9548637
TI - The evaluation of the child with a global developmental delay.
AB - The child with a global developmental delay presents a diagnostic challenge to
the practitioner. The spectrum of possible etiologic diagnosis and laboratory
investigations that could be pursued are quite extensive. This article presents
the rationale for diagnostic testing in this population and provides guidelines
to those tests that should be pursued.
PMID- 9548638
TI - Screening tests and standardized assessments used to identify and characterize
developmental delays.
AB - The appropriate choice, application, and interpretation of functional assessments
of children with problems of development are often challenging issues for
clinicians. The purposes of this communication are to share with clinicians an
understanding of the structure and properties of functional assessment measures;
to offer an orientation to the application of such measures to help evaluate a
child's developmental status; and to suggest issues that are important to
consider in the interpretation of the findings, and how these might be shared
with parents. Numerous references are cited for readers who wish to read more
about measures in general and about specific clinical assessment tools that are
most useful in applied child development.
PMID- 9548639
TI - Radiological findings in developmental delay.
AB - This article reviews the neuroimaging findings in patients with nonsyndromic
mental retardation and global developmental delays. The frequency and type of
abnormal neuroimaging findings in this patient population are discussed.
Specifically addressed are the issues of which patients should have neuroimaging
studies in light of (in the vernacular) "cost-benefit" analysis. The extension of
these studies to "milder" developmental delays, and other neurodevelopmental
disorders are also discussed.
PMID- 9548640
TI - Genetics and developmental delay.
AB - The discovery of new cytogenetic and molecular genetic techniques and principles
has been explosive in recent years. A secure diagnosis based on molecular
evidence has become possible for many syndromes previously only clinically
defined, which has helped enormously in predicting children's developmental
progress, in allowing knowledgeable surveillance for potential associated health
problems, in genetic counseling, and in prenatal diagnosis. This article reviews
several of the most significant recently described cytogenetic and molecular
genetic principles and techniques in relation to the child who presents with
developmental delay.
PMID- 9548641
TI - Electroencephalogram in developmental delay: specific electroclinical syndromes.
AB - The electroencephalogram (EEG) plays an important role in the evaluation of a
child with developmental delay. An EEG is often required to classify seizures in
children with developmental delay. Equally important is the role of the EEG in
the identification of specific electroclinical syndromes in children who may or
may not manifest seizures. Specific electroclinical syndromes include the
acquired epileptiform aphasia syndrome, Landau-Kleffner syndrome, and electrical
status epilepticus during slow wave sleep. Other clinical situations where the
EEG offers diagnostic and prognostic information, such as subacute sclerosing
encephalitis, progressive myoclonus epilepsies, Rett syndrome, and Lennox Gastaut
syndrome are also discussed.
PMID- 9548642
TI - The vulnerable preschool child: the impact of biomedical and social risks on
neurodevelopmental function.
AB - The scope of preschool children with biological risk and social disadvantage is
large and includes over 1 million (28%) newborns per year. Currently in 1996, 7%
of children are born with low birth weight, 1% are born with very low birth
weight, 20% have alcohol exposure, and 10% have other drug exposure. Poverty is
dynamic and impacts on 25% of children less than 6 years old with increased
frequency in children who are minority, have mothers with less than a high school
education, or are unmarried. There has been a markedly increased survival in very
low birth weight and extremely low birth weight infants in the past 10 years.
Outcomes of these neonatal populations reveals that parenchymal brain injury is
the major predictor of cerebral palsy which occurs in 7% to 10% of very low birth
weight survivors. However, poverty is the major predictor of low IQ. Fetal
alcohol syndrome occurs in 1.9 per 1,000 births and is most often associated with
mild mental retardation and educational underachievement. Studies investigating
cocaine revealed that it is a multifactorial problem overlapping with
polysubstance abuse and other risk factors for social disadvantage. The
overwhelming number of children do not have cerebral palsy or severe mental
retardation. The long-term impact is more subtle and needs more systematic
analysis as well as critical evaluation of cognitive impairments and educational
under-achievement. Hypoxic ischemic encephalopathy (HIE) cannot be determined by
one biological measure. Though multiple disability occurs in 70% of children with
Sarnat stage 3 HIE, 30% of survivors are not disabled. Children with mild to
moderate HIE have long-term outcomes that are influenced by 9- to 12-month
neurodevelopmental status and social disadvantage. By combining strategies to
lessen biological risks and enhance developmentally appropriate environments,
long-term outcomes of preschool children can be optimized.
PMID- 9548643
TI - Benefits of early intervention for children with developmental disabilities.
AB - Early intervention programs are designed to enhance the developmental competence
of participants and to prevent or minimize developmental delays. Children
targeted for early intervention may either include environmentally or
biologically vulnerable children, or those with established developmental
deficits. There is growing consensus based on the best available evidence that
early interventions can exert moderate positive effects. However, this literature
is limited by substantial methodological weaknesses in most studies. Therefore
further randomized clinical trials are needed to ascertain which programs best
meet the needs of children with or at risk for developmental disability.
PMID- 9548644
TI - Clinical ethics and developmental delay.
AB - The vulnerability of the young child with a developmental delay raises specific
concerns regarding the provision of medical care to this population. Specific
areas of concern include the means and standards by which a valid consent for
intervention is obtained and exercised, as well as the issue of justice that
refers, in this context, to the distribution of what are increasingly perceived
as scarce medical and economic resources. Furthermore, future advances in
providing care to this population will need to be predicated on clinical research
that needs to be ethically sound. This article highlights basic ethical
principles and their application to these specific issues with respect to
children with developmental delay.
PMID- 9548645
TI - The water absorption response: a behavioral assay for physiological processes in
terrestrial amphibians.
AB - Terrestrial amphibians take up water by abducting the hind limbs and pressing a
specialized portion of the ventral skin to a moist surface, using a
characteristic behavior called the water absorption response. An assay of the
water absorption response was used to quantify physiological factors associated
with thirst and water uptake. Dramatic changes in the water absorption response
resulted from subtle changes in hydration state and from altering the reserve
water supply in the urinary bladder. The water absorption response could be
induced by intraperitoneal and intracerebroventricular injection of angiotensin
II, demonstrating that components of the renin-angiotensin system on both sides
of the blood-brain barrier have a dipsogenic function in amphibians. These
experiments also demonstrated that the water absorption response could be
influenced by changes in barometric pressure. Toads avoided the water absorption
response on hyperosmotic substrates, and behavioral experiments showed that the
amphibian skin served a sensory function similar to that of the lingual
epithelium of mammals. The water absorption response assay has enormous potential
as a tool for the investigation of physiological processes and sensory
capabilities of amphibians.
PMID- 9548646
TI - Plasma corticosterone and testosterone levels during the annual reproductive
cycle of male brown anoles (Anolis sagrei).
AB - The objective of the present study was to determine the plasma levels of
testosterone and corticosterone in male Anolis sagrei during the annual
reproductive cycle and to examine the relationships between seasonal change in
the levels of these hormones, male reproductive activity, and body condition.
Both testosterone and corticosterone levels in adult males captured in the Miami,
Florida, area varied significantly with month and with season (i.e., breeding vs.
nonbreeding period), although they were not significantly correlated with each
other or with body mass. Mean monthly testosterone levels were higher during the
breeding season (March-August) than during the nonbreeding season, with the one
exception that the highest mean testosterone level occurred in February
immediately before the beginning of the breeding season. Testosterone levels in
the overall sample of 144 males were significantly correlated with testes mass
but not with any of the other measured variables. Corticosterone levels were
highest during the nonbreeding season and lowest during the breeding season.
Corticosterone levels on a monthly basis were negatively correlated with monthly
changes in testes mass and positively correlated with monthly changes in
abdominal fat-body mass.
PMID- 9548647
TI - Daily energy budgets of avian embryos: the paradox of the plateau phase in egg
metabolic rate.
AB - The metabolic rate of precocial bird eggs reaches a plateau when about 80% of the
incubation period has passed. This is unexpected, as in many species the embryo
continues to grow and maintenance costs must therefore increase. To investigate
this paradox, daily energy budgets were constructed for embryos of four galliform
species according to two models that used empirical data on egg metabolic rate
and embryo growth. In the first model, embryonic synthesis costs were estimated,
with an assumed synthesis efficiency, before calculating the maintenance costs.
In the second model, embryonic maintenance was calculated first, and no
assumptions were made on the synthesis efficiency. The calculations show that
assumptions of the synthesis efficiency had a major impact on the energy budget
calculations, because embryonic growth rate was high. During the plateau phase, a
galliform embryo allocated energy in favor of its maintenance costs in three
ways: by decreasing growth rate, by increasing synthesis efficiency, and by
depressing the formation of glycogen. Our study suggests that a reduction in
growth rate plays a minor role. An increase of synthesis efficiency is more
likely to explain the plateau in energy expenditure, since small increases in
synthesis efficiency can lead to great savings on synthesis costs.
PMID- 9548648
TI - Echocardiographic and hemodynamic determinations of the ventricular filling
pattern in some teleost fishes.
AB - The current concept of ventricular filling in elasmobranch and teleost fishes is
that atrial contraction is the primary, if not the exclusive, determinant of
ventricular filling. Recent echocardiographic and on-line hemodynamic data for
elasmobranchs, however, have demonstrated a biphasic ventricular filling pattern,
characterized by an early phase that occurs during ventricular relaxation and a
late phase that follows atrial systole. This study reports echocardiographic and
hemodynamic analyses of ventricular filling in three teleost genera (Paralabrax,
Channa, Monopterus) having markedly different heart morphologies. Both the
profiles of the atrioventricular pressure gradient in Paralabrax and the
ventricular inflow velocity in all three genera indicate a biphasic ventricular
filling pattern. Although the relative contribution of the early and late filling
phases differed among the species studied, interspecific differences in heart
structure did not obscure the biphasic pattern. Also, pericardiectomy did not
affect the biphasic ventricular filling pattern in Paralabrax. The presence of
biphasic filling in teleosts establishes a functional similarity with the
elasmobranchs and, because the biphasic ventricular filling pattern predominates
in higher vertebrates, suggests that this ventricular filling mechanism may be
present in the entire subphylum Vertebrata.
PMID- 9548649
TI - Test of a digestion optimization model: effects of costs of feeding on digestive
parameters.
AB - We tested predictions of a chemical reactor model of digestion by manipulating
the short-term costs of feeding and then measuring the effect on digestive
parameters. We compared residence time of digesta and extraction efficiency of
glucose in cold-acclimated waxwings (Bombycilla cedrorum) feeding ad lib. and in
birds whose costs of feeding were increased through the addition of intervals of
time when they received no food. Such a feeding schedule simulated the ecological
situation in which a frugivorous bird like a waxwing encounters food in patches
and experiences nonfeeding periods as it searches for new preferred food patches.
None of the results were consistent with the predictions of the optimal digestion
model: extraction efficiency was independent of costs of feeding, and residence
times did not increase as costs of feeding increased. This empirical evidence on
the passage of digesta in waxwings suggests that movement of digesta in the guts
of birds is much more complex than movement of material in an ideal chemical
reactor. Tests of the optimal digestion model have involved manipulating food
quality or the costs of feeding, and the conclusions are similar: compensatory
modulation of retention time or digesta mixing and not rate of hydrolysis and
absorption seem most important in maintaining the remarkably constant digestive
efficiency.
PMID- 9548650
TI - Ionic regulation and nitrogenous excretion in rainbow trout exposed to buffered
and unbuffered freshwater of pH 10.5.
AB - Rainbow trout exposed to unbuffered water of pH 10.5 initially showed significant
increases in blood pH, plasma cortisol and glucose, partial pressure of NH3
(PNH3), NH4+, and HCO3- values as well as loss of plasma Cl-, reduced partial
pressure of CO2 (PCO2), and inhibition of total ammonia excretion rate. After the
first day, fish resisted further change, and new levels were established (for
blood pH and plasma PCO2 and PNH3 levels) or imbalances corrected, either
partially (for total ammonia excretion) or completely (for plasma Cl-, HCO3-,
cortisol, and glucose values). During the 7-d exposure, 80% of fish in unbuffered
water survived, but in buffered water (0.75 mmol L(-1) glycine-buffered KOH at pH
10.5), survival was only 50% after 3 d, and ion regulatory failure was evident.
Fish in buffered and unbuffered alkaline waters had similar total ammonia
excretion rates, which suggests that glycine-buffered KOH was not sufficient to
significantly reduce gill boundary layer acidification. After 7 d in unbuffered
alkaline water, 30% of total ammonia excretion was linked with an amiloride
sensitive (0.1 mmol L(-1)) Na+ uptake mechanism. Treatment of alkaline-exposed
trout with waterborne acetazolamide (1.5 mmol L(-1)) indicated that gill boundary
layer H+ production, through hydration of CO2, had a role in excretion of total
ammonia. Exposure to 4-acetamino-4'-isothiocyantostilbene-2,2'-disulphonic acid
(SITS; 0.1 mmol L(-1)) following 24-h exposure to unbuffered alkaline water
resulted in increased plasma HCO3- and lowered plasma Cl- concentrations,
indicating the role of branchial Cl-/HCO3- exchange in regaining Cl- lost and
eliminating the HCO3- accumulated during exposure to alkaline water.
PMID- 9548651
TI - The effect of body mass and temperature on the heart rate, stroke volume, and
cardiac output of larvae of the rainbow trout, Oncorhynchus mykiss.
AB - The goal of this experiment was to determine whether the type of tight supply-and
demand relationship between cardiac output and metabolic demand for O2 seen in
juvenile and adult fish applies during larval development. To this end, we looked
at how the heart rate, stroke volume, and cardiac output of rainbow trout
(Oncorhynchus mykiss) larvae varied in response to changes in tissue mass and
incubation temperature. Previous studies have shown that both factors have a
profound influence on metabolic rate. Heart rate and stroke volume were estimated
using videomicroscopic methods and used to calculate cardiac output at five or
six approximately evenly spaced intervals between hatch (approximately 15 mg wet
tissue mass) and 150 accumulated thermal units (degrees C d) posthatch
(approximately 50 mg tissue mass) at 5 degrees, 10 degrees, 12 degrees, and 15
degrees C. Cardiac output (range 0.2-20 microL min(-1)) increased significantly
in response to increases in both tissue mass and incubation temperature. The
increase in cardiac output with tissue mass reflected significant increases in
stroke volume as well as heart rate. Temperature only had a significant effect on
heart rate (i.e., stroke volume was unaffected). The rate of increase in cardiac
output as a result of tissue growth was significantly faster than the rate at
which O2 demand increased (the allometric mass exponent [+/-SE] for cardiac
output was 1.78 +/- 0.08; literature values for O2 uptake average approximately
1.0), which suggests that the cardiovascular system was less important as a means
of delivering O2 to the tissues in small larvae than it was in larger larvae and
in juvenile and adult fish. Direct diffusion appeared to be the primary means of
O2 delivery in small larvae and embryos.
PMID- 9548652
TI - Comparative development in captive and migratory populations of the barnacle
goose.
AB - The development of the locomotory muscles and associated skeletal structures of
goslings and adults from a captive population of barnacle geese (Branta
leucopsis) was compared with that from a wild migratory population. There was no
significant difference between flight-muscle development of wild and captive
goslings up to 7 wk of age, when the birds are first able to fly. In contrast,
mass-specific citrate-synthase activity in the semimembranosus leg muscle of the
captive goslings was significantly lower than that of wild goslings by 5 wk of
age. During the postfledging premigratory period, captive geese showed
significantly higher values for both mass and mass-specific citrate-synthase
activity of the leg muscles than those of wild birds. Premigratory wild geese had
significantly higher citrate-synthase activity in the pectoralis muscles and
larger cardiac ventricular mass (by ca. 20%-25%) than both wild postmoulting and
captive premigratory adults. Total flight-muscle mass was only slightly reduced
(by ca. 10%) in long-term captive adults compared with wild premigratory adults.
Most of the differences between these two populations appear primarily to reflect
their relative levels of activity and/or differences in their ambient
environment, rather than any intrinsic differences in developmental or adult
physiology.
PMID- 9548653
TI - Blood volume and diving ability of the New Zealand sea lion, Phocarctos hookeri.
AB - We test the hypothesis that the New Zealand sea lion is physiologically better
equipped for prolonged, continuous diving than other otariids (fur seals and sea
lions) by measuring its blood volume, an important component of its oxygen
storage. Mass, hematocrit, and plasma volume were measured and blood volume
calculations were completed on 14 adult females and five juvenile females. Plasma
volume was determined using the Evans blue dye dilution technique. Mean plasma
volume for all subjects was 74 mL kg(-1). Mass-specific plasma volume was
significantly higher in adult females (15.3%) than in juveniles (14.6%). Blood
volume (150 mL kg(-1)) and hematocrit (51%) were not significantly different
between adults and juveniles. The aerobic dive limit can be estimated by dividing
the animal's oxygen stores by its metabolic rate. The estimated aerobic dive
limit for adult animals was between 5.5 and 7.8 min, depending on the assumed
metabolic rate. New Zealand sea lions have the highest blood volume yet reported
for an otariid, which supports the hypothesis that they have a physiological
capability suited to their unique diving behavior.
PMID- 9548654
TI - Regulation of water and sodium balance in the field by Australian honeyeaters
(Aves: Meliphagidae).
AB - We evaluated the use of water and sodium by free-living individuals of several
species of Australian honeyeaters (Acanthorhynchos superciliosus, Phylidonyris
novaehollandiae, Phylidonyris nigra, Manorina flavigula, and Anthochaera
carunculata). Water and Na fluxes were highly variable between species, largely
reflecting differences in diet. Water fluxes ranged from approximately 300% of
total body water per day in 10-g, nectarivorous A. superciliosus to approximately
45% of total body water per day, typical of a desert species, in M. flavigula, a
50-g, insectivorous, arid-zone bird. Similarly, Na fluxes ranged from nearly 60%
of Na pool per day in A. superciliosus to about 25% per day in M. flavigula.
Despite these different fluxes, values of regulated osmoregulatory variables,
including plasma osmolality, hematocrit, plasma concentrations of Na+ and K+, and
exchangeable Na pool, were relatively invariant both between species and within
species at different seasons. In contrast, values of variables reflecting the
operation of regulatory systems did differ between species and seasons. Urine
concentrations were highest in M. flavigula and, in A. carunculata, varied
seasonally (higher in summer than winter). Plasma concentrations of aldosterone
were lowest in A. carunculata (5-25 pg/mL), highest in P. novaehollandiae (70-200
pg/mL), and in the latter species were higher in winter than summer.
Concentrations of arginine vasotocin ranged from 5 pg/mL in A. carunculata to
greater than 30 pg/mL in M. flavigula. Our data demonstrate that within the
family Meliphagidae, there exists substantial variation in the fluxes of water
and Na and that these relate in part to body size variation but more importantly
to diet. The different fluxes between species are reflected in the values of
numerous osmoregulatory variables.
PMID- 9548655
TI - Dietary flexibility and intestinal plasticity in birds: a field and laboratory
study.
AB - The adaptive modulation hypothesis posits that the expression of digestive
proteins should be modulated in response to intake of their respective
substrates. A corollary of this hypothesis suggests that dietary flexibility and
digestive plasticity should be correlated. We examined these two hypotheses in
two granivorous Chilean birds (Zonotrichia capensis and Diuca diuca) that differ
in dietary breadth. D. diuca is a strict granivore, whereas Z. capensis also eats
insects. In field-caught birds, the activity of the intestinal dipeptidase
aminopeptidase-N was positively correlated with intake of insects in Z. capensis
but not in D. diuca. This is the first field documentation of modulation of
intestinal enzymes by diet in birds. Intestinal maltase and sucrase activities
were not correlated with seed (vs. insect) intake in either species. In the
laboratory, captive birds of both species exhibited similar modulation of
membrane-bound intestinal hydrolases when fed on synthetic diets of contrasting
carbohydrate and protein composition. Maltase, sucrase, and aminopeptidase-N
activities were significantly higher in birds fed on the carbohydrate-free than
those on the carbohydrate-containing diet. Activities of the three enzymes were
positively correlated. Therefore, this increase probably resulted from
nonspecific increases of all enzymes resulting from intake of the carbohydrate
free diet. Principal components analysis separating the effect of diet on
specific and on nonspecific modulation revealed that diet had a strong effect on
nonspecific activity of intestinal enzymes in both Z. capensis and D. diuca. Diet
also significantly affected aminopeptidase-N activities when the effect of diet
on nonspecific modulation was removed. Birds fed on the carbohydrate-free, high
protein diet had significantly higher specific aminopeptidase-N activities than
those fed on the carbohydrate-containing diet. Our results cast doubts on the
notion that dietary flexibility and the plasticity of the gut's enzymes are
necessarily correlated and on the general validity of the adaptive modulation
hypothesis.
PMID- 9548657
TI - Pancreatology in Japan: historical development--an overview.
PMID- 9548656
TI - Development of thermoregulation and posthatching growth in the altricial
cockatiel Nymphicus hollandicus.
AB - The development of thermoregulation and growth during the nestling period of
cockatiel Nymphicus hollandicus were examined in this study. It was hypothesised
that, in comparison to other altricial species of similar body mass, cockatiel
chicks develop endothermy earlier and consequently have less energy available for
growth, resulting in reduced growth rates. While poorly insulated and blind at
hatching, cockatiel developed endothermic responses in their first week, and were
individually effectively homeothermic (with 75% of adult ability to maintain body
temperature during exposure to 20 degrees-25 degrees C), by maintaining high
metabolic rates (at all ambient temperatures tested) above the predicted resting
rates of an adult of similar body mass before parental brooding ceased (12-13 d).
Mass-independent metabolic rates were equivalent to those of fledglings at only
20% of the nestling period (37 d), well before adequate insulation was obtained.
The Gompertz growth constants of cockatiel were significantly lower than those of
other altricial land birds, which supports the hypothesis of this study.
PMID- 9548658
TI - Pancreatic surgery in Japan: historical review.
AB - The advent of surgical techniques for the management of pancreatic cancer has had
a long and varied history in the Western culture. The development of current
surgical techniques and treatment modalities is based on (rooted in) techniques
developed over time. Although the first written anecdotes of pancreatic resection
-primarily from the 1600s through the late 1800s--did not alter the mortality of
pancreatic cancer, they did pave the way for advances in surgical techniques that
subsequently attained lower morbidity and mortality rates. Although there were
some meager attempts at pancreatic resection in Japanese institutions before and
during World War II, it was not until after the war, and particularly after the
mid-1950s, that pancreatic surgery developed tremendously. The development of
more radical approaches to pancreatic surgery developed tremendously. The
development of more radical approaches to pancreatic resection as well as other
surgical developments resulted in lower morbidity and mortality rates.
PMID- 9548659
TI - Pancreatic surgery: cutting-edge developments and technology.
AB - In the 1980s, Japanese pancreatic surgeons used aggressive strategies to treat
pancreatic cancer under the influence of Fortner's regional pancreatectomy and
developed several surgical approaches including extended lymph node and
connective tissue clearance with autonomic nerve dissection around the celiac and
superior mesenteric arteries. Nagakawa's "translateral retroperitoneal approach"
in extended radical pancreatectomy was accepted and used by many Japanese
surgeons; however, whereas this operation prolonged postoperative survival, it
also induced high rates of postoperative complications and ultimately failed to
improve the quality of the patient's life. A pylorus-preserving
pancreatoduodenectomy with modified extended dissection of the lymph node and
connective tissues did not decrease the survival rate for resected patients but
improved their quality of life. In the next decade, Takada developed duodenum
preserving total pancreatic head resection, which preserves the integrity of the
digestive and biliary tracts. This operation, to anastomose the main pancreatic
duct with the duodenum, is unique and is applicable to benign or low-grade
malignant lesions of the pancreas. Adjuvant treatments have not offered
satisfactory results as expected. Finally, it is recommended that the aggressive
Japanese surgical strategies be reevaluated in a formal trial with a prospective
randomized study to improve the quality and longevity of the patients' lives.
PMID- 9548660
TI - The epidemiology of pancreatic diseases in Japan.
AB - We reviewed the trends and death rates of pancreatic cancer and pancreatitis in
Japan over the past four decades. It is a disturbing fact that the death rate due
to pancreatic cancer is rising, parallel to that of lung cancer and colon cancer
and that it is affecting primarily the elderly 65 years and older in both sexes.
The cause of this increase is partially attributable to improvements in the
diagnosis, changes in life-style, and smoking. The death rate due to chronic and
acute pancreatitis has remained constant during the past four decades.
PMID- 9548661
TI - Japan Pancreatic Cancer Registry: current status.
AB - The Pancreatic Cancer Registration Committee of the Japan Pancreas Society
registered a total 17,130 patients with pancreatic cancer from 350 major
hospitals in Japan from 1981 through 1995. Diagnosis with ultrasonography and
computed tomography has become increasingly important as the methods used for
first detecting a pancreatic lesion. Tumor resection was performed in 36% of the
patients, and the 5-year survival rate of the patients who received resection was
18.2%. The rate of resection and results of surgical treatment have improved,
which may be attributed to the increase in detection of resectable tumor and
benefits of aggressive and extended surgery.
PMID- 9548662
TI - Criteria for diagnosis of acute pancreatitis in Japan and clinical implications.
AB - The Japanese grading system for severity of acute pancreatitis has evolved from
results of a national survey on 2,553 patients managed in 523 major medical
centers in Japan between 1982 and 1986. It was devised to embrace the predictive
factors that would offer high sensitivity and specificity in rendering an
accurate diagnosis. In this system, computed tomographic (CT) examination is used
for estimating the severity of acute pancreatitis. Combining criteria from
laboratory data, clinical signs, and CT findings, the system appears cumbersome.
However, it is actually more flexible in that only few criteria, from the wide
range of findings actually covered, are needed to predict severity. Its rationale
stems from a national effort to improve the outcome of this life-threatening
disease. Further prospective studies are needed to determine its accuracy and
superiority.
PMID- 9548663
TI - Criteria for pancreatic disease diagnosis in Japan: diagnostic criteria for
chronic pancreatitis.
AB - Chronic pancreatitis was not a clinical entity until around 1960 in Japanese
gastroenterology. The diagnosis of chronic pancreatitis had been vague and
difficult to ascertain. The diagnostic criteria for chronic pancreatitis were
first proposed in 1971, and they were subsequently revised in 1983. Patient
numbers of chronic pancreatitis were summed by national surveys under each of the
common diagnostic criteria. Total patient number and incidence rate of chronic
pancreatitis are recognized as increasing throughout Japan, based on results of
two national surveys of chronic pancreatitis. The diagnostic criteria for chronic
pancreatitis in Japan were again revised in 1995, because the 1983 criteria were
too complicated, and there had been more recent progress in clinical
investigations of the pancreas. The essential revised points of the Diagnostic
Criteria, 1995, are introduced in this review along with some discussion.
PMID- 9548664
TI - Stage classifications of pancreatic cancer: comparison of the Japanese and UICC
classifications and proposal for a new staging system. Union Internationale
Contre le Cancer.
AB - In the 4th edition of General Rules for the Study of Pancreatic Cancer by the
Japan Pancreas Society (JPS), published in 1993 (English version published in
1996), a system resembling the TNM classification by the Union Internationale
Contre le Cancer (UICC) was adopted, based on the results of precise analysis of
data from 11,317 cases of carcinoma of the pancreas registered by the JPS during
the 10-year period from 1981 to 1990. We compare the two TNM classifications and
staging groups, focusing on the simplicity and reproducibility of the diagnostic
criteria and the reliability of predicting outcome. To compare the prognostic
value of the two classification systems, we analyzed the published data on
resected cases registered by Pancreatic Cancer Registration Committee of the JPS.
The results showed that a major drawback of the JPS classification is that is
difficult to apply and has poor reproducibility. Survival rates differed
significantly among the four stages in the JPS classification, whereas the UICC
staging system did not reflect differences in outcome among the four stages,
especially between stages II and III. The prognostic value of the UICC T category
is better than that of the JPS T category, whereas the N category of JPS has
better prognostic value than that of the UICC system. Believing that a
combination of the two systems would solve this problem, we propose a new TNM
classification and stage-grouping system that draws on the merits of both. This
new system may provide improvements in staging classification that will lead to
the establishment of a more practical and universal staging system for ductal
carcinoma of the pancreas.
PMID- 9548665
TI - Exocrine pancreatic physiology: overview.
AB - Exocrine pancreatic physiology has been actively investigated in Japan during the
past 30 years. We selected three areas and reviewed them for this article. The
selected areas are perfusion of the isolated pancreas, cholecystokinin (CCK)
releasing factor from pancreatic juice (monitor peptide), and genetically
diabetic rats. The aim of this article is to present a brief overview of the
selected areas of exocrine pancreatic physiology in Japan so that future research
can be productively directed.
PMID- 9548666
TI - Ca2+ signaling in the pancreatic acinus.
AB - Change in cytosolic free calcium ion concentration [Ca2+]c, resulting from
receptor activation by an appropriate agonist, functions as a cardinal
intracellular signaling in the stimulus-secretion coupling in a wide variety of
secretory cells including the acini of the pancreas. Ratiometric imaging of
[Ca2+]c dynamics by UV-laser scanning confocal microscopy led us to conclude that
in the cholecystokinin (CCK)-8-induced recurrent [Ca2+]c, spiking increases
initially in the basolateral margin of the acinus and propagates to the luminal
margin. [Ca2+]c in this initial cell increased rapidly and uniformly to the
maximum level. The decrease in [Ca2+]c in the initial cell coincided with a small
increase in [Ca2+]c in the luminal regions of the bilateral neighboring cells
followed by uniform maximal increase in [Ca2+]c in these neighboring cells. A
series of [Ca2+]c dynamics was repeated to form recurrent Ca2+ spiking. The
temporal sequences of [Ca2+]c dynamics recorded during continuous stimulation
with CCK-8 at a physiologic concentration in individual acinar cells forming the
acinus were displayed on the identical time scale. The figure indicates that the
signaling is not synchronous in cells forming an acinus. From these and other
results, we proposed a model in which CCK-8 at a low physiologic concentration
binds to highly sensitive CCK receptor interacting with heterotrimeric guanosine
5'-triphosphate-binding proteins of the Gq class, generate Ins 1,4,5-P3, and
recurrent [Ca2+]c, spiking. The recurrent Ca2+ spiking maintains a sustained
secretory response, recurrent exocytosis of zymogen granules, and concomitant
secretion of isotonic NaCl.
PMID- 9548667
TI - Luminal feedback regulation, monitor peptide, CCK-releasing peptide, and CCK
receptors.
AB - We summarize the discovery of luminal feedback regulation of pancreatic secretion
in rats and its history. In rats, removal of proteolytic activity from the
intestine produced a significant increase in pancreatic protein (enzyme) output.
This increase was confirmed to be mediated by circulating cholecystokinin (CCK).
Subsequently, two CCK-releasing peptides, monitor peptide and luminal CCK
releasing factor (LCRF), were purified from the rat pancreatic juice and small
intestine, respectively, to elicit CCK release in luminal feedback regulation.
Furthermore, we emphasize the important physiologic roles of CCK and CCK
receptors by the discovery of disrupted CCK-A-receptor gene in rats. These
findings should help to determine the regulation of pancreatic secretion and CCK
functions in humans.
PMID- 9548668
TI - A new model for pancreatitis.
AB - Pancreatitis induced by ligation of the pancreatic duct produces morphologic
similarities to human pancreatitis. This model is easily performed in big
animals, but it is very difficult to perform pancreatic duct ligation in small
animals. Many experimental studies of pharmaceutical treatments for pancreatitis
used pancreatic duct-ligation models, but it is also difficult to evaluate the
efficacy of the drugs used, because the animals used are of different species
with individual differences. To overcome these problems, we ligated the main
pancreatic duct of the splenic lobe by a 5.0 absorbable suture by using a
surgical microscope and left the gastroduodenal lobe intact in the same rats.
This model produced damaged pancreatic tissue in one part and normal pancreatic
tissue in another part of the pancreas in the same animals, biochemically and
histologically. We evaluated the effect of a new protease inhibitor (ONO-3404) on
this preliminary model and found this new protease inhibitor demonstrated a
hypertrophic effect on the damaged pancreatic tissue and the normal pancreatic
tissue in the same animals. This model is also useful to study pharmaceutic
treatment for pancreatic insufficiency and to study chemically induced pancreatic
carcinogenesis in the damaged pancreatic tissue and the normal pancreatic tissue
in the same animals.
PMID- 9548669
TI - Pathophysiologic studies of experimental chronic pancreatitis in rats induced by
injection of zein-oleic acid-linoleic acid solution into the pancreatic duct.
AB - An experimental model of chronic pancreatitis was induced by a retrograde
injection of a viscous solution consisting of zein-oleic acid-linoleic acid (0.05
ml/100 g body weight) into the rat pancreatic duct. Histologic and biochemical
changes were investigated over a period of 6 months after induction of this
model. The treated rats gained weight, but pancreatic weight decreased with time.
Histologically, the widening of acinar lumen and cellular vacuolization occurred
within 24 h at the parenchyma neighboring the small ducts filled with the
injected solution. Degenerative parenchyma, interstitial edema, and inflammatory
cell infiltration were pronounced 1 week later. Thereafter, duct-like tubular
complex formation progressed, and the exocrine tissue exhibited marked atrophy of
the gland with irregular fibrosis and fat replacement over a period of 6 months.
Pancreatic contents of protein, amylase, DNA, and RNA markedly decreased, as did
pancreatic weight, whereas hydroxyproline content increased. Oral administration
of camostat did not affect pancreatic weight and contents of enzyme in this
model. Urinary para-aminobenzoic acid (PABA) excretion in the BT-PABA test
decreased to 54% at 6 weeks and 22% at 6 months. Although three quarters of
pancreatic immunoreactive insulin (IRI) content was lost after 6 months, overt
diabetes did not occur. The results suggest that an obstructive mechanism in the
small ducts plays an important role in the genesis and development of chronic
pancreatitis.
PMID- 9548670
TI - Mechanistic analysis of pancreatic ductal carcinogenesis in hamsters.
AB - In this article, we introduce our rapid-production model for pancreatic duct
adenocarcinomas and describe the mechanisms of pancreatic duct carcinogenesis so
far elucidated in Syrian golden hamsters. It is evident that a series of
histogenetic steps are involved, leading from hyperplasia through atypical
hyperplasia to intraductal carcinoma and invasive carcinoma. As DNA alters, K-ras
mutation appears to be an early event, whereas p53 mutations generally occur in
the tumor-progression phase. The induced cancer cells may show autocrine growth,
secreting TGF-alpha and vascular endothelial growth factor (VEGF), and are
immortalized with a shortened TRF length and increased telomerase activity. The
rapid-production model of pancreatic duct adenocarcinomas has not only provided a
major stimulus to understanding induction mechanisms but should also serve as a
bioassay to facilitate the identification of dietary risk factors and the search
for appropriate chemopreventive or chemotherapeutic agents or both to help
control this deadly disease.
PMID- 9548671
TI - Acute pancreatitis: overview of medical aspects.
AB - In this article we describe the current status of treatment of acute pancreatitis
in Japan and the guidelines established for the treatment of severe acute
pancreatitis. In 1987 the Research Committee for Intractable Diseases of the
Pancreas of the Ministry of Health and Welfare conducted a nationwide survey on
acute pancreatitis to determine the prevalence of the disease between 1982 and
1986 and the treatment modalities used. Based on a detailed assessment of the
results of the survey, the Committee developed criteria for rating the severity
of acute pancreatitis and guidelines for the treatment of acute pancreatitis,
which was revised in 1995. The five points cited as the principal aspects of
treatment of severe acute pancreatitis in Japan include (a) rating the severity
of the disease according to the severity rating criteria; (b) differentiating
between edematous and necrotic pancreatic lesions and performing dynamic CT of
the pancreas to define the extent of pancreatic necrosis; (c) performing
ultrasonography to determine whether there are gallstones; (d) in principle, not
performing surgery except in patients who clearly have early infection or
complications after the onset; and (e) providing conservative intensive care
immediately after the onset. In the absence of complications, the treatment of
acute pancreatitis in Japan is primarily medical. In contrast to other countries,
however, administration of antiprotease agents has become an important method of
treating acute pancreatitis in Japan. Special treatment modalities, such as
peritoneal lavage, blood purification, and continuous arterial infusion of
protease inhibitor, are being performed in severe acute pancreatitis, in addition
to intensive care.
PMID- 9548672
TI - Acute pancreatitis and cytokines: "second attack" by septic complication leads to
organ failure.
AB - Acute pancreatitis is accompanied by destruction and digestion of tissues,
causing hypercytokinemia and hyperreactivity of leukocytes (macrophages and
neutrophils) and vascular endothelial cells. As one of the biological defense
mechanisms in this condition, neutrophils infiltrate vital organs such as the
lung, liver, and digestive organs. When acute pancreatitis is complicated by
infection, hyperreactive macrophages release a large amount of proinflammatory
cytokines that activate primed neutrophils, as a "second attack." Utilizing
proteolytic enzymes and oxidant, neutrophils injure the infiltrated vital organs,
causing cellular damage and dysfunction of vital organs distant from the
pancreas. Multiple organ failure in acute pancreatitis with septic complications
can develop, at least in part, by proinflammatory cytokine release and neutrophil
activation.
PMID- 9548673
TI - Surgical aspects and management of acute necrotizing pancreatitis: recent results
of a cooperative national survey in Japan.
AB - A cooperative national survey between 1991 and 1994 recently clarified the status
of acute necrotizing pancreatitis in Japan. The overall mortality rate was 20.8%;
however, the mortality rate in patients with infection was 33.3%, and the
mortality rate in patients who underwent surgery was 27.4%. With regard to
surgical procedures, drainage procedures (mobilization of the pancreatic bed and
retroperitoneal drainage) were performed most frequently, and one third of the
patients who underwent drainage procedures needed reoperation. Although
debridement of the necrotic tissue (necrosectomy or resection of the pancreas)
was performed in 33.3%, the mortality rate was 35.3%. There was no difference in
the mortality rate between early and delayed operation. Recently two new
modalities have been advocated for the management of severe acute pancreatitis in
Japan. One is continuous regional arterial infusion of protease inhibitor and
antibiotics, and the other is continuous hemodiafiltration. Further work is
needed to establish the most effective procedures for the management of acute
necrotizing pancreatitis and debridement of pancreatic infection.
PMID- 9548674
TI - Chronic pancreatitis: overview of medical aspects.
AB - Based primarily on our experience, we review current problems on etiology,
pathogenesis, classification, diagnosis, and treatment of chronic pancreatitis.
Much of the confusion and difficulty associated with chronic pancreatitis
originates from the relative inaccessibility of this organ. A lack of specific
and sensitive markers that are suitable for the follow-up of a long natural
course of chronic pancreatitis also hinders our understanding of this disease.
The resolution of the present imaging tests, even by the latest technology, is
not good enough to detect early changes of the pancreas. In the past 10 years,
several subgroups of patients with alcoholic and idiopathic pancreatitis have
been identified based on the long-term follow-up study. Pain disappeared
spontaneously in many patients during the course of the disease, but its
mechanism is still poorly understood. Removal of pancreatic stones and protein
plugs by chemical, endoscopic, or extracorporeal shock-wave therapy has been
tried with some success, but their clinical values remain to be established.
Attempts have been made to understand the etiology and pathogenesis of chronic
pancreatitis at molecular levels. This approach, together with a prospective
follow-up of patients, will improve our understanding on chronic pancreatitis.
PMID- 9548675
TI - Pancreatic dysfunction and treatment options.
AB - Pancreatic steatorrhea and pancreatic diabetes are the dominant symptoms of
patients in the decompensated stage of chronic pancreatitis (CP). In this stage,
the nutritional state is greatly disturbed and hypoglycemia and labile infection
are involved. Pancreatic enzyme replacement therapy is the principal treatment
method for pancreatic steatorrhea. Before initiating this therapy, dietary fat
intake must be determined and pancreatic lipase and bicarbonate secretion
function must be evaluated. Upper small intestinal pH is regulated by gastric
acid secretion, and abnormal gastric emptying changes lipolysis. In addition,
precipitation of bile acids in the upper small intestine and ileal brakes due to
undigested fats and carbohydrates must be considered. Porcine pancreatin,
bacterial lipase, and acid-resistant fungal lipase are used as enzymes for
replacement therapy. Conventional, entero-coating, and enteric-coated microsphere
preparations of porcine pancreatin are available for treatment and are formulated
to protect against gastric acids, to dissolve enzymes at optimum pH, and to be
emptied simultaneously with food from the stomach. Gastric acid secretion
suppressants, such as H2 blockers or a proton pump inhibitor, can also be used
concomitantly with pancreatin preparations. In consideration of both strengths
and weaknesses of these preparations, types and dosages of enzyme replacement
therapy should be carefully prescribed, and fecal fats should be examined
repeatedly by a simple and rapid method during treatment. Attention should also
be paid to changes in body weight and nutritional indices (e.g., nutritional
parameters, fat-soluble vitamins). The relationship between carbohydrate
maldigestion/malabsorption in CP patients and treatment of pancreatic diabetes
are topics for future research.
PMID- 9548676
TI - Current surgical trends in Japan for managing chronic pancreatitis.
AB - The main aims of surgery for treating chronic pancreatitis are to relieve the
patient's persistent pain and to preserve pancreatic functioning. The indications
for surgery include treating complications, such as the presence of pancreatic
pseudocysts or biliary stenosis associated with chronic pancreatitis or both. A
resection, ductal drainage, or both, may commonly be required. Furthermore, some
surgeons recommend pancreatic denervation. We analyze the details of 2,936
patients with chronic pancreatitis who were treated surgically and were listed in
the 1985 National Statistics in Japan. We have also evaluated the present
surgical methods for treating chronic pancreatitis in Japan. In addition, we
discuss a new surgical method being used to treat chronic pancreatitis. This is a
recently improved technique involving a complete duodenum-preserving resection of
the head of the pancreas, which also preserves the biliary and alimentary tracts.
PMID- 9548677
TI - Chronic pancreatitis: functional testing.
AB - This article reviews the evolution of functional testing of the pancreas in Japan
for the diagnosis and treatment of chronic pancreatitis (CP), contrasting the pre
with the postsecretin test (S test) era. In the pre-S test era, the diagnosis
was based on symptoms, clinical findings, fasting serum diastase levels, and the
vagostigmin- and ether-stimulation test unless morphologic evidence was
available. The S test and CCK-pancreozymin (PZ) test (PS test) were introduced
into Japan around 1963 and have been used as the gold standard of the exocrine
pancreatic-function test. Through a series of attempts at standardization in
1971, 1985, and 1987, the method was standardized to collect duodenal juice for
60 min through a double- or triple-lumen tube after a bolus or during a
continuous i.v. injection of secretin (100 U). The S test, however, is an
invasive and cumbersome procedure. As a result, N-benzoyl-L-tyrosal-p
aminobenzoic acid (BT-PABA) testing and fecal chymotrypsin testing were
introduced into Japan in the middle and late 1970s, respectively. Although simple
and noninvasive, these two methods were found have lower sensitivity and
specificity than the conventional S test. These two methods, therefore, are
presently used more often for monitoring the course of disease and therapeutic
effects. Additionally, the glucose tolerance test can be performed to detect
endocrine pancreatic insufficiency.
PMID- 9548678
TI - Pancreatic cancer: medical aspects.
AB - Although pancreatic cancer (PC) continues to be a formidable disease, numerous
treatment strategies are evolving that we hope will result in improved patient
survival. To prolong the survival of patients with PC, it is essential to detect
PC at the earliest stage possible and to develop effective nonsurgical treatments
for this disease. The current strategies for the early diagnosis of PC include
the development of diagnostic modalities and screening programs for the early
detection of PC and the determination of high-risk groups for PC. K-ras mutations
in pancreatic juice obtained endoscopically have been studied recently in
association with the early diagnosis of PC, although the interpretation of the
presence of a mutated K-ras gene requires caution. The role of the current
nonsurgical treatments for PC has been limited. Identification of an effective
new chemotherapeutic agent is a high priority, and the enrollment of patients
with PC with metastatic disease into well-designed clinical trials is essential.
New targets for therapy based on the understanding of the molecular biology of PC
may provide avenues for future trials. We must continue to search actively for
more accurate methods of diagnosis and more effective methods of treatment for
PC.
PMID- 9548679
TI - Staging and extended resection for pancreatic cancer.
AB - Extended surgery is being widely performed to treat pancreatic cancer in Japan,
but it has not been evaluated in the same way as in other countries. We,
therefore, compared the Japanese Stage Classification (JPN-SC) with the Union
Internationale Contre le Cancer Stage Classification (UICC-SC) in the surgical
cases of pancreatic cancer treated in our department and then assessed the
results of extended resection and associated problems. Problems existed in the
resection rates and actuarial survival rates in stages II and III in the UICC-SC,
and the JPN-SC was found to reflect more accurately the outcome. On the other
hand, although improvements in curative resection and actuarial survival rate
have been achieved as a result of extended resection in Japan, the outcome in JPN
SC surgical stage IVb and highly advanced cases in which these resections proved
to be noncurative even though they were classified as surgical stage IVa was
extremely poor. In the future, it will be necessary to decide on a single-stage
classification that is accepted throughout the world and to conduct prospective
studies matched to the degree of tumor progression.
PMID- 9548680
TI - Problems in the diagnosis and treatment of a so-called mucin-producing tumor of
the pancreas.
AB - Reports of a so-called "mucin-producing tumor of the pancreas" are increasing
worldwide. Although the clinicopathologic features and therapeutic strategies of
this tumor have been enthusiastically investigated, there are still many
unanswered questions regarding this ailment. In this study, problems in the
diagnosis and treatment of mucin-producing tumor were analyzed, based on the 259
reported cases of this tumor. The overall 5-year survival rate for resected cases
is 83%, which is much higher than that for ordinary duct cell carcinoma (17.3%).
However, the 5-year survival rate for carcinoma cases with infiltration into
other organs is 28%, which is much lower than those for carcinoma cases without
infiltration (86%) and carcinoma cases with infiltration that remained within the
pancreatic parenchyma (74%). These results demonstrate that patients with this
tumor have a poor prognosis if the tumor infiltrates other organs. In addition,
when the spread of the tumor is >6 cm, the prognosis is significantly worse than
when the tumor has a spread of <6 cm. The significance of using the presence of K
ras mutation in the pancreatic juice for diagnosis of this tumor and problems of
duodenum-preserving pancreatic head resection are discussed.
PMID- 9548681
TI - Surgical aspect of enteroinsular axis after gastrointestinal surgery with
reference to incretin secretion.
AB - An alteration of the enteroinsular axis (EIA) may be an important etiologic
factor in postsurgical changes in gastrointestinal (GI) function. In this review,
we present recent works, both from our laboratory and others, on how changes in
the EIA function may be involved in postsurgical GI complications, especially
late dumping syndrome (LDS). We found no or minimal direct role for vagal signals
in the control of gastric inhibitory polypeptide (GIP) and enteroglucagon
secretion, which regulate EIA function. In gastrectomized patients, it is
suggested that the hypersecretion of glicentin and glucagon-like peptide-1 (GLP
1) induced by a rapid arrival of nutrients to the distal gut suppresses glucagon
secretion and may be a cause of LDS. In patients who underwent proctocolectomy,
we observed no significant postoperative changes in EIA function, although there
are some conflicting reports. It seems unlikely that ordinary pancreaticobiliary
diversion would cause a significant change in EIA function after an oral glucose
load. Our experimental model of ileojejunal transposition produced marked
hypersecretion of incretin secreted from the distal gut, which may alter EIA
function. Further elucidation of the regulatory mechanism of EIA may provide a
new strategy for the medical and surgical treatment of LDS.
PMID- 9548682
TI - Progress in the field of pancreatic endocrine tumors in Japan.
AB - Since the first report of pancreatic endocrine tumors by Wilder et al. in 1927
and the development of radioimmunoassay of gut hormone by Berson and Yallow in
1961, Japanese clinicians and scientists have contributed significantly in the
reporting, investigation, and management of patients with pancreatic endocrine
tumors and other multiple endocrine neoplasia. This article summarizes our
contribution in this field and contrasts our experiences with those reported in
the English literature.
PMID- 9548683
TI - Pancreatic diabetes in Japan.
AB - Pancreatic diabetes is usually a complication of other pancreatic disorders.
Diabetes was a complication in 55.5% of 2,774 patients with chronic pancreatitis
(CP) in Japan. More than half of alcoholic patients with CP in our clinic showed
diabetes, and approximately 50% of those patients with diabetes were treated with
insulin injections. On the other hand, cases of nonalcoholic CP showed mild
endocrine dysfunction in terms of diabetic frequency and severity. Epidemiologic
studies suggest that diabetes resulting from chronic pancreatitis accounts for
<0.8% of all Japanese patients with diabetes. In patients with CP, B-cell
dysfunction occurred first, followed by disturbances in A-cell function.
Decreased insulin secretion during postprandial periods plays an important role
in pancreatic diabetes. The fasting level of blood glucose is not useful for the
diagnosis of the early stage of pancreatic diabetes. The glucose-tolerance test
should be performed to diagnose early-stage diabetes in patients with CP with
normal fasting blood glucose levels. For control of blood glucose in diabetic
patients with CP, multiple injections of short-acting effective insulin before
the meal are necessary. The incidence of long-term diabetic complications,
diabetic retinopathy, nephropathy and neuropathy, in patients with CP with
diabetes are not less than those in patients with primary diabetes.
PMID- 9548684
TI - Preservation of pancreatic islets in rodent models.
AB - Islet-cell transplantation has some advantages over vascularized pancreas
transplantation, but data from clinical islet cells transplantation have shown
that some serious problems need to be overcome. One of them is the storage of
islet cells. We investigated methods of preserving islet cells using culture
preservation and cryopreservation. Cryopreservation is thought to be effective
for long-term preservation of large quantities of islet cells, because they can
be cryopreserved without loss of their physiologic activity using a relatively
rapid cooling rate of 25 degrees C/min. Moreover, in the allogenic
transplantation models of cryopreservation of dissociated islet cells, there was
a significant prolongation of survival time. These results suggest that
cryopreservation of islet cells involves not only variable preservation methods
but may also lead to a modification of graft immunogenicity.
PMID- 9548685
TI - Imaging of small pancreatic ductal adenocarcinoma.
AB - Symptoms and laboratory studies provide only limited assistance in the diagnosis
of small pancreatic carcinomas. Ultrasound and computed tomography are best
suited for screening small pancreatic carcinomas because of their ease and
accuracy. When findings of ultrasound and computed tomography suggest small
pancreatic carcinomas, MR cholangiopancreatography and endoscopic ultrasound
should be indicated. Both techniques can show very small tumors. Follow-up of 77
patients with pancreatic carcinoma in whom the tumor was resected showed a 100% 5
year survival rate of patients with tumor limited to the duct epithelium. The
majority of these tumors were <1 cm. These tumors are considered early pancreatic
carcinoma.
PMID- 9548686
TI - ERCP imaging.
AB - Localization and spread of pancreatic diseases has been a reality since the
availability of endoscopic pancreatography in the late 1960s, particularly after
development of a fiberscope for this purpose. Endoscopic pancreatography allowed
the clinician to discern the position and site of cancers, cysts, and localized
inflammations. Ductal anomalies, such as annular pancreas, nonfusion, and
anomalous junction of pancreatobiliary connection, were clearly recognized also.
The pancreatography opacified the real lumen instead of the virtual images of
ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI),
so that precise studies comparing histopathologic details could be performed. The
pancreatic ductal information visualized by using the fiberscope changed our
understanding of chronic inflammation of the pancreas. Chronic diffuse
pancreatitis, upstream pancreatitis, ductitis, and duct-narrowing pancreatitis
were specified from their pathogenetic differences. Although the noninvasive
methods such as US and CT will be the first choice for the diagnosis of
pancreatic diseases, pancreatography will still be important for the morphologic
studies of the pancreas in various disease conditions.
PMID- 9548687
TI - Peroral pancreatoscopy for the diagnosis of pancreatic diseases.
AB - The efficacy associated with peroral pancreatoscopy to diagnose and differentiate
pancreatic diseases is herein reviewed and clarified, and problems with this
modality are discussed. Three types of pancreatoscopes are presently available:
(a) a thin fiberscope with a diameter of 3.3 or 4.5 mm, which has an angulation
system and a forceps channel; (b) an ultrathin pancreatoscope with a diameter of
0.75 or 0.8 mm, which can be inserted via an ordinary endoscopic retrograde
cholangiopancreatography (ERCP) cannula without endoscopic sphincterotomy; and
(c) an ultrathin pancreatoscope combined with a catheter that has an outer
diameter of 1.67 mm. Peroral pancreatoscopy facilitates the detection of small
lesions of the duct in malignancy or chronic pancreatitis. In particular, it is
quite useful in differentiating pancreatic cancer from chronic pancreatitis in
cases with local stenosis or elevated lesions of the main pancreatic duct. Among
patients with a mucus-producing tumor of the pancreas, pancreatoscopy is also
very useful, especially in determining lesion extent. Despite some unresolved
problems, we predict that pancreatoscopy will retain a limited or specific and
definite role in diagnostic and therapeutic endoscopy for pancreatic diseases.
PMID- 9548688
TI - Endoscopic MRI.
AB - We used a new magnetic resonance endoscope with a small radiofrequent (RF) coil
attached to the tip. After insertion of the instrument into the second portion of
the duodenum, patients were placed in a magnetic resonance imaging (MRI) scanner.
Fast spoiled gradient-recalled acquisition (SPGR) pulse sequences were used for
this method. After plain scans, six axial scans were performed after intravenous
injection of 20 ml of gadolinium-diethylenetriaminepentaacetic acid (DTPA)
contrast medium. We performed endo-MRI on 22 patients, 13 with pancreatic
carcinoma, four with pancreatic cystoadenoma, and five with other diseases. In
the patients with pancreatic carcinoma, tumors were delineated as low-intensity
masses after injection of contrast medium. Dilated main pancreatic ducts were
clearly defined. In eight patients with carcinoma of the head of the pancreas,
tumors were clearly defined in seven (87.5%) cases. In the eighth case, motion
artifact prevented acquisition of a clear image of the pancreas. For diagnosis of
invasion of the portal vein, the sensitivity of endo-MRI was 80%, the specificity
was 100%, and overall accuracy was 87.5%. The new technique of endo-MRI allows
the precise diagnosis of pancreatic tumors.
PMID- 9548689
TI - Pancreatic diseases: evaluation with MR cholangiopancreatography.
AB - Magnetic resonance cholangiopancreatography (MRCP) is a noninvasive diagnostic
modality capable of producing high-quality images of the biliary tree and
pancreatic duct. We evaluated the MRCP capability of depicting the normal
pancreatic duct and, based on data achieved, studied the usefulness in the
pathologic pancreatic duct. MRCP was performed in 42 patients without any
pancreatic lesion and in 162 patients with pancreatic diseases, including
congenital anomalies of biliary tree and pancreatic duct. Results were compared
with endoscopic retrograde cholangiopancreatography (ERCP) in 93 patients. The
visualization of the pancreatic duct and its branches and the presence or absence
of dilatation, stenosis, and filling defects were recorded. All images were
interpreted retrospectively and blindly by three radiologists. Among control
patients, the main pancreatic duct (MPD) was depicted in the head, body, and tail
of the pancreas in 41 (98%), 39 (93%), and 31 (74%), and accessory pancreatic
duct and secondary branches in the head, body, and tail of the pancreas were
depicted in 11 (26%), eight (19%), four (10%), and two (5%) of these patients.
Compared with ERCP, MRCP overestimated the stenosis of MPD and underestimated the
dilatation of the branches and filling defects in the pancreatic duct in
pancreatic diseases, especially pancreatitis. However, MRCP was distinctly
advantageous over ERCP in diagnosing mucin-producing tumor of the pancreas,
cystic lesions, and depicting the whole, including the part distal to the
obstructed site. Four of the eight cases of pancreas divisum, and 10 of the 12
cases of anomalous pancreaticobiliary duct union also were demonstrated. MRCP can
accurately demonstrate the normal pancreatic duct as well as various pancreatic
duct abnormalities, including congenital anomalies of the biliary tree and
pancreatic duct.
PMID- 9548690
TI - Pharmaceutical development for treating pancreatic diseases.
AB - The efficacy of medications to treat pancreatic diseases, even when proven
effective by experimental studies, are difficult to prove by controlled clinical
trials. In the treatment of acute pancreatitis, prophylactic antibiotics,
somatostatin, protease inhibitors, and cholecystokinin (CCK)-receptor antagonists
are advocated for use in the early stages of acute pancreatitis, but the data are
insufficient to mandate prophylaxis use or recommend their use as a standard of
care. In the treatment of chronic pancreatitis, digestive enzymes, oral active
protease inhibitors, CCK-receptor antagonists, or somatostatin are administered
for pain relief. Extracorporeal shock-wave lithotripsy and oral dissolution
therapy with trimethadione are used to treat pancreatic stones. The goals of
treatment of acute pancreatitis should be to ameliorate the severity of
pancreatic inflammation or to prevent its complications. Although several
treatments seem to be promising from the studies reviewed, these medications
require prospective comparison with the standard procedures and long-term
evaluation.
PMID- 9548692
TI - Japan Pancreas Society research directory, 1998.
PMID- 9548691
TI - Brief history of the Japan Pancreas Society.
PMID- 9548693
TI - Deafferentation is insufficient to induce sprouting of A-fibre central terminals
in the rat dorsal horn.
AB - The mechanism by which A-fibres sprout into lamina II of the dorsal horn of the
adult rat after peripheral nerve injury, a region which normally receives input
from noci- and thermoreceptive C-fibres alone, is not known. Recent findings
indicating that selective C-fibre injury and subsequent degenerative changes in
this region are sufficient to induce sprouting of uninjured A-fibres have raised
the possibility that the structural reorganisation of A-fibre terminals is an
example of collateral sprouting, in that deafferentation of C-fibre terminals
alone in lamina II may be sufficient to cause A-fibre sprouting. Primary
afferents of the sciatic nerve have their cell bodies located predominantly in
the L4 and L5 dorsal root ganglia (DRGs), and the A-fibres of each DRG have
central termination fields that show an extensive rostrocaudal overlap in lamina
III in the L4 and L5 spinal segments. In this study, we have found that C-fibres
from either DRG have central terminal fields that overlap much less in lamina II
than A-fibres in lamina III. We have exploited this differential terminal
organisation to produce deafferentation in lamina II of the L5 spinal segment, by
an L5 rhizotomy, and then test whether A-fibres of the intact L4 dorsal root
ganglion, which terminate within the L5 segment, sprout into the denervated
lamina II in the L5 spinal segment. Neither intact nor peripherally injured A
fibres were seen to sprout into denervated lamina II after L5 rhizotomy.
Sprouting was only ever seen into regions of lamina II containing the terminals
of peripherally injured C-fibres. Therefore, it seems that the creation of
synaptic space within lamina II is not the explanation for A-fibre sprouting
after peripheral nerve section or crush, emphasising that injury-induced changes
in C-fibres and subsequent chemotrophic effects in the superficial dorsal horn
are the likely explanation.
PMID- 9548695
TI - Effects of monoamine oxidase A inhibition on barrel formation in the mouse
somatosensory cortex: determination of a sensitive developmental period.
AB - Genetic inactivation of monoamine oxidase A (MAOA) in C3H/HeJ mice causes a
complete absence of barrels in the somatosensory cortex, and similar alterations
are caused by pharmacological inhibition of MAOA in wild type mice. To determine
when and how MAOA inhibition affects the development of the barrel field, the
MAOA inhibitor clorgyline was administered to mice of the outbred strain OF1 for
various time periods between embryonic day 15 (E15) and postnatal day 7 (P7), and
the barrel fields were analyzed with cytochrome oxidase and Nissl stains in P10
and adult mice. High-pressure liquid chromatography measures of brain serotonin
(5-HT) showed three- to eightfold increases during the periods of clorgyline
administration. Perinatal mortality was increased and weight gain was slowed
between P3 and P6. Clorgyline treatments from E15 to P7 or from P0 to P7
disrupted the formation of barrels in the anterior snout representation and in
parts of the posteromedial barrel subfield (PMBSF). Treatments from P0 to P4
caused similar although less severe barrel field alterations. Clorgyline
treatments only during embryonic life or starting on P4 caused no detectable
abnormalities. In cases with barrel field alterations, a rostral-to-caudal
gradient of changes was noted: Rostral barrels of the PMBSF were most frequently
fused and displayed an increased size tangentially. Thus, MAOA inhibition
resulting in increased brain levels of 5-HT affects barrel development during the
entire first postnatal week, with a sensitive period between P0 and P4. The
rostral-to-caudal gradient of changes in the barrel field parallels known
developmental gradients in the sensory periphery and in the maturation
thalamocortical afferents. The observed barrel fusions could correspond to a
default in the initial segregation of thalamic fibers or to a continued,
exuberant growth of these fibers that overrides the tangential domain that is
normally devoted to individual whiskers.
PMID- 9548694
TI - Methionine enkephalin immunoreactivity in the brain of the budgerigar
(Melopsittacus undulatus): similarities and differences with respect to oscine
songbirds.
AB - The brain of the budgerigar (Melopsittacus undulatus), a small parrot that
acquires new vocalizations throughout life, was examined for immunoreactivity to
the opioid peptide methionine enkephalin (mENK). mENK is a highly prominent
feature of the chemical architecture of the forebrain vocal system of oscine
songbirds. Forebrain vocal control nuclei are believed to have evolved
independently in parrots and songbirds (Streidter [1994] J. Comp. Neurol. 343:35
56); however, recent studies have found similarities in the neural organization
of vocal control pathways in budgerigars and songbirds (Durand et al. [1997] J.
Comp. Neurol. 377:179-206). Among the similarities are the existence of recursive
pathways interconnecting vocal control neurons in the archistriatum, basal
ganglia (i.e., lobus parolfactorius), and dorsal thalamus. In the present study,
we found that all vocal control nuclei within the budgerigar forebrain exhibit
prominent mENK-like immunoreactivity (ELI) in fibers and somata. We also found
striking similarities between the morphology of ELI elements in budgerigar vocal
control nuclei and that described previously in songbird vocal nuclei. Despite
these similarities, the budgerigar dorsal striatopallidum (lobus parolfactorius,
paleostriatum augmentatum, and paleostriatum primitivum) and somatomotor
(anterior) archistriatum exhibit unique patterns of ELI. The dorsal
striatopallidum contained far less ELI, whereas the archistriatum contained far
more than would be expected on the basis of previous studies of opioid peptides
in other avian species, including pigeons, chickens, and songbirds. These
differences may reflect neural specializations unique to the budgerigar that
contribute to the extraordinary flexibility of the vocal motor system of this
species to acquire socially significant stimuli throughout life.
PMID- 9548696
TI - Localization of the origin of retinal efferents in the turtle brain and the
involvement of nitric oxide synthase.
AB - Previous studies have used selective neurochemical markers or retrograde tracers
to localize the cells in the brain giving rise to efferents to the turtle retina.
Because of the relative selectivity of the neurochemical markers or the lack of
sensitivity of the previously employed retrograde tracers, these studies did not
locate all the efferent cell bodies, or they could not describe the anatomy of
the efferent cells. In the present study, cholera toxin B was used as a highly
sensitive retrograde tracer to investigate the distribution, number, and
morphology of the retinal efferent or centrifugal cell system in turtle brain.
Previous studies of the turtle retina have indicated that nitric oxide synthase
may be found in some retinal efferents. Therefore, we also did colocalization
studies of the retrograde tracer with reduced nicotinamide adenine dinucleotide
phosphate (NADPH)-diaphorase histochemistry to investigate nitric oxide as a
possible transmitter used by efferent fibers and to localize these NADPH
diaphorase-positive efferent cell bodies in the turtle brain. We found that each
eye received projections from approximately 40 efferent cell bodies that were
located primarily in the contralateral midbrain. The majority of efferent cell
bodies were centered in the isthmic tegmentum; other efferent cells extended more
rostrally into the substantia nigra, and some efferent cells extended more
caudally into the nucleus raphes superior. The double-label results showed that
30% of the cholera toxin B-like immunoreactive cells were also positive for NADPH
diaphorase. The location of these double-labeled cells around the locus coeruleus
corresponded to the NADPH-diaphorase-positive efferent cells in the avian isthmo
optic field. The localization of NADPH-diaphorase in these efferents indicated
that they may use nitric oxide to modulate retinal function.
PMID- 9548697
TI - Horizontal cell connections with short wavelength-sensitive cones in the retina:
a comparison between New World and Old World primates.
AB - Recent studies in the Old World macaque monkey have shown that the two horizontal
cell types H1 and H2 differ with respect to their connections to short wavelength
sensitive (SWS) cones. We wanted to establish whether this pattern of
connectivity is common to all primates. The connections of horizontal cells with
SWS cones were studied in the retinas of two species of New World (marmoset and
tamarin) and two species of Old World (orangutan and chimpanzee) primates by
using a double-labelling technique. Horizontal cells were labelled with DiI and
then photoconverted; SWS cones were labelled immunocytochemically. The marmoset
shows a sex-linked polymorphism of colour vision: All males are dichromats,
whereas most females are trichromats. In contrast, Old World primates are usually
trichromats. Our results show that the horizontal cells of both New World and Old
World primates have a comparable pattern of connectivity with SWS cones and thus
indicate that the wiring of horizontal cells with SWS cones does not differ
between dichromats and trichromats and is common to all primates. The H1 cells
make no or only sparse contact with SWS cones. In marmoset, H1 cells have on
average 0.8% of their dendritic terminals at SWS cones. The H2 cells contact all
SWS cones in their dendritic field. In marmoset, H2 cells have on average 11.8%
of their dendritic terminals at SWS cones. The axon of H2 cells contacts SWS
cones but presumably also contacts other cones.
PMID- 9548698
TI - Spatiotemporal patterns of ontogenetic expression of parvalbumin in the superior
colliculi of rats and rabbits.
AB - We have examined the development of parvalbumin immunoreactivity in the superior
colliculi (SC) of the perinatal and mature rats and rabbits. In mature animals,
parvalbumin-expressing cells (PECs) and neuropil in the retinorecipient layers
were distributed in a continuous single band extending throughout the entire
extent of the colliculus, whereas those in the intermediate layers formed
distinct, radially oriented patches. Parvalbumin was expressed for the first time
on postconceptional day 34 (PCD 34, postnatal day 12) and PCD 42 (postnatal day
11) in the SC of rat and rabbit, respectively. During ensuing development, both
the thickness of the parvalbumin-expressing band in the retinorecipient layers
and the numbers of PECs in this band gradually increased, reaching adultlike
values by PCD 44 and PCD 50 in the rat and rabbit, respectively. In the rat,
monocular eye enucleations on PCD 23 resulted in approximately 55% reduction in
the number of PECs in the retinorecipient layers of the contralateral colliculi
examined on PCD 44 or PCD 50. Unilateral ablations of the entire visual cortex on
PCD 23 (before the first corticotectal fibers from visual cortices reach the SC)
or on PCD 28 (when about half of the corticotectal fibers have reached
colliculus) resulted in, respectively, approximately 55% and approximately 25%
relative reduction in the number of PECs in the retinorecipient layers of the
ipsilateral colliculi examined on PCD 44 or PCD 50. We conclude that the
ontogenetic expression of parvalbumin in most of PECs in the retinorecipient
collicular layers is induced by the activity of the contralateral retinotectal
and/or the activity of the ipsilateral corticotectal afferents.
PMID- 9548699
TI - Overexpression of nerve growth factor in epidermis disrupts the distribution and
properties of sympathetic innervation in footpads.
AB - Sympathetic and sensory neurons form distinct axonal arborizations in several
peripheral targets. The developmental mechanisms responsible for partitioning
sympathetic and sensory axons between potential target tissues are poorly
understood. We have used rodent footpads to study this process because three
populations of peripheral axons innervate topographically segregated targets in
the footpad; cholinergic sympathetic axons innervate sweat glands, noradrenergic
sympathetic axons innervate blood vessels, and sensory axons form a plexus at the
epidermal/dermal junction. To examine how nerve growth factor (NGF), a trophic
and survival factor for sympathetic and some sensory neurons, may contribute to
the generation of the patterned distribution of axons among targets, we studied
transgenic mice (K14-NGF mice) in which NGF expression was significantly
increased in the epidermis. Whereas the temporal sequence in which sensory and
sympathetic fibers arrived in the footpad was not affected, the normal
partitioning of axons between target tissues was disrupted. The two sympathetic
targets in footpads, sweat glands, and blood vessels lacked substantial
innervation and instead a dense plexus of catecholaminergic sympathetic fibers
was found commingled with sensory fibers in the dermis. Those sympathetic fibers
present in sweat glands expressed an abnormal dual catecholaminergic/cholinergic
phenotype. Our findings indicate that overexpression of NGF in skin interferes
with the segregation of sensory and sympathetic axonal arbors and suggests a role
for target-derived NGF in the establishment of distinct axonal territories. Our
data also suggest that by determining where axon arbors form, NGF can indirectly
influence the phenotypic properties of sympathetic neurons.
PMID- 9548700
TI - Hypothalamic effector neurons and extended circuitries activated in "neurogenic"
stress: a comparison of footshock effects exerted acutely, chronically, and in
animals with controlled glucocorticoid levels.
AB - Immunolocalization of Fos protein was used to identify and characterize
hypothalamic visceromotor populations responsive to acute and chronic
intermittent footshock stress, and candidate afferent mediators of hypothalamic
effects. Exposure to a single 30 minute footshock session induced maximal Fos
expression in the paraventricular hypothalamic nucleus (PVH) 2 hours after the
challenge; activated cells corresponded principally to hypophysiotropic neurons
expressing corticotropin-releasing factor, with secondary involvement of
magnocellular oxytocinergic and autonomic-related projection neurons.
Extrahypothalamic cell groups activated in response to acute footshock included
ones associated with the processing or modulation of somatosensory/nociceptive
inputs, the limbic region of the telencephalon, and visceral sensory mechanisms.
Rats with constant corticosterone levels displayed enhanced footshock-induced Fos
expression in the parvicellular compartment of the PVH, as well as in certain
limbic and somatosensory cell groups, the locus coeruleus, but not in medullary
catecholaminergic cell groups. Animals subjected to chronic intermittent stress
(2 sessions/day for 7 days) showed only modest evidence of habituation of
cellular activation responses in the PVH and most extrahypothalamic regions. Rats
bearing retrograde tracer deposits in the PVH and killed 2 hours after acute
footshock displayed Fos-positive retrogradely labeled neurons principally in
medullary catecholaminergic cell groups, with secondary foci in the hypothalamus,
limbic region, and pontine tegmentum. This characterization of footshock
responsive systems identifies cell groups that are in a position to (1) mediate
acute stress effects on hypothalamic visceromotor neurons, (2) comprise targets
for corticosteroid negative feedback effects, and/or (3) underlie habituation of
the neuroendocrine limb of the stress response.
PMID- 9548701
TI - Caregiving for children and adults with chronic conditions: introduction to the
special issue.
PMID- 9548702
TI - Role strain in couples with and without a child with a chronic illness:
associations with marital satisfaction, intimacy, and daily mood.
AB - This study examined marital role strain in 33 couples caring for a child with
cystic fibrosis (CF) and 33 couples with a healthy child. The relationship
between role strain, marital satisfaction, and psychological distress was tested.
Couples completed a structured interview, questionnaires, a card sort procedure,
and 4 daily diaries assessing activities and mood. Couples in the CF versus
comparison group reported greater role strain on measures of role conflict, child
care tasks, and exchanges of affection. They also spent less time in recreational
activities, but no reliable group differences were found in marital satisfaction
or depression. Regression analyses indicated that role strain was related to
marital satisfaction and depression and that recreation time accounted for
additional variance. Path analysis suggested that recreation mediated the
negative relationship between role strain and distress. The importance of using a
contextual, process-oriented approach is discussed.
PMID- 9548703
TI - Dynamic processes in health outcomes among caregivers of patients with spinal
cord injuries.
AB - The developmental trajectories of health outcomes in caregivers of patients with
spinal cord injuries (SCIs) were studied as a function of caregiver and patient
characteristics. Hierarchical linear modeling analysis examined (a)
intraindividual developmental patterns of depressive behavior, anxiety, and
physical symptoms over the 1st year of the caregiving career and (b) correlates
of heterogeneity in the developmental patterns among 62 caregivers of persons
with SCIs. Physical symptoms and anxiety were highly interdependent. Anxiety was
a salient predictor of initial levels of and the rate of change in physical
symptoms of caregivers. Physical symptoms and younger patient age were
significantly predictive of initial levels of anxiety. Physical symptoms and
positive affect predicted initial levels of depressive behavior among caregivers.
Expressive support predicted the rate of change in anxiety and depressive
behavior over time. These findings illustrate the value of studying caregiving as
a developmental process.
PMID- 9548704
TI - AIDS caregiving and health among midlife and older women.
AB - This study reports on analyses of survey data from 121 midlife and older women
engaged in AIDS caregiving in Los Angeles and San Francisco. These data revealed
that these women provided substantial support to persons living with HIV or AIDS
(PWAs) despite other role commitments associated with family and work. Although
the characteristics of these women differed according to their relationship to
the PWA (mother, wife, sister, or friend), they tended to be similar with regard
to both the amount of care provided and its impact on their health. The results
indicated that the severity of the PWA's illness and the duration of caregiving
were more consequential to health than were the hands-on tasks of caregiving.
PMID- 9548705
TI - Temporal profiles of physical health in family members of heart transplant
recipients: predictors of health change during caregiving.
AB - This study examined patterns of change in the physical health and well-being of
133 family caregivers to heart transplant recipients during the 1st year after
transplant. Caregivers were assessed at 2, 7, and 12 months after transplant.
Cluster analysis was used to identify temporal profiles reflecting unique
patterns of change in the direction and nature of caregivers' physical health;
their temporal profiles showed either (a) a worsening of general medical
condition, with weight gain (14% of the sample); (b) worsening medical condition
with weight loss (15%); (c) weight gain with stable medical condition (41%); (d)
weight loss with slightly improving medical condition (21%); or (e) worsening
health perceptions with relatively little objective evidence of change in medical
condition or weight (8%). Subsequent multivariate analyses indicated that
caregiver characteristics measured at baseline and reflecting caregiving burden,
coping styles, demographics, and health history reliably predicted membership in
the pattern-of-health-change groups. Among the findings, caregivers who showed a
pattern of medical decline with weight loss had a poorer health history and
weaker coping styles (lower mastery and higher use of avoidance coping) than
other caregivers. Caregivers who experienced medical decline with weight gain had
the greatest levels of caregiver burden. These findings are relevant to the
design of interventions to maximize not only caregivers' health, but the health
of the family members for whom they provide care.
PMID- 9548706
TI - Activity restriction and prior relationship history as contributors to mental
health outcomes among middle-aged and older spousal caregivers.
AB - In a sample of cancer patients (n = 75) and spousal caregivers (24 men and 51
women), restriction in caregiver routine activities mediated associations between
caregiving stress (patient symptom severity) and caregiver depressed affect and
resentment. Moreover, the antecedents and affective consequences of caregiver
activity restriction were consistent with the theory of communal relationships
(e.g., M. S. Clark & J. Mills, 1979, 1993). If a relationship had been communal
in the past (i.e., characterized by mutual concern for and responsiveness to one
another's needs), activity restriction was predicted by intimacy and affectional
loss (rather than by the severity of patient symptoms) and in turn predicted
caregiver depressed affect. Among caregivers in less communal relationships,
activity restriction was predicted by severity of patient symptoms (rather than
by intimacy and affectional loss) and in turn predicted resentment of care
recipients and the caregiving role.
PMID- 9548707
TI - Mastery in women's multiple roles and well-being: adult daughters providing care
to impaired parents.
AB - The current study focused on 296 adult daughter caregivers who were
simultaneously providing care to an impaired parent, mothers to children living
at home, wives, and employees. How mastery (perceived competence and control) in
each of these 4 roles was related to well-being was examined. Women experienced
higher levels of mastery in the employee role than in any other role. After
controlling for household income and dispositional optimism, only employee
mastery contributed unique variance to physical health, but mastery in each of
the 4 roles contributed unique variance to either depression or life
satisfaction. Results also suggest that women's satisfaction with life was
related to an accumulation of mastery across roles. The study expands previous
research by revealing that mastery in women's additional roles can supplement the
benefits of mastery stemming from parent care.
PMID- 9548708
TI - Caregiving from the recipient's perspective: negative reactions to being helped.
AB - This study investigated predictors of negative reactions to assistance provided
to a physically disabled spouse (n = 276, M age: 76.6 years) and the consequences
that negative reactions may have for the mental health of the care recipient.
Nearly 40% of recipients reported some emotional distress in response to help
they received. Fatalistic attitudes, perceived control, and lower self-esteem
predicted greater helping distress, whereas lower self-esteem, fatalistic
beliefs, and marital conflict were especially likely to lead to helping distress
for those who received higher levels of assistance. Helping distress was also
found to predict depression as much as 1 year later, suggesting that there may be
long-term consequences of negative reactions to assistance. These findings have
important implications for the study of caregiving and the relationship between
physical impairment and depression.
PMID- 9548709
TI - Cellular immune responses to acute stress in female caregivers of dementia
patients and matched controls.
AB - This study investigated whether the stress of caregiving alters cellular immune
responses to acute psychological stressors. Twenty-seven women caring for a
spouse with a progressive dementia (high chronic stress) and 37 controls matched
for age and family income performed a 12-min laboratory stressor. Cellular immune
function was assessed by both functional and quantitative measures taken before
(low acute stress), immediately after (high acute stress), and 30 min after
(recovery from stress) exposure to the laboratory stressors. The laboratory
challenges were associated with diminished proliferative responses but elevated
natural killer (NK) cell cytotoxicity; however, subsequent analyses suggested
that this elevated cytotoxicity was largely attributable to an increase in the
number of NK cells in peripheral blood. The results suggest that although the
stress of caregiving diminishes cellular immune function, caregiving appears to
have little effect on cellular immune responses to or recovery from brief
psychological challenges.
PMID- 9548710
TI - Predicting longitudinal changes in caregiver physical and mental health: a stress
process model.
AB - Alzheimer's family caregivers (N = 122) reported on physical and mental health,
as well as stress process variables, at baseline and at a 1-year follow-up.
Hierarchical regression analyses of stress process models revealed that increases
in primary stressors (e.g., patient self-care and behavioral problems) did not
directly affect changes in the mental and physical health outcome variables.
However, analyses of models of direct, mediated, and moderated effects revealed
that psychosocial resource variables (appraisals, coping responses, and social
support) were related to caregiver outcomes over time through several mechanisms.
In particular, benign appraisals of stressors, the use of approach coping, and
greater levels of social support were associated with more positive caregiver
health outcomes over time.
PMID- 9548711
TI - Centromere protein B null mice are mitotically and meiotically normal but have
lower body and testis weights.
AB - CENP-B is a constitutive centromere DNA-binding protein that is conserved in a
number of mammalian species and in yeast. Despite this conservation, earlier
cytological and indirect experimental studies have provided conflicting evidence
concerning the role of this protein in mitosis. The requirement of this protein
in meiosis has also not previously been described. To resolve these
uncertainties, we used targeted disruption of the Cenpb gene in mouse to study
the functional significance of this protein in mitosis and meiosis. Male and
female Cenpb null mice have normal body weights at birth and at weaning, but
these subsequently lag behind those of the heterozygous and wild-type animals.
The weight and sperm content of the testes of Cenpb null mice are also
significantly decreased. Otherwise, the animals appear developmentally and
reproductively normal. Cytogenetic fluorescence-activated cell sorting and
histological analyses of somatic and germline tissues revealed no abnormality.
These results indicate that Cenpb is not essential for mitosis or meiosis,
although the observed weight reduction raises the possibility that Cenpb
deficiency may subtly affect some aspects of centromere assembly and function,
and result in reduced rate of cell cycle progression, efficiency of microtubule
capture, and/or chromosome movement. A model for a functional redundancy of this
protein is presented.
PMID- 9548712
TI - Human autoantibodies reveal titin as a chromosomal protein.
AB - Assembly of the higher-order structure of mitotic chromosomes is a prerequisite
for proper chromosome condensation, segregation and integrity. Understanding the
details of this process has been limited because very few proteins involved in
the assembly of chromosome structure have been discovered. Using a human
autoimmune scleroderma serum that identifies a chromosomal protein in human cells
and Drosophila embryos, we cloned the corresponding Drosophila gene that encodes
the homologue of vertebrate titin based on protein size, sequence similarity,
developmental expression and subcellular localization. Titin is a giant
sarcomeric protein responsible for the elasticity of striated muscle that may
also function as a molecular scaffold for myofibrillar assembly. Molecular
analysis and immunostaining with antibodies to multiple titin epitopes indicates
that the chromosomal and muscle forms of titin may vary in their NH2 termini. The
identification of titin as a chromosomal component provides a molecular basis for
chromosome structure and elasticity.
PMID- 9548713
TI - The genomic sequences bound to special AT-rich sequence-binding protein 1 (SATB1)
in vivo in Jurkat T cells are tightly associated with the nuclear matrix at the
bases of the chromatin loops.
AB - Special AT-rich sequence-binding protein 1 (SATB1), a DNA-binding protein
expressed predominantly in thymocytes, recognizes an ATC sequence context that
consists of a cluster of sequence stretches with well-mixed A's, T's, and C's
without G's on one strand. Such regions confer a high propensity for stable base
unpairing. Using an in vivo cross-linking strategy, specialized genomic sequences
(0.1-1. 1 kbp) that bind to SATB1 in human lymphoblastic cell line Jurkat cells
were individually isolated and characterized. All in vivo SATB1-binding sequences
examined contained typical ATC sequence contexts, with some exhibiting homology
to autonomously replicating sequences from the yeast Saccharomyces cerevisiae
that function as replication origins in yeast cells. In addition, LINE 1
elements, satellite 2 sequences, and CpG island-containing DNA were identified.
To examine the higher-order packaging of these in vivo SATB1-binding sequences,
high-resolution in situ fluorescence hybridization was performed with both
nuclear "halos" with distended loops and the nuclear matrix after the majority of
DNA had been removed by nuclease digestion. In vivo SATB1-binding sequences
hybridized to genomic DNA as single spots within the residual nucleus
circumscribed by the halo of DNA and remained as single spots in the nuclear
matrix, indicating that these sequences are localized at the base of chromatin
loops. In human breast cancer SK-BR-3 cells that do not express SATB1, at least
one such sequence was found not anchored onto the nuclear matrix. These findings
provide the first evidence that a cell type-specific factor such as SATB1 binds
to the base of chromatin loops in vivo and suggests that a specific chromatin
loop domain structure is involved in T cell-specific gene regulation.
PMID- 9548714
TI - Cytoplasmic tail phosphorylation of the alpha-factor receptor is required for its
ubiquitination and internalization.
AB - G protein-coupled (GPC) receptors are phosphorylated in response to ligand
binding, a modification that promotes receptor desensitization or downregulation.
The alpha-factor pheromone receptor (Ste2p) of Saccharomyces cerevisiae is a GPC
receptor that is hyperphosphorylated and ubiquitinated upon binding alpha-factor.
Ubiquitination triggers Ste2p internalization into the endocytic pathway. Here we
demonstrate that phosphorylation of Ste2p promotes downregulation by positively
regulating ubiquitination and internalization. Serines and a lysine are essential
elements of the Ste2p SINNDAKSS internalization signal that can mediate both
constitutive and ligand-stimulated endocytosis. The SINNDAKSS serines are
required for receptor phosphorylation which, in turn, facilitates ubiquitination
of the neighboring lysine. Constitutive phosphorylation is required to promote
constitutive internalization, and is also a prerequisite for ligand-induced
phosphorylation at or near the SINNDAKSS sequence. Mutants defective in yeast
casein kinase I homologues are unable to internalize alpha-factor, and do not
phosphorylate or ubiquitinate the receptor, indicating that these kinases play a
direct or indirect role in phosphorylating the receptor. Finally, we provide
evidence that the primary function of phosphorylation controlled by the SINNDAKSS
sequence is to trigger receptor internalization, demonstrating that
phosphorylation-dependent endocytosis is an important mechanism for the
downregulation of GPC receptor activity.
PMID- 9548715
TI - Mannose 6-phosphate receptors are sorted from immature secretory granules via
adaptor protein AP-1, clathrin, and syntaxin 6-positive vesicles.
AB - The occurrence of clathrin-coated buds on immature granules (IGs) of the
regulated secretory pathway suggests that specific transmembrane proteins are
sorted into these buds through interaction with cytosolic adaptor proteins. By
quantitative immunoelectron microscopy of rat endocrine pancreatic beta cells and
exocrine parotid and pancreatic cells, we show for the first time that the
mannose 6-phosphate receptors (MPRs) for lysosomal enzyme sorting colocalize with
the AP-1 adaptor in clathrin-coated buds on IGs. Furthermore, the concentrations
of both MPR and AP-1 decline by approximately 90% as the granules mature.
Concomitantly, in exocrine secretory cells lysosomal proenzymes enter and then
are sorted out of IGs, just as was previously observed in beta cells (Kuliawat,
R., J. Klumperman, T. Ludwig, and P. Arvan. 1997. J. Cell Biol. 137:595-608). The
exit of MPRs in AP-1/clathrin-coated buds is selective, indicated by the fact
that the membrane protein phogrin is not removed from maturing granules. We have
also made the first observation of a soluble N-ethylmaleimide-sensitive factor
attachment protein receptor, syntaxin 6, which has been implicated in clathrin
coated vesicle trafficking from the TGN to endosomes (Bock, J.B., J. Klumperman,
S. Davanger, and R.H. Scheller. 1997. Mol. Biol. Cell. 8:1261-1271) that enters
and then exits the regulated secretory pathway during granule maturation. Thus,
we hypothesize that during secretory granule maturation, MPR-ligand complexes and
syntaxin 6 are removed from IGs by AP-1/clathrin-coated vesicles, and then
delivered to endosomes.
PMID- 9548716
TI - Peroxisome biogenesis: involvement of ARF and coatomer.
AB - Peroxisomal membrane protein (Pmp)26p (RnPex11p), a major constituent of induced
rat liver peroxisomal membrane, was found to contain a COOH-terminal,
cytoplasmically exposed consensus dilysine motif with the potential to bind
coatomer. Biochemical as well as immunocytochemical evidence is presented showing
that peroxisomes incubated with preparations of bovine brain or rat liver cytosol
recruit ADP-ribosylation factor (ARF) and coatomer in a strictly guanosine 5'-O
(3-thiotriphosphate)-dependent manner. Consistent with this observation, ldlF
cells expressing a temperature-sensitive mutant version of the epsilon-subunit of
coatomer exhibit elongated tubular peroxisomes possibly due to impaired
vesiculation at the nonpermissive temperature. Since overexpression of Pex11p in
Chinese hamster ovary wild-type cells causes proliferation of peroxisomes, these
data suggest that Pex11p plays an important role in peroxisome biogenesis by
supporting ARF- and coatomer-dependent vesiculation of the organelles.
PMID- 9548717
TI - A SecY homologue is required for the elaboration of the chloroplast thylakoid
membrane and for normal chloroplast gene expression.
AB - Results of in vitro and genetic studies have provided evidence for four pathways
by which proteins are targeted to the chloroplast thylakoid membrane. Although
these pathways are initially engaged by distinct substrates and involve some
distinct components, an unresolved issue has been whether multiple pathways
converge on a common translocation pore in the membrane. A homologue of
eubacterial SecY called cpSecY is localized to the thylakoid membrane. Since SecY
is a component of a protein-translocating pore in bacteria, cpSecY likely plays
an analogous role. To explore the role of cpSecY, we obtained maize mutants with
transposon insertions in the corresponding gene. Null cpSecY mutants exhibit a
severe loss of thylakoid membrane, differing in this regard from mutants lacking
cpSecA. Therefore, cpSecY function is not limited to a translocation step
downstream of cpSecA. The phenotype of cpSecY mutants is also much more
pleiotropic than that of double mutants in which both the cpSecA- and DeltapH
dependent thylakoid-targeting pathways are disrupted. Therefore, cpSecY function
is likely to extend beyond any role it might play in these targeting pathways.
CpSecY mutants also exhibit a defect in chloroplast translation, revealing a link
between chloroplast membrane biogenesis and chloroplast gene expression.
PMID- 9548718
TI - Occludin-deficient embryonic stem cells can differentiate into polarized
epithelial cells bearing tight junctions.
AB - Occludin is the only known integral membrane protein of tight junctions (TJs),
and is now believed to be directly involved in the barrier and fence functions of
TJs. Occludin-deficient embryonic stem (ES) cells were generated by targeted
disruption of both alleles of the occludin gene. When these cells were subjected
to suspension culture, they aggregated to form simple, and then cystic embryoid
bodies (EBs) with the same time course as EB formation from wild-type ES cells.
Immunofluorescence microscopy and ultrathin section electron microscopy revealed
that polarized epithelial (visceral endoderm-like) cells were differentiated to
delineate EBs not only from wild-type but also from occludin-deficient ES cells.
Freeze fracture analyses indicated no significant differences in number or
morphology of TJ strands between wild-type and occludin-deficient epithelial
cells. Furthermore, zonula occludens (ZO)-1, a TJ-associated peripheral membrane
protein, was still exclusively concentrated at TJ in occludin-deficient
epithelial cells. In good agreement with these morphological observations, TJ in
occludin-deficient epithelial cells functioned as a primary barrier to the
diffusion of a low molecular mass tracer through the paracellular pathway. These
findings indicate that there are as yet unidentified TJ integral membrane
protein(s) which can form strand structures, recruit ZO-1, and function as a
barrier without occludin.
PMID- 9548719
TI - Association of the myosin-binding subunit of myosin phosphatase and moesin: dual
regulation of moesin phosphorylation by Rho-associated kinase and myosin
phosphatase.
AB - The small GTPase Rho is believed to regulate the actin cytoskeleton and cell
adhesion through its specific targets. We previously identified the Rho targets:
protein kinase N, Rho-associated kinase (Rho-kinase), and the myosin-binding
subunit (MBS) of myosin phosphatase. We found that in MDCK epithelial cells, MBS
accumulated at the tetradecanoylphorbol-13-acetate (TPA)-induced membrane
ruffling area, where moesin, a member of the ERM (ezrin, radixin, and moesin)
family, was localized. Neither membrane ruffling nor an accumulation of moesin
and MBS at the free-end plasma membrane was induced when MDCK cells were
stimulated with TPA after the microinjection of C3, which ADP-ribosylates and
inactivates Rho. MBS was colocalized with moesin at the cell-cell contact sites
in MDCK cells. We also found that moesin was coimmunoprecipitated with MBS from
MDCK cells. Recombinant MBS interacted with the amino-terminal domains of moesin
and ezrin. Myosin phosphatase composed of the catalytic subunit and MBS showed
phosphatase activity toward moesin, which was phosphorylated by Rho-kinase. The
phosphatase activity was inhibited when MBS was phosphorylated by Rho-kinase.
These results suggest that MBS is recruited with moesin to the plasma membrane
and that myosin phosphatase and Rho-kinase regulate the phosphorylation state of
moesin downstream of Rho.
PMID- 9548720
TI - Image reconstructions of microtubules decorated with monomeric and dimeric
kinesins: comparison with x-ray structure and implications for motility.
AB - We have decorated microtubules with monomeric and dimeric kinesin constructs,
studied their structure by cryoelectron microscopy and three-dimensional image
reconstruction, and compared the results with the x-ray crystal structure of
monomeric and dimeric kinesin. A monomeric kinesin construct (rK354, containing
only a short neck helix insufficient for coiled-coil formation) decorates
microtubules with a stoichiometry of one kinesin head per tubulin subunit (alpha
beta-heterodimer). The orientation of the kinesin head (an anterograde motor) on
the microtubule surface is similar to that of ncd (a retrograde motor). A longer
kinesin construct (rK379) forms a dimer because of the longer neck helix forming
a coiled-coil. Unexpectedly, this construct also decorates the microtubule with a
stoichiometry of one head per tubulin subunit, and the orientation is similar to
that of the monomeric construct. This means that the interaction with
microtubules causes the two heads of a kinesin dimer to separate sufficiently so
that they can bind to two different tubulin subunits. This result is in contrast
to recent models and can be explained by assuming that the tubulin-kinesin
interaction is antagonistic to the coiled-coil interaction within a kinesin
dimer.
PMID- 9548721
TI - Defect in synaptic vesicle precursor transport and neuronal cell death in KIF1A
motor protein-deficient mice.
AB - The nerve axon is a good model system for studying the molecular mechanism of
organelle transport in cells. Recently, the new kinesin superfamily proteins
(KIFs) have been identified as candidate motor proteins involved in organelle
transport. Among them KIF1A, a murine homologue of unc-104 gene of Caenorhabditis
elegans, is a unique monomeric neuron- specific microtubule plus end-directed
motor and has been proposed as a transporter of synaptic vesicle precursors
(Okada, Y., H. Yamazaki, Y. Sekine-Aizawa, and N. Hirokawa. 1995. Cell. 81:769
780). To elucidate the function of KIF1A in vivo, we disrupted the KIF1A gene in
mice. KIF1A mutants died mostly within a day after birth showing motor and
sensory disturbances. In the nervous systems of these mutants, the transport of
synaptic vesicle precursors showed a specific and significant decrease.
Consequently, synaptic vesicle density decreased dramatically, and clusters of
clear small vesicles accumulated in the cell bodies. Furthermore, marked neuronal
degeneration and death occurred both in KIF1A mutant mice and in cultures of
mutant neurons. The neuronal death in cultures was blocked by coculture with wild
type neurons or exposure to a low concentration of glutamate. These results in
cultures suggested that the mutant neurons might not sufficiently receive
afferent stimulation, such as neuronal contacts or neurotransmission, resulting
in cell death. Thus, our results demonstrate that KIF1A transports a synaptic
vesicle precursor and that KIF1A-mediated axonal transport plays a critical role
in viability, maintenance, and function of neurons, particularly mature neurons.
PMID- 9548722
TI - Kinesin light chains are essential for axonal transport in Drosophila.
AB - Kinesin is a heterotetramer composed of two 115-kD heavy chains and two 58-kD
light chains. The microtubule motor activity of kinesin is performed by the heavy
chains, but the functions of the light chains are poorly understood. Mutations
were generated in the Drosophila gene Kinesin light chain (Klc), and the
phenotypic consequences of loss of Klc function were analyzed at the behavioral
and cellular levels. Loss of Klc function results in progressive lethargy,
crawling defects, and paralysis followed by death at the end of the second larval
instar. Klc mutant axons contain large aggregates of membranous organelles in
segmental nerve axons. These aggregates, or organelle jams (Hurd, D.D., and W.M.
Saxton. 1996. Genetics. 144: 1075-1085), contain synaptic vesicle precursors as
well as organelles that may be transported by kinesin, kinesin-like protein 68D,
and cytoplasmic dynein, thus providing evidence that the loss of Klc function
blocks multiple pathways of axonal transport. The similarity of the Klc and Khc
(. Cell 64:1093-1102; Hurd, D.D., and W.M. Saxton. 1996. Genetics 144: 1075-1085)
mutant phenotypes indicates that KLC is essential for kinesin function, perhaps
by tethering KHC to intracellular cargos or by activating the kinesin motor.
PMID- 9548723
TI - Drosophila centrosomin protein is required for male meiosis and assembly of the
flagellar axoneme.
AB - Centrosomes and microtubules play crucial roles during cell division and
differentiation. Spermatogenesis is a useful system for studying centrosomal
function since it involves both mitosis and meiosis, and also transformation of
the centriole into the sperm basal body. Centrosomin is a protein localized to
the mitotic centrosomes in Drosophila melanogaster. We have found a novel isoform
of centrosomin expressed during spermatogenesis. Additionally, an anticentrosomin
antibody labels both the mitotic and meiotic centrosomes as well as the basal
body. Mutational analysis shows that centrosomin is required for spindle
organization during meiosis and for organization of the sperm axoneme. These
results suggest that centrosomin is a necessary component of the meiotic
centrosomes and the spermatid basal body.
PMID- 9548724
TI - The distribution of polycomb-group proteins during cell division and development
in Drosophila embryos: impact on models for silencing.
AB - The subcellular three-dimensional distribution of three polycomb-group (PcG)
proteins-polycomb, polyhomeotic and posterior sex combs-in fixed whole-mount
Drosophila embryos was analyzed by multicolor confocal fluorescence microscopy.
All three proteins are localized in complex patterns of 100 or more loci
throughout most of the interphase nuclear volume. The rather narrow distribution
of the protein intensities in the vast majority of loci argues against a PcG
mediated sequestration of repressed target genes by aggregation into subnuclear
domains. In contrast to the case for PEV repression (Csink, A.K., and S.
Henikoff. 1996. Nature. 381:529-531), there is a lack of correlation between the
occurrence of PcG proteins and high concentrations of DNA, demonstrating that the
silenced genes are not targeted to heterochromatic regions within the nucleus.
There is a clear distinction between sites of transcription in the nucleus and
sites of PcG binding, supporting the assumption that most PcG binding loci are
sites of repressive complexes. Although the PcG proteins maintain tissue-specific
repression for up to 14 cell generations, the proteins studied here visibly
dissociate from the chromatin during mitosis, and disperse into the cytoplasm in
a differential manner. Quantitation of the fluorescence intensities in the whole
mount embryos demonstrate that the dissociated proteins are present in the
cytoplasm. We determined that <2% of PH remains attached to late metaphase and
anaphase chromosomes. Each of the three proteins that were studied has a
different rate and extent of dissociation at prophase and reassociation at
telophase. These observations have important implications for models of the
mechanism and maintenance of PcG- mediated gene repression.
PMID- 9548725
TI - A role for Dictyostelium racE in cortical tension and cleavage furrow
progression.
AB - The small GTPase racE is essential for cytokinesis in Dictyostelium. We found
that this requirement is restricted to cells grown in suspension. When attached
to a substrate, racE null cells form an actomyosin contractile ring and complete
cytokinesis normally. Nonetheless, racE null cells fail completely in cytokinesis
when in suspension. To understand this conditional requirement for racE, we
developed a method to observe cytokinesis in suspension. Using this approach, we
found that racE null cells attempt cytokinesis in suspension by forming a
contractile ring and cleavage furrow. However, the cells form multiple blebs and
fail in cytokinesis by regression of the cleavage furrow. We believe this
phenotype is caused by the extremely low level of cortical tension found in racE
null cells compared to wild-type cells. The reduced cortical tension of racE null
cells is not caused by a decrease in their content of F-actin. Instead, mitotic
racE null cells contain abnormal F-actin aggregates. These results suggest that
racE is essential for the organization of the cortical cytoskeleton to maintain
proper cortical integrity. This function of racE is independent of attachment to
a substrate, but can be bypassed by other signaling pathways induced by adhesion
to a substrate.
PMID- 9548726
TI - Accelerated nerve regeneration mediated by Schwann cells expressing a mutant form
of the POU protein SCIP.
AB - After injury, the peripheral nervous system (PNS) is capable of full regeneration
and recovery of function. Many molecular events that are the hallmarks of the
regenerating PNS are recapitulations of developmental processes. The expression
of one such molecule, the POU transcription factor suppressed cAMP-inducible POU
protein (SCIP), is required for the establishment of normal nerves and is
reexpressed during regeneration. Here we describe markedly accelerated
regeneration and hypertrophy of both myelin and axons in transgenic mice that
express an amino-terminal deletion of the SCIP molecule. This mutant SCIP
molecule retains the POU-specific and POU homeodomain moieties, which allow for
both DNA binding and some protein-protein interaction. We demonstrate that the
transgene indirectly effects dramatic axonal changes. This is the first
demonstration of a genetically controlled acceleration of neural regeneration.
PMID- 9548728
TI - Integrin and cadherin synergy regulates contact inhibition of migration and
motile activity.
AB - Integrin receptors play a central role in cell migration through their roles as
adhesive receptors for both other cells and extracellular matrix components. In
this study, we demonstrate that integrin and cadherin receptors coordinately
regulate contact-mediated inhibition of cell migration. In addition to promoting
proliferation (Sastry, S., M. Lakonishok, D. Thomas, J. Muschler, and A. Horwitz.
1996. J. Cell Biol. 133:169-184), ectopic expression of the alpha5 integrin in
cultures of primary quail myoblasts promotes a striking contact-mediated
inhibition of cell migration. Myoblasts ectopically expressing alpha5 integrin
(alpha5 myoblasts) move normally when not in contact, but upon contact, they show
inhibition of migration and motile activity (i.e., extension and retraction of
membrane protrusions). As a consequence, these cells tend to grow in aggregates
and do not migrate to close a wound. This phenotype is also seen with ectopic
expression of beta1 integrin, paxillin, or activated FAK (CD2 FAK) and therefore
appears to result from enhanced integrin-mediated signaling. The contact
inhibition observed in the alpha5 myoblasts is mediated by N-cadherin, whose
expression is upregulated more than fivefold. Perturbation studies using low
calcium conditions, antibody inhibition, and ectopic expression of wild-type and
mutant N-cadherins all implicate N-cadherin in the contact inhibition of
migration. Ectopic expression of N-cadherin also produces cells that show
inhibited migration upon contact; however, they do not show suppressed motile
activity, suggesting that integrins and cadherins coordinately regulate motile
activity. These observations have potential importance to normal and pathologic
processes during embryonic development and tumor metastasis.
PMID- 9548727
TI - p21 is a critical CDK2 regulator essential for proliferation control in Rb
deficient cells.
AB - Proliferation in mammalian cells is controlled primarily in the G1-phase of the
cell cycle through the action of the G1 cyclin-dependent kinases, CDK4 and CDK2.
To explore the mechanism of cellular response to extrinsic factors, specific loss
of function mutations were generated in two negative regulators of G1
progression, p21 and pRB. Individually, these mutations were shown to have
significant effects in G1 regulation, and when combined, Rb and p21 mutations
caused more profound defects in G1. Moreover, cells deficient for pRB and p21
were uniquely capable of anchorage-independent growth. In contrast, combined
absence of pRB and p21 function was not sufficient to overcome contact inhibition
of growth nor for tumor formation in nude mice. Finally, animals with the
genotype Rb+/-;p21(-/-) succumbed to tumors more rapidly than Rb+/- mice,
suggesting that in certain contexts mutations in these two cell cycle regulators
can cooperate in tumor development.
PMID- 9548731
TI - Heterobifunctional Cross-Linkers Containing 4,9-Dioxa-1,12-dodecanediamine
Spacers
PMID- 9548732
TI - Identification of the upper exciton component of the B850 bacteriochlorophylls of
the LH2 antenna complex, using a B800-free mutant of Rhodobacter sphaeroides.
AB - In this paper, we report the circular dichroism (CD) spectra of two types of LH2
only mutants of Rhodobacter sphaeroides. In the first, only the wild type LH2 is
present, while i the second, the B800 binding site of LH2 has been either
destabilized or removed. For the first time, we have identified a band in the CD
spectrum of LH2, located at approximately 780 nm, that can be ascribed to the
high exciton component of the B850 band. The experimental spectra have been
modeled by theoretical calculations. On this basis, the average interaction
strength between the monomers in the B850 ring can be estimated to be
approximately 300 cm-1. In addition, we suggest that in LH2 of Rb. sphaeroides
the angles made by the Qy transitions of the B850 BChls with respect to the plane
of the ring are slightly different from those calculated from the crystal
structure of the Rhodopseudomonas acidophila LH2 complex.
PMID- 9548729
TI - Modulation of beta1A integrin functions by tyrosine residues in the beta1
cytoplasmic domain.
AB - beta1A integrin subunits with point mutations of the cytoplasmic domain were
expressed in fibroblasts derived from beta1-null stem cells. beta1A in which one
or both of the tyrosines of the two NPXY motifs (Y783, Y795) were changed to
phenylalanines formed active alpha5 beta1 and alpha6 beta1 integrins that
mediated cell adhesion and supported assembly of fibronectin. Mutation of the
proline in either motif (P781, P793) to an alanine or of a threonine in the inter
motif sequence (T788) to a proline resulted in poorly expressed, inactive beta1A.
Y783,795F cells developed numerous fine focal contacts and exhibited motility on
a surface. When compared with cells expressing wild-type beta1A or beta1A with
the D759A activating mutation of a conserved membrane-proximal aspartate, Y783,
795F cells had impaired ability to transverse filters in chemotaxis assays.
Analysis of cells expressing beta1A with single Tyr to Phe substitutions
indicated that both Y783 and Y795 are important for directed migration. Actin
containing microfilaments of Y783,795F cells were shorter and more peripheral
than microfilaments of cells expressing wild-type beta1A. These results indicate
that change of the phenol side chains in the NPXY motifs to phenyl groups (which
cannot be phosphorylated) has major effects on the organization of focal contacts
and cytoskeleton and on directed cell motility.
PMID- 9548730
TI - Rho-mediated contractility exposes a cryptic site in fibronectin and induces
fibronectin matrix assembly.
AB - Many factors influence the assembly of fibronectin into an insoluble fibrillar
extracellular matrix. Previous work demonstrated that one component in serum that
promotes the assembly of fibronectin is lysophosphatidic acid (Zhang, Q., W.J.
Checovich, D.M. Peters, R.M. Albrecht, and D.F. Mosher. 1994. J. Cell Biol.
127:1447-1459). Here we show that C3 transferase, an inhibitor of the low
molecular weight GTP-binding protein Rho, blocks the binding of fibronectin and
the 70-kD NH2-terminal fibronectin fragment to cells and blocks the assembly of
fibronectin into matrix induced by serum or lysophosphatidic acid. Microinjection
of recombinant, constitutively active Rho into quiescent Swiss 3T3 cells promotes
fibronectin matrix assembly by the injected cells. Investigating the mechanism by
which Rho promotes fibronectin polymerization, we have used C3 to determine
whether integrin activation is involved. Under conditions where C3 decreases
fibronectin assembly we have only detected small changes in the state of integrin
activation. However, several inhibitors of cellular contractility, that differ in
their mode of action, inhibit cell binding of fibronectin and the 70-kD NH2
terminal fibronectin fragment, decrease fibronectin incorporation into the
deoxycholate insoluble matrix, and prevent fibronectin's assembly into fibrils on
the cell surface. Because Rho stimulates contractility, these results suggest
that Rho-mediated contractility promotes assembly of fibronectin into a fibrillar
matrix. One mechanism by which contractility could enhance fibronectin assembly
is by tension exposing cryptic self-assembly sites within fibronectin that is
being stretched. Exploring this possibility, we have found a monoclonal antibody,
L8, that stains fibronectin matrices differentially depending on the state of
cell contractility. L8 was previously shown to inhibit fibronectin matrix
assembly (Chernousov, M.A., A.I. Faerman, M.G. Frid, O.Y. Printseva, and V.E.
Koteliansky. 1987. FEBS (Fed. Eur. Biochem. Soc.) Lett. 217:124-128). When it is
used to stain normal cultures that are developing tension, it reveals a matrix
indistinguishable from that revealed by polyclonal anti-fibronectin antibodies.
However, the staining of fibronectin matrices by L8 is reduced relative to the
polyclonal antibody when the contractility of cells is inhibited by C3. We have
investigated the consequences of mechanically stretching fibronectin in the
absence of cells. Applying a 30-35% stretch to immobilized fibronectin induced
binding of soluble fibronectin, 70-kD fibronectin fragment, and L8 monoclonal
antibody. Together, these results provide evidence that self-assembly sites
within fibronectin are exposed by tension.
PMID- 9548733
TI - Generation of an angiostatin-like fragment from plasminogen by stromelysin-1 (MMP
3).
AB - Matrix metalloproteinase-3 (MP-3 or stromelysin-1) specifically hydrolyzes the
Glu59-Asn60, Pro447-Val448, and Pro544-Ser545 peptide bonds in plasminogen,
yielding a 55 kDa NH2-terminal angiostatin-like domain (comprising kringles 1-4),
a 14 kDa domain comprising kringle 5, and a 30 kDa domain comprising the serine
proteinases domain. The conversion is completely abolished in the presence of the
MMP inhibitors EDTA or 1,10-phenanthroline. Biospecific interactions analysis
indicates that binding of proMMP-3 and MMP-3 to plasminogen occurs with
comparable affinity (KA of 4.7 x 10(6) and 4.1 x 10(6) M-1, respectively) and is
mediated via the miniplasminogen moiety (kringle 5 plus the proteinase domain)
and via the catalytic domain of MMP-3. Thus, proteolytic cleavage of plasminogen
by MMP-3 generates angiostatin-like fragments.
PMID- 9548735
TI - A permanent hole burning study of the FMO antenna complex of the green sulfur
bacterium Prosthecochloris aestuarii.
AB - A permanent hole burning study on the Fenna-Matthews-Olson, or FMO, antenna
complex of the green sulfur bacterium Prosthecochloris aestuarii was carried out
at 6 K. Excitation resulted not only in relatively sharp features resonant with
the burn wavelength but also in broad absorbance changes in the wavelength region
of 800-820 nm. The shape of the latter changes was almost independent of the
wavelength of excitation. Evidence is given that they are induced by a different
mechanism than that which causes the resonant holes and that they may be due to a
conformational change of the protein. The original spectrum was restored upon
warming to 60 K. The effective dephasing times T2, as obtained from the
homogeneous line widths, increased from about 0.5 ps at 803 nm to >/=20 ps at 830
nm and are in good agreement with recent measurements of accumulated photon-echo
and time-resolved absorbance changes.
PMID- 9548734
TI - The 23 and 17 kDa extrinsic proteins of photosystem II modulate the magnetic
properties of the S1-state manganese cluster.
AB - An S1-state parallel polarization "multiline" EPR signal arising from the oxygen
evolving complex has been detected in spinach (PSII) membrane and core
preparations depleted of the 23 and 17 kDa extrinsic polypeptides, but retaining
the 33 kDa extrinsic protein. This S1-state multiline signal, with an effective g
value of 12 and at least 18 hyperfine lines, has previously been detected only in
PSII preparations from the cyanobacterium sp. Synechocystis sp. PCC6803
[Campbell, K. A., Peloquin, J. M., Pham, D. P., Debus, R. J., and Britt, R. D.
(1998) J. Am. Chem. Soc. 120, 447-448]. It is absent in PSII spinach membrane and
core preparations that either fully retain or completely lack the 33, 23, and 17
kDa extrinsic proteins. The S1-state multiline signal detected in spinach PSII
cores and membranes has the same effective g value and hyperfine spacing as the
signal detected in Synechocystis PSII particles. This signal provides direct
evidence for the influence of the extrinsic PSII proteins on the magnetic
properties of the Mn cluster.
PMID- 9548736
TI - Catalase-free photosystem II: the O2-evolving complex does not dismutate hydrogen
peroxide.
AB - A photosystem II (PSII) membrane-associated heme catalase has been identified as
a major source of the dark H2O2-dismutation reaction in PSII membrane samples
[Sheptovitsky, Y. G., and Brudvig, G. W. (1996) Biochemistry 35, 16255-16263].
Based on this finding, a catalase-free PSII membrane sample was prepared by using
mild heat treatment to deplete most of the PSII membrane-associated heme catalase
followed by inhibition of the residual catalase with 50 mM 3-amino-1,2,4
triazole, a specific heme catalase inhibitor that binds covalently to compound I.
After these treatments, the PSII membrane sample exhibited only 0.02% of the
original H2O2-dismutation activity when assayed in the presence of 20 mM 3-amino
1,2,4-triazole. This small residual H2O2-dismutation activity is attributed to
adventitious metal ions or the non-heme iron in PSII because the activity was
still present in a Mn-depleted PSII sample but was completely suppressed by
adding 5 mM ferricyanide to the assay buffer; the effect of ferricyanide is
attributed to oxidation of H2O2-dismutating cations. Although the H2O2
dismutation activity was completely eliminated by these treatments, the light
induced O2-evolution activity was retained. A single saturating flash given to
catalase-free PSII membranes did not induce any H2O2-dismutation activity. These
results demonstrate that the S1/S-1 and S2/S0 cycles of the O2-evolving complex
of PSII do not occur in the presence of H2O2, as proposed by Velthuys, B., and
Kok, B. [(1978) Biochim. Biophys. Acta 502, 211-221]. The light-induced O2
evolution activity in catalase-free PSII was found to be irreversibly impaired by
micromolar concentrations of H2O2. Thus, it is possible that the PSII membrane
associated heme catalase plays an important role in protection of the O2-evolving
complex from damage by H2O2.
PMID- 9548737
TI - Dynamics of the DNA binding domain of the fructose repressor from the analysis of
linear correlations between the 15N-1H bond spectral densities obtained by
nuclear magnetic resonance spectroscopy.
AB - The spectral densities of the backbone and arginine side chain NH bonds of the
DNA binding domain of the fructose repressor (FruR) were extensively analyzed in
order to extract reliable motions parameters. An accurate measurement of 15N NMR
relaxation rates allowed their calculation at three frequencies, zero, omegaN,
and omegaH + omegaN, using a reduced matrix approach. Linear correlations were
found between J(omegaN) and J(0) and between and J(0). The analysis
of the compatibility between the motions parameters obtained independently from
the two correlation lines allowed further development of the linear correlation
approach proposed recently [Lefevre, J. F., Dayie, K. T., Peng, J. W., and
Wagner, G. (1996) Biochemistry 35, 2674-2686]. The results demonstrate (i) the
existence of a concerted motion along the whole backbone with a global
correlation time equal to 5.95 ns.rad-1, and (ii) the presence of complex
internal movements at an intermediate time scale around 1 ns. The extracted
motion parameters have been related to those obtained with the extended Lipari
and Szabo approach but are incompatible with those obtained using the usual
simple Lipari and Szabo approach. They were correlated to the features of the NMR
structure of FruR(1-57)*. Some residues in the turns and in the third helix
experience slow motions in the micro- to millisecond time scale. Side-chain
motions are not correlated to the backbone dynamics. A direct examination of
spectral densities reveals a higher flexibility for the side chains of arginines
that are not involved in ionic bridges.
PMID- 9548738
TI - The crystal structure of phosphoribulokinase from Rhodobacter sphaeroides reveals
a fold similar to that of adenylate kinase.
AB - The essential photosynthetic enzyme phosphoribulokinase (PRK) is responsible for
the conversion of ribulose 5-phosphate (Ru5P) to ribulose 1,5-bisphosphate, the
substrate for the CO2 fixing enzyme ribulose 1,5-bisphosphate
carboxylase/oxygenase (Rubisco). We have determined the structure of the
octameric bacterial form of PRK to a resolution of 2.5 A. The protein is folded
into a seven-member mixed beta-sheet surrounded by alpha-helices, giving the
overall appearance of the nucleotide monophosphate family of kinases. Homology
with the nucleotide monophosphate kinases suggests a number of amino acid
residues that are likely to be important in catalysis and suggests the roles of
some amino acid residues that have been mutated prior to the determination of the
structure. Further, sequence identity across eukaryotic and prokaryotic species
and a calculation of the buried surface area suggests the identity within the
octamer of a dimer conserved throughout evolution. The width of the groove
leading to the active site is consistent with an oriented molecule of thioredoxin
controlling the oxidation state of two cysteines that regulate activity in the
eukaryotic enzymes. Although neither Asp 42 nor Asp 169 can be definitively
assigned as the catalytic base, the crystal structure suggests the location of a
ribulose 5-phosphate binding site and suggests a role for several of the
conserved basic residues.
PMID- 9548739
TI - A new class of HIV-1 Tat antagonist acting through Tat-TAR inhibition.
AB - The main transcriptional regulator of the human immunodeficiency virus, the Tat
protein, recognizes and binds to a small structured RNA element at the 5' end of
every viral mRNA, termed TAR. On the basis of published structural data of the
molecular interactions between TAR and Tat-related peptides, we defined
requirements for potential low-molecular weight inhibitors of TAR recognition by
the Tat protein. In accordance with the resulting concept, a series of compounds
was synthesized. In vitro evaluation of their potential to directly interfere
with Tat-TAR interaction was used to define a new chemical class of potent Tat
antagonistic substances. The most active compound competed with Tat-TAR
complexation with a competition dose CD50 of 22 nM in vitro and blocked HIV
expression in a cellular Tat transactivation system with an IC50 of 1.2 microM.
The close relation between structural features of the interaction between TAR and
a new type of inhibitory agent, "In-PRiNts" (for inhibitor of protein
ribonucleotide sequences), such as CGP 40336A and those of the Tat-TAR complex
was confirmed by RNase A footprinting and by two-dimensional NMR. Structural
implications for the complex between this class of compounds and TAR RNA will be
presented.
PMID- 9548740
TI - Biochemical characterization and crystallographic structure of an Escherichia
coli protein from the phosphotriesterase gene family.
AB - Phosphotriesterase homology protein (PHP) is a member of a recently discovered
family of proteins related to phosphotriesterase, a hydrolytic, bacterial enzyme
with an unusual substrate specificity for synthetic organophosphate triesters and
phosphorofluoridates, which are common constituents of chemical warfare agents
and agricultural pesticides. No natural substrate has been identified for
phosphotriesterase, and it has been suggested that the enzyme may have evolved
the ability to hydrolyze synthetic compounds in bacteria under selective pressure
to meet nutritional needs. PHP, which has 28% sequence identity with
phosphotriesterase, may belong to the family of proteins from which
phosphotriesterase evolved. Here we report the cloning, expression, initial
characterization, and high-resolution X-ray crystallographic structure of PHP.
Biochemical analysis shows that PHP is monomeric and binds two zinc ions per
monomer. Unlike phosphotriesterase, PHP does not catalyze the hydrolysis of
nonspecific phosphotriesters. The structure, similar to that of
phosphotriesterase, consists of a long, elliptical alpha/beta barrel and has a
binuclear zinc center in a cleft at the carboxy end of the barrel at the location
of the presumptive active site.
PMID- 9548741
TI - Structure of bovine pancreatic cholesterol esterase at 1.6 A: novel structural
features involved in lipase activation.
AB - The structure of pancreatic cholesterol esterase, an enzyme that hydrolyzes a
wide variety of dietary lipids, mediates the absorption of cholesterol esters,
and is dependent on bile salts for optimal activity, is determined to 1.6 A
resolution. A full-length construct, mutated to eliminate two N-linked
glycosylation sites (N187Q/N361Q), was expressed in HEK 293 cells. Enzymatic
activity assays show that the purified, recombinant, mutant enzyme has activity
identical to that of the native, glycosylated enzyme purified from bovine
pancreas. The mutant enzyme is monomeric and exhibits improved homogeneity which
aided in the growth of well-diffracting crystals. Crystals of the mutant enzyme
grew in space group C2, with the following cell dimensions: a = 100.42 A, b =
54.25 A, c = 106.34 A, and beta = 104.12 degrees, with a monomer in the
asymmetric unit. The high-resolution crystal structure of bovine pancreatic
cholesterol esterase (Rcryst = 21.1%; Rfree = 25.0% to 1.6 A resolution) shows an
alpha-beta hydrolase fold with an unusual active site environment around the
catalytic triad. The hydrophobic C terminus of the protein is lodged in the
active site, diverting the oxyanion hole away from the productive binding site
and the catalytic Ser194. The amphipathic, helical lid found in other
triglyceride lipases is truncated in the structure of cholesterol esterase and
therefore is not a salient feature of activation of this lipase. These two
structural features, along with the bile salt-dependent activity of the enzyme,
implicate a new mode of lipase activation.
PMID- 9548742
TI - Protein-induced changes in nonplanarity of the porphyrin in nickel cytochrome c
probed by resonance Raman spectroscopy.
AB - The influence of the protein on the nonplanarity of the macrocycle for nickel(II)
reconstituted cytochrome c (NiCyt-c) has been investigated with pH-dependent
resonance Raman and UV-visible absorption spectroscopy and molecular mechanics
calculations. The spectra reveal that NiCyt-c near neutral pH has axially
coordinated Ni, but below pH 3 and above pH 12, four-coordinate species
predominate. The shape of the structure-sensitive Raman line nu10 of NiCyt-c is
asymmetric and broad and it changes with pH. This broad line can be decomposed
well into at least two sublines, a low-frequency line that results from a
nonplanar conformer and a high-frequency line that arises from a nearly planar
conformer. Upon lowering the pH from 3.0 to 1.0, the amount of the nonplanar
conformer decreases relative to that of the planar conformer. The decreased
nonplanarity can be accounted for in terms of the disruption of a hydrogen
bonding network in the peptide backbone upon lowering the pH. Molecular mechanics
(MM) calculations on iron(III) and nickel(II) microperoxidase 5 (MP-5) as well as
some model heme derivatives have been carried out in order to locate the part of
the protein that causes the heme distortion observed in the X-ray crystal
structures of cytochromes c. The energy-optimized structures of MP-5 and the
model compounds were analyzed using the normal-coordinate structural
decomposition method to specify and quantify the out-of-plane macrocyclic
distortions. MM calculations for MP-5 show that two hydrogen bonds formed between
the amide groups in the peptide backbone are important in maintaining the ruffled
deformation of the macrocycle. All evidence presented supports the hypothesis
that the nonplanar distortion of the porphyrin of cytochromes c is largely
maintained by a relatively small protein segment including the cysteines, the
amino acids between the cysteines, and the adjacent histidine ligand. Hydrogen
bonding within the backbone of this segment is important in maintaining the
conformation of the peptide that induces the porphyrin distortion.
PMID- 9548743
TI - Hydroxyl radical footprinting of DNA complexes of the ets domain of PU.1 and its
comparison to the crystal structure.
AB - Hydroxyl radical footprinting has been used to probe interactions in complexes
between the ets domain of the murine transcription factor PU.1 and three
different DNA restriction fragments, each containing one copy of the recognition
sequence 5'-GGAA-3'. Two natural PU.1 binding sites, the SV40 enhancer site and
the lambdaB motif of Ig lambda2-4 enhancer, were used as well as the PU.1 binding
site present in the crystallized PU.1-DNA complex [Kodandapani, R., Pio, F., Ni,
C.-Z., Piccialli, G., Klemsz, M., McKercher, S. R., Maki, R. A., and Ely, K. R.
(1996) Nature 380, 456-460]. The footprints obtained for the three different DNA
sequences are almost identical. The extent of contact with the protein was
monitored for every base in the complex. Two concentration-dependent cleavage
sites on the complementary TTCC strand are evidence of a specific interaction
between PU.1 and the DNA. Two more protection sites and a hypersensitive cleavage
site on the GGAA strand were observed. Although these data confirm the global
structure of the PU.1-DNA complex as suggested by crystallography, the
footprinting data reveal differences between the protein-DNA contacts in solution
and in the crystal state. An additional interaction site not present in the
crystal structure was observed by hydroxyl radical footprinting.
PMID- 9548745
TI - Aminoacylation of coenzyme A and pantetheine by aminoacyl-tRNA synthetases:
possible link between noncoded and coded peptide synthesis.
AB - Isoleucyl-tRNA synthetase (IleRS) catalyzes transfer of isoleucine from the
enzyme-bound Ile-AMP and Ile-tRNA to the thiol group of coenzyme A, forming a
thioester, Ile-S-CoA. Identity of Ile-S-CoA has been confirmed by several
enzymatic and chemical tests. The synthesis of Ile-S-CoA, like the synthesis of
other isoleucyl thioesters, is strongly shifted toward products. Other aminoacyl
tRNA synthetases, such as MetRS, AspRS, and SerRS also use CoA-SH as an acceptor
for their cognate amino acids. Pantetheine also serves as an amino acid acceptor
in reactions catalyzed by AspRS, IleRS, and MetRS, forming corresponding
aminoacyl-S-pantetheine thioesters. It appears that CoA-SH reacts with activated
amino acids by binding to each synthetase at a site, separate from the tRNA and
ATP binding sites, that includes the thiol-binding subsite. These and other data
support a hypothesis that the present-day aminoacyl-tRNA synthetases have
originated from ancestral forms that were involved in noncoded thioester
dependent peptide synthesis, functionally similar to the present-day nonribosomal
peptide synthesis by multi-enzyme thiotemplate systems.
PMID- 9548744
TI - The DNA intercalating alkaloid cryptolepine interferes with topoisomerase II and
inhibits primarily DNA synthesis in B16 melanoma cells.
AB - Cryptolepine hydrochloride is an indoloquinoline alkaloid isolated from the roots
of Cryptolepis sanguinolenta. It is characterized by a multiplicity of host
mediated biological activities, including antibacterial, antiviral, and
antimalarial properties. To date, the molecular basis for its diverse biological
effects remains largely uncertain. Several lines of evidence strongly suggest
that DNA might correspond to its principal cellular target. Consequently, we
studied the strength and mode of binding to DNA of cryptolepine by means of
absorption, fluorescence, circular, and linear dichroism, as well as by a
relaxation assay using DNA topoisomerases. The results of various optical and gel
electrophoresis techniques converge to reveal that the alkaloid binds tightly to
DNA and behaves as a typical intercalating agent. In DNAase I footprinting
experiments it was found that the drug interacts preferentially with GC-rich
sequences and discriminates against homo-oligomeric runs of A and T. This study
has also led to the discovery that cryptolepine is a potent topoisomerase II
inhibitor and a promising antitumor agent. It stabilizes topoisomerase II-DNA
covalent complexes and stimulates the cutting of DNA at a subset of preexisting
topoisomerase II cleavage sites. Taking advantage of the fluorescence of the
indoloquinoline chromophore, fluorescence microscopy was used to map cellular
uptake of the drug. Cryptolepine easily crosses the cell membranes and
accumulates selectively into the nuclei rather than in the cytoplasm of B16
melanoma cells. Quantitative analyses of DNA in cells after Feulgen reaction and
image cytometry reveal that the drug blocks the cell cycle in G2/M phases. It is
also shown that the alkaloid is more potent at inhibiting DNA synthesis rather
than RNA and protein synthesis. Altogether, the results provide direct evidence
that DNA is the primary target of cryptolepine and suggest that this alkaloid is
a valid candidate for the development of tumor active compounds.
PMID- 9548746
TI - RNase H1 can catalyze RNA/DNA hybrid formation and cleavage with stable hairpin
or duplex DNA oligomers.
AB - Cleavage of a RNA target site by RNase H1 from Escherichia coli was examined in
the presence of complementary DNA sequences in the form of single-stranded,
duplex, and hairpin structures. The target site was a 15 nt sequence in the
middle of a 79 nt RNA transcript. DNA molecules employed included seven single
stranded oligodeoxynucleotides 10 or 15 nt long, and five hairpin DNAs each with
a 10 bp stem and 5 nt loop. The loop and 3' side of the stem of two of the
hairpin DNAs were fully complementary to the target site, while the other hairpin
DNAs had sequence changes. A 10 bp duplex DNA with one strand complementary to
the target site was also employed. A gel electrophoresis mobility shift assay
examined hybrid formation between the RNA and the single-stranded 15 nt DNA and
two hairpin DNAs that contained 15 complementary bases. RNA titration of the 32P
labeled single-stranded DNA produced a shifted band indicative of RNA/DNA complex
formation. No RNA/DNA complex was detected when the more stable (Tm = 71 degrees
C) hairpin DNA was combined with excess RNA. The less stable hairpin DNA (Tm = 62
degrees C) showed a small amount ( approximately 8%) of hybrid formation.
Thermodynamic analysis of RNA binding to the DNAs was in qualitative agreement
with the results. Although no RNA/DNA hybrid was expected from thermodynamic
calculations, a RNase H assay at 25 degrees C showed that hairpin or duplex DNAs
with a 10 nt complementary sequence catalyzed RNA degradation. A complementary
loop sequence in the hairpin DNA was not required. Cleavage of the RNA did not
occur with hairpin DNAs containing three or four noncomplementary bases in the
stem. The results show that RNase H can promote the formation and cleavage of a
RNA/DNA hybrid between an RNA site and a base paired strand of a stable hairpin
or duplex DNA at temperatures below their Tm.
PMID- 9548747
TI - Euplotes telomerase: evidence for limited base-pairing during primer elongation
and dGTP as an effector of translocation.
AB - The telomeric sequence repeats at the ends of eukaryotic chromosomes are
maintained by the ribonucleoprotein enzyme telomerase. Telomeric DNA primers are
bound by telomerase both at the active site, which includes base-pairing with the
RNA template, and at a second anchor site. The stabilities of Euplotes
aediculatus primer-telomerase complexes were determined by measuring their
dissociation rates (koff), using an assay involving photo-cross-linking at the
anchor site. The primer length was varied, and mismatched substitutions were
introduced in a systematic manner. We observed that koff does not scale with
primer length as expected for accumulated primer-template base-pairing. This
suggests that telomerase maintains a more-or-less constant number of base pairs,
similar to the transcription bubble maintained by RNA polymerase. An upper limit
was estimated by comparing the experimental koff for the primer-telomerase
complex to that of a model DNA-RNA duplex. All the binding energy could be
attributed to 10 or 11 base pairs; alternatively, there could be <10 base pairs,
with the remaining energy contributed by other parts of telomerase. Most primers
exhibited biphasic dissociation kinetics, with variations in both the amount in
each phase and the rate for each phase. Since the cross-links monitored in the
dissociation assay were all formed with the 5' region of the primer, the two
phases may arise from different base-pairing registers with the RNA template,
possibly representing pre- and post-translocation complexes. A shift from slow
phase to fast phase dissociation was observed in the presence of dGTP, which may
implicate dGTP as a positive effector of translocation.
PMID- 9548748
TI - Single amino acid substitutions at the N-terminus of a recombinant cytotoxic
ribonuclease markedly influence biochemical and biological properties.
AB - Onconase is a cytotoxic ribonuclease with antitumor properties. A semisynthetic
gene encoding the entire protein sequence was constructed by fusing
oligonucleotides coding for the first 15 and the last 6 of the 104 amino acids to
a genomic clone that encoded the remaining amino acid residues [Newton, D. L., et
al. (1997) Protein Eng. 10, 463-470]. The resulting protein product expressed in
Escherichia coli exhibited little enzymatic or cytotoxic activity due to the
unprocessed N-terminal Met amino acid residue. In this study, we demonstrate that
modification of the 5'-region of the gene to encode [Met-(-1)]Ser or [Met-(
1)]Tyr instead of the native pyroglutamate results in recombinant onconase
derivatives with restored activities. [Met-(-1)]rOnc(E1S) was more active than
[Met-(-1)]rOnc(E1Y) in all assays tested. Consistent with the action of native
onconase, [Met-(-1)]rOnc(E1S) was a potent inhibitor of protein synthesis in the
cell-free rabbit reticulocyte lysate assay, degrading tRNA at concentrations that
correlated with inhibition of protein synthesis. An interesting difference
between the recombinant onconase derivatives and the native protein was their
susceptibility to inhibition by the major intracellular RNase inhibitor, PRI
(onconase is refractory to PRI inhibition). [Met-(-1)]rOnc(E1S) and [Met-(
1)]rOnc(E1Y) inhibited protein synthesis in intact SF539 neuroblastoma cells with
IC50's very similar to that of onconase (IC50 3.5, 10, and 10 microg/mL after 1
day and 0.16, 0.35, and 2.5 microg/mL after 5 days for onconase, [Met-(
1)]rOnc(E1S), and [Met-(-1)]rOnc(E1Y), respectively). Similar to that of
onconase, cytotoxic activity of the recombinant derivatives was potentiated by
monensin, NH4Cl, and retinoic acid. Brefeldin A completely blocked the
enhancement of cytotoxicity caused by retinoic acid with all three proteins.
Thus, drug-induced alterations of the intracellular trafficking of the
recombinant derivatives also resembles that of onconase. Stability studies as
assessed in serum-containing medium in the presence or absence of cells at 37
degreesC showed that the recombinant proteins were as stable to temperature and
cell culture conditions as the native protein. Therefore, exchanging the Glu
amino acid residue at the amino terminus of onconase with an amino acid residue
containing a hydroxyl group produces recombinant proteins with ribonuclease and
cytotoxic properties similar to native onconase.
PMID- 9548749
TI - Misincorporation of nucleotides opposite five-membered exocyclic ring guanine
derivatives by escherichia coli polymerases in vitro and in vivo: 1,N2
ethenoguanine, 5,6,7,9-tetrahydro-9-oxoimidazo[1, 2-a]purine, and 5,6,7,9
tetrahydro-7-hydroxy-9-oxoimidazo[1, 2-a]purine.
AB - A variety of exocyclic modified bases have been shown to be formed in DNA from
various procarcinogens (e.g., acrolein, malonaldehyde, vinyl chloride, urethan)
and are also found in untreated animals and humans, presumably arising as a
result of lipid peroxidation. 1, N2-Ethenoguanine (1,N2-epsilon-Gua), a product
known to be formed from several 2-carbon electrophiles, was placed in a known
site (6256) in bacteriophage M13MB19 and mutations were analyzed in Escherichia
coli, with 2.05% G-->A, 0.74% G-->T, and 0.09% G-->C changes found in uvrA-
bacteria. 5,6,7, 9-Tetrahydro-7-hydroxy-9-oxoimidazo[1,2-a]purine (HO-ethanoGua),
formally the hydrated derivative of 1,N2-epsilon-Gua, is a stable DNA product
also derived from vinyl halides. When this base was placed in the same context,
the mutation rate was 0.007-0.19% for G-->A, C, or T changes. The saturated
etheno ring derivative of 1, N2-epsilon-Gua, 5,6,7,9-tetrahydro-9-oxoimidazo[1,2
a]purine (ethanoGua) produced G-->A and G-->T mutations (0.71% each). All mutants
were SOS-dependent and were attenuated by uvrA activity in E. coli. In vitro
studies with four polymerases showed strong blocks to addition beyond the adduct
site in the order ethanoGua > HO-ethanoGua > 1,N2-epsilon-Gua. Both E. coli
polymerases (pol) I exo- and II exo- and bacteriophage pol T7 exo- showed
extensive misincorporation opposite ethanoGua in vitro, with pol I exo-
incorporating G and T, pol II exo- incorporating A, and pol T7 exo- incorporating
A and G. All modified bases reduced the use of the minus strand bearing the
modified guanine in E. coli cells. It is of interest that even though the normal
base pairing site of guanine is completely blocked, all of the five-membered ring
derivatives incorporate the normal base (C) in >80% of the replication events in
E. coli. Major differences in blockage and misincorporation are seen due to what
might appear to be relatively modest structural differences, and polymerases can
differ dramatically in their selectivities.
PMID- 9548750
TI - Escherichia coli cAMP receptor protein-DNA complexes. 1. Energetic contributions
of half-sites and flanking sequences in DNA recognition.
AB - In Escherichia coli, the cyclic AMP receptor protein (CRP) serves as a sensor of
the intracellular level of cyclic AMP. At increasing concentrations of cyclic
AMP, CRP becomes activated upon binding a cyclic AMP molecule. The activated CRP
is capable of regulating the expression of more than 20 genes by binding to
specific DNA sites. The specific DNA sequences recognized by CRP consist of two
half-sites of the consensus sequence TGTGA......XCAXA. At present, the relative
contributions of the two half-site and flanking sequences in the energetics of
CRP recognition have not been quantitatively defined. A series of 20 DNA
sequences was designed to dissect the contributions of individual half-sites and
flanking sequences using the natural gal P1 and lac P1 sequences as the initial
targets. The binding of CRP to these DNA sequences was monitored by fluorescence
anisotropy. None of the individual half-sites or flanking sequences contributes
more to the binding energetics than a random sequence. In the lac P1 sequence,
the combination of both half-sites leads to a >100-fold increase in affinity
compared to that of an individual half-site in CRP-DNA complex formation. The
flanking sequence of lac P1 exhibits a 10- and 0-fold enhancement in affinity for
CRP compared to that of a random sequence in the presence and absence of the two
half-sites, respectively. The observations of the gal P1 sequence differ from
those of the lac P1 sequence. The combination of both half-sites exhibits no
significant increase in affinity, but the flanking sequence exhibits a 100-fold
enhancement in the presence of the two half-sites. However, there is a
disproportionate contribution from the flanking sequence proximal to the
conserved TGTGA motif. The total energetics of the gal-CRP complex formation is
essentially due to the presence of the conserved half-site and its adjacent
flanking sequence. Thus, the relative contributions of the half-site and flanking
sequences to the energetics of DNA recognition are operon specific.
PMID- 9548751
TI - Escherichia coli cAMP receptor protein-DNA complexes. 2. Structural asymmetry of
DNA bending.
AB - The effect of DNA sequence variability and the degree of cyclic AMP receptor
protein (CRP)-induced bending of the flanking ends of fluorescently labeled DNA
were investigated by steady-state fluorescence and differential phase
polarization studies in the presence and absence of CRP. Six sequences, including
the primary CRP binding sites of lac P1 (class I) and gal P1 (class II), were
studied. Excitation and emission spectra of CPM-DNA upon binding CRP were
observed to be qualitatively similar to one another, regardless of the CRP
binding site sequence examined or the location of the probe. This result implies
that the probe is not interacting with the protein. However, the magnitude of the
changes in the fluorescence intensities of sensitized emission spectra of CPM-DNA
is apparently dependent on the DNA sequence, indicating that the environments of
the flanking ends of DNA may be different from one another in the protein-DNA
complex. Differential phase polarization results were qualitatively consistent
with the fluorescence energy transfer measurements. The implication of this study
supports the idea that the DNA is bent symmetrically in the lac-CRP complex but
is asymmetrically bent in the gal-CRP complex. The sequence in the half-site in
conjunction with the flanking sequence defines the geometry of the bent DNA. It
appears that the CRP-induced bend in the DNA may also be class dependent. This
may be an important feature used by the system to regulate transcription at
different promoter sites.
PMID- 9548752
TI - Effect of nucleosome structure on DNA interstrand cross-linking reactions.
AB - Antitumor agents of the nitrogen mustard family and mitomycin C form interstrand
cross-links in duplex DNA. To provide information about the cellular mechanism by
which these compounds exert their cytotoxic effects, we examined cross-linking of
a nucleosomal core particle formed on a fragment of the 5S RNA gene of Xenopus
borealis. For the mustards mechlorethamine, chlorambucil, and melphalan, both
sites of monoalkylation and interstrand cross-linking were similar in nucleosomal
and free DNA. Some small (two- to three- fold) differences in intensity of cross
linking at some sites were apparent. However, these differences did not appear to
correlate with rotational or translational positioning. For mitomycin C, cross
linking was inhibited five- to ten-fold at the nucleosomal dyad and showed
attenuation of inhibition toward the ends. Furthermore, rotational positioning
also appeared to be a factor, with sites facing inward in the nucleosome less
accessible for mitomycin cross-linking. None of these agents demonstrated the 10
base pair periodicity exhibited by hydroxyl radical cleavage of nucleosomal DNA.
PMID- 9548753
TI - Formation of native disulfide bonds in endothelin-1. Structural evidence for the
involvement of a highly specific salt bridge between the prosequence and the
endothelin-1 sequence.
AB - The [Lys-Arg]-endothelin-1 analogue (KR-ET-1) yields almost selectively the
native disulfide pattern (96%), in contrast to endothelin-1 (ET-1) that gives at
least 25% of the non-native disulfide pattern. We have previously shown that the
carboxylate-state structure of KR-ET-1 is more constrained and stabilized by a
salt bridge between Arg(-1) and the Asp8 or Glu10 side chain [Aumelas et al.
(1995) Biochemistry 34, 4546-4561]. To identify this salt bridge and its
potential involvement in the disulfide bond formation, [E10Q], [D18N], and [D8N]
carboxamide analogues were studied, which led to the unambiguous identification
of the Arg(-1)-Asp8 salt bridge. Furthermore, while [E10Q] and [D18N] analogues
gave a high yield of the native isomer (>/=90%), the [D8N] analogue afforded a
ratio of the two isomers close to that observed for ET-1 (68%) [Kubo et al.
(1997) Lett. Pept. Sci. 4, 185-192]. Assuming that the formation of disulfide
bonds occurs in a thermodynamically controlled step, we have hypothesized that
the Arg(-1)-Asp8 salt bridge and concomitant interactions could be responsible
for the increase in yield of the native isomer of KR-ET-1. In the present work,
we describe the structural studies of the carboxamide analogues and of the minor
non-native KR-ET-1 isomer. On the basis of 1H NMR and CD spectra as a function of
pH, [E10Q] and [D18N] analogues display a conformational change similar to that
of the parent peptide, whereas the structure of the [D8N] analogue is unchanged.
For the non-native isomer, we measured a lower helical content than for the
native isomer and observed a marked difference in the orientation of the KRCSC
backbone. In addition, no salt bridge was experimentally observed. Altogether,
these results allow us to hypothesize that the salt bridge between two highly
conserved residues, one belonging to the prosequence [Arg(-1)] and the other to
the mature sequence [Asp8], is involved in the formation of the native disulfide
isomer of ET-1. The involvement of the prosequence in the formation of the native
disulfide isomer strongly suggests that, in the maturation pathway of ET-1,
cleavage of the Arg52-Cys53 amide bond occurs after native disulfide bond
formation.
PMID- 9548754
TI - ATP-Dependent human erythrocyte glutathione-conjugate transporter. I.
Purification, photoaffinity labeling, and kinetic characteristics of ATPase
activity.
AB - Dinitrophenyl S-glutathione (DNP-SG) ATPase is a 38 kDa membrane protein
expressed in erythrocytes and other tissues. Although stimulation of ATP
hydrolysis catalyzed by DNP-SG ATPase has been demonstrated in the presence of
several structurally unrelated amphiphilic ions, structural and functional
properties of this protein have not been well-defined. In the present study, we
have developed an improved protocol for the purification of DNP-SG ATPase and
investigated its kinetic and substrate-binding properties. The purification
procedure was based on highly specific elution of the 38 kDa protein from DNP-SG
affinity resin in the presence of ATP. The protein could not be eluted using
either ADP or adenosine-5'-[beta,gamma-methylene]triphosphate (methylene-ATP), a
nonhydrolyzable analogue of ATP. Doxorubicin (DOX), a weakly basic anthracycline
chemotherapy agent, was found to be the preferred activator for stimulation of
ATP hydrolysis by the enzyme. ATP binding to the enzyme was demonstrated using 8
azido-ATP photoaffinity labeling and binding of trinitrophenyl (TNP)-ATP, a
fluorescent analogue of ATP. The photoaffinity labeling of DNP-SG ATPase (38 kDa)
was saturable with respect to 8-azido ATP (Kd = 2 microM), indicating that the
enzyme was capable of specific and saturable binding to ATP. DNP-SG binding was
evident from the purification procedure itself and was also demonstrable by
quenching of tryptophan fluorescence. Results of quenching of tryptophan
fluorescence as well as radioactive isotope-binding studies indicated that DOX
was bound to the purified protein as well.
PMID- 9548755
TI - ATP-Dependent human erythrocyte glutathione-conjugate transporter. II. Functional
reconstitution of transport activity.
AB - Purified dinitrophenyl S-glutathione (DNP-SG) ATPase was reconstituted into
artificial liposomes prepared from soybean asolectin. Electron micrography
confirmed the formation of unilamellar vesicles with an average radius of 0.25
micron. Intravesicular volume estimated by incorporation of radiolabled inulin
into the vesicles was found to be 19.7 +/- 1.3 microL/mL reconstitution solution.
Accumulation of the glutathione-conjugate of CDNB, DNP-SG, and of doxorubicin
(DOX) in the proteoliposomes was increased in the presence of ATP as compared to
equimolar ADP or adenosine 5'-[beta,gamma-methylene]triphosphate tetralithium.
ATP-dependent transmembrane movement of DOX and DNP-SG into DNP-SG ATPase
reconstituted vesicles was saturable with respect to time, sensitive to the
osmolarity of the assay medium, and temperature dependent. The energy of
activation was found to be 12 and 15 kcal/mol for DNP-SG and DOX, respectively.
Optimal temperature for transport was 37 degrees C. Saturable transport was
demonstrated for DNP-SG (Vmax of 433 +/- 20 nmol/min/mg of protein, KmATP = 2.4
+/- 0. 3 mM and KmDNP-SG = 36 +/- 5 microM) as well as DOX (Vmax = 194 +/- 19
nmol/min/mg of protein, KmATP = 2.5 +/- 0.6 mM and KmDOX = 2.4 +/- 0.7 microM).
The kinetic data for both DNP-SG and DOX transport were consistent with a random
bi-bi sequential reaction mechanism. DOX was found to be a competitive inhibitor
of DNP-SG transport with Kis of 1.2 +/- 0.2 microM and DNP-SG was found to be a
competitive inhibitor of DOX transport with Kis of 13.3 +/- 2.6 microM.
PMID- 9548756
TI - Regulation of RhoA GTP hydrolysis by the GTPase-activating proteins p190,
p50RhoGAP, Bcr, and 3BP-1.
AB - The small GTP-binding protein RhoA becomes inactivated by hydrolyzing bound GTP
to GDP through its intrinsic GTPase activity which is further stimulated by a
family of Rho GTPase-activating proteins (GAPs). Here we have compared the
kinetics of interaction between recombinant RhoA and the RhoGAP domains of p190,
p50RhoGAP, Bcr, and 3BP-1. The intrinsic rate of GTP hydrolysis by RhoA is
relatively slow when compared to other Rho-family GTPases such as Cdc42 or Rac1
with a rate constant of 0.022 min-1, which can be further stimulated at least
4000-fold by p190 or p50RhoGAP. The RhoGAP domains of Bcr and 3BP-1, which were
thought to be inactive toward RhoA, are also found capable of stimulating the
GTPase activity of RhoA in a dose-dependent manner. The supreme catalytic
activities of p190 and p50RhoGAP toward RhoA reside mostly in their lower Km
values (1.79 and 2.83 microM, respectively) which correlate well with their
binding affinity for GMP-PNP-bound RhoA (2.18 and 2. 47 microM, respectively), in
contrast with Bcr and 3BP-1 which interact with the activated RhoA with much
higher Km (89 microM). However, the mechanisms of catalysis by p190 and p50RhoGAP
are distinct in at least three aspects: (1) p50RhoGAP displays an effect of
product inhibition by binding to the GDP-bound form of RhoA with a Kd of 6 microM
in comparison with the Kd for p190 of 33 microM; (2) the Km of p190 increases
drastically upon the increase of salt and Mg2+ concentrations, conditions under
which only modest changes of Km for p50RhoGAP are observed; and (3) p50RhoGAP
remains partially active toward the effector domain mutants of RhoA, Y34K, and
T37A, whereas p190 is completely inactive toward Y34K and T37A. These results
suggest that there exists a unique mechanism of functional interaction between
RhoA and individual RhoGAP which involves distinct structural determinants of the
small G-protein to cause the apparent differences in kinetic properties.
PMID- 9548757
TI - Cross-class inhibition of the cysteine proteinases cathepsins K, L, and S by the
serpin squamous cell carcinoma antigen 1: a kinetic analysis.
AB - The human squamous cell carcinoma antigens (SCCA) 1 and 2 are tandemly arrayed
genes that encode two high-molecular-weight serine proteinase inhibitors
(serpins). Although these proteins are 92% identical, differences in their
reactive site loops suggest that they inhibit different types of proteinases. Our
previous studies show that SCCA2 inhibits chymotrypsin-like serine proteinases
[Schick et al. (1997) J. Biol. Chem. 272, 1849-1855]. We now show that, unlike
SCCA2, SCCA1 lacks inhibitory activity against any of the more common types of
serine proteinases but is a potent cross-class inhibitor of the archetypal
lysosomal cysteine proteinases cathepsins K, L, and S. Kinetic analysis revealed
that SCCA1 interacted with cathepsins K, L, and S at 1:1 stoichiometry and with
second-order rate constants >/= 1 x 10(5) M-1 s-1. These rate constants were
comparable to those obtained with the prototypical physiological cysteine
proteinase inhibitor, cystatin C. Also relative to cystatin C, SCCA1 was a more
potent inhibitor of cathepsin K-mediated elastolytic activity by forming longer
lived inhibitor-proteinase complexes. The t1/2 of SCCA1-cathepsin S complexes was
>1155 min, whereas that of cystatin C-cathepsin complexes was 55 min. Cleavage
between the Gly and Ser residues of the reactive site loop and detection of a
stable SCCA1-cathepsin S complex by sodium dodecyl sulfate-polyacrylamide gel
electrophoresis suggested that the serpin interacted with the cysteine proteinase
in a manner similar to that observed for typical serpin-serine proteinase
interactions. These data suggest that, contingent upon their reactive site loop
sequences, mammalian serpins, in general, utilize their dynamic tertiary
structure to trap proteinases from more than one mechanistic class and that
SCCA1, in particular, may be involved in a novel inhibitory pathway aimed at
regulating a powerful array of lysosomal cysteine proteinases.
PMID- 9548758
TI - Role of zinc in the structure and toxic activity of botulinum neurotoxin.
AB - Zn2+-protease activity of botulinum neurotoxin causes the blockage of
neurotransmitter release resulting in botulism disease. We have investigated the
role of Zn2+ in the biological activity of type A botulinum neurotoxin by
removing the bound Zn2+ by EDTA treatment, followed by monitoring its structure
in terms of secondary and tertiary folding (second derivative UV, FT-IR, and
circular dichroism spectroscopy) and function in terms of its effect on the
release of norepinephrine from PC12 cells. The single Zn2+ bound to each
neurotoxin molecule was reversibly removed by EDTA treatment, whereas the
biological activity of the neurotoxin was irreversibly lost. Based on the Amide
III IR spectral analysis, the alpha-helical content of neurotoxin increased from
29% to 42% upon removal of Zn2+, which reverted to 31% upon treatment with 1:5
molar excess of exogenous Zn2+. Second derivative UV spectroscopy revealed no
change in surface topography of Tyr residues with removal of Zn2+. However, near
UV circular dichroism signals suggested significant alterations in the topography
of Phe and Tyr residues that could be buried in the protein matrix. Thermal
unfolding experiments suggested that removal of Zn2+ results in the formation of
the molten globule-like structure of type A botulinum neurotoxin. Tertiary
structural changes introduced by Zn2+ removal were irreversible, which correlated
well with the irreversibility of the biological activity of the neurotoxin. On
the basis of these results, we suggest that Zn2+ plays a significant structural
role in addition to its catalytic role in Zn2+-protease activity of type A
botulinum neurotoxin.
PMID- 9548759
TI - Effect of ligand conformation on melanoma cell alpha3beta1 integrin-mediated
signal transduction events: implications for a collagen structural modulation
mechanism of tumor cell invasion.
AB - The importance of three-dimensional interactions between receptors with their
respective ligands has been extensively explored during the binding process, but
considerably less so for postbinding events such as induction of signaling
pathways. Tumor cell receptor association with basement membrane proteins is
believed to facilitate the metastatic process. Melanoma and ovarian carcinoma
cells have been shown to utilize the alpha3beta1 integrin to bind to models of
the alpha1(IV)531-543 sequence from basement membrane (type IV) collagen [Miles,
A. J., et al. (1994) J. Biol. Chem. 269, 30939-30945; Miles, A. J., et al. (1995)
J. Biol. Chem. 270, 29047-29050]. In the present study, the effects of ligand
three-dimensional structure on possible signal transduction pathways induced by
alpha3beta1 integrin binding have been evaluated. Human melanoma cell binding to
type IV collagen resulted in Tyr phosphorylation of p125(FAK), consistent with
prior studies correlating beta1 integrin subunit binding to collagen and
p125(FAK) Tyr phosphorylation. Cross-linking of an anti-alpha3 integrin subunit
monoclonal antibody also induced p125(FAK) Tyr phosphorylation. Incubation of
melanoma cells with single-stranded or triple-helical peptide models of
alpha1(IV)531-543 induced Tyr phosphorylation of intracellular proteins.
Immunoprecipitation analysis identified one of these proteins as pp125(FAK).
Induction of p125(FAK) Tyr phosphorylation was enhanced and the time of induction
was shortened when the ligand was used in triple-helical conformation. Subsequent
clustering of either the single-stranded or the triple-helical ligand also
increased the level of p125(FAK) phosphorylation compared to unclustered ligand.
The clustered triple-helical peptide ligand induced more rapid paxillin Tyr
phosphorylation than the single-stranded ligand. In addition, the induction of
activated proteases was found to be more rapid due to ligand triple helicity.
Overall, these studies have shown that (i) a model of an isolated sequence from
type IV collagen, alpha1(IV)531-543, can induce alpha3beta1 integrin-mediated
signal transduction in melanoma cells and (ii) ligand conformation (secondary,
tertiary, and/or quaternary structure) can directly influence several alpha3beta1
integrin-mediated signal transduction events. The effects of ligand conformation
suggest that a "collagen structural modulation" mechanism may exist for tumor
cell invasion, whereby triple-helical collagen promotes cell binding and
induction of signal transduction, subsequently leading to collagen dissolution by
proteases, decreased signal transduction, and enhanced tumor cell motility.
PMID- 9548760
TI - Interaction of mant-adenosine nucleotides and magnesium with kinesin.
AB - Displacement of the fluorescent substrate analogue methylanthraniloyl ADP (mant
ADP) from kinesin by excess ATP results in a biphasic fluorescent transient. The
pH and microtubule dependence of the rates and amplitudes indicates that the two
phases are produced by release of bound mant-ADP, with an excess of the 3'
isomer, followed by the subsequent relaxation of the free 2'- and 3'-isomers to
their equilibrium distribution. The first phase for release of mant-ADP is
accelerated by microtubules and occurs at the same rate as ADP release measured
using [32P]ADP. The second phase is subject to base catalysis and occurs at the
same rate as the isomerization of isolated 2'- or 3'-mant-ATP over a 100-fold
range of rates. The bound mant-ADP isomers undergo isomerization rapidly when
bound to kinesin at pH 8.2, whereas mant-ADP isomers interconvert only slowly
when bound to myosin. No fluorescence resonance energy transfer occurs between
the single tryptophan in the kinesin neck domain and bound mant-ADP, but
efficient energy transfer does occur from protein tyrosine groups. The rate of
mant-ADP release in the absence of microtubules is minimal (0.005 s-1) at pH 7-8,
2 mM Mg2+, and 25 mM KCl but is accelerated at lower pH (0.04 s-1 at pH 5.5) and
either lower or higher [KCl] (0.01 and 0. 06 s-1 at 0 and 800 mM KCl,
respectively). The microtubule-stimulated rate of ADP release is accelerated at
low pH and inhibited by high concentrations of monovalent salts. Reduction of the
free Mg2+ by addition of excess EDTA increases the release of mant-ADP from
E.MgADP to 0.03 s-1. This acceleration at low Mg2+ likely represents sequential
release of Mg2+ at 0.03 s-1 followed by rapid release of ADP, as the rate of ADP
release from Mg-free E.ADP is fast (>0.5 s-1). At high Mg2+, rebinding of Mg2+ to
E.ADP forces release of ADP from the E.MgADP complex at 0.005 s-1.
PMID- 9548761
TI - Glucosylation and ADP ribosylation of rho proteins: effects on nucleotide
binding, GTPase activity, and effector coupling.
AB - We studied the effects of glucosylation of RhoA, Rac1, and Cdc42 at threonine-35
and -37 by Clostridium difficile toxin B on nucleotide binding, GTPase activity,
and effector coupling and compared these results with the ADP ribosylation of
RhoA at asparagine-41 catalyzed by Clostridium botulinum C3 transferase. Whereas
glucosylation and ADP ribosylation had no major effects on GDP release from RhoA,
Rac1, and Cdc42, the rate of GTPgammaS release from Rho proteins was increased 3
6-fold by glucosylation. ADP ribosylation decreased the rate of GTPgammaS release
by about 50%. Glucosylation reduced the intrinsic activities of the GTPases by 3
7-fold and completely blocked GTPase stimulation by Rho-GAP. In contrast, ADP
ribosylation slightly increased GTPase activity ( approximately 2-fold) and had
no major effect on GAP stimulation of GTPase. Whereas ADP ribosylation did not
affect the interaction of RhoA with the binding domain of protein kinase N,
glucosylation inhibited this interaction. Glucosylation of Rac1 markedly
diminished its ability to support the activation of the superoxide-generating
NADPH oxidase of phagocytes. Glucosylated Rac1 did not interfere with NADPH
oxidase activation by unmodified Rac1, even when present in marked molar excess,
indicating that it was incapable of competing for a common effector. The data
indicate that the functional inactivation of small GTPases by glucosylation is
mainly caused by inhibition of GTPase-effector protein interaction.
PMID- 9548762
TI - Probing catalytic hinge bending motions in thermolysin-like proteases by glycine
-> alanine mutations.
AB - The active site of thermolysin-like proteases (TLPs) is located at the bottom of
a cleft between the N- and C-terminal domains. Crystallographic studies have
shown that the active-site cleft is more closed in ligand-binding TLPs than in
ligand-free TLPs. Accordingly, it has been proposed that TLPs undergo a hinge
bending motion during catalysis resulting in "closure" and "opening" of the
active-site cleft. Two hinge regions have been proposed. One is located around a
conserved glycine 78; the second involves residues 135 and 136. The importance of
conserved glycine residues in these hinge regions was studied experimentally by
analyzing the effects of Gly --> Ala mutations on catalytic activity. Eight such
mutations were made in the TLP of Bacillus stearothermophilus (TLP-ste) and their
effects on activity toward casein and various peptide substrates were determined.
Only the Gly78Ala, Gly136Ala, and Gly135Ala + Gly136Ala mutants decreased
catalytic activity significantly. These mutants displayed a reduction in kcat/Km
for 3-(2-furylacryloyl)-L-glycyl-L-leucine amide of 73%, 62%, and 96%,
respectively. Comparisons of effects on kcat/Km for various substrates with
effects on the Ki for phosphoramidon suggested that the mutation at position 78
primarily had an effect on substrate binding, whereas the mutations at positions
135 and 136 primarily influence kcat. The apparent importance of conserved
glycine residues in proposed hinge-bending regions for TLP activity supports the
idea that hinge-bending is an essential part of catalysis.
PMID- 9548763
TI - A single calcium binding site is crucial for the calcium-dependent thermal
stability of thermolysin-like proteases.
AB - Thermostable thermolysin-like proteases (TLPs), such as the TLP of Bacillus
stearothermophilus CU-21 (TLP-ste), bind calcium in one double (Ca1,2) and two
single (Ca3, Ca4) calcium binding sites. The single sites are absent in
thermolabile TLPs, suggesting that they are determinants of (variation in) TLP
stability. Mutations in the Ca3 and Ca4 sites of TLP-ste indeed reduced thermal
stability, but only mutations in the Ca3 site affected the calcium-dependence of
stability. The predominant effect of the Ca3 site results from the fact that the
Ca3 site is part of a region of TLP-ste, which unfolding is crucial for thermal
inactivation. Thermal inactivation is not caused by the absence of calcium from
the Ca3 site per se, but rather by unfolding of a region of TLP-ste for which
stability depends on the occupancy of the Ca3 site. In accordance with this
concept is the observation that the effects of mutations in the Ca3 site could be
compensated by stabilizing mutations near this site. In addition, it was observed
that the contribution of calcium binding to the Ca3 was substantially reduced in
extremely stable TLP-ste variants containing multiple stabilizing mutations in
the Ca3 region. Apparently, in these latter variants, unfolding of the Ca3 region
contributes little to the overall process of thermal inactivation.
PMID- 9548764
TI - Equilibrium and kinetic unfolding properties of dimeric human glutathione
transferase A1-1.
AB - The equilibrium and kinetic unfolding properties of homodimeric class alpha
glutathione transferase (hGST A1-1) were characterized. Urea-induced equilibrium
unfolding data were consistent with a folded dimer/unfolded monomer transition.
Unfolding kinetics were investigated, using stopped-flow fluorescence, as a
function of denaturant concentration (3.5-8.9 M urea) and temperature (10-40
degrees C). The unfolding pathway, monitored by tryptophan fluorescence, was
biphasic with a fast unfolding event (millisecond time range with enhanced
fluorescence properties) and a slow unfolding event (seconds to minutes time
range with quenched fluorescence properties). Both events occurred simultaneously
from 3.5 M urea. Each phase displayed single-exponential behavior, consistent
with two unimolecular reactions. Urea-dependence studies and thermodynamic
activation parameters (transition-state theory) suggest that the transition state
for each phase is well-structured and is closely related to native protein in
terms of solvent exposure. The apparent activation Gibbs free energy change in
the absence of denaturant, DeltaG (H2O), indicates that the slow unfolding event
represents the transition state for the overall unfolding pathway. The rate and
urea independence of each phase on the initial condition exclude the possibility
of a preexisting equilibrium between various native forms in the pretransition
baseline. The unfolding pathways monitored by energy transfer to or direct
excitation of AEDANS covalently linked to Cys111 in hGST A1-1 were monophasic
with urea and temperature properties similar to those observed for the slow
unfolding event (described above). A sequential unfolding kinetic mechanism
involving the partial dissociation of the two structurally distinct domains per
subunit followed by complete domain and subunit unfolding is proposed.
PMID- 9548765
TI - Small-angle X-ray solution-scattering studies on ligand-induced subunit
interactions of the thiamine diphosphate dependent enzyme pyruvate decarboxylase
from different organisms.
AB - The quaternary structures of the thiamine diphosphate dependent enzyme pyruvate
decarboxylase (EC 4.1.1.1) from the recombinant wild type of
Saccharomycescerevisiae and Zymomonas mobilis and from germinating Pisum sativum
seeds were examined by X-ray solution scattering. The dependence of the subunit
association equilibrium on the pH and the presence of the cofactors thiamine
diphosphate and magnesium ions were compared, and the differences between the
catalytic properties of the different enzymes are discussed. The influence of
amino acid substitutions at the cofactor binding site of the enzyme from
Saccharomyces cerevisiae (E51 is substituted by Q or A and G413 by W) on the
subunit association was examined. Low-resolution models of the P. sativum,
Z.mobilis, and S. cerevisiae enzymes were evaluated ab initio from the scattering
data. The enzyme from the bacterium and yeast appear as a dimer of dimers,
whereas the plant enzyme is an octamer formed by two tetramers arranged side-by
side. The shape of the S. cerevisiae enzyme agrees well with the atomic structure
in the crystal but suggests that the dimers in the latter should be tilted by
approximately 10 degrees. The resulting modification of the atomic structure also
yields a significantly better fit to the experimental solution scattering data
than that calculated form the original crystallographic model.
PMID- 9548766
TI - Probing the structure of the cytoplasmic domain of the aspartate receptor by
targeted disulfide cross-linking
PMID- 9548767
TI - Anaerobic dechlorinating bacteria.
AB - Anaerobic dehalogenation is attracting great interest since it opens new research
horizons based on the novel biochemical mechanisms identified in this field such
as halorespiration, i.e. the utilization of halogenated compounds as electron
acceptors. Moreover, anaerobic bacteria seem to be more efficient than their
aerobic counterparts in removing halogen atoms from polyhalogenated compounds.
Thus, anaerobic dehalogenation can be considered as a promising means for
bioremediation treatments of persistently polluted environments. In this line,
identification of pure strains capable of dehalogenation will give important
information about the diversity of organisms implicated in this process and also
fundamental explanations of the diverse biochemical mechanisms involved. In light
of these considerations, we chose to focus this review on the physiological
descriptions, dechlorination activities, phylogenetic diversity, and potential
biotechnological applications of these pure anaerobic strains capable of
dehalogenation.
PMID- 9548768
TI - Synthesis of bisected glycoforms of recombinant IFN-beta by overexpression of
beta-1,4-N-acetylglucosaminyltransferase III in Chinese hamster ovary cells.
AB - Genetic engineering of oligosaccharide biosynthesis pathways in mammalian cells
makes possible generation of new recombinant glycoproteins of potential
importance in the biopharmaceutical industry. Most prior investigations of
glycosylation engineering of secreted heterologous glycoproteins involve terminal
steps of oligosaccharide biosynthesis. In particular, increasing the frequency of
bisected structures within the glycoform distribution has not before been
considered. A Chinese hamster ovary (CHO) cell line capable of producing bisected
oligosaccharides on glycoproteins was created by overexpression of a recombinant
N-acetylglucosaminyltransferase III (GnT-III). Interferon beta (IFN-beta) was
chosen as a model and potential therapeutic secreted heterologous protein to
demonstrate the effect of recombinant GnT-III-expression on product
glycosylation. IFN-beta with bisected oligosaccharides was produced by the GnT
III-engineered CHO cells but not by the unmodified parental cell line.
PMID- 9548769
TI - Dynamic cell seeding of polymer scaffolds for cartilage tissue engineering.
AB - Cell seeding of three-dimensional polymer scaffolds is the first step of the
cultivation of engineered tissues in bioreactors. Seeding requirements of large
scaffolds to make implants for potential clinical use include: (a) high yield, to
maximize the utilization of donor cells, (b) high kinetic rate, to minimize the
time in suspension for anchorage-dependent and shear-sensitive cells, and (c)
high and spatially uniform distribution of attached cells, for rapid and uniform
tissue regeneration. Highly porous, fibrous polyglycolic acid scaffolds, 5-10 mm
in diameter and 2-5 mm thick, were seeded with bovine articular chondrocytes in
well-mixed spinner flasks. Essentially, all cells attached throughout the
scaffold volume within 1 day. Mixing promoted the formation of 20-32-micron
diameter cell aggregates that enhanced the kinetics of cell attachment without
compromising the uniformity of cell distribution. The kinetics and possible
mechanisms of cell seeding were related to the formation of cell aggregates by a
simple mathematical model that can be used to optimize seeding conditions for
cartilage tissue engineering.
PMID- 9548770
TI - Screening tool for hollow-fiber bioreactor process development
AB - Fundamental research of factors affecting cell growth in hollow-fiber bioreactors
is hindered by the lack of an efficient screening tool. To address this issue, a
hollow-fiber micro-bioreactor has been developed. Hollow fibers with 10 kDa
molecular weight cutoffs are housed within a piece of silicone tubing. Cells are
inoculated within the hollow fibers which provides a 0.2-mL culture volume. The
space between the fibers and silicone tubing (5 or 16 mL) is used as a medium
reservoir sufficient to feed the cells for at least 24 h. Oxygenation is provided
directly through the silicone tubing so that a pump for medium recirculation is
not required. As a result, many conditions can be tested simultaneously in a
single incubator. Three days after inoculation at 5 x 10(6) cells/mL in the micro
bioreactor, the rho 1D4 murine hybridoma cell line reached 2.8 x 10(7) cells/mL
with an antibody concentration of 0.17 mg/mL. When inoculated at 5 x 10(7)
cells/mL, the cell concentration reached 1.8 x 10(8)/mL after 3 days with an
antibody concentration of 1.0 mg/mL. Results from a series of experiments with
the micro-bioreactor suggested that the initial growth phase of this cell line in
a hollow-fiber system is dependent on the serum concentration in the medium
reservoir. This prediction was tested by simultaneously inoculating two
production-scale hollow-fiber bioreactor systems. The cell side of the membrane
for each bioreactor contained 10% serum, but serum was added to the reservoir
side of only one of the bioreactors. The cells with only basal medium in the
reservoir died after a few days, while the cells with 10% serum in the medium
reservoir grew rapidly. These results demonstrate that the micro-bioreactor
developed here can support good cell growth and that it can be used as a research
tool to predict the performance of large-scale hollow-fiber systems.
PMID- 9548771
TI - Heat-induced translocation of cytoplasmic beta-galactosidase across inner
membrane of Escherichia coli.
AB - The behaviors of heat-induced translocation of cytoplasmic beta-galactosidase to
periplasm across the inner membrane of Escherichia coli cells were investigated
in order to apply such phenomena to the process for production and separation of
intracellular biomolecules. The heat stress was found to induce translocation of
cytoplasmic beta-galactosidase (beta-gal) together with reduction of the amounts
of intracellular soluble proteins and formation of their inactive aggregates. The
translocation of beta-gal was then analyzed using (a) the location factor of beta
gal (LFG), which meant enzyme location in the cells and could be determined from
the kinetic analysis of enzyme release process, and (b) the percentage of beta
gal activity in periplasm after solublizing the outer membrane of E. coli cells
by lysozyme/EDTA treatment. The LFG values were maximized when cells were
stressed at the temperature of 42-47 degrees C. From the results on the surface
properties of both beta-gal and cell membrane under the heat stress, it is
suggested that (1) the conformational change of cytoplasmic oligomeric beta-gal
to the partially dissociated and/or unfolded state with higher local
hydrophobicity, (2) the increase in membrane fluidity of inner membrane, (3) the
enhancement of hydrophobic interaction between lipid and protein, and (4) the
inhibition of its translocation by GroEL restabilizing the proteins could
underlie the heat-induced translocation of beta-gal across the inner membrane.
The possibility to apply the heat-induced translocation of beta-gal for the
enhancement of the target selectivity at the process upstream is finally
presented.
PMID- 9548773
TI - Appearance of protease activities coincides with p10 and polyhedrin-driven
protein production in the baculovirus expression system: effects on yield.
AB - A study of proteolysis effects on recombinant protein yield was completed using
the insect cell (Sf-9)-baculovirus (AcNPV) expression system. Activities of
protease and beta-galactosidase (beta-gal), a marker heterologous protein, were
assayed at various multiplicities of infection (MOI = 1, 5, and 20) on a time
course postinfection. Also, several protein-substrate gel electrophoresis assays
were run using gelatin, beta-gal, and bovine serum albumin (BSA) in the gel
matrix, to determine the protein specificity of the proteases. The most abundant
protease activity (cysteine), found at 49 kDa, degraded all three substrates, pre
and post-infection. Two other protease activities (40 and 36 kDa) appeared on
polyacrylamide gel electrophoresis (PAGE) gels after 72 hpi (hours
postinfection). In addition, the culture with the highest MOI had the highest
beta-gal activity until 72 hpi, when the activity dramatically decreased
coincidentally with a 2.5-fold increase in protease activity. This result and the
electrophoresis evidence that the protease is specific to beta-gal, indicate that
there is a negative correlation between protease activity and recombinant protein
yield. These results guide efforts to control product-degrading proteolysis in
insect cell-baculovirus expression systems by harvest timing and the addition of
protease inhibitors.
PMID- 9548772
TI - Model system for heat-induced translocation of cytoplasmic beta-galactosidase
across phospholipid bilayer membrane.
AB - The possibility of the translocation of the enzyme across the phospholipid
bilayer membrane was investigated by using the liposomes prepared by 1-palmitoyl
2-oleoyl-sn-glycero-3-phosphocholine (POPC) in which beta-galactosidase (beta
gal) was entrapped. Exposing the POPC liposomes entrapping beta-gal inside to
heat treatment (40-50 degrees C, 1-60 min) was found to induce its translocation
across the liposome membrane. The translocated activity of beta-gal from inner to
outer aqueous phase of liposomes indicated the maximal value when the liposomes
entrapping beta-gal were heated at 45 degrees C for 30 min. The gel permeation
profiles of the liposomes before and after heat treatment (45 degrees C, 30 min)
also supported the translocation of beta-gal across the liposome membrane. The
membrane fluidity of liposomes was found to be increased with increasing
temperature, so that the hydrophobicity of liposome membrane was also increased.
The local hydrophobicity of beta-gal was maximized at the temperature of 40-50
degrees C. The mechanisms of beta-gal translocation have been suggested to be
triggered by the enhancement of hydrophobic interaction between the liposome
surface and beta-gal molecules. Finally, a minimal scheme of possible mechanism
on the heat-induced translocation of beta-gal has been presented on the basis of
the hydrophobic interaction between the liposome and the proteins. The
experimental data on the heat-induced translocation of beta-gal were well
corresponding to those from model calculation.
PMID- 9548774
TI - Influence of morphology on product formation in aspergillus awamori during
submerged fermentations
AB - The relationship between fungal morphology and heterologous protein production
was examined for an Aspergillus awamori strain during a series of fermentations
with a batch phase followed by a fed-batch phase. Agitation rate and inoculation
concentration were used as controlled variables to generate different fungal
morphologies in 20-dm3 stirred tank reactors. Morphology was quantitatively
characterized using Image Analysis. The different agitation rates and inoculum
concentrations had large effects on the development in hyphal length and number
of tips during the fermentations. A reduced inoculum concentration resulted in a
more branched mycelium. The different agitation rates affected the morphology
after 30 h of fermentation significantly but did not affect the start time of
fragmentation. A 3-fold increase in hyphal length increased the apparent
viscosity by a factor of 7. The observed morphological differences had only a
limited effect on product formation, suggesting that the structural features such
as hyphal length and number of tips are of less importance for product formation.
The primary effect of morphology on product formation is due to viscosity.
PMID- 9548776
TI - Computational fluid dynamics model for predicting flow of viscous fluids in a
large fermentor with hydrofoil flow impellers and internal cooling coils
AB - Considerable debate has occurred over the use of hydrofoil impellers in large
scale fermentors to improve mixing and mass transfer in highly viscous non
Newtonian systems. Using a computational fluid dynamics software package (Fluent,
version 4.30) extensive calculations were performed to study the effect of
impeller speed (70-130 rpm), broth rheology (value of power law flow behavior
index from 0.2 to 0.6), and distance between the cooling coil bank and the
fermentor wall (6-18 in.) on flow near the perimeter of a large (75-m3) fermentor
equipped with A315 impellers. A quadratic model utilizing the data was developed
in an attempt to correlate the effect of A315 impeller speed, power law flow
behavior index, and distance between the cooling coil bank and the fermentor wall
on the average axial velocity in the coil bank-wall region. The results suggest
that there is a potential for slow or stagnant flow in the coil bank-wall region
which could result in poor oxygen and heat transfer for highly viscous
fermentations. The results also indicate that there is the potential for slow or
stagnant flow in the region between the top impeller and the gas headspace when
flow through the coil bank-wall region is slow. Finally, a simple guideline was
developed to allow fermentor design engineers to predict the degree of flow
behind a bank of helical cooling coils in a large fermentor with hydrofoil flow
impellers.
PMID- 9548775
TI - Bacterial acid phosphatase gene fusions useful as targets for cloning-dependent
insertional inactivation.
AB - The Morganella morganii phoC gene, encoding a class A acid phosphatase, was used
to generate gene fusions with modified amino-terminal moieties of the Escherichia
coli lacZ gene carrying a multiple-cloning site flanked by phage-specific
promoters and recognition sites for universal sequencing primers. The
corresponding hybrid proteins retained a PhoC-like enzymatic activity which is
easily detectable by a plate histochemical assay, rendering similar gene fusions
potentially useful as targets for cloning-dependent insertional inactivation.
Cloning experiments performed in plasmids carrying similar lacZ-phoC fusions
confirmed their usefulness as cloning vectors for direct screening of
recombinants. As compared to conventional lacZ alpha-complementation-based
vectors, which can only be used in E. coli hosts carrying specific lacZ
mutations, the lacZ-phoC fusion-based vectors can be used in combination with any
E. coli host and require a less expensive histochemical assay for screening of
recombinants, while retaining all the advantageous features that made the former
so popular as general purpose cloning vehicles.
PMID- 9548777
TI - Production of cell-free xanthan fermentation broth by cell adsorption on fibers
AB - Xanthan gum is a microbial polysaccharide widely used in food and oil-drilling
industries. Xanthan gum produced from the current commercial fermentation process
usually contains cells and cell debris, which lower the filterability of the
xanthan solution and limit its applications. The production of cell-free xanthan
gum fermentation broth is thus desirable. The feasibility of removing cells from
the xanthan fermentation broth by cell adsorption to various woven fibrous
materials was studied. It was found that both cotton and polyester fibers could
be used to adsorb Xanthomonas campestris cells present in the fermentation broth
either during batch fermentation or after the fermentation. Almost all cells were
removed from the fermentation broth by adsorption to fibers. Cotton terry cloth
had rough surfaces and was the preferred material for cell adsorption. Cell
adsorption to cotton was faster than to polyester fibers. The adsorption kinetics
can be modeled by a first-order rate equation. The adsorption rate constants were
30-40% higher for cotton than for polyester. Cell adsorption was not efficient in
the absence of xanthan gum, suggesting that the exopolysaccharide, xanthan gum,
was important for efficient cell adsorption to fibers.
PMID- 9548778
TI - Enhancing xanthan fermentations by different modes of glucose feeding
AB - This paper is the fourth in a series aimed at improving the understanding and
operation of conventional agitated fermenters for the production of the
commercially important gum, Xanthan. In the first, reproducible fermentations
were established and this protocol was used in studies of different agitator
types and of bulk mixing and dissolved oxygen concentration in the next two.
Here, building on the previous work, the influence of different glucose feeding
strategies on Xanthan production in a 20-L agitated fermenter under equivalent
conditions of agitation and dissolved oxygen is reported. The biological
performances in three types of fed-batch cultures (a two-step glucose addition,
multiple glucose-pulse feeding and continuous feeding of glucose) are compared to
two batch fermentations with different initial glucose concentrations. The work
confirmed that improved performance cannot be achieved by increasing the initial
glucose concentration above 50 g/L nor by a single 10 g/L pulse addition (initial
glucose concentration of 40 g/L) while significant nitrogen is still present. On
the other hand, the simple pulse and continuous feeding strategies, after
nitrogen has been essentially exhausted and under conditions of nonlimiting
dissolved oxygen and similar bulk mixing, can result in a greatly enhanced
performance compared to batch fermentations. Using the final Xanthan gum
concentration, the yield on glucose and the overall productivity as performance
indices, values of 62 g/L, 0.82 g of Xanthan/g of glucose, and 0.72 g/(L.h),
respectively, were obtained compared to literature values for conventional
stirred bioreactors of 15-30 g/L, 0.27-0.86 g of Xanthan/g of glucose, and 0. 12
0.43 g/(L.h).
PMID- 9548779
TI - Production of 2-phenylethyl alcohol by Kluyveromyces marxianus.
AB - Among the numerous yeasts able to produce flavor compounds, several strains of
Kluyveromyces species are known for the synthesis of large amounts of aromatic
compounds. In particular, the accumulation of 2-phenylethyl alcohol in liquid
cultures of Kluyveromyces marxianus was observed after incubation on a
semisynthetic medium at 30 degrees C, 125 rpm. Changes in the carbon sources led
to a significant modification of the amount of this aromatic compound; moreover,
the variations in the level of DL-phenylalanine and the exclusive use of a
precursor isomer (L) also affected the synthesis of 2-phenylethyl alcohol.
Finally, this study revealed the growth inhibition of K. marxianus when the
concentration of 2-phenylethyl alcohol reached a critical value near 1.4 g/L; the
use of an exponential model allowed the inhibition constant ki to be determined
(ki = 0.35 g/L).
PMID- 9548780
TI - Factors influencing parathion degradation by recombinant Escherichia coli with
surface-expressed organophosphorus hydrolase.
AB - A unique approach for organophosphorus pesticides detoxification was developed
previously by anchoring organophosphorus hydrolase (OPH) onto the surface of
Escherichia coli with a tightly regulated tac promoter. The resulting recombinant
cells degraded parathion very effectively without the diffusional limitation
observed in cells expressing OPH intracellularly. However, the precise conditions
for surface targeting or pesticide degradation were not fully understood. In this
paper, several factors influencing parathion degradation were investigated.
Production of active OPH onto the cell surface was highly host-specific; a high
rate of parathion degradation was observed from strains JM105 and XL1-Blue, which
regulated production of the OPH fusion very tightly. However, in the absence of
ampicillin selection, plasmids were only favorably maintained in strain XL1-Blue.
OPH activity was highly dependent on growth conditions. Optimal OPH activity was
observed when cells were grown in Luria-Bertani (LB)-buffered medium at 37
degrees C. OPH activity was further improved by supplementing the growth medium
with cobalt chloride, which favors the formation of the metal active center. The
timing of cobalt addition also influenced parathion degradation. Maximum OPH
activity was obtained by adding cobalt to induced cultures during the late
stationary phase. The resulting cultures grown under the optimized conditions had
an eight-fold increase in parathion degradation.
PMID- 9548781
TI - Effect of cell morphology on dead-end filtration of the dimorphic yeast
Kluyveromyces marxianus var. marxianus NRRLy2415.
AB - The dead-end filtration characteristics of the dimorphic yeast Kluyveromyces
marxianus var. marxianus (formerly fragilis) NRRLy2415 were investigated for a
range of mean cell morphologies, ranging from predominantly yeast-like to
predominantly filamentous. Semiautomated image analysis was used to measure the
mean cell specific surface area, Sv, and the mean ratio of cell length to
equivalent cylindrical diameter, Ldm, in each broth. The method of Ju and Ho
(Biotechnol. Bioeng. 1988, 32, 95-99) was used to show that for broths with Ldm
values between 1.72 and 10.03, the voidage of cell pellets formed by
centrifugation increased with increasing Ldm. In the pressure range 30-180 kPa,
the specific filter cake resistance, alpha, was found to be related to pressure,
DeltaP, through the equation alpha = alpha0(1 + kcDeltaP). The dependence of
alpha0/Sv2 on Ldm was found to be qualitatively consistent with the pellet
voidage data and the Carman-Kozeny equation. Considerably better agreement with
the experimental data was obtained when the Kozeny constant, K, was treated as
variable and related to Ldm through the equation K = 4.83 + 7.08 log10 Ldm. The
cake compressibility constant, kc, was found to increase with increasing Ldm, a
phenomenon consistent with the wide range of voidages that can be displayed by
beds of long cylinders.
PMID- 9548782
TI - Optimization considerations for the purification of alpha1-antitrypsin using
silica-based ion-exchange adsorbents in packed and expanded beds.
AB - The influences of the fluid superficial velocity, sample concentration, loading
volume, and wash cycle on the recovery and corresponding purification factors for
alpha1-antitrypsin [syn. alpha1-proteinase inhibitor (alpha1-PI)] from crude
mixtures of human plasma proteins were investigated using packed and expanded
beds of DEAE-Spherodex LS. As part of this study, the effect of fluid superficial
velocity on the bed dispersion number (Dv) and dispersion coefficient (D) for
this adsorbent in expanded beds was determined with feedstocks containing human
serum albumin (HSA), the most abundant of the contaminating proteins in human
plasma protein preparations used for the isolation of alpha1-PI. When
multicomponent protein feedstocks prepared from human plasma were examined with
DEAE-Spherodex LS, reduced chromatographic productivity was observed for alpha1
PI as the extent of column utilization and the superficial velocity were
increased, yet the opposite trend was evident for HSA. In particular, higher
adsorption capacities and recoveries were obtained for alpha1-PI at lower fluid
superficial velocities with both packed and expanded bed conditions. These
findings indicate that for process scale purifications of alpha1-PI from
multicomponent feedstocks with expanded beds containing this silica-based ion
exchange adsorbent, the optimal range of superficial velocities to achieve the
highest bed productivity will not be synonymous with maximally fluidized modes of
operation. Rather, the results confirm that the adsorbent has an optimum
operational performance when fluidization procedures corresponding to plug flow
expansion are employed for the capture of alpha1-PI. These findings also indicate
that advantage can be taken of displacement effects between closely related
protein species with packed and expanded bed systems containing the DEAE
Spherodex LS type of ion-exchange porous silicas.
PMID- 9548783
TI - Purification of alcohol dehydrogenase from four genotypes of the olive fruit fly
Bactrocera (Dacus) oleae.
AB - This is the first report describing the purification of alcohol dehydrogenase
(ADH) from four genotypes of the olive fruit fly Bactrocera oleae, the most
important pest of olives in the Mediterranean region. The purified enzyme shows a
single band after SDS-PAGE analysis, corresponding to subunit mass of 26 kDa. The
native ADH shows a molecular mass of 48 kDa, after gel filtration HPLC analysis.
The purification method incorporated a preliminary ammonium sulphate
precipitation step, followed by an anion-exchange DEAE chromatography step, a dye
affinity chromatography step on Cibacron blue 3GA, and an anion-exchange DEAE
chromatography step employing the same column of the first step. The present
method offers good overall recovery (40%) and high enzyme purity, and it is
applicable to different genotypes. Furthermore, the method is rapid and
economical, as it employs two cheap, widely used, and commercially available
chromatography materials.
PMID- 9548784
TI - Protein focusing in a conductivity gradient.
AB - Conductivity gradient focusing (CGF) is one member of a family of gradient
focusing techniques, characterized by two opposing forces which produce a dynamic
equilibrium and which are able to simultaneously separate and concentrate
proteins. In CGF, the two counteracting forces result from a constant convective
flow of buffer opposed by an electric field gradient. This gradient in the
electric field is formed by gradually decreasing buffer conductivity, i.e., when
a slow-moving, relatively high conductivity buffer is dialyzed against a low
conductivity purge buffer. This paper presents the design of an analytical-scale
CGF device and the results of several experiments with colored proteins, both in
free solution and with the use of a 45 micron size-exclusion (SEC) packing to
decrease dispersion. Experimental results with hemoglobin suggest that CGF may
one day be capable of resolving proteins with small charge differences. A linear
computer model of conductivity gradient focusing is derived, and some suggestions
are made for further development of this new electrophoretic method.
PMID- 9548785
TI - Preparation and characterization of bifunctional biopolymers for receptor-based
liposomal immunosensing.
AB - In this study, we prepared bifunctional biopolymers for development of a novel
liposomal immunosensing element. These biopolymers were produced such that a rat
monoclonal antibody fragment Fab' was linked to a cardiac protein Troponin I
(TnI) peptide by a cross-linking reagent, o-phenylenedimaleimide (o-PDM) or N
sucinimidyl 3-(2-pyridyldithio)propionate (SPDP). The biopolymer formation yields
were approximately 10% for Fab-TnIMal and 30% for Fab-TnISPDP. Molar ratios of
Fab' to SPDP or o-PDM and conjugated Fab' to TnI peptide and conjugation pH have
considerable effects on the biopolymer yield. Purification of these biopolymers
was achieved by employing size-exclusion HPLC. These biopolymers can bind to
receptor channels on one end, while the peptide end can be recognized by an anti
TnI antibody serving as a protein linker to block the channels in the
immunosensing element. Then reactions may be used where free analyte competes for
cross-linker binding sites whereby channels are rendered active. Characterization
of purified biopolymers was performed using gel electrophoresis, ELISAs, and a
BIAcore instrument. Furthermore, results of real-time biospecific interaction
experiments with use of the BIAcore show that competition binding reactions of
free TnI peptide occurred in this new immunosensing design. The binding
activities of these two biopolymers are slightly different.
PMID- 9548786
TI - Correlation of fermentation yield with yeast extract composition as characterized
by near-infrared spectroscopy
AB - Complex, ill-defined mixtures of natural origin are often used as nutrients in
the production of biological products through microbial fermentation. Product
yields are affected by variation in these natural products. It was desired to
examine near-infrared spectroscopy as a rapid screening tool for qualifying raw
material lots. Specifically, the characterization of yeast extract was
investigated. The model system consisted of a Merck & Co., Inc., microbial
fermentation process. Cell mass and specific product yields are dependent upon
variations in the yeast extract used in the medium. Partial least-squares
regression on the second-derivative spectral absorbances of various yeast
extracts in the ranges 1150-1380, 1554-1826, and 2100-2300 nm resulted in the
development of models with multiple correlation coefficients of 0.99 for cell
mass yields and 0.96 for specific product yields in large-scale fermentations.
These models could also be used to predict cell mass yields in 15 L batch
fermentations and specific product yields in 2-L shake flasks.
PMID- 9548787
TI - Steam-sterilizable, fluorescence lifetime-based sensing film for dissolved carbon
dioxide.
AB - An autoclavable sensing film was developed for monitoring dissolved CO2. The
sensing film, based on fluorescence resonance energy transfer (FRET), consisted
of a fluorescent donor, an acceptor, and a quaternary ammonium hydroxide, which
were doped in a two-component silicone film. As no aqueous solution was used in
the sensing film matrix, the sensing film was unaffected by osmotic pressure.
Fluorescence lifetime was selected as the sensing parameter, and measured in
frequency domain using phase fluorometry. Upon exposure to 20% CO2-saturated
water, a 43 degrees increase in phase angle was observed at 100 MHz. The process
was fully reversible when the sensing film was exposed to nitrogen-saturated
water. The estimated response and recovery times for 90% signal change were 1 min
(for a step change from 0 to 6.7% CO2-saturated water) and 1.5 min (for a step
change from 6.7 to 3.3% CO2-saturated water). When used for on-line monitoring of
dissolved CO2 produced by a culture of Escherichia coli, the sensing film showed
a similar trend to that obtained from off-line measurements using a wet chemistry
analyzer.
PMID- 9548788
TI - Purification of antibodies from protein mixtures and mouse ascites fluid using
Zeolite X.
AB - Zeolite A and calcium phosphate modified Zeolite A have been shown to be a new
effective packing material in ion exchange chromatography for the purification of
immunoglobulin G (IgG) from binary mixtures and mouse ascites fluid. This study
was to determine the effectiveness of purifying IgG using Zeolite X and
dealuminated Zeolite X with twice the pore size of Zeolite A. Binary mixtures
(IgG-albumin and IgG-transferrin) and a mouse ascites fluid were purified in
Zeolite X (in Na+, K+, or NH4+ form) chromatographic columns and with
dealuminated Zeolite X under a variety of operational conditions. The biological
activity of the purified IgG from the mouse ascites fluid was confirmed by ELISA.
The characteristics of zeolites in the present study suggest that functional
groups of a protein displace the cations of zeolites near the crystal surfaces
and create a different strength of affinity. The study demonstrated that Zeolite
X and dealuminated Zeolite X are also promising new packing materials for the
purification of IgG from biological materials.
PMID- 9548789
TI - Effects of secondary flow caused by a curved channel on plasma protein adsorption
to artificial surfaces.
AB - The effects of secondary flow induced by a curved channel on fibrinogen
deposition and replacement on a glass surface were studied. Platelet adhesion to
surface-bound fibrinogen was also studied to indicate how secondary flow may
affect thrombogenesis on artificial surfaces. A saline pre-wetted channel with
straight and curved sections was exposed to flowing plasma at a Reynolds number
of 28.6. Results show that fibrinogen deposited on the surface at a shear rate of
175 s-1 was replaced faster in regions of secondary flow (Dean numbers from 11 to
19) than in adjacent regions of shear flow. Platelets adhered only to those
surfaces where fibrinogen had been detected.
PMID- 9548790
TI - Recovery and reuse of the molecular chaperone GroEL for in vitro protein
refolding.
AB - The chaperones GroEL and GroES from Escherichia coli are known to improve in
vitro protein refolding yields. We show that, for the molecular chaperone
assisted refolding of hen egg white lysozyme, GroES is not an essential
requirement and that activity is recovered with GroEL and ATP alone. The
refolding yields of lysozyme in the presence of GroEL are much greater than those
obtained by dilution because of a reduction in protein aggregation. On the basis
of the large difference in molecular weight between the GroEL complex (MW 840
000) and lysozyme (MW 14 600), we have demonstrated that using an ultrafiltration
membrane (MW 30 000) GroEL may be easily retained after refolding while lysozyme
passes freely into the permeate. The chaperonin recovered from the refolding
solution was then reused several times for further refolding experiments. The
effectiveness of GroEL-assisted refolding was found to decrease with reuse, and
this has been attributed to a reduction in the GroEL:lysozyme molar ratio.
PMID- 9548791
TI - Crystallization and X-ray diffraction of crystals formed in water-plasticized
amorphous lactose.
AB - Effects of storage time and relative humidity on crystallization and crystal
forms produced from amorphous lactose were investigated. Crystallization was
observed from time-dependent loss of sorbed water and increasing intensities of
peaks in X-ray diffraction patterns. The rate of crystallization increased with
increasing storage relative humidity. Lactose crystallized mainly as alpha
lactose monohydrate and anhydrous crystals with alpha- and beta-lactose in a
molar ratio of 5:3. The results suggested that the crystal form was defined by
the early nucleation process. The crystallization data are important in modeling
of crystallization phenomena and prediction of stability of lactose-containing
food and pharmaceutical materials.
PMID- 9548792
TI - Green fluorescent protein as a real time quantitative reporter of heterologous
protein production.
AB - Since its cloning and commercial availability, applications of green fluorescent
protein (GFP) as a reporter gene have become prevalent in many aspects of
science. The attributes of GFP could also be applied to the area of heterologous
protein production. The work described here represents the first experiments to
use GFP as a generic tool to monitor protein production in bioprocess
development. We have constructed a plasmid containing an operon fusion of the two
reporter genes GFP and chloramphenicol acetyl transferase (CAT). CAT served as a
"model" recombinant protein product to demonstrate the in situ quantifiable
reporting mechanism of GFP. Our results indicate there is a direct correlation
between the fluorescence intensity of GFP and the functional activity of the
downstream CAT protein. In addition, there is a quantitative relationship between
the level of CAT protein concentration and GFP fluorescence. These experiments
provide the groundwork for using GFP as an in situ reporter gene for scale-up and
process optimization of recombinant protein production.
PMID- 9548793
TI - Free radical formation in the peroxynitrous acid (ONOOH)/peroxynitrite (ONOO-)
system.
AB - The rate constant of homolysis of peroxynitrite, ONOO-, into O2- and NO was
determined to be 0.017 s-1 at 20 degrees C. In combination with other
experimental data taken from the literature, this value yields the Gibbs free
energy of formation of ONOO-, delta f G o(ONOO-) = 16.6 kcal/mol. On the basis of
this result, we conclude that peroxynitrous acid homolyzes to yield nitrogen
dioxide (NO2) and hydroxyl (OH) free radicals and derive delta f G o(ONOOH) = 7.7
kcal/mol. The rate constant of the reaction between NO and ONOO- was found to be
5 x 10(-)2 M-1 s-1 at most. The implications of the two homolysis reactions are
discussed.
PMID- 9548794
TI - Structural characterization of a 4-hydroxy-2-alkenal-derived fluorophore that
contributes to lipoperoxidation-dependent protein cross-linking in aging and
degenerative disease.
AB - Modification of proteins by products of lipid peroxidation results in various
fluorescent adducts associated with oxidative stress pathophysiology in
degenerative disease. Using n-butylamine as a model for the lysine side chain,
the structure of the probable major ex/em 360/430-nm fluorophore that arises from
cross-linking of two protein-based lysines by one 4-hydroxy-2-alkenal is shown to
be a 2-alkyl-2-hydroxy-1,2-dihydropyrrol-3-one iminium. That this fluorophore can
be independently generated in higher yield from either 4-oxo-2-alkenals or 3,4
dioxoalkanals supports a proposed mechanistic pathway that involves two 2e
oxidations following initial Schiff base formation.
PMID- 9548795
TI - Inactivation of cytochrome P450 3A4 by bergamottin, a component of grapefruit
juice.
AB - Grapefruit juice has been found to significantly increase oral bioavailability of
several drugs metabolized by cytochrome P450 3A4 (P450 3A4) through inhibiting
the enzymatic activity and decreasing the content of intestinal P450 3A4.
HPLC/MS/MS and HPLC/UV analyses of ethyl acetate extracts from grapefruit juice
revealed the presence of several furanocoumarins of which bergamottin (BG) is the
major one. BG was shown to inactivate P450 3A4 in a reconstituted system
consisting of purified P450 3A4, NADPH-cytochrome P450 reductase, cytochrome b5,
and phospholipids. Inactivation was time- and concentration-dependent and
required metabolism of BG. The loss of catalytic activity exhibited pseudo-first
order kinetics. The values of kinactivation and KI calculated from the
inactivation studies were 0.3 min-1 and 7.7 microM, respectively. While
approximately 70% of the erythromycin N-demethylation activity was lost during
incubation with BG in the reconstituted system, P450 3A4 retained more than 90%
of the heme as determined either by UV-visible spectroscopy or by HPLC. However,
approximately 50% of the apoP450 in the BG-inactivated P450 3A4 incubation
mixture could not be recovered from a reverse-phase HPLC column when compared
with the -NADPH control. The mechanism of the inactivation appears to involve
modification of the apoP450 in the active site of the enzyme instead of heme
adduct formation or heme fragmentation. These results indicate that BG, the
primary furanocoumarin extracted from grapefruit juice, is a mechanism-based
inactivator of P450 3A4. BG was also found to inhibit the activities of P450s
1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in human liver microsomes.
PMID- 9548796
TI - Nuclear magnetic resonance spectroscopic and principal components analysis
investigations into biochemical effects of three model hepatotoxins.
AB - 1H NMR spectroscopy of urine combined with pattern recognition (PR) methods of
data analysis has been used to investigate the time-related biochemical changes
induced in Sprague-Dawley rats by three model hepatotoxins: alpha-naphthyl
isothiocyanate (ANIT), d-(+)-galactosamine (GalN), and butylated hydroxytoluene
(BHT). The development of hepatic lesions was monitored by conventional plasma
analysis and liver histopathology. Urine was collected continuously postdosing up
to 144 h and analyzed by 600-MHz 1H NMR spectroscopy. NMR spectra of the urine
samples showed a number of time-dependent perturbations of endogenous metabolite
levels that were characteristic for each hepatotoxin. Biochemical changes common
to all three hepatotoxins included a reduction in the urinary excretion of
citrate and 2-oxoglutarate and an increased excretion of taurine and creatine.
Increased urinary excretion of betaine, urocanic acid, tyrosine, threonine, and
glutamate was characteristic of GalN toxicity. Both GalN and ANIT caused
increased urinary excretion of bile acids, while glycosuria was evident in BHT-
and ANIT-treated rats. Data reduction of the NMR spectra into 256 integrated
regions was used to further analyze the data. Mean values of each integrated
region were analyzed by principal components analysis (PCA). Each toxin gave a
unique time-related metabolic trajectory that could be visualized in two
dimensional PCA maps and in which the maximum distance from the control point
corresponded to the time of greatest cellular injury (confirmed by conventional
toxicological tests). Thereafter, the metabolic trajectories changed direction
and moved back toward the control region of the PR map during the postdose
recovery phase. The combination of urinary metabolites which were significantly
altered at various time points allowed for differentiation between biliary and
parenchymal injury. This NMR-PR approach to the noninvasive detection of liver
lesions will be of value in furthering the understanding of hepatotoxic
mechanisms and assisting in the discovery of novel biomarkers of hepatotoxicity.
PMID- 9548797
TI - Inorganic and methylated arsenic compounds induce cell death in murine
macrophages via different mechanisms.
AB - We demonstrate in this study the cytotoxic effects of inorganic arsenicals,
arsenite and arsenate, and organic arsenic compounds, monomethylarsonic acid
(MAA), dimethylarsinic acid (DMAA), and trimethylarsine oxide (TMAO), which are
metabolites of inorganic arsenicals in human bodies, using murine macrophages in
vitro. Inorganic arsenicals, both arsenite and arsenate, are strongly toxic to
macrophages, and the concentration that decreased the number of surviving cells
to 50% of that in untreated controls (IC50) was 5 or 500 microM, respectively.
These inorganic arsenicals mainly caused necrotic cell death with partially
apoptotic cell death; about 80% of dead cells were necrotic, and 20% were
apoptotic. The inorganic arsenicals also induced marked release of an
inflammatory cytokine, tumor necrosis factor alpha (TNF alpha), at cytotoxic
doses. This strong cytotoxicity of an inorganic arsenical, arsenite, might be
mediated via active oxygen and protease activation because it was inhibited by
the addition of some antioxidant reagents, such as superoxide dismutase (SOD),
catalase, and GSH, or by a peptide inhibitor of interleukin-1 beta-converting
enzyme (ICE). It is likely that these immunotoxic effects of inorganic arsenicals
may evoke both immunosuppression and inflammation, and they may be central
factors causing carcinogenesis and severe inflammatory responses, such as
hepatomegaly and splenomegaly, in chronic arsenicosis patients who daily ingested
arsenic-contaminated well water. In contrast, the cytotoxic effects of methylated
arsenic compounds were lower than those of inorganic arsenicals. The IC50 value
of DMAA was about 5 mM, and MAA and TMAO had no toxicity even at concentrations
over 10 mM. Additionally, these methylated chemicals suppressed the TNFalpha
release from macrophages. DMAA induced mainly apoptotic cell death in macrophages
as indicated by cellular morphological changes, condensed nuclei, terminal
deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL), and
DNA fragmentation. However, the cytotoxicity of DMAA might be induced via a
different mechanism from that of inorganic arsenicals because it was not
abolished by the additions of SOD, catalase, or ICE inhibitor. Conversely, GSH
enhanced the toxicity of DMAA. These data suggest that methylation of inorganic
arsenicals in mammals plays an important role in suppression of both severe
immunosuppression and inflammatory responses caused by inorganic arsenicals.
PMID- 9548798
TI - Structures of acrolein-guanine adducts: a semi-empirical self-consistent field
and nuclear magnetic resonance spectral study.
AB - The structures and conformations of adducts formed by reaction of guanosine with
several mutagenic alpha,beta-unsaturated carbonyl compounds have been
investigated by semi-empirical molecular orbital calculations and compared with
NMR spectral results. Two cyclization processes taking place on the pyrimidine
ring of guanine leading to two sets of regioisomers, 11-hydroxy- and 13
hydroxytetrahydropyrimidinoguanines (THPG), were considered. Relative stabilities
and geometries of all configurations and conformations of adducts with acrolein,
crotonaldehyde, and alpha-chloroacrolein were calculated by PM3, AM1, and MNDO
methods. PM3 results were the most compatible with experimental structures based
on 400-MHz 1H NMR spectroscopy. The most stable structures for the 11-hydroxy and
13-hydroxy THPG isomers from acrolein are predicted to have chair-like structures
for the tetrahydropyrimidine ring and axial hydroxyl groups, as suggested by the
NMR spectra of the isolated adducts. Of the possible isomers from guanine and
crotonaldehyde, cis-11-hydroxy-13-methyl THPG with methyl and hydroxyl groups
axial is predicted to be the most stable. The only isolated adduct is the trans
13-hydroxy-11-methyl THPG with methyl shown to be equatorial and hydroxyl axial
by 1H NMR. This is completely consistent with the geometry predicted by PM3 for
the 13-hydroxy regioisomer of crotonaldehyde. In the case of adducts of alpha
chloroacrolein, one stereoisomer predominates for each of the two possible
regioisomers. For the 12-chloro-11-hydroxy isomer, the cis configuration with
chlorine axial and hydroxyl quasi-axial is calculated to have the most stable
geometry. In contrast, the 1H NMR spectrum supports a trans diaxial orientation,
although the cis computed structure could also be accommodated by the spectrum.
The 12-chloro-13-hydroxy regioisomer is unambiguously assigned as trans diaxial
by PM3 calculations and 1H NMR spectroscopy.
PMID- 9548799
TI - Oxidation of acetaminophen to its toxic quinone imine and nontoxic catechol
metabolites by baculovirus-expressed and purified human cytochromes P450 2E1 and
2A6.
AB - Acetaminophen (APAP), a widely used analgesic and antipyretic agent, is
bioactivated by cytochromes P450 to cause severe hepatotoxicity. APAP is oxidized
by two pathways to form a toxic intermediate, N-acetyl-p-benzoquinone imine
(NAPQI), and a nontoxic catechol metabolite, 3-hydroxy-APAP (3-OH-APAP). We
investigated the role of P450 2E1 and 2A6 in APAP oxidation by using baculovirus
expressed and highly purified forms of human P450 2E1 and 2A6. An electrochemical
HPLC assay was developed to quantify both oxidative metabolites simultaneously.
For the first time, it was demonstrated that human P450 2E1 selectively oxidized
APAP to NAPQI (assayed as its glutathione conjugate, GS-APAP), whereas human P450
2A6 selectively oxidized APAP to 3-OH-APAP. At 1 mM APAP, the relative ratio for
the formation of GS-APAP vs 3-OH-APAP with human P450 2E1 was approximately 6:1,
whereas the ratio with human P450 2A6 was 1:3. Apparent Km and Vmax values for
the formation of GS-APAP by human P450 2E1 were 1.3 mM and 6.9 nmol/min/nmol of
P450, respectively, whereas they were 4.6 mM and 7.9 nmol/min/nmol of P450 for
P450 2A6. Apparent Km and Vmax values for the formation of 3-OH-APAP by human
P450 2E1 were 4.0 mM and 2.5 nmol/min/nmol of P450, respectively, whereas they
were 2.2 mM and 14.2 nmol/min/nmol of P450, respectively, for P450 2A6. Thus,
although at toxic doses of APAP P450 2E1 is the more efficient catalyst for the
formation of the toxic metabolite NAPQI, P450 2A6 also can contribute
significantly to NAPQI production.
PMID- 9548800
TI - Formation of hemoglobin and albumin adducts of benzene oxide in mouse, rat, and
human blood.
AB - Little is known about the formation and disposition of benzene oxide (BO), the
initial metabolite arising from oxidation of benzene by cytochrome P450. In this
study, reactions of BO with hemoglobin (Hb) and albumin (Alb) were investigated
in blood from B6C3F1 mice, F344 rats, and humans in vitro. The estimated half
lives of BO in blood were 6.6 min (mice), 7.9 min (rats), and 7.2 min (humans).
The following second-order rate constants were estimated for reactions between BO
and cysteinyl residues of Hb and Alb [in units of L (g of Hb- or Alb-h)-1]: mouse
Hb = 1.16 x 10(-)4, rat Hb = 15.4 x 10(-)4, human Hb = 0.177 x 10(-)4, mouse Alb
= 2.68 x 10(-)4, rat Alb = 4.96 x 10(-)4, and human Alb = 5.19 x 10(-)4. These
rate constants were used with BO-adduct measurements to assess the systemic doses
of BO arising from benzene in vivo in published animal and human studies. Among
rats receiving a single gavage dose of 400 mg of benzene/kg of body weight, the
BO dose of 2.62 x 10(3) nM BO-h, predicted from Alb adducts, was quite similar to
the reported AUC0-infinity = 1.09 x 10(3) nM BO-h of BO in blood. Interestingly,
assays of Hb adducts in the same rats predicted a much higher dose of 14.7 x
10(3) nM BO-h, suggesting possible in situ generation of adducts within the
erythrocyte. Doses of BO predicted from Alb adducts were similar in workers
exposed to benzene [13.3 nM BO-h (mg of benzene/kg of body weight)-1] and in rats
following a single gavage dose of benzene [8. 42 nM BO-h (mg of benzene/kg of
body weight)-1]. Additional experiments indicated that crude isolates of Hb and
Alb had significantly higher levels of BO adducts than dialyzed proteins,
suggesting that conjugates of low-molecular-weight species were abundant in these
isolates.
PMID- 9548801
TI - Polymerase blockage and misincorporation of dNTPs opposite the ethylene dibromide
derived DNA adducts S-[2-(N7-guanyl)ethyl]glutathione, S-[2-(N2
guanyl)ethyl]glutathione, and S-[2-(O6-guanyl)ethyl]glutathione.
AB - The carcinogen ethylene dibromide (EDB) has been shown to cause glutathione (GSH)
dependent base-substitution mutations, especially GC to AT transitions, in a
variety of bacterial and eukaryotic systems. The known DNA adducts S-[2-(N7
guanyl)ethyl]GSH, S-[2-(N2-guanyl)ethyl]GSH, and S-[2-(O6-guanyl)ethyl]GSH were
individually placed at a site in a single oligonucleotide. Polymerase extension
studies were carried out using Escherichia coli polymerase I exo- (Klenow
fragment, Kf-) and polymerase II exo- (pol II-), bacteriophage T7 polymerase exo
, and human immunodeficiency virus-1 reverse transcriptase in order to
characterize misincorporation events. Even though extension was not as efficient
as with the nonadducted template, some fully extended primers were observed with
the template containing S-[2-(N7-guanyl)ethyl]GSH using all of these polymerases.
dCTP was the most preferred nucleotide incorporated opposite S-[2-(N7
guanyl)ethyl]GSH by most of polymerases examined; however, dTTP incorporation was
observed opposite S-[2-(N7-guanyl)ethyl]GSH with pol II-. Both S-[2-(N2
guanyl)ethyl]GSH and S-[2-(O6-guanyl)ethyl]GSH strongly blocked replication by
all polymerases. Only dATP and dGTP were incorporated opposite S-[2-(N2
guanyl)ethyl]GSH by both Kf- and pol II-. S-[2-(O6-Guanyl)ethyl]GSH was shown to
strongly code for dATP incorporation by Kf-. With pol II-, dTTP was incorporated
opposite S-[2-(O6-guanyl)ethyl]GSH. In conclusion, all three GSH-guanyl adducts
derived from the carcinogen EDB blocked the polymerases and were capable of
miscoding.
PMID- 9548802
TI - Reactions of 4-hydroxy-2(E)-nonenal and related aldehydes with proteins studied
by carbon-13 nuclear magnetic resonance spectroscopy.
AB - In order to understand the modifications of proteins produced by aldehydes of
lipid peroxidation, [1-13C]-2(E)-hexenal, [1-13C]-4-oxopentanal, and a mixture of
[1-13C]- and [2-13C]-4-hydroxynon-2(E)-enal were synthesized and the reaction of
each of the labeled aldehydes with bovine serum albumin was analyzed by 13C NMR
spectroscopy. Protein nucleophiles add to the 3-position of hexenal, and the
resulting propanal moieties appear to undergo aldol condensation, form imine
cross-links with lysyl residues, or lead to pyridinium rings. During the reaction
of 4-oxopentanal with the lysyl residues of bovine serum albumin, only 1-alkyl-2
methylpyrrole and a possible intermediate leading to the pyrrole were observed.
Hydroxypyrrolidine cross-links such as 25 could not be detected, leaving the
pyrrole as the mediator of protein cross-linking. The Michael adducts are the
major products in the reaction between 4-hydroxynon-2-enal and proteins. They
exist almost exclusively in the cyclic hemiacetal form and do not appear to cross
link through imine formation with lysyl residues. A minor pathway involves the
reaction of 4-hydroxynon-2-enal with the lysyl amino groups of protein resulting
in 2-pentylpyrrole adducts that may mediate protein cross-linking. The Michael
adducts appear not to be the direct source of the pyrrole, but the imine 32 and
the enamine 35 are likely intermediates toward the five-membered ring.
PMID- 9548803
TI - A single cyclic p-benzoquinone adduct can destabilize a DNA oligonucleotide
duplex.
AB - p-Benzoquinone (p-BQ), a stable metabolite of the human carcinogen benzene, forms
two-ring benzetheno exocyclic base adducts with C, A, and G bases in DNA. As a
part of a project for studying the biological effect of the p-BQ adducts, we
report here on the first biophysical characterization of oligodeoxyribonucleotide
duplexes containing a single site-specific p-BQ-C, using thermal denaturation and
circular dichroism (CD). We find that the thermal and thermodynamic stabilities
of the control duplex are reduced by p-BQ-C. The Tm value decreases by 12.6
degrees C at the duplex concentration of 1.5 microM and the Delta G o by 10.2
kcal/mol. The latter was determined from the concentration dependence of the Tm
values. The destabilization has little dependence on the nature of the opposite
base. This reduction is higher than that of the single base mismatches studied (
4.9 to -7.9 kcal/mol) and is close to that observed with an adjacent double
mismatch-containing duplex (-11.3 kcal/mol). The overall B-conformation of the
duplex with a p-BQ-C is, however, only slightly altered, relative to the parent
duplex, as shown by CD spectra. The p-BQ-C-containing duplex has been found
recently to be a good substrate for the major human AP endonuclease as compared
to an abasic site-containing duplex [Hang, B., et al. (1997) Biochemistry 36,
15411-15418]. We now find that the thermodynamic properties and the localized
conformational changes of a p-BQ-C-containing duplex are apparently related to
those reported for a duplex containing an abasic site.
PMID- 9548804
TI - Effect of ring size on conformations of aromatic amine-DNA adducts: the aniline
C8 guanine adduct resides in the B-DNA major groove.
AB - While the one-ring amine aniline (AN) has only slight genetic activity, the
polycyclic aromatic amines 2-aminofluorene (AF) and 1-aminopyrene (AP) are
significant mutagens and carcinogens. Moreover, the bulkier AP is more mutagenic
per adduct than AF in the tetracycline-resistance gene of plasmid pBR322
[Melchior et al. (1994) Carcinogenesis 15, 889]. To elucidate possible
conformational origins of the differing mutagenic effects of these three adducts,
which may stem from their differing ring sizes, we have examined their
conformations in two mutation-susceptible sequences from the above gene:
TTGAG*GCCG (sequence I) and GAATG*GTGC (sequence II), where G* = C8-modified
guanine. No experimental high-resolution NMR data are yet available for the
aniline adduct in a DNA duplex. Minimized potential energy calculations were
carried out, using the molecular mechanics program DUPLEX to explore the
conformation space of these adducts. In the case of AN, a relatively unperturbed
B-DNA helix with the amine in the major groove was strongly favored in both
sequences. In the case of AF- and AP-modified DNA, however, several differing
conformations were competitive in energy. They included major groove structures,
as well as conformations with syn-modified guanine and the polycyclic amine in
the minor groove, or the amine rings intercalated into the helix with
displacement of the modified guanine, in overall harmony with high-resolution NMR
solution structures. Thus, aniline distorts DNA structure to a lesser extent than
larger aromatic amine ring systems, since a number of different conformations are
energetically feasible and have been observed for the larger systems. This result
may be relevant to their enhanced mutagenicity and their repair propensity, in
contrast to aniline's low mutagenic effect.
PMID- 9548805
TI - Development of an enzyme-linked immunosorbent assay for atrazine mercapturic acid
in human urine.
AB - Improved assessments of human exposure to electrophilic chemicals require rapid
and inexpensive analytical techniques that can detect specific urinary
metabolites at low levels as needed for epidemiological screenings of large
populations. The first aim of this study has been to apply rational hapten design
strategies to develop a more sensitive and selective enzyme-linked immunosorbent
assay for atrazine mercapturic acid. Polyclonal sheep antiserum was generated
against an improved hapten, numerous coating antigen chemistries were evaluated,
and assay conditions were optimized. An assay was developed with an IC50 of 0.08
+/- 0.02 micrograms/L (K approximately with 10(-)10 M) for atrazine mercapturic
acid. The assay exhibited greatest recognition of atrazine mercapturic acid
relative to other known urinary metabolites of atrazine as well as other triazine
herbicides. The assay was surprisingly selective to atrazine mercapturic acid
over the structurally similar simazine mercapturic acid. Urine samples presented
matrix effects due in part to the nonspecific effects of urinary salts, but 4
fold dilution of urine achieved an overall method limit of quantitation of 0.3
micrograms/L. Solid-phase extraction strategies were also developed in an attempt
to increase the sensitivity of the overall method. However, a weak positive assay
response was present in the solid-phase extracts of unspiked urines, resulting in
accurate recovery of atrazine mercapturic acid at microgram/L.
PMID- 9548806
TI - Dialkylquinonimines validated as in vivo metabolites of alachlor, acetochlor, and
metolachlor herbicides in rats.
AB - The oncogenicity of chloroacetanilide herbicides (1-5) is proposed to involve
bioactivation to 2,6-dialkylbenzoquinonimines (quinonimines, 9) based on two
earlier observations: (1) in vitro conversion of the alachlor (1) metabolite
diethylaniline (7Et2) to 2, 6-diethylquinonimine (9Et2) which reacts readily with
GSH and (2) induction of sister chromatid exchanges in human lymphocytes for the
parent herbicides and their purported 9 metabolites. This hypothesis lacks in
vivo evidence for 9 formation which might be provided by analysis of urine and
tissue for thiol adducts of 9. Accordingly, two mercapturates (10Et2 and 10Me2)
and a cysteine conjugate (11Me2) were prepared by addition of N-acetylcysteine or
cysteine to 9Et2 and the 2,6-dimethyl homologue (9Me2). Mercapturate 10Et2 was
characterized by HPLC using the urine of rats treated ip with hydroxyaniline
8Et2, and both mercapturate 10Me2 and cysteine conjugate 11Me2 were found in the
urine of mice administered hydroxyaniline 8Me2. The mercapturates were then
converted to the N, N-dimethyl-2,6-dialkyl-4-methoxy-3-(methylthio)anilines
(12Et2, 12EtMe, and 12Me2) by alkaline permethylation, thereby providing a method
for analysis of 9-derived thiol adducts in urine and liver as the 12 derivatives
by GC/MS with selected ion monitoring. The urine of rats 0-6 h after ip treatment
with 1, butachlor (2), acetochlor (3), metolachlor (4), and dimethachlor (5) at
0.74 mmol/kg yields permethylated derivatives which are definitively diagnostic
for the 9 intermediates from each of the herbicides in amounts of 3-24-fold above
the minimum detectable limit, as well as 1 and 2 orders of magnitude higher from
the corresponding anilines (7) and hydroxyanilines (8), respectively. Similar
liver analyses reveal tissue thiol adducts of 9 6 h after treatment with 7 and 8
but not with the parent herbicides. The yields of urinary 9 derivatives from the
parent herbicides are higher from the 2,6-diethyl series (1 and 2) and the 2
ethyl-6-methyl derivatives (3 and 4) than from the 2, 6-dimethyl analogue (5).
These findings provide direct evidence in vivo that quinonimines are metabolites
of 1-5 in rats.
PMID- 9548807
TI - Induction of p53 by the concerted actions of aziridine and quinone moieties of
diaziquone.
AB - The biologic functions attributed to the nucleophosphoprotein p53 have been
increasing in recent years. Some studies suggested that wild type p53 is
responsible for cell cycle arrest brought about as a response to exposure of
mammalian cells to DNA-damaging agents. This cell cycle arrest occurs in order
for cells to repair the damaged macromolecules. Extensively damaged cells are
also thought to undergo apoptosis via the p53-dependent or -independent signal
transduction pathways. In this study, we investigated the ability of
diaziridinylbenzoquinones to increase p53 levels in the human breast cancer cell
line MCF-7. Diaziquone (AZQ), an anticancer agent, and its derivatives,
diaziridinequinone (DZQ) and methyldiaziridinequinone (MeDZQ), induced p53 in a
dose- and time-dependent manner as measured by the electrophoretic mobility shift
assay. Wild type p53 induction by AZQ was suppressed when DT-diaphorase activity
was inhibited by pretreating the cells with dicumarol. Aside from their potent
alkylating activity, these agents also undergo redox cycling as evidenced by
oxygen consumption and the production of reactive oxygen species (ROS).
Inhibition of ROS production by the antioxidant enzyme catalase reduced AZQ- and
DZQ-mediated p53 induction by about 45%. Thiotepa, a non-quinone aziridine
containing agent, and 1,4-benzoquinone (p-BQ), a redox cycling quinone, increased
p53 levels. The nonalkylator oxygen-radical-generating agent menadione (MD)
caused p53 induction only when MCF-7 cells were allowed to recover in drug-free
media. On the basis of these data, we propose that the bioreductive activation of
AZQ is a prerequisite for p53 induction. Moreover, the induction of p53 by AZQ
requires both the quinone and the aziridine moieties of the AZQ molecule.
Although AZQ and its analogues increased p53 levels in MCF-7 cells, p53 induction
in these cells may not be responsible for the apoptosis seen upon treatment of
MCF-7 cells with these agents. The uncoupling of p53 induction and apoptosis is
evidenced by the generation of nucleosomal DNA laddering in aziridinequinone
treated T47D cells, a breast cancer cell line bearing a p53 mutation.
PMID- 9548808
TI - Synthesis and DNA reactivity of alpha-hydroxylated metabolites of nonsteroidal
antiestrogens.
AB - Tamoxifen [(E)-1-(4-(2-(N,N-dimethylamino)ethoxy)phenyl)-1, 2-diphenylbut-1-ene],
a nonsteroidal antiestrogen, induces liver tumors in rats by a genotoxic
mechanism. The mechanism of DNA adduct formation is believed to proceed via the
formation of a reactive carbocation at the alpha-position from the alpha
hydroxylated metabolite. Molecular mechanics calculations [Kuramochi, H. (1996)
J. Med. Chem. 39, 2877-2886] have predicted that 4-substitution will affect the
stability of the carbocation and thus will alter its reactivity toward DNA. We
have synthesized the putative alpha-hydroxylated metabolites of 4
hydroxytamoxifen [(E)-1-(4-(2-(N, N-dimethylamino)ethoxy)phenyl)-1-(4
hydroxyphenyl)-3-hydroxy-2-phenyl but-1-ene] and idoxifene [(Z)-1-(4-iodophenyl)
3-hydroxy-2-phenyl-1-(4-(2-(N-pyrrolidino) ethoxy)phenyl)but-1-ene] and compared
their reactivities with DNA with that of alpha-hydroxytamoxifen [(E)-1-(4-(2-(N,
N-dimethylamino)ethoxy)phenyl)-3-hydroxy-1,2-diphenylbut-1-ene]. As predicted,
the bis-hydroxylated compound reacted with DNA in aqueous solution at pH 5 to
give 12-fold greater levels of adducts than alpha-hydroxytamoxifen, whereas alpha
hydroxyidoxifene gave one-half the number of adducts. The results demonstrate
that idoxifene presents a significantly lower genotoxic hazard than tamoxifen for
the treatment and prophylaxis of breast cancer.
PMID- 9548809
TI - Chemical synthesis of a novel aromatic amine mutagen isolated from water of the
Nishitakase River in Kyoto and a possible route of its formation.
AB - Among five mutagenic compounds isolated from water samples, taken at sites below
the sewage plants of the Nishitakase River in Kyoto, Japan, the structure of
compound I has been determined to be 2-[2-(acetylamino)-4-[bis(2
methoxyethyl)amino]-5-methoxyphenyl]-5-am ino-7-bromo-4-chloro-2H-benzotriazole
(PBTA-1). Since this novel aromatic amine mutagen has characteristic substituents
in its molecule, it is postulated that the azo dye, 2-[(2-bromo-4, 6
dinitrophenyl)azo]-4-methoxy-5-[bis(2-methoxyethyl)amino]acetoanili de (AZO DYE
1), used as an industrial material, is converted to the corresponding 2
phenylbenzotriazole derivative with a reducing reagent and subsequently to PBTA-1
by chlorination. In fact, AZO DYE-1 changed to the dechlorinated derivative of
PBTA-1 (deClPBTA-1) on treatment with sodium hydrosulfite, and this reacted with
sodium hypochlorite to produce PBTA-1. Moreover, the presence of deClPBTA-1 was
confirmed in a river water sample, along with PBTA-1. PBTA-1 showed potent
mutagenic activities in Salmonella typhimurium TA98 and YG1024, inducing 88 000
and 3 000 000 revertants, respectively, per microg, with S9 mix. deClPBTA-1 was
also mutagenic, but less potent. From these observations, it is suggested that
PBTA-1 is produced from AZO DYE-1 through deClPBTA-1, during industrial processes
at dyeing factories and the treatment of wastewater at sewage plants.
PMID- 9548810
TI - Role of hydrophobic effects in the reaction of a polynuclear aromatic diol
epoxide with oligodeoxynucleotides in aqueous solutions.
AB - The need for large-scale direct synthesis of stereochemically defined and site
specific benzo[alpha]pyrenediol epoxide-oligodeoxyribonucleotide adducts for
detailed NMR and other biochemical and physicochemical studies has necessitated a
better understanding of variables that lead to an enhancement of the reaction
yields. It is shown that, in aqueous solution, the formation of noncovalent
hydrophobic complexes between 7r, 8t-dihydroxy-9t,10t-epoxy-7,8,9,10
tetrahydrobenzo[alpha] pyrene (BPDE) and the single-stranded oligonucleotide 5'
d(CCATCGCTACC) precedes the covalent binding reaction of BPDE with the single
deoxyguanosine residue. The yield of covalent reaction products (involving
reaction of BPDE at the C10 position with the exocyclic amino group of the dG
residue) increases with increasing DNA concentration and tends toward saturation
at oligonucleotide single-strand concentrations above approximately 3 mM. The
addition of NaCl (0.3 M) also tends to enhance the adduct reaction yields.
However, organic solvents such as tetrahydrofuran in the reaction mixtures (10
40%) decrease the stabilities of the noncovalent complexes, which in turn leads
to reductions in the yields of covalent BPDE-dG oligonucleotide adducts. The
efficiencies of formation of hydrophobic complexes were probed by fluorescence
and UV absorption techniques using the BPDE tetrol hydrolysis product 7,8,9,10
tetrahydroxytetrahydrobenzo[alpha]pyrene as a model system.
PMID- 9548811
TI - 4-Amino-2-[4-[1-(benzyloxycarbonyl)-2(S)- [[(1,1-dimethylethyl)amino]carbonyl]
piperazinyl]-6, 7-dimethoxyquinazoline (L-765,314): a potent and selective
alpha1b adrenergic receptor antagonist.
PMID- 9548812
TI - Inhibition of membrane-type 1 matrix metalloproteinase by hydroxamate inhibitors:
an examination of the subsite pocket.
AB - The membrane-type 1 matrix metalloproteinase (MT1-MMP) has been reported to
mediate the activation of pro-gelatinase A (proMMP-2), which is associated with
tumor proliferation and metastasis. MT1-MMP can also digest extracellular matrix
(ECM) such as interstitial collagens, gelatin, and proteoglycan and thus may play
an important role in pathophysiological digestion of ECM. We studied the
inhibitory effect of various hydroxamate MMP inhibitors, including known
inhibitors such as BB-94, BB-2516, GM6001, and Ro31-9790, on a deletion mutant of
MT1-MMP lacking the transmembrane domain (DeltaMT1) to further characterize the
enzyme and develop a selective inhibitor for MT1-MMP. The evaluation of the
inhibitory activities of various hydroxamates reveals general structural profiles
affecting selectivities toward MMPs. In particular, a longer side chain at the
P1' position is preferable for the binding to MMP-2, -3, and -9 and MT1-MMP. For
the P2' position, an alpha-branched alkyl group is critical for the binding
toward DeltaMT1, while the introduction of a bulky group at the alpha-position of
hydroxamic acid seems to diminish the activity against DeltaMT1. Summation of the
data on the sensitivity of DeltaMT1 to various hydroxamate inhibitors indicates
that (1) the volume of the S1' subsite of DeltaMT1 is similar to that of MMP-2,
3, and -9, which is bigger than that of MMP-1, and (2) the S1 and S2' subsites
are narrower than those in other MMPs. On the basis of these results, the
hydroxamates with a P1' phenylpropyl and P2' alpha-branched alkyl group were
synthesized and evaluated for inhibitory activity. These inhibitors (1h,i) showed
strong activity against DeltaMT1 over MMP-1, but no selectivity between DeltaMT1
and MMP-9. These results are explained using molecular modeling studies conducted
on MT1-MMP.
PMID- 9548813
TI - The selective 5-HT1B receptor inverse agonist 1'-methyl-5-[[2'-methyl-4'-(5
methyl-1,2, 4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydro-
spiro[furo[2,3-f]indole-3,4'-piperidine] (SB-224289) potently blocks terminal 5
HT autoreceptor function both in vitro and in vivo.
AB - 5-HT1 receptors are members of the G-protein-coupled receptor superfamily and are
negatively linked to adenylyl cyclase activity. The human 5-HT1B and 5-HT1D
receptors (previously known as 5-HT1Dbeta and 5-HT1Dalpha, respectively),
although encoded by two distinct genes, are structurally very similar.
Pharmacologically, these two receptors have been differentiated using
nonselective chemical tools such as ketanserin and ritanserin, but the absence of
truly selective agents has meant that the precise function of the 5-HT1B and 5
HT1D receptors has not been defined. In this paper we describe how, using
computational chemistry models as a guide, the nonselective 5-HT1B/5-HT1D
receptor antagonist 4 was structurally modified to produce the selective 5-HT1B
receptor inverse agonist 5, 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2, 4-oxadiazol
3-yl)biphenyl-4-yl]carbonyl]-2,3,6, 7-tetrahydrospiro[furo[2,3-f]indole-3,4'
piperidine] (SB-224289). This compound is a potent antagonist of terminal 5-HT
autoreceptor function both in vitro and in vivo.
PMID- 9548814
TI - Synthesis and antiviral evaluation of certain novel pyrazinoic acid C
nucleosides.
AB - Pyrazine (1,4-diazine) C-nucleosides constitute a rare class of nucleic acid
analogues that has only recently been reported in the literature. As part of our
ongoing investigation into the synthesis and reactivity of these compounds, we
have developed an electrophilic esterification of a lithiated pyrazine C
nucleoside (1) to give, following deprotection, the versatile intermediate ethyl
3,5-dichloro-6-(beta-d-ribofuranosyl)pyrazine-2-carboxylate (4). This
intermediate was subjected to a variety of reaction conditions to generate a
series of pyrazinoic acid C-nucleosides. These compounds, along with 3, 5
dichloro-2-(beta-d-ribofuranosyl)pyrazine (2) and 4, were evaluated for antiviral
activity and cytotoxicity. No significant activity was observed for compounds 2
and 5-9, but 4 was active against two herpes viruses and cytotoxic in the
micromolar range.
PMID- 9548815
TI - Design, synthesis, and antiviral evaluations of 1-(substituted benzyl)-2
substituted-5,6-dichlorobenzimidazoles as nonnucleoside analogues of 2,5,6
trichloro-1-(beta-D-ribofuranosyl)benzimidazole.
AB - We have recently reported that certain ribosylated polyhalogenated benzimidazoles
are potent and selective inhibitors of HCMV replication at noncytotoxic
concentrations. To extend the structure-activity relationship beyond these first
generation compounds, we alkylated 5,6-dichloro-2-substituted-benzimidazoles with
either a series of substituted benzyl halides or (2-bromoethyl)benzene to obtain
five series of nonnucleoside analogues. Evaluation of these compounds for
activity against herpes viruses revealed that the new compounds were less active
than the benzimidazole ribonucleosides against human cytomegalovirus (HCMV) and
inactive against herpes simplex virus type 1 (HSV-1). However, as part of our
broader antiviral testing, we found that some of these compounds were active
against HIV. Comparisons of the biological data revealed that a chloro or bromo
group was required at the 2-position for the best separation of activity against
HIV and cytotoxicity. Evaluation of the most active compounds against drug
resistant HIV suggested that they act by a mechanism other than inhibition of
reverse transcriptase.
PMID- 9548816
TI - Selective Pneumocystis carinii dihydrofolate reductase inhibitors: design,
synthesis, and biological evaluation of new 2,4-diamino-5-substituted-furo[2,3
d]pyrimidines.
AB - Nonclassical antifolates, 2,4-diamino-5-substituted-furo[2, 3-d]pyrimidines 3-12
with bridge region variations of C8-S9, C8-N9, and C8-O9 and 1-naphthyl, 2
naphthyl, 2-phenoxyphenyl, 4-phenoxyphenyl, and 2-biphenyl side chains were
synthesized as phenyl ring appended analogues of previously reported 2, 4-diamino
5-(anilinomethyl)furo[2,3-d]pyrimidines. The phenyl ring appended analogues were
designed to specifically interact with Phe69 of dihydrofolate reductase (DHFR)
from Pneumocystis carinii (pc) to afford selective inhibitors of pcDHFR.
Additional substituted phenyl side chains which include 2,5-dichloro, 3,4
dichloro, 3,4,5-trichloro, 3-methoxy, and 2,5-dimethoxy analogues 13-17 were also
synthesized. The compounds were prepared by nucleophilic displacement of 2,4
diamino-5-(chloromethyl)furo[2,3-d]pyrimidine(2) with the appropriate thiol,
amine, or naphthol. Compound 2 was obtained from 2,4-diamino-6-hydroxypyrimidine
and 1, 3-dichloroacetone. The compounds were evaluated as inhibitors against DHFR
from P. carinii, Toxoplasma gondii, and rat liver. Two analogues, 2,4-diamino-5
[(2'-naphthylthio)methyl]furo[2, 3-d]pyrimidine (5) and 2,4-diamino-5-[(2'
phenylanilino)methyl]furo[2,3-d]pyrimidine (11) showed significant selectivity
and potency for pcDHFR compared to trimethoprim. The X-ray crystal structure of 5
with pcDHFR was also carried out, which corroborated the design rationale and
indicated a hydrophobic interaction of the naphthalene ring of 5 and Phe69 of
pcDHFR which is responsible, in part, for the more than 18-fold selectivity of 5
for pcDHFR as compared with rat liver DHFR.
PMID- 9548817
TI - Synthesis and pharmacology of conformationally restricted raloxifene analogues:
highly potent selective estrogen receptor modulators.
AB - The 2-arylbenzothiophene raloxifene, 1, is a selective estrogen receptor
modulator (SERM) which is currently under clinical evaluation for the prevention
and treatment of postmenopausal osteoporosis. In vivo structure-activity
relationships and molecular modeling studies have indicated that the orientation
of the basic amine-containing side chain of 1, relative to the stilbene plane, is
an important discriminating factor for the maintenance of tissue selectivity. We
have constructed a series of analogues of 1 in which this side chain is held in
an orientation which is orthogonal to the stilbene plane, similar to the low
energy conformation predicted for raloxifene. Herein, we report on the synthesis
of these compounds and on their activity in a series of in vitro and in vivo
biological assays reflective of the SERM profile. In particular, we describe
their ability to (1) bind the estrogen receptor, (2) antagonize estrogen
stimulated proliferation of MCF-7 cells in vitro, (3) stimulate TGF-beta3 gene
expression in cell culture, (4) inhibit the uterine effects of ethynyl estradiol
in immature rats, and (5) potently reduce serum cholesterol and protect against
osteopenia in ovariectomized (OVX) rats without estrogen-like stimulation of
uterine tissue. These data demonstrate that one of these compounds, LY357489,4,
is among the most potent SERMs described to date with in vivo efficacy on bone
and cholesterol metabolism in OVX rats at doses as low as 0.01 mg/kg/d.
PMID- 9548819
TI - d-Fused [1]benzazepines with selective in vitro antitumor activity: synthesis and
structure-activity relationships.
AB - The synthesis of novel quinolino[3,2-d][1]benzazepines and pyrido[3,2
d][1]benzazepines is described. The in vitro antitumor activity of the compounds
has been tested in the antitumor screening of the National Cancer Institute
(NCI). Several 2,4-diarylpyrido[3, 2-d][1]benzazepin-6-ones and -thiones turned
out to exhibit considerable cytotoxicity for tumor cells. For studies of SAR
within these series, substituents were introduced into the aromatic rings of the
parent systems. Compounds from the thiolactam series tended to show higher
potency than the corresponding lactams. Prominent compounds with noteworthy
activity and remarkable selectivity for renal cancer cell lines are the lactams
10c, 10g, and 10h and the corresponding thiolactams 11c, 11g, and 11h.
Methylation of the azepine nitrogen leads to complete loss of activity, whereas
annelation of a triazolo ring at the lactam site or transformation of the
thiolactam function to a thiolactim ether results in decreased antitumor activity
and selectivity. Consequently, the secondary lactam or thiolactam structure of
the seven-membered ring has to be regarded as essential for selective antitumor
activity.
PMID- 9548818
TI - Synthesis and antiviral activity of novel acyclic nucleosides: discovery of a
cyclopropyl nucleoside with potent inhibitory activity against herpesviruses.
AB - A series of acyclic nucleosides with two hydroxymethyl groups mimicking the 3'-
and 5'-hydroxyl groups of the 2'-deoxyribose moiety were prepared and evaluated
for their antiherpetic activity. Among those, 9-[[cis-1', 2'
bis(hydroxymethyl)cycloprop-1'-yl]methyl]guanine (3) showed extremely potent
antiviral activity against herpes simplex virus type-1 (HSV-1) with good
selectivity. Both enantiomers of 3 were synthesized starting from chiral
epichlorohydrins, and only one of the enantiomers with 1'S,2'R-configuration (3a)
exhibited strong antiherpetic activity (IC50 of 0.020 microg/mL against HSV-1
Tomioka vs 0.81 microg/mL for acyclovir). Enantiomer 3a was also more inhibitory
than acyclovir against varicella-zoster virus (VZV) but ineffective against human
immunodeficiency virus (HIV). Compound 3a is phosphorylated by HSV-1 thymidine
kinase (TK) very efficiently. The relationship between conformation and
antiherpetic activity in this series of compounds is discussed.
PMID- 9548820
TI - Epidoxoform: a hydrolytically more stable anthracycline-formaldehyde conjugate
toxic to resistant tumor cells.
AB - The recent discovery that the formaldehyde conjugates of doxorubicin and
daunorubicin, Doxoform and Daunoform, are cytotoxic to resistant human breast
cancer cells prompted the search for hydrolytically more stable anthracycline
formaldehyde conjugates. Doxoform and Daunoform consist of two molecules of the
parent drug bound together with three methylene groups, two forming oxazolidine
rings and one binding the oxazolidines together at their 3'-amino nitrogens. The
4'-epimer of doxorubicin, epidoxorubicin, reacts with formaldehyde at its amino
alcohol functionality to produce a conjugate, Epidoxoform, in 59% yield whose
structure consists of two molecules of epidoxorubicin bound together with three
methylene groups in a 1, 6-diaza-4,9-dioxabicyclo[4.4.1]undecane ring system. The
structure was established from spectroscopic data and is consistent with products
from reaction of simpler vicinal trans-amino alcohols with formaldehyde.
Epidoxoform hydrolyzes at pH 7.3 to an equilibrium mixture with dimeric and
monomeric epidoxorubicin-formaldehyde conjugates without release of formaldehyde
or epidoxorubicin. The hydrolysis follows the rate law (A if B) if C + D where A
(Epidoxoform) is in rapid equilibrium with B, and B is in slow equilibrium with C
and D. The forward rate constant for A/B going to C+D gives a half-life of
approximately 2 h at 37 degrees C. At equilibrium the mixture is stable for at
least 2 days. At pH 6.0, hydrolysis proceeds with first-order kinetics to
epidoxorubicin and formaldehyde with a half-life of 15 min at 37 degrees C.
Epidoxoform and epidoxorubicin plus formaldehyde react with the self
complementary DNA octamer (GC)4 to yield five drug-DNA adducts which have
structures analogous to the doxorubicin-DNA adducts from reaction of Doxoform
with (GC)4. Epidoxoform is 3-fold more toxic to MCF-7 human breast cancer cells
and greater than 120-fold more toxic to MCF-7/ADR resistant cells than
epidoxorubicin. Epidoxoform in equilibrium with its hydrolysis products is
greater than 25-fold more toxic to resistant cells with respect to
epidoxorubicin.
PMID- 9548827
TI - Changes for Volume 61
PMID- 9548822
TI - Azapeptides as inhibitors and active site titrants for cysteine proteinases.
AB - Ester and amide derivatives of alpha-azaglycine (carbazic acid, H2NNHCOOH), alpha
azaalanine, and alpha-azaphenylalanine (i.e., Ac-l-Phe-NHN(R)CO-X, where X = H,
CH3, or CH2Ph, respectively) were synthesized and evaluated as inhibitors of the
cysteine proteinases papain and cathepsin B. The ester derivatives inactivated
papain and cathepsin B at rates which increased dramatically with leaving group
hydrophobicity and electronegativity. For example, with 8 (R = H, X = OPh) the
apparent second-order rate constant for papain inactivation was 67 600 M-1 s-1.
Amide and P1-thioamide derivatives do not inactivate papain, nor are they
substrates; instead they are weak competitive inhibitors (0.2 mM < Ki < 4 mM).
Inactivation of papain involves carbamoylation of the enzyme, as demonstrated by
electrospray mass spectrometry. Active site titration indicated a 1:1
stoichiometry for the inactivation of papain with 8, and both inactivated papain
and cathepsin B are highly resistant to reactivation by dialysis (t1/2 > 24 h at
4 degrees C). Azaalanine derivatives Ac-L-Phe-NHN(CH3)CO-X inactivate papain ca.
400- 900-fold more slowly than their azaglycine analogues, consistent with the
planar configuration at Nalpha of the P1 residue and the very substantial
stereoselectivity of papain for L- vs D- residues at the P1 position of its
substrates. Azaglycine derivative 9 (R = H, X = OC6H4NO2-p) inactivates papain
extremely rapidly (>70 000 M-1 s-1), but it also decomposes rapidly in buffer
with release of nitrophenol (kobs = 0.13 min-1); under the same conditions 8
shows <7% hydrolysis over 24 h. This nitrophenol release probably involves
cyclization to an oxadiazolone since 17 (R = CH3, X = OC6H4NO2-p), which cannot
form an isocyanate, releases nitrophenol almost as rapidly (kobs = 0.028 min-1).
Cathepsin C, another cysteine proteinase with a rather different substrate
specificity (i.e., aminopeptidase), was not inactivated by 8, indicating that the
inactivation of papain and cathepsin B by azapeptide esters is a specific
process. Their ease of synthesis coupled with good solution stability suggests
that azapeptide esters may be useful as active site titrants of cysteine
proteinases and probes of their biological function in vivo.
PMID- 9548821
TI - Structure-activity studies on anticonvulsant sugar sulfamates related to
topiramate. Enhanced potency with cyclic sulfate derivatives.
AB - We have explored the structure-activity relationship (SAR) surrounding the
clinically efficacious antiepileptic drug topiramate (1), a unique sugar
sulfamate anticonvulsant that was discovered in our laboratories. Systematic
structural modification of the parent compound was directed to identifying potent
anticonvulsants with a long duration of action and a favorable neurotoxicity
index. In this context, we have probed the pharmacological importance of several
molecular features: (1) the sulfamate group (6-8, 22-25, 27, 84), (2) the linker
between the sulfamate group and the pyran ring (9, 10, 21a,b), (3) the
substituents on the 2,3- (58-60, 85, 86) and 4, 5-fused (30-38, 43, 45-47, 52,
53) 1,3-dioxolane rings, (4) the constitution of the 4,5-fused 1,3-dioxolane ring
(2, 54, 55, 63-68, 76, 77, 80, 83a-r, 84-87, 90a, 91a, 93a), (5) the ring oxygen
atoms (95, 96, 100-102, 104, 105), and (6) the absolute stereochemistry (106 and
107). We established the C1 configuration as R for the predominant alcohol
diastereomer from the highly selective addition of methylmagnesium bromide to
aldehyde 15 (16:1 ratio) by single-crystal X-ray analysis of the major
diastereomer of sulfamate 21a. Details for the stereoselective syntheses of the
hydrindane carbocyclic analogues 95, 96, 100, and 104 are presented. We also
report the synthesis of cyclic imidosulfites 90a and 93a, and imidosulfate 91a,
which are rare examples in the class of such five-membered-ring sulfur species.
Imidosulfite 93a required the preparation and use of the novel sulfur dichloride
reagent, BocN=SCl2. Our SAR investigation led to the impressive 4,5-cyclic
sulfate analogue 2 (RWJ-37947), which exhibits potent anticonvulsant activity in
the maximal electroshock seizure (MES) test (ca. 8 times greater than 1 in mice
at 4 h, ED50 = 6.3 mg/kg; ca. 15 times greater than 1 in rats at 8 h, ED50 = 1.0
mg/kg) with a long duration of action (>24 h in mice and rats, po) and very low
neurotoxicity (TD50 value of >1000 mg/kg at 2 h, po in mice). Cyclic sulfate 2,
like topiramate and phenytoin, did not interfere with seizures induced by
pentylenetetrazole, bicucculine, picrotoxin, and strychnine; also, 2 was not
active in diverse in vitro receptor binding and uptake assays. However, 2 turned
out to be a potent inhibitor of carbonic anhydrase from different rat tissue
sources (e. g., IC50 of 84 nM for the blood enzyme and 21 nM for the brain
enzyme). An examination of several analogues of 2 (83a-r, 85-87, 90a, 91a, 93a)
indicated that potent anticonvulsant activity is associated with relatively small
alkyl substituents on nitrogen (Me/H, 83a; Me/Me, 83m; Et/H, 83b; allyl/H, 83e; c
Pr/H, 83j; c-Bu/H, 83k) and with limited changes in the cyclic sulfate group,
such as 4,5-cyclic sulfite 87a/b. The potent anticonvulsants 83a and 83j had
greatly diminished carbonic anhydrase inhibitory activity; thus, inhibition of
this enzyme may not be a significant factor in the anticonvulsant activity. The
alpha-L-sorbopyranoses 67, 68, and 80, which mainly possess a skew conformation
(ref 29), were nearly twice as potent as topiramate (1). The L-fructose
enantiomers of 1 (106) and 2 (107), synthesized from L-sorbose, were found to
have moderate anticonvulsant activity, with eudysmic ratios (MES ED50 in mice at
4 h, po) of 1:106 = 1.5 and 2:107 = 3.5. The log P values for 1 and 2 were
determined experimentally to be 0.53 and 0.42, respectively, which are less than
the optimal 2.0 for CNS active agents. However, analogues with more favorable
calculated log P (clogP) values, in conjunction with just minor steric
perturbation according to the developed SAR profile, such as 47 (clogP = 2.09),
83m (1.93), and 86 (1.50), did not display improved potency: 47 is less potent
than 1, 83m is equipotent with 2, and 86 is less potent than 2. Although the
measured log P value for diethyl analogue 31 is 1.52, this did not translate into
enhanced potency relative to 1. (ABSTRACT TRUNCATED)
PMID- 9548828
TI - Unusual Polyoxygenated Monoterpenes from the Antarctic Alga Pantoneura
plocamioides
AB - Six new polyoxygenated marine monoterpenes have been isolated from the Antarctic
alga Pantoneura plocamioides. The structure and relative stereochemistry of these
compounds, denominated pantopyranoids A-C (1-3), and pantoisofuranoids A-C (4-6)
were determined on basis of spectroscopic evidence.
PMID- 9548829
TI - Enantioselective Total Syntheses of (-)-7betaH-Eudesmane-4alpha,11-diol and (+)
ent-7betaH-Eudesmane-4alpha,11-diol
AB - The syntheses of (-)-7betaH-eudesmane-4alpha,11-diol (2) and (+)-ent-7betaH
eudesmane-4alpha,11-diol (ent-2) were carried out starting from (-)- and (+)
dihydrocarvones. As a result, the structure, including absolute configuration, of
the naturally occurring eudesmane-4,11-diol isolated from Pluchea arguta was
determined to be (+)-ent-7betaH-eudesmane-4alpha,11-diol (ent-2).
PMID- 9548830
TI - Tribenzylbutyrolactones and Dibenzyldiphenyl-4,5,6,7-tetrahydrobenzofuranones
from Kyrtuthrix maculans
AB - Ten novel compounds, maculalactones B-K (2-11), have been isolated from the
marine cyanobacterium Kyrtuthrix maculans. Their structures, which involve either
three benzyl groups substituted on a butyrolactone ring or two benzyl and two
phenyl groups substituted on a 4,5,6,7-tetrahydrobenzofuranone nucleus, were
determined by 2D NMR spectroscopy. Some speculation is made concerning the
biogenesis of these two novel classes of natural products.
PMID- 9548831
TI - Fractionation Protocol for the Isolation of Polypeptides from Plant Biomass
AB - A fractionation protocol for the isolation of a highly purified polypeptide
fraction from plant biomass is described. The procedure dereplicates ubiquitous
substance classes known to interfere with bioassays often used in natural product
based drug discovery programs. The protocol involves pre-extraction with
dichloromethane, extraction with ethanol (50%), removal of tannins with
polyamide, removal of low-molecular-weight components with size-exclusion
chromatography over Sephadex G-10, and final removal of salts and polysaccharides
with solid-phase extraction using reversed-phase cartridges. The method has been
applied to the aerial parts of Viola arvensis, resulting in the isolation of a
peptide fraction that on further separation yielded a novel 29-residue
macrocyclic polypeptide named varv peptide A, cyclo(
TCVGGTCNTPGCSCSWPVCTRNGLPVCGE-).
PMID- 9548832
TI - Donnaienin, a New Acetogenin Bearing a Hydroxylated Tetrahydrofuran Ring
AB - A novel Annonaceous acetogenin, donnaienin (1), was isolated from the roots of
Goniothalamus donnaiensis. Its structure and stereochemistry were elucidated on
the basis of spectral data and chemical evidence. This compound represents an
unusual type of Annonaceous acetogenin, bearing a hydroxylated tetrahydrofuran
ring.
PMID- 9548833
TI - Revised Relative and Absolute Stereochemistry of (+)-Purpurin
AB - The relative and absolute stereochemistries of (+)-purpurin (3), a flavanone
natural product from Tephrosia, were determined to be 2S,7aR,10S,10aS by
synthesis from semiglabrin in conjunction with X-ray crystallographic analysis.
PMID- 9548834
TI - Studies on the Synthesis of Elegan-Type Linear Diterpenes: The Efficient Total
Syntheses of Eleganolone, Eleganolone Acetate, Elegandiol, Eleganonal, and
Epoxyeleganolone
AB - The first total syntheses of five elegan-type linear diterpenes-eleganolone (1),
eleganolone acetate (2), elegandiol (3), eleganonal (4), and epoxyeleganolone (5)
were accomplished starting from (E,E)-farnesol (6) via four to six steps,
successively, with high overall yield. The key step was the alkylation reaction
of silyl cyanide with allylic iodide.
PMID- 9548835
TI - Dammarane Triterpenes from the Leaves of Securinega melanthesoides
AB - Two new dammarane triterpenoids, trans-securinegin [(20S)-24-methylidenedammarane
3alpha-yl(2E)-3-(4-hydroxyphenyl)-2-propenate (1)] and cis-securinegin [(20S)-24
methylidenedammarane-3alpha-yl(2Z)-3-(4-hydroxyphenyl)-2-propenate (2)], were
isolated from the leaves of Securinega melanthesoides, along with the known
compound bergenin. The structures of 1 and 2 were elucidated using spectroscopic
methods, mainly 2D NMR techniques.
PMID- 9548836
TI - Coluteol and Colutequinone B, More Antifungal Isoflavonoids from Colutea
arborescens
AB - The new antifungal compounds, coluteol (3',5'-dihydroxy-7,2',4'
trimethoxyisoflavan) and colutequinone B (7,4',6'-trimethoxyisoflavan-2',5'
quinone) have been isolated from the root bark of Colutea arborescens (common
bladder senna) and identified by a combination of 1H- and 13C-NMR techniques.
PMID- 9548837
TI - A Novel Insect Antifeedant Nonprotein Amino Acid from Calotropis gigantea
AB - Giganticine (1), a novel nonprotein amino acid, has been isolated from a methanol
extract of the root bark of Calotropis gigantea and its structure established by
spectroscopic methods. It exhibited a significant antifeedant activity against
nymphs of the desert locust Schistocerca gregaria.
PMID- 9548838
TI - New Sesquiterpene Lactones and Other Constituents from Helianthuspetiolaris
AB - Three new sesquiterpene lactones, 11alpha,13-dihydroxydehidrocostuslactone (1),
the unusual 5, 10-epoxygermacranolide 4,15-anhydrohelivypolide (2), and 3-methoxy
1,2-anhydridoniveusin A (4), together with the 5,10-epoxygermacranolide
helivypolide, four known 3,10-furanoheliangolides, and five known kaurane- and
trachylobane-type diterpenes, have been isolated from Helianthus petiolaris.
PMID- 9548839
TI - Geranyl Phenyl Ethers from the New Zealand Liverwort Trichocolea hatcheri
AB - Methyl 4-(geranyloxy)-3-hydroxybenzoate (6), previously unreported, has been
identified from the New Zealand liverwort Trichocolea hatcheri. Four new related
3-hydroxybenzoates 7-10 were also found, with a carbonyl at C-5 of the geranyl
group and various double bond arrangements. Two known geranyl phenyl ethers 1 and
3, found in other Trichocolea species, were also identified.
PMID- 9548840
TI - Strychnochrysine, a New Bisindole Alkaloid from the Roots of Strychnos nux
vomica1
AB - The reinvestigation of Strychnos nux-vomica resulted in the isolation of a
colored monoquaternary bisindole alkaloid from the roots. The structure of this
new orange substance, strychnochrysine (1), was defined by detailed spectroscopic
methods.
PMID- 9548841
TI - Malyngamides M and N from the Hawaiian Red Alga Gracilaria coronopifolia
AB - Two new malyngamides, M and N (1, 2), were isolated along with malyngamide I
acetate (3) from the Hawaiian red alga Gracilaria coronopifolia. Our results
suggest that malyngamide N (2) is a revised structure of deacetoxystylocheilamide
(5). The absolute configuration of malyngamide I acetate was deduced to be 3
using the reversed octant rule.
PMID- 9548844
TI - Combination of LC-MS and LC-NMR as a Tool for the Structure Determination of
Natural Products
AB - Application of both LC-MS and LC-NMR to a partially purified extract of Vernonia
fastigiataled to the direct identification of antibacterial sesquiterpene
lactones 1-9 without isolation of individual compounds. The rapid structural
analysis of both major and minor components of this class of compounds
demonstrated the power of structure-guided screening as a complementary method to
assay-guided screening.
PMID- 9548845
TI - Minor Flavanones from Erythrina abyssinica
AB - Four new prenylated flavanones, abyssinone-V 4'-methyl ether (1) and
abyssinoflavanones IV (2), V (3), and VI (4), have been isolated as minor
flavanones from the African medicinal plant, Erythrina abyssinica, together with
a known flavanone, sigmoidin D. The structure elucidation of compounds 1-4 by
spectroscopic studies is described.
PMID- 9548846
TI - Predomination of Dimers over Naturally Occurring Anthraquinones in Soil
AB - Four bianthraquinones and two monoanthraquinones were isolated as the major soil
anthraquinones from a volcanic ash soil in Japan. They were identified as a new
natural product 5,5'-biphyscion (named hinakurin) (3) and five known compounds,
chrysotalunin (1), (-)-7,7'-biphyscion (2), microcarpin (4), chrysophanol (5),
and physcion (6) using MS, 1D NMR, and 2D NMR techniques. Although the dimers (1
4) are rarely found as natural products, they, along with 5 and 6, were
ubiquitous and predominant over other anthraquinones in various soils from Japan
and Nepal.
PMID- 9548847
TI - Antibacterial steroidal alkaloids from Sarcococca saligna.
AB - Two new pregnane-type steroidal alkaloids, saligcinnamide [(20S,2'E)-20-(N,N
dimethylamino)-3beta-(3'-phenyl-2'-propenyl-N-meth ylamido)pregnane](1) and N(a)
methyl epipachysamine-D [(20S)-20-(N,N-dimethylamino)-3beta-(N
methylbenzamido)pregnane](2 ), along with a known base, epipachysamine D [(20S)
20-(N,N-dimethylamino)-3beta-(benzamido)pregnane] (3), were isolated from the
EtOH extracts of the roots and stems of Sarcococca saligna. The new bases
exhibited antibacterial activity against several human pathogenic bacteria. Two
derivatives of 1, dihydrosaligcinnarnide [(20S)-20-(N,N-dimethylamino)-3beta-(3'
phenylpropionoyl-N-meth ylamido)pregnane](4) and dihydrosaligcinnamine [(20S)-20
(N,N-dimethylamino)-3beta-N-(3'-phenylpropyl-N-methylamino)pre gnane](5), and a
derivative of 2, N(a)-methyl epipachysamine [(20S)-20-(N,N-dimethylamino)-3beta
(N-benzyl,N-methylamino)pregnane](6) were prepared and their antibacterial
activity determined.
PMID- 9548848
TI - Isolation and Identification of Two l-Azetidine-2-carboxylic Acid-Degrading Soil
Microorganisms, Enterobacter agglomerans and Enterobacter amnigenus
AB - Soil samples collected at several times during the growing season and at
different locations within Convallaria majalis beds in Ann Arbor, MI, were
screened for their ability to grow with the cyclic amino acid, l-azetidine-2
carboxylic acid (l-A-2-C), as their sole nitrogen source (i.e., metabolize l-A-2
C). Two different soil microorganisms were isolated, characterized, and
identified using fundamental selection methods, the standard battery of
biochemical characterization tests, and scanning electron microscopy. The
assignment of the identity of these organisms as Enterobacter agglomerans and
Enterobacter amnigenus was further verified by comparison with authentic
microbial samples obtained from ATCC that were able to utilize l-A-2-C as their
sole nitrogen source.
PMID- 9548849
TI - Calyxin H, Epicalyxin H, and Blepharocalyxins A and B, Novel Diarylheptanoids
from the Seeds of Alpinia blepharocalyx
AB - Four unprecedented diarylheptanoids-calyxin H (1) and epicalyxin H (2),
possessing a diarylheptanoid unit and a chalcone moiety, and blepharocalyxins A
(3) and B (4), possessing two diarylheptanoid units and a chalcone moiety-were
isolated from the seeds of Alpiniablepharocalyx. The structures of 1-4, including
absolute stereochemistry, were elucidated by spectroscopic means and after a
consideration of their biogenesis.
PMID- 9548850
TI - Six New Diarylbutane Lignans from Justicia procumbens
AB - Six new diarylbutane lignans, namely, justin A (1), (-)-dihydroclusin diacetate
(2), secoisolariciresinol dimethyl ether diacetate (3), 5-methoxy-4,4'-di-O
methylsecolariciresinol diacetate (4), justin B (5), and justin C (6), together
with three known diarylbutane lignans [2,3-demethoxysecisolintetralin acetate
(7), secoisolariciresinol dimethyl ether (8), and 5-methoxy-4,4'-di-O
methylsecolariciresinol (9)], were isolated from the whole plant of Justicia
procumbens. Their structures were established by spectral analysis.
PMID- 9548851
TI - New Sesquiterpene Lactones from Illicium floridanum
AB - In continuation of our phytochemical investigation of Illicium floridanum Ellis
(American star anise, star bush), three new sesquiterpene lactones possessing the
anisatin-type carbon skeleton (8,9-seco-prezizaane skeleton), 14-acetoxy-3
oxofloridanolide (1), 13-acetoxy-14-(n-butyryloxy)floridanolide (2), and 3beta
acetoxy-14-n-butyryloxy-10-deoxyfloridanolide (3), were isolated from fruits of
this plant. Their structures were elucidated by 1D and 2D NMR measurements. The
molecular structure of 1 was obtained by single crystal X-ray diffraction. The
11,3-delta-lactone structure of the compound previously described as
debenzoyldunnianin in our previous communication, on grounds of NMR spectral
evidence and X-ray crystallographic analysis is revised to a delta-lactone closed
between C-11 and C-7 (compound 4). The neurotoxic sesquiterpene lactone anisatin
(5) and its isomer 2alpha-hydroxyneoanisatin (3-deoxy-2alpha-hydroxyanisatin, 6)
were also isolated and identified by spectroscopic means. The presence of the
neurotoxin 5 in relatively high amounts in the fruits and leaves confirms and
explains early reports on the toxicity of this plant.
PMID- 9548852
TI - Three new diterpenes from the marine soft coral Lobophytum crassum.
AB - Three new terpenoid metabolites (1-3) were isolated from the CH2Cl2 extract of
the soft coral Lobophytum crassum together with the eudesmane derivative 4 and
the known cembrane (2S,7S,8S)-sarcophytoxide (5). Compound 1 is a new cembrane
based diterpene with an C7-C8-epoxide and a methyl ester functionality at C-16.
(3E,5Z)- (2) and (3Z,5E)-2-methyl-6-(4a'-methyl-8'-methylene-trans-perhydr
onaphthalen-2'-yl)hepta-3,5-dien-2-ol (3) represent two new carbon-carbon double
bond isomers of 4, which has the 3E,5E-configuration. The structures of 1-5 were
established by interpretation of their spectroscopic data, mainly 1D and 2D NMR
and MS. Biological activity evaluation of compounds 1 and 5 and the crude
extracts was carried out using agar diffusion assays toward microbial targets and
ELISA assays for investigating the inhibition of HIV-1 reverse transcriptase and
p56lck tyrosine kinase.
PMID- 9548853
TI - Isolation of 1-Methylherbipoline Salts of Halisulfate-1 and of Suvanine as Serine
Protease Inhibitors from a Marine Sponge, Coscinoderma mathewsi
AB - Bioassay-guided isolation of serine protease inhibitors from a marine sponge,
Coscinoderma mathewsi, has yielded 1-methylherbipoline salts of halisulfate-1 and
of suvanine. Structures of these compounds were identified by spectroscopic
analyses and literature data. Antithrombin and antitrypsin activity was
determined.
PMID- 9548854
TI - Gloeolactone, a New Epoxy Lactone from a Blue-Green Alga
AB - A novel lactone, gloeolactone (1), has been isolated from the blue-green alga,
Gloeotrichia sp. The structure of this compound has been elucidated from a
detailed analysis of the NMR spectra. This compound was shown to be toxic to
brine shrimp.
PMID- 9548855
TI - Synthesis of Cycleanine Mono-N-oxides
AB - Oxidation of cycleanine (3) with m-chloroperbenzoic acid gave two diastereomeric
N-oxides (1 and 2), and their stereochemistry was unambiguously determined on the
basis of spectroscopic evidence. The NMR spectra of synthetic cycleanine mono-N
oxides 1 and 2 were significantly different from those of the natural product
previously reported to be cycleanine N-oxide.
PMID- 9548856
TI - 10-Hydroxyaloin B 6'-O-Acetate, an Oxanthrone from Aloe claviflora
AB - Analysis of the leaf exudate of Aloe claviflora resulted in the isolation of a
new oxanthrone, 10-hydroxyaloin B 6'-O-acetate (1), whose structure was
determined on the basis of spectral evidence as well as by conversion to the
known compound 10-hydroxyaloin B (2).
PMID- 9548857
TI - New metabolites from the sponge Spongia agaricina.
AB - The sponge Spongia agaricina from Tarifa, Cadiz, Spain, contains two new 9,11
secosterols, [3-0-deacetylluffasterol B (1) and 3-0-deacetyl-22,23-dihydro-24,28
dehydroluffasterol B (2)] and two new sesterterpenoids [12,16-di-epi-12-0
deacetyl-16-0-acetylfuroscalarol (3) and 16-epi-scalarolbutenolide (4)], in
addition to the known compounds 5-15. The structures of all compounds were
elucidated by interpretation of' spectroscopic data. The metabolites 1-3 showed
significant cytotoxicity against four tumor cell lines (C50 1 microgram/mL).
PMID- 9548858
TI - A Trachylobane Diterpenoid from Xylopia aethiopica
AB - A new trachylobane derivative identified as 7alpha-hydroxytrachyloban-19beta-oic
acid (1) has been isolated from the bark of Xylopia aethiopica and its structure
elucidated by various NMR techniques and molecular modeling.
PMID- 9548859
TI - Madangamines B-E, Pentacyclic Alkaloids from the Marine Sponge Xestospongia
ingens
AB - Four new pentacyclic alkaloids, madangamines B-E (3-6), have been isolated from
the marine sponge Xestospongia ingens collected in Papua New Guinea.
PMID- 9548860
TI - Violarvensin, a new flavone di-C-glycoside from Viola arvensis.
AB - A new flavonoid di-C-glycoside, violarvensin (1), was isolated from the aerial
parts of Viola arvensis, together with the known derivative violanthin (2). The
structure of 1 was established as apigenin-6-C-beta-D-glucopyranosyl-8-C-beta-D-6
deoxygulopyrano side by spectral analysis.
PMID- 9548862
TI - Limaciamine, a New Diacylguanidine Isolated from the North Sea Nudibranch Limacia
clavigera
AB - Limaciamine (1), a new symmetrical diacylguanidine, has been isolated from skin
extracts of the North Sea dorid nudibranch Limacia clavigera.
PMID- 9548861
TI - Haliclorensin, a Novel Diamino Alkaloid from the Marine Sponge
Haliclonatulearensis
AB - Haliclorensin (1), a novel diamino alkaloid possessing an azacyclodecane ring,
has been isolated from the sponge Haliclona tulearensis. Its structure was
elucidated on the basis of spectroscopic data, as well as by comparison with
gamma-amino azacycloalkanes.
PMID- 9548863
TI - Quinoline Alkaloids: Synthesis of Pyrano
AB - Polyphosphoric acid (PPA)-catalyzed cyclization of 2-ono-3
vinylquinolinecarboxylic acid (1) yielded 3,4-dihydro-2,2-dimethyl-2H-pyrano[2,3
b]quinoline (4). The same reaction of 4-methoxy-2-oxo-3-vinylquinolinecarboxylic
acid (1g) afforded 4-methoxy-2,2-dimethylpyrano[2,3-b]quinoline (4g), which on
hydrolysis with ethanolic hydrochloric acid gave khaplofoline (5). The Prevost
reaction of 4-methoxy-3-prenylquinolin-2-one (6) using I2/HgO in acetic acid
yielded 4-methoxy-2-isopropylfuro[2,3-b]quinoline (7). Compound 7 on reduction
with H2/Pd-C followed by N-methylation and de-O-methylation afforded lunacrine
(10a). A similar reaction sequence on 6b gave demethoxylunacrine (10b).
PMID- 9548864
TI - The Synthesis of Phycopsisenone, a New Phenolic Secondary Metabolite from the
Sponge Phycopsis sp.
AB - A short first total synthesis of phycopsisenone (1) utilizing microwave
irradiation-induced aldol condensation and TiCl4-catalyzed reaction of silyl enol
ether (3) with acetone as key steps has been achieved in 29.4% overall yield.
PMID- 9548865
TI - Lathyrus saponin, a new trisaccharide glycoside from Lathyrus japonicus.
AB - A new triterpenoid saponin, named Lathyrus saponin (3), was isolated from the
whole plant of Lathyrus japonicus Willd. together with two known saponins,
azukisaponins II (1) and V (2). as their methyl esters. The structure of 3 was
determined to be soyasapogenol B 3-0-beta-D-glucopyranosyl(1-->2)-beta-D
glucopyranosyl(1-->2)-beta-D-glu curonopyranoside on the basis of physicochemical
and spectroscopic methods.
PMID- 9548866
TI - Trichoflectin, a bioactive azaphilone from the ascomycete Trichopezizella
nidulus.
AB - Trichoflectin (1), a new azaphilone belonging to the deflectin series, 6-deoxy-7
0-demethyl-3,4-anhydrofusarubin (2), and 6-deoxy-3,4-anhydrofusarubin (3) were
isolated from submerged cultures of the ascomycete Trichopezizella nidulus. All
compounds showed antimicrobial activity and inhibited dihydroxynaphthalene
melanin biosynthesis in fungi. The structure of trichoflectin (1) was elucidated
by spectroscopic methods.
PMID- 9548870
TI - New Briarane Stecholide Diterpenes from the Indonesian Gorgonian Briareum sp.
AB - The Indonesian gorgonian Briareum sp. has afforded two new briarane stecholide
diterpenes: 2,9-diacetyl-2-debutyrylstecholide H (1) and 13-dehydroxystecholide J
(2), the semisynthetic 2beta-acetoxy-2-(debutyryloxy)stecholide E acetate (3),
which was isolated as a natural product for the first time, along with the known
compounds stecholides I-M (4-8), stecholide A acetate (9), and stecholide C
acetate (10). The structures of the new compounds were deduced by extensive NMR
studies (1H, 13C, 1H-1H COSY, NOESY, HMQC, and HMBC) and FABMS data (HR and LR).
Cytotoxic activity was found for the first time in stecholide L (7).
PMID- 9548871
TI - Further Petroformynes from Both Atlantic and Mediterranean Populations of the
Sponge Petrosia ficiformis
AB - Five novel polyacetylenes (5-9) were isolated from two different populations of
the sponge Petrosia ficiformis collected in the Mediterranean Sea and the
Atlantic Ocean. Their structures were established by extensive NMR analysis and
by comparison with known petroformynes.
PMID- 9548872
TI - New Hydroxylated Withanolides from Salpichroa origanifolia
AB - From the leaves of Salpichroa origanifolia three new withanolides,
(20S,22R,24S,25S,26R)-5alpha,6alpha:22,26:24,25-triepoxy-15,26-dihydroxy-17(13-
>18)-abeo-ergosta-2,13,15,17-tetraen-1-one (salpichrolide G, 1),
(20S,22R,24S,25R)-5alpha,6alpha:22,26-diepoxy-24,25,26-trihydroxy-17(13-->18)
abeo-ergosta-2,13,15,17-tetraen-1-one (salpichrolide H, 2), and (20S,22R,25S)
5alpha,6alpha:22,26-diepoxy-25,26-dihydroxy-17(13-->18)-abeo-ergosta
2,13,15,17,23-pentaen-1-one (salpichrolide I, 3), were isolated and characterized
by spectroscopic methods and with the aid of molecular modeling. The latter two
compounds were obtained as an epimeric mixture at C-26.
PMID- 9548873
TI - Two novel compounds from Paeonia suffructicosa.
AB - A new hexacyclic triterpenoid, mudanpinoic acid A (1), and a new gallic acid
glycoside, mudanoside B (2), along with nine known compounds--benzoic acid,
resacetophenone, paeoniflorigenone, beta-sitosterol, betulinic acid, oleanoic
acid, quercetin, beta-sitosterol-beta-D-glucoside, and trans-caffeic acid stearyl
ester-were isolated from the dried root cortex of Paeonia suffruticosa. The
structures of the novel compounds were elucidated on the basis of spectral
methods, and that of compound 1 was confirmed by X-ray crystallographic analysis.
PMID- 9548874
TI - Modified Monoterpenes from Biotransformation of (-)-Isopiperitenone by Suspension
Cell Culture of Mentha piperita
AB - The biotransformation of (-)-(4R)-isopiperitenone (1) by suspension cell culture
of Mentha piperita yielded three new hydroxylated derivatives, 4-6, and two new
epoxidized derivatives, 7 and 8. (-)-7-Hydroxyisopiperitenone (2) and its
glucoside were previously isolated from the culture. The structures of 4-8 were
elucidated using spectral methods, and their absolute stereochemistry was
established by NMR experiments and correlation with compounds of known
configuration.
PMID- 9548875
TI - Four new bioactive lobane diterpenes of the soft coral Lobophytum pauciflorum
from Mindoro, Philippines.
AB - The marine soft coral Lobophytum pauciflorum collected from Mindoro Island,
Philippines, yielded four new lobane diterpene derivatives: the acetate congeners
of epoxylobatrienol and lobatrienediol (2 and 7, respectively), a methoxyl
congener of lobatetraene (10), and an oxepin congener of lobatrienetriol (11),
and six known derivatives (1, 3-6, and 8). The structures of the new compounds
were unambiguously established on the basis of NMR spectroscopic (1H, 13C, COSY,
1H-detected direct, and long-range 13C-1H correlations) and mass spectrometric
(EIMS) data. All of the compounds were active against the phytopathogenic fungus
Cladosporium cucumerinum. Compound 1 was found to be active against the Gram
positive bacteria Bacillus subtilis and the yeast Saccharomyces cerevisiae. The
isolated lobane diterpenes were also active in the brine shrimp lethality test.
In the latter bioassay, compounds 8 and 10 were the most active congeners with
LC50's of 0.64 and 4.18 micrograms/mL, respectively.
PMID- 9548876
TI - Isolation of a New Fumonisin from Fusarium moniliforme Grown in Liquid Culture
AB - A new fumonisin, iso-fumonisin B1 (iso-FB1, 1), has been isolated from liquid
cultures of the fungus Fusarium moniliforme (Sheldon) NRRL 13616. On the basis of
its spectroscopic data, its structure has been determined to differ from that of
fumonisin B1 only in the presence of a hydroxyl function at C-4 instead of C-5.
PMID- 9548877
TI - New Sulfated Polyhydroxysteroids from the Antarctic Ophiuroid Astrotomaagassizii
AB - Three new and two known sulfated steroidal polyols have been isolated from the
Antarctic ophiuroid Astrotoma agassizii. All of the new steroids possess a
terminal isopropenyl group and a C-21 sulfoxy moiety in the side chain but differ
in the steroidal nuclei. The structures of these new steroids were established
from spectral and chemical correlations with related steroids as (20R)-cholesta
5,24-diene-2beta,3alpha,21-triol 2,21-disulfate (1), (20R)-5alpha-cholest-24-ene
2beta,3alpha,21-triol 3,21-disulfate (3), and (20R)-cholesta-5,24-diene
2alpha,3alpha,4beta,21-tetrol 3,21-disulfate (5). Analysis of the nonsulfated
sterol fraction has shown the presence of cholest-5-en-3beta-ol, cholesta-5,24
dien-3beta-ol and (22E) cholesta-5,22-dien-3beta-ol as the major sterols.
PMID- 9548878
TI - A New Norlupene from the Leaves of Melaleuca leucadendron
AB - A new lupane-type nortriterpene and 13 known compounds were isolated from the
leaves of Melaleuca leucadendron L. Based on chemical and spectral methods, the
structure of the new compound was elucidated as 28-norlup-20(29)-ene-3beta,17beta
diol, while the known compounds were identified as (2E,6E)-farnesol, phytol,
squalene, alloaromadendrene, ledene, palustrol, viridiflorol, ledol,
betulinaldehyde, betulinic acid, 3beta-acetyl-lup-20(29)-en-28-oic acid, 3-oxolup
20(29)-en-28-oic acid, and platanic acid.
PMID- 9548879
TI - New Quinoid Glycosides from Forsythia suspensa
AB - Three novel compounds, suspenolic acid (1), forsythenside A (2), and
forsythenside B (3), have been isolated from the fruits of Forsythia suspensa.
Their structures were elucidated by spectral methods and chemical reactions.
PMID- 9548880
TI - Conrauinones A and B, Two New Isoflavones from Stem Bark of Millettia conraui1
AB - Two new isoflavones, named conrauinones A (1) and B (2), have been isolated from
the stem bark of Millettia conraui, in addition to known 5-methoxydurmillone. The
structures of the new compounds were determined by spectroscopic analysis
including 2D NMR techniques as 5,6,2'-trimethoxy-4',5'-(methylenedioxy)-2",2"
dimethylpyrano[5",6":7,8]isoflavone (1) and 6-methoxy-3',4'-(methylenedioxy)-7-O
[(E)-3",7"-dimethyl-7"-ol-2",5"-octadienyl]isoflavone (2).
PMID- 9548881
TI - A new lysine derivative and new 3-bromopyrrole carboxylic acid derivative from
two marine sponges.
AB - A novel lysine derivative, 1, has been isolated from the marine sponge Axinyssa
terpnis, in addition to 4alpha-isocyanogorgon-11-ene and related compounds (2-4).
From the marine sponge Axinella carteri, the new 3-bromopyrrole carboxylic acid
derivative, 5, was obtained along with the known compounds aldisin (6) and 2
bromoaldisin (7). Both sponges were collected from Chuuk Atoll, Federated States
of Micronesia. The compounds were characterized by spectroscopic and chemical
methods.
PMID- 9548882
TI - Two New Dichromenes from Evodia lepta
AB - Two new dichromenes, 1 and 2, were isolated from the aerial parts of Evodia
lepta. Their structures were determined by spectroscopic analysis.
PMID- 9548883
TI - Pyrrolidinoindoline Alkaloids from Psychotria colorata1
AB - Fractionation of an alkaloid extract of Psychotria colorata flowers led to the
isolation of six alkaloids, identified by UV, 1D and 2D NMR, and MS as (-)
calycanthine, isocalycanthine, (+)-chimonanthine, hodgkinsine, quadrigemine C,
and a new alkaloid (1), whose structure was deduced by X-ray analysis to be (8
8a),(8'-8'a)-tetradehydroisocalycanthine 3a(R), 3'a(R).
PMID- 9548884
TI - Synthesis and Stereochemistry of Axinastatin 4
AB - Axinastatin 4 from a marine sponge was synthesized by high-dilution BOP-Cl
cyclization of Trp-Val-Pro-Leu-Thr-Pro-Leu in 94% yield (only 2.5% at normal
dilution), showing the configurations of the last three amino acids to be S.
Synthetic axinastatin 4 was devoid of cytostatic activity.
PMID- 9548885
TI - 18-nor-Abietatrienes from the Cones of Larix kaempferi
AB - Two novel norditerpenediols, 18-nor-abieta-8,11,13-triene-4,15-diol (1) and 18
nor-abieta-8,11,13-triene-4,7alpha-diol (2), were isolated from the cones of
Larix kaempferi, together with two known diterpenes, abieta-8,11,13-triene-15,18
diol and abieta-8,11,13-triene-7alpha,18-diol. The structures of 1 and 2 were
determined on the basis of chemical and spectral evidence.
PMID- 9548886
TI - Isohelianol: A 3,4-seco-Triterpene Alcohol from Sasanqua Oil
AB - The structure of isohelianol isolated from the seeds of Camellia sasanqua Thunb.
was established to be 3,4-seco-19(10-->9)-abeo-8alpha,9beta,10alpha-eupha-4,24
dien-3-ol (1) on the basis of spectroscopic methods.
PMID- 9548887
TI - Dioflorin, a Minor Flavonoid from Dioclea grandiflora
AB - Dioflorin (1) was isolated as a minor constituent from the rootbark of Dioclea
grandiflora, the crude extract of which demonstrated analgesic activity. The
structure of 1 has been determined to be 5,7,2'-trihydroxy-8-methoxy-6-(3-methyl
2-butenyl)flavanone on the basis of spectral analysis.
PMID- 9548888
TI - Isolation and Structural Elucidation of Two Plant Ecdysteroids, Gerardiasterone
and 22-Epi-20-hydroxyecdysone
AB - Two minor plant ecdysteroids, 22-epi-20-hydroxyecdysone (1) and gerardiasterone
(2), were isolated from Serratula tinctoria L. (Compositae). The first compound,
a new natural product, was characterized by an unusual stereochemistry at C-22
(i.e., 22S). The second compound was identified as (20R,23S)-20,23
dihydroxyecdysone, a compound previously isolated from the Zooanthid Gerardia
savaglia.
PMID- 9548890
TI - Atmospheric pressure ionization LC/MS/MS techniques for drug disposition studies.
PMID- 9548891
TI - Human intestinal permeability.
AB - This review focuses on permeability measurements in humans, briefly discussing
different perfusion techniques, the relevance of human Peff values, and various
aspects of in vivo transport mechanisms. In addition, human Peff values are
compared with corresponding data from three preclinical transport models. The
regional human jejunal perfusion technique has been validated in several
important ways. One of the most important findings is that there is a good
correlation between the measured human effective permeability values and the
extent of absorption of drugs in humans determined by pharmacokinetic studies.
Estimations of the absorption half-lives from the measured Peff agree very well
with the time to maximal amount of the dose absorbed achieved after an oral dose
in humans. We have also shown that it is possible to determine the Peff for
carrier-mediated transported compounds and to classify them according to the
proposed biopharmaceutical classification system (BCS). Furthermore, human in
vivo permeabilities can be predicted using preclinical permeability models, such
as in situ perfusion of rat jejunum, the Caco-2 model, and excised intestinal
segments in the Ussing chamber. The permeability of passively transported
compounds can be predicted with a particularly high degree of accuracy. However,
special care must be taken for drugs with a carrier-mediated transport mechanism,
and a scaling factor has to be used. Finally, the data obtained in vivo in humans
emphasize the need for more clinical studies investigating the effect of
physiological in vivo factors and molecular mechanisms influencing the transport
of drugs across the intestinal and as well as other membrane barriers. It will
also be important to study the effect of antitransport mechanisms (multidrug
resistance, MDR), such as efflux by P-glycoprotein(s) and gut wall metabolism,
for example CYP 3A4, on bioavailability.
PMID- 9548892
TI - Role of plasma lipoproteins in modifying the biological activity of hydrophobic
drugs.
AB - The plasma lipoprotein distribution of potential drug candidates is not commonly
studied. For some hydrophobic drug candidates, attainment of similar plasma free
drug levels has not been associated with uniform production of pharmacological
activity in different animal species. It is well-known that plasma lipoprotein
lipid profiles vary considerably between different animal species. In addition,
human disease states can significantly influence plasma lipoprotein profiles,
resulting in altered therapeutic outcomes. Current research has shown that
lipoprotein binding of drug compounds can significantly influence not only the
pharmacological and pharmacokinetic properties of the drug, but the relative
toxicity as well. Elucidation of drug distribution among plasma lipoproteins is
expected to yield valuable insight into factors governing the pharmacological
activity and potential toxicity of the drug. This paper will present an
historical perspective and summarize the latest research in the area of
lipoprotein-drug interactions.
PMID- 9548893
TI - Preparation, characterization, and evaluation of miconazole-cyclodextrin
complexes for improved oral and topical delivery.
AB - The solubility of miconazole in water increased in the presence of cyclodextrins
(CDs). The apparent K1:1 values calculated from the phase solubility diagrams of
gamma-CD, hydroxypropyl-beta-CD, alpha-CD, hydroxyethyl-beta-CD, hydroxypropyl
gamma-CD, and beta-CD were 695 +/- 39.6, 363 +/- 34.1, 333 +/- 18.5, 312 +/-
31.0, 305 +/- 27.6, and 293 +/- 17.6 M(-1), respectively. Solid 1:1 molar
complexes were prepared by freeze-drying and kneading and characterized by UV
spectroscopy, differential scanning calorimetry, and electron microscopy. The
dissolution rate increased to 28-255-fold and the solubility to 9-55-fold. Oral
bioavailability in rats increased to 2.3-fold by complexation with hydroxypropyl
beta-CD. Human cadaver skin retained 2.6-fold more drug from the miconazole/alpha
CD complex and hairless mice skin retained 8.4-fold more drug from the HP-beta-CD
complex than from miconazole solution alone in 24 h.
PMID- 9548894
TI - Intestinal peptide and protein delivery: novel bioadhesive drug-carrier matrix
shielding from enzymatic attack.
AB - We have been developing a novel bioadhesive drug-carrier matrix that protects
embedded therapeutic peptides and proteins from degradation by the most abundant
intestinal proteases. Increasing amounts of the Bowman-Birk inhibitor (BBI) were
thereby covalently linked to chitosan-EDTA. The bioadhesive properties of the
resulting polymer-BBI conjugates and their inhibitory effect toward trypsin (EC
3.4.21.4), chymotrypsin (EC 3.4.21.1), elastase (3.4.21.36), carboxypeptidase A
(EC 3.4.17.1), and aminopeptidase N (EC 3.4.11.2) were evaluated in vitro.
Whereas unmodified chitosan-EDTA exhibited under our experimental conditions an
adhesive strength of 54.4 +/- 7.7 mN, it was determined to be 21.0 +/- 3.8 mN for
the comparably most adhesive polymer-BBI conjugate (mean +/- SD; n = 5). All
polymer-BBI conjugates showed a strong inhibitory activity toward the serine
proteases trypsin and chymotrypsin. However, the protective effect toward
elastase was markedly lower. Due to the high binding affinity of chitosan-EDTA
toward zinc, which represents an essential cofactor for carboxypeptidase A and
aminopeptidase N, all polymer-BBI conjugates displayed additionally a strong
protective effect toward these exopeptidases. The novel bioadhesive polymer-BBI
conjugates described in this study seem to be very useful drug-carrier matrixes
in overcoming the enzymatic barrier to orally administered peptide and protein
drugs.
PMID- 9548895
TI - Incorporation of drugs for the treatment of substance abuse into pigmented and
nonpigmented hair.
AB - Hair analysis for drugs may be useful for the long-term monitoring of recidivism
and treatment compliance. L-alpha-Acetylmethadol, buprenorphine, and methadone
are drugs that are used for the treatment of substance abuse. The purpose of this
study was to study the relationship between dose, plasma concentration, hair
concentration, and hair pigmentation for these compounds and their major
metabolites in an animal model. Male Long-Evans rats received either L-alpha
acetylmethadol (1 and 3 mg/kg; n = 6), buprenorphine (1 and 3 mg/kg; n = 5), or
methadone (4 and 8 mg/kg; n = 5) by intraperitoneal injection daily for 5 days.
Fourteen days after beginning drug administration, newly grown hair was collected
and analyzed for either L-alpha-acetylmethadol and two metabolites (L-alpha
acetyl-N-normethadol and L-alpha-acetyl-N,N-dinormethadol), methadone and two
metabolites (D,L-2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium and D,L-2-ethyl-5
methyl-3,3-diphenyl-1-pyrroline), or buprenorphine and one metabolite
(norbuprenorphine). The plasma time course (AUC) for each compound was also
determined after a single administration of each drug at the specified doses.
There was an approximate dose-dependent increase in measured hair concentration
of each parent drug in pigmented hair. The concentrations of L-alpha
acetylmethadol, methadone, and buprenorphine in nonpigmented hair were
significantly less than that measured in pigmented hair at either the high or low
dose. The metabolites L-alpha-acetyl-N-normethadol and D,L-2-ethyl-1,5dimethyl
3,3-diphenylpyrrolinium were detected at lower concentrations than their
respective parent compounds (L-alpha-acetylmethadol or methadone) in pigmented
hair. However, the L-alpha-acetyl-N,N-dinormethadol metabolite concentrations in
pigmented hair were significantly greater than those of the parent drug after
either the low or the high L-alpha-acetylmethadol dose. These data demonstrate
that L-alpha-acetylmethadol, methadone, buprenorphine, and metabolites are
distributed into hair in a dose-related manner with a preference for pigmented
hair.
PMID- 9548896
TI - Comparative biomembrane permeation of tacrine using Yucatan minipigs and domestic
pigs as the animal model.
AB - Tacrine (THA), a centrally acting acetylcholine-esterase inhibitor, is presently
administered perorally for the treatment of Alzheimer's disease (AD). However,
its low bioavailablity (i.e., 17%) and short half-life (2-4 h) demand the search
for alternative routes of administration. The primary objective of this study was
to assess the potential of absorptive mucosae and skin as routes for improving
the systemic delivery of THA. The Yucatan minipig, which has been used
increasingly in biomedical research as a useful model for humans, and the
domestic pig, which is available at low cost, were evaluated for their
suitability as animal model. Permeation kinetics of THA across various absorptive
mucosae (nasal, buccal, sublingual, and rectal) of both species of swine were
studied in the hydrodynamically well-calibrated Valia-Chien permeation cells. For
comparison, permeation through various intestinal segments (duodenum, jejunum,
and ileum) was also measured. Results indicated that both species display similar
permeation characteristics. However, the data obtained for the domestic pigs
shows lower intra- and inter-animal variabilities than that of the Yucatan
minipigs. The nasal mucosa was found to have the highest permeability, while the
buccal mucosa had the lowest among the absorptive mucosae. The intrinsic
permeabilities and diffusivity of THA across the four absorptive mucosae were not
significantly different between species but lower than that for the intestinal
segments for both species. Using dorsal skin as the model, the skin permeation of
THA was also investigated and the results indicated that the domestic swine has a
significantly higher skin permeability than the Yucatan minipig, with more than a
2-fold difference in intrinsic permeabilities. The intrinsic permeability,
partition coefficient, and diffusivity for domestic pig skin are very similar to
that for human cadaver skin. Considering the potential of bypassing the hepatic
"first-pass" elimination, the absorptive mucosae may be useful routes for
systemic delivery of THA to achieve improved bioavailability. With additional
advantages of lower variability, ease of membrane excision, good accessibility,
and lower cost, it is concluded that the domestic swine is a better animal model
than the Yucatan minipig for preclinical studies on the systemic delivery of
tacrine.
PMID- 9548898
TI - Migration of adhesive and nonadhesive particles in the rat intestine under
altered mucus secretion conditions.
AB - The migration rate of adhesive (polycarbophil) and nonadhesive (Eudragit RL-100)
particles was studied in the small and large intestine of the anesthetized rat
under altered mucus secretion conditions accomplished by cholinergic stimulation
(a previously developed in situ model which distinctly accounts for the effect of
regional changes in mucus turnover rate on mucoadhesion in the digestive tube of
the rat). It was found that in the proximal jejunum the relative recovery time
(RRT) of adhesive particles, but not nonadhesive particles, was decreased by
carbachol stimulation. However, adhesive particles agglomerated a short while
after their administration into this organ. In the colon RRT of both adhesive and
nonadhesive particles decreased in a similar manner as the mucus secretion
increased. It is concluded that, in the rat, interactions between intestinal
mucus layer and adhesive and nonadhesive particles are similar. The corresponding
similarity in the intestinal transit time for both types of particles raises
doubts about the advantage of nonspecific adherence in the design of oral
prolonged-release dosage forms.
PMID- 9548897
TI - Effects of various protease inhibitors on the stability and permeability of [D
Ala2,D-Leu5]enkephalin in the rat intestine: comparison with leucine enkephalin.
AB - The effects of various protease inhibitors on the stability of leucine enkephalin
(Leu-Enk) and [D-Ala2,D-Leu5] enkephalin (DADLE) were investigated, and the
permeability of these peptides was also examined in an in vitro Ussing chamber.
Captopril, thiorphan, bacitracin, bestatin, puromycin, amastatin, and sodium
glycocholate (Na-GC) were chosen as protease inhibitors. Regional differences in
the stability of Leu-Enk and DADLE were observed, and the rank order of the
stability of these peptides was colon > duodenum > ileum > jejunum. Na-GC,
amastatin, and puromycin were effective protease inhibitors for improving the
stability of these peptides, although captopril and thiorphan did not improve the
stability of Leu-Enk. In the transport studies, Leu-Enk did not cross the
intestinal membrane in the absence of protease inhibitors, but its transport was
improved in the presence of Na-GC. In addition, Na-GC, amastatin, and puromycin
improved the permeability of DADLE in both jejunum and colon, while the
permeability of DADLE was not improved by the addition of captopril, thiorphan,
and bestatin. Furthermore, the permeability of 6-carboxyfluorescein, a poorly
absorbable and stable compound, was also improved in the presence of Na-GC and
bacitracin at a concentration of 10 mM. These findings indicated that amastatin,
puromycin, and Na-GC at a concentration of 0.5 mM might increase the permeability
of DADLE due to the improved stability of DADLE in the donor site. However, Na-GC
and bacitracin at a concentration of 10 mM had absorption-enhancing activities
which might be also related to the enhanced permeability of DADLE across the
intestinal membrane.
PMID- 9548899
TI - Stereoselective inhibition by the diastereomers quinidine and quinine of uptake
of cardiac glycosides into isolated rat hepatocytes.
AB - The pharmacokinetic interaction between quinidine and digoxin in patients is well
known, in general requiring a dose reduction of digoxin in patients concomitantly
treated with quinidine. Quinine, the diastereomer of quinidine, has not been as
extensively studied in this respect. In addition to an interaction with the renal
clearance of digoxin by quinidine, both diastereomers have been reported to
inhibit the biliary clearance of digoxin in man. To further investigate the
mechanisms of these hepatobiliary transport interactions at the cellular level,
we compared the effects of quinidine and quinine, as well as of the calcium
antagonist verapamil, on the uptake of digoxin and ouabain in isolated rat
hepatocytes. Initial uptake rates of digoxin and ouabain were determined in the
presence of various concentrations of quinine and quinidine. A concentration
dependent inhibition of the cellular uptake of both cardiac glycosides by quinine
and quinidine was found, quinine being a more potent inhibitor than quinidine.
Our results indicate a stereoselective inhibition of the hepatocellular uptake by
the two diastereomers quinidine and quinine, the latter being about equipotent to
verapamil. This unequal inhibitory potency of the two basic drugs was detected
earlier in oocyte studies with the cloned organic cation transporter OCT1.
PMID- 9548900
TI - Synergistic effect of iontophoresis and a series of fatty acids on LHRH
permeability through porcine skin.
AB - The effect of chemical penetration enhancers (e.g., fatty acids) in combination
with iontophoresis was examined on the in vitro permeability of luteinizing
hormone releasing hormone (LHRH) through porcine skin. Porcine epidermis was
pretreated with either ethanol (EtOH) or 10% fatty acid/EtOH. The permeability
coefficient of LHRH was significantly (p < 0.05) greater through EtOH, lauric
acid/EtOH, palmitic acid/EtOH, oleic acid/EtOH, linoleic acid/EtOH, and linolenic
acid/EtOH treated epidermis than the control (untreated epidermis). Iontophoresis
further enhanced the permeability of LHRH (p < 0.05) through enhancer-pretreated
epidermis in comparison with corresponding passive permeability. Among saturated
fatty acids tested, 10% palmitic acid/iontophoresis showed the highest
permeability coefficient [(59.52 +/- 2.40) x 10(-4) cm/h], which was
approximately 16-fold higher than that of the control [(3.57 +/- 0.41) x 10(-4)
cm/h]. Unsaturated cis-octadecenoic acids were more effective penetration
enhancers when compared with octadecanoic acid. Among cis-octadecenoic acids in
combination with EtOH, the greater iontophoretic permeability coefficient [(59.18
+/- 12.43) x 10(-4) cm/h] was obtained through linolenic acid treated epidermis,
which was significantly greater (p < 0.05) than through saturated octadecanoic
acid treated epidermis [(29.08 +/- 3.18) x 10(-4) cm/h]. Also, pretreatment of
epidermis with 5% linolenic acid/propylene glycol (PG) resulted in greater (p <
0.05) iontophoretic flux of LHRH in comparison to 5% linolenic acid/EtOH.
Furthermore, increases in the degree of unsaturation in octadecenoic acids did
not produce corresponding increases in the degree of enhancement. Reversibility
studies revealed that the postrecovery passive flux of LHRH through 5% linolenic
acid in combination with EtOH or PG/iontophoresis treated epidermis was
significantly (p < 0.05) reduced than the prerecovery value but could not
completely recover to the baseline flux (i.e., flux of LHRH through untreated
epidermis).
PMID- 9548901
TI - Physiologically relevant one-compartment pharmacokinetic models for skin. 1.
Development of models.
AB - Many studies have used pharmacokinetic (compartment) models for skin to predict
or analyze absorption of chemicals through skin. In these studies, several
different definitions of the rate constants were used. The purpose of this study
was to develop a general procedure for relating compartment model rate constants
to dermal absorption parameters, such as permeability and partition coefficients,
and to assess whether different definitions of the rate constants produce
different results. Rate constant expressions were developed by requiring a one
compartment model to match a one-membrane model at specific conditions. Because a
membrane model contains more information than a compartment model, a compartment
model cannot match the membrane model in all respects. Consequently, many
compartment models (i.e., different definitions of the rate constants) can be
developed which match the membrane model for different conditions. Using this
procedure, 11 different compartment models were developed and compared to the
membrane model for four different dermal absorption scenarios. The compartment
model that most closely matches the membrane model depends on the specific
exposure scenario and what is to be predicted. One of the new compartment models
agrees reasonably well with the membrane model, for the cases considered.
PMID- 9548902
TI - Physiologically relevant one-compartment pharmacokinetic models for skin. 2.
Comparison of models when combined with a systemic pharmacokinetic model.
AB - Transport of chemicals through skin is best modeled as passive diffusion through
a membrane, but mathematical solutions for realistic conditions are cumbersome.
Compartment models, representing skin as a stirred tank, are mathematically
simpler but less physiologically relevant. In a previous paper, several different
compartment models were developed assuming constant blood and vehicle
concentrations. Here, five skin models (four of the previously described
compartment models and one membrane model) are combined with a one-compartment
systemic pharmacokinetic (PK) model to examine the effects of changing vehicle
and blood concentrations and to clarify how differences between skin models
affect the predicted systemic response. The skin-PK models were solved with the
same input parameters (i.e., permeability coefficients, partition coefficients,
skin thickness, and cutaneous blood flow rates) and compared for five different
exposure scenarios. Because the models have different underlying assumptions,
they do predict different results. For many exposure situations compartment
models give acceptable results, with the most pronounced differences from the
membrane model during short exposure times. Generally, the compartment model that
most closely represents the membrane model was developed by forcing it to match
the membrane model for conditions similar to those of the given exposure
scenario.
PMID- 9548903
TI - Freeze-drying of tert-butyl alcohol/water cosolvent systems: effects of
formulation and process variables on residual solvents.
AB - The objective of this study was to identify significant formulation and
processing variables affecting levels of tert-butyl alcohol (TBA) and isopropyl
alcohol (IPA) in freeze-dried solids prepared from TBA/water cosolvent systems.
The variables examined were the physical state of the solute (crystalline vs
amorphous), initial TBA concentration, freezing rate, cake thickness, and the
temperature and duration of secondary drying. Sucrose and glycine were used as
models for noncrystallizing and crystallizing solutes, respectively. The TBA
concentration above which eutectic crystallization takes place was determined by
differential scanning calorimetry. Model formulations were subjected to extremes
of freezing rate by either dipping in liquid nitrogen or by slowly freezing on
the shelf of a freeze-dryer. Dynamics of solvent loss during secondary drying was
determined by withdrawing samples as a function of time at different shelf
temperatures using a thief system. On the basis of these studies, the most
important determinant of residual TBA level is the physical state of the solute.
Freeze-dried glycine contained very low levels of residual TBA (0.01-0.03%)
regardless of freezing rate or initial TBA concentration. For freeze-dried
sucrose, residual TBA levels were approximately 2 orders of magnitude higher and
were significantly affected by initial TBA concentration and freezing rate. For
the sucrose/TBA/water system, relatively low residual TBA levels were obtained
when the initial TBA level was above the threshold concentration for eutectic
crystallization of TBA, whereas samples freeze-dried from solutions containing
TBA concentrations below this threshold contained significantly higher levels of
TBA. Residual IPA levels increased continuously with initial concentration of TBA
in the sucrose/TBA/water system. Formulations of sucrose/TBA/water which were
frozen rapidly contained residual TBA levels which were approximately twice those
measured in the same formulation after slow freezing and drying under the same
conditions. For the sucrose/TBA/water system, the temperature and time of
secondary drying had only minimal influence on residual TBA in the freeze-dried
solid. At low initial TBA concentrations (2%), residual TBA increases with
increased cake thickness, perhaps because of the influence of depth of fill on
effective freezing rate.
PMID- 9548904
TI - Animal pharmacokinetics and interspecies scaling of Ro 25-6833 and related
(lactamylvinyl)cephalosporins.
AB - From a series of six (lactamylvinyl)cephalosporins, candidates for clinical
evaluation were selected on the basis of their kinetic profile in animals and
predicted pharmacokinetics in man. Exploratory pharmacokinetic studies with Ro 25
6833 and five related cephalosporins were performed following intravenous
administration to rats, dogs, and cynomolgus monkeys. All compounds were
characterized by a high protein binding in rat, monkey, and human plasma (unbound
fraction < or = 5%), whereas in dog plasma, protein binding was markedly lower.
Accordingly, for most compounds, clearance was highest in dogs, and lowest in
monkeys. Comparison of the renal clearance of unbound drug with creatinine
clearance suggests a renal elimination of Ro 25-6833 by glomerular filtration in
both rats and dogs (urinary excretion in monkey was not determined due to drug
instability in monkey urine). All other compounds showed different renal
excretion mechanisms in rats and dogs, thus making the validity of allometric
scaling questionable. Unbound clearances in man were predicted by allometric
scaling (Ro 25-6833 only) and by a correlation analysis of cephalosporin
pharmacokinetics in monkey and man. Limitations of both methods are discussed.
When Ro 25-6833 was later studied in man, the predicted pharmacokinetic data in
man from both approaches were found to be in good agreement with the observed
values.
PMID- 9548905
TI - Solid-state characterization of two polymorphs of aspartame hemihydrate.
AB - From the known crystal structure of aspartame hemihydrate, designated form 1, the
theoretical powder X-ray diffraction (PXRD) pattern was calculated. This PXRD
pattern differs significantly from that of the commercially available aspartame
hemihydrate, which is therefore a different polymorph, designated form II. Form
II transforms to form I during ball-milling or on heating for 30 min at 160
degrees C in the presence of steam. The two polymorphs were compared by PXRD,
differential scanning calorimetry, thermogravimetric analysis, Karl Fischer
titrimetry, Fourier transform infrared (FTIR) absorption spectroscopy, 13C solid
state nuclear magnetic resonance (SSNMR) spectroscopy, scanning electron
microscopy, particle size analysis, and measurements of true density and
intrinsic dissolution rate. Comparison of the 13C SSNMR and FTIR spectra of the
two polymorphs suggests that the crystal structure of form II is less symmetric,
with the side chains located in multiple environments. Although both hemihydrate
polymorphs on heating in the absence of moisture dehydrate to a crystalline
anhydrate, form I does so at a lower temperature, suggesting weaker interactions
of water with aspartame molecules. At higher temperatures the anhydrate from both
hemihydrate polymorphs yields 3-(carboxymethyl)-6-benzyl-2,5-dioxopiperazine
(DKP) by a cyclization reaction for which the temperature, reaction enthalpy, and
activation energy are very similar. Both hemihydrate forms, when in contact with
liquid water, yield the 2.5-hydrate.
PMID- 9548906
TI - Hydration and dehydration behavior of aspartame hemihydrate.
AB - Previous studies have shown that aspartame in the solid state can exist as a
hemihydrate which occurs in two different polymorphic forms (I and II). The
present work shows that equilibration of either hemihydrate at 25 degrees C with
water vapor at relative humidities > or = 58% or with liquid water produces a 2.5
hydrate. Upon subjecting each of these crystalline hydrates to increasing
temperature, the same crystalline anhydrate is formed which thermally cyclizes at
a higher temperature to form the known compound 3-(carboxymethyl)-6-benzyl-2,5
dioxopiperazine. The activation energy of the cyclization reaction appears to
depend on the degree of crystallinity of the anhydrate that is formed at a lower
temperature. On increasing the temperature of the 2.5-hydrate, a hemihydrate
intervenes before the anhydrate is formed. This intervening hemihydrate is
similar to the commercial form (II) of aspartame hemihydrate but exhibits greater
amorphous character. The techniques employed were Karl Fischer titrimetry, powder
X-ray diffractometry, differential scanning calorimetry, thermogravimetric
analysis, solid-state 13C nuclear magnetic resonance spectroscopy, and Fourier
transform infrared absorption spectroscopy.
PMID- 9548907
TI - Inclusion complexation of propofol with 2-hydroxypropyl-beta-cyclodextrin.
Physicochemical, nuclear magnetic resonance spectroscopic studies, and anesthetic
properties in rat. trapani@ippo.uniba.it.
AB - An aqueous formulations of propofol 1 can be prepared by solubilizing it in the
presence of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD). This is potentially
useful for parenteral administration of the drug. The aqueous solubility of 1
linearly increased as a function of HP-beta-CD concentration and showed features
of an AL type diagram. Thermodynamic parameters were obtained by using the
temperature dependence of the stability constant at temperatures of between 25
and 37 degrees C. The results indicate that complex formation is enthalpically,
rather than entropically, driven and that it may involve van der Waals
(dispersive) forces, rather than hydrophobic interactions. The structure of the
inclusion complex propofol/HP-beta-CD was investigated in D2O, using 1H and 13C
NMR spectroscopy. These studies revealed that the whole aromatic ring, as well as
part of the isopropyl groups of the guest molecule, is located inside the HP-beta
CD cavity, while the hydroxy group is located at the rim of the wider cavity end.
The geometrical features of the inclusion complex 1-HP-beta-CD are confirmed by
1D NOE difference spectra and molecular modeling experiments. The anesthetic
activity in rat was investigated, and it was found that there are significant
differences in induction time and sleeping time between 1 solubilized in the
presence of HP-beta-CD and the formulation currently used (Diprivan), which is a
1% w/v oil/water emulsion.
PMID- 9548908
TI - Preparation of norfloxacin spherical agglomerates using the ammonia diffusion
system.
AB - Agglomerated crystals of norfloxacin were prepared by a spherical crystallization
technique using the ammonia diffusion system (ADS). This technique makes it
possible to agglomerate amphoteric drugs like norfloxacin, which cannot be
agglomerated by conventional procedures. When an ammonia-water solution of
norfloxacin is poured into an acetone dichloromethane mixture under agitation, a
small amount of ammonia is liberated in the system. The ammonia-water solution
plays a role both as a good solvent for norfloxacin and as a bridging liquid,
allowing the crystals' collection to take place in one step. It has been proven
that the agglomeration mechanism follows three steps: first acetone enters into
the droplets of ammonia-water (this emulsion is formed because of the system
characteristics); dissolved norfloxacin is consequently precipitated while the
droplets collect the crystals; simultaneously, a part of the ammonia contained in
the agglomerates diffuses to the outer organic solvent phase, thereby forming the
norfloxacin spherical agglomerates. The correct selection of solvents has enabled
us to obtain a suitable stable crystalline shape.
PMID- 9548909
TI - Determination of the optimum mixing time for a mixture of lactose and colloidal
silicon dioxide.
AB - The homogeneity of a mixture of colloidal silicon dioxide (CSD) and lactose is
examined by quantifying the dependence of the CSD content on the mixing time. CSD
concentration is determined photometrically as a blue silica-molybdic complex.
Its deviation from the expected content is taken to characterize the mixture
quality and the optimum mixing time. The conformity of this result with the flow
properties of the same mixture is studied by measuring the dependence of the
angle of repose on the mixing time.
PMID- 9548910
TI - Integration of in vitro data and brain weight in allometric scaling to predict
clearance in humans: some suggestions.
PMID- 9548914
TI - Protein folding dynamics: quantitative comparison between theory and experiment.
AB - The development of a quantitative kinetic scheme is a central goal in mechanistic
studies of biological phenomena. For fast-folding proteins, which lack
experimentally observable kinetic intermediates, a quantitative kinetic scheme
describing the order and rate of events during folding has yet to be developed.
In the present study, the folding mechanism of monomeric lambda repressor is
described using the diffusion-collision model and estimates of intrinsic alpha
helix propensities. The model accurately predicts the folding rates of the wild
type protein and five of eight previously studied Ala left and right arrow Gly
variants and suggests that the folding mechanism is distributed among multiple
pathways that are highly sensitive to the amino acid sequence. For example, the
model predicts that the wild-type protein folds through a small number of
pathways with a folding time of 260 micros. However, the folding of a variant
(G46A/G48A) is predicted to fold through a large number of pathways with a
folding time of 12 micros. Both folding times quantitatively agree with the
experimental values at 37 degrees C extrapolated to 0 M denaturant. The
quantitative nature of the diffusion-collision model allows for rigorous
experimental tests of the theory.
PMID- 9548915
TI - Rational design of novel antimicrobials: blocking purine salvage in a parasitic
protozoan.
AB - All parasitic protozoa obtain purine nucleotides solely by salvaging purine bases
and/or nucleosides from their host. This observation suggests that inhibiting
purine salvage may be a good way of killing these organisms. To explore this
idea, we attempted to block the purine salvage pathway of the parasitic protozoan
Tritrichomonas foetus. T. foetus is a good organism to study because its purine
salvage depends primarily on a single enzyme, hypoxanthine-guanine-xanthine
phosphoribosyltransferase (HGXPRTase), and could provide a good model for
rational drug design through specific enzyme inhibition. Guided by the crystal
structure of T. foetus HGXPRTase, we used structure-based drug design to identify
several non-purine compounds that inhibited this enzyme without any detectable
effect on human HGPRTase. One of these compounds, 4-[N-(3, 4
dichlorophenyl)carbamoyl]phthalic anhydride (referred to as TF1), was selected
for further characterization. TF1 was shown to be a competitive inhibitor of T.
foetus HGXPRTase with respect to both guanine (in the forward reaction; Ki = 13
microM) and GMP (in the reverse reaction; Ki = 10 microM), but showed no effect
on the homologous human enzyme at concentrations of up to 1 mM. TF1 inhibited the
in vitro growth of T. foetus with an EC50 of approximately 40 microM. This
inhibitory effect was associated with a decrease in the incorporation of
exogenous guanine into nucleic acids, and could be reversed by supplementing the
growth medium with excess exogenous hypoxanthine or guanine. Thus, rationally
targeting an essential enzyme in a parasitic organism has yielded specific enzyme
inhibitors capable of suppressing that parasite's growth.
PMID- 9548916
TI - Mapping the active sites of 3-phosphoglycerate kinase and glycerol kinase with
monoammine chromium(III) ATP.
AB - The 12 isomers of monoammine chromium(III) ATP have been used to probe the ATP
binding sites of yeast 3-phosphoglycerate kinase and glycerol kinase from Candida
mycoderma. Inhibition studies of 3-phosphoglycerate kinase show a dramatic
decrease in isomer binding only when the ammonia is in the Delta axial facial
anti position. This suggests an open site architecture with only one strong
contact point between the coordination sphere and the enzyme surface. These
results agree well with the computer modeling studies of bidentate chromium ATP
into the nucleotide site determined by X-ray crystallography [McPhillips, T., et
al. (1996) Biochemistry 35, 4118-4127]. Both methods describe an open site
strongly supporting the validity of the inhibition studies. Inhibition studies of
glycerol kinase show significant decreases in binding for all the tested ammonia
positions, suggesting a closed site architecture with many contacts between the
coordination sphere and the surface of the enzyme. This is in good agreement with
X-ray studies [Hurley, T., et al. (1993) Science 259, 673-677] on the Escherichia
coli glycerol kinase. Inhibition studies of hexokinase previously reported
[Rawlings, J., et al. (1993) Biochemistry 32, 11204-11210] more closely resemble
those of 3-phosphoglycerate kinase, suggesting the surprising result that however
closely hexokinase and glycerol kinase are related structurally the site around
the coordination sphere in hexokinase is functionally open like that of 3
phosphoglycerate kinase.
PMID- 9548917
TI - Characterization and functional role of the QH site of bo-type ubiquinol oxidase
from Escherichia coli.
AB - Cytochrome bo is a four-subunit terminal ubiquinol oxidase in the aerobic
respiratory chain of Escherichia coli that vectorially translocates protons not
only via directed protolytic reactions but also via proton pumping. Previously,
we postulated that a bound quinone in the high-affinity quinone binding site (QH)
mediates electron transfer from the low-affinity quinol oxidation site (QL) in
subunit II to low-spin heme b in subunit I as an electron gate and a transient
electron reservoir [Sato-Watanabe, M., Mogi, T., Ogura, T., Kitagawa, T.,
Miyoshi, H., Iwamura, H., and Anraku, Y. (1994b) J. Biol. Chem. 269, 28908
28912]. In the present study, we carried out screening of ubiquinone analogues
using a bound ubiquinone-free enzyme (DeltaUbiA1) that has been isolated from a
ubiquinone biosynthesis mutant, and identified PC24 (2-chloro-4, 6
dinitrophenol), PC32 (2,6-dibromo-4-cyanophenol), and PC52 (2-isopropyl-5-methyl
4,6-dinitrophenol) as potent QH site inhibitors. PC15 (2,6-dichloro-4
nitrophenol) and PC16 (2, 6-dichloro-4-dicyanovinylphenol), potent QL site
inhibitors, did not exhibit such a selective inhibition of the QH site. Binding
studies using the air-oxidized DeltaUbiA enzyme showed that PC32 and PC52 have 4-
to 7-fold higher affinity than ubiquinone-1. Reconstitution of the QH site with
PC32 and PC52 resulted in a decrease of the apparent Vmax value to 1/7 and 1/3,
respectively, of the control activity. These findings suggest that structural
features of the QL and QH sites are different, and provide further support for
the involvement of the QH site in intramolecular electron transfer and facile
oxidation of quinols at the QL site.
PMID- 9548918
TI - Reaction between S-nitrosothiols and thiols: generation of nitroxyl (HNO) and
subsequent chemistry.
AB - S-Nitrosothiols have been implicated to play key roles in a variety of
physiological processes. The potential physiological importance of S
nitrosothiols prompted us to examine their reaction with thiols. We find that S
nitrosothiols can react with thiols to generate nitroxyl (HNO) and the
corresponding disulfide. Further reaction of HNO with the remaining S
nitrosothiol and thiol results in the generation of other species including NO,
sulfinamide, and hydroxylamine. Mechanisms are proposed that rationalize the
observed products.
PMID- 9548919
TI - Methionine synthase exists in two distinct conformations that differ in
reactivity toward methyltetrahydrofolate, adenosylmethionine, and flavodoxin.
AB - Methionine synthase (MetH) from Escherichia coli catalyzes the synthesis of
methionine from homocysteine and methyltetrahydrofolate via two methyl transfer
reactions that are mediated by the endogenous cobalamin cofactor. After binding
both substrates in a ternary complex, the enzyme transfers a methyl group from
the methylcobalamin cofactor to homocysteine, generating cob(I)alamin enzyme and
methionine. The enzyme then catalyzes methyl transfer from methyltetrahydrofolate
to the cob(I)alamin cofactor, forming methylcobalamin cofactor and
tetrahydrofolate prior to the release of both products. The cob(I)alamin form of
the enzyme occasionally undergoes oxidation to an inactive cob(II)alamin species;
the enzyme also catalyzes its own reactivation. Electron transfer from reduced
flavodoxin to the cob(II)alamin cofactor is thought to generate cob(I)alamin
enzyme, which is then trapped by methyl transfer from adenosylmethionine to the
cobalt, restoring the enzyme to the active methylcobalamin form. Thus the enzyme
is potentially able to catalyze two methyl transfers to the cob(I)alamin
cofactor: methyl transfer from methyltetrahydrofolate during primary turnover and
methyl transfer from adenosylmethionine during activation. It has recently been
shown that methionine synthase is constructed from at least four separable
regions that are responsible for binding each of the three substrates and the
cobalamin cofactor, and it has been proposed that changes in positioning of the
substrate binding regions vis-a-vis the cobalamin binding region could allow the
enzyme to control which substrate has access to the cofactor. In this paper, we
offer evidence that methionine synthase exists in two different conformations
that interconvert in the cob(II)alamin oxidation state. In the primary turnover
conformation, the enzyme reacts with homocysteine and methyltetrahydrofolate but
is unreactive toward adenosylmethionine and flavodoxin. In the reactivation
conformation, the enzyme is active toward adenosylmethionine and flavodoxin but
unreactive toward methyltetrahydrofolate. The two conformations differ in the
susceptibility of the substrate-binding regions to tryptic proteolysis. We
propose a model in which conformational changes control access to the cobalamin
cofactor and are the primary means of controlling cobalamin reactivity in
methionine synthase.
PMID- 9548920
TI - Electrostatic evaluation of the signature motif (H/V)CX5R(S/T) in protein
tyrosine phosphatases.
AB - The catalytic activity of protein-tyrosine phosphatases (PTPs) is mediated by a
cysteine side chain which carries out a nucleophilic attack initiating the
phosphate cleavage. Experimentally, it has been observed that the active site
cysteine has a remarkably low pKa. In the present study, we have investigated the
origin of the low pKa by analyzing the electrostatic properties of four different
protein-tyrosine phosphatases: Yersinia PTP (bacteria), PTP1B (human), VHR
(human), and low molecular weight phosphatase (bovine). These phosphatases have
very low sequence homology and show very low structural similarity. However, they
share a common active site motif [the (H/V)CX5R(S/T) sequence] which adopts a
unique loop structure. We have applied the so-called single site titration
method, which is based on the Poisson-Boltzmann methodology, to (i) study the
influence of the architecture of the (H/V)CX5R(S/T) loop on the pKa of the active
cysteine and (ii) examine which parts of the active site region stabilize the
ionized form of the cysteine. Our results indicate that the architecture of the
(H/V)CX5R(S/T) loop has a major impact on the low pKa of the active cysteines.
The orientation of the microdipoles generated by the partial charges of the
backbone atoms (i.e., the CONHCalpha atoms) is essential for maintaining the low
pKa. Further, the electrostatic field generated by these microdipoles has a
larger impact than the electrostatic dipole generated by the central alpha-helix.
Interactions of the active cysteine with other ionizable side chains play a minor
role in stabilizing the thiolate anion. The only ionizable side chain
significantly influencing the pKa of the active site cysteine is the arginine,
which is an important part of the consensus sequence.
PMID- 9548921
TI - Loop closure and intersubunit communication in tryptophan synthase.
AB - Crystal structures of wild-type tryptophan synthase alpha2beta2 complexes from
Salmonella typhimurium were determined to investigate the mechanism of allosteric
activation of the alpha-reaction by the aminoacrylate intermediate formed at the
beta-active site. Using a flow cell, the aminoacrylate (A-A) intermediate of the
beta-reaction () was generated in the crystal under steady state conditions in
the presence of serine and the alpha-site inhibitor 5-fluoroindole propanol
phosphate (F-IPP). A model for the conformation of the Schiff base between the
aminoacrylate and the beta-subunit cofactor pyridoxal phosphate (PLP) is
presented. The structure is compared with structures of the enzyme determined in
the absence (TRPS) and presence (TRPSF-IPP) of F-IPP. A detailed model for
binding of F-IPP to the alpha-subunit is presented. In contrast to findings by
Hyde et al. [(1988) J. Biol. Chem. 263,17857-17871] and Rhee et al. [(1997)
Biochemistry 36, 7664-7680], we find that the presence of an alpha-site alone
ligand is sufficient for loop alphaL6 closure atop the alpha-active site. Part of
this loop, alphaThr183, is important not only for positioning the catalytic
alphaAsp60 but also for coordinating the concomitant ordering of loop alphaL2
upon F-IPP binding. On the basis of the three structures, a pathway for
communication between the alpha- and beta-active sites has been established. The
central element of this pathway is a newly defined rigid, but movable, domain
that on one side interacts with the alpha-subunit via loop alphaL2 and on the
other side with the beta-active site. These findings provide a structural basis
for understanding the allosteric properties of tryptophan synthase.
PMID- 9548922
TI - Three-dimensional structure of kappa-conotoxin PVIIA, a novel potassium channel
blocking toxin from cone snails.
AB - kappa-Conotoxin PVIIA from the venom of Conus purpurascens is the first cone
snail toxin that was described to block potassium channels. We synthesized
chemically this toxin and showed that its disulfide bridge pattern is similar to
those of omega- and delta-conotoxins. kappa-conotoxin competes with radioactive
alpha-dendrotoxin for binding to rat brain synaptosomes, confirming its capacity
to bind to potassium channels; however, it behaves as a weak competitor. The
three-dimensional structure of kappa-conotoxin PVIIA, as elucidated by NMR
spectroscopy and molecular modeling, comprises two large parallel loops
stabilized by a triple-stranded antiparallel beta-sheet and three disulfide
bridges. The overall fold of kappa-conotoxin is similar to that of calcium
channel-blocking omega-conotoxins but differs from those of potassium channel
blocking toxins from sea anemones, scorpions, and snakes. Local topographies of
kappa-conotoxin PVIIA that might account for its capacity to recognize Kv1-type
potassium channels are discussed.
PMID- 9548923
TI - Intracellular metabolism of human apolipoprotein(a) in stably transfected Hep G2
cells.
AB - Lipoprotein(a) [Lp(a)] consists of LDL and the glycoprotein apolipoprotein(a)
[apo(a)], which are covalently linked via a single disulfide bridge. The
formation of Lp(a) occurs extracellularly, but an intracellular assembly in human
liver cells has also been claimed. The human apo(a) gene locus is highly
polymorphic due to a variable number of tandemly arranged kringle IV repeats. The
size of apo(a) isoforms correlates inversely with Lp(a) plasma concentrations,
which is believed to reflect different synthesis rates. To examine this
association at the cellular level, we analyzed the subcellular localization and
fate of apo(a) in stably transfected HepG2 cells. Our results demonstrate that
apo(a) is synthesized as a precursor with a lower molecular mass which is
processed into the mature, secreted form. The retention times of the precursor in
the ER positively correlated with the sizes of apo(a) isoforms. The mature form
was observed intracellularly at low levels and only in the Golgi apparatus. No
apo(a) was found to be associated with the plasma membrane. Under temperature
blocking conditions, we did not detect any apo(a)/apoB-100 complexes within
cells. This finding was confirmed in HepG2 cells transiently expressing KDEL
tagged apo(a). The precursor and the mature forms of apo(a) were found in the ER
and Golgi fractions, respectively, also in human liver tissue. From our data, we
conclude that in HepG2 cells the apo(a) precursor, dependent on the apo(a)
isoform, is retained in the ER for a prolonged period of time, possibly due to an
extensive maturation process of this large protein. The assembly of Lp(a) takes
place exclusively extracellularly following the separate secretion of apo(a) and
apoB.
PMID- 9548924
TI - Dynamics in psoralen-damaged DNA by 1H-detected natural abundance 13C NMR
spectroscopy.
AB - The dynamics of the DNA oligomer d(GCGTACGC)2 and the 4'-(hydroxymethyl)-4,5',8
trimethylpsoralen-DNA furanside monoadduct (MAf) of this oligomer have been
determined from NMR relaxation parameters. Longitudinal and transverse 13C
relaxation rates and heteronuclear NOE relaxation data have been measured at
natural abundance and have been analyzed in the context of the Lipari and Szabo
model-free formalism. The generalized order parameters for methine carbons in the
octamer sequence d(GCGTACGC)2 (UM) are relatively and uniformly high for the
entire molecule. The generalized order parameters for methine carbons in the MAf
are significantly lower for the deoxyribose bearing the damaged thymidine base
and for the bases flanking the lesion on the undamaged strand, indicating
additional conformational flexibility due to the lesion. The order parameters for
the bases on the damaged strand flanking the lesion remain high. Analysis of the
relaxation data indicates substantial chemical exchange for the adenosine
residues in the UM TpA site, and this chemical exchange is quenched upon MAf
formation. These data are discussed in terms of a model for DNA damage
recognition by the nucleotide excision repair system.
PMID- 9548925
TI - Direct force measurements of insulin monomer-monomer interactions.
AB - Direct measurement of the forces involved in protein-protein and protein-receptor
interactions can, in principle, provide insight necessary for the advancement of
structural biology, molecular biology, and the development of therapeutic
proteins. The protein insulin is illustrative in this respect as the mechanisms
of insulin dimer dissociation and insulin-insulin receptor binding are crucial to
the efficacy of insulin medications for the control of diabetes. Insulin
molecules, modified with a photochemically active azido functionality on specific
residues, were attached to force microscope tips and opposing mica surfaces in
configurations that would either favor or disfavor dimer formation. Force curve
measurements performed in buffer solution revealed the complexity of the insulin
monomer-monomer interaction with multiple unbinding events occurring upon tip
retraction, suggesting disruption of discrete molecular bonds at the monomer
monomer interface. Furthermore, the force curves exhibit long-range unbinding
events, consistent with considerable elongation of the insulin molecule prior to
dissociation. The unbinding forces observed in this study are the result of a
combination of molecular disentanglement and dimer dissociation processes.
PMID- 9548926
TI - Thermodynamic analysis of calcium and magnesium binding to calmodulin.
AB - To elucidate some aspects still debated concerning the interaction of Ca2+ and
Mg2+ with CaM, the thermodynamic binding parameters of Ca2+-CaM and Mg2+-CaM
complexes were characterized by flow dialysis and isothermal microcalorimetry
under different experimental conditions. In particular, the enthalpy and entropy
changes associated with Ca2+ and Mg2+ binding to their sites were determined,
allowing a better understanding of the mechanism underlying cation-CaM
interactions. Ca2+-CaM interaction follows an enthalpy-entropy compensation
relationship, suggesting that CaM explores a subspace of isoenergetical
conformations which is modified by Ca2+ binding. This Ca2+-induced change in CaM
dynamics is proposed to play a key role in CaM function, i.e. in its interaction
with and/or activation of target proteins. Furthermore, data show that Mg2+ does
not act as a direct competitor for Ca2+ binding on the four main Ca2+ binding
sites, but rather as an allosteric effector. This implies that the four main Mg2+
binding sites are distinct from the EF-hand Ca2+ binding sites. Finally, Ca2+ is
shown to interact with auxiliary binding sites on CaM. These weak affinity sites
were thermodynamically characterized. The results presented here challenge the
current accepted view of CaM ion binding.
PMID- 9548927
TI - Native myosin from adult rabbit skeletal muscle: isoenzymes and states of
aggregation.
AB - The globular heads of skeletal muscle myosin have been shown to exist as
isoenzymes S1 (A1) and S1 (A2), and there are also isoforms of the heavy chains.
Using capillary electrophoresis, we found two dominant isoenzymes of the whole
native myosin molecule, in agreement with what has previously been found by
various techniques for native and nondenatured myosin from adult rabbits.
Findings about possible states of aggregation of myosin and its heads are
contradictory. By analytical ultracentrifugation, we confirmed the existence of a
tail-tail dimer. By laser light scattering, we found a head-head dimer in the
presence of MgATP. Capillary electrophoresis coupled with analytical
ultracentrifugation and laser light scattering led us to refine these results. We
found tail-tail dimers in a conventional buffer. We found tail-tail and head-head
dimers in the presence of 0.5 mM MgATP and pure head-head dimers in the presence
of 6 mM MgATP. All the dimers were homodimers. Naming the dominant isoenzymes of
myosin a and b, we observed tail-tail dimers with isoenzyme a (TaTa) and with
isoenzyme b (TbTb) and also head-head dimers with isoenzyme a (HaHa) and with
isoenzyme b (HbHb).
PMID- 9548929
TI - Roles of conserved arginine residues in the metal-tetracycline/H+ antiporter of
Escherichia coli.
AB - Seven arginine residues are conserved in all the tetracycline/H+ antiporters of
Gram-negative bacteria. Four (Arg67, -70, -71, and -127) of them are located in
the putative cytoplasmic loop regions and three (Arg31, -101, and -238) in the
putative periplasmic loop regions [Eckert, B., and Beck, C. F. (1989) J. Biol.
Chem. 264, 11663-11670]. These arginine residues were replaced by alanine,
lysine, or cysteine one by one through site-directed mutagenesis. None of the
mutants showed significant alteration of the protein expression level. The
mutants resulting in the replacement of Arg31, Arg67, Arg71, and Arg238 with
either Ala, Cys, or Lys retained tetracycline resistance levels comparable to
that of the wild type. Among them, only the Arg238 --> Ala mutant showed very low
transport activity in everted membrane vesicles, probably due to the instability
of the mutant protein. The replacement of Arg70 and Arg127 with Ala or Cys
resulted in a drastic decrease in the drug resistance and almost complete loss of
the transport activity, while the Lys replacement mutants retained significant
resistance and transport activity, indicating that the positively charged side
chains at these positions conferred the transport function. On the other hand,
neither the Ala, Cys, nor Lys replacement mutant of Arg101 exhibited any drug
resistance or transport activity. As for the reactivity of the Cys replacement
mutants, only two (Arg71 --> Cys and Arg101 --> Cys) were not reactive with NEM,
the other five mutants being highly or moderately reactive. The reactivity of the
cysteine-scanning mutants around Arg101 with NEM revealed that Arg101 is located
in transmembrane helix IV. It is not likely that Arg101 confers the protein
folding through a salt bridge with a transmembrane acidic residue because no
double mutants involving Arg101 --> Ala and the replacement of one of three
transmembrane acidic residues (Asp15, Asp84, and Asp285) showed the recovery of
any tetracycline resistance or transport activity. The effect of tetracycline on
the [14C]NEM binding to the combined mutants S65C/R101A and L97C/R101A suggests
that Arg101 may cause a substrate-induced conformational change of the putative
exit gate of TetA(B).
PMID- 9548928
TI - Utilization of a soluble integrin-alkaline phosphatase chimera to characterize
integrin alpha 8 beta 1 receptor interactions with tenascin: murine alpha 8 beta
1 binds to the RGD site in tenascin-C fragments, but not to native tenascin-C.
AB - The integrin alpha 8 beta 1 has been reported to bind to fibronectin,
vitronectin, and tenascin-C in cell adhesion or neurite outgrowth assays. Here,
we describe cDNA cloning of the murine alpha 8 subunit, purification of a
recombinant soluble heterodimer consisting of the extracellular domains of the
murine alpha 8 and beta1 subunits, and development of a sensitive binding assay
using a modified form of this heterodimer fused to alkaline phosphatase (AP). In
binding assays, the purified alpha 8 beta 1-AP chimera exhibited the same
divalent ion requirements for activation and binding specificity as cell surface
alpha 8 beta 1: in the presence of Mn2+ it bound to fibronectin and vitronectin
in an RGDS-peptide inhibitable manner. Contrary to previous reports, we found no
evidence that alpha 8 beta 1, expressed on K562 cells or as an AP chimera,
interacts strongly with native tenascin-C. In binding, adhesion, and spreading
assays, significant interactions were observed only to short fragments of
tenascin-C containing the third fibronectin type III repeat which contains an RGD
sequence. Full length tenascin-C and longer fragments containing this repeat did
not appear to serve as ligands, implying that the RGD site in native tenascin-C
is a cryptic binding site for this integrin, exposed by removal of adjacent
domains. Soluble integrin-AP chimeras should be generally useful for identifying
and characterizing integrin interactions with ligands.
PMID- 9548930
TI - Differential regulation of oxidative and osmotic stress induced Syk activation by
both autophosphorylation and SH2 domains.
AB - Syk, a nonreceptor protein-tyrosine kinase, is activated by both oxidative and
osmotic stress and plays different roles in the transduction of stress signals.
In this study, the regulation of oxidative and osmotic stress induced Syk
activation was investigated utilizing Syk-negative DT40 cells, expressing various
Syk mutants. Phosphorylation of Y518Y519 was demonstrated to be required for both
oxidative and osmotic stress induced Syk activation. Syk activation by these two
types of stress stimuli was a combination of both autophosphorylation and the
activities of additional tyrosine kinases. Oxidative stress induced Syk tyrosine
phosphorylation was almost completely attributed to autophosphorylation, whereas
other tyrosine kinases were largely responsible for osmotic stress induced Syk
tyrosine phosphorylation. Moreover, the Src homology 2 (SH2) domains of Syk
differentially regulated Syk activation. Both mSH2(N) Syk and mSH2(C) Syk, in
which the phosphotyrosine-dependent binding motif within the SH2 domains
contained point mutations, showed a significantly higher activity than that
observed in wild-type Syk, following osmotic stress treatment. In comparison, in
response to oxidative stress, only mSH2(N) Syk demonstrated a stronger activation
than wild-type Syk. Therefore, differential activation and regulation of Syk may
give an insight into the distinctive functions of Syk in oxidative and osmotic
stress signaling.
PMID- 9548931
TI - Structure and function of 6,7-dicarboxyheme-substituted myoglobin.
AB - Myoglobin was reconstituted with 6,7-dicarboxy-1,2,3,4,5, 8-hexamethylheme, a
compact synthetic heme with the shortest acid side chains, to pursue the
structural and functional consequences after intensive disruption of the heme
propionate-apoglobin linkages in the native protein. The electron-withdrawing
carboxylate groups directly attached to the porphyrin ring lowered the oxygen
affinity by 3-fold as compared with native myoglobin. Autoxidation of the oxy
derivative to the ferric protein proceeded with 1.6 x 10(-)2 min-1 at pH 7.0 and
30 degrees C. The crystallographic structure of the cyanomet myoglobin with 1.9 A
resolution shows that the heme adopts a unique orientation in the protein pocket
to extend the two carboxylates toward solvent sphere. The native globin fold is
conserved, and the conformations of globin side chains are almost intact except
for those located nearby the heme 6,7-carboxylates. The 7-carboxylate only weakly
interacts with Ser92 and His97 through two mediating water molecules. The 6
carboxylate, on the other hand, forms a novel salt bridge with Arg45 owing to
conformational flexibility of the guanidinium side chain. The proton NMR shows
that the small heme does not fluctuate about the iron-histidine bond even at 55
degreesC, suggesting that the salt bridge between Arg45 and heme 6-carboxylate is
of critical importance to recognize and fix the heme in myoglobin.
PMID- 9548932
TI - The cyanobacterium Spirulina platensis contains a long wavelength-absorbing
pigment C738 (F76077K) at room temperature.
AB - Spirulina platensis is a cyanobacterium which usually lives under high-light
conditions. Nonetheless, it is thought to contain the most red-shifted antenna
pigment of all known Chl a-containing phototrophic organisms, as shown by its 77
K fluorescence peaking at 760 nm. To exclude preparation artifacts and to exclude
the possibility that long wavelength-absorbing pigments form only when the
temperature is lowered to 77 K, we carried out experiments with whole cells at
room temperature. The combined analysis of stationary absorption and fluorescence
spectra as well as fluorescence induction and time-resolved fluorescence decays
shows that the pigment responsible for the 77 K fluorescence at 760 nm (i) has
the oscillator strength of approximately one Chl a molecule, (ii) absorbs
maximally at 738 nm (), (iii) is present only in the antenna system of PS I, (iv)
participates in light collection, and (v) does not entail a low photochemical
quantum yield. Other, more abundant but less red-shifted Chl a antenna pigments
lead to a significantly larger absorption cross section of the photosynthetic
unit of PS I above 700 nm compared to units that would not possess these long
wavelength-absorbing pigments. These results support the hypothesis that the
physiological role of long wavelength-absorbing pigments is to increase the
absorption cross section at wavelengths of >700 nm when in densely populated mats
the spectrally filtered light is relatively more intense at these wavelengths
[Trissl, H.-W. (1993) Photosynth. Res. 35, 247-263].
PMID- 9548934
TI - Room-temperature vibrational difference spectrum for S2QB-/S1QB of photosystem II
determined by time-resolved Fourier transform infrared spectroscopy.
AB - Time-resolved FTIR spectroscopy has been used to kinetically characterize the
vibrational properties of intact photosystem II-enriched membrane samples
undergoing the S1QB-to-S2QB- transition at room temperature. To optimize the
experimental conditions for the FTIR measurements, oxygen polarographic and
variable chlorophyll a fluorescence measurements were used to define the decay of
S2 and QA-, respectively. The flash-induced S2QB-/S1QB difference spectra were
measured at a temporal resolution of 4.44 s and a spectral resolution of 4 cm-1.
An intense positive band is observed at 1480 cm-1 in the difference spectrum and
shows a slow decay with a half time of approximately 13 s. Based on its decay
kinetics and analogy to the infrared absorption of QA- of photosystem II and QB-
in bacterial reaction centers, we conclude that the 1480 cm-1 band arises from QB
of PSII and tentatively assign it to the upsilon(CO) mode of the semiquinone
anion QB-. The infrared spectral features attributed to the S1-to-S2 transition
of the Mn cluster at room temperature show striking similarity to the S2/S1
difference spectrum measured at cryogenic temperatures (Noguchi, T., Ono, T.-A.,
and Inoue, Y. (1995) Biochim. Biophys. Acta 1228, 189-200).
PMID- 9548933
TI - Membrane-anchored cytochrome cy mediated microsecond time range electron transfer
from the cytochrome bc1 complex to the reaction center in Rhodobacter capsulatus.
AB - In Rhodobacter capsulatus, the soluble cytochrome (cyt) c2 and membrane
associated cyt cy are the only electron carriers which operate between the
photochemical reaction center (RC) and the cyt bc1 complex. In this work, cyt cy
mediated microsecond time range electron transfer kinetics were studied by light
activated time-resolved absorption spectroscopy using a mutant strain lacking cyt
c2. In intact cells and in isolated chromatophores of this mutant, only
approximately 30% of the RCs had their photooxidized primary donor rapidly
rereduced by cyt cy. Of these 30%, about half were reduced with a half-time of
approximately 5 micros attributed to preformed complexes, and the other half with
a half-time of approximately 40 micros attributed to cyt cy having to move from
another site. This slower phase was affected by addition of glycerol, indicating
its dependence on the viscosity of the medium. Cyt cy, despite its rereduction by
ubihydroquinone oxidation in the millisecond time range, remained virtually
unable to deliver electrons to other RCs which stayed photooxidized for several
seconds. Furthermore, using two flashes separated by a variable time interval, it
was shown that the fast electron donating complex was reformed in about 60
micros, a time span probably reflecting electron transfer from cyt c1 to cyt cy.
In the absence of the cyt bc1 complex, the steady-state level of cyt cy in the
chromatophore membranes obtained using cells grown in minimal medium was
decreased to approximately 50%. The remaining cyt cy , however, was able to form
the fast electron donating complex with the RC (half-time of approximately 5
micros), whereas the slower phase with a half-time of approximately 40 micros was
strongly decelerated. This finding suggests a role for the cyt bc1 complex in
stabilizing cyt cy and providing its "other" site, possibly via a close
association between these components. Taken together, it is concluded that
although cyt cy is present in substoichiometric amount compared to the RCs, it
supports efficiently photosynthetic growth of R. capsulatus in the absence of cyt
c2 because it can mediate fast electron transfer from the cyt bc1 complex to the
RC during multiple turnovers of the cyclic electron flow.
PMID- 9548935
TI - Spectroscopic comparisons of the pH dependencies of Fe-substituted (Mn)superoxide
dismutase and Fe-superoxide dismutase.
AB - We have compared the active sites of Escherichia coli Fe-substituted
(Mn)superoxide dismutase [Fe-sub-(Mn)SOD] and Fe-SOD to elucidate the basis for
the inactivity of Fe-sub-(Mn)SOD, despite its apparent similarity to Fe-SOD. The
active site of (reduced) Fe2+-sub-(Mn)SOD is qualitatively similar to that of
native Fe2+-SOD, indicating similar active site structures and coordination
environments for Fe2+. Its nativelike pK is indicative of nativelike local
electrostatics, and consistent with Fe2+-sub-(Mn)SOD's retention of ability to
reduce O2*- [Vance and Miller (1998) J. Am. Chem. Soc. 120(3), 461-467]. The
active site of (oxidized) Fe3+-sub-(Mn)SOD differs from that of Fe3+-SOD with
respect to the EPR signals produced at both neutral and high pH, indicating
different coordination environments for Fe3+. Although Fe3+-sub-(Mn)SOD binds the
small anions N3- and F-, the KD for N3- is tighter than that of Fe3+-SOD,
suggesting that the (Mn)SOD protein favors anion binding more than does the
(Fe)SOD protein. The EPR spectral consequences of binding F- are reminiscent of
those observed upon binding the first F- to Fe3+-SOD, but the EPR spectrum
obtained upon binding N3- is different, consistent with crystallographic
observation of a different binding mode for N3- in Thermus thermophilus Mn-SOD
than Fe-SOD [Lah, M., et al. (1995) Biochemistry 34, 1646-1660]. We find a pK of
8.5 to be associated with dramatic changes in the EPR spectrum. In addition, we
confirm the pK between 6 and 7 that has previously been reported based on changes
in the optical signal and N3- binding [Yamakura, F., et al. (1995) Eur. J.
Biochem. 227, 700-706]. However, this latter pK appears to be associated with
much subtler changes in the EPR spectrum. The non-native pKs observed in Fe3+-sub
(Mn)SOD and the differences in the Fe3+ coordination indicated by the EPR spectra
are consistent with Fe3+-sub-(Mn)SOD's inability to oxidize O2*- and suggest that
its low E degrees is due to perturbation of the oxidized state.
PMID- 9548936
TI - Gemcitabine 5'-triphosphate is a stoichiometric mechanism-based inhibitor of
Lactobacillus leichmannii ribonucleoside triphosphate reductase: evidence for
thiyl radical-mediated nucleotide radical formation.
AB - Ribonucleoside triphosphate reductase (RTPR) from Lactobacillus leichmannii
utilizes adenosylcobalamin and catalyzes the conversion of nucleoside
triphosphates to deoxynucleoside triphosphates. One equivalent of 2',2'-difluoro
2'-deoxycytidine 5'-triphosphate, F2dCTP, rapidly inactivates RTPR. Analysis of
the reaction products reveals that inactivation is accompanied by release of two
fluoride ions and 0.84 equiv of 5'-deoxyadenosine and attachment of 1 equiv of
corrin covalently to an active-site cysteine residue of RTPR. No cytosine release
was detected. Proteolysis of corrin-labeled RTPR with endoproteinase Glu-C and
peptide mapping at pH 5.8 revealed that C419 was predominantly modified. The
kinetics of the inactivation have been examined by stopped-flow (SF) UV-vis
spectroscopy and rapid freeze quench (RFQ) electron paramagnetic resonance (EPR)
spectroscopy. Monitoring DeltaA525 nm shows that cob(II)alamin is formed with an
apparent kobs of 50 s-1, only 2. 5-fold slower than a similar experiment carried
out with cytidine 5'-triphosphate (CTP). The same reaction mixture was thus
quenched at times from 22 ms to 30 s and examined by EPR spectroscopy. At early
time points the EPR spectrum resembled a thiyl radical exchange coupled to
cob(II)alamin. From 22 to 255 ms the total spin concentration remained unchanged
at 1.4 spins/RTPR, twice that predicted by the amount of cob(II)alamin determined
by SF. However, with time the signal attributed to the thiyl radical
cob(II)alamin disappears and new signal(s) with broad feature(s) at g = 2.33 and
a sharp feature at g = 2.00 appeared, suggesting formation of cob(II)alamin and a
nucleotide-based radical with only dipolar interactions. These studies have been
interpreted to support the proposal that an RTPR-based thiyl radical can give
rise to a nucleotide-based radical.
PMID- 9548937
TI - Effect of DNA secondary structure on human telomerase activity.
AB - Telomeres are specialized DNA-protein complexes located at the chromosome ends.
The guanine-rich telomeric sequences have the ability to form G-quadruplex
structures under physiological ionic conditions in vitro. Human telomeres are
maintained through addition of TTAGGG repeats by the enzyme telomerase. To
determine a correlation between DNA secondary structure and human telomerase,
telomerase activity in the presence of various metal cations was monitored.
Telomerase synthesized a larger proportion of products corresponding to four,
five, eight, and nine full repeats of TTAGGG in 100 mM K+ and to a lesser extent
in 100 mM Na+ when a d(TTAGGG)3 input primer was used. A more even product
distribution was observed when the reaction mixture contained no added Na+ or K+.
Increasing concentrations of Cs+ resulted in a loss of processivity but not in
the distinct manner observed in K+. When the input primer contained 7-deaza-dG,
the product distribution resembled that of reactions without K+ even in the
presence of 100 mM K+. Native polyacrylamide gel electrophoresis indicated that
d(TTAGGG)4, d(TTAGGG)5, d(TTAGGG)8, and d(TTAGGG)9 formed compact structures in
the presence of K+. The oligonucleotide d(TTAGGG)4 had a UV spectrum
characteristic of that of the G-quadruplex only in the presence of K+ and Na+. A
reasonable explanation for these results is that four, five, eight, and nine
repeats of TTAGGG form DNA secondary structures which promote dissociation of the
primer from telomerase. This suggests that telomerase activity in cells can be
modulated by the secondary structure of the DNA template. These findings are of
probable relevance to the concept of telomerase as a therapeutic target for drug
design.
PMID- 9548938
TI - Location of subunit-subunit contact sites on RNA polymerase II subunit 3 from the
fission yeast Schizosaccharomyces pombe.
AB - RNA polymerase II from the fission yeast Schizosaccharomyces pombe consists of 10
putative subunits. Subunit 3 (Rpb3) is a homologue of prokaryotic alpha subunit,
which plays a key role in the assembly of core enzyme subunits. Previously we
indicated that Rpb3 also plays an essential role in subunit assembly because it
interacts with at least four subunits, two large subunits (Rpb1 and Rpb2) and two
medium-sized subunits (Rpb3 and Rpb5) (1), and it constitutes a core subassembly
consisting of Rpb2, Rpb3, and Rpb11 (2). Using a synthetic mixture of equimolar
amounts of individual subunits, which were all purified from cDNA-expressed
Escherichia coli, we found here that Rpb3 also interacts with Rpb11, another
alpha homologue. By making a set of Rpb3 deletion derivatives, we carried out
mapping of the Rpb5- and Rpb11-contact sites on Rpb3. By far-Western blot and GST
pull-down assays, we found that the amino acid sequence between residues 105-263
of Rpb3 is involved in binding Rpb5, and the sequence between residues 105-297 is
required for binding Rpb11. Although the Rpb5- and Rpb11-contact sites on Rpb3
overlap each other, both subunits are able to associate with Rpb3 simultaneously.
The binding of Rpb5 stabilizes the Rpb3-Rpb11 heterodimer.
PMID- 9548939
TI - Binding of neomycin to the TAR element of HIV-1 RNA induces dissociation of Tat
protein by an allosteric mechanism.
AB - Neomycin inhibits the binding of Tat-derived peptides to the trans-activating
region (TAR) of HIV-1 RNA. Kinetic studies reveal that neomycin acts as a
noncompetitive inhibitor that can bind to the Tat-TAR complex and increase the
rate constant (koff) for dissociation of the peptide from the RNA. Neomycin
effects a conformational change in the structure of TAR that can be detected by
circular dichroism spectroscopy. The increase in ellipticity measured at 265 nm
upon binding of the aminoglycoside is opposite to the decrease seen when Tat
peptides bind to the RNA. Thus, the structural transition induced by neomycin is
apparently incompatible with the binding of Tat and underlies the inhibitory
action of the antibiotic. The binding site for neomycin on TAR was identified in
ribonuclease protection experiments and is located in the stem immediately below
the three-nucleotide bulge that serves as the primary identity element for Tat.
Apparent protection of residues in the bulge by neomycin may represent additional
contacts to the aminoglycoside, but more likely result from changes in the
structure of this region when the ligand binds to the RNA. Binding assays using
variants of TAR in which inosine residues were substituted for guanosine residues
support the results from the ribonuclease protection experiments. Inosine
substitutions in the lower stem, but not the upper stem, decrease the binding
constant for neomycin by approximately 100-fold. Neither of these variants
affected the binding affinity of Tat peptide. In addition, these latter
experiments suggest that the aminoglycoside may be located in the minor groove of
the stem. This mode of association may be a critical aspect of neomycin's ability
to bind to the Tat-TAR complex and could serve as a guide for the design of other
drugs that bind to specific RNA targets as noncompetitive inhibitors.
PMID- 9548940
TI - Cross-talk between protein kinase C-alpha (PKC-alpha) and -delta (PKC-delta): PKC
alpha elevates the PKC-delta protein level, altering its mRNA transcription and
degradation.
AB - Studies utilizing the overexpression of individual isoforms indicated that both
PKC-alpha and -delta promote a number of biological effects, including inhibition
of DNA synthesis associated with rearrangements of the actin cytoskeleton in the
murine B-cell lymphoma (Baf3), differentiation of the murine promyelocyte line
32D, and activation of MAP kinase in CHO fibroblasts. We postulated that these
results reflect some form of cross-regulation between PKC-alpha and -delta rather
than their functional redundancy. In this report, we show that overexpression of
PKC-alpha in Baf3 and 32D leads to an elevation of the endogenous PKC-delta mRNA
and protein levels. The elevated steady-state PKC-delta mRNA level results from a
combination of increased PKC-delta transcription and mRNA stability. Upregulation
of PKC-delta mRNA by PKC-alpha occurs even after a selective depletion of the PKC
delta protein. In addition, phorbol ester-induced elevation of PKC-delta mRNA and
protein levels can be prevented by the PKC inhibitor GF109203X, an indication of
the requirement for PKC kinase activity. Inhibition of new protein synthesis by
cycloheximide showed that upregulation of PKC-delta mRNA, as opposed to delayed
downregulation of the PKC-delta protein, is primarily responsible for the
accumulation of this isoform by PKC-alpha. In parental Baf3 and 32D cells and PKC
alpha overexpressers, PKC-alpha and PKC-delta are uniquely involved in cross
regulation, while PKC-epsilon, PKC-eta, and PKC-mu are not.
PMID- 9548941
TI - Role of phosphorylation in determining the backbone dynamics of the
serine/threonine-proline motif and Pin1 substrate recognition.
AB - Proline residues provide a backbone switch in a polypeptide chain, which is
controlled by the cis/trans isomerization about the peptidyl-prolyl bond.
Phosphorylation of serine- and threonine-proline motifs has been shown to be a
critical regulatory event for many proteins. The biological significance of these
motifs has been further highlighted by the discovery of a novel and essential
peptidyl-prolyl cis/trans isomerase Pin1. Pin1 is required for progression
through mitosis via catalyzing the isomerization of phosphorylated Ser/Thr-Pro
motifs specifically present in mitosis-specific phosphoproteins. However, little
is known whether the phosphorylation regulates the conformational switch of the
Ser/Thr-Pro bonds. Here, we report the synthesis and conformational
characterization of a series of peptides that contain the phosphorylated or
nonphosphorylated Ser/Thr-Pro motifs. Phosphorylation affected the rate of the
cis to trans isomerization of the Thr/Ser-Pro bonds. As determined by a protease
coupled assay, the isomerization rate of phosphorylated Thr-Pro bond was found to
be 8-fold slower than that of the nonphosphorylated analogue. Furthermore,
studies of the pH dependence of the isomerization of the phosphopeptides reveal
that both cis content and the rate constant of prolyl cis to trans isomerization
are lower for the dianionic state of the phosphothreonine-containing peptides.
These effects of phosphorylation are specific for phosphorylated Ser/Thr since
neither phosphorylated Tyr nor glutamic acid was able to affect the prolyl
isomerization. Finally, our experiments provide evidence that effective catalysis
of cis/trans isomerization of phosphorylated Ser/Thr-Pro bonds by Pin1 is
specific to the dianionic form of the substrate. Thus, our results demonstrate
that protein phosphorylation specifically regulates the backbone dynamics of the
Ser/Thr-Pro motifs and that Pin1 specifically isomerizes the certain conformation
of the phosphorylated Ser/Thr-Pro motifs.
PMID- 9548942
TI - Investigation of the cooperative structure of Fc fragments from myeloma
immunoglobulin G.
AB - The cooperative structure of Fc fragments prepared from myeloma human IgG1 was
studied using scanning microcalorimetry and fluorescence at pH 4.2-8.0. It was
shown that the first to be melted are CH2 domains whose interaction with each
other is rather weak, while that with CH3 domains is strong. Then CH3 domains
which form a single cooperative block are melted. The data for the structure of
the Fc fragment in solution agree with the X-ray data according to which the
interaction between CH2 domains is mediated by the carbohydrate moiety while the
two CH3 domains are strongly associated. The presence of intensive CH2-CH3
interaction is a distinctive feature of the state of the Fc fragment in the given
pH region as compared to that at pH <4.1 [Tischenko, V. M., et al. (1982) Eur. J.
Biochem. 126, 517-521; Ryazantsev, S., et al. (1990) Eur. J. Biochem. 190, 393
399]. First, cis interactions greatly increase the free energy of the native
structure stabilization in CH2 domains. Second, they decrease this energy for CH3
domains when compared to the state of the latter at pH 3.8 or within the Fc'
fragment (the dimer of CH3 domains). The temperature and enthalpy of melting of
CH2 domains coincide in all the samples studied despite heterogeneity of the
carbohydrate moiety. Thus, it may be postulated that the conservative part of CH2
domains makes a cardinal contribution to the interaction of these domains with
the carbohydrate moiety.
PMID- 9548943
TI - Interaction of a type II myosin with biological membranes studied by 2H solid
state NMR.
AB - Deuterium nuclear magnetic resonance spectroscopy (2H NMR) has been employed to
investigate the interaction of lung type II myosin protein with neutral bilayers
containing dimyristoylphosphatidylcholine (DMPC) as the only constituent and
mixed bilayers containing the negatively charged lipid
dimyristoylphosphatidylglycerol (DMPG). DMPC was deuterated at its headgroup by
substituting the four protons at the alpha- and beta-positions (DMPC-d4) and the
nine protons at the gamma-position (DMPC-d9). DMPG was perdeuterated at its
headgroup (DMPG-d5). No changes were observed in the quadrupole splittings or
spin-lattice relaxation times for the deuterated DMPC headgroup segments when
increasing amounts of myosin were added to liposomes, made exclusively of DMPC-d9
or of DMPC-d4. However, upon the insertion of the negatively charged lipid DMPG
at 1:1 molar ratio into the DMPC bilayers, myosin was found to interact
electrostatically with the liposomes, thereby affecting significantly both the
quadrupole splittings and spin-lattice relaxation rates of the alpha-, beta-, and
gamma-deuterons in labeled DMPC. Monitoring DMPG-d5 in mixed DMPC/DMPG bilayers
revealed a direct electrostatic interaction of DMPG with the protein, where
positively charged lysine residues located at the tail domain of myosin provide
the necessary sites for the interaction to occur. When ATP and Mg2+ were
complexed to the head domain of myosin, a reduced interaction with the negatively
charged bilayers was observed. The results clearly indicate that a type II myosin
can interact with membranes without the need for a specific hydrophobic domain or
an anchor in the protein molecule, provided that negatively charged lipids are
present in the bilayer.
PMID- 9548944
TI - Time-resolved circular dichroism studies of protein folding intermediates of
cytochrome c.
AB - The circular dichroism spectra of cytochrome c (cytc) in 4.6 M guanidine
hydrochloride (pH 6.5) indicate that the secondary structure in reduced cytc is
near-native, whereas in the CO-bound species (COCytc) it is substantially
unfolded. Photolysis of COCytc should thus induce large changes in the secondary
structure, which can be probed with time-resolved circular dichroism (TRCD)
spectroscopy in the far-UV region. Time-resolved absorption (TROA) and TRCD
methods were used to study the photolysis reaction of COCytc in efforts to
identify structural intermediates in cytc folding on time scales from nanoseconds
to seconds. TROA data from the Soret region, similar to previous studies, showed
four intermediates with lifetimes of 2, 50, 225, and 880 micros. The 2-micros
process is proposed to involve Fe(II)-Met80 coordination. Approximately 7% of the
native CD signal was observed in the TRCD signal at 220 nm within 500 ns, with no
significant additional secondary structure formation observed. Further folding
after 2 micros may be inhibited by ligation of His26/His33 with Fe(II), which is
suggested to be associated with the 50-micros phase. The two slowest components,
tau = 225 and 880 micros, are attributed to CO rebinding on the basis of mixed
gas experiments. CO rebinding is expected to compete with protein folding and
favor the unfolded state. However, when the two CO rebinding lifetimes are
extended into milliseconds by reducing the CO concentration, there is still no
significant increase in CD signal at 220 nm.
PMID- 9548945
TI - Internal motion of lysozyme studied by time-resolved fluorescence depolarization
of tryptophan residues.
AB - The internal motion of lysozyme was described by the steady-state and time
resolved fluorescence anisotropy of its tryptophan residues. The fluorescence of
mutant lysozymes W62Y- and W108Y-lysozyme, in which Trp62 or Trp108 of hen egg
white lysozyme was replaced with a tyrosine residue, could be respectively
assigned to Trp108 or Trp62 at the longer wavelength region of the total
fluorescence spectrum. The segmental motion of Trp62 as shown by its fluorescence
anisotropy decay was described with two components originating from the
fluctuational rotation of an indole moiety about the Calpha-Cbeta bond and
rotational wobble of the peptide segment adjacent to Trp62. Although Trp62 showed
a high degree of motional freedom, its motion was significantly suppressed by the
interaction of the mutant protein with a trimer of N-acetyl-D-glucosamine. By
contrast, the segmental motion of Trp108 is hindered by the local cage structure
at temperatures below 30 degreesC, but Relief from restricted motion occurred on
the formation of ligand complex or by thermal agitation. Because of overlaps of
the fluorescence spectrum, it is difficult to assign the segmental motion of
Trp28 or Trp111, the other two tryptophan residues in lysozyme. However, a
careful analysis of the fluorescence anisotropy decay of W62Y- and W108Y-lysozyme
showed that the fluctuation of the hydrophobic matrix box was greater than that
expected from lysozyme's crystal structure, although it was suppressed by the
binding of the ligand to the active site of lysozyme.
PMID- 9548946
TI - The apolar distal histidine mutant (His69-->Val) of the homodimeric Scapharca
hemoglobin is in an R-like conformation.
AB - The effect of the apolar mutation of the distal histidine (His69-->Val) has been
studied in the cooperative homodimeric hemoglobin from the mollusc Scapharca
inaequivalvis. Absorption, circular dichroism, and resonance Raman spectroscopy
point to a more symmetric heme structure of the deoxy derivative, which is
indicative of an R-like conformation of the deoxy heme. Resonance Raman
spectroscopy also brings out alterations in the geometry and interactions of the
bound CO molecule. The iron-carbon stretching frequency is decreased by about 30
cm-1 with respect to the native protein, while the diatomic ligand stretching
frequency is increased by about the same degree. Consistent with the structural
changes, the ligand binding properties are significantly altered. In the mutant
the overall rate and the affinity for CO binding are increased about 100-fold
with respect to the native protein, and cooperativity is abolished. In addition,
the amplitude and the rate of the geminate rebinding process increase
significantly. This finding may be correlated to the longer average residence
time of the photolyzed CO molecule within the heme pocket of the H69V mutant, as
indicated by molecular dynamics simulations.
PMID- 9548947
TI - Backbone cyclic peptide, which mimics the nuclear localization signal of human
immunodeficiency virus type 1 matrix protein, inhibits nuclear import and virus
production in nondividing cells.
AB - Here, we describe an application of the backbone cyclic (BC) proteinomimetic
approach to the design and the synthesis of a BC peptide which functionally
mimics the nuclear localization signal (NLS) region of the human immunodeficiency
virus type 1 matrix protein (HIV-1 MA). On the basis of the NMR structure of HIV
1 MA, a library of BC peptides was designed and screened for the ability to
inhibit nuclear import of NLS-BSA in digitonin-permeabilized HeLa and Colo-205
cultured cells. The screening yielded a lead compound (IC50 = 3 microM) which was
used for the design of a second library. This library led to the discovery of a
highly potent BC peptide, designated BCvir, with an IC50 value of 35 nM. This
inhibitory potency is compared to a value of 12 microM exhibited by the linear
parent HIV-1 MA NLS peptide. BCvir also reduced HIV-1 production by 75% in
infected nondividing cultured human T-cells and was relatively resistant to
tryptic digestion. These properties make BCvir a potential candidate for the
development of a novel class of antiviral drugs which will be based on blocking
nuclear import of viral genomes.
PMID- 9548948
TI - Synergistic effects of diacylglycerols and fatty acids on membrane structure and
protein kinase C activity.
AB - The synergistic effects of diacylglycerol (DAG) and fatty acid (FA) in activating
protein kinase C have been investigated by correlating their individual and
combined effects on enzymatic activity and on membrane structure in
phosphatidylcholine/phosphatidylserine (4:1) lipid mixtures using a combination
of specific enzymatic assays and 31P and 2H NMR. Addition of DAGs and unsaturated
FAs to the bilayers synergistically increased the tendency of the lipids to form
nonbilayer phases with a concomitant increase in PKC activity until a maximum was
achieved. Further increases in the DAG/FA concentration led to the formation of
the nonbilayer lipid phases under the conditions of the PKC activity assays and
correlated with decreased activity. The nonbilayer lipid phases still supported
PKC activity, although with less than 50% efficiency as compared with the bilayer
lipids. Long-chain saturated FA increased DAG-induced PKC activity by causing a
lateral phase separation of gel (Lbeta) and liquid-crystalline (Lalpha) domains.
Due to the preferential partitioning of DAGs into liquid-crystalline domains, the
local DAG concentration increased in these domains, leading to an increase in PKC
activity. Because a wide range of lipophilic compounds is capable of altering
curvature stress, and therefore the tendency for nonbilayer phase formation in
cellular membranes, these compounds would be expected to modulate PKC activity
and the activities of a number of other membrane-associated enzymes that are
sensitive to biophysical properties of lipid membranes.
PMID- 9548949
TI - Specific and reversible inactivation of protein tyrosine phosphatases by hydrogen
peroxide: evidence for a sulfenic acid intermediate and implications for redox
regulation.
AB - Protein tyrosine phosphatases (PTPs) catalyze the hydrolysis of phosphotyrosine
from specific signal-transducing proteins. Although regulatory mechanisms for
protein kinases have been described, no general mechanism for controlling PTPs
has been demonstrated. Numerous reports have shown that cellular redox status
plays an important role in tyrosine phosphorylation-dependent signal transduction
pathways. This study explores the proposal that PTPs may be regulated by
reversible reduction/oxidation involving cellular oxidants such as hydrogen
peroxide (H2O2). Recent reports indicated that H2O2 is transiently generated
during growth factor stimulation and that H2O2 production is concomitant with
relevant tyrosine phosphorylation. By use of recombinant enzymes, the effects of
H2O2 on three PTPs [PTP1, LAR (leukocyte antigen-related), and VHR (vaccinia H1
related)] and three distinct serine/threonine protein phosphatases (PPs:
PP2Calpha, calcineurin, and lambda phosphatase) were determined. Hydrogen
peroxide had no apparent effect on PP activity. In contrast, PTPs were rapidly
inactivated (kinact = 10-20 M-1 s-1) with low micromolar concentrations of H2O2
but not with large alkyl hydroperoxides. PTP inactivation was fully reversible
with glutathione and other thiols. Because of the slower rate of reduction,
modification occurred even in the presence of physiological thiol concentrations.
By utilization of a variety of biochemical techniques including chemical
modification, pH kinetic studies, and mutagenesis, the catalytic cysteine
thiolate of PTPs was determined to be the selective target of oxidation by H2O2.
By use of the electrophilic reagent 7-chloro-4-nitrobenzo-2-oxa-1, 3-diazole (NBD
Cl), it was shown that a cysteine sulfenic acid intermediate (Cys-SOH) is formed
after attack of the catalytic thiolate on H2O2. A chemical mechanism for
reversible inactivation involving a cysteine sulfenic acid intermediate is
proposed.
PMID- 9548950
TI - Conformational changes in the extrinsic manganese stabilizing protein can occur
upon binding to the photosystem II reaction center: an isotope editing and FT-IR
study.
AB - Photosystem II catalyzes the light-driven oxidation of water and reduction of
plastoquinone in oxygenic photosynthesis. The manganese stabilizing protein (MSP)
of photosystem II is an extrinsic subunit that plays an important role in
catalytic activity. This subunit can be extracted and re-bound to the photosystem
II reaction center. Extraction is associated with decreased stability of
manganese binding by the enzyme and by loss in high rates of oxygen evolution
activity; reconstitution reverses these phenomena. Since little is known about
the assembly of complex membrane proteins, we have employed isotope editing and
vibrational spectroscopy to obtain information about any changes in secondary
structure that occur in MSP upon functional reconstitution to photosystem II. The
spectroscopic data obtained are consistent with substantial changes in
conformation when MSP binds to photosystem II; approximately 30-40% of the
peptide backbone undergoes a change in secondary structure. These conclusions
were reached by comparing different aliquots, before and after binding, of the
same 13[C]MSP sample. Analysis of amide I band line shapes through Fourier
deconvolution and nonlinear regression suggests that binding of MSP to
photosystem II is associated with a decrease in random structure and an increase
in beta-sheet content. We conclude that binding of MSP to the reaction center can
induce folding of MSP. Our results also indicate that, in solution, MSP can
sample a variety of conformational states, which differ in hydrogen bonding of
the peptide backbone.
PMID- 9548951
TI - Amide modes of the alpha-helix: Raman spectroscopy of filamentous virus fd
containing peptide 13C and 2H labels in coat protein subunits.
AB - The filamentous virus fd consists of a single-stranded DNA genome sheathed by
2700 copies of a 50-residue alpha-helical subunit (protein pVIII) and serves as a
model assembly of alpha-helices. To advance vibrational assignments for the alpha
helix, we have investigated Raman spectra of fd virions containing 13C and 2H
(deuterium) labels at various main-chain sites of the pVIII subunits. 13C was
introduced at specific peptide carbonyls, while deuterium was introduced at
selected alpha-carbon (Calpha) and amide nitrogen positions. Interpretation of
the Raman spectra reveals a previously unrecognized alpha-helix band in the
spectral interval 730-745 cm-1, tentatively assigned to a carbonyl in-plane
bending mode (amide IV). Experimental evidence has also been obtained for a
distinctive alpha-helix marker near 1345 cm-1, assigned to a coupled Calpha-H
bending and Calpha-C stretching mode. The fd virions containing 13C-labeled
carbonyls exhibit unexpectedly complex amide I profiles, consisting of multiple
band components. Amide I splitting resulting from 13C substitution of carbonyls
is attributed to decoupling of transition-dipole interactions normally occurring
in the extended pVIII helix. The present study identifies novel conformation
dependent Raman bands in a native alpha-helix assembly, confirms amide I and
amide III assignments proposed previously for filamentous viruses, and
facilitates new Raman assignments for the packaged ssDNA. The alpha-helix markers
identified here should also be useful in conformation analyses of other proteins
by Raman spectroscopy.
PMID- 9548952
TI - Kinetic studies of sequence-specific binding of GCN4-bZIP peptides to DNA strands
immobilized on a 27-MHz quartz-crystal microbalance.
AB - Specific protein-DNA interaction was studied quantitatively by using a highly
sensitive 27-MHz quartz-crystal microbalance (QCM). Biotinylated DNA double
strands (21 bp, having a CRE site of 5'ATGACGTCAT3') were immobilized on an
avidin-bound QCM surface, and sequence-specific binding of bZIP 56-mer peptides
(having both the basic region for binding and the leucine zipper region for
dimerization) to the DNA strand on the QCM was observed. The binding amount
(Deltam) at the nanogram level and kinetic parameters such as association
constants (Ka) and binding and dissociation rate constants (k1 and k-1) could be
obtained from time courses of QCM frequency decreases. A bZIP peptide as a dimer
was observed to bind sequence-specifically to one DNA strand having a CRE site.
Ka values of ss-bZIP, in which the leucine-zipper region of bZIP was substituted
by a Cys-Cys linkage, were largely decreased, and the sequence selectivity also
disappeared. Ka values obtained by the QCM method showed good agreement with
those obtained from the conventional gel mobility shift assay or from circular
dichroism spectrum changes. When the specific sequence of the CRE site of DNA
strands was partly changed, Ka values decreased by about a half due to the
increase of the dissociation rate constant (k-1) independent of the binding rate
constant (k1).
PMID- 9548953
TI - The uvsY recombination protein of bacteriophage T4 forms hexamers in the presence
and absence of single-stranded DNA.
AB - A prerequisite to genetic recombination in the T4 bacteriophage is the formation
of the presynaptic filament-a helical nucleoprotein filament containing
stoichiometric amounts of the uvsX recombinase in complex with single-stranded
DNA (ssDNA). Once formed, the filament is competent to catalyze homologous
pairing and DNA strand exchange reactions. An important component in the
formation of the presynaptic filament is the uvsY protein, which is required for
optimal uvsX-ssDNA assembly in vitro, and essential for phage recombination in
vivo. uvsY enhances uvsX activities by promoting filament formation and
stabilizing filaments under conditions of low uvsX, high salt, and/or high gp32
(ssDNA-binding protein) concentrations. The molecular properties of uvsY include
noncooperative binding to ssDNA and specific protein-protein interactions with
both uvsX and gp32. Evidence suggests that all of these hetero-associations of
the uvsY protein are important for presynaptic filament formation. However, there
is currently no structural information available on the uvsY protein itself. In
this study, we present the first characterization of the self-association of
uvsY. Using hydrodynamic methods, we demonstrate that uvsY associates into a
stable hexamer (s020,w = 6.0, M = 95 kDa) in solution and that this structure is
competent to bind ssDNA. We further demonstrate that uvsY hexamers are capable of
reversible association into higher aggregates in a manner dependent on both salt
and protein concentration. The implications for presynaptic filament formation
are discussed.
PMID- 9548955
TI - Role of the [4Fe-4S] cluster in reductive activation of the cobalt center of the
corrinoid iron-sulfur protein from Clostridium thermoaceticum during acetate
biosynthesis.
AB - The corrinoid iron-sulfur protein (CFeSP) from Clostridium thermoaceticum
functions as a methyl carrier in the Wood-Ljungdahl pathway of acetyl-CoA
synthesis. The small subunit (33 kDa) contains cobalt in a corrinoid cofactor,
and the large subunit (55 kDa) contains a [4Fe-4S] cluster. The cobalt center is
methylated by methyltetrahydrofolate (CH3-H4folate) to form a methylcobalt
intermediate and, subsequently, is demethylated by carbon monoxide
dehydrogenase/acetyl-CoA synthase (CODH/ACS). The work described here
demonstrates that the [4Fe-4S] cluster is required to facilitate the reactivation
of oxidatively inactivated Cob(II)amide to the active Co(I) state. Site-directed
mutagenesis of the large subunit gene was used to change residue 20 from cysteine
to alanine, which resulted in formation of a cluster with EPR and redox
properties consistent with those of [3Fe-4S] clusters. The midpoint potential of
the cluster in the C20A variant was approximately 500 mV more positive than that
of the [4Fe-4S] cluster in the native enzyme. Accordingly, it was found that the
Co center in the C20A mutant protein could be reduced artificially but was
severely crippled in its ability to be reduced by physiological electron donors.
This is probably because the reduced cluster of the C20A protein cannot provide
the driving force needed to reduce Co(II) to Co(I), since the Co(II/I) midpoint
potential is -504 mV. The C20A variant also was unable to catalyze the steady
state synthesis of acetyl-CoA when CH3-H4folate or methyl iodide were provided as
methyl donors and CO and CODH/ACS as reductants. Addition of chemical reductants
rescued the catalytically crippled variant form in both of these reactions. On
the other hand, in single-turnover reactions, the methyl-Co state of the altered
protein was fully active in methylating H4folate and in synthesizing acetyl-CoA
in the presence of CO and CoA. The combined results strongly indicate that the
FeS cluster of the CFeSP is necessary for reductive activation of Co(II) to Co(I)
by physiological reductants but is not required for catalysis, e.g.,
demethylation of CH3-H4folate or methylation of CODH/ACS. We propose that, during
reductive activation, electrons flow from the reduced electron-transfer protein
(e.g., CODH/ACS or reduced ferredoxin (Fd)) to the FeS cluster which then directs
electrons to the cobalt center for catalysis. These results also support earlier
hypotheses that the methylation and demethylation reactions involving the CFeSP
are SN2-type nucleophilic displacement reactions and do not involve radical
chemistry.
PMID- 9548954
TI - Intra- vs intersubunit communication in the homodimeric restriction enzyme EcoRV:
Thr 37 and Lys 38 involved in indirect readout are only important for the
catalytic activity of their own subunit.
AB - EcoRV is a dimer of two identical subunits which together form one binding site
for the double-stranded DNA substrate. Concerted cleavage of both strands of the
duplex requires intersubunit communication to synchronize the two catalytic
centers of EcoRV. Here we address the question of how contacts to the DNA
backbone trigger conformational changes which lead to the activation of both
catalytic centers. The structure of the specific EcoRV-DNA complex shows that a
region including amino acids Thr 37 and Lys 38 is involved in interactions with
the DNA backbone and is a candidate for intersubunit communication. Homodimeric
EcoRV T37A and K38A variants have a 1000-fold reduced catalytic activity. To
examine whether Thr 37 and Lys 38 of one subunit affect the catalytic center in
the same subunit and/or in the other subunit, we have produced heterodimeric
variants containing a Thr 37 --> Ala or Lys 38 --> Ala substitution in one
subunit combined with a wild type (wt) subunit (wt/T37A and wt/K38A) or with a
subunit which contains an amino acid substitution (Asp 90 --> Ala) in the active
site (D90A/T37A and D90A/K38A). Cleavage experiments with supercoiled pAT153 show
that wt/T37A and wt/K38A preferentially nick the DNA. A steady-state kinetic
analysis of the cleavage of an oligodeoxynucleotide substrate shows that the
activity of wt/T37A and wt/K38A is half of that of wild type EcoRV, whereas
D90A/T37A and D90A/K38A are almost inactive. These results demonstrate that Thr
37 and Lys 38 affect primarily the catalytic center in their own subunit and that
both subunits of EcoRV can be activated independently of each other. We suggest
that Thr 37 and Lys 38 control the catalytic activity of the active site in their
own subunit by positioning alpha-helix B.
PMID- 9548956
TI - Self-association of disulfide-dimerized melittin analogues.
AB - Two cysteine substitutions of bee venom melittin have been synthesized to
investigate the effects of disulfide cross-linking on the self-association
properties of the peptide in solution. K23C melittin (mltK23C) was designed to
link nonpolar surfaces of the amphipathic melittin helix on the basis of the
close juxtaposition of pairs of K23 side chains in the crystal of the native
melittin tetramer. K23Q/Q25C melittin (mltQ25C) was designed to link the polar
surfaces of the peptide such that self-association in membrane bound states might
be stabilized. The mltK23C disulfide dimer, (mltK23C)2, is highly structured at
low pH under conditions where native melittin, and the mltK23C monomer, are
unstructured. High-resolution NMR, circular dichroism, and fluorescence
spectroscopy established that (mltK23C)2 is a helical monomer (pseudodimer) with
stable helical segments between residues 2-13 and 15-25. Although the symmetrical
nature of the pseudodimer prevented high-resolution structure determination,
analysis of calculated hydrogen bond lengths, chemical shifts, near-UV circular
dichroism, and urea denaturation demonstrated similarities with alpha-helical
coiled coils and with the structure of native melittin in methanol. Stopped flow
fluorescence showed that (mltK23C)2 underwent pH- and divalent anion-linked
dimerization to a melittin-like pseudotetramer, indicating that a pair of
disulfide bonds could be accommodated in a structure similar to the native
melittin crystal structure. Despite incorporation of two disulfide bonds into the
melittin tetramer, the folding free energy (DeltaGw) of [(mltK23C)2]2 was similar
to that for the native melittin tetramer under the condition used. Incorporation
of a disulfide bond on the polar helix face in melittin did not stabilize helical
structure in the absence of self-association. Instead, this molecule underwent pH
and divalent anion-linked self-association to an ill-defined aggregate which
precipitated.
PMID- 9548957
TI - Structural transitions accompanying the activation of peptide binding to the
endoplasmic reticulum Hsp90 chaperone GRP94.
AB - GRP94, the endoplasmic reticulum Hsp90 paralog, binds a diverse array of
peptides, a subset of which are suitable for assembly onto nascent MHC class I
molecules. At present, the mechanism, site, and regulation of peptide binding to
GRP94 are unknown. Using VSV8, the immunodominant peptide epitope of the
vesicular stomatitis virus, and native, purified GRP94, we have investigated
GRP94-peptide complex formation. The formation of stable GRP94-VSV8 complexes was
slow; competition studies demonstrated that peptide binding to GRP94 was
specific. VSV8 binding to GRP94 was stimulated 2-fold or 4-fold, respectively,
following chemical denaturation/renaturation or transient heat shock. The
activation of GRP94-peptide binding occurred coincident with a stable, tertiary
conformational change, as identified by tryptophan fluorescence and proteolysis
studies. Analysis of GRP94 secondary structure by circular dichroism spectroscopy
indicated an identical alpha-helical content for the native, chemically
denatured/renatured, and heat-shocked forms of GRP94. Through use of the
environment-sensitive fluorophores acrylodan and Nile Red, it was observed that
the activation of peptide binding was accompanied by enhanced peptide and solvent
accessibility to a hydrophobic binding site(s). Peptide binding to native or
activated GRP94 was identical in the presence or absence of ATP or ADP. These
results are discussed with respect to a model in which peptide binding to GRP94
occurs within a hydrophobic binding pocket whose accessibility is
conformationally regulated in an adenine nucleotide-independent manner.
PMID- 9548958
TI - Modulation of lipid polymorphism by the feline leukemia virus fusion peptide:
implications for the fusion mechanism.
AB - The structural effects of the fusion peptide of feline leukemia virus (FeLV) on
lipid polymorphism were studied, using differential scanning calorimetry (DSC),
31P nuclear magnetic resonance (NMR), and time-resolved X-ray diffraction. This
peptide lowers the bilayer to inverted hexagonal phase transition temperature,
TH, of dipalmitoleoylphosphatidylethanolamine (DiPoPE) at peptide mole fractions
of up to 1.5 x 10(-3) at pH 5.0 and at pH 7.4. The temperature at which isotropic
31P NMR signals for monomethyldioleoylphosphatidylethanolamine (MeDOPE) first
occurred is lowered by the FeLV peptide. The amount of isotropic signal seen at
40 degrees C is directly correlated to the peptide:lipid molar ratio. In the
peptide-containing samples, more lipid remains in the isotropic state over the
whole recorded temperature range. Isotropic 31P NMR signals were observed for
DiPoPE in the presence of the FeLV peptide for the entire recorded temperature
range of 35-50 degrees C, while pure DiPoPE showed no significant amount of
isotropic signal. X-ray studies of DiPoPE show the formation of a new lipid phase
with peptide, which is not seen in the pure lipid samples. Disordering of the
Lalpha phase is evidenced by broadening of the diffraction peaks, and the
hexagonal cell parameter is decreased with peptide present. Our results suggest
that the FeLV peptide is increasing the negative curvature of the lipid system,
which is thought to be crucial to the formation of highly bent, high-energy
structural fusion intermediates, such as the "stalk" model. Fusion activity for
this putative fusogenic peptide was also demonstrated, using a resonance energy
transfer (RET) lipid mixing assay. To our knowledge, this work provides the first
published experimental evidence of both fusogenic activity and effects on lipid
polymorphism for the FeLV fusion peptide.
PMID- 9548959
TI - Alpha 1-adrenergic receptor subtype determinants for 4-piperidyl oxazole
antagonists.
AB - Mutational studies in conjunction with ligand binding assays were used to examine
the basis of alpha1-adrenergic receptor subtype selectivity for a series of 4
piperidyloxazole antagonists. A set of chimeric alpha 1A receptors were created
by systematically substituting individual transmembrane domains from alpha 1D
adrenergic receptors. The oxazole antagonists exhibited significant reductions in
affinity against the receptor construct alpha 1A/D(TM2), and moderate reductions
in affinity versus constructs alpha 1A/D(TM5), alpha 1A/B(TM5), and alpha
1A/D(TM6). Antagonist affinities for these chimeras exceeded those found for wild
type alpha 1D and alpha 1B. Site-directed mutagenesis methods were then used to
explore the role that individual residues in TM2 and TM5 play in ligand binding
affinity and selectivity. These studies revealed that mutations at position 86 in
the second transmembrane domain and position 185 in the fifth transmembrane
domain of the alpha 1A receptor have a major impact on receptor subtype
selectivity.
PMID- 9548960
TI - Phosphoinositide 3-kinase in rat liver nuclei.
AB - Biochemical and immunochemical data from the present investigation reveal the
existence of a p85/p110 phosphoinositide 3-kinase (PI 3-kinase) in rat liver
nuclei. 32P-Labeling of membrane phosphoinositides by incubating intact nuclei
with [gamma-32P]ATP results in the formation of [32P]phosphatidyl-inositol 3,4, 5
trisphosphate [PtdIns(3,4,5)P3], accompanied by small quantities of
[32P]phosphatidylinositol 3-phosphate [PtdIns(3)P]. Studies with subnuclear
fractions indicate that the PI 3-kinase is not confined to nuclear membranes. The
nuclear soluble fraction also contains PI 3-kinase and an array of inositide
metabolizing enzymes, including phospholipase C (PLC), phosphoinositide
phosphatase, and diacylglycerol (DAG) kinase. As a result, exposure of
phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] to the nuclear extract in
the presence of [gamma-32P]ATP generates a series of 32P-labeled D-3
phosphoinositides and phosphatidic acid (PA) in an interdependent manner. On the
basis of the immunological reactivity and kinetic behavior, the nuclear PI 3
kinase is analogous, if not identical, to PI 3-kinase alpha, and constitutes
about 5% of the total PI 3-kinase in the cell. Moreover, we test the premise that
nuclear PI 3-kinase may, in part, be regulated through the control of substrate
availability by PtdIns(4,5)P2-binding proteins. Effect of CapG, a nuclear actin
regulatory protein, on PI 3-kinase activity is examined in view of its unique
Ca2+-dependent PtdIns(4, 5)P2-binding capability. In vitro data show that the
CapG-mediated inhibition of nuclear PI 3-kinase is prompted by PKC
phosphorylation of CapG and elevated [Ca2+]. This CapG-dependent regulation
provides a plausible link between nuclear PLC and PI 3-kinase pathways for cross
communications. Taken together, these findings provide definite data concerning
the presence of an autonomous PI 3-kinase cycle in rat liver nuclei. The nuclear
location of PI 3-kinase may lead to a better understanding regarding its
functional role in transducing signals from the plasma membrane to the nucleus in
response to diverse physiological stimuli.
PMID- 9548961
TI - Epimerization via carbon-carbon bond cleavage. L-ribulose-5-phosphate 4-epimerase
as a masked class II aldolase.
AB - Studies indicating that the E. coli L-ribulose-5-phosphate 4-epimerase employs an
"aldolase-like" mechanism are reported. This NAD+-independent enzyme epimerizes a
stereocenter that does not bear an acidic proton and therefore it cannot utilize
a simple deprotonation-reprotonation mechanism. Sequence similarities between the
epimerase and the class II l-fuculose-1-phosphate aldolase suggest that the two
may be evolutionarily related and that the epimerization may occur via carbon
carbon bond cleavage and re-formation. Conserved residues thought to provide the
metal ion ligands of the epimerase have been modified using site-directed
mutagenesis. The resulting mutants show low kcat values in addition to a reduced
affinity for Zn2+. These observations serve to establish that there is a
structural link between between the active site geometry of the epimerase and the
aldolase. In addition, the H97N mutant was found to catalyze the condensation of
dihydroxyacetone and glycolaldehyde phosphate to produce a mixture of L-ribulose
5-phosphate and D-xylulose-5-phosphate. This observation of aldolase activity
establishes that the epimerase active site is capable of promoting carbon-carbon
bond cleavage. Furthermore, glycolaldehyde phosphate was shown to be a
competitive inhibitor of the mutant enzyme (KI = 0.37 mM) but not of the wild
type enzyme. The mutation apparently causes the epimerase to become "leaky" and
enables it to bind/generate the normal reaction intermediates from the unbound
aldol cleavage products.
PMID- 9548962
TI - General base catalysis by the phosphatidylcholine-preferring phospholipase C from
Bacillus cereus: the role of Glu4 and Asp55.
AB - To assess what roles the active site residues Glu4 and Asp55 of the
phosphatidylcholine-preferring phospholipase C of Bacillus cereus (PLCBc) might
play in binding and catalysis, selected mutants were prepared through site
directed mutagenesis of the plc gene. The mutants were then expressed in
Escherichia coli and purified as fusion proteins with the maltose binding protein
(MBP). Kinetic analysis showed that mutations at Glu4 had only modest effects on
the catalytic activity, whereas those at Asp55 led to proteins whose values for
kcat/KM were 10(4)-10(6) times less than that of the wild-type enzyme. The modest
decrease in catalytic activity and the pH-dependent profile of the E4L mutant
strongly suggest that glutamic acid at position 4 is not the general base in the
PLCBc-catalyzed reaction. Rather, the results support the hypothesis that Glu4 is
primarily involved in substrate binding, perhaps by electrostatic stabilization
of the positive charge of the choline moiety of the phosphatidylcholine
substrate. Examination of X-ray crystallographic data of PLCBc and its various
complexes reveals that the carboxylate side chain of Asp55 is positioned such
that it could activate a water for nucleophilic attack on the substrate or serve
as a ligand for Zn1. However, the involvement of the side chain of Asp55 as an
important Zn1 ligand is not consistent with the atomic absorption and
thermostability data obtained for the D55L mutant, which are virtually identical
with that of the wild-type enzyme. The large reduction in the measured kcat/KM of
the D55E, D55N, and D55L mutants of PLCBc indicates that Asp55 plays a critical
role in catalysis and likely serves as the general base in the hydrolysis of
phosphatidylcholine by PLCBc.
PMID- 9548963
TI - Coexisting kinetically distinguishable forms of dialkylglycine decarboxylase
engendered by alkali metal ions.
AB - The pyridoxal phosphate (PLP) dependent enzyme dialkylglycine decarboxylase (DGD)
specifically binds alkali metal ions near the active site. Large ions (Rb+, K+)
activate the enzyme while smaller ones (Na+, Li+) inhibit it. Crystallographic
results have shown that DGD undergoes a metal ion size dependent structural
switch [Hohenester, E., Keller, J. W., and Jansonius, J. N. (1994) Biochemistry
33, 13561], but no evidence for multiple conformations in crystalline DGD was
obtained. Here, evidence is presented that DGD-K+ in solution exists in two
conformations differing in catalytic competence. Initial rate traces for DGD-K+
exhibit a high degree of curvature due to decreasing activity over time. DGD
remains tetrameric under the assay conditions as demonstrated by gel filtration
experiments, arguing against the possibility of subunit dissociation as the
source of activity loss. Likewise, the mass spectrum of DGD shows a single
covalent form. A hysteretic model that assumes two slowly interconverting enzyme
forms accounts well for the initial rate data when kinetic parameters from
biphasic pre-steady-state kinetics are employed. The fit of the model to the data
yields an estimate of 59 +/- 1% for the fast form. A cooperative model cannot
account for the data. Double reciprocal plots for coenzyme binding to DGD exhibit
two linear phases. Similarly, two kinetic phases are observed in PLP association
kinetics. The substitution of Na+ or Rb+ for K+ alters the steady-state kinetic
parameters of DGD. Preincubation of DGD-K+ with the competitive inhibitor 1
aminocyclopropane-1-carboxylate (ACC) lowers both kcat and KAIB apparently by
drawing the enzyme toward the less active, tighter binding form observed in the
pre-steady-state kinetics. These results suggest that the structure of the
protein around the alkali metal ion determines the conformational distribution.
The transamination reaction with l-alanine was coupled in the pre-steady-state to
the LDH-catalyzed oxidation of NADH. This experiment yields an estimate of 68 +/-
4% for the fast form, in agreement with the hysteretic fit to the steady-state
data. The reaction of DGD with dithiobis(nitrobenzoate) was used to probe the
preexisting forms of DGD. Preincubation of DGD with ACC, like the exchange of Na+
for K+, shifts the conformational distribution, in agreement with the steady
state kinetics. These experiments clearly demonstrate that DGD is a hysteretic
enzyme whose conformational distribution is controlled by the identity of the
alkali metal ion bound near the active site, and that cooperativity does not play
a role in catalysis or regulation.
PMID- 9548964
TI - Assessment of the role of an omega loop of cholesterol oxidase: a truncated loop
mutant has altered substrate specificity.
AB - The function of an active site loop (70-90) of cholesterol oxidase has been
ascertained by deleting five contiguous residues (79-83) from the tip of the
loop. From the crystal structure of the wild-type enzyme, it appears that this
truncation will not significantly perturb the structure of the rest of the
enzyme. The UV/vis and CD spectra of the mutant confirm that the enzyme is
properly folded with FAD bound. The mutant enzyme still transfers 2H from the
4beta-carbon of the intermediate, cholest-5-en-3-one, to the 6beta-carbon of the
product, cholest-4-en-3-one, during isomerization. The kcat/Km of the mutant is
increased 6-fold with dehydroepiandrosterone as substrate. Thus, the enzyme is
still catalytically active after deletion of the five loop-tip residues. With
micellar cholesterol, the kcat/Km of the mutant is decreased 170-fold relative to
wild type. This suggests that the tip of the loop is necessary for packing with
the "tail" of cholesterol and is responsible for substrate specificity at C17.
Increased release of intermediate cholest-5-en-3-one in the mutant-catalyzed
reaction is not observed. Truncation of the loop, therefore, does not affect the
grip of the enzyme on the intermediate. With lipid vesicle substrates (egg
phosphatidylcholine/cholesterol, 1:1), the initial velocity of the mutant is
reduced 3000-fold. The binding affinity for the vesicles, however, is only
reduced 2-fold. Consequently, the loop is not the primary determinant of binding
affinity for vesicles. It is concluded that the loop is important for movement of
cholesterol from the lipid bilayer. The tip residues form a hydrophobic pathway
between lipid membrane and active site to facilitate movement of substrate and
product in to and out of the active site.
PMID- 9548965
TI - Genetics of disease.
PMID- 9548967
TI - The beautifully simple but intriguingly complex world of small genomes.
PMID- 9548968
TI - WebWise: guide to the Institute of Molecular Biology Genome Sequencing Center
Jena web site.
PMID- 9548969
TI - The context of human genetic evolution.
AB - The debate on modern human origins has often focused on the relationship between
genes and fossils. Although more and more genetic evidence has been accumulating
in favor of a recent African origin for modern humans, it has been assumed by
many that the fossil evidence remains ambiguous. On the contrary, it has been
clear for some time that the fossil evidence does not support the multiregional
model: Fossils and archeology indicate a pattern of multiple dispersals from and
beyond Africa, against which the genetic data can be compared. The continuing
value of paleobiology is in complementing genetic information by revealing the
context of human evolution: locating the dispersals and extinctions of
populations in time and space, correlating these events with the environmental
forces that shaped them, and providing an increasingly detailed understanding of
the morphology and technology of early humans.
PMID- 9548970
TI - New insulin-like proteins with atypical disulfide bond pattern characterized in
Caenorhabditis elegans by comparative sequence analysis and homology modeling.
AB - We have identified three new families of insulin homologs in Caenorhabditis
elegans. In two of these families, concerted mutations suggest that an additional
disulfide bond links B and A domains, and that the A-domain internal disulfide
bond is substituted by a hydrophobic interaction. Homology modeling remarkably
confirms these predictions and shows that despite this atypical disulfide bond
pattern and the absence of C-like peptide, all these proteins may adopt the same
fold as the insulin. Interestingly, whereas we identified 10 insulin-like
peptides, only one insulin-like-receptor (daf-2) has been found. We propose that
these insulin-related peptides may correspond to different activators or
inhibitors of the daf-2 insulin-regulating pathway.
PMID- 9548971
TI - Multiple members of a third subfamily of P-type ATPases identified by genomic
sequences and ESTs.
AB - The Saccharomyces cerevisiae genome contains five P-type ATPases divergent from
both of the well-known subfamilies of these membrane ion transporters. This newly
recognized third subfamily can be further divided into four classes of genes with
nearly equal relatedness to each other. Genes of this new subfamily are also
present and expressed in multicellular organisms such as Caenorhabditis elegans
and mammals; some, but not all, can be assigned to the classes identified in
yeast. Different classes of genes and different genes within a class are
expressed differentially in tissues of the mouse. The recently cloned gene for
the mammalian aminophospholipid translocase belongs to this new subfamily,
suggesting that other subfamily members may transport other lipids or lipid-like
molecules from one leaflet of the membrane bilayer to the other.
PMID- 9548972
TI - Analysis of EST-driven gene annotation in human genomic sequence.
AB - We have performed a systematic analysis of gene identification in genomic
sequence by similarity search against expressed sequence tags (ESTs) to assess
the suitability of this method for automated annotation of the human genome. A
BLAST-based strategy was constructed to examine the potential of this approach,
and was applied to test sets containing all human genomic sequences longer than 5
kb in public databases, plus 300 kb of exhaustively characterized benchmark
sequence. At high stringency, 70%-90% of all annotated genes are detected by near
identity to EST sequence; >95% of ESTs aligning with well-annotated sequences
overlap a gene. These ESTs provide immediate access to the corresponding cDNA
clones for follow-up laboratory verification and subsequent biologic analysis. At
lower stringency, up to 97% of annotated genes were identified by similarity to
ESTs. The apparent false-positive rate rose to 55% of ESTs among all sequences
and 20% among benchmark sequences at the lowest stringency, indicating that many
genes in public database entries are unannotated. Approximately half of the
alignments span multiple exons, and thus aid in the construction of gene
predictions and elucidation of alternative splicing. In addition, ESTs from
multiple cDNA libraries frequently cluster over genes, providing a starting point
for crude expression profiles. Clone IDs may be used to form EST pairs, and
particularly to extend models by associating alignments of lower stringency with
high-quality alignments. These results demonstrate that EST similarity search is
a practical general-purpose annotation technique that complements pattern
recognition methods as a tool for gene characterization.
PMID- 9548973
TI - Characterization and comparison of the human and mouse GLC1A glaucoma genes.
AB - The GLC1A gene (which encodes the protein myocilin) has been associated with the
development of primary open angle glaucoma. Bacterial artificial chromosomes
containing the human GLC1A gene and its mouse ortholog were subcloned and
sequenced to reveal the genomic structure of the genes. Comparison of the coding
sequences of the human and mouse GLC1A genes revealed a high degree of amino acid
homology (82%) and the presence of several conserved motifs in the predicted
GLC1A proteins. The expression of GLC1A was examined by Northern blot analysis of
RNA from adult human tissues. GLC1A expression was observed in 17 of 23 tissues
tested, suggesting a wider range of expression than was recognized previously.
The comparison of the human and mouse GLC1A genes suggests that the mouse may be
a useful model organism in studying the molecular pathophysiology of glaucoma.
PMID- 9548974
TI - Bacterial contig map of the 21q11 region associated with Alzheimer's disease and
abnormal myelopoiesis in Down syndrome.
AB - We present a high-resolution bacterial contig map of 3.4 Mb of genomic DNA in
human chromosome 21q11-q21, encompassing the region of elevated disomic
homozygosity in Down Syndrome-associated abnormal myelopoiesis and leukemia, as
well as the markers, which has shown a strong association with Alzheimer's
Disease that has never been explained. The map contains 89 overlapping PACs,
BACs, or cosmids in three contigs (850, 850, and 1500 kb) with two gaps (one of
140-210 kb and the second <5 kb). To date, eight transcribed sequences derived by
cDNA selection, exon trapping, and/or global EST sequencing have been positioned
onto the map, and the only two genes so far mapped to this cytogenetic region,
STCH and RIP140 have been precisely localized. This work converts a further 10%
of chromosome 21q into a high-resolution bacterial contig map, which will be the
physical basis for the long-range sequencing of this region. The map will also
enable positional derivation of new transcribed sequences, as well as new
polymorphic probes, that will help in elucidation of the role the genes in this
region may play in abnormal myelopoiesis and leukemia associated with trisomy 21
and Alzheimer's Disease.
PMID- 9548975
TI - Xenoduplex analysis--a method for comparative gene mapping using hybrid panels.
AB - Somatic cell hybrid (SCH) panels and radiation hybrid (RH) panels are powerful
resources for comparative gene mapping because gene assignments are made without
the detection of genetic polymorphism as needed for linkage mapping. A frequently
encountered problem, however, is that the gene specific primers may amplify
homologous PCR products of equal length from the donor and recipient species of
the panel. Here, we describe a simple solution to this problem in which we
utilize the formation of interspecies heteroduplexes that can be easily
distinguished from the corresponding homoduplexes by native polyacrylamide gel
electrophoresis. We denote these DNA-DNA interspecies hybrids, xenoduplexes (xeno
= Gr. Xenos, foreigner). A merit of the method is that the formation of
xenoduplexes strongly suggests that the PCR products from the two species
represent homologous sequences. The method is thus particularly useful for
comparative gene mapping when the PCR primers have been designed by use of
sequence information from other species. In this study we have successfully used
xenoduplex analysis and a pig-rodent SCH panel to map seven porcine genes (ACADM,
AT3, HOXD, IL8RB, LEPR, PAX8, PKLR) for which no previous sequence information
was available. The assignment of the leptin receptor gene (LEPR) to pig
chromosome 6q32-35 excluded LEPR as a candidate gene for a QTL on pig chromosome
4 with a major effect on fatness.
PMID- 9548976
TI - Modification of bacterial artificial chromosome clones using Cre recombinase:
introduction of selectable markers for expression in eukaryotic cells.
AB - Bacterial artificial chromosome clones (BACs) are widely used at present in human
genome physical mapping projects. To extend the utility of these clones for
functional genomic studies, we have devised a method to modify BACs using Cre
recombinase to introduce a gene cassette into the loxP sequence, which is present
in the vector portion of the BAC clone. Cre-mediated integration is site specific
and thus maintains the integrity of the genomic insert sequences, while
eliminating the steps that are involved in restriction digest-based DNA cloning
strategies. The success of this method depends on the use of a DNA construct,
RETRObac, which contains the reporter marker green fluorescent protein (GFP) and
the selectable marker neomycin phosphotransferase (neo), but does not contain a
bacterial origin of replication. BAC clones have been modified successfully using
this method and the genomic insert shows no signs of deletions or rearrangements.
Transfection efficiencies of the modified BACs into human or murine cell lines
ranged from 1% to 6%. After culture in media containing G418 for 3 weeks,
approximately 0. 1% of cells previously sorted for GFP expression acquired stable
antibiotic resistance. Introduction of a human BAC clone that contains genomic
p53 sequences into murine NIH3T3 cells led to expression of human p53 mRNA as
determined by RT-PCR, demonstrating that sequences contained on the BAC are
expressed. We believe that GFP-neo modified BAC clones will be a valuable
resource in efforts to study biological effects of known genes as well as in
efforts to clone and analyze new genes and regulatory regions.
PMID- 9548977
TI - Endosperm developments
PMID- 9548978
TI - Cell-to-cell and phloem-mediated transport of potato virus X. The role of virions
AB - Movement-deficient potato virus X (PVX) mutants tagged with the green fluorescent
protein were used to investigate the role of the coat protein (CP) and triple
gene block (TGB) proteins in virus movement. Mutants lacking either a functional
CP or TGB were restricted to single epidermal cells. Microinjection of dextran
probes into cells infected with the mutants showed that an increase in the
plasmodesmal size exclusion limit was dependent on one or more of the TGB
proteins and was independent of CP. Fluorescently labeled CP that was injected
into epidermal cells was confined to the injected cells, showing that the CP
lacks an intrinsic transport function. In additional experiments, transgenic
plants expressing the PVX CP were used as rootstocks and grafted with
nontransformed scions. Inoculation of the PVX CP mutants to the transgenic
rootstocks resulted in cell-to-cell and systemic movement within the transgenic
tissue. Translocation of the CP mutants into sink leaves of the nontransgenic
scions was also observed, but infection was restricted to cells close to major
veins. These results indicate that the PVX CP is transported through the phloem,
unloads into the vascular tissue, and subsequently is transported between cells
during the course of infection. Evidence is presented that PVX uses a novel
strategy for cell-to-cell movement involving the transport of filamentous virions
through plasmodesmata.
PMID- 9548979
TI - Endosperm development after fusion of isolated, single maize sperm and central
cells in vitro
AB - We demonstrate here the possibility of endosperm development in vitro after the
fusion of pairs of an isolated sperm and an isolated central cell of maize. The
occurrence of karyogamy and the time course of the fusion of sperm and central
cell nuclei are presented. The fusion of the sperm nucleus occurred either with
one of the two polar nuclei or with the secondary nucleus and was completed
within 2 hr after in vitro cell fusion. The in vitro study of early events after
cell and nuclear fusion indicates that the resulting primary endosperm cell
develops into a characteristic tissue capable of self-organization apart from the
mother tissue. The technology presented here opens the way for new cellular and
molecular studies, especially of early events after sperm and central cell
fusion. These studies should lead to a better understanding of the processes of
double fertilization and endosperm development.
PMID- 9548980
TI - The movement protein of cucumber mosaic virus traffics into sieve elements in
minor veins of nicotiana clevelandii
AB - The location of the 3a movement protein (MP) of cucumber mosaic virus (CMV) was
studied by quantitative immunogold labeling of the wild-type 3a MP in leaves of
Nicotiana clevelandii infected by CMV as well as by using a 3a-green fluorescent
protein (GFP) fusion expressed from a potato virus X (PVX) vector. Whether
expressed from CMV or PVX, the 3a MP targeted plasmodesmata and accumulated in
the central cavity of the pore. Within minor veins, the most extensively labeled
plasmodesmata were those connecting sieve elements and companion cells. In
addition to targeting plasmodesmata, the 3a MP accumulated in the parietal layer
of mature sieve elements. Confocal imaging of cells expressing the 3a-GFP fusion
protein showed that the 3a MP assembled into elaborate fibrillar formations in
the sieve element parietal layer. The ability of 3a-GFP, expressed from PVX
rather than CMV, to enter sieve elements demonstrates that neither the CMV RNA
nor the CMV coat protein is required for trafficking of the 3a MP into sieve
elements. CMV virions were not detected in plasmodesmata from CMV-infected
tissue, although large CMV aggregates were often found in the parietal layer of
sieve elements and were usually surrounded by 3a MP. These data suggest that CMV
traffics into minor vein sieve elements as a ribonucleoprotein complex that
contains the viral RNA, coat protein, and 3a MP, with subsequent viral assembly
occurring in the sieve element parietal layer.
PMID- 9548981
TI - The organization and evolution of the spinach stress 70 molecular chaperone gene
family.
AB - The stress 70 molecular chaperones of plants are localized and function in all of
the major subcellular compartments of the cell. Collectively, all of the various
forms are encoded by a multigene family in the nucleus. At least 12 members of
this family have been found, and sequence and DNA blot analyses provide an
emerging description of the diversity of gene structure organization for this
family of evolutionarily conserved proteins in spinach. They exhibit not only
structural diversity in the organization of coding and noncoding regions but also
distinct expression patterns for different tissues and abiotic conditions. The
results of phylogenetic analyses are concordant with at least four major
evolutionary events that gave rise to stress 70 molecular chaperones in each of
four major subcellular compartments of plant cells: the plastid, mitochondrion,
cytoplasm, and endoplasmic reticulum. The varied expression patterns also
illustrate the complexity of effectively interpreting the role of any one of
these stress-related proteins in response to abiotic stress in the absence of
context to the other members of the family.
PMID- 9548983
TI - Induction of kranz anatomy and C4-like biochemical characteristics in a submerged
amphibious plant by abscisic acid
AB - The amphibious leafless sedge Eleocharis vivipara develops C4-like traits as well
as Kranz anatomy under terrestrial conditions, but it develops C3-like traits
without Kranz anatomy under submerged conditions. When submerged plants are
exposed to aerial conditions, they rapidly produce new photosynthetic tissues
with C4-like traits. In this study, experiments were performed to determine
whether abscisic acid (ABA), a plant stress hormone, could induce the formation
of photosynthetic tissues with Kranz anatomy and C4-like biochemical traits under
water in the submerged form. When the submerged plants were grown in water
containing 5 &mgr;M ABA, they developed new photosynthetic tissues with Kranz
anatomy, forming well-developed Kranz (bundle sheath) cells that contained many
organelles. The ABA-induced tissues accumulated large amounts of
phosphoenolpyruvate carboxylase, pyruvate orthophosphate dikinase, and NAD-malic
enzyme at the appropriate cellular sites. The tissues had 3.4 to 3.8 times more
C4 enzyme activity than did tissues of the untreated submerged plants. Carbon-14
pulse and carbon-12 chase experiments revealed that the ABA-induced tissues fixed
higher amounts of carbon-14 into C4 compounds and lower amounts of carbon-14 into
C3 compounds as initial products than did the submerged plants and that they
exhibited a C4-like pattern of carbon fixation under aqueous conditions of low
carbon, indicating enhanced C4 capacity in the tissues. This report provides an
example of the hormonal control of the differentiation of the structural and
functional traits required for the C4 pathway.
PMID- 9548982
TI - Uncoupling PR gene expression from NPR1 and bacterial resistance:
characterization of the dominant Arabidopsis cpr6-1 mutant.
AB - In Arabidopsis, NPR1 mediates the salicylic acid (SA)-induced expression of
pathogenesis-related (PR) genes and systemic acquired resistance (SAR). Here, we
report the identification of another component, CPR 6, that may function with
NPR1 in regulating PR gene expression. The dominant CPR 6-1 mutant expresses the
SA/NPR1-regulated PR genes (PR-1, BGL 2, and PR-5) and displays enhanced
resistance to Pseudomonas syringae pv maculicola ES4326 and Peronospora
parasitica Noco2 in the absence of SAR induction. cpr 6-1-induced PR gene
expression is not suppressed in the cpr 6-1 npr1-1 double mutant but is
suppressed when SA is removed by salicylate hydroxylase. Thus, constitutive PR
gene expression in cpr 6-1 requires SA but not NPR1. In addition, resistance to
P. s. maculicola ES4326 is suppressed in the cpr 6-1 npr1-1 double mutant,
despite expression of PR-1, BGL 2, and PR-5. Resistance to P. s. maculicola
ES4326 must therefore be accomplished through unidentified antibacterial gene
products that are regulated through NPR1. These results show that CPR 6 is an
important regulator of multiple signal transduction pathways involved in plant
defense.
PMID- 9548984
TI - Role of calcium in signal transduction during the hypersensitive response caused
by basidiospore-derived infection of the cowpea rust fungus
AB - The hypersensitive response (HR) of disease-resistant plant cells to fungal
invasion is a rapid cell death that has some features in common with programmed
cell death (apoptosis) in animals. We investigated the role of cytosolic free
calcium ([Ca2+]i) in the HR of cowpea to the cowpea rust fungus. By using
confocal laser scanning microscopy in conjunction with a calcium reporter dye, we
found a slow, prolonged elevation of [Ca2+]i in epidermal cells of resistant but
not susceptible plants as the fungus grew through the cell wall. [Ca2+]i levels
declined to normal levels as the fungus entered and grew within the cell lumen.
This elevation was related to the stage of fungal growth and not to the speed of
initiation of subsequent cell death. Elevated [Ca2+]i levels also represent the
first sign of the HR detectable in this cowpea-cowpea rust fungus system. The
increase in [Ca2+]i was prevented by calcium channnel inhibitors. This effect was
consistent with pharmacological tests in which these inhibitors delayed the HR.
The data suggest that elevation of [Ca2+]i is involved in signal transduction
leading to the HR during rust fungal infection.
PMID- 9548985
TI - A glycoprotein modified with terminal N-acetylglucosamine and localized at the
nuclear rim shows sequence similarity to aldose-1-epimerases.
AB - Several glycoproteins that are present at the nuclear rim and at the nuclear pore
complex of tobacco suspension-cultured cells are modified by O-linked
oligosaccharides with terminal N-acetylglucosamine (GlcNAc). Here, we report on
the purification of several of these glycoproteins, which are referred to as
terminal GlcNAc (tGlcNAc) proteins. In vitro galactosylation of the tGlcNAc
proteins generated glycoproteins with terminal galactosyl-beta-1, 4-GlcNAc and
thus permitted their isolation by Erythrina crystagalli agglutinin affinity
chromatography. Peptide sequence information derived from one tGlcNAc protein
with an apparent molecular mass of 40 to 43 kD, designated gp40, made it possible
to clone its gene. Interestingly, gp40 has 28 to 34% amino acid identity to
aldose-1-epimerases from bacteria, and no gene encoding an aldose-1-epimerase has
been isolated previously from higher organisms. Polyclonal antibodies were
generated against recombinant gp40. Consistent with its purification as a
putative nuclear pore complex protein, gp40 was localized to the nuclear rim, as
shown by biochemical fractionation and immunofluorescence microscopy.
PMID- 9548986
TI - Expression of lauroyl-acyl carrier protein thioesterase in brassica napus seeds
induces pathways for both fatty acid oxidation and biosynthesis and implies a set
point for triacylglycerol accumulation
AB - Expression of a California bay lauroyl-acyl carrier protein thioesterase (MCTE)
in developing seeds of transgenic oilseed rape alters the fatty acid composition
of the mature seed, resulting in up to 60 mol% of laurate in triacylglycerols. In
this study, we examined the metabolism of lauric acid and 14C-acetate in
developing seeds of oilseed rape that express high levels of MCTE. Lauroyl-CoA
oxidase activity but not palmitoyl-CoA oxidase activity was increased several
fold in developing seeds expressing MCTE. In addition, isocitrate lyase and
malate synthase activities were six- and 30-fold higher, respectively, in high
laurate developing seeds. Control seeds incorporated 14C-acetate almost entirely
into fatty acids, whereas in seeds expressing MCTE, only 50% of the label was
recovered in lipids and the remainder was in a range of water-soluble components,
including sucrose and malate. Together, these results indicate that the pathways
for beta-oxidation and the glyoxylate cycle have been induced in seeds expressing
high levels of MCTE. Although a substantial portion of the fatty acid produced in
these seeds is recycled to acetyl-CoA and sucrose through the beta-oxidation and
glyoxylate cycle pathways, total seed oil is not reduced. How is oil content
maintained if lauric acid is inefficiently converted to triacylglycerol? The
levels of acyl carrier protein and several enzymes of fatty acid synthesis were
increased two- to threefold at midstage development in high-laurate seeds. These
results indicate that a coordinate induction of the fatty acid synthesis pathway
occurs, presumably to compensate for the lauric acid lost through beta-oxidation
or for a shortage of long-chain fatty acids.
PMID- 9548987
TI - Accumulation of an acidic dehydrin in the vicinity of the plasma membrane during
cold acclimation of wheat
AB - Expression of the acidic dehydrin gene wcor410 was found to be associated with
the development of freezing tolerance in several Gramineae species. This gene is
part of a family of three homologous members, wcor410, wcor410b, and wcor410c,
that have been mapped to the long arms of the homologous group 6 chromosomes of
hexaploid wheat. To gain insight into the function of this gene family,
antibodies were raised against the WCOR410 protein and affinity purified to
eliminate cross-reactivity with the WCS120 dehydrin-like protein of wheat.
Protein gel blot analyses showed that the accumulation of WCOR410 proteins
correlates well with the capacity of each cultivar to cold acclimate and develop
freezing tolerance. Immunoelectron microscope analyses revealed that these
proteins accumulate in the vicinity of the plasma membrane of cells in the
sensitive vascular transition area where freeze-induced dehydration is likely to
be more severe. Biochemical fractionation experiments indicated that WCOR410 is a
peripheral protein and not an integral membrane protein. These results provide
direct evidence that a subtype of the dehydrin family accumulates near the plasma
membrane. The properties, abundance, and localization of these proteins suggest
that they are involved in the cryoprotection of the plasma membrane against
freezing or dehydration stress. We propose that WCOR410 plays a role in
preventing the destabilization of the plasma membrane that occurs during
dehydrative conditions.
PMID- 9548988
TI - Estimating the time between drinking and death from tissue distribution patterns
of ethanol.
AB - To establish a method for estimating the time between the last consumption of
alcohol and death, we examined the ethanol levels in body fluids and tissues of
rats that had been orally administered 1 g/kg ethanol. We observed the following
relationships between ethanol levels in the cardiac blood (blood in the heart
itself), vitreous humor, and urine: cardiac blood > vitreous humor > urine at 10
min (early absorption stage); vitreous humor > cardiac blood > urine from 20 to
50 min (late absorption stage); vitreous humor > urine > cardiac blood from 60 to
120 min (distribution stage); and urine > vitreous humor > cardiac blood at 180
min (excretion stage). It was also observed that, in cases of death immediately
following drinking, ethanol levels in the stomach contents are very high, and the
following ratios of ethanol levels were observed: skeletal muscle to cardiac
blood--less than 1; liver to cardiac blood--around 1. buccal mucosa to cardiac
blood-greater than 1. These ratios at equilibrium after drinking were around 1,
lower than 1 and around 1, respectively. We also measured alcohol levels in the
cardiac blood, urine, vitreous humor and stomach contents of nine cadavers who
had consumed alcohol prior to death. The relationships between the time since
last consumption of alcohol and relative ethanol levels in these specimens were
in good accordance with the results of the animal experiments.
PMID- 9548989
TI - Effects of antineoplastics, antibiotics and antidiabetics on acetaldehyde
metabolism after alcohol ingestion.
AB - The main purpose of this study was to evaluate the inhibitory effects of 5
fluorouracil antineoplastics, cephem antibiotics containing the
methyltetrazolylthiol (MTT) group and antidiabetics on aldehyde dehydrogenase
(ALDH) activity in vivo and in vitro. In in vivo experiments, rats were given a
100 mg/kg dose of drugs (10 mg/kg for glibenclamide) orally or intraperitoneally.
When each drug was administered singly immediately after an oral administration
of 1.5 g/kg ethanol, only carmofur, an antineoplastic, produced marked increases
in blood acetaldehyde concentrations. This action was also noted when ethanol was
ingested 15 h after administration. The remaining drugs did not increase blood
acetaldehyde concentrations. When rats were treated with carmofur at 12 h
intervals for 3 consecutive days and were given 1.5 g/kg ethanol after the final
treatment, blood acetaldehyde concentrations were elevated more significantly
than with a single administration of carmofur. Furthermore, daily administration
of cephem antibiotics containing the MTT group, latamoxef, cefamandole,
cefoperazone and cefbuperazone, significantly increased blood acetaldehyde
concentrations. Daily administration of sulfonylurea antidiabetics,
chlorpropamide and acetohexamide, slightly increased blood acetaldehyde
concentrations. Drugs causing increases in blood acetaldehyde concentrations when
administration was combined with ethanol ingestion also inhibited ALDH activity
in vitro. The results of the in vitro experiments roughly correlated with those
of the in vivo experiments. The inhibitory effects of drugs on ALDH activity were
in the following order: carmofur >> cephem antibiotics containing the MTT group >
sulfonylurea antidiabetics.
PMID- 9548990
TI - Fibrous structure and connection surrounding the metacarpophalangeal joint.
AB - The fibrous components of the metacarpophalangeal (MP) joint including the palmar
plate, the collateral ligament and the dorsal plate were studied with particular
attention paid to the fibrous structure of the fibrous tendon sheath and the deep
transverse metacarpal ligament. The tough fibrillar structure around the MP
joint, especially the force nucleus, consisted of three types of mixed fibers:
the fibrous tendon sheath of the A1 pulley, the deep transverse metacarpal
ligament, and the palmar plate. The tendon sheath was located on the ulnar side
in the index and middle fingers, on the central position in the ring finger, and
on the radial side in the little finger. These fibrous connections among the
fingers formed a transverse arch in the hand. The palmar plate of the MP joint
was relatively rigid and appears to function as a cushion when flexed. A fold
like protrusion of the synovial layer of the palmar plate of the MP joint had a
meniscoid function, which was larger than that of the proximal interphalangeal
joint. The capsule of the MP joint was thicker at the dorsal area, forming a
dorsal plate, which is a sliding floor of the extensor mechanism and has a
meniscoid function for joint congruity. The main lateral stabilizer consisted of
collateral ligaments and accessory collateral ligaments anchored to the palmar
plate. These structures act together as a "phalangeal cuff", connecting the
proximal phalanx to the metacarpal head and stabilizing the MP joint.
PMID- 9548991
TI - Developmental alterations of alpha-fetoprotein sugar chain in amniotic fluids
analyzed by lectin affinity electrophoresis.
AB - Affinity electrophoresis of human alpha-fetoprotein (AFP) in amniotic fluid from
pregnant women between 6 to 42 weeks of gestation and in the serum of a yolk sac
tumor was performed with concanavalin A (Con A), lentil lectin (LCA),
erythroagglutinating phytohemagglutinin (E-PHA) and Allomyrina dichotoma lectin
(allo A). Separated AFP bands were detected by sensitive antibody-affinity
blotting. In the first trimester, amniotic fluid AFP showed elevated percentages
of Con A-nonreacting AFP (AFP-C1) and LCA weakly-reacting AFP (AFP-L2) as
previously reported. Additionally, high percentages of E-PHA strongly-reacting
AFP (AFP-P5) and E-PHA-reacting AFP (AFP-P4) were observed. E-PHA-nonreacting AFP
(AFP-P1), E-PHA weakly-reacting AFP (AFP-P3f), allo A-nonreacting AFP (AFP-A1)
and asialo-AFP, AFP-A1 s, were present only in amniotic fluids from 6 to 17 weeks
of gestation. With advancing gestation, percentages of AFP-C1, AFP-P4 and AFP-P5
decreased and AFP-L2, AFP-P3f, AFP-A1, and AFP-A1 s disappeared by the end of 18
weeks. The glycoforms of serum AFP of the yolk sac tumor resembled those of
amniotic fluid AFP in the early gestational stages.
PMID- 9548992
TI - Mast cells in osteoarthritic and rheumatoid arthritic synovial tissues of the
human knee.
AB - The distribution and density of mast cells in the normal and diseased synovial
membranes were investigated. The mast cell count (MCC) in the osteoarthritic (OA)
synovium (36.9 +/- 26.9 cells/mm2) was significantly higher than that in the
rheumatoid arthritic (RA) synovium (18 +/- 12.3 cells/mm2). There was a marked
positive correlation between the MCC and the volume of joint fluid in OA (r =
0.544). There was a marked negative correlation between the MCC and the volume of
joint fluid in RA (r = -0.478). The synovial inflammatory score had a poor
correlation with the MCC in OA (r = 0.377) and RA (r = 0.305). No correlation was
noted between MCC and age, sex, roentgenographic grades, disease duration, C
reactive protein or leucocyte number in synovial fluid. Our data suggests, thus,
that mast cells could be involved in the pathogenesis of inflammatory diseases of
the synovium, especially in the mechanism of hydroarthrosis.
PMID- 9548993
TI - Antibody and cytokine responses in Helicobacter pylori-infected various mouse
strains.
AB - Helicobacter pylori (H. pylori) infection in the stomach is etiologically closely
associated with chronic active gastritis, peptic ulcer, gastric cancer and
gastric mucosa-associated lymphoid tissue lymphoma. In this study, we examined
the antibody responses and cytokine profiles of three strains of mice (BALB/c,
C3H/He, and C57BL/6) infected with H. pylori. Following this, correlations
between host-immune reactions and intensity of inflammation were analyzed. H.
pylori (ATCC43504) was intragastrically administered once a week to the mice from
4 weeks of age, and they were sacrificed at the ages of 4 and 7 months. In these
mice, we examined the histology of the stomach, antibody titers against H.
pylori, and serum levels of cytokines (IL-4, IL-10, TNF-alpha, IL-2 and
Interferon-gamma). In BALB/c mice, inflammation of the stomach was minimal.
Inflammation was observed in 63.6% of C57BL/6 mice and 33.3% of C3h/He mice. In
C57BL/6 and C3H/He mice, all the cytokines tended to increase. In contrast,
BALB/c mice were inactive in cytokine production except for IL-2. Two C3H/He mice
developed severe inflammation with lymph follicles; one showed a response largely
typical of Th-1, and the other showed a response largely typical of Th-2.
Although a definite correlation was not shown between Th-1/Th-2 response
evaluated by cytokine production and intensity of inflammation, it appears that
in H. pylori-induced inflammation both cell-mediated (Th-1) and humoral (Th-2)
immunity play a role in pathogenesis.
PMID- 9548994
TI - Involvement of the central catecholaminergic system in nicotine-induced tail
tremor in rats.
AB - The effect of 6-hydroxydopamine on repeated nicotine-induced tail-tremor was
investigated in rats. Tail-tremor induced by nicotine (0.5 mg/kg/day,
subcutaneously) became more pronounced in intensity with daily administration for
9 days. Rats pretreated with 6-hydroxydopamine (250 micrograms,
intracerebroventricularly) showed almost the maximum degree of tail-tremor during
the whole experimental period. However, in rats pretreated with 6-hydroxydopamine
plus desipramine, enhancement of tail-tremor was slight in the beginning but
increased with the daily nicotine administration. Fourteen-day administration of
nicotine did not result in significant changes in noradrenaline and dopamine
levels in the cortex, hypothalamus, striatum and nucleus accumbens. These results
suggest that nicotine-induced tail-tremor is associated with the supersensitivity
of postsynaptic catecholaminergic receptors in the central nervous system, and
that the noradrenergic system may be more important than the dopaminergic system
in this phenomenon.
PMID- 9548995
TI - Gastrobiliary dysmotility in patients with chronic pancreatitis as assessed by a
single noninvasive test.
AB - We simultaneously assessed gastric emptying and gallbladder contraction after
oral administration of a liquid meal by noninvasive ultrasonography in 17
patients with chronic pancreatitis (CP) and in 17 healthy controls.
Gastrointestinal (GI) transit was also assessed by a noninvasive radioopaque
marker method. Exocrine pancreatic function was evaluated by analyzing pure
pancreatic juice and by analyzing the autonomic nervous system by cardiovascular
reflex tests. Patients with CP showed impaired gallbladder contraction at 15 min
and hastened gastric emptying. The cause of the former is unclear, whereas the
latter was closely related with decreased pancreatic lipase output, but not with
autonomic dysfunction. GI transit time did not differ between controls and
patients with CP. In conclusion, we succeeded in clearly demonstrating impaired
gallbladder contraction and hastened gastric emptying in patients with CP by a
single noninvasive test, ultrasonography. We also revealed for the first time
that hastened gastric emptying is associated with insufficient pancreatic lipase
output.
PMID- 9548996
TI - Hematological manifestations in brucellosis cases in Turkey.
AB - The hematological findings of 233 patients with brucellosis are presented and the
possible pathologies discussed. Anemia was present in 128 patients (55%),
leukopenia in 49 (21%) and thrombocytopenia in 59 (26%). Bone marrow aspirates of
18 patients (8%) with pancytopenia were examined. The bone marrow was
hypercellular in 15 and normocellular in 3 patients. Granulomatous lesions were
detected in 12 cases (67%), and slight to moderate cytophagocytosis of
erythrocytes, granulocytes and platelets existed in all patients. Blood cell
counts reverted to normal within 2-3 weeks of initiating chemotherapy with
recovery from the disease.
PMID- 9548997
TI - Reconstruction of bone defect using the bone transport technique for a case of
osteosarcoma of the femur.
AB - There are few reports on skeletal reconstruction using the bone transport
technique to repair bone defects caused by resections of tumors associated with
osteosarcoma. We attempted to reconstruct a 23 cm bone defect after resection of
an osteosarcoma of the left femur, and succeeded in gaining 17 cm by bone
transport. Five years after surgery, this patient remains alive without
metastasis or local recurrence.
PMID- 9548998
TI - Alcohol and morality: does it matter where you live?
PMID- 9548999
TI - Association of alcohol consumption to morality in middle-aged U.S. and Russian
men and women.
AB - PURPOSE: The purpose of this paper is to assess the relationships of alcohol
consumption to total and cardiovascular disease mortality in U.S. and Russian men
and women after adjustment for several covariates. A secondary objective is to
determine how this relationship varies by country and gender. METHODS: Men aged
40-59 and women aged 40-69 screened in Russia and the U.S. between 1972 and 1982
were followed for mortality for 13 years as part of the Lipid Research Clinics
Prevalence and Follow-up Studies. Alcohol consumption was based on a 7-day recall
of drinks of beer, wine, mixed drinks, and liquors. Drinkers of alcohol were
classified into four levels based on amount consumed during the recall period.
RESULTS: Age-adjusted mortality rates were higher for non-drinkers than lower
level drinkers in both genders and countries, and there was an indication that
mortality rates for high level drinkers, especially in men, approached those of
non-drinkers. When mortality rates were adjusted for other risk factors they
remained higher for non-drinkers in U.S. men and women, but in Russia, with one
exception, there was no difference in mortality rates between drinkers and non
drinkers. Relative risks for cardiovascular disease mortality rates were similar
to those of total mortality. CONCLUSIONS: Beneficial association of alcohol
consumption and mortality may be limited depending upon the prevalence of other
risk factors in the studied population.
PMID- 9549000
TI - Alcohol consumption and micronutrient intake as risk factors for liver cirrhosis:
a case-control study. The Provincial Group for the study of Chronic Liver
Disease.
AB - PURPOSE: The purpose of this study was to assess the relationship of alcohol
consumption and intake of 15 selected micronutrients with risk of liver
cirrhosis. METHODS: Data from a case-control study performed in 1989-1990 in
central Italy involving 115 incident cases and 167 hospital controls were used.
RESULTS: Cases and controls did not differ for mean daily intake of calories,
carbohydrates, lipids, and proteins. Significant direct dose-response
relationships between the intakes of vitamin A and iron and the risk cirrhosis
were observed, while significant protective effects were obtained for the intakes
of vitamins B2 (riboflavin) and B12. Different patterns of the joint effect of
nutrients and alcohol were also observed. The intakes of vitamin A and iron were
significantly associated with the risk of cirrhosis in lifetime teetotalers (odds
ratios (OR) and 95% coincidence intervals (CI) of 33.6 (1.2-979.9) and 37.9 (1.8
819.4) for higher intake of vitamin A and iron, respectively) and in consumers of
< 50 g/day of alcohol (vitamin A: OR 45.0; 95% CI, (2.6-774.6); iron: OR, 73.6;
95% CI, 4.3-999). The OR associated with intakes of vitamins B2 (riboflavin) and
B12 were not significant for the first two categories of alcohol use, while a
higher intake of these two vitamins reduced the risk of cirrhosis associated with
alcohol consumption above 50 g/day; the ORs (95% CI) were 23.0 (2.7-198.9) and
104.4 (7.2-999), respectively, for higher and lower intakes of riboflavin and
12.8 (1.8-88.1) and 138.4 (14.0-999), respectively, for higher and lower intake
of vitamin B12. CONCLUSION: These findings might explain at least a portion of
the individual susceptibility to alcohol-induced liver damage.
PMID- 9549002
TI - HIV prevalence and risk behaviors among patients attending Los Angeles County
Tuberculosis Clinics: 1993-1996.
AB - PURPOSE: This study aimed to describe prevalence of and risk factors for HIV
among persons with newly diagnosed class III (confirmed) and class V (suspected)
cases of tuberculosis (TB) patients in Los Angeles County. METHODS: HIV testing
was performed on 1307 blood specimens after routine tests were completed at six
TB clinics in Los Angeles County. HIV test results were matched to demographic
and risk behavior information by use of an unlinked study methodology. RESULTS:
The overall HIV prevalence rate was 10.8%. By demographic characteristics, the
highest prevalence rates were observed among persons born in the United States
(15.7%), males (14.1%), blacks (14.3%), and those aged 30-44 years (14.4%).
Confirmed TB cases (14%) were more likely to be HIV-infected than were suspect
cases (9.6%). Risk behaviors associated with positive HIV serostatus included the
injection of nonprescription drugs, having sex with an injection drug user, and
use of noninjection forms of heroin, cocaine, and tranquilizers. Men who have sex
with men were more likely to be HIV-infected than were heterosexual males.
CONCLUSIONS: HIV testing and counseling should be a standard of care in TB
clinics. The observed high HIV prevalence rate reinforces the importance of
designing prevention strategies that specifically target patients with TB.
PMID- 9549001
TI - Prevalence of chronic disease risk and protective behaviors among American Indian
women living on the Hopi reservation.
AB - PURPOSE: There is a growing need for disease risk factor data for various chronic
diseases among American Indian (AI) populations. The purpose of this study was to
determine the prevalence of disease risk and protective behavior among AI women
living on the Hopi reservation. METHODS: 559 randomly selected AI women 18-89
years of age completed an interviewer-administered questionnaire which included
questions on smoking, alcohol consumption, weight, height, and self-identified
practices to keep healthy. RESULTS: The proportions of smoking and alcohol
consumption were low with only 5.4% women reported currently smoking and 23.1%
reported consuming any alcohol. Both these risk factors significantly decreased
with age and significantly increased with higher education. The proportions who
were overweight (body mass index (BMI) 27.3-32.2) and obese (BMI > or = 32.3)
were 36.2% and 27.0%, respectively, and were highest in the ages 25-64 years.
Over 80% of women reported practicing behaviors to keep healthy. Significantly
higher proportions of older women reported practicing behaviors to keep healthy
compared with younger women. CONCLUSIONS: To develop and evaluate programs aimed
at decreasing rates of chronic diseases among AI populations a disease risk
factor needs to be implemented by region and tribe.
PMID- 9549003
TI - Can regular multivitamin/mineral supplementation modify the relation between
maternal smoking and select adverse birth outcomes?
AB - PURPOSE: The purpose of this study was to examine whether or not regular
multivitamin/mineral supplementation can modify the relation between maternal
smoking and preterm birth (gestational age < 37 weeks), very-low-birthweight
(VLBW) (< 1500 g), moderately-low-birthweight (MLBW) (< 2499 g), or small-for
gestational-age (SGA) (< 10th percentile of birth weight for gestational age).
METHODS: Live birth data from the 1988 National Maternal and Infant Health Survey
(NMIHS) were used for the analysis. Maternal smoking referred to self-reported
average number of cigarettes smoked after recognition of pregnancy, while regular
multivitamin/mineral supplementation referred to use of multivitamin/mineral
supplements for at least three days per week during the three months before
and/or after recognition of pregnancy. Sample sizes included 9402 singleton
infants for the analysis of preterm birth, 9395 for very or moderately low
birthweight, and 9363 for small-for-gestational-age. Odds ratios were derived
from logistic regression analyses after adjusting for a number of demographic and
reproductive variables. RESULTS: Major results include: 1) increased risks for
the adverse outcomes studied were observed among smoking women; 2) no effect of
regular multivitamin/mineral supplementation in the absence of maternal smoking
was revealed; and 3) relative excess risks due to interaction at different
smoking levels and overall interactions between smoking and supplementation were
not observed. CONCLUSIONS: These results suggest that regular
multivitamin/mineral supplementation does not minimize the adverse effects
associated with maternal smoking.
PMID- 9549004
TI - Community occupational structure, medical and economic resources, and coronary
mortality among U.S. blacks and whites, 1980-1988.
AB - PURPOSE: To examine the association between coronary heart disease (CHD)
mortality, economic and medical resources, and county occupational structure.
METHODS: U.S. counties were classified into five occupational structure
categories based on the percentage of workers in white-collar occupations.
Directly age-adjusted CHD mortality rates (from vital statistics and Census data)
and economic and medical care data (from Census and Area Resource File data) were
calculated for each occupational structure category. Participants were black and
white, men and women, aged 35-64 years, in the U.S. during 1980-88. CHD mortality
rates and economic and medical care data were compared across occupational
structure categories. RESULTS: Among blacks, CDH rates were highest in counties
with intermediate levels of occupational structure; rates among whites were
inversely associated with occupational structure. Per capita levels of income and
numbers of medical-care providers were positively associated with occupational
structure. CONCLUSION: Strategies to improve the resources of disadvantaged
communities and the access of black workers to local occupational opportunities
may be important for CHD prevention in high risk populations.
PMID- 9549005
TI - The Kidney Outcomes Prediction and Evaluation (KOPE) study: a prospective cohort
investigation of patients undergoing hemodialysis. Study design and baseline
characteristics.
AB - PURPOSE: The purpose of the Kidney Outcomes Prediction and Evaluation (KOPE)
study, was to more fully characterize the end-stage renal disease (ESRD)
population with respect to social, psychological, and clinical characteristics,
and to prospectively study the biomedical, social, and psychological factors that
influence a range of ESRD outcomes in a large observational study of black and
white patients on hemodialysis. This paper focuses on the KOPE study design as
well as characteristics of patients at baseline. METHODS: KOPE was a prospective
cohort investigation of patients treated at four dialysis centers in Forsyth
County, North Carolina. Participants were interviewed at the dialysis centers,
semi-annually over a 3 1/2 year period. Prevalent cases who were being treated
with hemodialysis at the initiation of the study were enrolled into KOPE.
Incident cases were subsequently enrolled as they presented to the participating
units for hemodialysis. A total of 304 prevalent and 162 incident cases were
enrolled into the study. The baseline health and sociodemographic characteristics
of KOPE participants reported in this paper were obtained from medical records
and Southeast Kidney Council data. Laboratory values taken within a 30-day
interval around the baseline interview are also reported. RESULTS: KOPE
participants differ from national statistics on race, age, and gender.
Differences between KOPE participants and patients living in the region, but who
did not participate in the study, can be explained by our recruitment criteria.
CONCLUSIONS: KOPE will enable the characterization of the ESRD population,
identification of factors related to poor outcomes, and identification of
opportunities for interventions to prevent death and morbidity.
PMID- 9549006
TI - Bayesian estimation of asthma prevalence, and comparison of exercise and
questionnaire diagnostics in the absence of a gold standard.
AB - PURPOSE: To estimate the sensitivities, specificities, and predictive values of
exercise challenge and questionnaire, when these tests are used to diagnose
asthma in children. METHODS: Participants were children, predominantly aged 6 to
12 years, selected from three primary school grades among 18 different schools in
Montreal. Of 1111 participants, 989 successfully completed a six-minute free
running test at school and returned a respiratory questionnaire. A total of 952
children had complete information that could be used for analysis. A history of
wheezing in the past year in conjunction with a past diagnosis of asthma defined
current asthma by questionnaire. Exercise responsiveness was defined as a > or =
10% fall in FEV1 after a six-minute free run. As there is no perfectly accurate
diagnostic test for asthma, we analyzed the data using a previously published
Bayesian method that allows for the estimation of test properties when no gold
standard test is available. RESULTS: Current asthma by questionnaire was found to
have significantly higher specificity (94.9%, 95% credible interval (CI): 93.2
96.5 versus 82.6%, 95% CI: 79.9-85.1) and positive predictive value (53.8%, 95%
CI: 41.0-66.7 versus 19.2%, 95% CI: 12.3-27.8) in comparison to exercise
challenge. While there was no statistically significant difference between the
two tests with respect to sensitivity and negative predictive values, the
estimates were higher for current asthma (64.4%, 95% CI: 50.9-76.6 and 96.7%, 95%
CI: 94.6-98.1, respectively) in comparison to exercise challenge (51.3%, 95% CI:
37.8-64.5 and 95.4%, 95% CI: 93.2-97.1, respectively). Agreement between the two
diagnostic methods was poor and the combined use of the two tests did not
significantly improve the likelihood of correctly identifying children with
asthma. CONCLUSIONS: Our findings support the view that exercise testing adds
little to a well designed questionnaire in identifying subjects with asthma in
community based studies.
PMID- 9549007
TI - Tools for improvement: a systematic analysis and guide to accreditation by the
JCAHO.
AB - By viewing the Joint Commission on Accreditation of Healthcare Organizations'
(JCAHO) standards in the context of current accreditation practice, hospital
librarians can understand and clarify their role in realizing their
organization's mission, goals, and objectives. By broadening their view of the
information function as described in the accreditation standards, health sciences
librarians can enhance their position in the hospital's management team, improve
health information practice, and contribute to the overall performance of the
health care organization. The role of the librarian and the library throughout
the entire set of standards and interrelationships with other professionals and
units are described. Examples of ways to demonstrate conformity to the standards
are provide. Special emphasis is placed on Standard 9, Management of Information,
to provide guidance to the librarian undergoing JCAHO accreditation.
PMID- 9549008
TI - Electronic reserves: the changing landscape of instructional support.
AB - During the spring 1996 academic semester, the University of Maryland Health
Sciences Library implemented an electronic course-reserve system as a pilot
project with the university's School of Nursing. The pilot project has been very
successful because of thorough planning and the effectiveness of the system,
which enables library users to retrieve assigned readings easily. This success
inspired the staff to begin expanding the scope of the pilot project to include
other schools and limited remote access. This paper describes the planning and
implementation process, the issues that needed to be resolved, the response to
the project, and future plans. Particular attention is paid to issues of
copyright and cost recovery.
PMID- 9549009
TI - Positioning the library at the epicenter of the networked biomedical enterprise.
AB - The changing economic environment in which our biomedical enterprises operate
presents unparalleled opportunities to the profession of medical librarianship.
Evidence-based medicine, patient empowerment, asynchronous learning networks, and
research colaboratories each involve a new type of shared information, or access
to information in new ways or by different people. These tasks are ones with
which librarianship is directly involved. Librarians are therefore placed
perfectly to provide new products and services. To position the library at the
epicenter of the networked biomedical enterprise we must meet three challenges:
We must align the library's business strategy with that of the larger enterprise.
We must provide services in ways that will scale-up to enable new business
strategies. We must measure the effectiveness of services in ways that document
their role in supporting the enterprise.
PMID- 9549010
TI - The relationship between journal use in a medical library and citation use.
AB - The purpose of the study was to investigate the relationship between library
journal use and journal citation use in the medical sciences. The six-month
journal use study was conducted in the Library of the Veterans General Hospital
in Taipei. The data on citation frequency and impact factors were obtained from
Journal Citation Reports, 1993 microfiche edition. The study explored the use,
citation, and impact factor data, especially for heavily used, highly cited, or
high-impact-factor journals. The correlations between frequency of use and
citation frequency and between frequency of use and impact factor were determined
by using the Spearman rank and Pearson correlation tests. The same comparisons
were also made within four subject categories: clinical medicine journals, life
science journals, hybrid journals publishing both clinical medicine and life
science papers, and journals that publish neither clinical medicine nor life
science articles. The results of the study showed that there is a significant
correlation between frequency of use and citation frequency, and between
frequency of use and impact factor for all titles. There is also a significant
correlation between frequency of use and citation frequency and between frequency
of use and impact factor for journals that publish either clinical medicine or
life science articles, or both. However, the correlation is not significant for
other journals.
PMID- 9549011
TI - Who needs evidence-based health care?
AB - The vast amount of published material in clinical and biomedical sciences, and
conflicting results on diagnostic and therapeutic procedures may introduce doubts
in decision-making for patient care. Information retrieving skills and the
critical appraisal of published literature, together with elaboration of practice
guidelines based on epidemiological methodology, form the basis of the trend
towards evidence-based health care, which aims to overcome these problems. A
survey conducted by questionnaire at the Chaim Sheba Medical Center analyzed
which types of information sources are considered most relevant and useful for
patient care by a cross-section of physicians with varying degrees of experience.
They considered review articles and meta-analyses extremely reliable for
information purposes, while for practical patient-care purposes they tended to
rely more on the opinions of peers and experts. As the requirements of evidence
based health care may influence the attitudes of clinicians to the published
literature and its evaluation, they have implications for medical libraries and
information centers. Specifically, information specialists will be called upon
more and more to impart information-retrieval and critical appraisal skills to
clinicians. The involvement of information specialists in information gathering
and selection will provide added value to the expertise and knowledge of in-house
experts for decision-making.
PMID- 9549012
TI - Health sciences library building projects, 1996-1997 survey.
AB - Nine building projects are briefly described, including four new libraries, two
renovations, and three combined renovations and additions. The libraries range in
size from 657 square feet to 136,832 square feet, with seating varying from 14 to
635. Three hospital libraries and four academic health sciences libraries are
described in more detail. In each case an important consideration was the
provision for computer access. Two of the libraries expanded their space for
historical collections. Three of the libraries added mobile shelving as a way of
storing print materials while providing space for other activities.
PMID- 9549013
TI - A study of hospital and medical libraries in Riyadh, Kingdom of Saudi Arabia.
AB - The study reported examined the status of hospital libraries, their sponsoring
organizations, their staff, the academic qualifications of the head of the
library, collection size, available space, buildings, and services. The study was
limited to the hospitals with libraries for staff in Riyadh, the capital of Saudi
Arabia. The data were collected through questionnaires sent to a sample of
fifteen hospitals with medical libraries. Twelve libraries responded. This is the
first study of its kind in Saudi Arabia, and it is hoped that similar surveys
will be done covering the whole kingdom.
PMID- 9549014
TI - Complementary use of the SciSearch database for improved biomedical information
searching.
AB - The use of at least two complementary online biomedical databases is generally
considered critical for biomedical scientists seeking to keep fully abreast of
recent research developments as well as to retrieve the highest number of
relevant citations possible. Although the National Library of Medicine's MEDLINE
is usually the database of choice, this paper illustrates the benefits of using
another database, the Institute for Scientific Information's SciSearch, when
conducting a biomedical information search. When a simple query about red wine
consumption and coronary artery disease was posed simultaneously in both MEDLINE
and SciSearch, a greater number of relevant citations were retrieved through
SciSearch. This paper also provides suggestions for carrying out a comprehensive
biomedical literature search in a rapid and efficient manner by using SciSearch
in conjunction with MEDLINE.
PMID- 9549016
TI - Hospital library service and the changes in national standards.
AB - Two important sets of standards affecting hospital libraries were significantly
revised in 1994, those of the Medical Library Association (MLA) and the Joint
Commission on Accreditation of Healthcare Organizations (JCAHO). As part of its
continuing efforts to monitor library services within its region, the University
of California, Los Angeles Biomedical Library, Regional Medical Library for the
Pacific Southwest Region of the National Network of Libraries of Medicine (NN/LM)
conducted a survey in late 1994, in part to determine the effects of these
revised standards on regional hospital libraries. Data from the survey were also
used to provide a view of hospital libraries in the Pacific Southwest region, and
to make comparisons with similar data collected in 1989. Results showed that
while libraries remained stable in overall number, size, and staffing, services,
especially those associated with end-user searching and interlibrary loan,
increased enormously. With respect to the MLA standards, results show a high
compliance level. Interesting differences were seen between the perceptions of
library staff concerning their rate of compliance with the JCAHO standards and
their actual compliance as measured by the MLA criteria. While some libraries
appear to measure up better than their own perceptions would indicate, others may
be fully aware of their actual compliance level.
PMID- 9549015
TI - Scientific meeting abstracts: significance, access, and trends.
AB - Abstracts of scientific papers and posters that are presented at annual
scientific meetings of professional societies are part of the broader category of
conference literature. They are an important avenue for the dissemination of
current data. While timely and succinct, these abstracts present problems such as
an abbreviated peer review and incomplete bibliographic access. METHODS: Seventy
societies of health sciences professionals were surveyed about the publication of
abstracts from their annual meetings. Nineteen frequently cited journals also
were contacted about their policies on the citation of meeting abstracts. Ten
databases were searched for the presence of meetings abstracts. RESULTS: Ninety
percent of the seventy societies publish their abstracts, with nearly half
appearing in the society's journal. Seventy-seven percent of the societies supply
meeting attendees with a copy of each abstract, and 43% make their abstracts
available in an electronic format. Most of the journals surveyed allow meeting
abstracts to be cited. Bibliographic access to these abstracts does not appear to
be widespread. CONCLUSIONS: Meeting abstracts play an important role in the
dissemination of scientific knowledge. Bibliographic access to meeting abstracts
is very limited. The trend toward making meeting abstracts available via the
Internet has the potential to give a broader audience access to the information
they contain.
PMID- 9549017
TI - The medical librarian as chief information officer.
AB - The position of chief information officer (CIO) is gaining popularity, especially
in the health care field. The results of an informal electronic and telephone
survey indicate that few medical librarians have made a career move to CIO even
though this might seem like a logical step. This paper examines the qualities
required of an effective information management executive, the role CIOs play
within organizations, and the career advancement strategies for librarians
interested in becoming CIOs. Questionnaire responses are reported from three
medical librarians who have made the transition to CIO-type positions, and a case
study illustrates the responsibilities of CIOs in health care organizations.
PMID- 9549019
TI - Rehabilitation is always given a low priority.
PMID- 9549018
TI - Information on alternative medicine: a collection management issue.
AB - Collection management of library materials about alternative medicine may be a
growing problem for librarians because differing views exist regarding the
acceptability of this information in a public forum. The purpose of the study
reported was to investigate possible differences in the views of physicians,
medical students, and librarians regarding the availability of information about
alternative medicine for both medical students and the general public. Interviews
were conducted with two representatives from each group, all of whom are
affiliated with the Faculty of Medicine at The University of British Columbia or
its library. The study was exploratory in nature, conducted in part to determine
whether a larger research project in this area should be mounted. The data
revealed considerable differences in opinion about alternative medicine: the
librarians were more hesitant about the acceptability of radical or revolutionary
materials, particularly those containing information that could result in direct
harm to a patient. The physicians and medical students were more confident than
the librarians that traditional medical treatment (and therefore information
about it) should always be paramount.
PMID- 9549020
TI - Respect for autonomy: issues in neurological rehabilitation.
AB - OBJECTIVE: To examine the ethical principle of respect for autonomy within the
context of neurological rehabilitation. DISCUSSION: The nature of the principle
of respect for autonomy is examined, and specific difficulties to which it may
give rise in this area of practice are identified. These concern difficulties of
communication with neurologically impaired patients, issues of competence related
to patient decision-making, problems of consensus between patient and
professional, and the role of the patient's family in the rehabilitation process.
CONCLUSION: A number of strategies, based on a client-centred model of practice,
are suggested which may counteract these difficulties and assist in respecting
the patient's autonomy to the appropriate degree, while seeking to attain high
quality clinical outcomes.
PMID- 9549021
TI - Electromyographic biofeedback for gait training after stroke.
AB - OBJECTIVE: To examine the effects of electromyographic (EMG) biofeedback training
on the recovery of gait in the acute phase post stroke. DESIGN: Patients were
randomly assigned to EMG biofeedback or control groups. They received treatment
three times a week for six weeks. All patients were assessed prior to treatment,
after 18 treatment sessions, and at three months follow-up. SETTING: The study
was carried out at Scunthorpe General Hospital in North Lincolnshire. The
subjects were acute stroke patients who had been admitted on to the medical and
elderly wards. INTERVENTIONS: The EMG biofeedback group were treated using EMG as
an adjunct to physiotherapy. The patients were encouraged to facilitate or
inhibit abnormal muscle tone via auditory or visual signals transmitted from
electrodes placed over the appropriate muscles. The control group were treated
using the same techniques, electrodes were used with this group of patients, but
the EMG machine was turned off and faced away from the patient and the therapist
to control the placebo effect. OUTCOME MEASURES: A large battery of outcome
measures was used for physical and psychological assessment. The physical
measures consisted of active movement, muscle tone, sensation, proprioception,
mobility and activities of daily living (ADL). The psychological measures
included orientation, memory, spatial performance, language and IQ. RESULTS:
Twenty-one patients were included in the study. Scores were combined into four
groups: mild EMG, severe EMG, mild control and severe control. Results showed
that there was an improvement in physical scores for active movement, mobility
and ADL over time, but there was no significant difference between the EMG and
control groups. Scores on the psychological tests were within normal limits, and
there was no difference in performance between the EMG and control groups.
CONCLUSIONS: This study showed no significant differences in the rate of
improvement after stroke between the two groups. Although EMG biofeedback was
used as an adjunct to physiotherapy and represented clinical practice, the
results provide little evidence to support the clinical significance of using EMG
biofeedback to improve gait in the acute phase after stroke.
PMID- 9549023
TI - Ten-metre walk, with or without a turn?
AB - OBJECTIVE: To compare results obtained using different procedures to measure 10
metre walking time. DESIGN: Walking was timed over a straight 10 m, and over 5 m
with return. Further, the time taken to turn was measured directly. SETTING:
Rehabilitation department of a university hospital. SUBJECTS: Patients who had
walking disability after stroke. RESULTS: In the group of 43 patients, the time
taken to walk 5 m and return was 3.3 (SD 5.0)s longer than the time to walk 10 m
straight, but there was a large variation with some patients walking faster. The
measured time to turn in a second group of 27 patients was 3.2 (SD 1.6)s. The
times taken to walk 10 m straight and 5 m and return, and the time taken to turn
were all highly correlated (r = 0.69 or more). CONCLUSIONS: Timing walking over 5
m with a return is an acceptable alternative to the 10 m straight walk, but the
actual time taken varies. On average, the walk with a turn is 3.2 s longer but in
individual patients the difference may be much more or less. Sometimes the walk
with a turn is even faster than that without.
PMID- 9549022
TI - The treatment of lateral epicondylitis by iontophoresis of sodium salicylate and
sodium diclofenac.
AB - OBJECTIVE: To investigate the effectiveness of sodium diclofenac and sodium
salicylate applied by topical iontophoresis and to compare them in the treatment
of lateral epicondylitis. SUBJECTS: Forty patients with lateral epicondylitis
were randomized into two groups of 20 patients who were matched for age and sex.
INTERVENTIONS: The patients in one group were treated by iontophoresis of sodium
diclofenac and the other group were treated by iontophoresis of sodium
salicylate. Then infrared treatment was applied to patients in both groups. MAIN
OUTCOME MEASURES: Pain scores obtained before and after treatment were compared.
RESULTS: Pain produced by pressure on the lateral epicondyle, on resisting wrist
extension, during function and spontaneous pain at rest significantly decreased
in both groups after treatment (p < 0.001). When pain scores obtained after
treatment were compared, greater decrease was observed in the pain produced on
resisting wrist extension (p < 0.01) and by pressure on the lateral epicondyle (p
< 0.05) in the group treated with sodium diclofenac than in the group treated
with sodium salicylate. CONCLUSIONS: The results suggest some benefits from the
process of iontophoresis and the use of infrared in the treatment of lateral
epicondylitis and indicate that iontophoresis of sodium diclofenac is more
effective than that of sodium salicylate.
PMID- 9549024
TI - Neck semispinalis capitis muscle size in sitting and prone positions measured by
real-time ultrasonography.
AB - OBJECTIVE: To examine the reliability of measurements of semispinalis capitis
muscle (SECM) cross-sectional area (CSA) in prone and sitting positions, and to
compare the muscle size in these two positions. DESIGN: Semispinalis capitis CSA
was measured twice a day on two successive days with a real-time ultrasound
apparatus. SUBJECTS: Eighteen males (aged 19-34 years) and 28 females (aged 19-34
years) were studied for the reliability test. Seven males and 12 females were
randomly selected to compare SECM size in sitting and prone positions. RESULTS:
The intraclass correlation coefficient (ICC) for repeatability measurements was r
= 0.98 for the two positions. The correlation of the CSA in sitting and in prone
positions was r = 0.93 (p < 0.01). There were no significant differences between
CSA, linear dimensions and shape ratio of SECM in the two positions. CONCLUSIONS:
In this study SECM ultrasonography appeared to be an accurate method in both
positions, and position as such had no significant effects on the SECM cross
sectional size. Such accuracy allows neck muscle evaluation in clinical diagnosis
and in follow-up studies during neck rehabilitation programmes.
PMID- 9549025
TI - What do patients and their carers want to know about stroke? A two-year follow-up
study.
AB - OBJECTIVE: To clarify what issues are important to stroke patients and their
carers. To determine whether these issues change over time. DESIGN: Prospective
study of consecutive patients admitted to hospital with a diagnosis of an acute
stroke. Each participant had interviews at six and 24 months. In addition, a
subgroup of these patients (consecutive discharges over a two-month period) were
also seen at two weeks post discharge. SETTING AND SUBJECTS: Hospital-based
cohort of stroke survivors. Interviewed in their own homes. MAIN OUTCOMES
MEASURES: Documentation of the questions asked. RESULTS: At two weeks, six and 24
months, a median of three, two and three questions were asked by each patient
respectively. Enquiries about basic aspects of stroke were common but diminished
over time. Fear of recurrence was apparent at all three interview periods.
Enquiries about the psychological sequelae of stroke became more prevalent at six
and 24 months. At two years, 32% of respondents asked about concentration/memory
difficulties with smaller numbers commenting on tiredness, depression and
frustration. At two years, 18% of the sample were still uncertain of their
chances of further recovery. CONCLUSIONS: Patients with stroke continue to have
unanswered questions even two years after their stroke. The types of questions
asked changed over time.
PMID- 9549026
TI - Assault, post-traumatic amnesia and other variables related to outcome following
head injury.
AB - OBJECTIVE: To estimate how many patients who sustain a head injury might benefit
from intervention and support each year and to consider whether relationships can
be found between demographic data relating to patients' circumstances at the time
of head injury, and their outcomes six months later. DESIGN: Data collected on
625 patients through follow-up interviews and assessments by the Oxford Head
Injury Service for a randomized controlled trial of intervention conducted in
1993-94. SETTING: A mixed rural and urban Health District with a population of
approximately 560,000. PATIENTS: Patients were aged between 16 and 65 years and
resident in Oxfordshire. They presented over 13 months to accident and emergency
departments, or were admitted to hospital. All were diagnosed as having suffered
a head injury. OUTCOME MEASURES: The Rivermead Head Injury Follow Up
Questionnaire and the Rivermead Post Concussion Symptoms Questionnaire. RESULTS:
Data are given on age, sex, social circumstances, employment, cause of injury,
severity of associated injuries, post-traumatic amnesia (PTA), anticonvulsants,
postconcussion symptoms and activities of everyday life. Outcome at six months
was significantly worse for those who had been assaulted as against all other
causes of injury combined (p = 0.0001); and/or had been admitted to hospital (p =
0.0001)l and/or had sustained more severe additional injuries (p = 0.04); and/or
had experienced any PTA (p = 0.00001). The minimum incidence of such injuries in
those aged 16-65, calculated for Oxfordshire, is 292 per annum (74/100,000 aged
16-65 per year). CONCLUSIONS: In the general population 52/100,000 patients per
annum will experience more serious head injuries as indicated by hospital
admission and/or one or more fractures and/or any length of PTA and/or having
been assaulted. This group may benefit from monitoring and support and their
needs should be considered when planning services.
PMID- 9549027
TI - Manual dexterity and keyboard use in spastic hemiparesis: a comparison between
the impaired hand and the 'good' hand on a number of performance measures.
AB - OBJECTIVE: To assess the functional deficits in tapping performance of subjects
with spastic hemiparesis. DESIGN: In a pilot study, typing performance on a
computer keyboard was examined on a number of performance measures. SETTING:
Department of Research and Development at the Werkenrode Institute. SUBJECTS:
Four subjects (mean age 16.4 years, standard deviation 1.8 years) with cerebral
palsy and diagnosed as having spastic hemiparesis. INTERVENTIONS: Subjects had to
type a sequence of one or more keys as quickly as possible within an 8 second
period with the fingers of both hands separately. MAIN OUTCOME MEASURES: The
average number of good and false responses were calculated. Within the false
response category, four, mutually exclusive, types of errors were distinguished;
wrong key, repetition, registrations under 75 ms and holding. Speed and
regularity of the typing responses were also established. RESULTS: The 'good'
hand outperformed the impaired hand on all performance measures except on the
amount of repetition errors made. The holding error was only present for the
impaired hand, and there was an increase in holding errors from the index to the
little finger in this hand. In addition, the impaired hand performed the task
with a slower speed and in a more irregular fashion. CONCLUSIONS: The results are
discussed with reference to keyboard design. It is concluded that the standard
'QWERTY' keyboard hampers typing performance extensively, especially for subjects
with left spastic hemiparesis. A learning method is presented in which the role
of an external pacer (e.g. metronome) is discussed. This device can initially be
used to decrease movement variability and, eventually, for increasing movement
speed.
PMID- 9549028
TI - The effects of depression and abnormal illness behaviour on outcome following
rehabilitation from stroke.
AB - OBJECTIVE: To examine the relative effects of depression and abnormal illness
behaviour (AIB) on long-term rehabilitation outcome following stroke. DESIGN: A
longitudinal design, with assessments on admission to and discharge from
rehabilitation, and six and twelve months after discharge. SETTING: The study was
undertaken in the rehabilitation unit at Repatriation General Hospital, in
Adelaide, South Australia. SUBJECTS: Ninety-four twelve-month stroke survivors
who had undergone an inpatient rehabilitation programme. MAIN OUTCOME MEASURES:
AIB was assessed using the Illness Behaviour Questionnaire, and depression with
the Zung Self-Rating Depression Scale. The General Health Questionnaire and a
visual analogue mood scale were also used. Functional outcome was assessed with
the competence and performance assessments of the Australian ADL Index, and
lifestyle activities with the Frenchay Activities Index. RESULTS: Multivariate
analysis of outcome controlled for age and stroke severity. AIB was a better
predictor of functional competence and performance than either age or stroke
severity, at rehabilitation discharge and both six and twelve months later.
Depression was not related to functional competence and performance at any
assessment, but was strongly predictive of an inactive lifestyle at both six and
twelve months. By contrast, lifestyle activities were not related to AIB.
CONCLUSIONS: Depression and AIB appear to have quite distinct effects on outcome.
AIB emerged as a key determinant of long-term functional disability, while
depression was associated with poorer social functioning. The early recognition
and treatment of AIB and depression is important for the ultimate social and
functional outcomes of stroke rehabilitation patients.
PMID- 9549029
TI - The use of self-management strategies by people with rheumatoid arthritis.
AB - OBJECTIVE: To investigate seven common arthritis self-management methods used by
people with rheumatoid arthritis (RA) by studying their frequency of use and the
patients' belief in their benefits. Also to look at how people obtained
information about such methods. DESIGN: Cross-sectional survey. SUBJECTS AND
SETTING: Forty-one people with RA attending a rheumatology outpatient department
at a large district general hospital. RESULTS: Twenty-three recalled receiving
some self-management advice from rheumatology team members, but most stated the
commonest source of information was arthritis books and leaflets (n = 29). Two
thirds used technical aids and rest on a daily basis, half used exercise and heat
(half doing so daily). A quarter to a half used relaxation, joint protection and
working splints (half doing so daily). CONCLUSION: People with RA reported using
three or four self-management methods simultaneously to help control symptoms. In
the main, believing a method to be beneficial was strongly related to its use.
However, exercise and joint protection, whilst widely believed to be beneficial,
were less used. People reported problems with knowing how to do these correctly,
having insufficient time to practise sufficiently and difficulty in establishing
habits.
PMID- 9549030
TI - Environmental control systems--an audit of existing provision in three inner
London districts.
AB - OBJECTIVE: To undertake an audit of existing environmental control system (ECS)
provision to see what lessons could be applied to developing a new model of
service. DESIGN: Structured interviews and assessments making use of
questionnaires and algorithms. SUBJECTS: Users of environmental control systems
in the inner London boroughs of Lambeth, Southwark and Lewisham (population
720,000) supplied with equipment prior to April 1996 out of National Health
Service funds. SETTING: All users were assessed and interviewed in their own
homes. RESULTS: In all, 29 users of ECSs were surveyed. Six users were found to
have systems either so outdated or poorly planned as to be nearly useless. Seven
users were felt not to justify an ECS and many systems were felt to be over
specified, leading to wastage of equipment. Many medical and nonmedical needs,
not directly related to the users' ECSs, were identified. CONCLUSIONS: While the
recommendations of the British Society of Rehabilitation Medicine special
interest group on ECS are welcomed, it is thought that these do not go far
enough. In particular the role of the environmental control assessor needs to
extend to participation in the case conference where the exact equipment
requirements of the prescribed ECS is agreed, and thereafter to include
responsibility for ensuring regular review of users. In such a model of service
the current single payment for a one-off assessment is felt to be inappropriate.
PMID- 9549031
TI - Reproductive hormones and gastrointestinal motor disorders: a new dimension in
therapeutics.
PMID- 9549032
TI - Relationship of reproductive hormones and neuromuscular disease of the
gastrointestinal tract.
AB - Functional disorders of the gastrointestinal tract comprise a common but ill
defined group of diseases; they primarily afflict women. Although predominantly
involving nerve and muscle, the cellular and molecular bases of the pathogenesis
of these functional disorders are unknown. Clinical studies indicate that some
result from neural dysfunction within the enteric nervous system, others may be
due to muscular problems, and the causes of still others remain unknown.
Laboratory studies have shown that ovarian products such as progesterone,
luteinizing hormone, human chorionic gonadotropin, and relaxin (but not
estrogen), are neural antagonists of gastrointestinal motility. The production
and secretion of these ovarian substances are controlled by gonadotropin
releasing hormone (GnRH) released from the hypothalamus; they probably act on
gamma-aminobutyric acid receptors and alter chloride influx into the cell. GnRH
analogs are effective drugs that downmodulate the hypothalamic-pituitary-gonadal
axis and inhibit the secretion of gonadal products involved in such hormone
dependent diseases as endometriosis and prostate cancer. Acting on the GnRH
receptors (seven transmembrane domain receptors) on myenteric neurons, GnRH
analogs are also effective neural modulators in such disorders as functional
bowel disease. These analogs are a promising new group of compounds that may be
used to treat difficult gastrointestinal problems.
PMID- 9549033
TI - Use of botulinum toxin in the treatment of achalasia.
AB - Achalasia is a chronic esophageal motor disorder characterized by failure of the
lower esophageal sphincter (LES) to relax during swallowing, aperistalsis of the
esophageal body, and, often, an elevated resting LES pressure. Pneumatic dilation
and Heller cardiomyotomy have been the time-honored, accepted treatments, but
each may carry significant morbidity. Recently, intrasphincteric injection of
botulinum toxin has been shown to be an effective treatment for achalasia,
probably by reducing the excitatory cholinergic tone of the LES. Subjective and
objective improvement have been reported in many patients with few reported
adverse reactions. Clinical improvement generally lasts 2-6 months with patients
often requiring repeat treatment. Although studies directly comparing botulinum
toxin injection with pneumatic dilation and surgical myotomy are needed,
botulinum toxin injection has rapidly become another therapeutic option in the
treatment of achalasia.
PMID- 9549034
TI - Gene therapy for liver disease.
AB - With major advances in biomedical science over the last 2 decades, the
possibility of treating human disease at a genetic level has become a tantalizing
possibility. As a result, a growing number of investigators are focusing on the
development of techniques to deliver therapeutic genes into cells. The liver has
been a model organ in the development of this gene transfer technology. This
review focuses on the attributes and limitations of the current gene delivery
systems that have been explored in the context of liver disease and highlights
the obstacles that must be addressed before hepatic gene therapy becomes a
clinical reality.
PMID- 9549035
TI - A prokinetic approach to treatment of gastroesophageal reflux disease.
AB - Currently available medications for gastroesophageal reflux disease (GERD) vary
in mechanisms of action from neutralization or suppression of gastric acid to
improving underlying upper gastrointestinal dysmotility. This article reviews the
clinical efficacy of pharmacological agents used to treat GERD and provides a
rationale for considering a primary prokinetic approach to antireflux treatment
which will be applicable to many patients. Treatment trials in acute GERD have
demonstrated unexpectedly prolonged maintenance of high esophageal pH with tablet
and liquid antacid formulations. However, there are no well-designed placebo
controlled trials of antacids for esophageal mucosal healing. H2 receptor
antagonists (H2RAs) at conventional doses relieve reflux symptoms in at least 50%
of reported series of GERD patients, and they can also provide endoscopic healing
in 27-45% of the cases. Therapy with more potent acid-suppressive agents such as
proton pump inhibitors (PPIs) may lead to improved symptomatic relief and to
superior healing compared with H2RA therapy, especially in those patients with
more advanced erosive esophagitis. Promotility agents, particularly cisapride,
offer symptom relief and healing rates which are quite similar to standard H2RA
treatment. GERD tends to be a chronic and relapsing condition. Cisapride has been
shown to be quite effective in maintaining remission in GERD patients, including
endoscopic remission in the lesser degrees of esophagitis. This may be
accomplished with relatively low and cost-effective dosing in many individuals.
For the small proportion of patients who manifest severe grades of esophagitis,
PPI therapy is associated with lower relapse rates than either H2RA or prokinetic
treatment. Overall, a strong case can be made for the empirical selection of
promotility therapy for the large numbers of GERD patients who do not have
documented severe erosive disease.
PMID- 9549036
TI - Antimicrobial treatment of intra-abdominal infections.
AB - There have been several recent changes that influence the management of intra
abdominal infections. These changes include important developments in antibiotic
resistance such as increases in pneumococcal resistance, emergence of multi-drug
resistant enterococcal isolates, and decreasing sensitivity of anaerobes and gram
negative rods. In addition there are new antibiotics such as
piperacillin/tazobactam, and new antibiotic dosing regimens such as single daily
dosing of aminoglycosides. In this article, we will review the therapeutic
approach to intra-abdominal infections with special emphasis on the various forms
of peritonitis, cholecystitis, cholangitis, and diverticulitis. Several new
concepts about the treatment of enterococcus, the management of bacterial and
fungal peritonitis, and the prevention of spontaneous bacterial peritonitis will
also be reviewed. Specific recommendations for the management of the different
infections including antibiotic doses and costs will be provided. Finally the
role of invasive procedures in the management of some of the infections will be
explored.
PMID- 9549037
TI - Esophageal carcinoma with obstruction.
PMID- 9549040
TI - Synergistic insulinotropic action of succinate, acetate, and glucose esters in
islets from normal and diabetic rats.
AB - Succinic acid esters are currently under investigation as possible insulinotropic
tools in the treatment of noninsulin-dependent diabetes mellitus. The present
article introduces three novel nutrient esters and aims mainly to explore, in
both normal and GK rats, the secretory response to such esters when tested alone
or in combination. It documents that in pancreatic islets from normal rats,
methyl acetate (10 mM), which fails to augment basal insulin output, potentiates
the secretory response to succinate dimethyl ester (also 10 mM). It also reveals
that alpha-D-glucose pentaacetate (alpha GPA) (1.7 mM) stimulates insulin release
in the absence of any other exogenous nutrient and even more so in the presence
of succinate methyl ester. Moreover, the methyl esters of succinic acid (10 mM),
when used together with either methyl acetate or alpha GPA, provoked insulin
secretion in islets from diabetic GK rats incubated in the absence of D-glucose,
although no significant secretory response of such islets could be detected when
each of these agents was tested separately. These findings thus draw attention to
the insulinotropic potential in type 2 diabetes of selected combinations of
nutrient esters, including a D-glucose ester presumably able to enter into islet
cells without requiring the intervention of a hexose carrier.
PMID- 9549039
TI - Leptin, corticotropin-releasing hormone (CRH), and neuropeptide Y (NPY)in free
ranging pregnant bats.
AB - Leptin, the product of the obese gene first identified in mice, restores
fertility in obese mice, and accelerates puberty in mice. We hypothesized that
leptin's putative role in reproduction may extend to pregnancy and lactation.
Leptin levels were determined in Myotis lucifugus, the little brown bat, a free
ranging mammal with a seasonal breeding cycle. The present study shows that
plasma levels of leptin progressively rise during pregnancy, supporting a
potential role for leptin in the maintenancy of pregnancy. In contrast, leptin
was significantly lower during lactation, a time when most mammals, including
bats, demonstrate reduced fertility. In addition to its possible roles in
reproduction, leptin appears important in regulation of energy balance. M.
lucifugus spontaneously fasts for up to 16 h each day during the active season,
which allowed us to test the hypothesis that acute fasting was associated with
decreased leptin. Leptin was significantly lower in fasted (lactating) bats,
compared to those that recently returned from nightly foraging. Although
postprandial lactating bats had a significantly higher fat index than fasted
bats, plasma leptin and body fat were not significantly correlated, and were only
weakly correlated (r2 = 0.26) when both pregnant and lactating females were
included in the analysis. Similar changes during pregnancy, lactation, and the
daily feeding cycle were observed in the hypothalamic neuropeptide, corticotropin
releasing hormone (CRH), which is believed to play an important role in energy
balance and reproduction. By contrast, neuropeptide Y (NPY) increased during
pregnancy but did not change during fasting. These results suggest that leptin's
putative role in reproduction may extend to pregnancy and lactation, and that
spontaneous, acute fasting results in decreased circulating levels of leptin in
M. lucifugus.
PMID- 9549041
TI - Effects of GH on IGF-II-induced progesterone accumulation by cultured porcine
granulosa cells.
AB - A total of seven experiments were conducted to investigate the potential
facilitative interaction of growth hormone (GH) and insulin-like growth factor II
(IGF-II) in stimulating steroidogenesis by cultured porcine granulosa cells and
to examine the possible nature of this action. Porcine granulosa cells were
cultured in serum-free medium in the presence or absence of GH or prolactin, with
or without IGF-II or IGF-I. IGF-II by itself dose (with peak progesterone
production of 498 ng/mg DNA/24 h being observed at 100 ng of IGF-II/mL) and time-
(with minimum time requirement of 24-48 h) dependently increased progesterone
accumulation (P < 0.01). Neither GH (dose range 0, 5, 10, 50, 100, and 150 ng/mL)
nor prolactin (dose range 0, 0.01, 0.1, 1, 5, 10 micrograms/mL) alone stimulated
progesterone accumulation when compared with the control (P > 0.05). However, in
the presence of IGF-II, GH proved to be a potent amplifier of IGF-II in
progesterone production (P < 0.01) with a minimum GH time requirement of 24-48 h.
In contrast, prolactin did not influence IGF-II-induced progesterone accumulation
(P > 0.05). An inhibitory study showed that the presence of cycloheximide (3
micrograms/mL) or actinomycin D (1 microgram/mL) blocked both the stimulatory
effect of IGF-II on progesterone accumulation and the amplification of GH on IGF
II induced production (P > 0.01), suggesting GH amplification of IGF-II-induced
progesterone accumulation is a process involving gene transcription and
translation. Northern blot analysis further demonstrated that GH amplification of
IGF-II-induced steroidogenesis can be attributed, at least partially, to enhanced
IGF-II-induced cytochrome P450 cholesterol side-chain cleavage mRNA by GH.
PMID- 9549043
TI - Dopamine D2 receptor mediates both inhibitory and stimulatory actions on
prolactin release.
AB - Dopamine is considered to be the major physiological tonic inhibitor of prolactin
release, yet there is increasing evidence showing that it can also stimulate
prolactin release from lactotrophs. In primary cultured lactotrophs, the major
dopamine receptors responsible for inhibiting prolactin release are dopamine D2
receptors. A dopamine receptor subtype may be responsible for the stimulatory
action, yet one cannot exclude the possibility that a dopamine D2 receptor can
play dual roles. This study was therefore undertaken to investigate if dopamine
both stimulates and inhibits prolactin secretion through activation of the same
dopamine D2 receptor. GH4ZR7 cells, which have only one type of dopamine
receptors--D2s, were perifused with different concentrations of dopamine, and the
perifusate was assayed for prolactin; 10(-7) mol/L dopamine stimulated prolactin
release (p < 0.05; n = 5), whereas 5 x 10(-4) mol/L dopamine inhibited prolactin
secretion (p < 0.05; n = 5). In the pertussis toxin-treated cells, 10(-7) mol/L
dopamine stimulated prolactin release (p < 0.05; n = 5), and 5 x 10(-4) mol/L
dopamine did not significantly change the rate of prolactin release. These
results indicate that both the stimulatory and inhibitory actions of dopamine are
likely mediated by the same D2 receptor subtype, since GH4ZR7 cells express only
D2s receptors. They also confirm that the inhibitory action of dopamine is
mediated through a Gi protein; and the stimulatory action of dopamine is mediated
through a PTX-insensitive pathway. These findings suggest that D2 receptors are
coupled to both Gi and Gs proteins.
PMID- 9549038
TI - Is signal transduction modulated by an interaction between heterotrimeric G
proteins and tubulin?
AB - Although it is generally accepted that tubulin plays an important role in G
protein-mediated signal transduction in a variety of systems, the mechanism of
this phenomenon is not completely understood. G-protein-tubulin interaction at
the cell membrane and the cytosol, and the influence of such an interaction on
cellular signaling are discussed in this review article. Because the diameter of
a microtubule is 25 nm and the plasma membrane is 9-11 nm thick, it is not
possible for membrane-associated tubulin to assemble into a complete microtubule
in the membrane environment. However, tubulin heterodimers may be able to
function in the membrane environment as individual heterodimers or as polymers
arranged into short protofilaments. At the cell membrane, membrane-associated
tubulin may influence hormone-receptor interaction, receptor-G-protein coupling,
and G-protein-effector coupling. Structural proteins, such as tubulin, can
participate in cellular signaling by communicating through physical forces. By
virtue of its interaction with the submembranous network of cytoskeletal
proteins, tubulin, when perturbed in one locus, can transmit large changes in
conformations to other points. Thus, GTP binding to membrane-associated tubulin
might lead to a conformational change in either receptors or G proteins. This
may, in turn, influence the binding of an agonist to its receptor. On the other
hand, in the cell cytosol, subsequent to agonist-induced translocation of G
proteins from the membrane compartment to the cytosol, G-proteins may affect
microtubule formation. In GH3 and AtT-20 cells (stably expressing TRH receptor),
transiently transfected with Gq alpha cDNA, soluble tubulin levels decreased in
Gq alpha-transfected GH3 and AtT-20 cells, by 33% and 52%, respectively. These
results suggest that G-proteins may have a direct effect on the microtubule
function in vivo. Because tubulin and G-protein families are ubiquitous and
highly conserved, an interaction between these two protein families may occur in
vivo, and this, in turn, can have an impact on signal transduction. However, the
physiological significance of this interaction remains to be demonstrated.
PMID- 9549042
TI - Decreased osteoblast activity in spontaneously diabetic rats. In vivo studies on
the pathogenesis.
AB - Diabetes in both humans and rats is accompanied by low bone formation, which is
presumably caused by serum-borne factors. To explore its pathogenesis, we carried
out experiments in diabetic and nondiabetic BB rats, using plasma osteocalcin
concentrations (OC) as a marker for osteoblast activity. In nondiabetic rats, the
i.v. infusion of glucose (30%, 4 d) did not change OC; s.c. insulin infusion (4
U/d, 14 d) reduced OC by 27% (p < 0.01). In diabetic rats, OC were decreased from
the first day of glycosuria (71 +/- 5% of paired controls), declining
exponentially to 24 +/- 3% after 5 wk. Insulin infusion (1, 2, and 3 U/d, 14 d)
produced gradual restoration of OC. OC were better correlated with insulin-like
growth factor-I (IGF-I) than with insulin levels in these experiments. OC were
dramatically increased 4 d after adrenalectomy (ADX) in all diabetic rats (73 +/-
8 vs 22 +/- 4 micrograms/L before ADX; p < 0.001), but not if corticosterone was
administered. Ligand blotting of IGF binding proteins showed a marked decrease in
two bands (44-49 and 32-35 kDa) 10-14 d after diabetes onset; the density of
these bands was increased, but not normalized after ADX. Thus, decreased
osteoblast activity is present from the onset of diabetes, is dependent on
endogenous corticosterone, and cannot be reproduced by hyperglycemia in
nondiabetic rats.
PMID- 9549044
TI - Specific antibody recognition of rat pituitary adenylate cyclase activating
polypeptide receptors.
AB - Pituitary adenylate cyclase activating polypeptide (PACAP) is a new member of the
secretin/VIP family of peptides. The specific receptor for PACAP has been cloned
in rat, human, and bovine tissues. The distribution of the transcripts of PACAP
receptor genes has been studied in various tissues using in situ hybridization.
However, the unavailability of a specific antibody against the PACAP receptor has
hampered further study of the expression of receptor proteins. In the present
study, rabbit antisera were generated against a synthetic 25-residue peptide
corresponding to the C-terminal intracellular domain of the rat PACAP receptor.
To validate the specificity of the antisera, CHO cells and cells stably
transfected with rat PACAP receptor cDNA were prepared. Using one of these
antisera, the membrane and soluble fractions of the transformants were examined
by Western blot analysis. Three bands were observed in subcellular fractions from
the transfected CHO cells, but no bands were found in similar preparations from
the nontransfected cells. A distinct 57-kDa band, which corresponds to the size
of cloned rat PACAP receptor, was detected. In addition, a less intense band,
larger than 57 kDa, and a very weakly stained band, smaller than 57 kDa, were
demonstrated. All of these bands disappeared or were considerably diminished when
the antiserum was preabsorbed with the synthetic immunogen peptide. This suggests
that these bands are PACAP receptor-related proteins. The membranes from the
transfected CHO cells bound to [125I]PACAP27. The size of the ligand/protein
crosslinked product approximated 60 kDa, corresponding to the combined size of
the PACAP receptor and PACAP27. No additional bands were observed, indicating
that the immunopositive proteins larger or smaller than 57 kDa do not bind to the
ligand and are not functional. Unlabeled PACAP27 and PACAP38, but not VIP,
displaced the binding, suggesting that the receptors expressed in CHO cells are
specific for PACAP. Solubilized membrane fractions prepared from rat brains were
used for an immunoprecipitation study with [125I]PACAP27 and [125I]VIP. The PACAP
receptor antiserum recognized [125I]PACAP-, but not [125I]VIP-bound proteins in
the solubilized brain membrane fractions. Immunohistochemistry using this
antiserum showed a distribution of PACAP receptor-like immunoreactivities similar
to the distribution of the mRNA of PACAP receptor in the rat brain. Thus, the
PACAP receptor antiserum is sufficiently specific to be used as a tool for
studying the expression of PACAP receptors and related proteins.
PMID- 9549045
TI - Uterine estrogen sulfatase may play a more important role than the hepatic
sulfatase in mediating the uterotropic action of estrone-3-sulfate.
AB - The estrogenic activity of sulfonated estrogens results from the release of
active estrogens via desulfonation (hydrolysis) catalyzed by estrogen sulfatase.
In this study, the relative importance of uterine or hepatic estrone (E1)-3
sulfatase in mediating the uterotropic action of E1-3-sulfate is evaluated by
comparing its hormonal potency in animals that have comparable uterine E1-3
sulfatase activity but markedly different hepatic enzyme activity. Liver
microsomes from immature or adult female Sprague-Dawley rats contained 12- or 55
fold higher E1-3-sulfatase activity, respectively, than the liver microsomes from
immature or adult female CD-1 mice. In contrast, uterine whole homogenates from
immature female Sprague-Dawley rats contained approx twofold higher E1-3
sulfatase activity than was detected in the uterine whole homogenates from
immature female CD-1 mice. It is estimated that the total E1-3-sulfatase activity
in the liver of an immature female rat or mouse is approx 1080- or 260-fold
higher, respectively, than the activity in the uterus. The ED50 values for the
uterotropic effect of E1-3-sulfate and E1 in immature female CD-1 mice were 240
and 8 pmol/g body wt, respectively, and the corresponding ED50 values in immature
female Sprague-Dawley rats were 840 and 60 pmol/g body wt, respectively. The
difference in the ratios of the uterotropic ED50 for E1-3-sulfate over that for
E1 in immature rats and mice (14 and 30, respectively) is 1.14-fold, which
correlates very closely with their difference in the uterine E1-3-sulfatase
activity (approx twofold), but not their difference in the hepatic sulfatase
activity (approx 12-fold). The results of this study provide evidence suggesting
that E1-3-sulfatase in the uterus (an estrogen target organ) may play a more
important role than the hepatic sulfatase in mediating the uterotropic action of
sulfonated estrogens.
PMID- 9549046
TI - Insulin induction of pip 92, CL-6, and novel mRNAs in rat hepatoma cells.
AB - Insulin directly affects many aspects of cellular metabolism. An additional,
poorly studied effect of insulin is the regulation of multiple genes whose
products are important in many cellular functions. Using differential screening
techniques, we identified insulin-regulated genes induced in insulin-treated rat
H4IIE (H4) hepatoma cells. Two of the mRNAs identified were homologous to the
previously characterized mouse pip 92 and rat CL-6 immediate-early genes. The pip
92 clone was initially isolated from mitogen-stimulated mouse Balb/c 3T3
fibroblasts, whereas the CL-6 clone was first isolated from regenerating rat
liver. In this article, we demonstrated that in rat H4 cells, the transcription
rates of both pip 92 and CL-6 are induced by insulin alone. Additionally, we
showed that the transcription rates of two other genes, whose sequences are not
homologous to any other sequences in gene bank ("novel genes"), were rapidly and
transiently induced by insulin. These results demonstrate that insulin regulates
the expression of several novel genes with a time-course similar to members of
the immediate-early response gene family.
PMID- 9549047
TI - The effects of 17 beta-estradiol on chondrocyte differentiation are modulated by
vitamin D3 metabolites.
AB - Both 17 beta-estradiol (17 beta) and the vitamin D metabolites, 1,25
(OH)2D3(1,25) and 24,25-(OH)2D3(24,25), regulate endochondral bone formation in
vivo and in vitro. The effects of 17 beta are sex-specific and cell maturation
dependent. Similarly, the effects of 1,25 and 24,25 are cell maturation
dependent, with 1,25 affecting growth zone chondrocytes (GC) and 24,25 affecting
resting zone chondrocytes (RC). This study examined whether the response of
chondrocytes to 17 beta is altered after pretreatment with 1,25 or 24,25. Cells
were isolated from the costochondral cartilage of male or female rats. Confluent,
fourth-passage GC and RC cultures were pretreated with 1,25 or 24,25,
respectively, for 24 or 48 h followed by treatment with 17 beta for an additional
24 h. At harvest, cell proliferation ([3H]-thymidine incorporation),
differentiation (alkaline phosphatase specific activity [ALPase]), general
metabolism ([3H]-uridine incorporation), and proteoglycan production ([35S]
sulfate incorporation) were determined. 1,25 enhanced the inhibitory effect of 17
beta on [3H]-thymidine incorporation by female GC cells; in contrast, no effect
was observed in GC cells obtained from male rats. When male RC cells were treated
with 17 beta, [3H]-thymidine incorporation was inhibited; however, when these
cells were pretreated with 24,25 for 48 h, 17 beta stimulated [3H]-thymidine
incorporation 24,25 had no effect on 17 beta-dependent [3H]-thymidine
incorporation by female RC cells. 17 beta stimulated ALPase in female GC cells,
but had no effect on male GC cells. 1,25 pretreatment of female GC cells
inhibited the stimulatory effect of 17 beta on ALPase, but had no effect on
ALPase in male GC cultures. 17 beta had no effect on male RC cell ALPase and
stimulated ALPase in female RC cells. This was not affected by pretreatment with
24,25. Pretreatment with 1,25 increased the basal level of sulfate incorporation
only in female GC. No effect was found in RC cells. These results indicate that
pretreatment of rat costochondral chondrocytes with vitamin D metabolites
modulate the effect of 17 beta. Although the effect of vitamin D metabolites
alone on these chondrocytes is maturation-dependent and not sex-specific, the
influence of preincubation with vitamin D metabolites on the effect of 17 beta is
hormone-specific, sex-specific, and maturation-dependent.
PMID- 9549048
TI - Recruitment of individually (all-or-none) responding cells, rather than amplitude
enhancement, is the single-cell mechanism subserving the dose-responsive
activation of intracellular calcium second messenger signaling by the human
luteinizing-hormone receptor.
AB - We have investigated at the single-cell level how the human LH receptor mediates
a dose-responsive increase in intracellular free calcium-ion concentrations
([Ca2+]i). In human embryonic kidney cells (293 cells) stably transfected with
the full-length human LH receptor cDNA. Intact dimeric LH, but not LH beta- or
alpha-subunits, evoked specific [Ca2+]i signals. High-resolution fluorescence
(fura-2) video-microscopy demonstrated cell-to-cell variability in [Ca2+]i
signaling responses in individual cells, viz., an all-or-none spike (9%), spike
and-plateau (25%), or plateau (52%) types of temporal signal. Oscillatory [Ca2+]i
responses were observed in 12-14% of LH-stimulated cells unrelated to LH
concentration. The LH dose-response originated by higher concentrations of LH
recruiting more individually responding cells (rather than altering [Ca2+]i
signal amplitude), and eliciting a [Ca2+]i rise more rapidly, i.e., at reduced
latency. Cobalt did not abolish the LH-stimulated [Ca2+]i spike-and-plateau
response, but decreased the percentage of cells with a plateau pattern. Quench
experiments demonstrated influx of Mn2+ following the [Ca2+]i spike, thus
directly documenting divalent cation inflow during the plateau phase. Adenylyl
cyclase activation with forskolin or treatment with a cAMP analog failed to
elicit the biphasic [Ca2+]i response, and pertussis toxin (PTX) did not alter LH
stimulated [Ca2+]i signaling. However, overnight preincubation with LH reduced
the percentage of [Ca2+]i-responding cells following re-exposure to LH to 5.7%
(vs 72% in control), suggesting LH-induced desensitization of the LH-receptor
directed [Ca2+]i signal. In summary, the present studies of human LH receptor
signal transduction at the single-cell level show that increasing concentrations
of LH achieve a dose-dependent intracellular Ca2+ signaling response by
recruiting an increasing number of [Ca2+]i-responding cells, while concomitantly
decreasing the temporal latency of the biphasic [Ca2+]i signal without altering
the amplitude of its spike phase. Prolonged exposure to LH appears to desensitize
the LH receptor-driven [Ca2+]i signal.
PMID- 9549049
TI - Differential effects of estrogen and medroxyprogesterone on basal and stress
induced growth hormone release, IGF-1 levels, and cellular immunity in
postmenopausal women.
AB - We evaluated the influence of continual estrogen replacement therapy (ERT) as
presently practiced by postmenopausal women with conjugated estrogens and
medroxyprogesterone acetate (MPA) on the growth hormone/insulin-like growth
factor-1 (GH/IGF-1) axis and cellular immunity. Thirty-nine postmenopausal women
were evaluated (12 on no replacement, 14 on estrogen only, and 13 on estrogen and
MPA). In the women receiving only conjugated estrogens, increased GH levels and
decreased IGF-1 levels were found, which replicated previous research and
probably reflected estrogen inhibition of hepatic IGF-1 production with a
secondary increase in GH release because of reduced feedback inhibition. In women
taking both MPA and estrogen, GH was increased and the previously observed
estrogen induced decrease in IGF-1 levels was inhibited. In order to determine
the influence of ERT on psycho-social stress-induced GH release, math (mental
stress) and speech (social stress) challenges were utilized, and they produced
significant increases in heart rate in all three groups. The heart rate following
stress was significantly enhanced by estrogen replacement. These stressors also
led to increased GH secretion in the women taking estrogen and MPA, but not in
the other two groups. Gonadal steroids and GH can influence cellular immunity. We
observed that ERT in both groups was associated with significantly enhanced
lymphocyte responsiveness to the T-cell mitogens phytohemaglutinin (PHA) and
Conconavalin A (Con A), and basal GH levels were correlated with the PHA response
in the estrogen only group. ERT did not influence natural killer (NK) cell
activity. We also found significant differences in the steady-state expression of
latent Epstein-Barr virus (EBV) with increased antibody titers in the women in
the estrogen only group and lower antibody titers in the MPA plus estrogen group.
GH levels were correlated with EBV antibody titers in the estrogen plus MPA
group. This study supports the hypothesis that GH and immune modulation can be
influenced by ERT in postmenopausal woman. Given the extant literature on the
immune-enhancing effects of GH, these data suggest that ERT may slow the decline
of GH secretion with aging, an event that has been implicated in
immunosenescence.
PMID- 9549050
TI - Gonadotrophin and prolactin secretion in castrated male sheep following
subcutaneous or intracranial treatment with testicular hormones.
AB - Interactions between testosterone, estradiol, and inhibin in the control of
gonadotrophin secretion in males are poorly understood. Castrated rams were
treated with steroid-free bovine follicular fluid (bFF), testosterone, or
estradiol and for 7 d (2 x 2 x 2 factorial design). Given independently, none of
the exogenous hormones affected follicle-stimulating hormone (FSH)
concentrations, but the combination of one or both steroids with bFF reduced FSH
secretion. Testosterone and estradiol reduced luteinizing hormone (LH) pulse
frequency (there was no synergism), and bFF had no effect. Plasma prolactin
concentrations were not affected by any treatment. To locate the central sites of
steroid action, castrated rams were bilaterally implanted in the preoptic area
(POA), ventromedial nucleus (VMH), or arcuate nucleus (ARC). These implants did
not affect FSH or prolactin concentrations, or LH pulse amplitude. The frequency
of the LH pulses was not affected by testosterone in any site. Estradiol located
in the ARC, but not the POA or VMH, decreased LH pulse frequency. In summary, FSH
secretion is controlled by synergistic interactions between inhibin and estradiol
or testosterone, whereas GnRH/LH pulse frequency is controlled by testicular
steroids. Estradiol acts partly, at least, in the ARC, but the central site of
action, testosterone remains unknown.
PMID- 9549052
TI - Decreased insulin content and secretion in RIN 1046-38 cells overexpressing alpha
2-adrenergic receptors.
AB - Several Gi-protein-coupled receptors normally expressed in islet beta-cells
inhibit insulin secretion on binding of their respective agonists. To study the
effect of supraphysiologic expression of such a receptor in insulin-secreting
beta-cells, we stably transfected cDNA encoding the mouse alpha 2a-adrenergic
receptor into RIN 1046-38 cells. Four different cell lines were selected, each
overexpressing the alpha 2a-adrenergic receptor to varying degrees. Cell lines
showing the highest level of receptor expression showed significantly reduced
insulin content, and reduced basal and stimulated insulin secretion. Pertussis
toxin (PTX) treatment of cells was able to reverse partially the reduced insulin
secretory response. Our results suggest that overexpression of a Gi-protein
coupled receptor in beta-cells causes tonic inhibition of both insulin synthesis
and secretion. Abnormalities in expression or function of such receptors could be
a contributory factor in the impaired insulin secretion present in type II
diabetes.
PMID- 9549051
TI - Nicotinic activation of CRH neurons in extrahypothalamic regions of the rat
brain.
AB - Nicotine is known to have multiple effects on neuroendocrine, autonomic, and
behavioral responses. Its neuroendocrine effect on the stress-responsive hormone,
ACTH, depends on central pathways that act on corticotropin-releasing hormone
(CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN). Other CRH
neurons throughout the brain also are involved in coordinating aspects of the
stress response, but very little is known about the effect of nicotine on CRH
neurons in extrahypothalamic regions that are involved in the autonomic and
behavioral responses to stress. The current study sought to determine the extent
of nicotinic activation of extrahypothalamic CRH neurons, since these neurons may
be involved in mediating the central effects of nicotine. Freely moving rats were
pretreated with a low dose of colchicine, infused with nicotine (0.045 mg/kg/30 s
or 0.135 mg/kg/90 s, i.v.), and cardiac perfused 1 h later. Double-label
immunocytochemistry identified the activated (positive for cFos protein) CRH
neurons in limbic structures (bed nucleus of the stria terminalis [BNST] and
central nucleus of the amygdala [CNA]), the dorsal raphe (DR), and Barrington's
nucleus (BN); comparisons were made to the PVN. In all of these areas, nicotine
activated CRH neurons in a dose-dependent manner, showing differential
sensitivity and efficacy with respect to region. CNA CRH neurons were most
responsive and were maximally stimulated by the low dose of nicotine (62% of CRH
neurons were cFos+, compared to 10-27% of the CRH population in other regions,
including the PVN). Although the BNST also was activated by the low dose, only
the non-CRH+ neurons were involved; in contrast, 41% of the BNST CRH neurons
responded to the higher dose. Nicotinic activation of DR neurons was dose
dependent, with 22% of the CRH neurons activated by the high dose. Few BN neurons
were activated by the low dose of nicotine, but 26% of the CRH population
responded to the higher dose. These results indicate that the effect(s) of
nicotine on the brain may be mediated, in part, by the selective activation of
specific extrahypothalamic regions containing CRH neurons that also are involved
in autonomic and behavioral responses to stress. The large fraction of CRH
neurons responding to the low dose of nicotine in the CNA suggests that this
limbic region may be particularly important in mediating these CNS effects of
nicotine.
PMID- 9549054
TI - Lethal P-lacZ insertion lines expressed during pattern respecification in the
imaginal discs of Drosophila.
AB - The imaginal discs of Drosophila are a useful experimental system in which we can
study the origin and genetic determination of spatial patterns in development.
This involves the separation of the disc-cell population into distinct lineage
compartments, based on clonally transmitted expression states of a number of
known selector genes. However, these commitments can be abrogated and the
compartment boundaries redeployed, when repatterning occurs in cultured disc
fragments. This has so far only been explained using the idea of positional
information. The genetic basis of this property of the imaginal disc system and
its relationship to compartments have not been identified. Here we have screened
over 470 recessive lethal P-lacZ enhancer-trap insertions from the Berkeley
Drosophila Genome Project for expression after cell death, which initiates
pattern respecification in the imaginal discs. The positive lines obtained
identify essential genes that may be important for pattern formation. Most show
patterned imaginal disc expression, and many have maternal or zygotic effects on
embryonic development. One is an allele of schnurri, a gene that encodes a
component of the decapentaplegic (dpp) signal transduction pathway used for
positional signalling in the embryo and in imaginal discs.
PMID- 9549053
TI - Serotonin directly stimulates luteinizing hormone-releasing hormone release from
GT1 cells via 5-HT7 receptors.
AB - Luteinizing hormone-releasing hormone (LHRH release, which serves as the primary
drive to the hypothalamic-pituitary gonadal axis, is controlled by many
neuromediators. Serotonin has been implicated in this regulation. However, it is
unclear whether the central effect of serotonin on LHRH secretion is exerted
directly on LHRH neurosecretory neurons or indirectly via multisynaptic pathways.
The present studies were undertaken in order to examine whether LHRH secretion
from immortalized LHRH cell lines is directly regulated by serotonin and, if so,
to identify the receptor subtype involved. 8-hydroxy-2-(di-n-propylamino)tetralin
(8-OH-DPAT), a 5-HT1A/7 receptor agonist, stimulated LHRH release from GT1-1
cells. This effect was blocked by ritanserin, a 5-HT2/7 receptor antagonist, but
not by SDZ-216-525, a 5-HT1A antagonist. Basal LHRH release was not affected by
the 5-HT2 agonist DOI. Reverse transcription and polymerase chain reaction
technique (RT-PCR) was used in order to identify 5-HT1A and 5-HT7 receptor mRNA
in immortalized LHRH cell lines. GT1-1 cells express mRNA for the 5-HT7, but not
the 5-HT1A receptor subtypes. These results demonstrate a direct stimulatory
effect of serotonin on LHRH release via 5-HT7 receptor.
PMID- 9549055
TI - B-chromosome origin in the endemic New Zealand frog Leiopelma hochstetteri
through sex chromosome devolution.
AB - The endemic New Zealand frog Leiopelma hochstetteri has variable numbers of
mitotically stable B chromosomes. To assess whether the B chromosomes were
derived from the autosome complement, they were isolated by micromanipulation and
their DNA amplified by degenerate oligonucleotide primed PCR. Southern
hybridizations of B chromosome DNA probes to genomic DNA from males and females
characterized by differing numbers of B chromosomes demonstrated that the B
chromosomes were derived from the univalent W sex chromosome characteristic of
North Island populations. The presence of homologous B chromosome specific
sequences from geographically distinct populations indicates a single origin of
the B chromosomes. Furthermore, a primitive homology shared by B chromosomes and
the W sex chromosome from an ancestral WZ/ZZ karyotype, which is still present in
frogs from Great Barrier Island, shows that the B chromosomes originated soon
after the univalent W sex chromosome had originated. Sequence analysis revealed
that B chromosome DNA is composed of repeat sequences and has the potential to
form stable hairpin structures. The molecular dynamics of these structures may
reflect an inherent propensity to undergo rapid change in nucleotide sequence and
chromosome structure.
PMID- 9549056
TI - An apparent case of nonsymmetrical and sustained strand-specific hemimethylation
in the Dc8 gene of carrot.
AB - The Dc8 gene of carrot (Daucus carota L.) shows differential expression during
embryo development. Changes in methylation patterns of a segment of about 500 bp
(from base +120 to base -446) of Dc8 allele 6 were investigated by treating
genomic DNA, extracted from embryogenic callus at different stages of
development, with sodium bisulfite to modify nonmethylated cytosines. Following
asymmetric (strand-specific) amplification, base sequences for samples from each
developmental stage were determined for each strand directly from the PCR
products or from cloned PCR products. Different methylation patterns were
detected in the two strands. The 5' to 3' sense (coding) strand was almost
completely nonmethylated, whereas almost all the cytosines in the 3' to 5'
(template) strand were methylated. By 71 days after transfer to embryo-inducing
medium, few methylcytosines remained; those that were present were generally near
the TATA box or in a region beyond -300. The cytosines that were methylated were
not limited to CG or CNG sequences. The difference in the extent of methylation
between the two complementary strands implies either that there is a mechanism
for strand-specific methylation, or that complementary sequences can differ
greatly in sensitivity to bisulfite treatment or PCR amplification.
PMID- 9549057
TI - Characterization of MboI satellites in Cirrhina mrigala and Clarias batrachus
(Pisces).
AB - We have cloned and characterized two highly reiterated, tandemly repeated, and
A+T rich MboI DNA fragments, one in Cirrhina mrigala (Cyprinidae), with a monomer
size of 266 bp, and one in Clarias batrachus (Clariidae), with a monomer size of
227 bp. The MboI fragment in C. mrigala is species-specific and absent in other
carps, such as Catla catla and Labeo rohita. The MboI fragment in C. batrachus
was also present in two other catfishes tested, namely Clarias gariepinus and
Heteropneustes fossilis. In C, mrigala x C. catla and C. mrigala x L. rohita
hybrids, the C. mrigala specific MboI fragment is inherited uniparentally. In the
reciprocal hybrids of C. batrachus x H. fossilis, the satellite ladder contains
the bands of both parental species. The MboI satellite of carp may be useful in
genetic introgression analysis and that of catfish in distinguishing between
gynogenetic progeny and true hybrids.
PMID- 9549059
TI - Collinearity between a 30-centimorgan segment of Arabidopsis thaliana chromosome
4 and duplicated regions within the Brassica napus genome.
AB - Arabidopsis thaliana (the model dicotyledonous plant) is closely related to
Brassica crop species. Genome collinearity, or conservation of marker order,
between Brassica napus (oilseed rape) and A. thaliana was assessed over a 7.5-Mbp
region of the long arm of A. thaliana chromosome 4, equivalent to 30 cM.
Estimates of copy number indicated that sequences present in a single copy in the
haploid genome of A. thaliana (n = 5) were present in 2-8 copies in the haploid
genome of B. napus (n = 19), while sequences present in multiple copies in A.
thaliana were present in over 10 copies in B. napus. Genetic mapping in B. napus
of DNA markers derived from a segment of A. thaliana chromosome 4 revealed
duplicated homologous segments in the B. napus genome. Physical mapping in A.
thaliana of homologues of Brassica clones derived from these regions confirmed
the identity of six duplicated segments with substantial homology to the 7.5-Mbp
region of chromosome 4 in A. thaliana. These six duplicated Brassica regions (on
average 22 cM in length) are collinear, except that two of the six copies contain
the same large internal inversion. These results have encouraging implications
for the feasibility of shuttling between the physical map of A. thaliana and
genetic maps of Brassica species, for identifying candidate genes and for map
based gene cloning in Brassica crops.
PMID- 9549060
TI - Characterization of a microsatellite in the promoter region of the IGF1 gene in
domestic horses and other equids.
AB - Insulin-like growth factor 1 (IGF1) regulates growth and metabolic functions in
vertebrates. A dinucleotide repeat sequence located at the promoter region of the
IGF1 gene has been reported in several vertebrate species and may affect the
control of the transcriptional activity of this gene. The genotypes of animals
from seven horse breeds were determined in order to study the potential
association of allelic forms of this microsatellite with adult body size
differences found in domestic horses. Among these breeds, five alleles were
found. Breed-specific differences in adult body size could not be attributed to
the presence or absence of any of the alleles observed. In addition, animals
representing five other equid species were typed. Examples of apparent species
specific alleles were found. However, overlapping polymorphic size ranges
preclude this microsatellite from being an absolute identifier for species or
hybrid status in equids. The polymorphisms found at this IGF1 locus are useful
for synteny and linkage mapping.
PMID- 9549061
TI - Chromosome pairing in inter-racial hybrids of the house musk shrew (Suncus
murinus, Insectivora, Soricidae).
AB - Two chromosome races of the house shrew Suncus murinus that differ from each
other for five Robertsonian translocations (8.17, 9.13, 10.12, 11.16, and 14.15),
heterochromatic insertions in chromosomes 7 and X, and multiple rearrangements in
the Y chromosome were crossed and then intercrossed in captivity to produce a
hybrid stock. Electron-microscopic analysis of synaptonemal complexes in fertile
and sterile hybrid males was carried out. Meiosis in sterile males did not
progress beyond pachytene and was severely disrupted. Meiotic arrest was not
determined by structural heterozygosity: heterozygotes for all variant
chromosomes distinguishing two parental races were found in both sterile and
fertile male hybrids. Fertile hybrids demonstrated an orderly pairing of all
chromosomes. In heterozygotes for Robertsonian fusions, completely paired
trivalents were formed between the Robertsonian metacentrics and homologous
acrocentrics. In heterozygotes for chromosome 7, bivalents with a small buckle
were observed in a small fraction of pachytene cells. No differences were found
in the morphology and pairing pattern of sex bivalents, composed of the X and Y
chromosomes derived from the same or different parental races. Univalents,
multivalents, and associations between X and Y chromosomes and autosomal
trivalents, as well as associations of autosomal trivalents with each other, were
observed in a small fraction of the pachytene cells of fertile males. Our results
indicate that the system controlling male sterility in interracial hybrids of S.
murinus is of genic rather than of chromosomal type.
PMID- 9549062
TI - Development of sequence characterized DNA markers linked to a dominant
verticillium wilt resistance gene in tomato.
AB - Sequences were determined for codominant RAPD markers closely linked to the Ve
locus, a dominant verticillium wilt resistance gene in tomato. Analysis of the
sequences linked to Ve and ve revealed a perfectly homologous sequence with a
central polymorphic region comprising 79 nucleotide substitutions, insertions,
and deletions. Codominant and allele-specific SCARs were developed using
conserved and polymorphic sequences linked to the Ve locus. High resolution
linkage analysis using F2 progeny segregating for resistance and marker-assisted
selection indicated that linkage between the genetic markers and the Ve locus is
less than 0.67 +/- 0.49 cM. Sequences were useful in determining the molecular
structure of a polymorphic genomic region closely linked to the Ve locus and in
developing genetic markers that facilitated marker-assisted selection of the
resistant, susceptible, heterozygous, and homozygous genotypes.
PMID- 9549063
TI - [Natural hybridization between two subspecies of the house mouse, Mus musculus
domesticus and Mus musculus castaneus, near Lake Casitas, California].
AB - The house mouse Mus musculus is a polytypic species, distributed worldwide, with
three main subspecies: M. m. musculus in the North-East of Eurasia, M. m.
castaneus in South-East Asia, and M. m. domesticus in Europe, the Near-East, and
Africa. This last subspecies may also be found in Australia and the Americas,
where it was brought by European colonization. Previous studies, however, have
shown the presence of specific antiviral determinants of Asian origin in a mouse
population at Lake Casitas, California. In this study, an analysis of the
variability at 35 enzyme loci demonstrates the hybrid nature of this Californian
population intermediate between M. m. castaneus and M. m. musculus. Restriction
fragment length polymorphisms of two fragments of the mitochondrial DNA also
confirm unambiguously the presence of two types of matrilines in comparable
frequencies in our sample. Nevertheless, the study of a subspecies-specific Y
chromosome microdeletion in the Zfy2 gene reveals only the M. m. domesticus
haplotype at Lake Casitas, a phenomenon comparable with the one observed in other
hybrid zones of the M. musculus complex. These findings testify once more that
genetic exchanges between subspecies inside the broader M. musculus gene pool are
still possible.
PMID- 9549064
TI - Identification, characterization, and mapping of Ecm1, a locus affecting
extracellular matrix production and lesion size in Cochliobolus heterostrophus.
AB - A mutant of Cochliobolus heterostrophus lacking the outer layer of extracellular
matrix around its germ tubes and hyphae was obtained by mutagenizing protoplasts.
The mutant not only lacks the outer matrix, but also produces much smaller
lesions on corn leaves than nonmutant strains; the area of mutant lesions
averages 0.6 mm2 compared with 5.8 mm2 for nonmutant lesions. Genetic analysis
demonstrated that the failure to produce the outer matrix cosegregates with the
reduced lesion size, indicating that the two traits are controlled by the same
locus, designated Ecm1 (Extracellular Matrix Deficient). The mutant retains
normal growth on media and normal abilities to germinate, form appressoria, and
penetrate corn leaves. This indicates that the outer matrix is not necessary for
infection prior to entrance of the fungus into the leaf. It also indicates that
the pathogenicity defect in this mutant is manifested after penetration. To
facilitate future tests of whether the pathogenicity defect is caused by the lack
of the outer matrix, Ecm1 was mapped. Seven markers linked to Ecm1 were found by
analysis of amplified fragment length polymorphisms. Ecm1 maps to chromosome 4;
the closest markers to Ecm1 are 5 cM distant, which is estimated to represent
about 115 kb.
PMID- 9549065
TI - Genome-specific repetitive DNA and RAPD markers for genome identification in
Elymus and Hordelymus.
AB - We have developed RFLP and RAPD markers specific for the genomes involved in the
evolution of Elymus species, i.e., the St, Y, H, P, and W genomes. Two P genome
specific repetitive DNA sequences, pAgc1 (350 bp) and pAgc30 (458 bp), and three
W genome specific sequences, pAuv3 (221 bp), pAuv7 (200 bp), and pAuv13 (207 bp),
were isolated from the genomes of Agropyron cristatum and Australopyrum
velutinum, respectively. Attempts to find Y genome specific sequences were not
successful. Primary-structure analysis demonstrated that pAgc1 (P genome) and
pAgc30 (P genome) share 81% similarity over a 227-bp stretch. The three W genome
specific sequences were also highly homologous. Sequence comparison analysis
revealed no homology to sequences in the EMBL-GenBank databases. Three to four
genome-specific RAPD markers were found for each of the five genomes. Genome
specific bands were cloned and demonstrated to be mainly low-copy sequences
present in various Triticeae species. The RFLP and RAPD markers obtained,
together with the previously described H and St genome specific clones pHch2 and
pP1Taq2.5 and the Ns genome specific RAPD markers were used to investigate the
genomic composition of a few Elymus species and Hordelymus europaeus, whose
genome formulas were unknown. Our results demonstrate that only three of eight
Elymus species examined (the tetraploid species Elymus grandis and the hexaploid
species Elymus caesifolius and Elymus borianus) really belong to Elymus.
PMID- 9549066
TI - Nucleotide sequence and chromosomal mapping of the 5S rDNA repeat of the
crustacean Proasellus coxalis.
AB - In this investigation we analysed the 5S rRNA genes of the isopod crustacean
Proasellus coxalis, 5S rDNA hybridization of digested genomic DNA and
amplification by PCR demonstrate that these genes are organized in tandem repeats
of 589 bp, 120 of which represent the coding sequence and 469 the spacer
sequence. Proasellus coxalis is the first crustacean species in which 5S rRNA
genes have been found tandemly arranged without being linked to other repeated
genes. The PCR product has been used as a probe in FISH to locate the 5S rRNA
genes on two chromosome pairs of the P. coxalis karyotype. Comparison of the 5S
rRNA sequence of this species with previously published sequences of six other
crustacean species shows the existence of a good correlation between phylogenetic
relationships and sequence identity.
PMID- 9549067
TI - H genome specific repetitive sequence, pEt2, of Elymus trachycaulus in part of
Afa family of Triticeae.
AB - The H genome specific repetitive sequence of Elymus trachycaulus, pEt2, consists
of three units of a 337-339 bp repeat aligned in tandem. The sequence is
homologous to Afa-family sequences that are widely distributed in the genomes of
Triticeae (Gramineae) species.
PMID- 9549068
TI - Reversed-phase ion-pair liquid chromatographic determination of chlorophacinone
and diphacinone in steam-rolled oat baits and steam-rolled oat/wax baits.
AB - A reversed-phase ion-pair liquid chromatographic (LC) method was developed for
analysis of steam-rolled oat (SRO) baits fortified with either chlorophacinone or
diphacinone. Baits were prepared with and without paraffin wax. Chlorophacinone
or diphacinone was extracted from wax-free SRO baits with 5 mM tetrabutylammonium
phosphate methanolic ion-pairing solution. Wax baits were initially extracted
with petroleum ether and then cleaned up by liquid extraction into methanolic ion
pairing solution containing 20% water. SRO extracts were analyzed with reversed
phase ion-pair LC. Chlorophacinone and diphacinone were quantified by UV
absorption at 325 nm. Recoveries from SRO fortified with chlorophacinone at 25
and 150 micrograms/g were 90.7 and 90.8%, respectively, whereas for diphacinone
at the same levels, recoveries were 93.5 and 92.3%, respectively. Recoveries from
wax baits fortified at 25 and 75 micrograms/g chlorophacinone were 98.5 and 100%,
respectively, whereas for diphacinone at the same levels, recoveries were 93.6
and 98.0%, respectively. Method limits of detection for chlorophacinone and
diphacinone in SRO baits were estimated to be 1.0 and 0.76 micrograms/g,
respectively. Method limits of detection for chlorophacinone and diphacinone in
wax baits were estimated to be 4.2 and 2.8 micrograms/g, respectively.
PMID- 9549069
TI - Procedure for detecting and confirming pentobarbital residues in dog food by gas
chromatography/mass spectrometry.
AB - The method described detects and confirms presence of pentobarbital residues in
dry, extruded feeds at concentrations of 5-20 ppb. Dried feed is ground to a
uniform powder and shaken overnight in methanol. A portion of the methanolic
extract is evaporated, and the residue is reconstituted in phosphate-buffered
saline. The aqueous extract is cleaned with a solid-phase extraction cartridge
designed to extract barbiturate residues from biological matrixes. Dimethyl
sulfoxide, tetramethylammonium hydroxide, and iodomethane are added to derivatize
pentobarbital, 1,3-Dimethyl-pentobarbital is then acidified with dilute
hydrochloric acid and extracted with isooctane. The organic layer is transferred
and evaporated under a stream of nitrogen. The residue is reconstituted in a
small volume of ethyl acetate for analysis by gas chromatography/mass
spectrometry. The limit of detection is approximately 0.7 ppb. The method was
validated with pentobarbital-fortified feed samples containing high
concentrations of meat and bone meal.
PMID- 9549070
TI - A rapid and selective method for determining potential nitrosating agents in
cosmetic products by chemiluminescence detection of nitric oxide.
AB - A method was developed for rapid and selective determination of potential
nitrosating agents at the part-per-billion level in cosmetic products. These
compounds are chemically reduced to nitric oxide, which is determined by its
chemiluminescent reaction with ozone. Suspended materials and colors in cosmetic
products do not interfere. Hence their removal before analysis is not required. A
detection limit of 33 ppb, calculated as nitrite, was obtained. No false-positive
interferences were observed from antifoaming agents, several N-nitroso compounds,
and nitrate up to 20 ppm. Among cosmetic products surveyed, potential nitrosating
agents were found at levels ranging from 113 to 5021 ppb. No consistent
relationship was found between levels of potential nitrosating agents and N
nitrosamines in the same products. However, the highest levels of nitrosating
agents were most often associated with the highest levels of N-nitrosamines known
to be present in the products.
PMID- 9549071
TI - Determination of reserpine and rescinnamine in Rauwolfia serpentina powders and
tablets: collaborative study.
AB - A liquid chromatographic (LC) method for determining reserpine and rescinnamine
in Rauwolfia serpentine powders and tablets, which uses fluorescence detection,
was subjected to a collaborative study. The procedure for extraction and
purification is a simplified version of that used in the current official method
for analysis of these products. LC separations are performed on a normal-phase
column. The mobile phase is methanol to which a small volume of an aqueous
solution of 1-pentanesulfonic acid sodium salt can be added to achieve desired
elution characteristics. Reserpine and rescinnamine elute at approximately the
same time but can be individually quantitated by appropriate settings of the
fluorescence detector. Reserpine is determined at an excitation wavelength of 280
nm and an emission wavelength of 360 nm, because rescinnamine is completely non
fluorescent at these wavelengths. Rescinnamine is determined at an excitation
wavelength of 330 nm and an emission wavelength of 435 nm, because reserpine is
completely nonfluorescent at these wavelengths. The following materials were used
for the study: one sample of United States Pharmacopeia (USP) standard R.
serpentine powder, one tablet type labeled as containing 100 mg R. serpentine and
2 tablet types labeled as containing 50 mg R. serpentine. For each of the 4
materials, 2 pairs of blind duplicates were prepared. Three materials were
analyzed in duplicate by 8 laboratories. One of the 2 tablets labeled to contain
50 mg R. serpentine was analyzed only by 7 of 8 participating laboratories.
Average combined content of reserpine and rescinnamine was 0.144% for the USP raw
material and 0.132, 0.135, and 0.137% for the 3 commercial tablets.
Reproducibility relative standard deviation values were 5.72, 5.93, 8.61, and
3.48% and repeatability relative standard deviation values were 2.57, 4.87, 3.19,
and 1.99% for the 4 samples. The Associate Referee conducted a study to determine
recoveries of reserpine plus rescinnamine by this method from mixtures simulating
sample extracts. Average recovery of 15 determinations was 100.1%, with a
relative standard deviation of 1.3%. The LC method for determination of reserpine
and rescinnamine in R. serpentine powders and tablets has been adopted first
action by AOAC INTERNATIONAL.
PMID- 9549072
TI - Simultaneous liquid chromatographic analysis of the beta-lactam antibiotics
cefazolin, cefadroxil, cephalexin, ampicillin, and cephradine in solution.
AB - A liquid chromatographic method was developed for the determination of nanogram
quantities of 5 broad-spectrum structurally related beta-lactam antibiotics
(cefazolin, cefadroxil, cephalexin, cephradine, and ampicillin) in solution. The
method uses a C18 reversed-phase column, UV absorption (240 nm) detection, and an
aqueous mobile phase containing isopropyl alcohol and acetic acid. Relative
resolution between the antibiotic peaks ranged from 1.7 to 5.9 for all peaks.
Chromatographic retention times were 2.97, 3.92, 4.57, 5.37, and 6.56 min for
cefazolin, cefadroxil, cephalexin, ampicillin, and cephradine, respectively.
Accuracy, precision, linearity, and long term analytical reproducibility were
determined by statistical analysis. Use of the proposed method to evaluate the
degradation of cephradine solutions stored at room temperature illustrated its
potential as a stability-indicating assay.
PMID- 9549073
TI - Optical immunobiosensor assay for determining enrofloxacin and ciprofloxacin in
bovine milk.
AB - A rapid, sensitive optical immunobiosensor assay was developed and used to
determine enrofloxacin and its main metabolite, ciprofloxacin, in milk from
healthy cows and cows with clinical signs of mastitis after intramuscular
administration of enrofloxacin. Liquid chromatography (LC) was used to confirm
results of the biosensor assay. Despite incomplete cross-reactivity between
polyclonal enrofloxacin antibodies and ciprofloxacin, the biosensor assay could
be used for semiquantitative analysis of the sum of the 2 substances. LC analysis
showed that ciprofloxacin persisted at levels exceeding the expected future
maximum residue limit in milk for several days after the end of the withdrawal
period.
PMID- 9549074
TI - Comparison of monolayer and bilayer plates used in antibiotic assay.
AB - Standard curves of 5 antibiotics were determined in an antibiotic assay using
bilayer and monolayer agar plates and AOAC-specified test organisms and agar
media. Micrococcus luteus ATCC 9341a and antibiotic medium No. 2 were used to
prepare the penicillin G standard curve. The same organism and antibiotic medium
No. 11 were used to prepare the erythromycin standard curve. Standard curves for
streptomycin, tetracycline, and gentamicin were prepared, respectively, with
antibiotic medium No. 5 and Bacillus subtilis ATCC 6633, antibiotic medium No. 8
and B. cereus ATCC 11778, and antibiotic medium No. 11 and Staphylococcus
epidermidis ATCC 12228. Assays of inhibition by meat fortified with penicillin,
streptomycin, gentamicin, tetracycline, erythromycin also were performed on
monolayer and bilayer plates. Differences in standard curves and inhibitory
responses obtained with monolayer and bilayer plates were < 10%. Thus, monolayer
plates are acceptable for use in analyses of meat and poultry for antibiotics
residues, with savings in laboratory resources and time.
PMID- 9549075
TI - Direct 24-hour presumptive enumeration of Escherichia coli O157:H7 in foods using
hydrophobic grid membrane filter followed by serological confirmation:
collaborative study.
AB - Fifteen laboratories took part in a collaborative study to validate a method for
enumerating Escherichia coli O157:H7. The method is based on use of a hydrophobic
grid membrane filter and consists of 24 h presumptive enumeration on SD-39 Agar
and serological confirmation to yield a confirmed E. coli O157:H7 count. Six food
products were analyzed: pasteurized apple cider, pasteurized 2% milk, cottage
cheese, cooked ground pork, raw ground beef, and frozen whole egg. The test
method produced significantly higher confirmed count results than did the
reference method for milk, pork, and beef. Test method results were numerically
higher than but statistically equivalent to reference method results for cheese,
cider, and egg. The test method produced lower repeatability and reproducibility
values than did the reference method for most food/inoculation level combinations
and values very similar to those of the reference method for the remaining
combinations. Overall, 94% of presumptive positive isolates from the test method
were confirmed serologically as E coli O157:H7, and 98% of these were also
biochemically typical of E. coli O157:H7 (completed test). Corresponding rates
for the reference method were 69 and 98%, respectively. On the basis of the
results of this collaborative study and the precollaborative study that preceded
it, it is recommended that this method be adopted official first action for
enumeration of E. coli O157:H7 in meats, poultry, dairy foods, infant formula,
liquid eggs, mayonnaise, and apple cider.
PMID- 9549076
TI - LOCATE enzyme-linked immunosorbent assay for detection of Salmonella in food:
collaborative study.
AB - A collaborative study was performed in 27 laboratories to validate the enzyme
linked immunosorbent procedure LOCATE for rapid detection of Salmonella in foods.
Results were read visually and with a microtiter plate reader. The LOCATE method
was compared with the Bacteriological Analytical Manual (BAM)/AOAC INTERNATIONAL
culture method for detecting Salmonella in 6 foods: milk chocolate, nonfat dry
milk, dried whole egg, soy flour, ground black pepper, and ground raw turkey. Two
foods--dried whole egg and black pepper--required repeat rounds because
insufficient data sets were produced initially (AOAC INTERNATIONAL stipulates a
minimum of 15 sets per food type). Each laboratory tested one or more of the 6
foods. A total of 1 439 samples were analyzed, and no significant differences (P
< 0.05) were observed between LOCATE with either visual or reader detection and
BAM/AOAC INTERNATIONAL results. The LOCATE screening method with visual or reader
detection is recommended for Official First Action Approval.
PMID- 9549077
TI - Comparison of the VITEK Gram-Negative Identification Card and an enhanced version
for identification of Salmonella, Escherichia coli, and other Enterobacteriaceae:
method modification.
AB - The VITEK Gram-Negative Identification Card (GNI) was compared to an enhanced
version of the test kit, the GNI + Card. The GNI Card is an official AOAC method
(991.13) for identification of Salmonella, Escherichia coli, and other
Enterobacteriaceae in foods. In this comparison 5 replicates of 124 gram-negative
stock culture strains were evaluated to determine equivalency. Isolates were
obtained primarily from food sources, with 108 of the isolates representing 15
genera within the family Enterobacteriaceae. Overall agreement between the GNI
Card and the GNI + Card was 98.2%. Of the 23 strains of Salmonella tested, the
longest identification time for the GNI Card was 10 h, with 43.5% of the strains
identifying in 4 h or less. The longest identification time of the same
Salmonella strains tested with the GNI + Card was 8 h, with 95.7% of the strains
identifying within 4 h. The GNI + Card provided increased speed of identification
while retaining the accuracy of the GNI Card. The GNI method for identifying
Salmonella, Escherichia coli, and other Enterobacteriaceae was approved as a
method modification by AOAC INTERNATIONAL.
PMID- 9549078
TI - Determination of diarrheic shellfish toxins in mussels by microliquid
chromatography-tandem mass spectrometry.
AB - A fast, sensitive, and specific procedure for determining toxins that cause
diarrheic shellfish poisoning (DSP) using microliquid chromatography coupled with
tandem mass spectrometry (micro-LC-MS-MS) is reported. The lipophylic polyether
acidic toxins okadaic acid (OA), its isomer dinophysistoxin-2 (DTX-2), the 35
methylokadaic acid dinophysistoxin-1 (DTX-1), and the novel toxin dinophysistoxin
1B (DTX-2B; recently isolated from Irish mussels) were extracted from shellfish
tissues with acetone and chromatographed by isocratic elution at 10 microL/min
with CH3 CN-H2O, 80 + 20 (v/v), containing 0.1% trifluoroacetic acid, through a
C18 reversed-phase column (1.0 mm id). The chromatograph is coupled via an ion
spray interface to an atmospheric pressure ionization source. Collision-induced
dissociation (CID) ion mass spectra of the protonated molecule, [M + H]+, at m/z
805 for OA, DTX-2, and DTX-2B and at m/z 819 for DTX-1, were obtained in MS-MS
experiments to identify 2 diagnostic fragment ions for each analyte that could be
used for selected-reaction-monitoring (SRM) micro-LC-MS-MS analysis. The CID
spectrum of DTX-2B confirmed it to be a new OA isomer, like DTX-2. Standard
curves obtained by SRM micro-LC-MS-MS were linear (r2 > or = 0.9992) over the
range 0.05-1.00 micrograms/mL (i.e., 0.10-2.00 micrograms toxin/g
hepatopancreas), and a detection limit of 15 pg/injection was obtained for each
DSP toxin. Average recoveries ranged from 95 to 101%, and coefficients of
variation ranged from 1.8 to 3.4%. This novel SRM micro-LC-MS-MS method was used
to confirm acidic DSP toxins in Irish and Italian toxic mussels. It offers a high
degree of specificity because analyte confirmation is based on retention time,
molecular weight, structural information obtained from the presence of 2
diagnostic fragments for each analyte, and ion ratios. OA was found in both Irish
(< or = 0.7 micrograms/g hepatopancreas) and Italian (< or = 1.5 micrograms/g
hepatopancreas) mussels. DTX-1 was found only in Italian mussels (< or = 0.3
micrograms/g hepatopancreas). DTX-2 (< or = 6.1 micrograms/g hepatopancreas) and
DTX-2B (< or = 0.08 micrograms/hepatopancreas) were unique to Irish shellfish.
PMID- 9549079
TI - One-step solid-phase extraction cleanup and fluorometric analysis of
deoxynivalenol in grains.
AB - A rapid, quantitative, inexpensive, efficient method was developed to determine
deoxynivalenol (DON) in wheat, barley, corn, wheat middlings, wheat flour, bran,
malted barley, and oats. Samples are ground and extracted with acetonitrile-water
(86 + 14). A portion of the extract is cleaned up by passage through a MycoSep
No. 225 column, evaporated to dryness, and derivatized with zirconyl nitrate and
ethylenediamine in methanol. The resulting fluorescent derivative of DON is
identified and quantitated with a calibrated fluorometer containing a broad
wavelength pulsed xenon light source. This method quantitated DON concentrations
from 0.5 to 50 ppm without dilution and was linear when applied to samples of
noncontaminated wheat spiked at 0.5, 5, 10, 25, and 50 micrograms DON/g.
Correlation coefficients of the method with LC for multiple analyses (n > or = 14
for each commodity) applied to wheat, corn, barley, wheat flour, and wheat
middlings were 0.99, 0.99, 0.99, 0.93, and 0.98, respectively. Individual
analyses were conducted in < 30 min, and 24 samples were analyzed in 2 h.
PMID- 9549080
TI - Zero control reference materials for infant formula methods development.
AB - A zero control reference material (ZRM) for milk and soy-based infant formula was
manufactured and characterized. The ZRM was free of retinyl palmitate and all-rac
alpha-tocopheryl acetate. The composition was similar to commercially available
infant formula. The ZRM provides a valuable tool to ascertain method performance.
PMID- 9549081
TI - Optimization of selenium determination in human milk and whole blood by flow
injection hydride atomic absorption spectrometry.
AB - A flow injection hydride atomic absorption spectrometric (FI-HAAS) method was
developed for determining selenium in human milk and whole blood after microwave
digestion of the sample. The sample (2 mL human milk or 0.25 mL blood) was
introduced into the microwave vessel with 1.5 mL HNO3 and 0.25 mL H2O2 and 300 W
(4 min) and 600 W (4 min) were applied. The digestion was completed by heating to
140 degrees C (2-3 h). Se (VI) was reduced to Se (IV) with hydrochloric acid. The
instrumental conditions for FI-HAAS (concentrations of reducing agent and carrier
acid, flow rate of argon carrier gas, and sample volume injected) were optimized.
The detection limit of the proposed method was 0.23 ng/mL (assay) or 115 pg Se
(absolute) in biological samples (1.15 ng/mL milk, 10.4 ng/mL blood). The
precision values were 5.0% for milk and 4.0% for blood. The accuracy was
evaluated with 2 reference materials, National Institute of Standards and
Technology Non-Fat Milk Powder (found: 104.3 +/- 7.2 ng/g, certified: 110 +/- 10
ng/g) and Whole Blood Seronorm (found: 81 +/- 7.3 ng/mL, reference: 83 +/- 4
ng/mL). The results show the suitability of the method for selenium determination
in human milk and whole blood. The method was applied to whole blood samples
obtained from pregnant women and to human milk.
PMID- 9549082
TI - Ivermectin quantitation with an abamectin internal standard.
AB - The potent antiparasitic ivermectin is detected at low concentrations (ng/g) in
liver and muscle tissue by liquid chromatography after conversion to a
fluorescent derivative with 1-methylimidazole and trifluoroacetic anhydride. This
acetylation reaction can be compromised by residual water that leads to decreased
yields. Yields of derivatives of ivermectin and abamectin, a related avermectin,
are identical under all circumstances tested. Use of abamectin as an internal
standard eliminates derivative yield as a source of analytical variation.
PMID- 9549083
TI - Solid-phase extraction cleanup for ivermectin in liver tissue.
AB - Extraction of liver tissue with organic solvent produces coextractants with
compounds of interest. The solid-phase extraction (SPE) cleanup of liver tissue
developed for ivermectin removes nonpolar coextractants. Liver extract that has
been reduced to dryness is reconstituted in 0.5 mL acetonitrile. The mixture is
passed through 0.1 g C18 SPE column, and the eluate is collected. The column is
eluted further with 2 mL acetonitrile. Combined eluates are derivatized with 1
methylimidazole and trifluoroacetic anhydride, and the ivermectin derivative is
determined by liquid chromatography with fluorescence detection.
PMID- 9549084
TI - Determination of 4-hexylresorcinol in crab meat.
AB - A method is described for determining 4-hexylresorcinol in crab meat. 4
Hexylresorcinol is used to prevent melanosis in shrimp, and the same use has been
proposed for crab meat. Because 4-hexylresorcinol may be added illegally to crab
meat as a preservative, consumer protection requires that residues of the
compound be monitored in crab meat. 4-Hexylresorcinol is extracted from crab meat
with acetonitrile. After dilution with water, the extract is passed through a C18
solid-phase extraction column and 4-hexylresorcinol is eluted from the column
with ethanol. The compound is determined by reversed-phase liquid chromatography
with diode array detection at 206 nm. Limit of quantitation is 1.0 microgram/g.
Mean recovery in the range 1-20 micrograms/g is 89%, with a relative standard
deviation of 6.3.
PMID- 9549085
TI - Microwave power absorption in a multilayered cylindrical model of man near a flat
reflector.
AB - There are usually objects in the vicinity when a person is exposed to
electromagnetic waves. It is exceedingly difficult to calculate the whole-body
average specific absorption rate (SAR) in the microwave frequency region using a
realistic heterogeneous model of man. In this paper, we use a multilayered
cylinder model to numerically examine the average SAR of an adult standing near a
flat reflector exposed to microwave energy. We also offer a comparison with
existing data from a realistic model for an E-polarized wave below 600MHz.
PMID- 9549086
TI - Immunohistochemical identification of the cytoskeletal elements in the notochord
cells of bony fishes.
AB - The medulla of the unconstricted notochords of the shortnose sturgeon, Acipenser
brevirostratus, and African lungfish, Protopterus annectens, and the cellular
component of the intervertebral joint tissue of the teleost fish, Perca
flavescens, are comprised of cells with a large central vacuole. Previous studies
on the fine structure of this tissue revealed that the cytoplasm surrounding
these vacuoles consists of 10-nm-diameter intermediate filaments. Since in
mammals there are a large number of tissue-specific types of intermediate
filaments, this study uses antibodies to mammalian intermediate filaments to
determine the type of filaments present in the notochord cells of bony fishes.
Positive labeling using a polyclonal antibody to human skin keratins is observed
in the cytoplasm of the notochord cells in the intervertebral tissues of Perca.
These tissues are also probed with the AE series antibodies that label keratins
found in mammalian epithelial cells. In both Protopterus and Acipenser the
peripheral cytoplasm of the notochord cells is labeled with all three AE
antibodies. In Perca only the AE3 antibody probe produces positive staining.
These staining patterns are consistent with previous studies on the localization
of cytokeratins in fish tissues and indicate that the intermediate filaments in
the notochord cells of bony fishes are immunologically similar to the mammalian
keratins.
PMID- 9549087
TI - The structural basis of molecular adaptation.
AB - The study of molecular adaptation has long been fraught with difficulties, not
the least of which is identifying out of hundreds of amino acid replacements
those few directly responsible for major adaptations. Six studies are used to
illustrate how phylogenies, site-directed mutagenesis, and a knowledge of protein
structure combine to provide much deeper insights into the adaptive process than
has hitherto been possible. Ancient genes can be reconstructed, and the
phenotypes can be compared to modern proteins. Out of hundreds of amino acid
replacements accumulated over billions of years those few responsible for
discriminating between alternative substrates are identified. An amino acid
replacement of modest effect at the molecular level causes a dramatic expansion
in an ecological niche. These and other topics are creating the emerging field of
"paleomolecular biochemistry."
PMID- 9549088
TI - Phylogeny and biogeography of ratite birds inferred from DNA sequences of the
mitochondrial ribosomal genes.
AB - The origin of the flightless ratite birds of the southern continents has been
debated for over a century. Whether dispersal or vicariance (continental breakup)
best explains their origin depends largely on their phylogenetic relationships.
No consensus has been reached on this issue despite many morphological and
molecular studies. To address this question further we sequenced a 2.8-kb region
of mitochondrial DNA containing the ribosomal genes in representative ratites and
a tinamou. Phylogenetic analyses indicate that Struthio (Africa) is basal and
Rhea (South America) clusters with living Australasian ratites. This phylogeny
agrees with transferrin and DNA hybridization studies but not with sequence
analyses of some protein-coding genes. These results also require reevaluation of
the phylogenetic position of the extinct moas of New Zealand. We propose a new
hypothesis for the origin of ratites that combines elements of dispersal and
vicariance.
PMID- 9549089
TI - Improved tests for heterogeneity across a region of DNA sequence in the ratio of
polymorphism to divergence.
AB - The neutral theory of molecular evolution predicts that the ratio of
polymorphisms to fixed differences should be fairly uniform across a region of
DNA sequence. Significant heterogeneity in this ratio can indicate the effects of
balancing selection, selective sweeps, mildly deleterious mutations, or
background selection. Comparing an observed heterogeneity statistic with
simulations of the heterogeneity resulting from random phylogenetic and sampling
variation provides a test of the statistical significance of the observed
pattern. When simulated data sets containing heterogeneity in the polymorphism-to
divergence ratio are examined, different statistics are most powerful for
detecting different patterns of heterogeneity. The number of runs is most
powerful for detecting patterns containing several peaks of polymorphism; the
Kolmogorov-Smirnov statistic is most powerful for detecting patterns in which one
end of the gene has high polymorphism and the other end has low polymorphism; and
a newly developed statistic, the mean sliding G statistic, is most powerful for
detecting patterns containing one or two peaks of polymorphism with reduced
polymorphism on either side. Nine out of 27 genes from the Drosophila
melanogaster subgroup exhibit heterogeneity that is significant under at least
one of these three tests, with five of the nine remaining significant after a
correction for multiple comparisons, suggesting that detectable evidence for the
effects of some kind of selection is fairly common.
PMID- 9549090
TI - A novel family of short interspersed repetitive elements (SINEs) from cichlids:
the patterns of insertion of SINEs at orthologous loci support the proposed
monophyly of four major groups of cichlid fishes in Lake Tanganyika.
AB - Short interspersed repetitive elements (SINEs) have been shown to be excellent
markers of molecular phylogeny, since the integration of a SINE at a particular
position in a genome can be considered an unambiguous derived homologous
character. In the present study, we isolated a new family of SINEs from cichlids
in Lake Tanganyika, whose speciation and diversification have been regarded as
prime examples of explosive adaptive radiation. Members of this new SINE family,
which we named the AFC family, are about 320 bp in length, and each has a tRNA
related region in its 5' region, as do most of the members of SINE families
reported to date. A dot blot hybridization experiment showed that this family is
distributed extensively in the genomes of cichlids in Africa, with estimated copy
numbers of 2 x 10(3)-2 x 10(4) per haploid genome. Our investigations of the
patterns of insertion of members of this family at six orthologous loci
demonstrated clearly that four previously identified tribes, namely, the
Lamprologini, Ectodini, Tropheini, and Perissodini, each form a monophyletic
group. These results provide a basis for the elucidation of the phylogenetic
framework of the cichlid fishes in Lake Tanganyika.
PMID- 9549091
TI - Evolutionary divergence of AP-PCR (RAPD) patterns.
AB - Rates at which AP-PCR patterns diverge among isolated taxa were examined to test
whether they exhibit clocklike regularity. The results showed that rates of
divergence differed significantly among the groups examined (primates, antelopes,
and Hawaiian Drosophila grimshawi). Therefore, AP-PCR divergence rates cannot be
used as a "universal clock" with an invariant rate in all animals. Nevertheless,
within each group, a strong relationship existed between degree of AP-PCR pattern
divergence and time since separation of isolated taxa. Thus, AP-PCR divergence
may prove useful for dating evolutionary events if calibrated within a more
limited taxon.
PMID- 9549092
TI - Molecular characterization and phylogenetic relationships of a protein with
potential oxygen-binding capabilities in the grasshopper embryo. A hemocyanin in
insects?
AB - Arthropodan hemocyanins, prophenoloxidases (PPOs), and insect hexamerins form a
superfamily of hemolymph proteins that we propose to call the AHPH superfamily.
The evolutionary and functional relationships of these proteins are illuminated
by a new embryonic hemolymph protein (EHP) that is expressed during early stages
of development in the grasshopper embryo. EHP is a 78-kDa soluble protein present
initially in the yolk sac content, and later in the embryonic hemolymph. Protein
purification and peptide sequencing were used to identify an embryonic cDNA clone
coding for EHP. In situ hybridization identifies hemocytes as EHP-expressing
cells. As deduced from the cDNA clone, EHP is a secreted protein with two
potential glycosylation sites. Sequence analysis defines EHP as a member of the
AHPH superfamily. Phylogenetic analyses with all the currently available AHPH
proteins, including EHP, were performed to ascertain the evolutionary history of
this protein superfamily. We used both the entire protein sequence and each of
the three domains present in the AHPH proteins. The phylogenies inferred for each
of the domains suggest a mosaic evolution of these protein modules. Phylogenetic
and multivariate analyses consistently group EHP with crustacean hemocyanins and,
less closely, with insect hexamerins, relative to cheliceratan hemocyanins and
PPOs. The grasshopper protein rigorously preserves the residues involved in
oxygen binding, oligomerization, and allosteric regulation of the oxygen
transport proteins. Although insects were thought not to have hemocyanins, we
propose that EHP functions as an oxygen transport or storage protein during
embryonic development.
PMID- 9549094
TI - Estimating divergence dates from molecular sequences.
AB - The ability to date the time of divergence between lineages using molecular data
provides the opportunity to answer many important questions in evolutionary
biology. However, molecular dating techniques have previously been criticized for
failing to adequately account for variation in the rate of molecular evolution.
We present a maximum-likelihood approach to estimating divergence times that
deals explicitly with the problem of rate variation. This method has many
advantages over previous approaches including the following: (1) a rate constancy
test excludes data for which rate heterogeneity is detected; (2) date estimates
are generated with confidence intervals that allow the explicit testing of
hypotheses regarding divergence times; and (3) a range of sequences and fossil
dates are used, removing the reliance on a single calculated calibration rate. We
present tests of the accuracy of our method, which show it to be robust to the
effects of some modes of rate variation. In addition, we test the effect of
substitution model and length of sequence on the accuracy of the dating
technique. We believe that the method presented here offers solutions to many of
the problems facing molecular dating and provides a platform for future
improvements to such analyses.
PMID- 9549093
TI - Out of Africa and back again: nested cladistic analysis of human Y chromosome
variation.
AB - We surveyed nine diallelic polymorphic sites on the Y chromosomes of 1,544
individuals from Africa, Asia, Europe, Oceania, and the New World. Phylogenetic
analyses of these nine sites resulted in a tree for 10 distinct Y haplotypes with
a coalescence time of approximately 150,000 years. The 10 haplotypes were
unevenly distributed among human populations: 5 were restricted to a particular
continent, 2 were shared between Africa and Europe, 1 was present only in the Old
World, and 2 were found in all geographic regions surveyed. The ancestral
haplotype was limited to African populations. Random permutation procedures
revealed statistically significant patterns of geographical structuring of this
paternal genetic variation. The results of a nested cladistic analysis indicated
that these geographical associations arose through a combination of processes,
including restricted, recurrent gene flow (isolation by distance) and range
expansions. We inferred that one of the oldest events in the nested cladistic
analysis was a range expansion out of Africa which resulted in the complete
replacement of Y chromosomes throughout the Old World, a finding consistent with
many versions of the Out of Africa Replacement Model. A second and more recent
range expansion brought Asian Y chromosomes back to Africa without replacing the
indigenous African male gene pool. Thus, the previously observed high levels of Y
chromosomal genetic diversity in Africa may be due in part to bidirectional
population movements. Finally, a comparison of our results with those from nested
cladistic analyses of human mtDNA and beta-globin data revealed different
patterns of inferences for males and females concerning the relative roles of
population history (range expansions) and population structure (recurrent gene
flow), thereby adding a new sex-specific component to models of human evolution.
PMID- 9549095
TI - Contrasting levels of DNA polymorphism at the autosomal and X-linked visual color
pigment loci in humans and squirrel monkeys.
AB - The X-linked color pigment (opsin) locus is known to be highly polymorphic in the
squirrel monkey and other New World monkeys. To see whether this is also the case
for the autosomal (blue) opsin locus, we obtained 32 squirrel monkey and 30 human
blue opsin gene sequences. No amino acid polymorphism was found in either the
squirrel monkey sample or the human sample, contrary to the situation at the X
linked opsin locus. This sharp contrast in the level of polymorphism might be due
to differences in gene expression between the autosomal and the X-linked loci. At
the X-linked locus, heterozygote advantage can occur because, owing to X
inactivation, the two alleles in a heterozygote are expressed in different cone
cells, producing two types of cone cell, whereas at the autosomal locus,
heterozygote advantage cannot occur because the two alleles in a heterozygote are
expressed in the same cone cells, producing only one type of cone cell (i.e.,
phenotypically a homozygote). From the sequence data, the levels of nucleotide
diversity (pi, i.e., the number of nucleotide differences per site) are
estimated: for the human sample, pi = 0.00% per nondegenerate site, 0.00% per
twofold degenerate site, and 0.04% per fourfold degenerate site in the coding
regions and 0.01% per site in intron 4; for the squirrel monkey sample, pi =
0.00% per nondegenerate site, 0.00% per twofold degenerate site, and 0.15% per
fourfold degenerate site in the coding regions and 0.17% per site in intron 4.
The blue opsin genes from the common and pygmy chimpanzees, the gorilla, the
capuchin, and the howler monkey were also sequenced. Features critical to the
function of the opsin are well conserved in all known mammalian sequences.
However, the interhelical loops are, on average, actually more conservative than
the transmembrane helical regions. In addition, these sequence data and those
from some other genes indicate that the common and pygmy chimpanzees are not
closely related, their divergence data being from one third to one half the date
of the human-chimpanzee divergence.
PMID- 9549096
TI - A phylogenetic approach to the identification of phosphoglucomutase genes.
AB - The expanding molecular database provides unparalleled opportunities for
characterizing genes and for studying groups of related genes. We use sequences
drawn from the database to construct an evolutionary framework for examining the
important glycolytic enzyme phosphoglucomutase (PGM). Phosphoglucomutase plays a
pivotal role in the synthesis and utilization of glycogen and is present in all
organisms. In humans, there are three well-described isozymes, PGMI, PGM2, and
PGM3. PGM1 was cloned 5 years ago; however, repeated attempts using both
immunological approaches and molecular probes designed from PGM1 have failed to
isolate either PGM2 or PGM3. Using a phylogenetic strategy, we first identified
47 highly divergent prokaryotic and eukaryotic PGM-like sequences from the
database. Although overall amino acid identity often fell below 20%, the relative
order, position, and sequence of three structural motifs, the active site and the
magnesium--and sugar-binding sites, were conserved in all 47 sequences. The
phylogenetic history of these sequences was complex and marked by duplications
and translocations; two instances of transkingdom horizontal gene transfer were
identified. Nonetheless, the sequences fell within six well-defined evolutionary
lineages, three of which contained only prokaryotes. Of the two
prokaryotic/eukaryotic lineages, one contained bacterial, yeast, slimemold,
invertebrate, and vertebrate homologs to human PGM1 and the second contained
likely homologs to human PGM2. Indeed, an amino acid sequence, derived from a
partial human cDNA, that fell within the second cross-kingdom lineage bears
several characteristics expected for PGM2. A third lineage may contain homologs
to human PGM3. On a general level, our phylogenetic-based approach shows promise
for the further utilization of the extensive molecular database.
PMID- 9549098
TI - Microsatellite conservation, polymorphism, and GC content in shrews of the genus
Sorex (Insectivora, Mammalia)
PMID- 9549097
TI - A hominoid-specific nuclear insertion of the mitochondrial D-loop: implications
for reconstructing ancestral mitochondrial sequences.
AB - A nuclear integration of a mitochondrial control region sequence on human
chromosome 9 has been isolated. PCR analyses with primers specific for the
respective insertion-flanking nuclear regions showed that the insertion took
place on the lineage leading to Hominoidea (gibbon, orangutan, gorilla,
chimpanzee, and human) after the Old World monkey-Hominoidea split. The sequences
of the control region integrations were determined for humans, chimpanzees,
gorillas, orangutans, and siamangs. These sequences were then used to construct
phylogenetic trees with different methods, relating them with several hominoid,
Old Work monkey, and New World monkey mitochondrial control region sequences.
Applying maximum-likelihood, neighbor-joining, and parsimony algorithms, the
insertion clade was attached to the branch leading to the hominoid mitochondrial
sequences as expected from the PCR-determined presence/absence of this
integration. An unexpected long branch leading to the internal node that connects
all insertion sequences was observed for the different phylogeny reconstruction
procedures. This finding is not totally compatible with the lower evolutionary
rate in the nucleus than in the mitochondrial compartment. We determined the
unambiguous substitutions on the branch leading to the most recent common
ancestor (MRCA) of the mitochondrial inserts according to the parsimony
criterium. We propose that they are unlikely to have been caused by damage of the
transposing nucleic acid and that they are probably due to a change in the
evolutionary mode after the transposition.
PMID- 9549099
TI - Unusual observations in the histology of Pityriasis versicolor.
AB - Histological studies were carried out on 25 patients with various morphological
types of pityriasis vesicolor. In addition to the usual features, acanthosis
nigricans-like picture in papular lesions, dilated blood vessels in erythematous
lesions were observed. In sections stained with Periodic acid Schiff's stain
(PAS) absence of granular layer in areas of close approximation of filaments to
the stratum malpighii and presence of only mycelia in the vicinity of
acrosyringium were found unusual, interesting and are new findings to our
knowledge.
PMID- 9549100
TI - Aspergillosis in German cockroach Blattella germanica (L.) (Blattoidea:
Blattellidae).
AB - Natural infection of Aspergillus flavus was observed in adults of Blattella
germanica. Though the adult insects exhibited no external symptoms, they became
hypoactive and later died. The dead and experimentally infected insects
repeatedly yielded Aspergillus flavus in culture on Czapek's medium. Direct
microscopic observation of the tissues of infected insects revealed fungal
material. The blood films stained with Giemsa stain showed granulocytes (GRs)
engulfing fungal hyphae. A remarkable increase in GR and plasmatocyte (PL) counts
occurred in differential haemocyte counts (DHCs) of the infected insects. Two
main types of immunological responses of the insect noticed were phagocytosis and
encapsulation. DHC showed maximum involvement of GRs and PLs in immune mechanism.
PMID- 9549101
TI - Humoral immune response to Malassezia furfur in patients with pityriasis
versicolor and seborrheic dermatitis.
AB - Humoral immune responses against exoantigen components of oval, elliptic and
round yeast forms of Malassezia furfur were analysed by ELISA and Western
blotting assays, using sera from patients with pityriasis versicolor (PV),
seborrheic dermatitis (SD) and healthy adults (HA), as control. Sera from
patients with SD showed IgG anti-oval M. furfur titers ranging from 1/400 to
1/6400 showing geometric mean (GM) of 1/1472, higher than those obtained with
sera from patients with PV (1/200 to 1/6400, GM = 1/1239). Both patient groups
showed mean titres statistically superior (P < 0.05) than those obtained form HA
(GM = 1/229). Similar data were also obtained with the elliptic and round
antigens. However, the anti-oval IgG mean titers from patients' sera were much
higher than those obtained with elliptic or round antigenic components (p < 0.05)
Anti-M furfur IgM titers obtained from patient's sera with PV against all three
exoantigens were statistically superior (p < 0.05) than HA group. Patients with
SD showed IgM titers statistically superior (p < 0.05) only to oval yeasts of M.
furfur. The IgA mean titers from patients' groups against the different
morphological antigens were shown be slightly higher than those HA group. By
Western blot, using rabbit anti-sera, the different antigenic components of
M.furfur showed a close relationship mainly between oval and elliptic yeast cells
antigens. The 70 kDa component of the M. furfur exoantigen of oval morphology was
recognized by 84% of the PV patients' sera. On the other hand, SD patients' sera
recognized 3 principal components of 70 kDa (100%), 65 kDa (67%) and 84 kDa
(53%). These components may be considered immunological markers for PV and SD.
Twenty-five percent of HA sera recognized the components of 65, 70 and 94 kDa.
This investigation shows that M. furfur antigens can sensitize the host, mainly
the oval yeast form of M. furfur with a very important specific IgG response in
patients with SD and PV.
PMID- 9549102
TI - Effects of dietary sugars and, saliva and serum on Candida bioflim formation on
acrylic surfaces.
AB - The effect of two dietary sugars, glucose and galactose, on biofilm formation of
the oral fungal pathogen Candida on denture acrylic strips coated with saliva and
serum pellicles was examined in vitro using Candida albicans (3 isolates), C.
glabrata (2 isolates) and C. tropicalis (2 isolates). The degree of biofilm
activity was affected by both the dietary sugar and the nature of the pellicle
(ANOVA, p < 0.01). With most isolates the glucose grown yeasts demonstrated
significantly more bioflim activity than the galactose grown fungi, in the
presence of pellicles (ANOVA, p < 0.01 or P < 0.01). In contrast, one isolate of
galactose-grown yeast elicited significantly higher biofilm activity than glucose
grown yeasts on the control strips (ANOVA, p < 0.01). Taken together, these
results imply that a saliva or a serum pellicle, and the carbon source in the
environment, act a complex manner modulating Candida bioflim formation.
PMID- 9549103
TI - Isolation of Cryptococcus neoformans from pigeon (Columbia livia droppings in
northern Iran.
AB - Nine hundred and eighty three specimens of pigeon droppings, collected in
different regions of northern Iran, were examined. Of these samples, 175 (17.8%)
were positive for Cryptococcus neoformans. All isolates obtained were C.
neoformans var. neoformans. Most of these isolates of C. neoformans were from
pigeon shelters. There were significant differences in isolation frequency
between pigeon shelters and the other collection sites.
PMID- 9549104
TI - Expression of carboxymethylcellulase on the surface of Escherichia coli using
Pseudomonas syringae ice nucleation protein.
AB - Ice-nucleation protein (INP), an outer membrane protein from Pseudomonas
syringae, is able to catalyze the ice crystal formation of supercooled water. It
was exploited for anchoring of Bacillus subtilis carboxymethylcellulase (CMCase)
on the surface of Escherichia coli. A surface anchoring vector, pGINP21M, was
created that contains the multicloning sites including BamHI, SmaI and EcoRI at
the end of the 3' flanking region encoding the C-terminus of INP instead of the
stop codon for subcloning the foreign genes. The CMCase gene was in-frame
subcloned for making INP-CMCase fusion proteins. The ability of this vector for
directing the actual synthesis of INP-CMCase fusion proteins was confirmed by
Western blotting analysis. CMCase targeted on the surface of cells was verified
by measuring whole cell CMCase activity and ice-nucleation activity. CMCase
activity was mainly detected on the cell surface whereas no enzyme activity was
detected in the culture supernatant. Ice-nucleation activity was also maintained
even if an INP-CMCase hybrid was made. This means that the fusion protein is
functionally expressed and has its biological conformation on the surface. INP
CMCase fusion proteins were stable in the stationary phase. INP deleted of the
repeating domain, thus producing no ice-nucleation activity, could also direct
CMCase on the cell surface. This suggests that it has the secretion and targeting
signal to the outer membrane.
PMID- 9549105
TI - Characterization of galactosidases from Aspergillus niger: purification of a
novel alpha-galactosidase activity.
AB - An enzyme with beta-galactosidase activity and three proteins exhibiting alpha
galactosidase activity were purified from a culture filtrate of Aspergillus niger
grown on arabinoxylan. beta-galactosidase, optimally active at pH 4 and 60-65
degrees C, was active against p-nitrophenyl-beta-D-galactopyranoside, lactose,
and pectic galactan. It was not able to release galactose from sugar beet pectin
or lemon pectin. Its action on pectic galactan was increased by the presence of
beta-galactanase. The three forms of alpha-galactosidase activity that showed
different molecular masses and pIs were found to have the same mass after
deglycosylation with N-glycanase F and to be the same protein based on their N
terminal amino acid sequence data. The purified alpha-galactosidase was shown to
be different from alpha-galactosidase A from A. niger. This confirmed the
existence of at least two different alpha-galactosidases in A. niger. alpha
Galactosidase, optimally active at pH 4.5 and 50-55 degrees C, was active toward
p-nitrophenyl-alpha-D-galactopyranoside, melibiose, raffinose, stachyose, and
locust bean gum, on which substrate it exhibited synergism with beta-mannanase.
PMID- 9549106
TI - [Prognosis-determining systems in medicine].
PMID- 9549107
TI - [Rational distribution of resources in intensive medicine. Analysis of admission
and discharge criteria at intensive care units].
AB - Cost-containment in health care has become a major issue in today's practice of
medicine. With its needs in advanced technologies and skilled personnel,
intensive care is among the most expensive of all hospital activities. This fact
makes the analysis of indications for intensive care unit admission, as well as
early discharge, of paramount importance: patients who are not likely to benefit
from intensive care are at the extremes of disease severity, since low-risk
patients are not ill enough to need ICU admission and high-risk patients have a
very high mortality, irrespective of intensive care treatment. In this paper we
discuss, based on published evidence, the formulation of recommendations for
admission and early discharge from ICUs, and also present the Society of Critical
Care Medicine guidelines, on this subject.
PMID- 9549108
TI - [Computerization of a clinical chemical laboratory. A contribution for quality
assurance].
AB - The application of computer science to the practice of laboratory medicine, one
of the medical informatics fields, brings a complete revolution in laboratory
work and the clinical pathologists profile. The authors explain the methodology
for the implementation of such a system, in a perspective of quality assurance,
defining the goals, objectives, customer requirements and analysis of the
benefits they achieve. Finally the authors explain the future perspectives.
PMID- 9549109
TI - [Prevalence of arterial hypertension in Cushing's syndrome].
AB - OBJECTIVE: To determine the prevalence of hypertension (HT) in patients with
Cushing's syndrome. PATIENTS AND METHODS: We studied 23 patients with Cushing's
syndrome, 17 women (mean +/- SD age = 42.8 +/- 15.6 years) and 6 men (mean +/- SD
age = 34.8 +/- 10.2 years). The etiologies were: 16-Cushing's disease, 3
suprarenal adenoma, 2-suprarenal carcinoma and 2-iatrogenic. Blood pressure (BP)
was measured at least three times and we consider hypertension when systolic BP >
or = 140 mmHg and/or diastolic BP > or = 90 mmHg. RESULTS: The prevalence of HT,
at diagnosis, was 73.9% (64.7% in women and 100% in men) and the mean BP was 163
+/- 25/100 +/- 16 mmHg (158 +/- 26/97 +/- 15 mmHg in women and 182 +/- 5/114 +/-
10 mmHg in men). From the 16 patients with Cushing's disease, 13 (81%) had HT;
all the patients (n = 3) with suprarenal adenoma had HT; none with suprarenal
carcinoma (n = 2) had HT and only 1 of the 2 patients with iatrogenic Cushing's
syndrome had HT. After treatment, 14 patients entered remission, 6 persisted with
active disease and 1 was missed during the follow-up. In the group of patients
that entered remission, the prevalence of HT at diagnosis was 78.5% (n = 11),
57.1% (n = 8) being after treatment. CONCLUSIONS: In this study, we found a high
prevalence of HT at diagnosis (73.9%). After treatment and in the patients that
entered remission, the prevalence of HT remained high (78.5% vs 57.1%). The high
prevalence of HT in Cushing's syndrome, suggests its importance as a morbidity
factor and also as an important diagnostic indicator, when present.
PMID- 9549111
TI - [Relationships between basic sciences and medicine revisited].
AB - 1. The role of basic research in medical institutions and in particular in
Medical Schools is discussed. 2. Clinical practice is characterized, in its
technical aspects, as a branch of biological technology. 3. It is suggested that
the main functions of basic research practiced in medical institutions is to
promote the interaction between physicians and scientists in other fields and to
train physicians in the practices of other scientists. 4. It is suggested that
the introduction of basic research in medical institutions implies: the
recruitment of scientists from non-medical disciplines; a policy of funding that
does not favour exclusively the clinical sector; the setting up of a regular
graduate program, based on the scientifically active groups and adequately
regulated.
PMID- 9549110
TI - [Squamous cell carcinoma in individuals under 40 years of age].
AB - We reviewed all the cases of Squamous Cell Carcinoma in people under 40 years of
age, diagnosed histologically at the Dermatopathology Laboratory of the Santa
Maria Hospital, from January 1985 to December 1993. The 19 cases detected were
analysed for age, sex, occupation, anatomical site of the tumor, evolution, smoke
and alcoholic habits, skin phototypes, immunosuppression, previous viral
infections, previous radiotherapy or PUVA therapy and associated diseases. A
prevalence of an occupation involving more exposure to the sun was found. Males
were more affected than females (2.2/1). In 37% of the patients we detected heavy
alcoholic habits. The most frequent anatomical site was the lower lip (42%).
Patients with skin phototype I were more affected (53%).
PMID- 9549112
TI - [Ethics, science and utilitarianism].
AB - We begin this article with the distinction between Deontology, Moral and Ethics.
We also review the concept and the relevance of Bioethics, as the "science of
survival", and as part of Ethics, a section of Philosophy. We tried to answer two
further questions considering the role of Science in orienting Ethics, or the
possible place of utilitarianism in controlling Ethics. The author discusses some
new aspects of the doctor/patient relationship, and their evolution in the last
100 years, as well as the relations between patients and Health care
institutions. Some ethical problems were also raised related to the beginning and
the end of life. Finally the author reflects on the difficulties of defining
ethical concepts in the near future.
PMID- 9549113
TI - [Alcohol and free radicals. Various consequences: protein synthesis, endocrine
disorders, immunity. Role of stress].
AB - Ethanol is a powerful generator of oxygen free radicals, when metabolized in the
liver or in other organs. Isoenzyme 2E1 of cytochrome P450 and aldehyde oxidase
are the main mechanisms for the generation of these radicals. A consequence of
free radical generation is a decrease in protein synthesis. As a result we have
endocrine and immunity alterations. The paper ords with a brief discussion of
stress associated to alcoholism.
PMID- 9549114
TI - [Systemic effects of inhaled corticosteroids. Various pending questions].
AB - Inhaled steroids play a central and undisputed role in the management of
Bronchial Asthma, since inflammation has been recognised as the main
physiopathological mechanism in this disease. Indeed, the earlier introduction of
inhaled steroids in the therapy of Bronchial Asthma is currently being
recommended by several authors. However, accompanying the much broader use of
these drugs, concerns about the possibility of induction of adverse systemic
effects have appeared more and more frequently in the medical community and in
medical literature. This article addresses the main concerns related to the
systemic effects of inhaled corticotherapy, critically reviewing the clinical
significance of some of the more relevant published studies.
PMID- 9549115
TI - [Latex anaphylaxis].
AB - The authors present two case-reports of Latex Anaphylaxis--a rare but dangerous
manifestation of latex allergy--, one in a patient belonging to a risk group and
the other in a patient without previously identified risk factors. A review of
latex allergy, and particularly of latex anaphylaxis, is made focusing on risk
groups, aetiology, diagnosis, prevention and therapy. This paper also intends to
draw attention to this health problem and stress the fact that it raises several
medical and non-medical issues, requiring a multidisciplinary approach and
discussion.
PMID- 9549116
TI - [Adenocarcinoma of the Vater's ampulla associated with Von Recklinghausen's
neurofibromatosis].
AB - Von Recklinghausen's Neurofibromatosis is an autosomal dominant disease of
variable manifestations. Association with gastrointestinal and hepatobiliary
tumours is well documented, most of them being benign neurofibromas. Other
tumours, such as leiomyomas, sarcomas, ganglioneuromas and carcinoids are less
frequent. Much rarer is the development of epithelial malignancies and an
ontogenic relation is not clear. The authors reports a case of adenocarcinoma of
Vater's Ampulla and duodenal neurofibromas, in a patient with Von
Recklinghausen's disease, presenting obstructive jaundice.
PMID- 9549117
TI - [Hepatopulmonary syndrome].
AB - Hepatopulmonary Syndrome is an uncommon clinical situation of unknown cause. It
remains the focus of intense investigation and ongoing debate. The authors
present a case of a 77 year old man with chronic liver disease known for 5 years,
who developed central cyanoses, digital clubbing and hypoxemia. On searching for
the cause of these clinical features, the diagnosis of Hepatopulmonary Syndrome
was admitted and confirmed by contrast enhanced echocardiography using agitated
saline, and also by technetium 99m-labelled macroaggregated albumin scanning.
PMID- 9549119
TI - [Modified Body technique in the treatment of epithympanic cholesteatoma. Otologic
group, Piacenza].
AB - The Bondy technique is a particular radical, yet conservative, treatment where
the intact tympanic-ossicular system is preserved during the operation. This
technique was initially introduced by Gustave Bondy in 1910 and has been used at
the authors' center since December 1983 with a few modifications. In the twelve
years from December 1983 to December 1995 69 cases (66 patients) were treated
with this technique: 5.6% of all chronic cholesteatomatose otitis surgically
treated during that period. The following indications were applied: purely
epitymapnic cholesteatoma, average transmission gap equal to or lower than 25 dB
and intact bone chain. During the follow-up no signs of recurrent cholestatoma
were found. The average post-operative transmission gap was greater than 25 dB in
only 5 of the 54 cases with at least one year of follow-up. When used in selected
cases, the modified Bondy technique can be considered an excellent option in the
treatment of epitympanic cholesteatoma, making it possible to maintain the good
pre-operative hearing without requiring a second operation.
PMID- 9549118
TI - [Treatment of sudden hearing loss].
AB - A total of 27 patients affected by sudden idiopathic deafness (SID) and 3 with
sudden idiopathic anacousia (SIA) were treated within 10 days of onset of the
disorder. The treatment consisted of intramuscular or per os administration of
corticosteriods for 10 days and the simultaneous administration of carbogene for
5 days. At the 5th day of corticosonic treatment, if audiometry did not reveal
complete recovery, the treatment was associated for 7 days with Destrane 500 ml.
The cases included neurosensorial deafness of 30 dB or more over at least 3
adjacent frequencies and arising over a 12 hour period. Soft cord deafness was
not included in the study. The following variables were analyzed: 1) patient age;
2) extent of the hearing loss: average tone threshold for the frequencies of 500
1000-2000 Hz equal to or better than 70 dB HL (group A); tone threshold ranging
between 71 and 89 dB HL (group B), tone threshold ranging from 90 to 110 dB HL
(group C), anacousia (group D); 3) audiometric curve; 4) presence or lack of
vertigo. After treatment 25 subjects (83%) indicated a recovery ranging from good
to complete. It is significant that among this 83% there were 12 subjects, 9 with
profound deafness and 3 with anacousia. The therapeutic association adopted made
it possible to achieve two-fold activity: anti-edemagene and hemorheological. The
most highly implicated etiology for SID was viral causing not only neural but
also endothelial damage and leading to acute microcirculatory insufficiency.
PMID- 9549120
TI - [Photocoagulation of the hypertrophic lower turbinates using ND:YAG laser:
functional results].
AB - The difficult nasal respiration due to hyperplastic hypertrophy of the turbinates
is a broad topic of ongoing interest in otorhinolaryngology. The authors describe
a study of 71 patients suffering from hyperplastic hypertrophy of the lower
turbinates treated since 1994 by photocoagulation using a ND:YAG laser. The laser
treatment was performed on an outpatient basis, under local anesthesia and
assisted by the use of an Endo-Video Closed-Circuit Video-Camera. The authors
explain the details of the procedure used, emphasize surgical precision and the
numerous advantages, the scarcity of intra- and post-operative side effects, the
lack of post-operative nasal plugging. In addition, they present the satisfactory
functional results achieved. The patients treated were followed up for 6 months
prior to surgery and 30 months after laser photocoagulation. After surgery the
following tests were performed: fibroscopy, objective symptom evaluation,
rhinomanometry, rhinometry, muco-ciliary transport time (MCT), IgAS assay and
turbinate biopsy. The low cost of performing this procedure is certainly a plus.
The results obtained show a significant and permanent improvement in nasal
ventilation and this was both referred by the patients themselves and could be
objectively revealed by the ongoing controls. In conclusion, photocoagulation
using a ND:YAG laser is well accepted by both physician and patient. It can
improve nasal ventilation while respecting the anatomic and functional integrity
of the nasal fossae.
PMID- 9549121
TI - [Genetics of laryngeal cancer: an experimental study].
AB - Squamous cell laryngeal carcinoma accounts for 1% of all cancer deaths and 95% of
all laryngeal malignancies. It is most frequently found in smokers over 40 years
of age. This neoplasm is presently the object of cytogenetic studies in an
attempt to identify a specific chromosome pattern. In a study of 29 cases of
malignant primary laryngeal tumor, Nawroz (1993) found a loss of alleles in
different loci mapped in the short arm of chromosome 9 (9p) in more than two
thirds of the cases. In the same chromosome region, the loss of heterozygotes
(LOH) was previously described in other neoplasms (leukemia, hematic tumors,
melanomas). In an attempt to verify the predominant chromosome pattern and the
loss of heterozygotes in chromosome 9, a cytogenetic, genetic-molecular study was
performed on ten cases of laryngeal carcinoma. Among these subjects, two showed a
hyperdiploid chromosome pattern (metaphase with more than 46 chromosomes per
cell), five had a hypodiploid pattern (with less than 46 chromosomes per cell)
while, for the remaining three cases, it was not possible to identify any
metaphase. Numerous structural and numerical karyotype defects were found in
chromosomes 1, 3, 4, 5, 9, 10, 13, 14, 16, 18, and Y. In 6 of the cases
abnormality was found in chromosome 9 while in 10 it was apparently a homozygote.
The study was performed with the use of fluorescent in situ hybridization (FISH)
using a chromosome library specific for chromosome 9. A loss of the 9p segment
could be found as a result of different types of alterations: deletion (case 1,
2, 5, 7); non uniform transfer between chromosome 2 and chromosome 9 (case 2);
other transfers involving the 9p segment (case 1, 4, 5, 7, 10). In six cases,
analysis was further detailed at the molecular level by means of DNA
amplification methods (PCR) and electrophoresis on denatured 10% polyacrylammide
gels. LOH was studied using a polymorphic system specific for the short arm of
chromosome 9. Four of the cases examined showed LOH for the system used while one
case (case 4) gave no information. Case 9 did not show any loss of alleles. The
present study suggests that the loss of a DNA sequence on chromosome 9p is
primary to the neoplastic progression in laryngeal cancer.
PMID- 9549122
TI - [Adhesion molecules in squamous cell carcinoma of the larynx: possible indication
of prognosis].
AB - Thirty patients with laryngeal tumors were divided into two groups on the basis
of whether clinical and pathological features indicated good or bad prognosis.
Samples of each tumor group were selected and examined by immunohistochemistry
using mAbs, raised against integrin chains (beta 1, beta 4, alpha 2, alpha 3,
alpha 6) and their ligands laminin 1 and 5, collagen type IV, two fibronectin
isoforms (ED-A and ED-B) and two isoforms of tenascin known to be associated with
neoplasm. Controls were provided by samples of tumor-free laryngeal mucosa
removed during the surgical procedure. The normal topographical integrin pattern
and the continuity of the basement membrane components was altered in both groups
but the extent of these changes was significantly greater in those tumors with
poor prognosis. Therefore, the groups could easily and reliably be distinguished
by simply observing their immunohistochemical features. It is suggested that
performing immunohistochemical analysis on biopsies may aid in early diagnosis as
well as in adopting the proper therapeutic strategy to follow for these tumors.
The above molecules may become one of the diagnostic tools available for head and
neck surgical pathologists.
PMID- 9549123
TI - [Study of phospholipid components in bronchoalveolar wash surfactants in
laryngectomized patients].
AB - Surfactants serve to keep the dimension of the lower airways normal. They
regulate alveolar stability, guaranteeing uniform lung insufflation. In order to
evaluate pulmonary surfactant modifications during chronic obstructive disorders
of the airways, the phospholipid component in the surfactants was studied using
the Broncho-Alveolar Wash (BAW). Ten subjects who had undergone laryngectomy and
who were suffering from stable, chronic obstructive broncho-pneumopathy (COBP)
with marked hypersecretion were studied along with a control group of 7 smokers
showing no signs of COBP. As compared to the controls, the laryngectomy patients
showed a statistically significant reduction in the total phospholipid content
and a different concentration of some important phospholipid fractions. The
laryngectomy patients showed varying degrees of COBP because of their previous
smoking history: as in ex-smokers where a the "biochemical" damage induced by
cigarette smoking is partially repaired. On the other hand, while in the group of
smokers the damage, expressed as the total phospholipid content, was quite
noteworthy (reduction in this content was up to 10 times that found in the non
smoking subjects), the ex-smoking laryngectomy patients revealed less marked, yet
still significant, damage.
PMID- 9549124
TI - [Fronto-lateral laryngectomy using a combined endolaryngeal external approach].
AB - Functional laryngectomies-whether subtotal (with significant demolition) or
conservative (with limited latero-frontal and frontal demolition)-can, at times,
lead to significant post operative functional sequelae. Negative outcomes method
proposed calls for an internal, endolaryngeal approach along with an external
approach. The internal approach makes it possible to carefully delimit the
posterior extension of the laryngeal neoplasm. The external approach, on the
other hand, makes it possible to remove the anterior commissure and part of one
or both vocal cords in a single unit together with a smaller portion of the
thyroid cartilage. In particular, the endolaryngeal approach using suspension
microlaryngoscopy makes it possible to section the laryngeal structures all the
way up to the internal surface of the thyroid cartilage and, anteriorly, along
the midline from the incision to the lower edge of the cartilage. From above the
larynx is opened by means of a transfixed section of the thyroid membrane and of
the epiglottis at the upper edge of the thyroid cartilage. The ends of the
section are joined with the upper ends of the section prepared using the
endolaryngeal approach. Cranio-caudal dissection of the internal perichondrium of
the thyroid larynx is then performed, from behind, all the way to the
endolaryngeal sections and, from below, to the point where the cord ligaments are
inserted. The larynx is opened from below by means of a horizontal section in the
crico-thyroid membrane at the upper edge of the cricoid cartilage. The
trapezoidal section of the lower part of the protruding corner of the thyroid
cartilage. After having joined the edges of the crico-thyroid section with the
lower edge of the endolaryngeal sections, the entire piece is then removed in a
single unit. This method, for treatment of carcinoma of the anterior commissure
and of the anterior portion of one or both vocal cords (T1 and T2 N0 M0), must be
used after accurate clinical evaluation; it is particularly appropriate for
subjects with cordo-commissure carcinoma which was previously treated with
radiotherapy. The method meets the requirements of oncological radicalness,
permits one to perform both the external and internal sections under visual
control and maintains the endolaryngeal diameters nearly intact.
PMID- 9549125
TI - [Biopsy of the temporal artery].
AB - Horton temporal arteritis, or gigantocellular arteritis, is a panarteritis
involving the mid-size and large arteries, in particular the temporal surface
artery. This pathology is normally found in the elderly, particularly females. It
can be manifest with some typical symptoms (i.e. cephalea, fever, visual
disorders even leading to blindness mandibular claudication, high ESR, moderate
anemia), there may be aspecific, atypical signs (i.e. only cephalea and fever, or
widespread myalgia and artralgia) or it may arise following a cerebro-vascular
accident. Treatment of this form of arteritis is based on the use of high doses
of corticosteroids over a long period of time (at least 1-2 years). The present
work describes a surgical technique for biopsying the temporal artery. The
technique consists of withdrawal of a segment of the artery from the main branch
and the frontal branch of the temporal surface artery. Since this form of
arteritis often presents segmentary lesions, it is advisable to take a 4-5 cm
sample so as to prevent false negatives. This simple surgical procedure can be
performed under local anesthesia and is practically complication-free. The
authors then discuss the indications for temporal artery biopsy and report 3
clinical cases (case no. 1 is an example of the classical manifestation while
cases no. 2 and 3 are atypical, aspecific forms). Since both the classical and
atypical forms of gigantocellular arteritis require high doses of corticosteriods
over a long period of time, the temporal artery biopsy procedure is highly useful
in formulating an accurate diagnosis. The well known side effects to long-term
cortisone use make it necessary to use all the available instruments in making
the correct diagnosis. Bilateral biopsy can be performed in those cases where the
first biopsy proved negative but gigantocellular arteritis is still suspected.
PMID- 9549126
TI - [Pleomorphic adenoma of the lower turbinates: clinical case and review of
literature].
AB - A case of pleomorphic adenoma of the lower turbinate salivary glands is
presented. A careful review of the literature has revealed that this is a highly
unusual site for such neoplasms. The scarcity of symptoms is underlined as the
lesion can long go unrecognized. Moreover, it is pointed out that, since only a
small number of cases have thus far been presented for this benign lesion the
prognostic factors indicating a clinical evolution to malignancy are as yet
unknown. For this reason the authors feel it advisable to perform conservative
surgery and carry out a careful follow-up.
PMID- 9549127
TI - [Length of stay and diagnosis related groups (DRG) in otolaryngology in view of
total quality management].
PMID- 9549128
TI - [The first applications of radiotherapy in head and neck cancers].
PMID- 9549129
TI - [Rendu-Osler disease: treatment with iridium 192].
PMID- 9549130
TI - [Uniformed Requirements Manuscripts for biomedical journals (Vancouver
Conference). International Committee of Editors of Medical Journals].
PMID- 9549132
TI - [Response to sertraline in adolescents with obsessive-compulsive disorder].
AB - Previous studies have revealed that serotonin reuptake inhibitors are effective
for the treatment of obsessive compulsive disorder (OCD) in children and
adolescents. The clinical efficacy of sertraline (STL) for eight adolescents with
OCD is examined. The patients are between 12 and 17 years old, being 3 of them
female and 6 male. The severity is measured with OC-NIMH Scale and self-report
Leyton-20 questionnaire. Administration of STL was begun at 50-200 mg/day, with
maintenance dose of 50-150 mg/day. Seven patients responded adequately to STL for
more than six months; a girl, aged 16, require discontinuation of STL because of
untoward effects. The improvement starts before the 8th week of treatment. Six
months later improvement scores with OC-NIMH and Leyton-20 rated near the 50%. In
the seven patients with STL either have no untoward effects or mild effect.
Favorable results are observed either in adolescents who received STL and
cognitive therapy or those with STL as main treatment without any structure
psychotherapy. After 6-21 months with STL, improvement has continue of has been
increased.
PMID- 9549131
TI - [Limitations of the diagnosis of bipolar disorder].
AB - INTRODUCTION: It has been studied the possible confusion in the diagnosis of
bipolar disorder when there are no clear mania symptoms and other psychiatric
disorders, due to his clinic similarity. The diagnosis received from a group of
patients admitted in a Psychiatric Unit of a General Hospital by manic episode
were studied. METHODS AND MATERIAL: 84 admitted patients have been followed up
along an average of 32 months. By means logistic regression, there were found the
factors that explained the change in the diagnosis along the evolution. RESULTS:
87% of the patients after the follow up kept the diagnosis of bipolar disorder.
However, 63.1% had received other diagnosis. Two factors predicted to receive
other diagnosis: depressive clinic and not having stable couple. CONCLUSION:
Bipolar disorder presents a proper stability once diagnosis have been made. It
may be confused with psychotic sight, unipolar depression and B cluster
personality disorders. It is checked that patients which start with manic
psychosis phases are the ones that present biggest diagnosis stability.
PMID- 9549133
TI - [Psychoeducative ambulatory group in bulimia nervosa. Evaluation of a short-term
approach].
AB - This study examined the relative efficacy of a brief-psychoeducational treatment
approaches for bulimia nervosa. Our sample comprised 26 women who sought
consecutively treatment at the Eating Disorders Outpatient Unit. All subjects met
DSM-IV criteria for Bulimia nervosa. For the assessment were used commonly
applied questionnaires in the fiel of eating disorders such as: Eating Attitudes
Test (EAT-40), Eating Disorders Inventory (EDI) and the Beck Depression Inventory
(BDI). Outcome measures included also change in vomiting and binge-eating
episodes per week. Each patient was assessed before and after a 6 weeks brief
psychoeducational group therapy. At posttreatment, 30% of the patients were
abstinent from binge eating-purging and 62% reduced their weekly frequency in
binge eating and 56% reduced their weekly frequency in vomiting. Good-outcome
(EAT scores < 30) was observed in more than 35% of our patients. The authors
sought to identify factors that differentiate bulimic patients who improve while
receiving treatment from those who do not.
PMID- 9549134
TI - [Reliability of the evaluation of regional cerebral blood flow using SPECT in
chronic schizophrenia and bipolar disorder].
AB - OBJECTS: Demonstrate the reliability of cerebral SPECT using 99 mTc-HMPAO.
METHODS & MATERIALS: Evaluation of cerebral blood flow using SPECT in 24 patients
with schizophrenia, 24 patients with bipolar disorder and 20 controls. In the
study we have reliability between observers and intraobserver. In both cases
kappa statistic has been applied for measuring reliability. RESULTS: reliability
between observers represents a kappa coefficient of 0.71. Intraobserver
reliability, with a medium grade concordance slightly superior, shows a medium
kappa coefficient of 0.74. CONCLUSIONS: Visual evaluation of SPECT images using
99mTc--HMPAO is a trustworthy technique to document the different patterns of
regional cerebral blood flow. Reliability is determinate by the improvement,
during visual analysis of reliability between observers (kappa: 0.71) and
intraobservers (kappa: 0.74).
PMID- 9549135
TI - [Smoking in a psychiatric population].
AB - The relationship between tobacco consumption and psychiatric disorders is a
widely discussed topic that is generating a considerable yet controversial
bibliography, that can be approached from different points of view. The authors
make a revision and critical evaluation about smoking prevalence on psychiatric
population, in the different psychiatric disorders and discussing the theories
implicated.
PMID- 9549136
TI - [Naltrexone in the treatment of alcohol dependence].
AB - This paper reviews preclinical research which demonstrates the involvement of the
opioid system in the reinforcing effects of alcohol, and the effects of
naltrexone, a long-acting, nonselective opioid receptor antagonist to reduce
alcohol intake. Naltrexone (50 mg/day) may prevent the return to drinking by
blocking the pleasurable effects or "high" associated with alcohol drinking, and
relapse rates were reduced. The most common adverse effects reported include
nausea and vomiting and it does not appear to be hepatotoxic in dosages
recommend. Thus, naltrexone appears to offer significant therapeutic benefits,
when used with behavioural treatment for alcohol dependent patients.
PMID- 9549138
TI - [Bioavailability and bioequivalence. Studies in healthy volunteers].
PMID- 9549137
TI - [Prescription of generic drugs].
PMID- 9549139
TI - [Problems with generic drugs. Point of view of the pharmacist, the
pharmacologist, and the clinician].
PMID- 9549140
TI - [Physician battles in Spanish medicine of the 19th Century: from chaos to
revolution].
PMID- 9549141
TI - [Neurovegetative changes of the circadian rhythm in airline pilots in
transmeridianal flights].
PMID- 9549142
TI - [Artifact dermatosis].
PMID- 9549143
TI - [Health care human values in current and future gynecology and obstetrics].
PMID- 9549144
TI - [New commentaries on ataraxia y la asphaleia the security and domination of our
self].
PMID- 9549145
TI - [Tobacco/nicotine, habit or addiction?].
PMID- 9549146
TI - [Lingual actinomycosis. A case report].
PMID- 9549147
TI - [Esophageal achalasia and mongolism. Laryngeal papillomatosis and
dermatomyositis. A common origin? Review].
AB - Before the notorious increase of congenital malformations among individuals
belonging to rurality, which are faced to yield between watering by sprinklers
with weed-killers and the alarming growth of cardiovascular and pre--and
malignant diseases we decided to undertake a perusal among the agents regarded
since ever as bias toward to those pathologies. Following that conception we
found out a common tendency between malnutrition, diabetes, alcoholism, drug
addiction, weed-killers, and so on. The whole group generate energy reduction
(ATP) starting from which appears a biochemical complex competent to give way to
any cardiovascular pathology, autoimmune maladies or even congenital
malformations.
PMID- 9549148
TI - [In-depth study of the causes of sudden deafness. Physiopathological mechanisms
and their reversal].
AB - This article deals with an investigative work done by the AA. with the aim of
determine the final cause of sudden sensorial deafness. Three causes are accepted
as source of sudden deafness: viral infections, the tear away of labyrinthine
membranes and the vascular theory. An increase in antibody titer suggest a viral
origin. The labyrinthine membranes split has been observed at times when
performing an exploratory tympanotomy. But circulatory troubles are hardly
diagnosed, even with histopathological evidences of vascular upsets in temporal
bones belonging to patients who suffered from an auditory stroke, because there
are no diagnostic tests for "in vivo" control. Our intend is to investigate on
the physiopathology of unforeseen deafness and also try to know the possible
mechanisms of reversion of this calamitous pathology. We use, as investigative
method of actual vascular changes in sudden deafness, the following; the speed
analysis of the blood flow furnished by the A. labyrinthi through echography
Doppler color transcranialis and angiography and magnetic resonance (Angio-MR).
Both procedures are non invasive and harmless. We comment the findings of 13
patients. And find out, in 4 cases, an important trouble of the arterial
vertebrobasilaris flow. The A. labyrinthi, a branch of the A. cerebelli inferior
anterior (ACIA) and/or A. basilaris--rarely from the A. cerebelli inferior
posterior (ACIP)--showed a heavy hypoplasy of these vessels, stenosis or complete
blockage. In 2 of cases, 4 months later, a new exploration of the Doppler flow
and angio-MR, was performed, and detected an improvement of the vertebrobasilar
flow, in both instances. In those patients with an evident recovery of the
hearing, it was attributed to these two compensatory mechanisms: 1) reversal of
the flow at the level of cicle of Willis, at the expense of development of A.
communicans posterior, and 2) cessation of the vertebral A. spasm and decrease of
the vessel's tortuosity so improving the blood flow.
PMID- 9549149
TI - [Microbiological and auditory analysis before and after topical treatment of
chronic suppurative otitis media without cholesteatoma].
AB - The AA. present a study microbiologic and auditive as well about chronic,
suppurative otitis media non cholesteatomatous, before and after topical
treatment. They contemplate 178 samples of chronic discharging ears which were
treated with gentamycin 0.3 %, instillation 5 drops every 8 hours, during 10
days. Twelve days later were newly assessed both the otorrhea and the
cochleovestibular picture. Germs most frequently detected: Gram-negative 61.6 %,
Gram-positive 19.8 %, associated flora 6.4 % and mycosis 2.2 %, among other.
Clinic healing accounted for 97.29 % and not significative differences scored pre
-and post-treatment.
PMID- 9549150
TI - [Pleomorphic adenoma as a parapharyngeal tumor. The role of the CT in
differential diagnosis].
AB - We described 2 cases of pleomorphic adenoma as parapharyngeal masses, one of the
deep lobule of the parotid gland and the other one in palatine accessory salivary
glands. After computed tomography (CAT) we made the anatomopathological diagnosis
of pleomorphic adenoma with fine needle aspiration. We discuss about the role of
CAT in diagnosis of pleomorphic adenoma occupying the parapharyngeal space.
PMID- 9549151
TI - [The hamster's larynx as an experimental model].
AB - A macroscopic study and with light microscopy as well is performed in the larynx
of 4 hamsters. Morphology of hamster's larynx is described. Transitional
epithelium is found out on the epiglottis base and caudally to the vocal cords.
Hamster's larynx may be a good model for experimental study of changes during
carcinogenesis.
PMID- 9549152
TI - Bringing research to life.
PMID- 9549153
TI - Anger and blood pressure readings in children.
AB - This study investigated the relationship of state and trait anger measured by the
Jacob's Pediatric Anger Scale, patterns of anger expression measured by Jacob's
Pediatric Anger Expression Scale, and blood pressure readings (BPR) in 230 third
grade children. Analysis of data revealed significant inverse relationships
between anger suppression and diastolic BPR and anger reflection and control and
both diastolic and systolic BPR. As anger suppression increased, diastolic BPR
decreased. As anger reflection and control increased, both systolic and diastolic
BPR decreased. When gender was considered, the relationship between anger
reflection and control and systolic BPR was apparent only for girls, whereas the
relationship between anger reflection and control and diastolic BPR was apparent
only for boys. When correlations were computed based on gender and race, a
significant inverse relationship between anger reflection and control and
systolic BPR in Black girls was found. The results suggest that the influence of
race and gender on the relationships between anger expression and systolic and
diastolic BPR, which has been documented in adults, may be present in childhood.
PMID- 9549154
TI - Humor and well-being in spouse caregivers of patients with Alzheimer's disease.
AB - The relationship between the use of humor and well-being was studied in a
convenience sample of 96 elderly spouse caregivers of community-residing patients
with Alzheimer's disease (AD). Using hierarchical multiple regression analysis
and controlling for severity of illness, caregiver education, and income, the use
of humor accounted for 18.2% (p < .001) of variance in caregiver well-being.
Caregivers of patients with advanced AD symptoms used less humor and had more
psychological distress than those caregivers of patients who had mild symptoms.
Because humor helps to maintain a sense of well-being, nurses should develop and
encourage the use of humor in the spouse caregiver population.
PMID- 9549155
TI - Living with osteoarthritis: insiders' views.
AB - The purpose of this phenomenological study was to explore the day-to-day
experiences of older people with symptomatic osteoarthritis (OA) and to discover
if people in different socioeconomic strata differ in the ways in which they
manage OA. Data were collected through semistructured interviews with 20
respondents. The following four themes emerged from the data: refusing to give
up, pragmatism toward treatment strategies, staying in charge, and tangible
caring. Respondents more advantaged in socioeconomic status differed from less
advantaged respondents in problems reported, treatments preferred, and causes of
OA identified. Understanding the different ways people experience and live with
OA and the importance of tailoring interventions to individual circumstances is
essential to effective nursing management.
PMID- 9549156
TI - Delirium: comparison of four predictive models in hospitalized critically ill
elderly patients.
AB - Delirium, a cognitive and behavioral disorder affecting more than one third of
all hospitalized elderly patients, is often misdiagnosed or unrecognized by
caregivers, leading to higher patient morbidity and mortality rates. Prediction
of the disorder, based on known predisposing and precipitating risk factors, can
be used to target susceptible patients for prevention and early intervention.
Predictive models need to be evaluated for clinical application and predictive
value. Therefore, in this study, four predictive models were applied on a case-by
case basis to an elderly sample of 10 delirious patients and 10 nondelirious
patients to determine sensitivity, specificity, and predictive values in a
critical care setting. Results indicated six individual significant variables in
these models: age, infection, dementia, blood urea nitrogen-to-creatinine ratio,
severe illness, and comorbidity. A final multivariate model, derived from all
variables, exhibited a sensitivity of 100% and specificity of 90% in predicting
delirium in this study. Further studies are needed to substantiate these results.
Then, identified risk factors can be incorporated into delirium prevention
protocols for use by nurses at the bedside.
PMID- 9549157
TI - Promoting adherence to an electronic home spirometry research program after lung
transplantation.
AB - Adherence with any long-term treatment or research protocol is a challenge; this
has been found to be the case with lung transplant recipients participating in an
electronic home spirometry research program. Because the purpose of the current
study is to develop a system for detecting early infection and rejection in lung
transplant recipients, regular transmission of data by subjects to the research
data center is imperative to the success of the study. Various adherence
promoting strategies have been developed by the research team to increase subject
adherence with the program. An increased adherence rate has been reported after
implementation of these various strategies, yet work remains to promote
continually regular participation in the program by all subjects. It remains a
challenge for the research team to devise creative and effective strategies for
increasing adherence to regular spirometer use to provide data to develop a
computerized system for detecting early infection and rejection of transplanted
lung tissue.
PMID- 9549158
TI - Promoting nursing research through newsletters.
PMID- 9549159
TI - Nursing management structures: a research priority.
PMID- 9549160
TI - [The role of trans-rectal echography (TRE) in the evaluation and staging of
bladder tumors: comparison with suprapubic echography and computerized axial
tomography (CAT)].
AB - TAU and CT are, after cystoscopy, the two most largely used methods in the
diagnosis and the staging of the bladder tumors. TRUS is mostly used in the
pathologies of the prostate and the seminal vesicles. 38 patients (34 M and 4 F)
suffering from bladder cancer are included in this study in the period from July
1995 to January 1997. They are evaluated with TAU, TRUS and CT in order to
evaluate the sensitivity and the specificity of TRUS in the diagnosis and the
stadiation of bladder tumors. The patients included in this study are divided in
two subgroups as patients having superficial and infiltrating tumors according to
pathologic stage after TURB or radical cystoprostatectomy. Specificity and
sensitivity values, overstaging and undestaging rates are calculated for each
group. In the superficial tumors, TAU had a sensitivity and specificity of 72.2%,
while with CT these values were respectively 70% and 75%; in the infiltrating
tumors, TAU presented sensitivity of 65% and specificity of 70% while CT
presented respectively 72.2% and 77.5%. With TRUS these values were 88.8% and
94.4% in the superficial tumors and 90% and 95% in the infiltrating tumors. The
method with the highest overstaging rate was CT with 33.3% while the ones with
the highest understaging rates were TAU and CT with 22.2%. The sensitivity with
TRUS was 100% in a total of 29 infiltrating and superficial tumors of the trigone
while it was only 55.5% in the tumors of the lateral walls and the dome. With TAU
these values were respectively 82.7% and 22.2%, with CT respectively 79.3% and
44.4%. The specificity with TRUS was 100% for the tumors of the lateral walls and
77.7% of the dome; with TAU these values were respectively 75.8% and 55.5% with
CT 75.8% and 77.7%. In conclusion, TRUS may be used with a high sensitivity and
specificity in the diagnosis and the stadiation of infiltrating and superficial
bladder tumors situated at the peritrigonal zone and in the diagnosis of tumors
situated in other regions of the bladder.
PMID- 9549161
TI - Assessment of glomerular filtration rate by means of the three-compartment closed
model after a single intravenous injection.
AB - The two-compartment open model is currently used to assess glomerular filtration
rate (GFR) with multiple blood samples. Numerous limited sampling models have
been developed to reduce the number of blood samples. In the present study, the
three-compartment closed model was used to assess GFR after a single intravenous
injection. The three-compartment closed model includes blood, peripheral and
urine compartments, thus the samples in urine can be used to estimate parts of
pharmacokinetic parameters, thus to reduce the number of blood samples.
Theoretically, the three-compartment closed model can assess GFR with one blood
sample at any sampling time and three urine samples at any three sampling times.
PMID- 9549162
TI - Coexistence of orbital and retroperitoneal involvement in multifocal
fibrosclerosis: case report.
AB - OBJECTIVE: To report a rare case of multifocal fibrosclerosis involving the
retrobulbar tissue and the retroperitoneum. METHODS: A 59-year-old man presented
with bilateral exophthalmos, more serious in the right eye. Right orbital biopsy
showed fibrous tissue with inflammatory cells. After the failure of the radiation
therapy, a right orbital exenteration was required. Radiological examinations
demonstrated a retroperitoneal mass involving the perirenal fat, the aorta, the
presacral and the perivesical tissue. Renal function impaired. A left inferior
calycoureterostomy and a surgically placement of a right JJ stent were performed.
Histological examination of the retroperitoneal biopsies revealed fibrous
connective tissue. RESULTS: After 9 years of follow up, there was no change in
left visual or renal function (last creatinine: 1.3 mg/dl), and no symptoms or
signs of recurrences. CONCLUSION: This case is the ninth to document the
association of orbital pseudotumor and retroperitoneal fibrosis. It is important
that both the ophthalmologist and the urologist are aware of the existence of
this association, so that suitable treatment can be initiated without delay.
PMID- 9549163
TI - Ectopic adrenal tissue in the spermatic cord. Case report and review of the
literature.
AB - Ectopic adrenal tissue is a not uncommon clinical finding, especially in
children. These aberrant rests have been reported in various locations, such as
kidney, testis and related structures, female genital tract and
supradiaphragmatic region. The most common site in the male genital district is
the spermatic cord. We report a case of ectopic adrenal in the spermatic cord,
occasionally found in an asymptomatic 42-years-old man. No other pathologic
condition of urogenital tract was present. The nodule measured 0.5 cm in diameter
and was histologically arranged in three well defined layers, with predominance
of the zona fasciculata. No adrenal medullary tissue was observed. The
pathogenesis of this ectopic tissue near the testis can be explained by the
embryologic relationship between adrenal cortex and the gonad. Finally, we
reviewed the relevant literature and the main clinical implications of this
condition.
PMID- 9549164
TI - Use of new automated biopsy device for percutaneous testicular biopsy. A
preliminary clinical experience.
AB - Testicular biopsy is indicated in the azoospermic patients to determine if the
cause of azoospermia is ductal obstruction or testicular pathology and in certain
patients who have severe oligozoospermia. The technique traditionally used is an
open testicular biopsy. New Automated Biopsy Device has been used successfully
for renal diseases. This instrument is now used by the urologist for transrectal
prostate biopsy. The aim of this study was to evaluate whether percutaneous
testicular needle biopsy with new automated device can replace open testis biopsy
or not. 90 testes of 48 patients between 22 and 43 years olf underwent
percutaneous testicular biopsy with a new 18-gauge automated biopsy device.
Adequate samples were recovered from 90% cases (average 24.77 tubule sections per
testis). When needle biopsy and open biopsy samples were compared in 30 testes of
15 patients, complete agreement was obtained in 93%, whereas slight differences
in 7%. These results show that percutaneous needle biopsy with new automated
systems is cost-effective, quick, safe, repeatable, relatively painless and
effective way to obtain largest possible cores through full cut technique. No
serious complications were encountered during or after the procedure. The
diagnosis were found to be comparable to those obtained by open biopsy. For these
reasons, it is concluded that this new technique can replace the open biopsy.
PMID- 9549165
TI - [Endoscopic treatment of bladder diverticula].
AB - Since February 1993 six patients with bladder diverticula have undergone
resection of the diverticular neck and fulguration of the diverticular mucosa at
the time of transurethral resection of the prostate in 5 cases and urethral
dilation in one case. The mean dimension of the diverticular was 5.2 cm. After a
mean follow-up of 20 months the diverticulum has largely shrunk in one case and
has completely disappeared in 5 cases. Our paper demonstrates the effectiveness
of this technique in the treatment of bladder diverticular. In our opinion
endoscopic fulguration represents a valid alternative to open surgery for the
treatment of small bladder diverticular.
PMID- 9549166
TI - [Laparoscopic unilateral retroperitoneal lymphadenectomy in non-seminomatous
neoplasms of the testis in clinical stage I].
AB - Since June 1993, unilateral laparoscopic retroperitoneal lymph node dissection
(LRPLND) was performed in 6 patients diagnosed with clinical stage I
nonseminomatous germ cell tumors (NSGCT). All of the patients had undergone prior
radical orchiectomy. The testicular cancer was left-sided in three cases and
right-sided in three cases. Preoperative staging by means of tumor markers
assessment, computerized tomography scan (CT) of the chest and abdomen and chest
X-ray was unremarkable for metastatic disease. All procedures were accomplished
without any complications in a mean time of 325 min (275 to 420 min). The
estimated peri- and postoperative blood loss was minimal. Of note, the comparison
between the hematocrit and hemoglobin decrease of LRPLND and RPLND showed a
statistically significant reduction (3.1 vs 11.1% P < 0.01 and 1.1 vs 3.2 g/dl P
< 0.01). None of the patients required blood transfusion. In the case of the
first patient the hospital stay was 18 days due to a widespread subcutaneous
emphysema. In the remaining five cases the average hospitalization was 4.8 days
ranging between 4 and 6 days. The patients resumed normal activities within 12 to
27 days (mean 16.2 days) postoperatively. Mean number of lymph nodes removed was
6.8, ranging between 5 and 9. Histologic examination of the dissected lymph nodes
revealed microscopic metastases from embryonal carcinoma in two patients. Both of
these patients were subject to adjuvant chemotherapy. The mean follow-up period
is 33.3 months, ranging between 18 and 48 months. To date, no relapses have been
observed. In accordance with other reports, we believe that LRPLND is both
feasible and effective. However, larger and more comprehensive studies with long
term follow-up are required to determine whether this approach is reliable and
definitely superior to standard open surgery in the management of clinical stage
I NSGCT.
PMID- 9549167
TI - [Therapy of vasomotor syndrome in the treatment of advanced prostatic cancer:
apropos of 37 cases].
AB - Castration, whether surgical (orchiectomy) or pharmacological (androgen
blockade), used in the management of advanced prostatic carcinoma, induces as a
secondary effect, immediately following impotence, the onset of a vasomotor
syndrome characterized by hot flushes and sweating. This syndrome which may
present with such intensity and frequency as to severely affect the quality of
life and even the psychological equilibrium of the patient. Treatment with
progestinic agents leads to the release of opioid peptides at hypothalamic level,
thus decreasing the level of catecholamines responsible for the vasomotor
syndrome. In the 37 cases treated with progestogens, a therapeutic efficacy of
80% was observed following cyproterone acetate and of 70% following
medroxyprogesterone acetate.
PMID- 9549168
TI - The early effects of doxazosin on benign prostatic hyperplasia.
AB - It is known that selective alpha-1 adrenoceptor blockers diminish the symptoms
and improve the uroflowmetric parameters in benign prostatic hyperplasia (BPH) by
the effect on the dynamic component of BPH. The efficacy of doxazosin, a
selective alpha-1 adrenoceptor blocker was evaluated in the treatment of BPH by
assessing International Prostate Symptom Score (IPSS) and uroflowmetric
parameters. While 24 patients were given doxazosin in a daily dose of 4 mg, 19
patients were given placebo. Assessments of IPSS and uroflowmetric parameters
were obtained three weekly periods. After three weeks, the decrease in IPSS was
more prominent in doxazosin group when compared to placebo group (47% versus 12%
respectively, p < 0.05) but improvement in the uroflowmetric parameters was not
different statistically in the two groups (in Qmax 24% versus 16%, for doxazosin
and placebo groups respectively, p > 0.05). After six weeks the improvement in
IPSS continued and improvement in uroflowmetric parameters in doxazosin group was
more evident when compared to placebo group (in Qmax 34% versus 19% respectively,
p < 0.05). Objective results of doxazosin treatment in BPH can be observed after
sixth week of the treatment although symptomatic effects can start at third week.
PMID- 9549169
TI - Influenza activity in England and Wales remains low.
PMID- 9549170
TI - Humanitarianism and local service institutions in Angola.
AB - The role of local service institutions is not a major focus of current discourse
on humanitarianism and complex emergencies. These institutions, in the few places
where they are mentioned, are usually presented as either the seed of civil
society and future democracy, or as pawns and components of the predatory
economic, political and military elites. Few would deny that examples can be
found which conform to both of these stereotypes. This simplistic representation
of local institutions ignores the perspectives of the actors themselves--the
nurses, extension agents, school teachers and others who actually staff most NGO
supported projects. The debate has focused on what 'we' should do; the moral
dilemmas of aid agencies and their expatriate staff, inevitably leading to the
question of whether or not humanitarian workers should stay or leave situations
in which aid may be causing more harm than good. Without denying the fundamental
importance of these issues, it is important to consider also how the discourse
has unfortunately moved away from those humanitarian workers who have no such
choice, since they live there. Current concerns about keeping humanitarian aid
from feeding local political and military struggles may inadvertently and
paradoxically serve to constrain room for maneuver in the field, particularly
among those individuals with the greatest tacit understanding of the predatory
environment. There is a need to understand how actors in local service
institutions make sense of their own situations, including the factors which
frame their moral dilemmas and their day-to-day choices. By analysing the
organisational processes within local service institutions, this study is
intended to provoke consideration of how these individuals and their institutions
may be effectively supported in complex emergencies through a focus on how they
themselves deal with danger and complexity. It is suggested that there is a value
in considering the lessons learnt in recent years about how service organisations
in the North function in turbulent environments. This experience points to the
importance of allowing workers the discretion to develop a relationship with
their clients, and in so doing make sense of a confusing and ambivalent
environment.
PMID- 9549171
TI - The Northridge earthquake: community-based approaches to unmet recovery needs.
AB - The 1994 Northridge, California earthquake has proven to be one of the most
costly disasters in United States history. Federal and state assistance
programmes received some 681,000 applications from victims for various forms of
relief. In spite of the flow of US$11 billion in federal assistance into Los
Angeles and Ventura counties, many victims have failed to obtain adequate relief.
These unmet needs relate to the vulnerability of particular class and ethnic
groups. In response to unmet needs, a number of non-governmental organisations
(NGOs) have become involved in the recovery process. This paper, based on
evidence collected from hundreds of in-depth interviews with the people involved,
examines the activities of several community-based organisations (CBOs) and other
NGOs as they have attempted to assist vulnerable people with unmet post-disaster
needs. We discuss two small ethnically diverse communities in Ventura County, on
the periphery of the Los Angeles metropolitan region. The earthquake and
resultant disaster declaration provided an opportunity for local government and
NGOs to acquire federal resources not normally available for economic
development. At the same time the earthquake created political openings in which
longer-term issues of community development could be addressed by various local
stakeholders. A key issue in recovery has been the availability of affordable
housing for those on low incomes, particularly Latinos, the elderly and farm
workers. We discuss the successes and limitations of CBOs and NGOs as mechanisms
for dealing with vulnerable populations, unmet needs and recovery issues in the
two communities.
PMID- 9549172
TI - Environmental information systems in malaria risk mapping and epidemic
forecasting.
AB - Every year between one and two million African children under five die of
malaria. If one adds to this the contribution of malaria to all-cause infant
mortality then clearly the burden of the disease is catastrophic--a disaster
quietly happening each and every year. New tools are needed urgently to support
those currently available for control of the disease. An effective vaccine
remains elusive. This article outlines the potential contribution to malaria
control services of satellite information, which is being used by resource
managers in other sectors. In particular, it highlights the lessons which can be
learned from early warning systems in other areas, especially those designed to
respond to famine. An appendix provides a brief introduction to satellite data
and their interpretation.
PMID- 9549174
TI - Coping strategies in an ethnic minority group: the Aeta of Mount Pinatubo.
AB - The particular problems arising in the aftermath of natural disasters in
indigenous societies in the Third World, especially in ethnic or cultural
minorities, have until now received only little attention in social scientific
research. The potential of such indigenous groups to use their traditional
knowledge and behaviour patterns in coping with natural disasters has been badly
neglected. The example of the Aeta in Zambales, Philippines, a marginal group who
were hit directly by the eruption of Mt Pinatubo in 1991, shows how traditional
economic and social behaviour can in some measure determine their various
survival strategies.
PMID- 9549173
TI - Crop failure in Dalocha, Ethiopia: a participatory emergency response.
AB - This case study of an NGO's response to a food crisis due to crop failure focuses
on the extent of active community participation at each stage of the project.
With the current debate on the relationship between relief and development, and
in particular the focus on encouraging more active community participation in
relief responses, this study has relevance both in the Ethiopian context and
beyond. In this example the participation process was greatly facilitated by the
prior relationship between the international NGO and the communities, and also by
the high level of staff input into the project. Where resources or conditions are
less favourable, as might be the case in similar responses by local NGOs or
government agencies, the paper suggests that the participatory approach can be
adapted or partially implemented and still result in a more effective and locally
relevant operation.
PMID- 9549175
TI - [Molecular physiopathology of Alzheimer's disease].
PMID- 9549176
TI - [Infective endocarditis--a review of 21 cases in last 10 years].
AB - Twenty one cases of infective endocarditis in last 10 years were re-evaluated by
Duke's criteria. Fourteen strains of Streptococcus viridans, 4 of Enterococcus
faecalis, 1 of Haemophilus parainfluenzae were isolated from blood culture. As to
the minimum inhibitory concentration (MIC) of 8 strains of Streptococci, imipenem
revealed the lowest MIC value, following penicillin G, ceftriaxon not equal to
ampicillin, vancomycin and gentamicin. One strain of them was penicillin
resistant (0.8 micrograms/ml). Serum inhibitory test (SIT) and serum bactericidal
test (SBT) were undergone for 6 cases. The assay was efficient to determine
penicillin-tolerance of causative bacterium. Vegetations were observed in 18
cases of 21 by the echo-cardiography, especially transesophageal echocardiography
had better diagnostic sensitivity compared to transthoracic echocardiography.
However, it took 12 weeks from the first febrile episode to achieve definite
diagnosis. One of reasons to take such a long time to reach diagnosis was that
major causative organism was S. sanguis, whose inflammatory reaction to the host
was said to be strikingly weak.
PMID- 9549177
TI - Evaluation of increases in stature, upper extremity length and hand length in
children from school age to the cessation of growth in Ogi County, Japan: a
longitudinal study.
AB - Stature, upper extremity length (UEL) and hand length (HL) were measured once
yearly in children (171 males and 180 females) in Ogi County, Saga, Japan, from
the 1 st grade of primary school (6.5 years of age) for 12 years. Based on the
age of growth cessation, the order of growth cessation of stature, UEL and HL was
investigated, in addition to the relationship between this order and the
measurements obtained at 6.5 years of age. With regard to the order of growth
cessation of stature and UEL, growth cessation of UEL occurred earlier than that
of stature in 73.68% of males and 71.67% of females, growth cessation occurred
simultaneously in 23.98% of males and 25.56% of females, and growth cessation of
UEL occurred later than that of stature in 2.34% of males and 2.78% of females.
According, growth cessation of UEL occurred earlier than that of stature in most
subjects. In males, no significant differences were observed between subjects in
whom growth cessation of UEL and HL occurred simultaneously and those in whom
growth cessation of UEL occurred later than that of HL. However, in females,
significant differences were noted, since the latter case was observed 1.69 times
more frequently than the former. Nevertheless, growth cessation of stature, UEL
and HL occurred at almost the same age in both males and females when cross
sectional data was used for processing, in agreement with data reported by other
researchers. We also investigated whether there was any relationship between
stature and UEL at initial examination and the order of growth cessation. No
significant relationship was observed. Each measured value at initial examination
tended to be large in subjects in whom growth cessation of stature and UEL
occurred earlier. In addition, final stature was significantly taller in both
males and females in whom growth cessation of stature occurred later compared to
those in whom growth cessation occurred earlier.
PMID- 9549178
TI - A morphological study of the fetal ilium; focusing on the sexual differences of
the greater sciatic notch.
AB - A number of studies on sexual differences in the ilium have been reported.
However, most of these studies have focused on the adult ilium. With regard to
sexual differences in the fetal ilium, few studies have been carried out.
Especially, there have few studies regarding sexual differences in the fetal
ilium using dry bones. In the present study, sexual differences in the
morphological characteristics of the greater sciatic notch were investigated
using dry fetal iliac bones. We examined 212 fetuses (106 males and 106 females)
measuring 20.0 cm or more in fetal length with free of gross malformations or
deformities which were collected at Saga Medical School. The iliac bones were
excised from these fetuses and dried as materials for study. Fetal length was
measured in the fully extended position and was classified into six groups each
for males and females in 5-cm increments, giving a total of twelve groups. The
inner lateral surface of the greater sciatic notch was magnified 25x using
projector, traced, and the tracings were inputted to a computer (7600/120: Apple
Co. Ltd) using a flatbed scanner. The width and height of the greater sciatic
notch were measured, as well as the area of the greater sciatic notch. No sexual
differences were noted regarding the increase in the width of the greater sciatic
notch in fetuses up to 39.9 cm in fetal length. In fetuses measuring between 40.0
anf 44.9 cm, a significant sexual difference was observed, with the increase in
greater sciatic notch width markedly greater in females. With respect to the
increase in the height of the greater sciatic notch, no significant differences
were noted. No significant differences were observed in the total area of the
greater sciatic notch in fetuses up to 39.9 cm in fetal length. On the other
hand, a significant sexual difference was observed in fetuses measuring 40.0 cm
or more, with the total area markedly increased in females. In addition, no
significant differences were found in the area between the two sides of the
greater sciatic notch in fetuses up to 39.9 cm in fetal length, although
significant differences were observed in fetuses measuring 40.0 cm or more. In
female fetuses 40.0 cm or more in fetal length, the greater sciatic notch was
found to be wider than in males, and the peak of the greater sciatic notch was
displaced in the anteroinferior direction, farther from the auricular surface of
the ilium and nearer the pubic bone. Thus these female fetuses show morphological
characteristics of the adult female pelvic bone. Based on the results obtained,
it is concluded that sexual differences can be identified in fetuses from the 8th
month of pregnancy (fetal length 40.0 cm or more).
PMID- 9549179
TI - Effects of p,p'-DDE on male reproductive organs in peripubertal Wistar rats
following a single intraperitoneal injection.
AB - The effects of p,p'-DDE on male reproductive organs were investigated in detail
in peripubertal Wistar rats following a single intraperitoneal injection. 220
mg/kg of p,p'-DDE (1/4 of LD50) were injected once into prepubertal and
postpubertal Wistar rats and its effects were observed until 20 weeks of age.
Weights of the body and reproductive organs in p,p'-DDE-injected rats were
similar to those in control rats, who were injected with corn oil only. Sperm
profile parameters such as spermatid number within the testis, sperm number
within the epididymis, sperm motility and its morphology were not different
between the prepubertal or postpubertal p,p'-DDE-exposed group and the control
group. Like-wise, the histopathological examination at stage VII of the
seminiferous epithelium cycle, when the germ cells are sensitive to testosterone,
was similar in all three groups during the observation period. Serum levels of
testosterone also showed no significant changes by exposure to p,p'-DDE under the
conditions of this study. From these results, the antiandrogenic or estrogenic
activity attributed to p,p'-DDE was not confirmed in male reproductive organs and
no impairment of sperm profile was observed. This study confirmed that the
reproductive functions of matured animals are scarcely affected by p,p'-DDE
exposure during the peripubertal period and revealed that they might be
relatively resistant to exogenous endocrine-disrupting chemicals. p,p'-DDE may
threaten the hormonal equilibrium required for normal gonadal development during
the organogenesis period, at an earlier stage of life. Further studies are
necessary to fully reveal all the effects of p,p'-DDE on male reproductive organs
and sperm profile.
PMID- 9549180
TI - [Differences in the release of omeprazole in 4 commercial preparations: influence
of pH and ionic concentration].
AB - The influence of exposition to different ionic concentrations and pH values on
the subsequent in vitro dissolution of omeprazole at pH 6.8 was studied in four
enteric-coated commercial formulations. Assays were done using an experimental
protocol similar to that recommended in Delayed-Release (Enteric Coated) Articles
General Drug Release Standards (USP 23) slightly modified to achieve similar pH
values to commonly observed in patients under omeprazole treatment. Omeprazole
capsules were exposed during 1 or 2 hours to four different pH values: 4.8, 5.0,
5.2, and 5.4 and two NaCl concentrations: 75 and 225 mM. After that, dissolution
tests at pH 6.8 were performed. Three formulations (Emeproton, Pepticum and
Ulceral) released different percents of the encapsulated dose at the above acidic
mediums and, consequently, the omeprazole dissolved underwent a remarkable
degradation. The drug contained in the enteric-coated granules of Losec was not
released and therefore the amount of omeprazole dissolved at pH 6.8 from Losec
capsules was higher than the obtained with the other three preparations tested.
PMID- 9549181
TI - [Measurement of colonic transit time (total and segmental) with radiopaque
markers. National reference values obtained in 192 healthy subjects. Spanish
Group for the Study of Digestive Motility].
AB - The interest for the technique of colonic transit time (CTT) measurement with
radiopaque markers has been limited in our ambience, despite its documented
clinical usefulness in evaluating patients with severe chronic idiopathic
constipation. The aim of the present study was to contribute to the development
of the technique by establishing the upper limit of CTT in a large series of
healthy subjects in order to be used as national reference. Total and segmental
CTT have been determined in 192 healthy subjects (114 men, 78 women; median age:
33 yr; range: 18-88 yr) recruited in 18 hospitals of Spain. CTT measurement has
been carried out by means of daily administration of 20 radiopaque markers during
three consecutive days and plain abdominal X-ray taken at 4th, 7th and,
eventually, 10th day. The upper limit (95th percentile) of total, right, left and
rectosigmoid CTT was, respectively, 71.2, 22, 37.2 and 37.2 h. Women had
significantly longer transits than men for whole (p = 0.002), right and
rectosigmoid (p = 0.01, respectively) colon and near to statistical significance
(p = 0.076) for left colon. In this series, CTT were not related to age and
geographic area. Correlation between results obtained in the first reading of X
ray done in each center and a second reading done by an independent observer, was
excellent (p < 0.001). CTT measurement with radiopaque markers is a simple
technique, attainable to different assistance settings. The obtained values are
proposed as national reference given their independence from geographic area.
When employing the technique to clinical evaluation of patients with
constipation, the differences of CTT in function of gender should be kept in
mind.
PMID- 9549182
TI - [Malignant digestive tumor mortality in Castilla-La Mancha (1975-1990)].
AB - BACKGROUND: The study investigates the temporary trend of the mortality by
digestive malignant tumours in Castilla-La Mancha from 1975 to 1990. MATERIAL AND
METHODS: Standardized rates were calculated by direct method, using world and
european population as standard, truncated rates (35-64 years old) and cumulative
rates (0-74 years old) according to tumoral location and sex. RESULTS: In both
sexes the mortality by colon cancer has increased whereas the mortality by
stomach cancer has decreased. These changes observed are similar with those
observed in other epidemiologic studies. CONCLUSION: Driving a 15 year period a
significant change in mortality due to colonic and gastric cancer has occurred in
Castilla-La Mancha.
PMID- 9549183
TI - [Seven-day omeprazole, clarithromycin, and amoxicillin for the therapy of
Helicobacter pylori infection].
AB - BACKGROUND: There are few series reporting efficacy of seven-day therapy with
omeprazole, amoxicillin and clarithromycin for cure of Helicobacter pylori
infection in Spain. The aim of the present study was to evaluate the efficacy of
this treatment to eradicate H. pylori infection. PATIENTS AND METHODS: One
hundred consecutive patients with peptic ulcer disease and H. pylori infection
were evaluated for eradication therapy between January and November 1996. Four of
them were excluded because of reported penicillin allergy. The remaining 96
patients received a seven days course of omeprazole 20 mg/12h, clarithromycin 500
mg/12h and amoxicillin 1 g/12h. The efficacy of the treatment was evaluated at 2
4 months after therapy either by endoscopic biopsy or by 13C urea breath-test.
RESULTS: Seventy-eight patients were found to be cured at the control evaluation.
Intention to treat analysis showed a cure rate of 81.3% (95% CI: 74-89%). Per
protocol analysis showed a cure rate of 85.7% (95% CI: 79-93%)--78 out of 91
patient who returned for follow-up-. Compliance with the treatment was good in
94.5% of patients. Five patients presented mild side effects (diarrhea, abdominal
pain, oral candidiasis and metallic taste). None of them had to interrupt the
treatment. CONCLUSION: Seven-day therapy with omeprazole, amoxicillin and
clarithromycin achieves a 85% cure rate of H. pylori infection in our area.
PMID- 9549184
TI - [Mesenteric lymph node cavitation: a rare complication of celiac disease in the
adult].
AB - A case of coeliac disease (CD) and mesenteric lymph node cavitation (MLNC) in a
42-years-old female is presented. The other cases reported in the literature are
also reviewed. The most important ganglionar histological features are described
and a pathogenic explanation is suggested.
PMID- 9549185
TI - [Arterioportal fistula and hemobilia in a patient with hepatic transplant].
AB - The case of a 36-year old male liver transplant recipient hospitalized for upper
digestive hemorrhage, jaundice and pain in the right hypochondrium is herein
reported. Two hepatic biopsies had been performed 60 and 7 days prior to
admission. Bleeding was observed to be from the biliary tract by endoscopy and an
arterioportal fistula in the right hepatic lobe by echo-doppler and arteriography
was seen. Treatment with selective embolization by arteriography was satisfactory
with biliary tract drainage not being required. Doppler echography was used to
control the evolution of the patient.
PMID- 9549186
TI - [Malignant lymphoproliferative neoplasms and chronic hepatitis C virus
infection].
AB - It has been suggested that chronic hepatitis C virus (HCV) infection predisposes
to the development of benign and malignant lymphoproliferative disorders. We
present 2 cases of malignant lymphoproliferative neoplasias (a non-Hodgkin
lymphoma [NHL] and a chronic lymphoid leukemia [CLL]) associated to chronic
hepatitis C virus (HCV). The possible etiological role of HCV in the development
of these tumors is discussed.
PMID- 9549187
TI - [Acute hepatocellular lesion induced by amoxicillin-clavulanic acid].
AB - Since first description in 1988, numerous cases of amoxycillin-clavulanic acid
hepatotoxicity have been reported. Most of them are cholestatic hepatitis. A case
of acute hepatocellular injury by amoxycillin-clavulanic acid is reported in a 23
years-old male, with a favourable outcome after 18 weeks.
PMID- 9549188
TI - [Cheap omeprazole?].
PMID- 9549189
TI - [Drug hepatotoxicity: its prevention as an objective].
PMID- 9549190
TI - [Choledochal cysts: physiopathology and treatment].
PMID- 9549191
TI - [Computerized processing of endoscopic examinations: automation and
digitalization].
PMID- 9549192
TI - [Esophageal ulcer hemorrhage in HIV patient: treatment with argon laser].
PMID- 9549193
TI - [Multiple biliary hamartomatosis: a multidisciplinary diagnosis].
PMID- 9549195
TI - [New concepts on pathogenic mechanisms of Helicobacter pylori infection].
PMID- 9549196
TI - [Influence of Helicobacter pylori and the host in the pathogenesis of peptic
ulcer].
PMID- 9549197
TI - [What role does gastric acid secretion play in Helicobacter pylori infection? A
simple question with a complex response].
PMID- 9549198
TI - [Gastric lesion caused by NSAID and inflammation due to Helicobacter pylori. Is
there potentiation or attenuation?].
PMID- 9549199
TI - [Helicobacter pylori infection and recurrent abdominal pain in children. A proved
relationship?].
PMID- 9549200
TI - [Indications for the eradication of Helicobacter pylori. Reflections on the
Maastricht consensus conference].
PMID- 9549201
TI - [Helicobacter pylori and gastric adenocarcinoma: definitely related?].
PMID- 9549202
TI - [Helicobacter pylori and MALT-type gastric lymphoma: is it sufficient to
eradicate the infection?].
PMID- 9549203
TI - [Anti-Helicobacter vaccination: very far away or very close?].
PMID- 9549204
TI - Nursing--a maturing discipline?
PMID- 9549205
TI - The ties that bind.
PMID- 9549206
TI - Consultation--opportunity or opportunism?
PMID- 9549207
TI - Engaging in the policy dialogue.
PMID- 9549208
TI - International nursing education: challenges and strategies for success.
AB - The Nursing Education Partnership Program between Nell Hodgson Woodruff School of
Nursing at Emory University and Foo Yin Junior College of Nursing and Medical
Technology in Taiwan is in its third year. This program provides an opportunity
for associate-degree nurses from Taiwan to earn a bachelor of science degree in
nursing. The educational challenges, inherent in such a program, became evident
early in the first semester. This article outlines those challenges and the
educational strategies that were successful with this group. Implementation of
the curriculum reflects four culturally significant aspects of the educational
process: identifying community resources to meet basic needs for adaptation to a
foreign country; redesigning teaching and learning strategies for international
students; preparing faculty, clinical agency staff, patients, and other students
to accept and become actively involved in this international program; and
developing faculty-student relationships that promote mentoring and foster
professional role development. Although the strategies presented were used with a
group of students from Taiwan, they also can meet the needs of other
international students.
PMID- 9549209
TI - A prearranged mentorship program: can it work long distance?
AB - Mentoring is a supportive and nurturing relationship between an expert and a
novice. A formal mentorship program was embarked on by the Southern Council on
Collegiate Education in Nursing during the early 1990s. The purpose of this
article is to share the unique experience of two faculty who were assigned as
mentors through a written inventory process and who were able to establish a
successful mentorship, overcoming the barriers of time, distance, and an apparent
mismatch of interests and clinical skills. The authors recommend mentoring as an
important professional endeavor. Everyone-mentor, protege, and the nursing
profession as a whole-gains during the mentoring process.
PMID- 9549210
TI - The coming of age of military nursing research.
AB - An Institute of Medicine (IOM) committee recently reviewed the TriService Nursing
Research Program. In its report, The Program for Research in Military Nursing:
Progress and Future Direction, the IOM committee ' supported the continuation of
the program and made recommendations for improving it. The committee emphasized
the importance of developing and supporting programs of research, establishing an
environment of scientific excellence, determining areas for future research
funding, and allocating resources for program infrastructure, management, and
functions. This article expands that theme. It begins with an historical
perspective; addresses challenges facing military nurse researchers and the role
of programs of military nursing research; and offers a series of conclusions for
leadership necessary to establish an environment of scientific excellence.
PMID- 9549211
TI - Care: a value expressed in philosophies of nursing services.
AB - Philosophies are written to reflect the values of the institution. Nursing
service philosophies describe the essential features of nursing as practiced in a
specific site. In this study, 10 philosophies of nursing services from community
and teaching hospitals were content analyzed. Care emerged as a theme in each of
the philosophies. The care construct was further categorized as general care,
care approaches, and care descriptors: goal-directed, quality, safe, cost
effective, effective, competent, and ethical. An exhaustive description of care
as proposed by Colaizzi is presented.
PMID- 9549212
TI - A centralized, computerized, and relational data base for student clinical
placements.
AB - Quality clinical experiences are a critical component of advanced practice
nursing (APN) curricula. Historically, nursing instructors coordinated both the
didactic and clinical components of a course. Increasingly, course coordinators
organize the didactic component, and external preceptors working in the clinical
setting function as practicum teachers. Both scenarios involve labor-intensive
processes, and neither facilitate the scheduling of clinical experiences that
build on progressive learning across the student's curriculum. A centralized,
computerized, relational data base for efficient management of APN preceptors and
students across the curriculum was designed. One master's-prepared clinical
coordinator maintains the data base and performs all related functions. This
system offers numerous benefits to students, preceptors, ] faculty, and nursing
school, including balanced and progressively complex clinical learning
experiences for students from competent preceptors: consistent interface with
students and preceptors; faculty relief from time-consuming tasks; rapid
generation of a variety of tables, rosters, and reports; consistent tracking of
preceptor evaluations; timely acknowledgment of preceptor assistance; and
efficient communication among students, preceptors, faculty, and school
administration.
PMID- 9549213
TI - A concept analysis of autonomy.
AB - The nursing profession places a high value on the acquisition of autonomy as a
requisite for professional status. Although the literature is replete with
studies that examine autonomy and nurses, methods and results often are
inconsistent and inconclusive. Review of the literature reveals ambiguous or
absent definitions of autonomy. Nursing commonly confuses autonomy with related
concepts such as authority, accountability, power, professionalism, and
independence. A concept analysis of autonomy is done using Walker and Avant's
modification of Wilson's analysis procedure. This highly abstract concept emerges
as a discrete, empirically definable term referring to a potential human quality
in an existing state. The analysis includes antecedents, consequences, defining
attributes, model and borderline cases, and empirical referents.
PMID- 9549214
TI - The changing self-concept of pregnant and parenting teens.
AB - Self-concept has been recognized and researched as a powerful variable in
relation to teenage pregnancy. Low self-concept frequently has been identified as
a cause and consequence of teenage pregnancy as well as a factor in participation
and compliance with health care recommendations. Most of the research on self
concept and teenage pregnancy occurred in the 1970s to mid-1980s, and all found
lower self-concept in pregnant and parenting teens when compared with their
nonpregnant contemporaries and normative data. This study found the opposite to
be true. The 126 pregnant and parenting teens in this study had higher self
concepts than the reported normative group. Also, important variations in self
concept were found in relation to sociodemographics. This potentially suggests
that what was once known about this aggregate is no longer true, and a
reinvestigation is warranted. The purpose of this study was to reinvestigate the
self-concept of pregnant and parenting teens and compare them with published
normative data and to examine the relationship between sociodemographics and self
concept. The study employed a survey methodology. Data were analyzed using
frequencies, percentages, measures of central tendency and dispersion, t test,
chi-square test, and analysis of variance. This study found that pregnant and
parenting teens had a higher self-concept than the normative data on nonpregnant
teens reported by the research instrument authors. Furthermore, this older sample
of pregnant and parenting teens (mean age, 17.83 years) had self-concepts more
similar to the junior high school normative sample than their senior high school
age contemporaries. Also, this study found that self-concept varies according to
the pregnant and parenting teens; ages, years of schooling, types of schools
attended, income sources, and receipt of public assistance. This study has
implications for health care providers, health and public educators, and nursing
researchers in terms of program development and evaluation, health marketing, and
development of primary prevention strategies.
PMID- 9549215
TI - Factors associated with National Council Licensure Examination-Registered Nurse
success.
AB - Identification of factors associated with National Council Licensure Examination
Registered Nurse (NCLEX-RN) success is critical at public colleges of nursing
with diverse student populations. This issue was the purpose of this research
study. A descriptive correlational research design was used. Seventy-nine generic
senior students enrolled in an urban public university participated in the study.
Several internal and external blocks to success were described by the students,
including family responsibilities, emotional distress, fatigue, and financial and
work burdens. Significant correlations were found between success in the NCLEX-RN
and cumulative undergraduate nursing program grade point average, English as the
primary language spoken at home, lack of family responsibilities or demands, lack
of emotional distress, and sense of competency in critical thinking.
Establishment of a comprehensive data base-including factors associated with
success in the NCLEX-RN and programs of advisement, tutoring, and stress
management as well as classes in study skills, test taking, and NCLEX preparation
are recommended for public colleges of nursing with diverse student populations.
PMID- 9549216
TI - Education for nurses in administrative roles (supplement to the Essentials of
Master's Education for Advanced Practice Nursing). American Association of
Colleges of Nursing and American Organization of Nurse Executives.
PMID- 9549217
TI - Wellmark to offer Medicare managed care products.
PMID- 9549218
TI - IMS supports name-specific HIV reports.
PMID- 9549219
TI - Is Medicare running out of time?
PMID- 9549220
TI - Pharmacists take a shot at Medicaid reimbursement.
PMID- 9549221
TI - A technological meltdown could be the end....
PMID- 9549222
TI - The secret of low-load life insurance.
PMID- 9549223
TI - Uwe E. Reinhardt, PhD.
PMID- 9549224
TI - Bootstraps and jackknives: new, computer-intensive statistical tools that require
no mathematical theories.
PMID- 9549225
TI - Angiogenesis in rheumatoid arthritis: pathogenic and clinical significance.
AB - In summary, angiogenesis, the formation of new blood vessels, is important in
leukocyte extravasation and thus the pathogenesis of RA. The outcome of
neovascularization highly depends on the imbalance between angiogenic and
angiostatic mediators produced in the rheumatoid synovium. Therefore,
angiogenesis research is important for the understanding of the pathogenesis of
inflammatory arthritis. In addition, existing and potential angiostatic drugs may
be useful for future therapy of RA.
PMID- 9549226
TI - Simulated glomerular hypertension promotes mesangial cell apoptosis and
expression of cathepsin-B and SGP-2.
AB - BACKGROUND: Focal glomerulosclerosis (FGS) is characterized by the accumulation
of mesangial matrix and lack of mesangial cells (MC). We studied the role of
glomerular hypertension (GH) in the development of MC hypoplasia. METHODS: We
used an in vitro model of GH to study the effect of GH on MC apoptosis. Cultured
rat endothelial cells were grown in the intracapillary space and MCs were grown
in the extracapillary space. MC proliferation as well as apoptosis was evaluated
under simulated normal glomerular pressure (SNGP) as well as simulated glomerular
hypertension (SGH). Apoptosis was determined morphologically by DNA fragmentation
using Hoechst staining as well as with the use of DNA gel electrophoresis. MCs
grown under SNGP and SGH were also evaluated for the expression of genes
associated with active cell death. In addition, we evaluated the effect of direct
applied pressure on MC apoptosis. RESULTS: MCs grown under SGH were less
elliptical and had a tendency to develop a dome in the center. Direct applied
pressure promoted MC apoptosis in a dose and time dependent manner. DNA gel
electrophoresis from MCs grown under SGH also showed integer multiples of 180
base pairs (ladder pattern); whereas cells grown under SNGP showed no DNA
fragmentation. SGH increased mRNA expression of cathepsin-B (SNGP, 0.31 +/- 0.04
vs SGH, 0.57 +/- 0.03, P < 0.01, n = 3) and SGP-2 (SNGP, 0.55 +/- 0.05 vs SHG,
1.08 +/- 0.12, P < 0.01, n = 3) in MCs when compared to cells grown under SNGP.
CONCLUSIONS: The present in vitro study suggests that GH has the potential to
convert a hypercellular mesangium into a hypocellular one. This effect of GH is
associated with expression of genes associated with active cell death.
PMID- 9549227
TI - Enhanced lipid peroxidation in hepatic cirrhosis.
AB - BACKGROUND: Lipid peroxidation is thought to play a role in the evolution of
liver damage, based on evidence in experimental models. However, evidence that
lipid peroxidation occurs in patients with liver disease remains to be provided.
We addressed the hypothesis by measuring levels of 8-epi Prostaglandin F2 alpha a
bioactive prostaglandin isomer produced by free radical catalyzed peroxidation of
arachidonic acid, in patients with liver cirrhosis. METHODS: In 42 patients with
hepatic cirrhosis 8-epi Prostaglandin F2 alpha, factor VII activity, endotoxemia,
carotenoids and alpha-tocopherol were measured. In 10 patients 8-epi
Prostaglandin F2 alpha was also measured before and 30 days after 300 mg b.i.d.
vitamin E administration. RESULTS: Cirrhotic patients had significant higher 8
epi Prostaglandin F2 alpha, excretion than controls [median (range): 199.2 (60.0
812) vs 85.9 (55.6-160.0) pg/mg creatinine, p < 0.0001]. Patients with urinary 8
epi Prostaglandin F2 alpha above the range in controls were more likely to have
moderate or severe than mild liver failure (p < 0.004). They also had lower
factor VII activity (62 +/- 19 vs 74 +/- 15%, P < 0.02) than patients with normal
levels of the isoprostane. Urinary excretion of 8-epi Prostaglandin F2 alpha
correlated directly with endotoxemia (Rho = 0.56, p < 0.0002) and inversely with
factor VII (Rho = -0.39, p < 0.02). Cirrhotic patients given vitamin E showed a
significant decrease of urinary 8-epi Prostaglandin F 2 alpha [median (range):
342.5 (170 - 812) vs 292.5 (142-562) pg/mg creatinine, p < 0.04]. CONCLUSION:
This study demonstrated that lipid peroxidation is increased in vivo in patients
with cirrhosis and suggests that oxidant stress might contribute to the
deterioration of liver disease.
PMID- 9549228
TI - Lupus humoral autoimmunity induced in a primate model by short peptide
immunization.
AB - BACKGROUND: Systemic lupus erythematosus (SLE) is characterized by humoral
autoimmunity against the spliceosomal proteins, including Sm B/B'. In SLE
patients with anti-Sm B/B' antibodies the proline rich sequence, PPPGMRPP, is the
predominant Sm B/B' autoimmune epitope and appears to be an early target in the
development of the anti-Sm B/B' response. METHODS: Two female baboons were
immunized with the PPPGMRPP peptide from the Sm B/B' spliceosomal protein
constructed on a MAP backbone in Freund's adjuvant. One female control baboon was
immunized with Freund's adjuvant alone. Baboon sera were collected and assessed
for antibody binding to the spliceosomal proteins and compared to SLE patient and
control sera. RESULTS: Peptide immunized baboons developed antibodies to multiple
regions of the Sm B/B' protein, as well as reactivity against other spliceosomal
proteins. Consistent with serologic manifestations found in SLE, experimental
baboons also acquired anti-nuclear antibodies, anti-nuclear ribonucleoprotein
(nRNP) antibodies and, in one animal, anti-double stranded DNA antibodies. The
control animal had none of these immunologic findings. CONCLUSIONS: Immunization
with PPPGMRPP is capable of initiating a humoral autoimmune response in primates
against the Sm, nRNP complex from which the peptide was derived. The additional
autoantibody specificities generated in experimental animals are similar to those
found in human SLE sera. This study is the first evidence of peptide induction of
SLE humoral autoimmunity in a primate model.
PMID- 9549229
TI - Elevated carcinoembryonic antigen in patients with androgen-independent prostate
cancer.
AB - BACKGROUND: Extraordinarily high serum carcinoembryonic antigen (CEA) values have
been reported to be associated with many malignant disorders, including carcinoma
with primary sites in the colon, pancreas, stomach, bile duct, lung, and breast.
This study was undertaken to determine if a marked elevation of serum CEA levels
in androgen-independent prostate cancer patients exists, and to evaluate the
potential of using CEA monitoring as a marker for disease progression. METHODS:
Records from 141 patients with progressive androgen-independent prostate cancer
who were treated at the National Cancer Institute from 1990 to 1996 were
analyzed. Serum CEA concentrations were measured using a micro-particle enzyme
immunoassay. RESULTS: Among these cases of prostatic carcinoma, 69 (48.9%) had
abnormally elevated plasma CEA values (greater than the normal upper limit of 2.5
ng/mL) at some time during their treatment on a clinical investigation protocol.
No correlation was found between the elevated CEA concentrations and prostate
specific antigen (PSA). In comparison, 32.5% of patients with elevated CEAs had
disease that had metastasized to soft tissue (adenopathy, etc) versus 22.2% with
normal CEA who had soft tissue involvement (p = 0.3 X2). We examined the CEA
values with respect to survival time, defined as the interval from the date of
the earliest CEA level to the date of death and found no association (p > 0.3).
CONCLUSIONS: Based on these observations, it appears that in the context of
androgen-independent prostate cancer, CEA can be elevated but is an inviable
surrogate marker of disease progression with minimal prognostic value.
PMID- 9549230
TI - Rapid differentiation of Mycobacterium tuberculosis and Mycobacterium bovis using
glycerol susceptibility and quantitative polymerase chain reaction.
AB - BACKGROUND: The differentiation between Mycobacterium tuberculosis (MTB) and
Mycobacterium bovis has significant epidemiological and therapeutic implications,
such as their susceptibility to different drugs and the need for different
approaches to patient isolation. However, currently this differentiation is based
on laboratory methods that take 8 to 16 weeks. Simple qualitative polymerase
chain reaction (PCR) can not differentiate between MTB and M bovis because of
their genetic similarities. METHODS: We evaluated the use of quantitative PCR
(QPCR) and glycerol susceptibility to differentiate MTB from M bovis. Three
patient isolates of M bovis and 5 patient isolates of MTB were suspended in 7H9
broth containing 0.0%, 0.2%, or 0.6% glycerol. These suspensions were inoculated
on 7H11 plates and incubated at 37 degrees C and 5% CO2. QPCR was performed after
0, 3, and 6 days of incubation. RESULTS: After 6 days of incubation for M bovis
isolates, the mean DNA concentration decreased by one log in the presence of 0.6%
glycerol while for MTB isolates, the mean DNA concentration increased by one log
regardless of the glycerol concentration. CONCLUSION: These data suggest that
QPCR and glycerol susceptibility may be used to differentiate between MTB and M
bovis within 1 week.
PMID- 9549231
TI - Effects of diabetes and difluoromethylornithine treatment on hyperplasia,
activity of MAP-kinase, and activity and association with cyclin B of p34cdc2
kinase in rat jejunal mucosa.
AB - BACKGROUND: The different signal transduction pathways of rapidly proliferating
cells of the intestine are not clearly understood. We report here a possible
signaling pathway that involves regulation of activity of two closely related
kinases, MAP-K (mitogen-activated protein kinase) and p34cdc2 kinase, during
hyperplasia of diabetic jejunal mucosa. Our aim was to investigate the activity
and phosphorylation of MAP-K and activity and association of p34cdc2 kinase with
cyclin B during diabetes-induced jejunal mucosal hyperplasia in vivo. METHODS: We
studied untreated and difluoromethylornithine (DFMO) treated control rats and
rats with streptozotocin-induced type I diabetes. Assays were done 10 days after
the induction of diabetes. In diabetic rats there was jejunal hyperplasia as
indicated by increases in the jejunal mucosal weight/cm and DNA content as well
as increased activities of MAP-K and p34cdc2 kinase and association of the latter
with cyclin B as compared to corresponding values in control rats. Administration
of DFMO, an irreversible inhibitor of the proliferation-associated enzyme
ornithine decarboxylase (ODC), prevented diabetes-I induced jejunal hyperplasia
and decreased all of the above enzymic parameters in both diabetic and control
rats. In our previous in vivo study, DFMO administration also blocked diabetic
jejunal hyperplasia and in addition decreased ornithine decarboxylase and
tyrosine kinase activities jejunal and tyrosine phosphorylation of proteins.
CONCLUSION: Thus the jejunal mucosal hyperplasia found in diabetes appears to
involve activation of signal transduction pathways involving tyrosine kinases,
MAP-K, p34cdc2 kinase, and cyclin B.
PMID- 9549233
TI - Special issue on human behavioral genetics: synthesis of quantitative and
molecular approaches.
PMID- 9549232
TI - NADH-methemoglobin reductase (cytochrome b5 reductase) levels in two groups of
American blacks and whites.
AB - BACKGROUND: Sickle cell trait, glucose-6-phosphate dehydrogenase (G6PD)
deficiency and alpha-thalassemia trait are common genetic abnormalities among the
American Black population. Under oxidative stress, the presence of any of these
conditions would predispose the hemoglobin (Hb) to oxidation resulting in
accelerated methemoglobin (metHb) formation. It was hypothesized that red cells
phenotypic for these genetic variants should have more or different levels of
metHb reductase (cytochrome b5 reductase) activity. METHODS: To test this
hypothesis, we measured the red cell metHb reductase activity in 558 male
subjects (316 Blacks and 242 Whites), by the procedure described by Beutler. All
Black patients also had G6PD spot test and Hb electrophoresis. In addition, all
patients had a complete blood count (CBC). If the hematocrit was < 35% a
reticulocyte count was also done. Patients with corrected reticulocyte (retic
count X hematocrit/45) index over 2% were excluded regardless of other findings.
RESULTS: The results showed that Blacks had different metHb reductase activity
levels than Whites (mean = 3.19 vs 2.89 IU/gHb, respectively with p = 0.03).
However, the differences in metHb reductase activities in patients with sickle
cell trait, G6PD deficiency, and low MCV < 80 micron3 (presumptively having alpha
thalassemia) in small subgroups did not reach statistical significance (p = 0.2),
although, all 3 groups were comprised of small numbers. CONCLUSIONS: It is
concluded that American Blacks have significantly different metHb reductase
activity. The different metHb reductase activity in Blacks seems to be unrelated
to the presence of G6PD deficiency, sickle cell trait, or alpha-thalassemia and
it may be the result of genetic polymorphism. However, our study samples do not
exactly represent the cross-sections of the Black and White populations. In
addition, all patients were male in this study. Therefore, this study should be
confirmed using larger and more population-representative samples. The clinical
significance of this problem is not clear at this time.
PMID- 9549234
TI - Behavioral genetics and evolutionary psychology: unified perspective on
personality research.
AB - Behavioral geneticists and evolutionary psychologists have generally pursued
human behavioral analyses with little theoretical or methodological exchange.
However, significant benefits might accrue from increased communication between
these disciplines. The primary goals of this article are (1) to identify
meaningful junctures between behavioral genetics and evolutionary psychology, (2)
to describe behavioral genetic research designs and their applications to
evolutionary analyses, and (3) to reassess current personality research in light
of behavioral genetic and evolutionary concepts and techniques. The five-factor
model of personality is conceptualized as subsuming variation in normative
species-typical systems with adaptive functions in the human environment of
evolutionary adaptation. Considered as universal evolved mechanisms, personality
systems are often seen in dynamic conflict within individuals and as highly
compartmentalized in their functioning between settings. However, genetically
influenced individual differences in personality may also be understood within an
evolutionary framework. Studies of the heritability of personality traits
indicate broad-sense heritabilities in the 0.40-0.50 range with evidence of
substantial nonadditive genetic variation and nonshared environmental influences.
Evidence indicates that evolutionary theory (e.g., inclusive fitness theory)
predicts patterns of social interaction (e.g., cooperation and bereavement) in
relatives. Furthermore, variation in personality may constitute a range of viable
strategies matching the opportunities available in the complex niche environment
of human societies. Within this wide range of viable strategies, personality
variation functions as a resource environment for individuals in the sense that
personality variation is evaluated according to the interests of the evaluator
(e.g., friendships, coalitions, or mate choice).
PMID- 9549235
TI - Functional organization of the human mind: implications for behavioral genetics
research.
AB - It is proposed that the fundamental goal of human behavior is to organize and
control the social, biological, and physical environments that support
reproduction and survival and that the human mind is organized as a system of
social, biological, and physical modules that support attempts to seek such
control. More precisely, modules are systems of motivational, emotional,
cognitive, and behavioral processes that provide the interface between this
fundamental goal and the environments within which this goal must be achieved. An
outline of this functional systems approach to the human mind is provided and the
implications of this perspective for behavioral genetics research are discussed.
PMID- 9549236
TI - Innateness, evolution, and genetics of language.
AB - Our goal in this article is to review a debate over the evolution of language and
to suggest some keys to its resolution. We begin with a review of some of the
theoretical and empirical evidence for the innateness of language that has caused
renewed interest in the evolution of language. In a second section we review some
prominent theories of the evolution of language, focusing on the controversy over
whether language could have been adapted for some purpose. We argue that for
evolutionary studies of language to advance, theorists must make more persuasive
arguments for the purpose of language, and, furthermore, linguists must continue
to develop a detailed theory of syntax. Finally, we suggest ways that behavioral
and population genetics could help to inform studies of the evolution of
language.
PMID- 9549238
TI - Molecular approaches to the genetic analysis of specific reading disability.
AB - Specific reading disability is a complex phenotype that is under both genetic and
environmental influences. There is evidence for at least one major gene, which
may be detectable by parametric linkage analysis, but detection of other
quantitative trait loci may require nonparametric methods. Phenotype definition
may also be critical in identifying genes that affect different components of the
reading process. Current research from two separate laboratories supports the
localization of one gene influencing reading disability to the histocompatibility
region of chromosome 6p and suggests that another gene may be located on
chromosome 15. Actual identification of these and similar genes is complicated by
reduced penetrance and phenocopies in families, so that delineation of the
critical region using crossover analysis is problematic. This difficulty can
result in the identification of many candidate genes that need to be evaluated
through combinations of association analysis, functional analysis, and mutation
assays.
PMID- 9549237
TI - Multivariate behavioral genetic analysis of achievement and cognitive measures in
reading-disabled and control twin pairs.
AB - In recent years behavioral genetic studies have provided conclusive evidence that
reading disability and related learning disorders, such as mathematics
disability, are due at least in part to heritable factors (DeFries et al. 1987;
Alarcon et al. 1997). Although the observed relationship between performance in
these areas also may be due substantially to genetic influences (Light and
DeFries 1995; Thompson et al. 1991), relatively few studies have examined the
genetic and environmental etiology of this covariation in a multivariate
framework. In the present study data from 196 identical (monozygotic; MZ) and 155
same-sex fraternal (dizygotic; DZ) twin pairs in which at least one member of
each pair evidenced reading problems in school (reading disabled) were subjected
to a multivariate behavioral genetic analysis. Structural equation models were
fitted to twin data for verbal IQ (VIQ), phonological decoding ability (PHON),
reading performance (READ), and mathematics performance (MATH) to assess the
extent to which VIQ and PHON mediate the observed covariation between READ and
MATH. Results suggest that VIQ and PHON account for most of the covariation
between READ and MATH. Moreover, approximately 82% of the observed correlation
between READ and MATH was due to genetic factors that also influence VIQ and
PHON. When data from 132 MZ and 91 same-sex DZ control twin pairs in which
neither twin had a history of reading problems were subjected to the same
analyses, the covariation between READ and MATH was found to be due to both
genetic and shared environmental influences. Thus genetic factors that influence
VIQ and PHON also contribute to the observed covariation between READ and MATH in
both a reading-disabled and a control twin sample.
PMID- 9549239
TI - Genetic and environmental influences on adult intelligence and special mental
abilities.
AB - I review representative biometric studies of adult twins and adoptees that have
been used to generate estimates of genetic and environmental influence on
intelligence (IQ) and special mental abilities. The various studies converge on a
heritability estimate between 0.60 and 0.80 for IQ. Estimates of common
environmental influence from the same studies are near zero. Studies of twins
reared together and studies of unrelated individuals reared together yield
sizable estimates of common family environmental influence in childhood but also
demonstrate that this influence dissipates with age and approaches zero in
adulthood. Twin studies of the major special mental abilities (verbal, spatial,
perceptual speed and accuracy, memory) yield heritability estimates of about 0.50
and modest estimates of common environmental influence.
PMID- 9549240
TI - Molecular genetic studies of cognitive ability.
AB - Given that the evidence of a substantial genetic contribution to cognitive
ability is now convincing, the next challenge is to locate and identify the genes
involved. It is likely that there are several genes, each of only small effect.
Detection of such so-called quantitative trait loci contributing to polygenic
traits in plants and animals is facilitated by the ability to carry out
experimental crosses. However, in humans detection of quantitative trait loci
depends on studies of siblings or other relative pairs or on allelic association
studies aimed at detecting linkage disequilibrium in populations. The allelic
association approach is currently being applied to investigate cognitive ability
by using both candidate genes and DNA pooling methods that potentially allow
rapid screening of the whole genome for quantitative trait loci.
PMID- 9549241
TI - Genetics of spoken language disorders.
AB - If language is the result of specialized structures in the brain and if these
language-specific structures are genetically encoded, one would expect to find
evidence of the heritability of language. In this article I review the results of
family aggregation, pedigree, sex ratio, commingling, and segregation studies of
spoken language disorders. The results of these studies provide evidence that,
although spoken language disorders are genetically and behaviorally
heterogeneous, genetic factors may play a substantial role in many cases of
developmental spoken language disorders.
PMID- 9549242
TI - Molecular genetic approaches to the study of language.
AB - The application of the techniques of modern molecular biology to the study of the
genetic control of language development poses many significant challenges.
Because language is a complex function, disruption of any of a number of systems
can impair language development. The diagnostic classification of specific
language impairment includes individuals with an apparently inherited form of
disordered language development, and therefore some aspects of this clinical
phenotype may be useful for positional cloning studies of genes related to
language. Known genetic disorders with specific deficits in language functions
may also serve to identify candidate genes for language development. In addition
to these specific approaches, the current general strategies for positional
cloning and candidate gene studies are reviewed.
PMID- 9549243
TI - Human sexual orientation has a heritable component.
AB - We present an overview of behavioral genetics research on homosexual and
heterosexual orientation. Family, twin, and adoptee studies indicate that
homosexuality and thus heterosexuality run in families. Sibling, twin, and
adoptee concordance rates are compatible with the hypothesis that genes account
for at least half of the variance in sexual orientation. We note observations of
homosexual behavior in animal species, but the analogy to human sexual
orientation is unclear. We discuss the reproductive disadvantage of a homosexual
orientation and present possible mechanisms that could maintain a balanced
polymorphism in human populations.
PMID- 9549244
TI - Molecular investigations into complex behavior: lessons from sexual orientation
studies.
AB - A review of recent molecular genetic investigations into sexual orientation is
presented and used as a model to identify unique challenges encountered in
research on complex behavior. Five main themes are presented that are generally
applicable to most behavioral genetics investigations: (1) A precise definition
of the phenotype that, as much as possible, unambiguously differentiates the
study group from the control group must be achieved; (2) environmental and social
contributions to a trait may exhibit significant sex differences; (3) subsets
within the study sample may reveal important information about genetic and
environmental contributions to the trait that otherwise would be missed; (4) the
high degree of specificity required to define a study sample severely restricts
the application of results to general populations; and (5) studies attempting to
replicate data must strictly parallel the original methodology if valid
comparisons are to be made.
PMID- 9549245
TI - Developmental psychopathology, personality, and temperament: reflections on
recent behavioral genetics research.
AB - Personality, temperament, and psychopathology were until recently largely
distinct areas of study, each of which emphasized partitioning of heritable and
environmental variance. The emergence of the paradigm of developmental
psychopathology along with application of multivariate biometric models to
behavioral genetic data has defined a second phase of research in these domains.
Integrated research has begun to map dimensional liability-threshold models of
psychopathology and to evaluate empirically the categorical versus dimensional
etiology of traits and disorders. An interesting pattern in the data is that
psychopathology is probably not merely an extreme of temperament or personality
in many cases. Variations in temperament and personality are now known to be
heavily influenced by additive genetic and nonshared environmental factors and to
exhibit stable or increasing heritability across development. This pattern holds
for some measures of psychopathology but not for others. For example, shared
environment effects and decreasing heritability influence much adolescent
psychopathology, and comorbid problems in young children appear to be due in part
to shared environment effects. Other recent biometric work on the central problem
of comorbidity in psychopathology suggests that shared genetic covariation
accounts for some specific comorbidities but not others. A third phase of
research is now underway, featuring study of specific molecular gene mechanisms
by means of linkage and association studies in relation to behavioral phenotypes.
Complementary integration of discoveries from biometric behavioral studies and
molecular studies is expected to be the norm for the near future.
PMID- 9549246
TI - Molecular approaches to child psychopathology.
AB - Basic research into the genetics of childhood psychiatric disorders has
substantially increased during the last two decades. Specific genetic mutations
have been characterized in some developmental disorders (e.g., fragile X syndrome
and Prader-Willi syndrome), but thus far identification of etiological gene
mutations in psychiatric illnesses has been unsuccessful. Several psychiatric
disorders serve as examples of the current state of molecular approaches in child
psychopathology. Investigations to date of Gilles de la Tourette's syndrome (GTS)
have not resulted in the discovery of a gene of major effect. Some studies have
implicated the D2 and D4 dopamine receptors as having a direct role in the
etiology of GTS, but other studies have disputed those findings. However, the
dopamine D2 receptor may modulate the severity of GTS. Obsessive-compulsive
disorder has a reported association with a low-activity allele of the enzyme
catechol-O-methyltransferase; however, the low-activity genotype is also seen in
a significant proportion of unaffected individuals. For reading disability two
distinct phenotypes (phonological awareness and single-word reading) have been
linked to separate loci on chromosomes 6 and 15. Attention deficit hyperactivity
disorder (ADHD) has a reported association with the dopamine transporter.
Findings of a genetic locus for the personality trait of novelty seeking remain
controversial.
PMID- 9549247
TI - Nicotine: smoking gun or magic bullet?
PMID- 9549248
TI - A pilot study of the safety and tolerance of SCH 39166 in patients with
schizophrenia.
PMID- 9549249
TI - SSRI discontinuation syndrome related to fluvoxamine.
PMID- 9549252
TI - Light therapy to treat winter depression in adolescents in Iceland.
AB - OBJECTIVE: To determine whether light therapy during winter is beneficial to
adolescents with symptoms of seasonal affective disorder (SAD). SETTING: The 3
largest colleges in Reykjavik, Iceland. PARTICIPANTS: Eighteen college students,
18 and 19 years old, suffering from symptoms of SAD. OUTCOME MEASURES: School
attendance and self-reported change in indicators (concentration, ability to
awaken in the morning, and frequency of breakfast). RESULTS: Light therapy helped
some of the students concentrate and wake up in the morning, usually only to a
mild degree, but did not improve school attendance. CONCLUSIONS: The lack of
effect of light therapy on school attendance in a group of students with symptoms
of SAD indicates that school attendance is influenced by several complex factors,
of which seasonal disorders are not a major determinant, even in those most at
risk.
PMID- 9549250
TI - Nicotine: abused substance and therapeutic agent.
AB - Tobacco dependence is a complex phenomenon that is not fully understood. Nicotine
is the main alkaloid in tobacco and the addictive compound of tobacco. It can
improve both mood and cognitive functioning; these positive effects are strong
reinforcements for smokers and contribute to their addiction. Opposite results
also have been reported, however, and the effects of nicotine remain
controversial. Recent epidemiological and empirical studies have indicated that
smoking or nicotine or both may have protective effects against certain diseases.
These findings have suggested that nicotine may be used as a therapeutic agent.
However, because a variety of nicotinic cholinergic receptors are present in the
brain, new agonist compounds may prove to be more effective than nicotine for
therapeutic purposes. Studies are reviewed and the suggestion made that nicotine
may prove useful as a tool to help us understand normal and pathological brain
functioning.
PMID- 9549253
TI - What is the optimal approach to the pharmacological management of obsessive
compulsive disorder?
PMID- 9549251
TI - Calcitonin and bipolar disorder: a hypothesis revisited.
AB - Double-blind trials conducted in the early 1980s showed that subcutaneous
injections of salmon calcitonin in patients suffering from mania resulted in
significant decreases in irritability, euphoria and hyperactivity. Although these
results were promising, there were no follow-up studies in this area. A MEDLINE
search into the effect of calcitonin on neuronal tissues revealed that calcitonin
affects neuronal tissues in a manner similar to that of the currently accepted
mood-stabilizing agents--namely by modulating intracellular second messenger
signalling mechanisms, stabilizing neuronal membranes and inhibiting neuronal
calcium influx. We suggest that these effects of calcitonin on neuronal tissues,
combined with earlier clinical research showing its efficacy in treating the
acute symptoms of mania, make calcitonin a candidate for further research in the
treatment of bipolar disorder.
PMID- 9549254
TI - If a patient does not respond to a full dose of fluvoxamine for at least 12
weeks, what alternatives should be considered?
PMID- 9549256
TI - Name that drug ... a game with the FDA.
PMID- 9549255
TI - Better living through research.
PMID- 9549257
TI - The emperor's new clothes.
PMID- 9549258
TI - Oral and topical antihistamines: pharmacologic properties and therapeutic
potential in ocular allergic disease.
AB - BACKGROUND: Allergic eye disease is a common clinical occurrence in individuals
who experience local and systemic hypersensitivity reactions. The majority of
ocular symptoms involve the conjunctiva and lids, which are exposed to the
environment and thereby are sites of interaction between allergens and
immunocompetent cells. Signs and symptoms of ocular involvement can manifest as
itching, chemosis, tearing, swollen lids, and photophobia. METHODS: Histamine is
a key preformed mediator released when allergen molecules crosslink to antigen
binding components of adjacent IgE molecules on mast cells or basophil surface.
On its release, histamine acts on H1-receptors on a variety of tissues and cells,
including blood vessels, smooth muscle, and sensory nerves. RESULTS: Drugs
classified as H1-receptor antagonists, commonly referred to as the
antihistamines, are among the most efficacious and frequently used medications
for ocular and systemic allergy symptoms. CONCLUSION: This review focuses on the
pharmacologic actions and side effects of oral first-generation sedating or
classic H1-receptor antagonists; the second-generation, relatively nonsedating H1
receptor antagonists; and the topical ocular antihistamine/decongestants and
single-entity antihistamine formulations.
PMID- 9549259
TI - Pediatric contact lenses: case reports.
AB - BACKGROUND: Contact lenses may be a useful, even essential, treatment modality
for children with a variety of optometric needs. Many clinicians who are
experienced and capable contact lens practitioners but do not specialize in the
care of children may refrain from considering contact lenses as a treatment
option because of a host of perceived problems. Most of these concerns can be
readily overcome with patience, planning, and education. CASE REPORTS: Five cases
are presented to illustrate specific clinical problems and the clinical
application of contact lenses in the pediatric population. CONCLUSION: The case
reports illustrate the clinical application of contact lens fitting in children
with a variety of clinical needs. The use of contact lenses in children is an
ongoing process, requiring great flexibility and creativity on the part of the
optometrist. Educating the child and the family is an integral part of the
treatment. The use of contact lenses in children is both an opportunity and a
challenge that may result in great satisfaction for the child, the family, and
the optometrist.
PMID- 9549260
TI - Glaucoma medications, glaucoma therapy, and the evolving paradigm.
AB - BACKGROUND: Therapy for the glaucomas is dynamic, with changes evolving as new
medications or modalities are discovered. In comparing the method(s) of treating
open-angle glaucoma today, as compared to treatment in the 1980s, clear
differences emerge. While topical beta-blockers remain the mainstay for treatment
of open-angle glaucoma, other medications and modalities have recently become
available that supplement their use. Topical carbonic anhydrase inhibitors
(CAIs), introduced in 1995, have become an important addition to the glaucoma
armamentarium. They are more useful than their oral counterparts, since they
cause fewer systemic side effects, with similar efficacy. Brimonidine, a topical
alpha2-adrenergic agonist, and latanoprost, a topical prostaglandin, have become
important additions to the glaucoma regimen because of their ability to reduce
the intraocular pressure (i.o.p.) with an improved therapeutic index, as compared
to older medications. Finally, argon laser trabeculoplasty (ALT) appears to be a
safe technique and useful in reduction of IOP. CONCLUSION: The scheme for how the
anti-glaucoma medications and modalities are used for the therapy of open-angle
glaucoma will change over time. The evolution will occur as we continue to learn
more about the drugs presently being used.
PMID- 9549262
TI - Fluid blood level in cystoid space resulting from central retinal vein occlusion.
AB - BACKGROUND: A hemorrhagic and cystoid maculopathy developed in a patient with a
central retinal vein occlusion. There was an unusual finding of a fluid blood
level in the inferior region of the central large cystoid space. This clinical
finding has been associated with cystoid macular edema after aphakic/pseudophakic
cataract surgery. METHOD: A case report is presented and a review of the
literature was conducted to determine the frequency of this condition and gain
knowledge of the possibility of the pathophysiology. RESULTS: This is only the
second case reported in the literature of a fluid blood level seen in a patient
with obstructive venous retinopathy. The pathophysiology is likely to be the
transitory bleeding of a retinal vessel into the cystoid space. CONCLUSION: The
finding of a fluid blood level in a patient with a BRVO or CRVO is a rare event.
Since this condition has not been associated with diabetic hemorrhagic
retinopathy, any diabetic patient displaying such a clinical finding should be
suspected of having obstructive venous disease.
PMID- 9549263
TI - Preoperative embolization of meningiomas: comparison of superselective and
subselective techniques.
AB - We retrospectively compared the efficacy of preoperative superselective and
subselective embolization for intracranial meningiomas. Between January and
December 1996, 22 patients (7 men, 15 women, mean age 51 +/- 15.5 yr) underwent
superselective embolization with 45 to 150 mm polyvinyl alcohol particles after
superselective catheterization of the feeding vessels with a microcatheter
system. Another 30 patients (12 men, 18 women, mean age 50 +/- 12.9 yr) underwent
subselective embolization between January and December 1995 with 150 to 300 mm
Gelfoam particles after catheterization of the terminal external carotid artery
just proximal to the orifice of the maxillary artery with a 4- or 5-F
angiocatheter. The mean intraoperative blood loss (918 versus 1450 mL, p < 0.05),
amount of blood transfused (4.9 versus 7.5 units, p = 0.09), and surgical
resection time (422 versus 529 min, p < 0.05) were all lower in the
superselective group than in the subselective group, while the occurrence of
fresh ischemic necrosis (59% versus 53%, p = 0.68), hemorrhage (77% versus 60%, p
= 0.19), and embolic material (55% versus 13%, p < 0.05) on pathologic
examination were higher in the superselective group. No procedure-related
complications occurred in the superselective group, whereas two patients in the
subselective group had postoperative scalp necrosis. Our findings show that
superselective embolization is more effective than subselective embolization for
preoperative endovascular devascularization of meningiomas, with significant
reductions in intraoperative blood loss and surgery time. Preoperative
embolization of meningiomas, if indicated, should be done with the superselective
technique whenever feasible.
PMID- 9549261
TI - Cystoid macular edema associated with the use of latanoprost.
AB - BACKGROUND: Cystoid macular edema is a common clinical finding following
intraocular surgery. Certain medications have been associated with an increased
incidence of cystoid macular edema. This article describes the clinical findings
in two eyes of two patients in whom cystoid macular edema developed directly
following treatment with the anti-glaucoma medication latanoprost, and assesses
the possible causal relationship. CASE REPORTS: Clinical correlative and
angiographic studies of two patients in a referral practice are presented. The
main outcome measurement was visual acuity and fundus examination on
discontinuation of latanoprost. RESULTS: Cystoid macular edema developed in two
pseudophakic patients after the use of latanoprost. CONCLUSION: Latanoprost
should be used with caution in pseudophakic and aphakic patients--especially
those with retinal vascular fragility, any inflammatory uveal disease, or other
factors that may predispose to the breakdown of the blood-retinal barrier.
PMID- 9549264
TI - Analysis of corneal topography after excimer laser photorefractive keratectomy.
AB - Excimer laser photorefractive keratectomy (PRK) is an effective treatment for
myopia. We investigated the magnitude of optical zone decentration and
qualitative patterns of corneal topography after this treatment. We performed
computer-assisted videokeratography on 44 myopic eyes (29 patients) that had
undergone PRK before and 1, 6, and 12 months after the procedure. Associations of
clinical outcomes with decentration and topographic patterns were assessed. The
normalized scale of the topography 1 month postoperatively showed a mean
decentration of 0.33 +/- 0.23 mm (range 0-0.9). Thirty-four eyes had decentration
of less than 0.50 mm; 10 had an ablation zone decentered from 0.5 to 0.9 mm.
Analysis of geometric mean visual acuities between eyes with less than 0.5 mm
decentration and those with 0.5 to 0.9 mm decentration demonstrated minimal
differences. No eye was decentered more than 1 mm. Four main ablation patterns
were noted on subtraction analysis: homogeneous, semicircular, keyhole, and
central island. Over time, the number of eyes with a homogeneous pattern
increased. Eyes with a homogeneous ablation pattern had significantly better
uncorrected visual acuity than those with other patterns. The mean visual acuity
was 20/29.1 in the homogeneous group and 20/38.5 in the pooled irregular group 1
month postoperatively (p < 0.05). There was no significant difference among the
four ablation patterns at 6 or 12 months after PRK. Topographic patterns were not
significantly associated with best-corrected vision.
PMID- 9549265
TI - Absorbable PDS-II suture and nonabsorbable polypropylene suture in aortic
anastomoses in growing piglets.
AB - The long-term outcome of vascular anastomoses in children can be compromised by
stenosis when the growth of the anastomosis does not match that of the vessels.
This can be influenced by the suture material. We evaluated the suitability of
the new generation of polydioxanone (PDS-II), an absorbable synthetic
monofilament suture, in vascular surgery, in terms of permitting normal growth of
aortic anastomoses. Ten piglets underwent primary end-to-end anastomosis of the
thoracic aorta, five with PDS-II suture and five with conventional polypropylene
(Prolene) suture. Six months after surgery, an aortogram was obtained for each
animal. The piglets were then killed and the aortas were sent for pathologic
examination. Complete absorption of suture material with slight dilatation of the
anastomoses was found in all five pigs in the PDS-II suture group. We also found
thrombus formation in one pig in this group. Mild stenosis of the anastomotic
site was noted in all five pigs in the polypropylene suture group, but no
intraluminal thrombus formation was seen. The degree of dilatation or stenosis
within each group was not significantly different when intraluminal diameters
were compared at three distinct sites in the reconstructed aorta (p > 0.05). The
differences in vascular growth between the two groups were also not significant
(p > 0.05). Histologic examination revealed less tissue reaction in the PDS-II
suture group than in the polypropylene suture group. Thus, PDS-II seems to be a
suitable suture material for anastomoses as far as vascular growth is concerned,
but the possibility of aneurysm formation secondary to dilatation of the
anastomotic site should be kept in mind.
PMID- 9549266
TI - Factors affecting postoperative fecal soiling in Hirschsprung's disease.
AB - We retrospectively assessed the factors that may contribute to fecal soiling
after surgery for Hirschsprung's disease. Fifty-eight patients underwent surgery
for Hirschsprung's disease and returned for follow up. The patients were divided
into two groups based on the presence or absence of fecal soiling. The
postoperative period, level of bowel pulled through, stool frequency, stool
character, presence or absence of anorectal surgical complications, and
manometric findings of the two groups were compared. Forty-three patients (40
boys, 3 girls, mean age 9.5 yr) had soiling and 15 (10 boys, 5 girls, mean age
10.2 yr) did not. Patients with soiling had significantly higher rates of
anorectal surgical complications (60% vs 7%), abnormal stool character (75% vs
7%), stool frequency greater than three times per day (63% vs 20%), absence of
rectoanal inhibitory reflex (33% vs 2%), and narrow anorectal pressure gradient
(60% vs 13%) than those without. The results of manometric study suggested that a
damaged internal sphincter or irritable neorectum might have contributed to fecal
soiling. In conclusion, although anorectal surgical complications might result in
both irritable neorectum and damaged internal sphincter, their effect on the
neorectum (significantly increased rate of high resting rectal pressure) seemed
to outweigh that on the internal sphincter. A competent anal sphincter and a less
irritable neorectum after operation may therefore lower the likelihood of fecal
soiling.
PMID- 9549267
TI - Association of active myofascial trigger points and cervical disc lesions.
AB - We investigated the occurrence of active myofascial trigger points in specific
muscle groups in relation to the existence of cervical disc bulging at various
levels. One hundred and five patients (48 men, 57 women; mean age, 45.8 +/- 12.1
yr) who had active trigger points in the neck or upper back after trauma were
divided into two groups on the basis of magnetic resonance imaging (MRI) evidence
of bulging disc(s). The discN group consisted of 46 patients who had normal MRI
findings in the cervical spine. The other 59 patients, with mild cervical disc
bulging, were assigned to the disc' group. The correlations between specific
muscles with active trigger points (clinical finding) and cervical disc lesions
at specific levels (MRI finding) were analyzed. There were significant
associations between the level of disc lesion and the muscles with trigger
points, namely C3-4 lesions with levator scapulae and latissimus dorsi trigger
points; C4-5 lesions with splenius capitis, levator scapulae, and rhomboid minor
trigger points; C5-6 lesions with splenius capitis, deltoid, levator scapulae,
rhomboid minor, and latissimus dorsi trigger points; and C6-7 lesions with
latissimus dorsi and rhomboid minor trigger points. For each disc level, the
average pain intensity (assessed using a numerical analog scale) of trigger
points in certain correlated muscles (as indicated above) in the disc group was
significantly higher than that in the discN group (p < 0.05 for all disc levels).
We conclude that active trigger points are more likely to occur in certain
muscles in the presence of cervical disc lesions at specific levels.
PMID- 9549268
TI - Extravesical detrusorrhaphy for vesicoureteral reflux in children.
AB - Extravesical detrusorrhaphy is a simple and safe approach to antireflux surgery;
however, its use in Taiwan has seldom been reported. We report the outcomes of 15
patients (23 ureters) with primary vesicoureteral reflux who underwent
extravesical detrusorrhaphy between January 1995 and April 1996, and describe the
surgical technique. Overall, vesicoureteral reflux was cured in 22 of 23 ureters.
Postoperative morbidity and complications were minimal. None of the patients had
obstruction or significant hematuria. The discomfort related to bladder spasms
during the postoperative period was subjectively decreased compared to the
conventional transvesical technique. There was transient voiding inefficiency in
three patients, as well as urinary retention in one, which resolved spontaneously
after 4 weeks of Foley catheter drainage. Our experience showed that
detrusorrhaphy is an effective way to correct vesicoureteral reflux with minimal
morbidity and discomfort. Proper patient selection and strict adherence to the
surgical principle are important for high success rates.
PMID- 9549269
TI - Mucopolysaccharidosis type II (Hunter's syndrome) in Taiwan.
AB - The mucopolysaccharidoses are a group of inherited disorders of lysosomal storage
of glycosaminoglycans. Among them, mucopolysaccharidosis (MPS) type II (Hunter's
syndrome), caused by a deficiency in iduronate sulfatase, is the only one
inherited in an X-linked recessive manner. We describe 12 Hunter's syndrome
patients and seven carriers, with precise analysis of glycosaminoglycan content
in urine and iduronate sulfatase activity in cultured fibroblasts and plasma.
Their ages at the time of diagnosis ranged from 1 year 10 months to 11 years
(mean 4.3 yr). The delay in diagnosis was from 1 month to 5 years (mean 2.1 yr)
after the initial presentation. The most frequent initial complaints of the
patients were delayed developmental milestones (75%) and speech (67%), although
all patients were found to have coarsening of facial features at diagnosis. The
difficulties in disease recognition allowed disease recurrence in four of the 11
families. Prompt clinical suspicion and referral will be important in genetic
counseling for MPS type II and its management, if definitive therapy becomes
available.
PMID- 9549270
TI - Stress-reducing effect of physician's tape-recorded support on cardiac surgical
patients in the intensive care unit.
AB - Staying in an intensive care unit (ICU) is very stressful for patients after
heart surgery. Although it is a general belief that support from doctors is
important to reduce patients' tension, no quantitative data are available. We
investigated the stress-reducing effects of a tape-recorded message from the
physician which provided information regarding the surgery and emotional support
for heart surgery patients postoperatively in the ICU. Sixty patients who
underwent cardiac surgery were randomly allocated to two equal groups. The
patients in the experimental group listened to a tape-recorded message from their
attending surgeon soon after they recovered from anesthesia, while the control
group rested during the study period. The effectiveness of the tape-recorded
support program was evaluated by the influence on heart rate, blood pressure, and
finger skin temperature, as well as the degree of subjective pain, tension,
anxiety, depression, and anger. The pain and tension levels of the patients were
measured using a visual analogue scale, while the severity of anxiety,
depression, and anger was evaluated using the Brief Symptom Rating Scale.
Patients' evaluation of the usefulness of the program was also assessed. After
listening to the physician's recorded message, the mean increase in the skin
finger temperature in the experimental group was higher than in the control group
(0.44 degree C vs 0.25 degree C, p = 0.0513). The experimental group had
significant decreases in their mean scores of pain (-1.11 vs 0.36, p = 0.0043),
tension (-2.26 vs -0.25, p = 0.0001), anxiety (-1.3 vs -0.57, p = 0.0473), and
depression (-2.24 vs -0.37, p = 0.0253). The patients showed a high need for this
support program (mean need score 8.4). These findings show that a physician's
tape-recorded message providing information and emotional support can reduce
stress in heart surgery patients in the ICU postoperatively.
PMID- 9549271
TI - Ultrasound-guided fine needle aspiration biopsy in the diagnosis of pulmonary
cryptococcosis.
AB - The purpose of this study was to assess the safety and reliability of ultrasound
guided fine needle aspiration biopsy (US-guided FNAB) combined with modified
Papanicolaou's staining in the diagnosis of pulmonary cryptococcosis. The study
included 10 patients (9 men, 1 woman, 28-70 yr). Percutaneous US-guided FNAB was
performed through a puncture probe with central channel guidance (n = 8) or in a
'free-hand' manner (2), depending on the size of the lesion and the experience of
the operator. Sonography disclosed homogeneously hypoechoic lesions with air
bronchograms over the peripheral or central portion in nine patients, and
occasional heterogeneous echogenicity with necrotic tissue without air
bronchogram in one. Thirteen lesions were found on the chest radiographs of the
10 patients; these could be divided into three patterns: infiltrates (2), nodules
or masses (7), and consolidation (4). Using US-guided FNAB and immediate modified
Papanicolaou's stain, a diagnosis of pulmonary cryptococcosis was confirmed in
nine of the 10 patients. The remaining case was proven by surgical resection. No
major complications developed after US-guided FNAB. We conclude that this
technique, combined with modified Papanicolaou's staining, provides a safe,
rapid, and reliable method for diagnosing pulmonary cryptococcosis.
PMID- 9549272
TI - Evaluation of an automatic polymerase chain reaction assay for identification of
Mycobacterium tuberculosis in respiratory specimens.
AB - We evaluated the performance of an automatic polymerase chain reaction (PCR)
detection system for identification of Mycobacterium tuberculosis in respiratory
specimens. Six hundred and two respiratory specimens, including 557 sputa and 45
bronchial washing samples, were analyzed using the COBAS AMPLICOR Mycobacterium
tuberculosis (MTB) test. The results were compared with those obtained from acid
fast microscopy, conventional culture, and clinical history. In cases of
discrepancy between the results of the COBAS AMPLICOR MTB test and culture, the
medical history of the patient was reviewed, the COBAS AMPLICOR MTB test was
repeated, and the gene encoding M. tuberculosis superoxide dismutase was screened
using PCR (SOD-PCR). Fourteen samples were excluded because the internal control
test result was negative. Of 57 specimens that were culture positive for
Mycobacterium species, 40 appeared to have growth of M. tuberculosis and 21 were
smear positive for acid-fast bacteria. The sensitivity, specificity, and positive
and negative predictive values for the COBAS AMPLICOR MTB test evaluated at our
laboratory were 85.0% (34/40), 99.3% (544/548), 89.5% (34/38), and 98.9%
(544/550), respectively. Three specimens that were culture positive for M.
tuberculosis but negative by COBAS AMPLICOR MTB test were positive when rechecked
by both COBAS AMPLICOR MTB test and SOD-PCR. Among the four specimens with
positive reactions on both COBAS AMPLICOR MTB test and SOD-PCR that were culture
negative, two were from patients who had been receiving antituberculosis
treatment, one was from a patient who had been treated for tuberculosis for 1
year, and the other was from a patient who died of sepsis with adult respiratory
distress syndrome. In more than 70% of smear-negative and culture-positive
specimens and 86.4% of smear-positive specimens, M. tuberculosis was identified
by the COBAS AMPLICOR MTB test within 10 hours after receipt of the specimens.
Our data show that the COBAS AMPLICOR MTB test provides rapid and accurate
detection of M. tuberculosis in respiratory specimens.
PMID- 9549273
TI - Medullary cystic disease: a family study.
AB - Medullary cystic disease of the kidney is characterized by progressive
tubulointerstitial disease with medullary cyst formation and secondary glomerular
sclerosis. We treated a patient with chronic renal failure and investigated the
family history of renal disease. The patient, an 18-year-old woman, was admitted
due to poor appetite and fatigue for several months. Findings on physical
examination were normal except for a pale conjunctiva. Urinalysis revealed only
mild proteinuria with clear sediment. The hemogram showed normocytic normochromic
anemia with hemoglobin 86 g/L. The patient was azotemic and her creatinine
clearance rate was 10.7 mL/min. Renal sonography showed contraction of both
kidneys with a marked increase in cortical echogenicity. One small cyst was found
in the medullary area. Computed tomography (CT) and magnetic resonance imaging
revealed several medullary cysts. Percutaneous renal biopsy showed focal and
periglomerular sclerosis, marked tubular atrophy, and interstitial fibrosis. Ten
of her family members were examined for renal function, and by sonography and CT.
Five had medullary cysts, and three of the five showed abnormal renal function.
Medullary cystic disease should be considered in the differential diagnosis of
patients with renal disease and a positive family history.
PMID- 9549274
TI - Amebic liver abscess complicated with cardiac tamponade and mediastinal abscess.
AB - Amebic pericarditis is an extremely rare complication of liver abscess and an
uncommon etiology of sterile pericardial effusion with cardiac tamponade. The
association of mediastinal abscess in this clinical setting has not been reported
in the literature. Herein, we describe a case of amebic liver abscess complicated
with mediastinal abscess and amebic pericarditis with cardiac tamponade. A 44
year-old man was admitted to our hospital because of shortness of breath for the
previous 2 days. Cardiac tamponade was diagnosed and emergency pericardiectomy
was performed. Chocolate-like pus was found in the pericardial sac and
mediastinal space during surgery. Abdominal computed tomography revealed an ill
defined hypodense lesion over the left lobe of the liver, suggesting a liver
abscess. Amebic liver abscess and pericarditis were diagnosed on the basis of a
high serum titer of amebic antibodies on hemagglutination test. The patient was
treated with metronidazole for 2 weeks and discharged in good condition. This
case should alert clinicians to the possibility of amebic pericarditis in
patients with cardiac tamponade associated with chocolate-like sterile pus in the
pericardium and mediastinum. To establish the diagnosis of amebic pericarditis,
one should investigate the presence of a liver abscess, a high serum titer of
amebic hemagglutination antibodies, and the presence of Entamoeba histolytica
trophozoites in the pericardium or pericardial aspirate.
PMID- 9549276
TI - Diagnosis of pulmonary sequestration by magnetic resonance imaging.
AB - Pulmonary sequestration, an uncommon congenital anomaly, is traditionally best
diagnosed using arteriography; however, this is invasive and not without risk of
morbidity and mortality. We report two patients with pulmonary sequestration
diagnosed using magnetic imaging techniques. The first was a 22-year-old woman
and the second a 17-year-old boy, both of whom presented with symptoms of cough
and exertional dyspnea. Pulmonary sequestration was suspected from their chest
radiographs. Magnetic resonance imaging and magnetic resonance angiography
clearly demonstrated the aberrant artery arising from the aorta in a single
noninvasive examination that did not require the use of contrast medium. We
recommend magnetic resonance imaging as a safe, efficient, and noninvasive
modality for the diagnosis of pulmonary sequestration.
PMID- 9549275
TI - Successful resection of a teratoma of the third ventricle in a 3-year-old boy.
AB - Few cases of teratoma in the third ventricle have been reported in detail. We
describe a 3-year-old Chinese boy presenting with increased intracranial
pressure, headache, and vomiting. Preoperative computed tomography and magnetic
resonance imaging demonstrated a teratoma in the third ventricle. Complete
excision of the tumor was achieved through the interhemispheric transcallosal
approach. The patient did well and was without neurologic deficits
postoperatively. Although the majority of tumors located in the third ventricle
are malignant and can penetrate the brain tissues that constitute the wall of the
third ventricle, mature teratomas are an exception and total removal may be
possible.
PMID- 9549277
TI - [Emergencies (outpatients) in cardiosurgery: national multicenter study. Gruppo
di Studio SIAARTI "Anestesia e Rianimazione in Cardiochirurgia"].
AB - BACKGROUND: Heart Surgery Italian Centres participated in this study to define
the rate and the outcome of outpatients' cardiovascular emergencies. Hospital
patients and heart and/or lung transplants were excluded. METHODS: Data were
prospectively collected over 6 months (from April 1 through September 30, 1996)
and analyzed using SPSS stat programme. RESULTS: 731 emergencies (5.8% of 12551
cardiosurgical procedures) have been recorded. 85.8% of the patients were
admitted to the surgical units, coming from other hospitals. 31.6% of emergencies
were admitted in the night. 37.2% of the patients were admitted because of
myocardial infarction or unstable angina in spite of e.v. drugs; 28.3% because of
dissection of thoracic aorta; 18.2% were congenital heart diseases; 9.2% valvular
or valve prosthesis dysfunctions; 7.1% were affected by other cardiovascular
diseases. On admission, 48.7% of the patients were in cardiogenic shock or severe
heart failure, 27.9% presented respiratory failure, 11.8% renal failure, 5.1%
brain injury (coma and/or plegia or paresis). 500 (68.4%) patients needed
invasive and or not invasive diagnostic procedures. 33 (4.5%) patients died early
after admission to the hospital. 30 patients, who did not need surgery, were
discharged few days after admission. 668 (91.4%) patients underwent surgery.
Overall perioperative mortality was 21.7%: 31.6% in the aortic group, 21.6% in
the congenital heart disease group, 24.6% in the valve group, 15.2% in the
coronary group. CONCLUSIONS: The cost of outpatients' cardiovascular emergencies
is very high. First of all, overall mortality and perioperative mortality are
greater when compared to elective surgical procedures; moreover expensive tools
and continuous availability of skilled anaesthesiologists, cardiologists and
surgeons are mandatory. In order to optimize results (cost/benefit) and looking
for lowering mortality, the approach to outpatients' cardiovascular emergencies
in Italy must be reorganized, in order to refer emergencies to few, high
qualified, "ad hoc" organized Centres properly placed on the national territory.
PMID- 9549278
TI - [Neurologic prognosis after cardiocirculatory arrest outside the hospital].
AB - OBJECTIVE: To detect clinical signs and times of evaluation able to identify
patients with good neurologic prognosis after out-of-hospital cardiac arrest.
EXPERIMENTAL DESIGN: Retrospective study with 6 months-2 years of follow-up.
SETTING: General intensive care unit, from 1993 to 1995. PATIENTS: Twenty-three
patients aged 18-80 years, admitted with coma after out-of-hospital cardiac
arrest, who survived at least 24 hours, without concomitant neurologic disorders.
INTERVENTIONS: Neurologic outcome classification in three categories: complete
neurologic recovery (A), moderate to severe disability (B), death without
regained consciousness (C); A and B groups of patients are considered together as
a "good neurologic outcome" group. MEASUREMENTS: Evaluation of some neurological
parameters (GCS, motor response to pain, spontaneous motility, cranial nerve
reflexes, spontaneous breathing, seizures) 6 hours (t0), 24 hours (t1), 72 hours
(t2) and 7 days (t3) after arrest. RESULTS: Patients with good prognosis are
identified with 100% sensitivity from the following parameters: at t0 none; at t1
motor response to pain, GCS > 4, absence of seizures; at t2 the former
parameters, spontaneous breathing, brain stem reflexes, normal pupils; at t3 all
the former parameters and spontaneous motility. Specificity is greater than 50%
only for motor response to pain and GCS > 4. CONCLUSIONS: It is mostly impossible
to state a neurologic prognosis in the first hours after cardiac arrest. The
single predictor with the most reliable prognostic value is motor response to
pain which allows, if present, to identify all the patients with a good prognosis
as early as 24 hours after arrest.
PMID- 9549279
TI - [Measurement of cardiac output with continuous thermodilution. b1 Clinical
experience with the Intellicath-Vigilans system].
AB - BACKGROUND: Thermodilution cardiac output measurements are commonly obtained by a
manual bolus technique with a pulmonary artery catheter. METHODS: A new
thermodilution catheter has been developed which utilizes an integral thermal
filament and provides semicontinuous online cardiac output. The response of this
new device in 25 patients undergoing coronary artery bypass grafting was
examined. A total of 250 data pairs was obtained; the cardiac outputs ranged from
2.2 to 11.9 lts.min. RESULTS: The linear regression is represented by the
following equation: continuous thermodilution = 0.7196 bolus thermodilution
+1.038. The correlation coefficient was 0.75; the mean bias was 0.493 +/- 1.034.
CONCLUSIONS: The new technique provides acceptable accuracy in many clinical
situations except when sudden haemodynamic changes occur.
PMID- 9549280
TI - [An index of daily intensive care unit activity].
AB - OBJECTIVE: To set up an index for the evaluation of type of interventions and
procedures applied a prerequisite for the evaluation of appropriateness of ICU's
activity. DESIGN: Observation prospective study. PATIENTS: 2507 patients out of
the 5030 enrolled in the cohort study. MEASUREMENTS: A cross-sectional assessment
of the volume and intensity of treatment--level of care--delivered to patients
was performed at a preidentified index day. A check list of procedures was
utilized. Intensive high level treatment was demonstrated by the application of
procedures suggesting one or more organs or vital functions intensively
supported. Sub-intensive treatment was defined by the application of procedures
indicating monitoring or treatments not exclusively performed in intensive
environment. RESULTS: 3955 samples were collected over 9 index days; 2707 (68.3%)
resulted in intensive, 1227 (30.7%) subintensive or intermediate and 41 (1%) ward
treatments. Out of the intensive samples, 63.4% received only one intensive
procedure, while 27.9% two. Ventilatory support was the most frequently (90.4%)
utilized intensive procedure. Overall 99% of the samples were characterized by
treatments/procedures too invasive for normal ward. CONCLUSIONS: The proposed
method gives the opportunity to easily evaluate the level of care and then the
appropriateness of ICU care.
PMID- 9549282
TI - [Late awakening].
PMID- 9549281
TI - Treatment of severe acidemia in a young woman affected by diabetic ketoacidosis.
AB - The case of a 32-year-old woman admitted to Hospital for diabetic coma (GCS 8),
with arterial blood pH below usually reported vital range, is described. After
First Aid admittance an arterial blood gas analysis adjusted for patient's
temperature showed PaO2 10.77 kPa, PaCO2 7.8 kPa, pH 6.52, HCO3 5 mmol/L, BE
34.9. A significant increase of lactate and butyrate concentration was also
found. The patient was intubated and breathing was assisted for a 60 hour period
after ICU admission, while acidemia was treated by THAM and bicarbonate
associated to potassium i.v. infusion (infusions were titrated on acid-base and
electrolyte concentration direct monitoring). After progressive neurological and
biochemical improvement, 7 days after ICU admission the patient was moved to an
Internal Medicine department. This case demonstrated that during diabetic
ketoacidosis, despite very low pH (below reported vital range), an invasive
intensive treatment could give complete cure without neurological sequelae.
PMID- 9549283
TI - Comparison of cilostazol with warfarin as antithrombotic therapy after femoro
popliteal bypass surgery using an ePTFE graft.
AB - BACKGROUND: Cilostazol (6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4- dihydro
2(1H)-quinolinone) is a new antiplatelet agent with a vasodilating action. The
purpose of this study was comparison of cilostazol with warfarin as
antithrombotic therapy after femoro-popliteal bypass surgery using an expanded
polytetrafluorethylene (ePTFE) graft. EXPERIMENTAL DESIGN: This report is a
retrospective study and the patients were followed up for five years. SETTING:
Outpatients of university hospital. METHODS: Sixteen arteriosclerosis obliterans
patients, who were diagnosed as having only superficial femoral artery stenosis
or occlusion, underwent femoro-popliteal (above the knee) bypass using an ePTFE
graft 6 mm in diameter. Cilostazol (150-200 mg/day) was administered to 6 cases
(9 bypasses), and warfarin (prothrombin time was controlled to 15-25%.) was
administered to 10 cases (14 bypasses). RESULTS: No clinically characteristic
differences were found between the two groups. The cumulative 1-, 3-, and 5-year
primary and secondary graft patency rates were 69% and 80%, 69% and 80%, and, 69%
and 80% in the cilostazol group, vs 61% and 91%, 51% and 91%, and, 51% and 91% in
the warfarin group, respectively. These differences were not significant (p <
0.05). No hemorrhage complications were observed in the cilostazol group. The
management of cilostazol administration was safe and simple. CONCLUSIONS:
Although the number of cases was small in this study, cilostazol was considered
to be as effective as warfarin and suitable for the postoperative antithrombotic
therapy after the ePTFE bypass surgery.
PMID- 9549284
TI - [So-called "spontaneous" lesions of the popliteal artery].
AB - The term "spontaneous", when attributed to a stenotic or obliterative arterial
lesion, could seem ambiguous and doesn't completely explain the anatomical
substrate that is the basis of this morbid condition. However, it is true that
injuries can occur without the patient being aware of any traumatic event, and
can cause a symptomatology arising suddenly and, apparently, "spontaneously". In
this study, three cases of patients observed for acute or chronic lower limb
ischemia are presented. All patients were male, young and underwent an
angiographic examination that demonstrated, in an otherwise normal arterial tree,
filling defects or obstruction involving the popliteal artery. Two patients
underwent a reconstructive surgical procedure. The third was medically treated.
CAT or MNR examinations were performed in order to exclude developmental defect
such as an anomalous course of popliteal artery determined by a displacement due
to medial head of the gastrocnemius muscle. Actually in these three cases, a
definite etiology of the arterial damage was not demonstrated and therefore it is
suggested that a physical effort could have injured an already weakened arterial
structure.
PMID- 9549285
TI - [A case of deep vein thrombosis].
AB - The case of a woman admitted to hospital various times because of the onset of a
mantle-like oedematous syndrome is reported. Observations revealed a narrowing at
the level of the internal jugular and right subclavian veins with total
obliteration of the right anonymous vein caused by previous thrombosis induced by
intravenous implantation of a pace-maker.
PMID- 9549286
TI - [Thromboendarterectomy of the superficial femoral artery with a femoro-popliteal
endoprosthesis. Technical note on a preliminary experience].
AB - BACKGROUND: The authors report an early experience with a new endovascular
approach in the treatment of occlusive superficial femoral artery disease to
evaluate the efficacy and the feasibility of the new technique. METHODS AND
RESULTS: Four patients with disabling claudication or leg rest pain were treated
for long segment occlusion of superficial femoral artery (SFA). A remote
endarterectomy (EA) of SFAs has been performed using a single groin incision and
a conventional Vollmar ring stripper to remove the entire atheroma core for a
length of 20, 10, 9 and 8 cm. In 3 cases following complete extraction of intimal
core and a guidewire placement across from the distal endpoint, the
endarterectomized segment was lined endoluminally by implanting one or more Self
Expanding Coated Stent (Meadox Passager 6-10 mm); the stent was positioned under
fluoroscopic guidance to prevent dissection without any further balloon-dilation.
In 1 case a 5 mm diameter thin-walled PTFE endoluminal graft was positioned using
a Strecker stent for distal fixation. One patient had an immediate post-operative
occlusion of distal stent which required a femoro-popliteal autologous vein
bypass. In the remaining 3 cases no postoperative complications were observed and
the patients are asymptomatic with normal flow through the stent and the
endoluminal PTFE graft at 6 months. CONCLUSIONS: In this report a combined
surgical and endovascular procedure has been proposed. A prospective randomized
study is carrying on at our Institute to verify if EA+ endovascular grafting of
SFA represents an alternative to traditional femoro-popliteal vein bypass.
PMID- 9549287
TI - [Current role of thrombendarterectomy in chronic peripheral obstructive
arteriopathy].
AB - BACKGROUND: The authors report the present indications for thromboendarterectomy
(TEA) and the advantages it offers for the surgical treatment of steno
obstructive lesions of aortoiliac and femoro-popliteal regions. They illustrate
this method and the necessary instruments and describe the technique in detail,
for the good outcome of revascularization. METHODS: Then personal surgical
experience in 46 patients during the period from January 1985 to December 1995,
is reported. Epidemiological data (sex, average age, risk-factors, concomitant
diseases), different types of surgical operations (TEA "open air", TEA
"semiclosed", TEA in association with bypass), clinical and instrumental
preoperating study, invasive or not, medical therapy during and after operation,
immediate and remote check-up are then reported. RESULTS AND CONCLUSIONS: The
results in terms of cumulative pervious vessel and salvage of the arm, compared
with different stages of the disease and a 5 years- follow-up are reported. The
effectiveness of TEA is confirmed in the symptomatic improvement and salvage of
the arm, and the lower costs, when the indications and the accuracy of surgical
technique are respected.
PMID- 9549288
TI - Nitrite plasma levels in acute and chronic coronary heart disease.
AB - BACKGROUND: The authors carried out a study on the plasmatic levels of nitrites,
which are the sole stable metabolites of nitric oxide (NO), in a group of
subjects suffering from various clinical forms of coronary artery disease, aimed
at evaluating the endothelial production of NO in acute and chronic ischemic
conditions. METHODS: Our series consisted of 104 female subjects (mean age 65 +/-
5) subdivided into: a) 10 subjects with acute coronary heart disease (myocardial
infarction); b) 32 with chronic non hypertensive coronary heart disease (CHD); c)
30 with hypertensive CHD (arterial blood pressure over 160/95 mmHg); d) 32 with
CHD and hypercholesterolemia (values over 250 mg/dl). Thirty-seven female
subjects (mean age 58 +/- 7) without internistic diseases were considered as
control subjects. For each sample the plasmatic levels of nitrites were
determined by the Gutman and Hollywood method. RESULTS: We discovered that in the
patients with chronic coronary heart disease (CHD) the mean value of nitrites was
18 +/- 0.3 mumol/L, not significantly different from the controls (17 +/- 0.5
mumol/L). In the patients with acute CHD the nitrite plasma level were
significantly (p < 0.05) higher (30 +/- 2.2 mumol/L) compared to the controls and
the patients with chronic CHD. In the group of patients with hypertensive CHD the
mean nitrite value was 20 +/- 0.6 mumol/L, significantly (p < 0.05) higher in
comparison with the group of non-hypertensive CHD patients (14 +/- 0.3 mumol/L).
In the subjects with CHD and hypercholesterolemia the mean value of nitrites was
sharply elevated, (25 +/- 1.0 mumol/L), with a highly significant difference (p <
0.01) as compared to the normolipemic CHD patients. CONCLUSIONS: These results
lead to the hypothesis that: strong NO production may play a compensatory and
protective role during acute myocardial hypoxia; NO defective synthesis may
depend on an exhaustive endothelial adjustment in subjects with long-term CHD; a
significant increase of the relaxing factor in hypertensive conditions exists; a
highly enhanced synthesis of the plasmatic nitrites in hypercholesterolemic
patients means an engagement of NO to neutralize the endothelium-damaging
molecular substances and particularly the oxided LDL.
PMID- 9549289
TI - [Correlations between the efficacy of thrombolytic therapy and appearance of
abnormal Q waves in the early stages of acute myocardial infarction].
AB - BACKGROUND: The purpose of this study was to determine the time course of the
appearance of abnormal Q waves on the electrocardiogram (ECG) over the first 6
hrs of the symptoms of acute myocardial infarction (AMI) and to determine what
implications, if any, such Q waves have for the efficacy of thrombolytic therapy.
Severe myocardial ischemia can produce early QRS changes in the absence of
infarction. Abnormal Q waves on the baseline ECG may not be an accurate marker or
irreversibly injured myocardium. METHODS: A study of 232 patients with AMI
consecutively admitted to our coronary care units was carried out. Patients with
previous AMI were not included. The presence and number of abnormal Q waves, as
defined by Selvester, on the initial ECG was determined for each patient. The
presence or absence and magnitude of ST segment elevation and depression were
recorded and these data were used to estimate the left ventricular infarct size
should thrombolytic therapy not be given (Aldrich score). Quantitative thallium
201 tomographic imaging was performed after a mean of 42 +/- 40 days from
hospital discharge in 145 patients. RESULTS: In patients admitted within 1 hr of
symptoms, 53% had abnormal Q waves on the initial ECG independent of the duration
of symptoms before therapy (p < 0.001). Despite this finding, the presence of
abnormal Q waves on the admission ECG did not eliminate the effect of
thrombolytic therapy on reducing final infarct size (p < 0.001). CONCLUSIONS:
Abnormal Q waves are a common finding early in the course of AMI. However, there
is no evidence that abnormal Q waves are associated with less benefit in terms of
reduction of infarct size after thrombolytic therapy.
PMID- 9549290
TI - [Treatment of post-transplant erythrocytosis: comparison of lisinopril and
theophylline].
AB - OBJECTIVE: The proposal of this study is to compare the efficacy of lisinopril
and theophylline, alone or in association, on erythrocytosis in renal
transplanted patients. DESIGN: Prospectic, case-control study.
PATIENTS/ENVIRONMENT: 15 inpatients meeting 3 main criteria: 1) ACE therapy for
past erythrocytosis, 2) actual erythrocytosis, 3) symptomatic increase of
haematocrit (Hct). INTERVENTION: The treatment has been divided into 3
consecutive phases of 30 days each: 1) lisinopril (5 mg/die), 2) theophylline (4
mg/kg/die), 3) association of 2 drugs. MEASUREMENTS: The evaluations were
scheduled at the beginning and every month and consisted of renal function
control, haemochromocytometric exam, serum level of folates, B12 vitamin and
erythropoietin (EPO), iron level, cyclosporinemia, as well as clinic control and
adverse events detection. RESULTS: A significative decrease of Hct values and a
decrease of serum erythropoietin values was observed in patients treated with
lisinopril. Patients treated with theophylline showed a significant reduction of
Hct values causing a reduction of erythropoietin serum level in 8/13 patients.
Lisinopril and theophylline administered in combination presented a significant
decrease of Hct values, while EPO values diminished compared to basal values.
CONCLUSIONS: These data showed that lisinopril is a valid therapy for the
treatment of posttransplanted patients affected by erythrocytosis and, moreover,
has the benefit of antihypertensive action. Theophylline remains an alternative
therapy when ACEi are contraindicated. The combination of the 2 drugs doesn't
produce additional benefits.
PMID- 9549291
TI - [Longitudinal echocardiographic study of HIV positive patients].
AB - BACKGROUND: From May 1992 to June 1996 the authors have studied a group of 39
subjects with positive anti-HIV, with echo 2D color Doppler examination, to
evaluate with semi-annual controls, the wide variety of cardiac complications in
the various phases of clinical evolution of the illness. METHODS: At the moment
of recruiting, all the subjects with HIV infection were asymptomatic A1 (HIV +
As). The patients whose average age was 29 +/- 5, were composed of 60% drug
addicts, 17% homosexuals, 8% haemophiliacs and for the 15% heterosexual. RESULTS:
The most frequent cardiac complications are represented by hypokinesia of the
left ventricle (h-aLV) and by pericardial effusion (PE); more rarely of
endocardial vegetations (EV), dilatation of the left ventricle (dLV) and
tricuspid insufficiency (TI). The entity of damage and the number of cases
observed, are correlated with the grade of clinical severity of the illness.
CONCLUSIONS: In accordance with the literature data, cardiac pathologies,
particularly in the first phases of the illness, are asymptomatic or
paucisymptomatic, making the clinical-instrumental observation of the patient
useful also in cardiology.
PMID- 9549292
TI - [Precordial discomfort and ECG changes of repolarization associated with
hypomagnesemia in a young women following colectomy for diffuse colonic
lipomatosis].
AB - Aim of this paper is to describe and discuss, on the basis of the available
literature, the case of a young woman, previously colectomized for diffuse
lipomatosis of the colon, showing hypomagnesemia and symptomatic (precordial
discomfort) changes of repolarization phase, detected by ECG, probably due to
coronary spasm. This hypomagnesemia (1.4 mEq/1) was probably due to altered
intestinal absorption of magnesium, linked to a short bowel syndrome. The ECG
changes and the precordial symptom were completely reversed by a relative short
treatment with magnesium per os, which increased the magnesium level to low
borderline value (1.6 mEq/1). The observation of ECG changes with precordial
discomfort, probably linked to hypomagnesemia, suggests the need for routinary
magnesium determinations to detect deficiency of this electrolyte, with the scope
of improving the diagnosis and the treatment of several symptoms, otherwise
difficult to interpret.
PMID- 9549293
TI - [Oncologic and hematologic combined care in pediatrics].
PMID- 9549294
TI - [Genital lichen in girls. General aspects and clinical course].
AB - BACKGROUND: The authors re-examine the clinical aspects of infantile vulvar
Lichen sclerosus in the light of the latest reports in the literature. METHODS: A
group of 40 girls was studied with a mean age of 8 years old suffering from this
pathology; 8 of the subjects had reached a prepuberal age. The group received
different types of therapy and maintenance during a six-month and then annual
follow-up. The results are reported correlated to the type of treatment. The
results obtained were also evaluated depending on the age of the subject, the
onset of puberty in some during the course of the study, the age at onset of
disease. RESULTS: It was seen that recovery was mainly linked to aging and hence
the evolution of puberty rather than the type of treatment, given that every drug
has a predominantly symptomatic effect. The mean recovery time was 2.5 years
(namely the average interval between diagnosis and puberty). CONCLUSIONS:
Contrary to the findings reported in the literature, lesions with an early onset
(prior to adrenarche) recovered more slowly and later.
PMID- 9549295
TI - [Diagnosis in pediatric "allergic" patients].
AB - BACKGROUND: A clinician who deals with allergic patients needs the help of in
vivo and in vitro allergometric tests in order to decide difficult therapeutic
choices. METHODS: In the section of Clinical Immunology of the Institute of
Paediatrics (Palermo University) two allergologic tests, prick and MAST-CLA, have
been studied retrospectively, they were performed on patients observed for
allergic disorders over 5 years. The aim of this study was to evaluate the
diagnostic capacity of these tests "on the field". The study population is made
of 459 patients (age range from 6 months to 16 years) affected with asthma,
rhinitis, presumably allergic dermatitis, association of asthma and dermatitis,
urticaria, selected on the basis of anamnesis and clinical examination.
Eosynophils, basophils, total IgE, specific IgE with DHS-MAST-CLA and prick tests
(Bayropharm) for the allergens most frequently responsible of allergic disease in
our country, have been evaluated. A double controlled assay of 1040 pairs of
allergens with MAST-CLA has been performed. RESULTS: The agreement between prick
and MAST appeared to be satisfactory for inhaled allergens. Eosynophils count and
total IgE levels showed a significative difference between patients negative
versus patients positive for at least one allergen. CONCLUSIONS: The pattern of
the allergens most frequently positive changes with age and patients positive for
pollens showed positivity for vegetal food allergens with a frequency higher than
expected.
PMID- 9549296
TI - ["Pediatric" forms of Creutzfeldt-Jakob disease (nvCJD)].
AB - The authors propose the name of pediatric CJD disease (nvCJD) for those forms of
this pathology which appear in childhood and adolescence (about twenty cases have
been reported in Europe: 1996). The "pediatric form" differs both in terms of age
("teenagers" and also 16-year-old), but also owing to its long course (mean of 14
to 35 months) and the early onset of psychiatric and sensory symptoms. Until a
few years ago, discussion of a new pediatric-adolescent form of the disease (new
variant of CJD) would have been laughable.
PMID- 9549297
TI - [A case of congenital hemangioma of the left lower extremity].
AB - A case of congenital hemangioma located in the lower left extremity is reported.
The evolution and the clinical characteristics are also discussed. The
angiogenesis theory can now explain the genesis and the evolution of hemangioma.
PMID- 9549298
TI - [L-arginine and immunity. Study of pediatric subjects].
AB - BACKGROUND: Nitric oxide (NO) play a pivotal role in many biological processes,
as in the vessel tone control, the atherogenesis, the platelets aggregation and
the immune system modulation. The physiologic precursor of NO is the L-arginine.
Evidence exists that the L-arginine administration can stimulate immune system in
children with recurrent infections. This clinical trial was designed to evaluate
the effects of oral administration of L-arginine on the number of infective
events and on the lymphocytes subsets in children suffering from airways
recurrent infections. METHODS: Forty outpatients, 21 male and 19 female, aging
from 2 to 13 yrs. Two balanced groups, treated for 60 days with L-arginine or a
placebo. Evaluation criteria: number of septic episodes; number of circulating
white blood cells, % of the lymphocytes; lymphocytes subsets. STATISTICAL
ANALYSIS: Descriptive analysis; inference tests: chi 2; "t" test; variance
analysis. Statistical significance: p = 0.05. RESULTS: Fifteen patients treated
with L-arginine and five treated with placebo (p < 0.01) were free from
infections. The percentage of CD3 and CD4 subsets significantly (p < 0.05)
increased in the L-arginine group than in the placebo group, while the CD8 subset
significantly decreased. The CD4/CD8 ratio raised from 1.05 +/- 0.29 to 1.51 +/-
0.46 (p < 0.01) in the L-arginine group, from 1.12 +/- 0.16 to 1.27 +/- 0.24 in
the placebo group. There were no side effects in both groups. CONCLUSIONS: L
arginine seems able to increase the immune system defences and to protect against
the airway infections.
PMID- 9549299
TI - [On ceftriaxone and biliary pseudolithiasis].
PMID- 9549300
TI - [Graves' disease].
PMID- 9549301
TI - The union drama unfolds.
PMID- 9549302
TI - U.S. physicians seek collective bargaining power.
PMID- 9549303
TI - The hospitalist trend. A work in progress.
PMID- 9549304
TI - Character healing: a fresh look at psychodynamic psychotherapy.
AB - Caught between the successes of modern psychopharmacology, the requests of
suffering patients for quick relief, and the shortsightedness of many third-party
payers, psychodynamic psychotherapy might seem to be on the ropes. It is,
however, thriving and providing crucial help to many individuals for whom
medication and brief counseling are insufficient. Meanwhile, many more who could
benefit from psychotherapy do not have an opportunity to do so. Although
psychodynamic psychotherapy originated and developed within a medical framework,
it has minimal visibility on the current medical scene, and many physicians have
been provided with little meaningful information about it. This article is
intended to give physicians a general idea of what psychodynamic psychotherapy is
and how it works.
PMID- 9549305
TI - Impediments to cost-effective care.
PMID- 9549306
TI - MMA blocks bill to triple statute of limitations.
PMID- 9549307
TI - MMA fights efforts to triple statute of limitations.
PMID- 9549308
TI - MMA supports improved bill to address fetal alcohol syndrome.
PMID- 9549309
TI - [Stress and alcohol: research with experimental animals].
AB - Research on the interaction of ethanol and stress with experimental animals are
briefly reviewed. There might be the two aspects of the interaction of stress and
ethanol, i.e., how stress affects ethanol ingestion and response to ethanol, and
how ethanol modifies stress response. In general, stress increases ingestion of
ethanol in animals exposed to various stresses including electric shock,
immobilization and psychological or emotional stresses, wherein the psychological
or emotional factors were predominantly involved. However, in most cases, ethanol
ingestion is increased after release from stress not during exposure to stress. A
variety of stressful stimuli caused marked increases in the neurotransmitter
release in many brain regions. Immobilization stress increased noradrenaline
release in the extended brain regions in rats. These increases were significantly
attenuated by pretreatment with ethanol in the rat amygdala and locus coeruleus,
but not in the hypothalamus, although ethanol by itself increased noradrenaline
release in the hypothalamus. Further, psychological stress, wherein the rats were
given no electrical shock, but exposed to the emotional responses such as
struggling, vocalization, jumping and defecation shown by the other electrically
shocked rats, increased noradrenaline release preferentially in the hypothalamus,
amygdala and locus coeruleus. Among the former two regions, stress-induced
increases in noradrenaline release were significantly attenuated by ethanol in
the amygdala, but not in the hypothalamus. Together with the finding that
increases, in noradrenaline release are closely related to the provocation of
anxiety and/or fear, ethanol, in part, reduced tension, as mentioned in the
tension reduction hypothesis, by attenuating stress-induced increases in
noradrenaline release in the amygdala and locus coeruleus. Moreover, ethanol,
administered i.p. and directly through the microdialysis probe, increased
dopamine release in the nucleus accumbens assessed by in vivo microdialysis,
similarly as addictive drugs such as amphetamine did. This might be, in part,
neurochemical basis for motivation of repeated drinking of ethanol.
PMID- 9549310
TI - Changes in sympathetic and parasympathetic function in alcoholic neuropathy.
AB - We examined sympathetic and parasympathetic function in 17 chronic alcoholics.
The subjects were divided into 4 groups; (1) alcoholics without neurologic
deficits, (2) alcoholics with mild neuropathy, (3) alcoholics with prominent
neuropathy, (4) patients with alcoholic neuropathy but long abstinence. We
measured pulsatile arterial pressure (AP) noninvasively and heart rate (HR) was
calculated from the AP signals. The sweat response on the palm and sole were
measured by ventilated capsular method, while the cutaneous blood flow response
by laser Doppler flowmetry. The AP, HR, sweating and cutaneous blood flow
response to the Valsalva maneuver were evaluated. In alcoholics with minimal and
prominent neuropathy, a pressor (overshooting) in phase IV of the Valsalva
maneuver were decreased significantly. The HR response (reflex bradycardia) in
phase IV of the Valsalva maneuver was significantly decreased only in alcoholics
with prominent neuropathy. The alcoholics with no or minimal neuropathy showed
exaggerated sweat responses on the palm and sole. In prominent alcoholic
neuropathy, the sweat response was greater on the palm, but diminished on the
sole. In no or minimal neuropathy, magnitude of the blood flow response was
markedly reduced on both sites. The low resting blood flow levels may contribute
to the diminished response. We also evaluated pupillary light reflex and response
to methacholine in 7 alcoholics with neuropathy by a portable infrared
pupillometer system that can be used with personal computers. Maximum
constriction velocity of the pupillary light reflex in patients with alcoholic
neuropathy was slower than that in the controls. Reflex amplitude was smaller in
the alcoholics than that in the control. However, local administration of
methacholine did not change pupillary size and light reflex in the alcoholics
same as the controls. The data suggest that preceding sympathetic hyperfunction
related with distressed autonomic center is existing with sympathetic
hypofunction involved from the sympathetic fibers, target organs and higher
center.
PMID- 9549312
TI - [Present status of respiratory infections in aged].
PMID- 9549311
TI - [Genetic polymorphism of human CYP2E1: new allels detected in exons and exon
intron junctions].
AB - Cytochrome P450-2E1 (CYP2E1) is a major component of the microsomal ethanol
oxidizing system (MEOS) and is also involved in the metabolism of a variety of
foreign compounds including carcinogens. It has been shown that there is an
interindividual variation in the expression of human hepatic CYP2E1. Gene
environmental interactions have been suggested to account for the difference. In
this study, we screened nine exons of the human CYP2E1 gene for detecting allelic
variants in genomic DNA samples obtained from 115 Japanese controls, 96 Japanese
alcoholics and 124 American control subjects. A novel missense mutation in exon 2
(V72L) was found in Japanese controls, and another missense mutation in exon 8
(D394G) was detected in American Caucasians. In addition, two novel silent
mutations in exon 6 (T303T) and exon 8 (F420F) were found in Japanese controls
and alcoholics. Especially the silent mutation in exon 8 was highly polymorphic
among three population groups. The mutation in exon 2 (V72L) was detected only in
Japanese controls, but not in alcoholics although it shows no significant
difference. Gene frequency of the silent mutation in exon 8 was significantly
higher in Japanese than American Caucasians (34.8% vs 21.0%, p < 0.02). Our data
indicated that nucleotide replacement in the open reading frame is no major
factor responsible for alcoholism. However, functional significance of the two
novel missense mutations remains to be detailed.
PMID- 9549313
TI - [Changes of pathogenic microbes in respiratory infections in aged].
PMID- 9549314
TI - [Physiological role and dynamics of cytokines in respiratory infections].
PMID- 9549315
TI - [Differential diagnosis of respiratory tract infections based on the symptoms and
test results].
PMID- 9549316
TI - [Progress on diagnostic imaging in respiratory tract infections].
PMID- 9549317
TI - [Gene diagnosis and its significance in respiratory tract infections].
PMID- 9549318
TI - [Primary care for respiratory tract infections].
PMID- 9549319
TI - [New antibiotic therapy of respiratory tract infections and prevention of the
adverse effects].
PMID- 9549321
TI - [Therapeutic countermeasure for respiratory tract infections caused by resistant
strains to antibiotics].
PMID- 9549320
TI - [Selection between oral and injection routes of antibiotic therapy for
respiratory infections based on clinical observations].
PMID- 9549322
TI - [Treatment of respiratory tract infections associated with respiratory failure].
PMID- 9549323
TI - [Therapeutic and preventive countermeasures for respiratory tract infections
associated with malignancies].
PMID- 9549324
TI - [Ideal joint clinical communication systems for therapy of respiratory tract
infections].
PMID- 9549325
TI - [Therapy of common cold--special reference to influenza].
PMID- 9549326
TI - [Therapy and prevention of aspiration pneumonia].
PMID- 9549327
TI - [Important points in therapy of pulmonary tuberculosis and atypical mycobacterium
respiratory infections].
PMID- 9549328
TI - [Therapy of respiratory tract infections in aged and management of their quality
of life (discussion)].
PMID- 9549329
TI - [Case of chronic kidney failure with thrombotic thrombocytopenic purpura due to
miliary tuberculosis].
PMID- 9549330
TI - [Anti-EJ antibody as diagnostic markers for a case of polymyositis].
PMID- 9549331
TI - [Three cases of Fitz-Hugh-Curtis syndrome detected in the early stage by
abdominal ultrasonography].
PMID- 9549332
TI - [Present status in analysis of atopic disease genes].
PMID- 9549333
TI - [Genetic diagnosis of cardiovascular diseases and the therapeutic application].
PMID- 9549334
TI - [Cytomegalovirus infections and hematopoietic disorders].
PMID- 9549335
TI - [Migraine and neurotransmitters].
PMID- 9549336
TI - [Drug delivery system for optimizing therapeutic effects: recent trends in
research].
PMID- 9549337
TI - [Recent development of nucleic acid drug].
AB - Oligonucleotides and their analogs have been utilized for the regulation of gene
expression since mid-1970. The so-called antisense strategy has recently acquired
its reality of the application to clinical therapeutic uses. In the course of the
development, it has been found that nucleic acids might have broad variety of
abilities to regulate gene expression. The abilities are classified as ribozymes,
antigenes, decoy DNAs (or RNAs) and aptamers, and they can be applied to clinical
uses as nucleic acid drugs in the near future.
PMID- 9549338
TI - [Molecular design of polymer-conjugated cytokines and its application for drug
delivery systems].
AB - In recent years, clinical application of recombinant cytokines has been expected
as a novel drug for various diseases. However, cytokines have generally poor
stability in vivo, so they required of very high doses to achieve sufficient
clinical effect. In addition, because cytokines have pleiotropic functions, they
would cause unfavourable side-effects. Therefore an drug delivery system (DDS) is
necessary for clinical use, which stabilizes the cytokines and potentiates only
the expected function from other unfavorable ones in vivo. Then we performed the
chemical modification of cytokines with water-soluble polymers to overcome such
problems as poor stability and pleiotropic activities. This approach includes
some advantages that decrease renal excretion rate of proteins and prevent the
degradation by proteases. This would result in prolonging the half-lives of
bioactive proteins and potentiating their clinical effects. Interestingly, we
found that the polymer-conjugated cytokines, that we named hybrid-cytokines, for
instance, polyethylene glycol-modified interleukin-6 (PEG-IL-6), were able to
increase selectively in their function of promoting platelet production, but not
in other unfavourable functions. This effects were suggested for a result of the
change in the systemic distribution pattern by pegylation of proteins. In this
review, we proposed that the DDS using hybrid-cytokines would be able to increase
the stability and regulate the spectrum of the functions of the cytokines by
controlling the pharmacokinetics and pharmacodynamics in vivo. This will provide
a fundamental information enabling us to design the hybrid-proteins applicable to
therapeutic use.
PMID- 9549339
TI - [Individualization of drug therapy and pharmacogenetics].
AB - This brief review discusses the relationship between genetic polymorphism of drug
metabolizing enzyme and drug's safety and efficacy. When elimination occurs via a
single metabolic pathway, individual differences in metabolic rates can lead to
large differences in drug and metabolite concentrations in the blood. Genetic
polymorphism leads to subpopulation of patients with decreased, absent or even
increased activities of certain reactions (e.g., CYP2C19, CYP2D6, CYP2C9, N
acetyltransferase, thiopurine methyltransferase polymorphism). The consequences
of a genetic polymorphism include not only altered kinetics of specific drug
substrate but idiosyncratic adverse drug reactions. Having these information will
aid in determining dosage of certain medications to the patients with an
inherited abnormality of drug metabolizing enzyme. Pharmacogenetics already has
influenced therapeutics.
PMID- 9549340
TI - [Application of ultrasound energy as a new drug delivery system].
AB - Ultrasound is frequently used in medicine for diagnostic purposes. Recently,
there have been numerous reports on application of ultrasound energy for
controlling drug release or targeting. This new concept of therapeutic ultrasound
combined with drugs has induced excitement in various areas. Ultrasound energy
can enhance effects of thrombolytic agents as urokinase. Ultrasound emitting
catheters are currently being developed for cardiovascular diseases. Device with
ultrasound transducers implanted in transdermal drug patches are also being
evaluated for possible delivery of insulin through the skin. Chemical activation
of drugs by ultrasound energy for treatment of cancers is another new field
recently termed as "Sonodynamic Therapy". Various examples of application of
ultrasound for drug delivery systems are discussed.
PMID- 9549341
TI - [Methodologies for regulation of intestinal absorption of biologically active
peptides].
AB - Oral bioavailability of biologically active peptides and proteins is generally
very low because they are extensively degraded by peptidases and proteases in the
gastrointestinal tract and impermeable through the intestinal mucosal membrane.
Consequently, although clinical application of peptide drugs is limited to
administration by injection, such frequent subjects the patients to considerable
pain, and there is also possibility of the manifestation of serious side effects.
Therefore various approaches have been examined to overcome the delivery problems
of peptide drugs. These approaches include (1) to use additives such as
absorption enhancers and protease inhibitors, (2) to modify the peptide molecules
to produce prodrugs and analogs, (3) to develop an administration method for
peptides that can serve as an alternative to oral and injection administration
and (4) to use the dosage forms to these peptide drugs. In this paper, we
introduce the approaches (1)-(3) and demonstrate that transmucosal absorption of
various biologically active peptides and proteins could be improved by using
these approaches. These approaches therefore may give us basic information to
improve the intestinal absorption of peptide and protein drugs.
PMID- 9549342
TI - [Improvement of drug bioavailability using protease inhibitors].
AB - Although many proteins and peptides were produced by gene-technology, their
administration routes are limited to be i.v. route. To increase the clinical use
of these products, oral dosage form is required. However, in the case of oral
administration, proteins are degraded by digestive fluid having strong protease
activity. To decrease the protease activity, protease inhibitors are administered
concomitantly with proteins. Aprotinin, soybean trypsin inhibitors and gel
forming polymer such as Polycarbophil are representative protease inhibitors. Gel
forming polymers have both protease inhibiting activity and absorption enhancing
effect on protein/peptides. The usefulness of these protease inhibitors have been
suggested as an additive for the oral delivery of G-CSF and vasopressin
derivatives.
PMID- 9549343
TI - [Improvement of intestinal absorption of peptide and protein drugs by chemical
modification with fatty acids].
AB - It is well known that the oral bioavailability of peptide and protein drugs is
generally poor because they are extensively degraded by proteases in the
gastrointestinal tract and impermeable through the intestinal mucosa. Therefore,
various approaches have been examined to overcome the delivery problems of these
peptides and to improve their absorption via the gastrointestinal tract. Of these
approaches, a potentially useful approach to solve these delivery problems may be
chemical modification of peptides and proteins to produce prodrugs and analogues.
Thus, it is plausible that this approach may protect peptides against degradation
by peptidases and other enzymes present at the mucosal barrier and renders the
peptides and proteins more lipophilic, resulting in increased bioavailability.
From these standpoints, we synthesized lipophilic derivatives of peptides and
proteins such as thyrotropin-releasing hormone (TRH), tetragastrin (TG),
calcitonin and insulin by chemical modification with fatty acids. The
pharmacological activities of these derivatives were relatively high as compared
with the native peptides. A significant increase in the intestinal absorption of
these derivatives of peptides was observed in comparison with native peptides.
Overall, the effects of acylation on the intestinal absorption of these peptides
were more predominant in the large intestine than those in the small intestine.
In addition, these derivatives were more stable than the parent peptides in
homogenates of the various intestinal mucosae. We also examined the intestinal
transport characteristics of TG and its acyl derivatives using Caco-2 cell
monolayers in order to assess the contribution of enzymatic and transport
barriers on their intestinal absorption. The degradation clearance of TG on the
apical membrane was decreased by chemical modification with fatty acids. In
addition, the permeability clearance of TG was improved by the acylation. On the
other hand, the intestinal absorption of thyrotropin releasing hormone (TRH),
which is transported by a carrier-mediated process, was also enhanced by chemical
modification with lauric acid. In summary, this chemical modification approach
may be useful to improve the intestinal absorption of peptide and protein drugs.
PMID- 9549344
TI - [Enhancement of drug absorption by iontophoresis and phonophoresis and clinical
application].
AB - Concepts of iontophoresis and phonophoresis are described. Main factors regarding
iontophoretic transdermal drug delivery of ionized drugs or non-ionized drugs and
clinical applications are outlined. Iontophoretic and sonophoretic transdermal
drug delivery has some advantages and disadvantages. However, its clinical use
for controlled drug delivery corresponding to chronopharmacology will bring more
benefit to patients in near future.
PMID- 9549345
TI - [Strategies for drug delivery to the brain across the blood-brain barrier].
AB - Designing drugs (including peptides) with greater lipophilicity are still
effective strategy for the enhancement of the permeability across the blood-brain
barrier (BBB), which is considered to be lipoidal membrane barrier of endothelial
cells which have tight junctions without fenestrations. However, for the
development of brain-specific drug delivery for neuroactive drugs, it may be
greater promising strategy to utilize the specific influx transporters existing
at the BBB for hexoses, amino acids, monocarboxylic acids, amines or to inhibit
the functions of the efflux transporters such as P-glycoprotein which pumps out
cytotoxic and/or lipophilic drugs. Attractive approach to the delivery of
peptides is to design the peptide to be transported across the BBB via
ologopeptide specific transporters, via insulin or transferrin receptor-mediated
transcytosis, or via adsorptive-mediated transcytosis specific for positively
charged peptides.
PMID- 9549346
TI - [Transdermal therapeutic systems].
AB - Advances in transdermal therapeutic systems (TTS) and the technology involved
have been rapid because of the sophistications of physiology and biology on skin,
enhancing methodology for the skin penetration of drugs, and material and polymer
sciences on the pharmaceutical additives. In this review paper, such progress was
introduced and the future on the TTS was augured.
PMID- 9549347
TI - [Delivery of macromolecular drugs to the vitreous and its peripheral tissues].
AB - We evaluated the release behavior of FITC-dextran with an average molecular
weight of 4,400(FD4), as a model peptide drug, from poly(DL-lactic acid) (PLA)
implant. The drug level in the vitreous and its peripheral tissues were measured
following the implantation in the rabbit vitreous. The release profile of FD4
from the PLA implant was biphasic; a fraction of the drug molecules incorporated
in the polymer implant was swiftly released; then slowly or even negligibly for a
certain period of time and finally complete bursting release probably due to bulk
erosion of the polymer. The time-course of drug concentration in the vitreous and
aqueous humor after implantation showed a constant level for 14 days and then
parabola, where the highest concentration appeared around 28 days. The drug
concentrations in the retina/ choroid was maintained a constant level for 28
days. After an injection of FD4 in the rabbit vitreous, the drug concentration in
those tissues approximately decreased mono-exponentially. These findings suggest
that the present implant could be a useful carrier for delivery of macromolecular
drugs to the vitreous and its peripheral tissues.
PMID- 9549348
TI - [PEG-liposome in DDS and clinical studies].
AB - The current status of newly developed polyethyleneglycol coated liposome (PEG
liposome) were described in this review. Liposomes have demonstrated considerable
promise as a carrier for the delivery of drugs in vivo. However, one of the
drawback is that most liposomes intravenously injected into animals are rapidly
removed from the blood circulation by uptake primarily in the cells of
reticuloendothelial system (RES). It has been found that PEG-liposome are not
readily taken up by the macrophages in the RES and hence stay in the circulation
for a relatively long period of time. Pharmacokinetic analysis and therapeutic
studies with tumor bearing mice revealed that PEG-liposomes have considerable
potential as drug carriers for cancer therapy. Elevated liposome accumulation has
been found in the tumor bearing mice model system. Results from clinical studies
with doxorubicin encapsulated into PEG-liposomes (DOXIL) in AIDS-related Kaposi's
sarcoma revealed an increased therapeutic efficacy compared to free-drug. These
new formulations of long-circulating liposomes (PEG-liposome) offer the
development of immunoliposomes with both long survival times in circulation and
target recognition being retained in vivo. Fab'-PEG-immunoliposome was newly
designed to gain long-circulating enough to extravasate to the targeted solid
tumor in vivo. An ultimate goal of Fab'-PEG-immunoliposome is the incorporation
of a fusogenic molecules that would induce fusion of liposome following their
binding to the target cells or their internalization by endocytosis. Such
liposomal formulations should be useful for endocytotic internalization of
plasmid DNA and other bioactive materials.
PMID- 9549349
TI - [Application of monoclonal antibody for drug delivery system--missile therapy for
cancer].
AB - Clinical applications of monoclonal antibody for selective delivery of anticancer
drug, toxin and radioisotope were reviewed. The difficulties in preparation and
clinical application of chemoimmunoconjugate were pointed out. Also the
difficulties of immunotoxin in clinical trial due to its high toxicity had been
discussed and it is assumed that development of blocked ricin may overcome many
problems related to toxicities. Clinically most advanced immunoconjugate seems to
be radioimmunoconjugate. Among three types of immunoconjugates preparation of
radioimmunoconjugate is easiest and some promising clinical trials were
introduced in this review.
PMID- 9549350
TI - [Targeting of anticancer drug using intelligent polymers].
AB - To fabricate the drug targeting system, it is very effective to combine passive
targeting with intelligent polymeric system such as temperature-responsive
polymers. We have been studying the passive targeting of anticancer drug bonded
with or physically trapped in polymeric micelle derived from poly (ethylene
oxide) (PEO) and poly (aspartic acid) block copolymer. On the other hand, Poly(N
isopropylacrylamide) (PIPAAm) is known to be a thermo-responsive polymer which
has lower critical solution temperature (LCST, 32 degrees C). PIPAAm shows the
reversible phase transition above and below LCST. Attempts to apply thermo
responsive drug carriers were made to enhance the site-specificity of polymeric
micelle. Namely, novel type of polymeric micelle were prepared from block
copolymers comprising N-isopropylacrylamide (IPAAm)-hydrophobic polymers. This
temperature responsive micelles were expected to induce selective accumulation
controlled by temperature modulation.
PMID- 9549351
TI - [Targeting technology utilizing magnetic microparticulate system for cancer
therapy].
AB - Organ level-targeting of anticancer drugs or other relating stimuli to tumor
tissues and their circumstances is important in cancer therapy. The successful
targeting results in the greater antitumor effect and the lower numerous side
effects. Application of a magnet from the outside of body is a useful tool to
increase the targeting efficacy. In this review paper, targeting technology
utilizing magnetic microparticulate system for cancer therapy was introduced and
the future on the magnetic targeting system was augured.
PMID- 9549352
TI - [Transferrin conjugated PEG-liposomes as intracellular targeting carrier for
tumor therapy].
AB - For the purpose of intracellular targeting carrier by systemic administration,
PEG-liposomes conjugating transferrin (TF) at the distal ends of PEG chain were
newly prepared. Biodistribution of TF-PEG liposome was examined in the colon 26
bearing mice. TF-PEG liposome were prolonged in the circulation and highly
accumulated into the tumor tissue. After extravasation, TF-PEG liposome retains
the specific binding ability to tumor cell surface. Uptake of TF-PEG liposome was
examined by electron microscopy. TF-PEG liposome was localized at the cell
surface, coated pits and endosome. These results show TF-PEG liposome was bound
and internalized by endocytosis. Such liposomes should be useful for
intracellular targeting carrier at the way of systemic administration.
PMID- 9549353
TI - [Pharmaceutical and pharmacological development of antitumor prostaglandins].
AB - Antitumor Prostaglandins such as delta 12PGJ2 and delta 7PGA1 possess a cross
conjugated dienone unit and exhibit unique antitumor effect. Lipid microshere
(w/o type emulsion) was selected as pharmaceutical formulation because of
physicochemical properties of prostaglandin. 13,14-Dihydro-15-deoxy-delta 7-PGA1
methyl ester (TEI-9826) were selected as a candidate for clinical trial. In a rat
and mouse serum in vitro, TEI-9826 rapidly metabolized to 13,14-dihydro-15-deoxy
delta 7-PGA1 (TOK-4528), but TOK-4528 is stable as well as delta 12PGJ2. Lipid
microshere containing TEI-9826 at the content of 5 mg/ml exhibited administration
route and schedule dependent antitumor effect in vivo using Colon 26 bearing
mouse model, which suggested that duration of serum concentration was important
for antitumor effect. One of the antitumor mechanism of antitumor PG might be an
induction of the cyclin-dependent kinase inhibitor p21. PPAR gamma also might be
important. New type homogenizer, high pressure jet flow type homogenizer was
developed in the study of antitumor prostaglandin.
PMID- 9549354
TI - [Controlled release using temperature-responsive poly(N-isopropylacrylamide)
gel].
AB - Poly (N-isopropylacrylamide) (PNIPAAm) gels were found to undergo discontinuous
swelling-deswelling changes in response to a limited alteration in external
temperatures. By utilizing such as thermosensitive characteristic of the PNIPAAm
gel, controlled drug release was studied extensively. Drug release profiles were
well established in connection with the temperature dependence of swelling ratio
for the gel. The thermal regulation of the swelling degree of the gel made it
possible for us to design several ways for performing a unique drug release
profile such as a "pulsatile" or "on-off" release of indomethacin. Attempts to
develop a more excellent drug release system have being made through studies of
molecular design and synthesis for PNIPAAm-based thermosensitive gels.
PMID- 9549356
TI - [Design and application of oral sustained-release anticancer drug--a new oral
dosage form of cisplatin].
AB - As compared to the conventional standard chemotherapy of solid cancer such as
lung, biochemical modulation (BCM) therapy has been proven to have a good
therapeutic efficiency. BCM therapy uses the low dose and low infusion rate of
anti-cancer drug. To increase of the QOL of cancer patients, oral BCM therapy is
needed. For this purpose, two kinds of new oral sustained-release cisplatin
preparations were developed, micro-porous CDDP capsule made of ethylcellulose(EC)
and CDDP-EC-stearic acid solid dispersion. After oral administrations of these
preparations, serum CDDP levels were maintained over 0.2 microgram/ml for 24h.
Experimental therapy using P815 tumor cells transplanted mice suggested the
usefulness of CDDP solid dispersion preparation.
PMID- 9549355
TI - [Design and development of controlled release of drugs from injectable
microcapsules].
AB - Monolithic microcapsules were designed and developed for controlled release of
leuprorelin for one month following a single injection. Copoly (DL
lactic/glycolic) acid (PLGA) of copolymer ratio of 75/25 and average molecular
weight of 14,000 was suitable for achieving steady serum leuprorelin levels in
rats and dogs for 4 weeks. The clinical efficacy of these injectable
microcapsules of leuprorelin has been widely proved for prostate cancer,
endometriosis, and other sex hormone dependent diseases in about sixty countries.
The interaction between the basic functional group of the drug and the carboxylic
end group of PLGA was found to be the most important factor in preparing the
microcapsules with a small initial burst, as shown with thyrotropin releasing
hormone (TRH) and a water-soluble GPIIb/IIIa antagonist (TAK-029).
PMID- 9549357
TI - [Drug delivery system (DDS) for the use of antisense oligodeoxynucleotide
phosphorothioate in controlling gene expression].
AB - Synthetic antisense oligodeoxynucleotide phosphorothioates (ODNs) are widely used
as therapeutic tools in various in vitro and in vivo systems. Here, we applied
ODNs to inhibit viral gene expression. Human T-cell leukemia virus type I (HTLV
I) is a retrovirus, and is closely linked to adult T-cell leukemia (ATL), HTLV-I
associated myelopathy/tropical spastic paraparesis(HAM/TSP), and other HTLV-I
associated diseases. With an attempt to control viral replication in vitro, ODNs
to HTLV-I tax gene were synthesized and applied. In addition, 1,2-dioleoyloxy-3
(trimethylammonio) propane, DOTAP as a drug delivery system, was exploited to
increase the cellular uptake of ODNs. Combination of ODNs and DOTAP was more
effective to suppress viral antigen expression than ODNs only. Therefore this
combination method may be useful in clinical trials for HTLV-I-associated
diseases.
PMID- 9549358
TI - [Drug delivery systems in gene therapy].
AB - The use of nonviral vectors is an attractive in vivo gene delivery strategy that
is simpler and lacks some risks inherent in viral systems. Liposomes and receptor
mediated polycation systems are promising carriers for delivery and expression of
plasmid DNA encoding genes into the target cells. Many barriers need to be
overcome for successful in vivo DNA delivery using these carrier systems. Various
factors such as the extent of DNA condensation, particle size of the DNA complex,
route of administration, stability against nucleases, target sites, in vivo
disposition, binding to cell surface receptor and internalization, intracellular
trafficking affect the in vivo gene delivery and expression. This chapter will
focus on the current status and perspectives of the plasmid DNA delivery systems
for in vivo gene therapy.
PMID- 9549359
TI - [Study of T cell-directed gene transfer for a patient with ADA deficiency].
AB - We have been undertaking the gene therapy for a 6 year-old boy with ADA
deficiency and performed 11 cycles of the infusion of the peripheral T cells
transduced with retroviral vector LASN since August 8th 1995. The percentage of
the peripheral blood lymphocytes carrying the transduced ADA gene has remained
stable at 10% to 20% since the 4th infusion. ADA enzyme activity in his
circulating T cells increased to levels comparable to 1/3 of a heterozygous
carrier individual and was associated with increased T lymphocytes counts and
improvement in both humoral and cellular immune function. The results obtained in
this clinical study support the usefulness of T lymphocyte-directed gene transfer
in the treatment of ADA deficiency.
PMID- 9549360
TI - [Gene delivery using adeno-associated (AAV) vectors].
AB - Gene transfer vectors based on the replication-defective adeno-associated virus
(AAV) are emerging as promising vehicles for gene therapeutic approaches for the
neurologic disease, cystic fibrosis and cancers. AAV vectors have been used to
efficiently transduce genes into cells in vitro and in vivo. However, transduced
recombinant AAV vectors are integrated into human chromosomes. Thus we have
discussed that the review about the AAV vectors and transduction, and reported
the results used AAV vectors for expression of ribozyme.
PMID- 9549361
TI - [Cationic liposomes in gene delivery].
AB - Cationic liposomes have been extensively explored as gene delivery vector for
several reasons. It is because disadvantages of viral vectors include risk of
replication, possible immunogenicity, and the difficulty of obtaining a large
quantity of viral vectors. Currently, a variety of cationic components for
liposome formulations have been developed. The components are broadly divided
into two classes based on the chemical structure of hydrophobic moieties: long
aliphatic (saturated or unsaturated) hydrocarbons and cholesterol ring. A variety
of hydrophilic moieties also include tertiary amines, ammonium salt and spermine.
The role of liposomes is to condense DNA to form complexes with high affinity to
cell surfaces where possible fusion or destabilization of the membrane and/or
endocytosis are involved. However, at present, little structure-activity
relationships are known. Some vectors are on clinical trials approved by NIH.
PMID- 9549362
TI - [Gene introduction into animal tissues by fusogenic liposomes].
AB - The future success of gene therapy relies largely upon the development of ideal
gene-transfer vehicles (vectors) that can efficiently and stably introduce and
express therapeutic genes into non-dividing tissue cells. We have developed a
fusogenic liposome that can deliver the encapsulated DNA into the cytoplasm
through fusion with the cell membrane. For targeting the DNA into the nucleus, we
attend to lambda phage particles that encapsulate up to 48 kbp DNA in their small
head (55 nm in diameter). When a strong NLS signal is attached on the surface of
the phage head by recombinant DNA technology, the particles efficiently
accumulate in the nucleus. Reconstitution of the ideal gene-transfer system
through a detailed analysis of biological phenomena is discussed.
PMID- 9549363
TI - [Intracellular gene delivery by polymer micelle vectors].
AB - This review paper deals with the development of novel vector system for gene and
antisense oligonucleotides. The system is based on the self-association of
poly(ethylene glycol)-poly(L-lysine) block copolymer with DNA to form polyion
complex micelles with unimodel size distribution in the range of 50-100 nm. DNA
molecules are compactly assembled into the core of the micelle, surrounding with
the dense corona of poly(ethylene glycol). High resistance to nuclease attack was
demonstrated for micellized DNA in the serum-containing medium, indicating the
potential of micelle vector system to stabilize DNA in physiological condition.
Significant gene expression was confirmed by luciferase assay using 293 cell-line
for these micelle vector systems with slightly cationic character.
PMID- 9549364
TI - [Gene delivery into human cancer cells via transferrin receptor].
AB - At present, vectors widely used for gene transduction are retroviruses and
adenoviruses. However, the transduction using these vectors are primarily
conducted ex vivo. The direct in vivo gene delivery method to target tumor cells
are required. Trials to augment specificity of gene targeting to tumor cells have
been in progress including approaches to use modified virus particles by gene
technology instead of wild type particles or to take advantage of ligand-receptor
or antibody-antigen systems by allowing vector DNAs to bind these ligand and
antibodies. Transferrin receptor (TfR) is widely distributed on actively
proliferating cells and is therefore an appropriate target for in vivo gene
delivery into those cells. We developed a simple method to conjugate biotinylated
double-stranded DNA to biotinylated Tf via streptavidin and demonstrated
successful transduction of the conjugate into TfR-positive human cancer cells.
The present method may provide a novel technique for gene transduction, which may
be used especially to transfer various DNA vectors into cells specifically
expressing TfR, in vivo as well as in vitro.
PMID- 9549365
TI - [Targeting delivery of therapeutic genes using monoclonal antibody; immunogene
approach].
AB - We are developing the "immunogene" system for the targeted delivery of
therapeutic genes. The immunogene system utilizes the EGF receptor-mediated
endocytosis. The Fab fragment of monoclonal antibody B4G7 against human EGF
receptor was conjugated with polylysine to form an "Fab immunoporter", which
forms an affinity complex with DNA. The transfection efficiency of Fab immunogene
was approximately 10-fold higher than the Lipofectin. Gene transfer of HSV-tk
gene into A431 tumor cells with Fab immunoporter was successful and the
subsequent treatment with ganciclovir induced remarkable suicide effects
conferring 1000-fold higher drug sensitivity. Thus, the immunogene system could
be useful as a gene transfer vehicle targeting the EGF receptor-hyperproducing
tumor cells.
PMID- 9549366
TI - [Drug delivery system in cardiovascular drugs].
AB - Various drug delivery systems are available when cardiovascular drugs are used.
Various kinds of receptor inhibitors such as beta blockade or angiotensin II
receptor inhibitor are frequently used in the daily cardiovascular clinic.
Several different routes of drug administration exist. Conventional tablet or its
liquid spray by sublingual or lingual administration is rapidly absorbed and
specified oral tablet or transdermal patch for maintaining longtime is slowly
absorbed from the digestive tract or skin. Some drugs have different type of
tablets for obtaining different pharmacodynamics. Nifedipine has 3 kinds of
tablets showing short, long and very long-time effect. Recent advance in drug
delivery system makes possible to administer the drug to the small local area
through stent or balloon catheter at the coronary interventional therapy.
PMID- 9549368
TI - [Drug delivery system for diabetes].
AB - Long-term intensified insulin therapy composing of multiple insulin injection and
self-blood glucose monitoring enables glycemic control of insulin-requiring
diabetics. For reducing inconvenience of this therapy, several delivery route of
insulin are under investigation. Nasal administration of insulin aerosol
effectively controlled insulin-dependent diabetics for up to 6 months because its
high bioavailability and rapid absorption. By means of ionophoresis or ultrasound
approach, insulin was shown to be absorbed transdermally. Polymer containing
modified insulin and immobilized enzyme could increase insulin release against
hyperglycemia. These new approach of insulin delivery might increase convenience
of insulin administration.
PMID- 9549367
TI - [Drug delivery system for the treatment of osteoporosis].
AB - The number of agents for the treatment of osteoporosis has increased over the
past few years allowing more and more differentiated therapy. Calcitonin, vitamin
D3, bisphosphonate, estrogen, vitamin K2 and calcium are administered for the
treatment of osteoporosis in Japan. The purpose of drug delivery system (DDS) is
to provide a practical approach to increasing efficacy and minimizing side
effects of the drugs. In fact by the development of DDS, topical administration,
prodrug and targeting therapy are used in the treatment for osteoporosis. It is
well known that calcitonin in susceptible to proteolysis in the intestine. So,
calcitonin must be given intramuscular or subcutaneous injection for therapy. DDS
of calcitonins is studying in many routes of administration, such as nasal,
transdermal, ocular, oral, bronchial, rectal and vaginal.
PMID- 9549369
TI - [Drug delivery system for infectious diseases].
AB - Various types of antimicrobial agents have been evolved to inhibit growth of or
to kill different microorganisms. In recent years, encapsulation of antimicrobial
agents in lipid formulations has been a popular practice in research work related
to drug delivery system, although most of the studies are based primary on animal
models. The recent developments of lipid formulations of anti-infectious drug
(antibiotics, antifungals, and antiviral agents) with longer half-life opens new
therapeutic avenues in treating infections. The passive targeting of liposomes to
the sites of infection is of great value with respect to clinical application.
Liposome entrapment can exchange their pharmacokinetics and, hence reduce their
toxicity.
PMID- 9549370
TI - [New drug delivery systems for the therapy of bronchial asthma].
AB - Inhalation therapy gives us ideal topical therapy for the airway diseases without
significant major side-effects. As new century approaches, a major goal for
asthma therapy will be to provide more effective therapeutic drugs to prevent
airway inflammation and its spasmus. It is also important to produce excellent
inhalant devices that are easy to use and do not contain substances that are
harmful to the environment. Future inhalers should target the drug to the correct
sites in the airways and thus enable optimal therapeutic effects to be achieved.
There are many exciting new developments available in this field. And we should
finally obtain special therapeutic drugs to prevent the process to the sudden
onset of asthmatic death.
PMID- 9549371
TI - [Anti-HIV drugs and drug delivery system].
AB - A number of candidate drugs for therapy of HIV-1 infection which show significant
activity against the virus in vitro were reported; however, many of them have
been dropped from drug development due to (i) insufficient intracellular
activation in certain human target cells (particularly in case of nucleoside
reverse transcriptase inhibitors), (ii) poor pharmacokinetic profiles, or (iii)
intolerable in vitro and/or in vivo toxicities. To circumvent some of these
problems, certain drug delivery systems have been applied and several candidate
drugs including two novel nucleoside reverse transcriptase inhibitors, abacavir
and adefovir, have acquired favorable properties in the clinical setting. This
paper reviews several avenues for developing prodrugs of anti-HIV-1 agents to
overcome their inherent limitations.
PMID- 9549372
TI - [Monoclonal antibodies as an immunotherapy of rheumatoid arthritis].
AB - Rheumatoid arthritis(RA) is a chronic, deforming and destructive arthritis of
unknown etiology. For the medical treatment of RA, NSAID has been the first
choice of drug. Recently it has been known that early use of DMARD may result in
clinical remission. Understanding of the pivotal role of cytokines and adhesion
molecules for the rheumatoid joint destruction enabled us to target these
cytokines and molecules as therapeutic measures. Monoclonal antibodies were
produced against the cytokines and adhesion molecules such as IL-1, IL-6, IL-6R,
TNF-alpha, as well as CD4 molecules. Clinical use of these monoclonal antibodies
was found to be effective for rheumatoid arthritis. However these therapeutic
measures have several disadvantages such as transient efficacy and side effect.
PMID- 9549373
TI - [Drug delivery system of anti-inflammatory and anti-rheumatic drugs].
AB - Anti-rheumatic drugs such as nonsteroidal anti-inflammatory drugs,
glucocorticoids, and disease modifying anti-rheumatic drugs are valuable
medications for patients with rheumatoid arthritis available for physicians now.
This review provides a practical approach for increasing efficacy and minimizing
adverse response of some of these drugs by the development of drug delivery
system.
PMID- 9549374
TI - [Ulcerative colitis--colon delivery of 5-aminosalicylic acid].
AB - Ulcerative colitis, Crohn's disease and hemorrhage colitis are typical example of
colon specific diseases. The targeting of the drugs for these colon specific
diseases was attempted by a new technology, where ethylcellulose (EC) was used as
pharmaceutical material. Especially, pressure-controlled colon delivery capsule
(PCDC) made of EC is a unique system. PCDC was prepared by coating the inner
surface of gelatin capsule with water-insoluble polymer, EC. By adjusting the
coating thickness of EC membrane to be approximately 40 microns, colon delivery
of dug were obtained both in beagle dogs and human volunteers. PCDC containing 5
ASA was prepared and was administered orally to beagle dogs. After
administration, 5-ASA appeared into the systemic circulation at 3-5 h which
corresponds to the colon arrival time confirmed with sulfasalazine.
PMID- 9549375
TI - [Molecular modeling of immunological proteins by bioinformatics].
AB - The antibody combining site is composed of six complementarity determining
regions (CDRs), whose typical structures have been classified as "canonical
structures" except CDR-H3, depending upon the segment lengths and the positions
of specific amino acid residues in the segments. Using the method of structural
bioinformatics, we have proposed a novel classification of the CDR-H3 structures,
and revealed several remarkable relationships between their sequences and the
loop conformations. Based upon the canonical structures and our new rules,
structural models of antibodies have been built in order to understand the
molecular basis of antigen recognition. Another new computational method of
almost exhaustive conformational search is introduced for future applications.
PMID- 9549376
TI - [Human immunodeficiency virus and AIDS in terms of reverse transcriptase and
molecular evolution].
AB - Human immunodeficiency virus type 1 (HIV-1) evolves rapidly in the host. The
computer analysis of the HIV-1 genome has shown that the mutation manner is
dependent on oligonucleotide sequences (in particular, six bases long); thus HIV
1 adaptively evolves. The six-base-long interaction between template-primer
oligonucleotide and the reverse transcriptase (RT) has been revealed by the
crystal structure of RT, in vitro termination assay of plymerization, and
hydroxyl radical footprint analysis. It has been thought that AIDS is caused by
the large numbers of HIV-1 quasispecies yielded by the adaptive and rapid
evolution in the host. However, the slow evolution and the high levels of viral
RNA in the progressive HIV-1 infected individuals (progressives) were recently
reported; in contrast, the adaptive and rapid evolution and the low viral-RNA
levels were reported in the non-progressives. This suggests that the
physiological environment, e.g. pH and dNTP balance, in which RT works in the
progressives is different from that in the non-progressives.
PMID- 9549377
TI - [Imaging of myocardial perfusion and metabolism with positron emission
tomography].
AB - Positron emission tomography (PET) has been providing new information in the
diagnosis and the pathophysiological assessment of heart diseases. The PET
tracers commonly used in Japan are 13N-ammonia, 18F-fluorodeoxyglucose (FDG) for
imaging of myocardial perfusion and metabolism, respectively. Measurement of
regional myocardial blood flow by 13N-ammonia dynamic PET scan and a compartment
model analysis is applied to the functional estimation of coronary stenotic
lesions and the detection of perfusion abnormalities in hypertrophic heart
diseases, familial hyperchlesterolemia and other diseases with possible
microvascular lesions. 18F-FDG is commonly used to differentiate ischemic but
viable tissue from myocardial scar in coronary artery disease and also used to
detect cardiac tumor and the cardiac involvement in sarcoidosis. In addition to
these two tracers, 11C-acetate is now expected to provide the clinical analysis
of pathophysiology of heart failure by estimating the efficiency of energy
conversion of the heart into external work.
PMID- 9549378
TI - [Helicobacter pylori, gastric pathology, and histopathological diagnosis].
PMID- 9549379
TI - [Chronic gastritis. Guidelines and minimum diagnostic criteria. Italian Digestive
System Pathologists Group].
PMID- 9549380
TI - [A variety of mediastinal bronchogenic cyst: the broncho-alveolar cyst].
AB - Congenital bronchogenic cysts are usually located in the mediastinum or develop
as intrapulmonary cysts. Gross examination of excised bronchogenic cysts shows
them to be unilocular; histologically, these lesions are characterized by the
presence of respiratory-type pseudostratified epithelium as well as small islands
of cartilage and seromucinous glands. We report a case of a mediastinal
bronchogenic cyst having pulmonary parenchyma within the cyst wall. The rarity of
our case, the pathological and clinical features and the embryological
development of bronchogenic cysts are briefly discussed.
PMID- 9549381
TI - [Lymph node inflammatory pseudotumor. Description of a case].
AB - A case of inflammatory pseudotumor of lymph node in a 56-year-old man is
described. The awareness of this benign reaction pattern is of great importance
for differential diagnosis with many nodal lesions.
PMID- 9549382
TI - [Lipoleiomyoma of the uterus].
AB - The presence of fatty tissue in the myometrium is anomalous; this alteration has
been interpreted either as a lipomatous degeneration or as a metaplasia of smooth
muscle cells or, still, as a real neoplasm, frequently associated with a
leiomyoma, the so-called lipoleiomyoma. The observation of a case of
lipoleiomyoma stimulated us to ascertain the real incidence of this lesion which
is commonly considered to be rare. We examined 620 single or multiple uterine
leiomyomas with extensive sampling of all the areas suspected to contain fatty
tissue islands. Five times out of seven the presence of fat cells in a leiomyoma
resulted to be a true lipoleiomyoma. It has thus been possible to ascertain the
incidence of lipoleiomyoma versus uterine leiomyomatosis (0.8%). Futhermore we
observed a prevalence in menopause, an association with multiple leiomyoma and a
preferential onset in the subserosa. The pathogenesis of this lesion, which can
be fully ascribed to a mixed, benign, heterologous, mesenchymal neoplasm, is
briefly discussed.
PMID- 9549384
TI - [Why physicians should read books (medical)?].
PMID- 9549383
TI - [Sarcoid-like hepatic granulomas, associated with gastric neoplasia. Description
of a case].
AB - Giant cell granulomas in liver biopsies is a relative common finding. Among the
many causes of granulomatous lesions of the liver primary biliary cirrhosis and
sarcoidosis are the most frequently diagnosed. On the other hand sarcoid-like
granulomatous reaction can be encountered associated to malignant tumours.
Purpose of the present paper is to describe a case of a sarcoid-like reaction of
the liver associated to gastric adenocarcinoma. The patient was a 66 yr old man
who underwent gastrectomy for a signet-ring cell adenocarcinoma. Pathological
anamnesis was unremarkable. Liver function tests were within normal limits. Chest
x ray was normal. A liver biopsy was performed during surgery as the liver
presented an irregular surface. On histology giant cell granulomas with sarcoid
like features were seen in the hepatic parenchyma. Same reaction was present in
the perigastric lymph nodes. The patient died immediately after surgery due to
massive pulmonary embolism. No autopsy was performed. Among the possible
diagnoses primary biliary cirrhosis, sarcoidosis and paraneoplastic sarcoid-like
granulomatous reaction were considered. Primary biliary cirrhosis and sarcoidosis
were excluded on the basis of the past clinical history of the patient, that was
unremarkable; furthermore liver function tests performed preoperatively were
within normal ranges. Thus paraneoplastic sarcoid-like reaction involving the
liver was regarded as the most likely diagnosis.
PMID- 9549385
TI - [Hypnotic drugs in a population. Prescriptions by the specialist and the general
practitioner].
AB - The aims of our survey were to estimate the prevalence of hypnotic drug
prescription in a representative sample of population in 5 cities of Northern
Italy and to analyse the pattern of prescription of these drugs by general
practitioners (GPs) and psychiatrists. The data were collected with the
collaboration of pharmacists working in 145 pharmacies. All consecutive patients
presenting a prescription for a hypnotic drug were interviewed by the pharmacists
during a two-week period. The pharmacists interviewed 7744 consecutive patients.
The highest prevalence of prescriptions for hypnotic drugs was found in the
elderly and in women. The majority of prescriptions were for benzodiazepines
(BDZ), with lorazepam and triazolam accounting for about 50% of the total
prescriptions. Short-acting and ultra-short-acting BDZ were more frequently
prescribed for sleep induction by GPs than by psychiatrists. Approximately 73% of
subjects reported that they had been taking the prescribed drug for one year or
more. The high proportion of long-term BDZ users may be a consequence of the
short period surveyed, which produced data weighted toward long-term consumption.
Our data, however, do not permit to establish whether long-term use is
appropriate from a clinical point of view or is the consequence of a physical
dependence. We must be aware that this practice needs to be studied more
accurately, with the aim to assess the risk/benefit ratio of long-term BDZ use.
PMID- 9549386
TI - [Therapy of refractory rheumatoid arthritis. Cyclosporin and methotrexate
combination].
AB - Rheumatoid arthritis (RA) is a chronic multisystemic disease affecting mainly the
joints and characterised by a poor prognosis. In a four month open study we
evaluated the efficacy and tolerability of a combination therapy in 14 patients
with active and refractory RA (non responsive to MTX or CsA monotherapy). After
three pulses of methyl-prednisolone (125 mg/die i.v. for 3 days), at day the 4
patients received methotrexate (MTX 15/mg/week p.os) and cyclosporine (CsA 3
mg/kg/day p.os). At the end of treatment period, patients had a statistically
significant improvement in the tender-joint count (Ritchie Index) in the swollen
joint count and in the pain as recorded on a 100-mm visual-analogue scale.
Following the criteria of the American College of Rheumatology for response to
treatment in RA, 6 patients (60%) met these criteria, whereas 2 had a worsening.
We could not detect any clear difference in serological parameters (ESR, CRP and
Hb levels) between the beginning and the end of the therapy. A significant
difference in the score of edema/joint effusion was documented at the RM
analysis. Side-effects were not substantially increased as compared to MTX or CsA
in single therapy. Combination therapy with CsA and MTX seems to be a safe and
effective treatment for patients with active and refractory RA.
PMID- 9549387
TI - [Combined drug therapy in recent-onset rheumatoid arthritis. Evaluation after 1
year of treatment].
AB - The aim of our study is to evaluate the efficacy and safety of a combination
therapy with hydroxycloroquine, gold sodium thiomalate and methotrexate in
patients affected by recent onset active rheumatoid arthritis. Twenty-five
patients (6 men e 19 women, average age 46.2 +/- 12.2) were enrolled in this
study and 18 of them have been treated for 1 year with the three above-mentioned
drugs at optimal doses. Drug toxicity was carefully monitored. Clinical and
hematochemical parameters of efficacy were evaluated every three months.
Radiographic joint study was performed at the beginning and at the end of the
study. Seven patients dropped out, six of them for side effects, due to
hydroxycloroquine in 1 case and to gold sodium thiomalate in 5 cases; 1 patient
withdrew his consent. No life-threatening or irreversible adverse reactions were
observed. The eighteen patients who completed the one year trial presented a
remarkable improvement of clinical and hematochemical parameters. In only 1 case
one erosion appeared at the end of the study. In conclusion, the combination
therapy with hydroxycloroquine, gold sodium thiomalate and methotrexate seems to
be effective and burdened by an acceptable level of toxicity.
PMID- 9549388
TI - High dose dexamethasone as first line therapy of multiple myeloma? A case report.
AB - The authors describe a case of multiple myeloma in which a complete remission was
obtained by treatment with high dose dexamethasone. This was the only therapy
suitable for the patient because of heavy myelosuppression due to disease and to
one course of conventional treatment with melphalan and prednisone. Further
trials are needed to evaluate the usefulness and safety of this treatment as
first line therapy, especially in the elderly, with pancytopenia and bad
performance status.
PMID- 9549389
TI - [Microscopic polyangiitis. A case report].
AB - We describe a 36 year old male patient affected by microscopic polyangiitis; he
was treated with corticosteroic and cyclophosphamide pulses obtaining clinical
improvement and remission and acute flogistic index normalization. The peculiar
aspect is a stable remission during a four years follow up; the only relapse was
controlled with low dose of corticosteroids.
PMID- 9549390
TI - [Prevention of cancer: epidemiology and prospects].
PMID- 9549391
TI - [Relationship between polymyalgia rheumatica and temporal arteritis].
PMID- 9549393
TI - [Nuclear cardiology toward the year 2000].
PMID- 9549392
TI - [Fever of unknown origin in rheumatology].
AB - Fever occurs frequently in several rheumatic disorders, and remains a diagnostic
and therapeutic challenge to the rheumatologist in spite of the great advances
made in the fields of medical diagnosis and technology. It can be the initial
symptom of a rheumatic disease, but it can also be the expression of a disease
flare, of an infectious complication, of a secondary neoplasm or be of iatrogenic
origin. The pathogenesis of fever in rheumatic diseases is still quite unclear;
however, recently IL-1, IL-6 and other endogenous pyrogens, such as Tumor
necrosis factor, have been shown to play a pivotal role in causing pyrexia during
inflammatory conditions. In the presence of longstanding fever of unknown origin,
it is mandatory to carry out a number of selected appropriate examinations with
the patient's informed consent. The aim of this study was to review the frequency
and the characteristics of fever at the onset and in the course of a number of
rheumatic diseases, such as chronic inflammatory arthropathies, connective tissue
diseases, reactive arthritis and dysmetabolic arthropathies. Finally, we have
reviewed the features of fever during arthritis complicating non-rheumatic
diseases and during adverse reactions related to drugs that are widely prescribed
for the treatment of rheumatic disorders.
PMID- 9549394
TI - [Quantification of left-to-right shunt in atrial septal defect using oximetry,
isotopes, and Doppler echocardiography. Is there a method of reference?].
AB - INTRODUCTION: Determination of pulmonary to systemic blood flow ratio (QP/QS) is
considered to be important for the management of patients with atrial septal
defect. The QP/QS provides information on shunt severity and is usually
determined by three methods: oximetry, first-pass radionuclide angiocardiography
and Doppler echocardiography. The aim of the present study was to assess the
accuracy and concordance level of these three methods in QP/QS quantification in
atrial septal defects. PATIENTS AND METHODS: Sixty-four adult atrial septal
defects patients in whom QP/QS was determined by these three methods with a 6
month interval were studied. Nuclear and echocardiographic post-surgical studies
were repeated in 36 patients. RESULTS: QP/QS values determined by the three
techniques had a low correlation between them: oximetry (r = 0.52; SEE = 0.74);
radionuclide angiocardiography (r = 0.40; SEE = 0.79) and Doppler
echocardiography (r = 0.72; SEE = 0.57). Radionuclide angiocardiography
underestimated QP/QS > 3 (-0.61 +/- 1.21; p < 0.01). Only in 33% of studies there
concordance (differences < 0.5) among the three methods and in 58% between two
methods. Right ventricular dilatation and tricuspid regurgitation influenced
radionuclide accuracy. Nevertheless, the correlation between this technique and
echocardiography was satisfactory when the 36 post-surgical were included (r =
0.75); both techniques agreed in the diagnosis of the two cases with residual
post-surgical shunt. CONCLUSIONS: Inter-method disparity in QP/QS quantification
is high and no method can be used as a gold standard; clinical decisions
therefore based on QP/QS quantification by one technique alone are ill-advised.
PMID- 9549395
TI - [Determination of ejection fraction and left ventricular fraction using isotopic
ventriculography and bidimensional echocardiography. Comparison with contrast
ventriculography].
AB - OBJECTIVES: The aim of this study was to determine the correlation and agreement
between the values of left ventricular ejection fraction and volumes assessed by
echocardiography and radionuclide ventriculography with the results obtained by
contrast angiography, as well as the variability of each method in these
measurements. PATIENTS AND METHODS: In a group of 59 patients with a first acute
myocardial infarction we have determined left ventricular ejection fraction and
volumes by two-dimensional echocardiography, equilibrium radionuclide
ventriculography and contrast angiography initially and six months after
myocardial infarction. We also assess the variability in the determinations in
these three methods. RESULTS: We found significant correlations in ejection
fraction and volumes by radionuclide ventriculography and echocardiography with
contrast angiography. The correlation was higher in ejection fraction and end
systolic volume by radionuclide ventriculography (r = 0.88 and r = 0.73) than by
echocardiography (r = 0.55 and r = 0.63; p < 0.01), whereas the correlation of
end-diastolic volume was moderate by both methods (r = 0.58 and r = 0.47),
without significant differences. The agreement between contrast angiography and
radionuclide ventriculography was higher, with narrower limits of agreement than
between contrast angiography and echocardiography in ejection fraction as well as
in ventricular volumes. We have found high and significant correlations between
two determinations by each method in all parameters, although they were higher in
ejection fraction by contrast angiography (r = 0.96) and radionuclide
ventriculography (r = 0.98) than by echocardiography (r = 0.70; p < 0.01). The
limits of agreement were always wider in echocardiography, narrower in contrast
angiography and the narrowest in radionuclide ventriculography, showing its
superior reproducibility. CONCLUSIONS: In this group of myocardial infarction
patients, the variability in the measurements was lower by radionuclide
ventriculography than by echocardiography, this could be the reason for overall
better results found in correlation and agreement between radionuclide
ventriculography and contrast angiography than between echocardiography and
contrast angiography in the assessment of left ventricular ejection fraction and
volumes.
PMID- 9549396
TI - [Impact of the correction of the attenuation in myocardial perfusion image with
SPECT].
AB - BACKGROUND: The aim of this study was to assess the effect of attenuation
correction on gender differences in normals and to evaluate its effect on the
size and severity of lateral wall perfusion defects in patients with circumflex
artery disease. MATERIAL AND METHODS: Tomographic myocardial perfusion imaging
with and without attenuation correction was performed on 32 patients with
circumflex artery stenosis and compared with patients with less than 5%
likelihood of coronary disease. Images were acquired with a triple headed scanner
and reconstructed using an iterative algorithm and re-sliced in the short axis
plane. Regional count densities were measured on selected short axis slices from
the base to the apex in both patients and normals. RESULTS: All attenuation
corrected images were found to be more uniform than the non attenuation corrected
images on the patients with less than 5% likelihood of coronary artery disease.
The coefficient of variation was 12.5% for non attenuation corrected images
versus 9.9% for attenuation corrected images (p < 0.0001). When female and male
segmental count distributions were compared, significant differences were found
which were resolved after attenuation correction. In patients with circumflex
artery stenosis, the anterolateral and lateral count densities were lower at all
levels with attenuation corrected images with an increasing difference from base
to apex. CONCLUSIONS: The use of attenuation correction results in a greater
uniformity in normals and an improved estimation of extent and severity of
perfusion defects in the territory of the circumflex artery.
PMID- 9549397
TI - [Study of myocardial viability using single-photon emission computed tomography
with 201-thallium and re-injection in 4 series (early and late images].
AB - OBJECTIVE: The present study was designed to determine whether 24-hour imaging
after thallium reinjection or imaging obtained shortly after reinjection provides
better results regarding reversibility of fixed perfusion defects observed in
conventional stress-redistribution imaging. PATIENTS AND METHODS: We studied 24
patients undergoing stress-redistribution thallium tomography with fixed defects
(15 exercise, 6 adenosine, 3 dobutamine). All patients had coronary angiography
and 17 a history of myocardial infarction. After obtaining the redistribution
images, 1 mCi thallium was injected at rest, and images were acquired at 30
minutes and 24 hours after reinjection. The tomograms obtained were divided into
12 segments and analyzed quantitatively. RESULTS: Of the 190 abnormal segments on
the stress images, 53 (28%) demonstrated improved thallium uptake on
redistribution images and 137 had persistent defects. Shortly after reinjection,
33 (24%) segments had improved thallium uptake and 104 had persistent defects, 29
(28%) of which showed further improvement in the 24-hour study. In patients with
myocardial infarction, of the 36 fixed severe defects, 9 (25%) had improved
thallium uptake shortly after reinjection, increasing activity from 36 +/- 10% to
53 +/- 8%, and 22 (61%) defects improved at 24 hours, increasing activity from 37
+/- 8% to 56 +/- 6%. Therefore, 13 irreversible segments in the short-term study
after reinjection were reversible on 24-hour images. CONCLUSION: These data
indicate that 24-hour imaging after thallium reinjection provides better results
regarding reversibility of fixed perfusion defects observed in conventional
stress-redistribution imaging than imaging obtained shortly after reinjection.
PMID- 9549398
TI - [Evaluation of myocardial viability using perfusion cardiac SPECT. 201-thallium
rest/redistribution, 201-thallium rest/reinjection and technetium 99m tetrofosmin
rest/postnitrates].
AB - INTRODUCTION AND OBJECTIVES: It has been demonstrated that nitrate administration
enhances the detection of myocardial viability in thallium-201 and technetium-99m
sestamibi myocardial perfusion studies. The aim of this study was to assess the
influence of nitrate administration on technetium-99m tetrofosmin myocardial
uptake in patients with coronary artery disease and left ventricular dysfunction.
PATIENTS AND METHODS: Twenty eight patients with coronary artery disease,
previous myocardial infarction and left ventricular ejection fraction < 40%
underwent, within 48 hours, rest/postnitroglycerin (0.4 mg sublingually)
technetium-99m tetrofosmin single photon emission tomography (SPET), comparing
these results with that of thallium-201 rest/redistribution SPET in 13 patients
(first group) and with that of thallium-201 rest/reinjection SPET in the other 15
patients (second group). Tomograms based on the 3 spatial planes were divided
into 15 segments and regional tracer uptake was quantitatively analysed.
Viability was defined as presence of tracer uptake > or = 50% of peak activity.
RESULTS: The percentage of peak activity at rest or after nitrate administration
of technetium-99m tetrofosmin correlated, with that of thallium-201, at rest and
after redistribution or reinjection (r = 0.8; p < 0.001). On resting technetium
99m tetrofosmin studies 167 of the 420 segments that were analysed had < 50% of
peak activity. 14.5% of these segments showed reversibility after nitrate
administration, with an increase in 99mTc-tetrofosmin uptake from 45 +/- 5% to 55
+/- 4% of peak activity (p = 0.001), in the first group, and from 40 +/- 9% to 57
+/- 9% of peak activity (p = 0.003), in the second group. Overall agreement
between rest/postnitroglycerin technetium-99m tetrofosmin SPET studies and
rest/redistribution or rest/reinjection thallium-201 SPET studies, regarding the
presence of myocardial viability, was 87% and 90%, respectively. All except one
reversible segments on tetrofosmin studies after nitrates had viability criteria
on thallium studies. CONCLUSIONS: Nitrate administration at rest enhances the
detection of myocardial viability using technetium-99m tetrofosmin SPET,
correlating with viability criteria observed on thallium studies. It represents a
simple and useful technique in the assessment of myocardial viability.
PMID- 9549399
TI - [Study of active myocardial damage in children with suspected myocarditis using
antimyosin monoclonal antibodies (AMMoAb-111In)].
AB - BACKGROUND: The study with monoclonal antimyosin antibody-111In has proved to be
useful in the detection of the myocardial damage present in different processes.
There is active myocardial damage and specific antimyosin uptake in myocarditis,
as both experimental and clinical trials have shown. In experimental models the
evolution of myocardial damage has been studied, where a parallelism between the
histological changes of the myocardial damage and the evolution on the antimyosin
uptake has been found. In clinical myocarditis it is difficult to do an
histological follow up of the inflammatory process, and therefore the evolution
of myocardial damage present in myocarditis is unknown. The antimyosin antibody
images allow a non-invasive study of this evolution. OBJECTIVES: a) to study with
monoclonal antimyosin antibody-111In, the myocardial damage present regarding the
disease evolution in children with suspected clinical diagnosis of myocarditis;
b) to evaluate the evolution of the active myocardial damage reflected on the
changes on the monoclonal antimyosin antibody-111In uptake. METHODS: A study with
monoclonal antimyosin antibody-111In was carried out on 43 children, 16 males and
27 females with a median age of 39 months (SD 48 m; range: 2-167) with suspected
diagnosis of acute myocarditis defined as the presence of congestive cardiac
failure or severe ventricular arrhythmia with less than 12 months of evolution.
The image evaluation was done visually and through the heart to lung ratio.
Twenty of these patients were also followed up with antimyosin antibody scan for
a period of 19 +/- 9 months, and 3.8 +/- 1.7 studies were performed on them in
this time. RESULTS: The prevalence of positive myocardial uptake was 83.72%.
There is a negative correlation (r = -0.352; p < 0.02) between the evolution time
of the process and the heart to lung ratio: patients studied before two months,
have a higher heart to lung ratio and greater prevalence of positive studies than
those studied later (heart to lung ratio 2.09 vs 1.74; p = 0.013; 90% vs 69.2%).
Of the patients followed up with antimyosin antibody scans, 6 showed a clinical
relapse which increased their heart to lung ratio. The other 14 showed an
progressive decrease of the heart to lung ratio reaching normality in 14 +/- 6
months. CONCLUSIONS: a) the uptake intensity of monoclonal antimyosin antibody
111In, as a reflection of the myocardial damage, depends on the disease evolution
time, as in the first two months is when the major damage happens; b) the uptake
intensity slowly decreases, tending to normality around the 14th month, although
this evolution may be altered by the appearance of relapses.
PMID- 9549400
TI - [Evaluation of cardiac sympathetic innervation with 123I-metaiodobenzylguanidine
in patients with diabetes mellitus].
AB - OBJECTIVES: To evaluate the usefulness of iodine-123 metaiodobencylguanidine
(123I-MIBG) in the study of the cardiac autonomic neuropathy in insulin-dependent
diabetic patients, by means of: a) analysis of heart to mediastinic ratio and
tomographic images with 123I-MIBG; b) comparison with conventional non-invasive
cardiac reflex test, and c) analysis of left ventricle ejection fraction.
POPULATION AND METHODS: Ten patients submitted for cardiac evaluation with 123I
MIBG were compared with a control group of 11 patients. In both groups we
excluded the presence of coronary pathology by means of an exercise test. We
carried out planar and SPECT studies, using 123I-MIBG, and the calculation of the
ejection fraction by equilibrium ventriculography. RESULTS: The uptake of 123I
MIBG in diabetic patients was significantly smaller than the control group in the
calculated index (heart to mediastinic ratio: 1.64 +/- 0.20 vs 2.00 +/- 0.26; p <
0.001; SPECT index: 44.87 +/- 8.37 vs 55.54 +/- 3.96; p < 0.001). In polar images
we noted a more reduced uptake in the diabetic group in the inferior wall (p =
0.020). Patients with cardiac sympa-thetic dysinnervation demonstrated less
uptake in both indexes (p < 0.05 and 0.005, respectively), essentially in the
inferior wall and in basal and medium territories (p < 0.05). No differences in
respect to the ejection fraction parameter were found. CONCLUSIONS: Despite the
small sample population, insuli-dependent diabetic patients in show a significant
reduction of the uptake of 23I-MIBG, more accentuated in the base. Scintigraphy
using 123I-MIBG can be an approach to investigate the pattern and the natural
history of the sympathetic innervation in these patients.
PMID- 9549401
TI - [Identification of the ischemic origin of dilated myocardiopathy using positron
emission tomography].
AB - INTRODUCTION AND OBJECTIVES: The aim of this study was to differentiate ischemic
from nonischemic dilated cardiomyopathy with positron emission tomography. This
differentiation is necessary to establish an adequate treatment, and it is often
difficult with non-invasive diagnostic procedures. METHODS: Ten patients with an
echocardiographic diagnosis of dilated cardiomyopathy who had undergone coronary
angiography were selected. The presence or absence of angiographic coronary
lesions was used to define the ischemic (n = 6) and the nonischemic group (n =
4). The ejection fraction was depressed in both groups, with no significant
differences found. A perfusion study with 13N-ammonium and a metabolic imaging
with 18F-florodeoxyglucose were performed on each patient. The images were
quantitatively and qualitatively analysed, defining three criteria: accumulation
defect (areas with activity under 50% of the maximal radioactivity), degree of
heterogeneity, and match of images with both tracers. To determinate the degree
of heterogeneity, nine segments on the three standard tomographic planes were
studied. Based on the following heterogeneity features: irregular borders,
coexisting different degrees of accumulation, and patched accumulation, a score
ranging from 0 to 3 points was assigned to these segments. To analyse the
radioactivity defects and the matching of studies with both tracers, the
accumulation defects or the accumulating surface were outlined on a
midventricular level coronal plane. RESULTS: The ischemic group has contrary to
the nonischemic one, wider perfusion (0.26 +/- 0.21 vs 0.00) and metabolism
defects (0.38 +/- 0.30 vs 0.06 +/- 0.09; p < 0.05). The degree of heterogeneity
is significantly higher in the nonischemic group, either in perfusion (14.5 +/-
8.38 vs 2.5 +/- 1.04; p < 0.05) or in metabolism studies (15.5 +/- 3.31 vs 2.33
+/- 1.50; p < 0.005). Assigning wide defects and homogeneous accumulation to
ischemic cardiomyopathy, and absence of defects and heterogeneous accumulation to
nonischemic cardiomyopathy, the aetiology of the disease was identified in 9 of
the 10 cases in the perfusion study and 100% of them with the metabolism imaging.
CONCLUSIONS: Positron emission tomography allows to identify the aetiology of
dilated cardiomyopathy, either with coronary perfusion or with myocardial glucose
metabolism studies. Thus, only one of both PET studies could be used. Ischemic
cardiomyopathy is characterised by wide defects and homogeneous radioactivity,
and the nonischemic one by the absence of defects and heterogeneous accumulation
of the tracer.
PMID- 9549402
TI - Prions--tri-dimensional carriers of biological information. A bridge between
biology and physics?
PMID- 9549403
TI - Role of a transcription factor (CREB) in memory processes.
AB - Memory storage includes a short-term phase (STM) which requires the
phosphorylation of pre-existing proteins, and a long-term phase (LTM) which needs
the novel synthesis of RNA and proteins. Cyclic AMP and a specific transcription
factor (cAMP response element binding protein or CREB) play a central role in the
formation of LTM in aplysia, drosophila and mice. Following its phosphorylation
by protein kinase A, CREB binds to the enhancer element CRE which is located in
the upstream region of cAMP-responsive genes, thus triggering transcription. Some
of the newly-synthesized proteins are additional transcription factors that
ultimately give rise to the activation of late response genes, whose products are
responsible for the modification of synaptic efficacy leading to LTM. In aplysia,
CREB activation has been interfered with by microinjection of CRE containing
oligonucleotides into cultured neurons. Under these conditions LTM is blocked
while STM remains unchanged. In drosophila, CREB function has been disrupted
using a reverse genetic approach. Thus, LTM has been specifically blocked by the
induced expression of a CREB repressor isoform, and enhanced by the induced
expression of an activator isoform. In mouse, the role of CREB has been confirmed
by behavioural analyses of a knock-out line with a targeted mutation in the CREB
gene. In these mutants, learning and STM are normal, whereas LTM is disrupted. On
the whole, the data suggest that encoding of long term memories involve highly
conserved molecular mechanisms.
PMID- 9549404
TI - A structuralist theory of evolution reconsidered.
AB - The structuralist theory of evolution is reconsidered in the light of new
discoveries. According to this theory, the evolutionary potentialities are in the
genotype (a hierarchically ordered set of interacting elements) and manifest
themselves in the course of morphogenesis in association with changes in the
environment. It is demonstrated that this theory is in fact the development of a
long philosophical tradition, in which Darwin and Neo-Darwinism did not
participate. New discoveries in the field of molecular cytogenetics confirm the
ideas of evolutionary potentiality and hierarchical genotypic ordering. It is
demonstrated that gene regulation can manifest itself in association with
instabilities of the morphogenetic field and the attainment of a new equilibrium;
this change could be connected with changes in the environment, but has nothing
to do with natural selection.
PMID- 9549405
TI - Asialoglycoprotein (ASGP) receptors induced by apoptosis. Their
immunohistochemical localization in neonatal rat hepatocytes.
AB - Immunohistochemical detection of asialoglycoprotein (ASGP) receptors has been
performed on neonatal rat hepatocytes in primary cultures, incubated with TGF
beta, TNF alpha and retinoic acid. These substances account for the increase in
the rate of apoptosis of the cell cultures and for the increase of the expression
of ASGP receptors. Both modifications are higher at 24 hours of incubation.
PMID- 9549406
TI - [Diversity of inwardly rectifying K+ channels; their regulations and functions].
PMID- 9549407
TI - [Chemistry and biology of peroxynitrite].
PMID- 9549408
TI - [Structure of heparin/heparan sulfate for regulation of activities of fibroblast
growth factor].
PMID- 9549409
TI - [RNA editing in transfer RNAs of metazoan mitochondria].
PMID- 9549410
TI - [Gene organization and genetic defect of bilirubin-glucuronosyl transferase].
PMID- 9549411
TI - [Biological functions of ceramide glucosylation].
PMID- 9549412
TI - [Function of LCR-binding protein Bach1 as an architectural transcription factor].
PMID- 9549413
TI - [Analysis of homologous DNA recombination in a chicken B lymphocyte line, DT40].
PMID- 9549414
TI - Causes of unintentional deaths from carbon monoxide poisonings in California.
AB - The purpose of this study was to determine the annual number and incidence of
unintentional deaths from carbon monoxide (CO) poisonings in California and to
identify specific factors that caused or contributed to the deaths. Unintentional
CO deaths in California over a ten-year period (1979 to 1988) were identified
from the database of the California Master Mortality File and coroners'
investigation reports. Factors associated with unintentional CO deaths were
determined based on the information from the investigation reports. The annual
number of unintentional CO deaths varied from 27 to 58 over the ten years
examined, with an average annual death incidence of 1.7 x 10(-6). Death rates
were high among males and African-Americans. Alcohol appeared to be a factor in
31% of the cases. The types of combustion sources associated with unintentional
CO deaths were: heating or cooking appliances; motor vehicles; charcoal grills
and hibachis; small engines; and camping equipment. Factors associated with
unintentional CO deaths interact in a complex way. To reduce the rate of
unintentional CO deaths effectively, joint efforts involving several prevention
methods are suggested.
PMID- 9549416
TI - Nitric oxide and septic shock. From bench to bedside.
AB - Refractory hypotension with end-organ hypoperfusion is an ominous feature of
inflammatory shock. In the past fifteen years, nitric oxide (a diffusible, short
lived product of arginine metabolism) has been found to be an important
regulatory molecule in several areas of metabolism, including vascular tone
control. Vascular endothelial cells constitutively produce low levels of nitric
oxide that regulate blood pressure by mediating adjacent smooth-muscle
relaxation. In an inflammatory shock state, cytokines, like interleukin-1 and
tumor necrosis factor-alpha, induce a separate, high-output form of the enzyme
that synthesizes nitric oxide in both endothelial and smooth-muscle cells. The
ensuing high rates of nitric oxide formation result in extensive smooth-muscle
relaxation, pressor refractory vasodilation, and--ultimately--shock. The concept
of the pathogenesis of inflammatory shock explains many limitations of current
therapies and may foster the development of new interventions to mitigate the
effects of nitric oxide overproduction in this syndrome.
PMID- 9549415
TI - Use of medical informatics to implement and develop clinical practice guidelines.
AB - Clinical practice guidelines have enormous potential to improve the quality of
and accountability in health care. Making the most of this potential should
become easier as guideline developers integrate guidelines within information
systems and electronic medical records. A major barrier to such integration is
the lack of computing infrastructure in many clinical settings. To successfully
implement guidelines in information systems, developers must create more specific
recommendations than those that have been required for traditional guidelines.
Using reusable software components to create guidelines can make the development
of protocols faster and less expensive. In addition, using decision models to
produce guidelines enables developers to structure guideline problems
systematically, to prioritize information acquisition, to develop site-specific
guidelines, and to evaluate the cost-effectiveness of the explicit incorporation
of patient preferences into guideline recommendations. Ongoing research provides
a foundation for the use of guideline development tools that can help developers
tailor guidelines appropriately to their practice settings. This article explores
how medical informatics can help clinicians find, use, and create practice
guidelines.
PMID- 9549417
TI - Noninvasive ventilatory support--saving a life without intubation.
PMID- 9549418
TI - Intravenous amiodarone for treating acute life threatening arrhythmias.
PMID- 9549419
TI - Emergency department management of falls in the elderly.
PMID- 9549420
TI - Fosphenytoin in the emergency department.
PMID- 9549421
TI - Adult sexual assault examination.
PMID- 9549422
TI - Treatment of deep venous thrombosis with low molecular weight heparins.
PMID- 9549423
TI - gamma-Hydroxybutyric acid poisoning.
PMID- 9549424
TI - Limited bedside ultrasound imaging by emergency medicine physicians.
PMID- 9549425
TI - The placenta and cultural values.
PMID- 9549426
TI - Zygomycotic gangrenous cellulitis in a patient with non-insulin dependent
diabetes mellitus.
PMID- 9549427
TI - Administration of a neuromuscular blocking agent and a narcotic agent mimicking
posterior urethral valves.
PMID- 9549428
TI - Immunizations for international travelers.
AB - Each year more than 45 million Americans travel abroad for work or pleasure, and
over 20 million of these travel to rural areas or developing countries. While the
major medical risks of international travel are often exaggerated, the incidence
of minor illness is not. Persons going to Asia, Africa, or Latin America for one
month run a 65% to 75% chance of becoming ill, although only 1% will require
hospitalization. The two most common illnesses that affect travelers, which do
have immunizations and are often overlooked by physicians, are influenza and
hepatitis A. The risk of illness to the traveler varies by health and age status,
by the region to be visited, by the time of year, and by the length of the
journey. Immunization advice for the traveler, therefore, is complicated and is
best approached in a systematic manner. This article outlines six steps to sound
immunization advice. These steps include ascertaining the traveler's special
individual needs, routine immunization status, and routine travel immunization
status, as well as the entry requirements for the country to be visited,
geographically indicated vaccines, and immunizations as indicated for extended
stays abroad.
PMID- 9549430
TI - Ethics and economics. Antagonists or allies in making health policy?
PMID- 9549431
TI - [The chemical structure of new substance as the metabolite of baicalin and time
profiles for the plasma concentration after oral administration of sho-saiko-to
in human].
AB - Baicalin (BG) is one of the major components of Sho-Saiko-To. We found a new
substance as the metabolite of BG in human plasma after oral administration of
Sho-Saiko-To. The metabolite was identified as baicalein 6-O-sulfate (BS) by
comparing its retention time in HPLC and electrospray ionization mass spectra
(ESI-MS)/MS methods with that of an authentic sample. Time profiles for the
plasma concentrations of BS and BG after oral administration of Sho-Saiko-To (EK
9) at a daily dose (6 g), were investigated in 14 healthy male volunteers. The
determination for the concentrations of BS and BG in human plasma was developed
by the HPLC method using electrochemical detector (ECD). Each 1 ml of the plasma
specimen was used for the solid phase extraction. The calibration curves of BS
and BG showed a good linearity between 5 and 300 ng/ml. The quantitative limits
of BS and BG in human plasma were 5 ng/ml. Using this method, BS was detected
after 1 h, reached a maximum level at 5 h and then decreased to the level less
than the quantitative limit after 36 h, and the plasma level of BS showed a
slight peak at 24 h. BG was detected after 1 h, reached a maximum level at 5 h
and then decreased to the level less than the quantitative limit after 36 h, and
the plasma level of BG showed two peaks at 12 h and 24 h.
PMID- 9549429
TI - The clinician's approach to the management of headache.
AB - Headache is a ubiquitous complaint, yet it is one that often elicits anxiety in
both patients and physicians. When a patient presents with headache, the
clinician must answer the following questions: (1) Is the headache "worrisome"
(secondary to underlying disease)? (2) If the headache is benign, what type is
it? (3) How is the acute headache best treated? and (4) How may future headaches
be prevented? The following review is intended to aid primary care physicians in
answering these questions.
PMID- 9549432
TI - [Synthesis and antiulcer activity of N-2-(2-hydroxy-2-phenyl)ethyl-N"
(methanesulfonyl)guanidine analogue of ranitidine. Development of a new antiulcer
agent T-593].
AB - A series of the aryl-substituted N'-2-(2-hydroxy-2-phenyl)ethyl derivatives of N"
methanesulfonyl-N-2-((5-dimethylaminomethyl or 5-methylaminomethyl)
furfurylthio)ethylguanidine have been synthesized as potential antisecretory and
mucosal protective antiulcer agents. The synthetic routes involves, at the last
stage, the reaction of 2-hydroxy-2-phenylethylamines with N-2-(furfurylthio)
ethyl-N'-methanesulfonyl-S-methylisothiourea or its O-phenylisourea counterpart.
The primary screening test to assess the inhibitory activity of the synthetic
compounds on histamine-induced gastric acid secretion was carried out in
anesthetized rats by the lumen-perfusion technique of Ghosh and Schild and also
by the pylorus-ligated preparation method. The best profile of histamine H2
antagonist activity was much better than that of the prototype ranitidine, and
obtained with N'-(2-(2-hydroxy-2-(4-hydroxyphenyl)) ethyl-N"-methanesulfonyl-N-2
(5-(methylaminomethyl)furfurylthio)et hylguanidine (12f), which was also
characterized by enhancing the gastric mucosal blood flow in rabbits as observed
by the thermoelectric method. This compound 12f, designated as T-593,
significantly inhibited the formation of the indomethacin-induced gastric lesions
in rats; 3.5-fold more potent than ranitidine, but 4-fold less active than
famotidine. On the other hand, T-593 and famotidine displayed comparable
activities in healing the acetic acid-induced gastric ulcer with and without the
dosing of indomethacin. Additional notable features of T-593, as determined in
rats, are that its protective effect on the hemorrhagic shock-induced lesion
under the prior dosing of histamine is ca. 10- and 2-fold greater than ranitidine
and famotidine, respectively, and that a decrease in the gastric mucosal blood
flow caused by a partial blood-withdrawal is more strongly recovered with T-593
than with famotidine. These experimental results suggest that the antiulcer
efficacy of T-593 can be explained by its dual activities: antisecretion of
gastric acid and, more importantly, protection of gastric mucous membrane.
PMID- 9549433
TI - The latest skinny on fat.
PMID- 9549434
TI - Treating cardiac arrests on airlines.
PMID- 9549435
TI - Can an old drug prevent restenosis after PTCA?
PMID- 9549436
TI - Guidelines for users of diet pills.
PMID- 9549437
TI - Hormone therapy versus statins for cholesterol reduction.
PMID- 9549438
TI - Calcium channel blockers and breast cancer.
PMID- 9549439
TI - My doctor says that I have both heartburn and angina. How can I tell the
difference?
PMID- 9549440
TI - I am diabetic and have a hard time controlling my blood sugar. I take two types
of diabetes pills, twice a day. I had a five-way bypass last spring and would
like to know what I should eat.
PMID- 9549441
TI - I'm 79 years-old and had a triple bypass about 10 years ago. I took to heart your
advice to lower my LDL cholesterol. With my doctor's support, I started daily
doses of lovastatin (Mevacor) and cholestyramine (Prevalite). After five weeks,
my LDL cholesterol was 87, and my total cholesterol was 164. So, how long should
I pursue such aggressive therapy?
PMID- 9549442
TI - Corticosteroids in rheumatoid arthritis.
PMID- 9549443
TI - Proteases as prognostic markers in cancer.
PMID- 9549444
TI - Interrupting the sympathetic outflow in causalgia and reflex sympathetic
dystrophy.
PMID- 9549445
TI - Refugee children.
PMID- 9549446
TI - Europe's health research: getting the right balance.
PMID- 9549447
TI - Putting the rest cure to rest--again.
PMID- 9549448
TI - AIDS drug scandal in South Africa continues.
PMID- 9549449
TI - The effects of postnatal health education for mothers on infant care and family
planning practices in Nepal: a randomised controlled trial.
AB - OBJECTIVES: To evaluate impact of postnatal health education for mothers on
infant care and postnatal family planning practices in Nepal. DESIGN: Randomised
controlled trial with community follow up at 3 and 6 months post partum by
interview. Initial household survey of study areas to identify all pregnant women
to facilitate follow up. SETTING: Main maternity hospital in Kathmandu, Nepal.
Follow up in urban Kathmandu and a periurban area southwest of the city.
SUBJECTS: 540 mothers randomly allocated to one of four groups: health education
immediately after birth and three months later (group A), at birth only (group
B), at three months only (group C), or none (group D). INTERVENTIONS: Structured
baseline household questionnaire; 20 minute, one to one health education at birth
and three months later. MAIN OUTCOME MEASURES: Duration of exclusive breast
feeding, appropriate immunisation of infant, knowledge of oral rehydration
solution and need to continue breast feeding in diarrhoea, knowledge of infant
signs suggesting pneumonia, uptake of postnatal family planning. RESULTS: Mothers
in groups A and B (received health education at birth) were slightly more likely
to use contraception at six months after birth compared with mothers in groups C
and D (no health education at birth) (odds ratio 1.62, 95% confidence interval
1.06 to 2.5). There were no other significant differences between groups with
regards to infant feeding, infant care, or immunisation. CONCLUSIONS: Our
findings suggest that the recommended practice of individual health education for
postnatal mothers in poor communities has no impact on infant feeding, care, or
immunisation, although uptake of family planning may be slightly enhanced.
PMID- 9549450
TI - Meta-analysis of short-term low dose prednisolone versus placebo and non
steroidal anti-inflammatory drugs in rheumatoid arthritis.
AB - OBJECTIVE: To determine whether short-term, oral low dose prednisolone (< or = 15
mg daily) is superior to placebo and non-steroidal anti-inflammatory drugs in
patients with rheumatoid arthritis. DESIGN: Meta-analysis of randomised trials of
oral corticosteroids compared with placebo or a non-steroidal anti-inflammatory
drug. SETTING: Trials conducted anywhere in the world. SUBJECTS: Patients with
rheumatoid arthritis. MAIN OUTCOME MEASURES: Joint tenderness, pain, and grip
strength. Outcomes measured on different scales were combined by using the
standardised effect size (difference in effect divided by SD of the
measurements). RESULTS: Ten studies were included in the meta-analysis.
Prednisolone had a marked effect over placebo on joint tenderness (standardised
effect size 1.31; 95% confidence interval 0.78 to 1.83), pain (1.75; 0.87 to
2.64), and grip strength (0.41; 0.13 to 0.69). Measured in the original units the
differences were 12 (6 to 18) tender joints and 22 mm Hg (5 mm Hg to 40 mm Hg)
for grip strength. Prednisolone also had a greater effect than non-steroidal anti
inflammatory drugs on joint tenderness (0.63; 0.11 to 1.16) and pain (1.25; 0.26
to 2.24), whereas the difference in grip strength was not significant (0.31;
0.02 to 0.64). Measured in the original units the differences were 9 (5 to 12)
tender joints and 12 mm Hg (-6 mm Hg to 31 mm Hg). The risk of adverse effects
during moderate and long term use seemed acceptable. CONCLUSION: Prednisolone in
low doses (< or = 15 mg daily) may be used intermittently in patients with
rheumatoid arthritis, particularly if the disease cannot be controlled by other
means.
PMID- 9549451
TI - Effects of the Heartbeat Wales programme over five years on behavioural risks for
cardiovascular disease: quasi-experimental comparison of results from Wales and a
matched reference area.
AB - OBJECTIVE: To assess the net 5 year effects of intervention of a community based
demonstration project, the Heartbeat Wales programme, on modifiable behavioural
risks for prevention of cardiovascular disease. DESIGN AND SETTING: Quasi
experimental design comparing results from two independent cross sectional
population surveys conducted in 1985 and 1990 in Wales and a matched reference
area in north east England. SUBJECTS: Random, stratified samples of people aged
18-64 years (18,538 in 1985 and 13,045 in 1990) in Wales and in north east
England (1483 and 4534, respectively). INTERVENTION: A coordinated range of
activities for heart health promotion in Wales entailing public education
campaigns along with supportive policy and infrastructure change. In the
reference area no additional community heart health promotion was planned, though
considerable activity did take place, "contaminating" the reference area. MAIN
OUTCOME MEASURES: Fifteen self reported behavioural indicators relating to
dietary choice, smoking, frequency of exercise, and weight. RESULTS: Positive
changes (for health) in behavioural outcomes were observed among the population
in Wales, including a reduction in reported smoking prevalence and improvements
in dietary choice. There was no net intervention effect for the programme over
and above observed change in the reference area. CONCLUSIONS: No definite
conclusions can be drawn concerning the efficacy of the programme in terms of
behavioural outcomes. With hindsight, the difficulties of evaluating such a
complex multifaceted intervention were underestimated. Further debate on the most
appropriate methods for assessing the effectiveness of community based health
promotion programmes is called for.
PMID- 9549452
TI - Risk factors for coronary artery disease in non-insulin dependent diabetes
mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23)
AB - OBJECTIVE: To evaluate baseline risk factors for coronary artery disease in
patients with type 2 diabetes mellitus. DESIGN: A stepwise selection procedure,
adjusting for age and sex, was used in 2693 subjects with complete data to
determine which risk factors for coronary artery disease should be included in a
Cox proportional hazards model. SUBJECTS: 3055 white patients (mean age 52) with
recently diagnosed type 2 diabetes mellitus and without evidence of disease
related to atheroma. Median duration of follow up was 7.9 years. 335 patients
developed coronary artery disease within 10 years. OUTCOME MEASURES: Angina with
confirmatory abnormal electrocardiogram; non-fatal and fatal myocardial
infarction. RESULTS: Coronary artery disease was significantly associated with
increased concentrations of low density lipoprotein cholesterol, decreased
concentrations of high density lipoprotein cholesterol, and increased
triglyceride concentration, haemoglobin A1c, systolic blood pressure, fasting
plasma glucose concentration, and a history of smoking. The estimated hazard
ratios for the upper third relative to the lower third were 2.26 (95% confidence
interval 1.70 to 3.00) for low density lipoprotein cholesterol, 0.55 (0.41 to
0.73) for high density lipoprotein cholesterol, 1.52 (1.15 to 2.01) for
haemoglobin A1c, and 1.82 (1.34 to 2.47) for systolic blood pressure. The
estimated hazard ratio for smokers was 1.41 (1.06 to 1.88). CONCLUSION: A quintet
of potentially modifiable risk factors for coronary artery disease exists in
patients with type 2 diabetes mellitus. These risk factors are increased
concentrations of low density lipoprotein cholesterol, decreased concentrations
of high density lipoprotein cholesterol, raised blood pressure, hyperglycaemia,
and smoking.
PMID- 9549453
TI - Association between plasma concentrations of plasminogen activator inhibitor-1
and survival in patients with colorectal cancer.
PMID- 9549454
TI - Management of deliberate self poisoning in adults in four teaching hospitals:
descriptive study.
PMID- 9549455
TI - Survival rates from interval cancer in NHS breast screening programme.
PMID- 9549458
TI - ABC of allergies. Summer hay fever.
PMID- 9549457
TI - Secondary prevention in acute myocardial infarction.
PMID- 9549456
TI - Contribution of parental blood pressures to association between low birth weight
and adult high blood pressure: cross sectional study.
AB - OBJECTIVE: To examine the possibility that low birth weight is a feature of the
inherited predisposition to high blood pressure. DESIGN: Cross sectional study.
SETTING: Primary care medical centre in Edinburgh. SUBJECTS: One offspring of 452
families (231 men and 221 women aged 16-26 years) in whom blood pressure, weight,
and height were measured in 1986 and whose parents had blood pressure measured in
1979. Birth weights were obtained from case records (270 offspring) or by
questionnaires sent to the mothers (182 offspring). MAIN OUTCOME MEASURES: Birth
weight and adult systolic blood pressure in offspring in relation to parental
blood pressure. RESULTS: If parental blood pressures were not considered, a 1 kg
decrease in birth weight was associated with a 2.24 mm Hg increase in systolic
blood pressure of offspring (P = 0.06) after correction for current weight and
sex. However, parental blood pressures correlated positively with blood pressure
of offspring, and higher maternal blood pressure was associated with lower birth
weight (-3.03 g/mm Hg, P < 0.01). After correction for parental blood pressures,
a 1 kg decrease in birth weight was associated with only a 1.71 mm Hg increase in
the systolic blood pressure of the offspring (P = 0.15). CONCLUSIONS: Low birth
weight is a feature of the inherited predisposition to hypertension, perhaps
because it is associated with higher maternal blood pressure during pregnancy.
Parental blood pressure may be an important confounding factor in the relation
between low birth weight and subsequent hypertension.
PMID- 9549459
TI - Risk of diabetic nephropathy in potential living related kidney donors.
PMID- 9549460
TI - Management of metastatic melanoma during pregnancy.
PMID- 9549461
TI - Commentary: pregnancy should not have affected treatment for melanoma.
PMID- 9549462
TI - Commentary: self interest is not the sole legitimate basis for making decisions.
PMID- 9549463
TI - Genetic testing and public policy.
PMID- 9549464
TI - Bereavement in adult life.
PMID- 9549465
TI - Effectiveness and cost effectiveness of compression bandages should be shown.
PMID- 9549466
TI - Claim for major advance in treatment of perforated peptic ulcer seems premature.
PMID- 9549467
TI - Debate over screening for gestational diabetes. Screening should take place only
in context of good quality controlled trials.
PMID- 9549468
TI - Debate over screening for gestational diabetes. Scientific uncertainty is
mirrored in clinical practice in Italy.
PMID- 9549469
TI - Debate over screening for gestational diabetes. Evidence from randomised
controlled trial is needed.
PMID- 9549470
TI - Health status instruments should satisfy full range of methodological criteria.
PMID- 9549471
TI - Effect on mortality of switching from cigarettes to pipes or cigars. Study
underestimated difference in risk.
PMID- 9549472
TI - Effect on mortality of switching from cigarettes to pipes or cigars. Patterns of
inhalation are important.
PMID- 9549473
TI - Effect on mortality of switching from cigarettes to pipes or cigars. "Switchers"
will have had higher cumulative exposure to tobacco.
PMID- 9549474
TI - Effect on mortality of switching from cigarettes to pipes or cigars. American
study supported conclusions.
PMID- 9549475
TI - Fact that no SHO post was given five years approval is worrying.
PMID- 9549476
TI - BUPA and the tobacco industry. Chairperson of BUPA in Republic of Ireland is also
chairperson of tobacco producer.
PMID- 9549477
TI - Community based programmes can help to manage tuberculosis more effectively.
PMID- 9549478
TI - Cognitive dysfunction after concussion. Authors did not to comment on the single
truly significant result.
PMID- 9549479
TI - Determining prognosis after acute myocardial infarction in the thrombolytic era.
Rescue angioplasty after failed thrombolysis may put patients at risk.
PMID- 9549480
TI - Number of unexplained symptoms and diseases is decreasing.
PMID- 9549481
TI - The caring doctor is an oxymoron. General practice will develop best if "caring"
is replaced by professionalism.
PMID- 9549482
TI - The caring doctor is an oxymoron. Frequent callers to cooperatives provoke same
feelings there.
PMID- 9549483
TI - The caring doctor is an oxymoron. Out of hours emergencies and continuing
problems need different approaches.
PMID- 9549484
TI - The caring doctor is an oxymoron. GPs could refer patients to clinical
hypnotherapists.
PMID- 9549485
TI - The role of magnetic resonance techniques in understanding and managing multiple
sclerosis.
AB - Magnetic resonance (MR) techniques have had a major impact in the last 10-15
years in understanding and managing multiple sclerosis. This review summarizes
the current uses of MR in multiple sclerosis, based on the proceedings of a
recent international workshop, under four headings: (i) technical issues; (ii)
role in diagnosis; (iii) natural history studies in understanding the disease;
(iv) application in clinical trials. The theory and methodology of relevant
technical issues is outlined, in order to provide a framework with which to
understand the potential and limitations of MR in addressing biological and
clinical questions in multiple sclerosis. The principles underlying signal-to
noise and contrast-to-noise ratio are discussed, along with the techniques and
clinical results for conventional and fast spin echo T2-weighted imaging, fluid
attenuated inversion recovery, detection of blood-brain barrier break down and
hypointense lesions on T1-weighted images, magnetization transfer, T2 decay-curve
analysis, MR spectroscopy, spinal cord imaging, diffusion imaging, and
quantification of lesion load and atrophy. MRI has an extremely valuable role in
confirming the clinical diagnosis of multiple sclerosis. T2-weighted brain
imaging remains the standard diagnostic tool, but in some instances it is
usefully complemented with gadolinium enhancement and spinal imaging. The caveat
that the diagnosis of multiple sclerosis remains primarily a clinical one cannot
be over-emphasized. Serial MRI studies have added much to our understanding of
the natural history and pathophysiology of the disease. Blood-brain barrier
breakdown is a consistent early feature of new lesion development in relapsing
remitting and secondary progressive multiple, sclerosis, and this usually
correlates with active inflammation and myelin breakdown. A number of the acute
MR changes are reversible, but chronic persistent abnormalities in a number of MR
parameters, such as reduced N-acetyl aspartate, low magnetization transfer
ratios, atrophy and T1-hypointensity, suggest the presence of demyelination
and/or axonal degeneration in many chronic lesions. The presence and extent of T2
weighted MRI abnormalities at first presentation with a clinically isolated
syndrome suggestive of demyelination strongly predicts the risk of developing
clinically definite multiple sclerosis in the next few years. In established
multiple sclerosis, however, the correlations between T2 abnormalities and
disability are modest. This poor relationship partly relates to the discrepancy
between lesion site and function in attempting to correlate locomotor disability
with brain MRI findings. However, the correlations between brain lesion load and
cognitive dysfunction in multiple sclerosis, whilst more evident, are still
modest. A more important limitation is the low pathological specificity of
abnormalities seen on T2-weighted images. Stronger correlations have been found
between disability and new putative MR markers for demyelination and/or axonal
degeneration. Serial studies using multiple MR techniques are now needed to
further clarify pathophysiological mechanisms in multiple sclerosis. Serial MR
has become an important tool in monitoring treatment efficacy. It provides data
which can be readily analysed in a blinded fashion and which directly inspects
the pathological evolution; it also enables a rapid and sensitive measure of
treatment outcome in early relapsing-remitting and secondary progressive disease.
Because of the modest clinical correlations it is, however, still appropriate
that the definitive determinant of treatment efficacy remains a clinical one.
Further work is needed to address issues of quality control in serial studies,
statistical calculation of appropriate sample sizes, and optimization of the
nature and frequency of MR outcomes measured.
PMID- 9549486
TI - The Riddoch syndrome: insights into the neurobiology of conscious vision.
AB - We have studied a patient, G.Y., who was rendered hemianopic following a lesion
affecting the primary visual cortex (area VI), sustained 31 years ago, with the
hope of characterizing his ability to discriminate visual stimuli presented in
his blind field, both psychophysically and in terms of the brain activity
revealed by imaging methods. Our results show that (i) there is a correlation
between G.Y.'s capacity to discriminate stimuli presented in his blind field and
his conscious awareness of the same stimuli and (ii) that G.Y.'s performance on
some tasks is characterized by a marked variability, both in terms of his
awareness for a given level of discrimination and in his discrimination for a
given level of awareness. The observations on G.Y., and a comparison of his
capacities with those of normal subjects, leads us to propose a simple model of
the relationship between visual discrimination and awareness. This supposes that
the two independent capacities are very tightly coupled in normal subjects
(gnosopsia) and that the effect of a VI lesion is to uncouple them, but only
slightly. This uncoupling leads to two symmetrical departures, on the one hand to
gnosanopsia (awareness without discrimination) and on the other to agnosopsia
(discrimination without awareness). Our functional MRI studies show that V5 is
always active when moving stimuli, whether slow or fast, are presented to his
blind field and that the activity in V5 co-varies with less intense activity in
other cortical areas. The difference in cerebral activity between gnosopsia and
agnosopsia is that, in the latter, the activity in V5 is less intense and lower
statistical thresholds are required to demonstrate it. Direct comparison of the
brain activity during individual 'aware' and 'unaware' trials, corrected for the
confounding effects of motion, has also allowed us, for the first time, to
titrate conscious awareness against brain activity and show that there is a
straightforward relationship between awareness and activity, both in individual
cortical areas, in this case area V5, and in the reticular activating system. The
imaging evidence, together with the variability in his levels of awareness and
discrimination, manifested in his capacity to discriminate consciously on some
occasions and unconsciously on others, leads us to conclude that agnosopsia,
gnosopsia and gnosanopsia are all manifestations of a single condition which we
call the Riddoch syndrome, in deference to the British neurologist who, in 1917,
first characterized the major aspect of this disability. We discuss the
significance of these results in relation to historical views about the
organization of the visual brain.
PMID- 9549487
TI - A neuromodulatory role for the human amygdala in processing emotional facial
expressions.
AB - Localized amygdalar lesions in humans produce deficits in the recognition of
fearful facial expressions. We used functional neuroimaging to test two
hypotheses: (i) that the amygdala and some of its functionally connected
structures mediate specific neural responses to fearful expressions; (ii) that
the early visual processing of emotional faces can be influenced by amygdalar
activity. Normal subjects were scanned using PET while they performed a gender
discrimination task involving static grey-scale images of faces expressing
varying degrees of fear or happiness. In support of the first hypothesis,
enhanced activity in the left amygdala, left pulvinar, left anterior insula and
bilateral anterior cingulate gyri was observed during the processing of fearful
faces. Evidence consistent with the second hypothesis was obtained by a
demonstration that amygdalar responses predict expression-specific neural
activity in extrastriate cortex.
PMID- 9549488
TI - A study of medial pallidotomy for Parkinson's disease: clinical outcome, MRI
location and complications.
AB - We have studied the effects of unilateral ventral medial pallidotomy in 26
patients with medically intractable Parkinson's disease with marked drug-induced
dyskinesias. Preoperatively, all patients were assessed during one 5-day
admission according to the Core Assessment Programme for Intracerebral
Transplantation (CAPIT) protocol, including rating in the 'practically defined
off' and 'best on' states before and during a single-dose levodopa challenge.
Motor performance was assessed with subset categories of the Unified Parkinson's
Disease Rating Scale (UPDRS), timed motor tests and a standard dyskinesia rating
scale. Pallidotomy was performed under stereotaxic CT guidance with intra
operative extracellular microelectrode recording made from the basal ganglia. All
patients were re-assessed 3 months postoperatively and a subgroup (n = 9) have so
far also been re-assessed after 1 year. Pre- and postoperative performance scores
were compared in order to determine which categories of performance improved
postoperatively. Significance was accepted at P < 0.005 in order to take into
account the multiple number of comparisons performed. Patient medication was
compared pre- and postoperatively and the morbidity associated with surgery was
also recorded. The most significant improvement postoperatively was the
diminution of 'on' dyskinesias contralaterally (67%, P = 0.0001); however,
ipsilateral (45%, P = 0.0006) and axial (50%, P = 0.0008) dyskinesias also
improved. Contralateral to pallidotomy, the median 'off' motor UPDRS score
improved by 27% (P = 0.001) and a significant improvement was also observed in
contralateral rigidity by 25% (P = 0.001). There were trends towards improvement
in contralateral tremor (33%, P = 0.016) and bradykinesia (24%, P = 0.013)
scores. Ipsilateral rigidity improved by 22% (P = 0.005), but other ipsilateral
motor scores did not alter significantly. The 'off' gait/postural instability
score and 'off' walking time showed marginally significant improvements by 7% (P
= 0.007) and 29% (P = 0.014), respectively. On medication, no significant
postoperative improvements in parkinsonism were detected. Anti-parkinsonian
medication increased by 11% postoperatively. In the subgroup who were available
for assessment 1 year postoperatively, responses were generally maintained. Two
(7.7%) of the 26 patients had fatal complications (one cerebral haemorrhage and
one haemorrhagic infarct) directly related to surgery. Among the remaining 24
patients, four (15.4% of the total 26) had major complications (two persisting
and two transient). Ten patients (38.5%) had minor complications. The majority of
the complications (major and minor) occurred in the earlier operated patients and
the complication rate subsequently declined with increasing operative experience.
The remaining 10 patients (38.5%) had no significant side-effects. One of these
10 patients died from an incidental malignant glioma 6 months postoperatively.
These findings confirm that levodopa-induced dyskinesias are dramatically reduced
following ventral medial pallidotomy and constitute the principal indication for
pallidotomy. Improvements in underlying parkinsonism were of smaller magnitude.
Pallidotomy may also offer some patients an opportunity to increase
antiparkinsonian medication. Patient selection for medial pallidotomy should,
therefore, be based largely on anticipated improvements in levodopa-induced
dyskinesias, but this must be balanced against the associated morbidity and
mortality.
PMID- 9549489
TI - Dynamic aphasia: an inability to select between competing verbal responses?
AB - In this study we report a patient (A.N.G.) who, following a malignant left
frontal meningioma impinging upon Brodmann area 45, presented a 'pure' dynamic
aphasia. Her spontaneous speech was markedly reduced in the absence of any
syntactical impairment. Her naming, repetition and reading skills were completely
normal. Two experimental investigations were carried out. The first investigation
found that A.N.G. had a profound impairment in phrase and sentence generation
tasks given a verbal context. However, her verbal generative skills were normal
when she was asked to describe pictorial scenes and complex actions. Moreover, it
was found that A.N.G. had no difficulty ordering the constituent words of a
sentence. Thus, it was concluded that her verbal planning skills were intact. The
second investigation tested a hypothesis that dynamic aphasia is due to an
inability to select a verbal response option whenever the stimulus activates many
competing verbal responses. Predictions based upon this hypothesis were confirmed
on three different verbal generation tasks. It was found that our patient's grave
verbal generative impairment was present for tasks involving stimuli which
activate many potential responses. However, it was absent for tasks involving
stimuli which activate few or only a single 'prepotent' response. The findings
are discussed with reference to traditional interpretations of dynamic aphasia
and more general interpretations of prefrontal cortex functioning. On the basis
of a computational model of prefrontal cortex functioning, we propose that pure
dynamic aphasia may be caused by damage to a 'context' module containing units
responsible for selection of verbal response options. Moreover, it is suggested
that our findings support the view that Brodmann area 45 is involved in verbal
response generation to stimuli which activate many potential response options.
PMID- 9549490
TI - What is straight ahead to a patient with torticollis?
AB - Vestibular and neck proprioceptive signals are known to be used in judging the
locations of objects in space and relative to the body. Given that these signals
are asymmetric in patients with spasmodic torticollis, one would expect such
patients to have abnormal spatial perception. We tested this idea by measuring
patients' perception of visual straight ahead (VSA) under various conditions:
with the body in its primary position, i.e. with the head and trunk as closely
aligned as possible, and after well defined passive rotations of the head and/or
trunk. In the primary body position, patients' VSA direction showed considerable
variations which were similar, however, to those of normal subjects; it was
independent of torticollis direction, of the head torque it produced, and of the
weak spontaneous nystagmus recorded in seven of the 10 patients. After whole-body
rotations, i.e. where head and trunk underwent the same motion, the VSA was
shifted in both patients and normal subjects, and in both groups the shift was
symmetrical after rotations to the right or left. After motions where the trunk
rotated under the stationary head (neck proprioceptive stimulation) or the head
on the stationary trunk (combined vestibular and neck stimulus), the VSAs of
normal subjects coincided rather well with their head midsagittal planes, whereas
the VSAs of patients were shifted considerably towards the trunk, again in a
symmetrical way. We suggest two mechanisms to explain the findings in patients:
(i) a central compensation which restores symmetry of the afferent inflow in the
patients (unlike the motor efference); (ii) shifting of the reference for the VSA
from the head towards the trunk, because the trunk is a more reliable egocentric
reference than the head in the patients. Our findings do not support the
assumption that asymmetries in afferent inflow are responsible for the asymmetry
of motor output in spasmodic torticollis.
PMID- 9549491
TI - Imaging axonal damage of normal-appearing white matter in multiple sclerosis.
AB - The current study was designed to determine the relative distribution of
decreases of N-acetylasparate (NAA), a marker of axonal damage, between lesions
and normal-appearing white matter of patients with established multiple sclerosis
and to test for associations between changes in the ratio of NAA to
creatine/phosphocreatine (NAA:Cr) in those compartments and changes in
disability. Data were collected from a 30-month longitudinal study of 28 patients
with either a relapsing course with partial remissons and no progression between
attacks (relapsing/remitting) (11 patients) or a course of progressively
increasing disability, following a period of relapsing/remitting disease
(secondary progressive) (17 patients). Proton magnetic resonance spectroscopic
imaging (MRSI) and conventional MRI examinations were performed at 6-8-month
intervals with concurrent clinical assessments of disability. General linear
models were used to test associations between MRSI, MRI, lesion volume and
clinical data. Analysis confirmed that the NAA:Cr ratio is lower in lesions than
in the normal-appearing white matter (-15.3% in relapsing/remitting multiple
sclerosis and -8.8% in secondary progressive multiple sclerosis). The lower
NAA:Cr ratio per unit lesion volume previously observed for secondary progressive
relative to relapsing/remitting patients was found to result from a lower ratio
(8.2%, P < 0.01) in the normal-appearing white matter rather than from any
differences within lesions. The importance of changes in the normal-appearing
white matter was emphasized further with the observation that the NAA:Cr ratio in
the normal-appearing white matter accounted for most of the observed 15.6% (P <
0.001) decrease in the NAA:Cr ratio in the brains of relapsing/remitting patients
over the period of study. The decrease in the NAA:Cr ratio in normal-appearing
white matter correlated strongly (P < 0.001) with changes in disability in the
relapsing/remitting subgroup. These results add to data suggesting that axonal
damage or loss may be responsible for functional impairments in multiple
sclerosis. The accumulation of secondary axonal damage in the normal-appearing
white matter may be of particular significance for understanding chronic
disability in this disease.
PMID- 9549492
TI - A case of primary progressive aphasia. A 14-year follow-up study with
neuropathological findings.
AB - Primary progressive aphasia has been clinically defined as a progressive language
deficit leading to the dissolution of almost all language functions with relative
preservation of other cognitive functions until late in the course of the
disease. Two types of language impairment have been described for primary
progressive aphasia, which differ with respect to the degree of fluency of
spontaneous speech. Whereas some authors have emphasized non-fluency as a
defining characteristic of primary progressive aphasia, others have proposed that
phonemic rather than semantic paraphasias in naming, both in the fluent and the
non-fluent subtype, should be used as a criterion to distinguish primary
progressive aphasia from slowly progressive aphasia in other forms of
degenerative brain disease. Patients with fluent speech and semantic dementia, as
typically seen in Alzheimer's disease, produce semantic paraphasias and
circumlocutions rather than phonemic errors in naming. This paper reports the
long-term follow-up of a patient with fluent aphasic speech, whose language
profile over a decade was similar to that of patients with semantic dementia.
Neuropathological examination revealed no evidence of Alzheimer's disease. Pick's
disease or Pick variant, but showed spongiform changes of cortical layers (II and
III) in temporal and, less severely, in frontal gyri. The present case indicates
that semantic dementia is not a reliable indicator of probable Alzheimer's
disease and supports the notion that there are different subtypes of primary
progressive aphasia which cannot be defined by fluency or by the presence of
phonemic paraphasia. Progress in identifying the neuropathological correlates of
these subtypes in cases with lobar atrophy and spongiform changes should be
expected from hereditary variants of progressive disorder.
PMID- 9549493
TI - Endozepine stupor. Recurring stupor linked to endozepine-4 accumulation.
AB - Recurring stupor can be caused by repeated metabolic, toxic or structural brain
disturbances. Recently, cases of recurring stupor, with fast EEG activity were
shown to display increased endogenous benzodiazepine-like activity during the
episodes of stupor. Patients with recurring stupor underwent extensive metabolic
and toxicologic screening, EEG and brain imaging. Endozepines and exogenously
administered benzodiazepines were assayed in plasma and CSF by means of mass
spectrometry. Flumazenil, a benzodiazepine antagonist was administered and the
behavioural and EEG responses monitored. Treatment with oral flumazenil was
attempted in selected cases. Twenty patients were found with recurring stupor.
Episodes had begun between ages 18 and 67 years, and in nine patients, had
disappeared spontaneously after 4-6 years with symptoms. Stupor lasted hours or
days. Onset of the episodes and frequency were unpredictable. Patients were
normal between attacks. Stupor was characterized by initial drowsiness,
staggering and behavioural changes, followed by deep sleep and spontaneous
recovery with post-ictal amnesia. Biochemical screening and brain imaging were
always normal. Ictal EEG showed fast background activity, and flumazenil
transiently awoke the patients and normalized the EEG. In the nine cases
examined, endozepine-4 levels were increased during the stupor. Oral flumazenil
reduced the frequency of the attacks in three of these nine patients. Recurring
episodes of stupor may be due to increased endozepine-4. We propose the term
'endozepine stupor' for such episodes. Endozepine-4 is an endogenous ligand for
the benzodiazepine recognition site at the GABAA receptor, with unknown molecular
structure.
PMID- 9549494
TI - Cognitive process in preclinical phase of dementia.
AB - Several recent prospective studies have demonstrated the existence of a
preclinical stage of dementia, identifiable by neuropsychological assessment
showing impairments with a great variety of cognitive tests. However, test scores
are often colinear, largely because common cognitive components are involved in
different tests; in spite of an apparent heterogeneity, it is still possible that
a common cognitive component may be responsible for the deterioration shown in
different tests in the preclinical phase. We studied the cognitive performances
of 1159 elderly residents in the PAQUID (Personnes Agees quid) cohort, at a fixed
lag time of 2 years before the clinical diagnosis of dementia. Seven
neuropsychological tests were administered (Mini-Mental Status Examination,
Benton Visual Retention Test, Wechsler Paired-Associates Test, Isaacs Set Test,
Zazzo's Cancellation Task, Digit Symbol Substitution Test and Wechsler
Similarities Test). Among the initially non-demented 1159 subjects, 25 developed
a dementia 2 years later, of whom 16 were classified as cases of Alzheimer's
disease. In order to dissect the multicolinearity of the tests we used a
multivariate approach with principal component analysis (PCA). The patients'
loading on each of the first four PCA factors were subsequently correlated with
the risk of dementia and Alzheimer's disease 2 years later. The logistic
regression with backward stepwise selected only the first factor as an
independent predictor of dementia or Alzheimer's disease. Analysis shows that
there are good reasons to suspect that the first PCA factor represents a general
factor corresponding to aspects of control in the tasks used. Our results
therefore seem to show that preclinical deficits in dementia and Alzheimer's
disease reflect the deterioration of a general cognitive factor, which may be
interpreted as the disturbance of central, control processes.
PMID- 9549495
TI - Human cerebral activity evoked by motion reversal and motion onset. A PET study.
AB - In this PET study, we have investigated the human brain activity evoked by a
visual motion paradigm commonly used to measure motion-related visual evoked
potentials (VEPs). Because standard PET activation studies have been performed
with motion along four axes, we first determined the pattern of brain activation
when motion was restricted to a single axis. Motion back and forward along a
single horizontal axis compared with a static condition revealed weak
differential activations in the cuneus and the parietal cortex. Human area MT/V5
(middle temporal area) was hardly activated at all in this subtraction.
Additional functional MRI experiments proved that MT/V5 activity is significantly
higher for motion along four axes than for motion along a single axis. Secondly,
we attempted to isolate the pattern of brain activity related to the reversal of
motion direction and to the onset of motion, i.e. two transient motion components
commonly used in measuring motion-related VEPs. To that end, we added a
continuous linear contrast modulation, that reached maximum contrast at reversal
or onset of motion, and compared both conditions with a contrast-modulated static
or continuous motion condition. Subtraction of the static random dot pattern
condition from the single-axis motion reversal condition, both contrast
modulated, revealed three significant activations: the anterior parieto-occipital
sulcus, the lateral sulcus and the anterior claustrum. Additional analysis showed
that these activations were not due to motion appearance or disappearance, but
were due to the combination of motion reversal and contrast modulation. Hence,
these activations do not reflect the motion reversal transient per se. In order
to isolate a metabolic response to the reversal transient per se, we used a
conjunction analysis, which suggests that activity in human MT/V5, the cuneus and
a parietal insular region could underlie the motion reversal VEP in our
experiments. Subtraction of the static random dot pattern condition from the
single-axis motion onset condition, both contrast-modulated, revealed a single
significant activation in the posterior cingulate cortex. Although the
significance of this activation is unclear, it adds further evidence for the
visual function of this region.
PMID- 9549496
TI - Matrix metalloproteinase-9 and -7 are regulated in experimental autoimmune
encephalomyelitis.
AB - Matrix metalloproteinases (MMPs) comprise a group of proteolytic enzymes that are
implicated in the pathogenesis of inflammatory diseases of the nervous system
such as multiple sclerosis. However, the exact function and expression pattern of
MMPs in the inflamed nervous system are not known. In the present study we
investigated the expression of 92-kDa gelatinase (MMP-9) in spinal cord from
animals with adoptive transfer experimental autoimmune encephalomyelitis (AT
EAE), using a semiquantitative competitive reverse transcriptase-polymerase chain
reaction assay. Increased levels of MMP-9 mRNA were found with peak values at
times of maximum disease severity. Increased mRNA expression was associated with
enhanced proteolytic activity of this enzyme, as demonstrated by gelatin
zymography. Immunohistochemistry revealed immunoreactivity along the meninges,
around blood vessels and within the parenchyma, in diseased but not in normal
spinal cord. Furthermore, the expression pattern of five other MMPs was
investigated. Matrilysin (MMP-7) was also found to be upregulated with maximum
mRNA levels at the peak of the disease. In contrast, mRNAs for collagenase-3, 72
kDa gelatinase, and stromelysin-1 and -3 were not changed. Our findings indicate
that 92-kDa gelatinase and matrilysin are selectively upregulated during AT-EAE
and thus may contribute to the pathogenesis of inflammatory diseases of the CNS.
PMID- 9549497
TI - Reliance on external cues for movement initiation in Parkinson's disease.
Evidence from movement-related potentials.
AB - The aim of this study was to investigate the neurophysiological mechanisms
underlying Parkinson's disease patients' increased reliance on external cues for
the initiation of movement. Lateralized movement-related cortical potentials were
recorded in a noise-compatibility task with seven patients and seven age-matched
control subjects. In this two-choice task, visual stimuli containing incompatible
target and distractor elements, which simultaneously instructed for responses
from both hands, initially caused activation of the motor cortex controlling the
wrong response hand. The incorrect response activation was of higher amplitude in
patients than in control subjects, causing a longer response delay relative to
response times when target and distractors instructed the same hand. In addition,
hand-specific motor cortex activation started earlier in patients than in control
subjects. These results indicate that visual stimuli exerted an earlier and
stronger influence on movement initiation in patients than in control subjects.
We hypothesize that information from sensory stimuli relevant for the generation
of a response can have rapid access to motor structures in Parkinson's disease
patients, thereby facilitating the initiation of movement. The findings may
reflect a compensatory mechanism, but could also be related to excitability
changes in the motor cortex intrinsic to the pathophysiology of Parkinson's
disease.
PMID- 9549498
TI - Cochlear sound-movement and musical misperception.
PMID- 9549499
TI - Neurological abnormalities in familial and sporadic schizophrenia.
AB - Neurological assessment was carried out on patients with schizophrenia from
multiply and singly affected families, their relatives, and a normal control
group (214 subjects). A systematic examination was used in which abnormal signs
were divided into 'primary' and 'integrative' signs. Primary signs were elicited
by a standard clinical neurological examination and included signs of focal
damage to nuclei and tracts, whilst integrative signs were selected as reflecting
distributed brain function. The assessments were carried out to test the
hypotheses that (i) neurological abnormalities are present in schizophrenia, (ii)
the pattern of abnormality is different in familial and sporadic schizophrenic
subjects, and (iii) the well relatives of familial (but not sporadic)
schizophrenic subjects will show neurological abnormalities. An excess of primary
signs compared with the controls was demonstrated in the sporadic schizophrenic
group only. Both the familial schizophrenics and their first-degree relatives
(but not their sporadic counterparts) showed an increase in integrative signs.
The results support the existence of different mechanisms of underlying brain
dysfunction in familial and sporadic schizophrenia.
PMID- 9549500
TI - Autosomal dominant nocturnal frontal lobe epilepsy. A video-polysomnographic and
genetic appraisal of 40 patients and delineation of the epileptic syndrome.
AB - A number of clinical and aetiological studies have been performed, during the
last 30 years, on patients with abnormal nocturnal motor and behavioural
phenomena. The aetiological conclusions of these studies were often conflicting,
suggesting either an epileptic or a non-epileptic origin. Among the clinical
characteristics of these patients, the familial clustering was one thoroughly
accepted. A nocturnal familial form of frontal lobe epilepsy (autosomal dominant
nocturnal frontal lobe epilepsy, ADNFLE), often misdiagnosed as parasomnia, has
been recently described in some families. In one large Australian kindred, a
missense mutation in the second transmembrane domain of the neuronal nicotinic
acetylcholine receptor alpha 4 subunit (CHRNA4) gene, located on chromosome 20
q13.2-13.3, has been reported to be associated with nocturnal frontal lobe
epilepsy. We performed an extensive clinical and video-polysomnographic study in
40 patients complaining of repeated abnormal nocturnal motor and/or behavioural
phenomena, from 30 unrelated Italian families. Thirty-eight patients had an
electroclinical picture strongly suggesting the diagnosis of ADNFLE. They had a
wide clinical spectrum, ranging from nocturnal enuresis to sleep-related violent
behaviour, thus including all the main features of the so-called 'typical'
parasomnias. The video-polysomnographic recording confirmed the wide spectrum of
abnormal manifestations, including sudden awakenings with dystonic/ dyskinetic
movements (in 42.1% of patients), complex behaviours (13.2%) and sleep-related
violent behaviour (5.3%). The EEG findings showed ictal epileptiform
abnormalities predominantly over frontal areas in 31.6% of patients. In another
47.4% of patients the EEG showed ictal rhythmic slow activity over anterior
areas. Only 18.4% of the patients had already received a correct diagnosis of
epilepsy. In 73.3% of the patients treated with anti-epileptic drugs the seizures
were readily controlled. Pedigree analysis on 28 of the families was consistent
with autosomal dominant transmission with reduced penetrance (81%). DNAs from 20
representative affected individuals were sequenced in order to check for the
presence of the missense mutation in the CHRNA4 gene found in the Australian
kindred affected by ADNFLE. Nucleotide sequence analysis did not reveal the
presence of this mutation, but it did confirm the presence of two other base
substitutions, not leading to amino acid changes. These two intragenic
polymorphisms, together with a closely linked restriction fragment length
polymorphism at the D20S20 locus, have been used for linkage analysis of ADNFLE
to the terminal region of the long arm of chromosome 20 in five compliant
families. The results allowed us to exclude linkage of ADNFLE to this chromosomal
region in these families, thus confirming the locus heterogeneity of the
disorder. Large and full video-polysomnographical studies are of the utmost
importance in order to clarify the real prevalence of both nocturnal frontal lobe
epilepsy and parasomnias, and to provide a correct therapy.
PMID- 9549501
TI - Secondary progressive multiple sclerosis: the relationship between short-term MRI
activity and clinical features.
AB - We report the findings in 60 patients with secondary progressive multiple
sclerosis who had monthly brain MRI studies for 4 months (one baseline and three
follow-up scans). The purpose was to define the short-term MRI natural history in
a large cohort with secondary progressive disease and to ascertain its
relationship with other clinical and MRI features. The patients were
participating in either a natural history study or the placebo arm or non
treatment phase of a therapeutic trial. The cohort had clinical features typical
of secondary progressive disease: thus, all had moderate or severe locomotor
disabilities [Expanded Disability Status Scale (EDSS), score 3.5-8], with a
median disease duration of 12 years. There was equal representation of males and
females. During the 3 months of follow-up there was a total of 362 new enhancing
lesions seen in 42 patients, and there were 24 relapses in 20 patients. There was
no correlation between new enhancing lesions and age at study entry, age of
disease onset, gender disease duration or EDSS, but there was a strong
correlation with the number of enhancing lesions on the baseline scan (r = 0.65,
P < 0.0001) and subsequent activity. There was a non-significant trend for higher
numbers of new enhancing lesions in those having relapses during the 3 months of
scanning (P = 0.14) or in the preceding 6 months (P = 0.06). The 34 patients who
did not relapse in either period had significantly fewer new active lesions (P =
0.02) than those who relapsed at some stage during the 9 months. Nevertheless,
considerable activity was seen in the non-relapsing cohorts: there was a mean of
3.5 (median 2) new enhancing lesions in those not relapsing during the 3 month
study, and 5.5 (median 2) in those not relapsing in the previous 6 months. We
conclude that short-term MRI activity is generally high in secondary progressive
disease, confirming a useful role for the technique in exploratory trials.
Further work should concentrate on elucidating the mechanisms of secondary
progression by longer term follow-up studies of larger cohorts using multiple MRI
and clinical measurements.
PMID- 9549502
TI - Visual evoked potentials during long periods of pattern-reversal stimulation in
migraine.
AB - We have previously shown that during repetitive pattern-reversal stimulation,
lasting 2 min, the amplitude of the visual evoked potential (PR-VEP) increases in
migraineurs when tested interictally whereas it decreases in healthy control
subjects. According to Sappey-Marinier et al. (J Cereb Blood Flow Metab 1992; 12:
584-92) habituation of the PR-VEP in normal subjects is maxima after 12 min, at a
time when there is a decrease of stimulation-enhanced lactate levels in the
occipital cortex. We have therefore compared PR-VEP during long periods of
repetitive stimulation in healthy control subjects (n = 25) and in patients
suffering from migraine without (n = 25) and with aura (n = 15) between attacks.
During uninterrupted stimulation at 3.1 Hz VEPs were sequentially averaged in
blocks of 100 responses for a total duration of 15 min and analysed in terms of
latencies and peak-to-peak amplitudes of N1-P1 and P1-N2 peaks. Amplitude changes
from the baseline were calculated for each block, by comparison with the first
block, and analysed statistically using Zerbe's method. The N1-P1 and P1-N2
amplitudes in the first block tended to be lower in migraineurs than in healthy
control subjects. During the 15 min of stimulation, amplitudes of both components
progressively decreased in control subjects, but remained stable in both groups
of patients. The difference between patients and control subjects proved to be
significant (P < 0.05). The neurophysiological data were not correlated with
clinical features such as attack frequency or duration of illness. These results
are yet another demonstration in migraine of an interictal habituation deficit in
cortical information processing, which might favour lactate accumulation in
sensory cortices during sustained activation.
PMID- 9549503
TI - Status dystonicus: the syndrome and its management.
AB - Patients with dystonic syndromes sometimes develop increasingly frequent and
relentless episodes of devastating generalized dystonia which we call status
dystonicus. Twelve cases of status dystonicus, of various underlying aetiologies,
are presented. Possible precipitating factors were identified in only five cases:
intercurrent infection (one); discontinuation of lithium (one) and tetrabenazine
(one); and the introduction of clonazepam (two). Nine patients required
mechanical ventilation and three others were sedated with intravenous
chlormethiazole. Drug therapy used included benzhexol, tetrabenazine, pimozide,
baclofen, chlorpromazine, haloperidol, carbamazepine and acetozolamide. Two
patients underwent thalamotomies, one of whom improved. Two patients died, five
returned to their pre-status dystonicus condition, two eventually made a full
recovery and three were worse. Patients with status dystonicus should be managed
on an intensive care unit as they may develop bulbar and respiratory
complications which may require ventilation. Metabolic problems encountered can
include rhabdomyolysis with acute renal failure. Drug therapy with benzhexol,
tetrabenazine and pimozide or haloperidol may be beneficial in some cases.
PMID- 9549504
TI - The functional neuroanatomy of simple and complex sequential finger movements: a
PET study.
AB - The brain regions activated by simple repetitive and sequential finger movements
of different length were localized by measuring regional cerebral blood flow
(rCBF) with PET. The experimental design consisted of finger movements cued by
auditory pacing at 0.5 Hz. In all conditions of different sequence length the
contralateral primary sensorimotor and premotor cortex, supplementary motor area
and ipsilateral cerebellar cortex were activated. These areas showed a large
increase in activation from rest to simple repetitive movement, and a further
increase with the shortest sequence, suggesting an executive role in running
sequences. The ipsilateral premotor area (Brodmann area 6), bilateral posterior
parietal areas (Brodmann area 7) and precuneus showed an increase in rCBF related
only to the length of the sequences, without any change from rest to simple
repetitive movement. These areas are more selectively related to sequence
performance. This finding is consistent with the hypothesis that these areas
function in the storage of motor sequences in spatial working memory. Our results
suggest that sequential finger movements recruit discrete sets of brain areas
with different functions.
PMID- 9549505
TI - Clustering of slowly adapting type II mechanoreceptors in human peripheral nerve
and skin.
AB - The intrafascicular organization of human peripheral nerves was studied with
percutaneous microneurography in the median, radial and peroneal nerves with one
surface or two-surface thin diameter concentric needle electrodes. Data from 33
recording sites containing 47 slowly adapting type II (SAII) units were analysed.
At many sites two, sometimes even three, neighbouring SAII units were recorded
from the explored nerve fascicle and they had adjacent or even overlapping
cutaneous receptive fields. Among pairs of SAII units found at the same site, one
unit often had ongoing discharge, whereas the other was silent under resting
conditions. The neighbouring SAII units were optimally activated by stretching
the skin in different directions. Stretching the same skin area in different
directions produced different unit recruitment. Clustered SAII units were often
found in sites where Pacinian afferents and skin sympathetic activity were also
recorded. No significant difference was observed in the degree of grouping of
SAII units either between recordings obtained with one-surface versus two-surface
electrodes or between glabrous and hairy skin. The data do not support the notion
that myelinated fibres are randomly organized in peripheral nerve fascicles.
Instead, the findings suggest that SAII units tend to be clustered in human
peripheral nerves. Furthermore, the response of groups of SAII units to skin
stretch suggests that they play a role in proprioception. Dual channel recordings
with two-surface concentric needle electrodes may provide a novel approach to
study fibre organization in human peripheral nerves and the behaviour of groups
of nerve fibres.
PMID- 9549506
TI - Somatosensory-evoked blink response: investigation of the physiological
mechanisms.
AB - The somatosensory-evoked blink response (SBR) is a newly identified blink reflex
elicited by electrical stimulation of peripheral nerves. The present study was
performed to investigate the physiological mechanism underlying the SBR elicited
by median nerve stimulation in normal subjects. The peripheral afferents
responsible for the SBR included low-threshold cutaneous fibres. In the SBR
positive subjects, the late (R2) component of the blink reflex elicited by
supraorbital nerve stimulation and the SBR facilitated each other when both
responses were induced at the same time, but they each caused long-lasting
inhibition in the other when one stimulus was given as a conditioning stimulus.
The extent of inhibition was correlated with the size of the preceding SBR. In
the SBR-negative subjects, simultaneous inhibition of R2 was observed when median
nerve stimulation was applied as a conditioning stimulus. Brainstem excitability,
as evaluated by blink-reflex recovery studies, did not differ between SBR
positive and SBR-negative subjects. Therefore, based on anatomical and
physiological findings, it appears that the reflex pathways of the SBR and R2
converge within the brainstem and compete with each other, presumably by
presynaptic inhibition at the premotor level, before entering the common blink
reflex pathway. The influence of median nerve stimulation upon tonic contraction
of the orbicularis oculi muscle was studied to detect the latent SBR. There was
not only a facilitatory period corresponding to the SBR but also an active
inhibitory period (exteroceptive suppression), suggesting that the mechanism
generating the SBR is not only influenced by blink-reflex volleys but also by
active exteroceptive suppression. Thus, the SBR may appear as a result of
integration of facilitatory and inhibitory mechanisms within the brainstem.
PMID- 9549507
TI - Identification of the adult resting progenitor cell by autoradiographic tracking
of oligodendrocyte precursors in experimental CNS demyelination.
AB - The new population of oligodendrocytes remyelinating an experimental
demyelinating optic nerve lesion has been tracked backwards in time. Using
autoradiography combined with electron microscopy and immunocytochemistry, serial
sections of optic nerves from young adult cats were studied from 42 h (2 days)
post-injection to 93 h (4 days) post-injection. The remyelinating oligodendrocyte
lineage was found to commence with the single division of a resting progenitor
cell residing in a central fascicular location outside the demyelinative lesion.
The division of the founding progenitor cell occurs at 2 days post-lesion and
results in two motile daughter cells. These cells, previously described by us as
precursor cells, migrate to the lesion, closely appose demyelinated axons,
produce axon wrapping processes and differentiate to become remyelinating
oligodendrocytes. This study confirms that remyelinating oligodendrocytes
originate from resting progenitor cells outside the lesion and not from mature
oligodendrocytes, and implies that repeated demyelinative injury could exhaust
the reparative capacity of such a region.
PMID- 9549508
TI - Clinical and genetic analysis of a large Dutch family with autosomal dominant
vascular retinopathy, migraine and Raynaud's phenomenon.
AB - We describe an extended Dutch family with a new hereditary disorder: autosomal
dominant vascular retinopathy, migraine and Raynaud's phenomenon. Information was
obtained on 289 family members (151 males, 138 females), of whom 198 were
personally interviewed. Retinopathy was found in 20 (6.9%) of the family members,
migraine in 65 (22.5%) and Raynaud's phenomenon in 50 (17.3%). A combination of
all three symptoms was found in 11 subjects. In a genetic linkage analysis we
firstly excluded several candidate loci. Subsequently, 75% of the autosomal
genome was excluded in a genome-wide search. The following conclusions were
drawn. First, genetic factors are involved in Raynaud's phenomenon. Secondly, the
genetic linkage of migraine with vascular retinopathy and Raynaud's phenomenon
supports a vascular aetiology of this disorder. Finding the gene for this family
may help to elucidate the genetic background of migraine and of vascular
disorders in general.
PMID- 9549509
TI - The subjective handicap of epilepsy. A new approach to measuring treatment
outcome.
AB - It is now widely acknowledged that the impact of epilepsy on the individual
extends beyond the occurrence of seizures, and that there is a need for outcome
measures sensitive to these consequences. Until now these instruments have
largely been developed within a 'quality of life' framework. The technical and
conceptual difficulties that arise with measuring quality of life have led us to
develop a more focused measurement model, the 'Subjective Handicap of Epilepsy'
(SHE) scale, based on the World Health Organization's concept of handicap. The
scale contains 32 items in six subscales: 'Work and activities' (eight items),
'Social and personal' (four items), 'Self-perception' (five items), 'Physical'
(four items), 'Life-satisfaction' (four items) and a 'Change' scale (seven
items); and it takes on average < 10 min to complete. The scale's test-retest
reliability was found to be satisfactory (intra-class correlation coefficient was
0.8-0.9 in 110 subjects). The test-retest interval (24 h to 8 weeks) had no
influence on the reliability. The reliability was also not affected by minor
recent fluctuations in seizure frequency. The internal consistency of the scales
was 0.8-0.9 (Cronbach's alpha). The construct validity of the scale was examined
in a sample of 287 clinic attendees at a university neurology clinic in the UK.
The scales were highly sensitive to the handicapping effects of increasing
seizure frequency, employment status, the impact of epilepsy on career choice and
the subject's own opinion as to the major determinant of their quality of life.
The scales were also sensitive, retrospectively, to the benefits of successful
epilepsy surgery in a cohort of 105 patients. Scales focusing specifically on
handicap were more sensitive to group differences in seizure frequency in the
clinic population, and to outcome after epilepsy surgery, than the 'Life
satisfaction' scale and the Epilepsy Surgery Inventory 55 (ESI-55) scales. This
supports the contention that measuring 'subjective handicap' may be a more
sensitive, and more useful, approach to assessing the impact of interventions on
the long-term consequences of epilepsy than current methods.
PMID- 9549510
TI - Allodynia after lateral-medullary (Wallenberg) infarct. A PET study.
AB - We used PET to study regional cerebral blood flow (rCBF) changes in nine patients
with unilateral central pain after a lateral medullary infarct (Wallenberg's
syndrome). All patients presented, on the abnormal side, a combination of
hypaesthesia to noxious and thermal stimuli and allodynia to rubbing of the skin
with a cold object (i.e. abnormal pain to innocuous stimulation). The rCBF
responses during allodynia were compared with those obtained during stimulation
of the normal side using (i) a cold non-noxious stimulus identical to that
applied to the painful side, and (ii) an electrical high-frequency stimulus at
painful ranges. Statistical analysis disclosed two abnormal patterns of rCBF
change during allodynia. First, there is a quantitative change whereby the blood
flow response was out of proportion with the actual intensity of the stimulus,
i.e. the pattern of activation by innocuous rubbing of the skin was in our
patients identical to that previously reported in response to painful stimuli in
normal subjects. This pattern concerned primarily the contralateral thalamus in
its lateral half and the primary and somatosensory areas, as well as inferior
parietal [Brodmann area (BA) 39/40], anterior insular (BA 6) and medial
prefrontal (BA 10) cortices. Thalamic over-activity may reflect abnormal
transduction and amplification of sensory inputs after spinothalamic
deafferentation. This might be responsible for both increased rCBF in multiple
cortical targets and the perceived shift of stimulus intensity from innocuous to
painful ranges. The second abnormality associated with allodynic sensation was
qualitative. It concerned exclusively the contralateral cingulate gyrus, which
did not exhibit the usual pain-related rCBF increase reported in normal subjects.
This abnormal cingulate response may account for the peculiar response of lateral
medullary infarct patients to allodynic pain, which is not simply perceived as an
exaggerated pain sensation, but as a new, strange and extremely unpleasant
feeling, not previously experienced by the patients.
PMID- 9549511
TI - Influence of vision on upper limb reaching movements in patients with cerebellar
ataxia.
AB - The effects of vision on spatial and temporal characteristics of free
unrestrained reaching movements of the arm were examined in 17 patients with
ataxic syndromes due to degenerative disease of the cerebellum and its
connections. Subjects were required to reach out and touch a visually presented
target either in the dark or with the target and their finger visible. Overall,
patients had prolonged reaction times and their movements were performed slower
than normal. The spatial paths described by their fingertips were more
circuitous, being of greater length than normal, a characteristic that was
uninfluenced by visual conditions. Ataxic movements were less accurate than
normal in two ways. First, there was greater spatial variability between repeat
paths to the same target. The increased variability was present very early in the
movement trajectory and at that stage was not influenced by visual feedback.
Secondly, there were large constant errors at the end of movement, but only when
moving in darkness. Patients with Friedreich's ataxia as well as those with
intrinsic cerebellar degeneration showed the above abnormalities, although there
were some quantitative differences between the two groups. We suggest these
spatial errors arise because the cerebellum contributes either directly or
indirectly to preparatory motor processes which, based on limb proprioceptive and
retinal information, compute the pattern of muscle activity required to launch
the limb accurately towards a target. Patients were largely successful at using
visual guidance to make midflight adjustments to their movements in order to
improve accuracy. This manifested as a reduction in spatial variability between
repeat paths as the target was approached and a reduction in constant error.
However, the visual correction mechanism did not appear normal. Under visual
guidance, the end-phase of movement was often prolonged and characterized by
excessive deviations or direction changes in the path. These deviations may be
the expression of a visual guidance system producing corrections which themselves
contain error requiring further correction. Thus, this process may be abnormal
for the same reason that the initial pattern of muscle activity is misjudged.
PMID- 9549512
TI - Electrical stimulation over muscle tendons in humans. Evidence favouring
presynaptic inhibition of Ia fibres due to the activation of group III tendon
afferents.
AB - Electrical stimulation over muscle tendons produces a transient suppression of
voluntary EMG activity; its onset latency is approximately 55 ms in the forearm
extensor muscles. This phenomenon has been attributed to the activation of a
polysynaptic inhibitory pathway originating from Ib afferent fibres. To clarify
its origin we conducted several experiments in 10 normal healthy subjects. The
EMG silence after tendon stimulation appeared at relatively high stimulus
intensities (> 50 mA); conditioning cutaneous stimulation left it unchanged, and
the inhibition had a short recovery cycle (50 ms). Tendon stimulation still
evoked EMG suppression during an ischaemic block of fast-conducting afferents.
The motor potentials evoked by transcranial magnetic stimulation of the motor
cortex during the EMG silence remained almost unchanged, whereas the H reflex was
strongly inhibited. Hence we conclude that tendon stimulation activates slow
conducting tendon afferents, possibly group III fibres, connected not through a
polysynaptic pathway originating from Ib afferents but through an oligo- or
disynaptic inhibitory circuit. The EMG suppression after tendon stimulation
probably represents a dysfacilitation of the alpha-motor neurons due to
presynaptic inhibition of Ia fibres produced by tendon afferent input to the
spinal cord.
PMID- 9549513
TI - Cranial nerve syndrome in thrombosis of the transverse/sigmoid sinuses.
AB - Cerebral venous thrombosis (CVT) is a cerebrovascular disease associated with a
wide variety of clinical signs and symptoms, which may often delay appropriate
diagnosis. Single or multiple cranial nerve palsies (III-VIII) without evidence
of other signs and symptoms have not, so far, been considered a relevant syndrome
of CVT. This event turned out to be a characteristic finding in five patients
with thrombosis of the ipsilateral transverse/sigmoid sinus, who were recruited
prospectively over a 14-month period. The diagnosis was supported by non-invasive
MRI with the application of a newly developed subtraction technique. In view of
the considerable mimics of the syndrome, and the long-standing need for
conventional angiography to confirm the disease, it is likely to have been
underestimated in the past; since appropriate treatment seems possible the
diagnosis and utility of early MR venography should be considered in patients
with single or multiple cranial nerve lesions of uncertain aetiology.
PMID- 9549514
TI - Transcranial Doppler detected cerebral microembolism following carotid
endarterectomy.
PMID- 9549515
TI - Transcranial magnetic stimulation.
PMID- 9549516
TI - Hereditary motor and sensory neuropathy--Lom, a novel demyelinating neuropathy
associated with deafness in gypsies. Clinical, electrophysiological and nerve
biopsy findings.
AB - A previously unrecognized neuropathy was identified in Bulgarian gypsies, and was
designated hereditary motor and sensory neuropathy-Lom (HMSNL) after the town
where the initial cases were found. It was subsequently identified in other gypsy
communities. The disorder, which is of autosomal recessive inheritance, was
mapped to chromosome 8q24. It begins consistently in the first decade of life
with gait disorder followed by upper limb weakness in the second decade and, in
most subjects, by deafness which is most often first noticed in the third decade.
Sensory loss affecting all modalities is present, both this and the motor
involvement predominating distally in the limbs. Skeletal deformity, particularly
foot deformity, is frequent. Severely reduced motor nerve conduction velocity
indicates a demyelinating basis, which was confirmed by nerve biopsy. The three
younger patients biopsied showed a hypertrophic 'onion bulb' neuropathy. The
hypertrophic changes were not evident in the oldest individual biopsied and it is
likely that they had regressed secondarily to axon loss. In the eight cases in
which brainstem auditory evoked potentials could be recorded, the results
suggested demyelination in the eighth cranial nerve and also abnormal conduction
in the central auditory pathways in the brainstem. As no myelin genes are known
to be located at chromosome 8q24, the disorder may involve a gene for a novel
myelin protein or be due to an abnormality of axon-Schwann cell signalling.
PMID- 9549517
TI - Different activation patterns in the visual cortex of late and congenitally blind
subjects.
AB - A key issue in developmental neuroscience is the role of activity-dependent
mechanisms in the epigenetic induction of functional organization in visual
cortex. Ocular blindness and ensuing visual deprivation is one of the rare models
available for the investigation of experience-dependent cortical reorganization
in man. In a PET study we demonstrate that congenitally blind subjects show task
specific activation of extrastriate visual areas and parietal association areas
during Braille reading, compared with auditory word processing. In contrast,
blind subjects who lost their sight after puberty show additional activation in
the primary visual cortex with the same tasks. Studies in blind-raised monkeys
show that crossmodal responses in extrastriate areas can be elicited by
somatosensory stimulation. This is consistent with the crossmodal extrastriate
activations elicited by tactile processing in our congenitally blind subjects.
Since primary visual cortex does not show crossmodal responses in primate
studies, the differential activation in late and congenitally blind subjects
highlights the possibility of reciprocal activation by visual imagery in subjects
with early visual experience.
PMID- 9549518
TI - The long-term effect of intravenous immunoglobulin treatment in multifocal motor
neuropathy.
AB - We studied the long-term effect of intravenous immunoglobulin (IV Ig) treatment
in seven patients with multifocal motor neuropathy. In six patients, treatment
with a full IV Ig course (0.4 g/kg for 5 consecutive days) improved muscle
strength but for not longer than 12 weeks. These patients received IV Ig
maintenance treatment consisting of one infusion every week for 2-4 years. One
patient in whom the effect of the initial full IV Ig treatment lasted for more
than 1 year received incidental IV Ig treatment when muscle strength
deteriorated. In all patients IV Ig treatment had a beneficial effect on most
muscle groups during the follow-up period. However, in three of the seven
patients muscle strength deteriorated during IV Ig maintenance treatment in four
of the 28 muscle groups that had initially shown an improvement of muscle
strength after the start of IV Ig treatment, and in two muscle groups with normal
strength at the start of IV Ig treatment. The electrophysiological follow-up
studies indicated that there was an improvement of conduction block, but also
that there were new sites of conduction block and ongoing axonal degeneration
during IV Ig maintenance treatment.
PMID- 9549519
TI - Transcranial magnetic stimulation over the posterior cerebellum during smooth
pursuit eye movements in man.
AB - Recent neurophysiological experiments in the monkey have demonstrated that the
flocculus and the posterior vermis, lobules VIc-VII (oculomotor vermis), are
involved in the generation of pursuit eye movements. Whereas the functions of the
flocculus in the control of smooth pursuit have been intensively investigated,
sufficient data are not available for a profitable discussion of the functions of
the oculomotor vermis in the control of smooth pursuit. We previously indicated
that the posterior vermis can be electrically stimulated by a focal transcranial
magnetic stimulation (TMS) device through the skull in man, and that focal TMS of
the posterior vermis can modulate saccadic eye movements. In this study we
investigated the effects of cerebellar stimulation on smooth pursuit metrics in
man using a focal TMS device. Focal TMS was applied over the posterior cerebellum
in an area approximately 7 mm lateral and caudal to the inion, where saccadic eye
movements are modulated by TMS, during horizontal smooth pursuit elicited by a
step-ramp target with a constant velocity of 15 degrees/s in four normal
subjects. The TMS device was triggered after the onset of smooth pursuit during
the initial acceleration phase (latency range = 40-80 ms) or the steady-state
tracking phase (latency range = 300-340 ms). We investigated the effect of TMS on
the velocity and acceleration of smooth pursuit. For smooth pursuit directed
ipsilateral to the stimulation side (ipsiversive), focal TMS of the posterior
cerebellum produced abrupt acceleration of pursuit in both initial acceleration
and steady-state tracking phases. On the other hand, TMS produced abrupt
deceleration of contraversive pursuit in both initial acceleration and steady
state tracking phases. These findings suggest that the posterior vermis controls
smooth pursuit velocity in a direction-selective manner in both initial
acceleration and steady-state tracking phases.
PMID- 9549520
TI - Transcranial stimulation excites virtually all motor neurons supplying the target
muscle. A demonstration and a method improving the study of motor evoked
potentials.
AB - Transcranial stimulation has become an established method in the evaluation of
corticospinal tract function. Clinical studies mainly address slowing of
conduction through measurement of increased central conduction time (CCT) and
'failures' of conduction through observation of marked reductions in the size of
the motor evoked potential (MEP). While CCT is of great interest in detecting
subclinical slowing of conduction, the method discloses only gross failures of
conduction, since the size of the MEP varies markedly between normal subjects and
from one stimulus to another, leading to a broad range of normal values.
Furthermore, transcranial stimulation does not appear to achieve depolarization
of all spinal motor neurons leading to the target muscles, since in most normal
subjects MEPs are smaller in amplitude than the responses evoked by peripheral
nerve stimulation. We have developed a triple stimulation technique (TST) which,
through two collisions, links central to peripheral conduction and suppresses
desynchronization of MEPs. This technique shows that transcranial stimulation
does achieve depolarization of all, or nearly all, spinal motor neurons supplying
the target muscle in healthy subjects. Our data thus demonstrate that the
amplitudes of MEPs are (i) smaller than those of peripheral responses, mostly due
to phase cancellation of the action potentials caused by the desynchronization
occurring within the corticospinal tract or at spinal cell level and (ii)
variable between normal subjects and from one stimulus to another, mostly due to
variability of this desynchronization. This technique provides new insights into
normal corticospinal tract conduction. It will improve detection and
quantification of central motor conduction failures.
PMID- 9549521
TI - Subthalamic nucleus or internal pallidal stimulation in young onset Parkinson's
disease.
AB - The aim of this study was to compare, retrospectively, the value of chronic
bilateral stimulation of the internal globus pallidus (GPi) and the subthalamic
nucleus (STN) in patients with young onset Parkinson's disease. We selected 13
consecutive patients with similar characteristics at the time of surgery: age at
onset < 40 years, disabling motor fluctuations (Hoehn and Yahr stage 4 or 5 in
off-drug phases) and levodopa-induced dyskinesias (LID). Eight patients were
operated on in the STN and five in the GPi. The Unified Parkinson's Disease
Rating Scale (UPDRS), timed motor tests and a LID scale were compared in on- and
off-drug conditions before surgery and 6 months after surgery on stimulation
using the chronic electrical parameters found to improve best the motor state of
the individual patient, without adverse effects. In off-drug phases, the motor
score of the UPDRS was improved by 71% with STN stimulation and by 39% with GPi
stimulation on average. This difference was statistically significant (P < 0.05).
Whereas rigidity and tremor showed good improvement in both groups, the decrease
in the akinesia score was more pronounced in the STN group. In the STN group, the
improvement of all motor symptoms was very close, or equal, to the best levodopa
response. Thus the levodopa test was predictive of outcome. The improvement in
off-drug period motor handicap allowed a decrease in the levodopa-equivalent dose
only in the STN group (-56%). The voltage, frequency and pulse width used for
chronic stimulation were lower in the STN group. In the on-drug phases there was
a marked improvement in LID in the GPi group, as measured by the dyskinesias
score during an acute levodopa test, whereas there was only a small decrease in
the STN group (P < 0.05). However, in the long term, the reduction of levodopa
dosage in the STN group led to an indirect reduction of LID similar to that in
the GPi group during activities of everyday life. In conclusion, the overall
results favour the neurosurgical treatment of Parkinson's disease by stimulating
the STN rather than the GPi.
PMID- 9549522
TI - The role of the SCA2 trinucleotide repeat expansion in 89 autosomal dominant
cerebellar ataxia families. Frequency, clinical and genetic correlates.
AB - The spinocerebellar ataxia type 2 (SCA2) is caused by a trinucleotide (CAG)
expansion in the coding region of the ataxin 2 gene on chromosome 12q.89 families
with autosomal dominant cerebellar ataxia (ADCA) types I, II and III, and 47
isolated cases with idiopathic late onset cerebellar ataxia (ILOCA), were
analysed for this mutation. The identification of the SCA2 mutation in 31 out of
38 families with the ADCA I phenotype, but in none of those with ADCA II, ADCA
III or ILOCA confirms the specificity of this mutation. A clinical comparison of
the ADCA I patients with the three known mutations (SCA1, -2 or -3) highlights
significant differences between the groups; SCA2 patients tended to have a longer
disease duration, a higher frequency of slow saccades and depressed tendon
reflexes. However, these neurological signs were also seen in an ADCA I family in
which the SCA2 mutation was not identified, illustrating the importance of a
direct genetic test. The SCA2 families were from different geographical and
ethnic backgrounds. However, haplotype analysis failed to show evidence of a
founder mutation, even in families from the same geographical origin. The range
of normal alleles varied from 17 to 30 CAG repeats and from 35 to 51 repeats for
the pathological alleles. Similar to the other diseases caused by unstable
trinucleotide repeats, a significant inverse correlation has been found between
the number of repeats and age of onset, and there is a significantly higher
paternal instability of repeat length on transmission to offspring. The SCA2
mutation is the most frequent amongst ADCA I patients, accounting for 40%,
compared with SCA1 and SCA3 which account for 35% and 15%, respectively.
PMID- 9549523
TI - Macrophage differentiation antigens in acute and chronic autoimmune
polyneuropathies.
AB - The pathological differential diagnosis between potentially treatable autoimmune
neuropathies and degenerative neuropathies is often difficult if major T-cell
infiltrates are absent in sural nerve biopsies. Since it is suggested that
macrophages play a central pathogenetic role in inflammatory neuropathies, we
investigated the expression of macrophage differentiation antigens associated
with acute (MRP14 and 27E10 antigens) and more chronic inflammation (MRP8 and
25F9 antigens) in 76 sural nerve biopsies from patients with Guillain-Barre
syndrome, chronic inflammatory demyelinating polyneuropathy, other inflammatory
neuropathies, hereditary neuropathies and normal sural nerves. Macrophage
differentiation antigens were immunocytochemically detected in a majority of
inflammatory biopsies but rarely in non-inflammatory disease controls and normal
looking nerves. Quantification of labelled endoneurial cells revealed
significantly elevated cell counts compared with controls. In individual
biopsies, elevated levels of one differentiation antigen were not necessarily
associated with high expression of the other antigens, pointing to functional
heterogeneity of endoneurial macrophages. Endoneurial cell counts for at least
one of the differentiation markers that were greater than in any of the non
inflammatory control nerves were found in two-thirds of all inflammatory
biopsies, whereas T-cell counts and in particular total macrophage counts were
less sensitive in picking up biopsies from patients with inflammatory
neuropathies. Antibodies to macrophage differentiation antigens are additional
simple and helpful diagnostic tools in differentiating autoimmune from non
inflammatory neuropathies in sural nerve biopsies.
PMID- 9549524
TI - Matrix metalloproteinase expression during experimental autoimmune neuritis.
AB - Experimental autoimmune neuritis (EAN) is an animal model of Guillain-Barre
syndrome. We have shown recently that BB-1101, a broad-spectrum matrix
metalloproteinase (MMP) inhibitor, prevents development of EAN when given from
the day of immunization and, more important clinically, reduces disease severity
when given from symptom onset. This suggests the involvement of MMP activity in
the pathogenesis of EAN. However, the exact function and expression patterns of
MMPs in acute inflammation of the PNS have not been investigated. MMP-like
enzymes are also involved in the processing of tumour necrosis factor-alpha (TNF
alpha), which has been implicated previously in the pathology associated with
EAN. In the present study we investigated the profile of MMP and TNF-alpha
expression and their localization in sciatic nerve tissue during EAN, using a
semiquantitative competitive reverse transcriptase-coupled polymerase chain
reaction and immunohistochemistry. In the normal rat PNS, four of the 10 MMPs
studied were constitutively expressed and four MMPs were differentially regulated
during EAN. Expression of TNF-alpha was elevated at peak disease severity and
localized to Schwann cells, macrophages and endoneurial blood vessels. Expression
levels of 92 kDa gelatinase and stromelysin-1 were significantly increased early
in the development of EAN and continued to rise, peaking at day 15 coincident
with maximum disease severity. Schwann cells and endothelial cells were the main
cellular source of these enzymes. Prominent infiltration of inflammatory cells
into the sciatic nerve was concordant with a significant increase in the
expression levels of matrilysin and macrophage metalloelastase. Both matrilysin
and macrophage metalloelastase were detected in invading macrophages, T
lymphocytes and resident Schwann cells. The selective upregulation of specific
MMPs during EAN and their varied cellular localization suggests that MMPs play a
multifactorial role in the aetiology of EAN. Activity of MMPs could participate
in the disruption of the blood-nerve barrier, breakdown of the myelin sheath, the
release of TNF-alpha, and facilitate leukocyte invasion into the PNS. These
observations highlight MMPs as potential targets for therapeutic intervention in
acute peripheral neuropathies, such as Guillain-Barre syndrome.
PMID- 9549525
TI - The prognostic value of brain MRI in clinically isolated syndromes of the CNS. A
10-year follow-up.
AB - A definitive diagnosis of multiple sclerosis cannot be made at presentation on
patients with a clinically isolated syndrome of the optic nerve, spinal cord or
brainstem suggestive of demyelination, as dissemination in time is not
established. To determine the long-term risk of abnormalities on brain MRI for
the development of multiple sclerosis and disability we performed a 10-year
follow-up on 81 such patients who had T2-weighted brain MRI at presentation.
Initial brain MRI was abnormal in 54 (67%). Follow up of those patients with an
abnormal MRI revealed progression to clinically definite multiple sclerosis in 45
out of 54 (83%), of whom 11 (20%) had relapsing/remitting disease (EDSS > 3), 13
(24%) secondary progressive and 21 (39%) benign (relapsing/remitting with EDSS <
or = 3) disease. For those with a normal MRI progression to clinically definite
multiple sclerosis occurred in only three out of 27 (11%), all benign. There was
a significant relationship between the number of lesions at presentation and both
EDSS (r = 0.45, P < 0.001) and the type of disease at follow-up (P < 0.0001).
Brain MRI at presentation with a clinically isolated syndrome is predictive of
the long-term risk of subsequent development of multiple sclerosis, the type of
disease and extent of disability.
PMID- 9549526
TI - Training improves the speed of aimed movements in Parkinson's disease.
AB - In this study, the extent to which bradykinesia in patients with idiopathic
Parkinson's disease can be influenced by practice and by specific training
strategies was investigated. Fifteen patients with Parkinson's disease tested
after withdrawal of anti-Parkinson medication, and 15 matched control subjects,
practised a ballistic aiming task. Performance was tested before, during and
after training and again 1 h later. The Parkinson's disease patients and control
subjects were randomly assigned to one of two training schedules, practising with
or without rhythmic auditory cues. At baseline, the Parkinson's disease patients
showed longer movement times, with a marked decrease in maximum acceleration and
deceleration in the initial open-loop phase compared with those of the control
subjects. With training, they were able to make significant improvement in the
speed of aimed movements, particularly in the early movement phase, without any
deterioration in accuracy. These effects transferred to an untrained limb and
were at least partially maintained after a 1-h delay. While patients remained
impaired relative to control subjects at all phases of training and follow-up,
the patients' performance at the end of training did not differ significantly
from the control subjects' baseline function. Contrary to expectation, rhythmic
auditory cues did not enhance improvement in the speed of aimed movements in
either patients or control subjects. If anything, less improvement was shown in
the cued groups, although there were suggestions that the aiming skill was
retained better over the delay period. The results demonstrate preserved
abilities to improve speed of single ballistic aiming movements in Parkinson's
disease patients and the possibility of reducing bradykinesia by training.
PMID- 9549527
TI - Relationships between timing of muscle excitation and impaired motor performance
during cyclical lower extremity movement in post-stroke hemiplegia.
AB - We used an ergometer pedalling paradigm to relate abnormalities in the timing of
muscle excitation to the impaired ability to perform mechanical work in the
plegic lower limbs of persons with hemiplegia. The EMGs of seven leg muscles and
pedal forces were measured bilaterally during pedalling for 15 persons with
hemiplegia and 12 neurologically intact age-matched control subjects. Subjects
were asked to pedal at a moderate workload (135 J) and cadence (40 r.p.m.). While
intersubject variability was high, the external mechanical work output of the
plegic leg was significantly less (from 79.6% to -28.9% of the work produced by
average leg of control subjects) as a result of less positive work and more
negative work being done. The timing of EMG in individual plegic limb muscles
exhibited two distinct types of abnormalities that were significantly correlated
with this lesser work production: prolonged excitation in the vastus medialis and
phase-advanced excitation (both early initiation and early termination) in the
rectus femoris and semimembranosus. These results suggest that muscles were
differently affected depending on their function, external power-producing
muscles (e.g. vastus medialis) showing prolonged excitation and muscles that
normally maintain crank progression during limb transitions (e.g.
semimembranosus) showing phase-advanced excitation.
PMID- 9549528
TI - Cortical motor overactivation in parkinsonian patients with L-dopa-induced peak
dose dyskinesia.
AB - We have studied the regional cerebral blood flow (rCBF) changes induced by the
execution of a finger-to-thumb opposition motor task in the supplementary and
primary motor cortex of two groups of parkinsonian patients on L-dopa medication,
the first one without L-dopa induced dyskinesia (n = 23) and the other with
moderate peak-dose dyskinesia (n = 15), and of a group of 14 normal subjects.
Single photon emission tomography with i.v. 133Xe was used to measure the rCBF
changes. The dyskinetic parkinsonian patients exhibited a pattern of response
which was markedly different from those of the normal subjects and non-dyskinetic
parkinsonian patients, with a significant overactivation in the supplementary
motor area and the ipsi- and contralateral primary motor areas. These results are
compatible with the hypothesis that an hyperkinetic abnormal involuntary
movement, like L-dopa-induced peak dose dyskinesia, is due to a disinhibition of
the primary and associated motor cortex secondary to an excessive outflow of the
pallidothalamocortical motor loop.
PMID- 9549529
TI - Disseminating and applying best evidence.
PMID- 9549530
TI - Heparin in the home: risks and benefits.
PMID- 9549531
TI - Hospital-in-the-home care: is it worth the hassle?
PMID- 9549532
TI - Reforming Medicare.
PMID- 9549533
TI - Use of systematic reviews of randomised trials by Australian neonatologists and
obstetricians.
AB - OBJECTIVE: To determine what proportion of Australian neonatologists and
obstetricians report using systematic reviews of randomised trials. DESIGN: Cross
sectional survey using structured telephone interviews. SETTING: Australian
clinical practice in 1995. PARTICIPANTS: 103 of the 104 neonatologists in
Australia (defined as clinicians holding a position in a neonatal intensive care
unit); a random sample of 145 members of the Royal Australian College of
Obstetricians and Gynaecologists currently practising in Australia. MAIN OUTCOME
MEASURES: Information sources used in clinical practice; reported awareness of,
access to and use of systematic reviews, and consequent practice changes.
RESULTS: Response rates were 95% (neonatologists) and 87% (obstetricians); 71
neonatologists (72%) and 55 obstetricians (44%) reported using systematic
reviews, primarily for individual patient care. Databases of systematic reviews
were used with a median frequency of once per month. Among neonatologists,
systematic reviews were used more commonly by those who were familiar with
computers, attended professional meetings, and had authored research papers.
Among obstetricians, they were used more commonly by those who were familiar with
computers, had less than 10 years' clinical experience, attended more deliveries,
and were full-time staff specialists in public hospitals. Of neonatologists who
reported using systematic reviews, 58% attributed some practice change to this
use. For obstetricians, the corresponding figure was 80%. CONCLUSIONS: There is
evidence that Australian neonatologists and obstetricians use systematic reviews
and modify their practice accordingly. Dissemination efforts can benefit from
knowledge of factors that predict use of systematic reviews.
PMID- 9549534
TI - Dalteparin for deep venous thrombosis: a hospital-in-the-home program.
AB - OBJECTIVE: To assess the efficacy, safety and cost savings of home treatment of
lower-limb deep venous thrombosis (DVT). SETTING: A hospital-in-the-home
treatment program. PATIENTS: One hundred patients with acute lower limb DVT (53
proximal, 47 distal), and no contraindication to home treatment, were entered
into the program from March 1995 to February 1997. INTERVENTION: All patients
received dalteparin, 200 units/kg subcutaneously, once daily for a minimum of
five days, with commencement of oral anticoagulation (warfarin) on Day 2.
Patients with proximal DVT had lung ventilation-perfusion scans performed and
were admitted to hospital for at least 24 hours. Patients with distal DVT were
discharged directly to home treatment. MAIN OUTCOME MEASURES: Clinical responses
and the results of sequential duplex ultrasonography at one week, one month,
three months and six months. RESULTS: There were no major, but six minor,
bleeding complications, two of which led to dalteparin being withdrawn. Sixteen
patients had lung ventilation-perfusion scans showing a high probability of
pulmonary embolism. All were asymptomatic, and follow-up for at least three
months showed no symptomatic thromboembolic events. Duplex ultrasonography showed
progression of thrombosis in the first week of therapy in 13.2% of distal and
2.7% of proximal thromboses. Thereafter, distal DVT improved at a much greater
rate than proximal DVT; after six months complete resolution was seen in 60.7% of
distal and 18.5% of proximal thromboses, respectively. Cost saving was $197 per
bed-day equivalent compared with inpatient care. At 15 months' follow-up,
swelling and/or pain was reported by 49% of patients with distal DVT and 66% of
those with proximal DVT. CONCLUSIONS: Once-daily dalteparin therapy for DVT in a
hospital-in-the-home setting was safe, efficacious and cost effective. However,
DVT resolution is a slow process, with significant long term morbidity.
PMID- 9549535
TI - How safe is hospital-in-the-home care?
AB - OBJECTIVE: To describe the rate of negative, unexpected and adverse events
associated with hospital-in-the-home (HIH) care in an established unit, and to
validate indicators of safety for HIH care. DESIGN: Prospective descriptive
survey. PATIENTS AND SETTING: 231 patients, who would otherwise have required
hospitalisation, accepted for acute home-based care by the HIH unit at Frankston
Hospital, a 350-bed hospital serving a population of 240,000 on the south-eastern
boundary of Melbourne. MAIN OUTCOME MEASURES: The following indicators of safety:
patient telephone calls to the on-call service; unscheduled staff callout to
patients' homes; return to hospital during an HIH admission; and return to
hospital after discharge. RESULTS: 190 acute admissions were examined. Planned
same-day admissions were uneventful and excluded from the analysis. The therapies
provided were intravenous therapy (mainly antibiotics), anticoagulation, and
wound care. Unplanned patient telephone calls were received in 6.3% of
admissions; 5.8% of acute admissions required an unscheduled staff home
attendance; 4.2% of episodes resulted in a return to hospital, of which 2.6%
required continued care in hospital; 2.2% of episodes resulted in a return to
hospital within 14 days of discharge for a related problem. The rate of
iatrogenic adverse events was 3.5%. CONCLUSIONS: HIH care is very safe. This
study may help define safety standards for HIH care so that future studies can
compare them with those of traditional inpatient care.
PMID- 9549536
TI - Infant pertussis deaths in New South Wales 1996-1997.
AB - Since 1996, south-eastern Australia has been experiencing a pertussis epidemic
which has resulted in the deaths of several infants, including four from NSW in
the 12 months to July 1997. All were less than six weeks of age and died from
overwhelming cardiovascular compromise despite intensive care support. This
excessive infant mortality from a preventable disease demonstrates the need for
better pertussis immunity in the community and for erythromycin treatment of all
suspected cases and family contacts, especially infants.
PMID- 9549537
TI - Towards an improved and more cost effective health system for Australia.
AB - A new health system is proposed, based on the best aspects of the current system
but with built-in incentives for containing costs. Universal cover is retained
and access to the hospital system is improved. The division of health
responsibilities between Federal and State governments is greatly simplified and
the proposed system could be readily implemented.
PMID- 9549538
TI - Unemployment and health: the healthcare system's role.
AB - Experts from the South Western Sydney Area Health Service and the University of
New South Wales say there are few reports of healthcare interventions to address
the impact of unemployment on health. They outline possible strategies, which
include providing accessible and appropriate healthcare; developing the
healthcare system's capacity to deal with the health problems of unemployed
people; collaborating with other agencies and sectors working on this issue;
acting as an advocate for unemployed people; undertaking research; and providing
training, work experience and employment opportunities within the healthcare
system. Long term solutions lie in increasing employment and training
opportunities. Nevertheless, there is a clear role for the healthcare system in
reducing the health impacts of unemployment and ensuring that poor health does
not act as a barrier to returning to work.
PMID- 9549539
TI - Death is a journey to be undertaken.
PMID- 9549540
TI - Assessing and managing old age psychiatric disorders in community practice.
PMID- 9549541
TI - Brain tumours and mobile phones?
PMID- 9549542
TI - Brain tumours and mobile phones?
PMID- 9549543
TI - Brain tumours and mobile phones?
PMID- 9549544
TI - Brain tumours and mobile phones?
PMID- 9549546
TI - Reproductive medicine and the social state of childlessness.
PMID- 9549547
TI - Dwindling supplies of anti-D.
PMID- 9549548
TI - Dwindling supplies of anti-D.
PMID- 9549549
TI - A study of 100 anabolic-androgenic steroid users.
PMID- 9549550
TI - Copper-salicylate gel for pain relief in osteoarthritis.
PMID- 9549551
TI - A mnemonic for thrombophilia screening tests.
PMID- 9549553
TI - Zinc: a critical nutrient in growth and development.
PMID- 9549552
TI - The choice of antibacterial drugs.
PMID- 9549554
TI - Social inequality and general practitioner utilisation: assessing the effects of
financial barriers on the use of care by low income groups.
AB - AIMS: To evaluate the extent to which financial barriers are still important
deterrents to the utilisation of primary care by low income groups and to examine
whether the willingness of patients to switch doctors is associated with ability
to pay. METHOD: A practice and a population survey was used to compare the
importance of price barriers, patient satisfaction and utilisation rates in two
low income areas of Christchurch. Comparisons are made on the basis of gender,
age, perceived health status, housing tenure, benefit status, income and
ethnicity. RESULTS: Despite the introduction of the Community Services Card,
delays in using services because of the cost of care remain significant for many
groups of patients, including cardholders themselves. The removal of price
barriers at the free clinic raised utilisation rates for all groups. Patterns of
use at the free clinic show a consistent inverse relationship between income and
consultation rates. However, this was not evident among patients in the
population sample who continued to use fee-for-service providers. Further, the
results do not support arguments that patients are insensitive to price when
changing their doctors. CONCLUSIONS: Despite the removal of part-charges for
children, financial barriers remain significant for many low income adults. To a
large extent these barriers reflect the nature of welfare reform, particularly
the detrimental effects of pro-market housing policies in limiting the disposable
incomes of poorer New Zealanders.
PMID- 9549555
TI - Compliance with guidelines for the investigation and management of patients with
suspected pulmonary embolism at Christchurch Hospital.
AB - AIMS: (1) To assess the level of compliance of clinicians at Christchurch
Hospital with published local guidelines for the diagnostic management of
indeterminate lung scans and for the treatment of pulmonary embolism. (2) To
evaluate diagnostic outcomes and the methods used to arrive at the diagnosis.
METHODS: Retrospective case analysis of 94 consecutive cases of suspected
pulmonary embolism referred for a lung scan after August 1993 and a further 70
consecutive cases referred after August 1995. RESULTS: Few clinicians followed
the recommendations for the further assessment of indeterminate lung scans.
Pulmonary angiography was rarely performed and serial femoral ultrasound was
never employed. The majority of patients diagnosed with pulmonary embolism did
not have a high probability ventilation/perfusion (VQ) scan or a pulmonary
angiogram to support the diagnosis. The use of heparin was overcautious and
inconsistent. Major divergences from recommendations were observed in over 50% of
cases in which heparin was used to treat pulmonary embolism. CONCLUSIONS: This
audit has uncovered a wide diversity of practice in many aspects of the
assessment and management of pulmonary embolism and significant deviations from
the published guidelines. Underutilisation of objective imaging methods for
establishing the diagnosis implies overreliance on clinical impressions, which
are known to be unreliable. A review of the guidelines and further educational
initiatives are indicated.
PMID- 9549556
TI - The cost of childhood immunisation in general practice.
AB - AIM: To estimate the cost, to general practices in the Wellington Immunisation
Network, of the audit process of recalling and immunising children according to
the New Zealand Immunisation Schedule. METHOD: Practices recorded all clinical
and clerical time spent on immunisation as well as the materials used throughout
one audit cycle. Staff time and materials were costed directly. Practice
overheads were apportioned to immunisation according to the actual time spent on
each of the tasks relating to immunisation relative to the total staff hours at
the practice. RESULTS: The average cost of immunising a child who attended a non
capitated practice after a single reminder or recall was $15.15. The cost to the
practice after taking the practice nurse subsidy and GMS into account was $8.51.
The cost of immunising children who were not immunised at the first recall
increased in proportion to the number of recall reminders. The annual average
cost of immunisation to practices in the study exceeded the revenue obtained from
the Immunisation Benefit. CONCLUSION: Overall, given the frequency of recall
reminders, there was a net cost to practices for childhood immunisation after
deducting the current immunisation benefit rate of $9.78 excluding GST. Thus, the
practices in this study made a "loss" in carrying out childhood immunisations.
PMID- 9549557
TI - A complaints management system: strengths and weaknesses.
AB - AIMS: To describe the complaints management process in a base hospital and to
outline its guiding principles. METHOD: A review and analysis of the complaints
lodged during 1996 with the Complaints Management System of the hospital.
RESULTS: There were 146 complaints lodged after 132,400 patient contacts. Overall
resolution time was 14 days, but 24 appeals were lodged against the initial
opinion and were all subsequently resolved satisfactorily. CONCLUSION: The
complaints process should be user friendly, result in a quick response and be
seen as a quality rather than a disciplinary tool.
PMID- 9549558
TI - Monitoring of health research by ethics committees.
AB - AIMS: All health related research carried out within New Zealand requires
appraisal from an accredited ethics committee. The purpose of this project was to
pilot an active monitoring programme and to assess the effectiveness of such a
programme for future monitoring by ethics committees. METHODS: In this
qualitative study interviews were undertaken by representatives from the
Wellington and Manawatu-Whanganui ethics committees with principal investigators
for sixteen research proposals which had been given ethical approval from the
appropriate ethics committee. Issues discussed during the interviews included the
protocol and any changes to the methods or research personnel, recruitment of
participants, issues arising from informed consent, reporting of adverse events,
funding and payment to researchers. Researchers were given the opportunity to
provide feedback on the ethical review process and suggestions for improvement.
RESULTS: The most significant deviation from the approved protocol concerned
access to patient information. Some minor discrepancies between the approved
protocols and subsequent research undertaken and the requirements for extending
ethical approval of projects beyond the initial approval date were also
discussed. CONCLUSIONS: The monitoring programme fulfilled an educational role,
providing an opportunity for information sharing between ethics committees and
researchers. An active monitoring programme by an ethics committee can detect
deviations from the approved protocol beyond the current requirements for
researchers to provide annual progress reports. Future monitoring should include,
where relevant, access to consent forms and patients' notes.
PMID- 9549559
TI - Ticlopidine induced agranulocytosis managed with granulocyte colony stimulating
factor.
PMID- 9549561
TI - Sporadic amoebic liver abscess in the North Island.
PMID- 9549560
TI - Staphylococcus aureus highly resistant to mupirocin is now common in Auckland.
PMID- 9549562
TI - Strongyloides stercoralis and severe pre-eclampsia.
PMID- 9549563
TI - The hematological responses of rats exposed to conditions of simulated
microgravity and acute exercise.
AB - BACKGROUND: Although humans have experienced microgravity since 1961, it is
unknown whether PaO2 or PaCO2 will change in humans or in animals exposed to
similar conditions. Reports from subjects participating in long-term head down
tilt studies indicate that PAO2 will decrease and PaCO2 will increase, presumably
because of impairments in oxygen delivery and carbon dioxide transport. To
investigate this topic with suspended (HDS) rats, we hypothesized that 14 d of
HDS would lower resting PaO2 and elevate PaCO2 pressures when compared with
control rats. Since returning astronauts, previously bed rested subjects, and
suspended rats had exhibited decreases in maximum aerobic capacity, we predicted
after 2 weeks of HDS, rats performing maximum exercise would demonstrate
significant decreases in PaO2 and elevations in hydrogen ions. RESULTS: Blood gas
results during HDS indicated PaO2 and PaCO2 partial pressures were significantly
decreased during the first week of suspension. Maximal exercise significantly
increased PaO2 pressures in both animal groups, but during exercise the suspended
rats exhibited significant increases in lactic acid and hydrogen ion
concentrations when compared with control animals. CONCLUSIONS: The suspended rat
model effectively characterized PaO2 changes that have been reported for humans
exposed to conditions of simulated microgravity. However, the decreases in VO2max
reported for exercising humans and animals could not be explained by PaO2 changes
and the rat model was not effective in predicting changes in blood PaCO2.
RECOMMENDATIONS: NASA should encourage and support studies that characterize PaO2
and PaCO2 change in humans and animals, in space and after they return to a 1-G
environment.
PMID- 9549564
TI - Pulmonary capillary blood volume during lower body negative pressure: effect of
gender.
AB - BACKGROUND: The purpose of this study was to examine the changes in pulmonary
capillary blood volume (VC) in men and women during lower body negative pressure
(LBNP). Additionally, the components of lung diffusion capacity were measured and
evaluated for the effect of gender and LBNP. METHODS: There were 6 men and 6
women who underwent a staged LBNP protocol to -40 mm Hg. The diffusion of the
lung for carbon monoxide (DLCO) was determined at two levels of inspired oxygen
(21% and 60%). DLCO was separated into the diffusion capacity of the membrane
(DLM) and the diffusion capacity of blood. RESULTS: During supine rest, DLCO
values for men were larger than for women and were 39.8 +/- 3.8 and 32.2 +/- 2.2
ml.min-1.mm-1 Hg, respectfully. DLCO decreased equally with each stage of LBNP
for men and women. VC during supine rest was greater for men (131 +/- 8 ml) than
for women (92.7 +/- 7 ml). VC also declined with each stage of LBNP, and the
decline was similar for men and women. DLM did not change with LBNP. CONCLUSION:
The decrease in DLCO with LBNP is due to the reductions in thoracic blood volume
in both men and women. These thoracic blood volume changes do not explain the
previously reported reduced tolerances to LBNP for women because the reductions
in thoracic blood volume were similar for men and women.
PMID- 9549565
TI - The effects of moderately elevated ambient carbon dioxide levels on human
physiology and performance: a joint NASA-ESA-DARA study--overview.
PMID- 9549566
TI - The influence of CO2 in a space-like environment: study design.
AB - For the operation of manned spacecraft, the removal of CO2 from the cabin
atmosphere, produced by its inhabitants, is essential. This is accomplished by
chemical absorption in a gas processing unit, a process which requires energy and
consumables. Therefore, in terms of resource management, the CO2-level should be
kept as high as possible. Otherwise, considering crew health and performance and
also the interference with life science experiments, the CO2 load should be as on
Earth, close to zero. In order to obtain more information about the permissible
CO2 level for future space missions and also to clarify Space Station design
criteria, NASA-ESA-DARA have initiated a ground-based simulation study with two
different CO2 levels: 0.7% (first campaign) and 1.2% CO2 (second campaign). For
this study the deep diving facility of DLR was used to provide atmospheric
control and long-term habitation for the test subjects in studying the effect of
increased CO2 on physiological and psychological functions. A number of
experiments were implemented, which tested selected effects of raised CO2 on
humans. Four male subjects stayed in the chamber for 26 d in each campaign, in
order to perform the different tests in repeated trials, with the aim of
evaluating possible long-term effects. CO2 was controlled by absorption with soda
lime, flushing with fresh air and the addition of CO2, if necessary. Essentially,
the CO2 produced by the subjects was used to maintain the level at 0.7 and 1.2%,
respectively. Basic control of CO2 was carried out in the soda lime container of
the Life Support System. In order to maintain the required level, the amount of
gas flowing through the soda lime could be adjusted by a remote controlled
bypass. With this set-up it was possible to keep CO2 at an average level between
0.67 and 0.73% in the first campaign and between 1.17 and 1.23% in the second
campaign. The results of the experiments support the current CO2 limits for space
operations, insofar as values around 1% do not impose any severe restrictions to
human habitation for at least several weeks, whereas life sciences experiments
especially sensitive to CO2 influences have to be carefully evaluated for
possible interferences.
PMID- 9549567
TI - Effects of elevated carbon dioxide environment on calcium metabolism in humans.
AB - BACKGROUND: Chronic respiratory acidosis induced by an elevated carbon dioxide
(CO2) environment should provoke hypercalciuria with related total body and
subsequent bone calcium losses. We examined this hypothesis in four healthy male
volunteers, who were exposed during a 25-d period to an 0.7% CO2 environment
within a deep diving isolation chamber. Three months later the same subjects were
reexamined during a second campaign being exposed to a 1.2% CO2 atmosphere.
METHODS: The subjects received a constant calcium intake (1.4 g.d-1) and vitamin
D supplement (1000 IU.d-1) during both campaigns. Calcium balance (oral calcium
intake minus urinary and fecal calcium output) was evaluated. Serum calcium
concentrations and biomarkers of bone metabolism were measured, in order to
evaluate bone turnover. Additionally, the response to an acute oral calcium load
was examined as a sensitive measure of changes in calcium metabolism. RESULTS:
Both, urinary calcium excretion (from 245 +/- 38 to 199 +/- 31 mg.d-1; mean +/-
SE, 0.7% and 1.2%, respectively) and fecal calcium losses (from 1229 +/- 128 to
996 +/- 62 mg.d-1) were significantly reduced in the higher (1.2%) CO2
atmosphere. Although more calcium was retained in the body during the 1.2% than
during the 0.7% CO2 campaign, serum calcium concentrations and biomarkers of bone
formation were significantly lower in the higher CO2 campaign. Furthermore, bone
resorption was slightly increased in the 1.2% experiment. CONCLUSION: Elevated
CO2 atmosphere may dose-dependently preserve body calcium without a parallel
improvement of bone substance.
PMID- 9549568
TI - Effects of sustained low-level elevations of carbon dioxide on cerebral blood
flow and autoregulation of the intracerebral arteries in humans.
AB - Cerebral blood flow velocity (CBFv) was measured by insonating the middle
cerebral arteries of four subjects using a 2 Mhz transcranial Doppler. Ambient
CO2 was elevated to 0.7% for 23 d in the first study and to 1.2% for 23 d in the
same subjects in the second study. By non-parametric testing CBFv was elevated
significantly by +35% above pre-exposure levels during the first 1-3 d at both
exposure levels, after which CBFv progressively readjusted to pre-exposure
levels. Despite similar CBFv responses, headache was only reported during the
initial phase of exposure to 1.2% CO2. Vascular reactivity to CO2 assessed by
rebreathing showed a similar pattern with the CBFv increases early in the
exposures being greater than those elicited later. An increase in metabolic rate
of the visual cortex was evoked by having the subjects open and close their eyes
during a visual stimulus. Evoked CBFv responses measured in the posterior
cerebral artery were also elevated in the first 1-3 d of both studies returning
to pre-exposure levels as hypercapnia continued. Cerebral vascular autoregulation
assessed by raising head pressure during 10 degrees head-down tilt both during
the low-level exposures and during rebreathing was unaltered. There were no
changes in the retinal microcirculation during serial fundoscopy studies. The
time-dependent changes in CO2 vascular reactivity might be due either to
retention of bicarbonate in brain extracellular fluid or to progressive increases
in ventilation, or both. Cerebral vascular autoregulation appears preserved
during chronic exposure to these low levels of ambient CO2.
PMID- 9549570
TI - The history of the United States Navy flight surgeon/naval aviator program.
AB - Early in the history of aviation the need for a special kind of physician who
could understand the physical and psychological problems encountered by flyers
was well recognized. These physicians were called flight surgeons. In 1922, RADM
W. A. Moffett, USN, the first Chief of the Bureau of Aeronautics and the "Father
of Naval Aviation," called for a group of Navy medical officers to be trained as
flight surgeons. He believed that all Navy flight surgeons should be trained as
pilots "primarily in order that they may experience the emergencies and
conditions that arise in flying." This article traces the history of the Navy
flight surgeon/naval aviator. It chronicles the evolution of the Navy's flight
surgeon/naval aviator program from the World War I doctor who flew seaplanes at a
Naval Air Station in Italy to the present day flight surgeon/naval aviator who
flys operational and test aircraft as a research pilot.
PMID- 9549569
TI - Carotid artery dissection presenting as a painless Horner's syndrome in a pilot:
fit to fly?
AB - We describe a case of a middle-aged Caucasian pilot who presented to us with a
painless left Horner's syndrome due to a focal dissection of the infra-petrous
portion of the ipsilateral internal carotid artery. He did not suffer symptoms of
cerebral ischemia at the time of onset, or during the following 2 yr. The
Horner's syndrome persisted unchanged throughout follow-up. Serial magnetic
resonance angiograms showed some regression of the focal stenosis at 12 mo, with
no further change over the next 10 mo. The literature suggests that the risk of
stroke after onset of dissection is usually in the first month, and the risk of
recurrence of dissection is about 1% per year after the first year. Our patient
was prescribed aspirin 300 mg.d-1, and certified to fly as or with a co-pilot
commencing 1 yr after onset of his symptoms.
PMID- 9549571
TI - Test your knowledge of brain lesions and aeromedical certification.
PMID- 9549572
TI - A far from routine mission.
PMID- 9549573
TI - GZ-induced neck injuries.
PMID- 9549574
TI - Cementless primary total hip replacement. Four to eight year results with the
Zweymuller-Alloclassic prosthesis.
AB - One hundred and twenty-nine consecutive cementless primary total hip
arthroplasties with Zweymuller-Alloclassic grit-blasted titanium components were
evaluated prospectively at an average follow-up of 5.9 years. The clinical
results were graded as excellent or good in 116 hips (90%), fair in 12, and poor
in one due to a fracture of the femoral shaft at operation leading to early stem
loosening and delayed ring loosening. Failure was defined as definite aseptic
loosening, and the final survivorship at 8 years was 99.3% for the SL-stem, and
99.1% for the CSF-threaded cup. These early results compare favourably with those
of total hip arthroplasties using new cementing techniques.
PMID- 9549575
TI - Prophylaxis for deep vein thrombosis with aspirin or low molecular weight dextran
in Korean patients undergoing total hip replacement. A randomized controlled
trial.
AB - 150 Korean patients undergoing primary uncemented total hip replacement were
randomized into 3 treatment groups for deep vein thrombosis (DVT) prophylaxis.
Group A(50) were controls; Group B(50) received aspirin 1.2 g daily in 3 divided
doses from 2 days before, to 14 days after surgery; Group C(50), received low
molecular weight dextran 500 ml, infused intravenously at 50 ml/hour during
surgery, and on each of the following 2 days. Contrast venograms were performed
prior to surgery and 7-10 days after. The incidence of DVT was 20% in the control
group, 12% in the aspirin group (p < 0.1 vs control), and 6% in the dextran group
(p < 0.05 vs control). In patients developing DVT, the ratio of proximal to
distal thrombi was increased in the control group as compared to treated groups
(4:1 in the control group vs 1.5:1 in the treated groups). Both aspirin and
dextran were well tolerated. Obesity (p < 0.05) and long-term administration of
steroids (p < 0.05) were risk factors for deep vein thrombosis which reached
statistical significance in the control group. Intraoperative venograms performed
on 10 patients, showed that hip flexion (mean 40.4 degrees) plus adduction (mean
11.5 degrees) plus internal rotation (mean 81.5 degrees), resulted in severe
twisting or kinking of the femoral vein with stagnation of blood flow. Low
molecular weight dextran significantly reduce the incidence of deep venous
thrombosis and aspirin, though less effective, had a similar effect.
PMID- 9549576
TI - Structural changes in blood vessels entering the growth plate during growth in
rats.
AB - We observed the structural changes in blood vessels entering the growth plates of
the femur and tibia of rats during growth using scanning electron microscopy. The
penetrating vessels had blind endings which were bulbous at a time when rats
showed rapid skeletal development. With subsequent slowing of development, the
density of the vessels decreased and the blind endings became short stumps. These
changes were more prominent in the proximal femur than in the distal femur and
proximal tibia. The present study indicates an intimate relation between
endochondral ossification in the growth plate and the structure of the
penetrating vessels.
PMID- 9549577
TI - Malignant giant-cell tumours of bone. Clinico-pathological types and prognosis: a
review of 29 cases.
AB - Twenty-nine patients with malignant giant-cell tumours of bone (GCT) were
followed-up for between 6 months and 18 years. Seventeen of the tumours were
primary and 12 were due to malignant degeneration of initially benign lesions.
The clinical features did not differ from those of benign GCT, except for a
higher incidence in the distal tibia and sacrum. Anaplastic GCTs were included in
the study because their clinical and radiographic features and prognosis were no
different from those of the GCT grade III of Jaffe. Eighteen of the tumours were
grade III, and 11 were anaplastic. This retrospective study was intended to
assess the effects of chemotherapy and surgery for malignant GCT. Three treatment
groups were selected, in which treatment was either by surgery alone, surgery
plus chemotherapy, or radiotherapy alone.--The prognosis was poor and the 5 year
tumour-free survival rate in the series was 50%. The prognosis was the same for
primary as for secondarily malignant tumours. There was no statistical difference
in survival between malignant grade III and anaplastic malignant tumours. The one
year survival rate for patients treated by chemotherapy and surgery was
statistically higher (chi2 test) than for persons treated by surgery alone.
However, the five-year survival rate and the actuarial survival curves were not
statistically different in the two groups (log rank test).--Chemotherapy appears
to be of some value in the treatment of these malignant tumours but a larger
series is required to confirm the efficacy of this approach.
PMID- 9549578
TI - Expanding prostheses in conservative surgery for lower limb sarcoma.
AB - Conservative resection of bone sarcoma in the lower limbs in children is very
likely to be followed by a progressive problem of leg length inequality resulting
from removal of the growth cartilage. To overcome this we have been using an
expanding prosthesis and we report our experiences during the period 1985-1996.
The prostheses are made of titanium and comprise 3 parts: an articular component,
an expanding mechanism, and tibial and femoral stems. The degree of possible
lengthening of the prostheses is virtually unlimited, and they can be inserted in
children of 5 or more years of age. We report the use of 28 prostheses in
patients aged from 5 to 18 years, of which 4 were tibial, 5 total femur, and 16
distal femur. There were 6 Ewing's sarcoma, 21 osteosarcoma, and 1 synovial
sarcoma. The average follow-up was for 5 years. Five patients died from their
disease, and 21 benefited from an average lengthening of 2.6 cm (range: 2 mm-120
mm). Using the Societe Europeenne des Tumeurs Osseouses (EMSOS) criteria, the
functional results were excellent or very good in 16, fair in 7 and bad in 5.
Five patients developed an infection; one required amputation and the others
received a new expanding prosthesis. We conclude that an expanding prosthesis is
an excellent alternative to amputation in young children. However, the risk of
infection associated with repeat surgery has led us to develop a prosthesis which
can be lengthened externally, without the need for reopening the wound.
PMID- 9549579
TI - Treatment of chronic osteomyelitis using the Papineau technique.
AB - From 1984 to 1994, 41 cases of chronic osteomyelitis were treated in Kinshasa by
the Papineau technique; 75.5% were men and 24.5% women. The mean age was 28 years
(range: 7-77), and the average duration of the infection was 3 years (range: 1
month to 28 years). The aetiology was "trauma" in 53.5%, haematogenous in 44% and
drepanocytosis in 2.5%. Infections of the femur and tibia each constituted 41.5%
of the cases. Immobilisation was by external fixation in 44%, and by a cast in
39%. Wound healing was complete after an average of 3 months with spontaneous
healing, and in 4.5 months after skin grafting. Control of the infection and bone
healing were obtained in 89% after a period of 3-7 months. We discuss the
Papineau technique and the modifications which were required in Kinshasa.
PMID- 9549580
TI - Primary pyogenic abscess of the psoas muscle.
AB - During a six-year period, eleven persons with primary pyogenic abscess of the
psoas muscle were treated at the Mackay Memorial Hospital. Five were males and
six were females and their average age was 47.2 years (range 6-83 years). The
abscess was identified by CT in 7 patients, MRI in 2 and ultrasonography in 1.
One abscess was found during laparotomy. Treatment included extraperitoneal
drainage of the abscess in 7 patients and CT guided aspiration in 3. One patient
improved after antibiotic therapy and they all recovered after treatment. The
diagnosis of primary pyogenic abscess requires a high index of suspicion and the
best treatment is early operative drainage and administration of systemic
antibiotics.
PMID- 9549581
TI - Experimental model of multidirectional disc hernia in rats.
AB - We have carried out an experimental investigation of lesions of the
intervertebral disc produced by flexion, lateral bending and rotational forces in
an attempt to produce disc herniations. Adult Wistar rats were divided into 4
groups: control and posterior, lateral and rotational herniation. There were 10
rats in each group. The tail between the 5th and 8th vertebral segments was used.
A Kirschner wire was inserted into each of 2 adjacent vertebrae and the movement
produced had an apex which was anterior or lateral depending on the group
involved. Variables such as rupture of the annulus, the cellularity of the
nucleus pulposus and the site of the lesion in the disc were studied
histologically. The height of the disc, the protrusion, the thickness, and the
surfaces of the annulus fibrosus and the nucleus pulposus were measured. In every
case we found a nuclear displacement which did not become a protrusion. The
surface parameters and the cellularity of the nucleus pulposus are most useful
indicators and should be included in any study examining the disc after the
injection of substances for treatment.
PMID- 9549582
TI - Stimulation of bone formation by intraosseous injection of basic fibroblast
growth factor in ovariectomised rats.
AB - The effect on intraosseous bone formation of a single local injection of
recombinant human basic fibroblast growth factor into trabecular bones was
examined in ovariectomised osteoporotic rats. Fibroblast growth factor (400
micrograms), or the vehicle alone, was injected into the ilium at 16 weeks after
ovariectomy or a simulated operation. Bone mineral density in the ovariectomised
rats increased to a level similar to the latter at 2 weeks and reached a maximum
at 8 weeks. After 8 weeks, BMD decreased slowly and the value at 24 weeks was
still higher than that in the ovariectomised rats. Fibroblast growth factor
stimulated osteoid formation in the first 2 weeks, bone volume reaching a peak at
8 weeks. From 8 to 12 weeks, bone resorption increased, resulting in decreases in
bone volume to the levels of the group with simulated operations at 24 weeks.
Structural analysis at 8 and 24 weeks showed that ovariectomy decreased the
continuity of trabeculae and the injection of fibroblast growth factor restored
it to levels higher than, or equal to, those who had the simulated operation. The
present study demonstrated that intraosseous fibroblast growth factor given to
ovariectomised rats restored bone volume and quality to the levels of the rats
who had a simulated operation only.
PMID- 9549584
TI - The disappearing exostosis? A report of an unusual case.
AB - A girl aged 11 years was referred to us with a medial upper right tibial
exostosis. As the lesion was asymptomatic, surgery was not undertaken. The
patient defaulted from follow up, and, when reviewed 32 months later, there was
no clinical or radiographic evidence of the exostosis. Spontaneous involution of
an exostosis may occasionally occur in childhood.
PMID- 9549583
TI - Isolation and differential secretion of metalloproteinase by superficial
chondrocytes in articular cartilage.
AB - Chondrocytes from superficial layers of articular cartilage have distinct
phenotypic properties which are different from those of cells obtained from the
deeper areas. We describe a method that isolates highly purified articular
cartilage chondrocytes from the superficial layers. When the superficial cells
are stimulated in vitro with a source of cytokines, they secrete greater amounts
of metalloproteinase compared to chondrocytes obtained from a deeper area.
PMID- 9549585
TI - Fracture of the upper radius with ipsilateral dislocations of the elbow and
superior radio-ulnar joints. A case report.
AB - We report the rare combination of a closed fracture of the upper third of the
radius with ipsilateral posterior dislocation of the elbow joint and disruption
of the superior radio-ulnar joint. Although in the Bado classification there is a
fourth type that describes fractures of both radius and ulna with dislocation of
the superior radio-ulnar joint, it does not include the injury we report. We
review of the literature and put forward an extension of Bado's classification so
that fractures of either, or both, the radius and ulna associated with
pericubital dislocations will be included.
PMID- 9549586
TI - Simultaneous anterior dislocation of the shoulder and fracture of the ipsilateral
humeral shaft. Two case reports.
AB - Two patients with anterior dislocation of the shoulder and ipsilateral fracture
of the shaft of the humerus have been studied and the mechanism of their injuries
has been documented. Closed reduction of the dislocations was performed under
anaesthesia during surgery for humeral fixation with a dynamic compression plate.
The fractures and dislocations healed without any problems at 6 to 9 months
postoperatively. At recent follow-up, one patient had returned to work and
regained normal mobility. The other patient had the sequelae of a brachial plexus
injury. The literature on this subject is reviewed.
PMID- 9549587
TI - Assessment of International Psychogeriatrics: the Journal of the International
Psychogeriatric Association.
AB - In 1996, new editorial management took over International Psychogeriatrics (IP),
only a year after the frequency of its publication increased from semiannual to
quarterly. At the request of the editorial board, an assessment of the journal
was conducted by comparing it to other journals in the field of geriatrics and,
specifically, geriatric psychiatry. The evaluation included both a modified
citation analysis and a review of journal content. The study was undertaken in
order to identify the position the journal has within its discipline. Further, it
was to identify the journal's strengths and weaknesses with the overall goal of
recommending changes to IP's current content and format. IP ranked seventh of 15
journals in terms of impact factor. It is primarily oriented towards the
publication of original research, and features fewer longer articles than others
in the field. Adding a wider variety of content may increase the overall interest
in the journal. However, these changes must be weighed against the goals of the
journal and its reputation as a source of original research in the field of
geriatrics.
PMID- 9549588
TI - A detailed phenomenological comparison of complex visual hallucinations in
dementia with Lewy bodies and Alzheimer's disease.
AB - Visual hallucinations (VH) are a core feature of dementia with Lewy bodies (DLB),
but little is known about their phenomenology. A total of 73 dementia patients
(42 DLB, 30 Alzheimer's disease [AD], 1 undiagnosed) in contact with clinical
services were assessed with a detailed standardized inventory. DLB was diagnosed
according to the criteria of McKeith and colleagues, AD was diagnosed using the
NINCDS-ADRDA criteria. Autopsy confirmation has been obtained when possible. VH
were defined using the definition of Burns and colleagues. Detailed descriptions
of hallucinatory experiences were recorded. Annual follow-up interviews were
undertaken. The clinical diagnosis has been confirmed in 18 of the 19 cases that
have come to autopsy. A total of 93% of DLB patients and 27% of AD patients
experienced VH. DLB patients were significantly more likely to experience
multiple VH that persisted over follow-up. They were significantly more likely to
hear their VH speak but there were no significant differences in the other
phenomenological characteristics including whether the hallucinations moved, the
time of day that they were experienced, their size, the degree of insight, and
whether they were complete. VH may be more likely to be multiple, to speak, and
to be persistent in DLB patients. These characteristics could potentially aid
accurate diagnosis.
PMID- 9549589
TI - Can neuroimaging techniques identify individuals at risk of developing
Alzheimer's disease?
AB - Recent studies indicate that neuroimaging techniques such as magnetic resonance
imaging, positron emission tomography, and single-photon emission computed
tomography can accurately differentiate patients with Alzheimer's disease (AD)
from elderly controls. This report reviews the results of neuroimaging studies of
two at-risk populations: subjects with the epsilon 4 allele of the apolipoprotein
E and those with mild cognitive impairment. The results of the work published to
date indicate that the presence of the epsilon 4 allele is a risk factor for AD
and that its predictive validity can be enhanced by neuropsychological and/or
neuroimaging evaluation. The results also show that patients with mild cognitive
impairment display a number of structural and functional imaging abnormalities
that are more pronounced in the temporal and parietal lobes. We suggest that the
use of neuroimaging techniques can improve the detection of subjects early in the
course of AD, although the sensitivity and the specificity of this approach still
await a more detailed prospective evaluation.
PMID- 9549590
TI - Efficacy of psychosocial treatments for noisemaking in severe dementia.
AB - Noisemaking is one of the most disturbing behavior disorders associated with
dementia. Standard management practices, including pharmacological interventions,
are not very successful in treating the behavior. Very little research has been
carried out to evaluate innovative treatments or to determine the etiology of
noisemaking. In this article, we report on a series of 12 case studies in which
we tested the efficacy of some psychosocial interventions in reducing the
frequency of noisemaking in long-term-care residents with severe dementia.
Interventions were contingent reinforcement of quiet behavior and environmental
stimulation tailored to individual preferences. Of the 12 patients recruited into
the study, 2 died during the course of observations, 3 were not observed to be as
noisy as reported by staff, and 3 showed a clear reduction in noise during the
intervention period. Four patients did not show any overall reduction in
noisemaking during psychosocial interventions. Future research could
differentiate between types of interventions in successful cases and attempt to
control further for the consistent application of interventions by long-term-care
staff.
PMID- 9549591
TI - Effect of a program of diverse activities on disturbed behavior in three severely
demented patients.
AB - The effects of a daily program of various activities on disturbed behavior were
studied prospectively in three patients with severe dementia. Prior to the study,
patients had not responded to treatment with benzodiazepines and/or neuroleptics.
The study consisted of three periods, each lasting for 4 weeks: i.e., baseline,
intervention, and follow-up. During each period, behavior was assessed by means
of observation scales: GIP, SDAS, and CGI. Psychotropic medication was held as
constant as possible. During intervention, the patients took part in a program of
activities, including group, musical, physical, and social activities. During
baseline and follow-up, patients followed the regular ward activities. The
patients showed different responses, probably related to personal interests.
Possible implications for the treatment of patients with dementia, complicated by
disturbed behavior, and suggestions for future research are discussed. The
enthusiasm of the nursing staff dealing with these patients was a promising
result.
PMID- 9549592
TI - Clinical experience with risperidone, haloperidol, and thioridazine for dementia
associated behavioral disturbances.
AB - The efficacy and safety of risperidone, haloperidol, and thioridazine for
treating dementia-associated behavioral disturbances were evaluated in a
retrospective study of 186 patients aged 65 years or older with DSM-III-R or DSM
IV diagnoses of Alzheimer's dementia, senile dementia NOS, or organic brain
syndrome. Study patients were selected from the charts of 12,000 residents of 60
long-term-care facilities in New Jersey if they were treated with one of the
three agents for behaviors dangerous to themselves or others. The 186 selected
patients included 60 treated with risperidone (mean, 1 mg/day), 83 with
haloperidol (mean, 2 mg/day), and 43 with thioridazine (mean, 33 mg/day). Target
behaviors were violence (74 patients), shouting (31), delusions (26), paranoia
(19), pacing (3), and mixed behaviors (33). Target behaviors improved in 94% of
patients given risperidone, 65% given haloperidol, and 67% given thioridazine (p
< .001). Treatment failures (treatment discontinued in patients because of side
effects or no improvement) were more frequent in patients started on haloperidol
(28) or thioridazine (15) than on risperidone (3). Extrapyramidal symptoms were
reported in 7% of patients taking risperidone, 22% taking haloperidol, and 18%
taking thioridazine. Safe, effective doses are readily achieved with risperidone
but difficult to achieve with haloperidol or thioridazine because their effective
doses often cause unacceptable side effects. These data are only suggestive
because no guidelines exist for defining or measuring behavioral disturbances or
for how they are affected by social, psychological, or environmental factors.
PMID- 9549593
TI - Temporary institutional respite in dementia cases: who utilizes this form of
respite care and what effect does it have?
AB - In the studies on the effects of temporary institutional respite (TIR) published
to date, a slight reduction of subjective burden has been established. The hope
that this form of respite care might have a positive effect on the activities of
daily living or on the health of the care recipients has not yet been confirmed.
A considerable deficit in the methodology applied might be a reason for this.
There is no denying the fact that there is a clear need for respite services,
particularly because every seventh person providing care for a dementia patient
requiring personal care belongs to a high-risk group that is characterized by
serious reduction in his or her physical health and psychological well-being. TIR
is primarily utilized by adult child caregivers (daughters and daughters-in-law)
affected by high subjective burden who are providing care for dementia patients
with extensive nursing needs.
PMID- 9549594
TI - Factor structure of the Dementia Mood Assessment Scale in a cohort of community
dwelling elderly.
AB - We examined the factor structure of the 28-item Dementia Mood Assessment Scale
(DMAS), an instrument to assess depressive symptoms in older adults with
cognitive impairment, in a cohort of 165 community-dwelling elderly with varying
degrees of cognitive impairment. Factor analysis using principal components
analysis and varimax rotation was performed to explore the presence of subscales
and examine construct validity. A five-factor structure involving all 28 items
accounting for 63.2% of the variance in the DMAS scores was derived. Factors were
named: Depressed Affect, Environmental Interaction, Diurnal Patterns,
Agitation/Suspicion, and Somatic Indicators. This factor structure reflects the
often differing presentations of depressive symptoms in older adults with varying
degrees of cognitive function and establishes the construct validity of the DMAS
in this population. We conclude that the DMAS may be used for differentiated
clinical assessment of depressive symptoms along major dimensions of depressive
illness in this cohort of elderly.
PMID- 9549595
TI - Delusional parasitosis in the elderly: a review and report of six cases from
northern Finland.
AB - A patient with delusional parasitosis has a strong conviction of being infested
with parasites: for example, lice or worms. Such a patient is not satisfied with
assurances or test results that no parasites are present, but is so convinced
that he or she will go as far as to bring the parasites in "matchboxes" to a
physician. Subjectively worried, the patient may try to pick the parasites out of
the skin, causing cutaneous lesions and even ulcerations. The condition is
classified as a delusional/paranoid disorder, somatic type according to DSM-III
R. Not much is known epidemiologically of this rare disorder, which usually
affects older women who often are isolated socially. Therapy is regarded as
difficult, and a wide variety of treatment methods have been attempted. In this
article six female cases are presented, showing that a typical patient is an
elderly woman who has suffered losses or is socially isolated. These patients
lack deeper psychiatric insight into their problem, so they are mostly in the
care of nonpsychiatric physicians. Treatment with a low dose of high-potency
neuroleptics combined sometimes with antidepressants appears to be effective.
Reducing social isolation is also important.
PMID- 9549596
TI - Psychiatric manifestations of normal-pressure hydrocephalus: a short review and
unusual case.
AB - Normal-pressure hydrocephalus (NPH) is a common cause of potentially reversible
dementia. It can present with psychiatric manifestations that may hinder its
diagnosis. A 68-year-old man presented with a paranoid psychosis and mild
cognitive impairment, but not neurological signs or classic "triad." Gait
disturbance and urinary incontinence developed later in the course of illness
after the diagnosis of NPH had already been made on computed tomographic (CT)
scanning. A lumbo-peritoneal shunt was performed, followed by full remission of
psychotic symptoms, as well as considerable improvement in functioning,
continence, and gait. This case demonstrates the need to consider NPH when older
patients present with psychotic symptoms, particularly in the presence of
cognitive impairment, gait disturbance, or incontinence. The decision whether to
perform a shunting operation is often difficult, because selection of patients
with good prognosis is still inaccurate. CT scanning of the brain is an important
investigation in older patients presenting with both functional and organic
disorders.
PMID- 9549597
TI - The relationship between two scales measuring aggressive behavior among
continuing-care psychogeriatric inpatients.
AB - Aggressive behavior among the elderly is a neglected area of research. An 18-week
prospective study of aggressive behavior on a continuing-care psychogeriatric
ward provided data to examine the relationship between two aggression scales
(SOAS and RAGE). There was a strong and significant correlation between the SOAS
and RAGE scales for the total and the subscale scores. Both these scales appear
useful in measuring aggressive behavior among continuing-care psychogeriatric
inpatients. Also, the nursing staff can be trained to complete these scales
effectively.
PMID- 9549598
TI - Smoking and illicit drug use--a lesson yet to be learned.
PMID- 9549599
TI - Tobacco smoking and nicotine dependence: biological basis for pharmacotherapy
from nicotine to treatments that prevent relapse.
PMID- 9549600
TI - Neuropharmacological actions of cigarette smoke: brain monoamine oxidase B (MAO
B) inhibition.
AB - We measured the concentration of brain monoamine oxidase B (MAO B; EC 1.4.3.4) in
8 smokers and compared it with that in 8 non-smokers and in 4 former smokers
using positron emission tomography (PET) and deuterium substituted [11C]L
deprenyl ([11C]L-deprenyl-D2) as a radiotracer for MAO B. Smokers had
significantly lower brain MAO B than non-smokers as measured by the model term
lambda k3 which is a function of MAO B activity. Reductions were observed in all
brain regions. Low brain MAO B in the cigarette smoker appears to be a
pharmacological rather than a genetic effect since former smokers did not differ
from non-smokers. Brain MAO B inhibition by cigarette smoke is of relevance in
light of the inverse association between smoking and Parkinson's disease and a
high prevalence of smoking in psychiatric disorders and in substance abuse.
Though nicotine is at the core of the neuropharmacological actions of tobacco
smoke, MAO B inhibition may also be an important variable in understanding and
treating tobacco smoke addiction.
PMID- 9549601
TI - Cigarette smoking and major depression.
AB - The authors review recent literature that has demonstrated an association between
cigarette smoking behavior and major depression. Persons with major depression
are more likely to smoke and to have difficulty when they try to stop. When they
manage to succeed in stopping, such persons are at increased risk of experiencing
mild to severe states of depression, including full blown major depression. The
period of vulnerability to a new depressive episode appears to vary from a few
weeks to several months after cessation. This knowledge suggests a relationship
between smoking and depression that is complex, pernicious, and potentially life
long. It is recommended that cessation treatments incorporate screening
procedures that will identify those patients with a propensity to depression and
monitor the emergence of postcessation depression, particularly in those with a
history of depression.
PMID- 9549602
TI - Caffeine and nicotine use in an addicted population.
AB - This study was undertaken to examine differences in caffeine and nicotine use
between the psychiatric population and the addicted population in a private
psychiatric inpatient facility. Eighty-six patients on an adult addictive disease
inpatient unit and 80 patients on an adult psychiatry unit in a private
psychiatric hospital were interviewed with regard to their use of nicotine and
caffeine. In addition, demographic information and primary diagnoses were
obtained from the psychiatric admission assessment in the medical record as
listed by the admitting psychiatrist. Although there was little difference in
psychiatric patients vs. chemically dependent patients with regard to the
percentage of caffeine users, the chemically dependent individuals drank more
coffee, soft drinks, and tea. A much greater percentage of the chemically
dependent individuals also smoked cigarettes, although not in a greater amount
than the psychiatric patients who smoked. Because group assignment was not
random, ordinary least squares (OLS) regression analyses were conducted to
determine the independent associations of age, sex, education, and treatment
population in predicting levels of caffeine and tobacco use. Even after
controlling for demographic differences between the two samples, chemically
dependent patients still reported higher levels of daily caffeine and tobacco use
than patients on the general psychiatric unit.
PMID- 9549603
TI - Comorbid cigarette and alcohol addiction: epidemiology and treatment.
AB - The close association of nicotine addiction and alcoholism is well established.
As many as 80% of alcoholics smoke, and 30% of smokers are alcoholics. The
mortality from cigarette smoking and alcoholism individually is very high, as an
estimated 400,000 deaths from tobacco and 100,000 deaths from alcoholism are
reported annually. Cigarettes and alcohol interact to cause certain cancers,
e.g., head and neck. Only recently has attention been focused on the role of
tobacco in abstinent alcoholics. An important study found high rates of mortality
from tobacco in abstinent alcoholics in recovery. However, the mortality rates
from alcoholism were high and predominant. Of great importance is that studies
show that abstinence from alcohol essentially eliminates the premature deaths or
increased mortality rates from active alcoholism. Similar studies showing a
reduction in mortality from abstinence in nicotine addiction have not been
forthcoming. The importance of treating nicotine addiction, however, is clear to
reduce the high mortality rates from tobacco smoking in active or abstinent
alcoholics.
PMID- 9549604
TI - Tobacco, alcohol, and drug use in a primary care sample: 90-day prevalence and
associated factors.
AB - BACKGROUND: Primary care settings are an ideal system in which to identify and
treat substance use disorders. OBJECTIVE: To ascertain the prevalence of tobacco,
alcohol, and drug use in the office of 88 primary care clinicians by gender, age
and ethnicity. METHOD: 21,282 adults ages 18-65 completed a self-administered
Health Screening Survey while participating in a trial for early alcohol
treatment. RESULTS: The period prevalence of tobacco use was 27%. For alcohol:
abstainers 40%, low risk drinkers 38%, at-risk drinkers 9%, problem drinkers 8%,
and dependent drinkers 5%. Twenty percent of the sample reported using illicit
drugs five or more times in their lifetime and 5% reported current illicit drug
use. There were marked differences in alcohol use disorders by age and ethnicity.
The majority of persons who smoked reported the desire to cut down or stop using
tobacco. SIGNIFICANCE: This is the first report on the combined prevalence of
tobacco, alcohol and drug disorders in a large sample of persons attending
community-based non-academic primary care clinics. This report confirms the high
prevalence of these problems and suggests that patients will accurately complete
a self-administered screening test such as the Health Screening Survey. The
office procedures developed for this study provide Managed Care Organizations
with a system of care that can be used to screen all persons for tobacco, alcohol
and drug use disorders.
PMID- 9549605
TI - Incorporating nicotine dependence into addiction treatment.
AB - An addiction treatment program devoted two years to preparing to become a
smokefree treatment unit that addressed nicotine dependence as another drug
dependency. Data collected from September 1990 to July 1995 on 263 admissions
before becoming smokefree and 2182 admissions after making the transition
revealed that going smokefree did not affect the incidence of premature
discharges or aggressive behavior, and did not change the overall rate of program
completion by either smokers or nonsmokers. During the first three months after
going smokefree, the program completion rate dropped for both smokers and
nonsmokers; by the fourth month, it had returned to previous levels. Seventeen
months after going smokefree, the program completion rate was higher than it had
ever been. This suggests that the drop in the program completion rate was due to
the disruption caused by a significant programmatic change and not due to the
unit's smokefree status, and that the increasing experience of staff in treating
nicotine dependence resulted in improved patient outcomes.
PMID- 9549606
TI - Social anxiety and history of behavioral inhibition in young adults.
AB - To evaluate the relationship between the childhood temperament behavioral
inhibition (BI) and anxiety symptomology, we investigated differences in
retrospective reports of childhood BI among undergraduates reporting one of the
following: (a) Social anxiety (n = 10), (b) generalized anxiety (n = 13), (c)
both social and generalized anxiety (n = 15), and (d) minimal social and
generalized anxiety (n = 38). Contrary to the hypothesis that BI acts as a
nonspecific risk factor for anxiety symptoms, our findings revealed that a
history of childhood BI was associated with symptoms of social phobia but not
generalized anxiety disorder. Moreover, participants displaying symptoms of both
generalized anxiety disorder and social phobia were no more likely to show a
childhood history of BI than participants displaying social phobia symptoms
alone. These data suggest that a childhood history of BI may be more strongly
associated with adult social anxiety than some other types of anxiety pathology.
PMID- 9549607
TI - Posttraumatic stress disorder and comorbid major depression: is the correlation
an illusion?
AB - We have examined data from 107 motor-vehicle accident (MVA) victims with regard
to whether the presence of comorbid depression is important clinically, and with
regard to whether the threshold for diagnosing the comorbid depression should be
raised because of symptom overlap between posttraumatic stress disorder (PTSD)
and major depression. Of the 62 MVA victims who met the criteria for PTSD 1 to 4
months post-MVA, 33 also met the criteria for major depression, with 27 cases for
which the depression occurred post-MVA. A LISREL 8.12a analysis indicates that
PTSD and major depression are correlated, but independent, responses to trauma.
Those with PTSD and depression are more subjectively distressed, suffer more
major role impairment, and remit less readily over the first 6 months of
prospective follow-up than those with PTSD alone. The threshold for diagnosing
comorbid depression (5 or 6 depressive symptoms versus 7 to 9 depressive
symptoms) has no important effects on any of the indicators of "caseness."
PMID- 9549608
TI - Don't worry and beware of white bears: thought suppression in anxiety patients.
AB - The ability to suppress unwanted thoughts was investigated in patients with
Generalized Anxiety Disorder (GAD; n = 29), Speech Phobics (n = 25), and
nonanxious controls (n = 28). All participants spent 5 minutes thinking aloud
about anything that came to mind while trying not to think of white bears. In
another task, they thought aloud for 5 minutes while trying not to think of their
main worry. Intrusions of unwanted thoughts were signaled by button presses and
recorded on tape. In accordance with the disorder's definition and complaints of
the GAD patients, they showed more intrusions of their main worry than of white
bears. The opposite was true for other participants. Compared to a baseline
measure, all participant groups were unable to reduce duration of main worry
thoughts when trying to suppress them.
PMID- 9549609
TI - Posttraumatic stress disorder and work-related injury.
AB - The literature indicates a substantial overlap between chronic pain and
posttraumatic stress disorder (PTSD) symptoms in individuals who sustain
accidental injury. To date, however, there have been no studies of PTSD symptoms
in individuals who experience work-related injury. Consequently, we assessed 139
consecutive injured workers using the Modified PTSD Symptom Scale (Falsetti,
Resnick, & Kirkpatrick, 1993), as well as a number of general measures of
psychopathology. Most participants reported chronic pain and all were receiving
workers compensation. Results indicated that 34.7% and 18.2% of the sample
reported symptoms consistent with PTSD and partial PTSD, respectively. When PTSD
symptom frequency and severity were considered criterion variables in multiple
regression analyses, depression was found to be significantly associated with the
former and anxiety sensitivity, social fears, and somatic focus with the later.
Finally, these measures of general psychopathology correctly classified 78.6% of
individuals with PTSD and 81.3% of those with no PTSD. These results suggest that
a considerable proportion of injured workers display symptoms consistent with
PTSD and that these symptoms are related to general negative affect.
Implications, including the suggestion of clinical intake screening of PTSD in
this population, are discussed.
PMID- 9549610
TI - Deja vu all over again: critical misunderstandings concerning anxiety sensitivity
and constructive suggestions for future research.
AB - The debate concerning the relation between anxiety sensitivity (AS) and trait
anxiety has been constructive for the field and has suggested a number of
important directions for future research. Reiss' (1997) commentary on AS and
trait anxiety in this journal, however, contains several serious factual mis
statements and logical errors that confuse, rather than clarify, many of the
central issues in this debate. These misunderstandings are corrected and the
implications of the issues raised by Reiss are addressed here. The authors
suggest that future research on AS (a) embed this construct within the context of
broader temperamental and personality variables and (b) explicitly recognize the
biodirectionality of emotional and cognitive influences.
PMID- 9549611
TI - Bone cell behavior on Matrigel-coated Ca/P coatings of varying crystallinities.
AB - Rat calvarial cell mitogenic behavior was investigated on various biomaterials
coated with Matrigel, a basement membrane matrix containing growth factors. Low
(20-40%) and high (70-90%) crystallinity hydroxyapatite (rHA and cHA), rough
titanium (Ti), and tissue culture polystyrene (TP) surfaces were compared.
Surface chemistry and calcium resorption of HA coatings, alkaline phosphatase
activity (APA), and growth of cells were measured for Matrigel-coated and
uncoated surfaces at 2, 7, and 14 days. Gene expression for four noncollagenous
bone-related proteins (osteonectin, osteopontin, alkaline phosphatase, and
osteocalcin) was also investigated by reverse transcription and polymerase chain
reaction up to 28 days. Ca concentration in incubating solutions increased with
time for the two types of HA coatings and was always greater for rHA than cHA.
Surface chemistry and coating dissolution rates were not affected by the presence
of Matrigel or cells throughout the study. APA of cells on the two HA-coated
surfaces was comparably enhanced in the presence of Matrigel and was greater than
on Ti surfaces. Only HA surfaces showed an increased APA of cells with time in
the presence of Matrigel. Cell growth peaked at 7 days and was greatest for cells
on the two HA surfaces and without Matrigel. At 14 days, cell growth was
comparable on the four surfaces. The presence of HA and Matrigel enhanced cell
specific APA at 14 days. Gene expression for all four proteins investigated
showed no differences between surfaces after 7 days. At 2 and 7 days, gene
expression was indicative of proliferation for Ti, and of proliferation,
differentiation, and mineralization for HA and TP more so without Matrigel. The
addition of this matrix significantly enhanced mitogenicity of calvarial cells on
HA only after 14 days. Matrigel eliminated differences seen between the two HA
coatings. Gene expression was not enhanced or inhibited by the presence of
Matrigel.
PMID- 9549612
TI - Platelet adhesion onto chargeable functional group gradient surfaces.
AB - Functional group gradients were prepared on low-density polyethylene (PE) sheets.
The surface density of grafted functional groups was gradually changed along the
sample length by way of corona discharge treatment with gradually increasing
power following graft copolymerization of acrylic acid (AA), sodium p-styrene
sulfonate (NaSS), or N,N-dimethyl aminopropyl acrylamide (DMAPAA). AA and NaSS
are negatively chargeable and DMAPAA is positively chargeable in phosphate
buffered saline or plasma solution at pH 7.3-7.4. The prepared functional group
gradient surfaces were characterized by measurement of the water contact angle,
by electron spectroscopy for chemical analysis, and by Fourier transform infrared
spectroscopy in the attenuated total reflectance mode. All these measurements
indicated that the functional groups were grafted onto the PE surfaces with
gradually increasing density. The platelets adhered to the functional group
gradient surfaces along the sample length were counted and observed by scanning
electron microscopy. It was observed that the platelet adhesion to the gradient
surfaces decreased gradually with the increasing surface density of functional
groups. This may be related to the hydrophilicity of the surfaces. The DMAPAA
grafted surface showed a large amount of platelet adhesion, probably due to its
positive charge character, while the AA-grafted surface, which is charged
negatively, showed poor platelet adhesion. However, the NaSS-grafted surface,
which is also charged negatively, showed a relatively large amount of platelet
adhesion. This may be associated with the existence of an aromatic ring close to
the ionizable group in NaSS. It seems that surface functional groups and their
charge character, as well as wettability, play important roles for platelet
adhesion.
PMID- 9549613
TI - In vitro engineering of human skin-like tissue.
AB - Coverage of large, full-thickness burns presents a challenge for the surgeon due
to the lack of availability of the patient's own skin. Currently, tissue
engineering offers the possibility of performing a suitable therapeutic wound
coverage after early burn excision by using cultured keratinocyte sheets
supported by a dermal layer. The aim of this study was to develop and
characterize a skin substitute composed of both epidermal and dermal elements.
For this purpose we grew keratinocytes and fibroblasts separately for 15 days
within two different types of biomaterials. Cells then were co-cultured for an
additional period of 15 days, after which samples were taken and processed with
either classic or immunohistochemical stainings. Results showed that (1) human
fibroblasts and keratinocytes can be cultured on hyaluronic acid-derived
biomaterials and that (2) the pattern of expression of particular dermal
epidermal molecules is similar to that found in normal skin. The data from this
study suggest that our skin equivalent might be useful in the treatment of both
burns and chronic wounds.
PMID- 9549614
TI - Adsorption of proteins onto poly(ether urethane) with a phosphorylcholine moiety
and influence of preadsorbed phospholipid.
AB - In a previous report we demonstrated that the blood compatibility of poly(ether
urethane) (PEU) was improved by grafting phosphorylcholine (PC) groups on the
surface. The improved blood compatibility was indicated by decreased platelet
adsorption/activation and reduced thrombin formation at the polymer surface in
experiments in which the surfaces were contacted with platelet-rich plasma in
vitro. In the present study, we investigated the effect of grafted PC groups at a
PEU surface on protein and phospholipid adsorption. Adsorption of human
fibrinogen (Fg), human serum albumin (Alb), human high-molecular-weight kininogen
(HMWK), and dioleoyl phosphatidylcholine (DOPC) vesicles was measured by
ellipsometry. For this purpose, thin PEU films were cast on silicon wafers. The
polymer film was photochemically modified with a PC-containing aryl azide. The
presence of PC groups on the polymer surface was demonstrated by ESCA (Electron
Spectroscopy for Chemical Analysis). The hydrophilicity of the polymer surface
increased by the surface modification, as indicated by a decrease of the contact
angle from 59 degrees before to 43 degrees after modification. Our data show that
the presence of PC groups has little effect on the adsorption of proteins to a
PEU surface. The highest adsorption was observed for Fg (0.49 microgram/cm2 on PC
modified PEU and 0.50 microgram/cm2 on PEU), followed by HMWK (0.28 microgram/cm2
on both PC-modified PEU and PEU), and Alb (0.16 microgram/cm2 on PC-modified PEU
and 0.18 microgram/cm2 on PEU). Protein adsorption was further studied on a
"biomembrane-like" DOPC bilayer formed on hydrophilic silicon. We found no
protein adsorption on this DOPC bilayer. The adsorption of small unilamellar DOPC
vesicles on the polymer surfaces amounted to about 0.06 microgram/cm2
(corresponding to circa 30% of monolayer coverage) and was similar for PC
modified PEU and PEU. Despite this partial surface coverage, preadsorbed DOPC on
the polymer surface diminished the subsequent adsorption of proteins
considerably. These results show that the mere presence of phosphorylcholine
groups on a PEU surface is insufficient to suppress protein adsorption. The
highly ordered structure of natural phospholipid bilayers seems to be required to
suppress protein adsorption effectively.
PMID- 9549615
TI - Release of bioactive human growth hormone from a biodegradable material:
poly(epsilon-caprolactone).
AB - We have characterized the biodegradable material poly(epsilon-caprolactone) (PCL)
as a delivery system for recombinant human growth hormone (hGH). Two contrasting
methods for the manufacture of the biomaterial were investigated: namely, solvent
casting and solvent casting particulate leaching; the latter yielded porous PCL
discs. The degree of porosity, which was assessed by scanning electron
microscopy, could be controlled by incorporating selected concentrations of
particulate sodium chloride during the manufacturing process. Bioactive hGH
released from the PCL preparations was quantified with a highly sensitive and
precise bioassay which was based upon hGH activation of rat lymphoma Nb2 cells.
Eluates obtained from control discs of PCL which had not been loaded with hGH
proved to be nontoxic when tested on these cells. The release of bioactive hGH
from hormone-loaded nonporous discs of PCL was found to be a direct function of
the initial hormone loading dose. Increased porosity of the discs manufactured by
solvent casting particulate leaching increased the delivery of hGH from discs
which had been immersion loaded. However, hGH release after surface loading was
independent of porosity. Hormone concentrations were also assessed by immunoassay
so that the ratios of bio- to immunoactivity (B:I ratio) of the hormone release
could be determined. We found that the B:I ratio of the hormone after release
from unstored discs was identical to that of the hormone prior to its
incorporation into the PCL, demonstrating that the mild incorporation procedures
utilized had not adversely affected the structural integrity of the hormone.
However, if the hormone-loaded discs were stored at 37 degrees C prior to
elution, the B:I ratios of the hGH released decreased indicating that this
compromised the bioactive site.
PMID- 9549616
TI - Study of creep behavior of ultra-high-molecular-weight polyethylene systems.
AB - The short- and long-term creep behaviors of ultra-high-molecular-weight
polyethylene (UHMWPE) systems (compression-molded UHMWPE sheets and self
reinforced UHMWPE composites) have been investigated. The short-term (30-120 min)
creep experiment was conducted at a load of 1 MPa and a temperature range of 37
62 degrees C. Based on short-term creep data, the long-term creep behavior of
UHMWPE systems at 1 MPa and 37 degrees C was predicted using time-temperature
superposition and analytical formulas. Compared to actual long-term creep
experiments of up to 110 days, the predicted creep values were found to well
describe the creep properties of the materials. The creep behaviors of the UHMWPE
systems were then evaluated for a creep time of longer than 10 years, and it was
found that most creep deformation occurs in the early periods. The shift factors
associated with time-temperature superposition were found to increase with
increasing temperature, as per the Arrhenius equation. The effects of
temperature, materials, and load on the shift factors could be explained by the
classical free volume theory.
PMID- 9549617
TI - Effects of curing time and filler concentration on curing and postcuring of
urethane dimethacrylate composites: a microcalorimetric study.
AB - The isothermal enthalpy changes with time of a dental composite were examined by
microcalorimetry to isolate the effects of different filler concentrations and
curing times on chemical aging of these composites. Urethane dimethacrylate
(UDMA) monomer, zirconia-silica (ZS) powder, and 3
methacryloxypropyltrimethoxysilane (MAPM) were used as organic and inorganic
matrices, and a coupling agent, respectively. The composite was mixed in
different ratios and cured by visible light. The enthalpy changes with time for
0, 15, 45, 75% ZS-filled UDMA and 75% MAPM-silanated ZS-filled UDMA cured for 13,
30, 90, 150, and 300 s were measured at 37.0 degrees, 57.0 degrees, and 65.5
degrees C until equilibrium. Increased curing time and filler concentration
caused the excess enthalpy changes (dH) and their rate of change (dH/dt) to
increase with annealing time and apparent equilibrium was reached faster. In
addition, dH showed nonlinear dependence with the increase in filler
concentration by showing a maxima for samples containing 25 wt% filler. Further,
filler silanation caused dH/dt to increase and required shorter times to reach
apparent equilibrium. dH also reached a minimum when samples contained silanated
filler, compared to composites containing unsilanated filler. It was concluded
that the shorter curing time caused the occurrence of spontaneous densification,
which facilitated continual resin curing; and longer curing time caused higher
crosslinking of the organic phase. Moderate concentration of inorganic phase
restricts the molecular motion of the surface layer of polymer onto filler
particles, and the polymer is regarded as highly crosslinked, while a higher
filler concentration forms aggregates that are covered by the polymer which
causes a decrease in the molecular packing of the resin, and is reflected as low
enthalpy values. Finally, silanation of the filler showed a highly endothermic
reaction that is probably due to breaking and forming of bonds at the interface
between the organic and the inorganic phases in the composites.
PMID- 9549618
TI - Step-polarization impedance spectroscopy of implant alloys in physiologic
solutions.
AB - A novel test method is presented whereby the polarization behavior and impedance
characteristics of an electrochemical interface can be determined simultaneously
from potential-step current transient responses. In this test, small incremental
steps in potential are applied to an electrochemical interface and the current
transient response is collected digitally. Then, the data are subjected to a
numerical Laplace transform technique to obtain the frequency-dependent
admittance (reciprocal impedance) of the interface. From this analysis, several
interesting and relevant parameters, including the high- and low-frequency
resistances, interfacial capacitance, and polarization behavior, can be obtained.
The mathematical basis for this technique is presented and the methodology is
applied to three implant alloys (titanium, Co-Cr-Mo, and platinum).
Electrochemical tests were performed in 0.9% NaCl at room temperature. Starting
at an initial negative potential, the samples were stepped in 50-mV increments
every 10 or 100 s up to a maximum potential and then reversed back to the
starting potential. The impedances were calculated and used to evaluate the
behavior. From these tests, one can determine the potential dependence of the
oxide film thickness as well as the changes in the underlying electrochemical
state of the interfaces with potential. This technique is inexpensive and easily
applied to any electrochemical system, and yields significantly more
electrochemical information than either anodic polarization or electrochemical
impedance spectroscopy alone.
PMID- 9549619
TI - Variation of oxide films on titanium induced by osteoblast-like cell culture and
the influence of an H2O2 pretreatment.
AB - Variations of titanium oxide films induced by osteoblast-like cells in a rat
calvaria culture system and the influence of an H2O2 pretreatment have been
investigated by using X-ray photoelectron spectroscopy and electrochemical
impedance spectroscopy. For abraded titanium, the results revealed that phosphate
and calcium ions may incorporate into the surface oxide film during the cell
culture, forming a precipitate with a Ca/P ratio near that of hydroxyapatite.
Oxidized carbon also was found in the surface layer, most likely precipitated
hydroxylcarbonated apatite (HCA). The H2O2 pretreatment of titanium in a
phosphate-buffered saline solution results in a 10-fold thickened porous oxide
film and large amounts of surface hydroxyl groups as well as a certain amount of
phosphate ions inside the oxide film. During the cell culture, the H2O2-treated
titanium surface favors the ion incorporation and precipitation of the HCA-like
compound, which probably is inlaid into the oxide film. Osteoblast-like cells on
the H2O2-treated titanium showed a more active morphology during the initial
stage compared with cells on abraded titanium. Moreover, bone-like nodule
formation and mineralization appear to be related to the precipitation of the HCA
like compound on the surface. The results are discussed with respect to corrosion
resistance, ion incorporation and precipitation of the HCA-like compound on the
surface, osseointegration, and bioactivity of titanium implants.
PMID- 9549620
TI - Covalent bonding of PMMA, PBMA, and poly(HEMA)to hydroxyapatite particles.
AB - In our earlier study, we showed that the surface hydroxyl groups of
hydroxyapatite have the ability to react with organic isocyanate groups. In this
study, the feasibility of grafting poly(methyl methacrylate) (PMMA), poly(n-butyl
methacrylate) (PBMA), and Poly(hydroxyethyl methacrylate) [poly(HEMA)] by using
the reaction of isocyanate groups with the hydroxyl groups on the surface of HA
was investigated. Double bonds were introduced to the surface of HA via the
coupling reaction of isocyanateoethyl methacrylate (ICEM) with HA, or through
hexamethylene diisocyanate (HMDI) with hydroxyethyl methacrylate (HEMA) and HA,
followed by radical polymerization in MMA, BMA, or HEMA. Infrared spectra
indicated the existence of polymers on the surfaces of HA. Thermogravimetric
analysis also confirmed the presence of grafted polymers on the surface of HA
powder particles (20-26 wt%). The polymers gave typical PMMA, PBMA, or poly(HEMA)
infrared spectra, with the exception of amide bands, a result of the coupling
reaction of ICEM or HMDI with hydroxy groups of HA or HEMA. Therefore it is
concluded that the polymers were chemically bonded to the surface of HA through
the isocyanate groups of ICEM or HMDI.
PMID- 9549621
TI - Bioactive surface coatings for nanoscale instruments: effects on CNS neurons.
AB - A method is described for depositing onto medical instruments highly
biocompatible and bioactive surface coatings that can promote and stabilize cell
attachment. The coatings were made by first depositing thin films of materials,
such as diamond-like carbon, or metals, including tantalum, tungsten, platinum,
gold, iridium, palladium, and brass. These surfaces were further altered to
either promote or inhibit cell growth and spreading by an additional overcoat of
biological materials, including the extracellular matrix proteins, laminin,
fibronectin, and collagen IV. The deposition technique used a metal or carbon
plasma, and the important properties of film adhesion, hardness, density, and
smoothness are tailored by control of the ion bombardment energy. The films are
translucent enough to permit high resolution light microscopy for rapid and
detailed examination of tissue response. These bioactive substrates have been
tested on primary central nervous system neurons, and the growth response is
excellent. Equally successful have been our attempts to anchor neurons, without
associated proliferation of non-neuronal cells, using coatings of poly-d-lysine.
The method and the materials could have important ramifications in a number of
areas of research and biotechnology, for example for chronic implantation of
microelectrode arrays in the cerebral cortex for neuroprosthetic and neural
monitoring application and for research on the human central nervous system.
Possible application in nonneuronal fields, such as for coronary artery stents
and pacemaker electrodes, also are discussed.
PMID- 9549622
TI - Fluorescent and radiolabeling of polysaccharides: binding and internalization
experiments on vascular cells.
AB - Glycosaminoglycans (GAGs) such as heparan sulfates are complex carbohydrate
polymers. These structural components of the extracellular matrix are essential
for the adhesion, migration, and regulation of cellular growth. To understand the
physiological role of GAGs and GAG analogues, a practical approach consists of
labeling and detecting them in cell extracts, or analyzing binding domains and
their distributions into the cells. We propose a convenient and reliable method
for preparing and labeling amino-enriched, polysaccharides with the fluorescent
derivative 5-[(4,6-dichlorotriazine-2-yl)amino]-fluorescein (DTAF).
Radioiodination is then performed on the DTAF moiety. This method was applied to
polysaccharides known to inhibit vascular smooth-muscle cell (SMC) proliferation
such as functionalized dextrans derived from poly(alpha 1-6 glucose) and fucan,
poly(L-fucose 4-sulfate) extracted from brown seaweed. Using autoradiography and
confocal microscopy, we observed the fixation and internalization of labeled
antiproliferative products in SMCs from rat aorta. These probes can be useful for
the understanding of polysaccharide-cell interactions. In addition, the method
presented here can be applied to various synthetic or natural biomedical
materials.
PMID- 9549623
TI - An in vitro system for studying osteointegration of dental implants utilizing
cells grown on dense hydroxyapatite disks.
AB - A proposed in vitro system is described where chick osteoblasts are cultured on
the flat surfaces of dense, nonporous HA disks to facilitate the study of bone
formation at the cell-HA interface. During early bone formation cell-coated HA
disks were retrieved, fixed with buffered 2% glutaraldehyde, and embedded in
epon/araldite. The underlying HA disks were demineralized in diluted acid, and
the intact cell-HA interfaces were re-embedded and thin sectioned for routine
transmission electron microscopy. Morphologic studies indicated that osteoblasts
proliferated and formed nodules of cells on the surfaces of HA disks. With
increasing time in culture, they deposited orthogonally packed collagen fibrils
between the cell layers that were enveloped by electron-dense mineralized
globules. Eventually, small spicules of mineralized HA formed along collagen
fibrils. An electron-dense layer about 50 nm thick was observed on the surface of
the HA disks. Biochemical studies indicated that cell proliferation, as judged by
3H-thymidine uptake, increased rapidly during the first 3 days, reached a maximum
around 6 days, and then declined by 12 days in culture. AP activity and collagen
synthesis, as determined by 3H-hydroxyproline formation, increased as cellular
proliferation declined. Mineralization, as judged by 45Ca uptake and spicule
formation, occurred, as expected, following the increase in AP activity and
deposition of densely packed collagen fibrils. Thus, all morphological and
biochemical parameters studied indicate that the proposed in vitro system is
reproducible and can facilitate the study of the osteointegration of HA-coated
implants.
PMID- 9549624
TI - Orientation of ECM protein deposition, fibroblast cytoskeleton, and attachment
complex components on silicone microgrooved surfaces.
AB - The microfilaments and vinculin-containing attachment complexes of rat dermal
fibroblasts (RDF) incubated on microtextured surfaces were investigated with
confocal laser scanning microscopy (CLSM) and digital image analysis (DIA). In
addition, depositions of bovine and endogenous fibronectin and vitronectin were
studied. Smooth and microtextured silicone substrata were produced that possessed
parallel surface grooves with a groove and ridge width of 2.0, 5.0, and 10.0
microns. The groove depth was approximately 0.5 micron. CLSM and DIA make it
possible to visualize and analyze intracellular and extracellular proteins and
the underlying surface simultaneously. It was observed that the microfilaments
and vinculin aggregates of the RDFs on the 2.0 microns grooved substrata were
oriented along the surface grooves after 1, 3, 5, and 7 days of incubation while
these proteins were significantly less oriented on the 5.0 and 10.0 microns
grooved surfaces. Vinculin was located mainly on the surface ridges on all
textured surfaces. In contrast, bovine and endogenous fibronectin and vitronectin
were oriented along the surface grooves on all textured surfaces. These proteins
did not seem to be hindered by the surface grooves since many groove-spanning
filaments were found on all the microgrooved surfaces. In conclusion, it can be
said that microtextured surfaces influence the orientation of intracellular and
extracellular proteins. Although results corroborate three earlier published
hypotheses, they do not justify a specific choice of any one of these hypotheses.
PMID- 9549625
TI - Biocompatibility analysis of different biomaterials in human bone marrow cell
cultures.
AB - A cell culture system for biocompatibility testing of hip implant materials is
described. Human bone marrow cells have been chosen because these cells are in
direct contact with the biomaterial after implantation in situ. The sensitivity
of this method is evaluated for materials which are already being used as
implants in humans and animal, e.g., hydroxyapatite (HA) ceramic, pure titanium,
and ultra-high-molecular-weight polyethylene (UHMWPE). As indicative parameters
of biocompatibility primary cell adherence, cell number, cell proliferation,
production of extracellular matrix, cell vitality, and cell differentiation are
described. After 2 weeks in culture, obvious differences between the biomaterials
with respect to the indicative parameters could be observed. Cell numbers were
greatest on the HA specimens. In the case of titanium alloys, we observed a
decreased number of cells. The production of extracellular matrix was high for
the HA ceramics but reduced for titanium specimens. The polymers allowed only a
few adherent cells and showed no signs of extracellular matrix production. The
results can be correlated astonishingly well to animal experiments and clinical
experiences. Therefore, we suggest that this cell culture system seems to be a
useful tool for biocompatibility testing of bone implantation materials. It also
helps reduce animal experiments. With the help of flow cytophotometry, we
analyzed the influence of biomaterials on large numbers of cells with respect to
differentiation. There were similar populations of T cells and monocytes on all
specimens tested. Extended B-cell and granulocyte populations, however, were
observed with titanium and UHMWPE. Most osteocalcin-containing cells adhered to
the HA ceramics.
PMID- 9549626
TI - Histochemical and morphometric observations on the new tissue formed around
mammary expanders coated with pyrolytic carbon.
AB - The authors investigated tissue reaction around implanted silicone expanders,
focusing on clinical morphological and morphometrical aspects. For use in breast
reconstruction in post mastectomy patients, the surface of a medical-grade
silicone elastomer was modified, without changing its bulk properties, by the
addition of a pyrolytic carbon film. The presence of lipophagy, the number of
foreign-body giant cells of histiocytic origin, and the number of MIB-1 positive
nuclei (an index of proliferation for the reactive stromal population) were all
seen to be influenced by the pyrolytic carbon coating. Indeed, all these
parameters were lower in the membrane formed around Carbofilm TM-coated
expanders, thus demonstrating the effective protective properties of pyrolytic
carbon coating.
PMID- 9549627
TI - Platelet adhesion onto segmented polyurethane surfaces modified by PEO- and
sulfonated PEO-containing block copolymer additives.
AB - Polyethylene oxide (PEO) surfaces were prepared by the addition of PEO- and
sulfonated PEO-containing amphiphilic block copolymers as surface-modifying
additives in a segmented polyurethane (PU). PEO-PPO-PEO triblock copolymers
(Pluronics) with different PEO chain lengths (from 2 to 80) were used as
additives. The prepared film surfaces were characterized by the measurement of
dynamic water contact angles and electron spectroscopy for chemical analysis. It
was observed that the PU films containing 10 wt% of PEO additives were surface
saturated with the additives regardless of their PEO chain length, but the PEO
chains were more projected from the film surfaces containing the additives with
longer PEO chains. The water absorption of the films increased largely with the
increasing PEO chain length of the additives. The addition of PEO additives
produced film surfaces that were in a gel-like state. The films demonstrated some
extraction of the PEO additives. However, the additives with higher molecular
weights were entrapped more stably into the PU matrix. The mechanical properties
(tensile strength and elongation) of the films were changed by the addition of
PEO additives, but the differences were not significant compared to the control
PU. The platelet adhesion on the film surfaces decreased with increasing PEO
chain length of the additives. The film surface containing additives with long
PEO chains (chain length of 80) was particularly effective in preventing platelet
adhesion. The effect of negatively charged sulfonate groups on the prevention of
platelet adhesion appeared only on the film surfaces containing additives with
short PEO chains. For longer PEO chains, the chain mobility effect was more
dominant than the negative charge effect on the prevention of platelet adhesion.
PMID- 9549628
TI - Chemical modification of titanium surfaces for covalent attachment of biological
molecules.
AB - The surface of implantable biomaterials is in direct contact with the host tissue
and plays a critical role in determining biocompatibility. In order to improve
the integration of implants, it is desirable to control interfacial reactions
such that nonspecific adsorption of proteins is minimized and tissue-healing
phenomena can be controlled. In this regard, our goal has been do develop a
method to functionalize oxidized titanium surfaces by the covalent immobilization
of bioactive organic molecules. Titanium first was chemically treated with a
mixture of sulfuric acid and hydrogen peroxide to eliminate surface contaminants
and to produce a consistent and reproducible titanium oxide surface layer. An
intermediary aminoalkylsilane spacer molecule was then covalently linked to the
oxide layer, followed by the covalent binding of either alkaline phosphatase or
albumin to the free terminal NH2 groups using glutaraldehyde as a coupling agent.
Surface analyses following coating procedures consisted of X-ray photoelectron
spectroscopy (XPS), scanning electron microscopy (SEM), and atomic force
microscopy (AFM). Enzymatic activity of coupled alkaline phosphatase was assayed
colorimetrically, and surface coverage by bound albumin was evaluated by SEM
visualization of colloidal gold immunolabeling. Our results indicate that the
linkage of the aminoalkylsilane to the oxidized surface is stable and that bound
proteins such alkaline phosphatase and albumin retain their enzymatic activity
and antigenicity, respectively. The density of immunolabeling for albumin
suggests that the binding and surface coverage obtained is in excess of what
would be expected for inducing biological activity. In conclusion, this method
offers the possibility of covalently linking selected molecules with known
biological activity to oxidized titanium surfaces in order to guide and promote
the tissue healing that occurs during implant integration in bone and soft
tissues.
PMID- 9549629
TI - Polymyxin B inhibits biphasic calcium phosphate degradation induced by
lipopolysaccharide-activated human monocytes/macrophages.
AB - Numerous cell types, such as monocytes and osteoclasts, are involved in calcified
matrix degradation. In this context, calcium-phosphate ceramics present similar
degradation processes in vivo and in vitro to those found in a natural calcified
substrate. As the monocyte/macrophage lineage is among the first cells to appear
in ceramic implantation sites, it is a key protagonist in inflammatory reaction
and biodegradation mechanisms. This study investigated the ability of human
monocytes/macrophages activated by various agents [lipopolysaccharides (LPS),
polymyxin B (PMB)] to degrade biphasic calcium-phosphate ceramics. PMB sulfate is
a bacteriostatic antibiotic that modulates LPS-induced cell activities in vivo
and in vitro. Degradation pits (about 10 microns) produced on the pellet surface
by these monocytes were discrete, with well defined margins. LPS increased the
degradation of calcium-phosphate ceramic (number of lacunae, mean pellet surface
area degraded) in a dose-dependent manner whereas polymyxin B downmodulated it
significantly. The addition of 2 micrograms/mL of polymyxin B reduced the number
of degradation lacunae and the extent of degraded surface area induced by 0.1
microgram/mL LPS by 87% and 64%, respectively. Thus this cell culture system can
be very useful in the study of cellular degradation of biomaterials and of the
influence of therapeutic agents that may modulate these cell activities.
PMID- 9549630
TI - Defining the maximum tolerated dose: investigator, academic, industry and
regulatory perspectives.
PMID- 9549631
TI - Prevention and treatment of stroke: where do we stand?
PMID- 9549632
TI - Elevation of liver enzymes in multiple dose trials during placebo treatment: are
they predictable?
AB - The present study examined the increase in transaminases, especially in ALT in
young healthy males during placebo treatment in phase I multiple dose trials. The
primary objective was to investigate whether volunteers showing increasing ALT
levels also present characteristic patterns of demographic data, laboratory
parameters, and vital signs. The secondary objective was to determine whether
there is a possibility to predict increases of ALT during a trial by analyzing
demographic data and baseline levels of routine safety laboratory parameters and
vital signs. In a meta-analysis of 13 placebo-controlled multiple dose phase I
studies, volunteers showing elevations of ALT during placebo treatment were
compared with those presenting no clinically significant changes of ALT levels.
Demographic data as well as routine safety laboratory values and vital signs
measured at screening and on the first day of the in-house stay were subject to
the analysis. Using Wilcoxon's rank sum test, significant differences between ALT
susceptibles and ALT-nonsusceptibles were found for baseline values (mean values
of screening and the first day of the in-house stay) of ALT, gamma GT, AST/ALT,
and AST/ gamma GT. Differences found for the screening values of the heart rate
were statistically rather than clinically significant. Cut-off values were found
for baseline levels of ALT and AST/ALT ratio. Their use resulted in a sensitivity
of 73% and a specificity of 74% with regard to predictability of ALT levels
increasing during the trial.
PMID- 9549633
TI - A pharmacokinetic-pharmacodynamic model of d-sotalol Q-Tc prolongation during
intravenous administration to healthy subjects.
AB - The objective of this study was to assess the pharmacokinetics and
pharmacodynamics of the dextro (d-) isomer of sotalol, a class III antiarrhythmic
agent, in healthy young men and women after a single intravenous bolus dose. The
design was open-label, randomized, parallel group. Each group (4 men and 4 women)
received either 0.5, 1.5, or 3.0 mg/kg d-sotalol as an intravenous infusion for 2
minutes. Serial measurements of the d-sotalol plasma concentration and the Q-Tc
interval data were recorded before, during, and for 72 hours after drug
administration. The pharmacokinetics of d-sotalol were found to be well described
by a three-compartment model with linear elimination clearance from the central
compartment. There were no significant differences in the elimination clearance
or volume of the central compartment between dose levels or between men and
women. However, women were found to have a lower steady-state volume of
distribution than men (1.20 L/Kg versus 1.43 L/Kg). The Q-Tc versus d-sotalol
plasma concentration data were fitted to a model that assumed a distinct "effect
compartment" and sigmoidal Emax response. The baseline Q-Tc, determined from the
fittings, was found to be significantly higher in women (0.40 versus 0.38
seconds). The effect compartment clearance was found to be highly variable, with
a median of 12.3 (range, 0.2-671,300) L/h. There were statistically significant
differences in the effect compartment clearance by dose among men and by gender
at a dose of 1.5 mg/kg. There were no significant differences detected between
dose groups or genders for the d-sotalol effect site concentration at one half
the maximum Q-Tc prolongation from baseline (EC50), EMAX, (the maximum Q-Tc
prolongation from baseline) or the Hill coefficient. In conclusion, the
pharmacokinetics of d-sotalol after intravenous administration are independent of
dose and gender, because the difference between men and women in volume of
distribution at steady-state is not clinically significant. The pharmacodynamics
of Q-Tc prolongation produced by d-sotalol appear to be independent of dose and
gender; however, there is considerable variability in the time course of effects
on Q-Tc between individuals.
PMID- 9549634
TI - Clinical utility of long-term enalapril/diltiazem ER in stage 3-4 essential
hypertension. Long-term Use of Enalapril/Diltiazem ER in Stage 3-4 Hypertension
Group.
AB - The use of angiotensin converting enzyme inhibitors and calcium channel blockers,
as monotherapies and in combination, is common in the management of hypertension.
Clinical studies have documented the augmentation of blood pressure reduction
when these agents are combined compared with the individual agents, in short-term
studies. In the present investigation, 93 patients with stage 3-4 essential
hypertension, who successfully completed a short-term double-blind study,
participated in a 40-week open-label treatment phase. The patients were
maintained on their previous doses of enalapril/diltiazem ER (E/D) with or
without additional antihypertensive medications. Doses of medication could be
adjusted as necessary for blood pressure control. Of the 93 patients, 68% were
male and 82% were white; they averaged 52.7 years of age and had a baseline mean
sitting blood pressure (SiBP) of 167/111 mmHg. The use of E/D alone (n = 14)
reduced mean SiBP by 14.5/14.4 mmHg from baseline, whereas the use of E/ D with
other agents (n = 79) decreased it by 27/20.5 mmHg from baseline. E/D alone or in
combination with other drugs was well-tolerated, and no serious adverse events
were noted. This long-term open-label study demonstrated that the E/D combination
alone or with the addition of other antihypertensive drugs was effective, safe,
and well-tolerated after prolonged administration.
PMID- 9549635
TI - Renal dysfunction does not alter the pharmacokinetics or LDL-cholesterol
reduction of atorvastatin.
AB - The objective of this study was to determine the effects of renal dysfunction on
the steady-state pharmacokinetics and pharmacodynamics of atorvastatin, a 3
hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Nineteen subjects with
calculated creatinine clearances ranging from 13 mL/min to 143 mL/min were
administered 10 mg atorvastatin daily for 2 weeks. Pharmacokinetic parameters and
lipid responses were analyzed by regression on calculated creatinine clearance.
Correlations between steady-state atorvastatin pharmacokinetic or pharmacodynamic
parameters and creatinine clearance were weak and, in general, did not achieve
statistical significance. Although the elimination rate constant, lambda z
(0.579), was significantly correlated with creatinine clearance, neither maximum
plasma concentration (Cmax, -0.361) nor oral clearance (Cl/F, 0.306) were; thus,
steady-state exposure is not altered. Renal impairment has no significant effect
on pharmacodynamics and pharmacokinetics of atorvastatin.
PMID- 9549637
TI - Pharmacokinetics of isosorbide dinitrate in healthy volunteers after 24-hour
intravenous infusion.
AB - No studies have examined the pharmacokinetics of isosorbide dinitrate (ISDN)
after infusion of long duration, even though such infusions are used in patients.
We therefore measured ISDN and its active metabolites, isosorbide-5-mononitrate
(IS5MN) and isosorbide-2-mononitrate (IS2MN), in plasma of 9 healthy volunteers
who received a continuous intravenous infusion of ISDN for 24 hours at a dose
rate that lowered diastolic blood pressure by 10% during the first 30 minutes of
infusion. All subjects tolerated the infusion except one who experienced
intolerable headache. Five subjects received 1 microgram.min-1.kg-1, one 2
micrograms.min-1.kg-1, and two 4 micrograms.min-1.kg-1 ISDN, whereas the full
rate of 6 micrograms.min-1.kg-1 was used continuously in one subject. At all
infusion rates the plasma concentrations of ISDN were higher at 24 hours than at
earlier times, suggesting that a steady-state condition had not been reached at
that time. The same was true for the mononitrate metabolites, which reached
higher plasma concentrations and were cleared more slowly than the parent
compound after the end of the infusion. Apparent elimination half-lives of ISDN,
IS2MN, and IS5MN were 67 +/- 10 minutes, 115 +/- 13 minutes, and 272 +/- 38
minutes, respectively. Comparison of low-rate infusions (1 and 2 micrograms.min
1.kg-1) with high-rate infusions (4 and 6 micrograms.min-1.kg-1) showed that the
plasma concentration ratios at 24 hours of mononitrate metabolites to parent drug
and apparent plasma clearance of ISDN were almost halved at the higher infusion
rates.
PMID- 9549636
TI - Single- and multiple-dose pharmacokinetics of riluzole in white subjects.
AB - Riluzole is a novel neuroprotective agent that has been developed for the
treatment of amyotrophic lateral sclerosis. A series of studies was undertaken to
establish its pharmacokinetics on single- and multiple-dose administration in
young white male volunteers. The mean absolute oral bioavailability of riluzole
(50-mg tablet) was approximately 60%. Maximum plasma concentration (Cmax) and
area under the concentration-time curve (AUC) values were linearly related to
dose for the range studied. Cmax occurred at 1.0 hour to 1.5 hours after
administration. Plasma elimination half-life appeared to be independent of dose.
After repeated administration of 100 mg riluzole for 10 days, some
intraindividual variability in bioavailability was seen. A high-fat meal
significantly reduced the rate (tmax = 2 hours compared with 0.8 hours; Cmax =
216 ng.mL-1 compared to 387 ng.mL-1) and extent of absorption (AUC = 1,047
ng.hr.mL-1 versus 1,269 ng.hr.mL-1). With multiple-dose administration, riluzole
showed dose-related absorption, although the terminal plasma half-life was
prolonged slightly. Steady-state plasma concentrations were achieved within 5
days. Steady-state trough plasma concentrations were significantly higher with a
75-mg dose twice daily than with a 50-mg dose three times daily, although AUC
values did not differ.
PMID- 9549638
TI - Pharmacokinetics of fosinoprilat in Chinese and whites after intravenous
administration.
AB - The pharmacokinetics of fosinoprilat was studied in 12 healthy Chinese men after
a 7.5 mg intravenous dose of fosinoprilat. The data were compared with those from
an earlier study using the same protocol in nine healthy white men. Blood and
urine samples were obtained before and at various time intervals after
fosinoprilat administration up to 24 hours and 48 hours, respectively.
Pharmacokinetic parameters were calculated by fitting the plasma or serum
concentrations to a three-compartment model. The total clearance (Clt), renal
clearance (ClT), and nonrenal clearance (ClNR) were significantly lower in
Chinese (16.29 +/- 6.92, 6.85 +/- 2.97, and 9.44 +/- 5.08 mL.hr-1.kg-1) than
those obtained in whites (29.88 +/- 6.36, 13.55 +/- 3.45, and 16.33 +/- 5.07
mL.hr-1.kg-1). The Chinese subjects had a significantly lower volume of
distribution (Vc [volume of distribution of central compartment] and Vdss [volume
of distribution at steady state]) (29.38 +/- 21.12 and 73.67 +/- 40.20 mL/kg)
than white men (58.14 +/- 15.01 and 152.49 +/- 24.89 mL/kg). The Chinese men also
had a shorter elimination half-life than whites, although not statistically
significant. The respective half-lives in Chinese and whites were 5.51 +/- 1.53
and 8.24 +/- 1.99 hours. The significant differences in ClNR and ClR may be
related to lower liver elimination function and lower kidney excretory function,
respectively. Plasma protein binding may contribute to part of the difference in
the volume of distribution. Chinese men have smaller volume of distribution and
clearances of fosinoprilat after intravenous administration compared with white
men. The cumulative urine excretion of fosinoprilat was not different between
Chinese and whites. Chinese may require a lower fosinoprilat dosage to obtain
plasma concentrations similar to whites after intravenous administration.
However, since a relatively high variation was found in fosinopril oral
absorption, the oral dosage of fosinopril for Chinese and whites may not be
different. Further study is obviously needed to elucidate whether the
pharmacodynamic effect may be different between Chinese and whites.
PMID- 9549639
TI - Chelation therapy in cardiovascular disease: ethylenediaminetetraacetic acid,
deferoxamine, and dexrazoxane.
AB - This review was conducted to assess whether there is sufficient evidence for the
clinical use of chelation therapy in cardiovascular disease based on original
articles and abstracts published in the last 30 years, with emphasis placed on
the most recent placebo-controlled studies. Articles postulating the mechanisms
of chelation also were included. The majority of the literature focused on three
chelators in particular, ethylenediaminetetraacetic acid (EDTA), deferoxamine,
and dexrazoxane (ICRF-187). Historically, much has been written on the beneficial
effects of EDTA. However, there are few controlled studies, and the mechanism of
action of EDTA is poorly understood. Although studies of deferoxamine are more
recent, most of the research is limited to animals and ex vivo models. Recently,
dexrazoxane was approved, but only for parenteral use for reducing the incidence
and severity of cardiomyopathy associated with doxorubicin administration in
women with metastatic breast cancer. Given these limitations, it is concluded
that more controlled studies are required to determine the efficacy of chelation
therapy in cardiovascular disease before it can be used broadly in the clinical
setting.
PMID- 9549640
TI - Protease inhibitors as inhibitors of human cytochromes P450: high risk associated
with ritonavir.
AB - Four protease inhibitor antiviral agents (ritonavir, indinavir, nelfinavir,
saquinavir) were evaluated as in vitro inhibitors of the activity of six human
cytochromes using an in vitro model based on human liver microsomes. Ritonavir
was a highly potent inhibitor of P450-3A activity (triazolam hydroxylation),
having inhibitory potency slightly less than ketoconazole. Indinavir was also a
potent 3A inhibitor, while nelfinavir and saquinavir were less potent. Ritonavir
had high inhibition potency against cytochrome P450-2C9 (tolbutamide
hydroxylation), -2C19 (S-mephenytoin hydroxylation), and -2D6 (dextromethorphan O
demethylation and desipramine hydroxylation), while the other protease inhibitors
had one or more orders of magnitude lower inhibitory activity against these
reactions. None of the protease inhibitors had important inhibitory potency
against P450-1A2 (phenacetin O-deethylation) or -2E1 (chlorzoxazone
hydroxylation). Thus, among available protease inhibitors, ritonavir carries the
highest risk of incurring drug interactions due to inhibition of cytochrome P450
activity.
PMID- 9549642
TI - Pharmacokinetics of metoclopramide in neonates.
AB - Despite its wide use as a prokinetic agent in neonates and infants with
gastroesophageal reflux (GER), the pharmacokinetics of metoclopramide have not
been characterized in this pediatric subpopulation. A single-dose pharmacokinetic
study of oral metoclopramide (0.1 to 0.15 mg/kg) was performed in 10 fasted
premature infants (weight 1.1 to 3.2 kg) ranging from 31 to 40 weeks
postconceptional age. Metoclopramide was quantitated from repeated blood samples
(n = 9 over 24 hours) by high-performance liquid chromatography. A one
compartment open model with first-order absorption best described the plasma
concentration-time data. No correlations were observed between gestational,
postnatal, or postconceptional age and any of the pharmacokinetic parameters
studied. Comparison of the pharmacokinetic parameters from the study cohort and
those reported previously from a similar study of older infants revealed no
statistically significant differences. However, a prolonged apparent plasma
clearance (Cl/F) of metoclopramide was observed in 30% of the infants studied,
and the mean Cl/F and apparent steady-state volume of distribution (Vdss/F) were
approximately 1.4- and 2.1-fold higher, respectively, than values reported in
previous studies of metoclopramide disposition in adults. These data suggest that
metoclopramide pharmacokinetics may exhibit a developmental dependency. Thus, a
metoclopramide dose of 0.15 mg/kg given orally every 6 hours is recommended for
the initiation of prokinetic therapy with this agent in infants who are < or = 31
weeks postconceptional age.
PMID- 9549641
TI - Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro:
dominance of CYP 2C19 and 3A4.
AB - The human cytochromes P450 (CYPs) mediating amitriptyline N-demethylation have
been identified using a combination of enzyme kinetic and chemical inhibition
studies. Amitriptyline was N-demethylated to nortriptyline by microsomes from
cDNA transfected human lymphoblastoid cells expressing human CYPs 1A2, 2C9, 2C19,
2D6, and 3A4. CYP 2E1 showed no detectable activity. While CYP 2C19 and CYP 2D6
showed high affinity, CYP 3A4 showed low affinity; CYP 2C9 and 1A2 showed
intermediate affinities. Based on these kinetic parameters and estimated relative
abundance of the different CYPs in human liver, CYP 2C19 was identified as the
major amitriptyline N-demethylase at low (therapeutically relevant) amitriptyline
concentrations, whereas CYP 3A4 may be more important at higher amitriptyline
concentrations. Chemical inhibition studies with ketoconazole and omeprazole
indicate that CYP 3A4 is the major amitriptyline N-demethylase at 100 mumol/L
amitriptyline, while CYP 2C19 is equally important at a substrate concentration
of 5 mumol/L. The CYP 1A2 inhibitor alpha-naphthoflavone and the CYP 2C9
inhibitor sulfaphenazole produced much less inhibition of amitriptyline N
demethylation at both substrate concentrations. Quinidine produced no detectable
inhibition. The kinetics of amitriptyline N-demethylation by human liver
microsomes were consistent with a two enzyme model, with the high affinity
component exhibiting Michaelis Menten kinetics and the low affinity component
exhibiting Hill enzyme kinetics. No difference was apparent in the kinetics of
amitriptyline N-demethylation in two liver samples with low levels of CYP 2C19
activity compared with two other samples with relatively normal 2C19 activity.
This may reflect the importance of higher substrate concentration values in
estimation of kinetic parameters in vitro.
PMID- 9549643
TI - Pharmacokinetics and protein binding of eprosartan in healthy volunteers and in
patients with varying degrees of renal impairment.
AB - This was an open-label, parallel group study to compare the pharmacokinetics of
multiple oral doses of eprosartan in subjects with normal renal function (Clcr >
80 mL/min; n = 8) and patients with mild (Clcr 60-80 mL/min; n = 8), moderate
(Clcr 30-59 mL/min; n = 15), or severe (Clcr < 30 mL/min; n = 3) renal
insufficiency. Each subject received oral eprosartan 200 mg twice daily for 6
days and a single dose on day 7. Mean total maximum concentration (Cmax) and area
under the concentration-time curve from 0 to 12 hours (AUC0-12) were similar for
healthy subjects and those with mild renal impairment, but were an average of 25%
to 35% and 51% to 55% greater for patients with moderate and severe renal
impairment, respectively, compared with healthy subjects. Mean renal clearance
(Clr), which was similar for healthy subjects and patients with mild renal
impairment, was decreased an average of 41% and 95% in the groups with moderate
and severe renal impairment, respectively, compared with normal subjects.
Eprosartan was highly bound to plasma proteins in all groups; however, the
unbound fraction was increased approximately two-fold in the group with severe
renal impairment. Mean unbound Cmax and AUC0-12 were an average of 53% to 61% and
185% to 210% greater for the patients with moderate and severe renal impairment,
respectively, compared with healthy subjects. Headache was the most common
adverse experience reported in all subgroups. Eprosartan was safe and well
tolerated regardless of degree of renal impairment. Cmax and AUC were increased
and renal clearance decreased in patients with moderate to severe renal
impairment in comparison to healthy subjects and patients with mild renal
impairment. However, based on the moderate renal clearance and known safety
profile of eprosartan, it is not necessary to adjust the dose of eprosartan in
patients with renal insufficiency.
PMID- 9549644
TI - Accumulation of fluconazole in scalp hair.
AB - The accumulation in scalp hair of the antimycotic triazole, fluconazole, was
studied during and after administration. Fluconazole 50 mg was administered to 12
healthy subjects as a single capsule each day for 28 days. The concentration of
fluconazole 5 hours after administration was measured in different 1-cm sections
of scalp hair at intervals during treatment and for 6 months after the end of
treatment. In each section of scalp hair the concentration of fluconazole
increased during treatment and was consistently higher than values found in
plasma. For example, the mean concentration in the first hair section on day 28,
19.8 micrograms/g, corresponded to a mean penetration ratio relative to plasma of
9.42. During administration, the maximal concentration of fluconazole was found
in the first hair section. After cessation of administration, the measured
concentrations of fluconazole decreased and greater concentrations were found in
the distal hair sections, presumably as a result of hair growth. Fluconazole was
detectable, however, in the hair of 9 of the 12 subjects even 6 months after
treatment. The mean concentration of fluconazole in hair bulbs on day 28 was 12.1
micrograms/g (n = 6), corresponding to a mean penetration ratio of 5.99. In a
second study, fluconazole was administered as a single oral 150-mg capsule per
week for 4 weeks to a group of 8 healthy subjects. The mean fluconazole
concentration in whole scalp hair 5 hours after the last dose was 3.2
micrograms/g.
PMID- 9549645
TI - Pharmacokinetics of multiple-dose oral cilostazol in middle-age and elderly men
and women.
AB - Cilostazol is being developed for the treatment of intermittent claudication due
to peripheral arterial disease (PAD). This study was conducted to investigate the
effects of age and gender on the pharmacokinetics of cilostazol after multiple
dose administration. It was an open label, multiple-dose study of cilostazol
administered to male and female subjects 50 years of age and older at a dose of
100 mg (oral tablet) twice daily for 7 days. Equal numbers of healthy male and
female (7 per group), nonsmoking subjects stratified into age groups of 50 to 59
years, 60 to 69 years, and 70 years or older were enrolled. Serial plasma samples
were obtained. Data were analyzed by model-independent methods. Cilostazol was
absorbed at a moderate rate, with peak plasma concentrations occurring at an
overall mean of 2.4 hours after administration. Cilostazol is extensively bound
(95%), primarily to albumin. A trend toward increasing cilostazol free fraction
with age was observed in the male subjects, which was explained by a decrease in
plasma albumin concentration with age. Differences in plasma protein binding
between age and gender groups (less than 15%) are not expected to have any
clinical significance. Plasma cilostazol concentrations reached steady state by
day 4. The pharmacokinetic characteristics of cilostazol were not affected by age
or gender.
PMID- 9549646
TI - Vasoreactivity in pre- and postmenopausal women: evaluation by pharmacodynamic
modeling.
AB - Postmenopausal women experience an increase in cardiovascular mortality and
morbidity compared with their premenopausal counterparts. This study was
undertaken to develop a pharmacodynamic model to determine whether vascular
reactivity in postmenopausal women differed from that in premenopausal women.
Eleven subjects in each group were recruited. Graded doses of norepinephrine and
insulin were infused via the dorsal hand vein. Venous diameter was measured by
ultrasound. Dosage and venous diameter were fit to a Hill-type pharmacodynamic
model in which norepinephrine acts as a vasoconstrictor and insulin counteracts
varying fractions of norepinephrine constriction. Fitted pharmacodynamic
parameters for norepinephrine did not differ uniformly between groups, but at
norepinephrine infusion rates between 14 and 46 ng/mL, postmenopausal women
demonstrated increased norepinephrine-induced vasoconstriction. Also, the modeled
maximal response to insulin (Emaxi) was greater in premenopausal women. By
stepwise linear regression, maximal response to insulin was found to be related
to menopausal status and diastolic blood pressure. Postmenopausal women showed
differences in vasoreactivity that may have important implications in the
pathogenesis of hypertension.
PMID- 9549647
TI - Droperidol elimination after cardiopulmonary bypass surgery.
AB - A high-dose (0.75 to 2.8 mg/kg) pharmacokinetic study of droperidol was
undertaken in patients during the recovery phase after cardiac surgery involving
hypothermic cardiopulmonary bypass (CPB). The elimination half-life of droperidol
in these patients, determined from concentration-time data obtained after CPB,
was significantly prolonged relative to previously reported mean values in
younger surgical patients not undergoing CPB and receiving lower doses of the
drug (0.05-0.20 mg/kg). On stratification of the patients by droperidol dose,
there was an inverse correlation between the size of the dose and the elimination
half-life of droperidol: mean half-life decreased as mean dose increased. This
difference in elimination half-life was not related to the duration of the CPB
procedure, or the total anesthetic time, both of which were not significantly
different between the patient groups receiving the three different doses of
droperidol. The magnitude or duration of hypothermia after CPB did not differ
between the three patient groups. The differences in half-lives are more likely
due to the clinical condition of the patients, such that the patients who
received the higher doses of droperidol were also judged clinically to be less
ill and thus eliminated droperidol more efficiently. This hypothesis, however,
could not be supported due to the small number of patients studied. The results
obtained in this study indicate that droperidol elimination is significantly
prolonged after high-dose administration to elderly patients undergoing
hypothermic CPB procedures during cardiac surgery.
PMID- 9549648
TI - Steady-state pharmacokinetics of zonisamide, an antiepileptic agent for treatment
of refractory complex partial seizures.
AB - A 56-day pharmacokinetic study of zonisamide was conducted in 24 healthy
volunteers. Steady state was achieved in 29 days including two dose escalations,
and in an average of 15 days from the last dose adjustment. Twice-daily
administration of 200 mg every 12 hours produced a 14% serum level fluctuation at
steady state. After once-daily administration of 400 mg, a 27% serum level
fluctuation was observed. The terminal-phase half-life after the last dose was 63
to 69 hours, which is consistent with the half-life of 52 to 60 hours found in
single-dose studies. This result demonstrates that zonisamide is not an
autoinducer. Serum oral clearance of 0.60 to 0.71 L/hr (0.121-0.132 mL/min/kg)
was similar to that observed in other multiple-dose studies.
PMID- 9549649
TI - Efficacy of intravenous granisetron in suppressing the bradycardia and
hypotension associated with a rabbit model of the Bezold-Jarisch reflex.
AB - This study investigated whether granisetron, a 5-HT3 receptor antagonist, can
alter the Bezold-Jarisch reflex (i.e., hypotension and inappropriate heart rate
slowing). A hemorrhagic rabbit model that has been shown to induce the Bezold
Jarisch reflex was used. In 11 rabbits (3.8 kg), catheters were placed in the
carotid arteries one day before experimental hemorrhage. On the day of the study,
the rabbits were given intravenous granisetron (50 micrograms/kg) or an equal
volume of saline. Five minutes after administration of granisetron or saline,
hemorrhage was induced by continuous blood withdrawal at 5 mL/min and blood
pressure (BP) and heart rates were obtained at frequent intervals until systolic
BP declined to 80 mmHg. Six rabbits received saline and five granisetron. An
average of 77.6 mL +/- 16.4 mL of blood was removed in the group receiving
granisetron (compared with 56.5 mL +/- 13.1 mL for the saline group) before
achieving the target systolic BP of 80 mmHg. The group receiving granisetron
demonstrated the same ability to increase their heart rate from baseline as the
saline group. However, the granisetron group had a final heart rate that was
closer to their maximal heart rate than the saline group. In this animal model,
granisetron was significantly more effective at preventing inappropriate heart
rate slowing and allowed significantly more blood to be removed before reaching
the target blood pressure. This implies that granisetron may be effective in
preventing vasovagal syncope, although further study should be carried out to
verify these potentially interesting findings.
PMID- 9549650
TI - Effect of troglitazone on steady-state pharmacokinetics of digoxin.
AB - Twelve healthy subjects participated in a study to determine the effect of
multiple doses of troglitazone on the steady-state pharmacokinetics of digoxin.
Subjects received digoxin 0.25 mg orally once daily on days 1 through 20 and 400
mg of troglitazone orally once daily on days 11 through 20. Serial plasma samples
and 24-hour urine samples collected before and after the doses on days 10 and 20
were analyzed for digoxin using a radioimmunoassay method. Eleven subjects
completed the study. Administration of multiple oral doses of digoxin and
troglitazone was well tolerated. Mean values for maximum concentration (Cmax),
time to Cmax (tmax), and area under the concentration-time curve from 0 to 24
hours (AUC0-24) of digoxin on day 10 were similar to those on day 20. Mean day 10
digoxin values for minimum concentration (Cmin), apparent oral clearance (Cl/F),
total urinary excretion from 0 to 24 hours (Ae0-24), and renal clearance (Clr)
were also similar to corresponding values on day 20. Thus, concomitant
administration of multiple-dose troglitazone does not alter the steady-state
pharmacokinetics of digoxin.
PMID- 9549651
TI - Evaluation of the potential interaction between felbamate and erythromycin in
patients with epilepsy.
AB - Effects of erythromycin on hepatic CYP450 3A4 isozymes can profoundly influence
the metabolism of many therapeutic agents. An open-label, randomized, two-period,
crossover study was therefore conducted to evaluate the pharmacokinetics of
felbamate before and after a concurrent 10-day regimen (333 mg three times daily)
of erythromycin. Patients were receiving either 3,000 or 3,600 mg/day felbamate
monotherapy for treatment of epilepsy. Mean dose-normalized values for maximum
concentration (Cmax) and area under the concentration-time curve (AUC tau) of
felbamate were not statistically different in patients taking felbamate as
monotherapy than in patients after erythromycin coadministration. Estimates of
time to Cmax (tmax), minimum concentration (Cmin), apparent clearance (Cl/kg),
average concentration (Cav), and degree of fluctuation (DFss) were likewise
unchanged. The incidence of mild and moderate adverse events increased during
coadministration of the two drugs. Because patients with epilepsy can not be
treated with erythromycin alone, it could not be determined whether the adverse
events were attributable to erythromycin or to the combination of the two drugs.
Steady-state pharmacokinetic parameters of felbamate were not influenced by
erythromycin coadministration.
PMID- 9549652
TI - (R)- ketoprofen in clinical trials.
PMID- 9549653
TI - Stereoselective pharmacokinetics and inversion of (R)- ketoprofen in healthy
volunteers.
AB - The pharmacokinetics of ketoprofen enantiomers were evaluated after 25-, 50-, and
100-mg doses of (R)- ketoprofen and 100 mg of racemic ketoprofen in 25 healthy
volunteers (12 male and 13 female). The fractional inversion (Finv) of (R)-
ketoprofen was 8.9 +/- 3.3% using plasma data and 10.0 +/- 2.2% using urine data.
There were small (< 5%) but significant differences between the enantiomers for
areas under the plasma concentration-time curve (AUC) after the racemic dose (P <
0.005). Half-lives were 130-144 minutes for (R)- ketoprofen and 132-209 minutes
for (S)- ketoprofen. Dose proportionality in AUC and maximum plasma concentration
(Cmax) values was noted for both enantiomers. A total of 69% of the dose was
recovered in the urine as (R)- and (S)- ketoprofen and conjugates. The
elimination rate constant of (R)- ketoprofen was significantly different (P <
0.05) between men and women. Exposure to cyclooxygenase inhibiting (S)-
ketoprofen was approximately 10% of the dose after the administration of pure (R)
ketoprofen and was independent of gender.
PMID- 9549654
TI - Analgesic efficacy and safety of (R)- ketoprofen in postoperative dental pain.
AB - This double-blind, randomized, parallel-group study compared the analgesic
efficacy and safety of single doses of (R)- ketoprofen 25 mg and 100 mg to that
of acetaminophen 1,000 mg and placebo in 177 patients experiencing moderate to
severe pain after surgical removal of their impacted third molars. Both (R)-
ketoprofen 100 mg and acetaminophen 1,000 mg were significantly (P < 0.05) more
efficacious than placebo for all summary analgesic measures. Other than a more
rapid analgesic onset (45 minutes versus 60 minutes) for acetaminophen 1,000 mg,
(R)- ketoprofen 100 mg and acetaminophen 1,000 mg were statistically equivalent
to each other. The 25 mg dose of (R)- ketoprofen appeared to approach the
analgesic threshold dose, being numerically but not statistically superior to
placebo for all summary measures. There were no serious adverse events observed
in this study, with the overall incidence of side effects being somewhat less in
the (R)- ketoprofen groups than in the acetaminophen 1,000 mg group. (R)-
Ketoprofen possesses analgesic activity and an acceptable side-effect profile in
the oral surgery pain model.
PMID- 9549655
TI - Clinical endoscopic evaluation of the gastroduodenal tolerance to (R)-
ketoprofen, (R)- flurbiprofen, racemic ketoprofen, and paracetamol: a randomized,
single-blind, placebo-controlled trial.
AB - Ketoprofen, a nonsteroidal anti-inflammatory drug (NSAID) of the 2-arylpropionic
acid class, causes gastroduodenal hemorrhages and erosions in 10-15% of patients.
The (S)- enantiomer exhibits most of the anti-inflammatory properties, with
concomitant gastrointestinal toxicity. The (R)- enantiomer, however, was recently
found to have analgesic properties independent of prostaglandin inhibition.
Seventy-two healthy male volunteers not receiving NSAIDs, alcohol, or anti-ulcer
drugs, were enrolled in a randomized, investigator-blind, placebo-controlled
trial to evaluate the gastroduodenal tolerance of (R)- ketoprofen 100 mg b.i.d.,
(R)- flurbiprofen 100 mg b.i.d., racemic ketoprofen 100 mg b.i.d., and
paracetamol 1,000 mg b.i.d. Gastroduodenal endoscopies at baseline and after 2.5
days of dosing were used to detect newly occurring hemorrhages and erosions.
Adverse events were also recorded. The incidence of submucosal hemorrhages was
4/16 in the (R)- ketoprofen group, 5/16 in the (R)- flurbiprofen group, 12/16 in
the racemic ketoprofen group, 1/16 in the paracetamol group, and 1/8 in the
placebo group. The incidence of erosions was 2/16 in the (R)- ketoprofen group,
4/16 in the (R)- flurbiprofen group, 10/16 in the racemic ketoprofen group, 0/16
in the paracetamol group, and 2/8 in the placebo group. The differences in
hemorrhages and erosions among treatments were statistically significant (gastric
hemorrhages P = 0.0008; duodenal hemorrhages P = 0.00062; gastric erosions P =
0.0004; duodenal erosions P = 0.0062, Kruskal-Wallis test). At 100 mg b.i.d., (R)
ketoprofen caused fewer gastroduodenal hemorrhages and erosions than racemic
ketoprofen (P = 0.019, P = 0.0112, P = 0.0097, P = 0.0139 for gastric, duodenal
hemorrhages and gastric, duodenal erosions, respectively). The difference between
100 mg b.i.d. (R)- ketoprofen and 100 mg b.i.d. (R)- flurbiprofen was not
statistically significant. The dissociation between analgesic and anti
inflammatory properties for (R)- ketoprofen suggests that it may represent a
unique analgesic with a favorable safety profile.
PMID- 9549656
TI - Preclinical enantioselective pharmacology of (R)- and (S)- ketorolac.
AB - Many of the nonsteroidal anti-inflammatory drugs (NSAIDs) are marketed as racemic
mixtures, composed of (R)- and (S)- enantiomers. Racemic NSAIDs are potent
cyclooxygenase (COX) inhibitors only through the action of the (S)- enantiomers,
as the (R)- enantiomers do not exhibit COX inhibition. However, the (R)-
enantiomer of ketoprofen exhibits potent analgesic activity and minimal
ulcerogenic potential. To extend these observations, we examined the (R)- and (S)
enantiomers of RS- ketorolac, (S)- ketorolac exhibited potent COX1 and COX2
enzyme inhibition, whereas (R)- ketorolac was > 100-fold less active on both COX
subtypes. Both enantiomers did not affect norepinephrine or serotonin uptake
sites, and nitric oxidase or lipoxygenase activities, nor did they demonstrate
any affinity for opioid receptors (mu, delta, or kappa). In experimental models,
(S)- ketorolac exhibited about 10-fold greater activity than (R)- ketorolac in
the murine phenylquinone writhing model. In this model, morphine sulfate was
effective at much lower doses, however, and neither (R)- nor (S)- ketorolac
showed any morphine-sparing effect. In the rat gait test for analgesia in the
foot paw after injection of brewers yeast suspension, neither (R)- nor (S)-
ketorolac affected paw volume. However, both provoked changes in gait scores, the
(S)- enantiomer being 30-fold more potent than the (R)- enantiomer. A similar
reduction was observed with respect to ulcerogenic potential, measured by direct
microscopic changes after test conclusion. These findings suggest that (R)-
ketorolac may possess analgesic activity that is independent of COX inhibition
and may be associated with reduced ulcerogenic potential compared to effects
exhibited by (S)- ketorolac.
PMID- 9549657
TI - Products approved for marketing during 1997.
PMID- 9549659
TI - Stable isotope techniques in early drug development: an economic evaluation.
AB - Stable isotope labeled (SIL) drug methods are compared with standard methods for
performing early (phases I and IIa) drug development studies (mass balance,
bioavailability, single-dose volunteer and patient, multiple-dose volunteer and
patient). SIL methods offer considerable reduction in the cost (> 50%) and number
of subjects (67%) required for bioavailability and multiple-dose patient studies.
Moreover, a complete early drug development program is described for optimally
combining SIL and standard studies, which can reduce cost by 23% and number of
subjects by 36% compared with a program using standard methods. These reductions
should result in development time savings of at least one year.
PMID- 9549658
TI - The importance of arterial compliance in cardiovascular drug therapy.
AB - Arterial compliance, defined as a change in dimension in response to a given
change in stress, is becoming an increasingly important clinical parameter.
Related concepts, such as distensibility, elasticity, and stiffness, and more
traditional concepts such as resistance, afterload, and impedance need to be
differentiated from compliance, although they are frequently (inappropriately)
used interchangably. Many studies cannot differentiate between compliance changes
due to a drug's effect on blood pressure and those due to a drug's effect on
vessel wall integrity. This differentiation is important because a more
physiologic therapy, one that benefits pulsatile and nonpulsatile flow, should be
of greater clinical benefit than a therapy that only lowers blood pressure. A
number of methods have been used to estimate compliance, but to date there is no
generally agreed-on best method. There also are no longitudinal studies that
relate abnormal compliance and drug effects to outcome. Nonetheless, patients at
risk from a variety of disease states, such as hypertension, diabetes mellitus,
and hypercholesterolemia, may benefit from earlier recognition of abnormal
compliance. Earlier recognition may lead to interventions that would reduce their
risk. This review includes a discussion of compliance and related estimates of
blood vessel function and attempts to summarize the data currently available
regarding the effects of cardioactive drugs on arterial compliance.
PMID- 9549660
TI - Ignorability and parameter estimation in longitudinal pharmacokinetic studies.
AB - In the analysis of longitudinal pharmacokinetic data, both balanced (equal number
of samples per subject) and unbalanced data are used. It is implicitly assumed
that the process that caused the missing data can be ignored. A simulation study
was performed to determine the effect of ignoring the missing data (i.e.,
"ignorability") on the accuracy and precision of parameter estimation in
longitudinal pharmacokinetic studies. A two-compartment model with multiple
intravenous bolus inputs was assumed. Subjects with balanced data sets had six
samples, and those with unbalanced data had 1 to 5 samples missing (i.e.,
supplied in a decreasing order from 5 to 1 samples). The proportion of subjects
with 1 to 5 samples missing varied from 25% to 75% in a fixed sample size of 100.
The effect of ignorability was studied at intersubject variability ranging from
15% to 60% for a drug assumed to be dosed at its elimination half-life. One
hundred replicate data sets of 100 subjects each were simulated for each missing
data scenario. The accuracy of parameter estimation was not significantly
affected by the amount of ignorable missing data at any given level of
variability. However, the precision of parameter estimation was affected by the
degree of "missingness."
PMID- 9549661
TI - Population pharmacokinetics and pharmacodynamics of pyridostigmine bromide for
prophylaxis against nerve agents in humans.
AB - This study was conducted to determine the pharmacokinetics and pharmacodynamics
of pyridostigmine given as 30 mg of pyridostigmine bromide every 8 hours in
healthy subjects. Plasma pyridostigmine concentration and red blood cell
acetylcholinesterase activity were measured in blood samples collected during a 3
week period. Population analysis was performed using standard pharmacokinetic and
pharmacodynamic models with the nonlinear mixed-effect modeling software
(NONMEM). The pharmacokinetic model that best fit the pyridostigmine plasma
levels was a two-compartment open model with first-order absorption, a lag time,
and first-order elimination from the central compartment. The pharmacodynamic
model that best fit red blood cell acetylcholinesterase activity was an
inhibitory Emax model with an effect compartment linked to the central
compartment. The results showed that the pharmacokinetics of pyridostigmine
bromide are both gender and weight dependent. The pharmacodynamic effect does not
lag significantly from the plasma concentration and returns to near normal within
8 hours. With the present dosage regimen of 30 mg every 8 hours, 30% of
individuals may not have red blood cell acetylcholinesterase inhibition > 10% at
the time of the trough.
PMID- 9549662
TI - Pharmacokinetics, pharmacodynamics, and safety of metrifonate in patients with
Alzheimer's disease.
AB - Metrifonate is converted nonenzymatically to 2.2, dimethyl dichlorovinyl
phosphate (DDVP), an inhibitor of acetylcholinesterase (AChE). This 21-day,
randomized, double-blind, placebo-controlled trial of metrifonate in patients
with Alzheimer's disease (n = 27) evaluated four doses, each administered orally
once daily. All patients received a loading dose (LD) for 6 days followed by a
maintenance dose (MD) for 15 days. The treatment groups were: panel 1, LD = 1.5
mg/kg (75-135 mg), MD = 0.25 mg/kg (12.5-25 mg); panel 2, LD = 2.5 mg/kg (125-225
mg), MD = 0.40 mg/kg (20-35 mg); panel 3, LD = 4.0 mg/kg (200-335 mg), MD = 0.65
mg/kg (30-60 mg); and panel 4, LD = 4.0 mg/kg (200-335 mg), MD = 1.0 mg/kg (50-90
mg). All metrifonate doses were well tolerated. Most adverse events were mild to
moderate in intensity, gastrointestinal in nature, and transient. Mean area under
the concentration-time curve (AUC) and maximum concentration (Cmax) for both
metrifonate and DDVP increased in relation to dose. Metrifonate and DDVP had
similar, largely dose-independent mean values for time to Cmax (tmax) and half
life (t1/2). There was little or no accumulation of either metrifonate or DDVP
with long-term administration. After 21 days of treatment, mean percent
erythrocyte AChE inhibition was 14%, 35%, 66%, 77%, and 82% for placebo and
panels 1 through 4, respectively. Cognitive improvement was observed with the two
highest metrifonate doses. These results reflect favorable safety and
pharmacokinetic profiles for the use of metrifonate in the treatment of
Alzheimer's disease.
PMID- 9549663
TI - Pharmacokinetics and pharmacodynamics of irbesartan in healthy subjects.
AB - The safety, pharmacokinetics, and pharmacodynamics of single and multiple doses
of the angiotensin II (AII) AT1 blocker irbesartan were assessed in healthy
subjects. In this single-center, placebo-controlled, double-blind within dose
group, sequential, dose-ascending study, 48 men were randomized to receive
irbesartan at doses of 150 mg, 300 mg, 600 mg, or 900 mg daily. Subjects received
a single dose of irbesartan (n = 9 per group) or placebo (n = 3 per group),
followed by 3 days of placebo, and then multiple doses of irbesartan or placebo
once daily for 7 days. The values for plasma area under the concentration-time
curve (AUC) of irbesartan were dose proportional up to 600 mg. There were no
significant differences between the dose groups in time to maximum concentration
(tmax) or half-life (t1/2) after single and multiple doses. After multiple doses,
urinary recovery was significantly lower in the 600-mg and 900-mg dose groups
compared with the 150-mg and 300-mg dose groups. Steady-state concentrations of
irbesartan were achieved within 3 days of administration with no clinically
important accumulation. Irbesartan produced dose-dependent increases in plasma
renin activity and AII levels. Irbesartan was well tolerated at doses from 150 mg
to 900 mg daily; a maximally tolerated dose was not reached. Modest decreases in
blood pressure without orthostatic symptoms were observed at irbesartan doses of
300 mg or higher. These results demonstrated the dose-proportionality of
irbesartan 150 mg to 600 mg and indicated that doses up to 900 mg daily were well
tolerated.
PMID- 9549664
TI - Absolute bioavailability and electroencephalographic effects of conventional and
extended-release formulations of venlafaxine in healthy subjects.
AB - Venlafaxine is currently marketed for treatment of depressive disorders as a
conventional tablet formulation with a twice or three times daily dosage regimen.
The absolute bioavailability of the conventional (CF) and extended-release (XR)
formulations and their effects on electroencephalograms (EEG) and on a visual
analog scale (VAS) for nausea were assessed in a randomized, double-blind, four
way crossover, placebo-controlled study of 16 healthy young men who were given
either a single oral dose of 50 mg of CF venlafaxine, 75 mg of XR venlafaxine, or
an intravenous dose of 10 mg of venlafaxine, or a placebo at 1-week intervals.
The absolute bioavailability of venlafaxine was between 40% and 45% and was
similar for both the CF and XR formulations. Venlafaxine produced central effects
of a desipramine-like antidepressant. Regardless of formulation tested, the main
EEG changes were an increase in fast beta (20-30 Hz) energy, which was more
pronounced over the frontotemporal regions and extended within the full beta
range (16-40 Hz). Maximum effect was reached at 6 hours for the CF and reached a
plateau from 10 to 24 hours for the XR formulation. A dose-proportional increase
in central activity, expressed as area under the effect curve (AUE) of the beta
band, was observed between the CF (50 mg) and XR (75 mg) formulations. Compared
with the CF tablet, the XR formulation also produced a much less intense maximum
effect and a decrease of 63% in the AUE of nausea normalized by dose. The XR
formulation has the same absolute bioavailability and the same central activity
as assessed by EEG, but produced less intensive nausea than CF venlafaxine. The
present findings suggest that a once-daily dosage regimen should be sufficient.
This was confirmed by several clinical trials in depressive patients.
PMID- 9549665
TI - Pharmacokinetics of mycophenolic acid in renal transplant patients with delayed
graft function.
AB - The pharmacokinetics of mycophenolic acid (MPA), the immunosuppressant form of
the prodrug mycophenolate mofetil (MMF), and the primary glucuronide metabolite,
MPAG, were characterized in renal transplant patients with delayed graft function
using random effects piecewise linear models. Eight patients were evaluated after
receiving their first and subsequent daily oral doses of 1.5 g mycophenolate
mofetil twice daily on study days 1 (n = 8), 7 (n = 8), 14 (n = 5), 21 (n = 2),
and 28 (n = 7). The area under the concentration-time curve from zero to 12 hours
(AUC0-12) for MPA, MPAG, MPA free fraction, and free MPA were analyzed in serial
plasma samples using validated high-performance liquid chromatography and
ultrafiltration procedures. Random effects piecewise linear models, fit by
maximum likelihood methods, were applied to AUC0-12 of MPA and MPAG, MPA free
fraction, AUC0-12 of free MPA, and serum creatinine concentration, the index of
renal function used in this study. Two hemodialysis sessions did not lower MPA
plasma concentration, although some MPAG was removed. The AUC0-12 of MPA
increased as a function of time, although it was not possible to fit a
statistical model to the data due to considerable among-patient variation in the
pattern of increase with time. The AUC0-12 of MPAG, MPA free fraction, and AUC0
12 of free MPA reached maximal values on day 7; each of these parameters had
unique day 1 to 7 positive slope values and unique day 7 to 28 negative slope
values. The average creatinine concentration was maximal at day 1 and a unique
negative slope was obtained between days 7 and 28. Thus, this study provides
statistical models for the alteration of AUC0-12 of MPAG, MPA free fraction, AUC0
12 of free MPA, and serum creatinine in renal transplant patients with delayed
graft function. These results provide evidence that renal dysfunction is
associated with altered pharmacokinetics of MPA, particularly increased AUC0-12
of MPAG, MPA free fraction, and AUC0-12 of free MPA. The perturbed
pharmacokinetics normalized with improving renal function.
PMID- 9549666
TI - Single-dose pharmacokinetics of modafinil and methylphenidate given alone or in
combination in healthy male volunteers.
AB - Modafinil is a novel wake-promoting agent being developed for treatment of
excessive daytime sleepiness associated with narcolepsy. An open, 3 x 3 Latin
square, randomized, cross-over study was performed in healthy males to compare
the pharmacokinetics of single-dose oral modafinil (200 mg) and methylphenidate
(40 mg) administered alone or in combination. Blood samples were obtained for
analysis of d- and l-threo-methylphenidate and modafinil and its acid and sulfone
metabolites. Pharmacokinetic parameters were determined by noncompartmental
methods, but could not be evaluated for modafinil sulfone due to plasma levels
that were close to the assay quantitation limit. Although sporadic differences in
plasma concentrations were observed between treatments, coadministration of
modafinil and methylphenidate did not significantly alter the plasma
concentrations of modafinil, modafinil acid, modafinil sulfone, or
methylphenidate enantiomers compared with administration of these agents alone.
Half-life (t1/2), maximum concentration (Cmax), area under the concentration-time
curve (AUC0-infinity), total clearance (Cl/F), and apparent volume of
distribution (Vd/F) for modafinil and t1/2, Cmax, and AUC0-infinity for modafinil
acid were not affected by concomitant administration of methylphenidate. Small
but statistically significant increases in time to Cmax (tmax) were observed for
modafinil and modafinil acid after methylphenidate coadministration compared with
modafinil alone. Modafinil coadministration did not significantly alter the
pharmacokinetics of d- or l-threo-methylphenidate, except for a small decrease in
Vd/F of l-threo-methylphenidate. Concomitant methylphenidate may cause a delay in
the oral absorption of modafinil, but this delay might not be relevant
clinically. Coadministration did not alter the extent of oral absorption and
disposition of either agent. Therefore, a pharmacokinetic interaction between
modafinil and methylphenidate would be unlikely.
PMID- 9549667
TI - Paradoxical hypotension and bradycardia after intravenous arginine vasopressin.
AB - Standard therapy for variceal bleeding includes endoscopic sclerotherapy and
esophageal balloon tamponade. In addition, pharmacologic therapies, including
arginine vasopressin (AVP), are frequently used in hemodynamically unstable
patients or where sclerotherapy has been unsuccessful. A case is described herein
of a 30-year-old woman with a history of ethanol abuse, hematemeisis, and biopsy
proven hepatic cirrhosis in which the addition of AVP to an antivariceal regimen
of octreotide was associated with a paradoxical episode of hypotension,
bradycardia, and hypoxia. Indeed, within 15 minutes after initiation of an AVP
infusion, the patient exhibited hypotension with a systolic blood pressure of 80
mmHg, a relative bradycardia to 76 beats per minute, and a desaturation of blood
oxygen to 84%. The AVP infusion was discontinued 2 hours later and blood
pressure, heart rate, and oxygen saturation rapidly returned to baseline. This
temporal correlation between the onset and termination of the physiologic effects
and the initiation and discontinuation of the AVP infusion suggests a causal
relationship. The paradoxical physiologic effects might reflect cardiac ischemia
secondary to vasospasm and/or central suppression of the autonomic nervous system
induced by AVP.
PMID- 9549668
TI - A social interactionist view of autism and its clinical management.
PMID- 9549669
TI - Describing the unusual behavior of children with autism.
AB - The behaviors of children with autism have been described by professionals, by
family members, and also by those with autism. This article analyzes four
different types of reports that contain descriptions of those with autism: (1)
case studies, (2) diagnostic reports and single-subject research studies, (3)
family accounts, and (4) autobiographical descriptions. Authors describe the
behaviors of those with autism differently depending upon their relationship with
the person they are describing, their intended audience, their goals, and the
genre they use for conveying their descriptions. Authors were found to use the
following types of descriptions, to varying degrees in order to achieve their
goals: (1) descriptions of what a child did on a particular occasion; (2)
descriptions of what a child typically does or did; (3) descriptions of what a
child should have done; (4) descriptions of how behavior was experienced by a
child or family member; (5) descriptions of how a third party reported a
behavior; (6) metaphoric descriptions of behaviors; and (7) descriptions of how
behaviors mesh with traits often associated with autism. A detailed examination
of how behaviors of children with autism are described indicates that the way
someone with autism is regarded and described is strongly related to what the
describer wants to accomplish.
PMID- 9549670
TI - Structural patterns in conversations with a woman who has autism.
AB - The experience of conversing with a person who has autism is often described as
unsatisfactory. This article offers some suggestions as to why that might be.
Conversation between an adult diagnosed as autistic and a researcher was
transcribed and analyzed using the methodology of Conversation Analysis. The
analysis highlights differences in conversational style between the two
participants based on features such as topic movement, topic maintenance,
repairs, interference from earlier structures and common collocations, overlaps,
latching, and pauses. It is suggested that many of the features of the subject's
talk which result in an overly repetitive style may be cognitively motivated.
PMID- 9549671
TI - Influence of question type on response adequacy in young adults with autism.
AB - Sources of difficulty in comprehending conversational questions for individuals
with autism may be multifarious, given the complexity of the disorder. This study
investigated success in responding to naturalistic conversational questions by
six young adults with autism, using a quantitative discourse analytic method.
Subjects, aged 19-21, who were able to converse in at least simple sentences,
were engaged in conversation about events and activities in their lives. From the
transcripts of these conversations, four types of questions were isolated for
analysis: more than seven words in length; multiclausal; requiring inference; and
indirect requests for information. It was predicted that inference-based
questions would be more difficult than the other types. Findings did not support
this prediction. All four types showed a higher failure rate than the overall
failure rate for responses to conversational questions. Clinical implications
include the need for conversational assessment of receptive language functioning
for individuals with autism. Suggestions for such assessments are provided.
PMID- 9549672
TI - Augmentative and alternative communication to support receptive and expressive
communication for people with autism.
AB - In this article the authors discuss the use of augmentative and alternative
communication (AAC) as used to enhance comprehension and expression of people
with autism. A theoretical model for AAC assessment and intervention planning is
presented. Application of the model is illustrated through a case report of a 6
year-old boy with autism who had severe expressive and receptive language
impairments.
PMID- 9549673
TI - An intervention technique for children with autistic spectrum disorder: joint
attentional routines.
AB - Virtually all children with autism are deficient in joint attentional skills. The
impact of this deficit may be understood in the context of pragmatically based
explanations of language acquisition. In this view, each step in the ontongeny of
joint attention is consequential for language development. Thus, it is important
that speech-language pathologists understand the developmental course of joint
attention so that intervention may start at the earliest step possible. In this
article, we review the literature on joint attention and its relationship with
other rule systems of language. We discuss the ontogeny of joint attention in
typical children. Finally, we describe the developmental course of joint
attention as a framework for language intervention through the study of one case.
PMID- 9549674
TI - Doctors should not try to ban boxing--but boxing's own ethics suggests reform.
PMID- 9549675
TI - Treating anorexics without consent: some reservations.
PMID- 9549676
TI - Against medical ethics: opening the can of worms.
AB - In a controversial paper, David Seedhouse argues that medical ethics is not and
cannot be a distinct discipline with it own field of study. He derives this claim
from a characterization of ethics, which he states but does not defend. He claims
further that the project of medical ethics as it exists and of moral philosophy
do not overlap. I show that Seedhouse's views on ethics have wide implications
which he does not declare, and in the light of this argue that Seedhouse owes us
a defence of his characterization of ethics. Further, I show that his
characterization of ethics, which he uses to attack medical ethics, is a
committed position within moral philosophy. As a consequence of this, it does not
allow the relation between moral philosophy and medical ethics to be discussed
without prejudice to its outcome. Finally, I explore the relation between
Seedhouse's position and naturalism, and its implications for medical
epistemology. I argue that this shows us that Seedhouse's position, if it can be
defended, is likely to lead to a fruitful and important line of inquiry which
reconnects philosophy and medical ethics.
PMID- 9549678
TI - Xenografting: ethical issues.
AB - This paper considers the ethical issues raised by xenotransplantation under four
headings: interfering with nature; effects on the recipient; effects on other
humans; and effects on donor animals. The first two issues raise no insuperable
problems: charges of unnaturalness are misguided, and the risks that
xenotransplantation carries for the recipient are a matter for properly informed
consent. The other two issues raise more serious problems, however, and it is
argued that if we take seriously the risk of transferring new infectious agents
from animal to human populations and the interests of donor animals, then a
moratorium on xenotransplantation is called for. The paper finds that the recent
Nuffield Council and Department of Health reports on xenotransplantation are
insufficiently cautious in the conclusions that they draw from these
considerations.
PMID- 9549679
TI - Postmodernity and a hypertensive patient: rescuing value from nihilism.
AB - Much of postmodern philosophy questions the assumptions of Modernity, that period
in the history of the Western world since the Enlightment. These assumptions are
that truth is discoverable through human reason; that certain knowledge is
possible; and furthermore, that such knowledge will provide a basis for the
ineluctable progress of Mankind. The Enlightenment project is underwritten by the
conviction that knowledge gained through the scientific method is secure. In so
far as biomedicine inherits these assumptions it becomes fair game for postmodern
deconstruction. Today, perhaps more than ever, plural values compete, and
contradictory approaches to health, for instance, garner support and acquire
supremacy through consumer choice and media manipulation rather than evidence
based science. Many doctors feel a tension between meeting the needs of the
patient face to face, and working towards the broader health needs of the public
at large. But if the very foundations of medical science are questioned, by
patients, or by doctors themselves, wherein lies the value of their work? This
paper examines the issues that the anti-foundationalist thrust of postmodernism
raises, in the light of a case of mild hypertension. The strict application of
medical protocol, derived from a nomothetic, statistical perspective, seems
unlikely to furnish value in the treatment of an individual. The anything goes,
consumerist approach, however, fares no better. The author argues that whilst
value cannot depend on any rationally predetermined parameters, it can be
rescued, and emerges from the process of the meeting with the patient.
PMID- 9549680
TI - Advance directives for non-therapeutic dementia research: some ethical and policy
considerations.
AB - This paper explores the use of advance directives in clinical dementia research.
The focus is on advance consent to participation of demented patients in non
therapeutic research involving more than minimal risks and/or burdens. First,
morally relevant differences between advance directives for treatment and care,
and advance directives for dementia research are discussed. Then attention is
paid to the philosophical issue of dementia and personal identity, and the
implications for the moral authority of research advance directives. Thirdly, a
number of practical shortcomings of advance directives for non-therapeutic
dementia research are explored and attention is paid to the role of proxies. It
is concluded that upon a closer look the initial attractiveness of advance
directives for dementia research is lessened, and that it is doubtful whether
these instruments can compensate for the lack of subject consent in case of non
therapeutic dementia research involving more than minimal risks and/or burdens
for the incompetent demented subject.
PMID- 9549681
TI - The ethics of compulsory removal under section 47 of the 1948 National Assistance
Act.
AB - Orders for removal under Section 47 of the 1948 National Assistance Act are
little discussed. However, they involve severe infringements of the civil
liberties of those affected. It is argued that all previously presented
justifications for the use of these orders fail. Repeal of the act is called for.
The Law Commission has drafted alternative legislation, but this has not been
enacted. Until this occurs local authorities, the Faculty of Public Health
Medicine and individual public health physicians should refuse to be involved in
its use.
PMID- 9549682
TI - Autonomy and paternalism in geriatric medicine. The Jewish ethical approach to
issues of feeding terminally ill patients, and to cardiopulmonary resuscitation.
AB - Respecting and encouraging autonomy in the elderly is basic to the practice of
geriatrics. In this paper, we examine the practice of cardiopulmonary
resuscitation (CPR) and "artificial" feeding in a geriatric unit in a general
hospital subscribing to jewish orthodox religious principles, in which the
sanctity of life is a fundamental ethical guideline. The literature on the
administration of food and water in terminal stages of illness, including
dementia, still shows division of opinion on the morality of withdrawing
nutrition. We uphold the principle that as long as feeding by naso-gastric (N-G)
or percutaneous endoscopic gastrostomy (PEG) does not constitute undue danger or
arouse serious opposition it should be given, without causing suffering to the
patient. This is part of basic care, and the doctor has no mandate to withdraw
this. The question of CPR still shows much discrepancy regarding elderly
patients' wishes, and doctors' opinions about its worthwhileness, although up to
10 percent survive. Our geriatric patients rarely discuss the subject, but it is
openly ventilated with families who ask about it, who are then involved in the
decision-making, and the decision about CPR or "do-not-resuscitate" (DNR) is
based on clinical and prognostic considerations.
PMID- 9549683
TI - Doctors, ethics and special education.
AB - This discussion paper is drawn from a qualitative research project comparing the
effect of special and ordinary schools on the lives of children, young people and
their families. Special schools are recommended by health professionals who
seldom know how ineffective these schools are. We question the beneficence and
justice of health professionals' advice on education for children with
disabilities and other difficulties. Cooperation with local education authorities
(LEAs) plays a considerable part in the work of community paediatricians,
clinical medical officers, therapists and other health professionals encountering
children with "special needs". The "needs" range from physical disability and
sensory impairment to learning difficulties and emotional or behavioural
difficulties. This cooperation involves routine administrative problems, but it
raises broad ethical issues too, particularly in respect of current tendencies in
state schooling towards the integration or inclusion of these children in
mainstream schools and classes.
PMID- 9549684
TI - Freedom to box.
AB - The british Medical Association wants to criminalise all boxing. This article
examines the logic of the arguments it uses and finds them wanting. The move from
medical evidence about the risk of brain damage to the conclusion that boxing
should be banned is not warranted. The BMA's arguments are a combination of
inconsistent paternalism and legal moralism. Consistent application of the
principles implicit in the BMA's arguments would lead to absurd consequences and
to severe limitations being put on individual freedom.
PMID- 9549685
TI - Nuclear cardiology, Part I: Anatomy and function of the normal heart.
AB - This is the first article of a four-part series on nuclear cardiology. This
article introduces and reviews the anatomy and function of the normal heart.
Future articles will develop the contribution of nuclear medicine techniques in
evaluating myocardial perfusion, function and viability. This article describes
the external and internal features of the heart and its vascularization,
conducting system and physiological function. After reading this article, the
reader should understand the anatomy and the function of the normal heart.
PMID- 9549686
TI - Scintillation camera quality control, Part I: Establishing the quality control
program.
AB - This is the first article in a four-part series on scintillation camera quality
control. This series of articles will include both theory and practical knowledge
on setting up a quality control program, acceptance testing and quality control
for planar, SPECT and special imaging procedures. On completion of this article
the reader should be able to: (a) discuss the purpose of a quality control
program; (b) know how to establish the performance criteria for a scintillation
camera; (c) know how to design a quality control program; (d) be able to set up
the schedule for the quality control program; (e) understand the economics of
quality control; and (f) justify the expenditure of the institution's resources
on quality control.
PMID- 9549687
TI - Thinking nuclear medicine--PET activation.
AB - PET activation, although restricted to a limited number of research centers, is
currently the gold standard for mapping functional areas of the brain. This paper
outlines how and why activation studies are performed and reviews the major uses
of this technique. Special emphasis is on cognitive neuropsychology including the
results of a project designed to map the areas of the brain responsible for
controlling automatic counting and simple calculation. These fascinating studies
are, by definition, a part of nuclear medicine. As such, we argue that knowledge
of PET activation is an essential component of professional development and that,
given opportunity, commitment and the will to learn, nuclear medicine
technologists have the potential for involvement, collaboration or leadership in
this area of research.
PMID- 9549688
TI - Off-site determinations of effective renal plasma flow using technetium-99m-MAG3
and single blood sampling.
AB - This study evaluated the feasibility of determining effective renal plasma flow
(ERPF) at an off-site central laboratory by transferring blood samples from the
on-site laboratory. METHODS: Blood samples were obtained from 66 patients
referred for renal imaging with 99mTc-MAG3. ERPF values were determined using the
single blood sample method (BSM) at both on- and off-site laboratories. The ERPF
values were classified clinically as normal or abnormal. Both the ERPF values and
clinical classification were compared between on- and off-site laboratories.
RESULTS: The off-site ERPF overestimated those on-site by 2.8% (paired Student's
t-test p < 10(-5)). However, off-site ERPF values highly correlated with the
values obtained on-site (r = 0.99; p < 10(-5)). In addition, the clinical
classification for each patient determined at each site was identical.
CONCLUSION: ERPF can be determined accurately off-site. This method should allow
many nuclear medicine departments access to the ERPF determination by the BSM at
a central off-site laboratory.
PMID- 9549689
TI - The lung scan in patient selection for lung volume reduction surgery.
AB - The lung scan is one of the most important diagnostic tests used for selecting
candidates for lung volume reduction surgery (LVRS) and for determining the
actual percentage of lung to be resected during the surgery (McKenna R, personal
communication, 1997). This article describes the anatomical quantitation of the
lungs. METHODS: We used automatic and manual regions of interest in the
posterior, and both posterior obliques of lung perfusion images to calculate the
percent function in each individual lung lobe. RESULTS: We evaluated 172 patients
with this technique. Subsequently 136 of these patients had LVRS. CONCLUSION: The
anatomical placement of regions of interest in the lung perfusion image aids the
thoracic surgeon in selecting LVRS candidates and in determining the amount of
lung to be resected during surgery.
PMID- 9549690
TI - Occult intestinal bleeding imaged by technetium-99m-HSA-D radionuclide
angiography: a case report.
AB - Radionuclide angiography (RNA) with 99mTc-diethylenetriamine pentaacetic acid
human serum albumin (99mTc-HSA-D) is a sensitive screening method for diagnosing
systemic perfusion abnormalities. Sometimes the results produce unexpected
information. This information is helpful when considering the clinical perfusion
pathophysiology. Recently, we were able to detect an intestinal bleeding lesion
clearly for a patient by using RNA.
PMID- 9549691
TI - Dose from syringe procedures during technetium-99m radiopharmaceutical
preparation.
AB - We examined the dose from 99mTc contained in syringes and shielded vials to
assess in detail the dose burdens in a central pharmacy. METHODS: Absorbed-dose
rates at the end of the plunger of a shielded syringe, when 99mTc is contained
either in the syringe or in a shielded vial from which the activity would be
drawn, were measured with CaF2 dosimeters. The dose rates also were calculated
with a Monte Carlo model. RESULTS: When activity was contained in either 3-ml or
10-ml disposable syringes shielded by lead glass, the absorbed-dose rates were
1.35-1.62 mGy hr-1 GBq-1 (5-6 mrad hr-1 mCi-1). When the activity was contained
in either a shielded elution or product kit vial, the absorbed-dose rates at the
end of the syringe plunger were about 0.40 mGy hr-1 GBq-1 (1.4-1.5 mrad hr-1 mCi
1). These results were reproduced with reasonable accuracy by Monte Carlo
simulations. CONCLUSION: The dose burden per unit of activity handled from 99mTc
in procedures using syringes is likely to be two to five times larger than the
dose burden from calibrating generator eluate. The Monte Carlo simulations
suggest that lead K x-rays may be responsible for a significant fraction of the
total dose to the fingers and hand of the pharmacist when lead-glass syringe
shields are used.
PMID- 9549692
TI - Using the ACNP Proficiency Testing Program to develop critical thinking. American
College of Nuclear Physicians.
AB - Critical thinking is cited as one of the essential skills for clinical practice.
Educators need to be aware of barriers that may hinder the development of this
skill in students and cultivate strategies to encourage it. This article
describes one strategy to develop critical thinking. METHODS: Students
participated in a critical thinking exercise by imaging the American College of
Nuclear Physicians (ACNP) Renal Imaging Proficiency Test Phantom, critiquing
their results, and comparing their results to results collected nationally in
other nuclear medicine facilities and the true values reported by the ACNP.
Students were instructed to review pertinent imaging principles before discussing
the imaging results. They also were supplied with a list of questions pertinent
to the review. RESULTS: Students experienced the complexity of designing a SPECT
imaging protocol and how the final results are affected by the choices made by
the technologist. They learned the importance of and method for proper matrix
selection, determination of pixel size and the necessity for quality control.
CONCLUSION: The imaging exercise was a successful means of helping students
connect clinical practice with theory through the use of critical thinking.
PMID- 9549693
TI - Technetium-99m DTPA aerosol contamination in lung ventilation studies.
AB - Contamination of working areas by 99mTc DTPA aerosol is of concern to nuclear
medicine technologists. This study sought to determine the extent of 99mTc DTPA
contamination to technologists, and to localize sources of aerosol leakage so
that methods could be identified that would minimize contamination. METHODS:
Fifty to eighty millicuries 99mTc DTPA, diluted to a volume of 4-5 ml with normal
saline, were injected into the nebulizing chamber of two commercially available
inhalation aerosol systems. The patient's nostrils were clamped and a damp
washcloth was wrapped around the patient's mouth. An alcohol swab was placed in
the exit port of the exhaust filter in each delivery system, and the technologist
involved wore a face mask during the inhalation phase. The patient breathed DTPA
labeled aerosol by mouth until the counting rate in the lungs was four times
greater than the counting rate from the pulmonary perfusion phase. Connecting
joints of the delivery system were then wipe tested. Last, a Geiger-Mueller
detector (pancake probe) was used to survey all device components. Readings above
0.05 mR/hr were considered contaminated. RESULTS: The patient was the greatest
source of leakage as determined by the damp washcloth, followed by the joints of
the tubes of the delivery system and, finally, the system's exhaust filter.
Contamination readings from face masks worn by technical personnel during the
lung ventilation studies were slightly greater than 0.05 mR/hr. CONCLUSION: The
findings support trace levels of contamination to both the technologist and room
while performing 99mTc DTPA aerosol ventilation studies. Comparative data using
the two delivery systems revealed little difference in sources of leakage and
little variation in contamination measurements.
PMID- 9549694
TI - Performance and responsibility guidelines for the nuclear medicine technologist:
1998 revision. Society of Nuclear Medicine-Technologists.
PMID- 9549695
TI - NMTCB 1997. Task analysis report. Nuclear Medicine Technology Certification
Board.
PMID- 9549696
TI - Fetal monitoring terminology.
PMID- 9549697
TI - Something to talk about: sexual risk communication between young women and their
partners.
AB - OBJECTIVES: To describe sexual risk communication between young women and their
male sexual partners and examine its impact on women's perceptions of sexual
risk. DESIGN: The study and results reported were part of a larger descriptive,
retrospective study in which data were collected from young women and their male
partners via telephone interviews. PARTICIPANTS: Participants included 93
unmarried, sexually active heterosexual women, ages 17 to 26 years, and 82 of
their male sexual partners. The sample was predominantly white; all other ethnic
groups were underrepresented. RESULTS: Nearly all of the women described their
partners as "no risk" or "low risk," despite the fact that nearly half never
discussed their partner's sexual risk histories. Women gave three primary reasons
why sexual risk was not discussed: (a) did not know the partner well enough/too
embarrassed to ask; (b) "knew" the partner was low risk/no need to discuss it;
and (c) did not think of it. CONCLUSIONS: Nurses should adopt and promote the
premise that all sexually active women are at some risk for sexually transmitted
diseases (STDs), including human immunodeficiency virus (HIV). Furthermore,
sexually active women should be advised to distinguish between what they think
they know about their partners and what they actually know. As client advocates,
nurses should empower women to recognize that they have the right to insist on
full sexual history disclosure and STD/HIV testing, to question whether they want
to have sexual relations, and to refuse to engage in sexual activity if they
wish.
PMID- 9549698
TI - Clinical presentation of women readmitted with postpartum severe preeclampsia or
eclampsia.
AB - OBJECTIVE: To identify symptoms that prompted a group of women readmitted for
postpartum severe preeclampsia or eclampsia to seek medical care. DESIGN:
Retrospective, case-control. SETTING: Tertiary-care teaching hospital. SUBJECTS:
The study group consisted of 53 women readmitted in the postpartum period with
severe preeclampsia or eclampsia. The control group was matched two-to-one with
an index study participant and consisted of 106 women who had intrapartum severe
preeclampsia or eclampsia. MAIN OUTCOME MEASURES: Patient symptoms, physical
findings, laboratory assays. RESULTS: Neurologic complaints, malaise, and nausea
and vomiting were reported more often in women who were readmitted than in
mothers with intrapartum preeclampsia (all p values less than .001). Headaches
were positively correlated with systolic, diastolic, and mean arterial blood
pressure in women who were readmitted (all p values less than .05), although
there was no relationship between blood pressure and headaches in the control
group. In addition, multivariate analysis revealed that study participants were
more likely to deliver at full term, have headaches and malaise, have normal
platelet values, and develop seizures than mothers in the control group, chi 2 =
155.7, p < .001. CONCLUSIONS: Women readmitted for postpartum severe preeclampsia
or eclampsia have a clinical presentation that differs from that of intrapartum
preeclampsia or eclampsia.
PMID- 9549700
TI - Lifestyle factors related to postpartum weight gain and body image in bottle- and
breastfeeding women.
AB - OBJECTIVE: To explore the relationship of lifestyle variables to postpartum
weight gain and body image attitudes of bottle- and breastfeeding women. DESIGN:
Mail survey of new mothers at approximately 4 months postpartum. SETTING:
Southwestern community. PARTICIPANTS: One hundred one bottle-feeding women (69%
white, 20% Hispanic, 11% other) and 106 breastfeeding women (76% white, 19%
Hispanic, 5% other) without diabetes. Bottle- and breast-feeding women did not
differ on gestational weight gain or weight gain sustained postpartum. MAIN
OUTCOME MEASURES: Postpartum weight gain (relative to prepregnancy weight) and
body image attitudes. RESULTS: Feeding method (breast or bottle) was not
associated with postpartum weight gain in the sample as a whole. Bottle-feeding
mothers with higher postpartum gains exercised less, had higher fat intake
habits, and were more dissatisfied with body image than mothers with lower gains.
Breast-feeding mothers with higher and lower gains did not differ on any
lifestyle factors. Overall lifestyle and psychologic skill in managing emotions
were related negatively to postpartum body image dissatisfaction in both groups
of women. CONCLUSIONS: Breastfeeding women did not differ from bottle-feeding
women in sustained postpartum weight gain. In bottle-feeding women, lifestyle
factors were associated with levels of weight gain. Lifestyle-focused programs
for weight management would potentially benefit these women.
PMID- 9549699
TI - Early postpartum discharge: how are mothers managing?
AB - OBJECTIVE: To describe maternal concerns at 2 weeks and mothers' ability to
function in various roles at 4 weeks postpartum. DESIGN: Subjects were mailed
questionnaires at 2 and 4 weeks postpartum. SETTING: A mid-Atlantic hospital that
is a part of an academic health center. PARTICIPANTS: A convenience sample of 100
healthy women who were discharged < or = 48 hours postpartum and met the study
criteria. MAIN OUTCOME MEASURES: Instruments included a demographic
questionnaire, the Maternal Concerns Questionnaire, and the Inventory of
Functional Status After Childbirth. RESULTS: Physiologic concerns during the
early postpartum period related primarily to perineal sutures, breast care, body
image, and fatigue. More than 25% of the women continued to experience depression
at 2 weeks, and 40% had days at 1 month when they never got dressed. Much concern
was expressed about the mothering role but little about interaction with the
mate. Older maternal age was associated with a longer hospital stay, and the
trend suggested improved functioning at 1 month with longer hospitalization. More
than half of the participants said they would visit a nurse-run clinic during the
1st postpartum week if given the opportunity. CONCLUSIONS: The results provide
descriptive information about effects of early hospital discharge. Mothers
discharged in 48 hours or less adjust to motherhood without the education and
assessment that was formerly possible with extended hospitalization. The current
study reinforces the need for nurses to explore strategies in hospitals or
communities to provide early care for postpartum mothers.
PMID- 9549701
TI - Postpartum teaching priorities: the viewpoints of nurses and mothers.
AB - OBJECTIVE: To compare mothers' and nurses' perceptions of postpartum learning
needs and effective teaching modalities. DESIGN: Cross-sectional research design.
Mothers were given a questionnaire during their postpartum stay to rate how
important it was for them to learn about 44 maternal-infant topics before
discharge. Nurses rated similar items on the basis of their perception of what is
most important for mothers to learn during their postpartum stay. SETTING:
Postpartum units in six hospitals that are part of a large midwestern health care
system. PARTICIPANTS: English-speaking women who delivered either vaginally or by
cesarean section without complications and the nurses on their postpartum units.
MAIN OUTCOME MEASURES: Identification of preferred topics and methods for
postpartum teaching. RESULTS: Mothers and nurses agreed that topics related to
immediate physical health needs were most important. Unmarried mothers considered
topics related to personal care and mobility as particularly important. First
time mothers rated more topics as important than did experienced mothers.
Individual teaching was rated most effective by both groups. Classroom teaching
and the use of audiovisual media were considered less effective. CONCLUSIONS:
This study supports postpartum education that focuses on the physical needs of
mothers and infants, as well as individual teaching models. The special learning
needs of new mothers, including those who are not married, must be considered.
PMID- 9549702
TI - Mother-infant interaction and breastfeeding outcome 6 weeks after birth.
AB - OBJECTIVE: This study explored the relationship of early postpartum maternal
infant interactions to breastfeeding outcome at 6 weeks postpartum. DESIGN:
Prospective, comparative descriptive study. SETTING: Women, Infants, and Children
Supplemental Nutrition Program and Comprehensive Perinatal Services Programs in
northern California. PARTICIPANTS: Forty-two Latina participants were recruited
in the 3rd trimester of pregnancy. Eligibility criteria included age 18 years or
older, primiparous at recruitment, antepartum desire to breastfeed 8 weeks or
longer postpartum, planned hospital birth, full-term vaginal birth of a healthy
newborn, and an uncomplicated, immediate postpartum course for mother and
newborn, including being discharged together. MAIN OUTCOME MEASURES: The study
examined breastfeeding dyads' early postpartum scores on Barnard's Nursing Child
Assessment Feeding Scale (NCAFS) in relation to breastfeeding outcome 6 weeks
postpartum. NCAFS tests were performed 28-90 hours postpartum in the
participants' homes, and breastfeeding status was assessed by phone contact 6
weeks postpartum. RESULTS: Dyads continuing to breastfeed at 6 weeks postpartum
had significantly higher early postpartum NCAFS scores than did dyads who had
weaned from the breast by 6 weeks postpartum. CONCLUSIONS: Optimal maternal
infant interactions, as evidenced by higher scores on Barnard's NCAFS, were
related to longer breastfeeding duration. Lower scores on the NCAFS, suggesting
difficulties in maternal-infant interaction, were related to weaning earlier than
planned.
PMID- 9549703
TI - Attitudes and practices of registered nurses toward women who have experienced
abuse/domestic violence.
AB - OBJECTIVE: To compare the education, attitudes, and practices related to domestic
violence of perinatal nurses from three types of practice sites. DESIGN: A
descriptive study of responses to a questionnaire administered to a convenience
sample and through a mailing. SETTING: Education conferences and responses to a
mailing. PARTICIPANTS: Two hundred seventy-five nurses in perinatal practice (87
public health, 71 hospital, 117 private office). MAIN OUTCOME MEASURES: Primary
outcomes were attitudes and beliefs about domestic violence and nursing behavior
when domestic violence was identified. The effects of education about domestic
violence on practice and the effect of a personal/family history of domestic
violence on practice were examined. RESULTS: Some differences were found in the
attitudes and beliefs of nurses from different practice sites, but more
differences were found in their behaviors. Only 54% of the total sample reported
having education about domestic violence, received in formal or continuing
education programs. Public health nurses were the most likely to have such
education. Education affected both attitudes and behavior. In the total sample,
31% of nurses reported abuse of themselves or family members. CONCLUSIONS:
Nursing care for women who have experienced domestic violence includes assessment
and appropriate counseling. Many nurses in this study lacked education about
domestic violence. The provision of education about abuse and domestic violence
is a first step toward a change in nursing practice.
PMID- 9549704
TI - Pregnancy after perinatal loss: the relationship between anxiety and prenatal
attachment.
AB - OBJECTIVE: To determine the difference between levels of pregnancy-specific
anxiety and prenatal attachment in a group of pregnant women who previously had a
late pregnancy loss and a group of primiparous women of similar gestational age.
To also determine the relationship, if any, between anxiety and prenatal
attachment in both groups. DESIGN: A nonrandom, comparative descriptive design.
SETTING: Participants recruited from medical offices, childbirth classes, and
perinatal support groups and newsletters. PARTICIPANTS: A convenience sample of
31 expectant mothers (15 primiparae and 16 who previously experienced a late
pregnancy miscarriage, stillbirth, or neonatal death). Both groups of women were
in the 2nd or 3rd trimester of their current pregnancy. MAIN OUTCOME MEASURES:
Anxiety was measured using the Pregnancy Outcome Questionnaire; prenatal
attachment was measured using the Prenatal Attachment Inventory. RESULTS: The
loss group showed significantly greater levels of anxiety and significantly lower
levels of prenatal attachment compared with a group of primiparous women of a
similar gestational age. CONCLUSIONS: Women who experienced a previous late
pregnancy loss had a higher level of anxiety related to concerns about the
pregnancy and decreased prenatal attachment with the child in the current
pregnancy. Women in their first pregnancy had decreased anxiety compared with the
loss group. Higher levels of prenatal attachment also were shown in the
primiparous group.
PMID- 9549705
TI - Childbearing in Malawi, Africa.
AB - Malawi is a small, landlocked country in South Eastern Africa that faces many
challenges in providing health care to childbearing women. Through a partnership
between the faculty of the University of Pennsylvania, School of Nursing, faculty
of the Kamuzu College of Nursing in Malawi, and the Malawi Ministry of Health and
Population, an ongoing collaboration has led to research and demonstration
projects designed to improve the health of women and children in Malawi. To
underscore the cultural context within which childbearing occurs, care of the
childbearing family in Malawi is described, as is research that has documented
some of the similarities and differences between childbearing in Malawi and the
United States.
PMID- 9549706
TI - Developing a research mentoring partnership in Israel.
AB - A relationship begun in 1985 between the University of Pennsylvania School of
Nursing and the Henrietta Szold Hadassah/Hebrew University has included a student
exchange program and a faculty mentoring partnership. The student exchange
focused on maternal-child nursing and led to the development of the faculty
mentoring program. The goals of the latter program are to increase the expertise
of the Israeli nursing faculty in the development of grant applications,
publications, and abstracts and to develop a National Institutes of Health
supported research project with an Israeli nursing faculty as principal
investigator.
PMID- 9549707
TI - Nursing in the newly independent states of the former Soviet Union: an
international partnership for nursing development.
PMID- 9549708
TI - An effort to upgrade perinatal nursing practice in Albania.
AB - In 1994 the Jacobi Medical Center in Bronx, New York, and the University Hospital
in Tirana, Albania, entered into a partnership designed to upgrade certain
aspects of the health care system in Albania. During a 2-week trip, an American
contingent of nurses and nurse-midwives worked to increase the knowledge base of
Albanian nurses about some of the most important issues in perinatal care and of
the roles of nurses and nurse-midwives in the United States as patient advocates
and educators.
PMID- 9549709
TI - Functional ability perceived by individuals following total knee arthroplasty
compared to age-matched individuals without knee disability.
AB - A comparison of function of individuals 1 year after total knee arthroplasty
(TKA) with healthy control subjects (controls) meaningfully describes outcome in
these patients. Perception of function measured by two questionnaires, the Lower
Extremity Activity Profile (LEAP) and the Western Ontario McMaster Osteoarthritis
Index (WOMAC), and walking and stair performance was compared between 29
patients, 1 year after TKA, and 40 controls. There was significantly greater
perceived difficulty with function in patients with TKA than in controls. In TKA
men, LEAP and WOMAC scores correlated respectively with self-paced walk speed (r
= -.71 and -.55) and stair performance time (r = 0.70 and 0.68). In TKA women,
LEAP difficulty score correlated with self-paced walk speed (r = -.41) and stair
performance time (r = -0.71). By 1 year, TKA subjects regained 80% of the
function of controls. Perception of function after TKA can be measured by either
questionnaire in men; however, the LEAP is the preferable questionnaire with
women.
PMID- 9549710
TI - Effect of coordination training on proprioception of the functionally unstable
ankle.
AB - Exercises to improve joint proprioception and coordination of the functionally
unstable ankle are advocated throughout the literature, yet there is little
evidence that these exercise have any effect on proprioception and balance. The
purpose of this study was to determine the effects of a 6-week coordination and
balance training program on proprioception of subjects with functional ankle
instability. Forty-five subjects (age = 22.53 +/- 3.95 years, height = 172.04 +/-
10.0 cm, weight = 71.72 +/- 15.7 kg) were randomly placed into a control (Group
1), sham (Group 2), or experimental (Group 3) group. The experimental group
trained 3 days per week, 10 minutes each day, performing various balance and
proprioception exercises. Postural sway and active and passive joint position
sense were assessed. Analysis of variance for postural sway modified equilibrium
score for anterior and posterior sway, as well as medial and lateral sway
revealed significant four-way interactions. Tukey post hoc analyses revealed that
Group 3 performed significantly better (p < .05) than Group 1 and Group 2 on the
posttests. There were no significant differences for joint position sense or
postural sway index. Results suggest that balance and coordination training can
improve some measures of postural sway. It is still unclear if joint position
sense can be improved in the functionally unstable ankle.
PMID- 9549711
TI - Clinical tests for ankle syndesmosis injury: reliability and prediction of return
to function.
AB - Despite the severity of ankle syndesmosis injuries, it has been argued that they
are relatively poorly detected. This study investigated the interrater
reliability of four orthopaedic tests for ankle syndesmosis injury and assessed
their ability to predict the extended recovery times that have been reported as a
consequence of this injury. Nine physiotherapists, working in random pairings,
examined 53 subjects, all receiving treatment for ankle injury at two private
clinics. Each subject was tested by two physiotherapists who independently
performed the palpation test, external rotation test, squeeze test, and
dorsiflexion-compression test. Kappa coefficient testing indicated that the
external rotation test had the best interrater reliability (kappa = 0.75). The
squeeze test was found to have moderate reliability (kappa = 0.50), and the
palpation and dorsiflexion-compression tests both had only fair reliability
(kappa = 0.36). The degree of pair-wise association between the results of the
four tests was low (phi < or = 0.30 for all test combinations), suggesting that
if all four tests were performed on the same subject, it was not likely that they
would achieve similar results. Follow-up interviews were conducted to determine
the time taken for subjects to walk 10 m without pain and, for sports injuries,
the time taken to return to training and then to competition. For each test, Mann
Whitney U values showed no significant difference between the recovery times of
subjects with positive or negative test results, although subjects with recovery
times markedly longer than normal were detected by three of the four tests. When
an either/or combination of the external rotation and dorsiflexion-compression
tests was considered, subjects with a positive test result took significantly
longer to return to playing sports.
PMID- 9549712
TI - Reliability and validity of rigid lift and pelvic leveling device method in
assessing functional leg length inequality.
AB - Clinicians commonly include an assessment of leg length inequality (LLI) as a
component of a musculoskeletal examination. Little research is available,
however, documenting reliability and validity of clinical methods for assessing
LLI. The purpose of this study was to determine the reliability and validity of
assessing functional LLI using a pelvic leveling device. Subjects were 19 women
and 13 men between the ages of 18 and 55 who reported having a diagnosed or
suspected LLI. Clinical determination of LLI was made by placing rigid lifts
under the suspected shorter lower extremity until the leveling device indicated
that the iliac crests were level. This measurement was made twice by one
investigator and once by a second investigator. Standing radiographic
measurements of LLI using rigid lifts were used to establish validity of the
clinical method. Intraclass correlation coefficients [ICC(2,1)] and absolute
difference values were computed to assess reliability and validity. The mean
absolute difference between the two clinical measurements of LLI by the same
investigator was 0.29 cm (+/- 0.52), with an ICC = 0.84. The mean absolute
difference between clinical measurements of LLI by the two investigators was 0.49
cm (+/- 0.46), with an ICC = 0.77. The ICC and mean absolute difference
reflecting agreement between radiographic measurements and clinical measurements
of LLI was 0.64 and 0.58 cm (+/- 0.58), respectively, for one investigator and
0.76 and 0.55 cm (+/- 0.37), respectively, for the second investigator. The
intratester reliability, intertester reliability, and validity assessments
included instances in which paired observations disagreed regarding which lower
extremity was the shorter lower extremity. Factors that may be associated with
the unacceptable reliability and validity of the clinical assessment method
include asymmetric positioning of the ilia, body composition of the patient, and
design of the clinical instrument. The authors discuss clinical implications
related to assessment of LLI.
PMID- 9549713
TI - The effect of static stretch and dynamic range of motion training on the
flexibility of the hamstring muscles.
AB - To date, limited information exists describing a relatively new stretching
technique, dynamic range of motion (DROM). The purpose of this study was to
compare the effects of DROM with static stretch on hamstring flexibility. Fifty
eight subjects, ranging in age from 21 to 41 years and with limited hamstring
flexibility (defined as 30 degrees loss of knee extension measured with the femur
held at 90 degrees of hip flexion), were randomly assigned to one of three
groups. One group performed DROM 5 days a week by lying supine with the hip held
in 90 degrees of flexion. The subject then actively moved the leg into knee
extension (5 seconds), held the leg in end range knee extension for 5 seconds,
and then slowly lowered the leg to the initial position (5 seconds). These
movements were performed six times per session (30 seconds of total actual
stretching time). The second group performed one 30-second static stretch, 5 days
per week. The third group served as a control group and did not stretch. Before
and after 6 weeks of training, flexibility of the hamstring muscles was
determined in all three groups by measuring knee extension range of motion (ROM)
with the femur maintained in 90 degrees of hip flexion. Data were analyzed with a
2 x 3 (test x group) two-way analysis of variance (ANOVA) with repeated measures
on one variable (test) and appropriate post hoc analyses. The results of the two
way ANOVA revealed a significant interaction. Further statistical post hoc
analysis of data to interpret the interaction revealed significant differences
between the control group (gain = 0.70 degree) and both stretching groups, as
well as a significant difference between the static stretch group (gain = 11.42
degrees) and the DROM group (gain = 4.26 degrees). The results of this study
suggest that, although both static stretch and DROM will increase hamstring
flexibility, a 30-second static stretch was more effective than the newer
technique, DROM, for enhancing flexibility. Given the fact that a 30-second
static stretch increased ROM more than two times that of DROM, the use of DROM to
increase flexibility of muscle must be questioned.
PMID- 9549714
TI - Intramuscular temperature responses in the human leg to two forms of cryotherapy:
ice massage and ice bag.
AB - Cryotherapy is often used to affect the muscle underlying skin and subcutaneous
tissues. However, the relationship between the penetrative ability of various
cryotherapy methods and treatment time is not thoroughly understood. The purpose
of this study was to measure muscle temperature responses during two frequently
used cryotherapy techniques. A 23-gauge hypodermic needle microprobe was inserted
to one-half skin-fold thickness plus 1 cm into the medial aspect of the
gastrocnemius muscle of 14 subjects. Two groups of seven subjects each were
measured for temperature changes during ice bag or ice massage treatment. Each
treatment consisted of a 15-minute application of the selected method. A
significant difference between the two methods was observed (t = -2,157, p < or =
0.05). Ice massage achieved its lowest temperature in an average of 17.9 +/- 2.4
minutes, while ice bag reached its lowest temperature in 28.2 +/- 12.5 minutes.
Ice massage appears to cool muscle more rapidly than ice bag.
PMID- 9549715
TI - Differential diagnosis of the hip vs. lumbar spine: five case reports.
AB - With recent health care policy changes and the implementation of direct access in
many states, physical therapists must be able to identify pathology that is
beyond their scope of practice. The five case reports presented in this series
required the differential diagnosis of hip vs. lumbar spine pathology. All of the
cases required a referral from the physical therapist to either the patient's
physician or a specialist because of abnormal screening test results. Each
referral resulted in a new diagnosis of pathology that was beyond the scope of
physical therapy. Cyriax's concepts of capsular and noncapsular patterns of joint
restriction and the "Sign of the Buttock" proved useful in differentiating
between hip and lumbar spine pathology in each patient. Our clinical experience
indicates that utilizing the presence/absence of a capsular pattern and a "Sign
of the Buttock" to screen out hip pathology in patients may be effective;
however, further research is needed to support these claims.
PMID- 9549716
TI - [Long-term strategy for the management of Parkinson patients].
PMID- 9549717
TI - [Current strategies in the therapy of epilepsy].
PMID- 9549718
TI - Status of risk factors for vascular dementia.
AB - The two most common causes of vascular dementia (VAD) are dementia evolving in
connection with multiple small or large strokes and dementia related to ischemic
white-matter lesions (WMLs) of the brain. The knowledge about risk factors for
these disorders is still scarce. Besides sharing risk factors with stroke,
dementia with multiple small or large brain infarcts is also associated with non
vascular risk factors such as high alcohol consumption, psychological stress in
early life, lower formal education, blue collar occupation, and occupational
exposures. Risk factors for dementia in stroke victims include stroke-related and
non-stroke related risk factors. Non-stroke-related factors are similar to those
found in Alzheimer's disease. The main risk factors for ischemic WMLs are
hypertension or increased blood pressure, but WMLs have also been associated with
a number of other vascular risk factors. In recent years, Alzheimer's disease
(AD) has also been reported to be associated with vascular risk factors,
including hypertension, coronary heart disease, atrial fibrillation, diabetes
mellitus, and WMLs. Although these associations may reflect an overdiagnosis of
AD in cases with silent cerebrovascular disease, or that cerebrovascular disease
increases the possibility that individuals with Alzheimer lesions will express a
dementia syndrome, there are also alternative explanations. AD and
cerebrovascular disease may for instance share similar risk factors or etiologic
pathways. The pathogenetic implications for the association between AD and
vascular factors need to be further explored. There is also a need for more
studies on risk factors for VAD and risk factors for dementia in stroke samples,
as well as studies on non-vascular risk factors for ischemic WMLs.
PMID- 9549719
TI - Status of treatment of vascular dementia.
AB - The therapeutic goal in treating vascular dementia has been based on its presumed
association with cerebral arteriosclerosis. Therefore, it is necessary to control
risk factors for arteriosclerosis. In this connection, application of platelet
aggregating substances has been used extensively. Promising results have also
been observed by altering the hemorheologic profile because hemorheologically
active substances may be able to ameliorate the course of vascular dementia.
Further improvement could be achieved by application of the HELP system to
enhance the effect of hemorheologically active drugs. Using the HELP system, LDL,
cholesterol, triglycerides and fibrinogen can be lowered considerably and may
result in clinical improvement or slowing of the progression of vascular
dementia.
PMID- 9549720
TI - Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's
disease.
AB - The epsilon 4 allele of the apolipoprotein E (apoE) is associated with
Alzheimer's disease (AD) and also with elevated serum total cholesterol and low
density lipoprotein levels. However, the interrelationships between apoE
genotype, plasma cholesterol levels and AD risk have been studied very little. We
examined the possible role of serum total cholesterol in the pathogenesis of AD
in a population-based sample of 444 men, aged 70-89 years, who were survivors of
the Finnish cohorts of the Seven Countries Study. Previous high serum cholesterol
level (mean level > or = 6.5 mmol/l) was a significant predictor of the
prevalence of AD (odds ratio = 3.1; 95% confidence interval = 1.2, 8.5) after
controlling for age and the presence of apoE epsilon 4 allele. In men who
subsequently developed AD the cholesterol level decreased before the clinical
manifestations of AD. We conclude that high serum total cholesterol may be an
independent risk factor for AD and some of the effect of the apoE epsilon 4
allele on risk of AD might be mediated through high serum cholesterol.
PMID- 9549721
TI - Disposition after acute stroke: who is not sent home from hospital?
AB - BACKGROUND: Known demographic and clinical characteristics of stroke survivors
that affect selection of the facility to which they are discharged after
hospitalization for an acute stroke are, for the most part, not population based
and therefore may be unrepresentative. We present an analysis of such
characteristics using the Lehigh Valley stroke cohort which is population based.
METHOD: We enrolled patients within 1 month of onset of their initial acute
stroke who were hospitalized between 1987 and 1989 at one of the eight hospitals
in the Lehigh Valley, and 662 patients were discharged alive. The facility to
which they were discharged was known for 660. Data on age, sex, presence of five
selected comorbidities (hypertension, myocardial infarction, cardiac arrhythmia,
diabetes mellitus and transient ischemic attacks), length of hospitalization and
neurologic deficits from the stroke were systematically collected on standardized
forms. Polytomous logistic regression was used to determine the factors
associated with not being discharged home. Relative risk (RR) associated with
discharge to a nursing or rehabilitation facility for each independent predictor
was calculated using as the referent, those who went home. RESULTS: Older age was
a statistically significant predictor of not being sent home (RR = 1.2 for
nursing home placement), but gender and living with a spouse were not. Having a
selected comorbidity did not increase the RR of not being sent home regardless of
the type, nor did risk of not being sent home increase with more than one
illness. Considering neurologic deficits from the stroke, patients with lower
extremity weakness had a 2.6- and 3.5-fold risk of being sent to a nursing or a
rehabilitation facility, respectively, compared to those without such weakness
while for those with upper extremity weakness, the RR was 1.5 and 4.9,
respectively. Language deficit imposed a RR of 3.1 and 2.3 of going to a nursing
or rehabilitation facility, respectively. Right facial weakness also emerged as a
significant risk factor for not being discharged home, perhaps because of its
association with language deficit. The longer a patient was hospitalized after a
stroke, the less likely it was that such a patient would go home (RR =
1.1/hospitalization day). CONCLUSION: Using population-based data on stroke
survivors, our study showed the characteristics of patients who are less likely
to be discharged home and, instead, are discharged to a nursing or a
rehabilitation facility. Data like ours which were population based may be useful
in discharge planning for stroke patients by policy makers and health care
providers.
PMID- 9549722
TI - Hospital-based diabetic neuropathy: prevalence in eastern Black Sea region of
Turkey.
PMID- 9549723
TI - Analysis of the PTEN gene in human meningiomas.
AB - Previous observations demonstrated that the neurofibromatosis type 2 gene (NF2)
plays an important role in the pathogenesis of the transitional, fibroblastic and
malignant variants of human meningiomas. No specific genes have been associated
with the pathogenesis of meningothelial meningiomas and with the progression to
anaplastic meningiomas. However, allelic losses on chromosomal arms 1p, 10q and
14q have been implicated in the process of malignant progression. Recently, PTEN
(phosphatase and tensin homolog deleted on chromosome ten) also termed MMAC1
(mutated in multiple advanced cancers 1) or TEP1 (TGF--regulated and epithelial
cell-enriched phosphatase), emerged as a candidate gene on chromosome 10q23.3.
Initial studies revealed mutations of PTEN in limited series of glioblastomas,
breast, kidney and prostate carcinomas mainly as cell lines. In order to evaluate
the involvement of PTEN in the development of meningiomas, we have analysed the
entire coding sequence of the gene in a series of 55 meningiomas (WHO grade I).
10 atypical meningiomas (WHO grade II) and 10 anaplastic meningiomas (WHO grade
III). No PTEN mutations were seen in the WHO grade I meningiomas. However, one of
the anaplastic meningiomas carried a somatic mutation. In addition, all tumours
were examined for the presence of homozygous deletions of PTEN but these were not
detected in any of the meningiomas. Our data suggest that mutations in PTEN are
not involved in the formation of low grade meningiomas, but may contribute to
malignant progression in a fraction of anaplastic meningiomas.
PMID- 9549724
TI - gp130RB13-6-positive neural progenitor cells are susceptible to the oncogenic
effect of ethylnitrosourea in pre-natal rat brain.
AB - Proliferation-competent rat brain precursor cells of glial lineages are thought
to preferentially undergo malignant transformation after transplacental exposure
to ethylnitrosourea (EtNU). We recently have reported that monoclonal antibody
(mAb) RB13-6 recognizes a developmentally regulated 130 kDa cell surface
glycoprotein (gp130RB13-6) transiently expressed by a small subpopulation of
glial progenitor cells in pre-natal rat brain. The expression of gp130RB13-6 has
now been analysed immunocytochemically in malignant gliomas induced on day 15, 18
or 21 of gestation and in long-term cultures of fetal brain cells (FBC) isolated
after in vivo-exposure to EtNU on day 18 of gestation. Malignant gliomas induced
at different gestational stages contained varying proportions of gp130RB13-6
positive cells, whereas a subpopulation of proliferative neural progenitor cells
exhibiting sustained gp130RB13-6 expression persisted in long-term FBC cultures
after 3 months. This subpopulation, which was not selected for in control
cultures of FBC derived from buffer-treated rats, gave rise to malignant cell
lines after a period of time similar to the latency period required for glioma
development in vivo. These data suggest that gp130RB13-6-positive cells of the
immature rat nervous system may represent a subset of neural progenitor cells
particularly susceptible to the oncogenic effect of EtNU.
PMID- 9549725
TI - Proliferation and cell death in oligodendrogliomas.
AB - The rates of cell proliferation and of cell loss influence the growth rate of a
tumour and reflect genetic changes. We studied proliferation and apoptosis in
oligodendrogliomas and their relationship to progression of the tumours. Thirty
two cases of oligodendroglioma were retrieved spanning a 10-year period. The
diagnosis and grade were reviewed and follow-up data obtained. Mitotic index (MI)
and apoptotic index (AI) were determined from haematoxylin and eosin (H & E)
stained sections. A labelling index (LI) of proliferating cells was obtained
using the MIB1 antibody to the Ki-67 antigen. A further index of apoptosis was
obtained using in situ end-labelling of DNA strand breaks (TUNEL index, TI).
Fourteen cases were graded as II, 18 as III (1993 WHO). LI was significantly
higher in grade III than in grade II tumours (P < 0.01) but the difference in
apoptotic indices between grades was not significant. There was a significant (P
= 0.036) positive correlation between the logarithms of TI and LI. Construction
of survival curves demonstrated a significant difference in survival according to
histological grade (P < 0.05). Stratification of cases by LI alone did not
predict significantly different survival outcomes, and apoptotic indices did not
demonstrate a relationship to survival. A positive relationship was demonstrated
between proliferation and apoptosis in oligodendrogliomas. The levels of
apoptosis observed indicate that this phenomenon may have an important influence
on the overall rate of tumour growth.
PMID- 9549726
TI - Immunohistochemical detection of vascular endothelial growth factor (VEGF) in the
vasculature of oligodendrogliomas.
AB - Vascular endothelial growth factor (VEGF) appears to be implicated in tumour
angiogenesis. In the present study immunohistochemical expression of VEGF was
evaluated in 34 oligodendrogliomas (13 grade II, 21 grade III [WHO]). VEGF
immunoreactivity was found in 31 of 34 cases. Expression of VEGF was observed in
endothelial cells and some vascular smooth muscle cells, but not in neoplastic
oligodendrocytes. Vessel counts, percentages of VEGF-positive vessels and vessels
with vascular endothelial proliferation were assessed. The degree of VEGF
labelling and vascular-endothelial proliferation in each vessel were evaluated
using a 3 degree intensity score. Expression of VEGF was higher in grade III than
in grade II oligodendrogliomas as assessed by percentage of VEGF positive vessels
(55.8 +/- 29.2% vs 17.0 +/- 19.0% [P < 0.001]) and by VEGF immunostaining
intensity (1.90 +/- 0.60 vs 0.90 +/- 0.40 [P < 0.001]). VEGF expression did not
correlate with vessel density. Intensity of VEGF expression correlated positively
with that of vascular-endothelial proliferation in grade III tumours (r = +0.47
[P < 0.05]). The percentage of VEGF positive vessels showed some degree of
positive correlation with the percentage of vessels showing vascular-endothelial
proliferation (r = +408 [P < 0.10]). Within individual grade III tumours 67.5 +/-
29.6% of all vessels with vascular-endothelial proliferation were VEGF-positive
and 31.0 +/- 20.5% of all VEGF-positive vessels showed no evidence of vascular
endothelial proliferation. We conclude that (i) expression of VEGF is observed in
the vasculature of oligodendrogliomas; (ii) marked expression of VEGF is observed
in grade III oligodendrogliomas; (iii) VEGF may be one of the interrelated
causative stimuli acting in concert to induce vascular-endothelial proliferation.
PMID- 9549727
TI - Degeneration of the cerebellar granule cell layer in transgenic mice expressing
genes of human foamy virus.
AB - Transgenic mice expressing various combinations of structural and regulatory
genes of human foamy virus (HFV) develop a neurodegenerative syndrome. delta gpe
transgenic mice (which express the auxiliary bel-1 and bet genes along with
truncated forms of gag, pol, and env) develop a severe neurological syndrome
consisting mainly of spastic tetraparesis and blindness, and show neuronal loss
in the hippocampus and cerebral cortex. In addition, mice in two of eight delta
gpe lines developed an ataxic gait. Here we studied the phenotype of these two
lines, and show that these mice exhibit progressive degeneration of their
cerebellar granule cells beginning at 4-8 weeks of age. Transgenic mRNA and HFV
proteins accumulate in cerebellar granule cells immediately before the onset of
degeneration. The Purkinje cell layer is largely unaffected by this pathological
process. Probably due to the loss of granule cell processes, the cerebellar
molecular layer is narrowed in the late stages of the disease. These findings
indicate that HFV gene products can be neurotoxic for cerebellar granule cells.
PMID- 9549728
TI - Fractionator analysis shows loss of neurons in the lateral geniculate nucleus of
macaques infected with neurovirulent simian immunodeficiency virus.
AB - Infection of macaques with neurovirulent strains of simian immunodeficiency virus
(SIVmac) is an experimental model for the neurological manifestations of AIDS.
Loss of neurons has been reported in the cerebral cortex following
immunodeficiency viral infection, but thalamic structures which may contribute to
electrophysiological changes and neurological deficits have not been examined. In
this study, the lateral geniculate nucleus (LGN) of macaques inoculated with
macrophage-tropic, neurovirulent virus SIVmac239 (R71 and 17E) was examined for
neuron loss using the optical fractionator method. Estimates of the number of
neurons in the P layers of the lateral geniculate nucleus of age-matched control
macaques ranged from 1.0 to 1.3 x 10(6), while the number of neurons in SIV
infected macaques ranged from 0.8 to 1.1 x 10(6), reflecting neuron loss of up to
28%. Neuron loss was not observed in the magnocellular layer. The total number of
glia and glial density were unchanged. Loss of neurons in the lateral geniculate
nucleus was correlated with the pattern of neuropathological changes. Neuron loss
was most severe in animals with encephalitis concentrated in the brain stem and
subcortical white matter and was less apparent in animals with diffuse
encephalitis. Neuron loss in the lateral geniculate nucleus did not explain
changes observed in the visual evoked potential, which was severely affected in
two animals which showed a loss of 24 and 26%, while it was normal in a third
animal which showed neuron loss of 28%.
PMID- 9549729
TI - Argyrophilic grains of Braak: occurrence in dendrites of neurons containing
hyperphosphorylated tau protein.
AB - Braak's argyrophilic grains (ArGs) are spindle-shaped neuropil structures
originally found in patients afflicted with adult onset dementia. We recently
observed that tau protein is hyperphosphorylated in most nerve cells in areas
rich in ArGs, suggesting that these grains may be a morphological expression of
tau protein pathology in local neurons. The aim of this study was therefore to
determine in three cases with ArGs whether grains are associated with individual
neurons containing hyperphosphorylated tau. A combination of Gallyas silver
staining and AT8 immunocytochemistry was used. AT8 is a monoclonal antibody that
recognizes tau in a phosphorylation-dependent manner. Up to 80% of pyramidal
cells of sector CA1 showed diffuse AT8 staining of their cell bodies and
dendrites. Most grains were freely scattered throughout the neuropil. However,
some were clearly located in side-branches of apical dendrites of AT8
immunoreactive pyramidal neurons. Dendritic branches often formed bush-like
ramifications containing clusters of ArGs. Other dendrites consisted of a single
stump containing one or two large grains at their tips. Spheroidal enlargements
of dendritic branches, with a size corresponding to ArGs, were also found in
Golgi Cox preparations of cases with ArGs but not in Alzheimer's disease cases or
in controls. Our results show that some ArGs are formed within dendrites of
neurons whose most obvious pathology is a diffuse hyperphosphorylation of the tau
protein. Furthermore, morphology of dendrites containing grains suggests that a
process of progressive shrinkage of dendrites is taking place in neurons bearing
ArGs.
PMID- 9549730
TI - Endothelial changes in muscle and skin biopsies in patients with CADASIL.
AB - Cerebral autosomal dominant arteriopathy with subcortical infarcts and
leucoencephalopathy (CADASIL) is characterized by the deposition of granular
osmiophilic material in association with vascular smooth muscle cells in many
different organs. However, the cause of the subsequent destruction of smooth
muscle cells that are surrounded by granular osmiophilic material is unclear. In
the present study, the ultrastructural changes that occur in endothelial cells in
CADASIL have been evaluated by examining blood vessels in six skin biopsies and
seven muscle biopsies belonging to three different CADASIL pedigrees. The
appearances have been compared with five skin biopsies and five muscle biopsies
from age-matched controls without vascular disease. The most striking features
observed in vessels in the skin of CADASIL patients were attenuation of
endothelial cells and increased density of endothelial cytoplasm, accompanied by
the presence of compact bundles of microfilaments within the cytoplasm of
endothelial cells. Endothelial cells in muscle biopsies from CADASIL patients, on
the other hand, were swollen until destruction of tight junctions were observed.
These findings suggest that impaired permeability of vascular endothelium may
play a role in the destruction of vascular smooth muscle cells in CADASIL.
Furthermore, the results of this study suggest that further fine structural
investigation of blood vessel endothelium and underlying smooth muscle may lead
to a better understanding of the pathophysiology of CADASIL.
PMID- 9549731
TI - Differential labelling of laminin alpha 2 in muscle and neural tissue of dy/dy
mice: are there isoforms of the laminin alpha 2 chain?
AB - Laminin alpha 2, a sub-unit of the basement membrane component laminin-2, is
deficient in the dy/dy and allelic dy2 J/dy2 J mouse. It is also the defective
protein in a proportion of children with congenital muscular dystrophy. Linkage
and mutational analysis have established that this is a primary effect caused by
defects in the LAMA2 gene. Laminin alpha 2 has previously been shown to be
deficient in dy/dy skeletal muscle, peripheral nervous system and brain. We
report here preliminary observations on differences in detection of laminin alpha
2 in muscle, peripheral nerves and brain of dy/dy mice using three, well
characterized antibodies. In normal muscle laminin alpha 2 is localized to the
basement membrane of the myofibres and the Schwann cells of peripheral nerves,
whilst in adult brain it is only detected on blood vessels. Our results show that
there is appreciable, but slightly reduced, expression of laminin alpha 2 in
skeletal muscle of dy/dy mice but almost no detectable protein in the brain,
peripheral nerve and spinal nerve roots. Our observations are at present
unexplained but they raise the possibility for the first time that there may be
different tissue specific isoforms of laminin alpha 2. Molecular characterization
of possible differences responsible for our observations may aid the
identification of the mutation in the dy/dy mouse and lead to a better
understanding of the role and expression of laminin alpha 2 in pathological
conditions.
PMID- 9549733
TI - Gastro-oesophageal reflux: theory over experience?
PMID- 9549732
TI - Local expression of cytokines in idiopathic inflammatory myopathies.
AB - The idiopathic inflammatory myopathies (IIM), including dermatomyositis (DM),
polymyositis (PM), and inclusion body myositis (IBM), are regarded as autoimmune
diseases. They are characterized by chronic lymphocytic and macrophagic
infiltration in muscle tissue. Of particular importance in understanding the
immune response to IIM is the specific pattern of locally produced cytokines.
Frozen muscle tissues from IIM (5 DM, 3 PM, and 1 IBM) were used to investigate
the cytokine responses. The RT-PCR technique was instrumental to determine the
pattern of expression of pro-inflammatory (IL-1 beta, IL-6, TNF-alpha), Th1 (IFN
gamma IL-2), and Th2 (IL-4) cytokines. Immunohistochemistry was also used to
localize morphologically IFN-gamma and IL-4. Our results show that pro
inflammatory cytokines and Th1 cytokines are mainly expressed in IIM. The
accumulation of mononuclear inflammatory cells and the inflammatory syndrome in
IIM are probably related in part to the production of pro-inflammatory cytokines.
Moreover, the pattern of local cytokine expression is consistent with a Th1
immune response related to autoimmune diseases.
PMID- 9549734
TI - Chronic pain management in children. Part II: Reflex sympathetic dystrophy.
PMID- 9549735
TI - Children who withdraw consent for elective surgery.
AB - Parents and legal guardians have authority to consent to medical treatment on
behalf of minors. Recently, the concept of emerging competence has been
popularized, whereby a child may achieve sufficient understanding and maturity to
enable him/her to make a wise choice in his/her own interests. Although there are
undoubted merits in involving children in their medical treatment, the ultimate
legal authority for consent rests with parents and guardians acting on the advice
of doctors and in the child's best interests. We describe two cases in which
children withdrew their consent to elective surgery, despite the help and
encouragement of their parents and doctors. Surgery was cancelled rather than use
force to induce anaesthesia. In practice, it seems that a child must demonstrate
a greater maturity and understanding to refuse medical treatment than to agree to
it. Some advice is given to clinicians facing similar situations.
PMID- 9549737
TI - Early intravenous cannulation in children during inhalational induction of
anaesthesia.
AB - Intravenous cannulation is obtained in almost all patients scheduled for
operative intervention under anaesthesia. In our practice, inhalational induction
precedes cannulation in children in order to avoid pain and discomfort, and
cannulation is delayed until the child is adequately anaesthetized in fear of
precipitating laryngospasm due to painful stimulus of venepuncture in the light
stage of anaesthesia. This study was performed on 150 patients between two to
eight years of age to determine if there is a difference in the incidence of
untoward incidents, if cannulation is performed when children are lightly
anaesthetized (Early, Group E), as compared to when they are deeply anaesthetized
(Late, Group L). In patients randomized to early cannulation, the results showed
that there was a significantly shorter time from induction to venous cannulation,
the halothane concentration was lower at the time of cannulation, there was a
greater incidence of movement on cannulation and a greater incidence of changes
in heart rate, blood pressure, and respiratory rate. There was no significant
differences in the incidence of laryngospasm or in the success rate of
intravenous cannulation between the two groups. We conclude that venous
cannulation can be safely performed during the light stages of anaesthesia.
PMID- 9549736
TI - Oral midazolam premedication and postoperative behaviour in children.
AB - We examined the effect of oral midazolam premedication on postoperative
behaviour. Seventy children (ASA Physical Status 1 and 2; aged 1-10 yrs) were
assigned randomly in a prospective, blinded fashion to receive either midazolam
0.5 mg.kg-1 (maximum 10 mg) or placebo. Behaviour assessments were made prior to
medication, during induction of anaesthesia and 15 min following arrival to
recovery room. The baseline behavioural evaluation scores were not significantly
different. The children receiving midazolam cried significantly less during
induction (P < or = 0.02). At one week follow-up, eight of 35 subjects receiving
placebo had experienced adverse behaviour changes (nightmares, night terrors,
food rejection, anxiety, negativism); 19 of 35 of the midazolam group experienced
these changes (P < or = 0.02). At four week follow-up, most behaviour changes had
resolved. Children given preoperative oral midazolam were less likely to cry and
fight while being anaesthetized, and preoperative sedation was associated with
increased incidence of adverse postoperative behaviour changes.
PMID- 9549738
TI - Ropivacaine in paediatric surgery: preliminary results.
AB - In a double blind study 40 patients, aged 1-9 years, undergoing elective minor
surgery were examined and randomly divided in two groups (20 children each).
After light general anaesthesia Group 1 received caudal injection of bupivacaine
0.25% 2 mg.kg-1 while Group 2 received 0.2% ropivacaine 2 mg.kg-1. No differences
were observed in demographic data, HR, BP and duration of surgery; the onset time
of anaesthesia was 12 min and 9 min in Group 1 and 2 respectively. Ten patients
in Group 1 received paracetamol in the first 24 h after surgery while only two
children in Group 2 needed analgesic; even the duration of analgesia in the
patients requiring paracetamol was superior in group 2 (520 min vs 253 min). No
motor block was apparent at awakening in either group and no side effect was
noticed. In conclusion ropivacaine seems to be an effective and safe drug in
paediatric regional anaesthesia.
PMID- 9549740
TI - Reference values of gastric intramucosal pH in children.
AB - To determine the reference values of gastric intramucosal pH (pHi) by tonometry
in paediatric patients, we studied 17 children (nine males, eight females) with
no systemic or gastrointestinal disease, aged six months to 12 years undergoing
minor reconstructive surgery. Following anaesthetic induction a sigmoid tonometry
catheter was inserted (Tonometrics, Inc.) into the stomach of the patients under
direct vision. All children were normoventilated and were haemodynamically
stable. After an equilibration period of 30 min, gastric pHi was calculated by
applying the Henderson-Hasselbalch equation on the PCO2 obtained with the
tonometer and the bicarbonate from the arterial blood gas analysis. The mean
gastric pHi in our patients was 7.35 +/- 0.06 (SD). The normal pHi in the general
population is estimated to be 7.31-7.40, with a confidence interval of 99%. No
correlation was found between pHi and arterial pH, bicarbonate or base excess.
Under conditions of normal ventilation and haemodynamic stability, healthy
children during general anaesthesia have gastric intramucosal values similar to
those of adults.
PMID- 9549739
TI - The advantages of intrathecal opioids for spinal fusion in children.
AB - Two groups of 40 homogeneous patients (ASA physical status (1-2)) with idiopathic
scoliosis undergoing spinal fusion with CD instrumentation were studied
prospectively. Group A (intrathecal) received a mixture of morphine and
sufentanil administered intrathecally at the level of L3-L4 after the induction
of anaesthesia. Group B (control) had inhalation and intravenous narcotic
anaesthesia. The use of intrathecal opioids resulted in a significant reduction
of blood pressure without the use of any hypotensive agents and produced
prolonged postoperative analgesia. There was no adverse effect on somatosensory
evoked potentials. The dose requirement for the anaesthetic agents was
significantly reduced and the blood loss was 27% of their blood volume compared
with 53% in the control group. No long or short term impairment of cerebral or
spinal function was observed. The use of intrathecal opioids supplemented with
other anaesthetic agents is an alternative method with multiple benefits for any
major surgery such as spinal fusion.
PMID- 9549741
TI - The effect of circuit compliance on delivered ventilation with use of an adult
circle system for time cycled volume controlled ventilation using an infant lung
model.
AB - This in vitro study examined the effect of circuit compliance on delivered
ventilation (VE) using a time-cycled, volume controlled circle system in an
infant lung model. A Bio-Tek ventilator tester set to simulate normal and
abnormal lung compliance measured VE delivered by the Narkomed 2B system. Circle
circuits of varied compliance (2.75, 1.22 and 0.73 microliters.cm H2O-1) were
tested. Tidal volume was adjusted to peak inflation pressures (PIP) of 20, 30,
40, and 50 cm H2O with three circuits, two lung compliances, and four different
size tracheal tubes (TT) (2.5, 3.5, 4, 4.5 mm ID). Data were analysed using the
multiple regression technique. Delivered VE was directly related to PIP and lung
compliance. Delivered VE was not affected by the choice of circuit. TT size had
minimal effects on VE when lung compliance was low; TT size was a more important
factor when test lung compliance was normal. Extrapolating this data to the
clinical setting, adequate ventilation of infants can be achieved with an adult
circle system if an appropriate PIP is chosen, regardless of the compliance of
the circuit used. Infants with poor lung compliance may require very high PIP for
adequate ventilation.
PMID- 9549742
TI - Transcutaneous CO2 tension effects of clonidine in paediatric caudal analgesia.
AB - In adults, clonidine when added to bupivacaine, results in no detectable
respiratory depressant effect except when carbon dioxide challenge is performed.
However, to date no investigations have quantified this in children. Twenty-four
children (nine months to seven years) were randomized in a double-blind study
into two groups. After induction, a caudal block was performed with 1 ml.kg-1
0.25% bupivacaine. Clonidine 1 microgram.kg-1 was added in the clonidine group,
and 1 ml normal saline in the placebo group. Patients were monitored in the
recovery room for three h from arrival to discharge with continuous pulse
oximetry, respiratory rate, a transcutaneous CO2 tension (tcPCO2) every 15 min,
and a four point sedation score every 30 min. Mean tcPCO2 and respiratory rate
values were not different between the two groups. Apnoea and desaturation less
than 97% were not observed. The sedation score decreased with time in both
groups, and the score time interval was significantly higher in the clonidine
group (P < 0.05). All the patients left the recovery room with a sedation score
of 1, excepting four in the clonidine group with a sedation score of 2. Clonidine
1 microgram.kg-1 with 0.25% bupivacaine mixture in caudal analgesia in children
did not induce an increase in tcPCO2 despite prolonged sedation.
PMID- 9549743
TI - Prophylactic therapy with granisetron in the prevention of vomiting after
paediatric surgery. A randomized, double-blind comparison with droperidol and
metoclopramide.
AB - The antiemetic efficacy of droperidol, metoclopramide and granisetron was
compared with placebo in the reduction of vomiting after paediatric surgery (the
extremities; inguinal hernia; and phimosis) during general inhalational
anaesthesia. One hundred children, ASA physical status I, 4-10 years of age, were
enrolled in a prospectively, randomized, double-blind investigation and assigned
to one of four treatment regimens: placebo (saline, n = 25), droperidol (50
micrograms.kg1, n = 25), metoclopramide (0.25 mg.kg-1, n = 25) or granisetron (40
micrograms.kg-1, n = 25). These drugs were administered intravenously (i.v.)
after inhalation induction of anaesthesia. A complete response, defined as no
emesis and no need for another rescue antiemetic during the first 24 h after
anaesthesia, occurred in 60%, 76%, 68% and 88% of patients who had received
placebo, droperidol, metoclopramide and granisetron, respectively (P < 0.05;
overall Fisher's exact probability test). The incidence of adverse events
postoperatively was not different among the treatment groups. In conclusion,
granisetron 40 micrograms.kg-1 is a better antiemetic than droperidol and
metoclopramide when compared to placebo for the prevention of postoperative
emesis in children.
PMID- 9549744
TI - Anaesthetic management of a patient with Plott's syndrome.
AB - There are only seven reported cases of Plott's syndrome and no anaesthetic
descriptions of this rare syndrome which is characterized by vocal cord
paralysis, psychomotor retardation and sixth nerve palsy. The major anaesthetic
implication is postoperative upper airway control. We describe the anaesthetic
management of a 15-year-old boy who presented for magnetic resonance imaging
[MRI] of his brain.
PMID- 9549745
TI - Anaesthetic implications of Cornelia de Lange syndrome.
AB - Cornelia de Lange syndrome is a congenital disease characterized basically by
psychomotor retardation associated with a series of malformations (mainly
skeletal craniofacial deformities together with gastrointestinal and cardiac
malformations). We present the case of a patient who underwent trauma surgery,
discuss the anaesthetic problems involved and their relationship to the
malformations that constitute this syndrome.
PMID- 9549746
TI - Anaesthetic management of a prematurely born infant with Cantrell's pentalogy.
AB - Cantrell's pentalogy (CP) is a rare congenital syndrome combining a defect of the
supraumbilical abdominal wall, the agenesis of the lower part of the sternum and
of the anterior portion of the diaphragm, the absence of the diaphragmatic part
of the pericardium, and a cardiac malformation. It was first described by
Cantrell in 1958 (1,2). We report the case of a prematurely born infant with CP
and Wolff-Parkinson-White (WPW) syndrome who required surgery first for bilateral
inguinal hernia repair and later for Blalock-Taussig shunt. During these two
procedures, our anaesthetic plan was to preserve the fragile equilibrium of both
the pulmonary and the cardiovascular systems.
PMID- 9549747
TI - Sevoflurane for controlled hypotension during spinal surgery: preliminary
experience in five adolescents.
AB - The physical properties of sevoflurane suggest that it may be a suitable agent
for controlled hypotension. With its low blood:gas partition coefficient of 0.69,
it has a rapid onset of action making it easy to rapidly control blood pressure.
The current report outlines preliminary experience with sevoflurane for
controlled hypotension during posterior spinal fusion in five adolescents. The
patients ranged in age from 12 to 16 years and in weight from 49 to to 72kg. The
duration of controlled hypotension varied from two to three h. The expired
sevoflurane concentration required to maintain the mean arterial pressure (MAP)
at 55 to 65 mmHg varied from 2 to 4%. With sevoflurane, there was an increase in
heart rate from baseline of 74 +/- 7 beats.min-1 to a maximum of 83 +/- 13
beats.min-1 (P = 0.038). One patient required three intravenous doses of esmolol
(10mg each) for a heart rate in excess of 100 beats.min-1. Estimated blood loss
varied from 300 to 850 ml. No patient received homologous blood. No excessive
hypotension was noted with sevoflurane. No patient required calcium, alpha
adrenergic agonists, or ephedrine for excessive hypotension. When controlled
hypotension was no longer necessary, the sevoflurane concentration was decreased
to 1%. After decreasing the sevoflurane to 1%, the time to return of the MAP to
baseline varied from 4 to 8 min (5.6 +/- 1.8 min).
PMID- 9549748
TI - Twelve hours of gastric ventilation: a recipe for disaster (a suggested remedy).
AB - A forty-three-day-old infant was intubated by the Neonatal Intensive Care Unit
(NICU) staff. A nasogastric tube was in place for the duration. The patient's
vital signs remained stable during 12 h of positive pressure ventilation. A
Broviac catheter placement was scheduled in the NICU. The position of the
tracheal tube (TT) was not verified prior to induction of anaesthesia. After the
induction, the patient's condition deteriorated. The TT was found to be
positioned within the oesophagus. A near catastrophe was successfully averted by
discovering the malpositioned TT and replacing it with a properly positioned TT.
We believe that had we clamped the existing nasogastric tube preoperatively, a
noticeable abdominal distention would have occurred alerting us to a
malpositioned TT. We suggest that clamping a preexisting nasogastric tube may
have merit to alert one to a malpositioned TT.
PMID- 9549749
TI - Anaesthetic management of a patient with Freeman Sheldon syndrome.
AB - We present a case of Freeman Sheldon (Whistling Face) syndrome. The anaesthetic
management of an additional cervical kyphoscoliosis is discussed.
PMID- 9549750
TI - Anaesthetic implications of Cornelia de Lange syndrome.
PMID- 9549751
TI - Rectus sheath block in infants: what suitability?
PMID- 9549752
TI - Down's syndrome and anaesthesia.
PMID- 9549753
TI - Is there still a place for halothane in paediatric anaesthesia?
PMID- 9549754
TI - There is no longer a place for halothane in paediatric anaesthesia.
PMID- 9549755
TI - Signal transduction pathways regulating hematopoietic differentiation.
PMID- 9549756
TI - Aldose reductase in glucose toxicity: a potential target for the prevention of
diabetic complications.
PMID- 9549757
TI - The pharmacology of the ductus arteriosus.
PMID- 9549758
TI - Therapeutic inhibition of the complement system.
AB - The use of powerful methodologies in molecular biology, biochemistry, and
physiology in the last 2 decades had led to impressive progress in our
understanding of the mechanisms of complement activation and its role as either a
protective or a pathogenic factor in human disease. With respect to disease
pathogenesis, the complexity of the complement cascade provides opportunities for
several different therapeutic targets within the complement pathways. More than a
century after complement was first described, we are about to witness in the near
future the availability of a variety of complement inhibitors for specific
therapies. Progress in the area of xenotransplantation has been substantial, but
formidable obstacles remain to selective inhibition of the factors that block
successful clinical xenotransplantation. Bispecific antibodies, designed to
enhance rather than inhibit existing complement pathways, hold strong promise for
the clearance of viral and bacterial pathogens from the circulation.
PMID- 9549759
TI - Perchlorate and the thyroid gland.
AB - Perchlorate competitively blocks iodide from entering the thyroid by an effect on
the Na+/I- symporter thus preventing the further synthesis of thyroid hormone but
has no effect on the iodination process itself. It is concentrated by thyroid
tissue in a manner similar to iodide but is not significantly metabolized in the
gland or peripherally. What is not settled is whether there are additional
perchlorate effects on iodide transport. Perchlorate has a fast turnover in the
body and requires frequent daily doses for therapy of thyrotoxicosis. Perchlorate
appears to be substantially more effective against large iodide loads than the
thionamides, and, with long-term iodide contamination, combined therapy of
perchlorate (with < or = 1 g/day) and thionamides is recommended for the more
severe cases of thyrotoxicosis that may result from excess iodide or iodide
generating organic compounds, as for example with amiodarone. After approximately
30 days, the perchlorate dosage can be tapered or stopped, continuing with
thionamides alone. This markedly increases its safe use. Despite serious side
effects during its early use, lower dosages and shorter treatment periods appear
to have prevented such reactions in its recent reintroduction, mostly for
amiodarone-induced thyroid dysfunction. Perchlorate can also protect against
inhibition of thyroid function and the resulting hypothyroidism caused by excess
iodide, presumably by reducing the formation of an iodinated inhibitor. The
reduction of the iodide pool by perchlorate thus has dual effects--reduction of
excess hormone synthesis and hyperthyroidism, on the one hand, and reduction of
thyroid inhibitor synthesis and hypothyroidism on the other. Perchlorate remains
very useful also as a single dose application in tests measuring the discharge of
radioiodide accumulated in the thyroid as a result of many different disruptions
in the further metabolism of iodide in the thyroid gland.
PMID- 9549760
TI - Renal drug metabolism.
PMID- 9549761
TI - XVI. International Union of Pharmacology recommendations for the nomenclature of
neuropeptide Y, peptide YY, and pancreatic polypeptide receptors.
PMID- 9549762
TI - The genetics of sporadic and inherited breast cancer.
PMID- 9549763
TI - Mammographic evaluation of the augmented breast.
PMID- 9549764
TI - Survey of alcohol, drug use by radiologic technologists. ASRT Research and
Development Committee.
AB - This article describes the results of a survey investigating use of alcohol and
illicit drugs by radiologic technologists. Overall, survey results suggest that
few radiologic technologists have a problem with the abuse of alcohol and drugs.
However, the survey indicates that approximately 3% to 4% of radiologic
technologists may suffer from some type of substance abuse problem, with alcohol
abuse more common than drug abuse. These findings correlate with studies that
reveal similar rates of substance abuse among physicians, nurses and pharmacists.
Because the abuse of alcohol and drugs affects the quality of patient care, the
authors recommend that professional organizations identify and assist radiologic
technologists who suffer from substance abuse and that they promote greater
awareness of the problem through education. The authors also recommend that an
awareness of the effects of substance abuse be included in the professional
curriculum.
PMID- 9549765
TI - Fast FLAIR techniques in MR imaging of the brain.
AB - Fast FLAIR (fluid attenuated inversion recovery) is a magnetic resonance imaging
technique used primarily for neurological imaging of the brain. This technique
uses an advanced software package that employs basic inversion recovery
principles to help differentiate between pathology and normal brain parenchyma
without interference from high-signal cerebral spinal fluid. This article reviews
the applications of fast FLAIR techniques in MR imaging of the brain.
PMID- 9549766
TI - Neonatal shielding: a danger or a benefit?
PMID- 9549767
TI - CE is one path to professionalism.
PMID- 9549768
TI - Positioning technique needs attention.
PMID- 9549769
TI - Prolonging life for mesothelioma patients.
PMID- 9549770
TI - Curly cues.
PMID- 9549771
TI - Ulna deviation: this way or that way?
PMID- 9549772
TI - How to make active learning work for you.
PMID- 9549773
TI - Schizophrenia as a transcallosal misconnection syndrome.
AB - Schizophrenic symptoms are conceived as arising from inter-individual variability
in the distribution of those fibres that connect asymmetrical regions of the
hemispheres related to language. Language (a bihemispheric phenomenon) arose as a
result of a genetic change that allowed the two hemispheres to develop with a
degree of independence. One component, the phonological output sequence, became
localised to the dominant hemisphere, interacting through the corpus callosum
with other component functions, including the associated meanings, in the non
dominant hemisphere. Nuclear symptoms are a consequence of failure of segregation
of these two functions. This failure is associated with abnormal connectivity
between the hemispheres and relates particularly to those regions that are late
developing and differ between the sexes.
PMID- 9549774
TI - The disconnection hypothesis.
AB - This article reviews the disconnection hypothesis of schizophrenia and presents a
mechanistic account of how dysfunctional integration among neuronal systems might
arise. This neurobiological account is based on the central role played by
neuronal plasticity in shaping the connections and the ensuing dynamics that
underlie brain function. The particular hypothesis put forward here is that the
pathophysiology of schizophrenia is expressed at the level of modulation of
associative changes in synaptic efficacy; specifically the modulation of
plasticity in those brain systems responsible for emotional learning and memory,
in the post-natal period. This modulation is mediated by ascending
neurotransmitter systems that: (i) have been implicated in schizophrenia; and
(ii) are known to be involved in consolidating synaptic connections during
learning. The proposed pathophysiology would translate, in functional terms, into
a disruption of the reinforcement of adaptive behaviour that is consistent with
the disintegrative aspects of schizophrenic neuropsychology.
PMID- 9549775
TI - Does dysplasia cause anatomical dysconnectivity in schizophrenia?
AB - Evidence is reviewed that dysplastic brain development in the second half of
pregnancy predisposes to schizophrenia. We suggest that an important corollary of
aberrant development at this stage of ontogenesis is abnormal afferentation of
the cortical plate, and that this may be macroscopically measurable in terms of
abnormal correlational structure in adult brain imaging data. This prediction is
tested by analysis of multiple cortical volume measures on magnetic resonance
imaging data acquired from 35 male right-handed schizophrenics and 35 matched
controls. There are no significant differences between groups in global, intra
hemispheric or inter-hemispheric correlational structure; but schizophrenics are
shown to have significantly reduced dependencies between frontal and temporal
lobe volumes, and frontal and hippocampal volumes, in the left hemisphere. We
conclude that anatomical dysconnectivity (between frontal and temporal cortex) in
schizophrenia may be caused by dysplasia.
PMID- 9549776
TI - Reduced corticocortical connectivity can induce speech perception pathology and
hallucinated 'voices'.
AB - Reciprocal interactions between multiple cortical areas are required for higher
order cognitive processes in animals and humans. A growing body of evidence
suggests that reduced cortical connectivity is associated with schizophrenia. We
have used neural network computer simulations to characterize symptoms and
cognitive pathology that could arise from connectivity reductions. When this
pathology was reproduced in simulations of speech perception networks,
spontaneous percepts analogous to hallucinated speech were induced due to the
emergence of 'locked-in' or 'parasitic' states. We propose that these simulations
provide a model for hallucinated 'voices' reported by actual schizophrenic
patients. The 'hallucinogenic' model of speech perception also demonstrated
subtle speech perception impairments. We have demonstrated similar impairments
when assessing schizophrenic patients reporting 'voices', but not when assessing
similarly diagnosed patients not reporting this symptom. The model also
demonstrates how a 'hypodopaminergic' state can reverse cognitive pathology
arising from connectivity disturbances.
PMID- 9549777
TI - Schizophrenia as a consequence of brain evolution.
AB - Connectionist integration of central nervous system function may have proceeded
by a process of biological trial and error throughout brain evolution. As
existing structures enlarged, and as new elements of brain function were added,
misconnectionist variants could arise. This might account for a number of
developmental syndromes in the human brain including schizophrenia. Ultimately,
these would derive from aspects of hominid brain evolution and its vertebrate
ancestry.
PMID- 9549778
TI - No association of apolipoprotein epsilon 4 allele with schizophrenia even in
cognitively impaired patients.
AB - Given the strong association of the apolipoprotein E (apoE) allele epsilon 4
(epsilon 4) with Alzheimer's disease or cognitive decline in elderly, we tested
whether cognitive performance in schizophrenic subjects is associated with an
increase in the frequency of the ApoE epsilon 4 allele. Our data indicate that in
our sample: (1) there is no association between schizophrenia and the ApoE
epsilon 4 allele; and (2) the ApoE epsilon 4 allele is not of major importance
with regard to the cognitive decline observed in schizophrenia.
PMID- 9549779
TI - Types and characteristics of remote memory impairment in schizophrenia.
AB - Remote memory, as the term is used in the present study, refers to semantic
information or autobiographical information for events and facts that are thought
to be stored in the neocortex. In schizophrenia, findings of abnormalities in
remote memory have been reported. However, it is unclear whether these are due to
retrieval factors or other factors (e.g. paucity of information, disorganized
lexicosemantic representations). Furthermore, it is unclear whether there is a
temporal gradient in remote memory. In the first study, we utilized a cueing
procedure for semantic fluency in order to determine whether retrieval factors
play a marked role in impairments. In comparing patients with schizophrenia to
patients with affective disorder and normal controls, we found that cueing had an
equivalent effect upon all groups, suggesting that marked retrieval deficits were
not the primary determinant of poor performance in fluency. Furthermore, we found
that semantic fluency was disproportionately impaired vis-a-vis phonologic
fluency, suggesting that abnormalities may be greater in storage areas presumed
to be in temporal parietal cortex rather than in prefrontal cortex (which has
been associated with retrieval deficits). In the second study, we examined the
temporal gradient of autobiographical memory in patients with schizophrenia and
normal controls. Whereas normal controls exhibited high and equivalent
performance across childhood, early adult, and recent memories, patients with
schizophrenia exhibited a u-shaped profile perhaps unique in the neuropsychiatric
literature. This may reflect a combination of secondary memory impairments which
effect the acquisition of new information coupled to very mildly accelerated rate
of forgetting, 'recency' effects, and/or inefficient encoding. Taken together,
these studies provide further support for the notion that schizophrenia has a
relatively unique pattern of neuropsychological deficit based on neocortical
dysfunction that includes, though is not restricted to, temporoparietal regions.
PMID- 9549780
TI - Assessing intellectual functioning in persons with schizophrenia spectrum
disorders using a seven subtest short form of the WAIS-R.
AB - The purpose of this study was to examine the concurrent validity of a Wechsler
Adult Intelligence Scale-Revised (WAIS-R) seven subtest short form. Researchers
have shown that the IQ scores estimated by this short form correlate highly with
full-form IQ scores in several patient populations. We compared the full WAIS-R
scores with the seven subtest short form estimated IQs in a sample of patients
with psychotic disorders (n = 190). The VIQs, PIQs, and FSIQs estimated by the
short form were highly correlated with the full form IQs (rs ranging from 0.95 to
0.98). Similar to previous research, the mean difference scores were small
(ranging from one point to virtually no difference). In general, the seven
subtest short from has adequate concurrent validity and is suitable for assessing
intellectual functioning in persons with psychotic disorders.
PMID- 9549781
TI - Operant conditioning and the orbitofrontal cortex in schizophrenic patients:
unexpected evidence for intact functioning.
AB - Neuroimaging and neuropsychological studies have consistently implicated
dorsolateral prefrontal cortex as abnormal in schizophrenia. However, other areas
of frontal cortex have received far less attention. In particular, few studies
have examined orbital frontal regions with other than olfactory tests. In the
present study we wished to assess the functional capability of orbital frontal
cortex using a test developed by Bechara et al. (1994) that assesses a subject's
capacity to acquire a preference through reward and punishment, using a gambling
task that involved gains and losses of play money. Thirty normal subjects and 12
patients with schizophrenia (three undifferentiated, eight paranoid, one
schizoaffective) comprised the sample in the present study. We found that
patients with schizophrenia exhibited a pattern of findings similar to that of
normals and dissimilar to that of patients with known orbital frontal damage. In
our study, both normal subjects and schizophrenic patients chose most frequently
from decks of cards in which there were frequent rewards and infrequent
penalties, as might be expected on the basis of operant conditioning literature.
We also found that performance on this task was not correlated with tests of
working memory or long-term memory, suggesting that the development of a
preference may occur implicitly. Our findings also argue against a general
deficit in schizophrenia, as performance on the gambling task appeared relatively
uncompromised.
PMID- 9549782
TI - Brain torque and sex differences in schizophrenia.
AB - The opposing asymmetry of the frontoparietal brain regions has been referred to
as 'torque' and may be used as an index of speed of neurodevelopment. It has been
recently suggested that torque is minimized in male schizophrenia, reflecting
anomalous neurodevelopment. This study examined volumetric and linear torque in a
group of 20 schizophrenia patients and 20 healthy individuals; all were right
handed and under the age of 46 years. None of the main or interaction effects on
torque were statistically significant, although the sex difference in torque
among schizophrenia patients (male larger than female) was more than seven times
that in healthy subjects. Torque was significantly associated with years of
education and age of illness onset (schizophrenia). These findings support the
hypothesis that slowed neurodevelopment may be associated with male schizophrenia
and may contribute to earlier age of onset and fewer years of education.
PMID- 9549783
TI - Spatial accuracy of primary and secondary memory-guided saccades in schizophrenic
patients.
PMID- 9549784
TI - Potential role for the narcolepsy- and multiple sclerosis-associated HLA allele
DQB1*0602 in schizophrenia subtypes.
PMID- 9549785
TI - Anatomic considerations of C2 nerve root ganglion.
AB - STUDY DESIGN: Dissection and observation of the dorsal root ganglion of the
second cervical spinal nerve bilaterally. OBJECTIVES: To determine the position
of the C2 dorsal root ganglion and the heights of the C2 ganglion and its
corresponding foramen. SUMMARY OF BACKGROUND DATA: The dorsal root ganglion has
been well studied in the middle and lower cervical spine and in the lumbar spine.
In no previous study are the position and height of the C2 dorsal root ganglion
and its corresponding foramen described. METHODS: Fifteen cadaveric cervical
spines were exposed posteriorly. The C2 nerve roots and ganglia were dissected
between the arch of the atlas and the lamina of the axis. The heights of the C2
ganglion and foramen were measured. The location of the C2 ganglion was also
macroscopically observed. RESULTS: The heights of the C2 ganglion and foramen are
5.7 +/- 0.8 mm and 7.7 +/- 1.2 mm, respectively. The C2 ganglion occupies 76% of
the foramen height. All C2 dorsal root ganglia are confined within foramens
between the arch of the atlas and the lamina of the axis. CONCLUSIONS: The C2
dorsal dorsal root ganglia are all proximally placed and occupy most of the
foramen height, which may render the C2 ganglion vulnerable to entrapment.
PMID- 9549786
TI - The role of prophylactic antibiotics in spinal instrumentation. A rabbit model.
AB - STUDY DESIGN: A rabbit model was used to test the efficacy of cefazolin
administered in various therapeutic regimens in preventing iatrogenic
Staphylococcus aureus infections during spinal instrumentation. OBJECTIVE: To
assess the efficacy of various prophylactic therapeutic regimens of cefazolin in
preventing iatrogenic S. aureus infections during spinal instrumentation. SUMMARY
OF BACKGROUND DATA: Previous studies have not dealt specifically with the
occurrence of iatrogenic S. aureus infections during spinal instrumentation in a
prospective fashion. METHODS: Twenty New Zealand White rabbits underwent a
posterior approach to the lumbar spine. Fifteen of the animals then had double
braided 26-gauge surgical wire placed around bilateral L3-L4 and L4-L5 facet
joints. A standardized volume of a 103 S. aureus/mL of solution was then
inoculated onto the fusion-hardware site in all rabbits. The rabbits were divided
into four groups receiving various antibiotic dose regimens. Five days after
surgery, the animals were killed, and cultures were obtained. RESULTS: All of the
rabbits receiving no antibiotic had fusion sites infected with S. aureus. None of
the animals who received prophylactic cefazolin produced cultures that grew S.
aureus. A specimen from one fusion site cultured Staphylococcus epidermidis,
which is not sensitive to cefazolin. Analysis of these data using Fisher's exact
test resulted in a P value of 0.008 when results in antibiotic groups were
compared with those in a group receiving no antibiotics and a P value of 0.0003
when all groups were compared. CONCLUSIONS: This model was valid and reproducible
for the study of spinal instrumentation and infection. In addition, the data
support the efficacy and use of prophylactic intravenous antibiotics in
preventing infection in spinal instrumentation and fusion surgery.
PMID- 9549787
TI - Keratan sulfate as a potential biomarker of loading of the intervertebral disc.
AB - STUDY DESIGN: A review of the literature. OBJECTIVE: To investigate the potential
of serum levels of keratan sulfate as a biomarker of the effects of loading of
the spine. SUMMARY OF BACKGROUND DATA: Exposure to mechanical loading of the
spine causes changes in metabolism of intervertebral discs, eventually leading to
accelerated disc degeneration. This process is characterized by the degradation
of proteoglycans, which is reflected by an increase in the blood level of
proteoglycan components. The serum level of keratan sulfate, an epitope present
on these proteoglycan components, has been suggested as a marker of changes in
metabolism of cartilaginous tissues. METHODS: A review of the literature on serum
keratan sulfate levels in relation to degenerative changes in cartilaginous
tissue. RESULTS: In a number of studies keratan sulfate in serum was reported to
be related to degeneration of articular cartilage in patients with
osteoarthritis. In addition, massive and rapid degradation of intervertebral
discs was determined to result in a large rise in serum keratan sulfate levels.
Whether degenerative changes of intervertebral discs induced by mechanical stress
also cause a detectable increase in serum keratan sulfate should be subjected to
further investigation. CONCLUSION: Quantification of keratan sulfate in serum
offers a promising measure for the early effects of mechanical loading of the
spine, but research is needed for validation.
PMID- 9549788
TI - Reinforcement of thoracolumbar burst fractures with calcium phosphate cement. A
biomechanical study.
AB - STUDY DESIGN: A biomechanical study on the stabilization of thoracolumbar burst
fractures. OBJECTIVE: To demonstrate that the addition of a calcium phosphate
cement into the fractured vertebral body through a transpedicular approach is a
feasible technique that improves the stiffness of a transpedicular screw
construct. SUMMARY OF BACKGROUND DATA: Short segment pedicle screw
instrumentation is a commonly used method for reduction and stabilization of
unstable burst fractures. Recent investigators, however, have reported a high
rate of instrumentation failure and sagittal collapse when there is a loss of
anterior column support. In this study, the ability of a new hydroxyapatite
cement to augment anterior column support was investigated in a burst fracture
model. METHODS: A cadaveric L1 burst fracture model was stabilized using short
segment pedicle screw instrumentation. Specially instrumented-pedicle screws
recorded screw-bending moments. The L1 vertebral body was reinforced with the
hydroxyapatite cement through a transpedicular approach. Mechanical testing of
the instrumented and instrumented-reinforced constructs were performed in
flexion, extension, side bending, and torsion. Construct stiffness and screw
bending moments were recorded. RESULTS: Transpedicular vertebral body
reconstruction with hydroxyapatite cement reduced pedicle screw-bending moments
by 59% in flexion and 38% in extension. Mean initial stiffness in the flexion
extension plane was increased by 40% (P < 0.05). There were no statistically
significant differences in these parameters with lateral bending or torsional
movements. CONCLUSIONS: This hydroxyapatite cement compound augments anterior
column stability in a burst fracture model. This technique may improve outcomes
in burst fracture patients without the need for a secondary anterior approach.
PMID- 9549789
TI - The effects of spinal fixation and destabilization on the biomechanical and
histologic properties of spinal ligaments. An in vivo study.
AB - STUDY DESIGN: An animal study was conducted to assess whether different surgical
procedures of spinal fixation and destabilization would influence the
biomechanics and histology of lumbar spinal ligaments. OBJECTIVES: To investigate
the effects of spinal fixation and destabilization as well as surgical
intervention itself on the biomechanical and histologic properties of lumbar
spinal ligaments. SUMMARY OF BACKGROUND DATA: Although several investigators have
reported normal biomechanical properties of different spinal ligaments, there
have been no studies in which changes in spinal ligament properties, secondary to
the altered biomechanical environment provided by such surgical procedures as
spinal fixation and destabilization, have been investigated. METHODS: Thirty-six
mature sheep were divided into four groups: Group I: nonsurgical control: Group
II: sham operation consisting of bilateral posterolateral exposure at L4-L5;
Group III: spinal fixation using transpedicular screws and plates and bilateral
posterolateral bone graft at L4-L5; and Group IV: spinal destabilization
consisting of bilateral facetectomy and anterior discectomy at L4-L5. Four months
after surgery, the biomechanical analysis included destructive tensile testing of
four different bone-ligament-bone complexes at the operative and proximal
adjacent levels: anterior longitudinal ligament, posterior longitudinal ligament,
ligamentum flavum, and supraspinous and interspinous ligaments combined.
Histomorphometric analyses of the vertebral body and spinal ligaments were
performed histomorphometrically. RESULTS: Biomechanical analysis results
demonstrated remarkable changes in the structural and mechanical ligament
properties at the operative level. The fixation group's ligaments showed
consistent decreases in the ultimate load and elastic modulus compared with those
parameters in the control group (P < 0.05). Histologically, the fixation group's
ligamentum flavum showed marked vacuolation in the ligament substance, whereas
the interspinous ligament exhibited significant insertion changes compared with
little change in substance. In all eight sheep in Group IV, unintentional
bilateral facet fusions were obtained; and in all eight animals in Group III with
pedicle instrumentation and posterolateral fusion, solid arthrodesis was
exhibited. This allowed a distinction to be made between the stress-shielding
effect of spinal instrumentation and arthrodesis (Group III) versus spinal fusion
alone (Group IV) on both spinal ligament and vertebral body. Group II (sham) had
a significant decrease in supraspinous and interspinous ligaments, but
nonsignificant decreases in the stress-shielding effect of 10-12% in other
ligaments. CONCLUSIONS: Posterior spinal instrumentation and fusion led to
decreased biomechanical properties of the ligamentum flavum, posterior
longitudinal ligament, and interspinous and supraspinous ligaments. The stress
shielding effects were ligament dependent and were most pronounced on the
posterior side. The altered biomechanical environment produced by spinal
fixation, surgical intervention itself, or nonphysiologic mobilization can affect
the ligamentous properties in vivo, possibly serving as the impetus for low back
pain.
PMID- 9549790
TI - Prediction of load sharing among spinal components of a C5-C6 motion segment
using the finite element approach.
AB - STUDY DESIGN: A finite element model of the ligamentous cervical spinal segment
was used to compute loads in various structures in response to clinically
relevant loading modes. OBJECTIVE: To predict biomechanical parameters, including
intradisc pressure, tension in ligaments, and forces across facets that are not
practical to quantify with an experimental approach. SUMMARY OF BACKGROUND DATA:
Finite element models of the cervical spine in their present form, because of
inherent assumptions and simplifications, are not entirely satisfactory for
studying the biomechanics of the intact, injured, and stabilized cervical spinal
segment. METHODS: A three-dimensional finite element model of a C5-C6 motion
segment was developed from serial computed tomographic scans of a ligamentous
cervical spinal segment. This model included nonlinear ligament definition, fully
composite intervertebral disc, fluid nucleus, and Luschka's joints. The model
based displacement predictions were in agreement with the experimental data. This
model was used to predict load sharing and other related parameters in spinal
elements in response to various loading modalities. RESULTS: In axial
compression, 88% of the applied load passed through the disc. The interspinal
ligament experienced the most strain (29.5%) in flexion, and the capsular
ligaments were strained the most (15.5%) in axial rotation. The maximum intradisc
pressure was 0.24 MPa in the flexion with axial compression mode (1.8 Nm + 73.6
N). The anterior and posterior disc bulges increased with the increase in axial
compression (up to 800 N). CONCLUSIONS: The results provide new insight into the
role of various elements in transmitting loads. The model represents significant
and essential advancement in comparison with previous finite element models,
making it possible for such models to be used in investigating a broad spectrum
of clinically relevant issues.
PMID- 9549791
TI - Metallic artifacts in magnetic resonance imaging of patients with spinal fusion.
A comparison of implant materials and imaging sequences.
AB - STUDY DESIGN: Devices for spinal fusion were compared with respect to their
influence on magnetic resonance images. In addition, different magnetic resonance
pulse sequences were evaluated to elicit their susceptibility to imaging
artifacts. OBJECTIVES: To determine the implants with the least imaging artifacts
as a recommendation for the spine surgeon and to assess the best imaging strategy
for the radiologist. SUMMARY OF BACKGROUND DATA: For patients who have had
surgical spinal fusion with instrumentation, magnetic resonance imaging is the
most favorable diagnostic method. Unfortunately, metallic implants lead to severe
degradation of image quality. These artifacts depend on the material of the
implant and on the choice of the pulse sequence. METHODS: The fusion devices were
mounted on a simple plastic phantom in various combinations and were imaged on
1.5-T magnetic resonance units. Frequently used types of plates and screws made
of titanium or steel in various alloys were examined on the phantom with
routinely used pulse sequences. The results of these examinations were compared
with those in patient studies involving the same implants as well as the same
pulse sequences. RESULTS: The least imaging artifacts were caused by titanium
implants, especially when using shorter screws, wider screw placement, and
thinner titanium plates. Nevertheless, there were distinct image distortions that
could lead to erroneous image interpretation. The best images were acquired by
spin echo (T1), turbo spin echo (T1, T2), and half Fourier single shot turbo spin
echo (HASTE) sequences. Sequences containing any gradient echo components
(gradient echo or turbo gradient and spin echo sequence or frequency-selective
fat saturation techniques) resulted in the highest amount of image degradation.
CONCLUSION: By choosing appropriate spinal fusion devices as well as pulse
sequences, postoperative magnetic resonance imaging examinations can give
acceptable results, in spite of the presence of metallic implants.
PMID- 9549792
TI - Reciprocal angulation of vertebral bodies in the sagittal plane in an
asymptomatic Greek population.
AB - STUDY DESIGN: A prospective study conducted on several roentgenographic
parameters of the standing sagittal profile of the spine in an asymptomatic Greek
population. OBJECTIVES: To perform segmental analysis of the sagittal plane
alignment of the normal thoracic, lumbar, and lumbosacral spines and to compare
the findings with those derived from similar populations. SUMMARY OF BACKGROUND
DATA: Until recently, little attention has been paid to the sagittal segmental
alignment of the spine, and there are only a few studies (in French and American
populations) in which radiographic analysis of sagittal spinal alignment is
investigated. METHODS: Ninety-nine consecutive asymptomatic Greek volunteers (38
men, 61 women), an average age of 52.7 +/- 15 years old (range, 20-79 years),
were included in this prospective study, on the basis of several inclusion
criteria. These volunteers were divided into six distinct age groups. The
radiologic parameters, which were measured (by Cobb's method) on the lateral
standing roentgenograms of the whole spine were: thoracic kyphosis (T4-T12),
lumbar lordosis (L1-L5), total lumbar lordosis (T12-S1), distal lumbar lordosis
(L4-S1), sacral inclination (measured from the line drawn parallel along the back
of the proximal sacrum and the vertical line), pelvic tilting, vertebral body
inclination, and relative segmental inclination between pairs of adjacent
vertebrae. RESULTS: Thoracic kyphosis and lumbar lordosis (T12-S1, L1-L5) were
not gender related. Thoracic kyphosis increased with age (P < 0.001), the lumbar
spine (L1-L5) gradually became less lordotic as the thoracic kyphosis increased
(P < 0.003), and total lumbar lordosis was not age related. Sacral inclination
correlated strongly with both thoracic kyphosis (P < 0.002) and L1-L5 lordosis (P
< 0.001). Pelvic tilting correlated strongly with L1-L5 lordosis (P < 0.0075),
but did not correlate with thoracic kyphosis and age. Vertebral body inclination
showed a narrow variability in T6-T12 and in L4 and a wide variability in T4, T5,
L1-L3, and S1. Distal lumbar lordosis represents the 68.6% of the total lumbar
lordosis. CONCLUSIONS: In the results of this study, a reliable table of
reference for roentgenographic parameters in the sagittal plane of the spine was
established in an asymptomatic Greek population. The parameters are similar to
those used in previous studies. Thus, these data should be considered in
preoperative planning and postoperative evaluation of achieved correction during
restoration procedures of the spine in the sagittal plane.
PMID- 9549793
TI - An assessment of complex spinal loads during dynamic lifting tasks.
AB - STUDY DESIGN: An electromyogram-assisted free-dynamic lifting model was used to
quantify the patterns of complex spinal loads in subjects performing various
lifting tasks. OBJECTIVES: To assess in vivo the three-dimensional complex spinal
loading patterns associated with high and low risk lifting conditions that
matched those observed in industrial settings. SUMMARY OF BACKGROUND DATA:
Combined loading on the spine has been implicated as a major risk factor in
occupational low back disorders. However, there is a void in the literature
regarding the role of these simultaneously occurring complex spinal loads during
manual lifting. METHODS: Eleven male subjects performed symmetric and asymmetric
lifting tasks with varying speed and weight. Reactive forces and moments at L5-S1
were determined through the use of electrogoniometers and a force plate. An
electromyogram-assisted model provided the continuous patterns of three
dimensional spinal loads under these complex lifting tasks. RESULTS: The results
showed that complex dynamic motions similar to those observed in risky industrial
tasks generated substantial levels of combined compressive and shear loads. In
addition, higher loading rates were observed under these conditions. Unlike
loading magnitudes, loading rate was a better indicator of dynamic loading
because it incorporated both the duration and magnitude of net muscle forces
contributing to total spinal loading during the lifting conditions. CONCLUSIONS:
Quantification of spinal combined motions and loading in vivo has not been
undertaken. This study provided a unified assessment of the effects of combined
or coupled motions and moments in the internal loading of the spine. Dynamic
lifting conditions similar to those observed in risky industrial situations
generated unique complex patterns of spinal loading, which have been implicated
to pose a higher risk to the spinal structure. The higher predicted loading and
loading rate during asymmetric lifting conditions can be avoided by appropriate
ergonomic workplace modifications.
PMID- 9549794
TI - Functional restoration for chronic low back pain. Two-year follow-up of two
randomized clinical trials.
AB - STUDY DESIGN: Two randomized, prospective clinical trials involving 238 chronic
low back disability patients were carried out. Results at 2-year follow-up are
presented. OBJECTIVES: To compare the clinical outcomes of a multidisciplinary
functional restoration program with a nontreated control group (Project A) and
with two less intensive but different training programs (Project B). SUMMARY OF
BACKGROUND DATA: The effectiveness of functional restoration programs has not
been firmly established. Results from trials carried out in the United States
differ from those in trials conducted in other countries. Only a few of these
studies have been carried out as prospective and randomized clinical studies.
METHODS: Two hundred thirty-eight patients with chronic low back disability of at
least 6 months' duration were included. There were 106 patients in project A and
132 patients in project B. Two years after completion of treatment patients were
mailed a questionnaire that included questions regarding their work status, pain
and disability levels, number of sick leave days, number of medical care
contacts, medication use, physical activity levels, and subjective overall
assessment of their "back life situation." RESULTS: Patients in both studies were
comparable at inclusion, except that patients in Project A were recruited from
all of Denmark, whereas those in Project B were from the greater Copenhagen area.
Thirteen patients did not report for treatment after randomization. Of the
remaining 225 patients, 20 (9%) did not complete treatment. The questionnaire
response rate was 94%. In Project A, those patients receiving treatment
(functional restoration) reported significantly less contact with the health care
system, fewer sick leave days, and a less disabled life style during the follow
up period, compared with reports of patients in the control group. Other effect
parameters did not demonstrate a significant difference between the two groups.
In Project B, all effect parameters reported, except leg pain and medication
usage, were significantly in favor of functional restoration, compared with
reports from the less intensively treated groups. CONCLUSIONS: The functional
restoration program seems effective in various parameters compared with the less
intensive programs, but the differences in outcome in the two parallel studies
indicate the necessity of testing a treatment program in different settings, in
that the statistical variation may be a major factor in results of different
studies.
PMID- 9549795
TI - Factors influencing wound healing after surgery for metastatic disease of the
spine.
AB - STUDY DESIGN: The study group consisted of 53 patients who underwent 75
operations for spine metastases. Patient and tumor demographic factors,
preoperative nutritional status, and perioperative adjunctive therapy were
retrospectively reviewed. OBJECTIVE: To determine the risk factors for wound
breakdown and infection in patients undergoing surgery for spinal metastases.
SUMMARY OF BACKGROUND DATA: Spinal fusion using spine implants may be associated
with an infection rate of 5% or more. Surgery for spine metastases is associated
with an infection rate of more than 10%. Factors other than the type of surgery
performed may account for the greater infection rate. METHODS: Data were obtained
by reviewing patient records. Age, sex, and neurologic status of the patient;
tumor type and site; and surgical details were noted. Adjunctive treatment with
corticosteroids and radiotherapy was recorded. Nutritional status was evaluated
by determining serum protein and serum albumin concentrations and by total
lymphocyte count. RESULTS: Wound breakdown and infection occurred in 15 of 75
wounds. No patient or tumor demographic factors other than intraoperative blood
loss (P < 0.1) were statistically associated with infection. The correlation
between preoperative protein deficiency (P < 0.01) or perioperative
corticosteroid administration (P < 0.10) and wound infection was significant.
There was no statistical correlation between lymphocyte count or perioperative
radiotherapy and wound infection. CONCLUSIONS: The results indicate that
preoperative protein depletion and perioperative administration of
corticosteroids are risk factors for wound infection in patients undergoing
surgery for spine metastases. Perioperative correction of nutritional depletion
and cessation of steroid therapy may reduce wound complications.
PMID- 9549796
TI - An unusual cause of lumbar discitis.
AB - STUDY DESIGN: Case report. OBJECTIVE: To identify an unusual cause of lumbar
discitis. SUMMARY OF BACKGROUND DATA: Discitis resulting from a foreign body has
not been reported in the English-language literature. METHOD: A case report is
reviewed identifying the presence of this foreign object (titanium), erroneously
implanted into the disc space at L5-S1. Imaging studies identify the location and
surrounding reaction. RESULTS: The surgical exploration of this disc revealed an
inflammatory response surrounding the disc with degeneration within the disc
space. CONCLUSION: If this gynecologic procedure is performed using bone anchors,
care must be take to ensure that the sacrum is identified before insertion.
PMID- 9549797
TI - Asymptomatic grotesque deformities of the cervical spine. An occupational hazard
in railway porters.
AB - STUDY DESIGN: A case report. OBJECTIVE: To illustrate an extremely rare
occurrence of chronic, occupational, low-grade trauma leading to asymptomatic
grotesque cervical spine deformities in railroad station porters. SUMMARY OF
BACKGROUND DATA: Occupational trauma causing spinal deformities has been
described in relation to thoracic and lumbar spines in miners. To the authors'
knowledge, this is the first reported case of asymptomatic cervical spinal
deformity in railway porters as a result of chronic occupational trauma. METHODS:
A magnetic resonance imaging study was performed on both patients. RESULTS: The
magnetic resonance images showed advanced degenerative changes in the cervical
spine causing obvious deformities, along with apparently normal cord signal
intensity. CONCLUSIONS: Chronic, occupational, low-grade trauma of the cervical
vertebral region is extremely unusual in industrialized countries. Nevertheless,
in view of the increasing mobility of people in general and of the labor force in
particular, this complication of an occupational exposure deserves attention as
an unusual cause of cervical spinal deformity.
PMID- 9549799
TI - Efficacy of five cervical orthoses in restricting cervical motion: a comparison
study.
PMID- 9549798
TI - Symptomatic monostotic fibrous dysplasia of the thoracic spine.
AB - STUDY DESIGN: A case report of monostotic fibrous dysplasia of the thoracic spine
with symptoms of chest and back pain. OBJECTIVE: To treat this lesion with
surgery. SUMMARY OF BACKGROUND DATA: Monostotic fibrous dysplasia of the thoracic
spine is rarely seen. Few reports of this disorder appear in the literature. This
is the fifth case of monostotic fibrous dysplasia of the thoracic spine presented
to date. METHODS: The patient was a 48-year-old woman with monostotic fibrous
dysplasia involving the thoracic spine of the 10th vertebral body and the 10th
left rib. Surgical removal of the tumor was carried out. The defect was packed
with hydroxyapatite graft material. Arthrodesis or internal fixation was not
made. RESULTS: The diagnosis of fibrous dysplasia was made histologically. No
obvious recurrence of the lesion has been seen for 3 years. CONCLUSION: Surgical
removal of the tumor and transplantation of hydroxyapatite was effective
treatment for the reported patient.
PMID- 9549800
TI - Thermal transport during radiofrequency current therapy of the intervertebral
disc.
PMID- 9549801
TI - Missing quality of life data in cancer clinical trials: serious problems and
challenges.
AB - Measurement of quality of life (QOL) in cancer clinical trials has increased in
recent years as more groups realize the importance of such endpoints. A key
problem has been missing data. Some QOL data may unavoidably be missing, as for
example when patients are too ill to complete forms. Other important sources are
potentially avoidable and can broadly be divided into three categories: (i)
methodological factors; (ii) logistic and administrative factors; (iii) patient
related factors. Logistic and administrative factors, for example, staff
oversights, have proven to be most important. Since most QOL measurements require
patient self-report, it is usually not possible to rectify the failure to collect
baseline data or any follow-up assessments. There is strong evidence that such
data are not 'missing at random', and cannot be ignored without introducing bias.
Although several approaches to the analysis of partly missing data have been
described, none is entirely satisfactory. Prevention of avoidable missing data is
better than attempted cure. In July 1996, an international conference on missing
QOL data in cancer clinical trials reported the experience of most major groups
involved. This paper will serve as an introduction to the problem and provide an
estimation of its magnitude, and approaches to its prevention and solution.
PMID- 9549802
TI - Quality of life studies of the Australian New Zealand Breast Cancer Trials Group:
approaches to missing data.
AB - The purpose of this paper is to describe the degree of compliance with quality of
life measures in two clinical trials conducted by the Australian New Zealand
Breast Cancer Trials Group comparing different chemotherapy policies for
metastatic breast cancer. Quality of life was assessed by the patient using
linear analogue scales and by the physician using the Spitzer QLI. Compliance was
generally good, ranging from 66 per cent to 79 per cent in the earlier study, and
from 63 per cent to 97 per cent in the later study. Compliance with physician
rated quality of life was consistently slightly better than for patient self
assessment. The results of physician and patient assessments were generally
consistent, but there was a systematic bias toward lower quality of life (as
assessed by the physician) in patients who failed to comply with self-assessment.
Our conclusions were that quality of life can be assessed in large scale multi
institution clinical trials in metastatic breast cancer. The results are
important in assessing treatment comparisons. Missing data cannot be assumed to
be similar to those available. Optimal assessment of quality of life therefore
requires careful prospective attention to complete data collection.
PMID- 9549803
TI - Compliance issues in quality of life assessment: experiences of two Cancer
Research Campaign sponsored groups.
PMID- 9549804
TI - Missing data in quality of life research in Eastern Cooperative Oncology Group
(ECOG) clinical trials: problems and solutions.
AB - Incorporation of quality of life (QOL) investigation into Eastern Cooperative
Oncology Group (ECOG) multi-centre clinical trials has led to innovative
strategies for protocol design and high quality data collection. A scientific
advisory committee reviews protocol design components, measurement selection,
timing of assessments and compliance issues. Extensive educational programmes
provide information about the scientific and clinical relevance of QOL protocols,
as well as practical strategies for data collection and management. Compliance
with QOL data collection standards is prospectively monitored and evaluated.
Preliminary results from eight ECOG-run protocols found overall compliance to be
approximately 85 per cent (94 per cent at baseline and 73 per cent during
treatment). Selected patient and institutional factors were evaluated for their
association with compliance.
PMID- 9549805
TI - Quality of life as an endpoint in EORTC clinical trials. European Organization
for Research and Treatment for Cancer.
AB - For more than 30 years the European Organization for Research and Treatment for
Cancer (EORTC) has conducted, co-ordinated, and stimulated research on the
experimental and clinical bases of treatment of cancer and related problems. For
more than a decade the EORTC has included quality of life as an outcome measure
in some of its trials. The number of clinical studies that include QOL as an
evaluation endpoint has increased rapidly in the last few years, and is still
increasing steadily. This necessitated a careful and critical evaluation of
procedures and results so far in order to generate appropriate guidelines and
procedures for incorporating QOL issues in all stages of the clinical trial
process, including protocol writing, data collection, data analysis, and
reporting of results. This paper provides an overview of the types and the design
of studies, data management of quality of life assessment, compliance, missing
data and lessons learned during the past years with respect to QOL assessments in
the EORTC studies.
PMID- 9549806
TI - Compliance with QOL assessment in multi-centre German breast cancer trials.
AB - The compliance with QOL assessment in German breast cancer trials is reported.
The results indicate that the response to fill in QOL forms in cancer clinical
trials seems to depend more on the clinical centre and the attitude of the
treating physician than the individual patient. A strategy of globally
eliminating centres that produce high rates of missing QOL data from the analysis
of QOL is discussed. The adoption of such a strategy will reduce the number of
patients available for analysis, but on the other hand increase the relative
amount of non-missing data.
PMID- 9549807
TI - The multi-centre assessment of quality of life: the Interdisciplinary Group for
Cancer Care Evaluation (GIVIO) experience in Italy.
AB - One of the main issues to be considered in conducting clinical trials concerns
the presence of missing data. This aspect is particularly relevant in oncology
longitudinal studies, characterized by a long follow-up, and especially in
quality of life studies where there is still little knowledge about patients'
characteristics that predict loss of data. Since the middle of the 1980s the
GIVIO (Interdisciplinary Group for Cancer Care Evaluation) co-operative group has
been involved in conducting quality of life assessment studies, also focusing on
the development of some strategies aimed at the minimization of missing data. In
this paper we report on the results of two trials, which are now completed,
concerning the quality of life assessment in a sample of breast and colon cancer
patients. In order to cope with the problem of missing data, in both the trials
the strategy of follow-up mailing was adopted, which proved to be an effective
way to increase the response rate by nearly 50 per cent at each time point.
PMID- 9549808
TI - Quality of life assessment in International Breast Cancer Study Group (IBCSG)
trials: practical issues and factors associated with missing data.
AB - We report on our experience of quality of life (QL) assessment in adjuvant
clinical trials of the International Breast Cancer Study Group (IBCSG), with
special emphasis on cultural and logistical aspects of international organization
that are unique to this group. Data are presented regarding submission rates of
assessments before and after treatment failure, and timing of assessments
relative to chemotherapy administration. To identify areas where rates might be
improved, we investigated the association between missing data and
sociodemographic and biomedical factors, treatment assignment, institution,
chemotherapy compliance and toxicity in a trial of adjuvant chemoendocrine
therapy for post-menopausal patients with breast cancer (IBCSG VII). The factors
most highly associated with missing data were institution and chemotherapy
compliance.
PMID- 9549809
TI - Completion rates in health-related quality-of-life assessment: approach of the
National Cancer Institute of Canada Clinical Trials Group.
AB - The approach of the National Cancer Institute of Canada Clinical Trials Group to
measuring compliance, that is, completion rates, for health-related quality of
life questionnaires is presented. Completion rates can be measured at the
institutional, patient, questionnaire and item levels for baseline, on-treatment
and off-treatment follow-up study periods. Time windows are defined for each
expected completion time. In seven completed clinical trials, completion rates
were high with more than 93 per cent of patients completing questionnaires in the
specified time windows at baseline and while on-treatment. The rate while on off
treatment follow-up is still acceptable at 85 per cent. The proportions of
analysable questionnaires were 97.6 per cent, 82.0 per cent and 77.0 per cent
respectively, at the three study periods. Item completion rates within
questionnaires were high at 95.5 per cent or more. The variables most likely to
influence baseline and on-treatment questionnaire completion rates were breast
cancer, ovarian cancer, metastases and study centre size.
PMID- 9549810
TI - Compliance with quality of life data collection in the National Surgical Adjuvant
Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial.
AB - This paper describes compliance with the completion of a quality of life
questionnaire in the Breast Cancer Prevention Trial, a large multi-centre
randomized trial that is studying the efficacy of Tamoxifen in preventing breast
cancer. In the first 4875 women enrolled in the control arm of the study, there
was a very high rate of questionnaire completion at baseline, 3 months, 6 months
and 12 months of follow-up (89.8 per cent completed forms at 12 months). The
sample was examined according to demographic and risk factors, as well as by
recruitment cohort. There was a significantly poorer compliance rate for the most
recently recruited cohort that was followed-up during a time of substantial
external negative publicity related to clinical trial research. Nevertheless, the
overall compliance with completion of quality of life data in this trial is very
high, which is probably attributable to the high educational status of the trial
participants.
PMID- 9549811
TI - Compliance in quality of life data: a Norwegian experience.
AB - Compliance is of extreme importance in assessing quality of life since lost data
never can be retrieved. In order to assess this issue in various studies, a cross
sectional study in cured cancer patients, three prospective trials and a
normative study were explored. In the cross-sectional study 82 per cent of the
patients completed the questionnaires after one reminder. More females than males
answered the questionnaires. The compliance rate varied from 99 per cent to 62
per cent in the prospective studies depending upon time after inclusion. It seems
that compliance decreases during follow up, primarily because of disease
progression. In one of the prospective studies low compliance rate (approximately
30 per cent) was found in the questionnaire assessing religious issues. In the
normative study 68 per cent of the population completed the questionnaire. No
gender differences were found, but younger males and elderly women were poor
compliers. In conclusion, our data support that most patients complete quality of
life questionnaires. It seems that patients with inferior education, reduced
physical function and with progressive/terminal disease are low compliers.
Introduction of the first quality of life questionnaires to the patients is of
great importance. Detailed information about the study should be given and the
importance of completing the questionnaires should be underlined.
PMID- 9549812
TI - Practical issues in quality of life assessment in multicentre trials conducted by
the Swiss Group for Clinical Cancer Research.
AB - Quality of life (QOL) assessment has become an integrated part in some advanced
disease trials and to a lesser extent in early disease trials conducted by the
Swiss Group for Clinical Research (SAKK). In general, the concept of QOL
endpoints and the additional work of collecting these data is well accepted by
patients, nurses and physicians. The QOL form submission rates in recently
completed trials in advanced disease have improved in response to ongoing staff
training and supervision as well as direct and personal interventions in the
local centres, with 82-86 per cent before treatment failure, and 59-88 per cent
at failure. The main source of missing data are local administrative problems, in
particular staff oversights.
PMID- 9549813
TI - Ensuring the quality of quality of life data: the Southwest Oncology Group
experience.
AB - The Southwest Oncology Group (SWOG) has successfully included quality of life
(QOL) questionnaires in selected oncology treatment trials. Extensive quality
control procedures have been necessary for obtaining and maintaining good
questionnaire submission rates. Since the first QOL study was activated in SWOG
in 1990, the Group has found it increasingly necessary to incorporate centralized
monitoring of the QOL assessment schedule. Successful quality control strategies
are presented. Current submission rates for five SWOG phase III treatment trials
(both open and closed) and one chemoprevention trial are presented for those
scheduled QOL assessments for which we have follow-up data. Reasons for missing
QOL questionnaires and the extent of missing data within submitted QOL
questionnaires are described for two different disease contexts: a trial for
patients with advanced stage disease, and a trial for patients with earlier stage
disease.
PMID- 9549814
TI - Statistical analysis of quality of life with missing data in cancer clinical
trials.
AB - We summarize issues that arise when considering quality of life (QOL) data in
cancer clinical trials, especially those related to missing data. We describe
different types of missing data mechanisms, and discuss ways of assessing and
testing missing data mechanisms. A section on presentation of study design and
results describes how graphical displays can effectively document the extent of
the missing data problem, as well as describe its impact on interpretation of
results. Finally, we describe several different statistical methods used to
analyse repeated measures, with an emphasis on their properties and their ability
to adequately handle different types of missing data mechanisms. We make
recommendations as to the most appropriate methods, and suggest important
directions for future research.
PMID- 9549816
TI - Incomplete quality of life data in randomized trials: missing items.
AB - Missing data has been a problem in many quality of life studies. This paper
focuses upon the issues involved in handling forms which contain one or more
missing items, and reviews the alternative procedures. One of the most widely
practised approaches is imputation using the mean of all observed items in the
same subscale. This, together with the related estimation of the subscale score,
is based upon traditional psychometric approaches to scale design and analysis.
We show that it may be an inappropriate method for many of the items in quality
of life questionnaires, and would result in biased or misleading estimates. We
provide examples of items and subscales which violate the psychometric
foundations that underpin simple mean imputation. A checklist is proposed for
examining the adequacy of simple imputation, and some alternative procedures are
indicated.
PMID- 9549815
TI - Why are missing quality of life data a problem in clinical trials of cancer
therapy?
AB - Assessment of health related quality of life has become an important endpoint in
many cancer clinical trials. Because the participants of these trials often
experience disease and treatment related morbidity and mortality, non-random
missing assessments are inevitable. Examples are presented from several such
trials that illustrate the impact of missing data on the analysis of QOL in these
trials. The sensitivity of different analyses depends on the proportion of
assessments that are missing and the strength of the association of the
underlying reasons for missing data with disease and treatment related morbidity
and mortality. In the setting of clinical trials of cancer therapy, the
assumption that the data are missing completely at random (MCAR) and analyses of
complete cases is usually unjustified. Further, the assumption of missing at
random (MAR) may also be violated in many trials and models appropriate for non
ignorable missing data should be explored. Recommendations are presented to
minimize missing data, to obtain useful documentation concerning the reasons for
missing data and to perform sensitivity analyses.
PMID- 9549817
TI - Incomplete quality of life data in randomized trials: missing forms.
AB - Analysing quality of life (QOL) data may be complicated for several reasons, such
as: repeated measures are obtained; data may be collected on ordered categorical
responses; the instrument may have multidimensional scales, and complete data may
not be available for all patients. In addition, it may be necessary to integrate
QOL with length of life. The major undesirable effects of missing data, in QOL
research, are the introduction of biases due to inadequate modes of analysis and
the loss of efficiency due to reduced sample sizes. Currently, there is no
standard method for handling missing data in QOL studies. In fact, there are very
few references to methods of handling missing data in this context. The aim of
this paper is to provide an overview of methods for analysing incomplete
longitudinal QOL data which have either been presented in the QOL literature or
in the missing data literature. These methods of analysis include complete case,
available case, summary measures, imputation and likelihood-based approaches. We
also discuss the issue of bias and the need for sensitivity analyses.
PMID- 9549818
TI - Suggestions for the presentation of quality of life data from clinical trials.
AB - Quality of life (QOL) data is complex since it is both multidimensional and
longitudinal. This complexity is compounded with its unbalanced nature through
missing observations as a consequence of patient non-compliance with assessment
schedules, and, for example, in cancer clinical trials data absence due to
patient attrition often through death. QOL data poses difficulties for
presentation and analysis and hence interpretation. This paper illustrates, using
data from a randomized trial of the United Kingdom Medical Research Council Lung
Cancer Working Party, a step-by-step approach to presentation of QOL data. This
begins with a description of compliance and its relationship with patient
attrition caused by death, to a final summary profile to indicate change over
time. We recognize that no single summary statistic is likely to be able to
encapsulate all the subtleties of QOL data. We stress the importance of examining
data graphically before performing detailed analysis and also to facilitate
interpretation in the final clinical report. Although a description of analytical
methods is not the purpose of this paper, we draw attention to the need for
imputing missing values and to the (multi-level) modelling approach to
summarizing the data, both essential adjuncts to the less formal methods
described here.
PMID- 9549819
TI - Practical approaches to minimize problems with missing quality of life data.
AB - Missing information on quality of life (QOL) is a significant problem in many
cancer trials particularly for patients with advanced disease, where clinical
deterioration may be a reason for not responding to quality of life assessments.
Examples from four clinical trials are presented where non-respondents to quality
of life assessments have poorer health than respondents. In this context,
auxiliary outcome variables, such as health status, may be useful proxies in
assessing the impact of missing QOL data on estimated treatment effects. This
approach is illustrated in a trial of palliative treatment in advanced cancer. A
method for imputation of missing QOL data based on auxiliary outcome variables is
also illustrated. However, the most effective method of minimizing the problem of
missing data is in designing the trial with preventative strategies in place.
Since some missing data due to deteriorating health may still occur, the design
should include the collection of auxiliary QOL information. Preventative
strategies are illustrated with an ongoing trial in advanced breast cancer.
PMID- 9549820
TI - Identifying the types of missingness in quality of life data from clinical
trials.
AB - This paper discusses methods of identifying the types of missingness in quality
of life (QOL) data in cancer clinical trials. The first approach involves
collecting information on why the QOL questionnaires were not completed. Based on
the reasons provided one may be able to distinguish the mechanisms causing
missing data. The second approach is to model the missing data mechanism and
perform hypothesis testing to determine the missing data processes. Two methods
of testing if missing data are missing completely at random (MCAR) are presented
and applied to incomplete longitudinal QOL data obtained from international multi
centre cancer clinical trials. The first method (Ridout, 1991) is based on a
logistic regression and the second method (Park and Davis, 1993) is based on an
adaptation of weighted least squares. In one application (advanced breast cancer)
missing data was not likely to be MCAR. In the second application (adjuvant
breast cancer) the missing mechanism was dependent on the QOL scale under study.
MCAR and missing at random (MAR) have distinct consequences for data analysis.
Therefore it is relevant to distinguish between them. However, if either MCAR or
MAR hold, likelihood or Bayesian inferences can be based solely on the observed
data, although for MAR, depending on the research question, modelling the dropout
mechanism may still be necessary. Distinguishing between MAR and missing not at
random (MNAR) is not trivial and relies on fundamentally untestable assumptions.
PMID- 9549822
TI - A comparative analysis of quality of life data from a Southwest Oncology Group
randomized trial of advanced colorectal cancer.
AB - Longitudinal quality of life measurements from an advanced-stage cancer clinical
trial are analysed using a variety of methods, and the results compared. The
methods used require different assumptions about the mechanism that produces the
missing data. They include analyses that require the data to be missing
completely at random; fixed-effects models and weighted generalized estimating
equations, which require missing at random data; and a fully parametric approach
where the outcomes and the missingness mechanism are jointly modelled, allowing
non-ignorable missing data. The data show evidence of non-random missingness, but
a formal test of non-ignorable missing data is not significant.
PMID- 9549821
TI - Growth curve model analysis for quality of life data.
AB - There is increasing interest in measuring health related quality of life in
cancer clinical trials. Most quality of life data are measured repeatedly over a
fixed time schedule to capture changes and to reflect relative advantages of
study treatments. A multivariate repeated measures model is usually used to
analyse this type of data. However, one of the difficulties of this analysis is
that quality of life may be affected by the occurrence of some critical events
experienced by patients. We may separate a patient's lifetime during study into
different 'health states'. The duration of these health states may vary among
patients, and may relate to the efficacy of the study treatment. In some cases
quality of life data may be missing due to one of the many different types of
missing data mechanisms specific for a health state. It is reasonable to assume
that the missing data mechanism for a treatment arm is homogeneous within a
defined health state, and to control for the potential confounding effect to
appropriately assess the impact of treatment on the quality of life. In this
paper, we propose a growth curve model conditional on a time-dependent variable
of defined health states in order to assess the overall treatment effect while
taking into account occurrences of missing data and measurements from irregular
visits. A specific contrast can be drawn within the overall model for testing a
specific hypothesis without relying on the analysis of subgroups of patients
based on a smaller number of repeated measurements. Quality of life data from a
recently completed small-cell lung cancer randomized trial are used to illustrate
this method.
PMID- 9549823
TI - Comparison of several model-based methods for analysing incomplete quality of
life data in cancer clinical trials.
AB - This paper considers five methods of analysis of longitudinal assessment of
health related quality of life (QOL) in two clinical trials of cancer therapy.
The primary difference in the two trials is the proportion of participants who
experience disease progression or death during the period of QOL assessments. The
sensitivity of estimation of parameters and hypothesis tests to the potential
bias as a consequence of the assumptions of missing completely at random (MCAR),
missing at random (MAR) and non-ignorable mechanisms are examined. The methods
include complete case analysis (MCAR), mixed-effects models (MAR), a joint mixed
effects and survival model and a pattern-mixture model. Complete case analysis
overestimated QOL in both trials. In the adjuvant breast cancer trial, with 15
per cent disease progression, estimates were consistent across the remaining four
methods. In the advanced non-small-cell lung cancer trial, with 35 per cent
mortality, estimates were sensitive to the missing data assumptions and methods
of analysis.
PMID- 9549824
TI - Cold snare excision is a safe method for diminutive colorectal polyps.
AB - Cold snare excision (CSE) has proved to be an effective method for the
destruction of diminutive polyps of the colon and rectum. We investigated the
correlation between polyp size and bleeding time at the resected end after CSE,
and also an appropriate measuring method using CSE. Eighty patients with single
polyps were examined. Each polyp was identified as being 5 mm in diameter or
smaller using the open-biopsy forceps technique (OBFT). The size of the polyp was
calculated using our measuring system (SMS). Of the polyps identified as being 5
mm in diameter or less using OBFT, 15% were 6 mm or more using the SMS. CSE was
performed for each polyp, and the time taken for the hemostasis (bleeding time of
the CSE; BTCSE) was determined. In seventy-seven polyps that were 6 mm or smaller
in SMS, a correlation was noted between SMS and BTCSE. In three polyps that were
7 mm or more by SMS, hemostasis took 10 min or more after CSE, and required
electrocoagulation. These results suggest that CSE is a safe method for the
removal of polyps determined to be 6 mm in diameter or smaller using the SMS.
PMID- 9549825
TI - Polymorphism of short tandem repeat (STR) loci PLA2, D3S2459, D8S315 (kw38),
CYP19, D3S1359, FGA, and D8S1132 in the Japanese and Chinese populations.
AB - We report a study of polymorphism for seven short tandem repeat (STR) loci in
Japanese and Chinese populations. Among 104 to 134 individuals in the both
population samples, eight alleles were revealed for locus PLA2, thirteen for
D3S1359, eleven for FGA, eight for D8S315 (kw38), ten for D8S1132, five for
CYP19, and seven for D3S2459. They correspondingly constituted 10 to 39 genotypes
therein. For most of the STRs, there was only a single allele active as the most
frequent one among the others, except locus D3S1359 in Chinese samples (two
alleles, 206 bp and 210 bp, frequency = 0.273 each). Also, the population
genotype configurations were locus specific, varying in the patterns of commonest
genotypes on each locus, e.g., one pattern for loci CYP19, D3S1359, and D8S315,
one and two for loci PLA2 and D3S2459, two for locus D8S1132, and one and four
for locus FGA. The distributions of observed genotypes were in Hardy-Weinberg
Equilibrium. Furthermore, the seven STRs were exhibited highly polymorphic and
informative for the both populations, and the alleles could be easily separated
in electrophoresis and correctly interpreted with side-to-side allelic ladders.
Together, the results suggest that the tri- and tetra-meric STRs are useful
genetic markers for forensic practice.
PMID- 9549826
TI - Capnometry as a tool to unmask silent pulmonary embolism.
AB - Because pulmonary embolism is often silent, simple clinical procedures are
desirable to identify patients with a low to intermediate probability of
pulmonary embolism. Among 19,467 patients managed under general anesthesia, we
had one bile tract surgery case and three neurosurgical cases whose silent
pulmonary embolism was initially suggested by an increase in the arterial to end
tidal CO2 gradient (from 17 to 27 mmHg) after general anesthesia was induced or
their trachea was intubated. During the preoperative assessment, the patients
presented no clinical manifestations suggestive of pulmonary embolism. Our
initial diagnosis was confirmed by scintigraphy and/or angiography done
immediately after the operations. Because capnometry has been shown to be
applicable to non-intubated, spontaneously breathing patients, we suggest that
measuring the gradient may serve as an additional method for unmasking silent
pulmonary embolism in patients at risk or with disturbed consciousness, whether
they are scheduled for operations or not.
PMID- 9549827
TI - Dibutyryl cAMP inhibits endotoxin-induced increases in pulmonary vascular
resistance and fluid filtration coefficient in the perfused rat lung.
AB - We investigated the effects of pre-treatment with dibutyryl cAMP (db-cAMP) or
cGMP on endotoxin-induced hemodynamic changes and pulmonary vascular permeability
in isolated perfused rat lungs. Intraperitoneal injection of Salmonella
enteritidis endotoxin (2 mg/kg) caused increases in pulmonary arterial resistance
(Ra) after venous reservoir elevation, in pulmonary filtration coefficient (Kf)
and in lung wet-to-dry (W/D) weight ratio. Pre-treatment with db-cAMP blocked
endotoxin-induced increases in Ra, Kf and W/D weight ratio. Pre-treatment with
cGMP attenuated only the increase in Ra caused by endotoxin. Moreover,
administration of db-cAMP 2 hours after endotoxin injection attenuated the
increase in Ra induced by endotoxin treatment. The increases in Kf and W/D weight
ratio caused by endotoxin were not affected by post-treatment with db-cAMP. Since
the increases in Ra, Kf and W/D weight ratio caused by endotoxin were blocked by
pre-treatment with db-cAMP, agents that increase intracellular cAMP level may be
useful to prevent acute pulmonary vascular injury.
PMID- 9549828
TI - The effect of haloperidol on the histaminergic neuron system in the rat brain.
AB - In this study, the effect of haloperidol on histamine (HA) levels, histidine
decarboxylase (HDC) activities and the bindings of [3H]-(R)-alpha-methylhistamine
([3H]-(R)-alpha-MeHA) to histamine H3 receptors were investigated in the rat
brain. Administration of 10 mg/kg of haloperidol decreased HA levels in the rat
striatum and diencephalon, but increased HDC activities in rat striatum and
diencephalon, although that of 5 mg/kg did not change them. Meanwhile,
haloperidol inhibited the bindings of [3H]-(R)-alpha-MeHA to H3 receptor sites in
the rat striatal membrane with a Ki value of 10.5 +/- 0.45 microM. These findings
suggest that only a high dose of haloperidol increases HA synthesis and release
as a histamine H3 receptor antagonist in the rat brain.
PMID- 9549829
TI - A press-through-pack in the larynx.
AB - A case of a 96-year-old male with a foreign body in the larynx is reported. The
foreign body was a press-through-pack (PTP), a plastic packing for medicine, 16
mm x 16 mm x 3 mm in size. The PTP was safely removed from the larynx under
general anesthesia.
PMID- 9549830
TI - Detection of minimal residual disease in cerebro-spinal fluid of a patient with
acute myelogenous leukemia with t(16;21)(p11;q22) translocation by reverse
transcriptase-polymerase chain reaction.
AB - We describe a patient with acute myelogenous leukemia (AML) with
t(16;21)(p11;q22) translocation, whose minimal residual disease (MRD) both in
cerebrospinal fluid (CSF) and bone marrow (BM) was monitored by reverse
transcriptase-polymerase chain reaction (RT-PCR). A TLS/ERG-FUS fusion
transcript, which is known to be expressed by t(16;21)(p11;q22) translocation,
was detectable by RT-PCR both in BM and CSF cells in the first complete
remission, suggesting the existence of MRD. The disease relapsed 6 months after
its onset and allogeneic peripheral blood stem cell transplantation (PBSCT) was
undergone. A TLS/ERG-FUS fusion transcript became rapidly below the detection
level after PBSCT. These findings suggest the usefulness of RT-PCR for the
detection of MRD in CSF, which contains a limited number of cells, as well as BM.
PMID- 9549831
TI - Paraparesis associated with mild congenital kyphoscoliosis in an adult.
AB - A 48-year-old man suffering from paraparesis had congenital kyphoscoliosis due to
fused wedged vertebrae between T2 and T4. The kyphoscoliosis consisted of left
convex scoliosis measuring 26 degrees and kyphosis measuring 27 degrees. On CT
myelograms and axial MR images, the dura and spinal cord were deviated
anterolaterally to the concave side of the curve around its apex. The spinal cord
was stuck and flattened against the posterolateral margin of the vertebral body
to the base of the pedicle with the posterior subarachnoid space preserved.
Anterior decompression from the concave side through a transthoracic approach
resulted in a remarkable neurological improvement. The paraparesis may have been
caused by compression of the spinal cord through a tethering effect due to its
developmental tightness around the apical vertebra and the additional tension
created by motions of the neck.
PMID- 9549832
TI - Developmental fetal malformations: time to change terminology.
PMID- 9549833
TI - Nitrovasodilators--will they be useful in lowering uterine artery resistance in
pre-eclampsia and intrauterine growth restriction?
PMID- 9549835
TI - The impact of fetal, maternal and external factors on prediction of the day of
delivery by the use of ultrasound.
AB - In a non-selected population comprising 15,241 women, an evaluation was performed
of the impact of fetal, maternal and external factors on the ultrasonic
measurement of the biparietal diameter (BPD) and the day of delivery. The 7824
women who constituted the study population had singleton pregnancies and reliable
menstrual histories, and they delivered spontaneously after 37 weeks. Multiple
linear regression analysis was used. There was a difference in the size of the
BPD at the ultrasound scan related to the gender, parity, maternal age,
gestational age according to the last menstrual period and the experience of the
operators. There was a total difference of +/- 1 day in the day of delivery as
determined by ultrasound and the factors above. The effect on the day of delivery
is explained by the differences in the BPD. An effect of gender on gestational
length was present as well, which partly compensated for the difference in the
BPD. In conclusion the accuracy of prediction of the day of delivery by
ultrasound is influenced by the gender, parity, maternal age and the experience
of the operator, but these differences are small and of no clinical importance.
PMID- 9549834
TI - The effect of a nitric oxide donor on Doppler flow velocity waveforms in the
uterine artery during the first trimester of pregnancy.
AB - Our objectives were to study the effect of a nitric oxide donor on uterine blood
flow velocity waveforms and maternal heart rate and blood pressure during the
first trimester of pregnancy. Eleven women were examined at 8-12 weeks'
gestation, prior to elective termination of pregnancy. Each woman was randomly
given a sublingual tablet containing 5 mg of isosorbide dinitrate or placebo, on
two consecutive days. Measurements of maternal blood pressure, heart rate and
Doppler flow velocity waveforms of the ascending branch of the main uterine
artery were obtained before, and every 2 min (for 20 min) after taking the drug
or placebo. Following administration of isosorbide dinitrate, the mean arterial
blood pressure fell from a control value of 82.5 +/- 5.6 mmHg to a nadir of 73 +/
4.1 mmHg at 16 min (p < 0.0001). The mean maternal heart rate increased from a
control value of 80.9 +/- 2.8 beats/min to a peak of 90.4 +/- 4.6 beats/min at 10
min (p < 0.001). The mean resistance index in the uterine artery fell from a
control value of 0.80 +/- 0.02 to a nadir of 0.73 +/- 0.03 at 10 min (p <
0.0001). Analysis of covariance was employed to compensate for the effect of
heart rate on the resistance index. The drug had a significant effect on the
resistance index in the uterine artery, independent of maternal heart rate. These
results suggest that drugs such as isosorbide dinitrate may have a potential
benefit under such conditions where the production of nitric oxide (i.e.
endothelium-derived relaxing factor) is decreased.
PMID- 9549836
TI - Pregnancy outcome among non-participants in a trial on ultrasound screening.
AB - Our objective was to characterize and evaluate pregnancy outcome in women who
declined participation in a trial on ultrasound screening in the second
trimester. Between 1985 and 1987, 8768 women were recruited for a trial on
ultrasound screening. By randomization, 4997 women were assigned to either a
screening or a non-screening group. Of the 1414 excluded women, data were
retrieved from 1211 (86%). Participation was declined by 526 of these 1211 women,
either because of anxiety regarding harmful effects of ultrasound or because they
could see no benefits of ultrasound scanning. Non-participants and participants
were compared. The non-participants were older, had a higher birth/pregnancy
ratio, were less often smokers, and had fewer ultrasound examinations than the
participants. There was a longer mean pregnancy length, an increased number of
post-term deliveries, more suspicions of small-for-gestational-age fetuses and
later detections of multiple pregnancies among non-participants as compared with
the screening group. No differences in neonatal morbidity were found except for a
greater number of mild respiratory disorders in the non-participant group. The
non-participant women were more obstetrically experienced and showed indications
of a healthier lifestyle in comparison with participants. The differences found
in pregnancy outcome could be explained by the ultrasound screening procedure.
There were no major differences in neonatal morbidity between the groups.
PMID- 9549837
TI - Conditional centiles for the quantification of fetal growth.
AB - A total of 274 low-risk pregnancies underwent predetermined, scheduled, serial
ultrasound examinations and measurement of the biparietal diameter, fetal
abdominal area, femur length and estimated fetal weight. The longitudinal nature
of this dataset permits the construction of conditional centiles for these
measurements, whereby the dimensions of an individual fetus at a given
gestational age can be extrapolated to give a range of expected values (expressed
as centiles) at a later gestational age. Examples of conditional centiles based
upon 4-week measurement separations are presented. These conditional centiles
permit the appropriate quantification and subsequent evaluation of time-dependent
changes in fetal dimensions to be made.
PMID- 9549838
TI - Normal fetal thyroid volume.
AB - A prospective study of 289 normal fetal thyroids was undertaken between 20 and 36
weeks of gestation in 289 mothers without any history of thyroid disease or
maternal disease that could cause intrauterine growth restriction. The fetal
thyroid volume was calculated by the ellipsoid equation, with the assumption that
each lobe was an ellipse. A nomogram relating fetal thyroid volume to gestational
age was established. The mean fetal thyroid volume was found to be 0.23 +/- 0.18
cm3 (median 0.17 cm3; range 0.022-0.85 cm3). The ratio of fetal thyroid volume to
estimated fetal weight (V/W ratio) (at 0.163 +/- 0.079 cm3/kg) was constant
throughout gestation. The value was smaller than those of the child and the adult
reported in other studies, indicating that fetal thyroid enlargement is likely to
be underestimated if based on postnatal criteria. It was found that the mean
fetal thyroid volume was significantly correlated with estimated fetal weight and
gestational age, in which the former dominated the effect. The fetal thyroid
increased in size much faster after 32 weeks, suggesting that evaluation of
possible fetal goiter should take into account gestational age and the nomogram
developed in this study.
PMID- 9549839
TI - Psychological outcomes following missed abortions and provision of follow-up
care.
AB - This cross-sectional study of 204 women who had experienced a missed abortion,
diagnosed at 10-14 weeks of pregnancy, examined the availability and desirability
of routine follow-up care, and whether such care is associated with reduced
psychological morbidity in the aftermath of miscarriage. Clinically elevated
anxiety and depression were observed in 45% and 15% of women, respectively, and
the mean score of grief was 2.52 which is similar to that observed in people who
suffer death of a close relative. A follow-up appointment after the miscarriage
was thought to have been desirable by 92% of women but was offered to only 30%.
No significant association between such care and reduced psychological morbidity
was identified. However, there were significantly more women with clinically
elevated levels of anxiety among those who felt that they were not provided with
an opportunity to discuss their feelings during the follow-up, suggesting that
such a follow-up either had a deleterious effect on women's psychological state
or the distress itself led to such a perception of care. One-third of women in
our sample would have liked psychological counselling to help them deal with the
emotional aspects of their loss.
PMID- 9549840
TI - Unexpected effect of a nitric oxide donor on uterine artery Doppler velocimetry
in oligomenorrheic women with polycystic ovaries.
AB - We compared uterine artery vascular responses following administration of the
nitric oxide donor glyceryl trinitrate to ten women with oligomenorrhea and
ultrasound evidence of polycystic ovaries with those of nine women with a normal
menstrual cycle and ultrasonically normal ovaries. Mean arterial blood pressure,
pulse rate and uterine artery flow velocity waveforms were recorded before and 60
75 min after glyceryl trinitrate patch application. The pulsatility index and
resistance index were calculated to describe changes in impedance to flow in the
uterine artery. Peak systolic and time-averaged velocities were also measured.
Pretreatment median arterial pressure was higher in women with polycystic ovaries
(90 mmHg) compared to those with regular cycles (80 mmHg) (p < 0.05). No
differences were found in pulse rate and uterine artery blood flow indices
between the two groups. After glyceryl trinitrate patch administration, there was
no change in blood pressure or pulse rate in either group. In women with
polycystic ovaries, there was an increase in uterine artery resistance index
(0.93 to 1.00; p < 0.05) and pulsatility index (3.77 to 4.99; p < 0.05) and a
decrease in peak systolic (36.8 to 32.3 cm/s; p < 0.05) and time-averaged maximum
(8.5 to 5.0 cm/s; p < 0.05) velocities. Uterine artery Doppler parameters
remained unchanged in women with normal cycles. Uterine artery vascular responses
to the nitric oxide donor glyceryl trinitrate are different in women with normal
cycles compared to oligomenorrheic women with polycystic ovaries. This may be
relevant to an understanding of the pathophysiology underlying the higher risk of
cardiovascular morbidity and mortality associated with polycystic ovarian
syndrome.
PMID- 9549841
TI - 3D Color Power Angio imaging: a new method to assess intracervical
vascularization in benign and pathological conditions.
AB - It is well known that angiogenesis is a fundamental event in the growth of tumors
as well as in physiological conditions. In an ongoing prospective study involving
eight women, we investigated the microvasculature within the cervix by the use of
3D Color Power Angio imaging. The ultrasound equipment was used in conjunction
with specialized software providing high-resolution '3D-Angiomode'. The system
provides the ability to visualize blood flow in small vessels that are
undetectable by conventional color Doppler techniques and also to study the
architecture and determine the number of blood vessels. Comparison of the vessels
in the normal cervix with those in the cervix affected by carcinoma or bacterial
or viral infection demonstrated that, in malignant tissue, there is a chaotic
network of tortuous vessels traversing the tumor mass, whereas, in benign tissue
or tissue that is inflamed as a result of infection, the course of the vessels
has a regular structure.
PMID- 9549842
TI - The upper neck pouch sign: a prenatal sonographic marker for esophageal atresia.
AB - Prenatal suspicion of esophageal atresia is usually based on the finding of a
small or absent fetal stomach in association with polyhydramnios. As similar
findings may be generated by other abnormalities, confirmation of the diagnosis
is generally not possible until birth. We present a case in which the suspicion
of esophageal atresia was raised in the 22nd week of pregnancy in the presence of
a small stomach bubble associated with a persistent left superior vena cava. The
diagnosis was confirmed 4 weeks later by direct visualization of the fluid-filled
blind-ending esophagus during fetal swallowing, which we called the upper neck
pouch sign. This is the first case in which the onset of this sonographic entity
was specifically observed on serially repeated sonograms as early as the 22nd
week. The appearance of this direct sign of esophageal atresia is described, and
the literature is reviewed.
PMID- 9549843
TI - Prenatal diagnosis and perinatal management of a lingual lymphangioma.
AB - We describe the prenatal ultrasonographic features that led to the diagnosis of a
lingual lymphangioma. The risk of upper airway obstruction, which is associated
with this rare abnormality, prompted us to plan careful perinatal management. We
believe that, in cases of suspected lymphangioma of the tongue or other
oropharyngeal tumors, elective delivery should be carried out in a tertiary
referral center in which emergency ventilation and tracheostomy are possible.
PMID- 9549845
TI - Antenatal diagnosis and management of a ranula.
AB - We describe a case of congenital ranula or retention salivary cyst diagnosed at
26 weeks of gestation. The fetal karyotype was obtained by amniocentesis and
chorionic villus sampling, and was normal. Follow-up ultrasound scans revealed no
changes in the size or the position of the cyst. Surgical treatment was performed
2 days after a normal vaginal delivery, with excellent results.
PMID- 9549844
TI - Prenatal diagnosis of congenital granular cell epulis.
AB - Congenital granular epulis is a benign tumor that has rarely been diagnosed
prenatally, although there have been numerous reports on its postnatal diagnosis.
We report a case of large granular epulis diagnosed at 31 weeks' gestation in a
woman whose previous anomaly scan had been normal. The lesion was 2.5 cm in
diameter, pedunculated, and arose from the maxilla. It was completely surgically
removed following preterm vaginal birth and histologically examined. The tumor
did not prevent deglutition of the amniotic fluid and did not interfere with
feeding or respiration, but prevented complete closure of the lips. We discuss
the fetal management and the theories of histogenesis, and highlight the
importance of early diagnosis and treatment.
PMID- 9549846
TI - Prenatal ultrasound observations in subsequent pregnancies with Perlman syndrome.
AB - Perlman syndrome is a rare disease with a poor prognosis. Until now, the specific
antenatal diagnostic criteria of this syndrome have not been documented. We
report on two pregnancies with Perlman syndrome, in the same woman, in which
karyotyping and ultrasound examination were performed. In the first pregnancy,
the final diagnosis was made only postnatally, whereas, in the second affected
pregnancy, nuchal translucency was seen at 11 weeks. From 23 weeks onwards the
classical signs of renal and abdominal enlargement were observed. The impact of
non-specific early ultrasound markers on decision-making in pregnancies with
family risks, where specific tests are not yet available, must be evaluated.
PMID- 9549847
TI - Hydronephrotic pelvic kidney mimicking an ovarian cyst.
PMID- 9549848
TI - Sonographic differential diagnosis of persistent ovarian cysts.
PMID- 9549849
TI - Fetal hydrometrocolpos: not only diagnostic but also therapeutic dilemmas.
PMID- 9549850
TI - Serological evidence of morbillivirus infection in small cetaceans from the
Southeast Pacific.
AB - The presence of morbillivirus-specific serum antibodies was examined by an
indirect enzyme linked immunosorbent assay (iELISA) and virus neutralization
tests in serum samples from 30 dusky dolphins (Lagenorhynchus obscurus), 8 long
snouted common dolphins (Delphinus capensis), 2 inshore and 6 offshore bottlenose
dolphins (Tursiops truncatus) and 20 Burmeister's porpoises (Phocoena
spinipinnis) taken in fisheries off central Peru in 1993-1995. The sera from six
dusky dolphins, one common dolphin and three offshore bottlenose dolphins were
positive on a coat of dolphin morbillivirus (DMV) antigen in the iELISA. Several
of these sera were also positive when tested against peste des petits ruminants
and rinderpest virus antigen. Porpoise morbillivirus and/or DMV neutralizing
antibodies were detected in the sera of two bottlenose and three dusky dolphins
that reacted positively with DMV antigen in iELISA and also in the sera of one
common, one dusky and one bottlenose dolphin that were negative in the iELISA.
These results strongly suggest that viruses closely related, or identical, to the
cetacean morbillivirus present in the North Atlantic and the Mediterranean Sea
infect several species of Delphinidae of the Southeastern Pacific. No convincing
morbillivirus-specific antibody positive reactions were detected in the sera from
either the Burmeister's porpoises or the inshore bottlenose dolphins.
PMID- 9549851
TI - A nested PCR for detection of North American isolates of bluetongue virus based
on NS1 genome sequence analysis of BTV-17.
AB - A nested polymerase chain reaction (PCR)-based assay, for detection of bluetongue
virus (BTV) ribonucleic acid in cell culture and tissue samples, was developed.
Two pairs of oligonucleotide primers (BTV1 and BTV4 and BTV2 and BTV3), selected
from non-structural protein 1 (NS1) gene of BTV-17, were used for the nested PCR
in two amplification steps. First a 826-bp product was amplified using an outer
primer pair BTV1 and BTV4. The second amplification, using nested or internal
primer pair BTV2 and BTV3, produced a 517-bp PCR product. RNA from North American
prototype serotypes 2, 10, 11, 13 and 17, propagated in cell cultures, were
detected by this nested PCR-based assay. The nested primers BTV2 and BTV3
increased the sensitivity of the BTV PCR assay, and as little as 0.1 fg of BTV
RNA (equivalent to 5 viral particles) could be detected. Amplification products
were not detected when the PCR-based assay was applied to RNA from a closely
related orbivirus, epizootic hemorrhagic disease virus (EHDV) prototype serotypes
1 and 2; total nucleic acid extracts from uninfected BHK-21 cells; or whole blood
from calves and deer that were BTV-seronegative and virus isolation negative.
Application of this nested BTV PCR-based assay to clinical samples resulted in
detection of BTV RNA from a variety of tissues collected from calves and deer
with natural and experimental BTV infections. The described BTV PCR-based assay
provides a valuable tool to study the epidemiology of BTV infection in
susceptible wild ruminants and domestic livestock.
PMID- 9549853
TI - Iron-regulated outer membrane proteins of Pasteurella multocida and their role in
immunity.
PMID- 9549852
TI - Humoral and bronchial immune responses in cattle experimentally infected with
Mycoplasma mycoides subsp. mycoides small colony type.
AB - The course of immune reactions of the manifold antigens of Mycoplasma mycoides
subsp. mycoides small colony type (SC) was analysed in serum and bronchial lavage
of cattle experimentally infected with the African strain Afade and the European
strain L2 using Western-blots and complement fixation. Western-blot analysis of
total antigens of both strains with sera from animals infected with the
homologous and heterologous strain revealed the common dominant immunogenic
antigens with the molecular masses of 110, 95, 85, 80, 72, 62, 48 and 39 kDa. The
sequential sampling of the blood and bronchial lavages before and after contact
infections allowed us to identify the antigens of 85, 80, 72, 48 and 39 kDa as
particularly early immunogens. The IgA Western blots of the bronchial lavages
showed distinct, early and persistent reactions to the 110, 85, 80, 72, 48 and 45
kDa proteins. These proteins were the predominant lipoproteins as determined by
[14C]palmitic acid labelling. Only relatively weak reactions of the bronchial
lavages were detected with IgG. In general immune responses were significantly
stronger in the animals infected with the African strain Afade, which gave
positive results two weeks after contact infection. In contrast, the animals
infected with the European strain L2 induced much lower reactions with a delay of
three months after contact infection. In one animal strain L2 caused no sero
conversion and no infection. The results indicate a difference in virulence
between the African strain Afade and the European strain L2.
PMID- 9549854
TI - Exoprotein and slime production by coagulase-negative staphylococci isolated from
goats' milk.
AB - Milk from mastitis-free goats from French herds was examined for the presence of
coagulase-negative staphylococci (CNS), and 165 positive isolates were evaluated
for their capacity to produce exoproteins. Most isolates were identified as
Staphylococcus caprae (N = 91) or S. xylosus (N = 36), but members of at least
nine other species were present. Overall, some 57% of isolates produced toxins
with phenotypic properties of alpha-hemolysin, and 75% produced toxins resembling
S. aureus beta and/or delta-hemolysins. Thermostable desoxyribonuclease (TNAse)
was secreted by 29% of isolates and thermolabile DNAse by 66%. Slime was produced
by 42% of our cultures and, although none of them showed activity to insoluble
elastase, over 70% lysed the soluble substrate. No clinical consequences were
observed to correlate with exoprotein production, which proved to be inconstant
within individual CNS species.
PMID- 9549855
TI - Isolation of Actinobacillus equuli from the oral cavity of healthy horses and
comparison of isolates by restriction enzyme digestion and pulsed-field gel
electrophoresis.
AB - Swab samples were collected from the oral cavity of 174 horses in 10 farms and
cultured selectively for Actinobacillus equuli. A. equuli could be isolated from
37% of all samples, varying between 12 and 88% in the different farms. Eight
horses were sampled repeatedly for several days, with a variation in isolation
frequency between 50 and 88%. Isolates were compared by restriction enzyme
digestion and Pulsed-Field Gel Electrophoresis. A high degree of strain
variability was found within each horse population as well as some variability
over time between strains isolated from the same horse.
PMID- 9549857
TI - Restriction endonuclease analysis and plasmid profiling of Actinobacillus
pleuropneumoniae serotype 7 strains.
AB - Seventeen serotype 7 Actinobacillus pleuropneumoniae strains isolated in New
Zealand and A. pleuropneumoniae serotypes 1-12 reference strains were typed by
restriction endonuclease analysis of chromosomal DNA and plasmid profiling. All
serotype 7 strains produced similar DNA cleavage patterns and were significantly
different to other reference serotype strains. Minor differences in the cleavage
patterns enabled the 17 serotype 7 strains to be grouped into seven profiles.
Plasmids were identified in all but three strains but the banding patterns did
not account for the differences in the chromosomal profiles. The study showed
that restriction endonuclease analysis and plasmid profiling are useful in
epidemiological studies of porcine pleuropneumonia.
PMID- 9549856
TI - Characterisation of epitopes of type 1 fimbriae of Salmonella using monoclonal
antibodies specific for SEF21 fimbriae of Salmonella enteritidis.
AB - Monoclonal antibodies (mAbs) were used to identify and characterise epitopes of
type 1 (SEF21) fimbriae of Salmonella enteritidis. The distribution of the
epitopes among salmonellas and other enterobacteria was investigated, as well as
the influence of growth media and temperatures on their expression. At least four
different epitope clusters were identified on SEF21 fimbriae of S. enteritidis.
Two of these clusters were associated with fimbrial haemagglutinins that were
either common to all salmonellae tested, or restricted only to S. enteritidis and
S. dublin. The four epitope clusters were identified on type 1 fimbriae of most
Salmonella serotypes, as well as non-haemagglutinating type 2 fimbriae of S.
pullorum and S. gallinarum, and on many other enterobacterial species. The
expression of the epitopes was affected by growth conditions.
PMID- 9549858
TI - Distribution and characterization of faecal necrotoxigenic Escherichia coli CNF1+
and CNF2+ isolated from healthy cows and calves.
AB - Faecal swabs obtained from a random sample of 268 cows and 90 calves on 19 Lugo
(northwestern Spain) farms were examined for necrotoxigenic Escherichia coli
(NTEC) producing the cytotoxic necrotizing factors type 1 (CNF1) and type 2
(CNF2). We found NTEC CNF1+ and CNF2+ on 11% and 95% of the farms, respectively,
NTEC producing CNF2 were significantly more frequently isolated from calves (58%)
than from cows (17%) (P < 0.001). The proportion of animals colonized with CNF2+
strains on each farm ranged from 0% to 60%. NTEC strains producing CNF2 isolated
from healthy cattle belonged to 27 O serogroups; however, 64% were of one of 12
serogroups (O2, O8, O8-O75, O14, O15, O55, O86, O88, O115, O121, O147, and O168).
Furthermore, the serogroups determined in CNF2+ strains isolated from cows (O2,
O8, and O14) were different from those found in NTEC producing CNF2 isolated from
calves (O8-O75, O15, O55, O86, O88, O115 and O147).
PMID- 9549859
TI - The effects of inoculation of Listeria monocytogenes into the ovine mammary
gland.
AB - In each of two experiments, the effects of inoculation of Listeria monocytogenes
into the ovine mammary gland were studied. In the first experiment, ewes were
challenged with one or other of five different Listeria spp. isolates to study
differences in their pathogenicity. In the second, ewes were challenged with L.
monocytogenes serotype 1/2a to study the sequential features of the infection.
The reaction of the mammary glands was assessed by bacteriological, cytological
and histological methods. No distinct variation in the pathogenicity of L.
monocytogenes isolates was evident: all produced subclinical mastitis,
independently of their origin or serotype; a L. innocua isolate caused only a
transient increase of milk somatic cell counts. After challenge, L. monocytogenes
was isolated for 88 days from the milk of inoculated glands, whose milk somatic
cell counts were greater than 1.0 x 10(6) cells ml-1. The organism was also
isolated from the mammary lymph nodes, but not from any internal organ of any
inoculated ewe. In early stages of the infection neutrophilic infiltration was
the predominant histological feature, but hyperaemia, and degeneration of
alveolar epithelial cells were also recorded. Later, chronic inflammatory
features predominated, with lymphocytes as the principal cell types, destruction
of alveoli and fibrous tissue proliferation. In the final stage of the
experiment, fibrosis was the salient finding. It is concluded that L.
monocytogenes can cause subclinical mastitis after intramammary inoculation into
ewes.
PMID- 9549860
TI - Multiple receptors on porcine intestinal epithelial cells for the three variants
of Escherichia coli K88 fimbrial adhesin.
AB - We evaluated intestinal epithelial membrane preparations from five phenotypes of
pigs, distinguished by the variant of K88 fimbrial adhesin (K88ab, K88ac, K88ad)
which bind to their intestinal epithelial cells (A-all three variants, B-K88ab
and K88ac, C-K88ab and K88ad, D-K88ad, and E-none of the variants), for the
presence of K88 adhesin receptors. Intestinal brush border membranes were
prepared from 20 animals (four from each phenotype). Brush border proteins, that
had been separated using SDS-PAGE and transferred to nitrocellulose membranes,
were overlaid with biotinylated K88 adhesin, 35S-labelled K88+ Escherichia coli,
or biotinylated K88+ E. coli. Biotinylated K88ab and K88ac fimbrial adhesins and
labelled E. coli expressing K88ab or K88ac adhesin bound to 210- and 240-kDa
receptors in phenotype A and B, but not phenotype C, D, or E animals. In
contrast, no phenotype-specific receptors were identified for the K88ad adhesin.
Previously, purified K88ab and K88ac fimbriae were shown to block K88ad binding,
but purified K88ad fimbriae were unable to block K88ab or K88ac binding in
phenotype A animals. These results point to the existence of three K88 adhesin
receptors to account for the observed phenotypes: (1) Receptor bcd binds all
three variants and is found in phenotype A pigs, (2) Receptor bc (210- and 240
kDa receptors) binds K88ab and K88ac and is found in phenotype A and B pigs, and
(3) Receptor d binds K88ad and is found in phenotype C and D pigs.
PMID- 9549862
TI - Phenotypic and genotypic variation of feline calicivirus during persistent
infection of cats.
AB - Amino acid sequence of the capsid protein hypervariable region of nine feline
calicivirus (FCV) isolates recovered from cats persistently infected after
inoculation with the FCV strain 255 parent virus is reported. Capsid proteins
from all the isolates were highly cross reactive by Western blot analysis using
polyclonal antisera to FCV. Reverse-transcription PCR was used to obtain sequence
information of the FCV capsid protein highly variable E region. Amino acid
substitutions occurred between residues 426 and 458 of the FCV capsid protein E
region. The sequence data and phylogenetic reconstructions based on the sequence
information correlated well with antigenic differences among isolates determined
by two-way cross neutralization. These results agree with previous reports using
divergent isolates of FCV that correlated amino acid differences with serology.
This further supports the hypothesis that the FCV capsid protein E region from
residues 426 to 458 contains the serotypic determinants of FCV important to
antigenic variation.
PMID- 9549861
TI - Characterization of an immuno-dominant antigen in Brucella ovis and evaluation of
its use in an enzyme-linked immunosorbent assay.
AB - A panel of 45 Brucella ovis serologically positive sera were tested in
immunoblots against B. ovis outer membrane proteins Omp31 and Omp25, purified by
preparative SDS-gel electrophoresis. Forty-three sera reacted with Omp31, while
only 11 reacted with Omp25, suggesting that Omp31 is identical to the previously
reported immuno-dominant 29-kDa protein. Attempts to purify Omp31 on a larger
scale by using procedures such as ion exchange-, reversed phase-, affinity- and
gel filtration chromatography suggested that the outer membrane proteins were
aggregated with rough lipopolysaccharide. Only denaturing SDS-gel filtration
chromatography was able to separate proteins of about 29 kDa from rough
lipopolysaccharide but did not separate Omp31 from Omp25 in B. ovis preparations.
When used in an enzyme-linked immunosorbent assay, this 29-kDa protein
preparation was less sensitive and less specific than the routinely used heat
extracted B. ovis antigen. A readily available recombinant E. coli, expressing
the gene for Omp31 from Brucella melitensis 16 M, was used to extract and enrich
recombinant Omp31 by a temperature-dependent Triton X-114-based technique. When
this material was used in immunoblots with the 45 sera from B. ovis-infected
sheep and with 10 monoclonal antibodies, raised against B. ovis Omp31, major
differences in the antibody reactivity between the recombinant B. melitensis
Omp31 and the B. ovis Omp31 were found. Such differences were unexpected because
of the known structural and immunological relatedness of outer membrane proteins
from various Brucella species. These results indicated that the antibody-response
in B. ovis naturally-infected sheep against the immuno-dominant Omp31 was
directed against epitopes which were only accessible when the protein was
aggregated with rough lipopolysaccharides, or which were formed after aggregation
but were not present in the recombinant protein.
PMID- 9549863
TI - Molecular analysis of the nucleocapsid protein of recent isolates of canine
distemper virus in Japan.
AB - We analyzed the molecular properties of the nucleocapsid protein (NP) of canine
distemper viruses (CDV), isolated between 1992 and 1995 in Japan. Four CDV field
isolates (Yanaka, Ueno, Hamamatsu, and Adachi strains) obtained were
antigenically identical. Sequence analysis of entire region of the NP gene of a
field isolate, the Yanaka strain, revealed that the NP gene contained 1683
nucleotides and was 93.2% homologous with a laboratory strain, the Onderstepoort
strain. The deduced amino acid sequence contained 523 amino acids and was 95.2
and 99% homologous with those of the Onderstepoort and a virulent strain, A75/17
strain, respectively. Since most of the diversities in amino acid sequence
occurred in two domains, at the N'- and the C'- termini, we further sequenced 3'
terminal regions of the remaining three field isolates. Based on the sequences,
the new CDV isolates had one cluster that distinguished them from the laboratory
strain.
PMID- 9549865
TI - Exploratory study on the economic value of a closed farming system on Dutch dairy
farms.
AB - A closed farming system may prevent the introduction of infectious diseases on to
dairy farms and could be a good starting point for the eradication of these
diseases. In order to introduce a closed farming system, farmers need to be made
aware of how these diseases are introduced into the herd. Farmers will be more
likely to implement a closed farming system when the economic value is quantified
and attractive. An exploratory study was carried out to investigate the technical
and economic results of closed dairy farms. Farms that purchased cattle and/or
shared pasture (defined as 'open' farms) differed in technical results from farms
that did not ('closed' farms). The results of the discriminant analysis showed
that the 'closed' farms incurred lower costs for veterinary services, had a lower
average age at first calving and a higher birth rate per 100 dairy cows. A linear
regression analysis was carried out to investigate the influence of the farming
system on economic performance. Being 'closed' was found to increase the net
profit by 0.31 Pound per 100 kg of milk, or approximately 25 Pounds per cow per
year or 5 per cent of the typical net return to labour and management (1 Pound =
Dfl 2.80 in November 1996).
PMID- 9549864
TI - Investigations into field cases of porcine colitis with particular reference to
infection with Serpulina pilosicoli.
AB - Investigations into the possible causes of colitis and typhlocolitis were carried
out on 85 pig units in the United Kingdom between 1992 and 1996. Serpulina
pilosicoli was identified most commonly, occurring as the suggested primary agent
on 21 (25 per cent) of the units but forming part of mixed infections on another
23 (27 per cent) of the units, the main co-infections being Yersinia
pseudotuberculosis (eight units), proliferative enteropathy (six units),
Salmonella species (four units) or Serpulina hyodysenteriae (two units).
'Atypical' Serpulina species, S hyodysenteriae, Salmonella typhimurium, Y
pseudotuberculosis and Lawsonia intracellularis (proliferative enteropathy) were
the suggested primary agents on seven, six, four, four and three units,
respectively. Various combinations of mixed infections involving the latter
organisms and other possibly incidental agents were recorded on another 10 units.
Investigations on a further six units failed to detect any recognised pathogens.
On units where S pilosicoli was the suggested primary agent, pigs ranging between
20 to 40 kg (eight to 16 weeks of age), but occasionally up to 50 kg, had
diarrhoea and grew poorly over a period of two to three weeks. The prevalence was
estimated to be between 5 and 15 per cent in affected batches, with a mortality
of approximately 1 per cent. The clinical signs usually developed seven to 14
days after the moving and mixing of pigs. At postmortem examination, affected
pigs had liquid contents in their colon, which contained accumulations of mucus
in some chronic cases. Gross and histological lesions of colitis were prominent
in the mid-spiral region of the colon. In mixed infections with Y
pseudotuberculosis, Salmonella typhimurium or S hyodysenteriae, lesions were more
extensive and affected the caecum as well as the colon. In the colon, lesions of
proliferative enteropathy were usually confined to the proximal half of the
ascending spiral but mixed infection with S pilosicoli caused more extensive
colitis. Mixed infections were reported to prolong the time taken for pigs to
recover naturally and to have a more detrimental effect on growth rates than S
pilosicoli infection alone. Despite the successful treatment of batches of pigs
with tiamulin or lincomycin, S pilosicoli infection persisted as a chronic
problem on many units, with diarrhoea and colitis in successive batches of pigs
unless prophylactic medication was used.
PMID- 9549866
TI - Effect of hoof characteristics on the propensity of cattle to slip.
AB - Bovine hooves were assessed for their linear and volumetric characteristics and
ranked in sets of four for hoof volume. An artificial cow was constructed with
the hooves set into metal cylinders underneath a platform containing a known
weight. The device was connected via a strain gauge to a pulling handle operated
by two people, and the horizontal force required to move each set of hooves was
determined three times. The coefficient of friction, calculated as the horizontal
force divided by the fixed vertical force, was positively correlated with hoof
volume. The same exercise was repeated with the hooves ranked for toe angle, and
the hooves with steep toe angles had a lower coefficient of friction than the
hooves with shallow toe angles. However, since both hoof volume and toe angle
were related to toe length, the relationship between friction and toe angle was
believed to derive from the larger size of claws with shallow toe angles. The
results indicate that young cattle that have small claws with smooth surfaces and
steep toe angles are more likely to slip.
PMID- 9549867
TI - A neuronal vacuolar disorder in young rottweiler dogs.
AB - Four rottweiler pups from two litters developed severe progressive signs of
spinal ataxia, cerebellar ataxia and tetraparesis/paralysis. The signs started
with ataxia of the pelvic limbs at seven to eight weeks of age and progressed to
tetraparesis and paralysis within three to five weeks. Postmortem, a vacuolar
neuronal disorder was found in the cerebellum, brainstem and the spinal cord,
associated with Wallerian type degeneration in the brainstem, cerebellar
peduncles and the medullary cord. Electron microscopy revealed empty membrane
bound vacuoles. Immunohistochemistry for PrPSc was negative. The disorder differs
clinically and pathologically from other neurological disorders in the breed and
a new (familial) neurological disorder in the rottweiler is suspected.
PMID- 9549868
TI - Metastatic melanoma causing spinal cord compression in a horse.
PMID- 9549869
TI - Anthropogenic mortality of the common toad (Bufo bufo) in Scotland.
PMID- 9549870
TI - Segmental aplasia of the epididymis in a Siberian husky.
PMID- 9549871
TI - Primary bronchiolo-alveolar adenocarcinoma in a dromedary camel (Camelus
dromedarius).
PMID- 9549872
TI - Ciprofloxacin-resistant Salmonella typhimurium DT104.
PMID- 9549873
TI - Ivermectin-resistant Cooperia species from calves on a farm in Somerset.
PMID- 9549874
TI - 'Stray voltage' and sudden collapse in horses and cattle.
PMID- 9549875
TI - 'Stray voltage' and sudden collapse in horses and cattle.
PMID- 9549876
TI - Role of paraprofessionals in practice.
PMID- 9549877
TI - Child sexual abuse evaluations: the scientist-practitioner model.
AB - The scientist-practitioner model is presented as a format for conducting child
sexual abuse evaluations. This model bases conclusions on empirically established
relationships between data and the behavior of interest, rather than on
subjective opinions. Using empirically derived evidence, the scientist
practitioner defines child sexual abuse as a life event rather than a clinical
syndrome, relies on base rates of behavior for distinguishing and understanding
differences between nonsexually abused and sexually abused children, and
considers issues of instrument sensitivity and specificity when utilizing
assessment tools in child sexual abuse evaluations. This model enlists safeguards
to keep the evaluator from inappropriately forming cause and effect associations
between a child's single response (e.g., behavioral and emotional symptoms,
interactions with anatomically detailed dolls, drawing genitalia) and the
occurrence of an event (e.g., sexual abuse).
PMID- 9549878
TI - The assessment of child sexual abuse allegations: using research to guide
clinical decision making.
AB - As reports of child sexual abuse (CSA) have risen, greater attention has been
focused on how clinicians evaluate allegations of abuse. A common theme in the
CSA assessment literature is to encourage comprehensive, multimodal assessments.
This recommendation, however, is rarely accompanied by suggestions regarding how
clinicians might integrate and differentially weight the information gathered.
The present article is designed to address the issue of which sources of
information clinicians should rely upon when conducting CSA assessments.
Specifically, the commonly used indicators and procedures for assessing
allegations of abuse are identified and then examined in light of their
respective empirical literatures. It is concluded that medical examinations and
the child's report are among the best sources of information, and should
therefore be most heavily relied upon to arrive at accurate decisions. Clinicians
are encouraged to adopt the mind set of a scientist conducting an a priori,
hypothesis-driven research investigation. This approach should help clinicians
avoid the temptation of post hoc analyses that reflect personal biases more than
the actual data.
PMID- 9549879
TI - An analysis of competency to stand trial: an integration of case law and clinical
knowledge.
AB - In the past three decades competency to stand trial has emerged as a central
issue in mental health law and forensic psychology. This article combines legal
and clinical frameworks for a more integrated understanding of competency to
stand trial. The legal framework focuses on Supreme Court decisions beginning
with Dusky and reviews several legal theories of competence. The empirical
framework is investigated within Grisso's (1986) conceptualization of legal
competencies. In addition, the efficacy of specialized forensic assessments is
evaluated, including the newly developed MacArthur Structured Assessment of the
Competencies of Criminal Defendants (MacSAC-CD). The article concludes with
observations of competency as a construct and their implications for forensic
practice.
PMID- 9549880
TI - Integrating base rate data in violence risk assessments at capital sentencing.
AB - Prediction of violence in capital sentencing has been controversial. In the
absence of a scientific basis for risk assessment, mental health professionals
offering opinions in the capital sentencing context are prone to errors.
Actuarial or group statistical data, known as base rates, have proven far
superior to other methods for reducing predictive errors in many contexts,
including risk assessment. Actuarial follow-up data on violent recidivism of
capital murderers in prison and post release have been compiled and analyzed to
demonstrate available base rates for use by mental health experts conducting risk
assessments pertaining to capital sentencing. This paper also reviews various
methods for individualizing the application of base rates to specific cases.
PMID- 9549881
TI - Hypnotic interviewing: the best way to interview eyewitnesses?
AB - It has been suggested that hypnosis techniques may have the potential to enhance
eyewitness memory in forensic investigations. However, laboratory research shows
that increases in recall with hypnosis techniques are often associated with
decreases in accuracy, false confidence in incorrect information, and increased
suggestibility to leading questions and misleading post-event information. These
problems limit the usefulness of hypnosis as an interviewing procedure. However,
in practical investigations, many factors associated with hypnosis, apart from
the hypnotic induction itself, might lead to memory enhancement compared with
standard police interviews. For example, hypnotic interviewers, because of their
psychological, clinical, and interpersonal skills, may be better interviewers
than police officers. They may use effective interviewing strategies such as
those associated with the "cognitive interview"; a procedure which has the
potential to enhance recall by approximately 35% without the problems of memory
distortion associated with hypnosis. It is concluded, therefore, that a cognitive
interview procedure should be used in preference to hypnosis.
PMID- 9549882
TI - Naphthoquinone esters from the root of Rhinacanthus nasutus.
AB - Reinvestigation of the root of Rhinacanthus nasutus afforded, in addition to
rhinacanthin-A to -D reported previously, two new
dimethyldihydropyranonaphthoquinone esters (5, 6) and eight new 2-hydroxy-1,4
naphthoquinone esters (7-14) were isolated. The stereochemistry of rhinacanthin-A
was determined as the R configuration. Compounds rhinacanthin-G to -N, belong to
a class of 2-hydroxy-3-(3-hydroxy-2,2-dimethylpropyl)-1,4-naphthoquinone esters,
and so far have been isolated only in this plant. Their biosynthesis is also
discussed.
PMID- 9549883
TI - Synthesis of optically active alpha-(p-chlorophenyl)pyridylmethanols with plant
cell cultures.
PMID- 9549884
TI - Immunosuppressive components from an Ascomycete, Diplogelasinospora grovesii.
AB - Two known fungal metabolites, macrophin and colletodiol, and a new stereoisomer
of colletodiol named 10-epi-colletodiol, were isolated as immunosuppressive
principles from an Ascomycete, Diplogelasinospora grovesii. The IC50 values of
the major active component among them, macrophin, were calculated to be 0.4 and
0.3 microgram/ml against concanavalin A- and lipopolysaccharide-induced
proliferations of mouse spleen lymphocytes, respectively. A new natural product,
4,8-dimethyl-1,5-dioxacyclooctane-2,6-dione, and a known fungal metabolite,
isosclerone, which showed no immunosuppressive activity, were also isolated from
this fungus.
PMID- 9549885
TI - Synthesis of phenoxyacetic acid derivatives as highly potent antagonists of
gastrin/cholecystokinin-B receptors.
AB - A novel series of phenoxyacetic acid derivatives was synthesized based on
considerations of the three-dimensional structural similarity of YM022 and
RP72540. The gastrin/cholecystokinin (CCK)-B and CCK-A receptor antagonist
activities of these compounds were evaluated by investigation of their affinities
for human gastrin/CCK-B receptors and human CCK-A receptors, respectively. It was
found that N-methyl-N-phenyl-2-[2-[N-(N-methyl-N-phenyl-carbamoylmethyl)-N-[2 -[3
(3- methylphenyl)ureido]acetyl]amino]phenoxy]acetamide (20k, DZ-3514) exhibited
high affinity for gastrin/CCK-B receptors and high selectivity over CCK-A
receptors.
PMID- 9549886
TI - A new 5-HT3 receptor ligand. II. Structure-activity analysis of 5-HT3 receptor
agonist action in the gut.
AB - Several modified 2-piperazinyl benzoxazole derivatives, which exhibit an
agonistic effect on gastrointestinal motility, were synthesized and their effects
on the contraction of guinea-pig ileum were examined. The quaternary piperazinyl
benzoxazole structure has a restricted conformation and stereostructure compared
to those of the other 5-HT3 receptor agonists, serotonin and meta
chlorophenylbiguanide. The mutual positions of the aromatic ring, nitrogen atom
and terminal amine are considered to form the pharmacophore of the 5-HT3 receptor
agonist in the gut. In the serotonin-evoked reflex bradycardia [Bezold-Jarisch (B
J) reflex] inhibition test using rats the B-J reflex-inducing ratio was different
for each synthesized compound. These results suggest that, in these 5-HT3
receptor agonists, the substituents of the benzoxazole ring influence the B-J
reflex-inducing activity in rats.
PMID- 9549887
TI - Design of plasma kallikrein inhibitors: functional and structural requirements of
plasma kallikrein inhibitors.
AB - The synthetic plasma kallikrein (PK) inhibitor trans-4
aminomethylcyclohexanecarbonylphenylalanine-4-carboxyme thylanilide (PKSI-527)
consists of three parts. Each part was replaced by analogues in an attempt to
improve the potency and the selectivity of PKSI-527. Among the peptides examined,
trans-4-aminomethylcyclohexanecarbonylphenylalanine-4-carboxyan ilide (peptide
16) inhibited PK with a high selectivity and an IC50 value of 2.7 microM, being
as potent as PKSI-527.
PMID- 9549888
TI - Design and racemic synthesis of conformationally restricted carbocyclic
pyrimidine nucleoside analogs based on the structure of the L-nucleoside residue
in heterochiral DNA.
AB - Carbocyclic pyrimidine nucleoside analogs which have restricted glycosidic
conformation at chi approximately 180 degrees were designed, based on the
conformational features of the L-nucleotide residue in heterochiral DNA, and
synthesized. The synthesis of (+/-)-carbocyclic 6,6'-O-cyclo-2'-deoxyuridine was
achieved via bromination and subsequent intramolecular cyclization of carbocyclic
6'beta-hydroxy-2'-deoxyuridine. (+/-)-Carbocyclic 6,6'-O-cyclo-2'-deoxycytidine
was synthesized from protected carbocyclic 6,6'-O-cyclo-2'-deoxyuridine via the 4
triazole intermediate.
PMID- 9549889
TI - Dissolution difference between acidic and neutral media of acetaminophen tablets
containing a super disintegrant and a soluble excipient. II.
AB - The disintegration and dissolution of acetaminophen tablets containing sucrose
and Ac-Di-Sol/Primojel was significantly different between acidic and neutral
media. The purpose of this study was to investigate the mechanism of this
phenomenon and to propose a way of reducing the dissolution difference between
the two media. Tablets of different combinations of active ingredient, sucrose,
and Ac-Di-Sol/Primojel were prepared and their dissolution in various media was
evaluated. The dissolution differences were found to be largely related to the
hydrophobicity of the active ingredient and pH difference of the two media. This
difference was even more evident under the condition where acetaminophen,
sucrose, and Primojel were combined. The dissolution difference was therefore
attributed to the depressed function of Primojel in the acidic medium, the
stronger binding of sucrose, the hydrophobicity of the active ingredient and pH
difference of the two media. Increasing the concentration of Primojel or
incorporating the surfactant in the tablet can thus greatly decrease the
dissolution difference between acidic and neutral media.
PMID- 9549890
TI - Influence of water-soluble polymers on the dissolution of nifedipine solid
dispersions with combined carriers.
AB - The objective of this investigation was to clarify the influence of water-soluble
polymers on the dissolution behavior of nifedipine from solid dispersions with
combined carriers. All the solid dispersions of nifedipine were prepared by the
fusion method using nicotinamide and 4 different water-soluble polymers,
hydroxypropylmethyl-cellulose (HPMC), polyvinylpyrrolidone (PVP), partially
hydrolyzed polyvinyl alcohol (PVA) and pullulan. HPMC, PVP or PVA dissolved in
the fused liquid of nicotinamide and operated efficiently on the amorphous
formation of nifedipine in solid dispersions. In dissolution studies, the drug
concentration for these dispersions increased to more than twice intrinsic drug
solubility. The rank order of the drug concentration was HPMC > PVP > PVA.
However, since pullulan did not dissolve in the fused nicotinamide, nifedipine
was present as a crystalline state in the solid dispersion; the supersaturation
behavior of the drug was scarcely observed. The compatibility, namely, the
solubility and miscibility, between nicotinamide or nifedipine and the polymers,
was determined by differential scanning calorimetry using the mixtures treated
with fusing and subsequent rapid cooling. Both HPMC and PVP exhibited high
compatibility not only with nicotinamide but also with nifedipine. The
crystallization behavior of nifedipine from a supersaturated solution containing
nicotinamide or the polymers was studied. The inhibitory effect of HPMC or PVP
for drug crystallization was evident, which would be related not to the
solubilizing effect but to the adhesive force of the polymer for the drug.
Therefore, it was understood that the use of a polymer with high compatibility
and adhesion with nifedipine provides a high supersaturation level of the drug in
dissolution. Further, the solubility parameter was found to be useful for
selecting a suitable polymer as a component of combined carriers.
PMID- 9549891
TI - Structural determination of unknown subsidiary colors in commercial food red Nos.
2 and 102.
AB - Major subsidiary colors A (Sub A) and B (Sub B) in commercial Food Red No. 102,
and colors C (Sub C) and D (Sub D) in commercial Food Red No.2 were isolated.
These structures were characterized by physicochemical evidence. The structures
of Sub A, B, and C are trisodium salt of 7-hydroxy-8-(6-sulfonaphthyl-2-azo)-1,3
naphthalenedisulfonic++ + acid, disodium salt of 4-amino-3-(4-sulfonaphthyl-1
azo)-1-naphthalenesulfonic acid and trisodium salt of 3-hydroxy-4-(6
sulfonaphthyl-2-azo)-2,7-naphthalenedisulfonic++ + acid, respectively. Sub D was
identified as Sub B.
PMID- 9549893
TI - A new oleanene glucuronide having a branched-chain sugar from Melilotus
officinalis.
AB - A new oleanene glucuronide called melilotus-saponin O1 (1) was isolated together
with three known ones from the roots of Melilotus officinalis (L.) PALLAS
(Leguminosae). The structure of 1 was determined to be 3-O-alpha-L
rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranosyl-(1--> 3)]- beta-D
galactopyranosyl-(1-->2)-beta-D-glucuronopyranosyl soyasapogenol B by
spectroscopic and chemical methods.
PMID- 9549892
TI - Comparative study of seventeen Salvia plants: aldose reductase inhibitory
activity of water and MeOH extracts and liquid chromatography-mass spectrometry
(LC-MS) analysis of water extracts.
AB - The dry root and rhizome of Salvia miltiorhiza (Lamiaceae) are used as a crude
drug Danshen, while those of S. deserta (Xinjiang-Danshen) are mixed in Danshen
at Xinjiang province when the former is in short supply. The water and MeOH
extracts of S. deserta showed strong aldose reductase (AR) inhibitory activity,
and their active constituents were determined to be polar compounds different
from "tanshinones" of S. miltiorhiza, i.e., lithospermic acid B (1), salvianolic
acid K (2), salviaflaside (3), and rosmarinic acid (4) (IC50, 2.63-3.91 microM).
We also examined the AR inhibitory activity of water and MeOH extracts of
seventeen Salvia plants, including ten species of Danshen resources (S.
bowleyana, S. deserta, S. miltiorhiza, S. miltiorhiza var. miltiorhiza f. alba,
S. paramiltiorhiza, S. paramiltiorhiza f. purpureo-rubra, S. przewalskii, S.
przewalskii var. mandarinorum, S. sinica f. purpurea, S. trijuga), and their
water extracts were also analyzed by liquid chromatography-mass spectrometry (LC
MS). The results indicated that there were four types with regard to the AR
inhibitory activity and three types with regard to the amount of 1. Ten species
used as Danshen resources showed good correlation between the AR inhibitory
activity and the morphological classification. However, the intensities of their
AR inhibitory activity varied, and they contained 1 in varying amounts. These
facts suggested that the ten species were not the same, and thus their use as a
Danshen resource should be based on their activity and/or active constituents.
PMID- 9549894
TI - Cytotoxic principles of a Bangladeshi crude drug, akond mul (roots of Calotropis
gigantea L.).
AB - Three cardenolide glycosides, calotropin (1), frugoside (2), and 4'-O-beta-D
glucopyranosylfrugoside (3), were obtained as the cytotoxic principles of "akond
mul" (roots of Calotropis gigantea L.). The cytotoxicity of these compounds
against various cell lines of human and mouse origin was tested. They showed
similar cell line selectivity to those of cardiac glycosides such as digoxin and
ouabain: they are toxic to cell lines of human origin, but not to those from
mouse at 2 micrograms/ml.
PMID- 9549895
TI - Application of tumbling melt granulation method to prepare controlled-release
beads by coating with mixture of functional non-meltable and meltable materials.
AB - A new coating method for use in preparing controlled-release beads was developed
by modifying the tumbling melt granulation technique. The dissolution rate of the
drug from the beads was controlled by coating the mixture of meltable and non
meltable materials by heating in a centrifugal fluidizing granulator without
using any solvent. In experiments using talc as the non-meltable material, the
resultant beads showed the sufficient ability to suppress the dissolution of the
drug and no change in the dissolution characteristics by wetting agent and in a
stability test at high temperature. Using functional polymer as the non-meltable
material, the controlled-release beads with various dissolution characteristics
could be prepared: entero-soluble-release beads using entero-soluble polymer, and
zero-order-release beads using hydrophilic gel-forming agent and talc.
PMID- 9549896
TI - Application of tumbling melt granulation (TMG) method to prepare controlled
release fine granules.
AB - The tumbling melt granulation (TMG) method was applied to prepare controlled
release fine granules of diltiazem hydrochloride (DH). The entire process, from
the preparation of the cores by the adherence of DH to the sucrose crystal to the
subsequent coating of the controlled-release layer, was performed without using
any solvent. A mixture of meltable material, talc, and ethylcellulose was used
for the controlled-release layer and controlled-release fine granules
approximately 400 microns in diameter were obtained with excellent producibility.
The dissolution rate of DH from these fine granules was similar to that of a once
a-day dosage form obtained in the market; further, the dependency of the
dissolution profile on pH of the media was less. Thus, it was concluded that this
TMG method was very useful for preparing not only controlled-release beads of
granule size (usually 500 to 1400 microns) but also fine granules.
PMID- 9549897
TI - Reduction of Mn(3+)-tetrakis(4-methylpyridyl)porphine with albumin observed in
resonance Raman spectra.
AB - When the resonance Raman spectra of Mn(3+)-tetrakis(4-methylpyridyl)-porphine are
measured in the presence of albumins, the resonance Raman bands of Mn(2+)
tetrakis(4-methylpyridyl)porphine are frequently observed. This reduction of Mn3+
to Mn2+ could be caused by an action of unfolding albumins resulting from heat
and/or light.
PMID- 9549899
TI - Lethal monointoxication by overdosage of MDEA.
AB - A 19-year-old man died after the intake of ten tablets of Ecstasy containing 3,4
methyl-enedioxy-N-ethylamphetamine (MDEA) as the main active ingredient.
According to an eyewitness the symptoms of intoxication were strong sweating,
sudden aggressiveness followed by hallucinations, subsequent failure of motoric
coordination, severe spasms of arms and back, complete depression of the
respiratory system, unconsciousness, and collapse. Resuscitation by an emergency
doctor failed. Major autopsy findings were severe vascular congestion of all
internal organs, liquid post-mortem blood, numerous subpleural and subepicardial
petechial haemorrhages. By GC/MS analysis, MDEA was found in large amounts in
serum (12 mg/l in femoral vein, 22 mg/l in heart blood serum), urine (201 mg/l),
brain (18 to 28 mg/l) and in other tissue samples. Scalp-hair was highly positive
for MDEA (17 ng/mg). Besides MDEA and its metabolites only trace amounts of MDMA
could be found in urine and blood; no other drugs were detected. It can be
concluded that the cause of death was a monointoxication by overdosage of MDEA.
PMID- 9549898
TI - The different mobility of complementary strands depends on the proportion AC/GT.
AB - The electrophoretic mobility of DNA fragments on denaturing polyacrylamide gel
depends on various factors. One of these is the base composition of a single
stranded DNA (ssDNA). We confirmed that one strand and its complementary strand
of polymerase chain reaction (PCR) products migrated with different mobilities in
all alleles detected at 12 out of the 13 short tandem repeat (STR) loci studied.
The mobility differences between complementary strands (MD) were also observed
regardless of end-polishing with Pfu DNA polymerase. MD was therefore not
influenced by additional nucleotides to each strand of the PCR products. We then
analyzed the relation between MD and the base composition using one
representative allele at each of the 13 loci. The results indicated that MD was
affected by the adenine plus cytosine (AC) content in the ssDNA and was
proportional to the values of the AC content divided by the guanine plus thymine
(GT) content in the AC-rich strand (the proportion AC/GT). When the proportion
AC/GT was well-balanced, MD decreased. The same tendency was observed even in the
end-polished strands. In this study, the electrophoretic mobility of an ssDNA on
denaturing polyacrylamide gels was shown to depend on the proportion AC/GT.
Unless the same side of the PCR products is labelled in the context of a PCR
based STR typing, distinct alleles may be mistaken for identical ones because of
the different mobility of complementary strands. Accordingly, the labelled strand
should be described if only one strand of the PCR products is detected. When
using an allelic ladder marker as a size standard, the labelled side should be
unified between STR alleles and the allelic ladder alleles.
PMID- 9549900
TI - German population data of three tetrameric short tandem repeat loci--D3S1744,
D12S1090 and D18S849.
AB - Allele and genotype frequencies of the three tetrameric short tandem repeat (STR)
1 Oci D351744 D1251090 and D185849 were analyzed in a German sample population
using a multiplex PCR and electrophoresis of amplified products in denaturing
gels followed by silver staining. Testing for Hardy-Weinberg equilibrium showed
no significant deviation at the three loci.
PMID- 9549901
TI - Exploitation of autopsy in determining natural cause of death: trends in Finland
with special reference to the diagnostics of ischemic heart diseases and
cerebrovascular diseases in middle-aged males, 1974-1993.
AB - Finnish mortality statistics show a marked decrease in coronary disease mortality
especially among middle-aged males during the last 20 to 25 years. At the same
time, the overall autopsy rate in deaths due to natural, non-violent causes has
diminished in Finland. National mortality statistics are based on medical
information given in death certificates. How often are the causes of death based
on autopsy and is there any definitive trend? Possible changes in cause-of-death
determination practices may have contributed to the mortality changes observed.
In this study, deaths due to ischemic heart diseases (IHD) and cerebrovascular
diseases (CVD) from 1974 to 1993 in Finland were compared with natural deaths,
i.e. all of the deaths due to natural causes, in regard to use of autopsy. It was
found that IHD-diagnosis as the underlying cause-of-death was, unlike natural
deaths and CVD in particular, increasingly based on autopsy. It is thus concluded
that the recent decline in coronary disease mortality among middle-aged men in
Finland cannot be explained by any deterioration in cause-of-death examination
practices.
PMID- 9549902
TI - Study of the diagnostic value of strontium, chloride, haemoglobin and diatoms in
immersion cases.
AB - Tests of haemoglobin (Hb), strontium (Sr) and chloride (Cl), as well as diatoms,
toxicological and pathological studies were performed in biological samples from
133 immersion fatalities occurred since 1991 to 1996 in central and northern
Spain. Hb, Sr, and Cl where analyzed in blood samples where increasing
decomposition could be demonstrated in most of the cases. The samples were
frequently accompanied with well documented forensic reports, including autopsies
findings and other circumstances of the death. The goal of our study is to
evaluate the difference of blood Sr concentration between the left and right side
of the heart (LVSr-RVSr) as a marker of drowning. For this purpose, the cases
investigated were classified in 'typical drowning' (TD) cases and 'atypical
drowning' (AD) cases. This last group was used as a control. The comparison of
the LVSr-RVSr between TD and AD cases was highly significant (P = 0.0002) in
blood specimens extracted from cases occurred in putative drowning media where Sr
concentration was higher than 800 micrograms/l. No significant differences were
found comparing neither Cl nor Hb biventricular concentrations between TD and AD
cases in blood samples extracted from bodies found in both fresh and seawater.
PMID- 9549903
TI - Phrenic nerves and diaphragms in sudden infant death syndrome.
AB - Disturbances of the respiratory system may be an important factor in the cascade
of events leading to sudden infant death syndrome (SIDS). Even though the
diaphragm is the major respiratory muscle in infants, little is known about
alterations of this muscle and of the phrenic nerve in SIDS. In the present
study, diaphragms and phrenic nerves of 24 SIDS infants and seven controls were
analyzed. Morphometric analysis revealed only slightly larger cross sectional
areas of phrenic nerve axons but no increase in myelin sheath thickness in SIDS
cases. However, in one SIDS case, myelinated nerve fibre density was severely
reduced. Using electron microscopy, several nerve fibres of SIDS infants showed
focal accumulations of neurofilaments. Muscle fibre diameters in SIDS diaphragms
were significantly larger compared to controls (P < 0.0001). However, in almost
all SIDS and control cases, axons and myelin sheaths were artificially swollen,
and acute segmental muscle fibre ruptures and contracture bands were found. These
prominent nonspecific ultrastructural alterations should advise caution in the
interpretation of morphometric data. Thus, in some cases exemplified by one case
of the present series, decreased density of phrenic nerve myelinated axons might
contribute to SIDS. Still, the present results indicate that development of
phrenic nerves and diaphragms is not delayed in most SIDS infants.
PMID- 9549904
TI - A contribution to a possible differentiation between SIDS and asphyxiation.
AB - The singular and combined appearance of conjunctival petechiae, of acute
pulmonary emphysema and of signs of aspiration was evaluated in resuscitated and
non-resuscitated children dying of SIDS (n = 115), of other causes of natural
death (n = 17), of severe head injury (n = 10) and of asphyxiation/strangulation
(n = 7). Conjunctival petechiae occurred in all of the asphyxiated victims and in
five out of 10 children dying of severe head injury, but were exclusively found
in four resuscitated babies and one baby with questionable resuscitation trials
of the SIDS-group (4%), furthermore in one resuscitated child dying of a
congenital heart defect. Acute pulmonary emphysema was detected in six out of the
seven children of the asphyxiation/strangulation group, in two resuscitated
children with head injury and in five resuscitated babies dying of SIDS. Both
parameters were observed exclusively in the asphyxiation/strangulation group (71%
of the cases) but not in the control cases. Therefore, it can be concluded that
the simultaneous appearance of conjunctival petechiae and of acute pulmonary
emphysema strongly indicates death by asphyxiation.
PMID- 9549905
TI - Statistical analysis of sexual offenders--a preliminary study.
AB - It is suggested that persons arrested and incarcerated for sexual offences are in
some ways different than other inmates. This paper examines various
characteristics of sexual offenders in an Irish prison and determines if
perceived differences are statistically valid using some of the techniques
available through offender profiling. Statistical differences (chi 2; P = 0.01)
in some characteristics were found between other prisoners and sexual offenders.
PMID- 9549906
TI - Fluid transport in vascularized tumours and metastasis.
AB - In this paper we propose a modification to a model of R. K. Jain and L. T. Baxter
used to describe fluid transport in vascularized tumours. The model predicts high
interstitial pressure in the interior of the tumour together with a rapid
decrease in pressure to its periphery in agreement with experiment and the
predictions of the Jain-Baxter model. By the addition of a pressure-curvature
(Gibbs-Thomson) condition on the periphery of the tumour we are able to show by a
perturbation analysis that a lowering of the interstitial pressure can retard
tumour growth. Lowering interstitial pressure may also be beneficial to the
targeting of therapeutic drugs.
PMID- 9549907
TI - The competent graduate.
PMID- 9549908
TI - Specialisation in oral surgery.
PMID- 9549909
TI - Advances in periodontal diagnosis. 4. Potential microbiological markers.
AB - The potential of bacterial markers for the detection of periodontal disease
activity is discussed. Chronic periodontitis has been associated with subgingival
bacteria. Techniques are available to detect and distinguish different bacteria.
In subgingival plaque, bacterial proteases can be detected. Commercial diagnostic
tests based on bacterial factors are described.
PMID- 9549910
TI - Powered toothbrushes.
AB - Powered toothbrushes were first developed over 50 years ago. More recent advances
in design and technology mean that there are now a considerable number of
different models available on the market. It is not surprising, therefore, that
patients, when considering buying a powered toothbrush, often turn to their
general dental practitioner for advice.
PMID- 9549911
TI - A psychodynamic theory for dental phobia.
AB - Dentists recognise various degrees of dental anxiety in their patients. There are
those who are relaxed, those who are anxious and those who are dentally phobic.
The question remains why should disagreeable dental experiences result in dental
anxiety in one patient, have little effect upon another and cause dental phobia
in a third? The aim of this paper is to propose a psychodynamic theory for dental
phobia based upon the ideas of false connections and displacement.
PMID- 9549912
TI - Enthusiastic welcome for the pilot peer review scheme for GDPs working in the
GDS.
PMID- 9549913
TI - Most referrals for periradicular surgery do not match the accepted guidelines.
PMID- 9549914
TI - An accurate method for the measurement of blood loss during dental procedures.
PMID- 9549915
TI - A report of an evaluation of the pilot peer review scheme for general dental
practitioners working in the general dental services in England.
AB - OBJECTIVE: To evaluate the pilot peer review scheme for general dental
practitioners, working in the general dental services in England. DESIGN: A
retrospective analysis of a 50% random sample of end of project resumes. SETTING:
The scheme was piloted from August 1991 to April 1996. At the end of each project
a resume was completed. METHODS: The random sample of resumes was subjected to
content analysis by three reviewers who had previously undergone consistency
training. MAIN OUTCOME MEASURES: The range of topics reviewed, the choice of
single or multiple topics, the direct relevance of projects to patient care and
the comments of the scheme's participants. RESULTS: 332 resumes were analysed,
89% included positive comments. Overall 42% of projects reviewed single topics,
with participants in 4 out of 13 regions favouring this approach. 61% of topics
related directly to patient care. CONCLUSIONS: The pilot peer review scheme was
enthusiastically welcomed by the participants and achieved its objectives of
encouraging initiatives to improve patient services and testing different types
of peer review.
PMID- 9549916
TI - A study of suitability of referrals for periradicular surgery.
AB - OBJECTIVE: To determine if the clinical and radiographic presentation of patients
referred by their general dental practitioner requesting periradicular surgery
fulfilled a set of predetermined guidelines as to the appropriateness of the
procedure. DESIGN: Multicentre prospective study. SETTING: Maxillofacial
departments of district general hospitals. METHOD: Consecutive analysis of
referrals within four hospitals over a 1-year period between 1995 and 1996.
RESULTS: From 205 referrals, mostly of patients in the 30 to 40 years age group,
79.5% (n = 163) of referrals failed to meet the criteria, mainly because of an
unsatisfactory root canal filling, but also due to obvious coronal microleakage
and adjacent teeth contributing to the disease process not yet having received
endodontic treatment. In only 6.3% (n = 13) of patients had there been an attempt
to retreat the pulp space infection by conventional means. CONCLUSION: The
majority of referrals in this study did not fulfil the guideline criteria on the
provision of periradicular surgery. The factors influencing failure in
endodontics and periradicular disease did not appear to have been appreciated, or
were not acted upon. Conventional retreatment of the pulp space needs to be
considered or attempted prior to referral for surgery.
PMID- 9549917
TI - A randomised trial of calcium alginate swabs to control blood loss in 3-5-year
old children.
AB - OBJECTIVE: To compare the effectiveness of calcium alginate swabs and traditional
cotton swabs in the control of blood loss after extraction of deciduous teeth
from healthy children, aged 3-5 years, under general anaesthetic. DESIGN:
Prospective, randomised clinical trial. SETTING: General anaesthetic suite in a
dental teaching hospital. SUBJECTS: 101 patients were recruited to the study,
comprising 50 randomised to be treated with cotton swabs and 51 with alginate
swabs. INTERVENTIONS: Teeth were extracted under general anaesthesia and blood
collected for measurement in order to compare blood loss using the two systems.
MAIN OUTCOME MEASURES: The number of teeth extracted ranged from 1-14. The total
blood loss ranged from 0.53-78.13 ml with a median of 12.9 ml. CONCLUSION:
Calcium alginate swabs were not found to produce any clinical or statistical
advantage over traditional cotton swabs in this surgical setting.
PMID- 9549918
TI - An innovation in the assessment of future dentists.
AB - 'The assessment of students is a serious and often tragic enterprise.' The
central question in assessment is 'What is one trying to assess?'. Is it factual
knowledge, ability to apply and problem solve, clinical competencies or indeed
other attributes? The domain being assessed requires appropriate methods.
Professionals involved in examination development have identified three
characteristics which all assessment methods demand: reliability, validity and
feasibility. This article sets out to describe these features.
PMID- 9549919
TI - Pathogenesis of polycythemia vera: do we have the right pieces to the puzzle?
PMID- 9549920
TI - Expression of adhesion molecules in chronic B-cell lymphoproliferative disorders.
AB - BACKGROUND AND OBJECTIVE: Abnormalities in the expression of cell adhesion
molecules (CAM) are thought to influence the patterns of intranodal growth and
hematogeneous spread of malignant cells in chronic lymphoproliferative disorders
(LPD). Therefore, the characterization of CAM phenotypic profiles of the
neoplastic clones in LPD may help to identify distinct subtypes with prognostic
implications. In this work we sought to investigate whether the expression of CAM
by circulating malignant cells in patients with B-cell LPD differed from that of
normal peripheral blood B-lymphocytes (PBL) and whether the observed phenotypic
patterns could be correlated to other biological and clinical parameters of known
clinical relevance. DESIGN AND METHODS: Peripheral blood mononuclear cells were
obtained from 148 patients with B-cell chronic lymphocytic leukemia (B-CLL), 52
with B-cell non-Hodgkin lymphomas (NHL) and 10 with hairy cell leukemia (HCL).
The expression of CAM was analyzed by flow cytometry using monoclonal antibodies
against CD49d, CD29, CD11a, CD11b, CD11c, CD18, CD62L, CD54 and CD44. RESULTS:
All CAM were detected in normal peripheral blood B-lymphocytes, except CD11c and
CD54, which were present in only a minority of cells. Fluorescence mean channel
values (FMC) showed that all molecules, with the exception of CD44, were
expressed with dim intensity. Emerging patterns of CAM expression, as assessed by
FMC values, were observed in different LPD: thus, B-CLL is characterized by a
very low expression of CD49d/CD29 and beta 2 integrins. In this disorder,
CD49d/CD29, CD11a, and CD54 increase with tumor burden; NHL show high expression
of CD29 and CD54; strong expression of all molecules (except CD11a) was found in
HCL, particularly CD11c (FMC values 60 times higher than normal). CD62L was
faintly expressed in all diagnostic groups, whereas CD11c showed consistently
high FMC values. INTERPRETATION AND CONCLUSIONS: The data shows that the
phenotypic characterization of LPD can be further refined by the analysis of
their patterns of CAM expression which may help to identify distinct subsets
within each nosological group.
PMID- 9549921
TI - Cytoskeletal reorganization after preparation of platelet concentrates, using the
buffy coat method, and during their storage.
AB - BACKGROUND AND OBJECTIVE: The use of platelet transfusions has risen considerably
in the last years. Changes occur in platelet biochemical and membrane properties
during storage. We have analyzed the effect of platelet preparation and storage
of platelet function through the evaluation of platelet cytoskeletal
reorganization. METHODS: A blood sample was obtained from the donor and platelets
were separated as standard platelet-rich plasma (PRP) (120 g, 20 min) (PRE
sample). Aliquots were also collected immediately after preparation using buffy
coat procedure of platelet concentrates (day 0) and after 1, 3 and 5 days of
storage. Cytoskeleton composition in both low- and high-speed cytoskeletal
fractions of detergent-lysed platelets was analyzed by gradient SDS
polyacrylamide gel electrophoresis (SDS-PAGE). Presence of each contractile
protein was quantified by densitometry. RESULTS: The method used to prepare
platelet concentrates induced actin polymerization (actin increased to 163.5 +/-
4.8%, mean +/- SEM, n = 8, p < 0.001, considering actin values in PRE sample as
100%) with a concurrent increase in the association of actin-binding protein
(ABP), myosin and alpha-actinin to the low-speed cytoskeletal fraction. During
the first 24 hours of storage, cytoskeletal assembly was partially reversed
(134.8 +/- 2.6% of actin, p < 0.001) and actin polymerization increased gradually
to 144.3 +/- 5.8% and 153.2 +/- 5.1% at days 3 and 5, respectively (p < 0.001 for
both days). ABP, myosin and alpha-actinin showed similar tendencies to those
referred for actin. Conversely, during platelet preparation and storage, the
contractile proteins associated with the high-speed cytoskeletal fraction
decreased, due to reorganization of the contractile proteins to the low speed
fraction. INTERPRETATION AND CONCLUSIONS: The method used to prepare platelet
concentrates (buffy coat procedure) induced cytoskeletal polymerization. This
activating effect was partially reversed after 1 day of storage, although it
increased progressively after 3 days of storage. The storage lesion may lead to
defective cytoskeletal assembly in response to further stimulus. Analysis of
cytoskeletal assembly is a sensitive method for detecting platelet activation
caused by the concentrate preparation method and the storage conditions.
PMID- 9549923
TI - Therapeutic options and treatment results for patients over 75 years of age with
acute myeloid leukemia.
AB - BACKGROUND AND OBJECTIVE: Acute myeloid leukemia (AML) is a prevalent disease of
the elderly. Given the progressive aging of the general population, the frequency
of the disease will further increase, especially in very old individuals. In a
cohort of 70 consecutive AML patients aged over 75 years, we investigated the
clinico-hematological characteristics and treatment results. DESIGN AND METHODS:
Seventy patients aged > 75 were diagnosed at our institutions as having AML
between January 1987 and December 1996. This figure represents 8% of the whole
AML patient population observed during the same period. These patients were
studied concerning the main clinical and hematological features at presentation,
therapeutic approach and clinical outcome. RESULTS: A myelodysplastic syndrome
preceded the onset of AML in 10 patients (14%). Trilinear myelodysplasia was
present in 28 patients (40%). Hypocellular leukemia was diagnosed in 12 cases
(17%). An active infection was found in 12 patients (17%). Aggressive
chemotherapy was given to 22 patients (31%), low-dose ARA-C (LDARA-C) to 7
patients (10%), while 41 (58%) were managed with supportive care and/or
hydroxyurea (HU). Therapeutic choice was significantly influenced by performance
status (p = .03), infections (p = .0001), severe co-morbid disease (p = .0001),
and hypocellular AML diagnosis (p = .0001). Complete remission (CR) was obtained
in 7/22 patients aggressively treated (32%), 0/7 in the LD-ARA-C group, and in
one patient treated with HU. The median survival for the whole patient population
was 18 weeks. There was no significant difference among the three treatment
groups. However, patients achieving CR experienced significantly longer survival
as did those with hypocellular leukemia. INTERPRETATION AND CONCLUSIONS: In spite
of a relevant selection at diagnosis, intensive chemotherapy is not appropriate
for the majority of very old patients with AML. However, since a minority of
patients takes substantial advantage from an aggressive approach, any effort
should be made to preliminarily identify this subset at diagnosis.
PMID- 9549922
TI - The effect of dietary magnesium supplementation on the cellular abnormalities of
erythrocytes in patients with beta thalassemia intermedia.
AB - BACKGROUND AND OBJECTIVE: Reduced serum or erythrocyte Mg have been reported in
human beta thalassemia. These deficiencies may play a role in the cellular
abnormalities characteristic of this disorder. We have therefore studied the
effect of dietary Mg supplementation in patients with beta thalassemia intermedia
in order to establish whether it improves the abnormalities of thalassemic
erythrocytes. DESIGN AND METHODS: Plasma and erythrocyte Mg were determined in 11
patients with b thalassemia intermedia, not requiring chronic transfusion
therapy, and in 17 normal controls. Inclusion criteria included normal renal and
liver function and performance status of 70% or greater. Seven patients were
enrolled for the Mg supplementation study, after the appropriate informed consent
was obtained. They were given a starting dose of 0.6 mEq/kg/day of magnesium
pidolate, divided into two oral daily doses, for four weeks. In a 70-kg subject,
a daily Mg dose of 42 mEq corresponds to 504 mg of Mg, with the daily Mg intake
of normal subjects being 418 +/- 120 mg for males and 343 +/- 94 mg for females.
After 28 days of treatment, five of the patients continued the protocol with a
daily dosage increased to 1.2 mEq magnesium pidolate/kg/day, divided into two
oral administrations, for an additional four weeks. RESULTS: In patients with
untransfused beta thalassemia intermedia we found reduced erythrocyte Mg (in
mmol/kg Hb, 6.12 +/- 1.5, n = 11 vs. 8.69 +/- 0.89, n = 17, respectively, p <
0.0001) and normal serum Mg. In the seven patients given oral Mg supplements, at
Mg dosages of 0.6 mEq/kg/day we observed significant increases in erythrocyte Mg,
and significant improvement in some of the characteristic abnormalities of beta
that erythrocytes (increased Na-K pump, KCl cotransport, cell dehydration,
increased osmotic resistance). These changes were maintained in the 5 patients
who were treated with 1.2 mEq of Mg/kg/day. Follow-up studies showed a return to
baseline conditions. There were no signs of Mg toxicity, with the only side
effect being diarrhea, which was generally mild, but led to discontinuation for
one patient after the first four weeks. INTERPRETATION AND CONCLUSIONS: These
data indicate that dietary Mg supplementation improves some of the characteristic
cellular function abnormalities of b thalassemia intermedia. The possible
therapeutic value of this strategy should be further tested in these patients.
PMID- 9549925
TI - Assessment of hematological and immunological function during long-term follow-up
after peripheral blood stem cell transplantation.
AB - BACKGROUND AND OBJECTIVE: Long-term hemopoietic and immunological profile after
autologous peripheral blood progenitor cells transplantation (PBPCT), in patients
affected by hematological malignancies is largely unknown. The aim of this work
was to detect the impact of high dose chemotherapy and PBPCT on hemopoietic and
immunological function compared to conventional chemotherapy. DESIGN AND METHODS:
Patients had to fulfill the following criteria: continuous complete remission
after PBPCT, follow-up longer than 12 months, no chemo or radiotherapy or
biological response modifiers after PBPCT. Twenty-five patients were considered
eligible for this analysis. Stable and complete hemopoietic reconstitution (Hb >
12 g/dL, WB > 4.0 x 10(9)/L, ANC > 1.5 x 10(9)/L and Pits count > 150 x 10(9)/L),
morphological examination of peripheral blood and bone marrow, cytogenetic
analysis and immunological profile were evaluated at 12 months and yearly
thereafter. RESULTS: Immunological reconstitution showed a persistent reduction
of CD4/CD8 ratio up to five years after PBPCT. This reduction was related to a
persistent increase of CD8+ lymphocytes and a constant reduction of CD4+
lymphocytes. INTERPRETATION AND CONCLUSIONS: Defects observed in PBPCT patients
are induced by the procedure itself, by the conditioning regimen or both. The
different behavior in the immune reconstitution of CD8+ subset after PBPCT may be
favored by an extrathymic origin of these cells while CD4+ subset recovery which
is thymus-dependent is impaired after PBPCT in adult population. Long-term
hemopoietic reconstitution after PBPCT is rapidly obtained and is stable over the
years, long-term immunological function seems to be abnormal in these patients
and these abnormalities are long-lasting.
PMID- 9549924
TI - A randomized trial of high dose polyvalent intravenous immunoglobulin (HDIgG) vs.
Cytomegalovirus (CMV) hyperimmune IgG in allogeneic hemopoietic stem cell
transplants (HSCT).
AB - BACKGROUND AND OBJECTIVE: The role of high dose intravenous IgG (HDIgG) and of
hyperimmune CMV IgG (CMV-IgG) in patients undergoing allogeneic hemopoietic stem
cell transplantation (HSCT) is still unclear. The aim of this study was to
compare prophylactic CMV-IgG with HDIgGin a randomized prospective trial in
allogeneic HSCT recipients: primary end point of the study was the occurrence of
post-transplant CMV antigenemia (CMVAg-emia). Secondary end-points were severity
of acute and chronic graft-versus-host disease (GvHD), infections and transplant
related mortality (TRM). DESIGN AND METHODS: Patients were randomized to receive
100 mg/kg/week of CMV-IgG (group A; n = 64) or 400 mg/kg/week of HDIgG (group B;
n = 64) from day -7 to day +100. The two groups were comparable for age,
diagnosis, disease status, and acute graft-versus host (aGvHD) prophylaxis.
RESULTS: The actuarial risk at 1 year of CMV antigenemia was lower for CMV-IgG
(61% vs. 71%) but not significantly (p = 0.37); CMVAg-emia occurred at the same
interval from HSCT (47 vs. 48 days, p = 0.9), with a comparable number of CMVAg
positive cells (3 vs. 3 p = 0.9). Eight patients died of interstitial pneumonia
(IP) (4 in each group), two in group A of CMV-IP. Acute GvHD was scored as O-I,
II and III-IV in 39 vs. 35, 23 vs. 22 and 2 vs. 7 patients respectively for the
two groups (p = not significant). The actuarial risk of developing acute GvHD
grade II-IV was lower for CMV-IgG (39% vs. 45%) but not significantly (p = 0.43).
Chronic GvHD scored as absent in 7 vs. 10 patients, limited in 39 vs. 37 and
extensive in 19 vs. 17 patients respectively (p = not significant). Numbered days
with intravenous antibiotics, days in hospital, days of fever, number of local
and disseminated infections, number of patients with fever of unknown origin were
not significantly different. Actuarial 1 year TRM is 18% vs. 19%, respectively (p
= 0.9). INTERPRETATION AND CONCLUSIONS: This study confirms that CMV antigenemia
is comparable in recipients of hyperimmune CMV-IgG and of polyvalent HDIgG,
although the former had a 32% lower cost. It also shows that the potential
immunomodulating effect on acute GvHD and transplant mortality is similar with
100 or 400 mg of IgG/kg/week: this is relevant, in view of the high cost of
prophylactic HDIgG.
PMID- 9549926
TI - Treatment of polycythemia vera.
AB - BACKGROUND AND OBJECTIVE: Current guidelines for the management of patients with
polycythemia vera (PV) derive from a few clinical trials and several uncontrolled
clinical studies. The purpose of this paper is to critically review the available
evidence in literature for selecting the best treatment in the single patient.
METHODS: The authors have been working in this field contributing original papers
whose data have been used for this study. In addition, the material analyzed in
this article includes papers published in the journals covered by the Science
Citation index and Medline. RESULTS: Therapeutic strategies for patients with PV
include both cytoreductive and antithrombotic drugs. Among cytoreductive
treatments, phlebotomy is associated with poor compliance and an increased
incidence of thrombosis in the first three-five years, whereas chemotherapy may
induce an higher risk of secondary malignancies after seven-ten years of follow
up. New cytoreductive drugs virtually devoid of mutagenic risk include alpha
interferon and anagrelide, but their role in reducing thrombotic complications or
mortality remains to be demonstrated. Antithrombotic drugs, such as aspirin, are
frequently used in PV, despite doubts regarding safety and efficacy. CONCLUSIONS:
The management of patients with PV is a difficult balance between the prevention
of thrombotic complications and the risk of drug side effects and toxicity.
Appropriate studies are needed and an European collaboration has been set up for
launching a randomized, placebo-controlled clinical trial (European Collaboration
on Low-Dose Aspirin-ECLAP study) aimed at testing the efficacy of low-dose
aspirin in preventing thrombosis and prolonging survival in PV patients.
PMID- 9549928
TI - Clinical use of allogeneic hematopoietic stem cells from sources other than bone
marrow.
AB - BACKGROUND AND OBJECTIVE: Peripheral blood stem cells (PBSC) are being
increasingly used as an alternative to conventional allogeneic bone marrow (BM)
transplantation. This has prompted the Working Group on CD34-Positive
Hematopoietic Cells to evaluate the current utilization of allogeneic PBSC in
clinical hematology. EVIDENCE AND INFORMATION SOURCES: The method employed for
preparing this review was that of informal consensus development. Members of the
Working Group met three times, and the participants at these meetings examined a
list of problems previously prepared by the chairman. They discussed the single
points in order to reach an agreement on different opinions and eventually
approved the final manuscript. Some of the authors of the present review have
been working in the field of stem cell transplantation and have contributed
original papers in peer-reviewed journals. In addition, the material examined in
the present review includes articles and abstracts published in journals covered
by the Science Citation Index and Medline. STATE OF THE ART: Review of the
current literature shows that unmanipulated allogeneic PBSC give prompt and
stable engraftment in HLA-identical sibling recipients. Despite the much higher
number of T-cells infused, the incidence and severity of acute GVHD after PBSC
transplant seems comparable to that observed with bone marrow (BM) cells. In
comparison to the latter, PBSC probably ensure faster immunologic reconstitution
in the early post-transplant period. Controversial results on the incidence and
severity of acute-GVHD have been reported when CD34+ selection methods are used.
Prospective randomized trials are underway to compare the results of PBSC and BM
allogeneic transplantation. In mismatched family donor transplants, T-cell
depleted PBSC successfully engraft immune-myeloablated recipients through a
megacell-dose effect able to overcome the HLA barrier. Experience with PBSC in
the context of unrelated donor transplants is currently anecdotal and prospective
trials should be completed before that practice becomes routine. Finally, there
is also limited evidence that, following induction chemotherapy, the addition of
PBSC to donor lymphocyte infusion (DLI) for treatment of leukemia relapse after
BMT may improve the safety and effectiveness of DLI itself. Concerning cord blood
(CB) transplants, the most interesting aspects are the ease of CB collection and
storage, the low risk of viral contamination and the low immune reactivity of CB
cells. This last property has its clinical counterpart in an apparently reduced
incidence and severity of acute GVHD both in sibling and unrelated CB
transplants, probably making the level of donor/recipient HLA disparity
acceptable a greater degree with respect to what is required for transplants from
other sources.
PMID- 9549927
TI - Pathogenesis of polycythemia vera.
AB - BACKGROUND AND OBJECTIVE: Polycythemia vera (PV) is an acquired clonal
myeloproliferative disorder characterized by increased production of mature red
cells. We still lack a molecular target responsible for this disorder; however,
recent investigations have focused on a number of molecules involved in signal
transduction pathways mediated by erythropoietin (Epo) and other growth factors.
Here we review the implication of these molecules in the pathogenesis of PV.
INFORMATION SOURCES: The material reviewed in this work includes articles
published in journals covered by Medline. We also include data obtained in our
laboratory regarding to the significance of apoptosis inhibitory proteins in
erythroid development. STATE OF THE ART AND PERSPECTIVES: Overproduction of
erythroid cells in PV is particular in that it occurs in the absence of a
recognizable physiologic stimulus, since circulating serum levels of Epo are
normal or lower than normal. Genetic analysis as well as in vitro studies, have
established an essential role for Epo in the survival and maturation of committed
erythroid progenitors. Epo initiates its cellular response by binding to the Epo
receptor (EpoR) expressed on the surface of immature erythroblasts. Following
ligand binding, EpoR is known to activate a cytoplasmic protein tyrosine kinase,
Jak2 which triggers a signal transduction cascade that leads to the development
of early erythroid progenitors into mature erythroblast cells. Although the
mechanism underlying the increased erythroid production in PV is not well
understood, a number of causes have recently came for which may provide insights
not only for the pathogenesis of PV but also for a fundamental biological
process: the mechanism whereby a multipotential stem cell gives rise to a
particular cell lineage.
PMID- 9549929
TI - Erythrocytosis in a patient with chronic obstructive pulmonary disease.
AB - Chronic obstructive pulmonary disease (COPD) can be accompanied by compensatory
secondary erythrocytosis. However, the exact prevalence of secondary
erythrocytosis in COPD is unknown. Although diagnostic criteria for polycythemia
vera versus secondary erythrocytosis are mutually exclusive, we describe here the
coexistence of polycythemia vera and COPD in the same patient.
PMID- 9549930
TI - Blast crisis of Ph1-CML, with the prevalent features of malignant histiocytosis.
PMID- 9549931
TI - Detection of megakaryocyte colonies in plasma clot cultures by immunoenzymatic
staining.
AB - In vitro induced megakaryocytic differentiation/maturation of megakayocyte (meg)
progenitors represents an important tool for investigating cytokine-induced in
vitro thrombocytopoiesis. We have developed an assay which allows the in situ
study of human meg progenitor-derived colonies, cultured on a plasma clot in the
presence of cytokines. Plates were immunostained by using an anti-alpha IIb beta
3 monoclonal antibody and an alkaline phosphatase-labeled secondary antibody.
alpha IIb beta 3-bearing cells were stained an intense red and were clearly
differentiated from the negative cells. Processed plates were stable for some
weeks at 4 degrees C. The described procedure is easy to perform and allowed us
to enumerate the meg colonies and assess colony morphology and cell ploidy.
PMID- 9549932
TI - Aggressive natural killer cell leukemia: report of a case in a Caucasian boy.
AB - We report a case of aggressive natural killer cell leukemia (ANKL) in a Caucasian
boy diagnosed on clinical, cytologic, immunophenotypic and genotypic grounds. An
anomalous karyotype and integration of Epstein-Barr virus (EBV) within the
leukemic population were identified.
PMID- 9549933
TI - Allison Kitson is thought-provoking.
PMID- 9549934
TI - What science is.
PMID- 9549935
TI - Youngsters caring for adults with cancer.
AB - PURPOSE: To describe the caregiving provided by children and adolescents for
adults with cancer. Because nurses are assuming an increasingly prominent role in
working with caregivers, it is necessary to understand young caregivers. DESIGN:
The population of interest was youngsters aged 10 to 19 caring for adults at home
with cancer. Eleven children and adolescents in seven families were recruited,
1993-1994, through purposive sampling from hospices and cancer clinics. METHODS:
Phenomenologic interviews, ethnographic interviews and selected participant
observation experiences, and identification of needs through an unstructured
survey were used. FINDINGS: "Hard, but gratifying" emerged as the dominant
phenomenologic description of caregiving. Emergent ethnographic themes indicated
caregiving by children and adolescents was an expectation of family life. School
and church were described as avenues for social support for youngsters in care
giving situations. CONCLUSIONS: Youngsters aged 10 to 19 are caring for adults
with cancer at home. Further descriptive study of youngsters caring for adults
with cancer is needed.
PMID- 9549936
TI - Emancipatory potential of storytelling in a group.
AB - PURPOSE: To examine the health-promoting functions of storytelling in a group of
women. DESIGN: Secondary analysis, descriptive. A convenience sample of 28 women
of African descent living in the Seattle-Tacoma region of the United States was
used. METHODS: Narrative analysis of 115 stories. Data were audio-taped in four
focus groups convened during a 6-week period in 1992. FINDINGS: Six major
functions of storytelling were identified: (a) contextual grounding, (b) bonding
with others, (c) validating and affirming experiences, (d) venting and catharsis,
(e) resisting oppression, and (f) educating others. CONCLUSIONS: Storytelling is
useful for learning more about historical and contextual factors affecting the
well-being of women of African descent and for improving their lives. Group
storytelling can create an environment that supports evaluation of experience and
promotes problem-solving.
PMID- 9549937
TI - Hampton, Nutting, and Rival gospels at The Johns Hopkins Hospital and Training
School for Nurses, 1889-1906.
AB - PURPOSE: To examine the attempts by Isabel Hampton Robb and Mary Adelaide Nutting
to reshape nurse training into an academic system of nursing education. As health
care delivery undergoes transformation in the 1990s, it is useful to consider the
strategies used as well as the successes and failures, of past nurse leaders.
DESIGN: Historical research. METHODS: Archival data were analyzed in 1996
pertaining to the creation in 1889 and administration of the nursing school and
hospital founded by Johns Hopkins in Baltimore, Maryland, USA. Events were
studied using published and unpublished writings by Hampton and Nutting, as well
as relevant secondary sources. FINDINGS: Separated by class from those with
power, and limited by 19th century notions of women's place, Isabel Hampton Robb
and Adelaide Nutting helped inaugurate nursing's quest for professionalization.
Undaunted by adversity, they achieved novel accomplishments for women and nurses.
Hampton and Nutting possessed vision, intelligence, the capacity to motivate,
political skills, good judgement, and managerial competence. CONCLUSIONS:
Hampton's and Nutting's inability to strengthen the link between the school of
nursing and the Johns Hopkins University and the lack of unity within nursing
limited their success. This research illuminates some of the controversies
pertaining to nursing during an earlier period of sweeping health care change.
PMID- 9549938
TI - Nursing education and international health in the United States, Latin America,
and the Caribbean.
AB - PURPOSE: To identify international health activities in United States, Latin
American, and Caribbean schools of nursing. In the international community,
nurses face challenges similar to those in related professions, but without the
benefit of a long tradition. There is little research about how nursing education
and associated activities prepare nurses to deal with international health, and
little information about the extent of international health activities in U.S.
schools of nursing. DESIGN: Descriptive. METHOD: Using a questionnaire with 16
items, a survey was conducted in 1995 on a random sample of representatives from
100 university schools of nursing in the United States plus 15 schools with known
international activities (10 from the United States and 5 from Latin America and
the Caribbean). FINDINGS: International health as a program topic was found in
one-third of U.S. schools of nursing. However, nursing curriculums do not
integrate international health with other subjects. Also, partnerships with
foreign institutions are incipient and international health activities are
usually individual initiatives with little institutional support. CONCLUSIONS:
For nurses to become major contributors to international health, nursing
curriculum content must shift from "international nursing" to "international
health." Programs of nursing education should include study of social, economic,
and political factors that affect health care systems. Schools should develop
partnership agreements.
PMID- 9549939
TI - Around-the-clock nursing care for the elderly in Japan.
AB - PURPOSE: To describe the first phase of creating a Japanese model of community
based long-term care, called around-the-clock care (ACC), by operationally
defining the components of ACC, identifying those eligible for the program,
clarifying methods of planning and organization, and exploring outcomes. DESIGN:
Exploratory evaluation for the population of frail elderly Japanese citizens
living at home. A convenience sample of 44 patients receiving care from four
visiting-nurse-service stations during 3 months in 1994 was used. METHODS: Needs
assessments; record reviews of patient encounters; evaluations by patients,
families, and visiting nurses; and reviews of administrative data. FINDINGS:
Nurses perceived that ACC stabilized medical status, reduced the emotional and
physical burden of treatment, and improved hygiene. It also reduced family
caregiving burdens and the stress of family caregivers' employment
responsibilities. The highest rating of ACC by patient and families was for those
with the most complex physical needs. Skilled nursing at home permitted early
identification and treatment of problems before they became crises or required
hospitalization. CONCLUSIONS: Early findings suggest 24-hour nurse-home helper
teamwork may be an effective system of community-based long-term care and should
be considered a key element of future Japanese health policy.
PMID- 9549940
TI - Quality health outcomes model. American Academy of Nursing Expert Panel on
Quality Health Care.
AB - PURPOSE: Donabedian's 1966 framework of structure, process, and outcome has
guided three decades of study in the United States of the elements needed to
evaluate and compare medical care quality. Donabedian's perspective was
essentially linear, assuming that structures affect processes, which in turn
affect outcomes. Patient characteristics are sometimes considered as mediating
outcomes and clinical interventions are considered to be processes. A model is
presented in the following article that relates multiple factors affecting
quality of care to desired outcomes. It extends previous models by positing
dynamic relationships with indicators that not only act upon, but reciprocally
affect the various components. SCOPE AND SOURCES: The proposed model was derived
from a synthesis of the authors' experience in quality of care practice and
research, as well as selected previous theories. CONCLUSIONS: The quality health
outcomes model is sufficiently broad (a) to guide development of databases for
quality improvement and outcomes management, (b) to suggest key variables in
clinical intervention research, and (c) to provide a framework for outcomes
research and outcomes management that compares not only treatment options, but
organizational or system level interventions. The model also has several policy
implications.
PMID- 9549941
TI - Review of the literature on falls among the elderly.
AB - PURPOSE: To review and summarize the literature from nursing, medical, and
ancillary fields on falls among the elderly. Major injuries from falls are
associated with mortality, especially among the elderly. Researchers indicate
that, in many cases, falls can be prevented. A summary of the available
literature provides information which can be used to plan interventions.
ORGANIZING FRAMEWORK: Over 100 publications, 1979-1996 related to falls by
elderly were reviewed. Descriptive terms used for searching MEDLINE were falls,
elderly, and accidents. Literature from several disciplines was reviewed.
FINDINGS: Fall risk can be predetermined and nursing actions can be taken to
reduce the occurrence and severity of falls. CONCLUSIONS: To reduce the
deleterious effects of falls in the elderly, knowledge-based practice is
essential.
PMID- 9549942
TI - New definition of mental retardation for the American Association of Mental
Retardation.
AB - PURPOSE: To describe the new definition of mental retardation developed by the
American Association of Mental Retardation (AAMR) published in 1992. The previous
definition was based on a deficiency model that identified "subaverage
intelligence" using an intelligence quotient (IQ) score equal to or less than 70.
The new definition places greater emphasis on adaptive skills and environmental
support needs. SCOPE: Defining mental retardation according to AAMR criteria
reflects a significant paradigm shift from an absolute trait to a functional
conception. The new definition is dynamic, attends to context, is inherently
holistic--and, therefore--closely aligned with nursing theory. Diagnosis is a
three-step process by which functional strengths and weaknesses are identified
along 4 dimensions and 10 adaptive-skill areas. Identification of needed supports
is incorporated within the three-step process. CONCLUSIONS: Nurses can enhance
holistic care by working to have AAMR's new definition adopted by government
legislators and administrators of state and county agencies that provide mental
retardation services. Nurses should become active participants as
interdisciplinary diagnostic team members as well as case managers. Nurse
researchers and educators can contribute toward further developing AAMR's
definition by standardizing assessment instruments, working to make diagnostic
procedures more user-friendly, and researching the construct validity of adaptive
skill areas. Finally, nurses should help legislators and policy makers understand
the sociocultural ramifications of AAMR's new definition.
PMID- 9549943
TI - Adapting to and managing diabetes.
AB - PURPOSE: To advance understanding of the lived experience of diabetes as
described in published research and theses. Meta-analysis extends the analysis of
individual research studies beyond individual experience to incorporate dominant
system beliefs and health system ideologies. ORGANIZING FRAMEWORK: Curtin and
Lubkin's (1990) conceptualization of the experience of chronic illness. SOURCES:
Forty-three qualitative interpretive research reports in six computerized data
bases 1980-1996 pertaining to the lived experience of diabetes and published in
nursing, in the social sciences, and in allied health journals were used.
METHODS: Meta-ethnography in which trustworthiness was achieved by using multiple
researchers, identifying negative or disconfirming cases, and testing rival
hypotheses FINDINGS: Balance is the determinant metaphor of the experience of
diabetes. People learn to balance diabetes through their experience and
experimentation with strategies for managing their illness. CONCLUSIONS: Learning
to balance is a developmental process in which one learns to assume control of
diabetes management. Support for such development requires that nurses know their
clients as individuals and value the expertise they have gained in living with
diabetes. Control of blood sugar levels within a prescribed range may be a goal
established by professionals, but the goal of healthy balance determines a
person's willingness to assume an active role in self-care.
PMID- 9549944
TI - Conceptualization and measurement of doing family caregiving well.
AB - PURPOSE: To review progress in the conceptualization and measurement of five
concepts related to doing family caregiving well: caregiving mastery, self
efficacy, competence, preparedness, and quality. Families are increasingly
involved in providing complex care to ill or aged family members at home. Their
ability to do caregiving well is vitally important and a focus of nursing
practice in many clinical settings. ORGANIZING FRAMEWORK: Concepts were organized
into two groups: those that refer to caregivers' perceptions of how well they are
providing care and those that refer to professional assessment of the quality of
care provided. SOURCES: Family caregiving literature from nursing, gerontology,
psychology, and social work, 1987-1996. FINDINGS: There is growing interest in
doing family caregiving well. However, research in this area is limited by the
current state of development of ideas and measures. CONCLUSIONS: Two issues that
should be addressed to advance research are the perspective taken on doing
caregiving well and change over time in doing caregiving well.
PMID- 9549945
TI - Nursing model of hospitalization events.
AB - PURPOSE: To provide a model of hospitalization events from a nursing perspective.
Hospitalization has become an event of highly technical care coupled with intense
nursing care requirements. This proposed model is needed to support clinical
nursing research among hospitalized patients. SCOPE: Hospitalization occupying
space and time as a discrete event on the health-illness continuum. First
developed to provide a framework for a descriptive study, the model shows the
factors involved in hospitalization and provides a framework for understanding
the nursing care that occurs. Selected results from descriptive research that
used patients hospitalized with AIDS as subjects are reported as an example of
use of the model. CONCLUSIONS: Research about hospitalization events continues to
be critical for the advancement of clinical nursing. This model is presented to
provide a conceptual framework for future research.
PMID- 9549946
TI - Using literature to create cultural competence.
AB - PURPOSE: To describe how literature can be used to promote cultural competence.
Cultural competence is essential for nurses who practice in diverse societies
like the United States. ORGANIZING FRAMEWORK: Cultural competence is viewed as a
dynamic process of framing assumptions, knowledge, and meanings from a culture
other than one's own. Selected excerpts from "The Color Purple" by Alice Walker
are used to illustrate the method. Isler's readers' response theory serves as a
guide for imaginative engagement and reflective discussion of the concept of
health. CONCLUSIONS: Literature helps to dispel the false notion of a monolithic
culture. Reflecting on reputable literature helps us hear the stories of those we
hope to help and heal.
PMID- 9549947
TI - Professional, ethical, and legal implications for spiritual care in nursing.
AB - PURPOSE: To highlight nurses' professional and ethical responsibility to
consistently provide spiritual care. The legal issue of nurse-client privilege in
relation to spiritual care is also discussed. Spiritual care is consistent with
the model of holistic care. Yet spiritual care often remains a neglected focus of
current nursing practice. CONCLUSIONS: Spirituality, as an important aspect of
wellness, is indispensable in nursing care. Nurses are obligated to take an
active role in meeting the spiritual needs of patients.
PMID- 9549948
TI - Nurses, indirect trauma, and prevention.
AB - PURPOSE: To begin examining the nature of vicarious or indirect trauma and to
discuss risk factors and prevention strategies. Despite the fact that many nurses
are traumatized indirectly, few recognize the insidious development of such
trauma. The dynamics of indirect trauma are relevant to nursing as are risk
factors and prevention strategies. SCOPE: Brief review of the literature (1974
1997) on vicarious trauma, compassion fatigue, secondary traumatic stress
disorder, and traumatic countertransference using short vignettes for
illustration. CONCLUSION: Nurses who are informed about vicarious trauma and who
actively maintain a balanced personal and professional life are in the best
position to bring themselves and their clients through the many hazards of trauma
work. The implications of vicarious or indirect trauma for nurses and clients are
serious and complex requiring thoughtful analysis and research to clarify its
effects.
PMID- 9549949
TI - Definition of ADHD.
PMID- 9549950
TI - Medication for learning disorders.
PMID- 9549952
TI - Stimulant use and trichotillomania.
PMID- 9549953
TI - Obsessive-compulsive disorder and separation anxiety.
PMID- 9549951
TI - Mania in young children.
PMID- 9549954
TI - Anorexia nervosa and bulimia nervosa in children and adolescents: a review of the
past 10 years.
AB - OBJECTIVE: To critically review the research in juvenile anorexia nervosa and
bulimia nervosa over the past 10 years and highlight recent advances in normal
development as it pertains to these disorders and their diagnosis, prevention,
and treatment. METHOD: Computerized search methods were combined with manual
searches of the literature. A detailed review of the most salient articles is
provided. Preference was given to studies involving children and adolescents that
approached the subject from a developmental perspective. RESULTS: The information
from these studies is presented in a developmental framework. Research in eating
disorders has progressed, but definitive longitudinal data are still absent from
the literature. Research specific to treatment of child and adolescent eating
disorders remains rare. CONCLUSIONS: Data approaching eating disorders from a
developmental perspective are available in only a few studies. Research is needed
addressing normative data on the development of eating behavior and specific risk
and resilience factors for pathology in specific developmental periods.
Especially lacking are studies regarding the continuities and discontinuities of
eating disturbances across the life span. Best documented are epidemiological
studies of prevalence and incidence, long-term outcome in anorexia nervosa, and
short-term treatment response in bulimia.
PMID- 9549955
TI - Commentary: unmasked and uncontrolled medication trials in child and adolescent
psychiatry.
PMID- 9549956
TI - An open clinical trial of buspirone in children with attention
deficit/hyperactivity disorder.
PMID- 9549957
TI - An open trial of risperidone in young autistic children.
AB - OBJECTIVE: To assess the benefits and side effects of risperidone in young
autistic children. METHOD: In this open, prospective trial, subjects were treated
with risperidone for 12 weeks. All subjects were started at 0.5 mg daily with
individual titration to a maximum of 6 mg or 0.1 mg/kg daily. Behavioral ratings,
completed by the investigators and the children's parents, included the Clinical
Global Impressions (CGI), Children's Psychiatric Rating Scale, Conners Parent
Teacher Questionnaire, Childhood Autism Rating Scale, and Abnormal Involuntary
Movement Scale. RESULTS: Ten boys, aged 4.5 to 10.8 years, were enrolled in the
study and all completed the 12-week protocol. The mean final dose was 1.3 mg/day
(range = 1 to 2.5 mg/day). On the basis of CGI-rated improvement, 8 of the 10
children were considered to be responders. Improvement was also demonstrated on
the other scales. Transient sedation was common, and the children gained an
average of 3.5 kg over the 12 weeks of the study. There was no evidence of either
extrapyramidal symptoms or tardive dyskinesia. CONCLUSIONS: These results suggest
that risperidone may be safe and leads to improvements in several behavioral
symptoms in young children with autism. Controlled studies of risperidone in
young autistic children are warranted.
PMID- 9549958
TI - Childhood-onset schizophrenia: an open-label study of olanzapine in adolescents.
AB - OBJECTIVE: Olanzapine, a potent 5-HT2a/2c, dopamine D1D2D4 antagonist with
anticholinergic activity, has a profile of known receptor affinity similar to
that of clozapine. This pilot study examined the efficacy of olanzapine for
treatment-refractory childhood-onset schizophrenia in eight patients who had
received 8-week open-label trials. For comparison, data are included from 15
patients who had received 6-week open-label clozapine trials using identical
rating instruments (largely by the same raters) in the same treatment setting.
METHOD: Twenty-three children and adolescents with an onset of DSM-III-R
schizophrenia by age 12 for whom at least two different typical neuroleptics had
been ineffective participated in the two separate studies. Some of the patients
were intolerant of clozapine, although it had been effective (n = 4). Patients
receiving olanzapine were evaluated over 8 weeks with the Brief Psychiatric
Rating Scale (BPRS), the Scale for the Assessment of Positive Symptoms, the Scale
for the Assessment of Negative Symptoms, and the Clinical Global Impressions
Scale for Improvement. RESULTS: For the eight patients who received olanzapine
trials, at week 8 there was a 17% improvement in the BPRS total score, a 27%
improvement in the Scale for the Assessment of Negative Symptoms, and a 1%
improvement in the Scale for the Assessment of Positive Symptoms, relative to
"ideal" admission status on typical neuroleptics. In contrast, the magnitude of
the effect sizes for each of the clinical ratings was larger at week 6 of the
previous clozapine trial than for an 8-week olanzapine trial, relative to
admission status on typical neuroleptics. For the four children who had received
both clozapine and olanzapine, BPRS total scores were significantly lower at week
6 of clozapine treatment compared with week 6 of olanzapine treatment (p = .03).
CONCLUSION: These data provide preliminary evidence for the efficacy of
olanzapine for some children and adolescents with treatment-refractory
schizophrenia, but they also suggest the need for a more rigorous double-blind
comparison of these two atypical antipsychotics.
PMID- 9549959
TI - Sertraline treatment of children and adolescents with obsessive-compulsive
disorder or depression: pharmacokinetics, tolerability, and efficacy.
AB - OBJECTIVE: To evaluate the pharmacokinetics, safety, and efficacy of sertraline
in children (6 to 12 years old) and adolescents (13 to 17 years old). METHOD:
Children (n = 29) and adolescents (n = 32) with major depression, obsessive
compulsive disorder (OCD), or both received a single dose of 50 mg of sertraline
followed, 1 week later, by 35 days of sertraline treatment as follows: (1) either
a starting dose of 25 mg/day titrated to 200 mg/day in 25-mg increments or (2) a
starting dose of 50 mg/day titrated to 200 mg/day in 50-mg increments. Sertraline
and desmethylsertraline pharmacokinetics were determined approximately weekly,
and efficacy measures were assessed before drug administration and at the end of
treatment. RESULTS: Mean area under the plasma concentration-time curve (AUC),
peak plasma concentration (Cmax), and elimination half-life (t1/2) for sertraline
and desmethylsertraline were similar to previously reported adult values. No
titration-dependent pharmacokinetic or safety differences were seen. While Cmax
and AUC0-24 were greater for children versus adolescents, these differences
disappeared after parameters were normalized for body weight. Sertraline was well
tolerated in both children and adolescents, with adverse experiences similar to
those previously reported by adult patients. Efficacy measurements indicated
improvement (p < .001) in depression and OCD symptomatology. CONCLUSIONS:
Sertraline can be safely administered to pediatric patients using the currently
recommended adult titration schedule.
PMID- 9549960
TI - Cognitive-behavioral treatment of school-refusing children: a controlled
evaluation.
AB - OBJECTIVE: To evaluate the efficacy of a 4-week cognitive-behavioral treatment
program for children who refuse to go to school. METHOD: Thirty-four school
refusing children (aged 5 to 15 years) were randomly assigned to a cognitive
behavioral treatment condition or a waiting-list control condition. Treatment
consisted of individual child cognitive-behavioral therapy plus parent/teacher
training in child behavior management skills. Measures taken before and after
treatment included school attendance, child self-report of emotional distress and
coping, caregiver reports on emotional and behavioral problems, and clinician
ratings of global functioning. RESULTS: Relative to waiting-list controls,
children who received cognitive-behavioral therapy exhibited a significant
improvement in school attendance. These children also improved on self-reports of
fear, anxiety, depression, and coping. Significant improvements also occurred in
relation to caregiver reports and clinician ratings. Maintenance of therapeutic
gains was demonstrated at a 3-month follow-up assessment. CONCLUSIONS: Cognitive
behavioral treatment of school refusal was efficacious and acceptable. The
relative contributions of child therapy and parent/teacher training require
further study.
PMID- 9549961
TI - Cognitive-behavioral treatment of school phobia.
AB - OBJECTIVE: To conduct a controlled group outcome investigation of the efficacy of
cognitive-behavioral treatment for school phobia. METHOD: Fifty-six children with
school phobia were randomly assigned to 12 weeks of cognitive-behavioral therapy
or an attention-placebo control condition. Pre- and posttreatment school
attendance, self-reported anxiety and depression, and diagnostic status were
compared. RESULTS: Both the experimental and control treatments were equally
effective at returning children to school. Both treatments also were effective in
reducing children's anxiety and depressive symptoms. Follow-up revealed no
differences between groups when the children reentered school the next school
year. CONCLUSIONS: Overall, results suggest that psychosocial treatments are
effective at returning school-phobic children to school and that the highly
structured cognitive-behavioral approach may not be superior to more traditional
educational and supportive treatment methods.
PMID- 9549962
TI - Cognitive-behavioral treatment of pediatric obsessive-compulsive disorder: an
open clinical trial.
AB - OBJECTIVE: The purpose of this open clinical trial was to examine the efficacy of
cognitive-behavioral treatment involving exposure and ritual prevention for
pediatric obsessive-compulsive disorder (OCD). METHOD: Children and adolescents
with diagnosed OCD (N = 14) received cognitive-behavioral treatment, seven
patients received intensive treatment (mean = 18 sessions over 1 month) and seven
received weekly treatment (mean = 16 sessions over 4 months). Eight of these
patients received concurrent treatment with serotonin reuptake inhibitors and six
received cognitive-behavioral treatment alone. Outcome was assessed via
interviewer ratings on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS),
Obsessive Compulsive Rating Scales for Main Fear and Main Ritual, and Hamilton
Depression Rating Scale. RESULTS: Cognitive-behavioral treatment was effective in
ameliorating OCD symptoms. Twelve of the 14 patients were at least 50% improved
over pretreatment Y-BOCS severity, and the vast majority remained improved at
follow-up; mean reduction in Y-BOCS was 67% at posttreatment and 62% at follow-up
(mean time to follow-up = 9 months). CONCLUSIONS: Results suggest that cognitive
behavioral treatment by exposure and ritual prevention is effective for pediatric
OCD. Controlled studies with random assignment to conditions are warranted to
evaluate the relative efficacy of cognitive-behavioral pharmacological, and
combined treatments.
PMID- 9549963
TI - Is juvenile obsessive-compulsive disorder a developmental subtype of the
disorder? A review of the pediatric literature.
AB - OBJECTIVE: To examine the clinical correlates of obsessive-compulsive disorder
(OCD) in children and adolescents. METHOD: A systematic review of the extant
literature on juvenile OCD was conducted examining age at onset, gender
distribution, symptom phenomenology, psychiatric comorbidity, neurological and
perinatal history, family psychiatric history, cognitive and neuropsychological
profiles, and treatment and outcome in juvenile OCD subjects. RESULTS: Juvenile
OCD was associated with a unique peak of age at onset indicating a bimodal
incidence of the disorder, male preponderance, a distinct pattern of comorbidity
with attention-deficit/hyperactivity disorder and other developmental disorders
as well as frequent associated neuropsychological deficits, an increased familial
loading for OCD, and frequent absence of insight. CONCLUSION: These findings show
that juvenile OCD is associated with a unique set of correlates that appear to
differ from findings reported in studies of adult OCD subjects. Although in need
of confirmation, these findings suggest that juvenile OCD may be a developmental
subtype of the disorder. Since juvenile OCD is likely to continue into adulthood,
these findings stress the importance of considering age at onset in clinical and
research studies of adults with OCD.
PMID- 9549964
TI - Individual and familial predictors of impairment in childhood anxiety disorders.
AB - OBJECTIVE: To determine which correlates of childhood anxiety disorders are
predictive of impaired functioning as judged by clinicians. METHOD: Seventy-four
families of children with anxiety disorders attending a hospital outpatient
clinic completed questionnaires measuring child symptoms of anxiety and
depression, maternal psychopathology, maternal ratings of child psychopathology,
and developmental and environmental difficulties. Clinicians completed the Global
Assessment of Functioning (GAF) for each child, and correlations between it and
the other measures were ascertained. RESULTS: Maternal ratings of child conduct
problems, child symptoms of depression, maternal phobic anxiety, developmental
difficulties, and psychosocial adversity were significantly correlated with GAF.
Results of a multiple regression analysis revealed that these variables accounted
for 25% of the variance in GAF scores. The first four variables were significant
predictors of impairment in children with phobic disorders. Psychosocial
adversity was the only significant predictor of impairment in children with
generalized anxiety disorder. CONCLUSIONS: In addition to child depression and
developmental or psychosocial adversity, impairment in childhood anxiety
disorders appears to be related to parental anxiety and behavior management
difficulties, particularly in phobic disorders. Addressing the latter factors may
enhance treatment efficacy.
PMID- 9549965
TI - Validity of DSM-IV subtypes of conduct disorder based on age of onset.
AB - OBJECTIVE: To present data from the DSM-IV field trials that led to the
distinction between subtypes of conduct disorder (CD) that emerge in childhood or
adolescence. In addition, data from a household sample were used to attempt to
cross-validate these findings. METHOD: Differences between youths who met
criteria for the two subtypes of CD were examined in the field trials sample of
440 youths aged 4 through 17 years and in a household sample of 1,285 youths aged
9 through 17 years. RESULTS: In both samples, there was a steep decline in
aggression occurring around an age of onset of 10 years, but the number of
nonaggressive behaviors was unrelated to the age of onset of CD. In the field
trials sample, youths who met criteria for the adolescent-onset type were more
likely to be girls, less likely to meet criteria for oppositional defiant
disorder, and less likely to have a family history of antisocial behavior than
the childhood-onset type, but these latter findings were not confirmed in the
household sample. CONCLUSIONS: The DSM-IV approach to subtyping CD distinguishes
subgroups that differ markedly in level of physical aggression. The advantages of
a developmental approach to subtyping are discussed.
PMID- 9549966
TI - Case study: behavioral treatment of obsessive-compulsive disorder in a boy with
comorbid disruptive behavior problems.
AB - Comorbid psychiatric conditions often complicate the treatment of childhood
obsessive-compulsive disorder (OCD). Behavioral treatment of OCD using exposure
plus response prevention for a boy with disruptive behavior disorders and two
previous unsuccessful medication trials is described. Treatment was adapted to
his developmental level, his mother was highly involved in treatment, and a
contingency management program contained his disruptive behavior so that he could
participate in therapy. Posttreatment and 2- and 6-month follow-up measures
indicated marked improvement in OCD symptoms. The possibility of successful
behavioral treatment of OCD in medication-free children with disruptive behavior
problems is highlighted.
PMID- 9549967
TI - Cytochromes: a primer for child and adolescent psychiatrists.
PMID- 9549968
TI - Development of the cerebral cortex: IV. Transcription factors.
PMID- 9549969
TI - CDC reports first-ever decline in AIDS diagnoses--treatment and prevention
advances spur new trend.
PMID- 9549970
TI - Instilling happiness into medical school. The University of Arkansas College of
Medicine's Medical Student Mental Health Program.
AB - The University of Arkansas for Medical Sciences (UAMS), College of Medicine's
Medical Student Mental Health Services Program, initiated in 1992, has grown into
a comprehensive, readily accepted service utilized by one out of four medical
students during their matriculation. Students rely on the service to help them
with a wide variety of issues and feel secure that their care is confidential.
PMID- 9549971
TI - Cardiac AL-amyloidosis in multiple myeloma.
PMID- 9549972
TI - Radiological case of the month. Adrenal adenoma.
PMID- 9549973
TI - Tumor necrosis factor alpha.
PMID- 9549974
TI - Acanthosis, albumin, and cancer.
PMID- 9549975
TI - Teenage pregnancy.
PMID- 9549976
TI - Intra-aortic balloon pump: indications and complications.
AB - Results obtained with intra-aortic balloon pumps (IABPs) at Harbor-UCLA Medical
Center from 1990 to 1995 were reviewed to analyze the indications for its use as
well as the incidence and types of vascular complications that occurred. Of 86
patients (53 men and 33 women) in whom pumps were used, 66 underwent coronary
bypass, 14 underwent valve replacement, and 6 underwent both coronary
bypass/valve replacement. Thirteen (15%) deaths occurred (8 coronary bypass
patients, 4 valve replacement patients, and 1 coronary bypass/valve replacement
patient). The indications for IABP were broadly classified as prophylactic or
inability to wean. Prophylactic IABP placement preoperatively occurred in 35
(41%) patients for profound ventricular dysfunction (27 patients), compelling
coronary anatomy including critical left main disease (7 patients), and unstable
angina (1 patient). Inability to wean occurred in 51 (59%) patients. Three
patients (3.5%) developed major vascular complications resulting in limb
ischemia. All three underwent thrombectomies, fasciotomies, and above-knee
amputations; two patients subsequently died. Vascular reconstruction was
performed in two patients as a direct result of their vascular process. All three
vascular complications occurred in women. Besides gender, there was no difference
between IABP patients with or without vascular complications in terms of age or
presence of diabetes, hypertension, smoking history, obesity, or known peripheral
vascular disease. These results indicate that IABPs are effective both
prophylactically and intraoperatively in patients who would not otherwise survive
cardiac surgery.
PMID- 9549977
TI - The recruitment triangle: reasons why African Americans enroll, refuse to enroll,
or voluntarily withdraw from a clinical trial. An interim report from the African
American Antiplatelet Stroke Prevention Study (AAASPS).
AB - Recruitment and retention of study subjects are key to the success of a clinical
trial. In the case of minority patients, this may be challenging as minority
patients have been underserved by the medical health-care system. Furthermore,
minority patients are more likely to experience barriers to entry into a clinical
trial such as mistrust of the medical system, economic disadvantages, lack of
awareness of study programs, and communication barriers. An open-ended
questionnaire was used to determine reasons why subjects in the African-American
Antiplatelet Stroke Prevention Study (AAASPS) remained in the study or
voluntarily withdrew in the absence of an adverse event. Potential enrollees who
refused to participate in the AAASPS also were queried. Enrollees who remained in
the program consistently stated that they participated to reduce the risk of
stroke recurrence and to help others by finding a "cure" for stroke. Those who
withdrew or refused to participate consistently stated that they were afraid of
being used as "guinea pigs." A "recruitment triangle" emerged that might predict
a patient's likelihood of participation in a clinical trial. The sides of the
triangle include the patient, key family members and friends, and the primary
medical doctor and other medical personnel. The organizers of a clinical trial
need to be aware of the "recruitment triangle" and establish strategies to
heighten and maintain its integrity.
PMID- 9549978
TI - Diabetes mellitus and its complications in an African-American community: project
DIRECT.
AB - Project DIRECT (Diabetes Intervention Reaching and Educating Communities
Together) is a multilevel community-based intervention project designed to
address diabetes and its complications in an African-American community. This
article presents results of the Project DIRECT pilot study and describes risk
factors for diabetes, diabetes prevalence, complications, and care practices.
During 1993, a pilot study was conducted among persons 20 to 74 years of age in
Wake County, North Carolina. The study involved household interviews and
examinations, and more extensive health center interviews and examinations based
on the race of the head of the household, previous diagnosis of diabetes, and
results of capillary glucose tests done in the household. Of the black population
aged 20 to 74 years, 52 +/- 3% reported being inactive and 51 +/- 3% were
overweight; the prevalence of diagnosed diabetes was 5.2 +/- 0.9%; the prevalence
of undiagnosed diabetes was 5.7 +/- 2.7%; and the prevalence of impaired glucose
tolerance was 11.4 +/- 7.5%. Blacks with diabetes were significantly more likely
than nonblacks with diabetes to have uncontrolled hypertension and to smoke
cigarettes. Blacks with diabetes were significantly less likely to report having
health insurance or to have a private health-care provider. Diabetes mellitus is
a major public health problem in the African-American community of Wake County.
Modifiable risk factors for diabetes and undiagnosed diabetes are common. Project
DIRECT is attempting to improve the health-related quality of life of this
population by reducing the burden of diabetes and its complications through a
multilevel, community-based intervention.
PMID- 9549979
TI - Increased circulating levels of soluble HLA class I heterodimers in patients with
sickle cell disease.
AB - This study examined the presence of a persistent state of low-grade inflammation
in sickle cell anemia patients by measuring circulating sHLA-I heterodimers and C
reactive protein during the steady state and after recent crises. Thirty-nine
pediatric sickle hemoglobinopathy patients were studied during the steady state
and 11 patients were evaluated within 1 month of a painful crisis. A disease
severity score was generated for each patient, and soluble HLA-I (sHLA-I) and C
reactive protein levels were determined. Soluble HLA-I was significantly elevated
in 55% of the steady-state group and in 36% of the recent-crisis group. The
percentage of patients with elevated sHLA-I differed in the various disease
subgroups in the steady state: 46% of Hb SS patients, 70% of Hb SC patients, 75%
of Hb S beta-thal patients, and 20% of Hb SSF patients. Steady-state and recent
crisis sHLA-I levels were not significantly different. C-reactive protein levels
were elevated in 11% of steady-state patients and in 9% of recent-crisis
patients. Soluble HLA-I levels did not correlate with C-reactive protein levels
or disease severity score, age, hemoglobin, reticulocyte count, platelet count,
or white cell count. These results show that the majority of sickle
hemoglobinopathy patients have elevated sHLA-I levels during the steady state and
after recent crisis, suggesting the presence of chronic inflammation during the
steady state.
PMID- 9549981
TI - Measurement of self-esteem in repeat assault victims.
AB - Background characterization of assault-related injuries have demonstrated that
lifestyle, substance abuse, education, employment, mental illness, and high-risk
behavior contribute to low self-esteem in repeat assault victims. Recurrent
assault patients have never been studied with respect to self-esteem. This study
evaluated self-esteem and assault-related injury in 28 consecutive male assault
patients (11 first-assault and 17 recurrent-assault patients) and 19 controls
with no previous assault history. Study participants were administered the Walmyr
Assessment Scales Index of Self-Esteem (WASISE) as part of a three-item survey to
determine the relationship between self-esteem and assault-related injury. No
demographic differences were found between the groups. The mean (+/- standard
error) WASISE score for recurrent-assault patients (34.9 +/- 3.4) was
significantly higher than mean scores for no-assault and first-time assault
injured patients (14.7 +/- 1.4 and 15.0 +/- 2.3, respectively). The recurrent
assault patients had a lower mean education level than both no-assault and first
time assault-injured patients (2.1 +/- 0.26 and 1.9 +/- 0.57, respectively).
Eighteen (2%) first-time assault-injured and 11 (7%) recurrent-assault patients
were employed. These data suggest that self-esteem, education, and employment
history need to be considered when evaluating and developing interventions for
repeat-assault patients.
PMID- 9549980
TI - Cultural sensitivity and readability of breast and prostate printed cancer
education materials targeting African Americans.
AB - Cancer prevention materials such as pamphlets, booklets, and fact sheets play a
significant role in reducing cancer disparities. Little is documented in the
literature about the cultural sensitivity of materials targeting African
Americans. The Cancer Prevention Materials and African Americans project was
conducted to assess the cultural sensitivity and readability of printed cancer
education materials targeting African Americans. Results showed current breast
and cancer materials are not written at appropriate reading levels, and only 54%
of the breast and 40% of the prostate cancer materials were found to be
culturally sensitive. Even though the materials are being developed and
disseminated in health fairs, physician offices, barber shops, and other
locations, the materials are still not reflective of the African-American
populations and do not consider literacy, visual, written messages, and format as
factors in their utilization. Future studies should assess the appropriateness of
materials for African Americans to promote and prevent cancer in African
Americans.
PMID- 9549983
TI - Fiberoptic bronchoscopic removal of intratracheal pledgetted repair sutures.
AB - This article describes the use of a flexible bronchoscope to remove pledgetted
repair sutures within the trachea. The use of a flexible scope to remove densely
adherent material is difficult but occasionally necessary.
PMID- 9549982
TI - Postpartum surveillance of bacteriuria in term vaginal deliveries.
AB - This study examined the prevalence of bacteriuria in early postpartum period
after term vaginal delivery in Trinidad, West Indies. Asymptomatic bacteriuria
occurred in 58 (34.5%) of 168 patients tested. The prevalence of bacteriuria was
significantly higher in non-catheterized patients than in catheterized patients
and occurred more commonly in patients who were 20 to 29 years old and who were
primigravida rather than multigravida. Forty-four patients had a history of
urinary tract infection; 18 (40.9%) of these patients had positive urine
cultures. Although 10 patients had a vaginal discharge in the late third
trimester, none presented with postpartum bacteriuria. Because of the high
prevalence of postpartum bacteriuria and the potential to progress to
pyelonephritis and chronic renal disease, quantitative urine cultures for all
postnatal patients and curative treatment for all positive cultures are
recommend.
PMID- 9549984
TI - A look at oral health within the context of diverse populations: foreword.
PMID- 9549985
TI - Ethnicity, aging, and oral health outcomes: a conceptual framework.
AB - An expanded version of Andersen's Behavioral Model of Health Services Utilization
is used as the theoretical and analytical framework for the International
Collaborative Study of Oral Health Outcomes (ICS-II). The conceptual framework
for understanding determinants of oral health is based on a "systems"
perspective. The framework posits that characteristics of the external
environment, the dental care delivery system, and the personal characteristics of
the population influence oral health behaviors. The expanded behavioral model
conceptualizes health behaviors (oral hygiene practices and dental services
utilization) as intermediate dependent variables, which in turn influence oral
health outcomes (evaluated, perceived, patient satisfaction). The framework is
presented with an increased focus on the effects of race-ethnicity and age
cohort, the major exogenous variables used in this study for systematic
assessment of the differences in the multitude of factors influencing oral
health. The framework can be applied by policy analysis and health services
managers to help describe, predict, and explain population-based health behaviors
and health outcomes.
PMID- 9549986
TI - ICS-II USA research locations: environmental, dental care delivery system, and
population sociodemographic characteristics.
AB - Secondary data sources are used to describe the ICS-II USA research locations in
terms of external environment, dental care delivery system, and population
sociodemographics. The Native American reservations located in Arizona, New
Mexico, and South Dakota were rural, while the other research locations were
primarily urban. Baltimore, Maryland, and the Native American communities had
fluoridated water, but San Antonio did not. Dental services in Baltimore and San
Antonio were predominantly financed by private sources, with a small public
health component. Dental care services in Native American communities were
largely Indian Health Services (IHS) financed by the US Government. Each
geographical area exhibited diverse characteristics indicating unique challenges
for the delivery of community and clinical dental services.
PMID- 9549987
TI - ICS-II USA research design and methodology.
AB - The purpose of the WHO-sponsored International Collaborative Study of Oral Health
Outcomes (ICS-II) was to provide policy-markers and researchers with detailed,
reliable, and valid data on the oral health situation in their countries or
regions, together with comparative data from other dental care delivery systems.
ICS-II used a cross-sectional design with no explicit control groups or
experimental interventions. A standardized methodology was developed and tested
for collecting and analyzing epidemiological, sociocultural, economic, and
delivery system data. Respondent information was obtained by household
interviews, and clinical examinations were conducted by calibrated oral
epidemiologists. Discussed are the sampling design characteristics for the USA
research locations, response rates, samples size for interview and oral
examination data, weighting procedures, and statistical methods. SUDAAN was used
to adjust variance calculations, since complex sampling designs were used.
PMID- 9549988
TI - Predisposing, enabling, and need for dental treatment characteristics of ICS-II
USA ethnically diverse groups.
AB - Personal characteristics (predisposing, enabling, and need) are described for the
population-based samples of adults interviewed in the International Collaborative
Study of Oral Health Outcomes (ICS-II) USA research locations. Differences in
sample characteristics are compared by ethnic group (African-American, Native
American, Hispanic, and White) and age cohort (35-44 and 65-74 years old) by
means of Bonferroni multiple-means tests and Student's t tests. Differences in
the personal characteristics of these diverse comparison groups abound. Bivariate
results indicated that White adults from both age cohorts had higher
socioeconomic levels, more positive self-rated health status, and greater
proportions of individuals with dental benefits. Lakota adults from both age
cohorts reported lower self-rated health status and were most likely to report
total tooth loss. Hispanic persons were significantly less likely to report a
usual source of dental care or dental benefits. Need for dental treatment (oral
pain and oral symptoms index) was generally higher amng Native American and
Hispanic groups. It is critical that the differences highlighted between the
among these groups be studied in appropriate strategies for improving the oral
health of USA adults are to be determined.
PMID- 9549989
TI - Oral health beliefs in diverse populations.
AB - Using data from population-based samples of adults participating in the ICS-II
USA study, and using principal components analysis, we constructed oral health
belief measures corresponding to the Health Belief Model (HBM) dimensions. Tests
of validity and reliability were performed. Scales measuring perceived benefit of
preventive practices and seriousness of oral disease had the highest validity and
reliability. We used multiple regression analysis to examine sociodemographic
predictors of perceived benefits of preventive practices. Race-ethnicity and age
cohort were significant predictors among Baltimore and San Antonio adults. White
adults and middle-aged persons in both research locations were more likely to
believe in the benefit of preventive practices. Female gender, higher educational
attainment, and better self-rated health were significant indicators of more
positive oral health beliefs in every research location. Results also
characterize persons who place lower value on preventive practices (i.e., males,
less-educated persons, and those reporting poorer self-rated health). The design
of effective dental public health messages and outreach efforts requires an
analysis of the individual's health orientation and the factors influencing oral
health beliefs. Oral health education interventions designed to improve health
beliefs should contain an evaluation component for assessing the impact of
education on health practices and oral health status.
PMID- 9549990
TI - Socio-behavioral determinants of oral hygiene practices among USA ethnic and age
groups.
AB - In this study, socio-behavioral determinants of oral hygiene practices were
examined across several dentate ethnic and age groups. Oral hygiene scale scores
were constructed from toothbrushing and dental floss frequencies self-reported by
population-based samples of middle-aged (35-44 years) and older (65-74 years)
dentate adults representing Baltimore African-American and White, San Antonio
Hispanic and non-Hispanic White, and Navajo and Lakota Native American persons
participating in the WHO International Collaborative Study of Oral Health
Outcomes (ICS-II) survey. Female gender, education, certain oral health beliefs,
household income, and the presence of a usual source of care were revealed with
multivariate analysis to show a significant positive relationship with higher
oral hygiene scale scores (indicating better personal oral hygiene practices).
Other socio-behavioral variables exhibited a more varied, ethnic-specific pattern
of association with oral hygiene scale scores.
PMID- 9549991
TI - Determinants of dental care utilization for diverse ethnic and age groups.
AB - Dental services utilization in the past 12 months was compared across population
based samples of African-American, Navajo, Lakota, Hispanic, and White adults
participating in the WHO International Collaborative Study of Oral Health
Outcomes (ICS-II) at USA research locations. Bivariate results revealed that
ethnic minority groups in both age cohorts reported significantly fewer dental
visits in the past 12 months compared with White adults. When dentate status was
controlled for, age cohort differences were not significant in Baltimore (African
American and White) and San Antonio (Hispanic and White) research locations. In
contrast, older Native Americans (65-74 years) reported visiting the dentist
significantly less often compared with their middle-aged (35-44 years)
counterparts. Multivariate results indicated that generalizable variables were
associated with dental contact in every ICS-II USA ethnic group (i.e., dentate,
usual source of dental care, oral pain). Among the diverse ethnic groups, other
determinants presented a varied pattern of risk factors for underutilizing dental
care. Information on ethnic-specific risk factors can be used to design
culturally appropriate and acceptable oral health promotion programs.
Generalizable risk factors across ethnic groups inform oral health policy-makers
about changing national priorities for promoting oral health.
PMID- 9549992
TI - Clinical measures and treatment needs.
AB - Clinically evaluated oral health outcome variables from the ICS-II USA data set
were examined in the diverse ethnic groups, for two adult age cohorts (35-44 and
65-74 years). These measures were derived from epidemiological examinations and
include the DMFT components, loss of attachment, and an indicator of treatment
need--the ratio of decayed teeth over decayed and filled teeth. The ratio of
decayed over decayed and filled teeth was used in multivariate analysis, since
this measure represents an area where public policy could have an impact if
determinants were understood. The most important independent variables were race
ethnicity, educational attainment, no fear of dental visits because of pain, and
oral hygiene practices. Having a usual source of dental care and visiting the
dentist within the past 12 months did not appear to be as important in predicting
unmet needs as these other variables. To bridge the gap between the oral health
status of majority and minority populations, health educators in minority
communities need to become more accessible, have a pro-active interest in oral
health, and also be cognizant of the various socio-cultural issues influencing
oral health. The problems regarding Native American adults are more complex and
require more careful study.
PMID- 9549993
TI - Perceived oral health in a diverse sample.
AB - Measures of perceived oral health represent subjective, individual perspective of
one's health. One measure commonly used is the single-item perceived oral health
rating: How would you rate your overall oral health? These analyses examine the
associations among age, ethnicity, and perceived oral health within the context
of a comprehensive battery of 21 predisposing, enabling, and need variables. The
study of compares the adult data from three United States research locations of
the International Collaborative Study of Oral Health Outcomes (ICS-II). Only
social survey data were used for this analysis. The multiple regression model
explains over 30% of the variance in perceived oral health, with R squares
ranging from 0.324 for Indian Health Service sites to 0.391 for San Antonio. The
most important significant predictors include ethnic group, education, perceived
general health status, being edentulous or not having a partial denture, having
no oral pain, fewer oral symptoms, and having one or more dental visits. The
predictors of positive perceived oral health for the diverse groups highlight
interesting age and ethnic differences. The only universal predictor for the
middle-aged adults was having fewer oral symptoms. For the older adults, being
edentulous or not having a partial denture was the only universal predictor. The
findings suggest that perceived oral health may be a useful outcome measure in
dentistry because of its relation to predisposing sociodemographics and dental
utilization.
PMID- 9549994
TI - Consumer satisfaction.
AB - Patient satisfaction with dental care is compared across six United States
groups: Whites in Baltimore and San Antonio, African-Americans in Baltimore,
Hispanics in San Antonio, and Native Americans in the Southwest and the Dakotas.
First, differences in patient satisfaction across ethnic groups and between two
age groups (65-74 years old and 35-44 years old) are considered. Generally,
people from all age and ethnic groups were satisfied with the last dental visit.
Second, patient satisfaction is conceptualized as an oral health outcome
influenced by characteristics of the dental service utilizer: predisposing
sociodemographic characteristics, predisposing oral beliefs, enabling
characteristics, oral needs, oral health behaviors, and oral health status.
Multivariate analyses by age and ethnic group are used to identify
characteristics that influence patient satisfaction. Sociodemographic
characteristics were important among the elderly. Strong oral health beliefs
influenced patient satisfaction among younger adults. Enabling characteristics
were important predictors among the Native American groups. This model explained
15%-30% of the variability in patient satisfaction among the study age and ethnic
groups.
PMID- 9549995
TI - Oral health policy and programmatic implications: lessons from ICS-II.
AB - The conceptual model used in the ICS-II USA Ethnicity and Aging project helps to
identify who among the elderly should be targeted for oral health promotion
initiatives and the kinds of initiatives most likely to promote positive oral
health outcomes. Outcomes have been measured in this study as perceived by the
individual and as clinically assessed by the oral epidemiologists. For policy
purposes, achieving both types of outcomes is important. A typology of oral
health promotion priorities is used to rank the diverse racial-ethnic groups. In
the analysis, groups with both low perceived and low evaluated oral health status
receive highest priority. By these criteria, the older Native American
populations have the highest priority, followed, in order, by Hispanics, African
Americans, and non-Hispanic Whites. Policy implications of the empirical analyses
presented in earlier articles are discussed by use of the conceptual model and
the typology of oral health promotion priorities. Having a usual source of care
and/or regular dental visits appears to be a promising avenue for the promotion
of better-perceived oral health status among most older ethnic groups. Improved
oral hygiene practices, as represented by both regular toothbrushing and dental
floss use, promote better clinically evaluated oral health status among many
older ethnic groups.
PMID- 9549997
TI - CAD/CAM system to fabricate dental prostheses--CAD for bridge restoration.
AB - An original CAD process for bridge restoration was developed, and CAD for a
maxillary left three unit bridge was attempted. The measured shape data of the
standard crown of a second premolar and molar were deformed, and were applied on
the dies. The measured pontic data were inserted between two molars. Here, bite
data of the opposing teeth were introduced, and the occlusal relationship with
the applied molars was adjusted. The bite data were then replaced by the FGP
data, and the occlusal surface interference with FGP data was eliminated.
Connection processes were then carried out. The clearances between the pontic and
molars were filled with interpolation, and the ends of the applied second molar
and premolar were connected with the margin of each die. Finally, the data above
the margin of each die were extracted, and used as the inner crown data for the
bridge. The whole bridge was designed using a newly developed computer program.
PMID- 9549996
TI - Effects of various collagen crosslinking techniques on mechanical properties of
collagen film.
AB - We examined the relationship between collagen crosslinking techniques and
dentinum reinforcement. In the present study, the tensile tests, imbibition test
and antienzyme test were performed on collagen films mainly composed of type I
collagen after ultraviolet irradiation and immersion in tannic acid and
glutaraldehyde. The elastic modulus increased with the reaction time, but
reduction of elongation at breaking point and increased stiffness were observed.
This tendency was enhanced by ultraviolet irradiation. Tannic acid treatment
resulted in slower crosslinking than the other two techniques. Antienzyme
activity was markedly increased by treatment with tannic acid and glutaraldehyde.
PMID- 9549998
TI - Basic study of a new denture base resin applying hydrophobic methacrylate
monomer.
AB - To improve the water sorption of poly(methyl methacrylate), new hydrophobic
monomers, such as norbonyl and phenyl methacrylate, were studied to determine the
resin with lower water sorption with no decrease in mechanical property. Water
sorption of the copolymers of the hydrophobic monomers and MMA decreased with the
increase in the concentration of the monomers. Compressive and bending strength
of the copolymers were higher than that of PMMA, and the elastic modulus in
bending was the same as that of PMMA. In addition, the transverse-deflection
values satisfied ADA specifications. Dynamic mechanical thermal analysis of the
copolymers showed a similar tendency to that of PMMA in spite of the introduction
of bulky groups, such as norbonyl and phenyl, in the polymer molecule. The
polymerization shrinkage in volume was in the following order: norbonyl < phenyl
< methyl methacrylate.
PMID- 9549999
TI - New initiator system for bonding to dentin using methylcyclohexanedione.
AB - As a part of a series of studies to examine the role of the initiator system in
dentin bonding, the effectiveness of a new polymerization initiator system
consisting of 2-methyl-1,3-cyclohexanedione (MCHD) and CuCl2 in dentin bonding
was investigated in terms of the effects of dentin conditioners and CuCl2
concentration formulated in MMA/PMMA resins. Curing time and tensile bond
strength to bovine dentin were measured using resins composed of MMA containing
0.001-0.03 wt% CuCl2 and PMMA powder containing 2 wt% MCHD. The dentin surfaces
were treated with six conditioners consisting of 10 wt% phosphoric acid or citric
acid containing 0-3 wt% FeCl3 or CuCl2. The bond strengths of about 10 MPa
obtained under optimal conditions were comparable to those reported for
tributylborane-initiated MMA resin which is one of the most effective bonding
resins available. Thus, the resin using MCHD/CuCl2 system was concluded to be
very effective for dentin bonding, especially when dentin was treated with acidic
conditioners containing ferric or copper chloride.
PMID- 9550000
TI - Shear bond strengths of a single-step bonding system to enamel and dentin.
AB - An experimental primer was developed as a single-step bonding system for resin
modified glass ionomer cements (GIC). Efficacy of this primer on adhesion of
resin-modified GICs and resin composite to enamel and dentin was evaluated by
shear bond test and SEM observation. Good bond strengths to enamel were obtained
(> 11 MPa), whereas significantly low bond strengths to dentin were obtained
using a single coat of the primer. However, double-coating improved the bond
strengths to dentin (> 8 MPa). SEM observations indicated that the primer
functioned as a mild conditioner to remove the smear layer on enamel or dentin
surfaces. A hybrid layer was observed at the cross-sectional view of the
GIC/dentin interface. These findings suggested that good adhesion to enamel and
dentin could be achieved using a single-step bonding system.
PMID- 9550001
TI - Anisotropic expansion in gypsum-bonded cristobalite investment mold.
AB - Expansion of a gypsum-bonded investment mold was investigated using a fused
quartz tube pattern. Two hours after mixing, a fusible alloy was cast into the
space around the pattern induced by setting expansion. The other molds were
heated up to 700 degrees C, then a dental silver alloy was cast into the space
around the pattern induced by total expansion of the mold. Thickness of the
castings was measured at every thirty degrees on seven cross-sections. The
setting expansion was almost uniform, but the total expansion was not.
Especially, a large amount of total expansion was produced toward the open ends
of the casting ring and toward a seam of the asbestos liner. The thermal
expansion of the mold was anisotropic because the investment was a mixture of
calcium sulfate and silica, and was affected considerably by its environment.
PMID- 9550002
TI - Effect of light wavelength on polymerization of light-cured resins.
AB - Experimental light-cured composite resins were exposed to a narrow-band light at
a constant quantum number using a narrow-band interference filter. The IR spectra
of the cured resin specimens were measured before and after extraction of
residual monomers. Degree of conversion (DC) and polymerization conversion (PC)
were calculated from these IR spectra. The light in 410-550 nm could be
polymerized. With a brief exposure (5 s), DC and PC were affected by the
wavelength. The effect of wavelength between 410 and 490 nm decreased with
increasing duration of exposure. The most efficient wavelength was 470 nm and the
most adequate wavelength was in the 450-490 nm wavelength range. The absorbance
of camphorquinone strongly affected polymerization, especially during the initial
stage. However, from the relationship between DC or PC and exposure energy,
polymerization depended not only on the wavelength of the light, but also on the
exposure energy.
PMID- 9550003
TI - Effect of adding ethylene glycol dimethacrylate to resin cements: durability
against thermal stress of adhesion to titanium.
AB - The present study was conducted to examine the effect of the addition of a
dimethacrylate to resin cements on bond strength between titanium and resin after
thermocycling. Titanium disks, polished and treated with a phosphate monomer,
were bonded to acrylic rods using two types of experimental resin cements. The
cements were composed of methyl methacrylate (MMA) containing a tributylborane
initiator and 0-10 wt% of ethylene glycol dimethacrylate (EGDMA) and two types of
polymer component of hard poly (MMA) or soft fluoropolymer (2-6F). The bonded
specimens were subjected to a thermocycling test in water and then to tensile
strength testing. The addition of 5% or more dimethacrylate monomer to the two
MMA-based resin cements caused a drastic decrease in bond strength to the metal
after the thermocycling test. The resin prepared with soft 2-6F as a polymer
component was significantly more durable than the rigid type resin based on PMMA.
However, even a 1% addition of ECDMA to the 2-6F resin resulted in a significant
decrease in durability.
PMID- 9550004
TI - Thermal diffusivity and specific heat of dental casting alloys at room and
elevated temperatures.
AB - Thermal diffusivity and specific heat of four groups of dental casting alloys (Ag
based, Au-Pd, high karat and Ni-based alloys) were determined. Measurements were
carried out from room temperature to 750 degrees C in an evacuated electric
furnace with a laser flash thermal constant analyzer. There was no significant
difference between the values of thermal diffusivity in the Ag-based and high
karat alloys; 18-24 and 40-53 mm2/s, at room temperature and at 600 degrees C,
respectively. For Au-Pd and Ni-based alloys, diffusivity was 8-12 and 3-4 mm2/s
at room temperature, and 19-22 and 5-6 mm2/s at 600 degrees C, respectively. The
thermal diffusivity of the alloys was significantly low compared to that of the
pure-metals of which they were composed. Specific heat was determined as 0.14
0.16, 0.24-0.34, 0.17-0.19 and 0.45-0.51 kJ/(kg.K) for high karat, Ag-based, Au
Pd and Ni-based alloys, respectively, at room temperature. Oxidation of the Ni
based alloy at elevated temperature affected the value of specific heat measured.
PMID- 9550005
TI - Effect of dimethacrylates in resin cement on durability against thermal stress of
adhesion to titanium.
AB - The present study examined the effect of crosslinking of resin cement on
durability of adhesion between titanium and resin against repeated thermal
stress. Titanium disks, polished and treated with a phosphate monomer, were
bonded to acrylic rods with resins composed of poly (methyl methacrylate), methyl
methacrylate containing 0 approximately 5% dimethacrylates or diacrylate as
crosslinking agent, and a benzoyl peroxide/amine initiator system. The bonded
specimens were subjected to thermocycling in water and then tensile strength
testing. The addition of 5% crosslinking agent, irrespective of its type, to the
resin resulted in a significant decrease in bond strength after 500 thermocycles.
No significant difference in durability was revealed among the five crosslinking
agents studied.
PMID- 9550006
TI - Titanium in dentistry: development and research in the U.S.A.
AB - Titanium has received a great deal of attention from dental researchers and
clinicians. In the United States, the history of the application of titanium as a
biomaterial started as early as 1940 when experiments with titanium implants were
done using laboratory animals. It appears that in 1959, two American researchers
were the first to suggest casting titanium to fabricate implant posts. The use of
cast titanium for dental prostheses in the U.S. was first reported in 1977. The
present survey revealed that during the last decade, the number of research
projects on the applications of titanium to dentistry that were presented at
annual IADR/AADR meetings has steadily increased. The majority of these
presentations have been made by American researchers, and 59% of these were
related to dental implantology. The numbers of reports on casting and
prosthodontic applications have steadily increased, but they are still more
limited. The purpose of this review was to provide information on the development
and the current status of research on titanium in dentistry in the U.S.
PMID- 9550007
TI - Properties of magnetically attractive experimental resin composites.
AB - SUS444 stainless steel filled chemically cured resin composites that can attract
magnet were fabricated. The filler was treated with various concentrations of
silane. The experimental composite was easy to handle and showed a good shelf
life. The maximal properties obtained are as follows; The attraction force to a
magnetic attachment was 1/3-1/4 lower than the commercially available magnet
keeper system for dental magnetic attachment. Flexural strength and Knoop
hardness of the composite were 76MPa (7.7 kgf/mm2) and 64 KHN. These values were
lower than the commercially available chemically cured composite used as a
reference. Eluted metal from the composite in 1% lactic acid solution for 7 days
showed 0.7 mg/cm2, but in 0.9% NaCl solution for 7 days, it could not be
detected.
PMID- 9550008
TI - Effect of shape and size of silanated fillers on mechanical properties of
experimental photo cure composite resins.
AB - The binary system of hybrid fillers selected from four irregular fillers (1.7
21.5 microns), five spherical fillers (0.46-31.2 microns), and a microfiller of
0.04 micron, were applied to photo cure composite resin and mechanical properties
were measured. The strength for the hybrid of irregular and spherical fillers
tended to increase as the size of component fillers decreased. The strength for
the hybrid of the same fillers in shape also increased as the size of fillers
decreased. The strength for the hybrid containing 30% microfiller showed the same
trend, especially, the largest strength was obtained from hybrids containing
small spherical fillers.
PMID- 9550009
TI - Effect of barium in porcelain on bonding strength of titanium-porcelain system.
AB - The bonding strength to titanium, thermal expansion, and bending strength of
glassy porcelain containing barium of 5, 10, and 15 mass% were estimated and
compared with those of barium-free porcelain, to estimate the effect of barium
content on bonding strength to titanium. The three different glassy porcelains
containing barium were made by melting at 950 degrees C. The bonding strength of
a commercial porcelain to titanium increased with the addition of barium. Bending
strength and thermal expansion were not affected by the barium content.
Therefore, the addition of barium to porcelain is effective for strengthening the
bonding of porcelain to titanium.
PMID- 9550010
TI - Simulation of transient thermal stress in gypsum-bonded investment.
AB - The aim of this study was to clarify the effect of heating rate on the
development of both transient and residual stresses in investment molds. Solid,
cylindrical, gypsum-based molds were modeled and theoretical calculations made of
temperature distributions with a constant heating rate. These calculations used
experimental thermal diffusivity data obtained with a laser flash method. The
simulations calculated transient thermal stresses during heating and at the end
of heating for two surface conditions: an unrestricted surface, and a surface
restricted by a casting ring. The simulation model developed nonuniform strains
and stresses at casting temperature; tangential stress was compressive at the
surface and tensile at the mid-point for the unrestricted surface model. The
surface restricted model developed compressive tangential stresses throughout the
mold at the casting temperature. This resulted in significant thermal strain
differences compared to the magnitudes of expansion of the mold due to heating.
PMID- 9550011
TI - Effect of 4-acryloxyethyltrimellitic acid in a self-etching primer on bonding to
ground dentin.
AB - To develop a self-etching primer for ground dentin, 4-acryloxyethyltrimellitic
acid (4-AET) was newly synthesized, and the effect of concentrations varying from
0 (control) to 56.5 wt% 4-AET in the water/ HEMA primer on bonding to the dentin
was investigated. Bond strength to the dentin was significantly affected by the
inclusion of 4-AET in the primer which also contained N,N-di(hydroxyethyl)-p
toluidine (DEPT) when compared with the control (0% 4-AET) (p < 0.01). The
optimum 4-AET-concentration and the mean bond strength (SD) were found to be 6.5
wt%: 24.2 (3.6 MPa, 37.4 wt%: 25.3 (4.4) MPa, 47.2 wt%: 26.9 (11.6) MPa and 54.4
wt%: 29.7 (12.9) MPa. The role of DEPT in the 4-AET/HEMA primer was assessed, and
the optimum DEPT-concentration was found to be 0.154 and 0.307 mol%. Regarding
the hypothetical bonding mechanism to dentin, it was thought that the ionized 4
AET in water/HEMA would penetrate into dentin substrates, and DEPT as an
accelerator in situ would facilitate photo-polymerization at the dentin-resin
interface, and result in increased bond strength to ground dentin.
PMID- 9550012
TI - Effects of aminobenzoic acid derivatives with 4-AET/HEMA in self-etching primer
on bonding to ground dentin.
AB - The effect of the inclusion of aminobenzoic acid derivatives (ABAD) in a self
etching primer comprising 4-acryloxyethyltrimellitic acid (4-AET), HEMA and water
on shear bond strength to ground dentin was investigated. The mean bond strengths
to dentin were significantly increased by the inclusion of 0.307 mol% ABAD in the
4-AET/HEMA primer, when compared with the control (0 wt% ABAD) (p < 0.01). A
particularly high value (38.0 MPa) of shear bond strength was obtained in the use
of the primer containing p-nitroanthranilic acid (p-NAA). It seemed to assume
that the effect of p-NAA could be caused by the strong electron-withdrawing group
of -NO2. From SEM observation, it was found that bonding resin appeared to adhere
strongly to the ground dentin without formation of any resin-tags in the dentinal
tubules. It was thought that the ABAD with 4-AET/HEMA could perform facilitating
photo-polymerization at the bonding interface, and resulted in increased bond
strength to ground dentin, and that the bond strength could be affected by the
electronegativities of substitutional groups of ABAD.
PMID- 9550013
TI - Effects of radical polymerizable spirocyclic monomers with new polymerization
initiator systems on adhesion.
AB - To develop a non-polymerization shrinkage adhesive resin, the effects of the
contents varying 0-20 wt% radical polymerizable spirocyclic monomers of 2
methylene-1, 4, 6-trioxyaspiro [4, 6] undecane (MTSU) and 2-methylene-8, 9-benzo
1, 4, 6 trioxyaspiro [4, 4] nonane (BTSN) together with three kinds of initiator
systems in adhesive resin on bonding to both Ni-Cr alloy and unetched enamel were
investigated. Tensile bond strength to either Ni-Cr alloy or unetched enamel was
affected by the inclusion of MTSU or BTSN, and indicated that increased contents
of MTSU or BTSN resulted in decreased bond strength to the metal in the negative
correlations. Regarding the bond strength to Ni-Cr alloy, however, the effective
concentration of BTSN was found to be 5 wt%, and the mean bond strength was 58.5
and 58.6 MPa, respectively. The data of differential scanning calorimeter
measurement, on the other hand, showed that the copolymerization of MTSU with
conventional methacrylate monomers was not completely achieved.
PMID- 9550014
TI - Initial mercury evaporation from amalgams made with in-containing commercial
alloys.
AB - This study examined the Hg evaporation behavior during the early setting of
amalgams that contain In in the alloy powders. Two different types of
commercially available In-containing alloys were tested: an In-particle admixed
powder (Indisperse, D) and an In-containing single-composition powder (Indiloy,
S). Mercury evaporation from specimens (4 mm in dia, 8 mm tall) was monitored 10
min after trituration to 180 min using a mercury vapor analyzer according to the
methods used in a previous study. The amounts released from 10 min to 180 min
were compared with the results of our previous study on a single-composition
amalgam (Tytin, T) with pure Hg and with Hg-In liquids (5 or 10%). Amalgam S and
In-containing T terminated Hg evaporation within 180 min. There was no
significant (p > 0.05) difference in the amount released between T amalgam made
using pure mercury and D, and between T amalgam made with 5% In-containing
mercury and S amalgam. Mercury release from amalgam D was significantly (p <
0.05) higher than from S or both types of In-containing T amalgam. Adding In to
mercury or alloying In into the alloy particles appeared to be more effective in
reducing the mercury vapor than admixing pure In particles into the amalgam.
PMID- 9550015
TI - Adhesion to dentin with resin using sulfinic acid initiator system.
AB - A study was made on the dentin bonding of MMA/PMMA resin using sulfinic
acid/BPO/amine polymerization initiator, to examine: 1) the effect of ferric and
copper chloride contained in phosphoric acid or citric acid dentin conditioners,
and 2) the effect of the addition of acidic monomers to the resin. Tensile bond
strength was significantly improved by conditioning dentin with 10% phosphoric
acid containing 3% ferric chloride. The citric acid-based conditioners and the
addition of the copper salt to the acidic conditioners were less effective in
improving bond strength. The mechanism of the improved bond strength is discussed
in terms of polymerization promoting action of ferric ion at the dentin-resin
interface. For improving bond strength, the presence of a suitable acidic monomer
was essential. Its effectiveness depended on the types of acids: Two phosphoric
acid ester monomers were effective but methacrylic acid had little effect.
PMID- 9550016
TI - Evaluation of water durability at adhesion interfaces by peeling test of resin
film.
AB - The water durability at adhesion interfaces was investigated by measurement of
the peeled area of thin resin films bonded with 4-META resin on metal surfaces
after imposing thermal stress using liquid nitrogen. Thermal stress at the
adhesion interface was calculated by a computer-aided finite element method. On
18-8 stainless-steel specimens which bond strongly with 4-META resin, total
interface failure occurs on specimens with resin thicker than 0.55 mm in dry
condition. A resin layer of 0.25 mm was chosen to study degradation of the
adhesion interface by water. The shearing stress was calculated as 16 MPa for a
0.25 mm thick resin layer. On mild-steel adherent interface with 4-META resin
which degrades rapidly by water molecule, the relationship between water
immersion time and degradation at the adhesion interface was discussed together
with the amount of water penetrated at the interface. The method proposed in the
present study is effective as a quick evaluation method for water durability at
the adhesion interface.
PMID- 9550018
TI - Adherence of oral streptococci to composite resin of varying surface roughness.
AB - The adherence of oral bacteria to composite resins plays an important role in the
development of secondary caries. The present study deals with the adherence to
composite resin having various surface roughness of S.oralis, which is frequently
isolated from composite resin squares attached to maxillary first molars.
available commercial resin was used in this experiment. In vitro bacterial
adhesion test was carried out under a sucrose independent conditions. The surface
roughness values of each specimen ranged between 0.2 micron and 3.0 microns. No
relationship was observed between the surface roughness values and bacterial
adhesion because S. oralis adhered firmly to the filler particles of all
composite resin surfaces.
PMID- 9550017
TI - Marginal sealability of resin-modified glass ionomers for base/liner: effect of
hygroscopic expansion and bond strength.
AB - The present study investigates the effect of storage in water on hygroscopic
expansion and shear bond strength to dentin at periods up to 1 week, of the resin
modified glass ionomers for base/liner, and to analyze the effect on the marginal
gaps in dentin cavities. For polishing after storage in water for 1 day, the
material indicated significantly smaller marginal gaps both in dentin and in
Teflon cavities than in those immediately after light-activation. For the results
of after storage in water for 1 day, the material indicated significantly greater
bond strength than material immediately after light-activation. The improvement
of marginal sealability in dentin cavities may be performed not only by
hygroscopic expansion during storage in water but also by greater bond strength
after the setting reaction which continues to advance during storage in water.
PMID- 9550019
TI - Effect of frozen storage and boiling on tensile strength of bovine dentin.
AB - Bovine teeth are used for dental research as a substitute for human teeth. In the
present study the effects of storage on the tensile strength of bovine dentin
were investigated. Storage conditions selected were frozen storage for 1 week, 4
weeks, and 1 year. Boiling in water for 45 minutes was also employed to clarify
the effect of heat. Dumbbell-shaped specimens were prepared from teeth of each
condition and tensile tests were performed immediately. The same tests were also
performed on specimens, as a control, prepared from bovine teeth within 8 hours
of extraction. The tensile strength of the control was 76.1 MPa; 1 week frozen
storage, 78.7 MPa; 4 weeks, 79.9 MPa; 1 year, 79.0 MPa. The tensile strength of
bovine dentin remained unchanged during one year frozen storage. On the other
hand, the tensile strength of bovine dentin after boiling was 70.3 MPa, showing
that tensile strength had decreased.
PMID- 9550020
TI - Possible segregation caused by centrifugal titanium casting.
AB - The possibility of the segregation under solidification process using a
centrifugal casting machine was investigated using an electron probe
microanalyzer with elemental distribution map, line analysis and quantitative
analysis. When a very small quantity of platinum was added to local molten
titanium during the casting process, macroscopic segregation was observed under
conditions of density difference of 0.1 g/cm3 at the most, confirming that the
centrifugal force of the casting machine is extremely strong. When a Ti-6Al-4V
alloy was cast, however, no macroscopic segregation was observed. The centrifugal
force of the casting machine examined in the present study hardly results in the
body-force segregation in this titanium alloy.
PMID- 9550021
TI - Disinfection of removable dentures using ozone.
AB - Over time, removable dentures tend to become unsanitary and emit unpleasant
odors, and oral mucosa sometimes becomes inflamed or denture stomatitis is caused
by denture plaque. Recently, various cleaning products designed to keep removable
dentures sanitary have appeared on the market. It is known that denture plaque is
mainly composed of Candida albicans (C. albicans), and that ozone seems to
inhibit these micro-organisms. Accordingly, a denture cleaner using ozone bubbles
(ozone concentration of about 10 ppm) was considered as clinically appropriate
because of its strong disinfecting and deodorizing power, and high biological
safeness. The effectiveness of this cleaner against C. albicans was investigated
using. Results showed that C. albicans decreased to about 1/10 after 30 min and
to 1/10(3) after 60 min.
PMID- 9550022
TI - Evaluation of skin irritation and sensitization of two diol solutions used as
experimental dentin primers in humans and guinea pigs.
AB - The purpose of the present study was to evaluate the safety of ethylene glyco
(EG) and 1,6-hexanediol (HD) solutions as experimental dentin primers when
subjected to the guinea pig maximization test (GPMT), primary irritation test,
cumulative skin irritation test and human patch test. No primary and cumulative
skin irritation resulting from the use of 62.5% EG or 45% HD solutions was
observed. In the case of GPMT, the animals sensitized with 2-hydroxyethyl
methacrylate (2-HEMA) responded to 100% HD. 62.5% EG and 45% HD as dentin primers
were safer than 2-HEMA such as a methacrylic primer.
PMID- 9550023
TI - Comparative in vitro investigation of different methods for temporary root canal
filling with aqueous suspensions of calcium hydroxide.
AB - Three methods for temporarily filling root canals with calcium hydroxide pastes
were compared. Each of 20 root canals of extracted, human, single-rooted teeth
was shaped with hand instruments under standardized conditions up to ISO size 50
and filled using a syringe system, a lentulo spiral or an endodontic reamer.
Quality of fillings was assessed radiographically and by inspecting ground
preparations. Ridit (relative to an identified distribution) analysis was
employed to confirm differences in frequencies of certain quality criteria
obtained with various application methods. With regard to degree of obturation
and occurrence of porosities, application of temporary fillings with a lentulo
spiral or syringe system revealed significantly better results than application
with hand instruments (reamer). No differences with regard to degree of
obturation were detected when comparing results obtained with syringe or lentulo.
Fewer porosities in the apical part of the root canal were seen, both on
radiographs and ground sections, with the syringe system compared with the
lentulo spiral. In the presence of some contradictory reports found in the
literature, the present study suggests that, after straight or slightly curved
root canals have been shaped up to at least ISO size 50, high quality temporary
root canal fillings may be obtained by application of an aqueous suspension of
calcium hydroxide with a syringe system.
PMID- 9550024
TI - Periodontal healing of extracted dogs' teeth air-dried for extended periods and
soaked in various media.
AB - The aim of this study was to determine the periodontal healing of replanted dogs'
teeth which, after extended extra-oral dry times, had been soaked in various
media before replantation. Incisors and premolars of beagle dogs were root canal
treated, extracted and bench dried. The teeth were grouped according to dry times
of 30, 45 and 60 minutes. Each group of teeth was soaked in one of three media,
Hank's balanced salt solution, ViaSpan (Belzer UW-CSS, Dupont Pharmaceuticals),
or Conditioned Medium (supernatant of confluent culture of human gingival
fibroblasts) for 30 minutes before replantation. Controls consisted of teeth
extracted and replanted without drying on soaking (negative control), and bench
dried teeth replanted without soaking in the media (positive control). The dogs
were killed 6 months after replantation of the teeth, which were prepared for
histologic evaluation. Five microns cross-sections (every 70 microns) of the root
and surrounding tissue were evaluated for healing/resorption according to
Andreasen's criteria. The best healing occurred for the roots which had been
immediately replanted. Healing in the positive control groups decreased with
increased dry time. For the 30-minute dry time groups, soaking in media had no
beneficial effect on periodontal healing compared with the controls. Soaking in
ViaSpan resulted in an increased healing incidence for both the 45- and 60-minute
bench-dried groups while soaking in the other media had no consistent beneficial
effect. It appears from this study that an avulsed tooth that has been left dry
for 30 minutes should be replanted immediately without soaking. However, teeth
that have been dry for 45 or 60 minutes would benefit from soaking for 30 minutes
in ViaSpan.
PMID- 9550025
TI - Hydroxyl radical activity in thermo-catalytically bleached root-filled teeth.
AB - Intra-coronal bleaching of root-filled teeth has been associated with invasive
cervical root resorption. It is considered that during bleaching hydrogen
peroxide diffuses through the tooth structure into the cervical periodontium,
resulting in periodontal tissue destruction and initiating a resorptive process.
Hydrogen peroxide is capable of generating hydroxyl radical, an oxygen-derived
free radical, in the presence of ferrous salts. Hydroxyl radicals are extremely
reactive and have been shown to degrade components of connective tissue,
particularly collagen and hyaluronic acid. The aim of the present study was to
determine whether hydroxyl radicals are generated during the bleaching of root
filled teeth which have been discoloured by blood. Forty extracted human premolar
teeth were root-filled with gutta-percha and AH26 sealer cement. Twenty of the
teeth were experimentally discoloured by blood. All teeth were then thermo
catalytically bleached using 30% hydrogen peroxide while tooth roots were seated
in a test solution of sodium salicylate. Hydroxyl radical generation was
determined by the detection of reaction products of this radical with salicylate
using high performance liquid chromatography with electrochemical detection (HPLC
ECD). The presence of hydroxyl radicals was detected in twenty-five of the teeth.
There was a significant association between the production of hydroxyl radicals
and the presence of tooth discolouration caused by blood components. Greatest
yields of hydroxyl radicals occurred in teeth in which EDTA had been used to
clean the pulp chamber prior to bleaching. It was concluded that hydroxyl
radicals are generated during the thermo-catalytic bleaching of root-filled
teeth. Generation of this toxic chemical species may be one mechanism underlying
periodontal tissue destruction and root resorption after intra-coronal bleaching.
PMID- 9550026
TI - Electrical impedance measurements of root canal length.
AB - Electronic methods are now widely used during endodontic treatment for the
assessment of root canal length. These commonly measure the electrical resistance
or impedance between the root canal and the buccal mucosa. A number of studies
have been undertaken to determine the accuracy of commercially available
instruments. The aims of this investigation were to determine the electrical
impedance characteristics of the root canal and periapical tissues in vivo,
measure the changes relative to the distance of an endodontic instrument from the
apical constriction and propose an equivalent circuit modelling the periapical
tissues. The length of the root canals of 20 previously untreated teeth were
determined using radiographic and electronic methods. Minimal canal preparation
was carried out and measurements were made with a size 10 K-Flex file. A
microprocessor-controlled LCR analyser was used to measure the electrical
impedance characteristics of each root canal. The instrument measured the series
and parallel resistive (RS, RP) and capacitance (CS, CP) component of the tissues
at two test frequencies, 100 Hz and 1 kHz. Measurements were made for each root
canal when the diagnostic file was placed at the apical constriction and repeated
when the file was withdrawn to -0.5, -1.0, -1.5, -2.0 and -5.0 mm from the
foramen. Readings were taken for each canal after the canal had been dried with
paper points, and flooded first with deionised water and then with sodium
hypochlorite. The root canals were then prepared, cleaned and obturated using
standard endodontic procedures. The LCR analyser selected the series resistance
component as the major measurement parameter. There was a clear increase in
series resistance (RS) with increasing distance from the radiographic apex for
dry canals and those containing deionised water and sodium hypochlorite. The mean
resistance for dry canals was markedly higher than for those containing fluid,
ranging from 22.19 k omega to 92.07 k omega in comparison with 9.32 k omega to
12.10 k omega for deionised water and from 7.46 k omega to 8.92 k omega for
canals containing sodium hypochlorite. There was a marked change in the series
and parallel resistive component with distance from the apex, suggesting a
complex relationship between the impedance of the smear layer and bulk dentine.
The impedance characteristics of a root canal were a complex electrical network
comprising resistive and capacitive series and parallel elements.
PMID- 9550028
TI - Effect of laser treatment on the root canal of human teeth.
AB - The purpose of this study was to examine the morphological and temperature
changes of the apical portion of human extracted teeth treated by Nd: YAG, CO2
and Argon-lasers. Seventy-two single-rooted human teeth were studied. The root
canals were prepared conventionally. Laser treatment of the apical portion of the
canal was carried out by means of an optic fiber or metal tip. Temperatures were
recorded thermographically. Two-thirds of the specimens were stained with black
India ink and 36% silver ammonium fluoride solution. All specimens were
irradiated by the three types of lasers at several intensities and the
temperatures were recorded. Half of the specimens were prepared for the
telescopic light microscope and for scanning electron microscopic observation,
and the rest for histopathological examination by light microscope. The scanning
electron microscopic evaluation showed that the laser energy vaporized the
deposited debris, producing a glaze-like surface. The histopathological
investigation revealed a tapered, enlarged apical lased area. All three laser
devices were capable of vaporizing the debris in this way but the degree of
morphological change was highly dependent on energy level and duration. The Argon
laser produced the highest temperatures.
PMID- 9550027
TI - Tooth discoloration by blood: an in vitro histochemical study.
AB - An in vitro model, using a modification of a technique devised by Freccia &
Peters, was developed to investigate tooth staining following pulpal haemorrhage.
Samples of whole blood, erythrocytes, plasma and platelet concentrate and saline
were individually placed in the pulp chambers of groups of five teeth and
centrifuged twice daily for 25 min over a period of 3 consecutive days. This
confirmed that the blood pigment responsible for the staining was found only in
those samples containing erythrocytes. Teeth stained with packed red cells were
then prepared for histological examination and subjected to four histochemical
tests: (1) benzidine, (2) zinc leuco, (3) Perl's and (4) Turnbull Blue to analyse
some of the biochemical changes following haemorrhage into the pulp chamber.
These tests showed that, following haemolysis of erythrocytes within dentine,
haemoglobin was found either intact or as one of the haematin molecules with no
further breakdown of the haem structure and no evidence of any free ferric ions
or haemosiderin.
PMID- 9550029
TI - A case of severe vestibular root angulation.
AB - In this article, we describe the appearance and management of an impacted
permanent tooth with severe vestibular root angulation. In addition, the possible
origin of this type of root malformation as well as some of their epidemiologic
aspects are discussed.
PMID- 9550030
TI - Endodontic therapy for a fused mandibular molar.
AB - Variations in tooth morphology present a clinical challenge when endodontic
treatment is required. A case of conservative endodontic therapy for a fused
mandibular second and third molar is presented.
PMID- 9550031
TI - Root canal instruments for manual use: a review.
AB - Root canal instruments can be subdivided into instruments made of different
alloys (stainless steel, nickel-titanium and nickel-aluminium) and instruments
with different geometric forms (e.g., instruments with short cutting segments).
Several types of stainless steel and titanium-based instruments are presented and
assessed by a review of the current literature. In summary, flexible stainless
steel instruments with noncutting tips seem to be a decisive improvement in the
development of an ideal root canal instrument. They are superior to titanium
based instruments in both cutting efficiency and instrumentation of curved root
canals.
PMID- 9550032
TI - A comparison of dentine removal using safety or conventional Hedstrom files.
AB - Mandibular molars (n = 20) were divided and the mesial roots mounted in an
acrylic mould which allowed them to be removed, sectioned horizontally and then
reassembled. The furcal root canal wall thickness 7 mm from the apex was measured
prior to instrumentation. The roots were allocated to two groups (n = 10). One
group was instrumented using the step back technique with safety Hedstroms in one
canal and conventional Hedstrom files in the other canal. The second group was
instrumented using a crown down approach (using files and Gates Glidden drills to
provide early radicular access). The furcal root canal wall thickness was then
remeasured and the amount of dentine removed calculated. The results showed that
the safety Hedstrom file removed less dentine from the furcal region of the canal
compared to the conventional Hedstrom file. This however was not statistically
significant (Paired t test, n = 10, p > 0.05). The amount of dentine removed
using the crown down technique was significantly greater than that using the step
back technique (Two sample t, n = 20, p < 0.01). In conclusion, less dentine was
removed from the furcal region with safety Hedstrom files compared to
conventional Hedstrom files; however, Gates Glidden drills removed more dentine
than either type of hard file.
PMID- 9550033
TI - Periapical status, quality of root canal fillings and estimated endodontic
treatment needs in an urban German population.
AB - The objective of this study was to determine the periapical status and the
quality of root canal fillings and to estimate the endodontic treatment needs in
a German population. Clinical and radiographic data and the operative procedures
performed were evaluated on 323 patients coming to a dental surgery in Stuttgart,
Germany, in 1993. In 182 individuals at least one tooth exhibited a root canal
filling, a necrotic pulp or an irreversible pulpitis. Out of the 7897 teeth
examined, 215 (2.7%) had a root canal treatment (category A), 122 being non
endodontically treated (1.5%) did not respond to the sensitivity test (category
B) and 53 (0.7%) were diagnosed as having irreversible inflamed pulp tissue
(category C). The prevalence of teeth associated with radiographic signs of
periapical pathosis was 61% in the group of root canal filled teeth and 88% in
the group of pulpless and non-endodontically treated teeth. Using the level and
the density of the root canal filling as criteria for evaluating the technical
standard, only 14% of the endodontic treatments of non-apicectomized teeth were
qualified as adequate. The minimal endodontic treatment need is 2.3% related to
all examined teeth when the root canal filled teeth with clinical symptoms of
periapical periodontitis (category A) and those of categories B and C are
included. The real endodontic treatment need is suggested to be larger when
considering that the technical quality of the obturation is poor in most
symptomless endodontically treated teeth associated with a periapical lesion. In
the case of retreatment of these teeth, the endodontic treatment need would then
be calculated at 3.7%.
PMID- 9550034
TI - Prognosis of permanent teeth with internal resorption: a clinical review.
AB - This study was performed in order to report the clinical features of internal
resorption cases and evaluate their prognosis after endodontic treatment. Twenty
seven patients with 28 teeth with internal resorption were referred to our clinic
and 20 teeth were treated endodontically. Sixteen teeth had non-perforating
internal resorption and were treated by conventional root canal therapy. The
remaining 4 teeth had perforating internal resorption and were initially treated
by remineralization therapy with calcium hydroxide. The teeth treated by
conventional root canal therapy showed clinical and radiographic evidence of
healing. However, the remineralization therapy was successful in only one case.
The three failed cases were subsequently treated by endodontic surgery. The
surgical therapy was unsuccessful in one case due to extensive loss of marginal
alveolar bone and increased tooth mobility.
PMID- 9550035
TI - Coronal leakage in teeth root-filled with gutta-percha and two different sealers
after long-term storage.
AB - This in vitro study investigated the effect of long-term storage on the coronal
leakage of a microbial marker in teeth root-filled with lateral condensation of
cold gutta-percha and one of two sealers. Sixty single-rooted teeth were prepared
chemomechanically to a size 40 master apical file. The teeth were divided into
two groups of 20 teeth each and obturated with gutta-percha using either Apexit
or Tubliseal EWT sealer. The teeth were stored for 6 months in artificial saliva
and tested for leakage using a marker consisting of Anaerobic streptococci and
Prevotella intermedia. The teeth were checked for bacterial leakage daily for 90
days. All positive control teeth leaked within 48 hours, while the negative
control teeth remained uncontaminated throughout the test period. Leakage in the
experimental teeth started at times varying from 10 to 71 days; 30% and 75% of
the specimens of the Apexit and Tubliseal EWT groups respectively showed leakage
at 90 days. The Tubliseal EWT group showed significantly more leakage (p < 0.05)
than the Apexit group.
PMID- 9550036
TI - Possible application of transmitted laser light for the assessment of human
pulpal vitality.
AB - The purpose of this study was to determine whether use of transmitted laser light
would enable a better assessment of human pulpal vitality than back-scattered
light does (LDF: laser Doppler flowmetry). The experiments were carried out on
ten upper central incisors in six subjects aged 23-28 years; five of the teeth
were vital with no restoration, and five were non-vital. For use with transmitted
laser light, the fibers within the probe of a conventional LDF apparatus were
used, one for transmitting light onto the buccal surface, the other for receiving
it at the palatal surface of the same tooth. For LDF, the probe was fixed at the
buccal surface. Blood flow was measured at three different locations on each
experimental tooth: the incisal third, the center and the cervical third of the
tooth crown. In non-vital teeth, 1) output signals with transmitted laser light
all registered zero, and no oscillation could be seen in recordings from any
location on the tooth, but 2) LDF signals were above zero, there were regular
oscillations related to heart rate, and passive increases in blood flow
(corresponding to blood pressure increases) were recorded from both the center
and the cervical third of the tooth, indicating that LDF registered blood flow of
non-pulpal origin. In vital teeth, LDF signals were significantly higher than in
non-vital teeth at each location on the tooth. At the central site on vital
teeth, the output signals for transmitted laser light were about twice those seen
with LDF, and passive blood flow changes corresponding to blood pressure
increases were more clearly observed. These results indicated that transmitted
laser light would be useful for the assessment of tooth pulp vitality both
because the blood flow signals did not include flow of non-pulpal origin, and
because its output signals and response to blood flow changes were clear and
could easily be monitored.
PMID- 9550037
TI - Intra-alveolar surgical uprighting of impacted teeth: a case report.
AB - Although orthodontic repositioning of impacted teeth is widely used, the
treatment has its limitations. Autotransplantation or intra-alveolar surgical
repositioning of teeth is an alternative therapy that may be used in selected
cases of desperate impactions, when orthodontic extrusion is unsuccessful or when
orthodontic treatment is rejected by the patient. A case report is presented to
stress both the indications and limitations of a modified technique of intra
alveolar surgical uprighting of impacted teeth.
PMID- 9550038
TI - Endodontic treatment of an unusual mandibular second molar.
AB - A case involving unusual pulpal morphology due to fusion or gemination was
treated by conservative endodontic treatment. Clinically, the involved mandibular
second molar had an enlarged clinical crown and an extra cusp with a deep carious
lesion. Careful negotiation, instrumentation and obturation of the root canal
system led to successful treatment.
PMID- 9550039
TI - Concomitant intrusive luxation and root fracture of a central incisor--report of
a case.
AB - A case of a 9-year-old boy who presented with intruded maxillary central
incisors, one of which had also sustained a middle third root fracture, is
reported. The root fracture was diagnosed after orthodontic extrusion was
started, which resulted in separation of the apical and coronal fragments. The
hypermobile coronal fragment was stabilised by passing a K file through a palatal
access cavity into the root canal of the apical fragment. Orthodontic alignment
was completed and the fractured incisors were restored with the file left in
situ. At a 10-year follow-up, the incisors were clinically healthy and continued
to satisfy aesthetic and functional demands.
PMID- 9550040
TI - Avulsed permanent teeth: a review of the literature and treatment guidelines.
AB - Dental trauma represents one of the few situations where dentists are called upon
to make unscheduled diagnostic and treatment decisions in an area that is outside
their routine experience. Since patients who sustain an avulsion present
infrequently, except in child-oriented or emergency-based practices, clinicians
often make diagnostic and management decisions based upon their previous rare
treatment experiences. Clinicians also rely on published guidelines for this
aspect of their practice and expect these standards to be up-to-date and based on
current research information. None of the current protocols has been tested by a
prospective longitudinal outcome study in humans. Nevertheless, current
guidelines have become the standard for clinical practice around the world. An
effort must be made to develop treatment protocols that are based upon the
biological mechanisms that underlie periodontal wound healing.
PMID- 9550041
TI - An evaluation of after-office-hour dental trauma in Singapore.
AB - The purpose of this study was to assess the post-traumatic sequelae and treatment
outcome and the corresponding prognostic factors at the initial emergency visit.
Over a 5-year period, the authors collected case records from 129 dental trauma
patients. These patients had been referred subsequent to receiving emergency
treatment after office hours at the Accident and Emergency Department of
Singapore General Hospital. After the exclusion of 31 cases with concomitant
fracture of maxilla and/or mandible and cases with insufficient documentation,
the final study sample consisted of 98 patients (41 males, 57 females) who had
sustained injuries to 264 permanent teeth. The main cause of dental trauma was
falls (56%), and the main type of injuries was periodontal tissue injuries with
or without concomitant injuries to hard tissue, including root fracture (73%).
For the final evaluation, teeth with insufficient recall period were excluded
before univariate and multivariate stepwise logistic regression analysis. It was
found that for 100 teeth with luxation type of injuries, the presence of
concomitant hard tissue injuries retained prognostic significance for pulpal
outcome (p < 0.001) after adjusting for severity of luxation, while the severity
of luxation was the only significant factor for periodontal outcome (p < 0.001).
For 34 avulsed teeth, the stage of root development was the major factor
associated with the pulpal outcome (p = 0.003), while extra-alveolar storage
media were found to be significantly related to the periodontal outcome (p <
0.001). For 72 teeth with hard tissue injuries, first-visit interval played a
significant role in the outcome (p = 0.03). Although the sample size in the root
fracture group was too small for such statistical analysis, the results indicated
that patient education on dental trauma was an important factor. Thorough
standardized documentation was also recommended to facilitate optimal follow-up
management and future research as well as medico-legal purposes.
PMID- 9550043
TI - Radiological assessment of the effects of potential root-end filling materials on
healing after endodontic surgery.
AB - The effects of three root-end filling materials on healing following endodontic
surgery were assessed radiologically and correlated with histological findings
reported elsewhere. The materials compared were a light-cured glass ionomer
cement (Vitrebond), a reinforced zinc oxide-eugenol cement (Kalzinol) and
amalgam. The root canals of 27 two-rooted mandibular premolar teeth of six beagle
dogs were inoculated with endodontic pathogenic bacteria to induce periradicular
lesions. The roots were apicected and root-end cavities filled with the tested
filling materials. The teeth and surrounding jaw were removed after 4 weeks (30
roots) or 8 weeks (24 roots). Radiographs were taken of each jaw section and
subjected to image analysis. Healing was evaluated based on measurements of the
size of the periradicular radiolucent areas. ANOVA disclosed no statistically
significant differences in the size of the periradicular areas either between
time periods or between materials. These results did not correlate with the
tissue responses in the same material as assessed histologically and previously
reported. The use of radiographs alone to assess healing after endodontic surgery
in the dog mandible is unsatisfactory, and should not be regarded as a substitute
for histological examination for the determination of healing.
PMID- 9550042
TI - The role of the socket in the periodontal healing of replanted dogs' teeth stored
in ViaSpan for extended periods.
AB - In a previous study on the extended storage of extracted dogs' teeth, it was
hypothesized that changes in the socket environment might play a role in the
periodontal healing of these teeth. The purpose of this study was to evaluate the
role of the socket in the periodontal healing of replanted dogs' teeth. Extracted
endodontically treated dogs' teeth were stored in ViaSpan for 6 hours and
replanted into sockets after 6, 48 or 96 hours. Controls included teeth extracted
and replanted immediately, 48-hour stored teeth replanted into 48-hour sockets
and 96-hour stored teeth replanted into 96-hour sockets. After 6 months the dogs
were killed and the teeth prepared for histologic evaluation according to
Andreasen. Overall healing for the groups and healing for teeth within the groups
were evaluated and compared. The best results were obtained when the teeth were
replanted immediately. For the teeth stored in ViaSpan for 6 hours, complete
healing decreased significantly as the age of the socket increased. In addition,
the rate of replacement resorption increased significantly with increasing socket
age for the 6-hour stored teeth. Forty-eight-hour stored teeth replanted into 48
hour sockets had the lowest healing rate with levels of inflammatory resorption
not seen in the other groups. According to the results of this study, the socket
environment plays an important role in the healing of replanted teeth in dogs.
PMID- 9550044
TI - Accuracy of apex locator.
AB - An evaluation of the accuracy of the "Root ZX" apex locator was conducted on 20
single-rooted teeth that had been extracted because of severe disease or
orthodontic treatment. After the pulp chamber had been accessed and the tooth
length determined using the Root ZX apparatus, the file was fixed to the tooth
with light-cured composite resin. After extraction, the tooth was longitudinally
ground with a diamond bur until the file was visible. The distance between the
file tip and the apical foramen was measured under a microscope (x 100). The
results showed that the tip of the instrument reached the apical foramen in all
teeth.
PMID- 9550045
TI - Direct digital radiography for the detection of periapical bone lesions: a
clinical study.
AB - The aim was to compare the observer performance of direct digital radiography,
with and without image processing, with that of conventional radiography, for the
detection of periapical bone lesions. For 50 patients, a conventional periapical
radiograph using E-speed film was taken. Then, a direct digital image of the same
area was made. The images presenting the periapical bone tissue of 59 roots were
assessed by seven observers using a 5-point confidence scale. The digital images
were first presented as original images, with default contrast and brightness set
by the computer system. Following this, the observers were allowed to use the
processing facilities for greyscale treatment. The results for original and
processed direct digital images and for conventional radiographs were compared by
Receiver Operating Characteristic (ROC) analysis. The area under the ROC curve,
calculated as P(A) value, was 0.88 for conventional film, 0.82 for original
digital images and 0.78 for processed images. Corresponding Az values were
slightly higher, 0.89, 0.84 and 0.81. Statistically significant differences
between ROC areas calculated as P(A) values for the methods were found.
Comparison between Az values showed no significant differences between
conventional radiographs and original digital images, whereas the difference
between Az values for original and processed digital images was still
significant. It was concluded that conventional film radiography performed
slightly better for the detection of periapical bone lesions than direct digital
radiography and that image processing did not improve the observer performance.
PMID- 9550046
TI - Long-term follow-up of conservative treatment of severely traumatized maxillary
incisors.
AB - We present the case of a 26-year-old man who at the age of 9 suffered severe
trauma to both maxillary central incisors. The underlying malocclusion was
skeletal and classified as dental Class II/1 with severe crowding. Both the
maxillary central incisors and the two lower first premolars were extracted and
the patient was treated with an edgewise appliance for 2 years. Acceptable
occlusal relationships were achieved following orthodontic and adjunctive
treatment which consisted of reshaping the maxillary lateral incisors with
composite materials and grinding the canines to resemble lateral incisors. A
critical evaluation of the esthetic and functional results at the age of 26 years
is presented.
PMID- 9550047
TI - Crown-root fracture of lower molar--restorative procedures.
AB - Endodontically treated teeth may undergo crown, crown-root, or root fractures.
The treatment of fractured teeth can be complicated, sometimes because of
difficulties with the final restoration. This case report describes a case of
crown-root fracture of a left lower first molar in which endodontic treatment and
rapid orthodontic eruption of the tooth made a good prosthetic restoration
possible.
PMID- 9550048
TI - Multiple dens invaginatus affecting maxillary lateral incisors and a
supernumerary tooth.
AB - Dens invaginatus is a developmental variation resulting from an alteration in the
normal growth pattern of the dental papilla of a tooth. This anomaly occurs
predominantly in maxillary permanent lateral incisors. Multiple occurrence in
maxillary incisor teeth in the same patient has frequently been reported, and
examination of bilateral teeth for the anomaly is often carried out routinely.
This paper reports an unusual case of multiple invaginations, including dens
invaginatus affecting maxillary lateral incisors and a supernumerary tooth and
minor invaginations of the upper canines. Moreover, the case illustrates the
importance of examining all the teeth in patients who present with dens
invaginatus and palatal pits in incisors and canines. The possibility that the
supernumerary tooth had resulted from gemination of the lateral incisor tooth
germ is discussed.
PMID- 9550049
TI - Endodontic hand instruments: cutting efficiency, instrumentation of curved
canals, bending and torsional properties.
AB - In an assessment of the usefulness of different root canal instruments, two
aspects are of particular interest for the endodontist: the cutting efficiency of
the instruments and their ability to enlarge curved canals without undesirable
changes of the canal shape such as the formation of zips and elbows. This review
paper is based on own investigations on the cutting efficiency and
instrumentation of curved canals. Additionally, two parameters which are
described in ISO 3630-1, resistance to bending and resistance to fracture, are
discussed. With regard to cutting efficiency in rotary motion, flexible stainless
steel reamers and K-files clearly display the best results and are superior to
conventional stainless steel as well as titanium-based reamers and K-files.
Regarding cutting efficiency in linear motion, stainless steel Hedstrom files
made by certain manufacturers are significantly superior to stainless steel and
titanium-based Hedstrom files of other brands. Flexible stainless steel
instruments with modified noncutting tips clearly produce the best canal shape in
curved canals. With only rare exceptions, all the instruments tested fulfilled
the requirements of the ISO standard concerning resistance to fracture and
resistance to bending.
PMID- 9550050
TI - A histological and quantitative histomorphometric study of apexification of
nonvital permanent incisors of vervet monkeys after repeated root filling with a
calcium hydroxide paste.
AB - The purpose of this study was to compare the effect of a monthly refilling of the
root canals with calcium hydroxide paste with a single packing or replacement of
the paste at 3 months on the apexification of nonvital maxillary incisors of
vervet monkeys. Forty-eight maxillary incisors from 12 monkeys were used
following radiographic determination that root development was incomplete. The
pulps were extirpated under general anesthesia and the root canals filed and
cleaned. The root canals were filled with a commercial calcium hydroxide paste,
Calxyl, and a temporary cavity filling placed. Twelve teeth were left without
further treatment. The calcium hydroxide paste was replaced in 12 teeth after a 3
month interval, and in the remaining 24 teeth the calcium hydroxide root filling
was replaced five times at monthly intervals. The monkeys were killed after 6
months, and blocks of the teeth and surrounding tissues were embedded,
decalcified and 6 microns serial sections prepared and stained. The sections were
studied histologically to evaluate 11 parameters. Significant differences were
found in the amount of calcium hydroxide at the apices, the presence of new
cementum on the roots and the degree of inflammation, all of which were better in
the monthly refill group. Histomorphometric measurements to evaluate the
obturation of the open apices and the volume of new primary osteocementum showed
no significant difference between the three groups. It was suggested that after
the initial root filling with calcium hydroxide there was nothing to be gained by
repeated root filling either monthly or after 3 months, for at least 6 months.
PMID- 9550051
TI - Computerized 3-D reconstruction of two "double teeth".
AB - "Double teeth" is a root malformation in the dentition and the purpose of this
study was to reconstruct three-dimensionally the external and internal morphology
of two "double teeth". The first set of "double teeth" was formed by the
conjunction of a mandibular molar and a premolar, and the second by a conjunction
of a maxillary molar and a supernumerary tooth. The process of 3-D reconstruction
included serial cross-sectioning, photographs of the sections, digitization of
the photographs, extraction of the boundaries of interest for each section,
surface representation using triangulation and, finally, surface rendering using
photorealistic effects. The resulting three-dimensional representations of the
two teeth helped us visualize their external and internal anatomy. The results
showed: a) in the first case, fusion of the radical and coronal dentin, as well
as fusion of the pulp chambers; and b) in the second case, fusion only of the
radical dentin and the pulp chambers.
PMID- 9550052
TI - Tritiated thymidine uptake in periodontal ligament cells of dogs' teeth stored in
various media for extended time periods.
AB - The purpose of this study was to evaluate a new storage solution, Conditioned
Medium, vs Hank's balanced salt solution and ViaSpan with respect to the
viability of periodontal ligament cells of exarticulated teeth. Teeth were stored
for periods of 6, 48, and 96 hours in Hank's balanced salt solution, ViaSpan
(Dupont Pharmaceuticals), or Conditioned Medium. Teeth were cultured for 24 hours
in Dulbecco's medium supplemented with tritiated thymidine. The cultured teeth
were sectioned and evaluated with autoradiography. Control teeth were extracted
and immediately treated as above without storage. Mitotic activity was indicated
by clusters of five or more grains over the nuclei of fibroblasts in the
remaining periodontal membrane. The ratio of labeled to unlabeled cells (labeling
index) was calculated for each treatment group. When storage time was compared
across all groups, 96 hours was significantly different from 6 and 48 hours (P <
0.001 and P < 0.012 respectively). Storage time of 6 hours was not significantly
different from 48 hours (P > 0.10). After comparison of the nine experimental
groups with the control group, only Hank's balanced salt solution at 96 hours was
significantly different (P < 0.004).
PMID- 9550053
TI - Cutting pattern of Flexogate instruments in plastic blocks.
AB - Design modifications of endodontic instruments have been made to improve
instrumentation in curved root canals. A new instrument, the Flexogate
(Maillefer), has been introduced to overcome some of the problems associated with
preparation of the apical part of the root canal. The purpose of this study was
to investigate the cutting pattern of Flexogates in curved canals (45 degrees) in
clear plastic blocks, prepared by four different operators. Image analysis was
used to take accurate measurements of canal shape before and after
instrumentation to calculate cutting patterns. The results showed that Flexogates
did not remain centred in the canal of a plastic block during cutting; maximum
transportation occurred in the apical third of the outer curve, with little or
none in the middle and coronal thirds. The clinical implications of this study
require further investigation of the effect of coronal preflaring, and
experimentation in teeth.
PMID- 9550054
TI - Effect of XeCl-308nm excimer laser on the mineral content of human dentin.
AB - The effect of the XeCl-308nm excimer laser on the mineral content and surface
morphology of cut dentin was examined in ten extracted human teeth. Each dentin
specimen was lased for 4 s at a fluence of 1 J/cm2 and a frequency of 25 Hz. Non
lased area of the same specimen served as control. Scanning electron microscopy
and energy dispersive spectrometry revealed a significant decrease in the
phosphorus levels following laser treatment. A decrease in calcium levels also
occurred but was not statistically significant. Nonsignificant changes in sulphur
and potassium levels were also noted. Morphologically, the lased dentin showed an
apparently melted surface with partial obstruction of the dentin tubules as well
as cracks along the lased surface. Therefore, it appeared that laser treatment
may alter the chemical structure as well as the surface morphology of the dentin.
PMID- 9550055
TI - Urinary catecholamine levels and dentofacial injuries in children.
AB - This study investigated the relationship between urinary catecholamine levels and
dentofacial injuries in 221 children, boys and girls, aged 8 to 10 years.
Dentofacial injuries were recorded by a questionnaire and a clinical examination.
Three 24-h urine samples, taken with an interval of 1 year between each, were
available for each subject. A representative urine sample from each examination
was analyzed by the high-performance liquid chromatography technique to assay the
catecholamine content. Socioeconomic factors were recorded by a questionnaire. Of
the examined children 58 (24 boys and 34 girls) with complete 24-h urine samples
showed neither historical nor clinical evidence of dentofacial injuries and
constituted the control group. Two case groups, A and B, with historical and/or
clinical evidence of dentofacial injuries were matched by age and gender.
Differences in the quantitative and qualitative data were tested by the paired t
test and the chi 2 test, respectively, while a regression analysis was applied to
measure the effects of norepinephrine on epinephrine and dopamine. The 95%
probability level was used. The results showed significant differences between
control and case group A in the epinephrine and norepinephrine levels of the
second urine sample. Significant differences were also found between control and
case group B at the first urine sample in epinephrine and dopamine and at the
second in epinephrine. Injured boys had significantly higher values of all
catecholamines except for epinephrine in the second urine sample than injured
girls. The only significant difference found between boys and girls without
dentofacial injuries was in norepinephrine in the second urine sample. The data
suggested that children with dentofacial injuries are more frequently under
emotional stress and consequently emotionally stressful children run a greater
risk of sustaining such injuries.
PMID- 9550056
TI - Toothache with a multifactorial etiology: a case report.
AB - A case report of orofacial pain originating from both dental and nondental
conditions is presented. The spontaneous throbbing pain initiated from the left
maxillary second premolar and spread throughout the entire upper part of the face
to the frontoparietal area. Root canal treatment of the maxillary second premolar
did not resolve the chief complaint. Magnetic resonance imaging examination
revealed hypertrophy of the left inferior turbinate and soft tissue haziness in
the left maxillary sinus floor. After antrostomy, submucosal turbinectomy, and
endodontic treatment, the patient was free from pain. The final diagnosis of this
case, in addition to pulpitis, was maxillary sinusitis with chronic rhinitis. The
multiple factors associated with the etiology made the diagnosis difficult. The
mechanism of referred pain from the maxillary sinus and paranasal mucosa to the
maxillary teeth and face is discussed.
PMID- 9550058
TI - Provisionalization for ceramic laminate veneer restorations: a clinical update.
AB - At the inception of ceramic veneer restorations in the early 1980s, provisional
veneer restorations were not customarily placed over teeth which had undergone
tooth reduction. During the last several years, provisional veneer restorations
have been utilized with increased frequency for a variety of valid reasons. The
learning objective of this article is to examine the reasons for the increased
utilization of provisional veneer restorations and to describe a selection of the
clinical methods employed for direct and indirect fabrication. The indications
and contraindications for provisionalization are presented. Four case reports are
utilized to describe and illustrate the various clinical circumstances, the
provisionalization procedures, the appropriate instruments, and the materials
that facilitate the fabrication of aesthetic, functionally sound, and
biocompatible provisional restorations.
PMID- 9550057
TI - Treatment of a horizontal root fracture by vital root submergence.
AB - Cervical third horizontal root fractures in immature permanent teeth often
present complicated and unpredictable treatment options. This case report
describes the successful management of a horizontal root fracture in an open apex
tooth by vital root submergence and subsequent nonsurgical root canal therapy.
PMID- 9550059
TI - Bone rehabilitation to achieve optimal aesthetics.
AB - Treatment involving oral implants has established a high success rate, including
implant survival on a long-term basis. The challenge facing the clinicians today
is to achieve an optimal long-term aesthetic result. To address this challenge,
the volume of the underlying hard and soft tissue must be restored either prior
to or simultaneously with the implant placement. The learning objective of this
article is to review the critical biologic and clinical criteria essential in
achieving a predictable success in aesthetic enhancement of the implant site. The
article discusses the five phases of ridge reconstruction, utilization of bone
grafts (with or without membranes), and the use of membranes alone. Soft tissue
management and augmentation in aesthetic and nonaesthetic regions are
differentiated and presented. Surgical complications are recognized as a clinical
reality, and exposure of the membranes is evaluated and discussed. Four cases are
used to describe and illustrate the clinical procedure.
PMID- 9550060
TI - The aesthetic composite anterior single crown restoration.
AB - Achieving natural aesthetics by harmoniously matching the shape and color of a
single anterior crown is perhaps one of the greatest challenges in restorative
dentistry. The clinician must often rely on the artistic skills of a laboratory
technician who has no direct access to the patient. The shade selection process
is, therefore, impaired, and the final result may be a restoration which does not
emulate the aesthetics of the adjacent natural dentition. The learning objective
of this article is to present an innovative technique which utilizes the
qualities of high strength laboratory processing in association with the
application of light curing and freehand bonding of composite resins. This
combination allows the clinician to predictably achieve aesthetic results with
single anterior crowns. The direct, indirect, and indirect/direct restorations
are discussed, and the laboratory and clinical procedures are reviewed.
PMID- 9550062
TI - Winning with goals.
PMID- 9550061
TI - The aesthetic composite bridge.
AB - New developments are constantly introduced in the search for the optimal
treatment modality to restore a single anterior tooth. The patient attention has
shifted to aesthetics of the restoration, biocompatibility of the dental
materials utilized, conservative preparation of the teeth to be restored, and the
retention of intact adjacent dentition. The learning objective of this article is
to review the methods currently utilized and to present a recently introduced
treatment modality--the two-component bridge, which combines the strength and
resiliency of composite resin with the aesthetic advantages of porcelain. The
technology of the material is reviewed, the predominantly lingual tooth
preparation procedures are outlined, and the bridge try-in is described. The
advantages of the two-component bridge are presented along with the
contraindications and suggestions of careful case selection. Three cases with
congenitally missing maxillary lateral incisors in youthful patients are
presented to supplement the theoretical outline and to describe and illustrate
the clinical procedure.
PMID- 9550063
TI - Sphenopalatine ganglion neuralgia.
PMID- 9550064
TI - Electronic dental anesthesia: an injection-free alternative--a review.
PMID- 9550065
TI - Considerations for the aesthetic restoration of endodontically treated anterior
teeth following intracoronal bleaching.
AB - The major considerations in restoring the pulp chamber following bleaching of
endodontically treated anterior teeth include aesthetics, function, appropriate
endodontic access preparation, amount of remaining tooth structure, type of
restorative material, prevention of microleakage, and prevention of iatrogenic
perforation. The learning objective of this article is to review the
considerations that must be made when placing aesthetic restorations in the pulp
chamber and access opening of endodontically treated teeth following intracoronal
bleaching. The advantages and disadvantages of the proposed techniques and
materials are discussed, as are the methods for avoiding excessive removal of the
tooth structure. Two case reports are used to demonstrate the clinical
procedures. The authors suggest placing white gutta-percha stopping material in
the pulp chamber and a composite restoration in the access opening following root
canal treatment and/or bleaching procedures in the anterior dentition.
PMID- 9550066
TI - Megabrasion: a conservative strategy for the anterior dentition.
AB - Continuous developments in adhesive restorative techniques, tooth whitening
procedures, and restorative materials have significantly broadened the initially
defined spectrum of indications for composite restorations. These developments
have thereby contributed to the achievement of one of the major objectives of
conservative restorative dentistry--the maximum preservation of sound tooth
structure. In order to optimize the application of modern composite resin
technology, mastering the basic principles of natural aesthetics is an essential
prerequisite. The learning objective of this article is to discuss the etiology
of enamel discoloration and conservative treatment strategies, including
microabrasion and masking procedures. Emphasis is placed on a simple procedure-
the megabrasion technique--which does not depend extensively on the artistic
skills of the operator. It represents a useful and predictable approach for the
elimination of white opaque stains on the enamel and yellow-brown enamel
discolorations.
PMID- 9550067
TI - Generational differences in implant prosthodontics: a biomechanical solution.
AB - Correct placement of implants is facilitated by the parameters that are already
established, dictated by the struts and borders of the existing implant frame.
The root-form implants should be: Contained in the anterior symphysis of the
mandible. Completely encompassed in bone, without any contact with the Vitallium
frame. As long as possible, to enhance biomechanical support of the superimposed
bar and prosthesis. Evenly dispersed, in order to support a Hader bar.
Independent of the previous implant system. Placed to fill the anteroposterior
spread as completely as possible. The rationale and approach should comprise
these requirements in order to achieve a predictable solution to mechanical
failure of a subperiosteal implant, in an efficient manner, with the least
possible trauma to the patient.
PMID- 9550068
TI - Conservative direct and indirect resin posterior restorative alternatives for
cracked dentition.
AB - Cracked posterior teeth are often discovered when an existing restoration is
removed for routine treatment. When the entire cusp is completely worn or
fractured, recent advances in dentin bonding technology, ceramic systems, and
composite restorative materials allow conservative onlay restorations as opposed
to the aggressive removal of sound tooth structure for a full-coverage crown
restoration. Questions have arisen as to what is the optimal treatment when
cracks are discovered in posterior dentition when the cusps remain intact, i.e.,
whether the unaffected cusps should be removed. The learning objective of this
article is to present conservative alternatives to the aggressive removal of
sound tooth structure, utilizing direct resin restorative materials and current
adhesive technology.
PMID- 9550069
TI - Effects of dental trauma on the pulp.
AB - Infection of the root canal system following dental trauma induces pulp and
periapical disease and prevents healing of previously healthy pulp. A clinical
goal in treating trauma is the maintenance of pulp vitality, and clinicians
should be aware of factors that influence pulp healing. The learning objective of
this article is to review the factors and techniques that influence pulp vitality
and examine the influence pulp has on the healing of adjacent tissues. The
potential routes for bacterial infection of the root canal system are discussed,
with the clinical crown as the primary portal of entry. Uncomplicated and
complicated crown fractures, as well as the crown-root and root fractures, are
reviewed. Complications in pulp healing include canal obliteration, disturbed
root development, apexogenesis, apexification, and the various forms of
resorption.
PMID- 9550070
TI - Restoring Class V lesions Part I: Carious lesions.
PMID- 9550071
TI - Pain management. Choices.
PMID- 9550072
TI - Replacement of missing mandibular lateral incisors with a single pontic all
ceramic prosthesis: a case report.
AB - The conventional approach for replacing congenitally missing mandibular lateral
incisors dictates the placement of either a conventional porcelain-fused-to-metal
(PFM) bridge, Maryland bridge, or fiber-reinforced composite veneer bridge.
However, several appearance-related disadvantages have been reported in the use
of a prosthesis which incorporates a metal substructure. To address these
limitations, metal-free restorative alternatives have been recently developed to
expand the clinical options when fabrication of these prostheses is indicated.
The learning objective of this article is to present the utilization of a single
pontic all-ceramic resin-bonded bridge to replace congenitally missing mandibular
lateral incisors, where the existing mesiodistal spaces were narrow and the
abutment teeth exhibited insufficient substance for the conventional treatment
modality.
PMID- 9550073
TI - An orally administered drug for treatment of periodontal disease.
PMID- 9550074
TI - Dentoalveolar morphology: evaluation of natural root form versus cylindrical
implant fixtures.
AB - The function of implant-supported restorations is now routinely achieved. As a
result, the emphasis in restorative implant dentistry has shifted from function
to aesthetics and the biocompatibility of the materials utilized. The learning
objective of this article is to review the three major components essential to
achieving natural aesthetics in implant-supported restorations--hard tissue
dynamics, soft tissue dynamics, and dental aesthetics. Particular emphasis is
directed to the dentoalveolar anatomy and morphology. Analysis of the tooth root
morphology and dimensions has resulted in the design and fabrication of
restorative components with dimensions that closely resemble the natural tooth
anatomy and aesthetics. A system of transmucosal abutments has been designed, and
its utilization is presented in this review.
PMID- 9550075
TI - Clinical analysis and treatment of spaced dentition.
AB - Spaced dentition is a common clinical finding, caused by a variety of factors. In
each case, careful analysis of clinical symptoms is mandatory for effective
treatment planning. Care should be taken to apply the least complicated treatment
plan for obtaining the most successful result. Spaced dentition often exists in
the presence of otherwise intact teeth; therefore, special care should be taken
in order to prevent overtreatment. Surgical fibrotomies, complex orthodontic
treatment, and prosthetic solutions that require sacrifice of sound tissue are
often unnecessary. This article describes a case of large maxillary and
mandibular midline diastemata, controlled by a combination of orthodontic therapy
with porcelain laminate veneer restorations. The learning objective of this
article is to develop a rational approach to spaced dentition analysis that leads
to the most appropriate treatment plan for each individual case.
PMID- 9550076
TI - Restoring Class V lesions Part 2: Abfraction lesions.
PMID- 9550077
TI - Dramatic misalignment of maxillary anterior teeth and generalized destruction of
bone and periodontal tissue.
PMID- 9550079
TI - Periodontics: past and present.
PMID- 9550078
TI - Post and core reconstruction for fixed prosthodontic restoration.
AB - If the previous restorative therapy or dental caries has resulted in substantial
loss of tooth structure, the abutment teeth for fixed prosthodontic restorations
require a core reconstruction or a post and core. Small dentin defects can be
restored with bonded cores; more extensive dentin defects that are often
accompanied by previous endodontic treatment generally require additional support
for the core material. A direct procedure with a bonded post is a viable
treatment method. The decision to use either light-conducting all-ceramic
zirconium or titanium as a post material depends on the aesthetic requirements
present. The indications for a cast post and core as an indirect procedure for
prosthodontic reconstructions appear to be decreasing. The learning objective of
this article is to review the past and current post and core materials and
techniques. Indications for core reconstruction with vital teeth and posts and
cores for pulpless teeth are discussed.
PMID- 9550080
TI - Operative dentistry: the missing clinical standards.
AB - Since the development of advanced adhesive technology, the use of amalgam has
declined significantly. The search for amalgam substitutes, i.e., restorative
materials which maintain similar clinical function and cost-effectiveness as
amalgam, has so far been unsuccessful. It has also become evident that a
considerable confusion prevails regarding the objectives of restorative
procedures. In absence of national and international standards, the products--the
restorations--are assessed according to varied criteria. In placing restorations,
three objectives are attained, at most: a) tooth preservation, b) tooth
preservation and function, and c) tooth preservation, function, and imperceptible
restitution. The learning objective of this article is to discuss the positive
effects that could be attained by defining the standards, terminology, and the
quality assessment criteria for operative dentistry in regard to the patients and
the dental profession.
PMID- 9550081
TI - Sometimes, it's all in the timing!
PMID- 9550083
TI - TMJ injuries from direct trauma.
PMID- 9550082
TI - The effect of core translucency on the aesthetics of all-ceramic restorations.
AB - Recent advances in ceramic technology have revolutionized aesthetic dentistry.
When treating a single anterior tooth in need of a full-coverage restoration, a
multitude of options in restorative materials and techniques is available to the
clinician. The learning objective of this article is to present and evaluate a
selection of all-ceramic dental materials currently available for aesthetic full
coverage crown restorations. When selecting an all-ceramic system, there are
several major factors to consider, including the inherent translucency of the
ceramic material and of the adjacent dentition, the color of the prepared tooth,
and the forces anticipated in that region. Preparation and restoration of
discolored and nondiscolored tooth structure are reviewed. The techniques
presented can be utilized to obtain predictable results in the anterior region
for aesthetic all-ceramic full-coverage restorations.
PMID- 9550084
TI - Dens invaginatus--a pathway to pulpal pathology: a literature review.
AB - Dens invaginatus is the most common dental anomaly in a group of dental
anomalies, related by their embryologic development and by the fact that their
defects provide a potential pathway for bacteria to cause pulpal pathology. It
occurs when the inner enamel epithelium invaginates into the dental papilla prior
to calcification. It exists in erupted teeth as an enamel-lined tract, which
either ends in a blind sac inside the crown or root or exits into the periodontal
ligament. The lining may be incomplete in areas and may not protect the pulp.
Methods of providing preventive treatment for teeth with dens invaginatus are
described. When pulpal pathosis occurs, the dens may displace the pulp and
complicate access cavity preparation and subsequent endodontic treatment,
adversely affecting the prognosis. The learning objective of this article is to
present treatment planning considerations and suggestions.
PMID- 9550085
TI - A study of baker's yeast reduction of piperidone-carboxylates.
AB - The stereoselective baker's yeast reduction of various N-protected piperidone
carboxylic acids have been studied, and the enantioselectivity was found to be
widely dependent on whether fermenting or non-fermenting conditions were
employed. Thus reaction of N-tert-butoxycarbonyl-4-oxopiperidine-3-carboxylic
acid ethyl ester (6) with fermenting baker's yeast gave almost racemic N-tert
butoxycarbonyl-4-hydroxypiperidine-3-carboxylic acid ethyl ester (7), however,
with complete diastereoselectivity. Reduction of 6 with non-fermenting yeast gave
7 with a 24-41% enantiomeric excess. Similarly, reduction of N-tert
butoxycarbonyl-3-oxopiperidine-4-carboxylic acid ethyl ester (17) with fermenting
baker's yeast gave racemic N-tert-butoxycarbonyl-3-hydroxypiperidine-4-carboxylic
acid ethyl ester [(+/-)-18] diastereoselectively. A convenient method for
determining the enantiomeric excess of the hydroxypiperidine carboxylic acids
derivatives was found in the reaction with Sanger's reagent followed by HPLC on a
chiral column.
PMID- 9550086
TI - Synthesis of substituted chiral piperazones resembling aza-sugars.
AB - (6R)-6-(Hydroxymethyl)piperazin-2-one (1), (6S)-6-(hydroxymethyl)piperazin-2-one
(2) and (6S)-6-[(1R, 2S, 3R)-1,2,3,4-tetrahydroxybutyl]piperazin-2-one (3) have
been prepared in optically pure forms starting from D-glucosamine hydrochloride
(4). The compounds (1-3) were tested for glycosidase inhibition.
PMID- 9550087
TI - Synthesis of meiosis-activating sterols containing fluorine.
AB - It is documented that specific types of sterol play a major role in the
resumption of meiosis in oocytes from mice in vitro. 4,4-Dimethyl-5 alpha
cholesta-8,14,24-trien-3 beta-ol (FF-MAS) isolated from human follicular fluid
and 4,4-dimethyl-5 alpha-cholesta-8,24-dien-3 beta-ol (T-MAS) isolated from bull
testicular tissue, have been shown to activate (promote) meiosis in vitro. In
order to evaluate the biological activity and stability of such compounds, new
demethylsterol derivatives have been synthesised. Using diethylaminosulfur
trifluoride (DAST) it was possible to synthesise selected delta 8, delta 14
sterols with mono and difluoro substitution at C3.
PMID- 9550088
TI - 1-Thiopsoralen, a new photobiologically active heteropsoralen. Photophysical,
photochemical and computer aided studies.
AB - 1-Thiopsoralen (7H-thieno[3,2-g]benzofuran-7-one) 1, a lead compound of a series
of heteropsoralens, was investigated. The electronic transitions involved were
studied. Fluorescence quantum yield is very low, while laser flash photolysis
showed that the triplet state is practically the sole transient of 1.
Fluorescence quantum yield (phi F) and triplet lifetime (tau F) as well as
triplet quantum yield (phi T) and lifetime (tau T) were determined. The
production of singlet oxygen was also evaluated by photophysical measurements.
Photophysical data suggest that DNA photobinding of 1, owing to short
fluorescence lifetime value and high triplet quantum yield, occurs likely through
triplet mechanism. Interactions between 1 and DNA were studied both in the ground
and the excited state. In the ground state 1 undergoes intercalation inside
duplex DNA. This fact is also supported by molecular modeling studies. By UVA
light activation 1 photobinds covalently to DNA forming mono and diadducts. The
furan side 1-thymine monoadduct, isolated from DNA photomodified by thiopsoralen,
shows a cis-syn stereochemistry, in agreement with quantum mechanics studies.
Compound 1 photobinds also with linolenic acid, component of lecithins, giving a
C4-cycloaddition, and supporting that this compound also induces photolesions at
the level of cell membrane, like psoralen. Compound 1 exhibits strong skin
phototoxicity.
PMID- 9550089
TI - Photoreaction of furocoumarins with DNA is similarly inhibited by minor and major
groove-interacting ligands.
AB - It was found that methyl green, a major groove binding ligand and the minor
groove binding ligands, netropsin and 2,7-di-tert-butylproflavine inhibit, to a
similar extend a monoadduct forming benzopsoralen and monoadduct and diadduct
forming derivatives of psoralen (8-methoxypsoralen and 3,4'-dimethyl-8
methoxypsoralen). Caffeine exhibits an inhibitory effect on furocoumarin
photobinding to DNA at 10(3) fold higher concentration. Together with the
previously published results it is concluded that both occupancy of the major and
minor groove as well as intercalation hinder photobinding of furocoumarins to
DNA.
PMID- 9550090
TI - Transformation of some pyrido[2,3-d]pyrimidine derivatives into other di- and
triheterocyclic systems.
AB - It was stated that three analogous ethyl 2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3
d]pyrimidine-5-carboxylates (7-9) react with hydrazine hydrate giving derivatives
of the new heterocyclic system pyrido[2,3,4-ef]pyridazino[3,4-e]-1,2,4-triazepine
(10-12), pyrido[3,4-d]pyridazine (16-18) and pentaazaphenalene (13-15). The
latters were formed in low yields. The results of the preliminary pharmacological
study of 2 of these compounds are reported.
PMID- 9550091
TI - One-step synthesis and pharmacological activity of new (N-substituted)amino
spiroalkan-dione derivatives.
AB - The synthesis of (N-substituted)amino-spiroalkan-dione derivatives 3 is described
starting from enamines 1 and carbon suboxide 2, and their inhibitory effects on
blood coagulation in vivo and on platelet aggregation in vitro are determined.
Some of synthesized compounds showed a strong anticoagulant activity. A
comparative pharmacological study of the anticoagulant effects of the new
compounds versus Warfarin suggests that their behaviour is analogous, though the
action mechanism is different.
PMID- 9550092
TI - Glycosidopyrroles. Part 2. Acyclic derivatives: 1-(1,3-dihydroxy-2
propoxy)methylpyrroles as potential antiviral agents.
AB - The series of 1-(1,3-dihydroxy-2-propoxy)methylpyrroles 2a-o were prepared in
good overall yields according to Scheme I. When evaluated for antiviral activity
against HIV-1, only compounds of the triphenyl series (R3 = NH2, N3, Br) were
found to inhibit the HIV-1 replication at concentrations that were very not
cytotoxic for MT-4 cells, with selectivity index 1.5-9.3. None of these compounds
showed antibacterial or antifungal activity.
PMID- 9550093
TI - Anti-HIV agents. V. Synthesis, structure and in vitro anti-HIV activity of novel
1H,3H-naphtho[2',3':4,5]imidazo[1,2-c]thiazoles.
AB - A series of 1H,3H-naphtho[2',3':4,5]imidazo[1,2-c]thiazoles, TBZ analogues, was
prepared in order to explore the influence on anti-HIV activity of the spatial
requirements of the hydrophobic moiety fused to imidazothiazole system. In spite
of a butterfly-like conformation evidenced by X-ray analysis of compound 4g, the
results of in vitro screening suggest that the replacement of the benzene fused
ring by the naphthyl moiety negatively influences the activity of analogous
thiazolobenzimidazole derivatives, some of which are potent non-nucleoside HIV-1
RT inhibitors.
PMID- 9550094
TI - Synthesis and antimicrobial activity of some new derivatives of 6,12
dihydroindolo[2,1-b]quinazolin-6,12-dione.
AB - Some derivatives of tryptantrine were prepared in order either to increase
solubility and to study structure-activity relationship. All synthesized
compounds were tested for antimicrobial activity.
PMID- 9550095
TI - Synthesis and microbiological activity of some novel N-(2-hydroxyl-5
substitutedphenyl)benzacetamides, phenoxyacetamides and thiophenoxyacetamides as
the possible metabolites of antimicrobial active benzoxazoles.
AB - Synthesis of some novel N-(2-hydroxyl-5-substitutedphenyl)benzacetamides,
phenoxyacetamides and thiophenoxyacetamides (5a-k) were described in order to
determine their in vitro antimicrobial activity against 3 Gram-positive, 3 Gram
negative bacteria and the fungus Candida albicans comparing with several control
drugs. The derivative 5e was found active at a MIC value of 25 micrograms/ml
against the whole tested Gram-positive bacteria strains and the Gram-negative
microorganism Klebsiella pneumoniae. Moreover, the synthesized compounds 5a-k
exhibited significant antibacterial activity against the enterobacter Pseudomonas
aureginosae when compared to the control drugs. For the antifungal avtivity
against C. albicans, the compound 5k was found more active than the other
synthesized derivatives. On the other hand, the antimicrobial activity of some of
these acetamide derivatives (5c, 5d, 5e, 5j and 5k) which are the possible
metabolites of benzoxazoles, were also compared with their cyclic analogues 6-10.
However, most of the MIC values of the benzoxazole derivatives provided better
activity than the compared acetamides, while some others of the acetamide
derivatives possessed either one fold improved (5d, 5e and 5j) or the same
potency (5c, 5d, 5e, 5j and 5k) against the tested microorganisms.
PMID- 9550096
TI - Evaluation of antimycobacterial and anticonvulsant activities of new 1-(4
fluorobenzoyl)-4-substituted-thiosemicarbazide and 5-(4-fluorophenyl)-4
substituted-2,4-dihydro-3H-1,2,4-triazole-3-thione derivatives.
AB - Some new 1-(4-fluorobenzoyl)-4-alkyl/arylthiosemicarbazide (2a-g), 5-(4
fluorophenyl)4-alkyl/aryl-2,4-dihydr-3H-1,2,4-triazole-3-thio ne (3a-g)
derivatives, 3-(benzylthio)-5-(4-fluorophenyl)-4-phenyl-4H-1,2,4-triazole (3h)
and 2-acetyl-5-(4-fluorophenyl)-4-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thi one
(3i) were prepared and tested for their antimycobacterial and anticonvulsant
activities. The structure of compounds was confirmed by elemental analyses and
spectroscopic techniques. The antimycobacterial activity of the synthesized
compounds was investigated against M. fortiutum ATCC 6841 and most of them were
found active against the above strain with MIC values of 64 or 32 micrograms/ml.
The anticonvulsant activity of the 2d, 3d-i was determined against
pentylenetetrazole induced seizures. 3f-i showed anticonvulsant activity (10 to
30% protection).
PMID- 9550097
TI - Bioabsorbable polyphosphazene matrices as systems for calcitonin controlled
release.
AB - To provide a suitable delivery system for the calcitonin controlled release 80 mg
bioabsorbable polyphosphazene matrices were obtained with entrapped 50 or 250
micrograms calcitonin. The in vitro behaviour demonstrated a release burst for
about 24 hours, followed by a period of slow release of the peptide lasting for
weeks. Matrices containing 250 micrograms calcitonin were implanted under general
anaesthesia in osteoporotic female rats, while a group of animals (control group)
received unloaded matrices. After thirty days a second batch of matrices was
implanted in both groups to prolong the period of treatment until two months. The
explanted matrices were histologically evaluated together with the surrounding
tissues, and the dosage of the residual calcitonin was also performed. Results
demonstrated the good biocompatibility of the system and the complete release of
the calcitonin from the matrices 30 days after implantation. The therapeutic
effect, after sixty days of treatment was confirmed by the better densitometric
values observed in the femoral bone of treated animals than in controls.
PMID- 9550098
TI - Effects of a benzimidazole compound on monooxygenase activities.
AB - A retinoid-type benzimidazole compound (benzimidazole-tetranaphthalene, BITN) was
synthesized and its effects on hepatic cytochrome P450 (CYP) dependent
ethoxyresorufin O-deethylase (EROD) and pentoxyresorufin O-depentylase (PROD)
enzyme activities were determined in rats in vitro. In vitro addition of BITN in
10(-3) M concentration to the reaction medium caused inhibitions in EROD (94%)
and PROD (82%) activities. With the same concentration (10(-3) M) all-trans
retinoic acid (RA) was able to inhibit EROD activity 65% and PROD activity 59%
whereas buthylated hydroxytoluen (BHT) inhibited EROD and PROD activities 73% and
62%, respectively. The specific inhibitors of EROD activity (caffeine) and PROD
activity (SKF 525A) at 10(-3) M concentration inhibited the corresponding enzymes
33% and 77%, respectively. Thus, these results reveal that the BITN has a
stronger inhibitory effect than RA, BHT, caffeine and SKF 525 A on the enzyme
activities. Since these enzymes (EROD, CYP 1A1/2 and PROD, CYP2B1) activate
polycyclic hydrocarbons, aromatic amines and aliphatic halogenated hydrocarbons
to their ultimate mutagenic or carcinogenic forms, and are effective in producing
reactive oxygen species such as superoxide, hydroxyl radical and hydrogen
peroxide, the new compound, BITN, appears to have a greater anticarcinogenic and
antioxidant potential than RA and BHT.
PMID- 9550099
TI - Synthesis, lipophilicity and biological properties of some novel 1H-1,2,4
triazole derivatives.
AB - A series of new 1H-1,2,4-triazole derivatives was synthesized and evaluated as
potential antiviral (i.e. anti-influenza virus), antibacterial and antifungal
agents. The lipophilicity of the compounds was also investigated using
calculation procedures. Among the test compounds none showed specific activity
against influenza virus, although compound 3a, the most hydrophilic member of the
series, showed weak activity against Bacillus subtillis.
PMID- 9550100
TI - Maintaining fixed band spacing when changing column dimensions in gradient
elution.
AB - In gradient elution separations, it may be required to change either column
length (to increase resolution or shorten run time) or column diameter (for an
increase in sensitivity or for preparative separations). In either of these
changes of column dimensions, it is usually desired to maintain the same relative
band spacing (selectivity), so as to increase resolution in proportion to (column
plate number)1/2 when increasing column length, or to maintain constant
resolution when changing column diameter. A general rule for avoiding changes in
band spacing in these situations is to maintain the quantity [(gradient time) x
(flow-rate)/(column volume)] constant, while holding the initial and final
gradient mobile phase compositions (%B) fixed. This rule is only valid as long as
the equipment hold-up volume (dwell volume) is negligible, or if all sample
components are strongly retained at the start of the gradient. When neither of
the latter conditions apply, then significant changes in band spacing may result
when changing column size. Rules are presented for recognizing this potential
problem for a given sample/HPLC-equipment combination, and adjustments in
separation conditions that can avoid this problem are discussed. Changes in band
spacing as a result of change in column size are of special concern when
developing procedures for preparative chromatography under gradient conditions.
PMID- 9550101
TI - Dye-ligand and metal chelate poly(2-hydroxyethylmethacrylate) membranes for
affinity separation of proteins.
AB - Cibacron Blue F3GA was covalently immobilized onto poly(2-hydroxyethyl
methacrylate) pHEMA) membranes via the nucleophilic reaction between the chloride
of its triazine ring and the hydroxyl group of pHEMA. Then, Fe3+ ions were
complexed by chelation with the immobilized Cibacron Blue F3GA molecules.
Different amounts of Fe3+ ions were loaded on the membranes by changing the
concentration of Fe3+ ions and pH of the reaction medium. Membranes with or
without Fe3+ were used in the adsorption of glucose oxidase, catalase and bovine
serum albumin. The adsorption capacities of these membranes were determined by
changing pH and the concentration of the proteins in the adsorption medium. The
adsorption phenomena appeared to follow a typical Langmuir isotherm. The maximum
capacities (qm) of the Fe3+ complexed membranes for glucose oxidase, catalase and
bovine serum albumin (8.70 x 10(-3) mumol m-2, 2.15 x 10(-3) mumol m-2 and 2.21 x
10(-3) mumol m-2) were greater than those of the untreated membranes (6.79 x 10(
3) mumol m-2, 1.34 x 10(-3) mumol m-2 and 1.94 x 10(-3) mumol m-2) respectively.
The nonspecific adsorption of the enzymes and the protein on the pHEMA membranes
was negligible.
PMID- 9550102
TI - Trace determination of methanol in water-ethanol solution by derivatization and
high-performance liquid chromatography.
AB - A simple and sensitive high-performance liquid chromatographic method has been
established for the determination of methanol in water-ethanol solution. The
method is based on the transfer of the methoxide anion, which is formed from
methanol under strong alkaline treatment in aqueous solution, by benzalkonium
chloride into the dichloromethane organic phase for derivatization with 3
bromomethyl-7-methoxy-1,4-benzoxazin-2-one. The derivative obtained was separated
on a LiChrospher diol column with n-hexane-dichloromethane (9:1, v/v) as the
mobile phase. Several parameters affecting the partition/derivatization of
methanol were investigated. The linear range for the determination of methanol
was 2-20 mumol/ml; the detection limit (signal-to-noise ratio = 5; sample size,
10 microliters) of methanol was about 0.10 mumol/ml (R.S.D. = 16%, n = 3). The
method has been satisfactorily applied to the assay of methanol in spiked
commercial liquors.
PMID- 9550103
TI - Quantitative analysis of flavonols, flavones, and flavanones in fruits,
vegetables and beverages by high-performance liquid chromatography with photo
diode array and mass spectrometric detection.
AB - A high-performance liquid chromatographic (HPLC) separation method with photo
diode array (PDA) and mass spectrometric (MS) detection was developed to
determine and quantify flavonols, flavones, and flavanones in fruits, vegetables
and beverages. The compounds were analysed as aglycones, obtained after acid
hydrolysis of freeze-dried food material. Identification was based on retention
time, UV and mass spectra by comparison with commercial standards, and the UV
peak areas were used for quantitation of the flavonoid contents. Examples of HPLC
MS, analyses of orange pulp, tomato, and apple are presented. The method has been
used to screen foods on the Danish market, and the contents of flavones,
flavonols, and flavanones were measured.
PMID- 9550104
TI - Separation of indenestrol A and B isomers and enantiomers by high-performance
liquid chromatography.
AB - High-performance liquid chromatography (HPLC) methods have been developed for the
separation of substituted indenestrol A and B isomers on different columns. The
isomers were separated by normal-phase liquid chromatography with a silica gel
column. Enantiomers of these compounds were separated by chiral HPLC and the most
successful separations were achieved with a Chiralcel OJ column.
PMID- 9550105
TI - Zn(2+)-selective purification of recombinant proteins from the milk of transgenic
animals.
AB - The milk of transgenic livestock is becoming a viable, large-scale source of post
translationally complex, recombinant therapeutic proteins. Recombinant vitamin K
dependent proteins such as human protein C (rhPC) and Factor IX can be produced
in milk. However, rate limitations in post-translational modification such as
intrachain proteolytic cleavage and gamma-carboxylation occur in the mammary
gland. Thus, most desirable recombinant products often exist as sub-populations
in milk because the mammary gland tends to secrete incompletely processed
polypeptides. In general, a nonaffinity purification strategy by which to purify
mature recombinant proteins from milk is desirable. Zn2+ is used to selectively
modify ion-exchange adsorption behavior of endogenous and recombinant milk
proteins through conformational changes which cause aggregation and or
precipitation. Zn(2+)-selective precipitation of milk and recombinant proteins
results in the purification of active rhPC at high yield from the milk of
transgenic pigs using expanded bed chromatography. This method selects for rhPC
which is both heterodimeric and properly gamma-carboxylated. Due to the homology
of milk proteins among different species, this same Zn(2+)-selective
precipitation strategy is useful for developing purification methods for other
recombinant proteins from the milk of transgenic livestock.
PMID- 9550106
TI - Affinity chromatography of thiol ester-containing proteins.
AB - A method is described for the affinity chromatographic purification of thiol
ester proteins. These comprise the complement proteins C3 and C4 and the protease
inhibitor alpha 2-macroglobulin (alpha 2M) and are known to contain an internal
beta-cysteinyl-gamma-glutamyl thiol ester. The method employs aminoalkyl ligands
coupled to a divinylsulfonyl-derivatized agarose matrix, and the length of the
aminoalkyl spacer arm was found to be important for the effectiveness of the
matrix. Optimal results were obtained with diaminododecyldivinylsulfonyl-agarose.
Employing this matrix the thiol ester proteins C3, C4 and alpha 2M were isolated
from human pregnancy serum. Application of the method to chicken and rainbow
trout serum gave rise to isolation of several proteins including chicken and
rainbow trout alpha 2M.
PMID- 9550107
TI - Determination of some physicochemical parameters of microcystins (cyanobacterial
toxins) and trace level analysis in environmental samples using liquid
chromatography.
AB - Some physicochemical parameters of three microcystin standards, known to be
potent hepatotoxins produced by cyanobacteria, were determined using well defined
chromatographic measurements. The logarithm of their retention factor on
octadecylsilica (ODS) with water as the eluent, which is an estimation of the
hydrophobicity of a molecule, was assessed at pH 7 at 3.9, 4.2 and 4.4 for
microcystins-YR, -LR and -RR, respectively. Though being rather hydrophobic,
microcystins also possess polar functions, namely carboxylic acids, amino and
amido groups. The ionization of carboxylic groups occurs at pH values of 3.3-3.4.
In environmental waters, microcystins are neutral or anionic. They are readily
soluble in water, the solubility of microcystin-LR being higher than 1 g/l. Owing
to their hydrophobicity and their polar functions, microcystins remain in the
aqueous phase rather than being adsorbed on sediments or on suspended particulate
matter. In a river water spiked with microcystins at 5 micrograms/l, only 10% was
adsorbed on particles and 7% on the sandy sediment after three days. A method
using solid-phase extraction on ODS followed by high-performance--or micro-
liquid chromatography was optimized to detect microcystins at trace level in
water. A clean-up was introduced to eliminate part of the interfering compounds
coextracted during the sample percolation. Good recoveries (75-80%) were
obtained. The method was linear, reproducible (with relative standard deviations
ranging from 5 to 8%) and enabled the determination of microcystins at levels as
low as 30 ng/l in drinking water and 100-200 ng/l in surface waters. The
production of toxins by two strains of cyanobacteria was evaluated. Variations in
the microcystin-LR content in the cells and in the medium of Microcystis
aeruginosa PCC7806 were recorded over a five-week period. Toxin production was
not correlated to the biomass but depended on the growth stage and was maximal at
the end of the exponential growth phase. The release of toxin in water occurred
essentially in old cultures where microcystin-LR was determined at concentrations
of 170 and 280 micrograms/l in the media of M. aeruginosa PCC7806 and M.
aeruginosa PCC7813, respectively. Other microcystins are likely to be synthesized
by these strains. But owing to the lack of standards, mass spectrometric
detection is required for further identification. This study points out the need
of having other standards for water quality monitoring.
PMID- 9550108
TI - Chiral and nonchiral determination of ketoprofen in pharmaceuticals by capillary
zone electrophoresis.
AB - The new method for the enantiomeric resolution of various 2-arylpropionic acids
by capillary zone electrophoresis (CZE) using heptakis-tri-O-methyl-beta
cyclodextrin as chiral selector was applied to the determination of ketoprofen in
different commercially-available pharmaceutical preparations. The analyte was
determined under chiral and nonchiral conditions (viz. in the presence and
absence of 50 mM heptakis-tri-O-methyl-beta-cyclodextrin in the background
electrolyte), with significantly similar results and relative standard deviations
from 1.2 to 6.5% in both cases. The limits of detection and determination for the
inactive enantiomer, R-(-)-ketoprofen, were calculated to be 7.0 x 10(-7) and 1.6
x 10(-6) M, respectively. The proposed method was successfully used to determine
enantiomeric purity in the drugs studied, with results comparable to those
provided by the chiral HPLC method.
PMID- 9550109
TI - Circadian rhythms.
AB - 1997 marks the 25th anniversary of the discovery of the master circadian
pacemaker in mammals in the hypothalamic suprachiasmatic nucleus. Remarkable
progress has been made over the last 25 years in elucidating the physiological
mechanisms involved in the entrainment, generation and expression of circadian
rhythms at the cellular and systems levels. The recent discovery and cloning of
the first mammalian clock gene is expected to lead to rapid advances in the
understanding of the genetic and molecular mechanisms underlying circadian
rhythmicity in mammals. Indeed, the impressive and extensive database on
circadian rhythms in mammals obtained over the past 25 years provides a
foundation for making rapid progress in utilizing future genetic and molecular
findings for discovering the fundamental mechanisms controlling 24-hour temporal
organization.
PMID- 9550110
TI - Processes underlying sleep regulation.
AB - Sleep is regulated by homeostatic, circadian and ultradian processes. Slow waves
and sleep spindles are EEG markers of sleep processes which have counterparts at
the cellular level. The interaction of homeostatic and circadian sleep regulation
has been formalized in the two-process model and validated in experiments. Sleep
is not only a global brain phenomenon but also a regional cerebral process whose
intensity may be influenced by prior activity during waking.
PMID- 9550111
TI - Effect of seasonal changes in daylength on human neuroendocrine function.
AB - The circadian pacemaker imposes stereotypic patterns of daily variation on the
activity of human neuroendocrine systems. In a number of cases, these patterns
exhibit waveforms that are characterized by distinct diurnal and nocturnal
periods with relatively discrete transitions between them (corresponding to a
biological day, a biological dusk, a biological night, and a biological dawn). In
humans, for example, diurnal periods of absence of melatonin secretion, low
prolactin secretion, and falling levels of cortisol alternate with nocturnal
periods of active melatonin secretion, high prolactin secretion and rising levels
of cortisol. In response to light, the circadian pacemaker synchronizes the
timing of the biological day and night so that their timing and duration are
appropriately matched with the timing and duration of the solar day and night. As
the pacemaker carries out this function, it is able to adjust the duration of the
biological day and night to match seasonal variation in the duration of the solar
day and night. Thus, after humans have been chronically exposed to long nights
(scotoperiods), the duration of nocturnal periods of active melatonin secretion,
high prolactin secretion and rising levels of cortisol is longer than it is after
they have been chronically exposed to short nights. Furthermore, the sleep
related peak of growth hormone secretion is half as high after exposure to long
nights as it is after exposure to short nights. These responses to seasonal
changes in duration of the natural scotoperiod are suppressed in most individuals
- especially men - who live in modern urban environments in which they are
exposed to artificial light after dark and artificial darkness during the
daytime.
PMID- 9550112
TI - Effects of hormones on sleep.
AB - Administration of hormones to humans and animals results in specific effects on
the sleep electroencephalogram (EEG) and nocturnal hormone secretion. Studies
with pulsatile administration of various neuropeptides in young and old normal
controls and in patients with depression suggest they play a key role in sleep
endocrine regulation. Growth hormone (GH)-releasing hormone (GHRH) stimulates GH
and slow wave sleep (SWS) and inhibits cortisol, whereas corticotropin-releasing
hormone (CRH) exerts opposite effects. Changes in the GHRH:CRH ratio contribute
to sleep-endocrine aberrations during normal ageing and acute depression. In
addition, galanin and neuropeptide Y promote sleep, whereas, in the elderly,
somatostatin impairs sleep. The rapid eye movement (REM)-nonREM cycle is
modulated by vasoactive intestinal polypeptide. Cortisol stimulates SWS and GH,
probably by feedback inhibition of CRH. Neuroactive steroids exert specific
effects on the sleep EEG, which can be explained by gamma-aminobutyric acid(A)
receptor modulation.
PMID- 9550113
TI - Ultradian rhythms in hydromineral hormones.
AB - The maintenance of hydromineral homeostasis depends on the coordinated action of
arginine vasopressin (AVP), atrial natriuretic peptide (ANP), the renin
angiotensin-aldosterone system and other recently identified endocrine or
paracrine hormones. Several reports have pointed out the changes in urinary
excretion and osmolality during the sleep-wake cycle and the rapid eye movement
(REM)-non(N)REM sleep cycles. No such changes occur for ANP levels which have a
flat profile over 24 h. The pulsatile fluctuations of AVP are described as
random. The ultradian rhythm of plasma renin activity (PRA) depends on the
regularity of the REM-NREM sleep cycles and the nocturnal curves reflect all
disturbances in the internal sleep structure. A study with a shift in the normal
sleep time clearly demonstrated that both PRA and aldosterone oscillations are
sleep-stage dependent. These hormones could account for the ultradian variations
in renal function. The nocturnal oscillations in sympathovagal balance may play
an additional role. It is suggested that a central generator synchronizes
endocrine, renal, autonomic and sleep processes.
PMID- 9550114
TI - The physiology and pharmacology of melatonin in humans.
AB - Melatonin (MLT) is a methoxyindole secreted principally by the pineal gland. It
is synthesized at night under normal environmental conditions. The endogenous
rhythm of secretion is generated by the suprachiasmatic nuclei and entrained by
the light/dark cycle. Light is able to both suppress or entrain MLT production on
light schedule. The nyctohemeral rhythm of this hormone can be determined by
repeated measurement of plasma or saliva MLT or urine sulfatoxy-MLT, the main
hepatic metabolite. MLT can be considered as the output (the hand) of the
endogenous clock. Since the regulating system follows a central and sympathetic
nervous pathway, an abnormality at any level could unspecifically modify the MLT
secretion, especially in patients with sympathalgia or dysautonomia. MLT plays
the role of an endogenous zeitgeber on core temperature or sleep-wake cycle.
Exogenous MLT is able to influence the endogenous secretion of the hormone
according to a phase-response curve. There are practical implications for this
property in situations when biological rhythms are disturbed (jet-lag syndrome,
delayed sleep phase syndrome, insomnia in blind people, shift-work, insomnia in
elderly people). Improvement of pharmaceutical forms (controlled release
preparations) or development of MLT analogs could lead to decisive progress.
PMID- 9550115
TI - Therapeutic applications of melatonin and related compounds.
AB - Increasing knowledge of the pharmacological effects of melatonin has suggested
various possible therapeutic applications for the hormone. Because, as a natural
substance, melatonin cannot be patented, melatonin-related compounds have been
synthesized by industrial groups. The scope of such compounds is also to
specifically target the recently discovered melatonin receptor subtypes. The
sleep-inducing properties of melatonin are disputed, but are distinct from those
of benzodiazepines. The observed effects on sleep latency or sleep efficiency,
which remain to be confirmed, could be accounted for by the effects of melatonin
on core body temperature and on circadian rhythms. There is also an urgent need
for safety data, both in animals and in humans, particularly when long-term use
is envisaged.
PMID- 9550116
TI - Alterations of circadian rhythmicity and sleep in aging: endocrine consequences.
AB - All 24-hour endocrine rhythms partially reflect the interaction of circadian
rhythmicity with sleep-wake homeostasis but their relative contributions vary
from one system to another. In older adults, many 24-hour rhythms are dampened
and/or advanced, including those of cortisol and GH. Amplitude reduction and
phase advance of 24-hour rhythms may represent age-related changes in the central
nervous systems underlying circadian rhythmicity and sleep-wake homeostasis. Age
related alterations in circadian function could also reflect decreased exposure
and/or responsivity to the synchronizing effects of both photic (e.g. light
exposure) and nonphotic (e.g. social cues) inputs. There are pronounced age
related alterations in sleep quality in aging which consist primarily of a marked
reduction of slow-wave sleep, a reduction in REM stages and a marked increase in
the number and duration of awakenings interrupting sleep. Alterations in slow
wave sleep occur abruptly in young adulthood (30-40 years of age) whereas
disturbances in amounts of REM and wake appear more gradually. This article
reviews evidence indicating that deficits in characteristics of sleep-wake
homeostasis and circadian function may mediate age-related alterations in
somatotropic and corticotropic function. Because sleep loss in young subjects
results in endocrine disturbances which mimic those observed in aging, it is
conceivable that the decrease in sleep quality which characterizes aging may
contribute to age-related alterations in hormonal function and their metabolic
consequences.
PMID- 9550117
TI - Endocrine secretions under abnormal light-dark cycles and in the blind.
AB - Both endogenous and exogenous factors are involved in regulation of endocrine
secretions. Among the exogenous ones, light plays an important role both in
animals and in humans. Pineal gland mediates light action on the endocrine
system, by means of variations of melatonin (MT) secretion. Here we discuss about
the influence of abnormal light-dark cycles and in particular of blindness on
pineal and pituitary secretions and on those of correlated glands. MT secretion
is usually inhibited by light: thus it reaches the highest levels at night.
Exposure to short or long photoperiod causes variations in circadian or infradian
MT rhythmicity. Blind patients can show higher daytime levels with a phase
advanced or phase-delayed circadian rhythm. Lack of light stimulus affects
cortisol rhythm shifting the zenith of secretion and inducing a free-running
rhythm. Blindness can abolish nocturnal growth hormone (GH) peak and impair the
GH response to some stimuli; moreover it impairs the growth of affected patients.
Light stimulus influences favorably gonadal function both in animals and in man.
In animals, sexual activity and gonadal function decline during the seasons with
reduced luminosity. A similar finding has been described in women living in a
region with a strong seasonal contrast in luminosity. Blindness can impair
luteinizing hormone, follicle-stimulating hormone, prolactin and testosterone
secretion in prepubertal boys causing pubertal delay or more severe hypogonadism;
it can affect pubertal development and fertility in women. Light can influence
thyroid function in animals. Lack of light stimulus in blind man seems to cause
different effects on thyroid function before and after puberty. Increase of free
thyroid hormone levels has been found in prepubertal but not in adult blind
patients, probably due to a resetting of the threshold for thyrotropin feedback
suppression after puberty in these patients.
PMID- 9550118
TI - Sleep and circadian disturbances in shift work: strategies for their management.
AB - More and more businesses are providing their full range of services 24 h a day, 7
days a week, thus forcing their employees to work either rotating shifts or fixed
night shifts. Dictates of our endogenous circadian clock prevent our brains and
bodies to be indefinitely adaptable to those work schedules. Shift work
operations are thus associated with serious healthy and social problems for the
workers. Various interventions can counteract circadian desynchronization, sleep
disturbances, and social disruption associated with shift work: changes in work
schedules, sleeping and napping strategies, use of appropriately timed exposure
to bright light, experimental drug treatments, or exercise.
PMID- 9550119
TI - Gonadotropin pulsations across development.
AB - Initiation and maintenance of the reproductive axis in the human is contingent
upon the pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the
hypothalamus. In man, tracking endogenous GnRH secretion relies on frequent
peripheral sampling of three glycoprotein products of the gonadotrope,
luteinizing hormone (LH), follicle-stimulating hormone (FSH) and free alpha
subunit (FAS). FAS is superior to LH as a surrogate marker of GnRH secretory
dynamics in those circumstances where GnRH secretion is rapid or where the
pituitary LH response is low. The pattern of GnRH secretion is constantly
changing across development; from high levels during the neonatal period, through
a period of quiescence in mid-childhood, followed by sleep-entrained reactivation
of the reproductive axis at the onset of puberty, ultimately culminating in the
adult pattern of pulsatile secretion which in the male is approximately every 2 h
and in the female varies with the stage of the menstrual cycle. This episodic
mode of secretion allows differential impact of feedback mechanisms on the GnRH
neurons and facilitates the maintenance of the reproductive axis during periods
of stress by allowing frequency and amplitude modulations.
PMID- 9550120
TI - Interaction between menstrual cyclicity and gonadotropin pulsatility.
AB - Pulsatile gonadotropin secretion is a critical endocrine component of the
regulation of the normal menstrual cycle. Pulsatile luteinizing hormone (LH)
secretion changes dynamically across the menstrual cycle. Derangements of
pulsatile LH secretion are found in virtually every menstrual disorder. This
article summarizes the key features of pulsatile LH secretion in the normal
menstrual cycle and in ovulatory disorders.
PMID- 9550121
TI - Central nervous system control of thyrotropin secretion during sleep and
wakefulness.
AB - Thyrotropin (TSH) is a pulsatile secreted hormone with a pronounced circadian
rhythmicity and a characteristic nightly surge based on an augmentation of
pulsatile release. A number of physiological factors influence TSH secretion via
an alteration in the amount of pulsatile released hormone. An increase in
somatostatinergic tone during fasting appears to decrease TSH pulse amplitude and
sequentially mean TSH serum levels. In contrast, blockade of dopaminergic tone by
metoclopramide infusion when circulating TSH levels are low during the afternoon
hours increase TSH pulse amplitude to levels comparable to the nightly TSH surge
suggesting a physiological dampening of TSH pulse amplitude by dopamine during
the daytime.
PMID- 9550122
TI - Temporal profiles and clinical significance of pulsatile insulin secretion.
AB - In this article, recent experiments are reviewed which have addressed the role of
oscillatory insulin secretion in the pathophysiology of glucose intolerance and
diabetes. The ultradian oscillations of insulin secretion appear to be an
integral part of the feedback loop between glucose and insulin secretion and as a
result are abnormal in states of glucose intolerance. Treatment of impaired
glucose tolerance with troglitazone, a thiazolidinedione that improves insulin
sensitivity, leads to an improvement in the ability of the beta-cell to sense and
respond to a glucose stimulus restoring the ability of glucose to entrain the
ultradian oscillations. The rapid oscillations of insulin secretion appear to be
an inherent feature of the cellular mechanisms of insulin secretion since they
persist in the isolated perfused pancreas and in perifused islets. These
oscillations are paralleled by changes in intracellular Ca2+ and are also
abnormal in states of glucose intolerance and diabetes. Available evidence
indicates that these alterations are due to decreased expression of voltage
dependent Ca2+ channels on the beta-cell membrane.
PMID- 9550123
TI - Ultradian pulsatility of plasma glucose and insulin secretion rate: circadian and
sleep modulation.
AB - Insulin release is a complex oscillatory process with rapid pulses (10 min)
superimposed on slower circhoral oscillations (50-100 min). The exact mechanism
of the circhoral oscillations, which are probably in part the consequence of a
negative feedback loop linking glucose and insulin secretion rate, remains
unclear. Stimulatory effects of sleep on insulin secretion are achieved by an
enhancement of the oscillation amplitude which could be partly mediated by GH.
The different patterns observed after acute or chronic shift of sleep suggest
however an interaction between sleep influence and circadian rhythmicity, as
described for numerous pituitary hormones. The intra-sleep awakenings have a
modulatory effect on glucose levels but no systematic relationship exists between
glucose or insulin secretion rate oscillations and the REM-NREM sleep cycles.
Irrespective of the mechanisms involved, sleep or GH stimulatory effects result
from a modulation of the oscillation amplitude rather than of their frequency
which is probably an important feature of insulin efficacy.
PMID- 9550124
TI - The roles of time of day and sleep quality in modulating glucose regulation:
clinical implications.
AB - Consistent variations in glucose regulation across the 24-hour cycle are present
in normal subjects. These diurnal variations are altered in various states of
impaired glucose tolerance (aging, obesity, diabetes). Changes in insulin
secretion, clearance and/or action across the day have been demonstrated. Studies
in subjects receiving continuous intravenous glucose infusion have shown that
major alterations of glucose tolerance occur during sleep and that sleep quality
markedly influences glucose utilization. Diurnal variations in glucose tolerance
result from the alternation of wake and sleep states as well as from intrinsic
effects of circadian rhythmicity. The important roles of physiological variations
in levels of counterregulatory hormones which are markedly dependent on sleep
(i.e. growth hormone) or circadian rhythmicity (i.e. cortisol) have only begun to
be appreciated. The modulatory effects of sleep and circadian rhythmicity on
glucose regulation may have important clinical implications for the diagnosis and
treatment of abnormalities of carbohydrate metabolism.
PMID- 9550125
TI - Expression and degradation of rat androgen receptor following castration,
testosterone replacement and antiandrogens administration: analysis by Western
blot and immunohistochemistry.
AB - To elucidate the autoregulation of androgen receptor (AR) by androgen and
antiandrogen, Western blot analysis and immunohistochemical study were performed.
Castration reduced the immunodetected AR content, and nuclear staining was lost
without cytoplasmic staining. Testosterone (T) supplement restored AR content.
Quick response of AR content restoring following single administration of T was
observed 48 hours after castration. The recovery of AR content detected by
Western blot under each condition was accompanied by recovery of the reduced
unclear staining intensities in the epithelia. Neither steroidal nor non
steroidal antiandrogens, chlormadinone acetate and flutamide, altered the AR
content in normal rat ventral prostate 5, 12, 24 or 48 hours after single
administration. Furthermore, neither of the drugs at various doses altered AR
levels 12 hours after single administration. In summary, the rat AR is
upregulated by androgen. Single administration of antiandrogens have no effect on
immunodetected AR content.
PMID- 9550127
TI - Signal transduction of granulocyte macrophage-colony stimulating factor in a
human endothelium-derived cell line.
AB - Granulocyte macrophage-colony stimulating factor (GM-CSF) regulates the growth
and differentiation of hematopoietic cells and is also involved in angiogenesis.
The induction of protein tyrosine phosphorylation is critical for cytokines and
growth factor-mediated signal transduction. The protein tyrosine kinase (PTK),
JAK2 is involved in signaling through a number of cytokine receptors, including
GM-CSF receptors. In the present study, we investigated the effect of GM-CSF on
the cell cycle and protein tyrosine phosphorylation in a human endothelial cell
derived cell line, EA.hy 926 cells. GM-CSF induced the cell cycle progression and
tyrosine phosphorylation of cellular proteins including JAK2 kinase in EA.hy 926
cells. Herbimycin A, a PTK inhibitor, completely blocked the GM-CSF-induced cell
cycle progression, protein tyrosine phosphorylation and JAK2 kinase activation in
EA.hy 926 cells. Our results demonstrate that protein tyrosine phosphorylation
and JAK2 kinase activation are closely related to the GM-CSF-mediated signal
transduction and growth in vascular endothelial cells, and suggest the efficacy
of herbimycin A in controlling angiogenesis.
PMID- 9550126
TI - Pioglitazone (AD-4833) ameliorates insulin resistance in patients with NIDDM. AD
4833 Glucose Clamp Study Group, Japan.
AB - We evaluated the effect of pioglitazone, a thiazolidinedione compound, on insulin
stimulated glucose disposal (Rd) and its efficacy on carbohydrate and lipid
metabolism in patients with non-insulin-dependent diabetes mellitus (NIDDM).
Twenty NIDDM subjects (mean age 58.2+/-9.4 year, body mass index (BMI) 23.9+/-3.4
kg/ m2 (mean+/-S.D.], three with diet alone, 17 with sulfonylureas [SU])
participated in this trial from five diabetes clinics. Euglycemic (5.3
mmol/liter) hyperinsulinemic (insulin infusion rate 9 micromoles x kg[-1] x min[
1]) clamp studies were performed before and after oral administration of
pioglitazone (30 mg/day) for 87+/-10 days. The Rd significantly improved from
5.5+/-2.5 to 8.3+/-3.1 mg x kg(-1) x min(-1). Fasting plasma glucose (FPG) level
significantly decreased from 11.0+/-2.0 mmol/liter to 8.9+/-1.1 mmol/liter with a
significant improvement in the hemoglobin A1c level from 9.2+/-1.8% to 8.3+/
1.5%. Fasting serum insulin and C peptide levels decreased from 83+/-36
pmol/liter and 0.62+/-0.21 nmol/liter to 66+/-29 pmol/liter and 0.58+/-0.25
nmol/liter, respectively. Fasting serum triglyceride and free fatty acids levels
significantly decreased with concomitant increase of fasting serum HDL
cholesterol levels from 1.2+/-0.2 to 1.5+/-0.3 mmol/liter. The change in Rd
between before and after pioglitazone administration correlated with baseline
values of FPG (rho=0.633), serum insulin (rho=0.653), BMI (rho=0.456), Rd (rho
0.558) and 1,5-AG (rho=-0.522). These data indicate that pioglitazone enhances
the insulin action in NIDDM patients on diet alone or SU, and thereby improves
both plasma glucose level and lipid profiles.
PMID- 9550128
TI - Homology of E2 gene in 8 child-mother pairs infected with hepatitis C virus.
AB - The frequency of genetic homology of hepatitis C virus (HCV) E2 gene in 8 child
mother pairs was investigated. The route of HCV infection of all children
suggested mother-to-child infection by their past history. In this study, we
analyzed at least 5 complementary DNA (cDNA) clones for each case. In 6 of the 8
(75%) child-mother pairs, for the region between hypervariable region (HVR)-1 and
HVR-2, the similarity of the nucleotide sequence of all 5 cDNA clones between
each child and the mother was higher than that between the child and the other
children, the other mothers and the sequences from GenBank. One of the 8 (13%)
child-mother pairs showed a great similarity in parts of all cDNA clones. This
was also confirmed by phylogenetic analyses of the sequences of cDNA clones from
families and that from GenBank. These results suggested that the homology search
of nucleotide sequence of this region was useful to confirm mother-to-child
transmission of HCV.
PMID- 9550129
TI - Urban-rural difference in cereal consumption by people in Shandong Province,
China.
AB - In October, 1996, 24-hour food duplicate samples were collected from two groups
of 50 adult women each; one group was in Jinan, the capital city of Shandong
Province in China, and the other in a farming village of Baiquan in Zhangqiu area
some 30 km away from the city. Perusal of food menus showed that wheat, rice,
foxtail millet and maize were major cereals for the two groups. Nutritional
analysis of the food duplicate samples were conducted taking advantage of weight
of each food item and the standard food composition tables for Chinese
populations. Whereas wheat was the leading source in both groups (73% of cereal
based energy in the city and 64% in the village), further urban-rural comparison
showed that women in the village took substantial amounts of millet (19%) and
maize (12%) in contrast to small consumption by the city people (millet by 5% and
maize by 2%). Rice consumption was larger in the city (20%) than in the village
(5%). The differences between the two groups were all significant for each of the
four cereals. Nutritional significance of consumption of maize in particular and
also that of millet were discussed.
PMID- 9550130
TI - Cyclooxygenase metabolites possibly produced by endothelial cells mediate the
lung injury caused by mechanically stimulated leukocytes.
AB - To determine whether mechanically stimulated leukocytes increase pulmonary
vascular permeability and resistance and, if so, whether cyclooxygenase
metabolites mediate the increase, we assessed the effects of stimulated and
unstimulated leukocytes, and of a cyclooxygenase inhibitor on pulmonary vascular
permeability and resistance in isolated perfused lungs from Sprague-Dawley rats.
Leukocytes were stimulated by gentle agitation in a glass container for 10
seconds. After baseline measurements were made, stimulated or unstimulated
leukocytes were added to the perfusate. The effects of the cyclooxygenase
inhibitor, meclofenamate, on the pulmonary vascular filtration coefficient and
pulmonary vascular resistance were measured. In the rats that received stimulated
leukocytes, the pulmonary vascular filtration coefficient and the vascular
resistance were about 2.5 times and 3.3 times higher, respectively, than those in
the rats that received unstimulated leukocytes. These increases were completely
and partly blocked by meclofenamate. Histological examination indicated that
meclofenamate did not prevent the adhesion of leukocytes to the pulmonary
vascular endothelium. These findings suggest that mechanically stimulated
leukocytes increase pulmonary vascular permeability and that cyclooxygenase
metabolites produced by endothelial cells may injure the cells.
PMID- 9550131
TI - A case report of salivary duct carcinoma.
AB - We present a 65-year-old man with an enlarged mass in the right parotid gland. A
fine-needle aspiration cytology suspected Warthin's tumor. The ill-defined margin
of the tumor in diagnostic imaging and unexpected clinical course of the
occurrence of facial nerve paralysis suggested malignant neoplasm. The patient
was treated with surgical resection of the primary site and neck following
radiation therapy. Pathologic diagnosis was a salivary duct carcinoma. Difficulty
in early diagnosis of this tumor may result in local extension, early metastasis
to regional lymph nodes and distant sites, and death.
PMID- 9550132
TI - Introduction to histology of the ventricular walls of the brain.
PMID- 9550133
TI - Ependymal development, proliferation, and functions: a review.
AB - A survey of the literature shows that proliferation of ependyma occurs largely
during the embryonic and early postnatal periods of development in most species.
Differentiation of these cells proceeds along particular regional and temporal
gradients as does the expression of various cytoskeletal (vimentin, cytokeratins,
glial fibrillary acidic protein) and secretory proteins (S-100). Turnover
declines significantly postnatally, and only low levels of residual activity
persist into adulthood under normal conditions. Although the reported response of
ependyma to injury is somewhat equivocal, only limited regenerative capacity
appears to exist and to varying degrees in different regions of the neuraxis.
Proliferation has been most often observed in response to spinal cord injury.
Indeed, the ependyma plays a significant role in the initiation and maintenance
of the regenerative processes in the spinal cord of inframammalian vertebrates.
In the human, however, ependyma appears never to regenerate at any age nor re
express cytoskeletal proteins characteristic of immature cells. The functions of
ependyma including tanycytes, a specialized form of ependymal cell that persists
into adulthood within circumscribed regions of the nervous system, are still
largely speculative. Fetal unlike mature ependyma is believed to be secretory and
is believed to play a role in neurogenesis, neuronal differentiation/axonal
guidance, transport, and support. In the adult brain, mature ependyma is not
merely an inert lining but may regulate the transport of ions, small molecules,
and water between the cerebrospinal fluid and neuropil and serve an important
barrier function that protects neural tissue from potentially harmful substances
by mechanisms that are still incompletely understood.
PMID- 9550134
TI - Histochemistry and immunocytochemistry of the developing ependyma and choroid
plexus.
AB - The adult human ependyma expresses no intermediate filament proteins or secretory
proteins; the fetal ependyma shows strong immunocytochemical (ICC) expression of
vimentin, glial fibrillary acidic protein (GFAP), cytokeratins (CKs) of high
molecular weight, glycoproteins, and S-100beta protein. Each has a precise and
specific spatial distribution within the developing ependyma and a predictable
time of appearance and regression in each region of the ventricular system.
Several are coexpressed, but some appear earlier or persist longer than others.
Secretory proteins of ependymal cells are important in several developmental
processes such as the guidance of axonal growth cones. GFAP is not expressed in
the floor plate ependyma at any stage of development, unlike vimentin and CK. The
choroid plexus epithelium is a specialized ependyma, with an ICC profile that
differs from the surface ependyma: vimentin, CK, and S-100beta protein continue
to be expressed throughout fetal and adult life, but GFAP is not expressed.
Certain cerebral malformations are associated with specific ICC abnormalities:
ependymal S-100beta protein continues to be immunoreactive in disorders of
neuroblast migration; ependymal vimentin is focally upregulated in Chiari
malformations and congenital aqueductal stenosis. Other mammalian and
nonmammalian species have characteristic profiles of ependymal immunoreactivity
to the same proteins expressed in humans but exhibit interspecific differences.
PMID- 9550135
TI - Tanycytes and pituicytes: morphological and functional aspects of neuroglial
interaction.
AB - The hypothalamo-hypophyseal system is supplied with two types of specialized
glial cells that interact in neuroendocrine functional dynamics: the tanycytes
and the pituicytes. Tanycytes are the dominating glial cells within the median
eminence. Similar to radial glia, they extend from the floor of the third
ventricle to the neurohemal surface of the median eminence. Pituicytes, as
specialized astrocytes, are the main glial cells of the neural lobe. They are in
intimate contact with the perivascular space of the sinusoidal vessels.
Morphological similarities between the two cell types focus on their interaction
with terminal branches of hypothalamic neurons in both regions of the
neurohypophysis, the median eminence and the neural lobe. Release of hypothalamic
hormones is apparently influenced by pituicytes and tanycytes. For instance, both
types of cells are capable of closing or opening the access to the vessels.
Thereby, in contrast to the "blood-brain-barrier" function of astrocytes,
pituicytes and tanycytes display "brain-blood-barrier" functions. Pituicytes are
characterized by the expression of specific membrane-bound receptors for opioids,
vasopressin, and beta-adrenoceptors, indicating that they receive input by
numerous neuroactive substances. Integration of these incoming signals may result
in a regulation of neurosecretion, especially by morphological changes and by
modulation of extracellular ion concentrations. Comparable modulatory mechanisms
of tanycytes have not yet been elucidated in a convincing manner. Besides
possible regulatory functions, tanycytes are considered to possess guiding
functions for hypothalamic axons and to be involved in transport mechanisms
between ventricle and blood vessels of the portal system.
PMID- 9550136
TI - Origin, nature, and some functional considerations of intraventricular
macrophages, with special reference to the epiplexus cells.
AB - Intraventricular macrophages encompass the supraependymal, free-floating, and
epiplexus (Kolmer) cells; the supraependymal cells lie in close apposition to the
ventricular ependyma, the epiplexus cells are closely associated with the choroid
plexus epithelium, and the free-floating cells are at a variable distance from
the epithelial surface. Although the three cell types are regarded as one
cellular entity, the epiplexus cells preponderate. On scanning electron
microscopy, the epiplexus cells display diverse morphological forms, ranging from
round to bipolar to stellate, and bear a variable number of cytoplasmic
processes. Transmission electron microscopy shows the presence of large numbers
of lysosomes. The phagocytic nature of epiplexus cells is shown by their intense
staining for nonspecific esterase and active uptake of tracers, e.g., horseradish
peroxidase and rhodamine isothiocynate, administered intravenously or
intraperitoneally. The mode of entry of these tracers in the cerebral ventricles
is by way of transepithelial transport. In rats, the population of
intraventricular macrophages increases steadily after birth until 17 days of age;
thereafter, their cell population remains relatively unchanged. The early upsurge
is attributed to proliferation of residential cells and/or influx of circulating
monocytes/stromal macrophages through the process of "emperipolesis." The
immunophenotypic features of intraventricular macrophages are consistent with
other mononuclear phagocytes being immunoreactive for OX-42, OX-18, OX-6, and OX
1 and ED1 for the detection of CR3 receptors, MHC class I and II antigens,
leucocyte common antigen, and macrophage antigen, respectively. The expression of
these antigens is noticeably enhanced following the injection of
lipopolysaccharide (LPS) into postnatal rats. Remarkably, the intraventricular
macrophages are induced to express MHC class II (Ia) antigen after LPS or
interferon-gamma injections. Furthermore, the expression of transferrin receptors
as detected with OX-26 is also upregulated after these treatments. Epiplexus
cells are also elicited to display a de novo expression of nitric oxide synthase
like immunoreactivity following intracerebral injection of LPS. They also respond
vigorously to a single nonpenetrative blast. Results of our series of studies
suggest that, besides their primary function as scavenger cells, the
intraventricular macrophages partake in possible immunological responses and iron
regulation in the ventricular system or the brain as a whole.
PMID- 9550137
TI - Actual problems of the cerebrospinal fluid-contacting neurons.
AB - Cerebrospinal fluid (CSF)-contacting neurons form a part of the circumventricular
organs of the central nervous system. Represented by different cytologic types
and located in different regions, they constitute a CSF-contacting neuronal
system, the most central periventricular ring of neurons in the brain organized
concentrically according to our concept. Because the central nervous system of
deuterostomian echinoderm starfishes and the prochordate lancelet is composed
mainly of CSF-contacting-like neurons, we hypothesize that this cell type
represents ancient cells, or protoneurons, in the vertebrate brain. Neurons may
contact the ventricular CSF via their dendrites, axons, or perikarya. Most of the
CSF-contacting nerve cells send their dendritic processes into the ventricular
cavity, where they form ciliated terminals. These ciliated endings resemble those
of known sensory cells. By means of axons, the CSF-contacting neurons also may
contact the external CSF space, where the axons form terminals of neurohormonal
type similar to those known in the neurohemal areas. The most simple CSF
contacting neurons of vertebrates are present in the terminal filum, spinal cord,
and oblongate medulla. The dendritic pole of these medullospinal CSF-contacting
neurons terminates with an enlargement bearing many stereocilia in the central
canal. These cells are also supplied with a 9 x 2 + 2 kinocilium that may contact
Reissner's fiber, the condensed secretory material of the subcommissural organ.
The Reissner's fiber floating freely in the CSF leaves the central canal at the
caudal open end of the terminal filum in lower vertebrates, and open
communication is thus established between internal CSF and the surrounding tissue
spaces. Resembling mechanoreceptors cytologically, the spinal CSF-contacting
neurons send their axons to the outer surface of the spinal cord to form
neurosecretory-type terminals. They also send collaterals to local neurons and to
higher spinal segments. In the hypothalamic part of the diencephalon, neurons of
two circumventricular organs, the paraventricular organ and the vascular sac, of
the magnocellular neurosecretory nuclei and several parvocellular nuclei, form
CSF-contacting dendritic terminals. A CSF-contacting neuronal area also was found
in the telencephalon. The CSF-contacting dendrites of all these areas bear
solitary 9 x 2 + 0 cilia and resemble chemoreceptors and developing
photoreceptors cytologically. In electrophysiological experiments, the neurons of
the paraventricular organ are highly sensitive to the composition of the
ventricular CSF. The axons of the CSF-contacting neurons of the paraventricular
organ and hypothalamic nuclei terminate in hypothalamic synaptic zones, and those
of magno- and parvocellular neurosecretory nuclei also form neurohormonal
terminals in the median eminence and neurohypophysis. The axons of the CSF
contacting neurons of the vascular sac run in the nervus and tractus sacci
vasculosi to the nucleus (ganglion) sacci vasculosi. Some hypothalamic CSF
contacting neurons contain immunoreactive opsin and are candidates to represent
the "deep encephalic photoreceptors." In the newt, cells derived from the
subependymal layer develop photoreceptor outer segments protruding to the lumen
of the infundibular lobe under experimental conditions. Retinal and pineal
photoreceptors and some of their secondary neurons possess common cytologic
features with CSF-contacting neurons. They contact the retinal photoreceptor
space and pineal recess, respectively, both cavities being derived from the third
ventricle. In addition to ciliated dendritic terminals, there are
intraventricular axons and neuronal perikarya contacting the CSF. Part of the CSF
contacting axons are serotoninergic; their perikarya are situated in the raphe
nuclei. Intraventricular axons innervate the CSF-contacting dendrites,
intraventricular nerve cells, and/or the ventricular surface of the ependyma.
(ABSTRACT TRUNCATED)
PMID- 9550138
TI - Developing grasshopper neurons show variable levels of guanylyl cyclase activity
on arrival at their targets.
AB - The ability of certain grasshopper neurons to respond to exogenously applied
donors of nitric oxide (NO) by producing cyclic GMP (cGMP) depends on their
developmental state. ODQ, a selective blocker of NO-sensitive guanylyl cyclase,
blocks cGMP production at 10(-5) M, thus confirming the nature of the response.
Experiments in which the distal axon is separated from its proximal stump before
application of an NO donor show that guanylyl cyclase is distributed uniformly
throughout the neuron. In the locust abdomen, where segments are formed
sequentially, the pattern of guanylyl cyclase up-regulation is predictable and
sequential from anterior to posterior. There are two patterns of innervation by
cGMP-expressing motor neurons. In the first, typified by muscle 187, an
innervating neuron begins to be NO responsive on arrival at its muscle and
continues to be so over most of the remainder of embryonic development, including
the formation of motor end plates. In the second, typified by a neuron
innervating muscle 191, the neuron extends well along the muscle, apparently
laying down a number of sites of contact with it, before it becomes NO
responsive. In both patterns, however, NO responsiveness marks the neuron's
transition from growth cone elongation to the production of lateral branches.
Individual muscles receive innervation from multiple motor neurons, some of which
express transient NO sensitivity during development and others which do not. With
the exception of the leg motor neuron SETi, the first motor neuron to reach any
muscle is usually not NO responsive. We suggest that cGMP plays a role in, or
reflects, the early stages of communication between a target and specific
innervating neurons.
PMID- 9550139
TI - Comparison of neural elements in sexually dimorphic segments of the grasshopper,
Schistocerca americana.
AB - A uniquely female behavior in grasshoppers, oviposition, is driven by neural
circuitry in the terminal abdominal segments of the female's central nervous
system. Because it is known that the embryonic pattern of neuroblasts is sexually
monomorphic in these animals, we were interested to know how the central nervous
system of adults is organized to support the obvious behavioral dimorphism. Here,
we compare three classes of identifiable adult neurons: ovipositor motor neurons,
efferent dorsal unpaired median (DUM) neurons, and DUM interneurons in the eighth
abdominal neuromere. Cobalt backfills of the eighth tergal nerves revealed
identical complements of motor neurons in males and females. Included among these
neurons in the male were putative homologues of two sets of ovipositor muscle
motor neurons. Whereas these motor neurons supply two ovipositor muscles in the
female, they are divided to supply three muscles in males. The eighth abdominal
neuromere of both sexes contained seven efferent DUM neurons, but peripheral axon
projections varied between males and females in accordance with gender-specific
targets. In the eighth neuromere of females, some 22 small cell bodies of DUM
interneurons were stained with Toluidine blue, whereas only three male DUM
interneurons were found. Male muscle homologues were induced to express a
rhythmical motor pattern by experimental methods that activate the oviposition
pattern in females. The induced pattern in males is of unknown behavioral
significance. Although oviposition normally occurs only after sexual maturity,
the motor pattern could be activated at all life stages in females, including
embryos, as early as 90% of embryonic development.
PMID- 9550140
TI - Autoradiographic localisation of [3H]-SCH23390 and [3H]-spiperone binding sites
in honey bee brain.
AB - In the brain of the honey bee, dopamine receptors have been identified by using
the vertebrate D1 dopamine antagonist [3H]-SCH23390 and the vertebrate D2
dopamine antagonist [3H]-spiperone. This study uses light microscope
autoradiography to investigate the anatomical distributions of the binding sites
labelled by [3H]-SCH23390 and [3H]-spiperone in tissue sections cut at three
depths from the anterior surface of the brain. The binding of these radioligands
differed significantly, in both density and distribution. Specific binding of
[3H]-SCH23390, defined by using 5 x 10(-6) M cis-(Z)-flupentixol, was densest in
regions of somata, such as the deutocerebral somatal rind, the somatal layer
beneath the calyces of the mushroom bodies and the ventral protocerebral somatal
group. High levels of [3H]-SCH23390 binding were also measured in the lateral
protocerebrum. [3H]-Spiperone binding site density estimates were consistently
lower than those of [3H]-SCH23390. Specific binding of [3H]-spiperone, determined
by subtracting binding in the presence of 10(-4) M domperidone from the total
binding, was highest in the alpha lobes, beta lobes, and calyces of the mushroom
body neuropil. Relatively high binding was also measured in the central body and
lateral protocerebral neuropil. These results suggest that the distribution of
dopamine receptors in the brain of the bee is subtype specific, and they support
the view that dopamine plays many roles in the insect central nervous system.
PMID- 9550141
TI - Normal and injury-induced sympathetic innervation of rat dorsal root ganglia
increases with age.
AB - In rats, partial injury to a peripheral nerve often leads to sympathetically
maintained pain (SMP). In humans, this condition is especially apparent in the
elderly. Nerve injury also causes perivascular sympathetic axons to sprout into
the dorsal root ganglion (DRG), forming a possible anatomical substrate for SMP.
Here, we describe the effects of chronic sciatic nerve constriction injury (CCI)
in young (3 months) and old (16 months) rats on neuropathic pain behavior and on
sympathetic sprouting in DRG. Behavioral tests assessed changes in thermal
allodynia and hyperalgesia and in mechanical allodynia. We found that 1)
sympathetic innervation of the DRG increased naturally with age, forming
pericellular baskets mainly around large DRG neurons, and that sympathetic fibers
were often associated with myelinated sensory axons; 2) sympathetic fiber density
following CCI was also greater in old than in young rats; and 3) in old rats,
thermal allodynia was less pronounced than in young rats, whereas thermal
hyperalgesia and mechanical allodynia were more pronounced. These results
highlight the possibility that sympathetic sprouting in the DRG is responsible
for the sympathetic generation or maintenance of pain, especially in the elderly.
PMID- 9550142
TI - The region of the pontine parabrachial nucleus is a major target of dehydration
sensitive CRH neurons in the rat lateral hypothalamic area.
AB - Neurons in a restricted part of the lateral hypothalamic area (LHA) show
increased expression of corticotropin-releasing hormone (CRH) mRNA as a
consequence of cellular dehydration. In the present study, we have investigated
the organization of their efferent projections by using anterograde and
retrograde tracing techniques. Additionally, we have compared the distribution of
CRH mRNA-containing neurons after cellular dehydration and intraventricular
(i.c.v.) colchicine injections. Our results show that cellular dehydration
activates a more restricted neuronal population than does i.c.v. colchicine.
Iontophoretic injections of Phaseolus vulgaris leucoagglutinin (PHAL) were placed
in the LHA of animals drinking hypertonic saline and their proximity to activated
CRH neurons determined by in situ hybridization for CRH mRNA. Although labelled
fibers from these injections were seen throughout the brain, the region of the
parabrachial nucleus and nucleus of the solitary tract (NTS) were most
conspicuous in also having CRH immunoreactive fibers. Injections of Fluoro-Gold
placed in these two structures were used to confirm these findings in dehydrated
animals. Significant numbers of neurons containing both Fluoro-Gold and CRH mRNA
were seen in the lateral hypothalamus after injections in the lateral and medial
parts of the parabrachial nucleus; far fewer were seen after injections in the
NTS. These results strongly suggest that the CRH neurons in the LHA activated by
cellular dehydration provide an input to the region of the parabrachial nucleus.
The altered biochemical composition of this pathway may well be able to modify
sensory and motor patterns both during and after dehydration.
PMID- 9550143
TI - Developmental expression of VGF mRNA in the prenatal and postnatal rat.
AB - VGF is a developmentally regulated, secretory peptide precursor that is expressed
by neurons and neuroendocrine cells and that has its transcription and secretion
induced rapidly by neurotrophins and by depolarization. To gain insight into the
possible functions and regulation of VGF in vivo, we have characterized the
distribution of VGF mRNA in the developing rat nervous system. VGF expression was
first detectable at embryonic day 11.5 in the primordia of cranial, sympathetic,
and dorsal root ganglia, and its distribution expanded throughout development to
include significant expression throughout the brain, spinal cord, and retina of
the adult rat. The earliest expression of VGF, therefore, appeared in the
peripheral nervous system as developing neurons settled in their designated
ganglia. In many regions of the brain, VGF mRNA levels were found to be highest
during periods when axonal outgrowth and synaptogenesis predominate. Areas of the
central nervous system that contain predominantly dividing cells never displayed
any VGF mRNA expression, nor did the vast majority of nonneural tissues.
PMID- 9550144
TI - Expression of VGF mRNA in the adult rat central nervous system.
AB - VGF is a secretory peptide precursor that is expressed and processed by neuronal
cells in a cell type-specific fashion. In addition, VGF transcription and
secretion are rapidly and relatively selectively induced by neurotrophins and
depolarization in vitro. To gain insight into the possible function(s) of VGF in
the nervous system, we have carried out a detailed examination of the
distribution of VGF mRNA in the adult rat central nervous system by using in situ
hybridization. Robust expression was detected in many neurons throughout the
brain and spinal cord, in several types of neurons in the retina, and in
presumptive chromaffin cells of the adrenal medulla. In the brain, prominent
expression of VGF mRNA was observed in neurons of the main and accessory
olfactory bulbs; in the anterior olfactory nucleus; in the induseum griseum and
taenia tecta; in the olfactory tubercle; in CA1-CA3, the hilus of the dentate
gyrus, and the subicular complex of the hippocampal formation; in the piriform,
periamygdaloid, transitional, and lateral entorhinal cortices; in the
endopiriform nucleus; in the hypothalamus, particularly the preoptic,
periventricular, supraoptic, suprachiasmatic, and arcuate nuclei; and in a number
of septal, thalamic, amygdaloid, and brainstem nuclei. Labeling was also seen in
neurons of the neocortex and transitional cortical areas, particularly in layer
V, and in basal ganglia and cerebellum. These data demonstrate that VGF mRNA is
expressed much more extensively in the brain than has been described in previous
RNA or immunohistochemical studies, and, furthermore, that VGF is widely
expressed in the spinal cord and retina.
PMID- 9550145
TI - Rostral cerebellar malformation (rcm/rcm): a murine mutant to study
regionalization of the cerebellum.
AB - A recently described recessive mouse mutant, rostral cerebellar malformation
(rcm/rcm), demonstrates a swaying gait at approximately 12 days of age (Lane et
al. [1992] J. Hered. 83:315-318). The mutant cerebellar (Cb) phenotype consists
of cerebellar tissue that extends rostrally, beyond the usual distinct anterior
cerebellar boundary, into the midbrain (Lane et al. [1992] J. Hered. 83:315-318;
Ackerman et al. [1997] Nature 386:838-842). Interestingly, the cerebellar ectopia
occurs in the absence of any significant alterations in the distribution of
nuclear groups within the brainstem. The ectopic Cb tissue is 1) adherent to the
posterior and lateral aspects of the inferior colliculus and to the lateral
aspect of the rostral brainstem and 2) contains acellular regions within the
inner granular layer (igl) and ectopic, calbindin-immunoreactive Purkinje cells
(PCs) deep to the igl. Within the Cb proper, PC organization, as revealed by
zebrin II immunoreactivity, is generally normal. In the ectopic Cb tissue PCs
also exhibit a banded zebrin distribution. Analysis of the spinocerebellar
projection in the mutant suggests a lobular distribution similar to that seen in
the normal mouse. Within the anterior region, however, the normal parasagittal
banding pattern is somewhat obscured. Spinocerebellar innervation of the ectopic
Cb tissue exists, but it is almost exclusively to the region adjacent to the
caudal inferior colliculus. In conjunction with the recent finding that the
mutation appears to affect a UNC-5-like receptor protein for netrin-1, a molecule
that may be involved in axonal guidance and cell migration (Ackerman et al.
[1997] Nature 386:838-842), our results suggest that this mutant is an important
model for the analysis of cerebellar development and regionalization.
PMID- 9550146
TI - In situ detection of H1-receptor mRNA and absence of apoptosis in the transient
histamine system of the embryonic rat brain.
AB - In the developing brain, histamine is one of the first neurotransmitters to
appear. The concentration of histamine in the prenatal brain is fivefold that of
adult levels. During the prenatal development a large transiently histamine
immunoreactive cell population distinct from the adult histaminergic system can
be found within a subpopulation of the developing serotonergic raphe nuclei
neurons. Also histamine-immunoreactive nerve fibers are widely distributed
already during the prenatal development extending to the diencephalon, the
thalamus, the cortex, and the spinal cord. Large numbers of histamine-containing
mast cells also migrate into the brain during the late prenatal life. The wide
distribution and high prenatal concentrations imply important functions for the
histaminergic system during intrauterine development. However, little is known
about the actual functions of histamine during development, and which of the
histamine receptors are present in the prenatal rat brain is currently unknown.
In the present study, we used in situ hybridization to study the distribution of
H1-receptor (H1R) mRNA in the embryonic rat brain and spinal cord. H1R mRNA could
be detected in rat brain and in spinal cord on embryonic day (E) 14, and the
expression pattern seemed to partially localize in areas containing histamine
immunoreactive nerve fibers through E14-E20. H1R mRNA was also detected by
reverse transcriptase polymerase chain reaction from embryonic brain samples and
by Northern hybridization. The possible involvement of apoptosis in the
disappearance of the developing transiently histaminergic system was studied by
using apoptosis detection based on the terminal dUTP nick end labeling (TUNEL)
technique and with c-Fos immunostaining. Although histamine immunoreactivity
disappears dramatically from the developing raphe nuclei after E18, only
occasional apoptotic nuclei could be seen in the histamine-immunoreactive cell
bodies. The presence of H1R mRNA during the embryonic development renders it
possible that histamine could exert an H1R-specific function at the time of the
embryonic histamine peak.
PMID- 9550147
TI - Localization of mRNA encoding the P2X2 receptor subunit of the adenosine 5'
triphosphate-gated ion channel in the adult and developing rat inner ear by in
situ hybridization.
AB - Localization of expression of the adenosine 5'-triphosphate (ATP)-gated ion
channel P2X2 receptor subunit (P2X2R) in the rat inner ear at different stages of
development was achieved by using in situ mRNA hybridization. In the adult, P2X2R
mRNA was strongly expressed in many of the cells bordering the cochlear
endolymphatic compartment. This included the interdental cells of the spiral
limbus, all cells of the inner sulcus and organ of Corti, and cells of the spiral
prominence. In the vestibular labyrinth, strong expression was noted in the
transitional cells at the base of the crista ampullaris and in the sensory
epithelium of the crista and maculae. During development, P2X2R mRNA expression
was evident in the precursors of these structures at the earliest period studied,
embryonic day 12 (E12). Expression increased during the ontogeny in both the
cochlear and the vestibular end organs. In addition, both the spiral and
vestibular ganglia showed developmental expression. In contrast to the supporting
cells of the organ of Corti, both inner and outer hair cells exhibited P2X2R mRNA
only after postnatal day 10 (P10) through P12, concomitant with the onset of
hearing. P2X2R expression levels in all cells fell from a maximum at P12-P18 to
lower levels in the adult. In the adult, P2X2R mRNA levels were modest in outer
hair cells in the basal (high-frequency) encoding region of the cochlea, and
inner hair cell labeling was low throughout the cochlea. Reissner's membrane,
which maintains an electrochemical barrier between scala vestibuli and scala
media, showed considerable expression of P2X2R mRNA in early postnatal
development, and expression was maintained at moderate levels in the adult
cochlea. These data are consistent with a role for the P2X2R subunit in the
processes of labyrinthine development and the regulation of the electrochemical
gradients supporting auditory and vestibular sensory transduction.
PMID- 9550148
TI - Early development of the peripheral nervous system in a lancelet species.
AB - The developmental pattern of the lancelet (amphioxus) peripheral nervous system
from embryos to larvae has been studied by using wholemount immunostaining and
transmission electron microscopy. The peripheral nerves first appeared on the
anterior dorsal surface of the medulla at the middle neurula stage, when the
anterior nerve cord was just closing. A single axon with a large growth cone was
the progenitor of each nerve. The nerve roots adopted an asymmetric arrangement
soon after. The first nerve, likely a pair of pure sensory nerves, sprouted from
the anterior tip of the nerve cord. This nerve may be comparable topographically
to the preoptic nerve (the posterior branch of the terminal nerve) in lungfishes.
However, the neuron that first extends its axon was located in the medulla, as in
the other posterior nerves. One of the extramedullary primary sensory neurons,
the corpuscles of de Quatrefages, appeared in larvae with the mouth and two
anterior gill pores. Their axons were seemingly fasciculated with the efferent
axon of the first nerve. The second nerve, the most complex one to appear during
embryonic and early larval development, innervated the preoral pit and the buccal
region. The third and fourth nerves on the left side also innervated the buccal
region. The larval innervation patterns in the anterior region differed from the
adult organization, suggesting a segmental rearrangement of the nerve supply
during development. There was no evidence to dichotomize the peripheral nerves
into cranial and spinal nerves, as exist in vertebrates. These characteristics of
the peripheral nervous system in the lancelet indicate that this animal has a
rather derived or primitive developmental system of peripheral nerves, making the
analysis of homology with vertebrates difficult.
PMID- 9550149
TI - ZENK protein regulation by song in the brain of songbirds.
AB - When songbirds hear the song of another individual of the same species or when
they sing, the mRNA levels of the ZENK gene increase rapidly in forebrain areas
involved in vocal communication. This gene induction is thought to be related to
long-term neuronal change and possibly the formation of song-related memories. We
used immunocytochemistry to study the levels and distribution of ZENK protein in
the brain of zebra finches and canaries after presentation of song playbacks.
Birds that heard the playbacks and did not sing in response showed increased ZENK
protein levels in auditory brain areas, including the caudomedial neostriatum and
hyperstriatum ventrale, fields L1 and L3, the shelf adjacent to the high vocal
center (HVC), the cup adjacent to the nucleus robustus archistriatalis (RA), and
the nucleus mesencephalicus lateralis pars dorsalis (MLd). No ZENK expression was
seen in song nuclei in these birds. Males that sang in response to the playbacks
showed, in addition to auditory areas, increased ZENK protein in several song
control nuclei, most prominently in HVC, RA, area X, and the dorsomedial nucleus
(DN) of the intercollicular complex. The rise in ZENK protein followed that
described previously for ZENK mRNA by a short lag, and the distribution of ZENK
labeled cells was in agreement with previous analysis of mRNA distribution. Thus,
ZENK protein regulation can be used to assess activation of brain areas involved
in perceptual and motor aspects of song. Possible implications of ZENK induction
in these areas are discussed.
PMID- 9550150
TI - Circuitry and role of substance P-immunoreactive neurons in the primate retina.
AB - In this paper, we extend our previous light microscopic (LM) study of substance P
(SP)-containing amacrine and ganglion cell types of the human retina (Cuenca et
al. [1995] J. Comp. Neurol. 356:491-504) to an electron microscopic (EM) and
confocal-imaging study in order to reveal synaptic circuitry and putative input
and output neurons. SP-immunoreactive (-IR) amacrine cells in primate retina are
typically wide-field cells with large cell bodies occurring in normal or
displaced positions relative to the inner plexiform layer (IPL). Their main
dendrites bear many spines and are monostratified in stratum 3 (S3) of the IPL.
Axon-like processes arise from dendrites close to the cell body and run for
hundreds of microns at the same level as the dendrites, thus forming a relatively
dense plexus in S3 of the IPL. SP-IR axon processes also climb to S1 to surround
some amacrine cell bodies, and others pass into the outer plexiform layer (OPL).
Still other axons run down to the ganglion cell layer, where they encircle SP-IR
ganglion cells and pass on to end in the nerve fiber layer. The SP-IR ganglion
cell types have large cell bodies (20-22 microm diameter) and dendrites that
costratify in S3 among the SP-IR amacrine cell processes. Double immunostaining
and study by confocal microscopy reveals that SP-IR amacrine cells in the monkey
colocalize gamma-aminobutyric acid (GABA). Their main plexus of dendrites in S3
of the IPL is skirted on the S2/S3 border by cone bipolar axons that stain for
calbindin but intermingles primarily with glycinergic bipolar cell types of S3
and S3-S4. Strongly GABA-IR/weakly glycine-IR amacrine cell bodies, in addition
to the SP-IR large-bodied ganglion cell type, are targets of encircling SP-IR
axon processes. EM study of the human SP-IR amacrine cell indicates that input
synapses to its dendrites are from bipolar cell axons of the S2/S3 border, S3,
and the S3/S4 border of the IPL neuropil (33% of the synaptic input) and from
amacrine cell processes (67% of the synaptic input). The input amacrine cells are
of at least two distinct types based on cytological criteria. Synaptic output
from the SP-IR amacrine cell dendrites is to bipolar cell axons as reciprocal
synapses (31%), to amacrine cells (40%), and to ganglion cell profiles, primarily
in S3 (29%) of the IPL. The SP-IR axons synapse upon SP-IR ganglion cell bodies
and axons, upon normally placed and displaced amacrine cell bodies, and upon
bipolar cell dendrites in the OPL. In addition, they appear to synapse among
themselves. We shall discuss a wiring diagram and the possible role of SP-IR
amacrine cells in the primate retina.
PMID- 9550151
TI - Spatial coding of odorant features in the glomerular layer of the rat olfactory
bulb.
AB - In order to determine whether molecular features of odorants are represented
spatially in the glomerular layer of the olfactory bulb, we used metabolic
mapping of [14C] 2-deoxyglucose uptake in rats exposed to equal vapor
concentrations of odorants differing systematically in chemical structure. The
odorants were ethyl acetate, ethyl butyrate, isoamyl acetate, and isoamyl
butyrate. Statistical analysis of anatomically standardized arrays of uptake
revealed that each ester produced a characteristic spatial pattern of activity in
the glomerular layer. The patterns were similar in different rats exposed to the
same odorant, and their complexity increased with increasing odorant carbon
number. This finding suggests that the presence of more potentially recognized
molecular features is associated with a greater number of activated receptors.
Individual regions of the glomerular layer responded specifically to isoamyl
esters, and other regions preferred ethyl esters. Regions of similar specificity
occurred in lateral and medial aspects of the bulb, the medial representation
being more caudal and ventral than the lateral one. This pattern correlates with
projections of olfactory sensory neurons expressing the same putative olfactory
receptor gene. The patterns overlapped greatly in the posterolateral and
posteromedial glomerular layer, a finding one should predict, given the large
overlap in chemical structure across the aliphatic esters. Thus, molecular
features appear to be encoded spatially in the glomerular layer, and the identity
of the odorant may be determined by a subsequent decoding of the combination of
molecular features represented in the glomerular layer.
PMID- 9550152
TI - Induction of cell division in olfactory basal epithelium following intranasal
irrigation with wheat germ agglutinin-horseradish peroxidase.
AB - The lectin, wheatgerm agglutinin (WGA) conjugated to horseradish peroxidase
(HRP), previously was shown to be transported into the central nervous system
following application by intranasal irrigation. The current study investigated
the hypothesis that uptake of molecules, such as the lectin-conjugate, by
olfactory receptor cells would mimic internalization of other substances
including odorants. This process would result in both premature death of receptor
cells and increased turnover of their precursors, globose basal cells.
Tetramethylbenzidine histochemical analysis showed the presence of significant
amounts of the lectin-conjugate in both the receptor epithelium and olfactory
bulb until at least 2 weeks postintranasal application. Neither supporting nor
globose basal cells contained WGA-HRP, suggesting that uptake was primarily into
olfactory receptor cells. Cell turnover, assessed by tritiated-thymidine
(thymidine) autoradiography, increased both 1 and 2 weeks, but not 3 and 4 weeks,
following intranasal irrigation with WGA-HRP. Most of the cells containing
thymidine labelling appeared to be globose basal cells, although supporting cells
also occasionally exhibited labelling. Survival of either mature or immature
receptor cells in the epithelium, indicated by epithelial thickness and cell
density of the septal epithelium, also declined following treatment. These data
suggest that uptake of substances may result in cell loss from the olfactory
epithelium and increased mitotic activity of basal cells.
PMID- 9550153
TI - Regulated spacing of synapses and presynaptic active zones at larval
neuromuscular junctions in different genotypes of the flies Drosophila and
Sarcophaga.
AB - Synapses at larval neuromuscular junctions of the flies Drosophila melanogaster
and Sarcophaga bullata are not distributed randomly. They have been studied in
serial electron micrographs of two identified axons (axons 1 and 2) that
innervate ventral longitudinal muscles 6 and 7 of the larval body wall. The
following fly larvae were examined: axon 1--wild-type Sarcophaga and Drosophila
and Drosophila mutants dunce(m14) and fasII(e76), a hypomorphic allele of the
fasciclin II gene; and axon 2--drosophila wild-type, dunce(m14), and fasII(e76).
These lines were selected to provide a wide range of nerve terminal phenotypes in
which to study the distribution and spacing of synapses. Each terminal varicosity
is applied closely to the underlying subsynaptic reticulum of the muscle fiber
and has 15-40 synapses. Each synapse usually bears one or more active zones,
characterized by dense bodies that are T-shaped in cross section; they are
located at the presumed sites of transmitter release. The distribution of
synapses was characterized from the center-to-center distance of each synapse to
its nearest neighbor. The mean spacing between nearest-neighbor pairs ranged from
0.84 microm to 1.05 microm for axon 1, showing no significant difference
regardless of genotype. The corresponding values for axon 2, 0.58 microm to 0.75
microm, were also statistically indistinguishable from one another in terminals
of different genotype but differed significantly from the values for axon 1.
Thus, the functional class of the axon provides a clear prediction of the spacing
of its synapses, suggesting that spacing may be determined by the functional
properties of transmission at the two types of terminals. Individual dense bodies
were situated mostly at least 0.4 microm away from one another, suggesting that
an interaction between neighboring active zones could prevent their final
positions from being located more closely.
PMID- 9550154
TI - Metabotropic glutamate receptor subtypes in axon terminals of projection fibers
from the main and accessory olfactory bulbs: a light and electron microscopic
immunohistochemical study in the rat.
AB - Localization of metabotropic glutamate receptor subtypes, mGluR1, mGluR1alpha,
mGluR2/3, mGluR4a, mGluR5, mGluR7a, mGluR7b, and mGluR8, was examined in some of
the target areas of projection fibers from the main and accessory olfactory bulbs
(MOB and AOB) by using subtype-specific antibodies. The superficial layer of the
olfactory tubercle and layer Ia of the piriform cortex, the target areas of MOB,
showed marked mGluR1-, mGluR5-, mGluR7a-, and mGluR8-like immunoreactivities (
LI), and rather weak mGluR2/3-LI. The periamygdaloid cortical region including
the target areas of both MOB and AOB showed intense mGluR2/3-LI as well as marked
mGluR1-, mGluR5-, mGluR7a-, and mGluR8-LI. No significant mGluR1alpha-, mGluR4a-,
or mGluR7b-LI was seen in these regions. After transection of the lateral
olfactory tract, mGluR2/3-, mGluR7a-, and mGluR8-LI were reduced markedly in the
target regions on the side ipsilateral to the transection; no significant changes
were detected in mGluR1- or mGluR5-LI. Double labeling experiments indicated
light and electron microscopically colocalization of mGluR7a- and mGluR8-LI in
axon terminals on dendritic shafts of presumed interneurons in the superficial
layer of the olfactory tubercle and layer Ia of the piriform cortex. Electron
microscopically mGluR2/3-LI was seen in preterminal and terminal portions of
axons, whereas mGluR7a- and mGluR8-LI were associated with presynaptic membrane
specialization. Immunolabeled axon terminals were filled with round synaptic
vesicles and constituted asymmetric synapses with dendritic profiles. The results
suggest that glutamate release from axon terminals of projection fibers from MOB
and AOB is regulated presynaptically and differentially through mGluR2/3,
mGluR7a, and/or mGluR8.
PMID- 9550155
TI - Visuotopic organisation and neuronal response selectivity for direction of motion
in visual areas of the caudal temporal lobe of the marmoset monkey (Callithrix
jacchus): middle temporal area, middle temporal crescent, and surrounding cortex.
AB - On the basis of extracellular recordings in marmoset monkeys, we report on the
organisation of the middle temporal area (MT) and the surrounding middle temporal
crescent (MTc). Area MT is approximately 5-mm long and 2-mm wide, whereas the MTc
forms a crescent-shaped band of cortex 1-mm wide. Neurones in area MT form a
first-order representation of the contralateral hemifield, whereas those in the
MTc form a second-order representation with a field discontinuity near the
horizontal meridian. The representation of the vertical meridian forms the border
between area MT and the MTc. In both areas, the fovea is represented
ventrocaudally, and the visual field periphery is represented dorsorostrally.
Analysis of single units revealed that 86% of cells in area MT show a strong
selectivity for the direction of motion of visual stimuli. The proportion of
direction-selective cells in the MTc (53%), whereas lower than that in area MT,
is much higher than that observed in most other visual areas. Neurones in the
cortex immediately rostral to area MT and the MTc are direction selective, with
receptive fields predominantly located in the visual field periphery. In
contrast, only a minority of the cells in the cortex ventral to the MTc are
direction selective, and their receptive fields emphasise central vision. The
results suggest that the MTc is functionally closely related to area MT, and
distinct from the areas forming the dorsolateral complex. The MTc may have a role
in combining information about motion in the visual field, processed by area MT,
with information about stimulus shape, processed by the dorsolateral complex.
PMID- 9550156
TI - Association of ecto-5'-nucleotidase with specific cell types in the adult and
developing rat olfactory organ.
AB - A unique feature of the olfactory epithelium is its ability to give rise to new
sensory neurons throughout life and also following injury. Cells at the basal
side of the epithelium serve as neurogenic progenitor cells. The enzyme ecto-5'
nucleotidase is expressed at the surface of developing nerve cells and is
regarded as a marker of neural development. To study the expression pattern of
the enzyme, we analyzed its distribution in the adult and developing rat
olfactory organ. Labeling is restricted to specific cell types and varies between
the epithelia investigated. At the basal side of the olfactory epithelium,
activity of 5'-nucleotidase is associated specifically with the dark/horizontal
basal cells. Neither the light/globose basal cells, which are the immediate
precursors of the sensory receptor cells, nor subsets of potentially immature
olfactory receptor cells are labeled. On the other hand, microvillar cells
dispersed at the lumenal side of the epithelium contain 5'-nucleotidase activity.
The enzyme is also present at the inner lining of the ducts of Bowman's glands as
they traverse the epithelium. Within the respiratory epithelium, activity of 5'
nucleotidase is associated with basal cells as well as with the epithelial
surface. During development, 5'-nucleotidase is initially limited to the
respiratory epithelium, including its basal cells. Dark/horizontal basal cells of
the olfactory epithelium, which are positive for 5'-nucleotidase, first appear at
the border of the respiratory epithelium, suggesting that they might originate
from immigrating basal cells of the respiratory epithelium. Within the
vomeronasal organ, labeling is largely restricted to the receptor-free
epithelium. Although the functional role of 5'-nucleotidase in the olfactory
system needs to be further defined, the distribution of the enzyme can be used
successfully as a marker for defined cell types.
PMID- 9550157
TI - Deciphering dietary reference intakes.
PMID- 9550158
TI - ADA urges changes to HCFA's hospital Medicare rules.
PMID- 9550159
TI - When food becomes a cry for help. How dietitians can combat childhood eating
disorders. Interview by Nancy I Hahn.
PMID- 9550160
TI - Young children and dietary fat intake: how much is too little?
PMID- 9550161
TI - Are we making decisions based on evidence?
PMID- 9550163
TI - Weight training increases fat-free mass and strength in untrained young women.
AB - OBJECTIVE: To examine the effects of a weight training program on the resting
metabolic rate, fat-free mass, strength, and dietary intake of untrained young
women. DESIGN: A 12-week weight training program was completed by 20 previously
untrained women aged 19 through 44 years. SUBJECTS: Twenty-three study subjects
and 14 control subjects were recruited on a volunteer basis. Twenty study
subjects and 10 control subjects completed the study. INTERVENTIONS: Study
subjects participated in a 12-week moderate-intensity, progressive resistance
weight training program consisting of 2 supervised sessions per week with 6 types
of lifting exercises per session. Resting metabolic rate, fat-free mass,
strength, and dietary intake were measured before and immediately after the
study. STATISTICAL ANALYSES: Repeated measures analysis of variance and t tests
(unequal variance and paired) were used to determine interaction effects and
differences within and between groups. RESULTS: The study group increased their
fat-free mass (mean+/-standard deviation) from 44.2+/-5.4 kg to 46.2+/-6.0 kg
(P<.001). Elbow flexion, elbow extension, and knee flexion strength all increased
from 28.9+/-5.3 to 34.5+/-3.8, 16.9+/-4.9 to 22.1+/-5.3, and 39.5+/-8.6 to 48.6+/
7.3 ft-lb, respectively (P<.001). Percent body fat decreased from 29.8+/-2.8 to
27.2+/-2.6 (P<.001) without a significant change in body weight. Resting
metabolic rate did not change significantly (P>.05). APPLICATION: A moderate
intensity weight training program increased strength and fat-free mass and
decreased body fat in normal-weight young women. Favorable changes in body
composition were obtained without restricting food intake. The increase in fat
free mass did not increase resting metabolic rate significantly.
PMID- 9550162
TI - Persons successful at long-term weight loss and maintenance continue to consume a
low-energy, low-fat diet.
AB - OBJECTIVES: To describe the dietary intakes of persons who successfully
maintained weight loss and to determine if differences exist between those who
lost weight on their own vs those who received assistance with weight loss (eg,
participated in a commercial or self-help program or were seen individually by a
dietitian). Intakes of selected nutrients were also compared with data from the
third National Health and Nutrition Examination Survey (NHANES III) and the 1989
Recommended Dietary Allowances (RDAs). SUBJECTS: Subjects were 355 women and 83
men, aged 18 years or older, primarily white, who had maintained a weight loss of
at least 13.6 kg for at least 1 year, and were the initial enrollees in the
ongoing National Weight Control Registry. On average, the participants had lost
30 kg and maintained the weight loss for 5.1 years. METHODS: A cross-sectional
study in which subjects in the registry completed demographic and weight history
questionnaires as well as the Health Habits and History Questionnaire developed
by Block et al. Subjects' dietary intake data were compared with that of
similarly aged men and women in the NHANES III cohort and to the RDAs. Adequacy
of the diet was assessed by comparing the intake of selected nutrients (iron;
calcium; and vitamins C, A, and E) in subjects who lost weight on their own or
with assistance. RESULTS: Successful maintainers of weight loss reported
continued consumption of a low-energy and low-fat diet. Women in the registry
reported eating an average of 1,306 kcal/day (24.3% of energy from fat); men
reported consuming 1,685 kcal (23.5% of energy from fat). Subjects in the
registry reported consuming less energy and a lower percentage of energy from fat
than NHANES III subjects did. Subjects who lost weight on their own did not
differ from those who lost weight with assistance in regards to energy intake,
percent of energy from fat, or intake of selected nutrients (iron; calcium; and
vitamins C, A, and E). In addition, subjects who lost weight on their own and
those who lost weight with assistance met the RDAs for calcium and vitamins C, A,
and E for persons aged 25 years or older. APPLICATIONS: Because continued
consumption of a low-fat, low-energy diet may be necessary for long-term weight
control, persons who have successfully lost weight should be encouraged to
maintain such a diet.
PMID- 9550164
TI - Practice points: translating research into practice. Fueling their engines for
the long haul: teaching good nutrition to young athletes.
PMID- 9550165
TI - Nutritional status of female athletes with subclinical eating disorders.
AB - OBJECTIVE: To assess the energy and nutritional status of female athletes with
subclinical eating disorders and compare them with that of control subjects and
standard norms. DESIGN: Group classification (subclinical eating disorder or
control) was based on responses to a health and diet history questionnaire, a
battery of self-report eating disorder questionnaires, and an in-depth interview.
Energy and nutrient intakes and energy expenditure were determined by means of 7
day weighed food records and 7-day activity logs. Micronutrient status was
assessed for iron, zinc, magnesium, vitamin B-12, and folate. SUBJECTS: Twenty
four female athletes with subclinical eating disorders and 24 female control
athletes. STATISTICAL ANALYSES: Descriptive statistics were used to analyze
demographic data. One-way analysis of variance was used to determine group
differences in energy and nutrient intakes, energy balance, and blood values.
RESULTS: Groups were similar in age, height, weight, fat-free mass, and body mass
index. Mean energy intake was lower in the group with subclinical eating
disorders (1,989 kcal/day) than in the control group (2,300 kcal/day; P=.004),
whereas mean energy expenditures were similar (2,405 and 2,293 kcal/day,
respectively). The group with subclinical eating disorders had significantly
(P<.05) lower mean protein and fat intakes compared with the control group; mean
micronutrient intakes were not significantly different. Mean status measures for
iron, zinc, magnesium, vitamin B-12, and folate were within the normal ranges for
both groups and no differences were noted between the groups. A similar number of
athletes within each group used vitamin/mineral supplements < or = 4 times per
week. CONCLUSION: Although female athletes with subclinical eating disorders had
dietary intakes of energy, protein, carbohydrate, and certain micronutrients that
were below recommended levels, micronutrient status appeared relatively
unaffected, probably due to their use of supplements.
PMID- 9550166
TI - Assessment of energy intake underreporting by doubly labeled water and
observations on reported nutrient intakes in children.
AB - OBJECTIVE: To compare reported energy intake with energy expenditure using doubly
labeled water (DLW). Additionally, we compared reported nutrient intakes of our
subject population with national survey population data from the third National
Health and Nutrition Examination Survey (NHANES III). DESIGN: This was a cross
sectional study of children, balanced by race and gender, primarily characterized
by 4 body types: lean, obese, centrally fat, or peripherally fat.
SUBJECTS/SETTING: Children (n=118; mean age=10 years) kept 8-day food records,
with nutritionists recording weekday school lunch intakes. These subjects,
assisted by their parents, recorded all breakfasts, dinners, snacks, and weekend
lunches. STATISTICAL ANALYSES PERFORMED: Data were analyzed using least squares
analysis of variance with the general linear models procedure. Tukey's test was
used for multiple comparisons of predicted treatment means. RESULTS: Mean daily
energy intake was underreported by 17% to 33% of energy expenditure. The tendency
to underreport increased with age. Underreporting occurred in all groups and
subgroups studied. Reported mean intakes of vitamin A, vitamin E, vitamin B-6,
calcium, zinc, and copper were less than 70% of the Recommended Dietary Allowance
(RDA) for African-American girls, whereas African-American boys reported
similarly low intakes of copper. On average, white girls reported intakes less
than 70% of the RDA for zinc and copper, whereas white boys reported low intakes
of copper (60% of the RDA). Reported intakes in general were somewhat lower than
those reported in NHANES III. APPLICATIONS/CONCLUSIONS: Dietetics professionals
may modify the nutritional advice they give to patients/subjects based on food
intake records and other data. For children, particularly, it is imperative that
ethnic and gender differences be taken into consideration and that all foods
eaten be accounted for as much as possible.
PMID- 9550167
TI - A randomized controlled trial evaluating nutrition counseling with or without
oral supplementation in malnourished HIV-infected patients.
AB - OBJECTIVE: To evaluate the effects of nutrition counseling with or without oral
supplementation in malnourished patients infected with the human immunodeficiency
virus (HIV). DESIGN: Randomized controlled trial. SUBJECTS: HIV-infected men
(n=118) who were less than 90% of usual weight for height or who had lost more
than 10% of body weight. INTERVENTION: Nutrition counseling alone (control group)
vs nutrition counseling plus enteral supplementation (supplement group) for 6
weeks. All patients were instructed to consume a diet that exceeded estimated
total energy expenditure by 960 kcal/day. MAIN OUTCOME MEASURES: Weight, skinfold
thickness, fat-free mass, grip strength, quality of life, and cognitive function
(Buschke test). STATISTICAL ANALYSES: Differences in baseline variables and
outcomes were evaluated using analysis of variance or the Wilcoxon rank sum test.
RESULTS: Ninety-nine men completed at least 4 weeks of treatment, 49 in the
supplement group and 50 in the control group. Half the patients in each treatment
group achieved at least 80% of their energy target. No differences in weight,
skinfold thickness measurements, or quality of life were observed. Compared with
the control group, the supplement group had larger increases in fat-free mass and
grip strength, although the differences did not reach statistical significance.
APPLICATIONS: In the short term, nutrition counseling with or without oral
supplementation can achieve a substantial increase in energy intake in about 50%
of malnourished HIV-infected patients. Although further study is needed to
evaluate long-term effects, these findings suggest that nutrition counseling has
an important role in the management of malnourished HIV-infected patients.
PMID- 9550168
TI - The Harris-Benedict studies of human basal metabolism: history and limitations.
AB - In the early part of the 20th century, numerous studies of human basal metabolism
were conducted at the Nutrition Laboratory of the Carnegie Institution of
Washington in Boston, Mass, under the direction of Francis G. Benedict.
Prediction equations for basal energy expenditure (BEE) were developed from these
studies. The expressed purpose of these equations was to establish normal
standards to serve as a benchmark for comparison with BEE of persons with various
disease states such as diabetes, thyroid, and other febrile diseases. The Harris
Benedict equations remain the most common method for calculating BEE for clinical
and research purposes. The widespread use of the equations and the relative
inaccessibility of the original work highlights the importance of reviewing the
data from which the standards were developed. A review of the data reveals that
the methods and conclusions of Harris and Benedict appear valid and reasonable,
albeit not error free. All of the variables used in the equations have sound
physiologic basis for use in predicting BEE. Supplemental data from the Nutrition
Laboratory indicates that the original equations can be applied over a wide range
of age and body types. The commonly held assumption that the Harris-Benedict
equations overestimate BEE in obese persons may not be true for persons who are
moderately obese.
PMID- 9550169
TI - Dieting and binge eating among adolescents: what do they really mean?
AB - The study objectives were to gain insight into how the terms "dieting" and "binge
eating" are understood and used by adolescents and to assess whether
interpretations of these terms are consistent across age and gender. Twenty-five
focus groups were conducted with 203 adolescents (138 girls and 65 boys) in urban
public junior and senior high schools. Respondents were asked questions about
dieting and binge eating behaviors. In the majority of groups (n=19), healthful
eating behaviors, such as eating less fat or more fruits and vegetables, were
mentioned in reference to dieting. However, in many of the groups (n=13)
unhealthful eating behaviors, such as skipping meals or "starvation," were also
described. Dieting was frequently described as an umbrella term for different
behaviors aimed at weight control (ie, physical activity) or in nonbehavioral
terms (ie, as a desire or plan for weight loss). Although binge eating was
described as overeating by many participants, often it was not clear if youth
were referring to uncontrolled overeating. In nearly half of the groups,
participants indicated unfamiliarity with the term "binge eating." There was some
confusion between binge eating and other forms of disordered eating. The findings
suggest that prevalence rates of self-reported dieting and binge eating behaviors
should be interpreted with caution and it should not be assumed that the majority
of adolescents who self-report dieting are engaging in unhealthful behaviors. In
providing nutrition counseling to youth, and in assessing dieting and binge
eating behaviors in clinical settings and in research studies, specific behaviors
should be defined.
PMID- 9550170
TI - A model for making outcomes research standard practice in clinical dietetics.
AB - In today's rapidly changing health care environment, it is imperative that
dietitians demonstrate the importance of their role as health care providers by
initiating and participating in outcomes research. Patient care should be based
on empirical studies, and clinical dietitians should participate in or be at the
helm of such investigations. Nutrition research is usually accomplished and
reported by persons with MD or PhD degrees who do not have clinical training in
nutrition and does not often address situations encountered by dietitians in
clinical settings. This article examines the extent to which clinical dietitians
are conducting and reporting outcomes research, their attitudes about such
research, and how they think they could best acquire the skills needed to
incorporate outcomes research into their practice. Results indicate that clinical
dietitians are not writing a substantial percentage of articles and that reports
of outcomes research are not commonly included in clinical nutrition journals.
Clinical dietitians appear to value the inclusion of research in clinical
practice, but they are not spending a great amount of time doing research.
Dietitians report being comfortable about participating in research but not about
designing, conducting, and reporting research. Results from several surveys were
used to develop a model for integrating research in clinical practice. This model
includes the research process as a basis for clinical practice. A model for
collaborative efforts between clinical and academic dietitians is also proposed
and emphasizes the responsibility of academic dietetics training programs in the
integration of research and clinical practice.
PMID- 9550171
TI - Variation in perceptions of a medium' food portion: implications for dietary
guidance.
PMID- 9550172
TI - An elemental diet containing medium-chain triglycerides and enzymatically
hydrolyzed protein can improve gastrointestinal tolerance in people infected with
HIV.
PMID- 9550173
TI - Position of The American Dietetic Association: fat replacers.
PMID- 9550174
TI - President's page: Food security--take your place at the advocates' table.
PMID- 9550175
TI - A brief history of Doppler ultrasound in the diagnosis of peripheral vascular
disease.
AB - The history of Doppler ultrasound in peripheral vascular diagnosis is considered
in terms of basic developments, clinical applications and impact on medical
practice. Many early developments occurred at Osaka University in Japan and the
University of Washington in the United States. Through progressive steps, Doppler
ultrasound technology has provided clinical applications in blood-flow sensing,
waveform analysis, localizing blood flow and two-dimensional (2-D) mapping of
blood flow. An important advance was the development of duplex and color Doppler
scanning. Real time velocity measurements and flow mapping have led to many
clinical applications. Two important applications have been detection and grading
of atherosclerotic plaques in the internal carotid artery and the diagnosis of
deep venous thrombosis. Doppler ultrasound is the preferred noninvasive imaging
method for each of these clinical problems. The recent reaffirmation of carotid
endarterectomy as the appropriate management for certain categories of carotid
atherosclerotic occlusive disease has led to guidelines for selecting patients
for carotid endarterectomy. New Doppler ultrasound criteria are being developed
to identify categories of stenosis that relate to these guidelines. The
establishment of Doppler ultrasound has led to training programs for
technologists and physicians, certification of technologists and establishment of
standards and quality control measures for vascular laboratories.
PMID- 9550176
TI - Color Doppler imaging of the myocardium: current status and potential clinical
applications.
AB - Doppler myocardial imaging (DMI) is a new technique with potential clinical and
research applications. It applies traditional pulsed and color Doppler techniques
to the analysis of myocardial contractile velocity. A major area of focus is in
the quantitation of regional and global myocardial function and evaluation of
myocardial perfusion in conjunction with myocardial contrast studies. DMI may
also provide a direct, relatively load-independent assessment of diastolic
function. Further work is required to identify its role in clinical and research
studies.
PMID- 9550177
TI - Ultrasonic tissue characterization for coronary care unit patients with acute
myocardial infarction.
AB - The ultrasonic integrated backscatter of myocardium changes in infarction and
ischemia. On the third day after acute myocardial infarction, 30 patients
underwent ultrasonic tissue characterization from the parasternal short-axis
view. With a composite parameter, the phase-weighted variation, sensitivity,
specificity, and accuracy for diagnosing multivessel coronary artery disease were
84.6%, 52.9% and 66.6%, respectively. Using 67 degrees as the cutoff value for
the phase deviation of the backscatter power curve, the recanalization of the
infarct-related artery could be detected with a positive predictive value of
77.7% and a negative predictive value of 66.6%. Ultrasonic tissue
characterization is a feasible technique for detecting the multivessel coronary
artery diseases and the recanalization of infarct-related artery for patients
with acute myocardial infarction. The diminished cardiac cycle-dependent
variation in integrated backscatter and increased phase deviation can
differentiate patent coronary arteries from those coronary arteries with
anatomically significant stenoses.
PMID- 9550178
TI - Fetal biometry and outcome in monochorionic vs. dichorionic twin pregnancies; a
retrospective cross-sectional matched-control study.
AB - Fetal biometry, amniotic fluid volume distribution and perinatal outcome were
determined in a retrospective, cross-sectional matched-control study design,
including 20 monochorionic (MC) twin pregnancies and 20 dichorionic (DC) twin
pregnancies (historic controls). Intertwin differences for fetal abdominal
circumference were larger in the MC subset than in the DC subset. Fetofetal
transfusion syndrome, based upon a combination of oligohydramnios in one sac and
polyhydramnios in the other sac, existed in 40% (8 of 20) of the MC twin
pregnancies, but in none of the DC twin pregnancies. Mean gestational age at
delivery was significantly shorter in the MC subset (30.9 weeks) than in the DC
subset (34.3 weeks). The perinatal death rate was significantly higher in MC twin
pregnancies (50%) than in DC twin pregnancies (15%). No differences were
established for intertwin weight estimates by ultrasound and birth weight between
both subsets. The poor perinatal outcome in monochorionicity is mainly a result
of the degree of premature delivery.
PMID- 9550179
TI - Blood flow imaging and volume flow quantitation with intravascular ultrasound.
AB - Current intravascular ultrasound techniques produce real-time imaging of a vessel
cross-section with a scan plane approximately normal to blood flow. When a
cluster of randomly distributed blood particles moves across the ultrasound beam,
the received echo signals decorrelate as a function of time. This phenomenon may
be used to estimate blood velocities by measuring the decorrelation rate from a
sequence of blood scattering signals. A decorrelation-based method for measuring
local blood velocity and quantifying volume flow from cross-sectional radio
frequency intravascular echo signals was developed. Serial in vitro measurements
were performed with a flow phantom to test the principle of the proposed velocity
estimation method. An in vivo pig experiment was carried out to study the
feasibility of applying this method in clinical settings. Preliminary results of
this study indicate that the proposed decorrelation method is able to extract
cross-sectional velocity data and volumetric flow both in vitro and in vivo.
PMID- 9550180
TI - An in vivo method for measuring the mechanical properties of the skin using
ultrasound.
AB - In this study, we report a new and original device called the "echorheometer,"
comprising a suction system with an ultrasound scanner (A-mode, TM-mode and B
mode) that enables the simultaneous visualization and measurement of the
deformation of skin structures in vivo. With the scanner described here, high
resolution is obtained using a strongly focused, wide-band 20-MHz center
frequency transducer, with an axial resolution of 0.07 mm. This device can
determine, noninvasively, not only those skin structures that are involved in the
deformation, but also their morphological variation and their extent of
involvement with the degree of stress applied. Using this device, the behavior of
the dermis and subcutaneous fat, while under suction, was investigated on the
volar forearm of 10 volunteers. The results showed that the resistance to the
applied vertical stress is essentially due to the dermis rather than the
subcutaneous fat, and that there is a certain amount of infiltration of fluid
into the tissues under suction. In addition, it was shown that the dermal
response to an applied suction is initially due to its own natural tension and
that, with increasing deformation, the intrinsic dermal elasticity has a greater
contribution to the resistance of stress. With this information, we hope to
develop a mechanical model to define appropriate mechanical parameters for skin.
This will allow the evaluation of changes in the dermis and also enable
therapeutic intervention to be assessed. Furthermore, it could also be applied to
studies of skin ageing and the assessment of cosmetic product efficacy
(emolliency, hydratation, etc.).
PMID- 9550181
TI - Quantification of sonographic echogenicity with grey-level histogram width: a
clinical tissue characterization.
AB - Grey-level histogram width (GLHW) values obtained by common sonographic devices
were large in echogenic image and small in less echoic parts. The Aloka UIP-100
computer system, SSD-680, and Toshiba SSA-270A sonographs showed GLHW values not
significantly different when tested with RMI-412 phantom with the device contrast
set at the lowest level. No influence on the GLHW value was observed by the
changes of device gain, STC or image depth in the range of clinical practice.
Device contrast control influenced the value. Although two sonographs showed
significant differences from UIP-100, they were easily corrected by a small
factor. Normal ranges of GLHW values of the placenta were obtained every 2 weeks,
from 20 to 41 weeks, in 222 normal pregnancies measured by old scanners. GLHW
values of normal pregnancies measured by the new Aloka and Toshiba machines were
distributed within the normal ranges, and those of Grannum Grade III abnormally
echogenic placenta were greater than the upper normal range. GLHW is a
reproducible value among commercial ultrasonic devices, and the value is useful
in clinical practice. Manual and automated GLHW values were identical.
PMID- 9550182
TI - In vitro investigation of lymph node metastasis of colorectal cancer using
ultrasonic spectral parameters.
AB - Lymph node involvement is one of the major factors affecting the prognosis of
colorectal cancer. Various imaging methods, including ultrasound and computed
tomography, are not sufficiently sensitive or specific for reliably determining
lymph node involvement. We investigated the feasibility of using ultrasonic
tissue characterization (UTC) based on spectrum analysis of backscattered echo
signals for diagnosing lymph node metastasis of colorectal cancer in vitro. Forty
lymph nodes, including 17 metastatic and 23 nonmetastatic nodes, from 11
colorectal cancer operations were investigated. Lymph nodes were scanned using a
clinical instrument; B-mode imaging was performed for each lymph node, and
radiofrequency (RF) data were acquired. The UTC parameters, slope and intercept,
were calculated from the normalized power spectrum of the backscattered echo
signals from each lymph node. The mean values of UTC parameters of metastatic and
nonmetastatic lymph nodes were compared. The accuracy of UTC in distinguishing
metastatic from nonmetastatic lymph nodes was calculated using discriminant
analysis. Receiver operating characteristic (ROC) analysis was performed to
compare the classification efficacy of UTC and B-mode ultrasound. UTC parameters
demonstrated a significant difference in parameter values between metastatic and
nonmetastatic lymph nodes. The overall accuracy in diagnosing the lymph node
metastasis was 87.5% for UTC and 77.5% for B-mode ultrasound. ROC analysis
produced an ROC curve area of 0.92 or 0.89 for UTC (depending on the performance
assessment algorithm) and 0.84 for B-mode ultrasound, which indicated that UTC
performed markedly better than B-mode ultrasound in diagnosing metastatic lymph
nodes. The advantages of UTC over conventional B-mode ultrasound in
discriminating metastatic lymph nodes from nonmetastatic lymph nodes are
extremely encouraging, and warrant an in vivo UTC study.
PMID- 9550183
TI - Kinetics of the "black hole" phenomenon in ultrasound backscattering measurements
with red blood cell aggregation.
AB - The observation of a hypoechoic zone around the center of large tubes (the "black
hole" phenomenon) in ultrasound backscattering measurements with red blood cell
(RBC) aggregation was reported for the first time in 1989. Since then, a very
limited number of studies tried to explain its complex mechanisms. In this study,
blood models characterized by different RBC aggregation levels were prepared by
diluting horse blood plasma with a saline solution in different proportions. A
laser reflectometry technique was used to characterize the RBC aggregation
kinetics and cohesion forces between RBCs for each blood sample. The blood was
circulated in a 12.7 mm diameter vertical tube. For each experimental flow
condition tested, 25 or 15 power Doppler ultrasound measurements were performed
across the tube with a 10-MHz system and insonation angles varying between 40
degrees to 70 degrees. For flow rates varying between 100 and 1250 mL/min, the
"black hole" was observed in most measurements performed with different
aggregating RBC models. The "black hole" was more pronounced for RBCs with a high
kinetics of aggregation and measurements with increasing Doppler angles. Previous
studies suggested that this phenomenon is due to tube entrance effects, and the
reduction of RBC aggregation at very low shear rates around the center of the
tube. In the present study, the "black hole" was observed for shear rates up to
25 s(-1). It is suggested that the structural organization and orientation of RBC
rouleaux may participate in the mechanism leading to the "black hole" phenomenon.
A schematic representation of the rheological behavior of horse RBCs in a large
tube under steady flow is presented.
PMID- 9550184
TI - Experimental study of stability of a contrast agent in an ultrasound field.
AB - Attenuation coefficient and phase velocity measurements and direct optical
observations showed that microbubbles of a contrast agent (Albunex) in 5% bovine
albumin solution were not stable under ultrasonic irradiation. When the
concentration of Albunex was 0.41 microL/mL and a 2.5-MHz phased array transducer
of a Hewlett-Packard ultrasound imaging system (Model 77020AC) was used as the
ultrasound source (the compression and rarefaction peak pressure amplitudes were,
respectively, equal to 2 MPa and 1 MPa, the repetition frequency was 2.64 kHz),
the attenuation coefficient at 2.5 MHz dropped from 40 dB/cm to 16 dB/cm after 2
min of continuous insonification. Under a static condition, it was shown by
direct optical observations that the microbubbles shrank and aggregated to form
clusters or were destroyed under insonification; pressure amplitude was estimated
to be 0.5 MPa, frequency = 2.44 MHz, and the pulse repetition frequency was 5
kHz.
PMID- 9550185
TI - Temperature rise generated by ultrasound in the presence of contrast agent.
AB - Temperature elevation vs. time generated by a focused Gausssian ultrasound beam
in the presence of contrast agents has been calculated using a perfect absorbing
disc model. The results suggest that, if the contrast agent (Albunex) is
introduced into the body intravenously, the temperature rise in the heart, which
is 4.5 cm from the transducer, generated by 110-mW (the corresponding acoustic
intensity at the transducer front surface is 0.4 W/cm2) 2-MHz ultrasound is about
2 degrees C in 10 s. The relationship between temperature rise and the blood
perfusion, acoustic power and focal length is discussed.
PMID- 9550186
TI - Demonstration of potential noninvasive ultrasound brain therapy through an intact
skull.
AB - Utilization of therapeutic ultrasound in the brain has been seriously limited by
the commonly accepted view that these exposures would require that a piece of the
skull bone be removed to allow the ultrasound beam to propagate into the brain.
In this paper, the feasibility of delivering ultrasound therapy through the
intact skull was studied. Sonications were performed through a piece of human
skull with focused transducers at 0.248, 0.559, 1.0 and 1.68 MHz. The skull
attenuated and distorted the field; however, a sharp focal spot was created at
frequencies of 1 MHz or lower. At the higher frequency, the focus was destroyed.
To investigate the feasibility of compensating for the ultrasound field
distortion caused by the bone, phased array experiments were performed. Two
arrays with 64 elements, operating at 0.6 MHz and 1.58 MHz, were used in these
experiments. The phase shifts caused by the skull were measured for each element
of the arrays and then compensated for by phase-control circuitry. These phase
corrections allowed a sharp focus to be generated at both frequencies. Finally,
tissue destruction was induced by using pulsed sonication through a piece of
human skull in a rabbit brain in vivo at the frequency of 0.559 MHz. In summary,
the results showed that transcranial delivery of therapeutic ultrasound into the
brain may be feasible.
PMID- 9550187
TI - Enhancement of ultrasonically-induced hemolysis by perfluorocarbon-based compared
to air-based echo-contrast agents.
AB - Hemolysis induced by ultrasonic activation of various contrast-agent gas bodies
was investigated. Canine whole blood, with high concentrations of the agents held
in 1 mm thick chambers, was exposed in the nearfield of a 2.4-MHz ultrasound beam
in a 37 degrees C water bath. Sterile phosphate buffered saline (PBS) served as a
control agent without gas bodies. Albunex (Mallinckrodt Medical, St. Louis, MO)
and Levovist (Schering AG, Berlin, Germany) represented the air-based contrast
agents. The experimental agents FS069 (Optison, Molecular Biosystems Inc., San
Diego, CA) and modified MRX-130 (ImaRx Pharmaceutical Corp., Tucson, AZ)
represented perfluorocarbon-based contrast agents. No significant ultrasonically
induced hemolysis was detected for the PBS or Levovist suspensions. After 1 s
continuous exposure, ultrasonically-induced hemolysis was significant for Albunex
at 0.4 MPa or higher pressure amplitudes, for FS069 at 0.2 MPa and for modified
MRX-130 at 0.4 MPa. Hemolysis found after pulsed exposure with 10 micros pulses
and 1 ms pulse repetition period was significant for Albunex, FS069 and modified
MRX-130 above thresholds of 1.1 MPa, 0.57 MPa and 1.6 MPa, respectively. FS069
led to more hemolysis after pulsed mode exposures of 1 s duration or longer than
did Albunex. Reduced concentrations of gas bodies gave increased thresholds and
reduced hemolysis. These results indicate that improvements in persistence of
contrast agents, which increase their clinical utility, may also enhance the
potential for cavitational bioeffects.
PMID- 9550188
TI - In vivo pressure measurements of lithotripsy shock waves in pigs.
AB - Stone comminution and tissue damage in lithotripsy are sensitive to the acoustic
field within the kidney, yet knowledge of shock waves in vivo is limited. We have
made measurements of lithotripsy shock waves inside pigs with small hydrophones
constructed of a 25-microm PVDF membrane stretched over a 21-mm diameter ring. A
thin layer of silicone rubber was used to isolate the membrane electrically from
pig fluid. A hydrophone was positioned around the pig kidney following a flank
incision. Hydrophones were placed on either the anterior (shock wave entrance) or
the posterior (shock wave exit) surface of the left kidney. Fluoroscopic imaging
was used to orient the hydrophone perpendicular to the shock wave. For each pig,
the voltage settings (12-24 kV) and the position of the shock wave focus within
the kidney were varied. Waveforms measured within the pig had a shape very
similar to those measured in water, but the peak pressure was about 70% of that
in water. The focal region in vivo was 82 mm x 20 mm, larger than that measured
in vitro (57 mm x 12 mm). It appeared that a combination of nonlinear effects and
inhomogeneities in the tissue broadened the focus of the lithotripter. The shock
rise time was on the order of 100 ns, substantially more than the rise time
measured in water, and was attributed to higher absorption in tissue.
PMID- 9550189
TI - Subspecies of protein kinase C in the rat spinal cord.
AB - In this review, the developmental expression of alpha-, beta- and gamma
subspecies of protein kinase C (PKC) in the rat spinal cord was summarized, and
possible roles of this protein for neuronal differentiation were discussed. Faint
immunoreactivity (IR) for PKCs was first demonstrated in the cervical spinal cord
on embryonic day 13 (E-13). It gradually became stronger, and between E-18 and
postnatal day 0 (P-0), strong IR for these three subspecies was uniformly
distributed throughout the spinal cord. While thereafter, it irregularly
declined, and reached the adult pattern around P-28 or P-35. The motor neurons
began to express these three subspecies of PKC in the nucleus, perikaryal
cytoplasm, dendrites and axons, soon after they began to differentiate. In the
perikaryal cytoplasm, the IR was expressed mainly on ribosomes, and in the
dendrites, mainly on cytoskeletal elements. At the late embryonic and early
postnatal stages, IR for these PKCs was expressed both in the presynaptic
terminals and on the postsynaptic densities. While thereafter, the IR in the
former declined, and was detected only on the postsynaptic densities. The dorsal
corticospinal tract transiently expressed strong IR for these PKCs at the early
postnatal developmental stages, but thereafter, the IR rapidly declined. The
developing corticospinal tract fibers expressed strong IR mainly on cytoskeletal
elements. In contrast, in the mature fibers, IR for alpha-PKC was detected on
some cytoskeletal elements, and for beta-PKC on almost all cytoskeletal elements,
but IR for gamma-PKC, mainly on smooth surfaced endoplasmic reticulum. These
findings suggest that PKC might be involved in several aspects of neuronal
differentiation such as gene expression, protein synthesis, morphological
maturation and synapse formation.
PMID- 9550190
TI - The problem of assessing effective neuroprotection in experimental cerebral
ischemia.
AB - In animal models of global and focal ischemia neuroprotection is typically
determined by quantifying the degree of cell loss or reduction in infarct volume
shortly after the ischemic insult. These methods are unable to reliably detect
more subtle forms of neuronal death and dysfunction that arise from injury to non
homogeneous cell populations (e.g. hilar and striatal neurons), or to dendrites
(e.g. loss of structural proteins or decreased synaptic transmission). It is
argued that this type of covert injury contributes to a wide range of functional
impairments (e.g. decreased working memory, altered field potentials, loss of
forelimb dexterity) that are rarely used as outcome measures in experimental
studies even though they are of paramount importance clinically. The limitations
of a purely histological approach in assessing neuroprotection are clearly
illustrated using examples of protective drug therapies, mild hypothermia and
ischemic preconditioning. An alternative strategy that incorporates behavioural,
electrophysiological and histological endpoints is put forth as a more powerful
method for gauging neuroprotection. The strength of this approach will be
increased if these assessments are performed on the same animals. By
incorporating functional measures and longer postischemic survival into their
experimental protocols, investigators will increase the validity of their models
and hopefully reduce the likelihood of advancing ineffective therapies into
costly clinical trials.
PMID- 9550191
TI - Ontogeny of the primate fovea: a central issue in retinal development.
AB - The formation of the primate fovea has fascinated a substantial number of
histologists, pathologists, ophthalmologists and physiologists for more than a
century. In this article, using data from the literature as well as our own
observations, we identify events which we believe are crucial in this process and
present a developmental neurobiologist's view of the formation of the primate
fovea. The fovea is a region of the retina specialized for diurnal, high acuity
functions which require a high spatial density of cone photoreceptors as well as
a large number of inner retinal cells in order to establish the distinct
retinofugal pathways (ganglion cell axons) receiving from individual cones in the
foveal cone mosaic. A unique feature of the fovea is the displacement of cells
connected to the foveal cones onto the rim of the fovea. It is generally believed
that this displacement counteracts the problems caused by the scattering of the
incoming light by cells and blood vessels of the inner retina. We believe that
one of the crucial events in the formation of the primate fovea is the early
centripetal migration of photoreceptors towards the central area (centripetal
displacement). This process, initiated early in development, continues throughout
intrauterine life until some months or years postnatal. We propose that the
displacement of cells from the inner layers is related to the earlier
developmental accumulation of photoreceptors and inner retinal cells centrally.
This, we propose, leads to metabolic "starvation" of the inner retina, resulting
from the complete absence of retinal vessels from the vicinity of the incipient
fovea. It is suggested that these factors in turn trigger centrifugal
displacement of inner retinal cells towards the encroaching perifoveal capillary
network and lead to the formation of the foveal depression.
PMID- 9550192
TI - Glutamate receptors in the mammalian central nervous system.
AB - Glutamate receptors (GluRs) mediate most of the excitatory neurotransmission in
the mammalian central nervous system (CNS). In addition, they are involved in
plastic changes in synaptic transmission as well as excitotoxic neuronal cell
death that occurs in a variety of acute and chronic neurological disorders. The
GluRs are divided into two distinct groups, ionotropic and metabotropic
receptors. The ionotropic receptors (iGluRs) are further subdivided into three
groups: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), kainate and
N-methyl-D-aspartate (NMDA) receptor channels. The metabotropic receptors
(mGluRs) are coupled to GTP-binding proteins (G-proteins), and regulate the
production of intracellular messengers. The application of molecular cloning
technology has greatly advanced our understanding of the GluR system. To date, at
least 14 cDNAs of subunit proteins constituting iGluRs and 8 cDNAs of proteins
constituting mGluRs have been cloned in the mammalian CNS, and the molecular
structure, distribution and developmental change in the CNS, functional and
pharmacological properties of each receptor subunit have been elucidated.
Furthermore, the obtained clones have provided valuable tools for conducting
studies to clarify the physiological and pathophysiological significances of each
subunit. For example, the generation of gene knockout mice has disclosed critical
roles of some GluR subunits in brain functions. In this article, we review recent
progress in the research for GluRs with special emphasis on the molecular
diversity of the GluR system and its implications for physiology and pathology of
the CNS.
PMID- 9550193
TI - Species-dependence and relationship of morphological and electrophysiological
properties in nigral compacta neurons.
AB - The use of animal models in studying disorders of dopaminergic transmission in
humans, such as Parkinson's disease, depends on the assumption that morphological
and electrophysiological properties of dopaminergic neurons in the pars compacta
of the substantia nigra are relatively constant from rodents to monkeys and
humans. While the electrophysiological properties of nigral dopaminergic neurons
are highly characteristic and appear to be remarkably uniform, morphological
studies of nigral compacta neurons have shown significant size differences across
mammalian species. This discrepancy between morphological and
electrophysiological characteristics could be reconciled if scaling of neuronal
size between species was such that intrinsic properties and responses to afferent
inputs would not be affected. We review the principles of morphological scaling
of compacta neurons and address this problem by construction and analysis of
specific passive and active membrane models. These demonstrate that the size
differences between compacta neurons from rats to primates lead to distinct
intrinsic electrophysiological properties and that even conservative scaling is
not sufficient to ensure constant activity patterns unless further compensatory
mechanisms are present. Comparisons with experimental data show that the
electrophysiological properties of compacta neurons are characteristic compared
to other neuronal types but less uniform than generally recognized. The available
data are not sufficient to prove a specific relationship between morphological
and electrophysiological properties of compacta neurons but it is evident that
they provide no support to the assumption that dopaminergic neurons have similar
properties across mammalian species. Thus, comparative experimental studies are
required to establish the validity of animal models for nigral function and
pathology in humans.
PMID- 9550194
TI - Farewell to the 20th century and reproductive ill-health.
PMID- 9550195
TI - Preeclamptic nephropathy -- an endothelial lesion. A morphological study with a
review of the literature.
AB - OBJECTIVE: We investigated wether an endothelial lesion, postulated in
pathogenesis of preeclampsia (PE) in general, is also pathogenetically relevant
in the characteristic renal lesions of PE, presenting as special glomerular
alterations, designated as "preeclamptic nephropathy". STUDY DESIGN: Renal
biopsies of 90 women with PE were analyzed by light microscopy (LM),
immunohistology (IH) and electron microscopy (EM). Corresponding with clinical
data clinicomorphological correlations were performed. RESULTS: In IH and EM the
altered glomeruli demonstrate an endothelial lesion. Consecutive morphological
reactions could be revealed by EM, allowing a subdivision in different stages of
disease. The late stage indicates the reversibility of these renal lesions. Close
correlations were found between clinical and morphological data. Focal
glomerulosclerosis presents a hyperperfusion lesion, developing only
facultatively in PE as a result of hyperfiltration. CONCLUSION: In preeclamptic
nephropathy the first morphological substrate of renal changes with the key to
pathogenesis presents itself as an endothelial lesion. This results in a
disturbance of glomerular basement membrane permeability and in an imbalance of
different mediator systems, with dominance of vasoconstrictive reactions but also
coagulative-, reparation-, and proliferation-processes, leading to the
characteristic glomerular alterations of preeclamptic nephropathy.
PMID- 9550196
TI - Transient fetal cerebral dysfunction after road traffic accident. A case report.
AB - We present a case at 30 weeks gestation with transient abnormal fetal cerebral
function after a road traffic accident, with loss of fetal movements and abnormal
FHR tracings for almost 1 week. The pregnancy had after this incident a normal
course and a healthy baby boy was born at term. We suggest the mechanism to be
related to fetal hypoxia after excessive maternal psychological stress.
PMID- 9550197
TI - Effect of angiotensin infusion on plasma endothelin in pregnancy.
AB - OBJECTIVE: To study a possible role of plasma endothelin in angiotensin-induced
vasoconstriction. STUDY DESIGN: Plasma endothelin levels were measured before and
after an angiotensin sensitivity test at 32 gestational weeks in 19 nulliparous
women. RESULTS: No significant change in plasma endothelin occurred as a result
of angiotensin infusion. CONCLUSION: The angiotensin-induced rise in diastolic
blood pressure is not associated with changes in plasma endothelin.
PMID- 9550198
TI - Reproductive age mortality survey to study under-reporting of maternal mortality
in Surinam.
AB - OBJECTIVES: A nationwide confidential enquiry into maternal deaths was carried
out in Surinam during the years 1991-1993. Preliminary analysis showed a maternal
mortality ratio (MMR) of 240 per 100000 live births, which was almost four times
higher than the official MMR for the preceding decade. The question arose whether
maternal deaths had been under-reported for the years 1981-1990. For these 10
years official statistics revealed 65 maternal deaths. METHODS: For the period
1981-1990 a retrospective reproductive age mortality survey was carried out in
five urban hospitals covering 78% of all deliveries in Surinam. RESULTS: In these
hospitals 1216 women of age 10-49 years died. Due to disorganized filing 439
medical records (36%) could not be traced. By reviewing 64% of the records, 85
maternal deaths were identified (70 direct and 15 indirect). CONCLUSION: Although
only 64% of medical records could be reviewed, the number of maternal deaths
identified in five hospitals (85) was 1.3 times higher than the officially
reported number for the whole country (65). Maternal mortality was found
therefore to be under-reported in Surinam for the period 1981-1990.
PMID- 9550199
TI - The addition of indomethacin to betamimetics for tocolysis: any benefit for the
neonate?
AB - OBJECTIVE: To study the influence on the neonate of indomethacin administered to
the mother as an additional tocolytic. STUDY DESIGN: The neonatal outcome in 76
closely matched low birth weight infants was compared retrospectively: those
whose mothers received indomethacin together with betamimetics formed the study
group, those whose mothers received only betamimetics formed the control group.
RESULTS: There was an increased incidence of respiratory distress syndrome (RDS)
in the study group (97% versus 45%; P<0.001), an increased need for surfactant
use (68% versus 26%; P<0.001) and increased ventilatory support, and an increased
incidence of bronchopulmonary dysplasia (BPD) (47% versus 24%; P=0.03). Gestation
could not be prolonged significantly by the addition of indomethacin. CONCLUSION:
Indomethacin as an additional tocolytic agent was associated with an increased
incidence of RDS, surfactant use and BPD but did not significantly prolong
gestation.
PMID- 9550200
TI - Does lunar position influence the time of delivery? A statistical analysis.
AB - OBJECTIVE: To study the relationship between lunar position and the day of
delivery; to investigate the synodic distribution of spontaneous deliveries,
especially in relation to the presence of a full moon. STUDY DESIGN:
Retrospective analysis of 1248 spontaneous full-term deliveries in three-year
period (36 lunar months), setted at Department of Obstetrics and Gynaecology,
Civil Hospital, Fano (Marche, Italy), using circular statistics techniques.
RESULTS: A connection between the distribution of spontaneous full-term
deliveries and the lunar month was found. The effect of the phases of the moon
seems to be particularly relevant in multiparae and plurigravidae; in these
cases, the mean day of delivery corresponds to the first or second day after the
full moon. CONCLUSIONS: In this paper the effect of lunar phases on the time of
delivery is shown. This influence seems to be especially relevant in the case of
multiparae and plurigravidae. Nevertheless, it is too weak to allow for
prediction regarding the days with the highest frequency of deliveries.
PMID- 9550201
TI - Fetal macrosomia: risk factors and outcome. A study of the outcome concerning 100
cases >4500 g.
AB - OBJECTIVE: Because difficult vaginal delivery is more frequent with macrosomic
fetuses, some authors recommend routine caesarean section for the delivery of
fetuses >4500 g. The purpose of this study was to evaluate the appropriateness of
this recommendation, in particular, to analyze maternal and fetal complications
according to the mode of delivery. METHOD: Maternal and neonatal records of 100
infants with weights of at least 4500 g were identified retrospectively from
January 1991 to December 1996. Outcome variables included the mode of delivery
and the incidence of maternal and perinatal complications. RESULTS: The study
sample consisted of 100 infant and mother pairs. Macrosomic fetuses represented
0.95% of all deliveries during this period and only ten were >5000 g. Mean birth
weight was 4730 g (maximum, 5780 g). Gestational diabetes was present in nineteen
patients. Diabetes was present in three patients. A trial of labour was allowed
in 87 women, and elective caesarean delivery was performed in thirteen patients.
The overall cesarean rate, including elective caesarean delivery and failed trial
of labour, was 36%. Of those undergoing a trial of labour, 73% (64/87) delivered
vaginally. Shoulder dystocia occurred fourteen times (22% of vaginal deliveries)
and it was the most frequent complication in our series. There were five cases of
Erb's palsy, one of which was associated with humeral fracture, and four cases of
clavicular fracture. By three months of age, all affected infants were without
sequelae. There was no related perinatal mortality and only two cases of birth
asphyxia. Maternal complications with vaginal delivery of macrosomic infants
included a high incidence of lacerations requiring repair (eleven cases). No
complications were noticed in the patients who had a caesarean section.
CONCLUSION: Vaginal delivery is a reasonable alternative to elective cesarean
section for infants with estimated birth weights of less than 5000 g and a trial
of labour can be offered. For the fetuses with estimated birth weight >5000 g, an
elective caesarean section should be recommended, especially in primiparous
women.
PMID- 9550202
TI - Influence of leukotrienes on in vitro growth of human mammary carcinoma cell line
MCF-7.
AB - OBJECTIVES: The aim of this work was to study the action of leukotrienes on the
growth of human mammary cancer cells MCF-7. STUDY DESIGN: The growth of the cells
was measured by incorporation of 3H-thymidine. The action of leukotriene (LT)B4,
LTD4, LTC4, LTE4 or arachidonate (AA) was tested in human mammary cancer cells
MCF-7 in vitro. RESULTS: LTB4 or LTD4 but not LTC4 or LTE4 reduced significant
incorporation of 3H-thymidine in MCF-7 cells up to 52% or 56% respectively, when
administered in concentrations 0.1-1000 pM. Agents in concentrations of 0.01 pM
or 10000 pM did not effect 3H-thymidine incorporation. We have shown, that MCF-7
cells synthesise LTB4 when treated with calcium ionophor A23187 (10 microM).
Leukotriene-antagonist LY171883 (10 microM) lifts inhibitory effects of LTB4 or
LTD4. Arachidonic acid (10 microM) inhibits 3H-thymidine incorporation up to 72%.
5-lipoxygenase inhibitor MK-886 (100 nM) lifts the inhibitory effect of
arachidonate. CONCLUSIONS: LTB4 or LTD4 inhibits MCF-7 breast cancer cell growth.
LT-receptors mediate the growth-inhibitory effect of LTB4 or LTD4.
PMID- 9550203
TI - Selection bias in a study on how women experienced induced abortion.
AB - OBJECTIVE: One third of the women who had an induced abortion at the department
of gynecology and obstetrics in Malmo 1989 refused to participate in an interview
a year later to explore their experience and the care they had received. Using
data from the mandatory preoperative visit it was then possible to compare
participants with non-participants with regard to socio-demographic
characteristics. reproductive history and stated reason for abortion. By
continued follow-up of medical records it has furthermore been possible to
ascertain how many women conceived within a year, and how many of them applied
for another abortion and how many elected to continue the pregnancy to term.
SETTING: Department of Obstetrics and Gynecology, Lund University, University
Hospital, Malmo Sweden. This is the sole referral hospital serving the population
of Malmo (approx. 230000). SUBJECTS: All 1285 women who underwent induced
abortion at the department in 1989. + STUDY DESIGN: In each case information on
socio-demographic characteristics, reproductive history and stated reasons for
abortion was collected at the mandatory clinical visit prior to the abortion.
This information was used for comparison of participants and non-participants in
the planned 1-year follow-up interview. RESULTS: Young, unmarried women of low
educational status and without full-time employment or studying were
overrepresented in the non-participant group. The proportion of women with
children was however smaller in that group. Within 12 months after the abortion,
118 women 66 (7.7%) of the participants in the follow-up interview and 52 (12%)
of the non-participants conceived again but elected to continue the pregnancy to
term (P<0.05). whereas 124 of the women 80 (9.5%) and 44 (10.2%) of the
respective subgroups again applied for abortion within 12 months. CONCLUSION: One
third of the women who underwent induced abortion did not wish to be interviewed
about their emotional and somatic experience of the abortion 1 year later. Non
participation at the follow-up interview was associated with socio-demographic
factors which in studies about other medical problems have been shown to be
associated with increased vulnerability and morbidity. Non-participation was also
associated with an increased childbirth rate during the following 2 years. The
large proportion of non-participants is a matter for concern as to some extent it
reflects inability of the health care system to establish trustful relationships
with these women. How the participants in the follow-up study experienced this
relationship will soon be published in our next paper. Support from the women's
surroundings and the adviser the women met at the public health care system
clearly influenced the women's psychological reactions after the abortion. It is
therefore important to ascertain to what extent the management of abortion
applicants in fact fulfils their individual needs and expectations.
PMID- 9550204
TI - Screening for psychologically traumatized rape victims.
AB - OBJECTIVE: This study aimed to determine whether the General Health
Questionnaire, a simple psychological screening instrument, could be useful to
non-specialists in screening for psychologically traumatized rape victims. STUDY
DESIGN: 285 rape victims (mean age 22.5, men 8%) attending consecutively a
Consultation for Victims of Psychological Trauma at the University Hospital in
Tours, France, were assessed through the Structured Interview for Post-Traumatic
Stress Disorder (SI-PTSD), and the French 28-item version of the self-rated
General Health Questionnaire (GHQ-28). RESULTS: 70% had Post-Traumatic Stress
Disorder (PTSD) and 72% a GHQ-28 overthreshold score. The principal component
analysis of the GHQ-28 ratings yielded a 4-factor solution: social dysfunction,
feeling of foreshortened future type of depression, somatoform complaints and
hyperalertness anxiety. GHQ-28 reliability and validity in screening for PTSD
were studied through computation of Cronbach's alpha coefficient (0.95),
sensitivity (88%) and positive predictive value (86%). CONCCLUSION: Using the GHQ
28 is valid and appropriate for practical use.
PMID- 9550205
TI - Endometrial resectoscopic ablation in patients with menometrorrhagia as a side
effect of anticoagulant therapy.
AB - OBJECTIVE: The study was conducted to examine the effect of endometrial ablation
therapy for patients suffering from coagulation abnormalities and presenting with
failed medical treatment for menometrorrhagia. STUDY DESIGN: Eleven patients with
a mean age of 42 years (range 39-45) and with coagulation disorders in whom
medical therapy for abnormal uterine bleeding was unsuccessful, were treated by
the ablation procedure under video monitoring. Complications, length of
hospitalisation and long-term follow-up were noted. The age of the patients
ranged from 39-45 years. Menstrual characteristics were scored, but blood loss
before and after the procedure was not quantified. RESULTS: Uterine fibroids were
found in two patients. The duration of the ablation procedure was 20 min and was
prolonged for 30 to 40 min when fibroids were diagnosed. During the operation, no
excessive bleeding was noted in ten patients and postoperative recovery was rapid
in all. After a one-year follow-up the overall satisfaction of the patients was
high (10/11). CONCLUSIONS: Our initial experience with a selected group of
patients suffering from coagulation abnormalities is promising. Bearing in mind
the risks of a major operation in this group of patients, endometrial ablation
should be seriously considered.
PMID- 9550206
TI - Evaluation of ovarian tumors in postmenopausal women by transvaginal sonography.
AB - OBJECTIVE: The aim of the present study was the evaluation of simple reproducible
sonomorphological criteria for the preoperative evaluation of ovarian tumors in
postmenopausal women by use of transvaginal sonography. STUDY DESIGN:
Postmenopausal women (> or =1 year of secondary amenorrhea) with ovarian tumors
(n=378; tumors > or =3 cm and <3 cm but with solid parts) were examined in a
prospective study by transvaginal sonography prior to surgery between 1987 and
1993. The sonomorphological criteria were correlated with the histological
findings of the tumors. RESULTS: Of all ovarian tumors in postmenopausal women,
6.3% were functional cysts (follicular or corpus luteum cysts). Almost all of
them were detected within the first 5 years of postmenopause. The other ovarian
tumors were diagnosed as retention cysts (17.5%), benign neoplasms (39.4%), and
malignant tumors (36.8%). Simple ovarian cysts (monolocular, smooth inner wall)
represented sonomorphologically the second most frequent type of ovarian tumors
in postmenopausal women (35.7%). Of these tumors, 9.6% were diagnosed as
malignant. CONCLUSIONS: Simple reproducible sonomorphological criteria proved to
be a useful clinical parameter in the preoperative evaluation of ovarian tumors.
PMID- 9550207
TI - Pelvic floor exercises versus vaginal weight cones in genuine stress
incontinence.
AB - OBJECTIVE: To compare pelvic floor exercises and vaginal weight cones in the
treatment of genuine stress incontinence. STUDY DESIGN: Randomised controlled
trial. METHODS: Sixty ambulatory and fit white women (mean age 56 years) with
urinary stress incontinence, treated by a single physiotherapist as outpatients
during twelve weeks. Thirty women were allocated to a weekly session of pelvic
floor exercises. Thirty were allocated to using cones, they were seen every two
weeks. OUTCOME MEASURES: Objective: stress test, vaginal squeezing capacity.
Subjective: urinary diary, visual analogue scales. RESULTS: Characteristics of
both study groups were comparable. Unfortunately, there was an early withdrawal
of fourteen (47%) women in the group treated with cones, and none in the other
group. Therefore the pelvic floor exercise group was compared not only with the
group intended to be treated with cones, but also with the selected group that
only received cone therapy. No statistically significantly differences in outcome
measures were found between the groups: 53% in the group assigned to pelvic floor
exercises and 57% into the group assigned to cones, of which 50% in the group
actually treated with cones, considered themselves as cured or improved to a
significant degree. Long-term follow-up was not possible as all cone users
refused continued exercises with cones once the twelve weeks had ended.
CONCLUSION: Pelvic floor exercises and cones are equally effective in the
treatment of genuine stress incontinence. Cones are cost and time saving.
However, the low patient compliance with the cones importantly limits its
clinical applicability, especially in the long run. Therefore, we do not
recommend the use of cones.
PMID- 9550209
TI - Endometriosis and spontaneous abortion rate: a cohort study in infertile women.
AB - OBJECTIVE: To ascertain if there is an association between endometriosis and
spontaneous abortion. DESIGN: Prospective cohort study. SETTING: Medical School
Hospital. POPULATION: 174 infertile women laparoscopically diagnosed with
endometriosis and 174 infertile women in which endometriosis was ruled out by
laparoscopy, in the same period of time. MAIN OUTCOME MEASURE: Spontaneous
abortion. Non-progressive gestational sac and/or histological study. RESULTS: Per
woman abortion rate was 7.47% (13/174) in the endometriosis group, similar to
5.74% (10/174) in the infertile women without endometriosis (RR=1.32: CI=0.53
3.36). Nor were there any differences in the per pregnancy abortion rate: 20.96%
(13/62) in endometriosis vs. 16.94% (10/59) in non-endometriosis (RR=1.3; CI=0.47
3.57). The abortion rate was similar in the different AFS stages: 22.86% (8/35)
in stage I, 16.67% (3/18) in II, 25% (1/4) in III and 20% (1/5) in IV. In stage I
no differences were observed in patients who were managed expectantly or with
medical treatment. CONCLUSION: Endometriosis is not associated with an increased
abortion rate. The severity of disease expressed by AFS staging is not associated
with an increase in the abortion rate. In stage I the treatment of endometriosis
did not decrease abortion rates.
PMID- 9550208
TI - Treatment of carcinoma of the uterine cervix with concomitant cisplatin, 5
fluorouracil and split course hyperfractionated radiotherapy.
AB - To improve local and systemic control of bulky (>4 cm) and/or advanced primary
cancer of the uterine cervix, 35 patients were treated with concomitant cisplatin
(CDDP), 5-fluorouracil (5-FU) and split course hyperfractionated radiotherapy.
Radiation was administered to the pelvis in five-day courses at a dose of 1.5 Gy
twice daily every 21 days until a median dose of 45 Gy was reached. 15 Gy more
were administered to involved parametrium or central tumor by external
radiotherapy or brachytherapy. The irradiated zone was extended to include
paraaortic lymph nodes if necessary. CDDP was administered at a dose of 20 mg m(
2) and 5 FU at a dose of 500 mg m(-2) from day one to day five of each course.
The median number of combined treatment courses per patient was four (1-6). Local
responses were obtained in 19 out of 24 patients in whom evaluation was feasible
(i.e. who did not undergo surgery prior to combined therapy). Median survival was
not attained with a median follow up of 33 months, three year overall survival
was 62% and 52% in patients with local control and in the whole population
respectively. Several patients with stage III and IV tumors achieved a very long
survival. Acute toxicity was manageable but three patients required surgical
repair of late radiation complications. This combined chemotherapy and
radiotherapy resulted in good local control and did not rule out surgery.
PMID- 9550211
TI - Unusually prolonged ovarian function ending in endometrial cancer development. A
case report.
AB - An unusual case of overprolonged ovarian function in a 77-year-old woman that
ended in the development of endometrial cancer is presented in this paper. The
established knowledge of the correlation of uncontrolled oestrogen activity to
this type of cancer is evaluated and correlated with our patient's hormonal
readings.
PMID- 9550210
TI - Fetal Candida sepsis at midgestation: a case report.
AB - A patient presented with intrauterine fetal death at 21 weeks. A Candida
vaginitis was treated at 18 weeks of gestation. Fatal fetal Candida sepsis caused
by Candida albicans can occur in the absence of known risk factors such as
prolonged rupture of membranes, the presence of an intrauterine contraceptive
device or cervical cerclage.
PMID- 9550213
TI - Plasmodium falciparum: in vitro chloroquine susceptibility and allele-specific
PCR detection of Pfmdr1 Asn86Tyr polymorphism in Lambarene, Gabon.
AB - Plasmodium falciparum resistance to chloroquine has been described in many parts
of the world particularly in Africa where malaria is endemic. High levels of
chloroquine resistance in our study area, Lambarene-Gabon, has led to the use of
an alternative regimen for treatment and prevention of P. falciparum infection.
In this study, we examined the in vitro chloroquine sensitivity of 15 isolates
from this area and assessed the prevalence of a putative chloroquine resistance
associated Pfmdr1 polymorphism (Asn86Tyr) using a novel allele-specific
polymerase chain reaction (PCR). Only 4 of the isolates examined were chloroquine
sensitive. The allele-specific PCR shows that all 15 isolates carried the variant
(86Tyr) codon. Eleven of these were resistant to chloroquine suggesting a 73%
agreement between chloroquine resistance phenotype and the point mutation. This
molecular marker was examined in a further 73 Gabonese isolates, where 58 (79.5%)
showed 86Tyr and 15 (20.5%) showed 86Asn. In all, 4 (4.5%) of the 88 isolates
assessed carry both mutant and wild-type codons, suggesting mixed parasite
populations. The incomplete agreement found between chloroquine resistance
phenotype and Pfmdr1 (86Tyr) polymorphism would support the view that other
genetic factors as well as Pfmdr1 may be involved in chloroquine resistance.
While our results suggest a high prevalence of 86Tyr polymorphism in Lambarene,
the Asp1246Tyr polymorphism (a point mutation which to date has only been
associated with South American P. falciparum) seems to be absent in our study
area.
PMID- 9550212
TI - Development and comparison of quantitative assays for the dihydropteroate
synthetase codon 540 mutation associated with sulfadoxine resistance in
Plasmodium falciparum.
AB - A point mutation in codon 540 of the dihydropteroate synthetase (dhps) gene
affecting sulfadoxine resistance has previously been found in parasites from
patients with Plasmodium falciparum infection. Here, we investigated 4 methods of
identifying this mutation in clinical specimens and established a reliable
quantitative assay to estimate the percentage of resistant type in mixed
infections. A diagnostic PCR assay based on allele-specific amplification was
developed, which clearly typed the clinical specimens examined. The mutation in
codon 540 introduces an additional FokI cleavage site which provided a second
method to differentiate mutant from wild type, where the former gives rise to 2
characteristic fragments of 538 and 326 bp that are absent from the latter. To
calibrate quantitatively the ratio of alleles in mixed samples, we constructed
artificial mixes containing 2 plasmid DNAs, one carrying the mutation and the
other a wild-type insert. When 32P-labelling was employed, the allele-specific
PCR assay could detect the level of resistant type in a mixture down to 0.1-1%,
while for the restriction enzyme/PCR analysis, the figure was approximately 10%.
Furthermore, neither fluorescent dye-labelled terminator nor dye-labelled primer
cycle sequencing was able to detect the mutant allele if it was present at less
than 20-30%. We conclude that the allele-specific PCR assay is the most sensitive
method of detecting the codon 540 mutation in P. falciparum dhps, and the method
of choice for estimating the composition of mixed samples.
PMID- 9550214
TI - Vaccination of langur monkeys (Presbytis entellus) against Leishmania donovani
with autoclaved L. major plus BCG.
AB - The protective potential of killed Leishmania major (ALM) along with BCG was
evaluated against L. donovani in Indian langur monkeys in single and triple dose
schedules. A delayed protection was observed in monkeys after a single dose
schedule of ALM (3 mg)+BCG (3 mg) given intradermally 2 months before intravenous
challenge with L. donovani. Triple dose schedule each of 1 mg ALM + 1 mg BCG was
more effective. The status remained unchanged until the end of the experiment
(approximately 8 months). The study indicates that a combination of ALM + BCG may
be a good candidate vaccine for exploiting against human Kala-azar.
PMID- 9550216
TI - The effect of praziquantel treatment on glutathione concentration in Schistosoma
mansoni.
AB - A fluorescent dye monochlorobimane (MCB) that binds glutathione (GSH) was used as
a tool for measuring the concentration of GSH in skin and mechanically
transformed schistosomula. The specificity of MCB binding to GSH was confirmed by
thin layer chromatography (TLC) and high performance liquid chromatography
(HPLC). The MCB binding to GSH is an energy-dependent process since no labelling
could be seen at low temperature. When 24-h-old schistosomula were depleted of
GSH by buthionine sulfoximine (a specific inhibitor of GSH synthesis) for 18 h, a
significant decrease (P < 0.001) in fluorescence was observed. PZQ treatment of
the schistosomula after first labelling the parasites with MCB did not greatly
affect MCB binding to GSH. However, when the 24-h-old schistosomula were first
PZQ treated and afterwards labelled with MCB, the pattern of labelling was
identical to that of those of the non-labelled parasites. When 24-h-old
schistosomula were first PZQ treated, washed and labelled in the presence of 1 mM
GSH, the level of fluorescence was recovered. These results suggest that PZQ
depletes GSH from schistosomula, and may render them susceptible to the host's
immune system.
PMID- 9550215
TI - Metastasis of Theileria annulata macroschizont-infected cells in scid mice is
mediated by matrix metalloproteinases.
AB - Theileria annulata (Ta)-infected leucocytes are able to disseminate in scid mice.
The dose of virulent parasites of the Ta-Ode line required to achieve
quantifiable dissemination was found to be 2 x 10(6) cells given i.p.
Dissemination was higher on day 11 post-inoculation than on day 18. The
attenuated Ta-Ode cells were found to disseminate very poorly compared to their
virulent progenitors, which correlates with a marked reduction in matrix
metalloproteinase (MMP) expression. A daily i.p. injection of mice with BB94, a
synthetic inhibitor of MMPs, almost completely ablated dissemination compared to
controls. This provides strong evidence that metastasis of Theileria annulata
macroschizont-infected host cells is mediated by host MMPs induced by the
parasite. This has important implications for explaining a number of pathological
features of tropical theileriosis in cattle.
PMID- 9550217
TI - Schistosome-induced portacaval haemodynamic changes in Rattus rattus are
associated with translocation of adult worms to the lungs.
AB - The presence of naturally portacaval shunts has been investigated in the
vasculature of normal and Schistosoma mansoni-infected Rattus rattus. Using the
technique of injecting Polystyrene microspheres in the superior mesenteric vein,
we demonstrated that the presence of adult schistosomes in the lungs of R. rattus
was not due to an innate anomaly of the rat vasculature but resulted from the
formation of portacaval shunts during infection. In rats harbouring a bisexual
infection, microspheres were only detected in the lungs from week 7. The
development and increasing size of the shunts were maximal between weeks 7 and 10
and coincident with the translocation of adult worms from the portal tract to the
lungs. At weeks 20-25, only 1-2% of the microspheres were recovered from the
lungs, suggesting that the portacaval anastomoses have regressed due to reduction
in portal hypertension after worm translocation. R. rattus with a male-only
schistosome infection harboured adult worms in the lungs, indicating that the
development of shunts does not solely depend upon egg deposition in the liver to
generate hypertension. The relationships between the presence of the schistosomes
in the lungs, the portacaval shunting and the resistance to reinfection is
discussed.
PMID- 9550219
TI - Mast cell distribution in nodules of Onchocerca volvulus from untreated patients
with generalized onchocerciasis.
AB - Onchocercomata with a defined worm population were analysed to elucidate the
distribution of mast cells. Nodules with live females were classified according
to the presence or absence of microfilariae. Immunohistochemical staining was
performed using antibodies specific for mast cells or IgE. Mast cells appeared
singly or in diffuse accumulations perivascularly and in inflammatory infiltrates
between adult Onchocerca volvulus and in the capsular area. No mast cells were
detected in cystic parts. Only few, scattered mast cells were found in the
fibrous zone around the adult worm. They were increased with stronger
infiltration and hence, related to the inflammatory cells. Mast cells were never
localized directly at adult worms or microfilariae. A correlation of the mast
cell distribution to the occurrence of eosinophils was observed regarding higher
numbers of mast cells and eosinophils in nodules with microfilariae-producing
females. Nodules with single males revealed higher numbers of mast cells than
nodules with non-producing females, although both contained very few eosinophils.
Onchocercomata with dead worms contained significantly more mast cells than those
with live filariae. In conclusion, the localization and frequency of mast cells
is contingent on the vitality and productivity of the worms and therefore,
indirectly and directly on the release of O. volvulus antigens.
PMID- 9550218
TI - The relationship between microfilarial load in the human host and uptake and
development of Wuchereria bancrofti microfilariae by Culex quinquefasciatus: a
study under natural conditions.
AB - The uptake of Wuchereria bancrofti microfilariae (Mf) by Culex quinquefasciatus
and their development in relation to human Mf density were quantified by allowing
a total of 1096 wild mosquitoes to feed on 13 volunteers sleeping under partially
open bed-nets. For each volunteer, each hour between 18.00 and 06.00 h the Mf
density in finger-prick blood was determined and engorged mosquitoes collected.
Each hourly collection of mosquitoes was kept separately. Half of them was
dissected within 18 h post-feeding for the presence of ingested Mf, the other
half was reared for 12 days to allow for the development of L3 larvae. About 20%
of the latter mosquitoes died during these 12 days and these harboured
significantly more larvae than the surviving ones, which could be an indication
of excess-mortality among heavily infected mosquitoes. Assuming that variability
in Mf uptake and in the number of developed L3 larvae can be described by a
negative binomial distribution, a maximum-likelihood procedure was applied to
estimate the relationship between human Mf density and both the arithmetic mean
Mf uptake and L3 development. Both were adequately described by a saturating
hyperbolic function that significantly differed from linearity. The saturation
level for Mf was estimated at 29 (CI: 20-54) and for L3 larvae at 6.6 (CI: 4.3
17.0). Next, the L3 yield was related to Mf uptake indicating that the W.
bancrofti-C. quinquefasciatus complex shows 'limitation', i.e. a decreasing yield
for an increasing uptake. Both the number of Mf ingested and the number of L3
larvae developing per mosquito were found to be highly aggregated, with the level
of aggregation decreasing in a non-linear way with human Mf density.
PMID- 9550220
TI - Social structure of the mara (Dolichotis patagonum) as a determinant of gastro
intestinal parasitism.
AB - A one-year study of gastro-intestinal parasitism in a free-ranging population of
maras at Whipsnade Wild Animal Park, UK, revealed a strong relationship between
membership of social units and both intensity and prevalence of infection. The
mara, a hystricomorph rodent from southern Argentina, has a social organization
including both monogamy and communal denning of the young, an apparently unique
combination among mammals. From October 1992 to September 1993, strongyloid
parasite loads were estimated from faecal egg counts. A minimum adequate model
was fitted to the data using the Genstat statistical package. This showed that
family membership had a highly significant effect on the intensity of egg
shedding in faeces, and a significant effect on the prevalence of infection.
After controlling for both extrinsic environmental and intrinsic demographic
factors, homogeneity of infection was greater within than between families and
adult pairs.
PMID- 9550221
TI - Modulation of the motility of the vagina vera of Ascaris suum in vitro by FMRF
amide-related peptides.
AB - Ascaris suum contains a large number of FMRFamide-related peptides (FaRPs) of
which KNEFIRFamide (AF1), KHEYLRFamide (AF2) and KSAYMRFamide (AF8, also called
PF3) have been extensively studied and are known to exert actions on somatic
muscle strips of the worm. In the present study, the effects of AF1, AF2 and AF8
on the activity of the vagina vera of female A. suum have been examined in vitro.
The vagina vera is a muscular tube connecting the uterus and vagina uteri to the
gonopore and is probably involved in regulating egg output. The tissue exhibited
spontaneous, rhythmic contractions in vitro, which were modulated by each of the
FaRPs tested. The effects of each of the peptides were qualitatively and
quantitatively different, and in each case were reversible. AF1 (1 microM) caused
a biphasic response in the form of a transient lengthening of the preparation,
followed by a shortening; contractions were initially inhibited but resumed 5 min
post-addition of the peptide. Lower concentrations (< or = 0.1 microM) induced a
less marked effect, with rhythmic contractions returning 5 min post-addition. AF2
and AF8 reduced contraction frequency at concentrations > or = 0.1 microM. Both
peptides also caused the tissue to shorten, although the effects of AF8 on
baseline tension were inconsistent. The apparent potencies of AF1 and AF8 on
contraction frequency of the vagina vera were 10-fold greater than AF2 and,
unlike their actions on A. suum somatic body wall muscles, the actions of AF1 and
AF2 were qualitatively different. Indeed, the effects of each of these FaRPs on
the vagina vera were markedly different from those observed on the somatic
muscle.
PMID- 9550222
TI - Relative merits of nuclear ribosomal internal transcribed spacers and
mitochondrial CO1 and ND1 genes for distinguishing among Echinostoma species
(Trematoda).
AB - Cryptic species, belonging to the 37 collar-spine Echinostoma group, were
distinguished using nuclear rDNA ITS (884 bases) and mtDNA CO1 (257 bases) and
ND1 (530 bases) sequences. Sequences were obtained from five 37 collar-spine
species, Echinostoma trivolvis, E. paraensei, E. caproni, E. revolutum and E.
sp.I, a parthenogenetic isolate from Africa. Three geographic isolates of E.
caproni were compared. Average sequence divergence among the 37 collar-spine
species range from 2.2% in the rDNA ITS through 8% for the CO1 and 14% for the
ND1. In addition, genes were sequenced from 2 non 37 collar-spine species, E.
hortense and an undescribed Australian species, E. sp. (Aus). For each gene,
distances of terminals from a predicted ancestral sequence were calculated. These
indicated that ND1 is diverging significantly faster than the other 2 regions. In
the CO1 gene most substitutions are synonymous and saturation has been reached
for the majority of pairwise comparisons. The ND1 gene exhibits greater pairwise
divergence but less evidence of saturation due to weaker conservation of first
and second codon positions. The ITS has no amino acid coding constraints and
displays no evidence of saturation. Although all 3 regions successfully
distinguished the nominal species, ND1 appears to be the most informative region
for investigating relationships within the 37 collar-spine group.
PMID- 9550223
TI - Tension/stiffness ratio of skinned rat skeletal muscle fibre types at various
temperatures.
AB - It is well known that shortening velocity and maximal tension of muscle
preparations are strongly dependent on experimental temperature. Conversely,
studies about temperature effects on muscle fibre stiffness are scarce. In the
present study, we measured tension and stiffness of maximally Ca2+-activated
skinned rat skeletal muscle fibres of different types over a wide temperature
range. All fibre types exhibited a similar tension/stiffness ratio at each
experimental temperature. This ratio increased almost linearly from 6 to 18 nm
when the temperature was raised from 6 to 34 degrees C. Our results are discussed
in the light of the drastic discrepancies reported for the amount of compliance
inside and outside the attached myosin cross-bridges of activated muscle fibres
(Ford et al. 1981, Huxley et al. 1994, Kojima et al. 1994, Wakabayashi et al.
1994, Higuchi et al. 1995). The relation between these compliances had been
deduced from various experimental approaches executed at different temperatures.
The large temperature sensitivity of the tension/stiffness ratio found in this
study provides evidence for the assumption that the compliance outside the cross
bridges increases with rising temperature. This view would reconcile the
contrasting results reported for the relation of compliances inside and outside
the attached cross-bridges.
PMID- 9550224
TI - Hindlimb suspension induces the expression of multiple myosin heavy chain
isoforms in single fibres of the rat soleus muscle.
AB - To examine the expression patterns of myosin heavy chain (MHC) isoforms in single
fibres of the soleus muscle following weightlessness, 10-week-old male Wistar
rats were subjected to hindlimb suspension for 4 weeks. Hindlimb suspension
resulted in reduced body weight and absolute and relative mass of the soleus
muscle compared with controls (P < 0.01). A total of 975, 892 and 1098 single
fibres from pre-suspended controls, age-matched controls and suspension groups,
respectively, were subjected to MHC analyses using SDS-PAGE. Single fibres
containing only MHC I decreased (87.9 vs. 67.9%, P < 0.05) and single fibres
containing only MHC IIa disappeared after hindlimb suspension. On the contrary,
single fibres containing multiple type II MHC isoforms were observed as follows:
10.1% single fibres contained MHCs IIa and IId; 14.1% contained MHCs I, IIa and
IId; and some (1.4%) expressed the MHC IIb isoform with MHCs IIa and IId. The
relative content (%) of each MHC isoform in MHC hybrid single fibres was
calculated using densitometer scanning. The MHCs IIa and IId hybrid single fibres
contained the same amount of MHC IIa (51.3 +/- 6.3%) and MHC IId (48.7 +/- 6.3%).
In the MHCs I, IIa and IId hybrid single fibres, the percentage of MHC IIa was
distributed in a wide range (approximately 80%), whereas the percentage of MHC
IId was a relatively low range (approximately 40%), and the relative content of
MHC I was inversely correlated with that of MHC IIa and MHC IId, respectively.
The fibre type composition of suspended soleus muscle, analysed by histochemical
myosin ATPase staining, was changed, with a decrease in the percentage of type I
fibres and an increase in that of type IIA fibres. Our results indicate that
hindlimb suspension induces multiple type II MHC expression in the soleus single
fibres and suggest that the single fibres containing multiple type II MHC
isoforms should be classified into type IIA.
PMID- 9550225
TI - Effects of bedrest on deltoideus muscle morphology and enzymes.
AB - To examine the effects of unweighting on the structural and metabolic adaptations
of a non-postural muscle, deltoideus muscle biopsies were taken in seven male
healthy subjects, before and after a 37 day bedrest. Myofibrillar ATPase
histochemistry demonstrated no change in fibre type distributions (I, IIA, IIB),
in fibre cross-sectional areas nor in capillary supply. No difference was noted
in enzyme activities of oxidative metabolism (citrate synthase, 3-hydroxy-acyl
CoA dehydrogenase), and glycolysis (hexokinase, lactate dehydrogenase). Electron
microscopy showed a decrease in the volume density of lipids but no change in
mitochondrial volume density and distribution. The results indicate that bedrest
induces no major morphological and biochemical changes in deltoideus muscle,
contrary to what was previously reported in vastus lateralis muscle. This lack of
changes is probably related to an unaltered deltoideus muscle use.
PMID- 9550226
TI - Effects of selenium deficiency on diaphragmatic function after resistive loading.
AB - Diaphragmatic fatigue has been associated with increased production of reactive
oxygen species. Among the defenses against reactive oxygen species is the
glutathione redox system. The selenium-dependent enzyme glutathione peroxidase is
an important component of this system. Thus, we hypothesized that selenium
deficiency would lower glutathione peroxidase activity and render the diaphragm
more susceptible to a mild exertional protocol. Sprague-Dawley rats were fed a
selenium-deficient or control diet for 12 weeks then divided into four
experimental groups: (1) unloaded, basic diet with selenium supplementation
(control); (2) unloaded, selenium-deficient diet; (3) loaded, basic diet with
selenium supplementation; and (4) loaded, selenium-deficient diet. Diaphragmatic
in vitro contractile properties, glutathione peroxidase activity and glutathione
content were measured. During inspiratory resistive loading, the animals breathed
against an inspiratory resistor at 70% of maximal airway pressure until the
target pressure was not achieved for five consecutive breaths. Selenium
deficiency resulted in a significant decrease in diaphragmatic glutathione
peroxidase activity, without changes in total glutathione content. Neither
selenium deficiency nor inspiratory resistive loading alone impaired
diaphragmatic contractility. Selenium deficiency in conjunction with inspiratory
resistive loading resulted in a significant decrease in diaphragmatic twitch and
tetanic force, with a downward shift in the force/frequency curve. These data
suggest that selenium deficiency lowers diaphragmatic glutathione peroxidase
activity, and when these animals are subjected to the oxidative stress of
resistive loading, there is an impairment in muscle function. We conclude that a
functional glutathione peroxidase is necessary to protect the diaphragm against
the effects of resistive loading.
PMID- 9550227
TI - Increase in nitric oxide formation after chronic voluntary exercise in
spontaneously hypertensive rats.
AB - The effect of chronic voluntary exercise on the plasma level of nitrate, a major
stable metabolite of nitric oxide (NO) was studied in spontaneously hypertensive
rats (SHR). Exercise consisted of spontaneous running in wheels for 3-35 days.
Blood samples were collected after 3, 7, 14, 21 and 35 days of exercise and all
samples were drawn after the running wheel had been locked during the preceding
12 h. The plasma nitrate level was significantly (P < 0.05) elevated in SHR after
35 days of exercise. Surprisingly after 7 days of exercise a significant (P <
0.001) decrease in the nitrate level in plasma was noted. Further research is
needed to elucidate this biphasic change in nitrate seen in this study. The
elevated level of plasma nitrate seen after 35 days of voluntary exercise was
still present up to 36 h after termination of exercise. We conclude that exercise
training in SHR elicits an enhanced formation of NO.
PMID- 9550228
TI - Receptor potential characteristics during direct stereocilia stimulation of
isolated outer hair cells from the guinea-pig.
AB - The receptor potential as a function of stimulus amplitude and frequency was
studied with the patch-clamp technique in isolated outer hair cells (OHCs) with a
length ranging from 30 to 87 microm during direct mechanical stimulation of the
stereocilia. The amplitude and frequency of the stimulation were varied from 125
nm to 2 microm and from 100 Hz to 2.5 kHz, respectively. The mean resting
membrane potential before stimulation was -64.25 +/- 1.4 mV (mean +/- SE, n =
26). Irrespective of the frequency used, stereocilia stimulation produced a
combination of AC and DC responses, and both components showed saturation with
increasing stimulation. Frequency responses appeared to be a function of
intensity and resembled a low-pass filter with a time constant ranging from 0.2
to 2.0 ms. With increasing stereocilia stimulation, the relative contribution of
high frequencies to the AC component decreased, suggesting a decrease of the
corner frequency. The saturated amplitude of the AC component for low-frequency
stimulation (100 Hz) was proportional to cell length and increased with a mean
rate of 0.014 mV microm(-1). A relationship between the DC response of the
receptor potential and the pre-stimulus membrane potential was found. Recordings
with more negative membrane potentials had greater DC components, while more
depolarized recordings demonstrated smaller DC components. These fluctuations
seemed to be defined by the interaction between the probe and stereocilia bundle
and could be in the range of the transfer function for each cell.
PMID- 9550229
TI - Nervous control of alkaline secretion in the duodenum as studied by the use of
cholera toxin in the anaesthetized rat.
AB - There is experimental evidence for an axon reflex control of alkaline secretion
in the rat duodenum. We have investigated if there is also an intramural reflex
control of alkaline secretion similar to that demonstrated with regard to the
control of the fluid transport in the rat jejunum. Alkaline secretion in the
duodenum of an anesthetized rat was continuously monitored using an in situ
titration technique. The segment was extrinsically denervated. Exposing the
duodenal segment to 80 microg cholera toxin markedly increased alkaline
secretion. This response was abolished by hexamethonium (28 micromol (10 mg) kg(
1) body wt), a nicotinic receptor blocker, lidocaine (0.5 mL of a 1% solution on
the serosal surface), a local anaesthetic, and nifedipine (5.75 micromol (2 mg)
kg(-1) body wt i.v.), a calcium channel blocker. The response to cholera toxin
was partially abolished by granisetron (0.11 micromol (40 microg) kg(-1) body wt
i.v.), a 5-HT3 receptor blocker. Atropine (1.7 micromol (0.5 mg) kg(-1) body wt
i.v.), a muscarinic receptor blocker, had no effect. We therefore conclude that
the alkaline secretion in the rat jejunum evoked by cholera toxin exhibits the
same pharmacological properties as the fluid secretion caused by the toxin in the
jejunum. This suggests that the alkaline secretion in the rat duodenum is
controlled not only by an axon reflex but also by an intramural secretory reflex
similar to that controlling fluid transport in the rat jejunum.
PMID- 9550230
TI - Is for-profit managed care an oxymoron?
PMID- 9550231
TI - A physician-owned and -operated behavioral managed care company.
PMID- 9550232
TI - Estimation of costs of public psychiatric treatment.
PMID- 9550233
TI - Referrals to psychiatrists.
PMID- 9550234
TI - Managed care's responsibility for decisions to deny benefits: the ERISA obstacle.
Employee Retirement Income Security Act.
PMID- 9550235
TI - The computer as clinician assistant: assessment made simple.
PMID- 9550236
TI - A college reunion in the psychiatric emergency room.
PMID- 9550237
TI - Outpatient utilization patterns of integrated and split psychotherapy and
pharmacotherapy for depression.
AB - OBJECTIVE: This exploratory study examined utilization and costs among depressed
patients in two treatment models-integrated treatment, in which psychotherapy and
pharmacotherapy were provided by a psychiatrist, and split treatment, in which
pharmacotherapy was provided by a psychiatrist and psychotherapy by a
nonphysician psychotherapist. METHODS: A quasi-experimental retrospective design
was used to compare claims data from a national managed mental health care
organization for 191 patients in integrated treatment and 1,326 in split
treatment. RESULTS: During the 18-month study, patients receiving integrated
treatment used significantly fewer outpatient sessions and had significantly
lower treatment costs, on average, than those in split treatment. Integrated
treatment appeared to be associated with a pattern of utilization characterized
by frequent treatment episodes in contrast to that of split treatment, which was
characterized by more sessions with fewer breaks of 90 days or more. CONCLUSIONS:
The results do not support the prevailing assumption that integrated treatment is
more costly than split treatment in a managed care network. Despite limitations
in the study methods, the strength of these preliminary findings poses a powerful
challenge and invites further study.
PMID- 9550238
TI - Persons with severe mental illness in jails and prisons: a review.
AB - OBJECTIVE: The presence of severely mentally ill persons in jails and prisons is
an urgent problem. This review examines this problem and makes recommendations
for preventing and alleviating it. METHODS: MEDLINE, Psychological Abstracts, and
the Index to Legal Periodicals and Books were searched from 1970, and all
pertinent references were obtained. RESULTS AND CONCLUSIONS: Clinical studies
suggest that 6 to 15 percent of persons in city and county jails and 10 to 15
percent of persons in state prisons have severe mental illness. Offenders with
severe mental illness generally have acute and chronic mental illness and poor
functioning. A large proportion are homeless. It appears that a greater
proportion of mentally ill persons are arrested compared with the general
population. Factors cited as causes of mentally ill persons' being placed in the
criminal justice system are deinstitutionalization, more rigid criteria for civil
commitment, lack of adequate community support for persons with mental illness,
mentally ill offenders' difficulty gaining access to community treatment, and the
attitudes of police officers and society. Recommendations include mental health
consultation to police in the field; formal training of police officers; careful
screening of incoming jail detainees; diversion to the mental health system of
mentally ill persons who have committed minor offenses; assertive case management
and various social control interventions, such as outpatient commitment, court
ordered treatment, psychiatric conservatorship, and 24-hour structured care;
involvement of and support for families; and provision of appropriate mental
health treatment.
PMID- 9550239
TI - A strategic approach to the psychiatric workforce dilemma.
AB - To help build consensus in the field of psychiatry about future psychiatric
manpower needs, a 13-step strategic approach to the workforce issue is described.
The steps include recognizing the importance of the assumptions that underlie
workforce requirements; selecting credible and professional leadership with
vision and courage; adopting a strategic plan to clarify workforce assumptions;
re-examining the structure and function of established programs; preparing
trainees for work in the 21st century; preserving psychiatry's humanistic
tradition; enlisting the support of nonacademic psychiatrists; and reinforcing
involvement in the fiscal and political aspects of medicine. They also include
focusing attention on important policy issues; securing the support of patients,
families, and advocates; endorsing a multidisciplinary, biopsychosocial approach
to the evaluation and treatment of mental illness; minimizing divisive conflicts
within and between national organizations; and developing strategic alliances
with other medical disciplines. Implications of the 13-step approach are outlined
for psychiatric clinicians, educators, and researchers, as well as for the
organizations that serve them.
PMID- 9550240
TI - A national survey of "consumer empowerment" at the state level.
AB - OBJECTIVE: A national survey was conducted to determine the extent of consumer
empowerment in the public mental health system. METHODS: A questionnaire was sent
to mental health authorities in all U.S. states and territories asking whether
consumer empowerment or responsibility was defined in statutes, regulations, or
policies and whether consumers or family members were employed in central or
field offices of the authority. A rating scale measured the extent of consumer
empowerment, and correlations were examined between this rating and other
variables. RESULTS: The survey achieved a 100 percent response rate. Twenty-two
states (39 percent) addressed consumer empowerment and 16 (28 percent) consumer
responsibility in a statute, regulation, or policy. Twenty-seven states (48
percent) had paid positions for consumers in central offices, and three (5
percent) had such positions for family members. Half the states had paid
positions for consumers in field offices, and 12 states (24 percent) had such
positions for family members. The extent of a state's consumer empowerment had no
relationship to region of the country or the state's mental health budget. A
significant positive relationship was found between extent of empowerment and the
size of the state's population and the quality of its mental health services.
CONCLUSIONS: State mental health authorities vary widely in their direct
involvement with consumer empowerment. Results indicate that mental health
authorities need to make a greater commitment to the achievement of such
empowerment if it is to become a meaningful part of government involvement with
mental health services.
PMID- 9550242
TI - Use of psychotropic medications for persons with mental retardation who live in
Oklahoma nursing homes.
AB - OBJECTIVE: The study examined the use of psychotropic medications to treat
persons with mental retardation living in nursing homes in Oklahoma. METHODS:
Data were gathered on all 1,056 individuals funded through the Oklahoma mental
retardation service system in 1995 to live in nursing homes. The Developmental
Disabilities Quality Assurance Questionnaire was used to assess adaptive
behavior, living site conditions, health, use of medications, and other
variables. RESULTS: The most frequently used class of psychotropic medications
was antipsychotic medication, used by 31.8 percent of subjects. Sixteen percent
received anxiolytic medication, and 6.1 percent received antidepressant
medication. Stepwise multiple regression analysis indicated that use of
antipsychotic medication was marginally predictable (less than 15 percent of the
variance was explained) with a linear combination of six variables: mental health
problems; violence toward others; adaptive behavior; screaming, yelling, or
crying behavior; hyperactivity; and age. CONCLUSIONS: A relatively high
percentage of subjects received various forms of psychotropic medications,
especially antipsychotics. The presence of behavior problems or mental health
problems did not sufficiently explain the high rate of use of antipsychotic
medication. The risks of this type of medication and its lower rate of use in
group homes raise the question of the appropriateness of placing persons with
mental retardation in nursing homes as they are currently conceived.
PMID- 9550241
TI - Scheduled intermittent hospitalization for psychiatric patients.
AB - OBJECTIVE: The effect of scheduled intermittent hospitalization on the hospital
utilization, community adjustment, and self-esteem of persons with serious and
persistent mental illness was examined in an experimental study. METHODS: Fifty
seven male veterans, aged 65 or younger, with a primary axis I psychiatric
diagnosis who were frequent utilizers of inpatient care over the previous two
years were randomly assigned to two groups. Patients in the experimental group
were prescheduled for four hospital admissions, each lasting nine to 11 days, per
year for two years. Patients in the control group had traditional access to
hospital care. Psychiatric bed days, community adjustment, and self-esteem were
assessed during and after the intervention. RESULTS: No differences between the
groups on demographic or clinical variables were detected at study entry. The
experimental group showed improvement in self-esteem, affect, and complaints of
physical symptoms at one year. No statistically significant differences between
groups were found in hospital utilization, financial management, substance abuse,
or psychological well-being at one year. CONCLUSIONS: Scheduled intermittent
hospitalization may be an appropriate and promising alternative to traditional
care for revolving-door patients. This intervention could maintain patients at a
higher level of wellness than traditional care and reduce the recurrence of the
crises that precipitate hospitalization.
PMID- 9550243
TI - Moving psychiatric patients from hospital to community: views of patients,
providers, and families.
AB - OBJECTIVE: Differences in the perspectives of severely and persistently ill
patients, their family members, and clinical care providers on key aspects of
community-based care were examined to help inform community service planning and
development. METHODS: A sample of 183 patients being considered for relocation
from psychiatric facilities in Alberta, Canada, to community-based care, were
interviewed, as were their primary clinical care providers. Family members of 130
patients were also interviewed. RESULTS: Among the 130 patient-family pairs, 41
percent disagreed about the desirability of relocation, with fewer patients
favoring relocation than families. Forty-nine percent of the pairs disagreed
about the desired proximity to the family of the relocated patient, with the
patient desiring closer proximity than the family member in about half of these
cases. Fifty-three percent of the pairs disagreed about the amount of financial
and emotional support that the family would provide after relocation. In half of
these cases, patients believed the family would provide a higher level of support
than the family indicated it could. Among the patients, 49 percent preferred
independent living, whereas only 10 percent of family members and 17 percent of
clinical care providers preferred it. Fifty-five percent of patients expressed a
clear desire to work, whereas care providers believed that only 12 percent of
patients were employable. CONCLUSIONS: Persistently mentally ill residents of
psychiatric facilities express clear preferences about key aspects of community
based care when they are asked, and these preferences often reflect different
views from those expressed by either family members or clinical care providers.
PMID- 9550244
TI - Changes in the process of care for Medicaid patients with schizophrenia in Utah's
Prepaid Mental Health Plan.
AB - OBJECTIVE: Changes in the process of psychiatric care received by Medicaid
beneficiaries with schizophrenia were examined after the introduction of
capitated payments for enrollees of some community mental health centers (CMHCs)
under the Utah Prepaid Mental Health Plan. METHODS: Data from the medical records
of 200 patients receiving care in CMHCs participating in the prepaid plan were
compared with data from the records of 200 patients in nonparticipating CMHCs,
which remained in a fee-for-service reimbursement arrangement. Using the Process
of Care Review Form, trained abstracters gathered data characterizing general
patient management, social support, medication management, and medical management
before implementation of the plan in 1990 and for three follow-up years. Using
regression techniques, differences in the adjusted changes between third-year
follow-up and baseline were examined by treatment site. RESULTS: By year 3 at the
CMHCs participating in the plan, psychotherapy visits decreased, the probability
of a patient's terminating treatment or being lost to follow-up increased, the
probability of having a case manager increased, the probability of a crisis visit
decreased (but still exceeded that at the nonplan sites), and the probability of
treatment for a month or longer with a suboptimal dosage of antipsychotic
medication increased. Only modest changes in the process of care were observed at
the nonplan CMHCs. CONCLUSIONS: Change in the process of psychiatric care was
more evident at the sites participating in the plan, where traditional
therapeutic encounters were de-emphasized in response to capitation. The array of
changes raises questions about the vigor of care provided to a highly vulnerable
group of patients.
PMID- 9550245
TI - A naturalistic study of clinical use of risperidone.
AB - Follow-up data on 97 of the 101 patients at a university-based psychiatric
hospital for whom risperidone had been prescribed between February 1994, when the
medication was introduced, and October 1996 were reviewed an average of 102 weeks
after the start of the medication. Only 28.9 percent of the patients were still
on risperidone at follow-up. Patients who were maintained on risperidone were
able to tolerate a higher dose with fewer side effects. The most common reasons
for discontinuation were failure to achieve a therapeutic effect, noncompliance,
and adverse side effects. The findings of this naturalistic study represent a
cautionary consideration for the remarkable enthusiasm that surrounded the
introduction of risperidone.
PMID- 9550246
TI - A syndrome of increased affect in response to risperidone among patients with
schizophrenia.
AB - Six of 13 outpatients with schizophrenia who participated in a ten-week open
trial of risperidone had an initial good response to the medication followed by
development of intolerable affect, including feelings of agitation and depression
and periods of crying and insomnia. Patients who developed this syndrome did not
differ from other patients in baseline ratings on the Brief Psychiatric Rating
Scale (BPRS) and the Scale for the Assessment of Negative Symptoms, except that
patients who developed the syndrome had a significantly higher mean baseline
rating on the BPRS anxiety subscale. The authors suggest that risperidone may
increase affect in patients with schizophrenia and that some patients, especially
those with anxiety, may have difficulty managing the increase.
PMID- 9550247
TI - Practices related to HIV risk assessment in general hospital psychiatric units in
New York State.
AB - Semistructured interviews including (questions about practices related to HIV
risk assessment were conducted on 53 psychiatric units of general hospitals in
New York State in 1992 and 1993. Few units have adopted practices across the
board. Assessment of risk for many or almost all patients was reported by 25
units (47 percent). On three units (6 percent) all patients received information
about HIV, and on 13 (25 percent) many patients did. Twenty units (38 percent)
reported counseling only a few patients about risk, and eight (15 percent)
counseled almost none. Twenty-eight (53 percent) urged only a few patients to get
an HIV test, and nine (17 percent) urged almost none.
PMID- 9550248
TI - Effects of psychoeducational intervention for married patients with bipolar
disorder and their spouses.
AB - The relative benefit of adding a structured psychoeducational intervention to
standard medication treatment for married patients with bipolar disorder and
their spouses was assessed. Patients were randomly assigned to receive either
medication management or medication management plus a marital intervention with
their spouses for an 11-month period. Patients' symptoms, functioning, and
adherence to their medication regimens were measured at study entry and at 11
months. Significant effects favoring the combined treatments were observed for
overall patient functioning but not for symptom levels. The marital intervention
was associated with improved medication adherence. Combined psychosocial and
medication treatment does not affect patients' symptom levels beyond the effects
of medication alone, but it does result in significant incremental gains in
overall patient functioning.
PMID- 9550249
TI - Homelessness and mental illness in a professional- and peer-led cocaine treatment
clinic.
AB - The combined problems of substance abuse, mental illness, and homelessness among
the urban poor represent a major public health issue. The study evaluated 340
patients attending a cocaine day treatment program that integrates peer
leadership and professional supervision. Thirty-six percent of the sample had a
major mental illness, and 39 percent were homeless. Sixty-nine percent achieved
an acceptable final urine toxicology status, and the median number of program
visits was 46. Homelessness, a longer history of cocaine use, and a diagnosis of
schizophrenia were associated with positive treatment outcomes. The results
support the feasibility of a cocaine abuse treatment model combining professional
and peer leadership.
PMID- 9550250
TI - Denial of mental illness.
PMID- 9550251
TI - Denial of mental illness.
PMID- 9550252
TI - Primary physicians and adolescent health care.
PMID- 9550254
TI - Rapidly growing employee assistance programs face major changes, more intense
competition.
PMID- 9550253
TI - New publication highlights intimate relationship between substance abuse and
domestic violence.
PMID- 9550255
TI - GAO study finds state psychiatric hospitals get biggest share of supplemental
Medicaid payments.
PMID- 9550256
TI - Treatment of a local recurrence of a carcinoid tumor of the middle ear by
extended subtotal petrosectomy.
AB - A recurrence of a primary carcinoid tumor of the middle ear 15 years after
radical tympanomastoidectomy is reported. An extended subtotal petrosectomy using
a craniocervical approach with temporary infracondylar mandibulotomy was
performed, since imaging studies demonstrated an extensive tumor with a close
relationship to the tegmen tympani, facial nerve, and ascending and horizontal
portions of the carotid canal. The tumor was metabolically inactive.
Histopathological examination showed a solid, trabecular tumor that was positive
for pancytokeratin Lu5, neuron-specific enolase, pancreatic intestinal
polypeptide and glucagon. Neuroendocrine-granules were demonstrable under
electron microscopy. This case is reported to show that primary middle-ear
carcinoid tumors can recur years after radical tympanomastoidectomy.
PMID- 9550257
TI - An anomalous relationship of the descending portion of the facial canal to the
jugular notch in the human temporal bone.
PMID- 9550258
TI - A new epiglottoplasty procedure for the treatment of intractable aspiration.
AB - Intractable aspiration may require diversion of the airway from the pharynx. The
epiglottoplasty procedure involves suturing the epiglottis onto the perimeter of
the larynx without creating resistance to the natural lines of force of the
epiglottic cartilage. The procedure starts by an anterior subhyoid pharyngotomy.
The epiglottis is released from the pre-epiglottic space and the thyroepiglottic
ligament is sectioned. The disinsertion is completed in the laryngeal lumen by
sectioning the epiglottis on each side by following its edges. The
pharyngoepiglottic folds are preserved so as to serve as the rotational axis for
the freed epiglottis. The petiole of the epiglottis is anchored to the posterior
commissure and the free edge of the epiglottis above the ala and the angle of the
thyroid cartilage, while the lateral sides of the suprahyoid epiglottis are
sutured to the superior part of the arytenoids. This procedure was performed
successfully in three patients with intractable aspiration.
PMID- 9550259
TI - Feasibility of supracricoid laryngectomy based on pathological examination.
AB - Partial horizontal supracricoid laryngectomy with cricohyoidopexy at the
Department of Otolaryngology, Medical University of Bialystok, involves resection
of the entire thyroid cartilage with the pre-epiglottic and paraglottic spaces.
Experience has shown that this technique will permit adequate phonation,
respiration and deglutition in selected advanced cases of supraglottic and
glottic carcinoma. The purpose of this study was to verify histologically the
indications for this surgery by examining sections of whole-organ laryngeal
specimens. Post-laryngectomy specimens from 90 patients with otherwise previously
untreated supraglottic (48), transglottic (22) and glottic (20) carcinomas were
reviewed retrospectively. The majority (66) of the specimens were staged as pT4.
Findings showed that 22 of the specimens analyzed (mostly supraglottic tumors)
could have been eradicated by supracricoid laryngectomy alone. The present study
confirmed the principles of supracricoid laryngectomy for selected large tumors.
PMID- 9550260
TI - Argyrophilic nucleolar organizer region counts in squamous cell carcinomas of the
head and neck after irradiation and chemotherapy.
AB - After irradiation or chemotherapy of tumors of the head and neck, histological
alterations might be difficult to assess. In 30 cases of squamous cell carcinomas
of the pharynx, changes in argyrophilic nucleolar organizer region (AgNOR) counts
were investigated after therapy. After treatment a significant decrease of AgNOR
counts was detected (P < 0.001). No significant differences could be found
between groups treated with radiotherapy, chemotherapy or a combination of
radiotherapy and chemotherapy. These findings suggest that AgNOR counts might be
useful to assess cytotoxic effects on a subcellular level.
PMID- 9550261
TI - Acute vestibular dysfunction associated with interferon-alpha therapy.
PMID- 9550262
TI - A proximal element within the human alpha 2(I) collagen (COL1A2) promoter,
distinct from the tumor necrosis factor-alpha response element, mediates
transcriptional repression by interferon-gamma.
AB - Previous studies have shown that interferon-gamma (IFN-gamma) inhibits type I
collagen gene expression through both transcriptional and post-transcriptional
mechanisms (Kahari et al., 1990). In the present study, using transient cell
transfections of human dermal fibroblast cultures with a series of 5' deletion
promoter/CAT reporter gene constructs, we have identified the IFN-gamma-response
element of the human alpha 2(I) collagen gene (COL1A2) promoter. Specifically, we
have identified a segment of the proximal promoter region, located between
nucleotides -161 and -125 relative to the transcription start site, as critical
for down-regulation of COL1A2 promoter activity by IFN-gamma. This IFN-gamma
response element (IgRE) is clearly distinct from the previously described tumor
necrosis factor-alpha response element (TaRE) located between nucleotides -265
and -241 of the COL1A2 promoter, a difference which is likely to explain the
additive inhibitory effect of these two cytokines. The inhibitory effect of IFN
gamma was dose-dependent and rapidly induced, requiring less than 5 min exposure
of fibroblast cultures. Gel mobility shift assays indicated that a highly
specific nuclear protein complex bound to this 37-base pair region of promoter.
Competition experiments with oligonucleotides spanning discrete segments of this
promoter region mapped the binding element within a distinctive pyrimidine-rich
sequence. Point mutations within the latter revealed that this element plays a
crucial role not only in the IFN-gamma response, but also in the basal activity
of the proximal promoter. Substitution mutations within the IgRE of the -161/CAT
construct attenuated the promoter response to IFN-gamma, as measured in transient
cell transfections, and eliminated specific DNA/protein complex formation, as
measured by gel mobility shift assay. UV-crosslinking experiments indicated that
two DNA/protein complexes were formed with the IgRE, with molecular weights
around 55 kDa and 30 kDa, corresponding to proteins of approximately 30 kDa and
approximately 6 kDa, respectively. Our results further clarify the molecular
mechanisms involved in the regulation of type I collagen gene expression by IFN
gamma.
PMID- 9550263
TI - Characterization of collagens and proteoglycans at the insertion of the human
Achilles tendon.
AB - This study provides a unique correlation between a molecular biological and
biochemical analysis of the extracellular matrix (ECM) macromolecules in one half
of 28 human Achilles tendons with an immunohistochemical study of the other. Both
the insertion site and the mid-tendon were studied. The insertion (enthesis) is
characterized by three distinctive fibrocartilages, two in the tendon (enthesial
and sesamoid) and one on the heel bone (periosteal). Thus, its structure
contrasts markedly with the fibrous character of the mid-tendon. RT-PCR analyses
were performed on RNA extracted from mid-tendon and from the tendon
fibrocartilages to investigate transcription of collagens and proteoglycans.
Western blotting was also used to identify and characterize these macromolecules,
and immunohistochemistry to localize their distribution. The results demonstrate
striking differences in the ECM between the mid-tendon and its insertion. Types
I, III, V and VI collagens, decorin, biglycan, fibromodulin and lumican were
found in both the mid-tendon and the fibrocartilages, although their precise
distribution often differed with site. mRNA for type II collagen was constantly
present in the fibrocartilages, but it was only found in the mid-tendon of one
specimen. The patterns of distribution for versican and aggrecan mRNA were
complimentary - versican mRNA was present in the mid-tendon and absent from the
fibrocartilages, while aggrecan mRNA was present in the fibrocartilages and
absent from the mid-tendon. The range and distribution of ECM molecules detected
in the Achilles tendon reflect the differing forces acting on it - the mid-tendon
largely transmits tension and is characterized by molecules typical of fibrous
tissues, but the fibrocartilages must also resist compression and thus contain,
in addition, molecules typical of cartilage.
PMID- 9550264
TI - Primary structure and expression of a chicken laminin beta chain: evidence for
four beta chains in birds.
AB - Characterization of a full length cDNA sequence for a chicken laminin beta chain
is described which is most closely related to the mammalian beta 2 chain.
Comparison with published sequences shows that the chicken beta 2-like chain
corresponds to a fragment of a previously described laminin beta chain called B1
2 (O'Rear, 1992). The sequence of the chicken beta 2-like chain differed from
fragments of two other chicken laminin beta chains that were previously described
and designated B1-1 (now called beta 1; O'Rear, 1992) and beta x (Ybot-Gonzalez
et a1.,1995). In addition, the beta 2- like chain does not appear to be the
chicken equivalent of the mammalian laminin beta 3 chain, since it differs
markedly in cDNA sequence, possesses domain IV and has a transcript size of 6 kb.
We therefore propose that there are at least four laminin beta chains in the
chicken. Sequence comparison of the beta 2-like laminin chain with previously
cloned beta 1 and beta 2 chains shows a somewhat closer relationship to rat and
human beta 2 than to mouse and human beta 1, especially in domains I, II and
alpha. In addition, two expressed fragments of the chicken beta 2-like chain were
recognized by a monoclonal antibody (C4) regarded as specific for the rat beta 2
chain (Hunter et al., 1989a). The results therefore suggest that the laminin
chain previously described as a potentially novel chain called B1-2 (O'Rear,
1992) is likely to be the chicken equivalent of the mammalian beta 2 chain.
PMID- 9550265
TI - Overview of matrix metalloproteinase expression in cultured human cells.
AB - The matrix metalloproteinases (MMP) have been implicated in tumor invasion and
metastasis both by immunohistochemical studies and from the observation that
specific metalloproteinase inhibitors block tumor invasion and metastasis.
Oligonucleotide primers for thirteen MMPs (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP
9, MMP-10, MMP-11, MMP-12, MMP-13, MMP-14, MMP-15, MMP-16) were optimized for use
in RT-PCR. A semi-quantitative RT-PCR assay was used to determine the pattern of
MMP mRNA expression in 84 normal and transformed or carcinogen transformed human
cell lines and strains derived from different tissues. The results demonstrate
one or more cell lines which express thirteen members of the MMP family. In
addition, various oncogene transfected human fibroblast cell strains were
analyzed for MMP expression. We confirm that over-expression of the H-ras
oncoprotein correlates with up-regulation of MMP-9 and demonstrate that over
expression of v-sis also up-regulates MMP-9. A cell line immortalized following
myc expression was found to up-regulate MMP-7, MMP-11 and MMP-13. Inappropriate
expression of several MMP mRNAs was detected in breast, prostate, bone, colon and
oral tumor derived cell lines. Identification of at least one cell line
expressing each of thirteen MMPs and the observation of oncogene induced
expression of several MMPs should facilitate analysis of the transcriptional
mechanisms controlling each MMP.
PMID- 9550266
TI - Collagen IX: evidence for a structural association between NC4 domains in
cartilage and a novel cleavage site in the alpha 1(IX) chain.
AB - Collagen IX, a structural component of the extracellular matrix of connective
tissues, is synthesized as long and short forms which contain or lack,
respectively, a 27 kDa non-collagenous (NC) 4 domain at the N-terminus of the
alpha 1(IX) chain of the molecule. The long form occurs in cartilage and
developing cornea, but not in vitreous, suggesting a specialized function for the
NC4 domain, perhaps by interacting with other macromolecules. To test this
hypothesis, embryonic chick cartilage was treated with DTSSP, dissociated with
bacterial collagenase, and the NC4-containing DTSSP-cross-linked protein
complexes examined and purified. Analysis of cartilage extracts using an anti-NC4
antibody, and of purified NC4-containing complexes, identified a predominant NC4
dimer. A naturally-occurring N-terminal fragment of the alpha 1(IX) chain, whose
size is equivalent to the NC4-COL3-NC3 domains of the chain, was identified.
Association of collagen IX molecules via NC4 domains and the existence of a
cleavage site close to the NC3 domain of the molecule are likely to be of primary
importance in the growth and remodeling processes of cartilage, in health and
disease.
PMID- 9550267
TI - Molecular cloning and sequence analysis of the aggrecan interglobular domain from
porcine, equine, bovine and ovine cartilage: comparison of proteinase-susceptible
regions and sites of keratan sulfate substitution.
AB - Oligonucleotide primers which were designed based on identical peptide sequences
flanking the interglobular domain (IGD) of human, bovine and rat aggrecan were
used in RT-PCR reactions containing human, porcine, equine, bovine and ovine
cartilage RNA. Novel cDNAs encoding the IGD of the latter four species were
obtained and sequenced. The deduced amino acid sequences for these cDNAs were
aligned and compared with those described for six other species. Amino acid
sequences surrounding the major proteolytic cleavage sites in the IGD are highly
conserved, with some species-specific substitutions. Similarly, known sites of
keratan sulfate attachment in the IGD are highly conserved in all species. The
results provide essential amino acid sequence data for species commonly used in
model systems of cartilage degeneration.
PMID- 9550268
TI - Oro-palatal dysplasia Bettex-Graf--a new syndrome.
AB - Four cases of an until now undescribed syndrome have been observed in Berne in
the last 40 years. All four cases are members of the same family and have
occurred in three consecutive generations. They present with a U-shaped palatal
cleft, microstomia, hypoplasia of the mandibula and a partial anodontia. An
autosomal dominant heredity was demonstrated. Karyograms have been made in three
of the patients and in all patients showed an anomaly in the form of a "fragile
site" in one chromosome (16 fra 16 [q22]). Surgical and orthopedic treatments
were difficult.
PMID- 9550269
TI - Balloon dilatation of oesophageal strictures in children.
AB - During the last ten years balloon dilatation has become increasingly frequent in
the therapy of oesophageal strictures, both for diagnosis and treatment. From
1983 to 1994, balloon catheterization was performed in 36 children (oesophageal
atresia 28, tracheo-oesophageal fistula 3, congenital stenosis 1, acquired
oesophageal stricture subsequent to gastro-oesophageal reflux 1, to caustic
ingestion 3). Age at treatment varied from 2 weeks to 15 years. Thirty-nine (3
double) strictures were dilated a total of 171 times. Balloon dilatation was
successful in 31 cases (79%). In two children therapy was changed to conventional
bouginage and six strictures were resected. Advantages of the method may include
that forces are exerted radially and that the procedure may be performed under
better control since fluoroscopy is used.
PMID- 9550270
TI - Ultrasonographic "triangular cord": the most definitive finding for noninvasive
diagnosis of extrahepatic biliary atresia.
AB - Early diagnosis of extrahepatic biliary atresia (EHBA) is very important for a
successful bile drainage procedure. An urgent and extensive investigation is
warranted to make a differential diagnosis of EHBA from other cholestatic
disease, especially neonatal hepatitis (NH). The diagnosis may be made by
laparotomy with cholangiogram and liver biopsy but these procedure are invasive.
Because a cone-shaped fibrous tissue was always found at the porta hepatis during
Kasai's procedure and that type of fibrous tissue has never been seen in other
types of cholestatic jaundice, the authors have used ultrasonography (US) to
detect fibrous remnants at the porta hepatis in infants clinically suspected of
having EHBA and identified a triangular- or tubular-shaped echogenic density in
the bifurcation of the portal vein at the porta hepatis in EHBA and called it an
ultrasonographic "triangular cord (TC)". The authors determined that the presence
of TC denoted the EHBA. On the other hand, nonvisualization of TC was interpreted
as consistent with NH. In the present study, the authors reviewed
ultrasonographic examination and hepatobiliary scintigraphy in a series of 41
infants suspected of having EHBA or NH. The TC was identified in thirteen
infants. In twelve of thirteen infants with TC found by US, the diagnosis of EHBA
was confirmed at the time of Kasai's Roux-en-Y hepatoportojejunostomy operation.
The remaining one died at 15 months of age without having treatment. TC was not
visualized in 28 infants. Twenty-seven of 28 infants with absent TC improved
clinically through medical treatment for NH. The other, diagnosed to have NH by
needle and wedge liver biopsies, eventually showed a TC on follow-up US
examination performed 40 days after the initial examinations. Moreover, follow-up
percutaneous liver biopsy specimen showed typical findings of biliary atresia
with bile duct proliferation and portal fibrosis. The patient underwent a Kasai
hepatoportoenterostomy. On review of the hepatobiliary scintigraphy, all 13
infants with TC had no intestinal excretion of isotope. Thirteen of 28 infants
(46%) without TC also had no intestinal excretion of isotope in the 24hour follow
up but all of them were confirmed to have NH by percutaneous liver biopsy and
their subsequent clinical course confirmed NH with the detection of bile in their
stool except one. On the basis of these results, the authors conclude that
ultrasonographic TC is a very specific finding representing the fibrous cone at
the porta hepatis and is a quick, simple, and definitive tool in the noninvasive
diagnosis of EHBA. If TC is visualized, no further studies are necessary and
exploratory-laparotomy can be done. If TC is not visualized, hepatobiliary
scintigraphy is recommended to demonstrate bile duct patency. Percutaneous liver
biopsy is only required if neither TC nor intestinal excretion of isotope is
seen. However, early exploration or close US follow-up study is recommended in
any patient suspected of having EHBA clinically, even if liver biopsy confirms
the presence of NH.
PMID- 9550271
TI - Thirty-eight years experience of malignant hepatic tumors in infants and
childhood.
AB - A description is given of therapeutic experiences with 39 cases of malignant
liver tumors in infancy and childhood during the past 38 years. Of these
patients, 9 not undergoing hepatic resection all died, while 18 (60%) of 30
patients treated by hepatic resection survived. When only patients with
hepatoblastoma are considered, 14 of 24 patients are alive, although 3 of them
had local recurrence and had lung metastasis. Among patients with other types of
liver tumor, those with hepatocellular carcinomas (2 cases) and vascular
neoplasms all died in a short period of time, whereas 2 with yolk sac tumor and
one with metabolic pancreatic tumor are alive despite of tumor recurrence. In
summary, the results of surgical treatment of malignant liver tumors in infancy
and childhood, which formerly were poor, have been improved remarkably, which we
owe mainly to: 1) advances in diagnostic imaging techniques (e.g., angiography,
ultrasonography, CT and MRI) permitting early diagnosis, localization of tumor,
visualization of the coursing of major vessels (particularly, hepatic artery &
vein) and more accurate definition of resectability, 2) technical improvement of
hepatic resection and 3) progress of chemotherapy mainly with cisplatin and
adriamycin.
PMID- 9550272
TI - Spontaneous perforation of choledochal cyst: a study of 13 cases.
AB - Of the 187 cases of infantile choledochal cyst treated at our hospitals, we
encountered 13 with spontaneous perforation. All cases were under 4 years old.
Eight cases were found to have biliary peritonitis and 5 had a sealed
perforation. The shape of the extrahepatic bile duct was cystic in 8 and fusiform
in 5. The cyst wall around the perforation was filmy and bile was found to be
oozing through the thinned wall. Nine perforations were single while 4 cases had
multiple perforations. Four of 17 perforations occurred in the posterior part of
the cyst wall. Only 1 case of perforation was associated with protein plugs in a
common channel, while 7 of the 10 cases of choledochal cyst requiring
percutaneous biliary drainage due to signs of raised intrabiliary pressure were
found to have protein plugs. We consider that spontaneous perforation of a
choledochal cyst is not rare in infancy. The etiology of a perforation must be
epithelial irritation of the biliary tract due to refluxed pancreatic juice
caused by pancreatico-biliary malunion associated with mural immaturity due to
infancy, rather than an abnormal rise in ductal pressure or congenital mural
weakness at a certain point.
PMID- 9550273
TI - Meckel's diverticulum and laparoscopy of children. What's new?
AB - Laparoscopy has not changed the diagnostic approach in Meckel's diverticulum
(MD). Preoperative echography and scintigraphy are still indicated in case of
symptomatic diverticulum. During each submesocolic laparoscopy we must
meticulously look for Meckel's diverticulum. There are two surgical procedures
for MD resection: 1. Short intestinal resection after exteriorization (celio
assisted surgery) is advocated in young patients or in complicated MD. 2.
Laparoscopic resection by the Endo GIA stapler is advocated in older patients and
latent MD with a narrow base.
PMID- 9550274
TI - Sexuality and reproductive issues in children with myelomeningocele.
AB - Recent advancements in surgical and medical therapies have improved the life
expectancy of children with myelomeningocele. Yet, there has been a contrasting
lack of improvement with regards to sexual function and reproductive issues that
continue to infantilize this population. This article identifies five major risk
factors that contribute to these delays which invariably lead to irreversible
emotional trauma if they are not addressed early in childhood. Adequate
psychosexual education of myelomeningocele patients and their families is a
tremendous societal challenge. But, only with education will there be trends away
from policies of isolation to those that reinforce community integration of the
physically disabled.
PMID- 9550275
TI - External fixation of lower limb fractures in children.
AB - 26 children with 29 lower limb fractures, between the age of 2 and 15 years, were
treated with an external fixator. The average time to union and removal of the
fixator was 71 days for femoral and 73 days for tibial fractures. Complications
included pin problems in nine cases, two devices had to be replaced with a cast
and one refracture. Leg length discrepancies were noted in five children and
radiological malalignment in three. We recommend external fixation for all
femoral shaft fractures and all open or dislocated tibial and tibia and fibula
fractures beginning at the age of three to adolescence.
PMID- 9550276
TI - Hallux valgus in young patients: comparison of soft-tissue realignment and
metatarsal osteotomy.
AB - Two procedures of hallux valgus correction in young patients were compared by
long-term results: soft-tissue realignment (McBride) and Mitchell osteotomy. From
1970 to 1990, 33 hallux valgus deformities of 17 patients were corrected with one
of these procedures at the Orthopaedic Department of the University of Mainz.
Patients' age at operation ranged from 9 to 20 years and average follow-up was 16
years later. Reevaluation consisted of subjective criteria, such as pain, shoe
fitting, functional disability and cosmetics and objective parameters (hallux
valgus and intermetatarsal angle, osteoarthrotic changes and range of motion of
the metatarsophalangeal joint). They were assessed by report, interview,
radiograph and physical examination and determined the overall outcome. McBride
procedure showed 59% good, 12% satisfying and 29% dissatisfying long-term
results, whereas outcome after Mitchell osteotomy was graded as good in 69%,
satisfying in 12% and dissatisfying in 19% of the cases. Critical analysis
emerged, that each procedure has its own bounds of indication. Successful hallux
valgus correction can be achieved by an individual approach consisting of careful
study of the indications, well-performed surgery and appropriate postoperative
care.
PMID- 9550277
TI - Cancrum oris (noma) in children.
AB - Cancrum oris, noma or gangrenous stomatitis is a disease which affects primarily
undernourished and immunosuppressed young children. Frequent in underdeveloped
countries, it also is seen in rare cases of patients with AIDS and leukemia in
America and in Europe. Once fatal, the disease is now better understood and today
the repair of its terrible sequels is looked upon as a great surgical challenge.
This paper reports a case of noma in a 3-year-old black African female admitted
to this Service. In an already advanced stage of this illness with severe
sequelae, she presented with partial amputation of the lips (upper and lower),
right cheek, right side of the nose and maxilla. The choice of treatment of the
infected area and eventual reconstruction is discussed.
PMID- 9550279
TI - Abdominal situs inversus with congenital duodenal stenosis: rare association.
AB - Abdominal situs inversus carries a significant mortality because the majority of
cases (95 %) have associated cardiac and splenic defects. A review of all cases
reported in the English literature confirms in addition the presence of
significant gastro-intestinal pathologies, mainly annular pancreas, midgut
volvulus and duodenal atresia. We report on an additional case of abdominal situs
inversus without cardiac or splenic abnormalities, who had partial duodenal
obstruction secondary to a mucosal diaphragm. This seems to be the thirteenth
case associated with duodenal obstruction and the sixth case secondary to a
mucosal duodenal diaphragm, to date, in this setting.
PMID- 9550278
TI - A gastroschisis-like abdominal wall defect in the left hypochondrium. Case report
and literature review.
AB - Congenital abdominal wall defects are exceedingly rare on the left side. The
presented patient had an upper abdominal wall defect located just lateral to the
left rectus muscle. Additionally, upper parts of the abdominal flat muscles were
defective on that side. Because no report was found in the literature about the
defect described here, both its terminological and embryological backgrounds are
discussed.
PMID- 9550280
TI - Spleno-caval shunt in children using internal jugular vein graft: a case report.
AB - Several techniques for decompression of portal hypertension have been described.
The spleno-caval shunt is an easy and safe technique described in adult patients.
However, the procedures described in adults are not adapted to children. We
report an adaptation of this technique in a child, using the internal jugular
vein as an interposition graft for relief of portal hypertension.
PMID- 9550281
TI - Compression of the peroneal nerve by a cyst in a seven-year-old child.
AB - Compressions of the peroneal nerve are rare since only some sixty such cases have
been described since 1921. The authors report a new observation of compression
extrinsic to the peroneal nerve by a synovial cyst, the source of which was the
upper fibulo-tibial joint, in a child of seven years. As far as we know, this is
the youngest age found in the relevant literature. Because of a swiftly appearing
painful swelling, along with complete paralysis of the peroneal nerve, an
electromyogram and a nuclear magnetic resonance were performed, with a view to
confirming the diagnosis and to clarifying the topography of the cyst. The
removal of the latter led to the child being cured with complete recovery of the
peroneal nerve within three months.
PMID- 9550282
TI - Effect of oral and intravenous insulin and glutamic acid decarboxylase in NOD
mice.
AB - Islet cell antigens have been administered orally and intravenously (I.V.) to NOD
mice to assess their abilities to protect from or delay the onset of diabetes,
and thereby provide insights that may have therapeutic implications in human
trials. Whereas we and others have observed a delay in the onset of diabetes in
NOD mice that have been fed with insulin from early life, we report here for the
first time that feedings with porcine GAD65 alone (p = 0.226) or in combination
with insulin (p = 0.011), have anti-diabetic effects in a prolonged study period
(>400 days). While antigen-specific inhibitions of in vitro lymphocytic
proliferation responses were seen (p < 0.05), antibody levels were unaffected by
oral antigen treatments. IFN-gamma mRNA levels were downregulated in the islet
infiltrates following oral antigen treatments while IL-2 and TNF-beta were
expressed in all instances. We also observed that I.V. human recombinant GAD65,
and porcine GAD given at weaning, delayed diabetes onset (p = 0.004) while
similar treatments with a variety of inactive insulin preparations were generally
ineffective. These findings thus indicate varying effects of oral and I.V.
autoantigen administrations on the development of diabetes in NOD mice, and
describe the immunological processes induced by oral autoantigen treatments.
PMID- 9550283
TI - Interleukin-13 counteracts suppression induced by interleukin-1beta of glucose
metabolism but not of insulin secretion in rat pancreatic islets.
AB - The cytokine interleukin-1beta (IL-1beta) has been postulated to be involved in
beta-cell destruction in IDDM. It has also been suggested that this action by IL
1beta is mediated by nitric oxide (NO) generation. Recently it has been reported
that Th2-cell promoting cytokines e.g. interleukin-4 (IL-4) and interleukin-13
(IL-13) can reduce NO formation from activated macrophaghes after cytokine
activation. In the present study we examined the effect of IL-13 on IL-1beta
suppression of islet function. For this purpose rat pancreatic islets were
cultured in medium RPMI 1640 + 10% fetal calf serum and exposed for 42 h to human
IL-13 (0. 0.1, 1 and 10 ng/ml) in the presence or absence of human IL-1beta (25
U/ml) during the last 24 h of culture. IL-13 alone did not affect any islet
functions during prolonged exposure. The highest concentration of IL-13
counteracted IL-1beta suppression of islet glucose oxidation, but not insulin
release. Moreover, IL-13 failed to reduce IL-1beta stimulated NO production, as
measured by medium nitrite levels. Acute exposure to IL-13 caused a slight
stimulation of islet insulin secretion. When IL-4 (10 ng/ml) was combined with IL
13 no synergistic action of the two cytokines was observed in the counteraction
of IL-1beta mediated changes. In conclusion, the present study showed that IL-13
could partially prevent IL-1beta induced inhibition of the glucose metabolism,
and this effect appeared to be unrelated to NO levels. So far it has not been
possible to demonstrate in vitro that Th2-cell promoting cytokines such as IL-4
and IL-13 can effectively reduce cytokine-induced NO from islet cells, as has
been reported for macrophages. However, it cannot be excluded that Th2-cell
promoting cytokines can be effective in reducing a Th1-cell mediated anti-beta
cell response in vivo.
PMID- 9550284
TI - Administration of dehydroepiandrosterone sulfate retards onset but not
progression of autoimmune disease in NZB/W mice.
AB - NZB/W mice spontaneously develop an autoimmune disease characterized by the
formation of anti-DNA antibodies and subsequent development of a fatal immune
complex-mediated glomerulonephritis. Treatment of NZB/W F1 female mice with
DHEAS, a precursor of DHEA, beginning at 2 months of age delayed the onset of
autoimmune disease and prolonged survival. Animals treated with DHEAS beginning
at 2 months of age had significantly lower anti-dsDNA serum antibody titers when
compared to controls. Interestingly, DHEAS treatment had no effect on titers of
anti-phosphatidylcholine (PtC) "natural" antibodies. Serum levels of IL-10, which
increase with onset of disease, were also significantly reduced in mice treated
with DHEAS beginning at 2 months of age. In contrast, if DHEAS treatment was
started at 6 months of age, there was no effect on mortality rates. In addition,
treatment of animals with DHEAS beginning at 6 months of age did not lower serum
titers of anti-dsDNA and had no ameliorating effect on anti-PtC antibody
production. Serum levels of IL-10 were also unaffected in mice treated with DHEAS
beginning at 6 months of age. Together, these data suggest that parenteral
administration of DHEAS is effective at delaying autoimmune disease and
prolonging survival when given prior to the onset of symptoms. However, DHEAS
treatment does not affect the course of disease when treatment begins after the
onset of disease. We propose that DHEA(S) therapy used under similar conditions
would not provide a clinically beneficial effect in the specific symptoms of
immune complex-mediated glomerulonephritis.
PMID- 9550285
TI - Effects of HgCl2 on the expression of autoimmune responses and disease in
diabetes-prone (DP) BB rats.
AB - Repeated exposure of Brown Norway (BN) rats to relatively low doses of HgCl2
induces autoantibodies to renal antigens (e.g., laminin) and a membranous
glomerulonephropathy characterized by proteinuria. In contrast, Lewis (LEW) rats
are "resistant" to the autoimmune effects of mercury and, when exposed to this
metal, are protected against experimental autoimmune encephalomyelitis (EAE) and
Heymann's nephritis. To date, there is no information on "suppressive" effects of
mercury in naturally occurring (so-called "spontaneous") rat models of autoimmune
disease. Therefore, we have administered HgCl2 to diabetes-prone (DP) BB rats,
animals that spontaneously develop both insulin-dependent diabetes mellitus
(IDDM) and thyroiditis. We found that DP rats treated with mercury or water for a
period of 40-125 days developed autoantibodies to thyroglobulin, with a higher
incidence in HgCl2-injected animals (92% vs. 56% in H2O-injected controls). A
novel finding of our study was the detection of autoantibodies to laminin in the
same rats, again with an increased incidence after HgCl2 treatment (83% vs. 44%).
IgG2a was the most frequently detected isotype of antibodies to laminin, followed
by IgG1, IgG2b and IgG2c. The IgG isotype profile suggests that treatment with
HgCl2 may activate both Th1 and Th2 lymphocytes in BB rats. In spite of these
stimulatory effects on autoantibody responses, we found that there was no
difference in the incidence of IDDM and thyroiditis between HgCl2-treated and
control animals. We conclude that the suppressive effects of mercury previously
observed in EAE and Heymann's nephritis of LEW rats do not occur in "spontaneous"
autoimmune IDDM and thyroiditis of BB rats. Therefore, immune suppression caused
by HgCl2 cannot be considered a common phenomenon, but may be a genetically
determined characteristic of LEW rats, possibly related to a specific or unique
cytokine profile of this particular rat strain. In contrast, while mercury does
not seem to recruit, induce or rescue regulatory T cell function in DP rats, it
does stimulate autoantibody responses in these animals.
PMID- 9550286
TI - Anti-NGF autoantibodies and NGF in sera of Alzheimer patients and in normal
subjects in relation to age.
AB - It has been suggested that inflammation may be a possible cause of Alzheimer's
disease (AD). Increased anti-NGF autoantibody levels and increased NGF frequency
in serum have previously been associated with inflammatory responses. In this
study no changes in anti-NGF autoantibody titers or in NGF frequency were
detected in sera of AD patients, suggesting that they are not involved in the
neuroimmunological mechanisms underlying AD. There were neither age-associated
changes in NGF frequency in sera of four groups of normal subjects between 18-91
years of age. In contrast, anti-NGF autoantibodies were significantly increased
in sera of the 31-45 yr age group.
PMID- 9550287
TI - Characterization of elevated neutrophil-associated IgG in various autoimmune
disorders: not anti-neutrophil autoantibodies, but possibly immune complexes,
bind to neutrophils.
AB - Neutropenia is frequently observed in a variety of autoimmune disorders. As the
mechanism of neutropenia in these disorders, the destruction of neutrophils by
anti-neutrophil autoantibodies has been believed since elevated levels of
neutrophil-associated IgG (NAIgG) have been described. However, no data exists to
characterize the nature of NAIgG and show NAIgG is an anti-neutrophil
autoantibodies. We investigated whether the elevated NAIgG in these patients
consists of anti-neutrophil autoantibodies. The NAIgGs of 91 patients with
autoimmune disorders including 50 patients with idiopathic thrombocytopenic
purpura, 13 patients with systemic lupus erythematosus, 11 patients with
Hashimoto's thyroiditis and 10 patients with Graves' disease were analyzed. The
level of NAIgG was high in 36 of 91 patients. Elution studies were performed to
determine whether NAIgG has a nature of autoantibodies. In model experiments, the
ether eluate from neutrophils sensitized with neutrophil-specific alloantibody
(anti-NA2) reacted with donor neutrophils, whereas the eluates from those with
model immune complexes (ICs) failed. These data indicated that the ether elution
technique is useful to determine whether NAIgG consists of anti-neutrophil
autoantibodies. The NAIgG on patient's neutrophils was eluted with ether and the
reactivity of the eluate with normal neutrophils was investigated. The eluates
from 34 of 36 patients with various autoimmune disorders with elevated NAIgG
level failed to react with donor neutrophils. These data indicated that the
elevated NAIgG in the majority of these patients did not consist of anti
neutrophil autoantibodies, but possibly of ICs.
PMID- 9550288
TI - Effects of kinins on isolated stomachs of control and transgenic knockout B2
receptor mice.
AB - The aim of this study was to investigate the pharmacological profile of the kinin
B1 and B2 receptors in isolated stomachs from wild-type control and B2 receptor
knockout mice. Isometric contractions evoked by bradykinin (BK) (9 nM) and
desArg9BK (28 nM) were shown to be different. The contraction induced by
desArg9BK had a longer duration than that evoked by BK and increased during
incubation in vitro in stomachs of wild-type controls, while in the transgenic B2
receptor knockout mice, the contractions evoked by desArg9BK and BK were similar
and followed the B1 receptor agonist pattern. BK but not the carboxypeptidase
resistant analog, [Phe8psi(CH2-NH)Arg9]BK, was found to be active in the stomach
of B2 receptor knockout mice. BK-induced contractions were prevented by mergetpa
(a carboxypeptidase M inhibitor) (10 microM) and by a the B receptor antagonist,
AcLys[DbetaNal7,Ile8]desArg9BK (R 715) (0.88 microM), while not being influenced
by the B2 receptor antagonist HOE 140 (0.38 microM). BK and [Phe8psi(CH2
NH)Arg9]BK were potent contractants of the wild-type mice stomach and their
effects were not influenced by mergetpa or by the B receptor antagonist: they
were reduced by HOE 140. After incubation in vitro for 3-4 hours, the tissues
were treated with HOE 140 (4 microM) and FR-173657 (17 microM) to eliminate B2
receptor function. In these tissues, BK evoked a B1-like contraction which was
inhibited by mergetpa (10 microM) and antagonized by R 715 (8 microM). The
results indicate that BK acts primarily on B2 receptors. However, after
intramural conversion to desArg9BK, activation of B1 receptors of the mice
stomach occurs. In the tissues of B2 receptor knockout mice, BK behaves as a pure
B1 receptor agonist while in stomachs of control animals, the B2 receptor
contribution is overwhelming. After complete blockade of the B2 receptor, BK is
able to evoke B1-mediated responses similar to those observed in tissues of B2
receptor knockout mice. It is concluded that the disruption of the B2 receptor
gene eliminates the B2 receptor without influencing the B1 receptor system.
PMID- 9550289
TI - Evidence for the involvement of multiple mechanisms in the excitatory action of
bradykinin in the circular muscle of guinea-pig colon.
AB - We have investigated, by using the sucrose gap technique, the mechanisms of the
excitatory action of bradykinin in the circular muscle of the guinea-pig proximal
colon. In the presence of atropine (1 microM) and S-ketoprofen (3 microM), the
application of bradykinin (1 microM for 20 s) produced complex changes in
membrane potential and muscle tension. The prevailing response was a small
hyperpolarization followed by a slowly developing depolarization and a tonic
contraction. The selective B2 receptor antagonist, HOE 140 (0.3 microM) blocked
the responses to bradykinin (1 microM) while tetrodotoxin (0.3 microM) had no
affect. The selective B1 receptor agonist, [des-Arg9]bradykinin (1 microM) did
not affect the electrical or mechanical activities of the circular muscle. Apamin
(0.1 microM) blocked the transient hyperpolarization and potentiated the
bradykinin-induced depolarization and contraction. In the presence of apamin,
nifedipine (1 microM) blocked spikes (when present) and the phasic contraction
while leaving the tonic contraction unaffected. The excitatory action of
bradykinin was further investigated in the presence of atropine (1 microM), S
ketoprofen (3 microM), apamin (0.1 microM) and nifedipine (1 microM). The
depolarization but not the contraction induced by bradykinin was reduced by about
30% in low-Na+ (25 mM) but not in low Cl- (9.7 mM) Krebs solution. The
depolarization and contraction evoked by bradykinin were reduced (by about 30 and
75%, respectively) in Ca2+-free (2 min) Krebs solution. The blocker of the
sarcoplasmic reticulum Ca2+ pump, cyclopiazonic acid (CPA, 10 microM) reduced the
nifedipine-resistant depolarization and contraction induced by bradykinin by
about 40 and 60%, respectively. The inhibitor of receptor-operated cation
channels, SKF 96365 (50 microM) reduced the nifedipine-resistant bradykinin
induced depolarization and contraction by about 40 and 30%, respectively, whereas
the inhibitor of Ca2+-dependent chloride channels, niflumic acid (100 microM) was
without effect. The inhibitory effect of SKF 96365 (50 microM) and CPA (10
microM) was additive: in the presence of both drugs the bradykinin-induced
depolarization and contraction were reduced by about 70-80%. The protein kinase C
inhibitor, GF 109203x (10 microM) did not affect the nifedipine-resistant
bradykinin-induced depolarization and contraction. At a concentration of 30
microM, GF 109203x reduced the bradykinin-induced contraction by about 50% while
leaving the bradykinin-induced depolarization unaffected. The KCl (40 mM)-induced
contraction was significantly reduced (by about 30%) by GF 109203x (30 microM).
The present findings indicate that, in the presence of apamin and nifedipine, the
bradykinin-induced contraction of circular muscle of the guinea-pig colon is due
to the influx of extracellular Ca2+ via non-selective cation channels and, in
part, to the release of Ca2+ from a loosely bound internal store. Intracellular
Ca2+ facilitates the bradykinin-induced depolarization, a response which does not
involve a protein kinase C-dependent mechanism.
PMID- 9550290
TI - Labelling of recombinant human and native rat serotonin 5-HT1A receptors by a
novel, selective radioligand, [3H]-S 15535: definition of its binding profile
using agonists, antagonists and inverse agonists.
AB - The novel benzodioxopiperazine, 5-HT1A receptor weak partial agonist, S 15535 (4
(benzodioxan-5-yl)1-(indan-2-yl)piperazine) bound with high affinity and
selectivity to membranes of Chinese Hamster Ovary cells stably expressing the
human (h) 5-HT1A receptor (Ki = 0.6 nM versus [3H]-8-hydroxy-dipropylamino
tetralin, [3H]-8-OH-DPAT): its affinity at h5-HT1A receptors was more than 70
fold higher than its affinity at > 50 other binding sites. S 15535 was tritiated
to high specific activity (50 Ci/mmol) and its binding profile characterised. At
22 degrees C, [3H]-S 15535 associated and dissociated from h5-HT1A receptors with
half-times of 2.9 and 5.0 min, respectively, yielding a Kd estimate of 3.6 nM. In
saturation binding experiments, [3H]-S 15535 displayed a Bmax value for h5-HT1A
receptors (1630 fmol/mg), higher than that obtained with the agonist [3H]-8-OH
DPAT (1023 pmol/mg). Guanylyl imidodiphosphate (GppNHp, 100 microM) reduced the
binding of [3H]-S 15535 by only 25% compared with 79% for [3H]-8-OH-DPAT at h5
HT1A receptors. [3H]-S 15535 also showed high affinity, saturable binding to rat
hippocampal membranes (Bmax = 820 fmol/mg versus 647 fmol/mg for [3H]-8-OH-DPAT).
For both h5-HT1A and rat 5-HT1A receptors, the Ki values for competition binding
of 15 serotonergic ligands with [3H]-S 15535 was highly correlated with that of
[3H]-8-OH-DPAT. However, important differences were also observed. The agonist, 5
hydroxytryptamine (5-HT), displayed biphasic competition curves with [3H]-S 15535
but not with [3H]-8-OH-DPAT at h5-HT1A receptors. Similarly, the 'antagonists',
spiperone, methiothepin and (+)butaclamol, showed biphasic competition isotherms
versus [3H]-S 15535 but not [3H]-8-OH-DPAT. When [3H]-S 15535 competition binding
experiments were carried out in the presence of GppNHp (100 microM) the 5-HT and
8-OH-DPAT competition curves shifted to the right, whereas the spiperone and
methiothepin competition curves shifted to the left. In contrast, in the presence
of GppNHp, the competition isotherms for N-[2-[4-(2-methoxyphenyl)-1
piperazinyl]ethyl]-N-(2-pyridinyl)cyclo-h exanecarboxamide (WAY 100,635) were not
altered. Taken together, these data show that (i) [3H]-S 15535 is a highly
selective 5-HT1A receptor ligand which labels both G-protein-coupled and
uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield
monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists,
are not sensitive to the G-protein coupling state of the receptor, but (iii)
spiperone and methiothepin behaved as inverse agonists, their competition
isotherms with [3H]-S 15535 being modulated in an opposite manner to those of
agonists.
PMID- 9550291
TI - In vitro studies of endogenous noradrenaline and NPY overflow from the rat
hypothalamus during maturation and ageing.
AB - Marked changes in brain monoamine content and NPY content occur during maturation
and ageing. Earlier in vivo studies in our laboratory have reported blunted K+
stimulated noradrenaline release and reduced NPY overflow in aged animals using
microdialysis and push pull techniques. In this study, in vitro superfusion
techniques were established to measure endogenous noradrenaline, NPY, DOPAC and 5
HIAA overflow from the hypothalamus of 1, 5 and 16 month old Sprague-Dawley rats.
A period of high K+ (56 mM) stimulation was carried out to elicit maximal
release. Basal noradrenaline overflow was similar in all age groups of rats and
during K+-induced depolarisation similar 3-4 fold increases were observed. On the
other hand, basal and K+ stimulated NPY overflow were significantly greater in
the adult rats compared to 1 month and 16 month old rats. Despite differences in
absolute NPY overflow, the relative increase over resting was not significantly
different across age groups. The molar quantities of hypothalamic NPY overflow at
rest and under K+ stimulated conditions were three orders of magnitude lower than
noradrenaline. Results of these studies suggest that both NPY and noradrenaline
can be released from a similar hypothalamic pool. Basal and K+-evoked DOPAC and 5
HIAA overflow were similar between the 3 age groups. Thus the overflow of
hypothalamic noradrenaline, DOPAC and 5-HIAA under in vitro conditions was not
altered from 1 to 16 months. In contrast, 5 month old rats had significantly
higher NPY overflow than the other age groups (P < 0.05), consistent with a
reported decline in NPY content with advanced age. Hypothalamic noradrenaline
overflow was not affected by ageing, suggesting that a selective loss of NPY in
the arcuo-PVN projection, or other projections to the hypothalamus with ageing
may contribute to the reduction in NPY overflow in aged rats.
PMID- 9550292
TI - Effects of pharmacological inhibition of glutamate-uptake on ischaemia-induced
glutamate efflux and anoxic depolarization latency.
AB - It has been proposed that deficient glutamate uptake, by increasing the
extracellular concentration of this excitatory neurotransmitter, may contribute
to the pathophysiology of cerebral ischaemia. This study aimed to examine whether
pharmacological inhibition of glutamate uptake altered the kinetics of ischaemia
induced glutamate efflux, and precipitated anoxic depolarisation. Microdialysis
was used for application of the glutamate-uptake inhibitor L-trans-pyrrolidine
2,4-dicarboxylate (L-trans-PDC), recording of the EEG and extracellular direct
current (DC) potential with an electrode within the probe, and continuous
monitoring of changes in extracellular glutamate. L-trans-PDC was applied locally
from 8 min prior to cardiac arrest to the end of the recording period. L-trans
PDC (2.5 mM) barely altered the time course of postmortem glutamate efflux in the
cortex. Only the maximum rate of efflux during the first exocytotic phase, and
the concentration reached at the end of this phase, appeared slightly increased.
L-trans-PDC (5 mM) reduced significantly the delay between EEG silence and anoxic
depolarization in the cerebral cortex (59.2 +/- 9.2 s vs. 79.7 +/- 11.5 s; n =
6), but not in the striatum and hippocampus. These effects contrast with the
marked increase in dialysate glutamate that L-trans-PDC produces in all these
three brain regions. Together, these data do not support the hypothesis that
inhibition of glutamate uptake plays a critical role, early in cerebral
ischaemia. However, a contribution of reversed glutamate uptake to the secondary
Ca2+-independent phase of ischaemia-induced glutamate efflux cannot be ruled out.
PMID- 9550293
TI - H2 receptor-mediated facilitation and H3 receptor-mediated inhibition of
noradrenaline release in the guinea-pig brain.
AB - The effect of histamine and related drugs on the tritium overflow evoked
electrically (0.3 Hz) or by introduction of Ca2+ ions into Ca2+-free K+-rich (25
mmol/l) medium containing tetrodotoxin was studied in superfused guinea-pig brain
cortex, cerebellum, hippocampus or hypothalamus slices and in mouse brain cortex
slices preincubated with 3H-noradrenaline. The electrically evoked tritium
overflow in guinea-pig cortex slices was inhibited by histamine; the H3 receptor
antagonist clobenpropit reversed the effect of histamine to a slight
facilitation. The facilitatory effect of histamine (obtained in the presence of
clobenpropit) was not affected by the H1 receptor antagonist mepyramine but
abolished by the H2 receptor antagonist ranitidine. In the absence of
clobenpropit, ranitidine augmented the inhibitory effect of histamine. In slices
superfused in the presence of ranitidine, the evoked overflow was inhibited by
histamine and, more potently, by the H3 receptor agonist R-alpha-methylhistamine
in a concentration-dependent manner (maximum inhibitory effect obtained for both
agonists 30-35%). The concentration-response curve of histamine was shifted to
the right by the H3 receptor antagonist thioperamide. R-alpha-methylhistamine
inhibited the electrically evoked tritium overflow also in guinea-pig cerebellar,
hippocampal and hypothalamic slices. In cortex slices superfused in the presence
of clobenpropit, the H2 receptor agonists impromidine and, less potently, R
sopromidine facilitated the evoked overflow in a concentration-dependent manner.
S-Sopromidine only tended to increase the evoked overflow. The effect of
impromidine was counteracted by the H2 receptor antagonists ranitidine and
cimetidine. The extent of the maximum facilitatory effect of impromidine (by 15
20%) was about the same when (i) the Ca2+ concentration in the medium was reduced
from 1.3 to 0.98 mmol/l, (ii) the time of exposure to impromidine was reduced
from 28 to 8 min or (iii) cerebellar, hippocampal or hypothalamic slices were
used instead of cortical slices. The Ca2+-induced tritium overflow in guinea-pig
cortex slices was inhibited by histamine (in the presence of ranitidine); this
effect was abolished by clobenpropit. In slices superfused in the presence of
clobenpropit, impromidine failed to facilitate the Ca2+-evoked tritium overflow.
The electrically evoked tritium overflow in mouse brain cortex slices was
inhibited by histamine by about 60% (both in the absence or presence of
ranitidine). The inhibitory effect of histamine was abolished (but not reversed)
by clobenpropit. In conclusion, noradrenaline release in the guinea-pig brain
cortex is inhibited via presynaptic H3 receptors and facilitated via H2 receptors
not located presynaptically. In the mouse brain cortex, only inhibitory H3
receptors occur. The extent of the H3 receptor-mediated effect is more marked in
the mouse than in the guinea-pig brain cortex.
PMID- 9550294
TI - ATP release caused by bradykinin, substance P and histamine from intact and
cultured smooth muscles of guinea-pig vas deferens.
AB - Histamine (60 microM) produced ATP release from segments of guinea-pig vas
deferens which was blocked by pyrilamine and triprolidine, H1-blockers, but not
by ranitidine, an H2-blocker. The evoked-release was inhibited by the
mitochondrial inhibitors, carbonyl cyanide-m-chlorophenylhydrazone (CCCP) and
oligomycin. Bradykinin (BK) and substance P (SP) also caused substantial and
moderate release of ATP, respectively. The BK-evoked release of ATP was inhibited
by HOE140, a B2-antagonist, but not by [Des-Arg10] HOE140, a B1-antagonist. On
the other hand, VIP, angiotensin II (AII) and cholecystokinin-octapeptide (CCK-8)
failed to elicit a measurable release of ATP. Histamine and BK also enhanced the
release of ATP from superfused cultured smooth muscle cells. These results
suggest that ATP may be released as an autacoid from the smooth muscles in the
presence of these chemical mediators.
PMID- 9550295
TI - Depolarization evoked co-release of tachykinins from enteric nerves in the guinea
pig proximal colon.
AB - The aim of this study was to assess at which extent an even co-release of the
tachykinins, substance P (SP) and neurokinin A (NKA), occurs from enteric
neurons/nerves of the guinea-pig proximal colon during graded depolarization. In
this preparation, a sharply diverging NK1/NK2 receptor pattern of tachykininergic
co-transmission has been observed in physiological studies. The experiments were
performed in capsaicin-pretreated (10 microM for 15 min) mucosa-free smooth
muscle of guinea-pig proximal colon, to exclude the mucosa and the peripheral
endings of primary afferent nerves as possible sources of released tachykinins.
The content of extractable tachykinins was measured as SP- and NKA-like
immunoreactivities (-LI) by radioimmunoassay. Chromatographic characterization of
aqueous acetic acid extracts showed one peak of SP-LI corresponding to authentic
SP, whereas there were multiple peaks of NKA-LI, the major one co-eluting with
authentic NKA. An increased outflow of both SP- and NKA-LI was evenly produced in
a concentration-dependent manner when the preparations were superfused with a
high potassium (K) medium in which NaCl had been replaced with equimolar amounts
(20-100 mM) of KCl. The high K-evoked release of SP- and NKA-LI was dependent
upon the presence of extracellular calcium and was inhibited by about 50% in the
presence of the N-type voltage-dependent calcium channel blocker, omega-conotoxin
GVIA (0.1 microM). Omega-conotoxin MVIIC (1 microM), a non-selective blocker of N
, P- and Q-type voltage-dependent calcium channels, likewise produced about 40%
inhibition of evoked release of both peptides. No evidence for a role of L-type
channels in tachykinin release was obtained, since the addition of nifedipine (1
microM) or Bay K8644 (1 microM) did not significantly affect the response to high
K. Neither NK1 receptor agonist (septide, 0.1 microM) or antagonist (SR 140333,
10 nM) nor NK2 receptor agonists ([betaAla8]NKA(4-10) and GR 64349, 0.1 microM
each) or antagonist (SR 48968, 10 nM) did affect the high K-evoked release of
tachykinins. We conclude that SP and NKA are evenly co-released in response to
graded depolarization of enteric nerves in the guinea-pig colon. Therefore, the
specialization of tachykininergic transmission observed in functional studies
does not originate at the prejunctional level. The co-release of tachykinins
involves the influx of extracellular calcium via N-type but not L-type calcium
channels. No evidence for the presence of NK1 or NK2 autoreceptors affecting
tachykinin release from enteric neurons was obtained.
PMID- 9550296
TI - A therapeutic dosage of amlodipine prevents vascular hyporeactivity induced in
rats by lipopolysaccharide.
AB - The aim of this work was to investigate whether treatment with the 1,4
dihydropyridine Ca2+ antagonist amlodipine could affect the vascular
hyporesponsiveness induced by cytokines. Endotoxemia was induced by Salmonella
typhosa lipopolysaccharide (LPS) injection (4 mg kg(-1), i.p.). In endothelium
denuded rings of thoracic aorta from untreated rats, contractile response to
noradrenaline was decreased after LPS injection, this effect was partially
overcome by the addition of N(omega)-nitro-L-arginine (L-NNA, 100 microM) into
the bathing solution. In amlodipine-pretreated rats (15 mg kg(-1) day(-1),
orally, for one week), the effect of LPS was lower than in untreated ones and it
was completely reversed by L-NNA. The relaxation of the noradrenaline-induced
tone evoked by L-arginine (10 microM) in aortae of LPS-injected rats was reduced
in amlodipine-pretreated rats. Amlodipine-treatment reduced both the LPS-induced
Ca2+-independent NOS activity in homogenates of heart and the expression of iNOS
mRNA in aortae of LPS-injected rats. However, the vascular hyporeactivity induced
by exposing aortae to interleukin-1beta in vitro was not influenced by amlodipine
(10 nM). Amlodipine (10 microM) also did not affect the production of nitrite in
primary aortic smooth muscle cell culture challenged by LPS although nitrite
production in macrophage culture challenged with LPS was significantly inhibited.
The results show that rat pretreatment with amlodipine prevented the decrease of
vascular responsiveness induced by LPS, an effect that may be at least partly
related to reduction of in vivo NOS induction. The weak effect of amlodipine on
the in vitro NOS induction indicates that the protective action in endotoxemia
did not result from a short term interaction with L-type Ca2+ channels in
vascular smooth muscle. Alternative mechanisms are discussed.
PMID- 9550297
TI - Inhibition by Compound II, a sotalol analogue, of delayed rectifier current (iK)
in rabbit isolated sino-atrial node cells.
AB - The effects of Compound II, a sotalol analogue, on spontaneous electrical
activity and on three membrane currents (the delayed rectifier current, iK, the
long-lasting inward calcium current, i(Ca,L) and hyperpolarization activated
inward current, i(f)) were investigated in rabbit isolated sino-atrial node cells
by whole cell clamp with amphotericin-permeabilised patches. A submaximal
concentration of Compound II (50 nM) had a significant effect on the time and
voltage dependent activation of iK and caused a positive shift of the iK
activation curve. As well as blocking i(Kr), it caused some degree of block of
i(Ks). Block of iK by Compound II was found to be concentration dependent with an
IC50 of approximately 40 nM. 1 microM Compound II nearly completely blocked iK
without significantly affecting the peak current or I/V relationships of i(Ca,L)
or i(f). 50 nM Compound II caused a significant prolongation of APD100 and of
cycle length. It also decreased diastolic depolarization rate without
significantly affecting MDP and action potential amplitude. It is concluded that
Compound II, a sotalol analogue, slows spontaneous activity of isolated rabbit SA
node cells through a selective inhibition of iK.
PMID- 9550298
TI - Effect of disopyramide on potassium currents in rabbit ventricular myocytes.
AB - The effects of disopyramide (1-30 microM) on the 4-aminopyridine sensitive
transient outward current (I(to)), on the rapid component of the delayed
rectifier potassium current (I(Kr)) and on the inward rectifier potassium current
(I(kl)) were studied in single rabbit ventricular myocytes at 35 degrees C by
applying the whole-cell configuration of the patch clamp technique. Disopyramide
significantly decreased the amplitude of I(to) (from 1510 +/- 122 pA at control
to 1015 +/- 21 pA after 30 microM disopyramide at +50 mV; n = 5). This effect was
not voltage- or use-dependent. Disopyramide (10 microM) influenced neither the
recovery from inactivation of I(to) nor the steady-state inactivation curve. The
drug dose dependently decreased the time constant of the fast component of the
decay of I(to) (tau(f) = 6.41 +/- 0.25 ms, n = 24 for control; and 2.20 +/- 0.38
ms, n = 5 after 30 microM disopyramide at +50 mV). The fractional block caused by
30 microM disopyramide as a function of time was well fitted by a single
exponential function with time constant of 1.48 +/- 0.18 ms (n = 5), most likely
reflecting the binding kinetics of the drug to the open channel. The offset
kinetics of the drug was estimated by using a double-pulse protocol and its time
constant was 3.9 +/- 0.5 ms. Disopyramide (30 microM) did not influence
significantly the onset of inactivation measured at -20 mV. The estimated EC50
value for the I(to) block by disopyramide was 14.1 microM. Our results are
consistent with an open-channel block of I(to) by disopyramide, however, a weak,
drug-induced increase of the rate of inactivation and a moderate tonic block
cannot be excluded. The amplitude of the outward tail current attributed to I(Kr)
was depressed dose dependently by disopyramide (after clamping the cells back to
the holding potential from +30 mV, 139.5 +/- 10.9 pA for control, and 30.7 +/-
3.2 pA in the presence of 10 microM disopyramide; n = 11). The estimated EC50 was
1.8 microM. I(to) is thus less sensitive to disopyramide than I(Kr). I(kl) was
not influenced significantly by disopyramide, even when applied in the highest
tested concentration (30 microM). It is concluded that in rabbit ventricular
myocytes disopyramide blocks not only I(Kr), but also I(to), both of which may
play an important role in the well established repolarization lengthening and
antiarrhythmic effects of the drug.
PMID- 9550299
TI - Effects of three peptidase inhibitors, amastatin, captopril and phosphoramidon,
on the hydrolysis of [Met5]-enkephalin-Arg6-Phe7 and other opioid peptides.
AB - The contents of [Met5]-enkephalin-Arg6-Phe7 (met-enk-RF) and its six hydrolysis
products: Y, YG, YGG, YGGF, YGGFM, and YGGFMR were estimated after incubating met
enk-RF with either a guinea-pig ileal or striatal membrane fraction for various
times at 37 degrees C. After 45 min incubation with either ileal or striatal
membranes, met-enk-RF was completely hydrolyzed, yielding Y as the major product.
Incubation with either membrane preparation for 60 min in the presence of the
aminopeptidase inhibitor amastatin hydrolyzed 90 or 92% of met-enk-RF,
respectively, with YGG being the major product. If the dipeptidyl
carboxypeptidase I inhibitor captopril is also included in the incubation, met
enk-RF hydrolysis decreases by about half for both membranes, with YGG remaining
the major product. Inclusion of three peptidase inhibitors, amastatin, captopril,
and phosphoramidon (inhibition of endopeptidase-24.11) further reduced met-enk
hydrolysis, with 87% or more remaining intact. This shows that met-enk-RF was
mainly hydrolyzed by three enzymes, amastatin-sensitive aminopeptidase, captopril
sensitive dipeptidyl carboxypeptidase I and phosphoramidon-sensitive
endopeptidase-24.11, in both ileal and striatal membranes. Additionally,
estimations of [Leu5]-enkephalin (leu-enk), alpha- and beta-neoendorphins (alpha-
and beta-neoends), and dynorphin B (dyn B) contents after incubating the
individual peptides with striatal membrane for 60 min in the presence of the
three peptidase inhibitors showed that 98, 32, 5, and 23%, respectively, remained
intact. Our previous studies together with the data obtained here show that one
group of endogenous opioid peptides: met-enk, leu-enk, met-enk-RF, met-enk-RGL,
and dyn A-(1-8) are largely or almost exclusively hydrolyzed by the three
enzymes, amastatin-sensitive aminopeptidase, captopril-sensitive dipeptidyl
carboxypeptidase I, and phosphoramidon-sensitive endopeptidase-24.11, and
indicate that an unidentified fourth enzyme(s) is involved in the hydrolysis of
another group of peptides: alpha-neoend, beta-neoend, and dyn B.
PMID- 9550300
TI - Class I antiarrhythmic drugs alter the severity of myocardial stunning by
modulating ATP-sensitive K+ channels in guinea pig ventricular muscles.
AB - The effects of various class I antiarrhythmic drugs and glibenclamide were
examined on the recovery of contraction during reperfusion, in relation to the
action potential duration (APD) seen during ischemia. Action potential and
contractile tension were recorded from isolated guinea pig right ventricular
muscles perfused with oxygenated Tyrode solution via the coronary artery. Ten
minutes of no-flow ischemia shortened the APD at 90% of repolarization level
(APD90) to 58% of control (pre-ischemic values). The APD90 was completely
restored after 60 min of reperfusion. The developed tension was abolished during
ischemia and recovered to 87% of control after 60 min of reperfusion. In the
presence of Vaughan Williams class Ia drug cibenzoline (5 microM) or an ATP
sensitive potassium (K(ATP)) channel blocker glibenclamide (10 microM), the
shortening of the APD90 during ischemia was significantly attenuated. However,
the recovery of developed tension was significantly inhibited. Class Ic drug
pilsicainide (10 microM) did not affect the ischemia-induced shortening of the
APD90 or the recovery of developed tension after reperfusion. In the presence of
class Ib drug mexiletine (10 microM), the shortening of the APD90 during ischemia
was significantly facilitated. The recovery of developed tension in the presence
of mexiletine tended to be improved, although the difference was not
statistically significant. The developed tension measured after the 60 min
reperfusion period following 20 min of no-flow ischemia was markedly depressed,
indicating the presence of myocardial stunning. Mexiletine and pilsicainide
significantly improved the recovery of developed tension and diminished the
stunning. We conclude that cibenzoline and glibenclamide, which block cardiac
K(ATP) channels inhibit contractile recovery after reperfusion by attenuating the
shortening of APD during ischemia. In contrast, mexiletine, which activates
K(ATP) channels (in addition to blockade of Na+ channels) improves contractile
recovery by facilitating the shortening of APD during ischemia.
PMID- 9550301
TI - Different inhibition patterns of tedisamil for fast and slowly inactivating
transient outward current in rat ventricular myocytes.
AB - Tedisamil has been described as a selective inhibitor of a fast inactivating
transient outward current (i(to,f)) in rat ventricular myocytes. Because recent
reports demonstrated the existence of a second slowly inactivating transient
component (i(to,s)) we investigated i(to,s) and differentiated the effects of
tedisamil on both transient outward current components and their influence on
action potential duration. Standard electrophysiological techniques were used for
whole cell recordings at 24-26 degrees C from enzymatically isolated myocytes.
Inhibition of i(to,f) by tedisamil was the result of an acceleration of
inactivation at positive test potentials with a concentration for half-maximal
inhibition (EC50) of 4-7 micromol/l, which is confirmatory to reports from other
investigators. Our new results show that i(to,s) is more sensitive to tedisamil
with an EC50 of 0.5 micromol/l. Furthermore the pattern of i(to,s) inhibition is
different compared with i(to,f), because inactivation of i(to,s) is not
accelerated by tedisamil. Instead the amplitude of the steady state inactivation
curve of i(to,s) is attenuated which indicates a reduction of maximally available
current. I(to,s) was evaluated by three different methods as time-dependently
inactivating current (7.5 s test pulse duration), voltage-dependently inactivated
current and tedisamil-sensitive current. All approaches yield similar
inactivation curves. The potential for halfmaximal inactivation of i(to,s) lies
about 35 mV more negative than that for i(to,f) and the slope factor (K = -23 mV)
is different to that of i(to,f) (K = -3 mV). Effectiveness of tedisamil-induced
modulation of i(to,f) and i(to,s) on action potential repolarization was tested.
Action potentials stimulated at 0.5 Hz were not prolonged by 1 micromol/l
tedisamil (dominant i(to,s) block) at a repolarization level of 0 mV but
prolonged to about 120% of control at -70 mV. This indicates that i(to,f) was
sufficient to guarantee a regular early repolarization whereas decrease of
i(to,s) delayed the final repolarization. In conclusion, the observation that
tedisamil inhibits i(to,f) and i(to,s) differently supports the hypothesis that
the two i(to)-components are related to two different channel populations
expressed in rat ventricular myocytes.
PMID- 9550302
TI - Inhibition by ethanol of excitatory amino acid receptors in rat locus coeruleus
neurons in vitro.
AB - Intracellular recordings were made in a pontine slice preparation of the rat
brain containing the nucleus locus coeruleus (LC). In a first series of
experiments, various parameters of spontaneous action potentials were evaluated.
It turned out that ethanol (100 mM) does not alter the firing rate, the spike
amplitude and the afterhyperpolarization following a spike. In subsequent
experiments, the generation of action potentials was prevented by passing
continuous hyperpolarizing current via the recording electrode. Under these
conditions, ethanol (100 mM) had no effect on the membrane potential or input
resistance. Pressure-applied N-methyl-D-aspartate (NMDA), (S)-alpha-amino-3
hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and alpha,beta-methylene ATP
(alpha,beta-meATP) reproducibly depolarized LC neurons. While ethanol (100 mM)
depressed the NMDA- and AMPA-induced depolarization to a similar extent, it did
not interact with alpha,beta-meATP. Lower concentrations of ethanol (10 and 30
mM) had no effect on depolarizing responses to NMDA or AMPA. Noradrenaline
applied by pressure pulses reproducibly hyperpolarized LC cells. These
hyperpolarizations were unchanged by ethanol (100 mM). Biphasic synaptic
potentials consisting of early depolarizing (PSP) and late hyperpolarizing (IPSP)
components were evoked by electrical stimulation. Ethanol (100 mM) depressed the
PSP and increased the IPSP. Glutamatergic PSPs recorded in the combined presence
of picrotoxin (100 microM) and suramin (100 microM) were also inhibited by
ethanol (100 mM). However, IPSPs recorded under these conditions were insensitive
to ethanol (100 mM). In conclusion, ethanol may interfere with the AMPA (or NMDA)
receptor-mediated fraction of the PSP and slightly facilitate the alpha2
adrenoceptor-mediated fraction of the IPSP.
PMID- 9550303
TI - Hypersusceptibility to DMCM-induced seizures during diazepam withdrawal in mice:
evidence for upregulation of NMDA receptors.
AB - The present study investigated the role of NMDA (N-methyl-D-aspartate) receptors
in the hypersusceptibility to seizures induced by the benzodiazepine inverse
agonist DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) during
diazepam withdrawal in mice, using behavioral and biochemical approaches. The
seizure threshold of DMCM was markedly decreased during diazepam withdrawal,
reflecting withdrawal hyperexcitability in response to physical dependence. The
decrease in the seizure threshold of DMCM in diazepam-withdrawn mice was
inhibited by the non-competitive NMDA receptor antagonists MK-801 ((+)-5-methyl
10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate; 50 microg/kg, s.c.)
and ifenprodil (20 mg/kg, i.p.). The effective doses of these compounds were
lower than those required to prevent DMCM-induced seizures in chronically vehicle
treated mice. Since MK-801 and ifenprodil do not only bind to NMDA receptors but
also to sigma receptors, the present study also investigated the effects of sigma
receptor ligands. The decrease in the seizure threshold of DMCM in diazepam
withdrawn mice was not modified by the sigma receptor agonist, (+)-pentazocine (5
mg/kg, s.c.), or the sigma receptor antagonist, NE-100 (N,N-dipropyl-2-[4-methoxy
3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride; 5 mg/kg, i.p.).
Furthermore, the latency to the expression of wild running induced by
intracerebroventricular administration of NMDA (60 ng/mouse) was also
significantly lower in diazepam-withdrawn mice than in vehicle-treated control
mice. On the other hand, there was no difference in the spermidine concentration
between vehicle-treated control and diazepam-withdrawn mice. In a receptor
binding experiment, the Bmax value for [3H]-MK-801 binding was significantly
increased in cerebrocortical tissues from diazepam-withdrawn mice, while the Kd
value did not change in either group. However, the acute addition of a high
concentration of diazepam (10 and 100 microM) in vitro did not alter [3H]-MK-801
binding in cerebrocortical membrane preparations. The behavioral experiments
suggest that NMDA receptor antagonists may suppress benzodiazepine withdrawal
responses, while the biochemical study reveals upregulation of the NMDA receptor,
which may play an important role in the hypersusceptibility to DMCM-induced
seizure in diazepam-withdrawn mice.
PMID- 9550304
TI - Mitochondrial transmembrane potential and free radical production in excitotoxic
neurodegeneration.
AB - Excitotoxic cell death is involved in many forms of acute and chronic
neurodegeneration. We induced excitotoxic cell death in cultured rat hippocampal
neurons by brief exposure to two selective glutamate receptor agonists with
different neurotoxic potencies, N-methyl-D-aspartate (NMDA) and kainate (KA).
Digital video imaging was performed during exposure to the agonists to monitor
free radical production and changes in mitochondrial transmembrane potential,
psi(m). Brief exposure to NMDA (10 min) induced significant cell death in the
hippocampal neurons reaching a maximum at a concentration of 300 microM (57.2+/
2.6% cell death; P<0.001). In parallel imaging experiments we found that exposure
to NMDA (300 microM, 10 min) induced a significant increase in superoxide
production monitored with the oxidation-sensitive probe, hydroethidine (increase
of 280+/-33% above baseline; P<0.001). Rhodamine-123-based imaging revealed a
loss of psi(m) in 70.1+/-10.1 % of the hippocampal neurons during the exposure to
NMDA. In contrast to NMDA, brief exposure to KA (10 min) produced limited
neurotoxicity reaching a maximum at a concentration of 100 microM (10.2+/-4.0%
cell death; P<0.05). Exposure to KA (100 microM, 10 min) also caused a
significant increase in superoxide production. This increase, however, was
significantly less pronounced than that produced by NMDA (increase of 94+/-17%
above baseline; P<0.001 compared to controls or NMDA-exposed cultures). Moreover,
rhodamine-123-based imaging revealed that KA (100 microM) caused a collapse of
psi(m) in only 13.5+/-1.4% of the hippocampal neurons. In conclusion, the present
study demonstrates that early changes in intracellular superoxide production and
psi(m) relate to neuronal survival outcome in excitotoxic cell death.
PMID- 9550305
TI - Influence of Clostridium botulinum C2 toxin on Fc epsilonRI-mediated secretion
and tyrosine phosphorylation in RBL cells.
AB - We studied the effects of the binary Clostridium botulinum C2 toxin on stimulated
[3H]serotonin release and protein tyrosine phosphorylation in RBL 2H3 hm1 cells.
Actin was specifically ADP-ribosylated by C2 toxin in intact cells resulting in a
2-3 fold increase in antigen- or calcium ionophore (A23187)-induced
degranulation. The effects of C2 toxin were time- and concentration-dependent.
Toxin treatment, which dramatically changes the morphology of RBL cells, was not
sufficient to induce mediator release in the absence of activators of secretion.
Antigen- and A23187-stimulated tyrosine phosphorylation of 60-80 kDa and 110-120
kDa proteins was reduced or blocked after C2 toxin incubation. Treatment of RBL
cells with the tyrosine phosphatase inhibitor pervanadate reversed the inhibitory
effect of C2 toxin on stimulated protein tyrosine phosphorylation indicating
activation of phosphatases by C2 toxin. The data indicate that disassembly of the
actin cytoskeleton by C2 toxin facilitates Fc epsilonRI-mediated signal-secretion
coupling and suggest a role of the actin cytoskeleton in phosphatase regulation
in RBL cells.
PMID- 9550306
TI - Ocular pharmacokinetics of verapamil in rabbits.
AB - Previously, it had been demonstrated that cataract in diabetic rats can be
prevented by systemical administration of the calcium channel blocker verapamil.
In addition to that, 0.125% verapamil eye drops were found to significantly
reduce the intraocular pressure in ocular hypertensive human subjects. The
purpose of this study was to investigate the ocular penetration and elimination
of verapamil after topical administration of the drug in rabbits. Two drops of a
0.125% aqueous solution of RS-verapamil hydrochloride (corresponding to a total
dose of 125 microg RS-verapamil hydrochloride) were administered into the
conjunctival sac. Aqueous humor and blood samples were taken at different times
after administration and analysed for drug concentration by combined gas
chromatography-mass spectroscopy. Following the instillation of 0.125% verapamil
eye drops in a total dose of 125 microg RS-verapamil, mean (+/- SEM) aqueous
humor peak levels of 1607 +/- 272 ng/ml were achieved after 20 min. Mean half
life for the elimination from the aqueous humor was 33 min. Topical application
of verapamil produced very low serum peak concentrations (10.5 +/- 1.3 ng/ml).
The results of our study demonstrate that topically administered verapamil
readily penetrates into the anterior chamber leading to aqueous humor drug levels
in the microM range without producing serum levels that are high enough to cause
cardiovascular side effects.
PMID- 9550307
TI - Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in isolated
rat lung and liver.
AB - The tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK) is a strong lung carcinogen in all species tested. To elicit its
tumorigenic effects NNK requires metabolic activation which is supposed to take
place via alpha-hydroxylation, whereas N-oxidation is suggested to be a
detoxification pathway. The differences in the organ specific metabolism of NNK
may be crucial for the organotropy in NNK-induced carcinogenesis. Therefore,
metabolism of NNK was investigated in the target organ lung and in liver of
Fischer 344 (F344) rats using the model of isolated perfused organs. High
activity to metabolize 35 nM [5-3H]NNK was observed in both perfused organs. NNK
was eliminated by liver substantially faster (clearance 6.9 +/- 1.6 ml/min, half
life 14.6 +/- 1.2 min) than by lung (clearance 2.1 +/- 0.5 ml/min, half-life 47.9
+/- 7.4 min). When the clearance is calculated for a gram of organ or for
metabolically active cell forms, the risk with respect to carcinogenic mechanisms
was higher in lung than in liver. The metabolism of NNK in liver yielded the two
products of NNK alpha-hydroxylation, the 4-oxo-4-(3-pyridyl)-butyric acid (keto
acid) and 4-hydroxy-4-(3-pyridyl)-butyric acid (hydroxy acid). In lung, the major
metabolite of NNK was 4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone (NNK
N-oxide). Substantial amounts of metabolites formed from methyl hydroxylation of
NNK, which is one of the two possible pathways of alpha-hydroxylation, were
detected in lung but not in liver perfusion. Formation of these metabolites (4
oxo-4-(3-pyridyl)-butanol (keto alcohol), and 4-hydroxy-4-(3-pyridyl)-butanol
(diol) can give rise to pyridyloxobutylating of DNA. When isolated rat livers
were perfused with 150 microM NNK, equal to a dosage which is sufficient to
induce liver tumors in rat, glucuronidation of 4-(methylnitrosamino)-1-(3
pyridyl)-1-butanol (NNAL) was increased when compared to the concentration of 35
nM NNK. Nevertheless, the main part of NNK was also transformed via alpha
hydroxylation for this high concentration of NNK.
PMID- 9550308
TI - Effect of nicotine or cotinine on metabolism of 4-methylnitrosamino-1-(3-pyridyl)
1-butanone (NNK) in isolated rat lung and liver.
AB - The scope of the present study was to investigate whether nicotine or cotinine
will affect the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK) in isolated perfused rat lungs and livers and to study the effect of
starvation on pulmonary metabolism of NNK. NNK metabolism was investigated in
isolated perfused liver and lung of male F344 rats perfused with 35 nM [5-3H]NNK
in presence of a 1400-fold excess of the main tobacco alkaloid nicotine and its
metabolite cotinine. In perfused rat livers, nicotine and cotinine inhibited NNK
elimination and metabolism and led to a substantial increase of elimination half
life from 14.6 min in controls to 25.5 min after nicotine and 36.6 min after
cotinine co-administration, respectively. In parallel, the pattern of NNK
metabolites was changed by nicotine and cotinine. The pathway of alpha
hydroxylation representing the metabolic activation of NNK was decreased to 77%
and 85% of control values, whereas N-oxidation of NNK and glucuronidation of 4
(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was increased 2.6- and 1.2
fold in presence of nicotine and cotinine, respectively. When isolated rat lungs
were perfused with 35 nM NNK for 3 h neither the elimination nor the pattern of
metabolites were substantially affected due to co-administration of 50 microM
nicotine or cotinine. Cytochrome P450 2E1 is known to participate in the
activation of NNK and can be induced by starvation. However, isolated rat lungs
from male Sprague Dawley rats perfused with [1-14C]NNK at about 2 microM for 3 h,
revealed only small differences in pulmonary elimination and pattern of NNK
metabolites between fed and starved animals. These results suggest that nicotine
and its main metabolite cotinine inhibit the metabolic activation of NNK
predominantly in the liver whereas activation in lung, a main target organ of NNK
induced carcinogenesis, remained almost unaffected.
PMID- 9550309
TI - Isothiocyanatobenzyl imidazoline is an alkylating agent for I2-imidazoline
binding sites in rat and rabbit tissues.
AB - Isothiocyanatobenzyl imidazoline (IBI), the 4'-NCS analogue of tolazoline, has
been used to alkylate several receptor sites in rabbit iris muscles. Because of
the high affinity of tolazoline for the I2-imidazoline binding sites (Ki = 16-130
nM), this study was designed to assess whether IBI is also an alkylating agent
for these sites. In competition studies, IBI displayed moderate affinity (Ki
approximately 2-3 microM) against I2A-imidazoline sites in the rabbit cerebral
cortex and I2B-imidazoline sites in the rat cerebral cortex labelled by [3H]2-(2
benzofuranyl)-2-imidazoline ([3H]2-BFI). However, preincubation (30 min at 25
degrees C) of rat cortical and liver membranes with IBI (10(-7) M to 10(-3) M),
followed by extensive washing, markedly decreased (17% to 96%) the specific
binding of [3H]2-BFI to I2B-imidazoline sites. IBI (10(-5) M to 10(-3) M) also
bound irreversibly to I2A-imidazoline sites in rabbit cerebral cortex but with a
lesser efficacy (27% to 83% reduction of [3H]2-BFI binding). Saturation curves of
[3H]2-BFI binding in the rat cerebral cortex indicated that preincubation with
10(-6) M IBI reduced the total density (Bmax) without affecting the affinity (Kd)
of I2B-imidazoline sites for IBI. Acute treatments (6 h) with IBI (10 and 30
mg/kg, i.p.) also dose-dependently reduced (26% and 41%; respectively) the total
density of I2B-imidazoline sites. These results demonstrate the ability of IBI to
alkylate I2-imidazoline binding sites in vitro and in vivo and provide evidence
for the use of IBI as a new tool for the study of the functional implications of
imidazoline binding sites.
PMID- 9550310
TI - Unusual expression of S-100 protein in histiocytic neoplasms.
AB - Twenty-nine cases of histiocytic neoplasms, some resembling juvenile
xanthogranuloma (JXG) and others resembling reticulohistiocytoma (RH), were
evaluated. Immunohistochemical stains were performed. In this series, seven cases
were identified that expressed S-100 protein positive cells. The S-100 positive
cells were predominantly large mononuclear and multinucleated histiocytes with
eosinophilic cytoplasm, but also in some cases xanthomatous cells and Touton
giant cells. These cells also expressed a positive reaction for vimentin, KP-1,
and Factor XIIIa. There was no reactivity observed for monoclonal antibody
010(CD1a). A positive reaction for S-100 protein is conventionally accepted as a
useful differentiating feature between histiocytosis X and non-X histiocytosis
such as JXG and RH. The conflicting results of the immunohistochemical stains in
the lesions we studied could be potential pitfalls in diagnosing histiocytic
neoplasms.
PMID- 9550311
TI - Apoptosis and cellular proliferation in human epidermal squamous cell neoplasia.
AB - We examined cell loss (apoptosis) and proliferation in a histopathological
spectrum of epidermal squamous cell neoplasia, including 11 cases of solar
keratosis (SK), 18 Bowen's diseases (BD) and 19 invasive squamous cell carcinomas
(SCC). Apoptotic and proliferative cells were determined by terminal
deoxynucleotidyl transferase (TdT)-mediated dUTP-digoxigenin nick end labeling
(TUNEL) and by the detection of nuclear antigen Ki-67, respectively. Few
apoptotic cells were observed in normal epidermis, while TUNEL index (TI;
percentage of TUNEL-positive cells) was highest for SCCs, followed by BDs and
SKs, in the order given. Although the mean Ki-67 index did not differ between
SCCs and BDs, both disease types showed a significantly higher index than the
SKs. Of SCCs, both TI and Ki-67 index values were significantly higher in poorly
than in well differentiated carcinomas. TI was significantly higher in SCCs
without P53 immunohistochemical expression than in SCCs with P53 expression,
while TI and Ki-67 indices did not correlate with P53 expression in the SKs and
BDs. These results suggest that apoptosis reflects not only cell loss, but also
proliferative activity in the epidermal neoplastic lesions.
PMID- 9550312
TI - Differential expression of connective tissue growth factor gene in cutaneous
fibrohistiocytic and vascular tumors.
AB - Connective tissue growth factor (CTGF) is a member of a family of immediate early
gene products that may play an important role during tissue regeneration, wound
repair and skin fibrosis. In this study, CTGF gene expression in mesenchymal
tumors was investigated by in situ hybridization and CD34 antigen expression was
studied by means of immunohistochemical staining. CTGF mRNA was expressed in
fibroblasts of all nine dermatofibromas examined, but five of seven
dermatofibrosarcoma protuberans (DFSP) or two cases of malignant fibrous
histiocytoma were negative for its expression. In contrast, CD34 antigen was
expressed only in DFSP. In vascular tumors, CTGF mRNA was expressed in pyogenic
granuloma but not in angiosarcoma. In addition, the endothelial cells in
angiolipoma and angioleiomyoma, but not in venous lake, expressed CTGF mRNA.
These vascular lesions were all positive for CD34 expression. Tumors of other
origins were negative for CTGF mRNA. Our findings indicated that benign
fibroblasts and/or vascular endothelial cells have the capability to express CTGF
mRNA when activated, but these cells lose this ability when they achieve
malignant potency. Thus, examination of CTGF gene expression may be useful for
differentiating between benign and malignant mesenchymal tumors, or to determine
the origin of the tumors in connective tissue.
PMID- 9550313
TI - Atypical decubital fibroplasia: a series of three cases.
AB - We report three cases of atypical decubital fibroplasia (ADF), a benign, reactive
pathologic process that develops in the skin and subcutaneous tissue of
immobilized or debilitated patients. Two patients were immobilized, one
wheelchair bound, and one bedridden. The third patient frequently lay over the
affected area. Two were male, one female, ages 49, 66, and 89 (mean 68 years
old). Each patient presented with a subcutaneous mass, one with focal surface
ulceration, present for 5 months, 6 months, and 12 months (mean 7.7 months). The
locations included back, lateral thigh (over greater trochanter), and lateral
chest wall. No other lesions were present, and none had recurrences.
Histologically, atypical decubital fibroplasia is characterized principally by
dermal and subcutaneous tissue involvement with fibrinoid necrosis, reactive
fibrosis, and focal myxoid change with surrounding more cellular zones of
prominent reactive neovascularization including granulation tissue and ectatic
vessels with reactive atypical fibroblasts and fat necrosis. Other findings
include hyalinization of vessel walls, fibrin thrombi, red blood cell
extravasation, hemosiderin deposition, and acute and chronic inflammation.
Although the changes are predominantly deep, involving the dermis, subcutaneous
tissue and skeletal muscle, the overlying epidermis may ulcerate. Recognition of
atypical decubital fibroplasia is of paramount importance, for it may be
misinterpreted as a sarcoma, both clinically and histologically.
PMID- 9550314
TI - Immunohistologic differential diagnosis of basal cell carcinoma, squamous cell
carcinoma, and trichoepithelioma in small cutaneous biopsy specimens.
AB - The distinction between squamoid basal cell carcinoma and basaloid squamous cell
carcinoma (or between BCC and trichoepithelioma variants) is usually made readily
on the basis of defined histological criteria. However, these differential
diagnoses occasionally can pose difficult morphological problems. The stated
distinctions are clinically important because the risk of progressive disease is
significantly higher with squamous carcinoma of the skin than with basal cell
carcinoma (BCC), and a trichoepithelioma misinterpreted as BCC burdens the
patient with an inaccurate diagnosis that may result in inappropriate surgery.
Recent reports have suggested that reactivity with the monoclonal antibody Ber
EP4 is capable of separating histologically similar basal cell and squamous
carcinomas, and that the expression of bcl-2 or CD34 antigen is able to
distinguish BCC from trichoepithelioma. However, corroborative studies of these
contentions are few in number. In order to investigate the usefulness of the
stated immunostains in the above-cited differential diagnoses, the authors
analyzed 45 basal cell carcinomas and 22 squamous carcinomas, as well as 36
trichoepitheliomas. The monoclonal antibodies Ber-EP4, My10 (CD34), and anti-bcl
2 were applied to formalin-fixed paraffin sections in all cases, using a standard
avidin-biotin-peroxidase complex method. Most BCCs demonstrated strong, diffuse
cytoplasmic labeling with Ber-EP4 and anti-bcl-2. In contrast, the squamous
carcinomas were uniformly negative for the former marker and only focally
reactive for the latter in four examples. 'Peripheral' bcl-2 staining of
trichoepitheliomas was noted in 24 of 33 of the immunoreactive tumors, but the
remainder were marked diffusely and similarly to most BCCs. Among the latter,
immature trichoepitheliomas were diffusely reactive for this marker in 6 of 8
cases. Labeling of epithelium for CD34 failed to discriminate between any of the
tumor types under evaluation, whereas staining of peritumoral stroma was
characteristic of the majority of trichoepitheliomas and more than one-third of
metatypical basal cell carcinomas. These data support the suggestion that Ber-EP4
and bcl-2 are useful in the separation of BCC from squamous carcinomas.
Nevertheless, they also serve to caution against reliance upon bcl-2 and CD34
immunostains in attempting to distinguish BCC from trichoepithelioma in
histologically enigmatic cases. There is currently no certain method other than
conventional microscopy that can be applied successfully to the latter problem.
PMID- 9550315
TI - Cutaneous infiltrate of chronic lymphocytic leukemia and relationship to primary
cutaneous epithelial neoplasms.
AB - Chronic lymphocytic leukemia involves the skin in a small percentage of patients
and may portend an ominous prognosis in some patients. We report a series of
eight biopsies from seven different patients in which the cutaneous leukemic
infiltrate was confined exclusively to the region immediately surrounding primary
epithelial neoplasms including squamous cell carcinoma (6), basal cell carcinoma
(1) and actinic keratosis (1). The malignant lymphocytes appear to constitute a
host response to these neoplasms and do not appear to suggest a rapid downhill
course for these patients. These observations serve to 1) suggest a new pattern
of cutaneous involvement by leukemic cells and 2) offer some insights into
potential cellular trafficking patterns of these neoplastic cells.
PMID- 9550316
TI - Detection of human papillomavirus in verrucous carcinoma from HIV-seropositive
patients.
AB - Anogenital squamous cell carcinoma has been noted with increased frequency in HIV
seropositive patients. Verrucous carcinoma is a variant of squamous cell
carcinoma that tends to be locally invasive and non-metastasizing. Although human
papillomavirus (HPV) has been strongly implicated in other squamous neoplasms, it
has been variably associated with verrucous carcinoma and has not been examined
in these lesions in the HIV-positive population. The aim of this study was to
examine the association of HPV with anal verrucous carcinoma in patients with the
human immunodeficiency virus (HIV). HPV DNA in situ hybridization for HPV Types
6/11, 16/18, and 31/33/35 was performed on formalin-fixed, paraffin-embedded
tissue from six cases of verrucous carcinoma and four cases of condyloma
acuminatum in perianal specimens from HIV-seropositive patients. HPV DNA
sequences were identified in five of six cases of verrucous carcinoma and in all
cases of condyloma acuminatum. Of the five verrucous carcinomas that harbored
detectable HPV DNA, four contained HPV 6/11 and two contained HPV 16/18. One
contained both HPV 6/11 and HPV 16/18. All four cases of condyloma acuminatum
were positive for HPV 6/11. One patient included in this series had three
chronologically separate verrucous carcinomas. The initial lesion was negative
for HPV DNA. Subsequent verrucous carcinomas were positive for HPV type 6/11 and
type 16/18, respectively. The data presented support the concept that verrucous
carcinoma in the HIV-seropositive population is associated with HPV, which may
indeed play an important role in its pathogenesis.
PMID- 9550317
TI - Utility of deeper sections and special stains for dermatopathology specimens.
AB - Special (non-hematoxylin and eosin) stains and deeper sections are routinely used
in dermathopathology, although their utility has not been well established. All
cases requiring special stains or deeper sections over a three-month period were
reviewed to see how often these additional studies contributed to accurate
diagnosis. In our series, deeper sections provided diagnostic information to the
pathologist in 37.3% [95% confidence interval (CI) 28-46%] of the cases in which
they were performed. Deeper sections are more likely to provide a more accurate
diagnosis (23.6%, 95% CI 16-32%) rather than establish a new diagnosis not seen
on the original sections (13.6%, 95% CI 7-20%). Their use is especially helpful
in assessing the presence or absence of cutaneous malignancy rather than in
diagnosing inflammatory skin processes. Special stains contributed to the
diagnosis in 21.1% (95% CI 11-32%) of cases. When special stains were performed
to diagnose an infection they were effective in 14.7% (95% CI 6-24%) of the
cases. When special stains were performed to diagnose any other pathologic
processes (neoplasm, inflammation, collagen vascular disease, and amyloid) they
were effective in 31.8% (95% CI 24-44%) of the cases.
PMID- 9550318
TI - Signet-ring squamous cell carcinoma: a case report.
AB - A-50-year-old Hispanic man presented to the dermatology clinic with a 0.6-cm
eroded, erythematous, scaly plaque on the left side of his neck. On shave biopsy,
the lesion was composed of intra-epidermal and invasive dermal cells
characterized by a signet-ring appearance. One area suggestive of typical
squamous cell carcinoma prompted the inclusion of that entity in the differential
diagnosis. Mucicarmine stains were negative, while the extra-vacuolar cytoplasm
focally reacted with periodic acid-Schiff staining, the positive reaction for
which was abolished by diastase, consistent with glycogen. Malignant cells
expressed keratins by reacting to antibodies, Mak6, AE1/AE3, Ker 903, and CAM5.2.
Additionally, weak reactivity occurred with antibodies to CEA and EMA. Tumor
cells did not express S-100, HM-B45, Leu M1, or actin. By ultrastructural
examination, the large vacuoles corresponded to markedly dilated endoplasmic
reticulum. A diagnosis of signet-ring squamous cell carcinoma, a rare form of
cutaneous squamous cell carcinoma which has been described in only one case
report in the last 10 years, was made. Immunohistochemical staining provided
information useful in differentiating this lesion from other clear cell and
signet-ring cell tumors which involve the skin.
PMID- 9550319
TI - Does eccrine hidrocystoma exist?
PMID- 9550320
TI - Cutaneous infiltrates of myelogenous leukemia in association with pre-existing
skin diseases.
PMID- 9550321
TI - Intracellular signal transduction mediated by ligation of MHC class I molecules.
AB - A great deal of knowledge has accumulated regarding signal transduction after
ligation of MHC class I (MHC-I) molecules. In recent years focus has been given
to delineation of the intracellular signal pathways activated after MHC-I
ligation. Activation of tyrosine kinases leading to a rise in the intracellular
free calcium concentration ([Ca2+]i) is the major initial event occurring after
MHC-I ligation of T cells. Curiously, the MHC-I-induced signaling is not
dependent upon the cytoplasmic tail of the MHC-I molecule, suggesting that the
MHC-I molecule induces intracellular signaling through association with other
membrane-embedded molecules. More distal signaling events after MHC-I ligation
includes activation of the Jak/Stat pathway leading to Stat-3 activation, and
activation of the PI3-kinase leading to JNK activation and apoptosis. This review
will sum up what is currently known about signaling induced by ligation of MHC-I.
PMID- 9550322
TI - Genomic structure of PIR-B, the inhibitory member of the paired immunoglobulin
like receptor genes in mice.
AB - The genes encoding the murine paired immunoglobulin-like receptors PIR-A and PIR
B are members of a novel gene family which encode cell-surface receptors bearing
immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and their non
inhibitory/activatory counterparts. PIR-A and PIR-B have highly homologous
extracellular domains but distinct transmembrane and cytoplasmic regions. A
charged arginine in the transmembrane region of PIR-A suggests its potential
association with other transmembrane proteins to form a signal transducing unit.
PIR-B, in contrast, has an uncharged transmembrane region and several ITIMs in
its cytoplasmic tail. These characteristics suggest that PIR-A and PIR-B which
are coordinately expressed by B cells and myeloid cells, serve counter-regulatory
roles in humoral and inflammatory responses. In the present study we have
determined the genomic structure of the single copy PIR-B gene. The gene consists
of 15 exons and spans approximately 8 kilobases. The first exon contains the 5'
untranslated region, the ATG translation start site, and approximately half of
the leader peptide sequence. The remainder of the leader peptide sequence is
encoded by exon 2. Exons 3-8 encode the six extracellular immunoglobulin-like
domains and exons 9 and 10 code for the extracellular membrane proximal and
transmembrane regions. The final five exons (exons 11-15) encode for the ITIM
bearing cytoplasmic tail and the 3' untranslated region. The intron/exon
boundaries of PIR-B obey the GT-AG rule and are in phase I, with the notable
exception of the three boundaries determined for ITIM-containing exons. A
microsatellite composed of the trinucleotide repeat AAG in the intron between
exons 9 and 10 provides a useful marker for studying population genetics.
PMID- 9550323
TI - Heterogeneity of CD44 expression among human B-cell subpopulations.
AB - CD44 is a widely distributed cell surface glycoprotein that participates in a
number of cellular adhesion and signal transduction processes. Germinal center B
cells express very low levels of CD44, whereas their precursors and
differentiation products express much higher levels. In immunofluorescence
studies comparing 20 antibodies classified as being against the hematopoietic
isoform of CD44, one antibody, A1G3, was unreactive with germinal center B cells,
whereas the other antibodies showed low intensity but definite reactivity.
Western blotting and sequential immunoprecipitation studies of lysates from
density-separated lymphocyte fractions showed two bands that were differentially
expressed and reacted differently with A1G3 compared with the other CD44
antibodies. These results suggest that germinal center B cells and non-germinal
center B cells express different forms of CD44. Of 21 malignant B-cell
populations examined, 5 showed reactivity with a "standard" CD44 reagent and
significantly reduced reactivity with A1G3, while one sample showed the opposite
pattern and the remainder were positive for both reagents. Of 10 cell lines
studied, 5 were differentially stained by A1G3 and a standard CD44 antibody. PCR
amplification of reverse transcribed mRNA from sorted human tonsil B-cell
subpopulations and Southern blotting showed that B cells express a number of
splice isoforms of CD44. These results demonstrate that B cells express multiple
forms of CD44; both splice insert isoforms and variants distinguished by A1G3;
the form of CD44 expressed depends on B-cell differentiation state.
PMID- 9550324
TI - Failure of TGF beta1 and IL-12 to regulate human FasL and mTNF alloreactive
cytotoxic T-cell pathways.
AB - The effect of TGFbeta1 and IL-12 on calcium-independent cytotoxic pathways was
investigated. We have previously demonstrated that the regulatory effect of
TGFbeta1 and IL-12 on human alloreative CTL activity was associated with
regulation of perforin and granzyme B gene expression. To determine the effect of
both cytokines on the alternative cytotoxic pathway involving FasL and mTNF, we
first investigated the expression of both molecules on human primary
alloactivated T cells. Our results show that human allostimulated T lymphocytes
express FasL. Cell lysis experiments demonstrate that the FasL cytotoxic pathway
is involved in the killing of specific target cells mediated by human
alloreactive CTL. In addition, allogeneic stimulation induced significant mTNF
expression on both CD4+ and CD8+ responder T cells. Using TNF-sensitive target
cells, we also demonstrate that the mTNF-mediated cytotoxic pathway is involved
in the cytotoxic activity of human primary allostimulated T lymphocytes. Neither
TGFbeta1 nor IL-12 had an effect on FasL or mTNF expression. Furthermore,
addition of TGFbeta1 or IL-12 at the initiation of the MLR had no significant
effect on Fas- and mTNF-mediated cytotoxicity. Taken together, our results
provide a novel insight into the differences between regulation by cytokines of
perforin-dependent and -independent cytotoxic mechanisms. Unlike their role in
the perforin/granzyme B pathway, TGFbeta1 and IL-12 do not appear to mediate any
regulatory effect on FasL and mTNF cytotoxic pathways used by human alloreactive
primary CTL.
PMID- 9550325
TI - Phenotypical and functional characterization of Herpesvirus saimiri-immortalized
human major histocompatibility complex class II-deficient T lymphocytes.
AB - CD8+ T lymphocytes from two unrelated cases of MHC class II deficiency were
immortalized in vitro using Herpesvirus saimiri. In both cases, a lack of
expression of surface MHC class II molecules was ascertained, whereas variable
defects were shown for MHC class I, CD74 (invariant chain) and LAG-3 (an MHC
class II ligand). The functional analysis of both H. saimiri-immortalized T-cell
lines revealed the existence of a proliferation impairment in response to anti
CD3 but not to other surface or transmembrane stimuli. Further characterization
of this functional defect indicated that it was not associated with impaired
early activation events (like calcium flux) but, rather, with certain late
events, like the induction of IL-2. H. saimiri-immortalized T cells may be
valuable in studying the biological role of MHC class II molecules in activated
human T cells.
PMID- 9550326
TI - Human monoclonal antibody with T-cell-like specificity recognizes MHC class I
self-peptide presented by HLA-DR1 on activated cells.
AB - Alloreactive T cells recognize peptides presented in the binding groove of major
histocompatibility complex molecules (MHCs), whereas B cells mainly recognize the
MHCs independent of bound peptides. Here, we demonstrate that the human B-cell
repertoire comprises B cells which can be stimulated during pregnancy to produce
antibodies reacting with MHCs in a way similar to T cells. The human monoclonal
antibody UL-5A1 recognizes DR1(DRA/DRB1*0101) molecules on lymphoblastoid cell
lines only if they co-express HLA-A2 or if they have been loaded with HLA-A2
derived peptides. The effect of the HLA-A2 peptide 105-117 on UL-5A1 reactivity
was specific, time and dose-dependent. Reactivity increased when naturally
processed peptides were removed from DR1 molecules before the HLA-A2 peptide 105
117 was loaded. UL-5A1 reacted specifically with cells that had been activated.
The results imply a role of activation of cells in peptide processing and/or
loading.
PMID- 9550328
TI - HLA-DR and -DQ alleles in Italian patients with melanoma.
AB - Controversial data have been reported about HLA alleles and susceptibility to
melanoma. Our investigation was undertaken to analyze the relationship between
HLA alleles distribution in patients with melanoma and susceptibility to the
tumor, in order to study the possible correlation between HLA class II DQA1, DQB1
and DRB1 genes involved in immune recognition, and melanoma, usually considered a
highly immunogenic tumor. We therefore typed by means of PCR-SSP (sequence
specific primers) 53 Italian patients and 53 healthy random controls coming from
the same geographic area. We observed a decrease of all haplotypes bearing
DQB1*0301, DQB1*0302 and DQB1*0303 alleles but not of haplotype
DRB1*11;DQA1*0501;DQB1*0301. Our results seem to support the hypothesis of a
protective role of some DQ3-bearing haplotypic combinations in melanoma.
PMID- 9550327
TI - HFE codon 63/282 (H63D/C282Y) dimorphism in German patients with genetic
hemochromatosis.
AB - Genetic hemochromatosis (GH) is closely associated with genes of the major
histocompatibility complex (MHC) on chromosome 6. Recently, a candidate gene for
GH, with structural similarities to MHC class I genes, designated HLA-H and
presently named HFE, has been cloned. The HFE gene is localized telomeric to the
MHC and several reports have indicated that the HFE gene is mutated in GH
patients. In the present study we have analyzed the relationship of HFE gene
variants and disease manifestation in GH patients and family members. Fifty-seven
patients with GH, 73 family members and 153 healthy blood donors were studied for
the amino acid dimorphism at codon 63 (His63Asp=H63D) and codon 282 (Cys282Tyr=
C282Y) of the HFE gene. The codon 63 and 282 dimorphism were defined by PCR
amplification of genomic DNA samples and restriction enzyme digestion using
RsaI/SnaBI for C282Y and BclI/MboI for H63D. Ferritin, transferrin serum levels
and total iron-binding capacity were determined prior to therapeutic
intervention. The Tyr-282 substitution occurred in 53 (93%) of patients compared
with 8 (5.2%) of controls (OR=169, P<0.0001). Fifty-one (90%) patients were Tyr
282 homozygous. In contrast, the Asp-63 substitution was present in 5 (8.8%) of
the patients compared with 34 (22%) of controls (OR=0.39, P=NS) with none of the
patients being homozygous. In Tyr-282 homozygous GH patients serum ferritin
levels, transferrin saturation, liver iron and liver iron index were elevated
significantly compared to Tyr-282-negative patients, whereas no difference was
observed between Tyr/Cys-282 heterozygous and Tyr-282-negative patients.
PMID- 9550330
TI - Major histocompatibility complex class II alleles in an Uygur population in the
Silk Route of Northwest China.
AB - HLA class II (DRB1, DQA1, DQB1 and DPB1) genotyping was performed in 57 unrelated
Uygur individuals inhabiting the northwestern China area by the polymerase chain
reaction-restriction fragment length polymorphism (PCR-RFLP) method. Among 98
DRB1 alleles tested, 23 alleles were detected, and DRB1*0701 (16.7%) and
DRB1*0301 (14.0%) were the most and the second most common alleles, respectively.
In 8 DQA1 alleles detected, DQA1*05 (26.3%), DQA1*03 (21.9%) and DQA1*0201
(21.1%) were very frequent. Of 21 DQB1 alleles tested, 13 were observed. Among
them, DQB1*02 was highly predominant with the gene frequency of 32.5%. Of 46 DPB1
alleles tested, 15 were detected, among which DPB1*0401 (31.6%) was the most
frequent. Two haplotypes predominate clearly; DRB1*0701-DQA1*0201-DQB1*02 (15.5%)
and DRB1*0301-DQA1*05-DQB1*02 (12.6%). The dendrogram constructed by the
neighbour-joining (NJ) method based on the allele frequencies of the DRB1, DQA1,
DQB1 and DPB1 genes of 13 representative populations all over the world suggested
that Uygur belonged to the Asian group and lay at the closest genetic distance to
a Kazak population inhabiting the same area.
PMID- 9550329
TI - Association between autoantibody markers and subtypes of DR4 and DR4-DQ in
Swedish children with insulin-dependent diabetes reveals closer association of
tyrosine pyrophosphatase autoimmunity with DR4 than DQ8.
AB - HLA DQA1*0301-DQB1*0302 (DQ8) and DQA1*0501-DQB1*0201 (DQ2) are positively and
DQA1*0102-DQB1*0602 (DQ6) negatively associated with IDDM. In DQA1*0301-DQB1*0302
(DQ8)-positive patients, susceptibility is also mediated by DRB1*0401. The aim of
the study was to determine the association between HLA-DR4 and DQ and the
presence of GAD65, ICA512, and insulin autoantibodies as well as ICA in 425
Swedish children with IDDM and 367 controls in the age group of 0-15 years. We
found that ICA512 autoantibodies were associated primarily with DRB1*0401 and not
with DQA1*0301-DQB1*0302 (DQ8). No such hierarchy could be demonstrated for
insulin autoantibodies, which were associated with both DQA1*0301-DQB1*0302 (DQ8)
and DRB1*0401. GAD65 autoantibodies, known to be closely associated with
DQA1*0501-DQB1*0201 (DQ2)-DRB1*0301 haplotype, also showed no preferential
association with DQA1*0301-DQB1*0302 (DQ8) versus DRB1*04. These results suggest
that the immune response to different beta-cell autoantigens may be mediated via
HLA class II molecules from different loci. Design of the antigen-specific immuno
intervention trials should take into account these HLA-DR and DQ subtype
associations.
PMID- 9550332
TI - Soluble HLA class I and class II antigens in patients with multiple sclerosis.
AB - Soluble HLA class I (sHLA-I) and soluble HLA class II (sHLA-II) antigen levels
during different stages of disease were investigated in paired serum and
cerebrospinal fluid (CSF) samples from 37 patients with multiple sclerosis (MS)
using ELISA and Western blot analysis. Soluble HLA-II antigens in the serum of
untreated patients with the relapsing-remitting type of MS (RRMS) were found to
be significantly elevated in acute relapse as compared to values obtained from
patients under steroid treatment, in remission or healthy controls. No
significant differences in circulating sHLA-I levels could be detected. In
contrast, a trend towards increased intrathecal production of sHLA-I molecules in
the CSF was observed in untreated RRMS patients in acute relapse, whereas the
levels of soluble HLA-II antigens in the CSF were below the detection limit of
the ELISA method. Our observations underline the presence of systemic immune
activation in MS patients, as reflected in elevated serum sHLA-II antigen levels,
and reveal a dichotomy between sHLA class I and II antigen production in the
peripheral blood versus CSF in acute MS. Serial measurements of sHLA-II antigen
levels might represent a non-invasive method to assess disease activity in MS
patients.
PMID- 9550331
TI - Allele-specific HLA-B*15 typing by PCR-SSP and its application to four distinct
ethnic populations.
AB - We present a set of primer mixes for the allele-specific typing of the HLA-B*15
group by PCR-SSP. The set comprises 46 primer mixes which are designed to
unequivocally resolve all but two of the 666 possible combinations of the B*15
alleles, B*1501-37 (B*1536 sequence unavailable). A core subset of 34 of the 46
mixes can be used alone to give a high resolution B*15 typing set. This allows
for the identification of each B*15 allele when present as the only B*15 allele
and the majority of the possible B*15 homozygotic combinations. The method was
validated using reference DNA samples and the B*15 allele frequency in 4 distinct
ethnic populations was investigated. The results show that these populations
contain predominantly mutually exclusive sets of B*15 alleles.
PMID- 9550333
TI - Extended HLA haplotypes in Japanese homozygous typing cells.
AB - We have defined extended HLA haplotypes including the HLA class II genes, the non
HLA genes such as TAP1, TAP2 and LMP2, and the (CTG)n microsatellite repeats
within the NOTCH4 gene between DRA and 21OH in 33 Japanese HLA homozygous typing
cells (HTC). These conserved haplotypes characterized by unique linkage might be
maintained as a result of functional co-operation among them in the antigen
presentation pathway. These HTCs can be served as an original and ethnic-specific
standard panel, providing useful genetic markers in haplotypic diversity, disease
association, and anthropology studies.
PMID- 9550334
TI - MICA exon 5 microsatellite typing by DNA heteroduplex analysis: a new
polymorphism in the transmembrane region.
AB - MICA (MHC class I chain-related gene A) is localized 47 kb upstream from HLA-B on
the short arm of chromosome 6. It has been postulated that MICA protein folds
similarly to the class I chain and may have the capacity to bind short ligands.
Short tandem repeats (STR) within the transmembrane (TM) region of this gene have
been described and five alleles consisting of 4 to 9 GCT codons, each encoding an
alanine residue have been defined. We have applied DNA heteroduplex analysis to
type MICA trinucleotide repeats in order to develop a simple and reliable method
for their identification. This approach allowed the characterization of all MICA
alleles. Moreover, a new polymorphism within the TM region was identified.
PMID- 9550335
TI - HLA-A*02172* adds to the heterogeneity of HLA-A*02 alleles.
PMID- 9550336
TI - Nomenclature for factors of the HLA system, update September/October 1997.
PMID- 9550337
TI - Nomenclature for factors of the HLA system, update November/December 1997.
PMID- 9550338
TI - Parameters and symbols for use in nuclear magnetic resonance (IUPAC
recommendations 1997).
AB - NMR is now frequently the technique of choice for the determination of chemical
structure in solution. Its uses also span structure in solids and mobility at the
molecular level in all phases. The research literature in the subject is vast and
ever-increasing. Unfortunately, many articles do not contain sufficient
information for experiments to be repeated elsewhere, and there are many
variations in the usage of symbols for the same physical quantity. It is the aim
of the present recommendations to provide simple check-lists that will enable
such problems to be minimised in a way that is consistent with general IUPAC
formulation. The area of medical NMR and imaging is not specifically addressed in
these recommendations, which are principally aimed at the mainstream use of NMR
by chemists (of all sub-disciplines) and by many physicists, biologists,
materials scientists and geologists etc. working with NMR. The document presents
recommended notation for use in journal publications involving a significant
contribution of nuclear magnetic resonance (NMR) spectroscopy. The
recommendations are in two parts: (1) Experimental parameters which should be
listed so that the work in question can be repeated elsewhere. (2) A list of
symbols (using Roman or Greek characters) to be used for quantities relevant to
NMR.
PMID- 9550339
TI - Molecular dynamics in solid L-adrenaline by proton NMR.
AB - Proton NMR measurements of the spectrum, second moment, spin-lattice relaxation
time T1 and dipolar relaxation time T1D were carried out on polycrystalline L
adrenaline at 14 and 25 MHz between 55 and 400 K. Between 70 K and 250 K
relaxation is dominated by C3 reorientation of the single methyl group in each
molecule, characterized by an activation energy 8.3+/-0.3 kJ/mole. Below 70 K
tunnelling assisted relaxation is significant, characterized by an excitation
energy of 1.9+/-0.2 kJ/mole. Above 250 K an additional molecular motion becomes
significant, with activation energy above 28 kJ/mole, attributed to
conformational motion of the methylene group in the ethylamine side chain.
PMID- 9550340
TI - 13C CP MAS NMR study of 6-O-(beta-D-glucopyranosyl)- and 6-O-(beta-D
mannopyranosyl)-d-alpha-tocopherols.
AB - 13C NMR CP MAS data for three glycosyl alpha-tocopherol derivatives are reported.
The values of delta = delta(solution) - delta(solid state) provided information
about rigid and conformationally flexible fragments of alpha-tocopherol molecule
and the sugar moieties.
PMID- 9550341
TI - Five quantum coherence of I=5/2 nuclei: 27Al in polycrystalline AlCl3.
AB - Optimal conditions were calculated for the excitation and detection of the five
quantum coherence of quadrupolar nuclei with I = 5/2 in powder samples, observed
by the two-pulse sequence (theta1)x - tau1 - (theta2)alpha - tau2, where alpha is
the phase cycling angle. We varied the pulse lengths and the relative values of
the nutation frequency omega1 = gammaB1 and the quadrupolar frequency omegaQ.
Also, the effect of the resonance offset was studied under optimal conditions.
Besides, the conditions for obtaining the maximal echo amplitude after the two
pulse sequence with alpha = y were found. Theoretical results were compared with
experiments on 27Al nuclei in polycrystalline AlCl3.
PMID- 9550342
TI - Time symmetry: an application to shaped pulse excitation of spin-1 systems.
AB - The role of time symmetry in the design of amplitude-modulated (shaped) pulses
for spin-1 excitation is examined. The quaternion calculus is used to calculate
the quaternion elements (Euler-Rodrigues parameters) of each shaped pulse. In
this manner, it is shown how the simplicity and compactness of the Euler
Rodrigues parametrization can be used to significantly expedite a computer search
for optimal time-symmetric shaped pulses. Theoretical and experimental tests of a
new class of symmetric quadrupole-shaped (SQUASH) pulses identified by this
procedure show a significant improvement in both excitation bandwidth and
efficiency in comparison to the time-asymmetric QUASH shaped pulse previously
identified.
PMID- 9550343
TI - 1H/27Al TRAPDOR NMR studies on aluminum species in dealuminated zeolites.
AB - Aluminum species in several dealuminated zeolites (ultrastable HY, HZSM-5 and
mordenite) were investigated in detail by means of the newly introduced 1H/27Al
TRAPDOR method in combination with 27Al MAS NMR, and the quadrupole coupling
constants (Q[CC]s) for aluminum atoms associated with these species were
obtained. A signal at ca. 6.8 ppm, due to water molecules adsorbed on Lewis acid
sites, was observed in the 1H MAS spectra for all the three zeolites. The TRAPDOR
NMR provides direct evidence that there is a strong interaction between the
adsorbed water molecules and the aluminum atoms of the Lewis-acid sites. The
Q(CC) values for this aluminum species of 8.3, 6.7 and 11.3 MHz were determined
from the TRAPDOR profiles for the ultrastable HY, HZSM-5 and mordenite zeolites,
respectively. The Q(CC)s calculated from the TRAPDOR curves are usually larger
than 10 MHz for both Bronsted-acid sites (SiOHAI) and non-framework aluminum
species in the three zeolites. Three narrow peaks at 54, 30 and 0 ppm are
separately superimposed on a broad hump in the 27Al MAS spectra of the three
dehydrated zeolites, while the latter is associated with the 'NMR invisible' Al.
The NMR experimental results suggest that the three kinds of aluminum species
(non-framework aluminum species, Bronsted- and Lewis-acid sites) are all
responsible for the resonance of the broad hump in dehydrated zeolites, which
makes it difficult to explain the 27Al MAS spectra. Fortunately, the TRAPDOR NMR
provides a direct method for individually studying different aluminum species
with large Q(CC)s via their dipolar coupling to nearby proton nuclei.
PMID- 9550344
TI - Methyl tunnelling, reorientation and NMR relaxation in solid acetates.
AB - Rotational excitations of methyl groups in six solid acetates have been
investigated by 1H nuclear magnetic resonance (NMR) relaxation time measurements
at 15 MHz and 30 MHz and at temperatures between 10 K and the melting point.
Hindering barriers between 1.6 kJ/mol and 3.7 kJ/mol have been found that could
be correlated to the tunnelling frequencies observed by inelastic neutron
scattering. A consistent description of the relaxation rate dependences from the
classical regime at high temperatures to the quantum-mechanical regime at low
temperatures is possible by Haupt's equation. The rotational potentials are
mainly determined by inter-molecular interaction with an important influence of
water of crystallization, if present.
PMID- 9550345
TI - 23Na NMR studies of Na-DNA in the solid state.
AB - 23Na MAS, CP/MAS and quadrupole nutation NMR spectra and the 23Na spin-lattice
relaxation times in Na-DNA with and without competing species (Mg2+, ethidium
bromide and [Ru(phen)3]2+) reveal the presence of two sodium sites with different
NMR parameters. While in the presence of Mg2+, sodium resides far from the
surface of the DNA molecule, ethidium bromide and [Ru(phen)3]2+ displace sodium
closer towards the surface.
PMID- 9550346
TI - Conventions for tensor quantities used in NMR, NQR and ESR.
PMID- 9550347
TI - Effect of topical cyclosporin A on Thygeson's superficial punctate keratitis.
AB - Thygeson's superficial punctate keratitis (Thygeson's SPK) is a distinct clinical
entity, characterized by round conglomerates of discrete, granular, white-gray,
fine intraepithelial dots without conjunctival involvement. The only effective
treatment with regard to relieving symptoms and diminishing lesions has been
topical corticosteroids, but their prolonged use can be associated with severe
side-effects. The purpose of this study is to present the long-term results of
the use of 2% topical cyclosporin A in olive oil in Thygeson's SPK. Eight
patients diagnosed as having Thygeson's SPK were included. All the patients were
treated with 2% cyclosporin dissolved in olive oil four times a day for three
months, and two times a day for one month before withdrawing therapy. The follow
up period ranged from twelve to twenty-five months. The number of corneal lesions
varied between 5 and 15 before treatment. After cyclosporin treatment, no corneal
lesion was observed and the cornea remained clear after the follow-up period. In
conclusion, 2% cyclosporin in olive oil is a safe alternative to corticosteroids
in the treatment of Thygeson's SPK, and resulted in satisfactory control of the
condition.
PMID- 9550348
TI - Measuring contrast sensitivity in aretinopathic patients with Insulin Dependent
Diabetes Mellitus.
AB - Contrast sensitivity measurements were obtained from 66 patients with Insulin
Dependent Diabetes Mellitus (IDDM) and no visible diabetic retinopathy (Group A,
n = 30 prepubescent and pubescent subjects; Group B, n = 36 postpubescent
subjects). Contrast thresholds were determined for stationary and 6.87 Hz phase
alternating gratings at eight spatial frequencies from 0.18 to 15.7 c/deg. Data
from each group of diabetic patients was compared with data from puberty-matched
normal subjects. Mean value of the last four determinations of glycohemoglobin
Alc (HbAlc) was used as a index of glycemic control. We found that patients with
IDDM and no retinopathy had normal contrast sensitivity and that contrast
thresholds were not significantly related to sexual maturity, duration of
diabetes and glycemic control.
PMID- 9550349
TI - Comparative experimental study of 10% and 15% medical gelatin in the anterior
chamber and in the posterior eye segment as a viscosubstance in the viscosurgery.
AB - This article discusses the possibility of application of 15% medical gelatin
solution compared to 10% medical gelatin solution in the anterior chamber and in
the posterior eye segment as a viscosubstance in the viscosurgery. The
experimental investigations were performed on 24 Chinchilla rabbits, divided in
two groups consisting of 12 each. 0.5 ml of 10% and 15% of medical gelatin were
injected in the anterior chamber and 2 ml of 10% and 15% medical gelatin were
injected in the vitreous body of the tested eyes. 2% methyl cellulose and 0.89%
Sodium Chloride were injected in the vitreous body of the control eyes. Clinical,
biomicroscopical, ophthalmoscopical, tonometrical, histological and electron
microscopical examinations were performed. It was established that when the eyes
were injected with 10% and 15% medical gelatin, as well as with 0.89% Sodium
Chloride, the intraocular pressure was not increased but when the eyes were
injected with methyl cellulose the intraocular pressure was increased. We also
found that 15% of medical gelatin has longer effect than 10% medical gelatin.
Toxoallergic and inflammatory changes were not observed in the eyes injected with
10% and 15% medical gelatin. In the same eyes, histologically and by electron
microscopy, were not found any changes in the layers of the cornea and retina.
These substances could be used as viscosubstances and as instruments in surgical
interventions of the anterior eye segment and in the posterior eye segment
(vitrectomy).
PMID- 9550350
TI - Malondialdehyde serum concentration in type 1 diabetic with and without
retinopathy.
AB - Lipid peroxides are thought to be formed by free radicals and have been
implicated in the pathogenesis of diabetes complications. A convenient and
sensitive method for estimation of lipid peroxide concentration is the
quantitative estimation of their metabolic end-product malondialdehyde (MDA)
expressed in mmol/L using the thiobarbituric acid test (TBA-test). We have
measured the serum concentrations of MDA in 60 well controlled type I diabetic
patients (28 without retinopathy and 32 with retinopathy) and 13 age-matched
healthy subjects. Patients with retinopathy showed significantly increased MDA
level (2.65+/-1.00) compared to diabetics without retinopathy (1.80+/-0.81) and
healthy controls (1.47+/-0.45). The serum levels of MDA correlated best with
glycosylated haemoglobin (r=0.28), serum triglyceride concentration (r=0.29) and
serum cholesterol concentration. (r=0.47). Increased lipid peroxides suggesting
increased free radical activity is associated with retinopathy and this may have
pathogenetic implications.
PMID- 9550351
TI - Effects of allopurinol on free-radical-induced reduction of the proliferation of
retinal pigment epithelial cells.
AB - PURPOSE: To investigate the effects of allopurinol on free-radical-induced
reduction of growth of retinal pigment epithelial (RPE) cells. METHODS: Bovine
RPE cells were seeded at a density of 1 x 10(5) cells/Petri dish (60 x 15 mm)
containing 4 ml MEM-Earle plus 15% FCS plus antibiotics. Twenty-four hours after
seeding, cultures were exposed to a free radical generating system
hypoxanthine(HX)/xanthine oxidase (XO) (HX: 0.1 micromol/l; XO: 700 microU/ml)
for 10 or 60 min. Thereafter, the cells were washed. After washing the cells,
allopurinol was added at 500 or 1000 micromol. To evaluate the effect of the
radical generating system one group was not washed after treatment ('no wash').
The cultures were divided into eight groups: (1) no treatment (control); (2)
HX/XO, no wash; (3,4) HX/XO, washed after 10 or 60 min; (5,6) HX/XO, washed after
10 or 60 min, application of 500 micromol of allopurinol; (7,8) HX/XO, washed
after 10 or 60 min, application of 1000 micromol of allopurinol. Cell counts were
carried out 96 h post-seeding. The values are expressed as means +/- SE. RESULTS:
After 72 h (HX/XO, no wash), the radical generating system resulted in a
significant decrease in cell growth as compared to controls. When being
eliminated after 10 or 60 min, the radical generating system also led to
significant decrease in the values as compared to controls. Allopurinol
treatment: All therapy (scavenger) groups (4,5) were significantly different from
the respective control group; following exposition to the radical generating
system for 60 min, allopurinol showed significantly higher values when given at
1000 micromol as compared to 500 micromol. CONCLUSIONS: The results demonstrate
that allopurinol, when given at a scavenger dose (500-1000 micromol), can prevent
free-radical-induced cell damage and stop chain reactions. Thus, the possible
beneficial value of allopurinol on diseases with involvement of oxidative tissue
damage, such as age-related macular degeneration, should be investigated further.
PMID- 9550352
TI - Clinical experience with cyanoacrylate tissue adhesive.
AB - In this paper 385 cases treated with cyanoacrylate tissue adhesive during the
years 1980-1995 are studied. The indications, outcomes and complications of
cyanoacrylate adhesive are investigated and the results are analysed. It is
encouraging that except for three cases of ocular hypotony and two cases of
microbial infection no other complications occurred. Even in desperate cases with
corneal perforation greater than 3 mm and ocular infection, enucleation was
avoided. The early use of a bandage contact lens, inserted just after the glue
application and the coverage with topical antibiotics switched every 15 days
until the removal of the glue, may explain the small incidence of infection. Our
experience from the use of cyanoacrylate tissue adhesive in cases with corneal
perforation greater than 3 mm is very encouraging. In these cases a running 10.0
nylon suture was used to create a reticulum over the space of the corneal
perforation upon which the glue was applied. The use of cyanoacrylate tissue
adhesive offers to the clinician a safe technique for healing corneal wounds that
avoids tectonic penetrating keratoplasty with its associated complications.
PMID- 9550353
TI - Cytidin-5'-diphosphocholine enhances the effect of part-time occlusion in
amblyopia.
AB - Cytidin-5'-diphosphocholine (CDP-choline) has been shown to improve visual acuity
(VA), Contrast Sensitivity and Visual Evoked Responses at least temporarily, in
amblyopic patients beyond the plastic period of the visual system. In this paper
results are presented of a study conducted on forty-five patients with amblyopia
in one eye, aged 5-9 years and followed for one year. Of them, 15 (Group A) were
treated with CDP-choline (500 mg daily for 10 days every six months); 15 (Group
B) were treated with CDP-choline plus one hour of occlusion daily; 15 (Group C)
were treated with one hour of occlusion daily. The final VA values were
statistically different from the initial ones, for all three groups. Eleven of
the Group A patients showed an improvement in VA after the first treatment; a
gradual deterioration took place in 6 patients at the end of the fourth month; VA
further improved in 9 patients after the second treatment. At the end of the
year, VA was higher than at the beginning in 12 of the 15 patients. Group B had
an improvement of VA in 13 patients, starting 10 days from the beginning of
treatment. This improvement continued throughout the observation period. Group C
had an improvement after one month, which continued for 8 months, without
deteriorating. In conclusion CDP-choline enhances the effect of part-time
occlusion. CDP-choline could be employed also in younger patients. Longer
observation periods are still needed and better means of administration have to
be found.
PMID- 9550354
TI - A new electromechanical method for measuring intraocular pressure.
AB - A new electromechanical method to measure intraocular pressure is presented. A
light probe was made to collide with an eye (cornea or sclera) and to bounce
back. The impact was registered by an acceleration sensor or the duration of
contact with the eye was measured using the phenomenon of the electrical
conductivity of biological objects. Laboratory experiments were carried out using
pig eyes pressurized with water leveled to different heights. Preliminary
clinical trials were carried out comparing the values obtained with those of the
Goldmann applanation tonometer. The time of contact and the deceleration time
decreases and the deceleration maximum increases in proportion with IOP. A new
kind of tonometer can be constructed based on this principle. Measurement can be
performed to cornea or sclera without an anesthetic drop. Further study is
required to evaluate the accuracy and usefulness of this method.
PMID- 9550355
TI - Lumping and splitting: molecular biology in the genetics clinic.
PMID- 9550356
TI - Frequency analysis of autosomal dominant cerebellar ataxias in Japanese patients
and clinical characterization of spinocerebellar ataxia type 6.
AB - Using a molecular diagnostic approach, we investigated 101 kindreds with
autosomal dominant cerebellar ataxias (ADCAs) from the central Honshu island of
Japan, including spinocerebellar ataxia type 1 (SCA1), spinocerebellar ataxia
type 2 (SCA2), Machado-Joseph disease (MJD), dentatorubral and pallidoluysian
atrophy (DRPLA) and spinocerebellar ataxia type 6 (SCA6). In our unselected
series, MJD was the most common type of ADCA, accounting for 33.7% followed by
DRPLA (19.8%), SCA2 (5.9%) and SCA6 (5.9%). No SCA1 mutations were identified. We
analysed the clinical features of six molecular confirmed SCA6 kindreds: in each
family, there was an expanded allele in the alpha1A-voltage dependent calcium
channel comprising between 23 and 25 CAG repeats. The mean age at onset of
symptoms was 43+/-13 years. The clinical features consisted predominantly of
cerebellar ataxia, dysarthria and horizontal nystagmus, which was generally
consistent with ADCA type 3. However several new clinical features were found in
some patients: dramatic anticipation, rapid disease progression, severe ataxia
associated with action tremor or action myoclonus, and very early onset, which
are not described as the classical features of ADCA type 3.
PMID- 9550357
TI - Genotype-phenotype correlation in myotonic dystrophy.
AB - Myotonic dystrophy (DM) is caused by a mutation in the length of a trinucleotide
(CTG) repeat in the 3' untranslated region of the myotonin protein kinase gene
located on chromosome 19q13.3. The normal gene has between 5 and 36 CTG
trinucleotide repeats, whereas minimally affected individuals have 50 copies and
severely affected DM-patients have several thousands of such repeats. Since no
information on a genotype phenotype correlation in Austrian DM-patients is
available, we examined a small group of these patients for the unstable
trinucleotide repeat. Molecular analysis was used to clarify equivocal clinical
diagnoses and confirm clinical findings. We studied eight DM-families, a total of
57 individuals, of whom 18 were diagnosed with a trinucleotide repeat expansion.
Twenty-six unrelated individuals served as a control. Clinical assessment was
based on the muscular disability rating scale (MDRS) and a sum of symptoms score
(SSS). There was a significant correlation between the clinical scores (MDRS:
Spearman r = 0.51; p = 0.029: SSS: Spearman r = 0.538; p = 0.0259) used and the
size of the amplification of the trinucleotide repeat. The largest expansion
found in our group of patients was 6 kb. Furthermore, we observed both expansion
and contraction of the enlarged fragment during transmission from one generation
to the next.
PMID- 9550358
TI - The Asn9 variant of lipoprotein lipase is associated with the -93G promoter
mutation and an increased risk of coronary artery disease. The Regress Study
Group.
AB - Two mutations in the lipoprotein lipase (LPL) gene, a T to G transition at
position -93 of the proximal promoter region and an Asp9Asn substitution in exon
2, were examined in 762 Dutch males with angiographically-diagnosed coronary
artery disease (CAD) and 296 healthy normolipidemic Dutch males. The two
mutations exhibited strong linkage disequilibrium (D' = 0.975). A significantly
higher proportion of cases (4.86%) than controls (1.37%) carried the -93G/Asn9
allele (p = 0.008). In the combined sample of cases and controls, adjusted mean
plasma total cholesterol (TC) levels were significantly higher in -93G/Asn9
carriers (6.20+/-0.13 mmol/l) than in non-carriers (5.93+/-0.03 mmol/l; p =
0.048), while mean high-density lipoprotein cholesterol (HDL-C) levels were lower
in carriers (0.88+/-0.03 mmol/l) than in non-carriers (0.98+/-0.01 mmol/l; p =
0.002). There was a trend towards higher triglyceride (TG) levels in carriers
(1.96+/-0.14 mmol/l) compared with non-carriers (1.73+/-0.03 mmol/l) (p = 0.08).
Additionally, carrier frequencies in tertiles of TC, HDL-C, TG, and LPL activity,
suggested an association of the -93G/Asn9 variant with higher TC and TG levels,
and with lower HDL-C and LPL activity levels. Logistic regression revealed a
significant odds ratio (OR) for the combined -93G/Asn9 genotype in CAD cases
relative to controls (OR: 5.36; 95% CI: 1.57-18.24), with age, body mass index
(BMI), smoking, and plasma total- and HDL-cholesterol levels included in the
model. In conclusion, we show that the LPL Asp9Asn mutation is in non-random
association with a T G substitution at position -93 of the proximal promoter
region and that the combined -93G/Asn9 genotype predisposes to decreased HDL-C
levels and an increased risk of CAD.
PMID- 9550359
TI - A clinical, cytogenetic and molecular study of ten probands with supernumerary
inv dup (15) marker chromosomes.
AB - Ten probands with moderate to severe developmental delay were found to have a
supernumerary inv dup (15) chromosome. These patients and their families were
studied by both cytogenetic and molecular methods. Cytogenetic polymorphisms
associated with the 15p short arm suggested a maternal derivation for the marker
chromosome in all informative cases. One marker was directly maternally
inherited. Molecular analysis employing Southern blotting and polymerase chain
reaction (PCR) of microsatellite repeats demonstrated the presence of extra
alleles in the 15q11q13 region. All ten of the probands demonstrated an extra
band at one or more locus without recourse to densitometry. All of the inv dup
(15) markers were comparable in size to a G group chromosome but there were
differences in the positions of the breakpoints in 15q. There was an inconsistent
relationship between marker size, gene dosage and severity of phenotype.
PMID- 9550360
TI - Complete identification of cystic fibrosis transmembrane conductance regulator
mutations in the CF population of Saguenay Lac-Saint-Jean (Quebec, Canada).
AB - Over the past few years, we have conducted a systematic study of 230 cystic
fibrosis (CF) chromosomes in the Saguenay Lac-Saint-Jean (SLSJ) population which
has a high CF incidence (1/936 live births). We identified 11 mutations
accounting for 100% of the CF chromosomes found in patients born in SLSJ. Our
results indicate that denaturing gradient gel electrophoresis (DGGE) is a
powerful method of identifying CF mutations. They have also considerable
implications for genetic counselling and molecular characterization of doubtful
patients. They make carrier screening technically feasible in this population.
PMID- 9550361
TI - The incidence of cystic fibrosis in Scotland calculated from heterozygote
frequencies.
AB - The incidence of cystic fibrosis (CF) has previously been calculated from
epidemiological surveys and from neonatal screening. With the cloning of the CF
gene it has become possible to derive incidence figures from heterozygote
frequencies, provided that the distribution of mutant alleles among healthy
carriers is the same as among affected people. We have estimated the allele
frequencies for four CF mutations, AF508, G551D, G542X and R117H, in 14360
unselected women undergoing antenatal heterozygote screening. The proportion of
R117H, an allele of known mild effect, was much greater for heterozygotes than
for homozygotes. The incidence of CF was therefore calculated from the
heterozygote frequencies of AF508, G551D and G542X in a larger cohort of 27 161
successively screened women. The point estimate for the incidence of CF in the
Scottish population was 1 in 1984, with 95% confidence intervals of 1 in 1692 to
1 in 2336.
PMID- 9550362
TI - Severe cystic fibrosis associated with a deltaF508/R347H + D979A compound
heterozygous genotype.
AB - This report is concerned with twins with cystic fibrosis (CF). They are of mixed
parentage: Japanese mother and German father. One case is presented with meconium
ileus as a neonate. The other patient did relatively well until the age of 6
years when she was first hospitalized and diagnosed with pulmonary aspergillosis.
They have been receiving standard therapies for CF including digestive enzymes,
vitamins and periodic antibiotic therapy in the US. At 19 years of age, they were
tested for common mutations and one AF508 cystic fibrosis transmembrane
conductance regulator (CFTR) allele was found. Further testing of their CFTR gene
as well as those of their Japanese mother and grandmother revealed missense
mutations in exon 7 (R347H) and exon 16 (D979A). Although the D979A mutant is
very rare, this mutation combination seemed to be responsible for severe CF
phenotypes.
PMID- 9550363
TI - Association between asthma and an intragenic variant of CC16 on chromosome 11q13.
AB - The beta subunit of high affinity immunoglobulin E (IgE) receptor
(FcepsilonRIbeta) and the Clara cell derived inflammatory molecule, CC16 have
been cited as candidate genes for atopic asthma on chromosome 11q13. A genetic
association study was performed with an intragenic microsatellite repeat of CC16
gene on chromosome 11q12-13 in relation to atopic and non-atopic asthma. Whereas
variants of FcepsilonRIbeta at chromosome 11q13 show association with atopy and
asthma, no significant association was found between asthma and CC16 genotypes
irrespective of atopic status. These data support the candidacy of
FcepsilonRIbeta rather than CC16 for the atopic asthma locus on chromosome 11q.
PMID- 9550364
TI - ACTH receptor mutation in a girl with familial glucocorticoid deficiency.
AB - Familial glucocorticoid deficiency (FGD) has long been recognised as a clinical
entity, but molecular studies have so far been performed in only a few
individuals. We describe a girl born to consanguineous Pakistani parents with
clinical and biochemical features of FGD who is homozygous for the R146H mutation
of the adrenocorticotropic hormone (ACTH) receptor gene. This mutation creates a
new restriction enzyme site in the ACTH receptor gene, allowing accurate
characterisation of the mutation without DNA sequencing. Our patient is the third
child reported to be homozygous for the R146H mutation. Interestingly, she has a
tall stature, a clinical finding reported in several children who have ACTH
insufficiency and mutations of the ACTH receptor gene. We suggest that mutation
analysis of the ACTH receptor gene be considered in children with clinical
features of FGD and tall stature.
PMID- 9550365
TI - 22q11.2 deletions in a series of patients with non-selective congenital heart
defects: incidence, type of defects and parental origin.
AB - Previous studies have indicated a wide spectrum of incidences of 22q11.2
deletions in isolated and syndromic (sporadic or familial) cases of conotruncal
heart defects, whereby the detection rate of the deletion varied from 65% in one
study to 0 in another. We analysed 110 patients with non-selective syndromic or
isolated non-familial congenital heart malformations by fluorescence in situ
hybridization (FISH) using the D22S75 DiGeorge chromosome (DGS) region probe. A
22q11.2 microdeletion has been detected in 9/51 (17.6%) syndromic patients. Five
were of maternal origin and four of paternal origin. None of the 59 patients with
isolated congenital cardiac defect had a 22q11.2 deletion. We compared the
cardiac anomalies of our patients with a 22q11.2 deletion with those of
previously published series and we describe types of congenital heart defects
which appear to be often associated with a 22q11.2 deletion. The ability to
detect such types of heart defects and to provide an early diagnosis of 22q11.2
deletion is particularly relevant in very young infants, who often show only very
mild expression of the otherwise well-characterized phenotypes of the
DiGeorge/velo-cardio-facial syndrome (DG/VCFS).
PMID- 9550366
TI - The 4q-syndrome: delineation of the minimal critical region to within band 4q31.
AB - A consistent phenotype has been associated with deletion of the distal long arm
of chromosome 4. An invariant requirement for the phenotype in cases described so
far has been the deletion of material from within band 4q31 but few other cases
have been described that further aid the delineation of the minimum critical
region sufficient for the expression of the phenotype. We report a child with a
small interstitial deletion within band 4q31 who exhibits most of the features of
the established 4q-phenotype.
PMID- 9550367
TI - VSD, hypospadias and normal psychomotor development in a patient with inv dup
8(q13-q21.2).
AB - This paper describes a patient with a de novo inverted duplication of chromosome
8(q13-q21.2). He was born with a ventricular septum defect, glandular hypospadias
and protruding ears. At the age of 5 1/2 years he had normal psychomotor
development. Review of the literature on partial duplications of 8q reveals that
the associated phenotype may be mild. Normal psychomotor development, as in our
patient, however appears to be uncommon.
PMID- 9550369
TI - Genetic variation among 129 substrains: practical consequences.
AB - We designed a series of experiments to define the role of IFN-gamma in cellular
interactions mediating graft rejection by assessing the rejection of H-Y
disparate grafts in both ligand and receptor knockout mice and their control
inbred strain. In the course of these studies it became apparent that neither
knockout strain is histocompatible with the putative control and that the
putative control is not histocompatible with either knockout strain. In the
process of deducing why this might be so, it became apparent that the putative
control is not an inbred strain of mouse. Thus, in the absence of rigorous
genetic control, the utility of such knockout strains of mice for assessing the
effects of cytokines and receptors in transplantation and autoimmunity is
limited.
PMID- 9550368
TI - Induction of IL-10 synthesis by human keratinocytes through CD23 ligation: a
cyclic adenosine 3',5'-monophosphate-dependent mechanism.
AB - Ligation of the low affinity receptor for IgE, CD23/Fc epsilonRII, in human
keratinocytes (HK) and monocytes induces the synthesis of proinflammatory
cytokines (IL-6 and TNF-alpha), partly under the dependence of cAMP and nitric
oxide pathways. Moreover, CD23 ligation induces IL-10 production in human
monocytes. Since synthesis of IL-10 by HK is still a matter of debate, we
investigate whether keratinocytes could produce IL-10 upon CD23 stimulation.
Here, our data show that CD23 ligation induces significant IL-10 synthesis in HK,
a phenomenon inhibited by cAMP antagonists, but not by inhibitors of the nitric
oxide pathway. Accordingly, cAMP agonist induced significant IL-10 synthesis by
HK, while nitric oxide-releasing chemical did not. Treatment of HK with anti-IL
10 mAb potentiated their CD23-mediated TNF-alpha synthesis. These data indicate
that engagement of surface CD23 on human keratinocytes induces the synthesis of
IL-10, which, in turn, down-regulates their proinflammatory response.
PMID- 9550370
TI - Selective involvement of proteasomes and cysteine proteases in MHC class I
antigen presentation.
AB - CTL recognize peptides derived from protein Ags bound to MHC-class I molecules.
Proteasomes probably participate in the generation of these peptide epitopes. We
investigated the role of proteasomes in the presentation of endogenously
synthesized short viral proteins. To this end, we employed proteasome and
cysteine protease inhibitors and two closely related recombinant vaccinia viruses
that code for 17- and 19-amino acid-long products encompassing murine CMV 9pp89
epitope. Presentation of both minigene products required processing to shorter
peptides and was independent of ubiquitination. Proteasomes were necessary for
processing the 17-mer product, and cysteine proteases were not required. In
contrast, the 19-mer product could be processed in parallel either by proteasomes
or by cysteine proteases independently. These results highlight the diversity of
alternative processing pathways even for short peptidic Ags, provide evidence for
the involvement of cysteine proteases in MHC class I presentation, and show that
cleavage by cysteine proteases is governed by sequences flanking the epitope.
PMID- 9550371
TI - A role for Ras signaling in coreceptor regulation during differentiation of a
double-positive thymocyte cell line.
AB - Evidence suggests that the Ras/mitogen-activated protein kinase signaling pathway
is required for positive selection of thymocytes. We have asked whether Ras
activation is also sufficient to mediate changes in gene expression that are
associated with positive selection. To accomplish this, we expressed a
constitutively active form of Ras in the immature CD4+ 8+ DPK thymocyte cell
line. DPK cells that express active Ras have reduced levels of CD8alpha and
CD8beta at the level of cell surface protein and mRNA. These data provide
evidence of a direct link between Ras signaling pathways and coreceptor
regulation during positive selection. They also suggest that a sustained or
potent Ras signal may play a critical role in directing thymocytes into the CD4
lineage. DPK cells that express active Ras, however, were not fully
differentiated, indicating that Ras signaling provides only a partial signal for
double-positive thymocyte differentiation.
PMID- 9550372
TI - Immunostimulatory effects of a plasmid expressing CD40 ligand (CD154) on gene
immunization.
AB - Interaction of CD40 with its ligand (CD154) can induce CD40-bearing APCs to
express immune stimulatory accessory molecules that facilitate immune
recognition. We evaluated whether a plasmid vector encoding CD154 (pCD40L) could
influence the immune response to a transgene protein encoded by coinjected
plasmid DNA. We found that coinjection of pCD40L in BALB/c mice enhanced the Ab
response to beta-galactosidase induced by i.m. or intradermal injection of placZ,
a plasmid DNA vector encoding beta-galactosidase. Furthermore, i.m. or
intradermal coinjection of pCD40L with placZ enhanced the generation of CTL
specific for P815 cells transfected with placZ. This study indicates that pCD40L
can serve as a genetic adjuvant capable of augmenting humoral and cellular immune
responses to Ags encoded by plasmid DNA expression vectors.
PMID- 9550373
TI - Engagement of CD40 antigen with soluble CD40 ligand up-regulates peptide
transporter expression and restores endogenous processing function in Burkitt's
lymphoma cells.
AB - Cells from the EBV-associated tumor, Burkitt's lymphoma (BL), are known to be
highly inefficient at endogenous processing of class I-restricted CTL epitopes
due to a consistent loss of peptide transporters (TAP) and MHC expression. We
investigated the potential of CD40 engagement to up-regulate the expression of
class I-processing genes and to enhance the immunogenicity of these malignant
cells toward EBV-specific CTLs. Here we show that engagement of CD40 Ag with
soluble CD40 ligand (CD40L) up-regulates TAP-1 and HLA class I expression on BL
cells. More importantly, analysis of the Ag-processing function, using a
recombinant vaccinia virus to transiently express the EBV nuclear Ags, revealed
that CD40L-treated BL cells consistently processed endogenously synthesized viral
Ags for recognition by HLA class I-restricted, virus-specific CTLs. These
findings raise the possibility that CD40L treatment of tumor cells might be
exploited in immunotherapeutic protocols.
PMID- 9550374
TI - Evidence that the same gamma delta T cells respond during infection-induced and
autoimmune inflammation.
AB - Inflammatory responses are induced in both testes of a mouse following injection
of Listeria monocytogenes into one testis. Although the uninjected testis
contains no detectable bacteria, it undergoes an autoimmune attack. Normally, the
testis lacks lymphocytes, but in the infected and autoimmune state, both gamma
delta and alpha beta T cells are found as infiltrates. Here, we have examined the
repertoire of the infiltrating gamma delta T cells, using two different methods,
and found a high frequency of V gamma 6/V delta 1 gamma delta T cells in both
infected and autoimmune testes. All of these expressed the invariant V gamma 6/V
delta 1 TCR previously reported. However, secondary gamma and delta transcripts
present within V gamma 6/V delta 1 hybridomas indicated nonclonality.
Interestingly, some of these secondary transcripts were derived from gamma gene
rearrangements not previously found in this gamma delta T cell subset, implying a
difference in its origin. The increase in V gamma 6/V delta 1 cells observed here
in both infected and autoimmune testes, together with our previous finding of a
preferential response by the same subset in Listeria-infected liver, indicates
that their response is triggered by the inflammation rather than by the
infectious agent or because they are already resident in the tissue. We and
others have previously reported that the presence of gamma delta T cells during
certain inflammatory conditions correlates with less host tissue damage. This
result, together with the evidence presented here, further implies that a
response by the V gamma 6/V delta 1 subset in some way exerts a controlling
influence on the host inflammatory response.
PMID- 9550376
TI - Distinct biochemical signals characterize agonist- and altered peptide ligand
induced differentiation of naive CD4+ T cells into Th1 and Th2 subsets.
AB - We have recently shown that altered peptide ligands influence differentiation of
CD4+ T cells into Th1 and Th2 subsets. In the present study, we have examined the
biochemical signals in naive CD4+ T cells after priming with altered peptide
ligand (APL) that correlate with differences in cytokine expression. Although we
observed zeta-chain phosphorylation in APL-stimulated cells, other signaling
events such as ZAP70 and Lnk phosphorylation are not initiated. This altered
pattern observed in the early phosphorylation events correlates with a distinct
Ca2+ mobilization pattern that characterizes APL-stimulated cells. By changing
the calcium signaling environment during T cell priming, we present data
indicating that qualitative differences in calcium mobilization are associated
with differentiation of naive CD4+ T cells into Th1- and Th2-like effector
subsets.
PMID- 9550375
TI - VH gene replacement in hyperselected B cells of the quasimonoclonal mouse.
AB - The primary repertoire of the quasimonoclonal mouse is monospecific. However,
among peripheral B cells, there is a high frequency of variant cells with V(H)
replacements, which are also hypermutated. We show in this work that these
hyperselected cells expand in numbers as the animals increase in age, switch
their isotypes, and with increasing age become the almost exclusive contributors
to the pool of serum Ig. The fraction of such cells is higher in the peritoneum
than in peripheral blood, supporting the view that the peritoneum is a site of
production of nonspecific serum Ig. We have also isolated and partially sequenced
the replacing V(H) gene segments from B220-positive, Id-negative cells, and mu
negative, lambda-positive (i.e., switched) cells, and matched them with their
germline counterparts. V(H) families are represented proportional to the number
of members in the germline, a finding that is consistent with the idea that
environmental Ag pressure maintains the germline repertoire of V gene segment.
PMID- 9550377
TI - Resting B cells from autoimmune lupus-prone New Zealand Black and (New Zealand
Black x New Zealand White)F1 mice are hyper-responsive to T cell-derived stimuli.
AB - To determine whether B cells from New Zealand Black (NZB) and (New Zealand Black
x New Zealand White)F1 (NZB/W) mice possess intrinsic defects that lead to
altered immune responsiveness, we purified resting B cells from these mice and
compared their surface phenotype and function with those of resting B cells
isolated from BALB/c and DBA/2 nonautoimmune mouse strains. Flow cytometric
analysis of freshly isolated resting B cells revealed that NZB and NZB/W resting
B cells are conventional B2-type cells similar to their nonautoimmune
counterparts. Despite this, resting B cells from young NZB and NZB/W mice express
lower levels of CD23 on their surface and aberrant levels of intracellular IgM.
Upon stimulation, resting B cells from young NZB and NZB/W mice demonstrate
increased proliferation, IgM secretion, or enhanced expression of costimulatory
molecules in response to a variety of different T cell-derived stimuli, including
cytokines and signals generated through CD40. Therefore, B cell hyper
responsiveness to T cell stimuli is immunodominant or codominant in NZB/W mice.
Taken together, our results suggest that intrinsic B cell hyper-responsiveness
may play a role in the pathogenesis of autoimmune disease in NZB and NZB/W mice.
The increased clonal expansion of these B cells together with increased Ig
production and enhanced costimulatory capacity serve to amplify the immune
response. In the context of normal but incomplete T cell tolerance, B cell
hyperresponsiveness to the limited signals provided by partially tolerant T cells
may be sufficient to yield an autoantibody response.
PMID- 9550378
TI - Anti-CD3 epsilon F(ab')2 fragments inhibit T cell expansion in vivo during graft
versus-host disease or the primary immune response to nominal antigen.
AB - This study was undertaken to distinguish between several mechanisms responsible
for graft-vs-host disease (GVHD) protection in anti-CD3epsilonF(ab')2 fragment
(Fr)-treated recipients: TCR down-modulation, deletion, failure of expansion, or
anergy induction. To quantify alloreactive T cell expansion and function,
thoracic duct lymphocytes (TDL) were analyzed. Sixfold fewer donor TDL T cells
were recoverable from anti-CD3epsilonF(ab')2 Fr as compared with irrelevant
F(ab')2 Fr-treated recipients at the time of peak T cell expansion in vivo.
Kinetic analysis revealed that donor T cell expansion was inhibited and not
simply delayed by anti-CD3epsilonF(ab')2 Fr. Similar proportions of TDL T cells
in irrelevant and anti-CD3epsilonF(ab')2 Fr were undergoing apoptosis. Although
TCR modulation was observed, donor TDL T cells had intact anti-host alloresponses
as compared with irrelevant F(ab')2 Fr-treated recipients. Because donor CD4+ T
cells are primarily responsible for GVHD in this model, an adoptive transfer
system was used in which the function and kinetics of expansion of OVA-specific
CD4+ TCR transgenic cells could be physically tracked. Relevant Fr severely
blunted CD4+ TCR transgenic T cell clonal expansion after OVA administration.
Nonviable transgenic and nontransgenic T cells were proportionally similar in OVA
pulsed recipients, regardless of whether relevant or irrelevant F(ab')2 Fr were
given. After discontinuing Fr, transgenic T cells were found to have intact in
vitro OVA-specific responses. Our current and previous results suggest that
reduced donor T cell expansion and T cell depletion both contribute to GVHD
protection by anti-CD3epsilonF(ab')2 Fr. These data have implications for
designing therapeutic approaches directed toward TCR targeting in humans.
PMID- 9550379
TI - In vivo effects of T helper cell type 2 cytokines on macrophage antigen
presenting cell induction of T helper subsets.
AB - SJL mice provide an interesting paradigm to examine the role(s) of APC in the
differential induction of Th1 and Th2 cells. Immunization of young male SJL mice
results in the preferential induction of Th2 cells, whereas Th1 cells are induced
in age-matched female or older male SJL mice. The absence of Th1 responses in
young male mice is associated with in vivo IL-4 and IL-10 down-regulating Mac-3+
APC priming of Th1 cells. The present report examines the mechanism of this APC
dependent induction of Th subsets. Examination of the surface expression of MHC
class II, adhesion molecules (CD11a, CD11b, CD48, CD54, and CD102) or
costimulatory molecules (CD24, CD80, and CD86) showed no differences between male
and female-derived Mac-3+ APC populations. In addition, no differences were
detected in IL-1alpha, IL-1beta, IL-18, TNF-alpha, or IL-12 p35 mRNA expression.
However, reduced expression of both IL-10 and IL-12 p40 mRNA were found in Mac-3+
cells from male mice compared with those in Mac-3+ cells from female mice. Anti
IL-4 or anti-IL-10 mAb treatment of young male donor mice eliminated the
reduction of both IL-10 and IL-12 p40 mRNA, suggesting that the Th2 inducer
phenotype is related to a decreased IL-12 secretion. Consistent with this idea,
fewer IL-12 p40-secreting Mac-3+ cells were found in male mice compared with
female mice, and treatment with rIL-12 resulted in the priming of Th1 cells in
male mice. These data suggest that increased Th2 cytokines in vivo before
encounter with Ag inhibit APC expression of IL-12, resulting in the preferential
induction of Th2 cells in male SJL mice.
PMID- 9550380
TI - Immunohistochemical analysis of in vivo patterns of TRAF-3 expression, a member
of the TNF receptor-associated factor family.
AB - An immunohistochemical approach was used to explore the in vivo expression of TNF
receptor-associated factor 3 (TRAF-3), a putative signaling protein that binds to
the cytosolic domains of CD30, CD40, and lymphotoxin-beta receptors. TRAF-3
immunostaining was detected in many types of cells throughout the human body.
TRAF-3 immunostaining was only rarely present in thymocytes but was found in the
thymic epithelioreticular cells. Lymphocytes in the bone marrow were also
typically TRAF-3 immunonegative, whereas myeloid progenitor cells and
megakaryocytes were often TRAF-3 positive. Peripheral blood lymphocytes were
mostly TRAF-3 immunonegative, while granulocytes were TRAF-3 immunopositive.
Monocytes were strongly immunostained for TRAF-3, but macrophages in nodes
typically contained little or no TRAF-3 immunoreactivity. Some lymphocytes within
the germinal centers of secondary lymphoid follicles in normal and reactive nodes
were TRAF-3 immunopositive, as were occasional interfollicular lymphocytes in the
T cell regions of these organs, but most lymphocytes appeared to be TRAF-3
immunonegative or stained only weakly. Plasma cells, however, were strongly TRAF
3 positive. Stimulation of PBLs with anti-CD3 Ab induced marked increases in the
steady state levels of TRAF-3 protein in vitro as determined by immunoblotting,
while levels of TRAF-2 were unchanged, implying a dynamic regulation of TRAF-3
expression. The findings establish for the first time the cell type- and
differentiation-specific patterns of expression of a member of the TRAF family of
proteins.
PMID- 9550382
TI - TCR V alpha 24 and V beta 11 coexpression defines a human NK1 T cell analog
containing a unique Th0 subpopulation.
AB - Murine NK1 natural T (NT) cells are a population of alphabeta T cells that
express NK cell receptors and an invariant TCR rearrangement. These cells rapidly
produce large amounts of IL-4 upon activation and have been suggested to promote
Th2 differentiation. We sought to determine whether a human NK1 T cell analogue
could be detected in PBMC, and if so, characterize the TCR usage, cytokine
expression, and surface phenotype of this subset. Using flow cytometry, we have
demonstrated a distinct population of V alpha24+, V beta11+, CD56+ T cells
consistent with NT cells. Upon sequencing, these cells expressed an invariant V
alpha24-J alphaQ TCR rearrangement, verifying their identity as a human NK1 T
cell analogue. NT cells demonstrated increased frequencies of both IFN-gamma and
IL-4 production. Strikingly, 30 to 45% of CD4+ NT cells expressed IL-4, a sixfold
greater frequency than that seen in mainstream CD4+ alphabeta T cells. Contrary
to the pattern seen with mainstream T cells, virtually all IL-4-producing NT
cells coexpressed IFN-gamma, indicating that this subset of NT cells has a unique
Th0 phenotype. These data establish that V alpha24+ NT cells are a potent source
of IL-4 and as such, may play a role in Th2 priming in human immune responses.
This work demonstrates that human NT cells can be phenotypically identified and
functionally studied in the blood of healthy or diseased subjects.
PMID- 9550381
TI - Antigen presentation by epithelial cells induces anergic immunoregulatory CD45RO+
T cells and deletion of CD45RA+ T cells.
AB - The immunoregulatory effects of alloantigen presentation by tissue parenchymal
cells to resting peripheral blood CD4+ T cells was investigated. Coculture of
CD45RO+ (memory) and CD45RA+ (naive) T lymphocytes with primary cultures of MHC
class II-expressing epithelial cells rendered both populations of T cells
hyporesponsive to a subsequent challenge by the same MHC molecule expressed on
EBV-transformed lymphoblastoid B cell lines. However, the mechanisms responsible
for the allospecific hyporesponsiveness were distinct. For the CD45RO+ T cells,
responsiveness was restored by subsequent culture in the presence of IL-2; the
addition of IL-2 had no effect on the reactivity of the CD45RA+ T cells. In
contrast, the naive T cells were protected from the induction of
nonresponsiveness by the presence of a neutralizing anti-CD95 Ab during the
culture with thyroid follicular cells. In addition, the hyporesponsive CD45RO+ T
cells effected linked suppression, in that they inhibited proliferation against a
third-party DR alloantigen when the third-party alloantigen was coexpressed with
the DR Ag against which hyporesponsiveness had been induced. These results
suggest that recognition of Ag by T cells on tissue parenchymal cells plays an
important role in the maintenance of peripheral T cell tolerance, inducing
nonresponsiveness in naive and memory T cells by distinct mechanisms.
PMID- 9550383
TI - Cyclic-AMP modulates downstream events in CD40-mediated signal transduction, but
inhibition of protein kinase A has no direct effect on CD40 signaling.
AB - The role of cAMP/protein kinase A (PKA) in CD40 signal transduction is
controversial, with evidence both for and against its importance. In this study
we have used a tetracycline-repressible expression system to reversibly express a
dominant-negative form of the PKA regulatory subunit type I (PKA-R(G324D)) in a B
lymphoma line, M12. Expression of PKA-R(G324D) in M12 lymphomas inhibits both
cAMP-mediated growth inhibition and cAMP-mediated induction of B7-2. This
inhibition is reversed by tetracycline treatment of the cells to turn off
inhibitor expression. In contrast, the expression of the PKA-R(G324D) subunit has
no effect on CD40-mediated growth inhibition in M12 cells, nor on CD40-mediated
induction of B7-1, CD23, Fas, ICAM-1, or LFA-1. Thus, our data do not support a
direct role for cAMP/PKA in CD40-mediated signal transduction. However, we do
observe that cAMP can regulate CD40 signaling both positively and negatively.
Cyclic-AMP synergizes with CD40-mediated B7-1 induction in M12 lymphomas, while
inhibiting CD40-mediated CD23, Fas, and ICAM-1 induction.
PMID- 9550384
TI - Early and late events in Fc epsilon RI signal transduction in human cultured mast
cells.
AB - Protein tyrosine phosphorylation and other biochemical events have been shown to
occur after cross-linking of Fc epsilonRI in rodent mast cells. To investigate
the mechanism of Fc epsilonRI signal transduction in human mast cells, we used
human cultured mast cells (HCMC) generated from cord blood cells in the presence
of recombinant human stem cell factor and IL-6. We found that on cross-linking of
Fc epsilonRI: 1) HCMC released histamine; 2) rapid tyrosine phosphorylation of
multiple cellular substrates, including Syk, HS1, c-Cbl, ERK-1, and ERK-2, was
observed; 3) intracellular Ca2+ and inositol phosphate production were increased
within the first minute after Fc epsilonRI cross-linking; and 4) genistein, a
tyrosine kinase inhibitor, inhibited both protein tyrosine phosphorylation and
histamine release in a dose-dependent manner. These results were consistent with
previous studies in rodent mast cells. In contrast, no tyrosine phosphorylation
of phospholipase C gamma1 and Btk (Bruton's tyrosine kinase) were observed in our
experimental conditions. These results suggest that the greater part of the early
and late signaling events in HCMC is similar to those obtained with rodent mast
cells and indicated that the requirement of tyrosine phosphorylation in the
activation process of each of the signaling molecules might be different in HCMC
and rodent mast cells. Our finding indicates that HCMC may be useful for analysis
of Fc epsilonRI-mediated signal transduction in human mast cells.
PMID- 9550385
TI - Pharmacological control of antigen responsiveness in genetically modified T
lymphocytes.
AB - A chimeric TCR gene, comprising an anti-hapten single-chain Ab variable fragment
fused to the transmembrane and cytoplasmic regions of the human TCR zeta-chain,
was used to determine whether the tetracycline-regulatable system could be used
to regulate gene expression in T cells. Jurkat T cells were stably transfected
with a single vector encoding the tetracycline trans-activator protein,
controlled by a constitutive promoter, and the chimeric TCR, under the control of
a trans-activator protein-responsive promoter. In the absence of tetracyclines,
the transfected T cells were shown to express the chimeric receptor on the cell
surface and could be activated by its cognate Ag, leading to the secretion of IL
2. When the cells were exposed to increasing concentrations of tetracyclines,
surface expression of the chimeric receptor was suppressed in a dose-dependent
manner, and this suppression was sufficient to result in complete loss of
responsiveness to the targeted Ag. Prolonged suppression of trans-gene expression
for up to 7 days was observed after doxycycline was removed from the cultures,
but eventual recovery of surface expression was complete, and the absolute time
to recovery was directly proportional to the initial concentration of the drug.
Pharmacologic control of trans-gene expression in gene-modified T cells will not
only facilitate new approaches to the study of different aspects of T cell
biology, but will also provide the basis for new gene therapy strategies.
PMID- 9550386
TI - Proteasome activity limits the assembly of MHC class I molecules after IFN-gamma
stimulation.
AB - For an effective CD8+ cytotoxic T cell response to occur during infection, MHC
class I molecules must be loaded with antigenic peptides in the endoplasmic
reticulum. The cytosolic factor responsible for peptide generation is believed to
be the proteasome, with the TAP heterodimer mediating peptide transport into the
endoplasmic reticulum. However, the rate-determining step(s) in this
intracellular pathway of Ag presentation is currently unresolved. The
availability of a specific and irreversible proteasome inhibitor called
lactacystin has enabled us to determine the amount of proteasomes required for
the peptide loading of MHC class I molecules in four cell types. In the absence
of the IFN-gamma-inducible proteasome subunits LMP2 and LMP7, the trypsin-like
(but not the chymotrypsin-like) activity of the proteasome is directly related to
MHC class I peptide loading. However, IFN-gamma stimulation or assimilation of
catalytic LMP2 and LMP7 subunits into proteasomes causes both chymotrypsin- and
trypsin-like activities of the proteasome to become limiting for the loading of
class I molecules. Our data suggest that upon full IFN-gamma stimulation, peptide
supply by the proteasome is the limiting step in the assembly of MHC class I
polypeptides. This mechanism may enable the cell to prevent competition between
novel Ags and the pool of endogenous proteins for binding to MHC class I
molecules.
PMID- 9550387
TI - Mouse IL-1 receptor antagonist isoforms: complementary DNA cloning and protein
expression of intracellular isoform and tissue distribution of secreted and
intracellular IL-1 receptor antagonist in vivo.
AB - IL-1R antagonist (IL-1Ra) is a competitive inhibitor of the binding of IL-1 to IL
1R. IL-1Ra refers to two different proteins derived from the same gene by
alternate splicing of two different first exons. One protein contains a leader
sequence and is secreted (sIL-1Ra), whereas the other remains intracellular (icIL
1Ra). We describe the cloning of mouse icIL-1Ra cDNA, the expression of the
recombinant mouse icIL-1Ra protein, and the tissue distribution of sIL-1Ra and
icIL-1Ra mRNA and of icIL-1Ra protein in control and LPS-injected mice. As
described in the human and the rabbit, mouse icIL-1Ra protein differs from mature
mouse sIL-1Ra protein by seven amino acids at the amino terminus. In addition,
human and mouse icIL-1Ra are 77% identical. Regulation of IL-1Ra isoforms was
examined in normal mice and after LPS injection. Circulating levels were
undetectable in control mice, but were strongly increased 4 h after LPS
injection. Using a ribonuclease protection assay (RPA), we found that icIL-1Ra
mRNA was expressed constitutively in skin and in LPS-stimulated RAW 264.7 murine
macrophages. Consistent with the RNA studies, Western blot analysis showed that
murine icIL-1Ra protein was constitutively expressed in skin and in LPS
stimulated RAW 264.7 cells. In contrast, sIL-1Ra mRNA was not detected by RPA in
tissues of control mice, but was strongly up-regulated in the lung, spleen, and
liver after LPS injection. Using RPA, primer extension assay and 5' rapid
amplification of cDNA ends, we were able to demonstrate the presence of different
transcription start sites for murine sIL-1Ra mRNA.
PMID- 9550388
TI - Single amino acid mutations in the murine MHC class II A beta cytoplasmic domain
abrogate antigen presentation.
AB - Class II MHC molecules are heterodimeric transmembrane glycoproteins that
function in the presentation of Ag to CD4+ T cells. Deletion of the cytoplasmic
domains of the murine class II A alpha- and A beta-chains has previously been
shown to diminish Ag presentation and abrogate rejection of class II-transfected
tumor cells. To examine the contributions of individual amino acid residues of
the A beta cytoplasmic domain to Ag presentation and tumor rejection, we have
produced a series of cell lines expressing A beta class II molecules with site
directed mutations. An A beta(k) cDNA was constructed with mutations in the five
conserved amino acid residues, Q224, K225, L235, L236, and Q237 (delta5). In
addition, cDNA were produced in which alanine was individually substituted for A
beta(k) cytoplasmic domain residues 224 through 237 or doubly substituted at
residues G226 and P227 or L235 and L236. These mutant cDNAs were individually
cotransfected with wild-type A alpha cDNA into the class II-negative M12.C3 B
lymphoma and Sal sarcoma cell lines. As was previously reported for transfectants
lacking the entire A beta(k) cytoplasmic domain, the delta5 M12.C3 transfectant
could not effectively present Ag to an autoreactive Ak-restricted T cell hybrid,
and the delta5 Sal transfectant was not rejected when inoculated into syngeneic
hosts. A finer analysis revealed that alteration of the individual residue Q224
or the two residues G226 and P227 abrogated Ag presentation in vitro, while
mutation of G226 diminished tumor rejection in vivo. Thus, the function of the A
beta cytoplasmic domain in Ag presentation both in vitro and in vivo can be
disturbed by mutation of single amino acid residues.
PMID- 9550389
TI - Effects of CD28 costimulation on long-term proliferation of CD4+ T cells in the
absence of exogenous feeder cells.
AB - In this report, conditions for prolonged in vitro proliferation of polyclonal
adult CD4+ T cells via stimulation with immobilized anti-CD3 plus anti-CD28 have
been established. CD4+ cells maintained exponential growth for more than 60 days
during which a total 10(9)- to 10(11)-fold expansion occurred. Cell cultures
exhibited cyclical changes in cell volume, indicating that, in terms of
proliferative rate, cells do not have to rest before restimulation. Indeed,
electronic cell size analysis was the most reliable method to determine when to
restimulate with additional immobilized mAb. The initial approximately 10(5)-fold
expansion was autocrine, occurring in the absence of exogenous cytokines or
feeder cells. Addition of recombinant human IL-2 after the initial autocrine
expansion resulted in continued exponential proliferation. Phorbol ester plus
ionomycin also induced long-term growth when combined with anti-CD28 stimulation.
Analysis of the T cell repertoire after prolonged expansion revealed a diverse
repertoire as assessed by anti-TCR Vbeta Abs or a PCR-based assay. Cytokines
produced were consistent with maintenance of both Th1 and Th2 phenotypes;
however, the mode of CD3 and CD28 stimulation could influence the cytokine
secretion pattern. When anti-CD3 and anti-CD28 were immobilized on the same
surface, ELISAs on culture supernatants revealed a pattern consistent with Th1
secretion. Northern analysis revealed that cytokine gene expression remained
inducible. Spontaneous growth or cell transformation was not observed in more
than 100 experiments. Together, these observations may have implications for gene
therapy and adoptive immunotherapy. Furthermore, these culture conditions
establish a model to study the finite lifespan of mature T lymphocytes.
PMID- 9550390
TI - Role for IL-15/IL-15 receptor beta-chain in natural killer 1.1+ T cell receptor
alpha beta+ cell development.
AB - Mouse TCR alphabeta+ cells expressing NKR-P1 (NK1+ T cells in the C57BL/6 strain)
are classified as a unique subset that require beta2m-associated, MHC class I
like molecules for development and preferentially express particular V beta and V
alphaJ domains of the TCR. We show here that NK1+ T cells express the IL-2R
beta/IL-15R beta that is normally present on conventional NK cells, but not T
cells. In mice lacking IL-2R beta/IL-15R beta chain, the number of NK1+ T cells
is dramatically reduced. However, in IL-2-deficient mice, NK1+ T cells develop
normally. Moreover, NK1+ T cells proliferate upon stimulation by IL-15, and the
proliferation is blocked by the addition of anti-IL-2R beta/IL-15R beta Abs.
Collectively, our data indicate that NK1+ T cells require IL-2R beta/IL-15R beta
chain in an IL-2-independent manner and demonstrate that IL-15 plays a crucial
role during development.
PMID- 9550391
TI - Maternal immunization with a soluble TCR-Ig chimeric protein: long term, V beta-8
family-specific suppression of T cells by maternally transferred antibodies.
AB - Maternal transfer of TCR clonotypic Ab protected young NOD mice against the
adoptive transfer of diabetes by the BDC 2.5 T cell clone. The effect of maternal
anti-TCR Vbeta-8 Ab on T cell development and function has now been investigated.
SJL/J mice, which lack TCR Vbeta-8, were immunized with soluble, chimeric D10 TCR
IgG1 containing Vbeta-8.2. The (SJL/J x AKR/J) F1 offspring of immunized female
SJL/J mice were severely depleted of peripheral T cells bearing Vbeta-8 until 11
to 17 wk of age. The loss of Vbeta-8 expression did not appear to be due to
modulation of cell surface TCR. Since the Vbeta-8+ T cell population was
unperturbed in the (AKR/J x SJL/J) F1 offspring of D10 TCR-IgG1-immunized AKR/J
mothers making D10 clonotypic Ab, the effect was immunologically specific. The
deletion of Vbeta-8+ T cells had functional consequences. In the in vitro
response to the superantigen, staphylococcal enterotoxin B, the usually observed
participation of Vbeta-8.2+ T cells was largely suppressed, whereas the
recruitment of Vbeta-3+ T cells remained unaltered. In control mice, T cell
responses to the 134- to 146-residue peptide of conalbumin (pCA(134-146)) were
biased toward use of Valpha-2/Vbeta-8.2 TCR. In D10 TCR-IgG1 maternally immunized
(SJL x AKR/J) F1 mice, the T cell responses to pCA(134-146) were suppressed, and
T cell lines derived from these in vitro were devoid of Vbeta-8.2 expression.
With an increased understanding of TCR V gene usage in autoimmune diseases,
similar strategies for the depletion of autoreactive T cells may become feasible
in humans.
PMID- 9550392
TI - IgA plasma cells in vascular tissue of patients with Kawasaki syndrome.
AB - The etiology and pathogenesis of Kawasaki syndrome (KS) remain unknown. Clinical
and epidemiologic features of KS are consistent with an infectious cause. To
search for an etiologic agent of KS, a phage cDNA expression library was
constructed from the aorto-iliac junction of a patient with fatal acute KS and
screened with convalescent KS serum followed by anti-human Ig. Unexpectedly, 0.1%
of the clones in the library react with anti-human Ig, indicating the presence of
many Ig-producing B lymphocytes in the vasculitic tissue. To confirm this finding
and to determine the isotypes produced, frozen vascular tissue sections from the
patient and paraffin sections from coronary arteries from six additional patients
with fatal acute or subacute KS were incubated with Abs to Ig isotypes.
Histopathology of the tissues revealed the presence of many plasma cells in the
inflammatory infiltrate. IgA was the predominant isotype produced in vascular
tissue in all seven KS patients. IgM- and IgG-producing cells were less often
detected. We conclude that there is a marked plasma cell response within the
vasculitic tissue in KS, with unusual IgA production locally in this nonlymphoid,
nonmucosal tissue. We suggest that the prominence of IgA plasma cells in the
vascular infiltrate in the early, acute, and subacute stages of KS indicates an
Ag-driven immune response to an etiologic agent with a respiratory or
gastrointestinal portal of entry and speculate that this unusual immune response
is integral to the pathogenesis of the illness.
PMID- 9550393
TI - Strength of TCR signal determines the costimulatory requirements for Th1 and Th2
CD4+ T cell differentiation.
AB - Differentiation of naive CD4 T cells into cytokine-secreting effector Th1 and Th2
cells is influenced by several factors. We have previously reported that the
affinity of antigen for TCR and antigen dose can influence the differentiation of
Th1 and Th2 cells. Several in vitro and in vivo models have demonstrated a role
for the costimulatory molecules, B7-1 (CD80) and B7-2 (CD86), in the generation
of distinct effector T cell responses. To determine whether the strength of TCR
signaling controls the involvement of CD28 costimulation in selective CD4 T cell
differentiation, naive CD4 T cells bearing a transgenic TCR are primed by a weak
or strong TCR signal (signal 1) in the presence or absence of B7 costimulatory
molecules (signal 2). In this system, IL-4-producing Th2 cells are generated by
priming with a weak but not a strong TCR signal. Th2 cell differentiation is
dependent on CD28/B7 interactions in that disruption of CD28/B7 interactions
inhibits the priming of Th2 cells and cross-linking CD28 with anti-CD28 antibody
augments the priming of Th2 cells. In contrast, however, IL-4-producing Th2 cells
cannot be generated by priming with a strong TCR signal even in the presence of
strong costimulation or high doses of IL-2. Thus, our results suggest that naive
CD4 T cells are receptive to CD28-dependent IL-4 production only if they receive
a weak TCR signal.
PMID- 9550394
TI - IL-1 beta-converting enzyme (ICE) is present and functional in human alveolar
macrophages: macrophage IL-1 beta release limitation is ICE independent.
AB - Tissue macrophages readily produce intracellular pro-IL-1beta in response to
stimuli such as LPS, but are limited in mature IL-1beta release compared with
blood monocytes. The mechanism of this IL-1beta control may provide important
insights into the physiology of IL-1beta at the tissue level. Since it has been
hypothesized that IL-1beta processing by the IL-1beta-converting enzyme (ICE)
regulates IL-1beta release, we compared human alveolar macrophages and human
blood monocytes for relative ICE expression and activation. Using immunoblots and
enzyme-linked immunoassay for ICE, we demonstrate that alveolar macrophages do
not differ from blood monocytes in antigenic p45 ICE. Furthermore, an indirect
assay for functional ICE documents similar ICE activities in both monocytes and
alveolar macrophages, i.e., similar concentrations of soluble synthetic ICE
inhibitor (IC50 values of 0.3 +/- 0.01 and 0.6 +/- 0.2 microM, respectively) are
required to block mature IL-1beta generation. However, as has been reported for
THP-1 myelomonocytic cells, neither alveolar macrophages nor blood monocytes
contain directly quantifiable levels of functional ICE forms (p22/p20 and p10)
when assayed by immunoblots or by a sensitive capture ELISA that uses an
irreversible, biotinylated ICE inhibitor. These findings document that the
macrophage limitation in mature IL-1beta release is not due to a lack of ICE or
to an inability to activate ICE. Finally, using a staged release assay, the time
to half-maximum mature IL-1beta release is significantly depressed in macrophages
compared with that in monocytes. Taken together, these findings suggest that
macrophage IL-1beta export is regulated independently of ICE activation.
PMID- 9550396
TI - Exploiting the difference between intrinsic and extrinsic kinases: implications
for regulation of signaling by immunoreceptors.
AB - When receptors must interact with an extrinsic kinase to initiate signaling, the
kinase can play a regulatory role that is not available to intrinsic receptor
kinases. Whether control is exercised at this level depends critically on the
amount of kinase available to the receptors and on the potential for
redistribution of the kinase during signaling. This study demonstrates that the
high affinity receptor for IgE (Fc epsilonRI) on rat basophilic leukemia cells is
regulated by its initiating kinase. We present a mathematical model that allows
for the reversible recruitment of extrinsic kinases to phosphorylated
immunoreceptor tyrosine-based activation motifs. By comparing model predictions
to experimental time courses of phosphorylation, we infer that Lyn is limiting,
that redistribution occurs after receptors are aggregated, and that the
redistribution makes the relationship between tyrosine phosphorylation and
receptor aggregation nonlinear.
PMID- 9550395
TI - Human thymocytes become lineage committed at an early postselection CD69+ stage,
before the onset of functional maturation.
AB - Mature functional CD4 or CD8 single positive (SP) thymocytes differentiate from
immature CD4+ 8+ double positive (DP) precursors through a process of positive
selection and terminal differentiation. To study CD4/CD8 lineage commitment,
human postselection CD69+ thymocytes were separated into distinct subpopulations
based on the differential expression of CD27, CD1, and CD45RA/RO. We demonstrate
that these CD69+ subpopulations represent transitional stages of a common
differentiation pathway during which CD69+ thymocytes that are initially CD27-
CD1+ CD45RA- will sequentially up-regulate CD27, down-regulate CD1, and
eventually acquire CD45RA upon maturation. Examination of CD4 and CD8 expression
on these CD69+ subsets identified an early postselection CD69+ CD27- CD4SP
population that gives rise to both CD4SP and CD8SP mature T cells when cultured
in mouse thymus organs. In addition, a CD4+ 8+ DP population was identified that
is CD69+ and CD27+, which only gives rise to CD8SP progeny upon culture. Although
these results suggest that development of CD4SP and CD8SP cells may proceed
through distinct intermediates, examination of active biosynthesis of CD4 and CD8
by the various subsets demonstrated that cells that have selectively terminated
CD4 synthesis are already present in the CD27- CD4SP and CD27+ DP populations
before culture. These data support a model of thymocyte differentiation whereby
the decision of thymocytes to differentiate into one or the other lineage occurs
concomitantly with, or very soon after, acquisition of CD69 and before the cells
acquire CD27, down-regulate CD1, or acquire functional properties.
PMID- 9550397
TI - Activation-related differences in HLA class I-bound peptides: presentation of an
IL-1 receptor antagonist-derived peptide by activated, but not resting, CD4+ T
lymphocytes.
AB - We have compared by reverse phase HPLC the set of peptides eluted from HLA class
I molecules in resting and activated CD4+ Jurkat cells. Two peptides were
identified that are presented de novo upon activation. After sequencing, one of
these peptides turned out to derive from IL-1R antagonist (IL-1Ra). In keeping
with this observation, we found that activated, but not resting, Jurkat cells
express IL-1Ra. These data indicate that activation of a CD4+ T cell line may
result in presentation of peptides derived from proteins expressed de novo after
activation. Since IL-1Ra was not known to be expressed by cells of the T lineage,
we also investigated its pattern of expression in normal T lymphocytes. Reverse
transcriptase-PCR analyses allowed us to demonstrate that IL-1Ra is expressed
upon activation by normal CD4+ lymphocytes from peripheral blood and by
thymocytes, but not by CD8+ T cells. Interestingly, of the two forms of IL-1Ra
that have been detected in different cell lineages, the intracellular one and the
secreted one, only the former is expressed by activated CD4+ T cells.
PMID- 9550398
TI - CD40 and IL-4 regulate murine CD27L expression.
AB - It is well known that interactions between accessory molecules on T cells and
their ligands on APC play a key role in regulating T cell effector activity. The
factors controlling the expression of these molecules are thus important
determinants in the outcome of T cell activation. We have examined the expression
of the murine ligand for CD27, a costimulatory molecule on T cells. Evidence is
shown that CD27L is expressed at a low level on resting B cells but not on T
cells, and that activation of B cells by culture with LPS or anti-IgM Ab
increases the expression of CD27L. Interestingly, coligation of CD40 down
regulates CD27L on LPS-activated B cells but not on anti-Ig-activated cells.
These findings suggest that costimulation via the CD27-CD27L pathway may be
limited to interactions involving Ag-specific B cells, i.e., B cells specifically
activated via their Ig receptors. In addition, testing a spectrum of different
cytokines indicated that IL-4 and TGF, but not IL-2, IL-10, or IFN-gamma,
prevented up-regulation of CD27L expression on activated B cells even when
activation was induced by Ig signaling. The capacity of IL-4 to prevent CD27L
expression could thus serve to limit CD27-CD27L interactions to Th1-type T cell
responses.
PMID- 9550399
TI - CD94/NKG2 inhibitory receptor complex modulates both anti-viral and anti-tumoral
responses of polyclonal phosphoantigen-reactive V gamma 9V delta 2 T lymphocytes.
AB - Viral, bacterial, protozoal, and cancer-associated Ags elicit strong responses in
human gammadelta T lymphocytes. The majority of these cells in the peripheral
blood express the Vgamma9Vdelta2-encoded TCR and recognize nonpeptidic
phosphoantigens without an apparent MHC restriction. We have shown that
Vgamma9Vdelta2 T cells express the inhibitory CD94/NKG2 receptor for HLA class I
molecules. The anti-CD94 mAb inhibits 1) the Vgamma9Vdelta2 T cell proliferation
in response mycobacterial phosphoantigens and 2) the HIV-induced Vgamma9Vdelta2 T
cell expansion. Vgamma9Vdelta2 T cells stimulated with nonpeptidic mycobacterial
antigens produce IFN-gamma and TNF-alpha. Signaling through the CD94/NKG2
receptor interferes with the synthesis of these cytokines. The CD94/HLA class I
interaction is also involved in the cytotoxic activity of Vgamma9Vdelta2 T cells.
The Vgamma9Vdelta2 T cell regulation through the CD94 receptor may be important
for the potentially dual function in innate immunity, i.e., 1) NK-like and 2) TCR
ligand-induced cytolytic activities.
PMID- 9550400
TI - Independent regulation of cutaneous lymphocyte-associated antigen expression and
cytokine synthesis phenotype during human CD4+ memory T cell differentiation.
AB - Although considerable attention has been paid to the development of cytokine
synthesis heterogeneity during memory T cell differentiation, little information
is available on how this function is coregulated with homing receptor expression.
The development of skin-homing, CD4+ memory T cells in the human provides an
excellent model for such investigation, since 1) the skin supports both Th1- and
Th2-predominant responses in different settings, and 2) the skin-homing
capability of human memory T cells correlates with and appears to depend on
expression of the skin-selective homing receptor cutaneous lymphocyte-associated
Ag (CLA). In this study, we used multiparameter FACS analysis to examine
expression of CLA vs IFN-gamma, IL-4, and IL-2 synthesis capabilities among fresh
peripheral blood CD4+ memory T cells, and Th1 vs Th2 memory T cells generated in
vitro from purified CD4+ naive precursors by cyclic activation in polarizing
culture conditions. Among normal peripheral blood T cells, CLA expression was
essentially identical among the IFN-gamma- vs IL-4-producing CD4+ memory subsets,
clearly indicating the existence of in vivo mechanisms capable of producing both
Th1 vs Th2 skin-homing T cells. In vitro differentiation of naive CD4+ T cells
confirmed the independent regulation of CLA and all three cytokines examined,
regulation that allowed differential production of IFN-gamma-, IL-4-, and IL-2
producing, CLA+ memory subsets. These studies also 1) demonstrated differences in
regulatory factor activity depending on the differentiation status of the
responding cell, and 2) revealed CLA expression to be much more rapidly
reversible on established memory cells than cytokine synthesis capabilities.
PMID- 9550401
TI - Identification of shared tumor-associated antigen peptides between two
spontaneous lung carcinomas.
AB - CTLs recognize antigenic peptides bound to MHC class I Ags on the cell surface of
tumor cells. Tumor-associated Ag (TAA) peptides are 8 to 10 amino acids long and
can be derived from normal, mutated, or viral proteins. The majority of T cell
defined Ags have been identified in human melanoma cells. These were shown to be
commonly expressed by different allogeneic melanomas that share the same MHC
molecule. We have recently isolated Kb-restricted TAA peptides, which are
mutations of the gap junction protein connexin 37, from the spontaneous C57BL/6
Lewis lung carcinoma (3LL). These peptides, named MUT 1 and MUT 2, serve as CTL
epitopes and can induce CTL activity in vivo. Using CTL cross-reaction assays,
peptide extraction, HPLC fractionation, and reverse transcriptase-PCR
amplification, we show that clones of another spontaneous C57BL/6 lung carcinoma,
CMT 64, share TAA peptides with the 3LL carcinoma. Vaccination with synthetic MUT
1 or MUT 2 induces CTLs that efficiently lyse CMT 64-derived clones, protects
mice from CMT 64 metastasis, and affords therapy of established CMT 64
metastases. Hence, shared CTL epitopes exist between two spontaneous murine lung
carcinomas.
PMID- 9550402
TI - Deoxyribonucleic acid vaccines encoding antigens with rapid proteasome-dependent
degradation are highly efficient inducers of cytolytic T lymphocytes.
AB - We generated plasmid expression vectors encoding ubiquitin and beta-galactosidase
(beta-gal) with different intervening amino acids, allowing for the production of
processed protein products that have either stabilizing or destabilizing residues
at their N-termini. P815 cells transfected with plasmids encoding beta-gal with a
destabilizing N-terminus did not have detectable expression beta-gal unless they
were treated with inhibitors specific for the proteasome. Inhibitors of other
proteolysis pathways had no such effect. Nevertheless, transfectants expressing
beta-gal with different amino acid residues were equally sensitive to cytolysis
by a CTL clone specific for a beta-gal peptide presented in the context of H-2Ld.
In contrast to vectors encoding native beta-gal, plasmid vectors encoding beta
gal with a destabilizing residue did not induce detectable anti-beta-gal Abs when
injected into skeletal muscle of BALB/c mice. However, such vectors were
significantly more effective than vectors encoding native beta-gal or beta-gal
with a stabilizing residue in stimulating CTL specific for P13.2, a lacZ
transfectant of P815. We conclude that incorporation of strategies that enhance
proteasome-dependent degradation may generate DNA vaccines that are more
effective in inducing cellular immunity against targeted Ags.
PMID- 9550403
TI - Complex origin of the HLA-DR10 haplotype.
AB - The region of the HLA complex occupied by the DRB genes has undergone many
rearrangements in the course of primate evolution. The rearrangements have
produced a number of haplotypes differing from one another in the number and
composition of the DRB genes. Some of the rearrangements also affected the DRB
genes themselves. Selective intron sequencing has revealed the DR10 haplotype to
be composed of at least three segments, each of different origin. The haplotype
carries three DRB genes (gene fragments): DRB1*10, DRB6, and DRB9. The 5' end of
the DRB1*10 gene, from the promoter region to a site in intron 1 approximately
500 bp from the beginning of exon 2, is derived from a DRB1*03-like gene. The
segment of the DR10 haplotype encompassing the rest of the DRB1*10 gene and
extending to the region between the DRB1 and DRB6 genes is of independent origin;
it diverged from other DRB genes (DRB1*01 and DRB1*03) approximately 30 million
years ago. Finally, the third segment encompassing the remainder of the DR10
haplotype is derived from a DR1-like haplotype. Since the functional part of the
DR10 haplotype is of independent origin, there is little justification for the
currently common practice of placing the haplotype together with DR1 in the group
of DR1 haplotypes. The rearrangements in the DR haplotypes may constitute one of
several mechanisms for increasing diversity at the DRB loci. The region of high
instability seems to be flanked by conservatively evolving regions.
PMID- 9550404
TI - Linkage of LMP, TAP, and RING3 with Mhc class I rather than class II genes in the
zebrafish.
AB - The LMP2 and LMP7 genes code for subunits of the proteasome, a multimeric
enzymatic complex that degrades proteins into peptides. The two subunits replace
corresponding constitutively expressed subunits during the immune response. Some
of the peptides generated by the proteasome in the cytosol are transported by the
products of the TAP1 and TAP2 genes into the lumen of the endoplasmic reticulum
and are loaded onto the assembling MHC class I molecules. In mammals, the LMP2,
LMP7, TAP1, and TAP2 genes reside in the class II region of the Mhc, closely
linked to the RING3 gene. In the present study we identified, cloned, and
sequenced the LMP, TAP2, and RING3 genes of the zebrafish, Danio rerio. We
identified variants of these genes and used them in a segregation analysis of
haploid embryos derived from heterozygous mothers. The analysis revealed that in
zebrafish, the LMP2, LMP7, TAP12, and RING3 loci are closely linked but, in
contrast to mammals, the LMP/TAP/RING3 cluster resides not in the Mhc class II
but in the class I region. We also confirmed that in the zebrafish, the class I
and class II regions are not linked to each other. In this species, therefore,
the LMP/TAP/RING3 genes are clustered with the class I genes on a chromosome that
apparently does not contain any class II genes. The linkage of
LMP/TAP/RING3/class I may be the original and the LMP/TAP/RING3/class II a
derived arrangement of these genes.
PMID- 9550405
TI - Kappa and lambda rearrangement occur simultaneously in transformed pre-B cells.
AB - Murine B-lineage cells can express either kappa or lambda Ig light chains.
However, most of these cells express kappa protein, a phenomenon that appears to
be controlled in part at the level of gene rearrangement. This feature may
reflect a preference for the kappa locus by the recombinase machinery, or it may
indicate that kappa rearrangement begins before lambda rearrangement. These
possibilities can be distinguished by measuring the kinetics with which light
chain gene rearrangement at both loci actually occurs. To this end, we have used
pre-B cells transformed by temperature-sensitive mutants of Abelson virus that
undergo kappa and lambda gene rearrangement when shifted to the nonpermissive
temperature. Competitive PCR analyses of rearrangement kinetics demonstrate that
the kappa and lambda loci rearrange at about the same time in these cells.
Consistent with this, some clones isolated from cells induced for a short period
of time have rearranged only the lambda locus. However, the frequency with which
lambda genes are rearranged is three- to sixfold lower than that with which kappa
genes rearrange. These data indicate that the recombinase machinery targets both
light chain loci at the same time, but acts preferentially at the kappa locus.
The reduced ability of the recombinase machinery to target the lambda locus and
selection pressures occurring during B cell development probably both contribute
to the preferential usage of kappa genes in normal murine B lineage cells.
PMID- 9550406
TI - Determination of adenosine deaminase binding domain on CD26 and its
immunoregulatory effect on T cell activation.
AB - CD26, a 110-kDa cell surface glycoprotein, exhibits dipeptidyl peptidase IV
enzyme activity and plays an important role in T cell costimulation. In the
present study, we examined both the exact adenosine deaminase (ADA) binding
domain on CD26 and the functional consequences of mutated CD26 transfectants that
were deficient for cell surface ADA. Using CD26 deletion, human-rat swap, and
point mutations, we found that the residues of L340, V341, A342, and R343 on the
CD26 molecule were essential amino acids for ADA binding. When these amino acids
were mutated and transfected into Jurkat cells, the resultant CD26 transfectants
expressed only CD26, not ADA, on the cell surface. The amount of IL-2 produced by
wild-type and mutated CD26 transfectants was almost the same following
stimulation with anti-CD3 plus PMA. However, the mutated CD26 transfectants were
much more sensitive to the inhibitory effect of adenosine on IL-2 production than
were the wild CD26 transfectants. These data suggest that ADA on the cell surface
does not directly involve T cell activation. Conversely, CD26 alone does not
result in modulating the inhibitory effect of adenosine. Only the ADA bound to
CD26 on the cell surface was functional and could counteract the inhibitory
effect of elevated extracellular adenosine.
PMID- 9550407
TI - Comparison of the roles of CD8 alpha alpha and CD8 alpha beta in interaction with
MHC class I.
AB - The CD8 molecule is expressed either as an alpha/alpha homodimer or an alpha/beta
heterodimer on thymocytes and cytotoxic T cells, and functions as a coreceptor in
concert with TCR for binding the MHC class I/peptide complex. Although
CD8alpha/beta heterodimers have been shown to be more effective coreceptors, the
precise role of the beta-chain in TCR-mediated thymic maturation and T cell
activation is not understood. To understand the role of CD8beta in mediating
CD8/MHC class I interaction, we examined whether cell surface CD8alpha/beta
heterodimer promotes better cell-cell adhesion with MHC class I than the
CD8alpha/alpha homodimer. The abilities of different forms of CD8 to adhere to
MHC class I were measured with a cell-cell binding assay. Using a wild-type
CD8beta and -alpha, we found that CD8alphabeta heterodimers did not mediate
greater cell-cell adhesion than CD8alphaalpha homodimers. Furthermore, we found
that chimeric CD8beta-alpha homodimers afforded no detectable binding. These
results do not support the idea that CD8alphabeta binding to MHC class I is
greater than that of CD8alphaalpha. Rather, they point to an alternative
explanation in which CD8beta may play an role in promoting CD8/TCR interaction
and/or in signaling/regulatory pathways.
PMID- 9550408
TI - Influence of VH CDR3 arginine and light chain pairing on DNA reactivity of a
bacterial DNA-induced anti-DNA antibody from a BALB/c mouse.
AB - Anti-DNA induced in BALB/c mice by immunization with bacterial (Escherichia coli)
DNA resemble spontaneous anti-DNA from lupus mice in V gene use and cross
reactivity with other nuclear Ags, but lack the high V(H) CDR3 arginine content
seen in anti-DNA from lupus mice. Moreover, the induced anti-DNA bind bacterial
and mammalian single-stranded (ss) DNA and bacterial double-stranded (ds) DNA,
but do not bind mammalian dsDNA. This reactivity profile is in contrast to that
of the spontaneously arising anti-DNA of lupus mice, among which mammalian dsDNA
reactive Abs are prominent. In this study we demonstrate that the addition of
arginine to V(H) CDR3 of an induced anti-DNA confers the mammalian dsDNA binding
characteristic of anti-DNA from lupus mice. The ability to confer mammalian dsDNA
binding is dependent on both the position of the arginine in V(H) CDR3 and the
light chain with which the heavy chain is paired, suggesting the light chain
plays a more substantial role in DNA binding by this Ab than has previously been
reported for other anti-DNA. Our data support the argument that V(H) CDR3
arginines tend to confer antimammalian dsDNA reactivity, leading to censure of B
cells expressing these Abs and provides an explanation for the absence of
arginine-rich V(H) CDR3 in the bacterial DNA-induced response.
PMID- 9550409
TI - Characterization of the IFN-gamma-responsive element in the 5' flanking region of
the C1 inhibitor gene.
AB - Treatment of a variety of cell lines with IFN-gamma leads to enhanced synthesis
and secretion of C1 inhibitor (C1inh). The induction of C1inh synthesis by IFN
gamma is primarily regulated at the transcriptional level, and is controlled by
elements in the 5' flanking region and the first intron of the C1inh gene. Hep3B
cells transfected with reporter constructs containing truncated segments between
738 and -81 of the 5' flanking region and stimulated with IFN-gamma expressed
increased levels of chloramphenicol acetyl transferase. These data as well as the
data obtained from studies using constructs with mutated IFN-gamma-activated
sequence (GAS) indicate that the most proximal GAS element (GAS 4) that mapped to
nucleotides -126 to -118 is responsible for this IFN-gamma responsiveness.
Electrophoretic mobility shift assays using GAS 4 yielded a single band that
appeared within 5 min after stimulation with IFN-gamma. In competition
experiments, both GAS 4 and consensus GAS probes, but not a mutated GAS probe,
competed for the GAS binding protein present in Hep3B and U-937 cell extracts.
The identity of the GAS binding protein was confirmed using anti-STAT-1alpha Abs
in supershift assays. The results indicate that STAT-1alpha binds to GAS 4, which
is the primary element in the 5' flanking region responsible for IFN-gamma
induction of the C1inh gene.
PMID- 9550410
TI - Identification of class I genes in cartilaginous fish, the most ancient group of
vertebrates displaying an adaptive immune response.
AB - Sharks are members of the most primitive class of vertebrates (Chondrichthyes)
shown to have an adaptive immune system. Suprisingly, however, class I genes have
not been identified unambiguously in this taxon, and absence of class I loci or a
failure to express class I genes might explain some of the relatively "weak"
adaptive immune responses documented in cartilaginous fish. We report here the
isolation of three unique cDNA clones from two different species of sharks that
encode bona fide class I proteins. These clones exhibit different sequence and
expression profiles indicating that they are likely to represent both classical
and nonclassical class I lineages. In addition, our preliminary analysis suggests
that there may be transfer of gene segments among shark class I genes over
evolutionary time. The cloning of shark class I genes completes the
identification of molecules that define the adaptive immune system (including Ig,
TCR, and MHC class II proteins) in this taxon. Thus, simple models invoking a
total absence of certain molecular hallmarks of the immune system to account for
poor immune responsiveness in cartilaginous fish should be abandoned.
PMID- 9550411
TI - A filarial nematode secreted product differentially modulates expression and
activation of protein kinase C isoforms in B lymphocytes.
AB - Filarial nematodes, parasitic worms that cause elephantiasis, chronic skin
lesions, and blindness in the tropics, release a number of molecules, some of
which appear to be immunomodulatory/suppressive, into the host environment. Here
we demonstrate that ES-62, a phosphorylcholine-containing glycoprotein released
by the rodent filarial parasite Acanthocheilonema viteae, interferes with
activation of B lymphocytes by differential modulation of protein kinase C
isoform expression. Indeed, while ES-62 selectively down-regulates expression of
the alpha, beta, iota/lambda, delta, and zeta isoforms of PKC, it up-regulates
expression of PKC-gamma and -epsilon in B cells. Inhibitor studies suggest that
ES-62 appears to promote down-regulation of PKC isoforms mainly by stimulating
proteolytic degradation. ES-62 also disrupts the normal activation and nuclear
translocation patterns of the alpha and iota/lambda isoforms of PKC following
ligation of the Ag receptor. The effects of ES-62 on certain PKC isoforms were
found to be modified by coculture with IL-4. Of particular interest was the
observation that IL-4 prevented down-regulation of PKC alpha and iota/lambda,
isotypes considered to be active in transducing mitogenic signals.
Phosphorylcholine-containing secreted products (phosphorylcholine-ES) are also
released by human filarial parasites; hence we discuss how these findings may
relate to the nature of the human B cell response during filarial infections.
PMID- 9550412
TI - Immune responses induced by intramuscular or gene gun injection of protective
deoxyribonucleic acid vaccines that express the circumsporozoite protein from
Plasmodium berghei malaria parasites.
AB - The circumsporozoite protein (CSP) is a target for effector Ab and cell mediated
immunity against malaria parasites; DNA vaccination can induce both types of
effector response. The immunogenicity and efficacy of two DNA plasmids expressing
different amounts of Plasmodium berghei CSP were evaluated by immunizing BALB/c
mice i.m. or epidermally and by varying the number of immunizations (one to three
doses) and the interval between immunizations. Expanding the interval gave the
strongest effect, increasing efficacy and antibody boosting, and, in the case of
epidermal vaccination, promoting a switch in CSP-specific IgG isotypes from IgG1
to a balance with IgG2a. The strongest humoral immune response and the greatest
level of protection were induced by vaccinating epidermally with high expresser
plasmid, using a gene gun to administer three doses at 6-wk intervals. For this
group, the mean, repeat-specific, prechallenge antibody titer among mice not
infected after challenge was significantly higher than that in infected mice, but
the mean prechallenge titers for antibody reactive with whole sporozoites were
not significantly different. The interval-dependent induction of IgG2a antibodies
by epidermal vaccination contradicts the widely held belief that antibody
responses induced by this method are restricted to those that are Th2 dependent.
PMID- 9550414
TI - Glycoconjugates isolated from Trypanosoma cruzi but not from Leishmania species
membranes trigger nitric oxide synthesis as well as microbicidal activity in IFN
gamma-primed macrophages.
AB - In the present study, we investigated the role of glycosylphosphatidylinositol
anchored mucin-like glycoproteins (GPI-mucins) from Trypanosoma cruzi
trypomastigotes in triggering the synthesis of nitric oxide as well as the
microbicidal activity in murine macrophages. Our results show that GPI-mucins
isolated from trypomastigote membranes are potent inducers of nitric oxide
synthesis by IFN-gamma-primed macrophages, even at concentrations as low as 10
ng/ml. Our data also indicate the important role of glycosylphosphatidylinositol
anchors from GPI-mucins as the second signal responsible for induction of nitric
oxide synthesis by macrophages. To further investigate the role of these parasite
molecules in inducing parasiticidal function, we cultured macrophages in the
presence or absence of trypomastigote GPI-mucins and/or IFN-gamma and then
infected these cells with either Leishmania spp. or T. cruzi. IFN-gamma was
sufficient to induce microbial activity in macrophages infected with T. cruzi
trypomastigotes. In contrast, killing of different species of Leishmania was
further enhanced when macrophages exposed to IFN-gamma were also costimulated
with trypomastigote-derived GPI-mucins. Our results also indicate that different
glycolipids obtained from Leishmania major or Leishmania donovani (i.e.,
lipophosphoglycans or glycoinositolphospholipids) were unable to potentiate
nitric oxide synthesis and/or microbicidal activity displayed by IFN-gamma-primed
macrophages.
PMID- 9550413
TI - Identification of Trypanosoma cruzi trans-sialidase family members as targets of
protective CD8+ TC1 responses.
AB - CD8+ T lymphocytes play a critical role in immunity to Trypanosoma cruzi.
However, the target molecules of this T cell subset have not been elucidated. In
this work, we report the identification of an H-2Kb-restricted CTL epitope within
two trypomastigote surface Ags encoded by members of the T. cruzi sialidase/trans
sialidase gene superfamily. Octapeptide VDYNFTIV sensitized target cells for
lysis by CD8+ CTL generated from spleens of T. cruzi-infected mice. Peptide
specific CD8+ T cell lines were cytotoxic, secreted IFN-gamma and TNF-alpha, but
low to undetectable levels of IL-4 and IL-5, and were able, upon adoptive
transfer, to confer a high degree of protection against challenge infection.
Finally, the protective determinant appears to be conserved among parasites from
diverse geographic locations. This constitutes the first identified class I MHC
restricted epitope in T. cruzi and provides the basis for the search of
additional targets to be considered in the development of vaccines against
Chagas' disease.
PMID- 9550415
TI - A secreted/shed product of Helicobacter pylori activates transcription factor
nuclear factor-kappa B.
AB - Helicobacter pylori is an etiologic agent in the development of chronic
gastritis, duodenal ulceration, and gastric adenocarcinoma. Exposure of gastric
epithelial cells to H. pylori induces secretion of the cytokine IL-8, which plays
a pivotal role in the immunopathogenesis of H. pylori infections. Isolated
Helicobacter strains differ in their virulence and in their ability to induce
cytokine production. High degrees of virulence correlate with enhanced IL-8
production. However, the molecular mechanism of this variance in Helicobacter
pathogenicity remains poorly understood. Here we show that H. pylori-mediated IL
8 secretion requires activation of the transcription factor nuclear factor-kappaB
(NF-kappaB) in a gastric epithelial cell line. Several H. pylori strains which
fail to induce IL-8 secretion do not activate NF-kappaB, while all IL-8-inducing
strains activate the transcription factor. Moreover, the antioxidant curcumin,
which inhibits NF-kappaB activation, also completely suppresses IL-8 induction by
H. pylori. NF-kappaB activation is not mediated by LPSs, since purified H. pylori
LPS had no effect on gastric epithelial cells. In contrast, both IL-8 secretion
and NF-kappaB activation require a secreted H. pylori product, which is not
secreted by strains mutated in picB/cagE, a recently identified putative
transport protein.
PMID- 9550416
TI - Depressed Langerhans cell migration and reduced contact hypersensitivity response
in mice lacking TNF receptor p75.
AB - Epidermal Langerhans cells (LC) belong to the dendritic cell family and represent
the major APC within the skin. LC capture epicutaneous Ag, migrate into regional
lymph nodes, and present Ag to T cells, thereby initiating primary immune
response. The migratory properties of LC are an essential component of their
function. The molecular mechanisms responsible for LC migration are far less
defined. However, evidence has been accumulating to suggest that TNF-alpha, a
major proinflammatory cytokine, plays an important role in promoting DC
migration. To confirm the role of TNF-alpha in LC migration and to examine which
type of TNF receptor signaling is involved in such an event, we utilized gene
targeted knockout mice lacking TNF receptor p55 or p75. The migration of LC was
assessed by examining the frequency of hapten-bearing cells in draining lymph
nodes following hapten FITC painting, and the accumulation of dendritic cells in
draining lymph nodes after intradermal injection of TNF-alpha. While LC migration
was normal in p55-deficient mice, the migration was markedly depressed in p75
deficient mice. Receptor p75-deficient mice also demonstrated a
hyporesponsiveness in allergen-induced contact dermatitis, but a normal
responsiveness in irritant-induced contact dermatitis. These results suggest that
p75-dependent signaling plays a crucial role in the migration of LC and in the
initiation of cutaneous immune responses.
PMID- 9550417
TI - Regulation of IL-18 (IFN-gamma-inducing factor) gene expression.
AB - IL-18 (also known as IFN-gamma-inducing factor), although structurally unrelated
to IL-12, shares with it the role of activating NK cells and polarizing T cells
toward Th1 cell function. To understand how the IL-18 gene (and consequently Th1
function) is regulated, we have determined the gene structure and investigated
the mechanisms of transcriptional control and cell type expression. The mouse IL
18 gene comprises seven exons distributed over 26 kb. Exons 1 and 2 of this gene
are 5'-noncoding exons. Promoter activity was detected upstream of these
noncoding exons in two distinct regions. Both promoters are TATA-less and not G+C
rich. The promoter activity located upstream of exon 2 was shown to act
constitutively, while the activity located upstream of exon 1 was up-regulated in
activated macrophage and T cell lines. IL-18 gene expression may be regulated in
a wide range of cell types by the activities of these two distinct promoters. IL
18 is known to be synthesized as a precursor, pro-IL-18, and its maturation is
controlled by IL-1beta-converting enzyme (ICE). We observed concordant expression
of IL-18 and ICE mRNAs in a wide range of cell types, unlike the more restricted
expression of IL-12 p40 mRNA. The widespread IL-18 mRNA distribution and the
special relationship with ICE lead us to the hypothesis that IL-18 expression may
be coupled with apoptotic processes involving activation of ICE or ICE-like
proteinase.
PMID- 9550418
TI - EBV induces the production and release of IL-8 and macrophage inflammatory
protein-1 alpha in human neutrophils.
AB - As the first line of defense in the immune system, neutrophils may release a
variety of potent agents upon exposure to infectious agents. In this study we
have investigated the ability of human neutrophils to produce chemotactic
cytokines, or chemokine in response to EBV. Exposure of neutrophils to EBV led to
an increase in accumulation of mRNA for IL-8 and macrophage inflammatory protein
1alpha (MIP-1alpha). EBV stimulated a time-dependent production of immunoreactive
IL-8 and MIP-1alpha by neutrophils. The ability of EBV to stimulate the synthesis
of IL-8 and MIP-1alpha protein was reflected by both an accumulation of the
protein in the intracellular compartment as well as increased secretion. A
variety of control studies support the idea that infectious EBV is not required
for induction of chemokine gene expression; however, the response is dependent on
the interaction between the glycoprotein gp350 of the viral envelope and the
neutrophil surface. Since both IL-8 and MIP-1alpha are reported to be
chemoattractants in vitro for T cells and for T and B cells, respectively, the
ability of EBV to induce their production by neutrophils may enhance the ability
of this virus to infect B and T lymphocytes via increased recruitment to sites of
infection.
PMID- 9550419
TI - Second-hand smoke is an adjuvant for T helper-2 responses in a murine model of
allergy.
AB - Epidemiologic studies have suggested that "second-hand smoke" increases the
incidence and severity of allergies and asthma. To address this, we developed a
murine model that included generation of and exposure to environmental tobacco
smoke (ETS) followed by aerosolized Ag challenge. We report herein that exposure
of OVA-sensitized BALB/c mice to ETS elicits a rapid and prolonged exaggerated
response with respect to IgE, IgG1, eosinophils, and Th2 cytokines (particularly
IL-4 and IL-10). There was a significant increase (p = 0.0159) in the total cells
of the bronchoalveolar lavage in OVA-sensitized mice exposed to ETS when compared
with those in ambient air. This is the first experimental data to demonstrate
that "second-hand smoke" up-regulates the allergic response to inhaled Ag. The
results have important health implications for children and allergic individuals
residing in households with smokers.
PMID- 9550420
TI - Recognition of the E-C4 element from the C4 complement gene promoter by the
upstream stimulatory factor-1 transcription factor.
AB - Activation of complement gene expression plays a major role in the response to
antigenic challenge. The induction of complement synthesis occurs primarily in
liver and in macrophages and is mediated, at least in part, by increased
transcription of the complement genes. For example, transcription of the C4
complement gene, which plays a crucial role in the complement pathway, is induced
in response to acute inflammation or tissue injury. Previous work has defined the
elements present in the C4 complement gene promoter that are required for its
expression. Particularly important is an E-box motif, E-C4, that is conserved
between the mouse, human, and rat promoters and that directed up to 90% of
transcription from the mouse C4 promoter. Here we have purified the E-C4-binding
factor to homogeneity using a novel and rapid affinity purification procedure.
Following N-terminal microsequencing and subsequent isolation of the
corresponding cDNA, the factor binding the E-C4 element was identified as
upstream stimulatory factor-1 (USF-1), a basic helix-loop-helix-leucine zipper
transcription factor. We also show for the first time that in vivo USF-1 is a
phosphoprotein, but that phosphorylation of USF-1 is severely reduced in cells in
culture. Moreover, the phosphorylated form of USF-1 binds DNA preferentially,
indicating that phosphorylation may enhance the ability of USF-1 to bind DNA. The
implications of USF-1 phosphorylation for C4 complement gene expression and
transcription regulation are discussed.
PMID- 9550421
TI - Cytokine induction of the ability of human monocyte CD44 to bind hyaluronan is
mediated primarily by TNF-alpha and is inhibited by IL-4 and IL-13.
AB - Ligation of CD44 by hyaluronan (HA) is a key proinflammatory event that regulates
lymphocyte and monocyte adhesion and cytokine production. While most immune cells
express CD44, few immune cells constitutively bind HA. We have previously shown
that monocyte CD44 acquires the ability to bind HA after in vitro culture of PBMC
in human serum and, therefore, we have investigated a series of human cytokines
and bacterial LPS for their ability to induce and/or inhibit monocyte CD44 to
bind HA. We found that IL-1alpha, IL-1beta, IL-3, granulocyte macrophage (GM)
CSF, and TNF-alpha, as well as bacterial LPS, all directly induced peripheral
blood monocytes to bind HA. In contrast, IL-2 and IL-15 up-regulated monocyte
CD44 HA-binding in PBMC suspensions, but not in purified monocyte suspensions. An
anti-TNF-alpha-neutralizing Ab inhibited IL-1alpha-, IL-1beta-, IL-3-, and GM-CSF
mediated monocyte HA binding. In addition, treatment of IL-2- and IL-15
stimulated PBMC cultures with an anti-TNF-alpha Ab prevented IL-2- and IL-15
induced monocyte HA binding, thus identifying TNF-alpha as a lymphocyte-derived
factor that acted on monocytes to induce HA binding. In contrast, IL-4 and IL-13
were potent inhibitors of monocyte CD44-HA binding induced by either human serum
or by IL-1alpha, IL-1beta, IL-3, GM-CSF, or TNF-alpha. IL-10 had dual effects on
monocyte CD44-HA binding. Alone, IL-10 induced HA binding to PBMC monocyte CD44,
while in contrast, IL-10 inhibited IL-1-induced monocyte CD44 binding to HA.
Taken together, these studies identify a network of T cell and monocyte-derived
cytokines that regulate HA binding to peripheral blood monocyte CD44, primarily
through TNF-alpha.
PMID- 9550422
TI - Calcium-dependent neutrophil secretion: characterization and regulation by
annexins.
AB - To gain direct access to the secretory machinery and study the regulation,
mechanisms, and effectors of Ca2+-dependent neutrophil secretion, we developed an
efficient and reproducible method of plasma membrane permeabilization using
streptolysin O. We confirmed previous studies that permeabilized neutrophils
secrete in response to calcium alone, but we also found that the Ca2+ dose
response is biphasic. Secretion is detectable at <1.0 microM Ca2+ and reaches a
plateau between 1.0 and 60 to 80 microM. When stimulated with >80 microM Ca2+,
secretion is two- to threefold greater than at lower [Ca2+], suggesting that two
distinct mechanisms of Ca2+-dependent secretion that differ in their affinity for
Ca2+ exist in neutrophils. Although permeabilization allows 100% leak of lactate
dehydrogenase, maximum secretion from permeabilized cells is 80% that of f-met
leu-phe-stimulated intact cells, indicating that the essential components of the
Ca2+-dependent secretory apparatus are predominantly, if not entirely, membrane
bound. Permeabilization causes leakage of 100% of annexins V and VI, but 41% of
annexin I and 12% of annexin III are retained. Immunofluorescence microscopy
revealed that retained annexins I and III are associated with granule membranes.
Addition of soluble annexins I and III to permeabilized cells increased Ca2+
induced secretion up to 15% and 90%, respectively, implying that both annexins
participate in this secretory pathway. While annexin V is not required for
secretion, it inhibits the low Ca2+-affinity mechanism of secretion.
PMID- 9550423
TI - Induction of biologically active IL-1 beta-converting enzyme and mature IL-1 beta
in human keratinocytes by inflammatory and immunologic stimuli.
AB - IL-1beta, a major mediator of inflammatory and immunologic skin disease,
undergoes post-translational site-specific cleavage by a novel cysteine protease
termed IL-1beta-converting enzyme (ICE). Although in human skin keratinocytes
produce significant amounts of the 31-kDa IL-1beta precursor protein, they fail
under nonpathologic conditions to convert it to the 17.5-kDa bioactive form. In
this study, we examined whether haptens and inflammatory agents might serve as
stimuli for ICE activity in human keratinocytes, and, if so, whether ICE activity
might precipitate enzymatic processing of IL-1beta to its 17.5-kDa form. Baseline
levels of ICE mRNA were detected in keratinocyte cultures devoid of Langerhans
cells and were up-regulated by nontoxic concentrations of the reactive hapten
urushiol and by the irritant chemicals sodium lauryl sulfate and PMA. Although
untreated keratinocytes expressed the 31-kDa form of the protein, 17.5-kDa IL
1beta was easily detected in keratinocytes and keratinocyte supernatants treated
with either urushiol or the irritant chemicals. Enzymatic conversion from the 31
kDa to the 17.5-kDa form of IL-1beta was blocked by addition of a highly specific
aldehyde inhibitor that contained a tetrapeptide recognition sequence specific
for ICE, but not by an aldehyde inhibitor of a related ICE-like cysteine
protease. Induction of IL-1beta-converting enzyme by immunologic and inflammatory
stimuli may be one of the key regulatory elements in the pathogenesis of allergic
and irritant contact hypersensitivity.
PMID- 9550424
TI - Extracellular ATP and UTP control the generation of reactive oxygen intermediates
in human macrophages through the opening of a charybdotoxin-sensitive Ca2+
dependent K+ channel.
AB - Human monocyte-derived macrophages possess a NADPH oxidase that catalyzes
superoxide formation upon phagocytosis. Extracellular ATP per se does not
activate NADPH oxidase but potentiates superoxide generation triggered by
opsonized zymosan. UTP can substitute for ATP with the same efficiency,
suggesting that ATP mediates its effects specifically through P2U receptors.
Extracellular UTP stimulates a rapid increase in cytoplasmic Ca2+ concentration
in monocytic cells, which results from a release of intracellular Ca2+ stores.
Moreover, UTP-induced calcium increase is sufficient to activate a charybdotoxin
sensitive Ca2+-dependent outward K+ channel (K(Ca)). The activity of this channel
develops between 0.1 and 1.0 microM free cytoplasmic Ca2+ concentration; it is
half-blocked by 10 nM charybdotoxin but insensitive to iberiotoxin. Under
asymmetrical K+ conditions, this K(Ca) channel does not depend on membrane
potential and is characterized by a linear single-current voltage relationship in
the voltage range of -100 to +50 mV, giving a unitary conductance of 10 pico
Siemens. Interestingly, ATP/UTP-induced oxygen radicals release was inhibited by
charybdotoxin in the same range of concentration as the UTP-induced K(Ca)
channel. Furthermore, we show that ATP or UTP fail to enhance oxygen radicals
production before K(Ca) channel is expressed (3 days). The electrogenic nature of
the NADPH oxidase, i.e., its level of activation, being dependent on the plasmic
membrane potential, might provide the causal link between the reactive oxygen
intermediates generation and the opening of the K(Ca) channel.
PMID- 9550425
TI - Potent induction of a neutrophil and eosinophil-rich infiltrate in vivo by human
mast cell tryptase: selective enhancement of eosinophil recruitment by histamine.
AB - Tryptase is the most abundant protein constituent of the secretory granules of
human mast cells, but little is known of the contribution of this serine
proteinase in acute allergic reactions. We have purified tryptase from human lung
tissue by immunoaffinity procedures, and have investigated its potential to
provoke an inflammatory infiltrate in vivo. Within 6 h of injection into the skin
of guinea pigs, the accumulation of large numbers of neutrophils and eosinophils
was observed, and those eosinophils closest to the injection site were partially
degranulated. Similarly, injection of tryptase into the peritoneum of mice, even
in quantities as low as 5 ng, stimulated the ingress of neutrophils. The response
was dose dependent at 3, 6, and 16 h, with increases in median numbers of up to
400-fold. At the later time points eosinophil numbers were increased by up to 10
fold, and there were elevations also in the numbers of lymphocytes and
macrophages. In both models, the actions of tryptase appeared to be dependent on
an intact catalytic site. Coinjection of heparin with tryptase had relatively
little effect on tryptase-induced responses. On the other hand, although
histamine did not itself stimulate cell accumulation, over a range of
concentrations it altered the cellular composition of the infiltrate induced by
tryptase. Addition of histamine to tryptase provoked selective increases in
eosinophil numbers of up to fivefold in the mouse peritoneum. Tryptase may
provide an important stimulus for granulocyte recruitment in allergic disease.
PMID- 9550426
TI - IFN-gamma and IL-10 inhibit induction of IL-1 receptor type I and type II gene
expression by IL-4 and IL-13 in human monocytes.
AB - The Th2-type cytokines IL-4 and IL-13 induce expression of a distinct subset of
genes in human monocytes. These include Fc epsilonRII (CD23), 15-lipoxygenase, IL
1 receptor antagonist (IL-1ra), and type I and type II IL-1 receptors (IL-1R).
IFN-gamma has been shown to inhibit induction of CD23 and 15-lipoxygenase in
monocytes; however, the effects of IFN-gamma on type I and type II IL-1R gene
expression have not been defined. We examined the effects of IFN-gamma on both
basal and IL-4/IL-13-induced IL-1R gene expression in primary monocytes. IL-4 and
IL-13 induced dose- and time-dependent increases in IL-1RI and IL-1RII mRNA
levels. IFN-gamma decreased basal expression as well as the induction of these
genes by IL-4 and IL-13. Inhibition of IL-1RI and IL-1RII mRNA levels by IFN
gamma was transcriptionally mediated, and correlated directly with decreased
production of soluble IL-1RII. Furthermore, the ability to suppress IL-1RI and IL
1RII mRNA levels was not unique to IFN-gamma because IL-10 also inhibited
expression of these genes in IL-4/IL-13-stimulated monocytes. Inhibition of IL-1R
gene expression by IFN-gamma and IL-10 was not due to down-regulation of surface
IL-4R because pretreatment with these cytokines did not decrease the number of IL
4 binding sites per cell. However, suppression of IL-1R gene expression by IFN
gamma and IL-10 was associated with decreased tyrosine phosphorylation and
nuclear translocation of the IL-4/IL-13-inducible transcription factor, Stat6,
suggesting a potential mechanism by which IFN-gamma and IL-10 may mediate their
suppressive effects. These findings demonstrate that certain cytokines, including
IFN-gamma and IL-10, antagonize the ability of IL-4 and IL-13 to induce increased
expression of the IL-1RI and IL-1RII genes in monocytes.
PMID- 9550427
TI - TNF and lymphotoxin-alpha polymorphisms associated with common variable
immunodeficiency: role in the pathogenesis of granulomatous disease.
AB - A subgroup of common variable immunodeficiency (CVID) patients have distinct
clinical features, particularly granulomata splenomegaly, characteristic blood
lymphocyte phenotype, and elevated circulating TNF levels. To investigate the
genetic basis for this phenotype, 150 CVID patients and 200 controls were
genotyped for six biallelic TNF and lymphotoxin-alpha (LT alpha) polymorphisms
and eight class I and II HLA loci using PCR and sequence specific primers (PCR
SSP) sequence-specific primers. Clinical and immunophenotypic data were collected
for 90 patients to examine associations with CVID patient subgroups. The presence
of granulomata (22% of patients) was strongly associated with splenomegaly, T and
B lymphopenia, reduced CD4+ CD45RA+ T cells, and CD8+ CD57+ lymphocytosis,
confirming the concept of a subgroup of patients with distinct clinical and
laboratory features. The uncommon TNF +488A allele was strongly associated with
this subgroup (p = 0.0005). The association between "granulomatous" CVID and TNF
+488A was independent of HLA class I and II associations. We postulate that the
presence of the TNF +488A allele, or alleles in linkage disequilibrium with it,
contributes to the high levels of TNF and granulomatous complications
characteristic of this subgroup of patients.
PMID- 9550428
TI - Identification and characterization of multiple HLA-A24-restricted HIV-1 CTL
epitopes: strong epitopes are derived from V regions of HIV-1.
AB - HIV-1-specific CTL has a crucial role in the elimination of the virus. However, a
restricted number of common HLA class I alleles has been studied for their
presentation of HIV-1 CTL epitopes. We have attempted to identify HIV-1 CTL
epitopes presented by HLA-A*2402 using reverse immunogenetics. Fifty-three HLA
A*2402-binding HIV-1 peptides were used to induce specific CTL in PBL of four HIV
1-infected individuals carrying HLA-A24. Twelve peptides were strongly suggested
to be HLA-A*2402-restricted HIV-1 CTL epitopes because these peptides induced the
specific CTL that killed both the target cells pulsed with the specific peptides
and those infected with the vaccinia HIV-1 recombinant virus in at least one HIV
1-infected individual. Of these epitopes, 11 were confirmed by the generation of
the specific CTL clones. Six were the Env epitopes while three, one, and one were
derived from Gag, Pol, and Nef proteins, respectively. Analysis of 12 HIV-1
infected individuals using these peptides showed that 5 derived from the Env
protein and one from the Nef protein were strong epitopes. These strong epitopes
were derived from the diverse region of HIV-1 while weak epitopes were conserved
in the HIV-1 clade B strain. Analysis of CTL recognition of mutations in these
strong epitopes suggested that the mutations in the Env epitopes may critically
influence CTL recognition in vivo.
PMID- 9550430
TI - Diminished class II-associated Ii peptide binding to the juvenile dermatomyositis
HLA-DQ alpha 1*0501/DQ beta 1*0301 molecule.
AB - HLA class II molecules bind and present peptide Ags to T cells, binding specific
sets of peptides due to polymorphism in the peptide binding groove. Class II
proteins associate with the invariant chain (Ii chain) and its derived class II
associated Ii peptide (CLIP). Ii chain association is important for normal
trafficking of class II proteins to the peptide loading vesicles and for blocking
premature access of peptides to HLA class II molecules during maturation. We have
previously shown that juvenile dermatomyositis is associated with the HLA
DQA1*0501 allele. There is limited information available about the interaction of
any DQ molecule with the Ii chain and little information about binding of
individual peptides to HLA-DQalpha1*0501/DQbeta1*0301. We sequenced peptides
eluted from the juvenile dermatomyositis-associated class II allele HLA
DQalpha1*0501/DQbeta1*0301. Surprisingly, we found no Ii chain or CLIP. Further
examination of peptide binding to the HLA-DQalpha1*0501/DQbeta1*0301 molecule
demonstrated poor CLIP binding. However, newly synthesized HLA
DQalpha1*0501/DQbeta1*0301 molecules do associate with intact Ii chain. Molecular
modeling suggests that CLIP binds differently to HLA-DQalpha1*0501/DQbeta1*0301
than to DR molecules. The lack of CLIP association suggests that HLA
DQalpha1*0501/DQbeta1*0301 has access to peptides earlier in the processing
pathway and so might encounter novel peptides that induce autoimmunity.
PMID- 9550429
TI - Suppression of TNF-alpha expression, inhibition of Th1 activity, and amelioration
of collagen-induced arthritis by rolipram.
AB - Rolipram is a type IV phosphodiesterase inhibitor that suppresses inflammation
and TNF-alpha production. As anti-TNF-alpha therapy is effective in rheumatoid
arthritis, we investigated the effect of rolipram on collagen-induced arthritis
(CIA), a murine model of rheumatoid arthritis. Rolipram was administered after
the onset of clinical arthritis at doses of 0.5, 3, 5, or 10 mg/kg twice daily,
with a dose-dependent therapeutic effect on clinical severity and joint erosion.
Immunohistochemical analysis of joints of rolipram-treated mice revealed 67%
reduction in TNF-alpha-expressing cells compared with control arthritic mice. In
vitro studies using bone marrow-derived macrophages confirmed that rolipram
directly suppressed TNF-alpha and IL-12 production following stimulation with IFN
gamma and LPS. The effect of rolipram on T cell activity was studied by measuring
Th1/Th2 cytokine production by collagen-stimulated draining lymph node cells from
arthritic mice treated in vivo with rolipram. Rolipram reduced IFN-gamma
production and increased IL-10, indicating that rolipram down-regulated the
ongoing Th1 response to type II collagen. Finally, the effect on CIA of
combination therapy was studied using rolipram plus either anti-TNF-alpha or anti
CD4 mAbs. Rolipram plus anti-TNF-alpha was not therapeutically additive, whereas
rolipram plus anti-CD4 mAb was clearly additive. This result indicates that the
therapeutic effects of rolipram overlap with TNF-alpha blockade, but are
complementary to anti-CD4 treatment. It is therefore proposed that a major
mechanism of action of rolipram in CIA is suppression of TNF-alpha activity.
These findings suggest that type IV phosphodiesterase inhibitors may be effective
in pathologic conditions, such as RA, with overexpression of TNF-alpha.
PMID- 9550432
TI - A role for TNF-alpha and mucosal T helper-1 cytokines in the pathogenesis of
Crohn's disease.
AB - Recent clinical studies of Crohn's disease patients demonstrated dramatic
clinical responses following one i.v. infusion of a chimeric mAb to TNF-alpha
(cA2). To assess the role of TNF-alpha in mucosal cytokine regulation, the
effects of TNF-alpha on lamina propria mononuclear cell (LPMC) Th1 production
were determined. Increased IFN-gamma production was demonstrated in anti-CD2
stimulated LPMC cultured in TNF-alpha. To determine the effects of cA2 on
cytokine production, TNF-alpha- and IFN-gamma-producing cells were quantitated in
LPMC from five Crohn's disease patients treated with cA2. In all four patients
who demonstrated clinical and endoscopic improvement, decreased numbers of LPMC
producing IFN-gamma and TNF-alpha following CD2/CD28 activation paralleled
improvement in disease activity over 8 wk. In one patient who did not improve,
increased numbers of TNF-alpha- and IFN-gamma-secreting LPMC were observed. In
three of four responding patients, CD2/CD28-activated PBMC demonstrated increased
IFN-gamma production over 8 wk. These observations suggest that TNF-alpha may be
a cofactor for mucosal Th1 responses, and improvement in clinical parameters and
intestinal inflammation induced by cA2 in Crohn's disease may be mediated by down
regulation of mucosal Th1 cytokines.
PMID- 9550431
TI - Inhibition of inducible nitric oxide synthase intensifies injury and functional
deterioration in autoimmune interstitial nephritis.
AB - T lymphocytes are exquisitely sensitive to the antiproliferative effects of
nitric oxide. We examined the effects of oral administration of two nitric oxide
synthase inhibitors, Nw-nitro-L-arginine methyl ester (L-NAME) and L-N6-(1
iminoethyl)lysine (L-NIL), on the course of T cell-dependent autoimmune
interstitial nephritis in Brown Norway rats. Kidneys from rats immunized to
produce interstitial nephritis display a net generation of nitric oxide end
products. By immunohistochemical staining, the cytokine-inducible nitric oxide
synthase (iNOS) is expressed in cortical tubular epithelial cells. Treatment with
either inhibitor results in markedly more severe disease following immunization.
Animals receiving L-NAME were hypertensive, while those treated with L-NIL, a
highly selective inhibitor of iNOS, were not. Evaluation of the expression of IFN
gamma, IL-2, and IL-4 in diseased kidneys by quantitative reverse transcriptase
PCR demonstrated that L-NAME-treated animals displayed significantly augmented
levels of IFN-gamma and IL-2 with preserved ratios of IFN-gamma/IL-4 and IL-2/IL
4, while L-NIL-treated animals had augmented levels of IL-2 and IFN-gamma with
augmented IFN-gamma/IL-4 and IL-2/IL-4 ratios. Animals treated with L-NAME or L
NIL both had augmented Ag-specific IgG responses. The L-NAME group demonstrated
increases in both the IgG2a and IgG1 subtypes, with a constant IgG2a/IgG1 ratio,
while the L-NIL group demonstrated an increase in the ratio of the IgG2a/IgG1
response. These Ab and cytokine data suggest that the L-NIL-treated animals had a
skewing of their immune response toward a Th1-like response. We conclude that in
autoimmune interstitial nephritis, generation of nitric oxide through the iNOS
pathway has host-protective effects, and suggest that this may be broadly
applicable to T cell-mediated pathologies.
PMID- 9550433
TI - Association of CD4+ T cell-dependent keratitis with genetic susceptibility to
Pseudomonas aeruginosa ocular infection.
AB - The role of T lymphocytes in susceptibility to Pseudomonas aeruginosa corneal
infection was studied in inbred C57Bl/6 (B6) beta2-microglobulin+/+ (beta2m+/+)
and beta2m-/- knockout (KO) mice on a B6 genetic background. The corneas of both
B6 and KO mice perforated by 7 days postinfection (p.i.). Histopathology revealed
a similar inflammatory response characterized by an infiltration of
polymorphonuclear neutrophilic leukocytes by 24 h p.i. in both groups of mice.
CD4+ and CD8+ (latter absent in KO) T cells were present in cornea by 3 days
p.i., and by 5 days, IL-2R-positive cells were positively immunostained. Corneas
of B6 beta2m+/+ mice depleted of CD4+ T cells and infected with P. aeruginosa did
not perforate at 7 days p.i. vs mice depleted of CD8+ T cells or treated with an
irrelevant mAb. Neutralization of IFN-gamma before infecting B6 mice prevented
corneal perforation and was associated with a lower delayed-type hypersensitivity
than in B6 mice similarly treated with an irrelevant mAb. These data provide
evidence that a CD4+ T cell (Th1)-dominated response following P. aeruginosa
corneal infection is associated with genetic susceptibility and corneal
perforation in inbred B6 mice.
PMID- 9550434
TI - Demonstration and functional analysis of IL-10 receptors in human epidermal
cells: decreased expression in psoriatic skin, down-modulation by IL-8, and up
regulation by an antipsoriatic glucocorticosteroid in normal cultured
keratinocytes.
AB - The chronic skin disease psoriasis is characterized by epidermal
hyperproliferation and inflammation. The exact etiology of the disease is still
unknown. At the molecular level, overexpression of growth factors and
proinflammatory cytokines such as IL-8 and the corresponding receptor has been
described in psoriatic plaques. On the other hand, the loss of inhibitory control
mechanisms is involved in the pathogenesis of the disease, as exemplified by the
reduced mRNA levels for the cell cycle inhibitor p53 found in lesional skin. Here
we extend these findings to a cytokine with negative regulatory functions, IL-10.
Only under certain conditions are human keratinocytes able to synthesize IL-10.
In skin, pathological overexpression of IL-10 was described om atopic dermatitis.
IL-10 exerts its effects via a specific receptor (IL-10R). We show here for the
first time the presence and functionality of IL-10R in epidermal cells and its
dramatically decreased expression in acute exanthematic psoriatic epidermis by in
vitro and in situ binding studies. These results were substantiated using
semiquantitative reverse transcriptase-PCR, demonstrating decreased expression of
the IL-10R gene in psoriatic skin, its down-modulation by the proinflammatory
cytokine IL-8, and its pharmacological induction in cultured cells. Biological
responsiveness of epidermal cells toward IL-10 could also be demonstrated by a
reduction of the growth rate and inhibition of IFN-gamma-induced HLA-DR
expression. Our results provide the first evidence for a role of the IL-10R gene
in the homeostasis of the epidermis and substantiate the concept of a loss of
negative regulatory peptides as a step in the eruption of psoriasis.
PMID- 9550435
TI - TNF-alpha down-regulates type 1 cytokines and prolongs survival of syngeneic
islet grafts in nonobese diabetic mice.
AB - Administration of TNF-alpha to autoimmune diabetes-prone nonobese diabetic mice
and biobreeding rats inhibits diabetes development; however, the mechanism(s) of
diabetes prevention by TNF-alpha has not been established. We used the model of
syngeneic islet transplantation into diabetic nonobese diabetic mice to study the
effects of TNF-alpha administration on the types of mononuclear cells and
cytokines expressed in the islet grafts and on autoimmune diabetes recurrence.
Twice daily i.p. injections of TNF-alpha (20 microg/day) from day 1 to day 30
after islet transplantation significantly prolonged islet graft survival; thus,
70% (16 of 23) of mice treated with TNF-alpha were normoglycemic at 30 days after
islet transplantation compared with none (0 of 14) of vehicle-treated control
mice. Islet grafts and spleens from TNF-alpha-treated mice at 10 days after islet
transplantation contained significantly fewer CD4+ and CD8+ T cells, and
significantly decreased mRNA levels of type 1 cytokines (IFN-gamma, IL-2, and TNF
beta) than islet grafts and spleens from control mice. Regarding type 2
cytokines, IL-4 mRNA levels were not changed significantly in islet grafts or
spleens of TNF-alpha-treated mice, whereas IL-10 mRNA levels were decreased
significantly in islet grafts of TNF-alpha-treated mice and not significantly
changed in spleens. TGF-beta mRNA levels in islet grafts and spleens were similar
in TNF-alpha-treated and control mice. These results suggest that TNF-alpha
partially protects beta cells in syngeneic islet grafts from recurrent autoimmune
destruction by reducing CD4+ and CD8+ T cells and down-regulating type 1
cytokines, both systemically and locally in the islet graft.
PMID- 9550436
TI - Autonomic innervation of the human middle ear: an immunohistochemical study.
AB - PURPOSE: Although there have been numerous studies of autonomic innervation of
the middle ear mucosa, and the mechanism of effusion into the middle ear cavity
in animals, the autonomic innervation of the human middle ear has not received
much attention. The purpose of this study is to show the presence of
catecholaminergic nerve fibers in the human middle-ear mucus membrane that may
play an important role in the pathogenesis of middle-ear effusion. MATERIALS AND
METHODS: A total of 126 celloidin-embedded temporal bone sections from the
temporal bone bank at the House Ear Institute were used for immunohistochemical
study. A polyclonal antibody to tyrosine hydroxylase enzyme was used to show the
presence of catecholaminergic nerve fibers. RESULTS: Tyrosine hydroxylase
immunoreactive nerve fibers containing numerous fine varicosities along their
course, characteristic of noradrenergic neurons, were observed throughout the
middle-ear mucosa including the promontary, sinus tympani, mesotympanum, and
hypotympanum. In addition, these nerve fibers were seen in close promixity to the
small-caliber blood vessels. A striking variation in the intensity of staining as
well as in the amount of nerve fibers was observed among the temporal bone
sections. CONCLUSION: It is possible that the catecholaminergic nerve fibers,
like elsewhere in the body, may exert a direct influence on the middle-ear
mucosal blood vessels. We speculate that the effusion into the middle-ear space
is an active, rather than a passive process. It is conceivable that cholinergic
sympathetic nerves might exist in the human middle-ear mucus membrane, and that
these autonomic nerves, in conjunction with the neuropeptides, may play an active
role in the pathogenesis of human middle-ear effusion.
PMID- 9550437
TI - Prognostic significance of vascular and perineural invasion in cancer of the
larynx.
AB - PURPOSE: Perineural and vascular invasion are generally recognized as poor
prognostic factors in cancer. The authors report the prognostic significance of
perineural and vascular invasion in cancer of the larynx. MATERIALS AND METHODS:
The laryngectomy specimens of 94 patients with squamous cell carcinoma of the
larynx were analyzed histopathologically for vascular and perineural invasion.
Prognostic significance of vascular and perineural invasion was evaluated related
to the cervical lymph node metastasis, recurrence, and disease-free survival.
RESULTS: Vascular invasion significantly influences cervical lymph node
metastasis for supraglottic tumors, yet not for glottic and transglottic tumors.
Perineural invasion has marginal significance in cases of cervical lymph node
metastasis of supraglottic tumors; it has no significance in cases of cervical
lymph node metastasis of glottic and transglottic tumors. Vascular invasion
significantly increases local and regional recurrence rate, but not distant
metastasis rate. Perineural invasion significantly increases local recurrence
rate, but not regional recurrence and distant metastasis rate. The disease-free
survival is significantly shortened by the presence of vascular and perineural
invasion. According to multivariant analysis, neither vascular nor perineural
invasion significantly effects the disease-free survival independently (P> .15).
The presence of vascular invasion significantly affects the recurrence
independently (P=.045). The presence of vascular invasion significantly reduces
the interval between surgery and the development of recurrence (P=.013).
CONCLUSION: The presence of vascular and perineural invasion should be checked in
every laryngectomy specimen because both have a significant prognostic value;
both influence the disease-free survival and recurrence significantly. Vascular
invasion significantly increase cervical lymph node metastasis of supraglottic
tumors; perineural invasion has only marginally significant effect on cervical
lymph node metastasis of supraglottic cancers. Vascular invasion plays an
independent role in determining the recurrence.
PMID- 9550438
TI - Donor site evaluation for fibula free flap transfer.
AB - PURPOSE: The role of routine preoperative angiography in patients undergoing
fibula flap transfer remains controversial. A recent survey of experienced
microvascular surgeons indicated that routine angiography may be unnecessary in
patients with no symptoms of peripheral vascular disease and normal lower
extremity pulses. To study the necessity of performing preoperative vascular
imaging studies, the incidence of congenital and acquired vascular anomalies that
prevented the harvest of a fibula flap is reported in a series of patients
undergoing evaluation for oromandibular reconstruction PATIENTS AND METHODS: A
series of 19 consecutive patients who underwent preoperative lower extremity
vascular imaging studies in anticipation of performing a fibula free flap is
presented. RESULTS: Angiographic findings significantly altered the surgical
reconstruction that was performed in 4 of 19 (21%) patients. Three patients with
a history or examination suggestive of peripheral vascular disease were excluded
on the basis of the findings at the time of radiographic study. In a fourth
patient, the contralateral leg was used for reconstruction when preoperative
angiography showed a dominant peroneal artery supplying the foot in the extremity
initially considered for flap harvest. CONCLUSION: History and physical
examination are not helpful in detecting most congenital vascular anomalies that
would place the foot at risk for ischemia if the peroneal artery is sacrificed.
The findings of this small series are consistent with the previously documented
incidence of anomalous blood supply to the foot and demonstrate the need for
preoperative vascular imaging studies in patients undergoing fibula free flap
transfer to avoid a potentially catastrophic complication.
PMID- 9550439
TI - The pectoralis major myofascial flap: clinical applications in head and neck
reconstruction.
AB - PURPOSE: The pectoralis major myofascial (PMMF) flap, a simple variant of the
pectoralis major myocutaneous (PMMC) flap, has been underemphasized as a
reconstructive method in head and neck surgery. MATERIALS AND METHODS: In the
present study, we review our experience using 18 PMMF flaps for a variety of
reconstructive purposes in 15 head and neck cancer patients treated at a tertiary
care hospital. Twelve of the study patients were undergoing surgical salvage of a
recurrent cancer, and 10 had received previous radiation. RESULTS: The overall
rate of flap complications in our series was 22%, and the incidence of major flap
complications requiring surgical revision was 11%. CONCLUSION: In our experience,
the use of the PMMF flap for a variety of reconstructive tasks in the head and
neck has been associated with a high overall success rate with avoidance of some
of the limitations of the PMMC flap.
PMID- 9550440
TI - Facial nerve function after cerebellopontine angle surgery and prognostic value
of intraoperative facial nerve monitoring: a critical evaluation.
AB - PURPOSE: Facial nerve monitoring is often used to predict postoperative facial
function after acoustic neuroma tumor removal. In this study, three methods of
predicting facial nerve function were compared. These methods used various
parameters of the evoked electromyographic monitoring. MATERIALS AND METHODS:
Thirty-four patients who underwent surgery for acoustic neuroma were
retrospectively reviewed. Amplitude of ongoing electromyographic activity,
stimulation current thresholds, and the amplitude of evoked response were
analyzed. The predictive value of the three methods was compared with actual
postoperative facial nerve function. RESULTS: One method predicted the final
postoperative facial function in 90% of the patients, one method in 84%, and the
final method failed to predict the final VIIth nerve function in patients with
current stimulation thresholds greater than 0.05 mA. CONCLUSION: Analysis of
prognostic value showed that one of the three studied proved superior in
predicting facial nerve function.
PMID- 9550441
TI - Globus sensation after laser-assisted uvulopalatoplasty.
AB - PURPOSE: To determine the cause of globus sensation following laser-assisted
uvulopalatoplasty (LAUP). MATERIALS AND METHODS: Sixty consecutive LAUP patients
were questioned regarding globus sensation. Palate sensation on globus patients
was mapped and compared with asymptomatic LAUP control patients. Symptomatic
patients were tested again 2 months later. RESULTS: There was a 25% incidence of
globus with 8% rated severe and 16% rated mild. The globus sensation corresponds
to an insensate area of palate (P < .01). Resolution of the symptoms coincides
with reemergence of sensation on the palate. CONCLUSION: Sensory dennervation of
the central palate is a likely source of post-LAUP globus sensation. As sensation
returns, symptoms abate. Palate surgery should be designed with this in mind. It
is possible that undiagnosed globus patients may have areas of anesthetic
pharynx.
PMID- 9550442
TI - Significance of trisomy 7 related to PCNA index in cholesteatoma.
AB - PURPOSE: To define the biological features of the variable aggressiveness of
cholesteatoma, we performed a retrospective cytogenetic and kinetic study.
MATERIALS AND METHODS: We studied 44 cases of cholesteatoma by using fluorescence
in situ hybridization with specific alpha-satellite DNA probes for chromosome 7
and immunohistochemical analysis of proliferating cell nuclear antigen (PCNA)
with PC10 monoclonal antibody. RESULTS: We observed the presence of three or four
chromosome 7 in elevated percentages of cells of 23 cases, and a high PCNA index
(above mean value) in 22 cases. CONCLUSION: Based on our results, we maintain
that the presence of an extra chromosome 7 is correlated with an increase of
proliferative activity. Therefore, trisomy 7 can be considered a prognostic
marker and an indicator of aggressive behavior in cholesteatoma.
PMID- 9550443
TI - Parathyroid preservation during thyroid surgery.
AB - PURPOSE: Even though thyroid surgery is generally quite safe, permanent
hypoparathyroidism is a very distressing complication. The incidence of
hypoparathyroidism is directly proportional to the extent of thyroidectomy, and
inversely proportional to the experience of the surgeon. It is also related to
the extent of invasion of thyroid cancer and of the degree of dissection in the
tracheo-esophageal groove. The incidence reported in the literature varies
between 1% to 29%. Total thyroidectomy results in a higher incidence of
hypoparathyroidism. MATERIALS AND METHODS: This report describes experiences with
600 thyroidectomies over a period of 11 years. The major indications for surgery
included suspicion or proof of malignancy, compression symptoms, and substernal
goiters. Twenty-six patients underwent surgery for Graves' disease. There were
221 men and 379 women, ranging in age from 16 to 89 years; 88% of the patients
had benign disease, whereas 12% of the patients had malignant pathology. The
surgical procedures included 62 total thyroidecotmies, 188 subtotal
thyroidectomies, and lobectomy and isthmectomy in 350 patients. RESULTS:
Meticulous tracheo-esophageal groove dissection, identification of parathyroids
and their preservation, including the blood supply, was routine in each case.
Even in patients undergoing unilateral lobectomy, every effort was made to
preserve the parathyroids. If any of the parathyroids or its blood supply was
injured, it was autotransplanted in the sternomastoid muscle. Only two patients
developed temporary hypoparathyroidism. CONCLUSION: Parathyroid
autotransplantation is performed whenever one or more of the parathyroids are
damaged. Parathyroid preservation during thyroid surgery is crucial in the
overall management of thyroid diseases.
PMID- 9550444
TI - Supraglottic laryngectomy.
PMID- 9550445
TI - Nasal tooth.
PMID- 9550446
TI - Vascular leiomyoma of the carotid sheath simulating a carotid body tumor.
PMID- 9550447
TI - Computer coregistration of positron emission tomography and magnetic resonance
images in head and neck cancer.
AB - PURPOSE: Early experience has shown that positron-emission tomography (PET) is a
useful technique for the detection of occult squamous cell carcinoma of the head
and neck. Although highly sensitive, PET lacks definition of anatomic detail and
therefore does not localize pathology precisely. To circumvent this limitation, a
computerized coregistration technique has been developed at the University of
California-Los Angeles to correlate PET and magnetic resonance images (MRI). This
method allows accurate, precise anatomic localization of areas of heightened
glucose metabolism, including subclinical tumors. MATERIALS AND METHODS: The
technique uses a coregistration computer program that precisely superimposes the
PET scan with the corresponding MRI image. RESULTS: Two cases are presented in
which PET-MRI coregistration was used to anatomically define the areas of
heightened glucose metabolism. Large tumors were selected because the precision
of the method can be verified. CONCLUSION: The coregistration technique is a
valuable addition to PET imaging, particularly in its ability to anatomically
localize PET findings. The most important application of this technique is to
facilitate the biopsy of subclinical lesions identified on PET.
PMID- 9550448
TI - Lingual thyroid: endoscopic management with CO2 laser.
PMID- 9550449
TI - Bilateral parotid gland metastases as the initial manifestation of a small cell
carcinoma of the lung.
PMID- 9550450
TI - The insulin system: influence of antioxidants.
PMID- 9550451
TI - Nutrition and physical activity with particular emphasis on bone health.
PMID- 9550452
TI - The glucose/insulin system and vitamin C: implications in insulin-dependent
diabetes mellitus.
AB - The cellular uptake of vitamin C (ascorbic acid, ASC) is promoted by insulin and
inhibited by hyperglycemia. If a rise in plasma ASC is uncoupled from insulin
replacement in insulin-dependent diabetes mellitus (IDDM) then the degree of
hyperglycemia could account for "tissue scurvy" in IDDM. Leukocyte ASC is lower
in IDDMs compared with nondiabetics when vitamin C consumption is adequate and
our data suggest that this is a variable component of the pathophysiology of
IDDM. The complications of diabetes mellitus are believed to result from either
the intracellular accumulation of sorbitol or the nonenzymatic glycoxidation of
proteins or both. With respect to the abnormal cellular accumulation of sorbitol,
vitamin C supplementation has been shown to be effective in several studies of
adults with diabetes; the situation regarding the prevention of protein
glycoxidations by supplementation is presently unclear. The roles of ASC as an
aldose reductase inhibitor and a water soluble antioxidant in body fluids are
potentially very important as adjuncts to tight glycemic control in the
management of diabetes. Tissue saturation and maximal physiologic function in
IDDM may require supplemental vitamin C intake.
PMID- 9550453
TI - Zinc, insulin and diabetes.
AB - The relationship between diabetes, insulin and zinc (Zn) is complex with no clear
cause and effect relationships. In Type 1 diabetes there is a lack of insulin
production, in Type 2 diabetes resistance to the effects of insulin are
predominant. Both Type 1 and Type 2 have the same long-term complications.
Diabetes effects zinc homeostasis in many ways, although it is most probably the
hyperglycemia, rather than any primary lesion related to diabetes, which is
responsible for the increased urinary loss and decreases in total body zinc. The
role of Zn deficiency, which could, at least potentially, exacerbate the cytokine
induced damage in the autoimmune attack which destroys the islet cell in Type 1
diabetes, is unclear. Since Zn plays a clear role in the synthesis, storage and
secretion of insulin as well as conformational integrity of insulin in the
hexameric form, the decreased Zn, which affects the ability of the islet cell to
produce and secrete insulin, might then compound the problem, particularly in
Type 2 diabetes. Several of the complications of diabetes may be related to
increased intracellular oxidants and free radicals associated with decreases in
intracellular Zn and in Zn dependent antioxidant enzymes. There appears to be a
complex interrelationship between Zn and both Type 1 and Type 2 diabetes. The
role of Zn in the clinical management of diabetes, its complications, or in its
prevention is, at best, unclear.
PMID- 9550454
TI - Comparative effects of chromium, vanadium and gymnema sylvestre on sugar-induced
blood pressure elevations in SHR.
AB - OBJECTIVE: Effects on systolic blood pressure (SBP) of ingesting three agents
reported to influence insulin metabolism, i.e., chromium polynicotinate,
bis(maltolato)oxovanadium (BMOV), and the herb, Gymnema sylvestre, were assessed
simultaneously in spontaneously hypertensive rats (SHR). METHODS: In the first
study, SHR were fed either a starch, sugar, or sugar diet containing chromium
polynicotinate, bis(maltolato)oxovanadium (BMOV), or G. sylvestre. Tail SBP was
estimated indirectly and various blood chemistries were measured. TBARS formation
was determined in hepatic and renal tissue. In a second study, tail SBP was
measured in SHR ingesting diets containing different concentrations of BMOV.
RESULTS: Compared to starch, SHR consuming sucrose showed a significant elevation
of SBP within days that was maintained for the duration of study. Addition of
chromium polynicotinate to the sucrose diet at the beginning of study prevented
the sucrose-induced elevation of SBP for 2 weeks, but SBP rose significantly
after that. BMOV at high concentrations overcame the sucrose-induced rise in SBP
and even decreased SBP below values seen in SHR eating the starch diet, but
marked weight loss was noted. A second study examined different concentrations of
BMOV. At 0.01% w/w concentration of BMOV, SBP was still significantly decreased,
even though SHR did not lose body weight (BW) early on. SHR consuming G.
sylvestre showed no change or even elevated SBP. Hepatic thiobarbituric acid
reacting substances (TBARS) formation, an estimate of lipid peroxidation, was
decreased by chromium polynicotinate and BMOV, and renal TBARS by chromium
polynicotinate. Circulating cholesterol concentrations were decreased in the SHR
consuming G. sylvestre. CONCLUSIONS: Chromium decreases the portion of SBP
elevated by high sucrose intake as shown previously, but high levels of sucrose
ingestion can eventually overcome this. BMOV overcame sucrose-induced elevation
of SBP as well as some of the "genetic hypertension." Different from chromium,
this decrease was not overcome by high levels of dietary sucrose. The significant
lowering of cholesterol with G. sylvestre ingestion indicates some effect on
metabolism, but G. sylvestre did not lower and even raised SBP.
PMID- 9550455
TI - The effect of a marathon run on plasma and urine mineral and metal
concentrations.
AB - BACKGROUND: Little data exist on the requirements of trace metals and minerals
for endurance athletes. Changes in body status of these elements must be examined
before specific nutritional recommendations can be made. This study was designed
to determine whether a marathon run was associated with changes in serum and
urine metal and mineral concentrations. METHODS: Forty subjects who planned to
complete the 1996 Houston-Tennaco marathon were recruited. Subjects had blood and
urine samples collected 2 weeks prior to the race and immediately following the
race. Blood and urine specimens were analyzed for copper, iron, magnesium and
zinc concentrations. Blood was also analyzed for calcium concentration and
ceruloplasmin activity. RESULTS: Twenty-six subjects (24 male, 2 female)
completed the marathon. Finish times varied between 2 hours 43 minutes and 5
hours 28 minutes. There was no significant change in serum calcium, copper or
zinc concentrations or ceruloplasmin activity. Serum and urine magnesium
concentration decreased significantly (19.55+/-1.73 to 16.55+/-1.53 ppm,
p=0.00001; 34.02+/-8.64 to 21.80+/-12.24 ppm, p=0.003, respectively). Serum iron
concentration increased significantly (1.06+/-0.48 to 1.35+/-0.42 ppm, p=0.006),
while urine copper and iron concentrations were below the limits of detection,
zinc concentration did not change. CONCLUSIONS: Serum and urinary magnesium
concentrations decrease during endurance running, consistent with the possibility
of magnesium deficiency. This may be related to increased demand in skeletal
muscle. Serum iron concentration increases, possibly related to tissue injury.
The exact etiology for these observations, as well as their clinical
significance, requires further investigation.
PMID- 9550456
TI - Stress fractures in female army recruits: implications of bone density, calcium
intake, and exercise.
AB - OBJECTIVE: To identify characteristics and factors associated with increased risk
for stress fractures in military women. DESIGN: Case-control study to
retrospectively examine physical activity, prior calcium intake, and bone density
as predictors of stress fractures. SETTING: A military training installation
which incorporates physical training for women. SUBJECTS: Forty-nine female
soldiers with confirmed stress fractures (cases) and 78 female soldiers with no
orthopedic injuries (controls), aged 18 to 33 years. MEASURES: Retrospective self
reports of habitual exercise, sports participation, and food intake; current
height, weight, and body mass index (BMI); demographic variables (age, ethnicity,
menstrual patterns, smoking habits); and bone density on radiologically defined
stress fractures. RESULTS: Cases and controls were similar in height, weight, and
BMI. Measurements of bone density (g/cm2) at the trochanter (cases, 0.77+/-0.09;
controls, 0.77+/-0.08); femoral neck (cases, 0.94+/-0.10; controls, 0.94+/-0.09);
Ward's triangle (cases, 0.91+/-0.11; controls, 0.93+/-0.11); lumbar spine (cases,
1.21+/-0.12; controls, 1.24+/-0.10); and radius shaft (cases, 0.67+/-0.09;
controls, 0.68+/-0.05) were not different between groups. Calcium intake was not
different between groups (cases, 1154+/-751 mg/day; controls, 944+/-513 mg/day)
and did not correlate with bone density (r=0.01 to -0.06 at four sites). Sports
participation positively correlated with bone density in the hip (r=0.49).
Leisure activity energy expenditure (kcal/day) tended toward association with
lower stress fracture risk as expenditure level increased (p=0.06). CONCLUSION:
Stress fracture in female Army recruits was not correlated with bone density or
calcium intake during adolescence, although a weak relationship to prior physical
activity was observed.
PMID- 9550457
TI - Relation of nutrition, body composition and physical activity to skeletal
development: a cross-sectional study in preadolescent females.
AB - OBJECTIVE: To examine the relation of anthropometric and growth parameters
(weight, stature, body composition, age, and skeletal age), nutritional factors,
and physical activity to the total body and radius bone mineral density and
content and radiogrammetry parameters of the second metacarpal. STUDY DESIGN: The
study was a cross-sectional evaluation of 456 healthy, Caucasian girls, ages 8 to
13 years. Multiple regression models were created based on Cp statistics to
determine the association between bone parameters and various independent
variables. RESULTS: Mean calcium intake was 956+/-381 mg/day, about 20% below the
RDA of 1200 mg/day and about 36% below the threshold intake of approximately 1500
mg/day. The most significant predictors for total body and radius bone mineral
density were corresponding bone areas, lean body mass, body fat, skeletal age,
dietary calcium, and stature (only for total body) with corresponding
R2(adjusted) of 48% and 36%. The total body and radius bone mineral content was
positively associated with corresponding bone areas, lean body mass, body fat,
calcium intake, and skeletal age with corresponding R2(adjusted) of 86% and 72%.
Energy expenditure (corrected for BMI) was stratified into quartiles and bone
mass parameters were distributed accordingly. A statistically significant
difference in total body and radius bone mineral density and content was noted
between the fourth and lower quartiles (ANOVA, p<0.05 to p<0.0001). CONCLUSION:
The most significant predictors of bone mass in preadolescent females evaluated
in this study are bone area, lean body mass, body fat, skeletal age and dietary
calcium.
PMID- 9550458
TI - Calciuric effects of short-term dietary loading of protein, sodium chloride and
potassium citrate in prepubescent girls.
AB - OBJECTIVE: Studies using adult human subjects indicate that dietary protein and
sodium chloride have negative effects on the retention of calcium by increasing
urinary calcium excretion, while alkaline potassium improves calcium retention
along with decreasing urinary calcium losses. This study investigated the effect
of these dietary factors on acute urinary calcium excretion in 14 prepubescent
girls age 6.7 to 10.0 years. METHODS: Subjects provided a fasting urine sample
then consumed a meal containing one of five treatments: moderate protein (MP)
providing 11.8 g protein, moderate protein plus 26 mmol sodium chloride (MP+Na),
high protein (HP) providing 28.8 g protein, high protein plus 26 mmol sodium
chloride (HP+Na), or high protein plus 32 mmol potassium as tripotassium citrate
(HP+K). Urine was collected at 1.5 and 3.0 hours after the meal. Supplemental
protein was given as 80:20 casein:lactalbumin. Test meals were isocaloric, and
unless intentionally altered, components of interest except phosphate were equal
between treatments. Each subject completed all five treatments. RESULTS: Urinary
calcium excretion rose after the meal, peaking at 1.5 hours. There were no
significant differences in calcium excretion between treatments at any time
point. The high protein treatments did not result in a significant increase in
either net acid or sulfate excretion at 1.5 hours compared to moderate protein.
Dietary sodium chloride had no effect on urinary sodium or calcium excretion over
the 3 hours. After the potassium treatment, sodium excretion increased (p< or
=0.002) and net acid excretion decreased (p<0.001) compared to other treatments
at 1.5 hours. CONCLUSIONS: In children, a simultaneous increase in protein and
phosphorus due to increased milk protein intake did not increase acute urinary
calcium excretion. An effect of dietary sodium chloride on acute urinary calcium
excretion was not observed. Both these findings were similar to those of adult
studies previously conducted in the same laboratory using similar format and
treatments. Potassium citrate was not hypocalciuric in children, a response
differing from that for adults, who have shown a decrease in acute urinary
calcium excretion in response to alkaline potassium treatment. Further
characterization of calciuric responses to dietary factors is required for
children, who may differ from adults in many respects.
PMID- 9550459
TI - Nightly enteral nutrition support of elderly hip fracture patients: a phase I
trial.
AB - OBJECTIVE: This non-blinded randomized controlled trial was the first phase of a
planned series of investigations designed to test the efficacy of aggressive post
operative enteral nutrition support to decrease the rate of post-operative
complications or improve long-term outcomes in specifically defined subgroups of
elderly patients who have sustained a hip fracture requiring surgery. METHODS:
Eighteen patients (17 males) were randomized to the treatment (eight male
subjects) or control groups. The control group (mean age 76.5+/-6.1 years)
received standard post-operative care. Subjects in the treatment group (mean age
74.5+/-2.1 years) received 125 cc/hour of nasoenteral tube feedings over 11 hours
each night in addition to standard post-operative nutritional care. RESULTS: Both
the treatment and control groups had reduced volitional nutrient intakes for the
first 7 post-operative days (3,966+/-2,238 vs. 4,263+/-2,916 kJ/day [948+/-535
vs. 1019+/-697 kcal/day], p=0.815), but the treatment subjects had a greater
total nutrient intake (7,719+/-2,109 vs. 4,301+/-2,858 kJ/day [1845+/-504 vs.
1028+/-683 kcal], p=0.012). On average, treatment subjects were tube fed for
15.8+/-16.4 days. There was no difference between the groups (treatment vs.
controls) in the rate of post-operative life-threatening complications (25 vs.
30%, p=1.00) or in-hospital mortality (0 vs. 30%, p=0.216). Mortality within 6
months subsequent to surgery was lower in the treatment group compared to the
controls (0 vs. 50%, p=0.036). DISCUSSION: We conclude that nightly enteral
feedings are a safe and effective means of supplementing nutrient intake. The
greatest impact of nutrition support may be to reduce mortality.
PMID- 9550460
TI - Plasma vitamins E and C concentrations of adult patients during cardiopulmonary
bypass.
AB - OBJECTIVE: This study was designed with two aims: 1) to determine if the coronary
artery bypass graft (CABG) procedure alters plasma vitamin E and C concentrations
of adult patients through repeated determinations of vitamin levels at time
points before, during and following CABG, and 2) to assess whether plasma vitamin
E concentrations reflect myocardial tissue content. METHODS: A consecutive sample
of 38 patients undergoing CABG surgery at a Midwest tertiary care hospital was
enrolled. Patients receiving blood transfusions before or during surgery were
excluded. RESULTS: Plasma vitamin E/total lipid ratios rose with reperfusion,
remained elevated immediately following bypass, and fell to preoperative
concentrations by 24 hours. Plasma vitamin E/total cholesterol levels varied
little throughout this time course. Both plasma uric acid and ascorbate
concentrations (corrected for hemodilution) also rose by the preischemic
interval, and remained elevated until a return to preoperative levels by 24
hours. Corrected malondialdehyde (MDA) concentrations rose by pre-ischemia but
returned more quickly to preoperative levels. Atrial appendage tissue vitamin E
concentrations bore a significant relationship to those of plasma prior to
surgery (r=+0.49, p=0.004). Reported supplement use, plasma concentrations and
body mass index contributed to the variability in atrial tissue concentrations of
vitamin E. CONCLUSIONS: In short, when not confounded by transfusions or
hemodilution, several peripheral indices of antioxidants increase with the
reperfusion segment of CABG procedure and return to baseline levels within 24
hours of surgery. Parallel changes in MDA were observed. The observed changes are
consistent with the hypothesis that oxidative stress accompanies the ischemia
reperfusion components of the CABG procedure.
PMID- 9550461
TI - Oxidative changes associated with beta-carotene and alpha-tocopherol enrichment
of human low-density lipoproteins.
AB - OBJECTIVE: To determine what effects enrichment of human low-density lipoprotein
(LDL) with combinations of alpha-tocopherol and beta-carotene would exert on LDL
oxidation and attempt to define the nature of the effects. METHODS: Human plasma
was pooled and alpha-tocopherol and beta-carotene was added in a four-by-four
design resulting in the enrichment of LDL with alpha-tocopherol and beta-carotene
in varying concentrations. Enriched and control LDL was oxidized in Cu2+ mediated
oxidation system and resistance of LDL to oxidation was determined by lag time,
thiobarbituric acid reactive substances (TBARS) activity, and rate of oxidation.
RESULTS: Increasing LDL alpha-tocopherol concentration had a linear relationship
with lag time and a negative correlation with rate of oxidation. LDL beta
carotene concentration was linearly correlated with the rate of LDL oxidation and
beta-carotene loss, and exponentially related to TBARS concentration.
CONCLUSIONS: These results support earlier findings for the protective effect of
a-tocopherol against LDL oxidation, and suggest that beta-carotene participates
as a prooxidant in the oxidative degradation of LDL under these conditions. Since
high levels of alpha-tocopherol did not mitigate the prooxidative effect of beta
carotene, these result indicate that increased LDL beta-carotene may cancel the
protective qualities of alpha-tocopherol.
PMID- 9550462
TI - The phenomenon of "picky eater": a behavioral marker in eating patterns of
toddlers.
AB - OBJECTIVE: To determine if toddlers who were considered "picky eaters" had lower
dietary scores than non-picky eaters, and if family environment and socioeconomic
status were significantly related to picky eater status and dietary scores.
METHODS: An incomplete block design provided two interviews at randomly assigned
times (24, 28, 32, or 36 months) of Caucasian mothers from upper socioeconomic
(n=74) and lower socioeconomic status (n=44). Using trained interviewers, 6 days
of food intake, two administrations of a questionnaire about toddler's eating
behavior, and one administration of the Family Environment Scales were collected
in the home. MANOVA, discriminant function analysis, and logistic regression
procedures were used to determine significant differences between picky and non
picky eater groups. RESULTS: Picky eaters had lower dietary variety (p=.03) and
diversity scores (p=.009) than non-picky eaters. Mothers of picky eaters compared
to those of non-picky eaters used persuasion (p=.0001) and ranked their child's
eating behaviors as more problematic (p=.0001). CONCLUSION: Toddlers perceived by
their mothers as picky eaters had significantly lower dietary variety and
diversity scores. Parents need information and strategies to increase the number
of foods acceptable to their toddlers and to develop a sound feeding plan.
PMID- 9550463
TI - Repleting hemoglobin in iron deficiency anemia in young children through liquid
milk fortification with bioavailable iron amino acid chelate.
AB - OBJECTIVE: To determine if repletion of hemoglobin was achievable in young
children presenting both severe (< or =9.4 g hemoglobin/dL blood) and less severe
iron deficiency anemia (9.5 to 11.0 g hemoglobin/dL blood) through fortification
of liquid 3.3% butterfat milk with a bioavailable ferrous iron amino acid chelate
(Ferrochel) at 3 mg iron/liter/day. METHODS: A group of 185 children were
selected from Tupa, Brazil who presented the above two stages of iron deficiency
anemia plus normalcy. Initially, 54% had severe iron deficiency anemia, 33% were
less severely anemic and 13% had normal hemoglobin concentrations. They received
iron-fortified milk for a mean of 222+/-2 days. Hemoglobin concentrations were
measured initially, at 133+/-13 days, and at 222+/-2 days. RESULTS: By mean 222
days, 57% of the childrens' hemoglobins were normal. Highest rates of repletion
were in the initially severe anemic group. Repeated measures ANOVAs demonstrated
that hemoglobins at 0, 133 and 222 days for the total group, as well as for the
severe and less severe iron deficiency anemic groups, represented statistically
different populations at alpha=0.0005. Children with initially normal hemoglobin
concentrations showed no change at 0, 133 and 222 days (alpha=0.10), suggesting
the possibility of absorptive regulation of this form of iron. CONCLUSIONS: Low
hemoglobin concentrations in young children can be increased through daily
consumption of fluid milk fortified with 3 mg ferrous amino acid chelate
(Ferrochel).
PMID- 9550465
TI - Immunopathology of mucous membranes and exocrine glands.
PMID- 9550464
TI - Confirmation of nasogastric tube placement by colorimetric indicator detection of
carbon dioxide: a preliminary report.
AB - BACKGROUND: Inadvertent insertion of nasogastric tubes into the trachea and
distal airways is reported to range from 0.3% to 15% of insertions. Critically
ill, mechanically ventilated patients are at a higher risk for such
complications, some of which can be fatal. OBJECTIVE: This preliminary
prospective clinical investigation was designed to determine whether a
colorimetric carbon dioxide (CO2) indicator device (Easy-Cap, Nellcor, Inc.,
Hayward, CA) attached to the proximal end of a small bore feeding tube (FT) would
reliably discriminate between those tubes passed into the airways and those
passed into the alimentary tract. METHODS: Ten critically ill, mechanically
ventilated trauma patients requiring a FT insertion were evaluated. An Easy-Cap
device was adapted to the proximal port of each FT. Each patient had one tube
inserted per the nasogastric route and then another through the endotracheal tube
while the Easy-Cap was observed for color changes consistent with the presence of
CO2. RESULTS: All transtracheal insertions showed immediate and unambiguous color
changes consistent with the presence of CO2. None of the nasogastric insertions
resulted in indicator color changes and all were confirmed with radiography
(sensitivity 100%, specificity 100%, accuracy 100%). CONCLUSIONS: This
preliminary report suggests colorimetric CO2 detection accurately and reliably
identifies transtracheal FT insertion.
PMID- 9550466
TI - Bone densitometry: clinical considerations.
PMID- 9550467
TI - A genome-wide screen for susceptibility loci in ankylosing spondylitis.
AB - OBJECTIVE: To localize the regions containing genes that determine susceptibility
to ankylosing spondylitis (AS). METHODS: One hundred five white British families
with 121 affected sibling pairs with AS were recruited, largely from the Royal
National Hospital for Rheumatic Diseases AS database. A genome-wide linkage
screen was undertaken using 254 highly polymorphic microsatellite markers from
the Medical Research Council (UK) (MRC) set. The major histocompatibility complex
(MHC) region was studied more intensively using 5 microsatellites lying within
the HLA class III region and HLA-DRB1 typing. The Analyze package was used for 2
point analysis, and GeneHunter for multipoint analysis. RESULTS: When only the
MRC set was considered, 11 markers in 7 regions achieved a P value of < or =0.01.
The maximum logarithm of odds score obtained was 3.8 (P = 1.4 x 10(-5)) using
marker D6S273, which lies in the HLA class III region. A further marker used in
mapping of the MHC class III region achieved a LOD score of 8.1 (P = 1 x 10(-9)).
Nine of 118 affected sibling pairs (7.6%) did not share parental haplotypes
identical by descent across the MHC, suggesting that only 31% of the
susceptibility to AS is coded by genes linked to the MHC. The maximum non-MHC LOD
score obtained was 2.6 (P = 0.0003) for marker D16S422. CONCLUSION: The results
of this study confirm the strong linkage of the MHC with AS, and provide
suggestive evidence regarding the presence and location of non-MHC genes
influencing susceptibility to the disease.
PMID- 9550468
TI - Synergistic effect between IL-10 and bcl-2 genotypes in determining
susceptibility to systemic lupus erythematosus.
AB - OBJECTIVE: To determine whether genes participating in programmed cell death,
including bcl-2, IL-10, Fas-L, and CTLA-4, may contribute to the genetic
predisposition to systemic lupus erythematosus (SLE). METHODS: First, intragenic
markers for the bcl-2, IL-10, Fas-L, and CTLA-4 genes were characterized and
their extent of polymorphism in normal populations was determined. The allelic
distribution of these gene markers in a large Mexican American SLE cohort of 158
patients and 223 ethnically matched controls was determined using fluorescent
labeled primers and semiautomated genotyping. RESULTS: The bcl-2, Fas-L, and IL
10 loci showed significantly different allelic distribution in SLE patients
compared with controls, indicating an association between these genes and SLE. No
association was found between SLE and the CTLA-4 gene. Further analysis revealed
a synergistic effect between susceptibility alleles of the bcl-2 and IL-10 genes
in determining disease susceptibility. Alone, the presence of each of these
alleles was associated with a moderate increase in SLE risk, while the occurrence
of these alleles together increased the odds of developing SLE by more than 40
fold. CONCLUSION: The results suggest that individuals carrying specific
genotypes of both bcl-2 and IL-10 are at significant risk of developing SLE.
PMID- 9550469
TI - Influence of antigen organization on the development of lupus autoantibodies.
AB - OBJECTIVE: To investigate the reason for grouping of antibodies against small
nuclear RNP (snRNP) particles, which are major autoantigens in systemic lupus
erythematosus (SLE). METHODS: Mice were immunized with biochemically purified
native snRNP particles or recombinant proteins, followed by assessment of
antibody and T cell responses. Since mouse (self) snRNPs are not immunogenic in
mice, a eukaryotic expression vector was constructed to induce high-level
expression of the human U1 snRNP-associated A protein in murine cells. Native
chimeric (mouse/human) snRNP particles were used to immunize normal mice of both
H-2k and H-2b backgrounds. We also disrupted the native snRNPs by digestion with
ribonuclease and used this mixture of proteins to immunize mice. RESULTS:
Immunization with native chimeric snRNPs resulted in the development of
antibodies against a set of snRNP-associated proteins, a response which was
accompanied by breakdown in T cell tolerance to mouse snRNPs in mice immunized
with chimeric snRNPs. We also demonstrated that the ordered production of these
antibodies was due to the fact that snRNP-associated proteins are grouped
together in snRNP particles, since disruption of the particles resulted in
development of antibodies in a random order, distinct from antibodies seen with
intact particles. CONCLUSION: Our findings directly demonstrate that the pattern
of development of antibodies to native snRNPs is similar to that which is
commonly observed in SLE, and that disruption of the particles results in
disappearance of this ordered pattern. These results suggest that the autoimmune
response to snRNPs, and possibly to other autoantigens, in lupus is a specific
reaction similar to that seen in a typical immune response to foreign immunogens.
PMID- 9550470
TI - Diminished ability of erythrocytes from patients with systemic lupus
erythematosus to limit opsonized immune complex deposition on leukocytes and
activation of granulocytes.
AB - OBJECTIVE: To compare the ability of normal erythrocytes and erythrocytes from
systemic lupus erythematosus (SLE) patients to bind immune complexes (IC),
thereby inhibiting IC deposition on polymorphonuclear leukocytes (PMN) and the
consequent induction of a PMN respiratory burst (RB). METHODS: The binding of
fluorescein isothiocyanate-labeled IC in 75% autologous serum to whole blood
cells or isolated leukocytes from 17 SLE patients and 10 controls was assessed by
flow cytometry. Reactive oxygen metabolite (ROM) production by PMN was measured
as the intracellular oxidation of dihydrorhodamine 123, on stimulation with
unlabeled IC. RESULTS: Erythrocyte-mediated inhibition of IC uptake by PMN
reached a mean +/- SD maximum of 68 +/- 18% in controls and 29 +/- 51% in SLE
patients (P < 0.05) and, in the patients, correlated inversely with disease
activity. In the presence of erythrocytes from various donors, IC binding to a
standard preparation of PMN and their ROM production were inversely proportional
to the number of type 1 complement receptors (CR1) per donor erythrocyte. Thus,
the ROM production was higher in the presence of SLE patients' erythrocytes (125
+/- 67 CR1/erythrocyte) than with erythrocytes from controls (235 +/- 118
CR1/erythrocyte). CONCLUSION: Erythrocytes from SLE patients are defective in
protecting their PMN against IC deposition and induction of the RB.
PMID- 9550471
TI - Platelet-derived growth factor, intimal hyperplasia, and ischemic complications
in giant cell arteritis.
AB - OBJECTIVE: To explore whether vasoocclusion in giant cell (temporal) arteritis
(GCA) is related to intimal hyperplasia and in situ production of platelet
derived growth factor (PDGF). METHODS: Temporal artery biopsy specimens from
patients with GCA were analyzed for the presence of intimal hyperplasia.
Expression of PDGF-A and PDGF-B was assessed by immunohistochemistry and
digitized image analysis. RESULTS: PDGF-A and PDGF-B were widely expressed in
inflamed arteries. CD68+ macrophages, smooth muscle cells, and multinucleated
giant cells produced PDGF, whereas hyperplastic intimal tissue did not. Arteries
with marked luminal narrowing and those with no or minimal luminal narrowing
differed in the extent and distribution of PDGF expression. Concentric intimal
hyperplasia was associated with the accumulation of PDGF-A- and PDGF-B-producing
CD68+ macrophages at the media-intima junction. PDGF+,CD68+ macrophages in close
proximity to the internal elastic lamina frequently coproduced matrix
metalloproteinase 2. Intimal hyperplasia of the temporal artery correlated with
ischemic complications of GCA, such as ocular involvement, jaw claudication, and
aortic arch syndrome. CONCLUSION: Production of PDGF has a role in arterial
occlusion in GCA. The excessive fibroproliferative response leading to luminal
narrowing can be distinguished from the stenosing process in atherosclerosis and
postangioplasty restenosis, suggesting that there are different response patterns
to arterial injury. In GCA, macrophages at the media-intima border are the
dominant source of PDGF. Since vasoocclusion is associated with a number of
serious complications in GCA, inhibition of intimal proliferation should be a
major goal of treatment.
PMID- 9550472
TI - Reduced cartilage proteoglycan loss during zymosan-induced gonarthritis in NOS2
deficient mice and in anti-interleukin-1-treated wild-type mice with unabated
joint inflammation.
AB - OBJECTIVE: To investigate the role of nitric oxide (NO) and interleukin-1 in (IL
1) joint inflammation and cartilage destruction during zymosan-induced
gonarthritis (ZIA). METHODS: Monarticular arthritis was elicited by
intraarticular injection of zymosan. The effect of NO deficiency on arthritis was
studied in mice with genetically disrupted NOS2. The role of IL-1 was examined by
treating wild-type mice with neutralizing anti-murine IL-1(alpha+beta)
antibodies. Joint swelling was measured externally by the increased uptake of
circulating 99mtechnetium pertechnetate. Proteoglycan (PG) synthesis was assessed
using 35S-sulfate incorporation into patellae ex vivo. Histology evaluated
exudation and infiltration of leukocytes and the extent of cartilage destruction.
RESULTS: The proinflammatory mediators NO, IL-1, and IL-6 were released by the
articular tissues during the first hours of inflammation. Interestingly, anti-IL
1 treatment moderately reduced, and NOS2 deficiency moderately enhanced, joint
swelling. However, the influx of neutrophils into the joint occurred
independently of IL-1 and NOS2 activities. In the first week of inflammation,
chondrocyte PG synthesis was significantly suppressed and chondrocytes became
unresponsive to their essential anabolic factor, insulin-like growth factor 1
(IGF-1). Anti-IL-1 treatment or NOS2 deficiency prevented the inhibition of PG
synthesis, and the chondrocytes remained IGF-1 responsive. Intraarticular
injections of IL-1alpha into NOS2-deficient mice did not affect PG synthesis,
thus proving that NO mediated this IL-1 effect in vivo. Furthermore, histology
showed that cartilage PG loss was markedly ameliorated in NOS2-deficient and anti
IL-1-treated mice. Intermediate cartilage pathology was found in mice that were
heterozygous for disrupted NOS2. CONCLUSION: IL-1 and NO play a minor role in
edema and neutrophil influx, but a major role in cartilage destruction of ZIA. In
this model of murine arthritis, cartilage destruction was, for the most part,
caused by pronounced suppression of PG synthesis and IGF-1 unresponsiveness of
the chondrocytes, which were induced by de novo-synthesized IL-1 and were
mediated by NOS2 activation.
PMID- 9550473
TI - Interleukin-1 receptor antagonist prevents expression of the metalloproteinase
generated neoepitope VDIPEN in antigen-induced arthritis.
AB - OBJECTIVE: To investigate the relationship between occurrence of the matrix
metalloproteinase-generated neoepitope VDIPEN and proteoglycan (PG) loss in
arthritis, and to examine the role of interleukin-1 (IL-1) in VDIPEN expression.
METHODS: VDIPEN expression was investigated in murine antigen-induced arthritis
by immunolocalization studies on joint sections. The involvement of IL-1 in
VDIPEN expression was studied by blocking of IL-1 using IL-1 receptor antagonist
(IL-1Ra). RESULTS: Profound PG loss was evident early in arthritis, without
significant VDIPEN expression. Full expression of the neoepitope appeared after a
few days, when PG depletion was severe, and disappeared at late stages when
cartilage showed recovery from PG depletion. At sites where chondrocyte death
occurred and cartilage did not recover from the initial cartilage depletion,
VDIPEN expression remained present. Prophylactic IL-1Ra treatment of arthritic
mice resulted in almost complete prevention of VDIPEN expression. However, IL-1Ra
had only a minor effect on PG depletion, emphasizing that there is no correlation
between VDIPEN and early PG depletion. CONCLUSION: This study indicates that IL-1
is involved in VDIPEN expression. Although VDIPEN-inducing metalloproteinases do
not seem to be involved in early PG depletion during antigen-induced arthritis,
metalloproteinase neoepitopes are present when PG depletion is severe.
PMID- 9550474
TI - Soluble Fas ligand in the joints of patients with rheumatoid arthritis and
osteoarthritis.
AB - OBJECTIVE: To investigate the expression and function of Fas ligand (FasL),which
can be in a membrane-bound or soluble form, in the joints of patients with
rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: The concentration of
soluble FasL (sFasL) in serum and synovial fluid (SF) from 24 OA and 38 RA
patients was measured using an enzyme-linked immunosorbent assay. The expression
of FasL on SF lymphocytes (SFL) and peripheral blood lymphocytes (PBL) was
assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. A
cytotoxic killing assay of membrane-bound FasL and purified sFasL against
cultured synovial cells was also performed. RESULTS: Soluble FasL was detected in
the SF of patients with RA and OA, but not in their serum. The concentration of
SF sFasL was remarkably higher in patients with severe RA than in patients with
mild RA or with OA. RT-PCR showed that SFL, but not PBL, from RA patients
expressed messenger RNA for FasL. Membrane-bound FasL induced apoptosis in
cultured synovial cells from the RA and OA patients, but naturally processed
human sFasL did not. CONCLUSION: SFL from RA patients expressed FasL, and cleaved
sFasL accumulated in the SF of inflamed joints. The different killing activity of
membrane-bound FasL and sFasL against synovial cells may regulate Fas-mediated
apoptosis in synovial cells.
PMID- 9550475
TI - Quantitative microscopic analysis of inflammation in rheumatoid arthritis
synovial membrane samples selected at arthroscopy compared with samples obtained
blindly by needle biopsy.
AB - OBJECTIVE: To evaluate microscopic measures of inflammation in rheumatoid
arthritis synovial tissue samples selected at arthroscopy compared with those
obtained blindly by needle biopsy from the suprapatellar pouch (SPP) of the same
joint. METHODS: Samples were selected at knee arthroscopy from the SPP and the
lateral and medial gutters. Immediately following arthroscopy, a biopsy needle
was inserted through the same portal into the SPP by a second investigator, and 3
further samples were obtained blindly. Using standard immunohistologic methods,
all samples were analyzed by a single investigator without knowledge of the
original tissue location and biopsy technique. Following staining with anti-CD3
and anti-CD68 monoclonal antibodies, T lymphocyte and macrophage infiltration
were measured by quantitative analysis. RESULTS: Synovial tissues from 14
patients were analyzed. In comparing microscopic measures of inflammation using
the 2 procedures, mean scores of lining cell depth and the percentage of CD68+
cells in the lining layer correlated positively (tau = 0.59, P = 0.003 and tau =
0.73, P = 0.0003, respectively). In the sublining layer, CD3+ cell counts also
correlated significantly (tau = 0.71, P = 0.0004). Sublining CD68+ cell counts
did not correlate. This was explained by the observation that CD68+ cell
infiltration in areas adjacent to articular cartilage was significantly greater
than in the SPP (P = 0.01), suggesting preferential trafficking to this site by
macrophages, but not by T lymphocytes. Macroscopic appearance at arthroscopy did
not predict microscopic features. CONCLUSION: Most microscopic measures of
inflammation in synovial tissue samples obtained blindly from the SPP were
similar to those determined in samples selected at arthroscopy. However,
measurements in samples from the SPP may underestimate the intensity of
macrophage infiltration in areas more adjacent to cartilage. These observations
have important implications for future study of macrophage function in synovial
tissue.
PMID- 9550476
TI - Oral iloprost treatment in patients with Raynaud's phenomenon secondary to
systemic sclerosis: a multicenter, placebo-controlled, double-blind study.
AB - OBJECTIVE: To evaluate the efficacy and tolerability of an oral preparation of
iloprost, a prostacyclin analog, in patients with Raynaud's phenomenon (RP)
secondary to systemic sclerosis (scleroderma). METHODS: A multicenter,
randomized, parallel-group, placebo-controlled double-blind study was performed
at university and community-based medical centers. Patients were randomly
assigned to receive either 50 microg of iloprost orally twice daily or an
identical gelatin-coated capsule containing placebo for 6 weeks. Outcome measures
included average total daily duration of RP attacks, average number of RP
attacks, and RP condition scored via a standardized daily diary. RESULTS: Three
hundred eight patients with scleroderma (272 women, 36 men, mean age 49 years
[range 18-80]) were enrolled. One hundred fifty seven were assigned to receive
iloprost and 151 to receive placebo. One hundred forty-three patients in the
iloprost group (91.1%) and 144 in the placebo group (95.4%) completed the 6-week
treatment phase. Fifteen of these treated patients (8 iloprost, 7 placebo) failed
to complete all of the followup visits. The mean reduction in the average
duration of attacks from baseline to week 5-6 was 24.32 minutes in the iloprost
group and 34.34 minutes in the placebo group (P = 0.569). Likewise, the mean
reduction from baseline to week 5-6 in the daily frequency of attacks was 1.02 in
the iloprost group and 0.83 in the placebo group (P = 0.459). The Raynaud's
condition score, a patient-completed assessment of the severity of RP attacks,
was reduced by 1.32 in the iloprost group and 1.00 in the placebo group (P =
0.323). The lack of significant difference between treatment groups did not
change when a variety of factors, including use of other vasodilators, duration
of disease, classification of scleroderma (limited versus diffuse), or number of
baseline digital ulcers were taken into account. Premature withdrawal from the
study due to adverse events occurred in 10 patients (6.4%) in the iloprost group
and 3 (2.0%) in the placebo group (P = 0.058). CONCLUSION: Oral iloprost at a
dosage of 50 microg twice daily is no better than placebo for management of RP
secondary to scleroderma, either during 6 weeks of treatment or during 6 weeks of
posttreatment followup.
PMID- 9550477
TI - Frequency of recurrent lupus nephritis among ninety-seven renal transplant
patients during the cyclosporine era.
AB - OBJECTIVE: To determine the frequency of recurrent lupus nephritis (LN) in
patients with systemic lupus erythematosus (SLE) who underwent renal
transplantation. METHODS: We reviewed the posttransplant clinical course and
renal biopsy results in 97 consecutive SLE patients who underwent a total of 106
renal transplantation procedures at our center from January 1984 to September
1996. RESULTS: There were 81 female and 16 male patients, with a mean age of 35
years. Mean duration of dialysis prior to transplantation was 33.5 months; 9
patients were never dialyzed. In all patients, the disease was clinically and
serologically quiescent at the time of transplantation. The mean
posttransplantation followup period was 62.6 months. Patients underwent a total
of 143 posttransplant biopsies. Nine patients had pathologic evidence of
recurrent LN. Six of the patients with recurrence had cadaveric grafts, 2 had
living-related grafts, and 1 had a living-unrelated graft. Recurrence occurred an
average of 3.1 years after transplantation; the longest interval was 9.3 years
and the shortest, 5 days. Histopathologic diagnoses on recurrence included
diffuse proliferative glomerulonephritis, focal proliferative glomerulonephritis,
membranous glomerulonephritis, and mesangial glomerulonephritis. In 4 patients,
recurrent LN contributed to graft loss. Three of the patients with recurrence had
serologic evidence of active lupus, but only 1 had symptoms of active lupus
(arthritis). Three patients who lost their grafts secondary to recurrent LN
underwent second renal transplantation procedures and had functioning grafts at
7, 30, and 35 months, respectively. CONCLUSION: In the largest single medical
center series of renal transplant patients with SLE, recurrent LN was more common
than reported in the literature, but was not always associated with allograft
loss. Recurrent LN was often present in the absence of clinical and serologic
evidence of active SLE.
PMID- 9550479
TI - Characteristic magnetic resonance imaging entheseal changes of knee synovitis in
spondylarthropathy.
AB - OBJECTIVE: To use magnetic resonance imaging (MRI) in patients with rheumatoid
arthritis (RA) and spondylarthropathy (SpA) to determine if the primary site of
abnormality differs. METHODS: Twenty patients with recent-onset knee effusion (10
with SpA and 10 with RA) were evaluated using fat-suppressed MRI. Knee joint
effusion and synovitis were confirmed using ultrasonography. MRI scans were
independently scored by 2 observers who were blinded to the patient's diagnosis.
RESULTS: All 10 of the SpA patients, but only 4 of the 10 RA patients, had focal
peri-entheseal high signal (compatible with fluid or edema) outside the joint (P
= 0.01). Six of the SpA patients had bone marrow edema that was maximal at
entheseal insertions; in 4 cases this was multifocal. No RA patients showed such
an abnormality (P = 0.01). CONCLUSION: Prominent entheseal abnormalities on MRI
are a consistent feature of new-onset synovitis in SpA, but are a minor feature
of RA. This finding has important implications for the diagnosis, classification,
and mechanisms of synovitis in patients with SpA.
PMID- 9550478
TI - Knee osteoarthritis after meniscectomy: prevalence of radiographic changes after
twenty-one years, compared with matched controls.
AB - OBJECTIVE: To study the long-term outcome of surgical removal of a meniscus in
the knee with regard to radiographic signs of osteoarthritis (OA). METHODS: Of
the 123 patients who underwent an open meniscectomy due to an isolated meniscus
tear in 1973 at Lund University Hospital, 107 were followed up 21 years later by
clinical examination and by review of knee radiographs obtained with weight
bearing. Seventy-nine of the 107 patients were men, and the mean age of the total
study group at examination was 55 years (range 35-77). Sixty-eight sex- and age
matched individuals with healthy knees served as controls. RESULTS: Mild
radiographic changes were found in 76 (71%) of the knees, while more advanced
changes, comparable with a Kellgren-Lawrence grade of 2 or higher, were seen in
51 (48%). The corresponding prevalence values in the control group were 12 (18%)
and 5 (7%), respectively. The relative risk for the presence of the more advanced
radiographic changes representing definite radiographic tibiofemoral OA was 14.0
(95% confidence interval 3.5-121.2), using age- and sex-matched pairs for
comparison. No correlation with sex, localization to compartment, type of
meniscus tear, or work load was found. Knee symptoms were reported twice as often
in the study group as in the controls. CONCLUSION: Surgical removal of a meniscus
following knee injury represents a significant risk factor for radiographic
tibiofemoral OA, with a relative risk of 14.0 after 21 years.
PMID- 9550480
TI - Anticardiolipin antibodies and giant cell arteritis: a prospective, multicenter
case-control study. Groupe de Recherche sur l'Arterite a Cellules Geantes.
AB - OBJECTIVE: To assess the prevalence and thrombogenic role of anticardiolipin
antibodies (aCL) in giant cell arteritis. METHODS: Two hundred eighty-four
patients with newly diagnosed temporal arteritis or polymyalgia rheumatica and
210 age- and sex-matched controls randomly selected from the general population
were included in a multicenter, prospective case-control study. Blood samples
were obtained at the time of diagnosis, data on initial clinical features were
collected in a questionnaire, and temporal artery biopsy findings were reviewed
by an experienced pathologist. RESULTS: Anticardiolipin antibodies were present
in 20.7% of patients compared with 2.9% of controls (P = 1.45 x 10(-9)). The
prevalence of aCL was higher in samples found positive for temporal arteritis
than in those found negative on biopsy (31.2% versus 16.7%; P = 0.04), and was
similarly higher in the biopsy-positive temporal arteritis group compared with
the polymyalgia rheumatica and control groups. Although aCL were associated with
thrombotic complications in univariate analysis, the positivity of the biopsy
findings remained the only predictive variable in stratified analysis.
CONCLUSION: In giant cell arteritis, aCL seem to function as reactive antibodies
in relation to endothelial lesions.
PMID- 9550482
TI - The association between different patterns of hand symptoms and objective
evidence of median nerve compression: a community-based survey.
AB - OBJECTIVE: To examine the association between different patterns of hand symptoms
and the presence of delayed nerve conduction in the general population. METHODS:
We performed a 2-stage screening survey involving a questionnaire on current hand
symptoms, and nerve conduction testing in samples of subjects with and without
symptoms. Of 648 respondents to the symptom questionnaire, 212 reported hand
symptoms. In all, 155 were tested for nerve conduction of sensory and motor
median nerve latencies, including 40 who had reported no symptoms. Patterns of
hand symptoms were compared with nerve conduction results and associations
weighted back to the general population. RESULTS: The presence of any hand
symptoms had only a 40% sensitivity for delayed nerve conduction on latency
testing. The presence of typical symptoms of carpal tunnel syndrome had a much
lower sensitivity. CONCLUSION: In a community setting, the distribution of hand
symptoms does not usefully correlate with the presence of delayed nerve
conduction in the median nerve.
PMID- 9550481
TI - Clinical, serologic, and immunogenetic features of familial idiopathic
inflammatory myopathy.
AB - OBJECTIVE: To describe the clinical, serologic, and immunogenetic features of
familial idiopathic inflammatory myopathy (IIM) and to compare these with the
features of sporadic IIM. METHODS: Clinical signs and symptoms, autoantibodies,
HLA-DRB1 and DQA1 alleles, and GM/KM phenotypes were compared among 36 affected
and 28 unaffected members of 16 unrelated families in which 2 or more blood
relatives developed an IIM. In addition, findings in patients with familial IIM
were compared with those in 181 patients with sporadic IIM. The families included
3 pairs of monozygotic twins with juvenile dermatomyositis, 11 families with
other siblings or relatives with polymyositis or dermatomyositis, and 2 families
with inclusion body myositis. RESULTS: The clinical features of familial IIM were
similar to those of sporadic IIM, although the frequency of myositis-specific
autoantibodies was lower in familial than in sporadic IIM. DRB1*0301 was a common
genetic risk factor for familial and sporadic IIM, but contributed less to the
genetic risk of familial IIM (etiologic fraction 0.35 versus 0.51 in sporadic
IIM). Homozygosity at the HLA-DQA1 locus was found to be a genetic risk factor
unique to familial IIM (57% versus 24% of controls; odds ratio 4.2, corrected P =
0.002). CONCLUSION: These findings emphasize that 1) familial muscle weakness is
not always due to inherited metabolic defects or dystrophies, but may be the
result of the development of IIM in several members of the same family, and 2)
multiple genetic factors are likely important in the etiology and disease
expression of familial IIM, as is also the case for sporadic myositis, but DQA1
homozygosity is a distinct risk factor for familial IIM.
PMID- 9550483
TI - Evaluative laboratory testing practices of United States rheumatologists.
AB - OBJECTIVE: Several laboratory tests can be used to monitor disease activity in
patients with rheumatic diseases. We sought to learn how rheumatologists use
evaluative laboratory tests in the care of patients with rheumatoid arthritis
(RA), systemic lupus erythematosus (SLE), and antineutrophil cytoplasmic antibody
(ANCA)-associated vasculitis. METHODS: We surveyed United States rheumatologists
by mailed questionnaire. Of the 976 rheumatologists who received the
questionnaire, 575 responded, for a response rate of 59%. RESULTS: Eighty-six
percent of the respondents reported using either the erythrocyte sedimentation
rate (ESR) or C-reactive protein level to monitor patients with RA, 92% used
either the anti-DNA antibody level or complement C3 level to monitor patients
with SLE, and 95% used either the ESR or ANCA levels to monitor patients with
ANCA-associated vasculitis. The frequency of testing was distributed over a broad
range, but testing was common. Testing on 50% of the visits or more was reported
by 52% of respondents for RA, 59% of respondents for SLE, and 64% of respondents
for ANCA-associated vasculitis. Between 7% and 11% of respondents reported
testing patients on every visit, regardless of clinical disease activity. The
majority of respondents reported not altering the treatment of clinically stable
patients based on these test results. CONCLUSION: Evaluative laboratory testing
is common, and is rarely used as an independent guide for treatment.
PMID- 9550484
TI - The camptodactyly-arthropathy-coxa vara-pericarditis syndrome: clinical features
and genetic mapping to human chromosome 1.
AB - OBJECTIVE: To delineate the clinical features in patients with the autosomal
recessive camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) and to
determine the location of the involved gene. METHODS: Eight affected individuals
(ages 2-15 years) with CACP from 4 consanguineous kindreds were clinically
evaluated. Four patients are newly described and 4 have been reported previously.
Findings were compared with those in 21 other previously reported cases. DNA
obtained from the 8 affected patients and their available siblings and parents
was used in a genome-wide search for linkage. RESULTS: Congenital camptodactyly
and childhood-onset noninflammatory arthropathy were present in all affected
patients. Seven patients developed bilateral coxa vara deformity, and 1 developed
coxa magna with cystic erosions. Two of the patients also had symptoms or signs
of pericarditis. A genome-wide search for linkage identified homozygosity for a
series of genetic markers on human chromosome 1q in all affected patients. The
marker D1S191 yielded a maximum logarithm of the odds ratio (LOD score) of 3.3 at
theta = 0. The CACP gene lies within a 1.9-cM candidate interval defined by the
markers D1S2107 and D1S222. CONCLUSION: The principal features of the CACP
syndrome are congenital or early-onset camptodactyly and childhood-onset
noninflammatory arthropathy. Coxa vara deformity or other dysplasia associated
with progressive hip disease may develop over time. Clinical pericarditis may
also occur. A locus responsible for causing CACP syndrome is assigned to a 1.9-cM
interval on human chromosome 1q25-31 by homozygosity mapping. This now
facilitates the identification of the responsible gene and permits testing for
locus homogeneity in other CACP kindreds.
PMID- 9550485
TI - A prospective study of the safety of joint and soft tissue aspirations and
injections in patients taking warfarin sodium.
AB - OBJECTIVE: To determine the safety of joint or soft tissue aspirations and
injections in patients taking warfarin sodium. METHODS: The outcome of 32 joint
or soft tissue aspirations or injections in patients receiving stable doses of
warfarin sodium was assessed through a standardized interview 4 weeks after the
procedure. The primary outcome measure was significant joint or soft tissue
hemorrhage, ascertained by patient-reported increases in swelling or warmth at
the procedure site. RESULTS: None of 32 procedures was complicated by joint or
soft tissue hemorrhage reported by the patients, yielding, by the "rule of
threes," a risk of significant hemorrhage of < 10% (with 95% certainty).
Diagnostic information was obtained for 53% of aspirated sites (8 of 15) and
therapeutic benefit was noted in 74% of corticosteroid-injected sites (17 of 23).
CONCLUSION: Joint or soft tissue injections and aspirations in selected patients
taking warfarin sodium are associated with a low risk of hemorrhage and are often
of diagnostic or therapeutic value.
PMID- 9550487
TI - Arthralgias and cryoglobulinemia during protease inhibitor therapy in a patient
infected with human immunodeficiency virus and hepatitis C virus.
AB - We present the case of a woman who had a chronic infection with human
immunodeficiency virus (HIV) and hepatitis C virus (HCV). She developed severe
polyarthralgias associated with type II mixed cryoglobulinemia during therapy
with an HIV-1 protease inhibitor. This therapy resulted in a dramatic increase in
her CD4+ T cell count, from 70/mm3 to 567/mm3, which was composed of a high
proportion (88%) of naive CD45RA+ CD62L+ cells, together with a recovery of her
CD4+ T cell reactivity to antigenic stimulation. This may suggest that rapid
recovery of immune competence in the CD4+ T helper subset might participate in
the development of immunopathologic events such as this patient's
cryoglobulinemia.
PMID- 9550488
TI - Antimalarial drug-induced aquagenic-type pruritus in patients with lupus.
PMID- 9550489
TI - Association between serum IgG antibodies to recombinant ribosomal P0 fusion
protein and neuropsychiatric systemic lupus erythematosus.
PMID- 9550490
TI - Rheumatoid burst fracture.
PMID- 9550491
TI - Colchicine clearance by high-flux polysulfone dialyzers.
PMID- 9550492
TI - Updating the American College of Rheumatology criteria for systemic lupus
erythematosus: comment on the letter by Hochberg.
PMID- 9550493
TI - The role of microvasculopathy in the catastrophic antiphospholipid syndrome:
comment on the article by Neuwelt et al.
PMID- 9550494
TI - New onset of rheumatoid arthritis during interferon beta-1B treatment in a
patient with multiple sclerosis: comment on the case report by Jabaily and
Thompson.
PMID- 9550495
TI - Mycoplasmas in the joints of patients with rheumatoid arthritis and other
inflammatory rheumatic disorders: comment on the article by Hoffman et al.
PMID- 9550496
TI - HLA phenotype and systemic sclerosis-rheumatoid arthritis overlap syndrome:
comment on the article by Horiki et al.
PMID- 9550497
TI - Neck injury and chronic pain syndromes: comment on the article by Buskila et al.
PMID- 9550498
TI - Fibroblastic rheumatism: a fifteen-year followup study.
PMID- 9550499
TI - Cholesterol lowering in the management of coronary artery disease: the clinical
implications of recent trials.
AB - Atherosclerotic vascular disease is the major cause of death and disability in
adult men and women living in the United States, where 13-14 million adults have
a history of coronary artery disease (CAD). One-third of the 1.5 million
individuals who experience a myocardial infarction (MI) each year will die and
one half of these deaths will occur within 60 minutes of the event. The relation
between elevated serum lipids and CAD has been corroborated by epidemiologic as
well as pathologic evidence. Approximately 96 million people have total
cholesterol levels > 200 mg/dL, with 38 million of these individuals having
values > 240 mg/ dL. The National Cholesterol Education Program (NCEP) identified
elevated low-density lipoprotein (LDL) cholesterol as a primary risk factor for
CAD in 1988. This conclusion, along with recommendations for assessment and
treatment, was reaffirmed in 1993. The NCEP also recommended that high-risk
patients, with or without clinical manifestations of coronary atherosclerosis,
should substantially lower their serum cholesterol levels. Specifically, the NCEP
recommends that patients with CAD need to maintain serum LDL cholesterol levels
of < or = 100 mg/dL; this means that the vast majority of patients need to
decrease LDL cholesterol levels by > or = 30%. Aggressive dietary and/or drug
therapy are recommended to achieve these reductions. In recent years, clinical
trials have demonstrated the efficacy of 3-hydroxy-3-methylglutaryl coenzyme A
(HMG-CoA) reductase inhibitors ("statins") in lowering elevated levels of LDL
cholesterol and decreasing the risk for clinical coronary events.
PMID- 9550500
TI - Risk factor modification: rationale for management of dyslipidemia.
AB - A number of recent clinical trials have clearly demonstrated the efficacy of
cholesterol lowering as a risk-reduction strategy for the primary and secondary
prevention of coronary artery disease (CAD). The Scandinavian Simvastatin
Survival Study (4S), the West of Scotland Coronary Prevention Study (WOSCOPS),
and the Cholesterol and Recurrent Events (CARE) trial, as well as numerous other
investigations, have established that decreasing elevated levels of low-density
lipoprotein (LDL) cholesterol will result in a reduction in CAD risk. This has
been reported since the 1980s, when the first of the 3-hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA) reductase inhibitors ("statins") became available. These
drugs were an important advance because they showed better patient compliance due
to fewer side effects when compared with other lipid-lowering agents.
Nonetheless, many physicians, for various reasons, have not done an adequate job
of ensuring that the millions of patients who could benefit from lipid-lowering
therapy actually receive the treatment they require.
PMID- 9550501
TI - Therapeutic efficacy of the lipid-lowering armamentarium: the clinical benefits
of aggressive lipid-lowering therapy.
AB - Hypercholesterolemia, particularly an elevated level of low-density lipoprotein
(LDL) cholesterol, is an unarguably established risk factor for coronary artery
disease (CAD). It is equally well established that lowering LDL cholesterol
levels will decrease CAD-related morbidity and mortality in patients with
established CAD. Although lipid-lowering therapy is known to retard the
progression of atherosclerosis in patients with native coronary arteries, its
effect in patients with coronary bypass grafts, which are particularly vulnerable
to occlusion, is less well understood. Moreover, whereas several major clinical
trials have documented the benefits of lowering LDL cholesterol in a variety of
patient subpopulations, there has been far less clarity surrounding the question
of whether aggressive lowering of LDL cholesterol is of greater benefit than
moderate lowering of LDL cholesterol. The Post Coronary Artery Bypass Graft (Post
CABG) trial, a multicenter, randomized, double-blind clinical trial comprising
1,351 patients with elevated levels of LDL cholesterol and a history of bypass
surgery was designed to determine whether aggressive lowering of LDL cholesterol
levels with therapy based on 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
reductase inhibitors ("statins") is more effective than moderate lowering in
delaying the progression of atherosclerosis in bypass grafts. Quantitative
computer-assisted angiography was conducted at baseline and again at an average
of 4.3 years. The primary angiographic outcome was the mean percentage per
patient of grafts with a decrease of > or = 0.6 mm in lumen diameter. Patients
who received aggressive therapy were significantly more likely than their
moderate-treatment counterparts to achieve and maintain LDL cholesterol levels
within the National Cholesterol Education Program's (NCEP's) recommended target
of < or = 100 mg/dL (< or = 2.59 mmol/L). Moreover, the mean percentage of grafts
with progression of atherosclerosis was 27% for aggressively treated patients,
compared with 39% for those who were randomized to the moderate-treatment group
(p < 0.001). This study demonstrates that aggressive lipid lowering is practical
and worthwhile in at-risk patients. Aggressive treatment is far more effective
than moderate treatment in lowering LDL cholesterol levels to the NCEP target
level of < or = 100 mg/dL (< or = 2.59 mmol/L), and this intervention decreases
the progression of atherosclerosis.
PMID- 9550502
TI - Current concepts in cardiovascular pathology: the role of LDL cholesterol in
plaque rupture and stabilization.
AB - Emerging evidence is redefining traditional concepts of coronary atherosclerosis.
Recent data indicate that severe stenoses, the traditional focus of attention, do
not cause most coronary events. Rather, interest has increased in the often less
stenotic but more vulnerable lesions that are characterized by thin fibrous caps,
large lipid accumulations, large numbers of macrophages, and depletion of smooth
muscle cells. Such lesions appear prone to rupture, which allows the blood to
come into contact with the highly thrombogenic material in the lipid core of the
plaque, thereby precipitating thrombosis. The fibrous cap may become weakened
through decreased synthesis of the extracellular matrix or increased degradation
of the matrix. The cytokine interferon-gamma, produced by T-lymphocytes, inhibits
the ability of smooth muscle cells to synthesize collagen, a structurally
important component of the fibrous cap. A family of enzymes known as matrix
metalloproteinases can degrade all major constituents of the vascular
extracellular matrix: collagen, elastin, and proteoglycans. Additional studies on
the biochemical mechanisms of atherosclerosis may provide a fuller understanding
of the ways in which lipid-lowering therapy can confer clinical benefit.
PMID- 9550503
TI - Profiling risk and new therapeutic interventions: looking ahead.
AB - The benefits of cholesterol lowering for primary and secondary prevention of
coronary artery disease (CAD) have been well established. However, to accurately
assess a patient's risk for CAD, clinicians must be aware of their patients'
specific levels of low-density lipoprotein (LDL) cholesterol, high-density
lipoprotein (HDL) cholesterol, and triglycerides, and not just total serum
cholesterol. Clinicians must also evaluate other factors in assessing a patient's
risk profile. These include smoking, weight, family history of CAD, age,
hypertension, and others. Absolute risk, rather than relative risk, can then be
determined. Although LDL cholesterol may be the most potent predictor of risk,
triglycerides are also an important indicator of CAD risk. Currently, 3-hydroxy-3
methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors ("statins") are first
line therapy for the reduction of elevated levels of LDL cholesterol. All statins
are effective in achieving some level of LDL cholesterol lowering. However,
atorvastatin, which was recently introduced in the United States, has greater
efficacy at maximal dosage in lowering LDL cholesterol, and also has a more
beneficial effect on elevated levels of triglycerides, than other statins.
PMID- 9550504
TI - Risk reduction therapies for patients with coronary artery disease: a call for
increased implementation.
AB - Recent decades have witnessed significant advances in the use of interventional
procedures and medical therapies for relief of symptoms associated with
obstructive coronary artery disease (CAD). At the same time, however, little
progress has been made in understanding and implementing preventive therapy and
risk reduction. Our traditional focus on treatment of severe coronary obstruction
has addressed only part of the problem. We now need to adopt a more comprehensive
approach aimed at the entire spectrum of atherosclerotic disease. Numerous
clinical trials have demonstrated that risk-reduction strategies can produce
marked decreases in the incidence of cardiovascular events as well as in total
mortality. Despite this strong body of evidence, risk-reduction therapies
continue to be underutilized. Comprehensive changes in healthcare delivery
systems are needed to ensure that risk-reduction strategies become a routine part
of care for patients with cardiovascular disease.
PMID- 9550505
TI - Hypervolemic hemodilution in acute ischemic stroke: the Multicenter Austrian
Hemodilution Stroke Trial (MAHST).
AB - BACKGROUND AND PURPOSE: Experimental studies suggest a beneficial effect of
hemodilution on acute ischemic stroke. This was not proven by previous
multicenter trials in the clinical setting. Various reasons have been suggested
for the failure of these studies, which we attempted to consider in the
Multicenter Austrian Hemodilution Stroke Trial (MAHST). METHODS: MAHST is a
randomized, double-blind, placebo-controlled study of hypervolemic hemodilution
(HHD) within 6 hours of a clinically first ischemic stroke localized in the
middle cerebral artery territory. The treatment consisted of 10% hydroxyethyl
starch 200/0.5 (HES) and was tested against pure rehydration with Ringer's
lactate over a period of 5 days. Our primary outcome measure was clinical
improvement within 7 days as measured by the Graded Neurologic Scale (GNS). We
performed an adaptive interim analysis to reevaluate the study goal after
entering half of the projected number of patients (n = 200). At least 600
patients per group would have been required for significant results, and
therefore we decided to terminate the trial. RESULTS: Ninety-eight patients
received HHD and 102 patients placebo. The baseline characteristics were
comparable between both groups. In the HHD group the absolute reduction of the
hematocrit was 2.5% on day 2 with a maximum of 3.7% on day 5, which compares with
a reduction in the placebo group of 1% and 1.9%, respectively. Intention-to-treat
analysis showed no significant difference of the change of the GNS scores between
HHD-treated (median, -8.5; 95% confidence interval, -14.2 to -4.0) and placebo
treated patients (median, -6.0; 95% confidence interval, -11.0 to 0.0) on day 7,
and GNS scores remained similar in both treatment groups throughout the trial. At
3 months, slightly more HHD patients showed complete independence on the Barthel
Index (28 versus 24), and fewer HHD than placebo patients had died (13 versus
17), but these differences were not statistically significant. HHD treatment was
not associated with any specific adverse event. CONCLUSIONS: Mild HHD is safe but
failed to demonstrate a significant beneficial effect over the pure rehydration
regimen in patients with acute ischemic stroke.
PMID- 9550506
TI - Multicenter review of preoperative risk factors for endarterectomy for
asymptomatic carotid artery stenosis.
AB - BACKGROUND AND PURPOSE: The benefit of carotid endarterectomy is highly dependent
on surgical risk. However, little data are available concerning factors affecting
the risk of endarterectomy performed for asymptomatic carotid artery stenosis
outside the setting of a randomized controlled trial. The purpose of this study
was to analyze the impact of potential preoperative risk factors on the frequency
of postoperative complications in patients undergoing the operation for
asymptomatic disease in academic medical centers. METHODS: Data regarding
postoperative complications were systematically abstracted from the medical
records of a random sample of patients who underwent carotid endarterectomy at 12
academic medical centers. RESULTS: Of 1160 procedures reviewed, 463 (40%) were
performed for asymptomatic disease. Postoperative stroke or death occurred in 13
(2.8%), and myocardial infarction occurred in 8 (1.7%). The rate of postoperative
stroke or death was lower in asymptomatic patients than in those with a history
of cerebrovascular symptoms in a different vascular distribution, but the
difference was not significant (1.8% versus 4.2%; P=.21). There were no
significant differences in these rates based on race, a history of angina, recent
myocardial infarction, chronic obstructive pulmonary disease, hypertension, the
degree of stenosis of the contralateral or ipsilateral carotid artery, or the
presence of angiographically recognized ulceration, intraluminal thrombus, or
siphon stenosis in the ipsilateral vessel (chi(2); P>.05). Postoperative stroke
or death was more frequent in women (5.3% versus 1.6% in men; P=.02), in those
aged 75 years or older (7.8% versus 1.8% in those younger than 75 years; P=.01),
and in those with a history of congestive heart failure (8.6% versus 2.3% in
those without a history of congestive heart failure; P=.03). The risk of stroke
or death was higher in the 16 patients who had carotid endarterectomy performed
in combination with coronary artery bypass surgery than in those who had only
endarterectomy (18.7% versus 2.1%; P<.001). CONCLUSIONS: The overall risk of
postoperative stroke or death was nearly twice that reported by Asymptomatic
Carotid Atherosclerosis Study (ACAS) investigators in the setting of a clinical
trial but was within acceptable guidelines. Women were at higher postoperative
risk than men, which supported ACAS findings. Additional high-risk groups were
those aged 75 years or older, those with a history of congestive heart failure,
and those undergoing prophylactic endarterectomy for asymptomatic stenosis in
combination with coronary surgery. Knowledge of these rates may help to better
assess an individual's postoperative risk and therefore the anticipated benefit
of surgery.
PMID- 9550507
TI - Increased oxygen extraction fraction is associated with prior ischemic events in
patients with carotid occlusion.
AB - BACKGROUND AND PURPOSE: The purpose of our study was to investigate the
relationship between misery perfusion (increased oxygen extraction fraction, OEF)
and baseline risk factors in patients with carotid occlusion. METHODS: One
hundred seventeen patients with atherosclerotic carotid occlusion were studied
prospectively by clinical evaluation, laboratory testing, and positron emission
tomography (PET). PET measurements of cerebral blood flow (CBF), cerebral blood
volume (CBV), and OEF were made on enrollment in the study. Increased ipsilateral
OEF was identified by comparison with 18 normal control subjects. Twenty-five
baseline clinical, epidemiological, and arteriographic risk factors were assessed
on study entry. Student t tests, chi(2) tests, and Fisher exact tests with
Bonferroni correction were used to assess statistical significance (P<.05).
RESULTS: Of 117 patients, 44 had increased OEF distal to the occluded carotid and
73 had normal OEFs. Thirty-nine of the 81 patients with prior ipsilateral
ischemic symptoms had high OEFs (42%), whereas only 5 of the 31 asymptomatic
patients had high OEFs (16%, P<.001). All of the other baseline risk factors were
similar between the two groups of patients. CONCLUSIONS: Investigations of the
relationship between hemodynamic factors and stroke risk must take into account
the lower frequency of hemodynamic abnormalities in asymptomatic patients.
PMID- 9550508
TI - Subclinical atherosclerosis in relation to hysterectomy status in black women.
AB - BACKGROUND AND PURPOSE: This study was designed to investigate whether black
women who underwent hysterectomy only (n = 59) or hysterectomy plus bilateral
oophorectomy (n=25) were at increased risk of subclinical carotid atherosclerosis
compared with black women who underwent natural menopause (n = 54). The effects
of both surgery and menopausal status were evaluated. METHODS: Women aged 34 to
58 years were recruited from the Pittsburgh, Pa, area. Postmenopausal status was
defined as a serum follicle-stimulating hormone level of >30 mIU/mL. Carotid
duplex scans were performed to assess the degree of focal plaque. RESULTS: Among
premenopausal women, focal plaque was present in 20% of nonhysterectomized versus
49% of hysterectomized-only women (P=.004). Among postmenopausal women, plaque
was present in 69% of nonhysterectomized women, 86% of women with hysterectomy
only, and 48% of women with oophorectomy and hysterectomy (P=.056). Among
postmenopausal women, hormone replacement therapy was used by 23% of women who
had undergone natural menopause, 0% of women with hysterectomy only, and 36% of
women with oophorectomy and hysterectomy. The prevalence of plaque was 33% among
hormone replacement therapy users versus 73% among nonusers (P=.014). In
multivariate analysis, independent associations with the presence of at least 1
plaque were postmenopausal status and hysterectomy only. CONCLUSIONS: These data
suggest that black women who undergo hysterectomy without oophorectomy may be at
higher risk of subclinical carotid atherosclerosis than black women who undergo
natural menopause or hysterectomy plus oophorectomy.
PMID- 9550509
TI - Relationship between blood pressure and subcortical lesions in healthy elderly
people.
AB - BACKGROUND AND PURPOSE: The relationship between blood pressure (BP) and heart
rate (HR) and MRI assessments of subcortical T2 hyperintensities was evaluated in
healthy elderly men and women. METHODS: Casual and 24-hour ambulatory BPs and HR
measurements were taken of 144 elderly individuals, aged 55 to 79 years. Subjects
had no evidence of previous health disorders. MRI scans of white matter,
subcortical gray matter, and insular subcortex were coded for severity of
hyperintensities. RESULTS: Mean casual BP for the group was 120/72 mm Hg. With
age and sex accounted for, individuals with the highest severity rating of white
matter hyperintensities had higher casual, awake, and sleep systolic BPs; higher
awake diastolic BPs; greater awake systolic BP variability; and a smaller
nocturnal fall in systolic and diastolic BPs than individuals with less severe
ratings. Higher severity ratings for subcortical gray matter hyperintensities
were associated with elevations in casual, awake, and asleep systolic BPs and a
smaller HR drop during sleep. Subjects with higher ratings for the insular
subcortex had higher systolic and diastolic BPs (casual, awake, and asleep),
greater HR variability during sleep, and a smaller nocturnal fall in HR.
CONCLUSIONS: Casual and 24-hour ambulatory BPs and some ambulatory HR measures
are associated with subcortical lesions of the brain. Longitudinal studies are
needed to further explore the relationship between white matter lesions and
cardiovascular measures, as well as the significance of these lesions for
cerebrovascular disease in healthy elderly subjects.
PMID- 9550510
TI - Distribution of Chlamydia pneumoniae infection in the athersclerotic carotid
artery.
AB - BACKGROUND AND PURPOSE: Chlamydia pneumoniae infection has recently become
noteworthy in relation to atherosclerosis. We investigated by
immunohistochemistry the distribution of C pneumoniae infection in the
atherosclerotic carotid artery. METHODS: Twenty carotid atherosclerotic lesions
that were resected during carotid endarterectomy were investigated. Parallel
sections were stained immunohistochemically with monoclonal antibodies for a C
pneumoniae-specific antigen, macrophages, and smooth muscle cells. RESULTS:
Immunoreactivity for the C pneumoniae-specific antigen was observed in 11 of 20
specimens (55%), and intense immunoreactivity was observed in 7 of 20 (35%). C
pneumoniae infection was observed in endothelial cells, macrophages and in smooth
muscle cells that had migrated into the atheromatous plaque, as well as in smooth
muscle cells and small arteries in the media underlying the atheromatous plaques.
C pneumoniae infection was most prominently observed in smooth muscle cells. The
severity of the infection as demonstrated by immunohistochemistry was not
significantly related to general risk factors for atherosclerosis. CONCLUSIONS: C
pneumoniae widely infects endothelial cells, macrophages, and smooth muscle cells
in the atherosclerotic carotid artery. The results of the present study can help
us to understand how C pneumoniae infection contributes to the progression of
carotid atherosclerosis.
PMID- 9550511
TI - Outcome of subacute stroke rehabilitation: a randomized controlled trial.
AB - BACKGROUND AND PURPOSE: Organized acute stroke treatment reduces mortality,
functional deficits, and the need of institutionalization after stroke. It is
largely unknown whether the effects of treatment are due to early or subacute
efforts. The aim of this randomized, controlled study was to test the hypothesis
that rehabilitation of stroke patients in the subacute phase in a hospital
rehabilitation unit is beneficial in reducing death and dependency and increasing
health-related quality of life. METHODS: 251 patients initially treated in the
hospital were randomized to subacute rehabilitation in a hospital rehabilitation
unit (n = 127) or to the health services in the municipality (n = 124) and were
followed up for 7 months. RESULTS: The combined outcome of patients being dead or
dependent (Barthel Index score of < 75) was 23% in the hospital group and 38% in
the municipality group (P=.01). Seven-month survival rates were 90.6% and 83.9%
(P=.11), respectively. Dependency in activities of daily living was 12.6% in the
hospital group and 25.0% in the municipality group (P=.07). Patients with a BI
score of < 50 before rehabilitation had significantly better outcome in the
hospital rehabilitation unit, with fewer patients becoming dependent (P=.005) and
patients having higher Scandinavian Stroke Scale (P=.026) and BI scores (P=.005).
No significant differences in health-related quality of life were found. Many
patients treated in the municipalities (30%) did not receive any organized
rehabilitation in this study. CONCLUSIONS: Subacute rehabilitation of stroke
patients in a hospital-based rehabilitation unit improves outcome. Patients with
moderate or severe stroke appear to benefit most.
PMID- 9550512
TI - Effect of a therapeutic intervention for the hemiplegic upper limb in the acute
phase after stroke: a single-blind, randomized, controlled multicenter trial.
AB - BACKGROUND AND PURPOSE: Arm function recovery is notoriously poor in stroke
patients. The effect of treatment modalities, particularly those directed at
improving upper limb function, has been studied primarily in chronic stroke
patients. The purpose of this study was to investigate the effect of a specific
therapeutic intervention on arm function in the acute phase after stroke.
METHODS: In a single-blind, randomized, controlled multicenter trial, 100
consecutive patients were allocated to either an experimental group that received
an additional treatment of sensorimotor stimulation or to a control group. The
intervention was applied for 6 weeks. Patients were evaluated for level of
impairment (Brunnstrom-Fugl-Meyer test) and disability (Action Research Arm test,
Barthel Index) before, midway, and after the intervention period and at follow-up
6 and 12 months after stroke. RESULTS: Patients in the experimental group
performed better on the Brunnstrom-Fugl-Meyer test than those in the control
group throughout the study period, but differences were significant only at
follow-up. Results on the Action Research Arm test and Barthel Index revealed no
effect at the level of disability. The effect of the therapy was attributed to
the repetitive stimulation of muscle activity. The treatment was most effective
in patients with a severe motor deficit and hemianopia or hemi-inattention. No
adverse effects due to the intervention were found. CONCLUSIONS: Adding a
specific intervention during the acute phase after stroke improved motor
recovery, which was apparent 1 year later. These results emphasize the potential
beneficial effect of therapeutic interventions for the arm.
PMID- 9550514
TI - Quality of life in patients and partners after aneurysmal subarachnoid
hemorrhage.
AB - BACKGROUND AND PURPOSE: Outcome after subarachnoid hemorrhage (SAH) is often
graded as "poor," "fair," or "good." Such categories are usually based on
physicians' assessments of physical abilities of patients rather than on how
patients themselves perceive their physical, psychological, and social well
being. We assessed functional outcome and quality of life (QoL) in patients with
SAH and their partners. METHODS: In a consecutive series of 64 patients and 51
partners studied 4 months after the SAH, we assessed functional outcome by means
of the Rankin Scale, and QoL by means of the SF-36, the Sickness Impact Profile
(SIP), and a visual analogue scale. Additionally, we asked two "simple questions"
about dependency and recovery. All questionnaires were completed in an interview
setting. The scores on the QoL instruments from patients and partners were
stratified according to the Rankin grades of the patients and were compared with
data from a Dutch reference population. RESULTS: Only patients who had no
symptoms at all (Rankin grade 0) had no reduction in QoL compared with the
reference population; some of these patients even indicated an improvement in QoL
from before the SAH according to the visual analogue scale. Patients who had
symptoms but were independent (Rankin grades 1 to 3) and therefore usually
designated as having "good outcome" often had reductions in QoL, on both the
physical and psychosocial subscores of the SIP and SF-36. The QoL of partners was
considerably reduced in several psychosocial domains. CONCLUSIONS: SAH has a
considerable impact on the QoL of patients and their partners. Only patients
without residual symptoms (Rankin grade 0) have a good outcome in terms of
physical performance and QoL.
PMID- 9550513
TI - Survival and functional status 20 or more years after first stroke: the
Framingham Study.
AB - BACKGROUND AND PURPOSE: We examined the 20-or-more-year survival and functional
levels of 148 stroke survivors and 148 age- and sex-matched control subjects from
the Framingham Study Cohort, whom we originally studied in 1972-1974 to ascertain
the survival and disability status of stroke survivors compared with that of
controls. METHODS: This long-term evaluation was done with use of data from the
1993-1995 Framingham Study Cohort Examination 23 on the 10 stroke survivors and
20 control subjects still living to identify and compare the host characteristics
and functional status of each group. The survival curves for both stroke
survivors and controls were derived from the ongoing Framingham Study database.
RESULTS: Twenty-plus-year stroke survivors experienced a greater mortality than
age- and sex-matched controls (92.5% and 81%, respectively). The slopes of the
two survival curves were essentially the same. Functional status (eg, walking and
independence in activities of daily living) of stroke survivors, however,
compared very favorably with that of the control subjects. Stroke survivors were
more likely to be female and to have a number of comorbidities, including
elevated blood pressures, greater use of medications, less use of alcohol, and
less depressive symptomology. CONCLUSIONS: In the Framingham cohort, 20-plus-year
stroke survivors showed greater mortality than age- and sex-matched control
subjects; functionally, however, the groups were very similar and in general
quite independent.
PMID- 9550515
TI - Intellectual decline after stroke: the Framingham Study.
AB - BACKGROUND AND PURPOSE: The causes and characteristics of cognitive decline after
stroke are poorly defined, because most studies have relied on the diagnosis of
dementia after stroke, without measurement of prestroke cognitive function.
METHODS: The Mini-Mental State Examination (MMSE) was used to assess the
cognitive performance of 74 subjects from the Framingham Study cohort who had
suffered a stroke during a 13-year period. We compared their poststroke cognitive
performance with the prestroke MMSE scores collected during their biennial
examinations, and their prestroke/poststroke changes in MMSE score were then
compared with those of 74 control subjects matched for age and sex. Cases and
controls underwent testing for symptoms of depression using the Center for
Epidemiologic Studies of Depression (CES-D) scale, and these findings were
correlated with their cognitive performance. Changes in cognitive performance in
the cases were correlated with the CT-documented characteristics of the stroke.
RESULTS: The cases had a significantly lower mean+/-SE MMSE score at prestroke
baseline (27.28+/-0.34) than did the control subjects (28.08+/-0.21), a
difference that became more pronounced (23.57+/-0.92 versus 28.31+/-0.25; P<.001)
after stroke. The poststroke decline in cognitive function in the cases was
correlated only with a large, left-sided stroke on CT. The CES-D scores were
significantly higher in the cases, but nondepressed cases had significantly lower
MMSE scores than nondepressed controls. CONCLUSIONS: Stroke is followed by a
significant decline in cognitive performance when prestroke and poststroke
measurements are compared. Although depression is more frequent in the stroke
patients, their intellectual decline appears to be independent from the presence
of depression.
PMID- 9550516
TI - Factor XIII Val 34 Leu: a novel association with primary intracerebral
hemorrhage.
AB - BACKGROUND AND PURPOSE: A common G-to-T point mutation (Val 34 Leu) in exon 2 of
the alpha-subunit of the factor XIII is strongly negatively associated with the
development of myocardial infarction. This result suggests that factor XIII Val
34 Leu is interfering with the formation of cross-linked fibrin. The role of
factor XIII Val 34 Leu in the pathogenesis of cerebral infarction and primary
intracerebral hemorrhage is unknown. METHODS: Six hundred twelve patients with
acute stroke, defined by World Health Organization criteria and cranial CT, and
436 age-matched control subjects free of cerebrovascular disease were genotyped
for the factor XIII Val 34 Leu mutation. Venous blood was drawn for the
determination of hemostatic variables and lipids. Factor XIII genotype was
determined through a single-stranded conformational polymorphism technique and
plasminogen activator inhibitor (PAI)-1 4G/5G promoter genotype by allele
specific polymerase chain reaction. RESULTS: The mutation was more frequent in
patients with primary intracerebral hemorrhage (n=62) (54.8%; P=.05) than in
control subjects (41.7%) or in patients with cerebral infarction (n=529) (46.5%;
P=.22). There was no relationship between PAI-1 levels and the PAI-1 4G/5G
genotype. CONCLUSIONS: There was a slightly higher incidence of factor XIII Val
34 Leu in patients with PICH. This may be related to impaired cross-linking of
fibrin and/or coagulation proteins.
PMID- 9550517
TI - Antioxidants inhibit ATP-sensitive potassium channels in cerebral arterioles.
AB - BACKGROUND AND PURPOSE: Hydrogen peroxide and peroxynitrite are capable of
generating hydroxyl radical and are commonly suspected as sources of this radical
in tissues. It would be useful to distinguish the source of hydroxyl radical in
pathophysiological conditions and to clarify the mechanisms by which antioxidants
modify vascular actions of oxidants. METHODS: We investigated the effect of three
antioxidants--dimethylsulfoxide (DMSO), salicylate, and L-cysteine--on the
cerebral arteriolar dilation caused by topical application of hydrogen peroxide
and peroxynitrite in anesthetized cats equipped with cranial windows. We also
tested the effect of these antioxidants on the vasodilation caused by pinacidil
and cromakalim, two known openers of ATP-sensitive potassium channels. RESULTS:
DMSO was more effective in inhibiting dilation from hydrogen peroxide, whereas
salicylate and L-cysteine were more effective in inhibiting dilation from
peroxynitrite. All three antioxidants inhibited dilation in concentrations that
were remarkably low (< 1 mmol/L). All three antioxidants inhibited vasodilation
from two known potassium channel openers, pinacidil and cromakalim. Their effect
was specific because they did not affect dilation from adenosine or
nitroprusside. CONCLUSIONS: The findings show that antioxidants block ATP
sensitive potassium channels in cerebral arterioles. This appears to be the
mechanism by which antioxidants inhibit the dilation from hydrogen peroxide and
peroxynitrite and not through scavenging of a common intermediate, ie, hydroxyl
radical. The differences between effectiveness in inhibiting dilation from
hydrogen peroxide and peroxynitrite by various antioxidants suggest that hydrogen
peroxide and peroxynitrite act at two different sites, one in a water-soluble
environment and the other in a lipid-soluble environment.
PMID- 9550518
TI - Treatment with the competitive NMDA antagonist GPI 3000 does not improve outcome
after cardiac arrest in dogs.
AB - BACKGROUND AND PURPOSE: We previously showed that treatment with a competitive N
methyl-D-aspartate (NMDA) receptor antagonist GPI-3000 (GPI) improved short-term
physiological recovery after incomplete global cerebral ischemia complicated by
dense acidosis. We tested the hypothesis that GPI administered after
resuscitation from cardiac arrest would improve a more long-term recovery as
measured by neurobehavioral assessment and neuropathology 4 days after
resuscitation. METHODS: Anesthetized dogs were subjected to 7 minutes of cardiac
arrest followed by vest cardiopulmonary resuscitation. Neurobehavioral outcomes
were scored daily on a score ranging from 0 (normal) to 500 (worst). On the
fourth day, the animals were killed, and neuropathology was evaluated in a
blinded manner in the hippocampus and the neocortex by hematoxylin and eosin
staining and by determination of percentage of injured neurons. Three groups of
animals were treated in a randomized, blinded protocol with either saline (SAL),
low-dose GPI (5 mg/kg followed by 1 mg/kg per hour for 2 hours), or high-dose GPI
(25 mg/kg, followed by 5 mg/kg per hour for 2 hours). RESULTS: The mortality rate
was higher in animals receiving GPI than in saline-treated control animals (4 of
15 deaths in SAL, 6 of 15 in the low-dose GPI group, and 9 of 18 in the high-dose
GPI group). Neurobehavioral scores were depressed in GPI-treated animals compared
with saline-treated control animals in a dose-dependent manner, with 96-hour
scores of essentially normal (9+/-2) in saline-treated animals compared with
those animals with significant impairment (181+/-47) treated with high-dose GPI.
Neuropathological damage in the neocortex was most severe in GPI-treated animals,
with the percentage of injured neurons dependent on the dose: 8.3%+/-2.7% SAL,
13.2%+/-6.4% low-dose GPI, and 39.4%+/-10.1%, high-dose GPI. CA1 neuronal damage
was severe regardless of treatment. CONCLUSIONS: Contrary to results seen in
experimental global and focal cerebral ischemia, in which NMDA receptor
antagonism may improve responses to injury, receptor antagonism with GPI does not
improve brain outcome after cardiac arrest and resuscitation in the dog.
Behavioral and histological outcomes both were worsened by GPI treatment at two
doses, and mortality was higher relative to saline control treatment. We
speculate that systemic drug effects, as well as potential neurotoxicity of the
drug under ischemic conditions, may be responsible for the deleterious outcomes
observed in our cardiac arrest model.
PMID- 9550519
TI - Inhibition of poly(ADP-ribose) polymerase: reduction of ischemic injury and
attenuation of N-methyl-D-aspartate-induced neurotransmitter dysregulation.
AB - BACKGROUND AND PURPOSE: The nuclear enzyme poly(ADP-ribose) polymerase (PARP) may
play a role in DNA repair. However, in cerebral ischemia, excessive PARP
activation may lead to energy depletion and exacerbation of neuronal damage. We
examined the effect of inhibiting PARP on (1) the degree of cerebral injury in a
rat model of transient focal ischemia and (2) the degree of neurotransmitter
dysregulation induced by local cortical perfusion of N-methyl-D-aspartate (NMDA).
METHODS: In experiment 1, rats were subjected to transient ischemia for 90
minutes by occlusion of the middle cerebral artery. After 22.5 hours of
reperfusion, lesions were quantified by tetrazolium staining. Untreated rats were
compared with those treated with the PARP inhibitor 3-aminobenzamide (10 mg/kg).
In experiment 2, rats were implanted with microdialysis probes in the cortex, and
1 mmol/L NMDA was perfused for 2 hours. Extracellular concentrations of
neurotransmitter and neuromodulator amino acids were measured. Untreated rats
were compared with those given 10 mg/kg 3-aminobenzamide. RESULTS: In experiment
1, PARP inhibition significantly reduced lesion volumes: 204+/-43 mm3 (untreated)
versus 90+/-24 mm3 (treated). Neuroprotection was primarily manifested in the
cortex. In experiment 2, NMDA perfusion resulted in large elevations of
glutamate, taurine, and the lipid component phosphoethanolamine. Levels of the
NMDA site modulator D-serine were reduced, and glycine levels appeared unchanged.
3-Aminobenzamide significantly attenuated the elevations in glutamate and
phosphoethanolamine but had no effects on D-serine and glycine. CONCLUSIONS:
Inhibition of PARP reduced injury after transient focal ischemia in rats and
attenuated NMDA-induced glutamate efflux and overall neurotransmitter
dysregulation. The deleterious effects of excessive PARP activation may be
related in part to amplification of excitotoxicity, possibly by cellular energy
depletion and additional transmitter release and/or reduced reuptake.
PMID- 9550520
TI - Potassium channel activators protect the N-methyl-D-aspartate-induced cerebral
vascular dilation after combined hypoxia and ischemia in piglets.
AB - BACKGROUND AND PURPOSE: Cerebral arteriolar dilation to N-methyl-D-aspartate
(NMDA) is a neuronally mediated multistep process that is sensitive to cerebral
hypoxia and ischemia (H/I). We tested the hypothesis that topical pretreatment
with the selective potassium channel agonists NS1619 and aprikalim preserves the
vascular response to NMDA after consecutive H/I. METHODS: Pial arteriolar
diameters were measured in anesthetized piglets with the use of a closed cranial
window and intravital microscopy. Arteriolar responses to NMDA (10(-5), 5 x 10(
5), and 10(-4) mol/L) were recorded before and 1 hour after 10 minutes of hypoxia
(8.5% O2 in N2) plus 10 minutes of ischemia (H/I). Ischemia was induced by
increasing intracranial pressure. Subgroups were topically pretreated with 10(-5)
mol/L NS1619, 10(-6) mol/L aprikalim, 10(-6) mol/L calcitonin gene-related
peptide (CGRP), or 10(-5) mol/L papaverine. We also examined the effects of H/I
on vascular responses to kainate (10(-4) mol/L) to assess specificity of neuronal
injury. RESULTS: Arteriolar responses to NMDA were significantly attenuated after
H/I. Baseline compared with post-H/I arteriolar diameters were 9+/-4% versus 3+/
2% at 10(-5) mol/L, 22+/-4% versus 4+/-2% at 5 x 10(-5) mol/L, and 33+/-4% versus
7+/-2% at 10(-4) mol/L (mean+/-SE; all P<.05, n=7). Pretreatment with NS1619 and
aprikalim preserved the arteriolar responses to NMDA after H/I. For NS1619 (n=6),
values were as follows: 9+/-2% versus 6+/-4% at 10(-5) mol/L, 19+/-6% versus 21+/
5% at 5 x 10(-5) mol/L, and 35+/-3% versus 31+/-5% at 10(-4) mol/L. For aprikalim
(n=7), values were as follows: 6+/-2% versus 8+/-2% at 10(-5) mol/L, 22+/-6%
versus 15+/-3% at 5 x 10(-5) mol/L, and 41+/-5% versus 32+/-6% at 10(-4) mol/L.
In contrast, piglets pretreated with CGRP (n=6) or papaverine (n=5) showed no
preservation of the vascular response to NMDA after H/I, although these compounds
dilated the arterioles to an extent similar to that with NS1619/aprikalim.
Kainate-induced arteriolar dilation (n=6) was largely preserved after H/I
compared with preischemic responses. CONCLUSIONS: (1) Vascular responses of
cerebral arterioles to NMDA after H/I are preserved by pretreatment with NS1619
or aprikalim, indicating a neuroprotective effect. (2) CGRP and papaverine do not
preserve the vascular response to NMDA despite causing vasodilation similar to
that with NS1619 or aprikalim. This suggests that activation of potassium
channels on neurons accounts for the protective effect of potassium channel
agonists. (3) Preserved arteriolar dilation to kainate suggests largely intact
functioning of neuronal nitric oxide synthase after H/I.
PMID- 9550521
TI - Low glucose enhances Na+/glucose transport in bovine brain artery endothelial
cells.
AB - BACKGROUND AND PURPOSE: Brain arteries are structurally characterized by the
tight junctions of the endothelium and by no vasa vasorum that feed arteries
themselves. This raises the question of how brain arteries are provided with
glucose. A possible explanation is that glucose uptake into arteries may be
mediated by both GLUT1, a facilitative glucose transporter, and a Na+/glucose
cotransporter (SGLT)-like glucose transporter. The functional role for the SGLT
like glucose transporter, however, is unknown. In the present study we
investigated SGLT-like glucose transporter-operated glucose uptake into brain
arterial endothelial cells by recording glucose-evoked Na+ currents and
monitoring uptake of [3H]-2-deoxy-D-glucose ([3H]-2-DOG). METHODS: Endothelial
cells were cultured from bovine cerebral cortical arteries. Whole-cell patches
were made to cells, and glucose-evoked currents were recorded. Cells were
incubated with [3H]-2-DOG, and the uptake was determined by a liquid
scintillation counter. RESULTS: Glucose and alpha-methyl-D-glucoside (alphaMeDG),
a specific compound for the SGLTs, evoked Na+ currents in a whole-cell voltage
clamp configuration, and the currents were enhanced in cells with over 30
minutes' preincubation in glucose-free media. Glucose-induced currents were
inhibited by alphaMeDG, by the selective SGLT inhibitor phlorizin, by
dinitrophenol (DNP), an inhibitor of energy metabolism, or by deletion of Na+
from extracellular solution, which indicates that glucose uptake into endothelial
cells was mediated by a Na+- and energy-dependent glucose transporter. Notably,
the currents were desensitized, reduced in a glucose concentration-dependent
manner, and markedly inhibited by either a second application of glucose or the
addition of glucose to the patch electrode filling solution; they were
potentiated, however, by treatment with cytochalasin B, a GLUT1 to GLUT5
inhibitor. Consistent with the results of patch-clamp recordings, uptake of [3H]
2-DOG into endothelial cells was enhanced by glucose-free insult, and the
enhancement was mediated by an SGLT-like glucose transporter. CONCLUSIONS: The
results presented demonstrate that an SGLT-like glucose transporter takes part in
glucose uptake into brain artery endothelial cells and that the uptake is
regulated by intracellular glucose concentrations; glucose-free insult and the
ensuing low cytosolic glucose enhance activity of the SGLT-like glucose
transporter. The SGLT-like glucose transporter in the brain arterial endothelium
thus may be important in the maintenance of an adequate glucose concentration in
the arterial wall under conditions of stress, such as hypoglycemia.
PMID- 9550522
TI - A novel endothelin antagonist, A-127722, attenuates ischemic lesion size in rats
with temporary middle cerebral artery occlusion: a diffusion and perfusion MRI
study.
AB - BACKGROUND AND PURPOSE: Endothelins (ETs) are potent vasoconstrictors. Plasma ET
levels increase during acute brain ischemia and may worsen the ischemic damage.
Diffusion-weighted MRI (DWI) and perfusion imaging (PI) are powerful tools for
evaluation of acute cerebral ischemia. We studied the effects of A-127722, a
novel ET(A)-selective ET antagonist, on cerebral ischemic lesion size using 2,3,5
triphenyltetrazolium chloride (TTC) staining postmortem, on acute ischemic lesion
development with DWI, and on the cerebral circulation using PI. METHODS: Twenty
male Sprague-Dawley rats received either 5 mg/kg of A-127722 or vehicle (n=10 per
group) intravenously 30 minutes and subcutaneously 4 hours after middle cerebral
artery occlusion (MCAO). Whole-brain DWI and single-slice PI were done before
initiation of treatment and repeated frequently thereafter up to 4 hours after
MCAO. The animals were reperfused in the MRI scanner 90 minutes after the onset
of MCAO. At 24 hours the animals were killed, and the brains were cut into six 2
mm-thick slices and stained with 2% TTC. Percent hemispheric lesion volume (%HLV)
was calculated for each animal. RESULTS: Physiological parameters, body weight,
neurological scores, and premature mortality (2 versus 2) did not differ between
the two groups. No hypotension, abnormal behavior, or other adverse effects were
seen. TTC-derived %HLV was 25.3+/-5.6% for controls and 16.2+/-9.6% for treated
animals (36% reduction, P<.02). Six animals in each group had successful
reperfusion as shown by PI. Among these animals, %HLV was 23.2+/-3.1% for
controls and 9.3+/-4.4% for treated animals (60% reduction, P=.0001). The
beneficial effect of A-127722 was limited to animals in which successful
reperfusion was demonstrated. No difference in PI-detected perfusion deficit size
was observed between the groups. DWI did not demonstrate significant in vivo
lesion size differences. CONCLUSIONS: A-127722 significantly reduced ischemic
lesion size in rats without observable adverse effects. It is not clear whether
the effect was due to vasodilatation of collateral arterioles not detectable by
PI or whether A-127722 has neuroprotective properties that are independent of
vascular effects.
PMID- 9550523
TI - Different apparent diffusion coefficient: water content correlations of gray and
white matter during early ischemia.
AB - BACKGROUND AND PURPOSE: Early and accurate diagnosis of brain edema in stroke
patients is essential for the selection of appropriate treatment. We examined the
correlations between the changes in the apparent diffusion coefficient (ADC),
regional water content, and tissue ultrastructure during early focal cerebral
ischemia. METHODS: The left middle cerebral arteries of cats were occluded with
an intramagnet occlusion/recirculation device. T2-weighted, diffusion-weighted,
and perfusion imaging were performed repeatedly during the initial 3 hours after
occlusion. The ADCs obtained from ADC maps were compared with the corresponding
tissue water content values determined by gravimetry and electron microscopic
water localization. RESULTS: ADC reduction was detected in areas of low perfusion
15 minutes after occlusion and thereafter. The water content increase correlated
linearly with the ADC decreases in both the gray and white matter. However, both
the water content corresponding to an ADC value and the rate of ADC change of the
gray and white matter differed significantly (P<.05) as follows: y = -10105x +
8533 (r=.86) and y = -6174x + 4611 (r=.67), respectively, where x is the water
content (grams water per gram tissue) and y is the ADC (x 10(-6) mm2/s). Hydropic
astrocytic swelling was seen in both structures, and in the white matter,
oligodendroglial and myelinated axonal swelling and periaxonal space enlargement
were observed. CONCLUSIONS: When early ischemic edema in experimental focal
cerebral ischemia is evaluated with ADC mapping, the different slopes and
intercepts of the water content and ADC correlation lines for the gray and white
matter, which probably reflect different ultrastructural localization of water,
should be taken into account.
PMID- 9550524
TI - Prevalence of stroke and stroke-related disability.
PMID- 9550525
TI - Causes and mechanisms of cerebellar infarction in young patients.
PMID- 9550526
TI - Hypertension control as an indicator of the geographical variation of stroke.
PMID- 9550527
TI - Autoimmunity in Down's syndrome: another possible mechanism of Moyamoya disease.
PMID- 9550528
TI - Homozygous C677T mutation of the 5,10 methylenetetrahydrofolate reductase gene
and hyperhomocysteinemia in Italian patients with a history of early-onset
ischemic stroke.
PMID- 9550529
TI - Interrater agreement on a simple neurological score in rats.
PMID- 9550530
TI - The Working Group report on Science-Based Categories for Abstracts: submitted to
the annual scientific sessions. The Committee on Scientific Sessions Program
(CSSP), American Heart Association.
PMID- 9550531
TI - Serum lipids during the first year following acute spinal cord injury.
AB - Patients with chronic spinal cord injury (SCI) have low levels of high-density
lipoprotein (HDL) cholesterol. The cause of this abnormality and its relation to
SCI are unknown. We studied 100 consecutively admitted males with acute SCI
prospectively for 1 year to determine changes in serum lipids following acute SCI
and the relation of these changes to the level of injury and physical activity.
Low-density lipoprotein (LDL), HDL, and total cholesterol and triglycerides were
all decreased following acute SCI and gradually increased toward normal by 1
year. Serum HDL, LDL, and total cholesterol levels correlated with the level of
SCI: levels were lower in quadriplegic compared with paraplegic patients. Serum
HDL showed the greatest change following SCI, increasing by 26% in quadriplegic
and 18% in paraplegic patients. These changes in serum lipid levels could not be
explained by changes in alcohol consumption or body weight. We estimated that
only 44% of the increase in HDL following SCI was associated with an increase in
physical activity. We postulate that interruption of the autonomic nervous system
influences lipid metabolism and serum lipid levels.
PMID- 9550532
TI - The effects of menopausal status and exercise training on serum lipids and the
activities of intravascular enzymes related to lipid transport.
AB - The study purpose was to compare the effect of exercise training on serum lipid
and apolipoprotein concentrations and the activities of intravascular enzymes
related to lipid transport in previously untrained eumenorrheic, premenopausal
(PRM) women (n = 21; mean age, 36 +/- 3 years) and estrogen-free postmenopausal
(POM) women (n = 16; mean age, 68 +/- 8 years). Subjects trained at a progressive
intensity and duration (50% to 75% maximal O2 consumption [VO2max], 200 to 300
kcal/session) 4 d/wk for 12 weeks. Before and after training, VO2max, body
weight, relative body fat, and fasting blood samples were obtained following 2
weeks on a standardized diet designed to maintain body weight and during the
early follicular stage for the PRM group. Blood samples were analyzed for serum
total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol
(HDL-C), the cholesterol content of the HDL3 subfraction, apolipoprotein (apo)A-I
and apoB, lipoprotein(a), and the activity of lecithin:cholesterol
acyltransferase (LCAT). Total and hepatic triglyceride lipase activity (HTGLA)
were determined from plasma samples obtained after heparin administration. The
cholesterol content of the low-density lipoprotein (LDL) and HDL2 subfractions
and endothelial-bound lipoprotein lipase activity (LPLA) were calculated. A two
(group) x two (time) multivariate ANOVA (MANOVA), with repeated measures for time
indicated that the exercise-induced changes in physiological measurements, serum
lipid or apolipoprotein concentrations, or enzyme activities did not differ
between groups. Serum concentrations of TC, LDL-C, and HDL3 cholesterol, TG, and
apo A-I and apoB were higher in POM women compared with the PRM group (P < .05
for all). For the combined groups, body weight and relative body fat did not
change with training, but VO2max increased an average of 18.5% (P < .05). LPLA,
HTGLA, and LCAT activity were unaltered with exercise training. Except for a
small but significant decrease in HDL-C (-5.5%) and an elevation in apoB (4.3%; P
< .05 for both), the concentrations of serum lipids and apolipoproteins did not
change over the training period. We conclude that in previously untrained women,
menopausal status does not influence the exercise training response of serum
lipids or apolipoproteins or activities of intravascular enzymes related to lipid
transport.
PMID- 9550533
TI - Intense nonpharmacological intervention in subjects with multiple cardiovascular
risk factors: decreased fasting insulin levels but only a minor effect on plasma
plasminogen activator inhibitor activity.
AB - Increased plasma levels of insulin and the fibrinolytic inhibitor, plasminogen
activator inhibitor type 1 (PAI-1), are two new cardiovascular risk factors. The
extent to which these two risk factors can be affected by nonpharmacological
intervention modalities has not been convincingly proven in subjects at high risk
for cardiovascular disease. This study assesses the effects on fasting plasma
insulin and plasma PAI-1 activity of an intervention program including a low-fat,
high-fiber diet and regular daily physical exercise. The intervention was
implemented by a 1-month learning and training session in a full-boarding
wellness center and included a follow-up evaluation after 12 months. The study
was conducted on 108 subjects (31 men and 77 women) referred for multiple risk
factor treatment. After 1 month of intense intervention, the physical condition
improved significantly, and this effect was maintained during the year. The body
mass index (BMI), fasting plasma insulin, and plasma lipids were significantly
decreased. In women, PAI-1 activity was significantly reduced. At follow-up study
in both sexes, the BMI and fasting insulin were still significantly decreased. In
women, PAI-1 activity reverted to the preintervention level. In subjects with
multiple risk factors, ie, the insulin resistance syndrome, the plasma insulin
level can be reduced by an intense nonpharmacological program. Also, at least in
women, plasma PAI-1 activity can be modestly modified. However, the magnitude of
the decrease in PAI-1 activity was probably too small to reverse the
hypofibrinolytic state characteristic of these subjects.
PMID- 9550535
TI - Dietary chromium decreases insulin resistance in rats fed a high-fat, mineral
imbalanced diet.
AB - The effects of chromium (Cr) supplementation on diet-induced insulin resistance
produced by feeding a high-fat, low-Cr diet were studied in rats to ascertain the
role of Cr in insulin resistance. Wistar male rats were maintained for 16 weeks
after weaning on a basal diet containing 40% lard, 30% sucrose, and 25% casein by
weight and adequate vitamins and minerals without added Cr (-Cr). Fasting levels
of insulin, glucose, and triglycerides and the responses during an intravenous
glucose tolerance test (IVGTT) were compared as indices of insulin resistance and
the effectiveness of dietary Cr. IVGTTs and blood sampling for data analyses were
performed over a 40-minute period after IV glucose injection (1.25 g/kg body
weight) in overnight-fasted animals under pentobarbital anesthesia (40 mg/kg body
weight). All animals were normoglycemic (-Cr, 109 +/- 3 mg/dL; +Cr, 119 +/- 5),
with fasting insulin levels elevated in the -Cr group (65 +/- 10 microU/mL)
versus the +Cr group (31 +/- 4 microU/mL). Increases in plasma triglycerides in
the -Cr group were not significant. Following glucose injection, the rate of
glucose clearance was lower in the -Cr group (1.74 +/- 0.22 v2.39 +/- 0.11%/min),
and 40-minute glucose areas in the -Cr group tended to be higher than in the +Cr
group. The insulin response to glucose injection was 20% higher in the -Cr group.
Forty-minute plasma triglyceride areas were lower in +Cr rats (875 +/- 62 v 1,143
+/- 97 mg/dL.min in -Cr rats). These data demonstrate that the insulin resistance
induced by feeding a high-fat, nutrient-stressed diet is improved by Cr.
PMID- 9550534
TI - Sex steroids increase cholesterol 7alpha-hydroxylase mRNA in nonhuman primates.
AB - One mechanism that may account for our prior observation that oral contraceptives
decrease the hepatic cholesterol concentration independently of the low-density
lipoprotein (LDL) receptor in sexually intact nonhuman primates is that sex
hormones increase biliary cholesterol secretion by increasing hepatic mRNA
abundance for cholesterol 7alpha-hydroxylase, the rate-limiting enzyme in the
conversion of cholesterol into bile acids. To examine the independent effect of
estrogen, progestin, and combined estrogen and progestin on the hepatic
cholesterol concentration and cholesterol 7alpha-hydroxylase mRNA abundance, 34
ovariectomized adult female cynomolgus monkeys were fed a moderately atherogenic
diet for 12 weeks with either oral conjugated equine estrogen ([CEE] n = 8),
medroxyprogesterone acetate ([MPA] n = 9), or combined CEE + MPA (n = 9) and
compared with a control group (n = 8) that did not receive exogenous sex
hormones. After 12 weeks, hepatic cholesterol was significantly lower in CEE
treated (6.2 +/- 1.2 mg/g liver) and CEE + MPA-treated (6.4 +/- 0.9 mg/g liver)
animals compared with the control (12.6 +/- 1.9 mg/g liver) and MPA-treated (14.6
+/- 1.6 mg/g liver) groups. Hepatic cholesterol 7alpha-hydroxylase mRNA abundance
was significantly increased in CEE-treated (0.553 +/- 0.08 pg/microg RNA), MPA
treated (0.734 +/- 0.12 pg/microg RNA), and CEE + MPA-treated (0.487 +/- 0.07
pg/microg RNA) animals compared with the controls (0.318 +/- 0.03 pg/microg RNA).
There was no significant difference in the plasma LDL cholesterol concentration
and hepatic LDL receptor mRNA abundance between the groups. These data support
but do not prove the hypothesis that low-dose oral estrogen induces an increase
in cholesterol 7alpha-hydroxylase mRNA abundance, which is correlated with
biliary cholesterol secretion and may result in depletion of hepatic cholesterol.
PMID- 9550536
TI - Insulin resistance and fat patterning with aging: relationship to metabolic risk
factors for cardiovascular disease.
AB - Both insulin resistance and abdominal fat patterning are related to aging, and
have been related to cardiovascular disease (CVD) risk factors such as
dyslipidemia and hypertension. However, previous studies have not used direct
methods to quantify the independent strength of the association of each of these
two putative primary factors with metabolic outcomes. We quantified overall
obesity by the body mass index (BMI) and used a previously validated magnetic
resonance imaging (MRI) method to quantify abdominal fat in 63 healthy
nondiabetic individuals aged 22 to 83 years. We also measured the glucose and
insulin response to an oral glucose tolerance test and the insulin sensitivity
([SI] by modified minimal model analysis). Body fat patterning was evaluated by
the waist to hip ratio (WHR) and by MRI, which allowed direct measurement of
subcutaneous (SCF) and intraabdominal (IAF) fat depots at the umbilicus in these
subjects. These independent parameters were related to risk factors for CVD
(blood pressure, lipids, and lipoproteins) and to plasma concentrations of free
fatty acids (FFAs). Measures of overall obesity (BMI), total fat [TF], and/or SCF
measured at the abdomen by MRI), glucose/insulin metabolism and SI, and central
fat patterning (WHR or IAF measured by MRI) were correlated with mean arterial
pressure (MAP), triglyceride (TG), and high-density lipoprotein cholesterol (HDL
C) levels in univariate analysis and after controlling for age and gender. An
index of central fat patterning (WHR) added to the informativeness of the insulin
area under the curve (IAUC) in explaining 24% of the variability in plasma TG
concentration, but measures of overall obesity were not independently related.
Both the BMI and TF contributed to the IAUC in explaining 32% to 34% of the
variability in MAP, but central fat patterning was not independently related. No
index of overall obesity, fat patterning, glucose/insulin metabolism, and/or SI,
was independently related to the plasma concentration of HDL-C after controlling
for any one of the other two. Direct measurement of glucose/insulin metabolism
and SI, as well as fat patterning, provides information on their relative
associations with CVD risk factors. The measures of glucose/insulin metabolism
and SI were more consistently related to dyslipidemia and hypertension than were
the overall obesity and fat patterning in this healthy population.
PMID- 9550537
TI - In vivo quantification of glucose uptake and conversion to glycogen in individual
muscles of the rat following exercise.
AB - Glycogen depletion is thought to be a potent stimulus for the substantially
increased glucose fluxes observed in skeletal muscle following exercise. The aim
of this study was to establish the relationships between the glycogen mass and
the rates of glucose uptake (Rg') and glucose incorporation into glycogen (Rgly)
in individual muscles of conscious adult Wistar rats following moderate
nonexhausting treadmill exercise (15 m/min at a 10 degree slope for 45 minutes,
approximately 65% VO2max). Muscle glycogen content was determined at 0, 20, 45,
90, or 135 minutes following exercise and compared with Rg' and Rgly measurements
at matched times. Muscle types varied in the rate of glycogen resynthesis.
Glycogen depots of glycolytic muscle (white gastrocnemius) were still
significantly (P < .01) lower than preexercise levels after 135 minutes; red
oxidative muscles (soleus and red gastrocnemius) were essentially repleted by 90
minutes. Immediately following exercise, Rg' and Rgly in red gastrocnemius and
soleus were 42 +/- 4 and 42 +/- 5 and 36 +/- 2 and 33 +/- 7 micromol/(min . 100
g), greater than the rates induced by maximal insulin stimulation in previous
studies. In red muscles, there was a strong inverse relationship between Rgly and
tissue glycogen content, consistent with a dominant role for the glycogen mass in
the regulation of glycogen resynthesis.
PMID- 9550538
TI - Alterations in rat pancreatic islet beta cells induced by Keshan disease
pathogenic factors: protective action of selenium and vitamin E.
AB - Keshan disease (KD) is an endemic cardiomyopathy occurring in certain areas of
China. A combined deficiency of selenium (Se) and vitamin E (VE) has been
implicated in the development of KD. In this study, morphological and functional
alterations in the islet beta cells of rats fed grain from an endemic area with
KD were investigated. Serum insulin levels and glutathione peroxidase (GSH-Px)
activity were markedly lower in rats on the experimental diet compared with
controls. In pancreatic islet beta cells of rats on the experimental diet, a
vacuolation of the Golgi apparatus, slight dilation of the endoplasmic reticulum,
and decrease in the number of secretory granules were seen. Supplementation of
either 100 mg/kg VE (alpha-tocopherol) and/or 0.1 mg/kg Se (as 0.22 mg/kg sodium
selenite) to the experimental diet prevented these islet beta-cell alterations
and returned serum insulin to normal levels. Our results demonstrate that the
pathogenic factors of KD can induce alterations in islet beta cells, and Se and
VE provide protective effects against these pathogenic factors.
PMID- 9550539
TI - Association of fasting insulin with serum lipids and blood pressure in Kuwaiti
children.
AB - To examine the association of hyperinsulinemia with the atherogenic risk profile
in children, we studied the relationships of the fasting plasma insulin level
with indices of obesity (body mass index [BMI] and sum of triceps and subscapular
skinfold thickness [SFT]), body fat distribution (waist to hip ratio [WHR]),
serum lipid, lipoprotein, and apolipoprotein levels, and blood pressure in a case
control study of 460 Kuwaiti prepubertal obese children aged 6 to 13 years
matched by age and sex to 460 prepubertal non-obese controls. Obese children were
ascertained in a representative cross-sectional study of 2,400 school children.
Fasting insulin levels were positively correlated (P < .001) with serum
triglyceride (TG) and very-low-density lipoprotein (VLDL) cholesterol levels and
negatively correlated with high-density lipoprotein (HDL) cholesterol levels. No
significant associations were observed between insulin and total cholesterol
(TC), cholesterol, low-density lipoprotein (LDL) or apolipoprotein A-I (apo A-I).
Stronger associations of insulin levels with lipoprotein fractions were observed
in obese versus non-obese controls. Obese children had a higher concentration of
apo B and a lower apo A-I:B ratio (P < .001). Insulin and the insulin to glucose
ratio increased with age in obese children, whereas there were slight changes in
non-obese children. TG and HDL cholesterol levels and systolic blood pressure
(SBP) were significantly different across insulin quartiles in boys and girls. We
conclude that the fasting plasma insulin level may be used as a marker for the
development of obesity-associated metabolic disorders and elevated blood pressure
in children.
PMID- 9550540
TI - Relative effects of prolactin excess and estrogen deficiency on bone in rats.
AB - Humans with prolactinoma are at risk for osteoporosis. The relative contributions
of hyperprolactinemia-induced hypogonadism and the prolactin (PRL) excess per se
have been unclear from clinical studies. To determine the effects of PRL excess,
two models of chronic hyperprolactinemia were used. In one, mild
hyperprolactinemia was produced in rats bearing extra anterior pituitary glands
under the kidney capsule. Severe hyperprolactinemia was produced by
subcutaneously transplanting the PRL-secreting MMQ tumor into other rats. To
control for estrogen deficiency, the rats were ovariectomized. In some
experiments, estrogen replacement was provided. Urinary calcium excretion was
increased in hyperprolactinemic rats compared with controls, regardless of
severity of PRL excess and estrogen status. This suggested that PRL excess itself
had some effect on calcium balance. More importantly, however, the spinal bone
mineral density (BMD; measured by dual-energy x-ray densitometry) of mildly
hyperprolactinemic ovariectomized rats was the same as control ovariectomized
rats. Similarly, tibial dry weight and ash weight were affected by the estrogen
status, but not by the severe PRL excess of the tumor-implanted rats. Thus,
despite the evidence for an increase in urinary calcium excretion in
hyperprolactinemic rats, estrogen deficiency is much more important in
determining bone mineral. Therefore, the present data indicate that the
osteoporosis of hyperprolactinemia is likely due to PRL-induced hypogonadism,
rather than a direct effect of PRL on calcium homeostatis.
PMID- 9550542
TI - The effect of menopause on serum uric acid levels in non-obese healthy women.
AB - Elevated circulating serum uric acid concentrations may be linked with an
increased risk of coronary heart disease (CHD). We measured serum uric acid
levels in 50 premenopausal and 88 postmenopausal non-obese white women who
underwent an intravenous glucose tolerance test. The uric acid concentration was
significantly higher in postmenopausal versus premenopausal women. Adjustment of
the data to take into account a number of confounding variables, including the
age and body mass index (BMI), revealed a highly significant independent
difference between the groups. BMI was found to be a significant independent
predictor of the uric acid concentration, but this was confined to premenopausal
women. Postmenopausal women were found to be more insulin-resistant, and
significant correlations were observed between components of the insulin
resistance syndrome and uric acid in both groups. We conclude that increases in
serum acid in postmenopausal women may result from changes in metabolism as a
consequence of the menopause, and may be associated with the increased risk of
CHD seen in these women.
PMID- 9550541
TI - Changes of serum leptin and endocrine and metabolic parameters after 7 days of
energy restriction in men and women.
AB - Circulating leptin decreases during fasting in rodents and humans; however, the
mechanism of the decrease is unknown. The aim of this study was to examine the
relationship between decrements of serum leptin concentrations and changes of
hormonal (insulin and cortisol) and metabolic (glucose, ketones, and fatty acids)
parameters involved in the metabolic adaptation to energy restriction in normal
weight humans. Because there are marked gender differences in circulating leptin,
both men and women were studied. The body mass index (BMI), percent body fat (%
body fat), and serum leptin, insulin, cortisol, glucose, beta
hydroxybutyrate,(BOHB), and nonesterified fatty acids (NEFA) were determined in
11 men and 13 women (age, 20 to 41 years; BMI, 21.2 to 26.8 kg/m2) before and
during 7 days of energy restriction (-68% +/- 1% of daily energy requirements).
Weight loss averaged about 4% in both men and women. Leptin in men was 3.7 +/-
0.5 and decreased to 2.1 +/- 0.4 ng/mL (percent change [%delta], -36% +/- 6.0%, P
< .0005) during restriction. Concurrently, insulin decreased from 7.2 +/- 0.6 to
1.8 +/- 0.3 microU/mL (%delta, -74% +/- 4%, P < .0001). In contrast, leptin was
higher in women before (16.2 +/- 1.9 ng/mL) and after (6.0 +/- 0.8 ng/mL)
restriction and decreased more than in men (%delta, -61% +/- 4%, P < .02 v men),
whereas the decrease of insulin in women was less than in men: 10.1 +/- 1.9 to
6.1 +/- 1.0 microU/mL (%delta, -31% +/- 9%, P < .0025; P < .0005 v men), perhaps
because glucose decreased less in women than in men. Overall, the changes of
leptin during fasting were independently correlated with the changes of glucose
(r = .53, P < .007), NEFA (r = .53, P < .01), and BOHB (r = .65, P < .001). In
addition, the change of leptin correlated with a combined index of the parameters
that reflect decreased glucose availability and increased lipolysis
([deltaglucose + deltainsulin + deltaNEFA]/3, r = .73, P < .0001) or a combined
index of parameters that would be expected to limit glucose uptake by adipocytes
([deltaglucose + deltainsulin + deltacortisol]/3, r = .48, P < .02). We conclude
that there are significant differences between men and women in the responses of
leptin and insulin to energy restriction. Furthermore, decreases of circulating
leptin during negative energy balance are related to changes of endocrine and
metabolic parameters, suggesting that leptin secretion may be regulated by
alterations of adipocyte glucose and lipid metabolism, ie, decreased glucose
uptake and metabolism and increased lipolysis.
PMID- 9550543
TI - Effect of beta-adrenoceptor blockade on postexercise oxygen consumption and
triglyceride/fatty acid cycling.
AB - In the recovery period after strenuous exercise, there is increased O2 uptake,
termed the excess postexercise O2 consumption (EPOC). One of the mechanisms
suggested to explain EPOC is activation of the triglyceride/fatty acid (TG/FA)
cycle by catecholamines. The purpose of this study was to determine the effect of
selective beta1- and nonselective beta-adrenoceptor blockade on EPOC and the
TG/FA cycle. Seven healthy young men each participated in three control and three
exercise experiments in a randomized and balanced sequence. In the exercise
experiments, subjects exercised for 90 minutes at 58% +/- 2% (mean +/- SD) of
maximal O2 uptake on a cycle ergometer, followed by a 4.5-hour bedrest. The
control experiments followed the same protocol, but without exercise. In one
control and one exercise experiment, the selective beta1-adrenoceptor antagonist
atenolol (0.062 mg.kg(-1) body weight) was administered intravenously immediately
after the exercise (EXAT) and at the corresponding time in the rest-control
experiment (REAT). In a second set of control and exercise experiments, the
nonselective beta-adrenoceptor antagonist propranolol (0.15 mg.kg(-1) body
weight) was administered (REPRO and EXPRO). In a third set of rest and exercise
experiments, an injection of saline was given instead of beta-antagonist (RE and
EX). TG/FA cycling was calculated by combining results obtained with a two-stage
glycerol infusion and indirect calorimetry. O2 uptake was significantly increased
above control levels throughout the recovery period after exercise with the
nonselective beta-adrenoceptor antagonist, beta1-adrenoceptor antagonist, and
saline. However, there was no difference between the time course or magnitude of
EPOC in the three situations. After 4.5 hours of bedrest, the mean increase in O2
uptake was 8% to 9% in all three conditions. TG/FA cycling was increased after
exercise, but no effects of beta-antagonists were observed. We conclude that EPOC
and the rate of TG/FA cycling are not attenuated by selective beta1- or
nonselective beta-adrenoceptor blockade after an acute prolonged exercise
protocol.
PMID- 9550544
TI - Insulin and glucosamine infusions increase O-linked N-acetyl-glucosamine in
skeletal muscle proteins in vivo.
AB - O-linked N-acetylglucosamine (O-GlcNAc) is an abundant posttranslational
modification of serine/threonine residues of nuclear and cytoplasmic proteins. We
determined whether insulin or coinfusion of glucosamine (GlcN) with insulin
alters O-GlcNAc of skeletal muscle proteins. Three groups of conscious fasted
rats received 6-hour infusions of either saline (BAS), insulin 18 mU/kg.min and
saline (INS), or insulin and GlcN 30 micromol/kg.min (GLCN) during maintenance of
normoglycemia. At 6 hours, the concentrations of muscle UDP-GlcNAc, UDP-N
acetylgalactosamine (UDP-GalNAc), UDP-glucose (UDP-Glc), UDP-galactose (UDP-Gal),
glycogen, and N and O-linked GlcNAc (galactosyltransferase labeling followed by
beta elimination) were measured in freeze-clamped abdominis muscle. Insulin
increased whole-body glucose uptake from 49 +/- 5 to 239 +/- 8 micromol/kg.min (P
< .001) and glycogen in abdominis muscle from 138 +/- 11 to 370 +/- 26 mmol/kg
dry weight (P < .001). Insulin increased the amount of cytosolic N - and O-linked
GlcNAc by 56% from 362 +/- 30 to 564 +/- 45 dpm/microg protein . 100 min (P <
.02), and O-GlcNAc from 221 +/- 16 to 339 +/- 27 dpm/microg . 100 min (P < .02).
Glycogen content was positively correlated with the amount of total (r = .90, P <
.005) and O-linked GlcNAc in insulin-infused animals. Coinfusion of GlcN with
insulin increased muscle UDP-GlcNAc about fourfold (100 +/- 6 nmol/g) compared
with insulin (27 +/- 1, P < .001) or saline (25 +/- 1, P < .001) infusion. GlcN
also decreased glucose uptake over 6 hours by 30% to 168 +/- 8 micromol/kg . min
(P < .001 for GLCN v INS) and muscle glycogen to 292 +/- 24 mmol/kg dry weight (P
< .05 for GLCN v INS). Both total (635 +/- 60 dpm/microg . 100 min, P < .002) and
O-linked GlcNAc (375 +/- 36 dpm/microg . 100 min, P < .002) in the cytosol were
significantly higher in GLCN rats (635 +/- 60 dpm/microg) versus BAS rats (P <
.002). As in INS rats, muscle glycogen and O-GlcNAc were positively correlated in
GLCN rats (r = .54, P < .05). Variation in total and O-linked GlcNAc in GLCN rats
was due both to GlcN (P < .02) and to variation in the glycogen content (P <
.005).
PMID- 9550545
TI - The significance of the Trp 64 Arg mutation of the beta3-adrenergic receptor gene
in impaired glucose tolerance, non-insulin-dependent diabetes mellitus, and
insulin resistance in Japanese subjects.
AB - It has been reported that the Trp 64 Arg mutation of the human beta3-adrenergic
receptor (beta3-AR) gene is related to an earlier age of onset of non-insulin
dependent diabetes mellitus (NIDDM) and features of insulin resistance and weight
gain in morbidly obese patients. However, such findings have not been consistent
in varying ethnic populations. In the present study, we investigated the
frequency of the Trp 64 Arg mutation of the human beta3-AR gene in Japanese
control subjects (n = 253) and in NIDDM (n = 314) and impaired glucose tolerance
(IGT) patients (n = 100). We compared the frequency of the mutation with the body
mass index (BMI) in these groups and with the metabolic clearance rate (MCR) of
glucose in the NIDDM patients. A Trp 64 Arg mutation was observed in 36.7%,
31.6%, and 37.0% of the control, NIDDM, and IGT subjects, respectively. The
frequency of the homozygotes for the mutation was 4.3%, 4.8%, and 3.0%,
respectively. Neither the genotype frequency (Trp/Arg, Arg/Arg) nor the frequency
of the mutated allele was significantly different among the three groups. The BMI
of the subjects with the mutation was not significantly higher than that of the
subjects without the mutation in each group. Furthermore, the allele frequency
(A) was not different among the subjects with different BMIs (BMI < 22.0, 22.0 <
or = BMI < or = 26.4, BMI > 26.4) in each group. In a separate group of NIDDM
patients, the MCR of the subjects with intermediate BMIs (22.0 < or = BMI < or =
26.4) with the mutation tended to be lower than that of those without the
mutation. In addition, the MCR of the subjects with the mutation in this group
was significantly lower compared with that of those with a BMI less than 22.
These results indicate that the Trp 64 Arg mutation of the beta3-AR gene may not
contribute to the development of NIDDM or be a determinant of obesity in the
Japanese population. However, the mutation may contribute to insulin resistance
in NIDDM patients with an intermediate BMI.
PMID- 9550546
TI - Arachidonic acid metabolites of the lipoxygenase as well as the cyclooxygenase
pathway may be involved in regulating preadipocyte differentiation.
AB - Conditions that trigger preadipocyte differentiation in vivo have yet to be
elucidated. To investigate the role of endogenous arachidonic acid (AA)
metabolites on adipose tissue growth, rat preadipocytes in primary culture were
induced to differentiate using medium conditioned by isolated mature adipocytes
(ACM). Differentiation was determined by assay of glycerol-3-phosphate
dehydrogenase (GPDH). When collected in the presence of indomethacin (10 nmol/L)
to inhibit prostaglandin (PG) synthesis by adipocytes, ACM induced greater
differentiation (GPDH activity, 405 +/- 68 nmol NADH used/min/mg protein) than
when indomethacin was added postcollection to inhibit preadipocyte PG synthesis
(205 +/- 24, P < .05) or ACM alone (304 +/- 55). This suggested that PGs released
by adipocytes inhibited differentiation, whereas those released by preadipocytes
appeared to act in an autocrine manner to stimulate differentiation. However, 24
hour collections of ACM contained 125 pmol/L PGE2 and 900 pmol/L PGI2,
concentrations too low to promote differentiation when added exogenously.
Nordihydroguaiaretic acid (NDGA; 10 pmol/L), an inhibitor of lipoxygenase (LOX),
stimulated the ACM-induced increase in GPDH activity (ACM, 99 +/- 13; ACM + NDGA,
369 +/- 130). In contrast, when differentiation was induced by a hormonal
cocktail (MIX), including insulin and corticosterone, NDGA decreased GPDH
activity (MIX, 329 +/- 66; MIX + NDGA, 142 +/- 40; P < .03). We concluded that
preadipocyte differentiation within adipose tissue may be subject to both
positive and negative regulators derived from AA metabolism resulting from both
LOX and cyclooxygenase (COX) activity.
PMID- 9550547
TI - Regional differences in adrenoceptor binding and fat cell lipolysis in obese,
postmenopausal women.
AB - In women there is an increase in visceral obesity, subcutaneous abdominal
adipocyte lipolysis, and risk of cardiovascular disease (CVD) associated with
weight gain after menopause. The mechanisms underlying this increase in
adrenoreceptor (AR)-agonist catecholamine-stimulated lipolysis and abdominal
obesity in postmenopausal women were studied in intact adipocytes isolated from
the abdominal and gluteal subcutaneous fat depots in 19 obese (48% +/- 1% body
fat, mean +/- SE) women with a mean +/- SE age of 58 +/- 1 years. The fat cell
size and adipose tissue lipoprotein lipase (ATLPL) activity were similar in both
sites. The maximal lipolytic responsiveness and sensitivity to isoproterenol were
higher (P < .05) in abdominal compared with gluteal adipocytes, but maximal
lipolytic response to a post-AR agent was similar. Abdominal adipocytes had a
higher beta-AR ([3H]-CGP-12177) and alpha2-AR ([3H]-yohimbine) affinity than
gluteal cells (P < .05), lower alpha2-AR density (P < .05), but similar beta-AR
density as gluteal cells. Both abdominal and gluteal cell size correlated with
alpha2-AR density (P < .01), but not with beta-AR density. Thus, a higher beta-AR
affinity and lower alpha2-AR relative to beta-AR density may explain the higher
in vitro catecholamine-mediated lipolysis in abdominal compared with gluteal
adipocytes in obese, postmenopausal women.
PMID- 9550548
TI - Effects of thyroid hormone (thyroxine) and testosterone on hepatic 11beta
hydroxysteroid dehydrogenase mRNA and activity in pubertal hypothyroid male rats.
AB - To investigate the effects of thyroid hormone and testosterone on 11beta
hydroxysteroid dehydrogenase type 1 (11beta-HSD1), we measured changes in hepatic
11beta-dehydrogenase activity and its mRNA levels in pubertal methimazole (MMI)
induced hypothyroid male rats following treatment with thyroxine ([T4] 50
microg/kg/d) or testosterone (250 microg/d) for 14 days. Hypothyroidism in male
rats markedly reduced hepatic 11beta-HSD1 mRNA levels and serum testosterone
concentrations (P < .01). Subcutaneous injection of T4 in the hypothyroid rats
significantly (P < .01) increased hepatic 11beta-HSD1 mRNA to approximately
normal levels and simultaneously increased serum testosterone levels. However,
the same daily dose of T4 administered to castrated male hypothyroid rats for 14
days did not elevate hepatic 11beta-HSD1 activity. Treatment with testosterone
for 14 days in castrated hypothyroid male rats and rats without gonadectomy
significantly (P < .01) increased the enzyme activity without administration of
T4. Variations in hepatic 11beta-HSD1 activity were demonstrated to be
accompanied by changes in serum testosterone levels in the rats following
alteration of the thyroid hormone state. These results suggest that the effect of
T4 in increasing the subnormal 11beta-HSD1 gene expression in hypothyroid male
rats is mediated by its ability to increase testosterone production in these
rats, because in castrated hypothyroid rats, T4 does not elevate 11beta-HSD1 gene
expression.
PMID- 9550549
TI - Low-density lipoprotein-apolipoprotein B metabolism following apheresis:
simulation studies of mass changes and tracer kinetics.
AB - Low-density lipoprotein (LDL) apheresis is an effective method to treat severe
hyperlipoproteinemia such as heterozygous familial hypercholesterolemia (FH). It
is unknown whether apheresis induces changes in metabolic parameters of LDL
apolipoprotein B (apoB) such as the fractional catabolic rate (FCR) or production
rate. We performed simulation studies to determine the effect of potential
changes in the LDL FCR on LDL-apoB mass and on exogenous and endogenous tracer
studies. For these studies, we assumed a two-compartment LDL model and the
following metabolic parameters: plasma LDL-apoB, 180 mg.dL(-1); LDL-apoB
production rate, 36 mg.dL(-1).d(-1) (approximately 14.4 mg.kg(-1).d(-1)); and LDL
apo FCR, 0.2 d(-1). It was also assumed that apheresis instantaneously decreased
the LDL-apoB concentration to 60 mg.dL(-1) and that LDL-apoB production was not
perturbed. The simulations examined three possible outcomes: (1) no change in
FCR, (2) a temporary doubling in FCR, and (3) a temporary tripling in FCR.
Monoexponential models were fit to the rebound of LDL-apoB mass data generated
using the different FCRs. In no instance did the FCR determined from the fit
match the FCR used to generate the data; FCRs were either higher or lower than
the original FCR used to generate the data. Simulations of the kinetics of
exogenously labeled LDL showed that if apheresis was performed on day 7 of a
turnover study, it would be possible to detect large changes in LDL-apoB FCR. In
contrast, during an endogenous labeling study, potential increases in FCR induced
by apheresis may not be detected. However, our simulations do show that
endogenous labeling studies performed before and after apheresis should yield
data that will permit detection of changes in the FCR. Thus, these studies
indicate that large differences in the LDL-apoB FCR induced by apheresis can be
detected by either an exogenous tracer experiment perturbed by apheresis or by
endogenous labeling experiments performed before and after apheresis. Small
changes in the FCR that may be induced by apheresis will probably be
indistinguishable from experimental noise.
PMID- 9550550
TI - SAAM II: Simulation, Analysis, and Modeling Software for tracer and
pharmacokinetic studies.
AB - Kinetic analysis and integrated systems modeling have contributed substantially
to our understanding of the physiology and pathophysiology of metabolic systems
and the distribution and clearance of drugs in humans and animals. In recent
years, many researchers have become aware of the usefulness of these techniques
in the experimental design. With this has come the recognition that the
discipline of kinetic analysis requires its own expertise. The expertise can
impact experimental design in many ways, from the collaborative and service
activities in which individuals interact in formal ways to the development of
software tools to aid in kinetic analysis. The purpose of this report is to
describe one such software tool, Simulation, Analysis, and Modeling Software II
(SAAM II). In the first part, we describe in general how the user can take
advantage of the capabilities of the software system, and in the second part, we
give three specific examples using multicompartmental models found in lipoprotein
(apolipoprotein B [apoB] kinetics) and diabetes (glucose minimal model) research.
PMID- 9550551
TI - Circulating transferrin receptor assay--coming of age.
PMID- 9550553
TI - Fundamentals of quality assessment of molecular amplification methods in clinical
diagnostics. International Federation of Clinical Chemistry Scientific Division
Committee on Molecular Biology Techniques.
AB - The increasing interest in molecular biology diagnostics is a result of the
tremendous gain of scientific knowledge in genetics, made possible especially
since the introduction of amplification techniques. High expectations have been
placed on genetic testing, and the number of laboratories now using the relevant
technology is rapidly increasing--resulting in an obvious need for
standardization and definition of laboratory organization. This communication is
an effort towards that end. We address aspects that should be considered when
structuring a new molecular diagnostic laboratory, and we discuss individual
preanalytical and analytical procedures, from sampling to evaluation of assay
results. In addition, different means of controlling contamination are discussed.
Because the methodology is in constant change, no general standards can be
defined. Accordingly, this publication is intended to serve as a recommendation
for good laboratory practice and internal quality control and as a guide to
troubleshooting, primarily in amplification techniques.
PMID- 9550552
TI - Molecular diagnosis of medium-chain acyl-CoA dehydrogenase deficiency by
oligonucleotide ligation assay.
PMID- 9550554
TI - Validation by isoelectric focusing of the anion-exchange isotransferrin
fractionation step involved in determination of carbohydrate-deficient
transferrin by the CDTect assay.
AB - Serum concentration of carbohydrate-deficient transferrin (CDT) is used for
laboratory diagnosis of chronic alcohol abuse. Using isoelectric focusing for
validation of the initial isotransferrin fractionation step involved in the
determination of CDT by the CDTect assay, we found a complete in vitro iron
saturation of transferrin and sufficient stability of the transferrin iron load
during column passage; effective separation of non-CDT-isotransferrins and CDT
isotransferrins at the microcolumns; partial coelution of trisialo-Fe2
transferrin, which did not significantly affect CDT measurement; partial
retention of CDT-isotransferrins, especially disialo-Fe2-transferrin, which may
cause falsely negative results for CDT at the upper reference limits; good
precision of the isotransferrin fractionation step; and no significant effects of
low concentrations of serum protein and transferrin. We strongly urge
standardization of CDT analysis and suggest isoelectric focusing for validation
of CDT analysis methods and verification of odd results.
PMID- 9550555
TI - Measurement of soluble transferrin receptor in serum of healthy adults.
AB - The concentration of soluble transferrin receptor (sTfR) in serum is reported to
be useful in the diagnosis of iron deficiency, especially for patients with
concurrent chronic disease, where routine tests of iron status are compromised by
the inflammatory condition. A new diagnostic assay for sTfR is calibrated against
natural plasma sTfR, thus minimizing calibration discrepancies that result from
differences between the analyte and the cellular transferrin receptor used in
other assays. Use of the new assay to measure sTfR concentrations in 225 healthy,
hematologically normal adults provided a reference interval against which
pathological samples could be compared. There was no difference in the reference
intervals for men and women and no correlation of [sTfR] with the age of the
subject. Black subjects had significantly higher concentrations than nonblacks,
and people living at high altitude had higher concentrations than those living
closer to sea level. These differences were additive.
PMID- 9550556
TI - Serum transferrin receptors are decreased in the presence of iron overload.
AB - To test the hypothesis that the quantities of circulating transferrin receptors
are reduced in iron overload, we studied serum transferrin receptors and indirect
measures of iron status in 150 subjects from rural Zimbabwe. We found significant
inverse correlations between serum concentrations of transferrin receptors and
ferritin, the ratio of ferritin to aspartate aminotransferase, and transferrin
saturation (r > or = 0.44; P < 0.001). The mean +/- SD concentration of serum
transferrin receptors in 23 subjects classified as having iron overload (ferritin
> 300 microg/L and transferrin saturation > 60%) was 1.55 +/- 0.61 mg/L,
significantly lower than the 2.50 +/- 0.62 mg/L in 75 subjects with normal iron
stores (ferritin 20-300 microg/L and transferrin saturation 15-55%; P < 0.0005)
and the 2.83 +/- 1.14 mg/L in 8 subjects with iron deficiency (ferritin < 20
microg/L; P = 0.001). In keeping with the regulation of transferrin receptor
expression at the cellular level, our findings suggest that serum transferrin
receptors are decreased in the presence of iron overload.
PMID- 9550557
TI - Clinical utility of the soluble transferrin receptor and comparison with serum
ferritin in several populations.
AB - Soluble transferrin receptor (sTfR) and ferritin concentrations were measured in
a variety of clinical settings to compare the ability of these two tests to
identify iron deficiency. Among 62 anemic patients who either had a bone marrow
aspirate performed or had a documented response to iron therapy, the diagnostic
sensitivity and specificity of sTfR (at a diagnostic cutoff of > 2.8 mg/L) were
92% and 84%, respectively, with a positive predictive value of 42% in this
population. Ferritin (< or = 12 microg/L) had a sensitivity of 25% and a
specificity of 98%. However, the sensitivity and specificity of ferritin could be
improved to 92% and 98%, respectively, by using a diagnostic cutoff value of < or
= 30 microg/L, resulting in a positive predictive value of 92%. Ferritin and sTfR
were also measured in 267 outpatient samples and 112 medical students. In the
outpatient group, the two tests agreed in 73% of the samples; however, 25% of the
samples had ferritin values > 12 microg/L and increased sTfR. Among the medical
students, there was 91% agreement between the two tests, but 7% of the samples
had ferritin < or = 12 microg/L and normal sTfR. Together, these data suggest
that measurement of sTfR does not provide sufficient additional information to
ferritin to warrant routine use. However, sTfR may be useful as an adjunct in the
evaluation of anemic patients, whose ferritin values may be increased as the
result of an acute-phase reaction.
PMID- 9550558
TI - Cardiac troponin I measurement with the ACCESS immunoassay system: analytical and
clinical performance characteristics.
AB - We evaluated the ACCESS cardiac troponin I (cTnI) immunoassay as a marker for
myocardial infarction (MI). Total imprecision was 6.0% to 13.5%, the minimum
detectable concentration was 0.007 microg/L, and the limit of quantitation was
0.046 microg/L. Comparison of cTnI measurement between the ACCESS and Stratus
systems (n = 114) showed a proportional difference: ACCESS cTnI = 0.0996 Stratus
cTnI + 0.049 microg/L (r = 0.811). Fifty-nine of 61 ambulatory patients without
cardiac symptoms had no detectable cTnI (95% range, 0.00 to 0.025 microg/L). The
optimum cutoff for discriminating MI (n = 289, 45 with MI) was 0.15 microg/L by
receiver operator characteristic curve analysis; at this cutoff, the ACCESS cTnI
assay showed a sensitivity of 88.9% (95% CI, 79.7-98.1%) and specificity of 91.8%
(95% CI, 88.4-95.2%). The ACCESS cTnI assay results showed 89.4% and 93.0%
concordance with the MB isoenzyme of creatine kinase (CK-MB) mass and Stratus
cTnI results, respectively, for classification of patients with suspected MI. The
ACCESS cTnI assay appears to show sensitivity and specificity comparable with
those of both CK-MB mass and Stratus cTnI assays for the diagnosis of MI in
patients presenting within 12 h of onset of symptoms.
PMID- 9550559
TI - X-chromosome inactivation in healthy females: incidence of excessive lyonization
with age and comparison of assays involving DNA methylation and transcript
polymorphisms.
AB - Skewed lyonization in healthy females represents the major disadvantage of X
chromosome-based clonality assays. Because most techniques are based on the
difference in DNA methylation between active and inactive X-chromosomes,
incomplete DNA digestion may occur, giving an unreliable clonality result. Here,
we compare two different techniques carried out in healthy females belonging to
three age groups and in a group of patients with essential thrombocythemia. The
first technique involved the human androgen receptor gene, the second the
transcript analysis of the iduronate-2-sulfatase, P55, and glucose-6-phospate
dehydrogenase genes. Results between both techniques were concordant in most
cases except in neonates, and the same pattern was observed in all fractions in
healthy females. We conclude that: (a) clonality assays involving DNA and RNA
polymorphisms are usually concordant except in neonates; (b) appropriate control
tissue embryologically related to the sample must be chosen to eliminate
excessive lyonization; (c) acquired skewing increases with age, whereas nonrandom
lyonization is a rare phenomenon.
PMID- 9550560
TI - Molecular diagnosis of medium-chain acyl-CoA dehydrogenase deficiency by
oligonucleotide ligation assay.
AB - Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a recessively inherited
defect in the mitochondrial beta-oxidation of fatty acids. A single nucleotide
change, the A985 --> G transition, in the MCAD gene accounts for approximately
90% of all the disease-causing mutations in the patients. We have used PCR to
amplify a segment of the human MCAD gene and typed the allelic sequence variation
at base 985 by a colorimetric oligonucleotide ligation assay (OLA). PCR/OLA
provides a technique that permits differentiation of the homozygotes,
heterozygotes, and normals for the A985 --> G allele in the MCAD gene. Genotyping
of 1908 random Finnish DNA samples by OLA identified 10 carriers of the mutant
allele, but no homozygotes were found. The calculated carrier frequency for the
A985 --> G mutation was 1:191 (95% confidence limits, 1:118-1:501), and the
calculated frequency for the A985 --> G homozygotes was 1:147,000 (95% confidence
limits, 1:56,000-1:1,004,000).
PMID- 9550561
TI - Exon 5 of the p53 gene is a target for deletions in ovarian cancer.
AB - Missense point mutations, leading to inactivation of the p53 tumor suppressor
gene product, are currently the most frequent alterations in human cancer.
Little, however, is known about small intragenic deletions or insertions
occurring in this locus of chromosome 17. We have analyzed 56 primary ovarian
tumors for the presence of such abnormalities. The analysis was based on
multiplex PCR amplification of exons 1 through 11 of the p53 gene and fragment
analysis of the generated PCR products. Mutations were detected in 14% (8 of 56)
of the tumors. Deletions were much more prevalent than insertions (seven vs one).
Six of the deletions and the insertion affected exon 5, and the other deletion
was in exon 7. Two deletions and the insertion did not disrupt the reading frame;
the protein product was expressed in the tumor at high concentrations in all
three cases. The other five deletions generated a frameshift, which is predicted
to result in the production of a truncated protein product. In the case of the
deletions, a 2-5-bp repeat was present close to the detected deletion, whereas
the insertion duplicated the sequence immediately upstream of the insertion site.
Overall our findings indicate that small intragenic p53 deletions/insertions are
not rare events in ovarian cancer, and that p53 exon 5 is the target in the vast
majority (88%) of the cases.
PMID- 9550562
TI - Immunoradiometric assay of succinylated corticotropin: an improved method for
quantification of ACTH.
AB - In this paper we describe the development and the evaluation of a new type of
immunoassay for human corticotropin (ACTH). We succeeded, by using an original
approach based upon immunization with ACTH derivatized with succinic anhydride,
in raising monoclonal antibodies against this poorly immunogenic peptide. Three
of the antibodies were selected to develop an immunoassay for ACTH. The assay
requires the prior succinylation of the plasma samples for optimal sensitivity
and specificity. This acylation treatment is fast, reproducible, and, in
addition, improves the stability of the ACTH molecule in plasma, thus
facilitating sample handling. The assay is performed in only 3 h with a detection
limit of 0.7 ng/L. Analytical evaluation showed excellent specificity,
reproducibility, and reliability. A comparison with two commonly used but time
consuming ACTH IRMAs was carried out by assaying several plasma samples in
parallel and gave in both cases very good correlation.
PMID- 9550563
TI - Rapid, automated assay for progesterone on the Abbott AxSYM analyzer.
AB - We describe an automated assay for progesterone (P4) in human serum and plasma
with the Abbott AxSYM random-access immunoassay analyzer. In this one-step
competitive assay, P4 immobilized onto latex microparticles competes with sample
P4 for binding to a conjugate of alkaline phosphatase (AP) and anti-P4 antibody.
Total CVs ranged from 3.4% to 8.2% in multiple precision studies conducted
according to the 20-day NCCLS EP5-T protocol. The detection limit (zero
calibrator + 2 SD) was 0.10 microg/L across 36 experiments. Values for diluted
samples were 83-116% of expected. Recovery of P4 added to serum specimens was 92
115%. Cross-reactivities with 43 natural and synthetic steroids were 0-6.3%. No
significant interference was detected from bilirubin, protein, erythrocytes,
hemoglobin, triglycerides, or cholesterol. In a multisite correlation study,
AxSYM P4 results compared well with results from a commercial RIA method (n =
1156; r = 0.976; slope = 1.03; y-intercept = 0.04). Assay throughput is >80 tests
per hour in batch mode, 60 tests per hour with mixed load list configurations.
PMID- 9550564
TI - Evaluation of the Sysmex UF-100 automated urinalysis analyzer.
AB - Urinalysis is a high-volume procedure that currently requires significant labor
to examine microscopic sediment. We evaluated the Sysmex UF-100 automated
urinalysis analyzer for performing this task. Instrument accuracy was assessed by
comparing continuous counts of microscopic elements from the UF-100 with ranges
of cells (per low-power field or high-power field) from manual microscopy
performed on centrifuged urines. Counts showed good agreement between methods
(gamma statistic: 0.880-0.970) for all microscopic elements in 252 urine samples.
Within-run imprecision of cell counts expressed as CV (mean cell count/microL)
was for erythrocytes (RBC) 31% (5), 18% (50), 2.4% (800); for leukocytes (WBC)
14% (10), 11% (100), 8.5% (400); for squamous epithelial cells (SEC) 18% (5), 12%
(30), 7.0% (100); for casts 45% (1), 17% (4); for bacteria 2-12% (entire range of
40-2500). Between-run imprecision on quality-control cell suspensions expressed
as CV (mean cell count/microL) was for RBC 6.1% (50), 2.7% (256); for WBC 26.9%
(54), 4.9% (228). Cells counted on dilution were 99.1% of expected for RBC,
102.0% for WBC, and 121.8% for bacteria. Carryover was <0.04% for RBC, <0.03% for
WBC, <0.14% for SEC, <0.29% for bacteria. We conclude that the UF-100 can
automatically perform reliable quantitative microscopic urinalysis in batches
without operator interaction.
PMID- 9550565
TI - Hematological indices in an older population sample: derivation of healthy
reference values.
AB - Factors affecting hematological values were explored, and healthy reference
values were estimated from a cross-sectional survey of a population (n = 4433),
ages 49 years or more, residing permanently in a defined geographic region.
Nursing home residents were excluded. Details of medication use and medical
history were obtained by interview, and participants were asked to return after
an overnight fast for blood sampling. The participation rate was 82.4%, of whom
88.4% provided a fasting blood sample. Hemoglobin, hematocrit, and erythrocyte
counts were higher in men, whereas platelet counts were higher in women.
Statistical associations between each hematological index and smoking, alcohol
intake, use of certain drugs, chronic disease, and high creatinine values were
tested by unpaired t-tests. Separate reference groups were defined for each
hematological index by excluding subjects with any of the factors found to be of
importance. The resulting reference values are particularly appropriate for
evaluating hematological test results in older individuals.
PMID- 9550566
TI - Variability and determinants of total homocysteine concentrations in plasma in an
elderly population.
AB - The variability of plasma total homocysteine (tHcy) was examined in 96
individuals over a 1-yr period. Blood tHcy concentrations varied from 7.1
micromol/L in the bottom quintile to 14.5 micromol/L in the top quintile. The
mean tHcy was 10.4 micromol/L, the between-person SD was 2.5 micromol/L, and the
within-person SD was 0.93 micromol/L. There was little seasonal variation, and
the reliability coefficient was 0.88. Mean tHcy concentrations were inversely
related to mean plasma folate (r = -0.36) and vitamin B12 (r = -0.35)
concentrations. Median tHcy concentrations were approximately 1 micromol/L higher
in men than in women and in older (70 to 74 years) than in younger (65 to 69
years) individuals and higher in those with the TT and CT genotypes for the
methylenetetrahydrofolate reductase polymorphism than in those with the CC
genotype (10.7 and 10.6 vs 9.6 micromol/L). Epidemiological studies based on
single tHcy measurements may underestimate the magnitude of any risk associations
with disease by 10-15%.
PMID- 9550567
TI - Quantifying the bias associated with use of discrepant analysis.
AB - Discrepant analysis is a widely used technique for estimating the performance
parameters of a laboratory test. In discrepant analysis, each specimen is
initially tested with the candidate test and a comparison method, and when the
results of the two tests disagree, a confirmatory test is used to resolve the
discrepancy. Discrepant analysis usually produces biased estimates. This report
quantifies this bias and shows that it is usually positive, leading to
overestimation of the performance parameters of a laboratory test. The direction
and magnitude of the bias are predictably influenced by the analytical
sensitivity and specificity of the candidate test, comparison method, and
confirmatory test. The proportion of abnormal specimens tested also affects the
magnitude of the bias, particularly the estimates of analytical sensitivity and
positive predictive value when this proportion is low. Alternative approaches are
suggested.
PMID- 9550568
TI - Statistically accurate estimation of hormone concentrations and associated
uncertainties: methodology, validation, and applications.
AB - We describe a data reduction procedure to assign statistically accurate estimates
of unknown hormone concentrations, with associated uncertainties, based on
experimental uncertainties in sample replicates and the fitted calibration curve.
Three mathematical calibration curve functions are considered. The one providing
optimal statistical characterization of reference calibrators is chosen for
unknown evaluation. Experimental error is addressed by assigning and propagating
uncertainty estimates for each measured response (including zero-dose responses)
by an empirically determined discrete uncertainty profile and by propagating
calibration curve uncertainty. Discrete uncertainty profiles account for both
response precision (replicability) and accuracy (deviation from predicted
calibration curves) without relying on assumed theoretical response variance
assay response relations. The validity of assigning variable response weighting
by this procedure was assessed by Monte Carlo simulations based on
chemiluminescence growth hormone calibration curves. Much-improved accuracy and
estimated precision are achieved for unknown hormone concentrations, particularly
extremely low concentrations, by using this variable response weighting
procedure.
PMID- 9550569
TI - Proficiency testing of creatine kinase and creatine kinase-2: the experience of
the Ontario Laboratory Proficiency Testing Program.
AB - The Ontario Laboratory Proficiency Testing Program has regularly monitored the
analytical performance of total creatine kinase (CK) (approximately 230
participants) and CK isoenzyme-2 (CK-MB) (approximately 160 participants)
throughout the entire province. Consistently, a wide dispersion of results has
been observed not only between different analyzer systems but also among
identical analyzers. Accordingly, the results of the last three proficiency
surveys for these analytes were examined statistically to establish both the
extent of these variations and the range of values reported for the male upper
reference ranges. The results of many of the analyzer systems were significantly
different from each other, as were many of the reference ranges. This
unsatisfactory situation may only be remedied by the use of reference materials
as shown by others. The consequences of these findings also effect the
reliability of epidemiological surveys such as the WHO MONICA Project
(Circulation 1994;90:583-612), which monitors deaths due to heart disease and
includes cardiac enzyme results in its criteria.
PMID- 9550570
TI - Plasma apolipoproteins A-I and B in survivors of myocardial infarction and in a
control group.
AB - The values of apolipoproteins (apo) A-I and B were determined in a population
sample of hospital outpatients with a standardized method to verify if the
cutpoints calculated in a cross-sectional study in the US are usable with other
populations. We also tested the apolipoproteins' ability to discriminate between
healthy people and survivors of myocardial infarction. In the studied population
the apo A-I value corresponding to the HDL-cholesterol decisional centile is 1.12
g/L for males and 1.17 g/L for females; the apo B value corresponding to the LDL
cholesterol decisional centile is 1.23 g/L for males and 1.14 g/L for females.
These values are quite close to the cutpoints proposed for the American
population (1.20 g/L for both apolipoproteins). In comparison with the LDL- and
HDL-cholesterol decisional concentrations, the cutpoints for apolipoproteins
allow a correct classification of a greater percentage of postmyocardial
infarction patients (16% higher for apo B and 5% for apo A-I). Standardized
assays coupled with a reference database allow a better clinical use of
apolipoprotein measurements.
PMID- 9550571
TI - Study of arsenic-protein binding in serum of patients on continuous ambulatory
peritoneal dialysis.
AB - Arsenic (As) bound to serum proteins in patients on continuous ambulatory
peritoneal dialysis (CAPD) was studied. A prior experiment by ultrafiltration
showed that 5.57% of total As was bound to serum proteins for 14 CAPD patients.
Further identification of the As species and protein molecules in serum of three
CAPD patients with high As concentrations was carried out by combining the
separation methods of size-exclusion, anion-exchange, and affinity fast-protein
liquid chromatography, detected by hydride generation atomic absorption
spectrometry. The results indicated that only inorganic As species are bound to
serum proteins. Transferrin is the main carrier. The concentrations of As bound
to proteins in serum for the three patients were 0.44 +/- 0.12, 0.19 +/- 0.09,
and 0.59 +/- 0.09 microg/L (n = 3), respectively.
PMID- 9550572
TI - Increased oxidative stress in dilated cardiomyopathic heart failure.
AB - In the present study, we assessed oxidative stress in patients with dilated
cardiomyopathy of ischemic or idiopathic etiology. For this reason we measured
whole blood reduced glutathione, erythrocyte superoxide dismutase, susceptibility
of erythrocyte membranes and erythrocytes to peroxidation, and SH content of
erythrocyte membranes in 12 patients (8 men and 4 women, ages 31 to 66 years)
with idiopathic dilated cardiomyopathy, in 11 patients (8 men and 3 women, ages
32 to 65 years) with ischemic dilated cardiomyopathy, and in 21 healthy
volunteers (12 men and 9 women, ages 25 to 67 years). There was no statistically
significant difference between the two patient groups for the indicators studied
(P >0.05). Blood glutathione, erythrocyte superoxide dismutase, and membrane SH
content of both groups of patients was decreased compared with controls (P
<0.05), whereas erythrocyte and membrane susceptibility to peroxidation were
increased (P <0.05). We conclude that patients with idiopathic or ischemic
dilated cardiomyopathy exhibit abnormalities of a range of markers of increased
oxidative stress. These abnormalities may contribute to contractile dysfunction,
increased incidence of fatal arrhythmias, and sudden death.
PMID- 9550573
TI - Mechanisms of dopamine and dobutamine interference in biochemical tests that use
peroxide and peroxidase to generate chromophore.
AB - Dopamine and dobutamine have recently been shown to produce a negative
interference in several biochemical tests that use peroxide and peroxidase to
generate a chromophore. To define the chemical mechanism of this interference, we
examined the effects of dopamine and dobutamine in various peroxidase-based
biochemical tests. Dopamine interfered stoichiometrically with peroxidase-based
tests that use 4-aminophenazone to form chromophore but interfered little in
those that use other compounds to generate chromophore. Dopamine reacts with 4
aminophenazone in the presence of peroxide and peroxidase to form a novel quinone
imine dye, with a smaller absorptivity than the chromophore formed in the absence
of dopamine. The smaller absorptivity of this novel chromophore results in
negative interference by reducing the total absorbance at the wavelength used to
measure analyte. In contrast, dobutamine interfered stoichiometrically with all
peroxidase-based tests studied, regardless of whether 4-aminophenazone was used
to form the chromophore. Dobutamine was rapidly oxidized by peroxide in the
presence of peroxidase, thus depleting the peroxide necessary to generate
chromophore. Dopamine and dobutamine demonstrate two distinct general mechanisms
of interference in peroxidase-based biochemical tests.
PMID- 9550574
TI - Neopterin concentrations in cerebrospinal fluid and serum as an aid in
differentiating central nervous system and peripheral infections in children.
AB - Neopterin is a sensitive indicator for cellular immune activation. Its
concentrations were determined in cerebrospinal fluid (CSF) and serum specimens
from 91 children with no evidence of central nervous system (CNS) or peripheral
inflammations, 43 with definite neuroborreliosis, 51 with other CNS infections,
and 33 with peripheral infections. The aim of our study was (a) to establish a
range of normal CSF neopterin concentrations in control children, and (b) to
inquire into the diagnostic potential of neopterin measurements in both body
compartments for aiding in differential diagnosis of inflammatory vs
noninflammatory diseases, and CNS vs peripheral inflammations. CSF neopterin
concentrations in controls were invariably low (up to 9.3 nmol/L), but in
children with neuroborreliosis and, even more so, with other CNS infections
neopterin concentrations were significantly (P <0.0001) increased. Children with
peripheral infections, however, rarely showed raised CSF neopterin
concentrations. Serum concentrations of neopterin, on the other hand, were not
significantly different between controls and children with neuroborreliosis.
Although serum concentrations were significantly different between controls and
children with other CNS infections, diagnostic efficiency was poor for this
comparison. Peripheral infections, in contrast, were associated with
significantly higher (P <0.0001) serum neopterin concentrations when compared
with controls. A classification tree was constructed on the basis of CSF and
serum neopterin concentrations, allowing with high accuracy the discrimination
between controls, children with CNS infections, and children with peripheral
infections. Thus, on the basis of a comparatively large control group, our data
underline the diagnostic validity of neopterin as an aid in differential
diagnosis of inflammatory vs noninflammatory diseases, and confirm that CSF
neopterin concentrations are not correlated with serum neopterin concentrations,
and, therefore, CSF neopterin appears to be produced intrathecally.
PMID- 9550575
TI - Ethylene glycol poisoning: toxicokinetic and analytical factors affecting
laboratory diagnosis.
AB - Ethylene glycol poisoning is an important toxicological problem in medical
practice because early diagnosis and treatment can prevent considerable morbidity
and mortality. When ingested in the form of antifreeze or other automotive
products, ethylene glycol results in central nervous system depression,
cardiopulmonary compromise, and renal insufficiency. Metabolism of ethylene
glycol to organic acids is required for metabolic derangement and organ damage.
Laboratory features of ethylene glycol poisoning include increased anion gap
metabolic acidosis, increased osmolal gap, calcium oxalate crystalluria, and
detectable ethylene glycol in serum. This Case Conference integrates discussion
of the toxicokinetic and analytical variables that affect the laboratory
diagnosis of ethylene glycol intoxication.
PMID- 9550576
TI - Direct molecular interaction of phenylalanine with DNA measured by reversed-phase
HPLC.
PMID- 9550577
TI - Serum paraoxonase and platelet-activating factor acetylhydrolase in chronic renal
failure.
PMID- 9550578
TI - High concentrations of prostate-specific antigen in urine of women receiving oral
contraceptives.
PMID- 9550579
TI - CpG-PCR combined with sample pooling and mutant enrichment for CpG mutation
screening in population studies.
PMID- 9550580
TI - When is an indole not an indole?
PMID- 9550581
TI - Whole-blood folate values in subjects with different methylenetetrahydrofolate
reductase genotypes: differences between the radioassay and microbiological
assays.
PMID- 9550582
TI - Simplified simultaneous assay of total plasma homocysteine and methionine by HPLC
and pulsed integrated amperometry.
PMID- 9550583
TI - The Sia euglobulin precipitation test revisited.
PMID- 9550584
TI - Analytical characteristics of seminal fluid PSA differ from those of serum PSA.
PMID- 9550585
TI - Human beings, nature and medicine: perspectives of internal medicine.
PMID- 9550586
TI - Informed consent in Japan.
PMID- 9550587
TI - Familial hemiplegic migraine.
PMID- 9550588
TI - Sjogren's syndrome and sarcoidosis.
PMID- 9550589
TI - The treatment of heart failure: the role of neurohumoral activation.
AB - Neurohumoral activation refers to increased activity of the sympathetic nervous
system, renin-angiotensin system, vasopressin and atrial natriuretic peptide. It
is now known that neurohumoral activation contributes to the transition from
ventricular dysfunction to clinical heart failure, and is an independent
predictor of poor prognosis in heart failure. Although the treatment of heart
failure has traditionally focused on drugs to improve ventricular function, there
is increasing evidence that therapeutic modulation of neurohumoral activation is
a key to successful treatment of heart failure. For example, there is mounting
evidence that angiotensin converting enzyme inhibitors (the unquestioned
cornerstone for treatment of heart failure), beta receptor blockers, digitalis,
and endurance exercise training exert their benefit in heart failure in large
part through neurohumoral modulation. This observation--discussed in this brief
review--highlights the concept that compensatory neurohumoral activation to
decreased cardiac function may itself contribute to the development of heart
failure and its poor prognosis.
PMID- 9550590
TI - Relationship among risk factors of atherosclerosis, leukocyte count, and soluble
intercellular adhesion molecule-1.
AB - We investigated the effects of risk factors of atherosclerosis on soluble
intercellular adhesion molecule-1 (sICAM-1) concentration and leukocyte count by
using multivariate statistical analysis. The subjects were 90 people who were
hospitalized for a complete check-up examination. Eight risk factors were
selected as candidates for predictor variables: age, body mass index (BMI), uric
acid, glycohemoglobin A1c, number of cigarettes smoked daily, total cholesterol,
triglyceride, and high density lipoprotein (HDL)-cholesterol. The predictor
variables were selected using a stepwise method, [criterion variable - predictor
variable (standardized regression coefficient)]; sICAM1 - age (0.1859), number of
cigarettes (0.2558), triglyceride (0.2447); leukocytes - number of cigarettes
(0.2827), triglyceride (0.2526), HDL-cholesterol (-0.2800); stab leukocytes -
number of cigarettes (0.2460); segmented leukocytes - glycohemoglobin A1c
(0.1495), number of cigarettes (0.2716), HDL-cholesterol (-0.3254); lymphocytes -
BMI (0.2639), number of cigarettes (0.1495), triglyceride (0.3520); monocytes -
glycohemoglobin A1c (0.2617). These findings indicated that the risk factors of
atherosclerosis may influence sICAM1 concentration and leukocyte count.
PMID- 9550591
TI - Compensatory excretion of prostacyclin and thromboxane metabolites in obstructive
sleep apnea syndrome.
AB - Since obstructive sleep apnea syndrome (OSAS) is often linked with systemic
hypertension, we sought to clarify the characteristics of prostanoid metabolism
in OSAS. In 7 OSAS patients (apnea-hypopnea index, 51.0 +/- 23.4) and 7 non
snorers as control, nocturnal urine was sampled and analyzed for stable
metabolites of prostacyclin (PGI2) and thromboxane A2 (TxA2), [6-keto-PGF1alpha
and thromboxane B2 (TxB2)]. The ratio of 6-keto-PGF1alpha to TxB2 was
significantly higher in OSAS (2.97 +/- 1.52) than in control (1.38 +/- 0.38).
Successful treatment with nasal continuous positive airway pressure (8.3 +/- 1.5
cmH2O) for 3 days caused a significant decrease in mean blood pressure in OSAS.
Moreover, the 6-keto-PGF1alpha to TxB2 ratio also significantly decreased to 1.74
+/- 0.58, a level which may not significantly different from control. These
results suggest that the production ratio of PGI2 to TxA2 is shifted toward
vasodilatation in untreated OSAS. We conclude that the production of prostanoids
plays a role in compensating for the systemic hypertension in OSAS.
PMID- 9550592
TI - Control of upper airway function in response to hypoxia in patients with
obstructive sleep apnea syndrome.
AB - To clarify the characteristics of upper airway muscles under hypoxic condition in
obstructive sleep apnea syndrome (OSAS), we performed the isocapnic progressive
hypoxia test during wakefulness in 8 controls and 7 OSAS patients.
Electromyographic activities were recorded from the genioglossal muscle (EMG(GG))
and diaphragm (EMG(DIA)) with ventilatory variables. Minute EMG (peak integrated
EMG x respiratory rate) activity against P(ET)O2 was calculated by exponential
equation, and its response slope represented the hypoxic sensitivity of each
muscle, slope(GG) and slope(DIA). There was no significant difference between the
slopes of OSAS and control. In contrast, the ratio of the two responses,
slope(GG)/slope(DIA), was significantly higher in OSAS (1.61 +/- 0.49 SD) than in
control (0.98 +/- 0.43). Moreover, the slope(GG)/slope(DIA) ratio was negatively
correlated with the ratio of sleep time with SpO2 lower than 90% to total sleep
time. We conclude that the neuromuscular compensatory mechanism of upper airway
muscles is effectively developed and plays an important role in preventing
nocturnal hypoxemia in OSAS.
PMID- 9550593
TI - Differences in clinical features and computed tomographic findings between
embolic and non-embolic acute ischemic stroke: a quantitative differential
diagnosis.
AB - A diagnosis based on the presumed mechanism of stroke onset is useful for
management strategies in acute ischemic stroke. Ninety-two patients with embolic
(cardiac or artery-to-artery) and 107 with non-embolic (thrombotic or
hemodynamic) stroke were diagnosed on strict cerebral angiographic criteria
alone. To clearly discriminate between these two groups, the neurological and
computed tomographic (CT) findings were then compared. Rapidity of onset,
vomiting, urinary incontinence, level of consciousness, cervical bruit,
anisocoria, tongue deviation, sensory disturbance, and CT findings (location of
hypodense area, findings of brain edema and hemorrhagic transformation) were
discriminatory factors between the two groups (p<0.01). According to these 11
items, we prepared a numerical table for quantitative differential diagnosis. A
diagnostic accuracy of 98.9% for embolic and 87.9% for non-embolic stroke in
internal verification, and 90.0% and 82.9%, respectively, in external
verification was observed. The differences in clinical features and CT findings
between embolic and non-embolic stroke may reflect the pathophysiological
mechanisms of the occlusive process of cerebral artery as well as the extent and
severity of ischemia.
PMID- 9550594
TI - Induction of torsades de pointes by dobutamine infusion in a patient with
idiopathic long QT syndrome.
AB - We used a provocative test with dobutamine infusion to diagnose long QT syndrome
(LQTS) in a girl with a history of syncope. When dobutamine was infused at a rate
of 10 microg/kg/min, the QT interval corrected for heart rate (QTc) was prolonged
from 460 ms to 620 ms with abnormal TU complexes and torsades de pointes
developed. In 5 control subjects the QTc did not change significantly during low
dose dobutamine infusion. Low-dose dobutamine, in addition to isoproterenol, may
be useful for evaluation of prolongation of the QT interval and abnormal TU
complexes in patients in whom LQTS is suspected.
PMID- 9550595
TI - Legionnaires' disease diagnosed by bronchoalveolar lavage.
AB - A 51-year-old woman who had been on steroid therapy for systemic lupus
erythematosus (SLE) developed a high fever 3 days after visiting a hot spring
resort. Chest X-ray films revealed an interstitial, pneumonia-like shadow in the
left lung field, which increased rapidly with a worsening of her symptoms. She
died of multiple organ failure one week after the onset of the pneumonia.
Although the serum antibody titer was negative, Legionella pneumophila was
recovered from her bronchoalveolar lavage (BAL) fluid. BAL seems to be a useful
method to diagnose Legionnaires' disease.
PMID- 9550596
TI - Systemic sarcoidosis with significant granulomatous swelling of the pharyngeal
tonsil.
AB - A pharyngeal tonsil biopsy specimen from a 27-year-old male revealed epithelioid
cell granulomas with noncaseating necrosis. Systemic enlargement of the lymph
nodes was present. Plain chest radiographic and computed tomography (CT) images
showed ground-glass attenuation in the lungs and bilateral hilar lymphadenopathy.
Biopsy of inguinal region nodes confirmed the diagnosis of systemic sarcoidosis.
Detailed examination of the nasopharynx should be performed in any case
presenting with systemic sarcoidosis because the specimen is readily removable
and the pathologic findings of the local lesion may support the diagnosis.
PMID- 9550597
TI - Cervical spinal epidural abscess following acupuncture: successful treatment with
antibiotics.
AB - A 67-year-old man with poorly controlled diabetes mellitus (DM) had acupuncture
several times a month for chronic shoulder muscle stiffness. A few days after
acupuncture in the posterior nuchal region, a low-grade fever and backache
developed, and subacutely progressed. Finally he complained of gait disturbance,
and then respiratory distress appeared. Magnetic resonance imaging (MRI)
demonstrated high cervical epidural abscess with massive soft tissue inflammation
and vertebral osteomyelitis. Conservative treatment with antibiotics was
effective and it was well documented by following serial MRIs. This case
suggested that needle acupuncture should be avoided for immunocompromised
subjects such as patients with poorly controlled DM.
PMID- 9550598
TI - Familial hemiplegic migraine with irreversible brain damage.
AB - Familial hemiplegic migraine (FHM) is an autosomal dominant syndrome
characterized by recurrent episodes of varying degrees of hemiparesis associated
with migraine. The aura including hemiparesis may be prolonged and in severe
attacks may often be associated with confusion or coma. We describe a case of FHM
whose aura was atypically prolonged and resulted in irreversible brain deficit
which on magnetic resonance imaging (MRI) was suggestive of cortical
hyperperfusion. A subsequent MRI showed left brain atrophy.
PMID- 9550599
TI - Rhabdomyolysis after infection and taking a cold medicine in a patient who was
susceptible to malignant hyperthermia.
AB - A case of rhabdomyolysis after a possible viral infection and the use of a cold
medication is reported. A 41-year-old man who presented with dysarthria,
dysphagia, progressive weakness of his muscles and a high grade fever was
admitted. He suffered from massive rhabdomyolysis, acute renal failure, and
bronchopneumonia. Hemodialysis, antibiotics, and hydration therapy were effective
in the treatment of his illness. Although the cause of the rhabdomyolysis was not
completely clear, he was subsequently shown to be susceptible to malignant
hyperthermia (MH) based on the results of a caffeine-halothane contracture test.
When a mild recurrence occurred during a follow-up muscle biopsy, intravenous
dantrolene sodium was administered and he improved immediately. This case
suggests that MH should be considered in patients with rhabdomyolysis when the
cause is unclear. The caffeine-halothane contracture test may also be helpful in
the diagnosis.
PMID- 9550600
TI - Primary Sjogren's syndrome complicated by sarcoidosis.
AB - Sjogren's syndrome and sarcoidosis share several common features, such as
keratoconjunctivitis sicca, swelling of parotid glands, lung involvement,
cutaneous anergy, T cell-mediated immunodeficiency, an increased CD4+/CD8+
lymphocyte ratio, and association with the human leucocyte antigen (HLA)-B 8 and
DR 3 haplotypes. However, only five patients with primary Sjogren's syndrome and
sarcoidosis have been previously reported in the English language literature. The
rare case of a 49-year-old Japanese woman with primary Sjogren's syndrome
complicated by sarcoidosis is described. The serum angiotensin-converting enzyme
level was increased, and histological examination of lung and skin biopsies
revealed noncaseating granulomas, indicating that her primary Sjogren's syndrome
was complicated by sarcoidosis.
PMID- 9550601
TI - Fas-induced apoptosis.
PMID- 9550602
TI - Role of apoptosis on morphogenesis and therapy in malignancy.
PMID- 9550604
TI - Hematological diseases and apoptosis.
PMID- 9550603
TI - Rheumatoid arthritis and apoptosis.
PMID- 9550605
TI - Apoptosis in liver disease.
PMID- 9550606
TI - Apoptosis in neurodegenerative disorders.
PMID- 9550607
TI - Endocrine disease and apoptosis.
PMID- 9550608
TI - Antithrombotic treatment in ischemic cerebrovascular disease.
PMID- 9550609
TI - Antiplatelet agents prevent cardiac events in patients with coronary artery
disease.
PMID- 9550610
TI - Ischemic heart disease (coronary thrombolysis).
PMID- 9550611
TI - Cardiogenic cerebral embolism associated with atrial fibrillation.
PMID- 9550612
TI - Anti-neutrophil cytoplasmic autoantibodies associated renal diseases and
thrombotic microangiopathy.
PMID- 9550613
TI - Nephrotic syndrome and anticoagulant therapy.
PMID- 9550614
TI - Vasopressin and related disorders.
PMID- 9550615
TI - Aquaporin-2, a vasopressin-sensitive water channel, and nephrogenic diabetes
insipidus.
AB - Two cases of autosomal recessive nephrogenic diabetes insipidus (NDI) were
evaluated. Both cases were found to be compound heterozygote for missense
mutations in the aquaporin-2 (AQP2) gene. To determine the structural-functional
relationship, the mutated AQP2 proteins, T125M, G175R, A190T, and P262L, were
expressed in Xenopus oocytes and examined by measurement of water permeability,
immunoblot, and immunocytochemistry. Our results suggest that T125M and G175R are
nonfunctional water channels, whereas the translocation to the plasma membrane is
impaired in A190T and P262L.
PMID- 9550616
TI - Therapeutic efficacy of vasopressin receptor antagonists.
PMID- 9550617
TI - Diuretic therapy.
PMID- 9550618
TI - Physiology and pathophysiology of acid-base homeostasis in the kidney.
PMID- 9550620
TI - Unopposed stimulation of the angiotensin AT2 receptor in the kidney.
PMID- 9550619
TI - A functional role for endogenous atrial natriuretic peptide in the maintenance of
body fluid balance in heart failure.
PMID- 9550621
TI - HIV-associated nephropathy: current concepts.
PMID- 9550622
TI - Nephron reduction in man--lessons from the Os mouse.
PMID- 9550623
TI - Progression of renal failure and lipids--is there evidence for a link in humans?
PMID- 9550624
TI - Is persistent TGFbeta1 expression the mechanism responsible for chronic renal
allograft loss?
PMID- 9550625
TI - Dietary salt restriction and reduction of dialysate sodium to control
hypertension in maintenance haemodialysis patients.
PMID- 9550626
TI - Dialysis hypertension: dry weight and dialysis time.
PMID- 9550627
TI - Change of paradigms in nephrology--a view back and a look forward.
PMID- 9550628
TI - Update on reversal of left ventricular hypertrophy in essential hypertension (a
meta-analysis of all randomized double-blind studies until December 1996).
AB - OBJECTIVE: To provide an update on the ability of different antihypertensive
drugs to reduce left ventricular hypertrophy in essential hypertension. DATA
SOURCES: Relevant medical databases including MEDLINE, BIOSIS PREVIEWS, EMBASE,
and SCISEARCH as well as review articles to December 1996. STUDY SELECTION: Meta
analysis of all published articles including only double-blind, randomized,
controlled clinical studies with parallel-group design. DATA EXTRACTION:
Literature search and data extraction according to a prefixed scheme performed
independently by two investigators. The primary parameter was reduction of left
ventricular mass by antihypertensive therapy with placebo, diuretics, beta
blockers, calcium channel blockers, or ACE-inhibitors. DATA SYNTHESIS: Fifty
studies published till the end of December 1996 were identified. They comprised a
total of 1715 patients in 13 placebo (n=165, age: 50+/-3 years) and 89 active
treatment arms (n=1550, age: 56+/-10 years) respectively. Overall, for active
treatment left ventricular mass index was the more reduced the greater the
decrease in systolic blood pressure, (r=0.27; P<0.05), the longer the duration of
therapy (r=0.36; P<0.001), and the higher the pretreatment value of left
ventricular mass index (r= 0.53; P<0.001). Left ventricular mass index was
decreased by 12% with ACE-inhibitors (95% CI: 9.0-14.5%), by 11% with calcium
channel blockers (95% CI: 7.8-13.7%), by 5% with beta-blockers (95% CI: 1.2-7.3%)
and by 8% with diuretics (95% CI: 3.9-11.1%) (overall P<0.01). Subsequent tests
revealed that ACE-inhibitors and calcium channel blockers were more effective
than beta-blockers in reducing left ventricular mass index (P<0.05). Similar
differences between drug classes were found with regard to effect on left
ventricular wall thickness (P<0.05). CONCLUSIONS: Decrease in systolic blood
pressure, duration of antihypertensive therapy, degree of pretreatment left
ventricular hypertrophy and antihypertensive drug class determined the reduction
of left ventricular hypertrophy. ACE-inhibitors and calcium channel blockers were
more potent in reducing left ventricular mass than beta-blockers, with diuretics
in the intermediate range.
PMID- 9550629
TI - Intoxication by star fruit (Averrhoa carambola) in six dialysis patients?
(Preliminary report)
AB - We observed six cases of patients in a dialysis programme who were apparently
intoxicated by ingestion of star fruit. After ingestion of 2-3 fruits or 150-200
ml of the fruit juice, the six patients, who had previously been stable in a
regular dialysis programme, developed a variety of symptoms ranging from insomnia
and hiccups to agitation, mental confusion and (in one case) death. In
preliminary investigations to characterize the hypothetical neurotoxin in the
fruit, an extract, when injected intraperitoneally or intracerebroventricularly
in rats, provoked persistent convulsions of the tonic-clonic type. It appears
that star fruit (Averrhoa carambola) contains an excitatory neurotoxin. Patients
with renal failure on conservative or dialysis treatment should be dissuaded from
ingestion of the fruit.
PMID- 9550630
TI - Cell-specific regulation of alpha1(III) and alpha2(V) collagen by TGF-beta1 in
tubulointerstitial cell models.
AB - BACKGROUND: TGF-beta1 modulates the cellular expression of extracellular matrix
(ECM) in several renal cell systems in vitro and is considered a determinant of
ECM accumulation in tubulointerstitial fibrosis. METHODS: We evaluated the
effects of TGF-beta1 on collagen transcription, expression, and removal of the
relevant collagens by rat tubuloepithelial cells (NRK 52E) and both rat and
monkey interstitial fibroblasts (NRK 49F, CV1) in vitro. RESULTS: TGF-beta1
upregulated the expression of alpha1(III) collagen by fibroblasts (+300%) without
affecting its removal. In parallel, a threefold increment of COL3A1 mRNA was
found. Experiments of cell transfection employing CV1 fibroblasts as the unique
suitable model, and chimaeric constructs of COL3A1 and COL5A2 promoters fused to
the luciferase reporter gene, demonstrated a twofold stimulation of a large 1436
COL3A1 promoter construct and negligible effects on shorter fragments, suggesting
the presence of a positive responsive element in a region of COL3A1 promoter
between -1375 and -579. TGF-beta1 did not influence COL5A2 mRNA and the relative
promoter activity in renal fibroblasts. With NRK 52E cell line, TGF-beta1 induced
comparable increment of both alpha1(III) collagen expression (+300%) and COL3A1
mRNA (+300%) without affecting the COL3A1 promoter activity of any constructs.
TGF-beta1 also upregulated the expression of alpha2(V) collagen chain (+500%) and
COL5A2 mRNA (+500%) with a stimulatory effect (+100%) on a 1177 bp fragment of
COL5A2 promoter. In this case a relevant inhibitory effect of TGF-beta1, on
removal of alpha2(V) by supernatants of NRK 52E was also observed, indicating a
double regulatory role of the cytokine on both transcription and removal of this
component of ECM. CONCLUSION: Taken together these data indicate that TGF-beta1
is a potent stimulator of alpha1(III) collagen expression by renal fibroblast
cell lines in vitro, the basic mechanism being stimulation of COL3A1
transcription. With renal epithelial cell lines, TGF-beta1 mainly upregulated the
expression of type V collagen with the most relevant effect on stimulation of
collagen transcription and inhibition of its removal. Tubular epithelial cells
and renal fibroblasts should play distinct roles in renal fibrosis induced by TGF
beta1 in vivo.
PMID- 9550631
TI - Regulation of the transcription of parathyroid-hormone/parathyroid-hormone
related peptide receptor mRNA by dexamethasone in ROS 17/2.8 osteosarcoma cells.
AB - Previous studies have shown that dexamethasone enhanced the expression of
parathyroid-hormone/parathyroid-hormone-related peptide (PTH/ PTHrP) receptor
mRNA in ROS 17/2.8 osteosarcoma cells. The aim of this study was to determine
whether the induction of PTH/PTHrP receptor expression in such osteoblast-like
cells is regulated at the gene level. Dexamethasone increased the steady-state
levels of PTH/PTHrP receptor mRNA twofold at 6 h, and nearly threefold at 24 h.
The half-life of the PTH/PTHrP receptor mRNA, in the presence of actinomycin D,
was 6 h both in untreated and in dexamethasone-treated cells. When measured by
nuclear run-on assay, the rate of PTH/PTHrP receptor gene transcription was
increased twofold at 24 h. PTH/PTHrP receptor mRNA expression was blocked
completely after 24 h of treatment with cycloheximide. The binding of PTH/PTHrP
to their receptor required the synthesis of new protein and was shown to be
specifically dependent on the interaction of dexamethasone with the
glucocorticoid receptor. These data indicate that the enhancing effect of
dexamethasone on PTH/PTHrP receptor expression is rapid, requires de novo protein
synthesis, and increases the transcription rate of the PTH/PTHrP receptor gene.
PMID- 9550632
TI - Effects of a nitric oxide synthesis inhibitor on renal sodium handling and
diluting capacity in humans.
AB - BACKGROUND: Inhibition of nitric oxide (NO) synthesis has antinatriuretic and
antidiuretic effects. Limited information is available on the role of NO in
tubular sodium transport in the human kidney. METHODS: We studied nine healthy,
sodium-replete males with clearance techniques during maximal diuresis. NG
monomethyl-L-arginine (L-NMMA, 3 mg/kg priming dose plus 3 mg/kg/h) was infused
for 3 h, to achieve steady-state inhibition of NO synthesis. Data were compared
with a time control study. RESULTS: The effects of L-NMMA were quickly
established and persisted through the entire infusion period. Mean arterial
pressure increased slightly from 85+/-3 to 91+/-3 mmHg (P<0.05). Renal plasma
flow decreased substantially, and glomerular filtration rate slightly. Large
decreases in absolute sodium excretion, from 79+/-10 to 34+/-5 micromol/min
(P<0.01), and fractional sodium excretion, from 0.5+/-0.0 to 0.3+/-0.0% (P<0.01),
were associated with significant reductions in fractional lithium excretion
(P<0.05) and maximum urine flow (P<0.01). Minimal urine sodium concentration
decreased from 5.8+/-0.04 to 3.9+/-0.4 mmol/l (P<0.01) whereas minimal urine
osmolality increased (P<0.05). Plasma renin activity, aldosterone and atrial
natriuretic peptide levels did not change, whereas urinary excretions of
guanosine 3'5'-cyclic monophosphate and of nitrite plus nitrate decreased
slightly. CONCLUSIONS: Inhibition of endogenous NO synthesis in humans to an
extent that raises blood pressure only mildly causes antinatriuresis, that can be
attributed to increases in sodium reabsorption both at proximal and distal
nephron sites. In addition, renal diluting capacity decreases. The effects in the
diluting segment have not been reported before, and may be due to medullary
vasoconstriction, similar to that described for angiotensin II.
PMID- 9550633
TI - Role of nitric oxide-related mechanisms in renal function in ageing rats.
AB - BACKGROUND: The impaired renal function and vasodilatation that accompany age
need to be re-addressed based upon the new knowledge concerning vascular nitric
oxide (NO)-dependent systems. The present study examined the effects of age on
the NO-related renal response. METHODS: The study was performed in euvolaemic,
conscious Wistar rats, aged 5 and 18 months. Renal function and haemodynamic
measurements with fluorescent microspheres were employed to assess differences
between groups. RESULTS: A first set of experiments showed that ageing rats had a
reduced natriuretic and diuretic response to acetylcholine, whereas the response
to sodium nitroprusside was preserved. In the same regard, a reduction of the
renal functional effects of L-arginine (L-Arg) and L-glycine (L-Gly) was found in
the older rats. In the ageing rats, these responses were accompanied by an
enhanced effect of the L-Arg competitive analogue, NwNLA, which provoked a marked
reduction of renal function. This effect of NwNLA was blocked by the simultaneous
administration of a small dose of L-Arg in the ageing but not in the young rats.
Systemic haemodynamic studies revealed that in ageing rats, NwNLA reduced renal
blood flow and increased renal vascular resistances in a significantly higher
proportion than in younger animals. However, flow to other organs, namely, brain,
spleen or liver, was affected in a similar manner in both young and old rats.
Ultrastructural alterations were found in endothelial cells, which might
constitute the anatomical basis for the observed functional derangements.
CONCLUSIONS: The present experiments reveal that ageing is accompanied by
significant differences in NO-related responses in the kidney which do not appear
to affect blood flow to other organs. The response to L-Arg and L-Arg competitive
analogues supports the existence of a marked dependency on NO-related mechanisms
in the ageing rats, but not of a decreased baseline activity of the NO-dependent
pathways.
PMID- 9550634
TI - Sequence analysis of the 'Goodpasture antigen' of mammals.
AB - BACKGROUND: Autoimmunity to the NC1 domain of the alpha3 chain of type IV
collagen (alpha3(IV)NC1), the Goodpasture antigen, is the cause of spontaneous
human antiglomerular basement membrane (anti-GBM) disease, and of anti-GBM
nephritis in several animal models. METHODS: We have derived amino acid sequences
from alpha3(IV)NC1 for a number of mammalian species (monkey, sheep, pig, dog,
rabbit, and rat) by RT-PCR and cDNA cloning. The GBM of some species was studied
comparatively for binding to Goodpasture autoantibodies. RESULTS: From this work
and other data the sequences of nine mammalian species can be aligned. Regions
and residues that may be functionally important are identified. Alpha3(IV)NC1
sequences were found to be less closely conserved across species than alpha1 and
alpha2(IV)NC1, 91 to 99% in comparison to a minimum of 97% for alpha1, but these
differences were unevenly distributed along the molecule. There was a
particularly striking homology between rodent and human sequences in the carboxyl
terminal region. Binding of Goodpasture autoantibodies to rat alpha3(IV)NC1 was
poor in comparison with other species. CONCLUSIONS: Comparison of sequences and
binding casts doubt on the importance of the carboxyl-terminal region for
antibody binding, a region identified as a potential major epitope in previous
studies. Sequence comparisons suggest possible reasons for the nephritogenicity
of alpha3(IV)NC1 in active models of anti-GBM disease.
PMID- 9550635
TI - Differences in glomerular leukocyte infiltration between IgA nephropathy and
membranoproliferative glomerulonephritis.
AB - BACKGROUND: An important aspect in glomerular nephritic processes is the enhanced
influx of leukocytes into the glomerulus. METHODS: To investigate the mechanisms
of intraglomerular leukocyte infiltration in IgA nephropathy (IgA-N) and
membranoproliferative glomerulonephritis type I (MPGN-I), we
immunohistochemically examined the intraglomerular expression of leukocyte
function-associated antigen-1 (LFA-1, CD11a/CD18), macrophage-1 (Mac-1,
CD11b/CD18) and intercellular adhesion molecule-1 (ICAM-1, CD54) together with
glomerular deposition of C3c and fibrinogen. RESULTS: In IgA-N (n=42), LFA-1+
cells were distributed mainly in glomeruli with intense expression of ICAM-1, and
there was a positive correlation (P<0.001) between the number of LFA-1+ cells and
the degree of ICAM-1 expression. Mac-1+ cells had no correlation with glomerular
C3c deposition, but had a significant correlation with fibrinogen deposition
(P<0.05). The number of LFA-1+ cells was significantly greater than of Mac-1+
cells (P<0.05). The number of LFA-1+ cells was strongly correlated with that of
CD68+ cells (P<0.00001). In MPGN-I (n= 43), on the contrary, Mac-1+ cells
correlated only with C3c deposition (P<0.001), and they were observed mainly in
peripheral loops of glomerular capillaries where C3c was deposited with a similar
distribution. However, there was no relationship between LFA-1+ cells and ICAM-1
expression. The number of Mac-1+ cells was greater than that of LFA-1+ cells
(P<0.0001), and most Mac-1+ cells were identical to CD15+ cells. CONCLUSION:
These results indicate the possibility that different mechanisms may cause
glomerular leukocyte infiltration in various forms of human glomerulonephritis.
The LFA-1/ICAM-1 pathway may play an important role in glomerular leukocyte
infiltration in IgA-N, while the Mac-1/complement pathway may be important in
MPGN-I. The former may promote mainly the infiltration of CD68+ cells, and the
latter may promote that of CD15+ cells. In addition, Mac-1+ cells may act as
fibrinogen and complement receptors in IgA-N and MPGN-I, respectively.
PMID- 9550636
TI - Dietary and urinary risk factors for stones in idiopathic calcium stone formers
compared with healthy subjects.
AB - BACKGROUND: The high social-economic cost of nephrolithiasis wholly justifies the
attempts to understand its mechanism and avoid recurrences. The influence of
dietary habits and urinary risk factors has been evaluated, but the results were
discrepant, probably because of differences in the methodologies used to compare
patients and controls. METHODS: The aim was to assess dietary and urinary risk
factors for urinary stones by comparison between 108 calcium stone formers (SF)
and 210 healthy subjects (HS). All subjects were recruited during the same 1 year
period. Personal characteristics, dietary habits (evaluated through a food
frequency questionnaire) and urinary biochemical parameters were collected. The
high predominance of men in the SF group led us to focus on the 79 SF and the 96
HS men. RESULTS: A familial history of stones was reported more frequently in SF
than in HS, 42.9% vs 17.6%, P<0.005. Body weight was higher in SF, 76.8+/-12.2 kg
vs 72.8+/-9.6 kg, P=0.02; and calcium intake was lower in SF, 794.8+/-294.1 mg vs
943.6+/-345.4 mg, P<0.01. For urinary parameters, calcium and oxalate output were
significantly higher in SF. Urinary urea, as a reflection of daily protein
intake, and uric acid were also higher in SF. Urinary citrate excretion related
to body weight was lower in SF. Calciuria was significantly correlated with
urinary urea in both SF and HS, but the correlation was stronger for SF.
Calciuria correlated significantly with natriuria only in HS. CONCLUSIONS: The
main differences between SF and HS were that SF had a family history of stones, a
higher body weight, a lower daily intake of calcium, and a higher urinary output
of calcium and oxalate. These results underline the combined role of genetic and
nutritional factors in the pathogenesis of urinary stone formation.
PMID- 9550637
TI - Stimulation of tubular secretion of creatinine in health and in conditions
associated with reduced nephron mass. Evidence for a tubular functional reserve.
AB - BACKGROUND: The increment in glomerular filtration rate (GFR) after a protein
load has been taken to reflect the renal reserve capacity; however, this response
is preserved in end-stage kidney disease. Tubular secretion of creatinine is
increased in relation to the GFR in renal failure, but little is known about the
tubular functional response to stimulation despite the fact that
tubulointerstitial lesions are always pre-eminent in chronic renal damage.
Therefore we decided to compare the urinary creatinine excretion (UcrV) and
tubular secretion of creatinine (TScr) induced by a test meat meal in normal
individuals and in individuals with reduced nephron mass. METHODS: We studied 12
normal subjects, seven healthy uninephrectomized (kidney donors) and eight
patients with chronic renal disease (serum creatinine ranging from 212.2 to 486
micromol/l). They had been on a standard diet for 5 days before the studies. The
test meal provided 80 g of animal protein. Three baseline and four stimulated
(post-meal) 30-min simultaneous inulin and creatinine clearances were carried
out. RESULTS: We found that normals increased more than twice the UcrV (post
meal=329.5 +/-SEM 13.1 nmol/min/kg) and 3.4 times the TScr (114.4+/-12.7
nmol/min/kg) after the test meal. In contrast, patients were unable to raise
their baseline values (P<0.001), despite a normal increment in GFR. The data in
kidney donors fell between normals and patients. Strong correlation existed
between the stimulated (but not the baseline) TScr (P=0.003) and GFR and between
UcrV post-meal/pre-meal ratio and GFR (P<0.0001). CONCLUSION: The increment in
TScr resulting from a protein meal is related to the functioning nephron mass.
Evaluation of this increment could have potential clinical relevance.
PMID- 9550638
TI - On the prognosis of IDDM patients with large kidneys.
AB - BACKGROUND: Approximately 10-30% of IDDM patients develop diabetic nephropathy
depending on the metabolic control. Previous examinations on the significance of
the kidney size prior to the manifestation of nephropathy produced varying
results. METHODS: The present study, therefore, was designed to assess the
correlation between sonographically determined kidney size and kidney function
over 8 years in a follow-up examination, and to evaluate a potential risk
pattern. Data could be collected from 73 (66%) of 110 IDDM patients with
initially normal serum creatinine whose sonographically determined kidney volume
(cm3 = L cm x W cm x D cm x pi/6) and kidney function (creatinine, albuminuria,
beta2-microglobulin in serum) had been examined in 1986, and who had a diabetes
duration of 1 month to 25 years at that time. RESULTS: 30% (11 of 37) patients
with large kidneys (>170 cm3) reached at least one serious renal end-point
(increase of serum creatinine by more than 50%, requirement of dialysis or kidney
transplantation, or death in end-stage renal disease) versus one of 36 patients
with normal kidney size (P<0.002). As many as 42% of patients with large kidneys
developed abnormal creatinine values (>106 micromol/l) in contrast to only 20% of
the patients with normal kidney volume (P<0.05). Six of seven patients with a
more than 50% increase of serum creatinine from baseline showed large kidneys in
1986, but had a normal serum creatinine, and four also a normal urine albumin
excretion. Furthermore all five patients with more severe end-points (two deaths
in end-stage renal disease and three patients presently requiring dialysis)
exhibited either an increased serum creatinine or large kidneys at baseline; four
of these, however, were still in the normoalbuminuric state in 1986. CONCLUSIONS:
These results indicate that large kidneys might be a morphological marker for
subsequent diabetic nephropathy, and as a consequence, renal insufficiency.
PMID- 9550639
TI - Progression of diabetic nephropathy--is diurnal blood pressure rhythm as
important as absolute blood pressure level?
AB - BACKGROUND: Hypertensive non-diabetic patients who lack the normal nocturnal
decline in blood pressure ('non-dippers') have an increased incidence of
cardiovascular complications. Poor blood pressure control is known to exacerbate
the decline in glomerular filtration rate in patients with diabetic nephropathy.
METHODS: The aim of this study was to assess the contribution of abnormal blood
pressure diurnal rhythm to the progression of diabetic nephropathy. We
retrospectively studied 26 diabetic patients with hypertension, proteinuria and
relentless progressive impairment of renal function due to diabetic nephropathy
between 1990 and 1996. Patients underwent ambulatory blood pressure monitoring
and were classified as either 'dippers' or 'non-dippers' according to their blood
pressure diurnal rhythm. Dippers were patients whose mean sleeping blood pressure
(both systolic and diastolic) was 10% less than blood pressure whilst awake.
Weight, glycated haemoglobin, serum creatinine (micromol/l) and blood pressure
(mmHg) were recorded on a 3-monthly basis. Twenty four hour urine protein
excretion and creatinine clearance were recorded annually. The rate of decline of
creatinine clearance was derived from serum creatinine estimation. RESULTS: In
the 'dipper' group, the rate of decline of creatinine clearance was -2.9
ml/min/year and in those with abnormal blood pressure diurnal rhythm it was -7.9
ml/min/year (P<0.05). There was no significant difference in day-time mean blood
pressures, glycated haemoglobin, age and numbers with insulin-dependent diabetes
mellitus. CONCLUSION: We found that there was a profound effect of non-dipping
upon the rate of decline of renal function in patients with diabetic nephropathy.
PMID- 9550640
TI - Norepinephrine-induced blood pressure rise and renal vasoconstriction are not
attenuated by enalapril treatment in microalbuminuric IDDM.
AB - BACKGROUND: In non-diabetic subjects, an attenuated systemic norepinephrine (NE)
responsiveness may contribute to the mechanisms of action of angiotensin
converting enzyme (ACE) inhibitor treatment. We determined whether ACE inhibitor
treatment influences systemic and renal haemodynamic responsiveness to exogenous
NE, as well as urinary albumin excretion during NE, in microalbuminuric insulin
dependent diabetic (IDDM) patients, representing a patient category that benefits
by strict blood pressure control. METHODS: In seven microalbuminuric IDDM
patients, systemic and renal responsiveness to NE, infused at individually
determined threshold [deltamean arterial pressure (MAP)=0 mmHg], 20% pressor
(deltaMAP=4 mmHg) and pressor (deltaMAP=20 mmHg) doses, were compared before and
after 8 weeks treatment with enalapril, 10 mg daily. Blood glucose was clamped at
5 mmol/l and insulin was infused at 30 mU/kg/h. RESULTS: Enalapril decreased MAP
(P<0.05) and microalbuminuria (P<0.05), whereas effective renal plasma flow
(ERPF) increased (P<0.01) and glomerular filtration rate remained unaltered. The
filtration fraction tended to decline (P=0.09). The ACE inhibitor-induced fall in
MAP disappeared at NE pressor dose, and the overall mean increase in MAP in
response to NE was even higher with than without enalapril (P<0.05). After
enalapril, the ERPF remained higher at all NE doses (P<0.05), but the magnitude
of the NE-induced fall in ERPF was not altered by ACE inhibition treatment.
Overnight urinary albumin excretion fell with ACE inhibition (P<0.05), but this
effect was not seen during NE infusion. The angiotensin II/active renin ratio and
serum aldosterone levels remained lower with enalapril at all NE doses (P<0.05).
CONCLUSIONS: Enalapril does not attenuate systemic and renal vascular
responsiveness to exogenous NE in microalbuminuric IDDM despite adequate
inhibition of the renin-angiotensin-aldosterone system. These findings suggest
that the effect of NE on vasoconstriction is not counteracted effectively by ACE
inhibition treatment alone.
PMID- 9550641
TI - Effects of low-dose nifedipine on urinary protein excretion rate in patients with
renal disease.
AB - BACKGROUND: The observation that proteinuria is an important determinant of the
progression of renal disease has prompted numerous studies on the effects of
antihypertensive agents on protein excretion. Reports on the proteinuric effects
of calcium-channel blockers are quite controversial. It has been suggested that
the short-acting dihydropyridine calcium-channel blocker nifedipine increases
protein excretion by interference with tubular protein reabsorption. METHODS: In
a randomized controlled trial 10 patients with renal disease and proteinuria were
treated with a dose of 10 mg nifedipine o.d. (slow release formulation) for 1
week. The acute effects on renal and systemic haemodynamics and on urinary
albumin, IgG, and beta2-microglobulin excretion were investigated during a
clearance study in the supine position after the first dose. After 1 week of
treatment urinary protein excretion rates were measured in 24-h urine samples
collected in the ambulatory patient in consecutive fractions of 4-8 h during
normal daily activities. RESULTS: After the first dose nifedipine lowered mean
arterial blood pressure in the supine position by 7+/-1 mmHg (<0.01), attenuated
proximal tubular sodium reabsorption (fractional excretion of sodium 3.48+/-0.49
vs 2.62+/-0.35% during control, P<0.02), but did not affect proximal tubular
protein reabsorption (fractional urinary excretion of beta2-microglobulin 0.97+/
0.30 vs 0.98+/-0.32% during control, NS). The decrease in blood pressure was not
accompanied by decreases in urinary albumin or IgG excretion rates. The
selectivity index as well as GFR, RPF, and FF did not change. Continued treatment
for 1 week with nifedipine did not influence 24-h protein excretion. However, we
observed a rise of proteinuria during daily activities in the first 4 h after
drug intake compared to the start of the study with the patients in supine
position. During control measurements there was a slight increase in proteinuria.
During nifedipine the increase in proteinuria was more marked and correlated with
the selectivity index. CONCLUSIONS: (1) Nifedipine 10 mg orally did not impair
tubular protein reabsorption. (2) Nifedipine had no immediate antiproteinuric
effect despite the observed blood pressure reduction. (3) Nifedipine increased
proteinuria in ambulatory urine collections. This latter observation might
explain the seemingly different effects of dihydropyridine calcium-channel
blockers as reported in previous studies.
PMID- 9550642
TI - The effect of metabolic control on rate of decline in renal function in insulin
dependent diabetes mellitus with overt diabetic nephropathy.
AB - BACKGROUND: Strict glycaemic control has been shown to reduce the risk of
developing diabetic nephropathy. In established nephropathy, however, the impact
of glycaemic control on prognosis is less clear. Therefore we investigated the
effect of long-term glycaemic control on the decline in renal function in insulin
dependent diabetic patients with overt nephropathy. METHODS: The study was
performed at two hospital-based diabetes centres in western Sweden. The study was
an observational retrospective follow-up study in 158 insulin-dependent diabetics
with proteinuria with a mean (+/-SD) age of 36+/-9 years and a diabetes duration
of 22+/-8 years. The change in glomerular filtration rate was measured as 51Cr
EDTA clearance for a median of 8 years (range 1-17). Glycaemic control was
determined with measurements of glycated haemoglobin A1c. RESULTS: The decline in
glomerular filtration rate was 3.8+/-3.7 ml/min/year. The blood pressure was
143/82+/-15/7 mmHg and the mean glycated haemoglobin was 8.7+/-1.6%. The
correlation coefficient between glycated haemoglobin and decline in glomerular
filtration rate was -0.39 (P<0.0001 ) and between decline in glomerular
filtration rate and systolic and diastolic blood pressure -0.17 (P=0.03) and
0.29 (P=0.003) respectively. In patients with glycated haemoglobin <8.0% and
diastolic blood pressure <85 mmHg the decline in glomerular filtration rate was
1.7+/-2.3 ml/min/year. CONCLUSIONS: In this retrospective observational study,
effective blood-pressure control was associated with a low rate of decline in
renal function and a low urinary albumin excretion. The correlation between
glycaemic control and decline in renal function indicates that poor glycaemic
control can accelerate the loss of renal function in diabetic nephropathy.
PMID- 9550643
TI - Evidence for disturbed S-adenosylmethionine : S-adenosylhomocysteine ratio in
patients with end-stage renal failure: a cause for disturbed methylation
reactions?
AB - BACKGROUND: Elevated homocysteine concentrations have been associated with
premature arteriosclerosis and with impairment of key methylation reactions
through accumulation of the homocysteine metabolite S-adenosylhomocysteine. In
end-stage renal failure high homocysteine concentrations are commonly found but
thus far the concentrations of related adenosylated metabolites in plasma have
not been assessed. METHODS: In this prospective study we determined plasma
homocysteine and related metabolites in 25 patients on regular haemodialysis, and
in 40 healthy volunteers. Blood samples from patients were drawn immediately
before and in 10 patients additionally after the dialysis session. RESULTS: Folic
acid and vitamin B12 in plasma were similar in patients (mean +/- SEM 25+/-2
nmol/l and 400+/-41 pmol/l respectively) and controls (24+/-3 and 324+/-23
respectively). In patients plasma homocysteine, S-adenosylmethionine and S
adenosylhomocysteine were markedly elevated (36.6+/-3.6 micromol/l, 381+/
32nmol/l and 1074+/-55 nmol/l respectively) compared to the control values (6.8+/
0.4 micromol/l, 60+/-3 nmol/l and 24.4+/-1.1 nmol/l respectively) whereas the
molar ratio of plasma S-adenosylmethionine and S-adenosylhomocysteine was
significantly decreased (0.36+/-0.02 and 2.7+/-0.2 in patients and controls
respectively). Haemodialysis failed to normalize the abnormal levels of these
metabolites. CONCLUSION: Since the ratio of S-adenosylmethionine : S
adenosylhomocysteine is closely linked to the activity of numerous enzymatic
methylation reactions, these results suggest that methylation may be impaired in
these patients.
PMID- 9550644
TI - Bone alkaline phosphatase in children with chronic renal failure.
AB - BACKGROUND: With the introduction of a new immunoradiometric assay based on two
monoclonal antibodies (Tandem-Ostase, Hybritech) the determination of bone
alkaline phosphatase (BAP) to evaluate bone metabolism in chronic renal failure
has become easier and more valid. SUBJECTS AND METHODS: Using this test we
investigated BAP in a total of 90 paediatric patients, 42 (9.2+/-5.5 years) with
chronic renal failure on conservative treatment, 22 (9.5+/-5.4 years) under
chronic dialysis, and 26 (16.2+/-5.9 years) after renal transplantation, compared
to 203 controls (10.1+/-5.7 years). RESULTS: The physiological age dependency
found in controls including two peaks during infancy and puberty was distinctly
disturbed in chronic renal failure. However, in patients BAP significantly
correlated with height velocity rather reflecting the last 6 (r=0.56 P<0.001)
than the last 12 months. Although BAP correlated well with total alkaline
phosphatase (TAP; r=0.95 P<0.001), a significant correlation with the serum level
of the intact parathyroid hormone could only be detected for BAP (r=0.45 P<0.001)
but not for TAP (r=0.19 n.s.). Furthermore, BAP positively correlated with
trabecular (n=40; r=0.40 P<0.05) and inversely with cortical bone density (n=19;
r=-0.58 P<0.01) but no relationship was found with conventional X-ray.
CONCLUSION: BAP determined by the new radioimmunoassay seems to represent an
additional diagnostic tool to assess growth and bone turnover in paediatric
patients with chronic renal failure that is complementary to the information
provided by X-ray and total alkaline phosphatase.
PMID- 9550645
TI - Signal-averaged ECG abnormalities in haemodialysis patients. Role of dialysis.
AB - BACKGROUND: Late potentials (LP) on the signal-averaged electrocardiogram (SAECG)
are predictive of malignant ventricular arrhythmias and sudden cardiac death in
patients with ischaemic and non-ischaemic cardiomyopathy. Cardiac dysfunction,
both regional and global, as well as supraventricular and ventricular arrhythmias
are reported in a high percentage of patients with end-stage renal failure
(ESRF). The aim of the study was to assess the prevalence of LP and the effects
of haemodialysis on the SAECG of ESRF patients. METHODS: SAECG was recorded
immediately before and within 30 min after the end of dialysis in 48 patients in
sinus rhythm, free of conduction disturbances on ECG and of signs of congestive
heart failure. Serum electrolytes were sampled together with the SAECG
recordings. An echo-Doppler exam was performed within 2 weeks of the study.
SAECGs were adequate for analysis in 45/48 patients. LP were present when at
least two of the following criteria were fulfilled: QRS duration < or = 115 ms,
LAS40 < or = 38 ms, RMS40 > or = 38 microV at 40 Hz high pass bidirectional
filter, and noise <0.7 microV. RESULTS: LP were detected in 12/45 patients (25%)
on the SAECG before dialysis; of these 12 patients, seven had a history of a
previous myocardial infarction and two had documented coronary artery disease
(CAD). A significant greater wall motion score index--calculated on a 16 segment
model--was reported in patients with LP (1.20+/-0.20 vs 1.01+/-0.03, P<0.01),
while left ventricular mass was comparable in the two groups of patients. At the
end of dialysis, a significant prolongation of fQRS duration was found both at 25
and 40 Hz filters (from 98+/-11 to 106+/-16 ms and from 97+/-12 s to 102+/-13 ms,
respectively, P<0.001). A significant inverse relationship was seen between the
percentage of dialysis-induced serum potassium reduction and fQRS changes at 40
Hz (r=-0.68, P<0.001). CONCLUSIONS: LP were detected in a significant proportion
of dialysis patients, probably related to underlying CAD with left ventricular
dysfunction. Prolongation of fQRS after dialysis could be explained by the acute
reduction in serum potassium levels.
PMID- 9550646
TI - Evidence for an independent role of metabolic acidosis on nutritional status in
haemodialysis patients.
AB - BACKGROUND: Malnutrition in haemodialysis (HD) patients has been referred to
underdialysis with low protein intake, and to acidosis. However, the separate
effects of underdialysis and acidosis on nutrition have not been clearly
demonstrated. To evaluate the role of the dialysis dose and of metabolic acidosis
on nutrition, we measured the predialysis serum HCO3, pH, serum albumin, PCRn,
Kt/V, and BMI in 81 uraemic patients on maintenance bicarbonate HD for 93+/-80
months. Patients with chronic liver diseases, malignancies, and cachexia were
excluded. RESULTS: Mean age was 59+/-17 years, Kt/V was 1.29+/-0.21, PCRn 1.06+/
0.22 g/kg/day, serum albumin 4.07+/-0.28 g/dl, BMI 23+/-4 kg/m2, HCO3 21.1+/-1.9
mmol/l, pH 7.36+/-0.04. Serum albumin showed a significant direct correlation
with: PCRn (P=0.001), HCO3 (P=0.001), pH (P=0.002), but no correlation with Kt/V
and BMI. Serum HCO3 correlated inversely with PCRn (P=0.027). Multiple regression
analysis confirmed the significant role of serum bicarbonate and age, but not of
Kt/V, on serum albumin concentrations. The role of PCRn appeared to be marginal
compared to serum bicarbonate in determining serum albumin levels. Dividing
patients into two groups, serum albumin was 3.96+/-0.22 g/dl with HCO3 < or = 20
mmol/l and 4.18+/-0.31 g/dl in those with serum HCO3 > or = 23 mmol/l (P=0.002).
PCRn in the same groups was respectively 1.14+/-0.24 g/kg/day and 1.01+/-0.23
g/kg/day (P=0.03). Most importantly, serum albumin levels did not appear to be
affected by the dialysis dose, with Kt/V ranging from 0.90 to 1.88. CONCLUSIONS:
In HD patients with adequate Kt/V, metabolic acidosis exerts a detrimental effect
on serum albumin concentrations partially independently of the protein intake, as
evaluated by PCRn. In the presence of moderate to severe metabolic acidosis, PCRn
does not reflect the real dietary protein intake of the patients, probably as a
result of increased catabolism of endogenous proteins. For this reason PCRn
should be considered with caution as an estimate of the dietary protein intake in
HD patients in the presence of metabolic acidosis.
PMID- 9550647
TI - Factor VII coagulant activity (VIIc) and hypercoagulability in chronic renal
disease and dialysis: relationship with dyslipidaemia, inflammation, and factor
VII genotype.
AB - BACKGROUND: Factor VII coagulant activity (VIIc) is implicated in cardiovascular
disease (CVD) risk in the general population. VIIc is correlated with
hyperlipidaemia and influenced by a polymorphism of the factor VII gene and could
contribute to thrombotic risk in patients with renal disease. METHODS: We studied
VIIc in 100 patients with chronic renal disease or on maintenance dialysis and
examined its relationship with dyslipidaemia, a marker of coagulation activation
prothrombin fragment F1+2 (F1+2), the acute-phase reactant and coagulation factor
fibrinogen, a mediator of the inflammatory response interleukin-6 (IL6), and the
factor VII R353Q polymorphism. RESULTS: VIIc (186+/-58 vs 140+/-37, % standard,
P<0.0001) and F1+2 (0.51 vs 0.30 nM, median, P<0.0001) were increased in the
patients with renal disease compared with the control group, consistent with a
hypercoagulable state. Patients and controls heterozygous for the factor VII
R353Q polymorphism, had 35% lower VIIc than homozygotes for the R353 allele,
indicating that the Q353 allele could confer genetic protection from thrombotic
risk. There was a significant correlation between VIIc and F1+2 (r=0.26, P<0.05),
total and VLDL cholesterol, and triglycerides, but the correlation with lipids
did not differ by genotype. VIIc and F1+2 also correlated with increased
concentration of IL6 and fibrinogen, and inversely with albumin, suggesting that
a persistent inflammatory response could contribute to a hypercoagulable state,
possibly via cytokine induced activation of the endothelium, or by induction of
monocytes to express tissue factor. Patients with CVD complications or a history
of myocardial infarction did not have higher VIIc or F1+2 than those without CVD.
CONCLUSIONS: VIIc was significantly increased in renal disease states and
strongly influenced by a common polymorphism of the factor VII gene, but the
increase in VIIc and its correlation with lipids was not genotype specific. VIIc
correlated with evidence of increased coagulation activation and persistence of
an inflammatory response. A persistent inflammatory response and the
dyslipidaemia of renal disease may contribute to coagulation activation and
increased cardiovascular risk. Prospective studies are required to evaluate
increased VIIc as a thrombotic risk factor in chronic renal disease.
PMID- 9550648
TI - The effects of exercise training on muscle atrophy in haemodialysis patients.
AB - BACKGROUND: Patients with end-stage renal disease on haemodialysis (HD) have
limited work capacity. Many structural and functional alterations in skeletal
muscles contribute to this disability. METHODS: To evaluate the effects of
exercise training on uraemic myopathy, seven HD patients (mean age 44.1+/-17.2
years) were studied. Open muscle biopsies were taken from their vastus lateralis
muscle before and after a 6-month exercise rehabilitation programme and examined
by routine light- and transmission electron-microscopy. Histochemical stainings
of frozen sections were performed and morphometric analysis was also applied to
estimate the proportion of each fibre type and the muscle fibre area.
Spiroergometric and neurophysiological testing and peak extension forces of the
lower limbs were measured before and after exercise training. RESULTS: All
patients showed impaired exercise capacity, which was associated with marked
muscular atrophy (mean area 2548+/-463 microm2) and reduction in muscle strength
and nerve conduction velocity. All types of fibres were atrophied, but type II
were more affected. The ultrastructural study showed severe degenerative changes
in skeletal muscle fibres, mitochondria, and capillaries. Exercise training had
an impressive effect on muscular atrophy; in particular the proportion of type II
fibres increased by 51% and mean muscle fibre area by 29%. Favourable changes
were also seen on the structure and number of capillaries and mitochondria. These
results were confirmed by a 48% increase in VO2 peak and a 29% in exercise time,
as well as an improvement in the peak muscle strength of the lower limbs and in
nerve conduction velocity. CONCLUSIONS: Skeletal muscle atrophy in HD patients
contribute to their poor exercise tolerance. The application of an exercise
training rehabilitation programme improved muscle atrophy markedly, and therefore
had beneficial effects in overall work performance.
PMID- 9550649
TI - Simultaneous peritoneal dialysis catheter insertion and removal in catheter
related infections without interruption of peritoneal dialysis.
AB - Catheter-related infections result in high patient morbidity, the need for
temporary haemodialysis, and high costs. These infections are the main cause of
limited technique survival in peritoneal dialysis. We introduced a protocol for
the simultaneous peritoneoscopic insertion and removal of peritoneal catheters in
patients with catheter-related infections. Peritoneal dialysis was continued the
day after surgery using low-volume dwells and a dry abdomen during the daytime.
The dialysate leukocyte count had to be below 100/mm3 before exchanging
catheters, which was performed under antibiotic therapy based on culture
sensitivity. The old catheter was removed after the new catheter had been
inserted in the opposite abdominal region. CAPD patients were switched to APD for
1 week, which made prolonged hospitalization necessary. Simultaneous catheter
insertion and removal was performed 25 times in 22 patients on CCPD and 15 times
in 14 patients on CAPD. In CCPD patients, peritoneal dialysis was restarted after
1.0+/-0.1 days in 24 cases. One patient had sufficient residual renal function
and discontinued CCPD until day 10. In 10 CAPD patients (11 procedures) APD was
started 1.3+/-0.2 days after the procedure with CAPD beginning 7.1+/-0.6 days
thereafter. Three CAPD patients preferred haemodialysis and restarted CAPD 10.0+/
2.1 days after surgery. One patient continued CAPD the day after surgery. In
addition to minor complications (e.g. position-dependent outflow problems),
dialysate leakage occurred in two patients. Two patients developed peritonitis
within the first 30 days after surgery, one of which was procedure related. One
patient had severe lower gastrointestinal bleeding 2 weeks after the procedure,
which was not related to the catheter replacement. Ultimately, in 38 of 40
procedures the patients could successfully continue peritoneal dialysis. We
conclude that simultaneous insertion and removal of a peritoneal dialysis
catheter without interruption of peritoneal dialysis is a safe procedure in
patients with catheter-related infections.
PMID- 9550650
TI - Race and delayed kidney allograft function.
AB - BACKGROUND: Allograft survival among black recipients is poorer than among
whites. Delayed allograft function is associated with a significant reduction in
renal allograft survival. The relationship between delayed allograft function and
black race is incompletely specified and was the focus of this investigation.
METHODS: A non-concurrent study of 325 recipients of cadaveric allografts
followed for the occurrence of delayed allograft function defined as dialysis
during the first week following transplantation for the principal analysis. A
secondary definition of delayed allograft function was formulated based on the
serum creatinine 2 weeks after transplantation. Unadjusted and adjusted logistic
regression analysis were used to examine the unconfounded relationship between
race and delayed allograft function. RESULTS: Fifty-seven of 91 (62.6%) black
recipients experienced delayed allograft function compared to 113 of 234 (48.3%)
whites. The odds ratio for black race as a predictor of delayed allograft
function was 1.80, P=0.02, (95% CI, 1.09, 2.95). This finding was stable despite
adjustment for other predictors of delayed allograft function in a multivariate
model, but the precision of this estimate was less (P=0.10) because of missing
data. Additionally, adjusted models with imputed values for missing covariates,
models using a secondary definition of delayed allograft function, and models
excluding patients whose cyclosporin therapy was delayed, all consistently
demonstrated a similar association between black race and delayed allograft
function. CONCLUSIONS: This study demonstrated an increased risk of delayed
allograft function among black recipients. This relationship may play a role in
the poorer allograft outcomes experienced by black recipients. Given the negative
effect of delayed allograft function on allograft survival, efforts to identify
its modifiable risk factors should be a high priority.
PMID- 9550651
TI - Advantage of antithymocyte globulin induction in sensitized kidney recipients: a
randomized prospective study comparing induction with and without antithymocyte
globulin.
AB - BACKGROUND: Sensitized kidney allograft recipients require special management to
improve their outcome. One strategy is heavy immunosuppression with
antilymphocyte antibodies. Controversy continues about the actual advantage of
induction protocols whilst infections and cancers are a constant risk. In
addition, little is known about how to handle sensitized patients with low levels
of sensitization. METHODS: In this study, we randomized sensitized renal
transplant recipients, who received prophylactic treatment with or without
antithymocyte globulin (ATG), in addition to a standard triple regimen consisting
of cyclosporin, steroids and azathioprine at ATG discontinuation. The induction
treatment consisted of a low-dose ATG course over 10 days. Randomization was
stratified on the maximum PRA, according to the five following classes: 5% < PRA
< or = 20%, 20% < PRA < or = 40%, 40% < PRA < or = 60%, 60% < PRA < or = 80% and
80% < PRA < or = 100%. RESULTS: Eighty nine patients were enrolled: 47 patients
received ATG and 42 did not. ATG induction lowered the incidence of biopsy-proven
acute rejection episodes from 64 to 38%, increased 1 year graft survival from 76
to 89% and was associated with a higher 1 year inulin clearance (37+/-15 vs 49+/
18 ml/min). ATG-associated side effects were restricted to leucopenia and
thrombocytopenia, whereas bacterial and viral infections, gammopathies and
cancers did not occur more frequently. ATG induction benefited all sensitized
patients, and not only the hypersensitized patients. CONCLUSIONS: We conclude
that ATG induction is beneficial for all sensitized patients, regardless of their
level of sensitization, with regard to acute rejection episodes, graft survival
and graft function. Low-dose ATG is sufficient and prevents additional
complications.
PMID- 9550653
TI - Combined heart-kidney transplantation: report on six cases.
AB - BACKGROUND: Combined heart-kidney transplantation has become a new therapeutic
solution for patients with coexisting, irreversible heart and kidney failure.
Though this combined approach has several theoretical advantages over sequential
transplantation, it has yet to be established that it does not jeopardize patient
and graft outcomes. We here report our experience with six cases of combined
heart-kidney transplantation from single donors and review the literature in
order to clarify this issue. METHODS: Four patients were kidney-transplant
candidates with severe heart failure and two were heart-transplant candidates
with independent chronic renal failure. Donors were selected on the basis of
weight and size matching, ABO compatibility, and negative T-cell cross-match.
RESULTS: The heart was always grafted first. The surgical procedure was
uneventful in all cases. Heart and kidney function recovered quickly in all
patients. Two patients died, one at day 45 from heart subacute rejection and the
other one at day 157 from cerebral haemorrhage. The four remaining patients are
alive 23-84 months after transplantation (2-year survival rate: 67%) and have
well-functioning kidneys (creatinine clearance 31-83 ml/min) and hearts (left
ventricular ejection fraction 53-83%). Remarkably, four of six patients had no
acute rejection episode of either organ. These patient and graft outcomes are in
agreement with previous reports and compare favourably with the results of
isolated heart and kidney transplantation. CONCLUSIONS: Combined heart-kidney
transplantation from the same donor should be proposed to patients who would
qualify for transplantation of each organ within a few years.
PMID- 9550652
TI - Expression of inducible lymphocyte costimulatory molecules in human renal
allograft.
AB - BACKGROUND: CTLA-4/CD28-B7 and CD40-CD40L interactions constitute two key
costimulatory pathways in lymphocyte signalling during experimental allograft
rejection. Studies on the expression of these molecules in human transplant
rejection are still lacking. METHODS: The immunohistochemical study was performed
on renal biopsies obtained for various clinical complications from 25 renal
transplant patients. Expression of B7-1 and B7-2 and their counter-receptor CTLA
4, and of CD40 and its counter-receptor CD40L was examined. RESULTS: In acute
rejection a focal intense infiltration of B7-1+ and B7-2+ cells (mainly CD20-
CD14+) and of CTLA-4+ T lymphocytes (mainly CD8+) was present. In contrast, CD40
and CD40L were rarely expressed. Accumulations of T lymphocytes were found in the
interstitium in the same area containing B7-1+ and B7-2+ cells. The scattered
CD40L+ cells found in the T-cell infiltrate exhibited the CD4+ phenotype. In
chronic rejection only a few B7-1+, B7-2+ or CTLA-4+ cells were detectable. In
contrast, several CD40L+CD4+ cells were present both in the interstitium and in
glomeruli. Moreover, an intense expression of CD40 on the endothelium was
observed. In patients with cyclosporin nephrotoxicity cells positive for B7-1, B7
2, CTLA-4, CD40, or CD40L were absent. CONCLUSIONS: These results demonstrate a
differential expression of costimulatory molecules in renal biopsies of allograft
recipients undergoing acute or chronic rejection. Moreover, their detection may
prove useful to discriminate rejection from cyclosporin nephrotoxicity.
PMID- 9550654
TI - Is blood pressure related to kidney size and shape?
AB - OBJECTIVE: To examine the relationship between blood pressure and the size and
shape of the kidneys in healthy volunteers from the community. DESIGN: A cross
sectional community-based study of normal volunteers in Portsmouth City,
Hampshire, UK. SUBJECTS: Subjects numbered 185 (99 female), aged 19-66 years.
RESULTS: Blood pressure was higher in men, and in those with higher body mass
index. Both systolic and diastolic blood pressure were correlated with the
derived kidney volume. However, when corrected for age, sex and BMI the
relationship was not statistically significant. Blood pressure correlated
inversely with the width : length ratio of the left kidney. CONCLUSIONS: Blood
pressure was not correlated with kidney size in this group of adults.
PMID- 9550655
TI - Hepatitis C virus genotypes in patients on renal replacement therapy.
AB - BACKGROUND: Chronic hepatitis C virus (HCV) infection is prevalent among patients
on renal replacement therapy. Viral genomic differences can contribute to
diversities in clinical manifestation. The distribution of HCV genotypes depends
on the geographical region and risk factors unique to the patient population. We
determined the HCV genotypes in patients on renal replacement therapy in order to
define the genotypic profile and examine the relationship between genotype, mode
of renal replacement therapy, and the prevalence as well as severity of liver
disease. METHODS: HCV genotypes were determined by restriction fragment length
polymorphism and sequencing of the 5'-untranslated region in 21 renal allograft
recipients, 29 patients on dialysis, and 26 non-renal failure controls. RESULTS:
The most prevalent genotype among patients with renal failure was 1b (78%),
followed by 1a (10%) and 6a (8%). 2 renal allograft recipients with 6a infection
probably acquired HCV from the same donor. The relative prevalence of HCV
genotypes was similar to that of controls. While renal allograft recipients
demonstrated more severe liver disease than dialysis patients, the prevalence and
severity of chronic hepatitis were similar between patients with 1b and non-1b
infection. CONCLUSIONS: Resemblance of genotype distribution in Hong Kong to that
of southern China and east Asia suggests common epidemiological evolution of HCV
infection in these regions. Our results imply that in addition to viral
characteristics, host factors such as the immunosuppressed state play an
important role in the pathogenesis of liver disease in these patients.
PMID- 9550656
TI - Angiotensin-converting-enzyme insertion/deletion genotype and long-term renal
allograft survival.
AB - BACKGROUND: Increased activity of the renin-angiotensin system has been
implicated in decreased long-term survival of renal allografts. Recent studies
suggest that a deletion variant of the angiotensin-converting enzyme, associated
with increased humoral and tissue activity of this enzyme, may be a risk factor
for the development of diabetic nephropathy and the progression of IgA
nephropathy. The present study was conducted to determine whether the deletion
variant of the angiotensin-converting-enzyme gene influences the long-term
outcome in renal-transplant recipients. METHODS: We examined the relationship
between recipient angiotensin-converting-enzyme genotype and clinical outcome in
patients with a surviving allograft of at least 10 years (median survival 156
months, n= 86). Patients with an allograft survival of less than 3 years served
as controls (median survival 10.4 months, n=87). RESULTS: Genotype distribution
in long-term renal allograft survivors (II, 18; ID, 41; DD, 27; qD, 0.55) was
similar to that in the control group (II, 12; ID, 53; DD, 22; qD, 0.56), and
there were no significant differences between the genotypic groups in either
cases or controls. Long-term survivors were more often female (58 vs 38%) and
less often hypertensive (67 vs 77%). Both recipient and donor age were markedly
lower in the long-term survivor group, whereas number of HLA mismatches and cold
ischaemia time were comparable between cases and controls. CONCLUSIONS: This
study does not support the hypothesis that the angiotensin-converting-enzyme
insertion/deletion polymorphism is an important determinant of long-term
transplant survival in Caucasian patients undergoing renal transplantation.
PMID- 9550657
TI - Stability of access resistance during haemodialysis.
AB - BACKGROUND: Access blood flow (Qac) is considered a useful indicator in the
surveillance of haemodialysis access function. However, changes in Qac may be due
to changes in blood pressure and/or to changes in access resistance (AR).
METHODS: Weekly readings of Qac, cardiac output, and arterial blood pressure
measured early and late during haemodialysis were obtained in 11 patients for a
period of 3 weeks. Qac was determined from thermodilution of extracorporeal blood
returning to the patient with reversed placement of blood lines and by
measurement of arterial and venous blood temperatures in the extracorporeal
circulation. Data are given as mean +/- SE. RESULTS: Qac dropped as mean arterial
pressure (MAP) and total peripheral resistance (TPR) decreased, but increased
when MAP and TPR increased. Linear regressions between the change in access flow
and the change in MAP (deltaQac%=0.80*deltaMAP%-1.6, r2=0.39), and the change in
TPR (deltaQac%= 0.54*deltaTPR%-9.2, r2=0.35) respectively, were significant
(P<0.001). Whereas Qac significantly decreased (-8.4+/-3.3%, P<0.01) during the
same treatment, AR remained unchanged (4.7+/-3.2%; P=NS). AR for all studies was
16.5+/-1.0 peripheral resistance units (1 PRU=2.226 kPa min l(-1)). There was a
trend for resistance to increase (5.1+/-2.6%, P=NS) and for flow to decrease (
6.1+/-2.3%, P=NS) during the 3 weeks of the study. CONCLUSION: Qac measured
during haemodialysis is variable and depends on haemodynamics, but AR is
constant. AR is related to the physical structure of the peripheral access.
Because of its intradialytic stability AR may be better suited as an indicator of
access function.
PMID- 9550658
TI - Adequacy of haemodialysis with cuffed central-vein catheters.
AB - Cuffed central-venous haemodialysis catheters are emerging as an alternative
permanent haemodialysis vascular access. There is limited data regarding the
adequacy of dialysis with prolonged used of these catheters. We conducted a
prospective study comparing three commonly used cuffed central-venous
haemodialysis catheters: (1) PermCath, Quinton Instrument Co, Seattle; (2) Tesio,
Med Comp, Inc, Harleysville PA; (3) VasCath Soft Cell, Bard Instrument Company,
Toronto, and compared them with control patients dialysing with arteriovenous
access (AV) access. We randomly assigned 64 patients who needed prolonged
temporary vascular access to placement of one of three catheters. The control
group comprised 222 patients dialysing simultaneously in the same units with AV
access. METHODS: All patients were dialysed with identical machines and kidneys.
Maximal effort were made with every catheter to optimize achievable blood flow.
Catheters with mechanical problems were treated first with urokinase and then
fibrin sheath catheter stripping. The mean blood flow was determined by averaging
mean blood flows from 30 consecutive treatments. Reliability of catheter was
defined as percentage of treatments that were performed at a median blood flow of
350 ml/min or above during these 30 treatments. Kt/V was measured monthly and
calculated using the single-pool Daugirdas formula. Haemodialysis prescription
were adjusted for Kt/V above 1.2. Recirculation was measured using two-needle low
blood-flow technique. RESULTS: The mean blood flows were (PermCath 383.6 ml/min,
Tesio 396.3 ml/min, VasCath 320.4 ml/min). PermCath and Tesio had comparable mean
blood flows and were significantly higher than VasCath (P<0.005). Reliability of
catheters were (PermCath 86.9%, Tesio 81.6%, VasCath 42.3%). Tesio and PermCath
were equally reliable and both were more reliable than VasCath (P<0.005). Had the
target for reliability been 300 ml/min all three catheters would have been
equally reliable. Negative arterial pressure in excess of 300 mmHg prevented
faster blood flows in 98% of instances. None of the catheters performed as well
as the control population with AV access (mean blood flow 437ml/min, reliability
96%, P<0.005). Recirculation rates were 3.7% for PermCath 3.9% for Tesio, and 4%
for VasCath. All patients weighing less than 85 kg acheived a Kt/V of 1.2 with a
4-h treatment. For comparison purposes when Kt/V was normalized to a 70-kg
patient the results were PermCath 1.42. Tesio 1.44, VasCath 1.19, AV access 1.64.
SUMMARY: All three catheters are capable of providing adequate haemodialysis
although large patients will need extended treatment times. The PermCath and
Tesio provide blood flow and reliability superior to the VasCath. Blood flow is
limited in all catheters by inflow, as evidenced by negative arterial pressure.
All catheters had acceptable recirculation. AV access is superior in terms of
blood flow and reliability to all tested catheters.
PMID- 9550660
TI - Irreversible tubulointerstitial nephropathy associated with prolonged, massive
intake of vitamin C.
PMID- 9550659
TI - Indinavir crystal deposits associated with tubulointerstitial nephropathy.
PMID- 9550661
TI - Propylthiouracil-induced acute interstitial nephritis with acute renal failure
requiring haemodialysis: successful therapy with steroids.
PMID- 9550662
TI - A case of Becker muscular dystrophy and massive myoglobinuria with minimal renal
manifestations.
PMID- 9550663
TI - Seizures complicating adult Henoch-Schonlein purpura.
PMID- 9550664
TI - Evaluation of a patient with hypertension and mild renal failure in whom facial
and digital abnormalities are noted.
PMID- 9550665
TI - Nephrotic syndrome after successful renal angioplasty.
PMID- 9550666
TI - Despite low plasma renin ACE inhibitor treatment causes recovery from acute renal
failure in a patient with malignant hypertension.
PMID- 9550667
TI - Steroids for deep-infection-associated glomerulonephritis: a two-edged sword.
PMID- 9550668
TI - Secondary hyperparathyroidism resistant to active vitamin D is not unique to
renal failure--observation in a patient with distal tubular acidosis and
pancreatogenic malabsorption.
PMID- 9550669
TI - Parvovirus B19 infection and unresponsiveness to erythropoietin therapy in
haemodialysis patients.
PMID- 9550670
TI - A patient on haemodialysis with necrotizing fasciitis of the left arm.
PMID- 9550671
TI - Reflex sympathetic dystrophy following vascular access surgery for haemodialysis:
influence of peripheral ischaemia?
PMID- 9550672
TI - The dialysis patient with headache and sudden hypotension: consider pituitary
apoplexy.
PMID- 9550673
TI - Kaposi's sarcoma and cold abscess of the graft in a renal transplant recipient.
PMID- 9550674
TI - Ureteric aspergilloma as the cause of ureteric obstruction in a renal transplant
recipient.
PMID- 9550675
TI - Ureteric obstruction: an unusual complication of total hip replacement.
PMID- 9550676
TI - Subcutaneous nodules and pneumonia in a kidney transplant recipient.
PMID- 9550677
TI - Images in nephrology. Vascular catheter apparently well-placed.
PMID- 9550679
TI - Contrast-associated nephropathy--old clinical problem and new therapeutic
perspectives.
PMID- 9550678
TI - Brains and bones.
PMID- 9550680
TI - The clinical spectrum of shunt nephritis.
PMID- 9550681
TI - The BSM-1 vitamin D receptor polymorphism and secondary hyperparathyroidism.
PMID- 9550682
TI - Perirenal haematoma as the presenting feature of polyarteritis nodosa: one more
case from Turkey.
PMID- 9550683
TI - Microscopic polyarteritis with antineutrophil cytoplasmic antibodies in
polyglandular autoimmunity.
PMID- 9550684
TI - Non-oliguric acute renal failure in non-fulminant acute viral hepatitis.
PMID- 9550685
TI - Renal tolerance of combined treatment with foscarnet and indinavir.
PMID- 9550686
TI - Paraoxonase activity stimulation by salts is higher in chronic renal failure
patients than in controls.
PMID- 9550687
TI - Subcutaneous erythropoietin alpha (Eprex) is more painful than erythropoietin
beta (Recormon)
PMID- 9550688
TI - Bilateral spontaneous avulsion of quadriceps tendons.
PMID- 9550689
TI - Significant removal of phenytoin during high flux dialysis with cellulose
triacetate dialyzer.
PMID- 9550690
TI - Early mammals: teeth, jaws and finally a skeleton!
AB - Suprising new fossils - a skeleton and a jaw - give us a much clearer picture of
mammals that lived during the time of non-avian dinosaurs; the new finds
illuminate the early evolution of the lineage leading to modern mammals, and
challenge traditional understanding of placental mammal evolution and
biogeography.
PMID- 9550692
TI - Cortical organization: modules, polymaps and mosaics.
AB - Recent studies of functional maps in the mammalian visual cortex fail to support
the widespread belief that the cortex contains millimetre-sized modules; instead,
they reveal a more fluid arrangement in which several separate maps are
superimposed, with relatively weak geometric linkages and no common modular
subunit.
PMID- 9550691
TI - Olfactory processing: a time and place for everything.
AB - The behavioral effects of pharmacologically desynchronizing neuronal firing in
the brain of the honeybee provide new evidence that the oscillatory
synchronization of neuronal activity plays an important role in fine olfactory
discrimination.
PMID- 9550693
TI - Gametogenesis: keeping the male element under control.
AB - Caenorhabditis elegans hermaphrodites switch from making sperm to oocytes. This
switch involves repression of fem-3 mRNA, mediated by a protein that binds RNA
through a conserved motif; a similar motif mediates RNA binding by the Drosophila
pattern-regulatory protein Pumilio.
PMID- 9550694
TI - Stroke: a double-edged sword for cleaving clots?
AB - The discovery that tissue plasminogen activator can promote neuronal degeneration
has uncovered a novel pathway leading to neuronal cell death and raises important
issues concerning the use of tissue plasminogen activator as a thrombolytic
therapy for stroke.
PMID- 9550695
TI - Mitochondrial import: crossing the aqueous intermembrane space.
AB - Mitochondrial protein import follows a general pathway for preproteins with amino
terminal presequences. The discovery of novel import components has now revealed
a distinct pathway for translocation of hydrophobic proteins across the
intermembrane space and into the inner membrane.
PMID- 9550696
TI - Genomics: re-evaluation of translation machinery evolution.
AB - Experiments based on genome sequence analysis have revealed unexpected complexity
in the evolution of the translation apparatus, including concerted evolution of
Gln-tRNA synthetase and Glu-tRNAGln amidotransferase, and a novel, class I Lys
tRNA synthetase shared by archaea and spirochaetes.
PMID- 9550697
TI - Tubulin family: kinship of key proteins across phylogenetic domains.
AB - Atomic structures obtained by electron microscopy for tubulin, and by X-ray
crystallography for bacterial FtsZ, show that the two proteins are highly
homologous. The complementarity between such high-resolution studies and low
resolution reconstructions of microtubule complexes is clear, but controversy
still abounds.
PMID- 9550698
TI - p27Kip1 alters the response of cells to mitogen and is part of a cell-intrinsic
timer that arrests the cell cycle and initiates differentiation.
AB - BACKGROUND: In many vertebrate cell lineages, precursor cells divide a limited
number of times before they arrest and terminally differentiate into postmitotic
cells. It is not known what causes them to stop dividing. We have been studying
the 'stopping' mechanism in the proliferating precursor cells that give rise to
oligodendrocytes, the cells that make myelin in the central nervous system. We
showed previously that the cyclin-dependent kinase inhibitor p27Kip1 (p27)
progressively accumulates in cultured precursor cells as they proliferate and
that the time course of the increase is consistent with the possibility that p27
accumulation is part of a cell-intrinsic timer that arrests the cell cycle and
initiates differentiation at the appropriate time. RESULTS: We now provide direct
evidence that p27 is part of the intrinsic timer. We show that although p27-/-
precursor cells stop dividing and differentiate almost as fast as wild-type cells
when deprived of mitogen, when stimulated by saturating amounts of mitogen they
have a normal cell-cycle time but tend to go through one or two more divisions
than wild-type cells before they stop and differentiate. Cells that are p27+/-
behave in an intermediate way, going through at most one extra division,
indicating that the levels of p27 matter in the way the timer works. We also show
that p27-/- precursor cells are more sensitive than wild-type cells to the
mitogenic effect of platelet-derived growth factor. CONCLUSIONS: These findings
demonstrate that p27 is part of the normal timer that determines when
oligodendrocyte precursor cells stop dividing and differentiate, at least in
vitro. It seems likely that p27 plays a similar role in many other cell lineages,
which could explain the phenotypes of the p27-/- and p27+/- mice.
PMID- 9550699
TI - The DEAH-box splicing factor Prp16 unwinds RNA duplexes in vitro.
AB - BACKGROUND: During pre-mRNA splicing, dynamic rearrangement of RNA secondary
structure within the spliceosome is crucial for intron recognition and formation
of the catalytic core. Splicing factors belonging to the DExD/DExH-box family of
RNA-dependent ATPases are thought to have a central role in directing these
rearrangements by unwinding RNA helices. Proof of this hypothesis has, however,
been conspicuously lacking. RESULTS: Prp16 is a DEAH-box protein that functions
in the second step of splicing in vitro. Using various RNA duplexes as substrate,
we have shown that Prp16 has an ATP-dependent RNA unwinding activity. This
activity is independent of sequence in either the single-stranded or duplexed
regions of the RNA substrate. A mutation (prp16-1) near the ATP-binding motif of
Prp16 inhibits both the RNA-dependent ATPase activity and the ATP-dependent RNA
unwinding activity. CONCLUSIONS: Our findings provide strong biochemical evidence
that Prp16 can disrupt a duplexed RNA structure on the spliceosome. Because the
purified protein lacks sequence specificity in unwinding RNA duplexes, targeting
of the unwinding activity of Prp16 in the spliceosome is likely to be determined
by other interacting protein factors. The demonstration of unwinding activity
will also help our understanding of how the fidelity of branchpoint recognition
is controlled by Prp16.
PMID- 9550700
TI - Evidence for two modes of cooperative DNA binding in vivo that do not involve
direct protein-protein interactions.
AB - BACKGROUND: The promoter regions of most eukaryotic genes contain binding sites
for more than one transcriptional activator and these activators often bind
cooperatively to promoters. The most common type of cooperativity is supported by
direct protein-protein interactions. Recent studies have shown that proteins that
do not specifically interact with one another can bind cooperatively to chromatin
in vitro. probably by the localized destabilization of nucleosome structure by
one factor, facilitating binding of another to a nearby site. This mechanism does
not require that the transcription factors have activation domains. We have
examined whether this phenomenon occurs in vivo. RESULTS: Unrelated non
interacting proteins can bind DNA cooperatively in yeast cells; this cooperative
binding can contribute significantly to transcriptional activation, does not
require that both factors have activation domains and is only operative over
relatively short distances. In addition to this 'short-range' mechanism,
unrelated non-interacting proteins can bind cooperatively to sites separated by
hundreds of base pairs, so long as both have potent activation domains.
CONCLUSION: Cooperative binding of transcription factors in vivo can occur by
several mechanisms, some of which do not require direct protein-protein
interactions and which cannot be detected in vitro using naked DNA templates.
These findings must be taken into account when evaluating mechanisms for
synergistic transcriptional activation.
PMID- 9550701
TI - Positional information in root epidermis is defined during embryogenesis and acts
in domains with strict boundaries.
AB - BACKGROUND: Cell position rather than cell lineage governs most aspects of
development in plants. However, the nature and the origin of positional
information remains elusive. Animal epidermal patterning relies in many cases on
positional information provided by cell-cell communication. The epidermal layer
of the Arabidopsis root is made of alternating files of two cell types and thus
presents a simple pattern to study positional mechanisms. RESULTS: Clonal
analysis of the root epidermis in combination with molecular and morphological
markers has shown that cell fate is determined by position relative to the
underlying cell layer, the cortex. The epidermal pattern appears to be organised
during embryogenesis. Fate is not fixed in the developing root, though, as cells
that move into a position previously occupied by neighbour cells ablated using
laser microsurgery change fate. In contrast, cell fate is not altered when
communication with living neighbour cells is impaired. Precise mapping of the
influence of the position of extracellular cues on cell fate has shown that
domains of positional information are organised with well-defined boundaries.
CONCLUSIONS: Cell-fate specification in the root epidermis relies on positional
information that is organised in stable domains with sharp boundaries. The
epidermal pattern is defined during embryogenesis and positional information
remains active in the root until the initiation of cell morphogenesis. The origin
of some positional cues might be extracellular.
PMID- 9550702
TI - Ras-dependent activation of the small GTPase Ral.
AB - The small GTPase Ral is a Ras-like GTPase [1] that has been implicated in growth
factor-induced and Ras-induced DNA synthesis [2-4], and Ras-induced oncogenic
transformation [3,5]. Recently, we and others found that three different Ral
guanine nucleotide exchange factors (Ral GEFs) - Ral GDS, Rgl and Rlf - bind
specifically to the GTP-bound form of several Ras-like GTPases [6-9]. Although
oncogenic Ras is able to activate these Ral GEFs [2,5,10], it is unknown whether
growth factors can induce the activation of Ral and, if so, which small GTPase is
involved in this process. Here, we show that stimulation of various growth factor
receptors, including receptor tyrosine kinases and serpentine receptors, results
in rapid activation of Ral. This activation correlates with the activation of
Ras, and dominant-negative Ras completely inhibits Ral activation induced by
insulin and epidermal growth factor (EGF). From these results, we conclude that
Ral activation is a direct downstream effect of growth-factor-induced Ras
activation.
PMID- 9550703
TI - Insulin-dependent translocation of ARNO to the plasma membrane of adipocytes
requires phosphatidylinositol 3-kinase.
AB - ADP-ribosylation factors (ARFs) are small GTP-binding proteins that are
regulators of vesicle trafficking in eukaryotic cells [1]. ARNO is a member of
the family of guanine nucleotide exchange factors for ARFs which includes
cytohesin-1 and GRP-1 [2] [3-5]. Members of this family contain a carboxy
terminal pleckstrin homology (PH) domain which, in the case of GRP-1, has been
shown to bind the second messenger phosphatidylinositol 3,4,5-trisphosphate
(PIP3) in preference to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and
phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) in vitro [3,4]. Here, we show
that recombinant ARNO has the binding characteristics of a PIP3 receptor and that
this activity is restricted to the PH domain. When expressed in murine 3T3 L1
adipocytes, ARNO tagged using green fluorescent protein (GFP) is localised
exclusively in the cytoplasm. Stimulation with insulin, however, causes a rapid
(< 50 second) PH-domain-dependent translocation of GFP-ARNO to the plasma
membrane. This translocation is blocked by the PI(4,5)P2 3-kinase (PI 3-kinase)
inhibitors wortmannin and LY294002, and by co-expression with a dominant-negative
p85 mutant, suggesting that the translocation is a consequence of insulin
stimulation of PI 3-kinase. Our data strongly suggest that ARNO binds PIP3 in
vivo and that this interaction causes a translocation of ARNO to the plasma
membrane where it might activate ARF6 and regulate subsequent plasma membrane
cycling events.
PMID- 9550704
TI - p53-dependent impairment of T-cell proliferation in FADD dominant-negative
transgenic mice.
AB - Members of the tumour necrosis factor (TNF) receptor family exert pleiotropic
effects and can trigger both apoptosis and proliferation [1]. In their
cytoplasmic region, some of these receptors share a conserved sequence motif -
the 'death domain' - which is required for transduction of the apoptotic signal
by recruiting other death-domain-containing adaptor molecules like the Fas
associated protein FADD/MORT1 or the TNF receptor-associated protein TRADD [2-4].
FADD links the receptor signal to the activation of the caspase family of
cysteine proteases [5,6]. Functional inactivation of individual receptor family
members often fails to exhibit a distinctive phenotype, probably because of
redundancy [7-9]. To circumvent this problem, we used a dominant-negative mutant
of FADD (FADD-DN) which should block all TNF receptor family members that use
FADD as an adaptor. We established transgenic mice expressing FADD-DN under the
influence of the lck promoter and investigated the consequences of its expression
in T cells. As expected, FADD-DN thymocytes were protected from death induced by
CD95 (Fas/Apo1), whereas apoptosis induced by ultraviolet (UV) irradiation, anti
CD3 antibody treatment or dexamethasone was unaffected, as was spontaneous cell
death. Surprisingly, however, we also observed profound inhibition of thymocyte
proliferation in vivo and of activation-induced proliferation of thymocytes and
mature T cells in vitro. This inhibition of proliferation was not due to
increased cell death and appeared to be p53 dependent.
PMID- 9550705
TI - Cooperation of intrinsic and extrinsic signals in the elaboration of regional
identity in the posterior cerebral cortex.
AB - Understanding the compartmentalization of the neocortex (isocortex) of the
mammalian brain into functional areas is a challenging problem [1-3] . Unlike
pattern formation in the spinal cord and hindbrain, it does not involve the
specification of distinct cells types: distinct areas differ in their patterns of
connectivity and cytoarchitecture. It has been suggested that signals intrinsic
to the neocortical neuroepithelium specify regional fate [3]. Alternatively,
spatial patterning might be imposed by extrinsic cues such as thalamocortical
projections [4-6]. Recent results highlight the ability of early precursor cells
of the telencephalic neuroepithelium to 'remember' their spatial position from
times before thalamic innervation [7,8] [9-12]. An influence from the thalamus,
however, cannot be ruled out as there is a precise invasion of the correct
cortical areas by the corresponding projections [13,14]. Furthermore, cortical
neuronal progenitors have been proposed to adopt new connection patterns after
transplantation [6,7], as well as when the thalamic input is rerouted [15,16].
Here, we describe the transient expression of the homeobox gene Otx2 in the
posterior, prospective visual, neocortex and use it to analyze the establishment
of posterior cortical fate. The results suggest that whereas intrinsic cortical
information is sufficient to specify regional fate, extrinsic signals from the
thalamus are involved in the expansion or maintenance of the population of cells
expressing Otx2 but not in regionalization.
PMID- 9550707
TI - Kim nasmyth: the universal truth
PMID- 9550706
TI - Regulation of gene expression is preserved in aging Drosophila melanogaster.
AB - Aging, and the deterioration of biological performance that characterizes it, are
routinely assumed to be due to a progressive global loss of homeostasis and a
general increase in dysregulation [1-4] . We tested this hypothesis directly by
measuring age-specific variability in gene expression. Analysis of the
transcriptional activity of six genes in various inbred lines of Drosophila
melanogaster unexpectedly failed to show an increase in variability among
individuals as they age and die. Although regulation of gene expression is a
central feature of life, a global decline in the control of gene expression does
not appear to be either a cause or a consequence of the process of aging.
PMID- 9550709
TI - Get alife
PMID- 9550708
TI - The knowledge industry
PMID- 9550711
TI - Hypersensitive fish
PMID- 9550710
TI - The complement system.
PMID- 9550712
TI - Continuing organizer function during chick tail development.
AB - Development of the posterior body (lumbosacral region and tail) in vertebrates is
delayed relative to gastrulation. In amniotes, it proceeds with the replacement
of the regressed node and primitive streak by a caudal blastema-like mass of
mesenchyme known as the tail bud. Despite apparent morphological dissimilarities,
recent results suggest that tail development in amniotes is in essence a
continuation of gastrulation, as is the case in Xenopus. However, this has been
inferred primarily from the outcome of fate mapping studies demonstrating
discrete, regionalized cell populations in the tail bud, like those present at
gastrulation. Our analysis of the tail bud distribution of several molecular
markers that are expressed in specific spatial domains during chick gastrulation
confirms these results. Furthermore, we present evidence that gastrulation-like
ingression movements from the surface continue in the early chick tail bud and
that the established tail bud retains organizer activity. This 'tail organizer'
has the expected properties of being able to recruit uncommitted host cells into
a new embryonic axis and induce host neural tissue with posteriorly regionalized
gene expression when grafted to competent host cells that are otherwise destined
to form only extra-embryonic tissue. Together, these results indicate that chick
tail development is mechanistically continuous with gastrulation and that the
developing tail in chick may serve as a useful experimental adjunct to
investigate the molecular basis of inductive interactions operating during
gastrulation, considering that residual tail organizing activity is still present
at a surprisingly late stage.
PMID- 9550713
TI - Genetic regulation of entry into meiosis in Caenorhabditis elegans.
AB - The Caenorhabditis elegans germline is composed of mitotically dividing cells at
the distal end that give rise to meiotic cells more proximally. Specification of
the distal region as mitotic relies on induction by the somatic distal tip cell
and the glp-1 signal transduction pathway. However, the genetic control over the
transition from mitosis to meiosis is not understood. In this paper, we report
the identification of a gene, gld-2, that has at least two functions in germline
development. First, gld-2 is required for normal progression through meiotic
prophase. Second, gld-2 promotes entry into meiosis from the mitotic cell cycle.
With respect to this second function, gld-2 appears to be functionally redundant
with a previously described gene, gld-1 (Francis, R., Barton, M. K., Kimble, J.
and Schedl, T. (1995) Genetics 139, 579-606). Germ cells in gld-1(o) and gld-2
single mutants enter meiosis at the normal time, but germ cells in gld-2 gld-1(o)
double mutants do not enter meiosis. Instead, the double mutant germline is
mitotic throughout and forms a large tumor. We suggest that gld-1 and gld-2
define two independent regulatory pathways, each of which can be sufficient for
entry into meiosis. Epistasis analyses show that gld-1 and gld-2 work downstream
of the glp-1 signal transduction pathway. Therefore, we hypothesize that glp-1
promotes proliferation by inhibiting the meiosis-promoting functions of gld-1 and
gld-2.
PMID- 9550714
TI - Bundle sheath cells and cell-specific plastid development in Arabidopsis leaves.
AB - Bundle sheath cells form a sheath around the entire vascular tissue in
Arabidopsis leaves and constitute a distinct leaf cell type, as defined by their
elongate morphology, their position adjacent to the vein and by differences in
their chloroplast development compared to mesophyll cells. They constitute about
15% of chloroplast-containing cells in the leaf. In order to identify genes which
play a role in the differential development of bundle sheath and mesophyll cell
chloroplasts, a screen of reticulate leaf mutants of Arabidopsis was used to
identify a new class of mutants termed dov (differential development of vascular
associated cells). The dov1 mutant clearly demonstrates a cell-specific
difference in chloroplast development. Mutant leaves are highly reticulate with a
green vascular pattern. The underlying bundle sheath cells always contain normal
chloroplasts, whereas chloroplasts in mesophyll cells are abnormal, reduced in
number per cell and seriously perturbed in morphology at the ultrastructural
level. This demonstrates that differential chloroplast development occurs between
the bundle sheath and mesophyll cells in the Arabidopsis leaf.
PMID- 9550715
TI - Genetic interactions and cell behaviour in blistered mutants during proliferation
and differentiation of the Drosophila wing.
AB - In this work, we analyse the blistered function in wing vein development by
studying genetic mosaics of mutant cells, genetic interactions with other genes
affecting vein development and blistered expression in several mutant
backgrounds. blistered encodes for a nuclear protein homologous to the mammalian
Serum Response Factor and is expressed in presumptive intervein cells of third
larval instar and pupal wing discs. Clones of blistered mutant cells proliferate
normally but tend to grow along veins and always differentiate as vein tissue.
These observations indicate that vein-determined wing cells show a particular
behaviour that is responsible for their allocation to vein regions. We observe
strong genetic interactions between blistered, veinlet and genes of the Ras
signaling cascade. During disc proliferation, blistered expression is under the
control of the Ras signal transduction pathway, but its expression is independent
of veinlet. During the pupal period, blistered and veinlet expression become
interdependent and mutually exclusive. These results link the activity of the Ras
pathway to the process of early determination of intervein cells, by the
transcriptional control of the blistered nuclear factor.
PMID- 9550716
TI - Genetic dissection of sperm individualization in Drosophila melanogaster.
AB - The morphogenesis of spermatids generally takes place within a syncytium, in
which all spermatid nuclei descended from a primary spermatocyte remain connected
via an extensive network of cytoplasmic bridges. A late step in sperm maturation
therefore requires the physical resolution of the syncytium, or cyst, into
individual cells, a process sometimes referred to as sperm individualization.
Despite the identification of specialized machinery involved in the
individualization of Drosophila spermatids (Tokuyasu, K. T., Peacock, W. J. and
Hardy, R. W. (1972) Z. Zellforsch 124, 479-506), and of many Drosophila genes
mutable to male-sterile phenotypes, little is known of the mechanisms by which
this extensive remodeling of the cyst is accomplished. Here, the identification
of a major cytoskeletal component of the individualization complex as actin is
confirmed with a simple fluorescence assay. Using rhodamine-phalloidin as a
probe, the individualization complex is readily visualized forming around bundles
of spermatid nuclei at one end of highly elongated cysts, then translocating
along the length of the cysts. The structure of the individualization complex in
a male-sterile clathrin heavy chain (Chc) mutant is observed to be reduced or
disrupted relative to wild-type, consistent with the individualization-deficient
phenotype of this mutant. Using the fluorescence assay, a sampling of male
sterile mutant phenotypes in which spermatogenesis proceeds to the assembly of
highly elongated cysts distinguishes at least four different phenotypic classes:
(1) mutations (nanking class) that block or significantly retard the assembly of
the actin-based individualization complex around the nuclear bundle, (2)
mutations (dud class) in which the individualization complex assembles in/around
the nuclear bundle, but fails to translocate down the cyst, (3) mutations (mulet
class) that allow the assembly of a morphologically normal individualization
complex around the nuclear bundle, but result in a breakdown in the complex after
it begins to translocate down the cyst, and (4) mutations (purity of essence
class) that allow the assembly of a motile but morphologically altered or reduced
individualization complex. Individualization also fails in a number of mutants
with altered nuclear shape, consistent with the hypothesis that spermatid nuclei
provide a physical scaffolding for the assembly of the individualization complex.
Genetic analysis suggests that a substantial number of additional loci with
phenotypes distinguishable with this assay remain to be identified. The large
proportion of male-sterile mutations resulting in a late block to
spermatogenesis, in which highly elongated cysts fail to be individualized,
suggest a substantial susceptibility of this process to a broad range of cellular
perturbations. The massive reorganization of cyst cytoplasm required at
individualization is expected to be a correspondingly complex function requiring
exquisite coordination of multiple cytoplasmic functions, and may account for the
previously noted high frequency with which Drosophila genes are mutable to male
sterile phenotypes.
PMID- 9550717
TI - The Drosophila sanpodo gene controls sibling cell fate and encodes a tropomodulin
homolog, an actin/tropomyosin-associated protein.
AB - Notch signaling is required in many invertebrate and vertebrate cells to promote
proper cell fate determination. Mutations in sanpodo cause many different
neuronal peripheral nervous system precursor cells to generate two identical
daughter neurons, instead of a neuron and sibling cell. This phenotype is similar
to that observed when Notch function is lost late in embryonic development and
opposite to the numb loss-of-function phenotype. Genetic interaction studies show
that sanpodo is epistatic to numb. sanpodo encodes a homolog of tropomodulin, an
actin/tropomyosin-associated protein. Loss of sanpodo leads to an aberrant F
actin distribution and causes differentiation defects of actin-containing sensory
structures. Our data suggest that an actin-based process is involved in Notch
signaling.
PMID- 9550718
TI - Sanpodo and Notch act in opposition to Numb to distinguish sibling neuron fates
in the Drosophila CNS.
AB - In Drosophila, most neuronal siblings have different fates ('A/B'). Here we
demonstrate that mutations in sanpodo, a tropomodulin actin-binding protein
homologue, equalize a diverse array of sibling neuron fates ('B/B'). Loss of
Notch signaling gives the same phenotype, whereas loss of numb gives the opposite
phenotype ('A/A'). The identical effect of removing either sanpodo or Notch
function on the fates of sibling CNS neurons indicates that sanpodo may act in
the Notch signaling pathway. In addition, sanpodo and numb show dosage-sensitive
interactions and epistasis experiments indicate that sanpodo acts downstream of
numb. Taken together, these results show that interactions between sanpodo, the
Notch signaling pathway and numb enable CNS sibling neurons to acquire different
fates.
PMID- 9550719
TI - Tbx genes and limb identity in chick embryo development.
AB - Tbx-2, Tbx-3, Tbx-4 and Tbx-5 chick genes have been isolated and, like the mouse
homologues, are expressed in the limb regions. Tbx-2 and Tbx-3 are expressed in
anterior and posterior domains in wings and legs, as well as throughout the
flank. Of particular interest, however, are Tbx-5, which is expressed in wing and
flank but not leg, and Tbx-4, which is expressed very strongly in leg but not
wing. Grafts of leg tissue to wing and wing tissue to leg give rise to toe-like
or wing-like digits in wing and leg respectively. Expression of Tbx-4 is stable
when leg tissue is grafted to wing, and Tbx-5 expression is stable when wing
tissue is grafted to leg. Induction of either extra wings or legs from the flank
by applying FGF-2 in different positions alters the expression of Tbx-4 and Tbx-5
in such a way that suggests that the amount of Tbx-4 that is expressed in the
limb determines the type that will form. The ectopic limb always displays a limb
like Tbx-3 expression. Thus Tbx-4 and Tbx-5 are strong candidates for encoding
'wingness' and 'legness'.
PMID- 9550720
TI - The Tlx-2 homeobox gene is a downstream target of BMP signalling and is required
for mouse mesoderm development.
AB - TGFbeta-related factors are critical regulators of vertebrate mesoderm
development. However, the signalling cascades required for their function during
this developmental process are poorly defined. Tlx-2 is a homeobox gene expressed
in the primitive streak of mouse embryos. Exogenous BMP-2 rapidly activates Tlx-2
expression in the epiblast of E6.5 embryos. A Tlx-2 promoter element responds to
BMP-2 signals in P19 cells, and this response is mediated by BMP type I receptors
and Smad1. These results suggest that Tlx-2 is a downstream target gene for BMP
signalling in the primitive streak where BMP-4 and other TGFbeta-related factors
are expressed. Furthermore, disruption of Tlx-2 function leads to early embryonic
lethality. Similar to BMP4 and ALK3 mutants, the mutant embryos display severe
defects in primitive streak and mesoderm formation. These experiments thus define
a BMP/Tlx-2 signalling pathway that is required during early mammalian
gastrulation.
PMID- 9550721
TI - HASTY: a gene that regulates the timing of shoot maturation in Arabidopsis
thaliana.
AB - In Arabidopsis thaliana, leaves produced at different stages of shoot development
can be distinguished by the distribution of trichomes on the abaxial and adaxial
surfaces. Leaves produced early in the development of the rosette (juvenile
leaves) have trichomes on their adaxial, but not their abaxial surface, whereas
leaves produced later in rosette development (adult leaves) have trichomes on
both surfaces. In order to identify genes that regulate the transition between
these developmental phases we screened for mutations that accelerate the
production of leaves with abaxial trichomes. 9 alleles of the HASTY gene were
recovered in this screen. In addition to accelerating the appearance of adult
leaves these mutations also accelerate the loss of adaxial trichomes (a trait
typical of bracts), reduce the total number of leaves produced by the shoot, and
have a number of other effects on shoot morphology. The basis for this phenotype
was examined by testing the interaction between hasty and genes that affect
flowering time (35S::LEAFY, 35S::APETALA1, terminal flower1), gibberellin
production (ga1-3) or perception (gai), and floral morphogenesis (leafy,
apetala1, agamous). We found that hasty increased the reproductive competence of
the shoot, and that its does not require gibberellin or a gibberellin response
for its effect on vegetative or reproductive development. The phenotype of hasty
is not suppressed by leafy, apetala1 and agamous, demonstrating that this
phenotype does not result from the inappropriate expression of these genes. We
suggest that HASTY promotes a juvenile pattern of vegetative development and
inhibits flowering by reducing the competence of the shoot to respond to LEAFY
and APETALA1.
PMID- 9550722
TI - Selective disruption of neuregulin-1 function in vertebrate embryos using
ribozyme-tRNA transgenes.
AB - The products of the neuregulin-1 gene constitute a set of polypeptide growth
factors whose signalling through the ErbB receptors is essential to the growth
and differentiation of many cell types in culture. Although studies with
neuregulin-1 mutant mice have demonstrated that these growth factors are also
essential regulators of cellular differentiation in vivo, the mid-embryonic death
of these mutants precludes an analysis of hypothesized neuregulin-1 roles in
later aspects of development. To circumvent this early lethality, we have pursued
a ribozyme-based strategy for the perturbation of neuregulin-1 function in
developing chick embryos. Early administration of a retrovirus carrying
neuregulin-1 hammerhead-type ribozymes to blastoderm-stage embryos leads to an
embryonic lethal phenotype that results from the failure of ventricular
trabeculation in the developing heart, a faithful phenocopy of the mouse
neuregulin-1 mutations. Later, more localized delivery of the ribozyme to the
developing retina inhibits both the differentiation of retinal ganglion cell
neurons and the proliferation of the neuroepithelial cells from which they
derive. These results suggest that neuregulin-1 promotes both muscle cell
differentiation in the heart and neuronal differentiation in the central nervous
system. In addition, they demonstrate the utility of hammerhead ribozymes as a
simple, effective and easily adaptable method of conditional gene inactivation in
vertebrates.
PMID- 9550723
TI - A role for the Drosophila Toll/Cactus pathway in larval hematopoiesis.
AB - In the Drosophila larva, blood cells or hemocytes are formed in the lymph gland.
The major blood cell type, called plasmatocyte, is small, non-adhesive and
phagocytic. Plasmatocytes differentiate into adhesive lamellocytes to form
multilayered capsules around foreign substances or, in mutant melanotic tumor
strains, around self tissue. Mutations in cactus or Toll, or constitutive
expression of dorsal can induce lamellocyte differentiation and cause the
formation of melanotic capsules. As maternally encoded proteins, Toll, Cactus and
Dorsal, along with Tube and Pelle, participate in a common signal transduction
pathway to specify the embryonic dorsal-ventral axis. Using the maternal pathway
as a paradigm, we investigated if these proteins have additional roles in larval
hemocyte formation and differentiation. Analysis of cactus mutants that lack
Cactus protein revealed that almost all of these animals have an overabundance of
hemocytes, carry melanotic capsules and die before reaching pupal stages. In
addition, the lymph glands of cactus larvae are considerably enlarged. The number
of mitotic cells in the cactus and TollD hemolymph is higher than that in the
wild-type hemolymph. The hemocyte density of mutant Toll, tube or pelle hemolymph
is significantly lower than that of the wild type. Lethality of mutant cactus
animals could be rescued either by the selective expression of wild-type Cactus
protein in the larval lymph gland or by the introduction of mutations in Toll,
tube or pelle. Cactus, Toll, Tube and Pelle proteins are expressed in the nascent
hemocytes of the larval lymph gland. Our results suggest that the Toll/Cactus
signal transduction pathway plays a significant role in regulating hemocyte
proliferation and hemocyte density in the Drosophila larva. These findings are
discussed in light of similar hematopoietic functions of Rel/I(kappa)B-family
proteins in mice.
PMID- 9550724
TI - An entire functional mammary gland may comprise the progeny from a single cell.
AB - Any epithelial portion of a normal mouse mammary gland can reproduce an entire
functional gland when transplanted into an epithelium-free mammary fat pad. Mouse
mammary hyperplasias and tumors are clonal dominant populations and probably
represent the progeny of a single transformed cell. Our study provides evidence
that single multipotent stem cells positioned throughout the mature fully
developed mammary gland have the capacity to produce sufficient differentiated
progeny to recapitulate an entire functional gland. Our evidence also
demonstrates that these stem cells are self-renewing and are found with
undiminished capacities in the newly regenerated gland. We have taken advantage
of an experimental model where mouse mammary tumor virus infects mammary
epithelial cells and inserts a deoxyribonucleic acid copy(ies) of its genome
during replication. The insertions occur randomly within the somatic genome.
CzechII mice have no endogenous nucleic acid sequence homology with mouse mammary
tumor virus; therefore all viral insertions may be detected by Southern analysis
provided a sufficient number of cells contain a specific insertional event.
Transplantation of random fragments of infected CzechII mammary gland produced
clonal-dominant epithelial populations in epithelium-free mammary fat pads.
Serial transplantation of pieces of the clonally derived outgrowths produced
second generation glands possessing the same viral insertion sites providing
evidence for self-renewal of the original stem cell. Limiting dilution studies
with cell cultures derived from third generation clonal outgrowths demonstrated
that three multipotent but distinct mammary epithelial progenitors were present
in clonally derived mammary epithelial populations. Estimation of the potential
number of multipotent epithelial cells that may be evolved from an individual
mammary-specific stem cell by self-renewal is in the order of 10(12)-10(13).
Therefore, one stem cell might easily account for the renewal of mammary
epithelium over several transplant generations.
PMID- 9550725
TI - Patterns and control of cell motility in the Xenopus gastrula.
AB - By comparing cells with respect to several motility-related properties and the
ability to migrate on fibronectin, three cell types can be distinguished in the
Xenopus gastrula. These occur in a distinct spatial pattern, thus defining three
motility domains which do not correspond to the prospective germ layers.
Migratory behavior is confined to a region encompassing the anterior mesoderm and
endoderm. When stationary animal cap cells are induced to migrate by treatment
with activin, cells become adhesive at low concentrations of fibronectin, show
polarized protrusive activity, and form lamellipodia. Adhesion and polarization,
but not lamellipodia formation, are mimicked by the immediate early response gene
Mix.1. Goosecoid, another immediate early gene, is without effect when expressed
alone in animal cap cells, but it acts synergistically with Mix.1 in the control
of adhesion, and antagonistically in the polarization of protrusive activity.
bFGF also induces migration, lamellipodia formation and polarization in animal
cap cells, but has no effect on adhesion. By the various treatments of animal cap
cells, new combinations of motile properties can be generated, yielding cell
types which are not found in the embryo.
PMID- 9550726
TI - Ventricular muscle-restricted targeting of the RXRalpha gene reveals a non-cell
autonomous requirement in cardiac chamber morphogenesis.
AB - Mouse embryos lacking the retinoic acid receptor gene RXR(alpha) die in
midgestation from hypoplastic development of the myocardium of the ventricular
chambers and consequent cardiac failure. In this study, we address the issue of
whether the RXRalpha gene is required in the cardiomyocyte lineage by generating
mice that harbor a ventricular restricted deficiency in RXRalpha at the earliest
stages of ventricular chamber specification. We first created a conditional
('floxed') allele of RXRalpha by flanking a required exon of the gene with loxP
recombination sequences. To achieve ventricular myocardium-specific gene
targeting, and to avoid potential transgenic artifacts, we employed a knock-in
strategy to place cre recombinase coding sequences into the myosin light chain 2v
(MLC2v) genomic locus, a gene which in the heart is expressed exclusively in
ventricular cardiomyocytes at the earliest stages of ventricular specification.
Crossing the MLC2v-cre allele with the floxed RXRalpha gene resulted in embryos
in which approximately 80% of the ventricular cardiomyocytes lacked RXRalpha
function, and yet which displayed a completely normal phenotype, without evidence
of the wide spectrum of congenital heart disease phenotype seen in RXRa-/-
embryos, and normal adult viability. We conclude that the RXRalpha mutant
phenotype is not cell autonomous for the cardiomyocyte lineage, and suggest that
RXRalpha functions in a neighboring compartment of the developing heart to
generate a signal that is required for ventricular cardiomyocyte development and
chamber maturation.
PMID- 9550727
TI - The RXRalpha gene functions in a non-cell-autonomous manner during mouse cardiac
morphogenesis.
AB - Germline mutation in mice of the retinoic acid receptor gene RXRalpha results in
a proliferative failure of cardiomyocytes, which leads to an underdeveloped
ventricular chamber and midgestation lethality. Mutation of the cell cycle
regulator N-myc gene also leads to an apparently identical phenotype. In this
study, we demonstrate by chimera analysis that the cardiomyocyte phenotype in
RXRalpha-/- embryos is a non-cell-autonomous phenotype. In chimeric embryos made
with embryonic stem cells lacking RXRalpha, cardiomyocytes deficient in RXRalpha
develop normally and contribute to the ventricular chamber wall in a normal
manner. Because the ventricular hypoplastic phenotype reemerges in highly
chimeric embryos, we conclude that RXRalpha functions in a non-myocyte lineage of
the heart to induce cardiomyocyte proliferation and accumulation, in a manner
that is quantitatively sensitive. We further show that RXRalpha is not epistatic
to N-myc, and that RXRalpha and N-myc regulate convergent obligate pathways of
cardiomyocyte maturation.
PMID- 9550728
TI - Initial anteroposterior pattern of the zebrafish central nervous system is
determined by differential competence of the epiblast.
AB - Analyses using amphibian embryos proposed that induction and anteroposterior
patterning of the central nervous system is initiated by signals that are
produced by the organizer and organizer-derived axial mesoderm. However, we show
here that the initial anteroposterior pattern of the zebrafish central nervous
system depends on the differential competence of the epiblast and is not imposed
by organizer-derived signals. This anteroposterior information is present
throughout the epiblast in ectodermal cells that normally give rise both to
neural and non-neural derivatives. Because of this information, organizer tissues
transplanted to the ventral side of the embryo induce neural tissue but the
anteroposterior identity of the induced neural tissue is dependent upon the
position of the induced tissue within the epiblast. Thus, otx2, an anterior
neural marker, was only ever induced in anterior regions of the embryo,
irrespective of the position of the grafts. Similarly, hoxa-1, a posterior neural
marker was induced only in the posterior regions. Furthermore, the boundary of
each ectopic expression domain on the ventral side was always at an equivalent
latitude to that of the endogenous expression of the dorsal side of the embryo.
The anteroposterior specification of the epiblast is independent of the
dorsoventral specification of the embryo because neural tissues induced in the
ventralized embryos also showed anteroposterior polarity. Cell transplantation
and RNA injection experiments showed that non-axial marginal mesoderm and FGF
signalling is required for anteroposterior specification of the epiblast.
However, the requirement for FGF signalling is indirect in that cells with
compromised ability to respond to FGF can still respond to anteroposterior
positional information.
PMID- 9550729
TI - A role for SOX1 in neural determination.
AB - In vertebrates, the delineation of the neural plate from a region of the
primitive ectoderm is accompanied by the onset of specific gene expression which
in turn promotes the formation of the nervous system. Here we show that SOX1, an
HMG-box protein related to SRY, is one of the earliest transcription factors to
be expressed in ectodermal cells committed to the neural fate: the onset of
expression of SOX1 appears to coincide with the induction of neural ectoderm. We
demonstrate a role for SOX1 in neural determination and differentiation using an
inducible expression P19 cell system as an in vitro model of neurogenesis.
Misexpression of SOX1 can substitute for the requirement of retinoic acid to
impart neural fate to competent ectodermal P19 cells. Using a series of antigenic
markers which identify early neural cell types in combination with BrdU labeling,
we demonstrate a temporal and spatial correlation between the differentiation of
cell types along the dorsoventral axis of the neural tube and the downregulation
of SOX1 expression. SOX1, therefore, defines the dividing neural precursors of
the embryonic central nervous system (CNS).
PMID- 9550730
TI - Monograph series on aging-related diseases: X. Prostate cancer.
AB - Prostate cancer is the most commonly diagnosed cancer among Canadian men,
excluding non-melanoma skin cancer. Prostate cancer incidence increases almost
exponentially with age; most cases are diagnosed in men aged 65 years or older.
With the possible exception of animal fat consumption, no known widespread
modifiable risk factors have been identified. Although the prognosis is good if
appropriate treatment occurs in the early stages of disease, the ability of
existing early detection techniques to decrease mortality has not yet been
demonstrated. The considerable economic and societal burden of prostate cancer
and its treatment, coupled with the projected large increase in the number of new
prostate cancer cases as the population ages, make this disease a very important
public health issue.
PMID- 9550731
TI - Pap smear utilization in Canada: estimates after adjusting the eligible
population for hysterectomy status.
AB - The 1994 National Population Health Survey (NPHS) confirmed that the trend in Pap
smear utilization has not changed in the past 10 years; 15% of Canadian women
reported never having had a Pap smear and an additional 15% reported not having
had one within 3 years prior to the survey. Most of these underserved women can
be characterized as disadvantaged. The overall prevalence of hysterectomy in
Canada in 1994 was 16.3%, and prevalence increased sharply to 30% between ages 35
and 55 years. Hysterectomy rates vary according to sociodemographic factors, with
women of lower income and education indicating a higher proportion of
hysterectomies. We adjusted the female population from the NPHS, by removing the
estimated proportion of women reporting hysterectomy, to reveal the true
population at risk of developing cervical cancer. Absolute prevalence of Pap
smear utilization increased (7 - 25%); the relative improvement was much higher.
Adjusting the eligible population could enable screening programs to better
estimate the size of their underserved population.
PMID- 9550732
TI - Firearms regulation: Canada in the international context.
AB - Gun deaths and injuries in Canada are a serious public health problem, claiming
more than 1200 lives each year and resulting in over 1000 hospitalizations. While
the issue has been hotly debated in recent years, considerable research in an
international context suggests that there is a relationship between access to
firearms and deaths and injuries caused by firearms. Interventions to reduce
access to firearms include regulation, education and engineering. Legislative
reforms aimed at reducing gun deaths and injuries have been introduced recently
in Canada and in many other countries. Although domestic controls can affect the
supply of guns, efforts are being co-ordinated increasingly on an
interjurisdictional basis to decrease the illegal trafficking of firearms. As
well, the United Nations Crime Prevention and Criminal Justice Commission
recently passed a resolution encouraging all countries who have not done so to
strengthen their domestic gun controls since weak controls in one country can
affect security in others.
PMID- 9550734
TI - [Joint decisions, how? Physician-patient communication about palliative
chemotherapy].
AB - The discomfort and benefits of a medical treatment may be appreciated differently
by different patients. This is one of the reasons why patients should be informed
thoroughly and included in the decision-making about treatment. The obligation to
inform was laid down in 1995 in the Decree on the Medical Contract. In a case of
metastasized cancer of the prostate it was decided more or less by mutual
agreement between doctor and patient to administer palliative chemotherapy. It
appeared subsequently that the physician had short-term palliation in mind, and
the patient prolongation of survival. Although both are of the opinion that the
patient was included actively in the decision-making, this was in reality not at
all the case. The question arises whether the Decree on the Medical Contract does
not demand too much from certain patients regarding their capacity to make a
decision about the treatment of a terminal disease.
PMID- 9550735
TI - ['Public Health Status Forecasting 1997': the sum of the parts].
AB - The 1997 edition of Public Health Status and Forecasts, a comprehensive
epidemiological overview of the health of the Dutch nation, suggests some
important new strategies for the development of a more 'evidence-based health
policy'. The growing gap between life expectancy in general and healthy life
expectancy demands a stronger effort in the prevention of unhealthy lifestyles,
especially smoking. Many indicators of health show the first signs of decline for
the coming 10-20 years. The growing burden of chronic diseases and longlasting
handicaps points towards a doubling of the present yearly rise in the health
budget to at least 2%. Methodological innovations in measuring health effects are
a striking feature of the 1997 'explorations' report.
PMID- 9550733
TI - The supercoiling sensitivity of a bacterial tRNA promoter parallels its
responsiveness to stringent control.
AB - In Salmonella typhimurium, expression of the hisR locus, a tRNA operon, decreases
upon inhibiting DNA gyrase. Here, the hisR promoter dependence on negative DNA
supercoiling was examined in vivo and in vitro. Mutant analysis showed the
sequence determinants of this dependence to lie in the region between the -10 box
and the transcription start site. As with most promoters subject to stringent
control, this portion of the hisR promoter is C-G-rich. Replacing a C/G bp with
T/A at position -7 partially relieves the supercoiling response while changing
the sequence between -5 and + 1 (-CCCCCG-) for -GTTAA- abolishes the response in
vitro and in vivo. The relief of the supercoiling dependence closely correlates
with increased promoter susceptibility to melting in vivo and a lesser
requirement for initiating nucleotides in the formation of stable initiation
complexes in vitro. Studies in isoleucine-starved cells showed that such sequence
changes mitigate and abolish the hisR promoter response to stringent control,
respectively. The data presented suggest that the hisR promoter's sensitivity to
stringent regulation arises from the same physical property that confers
supercoiling sensitivity, i.e. resistance to melting. We propose that the
stringent control mechanism acts by hampering the ability of RNA polymerase to
melt the DNA helix.
PMID- 9550736
TI - [Developments in the treatment of patients with chronic myeloid leukemia].
AB - In the treatment of chronic myelocytic leukaemia (CML) allogeneic bone marrow
transplantation (BMT) from a sibling donor is the treatment of choice in patients
younger than 50 years; the overall 5-year survival is about 60%. Donor lymphocyte
infusion without chemotherapy may serve as an efficacious therapy for recurrence
of CML after allogeneic BMT. Application of allogeneic BMT from a matched
unrelated donor is increasing, but the outcome is still inferior to that of
sibling BMT, largely due to more severe and more frequent complications.
Treatment with interferon-alpha has been shown to prolong the overall median
survival, but especially in a subgroup of patients (about 15%) who achieve a
major cytogenic response. Combination of interferon-alpha and low-dose cytarabine
leads to increased survival and a better cytogenic response than interferon-alpha
alone. Current investigations are aimed at further improving survival and
cytogenic response by using more intensive chemotherapy, such as high-dose
cytarabine, followed by interferon-alpha maintenance therapy.
PMID- 9550737
TI - [Current developments in preventive health care].
AB - On the occasion of the publication of the second revised edition of the
Preventiegids (Prevention guide), some recent developments in preventive health
care can be analysed and priorities for the near future can be formulated. Some
controversies have been resolved (e.g. periconceptional use of folic acid,
influenza vaccination of all elderly), a number of others still exist (e.g.
postmenopausal oestrogen substitution, screening for hypertension and
hypercholesterolaemia). Further health benefit can be obtained by preventive
activities, albeit to a limited extent. The focus should be on correct
implementation (standardisation) of existing prevention programmes plus
evaluation, with improvements where possible. There will also be opportunities
for new prevention programmes (e.g. use of the triple test in screening for Down
syndrome). It will be possible to discontinue existing inefficient programmes
(e.g. routine pregnancy ultrasonography, routine administration of iron to
pregnant women.
PMID- 9550738
TI - [Frequency of decisions to forgo (artificial) administration of food and fluids
at life's end].
AB - OBJECTIVE: To determine the frequency and characteristics of decisions to forgo
(artificial) feeding and hydration with hastening of death as a possible result.
DESIGN: Retrospective, descriptive study. SETTING: The Netherlands. METHODS: Data
were collected from questionnaires mailed to physicians attending 6060 deaths
identified from death certificates dating from August through November 1995
(response rate: 77%). RESULTS: Decisions to forgo feeding and hydration preceded
8% of all deaths studied; for deaths attended by nursing home physicians this
percentage was 23%, for deaths attended by general practitioners and specialists
it was 4%. In 68% of all these death cases, the patients had been 80 years of age
or over, and 76% of them had been partly or completely incompetent. The non
treatment decision had been discussed with relatives in 82% of all cases, and in
89% of the death cases attended by nursing home physicians. These patients had
had (possibly) life-shortening medication less frequently than other patients for
whom a medical decision concerning the end of life had been made. CONCLUSION:
Decisions to forgo (artificial) feeding and hydration were made relatively often
by nursing home physicians, and rarely by general practitioners and specialists.
These decisions were usually but not always made after discussion with relatives.
There were no indications that these decisions entailed a great deal of suffering
for the patients.
PMID- 9550739
TI - [Spontaneous pneumothorax in young women: possible lymphangioleiomyomatosis].
AB - (Recurrent) pneumothorax developed spontaneously in three women aged 33, 35 and
36 years, two of whom were pregnant. Morbid-anatomical examination of lung biopsy
samples in two of them revealed proliferation of smooth muscle cells which
through infiltration of pleura, septa, and alveoli had led to loss of pulmonary
parenchyma and formation of cystic lesions; the cystic lesions were visible in a
CT scan in all three patients. The diagnosis in 2 patients was
'lymphangioleiomyomatosis'; the third patient had anomalies compatible with
lymphangioleiomyomatosis, but these were interpreted as tuberous sclerosis
because of the presence of renal angiomyolipomas. This disorder occurs
exclusively in women in the reproductive age. Treatment consisted in drainage of
the pneumothorax, pleurodesis and pleurectomy, with administration of medroxy
progesterone. One year later, the pneumothorax had not recurred.
PMID- 9550740
TI - [HIV/AIDS in The Netherlands: improved treatment possibilities necessitate HIV
instead of AIDS surveillance].
AB - An abrupt decrease of the number of reported new AIDS cases took place in the
first half of 1997 in the Netherlands. This decrease was most prominent in
homosexual/bisexual men and intravenous drug users, and less conspicuous in
heterosexual men and women. The number of heterosexual patients with a non-Dutch
nationality even increased compared with the first half of 1996. The most
probable explanation of these observations is the introduction of improved
treatment possibilities for HIV-infected people starting July 1996, which lead to
a longer incubation period. Owing to these developments monitoring the HIV/AIDS
epidemic in the Netherlands will depend more and more on HIV status surveillance
instead of on registration of new AIDS cases.
PMID- 9550741
TI - [Deep venous thrombosis of the right leg caused by compression by an abdominal
aortic aneurysm].
PMID- 9550742
TI - [Adverse effects of minocycline in the treatment of acne vulgaris].
PMID- 9550743
TI - [An innocuous prolonged unilateral nose blockage?].
AB - A woman aged 35 and a man aged 59 had been suffering for years from unilateral
clogged nose. Adequate diagnostic examination revealed in both of them a
papilloma inversum from which a squamous carcinoma had developed. After extensive
surgical resection of the tumour and irradiation, tumour progression and
metastasization occurred. Both patients were given palliative chemotherapy; they
died soon after the last course. Problems concerning nasal breathing are common
in general practice. They are often attributed to common cold or to an allergy.
Unilateral blocking of the nose is usually caused by a congenital or a traumatic
deviation of the nasal septum. However, in adult patients, it may rarely be due
to a tumour.
PMID- 9550744
TI - [Immunology in medical practice. IV. Inflammatory bowel diseases: pathogenic
starting points for specific therapy].
AB - The cause of inflammatory bowel diseases is unknown, but T-cells play an
important part in the pathogenesis of Crohn's disease. It was shown in recent
years that activated T-cells produce certain cytokines that cause inflammation
(interferon-alpha, tumour necrosis factor-alpha or TNF-alpha), but also cytokines
(interleukin-10 or IL-10, transforming growth factor-alpha) which on the contrary
inhibit inflammation. On the basis of this knowledge, the mucosal inflammatory
reaction can be counteracted in a rational manner: antibodies against TNF-alpha
in most patients with Crohn's disease who failed to respond to corticosteroids
led to substantial reduction of disease activity. The first experiences with IL
10 treatment of Chrohn patients are also encouraging. It is expected that in the
near future still more forms of immunotherapy directed against cytokines will
become available.
PMID- 9550745
TI - [Consequences of a bipolar disorder and use of mood stabilizers for its
management during pregnancy].
AB - For patients with a bipolar disorder who are pregnant or consider pregnancy, the
following issues are of importance: Genetic counselling: genetic vulnerability is
virtually certainly the basis of the occurrence of a bipolar disorder.
MEDICATION: discontinuation of the medication may lead to recurrence;
continuation may cause intoxications in the woman and her child and congenital
anomalies in the child. Alternatives to mood stabilizers can be applied;
electroconvulsive therapy is a possibility as is medication with antidepressants,
antipsychotics and benzodiazepines during acute episodes of mood disorder.
Precautions for mother and child if mood-stabilizing treatment is continued: use
sustained-release preparations, regularly check blood levels and thyroid
function, administer vitamin K if necessary, perform ultrasonoscopy/examination
of amniotic fluid, have the child delivered in hospital. Management of the
newborn child: observation, determination of blood levels, regular checks of
thyroid function, if necessary administration of vitamin K.
PMID- 9550746
TI - [The use of drugs to improve athletic performance].
AB - In sports, medical drugs are applied for supposedly ergogenic effects. Forbidden
drug use (doping) implies that the drug enhances performance, which is not always
the case. Amphetamines are ergogenic particularly during short-term, explosive
exercise. Amphetamines exert an ergolytic effect on high-intensity endurance
exercise. Caffeine has an ergogenic effect on endurance performance in dosages of
3 to 6 mg/kg. Doping regulations allow a small amount of caffeine intake.
Androgenic and anabolic steroids elicit an increase in muscle growth and
strength. In females low doses appear to be ergogenic in all sport types. beta 2
adrenergic agonists appear to have a positive effect on strength and muscle
growth. The effects on endurance performance are still unknown. Although growth
hormone is used in sports, scientific studies show that compared with placebo no
difference in strength and muscle volume is observed. Blood doping and
administration of erythropoietin are effective in enhancing endurance
performance.
PMID- 9550747
TI - [Left ventricular hypertrophy; differences in the diagnostic and prognostic value
of electrocardiography and echocardiography].
AB - OBJECTIVE: To compare the electrocardiogram (ECG) and the echocardiogram for
demonstration of left ventricular hypertrophy (LVH) and the prognostic values of
these methods. DESIGN: Literature study. SETTING: Department of General Practice,
Social and Nursing Home Medicine, R.C. University of Nijmegen, the Netherlands.
METHOD: Using articles retrieved by means of a search action in Medline (1962
January 1996), a study was made of the differences between determination of LVH
by ECG and by echocardiography with regard to the sensitivities and specificities
for measuring anatomical LVH, and their predictive values concerning
cardiovascular morbidity and mortality. RESULTS: The sensitivity of
echocardiography for the prediction of anatomical LVH (88-93%) exceeded that of
ECG (21-54%), while both methods had a high specificity (77-97%). ECG-LVH seemed
a better predictor of cardiovascular complications than echo-LVH. CONCLUSION:
Echocardiography is the better instrument for screening for LVH, but ECG should
keep its place in the diagnostics of LVH in view of its high predictive value for
morbidity and mortality and its availability to primary health care. In regard to
LVH, echocardiography measures only morphological disorders, while ECG also
detects functional disorders.
PMID- 9550748
TI - [Hemophagocytic syndrome].
AB - A lymph node biopsy sample from a boy aged with fever, pneumonia,
hepatosplenomegaly, lymphadenopathy and pancytopenia, showed histiocytosis with
erythrophagocytosis, compatible with the haemophagocytic syndrome. Treatment
consisted of dexamethasone and etoposide, with cyclosporine added in a later
phase. During the subsequent remission phase, bone marrow transplantation was
carried out. Haemophagocytic syndrome is a rare condition, characterized by
fever, pancytopenia, hepatosplenomegaly and characteristic laboratory findings
(including a high interferon-gamma level) and morbid-anatomical findings
(haemophagocytic histiocytic cells in bone marrow, lymph nodes, liver and spleen,
but also in the CNS, kidneys and lungs). Recent pathophysiological discoveries
indicate an enhanced T-cell response, leading to hypercytokinaemia. As a rule the
patient dies from multiorgan failure and diffuse intravascular coagulation. Bone
marrow transplantation is the treatment of choice.
PMID- 9550749
TI - [Excessive terfenadine level due to drinking grapefruit juice].
AB - Doctors who prescribe drugs should be aware not only of potential drug-drug
interactions, but also of potential food-drug interactions. In particular, the
ingestion of grapefruit juice leads to enhanced systemic bioavailability of
terfenadine and of several important and frequently prescribed other drugs.
Components of grapefruit juice interfere with the function of intestinal
cytochrome P450 3A4, which degrades terfenadine. The resulting enhanced blood
levels of terfenadine may lead to heart rate disturbances. Selling the drugs
involved over the counter is consequently risky.
PMID- 9550750
TI - [Cystic fibrosis: special value of treatment at a center].
AB - A woman aged 30 and a man aged 40, both with a bad general condition due to
cystic fibrosis, showed a clear clinical improvement after they were treated in a
cystic fibrosis centre, while in a young adult male patient the diagnosis of
cystic fibrosis could be rejected. In the Netherlands there are approximately
1000 patients with cystic fibrosis. As a consequence most doctors have hardly any
experience of the treatment of such patients. To optimize the treatment of
patients with cystic fibrosis, it would seem wise to concentrate experience and
knowledge in several cystic fibrosis centres.
PMID- 9550751
TI - [Eye-preserving treatment of uveal melanoma. Leidse Oogmelanoom Groep].
AB - Over 100 new cases of uveal melanoma are diagnosed annually in the Netherlands.
In the absence of metastases, eye-preserving treatment is possible in principle.
Since 1984, Dutch patients are referred for eye-preserving treatment to Leiden
University Hospital which consequently has gained great experience. Brachytherapy
(with Ruthenium-106 applicators) is only suitable for uveal melanomas with a
diameter < or = 15 mm and a prominence (thickness perpendicular to the sclera) <
or = 5 mm; after 10 years, the eye was preserved in 80% of the patients; 75%
retained a visual acuity > or = 0.25. Proton irradiation is being applied for
large, strongly prominent melanomas in patients for whom enucleation is not
acceptable, for instance with a melanoma in the only eye still functioning. The
eyes could be preserved in 83.3% over a period of 5 years. Transpupillary
thermotherapy combined with episcleral Ruthenium-106 application is called
sandwich therapy; in a study involving 50 patients, 49 melanomas (98%) began to
regress within 4 weeks and after a follow-up period of 12 months all tumours with
a prominence < 5 mm had regressed completely.
PMID- 9550752
TI - [Dysplastic nevi and the risk of melanoma: a guideline for patient care.
Nederlandse Melanoom Werkgroep van de Vereniging voor Integrale Kankercentra].
AB - Consensus was recently reached in the Netherlands regarding the clinical
management of dysplastic naevi and the definitions in clinical and pathological
diagnostics. The term 'dysplastic' is reserved for histological diagnostics; the
term preferred for clinical use is 'clinically atypical naevus'. A naevus is
defined as clinically atypical if it meets three of the following five criteria:
> or = 5 mm in diameter, vaguely bordered, asymmetrically shaped, irregularly
pigmented and a red hue (erythema). Presence of clinically atypical naevi is a
main risk factor for melanoma. Dysplastic naevus syndrome (DNS) is present if a
patient has a melanoma and one or several clinically atypical naevi. The
diagnosis of 'familial DNS' (familial atypical multiple mole-melanoma syndrome,
abbreviation FAMMM syndrome) is made if at least two close relatives (including
the patient) are known with a melanoma with or without atypical naevi, while one
or several (other) relatives have atypical naevi. The risk of melanoma in a gene
carrier of familial DNS is close to 100%, while multiple melanomas develop in 30%
of the gene carriers. No DNA diagnostics is yet possible in most DNS/FAMMM
families, because of the involvement of genes yet unknown. Accordingly, at
present it is still too early for DNA diagnostics. Currently, therefore, the
diagnosis is based only on anamnestic, clinical and histological grounds.
PMID- 9550753
TI - [2nd revised consensus skin melanoma. De Nederlandse Melanoom Werkgroep].
AB - The 'Guideline melanoma of the skin, second revised consensus' was published in
March 1997. Some of the contents are cited: Over 1600 new melanomas are diagnosed
in the Netherlands each year; by now the mean 5-year survival amounts to over
80%. In examination of a pigmented lesion a dermatoscope is a valuable tool. The
recommended margin of the diagnostic excision was reduced from 5 mm to 2 mm of
macroscopically normal skin round the lesion; the margins in definite excision
are: 1 cm of normal skin for a Breslow thickness < or = 2 mm; 2 cm for a Breslow
thickness > 2 and < or = 4 mm. A margin of at least 2 cm seems also justified for
thicker melanomas. Elective (prophylactic) regional lymph node dissection is
advised against. Sentinel node biopsy appears to be an attractive method to
detect occult metastasis in regional nodes. In lymph node metastasis a
(therapeutic) regional lymph node dissection should be performed. In case of
inoperable tumourgrowth in an extremity regional isolated perfusion is indicated.
Radiotherapy may be applied curatively (e.g. if surgery is not possible),
palliatively (if desired in combination with hyperthermia) or postoperatively (if
non-radical resection is suspected). Adjuvant systemic therapy in melanoma
patients is still experimental; the earliest results of high doses of interferon
alpha are encouraging. Atypical (dysplastic) naevi and congenital naevi are
important risk factors for melanoma. No consensus was reached regarding
prophylactic removal of all congenital naevi. Regarding the duration of the
follow-up period, 5 years suffices in patients with a melanoma with a Breslow
thickness < or = 1.5 mm (provided there are no histological signs of regression),
while 10 years is required for melanomas with a Breslow thickness > 1.5 mm. The
patient should be actively involved in the follow-up (inspection, palpation).
Routine blood testing, roentgen examination or ultrasonography are considered to
be useless. There are no indications that hormonal alterations during pregnancy
or use of the pill stimulate the growth of micrometastases that may be present.
Excessive exposure to ultraviolet rays is discouraged.
PMID- 9550754
TI - [The white coat in pediatrics: link between medical history and preference for
informally dressed physicians].
AB - OBJECTIVE: To find out if children show a preference for a doctor in a white coat
or an informally dressed doctor, and what factors influence this preference.
Further to determine if children show a preference for a physician of their own
or of the other sex. METHOD: A series of 20 pairs of photographs showing varying
combinations of a male and a female doctor in a white coat or in informal dress
was presented to test subjects: 37 children without a medical history, 28
children with a minor and 16 with an extensive medical history, aged between 6
and 12 years. Out of each pair of photographs, the test subjects were invited to
choose the doctor they would prefer. RESULTS: On average, the test subjects opted
for a doctor in a white coat more often than for an informally dressed doctor (p
< 0.05). There was a significant difference in dress preference between children
with a less and with a more extensive medical history (p = 0.001): children with
no medical history more often chose a doctor in a white coat. Children with an
extensive medical history more frequently showed preference for informal dress.
The children opted more frequently for a doctor of their own sex (p < 0.001).
CONCLUSION: The preference of children for a doctor in a white coat or for an
informally dressed doctor depended on their medical history. The more extensive
the medical history, the more the preference shifted to an informally dressed
doctor. Also, the children preferred a doctor of their own sex.
PMID- 9550755
TI - [Prader-Willi syndrome in a young infant].
AB - Four children aged 2.5 years, 15.7 and 7 months, including a pair of twins, after
birth displayed hypotonia which necessitated tube feeding. Other features were a
narrow forehead and a thin triangular upper lip, but these abnormalities were not
conspicuous. An extensive supplementary examination for cerebral and muscular
disorders initially failed to produce a diagnosis. It was only when the Prader
Willi syndrome was suspected and a corresponding abnormality on chromosome 15 was
looked for that this diagnosis could be made. Early diagnosis of this syndrome
will avoid further invasive diagnostic procedures and make early treatment
possible.
PMID- 9550756
TI - [Arthritis caused by use of rifabutine++ in Mycobacterium avium infection].
AB - A 60-year-old HIV-seronegative man with a Mycobacterium avium pulmonary infection
was treated with rifabutin, ethambutol and clarithromycin. He developed a serious
arthritis which disappeared after interruption of the medication and recurred
after resumption. The arthritis was attributed to the use of rifabutin. This
adverse effect is more frequent with higher doses and in combination with the use
of macrolide antibiotics.
PMID- 9550757
TI - [Zidovudine-resistant HIV strains in untreated intravenous drug users and
homosexual men in Amsterdam infected in 1996].
AB - OBJECTIVE: To gain insight into the spread of HIV strains with different
sensitivities to antiretroviral drugs prescribed in the Netherlands. DESIGN:
Prospective cohort study in intravenous drug users and homosexual men. SETTING:
Amsterdam, the Netherlands. METHODS: HIV negative participants in the Amsterdam
cohort studies among homosexual men and intravenous drug users are tested two to
three times a year for HIV antibodies. The first positive serum sample of those
who seroconverted was used to determine, on the basis of the nucleotide sequence
of the reverse transcriptase gene of HIV, if viruses were present with a reduced
sensitivity to reverse transcriptase inhibitors. RESULTS: In 1996, 17 new HIV
infections occurred (8 in homosexual men and 9 in intravenous drug users). In two
new infections in homosexual men HIV strains with reduced sensitivity to
zidovudine were present.
PMID- 9550758
TI - [More rapid recovery and fewer recurrences following laparoscopic inguinal hernia
surgery than after conventional surgery; a prospective, randomized study].
PMID- 9550759
TI - [More rapid recovery and fewer recurrences following laparoscopic inguinal hernia
surgery than after conventional surgery; a prospective randomized study].
PMID- 9550761
TI - [Scratching for the itch in eczema; a psychodermatologic approach].
AB - Atopic dermatitis patients often complain of intense itching and excessive
scratching. Apart from standard therapies of antihistamines with sedative side
effects, there are patients who appear not to respond satisfactorily to standard
medical treatments. As itching can be a skin manifestation of psychological
disturbance, these patients may benefit from behaviour treatment of scratch
behaviour which can have a beneficial effect on the course of atopic eczema. The
scratch response is considered a classical conditioned habit and special
attention was given to the function of behaviour. Two patients, a man of 27 and a
girl of 11, were suffering from intractable atopic eczema. The first patient was
required to record his own scratching in a diary which is part of awareness
training regarding scratch situations. In the second patient impaired parent
child relationships were the main discriminative stimuli to provoke scratch
behaviour. It was shown that behaviour therapy helps patients who scratch
repeatedly to exercise voluntary control over it.
PMID- 9550762
TI - [Dutch drug registration: greater openness is urgently desired].
AB - The centralized European registration of drugs is characterized by relative
openness, like the publication of public assessment reports. In our country the
registration authorities should also be more focused on the users and become more
accountable for their decisions. Then, in their daily practice, the prescriber
and pharmacist can make better use of the available expertise.
PMID- 9550763
TI - [Immunology in medical practice. V. Constitutional eczema].
AB - Constitutional eczema (late atopic dermatitis) is a frequent condition: some 30%
of the skin diseases seen by the GP involve constitutional eczema. A number of
links with (external) factors have meanwhile been established. Patients with
constitutional eczema often suffer from food allergy (over 60% of the children
with the eczema) and many are allergic to airborne allergens (especially
housedust mite allergen). The skin of patients with constitutional eczema has a
diminished barrier function against irritants (soaps, acids, bases, water,
detergents, biological juices (fruit, meat, fish, vegetables). In 90% of the
patients with constitutional eczema the skin contains colonies of Staphylococcus
aureus (in 5% of people without eczema). S. aureus can influence the eczema
through exoantigens (so-called superantigens) and through conventional antigens
that may evoke an IgE-mediated immune response. Emotional stress may influence
the eczema. The close anatomical relationship between mast cells and nerve
endings and between Langerhans cells and nerve endings suggest that the
autonomous nervous system can modulate the immune system of the skin and
consequently, the eczema. These factors should be taken into account in the
treatment: reduction of exposure to food and airborne allergens and to irritants,
treatment and prevention of S. aureus infections and psychological support. New
therapies include cyclosporine, autologous IgG antigen complexes and
phototherapy.
PMID- 9550764
TI - [High-dose chemotherapy followed by hematopoietic stem cell transplantation as
therapy for systemic rheumatic autoimmune diseases].
AB - Remissions of autoimmune diseases can be accomplished in animals by myeloablative
chemotherapy followed by allogeneic or autologous bone marrow transplantation.
Remissions of autoimmune diseases have been reported in patients with concomitant
malignancies for which they were treated with myeloablative chemotherapy followed
by stem cell transplantation. Survival of patients with systemic rheumatic
autoimmune disease is reduced. Since transplantation related mortality after
autologous stem cell transplantation is less than 5%, this treatment becomes a
possibility for patients with severe systemic rheumatic autoimmune disease, such
as systemic sclerosis.
PMID- 9550765
TI - [Usefulness of the 'Mini-Mental State Test'for the diagnosis of dementia; study
of criterion validity in a Dutch rural population].
AB - OBJECTIVE: To establish the criterion validity of the MMSE for dementia in a
community-based population. DESIGN: Descriptive. SETTING: Eight rural general
practices and eight adherent institutions for long-term care near Zwolle, the
Netherlands. METHODS: In the first (screening) stage, the MMSE was applied, in
the second (diagnostic) stage the 'Cambridge examination for mental disorders of
the elderly' (CAMDEX) was used. After exclusion of subjects with clinically
relevant impairment of hearing and (or) vision, analyses were based on 2151
screened subjects. Based on a non-proportional, stratified randomized sampling
procedure using the MMSE score as the stratification variable, 390 of the
screened subjects were examined with the CAMDEX. Seventy-seven cases of DSM-III-R
dementia were identified. Based on 390 paired observations the relationship
between MMSE score and DSM-III-R dementia was modelled by logistic regression.
After extrapolation of this relationship to the total screened population,
sensitivity and specificity figures were calculated at several cut-offs of the
MMSE, and Receiver Operating Characteristic (ROC) curves were constructed for the
total population as well as for four subpopulations. (men, women, < 80, > or = 80
years). RESULTS: At the cut-off of 23/24, sensitivity was 0.76 and specificity
0.91 in the total population. However, the criterion validity of the MMSE varied
substantially between the four sex-age combinations. Criterion validity was
especially poor for women in the younger age range. CONCLUSION: The MMSE has only
limited value in clinical practice. Use of uniform cut-offs has to be rejected.
PMID- 9550766
TI - [Inguinal hernia in a young girl; sporadic manifestation of testicular
feminization].
AB - Examination of a woman aged 17 years with primary amenorrhoea revealed normal
breasts and external genital organs, hardly any axillary or pubic hair growth, a
blind vaginal pouch and no palpable uterus or adnexa. At additional examination,
uterus and adnexa proved to be absent, the serum testosterone concentration was
substantially increased and the karyotype was 46,XY. The diagnosis was
'testicular feminization' (androgen insensitivity syndrome). The patient in
childhood had undergone a bilateral inguinal hernia operation, at which 'ovaries'
were found in the hernial sacs. It might have been interpreted as the first sign
of the syndrome; such a finding necessitates further examination. Most patients
with testicular feminization seek medical advice because of primary amenorrhoea.
Early diagnosis is important because the risk of malignant degeneration of the
intra-abdominal testes increases with advancing age (sometimes also in
relatives). Also it makes it possible gradually to prepare the child for her
future.
PMID- 9550767
TI - [Endometriosis in the round ligament of the uterus as a cause of inguinal pain].
AB - Within one year three patients, women aged 31, 28 and 26 years, presented with a
cyclic painful small mass in the inguinal region. Histopathological examination
of the resected specimen showed a pattern consistent with an extra-abdominal
localization of endometriosis in the round ligament. The patients' complaints
disappeared after surgical resection. It is concluded that in case of a painful
mass in the inguinal region in a fertile woman endometriosis of the round
ligament should be considered.
PMID- 9550768
TI - [Acute perceptive hearing loss and metabolic acidosis as complications of the
topical treatment of psoriasis with salicylic acid-containing ointment].
AB - A 36-year-old woman, hospitalized because of an exacerbation of psoriasis,
developed fever, sudden deafness and severe metabolic acidosis after treatment
with a 10% salicylic acid containing ointment for four days. The use of salicylic
acid on large areas of inflamed skin enhances the risk of transcutaneous
resorption and intoxication. High serum concentrations (> 300 mg/l) of salicylic
acid deregulate the blood glucose metabolism and cause damage to the inner ear.
After timely intervention such symptoms are largely reversible.
PMID- 9550769
TI - [Stimulation Program Health Research. XI. Evaluation of the section
'Rehabilitation Medicine'].
AB - As a part of the SGO Health Research Promotion Programme a research programme on
rehabilitation medicine was realized. Aim of the programme was to strengthen
clinical research in this field by training clinical researchers and improving
clinical research infrastructure. Three clinical specialists have been trained to
become senior clinical researchers by a 4-year training programme, concentrated
within 2 clusters of a medical faculty, a university hospital and one or more
centres for rehabilitation medicine. As a follow-up to the programme a 6-week
educational course was developed for intending MDs in rehabilitation medicine and
five intending rehabilitation medicine specialists receive a PhD research
training during their clinical specialisation.
PMID- 9550770
TI - [Pain control in the terminal stage of life].
AB - A 67-year-old woman suffered from terminal cancer as a consequence of local
recurrence of endometrial carcinoma which had been treated by hysterectomy. She
had excruciating pains and was requesting euthanasia. Advanced techniques for
pain relief e.g. intrathecal administration and nerve blocks resulted in adequate
relief and postponed the request. Besides knowledge and skill, the application of
these techniques requires a logistic network in the home situation. An
alternative therapeutic approach for this patient would have been continuous
intravenous administration of morphine, which would have implied accepting an
earlier death. The Dutch National Inquiry on euthanasia and life ending
interventions revealed that in 19.1 per cent of the overall mortality in the
Netherlands, pain treatment had contributed to death. In 1.4 per cent (1900 cases
per year) death was even the main goal of pain treatment. A wider application of
advanced pain relieving techniques can diminish requests for euthanasia in the
Netherlands and also can curtail mismanagement of pain. An advice from 1991 of
the National Health Council for better hospital support for terminal patients in
the home situation is still awaiting implementation.
PMID- 9550771
TI - [Vulvodynia caused by vulvar vestibulitis syndrome].
AB - Vulvodynia is a puzzling disorder. Patients experience clear physical complaints
of vulvar burning. Often they have consulted many physicians and tried all kinds
of treatment. Vulvodynia is often caused by the vulvar vestibulitis syndrome
(VVS). To detect VVS an extensive medical and psychosexual history is necessary.
Thorough examination of the vaginal vestibule reveals the typical focal
erythematous lesions. The aetiology of VVS is unknown. Of the many causal and
perpetuating factors a sexual arousal disorder and pelvic floor hypertonia are
the main ones. The psychodynamic aspects of these two core symptoms are principal
issues in diagnosis and treatment of VVS. Treatment should include all physical,
psychological, relational and sexual aspects of the problem. Surgical
interventions should be limited to those rare cases in which an integrative
approach fails to free the patient from the vicious circle of pain, anxiety and
muscle tension.
PMID- 9550772
TI - [Effect of protein restriction on deterioration of kidney function].
AB - The results of meta-analyses and of the recent 'modification of diet in renal
disease' study show that dietary protein restriction slows down deterioration of
renal function in patients with a moderately impaired renal function. However,
this effect appears to be less pronounced than previously assumed. Protein
restriction probably leads to narrowing of the preglomerular blood vessel, which
reduces the raised intraglomerular pressure. The resulting decrease in the
filtering glomerular pressure initially leads to a slight loss of renal function,
but there after to a decelerated deterioration of renal function. The aim should
be a protein intake of 0.6-0.75 g per kg per day. Dietary compliance should not
be predicted anamnestically but should be calculated according to the (modified)
Maroni equation (protein intake = (0.18 x urinary urea excretion in mmol per 24
hours) + 15 + urinary protein excretion in g per 24 hours). This kind of protein
restriction as a rule does not lead to nutritional deficiencies.
PMID- 9550773
TI - [Multidisciplinary treatment of cerebral arteriovenous malformations: preliminary
results in 115 consecutive patients].
AB - OBJECTIVE: Preliminary evaluation of the combined treatment (surgery,
embolization and stereotactic gamma radiosurgery) of 115 consecutive patients
with a cerebral arteriovenous malformation (AVM). DESIGN: Retrospective. SETTING:
St. Elisabeth Hospital, Tilburg, the Netherlands. PATIENTS AND METHODS: In a 35
month period 115 consecutive patients presented with an AVM. The mean age was
41.8 years (range: 6-72). The main clinical presentation was haemorrhage in 65
patients (56.5%), seizures in 31 patients (27.0%), neurological deficit in 7
patients (6.1%) and hydrocephalus in 2 patients (1.7%); in 10 patients (8.7%) the
AVM was an incidental finding. Treatment consisted of surgery, radiosurgery with
the gamma knife and embolization. Embolization was mostly used to reduce the size
of an AVM before surgery or radiosurgery. RESULTS: Out of 115 patients 5 were
referred for a treatment advice only and treatment was performed elsewhere. Of
the remaining 110 patients 84 (76.4%) were treated and 26 (23.6%) were not
treated for various reasons. Of the 84 treated patients 17 (20.2%) had surgery
only, 17 (20.2%) had radiosurgery only, and 12 (14.3%) were treated with
embolization only. Surgery after embolization was performed in 8 patients (9.5%)
and radiosurgery after embolization in 26 patients (31.0%). In 4 patients an
unusual combination of these treatment methods was used for a variety of reasons.
At the time of writing 35 of 84 treated AVMs (41.7%) were completely cured, 39
patients were awaiting the definitive result of radiosurgery. Deliberate partial
embolization was performed in 5 patients. In 5 patients (6.0%), the pretreatment
objective was not achieved with embolization. Total permanent morbidity was 4.8%
(4 patients) and mortality was 1.2% (1 patient). CONCLUSIONS: Given a
multidisciplinary combination of treatment methods a treatment is indicated and
possible in the majority (76.4%) of patients with an AVM. There is a reasonable
chance of a complete cure with an acceptable complication rate.
PMID- 9550775
TI - [Invagination in adults].
AB - Two adult patients with intussusception were both diagnosed by colonoscopic
investigation. The first patient, a woman aged 39, suffered from persisting
abdominal discomfort with nausea and vomiting. Ultimately an ileo-ileocolic
intussusception caused by an inflammatory fibroid polyp of the ileum was found.
The other patient, a man of 79 years, complained of subacute cramping pain in the
right lower abdomen. This was due to an ileocolic intussusception caused by an
adenocarcinoma of the cecum. Both patients underwent an ileocecal resection;
their postoperative courses were uneventful.
PMID- 9550776
TI - [Sodium polystyrene sulfonate (Resonium A) as possible cause of rectal blood
loss].
AB - A 67-year-old man underwent laparotomy for a ruptured aneurysm of the abdominal
aorta. Postoperatively he was treated with haemodialysis because of
perioperatively developed acute renal failure. Hyperkalaemia was temporarily
treated with sodium polystyrene sulfonate (Resonium A) after which he lost blood
per rectum. A hemicolectomy was necessary because of intractable blood loss due
to ulceration of the colon. This complication is related to uraemia and the use
of sodium polystyrene sulfonate with or without sorbitol.
PMID- 9550777
TI - [Antithrombotic treatment following acute ischemic heart disease: acetylsalicylic
acid and (or) oral anticoagulants?; ASPECT-II, a new study].
AB - In order to compare the efficacy and safety of three regimens of long-term
antithrombotic treatment in patients with acute ischaemic syndromes, a
prospective, randomized, open-label, multicentre study is being conducted in
which 60-70 Dutch hospitals will participate. Eligible patients discharged
following hospitalization for acute myocardial infarction or unstable angina
pectoris are randomly assigned to receive either (a) adjusted full intensity oral
anticoagulation (target range: 3.0-4.0 International Normalised Ratio (INR), (b)
low dose aspirin or (c) combined therapy of low dose aspirin and adjusted low
intensity oral anticoagulation (target range INR: 2.0-2.5). It is planned to
enroll 8,700 patients within three years. During an estimated mean follow-up of
2.5 years the evolutions of total mortality, non-fatal myocardial infarction, non
fatal stroke and major bleeding complication will be assessed.
PMID- 9550778
TI - [Appeal for the reporting of unpublished clinical research].
PMID- 9550779
TI - [At which childbirth should endocarditis prophylaxis be given?].
PMID- 9550780
TI - [The maxillary sinus and odontogenic cysts].
AB - An unilateral maxillary sinusitis is frequently caused by dental pathology. An
odontogenic cyst in the maxillary sinus usually lacks accompanying symptoms of
infection. In three patients, a 35-year-old man and two women aged 16 and 28, an
odontogenic cyst in the maxillary sinus was diagnosed. Consultation of a
maxillofacial surgeon is needed because orthopantomographic imaging is
diagnostically most helpful. In these patients combined treatment by an ENT
surgeon and a maxillofacial surgeon is important.
PMID- 9550781
TI - [Indications for influenza vaccination in children with lung disorders. Dutch
Association for Pediatric Medicine].
AB - The Dutch Association for Paediatric Medicine has formulated guidelines regarding
influenza vaccination of children with pulmonary disease. Influenza virus is the
most frequent cause of airway infections in humans over two years of age. It may
lead to serious morbidity in children with pulmonary disease: exacerbations,
(transient) disturbances in pulmonary function, and symptoms lasting weeks, but
mortality is probably very low. The effects of influenza vaccination of children
with pulmonary disease are similar to those in normal healthy children. A
positive long-term effect on the asthma has never been demonstrated. It is
advised that children with moderate to severe asthma who require treatment to be
vaccinated against influenza every year. If the first vaccination ever occurs
before the age of six years, it should be followed by a booster vaccination after
four weeks. In both instances, a full vaccination dose should be administered.
PMID- 9550782
TI - [Bisphosphonates in the treatment and prevention of bone metastases].
AB - Bone metastases occur frequently in cancer and are commonly associated with bone
degradation due to the tumoral production of factors which stimulate the
development and activation of osteoclasts. During osteolysis growth factors are
released which stimulate tumour growth. Bisphosphonates inhibit osteoclastic bone
resorption. Recently, in several large randomised studies of patients with
multiple myeloma or bone metastases of breast cancer, long-term treatment with
clodronate or pamidronate gave significant bone protection.
PMID- 9550783
TI - [Treatment of asthma in children; revised guidelines by pediatric pneumologists.
Section of Pediatric Lung Diseases of the Dutch Association of Pediatric
Medicine].
AB - The diagnosis of 'asthma' is still based on anamnesis, physical examination and
lung function tests. Supplementary examinations (laboratory or roentgen) are
carried out only if indicated. Most young children with recurrent periods of
wheezing and coughing prove not to develop asthma in the long run. Oral
medication no longer has a place in the treatment of asthma, since inhalation
medication is now possible at all ages, among other things because of the current
availability of new nozzle attachments. Every child with asthma should have a
short-acting beta 2-agonist at hand. Furthermore, inhaled corticosteroids are the
maintenance drug of choice in children with moderate or severe asthma. Systemic
effects may occur with every inhaled corticosteroid, even with dosages usual for
children, but these are rarely relevant. Cromones nowadays play a very limited
part. Long-acting beta 2-agonists are indicated in children whose asthma cannot
be controlled with standard doses of inhaled corticosteroids. In the prevention
of allergic asthma of childhood, prescription of the allergen-tight mattress
cover plays a main part. The physician has an important task in discouraging
(passive) smoking. Young children who, in spite of treatment with inhaled
corticosteroids, have recurrent episodes of wheezing and coughing. and children
requiring high doses of inhaled corticosteroids (over 400 micrograms
beclomethasone/budesonide or 250 micrograms fluticasone) should be referred to a
paediatrician. The asthma nurse has an important task in instructing and advising
the asthmatic child and its parents. Self-management programmes may be of great
psychological value for the patient and his environment.
PMID- 9550784
TI - [Lung transplantation in children].
AB - The first lung transplantation in the Netherlands was carried out in 1990. Since,
the operation has been performed in over one hundred adults and two children (up
to 16 years) with chronic respiratory insufficiency. Most lung transplantations
in children are performed because of cystic fibrosis. After referral, the patient
is given information about the operation and the pre- and postoperative periods,
and the transplantation team advises on the time of screening. Some one-third of
the children referred ultimately undergo transplantation; the others refrain from
the operation, are rejected or die during the waiting period. Owing to a shortage
of donor lungs the waiting period for transplantation may last over one year. A
possible but controversial solution is donation of a pulmonary lobe by a close
relative. Undergoing lung transplantation places a heavy (psychic) burden on the
patient and his parents. Every patient after lung transplantation goes through an
average of two or three periods of acute rejection. Chronic rejection occurs in
20-40%. Other complications are connected to medication (infections, renal
dysfunction) or to the underlying disease (diabetes mellitus in cystic fibrosis).
The percentages of survival for 1, 2 and 4 years are approx. 60-70, 55-60 and 30
50, dependent in part on the type of lung transplantation (unilateral, bilateral
or combined heart-lung transplantation). A reasonable condition of the patient
owing to timely referral is a positive prognostic factor.
PMID- 9550785
TI - [Clinical judgment and decision making in medical practice. A patient with
shoulder symptoms].
AB - A 49-year-old man consulted his general practitioner because of left shoulder
pain. Analgesics brought no relief. He had a numb feeling in the left axilla.
Cervical MRI revealed a herniated disc Cv-Cvi, for which the patient was treated
surgically. However, the pain persisted. In retrospect, the axillary numbness
could not have been caused by a Cv-Cvi problem, because C6 does not innervate the
axilla. Repeated MRI, now of the cervicothoracic region, revealed a tumourous
process around TI-TII. Thoracotomy was performed and a mesothelioma was found.
The patient died shortly afterwards. It is stressed that the diagnostic
satisfaction of a positive MRI finding should not lead to disregarding
discrepancies between these radiological results and the clinical findings.
PMID- 9550786
TI - [Epidemiology of prenatal diagnosis and selective pregnancy termination because
of fetal neural tube defects in The Netherlands in comparison to other European
countries].
AB - OBJECTIVE: To describe the epidemiological impact of prenatal diagnosis and
selective abortion on the frequency of neural tube defects (NTD) in the period
1980-1992 in the Northern Netherlands in comparison with data from other European
regions. DESIGN: Descriptive. SETTING: 17 'European registration of congenital
anomalies' (EUROCAT) registrations, localized in 10 European countries. METHOD:
Data were collected actively and retrospectively from multiple sources fed by
voluntary registration of congenital anomalies in live births, stillbirths and
pregnancies terminated because of congenital anomalies. RESULTS: In Europe the
total birth prevalence of NTD in the period 1980-1992 ranged from 5.3 per 10,000
in Switzerland to 29.0 per 10,000 in Glasgow, a difference of a factor 5.5. In
live births the difference was ninefold: ranging from 2.0 per 10,000 in Paris to
18.8 per 10,000 in Dublin. The Netherlands had a conspicuously high prevalence
among live births, higher than in other regions in continental Europe. For spina
bifida the live birth prevalence both in other continental regions and in Glasgow
was also lower than in the Netherlands. In Glasgow serum alpha-foetoprotein
screening apparently led to frequent early prenatal diagnosis of NTD and to
frequent termination of pregnancy. In Paris the use of ultrasound screening
appears to lead to frequent later prenatal diagnosis, as well as frequent
termination of pregnancy. CONCLUSION: In the Netherlands the impact of prenatal
diagnosis and selective abortion is limited, so that primary prevention
(periconceptional use of folic acid) is more important than in some other
European countries.
PMID- 9550787
TI - [Heart tamponade: a life-threatening complication of a central venous catheter].
AB - A 57-year-old female patient initially admitted with acute pancreatitis became
extremely hypotensive, with increased central venous pressure, a few hours after
insertion of a central venous catheter into the right subclavian vein.
Echocardiography revealed a large amount of pericardial fluid, which was removed
by pericardiocentesis. A cardiac tamponade as a result of central venous
cannulation is a rare but serious complication with a high mortality rate. The
tamponade may be the result of perforation of the V. cava superior, the right
atrium or the right ventricle (as in the patient described). Cardiac tamponade
should be suspected in any patient with severe hemodynamic problems after
insertion of a central venous line.
PMID- 9550788
TI - [Residents not-in-training and hospital physicians: the pariahs in the
hospital?].
AB - Patient care in Dutch hospitals is performed by medical specialists and residents
in training for the various specialties. In addition there is an increasing
number of young physicians who are not (yet) in training: this category has
arisen because of a restriction of the number of medical specialists. Recently a
new career has been put forward in advertisements, offering training for
positions at a level below that of the traditional medical specialists. This
development is worrisome in view of the quality of patient care and the
perspectives of young doctors.
PMID- 9550789
TI - [MRI recommended for patients with axillary lymph node metastases from an occult
breast carcinoma].
PMID- 9550790
TI - [Pleurodesis in malignant pleural effusion].
PMID- 9550791
TI - [The 'medical work disability criterion'].
PMID- 9550792
TI - [Too old for diagnosis or treatment?].
AB - In three patients, two men aged 84 and 80, and a women aged 88, physicians had
advised against further diagnostic examination or treatment, mainly because of
the advanced age. One of the patients was not satisfied with his deterioration
and asked for further examination, the other two were brought to the hospital by
relatives in order to be further examined. In all three cases, additional
investigation revealed treatable disorders (Crohn's disease, depressive disorder
and complications of Parkinson's disease). It is argued that very old age as such
is not a sufficient reason to refrain from further diagnostic investigation or
treatment. Sufficient reasons are (a) certainty with respect to the diagnosis,
(b) knowledge of technical aspects of diagnosis and treatment, notably regarding
potential yield and stress for the patient, and (c) approval by the patient, his
representative or family members.
PMID- 9550793
TI - [Treatment of genital prolapse in very old women].
AB - An until recently mobile woman of 86 years developed problems with independent
living because of a genital total prolapse. After treatment by high perineoplasty
she was once more able to resume her social activities. In very old women a
genital prolapse can lead to significant morbidity due to hygienic problems and
increase of social loneliness due to impairment of mobility. Use of a pessary is
rarely an acceptable solution because of ulceration of the vaginal wall. Surgery
can be modified because preservation of vaginal function is hardly necessary
after the age of eighty. Efficient control of complaints can be achieved by
Labhardt high perineoplasty or Le Fort partial colpocleisis. Before such types of
operation cytology and ultrasonography of the uterus must be performed to exclude
a malignancy with reasonable certainty. Both operations can be done under local
anaesthesia with very short hospitalization.
PMID- 9550794
TI - [Diagnosis and treatment of non-Hodgkin lymphoma in elderly patients].
AB - Non-Hodgkin's lymphoma (NHL) is relatively frequent among elderly patients: more
than half of the diagnoses in the Netherlands concern patients aged 65 years or
above. The treatment depends on histological type, clinical stage and prognostic
group. Increasingly, a treatment decision is made after determination of the
prognostic group on the basis of the expected response and survival. In elderly
patients intensive treatment frequently has more toxic effects. The expected gain
in survival has to be weighed against more toxicity and loss of quality of life
during and after the therapy. This is notably important for patients with low
grade NHL, which requires only intermittent treatment. It is possible to cure
some elderly patients with NHL of intermediate or high grade malignancy provided
they are adequately treated with combination chemotherapy. Patients with low
grade NHL or poor clinical condition may benefit temporarily from palliative
treatment, in the planning of which quality of life has to be taken into account.
PMID- 9550795
TI - [Treatment of elderly patients with acute myeloid leukemia].
AB - More than 50% of patients with acute myelogenous leukaemia are 60 years or older.
Unlike the results of treatment of younger adults, the outcome in patients of
higher age has been disappointing because intensive chemotherapy is tolerated
less well, complications due to cardiac and pulmonary comorbidity occur sooner,
toxicity due to reduced hepatic and renal function occurs earlier and older
patients often present with leukaemia that is intrinsically of higher risk (e.g.
unfavourable cytogenetics). Remission-induction therapy with an anthracycline
derivative and cytarabine results in complete remission rates of approximately
50% in older patients; 15-20% of these remain free of leukaemia beyond 2-3 years
and have a good quality of life. The clinical use of hematopoietic growth factors
as adjuncts to chemotherapy to reduce complications and improve survival has not
(yet) fulfilled his promise. By selecting older patients without major
comorbidity for therapy and assessing the response to a first cycle of
chemotherapy one may identify patients with the best response to treatment and
avoid continued therapy in patients with poor prognosis. In this way the choice
of treatment of the individual older patient can be optimized.
PMID- 9550796
TI - [Infections in elderly patients].
AB - Infections are an increasing problem in the elderly population, because of the
often atypical presentation and the more frequent occurrence of complications,
which lead to increased morbidity and mortality. The increased prevalence of
infections in the elderly is due to a number of factors: increased exposure to
micro-organisms (especially in nursing homes); degeneration of various organs
(atherosclerosis, pulmonary emphysema, diverticulosis, prolapse); decreased
immune response; concomitant diseases (e.g. diabetes mellitus) and (or) use of
medication. There is often a delay in the diagnosis because the presentation of
infection in the elderly is frequently atypical and symptoms are attributed to
old age, rather than to infection. Treatment may be hampered by increased
resistance of micro-organisms, interaction with other drugs and toxicity
problems.
PMID- 9550797
TI - [Aging and cardiology; various physiological, pathophysiological and clinical
aspects].
AB - The main cardiovascular effect of aging is a rise of the systolic blood pressure
due to reduced impedance of the central arteries. The resulting increase of the
afterload leads to hypertrophy, increased rigidity and lengthening of the
relaxation period in the left ventricle. The manifestations of ischaemia or
arrhythmias are often atypical at more advanced ages and may delay diagnosis.
Ejection murmur due to stenosis of the aortic valve, to calcification or
degeneration, may be difficult to distinguish from a functional murmur. The cause
of heart failure is usually coronary sclerosis and, less often, hypertension or a
valvular defect. Systolic heart failure is associated with decreased
contractility of the left ventricle and compensatory dilation, diastolic heart
failure with reduced filling of the ventricles. Both forms respond well to acute
treatment with antihypertensive, diuretic and (or) vasodilator drugs; the
treatment in isolated diastolic heart failure should also focus on lowering the
increased blood pressure and reducing the heart rate to increase the filling
phase.
PMID- 9550798
TI - [Daily functioning and health care utilization among persons 85 years old and
older].
AB - OBJECTIVE: Description of the activities of daily living and the use of care in
relation to several determinants in persons aged 85 years and over. DESIGN: Cross
sectional survey. SETTING: General population from the city of Leiden, the
Netherlands. METHOD: A representative sample from the inhabitants aged 85 years
and over of the city of Leiden was enrolled. A physician visited 239 'oldest old'
(response rate 83%) at their places of residence, in 1991/'92. Data were obtained
on health (joint disorder, cardiovascular disease, diabetes mellitus, Parkinson's
disease; disorders in cognition, eyesight, hearing; limitation of mobility), self
care and household activities in daily living and the use of care (informal care
by neighbours or family, (geriatric) home help, district nurse, private help).
Statistical analysis was performed by non-parametric tests and logistic
regression. RESULTS: Of the 'oldest old' 111 (46%) lived independently, and 67 of
them (28% of the total group) had no professional help. Almost all 'oldest old'
had at least one health disorder. In all, 129 women (77%) and 43 men (61%) had
restrictions in basic and (or) instrumental activities of daily living. These
restrictions were strongly related to disorders in cognition, vision and
mobility, less related to chronic disease and not related to hearing disorders.
Restrictions in the activities of daily living were also related to the living
condition. This relation was particularly strong for women. Men living without a
partner were more likely to be institutionalised. Among the 'oldest old' who
lived independently, restrictions in the activities of daily living were related
to the use of care, with the exception of privately organised care. CONCLUSION:
One out of four persons aged 85 years and over lived without professional help.
Marked differences between the sexes were found for the interrelation between
activities in daily living and the use of care.
PMID- 9550799
TI - [Subnormal vitamin B6 levels in theophylline users].
AB - OBJECTIVE: To study the effect of theophylline use on the vitamin B-6 status.
DESIGN: Descriptive. SETTING: Department of Geriatric Medicine of Nijmegen
Academic Hospital and Department of Pulmonary Diseases, University of Nijmegen,
the Netherlands. PATIENTS AND METHODS: Vitamin B-6 status was determined by
measuring pyridoxal-5'-phosphate (PLP) in whole blood (using a high performance
liquid chromatography method, reference values: 35-107 mumol/l) in 141 patients
from the Geriatric department (84 non-chronic obstructive pulmonary disease
(COPD), 40 COPD patients without theophylline and 17 COPD patients with
theophylline) and in 25 non-geriatric COPD patients on theophylline. RESULTS: Of
the 84 geriatric non-COPD patients (mean age: 82 years; SD: 6) 56% had a
subnormal vitamin B-6 status, of the 40 geriatric COPD patients without
theophylline (82 years; SD: 6) 70%, of the 17 geriatric COPD patients on
theophylline (80 years; SD: 5) 94% and of the 25 non-geriatric COPD patients on
theophylline (62 years; SD: 11) 96%. CONCLUSION: In patients who used
theophylline a higher prevalence of subnormal vitamin B-6 status was found than
in patients who did not.
PMID- 9550800
TI - [Increased chance of dying among nursing home patients with lower body weight].
AB - OBJECTIVE: To investigate a possible relationship between changes in weight and
mortality among nursing home patients of 65 years and older, after adjustment for
age, sex and main diagnosis. DESIGN: Descriptive longitudinal study. SETTING:
Dutch nursing home in Delft, the Netherlands. METHODS: For three years after
admission the body weight of patients newly admitted from April 1st 1987 to April
1st 1989 was measured every three months under the same conditions. It was
recorded if a patient died or was discharged in this three-year period. The
effects of body weight at admission, sex, age and diagnostic category
(psychogeriatric, neurological, orthopaedic, oncological, other) on mortality
were analysed using the univariate Cox regression analysis. The effect of the
time-dependent covariate body weight on mortality in the nursing home was
analysed with a combined logistic regression analysis per 3-month interval.
RESULTS: The mean weight of the females increased from 59.7 kg (n = 194) at the
time of admission to 63.7 kg (n = 57) three years later and that of the males
from 64.7 kg (n = 70) to 70.3 (n = 11) due to the low body weight of those who
died. During the first 3 months after admission mortality was high (14%) and only
diagnosis related. In subsequent 3-month periods there was a significant
association between mortality and weight, weight change, age and sex: the risk of
mortality was higher for those with a lower body weight, weight loss, higher age
and male sex. CONCLUSION: Nursing home patients with a low body weight or loss of
weight after the first 3 months after admission, have an increased risk of death.
PMID- 9550801
TI - [Suppurative hidradenitis].
PMID- 9550802
TI - [Suppurative hidradenitis].
PMID- 9550803
TI - [Anglo-Saxon guidelines for the treatment of community-acquired pneumonia also
applicable in The Netherlands].
PMID- 9550804
TI - [Anglo-Saxon guidelines for the treatment of community-acquired pneumonia also
applicable in The Netherlands].
PMID- 9550805
TI - [Anglo-Saxon guidelines for the treatment of community-acquired pneumonia also
applicable in The Netherlands].
PMID- 9550806
TI - [Anglo-Saxon guidelines for the treatment of community-acquired pneumonia also
applicable in The Netherlands].
PMID- 9550807
TI - [Anglo-Saxon guidelines for the treatment of community-acquired pneumonia also
applicable in The Netherlands].
PMID- 9550808
TI - [Drug treatment of prostatic carcinoma].
PMID- 9550809
TI - [Continuation of pregnancy in infaust fetal prognosis].
AB - In three pregnant women, lethal anomalies of the fetus were diagnosed
ultrasonographically in the second trimester. These women decided to continue
their pregnancies for different reasons. One woman strongly regretted her
decision to abort a previous pregnancy. The second hoped that the doctors were
mistaken on the prognosis. The third woman was afraid of medical interventions.
In case of lethal anomalies of the fetus, doctors should advise their patients to
consider both options: termination as well as continuation of their pregnancy.
Irrespective of the women's choice, doctors ought to be committed to support the
pregnant women in such a troublesome situation.
PMID- 9550810
TI - [The relationship between health gain and effort in mass screening for breast
cancer].
AB - Mass screening for breast cancer reduces the mortality of this disease. In the
Netherlands, with a very high incidence of breast cancer, a well organized health
care system and a stable economic prosperity, the decision taken to implement
nationwide breast cancer screening for the female population aged 50-70 years
appears well-founded. The first data indeed suggest a reduction of breast cancer
in the coming years. The effects of screening as such will be difficult to
evaluate since the programme leads also to optimalization of breast cancer
treatment in general. Other factors, such as adjuvant therapy, may have a
beneficial effect on breast cancer mortality, reducing the yield of the screening
proper. This and the non-negligible negative aspects should not be hidden from
the public. Continuous evaluation and quality control, not only in mammography
techniques and reading, but also in the treatment of the detected cases, are
essential for a successful screening programme.
PMID- 9550811
TI - [Chronic hepatitis C in hemodialysis patients].
AB - Hepatitis C virus (HCV) is an important cause of chronic hepatitis in dialysis
patients. With regard to epidemiology, the time on haemodialysis, the (previous)
use of intravenous drugs as well as the number of blood transfusions received are
important risk factors. There are strong indications suggesting nosocomial
transmission of HCV. Strict application of infection prevention procedures in
haemodialysis units is mandatory to restrain spread of HCV infection. Preliminary
results show equal efficacy of alpha-interferon in normalisation of serum
transaminases in dialysis patients and in patients with normal kidney function.
However, in both groups relapses occur often, despite induction of remission.
Antiviral therapy (with interferon and ribavirin) is emerging as a valid option
to induce HCV eradication in dialysis patients. Thereafter, transplantation may
be considered.
PMID- 9550812
TI - [Salt sensitive blood pressure and the renin-angiotensin system in hypertension].
AB - The relationship between (excessive) use of sodium chloride and the blood
pressure is still equivocal. Blood pressure responses to alterations in dietary
salt consumption vary greatly between individuals, which has led to the concept
of salt sensitivity. Although the mechanisms which determine the degree of salt
sensitivity are not fully understood, the renin-angiotensin system seems to play
a key role. A relative inability of this system to respond promptly to
alterations in salt intake may underlie the development of salt sensitivity. By
administering drugs which block the renin-angiotensin system to patients with
essential hypertension, blood pressure is rendered more sensitive to the effects
of salt restriction and (or) diuretic treatment.
PMID- 9550813
TI - [Immunology in clinical practice. VI. Current immunosuppressive drugs].
AB - Immunosuppressive drugs are agents capable of modulating at least one type of
immune response in vivo at doses with tolerable side-effects. Classical
immunosuppressive drugs include corticosteroids, azathioprine, cyclophosphamide,
methotrexate and cyclosporine. In the past two years tacrolimus and mycophenolate
mofetil were registered as immunosuppressive drugs. Tacrolimus interferes with
the calcium-dependent signal transduction of T-lymphocytes. Mycophenolate mofetil
is an inhibitor of purine synthesis by inhibition of the enzyme inosine
monophosphate dehydrogenase. Both tacrolimus and mycophenolate mofetil have
proven efficacy in both prevention and treatment of acute allograft rejection.
The new drugs are stronger than the classical ones but do not cause more adverse
reactions. The value in clinical medicine of some new, promising
immunosuppressive drugs, i.e. sirolimus (rapamycin), mizoribine, brequinar and
leflunomide remains to be proven.
PMID- 9550814
TI - [HIV infection and risky sexual behavior in a new cohort of young homosexual men
in Amsterdam, 1995-1996].
AB - OBJECTIVE: The surveillance of HIV prevalence and incidence and of sexual risk
behaviour among young homosexual men. DESIGN: Cohort study, cross-sectional data
presentation. SETTING: Municipal Health Service of the City of Amsterdam, the
Netherlands. METHODS: At entry into the study participants were questioned about
their sexual behaviour and blood or saliva samples were collected for laboratory
determination of antibodies against HIV, hepatitis B and syphilis. RESULTS: In
June 1995-October 1996, 429 men with a mean age of 25 years were enrolled in the
cohort study. Of these 22 (5%) were positive for antibodies against HIV. Based on
the duration of homosexual activity of the participants the HIV incidence in this
group was estimated at 1% per year. Furthermore, 10% of the participants had
experienced hepatitis B infection and 1% had serological evidence of syphilis. Of
those under investigation 38% had practised unprotected anogenital intercourse
with steady or non-steady partners in the last six months. CONCLUSIONS: The data
suggest that HIV is spreading among young homosexual men. Given the high levels
of risk behaviour continued prevention activities in this group are necessary.
PMID- 9550815
TI - [Favorable results with intravenous antimicrobial therapy outside the hospital].
AB - OBJECTIVE: To determine whether intravenous home treatment with antimicrobial
drugs of patients with an infection is feasible. DESIGN: Descriptive. SETTING:
Academic Hospital, Leiden, the Netherlands. METHODS: In October 1992 a programme
for intravenous home treatment of patients with infectious diseases was started.
The programme was based on self-administration of the intravenous antibiotic
therapy by the patient. The hospital pharmacy provided the antibiotics and
infusion devices, an infectious diseases specialist supervised the home treatment
and the nursing staff of the First Aid Department was available to change
infusion cannulas. After assessment of their medical and psychosocial fitness in
which the general practitioner was involved, thorough instruction on use of the
infusion device and care of the infusion cannula, patients were sent home.
RESULTS: In the period October 1992-September 1996, 162 patients (median age:
45.0 years (range: 3-82)) were treated at home for a median period of 15 days (1
221). Osteomyelitis, arthritis, Lyme disease, septicaemia with secondary foci,
and herpes virus infections were the most frequent indications for home
treatment. Penicillins and cephalosporins were given in 70% of the cases,
teicoplanin and antiviral drugs in 12% and 14%, respectively. For intermittent
administration bolus injection, a mechanical or elastomeric pump were used, for
continuous infusion a syringe or cassette pump. The intention of the programme
that the patient performed the home treatment as much as possible without extra
professional help, was realised in 82% of the patients. In 60% of the cases the
patients were fully self supporting, in 22% family or friends played an important
role. CONCLUSION: Home treatment with antimicrobial drugs intravenously is quite
feasible. If this were fully implemented, about 1400 patients in the Netherlands
could be treated in this manner.
PMID- 9550816
TI - [A patient with generalized actinomycosis].
AB - A 36-year-old man was admitted because of haemoptysis and weight loss. Despite
elaborate investigations, including multiple biopsies of affected organs (pleura,
lung, kidney and liver) no diagnosis was established. The patient refused further
diagnostic procedures and left hospital for winti treatment in Surinam. He did
not take the prescribed pheneticillin and returned after seven weeks in a very
poor condition. The second admission was complicated by septic shock. Despite
intensive treatment he died. On autopsy actinomycosis abscesses were found in
lung, liver and kidney. Even when suspected, an infection with Actinomyces is
difficult to diagnose. Without adequate treatment this infection can lead to life
threatening complications.
PMID- 9550817
TI - [HIV/AIDS in The Netherlands: better treatment possibilities make HIV- instead of
AIDS-surveillance necessary].
PMID- 9550818
TI - [Joint decision making, how? Physician-patient communication on palliative
chemotherapy].
PMID- 9550819
TI - [Neurological presentation on non-Hodgkin lymphoma: a diagnostic problem].
PMID- 9550820
TI - [Nerve circuit disorders: determination of polyneuropathy].
AB - So many conditions, both hereditary and acquired, can lead to polyneuropathy that
a systematic approach is needed to identify the cause. Finding a cause is
necessary to inform the patient about prognosis, handicap and chances of
treatment. Three patients with polyneuropathy are described. The first was a man
aged 34 with a predominantly motor neuropathy who appeared to have a duplication
in the pmp-22 gene on chromosome 17PII.2. The diagnosis was hereditary
sensorimotor neuropathy type IA (hypertrophic form of Charcot-Marie-Tooth
disease). The second was a woman of 58 years; she had a sensory polyneuropathy as
the first manifestation of Hodgkin's disease. The last patient, a 67-year-old
man, had polyneuropathy due to vasculitis. He showed a prompt response to
treatment.
PMID- 9550821
TI - [The necessity for centralization of pediatric intensive care].
AB - Substantial evidence indicates that outcome of critically ill children, treated
in tertiary paediatric intensive care units (PICUs) is superior to that of those
treated in other settings. However, a significant number of children who require
this level of care are not admitted to such a unit e.g. due to capacity
constraints, reluctance of physicians of general hospitals to refer children to a
tertiary centre, and transportation problems. Centralization of care, as recently
proposed in the UK, is necessary in the Netherlands, as well, to improve the
quality of care. This will require a controlled number of PICU beds in a
restricted number of centres, adequate transport facilities and step-down or high
dependency units in large general hospitals.
PMID- 9550822
TI - [Polyneuropathy: diagnosis and management].
AB - A polyneuropathy is characterized by a symmetrical distribution of sensory or
motor abnormalities, more pronounced distally than proximally and usually more
evident in the lower than in the upper limbs. Polyneuropathies may be classified
on the basis of (a) clinical picture: acute/subacute/chronic,
sensory/motor/autonomous, axonal degeneration/segmental demyelinization, and (b)
cause: metabolic disorder, deficiency, infection, auto(dys)immunity, hereditary
and toxic/iatrogenic polyneuropathy, with idiopathic polyneuropathy as the
remaining group. Damaged nerves may recover as the result of spontaneous
remyelinization and axonal regeneration. Treatment is particularly successful in
immunomediated neuropathies. Withdrawal is often successful in intoxications and
suppletion in deficiencies. Even if no treatment is possible, the diagnosis is
important: the patient can be taught to accept his disease and the prognosis can
be determined, in connection with possible handicaps.
PMID- 9550823
TI - [Immunology in clinical practice. VII. Psoriasis].
AB - A new hypothesis of the pathogenesis of psoriasis holds that psoriasis is an
epidermal hyperproliferative disorder resulting from abnormal interaction between
T cells and basal layer stem cell keratinocytes. New therapies aimed at reducing
T cell activity are most successful, as exemplified by the efficacy of systemic
cyclosporine in severe cases of psoriasis. New developments in immunogenetics and
immunodermatology are anticipated and it is expected that they will fully explain
the chain of pathological events.
PMID- 9550824
TI - [Laboratory diagnosis of Lyme borreliosis].
AB - Three stages can be observed in Lyme borreliosis: the acute stage (with dermal
and systemic disease), an intermediate stage (with neurological and
cardiovascular complaints and myositis), and a chronic stage (with arthritis, low
back pain, dermatological and neurological complaints). If no acute stage with
erythema chronicum migrans is seen, laboratory tests must provide the diagnosis.
In the so-called two-test protocol at least two different tests must be positive
for a definite diagnosis. Because culture is difficult, serology (demonstration
of specific IgM and IgG antibodies against spirochaetal antigens) is the
preferred technique. Cross reactions, antigenic variations and differences in
antigenic expression in American and European strains may cause false-negative
and false-positive results with the current tests. Moreover, previous use of
antibiotics can interfere with the production of specific antibodies, and the
effect of therapy is not correlated with height and behaviour of antibody titres.
Additional investigation with immunoblot techniques, demonstrating specific
antibody patterns may be valuable. An interesting alternative, not yet fully
developed, is detection of specific antigens in tissues.
PMID- 9550825
TI - [Referral of patients with polyneuropathy by the family physician: influence of
type of symptoms but not of age].
AB - OBJECTIVE: To investigate the influence of the age of the patient and the nature
of a polyneuropathy on the referral behaviour of general practitioners (GPs).
DESIGN: Written questionnaire sent to GPs regarding paper case records of
polyneuropathy. SETTING: University Hospital Utrecht, the Netherlands. METHODS:
1590 GPs were asked about their differential diagnosis regarding a paper case
record of a patient with polyneuropathy. There were six case records, differing
in age (53, 64 and 73 years) and nature of the disease (sensory or sensorimotor
polyneuropathy). The GPs were divided into six groups with similar demographic
characteristics and type of practice. To avoid focus on polyneuropathy, all GPs
also received questions about three other neurological cases (amaurosis fugax,
radicular syndrome and vasovagal collapse). RESULTS: The mean response of the
questionnaire was 54% (n = 844). Most GPs diagnosed the polyneuropathy (analysis
of variance; p < 0.0001). The age of the patient did not influence the diagnosis
nor the referral behaviour. At least 73% of the patients with a sensory and 81%
of the patients with a sensorimotor polyneuropathy were referred to neurologists
for further investigations (chi(2)-test; p < 0.05). CONCLUSION: At least 73% of
the GPs referred a patient with polyneuropathy to a neurologist; patients with
muscle weakness were referred more often than patients with only sensory
disturbances. Referral was not influenced by the age of the patient.
PMID- 9550826
TI - [Nasopharyngeal carcinoma: epidemiology and treatment outcome].
AB - OBJECTIVE: To determine epidemiology, symptoms and treatment results of patients
with nasopharyngeal carcinoma. DESIGN: Descriptive and retrospective. SETTING:
The Dutch Cancer Institute (Antoni van Leeuwenhoek Hospital), Amsterdam, the
Netherlands. METHODS: The clinical, epidemiological and radiotherapy data of the
129 patients with a nasopharyngeal carcinoma referred between 1977 and 1993 to
our hospital were analysed. Twenty patients were referred for a second opinion
only, presented with recurrent disease, or had received their treatment
elsewhere. Data of 109 patients were analysed. RESULTS: During the last decade
more patients born in Asia and North-Africa were referred (p = 0.0057), a total
of 52 (48%) out of 109 referred patients. There were 62 (58%) patients in whom an
enlarged cervical lymph node at level II (upper jugular group) was the presenting
symptom. In 53 (50%) cases hearing loss due to otitis media with effusion was the
first symptom. In 54 (54%) patients the delay between the first symptoms and
diagnosis of carcinoma was > 20 weeks. 5-year survival was 48% (SE 6%) for the
whole group (n = 109) of patients and 52% (SE 6%) for the patients treated with
curative intent (n = 96). CONCLUSION: During the last decade the population of
patients with nasopharyngeal carcinoma in the Netherlands contained more patients
from Asia and North-Africa. Suspicious cervical lymph node swellings and (or)
(unilateral) otitis media with effusion may be indicative of a nasopharyngeal
carcinoma.
PMID- 9550827
TI - [Ovarian vein thrombosis].
AB - A 44 year-old woman was admitted with fever and lower abdominal pain at the right
side suggestive of appendicitis. Ovarian vein thrombosis was diagnosed by
sonography and confirmed by contrast-enhanced CT scan. After heparinisation the
complaints disappeared and fever resolved in less than 72 hours. Repeated
radiological investigation showed regression of the thrombus. Ovarian vein
thrombosis is an uncommon, potentially fatal disorder that can be adequately
treated with medication. The cornerstone of the diagnosis consists in non
invasive radiological investigation.
PMID- 9550828
TI - [Chronic fatigue syndrome].
PMID- 9550829
TI - [Chronic fatigue syndrome].
PMID- 9550830
TI - [Chronic fatigue syndrome].
PMID- 9550831
TI - [Chronic fatigue syndrome].
PMID- 9550832
TI - [Chronic fatigue syndrome].
PMID- 9550833
TI - [Chronic fatigue syndrome].
PMID- 9550834
TI - [Chronic fatigue syndrome].
PMID- 9550835
TI - [Sore throat in rheumatoid arthritis; 2 patients with crico-arytenoid arthritis].
PMID- 9550836
TI - [Left ventricular hypertrophy; differences in diagnostic and prognostic value of
electrocardiography and echocardiography].
PMID- 9550837
TI - [Suppurative hidradenitis].
PMID- 9550839
TI - [The use of drugs to improve athletic performance].
PMID- 9550840
TI - Extracting findings from narrative reports: software transferability and sources
of physician disagreement.
AB - While natural language processing systems are beginning to see clinical use, it
remains unclear whether they can be disseminated effectively through the health
care community. MedLEE, a general-purpose natural language processor developed
for Columbia-Presbyterian Medical Center, was compared to physicians' ability to
detect seven clinical conditions in 200 Brigham and Women's Hospital chest
radiograph reports. Using the system on the new institution's reports resulted in
a small but measurable drop in performance (it was distinguishable from
physicians at p = 0.011). By making adjustments to the interpretation of the
processor's coded output (without changing the processor itself), local behavior
was better accommodated, and performance improved so that it was
indistinguishable from the physicians. Pairs of physicians disagreed on at least
one condition for 22% of reports; the source of disagreement appeared to be
interpretation of findings, gauging likelihood and degree of disease, and coding
errors.
PMID- 9550841
TI - Cooperative problem solving with personal mobile information tools in hospitals.
AB - Health-care professionals have a broad range of needs for information and
cooperation while working at different points of care (e.g., outpatient
departments, wards, and functional units such as operating theaters). Patient
related data and medical knowledge have to be widely available to support high
quality patient care. Furthermore, due to the increased specialization of health
care professionals, efficient collaboration is required. Personal mobile
information tools have a considerable potential to realize almost ubiquitous
information and collaborative support. They enable to unite the functionality of
conventional tools such as paper forms, dictating machines, and pagers into one
tool. Moreover, they can extend the support already provided by clinical
workstations. An approach is described for the integration of mobile information
tools with heterogeneous hospital information systems. This approach includes
identification of functions which should be provided on mobile tools. Major
functions are the presentation of medical records and reports, electronic mailing
to support interpersonal communication, and the provision of editors for
structured clinical documentation. To realize those functions on mobile tools, we
propose a document-based client-server architecture that enables mobile
information tools to interoperate with existing computer-based application
systems. Open application systems and powerful, partially wireless, hospital-wide
networks are the prerequisites for the introduction of mobile information tools.
PMID- 9550842
TI - An integrated approach for a knowledge-based clinical workstation: architecture
and experience.
AB - Today, the demand for medical decision support to improve the quality of patient
care and to reduce costs in health services is generally recognized.
Nevertheless, decision support is not yet established in daily routine within
hospital information systems which often show a heterogeneous architecture but
offer possibilities of interoperability. Currently, the integration of decision
support functions into clinical workstations is the most promising way.
Therefore, we first discuss aspects of integrating decision support into clinical
workstations including clinical needs, integration of database and knowledge
base, knowledge sharing and reuse and the role of standardized terminology. In
addition, we draw up functional requirements to support the physician dealing
with patient care, medical research and administrative tasks. As a consequence,
we propose a general architecture of an integrated knowledge-based clinical
workstation. Based on an example application we discuss our experiences
concerning clinical applicability and relevance. We show that, although our
approach promotes the integration of decision support into hospital information
systems, the success of decision support depends above all on an adequate
transformation of clinical needs.
PMID- 9550843
TI - Analysis of data associated with seemingly temporal clustering of a rare disease.
AB - Three statistical tests aimed at detecting temporal clustering within a given
short series of diagnoses are presented. These tests are based on a standardized
time interval between consecutive diagnoses. Two of the tests (the Cuscore and
the Sets tests) are derived from sequential monitoring techniques which are
sensitive to temporal clustering within the data set. The third test (R test) is
not sequential and its sensitivity is focused on the average increase in the
overall rate of the disease rather than on clustering within the series. Power
curves are presented for conditions related to the intensity level of the subtle
epidemic, the cluster size and the number of diagnoses. None of the techniques
showed highest efficiency over all the specified conditions. The R test is the
most efficient when the relative risk is 2 or less, and the Cuscore test is the
most efficient method when the relative risk is > or = 2.5.
PMID- 9550844
TI - Determining first admissions in a hospital discharge file via record linkage.
AB - The aim of this study was to identify first admissions in a public hospital
discharge file with the greatest possible accuracy. Computerised data linkage was
used to link injury events. This involved the use of "internal" data linkage
(unduplication) which, in data linkage terms, is equivalent to matching two
identical files. Admission status indicators obtained from deterministic and
probabilistic linkages were compared with those obtained from a manual review.
Small absolute reductions in error were obtained using a probabilistic linkage
over a deterministic linkage. However, these reflected large relative reductions
in error. A validity check confirmed initial results and discounted against
possible bias due to the subjective nature of the probabilistic linking
procedure.
PMID- 9550845
TI - Indicators for the automated analysis of drug prescribing quality.
AB - Irrational and inconsistent drug prescription has considerable impact on
morbidity, mortality, health service utilization, and community burden. However,
few studies have addressed the methodology of processing the information
contained in these drug orders used to study the quality of drug prescriptions
and prescriber behavior. We present a comprehensive set of quantitative
indicators for the quality of drug prescriptions which can be derived from a drug
order. These indicators were constructed using explicit a priori criteria which
were previously validated on the basis of scientific data. Automatic computation
is straightforward, using a relational database system, such that large sets of
prescriptions can be processed with minimal human effort. We illustrate the
feasibility and value of this approach by using a large set of 23,000
prescriptions for several diseases, selected from a nationally representative
prescriptions database. Our study may result in direct and wide applications in
the epidemiology of medical practice and in quality control procedures.
PMID- 9550846
TI - Object-oriented modeling and terminologies for drug contraindications.
AB - There is no available standardized representation of contraindications that can
be used in drug knowledge bases. In this paper, an object-oriented representation
of contraindications is proposed that would allow computerized checking of drug
prescription safety. It distinguishes four types of contraindications:
pathological state, physiological state, findings of investigation procedures,
and diagnostic or therapeutic procedures. The vocabulary usable for expressing
the contraindications appropriate for automated prescription checking was also
investigated. ICD10 (International Classification of Diseases, tenth revision),
SNOMED III (Systematized Nomenclature of Medicine), ICPC (International
Classification of Primary Care), and ATC (Anatomic Therapeutic and Chemical
Classification) were studied as potential sources of standardized vocabulary. A
system to support entering data on contraindications into a drug knowledge base,
compatible with the proposed structure and using the identified vocabulary
sources, is also presented.
PMID- 9550847
TI - Randomized observational studies on the economics of therapies--biometrical
experience of two trials.
AB - Economic studies in medicine are intended to investigate costs, associated with a
particular problem dealing with the indication, diagnosis or therapy, for
instance, whether the high costs involved in a highly intensive or innovative
therapy could be balanced by the eventual savings made, due to the shorter
periods of treatment. In such situations a randomized controlled trial is
necessary to find out which therapy or which therapeutical strategy is least
expensive in the long run. Economic studies do, however, present some specific
problems. Making a list of all the cost-relevant treatment items can be very
laborious, but the use of flat rates and lump sums alone cannot lead to a
complete cost analysis. Often, costs between hospitals vary more than between
treatment regimens. Early and sudden deaths incur low costs and may bias the
results. Furthermore, costs are distributed with a long and heavy upper tail
including extreme outliers. This does, in fact, complicate the estimation of the
sample size. In this article, these problems are outlined and, with the help of
the data obtained from two randomized economic trials in health care, solutions
are proposed and discussed.
PMID- 9550848
TI - Diagnosis of acute appendicitis in two databases. Evaluation of different
neighborhoods with an LVQ neural network.
AB - The use of an artificial neural network system was studied in the diagnosis of
acute abdominal pain, especially acute appendicitis, with patients from Finland
and Germany. Separate Learning Vector Quantization (LVQ) neural networks were
trained with a training set from each database and also with a combined database.
Each neural network was evaluated separately with a test set of cases from each
database. With the combined database different neighborhood methods were compared
to find the optimal choice for this decision-making problem. The acute
appendicitis cases of the Finnish test data set were classified well with all the
networks, but the cases of the German test set were difficult to classify for the
Finnish network. The use of larger neighborhoods increased the sensitivity of the
classification by nearly 10%. The differences in the results of the Finnish and
German databases suggest that there are differences in the data collection or
patient populations between centers. Therefore, care must be taken when using
decision-support systems which have been developed in other centers. Neural
networks offer a method to evaluate differences between databases. With the use
of larger neighborhoods, the effects of the differences on the accuracy of the
classification can be partly diminished.
PMID- 9550849
TI - Best-link matching of Scottish health data sets.
AB - Methods are described used to link the Community Health Index and the National
Health Service Central Register (NHSCR) in Scotland to provide a basis for a
national patient index. The linkage used a combination of deterministic and
probability matching techniques. A best-link principle was used by which each
Community Health Index record was allowed to link only to the NHSCR record with
which it achieved the highest match weight. This strategy, applied in the context
of two files which each covered virtually the entire population of Scotland,
increased the accuracy of linkage approximately a thousand-fold compared with the
likely results of a less structured probability matching approach. By this means,
98.8% of linkable records were linked automatically with a sufficient degree of
confidence for administrative purposes.
PMID- 9550850
TI - Effects of record linkage errors on disease registration.
AB - Reliable record linkage is a prerequisite for high-quality population-based
disease registration. Rapid developments in computer processing have made record
linkage both more efficient and more reliable in recent years. At the same time,
concerns about confidentiality increasingly hinder record linkage in many disease
registries. This paper provides basic algebraic models describing the effects of
record linkage errors on monitoring disease incidence. Homonym errors, that is,
erroneous linkage of records that pertain to distinct individuals, lead to
underestimation of incidence in the registry population. The degree of
underestimation strongly depends on the discriminating power of personal
identifiers and the record linkage procedure on the one hand, and the number of
registered cases on the other hand. Synonym errors, that is, failure to link
notifications on the same individual, lead to overestimation of incidence in the
population base. The combined effects of record linkage errors are illustrated
with empirical examples. We conclude that it is the largest and most informative
disease registries that are potentially affected most by impediments of record
linkage procedures due to unduly restrictive confidentiality rules.
PMID- 9550851
TI - Towards a national patient card system in Japan.
AB - Patient Card Systems (PCS) have been applied on a regional level to improve
access to patient information. However, current projects lack a vision of future
integration on a national level. In addition, Integrated Circuit cards and
optical cards were introduced without considering that their cost and capacity
limits impose significant constraints for future integration. The major arguments
against PCS are the huge costs incurred by such a system and the limitations of
the card capacities. In addition, standards and legislation have not been
sufficiently developed. In this study, we propose a new model of PCS that employs
recent communication and card technologies as a key to access a national medical
information center. We demonstrate that PCS are feasible if implemented in
several distinct phases and if the acceptance and cooperation of physicians and
patients are achieved. However, political consensus about the necessity of reform
in the health care sector must be established so that the necessary legislation
can be enacted.
PMID- 9550852
TI - Review of biomedical knowledge and data representation with conceptual graphs.
AB - The basis of conceptual graphs theory is an ontology of types of concepts.
Concepts issued from the ontology are interlinked by semantic relationships and
constitute canonical conceptual graphs. Canonical graphs may be combined to
derive new conceptual graphs by means of formation rules. This formalism allows
to separate knowledge representation into a conceptual level and a domain
dependent level, and enables to share and reuse a representation. This paper
presents conceptual graph applications to biomedical data and concept
representation, classification systems, information retrieval, and natural
language understanding and processing. A discussion on the unifying role
conceptual graphs theory plays in the implementation of knowledge-based systems
is also presented.
PMID- 9550853
TI - The LYMFASIM simulation program for modeling lymphatic filariasis and its
control.
AB - The LYMFASIM modeling framework for the transmission and control of the tropical
parasitic disease lymphatic filariasis is described and its use in the context of
an endemic community in north-eastern Brazil is illustrated. Lymphatic filariasis
is a disease with a complex natural history with many unknowns. This complicates
decision making with respect to control strategies. With LYMFASIM, a variety of
hypotheses can be tested about the life history of the parasite Wuchereria
bancrofti, its transmission from man to man through mosquitoes, the role of the
immune system in regulating parasite numbers, the development of disease
symptoms, and the effects of control measures (drug treatment or mosquito
control). The implications of alternative assumptions and uncertainty about the
quantification of parameters for the effectiveness of control strategies can be
investigated. Thanks to the use of stochastic microsimulation, LYMFASIM is highly
flexible and can be adapted and extended as new knowledge emerges.
PMID- 9550854
TI - Towards the unification of inference structures in medical diagnostic tasks.
AB - The central purpose of artificial intelligence applied to medicine is to develop
models for diagnosis and therapy planning at the knowledge level, in the Newell
sense, and software environments to facilitate the reduction of these models to
the symbol level. The usual methodology (KADS, Common-KADS, GAMES, HELIOS,
Protege, etc) has been to develop libraries of generic tasks and reusable problem
solving methods with explicit ontologies. The principal problem which clinicians
have with these methodological developments concerns the diversity and complexity
of new terms whose meaning is not sufficiently clear, precise, unambiguous and
consensual for them to be accessible in the daily clinical environment. As a
contribution to the solution of this problem, we develop in this article the
conjecture that one inference structure is enough to describe the set of analysis
tasks associated with medical diagnoses. To this end, we first propose a
modification of the systematic diagnostic inference scheme to obtain an analysis
generic task and then compare it with the monitoring and the heuristic
classification task inference schemes using as comparison criteria the
compatibility of domain roles (data structures), the similarity in the
inferences, and the commonality in the set of assumptions which underlie the
functionally equivalent models. The equivalences proposed are illustrated with
several examples. Note that though our ongoing work aims to simplify the
methodology and to increase the precision of the terms used, the proposal
presented here should be viewed more in the nature of a conjecture.
PMID- 9550855
TI - Implementing HL7: from the standard's specification to production application.
AB - A C++ implementation of the HL7 health-care data interchange standard was
developed by automatic methods applied to the authoritative specification of the
standard. The reusable class library thus created presents an intuitive,
flexible, and easy-to-use application programming interface to the HL7 protocol.
This allows HL7 applications to be developed quickly while a high conformance to
the standard is ensured.
PMID- 9550856
TI - Physiological determinants of quality of life.
PMID- 9550857
TI - Assessing quality of life in respiratory disorders: chronic nonspecific lung
disease.
PMID- 9550858
TI - Quality of life and chronic respiratory failure.
PMID- 9550859
TI - An overview of recent overviews in the treatment of non-small cell lung cancer.
PMID- 9550860
TI - Neo-adjuvant chemotherapy prior to surgery in stage III non-small cell lung
cancer.
PMID- 9550861
TI - New prognostic factors in lung cancer.
PMID- 9550862
TI - Involvement of N-components in lung cancer.
PMID- 9550863
TI - The role of radiotherapy in the management of patients with small cell lung
cancer.
PMID- 9550864
TI - Management of idiopathic pulmonary fibrosis: prognostic indicators.
AB - There now exists a number of approaches that can be used to predict likely
responses to therapy and disease progression in idiopathic pulmonary fibrosis.
These tools should be used in management decisions. It must be remembered that
destroyed, fixed fibrotic lung will not improve and that the computed tomography
pattern and extent of the "fibrotic" pattern should be used to determine if the
best response to treatment that can be expected is a prevention of deterioration
rather than improvement.
PMID- 9550865
TI - Medical treatment for idiopathic pulmonary fibrosis.
PMID- 9550866
TI - Patient-ventilator interaction.
PMID- 9550867
TI - Acute severe asthma and treatment: a gas exchange perspective.
PMID- 9550868
TI - Acute respiratory failure: pulmonary thromboembolism.
PMID- 9550869
TI - Differential diagnosis of fever and pulmonary densities in mechanically
ventilated patients.
PMID- 9550870
TI - Advanced chronic obstructive pulmonary disease.
PMID- 9550871
TI - Epithelial adhesion molecules in airway repair.
PMID- 9550872
TI - Mechanisms of damage in COPD.
PMID- 9550873
TI - The functional consequences of airway remodeling in asthma.
AB - Structural changes in the airway walls involving extracellular matrix remodelling
are prominent features of asthma. These changes are probably driven by mediators
released as a consequence of chronic allergic inflammation. It is clear that
changes in the extracellular matrix have the capacity to influence airway
function in asthma. However, it is not clear how each of the many changes that
occur in the airway wall contribute to altered airway function in asthma.
Collagen deposition in the subepithelial matrix, and hyaluronan and versican
deposition around and internal to the smooth muscle would be expected to oppose
the effect of smooth muscle contraction. Conversely, geometric considerations
would result in exaggerated airway narrowing for a given degree of smooth muscle
shortening, as the airway wall is thickened by the deposition of these molecules
internal to the smooth muscle. Elastin and cartilage reorganization and
degradation in the airway walls would be expected to result in decreased airway
wall stiffness and increased airway narrowing for a given amount of force
generated by the smooth muscle. Degradation of matrix associated with the smooth
muscle may both decrease the stiffness of the parallel elastic component and
uncouple smooth muscle from the load provided by lung recoil, allowing
exaggerated smooth muscle shortening. Increase in muscle mass may be associated
with an increase, a decrease or no change in smooth muscle contractility. If an
increase in muscle mass was associated with preservation of its contractile
capacity modelling studies suggest that it could be the most important
contributor to exaggerated airway narrowing. Modelling studies also suggest that
the pattern of mucosal folding during smooth muscle contraction may be an
important determinant of airway narrowing. The greater the number of folds, and
the stiffer the subepithelial collagenous layer the more resistant the airway
will be to narrowing.
PMID- 9550874
TI - Airway structure to function relationships in asthma and COPD.
PMID- 9550875
TI - Report of the National Institutes of Health (NIH) Workshop on the Development of
Research Priorities in Eating Disorders.
AB - The National Institutes of Health (NIH) Workshop on the Development of Research
Priorities in Eating Disorders was convened in New York on April 24 and 25, 1996.
The goals of the workshop were (1) to identify important unanswered questions in
the study and treatment of eating disorders, (2) to discuss potentially fruitful
approaches to answering these questions through basic and clinical research, and
(3) to assist the NIH and other funding agencies in assigning priorities for
research on eating disorders. The program consisted of a series of brief
presentations by moderators, each followed by facilitated discussion of the topic
with members of the audience. Three reporters (CMG, MJD, FMC) took detailed notes
of the proceedings, which have been incorporated into this article. A summary of
this workshop is presented, along with recommendations for future research that
were identified by workshop participants.
PMID- 9550876
TI - Anorexia nervosa, obsessional behavior, and serotonin.
AB - Although many women diet, relatively few develop the extreme weight loss and the
clinical symptoms of anorexia nervosa. An underlying biological diathesis and
temperament may place someone at risk for developing anorexia nervosa. Certain
traits, such as negative affect, behavioral inhibition, compliance, high harm
avoidance, and an obsessive concern with symmetry, exactness, and perfectionism,
persist after recovery from anorexia nervosa. These persistent symptoms raise the
possibility that such traits exist premorbidly and contribute to the pathogenesis
of this disorder. Such traits could be associated with increased brain serotonin
activity. After recovery, anorexics have increased levels of 5-HIAA, the major
metabolite of serotonin, in the cerebrospinal fluid (CSF). Low CSF 5-HIAA levels
have been associated with impulsive and aggressive behaviors, which are opposite
to those typically found in anorexia nervosa. Increased serotonin activity could
contribute to many behavioral symptoms, such as increased satiety. Moreover,
recent data suggest that selective serotonin reuptake inhibitor (SSRI)-type
medication improves outcome and prevents relapse in people with anorexia nervosa.
These theoretical issues have important clinical implications in this era of
diminished support for treatment of eating disorders. Anorexia nervosa, like
other major psychiatric disorders, has contributory pathophysiology and can
benefit from and deserves appropriate treatment resources.
PMID- 9550877
TI - Research update on serotonin function in bulimia nervosa and anorexia nervosa.
AB - The extent to which dysregulation of serotonin function in the central nervous
system may contribute to core symptoms in patients with bulimia nervosa and
anorexia nervosa is currently an area of intensive psychobiological
investigation. Preclinical and clinical studies have demonstrated the involvement
of the neurotransmitter serotonin in the regulation of food intake, suggesting
that impaired serotonin-mediated satiety signals could contribute to patterns of
recurrent binge eating. Other symptom patterns in patients with eating disorders,
including mood dysregulation, impulsivity, and obsessionality, as well as
therapeutic response to serotonergic agents, suggest involvement of serotonergic
pathways. With a primary focus on serotonin function, this article reviews
clinical studies of neuroendocrine and behavioral response to pharmacological
challenges, levels of neurotransmitter metabolite in cerebrospinal fluid, and
platelet studies. Controlled clinical trials involving pharmacological treatment
with serotonergic medications are summarized. Considerations for future research
are discussed.
PMID- 9550878
TI - Behavior genetics and eating disorders.
AB - Behavior genetics is concerned with the genetic and environmental influences on
individual differences in the vulnerability to eating disorders. We should be
skeptical about simple genetic explanations for disorders whose development,
maintenance, and possible remission involve the interaction of individual
behaviors and environmental circumstances. Twin, family, and adoption studies can
help to delineate which phenotypes are most heritable, and which are most
responsive to family circumstances or individual environments. Subsequent
searches for individual genetic and environmental risk factors can be guided by
these results. Although there is consistent evidence of genetic factors
influencing vulnerability to eating disorders, the details are far from clear,
and additional studies will be useful. The further development of dimensional
indices of vulnerability will improve population-based and developmental genetic
research, as well as facilitating the search for individual genes.
PMID- 9550879
TI - Issues in mapping genes for eating disorders.
AB - Recent twin studies show that both genetic and environmental factors contribute
to the development of eating disorders. As in many other fields, there is much
enthusiasm regarding the possibility of locating the specific genes that
influence the risk of eating disorders. Advances in molecular and statistical
technology have made this task more feasible than it was in the past, and
continued enhancements in new technology are expected in the future. Despite
these advances, the resources required to map a gene for traits as complex as
eating disorders are likely to be enormous. Researchers considering such an
undertaking may wish to look for ways to reduce this demand, such as (1) using
multivariate analyses, (2) studying intermediate quantitative phenotypes, (3)
using large sibships, (4) analytic enhancements (e.g., multipoint analyses), (5)
reconceptualizing power, (6) data pooling, and (7) disequilibrium mapping.
PMID- 9550880
TI - Diagnostic criteria for eating disorders: current concerns and future directions.
AB - This article is a critical review of the evolution of diagnostic criteria for
anorexia nervosa, bulimia nervosa, and binge eating disorder. The shortcomings of
the current diagnostic criteria for all three disorders are addressed, as are the
primary nosological challenges facing the field.
PMID- 9550881
TI - Eating behavior and eating disorders: the interface between clinical research and
clinical practice.
AB - Cognitive-behavioral therapy (CBT) has been shown to be a highly effective form
of treatment for patients with bulimia nervosa and anorexia nervosa. Issues of
satiety disturbances, food restriction, and food choice are central to this form
of therapy; however, ingestive behavior research that directly addresses these
issues in eating disorder patients has often been overlooked by clinicians. These
areas of research are reviewed and the implications of the findings for more
effective CBT therapy with anorexics and bulimics are discussed.
PMID- 9550882
TI - Eating disorders and comorbidity: empirical, conceptual, and clinical
implications.
AB - The most common major comorbid disorders associated with eating disorders include
substance use disorders, personality disorders, mood disorders, anxiety
disorders, and obesity. To test conceptual models of the relationship between the
eating disorders and these comorbid disorders, complex research paradigms are
needed, including epidemiological studies, behavior-genetic studies, and
longitudinal research designs. Comorbidity may be a significant factor to
consider as approaches to the treatment of eating disorders continue to evolve.
PMID- 9550883
TI - Males with eating disorders: challenges for treatment and research.
AB - Males represent only 10 percent of eating disorder cases. This gender discrepancy
is among the most extreme in psychiatry and medicine. Determining what
differences in etiology and mechanism best explain the discrepancy presents an
intellectual challenge. Beginning at about the third grade, boys and girls
diverge in social development. Boys show significantly less desire to lose
weight, express dissatisfaction with the upper rather than the lower body, and
use dieting to achieve specific external goals rather than as a cultural norm.
Males reach a significantly higher body mass index (BMI) than females do before
they beginning dieting. (27.2 versus 24.3, p < .01). While overall treatment
principles are similar, males in treatment require attainment of a different
hormonal milieu (testosterone), attention to past and future sexual role,
amelioration of perception of stigma, and preparation for return to male social
roles. Males and females suffer comparable degrees of osteopenia and brain
shrinkage during anorexia nervosa. The effectiveness of antidepressants in males
with eating disorders (compared with that in females) has not been well studied.
Male gender is not an adverse factor in short-term or long-term treatment
outcome. Understanding the lower frequency of these illnesses in males may lead
to more effective means of protecting girls from eating disorders and from the
culturally induced distress about normal body size and shape that burdens
adolescent development and adult life.
PMID- 9550884
TI - Mechanisms and treatment options for bone loss in anorexia nervosa.
AB - Osteoporosis is present in over half of all patients with anorexia nervosa. Bone
loss often occurs at a young age and may persist even after recovery,
predisposing patients to debilitating spinal crush fractures. The pathogenesis of
bone loss in anorexia nervosa is not completely understood and may result from a
number of mechanisms, including estrogen deficiency, inadequate vitamin and
calcium intake, and nutritional effects on bone formation. Recent studies
demonstrate that estrogen itself is inadequate to increase bone density in a
majority of patients with anorexia nervosa and suggest that nutritionally
dependent factors such as insulin-like growth factor-I (IGF-I), a potent bone
trophic hormone, may be important in maintaining bone mass. IT is hoped that new
anabolic strategies to increase osteoblast function will become available in the
future. In the interim, weight gain, restoration of gonadal function, and calcium
supplementation remain the cornerstones of treatment in this disease.
PMID- 9550885
TI - The future of risk factor research in understanding the etiology of eating
disorders.
AB - This article explores whether particular risk factors are best seen as precursors
or as symptoms. Psychological, cultural, family, developmental, and biological
risk domains that may be important in the etiology of eating disorders are
briefly reviewed. We describe a 4-year prospective study assessing a wide range
of risk factors for development of eating disorders in a large school-based
sample of adolescents. For subjects who were relatively asymptomatic, a
personality or temperamental characteristic of negative affect/esteem measured at
study entrance was the only significant predictor of later risk score for both
girls and boys. The significant comorbidity demonstrated in a separate group that
had high risk for eating disorders suggests that negative affectivity may be a
vulnerability factor for overall psychopathology rather than a predisposition
specifically for eating disorders. Following subjects through the young-adult
years and later may further clarify the range of influences affecting disordered
eating. Primary prevention and early intervention programs in the schools are
also recommended.
PMID- 9550886
TI - Priorities in prevention research for eating disorders.
AB - This article discusses potential areas for research in the prevention of eating
disorders. Prevention research encompasses a large range of activities; reviews
are available (Crisp 1988; Shisslak et al. 1987; USDHHS/McKnight 1996). This
article focuses on school-based primary preventive interventions.
PMID- 9550887
TI - Prevention of eating disorders: directions for future research.
PMID- 9550888
TI - Does adjunctive fluoxetine influence the post-hospital course of restrictor-type
anorexia nervosa? A 24-month prospective, longitudinal followup and comparison
with historical controls.
AB - A 24-month naturalistic, prospective longitudinal followup study was conducted on
33 patients with anorexia nervosa who had participated in an intensive,
multidisciplinary inpatient treatment program and were receiving fluoxetine as
part of their continuing treatment regimen. Data on course, outcome, and
treatment exposure in this cohort were obtained using standardized, comprehensive
interviews administered at 6-month intervals after hospital discharge.
Longitudinal course data for these patients were compared with data for matched
historical controls who had received identical inpatient and followup treatment
but without adjunctive fluoxetine. Analyses failed to show that fluoxetine had a
significant effect on the cumulative probability of remaining at target weight
during the followup period, the risk of sustained weight loss, or other clinical
measures of outcome. Thus, adjunctive treatment with fluoxetine may not have
additive long-term therapeutic benefit when measured against the effects of
sustained and intensive followup treatment.
PMID- 9550889
TI - Pharmacotherapy of bulimia nervosa and binge eating disorder: longer-term
outcomes.
AB - The longer-term effects of antidepressant medication, with and without the
addition of psychotherapy, for the treatment of bulimia nervosa and binge eating
disorder are reviewed. The use of a single antidepressant agent results in
recovery of about 25 percent of patients entering treatment; continued treatment
is accompanied by relapse in about one-third of these patients. Substituting one
or more antidepressants for the initial agent in patients who fail to improve or
cannot tolerate side effects improves long-term maintenance. Adding cognitive
behavioral therapy (CBT) may prevent relapse once medication is discontinued, and
the combination of CBT and antidepressant treatment is more effective than a
single medication. There is also evidence that antidepressant treatment combined
with CBT is more effective than placebo plus CBT. The problem of how to sequence
medication and CBT has not been resolved, although a recent study demonstrating
that pharmacotherapy is more cost-effective than CBT suggests that treatment
might begin with medication.
PMID- 9550890
TI - Psychological treatment of bulimia nervosa and binge eating disorder.
AB - The field of eating disorders has grown rapidly, amassing an impressive body of
treatment research in the past 20 years. In particular, researchers have focused
on binge eating problems, which include bulimia nervosa (BN) and the more
recently recognized binge eating disorder (BED). Numerous controlled treatment
trials have shown cognitive-behavioral therapy (CBT) to be equally or more
efficacious than any other BN treatment to which it has been compared. Although
CBT also seems to be effective for BED, research is in a preliminary stage.
Further combinations and adaptations of treatments for BED are needed to address
the additional problem of obesity in this population. Preliminary data suggest
that behavioral weight control treatment for BED is effective in reducing binge
eating, and it may have the added benefit of weight loss. Interpersonal
psychotherapy (IPT), the combination of CBT and medication, and self-help manuals
are promising treatment alternatives for both BN and BED. Future treatment trials
should include longer-term followup periods and more consistent definitions of
successful treatment outcome. In addition, further study is needed in the areas
of treatment nonresponders, pre-treatment predictors, a stepped-care treatment
model, and methods for a wider dissemination of validated treatments.
PMID- 9550891
TI - RAYS 22,2,1997 the new frontiers of functional radiology of the lung.
PMID- 9550892
TI - The diabetic foot: epidemiology.
AB - The epidemiology of the diabetic foot is still unknown because this heterogeneous
pathologic condition is non uniformly classified and described. Lower limb
peripheral vascular disease has a preferential distal location strongly
associated with the classical factors of cardiovascular risk. Ulcers occur in 15%
of diabetics and 6-20% of all hospitalized diabetic patients are affected by
ulcers of the foot. There is a predictive feature of the severity of the ulcer in
relation to its location. In the USA, ischemia-related amputations are about 200
per million per year for non diabetics as against 3900 per million for diabetics;
furthermore the incidence of a second amputation rises to 51% 5 years after first
amputation. Risk factors for amputation are: smoking, hypertension, dyslipidemia,
elderly age, glycosylated hemoglobin levels. Although mortality has decreased in
the last 50 years, the diabetic foot is still a huge economic problem.
PMID- 9550893
TI - Charcot's foot.
AB - Diabetic osteoarthropathy is a chronic progressive arthropathy involving the
bones and joints being constantly associated to somatic and autonomic peripheral
neuropathy. The pathogenesis is related to sensory and motor neuropathy with
morphologic foot alterations, relaxation and abnormal position on walking till
complete collapse of the foot shown by the depressed longitudinal medial arch.
Bone reabsorption due to osteoclasis and increased blood flow until osteomalacia
appears, is characteristic of this arthropathy. The clinical features vary
according to the location and severity of articular impairment and the stage of
identification. The metatarsophalangeal or tarsometatarsal joint may be involved.
The typical manifestation of Charcot's foot is plantar ulcer of variable location
according to the weight-bearing area. Treatment tends to reduce the abnormal
stress predisposing to ulceration with tailored footwear and orthoses.
PMID- 9550894
TI - Lower limb ischemia.
AB - Diabetes mellitus is the major cause of nontraumatic amputations in the
industrialized countries. In 1980 the scientific societies of diabetology and the
patients' associations subscribed at St. Vincent a declaration together with the
WHO, where a 50% decrease in amputations was among the primary objectives of
clinical diabetology. The main cause of amputations is foot ischemia related to
obliterating peripheral arterial disease, more diffuse and severe in diabetics,
typically affecting the infrapopliteal vessels. Clinical patterns of foot
ischemia include superficial necrotic areas and gangrene involving the entire
foot with necrosis of all anatomic planes. Infection is a common complication
with a negative impact on prognosis. Definitive treatment of ischemia is achieved
with revascularization which at present due to the advances in diagnostic
procedures can be performed in diabetics with the same effectiveness observed in
non diabetics.
PMID- 9550895
TI - Infection of the diabetic foot.
AB - Infection may be the first manifestation of the diabetic foot or may complicate a
preexisting lesion. The increased susceptibility to infections of diabetics and
the particular anatomy of the foot make infections particularly severe and
rapidly progressive. The etiology is generally polymicrobial and a swab for
culture of microorganisms is immediately required to plan correct and adequate
antibiotic therapy based on the antibiotic sensitivity test. Infections can be
treated in specialized outpatient services, while hospitalization is reserved to
most severe cases with systemic manifestations. These specialized centers have
been shown to be the only structures able to decrease the frequency, severity and
recurrence of foot infections as well as their prevention.
PMID- 9550896
TI - Diagnostic imaging of the diabetic foot.
AB - Diagnostic imaging plays a major role in the osteoarticular disease of the foot
in diabetics, allowing the diagnosis and evaluation of alterations for therapy
planning. To-date conventional radiology is still of first choice in the study of
the diabetic foot with the evaluation of osteoarticular damage caused by
neuropathy and vascular disease. Major radiographic patterns are neuroarthropathy
and osteomyelitis. Main locations are at the level of forefoot and less
frequently of tarsus and tibiotarsal joint. Second choice procedures as US, CT
and MRI are useful for a more accurate evaluation of soft tissue lesions and
articular structures. US is the first choice procedure in soft tissue evaluation
to rule out the presence of abscesses which require surgery. MRI with some
limitations represents the gold standard for the study of joints and medullary
disease. Spiral CT though less specific and sensitive than MRI for soft tissue
and bone marrow study is still the exam of reference for the study of bone
structures with three-dimensional reconstructions useful to plan orthopedic
surgery.
PMID- 9550897
TI - The diabetic foot: role of color-Doppler US.
AB - Color Doppler US is a first choice instrumental exam for the diagnosis and
staging of peripheral arterial occlusive disease in diabetic patients. Normal and
pathological findings are analyzed to establish the potential and limitations of
the procedure. Color Doppler US is a noninvasive, reproducible and cost-effective
procedure. Direct morphologic and flowmetric evaluations of stenotic-occlusive
alterations, and indirect evaluations based on the interpretation of velocimetry
findings proximal and distal to the lesions, are feasible. The conventional basic
exam can be enhanced with the power module. Encouraging experimental results are
observed with the use of echographic contrast media. Disadvantages of the
procedure are related to the poor panoramic view, subjective (operator-dependent)
interpretation and limitations related to the physics of ultrasound.
PMID- 9550898
TI - Angiography and MR-angiography in the diagnosis of peripheral arterial occlusive
disease in diabetic patients.
AB - An invasive diagnostic procedure as angiography which involves direct arterial
injection of contrast through suitable catheters, is still considered the gold
standard in the evaluation of diabetic patients with peripheral arterial
occlusive disease. The accuracy of anatomical details is combined on angiography
with a pan view, indispensable for correct therapeutic planning. MR-angiography,
with the 2D time of flight sequences in particular, supplies images of great
anatomical accuracy and very sensitive in the detection of occlusive lesions
which compare well with angiography and superior in the assessment of the length
of occluded tracts. This noninvasive, cost-effective procedure seems bound to
replace angiography in the pretreatment evaluation of diabetic patients with
peripheral arterial occlusive disease.
PMID- 9550899
TI - Perioperative treatment of the diabetic patient.
AB - The diabetic patient is frequently undergoing surgery for the underlying disease
and its complications. Before referring the patient to surgery the diabetologist
should carefully evaluate the presence of complications, cardiovascular, renal
and neurologic disorders in particular. Generally no problems are posed by
patients with NIDDM undergoing elective surgery. For more demanding patients and
for those with IDDM the most effective and ready treatment is the continuous
intravenous infusion of glucose, insulin and potassium. With this regimen, it is
possible to perform major surgery in diabetics with a lower risk.
PMID- 9550900
TI - Cardiovascular disease in diabetes and operative risk.
AB - Among the complications of diabetes, cardiovascular disease is one of the most
frequent, severe and invalidating. In the era before the introduction of insulin
treatment, the most frequent cause of death in diabetes were acute metabolic and
infectious complications; at present, after the introduction of insulin therapy
and the consequent major change in the clinical evolution of the disease, the
most frequent cause of death is due to cardiovascular complications. From the
Framingham study it is possible to observe that in the adult diabetic population,
the annual incidence of death from cardiovascular causes is about 17%, both in
men and women, as against 8.5% in non diabetic males and 3.6% in non diabetic
females. Major clinical forms of cardiovascular disease in diabetics are
myocardial ischemia, autonomic neuropathy and cardiomyopathy.
PMID- 9550901
TI - Lower limb revascularization in diabetics.
AB - Treatment of critical lower limb ischemia in diabetics is often a complex
clinical problem for the diabetics' general condition and the local condition of
the territory to be revascularized. For these reasons, often the only treatment
for diabetics with ischemic-necrotic lesions is amputation. In the symptomatology
of arterial disease in diabetics there are three stages: claudication, rest pain,
ulcerative-necrotic lesions and two treatment modalities: conservative treatment
and revascularization. Conservation is based on the optimization of metabolic
control, correction of anemia, control of risk factors, removal of necrotic
areas, specific antibiotic treatment based on culture tests. No healing of
ulcerative-necrotic lesions after a reasonable period of optimum therapy,
quantified in 6 weeks, is suggestive for the presence of absolute or relative
ischemia and diagnostic angiography is suitable for the indication for
intravascular or surgical revascularization. The latter, in case of diabetics
with ischemic complications of the foot, is performed in specialized centers with
inverted saphenous veins or in situ in the supragenicular and subgenicular
district. Recently intravascular revascularization with balloons, atherotomes,
stents, less invasive and less traumatic than bypass revascularization, have
become available. At present, with peripheral revascularization, limb salvage at
5-years is feasible in 92% of diabetics with critical lower extremity ischemia.
PMID- 9550904
TI - In search of future role models in medicine.
PMID- 9550902
TI - The role of interventional radiology in the treatment of the diabetic foot.
AB - Although the pathologic features of arterial disease in diabetes do not differ
from those of simple atheromatous lesions, the plurisegmental involvement, the
predominant subpopliteal location of lesions and the association with impaired
cardiac and renal function in these patients imply peculiar problems in the
selection of an adequate therapy. At present, in interventional radiology a
number of procedures are available for intravascular therapy (angioplasty, stent,
locoregional fibrinolisis, mechanical atherectomy), particularly suitable for
diabetics who are affected by multisystem impairment. These procedures are not in
opposition to the conventional ones (surgical and medical) but rather integrate
them, allowing to extend the indications and improve the results in the treatment
of the vasculogenic diabetic foot. Based on the personal experience the potential
of intravascular procedures in this disease, is analyzed.
PMID- 9550903
TI - The foot clinic. Multidisciplinary management of the patient with diabetic foot.
AB - Treatment of a complex disease as the diabetic foot requires a multidisciplinary
management with the close collaboration of a team for care. The most important
members of the team are the diabetologist as coordinator, the vascular surgeon,
the orthopedist, the radiologist, the orthopedic technician, the podiatrist and
the nurse specialist. The care based on this arrangement should be carried out in
dedicated rooms and times to exploit at best the organizational potential in the
patient's interest, implemented in the foot clinic.
PMID- 9550905
TI - Clinical pathways--a new paradigm in healthcare?
PMID- 9550906
TI - Spontaneous corneal perforation in premature infants.
AB - Spontaneous corneal perforation in premature infants not due to birth trauma is a
rare event, with only 8 cases reported in the literature. We recently encountered
a case of spontaneous corneal perforation in an extremely premature infant born
at 26 weeks of gestation. The mechanism leading to this event was corneal
exposure resulting in corneal epithelial defect. Clinical evidence of secondary
infection ensued and this led to cornea thinning, descemetocoele formation and
subsequent perforation with extrusion of intraocular contents. Although other
mechanisms were responsible in the previously reported cases, we feel that
exposure keratopathy leading to this complication poses a potential hazard to all
premature infants. An awareness among care givers of this potential complication
together with avoidance of exposure keratopathy in this group of patients is
paramount in preventing this visually catastrophic event.
PMID- 9550907
TI - Clinical presentation of herpes zoster in a Singapore hospital.
AB - BACKGROUND: There is a direct correlation between increasing age and incidence of
herpes zoster. There is an increased risk of complications in the elderly and the
immunocompromised. OBJECTIVE: To study the clinical epidemiology of hospitalised
patients with herpes zoster. METHODS: Medical records of all patients
hospitalised with zoster were respectively analysed. RESULTS: Sixty-seven
patients (3% of total admissions) were studied. There were 35 males and 32
females with a mean age of 50.35 +/- 21.71. There was an increased proportion of
older patients in the study cohort. Nineteen patients (28.4%) were
immunocompromised with malignancy occurring in 9 patients. Thirteen had been on
cytotoxic and/or steroid therapy. The commonest symptoms were rash, pain and
fever. Eighty-five percent of the patients had complications (bacterial super
infection in (61%), dissemination (31%), ocular involvement (5%) and post
herpetic neuralgia (13.4%). There was an increasing frequency of duration of pain
with increasing age in the patients with post-herpetic neuralgia. Forty-three
patients were treated with acyclovir. The median time to healing of lesions was
11 days. The 41 patients with bacterial super-infection received antibiotics with
median time to healing of 12 days. CONCLUSION: Increasing age and
immunocompromised state appear to be risk factors for developing herpes zoster in
hospitalised patients.
PMID- 9550908
TI - Urological injuries in gynaecological practice--when is the optimal time for
repair?
AB - OBJECTIVE: This is a retrospective study to determine differences in outcome and
prognosis between patients with urological injuries treated immediately within 30
days by definitive repair and those in whom definitive treatment was delayed.
SUBJECTS: Patients who sustained urinary tract injuries after gynaecological
surgery and who were subsequently referred to the Urological Department of
(former) Toa Payoh Hospital during the period 1985-1991. RESULTS: There were nine
injuries sustained in eight patients: six to the ureters and three to the
bladder. One patient had a double injury: a vesico-vaginal fistula and a uretero
vaginal fistula. There were six patients whose injuries were repaired within 30
days of the primary gynaecological operation. They stayed an average of 10-14
days in hospital and were discharged well. They were well both clinically and
radiologically on follow-up. Two patients had initial drainage before definitive
surgery was undertaken. One patient recovered fully but had to endure the
morbidity of a prolonged, 3-month hospital stay. The other patient treated by
simple diathermy for her vesico-vaginal fistula, never fully recovered, and
subsequently defaulted follow-up. CONCLUSION: The old dictum of waiting 3 to 6
months to allow oedema to subside, tissue planes to be re-established and the
fistula to become smaller, before repair is attempted, should be reviewed.
Recently acquired fistulae may be repaired definitively soon after diagnosis of
the problem, with good results in competent hands, as supported in this series of
patients studied. This shortens the length of hospital stay for the patients and
alleviates much of the morbidity endured.
PMID- 9550909
TI - Quality of life survey among day release patients at View Road Hospital.
AB - OBJECTIVES: The aim of this study was to identify factors that contributed to the
chronic patient's quality of life from both the patients' and staff's point of
view. We were also interested in any lack of congruence between staff and patient
perception as these could have significant implications for planning long-term
care. METHOD: Fifty of the patients under the Day Release Scheme at View Road
Hospital and their staff were given a modified questionnaire concerning the
patients' quality of life. RESULTS: Generally the patients reported satisfaction
with life domain items covering their living conditions. The majority felt safe
in the current setting, enjoyed their work, their regular outings and parole to
the nearby shopping centers. Significant differences were observed between the
staff and patients' perception in life domain items relating to general well
being, knowledge and education, relationships, in-patient care, leisure and
vocational rehabilitation. The staff group perceived having good food, money,
good treatment and in employment as being important to their patients' well
being. Patients emphasised having money, family support or a partner, being
employed, having time for recreational activities and eating good food. Having
good health, medication and feeling at peace were also considered important by
many of our patient. CONCLUSIONS: The findings of the study are discussed with
regard to implications in planning rehabilitation services and improving the
quality of care given to patients.
PMID- 9550910
TI - The impact of the neonatal resuscitation program guidelines (NRPG) on the
neonatal mortality in a hospital in Zhuhai, China.
AB - AIM: The neonatal resuscitation program (NRPG) was first introduced in our
hospital to replace the traditional resuscitation (TR) program in 1993. TR has
been in existence in China for a long time. The implementation of NRPG was timely
in reducing the number of infant mortality and also to disseminate to the many
hospitals in China which are still practising TR. METHOD: A perspective study of
4,751 newborns with 366 asphyxiated babies in a period of 2 years was carried
out. A previous sample of 1,722 live births under the TR program was compared as
a controlled group statistically. RESULTS: From August 1993 to August 1995, when
NRPG was exclusively implemented in our hospital, only 16 newborns died within 7
days, out of 4,751 births (3.4%) with 2 deaths in the delivery room. Seventeen
newborns died within 7 days out of 1,722 births (9.9+) in the TR group, with 10
deaths in the delivery room. From the data shown, it can be clearly seen that
perinatal neonatal mortality rate was reduced almost 3 times after NRPG was
implemented (chi(2) = 10.54, p < 0.01). The follow-up results of 21 cases of
severe asphyxia at 2 months--1 year of age were normal except for one with
cerebral palsy. CONCLUSIONS: Our study showed that NRPG was indeed a very
effective and feasible technique during the delivery process in the reduction of
neonatal mortality. It is important to disseminate widely the knowledge and
technique of NRPG in places where TR is still being widely practiced especially
in developing countries.
PMID- 9550911
TI - An unusual case of acute onset of cardiac failure.
AB - Rupture of the aortic sinus of Valsalva is one of the rare causes of acute
dyspnoea. Modern advances have enabled diagnosis to be made easily with
echocardiography as illustrated in this case. The treatment of choice is surgery
with excellent prognosis if detected early. Therefore a high index of suspicion
is required to diagnose this potentially threatening but yet treatable condition.
PMID- 9550912
TI - Acute leukemia presenting as pericardial effusion--a case report.
AB - We report a patient with acute lymphoblastic leukemia, who presented with
pericardial effusion. There was no haematologic evidence of leukemia at the time
of presentation. The pericardial effusion resolved with chemotherapy. Although a
common finding at autopsy, clinically evident pericardial effusion is rare in
leukemia. It is also extremely rare for pericardial effusion to be the presenting
feature or to antedate haematologic evidence of leukemia. Physician awareness is
important to make a correct diagnosis.
PMID- 9550913
TI - Diagnostic difficulties associated with phaeochromocytoma--4 case illustrations.
AB - The diagnosis of phaeochromocytoma can be extremely difficult with 40%-76% of
cases escaping diagnosis during life. Until recently, the only available
biochemical test for the detection of phaeochromocytoma in Singapore has been the
24-hour urinary vanillyl mandelic acid (VMA). Urinary VMA has been reported to
have a high specificity (85%-100%) but variable sensitivity (28%-90%) in the
diagnosis of this disease. In 1993, high performance liquid chromatography (HPLC)
assays for the measurement of urinary catecholamines and metanephrines were
introduced at the Singapore General Hospital. Since 1993, 4 cases of
phaeochromocytoma have been detected at our institution. We report here, the
diverse clinical presentations of these patients. The urinary-free catecholamine
and catecholamine metabolite levels of these patients were compared with
corresponding levels from 12 non-phaeochromocytoma patients. Using the reference
value of 65.6 mumol/day, we found the urinary VMA to be a highly sensitive (100%)
test with a specificity of only 31%. In contrast, a urinary total metanephrine
level > or = 9,000 nmol/day was both sensitive (100%) as well as specific (100%).
PMID- 9550914
TI - Fluorescent in-situ hybridization--some of its applications in clinical
cytogenetics.
AB - Fluorescent in-situ hybridization (FISH) is becoming more and more relevant as an
important future tool in prenatal and pre-implantation genetic diagnosis and
cancer cytogenetics. This review describes the FISH technique as applied to whole
chromosome spreads and interphase cells and discusses its applications in
clinical cytogenetics. Information is presented on the various types of probes
and the subsequent hybridization and detection procedures. The potential use of
this novel FISH technique in the diagnosis of numerical and structural
chromosomal aberrations in routine karyotyping for prenatal diagnosis, tumour
cytogenetics and pre-implantation genetic diagnosis is outlined.
PMID- 9550915
TI - Clinics in diagnostic imaging (31). Adrenal neuroblastoma.
AB - A 3-year-old girl presented with epigastric pain and physical examination showed
a hard right upper quadrant mass. Urine VMA and HVA were found to be raised. CT
scan showed a large mass arising from the right adrenal gland, with necrotic
areas and ring calcification There was midline extension. The diagnosis of
neuroblastoma was confirmed by bone marrow aspiration biopsy. As the patient had
inoperable stage IV neuroblastoma, she was treated with multi-drug chemotherapy.
Follow-up CT scan showed excellent response to the chemotherapy, and the tumour
was successfully resected. Harvesting of autologous peripheral bone marrow stem
cells, megatherapy with Melphalan, and marrow rescue with the stem cells were
effective. The child has been well for three years to date. The clinical and
imaging features of neuroblastoma, particularly the role of imaging in staging,
are emphasised.
PMID- 9550916
TI - Voluntarism.
PMID- 9550917
TI - Closed head injuries in children following the use of a sarong cradle.
AB - INTRODUCTION: Sarong cradles are unique to South-East Asian culture. Their use
can lead to injuries from falls, over-enthusiastic rocking and defective
equipment. We present 19 children who attended the Accident and Emergency (A&E)
Department of a general hospital and who sustained injuries while in a sarong
cradle. All had closed head injuries. METHODS AND MATERIALS: The data was
collected over a 9-month period from September 1992 to May 1993. All patients
with a documented history of fall following the use of a sarong cradle, were
recruited into the study. The adults accompanying the patients were interviewed
with a structured questionnaire. The information was recorded by the doctor in
attendance. RESULTS: The ages of the 19 patients ranged from 13 days to 29
months. There were 17 Chinese, 1 Malay and 1 Indian. The types of closed head
injuries included minor head injury with no external signs of injury, scalp
lacerations, scalp haematomas and severe head injury with an extradural
haematoma. The majority (14) were discharged from the A&E Department with head
injury advice, 4 were admitted to the General Neurosurgical ward and one, to the
Neurosurgical Intensive Care Unit. There were no fatalities in this group. The
accidents happened while the children were either sleeping (14), playing (4) or
feeding (1). CONCLUSIONS: While most head injuries sustained in this manner are
usually mild, there is a potential that such injuries may lead to more serious
injuries. Care givers who use the sarong cradle should be aware of the dangers
and exercise due care during use.
PMID- 9550918
TI - A 5-year review of FIGO stage IB cervical cancer in an Asian population.
AB - OBJECTIVE: We studied the clinical patterns and outcome of patients with FIGO
(1985) Stage 1b cervical cancer. In particular, looking at the clinico
pathological characteristics in relation with disease recurrence. PATIENTS &
METHODS: Ninety-nine Asian patients were managed at (the former) K K Hospital,
Singapore, from 1987 to 1991. The mean and median follow-up periods were 67 and
60 months respectively. This study was performed in 1995. RESULTS: The majority
of the patients (81%) was treated by radical hysterectomy with or without
adjuvant radiotherapy/chemotherapy while 15% were treated by radical pelvic
radiotherapy alone and 4% of patients had pelvic radiotherapy following the
diagnosis of cervical cancer after a simple hysterectomy. Thirteen patients
developed tumour recurrence (13.1%). In these patients, there was a greater
proportion of adenocarcinomas (31% vs 13%, p = 0.1065), lymph node metastases
(45% vs 20%, p = 0.09) and surgical margins involvement (45% vs 7%) 7%, p =
0.004) while there seemed to be no difference in histological sub-types, vascular
space involvement and cytological grading. The relative risks of developing
tumour recurrence in patients with adenocarcinoma was 2.5 times (95% CI: 0.88
7.05), lymph-node metastasis: 2.3 times (95% CI: 0.96-4.93) and involved surgical
margins; 5.9 times (95% CI: 2.27-15.5). The mean time to recurrence were 21.7
months with all of them detected within 36 months following primary therapy. All
of them had abnormal physical findings while routine follow-up Pap smear was
positive in only one patient (8%). In general, the outcome of salvage treatment
was poor. CONCLUSIONS: In our group of patients with FIGO Stage lb cervix cancer,
majority had radical surgery performed initially. Thirteen percent had disease
recurrence, in which there were greater proportions of patients with
adenocarcinoma, lymph-node metastasis, and involved surgical margins. The mean
time-to-recurrence was 21.7 months with all detected by 36 months. Routine follow
up Pap smear seemed to be a poor indicator of disease status.
PMID- 9550919
TI - Efficacy of intravenous adenosine in treatment of paroxysmal supraventricular
tachycardia in the local population.
AB - In a prospective study conducted over 4 months at the Accident and Emergency
Department, 21 patients with 24 episodes of spontaneous paroxysmal
supraventricular tachycardia (PSVT) were treated with intravenous adenosine at
incremental doses of 3 mg, 6 mg, 9 mg and 12 mg until termination of the PSVT.
There were 6 males and 15 females. The mean age was 54 +/- 17 years (range from
23 to 83 years). The mean QRS rate was 171 +/- 21 per minute. When data were
expressed in a cumulative manner, the response to intravenous adenosine 3 mg, 6
mg, 9 mg and 12 mg in the 24 episodes of PSVT were 5 episodes (21%), 16 episodes
(67%), 20 episodes (83%) and 20 episodes (83%) respectively. Adverse effects were
present in 10 episodes (42%) of the PSVT. They were all mild and transient,
lasting less than 1 minute.
PMID- 9550920
TI - Anterior cruciate ligament reconstruction using patellar tendon autografts--a
review of results.
AB - AIM: The aim of this retrospective study was to review the results of anterior
cruciate ligament reconstruction using patellar tendon autografts. METHODS: Forty
one knees were available for evaluation at a minimum of 24 months follow-up.
Objective, subjective, functional and KT-1000 arthrometric tests were performed.
RESULTS: 92.7% had a negative or trace pivot shift at follow-up. None of the
patients had rupture of the autografts at review. The mean post-operative single
legged hop was 81%. The KT-1000 arthrometric evaluation post-operatively revealed
a mean maximum manual difference of 0.5 mm; 90.2% of these patients had a maximum
manual difference of less than 4 mm. Five patients (12.2%) had a "tighter"
reconstructed knee (a negative mean maximum manual difference). More than 70% of
the patients in this series had good to excellent results on functional,
subjective and objective evaluation scores. CONCLUSION: Excellent motion
recovery, reliable stabilisation rates, good arthrometric results and encouraging
post-operative functional, subjective and objective evaluation scores can be
expected in patients undergoing anterior cruciate ligament reconstruction with
patellar tendon autografts.
PMID- 9550921
TI - Clinics in diagnostic imaging (32). Opportunistic pneumonia in acquired
immunodeficiency syndrome (AIDS)
AB - A 24-year old HIV-positive patient presented with fever and productive cough.
Chest radiograph showed a cavitating pulmonary infiltrate. Diagnosis of
Nocardosis was made from modified acid-fast stain of his sputum specimen. He
responded well to antibiotics. The radiographic patterns of opportunistic
infection in patients with AIDS, with emphasis on cavitary pneumonia, is
discussed.
PMID- 9550923
TI - Connection between the medical profession and the pharmaceutical industry.
PMID- 9550922
TI - The Marei Ika Daigaku (Syonan Medical College) during the Japanese occupation of
Singapore (1942-1945).
AB - During the Japanese Occupation of Singapore (1942-1945), Singapore was renamed
Syonan (or Syonanto). The Japanese Military Administration established The
Medical College on 27 April 2603 (1943) and it was known as The Marei Ika Daigaku
or Syonan Medical College. It was sited at the Tan Tock Seng Hospital (Hakua
Byoin). The Ika Daigaku relocated to the General Hospital, Malacca in February
2604 (1944) where it functioned till the end of the Japanese Occupation in
September 1945. About 200 students from Singapore, Malaya, Sumatra and Java
attended the Syonan Medical College; the students were taught mainly Japanese
language and culture.
PMID- 9550924
TI - The elusive goal of transfusion safety.
PMID- 9550925
TI - Abnormal spinal fluid in hypertensive encephalopathy.
AB - A 44-year-old white male presented with marked hypertension and encephalopathy.
His spinal fluid showed a neutrophilic pleocytosis in the absence of infection.
While cases of hypertensive encephalopathy with concomitant minor lymphocytic
pleocytosis have been occasionally described, it is distinctly abnormal to have a
neutrophilic pleocytosis in this setting.
PMID- 9550926
TI - Ibuprofen use in pediatric patients.
PMID- 9550927
TI - Canalith repositioning procedure for relief of post-stapedectomy benign
paroxysmal positional vertigo.
AB - A 41-year-old woman underwent a successful stapedectomy for relief of conductive
hearing loss due to otosclerosis. Post-operatively, she developed persistent
symptoms of benign paroxysmal positional vertigo (BPPV). Eight weeks later, a
canalith repositioning procedure was performed in the office, with immediate
complete resolution of her vertigo. Anatomic and pathophysiologic implications of
these observations will be discussed.
PMID- 9550928
TI - A comparative longitudinal study of gastrostomy devices in children.
AB - Long-term gastrostomy is a predictable intervention to ameliorate the effects of
feeding and swallowing difficulties among children with severe spastic cerebral
palsy. The evidence evaluating the efficacy and implications of the available
gastrostomy devices in common use has focused primarily on the operative phase,
ignoring the long-term effects that may be critical from a nurse's or family
caregiver's point of view. In this study, the authors describe a sample of
children with gastrostomy, comparing skin-level and tube devices on measures of
nutritional outcome, complications, and caregiver satisfaction. In contrast to
manufacturer's claims about the superiority of skin-level devices, the results
presented here reveal few differences between the devices. The authors conclude,
therefore, that device selection should be determined by individualized
comprehensive assessment of the child and family circumstances.
PMID- 9550929
TI - The evaluation of motivation for sexual health among women.
AB - This study conducted a psychometric evaluation of the construct validity of the
Health Self-Determinism Index-Sexual (HSDI-S). The instrument was modified to
measure motivation related to sexual health rather than motivation of general
health in the Health Self-Determinism Index (HSDI). The HSDI-S was completed by
260 conveniently selected women (between the ages of 18 and 44) attending primary
care clinics in the southeastern United States. Confirmatory factor analysis
using LISREL did not validate the four subscales of the original HSDI. Subsequent
exploratory and confirmatory factor analysis isolated a single-factor model
composed of eight items: four judgment items and four external/internal cues
items. This finding is suggestive that changes in wording appear to have shifted
the responses from motivation for sexual health to that of women's perception of
their role in intimate relationships. The eight extrinsically worded items
isolate a single-factor model of social and cultural influences of child-bearing
age women's intimate relationships.
PMID- 9550930
TI - Establishing the nurse-family relationship in the intensive care unit.
AB - The nurse-family relationship in the intensive care unit (ICU) may replace the
traditional nurse-patient relationship due to the patient's compromised state. As
a result, the nurse-family relationship becomes extremely important. Nurses and
families may develop a relationship in which they work together to benefit the
patient, or an inadequate relationship may develop. In this study, strategies
used by nurses and families to either develop or inhibit the development of the
nurse-family relationship were identified. Using unstructured interviews with ICU
nurses and family members of ICU patients, categories of strategies were
identified and behaviors described. Nurses and families perceived that they each
displayed only positive behaviors yet identified inhibiting behaviors of the
other. Once the behaviors were shown to nurses as secondary informants, they were
able to identify with their negative behaviors. An understanding of these
strategies will help nurses to reevaluate their practice and enhance their
understanding of the behaviors of family members.
PMID- 9550931
TI - Hopefulness, self-esteem, and perceived social support among pregnant and
nonpregnant adolescents.
AB - The concepts of hope, self-esteem, and social support have been identified as
important factors in understanding a wide range of adolescent behaviors. The
purpose of this exploratory study was to examine the relationship of perceived
hopefulness, self-esteem, and social support with pregnancy status. Employing a
cross-sectional design, a sample of pregnant (n = 58) and nonpregnant (n = 91)
adolescents between the ages of 14 and 18 completed the Hopefulness Scale for
Adolescents (HSA), the Rosenberg Self-Esteem Scale (RSES), and the Norbeck Social
Support Questionnaire (NSSQ). Multiple regression analyses were used to assess
the association of pregnancy status with hopefulness, self-esteem, and social
support while controlling for age and socioeconomic status (SES). The effects of
pregnancy status on each psychosocial variable were examined independently.
Findings revealed pregnancy status was not associated with hopefulness, self
esteem, or perceived social support when age and SES were controlled.
PMID- 9550932
TI - Experiences of African American adolescent fathers.
AB - Social and cultural factors influence the experience of fatherhood. This
descriptive focus-group study describes the lived experience of fatherhood from
the perspectives of 5 unmarried, low-income, African American adolescent fathers
in a Midwestern urban area. Naturalistic inquiry approach guided the study. Seven
themes of fatherhood emerged: barriers to fatherhood, value of fatherhood,
introduction to fatherhood, competencies of fatherhood, role-set relationships,
social norms of fatherhood, and father-child contact. This study suggests that
nurses should support the involvement of adolescent fathers with their children.
Future study may determine the influence of adult female family members on the
decisions of adolescent fathers to remain involved with their children.
PMID- 9550934
TI - Learning how to do research.
PMID- 9550933
TI - Measuring organizational readiness for nursing research programs.
AB - Nursing research programs are important innovations for health services
organizations (HSOs). Evidence supports the positive impact that successful
programs have on both clinical practice and patient outcomes. In the current era
of scarce health care resources, decision makers must be able to accurately judge
HSO readiness for nursing research programs to facilitate their success. Judging
innovation readiness is an important and complex process for decision makers. An
Innovation Readiness Scale (IRS) was developed from research-based HSO contextual
cues identified by nurse researchers as supportive of successful hospital-based
nursing research programs. The IRS provides decision makers with a measure by
which to judge HSO readiness for nursing research programs. Psychometric results
are reported from a pilot and actual test of the IRS in two urban acute care
settings involved in nursing research program innovation.
PMID- 9550935
TI - Strategies for conducting intervention research in schools.
PMID- 9550936
TI - Computerized data collection: example of a time-motion study.
PMID- 9550937
TI - Research risks with diverse groups: issues and safeguards.
PMID- 9550938
TI - Adenosine and ATP: progress in their receptors' structures and functions.
PMID- 9550939
TI - New delta-opioid antagonists as pharmacological probes.
PMID- 9550940
TI - Striatal adenosine A2A receptors--where are they? What do they do?
PMID- 9550941
TI - Revisiting the effect compartment through timing errors in drug administration.
AB - The variations in the pharmacological effects induced by timing errors in drug
intake are compared for two drugs, one acting by way of an effect compartment and
the other directly from the central compartment. A simulation was performed for
two drugs having the same concentration-effect relationship at the receptor site,
the same mean effect at equilibrium and identical concentrations in the central
compartment. In this article. Patrice Nony, Michel Cucherat and Jean-Pierre
Boissel discuss how, for the same variability of concentrations in the central
compartment, the variations in mean effects are different. When there is a large
variability in the interval separating two consecutive doses, the model that
includes an effect compartment dampens the pharmacokinetic variability present in
the central compartment. Such an approach may be useful for the prescription
recommendations of drugs, especially those with narrow therapeutic indices.
PMID- 9550942
TI - Endocannabinoids: a new class of vasoactive substances.
AB - Endogenous cannabinoids (endocannabinoids) have recently been identified in the
CNS and attention has now turned to their cardiovascular actions. The prototypic
endocannabinoid, anandamide, derived from arachidonic acid, has been shown to be
a vasorelaxant, particularly in the resistance vasculature. This vasorelaxation
has been shown to be both endothelium-independent and -dependent, depending on
the vascular bed. It has been proposed that an endocannabinoid may mediate the
nitric oxide- and prostanoid-independent component of endothelium-dependent
relaxations, as these responses are sensitive to a cannabinoid receptor
antagonist and show similarities to anandamide-induced relaxations. This
hypothesis has generated much controversy and the emerging conflicts in the
literature are discussed in this article by Michael Randall and David Kendall.
Despite this controversy, it has recently been shown that anandamide is produced
by endothelial cells. Clearly, much work is required to adequately define the
physiological significance of endocannabinoids in the cardiovascular system.
PMID- 9550943
TI - To what extent have functional studies of ischaemia in animals been useful in the
assessment of potential neuroprotective agents?
AB - A general consensus is being reached on the use of a combination of mortality and
functional end-points in clinical trials of neuroprotective agents. However, to
date, few preclinical studies have examined the effects of putative
neuroprotective agents on functional outcome after ischaemia. The data described
in this review show the importance of combining both histopathological and
neurobehavioural studies when evaluating the neuroprotective efficacy of anti
ischaemic agents in animal models of cerebral ischaemia. Here, Jackie Hunter, Ken
Mackay and Derek Rogers argue that measures of functional improvement in models
of ischaemia should be incorporated to characterize further the neuroprotection
afforded by a compound that could aid the selection of doses and end-point
measures in early clinical trials.
PMID- 9550946
TI - Improving the health of NHS workers.
PMID- 9550944
TI - The role of stress in drug self-administration.
AB - Environmental experiences have an important effect on the sensitivity of an
individual to drugs of abuse. Studies of drug self-administration in laboratory
animals have shown that both physical and psychological stressors facilitate the
acquisition of drug self-administration, probably by increasing the reinforcing
efficacy of drugs of abuse. Stressors also facilitate the reinstatement of drug
taking even after prolonged periods of withdrawal. The adrenal hormones,
glucocorticoids, which increase the sensitivity of mesencephalic dopaminergic
neurones to drugs, seem to be one of the biological substrates of the effects of
stress on the propensity to develop drug intake. In this review, Pier Vincenzo
Piazza and Michel Le Moal discuss theories of drug abuse, the influence of
different stressful experiences on drug self-administration and their possible
mechanisms of action.
PMID- 9550945
TI - Informed consent: edging forwards (and backwards)
PMID- 9550947
TI - Chernobyl and public health.
PMID- 9550948
TI - Inflammatory responses and coronary heart disease.
PMID- 9550949
TI - Consultant suspended for not getting consent for cardiac procedure.
PMID- 9550950
TI - Labour talks tough on waiting lists.
PMID- 9550951
TI - WHO identifies 16 countries struggling to control tuberculosis.
PMID- 9550952
TI - The children's advocate. Interview by Kamran Abbasi.
PMID- 9550953
TI - Fluid resuscitation with colloid or crystalloid solutions in critically ill
patients: a systematic review of randomised trials.
AB - OBJECTIVE: To determine the effect on mortality of rescuscitation with colloid
solutions compared with resuscitation with crystalloids. DESIGN: Systematic
review of randomised controlled trials of resuscitation with colloids compared
with crystalloids for volume replacement of critically ill patients; analysis
stratified according to patient type and quality of allocation concealment.
SUBJECTS: 37 randomised controlled trials were eligible, of which 26 unconfounded
trials compared colloids with crystalloids (n = 1622). (The 10 trials that
compared colloid in hypertonic crystalloid with isotonic crystalloid (n = 1422)
and one trial that compared colloid in isotonic crystalloid with hypertonic
crystalloid (n = 38) are described in the longer version on our website
www.bmj.com). MAIN OUTCOME MEASURES: Mortality from all causes at end of follow
up for each trial. RESULTS: Resuscitation with colloids was associated with an
increased absolute risk of mortality of 4% (95% confidence interval 0% to 8%), or
four extra deaths for every 100 patients resuscitated. The summary effect measure
shifted towards increased mortality with colloids when only trials with adequate
concealment of allocation were included. There was no evidence for differences in
effect among patients with different types of injury that required fluid
resuscitation. CONCLUSIONS: This systematic review does not support the continued
use of colloids for volume replacement in critically ill patients.
PMID- 9550954
TI - Is day care equivalent to inpatient care for active rheumatoid arthritis?
Randomised controlled clinical and economic evaluation.
AB - OBJECTIVE: To test the clinical equivalence and resource consequences of day care
with inpatient care for active rheumatoid arthritis. DESIGN: Randomised
controlled clinical trial with integrated cost minimisation economic evaluation.
SETTING: Rheumatic diseases unit at a teaching hospital between 1994 and 1996.
SUBJECTS: 118 consecutive patients with active rheumatoid arthritis randomised to
receive either day care or inpatient care. MAIN OUTCOME MEASURES: Clinical
assessments recorded on admission, discharge, and follow up at 12 months
comprised: the health assessment questionnaire, Ritchie articular index,
erythrocyte sedimentation rate, hospital anxiety and depression scale, and
Steinbrocker functional class. Resource estimates were of the direct and indirect
costs relating to treatment for rheumatoid arthritis. Secondary outcome measures
(health utility) were ascertained by time trade off and with the quality of well
being scale. RESULTS: Both groups had improvement in scores on the health
assessment questionnaire and Ritchie index and erythrocyte sedimentation rate
after hospital treatment (P < 0.0001) but clinical outcome did not differ
significantly between the groups either at discharge or follow up. The mean
hospital cost per patient for day care, 798 Pounds (95% confidence interval 705
Pounds to 888 Pounds), was lower than for inpatient care, 1253 Pounds (1155
Pounds to 1370 Pounds), but this difference was offset by higher community,
travel, and readmission costs. The difference in total cost per patient between
day care and inpatient care was small (1789 Pounds (1539 Pounds to 2027 Pounds) v
2021 Pounds (1834 Pounds to 2230 Pounds)). Quantile regression analysis showed a
cost difference in favour of day care up to the 50th centile (374 Pounds; 639
Pounds to 109 Pounds). CONCLUSIONS: Day care and inpatient care for patients with
uncomplicated active rheumatoid arthritis have equivalent clinical outcome with a
small difference in overall resource cost in favour of day care. The choice of
management strategy may depend increasingly on convenience, satisfaction, or more
comprehensive health measures reflecting the preferences of patients, providers,
and service commissioners.
PMID- 9550955
TI - Benefit of heparin in peripheral venous and arterial catheters: systematic review
and meta-analysis of randomised controlled trials.
AB - OBJECTIVE: To evaluate the effect of heparin on duration of catheter patency and
on prevention of complications associated with use of peripheral venous and
arterial catheters. DESIGN: Critical appraisal and meta-analysis of 26 randomised
controlled trials that evaluated infusion of heparin intermittently or
continuously. Thirteen trials of peripheral venous catheters and two of
peripheral arterial catheters met criteria for inclusion. MAIN OUTCOME MEASURES:
Data on the populations, interventions, outcomes, and methodological quality.
RESULTS: For peripheral venous catheters locked between use flushing with 10 U/ml
of heparin instead of normal saline did not reduce the incidence of catheter
clotting and phlebitis or improve catheter patency. When heparin was given as a
continuous infusion at 1 U/ml the risk of phlebitis decreased (relative risk
0.55; 95% confidence interval 0.39 to 0.77), the duration of patency increased,
and infusion failure was reduced (0.88; 0.72 to 1.07). Heparin significantly
prolonged duration of patency of radial artery catheters and decreased the risk
of clot formation (0.51; 0.42 to 0.61). CONCLUSIONS: Use of intermittent heparin
flushes at doses of 10 U/ml in peripheral venous catheters locked between use had
no benefit over normal saline flush. Infusion of low dose heparin through a
peripheral arterial catheter prolonged the duration of patency but further study
is needed to establish its benefit for peripheral venous catheters.
PMID- 9550956
TI - Use of anticonvulsants in eclampsia and pre-eclampsia: survey of obstetricians in
the United Kingdom and Republic of Ireland.
PMID- 9550957
TI - Satisfaction with clinical nurse specialists in a breast care clinic:
questionnaire survey.
PMID- 9550958
TI - Health beliefs and folk models of diabetes in British Bangladeshis: a qualitative
study.
AB - OBJECTIVE: To explore the experience of diabetes in British Bangladeshis, since
successful management of diabetes requires attention not just to observable
behaviour but to the underlying attitudes and belief systems which drive that
behaviour. DESIGN: Qualitative study of subjects' experience of diabetes using
narratives, semi-structured interviews, focus groups, and pile sorting exercises.
A new qualitative method, the structured vignette, was developed for validating
researchers' understanding of primary level culture. SUBJECTS: 40 British
Bangladeshi patients with diabetes, and 10 non-Bangladeshi controls, recruited
from primary care. RESULT: Several constructs were detected in relation to body
image, cause and nature of diabetes, food classification, and knowledge of
complications. In some areas, the similarities between Bangladeshi and non
Bangladeshi subjects were as striking as their differences. There was little
evidence of a fatalistic or deterministic attitude to prognosis, and most
informants seemed highly motivated to alter their diet and comply with treatment.
Structural and material barriers to behaviour change were at least as important
as "cultural" ones. CONCLUSION: Bangladeshi culture is neither seamless nor
static, but some widely held beliefs and behaviours have been identified. Some of
these have a potentially beneficial effect on health and should be used as the
starting point for culturally sensitive diabetes education.
PMID- 9550959
TI - Using epidemiological data to guide clinical practice: review of studies on
cardiovascular disease and use of combined oral contraceptives.
AB - OBJECTIVE: To explore the usefulness of epidemiological data to guide clinical
practice by seeking an answer to the question "What is the risk of cardiovascular
disease among users of currently available, low dose, combined oral
contraceptives who are aged less than 35 years, do not smoke, and do not have a
medical condition known to increase the risk of vascular disease?" DESIGN: Review
of all relevant published studies identified from the library of references held
by Royal College of General Practitioners' Manchester Research Unit, checking of
reference lists of identified studies, and Medline search. MAIN OUTCOME MEASURES:
Identification of methodologically sound studies able to address the specific
clinical question. RESULTS: Our literature search identified 74 papers about the
relation between current use of combined oral contraceptives and cardiovascular
disease: 23 papers reporting risk of venous thromboembolism, 22 on ischaemic
stroke, 13 on haemorrhagic stroke or subarachnoid haemorrhage, 13 on all stroke,
and 33 on myocardial infarction. Only five papers provided information that
directly addressed our clinical question; all related to the risk of venous
thromboembolism. Fourteen of the discarded papers probably had the potential to
answer our clinical question. CONCLUSIONS: Much of the epidemiological data about
the risk of cardiovascular disease in users of combined oral contraceptives is
not useful to clinicians. Some of the discarded data could be made more useful to
clinicians by reanalysis. This situation is unlikely to be unique to use of
contraceptives.
PMID- 9550960
TI - Transferring medical images on the World Wide Web for emergency clinical
management: a case report.
PMID- 9550961
TI - When can odds ratios mislead?
PMID- 9550962
TI - Periodontitis for medical practitioners.
PMID- 9550963
TI - ABC of allergies. Asthma and allergy.
PMID- 9550964
TI - Informed consent in medical research.
PMID- 9550965
TI - Thrombolytic treatment for acute ischaemic stroke: consent can be ethical.
PMID- 9550968
TI - Separation and other problems that threaten relationships.
PMID- 9550966
TI - Informed consent and research.
PMID- 9550967
TI - Videos, photographs, and patient consent.
PMID- 9550969
TI - Economic evaluation: an introduction.
PMID- 9550970
TI - Clinical management of meningococcal disease. Lumbar puncture is still performed
in patients with contraindications.
PMID- 9550971
TI - Clinical management of meningococcal disease. Coning may occur without lumbar
puncture being done.
PMID- 9550972
TI - Clinical management of meningococcal disease. Laboratory confirmation is
important.
PMID- 9550973
TI - Clinical management of meningococcal disease. Prospective international
registration of patients may be needed.
PMID- 9550975
TI - Blood products produced from plasma from donors in UK are still being made.
PMID- 9550974
TI - Meta-analysis of cigarette smoking, bone mineral density, and risk of hip
fracture. Three studies were omitted from meta-analysis.
PMID- 9550976
TI - Lumbar puncture and headache. Obtaining fluid samples and measuring intrathecal
pressure may require different approaches.
PMID- 9550977
TI - Lumbar puncture and headache. Replacing the stylet before withdrawing the needle
may help to prevent headache.
PMID- 9550978
TI - Lumbar puncture and headache. "Atraumatic needle" is a better term than "blunt
needle".
PMID- 9550979
TI - Lumbar puncture and headache. Aspirating cerebrospinal fluid speeds up procedure.
PMID- 9550980
TI - Lumbar puncture and headache. Epidural blood patching can be used to treat
headache.
PMID- 9550981
TI - Smoking, alcohol and coffee consumption, and H pylori infection. Alcohol
consumption eliminates rather than prevents infection with H pylori.
PMID- 9550982
TI - Smoking, alcohol and coffee consumption, and H pylori infection. Cross sectional
study shows no protective effect of alcohol.
PMID- 9550983
TI - UN Declaration of Human Rights. NHS does not heed human rights declaration.
PMID- 9550984
TI - UN Declaration of Human Rights. Medical students need to learn humanitarian
values.
PMID- 9550985
TI - Medical Devices Agency wants to see prospective clinical study of contraceptive
device.
PMID- 9550986
TI - Patients offered treatment for CHD need full information to make decision.
PMID- 9550987
TI - Decline in cognitive function in Parkinson's disease may be due to dementia with
Lewy bodies.
PMID- 9550988
TI - Publication of pictures of patient on BMJ's website was mistake.
PMID- 9550989
TI - The prevention of perinatal HIV transmission in the less-developed world.
PMID- 9550990
TI - HIV research, ethics, and the developing world.
PMID- 9550991
TI - Trade-offs in prenatal detection of Down syndrome.
AB - OBJECTIVES: This paper presents the results of different screening policies for
prenatal detection of Down syndrome that would allow decision makers to make
informed choices. METHODS: A decision analysis model was built to compare 8
screening policies with regard to a selected set of outcome measures.
Probabilities used in the analysis were obtained from official administrative
data reports in Spain and Catalonia and from data published in the medical
literature. Sensitivity analyses were carried out to test the robustness of
screening policies' results to changes in uptake rates, diagnostic accuracy, and
resources consumed. RESULTS: Selected screening policies posed major trades-offs
regarding detection rates, false-positive results, fetal loss, and costs of the
programs. All outcome measures considered were found quite robust to changes in
uptake rates. Sensitivity and specificity rates of screening tests were shown to
be the most influential factors in the outcome measures considered. CONCLUSIONS:
The disclosed trade-offs emphasize the need to comprehensively inform decision
makers about both positive and negative consequences of adopting one screening
policy or another.
PMID- 9550992
TI - Rational Down syndrome screening policy.
PMID- 9550993
TI - Human rights and maternal-fetal HIV transmission prevention trials in Africa.
AB - The human rights issues raised by the conduct of maternal-fetal human
immunodeficiency virus transmission trials in Africa are not unique to either
acquired immunodeficiency syndrome or Africa, but public discussion of these
trials presents an opportunity for the United States and other wealthy nations to
take the rights and welfare of impoverished populations seriously. The central
issue at stake when developed countries perform research on subjects in
developing countries is exploitation. The only way to prevent exploitation of a
research population is to insist not only that informed consent be obtained but
also that, should an intervention be proven beneficial, the intervention will be
delivered to the impoverished population. Human rights are universal and cannot
be compromised solely on the basis of beliefs or practices of any one country or
group. The challenge to the developed countries is to implement programs to
improve the health of the people in developing countries both by improving public
health infrastructure and by delivering effective drugs and vaccines to the
people.
PMID- 9550994
TI - Placebo controls in HIV perinatal transmission trials: a South African's
viewpoint.
PMID- 9550995
TI - The debate over maternal-fetal HIV transmission prevention trials in Africa,
Asia, and the Caribbean: racist exploitation or exploitation of racism?
PMID- 9550996
TI - Ethical challenges in efficacy trials of vaginal microbicides for HIV prevention.
AB - This paper discusses some of the ethical challenges raised by advanced clinical
trials designed to assess the safety and efficacy of vaginal microbicides in
protecting women from HIV infection. The ethical principles that guide clinical
research involving human subjects require that all participants in such trials be
provided available measures known to reduce the risk of HIV infection. However,
this will reduce the ability of the study to assess the protective effect of the
test microbicide. In addition, providing extensive services to trial participants
may be construed as an undue inducement if the study is being conducted among
vulnerable groups such as sex workers or women from disadvantaged communities.
Suggestions are provided to resolve this dilemma in the planning and
implementation of HIV prevention services for trial participants.
PMID- 9550997
TI - Deficient dietary iron intakes among women and children in Russia: evidence from
the Russian Longitudinal Monitoring Survey.
AB - OBJECTIVES: This study evaluated the iron sufficiency of the Russian diet.
METHODS: Data were obtained from 24-hour dietary recalls conducted in 4 rounds
(1992 through 1994) of a nationally representative longitudinal survey of 10,548
women and children. Iron bioavailability was estimated via algorithms adjusting
for enhancers (heme, vitamin C) and inhibitors (tannins in tea, phytates in
grains) consumed at the same meal. RESULTS: Dietary iron intakes were deficient
in the most vulnerable groups: young children and women of reproductive age.
Poverty status was strongly associated with deficiency. After adjustment for
enhancers and inhibitors, estimated bioavailable iron intakes at 3% to 4% of
total iron were inadequate in all women and children. CONCLUSIONS: These dietary
data suggest that Russian women and children are at high risk of iron deficiency.
Grain products rich in phytates, which inhibit absorption, were the major food
source of iron in Russia. High intakes of tea and low consumption of vitamin C
also inhibited iron bioavailability. Since changes in eating behavior could
potentially double iron bioavailability, educational programs should be explored
as a strategy for improving iron nutriture.
PMID- 9550998
TI - Substance use among nurses: differences between specialties.
AB - OBJECTIVES: Valid data on factors that increase a health care worker's likelihood
of substance use are integral in ensuring professional standards and quality
health care for consumers. This study explored the association between nursing
specialty and past-year substance use. METHODS: In an anonymous mailed survey, a
balanced stratified sample of registered nurses (n = 4438) reported their use of
marijuana, cocaine, and prescription-type drugs, as well as cigarette smoking and
binge drinking. RESULTS: Prevalence of use of all substances was 32%. Rates
varied by specialty, even when sociodemographics were controlled. Compared with
nurses in women's health, pediatrics, and general practice, emergency nurses were
3.5 times as likely to use marijuana or cocaine (odds ratio [OR] = 3.5; 95%
confidence interval [CI] = 1.5, 8.2); oncology and administration nurses were
twice as likely to engage in binge drinking; and psychiatric nurses were most
likely to smoke (OR = 2.4; 95% CI = 1.6, 3.8). No specialty differences appeared
for prescription-type drug use. CONCLUSIONS: Certain nursing specialties were
more likely than others to be associated with substance use. The differences were
not explained by demographic characteristics. Inasmuch as a comparison of these
results for nurses with prior work on physicians found considerable agreement by
specialty, preventive initiatives should consider inter-disciplinary approaches
to substance use education.
PMID- 9550999
TI - Unemployment and the likelihood of detecting early-stage breast cancer.
AB - OBJECTIVES: The objective of this study was to test the hypothesis that
unexpectedly high unemployment in a community is associated with reduced odds
that registered breast tumors are local. METHODS: The hypothesis was tested with
data from San Francisco for the 132 months beginning with January 1983. RESULTS:
Registered breast tumors were less likely to be local during periods of
unexpectedly high unemployment (8% less likely among non-Hispanic White women and
24% less likely among African-American women). CONCLUSIONS: Job loss may restrict
access to health services. Fear of job loss may also distract women from breast
self-examination and the identification of suspicious breast signs.
PMID- 9551000
TI - The protective effect of condoms and nonoxynol-9 against HIV infection.
AB - OBJECTIVES: Whether or not spermicides can reduce the risk of human
immunodeficiency virus (HIV) transmission remains an important question for the
control of heterosexual HIV transmission. The authors provide estimates from a
reanalysis of one of the few observational studies on the efficacy of condoms and
spermicides, used separately and together, per vaginal contact. METHODS: In this
reanalysis, three different models were used to assess the efficacy of
spermicides and condoms: linear (Pearl index), exponential (maximum likelihood),
and monotonic (marginal likelihood). RESULTS: Reported use of barrier methods
among 27,432 contacts was as follows: condoms plus nonoxynol-9, 39%; condoms
alone, 25%; nonoxynol-9 alone, 24%; and unprotected, 11%. Under all three models,
the results indicate a strong protective effect for spermicidal suppositories.
The Pearl index indicated that spermicide alone is apparently efficacious, but
the efficacy per contact cannot be quantified with this approach. Maximum
likelihood estimates for the efficacy of nonoxynol-9 alone and condoms (with or
without nonoxynol-9) were 100% (95% confidence interval [CI95] = 43%, 100%) and
92% (95% CI95 = 79%, 100%), respectively. CONCLUSIONS: The data from this
observational study suggest that spermicides may be efficacious in reducing the
risk of HIV transmission.
PMID- 9551001
TI - Risk factors for congenital syphilis in infants of women with syphilis in South
Carolina.
AB - OBJECTIVES: This study examined risk factors for congenital syphilis in South
Carolina. METHODS: Case infants with presumptive and confirmed congenital
syphilis were compared with control infants born to women with reactive
serologies during pregnancy, allowing investigation of risk factors for
congenital rather than acquired transmission of syphilis. Data were collected
from congenital syphilis report forms and birth certificates for 186 case infants
and 487 controls born from 1991 to 1993. Odds ratios were calculated for maternal
risk factors. RESULTS: Significant statistical trends were found for timing of
first prenatal visit and number of visits. Other significant factors included
rural residence (odds ratio [OR] = 2.0, 95% confidence interval [CI] = 1.4, 2.9)
and previous pregnancy loss (OR = 0.3, 95% CI = 0.2, 0.6). CONCLUSIONS:
Prevention of congenital syphilis may be less effective among pregnant women with
syphilis in South Carolina who have fewer prenatal care visits. Health care
providers need further education on maternal/child syphilis management and
techniques for motivating and educating patients.
PMID- 9551002
TI - Changing fruit and vegetable consumption among children: the 5-a-Day Power Plus
program in St. Paul, Minnesota.
AB - OBJECTIVES: A randomized school based trial sought to increase fruit and
vegetable consumption among children using a multicomponent approach. METHODS:
The intervention, conducted in 20 elementary schools in St. Paul, targeted a
multiethnic group of children who were in the fourth grade in spring 1995 and the
fifth grade in fall 1995. The intervention consisted of behavioral curricula in
classrooms, parental involvement, school food service changes, and industry
support and involvement. Lunchroom observations and 24-hour food recalls measured
food consumption. Parent telephone surveys and a health behavior questionnaire
measured psychosocial factors. RESULTS: The intervention increased lunchtime
fruit consumption and combined fruit and vegetable consumption, lunchtime
vegetable consumption among girls, and daily fruit consumption as well as the
proportion of total daily calories attributable to fruits and vegetables.
CONCLUSIONS: Multicomponent school-based programs can increase fruit and
vegetable consumption among children. Greater involvement of parents and more
attention to increasing vegetable consumption, especially among boys, remain
challenges in future intervention research.
PMID- 9551003
TI - Prevalence and impact of disabling chronic conditions in childhood.
AB - OBJECTIVES: This study provides a current national profile of the prevalence and
impact of chronic conditions causing childhood disability. Disability is defined
as a long-term reduction in ability to conduct social role activities, such as
school or play, because of a chronic physical or mental condition. METHODS: A
cross-sectional descriptive analysis was performed on data from 99513 children
younger than 18 years who were included in the 1992-1994 National Health
Interview Survey. The response rate exceeded 93% during each year. RESULTS: A
significant proportion of children, estimated at 6.5% of all US children,
experienced some degree of disability. The most common causes of childhood
disability were respiratory diseases and mental impairments. Prevalence of
disability was higher for older children, boys, and children from low-income and
single-parent families. Childhood disability is estimated to result in 66 million
restricted activity days annually, including 24 million days lost from school.
Furthermore, disability in childhood results in an added 26 million physician
contacts and 5 million hospital days annually. CONCLUSIONS: Childhood disability
has profound impacts on children, the education system, and the health care
system.
PMID- 9551004
TI - Variation between studies in reported relative risks associated with
hypertension: time trends and other explanatory variables.
AB - OBJECTIVES: This study examined the variation in reported relative risks of
coronary heart disease and stroke associated with hypertension and determined
reasons for the interstudy variation. METHODS: Studies published since 1970 were
examined that reported the absolute number of events and person-years for men by
age and hypertensive status. The data were pooled in Poisson regression models
with the coronary heart disease or stroke rate as the dependent variable.
Independent variables were hypertensive status, age at entry, age of study,
duration of follow-up, diastolic blood pressure cut-off point, and interactions
of all these variables with hypertensive status. RESULTS: The reported relative
risks associated with hypertension ranged from 1.45 to 2.77 for coronary heart
disease and from 1.86 to 5.78 for stroke. Smaller relative risks were found in
more recent studies, in studies with long follow-up, and in studies using a lower
cut-off point to define hypertension. CONCLUSIONS: Part of the interstudy
variation in relative risks associated with hypertension can be attributed to
differences in duration of follow-up, blood pressure cutoff point, and time at
which blood pressure was measured, suggesting declining relative risks over time.
PMID- 9551005
TI - Body mass index and mortality in nonsmoking older adults: the Cardiovascular
Health Study.
AB - OBJECTIVES: This study assesses the relationship of body mass index to 5-year
mortality in a cohort of 4317 nonsmoking men and women aged 65 to 100 years.
METHODS: Logistic regression analyses were conducted to predict mortality as a
function of baseline body mass index, adjusting for demographic, clinical, and
laboratory covariates. RESULTS: There was an inverse relationship between body
mass index and mortality; death rates were higher for those who weighed the
least. Inclusion of covariates had trivial effects on these results. People who
had lost 10% or more of their body weight since age 50 had a relatively high
death rate. When that group was excluded, there was no remaining relationship
between body mass index and mortality. CONCLUSIONS: The association between
higher body mass index and mortality often found in middle-aged populations was
not observed in this large cohort of older adults. Over-weight does not seem to
be a risk factor for 5-year mortality in this age group. Rather, the risks
associated with significant weight loss should be the primary concern.
PMID- 9551006
TI - Modeling all-cause mortality: projections of the impact of smoking cessation
based on the NHEFS. NHANES I Epidemiologic Follow-up Study.
AB - OBJECTIVES: A model that relates clinical risk factors to subsequent mortality
was used to simulate the impact of smoking cessation. METHODS: Survivor functions
derived from multivariate hazard regressions fitted to data from the first
National Health and Nutrition Examination Survey (NHANES I) Epidemiologic
Followup Study, a longitudinal survey of a representative sample of US adults,
were used to project deaths from all causes. RESULTS: Validation tests showed
that the hazard regressions agreed with the risk relationships reported by
others, that projected deaths for baseline risk factors closely matched observed
mortality, and that the projections attributed deaths to the appropriate levels
of important risk factors. Projections of the impact of smoking cessation showed
that the number of cumulative deaths would be 15% lower after 5 years and 11%
lower after 20 years. CONCLUSIONS: The model produced realistic projections of
the effects of risk factor modification on subsequent mortality in adults,
Comparison of the projections for smoking cessation with estimates of the risk
attributable to smoking published by the Centers for Disease Control and
Prevention suggests that cessation could capture most of the benefit possible
from eliminating smoking.
PMID- 9551007
TI - Informed consent for HIV testing in a South African hospital: is it truly
informed and truly voluntary?
AB - OBJECTIVE: The purpose of this study was to assess informed consent to human
immunodeficiency virus (HIV) testing in a perinatal HIV transmission study in a
major referral hospital serving a largely Black population in South Africa.
METHODS: First-time antenatal clinic attenders who were randomly selected from
those enrolled in the perinatal HIV study (n = 56) answered questionnaires before
and after counseling. RESULTS: Knowledge of HIV transmission and prevention, high
at the outset, was little improved after counseling. The acceptance rate for HIV
testing was high. Despite assurances that participation was voluntary, 88% of the
women said they felt compelled to participate in the study. CONCLUSIONS: Informed
consent in this setting was truly informed but not truly voluntary.
PMID- 9551008
TI - Differences in the risk of homicide and other fatal injuries between postpartum
women and other women of childbearing age: implications for prevention.
AB - OBJECTIVES: This study compared injury deaths between postpartum women and other
women aged 15 to 44. METHODS: Risk ratios and 95% confidence intervals (CIs) were
computed for injury fatality rates. RESULTS: Fifty percent (29/58) of postpartum
injury deaths were homicides, compared with 26% (427/1648) of injury deaths among
nonpregnant, nonpostpartum women. For females aged 15 to 19, the homicide rate
was 2.6 times higher (95% CI = 1.17, 5.95) for postpartum females than for other
females. The motor-vehicle fatality rate was lower for postpartum females than
for nonpregnant, nonpostpartum females (risk ratio = 0.30, CI = 0.18, 0.48).
CONCLUSIONS: Postpartum females aged 15 to 19 years were at higher risk of
homicide. Postpartum women were at reduced risk of motor-vehicle fatalities.
PMID- 9551009
TI - Facilitating condom use with clients during commercial sex in Nevada's legal
brothels.
AB - OBJECTIVES: This study examined condom use in legal Nevada brothels. METHODS:
Forty female prostitutes in two brothels were interviewed about client resistance
to condoms and techniques for facilitating condom use. RESULTS: Of 3290 clients
in the previous month, 2.7% (95% confidence interval [CI] = 2.2%,3.4%) were
reluctant to use condoms. Of these individuals, 72% ultimately used condoms,
while 12% chose nonpenetrative sex without condoms. The remaining 16% left the
brothels without services. Condom use rates were markedly lower with nonpaying
sex partners (lowers) than with clients. CONCLUSIONS: Brothel prostitutes may be
at greater risk for acquiring HIV and other sexually transmitted diseases from
lovers than from clients.
PMID- 9551011
TI - Family planning in China: out of control?
AB - OBJECTIVES: This study examined sex ratios in 6 counties in China. METHODS: Data
from a household survey (n = 5756) were retrospectively analyzed. RESULTS: A
normal sex ratio was found for children less than 18 years of age. Significant
differences in sex ratios and family size were observed between the household
survey data and population registers. CONCLUSIONS: The findings indicate a high
number of unregistered female births and are consistent with calls for a
rethinking of Chinese population policies in the direction of a more
collaborative policy based on female education and participation.
PMID- 9551010
TI - Reducing pregnancy and induced abortion rates in China: family planning with
husband participation.
AB - OBJECTIVES: This study assessed the effectiveness of a family planning
intervention with and without husband's participation in reducing pregnancy and
abortion rates in Shanghai, China. METHODS: In this 3-arm randomized trial among
1800 nonsterilized married women, educational interventions targeting both
spouses and targeting the wife only were compared with usual family planning
care. RESULTS: Among women not using intrauterine devices (IUDs), the
intervention with husband's participation had an effect in reducing pregnancy
rates (adjusted odds ratio [OR] = 0.36, 95% confidence interval [CI] = 0.12, 1.1)
and abortion rates (adjusted OR = 0.29, CI = 0.09, 0.94) compared with control
subjects, and a significant effect in reducing pregnancy rates (adjusted OR =
0.29, CI = 0.10, 0.85) and abortion rates (adjusted OR = 0.24, CI = 0.07, 0.77)
compared with wife-only subjects. CONCLUSIONS: Family planning interventions
involving husbands may reduce pregnancy and abortion rates among non-IUD users.
PMID- 9551012
TI - Infant mortality differences between whites and African Americans: the effect of
maternal education.
AB - OBJECTIVES: Despite decreasing infant mortality in North Carolina, the gap
between African Americans and Whites persists. This study examined how racial
differences in infant mortality vary by maternal education. METHODS: Data came
from Linked Birth and Infant Death files for 1988 through 1993. Multiple logistic
regression models adjusted for confounders. RESULTS: Infant mortality risk ratios
comparing African Americans and Whites increased with higher levels of maternal
education. Education beyond high school reduced risk of infant mortality by 20%
among Whites but had little effect among African Americans. CONCLUSIONS: Higher
education magnifies racial differences in infant mortality on a multiplicative
scale. Possible reasons include greater stress, fewer economic resources, and
poorer quality of prenatal care among African Americans.
PMID- 9551013
TI - Rates and independent correlates of Pap smear testing among Korean-American
women.
AB - OBJECTIVES: This study reports population estimates of Pap smear testing among
Korean-American women and evaluates correlates of testing. METHODS: Korean
Americans in 2 California counties were surveyed by telephone. Frequencies were
age-adjusted to the 1990 census to produce population estimates of testing.
Logistic regression models were used to evaluate independent correlates of
testing RESULTS: Only 50% of the Korean-American women surveyed had a Pap test in
the previous 2 years. The strongest independent correlate was having had a
regular check-up in the previous 2 years (odds ratio 7.2, 95% confidence interval
4.2, 12.1). CONCLUSIONS: Rates of Pap testing among Korean-American women are
well below national objectives. Collaboration and community-sensitive research
are essential to collect data and design programs to improve the health of ethnic
minority communities.
PMID- 9551014
TI - Contraception and abortion in two Vietnamese communes.
AB - OBJECTIVES: The authors examined factors predicting abortion use in two communes
in northern Vietnam. METHODS: A survey of 504 rural and 523 urban women of
childbearing age was conducted. RESULTS: For the 13.6% of urban and 19% of rural
commune women having had an abortion in the previous year, logistic regression
analyses demonstrated that use of an intrauterine device reduced the likelihood
of subsequent abortion in both communes. Traditional method use in the rural
commune, however, increased women's likelihood of a subsequent abortion.
CONCLUSIONS: Contraceptive use in these 2 communes affected abortion more than
sociodemographic factors. Traditional method use by rural women is a risk for
abortion.
PMID- 9551015
TI - Differences in preconceptional and prenatal behaviors in women with intended and
unintended pregnancies.
AB - OBJECTIVES: This study examined whether pregnancy intention was associated with
cigarette smoking, alcohol drinking, use of vitamins, and consumption of
caffeinated drinks prior to pregnancy and in early pregnancy. METHODS: Data from
a telephone survey of 7174 pregnant women were analyzed. RESULTS: In comparison
with women whose pregnancies were intended, women with unintended pregnancies
were more likely to report cigarette smoking and less likely to report daily
vitamin use. Women with unintended pregnancies were also less likely to decrease
consumption of caffeinated beverages or increase daily vitamin use. CONCLUSIONS:
Pregnancy intention was associated with health behaviors, prior to pregnancy and
in early pregnancy, that may influence pregnancy course and birth outcomes.
PMID- 9551016
TI - The impact of mammography quality improvement legislation in Michigan:
implications for the National Mammography Quality Standards Act.
AB - OBJECTIVES: This study examined the impact of state legislation on mammography
quality and access in Michigan. METHODS: The impact of state legislation was
analyzed with respect to utilization, numbers of machines and facilities, and
image quality. RESULTS: The legislation had a positive effect on image quality
improvement, had no impact on utilization by women aged 50 years and above, and
resulted in few facility closures. CONCLUSIONS: Michigan's legislative
intervention appears to have had a positive effect on efforts to improve
mammography quality assurance with implications for other federal and state
efforts to achieve quality assurance in health care delivery.
PMID- 9551017
TI - Reporting sexual risk behavior for HIV: a practical risk index and a method for
improving risk indices.
AB - OBJECTIVES: As a means of enhancing public health efforts to control sexual
transmission of human immunodeficiency virus (HIV), methods were developed to
report on risk behavior in a manner that is comparable and widely interpretable.
METHODS: An elementary sexual behavior risk index (the vaginal episode equivalent
index) that is in accord with some of the essential knowledge about sexual
transmission of HIV is described, and a multivariate ordinal risk (MOR) method
that can be used to improve such risk indices is introduced. RESULTS: An example
shows that these approaches are applicable to observational studies of
seroconversion. CONCLUSIONS: The MOR represents a powerful new tool to develop
valid comparable measures of sexual risk behavior and, thereby, to advance HIV
prevention research.
PMID- 9551018
TI - Evaluation of a public-private certified nurse-midwife maternity program for
indigent women.
AB - OBJECTIVES: This study assessed the impact of a public-private certified nurse
midwife program on prenatal and delivery outcomes among medically indigent women.
METHODS: A population-based quasi-experimental design was used to compare 1
intervention county with 2 nonintervention counties. RESULTS: The program
significantly reduced the number of women who received no prenatal care and the
risk of acquiring less than adequate prenatal care. Reductions in the proportion
of infants born premature or with low birth-weights were of borderline
significance. The use of induction and/or stimulation of labor was statistically
elevated. CONCLUSIONS: These results suggest that the intervention program was
instrumental in reducing some, but not all, negative prenatal and delivery
outcomes.
PMID- 9551019
TI - Eliminating iodine deficiency in rural Sarawak, Malaysia: the relevance of water
iodization.
PMID- 9551020
TI - Promoting sunscreen in a community drugstore.
PMID- 9551021
TI - Few smokers know their cigarettes have filter vents.
PMID- 9551022
TI - Anonymous HIV testing.
PMID- 9551023
TI - HIV testing.
PMID- 9551024
TI - Not all behavior change is equivalent.
PMID- 9551025
TI - Outbreak of serogroup C meningococcal disease among preschool-aged children:
Illinois, 1996.
PMID- 9551026
TI - Health Check--smart eating made simple. The Heart and Stroke Foundation of
Canada.
PMID- 9551027
TI - Online cardiology journals--the desktop library.
PMID- 9551028
TI - Choosing among drugs of different price for similar indications.
PMID- 9551029
TI - Comparison of efficacy and cost among lipid-lowering agents in patients with
primary hypercholesterolemia.
AB - OBJECTIVE: To compare efficacy and cost of lipid-lowering agents in patients with
primary hypercholesterolemia. DESIGN: A meta-analysis was conducted to determine
estimates of efficacy for lipid-lowering agents. Efficacy was defined as the
change in the ratio of total cholesterol:high density lipoprotein (HDL) induced
by treatment. This ratio was selected because of its good predictive value for
the risk of coronary disease. Lipid-lowering agents were grouped into three
categories according to the decrease in the total cholesterol:HDL ratio.
Acquisition prices for drugs were obtained from the Quebec provincial drug
formulary. An analysis determined which drugs in each category 'purchased' the
greatest decrease in ratio for the lowest cost. SETTING: Clinical trial study
centres. PATIENTS: The population analyzed had a mean baseline total
cholesterol:HDL ratio of 7.3, an average age of 50.5 years and mean proportion of
men of 62.5%. INTERVENTIONS: Twelve lipid-lowering therapies at various doses
were investigated. RESULTS: Drugs that were more recently introduced had the
greatest effect on the total cholesterol:HDL ratio. A direct dose-effect
relationship was not evident, although there was a trend in this direction. In
each of the three categories, there was wide range of cost, suggesting that the
same effect is available at a broad range of prices. The drugs with the greatest
effect on the ratio at the lowest cost were fluvastatin 60 mg/day, fenofibrate
(micronized) 200 mg/day and simvastatin 20 mg/day. CONCLUSION: These results can
be useful for clinicians in the selection of agents that achieve a specified goal
of therapy at the lowest cost.
PMID- 9551030
TI - Physician specialty is associated with differences in warfarin use for atrial
fibrillation.
AB - OBJECTIVE: To determine whether physician specialty is associated with
prescription of warfarin to elderly persons with atrial fibrillation. DESIGN:
Cross-sectional survey. SETTING: One hundred and thirty-eight randomly selected
general practitioners--all 58 internists and all 27 cardiologists in southern
Alberta were surveyed by mail. INTERVENTION: Physicians identified their
preferred drug for stroke prevention generally and in response to two
hypothetical cases. MAIN RESULTS: Response rates were 66% (general
practitioners), 76% (internists) and 89% (cardiologists). Specialists (92%) were
more likely than general practitioners (76%) to choose warfarin (P = 0.007).
Findings were similar for questions related to case scenarios; however, the
magnitude of differences between specialists and general practitioners was less
pronounced. Specialists were more likely (77%) to prescribe warfarin for elderly
females than were general practitioners (62%, P = 0.08). Similar proportions of
specialists (77%) and general practitioners (67%) would prescribe warfarin to
elderly males. CONCLUSION: Physician specialty is associated with warfarin
prescription for elderly persons with atrial fibrillation.
PMID- 9551031
TI - Preparation, attitudes and behaviour in nonhospital cardiac emergencies:
evaluating a community's readiness to act.
AB - OBJECTIVE: To determine how people in a moderately sized Ontario city believe
they will react if they witness someone colapsing. DESIGN: Telephone survey.
SETTING: The cities of Kitchener and Waterloo, part of the Regional Municipality
of Waterloo, Ontario, with a combined population of 378,000. PARTICIPANTS:
Households were randomly contacted and a questionnaire was administered, provided
the respondent was over 44 years of age and agreed to be interviewed. Of 2479
households with eligible respondents, 811 (33%) completed the questionnaire.
OUTCOMES: Age, sex, educational level, cardiac risk factors and cardiopulmonary
resuscitation (CPR) training of respondents were determined, as well as actions
they would take if cardiac arrest occurred in a family member at home or in
stranger in the street, and associated emotions and barriers to implementing
actions. RESULTS: Among the first three actions that respondents who were not
prompted with possible responses said they would take, 311 (72%) witnessing a
collapse at home, compared with 166 (44%) witnessing a collapse on the street,
would call 911, the police or an ambulance. Other 'first three actions' in home
collapse were checking for breathing (120 [28%]), checking for pulse (91 [21%])
and administering CPR (34 [8%]); these actions were less commonly selected in
response to a strangers collapse and when respondents were not prompted.
Respondents felt they would be more likely to perform CPR on a friend than on a
stranger (OR 1.38, 95% CI 1.10 to 1.58). When asked how likely they would be to
perform specific acts when witnessing a collapse, 254 (69%) of respondents
thought they would call their family doctor and 179 (48%) thought they were
likely to begin chest compressions. Barriers to performing CPR centred around
legalities and disease transmission. CONCLUSION: Older people do not know how to
act effectively in a cardiac emergency. Traditional CPR and public awareness
programs have been ineffective in reaching this population; alternative means are
required to help the public respond more effectively to cardiac emergencies.
PMID- 9551032
TI - Postoperative laboratory and imaging investigations in intensive care units
following coronary artery bypass grafting: a comparison of two Canadian
hospitals.
AB - OBJECTIVES: To compare the utilization and cost of common laboratory and imaging
tests following admission to the intensive care unit (ICU) after coronary artery
bypass surgery in two hospitals. The hospitals use different strategies to order
tests postoperatively: one hospital uses a mandated protocol while the other does
not. DESIGN: Demographic and testing data were prospectively collected in both
hospitals as part of an ongoing ICU management program. Thirteen commonly
performed laboratory tests or imaging procedures were compared. Average costs for
each test were calculated, and utilization and cost of testing were compared per
admission and per day in ICU. SETTING: Two tertiary care ICUs in different
Canadian cities. PATIENTS: Consecutive patients admitted to ICU following
coronary artery bypass graft surgery over a two-year period. MAIN RESULTS: There
were 415 admissions to the Health Sciences Centre in Winnipeg, Manitoba and 504
to the Jewish General Hospital (JGH) in Montreal, Quebec. There were no
demographic, length of stay or ICU mortality differences. A postoperative
protocol for ordering investigations is used at JGH. Striking differences in test
utilization were noted, with more investigations performed per admission and per
unit day at JGH (P < 0.001). The average cost of the investigations was greater
at JGH ($160 more per admission; $75 more per intensive care day). CONCLUSIONS:
There are marked differences in the investigation pattern and costs for coronary
artery bypass patients admitted to ICU in these hospitals. It is suggested that
the benefits of frequent routine determinations of bloodwork, electrocardiograms
and chest radiographs should be reevaluated in this patient population.
PMID- 9551033
TI - Effects of combined endurance and strength training on left ventricular
morphology in male and female rowers.
AB - The effects of 10 weeks of combined endurance and strength training on left
ventricular (LV) morphology, muscular strength, maximal oxygen consumption
(VO2max) and rowing performance were assessed. Twenty-five subjects (eight males,
mean age 23.0 +/- 6.1 years, and 17 females, 22.7 +/- 5.0 years) were tested at
baseline and after five and 10 weeks of training. Combined training was
associated with significant improvements in VO2max, rowing performance and
muscular strength after 10 weeks of training. A significant increase in LV
diastolic dimension was found in males after 10 weeks of training; however, no
significant alteration was found for any other measured echocardiographic
variable. Therefore, with the exception of LV diastolic dimension in males, 10
weeks of combined endurance and strength training appears to be an insufficient
stimulus to elicit significant alterations in LV morphology despite changes in
VO2max, muscular strength or rowing performance.
PMID- 9551034
TI - Canadian Consensus Conference on Adult Congenital Heart Disease 1996.
PMID- 9551035
TI - Regulators of apoptosis in the heart: a matter of life and death.
AB - Programmed cell death or apoptosis is an active physiological process that
permits the removal of unwanted or damaged cells from the body through an
intrinsic cell-suicide program. Apoptosis is characterized by condensation of the
nucleus and cytoplasm without loss of membrane integrity. The occurrence of
apoptosis in the vasculature and myocardium has recently been described.
Inappropriate loss of myocardial cells is suggested to contribute to conduction
defects and ventricular remodelling after injury. The molecular mechanisms that
regulate programmed cell death in cardiac muscle cells are poorly defined.
However, recent evidence has suggested that specific genes can either provoke or
prevent apoptosis. In this regard, the tumour suppressor protein p53 has been
proposed to mediate apoptosis, while the Bcl-2 protein prevents it. Prevention of
apoptosis in the heart is potentially of significant therapeutic value given the
limited capacity of the heart to repair itself after injury. This study
determined that the expression of p53 in ventricular myocytes is sufficient to
trigger apoptosis. Moreover, p53 results in a significant increase in the
expression of the death-promoting protein Bax. Importantly, the antiapoptotic
factor Bcl-2 is sufficient to prevent p53-mediated apoptosis and p53-dependent
transcription of Bax in ventricular myocytes. The data substantiate a role for
p53 and Bcl-2 as crucial regulators of apoptosis in the heart.
PMID- 9551036
TI - Coronary artery fistula after cardiac transplantation.
AB - A cardiac transplant recipient with multiple coronary artery fistulae draining
into the right ventricle is described. These fistulae presumably resulted from
repeated endomyocardial biopsies. The diagnosis of coronary artery fistulae was
made at the annual coronary arteriography. The magnitude of the shunt remained
small over eight years of follow-up.
PMID- 9551037
TI - [Increased occurrence of esophageal hypermotility disorders in patients with
arterial hypertension].
AB - BACKGROUND AND OBJECTIVE: It has been noted in previous manometric examinations
of the oesophagus in patients with chest pain that abnormal motility was often
associated with arterial hypertension. A systematic study of this relationship
was therefore undertaken. PATIENTS AND METHODS: In 40 patients with chest pain
(18 women and 22 men, mean age 54.7 [24-70] years) and in 20 healthy volunteers
(12 men, 8 women, mean age 50.8 [22-63] years) standardized oesophageal manometry
and arterial blood pressure monitoring were performed over 24 hours. Coronary
heart disease and gastrointestinal lesions had been excluded by angiography and
endoscopy, respectively. RESULTS: 20 patients (group H) had hypertension (median
24-hour blood pressure > 135/85 mmHg), while 20 patients (group N) and the normal
controls (group K) were normotensive. Oesophageal manometry data differed
significantly between the three groups regarding distal pressure amplitude (in
hPa [hectopascals]; group H: 62 hPa*,**, group N 44 hPa* and group K 36 hPa**;
[*P < 0.0005]) and the proportion of simultaneous contractions (group H 23%,
group N 22%**, group K 10%***; ***P < 0.001). The hypertensive patients had
significantly more frequent motility abnormalities than normal controls (13/20 vs
4/20, P < 0.001); while normotensive patients had more frequent episodes of
abnormal propulsion in the oesophagus (proportion of propulsive contractions in
group H: 53%, in N: 44%, in K: 59%; P < 0.01). CONCLUSION: Oesophageal motility
differed significantly in patients with chest pain from that in healthy controls.
Patients with chest pain and hypertension more frequently had oesophageal
hypermotility. This suggests a generalized abnormality of smooth muscle.
PMID- 9551038
TI - [Polyposis of the gastrointestinal tract as a manifestation of diffuse follicular
lymphatic hyperplasia].
AB - HISTORY AND ADMISSION FINDINGS: A 21-year-old previously healthy Turkish man who
had been living in Germany for 15 years was admitted because of worsening cramp
like abdominal pain with nausea, vomiting and watery diarrhoea. Palpation
elicited diffuse muscular guarding over the entire abdomen and a mass of about 8
cm in the right lower abdomen. INVESTIGATIONS: Abnormal laboratory results were
erythrocyte sedimentation rate (55 mm), C-reactive protein (6.2 mg/dl), total
bilirubin (2.1 mg/dl), creatine kinase (137 U/l) and thymidine kinase (5.5 U/l).
There was a slight leucocytosis (13,700/microliter) and mild anaemia (haemoglobin
13.4 g/dl) with a normal differential count. Listeria ivanovii was repeatedly
cultured from stool. Ultrasonography and computed tomography of the abdomen
demonstrated a 6 cm mass in the right lower abdomen, splenomegaly (15.5 x 5 cm)
and several lymphomas, up to 1.8 cm in diameter. Endoscopy revealed dense, in
part grass-like, polyps, 3 to 6 mm deep, in the mucosa from the terminal ileum to
the rectum, and to a lesser extent also in the duodenum. Histological examination
of the polyps demonstrated diffuse follicular hyperplasia without evidence of
malignancy. TREATMENT AND COURSE: On antibiotic treatment with ofloxacin (2 x 400
mg intravenously) the symptoms quickly regressed, but the endoscopic findings
remained unchanged. CONCLUSION: Diffuse follicular lymphatic hyperplasia
manifested itself in this patient as diffuse gastrointestinal polyposis. Listeria
ivanovii cannot be ruled out as a causative factor.
PMID- 9551039
TI - [Lead poisoning caused by a Greek ceramic cup].
AB - HISTORY AND ADMISSION FINDINGS: A 24-year-old woman, an administrative employee,
was admitted with colicky abdominal pain and constipation, as well as breathing
related chest pain of recent onset with cough and sometimes blood-streaked
sputum. She had previously been unsuccessfully treated for gastritis and
adnexitis. On physical examination revealed diffuse, ill-defined abdominal pain
on pressure and mild tachycardia, but was otherwise unremarkable. INVESTIGATIONS:
Electrocardiogram, chest radiogram, lung scintigraphy, abdominal sonography,
oesophago-gastro-duodenoscopy and gynaecological examination indicated nothing
abnormal. Laboratory tests showed microcytic anemia, slight leucocytosis and
anisocytosis, as well as polychromasia and basophilic stippling of erythrocytes.
The 24-h urinary porphyrin concentration was elevated. DIAGNOSIS TREATMENT AND
COURSE: Precise differentiation of porphyrins in urine, stool and erythrocytes by
enzymatic measurement first raised the suspicion of lead poisoning. Whole-blood
lead concentration was markedly raised to 600 micrograms/l (normal up to 90
micrograms/l) and 170 micrograms/dl in urine (normal up to 80 micrograms/dl). A
ceramic cup from Greece was traced as the source of the lead, the patients having
regularly for over 2 1/2 months drunk lemon instant-tea from it. She was treated
with oral doses of DMPS (sodium salt of 2,3-dimercapto-1-propanesulphonic acid),
5-10 mg/kg 3x daily for 2 days, followed by 2.5 mg/kg 2 x daily, until lead
concentrations in blood and urine had become normal, when all symptoms
disappeared: detoxification was complete within 4 months. CONCLUSION: This case
impressively illustrates how difficult it can be to diagnose lead poisoning and
identify its source. Oral DMPS is a practicable and efficacious form of
treatment.
PMID- 9551040
TI - [The treatment of aortic isthmus stenosis in adults using balloon dilatation and
stent implantation].
PMID- 9551041
TI - [Interventional catheter closure of interatrial shunt connections in adults].
PMID- 9551042
TI - [Glycyrrhizin for the treatment of allergic diseases and chronic hepatitis].
PMID- 9551043
TI - [Smoking and hyperkinetic syndrome].
PMID- 9551044
TI - [Megaloblastic anemia caused by nutritional errors].
PMID- 9551045
TI - Endovascular treatment of isolated iliac artery aneurysms.
PMID- 9551046
TI - Endovascular interventions into the 21st century: what can we anticipate?
PMID- 9551047
TI - Prevention of spinal cord ischaemic complications after thoracoabdominal aortic
surgery.
AB - Since the publication of prior reviews on this topic, substantial clinical
experience with a variety of operative strategies to prevent ischaemic cord
complications has been reported. The available data on angiographic localisation
of critical intercostal vessels, and, in particular, the evoked potential
response to cross-clamping in patients indicates that risk of paraplegia varies
considerably even among patients with equivalent TAA extent. Factors such as
individual development of the ASA, patent critical intercostals, and the
particulars of collateral circulation when intercostal aortic ostia are already
occluded likely account for this variability. Information available from SSEP
monitoring relative to the dynamic course of cord ischaemia with cross-clamping,
and the parallel, if not, frustrating experience with angiographic localisation
and intercostal vessel reconstruction indicates that a narrow temporal threshold
of cord ischaemia with clamping is present in many patients. This reinforces the
importance of both expeditious clamp intervals, critical intercostal re
anastomoses, and the desirability of neuroprotective manoeuvres during cross
clamp induced cord ischemia. As suggested in compelling experimental work our
contemporary clinical experience, and predicted by prior reviewers, regional cord
hypothermia provides significant promise for limiting or eliminating, in
particular, immediate perioperative deficits. Avoidance of postoperative
hypotension, spinal cord oedema, and preservation of critical intercostal vessels
are additional strategies necessary to impact the development of delayed deficits
favourably.
PMID- 9551048
TI - Surgery on aneurysms in Byzantine times (324-1453 A.D.).
PMID- 9551049
TI - The increasing activity of a vascular ultrasound service.
AB - OBJECTIVES: To examine the change in activity of a vascular ultrasound service
over 7 years. DESIGN: Retrospective review. SETTING: Vascular studies unit,
University hospital. METHOD: Audit of the number of vascular ultrasound tests
carried out over the last 7 years using a prospective computerised database.
RESULTS: Data shows that the overall workload has tripled over the 7-year period.
In addition the complexity of investigations has increased during this time. The
number of carotid scans has increased four-fold while the number of graft
surveillance scans and vein scans has increased seven-fold. Assessment of lower
limb arteries has developed from simple pressure measurements to detailed
ultrasound scans and, as a consequence, the number of diagnostic angiograms has
fallen by 75%. The factors that have influenced these changes are discussed.
CONCLUSIONS: There has been an important increase in the role of colour Doppler
ultrasound as it becomes the "first line" vascular diagnostic test. However this
trend can only continue if vascular ultrasound services are appropriately
resourced. It is therefore essential to maintain an efficient audit system.
PMID- 9551050
TI - Outcome of infrainguinal bypass surgery for critical leg ischaemia in patients
with chronic renal failure.
AB - OBJECTIVE: To determine whether infrainguinal bypass surgery is worthwhile in
patients with critical limb ischaemia (CLI) and chronic renal failure. DESIGN:
Longitudinal observational study. MATERIALS AND METHODS: Twenty-two patients with
moderate renal failure indicated by serum creatinine level above 150 mumol/l, 10
patients with end-stage renal disease requiring dialysis, and three patients with
functioning kidney transplant, underwent 39 bypass procedures for critical limb
ischaemia. RESULTS: Six femoropopliteal, 14 femorocrural and 19 femoropedal
bypasses were performed. The immediate, 1-month, and 1-year primary patency rates
were 97%, 84% and 70%, respectively. The limb salvage was 93% at 1-month and 72%
at 1-year follow-up. One-year patency and leg salvage rates were 81% and 79% in
non-dialysis patients, and 47% and 37% in dialysis patients. At 1-year follow-up,
55% of surviving patients had salvaged limbs. None of the patients in dialysis
was alive with salvaged legs 4 months after revascularisation. Among preoperative
risk factors, only serum creatinine showed a statistical significance in
predicting leg salvage and survival. CONCLUSIONS: As the outcome of patients on
dialysis is very poor after infrainguinal bypass grafting, revascularisation is
seldom indicated. On the contrary, leg salvage can achieve good results in
patients not requiring dialysis.
PMID- 9551051
TI - Combined aortorenal reconstruction: is there an optimum method of exposure?
AB - OBJECTIVE: To determine the advantages and disadvantages of two different
transabdominal approaches to expose the pararenal aorta; infacolic (IC) and
medical visceral rotation (MVR). DESIGN: Retrospective study. METHODS: We
reviewed a consecutive series of concurrently treated patients undergoing
combined aortorenal reconstruction using one of these two approaches (IC n = 45;
MVR n = 30). RESULTS: The two groups were identical with respect to demographics,
risk factors and associated illnesses. Aortic aneurysmal disease predominated
among MVR patients, and occlusive disease among IC patients (p = 0.001). The most
common aortic reconstruction was aortofemoral bypass grafting. Renal
revascularisation was most often performed for symptoms; only in the MVR group it
was the result of involvement by aortic aneurysmal disease (p = 0.000).
Thromboendarterectomy was the most common renal reconstruction, though performed
only 10 times in the MVR group (p = 0.01). Except for supraceliac aortic cross
clamping, which was required more often in the MVR group (p = 0.004), operative
details did not differ between the groups. Although the overall perioperative
mortality and complication rate were equal, intraoperative splenic injury
occurred solely in the MVR group (p = 0.001), and these patients experienced more
pulmonary complications (p = 0.004) and they were hospitalised longer than the IC
group (29.7 +/- 35.8 vs. 17.2 +/- 15.4 days; p = 0.04). CONCLUSIONS: MVR has
increased morbidity, but its unrestricted continuous exposure is optimum for
combined aortorenal reconstruction involving pararenal aneurysmal disease.
Pararenal occlusive disease is adequately exposed in most cases by the IC
approach.
PMID- 9551052
TI - Chlamydia pneumoniae in human abdominal aortic aneurysms.
AB - OBJECTIVES: To investigate the presence of Chlamydia pneumoniae DNA in the wall
of infrarenal abdominal aortic aneurysms, and in the wall of non-aneurysmal
infrarenal abdominal aortas. DESIGN: Case-control study. MATERIALS AND METHODS:
The study group consisted of 40 patients operated transperitoneally for an
infrarenal abdominal aortic aneurysm (IAAA) (eight females, 32 males; mean age 69
years, median age 68 years). Specimens from the aneurysm wall were taken
peroperatively under sterile conditions. The control group consisted of 40
deceased persons without aortic aneurysms (14 females, 26 males; mean age 71
years, median age 70 years). Specimens from the non-aneurysmal infrarenal aortas
(NIAA) were collected within 48 h after death. The specimens from both groups
were frozen at -70 degrees C immediately after collection. A nested polymerase
chain reaction (PCR) method, using two sets of primers designed to detect a
fragment of the major outer membrane protein gene of C. pneumoniae, was used.
RESULTS: The detection of C. pneumoniae-specific DNA was significantly higher in
the study group (14/40 = 35%) than in the control group (2/40 = 5%); (p = 0.001).
No clinical factor predicting the presence of C. pneumoniae in the aneurysm wall,
could be found. CONCLUSION: Chlamydia pneumoniae was detected at a significantly
higher frequency in the wall of IAAAs than in the wall of NIAAs. Although this
finding does not prove that C. pneumoniae causes IAAAs, further studies on the
possible role of C. pneumoniae in the pathogenesis of aneurysms should be
performed.
PMID- 9551053
TI - Operative mortality and long-term survival of patients operated on for acute
lower limb ischaemia.
AB - OBJECTIVES: To investigate the operative mortality and long-term survival of
patients with lower limb embolism or acute thrombosis. DESIGN: A retrospective
survival analysis. MATERIALS: Eighty patients with acute thrombosis treated by
bypass and 192 patients with embolism treated by embolectomy during the years
from 1985 to 1996 were studied. METHODS: The observed survival rates were
calculated with the product limit method. The expected survival rates were
estimated from death-rate tables. The standard mortality rate was compared over a
5-year follow-up. RESULTS: The patients treated for embolism had an operative
mortality of 17% and a 5-year survival rate of 17%, which was significantly lower
than the expected rate of 62%. Those treated for acute thrombosis had an
operative mortality of 14% and a 5-year survival rate of 44%. This was
significantly higher than for the embolism group, but significantly lower than
the expected rate of 74%. Both groups had a standard mortality rate of 2.2 at 5
years. CONCLUSION: Patients with acute ischaemia have a poor short-term and long
term prognosis. The patients treated for embolism are older and they have a
shorter life expectancy than those treated for acute thrombosis. The standard
mortality rate of the two groups appears similar.
PMID- 9551054
TI - Effect of prolonged pulsatile shear stress in vitro on endothelial cell seeded
PTFE and compliant polyurethane vascular grafts.
AB - OBJECTIVES: Compliance mismatch between graft and native artery, and failure of
the graft to develop an endothelial lining are the two main factors in graft
failure. The objective of this study was to assess a new compliant graft for
effective cell attachment and cell retention at physiological levels of pulsatile
shear stress over a 6-hour period of physiological pulsatile flow. DESIGN:
Laboratory haemodynamic study. MATERIALS AND METHODS: Human umbilical vein
endothelial cells labelled with 111In-oxine were seeded on compliant polyurethane
(CPU) and polytetrafluoroethylene (PTFE) vascular grafts. These were then exposed
to varying shear stresses of up to 13.8 +/- 0.6 dyn/cm2 using a pulsatile flow
model. Dynamic scintigraphy images were acquired using a gamma camera linked to
an on-line computer during 6 h of perfusion and data presented as mean +/-
standard error of mean. RESULTS: Mean seeding efficiencies were significantly
different at 4,316 +/- 505 and 825 +/- 504 CPM/cm2 on the CPU and PTFE grafts,
respectively (p = 0.018). The flow experiment showed a higher percentage of cells
retained on the CPU graft after exposure to shear stress caused by pulsatile flow
compared to PTFE with respect to time. After 6 h pulsatile perfusion there was a
significantly higher proportion of initial cells attached to CPU graft compared
to PTFE graft (73 +/- 8% vs 42 +/- 8%, p = 0.018). The areas under the time
activity curves over the 6-hour period were 280 +/- 26.4 for CPU and 176.0 +/-
30.0 for PTFE, confirming a significant greater total cell loss from PTFE
compared with CPU grafts (51 +/- 7.0% vs 23 +/- 8.3%, p = 0.018, Wilcoxon matched
pairs signed-ranks test). CONCLUSIONS: This flow model provides an effective
method of assessing cell retention on graft materials under physiological
conditions over a 6-hour period; CPU combines both excellent compliance and
endothelial cell attachment rates after 6 h exposure to shear stress.
PMID- 9551055
TI - Influence of surgical experience on the results of carotid surgery. The Finnvasc
Study Group.
AB - OBJECTIVE: To assess the 30-day mortality and morbidity rates related to carotid
endarterectomy on a nation-wide basis. DESIGN: Retrospective cross-sectional
study based on vascular registry Finnvasc. MATERIALS AND METHODS: A total of
17,465 recorded vascular and endovascular procedures included exactly 1600
carotid endarterectomies performed by 104 surgeons in 23 hospitals. Fourteen per
cent of the patients were operated on for asymptomatic carotid stenosis. RESULTS:
The combined mortality and permanent stroke rate was 3.3%, without any difference
between operations done on symptomatic or asymptomatic patients. There was a
clear inverse association between surgeon's carotid case load and poor outcomes
in carotid surgery (p < 0.005), the critical patient mass per surgeon and year
being 10 operations. There was no association between outcome after carotid
surgery and hospital volume of carotid operations. CONCLUSIONS: Surgeon's
experience in carotid surgery clearly improves the results of carotid surgery.
PMID- 9551056
TI - Failure to demonstrate Chlamydia pneumoniae in symptomatic abdominal aortic
aneurysms by a nested polymerase chain reaction (PCR).
AB - OBJECTIVE: To investigate whether Chlamydia pneumoniae is present in symptomatic
abdominal aortic aneurysms (AAA). METHOD AND MATERIALS: After optimisation of DNA
extraction procedures an inhibitor-controlled nested polymerase chain reaction
(PCR) amplifying fragments of the gene encoding the C. pneumoniae specific major
outer membrane protein was performed on 124 wall-specimens from 20 patients with
symptomatic AAA. RESULTS: None of the specimens contained C. pneumoniae-specific
DNA. Minor inhibition of the PCR was noticed especially in media specimens.
CONCLUSION: Using a sensitive and specific nested PCR, we were not able to detect
C. pneumoniae in symptomatic AAA. The failure to detect C. pneumoniae in
symptomatic AAA, combined with previously reported positive findings in
atherosclerotic lesions, supports the hypothesis that AAA and atherosclerosis
might be two different disease entities.
PMID- 9551057
TI - Early experience with stenting for iliac occlusive disease.
AB - OBJECTIVES: To review our experience of iliac artery stenting for occlusive
disease. DESIGN: Prospective study of 50 consecutive patients with iliac
occlusive disease, November 1993-November 1996. The indications for stenting were
complete iliac occlusion (37) restenosis (four), donor site inflow for bypass
grafting (four) and difficult stenoses (> 90% and/or > 5 cm) (five). The majority
of patients (41) presented with intermittent claudication. RESULTS: All 13
stenoses were successfully stented. One occluded but the rest remain patent.
There were no other complications. By contrast, it was not possible to place a
stent across 10 of the 37 complete iliac occlusions. In this group there were
nine major complications, including five patients who required early embolectomy
(four femoral, one brachial) and one patient who developed a false aneurysm at
the site of the stent. The "intention to treat" primary cumulative patency for
iliac occlusions was 65% at 2 years but after excluding technical failures was
88%. CONCLUSIONS: There is a sharp learning curve and significant complication
rate associated with stenting complete occlusions. However, following successful
stenting patency rates are around 90% for both iliac stenoses and occlusions.
PMID- 9551058
TI - The treatment of aortoiliac occlusions by endovascular stenting with or without
adjuvant femorofemoral crossover grafting.
AB - We present four consecutive patients in whom we have used a combination of
vascular and endovascular techniques in order to revascularise ischaemic legs
caused by extensive aortoiliac occlusions. We believe that the techniques
presented offer a viable alternative to more conventional surgical approaches in
such cases.
PMID- 9551059
TI - Prevotella buccae bacteraemia associated with infection of a pseudoaneurysm.
PMID- 9551060
TI - Secondary haemorrhage from saphenous vein grafts caused by methicillin-resistant
Staphylococcus aureus.
PMID- 9551061
TI - Recurring aortoenteric fistula.
PMID- 9551062
TI - Nikolai S. Korotkov: a story of an unknown surgeon with an immortal name.
PMID- 9551063
TI - Primary pancreatic lymphoma.
AB - BACKGROUND: Primary pancreatic lymphoma is a rare neoplasm that may be confused
with pancreatic adenocarcinoma. We reviewed retrospectively our contemporary
experience with this disease to define more clearly the clinical presentation of
this disease and the proper role for percutaneous fine-needle aspiration biopsy
and surgery. METHODS: From 1980 to 1995, 11 patients with primary pancreatic
lymphoma were treated at The University of Texas M. D. Anderson Cancer Center.
Patient demographics, radiographic studies, fine-needle aspiration biopsy
findings, operative procedures, and other treatment data were reviewed. RESULTS:
The median age of the 11 patients was 64 years (range, 37 to 74 years). Abdominal
pain was the most common symptom at presentation. Five patients had an elevated
lactate dehydrogenase level, and only two patients had hyperbilirubinemia.
Computed tomography scan demonstrated encasement of the superior mesenteric
artery or superior mesenteric-portal vein confluence in six patients. Seven
patients underwent computed tomography-guided fine-needle aspiration; five had
findings of lymphoma. Two patients underwent distal pancreatectomy and
splenectomy, and one underwent pancreaticoduodenectomy. All patients were treated
with combination chemotherapy, and seven received radiotherapy. Only two patients
have died of disease (12 and 16 months after diagnosis) at a median follow-up
time of 67 months. CONCLUSIONS: In the majority of patients, pancreatic lymphoma
can be distinguished from pancreatic adenocarcinoma on the basis of symptoms,
laboratory and radiographic findings, and fine-needle aspiration biopsy results.
Once the diagnosis is established, all patients should undergo systemic
chemotherapy followed by involved-field radiotherapy if the tumor has not been
resected.
PMID- 9551064
TI - Diagnosis of anomalous pancreaticobiliary junction: value of magnetic resonance
cholangiopancreatography.
AB - BACKGROUND: Anomalous pancreaticobiliary junction (a long common channel), with
or without congenital choledochal cyst, is frequently associated with biliary
tract carcinoma. We assessed the diagnostic value of magnetic resonance
cholangiopancreatography (MRCP) for patients with anomalous pancreaticobiliary
junction (PBJ). METHODS: In 159 adult patients with pancreatobiliary disease,
breath-hold (1 to 18 seconds) MRCP was performed according to a half-Fourier
acquisition single-shot turbo spin-echo sequence. In all patients the length of
the common channel demonstrated by MRCP was compared with that demonstrated by
endoscopic retrograde cholangiopancreatography. In 11 patients with anomalous PBJ
(the common channel > or = 15 mm on endoscopic retrograde
cholangiopancreatography), the diagnostic accuracy of MRCP for associated biliary
diseases was evaluated. RESULTS: No complications were encountered in performing
MRCP. On MRCP, the length of the common channel was calculated to be 15 mm or
longer in nine (82%) of 11 patients with anomalous PBJ. In patients with normal
PBJ, MRCP identified PBJ with the channel measuring 0 mm in length. MRCP allowed
detailed visualization of congenital choledochal cyst (all seven patients) but
failed to depict carcinoma (one patient) and mucosal hyperplasia (five patients)
of the gallbladder. CONCLUSIONS: MRCP is a noninvasive and accurate imaging
method for diagnosing anomalous PBJ and congenital choledochal cyst.
PMID- 9551065
TI - Growth of intraportally transplanted islets under liver regeneration stimulus and
restoration of normoglycemia in streptozocin-diabetic rats.
AB - BACKGROUND: Limitation of beta-cell growth after intraportal islet
transplantation plays an important role in graft failure. To induce transplanted
beta-cell proliferation, we studied the effect of compensatory liver growth in
diabetic rats that had a subtherapeutic islet mass previously injected into the
liver. METHODS: Syngeneic rats were used as islet donors or recipients; diabetes
was induced by streptozocin. Three groups of streptozocin-treated rats were
studied. In group 1, 250 islets were selectively transplanted into the posterior
liver lobes and 10 days later anterior portal branch ligation (PBL) was performed
(n = 18); in group 2, 250 islets were transplanted into the posterior lobes and
10 days later sham PBL was performed (n = 13); in group 3, rats underwent a sham
transplantation and PBL (n = 6). Nonfasting blood glucose levels and body weight
were monitored. Six rats in groups 1 and 2 were killed 48 hours after PBL, liver
sections were stained for proliferating cell nuclear antigen, and islet cell
labeling index was calculated. The remaining rats were killed 30 days later.
Liver compensatory growth or atrophy was calculated and morphometric
determination of beta-cell area was assessed on insulin-immunostained sections of
the liver. RESULTS: In group 1 rats killed 48 hours after PBL, islet cell
labeling index was significantly higher than in group 2 (p < 0.0001). After PBL,
we observed normalization of nonfasting blood glucose levels in 10 of 12 rats. At
30 days, posterior liver lobes showed compensatory growth (218.5% +/- 18.6%)
accompanied by atrophy of the anterior lobes; morphometric study of liver
engrafted islets showed a significant increase of individual beta-cell area,
compared with group 2 (p < 0.0001). In groups 2 and 3, normoglycemia was not
achieved. CONCLUSIONS: In streptozocin-diabetic rats, normoglycemia was restored
after transplantation of a sub-therapeutic islet mass, followed by PBL-induced
liver regeneration. Histologic and morphometric results indicating islet cell
proliferation suggest that compensatory liver growth might have induced a
hypertrophic/hyperplastic response in the intraportally transplanted beta-cells.
PMID- 9551066
TI - Treatment of hepatoblastoma: less extensive hepatectomy after effective
preoperative chemotherapy with cisplatin and adriamycin.
AB - BACKGROUND: Although the prognosis of hepatoblastoma was improved by the
introduction of cisplatin and doxorubicin (Adriamycin) for adjuvant chemotherapy,
extensive hepatectomy continues to be the usual practice. We retrospectively
reviewed our recent experience with hepatoblastoma to determine whether the new
modality of intensive chemotherapy could change the resectability, extent of
hepatectomy, operative complications, and prognosis. METHODS: The clinical
features of 15 children with hepatoblastoma treated between 1985 and 1995 were
reviewed. Intensive chemotherapy was added before surgical resection not only
when a tumor was unresectable but also when it was large enough to increase the
risk of operative morbidity. RESULTS: There was 100% resectability, and the
overall mortality rate was only 6.7%. Fourteen patients have been free of disease
for 2 to 12 years. Preoperative chemotherapy enabled resection of six previously
unresectable hepatoblastomas. Moreover, hepatic resection tended to be less
invasive in several patients whose tumors had been much reduced after
preoperative chemotherapy. Intraoperative and postoperative complications were
minimal, with a short operative time and small amount of blood loss, especially
in the group with delayed primary operation. CONCLUSIONS: The preoperative
administration of cisplatin and Adriamycin reduced the tumor size so that a safe
hepatectomy could be performed with less blood loss and minimal technical
complications. Unnecessary sacrifice of the normal hepatic tissue was avoided by
performing the less extensive hepatectomy.
PMID- 9551067
TI - Hepatic insulin extraction after major hepatectomy.
AB - BACKGROUND: After major hepatectomy, the remaining liver compensates for its
reduced mass and maintains euglycemia through increased hepatic glucose output.
The mechanism of this compensation may be a diminished hepatic extraction of
portal insulin, which thereby decreases the suppressive effects of insulin on
gluconeogenesis. METHODS: Extraction of insulin by the liver was measured using
the isolated perfused rat liver model. Fasted Sprague-Dawley rats were studied at
1, 2, 3, 4, 6, and 14 days after 70% hepatectomy. Control rats had no operation,
and sham rats were studied 1 day after a sham laparotomy. The difference between
portal and caval insulin concentrations was determined and reported as micromoles
of insulin extracted per gram liver per minute. RESULTS: Insulin extraction
decreased from 191 +/- 22 microU/gm liver/min in control rats to 87 +/- 13.2
microU/gm liver/min at postoperative day 1 (p = 0.0001). Extraction normalized by
postoperative day 6. Extraction rates in rats recovering from sham laparotomy
were similar to control rats (p = 0.088), suggesting that decreased extraction in
hepatectomized rats was not due to postoperative stress. CONCLUSIONS: After 70%
hepatectomy, the remaining liver extracts less insulin per gram. This may explain
the ability of the reduced liver mass to maintain euglycemia after major
hepatectomy.
PMID- 9551068
TI - Hepatolithiasis: outcome of cholangioscopic lithotomy and dilation of bile duct
stricture.
AB - BACKGROUND: Cholangioscopic lithotomy (CSL) for hepatolithiasis, a minimally
invasive procedure, has a place in complicated or recurrent hepatolithiasis. CSL
itself, however, carries inherent risk for recurrence. We analyzed follow-up data
after CSL for primary or repeat hepatolithiasis to determine the frequency of
recurrence. METHODS: This retrospective analysis includes 21 patients with
hepatolithiasis admitted to the hospital from September 1992 to December 1995 who
underwent CSL. Through a percutaneous biliary drainage route, cholangioscopy was
inserted to remove calculi with basket forceps or electrohydraulic lithotripter.
Stenotic ducts, defined as less than 2 mm in diameter, were dilated with silicone
rubber stenting or a balloon dilator. RESULTS: Ten patients were treated for
primary hepatolithiasis and 11 for repeat hepatolithiasis. Of the patients with
primary hepatolithiasis, one died of complications and the other nine patients
underwent complete lithotomy. Among 11 patients who had repeat hepatolithiasis,
four had undergone hepatectomy for hepatolithiasis and two previous CSLs; 10
patients (91%) underwent complete lithotomy. During the follow-up, four (40%) of
the 10 patients with biliary stenosis at the time of cholangioscopic treatment
showed recurrent calculi, whereas all eight patients without stricture had
uneventful courses. Of the 19 patients who underwent complete lithotomy, calculi
recurred in four (21%), three cases of which recurred less than 1 year after CSL.
CONCLUSIONS: Against hepatolithiasis of primary and postoperative repeat cases,
CSL can allow complete lithotomy. The bile duct stricture, however, carries a
high risk for recurrent calculi; hence, permanent relief of stricture is
mandatory.
PMID- 9551069
TI - Experimental assessment of the risk of tumor recurrence after laparoscopic
surgery.
AB - BACKGROUND: The aim of this experimental study was to evaluate the risk of tumor
recurrence after laparoscopic cecal resection (LCR) of colonic carcinoma in the
rat. METHODS: The experimental cancer consisted of one million cells (DHK/K12),
incorporated in an extracellular matrix, placed and secured to the cecal serosa
in 110 BD9 rats. Four weeks later, all animals were reoperated through a
laparotomy to control tumor growth, and animals with diffuse carcinomatosis were
excluded. Eligible animals were randomized either to laparoscopic cecal resection
(group LCR, n = 10), to open resection (group OCR, n = 13), or to a control group
without resection (group C, n = 13). Resection was always considered as
macrocopically complete. All animals were killed 4 weeks after the resection to
determine the tumor recurrence and quantify carcinomatosis. RESULTS: We noted
diffuse carcinomatosis in 70% of rats in groups C and LCR versus 23% in group OCR
(p = 0.038). For tumors noted as S- (not extending outside the serosa), diffuse
carcinomatosis was observed in all animals of group C (3 of 3), in 6 of 8 in
group LCR, and 0 of 6 in group OCR (p = 0.004). The rate of port site or
incisional metastases was not significantly different between groups.
CONCLUSIONS: These preliminary results demonstrated the deleterious impact of the
laparoscopy for resection of large bowel malignancy. LCR increased significantly
the incidence of a diffuse carcinomatosis even when performed for locally
noninvasive tumors (S-).
PMID- 9551070
TI - Treatment of superficial cancer of the esophagus: a summary of responses to a
questionnaire on superficial cancer of the esophagus in Japan.
AB - BACKGROUND: Histopathologic characteristics and optimal treatment modality for
superficial esophageal cancer were reevaluated on the basis of 2418 patients from
143 institutions through a nationwide questionnaire to the members of the
Japanese Society for Esophageal Diseases. METHODS: A questionnaire was designed
for patients with preoperatively untreated superficial cancer of the esophagus
who had undergone either surgical or endoscopic treatment between January 1,
1990, and December 30, 1994. Mucosal cancer and submucosal cancer were divided
into three subclasses according to the criteria formulated by the Society.
RESULTS: The incidence of positive lymphatic invasion or lymph node metastases
tended to increase markedly as cancer infiltrates reached the lamina muscularis
mucosa. The majority of the cases with 0-I or 0-III components were submucosal
cancer. The indication of endoscopic mucosal resection (EMR) was limited to
mucosal 1 and mucosal 2 superficial cancer in 76% of the institutions surveyed.
Tumors measuring 2 cm or more in diameter were resected piecemeal in 94% of
patients. Complications of EMR, including perforation, stenosis, and hemorrhage,
were observed in approximately 6.8% of patients. Almost all patients with mucosal
1 or mucosal 2 cancer are still alive. There was no significant difference in
prognosis between mucosal 3 cancer and mucosal 1 or mucosal 2 cancer, but
submucosal 1 cancer showed worse prognosis than mucosal cancer. CONCLUSIONS:
Local resection of cancer lesions is regarded as the treatment of choice against
the superficial esophageal cancers limited to the lamina propria mucosae. Further
study is advocated to define the treatment strategy against mucosal 3 or
submucosal 1 cancer.
PMID- 9551071
TI - Usefulness of metyrapone treatment to suppress cancer metastasis facilitated by
surgical stress.
AB - BACKGROUND: One causative factor of tumor metastasis enhanced by surgical stress
is thought to be hypersecretion of endogenous glucocorticoids. This study
evaluated the effectiveness of metyrapone treatment and adrenalectomy in
preventing the harmful effects of glucocorticoids in the enhancement of tumor
metastasis resulting from surgical stress. METHODS: The effect of dexamethasone
on pulmonary metastasis of MRMT-1 cells and on the number of peripheral
lymphocytes was evaluated in rats. To evaluate the suppressive effect of
adrenalectomy and metyrapone treatment on operation-induced enhancement of
metastasis, several parameters such as induction of pulmonary metastasis, serum
corticosterone levels, and the number of blood lymphocytes and apoptotic
thymocytes were determined. RESULTS: With dexamethasone treatment, the number of
peripheral lymphocytes rapidly decreased; in contrast, pulmonary metastasis
increased. The serum corticosterone level was doubled at 1 hour, apoptotic
thymocyte numbers were increased about sevenfold at 3 hours and about fourfold at
6 hours, and blood lymphocyte numbers were decreased at 3 hours after laparotomy,
which facilitated about a 10-fold increase in the pulmonary metastasis. These
changes were almost completely suppressed by preoperative adrenalectomy and
metyrapone treatment. CONCLUSIONS: Preoperative metyrapone treatment, which
suppresses hypersecretion of endogenous glucocorticoids as a result of operation,
modulates the enhancement of cancer metastases and may be an effective treatment.
PMID- 9551072
TI - Less collagen production in smokers.
AB - BACKGROUND: An association between smoking and impaired wound healing has been
reported in retrospective studies. The smoking status of a surgical patient may
be confounded by social and medical parameters. We have evaluated the effect of
smoking in a test wound in volunteers, with special reference to a reliable
scientific match between smokers and nonsmokers. METHODS: In a prospective open
study with blinded assessment, 19 smoking (20 cigarettes/day) and 18 nonsmoking
healthy volunteers were matched with respect to baseline characteristics. The
deposition of total protein and mature collagen (expressed as hydroxyproline) was
assessed in an expanded polytetrafluoroethylene wound healing model implanted
subcutaneously for 10 days. RESULTS: The nonsmokers had a 1.8 times higher median
amount of hydroxyproline than the smokers (p < 0.01). The deposition of
hydroxyproline was negatively correlated with the consumption of tobacco both
before (r = -0.44; p < 0.01) and during the study (r = -0.48; p < 0.005). The
impairment was specific for the production of collagenous proteins and not other
proteins. CONCLUSIONS: The synthesis of subcutaneous collagen in smokers is
specifically impeded, indicating an impaired wound-healing process. Because
mature collagen is the main determinator of strength of an operative wound, the
results support the view that patients should be advised to stop smoking before
an operation.
PMID- 9551073
TI - Cyclosporine, but not FK506, selectively induces renal and coronary artery smooth
muscle contraction.
AB - BACKGROUND: Cyclosporine immunosuppression for organ transplantation is
associated with hypertension and nephrotoxicity. Because the effects of
cyclosporine as an immunosuppressant are mediated by the effect of cyclosporine
as a phosphatase inhibitor, and phosphatase inhibitors are potent vascular smooth
muscle contractile agents, we hypothesized that cyclosporine might induce
contraction of the renal artery vascular smooth muscle directly. METHODS: Strips
of bovine renal, carotid, superior mesenteric, or coronary arteries were obtained
fresh from an abattoir. The strips were equilibrated in a muscle bath, and the
contractile responses to cyclosporine and FK506 were determined. RESULTS:
Cyclosporine (50 to 5000 micrograms/ml), but not FK506, induced rapidly
developing, sustained contractions of renal and coronary artery smooth muscle.
The magnitude of the cyclosporine-induced contractions of carotid and superior
mesenteric artery smooth muscles was significantly less. The magnitude of renal
artery smooth muscle contractions induced by cyclosporine was enhanced in the
presence of an intact endothelium. CONCLUSIONS: Although these effects occurred
in vitro to relatively high doses of cyclosporine, these data suggest that
cyclosporine may selectively induce renal artery smooth muscle contraction
through activation of the Ca(2+)-dependent phosphatase (calcineurin) in the
smooth muscle, and these contractions may be enhanced by the release of
endothelial-derived contracting factors.
PMID- 9551074
TI - Formation of myointimal hyperplasia and cytokine production in experimental vein
grafts.
AB - BACKGROUND: The purpose of this study was to determine the correlation between
progression and regression of myointimal hyperplasia (MH) and cytokine production
in experimental vein grafts. Although the autologous vein is the best suitable
bypass conduit for reconstruction of peripheral arteries, at the end of the first
year thrombosis in the coronary and lower extremity circulation ranges from 20%
to 50%. Many of these failures are caused by MH. METHODS: In 76 inbred Lewis
rats, a 1 cm long segment of inferior vena cava was inserted at the level of the
abdominal aorta. The segments of inferior vena cava were obtained from syngeneic
Lewis rats. In 56 animals the arterial vein graft was explanted 3 days (n = 10),
7 days (n = 10), 4 weeks (n = 26), and 12 weeks (n = 10) after operation. In 20
animals the vein graft was explanted 4 weeks after being in the arterial system
and reimplanted as iliac venovenous bypass in syngeneic Lewis rats. These grafts
were explanted 2 weeks (n = 10) and 8 weeks (n = 10) later. Grafts were analyzed
by light and electron microscopy, morphometric study, and histochemical analysis
and were put in an organ culture to assess cytokine production. RESULTS: We
observed MH formation in arterial vein grafts and MH regression in reimplanted
vein grafts (p < 0.001). MH formation was correlated with production of platelet
derived growth factor, basic fibroblast growth factor, interleukin-1, and tumor
necrosis factor-alpha. MH regression was correlated with transforming growth
factor-beta 1 production. CONCLUSIONS: On the basis of the results of our study,
we conclude that MH formation in experimental vein grafts depends on production
of platelet-derived growth factor, basic fibroblast growth factor, interleukin-1,
and tumor necrosis factor-alpha, and MH regression depends on transforming growth
factor-beta 1 production. Cytokine therapy may represent a valuable new treatment
to prevent vein bypass failures caused by MH.
PMID- 9551075
TI - Duplex-directed vena caval filter placement: report of initial experience.
AB - BACKGROUND: Fluoroscopy, cost, and patient transport contribute to difficulties
occasionally associated with the placement of vena caval filters. Follow-up data
in the literature document the use of duplex ultrasonography in visualizing the
filter and determining caval patency. Filter placement at the bedside or in the
vascular laboratory with duplex ultrasonography may simplify this common
procedure. We have attempted to define the feasibility of this method. METHODS:
Patients referred to the vascular surgery service for vena caval interruption
were evaluated for ability to visualize the renal veins and inferior vena cava.
Location of renal veins, maximum diameter of the vena cava, and presence or
absence of thrombus were documented. If visualization was adequate, placement was
performed at the bedside for patients in intensive care or in the vascular
laboratory for nonmonitored patients. The initial 10 patients and subsequent
patients in whom there was a question of adequate deployment underwent completion
abdominal roentgenography. Patient follow-up was difficult. Duplex
ultrasonography was used to assess migration, thrombus adherent to the filter,
and vena caval patency. Patients in whom filter placement was prophylactic were
given anticoagulants at the discretion of the primary physician. Inadequate
visualization or vena caval size greater than 28 mm prompted fluoroscopic
placement of the vena caval filter, because only Greenfield titanium filters were
used in the study. RESULTS: Twenty-nine patients were referred for vena caval
interruption. Inadequate visualization occurred in four obese patients, and
filters were placed by fluoroscopy. There were no vena caval measurements greater
than 24 mm. Twenty-five filters were placed without technical difficulty. One
filter tilted into the right renal vein, requiring a suprarenal filter placed by
fluoroscopy. Patient retrieval for follow-up has been difficult, but by
ultrasonography there has been one vena caval thrombosis and no major filter
migration. There have been no reported pulmonary emboli other than the one
patient with initial tilt of the filter. CONCLUSIONS: Placement of vena caval
filters is feasible with duplex ultrasonography. Visualization is the only
limiting condition to placement and occurs rarely. Reducing the need for
fluoroscopy, lowering costs, and not needing to transport the critically ill
patient support the use of this system. Intravascular ultrasonography in selected
patients may eliminate the need for fluoroscopic placement of vena caval filters.
PMID- 9551076
TI - Use of split horseshoe kidney for transplantation.
PMID- 9551077
TI - Delayed splenic hematoma: an injury in evolution.
PMID- 9551078
TI - A case of axillary arterial bleeding caused by radiation-induced chest wall ulcer
after radiotherapy for carcinoma of the breast: extraanatomic bypass grafting for
upper limb salvage.
PMID- 9551079
TI - Autogenous patching of a kinked internal carotid artery.
PMID- 9551080
TI - Negative influence of RasG on chemoattractant-induced ERK2 phosphorylation in
Dictyostelium.
AB - The Dictyostelium ERK2 protein is transiently activated when cells are treated
with the chemotactic agents cAMP or folic acid. Activating phosphorylation is
markedly inhibited in strains overexpressing the constitutively activated RasG
protein. This is in marked contrast to mammalian cells where the highly related
mitogen-activated protein kinases (MAPKs) are stimulated by Ras activation.
PMID- 9551081
TI - Studies of perinuclear and nuclear translocation of the Raf-1 protein in rodent
fibroblasts.
AB - Raf-1, A-Raf and B-Raf comprise a small family of highly conserved
serine/threonine protein kinases, whose activities play a fundamental role in the
control of proliferation and differentiation. The best studied family member, Raf
1, is expressed ubiquitously and constitutively, and its activity is regulated by
post-translational mechanisms. Raf-1 can be activated by many signals that
include growth factors, tumor promoters, inflammatory cytokines, calcium
mobilization, DNA damaging agents, and oxygen radicals. Ras-mediated
translocation of Raf-1 to the plasma membrane is a crucial step in its activation
process, and is thought to facilitate phosphorylation by membrane-bound kinases.
Raf-1 has also been reported to undergo intracellular redistribution following
its activation: to the perinuclear space in murine NIH3T3 cells and rat hepatic
Ito cells, and into the nucleus in gerbil hippocampal pyramidal cells and human
MO7 leukemia cells. In contrast to the translocation to the plasma membrane, the
perinuclear and/or nuclear translocation of Raf-1 has not been investigated in
detail. In this paper, we report an examination of the subcellular localization
of endogenous Raf-1 in a fibroblastic cell line (Rat-1) commonly used in
transformation assays. Using the methods of cellular fractionation as well as in
situ immunofluorescence, we show that no detectable movement of Raf-1 to the
perinuclear or nuclear space can be observed. Tethering of activated Raf to the
plasma membrane does not interfere with its transforming activity.
PMID- 9551082
TI - Constitutive and interferon-gamma-induced expression of the human proteasome
subunit multicatalytic endopeptidase complex-like 1.
AB - Proteasomes generate peptides from intracellular endogenous and viral proteins
for presentation by MHC class I molecules. During viral infection, interferon
gamma (IFN-gamma) acts as a cytokine altering the catalytic specificity of
proteasomes by inducing the synthesis of the three proteasome subunits, low
molecular weight protein (LMP) 2, LMP7 and multicatalytic endopeptidase complex
like 1 (MECL1). LMP2 and LMP7 have been shown to favour the presentation of
certain antigenic peptides. These subunits are constitutively expressed in cell
lines related to the immune system and IFN-gamma-inducible in other cell lines.
Less is known about MECL1. To reveal the extent of constitutive and IFN-gamma
induced expression of MECL1, we studied MECL1 in different cell lines by Northern
and Western blotting. The two B cell lines IM9 and Reh showed high constitutive
expression of MECL1, only slightly induced by IFN-gamma stimulation. The B cell
line Daudi and the monocyte cell line THP-1 expressed MECL1 constitutively at an
intermediate level. The MECL1 protein level in the THP-1 cells increased markedly
in response to IFN-gamma. In cells unrelated to the immune system, a very low
constitutive expression of MECL1 was detected, highly inducible by IFN-gamma.
These results indicate that, similar to LMP2 and LMP7, MECL1 is constitutively
expressed at high levels only in certain cell lines and can be induced by IFN
gamma in other cell lines. The differential expression of MECL1 may be of
importance for which antigenic peptides are presented by different cells as well
as by the same cells at different IFN-gamma levels.
PMID- 9551084
TI - Hepatocyte growth factor plays a dual role in regulating skeletal muscle
satellite cell proliferation and differentiation.
AB - The role of hepatocyte growth factor (HGF) and its receptor, c-met, in
proliferation and differentiation of satellite cells was studied in primary
cultures of chicken skeletal muscle satellite cells and a myogenic C2 cell line.
HGF mRNA was expressed mainly in the myotubes of both cultures. The addition of
conditioned medium derived from those cultures had a scattering effect on the
canine kidney epithelial cell line, MDCK. In contrast, c-met mRNA levels
decreased during cell differentiation of C2 and primary satellite cells.
Application of exogenous HGF to chicken myoblasts resulted in their enhanced DNA
synthesis. Among several growth factors, HGF was the first to induce DNA
synthesis in quiescent satellite cells, thereby driving them into the cell cycle.
Ectopic expression of chicken HGF in primary satellite cells suppressed the
activation of muscle-regulatory gene reporter constructs MCK-CAT, MRF4-CAT, MEF2
CAT and 4Rtk-CAT, as well as the gene expression of MyoD and myogenin, and MHC
protein expression. Ectopic MyoD reversed HGF's inhibitory effect on MCK
transactivation. These data suggest that HGF inhibits cell differentiation by
inhibiting the activity of basic helix-loop-helix (bHLH)/E protein heterodimers,
thus inhibiting myogenic determination factor activity and subsequent muscle
specific protein expression. During muscle growth and regeneration, HGF plays a
dual role in satellite-cell myogenesis, affecting both the proliferation and
differentiation of these cells in a paracrine fashion.
PMID- 9551083
TI - Selection and characterisation of murine leukaemia L1210 cells with high-level
resistance to the cytostatic activity of the acyclic nucleoside phosphonate 9-(2
phosphonylmethoxyethyl) adenine (PMEA).
AB - An L1210 cell line showing a 300-fold resistance to the cytostatic effect of 9-(2
phosphonylmethoxyethyl)adenine (PMEA) (designated L1210/PMEA-1) was selected in
cell culture upon exposure of wild-type L1210/0 cells to stepwise-increased drug
concentrations. The mutant L1210/PMEA-1 cell line was characterized by an unusual
specificity in that the cytostatic activity was severely impaired only for PMEA
and the closely related 2,6-diaminopurine derivative PMEDAP, but not for its
guanine counterpart PMEG or for 9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine
(HPMPA). The L1210/PMEA-1 cell line showed poor resistance to the cytostatic
activity of the lipophilic PMEA prodrug bis(POM)PMEA and virtually kept its PMEA
resistance profile in the presence of indomethacin, excluding resistance of the
cells of PMEA and PMEDAP by an increased efflux of the drugs. Intracellular
purine nucleotide pool labelling studies with adenine, hypoxanthine and glycine
revealed that PMEA/PMEDAP resistance did not originate from a defect in the
enzymatic pathways of purine nucleotides. ATP, AMP and cAMP, but not adenosine,
adenine, HPMPA and inhibitors of nucleoside transport carriers markedly
interfered with PMEA uptake in L1210/0 cells. The L1210/PMEA-1 cells proved to
have less than 10% of the PMEA uptake capacity of wild-type L1210/0 cells as
measured by rapid sampling kinetics as well as long-term incubation experiments.
After a 24-h incubation period, the intracellular levels of [2,8-3H]PMEA and its
phosphorylated metabolites were approximately 10-fold lower in L1210/PMEA-1 cells
than in L1210/0 cells. Our observations point to a compromised and highly
specific PMEA/PMEDAP uptake as the molecular basis for the pronounced PMEA
resistance of the mutant L1210/PMEA-1 cells.
PMID- 9551085
TI - The calpain-calpastatin system and protein degradation in fusing myoblasts.
AB - Calpain (Ca(2+)-activated cysteine protease) induced proteolysis has been
suggested to play a role in myoblast fusion. We previously found that calpastatin
(the endogenous inhibitor of calpain) diminishes markedly in myoblasts during
myoblast differentiation just prior to the start of fusion, allowing Ca(2+)
induced calpain activation at that stage. Here, we show that a limited
degradation of some proteins occurs within the myoblasts undergoing fusion, but
not in proliferating myoblasts. The protein degradation is observed at the stage
when calpastatin is low. Protein degradation within the myoblasts and myoblast
fusion are inhibited by EGTA, by the cysteine protease inhibitors calpeptin and E
64d and by calpastatin. The degradation appears to be selective for certain
myoblast proteins. Integrin beta 1 subunit, talin and beta-tropomyosin are
degraded in the fusing myoblasts, whereas alpha-actinin, beta-tubulin and alpha
tropomyosin are not. A similar pattern of degradation is observed in lysates of
proliferating myoblasts when Ca2+ and excess calpain are added, a degradation
that is inhibited by calpastatin. The results support the notion that degradation
of certain proteins is required for myoblast fusion and that calpain participates
in the fusion-associated protein degradation. Participation of calpain is made
possible by a change in calpain/calpastatin ratio, i.e., by a diminution in
calpastatin level from a high level in the proliferating myoblasts to a low level
in the differentiating myoblasts. Degradation of certain proteins, known to be
responsible for the stability of the membrane-skeleton organization and for the
interaction of the cell with the extracellular matrix, would allow
destabilization of the membrane and the creation of membrane fusion-potent
regions.
PMID- 9551086
TI - Evidence that photodynamic stress kills Zellweger fibroblasts by a nonapoptotic
mechanism.
AB - Zellweger fibroblasts, which are devoid of peroxisomes and fail to synthesize
plasmalogens, are very sensitive to the killing effect triggered by UV-activated
12-(1-pyrene) dodecanoic acid (P12). Although in some studied performed, it is
assumed that reactive oxygen species (ROS) may damage plasma membrane causing
necrosis, other studies suggest that ROS are involved in apoptotic cell death
induced by a wide variety of stimuli. Analysing the P12 dose-response in
Zellweger fibroblasts, we observed that at high doses (1-2 microM), more than 75%
of the cells died after 24 h. This behaviour suggested that, at high doses, P12
kills the cells by unspecific lytic mechanisms or by necrosis, while at low doses
(0.1-0.5 microM), an apoptotic mechanism could be involved. Cytofluorimetric
analysis of Zellweger fibroblasts-treated with activated P12 (0.5 microM) did not
show morphological modifications typical of apoptotic cell death. This was
supported by comparative staining of fibroblast nuclei, DNA gel electrophoresis
and identification of poly(ADP-ribose) polymerase (PARP) cleavage and Bcl-2
expression, assayed by Western blots. Thus, our results, while confirming the
importance of plasmalogens in the protection against ROS, establish that
apoptosis is not involved in photodynamic death induced by activated P12.
Therefore, we can expect that in gene transfer experiments, the rescue of
Zellweger cells will be dependent only on the correction of peroxisomal
biogenesis.
PMID- 9551087
TI - A novel Arabidopsis thaliana protein protects tumor cells from tumor necrosis
factor-induced apoptosis.
AB - Recently we have cloned and characterized a novel, oxidative stress-induced
Arabidopsis thaliana gene (oxy5), and showed that expression of oxy5 protects
bacterial cells from death caused by oxidative stress. As oxidative stress is one
pathway of TNF cytotoxicity, we investigated whether the encoded protein could
also protect human tumor cells from TNF killing. We stably transfected the oxy5
gene into TNF-sensitive HeLa D98 cells (D98/O.5), and found that all examined
transfectants were highly TNF-resistant in the absence of the protein synthesis
inhibitor cycloheximide. The acquired TNF resistance of these clones was
accompanied by a sharp decrease in the intracellular formation of reactive oxygen
species, suggesting the activation of antioxidant enzymes like superoxide
dismutases (SODs). Indeed, D98/O.5 clones showed an increased manganous
superoxide dismutase (MnSOD) mRNA and protein expression in the absence or
presence of TNF stimulation, whereas the expression of the Cu/ZnSOD was not
affected. Furthermore, the elevated MnSOD expression in the D98/O.5 clones
correlated well with an increased antioxidative activity, which was specifically
due to MnSOD as measured by the suppression of xanthine oxidase. Our results
demonstrate a novel role for a plant-derived protein in resistance to TNF
cytotoxicity, and that the Arabidopsis thaliana protein Oxy5 can exert its
protective function across evolutionary boundaries through activation of
antioxidant enzymes like MnSOD.
PMID- 9551088
TI - Induction of the DNA-binding and transcriptional activities of heat shock factor
1 is uncoupled in Xenopus oocytes.
AB - The DNA-binding and transcriptional activities of the heat shock transcription
factor 1 (HSF1) are repressed under normal conditions and rapidly upregulated by
heat stress. Here, we tested for the ability of various stress agents to activate
HSF1 in the Xenopus oocyte model system. The HSE-binding activity of HSF1 was
induced by a number of chemical stresses including cadmium, aluminum, iron,
mercury, arsenite, ethanol, methanol, and salicylate. HSE-binding was not induced
by several stresses known to induce the synthesis of hsps in other cell types in
different organisms including zinc, copper, cobalt, manganese, recovery from
anoxia, UV-irradiation, and increased pH. The inability of several known inducers
of the stress response to activate the HSE-binding ability of HSF1 suggests that
certain stress activation pathways may be absent or inactive in oocytes. The
transcriptional activity of oocyte HSF1 was induced by heat, cadmium, and
arsenite, but many of the agents that induced HSE-binding failed to stimulate
HSF1-mediated transcription. The apparent uncoupling of inducible HSE-binding and
transcriptional activities of HSF1 under a variety of stress regimes indicates
that these events are regulated by independent mechanisms in the oocyte.
PMID- 9551089
TI - Role of arginine 86 of the insulin receptor in insulin binding and activation of
glucose transport.
AB - Mutations in the insulin receptor gene cause the inherited insulin resistant
syndrome leprechaunism. Patient Atl-1 with leprechaunism was homozygous for the
substitution of Arg-86 with Pro (R86P) in the alpha subunit of the insulin
receptor. Fibroblasts homozygous for the mutant receptor had defective insulin
binding, but increased glucose transport and receptor kinase activity. The R86P
mutation is located in a putative beta turn N-terminal to a proposed insulin
binding domain of the receptor [P. DeMeyts, J.L. Gu, R.M. Shymko, B.E. Kaplan,
G.I. Bell, J. Whittaker, Mol. Endocrinol. 4 (1990) 409-416]. To get further
insight into the mechanism of the paradoxical activation of receptor signalling
by the R86P mutation, the codons for proline, alanine, and glycine were
substituted in the R86 position of the insulin receptor cDNA by PCR-mediated
mutagenesis and stably transfected into Chinese hamster ovary (CHO) cells.
Insulin binding increased 10-20 fold in CHO cells transfected with the wild type,
the R86A, and the R86G insulin receptor cDNA, but did not increase in cells
expressing the R86P mutation. The R86P mutation caused a constitutive activation
of insulin receptor phosphorylation in CHO cells, but did not increase basal
glucose transport or its sensitivity to insulin stimulation. By contrast,
transfection with the wild type and the R86A receptors increased 20-30 fold the
sensitivity of glucose transport to stimulation by insulin. The R86G insulin
receptor bound insulin normally, but was four times less efficient than the wild
type or R86A insulin receptor in increasing the sensitivity for insulin
stimulation of glucose transport. These results indicate that position 86 of the
insulin receptor alpha subunit is tolerant to substitution by alanine, but not by
proline. Substitution with glycine allows insulin binding, but does not activate
normally glucose transport, further supporting an essential role of this position
in the initiation of insulin receptor signalling of glucose transport.
PMID- 9551091
TI - cGMP potentiates receptor-stimulated Ca2+ influx in Dictyostelium discoideum.
AB - Binding of extracellular cAMP to surface receptors induces at least two responses
in Dictyostelium discoideum, the G-protein-dependent activation of guanylyl
cyclase, and the opening of a plasma membrane Ca2+ channel. Some experiments
suggest that intracellular cGMP opens the Ca2+ channel, while others demonstrate
that the channel can open in the absence of functional G-proteins (and thus in
the absence of cGMP formation). We have analysed 45Ca2+ uptake in three mutants
with altered cGMP formation. Mutant stmF shows a prolonged cGMP response due to
deletion of an intracellular phosphodiesterase. Uptake of receptor-stimulated
45Ca2+ is enhanced about two-fold in this mutant if compared to wild-type cells,
suggesting that cGMP regulates the opening of the channel. Mutant KI-7 has very
low levels of surface cAMP receptors, but nevertheless an enhanced receptor
stimulated cGMP response due to a defect in the turn-off of guanylyl cyclase.
This mutant shows poor receptor-stimulated 45Ca2+ uptake, suggesting that cGMP
alone is not sufficient to open the Ca2+ channel. Finally, mutant KI-8 has no
cGMP due to the absence of nearly all guanylyl cyclase activity. The mutant shows
significant but reduced 45Ca2+ uptake (19% of wild-type; 60% if corrected for the
reduced level of surface cAMP receptors), suggesting that the channel can open in
the absence of cGMP. Taken together, the results demonstrate that receptor
stimulated Ca2+ influx is not directly induced by cGMP formation; it can occur in
the absence of cGMP, but is potentiated two- to four-fold by cGMP.
PMID- 9551092
TI - The mechanism of Ca2+ release from the SR of permeabilised guinea-pig and rat
ureteric smooth muscle.
AB - Recent work has indicated that there is a major difference in the Ca2+ store of
smooth muscle from rat and guinea-pig ureter; with the rat store being agonist
sensitive but ryanodine insensitive and the guinea-pig store being ryanodine
sensitive but agonist insensitive [Th. V. Burdyga, M.J. Taggart, S. Wray, J.
Physiol. 489 (1995) 327-335]. We have therefore examined directly the mechanism
of Ca2+ release from the internal Ca2+ store (SR). Following permeabilisation
with alpha-toxin or beta-escin the SR was Ca(2+)-loaded before application of
carbachol or caffeine. Only carbachol evoked a transient contraction in rat
ureter. The carbachol-induced contraction was blocked by heparin and
cyclopiazonic acid (CPA) but not ryanodine. Only caffeine produced contraction in
guinea-pig ureter, and this was blocked by ryanodine. Direct application of IP3
caused a small transient contraction in rat but not guinea-pig ureter. We
conclude that rat ureter possesses only an IP3 sensitive store while guinea-pig
ureter only has a ryanodine sensitive store.
PMID- 9551090
TI - Phosducin-like protein (PhLP), a regulator of G beta gamma function, interacts
with the proteasomal protein SUG1.
AB - Phosducin-like protein (PhLP) and phosducin are highly homologous proteins that
interact with the beta gamma subunits of guanine nucleotide binding proteins.
While phosducin has a well-characterized role in retinal signal transduction,
PhLP function remains unclear. To further understand the function of PhLP, we
have examined other potential protein:protein interactions with PhLP using the
yeast two-hybrid system. PhLP was found to interact with a mouse homologue of the
yeast SUG1, a subunit of the 26S proteasome which may also indirectly modulate
transcription. This interaction was further confirmed by an in vitro binding
assay and co-immunoprecipitation of the two proteins in overexpression studies.
Inhibition of proteasome function by lactacystin led to accumulation of high
molecular weight, ubiquitin-immunoreactive protein precipitated by PhLP
antiserum. We suggest that PhLP/SUG1 interaction may target PhLP for proteasomal
degradation.
PMID- 9551093
TI - [Result of antineoplastic agents screening: 7th report].
PMID- 9551094
TI - The DNA binding specificity of engrailed homeodomain.
AB - The engrailed gene of Drosophila melanogaster is an integral member of the highly
complex cascade which results in a fully developed fruitfly. The gene product of
engrailed contains a homeodomain which is responsible for DNA binding via a helix
turn-helix motif. The crystal structure of this 60 amino acid residue domain
complexed to DNA is analogous to structures of other homeodomain-DNA complexes,
consistent with the high degree of sequence conservation within both protein and
DNA. Despite the high degree of homology, homeodomains do exhibit distinct
preferences for certain DNA sequences. Such specificity may be at least partly
responsible for the interactions necessary for normal development. Using the
hydroxyl radical as a chemical probe, we have examined complexes of Engrailed
homeodomain with several DNA sequences to determine the protein's binding
specificity in solution. We find that Engrailed forms a single, specific complex
with a unique DNA binding site which is analogous to the complex seen in the co
crystal structure. In contrast, our chemical probe experiments show that the
binding site of Engrailed that was determined by in vitro selection and that also
was present in the co-crystal structure contains two possible binding sites.
Modification of the sequence of this site to yield single binding sites removes
the ambiguity, and results in two different, well-behaved Engrailed-DNA
complexes. Our results underscore the utility of chemical probe experiments for
defining the variety of modes of interaction of proteins with DNA that can occur
in solution, but that might not be apparent in a crystal structure.
PMID- 9551095
TI - Base-pairing of 23 S rRNA ends is essential for ribosomal large subunit assembly.
AB - In ribosomal RNA precursors the spacer sequences bracketing mature 16 S and 23 S
rRNA are base-paired to form long helices (processing stems). In pre-23 S rRNA,
the processing stem is continued by eight base-pairs of mature 23 S rRNA known as
helix 1. Recently, we have found that any part of 23 S rRNA between positions 40
and 2773 could be deleted without the loss of ribosome-like particle formation,
while both end regions were indispensable. In this paper we have analyzed the
role of the 5' and 3' end regions of 23 S rRNA during ribosomal 50 S assembly in
vivo by using mutants of the 23 S rRNA gene. Deletions and substitutions in both
strands of the helix 1 lead to the loss of plasmid derived 50 S formation.
Compensatory mutations restoring helix 1 were assembled into functional 50 S
subunits. We conclude that the helix 1 of 23 S rRNA is the main RNA determinant
for ribosomal large-subunit assembly. Deletions in both the 5' and 3' strand of
the processing stem reduced the ability of the 23 S rRNA to form ribosomal 50 S
subunits. However, even the complete removal of either the 5' or the 3' strand of
the processing stem did not abolish the 50 S assembly completely. Thus,
processing stem facilitates, but is not essential for assembly.
PMID- 9551096
TI - Mutations in the leader region of ribosomal RNA operons cause structurally
defective 30 S ribosomes as revealed by in vivo structural probing.
AB - The biogenesis of functional ribosomes is regulated in a very complex manner,
involving different proteins and RNA molecules. RNAs are not only essential
components of both ribosomal subunits but also transiently interacting factors
during particle formation. In eukaryotes snoRNAs act as molecular chaperones to
assist maturation, modification and assembly. In a very similar way highly
conserved leader sequences of bacterial rRNA operons are involved in the correct
formation of 30 S ribosomal subunits. Certain mutations in the rRNA leader region
cause severe growth defects due to malfunction of ribosomes which are assembled
from such transcription units. To understand how the leader sequences act to
facilitate the formation of the correct 30 S subunits we performed in vivo
chemical probing to assess structural differences between ribosomes assembled
either from rRNA transcribed from wild-type operons or from operons which contain
mutations in the rRNA leader region. Cells transformed with plasmids containing
the respective rRNA operons were reacted with dimethylsulphate (DMS). Ribosomes
were isolated by sucrose gradient centrifugation and modified nucleotides within
the 16 S rRNA were identified by primer extension reaction. Structural
differences between ribosomes from wild-type and mutant rRNA operons occur in
several clusters within the 16 S rRNA secondary structure. The most prominent
differences are located in the central domain including the universally conserved
pseudoknot structure which connects the 5', the central and the 3' domain of 16 S
rRNA. Two other clusters with structural differences fall in the 5' domain where
the leader had been shown to interact with mature 16 S rRNA and within the
ribosomal protein S4 binding site. The other differences in structure are located
in sites which are also known as sites for the action of several antibiotics. The
data explain the functional defects of ribosomes from rRNA operons with leader
mutations and help to understand the altered biogenesis pathway from mutations in
an rRNA leader region to the formation of functionally defective ribosomes.
PMID- 9551097
TI - Slipped misalignment mechanisms of deletion formation: analysis of deletion
endpoints.
AB - To gain insight into the mechanisms of deletion formation between tandem repeats,
Escherichia coli plasmids were engineered to carry a 101 bp tandem duplication
within the tetA gene such that deletion of one of the repeats restores an intact
tetA gene and tetracycline resistance to the cell. Four base-pair changes were
introduced into one of the tandem repeats to serve as genetic markers. After
selection for deletion, individual plasmid products were sequenced to deduce
where within the repeat the deletion had occurred. Our analysis shows most
deletions are fusions of the two repeats in a single 20 bp interval. This is
consistent with the simple replication slip-pair model for deletion formation and
suggests that this interval may have unusual features that promote deletion.
Dimer replicon products have experienced a sister-chromosome exchange event in
addition to deletion and carry two tetA loci: a deleted locus showing a similar
distribution of endpoints as seen-in the monomer products and an unchanged repeat
locus. Seemingly reciprocal dimers are occasionally recovered which carry both a
deleted and a triplicated tetA locus. These are not truly reciprocal in that the
sequence analysis showed that the deletion and triplication had occurred in
separate intervals. Sequence analysis of the dimeric products is consistent with
predictions from our sister-strand exchange model where slipped alignment of
nascent DNA strands induces deletion formation concomitant with sister-chromosome
exchange.
PMID- 9551098
TI - Thermodynamics of specific and non-specific DNA binding by the c-Myb DNA-binding
domain.
AB - The thermodynamics of the c-Myb DNA-binding domain (R2R3) interaction with its
target DNA have been analyzed using isothermal titration calorimetry and amino
acid mutagenesis. The enthalpy of association between the standard R2R3, the
Cys130 mutant substituted with Ile, and the cognate DNA is -12.5 (+/- 0.1) kcal
mol-1 at pH 7.5 and at 20 degrees C, and this interaction is enthalpically driven
throughout the physiological temperature range. In order to understand the DNA
recognition mechanism, several pairs of interactions were investigated using
single and multiple-base alterations with single and multiple-amino acid
substituted mutants. The interactions between the standard R2R3 and many non
cognate DNAs were accompanied by binding enthalpy changes and heat capacity
changes, although their affinities were reduced. The roles of the electrostatic
interactions in binding to the cognate and the non-cognate DNAs were also
analyzed from the dependency of the thermodynamic parameters on the salt
concentration. The heat capacity change was found to be significantly dependent
upon the salt concentration. Several mutant proteins bound to the multiple-base
altered DNA with very small enthalpy changes, although they bound to the cognate
and the single-base altered DNAs with detectable enthalpy and heat capacity
changes. From the thermodynamic cycles derived from the DNA binding of the amino
acid substituted R2R3 to the base substituted DNA duplexes, the individual
thermodynamic mechanisms of the specific DNA recognition of R2R3 were dissected.
The local folding mechanism was highlighted by the substitution of Pro with
either Gly or Ala at the linker between R2 and R3. The characteristic
thermodynamic features of specific and non-specific DNA binding are discussed.
PMID- 9551099
TI - Crystal structure of the IIB subunit of a fructose permease (IIBLev) from
Bacillus subtilis.
AB - The bacterial phosphoenolpyruvate-dependent phosphotransferase system (PTS)
mediates both the uptake of carbohydrates across the cytoplasmic membrane and
their phosphorylation. During this process, a phosphoryl group is transferred
from phosphoenolpyruvate via the general PTS proteins enzyme I, HPr and the sugar
specific components IIA, IIB to the transported sugar. The crystal structure of
the IIB subunit of a fructose transporter from Bacillus subtilis (IIBLev) was
solved by MIRAS to a resolution of 2.9 A. IIBLev comprises 163 amino acid
residues that are folded into an open, mainly parallel beta-sheet with helices
packed on either face. The phosphorylation site (His15) is located on the first
loop (1/A) at one of the topological switch-points of the fold. Despite different
global folds, IIBLev and HPr have very similar active-site loop conformations
with the active-site histidine residues located close to the N terminus of the
first helix. This resemblance may be of functional importance, since both
proteins exchange a phosphoryl group with the same IIA subunit. The structural
basis of phosphoryl transfer from HPr to IIAMan to IIBMan was investigated by
modeling of the respective transition state complexes using the known HPr and
IIAMan structures and a homology model of IIBMan that was derived from the IIBLev
structure. All three proteins contain a helix that appears to be suitable for
stabilization of the phospho-histidine by dipole and H-bonding interactions.
Smooth phosphoryl transfer from one N-cap position to the other appears feasible
with a minimized transition state energy due to simultaneous interactions with
the donor and the acceptor helix.
PMID- 9551100
TI - Crystal structure of tryptophanase.
AB - The X-ray structure of tryptophanase (Tnase) reveals the interactions responsible
for binding of the pyridoxal 5'-phosphate (PLP) and atomic details of the K+
binding site essential for catalysis. The structure of holo Tnase from Proteus
vulgaris (space group P2(1)2(1)2(1) with a = 115.0 A, b = 118.2 A, c = 153.7 A)
has been determined at 2.1 A resolution by molecular replacement using tyrosine
phenol-lyase (TPL) coordinates. The final model of Tnase, refined to an R-factor
of 18.7%, (Rfree = 22.8%) suggests that the PLP-enzyme from observed in the
structure is a ketoenamine. PLP is bound in a cleft formed by both the small and
large domains of one subunit and the large domain of the adjacent subunit in the
so-called "catalytic" dimer. The K+ cations are located on the interface of the
subunits in the dimer. The structure of the catalytic dimer and mode of PLP
binding in Tnase resemble those found in aspartate amino-transferase, TPL, omega
amino acid pyruvate aminotransferase, dialkylglycine decarboxylase (DGD),
cystathionine beta-lyase and ornithine decarboxylase. No structural similarity
has been detected between Tnase and the beta 2 dimer of tryptophan synthase which
catalyses the same beta-replacement reaction. The single monovalent cation
binding site of Tnase is similar to that of TPL, but differs from either of those
in DGD.
PMID- 9551101
TI - Folding intermediates of wild-type and mutants of barnase. I. Use of phi-value
analysis and m-values to probe the cooperative nature of the folding pre
equilibrium.
AB - It is difficult to determine whether transient folding intermediates have a
cooperative (or first-order) folding transition without measuring their rates of
formation directly. An intermediate I could be formed by a second-order
transition from a denatured state D that is progressively changed into I as
conditions are changed. We have not been able to monitor the rate of formation of
the folding intermediate of barnase directly, but have analysed its reactivity
and the equilibrium constant for its formation over a combination of wide ranges
of temperature, concentration of denaturant and structural variation. Phase
diagrams have been constructed for wild-type and 16 mutant proteins to map out
the nature of the energy landscape of the denatured state. The free energy of
unfolding of I, delta GD-I, changes with [urea] according to a highly cooperative
transition. Further, mD-I (= delta delta GD-I/delta [urea]) for wild-type and
several mutants is relatively insensitive to temperature, as would be expected
for an intermediate that is formed cooperatively, rather than one that melts out
according to a second-order transition. The phi-values for the formation of I
change abruptly through the folding transitions rather than have the smooth
changes expected for a second-order transition. There is a subset of mutants for
which both mD-I and phi-value analysis indicate that a second intermediate
becomes populated close to the melting temperatures of the native proteins. The
folding intermediate of barnase is, thus, a relatively discrete and compact
entity which is formed cooperatively.
PMID- 9551102
TI - Folding intermediates of wild-type and mutants of barnase. II. Correlation of
changes in equilibrium amide exchange kinetics with the population of the folding
intermediate.
AB - There is an unanswered question from previous studies of 1H/2H-exchange of amide
protons of barnase. Under certain conditions, there is a relatively abrupt change
from EX2 towards EX1 kinetics as the temperature is slightly increased. The
change in kinetics for different mutants is not directly related to their changes
in stability. We have measured the stability of the folding intermediate of
barnase (I) in 2H2O under a variety of conditions and calculated its population
at different temperatures. The change in kinetics correlates with the change in
the population of the folding intermediate. At higher temperatures and pH, the
free energy of I becomes higher than that of the denatured state, D, and the
kinetics becomes EX1. The data fit a simple kinetic scheme. Such changes in
kinetics may be used to detect the presence of intermediates in the folding
reaction at equilibrium in native conditions, but cannot distinguish whether they
are on or off-pathway.
PMID- 9551103
TI - Folding kinetics of the SH3 domain of PI3 kinase by real-time NMR combined with
optical spectroscopy.
AB - The refolding kinetics of the chemically denatured SH3 domain of
phosphatidylinositol 3'-kinase (PI3-SH3) have been monitored by real-time one
dimensional 1H NMR coupled with a variety of other biophysical techniques. These
experiments indicate that the refolding kinetics of PI3-SH3 are biphasic. The
slow phase (27 (+/- 8)% amplitude) is due to a population of substantially
unfolded molecules with an incorrectly configured cis proline residue. The fast
phase (73 (+/- 8)% amplitude) corresponds to the folding of protein molecules
with proline residues in a trans configuration in the unfolded state. NMR
experiments indicate that the first species populated after the initiation of
folding exhibit poor chemical shift dispersion and have spectra very similar to
that of the denatured protein in 8 M guanidine hydrochloride. Linear combinations
of the first spectrum and of the spectrum of the native protein accurately
reconstruct all of the spectra acquired during refolding. Consistent with this,
native side-chain and backbone H alpha atom packing (NMR), secondary structure
(far-UV circular dichroism), burial of aromatic residues (near-UV circular
dichroism), intrinsic fluorescence and peptide binding activity are all recovered
with effectively identical kinetics. Equilibrium unfolding and folding/unfolding
kinetics yield, within experimental error, identical values for the free energy
of unfolding (delta Gu-H2O = 3.38 kcal mol-1) and for the slope of the free
energy of unfolding versus denaturant concentration (meq = 2.33 kcal mol-1 M-1).
Together, these data provide strong evidence that PI3-SH3 folds without
significant population of kinetic well-structured intermediates. That PI3-SH3
folds slowly (time constant 2.8 seconds in H2O at 20 degrees C) indicates that
slow refolding is not always a consequence of kinetic traps but may be observed
even when a protein appears to fold via a simple, two-state mechanism.
PMID- 9551104
TI - Equilibrium folding intermediates of a Greek key beta-barrel protein.
AB - Protein S is a calcium-binding protein comprising two Greek key beta-barrel
domains. We have used NMR and optical spectroscopies to show that, in the absence
of calcium, the N-terminal domain of protein S forms two equilibrium folding
intermediates that are in slow exchange. The intermediates arise from
differential calcium-dependent folding of subdomains which are not contiguous
along the polypeptide chain. The structures of these intermediates are
incompatible with several previously proposed folding mechanisms for Greek key
beta-barrel domains. We proposed a different mechanism that involves multiple
nucleation sites for folding and sequential acquisition of native long-range
interactions.
PMID- 9551105
TI - [Value of dual-phase-helical CT in the preoperative diagnosis of pancreatic
cancer--a prospective study].
AB - PURPOSE: A prospective study was performed to evaluate the accuracy of dual phase
helical CT in suspected pancreatic cancer. METHODS: Within one year 136 patients
underwent helical CT with arterial and portal venous scans after bolus tracking
and NaCl bolus injection. Evidence of pancreatic cancer and assessment of
resectability were recorded using a standardised protocol. Suspected benign
disease was verified by follow-up examination and clinical data, suspected
malignant disease was correlated with biopsy or surgery. RESULTS: For the
detection of tumor the overall concordance was 92%, the sensitivity 98% and the
specificity 70% (6 false positive, 1 false negative). Resectability was correctly
assessed in 90% with a sensitivity of 92% and a specificity of 88% (4 false
positive, 4 false negative). Vascular invasion was detected correctly in 91%
(veins)-94% (arteries), lymph node invasion in 67% and liver metastasis in 94%.
CONCLUSION: Dual phase helical CT is a very reliable tool in the assessment of
resectability in pancreatic cancer.
PMID- 9551106
TI - [In vitro investigations for detection of vascular stenosis using spiral CT
angiography].
AB - PURPOSE: This experimental study investigates the suitability of spiral CT
angiography for detection of stenoses. MATERIAL AND METHODS: Three vessel
phantoms of 4, 7, and 10 mm diameter were scanned with spiral CT several times
using different scanning parameters each time. Axial scans were viewed in
different ways. Stenoses were adjusted axial, oblique, and parallel to the scan
plane, and in between. 7 radiologists had to make a total of 630 decisions about
the detectability of stenoses. RESULTS: Adequate scan and reconstructional
parameters improve detection of stenoses significantly. 100% recognition can be
reached with 5 mm layer thickness and table feed and 2 mm reconstructional
interval provided axial scans are viewed in cine mode on a monitor. Vessels
running parallel to the layer plane show better results than vessels axial to the
plane, which in turn show better results than those running oblique. Vessels of 4
to 10 mm diameter are almost equally suitable. CONCLUSIONS: Viewing axial scans,
the detectability is rather influenced by different locations of stenoses than by
varying vessel diameters.
PMID- 9551107
TI - [Acute ischemic cerebral infarct: prospective serial observations by magnetic
resonance imaging].
AB - AIM: Serial observations of acute ischaemic cerebral infarcts by MRI in order to
define signal patterns, contrast uptake, oedema and secondary haemorrhage over a
period of three months. METHODS: Prospective serial examinations of 34 patients
with acute cerebral ischaemia who were examined during the first 48 hours, on
days 3 or 4, 7, 14, 21, 28 and after three months by MRI (spin echo TR/TE
2200/100/20, 500/20, +/- Gd). RESULTS: T2 weighted spin echo sequences showed the
highest sensitivity (88%) during the first 8 hours of cerebral ischaemia when
compared with other spin echo sequences. Parenchymal contrast enhancement showed
a distinct peak during the second and third weeks. The use of contrast did not
improve diagnosis of an infarct during any stage. 87% of lesions showed
haemorrhage at some stage. Vascular enhancement was observed in 25% of infarcts
during the first 24 hours and was still present after three months in 20%.
Parenchymal and vascular enhancement, and haemorrhage correlate with the size of
the infarct. CONCLUSION: Focal cerebral ischaemia produces an abnormality of the
blood-brain barrier, oedema and finally necrosis, depending on the severity and
duration of the lesion. Haemorrhage in 87% was considerably more common than has
been described previously. Vascular enhancement is not an early sign of an
infarct, contrary to what has been described in the literature.
PMID- 9551108
TI - [T1-weighted dynamic MRI with new superparamagnetic iron oxide particles
(Resovist): results of a phantom study as well as 25 patients].
AB - PURPOSE: Evaluation of the diagnostic usefulness of the T1-effect of Resovist
(SPIO) for dynamic MRI of the liver. METHOD: In-vitro measurements of a dilution
series with T1-weighted FLASH and SE sequences and investigation of 25 patients
with known focal liver lesions with a T2-weighted TSE sequence and a dynamic T1
FLASH sequence. RESULTS: T1-weighted MRI with Resovist in vitro showed a positive
enhancement at low concentrations and a negative enhancement at higher
concentrations. In-vivo T1-weighted dynamic MRI liver parenchyma demonstrated a
positive enhancement 30 s post contrast, followed by a continuous slope of signal
intensity and a negative enhancement (> or = 60 s). Spleen, portal venous vessels
and haemangiomas showed an early increase in signal intensity followed by a
decreasing positive enhancement, but without negative enhancement. During the
perfusion phase metastases showed a small but not significant increase in signal
intensity. In 80% a positive ring enhancement could be observed around
metastases. CONCLUSION: Resovist exhibits a diagnostically useful T1-effect. An
evaluation of the perfusion of focal liver lesions during the distribution phase
is possible with dynamic T1-weighted MRI. This approach may further improve
characterisation of focal liver lesions.
PMID- 9551109
TI - [When is it meaningful to support magnetic resonance tomography by administering
a positive enteral contrast medium?--an account of practical experience].
AB - PURPOSE: To evaluate in which parts of the gastrointestinal tract and in what
clinical situations the diagnostic quality of MR examination may be improved by a
positive enteral contrast agent. METHODS: MR examinations of 37 patients
performed before and after application of a Gadolinium-DTPA preparation suitable
for oral and rectal application were evaluated. Exams were evaluated by two
independent observers. Neoplastic disease of the gastrointestinal tract
constituted the majority of indications followed by inflammatory changes and
extraenteral space-occupying lesions. RESULTS: The majority of examinations (62%)
were improved by the application of enteral contrast agent. No effect was
observed in 35%; in two patients image quality was poorer after contrast
application. The benefit of enteral contrast agents was highest in MR
examinations of the sigma and rectum. The enteral contrast agent was most
valuable in the detection of lymphoma if an evaluation according to indication
was performed. CONCLUSION: In selected cases, the diagnostic quality of abdominal
MRI can be improved by the application of an enteral contrast agent. Apart from
the effect of greater signal intensity, the contrast agent does complement MR
imaging by a functional aspect.
PMID- 9551110
TI - [Combined use of ECK-triggered 2D-phase contrast MR angiography and 2D-time-of
flight MR angiography for planning and follow up before and after vascular
intervention of pelvic and leg arteries].
AB - PURPOSE: To develop a strategy for the complete work-up of vessel lumen and
vessel wall for planning and follow-up of radiological interventions of lower
extremity arteries. METHODS: A total of 36 patients (21 pre-, 8 post- and 7 pre-
and postinterventional) were studied. MRA studies were performed using an ECG
triggered phase contrast technique for the demonstration of intraluminal flow and
an axial high resolution time-of-flight technique to assess the vascular wall.
All MRA studies were analysed by intraindividual DSA comparison for the
assessment of flow and wall structures. RESULTS: Combined MRA techniques provided
a good correlation with DSA for the assessment of vascular flow. The kappa test
revealed a value of greater than 0.61 for most on the vessel segments proving a
good correlation of both methods. Orthogonal high-resolution TOF-MRA provided
additional information for the assessment postinterventional wall haematomas and
hard plaques. CONCLUSION: Combination of PCA to study flow and axial TOF to study
wall pathology improves the usefulness of peripheral MRA.
PMID- 9551111
TI - [31P-mr spectroscopy of peripheral skeletal musculature under load: demonstration
of normal energy metabolites compared with metabolic muscle diseases].
AB - PURPOSE: 31P-MR spectroscopy of skeletal muscle under exercise was used to obtain
the range of normal variation and comparison was made for different neuromuscular
diseases. METHODS: 41 examinations of 24 volunteers and 41 investigations in 35
patients were performed on 1.5 T MR systems (Gyroscan 515 und S15/ACSII,
Philips). Localised 31P-MR spectra of the calf muscle were obtained in time
series with a resolution of 12 s. RESULTS: Two types of muscle energy metabolism
were identified from the pattern of spectroscopic time course in volunteers:
While the first group was characterised by a remarkable decline to lower pH
values during exercise, the second group showed only small pH shifts (minimum pH:
6.48 +/- 0.13 vs 6.87 +/- 0.07, p < 10(-6)) although comparable workload
conditions were maintained. The pH-values correlated well with blood lactate
analysis. Patients with metabolic disorders and chronic fatigue syndrome (CFS)
showed decreased resting values of PCr/(PCr + Pi) and increased pH levels during
exercise. PCr recovery was significantly delayed (0.31 vs 0.65 min-1, p <
0.00005) in metabolic muscle disorders but was normal in CFS patients.
CONCLUSION: Findings in volunteers indicate utilisation of different metabolic
pathways which seems to be related to the fibre type composition of muscle.
Reduced resting levels for PCr/(PCr + Pi), altered pH time courses, and decreased
PCr recovery seem to be helpful indicators for diagnosis of metabolic muscle
disorders.
PMID- 9551112
TI - [Duplex sonography of renal artery stenosis: potentials and limits of frequency
spectrum analysis of arterial segments compared with angiography].
AB - PURPOSE: The aim of this prospective study was to evaluate the potentials and
limits of Doppler waveform analysis of intrarenal vessels in patients with
suspected renal artery stenosis. MATERIAL AND METHODS: In a three-year study we
compared our colour Doppler results of 111 patients with the angiography results.
Evaluated parameters were acceleration time (AT), acceleration index (AI) and
early systolic peak (ESP). RESULTS: The sensitivity of severe stenoses (> or =
70%) was 89%. In moderate stenoses (50-70%) it was possible to increase the
sensitivity from 56% to 76% if a comparison with the contralateral side was
included. The specificity was 91%. Causes for limited sensitivity and specificity
were poor examination conditions, stenoses of accessory renal arteries and
moderate stenoses as well as diffuse non-stenosing lesions. CONCLUSION: In
comparison with angiography, the diagnostic value of Doppler waveform analysis in
the detection of renal artery stenoses has specific limitations. In significant
stenoses, however, additional valuable haemodynamic information, useful for PTA,
can be obtained by this easy and accessible method.
PMID- 9551113
TI - [Comparative findings of digital thoracic images and digital images of
statistical phantoms as film copy, a radiological work station and a PC].
AB - INTRODUCTION: An ROC analysis was carried out in order to determine the
reliability of digital luminescence radiography review at a PC and this was
compared with a radiological work station and with X-ray film on a viewing box.
MATERIAL AND METHOD: 54 chest images obtained by digital luminescence radiography
were selected, 31 of these contained small pulmonary nodules. In order to
evaluate critical detail, five images of a phantom showing round foci were used.
Five radiologists examined these, using a Siemens Magic View work station, a PC
with proprietary software (ViewMed) and X-ray films on a viewing box. Image
processing of the work station used the standard clinical application. ViewMed
performs linear scaling of grey levels to 8 Bit. The results were examined
statistically by means of a t-test. RESULTS: As far as the chest images were
concerned there was no significant difference in the diagnostic value of these
methods. There was, however, a highly significant loss of diagnostic information
with respect to the round focus phantom when using the PC compared with the other
methods. CONCLUSION: In the configuration in which it was used, the PC should not
be relied on as a primary means of examination since critical details cannot
always be seen. In routine use these play a subordinate role and there was no
significant diagnostic loss where the chest images were concerned. We expect that
by improvements in the frequency and contrast processing the PC accuracy will be
considerably increased.
PMID- 9551114
TI - [Radiation exposure of radiation-sensitive risk organs--ocular lens, parotid
gland, thyroid gland--in dacryocystography and therapy].
AB - PURPOSE: Evaluation of radiation dose to the radiosensitive head and neck organs
and tissues-ocular lens, parotid and thyroid glands--during dacryocystography and
fluoroscopy--guided dacryocystoplasty (DCP). METHOD: Radiation dose was
determined in an Alderson Rando phantom and in 13 patients. Radiation dose was
measured directly using Ca-F2-thermoluminescent dosimetry crystals (TLD) which
were placed on each eyelid, parotid gland and thyroid gland. RESULTS: The mean
radiation dose to the lens placed next to the path of radiation was 6.58 mGy in
the Alderson-Rando phantom and 5.43 mGy in patients during DCP. The mean
radiation dose to the contralateral lens was 1.37 mGy and 1.7 mGy to the parotid
gland placed next to the x-ray tube. Radiation dose to the thyroid gland was max.
0.4 mGy during DCP. CONCLUSION: Radiation dose to the ocular lens, parotid gland
and thyroid gland during fluoroscopy-guided DCP was 25 times higher than during
diagnostic dacryocystography. The radiation dose to radiosensitive head and neck
organs and tissues during fluoroscopy-guided DCP is much below the threshold dose
for ocular lens cataract.
PMID- 9551115
TI - [Treatment of arterial aneurysms of the pelvic leg vessels using dacron covered
nitinol stents].
AB - PURPOSE: To evaluate the success rates of the implantation of stent grafts in the
treatment of peripheral aneurysms. MATERIALS AND METHODS: In 13 patients with 15
aneurysms at the common iliac artery (n = 6), external iliac artery (n = 1),
hypogastric artery (n = 2), femoral artery (n = 2) or popliteal artery (n = 4),
implantation of dacron-covered nitinol stents was performed. The patients were
followed up for three to 20 months (mean, 8.8 months) with intravenous digital
subtraction angiography, CT or colour-coded Doppler sonography. RESULTS: In all
cases, the aneurysm was successfully occluded after stent implantation. In one
case with a popliteal aneurysm, kinking of the vessel caused thrombosis of the
stent. The stent was successfully reopened. The aneurysm however, had to be
surgically treated 9 months later. The primary and secondary patency rates at 6
months were 93% and 100%, respectively. CONCLUSION: The method described might be
an alternative therapy to surgery. There are some limitations in respect of
treatment of popliteal aneurysms.
PMID- 9551116
TI - [CT guided percutaneous drainage of retro- and extraperitoneal abscesses and
fluid collection].
AB - PURPOSE: Evaluation of course, success rate and complications after CT-guided
percutaneous drainage of retroperitoneal and extraperitoneal abscesses and fluid
collections (PAFD). METHODS: Retrospective review of 47 PAFD in 42 consecutive
patients (27 male, 15 female, age 58 [27-80] years) over a period of 7 years was
performed. RESULTS: 47 clinically suspected abscesses proved to be 40 abscesses,
three haematomas and 4 lymphoceles. Primarily, 67 drainage catheters were needed,
which included three catheters in 4 patients and 4 catheters in one patient.
Drainage time averaged 17.6 days (2-50). The most frequent drainage location was
the iliopsoas region (27/47 collections). The cure rate was 87.2% (41/47
collections). Temporization was achieved in 8.5% (4/47); there were two drainage
failures (one sepsis, one recurrence). No major complications were observed.
Three catheter dislocations occurred as minor complications. CONCLUSION: CT
guided percutaneous drainage of retroperitoneal and extraperitoneal abscesses and
fluid collections is safe, with a high cure rate and few complications.
PMID- 9551117
TI - [Stereo display of MR angiograms].
AB - PURPOSE: To provide methods for stereoscopic visual demonstration from 3D
reconstructed MR angiographic images. METHODS: Stereoscopic viewing can be
obtained with pairs of images that are displayed at angles of 15 degrees. Optical
devices as stereoscopic binoculars or minor stereoscopes facilitate stereoscopic
viewing. The possibility of stereoscopic projections for a larger auditorium is
mentioned. RESULTS: Using three clinical examples the advantages of stereoscopic
display of MR angiograms are demonstrated. CONCLUSIONS: MR angiography allows
stereoscopic viewing with simple methods, like CT- and conventional rotation
angiography. This principle, which has been known for 100 years, may thus acquire
a new significance.
PMID- 9551118
TI - [Compression therapy of a ruptured spurious aneurysm].
PMID- 9551119
TI - [Lipomatous hypertrophy of the interatrial septum: imaging by echocardiography,
CT and MRT].
PMID- 9551120
TI - [CT monitored transcervical puncture of an epidural abscess at the level of the
atlantodental joint].
PMID- 9551121
TI - [Pulmonary manifestation of juvenile laryngotracheal papillomatosis].
PMID- 9551122
TI - [Metastasis of a papillary cystadenocarcinoma of the ovary in an axillary lymph
node].
PMID- 9551123
TI - [Disputed concept in polytrauma: whole-body spiral CT as primary diagnosis (RoFo
166,5 (1997) 382-8)].
PMID- 9551124
TI - Modeling in manual materials handling.
AB - Manual materials handling (MMH) account for approximately $15.0 billion of
injuries cost in the United States alone. Because of the need to establish manual
handling guidelines, different approaches to achieve this goal were pursued. Such
approaches are based on biomechanics, work physiology, and psychophysics. In
order to better understand the MMH system's behavior, models were developed.
These models can be divided into biomechanical models, physiological models,
psychophysically based capacity models, safe load handling models, and simulation
models. This paper will present a sample of these models and discusses their
advantages and disadvantages.
PMID- 9551125
TI - Work-related musculoskeletal problems: Some ergonomic considerations.
AB - Musculoskeletal disorders (MSD) in industrialized and industrializing countries
are situated and discussed. Considerations are made on the registration of MSD
cases, on the consequences for humans, industry and society, on scientific
methodology and prevention strategies. These considerations are used to develop
proposals for future actions. These concern the development of structures, some
ideas about training and education as well as a common method for applied field
research enabling the use of data in all industries.
PMID- 9551127
TI - An improved method for describing the effects of heat radiation on men.
AB - At industrial workplaces radiant heat load is often the dominant heat stress
factor. Based on 900 climatic chamber experiments on humans, this study was
conducted to develop a physiologically validated index-method to evaluate
climates with intensified heat radiation. A comparison shows that the
international recommended heat stress indices are not suitable to evaluate such
climates correctly. By application of the new index-method into the commonly used
indices, the improvement for the prediction of thermal stress effects in view of
climates with increased heat radiation is discussed.
PMID- 9551126
TI - Factors affecting heat illness when working in conditions of thermal stress.
AB - In hot working conditions, high sweat rates with excessive loss of body fluids
may result in dehydration and electrolyte imbalance. It is well established that
dehydration and/or electrolyte disturbances will impair work performance, and, if
prolonged or severe, can pose a serious risk to health. The lesser condition of
hypohydration is undoubtedly widespread in the workplace, and may be indirectly
responsible for less than optimal performance and workplace accidents. With the
aid of a new sweat collection method, fluid and electrolyte loss from a
population of male workers with varying fitness and body composition has been
documented. This has provided the basis for prescribing guidelines of fluid
replacement when working in the heat. In addition, the minimum duration of heat
exposure required to trigger heat acclimmatization was sought using sweat sodium
as an indicator. Rehydration at the rate of 500 ml/h (250 ml every 30 min) is
recommended for people working in all but extreme heat (> 45 degrees C).
Electrolyte supplements (sodium and potassium) are not generally required in the
workplace, but may be warranted in certain circumstances to avoid hyponatremia (>
3 h). The ability to predict the susceptibility of an individual to fluid and
electrolyte disturbances cannot be made from age, body composition, ethnicity or
VO2max, although a high VO2max appears to enhance heat tolerance. Sodium loss in
sweat varies greatly and is not significantly related to sweat rate.
Acclimatization results in a significant decrease in sweat sodium and increased
sweat rate during summer compared with winter. This advantageous physiological
adaptation requires a minimum of 9 h of heat exposure to initiate.
PMID- 9551128
TI - Balinese dance exercises improve the maximum aerobic capacity.
AB - The maximum aerobic capacity can be used to predict the maximum working capacity.
The maximum working capacity plays an important role in achieving the best
performance. Therefore, physical fitness program for maintaining maximum working
capacity is a must. A study on the application of Balinese dance exercise was
carried out. Sixty young male Balinese, aged from 17 to 19 years were used as
subjects. They were divided into two groups: Experimental group (EG) and control
group (CG) based on their VO2max. The EG participated in a program of Balinese
dance exercise 3 x 50 min per week for 8 weeks. Pretest-posttest control group
design was applied. The maximum aerobic capacity was measured, based on the
Modified Harvard Step-up Test and nomogram of Astrand. The results are as
follows: there is a very significant improvement of VO2max from 2.7 +/- 0.5 l/min
or 51.1 +/- 9.1 ml/kg/min into 3.1 +/- 0.5 l/min or 58.9 +/- 9.8 ml/kg/min. Other
parameters such as resting heart rate, blood pressure and percent body fat were
decreased significantly. The study concludes that Balinese dance exercise could
be used as a program for physical fitness maintenance.
PMID- 9551129
TI - Use of physiological criteria for improving physical work conditions.
AB - Physical work is still present in many countries, specially in developing ones.
The physiological analysis of the work load could be conducted through two
different ways, referring to his energetic cost and/or to the mechanical power of
the human motor. The purpose of ergonomics is to organize any physical
professional task in order to maintain the workers as much as possible inside the
limits of a fatiguing activity. The process of fatigue affects differently a
"general activity" and a "local work." If a worker is engaged in a general hard
activity, like carrying a load or pushing a trolley, an increase of oxygen
consumption or/and an acceleration of the heart rate could be observed. This
latter, allowing to estimate the oxygen cost of the work, is more affected if the
work is performed in a hot environment. In order to establish the ratio between
the data observed at the work place and the maximal working capacity of the
organism, it is possible to experiment with the physiological effects of
transitory increases of the work stress, by increasing the load or/and the
frequency of the repetition of the "unit" of work done. When the task could be
described in terms of local work, the correct methodology is based upon the
general rules established respectively for the static and the dynamic work. In
both the cases, it is possible to determine the critical rate of the muscular
activity, the part of the muscular capacity engaged at the work place and the
probable time for local exhaustion, in order to limit the duration of each period
of work. It should be remembered that 50 years ago, Lucien Brouha proposed that
heart rate determinations at work be used as a criteria for a better organization
of human work by a non-sophisticated method.
PMID- 9551130
TI - Development of an anthropometric database for Hong Kong Chinese CAD operators.
AB - With the increasing popularity of using computer-aided design (CAD) in Hong Kong,
it is time to look into the design of a suitable workplace for the CAD operators
working in the industries. This can be achieved by applying anthropometric data
into the design for enhancing performance and reducing musculoskeletal problems.
In order to avoid any mismatches in anthropometric dimensions, which is believed
to be one of the main causes of fatigue and occupational illness among workers,
in the workplace design for them, eleven relevant body dimensions from a group of
150 Hong Kong male adults with ages ranging from 18 to 28 years were collected
and analyzed to develop a computerized anthropometric database for Hong Kong CAD
operators. The eleven anthropometric dimensions measured were: shoulder rest
height, elbow-fingertip length, shoulder breadth, hip breadth, sitting eye
height, elbow rest height, third lumbar disc-pan length, thigh clearance height,
popliteal height, buttock-popliteal length, and stature. The computerized
database can provide some useful statistics such as mean, standard deviation and
relevant percentiles of all the measured dimensions. With the aid of these
statistics, a new workplace for CAD operators was designed which improved
performance substantially.
PMID- 9551131
TI - Improvement of Tsukiji free fish market in Tokyo ("Kaizen" of work environment).
AB - "TSUKIJI" is one of the biggest and most famous Free Fish Markets in the world,
but there are many problems on the working condition because it was built about
60 years ago. Our investigation was held 1991 to 1993 to give some improvements
regarding layout of buildings, working time, heat condition at refrigerator,
working posture, and so on. We used a questionnaire on daily life and health care
of workers, time study with measurement of heartbeats, and checklist (using
Checklist for Improvement of Safety-Health and Working Conditions,' made by ILO).
The main occupations in TSUKIJI were seller, buyer, delivery worker, and
refrigerator maintenance worker. Their starting time was early in the morning,
usually between 2:00 a.m. and 5:00 a.m., but the hardest one was delivery workers
starting at 9:00 p.m. They used auto cargo car for carrying to shops from
refrigerator or from auction places many times. Sellers had two different types
of work. First, the seller set up the auction, numbering the fish (or cases of
seafood), arranging them in order, and so on. The rest of the work was
transaction of invoices, sometimes using VDU with almost sitting. These works did
not look well balanced. Buyer of tuna cut if like lumber by electric saws did not
have guard for protection and there were more than 200 machines. Overlooking the
market by checklist, some problems were clarified, and suggestions for
improvement include restructuring the whole layout of the market or reforming
buildings, standardization of the cases, adjustment of health facilities, safety
protection on tools and machines, management of working system, working posture,
health care, and so on.
PMID- 9551132
TI - Ergonomic task analysis in electronics industries: some case studies.
AB - The analyses of a few tasks were carried out in an electronics factory. The main
objectives are to identify the ergonomic and biomechanical hazards of problem
work tasks, to analyze each task systematically in order to evaluate the workers'
exposures to the risk factors of force, posture pressure and repetition and to
make recommendations to reduce the risks and hazards. The methodology includes
objective measures--detailed analysis by going through training manuals, job
description and production records. Subjective measures include interviewing the
operator and supervisors informally, the operators were also required to fill in
a structured questionnaire. The paper concludes by making recommendations to
reduce the ergonomic hazards by engineering solutions, redesign or administrative
controls or the implementation of procedures.
PMID- 9551133
TI - Improvement of working posture increases productivity of roof tile home industry
workers at Darmasaba Village, Badung Regency.
AB - In the production process of the roof tile home industry in Darmasaba Village,
Badung Regency, bad working postures such as bending and squatting positions were
observed. It caused an inefficient low speed of work as a consequence. Therefore,
an intervention study in forms of a demo-plot was carried out, introducing the
correct working posture and working method. The process of plating clay material
is done on the desk in a standing position and can be performed continuously,
without waiting for any other works. By so doing, it was found that productivity
of workers increased 20% per day.
PMID- 9551134
TI - Effects of working postures on low back pain.
AB - The prevalence of back pain in a sample of 100 employees in a clothes factory was
studied and predisposing factors especially working postures were analyzed. The
employee's ages were 17-40 years (mean 28 years). Durations of employment were
between 1 month to 21 years (mean 9.4 years). Working time per day was 8 h. The
subjects included 18 males and 82 females. The prevalence of back pain was 38%.
Working activities like lifting, pulling and pushing, bending and sitting were
highly associated with low back pain. Standing and walking were also associated
but with a lower prevalence.
PMID- 9551135
TI - Applying task analysis in design specification: current problems and a solution.
AB - This paper addresses the following criticisms of task analysis: its requirement
for an existing system; its focus on analysis rather than design; its limited
scope within the design cycle; its underspecification of the application domain;
and its inadequate documentation of design outputs. Such criticisms constitute
problems for the application of task analysis. Solutions to these problems have
emerged indirectly from the development of a structured method intended to
rectify the typically late involvement of human factors in system development,
e.g. only at the evaluation stage. This paper describes how task analysis has
been extended and incorporated throughout the design cycle.
PMID- 9551136
TI - Ergonomics application in the N250 aircraft design process, approach, analysis,
and assessment model.
AB - In the decade of the 1990's the human aspect has once again taken center stage in
the design and operation of commercial aircraft. As occupation health and safety
has gained importance in society in general, it has gained even more importance
in the design an operation of commercial aircraft. In aircraft design today, the
man-machine interface is considered in every task of the human workload. The
discipline of ergonomics truly impacts each phase of product or tool design. At
IPTN, the ergonomics effort is principally being applied to the design of the
cockpit, cabin and cargo compartment of the N250. The ergonomists at IPTN are
keenly aware that there would be a conflict between the user and his working
environment without proper attention to the human considerations in the design is
left for ergonomists and innovative programs like IPTN's participatory approach,
to ensure that the human aspect is optimized in the man-machine interface.
PMID- 9551137
TI - A study of impact of shift work on fatigue level of workers in a sanitary-ware
factory using a fuzzy set model.
AB - Work generally affects workers in terms of both physical and mental health.
Workers must adapt their life pattern to match shift-work styles which can result
in family problems, increased fatigue level, lower work efficiency, higher
accident rate, illnesses, and lower productivity. The project obtained an entry
permission to study the impact of shift work on fatigue level of workers in a
sanitary-ware factory. The objectives were: 1) to evaluate fatigue levels of
workers who worked in the morning shift and night shift, and 2) to prioritize
contributing factors affecting fatigue levels using a model of fuzzy set theory.
Twelve male workers participated in the study. Four subjects were recruited from
each of 3 departments, i.e., glazing, baking and quality inspection. The
measurement was conducted before and after the shift for both shifts. Variables
included heart rate monitoring throughout the work shift, critical flicker fusion
frequency, reaction time response, hand-grip strength, and wet-bulb globe
temperature. Results were analyzed using a computerized statistical package. It
was concluded from this study that mental fatigue from working in the morning
shift was significantly higher than the one for working in the night shift. The
same indication was also true in the case of physical fatigue, though it was not
statistically significant. From the fuzzy set analysis, it was confirmed that
working in the morning shift resulted in a higher fatigue level than working in
the night shift and the temperature of the work environment was the most
important factor contributing to the higher fatigue level.
PMID- 9551138
TI - Reliability of inferred age, and coincidence between inferred age and
chronological age.
AB - Outdoor research is restricted by many factors. The age inference was one of the
biggest problems for the outdoor researchers. We have investigated the
reliability of inferred age for the Japanese people, and took out the estimation
formula for the age, even if it was based on the inferred age. The age
classification was the most popular method for this purpose, and there were many
classifications. We took the classification of young, middle aged, and elderly
groups, in which classification of the SDs were rather small, that is, 4, 5, and
7 years for the young, middle aged, and elderly age groups, respectively.
PMID- 9551139
TI - Therapeutics in atopic dermatitis.
PMID- 9551140
TI - Neutrophilic tissue reactions.
PMID- 9551141
TI - Update on cutaneous drug reactions.
PMID- 9551142
TI - Generalized atrophic benign epidermolysis bullosa.
AB - Junctional EB was once considered a uniformly fetal autosomal recessive skin
disease. One of the first and best characterized forms of generalized JEB that
has a more favorable prognosis was GABEB. Since its initial description in 1976,
many additional cases have been compiled, all sharing the features of chronic
blistering from birth, nail dystrophy, hair loss, and abnormal teeth. In
addition, some patients have large melanocytic nevi that form at sites of prior
blisters. The first clues as to the protein defective in these patients was
provided by immunofluorescence microscopy studies, which showed absent or
decreased expression of type XVII collagen in these patient's epidermal BM. This
protein was a promising candidate because it is located in the ultrastructural
plane where blisters from in patients with GABEB. It is also the same
hemidesmosomal protein against which antibodies are directed in patients with
autoimmune blistering diseases: bullous, gestational, and cicatricial pemphigoid.
The demonstration of decreased expression of type XVII collagen in patients with
GABEB pointed the way to a crucial distinction that could not be based on
clinical and histologic findings--that of discriminating infants with GABEB from
those with the lethal Herlitz variant of JEB. These two diseases may be
differentiated because decreased expression of type XVII collagen is found
exclusively in GABEB, whereas decreased expression of laminin 5 is most likely
associated with Herlitz JEB. The molecular basis of GABEB has been determined.
The immunofluorescence microscopy studies mentioned above directed mutation
studies to the COL17A1 gene. Several mutations in COL17A1 have been described in
patients with GABEB, almost all of which result in a PTC. As a consequence of the
PTC, mutant COL17A1 transcripts are rapidly degraded by nonsense-mediated mRNA
decay, blocking production of type XVII collagen from the mutant allele.
Heterozygous carriers of the mutation are thus rendered untouched by the
mutation. In the homozygous state, however, this results in the absence of this
vital adhesion protein, leading to chronic blistering and skin fragility observed
in these patients. These studies also significantly increase our knowledge about
the normal functions of type XVII collagen. The fact that patients deficient in
type XVII collagen have fragile skin attests to the role of this protein in the
adhesion of basal keratinocytes to epidermal BM. The severity of GABEB, however,
is much less than that observed in patients with a complete deficiency of laminin
5, suggesting that type XVII collagen functions cooperatively with other
hemidesmosomal proteins in promoting adhesion. Studies using GABEB keratinocytes
will help characterize these kinds of interactions. The ultimate prospect of
mutation analysis in these patients is the hope of correcting their genetic
defect and curing their disease. Until then, the physician plays an important
role in making the diagnosis, providing general supportive skin care, advising
avoidance of trauma, treating infections, and supporting the patient's
psychosocial development. Further studies of patients with GABEB will lead to new
therapeutic approaches, as well as reveal additional complex functions of type
XVII collagen not only in skin, but also in hair, teeth, and nails.
PMID- 9551143
TI - The regulation and function of the p53 tumor suppressor.
PMID- 9551144
TI - Molecular genetics of skin cancer.
PMID- 9551145
TI - The role of immunohistochemistry in the diagnosis of cutaneous lymphoma.
PMID- 9551146
TI - Interferons in dermatology: biology, pharmacology, and clinical applications.
PMID- 9551148
TI - Photosensitivity disorders in childhood.
PMID- 9551147
TI - Minimal deviation melanoma: concept or quagmire?
PMID- 9551149
TI - Nail diseases in children.
PMID- 9551150
TI - Vascular tumors and vascular malformations (new issues).
PMID- 9551151
TI - Pitfalls in frozen section interpretation in Mohs micrographic surgery.
PMID- 9551152
TI - Laser resurfacing.
PMID- 9551153
TI - Treatment of benign vascular lesions with the Photoderm VL high-intensity pulsed
light source.
PMID- 9551154
TI - [Anatomo-clinical prognostic factors of papillary carcinoma of the thyroid.
Multivariate analysis: report of a series of 52 cases].
AB - A retrospective study about 52 cases of papillary thyroid carcinomas was carried
out with emphasis on histopathological features. The mean follow up period was 10
years. The survival curves were estimated using the Kaplan-Meier method and
compared using the log rank test. The multivariate analysis was performed using
the Cox's regression model. In univariate analysis, age, Tp (histopathological
extension of the tumor), histological differentiation, VAN score (Vascular
invasion nuclear Atypia tumor Necrosis) of Akslen and the LeuM1 expression were
significant prognostic factors. In multivariate analysis, the Tp and histological
differentiation were associated with high risks of poor outcome.
PMID- 9551155
TI - [Epstein-Barr virus: pathologic implications].
PMID- 9551156
TI - [Classification of primary kidney tumors in adults].
PMID- 9551157
TI - [Primary angiosarcoma of the central nervous system: report of a case].
PMID- 9551158
TI - [Lipoma of the internal auditory canal. Report of two cases simulating acoustic
neuroma].
AB - We report two cases of intra-auditory canal lipoma, presenting as acoustic
neuroma, observed in respectively 45 and 53 year old patients. Cerebellopontine
angle lipomas are unusual lesions, more exceptional than their intracranial
counter-parts. The knowledge of these tumoral lesions and of their close
relationships with cranial nerves incite to perform a frozen section when imagery
is evocative, to limit functional postoperative sequelae.
PMID- 9551159
TI - [Stomatococcus mucilaginosus infection. A rare cause of cutaneous histiocytic
infiltrate].
AB - We report the case of a systemic infection due to Stomatococcus mucilaginosus
with cutaneous localisations occurring in a neutropenic child. The histological
features of this cutaneous involvement are very unusual and the diagnosis can be
suggested before bacteriological results.
PMID- 9551160
TI - [Polycystic disease of the salivary glands: report of an attack of the
submaxillary glands].
AB - Bilateral dysgenetic polycystic disease of parotid glands is an extremely rare
pathologic condition in which salivary parenchyma is partially replaced by
multiple epithelial-lined cysts arising from intercalated ducts. Review of the
fourteen cases published in literature shows that it affects nearly exclusively
women with an history of asymptomatic progressive enlargement of almost always
both parotid glands. We report here the first case, to our knowledge, of a
polycystic disease involving both submandibular salivary gland in a man.
PMID- 9551161
TI - [A pulmonary mass with a raging fever].
PMID- 9551162
TI - [Nodule of the back of the foot with localized hyperhidrosis].
PMID- 9551163
TI - [A granulomatous hepatitis].
PMID- 9551164
TI - [Testicular metastasis revealing a gastric adenocarcinoma].
PMID- 9551165
TI - [Practice of microscopic diagnosis of Helicobacter pylori infection on gastric
biopsy in the laboratories of French Pathology. Hepatic and Digestive
Histopathology Club].
AB - The histological study of gastric biopsies is very much used for the diagnosis of
Helicobacter pylori infection. A survey was performed among the members of the
"Club d'Histopathologie Digestive et Hepatique" on the conditions of this
diagnosis. The diagnosis is performed systematically by 91% of the pathologists.
A special stain is used in 72% of cases (most often Giemsa), and
immunohistochemistry is very rarely used. The classifications of gastritis that
are frequently used are the Sydney system and the Whitehead's classification. In
conclusion, it appears that the methods in use in France for the histological
diagnosis of Helicobacter pylori infection are relatively homogeneous.
PMID- 9551166
TI - [Serine/threonine type protein kinase activity in cell-free extracts of
Streptomyces lividans].
AB - Cell-free extracts of Streptomyces lividans prepared at the physiological ionic
strength from the early logarithmic phase culture showed an endogenous protein
kinase activity. Incubation of the salt soluble fraction of S.lividans with
[gamma-32P]ATP led to incorporation of the labelled phospate into 6 to 7
polypeptide chains of 12-100 kDa. Addition of heparine, polylysine, spermine,
phosphatidylserine, kanamycin, cAMP and cGMP did not change the spectrum or level
of the polypeptide phosphorylation in the extract while Ca2+ ions stimulated the
protein phosphorylation. It was shown that the protein kinase(s) catalyzed
binding of the phosphate groups to the serine and thereonine residues in the
polypeptides with M(r) 100 and 35 kDa.
PMID- 9551167
TI - [Development of a solid-phase immunoenzyme analysis of gentamicin in human blood
serum].
AB - An enzyme immune test system was designed and optimized for quantitative assay of
gentamicin in human sera. Immunospecific reagents i.e. gentamicin conjugates with
ovalbumin (for sorption on polysterol plates) and with bovine serum albumin
(immunogen) were prepared. Gentamicin specific antisera were isolated and tested.
Conditions for the antigen sorption on polysterol plates were determined and
optimized. Different regimes of the competition reaction were investigated and
conditions for the antibiotic assay in human sera were determined. The assay
specificity was studied and the stability of the test system was checked. An
experimental lot of the reagent set was manufactured at the ZAO NPP Immunotech
and the correlation tests with the use of the fluorescence polarization
immunoassay were performed. The set is destined for the assay of 40 samples (in
duplicate). The method sensitivity is 1 ng/ml of gentamicin. The range of the
detectable concentration is 1 to 32 ng/ml of gentamicin in 1000-fold diluted
sera. The assay time is not more than 3 hours. The variation coefficient of the
results does not exceed 12 per cent. The shelf-life of the set is 0.5 years when
stored at a temperature of 2 to 8 degrees C.
PMID- 9551168
TI - [A new mathematical approach for determining antibiotic concentrations using the
agar diffusion method].
AB - A mathematical approach using the one-point intercept form of the equation of a
straight line for the assay of antibiotic biological activity by the agar
diffusion method is described. Insignificant alteration in the experimental
conditions made it possible to markedly lower the volume of work and materials
for the statistic processing. As distinct from the routine methods, the assay
substance in three different concentrations is applied to three cavities on a
dish and the standard substance in one control concentration is applied to the
other three cavities on the same dish. The antibiotic biological activity is
estimated from the equation lg cn = lg cst + (dn - dst)/bi when the relationship
between the dose logarithm and the size of the diameters of the test microbe
inhibition growth zones is direct. When the relationship is inverse e.g. when the
dose is expressed as the dilution, the equation lg cn = lg cst + (dst - dn)/bi is
used. Factor bi is determined experimentally for every sample by the mean value
of the sizes of the inhibition growth zone diameter by the programs of the simple
linear-regression.
PMID- 9551169
TI - [Effect of probiotics from bacilli on macrophage functional activity].
AB - The influence of new probiotics from bacilli i.e. biosporin and subalin on the
functional activity of murine peritoneal macrophages was studied. After a single
oral administration of the probiotics the maximum activation of the macrophages
was observed in 4 hours. The activation level depended on both the dose and the
probiotic. The highest value of the stimulation index was recorded with subalin.
Analogous regularities were stated with parenteral administration of the
probiotics. Some mechanisms of activation of peritoneal macrophages after oral
administration of probiotics from live microbial cultures are discussed.
PMID- 9551170
TI - [Antimicrobial properties of nitrogen oxide and regulation of its biosynthesis in
macroorganism].
PMID- 9551172
TI - [Lomefloxacin hydrochloride (Maxaquin), a long-acting fluoroquinolone
(information for specialists)].
PMID- 9551171
TI - [The difluoroquinolone lomefloxacin--an broad spectrum antimicrobial drug].
PMID- 9551173
TI - The zebrafish's swim to fame as an experimental model in biology.
AB - The zebrafish has long been the favorite organism in many scientific disciplines.
Although its attributes as a model were expounded for many years and thus were no
secret, the zebrafish sat in the wings while other more popular vertebrates such
as chick, amphibians, and mouse were examined at length. We cannot say there was
a resurgence in popularity, but more an explosion of research utilizing the
zebrafish beginning in the late 1970s when investigators at the University of
Oregon began using it as their model in neuroscience. Prior to this reawakening,
the zebrafish was one of the significant organisms in the study of teratology and
toxicology, development, and, to some extent, behavior. Recently, however, the
field of zebrafish genetics has gained immense popularity and success, in part
owing to the fact that zebrafish are diploid and are amenable to genetic
manipulations. Here we present an overview of the multidisciplinary research that
has laid some of the foundation of our present understanding of the biochemical,
cell biological, and molecular genetic events accompanying zebrafish development.
PMID- 9551174
TI - Heat shock genes and the heat shock response in zebrafish embryos.
AB - Heat shock genes exhibit complex patterns of spatial and temporal regulation
during embryonic development in a wide range of organisms. Our laboratory has
initiated an analysis of heat shock protein gene expression in the zebrafish, a
model system that is now utilized extensively for the examination of early
embryonic development of vertebrates. We have cloned members of the zebrafish
hsp47, hsp70, and hsp90 gene families and shown them to be closely related to
their counterparts in higher vertebrates. Whole mount in situ hybridization and
Northern blot analyses have revealed that these genes are regulated in distinct
spatial, temporal, and stress-specific manners. Furthermore, the tissue-specific
expression patterns of the hsp47 and hsp90 alpha genes correlate closely with the
expression of genes encoding known chaperone targets of Hsp47 and Hsp90 in other
systems. The data raise a number of interesting questions regarding the function
and regulation of these heat shock genes in zebrafish embryos during normal
development and following exposure to environmental stress.
PMID- 9551175
TI - DNA methylation and genome imprinting in the zebrafish, Danio rerio: some
evolutionary ramifications.
AB - Although methylation has been recognized as an important component in a number of
developmental processes in mammals, in zebrafish almost nothing is known about
this epigenetic modification. This is despite the fact that the zebrafish is
becoming increasingly popular as a developmental model system. The little work
that has been done on methylation and development in fish concerns genomic
imprinting. In mammals, imprinting results in an inability to reproduce
parthenogenetically because a genetic contribution from both parents is necessary
to successfully complete development. However, this is not true of zebrafish, and
a number of the theories that have been presented to explain the evolution of
imprinting are not consistent with imprinting in these fish. A new model is
presented that discusses some of the potential evolutionary ramifications of
methylation and imprinting and that leads to the suggestion that imprinting may
actually be a simple genetic mechanism to enhance the efficient evolution of both
individual genetic loci and combinations of loci with related functions, without
risking the population as a whole. This model can accommodate all of the
information known about imprinting, including its broad phylogenetic range,
imprinting by both males and females, and the diverse nature of the genes that
are known to be imprinted.
PMID- 9551176
TI - Repetitive elements and their genetic applications in zebrafish.
AB - Repetitive elements provide important clues about chromosome dynamics,
evolutionary forces, and mechanisms for exchange of genetic information between
organisms. Repetitive sequences, especially the mobile elements, have many
potential applications in genetic research. DNA transposons and retroposons are
routinely used for insertional mutagenesis, gene mapping, gene tagging, and gene
transfer in several model systems. Once they are developed for the zebrafish,
they will greatly facilitate the identification, mapping, and isolation of genes
involved in development as well as the investigation of the evolutionary
processes that have been shaping eukaryotic genomes. In this review repetitive
elements are characterized in terms of their lengths and other physical
properties, copy numbers, modes of amplification, and mobilities within a single
genome and between genomes. Examples of how they can be used to screen genomes
for species and individual strain differences are presented. This review does not
cover repetitive gene families that encode well-studied products such as rRNAs,
tRNAs, and the like.
PMID- 9551177
TI - Genetic dissection of vertebrate processes in the zebrafish: a comparison of
uniparental and two-generation screens.
AB - Genetic dissection is used to identify important genes in biological processes
and is accomplished through the generation and study of mutations in model
organisms. In diploid organisms, recessive mutations must be rendered hemizygous
or homozygous for the mutant phenotype to be detected. In zebrafish (Danio
rerio), this can be accomplished in two ways: (i) crosses between siblings who
are potential carriers (in two-generation screens) and (ii) the generation of
uniparental progeny. Two-generation screens have been the most productive to date
but require substantial resources. However, uniparental screens involving
haploids and half-tetrads (products of meiosis I) have also been productive, and
require more modest resources. In genetic screens, the fraction of an average
genome that is heterozygous (heterozygosity index) is inversely proportional to
the likelihood that separate recessive mutations will be homozygous at the same
time. Heterozygosity indices for haploid, half-tetrad, and two-generation screens
are 0, 66, and 87.5%, respectively. Family sizes required to minimize bias in
half-tetrad screens are also calculated. We conclude that gynogenetic half-tetrad
screens are genetically robust and technically accessible to the independent
researcher. The increasingly powerful genetic and experimental tools available
for work with zebrafish can be used to address a broad range of questions in
vertebrate biology.
PMID- 9551178
TI - High-resolution imaging at the cellular and subcellular levels in flattened whole
mounts of early zebrafish embryos.
AB - We describe a rapid and sensitive method for high-resolution imaging at the
cellular and subcellular levels in the whole-mount zebrafish embryo. The
procedure involves fixing and staining the embryo, followed by deyolking and
flattening it under a cover slip, to produce a planar mount that is 20 to 100
microns thick. Such a flattened whole mount allows imaging with a spatial
resolution of approximately 500 nm in the x-y plane and does not require the use
of embedding, sectioning, confocal microscopy, or computational deblurring
procedures. We can resolve all individual nuclei and chromosome sets in the
embryo, up to the late gastrula stage (10,000 cell stage). In addition, older
embryos (through the segmentation stage) can also be examined, with the
preservation of significant morphological detail. Because of its ability to
resolve subcellular detail, the flattened whole-mount method can provide
significant biological information beyond what can be obtained from conventional
(three-dimensional) whole mounts. We have used the flattened whole-mount method
to study subcellular events related to progression through the cell cycle or to
apoptosis, in cells of the early zebrafish embryo. A specific DNA-binding dye
(Hoechst 33258) or an antibody against a chromosomal protein (histone H1) was
used to stain the nuclei of individual cells in the embryo. This allowed us to
determine the spatial positions of all the individual cells, and also their
stages in the cell cycle. A terminal transferase (TUNEL) assay was used to detect
apoptotic cells. This combination of specific stains allowed us to study the
behaviors of groups of cells in situ, within the developing zebrafish embryo.
PMID- 9551179
TI - Regional cell movement and tissue patterning in the zebrafish embryo revealed by
fate mapping with caged fluorescein.
AB - Determination of fate maps and cell lineage tracing have previously been carried
out in the zebrafish embryo by following the progeny of individual cells injected
with fluorescent dyes. We review the information obtained from these experiments
and then present an approach to fate mapping and cell movement tracing, utilizing
the activation of caged fluorescein-dextran. This method has several advantages
over single-cell injections in that it is rapid, allows cells at all depths in
the embryo to be marked, can be used to follow cells starting at any time during
development, and allows an appreciation of the movements of cells located in a
coherent group at the time of uncaging. We demonstrate that the approach is
effective in providing additional and complementary information on prospective
mesoderm and brain tissues studied previously. We also present, for the first
time, a fate map of placodal tissues including the otic vesicle, lateral line,
cranial ganglia, lens, and olfactory epithelium. The prospective placodal cells
are oriented at the 50% epiboly stage on the ventral side of the embryo with
anterior structures close to the animal pole, and posterior structures nearer to
the germ ring.
PMID- 9551180
TI - Spatially distinct domains of cell behavior in the zebrafish organizer region.
AB - To determine the sequence of cell behaviors that is involved in the morphogenesis
of the zebrafish organizer region, we have examined the dorsal marginal zone of
vitally stained zebrafish embryos using time-lapse confocal microscopy. During
the late-blastula stage, the zebrafish dorsal marginal zone segregates into
several cellular domains, including a group of noninvoluting, highly endocytic
marginal (NEM) cells. The NEM cell cluster, which lies in a superficial location
of the dorsal marginal zone, is composed of both enveloping layer cells and one
or two layers of underlying deep cells. The longitudinal position of this
cellular domain accurately predicts the site of embryonic shield formation and
occupies a homologous location to the organizer epithelium in Xenopus laevis. At
the onset of gastrulation, deep cells underneath the superficial NEM cell domain
undergo involution to form the nascent hypoblast of the embryonic shield. Deep
cells within the NEM cell cluster, however, do not involute during early shield
formation, but instead move in front of the blastoderm margin to form a loose
mass of cells called forerunner cells. Forerunner cells coalesce into a wedge
shaped mass during late gastrulation and eventually become overlapped by the
converging lateral lips of the germ ring. During early zebrafish tail elongation,
most forerunner cells are incorporated into the epithelial lining of Kupffer's
vesicle, a transient teleostean organ rudiment long thought to be an evolutionary
vestige of the neurenteric canal. Owing to the location of NEM cells at the
dorsal margin of blastula-stage embryos, as well as their early segregation from
other deep cells, we hypothesized that NEM cells are specified by an early-acting
dorsalizing signal. To test this possibility, we briefly treated early-blastula
stage embryos with LiCl, an agent known to produce hyperdorsalized zebrafish
embryos with varying degrees of expanded organizer tissue. In Li(+)-treated
embryos, NEM cells appear either within expanded spatial domains or in ectopic
locations, primarily within the marginal zone of the blastoderm. These results
suggest that NEM cells represent a specific cell type that is specified by an
early dorsal patterning pathway.
PMID- 9551181
TI - Mutations resulting in transient and localized degeneration in the developing
zebrafish brain.
AB - In a large-scale mutagenesis screen in the zebrafish, Danio rerio, we have
identified a heterogeneous group of 30 recessive, embryonic lethal mutations
characterized by degeneration in the developing central nervous system that is
either transient or initially localized to one area of the brain. Transient
degeneration is defined as abnormal cell death occurring during a restricted
period of development. Following degeneration, the affected structures do not
appear to regenerate. In each case degeneration is identified after somitogenesis
is complete and is not associated with visually identified patterning defects.
These 30 mutations, forming 21 complementation groups, have been classified into
four phenotypic groups: group 1, transient degeneration (13 mutations); group 2,
spreading degeneration, early onset, in which degeneration is initially confined
to the optic tectum but subsequently spreads to other areas of the central
nervous system (7 mutations); group 3, late-onset degeneration, initially
identified after 4 days (6 mutations); and group 4, degeneration with abnormal
pigmentation (4 mutations). Although apoptotic cells are seen in the retina and
tectum of all mutants, the distribution, temporal progression, and severity of
degeneration vary between mutations. Several mutations also show pleiotropic
effects, with degeneration involving extraneural structures including the
pharyngeal arches and pectoral fins. We discuss some of the pathways important
for cell survival in the nervous system and suggest that these mutations will
provide entry points for identifying genes that affect the survival of restricted
neural populations.
PMID- 9551182
TI - Domains of retinoid signalling and neurectodermal expression of zebrafish otx1
and goosecoid are mutually exclusive.
AB - Retinoid signalling plays an important role in embryonic pattern formation.
Excess of retinoic acid during gastrulation results in axial defects in
vertebrate embryos, suggesting that retinoids are involved in early
anteroposterior patterning. To study retinoid signalling in zebrafish embryos, we
developed a novel method to detect endogenous retinoids in situ in embryos, using
a fusion protein of the ligand inducible transactivation domain of a retinoic
acid receptor and a heterologous DNA binding domain. Using this method, we show
that retinoid signalling is localized in zebrafish embryos in the region of the
embryonic shield, and towards the end of gastrulation in a posterior dorsal
domain. To investigate the relationships between the spatial distribution of
retinoid signalling and the regulation of retinoid target genes, we studied the
downregulation by retinoic acid of two genes expressed in anterior regions of the
embryo, goosecoid and otx1. These experiments show that expression of both genes
is strongly downregulated in the anterior neurectoderm of zebrafish embryos
treated with retinoic acid, whereas mesendodermal expression is only mildly
affected. Interestingly, a significant downregulation of goosecoid expression by
retinoic acid was observed only during midgastrulation but not in earlier stages.
In agreement with these results, spatial expression of goosecoid and otx1 does
not overlap with the region of retinoid signalling in the late gastrula. Our data
support the hypothesis that a localized retinoid signal is involved in axial
patterning during early development, at least in part through the repression of
anterior genes in posterior regions of the embryo. Furthermore, our data suggest
that the action of retinoids is spatially as well as temporally regulated in the
developing embryo.
PMID- 9551183
TI - Cross-interactions between two members of the Dlx family of homeobox-containing
genes during zebrafish development.
AB - The Dlx homeobox genes of vertebrates are transcribed in multiple cells of the
embryo with overlapping patterns but often with different onsets of expression.
Here we describe the interaction between two dlx genes, dlx3 and dlx4, during
zebrafish development. The observation that dlx3 expression precedes that of dlx4
in the otic vesicle led us to investigate whether dlx3 had the ability to control
expression of dlx4. Truncated versions of dlx3 were overexpressed in zebrafish
embryos and the expression patterns of dlx4 were examined later in development.
Overexpression of truncated forms of Dlx3 or of a Dlx3-Dlx2 chimera was found to
result in perturbations in dlx4 expression. In addition, cotransfection
experiments indicated the ability of Dlx3 to activate transcription through a 1.7
kb fragment of the 5' flanking region of dlx4. These results suggest that dlx4 is
one of the target genes of dlx3 in embryos and that cross-regulatory interactions
between Dlx genes may be one of the mechanisms responsible for their overlapping
expression.
PMID- 9551184
TI - Characterization of a cDNA encoding a novel band 4.1-like protein in zebrafish.
AB - Membrane skeleton protein 4.1 and other members of a family of proteins that link
the cytoskeleton to the plasma membrane may play an integral role in cell
communication during development. The polymerase chain reaction and degenerate
oligodeoxynucleotide primers to consensus sequences in the putative membrane
binding domain of the protein 4.1 superfamily were used to isolate cDNAs encoding
members of the zebrafish protein 4.1 family. Zebrafish stage- and tissue-specific
first strand cDNA was used in the PCR. After the reaction, amplicons of the
predicted size were sequenced to confirm their relationship to the protein 4.1
superfamily. One cDNA, with a high degree of similarity to a mouse novel band 4.1
like cDNA, was used to probe a zebrafish adult brain library. A 2.4-kb cDNA was
isolated and found to encode a 619 amino acid polypeptide homologous to mouse
novel band 4.1-like protein 4. Zebrafish nbl4 mRNA is maternally supplied and is
expressed throughout embryogenesis. In adults, nbl4 is found in the ovary, eye,
heart, and brain, but not in gut or skeletal muscle. When synthetic nbl4 mRNA is
translated in vitro it binds calmodulin in a calcium-dependent manner. These data
indicate that zebrafish nbl4 is a maternal transcript owing to its presence
before the midblastula transition, and it is present later on in specific adult
structures. The ability to bind calmodulin would suggest that the function of
nbl4 protein may be potentially regulated via a calcium-calmodulin dependent
mechanism.
PMID- 9551185
TI - Nuclear localization signals: a driving force for nuclear transport of plasmid
DNA in zebrafish.
AB - Nuclear localization signals (NLSs) are short peptides required for nuclear
transport of karyophilic proteins. We review in this paper how the nuclear
targeting property of NLS peptides has been taken advantage of to enhance the
efficiency of nuclear uptake of transgene DNA in zebrafish and how it may improve
the efficiency of transgenesis in this species. Synthetic NLS peptides can bind
to plasmid DNA by ionic interactions. Cytoplasmic injection of DNA-NLS complexes
in zebrafish eggs enhances the rate and the amount of plasmid DNA taken up by
embryonic nuclei. Nuclear import of DNA-NLS complexes has been duplicated in
vitro and exhibits energetic and cytosolic requirements similar to those for
nuclear protein import. Furthermore, binding NLSs to DNA increases expression
frequency of the transgene. We suggest that NLS peptides may constitute a
valuable tool to improve the efficiency of transgenesis in zebrafish and other
species.
PMID- 9551186
TI - Contribution of zebrafish-mouse cell hybrids to the mapping of the zebrafish
genome.
AB - The zebrafish, Danio rerio, is becoming an increasingly popular model for the
study of vertebrate development. Indeed, the biology of the fish offers great
advantages for such studies. The life cycle of the zebrafish is relatively short
(2-3 months) and the embryos develop outside the mother, facilitating the
visualization of any mutated phenotype. At present, more than 1000 embryonic
mutations have been reported. However, until recently, there was no physical or
genetic map for this organism. In an effort to generate such a map, we have
produced and characterized a panel of zebrafish-mouse cell hybrids. We have used
whole-cell fusion to transfer zebrafish chromosomes from two different zebrafish
cell lines into mouse recipient cells, thus generating more than 100 hybrids.
Using fluorescence in situ hybridization and polymerase chain reaction analysis,
we have determined the zebrafish chromosome composition of these hybrids. Here we
report that elements from the 25 linkage groups of the zebrafish genome are
present in our hybrids. These hybrids could identify the chromosomal location of
genes affected in zebrafish mutants.
PMID- 9551187
TI - Predictive significance of magnetic resonance imaging at 4 months of adjusted age
in infants after a perinatal neurologic insult.
AB - The aim of this prospective study was to evaluate the predictive significance of
magnetic resonance imaging (MRI) performed at 4 months of corrected age in 60
neonates after a perinatal neurologic insult. Follow-up ranged from 2 to 5 years
of chronological age. MRI examination was normal in 10; isolated external
hydrocephalus was found in 15 infants. Twenty-three of these infants developed
normally. Focal or multifocal lesions were shown in 6 infants, of whom 2
developed normally. Diffuse brain involvement was present in 29 cases as atrophy
(n = 18), leukomalacia (n = 5), basal ganglia lesions (n = 3), and delayed
myelination (n = 3). All but 4 infants showed neurologic impairment. MRI
performed at 4 months of adjusted age is of prognostic significance in neonates
who suffer a moderate or mild neurologic insult.
PMID- 9551188
TI - The production of pro- and anti-inflammatory cytokines in neonates assessed by
stimulated whole cord blood culture and by plasma levels at birth.
AB - The capability of neonates to achieve cytokine balance was evaluated. Production
of the pro-inflammatory cytokines TNF alpha and IL-8, of the natural anti
inflammatory cytokine IL10 and of the regulator of the acute phase response IL6
was assessed after whole blood stimulation by lipopolysaccharide in cord blood (n
= 10), adult volunteers serving as control (n = 17). Additionally, circulating
cytokines were determined in cord and in maternal blood immediately after
delivery (n = 27, respectively). Significant production of TNF alpha, IL8, IL10
and IL6 was observed in cord blood after lipopolysaccharide stimulation and was
similar to cytokine production in adult blood. The plasma concentrations of TNF
alpha were significantly higher in cord than in maternal blood, while plasma
concentrations of IL10 and IL6 were significantly lower. Our results demonstrate
fully developed capability of whole cord blood to synthesize pro- and anti
inflammatory cytokines in response to a pro-inflammatory stimulation in vitro. In
vivo, however, higher circulating TNF alpha and lower IL10 and IL6 levels in cord
blood suggest that the inflammatory stress associated with normal delivery does
not induce detectable anti-inflammatory response in neonates at birth.
PMID- 9551189
TI - The effect of phototherapy on renal blood flow velocity in preterm infants.
AB - Mean renal blood flow velocity (RBFV) was studied with two-dimensional/ pulsed
Doppler ultrasound and relative renal vascular resistance (RVR) was calculated
before, during, and after phototherapy treatment in 30 preterm infants
(gestational age < or = 32 weeks) who were treated for a minimum of 12 h with
phototherapy for nonhemolytic hyperbilirubinemia. RBFV decreased, whereas RVR
increased significantly after the initiation of phototherapy. In 'healthy'
(nonventilated) infants RBFV and RVR returned to baseline values after
discontinuation of phototherapy. Whereas in 'unhealthy' (ventilated) infants,
RBFV and RVR did not return to baseline values after discontinuation of
phototherapy. In 16 infants (> 50% of the cases) the ductus arteriosus reopened
during phototherapy.
PMID- 9551190
TI - Differential developmental effects of acute hypoxia on the rabbit
atrioventricular conduction axis.
AB - The differential developmental effects of hypoxia on antegrade fast and slow and
retrograde conduction through the atrioventricular junction are unknown. This
study describes the effects of hypoxia on fast and slow antegrade
atrioventricular node, infra-Hisian and retrograde conduction in immature and
mature hearts during premature pacing protocols in excise, perfused adult and
neonatal rabbits. The results are: (1) antegrade conduction delay through the
atrioventricular node is the same developmentally, but delay through the His
Purkinje system is greater in adults; (2) hypoxia reduces the extra delay in the
His-Purkinje system in adults; (3) fast atrioventricular node conduction is more
sensitive to hypoxia in neonates than in adults, and slow atrioventricular node
conduction is more sensitive to hypoxia in adults than in neonates, and (4)
retrograde atrioventricular node conduction is more resistant to hypoxia in
neonates than in adults.
PMID- 9551191
TI - Effect of inhaled nitric oxide in endothelin-1-induced pulmonary hypertension.
AB - The interaction of two vasoactive substances, the vasoidilator nitric oxide (NO)
and the complex-acting peptide endothelin-1 (ET-1), may help explain the
pathophysiology of pulmonary hypertension, an important part of many pulmonary
disorders in neonates. To understand better the interactions of inhaled NO and ET
1, we investigated the effects of ET-1 infusions with and without inhaled NO in
two groups of piglets, one group pretreated with L-nitro-arginine methylester (L
NAME) and the other not pretreated. Inhaled NO (60 ppm) was administered during
infusion of 1.0 microgram/kg or 2.5 micrograms/kg of ET-1. In animals not
pretreated with L-NAME, the increase in PVR and in SVR induced by either dose of
ET-1 was not reduced with administration of NO. The increase in systemic vascular
resistance with ET-1 was greater (mean increase of 50% above baseline with 1.0
microgram/kg ET-1 and 100% with 2.5 micrograms/kg ET-1 by 5 min) than the
increase in PVR, but the PVR/SVR ratio did not change during ET-1 administration.
In contrast, animals pretreated with L-NAME did demonstrate inhibition of ET-1
induced increase in PVR with NO. No differences in effects on SVR were noted. We
conclude that ET-1-induced increases in PVR are not diminished by 60 ppm of
inhaled NO unless there has been inhibition of endogenous NO production.
PMID- 9551192
TI - Effects of intravenous infusions of noradrenaline on renal function in
chronically catheterised fetal sheep.
AB - To determine the effects of circulating noradrenaline on fetal renal function
noradrenaline was infused intravenously into 7 chronically catheterised fetal
sheep (127-138 days) at a dose (1 microgram/kg/min) which resulted in plasma
levels similar to those which occur during hypoxia. Fetal mean arterial pressure
increased by approximately 14 mmHg (p < 0.001) and haematocrit rose (p < 0.005).
Glomerular filtration rate rose from 3.85 +/- 0.47 (SEM) to 4.70 +/- 0.50 ml/min
(p < 0.05) during the first hour and fractional reabsorption of sodium by the
proximal tubule fell (p < 0.05) during the second hour. Urine flow rate increased
from 0.61 +/- 0.13 to 1.18 +/- 0.24 ml/min (p < 0.001) and osmolar excretion
increased from 78 +/- 15 to 153 +/- 36 mu osm/min (p < 0.005). By contrast lung
liquid flow fell (p < 0.05), but the increase in urine flow was much greater than
the decline in lung liquid. These findings suggest that during hypoxia,
noradrenaline may play an important role in the maintenance of urine flow and
consequently amniotic fluid volume and, as suggested by others, in the
distribution of fluid between the vascular and interstitial compartments.
PMID- 9551194
TI - [Effect of L-glutamic acid on the reception of cytokines by HL-60 cells].
AB - L-Glutamic acid at a concentration of 0.1 microM was found to induce
differentiation of the cell line of HL-60 promyelocytic leukemia into
granulocytes or neutrophils. The HL-60 cells have no specific glutamate-binding
sites, but L-glutamic acid influences the reception of several cytokines by these
cells. At a concentration of 0.1 microM, L-glutamic acid completely inhibits the
high-affinity binding of 125I-labeled human recombinant interleukin-1 beta (Kd =
0.32 nM) to the HL-60 cells, but does not affect their low-affinity binding (Kd =
13.3 nM) and does not change the total number of the IL-1 beta-binding sites.
Preincubation of the HL-60 cells with 0.1 microM of L-glutamic acid increases 2.5
times the number of receptors for 125I-labeled human recombinant tumor necrosis
factor beta. These results suggest that L-glutamic acid plays an important role
in the differentiation of the blood myeloid cells.
PMID- 9551193
TI - Nitric oxide modulates anoxia-induced gasping in the developing rat.
AB - Gasping is an important mechanism for survival. Nitric oxide (NO) plays an
excitatory role in brainstem regions mediating respiratory responses to hypoxia.
We hypothesized that neural structures mediating anoxia-induced gasping would
display NO dependency. Two- to 15-day-old rat pups underwent anoxic exposures
with 100% N2 in a plethysmograph following administration of N-nitro-L-arginine
methyl ester (L-NAME), a nitric oxide synthase (NOS) blocker, L-arginine (L-Arg),
a NO precursor, or normal saline. In general, gasp latencies were significantly
shorter after L-Arg, and were prolonged with L-NAME. Furthermore, NOS inhibition
prolonged gasping duration and reduced gasping frequency at all postnatal ages,
although this effect was particularly increased with advancing postnatal age.
NADPH-diaphorase staining and Western blots of protein lysates from the lateral
tegmental field, the putative neural center underlying gasp generation, revealed
progressively increased neuronal NOS abundance with animal maturation. We
conclude that anoxia-induced gasping neurogenesis is modulated by NO mechanisms
in neonatal pups. We postulate that higher NO brainstem concentrations may favor
early autoresuscitation but be detrimental to overall survival during prolonged
asphyxia.
PMID- 9551195
TI - [Synthesis of new chromogenic substrates for aspartyl proteases].
AB - A general method was developed for the synthesis of new chromogenic substrates of
aspartyl proteases: Dnp-Ala-Xaa-Phe-Phe-Ala-Arg-NH2, where Xaa was Ala or Ser.
The synthetic scheme involved both chemical and enzymic stages, the condensation
of tripeptides in an organic medium by means of pepsin immobilized on Celite
being among the latters. The influence of organic solvents, reaction time, and
the composition and ionic strength of the buffers used in the reaction mixture
and at the pepsin immobilization step on the efficacy of the pepsin-catalyzed
synthesis was studied.
PMID- 9551196
TI - [Acyclic nucleotide analogues based on phosphonic acids].
AB - The synthesis of novel nucleotide analogues on the basis of ethylphosphonic acid
was described. A rigid structural element, an amide or a double bond, was
characteristics of the compounds synthesized. The antiviral and cytotoxic
activities of these compounds were studied in cell cultures.
PMID- 9551198
TI - [Interaction of short oligonucleotide derivatives with nucleic acids. V. Ligation
of short oligonucleotides in tandem on a complimentary DNA template].
AB - A tetranucleotide was highly specifically and quantitatively ligated with a pair
of flanking octanucleotides carrying both radioactive and nonradioactive reporter
groups. The sequence of the ligation of oligonucleotide components in a tandem on
a complementary template was studied. The first stage was found to be the enzyme
catalyzed activation of the phosphate group of octanucleotide, a tandem component
that possesses a higher hybridization capacity than the tetramer. It is shown
that the introduction of terminal reporter groups into octanucleotides does not
decrease the efficiency of their tandem ligation.
PMID- 9551197
TI - [Phosphorylation of 5'-O-phosphonylmethylthymidine and its incorporation into
HeLa cells DNA].
AB - [3H]5'-O-Phosphonylmethylthymidine with a specific activity of 71 Ci/mmol was
obtained by isotope exchange. Its incubation with a HeLa cell culture resulted in
the formation of [3H]-labeled 5'-O-(beta-phosphoryl-alpha
phosphonylmethyl)thymidine, 5'-O-(beta,gamma-diphosphoryl-alpha
phosphonylmethyl)thymidine, and [3H]DNA. This proved the ability of 5'-O
phosphonylmethylthymidine to undergo phosphorylation and incorporation into the
DNA of human cells.
PMID- 9551199
TI - [Interaction of short oligonucleotides derivatives with nucleic acids. VI.
Discrimination of mismatch-containing complexes upon ligation of a short
oligonucleotide tandem on DNA template].
AB - The high ligation specificity of a tetranucleotide with a pair of flanking
octanucleotides on DNA template by the action of T4 phage DNA ligase is shown. In
a tetranucleotide-DNA template complex containing a mismatch, almost no ligation
products are formed. The ligation of a tandem octanucleotide-tetranucleotide
octanucleotide makes it possible to identify accurately any single nucleotide
substitution in a tetranucleotide binding site.
PMID- 9551200
TI - [Irregular temperature dependence of the efficiency of nucleic acids site
directed modification by oligonucleotide reagents producing reactive
intermediates].
AB - A 22-mer target DNA pTGCCTGGAGCTGCTTGATGCCC (I) was modified by a
dodecadeoxyribonucleotide reagent GCATCAAGCAGCp[N(CH3)CH2RCl] (II) containing a
3'-terminal alkylating group (RCl = -C6H4N(CH3)(CH2CH2Cl). An anomalous, bell
shaped temperature dependence of the maximum extent of the modification was
found. Based on the analysis of the kinetic scheme of the modification, a
possible explanation for this experimental fact is given.
PMID- 9551201
TI - [Exon-intron structure of the fet5+ gene of Schizosaccharomyces pombe and
physical mapping of genome encompassing regions].
AB - Plasmid pYUK3 bearing the fet5+ gene of Schizosaccharomyces pombe was isolated
from a genomic library of the fission yeast, and a detailed physical map of the
whole genomic insert (ca. 9.6 Kbp) was constructed. The primary structure of the
fet5+ gene and its flanking regions is established. The gene contains a single 45
bp intron in its distal part. A typical TATA-box (TATAAG) was found in the 5'
noncoding region ca. 50 bp upstream of the putative start of transcription, and
the 3'-noncoding region contains AT-rich palindromes, which are probably involved
in termination of the fet5+ transcription. A previously unidentified gene of Sz.
pombe encoding a protein with some similarity to one of the transcriptional
activators from the TBP (TATA-binding protein) group of SPT factors of
transcription was found in the vicinity of the fet5+ gene. Taking into account
that cDNA of the fet5(+)-gene was isolated as a suppressor of the genetic-defect
of nuclear RNA polymerases I-III (Bioorg. Khim., 1997, vol. 23, No 3, pp. 234
237), this vicinity may be the first evidence of possible clustering, in the
genome of the fission yeast, of genes participating in transcription regulation.
PMID- 9551202
TI - [Expression of synthetic human interleukin-10 gene and its mutant variants in
Escherichia coli cells].
AB - The human interleukin-10 gene was obtained by chemico-enzymatic synthesis, and
vectors for cytoplasmic and periplasmic expression of the recombinant IL-10 gene
in Escherichia coli cells were constructed. Mutant IL-10 genes bearing
substitutions in a region upstream of the ATG codon and in the triplet coding for
the second amino acid residue in the protein were obtained by in vitro
mutagenesis. High levels of expression were observed for the fusion protein
composed of IL-10 and an N-terminal fragment of IL-3 and for the mutant IL-10
containing cysteine as the second amino acid residue.
PMID- 9551203
TI - [Synthesis and biological properties of 3,5-cyclophosphates- and -amidophosphates
of 1,2-O-alkylydene-6-deoxy-6-halogeno-alpha -D-glucofuranoses].
AB - 3,5-Cyclic phosphates and phosphoramides of 6-halogenated glucofuranoses were
synthesized via interaction of 3,5,6-bicyclophosphites of 1,2-O-alkylidene-alpha
D-glucofuranoses with halogens (followed by treatment with nucleophilic reagents)
and N-chloroamines. 3,5-Cyclic trans-dibutylphosphoramides of 6-chloro-6-deoxy
1,2-O-isopropylidene- and 6-chloro-6-deoxy-(R)-(2,2,2)-trichloroethylidene)-alpha
D-glucofuranoses were shown to possess antiproliferative activity against CaOv
human ovarian carcinoma cells in vitro (CE50 of approximately 10(-5) M). Cyclic
trans-dibutylphosphoramide of 6-chloro-6-deoxy-1,2,-O-isopropylidene-alpha-D
glucofuranose also displayed marked antitumor effect on P-388 transplantable
murine leukemia in vivo (the maximum increase in life span of 100% was reached at
the quintuple injection of 100 mg/kg daily).
PMID- 9551204
TI - [Synthesis of phthalocyanine conjugates with monoclonal antibodies in AOT/n
octane reversed micelles and in water-organic solvent mixtures].
AB - Conjugates of cobalt and aluminum phthalocyanines with monoclonal antibodies were
synthesized using an AOT/n-octane reversed micellar system or water-organic
mixtures with a low content of organic solvent as media. The effect of the degree
of hydration of the micelles and the concentration of phthalocyanines on the
composition of conjugates was studied. The immune activity of the resulting
conjugates in comparison to that of native antibodies was evaluated. The
catalytic activity of free cobalt phthalocyanines and their antibody conjugates
was studied in the reaction of ascorbic acid oxidation.
PMID- 9551205
TI - [New putative gene from human retrovirus-containing locus on chromosome 19].
AB - By means of cDNA selection, a cDNA clone corresponding to a putative gene was
isolated. The identified gene was mapped to human chromosome 19 (region 19q12) to
the locus containing the human endogenous retrovirus HERV-K LTR. The distance
between the LTR and the cDNA fragment is about 20 kb. RT-PCR analysis of the
total RNA revealed that the corresponding gene is preferentially expressed in the
brain.
PMID- 9551206
TI - Antimetabolites.
PMID- 9551207
TI - Bleomycin.
PMID- 9551208
TI - Mitomycins.
PMID- 9551209
TI - Taxanes.
PMID- 9551210
TI - DNA topoisomerase I inhibitors.
PMID- 9551211
TI - DNA topoisomerase II poisons and inhibitors.
PMID- 9551212
TI - Cisplatin.
PMID- 9551213
TI - Multidrug resistance.
PMID- 9551215
TI - Monoclonal antibody therapy of cancer.
PMID- 9551214
TI - New anticancer agents.
PMID- 9551216
TI - Cytokines and immunological monitoring.
PMID- 9551217
TI - Biological response modifiers.
PMID- 9551218
TI - Adoptive immunotherapy.
PMID- 9551219
TI - Strategies for cancer gene therapy.
PMID- 9551220
TI - Retinoids, neoplasia and differentiation therapy.
PMID- 9551221
TI - Hematopoietic growth factors in cancer chemotherapy.
PMID- 9551222
TI - Leukemias and plasma cell myeloma.
PMID- 9551223
TI - AIDS-related malignancies.
PMID- 9551224
TI - Head and neck cancer.
PMID- 9551225
TI - Lung cancer.
AB - In small cell lung cancer (SCLC) combination chemotherapy including agents such
as etoposide, teniposide, cisplatinum, carboplatin, and vincristine, doxorubicin,
and cyclophosphamide, or ifosfamide continues to be the back-bone of therapy. The
epipodophyllotoxin derivatives together with cisplatin or carboplatin are being
used increasingly as part of the initial therapy, and these combinations are by
most investigators considered standard therapy. Complete plus partial responses
to combination therapy occur in 80-90% of all patients with a median duration of
9-12 months. The median survival in these studies is at present 11-18 months
depending on the initial tumour stage. The 5-year survival data remain still
around 5% including a small fraction of patients (2%) initially presenting with
extensive disease. The tendency is to shorten the duration of treatment to 5-8
months. The results of intensifying the treatment with the use of haematopoietic
growth factors continue to be disappointing, although these are not conclusive.
With respect to squamous cell carcinoma, adenocarcinoma, and large cell carcinoma
several meta-analyses indicate that there is a statistically significant, albeit
small advantage favouring cisplatinum containing chemotherapy when added to
surgery in stage I and II disease and to radiotherapy in stage III NSCLC.
Similarly, cisplatin containing chemotherapy is statistically superior to best
supportive care in stage IV disease. The results from the latter analyses are
significant at 1 and 2 years, respectively, but not at 3 and 5 years of survival.
These data must, however, be considered in the light of their clinical relevance
and of the balance between quality of life, toxicity, and cost of chemotherapy.
The results of recently published phase III trials in stage III disease support
the use of combined modalities of chemotherapy and radiotherapy versus
radiotherapy alone. For both small cell and non-small cell lung cancer a number
of new agents have been evaluated over the last 2 to 3 years and among those
navelbine, topotecan, gemcitabine, and taxanes (taxol and taxotere) have yielded
the most encouraging results. For mesothelioma the therapeutic results are
unchanged, and no standard chemotherapy has yet been developed.
PMID- 9551226
TI - Upper gastrointestinal tumors.
PMID- 9551227
TI - Cancers of the large bowel and hepatobiliary tract.
PMID- 9551228
TI - Endocrine tumours.
PMID- 9551229
TI - Genitourinary malignancy.
PMID- 9551230
TI - Gynecologic cancers.
AB - In conclusion, significant advances have been made in ovarian cancer.
Specifically, these relate to the success of paclitaxel and platinum-based
regimens. The appropriate scheduling, dosing, and the selection of carboplatin vs
cisplatin remains controversial. The role of interval debulking surgery is still
investigational and we remain cautiously optimistic as to its long-term benefit.
The progress in the delivery of chemotherapy to patients with cervical carcinoma,
endometrial carcinoma, vaginal carcinoma, and vulvar carcinoma has been slowed by
the paucity of prospective-randomized trials. Although numerous single
institution non-randomized trials show promising regimens, they lack significant
power and appropriate study design to prove meaningful. Our goals in the future
should be to try to enter most of these patients into national collaborative
studies where significant conclusions can be made because of appropriate study
design and adequate patient numbers.
PMID- 9551231
TI - Breast cancer.
PMID- 9551232
TI - Soft tissue and bone sarcomas.
PMID- 9551233
TI - Brain tumors.
PMID- 9551234
TI - Biology and treatment of pediatric malignant solid tumors.
PMID- 9551235
TI - Supportive care.
PMID- 9551236
TI - In vitro activity of enoxacin versus ciprofloxacin, fleroxacin, lomefloxacin,
ofloxacin, pefloxacin, and rufloxacin against uropathogens.
AB - Minimum inhibitory concentrations (MIC) of enoxacin, ciprofloxacin, fleroxacin,
lomefloxacin, ofloxacin, pefloxacin and rufloxacin were determined against 400
uropathogens cultured from the urine of patients with complicated and/or hospital
acquired urinary tract infections (UTI) using an agar dilution method. The
bacterial spectrum consisted of Entero-bacteriaceae (34.5%), enterococci (31.5%),
staphylococci (21.2%) and non-fermenting bacteria (12.8%). Enoxacin inhibited all
but one strain (Enterobacter cloacae) of Enterobacteriaceae up to an MIC of 1
mg/l (MIC90 0.25 mg/l). Regarding the total bacterial spectrum, enoxacin
inhibited 54.5, 59.5, 76.0 and 83.8% up to an MIC of 1, 2, 4 and 8 mg/l,
respectively. If the same breakpoint of resistance for ofloxacin according to DIN
58,940 (NCCLS), i.e. MIC > or = 4 mg/l (> or = 8 mg/l), is also taken for the
other fluoroquinolones, and the 126 strains of enterococci are excluded, for
which alternative agents, e.g. aminopenicillins, should be considered instead,
the following resistance rates were found: ciprofloxacin and enoxacin 15.3%
(15.0%), ofloxacin 17.2% (15.3%), pefloxacin 18.2% (15.3%), fleroxacin 19.3%
(15.3%), lomefloxacin 19.7% (17.9%) and rufloxacin 31.8% (27.4%). According to
their in vitro activity, all fluoroquinolones tested besides rufloxacin show
similar rates of resistance against uropathogens and can therefore be considered
good alternative agents for the treatment of complicated UTI.
PMID- 9551238
TI - In vitro interaction between ofloxacin and cefotaxime against gram-positive and
gram-negative bacteria involved in serious infections.
AB - The checkerboard method was used to determine the antimicrobial activity of the
combination cefotaxime/ofloxacin against 217 bacterial isolates involved in
serious infections. Synergy or partial synergy was observed against 19 of 34
(55.8%) Staphylococcus aureus methicillin-susceptible isolates, 4 of 47 (8.4%)
Streptococcus pneumoniae isolates, 28 of 34 (82.2%) Escherichia coli isolates and
70 of 102 (68.5%) Pseudomonas aeruginosa isolates. Antagonism was not observed
with any of the isolates examined.
PMID- 9551237
TI - In vitro antibacterial activity of trovafloxacin and five other fluoroquinolones.
AB - The in vitro inhibitory and bactericidal activities of the investigational
fluoroquinolone trovafloxacin were studied and compared with those of five other
fluoroquinolones (ciprofloxacin, ofloxacin, pefloxacin, rufloxacin and
sparfloxacin) against a wide range of clinical isolates from Italian hospitals.
Against gram-positive bacteria, trovafloxacin was overall more active than the
other antibiotics tested, including sparfloxacin, another gram-positive-oriented
fluoroquinolone, and was active against all ciprofloxacin-resistant streptococci,
enterococci, and listeriae, all ciprofloxacin-resistant Staphylococcus aureus
isolates and most ciprofloxacin-resistant coagulase-negative staphylococci. Its
antistaphylococcal activity was not affected by oxacillin resistance or
susceptibility of the isolates, nor was its antipneumococcal activity affected by
whether isolates were susceptible or resistant to penicillin. Against gram
negative bacteria, trovafloxacin retained a high potency mostly comparable with
that of ciprofloxacin. Rufloxacin and pefloxacin were less active than the other
fluoroquinolones against most test strains of both gram-positive and gram
negative organisms. Trovafloxacin minimal bactericidal concentrations usually
equalled or exceeded by 2-4 times the minimal inhibitory concentration values,
indicating that the compound is overall highly bactericidal.
PMID- 9551239
TI - Therapeutic effects of an injectable new quinolone, pazufloxacin, against
polymicrobial infections in the uterine endometritis model.
AB - Polymicrobial infections with aerobes and anaerobes are common in female genital
tract infections. We evaluated the efficacy of an injectable new quinolon,
pazufloxacin, using a uterine endometritis model. Rats were infected with a mixed
inoculation of Escherichia coli plus Bacteriodes fragilis (MIC of pazufloxacin
and ceftazidime: E. coli: 0.05 and 1.56 micrograms/ml, respectively, B. fragilis:
3.13 and 3.13 micrograms/ml, respectively). After inoculating 10(7) cfu/rat of
each organism, pazufloxacin or ceftazidime (10 or 20 mg/kg, respectively, i.v.,
b.i.d., 3 days) was administered and compared with the nontreated group. The
viable cell counts of the uterine corpus and uterine cervix in pazufloxacin
treated and ceftazidime-treated groups were decreased, compared with the
nontreated group. The viable cell counts of the adnexa in the pazufloxacin
treated group were significantly decreased, compared with the ceftazidimetreated
group. These results suggest that pazufloxacin would be useful for the treatment
of polymicrobial infections, especially adnexitis.
PMID- 9551240
TI - Therapeutic effects of cefozopran on polymicrobial infections associated with
Enterococcus faecalis in a Rat pyometra model.
AB - Enterococcus faecalis plays an important role as a pathogen in polymicrobial
infections. We evaluated the efficacy of cefozopran (CZOP) using polymicrobial
pyometra rats. Rats were infected with a mixed intrauterine inoculation of E.
faecalis plus either Bacteroides fragilis or Prevotella bivia (minimal inhibitory
concentration of CZOP; E. faecalis: 6.25 micrograms/ml, B. fragilis: 12.5
micrograms/ml, P. bivia: 12.5 micrograms/ml). Immediately after inoculating 10(5)
CFU of each organism/rat, CZOP (either 40 mg/kg, i.v., q.i.d., for 5 days or 80
mg/kg, i.v., b.i.d., for 5 days) was administered. The intrauterine inflammatory
change and bacterial counts in the CZOP-treated group were compared with those in
the nontreated control group. CZOP significantly (p < 0.01) decreased the
bacterial counts except for B. fragilis in the regimen of 80 mg/kg b.i.d.
However, the 40 mg/kg, q.i.d., regimen significantly (p < 0.05) reduced bacterial
counts compared to 80 mg/kg, b.i.d. These results suggest that CZOP in a more
divided dose is efficacious for the treatment of polymicrobial infections
associated with E. faecalis in pyometra.
PMID- 9551241
TI - Evaluation of different antibiotics in inhibiting colonization of Vibrio cholerae
O1 and O139 in the rabbit intestine.
AB - The effects of furazolidone, erythromycin and azithromycin in inhibiting
colonisation of Vibrio cholerae O1 and O139 in the rabbit intestine were tested.
Both V. cholerae O1 and O139 highly colonised the gut in control rabbits. The
colonisation of furazolidone-resistant strains in the rabbit intestine was
prevented effectively by both erythromycin and azithromycin. In furazolidone
sensitive strains, the efficacies of erythromycin and azithromycin were very much
comparable to furazolidone. These results suggested that azithromycin may be
subjected to clinical trial in comparison to furazolidone and erythromycin for
the treatment of cholera due to O1 and O139 infection in children.
PMID- 9551242
TI - Antifungal activity of D0870 against murine infections and its mechanism of
action.
AB - We evaluated the in vivo antifungal activity of D0870, a new triazole agent, in
comparison with that of fluconazole in two murine infection models. The
therapeutic mechanism of D0870 in these models was also investigated in vitro. In
a pulmonary infection with Cryptococcus neoformans in immunosuppressed mice,
D0870 at 10-100 mg/kg significantly reduced viable counts in lungs infected with
C. neoformans to 1/10-1,000 of the control on day 14, whereas fluconazole, only
at 100 mg/kg, showed a significant reduction in the viable counts and was less
active than D0870 at 10 mg/kg. D0870 at 3-30 mg/kg also showed excellent
therapeutic efficacy against murine vaginal candidiasis and completely eliminated
viable yeasts from the vaginal cavity, whereas positive cultures were found in
20% of mice treated with 30 mg fluconazole/kg. At pH 7 and 37 degrees C, D0870
was active against C. neoformans in synthetic amino acid medium, fungal or
sabouraud dextrose broth. By reducing the pH of the medium, the in vitro
anticryptococcal activity of D0870 was enhanced and found to be fungicidal under
all culture conditions at pH 4-5. D0870 also showed a stronger fungistatic
activity against Candida albicans at pH 4. These results suggest that D0870 may
exhibit a potent activity against these two murine infections by exerting an
excellent antifungal activity at the infection sites thought to be acidic
environments.
PMID- 9551243
TI - A comparative study of the cytogenetic and antineoplasmatic effects induced by
carboplatin in combination with niacin in human lymphocytes in vitro and in
Ehrlich ascites tumor cells in vivo.
AB - Enhanced sister chromatid exchange (SCE) levels and cell division delays were
observed when cultured human lymphocytes treated with carboplatin (cPt) were
exposed to niacin. Cytogenetic damage was also observed by cPt when Ehrlich
ascites tumor (EAT) cells were exposed in vivo to nontoxic concentrations of
niacin. One hour before intraperitoneal injection of 5-bromodeoxyuridine,
adsorbed to activated charcoal, EAT-bearing mice treated intraperitoneally with
cPt appeared to have a dose-dependent increase in SCEs and cell division delays.
Niacin increased the survival time of the EAT-bearing mice treated with cPt and
markedly reduced the ascitic volume. Therefore the in vivo antitumor effect of
cPt in conjunction with niacin appears to correlate well with the in vitro or in
vivo synergistic effects on cytogenetic damage caused by the combined cPt plus
Niacin treatment upon human lymphocytes or EAT cells, respectively.
PMID- 9551245
TI - Once-daily use of ofloxacin for prophylaxis in breast cancer surgery.
AB - The 150 consecutive patients who were hospitalized for breast cancer at our
department between September 1992 and November 1995 were enrolled in this open
study after having given their informed consent. Patients were assigned randomly
to receive ofloxacin in daily doses of 200 mg to be taken in a single dose or a
total dose of 600 mg divided into three doses postoperatively for 5 days. Ten
patients (8 found to be without malignancies) were excluded from evaluation.
Wound infections developed in 8 (12%) of the 69 patients in the 200-mg group and
12 (17%) of the 71 patients in the 600-mg group. Postoperative wound care lasted
a median of 19 days (25th and 75th percentiles, 15 and 29 days) for patients
given 200 mg and 16 days (13 and 25 days) for those given 600 mg; the difference
was not statistically significant (Wilcoxon's U test). Signs or symptoms
suggesting ofloxacin toxicity were not observed, and several significant
differences were found in laboratory test results between the two groups both
before and after treatment. Abnormal changes after treatment were found in many
individuals, but the rate of occurrence was similar in the two groups (U test).
When ofloxacin is used for prophylaxis after breast surgery, we recommend a once
daily administration of 200 mg orally for financial reasons and increased patient
compliance.
PMID- 9551246
TI - Prospective comparison of ceftriaxone and cefotaxime for the short-term treatment
of bacterial meningitis in children.
AB - The effectiveness and safety of ceftriaxone and cefotaxime in the short-term
treatment of primary bacterial meningitis were compared using a prospective,
randomized, multicenter study design. Children between the ages of 6 weeks and 16
years received either ceftriaxone as a single dose (100 mg/kg on the first day
followed by 75 mg/kg/day) or cefotaxime as four divided doses (200 mg/kg/day) for
4-7 days. A total of 82 patients (44 ceftriaxone, 38 cefotaxime) with documented
bacteria in the CSF were studied. In patients receiving ceftriaxone, full
recovery occurred in 79.5% while a further 13.7% recovered with neurologic
sequelae. Full recovery was observed in 71.1% of children treated with cefotaxime
with sequelae in a further 23.6% (no statistically significant differences
between drugs). The time to clinical improvement and resolution of fever (3-4
days) was also similar for both drugs. All but 1 of the 82 patients studied had
negative CSF cultures within 24 h of the beginning of therapy consistent with the
excellent penetration into the CSF (trough concentrations of 2.7 mg/l for both
drugs at the end of therapy). No differences were observed in the incidence of
clinically significant adverse events. Ceftriaxone and cefotaxime are both
effective in the treatment of bacterial meningitis. Ceftriaxone offers an
advantage in case of administration since it is administered as a single daily
dose.
PMID- 9551244
TI - Paclitaxel is an effective antiproliferative agent on the human NCI-H295
adrenocortical carcinoma cell line.
AB - In view of a potential clinical use, we assessed the antiproliferative effect of
paclitaxel on the human steroid-secreting NCI-H295 adrenocarcinoma cell line. By
MTT, paclitaxel induced a dose-dependent inhibition of cell proliferation, with
IC50 lower than blood levels of the drug achieved in patients treated for other
malignancies. Cell exposure to paclitaxel for 24 h at the different IC50S
produced a dose-responsive increase in DNA fragmentation, morphologically
confirmed by electron microscopy. A time-dependent decrease in aldosterone,
cortisol and testosterone was observed. Paclitaxel is an effective
antiproliferative agent in this human adrenocortical carcinoma cell line.
Apoptosis induced by the drug in involved in neoplastic cell death. A potential
role of the drug in the treatment of patients with adrenocortical cancer could be
considered.
PMID- 9551247
TI - Neuroendocrine signals in the regulation of gonadotropin-releasing hormone
secretion.
AB - Gonadotropin-releasing hormone (GnRH) is a key hypothalamic peptide that controls
the secretion of pituitary gonadotropins, particularly luteinizing hormone (LH),
and hence gonadal function. Hypothalamic GnRH is released in a pulsatile manner.
In the female, the pattern of GnRH pulses, i.e., pulse frequency and amplitude,
varies during different reproductive stages and among different species. Several
central and peripheral signals modulate GnRH neuronal activities. Some of these
signals are stimulatory to GnRH release, e.g., norepinephrine (NE) and
neuropeptide Y (NPY); some are inhibitory, e.g., beta-endorphin and interleukin
1; others are both stimulatory and inhibitory, e.g., estradiol-17 beta (E2). The
neuronal structures and chemical interactions that result in pulsatile GnRH
release remain unresolved. However, the core of the so-called 'GnRH pulse
generator' likely involves NE and NE transporter (NET, the protein for pre
synaptic re-uptake of NE). Both secretion and re-uptake of NE may determine
hypothalamic NE availability. Many of the GnRH-stimulating and GnRH-inhibiting
signals may influence the 'pulse-generator' by acting on GnRH neurons as second
level signals. Hypothalamic GnRH is also released in a "surge" manner that is
triggered either by increasing levels of circulating steroids (E2 and
progesterone) during the preovulatory period in spontaneous-ovulating species, or
by coitus in induced-ovulating animals. The sequential steps and mechanisms by
which the GnRH surge occurs after E2 or coitus are not clear. However, it is
unlikely that the E2 or coital stimuli act directly on GnRH neurons; E2 receptors
have not been found in GnRH cells whereas coital signals must stop in the
brainstem before they reach the hypothalamus. The brainstem may be an extra
hypothalamic site where both E2 and coital stimuli are transformed into GnRH
stimulating signals. One such signal may be NE whose brainstem cell bodies send
terminals into the hypothalamus. Evidence from our laboratory suggests that a
hypothalamic NE surge occurs at the time of the preovulatory GnRH surge in both
the monkey and rabbit. Moreover, gene expression of both tyrosine hydroxylase
(the rate-limiting enzyme for NE synthesis) and NET (the rate-limiting factor for
synaptic NE transmission) in the brainstem increases after E2 in the monkey and
after coitus in the rabbit. Other hypothalamic and/or brainstem signals, i.e.,
NPY, galanin, beta-endorphin, nitrous oxide and gamma aminobutyric acid, are
likely involved in generating, maintaining and/or modulating the GnRH surge
process. A better understanding of the up-stream GnRH-regulating signals will
help improve treatments for many reproductive disorders associated with stress,
obesity, infection and aging.
PMID- 9551248
TI - The endocrine mechanism of sex reversal in the protandrous black porgy,
Acanthopagrus schlegeli: a review.
AB - Black porgy, Acanthopagrus schlegeli Bleeker, a marine protandrous hermaphrodite,
is a functional male for the first 2 years of life but begin to sexually reverse
to female after the third year. This sex pattern provides a very good model to
study the mechanism of sex reversal in fish. The gonad at 5 month of age
consisted of testicular tissue with few primary oocytes at 5 month of age. The
ovarian tissue became dominant at 18 months of age during the non-spawning
season. Testicular and ovarian tissues were separated by connective tissue.
Plasma estradiol-17 beta(E2), vitellogenin and 11-ketotestosterone (11-KT)
profiles in males were significantly different from those in the 3-year-old
reversing females. Peak levels of plasma E2 in the reversing females occurred
during the early prespawning season (in October). Lower levels of plasma E2 were,
however, observed in the males. Plasma 11-KT levels significant decreased but no
changes of plasma testosterone were detected in the reversing females. Exogenous
E2 suppressed the testicular development but induced the gonadal aromatase
activity, ovarian development and sex reversal in 2-year-old black porgy.
Exogenous T and LHRH analog did not have effects on the sex reversal. Higher
concentrations of pituitary GtH II and mRNA of GtH II-beta subunit were detected
in the reversed females. These data suggested that E2 and gonadal aromatase
closely associated to the occurrence of sex reversal. A working model of the sex
reversal in black porgy is proposed.
PMID- 9551249
TI - Abnormal gonadotropin release and carbohydrate metabolism in morbid obese women.
AB - Obese women are associated with clinical symptoms suggestive of abnormal
reproductive functions including irregular menses and infertility. Previous
studies of gonadotropin release in obese women, basal or after luteal hormone
releasing hormone (LHRH) stimulation, are controversial. Obese women are also
often characterized by glucose intolerance and hyperinsulinemia which might
relate to their excessive body fat. To understand the link between abnormal
gonadotropin release, carbohydrate metabolism and percent body fat, we examined
17 premenopausal morbid obese women with body mass index (BMI) 38.7 +/- 1.6 Kg/m2
(mean +/- SEM) and 16 age-matched lean controls with BMI 19.7 +/- 0.6 Kg/m2.
Plasma glucose, insulin and C-peptide values were measured before and 30, 60, 90
and 120 min after a 75 gm oral glucose tolerant test (OGTT). Each individual also
received LHRH test which involved determinations of serum LH and FSH values at
basal, 15, 30 and 60 min after injection of LHRH for 0.1 mg intravenously. Women
with morbid obesity had significantly greater responses of glucose, insulin and C
peptide values as compared with lean women (all p < 0.001, two-way ANOVA).
Despite that basal concentrations were not different, serum LH, FSH and ratio of
LH to FSH values in response to LHRH test showed significantly lesser increase in
obese women than lean controls. Percent body fat, determined by bioelectrical
impedance analysis, correlated positively with plasma glucose, insulin and C
peptide responses to OGTT while negatively with ratio of LH to FSH responses (r =
-0.418, p < 0.01) to LHRH test. Body mass index also correlated inversely with
ratio of LH to FSH responses (r = -0.472, p < 0.01). In conclusion, morbid obese
women had glucose intolerance, hyperinsulinemia and lower responses of serum LH
and FSH values as compared with lean women. Excessive body fat play an important
role in mediating these carbohydrate and gonadotropin abnormalities.
PMID- 9551250
TI - 17 beta-estradiol-induced increases in glucose-regulated protein 78kD and 94kD
protect human breast cancer T47-D cells from thermal injury.
AB - Heat shock alters the susceptibility of tumor cells to chemotherapeutic agents.
We conducted experiments to study the regulation of expression of heat shock
proteins (HSP) in 17 beta-estradiol-treated T47-D cells, a human breast cancer
cell line. Cells exposed to 17 beta-estradiol for 24-48 h displayed increased
expression of glucose regulated protein 78kD (GRP-78) and 94kD (GRP-94), as shown
by [35S]methionine incorporation and Western blotting experiments. The increase
was time (5 h to 48 h)-dependent at 1 nM and 1 microM 17 beta-estradiol. Cells
overexpressing GRP-78 and -94 after treatment with 17 beta-estradiol displayed
resistance against heat shock (47 degrees C for 50 min)-induced death. Removal of
external Ca2+ or treatment of cells with BAPTA (a Ca2+ chelator) did not alter
the synthesis of GRP-78 and -94, suggesting that the 17 beta-estradiol effect on
the synthesis of GRP-78 and -94 is Ca(2+)-independent. In addition, exposure of
cells to 17 beta-estradiol up to 100 microM did not increase [Ca2+]i, which
further supports the view that the estrogen-induced GRPs are not regulated by
[Ca2+]i. Treatment with H89 (a protein kinase A inhibitor, 1 microM, 30 min) or
GF-109203X (a protein kinase C inhibitor, 1 microM, 30 min) also did not change
the GRP synthesis, indicating that protein kinase A and C are not involved in
regulation of GRP synthesis.
PMID- 9551251
TI - Interaction between triiodothyronine and ovarian steroid hormones on the
regulation of the release of thyrotropin and thyrotropin-releasing hormone in
vitro.
AB - In vivo and in vitro experiments were designed to examine [1] the effect of
triiodothyronine (T3) and/or ovarian steroids on the spontaneous and thyrotropin
releasing hormone (TRH)-stimulated release of thyrotropin (TSH) by the anterior
pituitary gland (AP) in vitro; and [2] the in vivo effects of T3 and ovarian
steroids on TRH-release in vitro. In the experiment 1, ovariectomized
thyroidectomized (Ovx-Tx) rats were injected with triiodothyronine (T3, 2
micrograms/kg), estradiol benzoate (EB, 25 micrograms/kg), progesterone (P, 10
mg/kg), T3 plus EB, T3 plus P, EB plus P, or T3 plus EB and P for 6 days before
decapitation. The AP was incubated with Locke's medium, challenged with TRH (30
nM), recovered and then with T3 (10 nM) only or with T3+TRH, 30 min for each
interval. Mediobasal hypothalami (MBHs) were challenged with high potassium (60
mM) for 30 min. In the experiment 2, the APs of Ovx-Tx rats were enzymatically
dispersed and the AP cells were pretreated with or without EB (0-6 nM) for 72 h,
and further with T3 (10 nM) for 24 h, followed by an incubation for 30 min with
TRH (0-100 nM). The spontaneous and TRH-induced release of TSH in vitro from rat
APs, and pituitary TSH content were increased by T3, or T3 plus P as compared
with the animals injected with vehicle, or P alone. EB inhibits the effect of T3
on TSH release in vitro. Application of T3 in vitro prevented the release of TSH
in response to TRH. EB dose-dependently relieved the inhibitory effect of T3 on
TRH-induced TSH release in vitro. TRH release from MBH was increased by EB and
inhibited by T3 or P. EB prevented the inhibitory effect of T3 on TRH release. P
plus T3 potentiated the stimulatory effects of EB on TRH release. These results
suggest that [1] the reduction of the concentration of plasma TSH by T3 is at
least in part due to the inhibitory effects of T3 on TRH release from mediobasal
hypothalamus, and TSH release in response to TRH, [2] the increased content and
release of TSH from rat AP tissue by T3 via an in vivo effect may be involved in
a short feedback loop of TSH on TRH release, and [3] ovarian steroid hormones
play an inhibitory role in regulating T3 effects on the release of TSH and TRH.
PMID- 9551252
TI - Optimal insemination concentration for human in vitro fertilization (IVF).
AB - This study is looking for optimal insemination concentration to achieve optimal
IVF pregnancy. Sperm lateral head displacement, total abnormal form, Kruger
morphology and index, hypo-osmotic swelling test were significantly correlated
with fertilization in vitro. Based on those parameters, logistic regression
models were formulated. These models predict either fertilization probability
provided with an insemination concentration or insemination concentration
assigned with a definite fertilization percentage. These models showed that
increased insemination concentration can increase fertilization percentage. The
increase of fertilization didn't compensate for the significant loss of
implantation by increasing insemination concentration.
PMID- 9551253
TI - Blastocyst formation is a good indicator for attainment of assisted reproduction.
AB - Blastocyst formation is a late stage of embryogenesis before implantation. The
examination for the percentage of blastocyst formation (PBF) can predict the
viability/pregnancy of the assisted reproduction trials. The PBF significantly
correlates with age and pregnancy. The PBF is significantly lower in the
intracytoplasmic sperm injection (ICSI) treatment than the conventional IVF
treatment. The zygotes from immature oocytes give less blastocyst formation than
the zygotes from mature oocytes. One pronucleus "zygotes" have significantly less
chance to blastocyst than the normal 2 pronuclei zygotes. A mathematical model is
proposed, verified, and predicts the hatching/hatched is the rate limiting step
for the outcome of pregnancy.
PMID- 9551254
TI - Localization of protein kinase C alpha and zeta during the decidualization in
pseudopregnant rats.
AB - Our previous data showed that at least five PKC isoforms (alpha, delta, zeta,
lambda and tau) were present in the decidualization. In this study, we then
localized the PKC alpha and zeta by immunohistochemistry in the decidualized
uterine tissues. The decidualized uterine tissues were induced by trauma
stimulation and fixed in formalin. The immunofluorescence were photographed by
confocal microscope. The data revealed that the fluorescence of PKC alpha was
present in the deciduomata and myometrium. In the deciduomata, PKC alpha was
mainly located in the surrounding nuclear. This phenomenon of localization was
especially performed on day 2 and 3 of the decidualization, just on the time of
higher frequence of cell mitosis. Since the myometrium with hypertrophy did not
display the phenomenon of perinuclear localization, these suggested that the
expression and localization of PKC alpha may be associated with the cell
proliferation. On the other hand, the PKC zeta was also present and distributed
broadly in the deciduomata and myometrium. This expression was increased and
similar to the previous Western blot studies. Thus, the data confirmed that the
various expression and localization of PKC isoforms may be correlated with the
development of deciduomata.
PMID- 9551255
TI - [Searching for the ideal cuff].
PMID- 9551256
TI - [Indications for antireflux surgery of the esophagus].
AB - In the Western world gastroesophageal reflux disease constitutes the single most
common benign disorder of the upper gastrointestinal tract. Current medical
therapy with proton pump inhibitors allows physicians to provide complete symptom
relief and healing of acute esophageal mucosal injury in practically all affected
patients. However, up to 50% of patients require maintenance therapy to prevent
relapse. In these patients laparoscopic antireflux surgery offers an attractive
and cost-effective alternative to potentially life-long medical therapy.
Consequently, every patient with persistent or recurrent symptoms and/or
complications of gastroesophageal reflux who depends on maintenance medical
therapy to remain in remission is a potential candidate for laparoscopic
antireflux surgery, particularly if of young age, suffering from side effects of
medical therapy or worrying about long-term safety of the conservative treatment
alternatives. A careful selection of patients, objective documentation of
gastroesophageal reflux disease by 24-h esophageal pH monitoring, and meticulous
attention to the technical details of the procedure are essential for a
successful outcome of antireflux surgery.
PMID- 9551257
TI - [Open antireflux surgery].
AB - In over 80% of patients with gastroesophageal reflux disease, the Nissen
antireflux fundoplication gives good long-term results. Dysphagia, inability to
belch or vomit as well as the gas bloat syndrome are possible sequelae after
fundoplication. The frequency of these symptoms could be reduced by modification
of the original Nissen-Rossetti fundoplication into the so-called "floppy" Nissen
fundoplication, a short and loose wrap of mobilized gastric fundus. Failures of
the antireflux procedure are mainly due to disruption or displacement of the wrap
with the telescope phenomenon. Here, reoperation with refashioning of the
original wrap may lead to same functional results like a primary fundoplication.
Technical alternatives may selectively be chosen, when gastroesophageal reflux
disease is complicated by fixated hiatal hernia, esophageal shortening, or
serious esophageal motility disorders. Such specific anatomic or functional
abnormalities are detected by preoperative endoscopy, barium swallow, 24-h pH
monitoring, and manometry. Alternative techniques are mainly transthoracic
repairs, including the Nissen fundoplication, Collis gastroplasty, and the Belsey
Mark IV. Modifications of the 360 degrees Nissen operation are partial
fundoplications like the Hill repair and the Toupet dorsal fundoplication.
Because of a high failure rate in the long-term follow-up, application of the
ligamentum teres cardiopexy and of the Angelchik prosthesis is not recommended.
PMID- 9551258
TI - [Laparoscopic antireflux procedures].
AB - Laparoscopic antireflux surgery is rapidly replacing traditional operations for
the treatment of medically refractory gastroesophageal reflux disease. These
procedures are technically demanding. Troublesome side effects can be minimized
by carefully selecting patients and using a meticulous and appropriate technique.
Extensive follow-up data are now emerging and indicate that these procedures can
offer long-term control of symptoms with few permanent side effects.
PMID- 9551259
TI - [Endoscopic intraluminal valvuloplasty--a therapy of the future for
gastroesophageal reflux].
AB - A new endoscopic intraluminal valvuloplasty is described. The procedure provides
a simple, easy out-patient approach for antireflux surgery and is applicable to
patients with early gastroesophageal reflux disease as an alternative to chronic
life-long medical therapy. The feasibility, durability and efficacy of the
procedure in baboons are reported.
PMID- 9551260
TI - [Can "internal intestinal splinting" prevent ileus recurrence? Results of a
retrospective comparative study].
AB - The high rate of recurrence after the treatment of adhesive obstruction demands
special prophylactic treatment. In a 13-year period, 52 out of 95 patients with
major adhesions were provided with a long nasointestinal tube for intestinal
splinting intraoperatively. The was being left in situ on an average of 6.6 days.
After an observation period of at least 36 months a recurrence was seen in 2 of
these 52 patients (3.9%; causes: volvulus after 6 months/fibrinous peritonitis on
the 6th postoperative day). Amongst the 43 'non-splinted' patients, recurrence of
adhesive obstruction was documented in 8 cases (18.6%; causes: adhesions after
0.3-136.9 months). In the course of after-care abdominal complaints were
significantly fewer in patients who had been splinted. Complications concerning
the nasointestinal tubes did not occur. The rate of perioperative complications
was similar in both groups.
PMID- 9551261
TI - [Diverticulitis of the cecum and ascending colon].
AB - Right colon diverticulitis, representing 1-3.6% of cases of diverticular disease
is an uncommon cause of right lower quadrant pain. Its presentation is difficult
to distinguish from acute appendicitis. Patients are between 35 and 50 years old,
have a history of 2-3 days of abdominal pain and few gastrointestinal symptoms.
The diagnosis is best confirmed by computed tomography and colonoscopy.
Conservative treatment is justified in uncomplicated disease, whereas
perforations, abcesses and inflammatory tumors require resection. We describe the
cases of six patients treated at our institution from 1991 to 1996. Presentation,
geographic variations, diagnostic procedures and management are discussed.
PMID- 9551262
TI - [Success and failure in laparoscopic "gastric banding". A report of 3 years
experience].
AB - During 3 years, the adjustable gastric band (AGSB) was laparoscopically implanted
in 224 of 873 patients with morbid obesity. The operation was done by 7 surgeons.
Problems arising from the operative technique are: early pouch dilatation,
gastric slippage, gastric perforation, penetration of the band, port infection,
penetration of the port, defect of the band catheter. These can be avoided by
care and increasing experience. The late pouch dilatation and the insufficient
loss of excess weight arise from the unsatisfactory compliance of the patient.
Critical selection of patients is necessary. Total morbidity in this seria was
19%, the letality 0.4% and the average excess weight loss within 2 years was 50
+/- 28%. The results may be improved by restrictive selection of patients and
great operative routine.
PMID- 9551263
TI - [Prognostic value of e-cadherin in papillary thyroid carcinoma].
AB - The prognostic significance of e-cadherin in papillary thyroid carcinoma was
evaluated in a retrospective study. From September 1985 to December 1996, 113
patients underwent surgery for papillary thyroid carcinoma. Seventy-eight
formalin-fixed, paraffin-embedded tissue samples were available for
immunohistochemical analysis of e-cadherin expression. In 74 of these 78 patients
the postoperative course is known for 2 months to 35.2 years (median 3.6 years,
mean: 4.9 +/- 4.8 years). Reduced or negative e-cadherin expression (< or = 20%)
was associated with advanced T categories of the primary tumours and higher rates
of synchronous lymph node involvement and distant metastasis. During follow-up in
this group of patients locoregional tumour recurrence occurred more frequently
and survival was shorter than in patients with tumours which exhibited e-cadherin
expression of > 20%. Statistical analysis revealed e-cadherin expression (< or =
20%/ > 20%), synchronous distant metastasis (M0/pM1, cM1) and radicality of
resection (R0/R1, 2) as significant risk factors for survival. Our findings
provide evidence that e-cadherin is a prognostic factor in papillary thyroid
carcinoma.
PMID- 9551264
TI - [Guidelines as the principle of rational medical management].
PMID- 9551265
TI - ["Directions, guidelines, standards"--risk or advantage for physician and
patient?].
PMID- 9551266
TI - [Current assessment of physician manpower needs in surgery].
PMID- 9551267
TI - [Endoscopic surgery. 10 good reasons for integration of flexible endoscopy into
surgery].
PMID- 9551268
TI - [Report on the membership meeting of the Regional Westphalia Society of the BDC
12 November 1997 in Dortmund].
PMID- 9551269
TI - [Gliding nail osteosynthesis. A new universally applicable implant for management
of per- and subtrochanteric femoral fractures].
AB - Age, high physiological load and the great number and different fracture types of
the proximal femur are the main challenges for implants used in the management of
these fractures. For use in these types of fracture with immediate restoration of
full weight-bearing capacity and for reduction of the intra- and postoperative
complication rate, the gliding nail was developed. The development is based on a
large number of experimental and clinical examinations of per- and
subtrochanteric fractures. The advantages of an intramedullary implant and the
gliding screw systems are combined with increased moment of resistance of the
double-T femor-neck blade profile. We performed a prospective clinical evaluation
of the first 186 patients with per- and subtrochanteric fractures who were
treated between 15 September 1994 and 29 February 1996 in the Aschaffenburg
Trauma Department with a follow-up examination at least 3 months after the
operation. The intraoperative complication rate was 1.1%. The postoperative
complication rate was 4.9%. Change of the blade because of fracture impaction and
tractus iliotibialis problems was the most frequent problem with 2.2%. The most
severe complication (1.1%) were caused by subchondral placement of the blade in
the cranial one-third of the femur head. In these cases reosteosynthesis was
indicated. Ninety-three percent of the survivors were able to return home. The
rate of bed-ridden patients (7.7% and 11.7%) was not very different before or
after the operation. However, many patients do not reach the condition they had
before the fracture and they are one step worse in mobility and social
independence.
PMID- 9551270
TI - [Heparin-associated thrombocytopenia (HAT) type II. An underestimated
complication in prevention of thromboembolism with heparin].
AB - We report four patients who developed heparin-associated thrombocytopenia (HAT)
under heparin prophylaxis. One patient showed no clinical signs, but three had
severe complications (white-clot syndrome, acute adrenal failure and loss of limb
because of thromboembolic complication), leading to death in two cases.
PMID- 9551271
TI - [Salmonella enteritidis infected false aneurysm of the superficial femoral artery
in an HIV seropositive patient].
AB - In the course of an infection with human immunodeficiency virus, a large variety
of complications affecting all organ systems can occur. However, complications
affecting the vascular system demanding surgical intervention are rare. In the
case presented we report a 67-year-old HIV-seropositive patient who underwent
surgery for a huge abscess in the thigh. Intraoperatively unexpectedly we found a
mycotic aneurysm of the femoral superficial artery and the causactive bacterium
proved to be Salmonella enteritidis. Because of the rising number of HIV-infected
patients we suspect that the amount of complications involving the vascular
system and demanding surgical intervention will also increase. Therefore, when
diagnosing and deciding on therapy for patients with AIDS, the physician must be
aware that vascular complications due as a result of HIV infection might occur
more frequently in the future.
PMID- 9551272
TI - [Cystic echinococcosis of the spleen].
AB - Based on the portal infection root, the hydatid disease of the spleen represents
a rarity. Because of a lack of prospective studies, spleen-preserving procedures
and splenectomies were published as surgical therapy in case reports. In this
report, the case of a 72-year-old woman with symptomatic hydatid disease of the
spleen will be reported. Surgical and pharmaceutical strategy to minimize the
risk of an OPSI syndrome as well as the value of adjuvant therapy with
Albendazole will be discussed.
PMID- 9551273
TI - [Comparison between steam and gas sterilized optics. Costs, availability,
maintenance].
AB - METHODS: In a 300-bed acute-care hospital we compared optical instruments
employed, for orthopedic, urological and gynecological operations during their
use in practice. The comparison between 33 ethylene oxide(EO)-sterilized optical
instruments and 14 steam-sterilized optical instruments took into account the
following criteria: frequency of use; availability; sterilization cycles; kind,
cost and number of repairs. RESULTS: The 33 EO-sterilized optical instruments
were handled 1043 times and were repaired 10 times (at a cost of up to 2000 SFR).
The 14 steam-sterilized optical instruments were treated 1101 times and were
repaired 8 times (2000 SFR). The total costs were 77,000 SFR for the 14 steam
sterilized instruments and 132,000 SFR for the 33 EO-sterilized instruments.
INTERPRETATION: Steam-sterilization is a reasonable, safe and fast method of
sterilizing optical instruments. We prefer this method, given its advantages
(less toxicity, personal care and pollution control).
PMID- 9551274
TI - [Country-wide survey of therapeutic procedures in hemorrhoids and anal fissure].
AB - A survey among coloproctologists was performed to assess current therapeutic
concepts for the treatment of hemorrhoidal disease and anal fissure. A total of
261 clinical and non-clinical proctologists participated, representing the entire
range of therapies in hospital and practise. A wealth of widely differing, in
some aspects contradictory concepts were recorded, leaving almost no subject
entirely undisputed. There are controversies regarding the different therapeutic
alternatives as well as indications for surgery and choice of operative
procedure. Future research has to address the existing controversies in order to
reach a higher degree of standardization in the therapy of these common
proctological disorders.
PMID- 9551275
TI - [Postoperative analgesia after endoscopic abdominal operations. Comment on the
contribution by P. Steffen et al].
PMID- 9551276
TI - [Surgical wound treatment].
PMID- 9551277
TI - Health services clinical trials: design, conduct, and cost methodology.
AB - Randomized clinical trials and their developing methodology have had substantial
impact on the advancement of medical practice. With the emergence of managed care
and increased emphasis on the reduction of medical care expenditures, cost
evaluation is now becoming a part of clinical trial research. The papers by
Henderson et al. and Manheim that follow address the evolution of health services
research, its application to multicenter clinical trials in a major U.S. health
care system, and methods of assessing costs in health services clinical trials.
PMID- 9551278
TI - Cooperative studies in health services research in the Department of Veterans
Affairs.
AB - The Department of Veterans Affairs, through its Cooperative Studies Program, has
a long history of conducting large-scale, multihospital biomedical clinical
trials. The agency's Health Services Research and Development Service, although
newer, has a distinguished record of mainly single-site research into the
organization, delivery, and financing of health services. In 1990, a joint
program was initiated to conduct multicenter studies in health services research.
This article describes the studies developed in the new program and the research
design issues encountered in planning them. Identification of the patient
population, specification and measurement of the intervention, and description of
the control group, as well as attention to the unit of randomization and
analysis, outcome variables and choice of effect size, data quality, and ethical
considerations are among the important issues related to the design of these
studies and future studies in health services.
PMID- 9551279
TI - Health services research clinical trials: issues in the evaluation of economic
costs and benefits.
AB - The costs and benefits of treatment interventions are difficult both to
conceptualize and to measure. This paper discusses methodologic issues that arise
in measuring costs, distinguishing between social costs and transfer payments,
measuring the value of life and limb, and assessing the meaning of cost
differences. Long-run vs. short-run costs and average vs. marginal costs are
considered. Sensitivity analysis to assess the robustness of results to
alternative assumptions is stressed. Cost-benefit and cost-effectiveness analyses
are seen as important in assessing the policy implications of clinical trials; a
proper cost-benefit analysis allows the reader to understand how results relate
to the assumptions made in the analyses.
PMID- 9551280
TI - Do certain countries produce only positive results? A systematic review of
controlled trials.
AB - OBJECTIVE: To determine whether clinical trials originating in certain countries
always have positive results. DATA SOURCES: Abstracts of trials from Medline
(January 1966-June 1995). STUDY SELECTION: Two separate studies were conducted.
The first included trials in which the clinical outcome of a group of subjects
receiving acupuncture was compared to that of a group receiving placebo, no
treatment, or a nonacupuncture intervention. In the second study, randomized or
controlled trials of interventions other than acupuncture that were published in
China, Japan, Russia/USSR, or Taiwan were compared to those published in England.
DATA EXTRACTION: Blinded reviewers determined inclusion and outcome and
separately classified each trial by country of origin. DATA SYNTHESIS: In the
study of acupuncture trials, 252 of 1085 abstracts met the inclusion criteria.
Research conducted in certain countries was uniformly favorable to acupuncture;
all trials originating in China, Japan, Hong Kong, and Taiwan were positive, as
were 10 out of 11 of those published in Russia/USSR. In studies that examined
interventions other than acupuncture, 405 of 1100 abstracts met the inclusion
criteria. Of trials published in England, 75% gave the test treatment as superior
to control. The results for China, Japan, Russia/USSR, and Taiwan were 99%, 89%,
97%, and 95%, respectively. No trial published in China or Russia/USSR found a
test treatment to be ineffective. CONCLUSIONS: Some countries publish unusually
high proportions of positive results. Publication bias is a possible explanation.
Researchers undertaking systematic reviews should consider carefully how to
manage data from these countries.
PMID- 9551281
TI - Laboratory data in clinical trials: a statistician's perspective.
AB - Even though laboratory data provide the best indicators for systemic toxicities
in clinical trials of investigational medications, many applied statisticians
lack a basic understanding of the interpretation of such data. Understanding is
essential to a statistician's ability to help evaluate a patient's overall safety
experience in a trial, the latter being the primary objective for collecting
laboratory data in the trial. In this paper, we discuss the purpose of conducting
laboratory evaluations as well as some hidden issues concerning the current
practice of laboratory data analysis. The issues include the use of reference
ranges, the one-parameter-at-a-time approach, and the exploratory nature of
safety data analyses.
PMID- 9551282
TI - Threats to the validity of clinical trials employing enrichment strategies for
sample selection.
AB - Subject selection and exclusion criteria employed in typical clinical
effectiveness trials of investigational new drugs have two fundamental aims: (1)
to ensure that patients entering a study are truly suffering from the condition
the drug is intended to treat and (2) to maximize the likelihood that the study
will detect an effect of the drug if, in fact, one exists. Typical protocol
selection criteria not only specify exacting procedures for establishing and
documenting the diagnosis of those recruited for a study but also seek to
increase, relative to the prevalence in the general population, the proportion of
individuals in the sample likely to respond to pharmacological treatment. Because
it is ordinarily impossible to learn prior to extensive clinical experience with
a new drug which, if any, patient characteristics reliably predict a consistent
treatment response, strategies for sample "enrichment" typically operate by
excluding patients (for example, those with very advanced and/or complicated
illness, those with serious concomitant illness, those at the extremes of age,
those with very mild illness, and so forth) in whom a dependable response to
treatment seems unlikely on logical and/or generic grounds. Some studies use
positive strategies for sample "enrichment." In studies evaluating drugs intended
to treat recurrent episodes of psychiatric illnesses, many protocols recommend
selective recruitment of patients with a history of meaningful positive responses
to antipsychotic treatment during prior episodes. Sample selection procedures of
these kinds impose limits on the generalizability of a study's results (i.e.,
external validity), but the use of nonrandom patient samples is ordinarily held
to have no effect on the internal validity of the results. In short, studies
employing highly selected patient samples are, despite their limited external
validity, regularly accepted as valid sources of evidence bearing on a drug's
effectiveness. There are exceptions, however; this paper describes one in which
the use of a seemingly innocuous sample enrichment maneuver proved highly
damaging to the ultimate credibility of an important multicenter trial. In
particular, exposure to an experimental treatment during an open qualification
phase may invalidate drug-placebo comparisons made during a later randomized,
blinded, controlled phase. Our review of the trial also reveals that the
enrichment maneuver employed probably failed to accomplish its intended aims,
selecting patients whose improvements on the outcome variable may be as
reasonably ascribed to chance as to drug effect. This is all the more surprising
because the method of sample enrichment employed has much in common with those
long recommended in the clinical trial literature.
PMID- 9551283
TI - Comparative evaluation of two models for estimating sample sizes for tests on
trends across repeated measurements.
AB - Two equations for calculating sample sizes that are required for power in testing
differences in rates of change in repeated measurement designs have been
presented by different authors. One equation provides support for the conclusion
that increased frequency of measurements across a treatment period of fixed
duration enhances power of the tests. The other equation supports the
counterintuitive conclusion that increased frequency of measurements actually
tends to decrease power in the presence of realistic serial dependencies in the
data. Monte Carlo methods confirm that the equation providing support for the
latter conclusion is accurate, whereas the alternative equation tends to
underestimate sample sizes required for power in testing differences in slopes of
regression lines fitted to changes in the repeated measurements across time when
symmetry is absent from the covariance structure.
PMID- 9551284
TI - The cost-benefit of a randomized trial to a health care organization.
AB - Clinicians and patients make many decisions in situations where optimal treatment
is uncertain. Despite well-published advantages of clinical trials for reducing
such uncertainties, a trial may not be conducted because the sample size
indicated by classical, hypothesis-testing methods is so large that no one
institution could afford to sponsor the trial. By explicitly taking into
consideration the costs and benefits of a trial, Bayesian statistical methods
permit estimation of the value to a health care organization conducting a
randomized trial instead of continuing to treat patients in the absence of more
information. This paper describes a method for calculating the cost-benefit to a
health care organization conducting a clinical trial, and the expected sample
size to adequately resolve the uncertainties about which treatment is better. The
method is illustrated in the case of a proposed clinical trial of a drug to
prevent multiorgan system failure and death in patients admitted to the Stanford
University surgical intensive care unit. This method should permit health care
organizations to evaluate a proposed trial's expected cost-benefit and the
expected sample size that will resolve the question of interest, and thereby
assist in the process of deciding whether to conduct the trial.
PMID- 9551286
TI - Neurometabolic disease.
AB - Advances in knowledge of neurometabolic disease continues. Of great interest to
the neurologist are the definitions of the molecular defects in Niemann-Pick C
disease, Refsum disease, and five of the disorders of peroxisome biogenesis,
including rhizomelic chondrodysplasia punctata. Duplication of the proteolipid
protein gene is the most common molecular abnormality in Pelizaeus Merzbacher
disease. Therapies for guanidinoacetate methyltransferase deficiency and for 3
phosphoglycerated dehydrogenase deficiency appear promising. Animal models have
been developed for X-linked adrenoleukodystrophy, metachromatic leukodystrophy
and Zellweger syndrome and will aid in the understanding of pathogenesis and the
evaluation of therapy.
PMID- 9551285
TI - TRIPOD (TRoglitazone In the Prevention Of Diabetes): a randomized, placebo
controlled trial of troglitazone in women with prior gestational diabetes
mellitus.
AB - The TRoglitazone In the Prevention Of Diabetes (TRIPOD) trial is a single-center,
randomized, placebo-controlled, double-masked study. The primary aim of the
TRIPOD trial is to test the hypothesis that chronic administration of
troglitazone to nondiabetic women with prior gestational diabetes mellitus (GDM)
will improve whole-body insulin sensitivity and reduce the incidence of non
insulin-dependent diabetes (NIDDM). Because troglitazone is already known to
lower blood glucose concentrations in persons who have developed NIDDM, an
additional aim of the project will be to determine whether early intervention
with troglitazone will achieve better final glycemic control than can be achieved
by later intervention. In addition, since troglitazone treatment is expected to
improve insulin sensitivity and may prevent or delay a decline in glucose
tolerance, we also plan to determine whether long-term troglitazone treatment
alters the development or progression of atherosclerosis. In this article we
describe the experiment's design, the study's endpoints and methods for
determining those endpoints, methods for assessing quality of life, and proposed
methods for statistical analyses. The unique two-phase study design of the TRIPOD
trial will permit testing not only of the biological question about reversal of
insulin resistance and prevention of diabetes, but also of the clinical question
about whether early intervention is superior to late intervention. Results from
this trial will have an important impact on the monitoring and treatment of
patients at high risk for NIDDM.
PMID- 9551287
TI - Prevention of neural tube defects: vitamins, enzymes and genes.
AB - Neural tube defects can be prevented by folic acid, although the mechanism of
this action is unclear. Studies of a series of folate-related enzymes have so far
failed to pin-point the nature of the metabolic defect in the neurulation-stage
embryo that is corrected by folic acid. Approximately 30% of neural tube defects
appear resistant to folic acid and recent work in a mouse genetic model system
suggests that administration of myo-inositol may be a complementary therapeutic
option. The large number of mouse genes known to cause neural tube defects
provide a starting point for identifying the genetic basis of the human defects.
PMID- 9551288
TI - Craniofacial developmental abnormalities.
AB - Major advances have been made in the elucidation of the molecular basis of a
number of human dysmorphic syndromes involving abnormalities of craniofacial
development. This will lead, in turn, to a greater understanding of the
mechanisms that underlie normal craniofacial development.
PMID- 9551289
TI - Neuropsychiatric disorders.
AB - Neuropsychiatric disorders of childhood include autism spectrum disorders,
disorders comprising attention deficits (attention-deficit-hyperactivity disorder
and deficits in attention, motor control and perception), tics (motor or vocal,
or both), and obsessions and compulsions (obsessive-compulsive disorder). They
affect a small proportion of the child population. They can now reliably be
diagnosed, and are valid and clinically meaningful conditions. Effective
interventions are available for most of these disorders.
PMID- 9551290
TI - Developmental perspectives on epilepsy.
AB - This paper reviews current knowledge about epileptogenesis in the developing
brain. Animal studies indicate that the maturational balance of excitatory and
inhibitory neurotransmitter systems should result in an increased susceptibility
to seizures. However, the reason for specific age-locked syndromes and the high
rate of impairments secondary to early onset epilepsy remain mysterious. Present
research activity is directed to prevention and amelioration of these severe
cognitive and psychiatric impairments.
PMID- 9551291
TI - Integration of structural and functional data.
PMID- 9551292
TI - Mechanisms and experimental models of seizure generation.
AB - Over the past year evidence has accumulated against the idea that seizures
require re-entrant activity between spatially separate structures. Seizures in
vivo typically do involve interconnected, spatially separate brain regions, but
they often show no net phase lag around the putative circuit. In many cases
seizure-like events can arise from localized regions such as the entorhinal
cortex or hippocampus proper, through mechanisms that are starting to be
identified.
PMID- 9551293
TI - Febrile seizures: genetics and relationship to other epilepsy syndromes.
AB - The relationship between febrile seizures and epilepsy has long been debated. We
argue that there is some specificity to the types of epilepsy that follow febrile
seizures, rather than febrile seizures being a nonspecific marker of a lowered
seizure threshold. The relationship between febrile seizures and later epilepsy
is frequently genetic. Recent clinical and molecular genetic studies suggest that
there are a number of syndrome-specific genes for febrile seizures.
PMID- 9551294
TI - Differential diagnosis of sleep disorders, non-epileptic attacks and epileptic
seizures.
AB - Making a correct diagnosis in patients presenting with attack disorders is
important. The clinical features of autosomal dominant nocturnal frontal lobe
epilepsy and concussive seizures are reviewed. Recent work on the diagnosis and
investigation of psychogenic non-epileptic attacks, drop attacks, falls, syncope
and sleep disorders is discussed.
PMID- 9551295
TI - New drugs for epilepsy.
AB - Seizure freedom with no side-effects is the aim of treatment, and new
antiepileptic drugs have not lived up to expectations; only a few patients with
chronic epilepsy have been rendered seizure-free. These treatments have side
effects but their safety profile may be better than older alternatives, although
chronic effects have not yet been established. This article reviews newly
marketed antiepileptic drugs. It concentrates on shortcomings of current
antiepileptic treatment and on the way drugs are developed. A new approach to
treatment is long overdue. The development of rational antiepileptic treatments
should be strongly encouraged. More clinically relevant paradigms need to be
developed and incorporated into clinical trial programmes as these are presently
biased in their designs towards regulatory issues.
PMID- 9551296
TI - The epidemiology and management of status epilepticus.
AB - Status epilepticus refers to a prolonged seizure state, usually taken as lasting
30 min or longer. This review considers recent studies of the epidemiology of
status epilepticus; these have confirmed the high incidence and the high
associated mortality and morbidity. Advances in the management of status
epilepticus are also reviewed but despite these advances there is still a lack of
good comparative studies on which to base treatment regimens.
PMID- 9551297
TI - The current state of epilepsy surgery.
AB - Epilepsy surgery is an effective therapy for many patients with refractory
partial seizures. The results of epilepsy surgery have improved with advances in
the evaluation of patients for surgery and the care of patients during and after
surgery. This review looks at recent innovations in imaging modalities to
identify the candidates for surgery who will benefit most, to identify subtle
pathology, to resect the epileptogenic focus more precisely, and to preserve
functionally important cortex in order to achieve the best possible outcome.
Patient selection and the identification and removal of the epileptogenic focus,
in a safe manner, are crucial for good outcome.
PMID- 9551298
TI - Developmental disorders.
PMID- 9551299
TI - Seizure disorders.
PMID- 9551301
TI - The prevention of neural tube defects.
AB - The prevention of neural tube defects is a complex problem. The genetic
associations may ultimately allow the prepregnancy identification of women at
high risk of a neural tube defect. Education of both the public and healthcare
providers has been shown to increase awareness, but the majority of women do not
take folic acid before and in the early part of pregnancy. Food fortification
will be effective in increasing the folate levels of the population and will have
a benefit even at low doses of fortification.
PMID- 9551302
TI - Antenatal screening for aneuploidy.
AB - There are several methods of antenatal screening for aneuploidy. Most are aimed
at the identification of women at increased risk of Down syndrome, the most
common abnormal karyotype conferring a significant risk of serious long-term
morbidity. Traditional maternal-age-based screening has largely been replaced by
programmes based on biochemical markers in maternal serum in the second trimester
of pregnancy. However, in recent years there has been a considerable drive
towards earlier screening such that there are now a range of potential programmes
based on various combinations of maternal age, serum markers and ultrasound
findings. There is currently much debate as to which are the most effective
methods of screening for aneuploidy.
PMID- 9551303
TI - Applied molecular genetic techniques for prenatal diagnosis.
AB - Molecular laboratory techniques are increasingly important in the evaluation of
fetuses at risk for a single gene disorder or chromosomal abnormality and for the
detection of genetic or other conditions that can lead to an adverse fetal or
maternal outcome. The localization and identification of novel disease genes
allows for mutation analysis or linkage studies on fetuses at risk for these
disorders. New assays or techniques for mutation detection in single gene
disorders such as amplification refractory mutation system polymerase chain
reaction, fluorescent polymerase chain reaction, heteroduplex analysis and the
protein truncation test are now applied in prenatal diagnosis. Recent advances in
molecular cytogenetics, such as comparative genomic hybridization, the primed in
situ labeling technique, the development of new telomeric probes and spectral
karyotyping, are being evaluated for their role in the prenatal diagnosis of
chromosomal abnormalities. These methods may greatly improve the accuracy and
applicability of preimplantation genetic diagnosis or diagnosis on fetal cells
isolated from maternal blood.
PMID- 9551305
TI - Novel fetal imaging techniques.
AB - Fetal imaging technology is evolving rapidly, and new techniques are being
evaluated to establish their role in the assessment of the fetus. It is essential
that these methods of fetal imaging are carefully assessed to ascertain if they
provide additional information to assist in the clarification or understanding of
fetal disease states that is not already provided by current conventional imaging
techniques.
PMID- 9551304
TI - Stem cell transplantation into the fetal recipient: challenges and prospects.
AB - The interest in therapeutic intervention for those inherited disorders that can
be diagnosed early in pregnancy has recently intensified. In-utero
transplantation of haematopoietic stem cells (IUT-HSC), a therapy which could be
proffered before pathological manifestations of a disorder become apparent,
offers considerable potential benefit. However, as reports of IUT-HSC procedures
become more prolific, it is necessary to consider the optimum modus operandi for
each group of disorders targeted for therapy in order to develop effective
procedures that make a real difference to the outcome. This review outlines the
current status and prospects of IUT-HSC. It also offers a view of some of the
challenges for IUT-HSC to overcome to find wider clinical applications.
PMID- 9551306
TI - Fetal thrombocytopenia.
AB - In idiopathic thrombocytopenic purpura, the low risk of fetal bleeding in the
perinatal period does not justify routine cordocentesis. Platelet counts of
second newborns correlates well with that of their siblings. In neonatal
alloimmune thrombocytopenia, the initial platelet count at cordocentesis in the
second trimester is low in the next pregnancy. Weekly high doses of intravenous
gammaglobulin to the mother results in a rise of fetal platelet count in
approximately 70% of cases and may protect the fetus against intracranial
haemorrhage in cases without significant platelet rise. With the exception of
cases with a prior infant with spontaneous fetal intracranial haemorrhage, the
use of diagnostic fetal blood sampling to confirm neonatal alloimmune
thrombocytopenia is controversial.
PMID- 9551307
TI - Vertical transmission of viral infections.
AB - A variety of congenital viral infections are responsible for a large proportion
of the mortality and morbidity in infancy and childhood. Vertical transmission
may occur during primary maternal infection or during chronic or recurrent
infection, with different implications for counselling and testing in pregnancy.
Strategies for the diagnosis and prevention of mother-to-child transmission
differ according to the timing and mechanisms involved. As demonstrated by
hepatitis B research in the past and human immunodeficiency virus today,
multicenter cohort studies and clinical trials are a key to developing effective
interventions.
PMID- 9551308
TI - Pre-eclampsia--still a disease of theories?
AB - The pathophysiology of pre-eclampsia remains poorly understood. Moreover, there
is no reliable predictive test and no effective prophylactic therapy for this
disease. Advances have, however, recently been made in our understanding of the
genetics of pre-eclampsia and in the processes which lead to abnormal
trophoblastic invasion in pre-eclampsia. Prediction and prevention are intimately
linked, and both problems will only be solved by further unravelling of the
complex pathophysiology of pre-eclampsia.
PMID- 9551309
TI - Inherited thrombophilia and pregnancy.
AB - Inherited thrombophilia is associated with an increased risk of thrombosis.
Classically it consists of protein C and protein S deficiency, activated protein
C resistance and antithrombin III deficiency. In pregnancy, in addition to
thrombosis, inherited thrombophilia is associated with poor obstetric outcome,
including recurrent miscarriage, late fetal loss, abruption and pre-eclampsia.
Hyperhomocysteinaemia is a newly recognized cause of familial thrombophilia. It
is likely that further causes such as prothrombin gene mutations will be added to
the rapidly expanding list. The diagnosis of some forms of genetic thrombophilia
must, however, be approached with caution during pregnancy, particularly protein
S deficiency and activated protein C resistance.
PMID- 9551310
TI - Consequences of fetal growth restriction.
AB - An increasing number of diseases in child and adult life are now thought to have
their origins in the fetal period. Central to this predisposition is restriction
of fetal growth. During the period reviewed in this article, the associations
between adult hypertension and low birthweight were confirmed, and numerous
studies have investigated possible mechanisms by which the metabolism of an
individual may be programmed by an adverse intrauterine environment. The
consequences in adult life of intrauterine undernutrition now highlight prenatal
care as one of the most crucial issues in medicine and challenge many aspects of
current obstetric decision-making. Research targeting fetal growth and
development can be expected to result in improved health at all ages.
PMID- 9551312
TI - Prenatal diagnosis.
PMID- 9551311
TI - Preterm labour: recent advances in understanding of pathophysiology, diagnosis
and management.
AB - Recent advances in the importance of sociodemographic factors, including maternal
stress, as well as potential predictors of preterm birth are reviewed. The
recommended role of adjunctive antibiotic therapy, in women with preterm
premature rupture of the membranes but not in women with intact membranes, is
discussed. The possibility of causes other than those related to infection in
preterm rupture of the membranes is raised, and new information regarding the use
of glucocorticoids and tocolytics is presented. Despite steady improvements in
neonatal survival and morbidity rates over the past decade primarily as a result
of improved neonatal care, there has been no corresponding decrease in the
incidence of preterm birth. An improved understanding of the pathophysiology and
diagnosis of preterm birth remains one of the greatest challenges in obstetric
care in this decade.
PMID- 9551313
TI - Maternal-fetal medicine.
PMID- 9551314
TI - Coarctation of the aorta: an update.
PMID- 9551315
TI - [Enhancer of the scute gene can activate a promoter found at another locus].
PMID- 9551316
TI - [Possible participation of secondary biogenic radiation in appearance of an
"adaptive response"].
PMID- 9551317
TI - [Effect of certain opiates on the stability of an artificial lipid bilayer
membrane].
PMID- 9551318
TI - [Effect of helium-neon laser radiation on growth and development of newborn
rats].
PMID- 9551319
TI - [Paradoxical sleep--an indicator of various forms of hypometabolism in mammals
and birds].
PMID- 9551320
TI - [Myelopeptide-4--a new endogenous factor for differentiation of myeloid cells].
PMID- 9551322
TI - [Development of organs of hearing and balance in representatives of eared seals
(Eumetopias jubatus)].
PMID- 9551321
TI - [Seasonal dynamics of abdominal gland function and marking activity in Mongolian
(Meriones unguiculatus), midday (M. meridianus), and Tamarisk (M. tamariscinus)
gerbils].
PMID- 9551323
TI - [Protein products of zeste, e(y)1 and e(y)3 genes can effect the insulation
process].
PMID- 9551324
TI - [Electrocatalytic oxidation of substrates by immobilized Gluconobacter oxydans
cells in the presence of an electron transport mediator].
PMID- 9551325
TI - [Distance between homologous regions before pairing and probability of crossing
over in them].
PMID- 9551326
TI - [Dynamics of the contractile activity of murine uterus during pregnancy].
PMID- 9551327
TI - [Experimental study of the kinematics of the dolphin tail fin].
PMID- 9551328
TI - [Botulinum toxin A in dermatology].
AB - Based on its unique botulinum toxin is referred to as the most poisonous poison.
Its specific inhibition of the acetyl-cholin-dependent neuromuscular transmission
is used by ophthalmologists and neurologists for the relaxation of spastic or
dystonic muscles, preferably in muscle groups in the head and neck area.
Analogously, it is being used by dermatologists to remove facial wrinkles by
paralyzing mimic muscles which account for mechanically induced wrinkling. Apart
from this purely cosmetic use, botulinum toxin has gained recent attention in
dermatology as a potent treatment modality for circumscribed hyperhidrosis.
PMID- 9551329
TI - [p16(INK4A)/CDKN2--the "melanoma gene"? Status of research and outlook].
AB - The gene of the cyclin-dependent kinase 4 (CDK4)-inhibitor p16INK4A (CDKN2/MTS1)
has been proposed as a candidate for a tumor-suppressor gene located on
chromosome 9p21, a frequently deleted region in a series of human cancers
including malignant melanoma. An increasing and sometimes conflicting body of
data has accumulated regarding the frequency of homozygous deletions and
mutations as well as the importance of p16INK4A in malignant melanoma. The
purpose of this review is therefore to summarize the current knowledge on
p16INK4A and to discuss its biologic significance in the pathogenesis of
melanocytic tumors.
PMID- 9551330
TI - [Axillary hyperhidrosis: successful treatment with botulinum toxin A].
AB - Severe hyperhidrosis may present as a vexing condition for the patient and a
therapeutic challenge for the physician. As botulinum toxin-A (BT-A) can potently
block cholinergic sympathic innervation of sweat glands it was used in an open
trial for controlling severe axillary hyperhidrosis. After visualization of
hyperhidrosis using the iodine-starch-test BT-A (Dysport, 400 Units) was injected
intradermally in one axilla. One week later gravimetric quantification of sweat
secretion revealed a reduction of sweating to 4-9% of initial values. In order to
rule out daily variations as well as other factors interfering with sweat
production BT-A treatment was restricted to only one axilla in each individual
clearly demonstrating extensive anhidrotic efficacy on the treated side only. The
treatment was well tolerated without side-effects and was assessed as 'completely
satisfying' by all patients. BT-A may offer a fast, safe and highly effective
therapeutic option for severe hyperhidrosis.
PMID- 9551331
TI - [Desmoplastic squamous epithelial carcinoma of the skin and lower lip. A
morphologic entity with great risk of metastasis and recurrence].
AB - The desmoplastic type of the squamous cell carcinoma (DSCC) of the skin is an
entity which is readily distinguished by light microscopy. The DSCC has fine
branches surrounded by a desmoplastic stroma and shows in some cases typical
perineural, perivascular and widespread intradermal invasion (maximum 6 cm!).
This type accounts for 8.2% (n = 44) of our collective of 594 squamous cell
carcinomas (SCC) of the skin and vermilion border. Clinically DSCC look like
other malignant epithelial tumors of the skin. All tumors were followed up for at
least 3 years (maximum 10 years). The local recurrence rate was high (24.3%) even
though micrographic surgery was carried out. The rate of local or regional
metastasis was also very high (22.7%). In comparison the recurrence rate and the
rate of metastasis of the remaining common 91.8% SCC's (n = 550) was low: 2.6%
and 3.8%, respectively. The DSCC seems to be identical with the so called
neurotropic SCC, the fine stranded SCC or the SCC with perineural invasion which
have a high rate of local recurrence and metastasis as well, but DSCC is a better
generic histopathologic term for the entire group. The DSCC is best treated with
micrographic surgery and wider safety margins than any other type and should be
followed up very frequently.
PMID- 9551332
TI - [Therapy of hyperhidrosis with tap water iontophoresis. Positive effect on
healing time and lack of recurrence in hand-foot eczema].
AB - Hyperhidrosis is due to an overfunction of eccrine glands (triggered by the
autonomous nervous system) and may be a cofactor for palmoplantar eczema
(dermatitis). Tapwater iontophoresis was used in 54 patients with hyperhidrosis
manuum et pedum. After 10 applications directed by the dermatologist, 89% of
patients noted an improvement in their hyperhidrosis. 20 patients suffering from
palmoplantar eczema (dermatitis) who continued the treatment at home for at least
6 months were compared with a historical sex- and age-matched group of 20 eczema
patients without iontophoresis: The factors evaluated were the time needed for
clearing and the relapse-free interval. Though iontophoresis-treated patients had
a slightly faster clearing, this was statistically not significant (20 vs. 22.3
days; p > 0.05). However, the difference for relapse-free interval between the
two groups was statistically highly significant (24.8 weeks vs. 8.35 weeks; p <
0.0001). Tapwater iontophoresis seems to be effective not only to control
sweating. According to recently published data, galvanization seems to have a
capsaicin-like effect as well. Our hypothesis is therefore, that galvanization
with tapwater iontophoresis interrupts the neurogenic inflammation and prolongs
the relapse-free interval in hyperhidrotic palmoplantar eczema (dermatitis).
PMID- 9551333
TI - [Hereditary angioedema in the German-speaking region].
AB - A multicentre, retrospective study of hereditary deficiency of C1-esterase
inhibitor (C1-INH) function, a deficiency which clinically manifests as
hereditary angioedema (HAE), was performed in six centres in Germany, Austria and
Switzerland. 242 individuals were registered with proven functional or
quantitative deficiency of C1-INH who belonged to kindered with disease
manifestation in 2 to 6 generations. Considering the total population in the
three countries and the number of registered individuals, a frequency of the
deficiency of 0.02 x 10(-4) was calculated. As this epidemiological study
involved only 6 centres, a 10 to 100 times higher frequency of C1-INH deficiency
is estimated to be a more realistic value. Out of the 242 registered individuals
110 were evaluated for type and location of clinical manifestation of the
deficiency, the laboratory data and the therapy outcome. 86 (78.2%) of the
patients belonged to the "common type" and 24 (21.8%) to the "variant type" of
HAE. In 53.9% of the cases first manifestation of the disease was before the age
of 20 years. In only 3.9% of the patient population did the disease begin after
40 years of age. A mean time lag of 5,3 years was observed, between the first
manifestation and correct diagnosis. Initial diagnosis was correct in only 31.8%
of the cases of which dermatologists provided 51.7%. False diagnoses include
urticaria (41.3%), allergy (20%), acute abdomen (18.7%), angina (8%), rheumatoid
disease (5.3%) and intracranial haemorrhage, CNS tumour, epilepsy, migraine
(5.3%). The distribution pattern of HAE resembled that of intolerance reactions
and pseudoallergies. Urticarial lesions were not associated with C1-INH
deficiency. 24% of the patients had at least one episode of laryngeal edema. 40%
of patients were unable to identify a trigger of edema formation. The others
indicated as triggers trauma, hormonal changes, mental stress, insect stings and
in a few cases food and drugs. Menstruation and oral contraceptives aggravated or
made disease manifestations more frequent. In contrast, during pregnancy in many
cases clinical manifestations improved and delivery posed no problems. The
possibility of HAO is very much suggested by the tailure of edema to respond to
classical anti-allergic therapy. Therapy of choice of acute attacks is C1-INH
concentrate. No side reactions, antibody formation or virus transmission have
been observed. For long term prophylaxis danazol, an attenuated androgen, or
tranexamic acid, a protease inhibitor, was chosen. The daily dose of danazol
should be kept as low as possible because of its anabolic, anti-estrogenic, anti
gestagenic, and anti-gonadotropic effects. Indeed, adverse reactions were
observed in 41.7% of patients receiving danazol. Frequencies of adverse reactions
were twice as common in women as in men. Adverse reactions were dose dependent
and reversible except for one woman with irreversible deepening of her voice.
Measuring C1r is a effective way to assess C1-INH function and monitor therapy.
PMID- 9551334
TI - [Dose-dependent pellagroid skin reaction caused by carbamazepine].
AB - A 11-year-old girl suffering from grand mal epilepsy underwent antiepileptic
therapy with carbamazepine (600 mg/daily). Two weeks after increasing the dose
(900 mg/day) she suddenly developed relatively sharply limited, sunburn-like
brown reddish macular lesions with central scaling and partly hyperkeratotic
areas on the hands, feet, face, knees, gluteal and axillar regions. Otherwise no
health disorders were found; in particular no neurological or gastrointestinal
symptoms occurred. After reduction of the doses (450 mg/day) these skin lesions
faded away. With exception of elevated serum levels of carbamazepine,
nicotinamide and vitamin B6, all blood tests were in normal range. Interactions
of carbamazepine with the vitamin B6- nicotinamide metabolism are the reason for
these previously undescribed cutaneous side effects in connection with
carbamazepine therapy. The present case demonstrates a toxic, non-allergic
reaction during carbamazepine treatment with pellagroid skin symptoms.
PMID- 9551335
TI - [Allopurinol as an inducer of acute graft-versus-host-like drug reaction. Case
report with review of the literature].
AB - Although drug eruptions resembling graft-versus-host disease are rare, GvH-like
reactions to the sulfhydryl group of drugs (penicillamine, captopril, gold
sodium), phenobarbital and hepatitis vaccine have been described. Clinical
reports concerning acute GvH-like drug rash are very uncommon and restricted to
acetylsalicylic acid and spironolactone. We report on a patient who developed an
acute GvH-like drug reaction caused by allopurinol. To our knowledge this variant
of cytotoxic drug eruption has not yet been reported in literature.
PMID- 9551336
TI - [Annular erythema in childhood--a new eosinophilic dermatosis].
AB - Annular erythema of infancy is a rare and little-known entity. Since its initial
description by Peterson and Jarratt in 1981 only 4 further cases have been
reported. We present the first case in the German literature. A 4-year-old boy
developed non-itching erythematous papules on the trunk which evolved into
annular and gyrate erythemas within weeks. The condition showed a relapsing
course with disease-free intervals of several months duration. There were no
general complaints. Laboratory investigations including detailed serological
tests for infectious diseases were normal. Histopathology showed a striking
eosinophilic inflammatory infiltrate predominantly in perivascular areas, without
peripheral blood eosinophilia. The clinical differential diagnosis of annular
erythema of infancy includes erythema annulare centrifugum, while microscopically
one must exclude eosinophilic cellulitis (Wells' syndrome). The etiology is
unknown and there is no effective therapy. In our case, as well as in all
previously published cases, the disease resolved spontaneously. Therefore, it may
be considered benign and self-limited.
PMID- 9551337
TI - [Zosteriform lichen aureus].
AB - Lichen aureus is a special localized variant of purpura pigmentosa chronica. A
patient presented with an unusual striate and segmental or zosteriform
distribution of lichen aureus involving the left leg and lower abdominal area.
Histology showed the characteristic dense band-like infiltrate consisting mainly
of small lymphocytes and numerous hemosiderin-containing macrophages. No
underlying infection or medication could be identified as a trigger. The lesions
did not respond well to topical corticosteroid therapy.
PMID- 9551338
TI - [History of the Krefeld Dermatology Clinic].
AB - The dermatology clinic in Krefeld has treated a wide range of patients since its
founding in 1845. Nowadays the spectrum consists of allergology, occupational
dermatology, phototherapy, dermatosurgery, phlebology and proctology as well as
special clinics for andrology, sexually transmitted diseases and patients with
HIV-infection.
PMID- 9551339
TI - [HiVision video technique in international presentations--close to the skin even
in the last row of the auditorium].
PMID- 9551340
TI - [Thoughts of a (relatively) unknown beauty].
PMID- 9551341
TI - [Otto Braun-Falco Alumni Lecture, Heidelberg, 5 April 1997. Meeting report].
PMID- 9551342
TI - [Report on the 1st International "Molecular Andrology" Workshop in
Rauischholzhausen Castle, 5-6 May 1997].
PMID- 9551343
TI - [3rd International Conference on Varicella Zoster Virus (VZV) 9 to 11 March 1997,
Palm Beach, Florida, USA. Meeting report].
PMID- 9551344
TI - [Skin diseases and genetic instability. II. Genetic dermatoses with genetic
instability].
PMID- 9551346
TI - [Antibiotics and atherosclerosis].
PMID- 9551345
TI - [Skin-derived antimicrobial peptides. Interview with Prof. Dr. Jens Schroder,
Kiel University Dermatologic clinic. Interview by D. Petzoldt, J. Krutmann].
PMID- 9551347
TI - [Deep venous thrombosis and severe burns].
AB - Deep venous thrombosis (DVT) is a frequent and potentially serious complication
in severely burned patients. We report the case of a burned patient (40% of total
body surface burned), who had right femoral deep venous thrombosis and severe
pulmonary embolism, although a prophylaxis was conducted with low molecular
weight heparin, graduated compression stockings and rotating bed. This case shows
that DVT early diagnosis and prophylaxis is difficult in severely burned
patients. Systematic screening of DVT by duplex scan is possible only for femoral
veins, which renders duplex scan more suitable for femoral catheter follow up
than for systematic DVT screening. Computed tomography venography seems to be a
valuable tool in the diagnosis of proximal thrombosis. Prophylaxis is best
achieved with the use of preventive low molecular weight heparins, graduated
compression stockings, and early mobilisation when possible. However, the place
of low molecular weight heparins at high doses and external pneumatic calf
compression needs to be evaluated by prospective studies.
PMID- 9551349
TI - [Arterial thrombosis in the course of nephrotic syndrome. Report of three cases].
AB - Vascular thrombosis remains severe complication in patients with nephrotic
syndrome. Both venous and arterial thrombosis are observed. We report three new
cases of arterial thrombosis in patients with nephrotic syndrome. The role of
acquired hemostasis disorders, inducing hypercoagulability, is predominant.
Extramembranous glomerulonephritis remains the most frequent cause of nephrotic
syndrome, complicated by vascular thrombosis. Treatment is based on
anticoagulation and corticosteroid therapy. Search for proteinuria should be part
of the etiology work-up in all patients with vascular thrombosis of undetermined
origin.
PMID- 9551348
TI - [Carotid endarterectomy using eversion. One year radiologic results].
AB - A prospective study was done in 100 patients operated on for a stenosis of the
carotid artery by the eversion endarterectomy method of Van Maele (section
eversion-anastomosis) between January 1994 and August 1995. Ten patients were
operated on bilaterally (thus, 110 procedures). The distribution of the patients
was as follows 81 males and 19 females, mean age 71 years. Clinically, 50
patients were asymptomatic, 44 stage I, 2 stage II and 4 stage III. Arteriography
of these patients showed 42 stenoses greater than or equal to 90%, 56 stenoses
between 70 and 90% and 12 ulcerated plaques (according to the ESCT measurement
standards). Concerning the supra-aortic vessels, 24 lesions of the vertebral
subclavian branches and 21 lesions of the intra-cerebral vessels were observed.
Five endarterectomies out of the 110 (5.4%) could not be performed by this
eversion method because of the immediate poor technical result before
angiography. At the end of the procedure digital angiography was performed for
all the patients who underwent an eversion endarterectomy (105 cases). Six images
of the internal carotid artery presenting stenoses less than 30% were observed at
the level of the implantation site. Two narrow stenoses of the distal part of the
endarterectomy made the interposition of a PTFE graft necessary in 20% of the
cases, a secondary procedure was necessary after the peri-operative angiography 2
implantations of PTFE in the internal carotid artery, 8 additional
endarterectomies of the external carotid artery, 11 infiltrations with
Papaverine. The immediate post-operative results were 1 death after hemiplegia, 1
hemiplegia with sequelae (mortality/morbidity approximately 2%, i.e. 2/103
eversions), 3 regressive hemipareses. Angiographic follow-ups after 1 year were
performed on 100 out of 110 operated carotid arteries. With regard to the
internal carotid artery, 4 patients showed a stenosis less than 30%, 1 patient a
50% stenosis, 1 patient a pre-occlusive stenosis making an operation with the
interposition of a PTFE graft necessary (restenosis rate after one year 2%). All
the patients followed after one year remained asymptomatic. Eversion
endarterectomy is possible for the majority of the atheromatous stenoses of the
carotid artery (5.4% were not possible for technical reasons). We find this
method not appropriate when a shunt must be placed. Immediate results are
comparable to those of classical surgical endarterectomy with or without
patching. The restenosis rate at 1 year in our series is 2%. This technique
provides an excellent anatomic result by peri-operative angiography and can
especially be adapted to stenoses with excess of length of the carotid artery.
PMID- 9551350
TI - [Complications of vascular surgery].
AB - Vascular surgery, which in certain life-threatening situations is the only
possible therapeutic option, has progressed considerably since its beginning in
the 1950s. Because of the constant progression of vascular diseases, this surgery
will present, in the forthcoming years, a major public health problem. Because of
advances in medico-surgical management, evermore elderly and frail patients can
be treated. Perioperative mortality is constantly decreasing, but much progress
remains to be accomplished to prevent, avoid or treat, postoperative
complications. They are common and serious in these typical patients with
cardiovascular diseases (men over 50 years of age, heavy smokers, atheromatous
...). The AA divide these complications into 3 main groups depending on the
surgical procedure: abdominal aortic surgery, carotid surgery and arterial and
venous surgery of the lower limbs. There is much data on abdominal aortic surgery
because these long and complex procedures produce repercussions often involving
many systems. The postoperative complications are treated according to the system
they involve: cardiovascular, the most serious, respiratory, the commonest,
alimentary, neurological, renal, others, as well as combined systems. The AA do
not deal with the specific problems associated with cardiac and cardio-thoracic
surgery. The AA discuss the different epidemiological findings of the large
surgical series published in the 1970s and 1980s. The more recent literature
analyses the relationship between preoperative risk factors (atheroma, COAD,
hypertension ...), peroperative problems (surgical difficulties, emergencies,
massive transfusions, others) and the corresponding postoperative morbidity. Thus
a few general outlines of the physiopathology of these different complications
emerge. In the light of these notions the few proposed methods will be evaluated
in order to improve the preoperative condition of the vascular patient. The AA
also review the relevance of the preoperative investigation in patients for
vascular surgery. All these measures aim at reducing the incidence and severity
of perioperative morbidity.
PMID- 9551351
TI - [Physiopathologic introduction to anesthesia and resuscitation of the vascular
patient].
AB - Coronary artery disease (CAD), arterial hypertension, chronic bronchitis and
diabetes mellitus are the most frequently encountered diseases complicating the
clinical course of the vascular patient. Clinical signs of cardiac or pulmonary
disease are often absent in patients with decreased functional capacity due to
claudication. For instance, clinical evidence of coronary artery disease was
found in 36% of patients scheduled for different vascular surgical procedures,
whereas coronary angiography revealed significant stenoses in as many as 53-68%.
Patients with chronic hypertensive disease, coronary artery disease and increased
impedance to left ventricular ejection due to atherosclerosis frequently develop
impairment of left ventricular (LV) function. Even without clinical or
radiological evidence, approximately 20-35% of vascular patients have a LV
ejection fraction below 50% indicating impaired systolic LV function. The
incidence of diabetes mellitus in vascular surgical patients is around 18%. When
requiring insulin treatment, diabetes is an independent risk factor for
postoperative ischemic events and congestive heart failure. Those with autonomic
neuropathy are often asymptomatic as regards coronary artery disease. Coronary
artery disease is responsible for over 50% of the immediate, medium- and long
term mortality and morbidity. Unstable myocardial ischemia, acute myocardial
infarction which is detected by troponin I and ischemic pulmonary edema are the
most common immediate postoperative cardiac complications. A large number of
recent studies, using long-term ECG recording techniques, have allowed more
accurate estimation of the incidence and time course of perioperative myocardial
ischemia in vascular surgical patients. The highest incidence of ischemia when
compared to daily life activities has been noted during the first two days after
surgery but has been reported to remain elevated even 3-5 days after surgery.
Interestingly, the incidence of intraoperative ischemia is lower than that
observed during daily life. Knowledge of the etiology of perioperative myocardial
infarction is essential if one is to improve cardiac outcome after vascular
surgery. Many studies have addressed this important field in patients undergoing
vascular surgery. They have documented a relationship between perioperative
myocardial ischemia and postoperative myocardial infarction. Although
postoperative myocardial infarctions are in most cases limited to endocardium
(non Q wave infarction) they significantly reduce life expectancy of the vascular
surgical patients. The reduction of cardiac risk following general surgery should
focus on methods by which the incidence of myocardial ischemia, particularly
during the postoperative period, could be reduced. These methods include
intensive intraoperative analgesia or preventive administration of cardiovascular
treatment which limit postoperative stress: alpha-2 agonists or betablocking
agents. There are, at present, no studies which convincingly confirm an overall
decreased mortality if coronary bypass surgery is performed prior to peripheral
vascular surgery. Although it has been demonstrated that the mortality of the
peripheral procedure is reduced to approximately one half, the mortality of a
coronary bypass procedure in vascular surgical patients is five to eight times
that recorded in a coronary artery bypass population without peripheral vascular
disease. It remains to be shown if the use of coronary angioplasty prior to
peripheral vascular surgery can provide a more satisfactory overall outcome.
Several non-invasive techniques have been suggested to improve the identification
of high-risk patients undergoing vascular surgery. These tests include exercise
ECG, ambulatory ECG, dipyridamolethallium scintigraphy and determination of left
ventricular ejection fraction by gated radionuclide imaging. (ABSTRACT TRUNCATED)
PMID- 9551352
TI - [Preoperative evaluation of coronary circulation].
AB - It is not easy to define a plan for the preoperative assessment of the coronary
circulation: some studies carried out in the context of vascular surgery are
contradictory and no method has a sensitivity and specificity of 100%.
Nevertheless, it is essential to select patients with a high risk of
perioperative cardiac complications so that their medical treatment can be
reinforced or anatomical correction envisaged. A first assessment is obtained
from the history, the clinical examination and simple investigations (resting
ECG, chest X-ray). Surgical operations which do not impose a major strain on the
cardiovascular system do not require further investigations. The risk of
postoperative cardiac complications is low in the absence of the nine risk
factors defined by Goldman and/or an ischemic syndrome (residual angina after
mild physical activity, unstable angina, myocardial infarct). The problem arises
in patients with the Goldman risk factors and/or a history of coronary
insufficiency and/or coronary insufficiency risk factors (diabetes, tobacco,
hypercholesterolemia, age > 70 years, arterial hypertension), who require an
operation likely to cause a particularly serious strain on the cardiovascular
system. An exercise ECG, by the Holter method, is helpful, particularly in known
or potential coronary arteriopaths who cannot exercise. Echocardiography under
dobutamine has good sensitivity and good specificity when exercise is impossible.
Thallium-dipyridamole scanning has not been shown to be helpful in vascular
surgery. This method could be refined by a quantitative analysis of the number of
areas and segments involved. Finally, patients showing ischaemic changes on
continuous ECG recording, abnormalities on echocardiography under dobutamine,
abnormalities on thallium-dipyridamole myocardial scanning or on exercise ECG,
should be considered for coronary angiography with a view to a preliminary
anatomical correction.
PMID- 9551353
TI - [Perioperative problems posed by patients suffering from vascular diseases. The
viewpoint of the anesthetist-resuscitator].
AB - Patients undergoing vascular surgery present a major challenge for the medical
and surgery teams because patients admitted for vascular surgery frequently have
other associated disorders. Vital functions must be optimized preoperatively in
this population. Several problems may arise in the preoperative and postoperative
periods. The risk of hypothermia or cardiovascular instability and early
treatment of postoperative complications require careful management. Several
diagnostic and therapeutic tools are available but their routine use has not
always been validated by clinical trials in the pathophysiological setting of
vascular disease. We present several examples of discordance between the
pathophysiological models and results of clinical studies and raise the question
of therapeutic objectives.
PMID- 9551355
TI - [Recurrence of varicosities in the femoral canal following surgery of the
internal saphenous vein].
AB - Perforating veins in the femoral canal, which establish a communication, on the
medial aspect of the thigh, between the deep venous system and: either the trunk
of the long saphenous vein, single or double, or one or several separate trunks,
follow three anatomical patterns which clinical examination, phlebography and,
now, echo-doppler, can identify clearly. When they are incompetent, they increase
the natural progress of the varicose disease, after surgery of the long saphenous
vein. Often, they are associated with a redux at the level of the saphenofemoral
junction and also, sometimes, with an incompetence, primary or recurrent, at the
short sapheno-popliteal junction, or, furthermore, with an incompetence of the
medial gastrocnemial veins and their accompanying perforators, within the
popliteal venous complex. Anastomotic networks between the different superficial
venous territories in the inguino-genital region, the femoral canal and the
supero-medial aspect of the leg, explain the cross-evolution between different
systems. Sclerotherapy is effective when the perforators are not too large and
their reflux not too important. If it fails, it is necessary to operate after
precise localization of the sites of reflux through good imaging. A good picture
is obtained with B mode ultrasound examination and hemodynamic studies with
pulsed doppler and, even more reliably, with color Doppler. Thus, in recurrences
in the femoral region, color Doppler will show up certain perforators which,
despite being dilated, are nevertheless competent and do not need to be dealt
with.
PMID- 9551354
TI - [Postoperative recurrence of varicosities at the level of the popliteal fossa.
Anatomic data guiding the ultrasonographic exploration and surgical sequelae].
AB - The results of surgery of the short saphenous vein are less consistent than those
of the long saphenous vein. The difference has been clarified by anatomo-physio
pathological studies which, as a complement to clinical examination, first used
the different phlebography techniques and now benefit from pulsed colour
echodoppler. They have shown that, in varicose veins considered to be of the
short saphenous system, incompetence at its termination, with its anatomical
variations, does not account for all the findings. Thus, imaging and the findings
at surgery, have revealed a genuine venous complex in the popliteal fossa
situated in four areas: in the sapheno-aponeurotic area with a variable point of
termination of the short saphenous vein and important tributaries along its
convexity; in the area of the medial head of the gastocnemius muscle with a
voluminous trunk formed by the medial gastrocnemial veins which may run towards
the termination of the short saphenous vein or even drain into its concavity; in
the deep plane of the popliteal vein, which is sometimes double; in the short
saphenous network with its very variable vein in the popliteal fossa and the
lateral gastrocnemial veins. In practice, this classification helps to identify
congenital reduplications, abnormal of aberrant veins and to perform planned
surgery aimed at preventing postoperative recurrences. This is so because the
latter are due, albeit less frequently than at the saphenofemoral junction, to a
"new vein" which is in fact simply a missed tributary. Recurrences are mainly
associated with : a duplication of the terminal part of the vein which has been
missed; a short saphenous stump fed by a trunk from the medial gastrocnemial
veins which has a termination into the popliteal vein common with the short
saphenous vein; incompetent large medial gastrocnemial veins draining separately;
an incompetent popliteal fossa perforator. The last two occur not uncommonly
together and it has also been noted that failure to strip the short saphenous
trunk increases the likelihood of postoperative recurrences. Repeat surgery is
indicated in the presence of recurrences when there are important sources of
reflux which are fully identified and precisely located by imaging, which is
essential to prevent recurrent failure.
PMID- 9551356
TI - [An unusual way of detecting Horton's disease: inflammatory abdominal aortitis].
AB - We report an original case of giant cell arteritis, revealed by abdominal aortic
arteritis on CT-scan, which was performed because the patient presented with a
biological inflammatory syndrome. Course was favorable with steroid therapy. CT
scan, one month later, demonstrated a stable appearance of both regular and
concentric thickening of the abdominal aortic wall. Aortic involvement is rare
and occurs late in the course of giant cell arteritis. Usually clinical and
biological manifestations of aortitis associated with giant cell arteritis either
absent or non specific, leading to diagnostic difficulties. Furthermore, aortic
giant cell arteritis is a major cause of morbidity and mortality. Gravity of
aortic impairment is mainly linked to the risk of development of aneurysm and/or
acute dissection. A search for aortic involvement should therefore routinely be
carried out, once a year, in patients with giant cell arteritis, particularly a
complete vascular clinical examination and a chest X-ray. Finally, our case
report suggests that non invasive methods, notably CT-scan, may serve as a
helpful test in diagnosis and follow-up of aortic giant cell arteritis.
PMID- 9551357
TI - [Venous thrombosis of the arm consistent with a tumor of the first rib].
AB - Enchondroma of the first rib is a rare cause of Thoracic Outlet Syndrome (TOS)
manifested by deep venous thrombosis (DVT). Diagnostic difficulties and
therapeutic options are discussed. DVT of the upper limb represent 2%-4% of all
DVT and are divided into primary and secondary. Venous compression represents 8%
of TOS and generally results from a narrowing of the costo-clavicular space. A
post-thrombotic syndrome (PTS) is found in 40%-80% despite anticoagulation and
rest. However following local infusion of thrombolytic agents only 10% of the
subjects develop PTS. Follow-up studies reveal a complete recanalisation of the
vein in 45% of the patients treated with thrombolysis, whereas it occurs in only
4% under anticoagulation alone. This favourable result is obtained at the cost of
an increased risk of hemorrhagic complications (5%). The solitary enchondroma is
a benign cartilaginous tumor preferentially localised in the extremities, hands
and feet. A review of the literature reveals that a total of 40 cases of
enchondromas have been reported so far, among which 18 were localised in the
first rib. The proximity of the neuro-vascular elements and a possible malignant
transformation in 2% of the cases justify the ablation of the tumor. Thrombolysis
is still highly controversial but gives the best long term prognosis in young
patients.
PMID- 9551358
TI - [Is there a specific angiologic reasoning?].
PMID- 9551359
TI - Activated alpha 2-macroglobulin reverses the immunosuppressive activity in human
breast cancer cell-conditioned medium by selectively neutralizing transforming
growth factor-beta in the presence of interleukin-2.
AB - The immunosuppressive activity of tumor cells may be mediated by tumor-derived
cytokines such as transforming growth factor-beta (TGF-beta) and interleukin-10
(IL-10). A human breast cancer cell line derived from malignant ascites (BRC 173)
secreted TGF-beta, but not IL-10, into tissue culture supernatant (TCS). BRC 173
TCS suppressed natural killer (NK) and lymphokine-activated killer (LAK) cell
activity and also blocked the generation of HLA-A*0201-restricted tumor-reactive
cytotoxic T-lymphocyte (CTL) lines in vitro. Human alpha 2-macroglobulin (alpha
2M), a plasma protein and cytokine carrier that binds isoforms in the TGF-beta
family, was tested for its ability to neutralize the immunosuppressive activity
in BRC 173 TCS. alpha 2M was converted to its activated conformation by reaction
with methylamine (alpha 2M-MA) and then incubated with normal human peripheral
blood lymphocytes (PBL) in the presence of IL-2 and BRC 173 TCS. Lysis of NK
targets (K562) and LAK cell targets (DM6 melanoma) by the PBL was examined after
6 days of culture. PBL cultured in IL-2, without TCS or alpha 2M-MA, were lytic
for both target cells. BRC 173 TCS substantially suppressed the lytic activity of
the PBL in the presence of IL-2. When TGF-beta-neutralizing antibody was added to
the PBL culture medium with IL-2 and TCS, a majority of the lytic activity was
restored. alpha 2M-MA (280 nM) neutralized almost all of the immunosuppressive
activity in the TCS, restoring 80-100% of the lytic activity without any apparent
effect on the activity of IL-2. The ability of alpha 2M-MA to counteract
immunosuppressive cytokines in breast cancer TCS was evident in serum-containing
and serum-free medium. These studies demonstrate the activated alpha 2M can
function as a selective cytokine neutralizer to thereby promote the activation of
NK, LAK, and tumor-specific CTL responses.
PMID- 9551360
TI - Induction of melanoma antigen-specific cytotoxic T lymphocytes in vitro by
stimulation with B7-expressing human melanoma cell lines.
AB - Crosslinking of CD28 receptors on resting T lymphocytes by B7 costimulatory
molecules expressed by antigen-presenting cells (APCs) plays a critical role in T
cell activation. Human melanomas express major histocompatibility complex (MHC)
restricted tumor-associated antigens that can be recognized by cytotoxic T
lymphocytes (CTL), yet they remain poorly immunogenic. One mechanism for the
failure of T-cell response is the lack of expression of costimulatory molecules
by human melanoma cells. We have transfected the B7-1 gene into three HLA-A2
expressing human melanoma cell lines, and studied their capacity to stimulate
primary human T cells. B7-expressing melanoma cells were excellent inducers of T
cell proliferation, cytokine production, and cytolytic activity in allogeneic
mixed lymphocyte cultures through a process dependent on the function of the T
cell receptor as well as interactions between B7:CD28, CD2:LFA-3, and LFA-1:ICAM
1. Subset analysis demonstrated that CD4+ T cells or addition of exogenous
interleukin-2 was required for the induction of CD8+ CTL. Untransfected parental
melanoma cells were inert as APCs in these cultures. Rotating stimulation of T
cells with the three B7-expressing cell lines led to the generation of T-cell
lines that were cytolytic for HLA-A2+ melanoma cells and other HLA-A2+ targets
that were pulsed with HLA-A2-restricted MART-1 peptides. These data demonstrate
that expression of B7-1 by human melanoma cells converts them into effective APCs
for the in vitro induction of MHC-restricted, melanoma-specific CTL.
PMID- 9551362
TI - Third Keystone Symposium on Cellular Immunology and the Immunotherapy of Cancer.
Introduction.
PMID- 9551361
TI - Cyclophosphamide enhances the CTL precursor frequency in mice immunized with MUC1
mannan fusion protein (M-FP).
AB - We have previously described the induction of murine CD8+ major
histocompatibility complex class I restricted cytotoxic T cells to the 20 amino
acid repeat region of human Mucin 1 (MUC1) variable number of tandem repeats
region--a mucin greatly increased in expression in breast cancer and proposed as
a target for immunotherapy. Mannan-MUC1 immunization protocol induces a high
cytotoxic T lymphocyte (CTL) frequency, and some protection of mice against a
tumor challenge. The CTL frequency can be substantially increased using
cyclophosphamide (Cy), from 1/84,900 without Cy to 1/8,100 with Cy. Furthermore,
in the presence of Cy, established tumors are rapidly eradicated, which does not
happen in its absence. Cy clearly gives a major increase in the frequency of CTL
precursors (CTLp) to MUC1 and could be of therapeutic value in patients.
PMID- 9551363
TI - Tumor vaccines--a reality at last?
PMID- 9551364
TI - TAP-independent delivery of antigenic peptides to the endoplasmic reticulum:
therapeutic potential and insights into TAP-dependent antigen processing.
AB - We have taken several approaches to investigate the capacity of the secretory
pathway to liberate major histocompatibility complex (MHC) class I-restricted
antigenic peptides from precursor polypeptides. Cells lacking the peptide
transporter (TAP) are unable to deliver peptides from cytosolic antigens to class
I molecules. TAP can be bypassed by targeting peptides directly to the
endoplasmic reticulum (ER) using NH2-terminal signal sequences. This results in
the generation of enormous numbers of MHC class I complexes (50,000
peptides/cell), and recombinant vaccinia viruses expressing such peptides are
highly immunogenic. In contrast to signal sequence-targeted peptides, peptides
are liberated very inefficiently from internal locations in ER-targeted full
length proteins, indicating that the secretory pathway has a limited capacity for
generating antigenic peptides from most polypeptide contexts. We have, however,
identified a location in proteins from which peptides can be liberated in
numerous contexts in the secretory pathway. Placing a number of different
peptides at the COOH termini of a secreted protein and two proteins with type II
membrane anchors resulted in their TAP-independent presentation. These findings
demonstrate that the secretory compartment possesses proteases able to liberate
COOH-terminal antigenic peptides from virtually any context, entirely consistent
with a role for these proteases in the processing of TAP-transported antigenic
peptide precursors.
PMID- 9551365
TI - Hematopoietic progenitor cells of lymphocytes and dendritic cells.
AB - Lymphocytes and dendritic cells (DCs) are critical for immune responses, yet how
they develop from pluripotent hematopoietic stem cells is poorly defined. In
humans and mice, it is possible to isolate phenotypically defined subsets of bone
marrow (BM) cells that represent intermediate progenitors without long-term
repopulating characteristics but with specific lineage differentiation
properties. For instance, murine BM CD34+ CD45RA+ cells are progenitors for B and
T lymphocytes with no in vivo repopulation activity. In human BM, a small subset
(5%) of cells having the phenotype CD34+ Lin- CD10+ CD45RA+ CD38+ Thy-1- c-kit-
represents a new class of hematopoietic progenitor cells that gives rise to
lymphocytes [T, B, and natural killer (NK) cells] and to DCs but does not produce
myeloid or erythroid cells. The identification of such progenitor cells provides
the opportunity to define the differentiation and growth requirements for the
production of lymphocytes and DCs. Genes involved in lineage specification can
also be studied. Altogether, these studies have fundamental implications for
understanding the biology of pivotal lineages of immune cells. This understanding
could be used to treat a variety of immunodeficiencies and to design novel
immunotherapies particularly in the context of hematopoietic cell
transplantation.
PMID- 9551366
TI - Chimpanzee dendritic cells derived in vitro from blood monocytes and pulsed with
antigen elicit specific immune responses in vivo.
AB - Dendritic cells differentiated in vitro from blood and other sources using
cytokines hold particular promise as immunotherapeutic agents in cancer. However,
there are currently no data to show that human in vitro-derived dendritic cells
are immunogenic in vivo. We have developed a primate model of immunotherapy using
dendritic cells differentiated in vitro from blood monocytes by culturing with
human granulocyte/ macrophage colony-stimulating factor and interleukin-4. We
measured the immune response to antigen elicited by in vitro-derived and antigen
treated dendritic cells following a single intravenous inoculation an boost in
chimpanzees. The antigens tested were ovalbumin, a complex foreign protein, and a
peptide derived from the MUC-1 mucin tumor antigen, a relatively uncomplex self
antigen. Four chimpanzees were immunized either with antigen-pulsed dendritic
cells (two animals) or mock-treated dendritic cells (one animal) given
intravenously or both antigens given in adjuvant subcutaneously (one animal).
Each animal received a boost of both antigens in adjuvant 10 days later. All
animals responded with an IgG-mediated humoral response to ovalbumin measured in
the serum at day 24. This was associated with a proliferative cellular response
to ovalbumin in the inguinal lymph node draining the boost injection. In
contrast, antibody responses to mucin peptide were detected in one animal in
response to the boost injection, and no T cell proliferative responses to mucin
peptide were detected in the draining lymph node of any animal. To determine if
the single inoculation of antigen-pulsed dendritic cells elicited any immunity,
we measured the T cell response to ovalbumin in blood mononuclear cells harvested
prior to the boost. Ovalbumin-specific proliferative responses that were antigen
dose dependent were detected in one of two treated animals. In contrast,
ovalbumin given with adjuvant and mock-treated dendritic cells induced no
response. The three animals inoculated with dendritic cells, either antigen or
mock treated, had moderate T cell responses to bovine serum albumin, a
constituent of the medium used to culture cells prior to injection. We conclude
from these data that in vitro-derived dendritic cells can elicit T cell responses
to a complex foreign antigen following a single intravenous injection in a large
primate. It is likely that immunity to a simple self antigen, MUC-1 mucin
peptide, may require multiple inoculations. The results support the use of
dendritic cells differentiated in vitro as vehicles for immunotherapy in humans.
PMID- 9551367
TI - Autologous human dendriphages pulsed with synthetic or natural tumor peptides
elicit tumor-specific CTLs in vitro.
AB - The recent identification of tumor-associated antigens and tumor-associated
antigen-derived peptide epitopes recognized by cytolytic T lymphocytes (CTLs) in
the context of major histocompatibility complex (MHC) class I molecules has
prompted the development of peptide-based vaccines for the treatment of human
cancers, particularly melanoma. The design of such clinical protocols requires an
understanding of the inherent immunogenicity of the peptide(s) and a choice of a
facilitating adjuvant promoting cellular immunity against these peptides. We have
evaluated the abilities of a series of defined synthetic peptide epitopes derived
from MART-1/Melan-A, gp100, tyrosinase, and MAGE-3 or unfractionated peptides
naturally presented by melanoma MHC molecules to elicit HLA-A2-restricted and
melanoma-reactive CTLs from the peripheral blood of normal donors or patients
with metastatic melanoma. Autologous peripheral blood dendritic cells (DCs),
which were easily generated from all donors when cultured in the presence of
recombinant human interleukin-4 and recombinant human granulocyte-macrophage
colony-stimulating factor were pulsed with melanoma peptides and used to "prime"
and/or "boost" CTL cultures in vitro. Our results suggest that antimelanoma CTLs
may be reproducibly generated in short-term in vitro cultures in this manner
using either a subset of the defined synthetic peptides (MART-1/Melan-A27-35,
MART-1/Melan-A32-40, gp100(280-288), tyrosinase368-376, and MAGE-3(271-279)) or
unfractionated peptides (containing both idiotypic and shared melanoma epitopes)
derived from freshly isolated autologous melanoma lesions. These in vitro data
support the use of autologous DCs prepulsed with such peptides as an appropriate
antigen adjuvant delivery system in melanoma peptide-based vaccines.
PMID- 9551368
TI - Polycystic ovarian disease: current insights into an old problem.
AB - Recent studies have led to significant advances in the understanding of the
pathogenesis of polycystic ovary syndrome (PCOS), as well as to improvements in
the treatment of the commonly associated symptoms. New data continue to implicate
etiologic alterations in the hypothalamic-pituitary axis, beginning in the
perimenarcheal period, as well as derangements in insulin and insulin-like growth
factor metabolism. Current observations also support a role for an increase in
adrenal androgen production and an increase in adrenal sensitivity to trophic
hormone stimulation in the development of PCOS. Therapeutic regimens for those
patients unsuccessfully treated with traditional approaches have been further
validated, including the use of flutamide or gonadotropin-releasing hormone
agonist-steroidal "add back" for the treatment of hirsutism. Novel approaches to
the treatment of infertility are likewise discussed.
PMID- 9551369
TI - Progressive virilization of a pubertal phenotypic female: 17 beta-hydroxysteroid
dehydrogenase deficiency.
AB - 17 beta-Hydroxysteroid dehydrogenase deficiency is an uncommon inherited disorder
characterized by genital ambiguity and progressive pubertal virilization. We
describe the clinical and biochemical features in a 13-year-old 46, XY individual
who presented with progressive pubertal virilization.
PMID- 9551370
TI - Teaching pediatric and adolescent gynecology: a pilot study at one institution.
AB - PURPOSE: To assess resident physicians' clinical recognition skills in Pediatric
and Adolescent Gynecology. MATERIALS: 1) A questionnaire to identify demographic
data and self-assessment as to the ability to perform a gynecologic evaluation of
children. 2) Twenty color photographs of normal genitalia and common gynecologic
problems in children. PARTICIPANTS: Sixty-one University of Tennessee resident
physicians; 51 from the Memphis campus--20 obstetrics-gynecology (Ob-Gyn)
residents, 20 pediatrics residents, and 11 family practice residents--and 10 Ob
Gyn residents from the Chattanooga campus. MAIN OUTCOME MEASURES: Ability to
identify normal features of the prepubertal genitalia and to diagnose common
gynecologic disorders. RESULTS: Ob-Gyn residents from the University of
Tennessee, Memphis scored significantly better (58.1% correct) than did the other
three groups; 38.8, 36.9, and 39.1%, respectively (p = .009). Mean performance
score increased with higher pediatric gynecology PGY levels. PGY-4s performed
best, whereas PGY-1s scored the lowest, with mean scores of 57.5% and 35.3%,
respectively (p = .021). Residents who reported having a well-defined program in
pediatric gynecology scored significantly better than those who did not have such
a program, 55.3% and 39.5%, respectively (p < .001). CONCLUSIONS: A well-defined
program in pediatric gynecology enhances resident education and provides them
with better tools to perform gynecologic evaluations of children and adolescents.
PMID- 9551371
TI - Pubertal metrorrhagia.
AB - OBJECTIVE: To determine the clinical characteristics of pubertal metrorrhagia and
its treatment, depending on severity; to evaluate the frequency of etiologies and
the influence of hemostatic abnormalities; and to describe severe pubertal
metrorrhagia. Design, setting and participants. This retrospective study examined
all the files (n = 105) of adolescents presenting for pediatric gynecology
consultation at a children's hospital between January 1979 and June 1993.
RESULTS: The mean age of patients at the first consultation was 13 years.
Metrorrhagia began in the year after the first menstrual period in 85% of cases.
The causes were functional (83 cases), primary hemostatic disorder (14 cases),
hemostatic disorder secondary to renal or hepatic disease (7 cases), or tumor (1
case). The cases were assigned to one of three groups, according to the severity
of anemia; group I, mild anemia, hemoglobin Hb > 11 g%, 64 cases; group II,
moderate anemia, Hb 8-11 g%, 23 cases; and group III, severe anemia, Hb < 8 g%,
18 cases. Of the 14 patients suffering from primary hemostatic disorders, 7 had
been diagnosed before the onset of metrorrhagia; the disorder was revealed by the
metrorrhagia in the remaining 7. Only 1 of these patients was severely anemic
(known factor X deficiency). Four patients suffering from moderate von
Willebrand's disease were discovered after specific tests; they were mildly or
moderately anemic. The severe anemias (group III) all occurred during the first
three periods. This group had functional disorders in 15 of 18 cases. Treatment
continued to be required in 10 of 18 cases followed for more than 3 years.
Treatment was progestin for group I and II patients or an estroprogestin,
followed by a progestin, for group III. Curettage was never required.
CONCLUSIONS: The most common cause of pubertal metrorrhagia is a functional
disorder (80% of cases). Hemostatic disorders likely to cause severe menstrual
hemorrhage were known before the age of menarche; these disorders must be
controlled by hormone treatment begun before or at the time of the first
menstrual period. Severe forms that arise during the initial three menstrual
cycles are functional in most cases. These should be given a course of treatment
lasting several years. There is a high risk of recurrence. Treatment is medical
and hormonal in all cases.
PMID- 9551372
TI - Young adults' knowledge, attitudes, and behavior about abortions in young women.
AB - OBJECTIVE: To document opinions and decision-making strategies of young adults
regarding abortions for young women. METHODS: Eighty-nine male and 215 female
college students completed a questionnaire on abortion during routine visits to
their university health center. RESULTS: Among the salient findings, most
respondents took a pro-abortion stance for girls under 18 in cases of rape (92%
of students), incest (90%), or danger to the girl's health (90%). A much lower
priority was given for abortion in cases of fetal abnormalities (55% of
students), economic hardship (51%), or for girls who were married (55%). Abortion
was considered acceptable regardless of circumstances by 46% of students and
never a good idea by 18%. The outcome of unplanned pregnancies for minors should
be decided by the girl (90% of students), partner (55%), parents (29%), and state
or federal law (8%). Abortions for minors should require parental notification
(45%) or consent (33%). Although only one student felt illegal abortions were
safe, 19% would seek this kind of abortion and 4% of females would try to cause
their own miscarriage if abortions were outlawed in the United States.
CONCLUSIONS: The vast majority of young adults believed that girls under 18
should retain the right to decide the outcome of their pregnancy and should not
be subjected to governmental restrictions. The highest priority for abortion was
given to girls who had been victimized or whose health was at risk. Although
nearly all respondents are aware of the hazards of criminal abortions, many would
resort to such unsafe practices if legal alternatives were no longer available.
PMID- 9551373
TI - Abortion trends in Singapore: a 25-year review.
AB - STUDY OBJECTIVE: Abortion legislation in Singapore has gone through dramatic
changes in the past 25 years. In this paper, we studied the effect of abortion
legislation on abortion trends in Singapore. SETTING AND PARTICIPANTS: The
Ministry of Health, Singapore, collects data on all abortions performed in
Singapore. These data have been analyzed and are presented in this paper.
RESULTS: The liberalization of abortion legislation resulted in a dramatic
increase in the number of abortions performed beginning in 1974. The rate peaked
at 23,512 abortions in 1985, and in fact, 35% of all pregnancies were terminated
in 1985. The introduction of mandatory abortion counseling in 1986 resulted in a
decline in the number of abortions to 16,476 in 1993 with only 24.6% of
pregnancies being terminated. The teenage abortion rate was 0.2 per 1000 female
teenagers under 20 years of age in 1970. With the liberalization of abortions,
the rate reached a peak of 13.7 per 1000 female teenagers in 1985. In 1993, the
teenage abortion rate was 9.5%. The proportion of nulliparous women seeking
abortion has increased phenomenally from 0.5% in 1976 to 40.6% in 1993. Close to
95% of the women seeking abortions in 1993 did so for social reasons, 3.7% for
medical reasons, and 2.0% for failed contraception (Table 3). CONCLUSION:
Mandatory abortion counseling and a change in the government policy which now
encourages Singaporeans to have more children if they can afford it, have
resulted in a decrease in the number of abortions being performed. The problems
of teenage abortions, nulliparous abortions, and repeated abortions need to be
further addressed.
PMID- 9551374
TI - Cavernous lymphangioma presenting as a vaginal discharge in a six-year-old
female: a case report.
AB - STUDY OBJECTIVE: This case report is written to describe a new and unusual
presentation of retroperitoneal cavernous lymphangioma. INTERVENTIONS: A large
cystic abdominal mass was discovered during an examination under anesthesia to
evaluate a vaginal discharge in a 6-year-old girl. The mass was diagnosed by
computed tomography (CT) and removed via laparotomy with argon beam coagulation
of smaller cystic lesions. RESULTS: Six months postoperatively, the patient had a
negligible amount of vaginal discharge. CONCLUSIONS: Cavernous lymphangioma
should be considered as a rare cause of vaginal discharge in young females.
PMID- 9551375
TI - At what age should a virginal adolescent have her first pelvic examination?
PMID- 9551376
TI - What is your diagnosis? Subungual squamous cell carcinoma.
PMID- 9551377
TI - Feline chronic renal failure: calcium homeostasis in 80 cases diagnosed between
1992 and 1995.
AB - Eighty cats with chronic renal failure (CRF) were evaluated in a prospective
study to investigate the prevalence and aetiopathogenesis of renal secondary
hyperparathyroidism (RHPTH), using routine plasma biochemistry and assays of
parathyroid hormone (PTH), blood ionised calcium and 1,25
dihydroxycholecalciferol (1,25[OH]2D3). Hyperparathyroidism was a frequent
sequela of CRF, affecting 84 per cent of cats with CRF, the severity and
prevalence of RHPTH increasing with the degree of renal dysfunction. Compared
with an age-matched control population, plasma concentrations of phosphate and
PTH were significantly higher and 1,25(OH)2D3 concentrations were significantly
lower in the two groups of cats presenting with clinical signs of CRF.
Significant ionised hypocalcaemia was present only in cats with end-stage renal
failure. However, a number of cats were hyperparathyroid in the absence of
abnormalities in the parameters of calcium homeostasis measured in this study.
There was a significant correlation between plasma phosphate and PTH
concentrations.
PMID- 9551378
TI - Technique of lateral canthoplasty for the correction of macropalpebral fissure in
the dog.
AB - The various clinical anomalies associated with macropalpebral fissure in the dog
can be relatively successfully addressed by a reduction in functional eyelid
length and stabilisation of the lateral canthus. In this new technique the basic
principles of the Kuhnt-Szymanowski lateral canthoplasty have been extended to
include an additional shortening of the upper eyelid obtained by a triangular
split thickness resection. Results in a series of 22 patients have demonstrated
significant clinical improvement throughout, with optimum positioning of the
modified palpebral fissures being achieved in five of these patients by the
additional and subsequent resection of redundant forehead skin.
PMID- 9551379
TI - Salivary gland necrosis in dogs: a retrospective study of 19 cases.
AB - Salivary gland necrosis has been described in dogs and is characterised by
enlarged, hard, painful salivary glands, retching and vomiting or regurgitation.
The cause has yet to be determined. A retrospective study of 19 dogs with the
same clinical signs was undertaken for breed, age, gender, history and presenting
signs, diagnostic evaluations and findings, treatment and outcome. An underlying
association was identified in 16 of the 19 dogs. This included Spirocerca lupi
infestation (seven dogs), megaoesophagus (three dogs) and oesophagitis,
oesophageal diverticulum, giardiasis and suspected autoimmune sialadenitis.
Almost all associated lesions involved the oesophagus. Where the associated
disease was successfully treated, the salivary glands returned to normal and all
clinical signs resolved. It is hypothesised that an afferent vagal reflex may be
involved, and that the mechanism of disease is similar to the neural pathogenesis
suggested for hypertrophic osteopathy; in this instance, the efferent targets are
the salivary glands rather than the limbs.
PMID- 9551380
TI - Use of milbemycin oxime in the treatment of dogs with nasal mite (Pneumonyssoides
caninum) infection.
AB - Clinical diagnosis of canine nasal mite (Pneumonyssoides caninum) infection is
difficult due to the mite's location in the caudal nasal cavity and frontal
sinuses. The current study was performed to evaluate the efficacy of milbemycin
oxime in treating dogs with nasal mite infection. A prospective open uncontrolled
study included 20 dogs with case histories indicating possible nasal mite
infection. Inclusion criteria consisted of either nasal mites being demonstrated
(group 1, four dogs), or suspicious clinical signs with no other apparent causes,
combined with eosinophilia (group 2, 16 dogs). Milbemycin oxime 1 mg/kg was given
orally three times at 10-day intervals. In 17 (85 per cent) dogs, clinical signs
resolved completely following milbemycin therapy; within 10 days of the first
treatment in 13 cases (group 1, four dogs; group 2, nine dogs) and within 14 days
in four cases. In the remaining three dogs clinical signs persisted but were
diminished.
PMID- 9551381
TI - Management of disc-associated wobbler syndrome with a partial slot fenestration
and position screw technique.
AB - A previously unpublished surgical technique for the management of disc-associated
wobbler syndrome is described. A series of 17 middle-aged dobermanns (mean age
7.4 years) with this condition were managed by a technique of partial slot
fenestration and position screw fixation of the affected disc space (C6/7 in all
cases). One patient was lost to follow-up and, of the remaining 16 cases, 13
improved following surgery (81 per cent). The three failures were a consequence
of incorrect placement of one of the screws. Careful evaluation of immediate
postoperative radiographs allows this problem to be identified; the screw can
then be correctly repositioned with an immediate return to surgery.
PMID- 9551382
TI - Familial cutaneous vasculopathy and demodicosis in a German shepherd dog.
AB - A two-month-old female German shepherd dog was presented with a history of
ulcerated central pads of all four feet. On physical examination, the footpads
were swollen, soft and ulcerated. On the nasal planum there was a partially
depigmented nodule. Multiple biopsies were taken from the cutaneous lesions and
histological examination revealed focal collagen degeneration and vasculitis. A
diagnosis of familial cutaneous vasculopathy was made. Seven months later the
nasal nodule had disappeared and the footpads were still swollen but non
ulcerated. At this time, the dog manifested a generalised pustular demodicosis.
PMID- 9551383
TI - Prostatic carcinoma in two cats.
AB - Clinical, radiological and pathological features of two cats with prostatic
carcinoma are reported. In both cats the presenting history included signs of
lower urinary tract disease with haematuria and dysuria. Prostatomegaly was
visible radiographically in one cat; an irregular intraprostatic urethra was seen
on retrograde contrast urethrography in both cats. In one of the cats, neoplasia
was suspected on the basis of a transurethral catheter biopsy. Following a poor
response to palliative treatment in both cases, euthanasia was performed with
histological confirmation of the diagnosis.
PMID- 9551385
TI - Cat scratch disease.
PMID- 9551384
TI - Emphysematous cystitis and bladder trigone diverticulum in a dog.
AB - A 14-month-old, male German shepherd dog was evaluated for chronic, recurrent
Escherichia coli urinary tract infection. An initial diagnosis of emphysematous
cystitis was made, which resolved with appropriate antibacterial therapy. The
urinary tract infection, however, did not resolve and on further investigation a
bladder trigone diverticulum was evident, thought to be congenital in origin.
This report describes the apparent ultrasonographic and radiological changes, and
surgical repair of the diverticulum, and reviews the literature with regard to
both congenital bladder trigone diverticulum and emphysematous cystitis. The
former has never been documented in the dog and the latter is an unusual finding
in a non-diabetic dog.
PMID- 9551386
TI - Intestinal permeability in canine SIBO.
PMID- 9551387
TI - Meta-analysis as a clinical tool in nephrology.
PMID- 9551388
TI - Renal microvascular assembly and repair: power and promise of molecular
definition.
AB - Developmental assembly of the renal microcirculation is a precise and coordinated
process now accessible to experimental scrutiny. Although definition of the
cellular and molecular determinants is incomplete, recent findings have reframed
concepts and questions about the origins of vascular cells in the glomerulus and
the molecules that direct cell recruitment, specialization and morphogenesis. New
findings illustrate principles that may be applied to defining critical steps in
microvascular repair following glomerular injury. Developmental assembly of
endothelial, mesangial and epithelial cells into glomerular capillaries requires
that a coordinated, temporally defined series of steps occur in an anatomically
ordered sequence. Recent evidence shows that both vasculogenic and angiogenic
processes participate. Local signals direct cell migration, proliferation,
differentiation, cell-cell recognition, formation of intercellular connections,
and morphogenesis. Growth factor receptor tyrosine kinases on vascular cells are
important mediators of many of these events. Cultured cell systems have suggested
that basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and
vascular endothelial growth factor (VEGF) promote endothelial cell proliferation,
migration or morphogenesis, while genetic deletion experiments have defined an
important role for PDGF beta receptors and platelet-derived growth factor (PDGF)
B in glomerular development. Receptor tyrosine kinases that convey non
proliferative signals also contribute in kidney and other sites. The EphB1
receptor, one of a diverse class of Eph receptors implicated in neural cell
targeting, directs renal endothelial migration, cell-cell recognition and
assembly, and is expressed with its ligand in developing glomeruli. Endothelial
TIE2 receptors bind angiopoietins (1 and 2), the products of adjacent supportive
cells, to signals direct capillary maturation in a sequence that defines
cooperative roles for cells of different lineages. Ultimately, definition of the
cellular steps and molecular sequence that direct microvascular cell assembly
promises to identify therapeutic targets for repair and adaptive remodeling of
injured glomeruli.
PMID- 9551389
TI - Genetic studies into inherited and sporadic hemolytic uremic syndrome.
AB - Hemolytic uremic syndrome (HUS) in adults carries a high morbidity and mortality,
and its cause remains unknown despite many theories. Although familial HUS is
rare, it affords a unique opportunity to elucidate underlying mechanisms that may
have relevance to acquired HUS. We have undertaken a genetic linkage study based
on a candidate gene approach. A common area bounded by the markers D1S212 and
D1S306, a distance of 26 cM located at 1q32 segregated with the disease (Z max
3.94). We demonstrate that the gene for factor H lies within the region.
Subsequent mutation analysis of the factor H gene has revealed two mutations in
patients with HUS. In an individual with the sporadic/relapsing form of the
disease we have found a mutation comprising a deletion, subsequent frame shift
and premature stop codon leading to half normal levels of serum factor H. In one
of the three families there is a point mutation in exon 20 causing an arginine to
glycine change, which is likely to alter structure and hence function of the
factor H protein. Factor H is a major plasma protein that plays a critical
regulatory role in the alternative pathway of complement activation. In light of
these findings and previous reports of HUS in patients with factor H deficiency,
we postulate that abnormalities of factor H may be involved in the etiology of
HUS.
PMID- 9551390
TI - Dysregulation of cytokine expression in tubulointerstitial nephritis associated
with murine malaria.
AB - We examined the circulating levels of the proinflammatory cytokines tumor
necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 alpha, IL-6, granulocyte
macrophage-colony stimulating factor (GM-CSF), and the anti-inflammatory cytokine
IL-10, and their expression in kidneys acutely infected with murine malaria
parasite P. berghei ANKA in C57BL/6J mice. Groups of six mice sacrificed on days
5, 10, 15, and 20, and normal controls were used for cytokine analysis. High
concentrations of TNF-alpha and IL-10 were detected in plasma as shown by ELISA,
and elevated levels of mRNA specific for TNF-alpha and IL-10 in infected kidneys
were demonstrated by reverse transcription-polymerase chain reaction (RT-PCR)
analysis. Kidney sections stained with antibodies against TNF-alpha, IL-1 alpha,
IL-6, GM-CSF and IL-10 for immunohistochemistry showed markedly enhanced staining
for TNF-alpha, and progressively increased staining for IL-1 alpha and IL-6 both
in the tubules and the walls of arteries during the course of infection. The
endothelia of blood vessels and inflammatory cells located around small arteries
showed positive staining for GM-CSF from day 10 onwards. Unlike the staining for
proinflammatory cytokines, the anti-inflammatory cytokine IL-10 showed strongly
positive staining in normal tubules and walls of arteries, especially in the
brush border of proximal tubules, but the staining intensity decreased
dramatically after day 15 post-infection. A strongly positive correlation was
found between the antibody staining for TNF-alpha/IL-1 alpha in tubules, and the
severity of proteinuria. In contrast, there was an inverse correlation between
the staining for IL-10 with TNF-alpha/IL-1 alpha, and the degree of proteinuria.
Plenty of pigmented macrophages showed positive staining both for proinflammatory
and anti-inflammatory cytokines in the tubulointerstitium. Our findings imply
that the up-regulation of proinflammatory cytokines and the dysregulation of anti
inflammatory cytokines are involved in the pathogenesis of tubulointerstitial
nephritis associated with malaria.
PMID- 9551391
TI - Expression of connective tissue growth factor in human renal fibrosis.
AB - Chronic renal failure may occur in etiologically diverse renal diseases and can
be caused by hemodynamic, immunologic and metabolic factors. Initial damage may
evoke irreversible scarring, which involves production of a number of
proinflammatory and fibrogenic cytokines, including platelet-derived growth
factor (PDGF) and transforming growth factor beta (TGF-beta). Connective tissue
growth factor (CTGF), a cytokine of the family of growth regulators comprising
sef10, cyr61, CTGF and nov, has recently been described in association with
scleroderma and other scarring conditions. We investigated CTGF mRNA expression
in 65 human renal biopsy specimens of various renal diseases by in situ
hybridization. In control human kidney CTFG mRNA was mainly expressed in visceral
epithelial cells, parietal epithelial cells, and some interstitial cells.
Connective tissue growth factor was strongly up-regulated in the extracapillary
and severe mesangial proliferative lesions of crescentic glomerulonephritis, IgA
nephropathy, focal and segmental glomerulosclerosis and diabetic nephropathy. An
increase in the number of cells expressing CTGF mRNA was observed at sites of
chronic tubulointerstitial damage, which correlated with the degree of damage. in
the tubulointerstitial area the majority of the CTGF mRNA positive cells
coexpressed alpha-smooth muscle actin, and were negative for macrophage markers.
Our results indicate that CTGF may be a common growth factor involved in renal
fibrosis.
PMID- 9551392
TI - Estrogen induces glomerulosclerosis in analbuminemic rats.
AB - Progression of chronic renal disease is usually more rapid in males, both in
humans and in experimental animals. Estrogen-replacement studies indicate that
this may be related to the beneficial effects of estrogen on the lipoprotein
profile. However, in hyperlipidemic analbuminemic rats (NAR), females are more
prone to develop renal injury than males, and ovariectomy tends to decrease
triglyceride levels and prevent renal disease. Therefore, we studied the effects
of estrogen administration on lipoproteins, and the induction of renal injury in
uninephrectomized female and male NAR. Ovariectomized and orchidectomized
uninephrectomized NAR were treated with estradiol implants for 24 weeks. In an
additional group of ovariectomized rats, the implant was removed after 12 weeks.
Both in ovariectomized and orchidectomized NAR, estradiol caused severe
hypercholesterolemia (9 to 12 mmol/liter) and hypertriglyceridemia (6 to 8
mmol/liter) after six weeks. Subsequently, these rats developed severe
proteinuria, reaching 209 +/- 25 and 95 +/- 43 mg/day, respectively, after 24
weeks. At this point there was severe glomerular sclerosis, with a respective
score of 107 +/- 21 and 61 +/- 33. In terminal blood samples the most pronounced
increase in lipid levels were observed in very low density lipoproteins (VLDL),
intermediate density lipoproteins (IDL) and low density lipoproteins (LDL). In
contrast, ovariectomized NAR and orchidectomized NAR without exogenous estrogen
had much lower lipid levels (cholesterol 5 to 7 mmol/liter and triglycerides 1 to
2 mmol/liter) after six weeks. These rats, or ovariectomized NAR where the
estrogen treatment had been withdrawn, had practically no proteinuria (4 +/- 1,
19 +/- 11, and 13 +/- 4 mg/day, respectively) or renal damage (glomerulosclerosis
score 1 +/- 0.4, 5 +/- 3 and 3 +/- 1, respectively) after 24 weeks. Thus, in
hypertriglyceridemic analbuminemic rats, estrogen-treatment causes further
increases in both triglycerides and cholesterol. Most probably these changes
contribute to the development of renal injury by estrogen in this model. This
effect of estrogen, which has also been observed in the Zucker rat, is unique for
the hypertriglyceridemic state and deserves further study.
PMID- 9551393
TI - Glomerular expression of p27Kip1 in diabetic db/db mouse: role of hyperglycemia.
AB - Early diabetic nephropathy is characterized by glomerular hypertrophy. Previous
studies in vitro have demonstrated that mesangial cells exposed to high glucose
are arrested in the G1-phase of the cell cycle and express increased levels of
the cyclin-dependent kinase inhibitor p27Kip1. The present study was performed to
investigate the renal expression of p27Kip1 in db/db mice, a model of diabetes
mellitus type II. Glomerular p27Kip1 protein, but not mRNA expression, was
strongly enhanced in diabetic db/db mice compared with non-diabetic db/+
littermates. Immunohistochemical studies revealed that this stimulated expression
was mainly restricted to the nuclei of mesangial cells and podocytes, but
glomerular endothelial cells occasionally also stained positively. Quantification
of p27Kip1 positive glomerular cells showed a significant increase of these cells
in db/db mice compared with non-diabetic db/+ animals. Although tubular cells
revealed a positive staining for p27Kip1 protein, there was no difference between
db/+ and db/db mice. Immunoprecipitation experiments revealed that p27Kip1
protein associates with Cdk2 and Cdk4, but not with Cdk6. To test for the
influence of hyperglycemia on cell cycle arrest and p27Kip1 expression, mesangial
cells were isolated from db/+ and db/db mice. There was a similar basal
proliferation when these cells were grown in normal glucose-containing medium
(100 mg/dl). However, raising the glucose concentration to 275 to 450 mg/dl
induced cell cycle arrest in db/+ as well as db/db mesangial cells. Increasing
the medium osmolarity with D-mannitol failed to induce p27Kip1 expression in
mesangial cells. Transfection of cells with p27Kip1 antisense, but not missense,
phosphorothioate oligonucleotides facilitated cell cycle progression equally well
in db/+ and db/db mesangial cells. Furthermore, p27Kip1 expression was comparable
in both cell lines in normal glucose, but increased in high glucose medium. Our
studies demonstrate that p27Kip1 expression is enhanced in diabetic db/db
animals. This induction appears to be due to hyperglycemia. Expression of p27Kip1
may be important in cell cycle arrest and hypertrophy of mesangial cells during
early diabetic nephropathy.
PMID- 9551394
TI - Mesangiolytic glomerulopathy in severe congestive heart failure.
AB - To study the glomerular morphological abnormalities in congestive heart failure
(CHF), we analyzed 27 autopsy cases without other causes of renal disease. Their
mean age was 59 years, and they showed mild prerenal azotemia. They had generally
been treated with digitalis and diuretics, and a few of them with captopril or
nifedipine. The abnormal glomerular findings of enlargement, hyperemia, and
mesangial thickening were observed at high frequencies (61%, 64%, and 57%,
respectively). They characteristically showed mesangiolysis (ML) by the findings
of microaneurysms (81%) and mesangial degeneration (70%) such as loose reticular
matrix and poor matrix area. In addition, glomerular infiltration of mononuclear
leukocytes including macrophages was noted in 70% of the cases. Glomerular
enlargement was not correlated with the grade of hyperemia, but it was correlated
with the grade of ML index of % glomeruli with microaneurysms (F = 7.22, p <
0.004). There was an inverse relationship between the grades of mesangial
thickening and of the ML index (P < 0.005). The number of glomerular leukocytes
was positively correlated with mean glomerular size (P < 0.002) and with the ML
index (P < 0.03). Notably, the glomerular macrophage-positive cases showed a
prominently higher mean ML index than the negative cases (P < 0.005). There was
an inverse correlation between the mean glomerular size and the partial oxygen
pressure in arterial blood (PaO2; P < 0.01), and a positive correlation between
the mean glomerular size and hematocrit (Hct) levels (P < 0.02). The cases
positive for mesangiolytic mesangial degeneration showed significantly lower PaO2
values than the cases negative for this lesion (P < 0.04). In the analysis of the
various causes of CHF, the patients with congenital cardiac anomalies showed mean
levels of the lowest PaO2 (P < 0.02) and the highest Hct (P < 0.03) and
histologically the largest mean glomerular size (P < 0.04). There was no
difference in the ML index and the glomerular leukocyte number among the
subgroups classified by the causes. These results indicate that ML associated
with glomerular enlargement is the major glomerular abnormality characteristic in
patients with severe CHF and suggest that glomerular infiltration of leukocytes,
especially of macrophages, should play an important role in the progression of
both ML and glomerulomegaly. The contributions of persistent hypoxia and up
regulated angiotensin II as the causative factors of these glomerular
abnormalities in congestive heart failure are discussed.
PMID- 9551395
TI - Expression of the cyclin kinase inhibitor, p27kip1, in developing and mature
human kidney.
AB - It has been shown that glomerular visceral epithelial cells (VEC) proliferate
during glomerulogenesis, but differentiated VEC of the fetal kidney do not. It is
also recognized that the proliferative capacity of the VEC in mature kidneys is
very limited, and according to some investigators, may be completely absent. The
basis for this remains unknown. Cell proliferation is controlled by cell cycle
related proteins, of which one class, the cyclin kinase inhibitors (CKI), cause
cell cycle arrest and inhibit proliferation. A role for CKI in kidney development
is not known. Accordingly, we examined the expression of the CKI p27kip1 (p27) in
developing and mature human kidney tissue. Concomitant expression of markers of
cell proliferation, Ki-67-related antigen (Ki-67) and proliferating cell nuclear
antigen (PCNA), also were examined in fetal and mature human kidney tissue by
immunocytochemical techniques. In developing kidney, Ki-67 and PCNA expression
are most pronounced in the nephrogenic zone where expression correlates inversely
with increasing glomerular maturation. In well-differentiated glomeruli, Ki-67
and PCNA expression is present in some parietal epithelial cells but is absent in
the VEC. In contrast, p27 staining exhibits a reverse gradient of expression. p27
is absent in the proliferating tissue exhibiting the earliest stages of
differentiation, whereas expression is widespread in the differentiated
epithelial cells of more mature glomeruli, in which detectable cell proliferation
has ceased. Expression of p27 was not identified in fetal mesangial or glomerular
endothelial cells. In the mature human kidney, the pattern of p27 expression
identified in differentiated fetal glomeruli persists and appears to be
constitutive and specific for glomerular VEC. This pattern of p27 expression in
terminally differentiated VEC may explain their limited proliferative capacity in
response to injury. This is the first demonstration of a potential role for p27
in human renal development.
PMID- 9551396
TI - Accelerated apoptosis characterizes cyclosporine-associated interstitial
fibrosis.
AB - Recently we developed a model of cyclosporine nephropathy in rats characterized
by tubulointerstitial (TI) injury, macrophage infiltration, and progressive
interstitial fibrosis [1, 2]. To determine if the TI injury accompanying
cyclosporine A (CsA) nephropathy was associated with accelerated apoptosis and
ischemia, we treated rats for five weeks with CsA with or without losartan (to
block angiotensin II type 1 receptor), or hydralazine/furosemide (H/F) (protocol
#1). In protocol #2, rats received CsA with or without L-NAME (to block nitric
oxide) or L-arginine (to provide a precursor to nitric oxide formation).
Cyclosporine A treated rats had increased apoptosis of tubular and interstitial
cells documented by PAS, propidium iodide staining, TUNEL assay, and electron
microscopy compared to vehicle treated controls. Macrophages containing apoptotic
cells could be confirmed by TUNEL/ED-1 doublestaining and colocalized in areas of
TI injury. Animals treated with CsA + losartan had a statistically significant
decrease in apoptosis (TUNEL + cells/mm2) when compared to CsA treated animals
(6.0 vs. 19.9, P < or = 0.0001). The decrease in apoptosis in the CsA + H/F group
was not statistically significant. Animals treated with CsA + L-NAME had a
statistically significant increase in apoptosis compared to the CsA treated
animals (12.3 vs. 6.4, P = 0.001). L-arginine administration with CsA resulted in
a decrease in tubulointerstitial apoptosis versus CsA treated animals, however,
this did not reach statistical significance. The addition of L-arginine did
result in a significant reduction in interstitial fibrosis (P < 0.0001).
Regression analysis revealed a significant correlation between apoptosis and
interstitial fibrosis in both protocols. (CsA vs. CsA + losartan r = 0.63, P <
0.0001; CsA vs. CsA + L-NAME r = 0.83, P < 0.0001). We conclude that CsA
nephropathy is associated with a marked increase in apoptosis of tubular and
interstitial cells. Cyclosporine A induced apoptosis is partially mediated by
angiotensin II and nitric oxide inhibition, suggesting a role for renal ischemia
in this process, and CsA induced apoptosis correlates with interstitial fibrosis.
PMID- 9551397
TI - Adhesion molecules and urinary tumor necrosis factor-alpha in idiopathic
membranous glomerulonephritis.
AB - Adhesion molecules are required in several physiological processes, but their
altered function/expression is associated with the pathogenesis of inflammatory
diseases. In the present study on idiopathic membranous glomerulonephritis (MGN)
the expression of adhesion molecules (ICAM-1, VCAM-1, PECAM-1, E-selectin, LFA-1,
Mac-1) was analyzed in different cellular compartments of the kidney using an
indirect immunoperoxidase technique and monoclonal antibodies. Relationships
between the expression of these molecules and the clinical and morphological
activity of the disease and the urinary excretion of tumor necrosis factor alpha
(TNF-alpha) were studied in 20 patients. The results were compared with the
findings in ten normal kidneys and urinary TNF-alpha in 17 healthy subjects. The
expression of adhesion molecules in glomeruli and tubules was unchanged apart
from a diminished expression of VCAM-1 (P = 0.014) in glomerular parietal
epithelial cells and PECAM-1 in glomerular endothelial cells (P < 0.01).
Interstitial peritubular capillaries expressed significantly (P = 0.009) more E
selectin compared with the controls. The interstitial compartment had a highly
increased number of cells expressing ICAM-1 in MGN (32.4 +/- 4.6 cells/high power
field) compared with the controls (9.4 +/- 1.2; P < 0.001). Also, cells
expressing VCAM-1 (10.2 +/- 1.6 vs. 2.8 +/- 1.9; P = 0.005). PECAM-1 (25.9 +/-
5.3 vs. 7.4 +/- 2.1; P = 0.006), and LFA-1 (20.4 +/- 3.6 vs. 8.3 +/- 1.5; P =
0.041) were increased in the interstitium. Proteinuria correlated particularly
with the expression of E-selectin in peritubular capillaries (r = 0.63, P =
0.004). The number of LFA-1 expressing inflammatory cells in the interstitium
correlated with peritubular capillary E-selectin (r = 0.8, P < 0.001) and
interstitial ICAM-1 (r = 0.61, P = 0.009) expression, but histological
alterations did not correlate with the expression of adhesion molecules. Tumor
necrosis factor-alpha excretion was significantly increased in MGN (41 +/- 8
pg/mg creatinine) compared with the controls (13 +/- 2; P = 0.001), and in
particular, it correlated with the interstitial expression of LFA-1 (r = 0.71, P
= 0.002). This study suggests that active MGN leads not only to proteinuria but
also to increased urinary TNF-alpha excretion. These may serve as triggers for
the up-regulation of adhesion molecules in the peritubular capillaries and
interstitial cells thus enhancing the development of the interstitial injury.
PMID- 9551398
TI - Podocytes undergo phenotypic changes and express macrophagic-associated markers
in idiopathic collapsing glomerulopathy.
AB - Collapsing glomerulopathy (CG), a severe form of focal segmental
glomerulosclerosis (FSG), is characterized by tuft retraction and consolidation
in numerous glomeruli and changes in podocyte morphology and topography. Other
glomeruli are less affected. Collapsing glomerulopathy is also characterized by
tubulointerstitial atrophy and fibrosis. The pathophysiology of the glomerular
and tubulointerstitial lesions is poorly understood. We studied renal tissue of
five Black and three White patients, all human immuno-deficiency virus (HIV)
negative, with nephrotic syndrome, renal failure, and histological evidence of
CG. Immunohistochemistry identified normal podocyte phenotypes by podocalyxin,
vimentin and complement receptor 1 (CR1) labeling. Three monoclonal antibodies
were used to further characterize podocyte epitopes: anti-CD68 clone KP1, anti
CD68 clone PG-M1 and anti-M130 clone M18 (Ber-MAC3). Light microscopy of
collapsed glomeruli showed podocyte swelling, vacuolization, multinucleation,
"cobblestone-like" alignment around the glomerular tuft, and pseudo-crescent
formation in Bowman's space. In collapsed glomeruli, podocalyxin, vimentin and
CR1 labeling tagged both normal and vacuolated podocytes still attached to the
GBM, but labeling was not found in cobblestone-like podocytes or in podocytes
detached from the GBM. Conversely, numerous podocytes undergoing detachment and
shedding into Bowman's space expressed macrophagic-associated epitopes. Cells
with macrophagic-associated epitopes clumped in cystically dilated tubules and
were aligned in tubules of smaller caliber. Their appearance was that of viable
cells. There was no morphologic indication that these cells expressing macrophage
associated antigens originated from outside the glomeruli or outside the tubules.
We conclude that in CG podocytes detach from the GBM, lose their normal podocytic
phenotype and acquire macrophage differentiation antigens. The presence of cells
with such antigens in tubular lumens suggests that detached metaplastic podocytes
progress along the tubule or, alternatively, that CG tubular cells also undergo
metaplastic changes into macrophage-like cells.
PMID- 9551399
TI - Subtractive hybridization cloning: an efficient technique to detect overexpressed
mRNAs in diabetic nephropathy.
PMID- 9551400
TI - Anti-GBM glomerulonephritis in mice lacking nitric oxide synthase type 2.
AB - Nitric oxide is synthesized in experimental immune complex glomerulonephritis due
to local induction of type 2 nitric oxide synthase (NOS2). To determine the role
of NOS2, the course of accelerated anti-glomerular basement membrane
glomerulonephritis (anti-GBM) was examined in mice homozygous for disruption of
the NOS2 gene compared with heterozygous littermates. Disease in the wild type
strain (129Sv) was characterized by heavy albuminuria, glomerular neutrophil and
macrophage infiltration and glomerular thrombosis. NOS2, interleukin 1B (IL-1
beta) and tumor necrosis factor alpha (TNF alpha) mRNA were induced by 24 hours.
The NOS2-deficient mutant mice and the heterozygous mice displayed early (24 hr)
and full autologous phase (day 6) injury indistinguishable from the wild-type
mice. The equivalent degree of albuminuria and glomerular inflammation indicates
that NOS2 does not play an essential role in this form of glomerulonephritis in
the mouse.
PMID- 9551401
TI - Accelerated fibrosis and collagen deposition develop in the renal interstitium of
angiotensin type 2 receptor null mutant mice during ureteral obstruction.
AB - We examined the role of angiotensin in renal remodeling that is specifically
channeled through the angiotensin type 2 receptor (AT2 receptor). Previously, we
observed that in mouse embryonic kidneys the AT2 mRNA is predominantly expressed
in the mesenchyme. We therefore chose a model of unilateral ureteral obstruction,
characterized by activation of the renin-angiotensin system, while fibrosis
develops prominently within the renal interstitium. Male wild-type mice (Agtr2
/Y) and mice null mutant for the AT2 gene (Agtr2 -/Y) were subjected to a
complete unilateral ureteral ligation for 5 or 14 days. Obstructed kidneys of
Agtr2 -/Y mice showed more severe interstitial fibrosis than those of Agtr2 +/Y
mice, confirmed by increased collagen by point-counting on Masson trichrome
stained sections, and increased alpha 1(I) collagen mRNA expression by Northern
blot. Immunohistochemistry staining for PCNA (a marker of cell proliferation),
F4/80 (a marker of macrophages), vimentin (a marker of fibroblasts), and alpha
SMA (a marker of myofibroblasts) revealed that, while the two groups were
comparable in the degree of cell proliferation and macrophage infiltration,
fibroblasts/ myofibroblasts were present in a greater abundance in obstructed
kidneys of Agtr2 -/Y mice than in Agtr2 +/Y at both 5 and 14 days after
obstruction. Moreover, cells undergoing apoptosis were significantly less in
Agtr2 -/Y than in Agtr2 +/Y. Thus, the AT2 receptor significantly impacts the
remodeling process within renal interstitium, potentially by regulating the
population of collagen-producing cells.
PMID- 9551402
TI - Na/H exchange and H-K ATPase increase distal tubule acidification in chronic
alkalosis.
AB - We examined whether H(+)-ATPase, H(+)-K(+)-ATPase, and or Na+/H+ exchange
mediates increased distal tubule acidification in animals with chronic metabolic
alkalosis using pharmacological inhibitors of these H+ transporters in in vivo
perfused tubules of anesthetized rats. Chronic metabolic alkalosis was induced
with furosemide followed by minimum electrolyte diet and HCO3 drinking water. The
reduction in net HCO3 reabsorption was greater in distal tubules of alkalotic
compared to control animals perfused with Schering 28080 to inhibit H(+)-K(+)
ATPase (-6.4 +/- 0.9 vs. -1.4 +/- 0.5 pmol/mm.min-1, P < 0.02) and with EIPA to
inhibit Na+/H+ exchange (-11.1 +/- 1.7 vs. -6.6 +/- 0.9 pmol/mm.min-1, P < 0.01)
but was similar in distal tubules of alkalotic and control animals perfused with
bafilomycin to inhibit H(+)-ATPase. The greater reduction of distal tubule net
HCO3 reabsorption in alkalotic compared to control animals induced by EIPA was
eliminated by systemic infusion of the endothelin receptor antagonist bosentan (
4.6 +/- 0.7 vs. -4.4 +/- 0.7 pmol/mm.min-1, P = NS) but the greater reduction
induced by Schering 28080 persisted. Urine endothelin-1 (ET-1) excretion was
higher in animals with maintained alkalosis (164.5 +/- 23.7 vs. 76.6 +/- 10.8
fmol/day, P < 0.03), but decreased following KCl repletion to a value (86.7 +/-
10.0 fmol/day, P < 0.02 vs. respective before-KCl value) that was not different
from that for KCl-repleted control animals (79.9 +/- 8.7 fmol/day, P = NS vs. KCl
repleted alkalotic animals). The data support that augmented distal tubule
acidification in alkalotic animals is due to increased H(+)-K(+)-ATPase and
Na+/H+ exchange activity, the latter stimulated by endogenous endothelins.
PMID- 9551403
TI - Control of calcium oxalate crystal structure and cell adherence by urinary
macromolecules.
AB - Crystal polymorphism is exhibited by calcium oxalates in nephrolithiasis, and we
have proposed that a shift in the preferred crystalline form of calcium oxalate
(CaOx) from monohydrate (COM) to dihydrate (COD) induced by urinary
macromolecules reduces crystal attachment to epithelial cell surfaces, thus
potentially inhibiting a critical step in the genesis of kidney stones. We have
tested the validity of this hypothesis by studying both the binding of
monohydrate and dihydrate crystals to renal tubule cells and the effect of
macromolecular urinary solutes on crystal structure. Renal tubule cells grown in
culture bound 50% more CaOx monohydrate than dihydrate crystals of comparable
size. The effects of macromolecules on the spontaneous nucleation of CaOx were
examined in HEPES-buffered saline solutions containing Ca2+ and C2O4(2-) at
physiologic concentrations and supersaturation. Many naturally occurring
macromolecules known to be inhibitors of crystallization, specifically
osteopontin, nephrocalcin and urinary prothrombin fragment 1, were found to favor
the formation of calcium oxalate dihydrate in this in vitro system, while other
polymers did not affect CaOx crystal structure. Thus, the natural defense against
nephrolithiasis may include impeding crystal attachment by an effect of
macromolecular inhibitors on the preferred CaOx crystal structure that forms in
urine.
PMID- 9551405
TI - Contribution of endothelin receptors in renal microvessels in acute cyclosporine
mediated vasoconstriction in rats.
AB - Cyclosporine A (CsA), a widely used immunosuppressive agent, causes renal
vasoconstriction and systemic hypertension. Recent data suggest that the renal
effect of CsA is possibly mediated by endothelin (ET). We investigated the
effects of CsA on renal microvessels and the efficacy of ETA or ETA/ETB receptor
antagonists in ameliorating CsA effects in the hydronephrotic rat kidney.
Infusion of CsA (30 mg.kg-1) induced a transient increase (20%) in mean arterial
pressure (MAP) and a sustained reduction (85%) in glomerular blood flow (GBF) due
to preferential constriction of the arcuate artery (39%) and the proximal segment
of the interlobular artery (23%). Under basal conditions the ETA receptor
antagonist BQ-123 had marginal effects consisting of reduction in MAP, rise in
GBF and dilation of preglomerular vessels. The non-selective ETA/ETB receptor
antagonist PD 145065 also reduced MAP, but tended to decrease GBF and constrict
large preglomerular vessels. The difference in effects of the two antagonists
indicated that under basal conditions ETB blockade constricts large preglomerular
vessels and reduces GBF. After BQ-123 or PD 145065, the constriction of large
preglomerular vessels and reduction in GBF induced by CsA was attenuated by about
50%, but the rise in MAP was not influenced. Our data indicate that a sizable
part of renal vasoconstriction due to CsA is mediated via ET production in large
preglomerular arteries and can be avoided by the blockade of ETA receptors.
Additional blockade of ETB receptors does not attenuate the CsA effects further,
possibly because ETB receptors mediate both vasoconstriction and dilation.
PMID- 9551404
TI - The Na(+)-K(+)-ATPase beta 1 subunit is associated with the HK alpha 2 protein in
the rat kidney.
AB - The Na-K-ATPase beta 1 subunit acts as the beta subunit for the HK alpha 2
protein in the rat kidney. The colonic H(+)-K(+)-ATPase is a member of the P-type
ATPases, and has been shown to contribute to potassium transport by the mammalian
kidney and colon. The P-type ATPases often consist of an alpha subunit that
contains the catalytic site and a beta subunit that participates in regulation of
enzyme activity and targeting of the enzyme to the plasma membrane. The cDNA of
the alpha subunit (HK alpha 2) has been cloned and the HK alpha 2 protein has
been isolated from the rat kidney and colon. However, a unique beta subunit for
the colonic H(+)-K(+)-ATPase has not been described. To determine if one of the
known beta subunits present in the kidney might act as the beta subunit for the
colonic H(+)-K(+)-ATPase, microsomes enriched in the colonic H(+)-K(+)-ATPase
were isolated using an HK alpha 2-specific antibody (AS 31.7) and the Minimac
magnetic separation system. Immunoblots of rat kidney microsomal protein isolated
with antibody AS 31.7 were probed with antibodies directed against the gastric HK
beta subunit, Na(+)-K(+)-ATPase alpha 1, and Na(+)-K(+)-ATPase beta 1 subunits. A
band of the appropriate size was detected with Na(+)-K(+)-ATPase beta 1-specific
antibodies, but not those directed against HK beta 1. These data suggest that
Na(+)-K(+)-ATPase beta 1 could be the beta subunit for the colonic H(+)-K(+)
ATPase in the kidney.
PMID- 9551406
TI - Basic fibroblast growth factor is a morphogenic modulator in kidney vessel
development.
AB - During kidney organogenesis the development of renal vessels must be synchronized
with the maturation of nephrons and the collecting duct system. Several reports
showed that hormones and mitogenic peptides as basic fibroblast growth factor
(bFGF) or vascular endothelial growth factor (VEGF) are involved in this
regulatory process. It is a known fact that bFGF receptors are expressed by
differentiating tubular epithelium and mesenchyme, but little information is
available about the function of bFGF in kidney organogenesis. The role of bFGF
during kidney development was investigated using an organotypic culture system
and immunohistological techniques. Renal cortex explants were prepared from the
kidneys of neonatal rabbits with a microsurgical method, retaining the natural
tissue composition. The explants were cultured serum free under continuous medium
perfusion. Our results indicate a new and unexpected role of bFGF during the
differentiation process. When bFGF alone was applied, vessels could no longer be
detected. The inhibitory influence of bFGF could be overcome by addition of VEGF
or hormones such as retinoic acid and aldosterone/vitamin D3. The combination of
these factors with bFGF resulted in the expression of small vessel-like
structures. We conclude that bFGF has a morphogenic rather than a mitogenic
function during kidney vessel development.
PMID- 9551407
TI - Autocrine/paracrine role of adrenomedullin in cultured endothelial and mesangial
cells.
AB - Adrenomedullin (AM), a potent vasorelaxant and natriuretic peptide isolated from
human pheochromocytoma, is present in the kidney and secreted from endothelial
cells (EC) and vascular smooth muscle cells (VSMC), but the functional role of AM
is still unclear. To clarify the significance of AM as a local regulator, we
investigated its secretion and action in cultured cells, and examined the effects
of neutralization using a specific monoclonal antibody against AM. The prepared
antibody directed against the ring structure showed a high affinity for human and
rat AM. Using radioimmunoassay with this antibody, we found significant secretion
from cultured rat mesangial cells (MC) of a 6-kDa mature form of AM as seen from
EC and VSMC. The addition of AM into cultured cells dose-dependently increased
cAMP production and potently inhibited PDGF-stimulated thymidine incorporation.
Pretreatment with the monoclonal antibody completely abolished cAMP increase
induced by exogenous AM. Moreover, antibody neutralization of endogenously
secreted AM in cultured EC, but not in MC or VSMC, markedly (by approximately
70%) reduced basal cAMP production and significantly (1.7-fold) enhanced DNA
synthesis. These results indicate that AM, acting as an autocrine/paracrine
regulator, exerts an antiproliferative action on EC and MC, and suggest its role
as a local modulator of endothelial and mesangial function.
PMID- 9551408
TI - Angiotensin converting enzyme inhibitor-induced renal dysfunction in
atherosclerotic renovascular disease.
AB - Ischemic nephropathy due to bilateral renovascular disease (RVD) is increasingly
recognized as cause of end-stage renal failure in the elderly, but a reliable non
invasive method of detection is nor available. Angiotensin converting enzyme
inhibition (ACEi) may impair renal function in such patients, but a prospective
study of its diagnostic validity has not been undertaken. We studied the effects
of controlled exposure to ACEi on plasma creatinine in 108 patients at risk for
severe bilateral atherosclerotic RVD, and compared the findings with subsequent
angiography. ACEi was given for two weeks, or, to avoid acute renal failure, for
four days if plasma creatinine had increased by 20% or more. If after two weeks
of ACEi plasma creatinine had not increased by > or = 20%, while blood pressure
was still elevated, plasma creatinine was remeasured after blood pressure control
by addition of diuretics. The severity of RVD was scored by the stenosis grade of
the best perfused kidney. Fifty-two patients had severe bilateral RVD, defined as
> or = 50% stenosis to both kidneys (N = 23) or a solitary functioning kidney (N
= 29). Of the others, 21 had less severe bilateral RVD, 20 unilateral RVD, and 15
no apparent RVD. Basal plasma creatinine was higher in severe bilateral RVD
(median 170 mumol/liter, range 85 to 654 mumol/liter) than in the others (122
mumol/liter, 62 to 675 mumol/liter; P < 0.01), but not discriminative due to a
large variability. The increase during ACEi was correlated with the degree of RVD
(r = 0.53, P < 0.001). In 69 patients ACEi caused at least a 20% increase in
plasma creatinine, in 26 cases by four days, in 31 after two weeks, and in 12
only after blood pressure control by diuretics. Among these were all 52 patients
with severe bilateral RVD, 15 of the 41 patients with lesser forms of RVD, and
two with normal renal arteries. Thus, in this selected population the criterion
of > or = 20% rise in plasma creatinine upon ACEi was 100% sensitive to detect
severe bilateral RVD, while its specificity was 70%. No case of acute renal
failure was encountered, and plasma creatinine always recovered after stopping
ACEi. In conclusion, controlled exposure to ACEi in these patients is safe, and
ACEi-induced increase in plasma creatinine is a very sensitive detector of severe
bilateral RVD in a high risk population.
PMID- 9551409
TI - Increased VLDL in nephrotic patients results from a decreased catabolism while
increased LDL results from increased synthesis.
AB - Increased very low density lipoprotein (VLDL) in nephrotic patients results from
a decreased catabolism while increased low density lipoprotein (LDL) results from
increased synthesis. Hyperlipidemia is a hallmark of nephrotic syndrome that has
been associated with increased risk for ischemic heart disease as well as a loss
of renal function in these patients. The hyperlipidemia usually is characterized
by increased cholesterol levels, although hypertriglyceridemia may be present as
well. The factors that determine the phenotype of nephrotic dyslipidemia are not
understood, nor has the primary stimulus for nephrotic hyperlipidemia been
identified. One hypothesis is that nephrotic hyperlipidemia is the result of a
coordinate increase in synthesis of proteins by the liver. To address these
issues we simultaneously measured the in vivo rate of VLDL apolipoprotein B100
(apo B100) secretion, LDL apo B100 synthesis and albumin synthesis in patients
with a nephrotic syndrome (N = 8) and compared them with a control group (N = 7)
using a primed/continuous infusion of the stable isotope L-[1-13C] valine for six
hours. Kinetic data were analyzed by multicompartmental analysis. Patients
studied had combined hyperlipidemia as reflected by an significant increase in
both VLDL and LDL apo B100 pool sizes. In contrast, the albumin pool size was
significantly decreased. VLDL apo B100 levels were primarily increased as a
consequence of a decrease in fractional catabolic rate (FCR) rather than from an
increase in the absolute synthesis rate (ASR). Both VLDL apo B100 and
triglycerides were inversely related to the fractional catabolism (FCR) of VLDL
apo B100 (r2 = 0.708; P = 0.0088) while neither had any relationship to the ASR
of VLDL apo B100. In contrast to VLDL, increased LDL apo B100 was not a
consequence of decreased catabolism. The LDL apo B100 ASR was significantly
increased (P = 0.001) in the nephrotic patients compared to controls. Low density
lipoprotein apo B100 ASR was greater than that of VLDL apo B100 in some patients,
suggesting that LDL in these patients was not only derived from VLDL
delipidation, but also by an alternative secretory pathway. There was no clear
relationship between the ASR of VLDL apo B100 and the ASR of albumin within the
current study population. Our data indicate that increased VLDL in nephrotic
patients results from a decreased catabolism, while increased LDL results from
increased synthesis.
PMID- 9551410
TI - Angiotensin converting enzyme gene polymorphism and ACE inhibition in diabetic
nephropathy.
AB - The antiproteinuric effect of angiotensin converting enzyme (ACE) inhibition in
insulin-dependent diabetes mellitus (IDDM) patients with diabetic nephropathy
varies considerably. Therefore, we tested the potential role of an insertion
(I)/deletion (D) polymorphism of the ACE gene on this early antiproteinuric
responsiveness in an observational follow-up study. Sixty (II, N = 13; ID, N = 26
and DD, N = 21) young hypertensive IDDM patients suffering from diabetic
nephropathy were investigated during three months before and for the initial six
month period during ACE inhibition [captopril 44 (SD 22) mg/24 hr, no differences
in drug dose between groups]. Blood pressure (MABP) and albuminuria (ELISA) were
measured three (1 to 6) times before and three (1 to 13) times during ACE
inhibition. At baseline the groups (II/ID/DD) had comparable (1) mean arterial
blood pressure (MABP mm Hg) of 113 +/- 10/108 +/- 9/114 +/- 8, (2) albuminuria
(geometric mean with 95% CI) 1394 (747 to 2608)/1176 (844 to 1797) and 1261 (827
to 2017) mg/24 hr, and (3) serum creatinine (geometric mean with 95% CI), 80 (68
to 93)/85 (76 to 97)/103 (85 to 119) mumol/liter, respectively. Angiotensin
converting enzyme inhibition induced a significant reduction in MABP, albuminuria
and kidney function in all three groups (II/ID/DD; P < 0.05): (1) MABP (mean +/-
SD) 12 +/- 7/5 +/- 7/8 +/- 9 mm Hg (ANOVA, P = 0.02); (2) albuminuria [mean (95%
CI)] 61 (34 to 77)/22 (3 to 37)/31 (13 to 46) %, (ANOVA, P < 0.01); and (3)
increasing serum creatinine [mean (95% CI)] 8 (4 to 12)/9 (3 to 16)/8 (0 to 16) %
(ANOVA, NS), respectively. Adjusting for differences in reduction in MABP did not
change the association between decrease in albuminuria and ACE/ID genotypes (P <
0.01). A multiple linear regression analysis revealed that the ACE/ID
polymorphism, albuminuria and MABP at baseline independently influenced the
decline in albuminuria after initiation of ACE inhibition (R2 = 0.21, P < 0.01).
A significant association between changes in MABP and albuminuria was
demonstrated (R2 = 0.16, P < 0.01). Our data show that hypertensive albuminuric
IDDM patients with the II genotype are particularly susceptible to commonly
advocated renoprotective treatment.
PMID- 9551411
TI - Involvement of interleukin-8 in dialysis-related arthritis.
AB - To elucidate the role of interleukin (IL)-8, a chemotactic factor for
neutrophils, in dialysis-related arthritis (DRA) of patients on long-term
hemodialysis, the concentration of IL-8 was measured in the synovial fluids of
DRA patients with acute arthralgia and joint swelling, and was compared with
those in patients with rheumatoid arthritis (RA) and patients with osteoarthritis
(OA). We noted a marked elevation of IL-8 in the joint fluids of patients with
DRA and RA as compared with OA. Furthermore, to determine the role of IL-8 in
synovitis, we examined the in vivo effect of intra-articular injection of human
recombinant IL-8 on leukocyte infiltration into the joint space of rabbits. A
single injection of IL-8 to the joints of rabbits induced rapid infiltration of
neutrophils into the joint space and synovial tissues, which reached a maximum in
four hours. The oral administration of indometacin farnesil (a prodrug that is
converted to indomethacin after intestinal absorption) before the injection of IL
8 alleviated the infiltration of neutrophils. When human synovial cells were
incubated with tumor necrosis factor (TNF)-alpha, the expression of IL-8 mRNA and
IL-8 production in the cultured synovial cells were increased. The TNF-alpha
stimulated expression of IL-8 mRNA and IL-8 production in the cultured synovial
cells were markedly inhibited by dexamethasone. In conclusion, IL-8 levels were
markedly elevated in the joint fluids of patients with DRA. Interleukin-8
released from synovial cells may be an important factor to induce acute
inflammation in DRA. Dexamethasone and indomethacin may be effective for DRA by
inhibiting the production and chemotactic actions of IL-8, respectively.
PMID- 9551412
TI - Icodextrin with nitroprusside increases ultrafiltration and peritoneal transport
during long CAPD dwells.
AB - Addition of the nitric oxide (NO) donor nitroprusside to 1.36% glucose dialysate
enlarges the effective peritoneal surface area during four-hour dwells. The
theoretical positive effect on ultrafiltration is, however, counteracted by an
increase in glucose absorption. The absorption of the glucose polymer icodextrin
is much lower in comparison with glucose-based dialysis solutions, due to its
high molecular weight. In the present study 7.5% icodextrin dialysis solution
with and without the addition of 4.5 mg/liter nitroprusside was studied during
eight-hour CAPD dwells. Two Standard Peritoneal permeability Analyses, adapted
for eight-hour dwells, were performed in 10 stable CAPD patients. Nitrate and
cGMP were measured as parameters of NO synthesis. The transcapillary
ultrafiltration increased in a linear way with icodextrin (ICO) and was even
higher after the addition of nitroprusside (NP): 666 (ICO) versus 834 (NP) ml/8
hr, P = 0.03. The effective lymphatic absorption rate was not different. The
resulting net ultrafiltration increased with nitroprusside: 344 (ICO) versus 540
(NP) ml/8 hr, P < 0.01. The mass transfer area coefficient of urea increased 15%
and that of creatinine 26% with nitroprusside, consistent with the expected
enlargement of the vascular peritoneal surface area. The increase in protein
clearances was more pronounced the larger the protein: beta 2-microglobulin 19%,
albumin 47%, IgG 63% and alpha 2-macroglobulin 95%. Dialysate/plasma (D/P) ratios
of nitrate were not higher than the expected values on the basis of its molecular
weight (P < 0.001). They increased 19% with nitroprusside. Also, the D/P ratio
cyclic guanosine monophosphate (cGMP) after four hours increased with
nitroprusside (0.39, range 0.13 to 0.55 ICO, and 0.82, range 0.36 to 1.39 NP, P =
0.01). With nitroprusside the D/P ratio cGMP was higher than expected after four
and eight hours (P < 0.001). This points to local generation of NO after addition
of nitroprusside. The nitroprusside induced increase in the mass transfer area
coefficients (MTAC) of creatinine and in the ultrafiltration caused an increase
in the creatinine clearance from 4.2 ml/min to 5.0 ml/min during the eight-hour
dwell. This means that nitroprusside adds 3 liters/week to the peritoneal
clearance of creatinine. The adequacy of peritoneal dialysis can therefore be
improved by the addition of nitroprusside to 7.5% icodextrin, used for the long
exchange.
PMID- 9551413
TI - Universal precautions prevent hepatitis C virus transmission: a 54 month follow
up of the Belgian Multicenter Study. The Universitaires Cliniques St-Luc (UCL)
Collaborative Group.
AB - The isolation of anti-hepatitis C virus (HCV) in hemodialyzed (HD) patients has
been repeatedly advocated to prevent nosocomial HCV transmission. We evaluated
the incidence of seroconversion for HCV in Belgian HD patients, and demonstrate
the complete prevention of HCV transmission by adherence to the universal
precautions advocated by the Centers for Disease Control (Atlanta, GA, USA). All
(N = 963) HD patients from 15 units, none of which isolates anti-HCV positive
patients, were tested by a second or third generation enzyme-linked immunosorbent
assay (with confirmation by a second- or third-generation recombinant immunoblot
assay or the polymerase chain reaction) every 18 months from May 1991 to November
1995. Follow-up was available in 488 patients (drop-outs resulting from death or
transplantation mainly). The yearly incidence of seroconversion for HCV over the
initial 18 months was 1.41%, with evidence suggestive of nosocomial HCV
transmission. Universal precautions were therefore reinforced. The incidence of
seroconversion subsequently fell to 0.56% and 0%, respectively (P = 0.014),
despite the facts that the average transfusion load and the proportion of
patients with dialyzer reuse or with monitors disinfected after each session did
not change significantly. We conclude that the strict enforcement of universal
precautions fully prevents HCV transmission to HD patients. The isolation of anti
HCV positive patients is not warranted.
PMID- 9551414
TI - Anaphylactoid reactions during hemodialysis in sheep are ACE inhibitor dose
dependent and mediated by bradykinin.
AB - Anaphylactoid reactions (AR) have been attributed to the generation of bradykinin
(BK) when AN69 membranes are used together with angiotensin converting enzyme
(ACE) inhibitors during hemodialysis. However, conclusive evidence for the
involvement of the BK as the mediator of these AR is still lacking. This study
examined the degree of contact activation in an animal model caused by three PAN
membranes--AN69, PAN DX, and SPAN- and the effects of different doses of the ACE
inhibitor enalapril (ENA) and the BK B2-receptor antagonist icatibant on AR
during hemodialysis. Six sheep were dialyzed for one hour with or without ENA pre
treatment using the different membranes in random order. Severe AR were observed
only during hemodialysis with AN69 dialyzers together with ENA pre-treatment; the
severity of AR increased with the ENA dose. Mild hypotension was noted during
hemodialysis with AN69 without ACE inhibition and with PAN DX and 20 mg ENA.
Compared to pre-dialysis values, maximum generation of BK after blood passage
through the dialyzer was found at five minutes: 73-fold (AN69 without ENA), 161
fold (AN69 with 10 mg ENA), 97-fold (AN69 with 20 mg ENA), 108-fold (AN69 with 30
mg ENA), 154-fold (AN69 with 30 mg ENA and 0.1 mg/kg icatibant), 18-fold (PAN DX
without ENA), and 42-fold (PAN DX with 20 mg ENA). Elevated BK levels in arterial
blood were detected during hemodialysis with AN69 membranes even without ACE
inhibition (2.5-fold); pre-treatment with 20 mg ENA further increased arterial BK
concentrations (4-fold). Furthermore, a marked decline of prekallikrein and high
molecular weight kininogen concentrations was noted for both AN69 and PAN DX
membranes. Anaphylactoid reactions during hemodialysis were completely prevented
by icatibant even after pre-treatment with ENA and in the presence of high BK
concentrations. Concentrations of prekallikrein, high molecular weight kininogen,
and BK remained unchanged and no AR were observed during hemodialysis with SPAN
and pre-treatment with 20 mg ENA. Our findings confirm that AR during
hemodialysis with the negatively charged AN69 membrane are mediated by BK, since
they can be prevented by the BK B2-receptor antagonist icatibant.
PMID- 9551415
TI - Identification of operational clues to dry weight prescription in hemodialysis
using bioimpedance vector analysis. The Italian Hemodialysis-Bioelectrical
Impedance Analysis (HD-BIA) Study Group.
AB - In patients undergoing hemodialysis (HD) cyclic body fluid changes are estimated
by body weight variations, which may be misleading. Conventional bioelectrical
impedance analysis (BIA) produces biased estimates of fluids in HD due to the
assumption of constant tissue hydration. We used an assumption-free assessment of
hydration based on direct measurements of the impedance vector. The impedance
vector (standard BIA at 50 kHz frequency) was measured in 1367 HD patients, ages
16 to 89 years with BMI 17 to 31 kg/m2, 1116 asymptomatic (680 M and 436 F), and
251 with recurrent HD hypotension (118 M and 133 F) before and after two HD
sessions (thrice weekly bicarbonate dialysis, 210 to 240 min) removing 2.7 kg
fluid. The vector distribution of HD patients was compared to 726 healthy
subjects with the same age and BMI range. Individual vector measurements
(resistance and reactance components) were plotted on the gender specific 50th,
75th and 95th percentiles of the vector distribution in the healthy population
(reference tolerance ellipses) as a resistance-reactance graph (RXc graph). The
wet-dry weight cycling of HD patients was represented on the resistance-reactance
plane with a definite, cyclical, backward-forward displacement of the impedance
vector. The vectors of patients with HD hypotension were less steep and more
often shifted to the right, out of the reference 75% tolerance ellipse, than
asymptomatic patients. A wet-dry weight prescription, based on BIA indications,
would bring the vectors of patients back into the 75% reference ellipse, where
tissue electrical conductivity is restored. Whether HD patients with vector
cycling within the normal third quartile ellipse have better outcome awaits
confirmation by longitudinal evaluation.
PMID- 9551416
TI - Rapid activation of the complement system by cuprophane depends on complement
component C4.
AB - Hemodialysis with cuprophane dialyzer membranes promotes rapid activation of the
complement system, which is thought to be mediated by the alternative pathway.
Complete hereditary deficiency of complement C4, a classical pathway component,
in two hemodialysis patients provided the opportunity to investigate a possible
role of the classical pathway. In two hemodialysis patients with both C4
isotypes, C4A and C4B, and in one patient with C4B deficiency complement
activation occurred immediately after the onset of hemodialysis, with peak levels
of C3a and terminal complement complex (TCC) after ten to fifteen minutes. In
patients with complete C4 deficiency, C3a and TCC remained unchanged for fifteen
minutes and increased thereafter, reaching the highest level after thirty
minutes. The leukocyte nadir was also delayed from fifteen to thirty minutes. In
vitro incubation of normal, C4A- or C4B-deficient serum with cuprophane caused
complement activation after fifteen minutes. In contrast, no activation was
observed in sera of four C4-deficient patients. The addition of normal serum or
purified human C4 restored the capacity for rapid complement activation. In one
patient with severe immunoglobulin deficiency, C3a and TCC levels increased only
moderately after 25 minutes of cuprophane dialysis. This patient's serum also
exhibited delayed complement activation in vitro, which was normalized after
pretreatment of cuprophane with immunoglobulins. Preincubation of normal serum
with MgEGTA, a blocker of the classical pathway, inhibited rapid complement
activation through cuprophane. As basal levels of C4a are markedly increased in
hemodialysis patients (3450 +/- 850 ng/ml) compared to healthy controls (224 +/-
81 ng/ml), no further elevation of C4a was detectable during cuprophane
hemodialysis. Incubation of normal serum with cuprophane, however, caused a
slight increase in C4a after five minutes. These results indicate that the
initial deposition of complement C3b on the cuprophane membrane, necessary for
activation of the amplification loop of the alternative pathway, is mediated by
the classical pathway C3-convertase C4b2a. We propose an extended concept of
complement activation through cuprophane, which is based on four steps: (a)
binding of anti-polysaccharide antibodies, (b) classical pathway activation, (c)
alternative pathway activation and (d) terminal pathway activation.
PMID- 9551417
TI - Effect of on-line conductivity plasma ultrafiltrate kinetic modeling on
cardiovascular stability of hemodialysis patients.
AB - The aim of this multicenter, prospective, randomized cross-over study was to
clarify whether on-line conductivity ultrafiltrate kinetic modeling (treatment
B), as a substitute for sodium kinetic modeling, is capable of reducing
intradialytic cardiovascular instability in comparison with standard treatment
(treatment A), by reducing the sodium balance variability. Both treatments were
performed by means of a modified hemodiafiltration technique. Treatment A was
performed using fixed dialysate conductivity; treatment B made use of the
dialysate conductivity derived from a conductivity kinetic model, in order to
obtain an end-dialysis ultrafiltrate conductivity at each dialysis session that
was equal to the mean value determined in the same patient during the four-week
run-in period. Thus, during treatment B, the expected end-dialysis ultrafiltrate
conductivity value of each patient should have been constant. The study was
carried out according to a multicenter cross-over design of 16 weeks with two
treatments (A or B), two sequences (1 = ABB and 2 = BAA), a run-in period of four
weeks (period 1, treatment A), and three consecutive experimental periods of four
weeks each. Analysis of variance for a cross-over design was used for the
statistical analysis. Forty-nine hemodialysis patients prone to intradialytic
hypotension (> 25% of sessions) were enrolled from 16 participating centers, and
randomly assigned to either sequence 1 (26 patients) or sequence 2 (23 patients).
Six patients dropped out and four were protocol violators, which left 39 patients
selected for statistical analysis. There was no difference in the average
dialysate conductivity, predialysis and end-dialysis plasma water ultrafiltrate
conductivity or body weight between treatment A and treatment B. Thus, the
observed mean sodium balance was not different and, as expected, only the intra
patient variability of end-dialysis ultrafiltrate conductivity (index of sodium
balance variability) was reduced (21%). During treatment A, systolic blood
pressure decreased by 23 mm Hg (95% confidence intervals 21 to 24 mm Hg) at the
end of dialysis with respect to the pre-dialysis values. Treatment B reduced this
intradialytic decrease (P = 0.001) with a maximum effect at the third hour of
dialysis (4.4 mm Hg, 95% confidence intervals 1.9 to 6.9 mm Hg, 23% less than
during treatment A, P 0.0005) without any period or carry-over effect (P = 0.53
and 0.08, respectively). There was no treatment effect on intradialytic diastolic
blood pressure (P = 0.291). In conclusion, intradialytic cardiovascular stability
was significantly improved by matching the interdialytic sodium load with
intradialytic sodium removal using on-line conductivity ultrafiltrate kinetic
modeling as an alternative to sodium kinetic modeling. Although highly
significant, this effect was clinically not very large. By applying this
conductivity kinetic model to patients with a more variable sodium intake from
one session to another, a greater benefit can be expected.
PMID- 9551418
TI - Bicarbonate and bicarbonate/lactate peritoneal dialysis solutions for the
treatment of infusion pain.
AB - A randomized, double-blind, cross-over study was undertaken to determine the
effects of novel bicarbonate (38 mM) and bicarbonate (25 mM)/lactate (15 mM)
containing peritoneal dialysis (PD) solutions on infusion pain in patients who
experienced inflow pain with conventional lactate (40 mM) solution. Pain was
assessed using a verbal rating scale and the validated McGill Pain Questionnaire
(MPQ). Eighteen patients were recruited to the study. Both novel solutions
resulted in highly statistically significant reductions in inflow pain compared
to the control lactate solution, as assessed with both the verbal rating scale
and the MPQ. For all pain variables assessed, the bicarbonate/lactate solution
was more effective than the bicarbonate solution in alleviating pain. In
conclusion, both solutions reduced the infusion pain experienced with control
solution, but the bicarbonate/lactate solution appears to be the most effective.
In contrast to the most widespread current treatment, which is the manual
injection of sodium bicarbonate, the bicarbonate/lactate solution does not have
the associated increased risk of peritonitis.
PMID- 9551419
TI - Hemodialysis and L-arginine, but not D-arginine, correct renal failure-associated
endothelial dysfunction.
AB - In end-stage renal failure (ESRF) symptomatic hemodialysis-related hypotension
may prevent effective provision of renal replacement therapy. Endogenous
inhibitors of nitric oxide synthase accumulate in ESRF and are cleared by
dialysis. We, therefore, hypothesised that removal of these inhibitors by
hemodialysis would increase endothelial nitric oxide generation and promote
venodilation. In vivo responses of norepinephrine preconstricted dorsal hand
veins to locally active doses of acetylcholine (an activator of nitric oxide
synthase) and glyceryl trinitrate (GTN; a nitric oxide donor) were examined in
patients undergoing maintenance hemodialysis for ESRF and in healthy age- and sex
matched controls. Patient studies were undertaken before and after dialysis.
Studies before dialysis were repeated with co-infusion of either L-arginine or
its inactive enantiomer D-arginine. Venodilation in response to acetylcholine was
impaired before, and corrected by, dialysis whereas venodilation to GTN was
similar before and after dialysis. Venodilation in response to acetylcholine
before dialysis was restored by co-infusion of L- but not D-arginine. Therefore,
patients with ESRF undergoing hemodialysis have impaired acetylcholine-mediated
venodilation consistent with the accumulation in ESRF of functionally important
inhibitors of nitric oxide synthase that are cleared by dialysis.
PMID- 9551420
TI - Nocturnal hypoxemia, night-day arterial pressure changes and left ventricular
geometry in dialysis patients.
AB - It is well established that nocturnal hypoxemia in sleep apnea causes an
inversion of the circadian arterial pressure rhythm and triggers nocturnal
hypertension. Since sleep apnea is very frequent in dialysis patients, we
hypothesized that nocturnal hypoxemia may be a factor that contributes to alter
the 24-hour arterial pressure profile in these patients. To test the hypothesis
32 dialysis patients underwent 24-hour blood pressure (BP) monitoring and
continuous monitoring of arterial O2 saturation during the night-time.
Hemodialysis patients were studied during the non-dialysis day. All patients
underwent an echocardiographic study. Thirteen patients had no episode of
nocturnal hypoxemia (group I), 7 had at least one episode overnight but less than
2 episodes/hr (group II) and 12 had > or = 2 episodes/hr (group III). The average
daytime systolic pressure was similar in the three groups. However, the average
nocturnal systolic pressure fell in the first group (-2.5 +/- 4.2%) and rose in
the second (+2.0 +/- 3.6%) and in the third (+3.9 +/- 2.2%) group (one way ANOVA,
P < 0.005). The relative wall thickness of the left ventricle (RWT) was
significantly (P < 0.05) higher in group III than in group I, and in the
aggregate (N = 32) there was an inverse relationship between average nocturnal
SaO2 and RWT (r = -0.43, P = 0.015). The proportion of patients with concentric
remodeling or concentric hypertrophy was higher (P = 0.05) in the group with a
more severe degree of nocturnal hypoxemia (group III, 8 of 12) than in the other
two groups (group I, 3 of 13; group II, 2 of 7). Nocturnal hypoxemia is
associated with the "non-dipping" arterial pressure profile in dialysis patients.
Disturbed respiratory control during the night may represent an important
cardiovascular risk factor in dialysis patients.
PMID- 9551421
TI - Are HUS and TTP genetically determined?
PMID- 9551422
TI - Morphogenic cues that modulate podocyte growth.
PMID- 9551423
TI - A novel "bimodal" use of icodextrin peritoneal dialysis solutions.
PMID- 9551424
TI - Combined kidney-pancreas transplantation.
PMID- 9551425
TI - Cellular/molecular control of renal Na/Pi-cotransport.
AB - A type II Na/Pi-cotransporter located in the brush border membrane is the rate
limiting and physiologically regulated step in proximal tubular phosphate (Pi)
reabsorption. In states of altered Pi-reabsorption [for example, in response to
parathyroid hormone (PTH) and to altered dietary intake of Pi or as a consequence
of genetic abnormalities], brush border expression of the type II Na/Pi
cotransporter is accordingly modified. PTH initiates a regulatory cascade leading
to membrane retrieval, followed by lysosomal degradation of this transporter;
recovery from inhibition requires its de novo synthesis. Pi-deprivation leads to
an increased brush border expression of transporters that does not appear to
require de novo synthesis in the short term. Pi-overload leads to membrane
retrieval and degradation of transporters. Finally, in animals with genetically
altered Pi-handling (Hyp; Gy) the brush border membrane expression of the type II
Na/Pi-cotransporter is also reduced, suggesting that a genetically altered
protein (such as PEX in Hyp) controls the expression of this transporter.
PMID- 9551426
TI - P-glycoprotein functions and substrates: possible roles of MDR1 gene in the
kidney.
AB - There is a renewed attention on the multidrug resistance genes and their
products, P-glycoproteins, since recent molecular and functional studies revealed
unexpected functions in normal tissues. There are two types of human P
glycoprotein: Type I, encoded by the MDR1 gene, present in excretory organs and
in non-polarized cells; and Type II, encoded by MDR2, present in the canalicular
membrane of hepatocytes. MDR1 Pgp transports xenobiotics, peptides, steroids, and
phospholipids, and is also a regulator of swelling-activated chloride channels.
MDR2 Pgp is exclusively a phosphatidylcholine translocase. In the kidney, the
MDR1 gene and protein are expressed in mesangial, proximal tubule, thick loop of
Henle, and collecting duct cells. In mesangial and proximal tubule cells Pgp
transports xenobiotics. Concomitant exposure of kidney cells to two Pgp
substrates results in increased cell toxicity. Extracts from supernatants of
mesangial cell cultures inhibit Pgp-mediated transport, suggesting that a
mesangial-cell metabolite could be a substrate of Pgp. Active vitamin D3 and
platelet activating factor inhibit Pgp transport and are possible endogenous
substrates in proximal tubule and mesangial cells, respectively. Pgp could be
also a regulator of swelling-activated chloride channels present in the kidney.
PMID- 9551427
TI - Autocrine/paracrine control of renal phosphate transport.
PMID- 9551428
TI - Properties and regulation of medullary thick limb basolateral Cl- channels.
PMID- 9551429
TI - Transducing pathways involved in the control of NaCl reabsorption in the thick
ascending limb of Henle's loop.
AB - The thick ascending limb of Henle's loop (TAL) is involved in the urinary
dilution/concentration process by actively reabsorbing NaCl through a complex
mechanism. Some years ago, compelling evidence was provided that cAMP stimulates
NaCl reabsorption through the activation of adenylyl cyclase by several hormones
other than antidiuretic hormone (ADH). Synthesis of cyclic AMP is inhibited by
prostaglandin E2 (PGE2) and arachidonic acid per se, via the pertussis toxin
sensitive protein Gi activation. Cyclic GMP cascade down-regulates NaCl
reabsorption, through activation of both guanylyl cyclase receptors (by ANF and
urodilatin), and soluble guanylyl cyclase (by nitric oxide, NO). In TAL, NO is
produced by the cytokine-inducible form of NO synthase, but not by the
constitutive one. Agonists known to activate protein kinase C (PKC) in TAL elicit
opposite effects on NaCl reabsorption. Five PKC isoforms belonging to the
conventional, novel, and atypical enzyme subclasses have been recently defined in
TAL and might differently regulate NaCl flux. Increments in intracellular calcium
([Ca2+]i) inhibit NaCl reabsorption via three pathways: (i) a possible direct
effect on ion channels, (ii) a PLA2-mediated production of arachidonic acid
derivatives (20-HETE), and (iii) inhibition of the ADH-induced cAMP accumulation.
This last effect results from activation of phosphodiesterase (common to the
agents that increase [Ca2+]i), and inhibition of adenylyl cyclase (only elicited
by Ca2+c). Finally, the apical localization of some agonists effects is
documented.
PMID- 9551430
TI - H+ and HCO3- transporters in the medullary thick ascending limb of the kidney:
molecular mechanisms, function and regulation.
AB - The H+ and HCO3- transporters present in the medullary thick ascending limb
(MTAL) of the kidney are involved in several functions, such as transepithelial
transport, defense of cell pH and cell volume. Apical H+ secretion occurs via the
NHE-3 and NHE-2 isoforms of the Na+/H+ exchanger, and H(+)-ATPase. The apical
Na+/H+ exchanger is responsible for most of the apical step of transepithelial
HCO3- absorption and is unresponsive to cell acidification under isosmotic
conditions. Basolateral HCO3- efflux mechanisms may occur via the Cl-/HCO3-
exchanger and via the cotransporters K+/HCO3- (in the rat) and Na-3HCO3- (in the
mouse). However, the role of each transporter in transepithelial HCO3- absorption
is currently unknown. Inhibition of the basolateral Na+/H+ exchanger (NHE-1)
paradoxically inhibits the apical Na+/H+ exchanger. This cross talk is
independent of cell pH and may involve variations in cell volume. Arginine
vasopressin (AVP) and hyperosmolality induce a differential regulation of
basolateral NHE-1 and the apical Na+/H+ exchanger. They stimulate the basolateral
NHE-1, and the resulting cell alkalinization probably stimulates the pHi
sensitive AE2, which restores cell volume by cellular uptake of NaCl. They also
inhibit the apical Na+/H+ exchanger, which reduces net HCO3- absorption and thus
may prevent interstitial fluid alkalinization. Chronic metabolic acidosis
markedly increases HCO3- absorptive capacity of MTAL, by stimulating at least the
synthesis of apical NHE-3 protein, as in the proximal tubule. Conversely, chronic
metabolic alkalosis reduces the apical NHE-3 transport activity by decreasing the
synthesis of NHE-3 protein. The paradoxical increase in HCO3- absorptive capacity
of MTAL observed in the model of chronic NaHCO3-load alkalosis should be due to
other factors overcoming the inhibitory effect of alkalosis on NHE-3.
PMID- 9551431
TI - Atomic force microscopy of renal cells: limits and prospects.
AB - In this brief review, we present three-dimensional images of living Madin-Darby
canine kidney (MDCK) cells and CV-1 cells that illustrate the possibilities and
limits in the use of atomic force microscopy (AFM) for studying the topography of
the cell surfaces and of isolated biological membranes. We show that microvilli
can be imaged at the surface of living epithelial cells. However, when these
microvilli are abundant and close to each other, the geometry of the AFM tip only
allows an access to the upper part of the structures and precludes nanometer
range imaging of the cell surface. Such a nanometer range imaging was obtained
with other cell types like CV-1 cells and with isolated biological membranes. It
reveals that protruding particles 5 to 60 nm xy size, likely corresponding to
membranes proteins, occupy most of the membrane surface. These images indicate
that the AFM already gives an access to the cell surface structure at the
mesoscopic scale, which constitutes a major step for the understanding of the
structure-function relationships in membranes. Perspectives for a further step,
the imaging at molecular resolution of membranes, are discussed.
PMID- 9551432
TI - Regulation of sodium transport by steroid hormones.
AB - The main mechanisms involved in the regulation of sodium transport by steroid
hormones are briefly reviewed. The respective roles of the apical epithelial
sodium channel, which is likely to be the limitant step of steroid-regulated
transepithelial sodium transport, and Na,K-ATPase are described. Regulation of
these ion transporting proteins by aldosterone and glucocorticoid hormones,
probably via a two step mechanism (rapid activation of channels or pumps by
unknown regulators, and modulation of the transcription/translation rate of these
transporters), is discussed. The mechanisms of mineralocorticoid selectivity,
that is, the integrated process allowing a specific action of aldosterone, in
spite of high concentrations of glucocorticoids that crossbind with aldosterone
to the mineralocorticoid receptor (MR), are explained, as is the role of the
enzyme 11 beta-hydroxysteroid dehydrogenase and the differential interactions of
MR with steroid ligands and hormone responsive elements of DNA. Finally,
synergism between aldosterone and antidiuretic hormone for the stimulation of
sodium transport is evoked.
PMID- 9551434
TI - Nitric oxide/endothelin balance after nephron reduction.
AB - Nitric oxide (NO), an L-arginine derivative, is implicated in neuronal
transmission, immune response and vasodilation, besides acting as a platelet
function modulator. A number of recent studies in the experimental model of renal
mass reduction (RMR) in rats have proposed the hypothesis that abnormalities of
the NO synthetic pathway could have a key role in mediating the complex
hemodynamic and hemostatic disorders associated with the progression of renal
disease. Thus, renal NO generation is lower than normal in rats with RMR seven
days after surgery, and progressively worsens with time in close correlation with
signs of renal injury. This abnormality is due to a strong defect of inducible NO
synthase (iNOS) content in the kidney. In the same model, administration of
either the NO precursor, L-arginine, or a NO-releasing compound reduces
proteinuria, slows renal disease progression and prolongs survival. On the other
hand RMR is associated with a progressive increase of renal synthesis of the
potent vasoconstrictor peptide, endothelin-1 (ET-1), whose mRNA is expressed in
excessive amounts in cortical tubules early after surgical ablation. In this
setting, a marked reduction of NO, in the face of continuous local generation of
ET-1, may well contribute to intraglomerular capillary hypertension and cell
proliferation. Actually, administration of a selective ETA receptor antagonist to
RMR rats reduced abnormal permeability to proteins and prevented renal function
deterioration. In the same model the ETA receptor antagonist also corrected the
impaired renal NO synthesis, suggesting that excessive ET-1 bioactivity might
also be responsible for the progressive reduction of renal NO. In keeping with
this possibility are recent in vitro data that ET-1 inhibits iNOS transcription,
a process mediated by interaction of the peptide with subtype A receptors. Nitric
oxide and ET-1 have profound and opposite effects on glomerular and tubular
function. Thus, abnormalities of renal NO and ET-1 synthetic pathways, as
documented in the RMR model, likely have major and complementary roles in
promoting alteration in renal hemodynamics and functions in progressive
nephropathies.
PMID- 9551433
TI - Role of aquaporin-2 water channels in urinary concentration and dilution defects.
PMID- 9551435
TI - Early molecular mechanisms in the progression of renal failure: role of growth
factors and protooncogenes.
PMID- 9551436
TI - Progressive renal disease: the chronic hypoxia hypothesis.
PMID- 9551437
TI - Sodium transport in alveolar epithelial cells: modulation by O2 tension.
PMID- 9551438
TI - Role of distal airspace epithelium for resolving alveolar edema.
PMID- 9551439
TI - Inflammatory role of alveolar epithelial cells.
PMID- 9551440
TI - Ion transports in the middle ear epithelium.
AB - Ion transports in the middle ear epithelium have been recently characterized.
Experimental data using cell culture have found the existence of a sodium
transepithelial transport that drives a water flow. This is thought to play a key
role in the maintain of air-filled and fluid-free cavities. Impairment of this
process is involved in the pathogenesis of secretory otitis media, which is the
main cause of acquired hearing loss. Several modulations of this transport have
been evidenced: (i) reactive oxygen species induced an endogenous synthesis of
prostaglandin E2 (PGE2), which in turn increased the cAMP level and modulated ion
transport rate; (ii) steroids increased the expression of the alpha subunit
sodium channel mRNA, which changes paralleled the modulation of ion transport in
the middle ear epithelium; (iii) moderate hypoxia selectively and reversibly
decreased the rate of sodium transport, as a result of a parallel decrease in
alpha epithelial sodium channel subunit mRNA level. These modulations may explain
the course of middle ear pathology. However, the development of an in vivo model
has become mandatory to assess the relevance of these data in the pathophysiology
of the middle ear.
PMID- 9551441
TI - Mechanisms of endolymph secretion.
AB - In the inner ear, the membranous labyrinth, a tight heterogeneous sensory
epithelium, separates two compartments that are filled with fluids of completely
different composition. The lumen of the membranous labyrinth is filled with
endolymph, a K-rich, positively polarized fluid, whereas the surrounding spaces
are filled with perilymph, with a composition similar to an usual extracellular
fluid. The inner ear fluids play a major role in the cochlear and vestibular
physiology by the transmission of the mechanical stimulus to the hair cells, on
the one hand, and by the transduction of this signal to a nerve potential, on the
other hand. Numerous studies have been performed in order to know the chemical
and physical characteristics of the inner ear fluids. A high, positive
transepithelial potential has been evidenced in the cochlea together with a high
K concentration and a low Na concentration. During the last years, the
composition of the inner ear fluids, the origins of endolymph and perilymph, and
the cellular mechanisms involved in the secretion of these fluids have been a
great part elucidated. The present paper is a review of the contribution of the
lab to the understanding of the physiology of the inner ear.
PMID- 9551442
TI - Cell and molecular basis of hearing.
AB - The mammalian auditory organ is a specialized sensory epithelium capable of
detecting subnanometer movements produced by sound and transducing them into
electrical signals. It is a dual system consisting of two types of sensory cells:
the inner hair cells, which provide afferent input to the central nervous system,
and the outer hair cells, which provide frequency resolution and signal
amplification. The critical element in mechano-reception is the hair bundle, a
cluster of stereocilia located in the apical end of the sensory cells. Mechanical
stimulation causes deflection of ciliary bundles that leads to the opening or
closing of transduction channels located in the apical part of the plasma
membrane of the stereocilia. The current concept of auditory function requires an
active process of signal amplification within the cochlea. It is generally
believed that outer hair cells, functioning as both sensor and motor elements,
are responsible for this amplification process. The motor function consists of
changes in cell length produced by the concerted action of a large number of
independent molecular motors distributed along the length of the outer hair cell
lateral plasma membrane. Although experimental evidence suggests its association
with conformational changes in transmembrane proteins, the exact nature of the
outer hair cell force generation mechanism on a molecular level is still unknown.
PMID- 9551444
TI - [Gentle medicine, harmless medicine?].
PMID- 9551443
TI - [Presidency of the Society of Nephrology: passing the baton from France to
Switzerland].
PMID- 9551445
TI - [Drug-induced glomerulopathies].
PMID- 9551446
TI - [Use of insulin-like growth factor-I (IGF-I) in the treatment of acute renal
insufficiency].
AB - Despite numerous progresses, including extracorporeal epuration, acute renal
failure (ARF) remains associated with a high level of mortality and morbidity,
particularly in intensive care unit. Experimental research on different acute
renal failure models has clearly shown that growth factors and particularly
Insulin-like Growth Factor I (IGF-I) can reduce renal injury, improve renal
recovery and even reduce mortality. IGF-I, that is locally produced in injured
renal tubules, promotes the proliferation and differentiation of new tubular
cells. Moreover, IGF-I carriers (IGFBPs) and IGF-I receptor are altered in ARF
and modify the growth factor bioactivity. To date, only two clinical trials
studied IGF-I treatment in the ARF condition. Other studies are required to
demonstrate a role for IGF-I in treating or preventing acute renal failure.
PMID- 9551447
TI - [End-stage renal insufficiency associated with Chinese herbal consumption in
France].
AB - In May 1994 in Toulouse, there were two cases of end-stage renal failure (ESRF)
related to Chinese herbs similar to those incriminated in the case series
reported in Belgium in 1992-93, they led to an epidemiologic investigation aimed
at evaluating the risk linked to these plants in France. Studies carried out by
the Pharmacy Inspection showed that powders labelled Stephania Tetrandra, but
consisting instead of Aristolochia Fangji and containing aristolochic acid, were
sold in France between 1989 and May 1994. A systematic attempt to ascertain cases
of ESRF associated with ingesting Chinese herbs was carried out by analysing data
from the ERA-EDTA Registry of ESRF as well as from the French adverse drug
reaction monitoring system. Registry data showed no significant increase over
previous years in the number of new ESRF cases caused by tubulo-interstitial
nephritis (TIN) between 1990 and 1993. In eight regions of France, the files of
85 ESRF cases were examined, and all patients whose nephropathy began after 1989
were interviewed using a very detailed questionnaire. No association with Chinese
herb use was found in any of these cases. In 1996, two new ESRF cases were
reported in Nice; the regional adverse drug reaction monitoring center considered
the relationship with Aristolochia Fangji to be as possible (I2) for one case and
dubious (I1) for the other. Despite a lack of sensitivity of the methods used to
detect cases, it seems clear that no phenomenon as extensive as that observed in
Belgium occurred in France, although the same drugs prescribed at the same doses
have been widely distributed in our country. A possible explantation for the
difference in the number of cases in Belgium and France is that of an
unrecognised factor, promoting the toxicity of aristolochic acid or peculiar to
the Belgian clinic and causative. The precautionary principle led the authorities
to ban Stephania Tetrandra and Aristolochia Fangji from the market permanently.
PMID- 9551448
TI - [Acute renal insufficiency caused by Amanita proxima poisoning: experience of the
Poison Center of Marseille].
AB - In southern France, some Amanita species are usually eaten like Amanita ovoidea
(Quelet, 1872) which is a common white mushroom. In same areas, a similar and
less common fungus can be encountered: Amanita proxima (Dumee, 1916). The first
published cases of Amanita proxima poisonings with acute renal failure have been
reported in 1994 by a medical team from Montpellier. A second article was
published in 1995 by physicians from Marseille. In order to evaluate the
importance of the confusion between the 2 species, we looked after these mushroom
poisonings collected by the Poison Centre of Marseille. We found 31 cases
concerning 53 patients. We observed the first intoxication in 1968. Poisonings
took place in the south of Provence. Ingestions are in 26 cases (83% of the 31
cases) due to the confusion with Amanita ovoidea. The average delay between the
meal and the first signs was 13 hours and 12 minutes. All patients had gastro
intestinal symptoms, and for 14 of them, oliguria or anuria appeared in a few
days after ingestion. 11 patients needed temporary dialysis, and for 10 of them,
moderate hepatic cytolysis was observed. The severity of symptoms seems to be
dose-dependent: we collected cases in the same family with no signs after just
tasting the meal, digestive symptoms only when patients at more, and renal
failure for the hungry people.
PMID- 9551450
TI - [Arteriovenous fistula. Apropos of a local experience in Morocco].
AB - During eleven years (1983-1994), 684 arteriovenous fistulas (AVF) were realized
for 422 patients. The mean follow-up was 39 months. The most frequent AVF was
Cimino and Brescia and the most frequent seat was radial. The failure rate in the
immediate post-operative period was 10% and 8% after 48 hours. The permeability
of the AVF was 59%, 51% and 42% at 1, 2 and 3 years. The late complications were
thrombosis (28%), stenosis (15%) and false aneurysm (11%). In spite of recruiting
patients with chronic renal failure and deficiency in hospital basic equipment,
this experience permit us to start and then, to improve the activity of making
AVF and to be able to pick-up patients with chronic renal failure.
PMID- 9551451
TI - [Vaccination against hepatitis B in a hemodialysis center].
PMID- 9551449
TI - [Extracapillary glomerulonephritis secondary to D-penicillamine. Apropos of 1
case and review of the literature].
AB - Extracapillary glomerulonephritis was diagnosed in a 51-year-old woman after 11
months of D-Penicillamine treatment given for systemic sclerosis. Antineutrophil
cytoplasmic antibodies specific for myeloperoxydase were detected. Penicillamine
was stopped and the patient was treated with plasma exchanges, cyclophosphamide
and corticosteroids. The renal function progressively deteriorated leading to end
stage requiring dialysis. Previous reports of extracapillary glomerulonephritis
after D-penicillamine are analysed. Several cases with alveolar haemorrhage are
consistent with the diagnosis of microscopic polyangiitis.
PMID- 9551452
TI - [Johann Jakob Wepfer's book on apoplexy (1658). Critical comments on a classic in
neurology].
AB - The Swiss physician Johann Jakob Wepfer has been hailed as the author of the
"classic" modern treatise on apoplexy (1658). His name is known because he
demonstrated that apoplexy resulted from brain hemorrhage or occlusive diseases
of the vessels. A re-examination of the original text, however, reveals
surprising evidence that essential parts of Wepfer's book have been neglected so
far. These chapters demonstrate that Wepfer's medical thinking is deeply rooted
in pre-modern concepts, e.g. Galenic theories of brain function and iatrochemical
concepts of disease. A re-evaluation of the non-modern elements of Wepfer's
treatise leads to a better understanding of the whole text.
PMID- 9551453
TI - [The persecution of German neuropathologists. 1933-1939].
AB - The paper reminds of the many psychiatrists, neurologists, and pathologists
connected with scientific work in neuropathology who were expelled from Germany
between 1933 and 1939 because of defamation by the Nuremberg Laws or because of
their political opposition. Many of these colleagues saw their only way out as
suicide. Short biographies give an orientation about the destiny of the expelled
physicians in their host countries. The effort made after 1945 to give these
emigrated colleagues again an adequate position in Germany have not been very
intensive.
PMID- 9551454
TI - [Epilepsy in the elderly].
AB - The new occurrence of epileptic disorders increases continuously above the age of
60 years. The most frequent etiology of epilepsy in the elderly is vascular (32
54%). Tumors are the cause of epilepsy in the elderly in 11 to 33 per cent of
cases, with a peak around the age of 60. The etiology of about one third of the
cases of epilepsy newly diagnosed in old age cannot be clarified. The risks of
inducing epileptic disorders are: after cerebral ischemia 4-9%, intracerebral
hemorrhage 3%, and subarachnoidal hemorrhage 4-12%. It is important to recognize
confusional states, for they may be symptoms of a psychomotor status or a
prolonged postical phase. Occasional seizures occur more often in the elderly.
Due to altered pharmacokinetics and problems of compliance in old age, the
titration period of antiepileptic drugs should be planned with particular care
and patients given simple drug regimens.
PMID- 9551455
TI - [Semiologic classification of epileptic seizures].
AB - Recent advances in epileptology and epilepsy surgery require revision of the
currently used International Classification of Epileptic Seizures, which was
published 1981. We present a classification of epileptic seizures which is based
purely on the clinical seizure semiology. The advantages of a semiological
seizure classification are stressed.
PMID- 9551456
TI - [Juvenile myoclonic epilepsy (Janz syndrome). A well-known epilepsy syndrome?].
AB - Juvenile myoclonic epilepsy (JME) was described electroclinically by Janz and
Christian in 1957 and consists of myoclonic jerks in varying combination with the
absence of seizures and generalized tonic-clonic seizures, a typical circadian
distribution on awakening, sleep deprivation, alcohol consumption and flickering
stimuli as characteristic precipitating factors, typical EEG abnormalities with
generalized epileptiform discharges, normal physical and neuroradiological
findings, and often a family history of epilepsy. Although the misdiagnosis of
this well-classified and easily treatable syndrome is supposed to occur rarely in
Germany, we retrospectively investigated how often the wrong initial
classification had been made among patients who were finally treated in our
outpatient epilepsy unit. Between 1993 and 1995, 30 patients with a typical JME
like symptom constellation were identified who had been misdiagnosed initially.
In all patients, localization-related epilepsy had been classified, although
regional EEG abnormalities were rare (n = 5). All patients reported the typical
circadian distribution, abnormal neuroradiological findings were absent, and
typical EEG abnormalities were present in all cases. Under treatment with
appropriate antiepileptic drugs 97% of the patients became almost completely
seizure-free. Even 40 years after the first description of the syndrome, JME is
an underdiagnosed illness. The generally positive course underlines the
importance of its correct identification.
PMID- 9551457
TI - [Transcranial Doppler exercise test in patients with chronic tension headache].
AB - In the etiopathology of tension type headache, vascular and autonomic disorders
are discussed. Fifteen patients with chronic tension type headache according to
the criteria of the IHS were investigated using the TCD-ergometer-test--a method
used to evaluate the myogenic mechanism of cerebrovascular autoregulation--and
the results were compared with the findings in fifteen healthy control subjects.
The patients' Mean Flow Velocity (TAVmean) and Resistance Index (RI) at rest and
after exercise were significantly decreased (p < 0.05). During exercise they
normalized. The patients' endtidal pCO2 at rest and during exercise was
significantly lower than the corresponding values of the control group (p <
0.05). Regarding blood pressure elevation and heart rate increase during exercise
both groups did not differ significantly (p > 0.05). These findings suggest that
patients with tension type headache have a diminished vascular tone in the
cerebral vessels at rest which is normalised during exercise. The reduced
endtidal pCO2 is considered as a physiological response to increase vascular tone
via metabolic mechanism of cerebrovascular autoregulation. In conclusion it is
suggested that therapeutic procedures which activate sympathetic autonomic
nervous function to train cerebral vessels should be more carefully considered.
PMID- 9551458
TI - [Follow-up of myasthenia gravis. Results of a longitudinal study of the
significance of psychosocial predictors].
AB - Forty-two patients suffering from myasthenia gravis were examined in a
longitudinal study design. The aim of the study was to investigate possible
psychosocial predictors for the course of the disease. At the time of the first
examination (T1) the diagnosis myasthenia gravis had been established for no
longer than 1 year. Two further examinations were done at 6 months (T2) and 18
months (T3) after T1. Methods consisted of a personality questionnaire (FPI), a
coping questionnaire (FKV), an assessment of neurotic symptoms by interviewers
(PSKB) and an assessment of the doctor-patient relationship by the attending
physicians. Two different severity scores (Oosterhuis Index, Myasthenia Score)
served as criteria for the course of the disease. There was no connection between
the course of myasthenia gravis and neurotic symptoms like anxiety or depression
and the quality of the doctor-patient relationship (both assessed at T1). Also
demographic data were independent from the development of severity scores. The
personality factor extraversion was associated with a positive course of the
disease, aggressiveness and worrying about health with a negative one. Among the
coping behaviors religiousness and looking for sense were associated with a
favorable course but that was shown only regarding the Oosterhuis Index and not
the Myasthenia Score. As several T1 personality factors were predictive for the
severity scores at T3, these results may suggest a causal influence of
personality factors on the severity of the illness. Whether or not this
relationship is actually in operation, however, remains ellusive. Further studies
using an experimental design are needed to strengthen this hypothesis.
PMID- 9551459
TI - [Effect of cardiac embolism sources on origin of territorial cerebral infarcts].
AB - BACKGROUND AND PURPOSE: To test the association of cardiac sources of embolism
with territorial type brain infarcts. METHODS: From a prospective cerebral
ischemia data base the 106 consecutive patients with territorial type cerebral
infarcts on computerized tomography were analyzed. The 85 consecutive patients
with lacunar lesions served as a comparison group. The association of cardiac
sources of embolism with territorial types infarcts was assessed using univariate
Chi Square tests and logistic regression models. Cardiac sources of embolism were
defined as:atrial fibrillation, left cardiac thrombi, valvular vegetations, wall
motion and valvular abnormalities, left atrial enlargement, open foramen ovale,
septal aneurysm, mitral valve prolaps, and aortic arch atherothrombosis (all
findings--except for atrial fibrillation--assessed by echocardiography). RESULTS:
Atrial fibrillation was significantly associated with territorial type infarcts
(odds ratio 2.2, 95% confidence interval 1.01-4.8). This effect was independent
of additional cardiac diseases, other cardiac abnormalities, carotid artery
stenosis, and patient age. Most likely due to the small sample size, left cardiac
thrombi only showed a non-significant trend towards an association with
territorial infarcts (odds ratio 3.0, 95% confidence interval 0.7-12.3). The rate
of all other cardiac findings did not differ significantly between the comparison
groups. CONCLUSION: Atrial fibrillation and cardiac thrombi showed an association
with territorial type infarcts. Other so-called cardiac sources of embolism-
except for mechanical valves and bacterial endocarditis which were not
represented in our sample--revealed no clinically relevant association with
embolic brain infarct pattern.
PMID- 9551460
TI - [Asystolic seizures].
AB - Epileptic seizures may alter autonomic functions. This is especially the case
with complex focal seizures (of temporal lobe origin) and grand mal. Most
frequently, such seizures cause ictal tachycardia, sometimes tachypnea, probably
caused by the propagation of epileptic discharges to autonomic cerebral
structures. Ictal bradycardia and asystole are rare phenomena. However, they may
be life threatening. Their differentiation from primary cardiac arrest is
possible by the use of ictal EEG and ECG registration. Postictal serum prolactin
measurement does not differentiate syncope from seizure. However, a postictal
increase of creatine kinase is only measured after epileptic seizures and not
after syncope. Treatment of such epileptic seizures includes an optimization of
anticonvulsant drug therapy and the implantation of a cardiac demand stimulator.
There is growing evidence that ictal asystole is a cofactor in sudden unexplained
death in epileptic patients.
PMID- 9551461
TI - [Successful induction of tolerance in an epilepsy patient with phenobarbital
allergy].
AB - We report on a 32-year-old female patient who had had a history of complex
partial seizures since the age of 14. Phenobarbital was the most effective
anticonvulsant drug in this patient. However, the drug treatment was complicated
by a phenobarbital-induced exanthematous eruption. Reintroduction of the
phenobarbital some years later resulted in a skin rash again; therefore,
treatment with this substance had to be discontinued a second time. Because of
the satisfactory antiepileptic efficacy, phenobarbital was introduced a third
time using a desensitization procedure with increased oral doses, starting with a
dose of 1 mg. After a daily dose of 90 mg phenobarbital, on day 6 an
exanthematous eruption appeared. The exanthem disappeared parallel to a dose
reduction of phenobarbital and with a gradually increasing dosage up to a
maintenance dose of 200 mg. Tolerance to the allergic effect of phenobarbital was
preserved and the seizure frequency was significantly reduced by phenobarbital
monotherapy with a daily dose of 200-175 mg.
PMID- 9551462
TI - [Subacute encephalopathy with epileptic seizures in a patient with chronic
alcoholism (SESA syndrome)].
AB - Subacute encephalopathy with seizures in alcoholics (SESA syndrome) is a rare
disease entity following chronic alcohol ingestion. It is quite distinct from
alcohol withdrawal syndromes, such as delirium, withdrawal seizures or CNS
complications of alcohol, such as Wernicke-Korsakow syndrome, central pontine
myelinolysis or Marchiafava-Bignami disease, and was proposed in 1981 by
Niedermeyer and coworkers. This syndrome consists of multiple neurological
deficits, such as hemiparesis or hemianopia, and of recurrent focal and
generalized seizures associated with prominent EEG features (periodic lateralized
discharges, PLEDs). A 72-year-old Caucasian male with chronic alcoholism and an
otherwise unremarkable past medical history was admitted to our hospital because
of several secondary generalized simple partial seizures. Laboratory
investigations revealed elevated levels of gamma-glutamyltranspeptidase and of
mean corpuscular volume. Other laboratory investigations and the CSF examinations
on three occasions revealed normal values. Cranial computed and magnetic
resonance tomography showed cerebral microangiopathy and generalized atrophy.
Despite triple anticonvulsive therapy and an intravenous treatment with acyclovir
and thiamine, the epileptic seizures persisted. Several EEGs revealed left
parietooccipital periodic lateralized epileptiform discharges (PLEDs). The
patient died of an intercurrent pulmonary infection about 3 months after the
onset of symptoms. The described clinical picture resembles the symptoms of SESA
syndrome.
PMID- 9551463
TI - [Day time fatigue in frontal lobe epilepsy with primarily sleep-related seizures.
A case report].
AB - We present a 43-year-old patient who has had up to 15 frontal lobe seizures
nightly for 12 years. The patient had no complaints apart from excessive daytime
sleepiness. Neurological and psychiatric examination as well as cerebral computed
tomograph and magnetic resonance imaging were normal. After sleep deprivation an
interictal electroencephalogram demonstrated a recurrent excess of theta activity
over the right frontal and frontopolar area. A cerebral PET study showed
diminished glucose metabolism of the right cingular and frontomesial region. The
sleep structure was extremely fragmented. There was an excessive reduction of
slow-wave sleep and REM sleep. Carbamazepine therapy produced complete seizure
control lasting a few weeks, followed by return of up to 8 seizures per night.
Vigabatrin as add on therapy diminished the noctural seizures to 1 to 3 per
night.
PMID- 9551464
TI - [Acute intermittent porphyria with transient paresis and contracture. Evidence
for initial myopathic dysfunction?].
AB - A 70-year old man with acute intermittent porphyria had acute transient
bibrachial paresis with moderate contracture of the involved muscles, which
showed electrical silence in a conventional electromyographic investigation with
surface electrodes placed over the contracted muscle belly (filter: 20 Hz-2 Hz,
amplifier 50 microV). Slow finger movements were still possible and showed
typical muscle-action potentials. This electroclinical correlation points to
myopathic localized dysfunction, perhaps similar to rare case reports with
patients having metabolic myopathy of McArdle's type.
PMID- 9551466
TI - [Recommendation for organization of special stroke departments (stroke units).
1997 implementation].
AB - Stroke units are hospital-based special wards aiming at optimal care by a
specialized team with an integrated concept for patients with acute strokes.
Following the initial neurological and neuroradiological evaluation, early
treatment will be initiated based on the assumed pathophysiology of the stroke.
Acute management includes monitoring of physiological, parameters, care by
specialized nurses, and early implementation of physiotherapists, speech therapy
and occupational therapy. Despite the increased initial costs, the long-term
burden for the health system is decreased by shorter hospital stay and reduced
morbidity and disability.
PMID- 9551465
TI - [Adrenoleukodystrophy and adrenomyeloneuropathy. Clinical biochemical and
molecular genetic findings].
AB - Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disease affecting 1 in
20,000 males either as cerebral ALD in childhood or as adrenomyeloneuropathy
(AMN) in adulthood. Recently, the ALD gene has been identified by positional
cloning. We report three males patients with AMN and a fourth patient with
juvenile ALD. Biochemical studies showed elevated plasma concentration of
saturated very-long-chain fatty acids. Genomic DNA of the patients was analysed
for possible sequence variations in the ALD gene by PCR amplification and single
strand conformation polymorphism analysis. Three missense mutations (Ser515Phe,
Glu267Lys and Arg401Trp) and a 9-bp deletion were detected predicting,
respectively, the replacement and absence of amino acids in the deduced amino
acid sequence of the ALD protein. In the patients' families, detection of the
respective mutations allows the identification of carriers of ALD/AMN. Mutational
screening in ALD families is of practical importance in improving genetic
counseling.
PMID- 9551467
TI - [Dynamic cellular response following brain ischemia and reperfusion].
AB - Since the first documentation of the induction of heat shock protein following
transient cerebral ischemia, much experimental evidence suggested that all of the
cellular elements in the central nervous system show dynamic stress responses
depending on the degree of environmental changes induced by ischemia and
reperfusion. In this review, first I focused on the importance of the usage of an
appropriate experimental model for brain ischemia and reperfusion, and I
presented our work on mouse models of transient global and focal ischemia. Next,
I reviewed the pathogenic role of microvascular stasis (i.e., secondary ischemia)
caused by the primary ischemic event and demonstrated the important role of cell
adhesion molecules through the experiments using ICAM-1 knock-out mouse as a
model of brain ischemia/reperfusion. Thirdly, I discussed the ischemia-induced
neuronal cell responses in relation to the apoptosis-like selective neuronal
death and the induction of adopted stress responses including stress protein
synthesis and 'ischemic tolerance' phenomenon. A variety of stress proteins
induced by ischemic stress have been reviewed and a pivotal role of tyrosine
kinase system in selective neuronal death has been suggested in the gerbil model
of transient forebrain ischemia. Finally, I showed the important
pathophysiological roles of glial cells such as astrocytes and oligodendrocytes
in the cellular cross-talk triggered by an ischemic event. For the development of
a novel therapeutic agent against ischemic stroke, it is quite important to
clarify both the negative and positive cellular responses induced by brain
ischemia/reperfusion.
PMID- 9551468
TI - [Response of Na+/Ca2+ antiporter to ischemia and glial/neuronal death].
AB - Brain ischemia produces morphologic and biochemical alterations in astrocytes.
This mini-review summarizes astrocytic responses to brain ischemia including our
studies on the neuronal and astrocytic Na(+)-Ca2+ exchanger (NCX). NCX is
considered to cause Ca2+ efflux (forward mode) or Ca2+ influx (reverse mode),
depending on the electrochemical gradient of Na+ across the plasma membranes and
membrane potential. We demonstrated that NCX is present in cultured neurons and
astrocytes and that there are differences in their properties and distribution
ratio of the isoforms between neurons and astrocytes. We also found that Ca2+
depletion followed by reperfusion with Ca(2+)-containing medium caused cell death
in cultured astrocytes (Ca2+ paradox-like injury), but not in neurons. The study,
carried out by the use of a specific antisense oligomer, provides direct evidence
that Ca2+ paradox-like injury is mediated by NCX in the reverse mode. The injury
was attenuated by inhibitors of the Na(+)-Ca2+ exchanger, heat shock protein and
the calcineurin inhibitor FK506. In a preliminary experiment, we found that brain
ischemia decreases the mRNA level of NCX in the hippocampus. Further studies on
activation and cell injury of astrocytes will contribute to development of new
drugs that modulate the function of astrocytes.
PMID- 9551469
TI - [Involvement of calcineurin A alpha and A beta in neuronal death in a gerbil
model of cerebral ischemia].
AB - Treatment with FK506, an inhibitor of Ca2+/calmodulin dependent phosphatase
(calcineurin, CaN), within 1 hr after transient ischemia afforded protection from
apoptotic death in CA1 pyramidal neurons. To investigate isoform-specific roles
of CaN in the neuronal cell death, we localized CaN A alpha and CaN A beta in the
gerbil hippocampus using isoform-specific antibodies. In control gerbils,
immunoreactions of both isoforms were highly enriched in hippocampal CA1
pyramidal neurons. Four to seven days after the induced ischemia,
immunoreactivities of both isoforms were markedly reduced in the CA1 pyramidal
cell and lacunosum-molecular layers. The CaN A alpha immunoreactivity was
increased in the CA1 radiatum and oriens layers, whereas that of CaN A beta was
enhanced in reactive astrocytes in the CA1 region. These findings suggest that
CaN A alpha is involved in sprouting of afferent fibers in CA1 and that CaN A
beta is involved in the reaction of astrocytes such as assembly of glial fibril
acidic protein.
PMID- 9551470
TI - [The glial endothelin-nitric oxide system in ischemia-related neuronal cell
death].
AB - Both endothelin and nitric oxide (NO) have been proposed to act as
pathophysiological factors in ischemia-related neural damage. This review is
concerned with the participation of the glial endothelin-NO system in ischemia
related neuronal cell death. In the rat brain with cerebral apoplexy, endothelin,
endothelin receptors and NO synthase (NOS) were rich in the glial cells of
damaged brain areas. The brain subjected to transient forebrain ischemia
contained astrocytic endothelins and microglial expressions of the ETB-receptor
and NOS aggregating in the damaged CA1 subfield of the hippocampus at 7 days
after the ischemia. Astrocytic endothelin, ETB-receptor and NOS became more
apparent at 28 days after the ischemia, corresponding to a time when neural
tissue-repair/remodeling after damage occurs, whereas no activities of the
endothelin-NO system are observed in microglia. In the in vitro experiment,
endothelin was found to modulate the release of NO from the hippocampal slices
subjected to transient forebrain ischemia. There may be a cross-talk between the
endothelin system and NO in the astrocytes and microglia during the process of
ischemia-related neuronal cell death and neural tissue-remodeling.
PMID- 9551471
TI - [The involvement of cytokines, chemokines and inducible nitric oxide synthase
(iNOS) induced by a transient ischemia in neuronal survival/death in rat brain].
AB - Inflammatory/immunological processes underlie the survival/damage of neurons
after brain ischemia. In glial cells, cytokines such as IL-1 beta and TNF-alpha
are produced following ischemic stresses. On the other hand, it is suggested that
NO/iNOS is involved in neuronal apoptosis. We here review the ischemia-induced
production of cytokine/iNOS and the neurotrophic/neurotoxic effects. It is not
clear whether or not the neuronal death after brain ischemia is apoptosis or
necrosis. Under the condition of transient forebrain ischemia, however, we
obtained results suggesting apoptosis in the delayed neuronal death of the CA1
pyramidal neurons. The time course and cellular localization of postischemic iNOS
expression depend on the properties of the ischemic insult. The iNOS induction is
detected primarily in astrocytes after the transient forebrain ischemia when the
neuronal apoptosis is observed. We discuss a variety of cytokines with
neurotrophic/neurotoxic actions that are produced by ischemia or environmental
stresses in glial cells. From the neurotoxicological aspect of the neuro-glial
interaction, we also review recent findings on signalling pathways of the iNOS
induction in glial cells and the mechanisms of the cytotoxic actions of NO.
PMID- 9551472
TI - [Lack of evidence that inducible nitric oxide synthase participates in the
development of ischemic brain damage].
AB - We have already reported that the concentration of nitric oxide (NO) increases
during and after cerebral ischemia and a selective inhibitor of neuronal NO
synthase (nNOS) suppresses this increase and subsequently mitigates brain damage
in rats. Although the selective inhibition of nNOS is a promising pharmacological
strategy for the treatment of stroke, the role of inducible NOS (iNOS) remains to
be clarified. Toward this end, we investigated temporal alterations in iNOS mRNA
by the RT-PCR method in a rat model of middle cerebral artery (MCA) occlusion. We
found that iNOS mRNA in the ischemic hemisphere began to increase at 3 hr and
reached the maximum level at 24 hr of reperfusion following 3 hr of MCA
occlusion. However, quantitative analysis revealed that no significant difference
existed between 6 hr or 24 hr reperfusion group and their respective time-matched
sham operation group. In addition, neither Western blotting nor
immunocytochemical study disclosed an apparent induction of iNOS at any time
points examined. Similar results were obtained at 24 hr of permanent MCA
occlusion. Taken together, these data indicate that iNOS induction during and
after MCA occlusion may be not a critical event for the development of infarction
caused by ischemia itself.
PMID- 9551473
TI - [Transient cerebral ischemia and long-term potentiation in the rat hippocampus].
AB - Long-term potentiation (LTP) has been widely studied as a form of synaptic
plasticity that represents a cellular mechanism of learning and memory. Among
numerous processes and molecules that may be involved in LTP formation, a great
many of them including neurotrophic and transcription factors have been described
as those involved in neural death after ischemic insult. Nitric oxide (NO) is a
molecule that is known to also exert double-edged effects on LTP formation. Here
we will be describing recent advances with respect to the LTP mechanisms in the
hippocampal synapses, a critical brain region for learning and memory function.
In another context, we described our study elucidating the changes in hippocampal
LTP as a functional response to transient cerebral ischemic insult, from the
viewpoint of its relevance to NO production. As indices of NO production, nitrite
and nitrate levels were determined by in vivo microdialysis. It was demonstrated
that hippocampal LTP deficiency after transient cerebral ischemia was preceded by
an increase in hippocampal NO production. Direct or indirect inhibition of an
inducible NO synthase restored ischemia-induced LTP deficiency. These findings
suggest that NO production, in part via inducible NO synthase, is responsible for
LTP deficiency after transient cerebral ischemia in the rat hippocampus.
PMID- 9551474
TI - [A method of measuring eruptive movement of the rat incisor using a non
contacting displacement detector].
AB - The axial movements of rat incisors were recorded continuously for over 20 hr.
The rats were anesthetized with halothane delivered by intratracheal intubation
using an artificial respirator. A hemostatic clamp was used to immobilize the
jaw. The displacement detector that detects changes in the electric eddy current
exhibited high resolution, good linearity and low drift. The average eruption
rates of the rat incisor were estimated to be 406 and 516 microns/ 24 hr at 34
and 37 degrees C of the rectal temperature, respectively. The values were within
the normal range. We also measured the force needed to restrain eruptive movement
of the rat incisor using the same apparatus combined with a load cell. The
maximum pushing force was estimated to be 9 mN or 29 mmHg (converted value) on
average. Then the effects of adrenaline on axial movement of the incisor and
arterial blood pressure were examined. Adrenaline caused a rapid extrusive tooth
movement with a nearly simultaneous increase in the blood pressure, followed by a
marked intrusive tooth movement and a decrease in blood pressure. These results
support the view that the systemic arterial blood pressure and vasculature in the
tooth socket play important roles to determine the position of teeth. We assume
that our method would be useful to clarify the precise relationship between tooth
displacement and vascular change in the tooth socket.
PMID- 9551475
TI - Comparison of ELISA and HI for detection of antibodies against Wesselsbron
disease virus.
AB - A two-graph Receiver Operating Characteristic analysis was done to determine the
optimal cut-off value of an indirect enzyme-linked immunosorbent assay (ELISA)
for detection of antibodies to Wesselsbron disease (WSL) virus. When ELISA and
haemagglutination-inhibition (HI) results of WSL-positive and WSL-negative
control sheep sera were compared, the sensitivity of ELISA was 97.9% and that of
HI, 87.5%, while the specificity of ELISA and HI were 95.7% and 100%,
respectively. The ELISA's superior sensitivity was confirmed by the results of
the two assays performed on a simulated range of low-positive sera, which showed
that the ELISA was able to detect WSL-antibody levels at least ten times lower
than those the HI could. The ELISA was also less cross-reactive than the HI to
guinea-pig antisera against nine flaviviruses relevant to southern Africa. The
combination of the ELISA's ability to test untreated sera in single dilution and
its superior sensitivity and lower cross-reactivity as compared to that of the
traditional HI, makes it the assay of choice for automation and large-scale
screening of animals for antibodies to WSL virus.
PMID- 9551476
TI - The control of Glossina morsitans morsitans (Diptera: Glossinidae) in a settled
area in Petauke District (Eastern Province, Zambia) using odour-baited targets.
AB - A trial to control G. m. morsitans with the use of 980 odour-baited, insecticide
impregnated targets was conducted in a 300 km2 area in the Eastern Province of
Zambia between 1989 and 1991. The area is highly cultivated and cattle density is
high (about 8 cattle/km2). Targets were deployed along roads and tracks.
Deployment was restricted to suitable tsetse habitat. The effect of the targets
on the tsetse population and on the transmission of tsetse-transmitted
trypanosomosis was monitored by means of man-walked fly rounds and sentinel
herds, respectively. The apparent density of tsetse in the trial area and in
adjacent areas, declined rapidly after targets had been deployed. Trypanosomosis
incidence in the trial area decreased significantly but did not completely
disappear. Results from the trial show that odour-baited targets are effective in
controlling Glossina m. morsitans in highly cultivated areas even when deployment
is restricted to suitable tsetse habitat. It is concluded that tsetse control
operations should be chosen such that either the invasion pressure is low from
adjacent areas, or the size of the area is big enough, so that a central
challenge-free area can be created.
PMID- 9551477
TI - Seasonal abundance and parity of stock-associated Culicoides species (Diptera:
Ceratopogonidae) in different climatic regions in southern Africa in relation to
their viral vector potential.
AB - Seasonal abundance and parity in Culicoides populations, in the vicinity of
livestock, were determined at seven sites in five different climatic regions with
220 V down-draught blacklight-traps. In 418 collections made between October 1983
and December 1986, a total of 2,134,171 Culicoides, of which 342,571 were
identified to species level and sexed, were collected; 267 of these collections
(182,321 Culicoides) were graded for parity. In the frost-free summer rainfall
area, Culicoides were collected in large numbers in light-traps throughout the
year; this implies breeding and possible virus transmission throughout the winter
in certain parts of South Africa. However, where frost occurred, Culicoides
numbers usually peaked in late summer and dropped sharply after the first frost.
In the latter areas, small Culicoides collections during winter may be due to low
winter temperatures and rainfall; low temperatures negatively affect adult
activity and reduce the rate of development of larvae and pupae; low rainfall
would lead to a reduction of available larval habitats. Relatively large numbers
of Culicoides were collected in winter in the temperature frost-free winter
rainfall area. In each of the four summer rainfall areas, one Culicoides species
remained dominant throughout the year: at two of these areas this species was C.
imicola. Other abundant species in some of these summer rainfall areas were C.
schultzei s.l. and C. zuluensis. In the winter rainfall area, C. zuluensis, C.
magnus, C. gulbenkiani and C. imicola shared abundance. It was established that
abdominal pigmentation is an indicator of parity in C. imicola in South Africa.
With the increase in Culicoides numbers towards the end of summer, there was also
a rise in the proportion of parous (pigmented) females in most Culicoides
species, which signifies a higher vector potential for African horsesickness and
bluetongue towards the end of summer. This coincides with the seasonal occurrence
of viral diseases transmitted by Culicoides species. Nulliparous (unpigmented)
females of all Culicoides species were present throughout the year at all sites
where Culicoides were continuously collected, confirming uninterrupted breeding
in these areas.
PMID- 9551478
TI - Predation of livestock ticks by chickens as a tick-control method in a resource
poor urban environment.
AB - The possible use of chickens as predators of livestock ticks was studied.
Chickens were allowed to scavenge for 3 h among tick-infested cattle in a typical
township backyard during the milking period. Boophilus decoloratus, Hyalomma
marginatum rufipes, Rhipicephalus evertsi evertsi and Otobius megnini were
recovered from the crops and gizzards at necropsy. The numbers of ticks ingested
ranged from 0-128, with an average of 28.81 (+/- 8.42) per chicken. This study
has confirmed that chickens are natural predators of livestock ticks and that
chickens can be used as part of an integrated tick control plan in urban cattle
management systems in resource-poor communities in South Africa.
PMID- 9551479
TI - Salmonella isolated from crocodiles and other reptiles during the period 1985
1994 in South Africa.
AB - Over a 10-year period, 173 isolates of Salmonella were obtained during routine
isolation from reptiles. Of the 173 isolates, 92 different Salmonella serovars
were identified. Of them, 61 (66%) belonged to subspecies I, nine to subspecies
II and 21 to subspecies III (IIIa and IIIb), and one to subspecies IV. The
majority of isolates were from farmed Nile crocodiles (145), three from wild
caught African dwarf crocodiles, 11 from captive snakes, 13 from lizards and one
from a tortoise. The isolates from the tortoise and lizards were subspecies I
isolates (Zaire and Tsevie, respectively). Of the snakes, nine isolates were
S.III. The serovars isolated most often from the crocodiles were of subspecies I
(32 serovars). Eight were from subspecies II, seven from subspecies III and one
from subspecies IV. The most frequently identified serovars were Typhimurium
(seven), Tsevie (six), Duval (six), Schwerin (six), Tinda (six), and Tallahassee
(six). On two commercial crocodile breeding farms that had experienced ongoing
problems for about two years, many isolates of Salmonella were made. Some of
these serovars were isolated more than once, and also months apart. No single
Salmonella serovar predominated, nor did a single pathological condition. These
salmonellas were predominantly of subspecies I.
PMID- 9551480
TI - Parasites of South African wildlife. XV. Helminths of scrub hares, Lepus
saxatilis in the Kruger National Park.
AB - A total of 145 scrub hares from three localities in the Kruger National Park were
examined for helminths: 124 at Skukuza, 15 at Shingwedzi, and three each at
Pretoriuskop and Pafuri. Trichostrongylus deflexus was the most prevalent and
most abundant nematode, and was collected from hares from all four localities.
Trichostrongylus falculatus was present in three localities. Trichostrongylus
thomasi and Dermatoxys vlakhaasi occurred only at Skukuza in 50 and 23%,
respectively, of the hares examined. The cestode Mosgovoyia pectinata and the
nematode genus Impalaia were each recovered from three localities and Cooperia
hungi from two. There was no apparent seasonal pattern of abundance of the worms,
and the intensities of infection of male and female hares were similar. With the
exception of D. vlakhaasi, all the helminths recovered in this study represent
new records for scrub hares in South Africa.
PMID- 9551481
TI - The structure of the interstitial tissue of the active and resting avian testis.
AB - The interstitial tissue of the testis was studied in gonadally active and
gonadally inactive domestic fowl (Gallus gallus domesticus), guinea-fowl (Numida
meleagris), duck (Anas platyrhynchos) and Japanese quail (Coturnix coturnix
japonica). Gonadal inactivity in the fowl was induced by a single subcutaneous
injection of 50 mg oestradiol benzoate. The structure of this tissue was similar
in all the birds studied. Lymphatic vessels were mostly thin and meandered
between the peritubular tissue peripherally and the centrally located blood
vessels, Leydig cells and macrophages. The basal lamina rested on a closely
associated homogeneous microfibrillar layer free of collagen fibres. The
myofibroblast layer was several cells thick, and quite compact. The basal lamina
of gonadally resting birds was highly irregular, relatively electron-dense,
contained electron-lucent globules, and sent numerous finger-like processes or
plicae into the seminiferous epithelium, particularly into the Sertoli cells. The
Leydig cells were few but typical in structure. In gonadally inactive birds they
accumulated lipid droplets, dense heterogeneous bodies, probably lysosomes, and
appeared to degenerate. The avian testicular interstitium is similar to that of
the human and cat in possessing a multi-layered myofibroblast component, and to
that of the rodent in possessing a small number of Leydig cells, as well as in
the location of the lymphatic vessels. Thus the bird combines characteristics of
the interstitium found variably in mammals.
PMID- 9551483
TI - Evaluation of a 3 ml heartwater (cowdriosis) infective blood vaccine dose.
AB - Three milliliters of blood from the present commercially produced heartwater
infective blood vaccine (Ball3 stock) was experimentally tested in sheep and
cattle for infectivity and efficacy. Results obtained for this vaccine dose were
statistically not different from results for the prescribed 5 ml vaccine dose.
PMID- 9551484
TI - Seroepidemiological survey of sympatric domestic and wild dogs (Lycaon pictus) in
Tsumkwe District, north-eastern Namibia.
AB - Disease is a potential threat to many endangered populations and may originate
from sympatric domestic species. This paper describes a cross-sectional
serological survey of canine pathogens carried out in domestic (n = 70) and wild
dogs (Lycoan pictus) (n = 6), in Tsumkwe District, northeastern Namibia. Evidence
of past exposure to canine distemper virus, canine adenovirus and parainfluenza
virus was evident in both wild and domestic dogs with this, the first, documented
exposure of free-living wild dogs to canine distemper. Domestic dogs were also
exposed to rabies virus, canine parvovirus and coronavirus. There was no pathogen
to which wild dogs, but not domestic dogs, were exposed. With wild dogs known to
be susceptible to rabies and canine distemper, these may be the greatest threat
to this population of wild dogs, although some wild dogs can clearly survive
infection with canine distemper.
PMID- 9551482
TI - Toxorhynchites-fluorescent antibody system for the detection of bluetongue virus
from Culicoides midges (Diptera: Ceratopogonidae).
AB - A new system, the Toxorhynchites-fluorescent antibody (TFA) test in which the
larvae of Toxorhynchites splendens mosquitoes were used for the detection of
bluetongue virus (BTV) from Culicoides midges, was developed. Twenty-seven pools
of Culicoides midges were collected from bluetongue-prone areas of Tamil Nadu by
use of the light-trap and suction-trap methods. A suspension of each pool was
injected intrathoracically into T. splendens IV instar larvae and inoculated onto
Vero cell monolayers. An indirect fluorescent antibody technique and an
immunoperoxidase test were used to detect BTV antigen in smears of crushed
midges, crushed larval head smears after incubation for 7 d at 28 degrees and
cell monolayers showing cytopathic effects 48 h post inoculation. The suspensions
were also injected intravenously into embryonated chicken eggs, and the
characteristic BTV-induced lesion(s), viz. cherry-red appearance of embryos, were
observed after 48 h. Virus was confirmed by a qualitative neutralization test
conducted simultaneously in embryonated chicken eggs. A total of seven out of 27
samples (26%) were positive for the presence of BTV antigen in all the diagnostic
systems used. Since BTV propagates readily in experimentally infected T.
splendens larvae and the BTV antigen can be detected by the fluorescent antibody
technique with a sensitivity comparable to that for virus propagated in tissue
culture and embryonated eggs, the TFA system can be adopted as a new method for
the isolation of BTV from vectors. The advantages of the TFA system are
discussed.
PMID- 9551485
TI - Morphological evidence for infection of impala, Aepyceros melampus, platelets by
a rickettsia-like organism.
AB - Ultrastructural studies revealed the presence of a parasite, believed to be
Ehrlichia platys, in the blood platelets of impala. At the time of blood sampling
all the animals appeared healthy. This is the first report on the presence of
this rickettsia in these animals, previously described in canine platelets.
PMID- 9551486
TI - Graph theory and the entropy concept in histochemistry. Theoretical
considerations, application in histopathology and the combination with receptor
specific approaches.
PMID- 9551487
TI - Oesophageal damage and defence in reflux oesophagitis: pathophysiological and
cell biological mechanisms.
PMID- 9551489
TI - Psychopathologic domains and insight in schizophrenia.
AB - The earlier conceptualization of positive and negative symptom topologies for
schizophrenia has given way to more complex models that propose three-and-four
dimensions of psychopathology. These constructs may relate to neurobiologic
heterogeneity and discrete symptom clusters have been shown to have distinct
anatomical and cognitive correlates. Insight is an excellent example and the
understanding of insight at psychopathologic and cognitive levels has facilitated
new approaches to treatment and enhanced medication compliance.
PMID- 9551488
TI - The new epidemiology of schizophrenia.
AB - A confluence of findings from different vantage points has led to renewed
interest and direction in the epidemiology of schizophrenia. This article
provides an overview of prevalence and incidence data, examining the validity of
reported secular trends in the occurrence of schizophrenia. Advances in molecular
genetics have uncovered new linkage on chromosomes 6, 8, and 22 and have
suggested complex models, including anticipation, to explain the perpetuation of
genetic transmission in the face of low fecundity. Neurotropic viruses and
autoimmunity have emerged as pathoplastic mechanisms to explain recent intriguing
epidemiologic associations in schizophrenia. Environmental risk factors are also
important. With attention to particular risk factors (i.e., perinatal hypoxia), a
preventative approach may be realistic for some forms of schizophrenia.
PMID- 9551490
TI - Child and adolescent schizophrenia.
AB - Until only very recently, the occurrence of schizophrenia in childhood and early
adolescence had been largely neglected. Improved diagnostic formulations have
resulted in clarification of the boundaries between childhood schizophrenia,
other psychotic disorders, and pervasive developmental disorder. The study of
schizophrenia in childhood or adolescence provides a unique opportunity to
examine illness characteristics in the absence of the confounds of substance
abuse illness, chronicity, and medication effects. Additionally, current
etiopathologic models of schizophrenia can be tested in this patient subgroup.
PMID- 9551492
TI - Structural brain imaging in schizophrenia.
AB - The subtle pathomorphology of schizophrenia is gradually being unraveled through
the application of increasingly sophisticated brain imaging techniques. There is
now compelling evidence of subtle brain abnormalities in patients with
schizophrenia. It less clear, however, whether these reflect a widespread
cortical involvement, or more selective involvement among interconnected neural
systems, or more focal pathology. The extent of brain changes, their
etiopathologic significance, and putative clinical correlates are reviewed in
this article.
PMID- 9551491
TI - The neuroanatomy and neurochemistry of schizophrenia.
AB - Substantial progress, in part owing to recent refinements in methodology, has
been made in unraveling the anatomic correlates of schizophrenia. Subtle
pathomorphologic changes, distinct from those of well-known degenerative brain
disorders, have been observed. Neurochemical characterization has illuminated the
nature of these morphologic abnormalities and has pointed to complex
dysregulation of neurotransmitters and G proteins. New biochemical hypotheses
such as the glutamate hypothesis have replaced and revitalized more established
concepts in the neurochemistry of schizophrenia.
PMID- 9551493
TI - Chemical and physiologic brain imaging in schizophrenia.
AB - Technologic advances in functional brain imaging have provided exciting and
informative insights into the functional neuroanatomy and neurochemistry of
schizophrenia. Using MR spectroscopy, it has been possible to examine in vivo
brain metabolism and to relate observed changes to physiological processes
occurring at a cellular level. Positron emission tomography and single photon
emission computed tomography have revealed disturbances of cerebral blood flow
and glucose metabolism in patients with schizophrenia. More recently, these tools
have also proved most useful in studying the relative receptor occupancy of
typical and atypical antipsychotic medications.
PMID- 9551494
TI - Neurodevelopmental and neuroprogressive processes in schizophrenia. Antithetical
or complementary, over a lifetime trajectory of disease?
AB - The neurodevelopmental model of schizophrenia maintains ascendancy among current
etiopathologic perspectives on schizophrenia. However, inconsistencies across
studies and the absence thus far of pathognomic brain changes suggest the need
for complex conceptualization of neurodevelopmental arrest, including some
reconciliation with the competing neurodegenerative model of schizophrenia. This
article critically reviews the preponderance of evidence for each model and
provides an account of how these may interact or synergize to produce the
characteristic clinical expression of schizophrenia.
PMID- 9551495
TI - Emerging roles for novel antipsychotic medications in the treatment of
schizophrenia.
AB - Antipsychotic medications are the mainstay of treatment for schizophrenia. The
recent advent of atypical antipsychotics has provided new clinical options and
set higher expectations for the treatment of schizophrenia. It is not yet clear
how each different drug will fit within the therapeutic armamentarium and this
lack is most evident with considering patients with treatment refractory
schizophrenia. On the other hand, the expectation of superior efficacy, more
benign side effect profile and potential to impact the longitudinal course of
schizophrenia provide a rationale for the use of novel antipsychotics as a first
line treatment of schizophrenia.
PMID- 9551496
TI - Pharmacoeconomics of the new antipsychotics for the treatment of schizophrenia.
AB - Inevitably, the greater availability of more costly antipsychotic medications has
resulted in attempts to regulate the use of these agents. Early objections over
the cost of treatment with clozapine or risperidone have in part been mollified
by preliminary statistics on the cost effectiveness of these agents. However,
this issue is complex and requires careful consideration of pharmacoeconomic
principles in the development and clinical distribution of novel antipsychotics.
Future cost-effectiveness studies need to consider a balance of public and
private perspectives. These studies should be conducted in several settings,
preferably also within the context of broader, multimodal treatment intervention
strategies.
PMID- 9551497
TI - Standards of care and clinical algorithms for treating schizophrenia.
AB - Health care changes and improved understanding of the course and management of
schizophrenia have provided the propitious environment to develop guidelines for
treating patients with schizophrenia. This article describes two recent
guidelines and highlights how these may be used to enhance clinical practice.
Although still at a nascent stage that is awaiting more widespread acceptance by
clinicians, the introduction of guidelines represent a significant advance in
mental health care.
PMID- 9551498
TI - Public health policy, community services, and outcomes for patients with
schizophrenia.
AB - Amidst the specter of managed care, individual mental health services are
struggling to redefine their niche, consolidate with partners and provide a
realistic continuum of care for persons with serious and persistent mental
illness. Because of the chronicity of schizophrenia, its economic and social
ramifications, the disparity in health insurance for these patients and limited
resources, the development of community services has often proceeded in a
fragmentary manner. Several states have well coordinated community programs with
integration between private and public services. The Assertive Community
Treatment (ACT) model has proved successful, although this is costly to maintain.
Services that synergize optimum pharmacologic and psychosocial treatments can
achieve favorable patient outcome, as evaluated across clinical, rehabilitative,
humanitarian, and public welfare domains.
PMID- 9551499
TI - Advocacy, recovery, and the challenges of consumerism for schizophrenia.
AB - Advocacy organizations such as the National Alliance for the Mentally Ill (NAMI)
and patient consumer groups are playing an ever-increasing role in public health
policy and patient care in schizophrenia. The recovery philosophy which
recognizes the unique contributions of those who have experienced mental illness
is now a part of treatment approaches in many states. Several states have
extended these consumer initiatives to incorporate advance directives, an
approach that has generated much debate. The NAMI destigmatization campaign,
grounded in the neurobiology of major mental illness, is an unprecedented,
concerted effort to change public opinion and to achieve parity at all levels for
persons with severe and persistent mental illness. This article describes and
chronicles these initiatives and explores their implications for the management
of schizophrenia into the next millenium.
PMID- 9551500
TI - Fatigue in patients with cancer. Analysis and assessment.
AB - Although fatigue is the most frequent complaint in cancer patients, there is no
universally accepted definition. In this book a series of studies are presented
whose aims were definition of cancer-specific fatigue and the development of an
instrument which had the capacity to discriminate levels of fatigue in different
groups of cancer patients. The first study (chapter 2) explored the concept of
fatigue by comparing the personal experiences of cancer patients (n = 20) with
those of healthy individuals (n = 20). Using grounded theory, themes emerged
which classified fatigue into physical, affective and congitive components.
Differences were found in the expressions used by the two cohorts, particularly
in relation to the physical sensations experienced. The descriptors generated by
cancer patients were compared with those used in the currently available fatigue
instruments and illustrated considerable differences in content. They were
therefore used to develop a new fatigue instrument--the Fatigue Assessment
Questionnaire (FAQ). The second study (chapter 4) tested the reliability and
feasibility of the FAQ in a non-randomised, prospective, cross-sectional study of
cancer patients (n = 77) and healthy individuals (n = 77). It was found to
discriminate between fatigue experienced by cancer patients and that experienced
by healthy individuals. A tentative step-like theoretical explanation for the
production, perception and expression of fatigue proposed at the end of study one
was supported by factor analysis. It led to minor adaptations of the instrument.
The third study (chapter 5) subjected the FAQ to further validity testing. Four
hundred and ninety-nine cancer patients with a variety of tumour types and stages
were included in a prospective, non-randomised, cross-sectional study. Factor
analysis supported the theoretical framework and led to modifications which
resulted in a multi-dimensional, 20-item instrument. The FAQ discriminated
significantly different levels of fatigue and the distress that it caused in
patients with metastatic cancer, patients with localised cancer and patients
whose disease was in remission. High levels of fatigue were mainly associated
with advanced stages of cancer, in combination with high levels of depression.
The closing chapter represents a synthesis and discusses issues for further
research and implications for practice.
PMID- 9551501
TI - [Effectiveness of partial inpatient rehabilitation from the patient's viewpoint.
Results of an evaluation of a partial hospitalization model project at the
Ichenhausen specialty clinic].
AB - Partial-hospitalization rehabilitation is a relatively recent form of
rehabilitation, which, as opposed to the ambulatory approach, comprises the
entire programme available for inpatient medical rehabilitation except for
accommodation and full board. Great expectations are attached to partial
hospitalization: it is supposed to cost less than a comparable in-patient measure
but matching in terms of quality. However, hardly any empirical data exist so far
concerning the effects partial hospitalization rehabilitation is having in these
respects. The present article seeks to answer the question of whether from a
patient perspective, the outcome quality of this new model is comparable to that
of the classical full-hospitalization programmes. In terms of methodology,
questionnaires were used to raise the necessary data from two independent samples
(i.e., partial vs. full hospitalization) of former orthopaedic rehabilitees of
Fachklinik Ichenhausen (Bavaria). Data analysis included some 205 patient
questionnaires (57% return rate). High agreement was found among the two groups
concerning outcome evaluation, subjective health and patient satisfaction. From a
patient perspective, rehabilitation outcome on the majority of variables
considered, even is judged slightly better for partial hospitalization patients
than for the inpatient comparison group. As none of these results reach
statistical significance, these minor differences should however not be
overrated. While partial-hospitalization, rehabilitation, hence, has turned out
an option which matches traditional full-hospitalization programmes in terms of
quality, too great expectations nevertheless are unwarranted: Partial
hospitalization rehabilitation is no general alternative to inpatient programmes
as it will realistically be suitable for a small percentage of orthopaedic
patients only, hence be unable to replace full-hospitalization programmes to any
major extent. Undoubtedly, however, it is apt to contribute to greater
flexibility and needs orientation among the services and programmes available in
rehabilitation, and may thus be considered a valuable approach for complementing
inpatient and ambulatory forms of rehabilitation.
PMID- 9551502
TI - [Psychosomatic-psychotherapeutic rehabilitation of social medicine problem
patients--an exploratory study of findings, follow-up and treatment outcome].
AB - The group of social-medical problem patients was defined as comprising those
patients who are admitted during an on-going invalidity pension award procedure
or who are drawing a fixed-term pension, patients who have declared their
intention to apply for pension award and/or have been on sick leave for an
uninterrupted 6 months at the time of admission. In light of this definition,
some 25-30% of the patients referred to us would be considered social-medical
problem patients. The main focus of the present study had been to identify the
subgroup of patients who might be expected to profit from psychosomatic
rehabilitation notwithstanding their social-medical problems. Improvement in
physical symptoms was achieved in 34% of the patients, and in 43% relative to the
psychological symptoms present. The group of patients showing the greatest
measure of improvement can be described by the following prognostically
favourable factors: incapacity for work at the time of admission but no
application for pension award made or planned; lower average age, higher
motivation on admission, and lower severity of the social-medical problems, no
denial of psychosocial factors, and willingness to join group psychotherapy.
Prognostically unfavourable factors were found to be a fixed-term pension already
awarded, along with repeated participation in rehabilitation measures on purely
somatic grounds, and a higher age. Pertinent literature is reviewed in light of
these findings, underscoring the significance of the time factor in
chronification of neurotic disorders of the capacity for work and gainful
activity. Consequently, these patients should as speedily as possible undergo
efficient psychosomatic diagnosis and be referred for inpatient psychosomatic
rehabilitation.
PMID- 9551503
TI - [Changes in pensioning and psychosomatic assessment].
AB - Appropriate evaluation of a patient's handicapping or disabling conditions, of
his or her capacity for work and gainful activity rank among the recurring tasks
in inpatient rehabilitation. Published recently, the Beeintrachtigungsschwere
Score (BSS; a score for determining the severity of a condition) constitutes a
highly practicable instrument for these purposes, well suited to the clinical
setting. Particular difficulties are encountered in the assessment of patients
already in the pension award process, a population where the original disease
picture has been superimposed by numerous chronification factors of a
psychological, social and economic nature so that a so-called invalidity
pensioning career has set in. The article gives an overview of this phenomenon of
invalidity pensioning career and the sequence of its various phases, setting out
the use of the BSS for social-medical evaluation in an inpatient rehabilitation
setting.
PMID- 9551504
TI - [Psychosocial predictors for initiating a pension procedure after bypass
operation].
AB - From the psychologist's point of view, a routine coronary artery bypass operation
is often looked upon by patients as a negative situation. The patient develops
the feeling that his or her life has been dramatically altered, thus the patient
feels he must somehow make a change in the upcoming pattern of the future. The
patient, as well as his employer, is convinced of subjective models of etiology,
which cause the attitude that circumstances of living must change rapidly. In
this context continued employment is viewed as a significant burden and
hindrance, despite an excellent post-operative discharge diagnosis. According to
the hypothesis, emotions and attitudes directly concerning the working
environment, that lead to an application for early retirement should be
identified. Medical and psychological counseling before surgery and post-op
rehabilitation, should be carried out to ease the obsession with early retirement
and prevent possibly following psychopathological disturbances.
PMID- 9551505
TI - [Computer-assisted stress analysis in rehabilitation with ABBA (job requirements
and capacity analysis)].
AB - ABBA is a recently devised, ergology-based expert system software for vocational
analysis, documentation and evaluation--inter alia in the context of medical and
vocational rehabilitation-, drawing on some 20 years of experience in job
analysis with the AET (Arbeitswissenschaftliches Erhebungsverfahren zur
Tatigkeitsanalyse). Designed for broad and differentiated coverage, a PARADOX
data bank comprising the entire data collected enables comparison of job
requirements and client performance potential, reaching for beyond individual
analysis on account of its integration of job profiles for a given industry or
occupation, or for an entire company. The related, and easy-to use, software for
data processing and appraisal is now being made available by ABBA along with
dialogue-based ergological know-how.
PMID- 9551506
TI - [Experiences and effects with 6 years of judo training in ambulatory
rehabilitation of bronchial asthma in childhood].
AB - In view of backing up the potential for as normal a life as possible in the
presence of chronic obstructive respiratory disease, quality rehabilitation
concepts have for some ten years been discussed which recommend satisfactory
levels of motor activity in particular during childhood and youth as a factor in
stabilizing long-term health. A difficult prerequisite in this respect is
choosing a sport adapted to the child's age and condition as well as providing
adequate motivation, along with awareness of exercise- and training-induced
stress and strain reactions. Several years of experience with Judo have shown
that, in an ambulatory rehabilitation setting, the needs of schoolchildren with
bronchial asthma too, may be answered by this competitive sport provided that
several didactic and methodological premises are heeded. In light of its holistic
educational approach and intermittent stress and strain profile, Judo is cut out
for facilitating integration in the social community, hence contributing toward
valuable personality characteristics and growth in a rehabilitative context in
the face of the long-term course of the illness.
PMID- 9551507
TI - [Prohibiting prejudice against handicapped students in schools].
PMID- 9551508
TI - [The Duke Severity of Illness Checklist].
AB - Developed at the Duke University Medical Center of Durham, North Carolina,
U.S.A., the Duke Severity of Illness Checklist (DUSOI) is a tool for measuring a
person's illness severity. The instrument comprises four parameters of a health
problem, e.g. in a given diagnosis, namely: symptoms, complications, 6-months
prognosis without treatment, treatment potential. Using the numerical ratings
(from 0 to 4) for each parameter of every diagnosis, the following three types of
severity score (from 0 [lowest degree of severity] to 100 [highest degree of
severity]) can be calculated: (1) the DUSOI diagnosis score for each diagnosis
stated, (2) the DUSOI overall score for the set of all health problems stated for
a patient, and (3) the DUSOI comorbidity score, i.e., all problems except for any
one problem of principal interest. The DUSOI is suitable for patients from the
entire chain of medical and rehabilitative care, although it had initially been
developed for the ambulatory sector. Completing the DUSOI form is very economical
in terms of time needed, and is recommended to be done by the physician in charge
immediately following the patient's visit. Alternatively, the form could also be
filled in by a reviewer on the basis of the patient's medical record. A certain
level of judgement is required on the part of the physician or reviewer carrying
out the DUSOI assessments.
PMID- 9551509
TI - [The study of bronchial hyperreactivity in children].
PMID- 9551510
TI - [Asthma and household chemical pollutants (with the exception of tobacco)].
AB - The relationship between allergens in a domestic environment and asthma has been
extensively studied and it is only recently that studies have suggested the
possibility of the role of chemical pollutants in the internal environment in the
genesis of asthma. The pollutants studied are oxides of nitrogen (nitrogen
dioxide NO2), volatile organic components (COV), formaldehyde, ozone (O3) and
sulphur dioxide (SO2). The level of nitrogen dioxide in the interior of houses
may be greater than those met outside. Normal values are 400 mcg per metre3 per
hour and 150 mcg per metre3 in twenty four hours. In asthmatics challenge test to
nitrogen dioxide and epidemiological studies suggest that internal nitrogen
dioxide is capable of provoking asthmatic crises either by a direct pollutant
effect or by potentialising the allergenic crises either by a direct pollutant
effect or by potentialising the allergenic response of the bronchi. COV and
formaldehyde are liberated by urea formaldehyde foams and by chipboard furniture.
The levels of COV and formaldehyde inside a house may be up to 10 times higher
than those outside. COV and formaldehyde perhaps would have an effect on the
bronchi in asthmatics at significant levels which are rarely found in the
domestic environment. Ozone is an external pollutant. However, from 5-80% of the
external concentrations may be found inside some locations. Thus, in certain
conditions which are relatively rare, the interior concentrations of dwelling
places may attain levels which are capable of inducing, in healthy subjects who
are sensitive to ozone, a drop in the FEV1. As regards asthmatics, only
experimental work has been able to show any bronchospastic effect of ozone,
either by a direct effect on the bronchi or by the potentiation of a bronchial
response to allergens. It would be convenient to perform some epidemiological
studies to determine if there is a relationship between exposure to ozone
internally and to bronchial changes. The concentrations of SO2 inside houses
increases when coal is burnt. The levels provoking a bronchial reaction are much
greater than those found inside houses. The data and the literature which is
mostly recent seems to stress the role of NO2 ozone and SO2 as a factor which
might favour asthmatic crises induced by allergens in atopic subjects. However,
other studies will be necessary to confirm the initial data.
PMID- 9551511
TI - Long-acting beta-2 agonists. An attempted response to various questions which can
be posed by pneumonologists.
AB - The use of long acting beta 2 agonists is an undeniable improvement in the
treatment of certain types of asthma. It enables better control of unstable
asthma, improves and gives a superior quality of life. Current work confirms
however that when used in the long term they ought to be associated with anti
inflammatory treatment. If they do not produce any important secondary effects,
even when used for a long period, it is not currently possible to confirm that
their prolonged use does not change the intensity of their bronchodilator effect
and/or the intensity of the bronchodilator effect of the short acting beta 2
stimulants. Some studies have shown that their addition to basic treatment with
inhaled steroids is more effective than increasing the inhaled steroids. Other
studies are necessary to know if they may enable the reduction in inhaled
corticosteroids and how far.
PMID- 9551512
TI - [The effect of corticotherapy on respiratory muscles].
AB - Skeletal muscle myopathy is one of the main side-effects of systemically
administered corticosteroids, and involves respiratory as well as peripheral
muscles. After prolonged treatment with moderate doses of either fluorinated or
non-fluorinated corticosteroids, chronic myopathy may occur. In patients, such
myopathy is characterized by the gradual onset of proximal limb muscle weakness
and a sudden increase in creatine excretion in 24h urine. This myopathy is
associated with a generalized fiber atrophy of the quadriceps in which myopathic
changes are present. Since these changes were also observed in animal models, it
was concluded that steroid treatment was responsible for them. After cessation of
treatment, recovery of muscle force occurs but may be protracted. The severity of
corticosteroid-induced myopathy appears to depend upon the type of steroid used,
the treatment duration, the dose and the treatment regimen where repetitive burst
treatment effects are worse than those obtained with continuous treatment with
the same dose. During short-term treatment with massive doses of corticosteroids
as frequently used to treat status asthmaticus, acute myopathy may develop and is
characterized by generalized fiber necrosis and rhabdomyolysis. Because such
necrosis was not observed in animal studies, it was suggested that the necrosis
may result from the combined effect of corticosteroids with other agents such as
aminoglycoside antibiotics and/or muscle relaxants.
PMID- 9551513
TI - [The contribution x-ray computed tomography in chronic diffuse infiltrative lung
disease].
AB - Computed tomography (CT) may be useful at all stages of management of chronic
infiltrative lung disease. It contributes to diagnosis and evaluation of
inflammation and fibrosis, helping the therapeutic decision and appreciating the
response to treatment. It contributes to follow-up in the course of the disease.
Some further works are necessary to know the indications of CT and the frequency
of examinations.
PMID- 9551514
TI - [The value of surgery in the treatment of invasive pulmonary aspergillosis in
neutropenic patients].
AB - The aim of the study is to specify the indication for surgery in the treatment of
invasive pulmonary aspergillosis (API). From January 1991 to October 1996
nineteen patients who had been treated with chemotherapy and associated marrow
aplasia and suffering from API were operated on. At the time of the surgical
intervention all of the patients were treated with antifungal drugs. The delay
between the start of their symptoms and the start of treatment was 2.6 days
(range: 0-17 days). 1. The risk of a massive haemoptysis by contact between the
fungal infection and the pulmonary artery led to eight urgent surgical
operations: six lobectomies and two lobectomies associated with segmentectomy.
The mean level of polymorphonuclear neutrophils was 296 cell/mm3 (0-1,000).
Plastic surgery on the pulmonary artery was carried out in three patients. One
patient died after the operation with progression of the API. The duration of
postoperative stay was 13 days (6-18). 2. Planned surgery consisted of a
resection of the residual mass after antifungal treatment and a diagnostic
approach to the intraparenchymatous mass of indeterminate aetiology. A resection
of the residual masses (in spite of antifungal treatment) was carried out in
seven patients: before further haematological therapy in six cases and in one
case for a superinfected lesion. The type of resection was: a lobectomy (n = 4),
a lingulectomy (n = 1) and an atypical resection (n = 2). No postoperative deaths
were reported. The patients left the surgical service between the seventh and
twentieth day postoperatively. The surgery was used in four patients as the
diagnostic approach in view of intraparenchymal masses of unknown aetiology and
had enabled a fungal mycelium to be isolated at the centre of persisting
inflammation. Antifungal treatment sometimes associated with surgery allowed for
a better prognosis in patients suffering from invasive pulmonary aspergillosis.
PMID- 9551515
TI - [Oxygen transport capacity of blood in athletes with malarial infection].
AB - The purpose of the present investigation was to examine the effects of the
malaria parasite on the oxygen capacity of blood. 15 males basket-ball players
(mean +/- SE: age: 17-30 +/- 1,44 years; weight = 63.20 +/- 6.55 kg; height:
177.99 +/- 0.10 cm) were volunteered to take part in this study. Nine subjects
were infected by the malaria parasite, but seemed healthy. Six other subjects
were really healthy. The oxygen capacity of blood was decreased in the infected
group when compared with the noninfected group (15.86 +/- 1.59 ml vs 17.64 +/-
0.62 ml) (p < 0.05). The comparison of all other hematologic data showed them all
reduced in the infected group: total number of erythrocytes = 4.90 +/- 0.50 x
10(9)/ml vs 5.03 +/- 0.33 x 10(9)/ml (p < 0.05), mean cellular volume (CMV):
71.75 +/- 6.37 fl vs 77.67 +/- 5.74 fl (p < 0.01), hemoglobin concentration
([Hb]): 11.84 +/- 1.19 g/100 ml vs 13.16 +/- 0.46 g/100 ml (p < 0.05),
hematocrit: 35.22 +/- 2.86% vs 38.93 +/- 1.18% (p < 0.05). The chronic anemia
induced by the malaria might theorically limit the oxygen capacity of blood,
which constitutes an important factor for the aerobic performance.
PMID- 9551516
TI - [Patent and occult intra-alveolar hemorrhage in leptospirosis].
AB - PURPOSE: Pulmonary involvement (PI) is common in leptospiral infection, usually
characterized by hemoptysis and diffuse bilateral infiltrates on chest
radiographs. Alveolar haemorrhage (AH) has already been proved by autopsy and
some case-reports with fiberoptic bronchoscopy (FB) and bronchoalveolar lavage
(BAL). The purpose of this study was 1/to evaluate the incidence of AH in
leptospirosis 2/to define the impact of BAL on the early diagnosis of the
infection. PATIENTS AND METHODS: FB with BAL were performed in 23 consecutive
patients with leptospirosis (13 patients with patent signs of PI: group 1, 10
patients without: group 2). AH was defined by a percentage of siderophages > or =
20% and/or a Golde score > 100 and/or an haemorrhagic aspect of BAL fluid.
Culture tests were performed on specific medium. RESULTS: We diagnosed AH in all
patients of group 1 and in 7 patients of group 2. Filaments were seen in 6
specimens of BAL fluid, initially thought to be leptospires, but culture tests
were negative. CONCLUSION: AH is identified in all cases of leptospirosis with
PI. Occult AH often occurs to patients without any respiratory symptom.
Physicians should consider leptospiral infection in the differential diagnosis of
AH. Culture-tests for leptospirosis in BAL do no help in diagnosing
leptospirosis.
PMID- 9551517
TI - [Chronic obstructive pulmonary disease patients undergoing home oxygen therapy: a
study of clinical parameters, nutritional status and ambulatory capacity].
AB - AIM OF THE STUDY: The aim of the study was to document the nutritional status and
the calorie demands of patients suffering from severe chronic airflow obstruction
(BPCO) who were on continuous domiciliary oxygen therapy (OCD) and to correlate
this information with the clinical picture, the severity of the respiratory
disease and the daily distance walked, this to be measured in a prospective
manner. PATIENTS AND METHODS: Fifty clinically stable patients with chronic
airflow obstruction on continuous oxygen therapy for 33 months (range 4-106) in
whom the following measures were made at home: pulmonary function, maximal static
inspiratory and expiratory pressure (PIMAX and PEMAX), strength of hand, grip,
the mean distance walked daily (wearing a pedometer for one week), body mass
index (IMC), and the body composition by electrical bio-impedence and calorie
requirements. RESULTS: Thirty four per cent of patients presented with an
excessive body mass (IMC > 27 kg/m2), 42 per cent had normal nutrition (IMC 20-27
kg/m2) and 24 per cent were malnourished (IMC < 20 kg/m2). Malnourished patients
had, in a statistically significant manner, airflow obstruction of greater
severity and a lower oxygen saturation and a PEMAX as well as a lower daily
distance compared to over weight subjects. However, their net calorie
requirements were markedly higher (39 +/- 5 Kcal/kg/j) compared to patients
having normal weight (29 +/- 11 kcal/kg/j) or excess weight (25 +/- 8 kcal/kg/j).
From the clinical standpoint no malnourished patient fulfilled the clinical
criteria of chronic bronchitis. By contrast 61 per cent of subjects with normal
nutrition and 94 per cent of subjects with excessive weight were chronic
bronchitics. CONCLUSION: In the group of patients with severe airflow obstruction
on domiciliary oxygen, 25 per cent were malnourished and this was in spite of
netly increased calorie consumption which is superior to their theoretical need.
This suggests that the solution of increasing supplements to their dietary
requirements would be a difficult to realise. These subjects presented also with
a more marked ventilatory handicap and a clinical picture characterised by the
absence of the classical signs of chronic bronchitis.
PMID- 9551518
TI - [Attitude and behavior of hospital personnel toward smoking].
AB - Due to a lack of data available at the national level, on smoking behaviour of
hospital staff, a survey was carried out in a representative sample of hospitals.
This survey, which will be repeated in the future, should enable to evaluate
preventive actions at hospital and to measure the implication level of the
hospital staff in tobacco prevention. The analysis of data collected among 3082
persons shows that a third of the hospital staff smokes. Among these persons a
certain part smoke at their working place, this proportion is varying
considerably with the working area in the hospital. The more this area is close
to the patient the less is hospital staff smoking. More than one third of the
interviewers (37.3%) think that trying to convince people to stop smoking is part
of their role: this opinion varies considerably depending on the professional
activity in the hospital. In addition a very large majority (81.4%) of the
hospital staff considers that it has an exemplary role to play in front of
patients. This belief is shared equally by all the different groups of staff. The
smoking prevalence among hospital staff is equivalent to that of the general
population; this underlines the need and the necessity to realize anti-tobacco
campaigns among this health care population. Moreover since the exemplary role
they have to play, is very well accepted, preventive actions could rely on a good
level of participation.
PMID- 9551519
TI - [Bronchial casts associated with pulmonary lymphatic anomalies].
AB - We report a case of a patient who presented with bronchial moulds. The classic
causes, particularly bronchopulmonary aspergillosis could not be found. The
pulmonary radiology and CT of thorax revealed an alveolar syndrome. Lymphography
and lymphoscintigraphy showed evidence of lymphatic anomalies including the non
visualisation of the thoracic canal. In the absence of evidence for other
diseases, we would suggest that these anomalies were responsible for the
symptomatology.
PMID- 9551520
TI - [Tumors of the phrenic nerve].
AB - A schwannoma of the phrenic nerve is a rare disorder which presents as a tumour
of the anterior mediastinum. It is seen in adults and is usually latent. We
report two cases in elderly subjects in whom the phrenic nerve tumour had
achieved a significant size. One of these schwannomas had degenerated into
sarcomatous change which is the first case reported to the present time.
PMID- 9551521
TI - [Pulmonary artery hypertension in HIV seropositive drug addicts. Apropos of 10
cases].
AB - Pulmonary hypertension (PH) is a classic complication associated with intravenous
drug addiction. Various pathogenic mechanisms may be involved but HIV infection
now appears to be the main etiologic factor. We report herein 10 case of PH
occurred in HIV+ intravenous drug abusers. Each patient had several pathogenic
factors: HIV infection, pills crushed and intravenously injected (6 cases), heavy
and repeated consumption of amphetamines and cocaine (6 cases), cirrhosis with
portal hypertension (2 cases), anticardiolipid antibodies (2 cases). The clinical
findings were similar to those reported for PH in HIV seronegative patients;
however, in 5 cases, opiates could have alleviated dyspnea, which became
perceptible only at the time of drug withdrawal. Because drug addicts usually
exhibit a weak support for medical prescriptions, long term therapy needing
regular follow-up such as anticoagulation appears to be hazardous and even
dangerous. The prognosis remains poor, since the progression of PH led to the
death of one third patients within the year following the diagnosis.
PMID- 9551523
TI - [Very atypical lung disease].
PMID- 9551522
TI - [Percutaneous closure of an right-left interatrial shunt acquired after
pneumonectomy].
AB - Right to left shunt through a patent foramen ovale after pneumonectomy is a rare
complication. Its clinical presentation is a severe dyspnea with posture
dependency. The diagnosis is easily confirmed by contrast echocardiography. The
purpose of this article is to expose the interest of interventional
catheterization and transcatheter closure. This method appears to be a viable
alternative to surgery for those patients with precarious respiratory function.
PMID- 9551524
TI - Clinical evaluations of dorsiflexion assist controlled by spring ankle-foot
orthosis for hemiplegic patients.
AB - To examine the usefulness of Dorsiflexion Assist Controlled by Spring Ankle-Foot
Orthoses (DACS-AFO), 5 hemiplegic patients in Brunnstrom's recovery stage IV were
prescribed the DACS-AFO, after which their gait with the DACS-AFO was clinically
evaluated. Clinical observation did not reveal that their gait with the DACS-AFO
was better than that with an AFO which the patients usually used, except when one
patient walked on a slope. No significant difference in 10 m walking time was
found between when the DACS-AFO and shoehorn type AFO were used. Subjective
evaluations by the patients indicated that the DACS-AFO was as good as a shoehorn
type AFO in walking on flat and sloped surfaces, though its weight, noise, and
appearance caused by the cylinder of the DACS-AFO were regarded as poor. In spite
of the excellent biomechanical characteristics of the DACS-AFO, the patients did
not adopt it. The subjects in this study had already walked well with their own
shoehorn type AFO, and their selection may have been biased toward poor results.
However, we did not conclude that the DACS-AFO is superior to the shoehorn type
AFO for hemiplegic patients in the stage IV.
PMID- 9551525
TI - Pathological study of splenomegaly associated with cadmium-induced anemia in
rats.
AB - Splenomegaly was observed both in male and female Sprague-Dawley rats after 1
week of exposure to CdCl2 (0.6 mg Cd/kg/day). Spleen weight reached about double
that in controls by 8 weeks of Cd exposure. Histopathological examination of the
enlarged spleen revealed that iron- and lipid-laden histiocytes were clustered in
the periarterial lymphatic sheath, and the red pulp appeared to be expanded. It
is noteworthy that electron microscopy revealed marked poikilocytosis and Heinz
body formation in red blood cells (RBCs) in both the sinus and cord. Histiocytes
were swollen by a granular substance in the cytoplasm and also many secondary
lysosomes. These morphological findings indicate that degradation of damaged RBCs
induced by exposure to Cd might be promoted in the spleen and possibly cause
splenomegaly. This RBC damage-hemolysis-splenomegaly sequence is also considered
to be associated with the etiology of Cd-induced anemia. In addition to the
abnormal RBC degradation, nuclei of lymphocytes in the Cd-exposed spleen
exhibited high electron density, consistent with a preapoptotic state suggesting
the immunosuppressive effect of Cd.
PMID- 9551526
TI - [Two-phase helical hepatic CT. Contrast-injection protocol, optimal timing and
its usefulness in clinical cases].
AB - The usefulness of two-phase helical computed tomography (CT) of the liver was
evaluated in clinical cases. First, an optimal scanning protocol was determined
using time-attenuation analysis. Monophasic dynamic CT was performed with 100 ml
of contrast media (iodine 300 mg/ml) injected either at 3 ml/s or at 2 ml/s.
Aortic, hepatic and portal time-attenuation curves were made for each protocol.
The results showed that these two different injection protocols produce
equivalent enhancements and that the injection rate of 2 ml/s is satisfactorily
applicable to clinical cases. The first scanning (arterial phase) must be started
40-45 s after the beginning of the injection of contrast media and the second
scanning (delayed phase) 80-120 s after the beginning of injection. Using these
CT protocols, 327 cases were examined. In this study 83 hepatic lesions
(hepatocellular carcinoma : HCC, n = 29; suspected HCC, n = 30; hemangioma, n =
24) were evaluated. There were 15 HCCs smaller than 30 mm in diameter (71.4%)
detected by either arterial phase or delayed phase alone. This result indicates
that two-phase helical hepatic CT is very useful in the detection of small HCC.
Particularly, four of 5 HCCs of less than 10 mm in size (80%) showed a
hyperattenuation area in the arterial phase alone. HCCs which have sufficient
vascularity were also easily demonstrated. However, this two-phase helical
hepatic CT could not demonstrate 11 lesions (13.3%) with almost normal blood
supply. In such cases the complementary role of ultrasound (US) seems to be
important. Hence as a screening of hepatic mass lesions both CT and US are
necessary. Most HCC could be differentiated from hemangioma by an enhancement
pattern using this protocol. But the small liver lesions of less than 15 mm in
size with homogeneous hyperattenuation in the arterial phase and isoattenuation
in the delayed phase included HCC, hemangioma and metastatic tumors.
PMID- 9551527
TI - Comparison of the qualified occupational physician systems in the United Kingdom
and Japan.
AB - The British educational system of occupational medicine was compared to the
Japanese system. Furthermore, a comparison was carried out between the certified
occupational physician (COP) recognized by the Japan Society for Occupational
Health in Japan and the Associateship of the Faculty of Occupational Medicine
(AFOM) by the Faculty of Occupational Medicine (FOM) which is a part of the Royal
College of Physicians in the United Kingdom. Judging from the comparison of the
minimum total training period, the clinical training period, the occupational
health training period, the method of examination and the success rate between
COP and AFOM, it is suggested that the British system of occupational physicians
may be better as a training system for occupational medicine and may regard
occupational clinical training as more important than the Japanese system does. A
comparison of a Diploma in Occupational Medicine (Dip Occ Med) approved by the
FOM and the certification of occupational physicians by the Japan Medical
Association has shown that the former has an examination but there is no test
system in the latter. It should be discussed whether an examination system for
the certification of occupational physicians should be introduced into the
Japanese system in the near future.
PMID- 9551528
TI - [Virulence factors and host responses in urinary tract infections].
AB - Pathogenicity of urinary tract infection (UTI) has been reviewed mainly focussing
on the bacterial adherence in uropathogens and the inflammatory responses of
urinary mucosa. Bacterial fimbriae or pili, which are encoded by chromosomal gene
clusters played a major role in the adherence mechanisms of uropathogenic
bacteria, including Escherichia coli. Furthermore, inflammatory responses in
urinary mucosa including cytokine release was also investigated. The latest
information concerning pathogenicity of UTI is described and discussed here.
PMID- 9551529
TI - [Expertise in occupational health nursing (I). Report on a visit to US
occupational health institutions].
AB - As industries' structures have evolved and diversified recently, the framework of
occupational health nursing has been expanded on multidisciplinary bases. On the
occasion of the opening of the School of Health Sciences, University of
Occupational and Environmental Health, Japan (UOEH), the author was given an
opportunity to visit US administrations, academic institutions and some
industries to investigate occupational medicine and health nursing in that
country. And as the author took part in programming the 17th UOEH International
Symposium on Occupational Health Nursing Expertise that took place at the campus
of the University in October, 1997, these two events are reported in this paper.
The first part of the report is on the visit to the US occupational health
professionals including occupational health doctors, nurses, industrial
hygienists and other staffs. They have perceived that there has never been more
emphasis placed on the significance of occupational health services than in
recent years, and that young students have become more interested in occupational
health. The second report will be on the 17th UOEH International Symposium-
Occupational Health Nursing Expertise--the next time.
PMID- 9551530
TI - [Diversity of P 450: biology and application of diversozyme].
AB - Cytochrome P 450s (P 450s) are a gene superfamily of heme enzymes involved in
xeno-or endo-biotic metabolisms. They have approximately 500 isozymes via
evolution, immense diversity in their functions and a broad range of substrate
specificities. Thus, they are called diversozymes and their versatility is
understood as a mechanism for living via detoxification of toxicants. However,
some of the huge human-made chemicals are bioactivated by P 450s. To explain
diversity of P 450s, further studies regarding relations between crystal
structures and functions of P 450s are required. P 450s can be applied for
exposure-biomarkers of environmental pollution, screening of drug metabolism and
remedy for pollutants.
PMID- 9551531
TI - [Simultaneous laparoscopic therapy of cholecysto- and choledocholithiasis. An
analysis of results].
AB - INTRODUCTION: With the advent of laparoscopic cholecystectomy, ERCP has gained
importance in the treatment of choledocholithiasis. Laparoscopic cholecystectomy
with intraoperative cholangiography and common bile duct surgery allows diagnosis
and treatment of cholecystolithiasis and choledocholithiasis in a single
procedure. PATIENTS AND METHODS: Laparoscopic treatment of choledocholithiasis
was evaluated in 99 consecutive patients with choledocholithiasis. 28 patients
underwent successful preoperative ERCP. Of the patients with intraoperative
confirmation of choledocholithiasis, removal was attempted by a transcystic
approach in 36 and 23 underwent choledochotomy. 24 patients with a high operative
risk underwent postoperative ERCP. RESULTS: The transcystic approach was
successful in 72.2%. Choledochotomy was successful in 91.3%, yielding a combined
success rate of 80%, 3.4% had local complications and 8.4% had other
complications (complication rate 11.8%), 20.3% of the patients underwent ERCP
after failed laparoscopic procedures. One patient had a laparoscopic redo. There
was no mortality and no conversion to open surgery. CONCLUSION: ERCP and
laparoscopic common bile duct surgery are complementary, efficient and safe
modalities of treatment for choledocholithiasis. Choice of procedure is
influenced by the surgeon's experience and institutional infrastructure, and the
individual patient.
PMID- 9551532
TI - [Surgery of mitral valve insufficiency. Results of 10 years].
AB - From 1987 to 1996 we operated on 263 patients for mitral insufficiency. Multiple
valve operations were excluded, with the exception of tricuspid reconstruction
for functional regurgitation. The perioperative mortality was 3%, while the late
mortality rate during a mean follow-up period of 3.5 years amounted to 2% per
patient year and 1.7% if only cardiac causes were considered. The prognosis for
patients with rheumatic, endocarditic and ischemic valvular disease was much
worse compared to that for a degenerative cause. The latter group consisted of
209 patients with an operative mortality of 1.4% and a late mortality rate per
patient year of 1.4% and 0.9% for cardiac causes only. Further analysis showed a
significant prognostic improvement for patients with a preoperative ejection
fraction of more than 60% and a repairable valve.
PMID- 9551533
TI - [Hypokalemic periodic paralysis: new advances].
AB - We present a 56-year-old man with an episode of hypokalemic periodic paralysis.
There are several interesting aspects of this rare disease, such as the
suggestive history and clinical signs (sudden onset, symmetrical paralysis mainly
of the lower extremities, "walking-off" phenomenon, no symptoms or signs between
attacks) or the unexplained episodic character of the attacks. It belongs to the
recently recognized ion channel diseases, a group of disorders in which mutations
of genes encoding the channel protein are responsible for defective channel
function. Molecular studies of mutated channels or channel subunits should
provide insight into channel functioning and help to develop effective drug
treatment. Once diagnosis of hypokalemic periodic paralysis is established,
treatment and regular follow-up are necessary to prevent the development of
permanent muscle weakness. The increasing mobility of the world's population will
add to the frequency of thyrotoxic hypokalemic periodic paralysis (which is
relatively frequent in Asian populations) even in Western countries.
PMID- 9551534
TI - [Hypermobility syndrome. When too much activity causes pain].
AB - Hypermobility of joints and spine is a consequence of abnormal laxity of
ligaments, joint capsules and intervertebral discs. Hypermobility per se is a
state, not a disease. However, it may lead to generalized arthralgia or localized
symptoms (frequent ankle sprains, knee effusions, dislocations of the shoulders
of recurrent episodes of back pain). These events may occur even after minor
strains. Young women are preferentially affected. The term "hypermobility
syndrome" is defined as a combination of hypermobility with arthralgia, low back
pain, frequent dislocation or sprains. It is often the result of a hereditary
disorder of connective tissue. Individuals with hypermobility are at increased
risk for premature osteoarthrosis or polytopic disc degeneration of the spine.
However, the vast majority of hyperlax individuals are free of symptoms. Those
with symptoms who do not develop osteoarthrosis or disc degeneration usually
experience spontaneous improvement with increasing age, thus losing their
juvenile hyperlaxity. This usually occurs between the ages of thirty and forty.
The present review article also provides guidelines for management and patient
information.
PMID- 9551535
TI - [PPPP (post-proctoscopy periorbital purpura)].
PMID- 9551536
TI - [A temporary reduction of emotional reactivity in postweaning, prejuvenile rats:
examination by the Runway Test].
AB - Developmental change of emotional reactivity in Wistar rats was investigated by
two experiments using the Runway Test. Rats were tested at 20, 30, 40, 60, and 90
days of age for three successive days. First, a cross-sectional comparison of
behavior in the Runway Test showed that 30-day-old rats were faster to enter the
runway region, faster to reach the end section, and traversed more sections than
other age groups. Rats at 60 and 90 days of age defecated more bolles and
urinated more. Second, longitudinal comparisons showed that the ambulation of 30-
and 40-day-old rats increased gradually over test days, suggesting lowered
emotional reactivity. But 60- and 90-day-old rats showed asymptotic level of
ambulation and no increase between days and less defecation. These results
suggested that postweaning prejuvenile rats showed a temporary reduction of
emotional reactivity in novel environments. Also, their emotional reactivity
elevated gradually, and remained stable in each individual level.
PMID- 9551537
TI - [The effects of self-perception and attitudes to cultures on international
students' feeling of adjustment].
AB - Asian students of seven Japanese language schools participated, and data of 292
Chinese, Taiwanese, and Korean students were analyzed in this study. They were
asked about (1) attitudes toward their own and other cultures, (2) high regard
for their country and culture, (3) self-efficacy and social skills at the moment
and when they were in their country, (4) aspired level of social skills in this
country, and (5) feeling of adjustment to life in Japan. Main findings were as
follows: (1) psychological factors had stronger effects on the feeling than
demographic factors. Self-efficacy in particular had a strong effect. (2)
Attitudes to own and other cultures were related to self-efficacy and the
feeling. (3) Structural analysis revealed a difference in the feeling between
students from socialist and capitalist regions. Based on the analysis, a causal
model was proposed of psychological and demographic factors leading to feeling of
adjustment, and Asian students' adjustment to life in Japan was discussed in
terms of adjustment to their inner, psychological environment.
PMID- 9551538
TI - [Effect of vibrational factors on the evaluation of whole-body vibrational
intensity].
AB - The aim of this study is to obtain basic data useful to evaluate the riding
comfort of railway vehicles. The apparatus used in the present experiment made it
possible to simulate various vibrations of railway vehicles. Twenty-two adult
subjects participated in this experiment. They were exposed to lateral vibration
with varying peak and root mean square (rms) accelerations and frequencies. The
types and ranges of vibrations used in this experiment approximated to the
typical vibrations of railway vehicles. The subjects were asked to rate the
intensity of each vibration given to them successively, using the 7-step rating
scale. Results indicated that both peak and rms accelerations significantly
affected for the evaluation, although the effect of frequency was not
significant. As for interactions, it was found that there were significant
interacting effects between frequency and peak acceleration, between frequency
and rms acceleration, and between peak and rms accelerations. It was also found
that the relationship between the rms acceleration and the evaluated score
changed with varying peak accelerations.
PMID- 9551539
TI - [The effects of subliminal and supraliminal presentation of trait-related words
on person perception].
AB - The present experiment was conducted to investigate how prior information affects
subsequent person perception and when perceivers can control such an effect. One
of three types of trait related words (i.e., hostility-related, friendliness
related, and neutral words) was subliminally or supraliminally presented to
subjects, and subsequently, subjects rated the impression of four targets: a
hostile person, a friendly person, a neutral person and themselves. Although
results did not show that supraliminally presented words affected targets'
impressions, they showed that the impressions sometimes varied with the valence
of subliminally presented words regardless of targets' valence. The mechanism and
controllability of priming effects in person perception were discussed.
PMID- 9551540
TI - [The effect of self-enhancement expectation on selection of comparisons as a self
assessment strategy].
AB - Selection of others for comparison influences the outcome of self-assessment. The
present study attempted to examine the effect of expectation for self-enhancement
on strategic selection of comparisons. A questionnaire study was conducted with
169 undergraduates, who responded to four sets of questions. First, they listed
ten abilities each for three areas that desired to acquire in high-level, in
average-level, and undesired to acquire. Then, they evaluated themselves in
comparison with others on the thirty abilities, and indicated whom they chose as
comparisons. Finally, perceived probabilities were assessed of acquiring each
ability. Results showed that selection of superior others was more when evaluated
abilities were desired to acquire in high-level and perceived probability high
than otherwise. This suggested that comparison with superior others was made if
expectation for self-enhancement was high. The expectation therefore affects the
likelihood of self-assessment behavior, and self-assessment is a necessary
component of future self-enhancement.
PMID- 9551541
TI - [Relationship-enhancement and relative self-effacement].
AB - Two studies investigated the tendency of people to enhance their close
relationship and to efface oneself in front of their partners. In Study 1, 193
college students estimated the extent to which their best friendship is better
than other's best friendship. Overall, they showed a strong tendency of enhancing
own relationship; they rated their best friendship to be better than the average.
Within the close relationship, however, they showed self-effacement; they rated
their best friends, compared with themselves, in more positive way. In Study 2,
41 husband-wife couples attended as subjects. Again, they showed marital
relationship-enhancement and relative self-effacement. Furthermore, their
subjective happiness was mainly explained by own relationship enhancement. These
results were discussed from several points.
PMID- 9551542
TI - [The effect of prior information on perception of ongoing behavior of others:
information processing at the extraction stage].
AB - This study investigated the effect of prior information on the extraction stage,
particularly on the amount of behavior extraction, of information processing when
perceiving ongoing behavior of others. In terms of prior information they
received, 102 subjects were randomly assigned to three groups: familiarity,
desirability, and neutral conditions. Twelve video clips, each about 30 seconds
long, of a male stimulus actor in daily life were made. The theme of each clip
was one of the three: familiarity, desirability, or activity. The subjects were
instructed to form an impression of the male actor, and to press a button when
they saw an impression-relevant action and release it when it was over. Results
suggested that subjects extracted behavior that was relevant to prior information
more frequently, and extraction rates were higher for relevant video clips.
However, impression change was found after the observation-extraction task.
Hence, it implies that prior information affects the extraction stage, but not
the judgment stage, of perceiving ongoing behavior of others.
PMID- 9551543
TI - [Stress-buffering effects of perceived social supports from family members and
friends: a comparison of college students and middle-aged adults].
AB - This study investigated perceived social support, emotional as well as
instrumental, from family members and friends, and examined their stress
buffering effects on depression in college students and middle-aged adults in
Japan. For both samples, family members were relatively more important sources of
instrumental support, whereas friends were primarily perceived as emotional
support providers. No gender differences were found for the middle-aged adults,
but as in previous studies, women in the college sample perceived more support
for them than men. A series of hierarchical regression analyses with support by
stress interaction terms revealed distinctive patterns of support effects on
depression for men and women of each sample. Characteristics of perceived social
support in each sample were described, and overall results suggested that it is
essential in social support research to take the meanings of supportive
relationship into consideration, in the context of social and developmental
factors of the samples under study.
PMID- 9551544
TI - [The role of similarity and category in confirmation judgement of category-based
induction: an examination of the similarity-coverage model].
AB - Induction is called category-based induction if its premises and conclusion are
of the form "All members of a category C have property P." Osherson, Smith,
Wilkie, Lopez, and Shafir (1990) advanced similarity-coverage model. But their
data from a quantitative test of specific induction did not necessarily support
the model. Three experiments investigate whether their modeling of similarity and
coverage was not valid or their experiments were not valid. The following results
were obtained. Coverage did not affect confirmation judgement in premise
variation type induction which Osherson et al. (1990) dealt with, and coverage
effect was verified in conclusion-variation type induction which is more everyday
and needs less processing load. In the latter case, coverage had to be weighted
by typicality of conclusion in an inclusive category. And when mixed inductions
were included, confirmation judgement was based not on coverage but on a
belonging relation to an upper category and similarity between premise categories
and a conclusion category.
PMID- 9551545
TI - [On the relationship between recognition memory of items and test-retest effect].
AB - The main purpose of this paper is to examine the relationship of recognition
memory of test items to test-retest effect. For this aim, two tests consisting of
17 items from self-evaluative consciousness scale and 24 dummy items were
administered to 163 female college students at an interval of one week. Although
the results showed clear test-retest of type A and B (Hasegawa, 1995b), namely
the changes in their self-ratings on both positive and negative items toward a
more adjustive level, the test-retest effect of type II (Hayamizu, 1977), namely
the increase in internal consistency of subscale, did not appear. The results
also showed no influence of the rate of item recognition to the test-retest
effects, leading to a modification of some part of the hypotheses. This result
suggests that it is implicit memory rather than recognition memory that is
related to test-retest effect.
PMID- 9551546
TI - Revealing mechanisms for SH2 domain mediated regulation of the protein tyrosine
phosphatase SHP-2.
AB - The crystal structure of the protein tyrosine phosphatase SHP-2 reveals the
mechanism of auto-inhibition of phosphatase activity by its SH2 domains.
Phosphotyrosine peptide stimulation of the phosphatase activity, resulting from
peptide binding to the N-terminal SH2 domain, is linked to conformational changes
within the protein, including an unprecedented allosteric transition of the N
terminal SH2 domain.
PMID- 9551547
TI - NO news is good news.
AB - The recent determination of the crystal structure of microsomal cytochrome P450
reductase, a diflavin protein that shuttles electrons from NADPH to the P450
heme, represents a significant advance towards the understanding of cytochromes
P450. A similar advance was made in a related enzyme system, nitric oxide
synthase (NOS). The crystal structure of the NOS heme domain reveals a very
different architecture to that observed in P450s and offers significant insight
into the production of nitric oxide, one of nature's most important regulatory
molecules.
PMID- 9551548
TI - Marrying structure and genomics.
PMID- 9551549
TI - The Argonne Structural Genomics Workshop: Lamaze class for the birth of a new
science.
PMID- 9551550
TI - New aspects of electron transfer revealed by the crystal structure of a truncated
bovine adrenodoxin, Adx(4-108).
AB - BACKGROUND: Adrenodoxin (Adx) is a [2Fe-2S] ferredoxin involved in steroid
hormone biosynthesis in the adrenal gland mitochondrial matrix of mammals. Adx is
a small soluble protein that transfers electrons from adrenodoxin reductase (AR)
to different cytochrome P450 isoforms where they are consumed in hydroxylation
reactions. A crystallographic study of Adx is expected to reveal the structural
basis for an important electron transfer reaction mediated by a vertebrate [2Fe
2S] ferredoxin. RESULTS: The crystal structure of a truncated bovine adrenodoxin,
Adx(4-108), was determined at 1.85 A resolution and refined to a crystallographic
R value of 0.195. The structure was determined using multiple wavelength
anomalous dispersion phasing techniques, making use of the iron atoms in the [2Fe
2S] cluster of the protein. The protein displays the compact (alpha + beta) fold
typical for [2Fe-2S] ferredoxins. The polypeptide chain is organized into a large
core domain and a smaller interaction domain which comprises 35 residues,
including all those previously determined to be involved in binding to AR and
cytochrome P450. A small interdomain motion is observed as a structural
difference between the two independent molecules in the asymmetric unit of the
crystal. Charged residues of Adx(4-108) are clustered to yield a strikingly
asymmetric electric potential of the protein molecule. CONCLUSIONS: The crystal
structure of Adx(4-108) provides the first detailed description of a vertebrate
[2Fe-2S] ferredoxin and serves to explain a large body of biochemical studies in
terms of a three-dimensional structure. The structure suggests how a change in
the redox state of the [2Fe-2S] cluster may be coupled to a domain motion of the
protein. It seems likely that the clearly asymmetric charge distribution on the
surface of Adx(4-108) and the resulting strong molecular dipole are involved in
electrostatic steering of the interactions with AR and cytochrome P450.
PMID- 9551551
TI - Activation of Bacillus licheniformis alpha-amylase through a disorder-->order
transition of the substrate-binding site mediated by a calcium-sodium-calcium
metal triad.
AB - BACKGROUND: The structural basis as to how metals regulate the functional state
of a protein by altering or stabilizing its conformation has been characterized
in relatively few cases because the metal-free form of the protein is often
partially disordered and unsuitable for crystallographic analysis. This is not
the case, however, for Bacillus licheniformis alpha-amylase (BLA) for which the
structure of the metal-free form is available. BLA is a hyperthermostable enzyme
which is widely used in biotechnology, for example in the breakdown of starch or
as a component of detergents. The determination of the structure of BLA in the
metal-containing form, together with comparisons to the apo enzyme, will help us
to understand the way in which metal ions can regulate enzyme activity. RESULTS:
We report here the crystal structure of native, metal-containing BLA. The
structure shows that the calcium-binding site which is conserved in all alpha
amylases forms part of an unprecedented linear triadic metal array, with two
calcium ions flanking a central sodium ion. A region around the metal triad
comprising 21 residues exhibits a conformational change involving a helix
unwinding and a disorder-->order transition compared to the structure of metal
free BLA. Another calcium ion, not previously observed in alpha-amylases, is
located at the interface between domains A and C. CONCLUSIONS: We present a
structural description of a major conformational rearrangement mediated by metal
ions. The metal induced disorder-->order transition observed in BLA leads to the
formation of the extended substrate-binding site and explains on a structural
level the calcium dependency of alpha-amylases. Sequence comparisons indicate
that the unique Ca-Na-Ca metal triad and the additional calcium ion located
between domains A and C might be found exclusively in bacterial alpha-amylases
which show increased thermostability. The information presented here may help in
the rational design of mutants with enhanced performance in biotechnological
applications.
PMID- 9551552
TI - Copper amine oxidase from Hansenula polymorpha: the crystal structure determined
at 2.4 A resolution reveals the active conformation.
AB - BACKGROUND: Copper-containing amine oxidases (CAOs) are widespread in nature.
These enzymes oxidize primary amine substrates to the aldehyde product, reducing
molecular oxygen to hydrogen peroxide in the process. CAOs contain one type 2
copper atom and topaquinone (TPQ), a modified tyrosine sidechain utilized as a
redox cofactor. The methylamine oxidase from the yeast Hansenula polymorpha
(HPAO) is an isoform of CAO with a preference for small aliphatic amine or
phenethylamine substrates. The enzyme is dimeric with a subunit molecular weight
of 78 kDa. Structural studies are directed at understanding the basis for
cofactor biogenesis and catalytic efficiency. RESULTS: The X-ray crystal
structure of HPAO has been solved at 2.4 A resolution by a combination of
molecular replacement and single isomorphous replacement followed by refinement
using sixfold symmetry averaging. The electron density at the catalytic site
shows that the TPQ conformation corresponds to that of the active form of the
enzyme. Two channels, one on either side of TPQ, are observed in the structure
that provide access between the active site and the bulk solvent. CONCLUSIONS:
The structure shows TPQ in a position poised for catalysis. This is the first
active CAO structure to reveal this conformation and may help further our
understanding of the catalytic mechanism. On the substrate side of TPQ a water
containing channel leading to the protein surface can serve as an entrance or
exit for substrate and product. On the opposite side of TPQ there is direct
access from the bulk solvent of the dimer interface by which molecular oxygen may
enter and hydrogen peroxide depart. In addition, a network of conserved water
molecules has been identified which may function in the catalytic mechanism.
PMID- 9551553
TI - Human theta class glutathione transferase: the crystal structure reveals a
sulfate-binding pocket within a buried active site.
AB - BACKGROUND: Glutathione S-transferases (GSTs) comprise a multifunctional group of
enzymes that play a critical role in the cellular detoxification process. These
enzymes reduce the reactivity of toxic compounds by catalyzing their conjugation
with glutathione. As a result of their role in detoxification, GSTs have been
implicated in the development of cellular resistance to antibiotics, herbicides
and clinical drugs and their study is therefore of much interest. In mammals, the
cytosolic GSTs can be divided into five distinct classes termed alpha, mu, pi,
sigma and theta. The human theta class GST, hGST T2-2, possesses several
distinctive features compared to GSTs of other classes, including a long C
terminal extension and a specific sulfatase activity. It was hoped that the
determination of the structure of hGST T2-2 may help us to understand more about
this unusual class of enzymes. RESULTS: Here we present the crystal structures of
hGST T2-2 in the apo form and in complex with the substrates glutathione and 1
menaphthyl sulfate. The enzyme adopts the canonical GST fold with a 40-residue C
terminal extension comprising two helices connected by a long loop. The extension
completely buries the substrate-binding pocket and occludes most of the
glutathione-binding site. The enzyme has a purpose-built novel sulfate-binding
site. The crystals were shown to be catalytically active: soaks with 1-menaphthyl
sulfate result in the production of the glutathione conjugate and cleavage of the
sulfate group. CONCLUSIONS: hGST T2-2 shares less than 15% sequence identity with
other GST classes, yet adopts a similar three-dimensional fold. The C-terminal
extension that blocks the active site is not disordered in either the apo or
complexed forms of the enzyme, but nevertheless catalysis occurs in the
crystalline state. A narrow tunnel leading from the active site to the surface
may provide a pathway for the entry of substrates and the release of products.
The results suggest a molecular basis for the unique sulfatase activity of this
GST.
PMID- 9551554
TI - The structure of the complex of plastocyanin and cytochrome f, determined by
paramagnetic NMR and restrained rigid-body molecular dynamics.
AB - BACKGROUND: The reduction of plastocyanin by cytochrome f is part of the chain of
photosynthetic electron transfer reactions that links photosystems II and I. The
reaction is rapid and is influenced by charged residues on both proteins.
Previously determined structures show that the plastocyanin copper and cytochrome
f haem redox centres are some distance apart from the relevant charged
sidechains, and until now it was unclear how a transient electrostatic complex
can be formed that brings the redox centres sufficiently close for a rapid
reaction. RESULTS: A new approach was used to determine the structure of the
transient complex between cytochrome f and plastocyanin. Diamagnetic chemical
shift changes and intermolecular pseudocontact shifts in the NMR spectrum of
plastocyanin were used as input in restrained rigid-body molecular dynamics
calculations. An ensemble of ten structures was obtained, in which the root mean
square deviation of the plastocyanin position relative to cytochrome f is 1.0 A.
Electrostatic interaction is maintained at the same time as the hydrophobic side
of plastocyanin makes close contact with the haem area, thus providing a short
electron transfer pathway (Fe-Cu distance 10.9 A) via residues Tyr1 or Phe4
(cytochrome f) and the copper ligand His87 (plastocyanin). CONCLUSIONS: The
combined use of diamagnetic and paramagnetic chemical shift changes makes it
possible to obtain detailed information about the structure of a transient
complex of redox proteins. The structure suggests that the electrostatic
interactions 'guide' the partners into a position that is optimal for electron
transfer, and which may be stabilised by short-range interactions.
PMID- 9551555
TI - Adaptation of an enzyme to regulatory function: structure of Bacillus subtilis
PyrR, a pyr RNA-binding attenuation protein and uracil phosphoribosyltransferase.
AB - BACKGROUND: The expression of pyrimidine nucleotide biosynthetic (pyr) genes in
Bacillus subtilis is regulated by transcriptional attenuation. The PyrR
attenuation protein binds to specific sites in pyr mRNA, allowing the formation
of downstream terminator structures. UMP and 5-phosphoribosyl-1-pyrophosphate
(PRPP), a nucleotide metabolite, are co-regulators with PyrR. The smallest RNA
shown to bind tightly to PyrR is a 28-30 nucleotide stem-loop that contains a
purine-rich bulge and a putative-GNRA tetraloop. PyrR is also a uracil
phosphoribosyltransferase (UPRTase), although the relationship between enzymatic
activity and RNA recognition is unclear, and the UPRTase activity of PyrR is not
physiologically significant in B. subtilis. Elucidating the role of PyrR
structural motifs in UMP-dependent RNA binding is an important step towards
understanding the mechanism of pyr transcriptional attenuation. RESULTS: The 1.6
A crystal structure of B. subtilis PyrR has been determined by multiwavelength
anomalous diffraction, using a Sm co-crystal. As expected, the structure of PyrR
is homologous to those proteins of the large type I PRTase structural family; it
is most similar to hypoxanthine-guanine-xanthine PRTase (HGXPRTase). The PyrR
dimer differs from other PRTase dimers, suggesting it may have evolved
specifically for RNA binding. A large, basic, surface at the dimer interface is
an obvious RNA-binding site and uracil specificity is probably provided by
hydrogen bonds from mainchain and sidechain atoms in the hood subdomain. These
models of RNA and UMP binding are consistent with biological data. CONCLUSIONS:
The B. subtilis protein PyrR has adapted the substrate- and product-binding
capacities of a PRTase, probably an HGXPRTase, producing a new regulatory
function in which the substrate and product are co-regulators of transcription
termination. The structure is consistent with the idea that PyrR regulatory
function is independent of catalytic activity, which is likely to be extremely
low under physiological conditions.
PMID- 9551556
TI - Structural adaptations of the cold-active citrate synthase from an Antarctic
bacterium.
AB - BACKGROUND: The structural basis of adaptation of enzymes to low temperature is
poorly understood. Dimeric citrate synthase has been used as a model enzyme to
study the structural basis of thermostability, the structure of the enzyme from
organisms living in habitats at 55 degrees C and 100 degrees C having previously
been determined. Here the study is extended to include a citrate synthase from an
Antarctic bacterium, allowing us to explore the structural basis of cold activity
and thermostability across the whole temperature range over which life is known
to exit. RESULTS: We report here the first crystal structure of a cold-active
enzyme, citrate synthase, isolated from an Antarctic bacterium, at a resolution
of 2.09 A. In comparison with the same enzyme from a hyperthermophilic host, the
cold-active enzyme has a much more accessible active site, an unusual
electrostatic potential distribution and an increased relative flexibility of the
small domain compared to the large domain. Several other features of the cold
active enzyme were also identified: reduced subunit interface interactions with
no intersubunit ion-pair networks; loops of increased length carrying more charge
and fewer proline residues; an increase in solvent-exposed hydrophobic residues;
and an increase in intramolecular ion pairs. CONCLUSIONS: Enzymes from organisms
living at the temperature extremes of life need to avoid hot or cold denaturation
yet maintain sufficient structural integrity to allow catalytic efficiency. For
hyperthermophiles, thermal denaturation of the citrate synthase dimer appears to
be resisted by complex networks of ion pairs at the dimer interface, a feature
common to other hyperthermophilic proteins. For the cold-active citrate synthase,
cold denaturation appears to be resisted by an increase in intramolecular ion
pairs compared to the hyperthermophilic enzyme. Catalytic efficiency of the cold
active enzyme appears to be achieved by a more accessible active site and by an
increase in the relative flexibility of the small domain compared to the large
domain.
PMID- 9551557
TI - The structure of SAICAR synthase: an enzyme in the de novo pathway of purine
nucleotide biosynthesis.
AB - BACKGROUND: The biosynthesis of key metabolic components is of major interest to
biologists. Studies of de novo purine synthesis are aimed at obtaining a deeper
understanding of this central pathway and the development of effective
chemotherapeutic agents. Phosphoribosylaminoimidazolesuccinocarboxamide (SAICAR)
synthase catalyses the seventh step out of ten in the biosynthesis of purine
nucleotides. To date, only one structure of an enzyme involved in purine
biosynthesis has been reported: adenylosuccinate synthetase, which catalyses the
first committed step in the synthesis of AMP from IMP. RESULTS: We report the
first three-dimensional structure of a SAICAR synthase, from Saccharomyces
cerevisiae. It is a monomer with three domains. The first two domains consist of
antiparallel beta sheets and the third is composed of two alpha helices. There is
a long deep cleft made up of residues from all three domains. Comparison of
SAICAR synthases by alignment of their sequences reveals a number of conserved
residues, mostly located in the cleft. The presence of two sulphate ions bound in
the cleft, the structure of SAICAR synthase in complex with ATP and a comparison
of this structure with that of other ATP-dependent proteins point to the
interdomain cleft as the location of the active site. CONCLUSIONS: The topology
of the first domain of SAICAR synthase resembles that of the N-terminal domain of
proteins belonging to the cyclic AMP-dependent protein kinase family. The fold of
the second domain is similar to that of members of the D-alanine:D-alanine ligase
family. Together these enzymes form a new superfamily of mononucleotide-binding
domains. There appears to be no other enzyme, however, which is composed of the
same combination of three domains, with the individual topologies found in SAICAR
synthase.
PMID- 9551558
TI - The structure of the Escherichia coli phosphotransferase IIAmannitol reveals a
novel fold with two conformations of the active site.
AB - BACKGROUND: The bacterial phosphoenolpyruvate-dependent phosphotransferase system
(PTS) catalyses the cellular uptake and subsequent phosphorylation of
carbohydrates. Moreover, the PTS plays a crucial role in the global regulation of
various metabolic pathways. The PTS consists of two general proteins, enzyme I
and the histidine-containing protein (HPr), and the carbohydrate-specific enzyme
II (EII). EIIs are usually composed of two cytoplasmic domains, IIA and IIB, and
a transmembrane domain, IIC. The IIA domains catalyse the transfer of a
phosphoryl group from HPr to IIB, which phosphorylates the transported
carbohydrate. Knowledge of the structures of the IIA proteins may provide insight
into the mechanisms by which the PTS couples phosphorylation reactions with
carbohydrate specificity. RESULTS: We have determined the crystal structure of
the Escherichia coli mannitol-specific IIA domain, IIAmtl (M(r) 16.3 kDa), by
multiple anomalous dispersion analysis of a selenomethionine variant of IIAmtl.
The structure was refined at 1.8 A resolution to an R factor of 19.0% (Rfree
24.2%). The enzyme consists of a single five-stranded mixed beta sheet, flanked
by helices on both sides. The phosphorylation site (His65) is located at the end
of the third beta strand, in a shallow crevice lined with hydrophobic residues.
The sidechains of two conserved active-site residues, Arg49 and His111, adopt two
different conformations in the four independent IIAmtl molecules. Using a
solution structure of phosphorylated HPr, and a combination of molecular
modelling and NMR binding experiments, structural models of the HPr-IIAmtl
complex were generated. CONCLUSIONS: The fold of IIAmtl is completely different
from the structures of other IIA proteins determined so far. The two
conformations of Arg49 and His111 might represent different states of the active
site, required for the different phosphoryl transfer reactions in which IIAmtl is
involved. A comparison of the HPr-IIAmtl model with models of HPr in complex with
other IIA enzymes shows that the overall interaction mode between the two
proteins is similar. Differences in the stabilisation of the invariant residue
Arg17 of HPr by the different IIA proteins might be part of a subtle mechanism to
control the hierarchy of carbohydrate utilisation by the bacterium.
PMID- 9551559
TI - The 80S rat liver ribosome at 25 A resolution by electron cryomicroscopy and
angular reconstitution.
AB - BACKGROUND: The ribosome is central to protein synthesis in all living organisms.
Single-particle electron cryomicroscopy has recently led to the determination of
three-dimensional structures of bacterial ribosomes to approximately 20 A, which
have since revolutionised our understanding of ribosomal function. The structure
we present here of the 80S rat liver ribosome leads the way to similar progress
for mammalian ribosomes. RESULTS: Among the new details revealed by our 25 A
structure of the 80S rat liver ribosome are channels within the subunits, a large
'flat ribosomal surface' (FRS) on the outer surface of the large subunit and
structural extensions of the mammalian compared to the bacterial ribosome. The
main large subunit channel in both the bacterial and the mammalian species starts
at the peptidyl transferase centre, below the central protuberance, and ends in
the FRS, at the lower back of the large subunit. Structurally, the channels of
both species can be directly superimposed. CONCLUSIONS: The mammalian structural
extensions--none of which trespass the FRS--can be interpreted in terms of rRNA
inserts and additional protein content over that of bacterial ribosomes. The main
large subunit channel, which ends at the FRS, is the best candidate for the exit
channel for proteins targeted for the endoplasmic reticulum.
PMID- 9551560
TI - [Postprandial hemodynamic reactions].
PMID- 9551561
TI - [The characteristics of peptic ulcer in subjects with concomitant ischemic heart
disease].
AB - AIM: The study of clinical running of gastric or duodenal ulcer in associated
coronary heart disease (CHD). MATERIALS AND METHODS: 209 CHD patients with
gastric ulcer (GU) or duodenal ulcer (DU) were examined clinically plus
histological examination of gastric or duodenal mucosa biopsies was made.
RESULTS: In CHD patients GU occurred more frequently (56%) than DU. The lesions
involved more frequently lesser curvature of the stomach and pyloric part of the
stomach. Males developed ulcers 3.5 times more frequently than females. Ulcers
tended to a painless course without season exacerbations. The disease manifested
first with gastric bleeding in 52% of the patients. GU and DU ran with frequent
recurrences and long-term exacerbations (76% of patients) which coincided in time
with CHD exacerbations. 68% of patients developed exacerbations within 10 days
after myocardial infarction or aortocoronary bypass operation. Helicobacter
pylori was present as a resolving factor in arising ulcer in 26% of patients.
Microcirculatory disorders, reduced blood flow speed in gastric or duodenal
mucosa, hypocoagulation syndrome, dyslipidemia provoked exacerbations in 62% of
patients. Examinations of biopsies from gastric and duodenal mucosa showed marked
dystrophic changes in the mucosa, its connective tissue basis in the vessels in
the presence of mild inflammation at ulcer site. CONCLUSION: The onset of ulcers
and erosions in the mucosa of the gastrointestinal tract in CHD may be due to
circulatory disorders in gastric mucosa. The main factors of aggression are
hypoxia, hypoxia-induced trophic defects in gastric and duodenal mucosa,
circulatory disorders.
PMID- 9551562
TI - [The effect of combined treatment using bicycle exercise with a free choice of
the load parameters on the hemodynamics in peptic ulcer patients].
AB - AIM: To study the role of bicycle exercise in combined treatment of gastric and
duodenal ulcer, its effect on central hemodynamics and microcirculation.
MATERIALS AND METHODS: 94 patients with gastric and duodenal ulcer. 64 patients
received conventional antiulcer treatment plus exercised on bicycle ergometer in
free regimen of training. 30 patients on the routine treatment only served as
control. RESULTS: Doppler echocardiography demonstrated that ulcer patients have
eukinetic hemodynamic type more frequently. After combined treatment with bicycle
exercise hyper- and hypokinetic hemodynamic types transformed into the eukinetic
one, while the eukinetic type remained unchanged. Bicycle exercise contributed to
normalization of microcirculation (as shown by conjunctival biomicroscopy),
especially in location of ulcer in the duodenum. CONCLUSION: Introduction of
bicycle exercise in the treatment of ulcer promoted acceleration of ulcer defects
healing, especially in patients with hyperkinetic hemodynamics and duodenal
ulcer.
PMID- 9551563
TI - [The clinical and morphofunctional characteristics of different types of stomach
ulcer].
AB - AIM: The study of a complex of anamnestic, clinicoendoscopic and functional
morphological characteristics in type I and II (according to Johnson) gastric
ulcer. MATERIALS AND METHODS: Esophagogastroduodenoscopy, gastric secretion
tests, determination of blood group and Rh factor were performed in 91 patients
(52 patients with ulcer type I and 39 with ulcer type II). RESULTS: Ulcers type I
have arisen in the presence of long-term chronic gastritis. They were associated
with marked changes in the mucosa of gastric body, its atrophy and intestinal
metaplasia, persistent recurrences in the same gastric zone. Ulcers type II are
characterized by hereditary loading, 0(I) blood group, combination with
gastroduodenal erosions, season occurrence, trend to migration and recurrence in
different gastric or duodenal zones, HCl hypersecretion, high occurrence of
Helicobacter pylori infection. CONCLUSION: It is thought valid to include types
of gastric ulcer in current classification of ulcer.
PMID- 9551564
TI - [The diagnosis of chronic duodenal obstruction combined with duodenal peptic
ulcer].
AB - AIM: The study of clinical manifestations of chronic duodenal ileus (CDI) and
potential of specific methods of CDI diagnosis in its combination with duodenal
ulcer (DU). MATERIALS AND METHODS: Assessment of acid-producing gastric function,
duodenogastric reflux, manometry of the upper gastrointestinal tract,
fibrogastroduodenoscopy, ultrasonic and x-ray investigations were made in 1140
patients with chronic DU. RESULTS: 29.2% of the examinees were found to have CDI.
Specific features of CDI course are described. The diagnostic criteria are
defined. Higher informative value of the diagnostic methods can be achieved.
CONCLUSION: The findings can be used in the choice of DU treatment, for
formulation of indications to duodenocorrective interventions.
PMID- 9551565
TI - [The prognostic criteria of the course in newly detected duodenal peptic ulcer].
AB - AIM: Elucidation of the significance of various factors in prognosis of duodenal
ulcer (DU) severity. MATERIALS AND METHODS: The observational study entered 18
new cases of DU and 13 healthy controls. All the patients were followed up for 7
years with annual esophagogastroduodenoscopy. RESULTS: 10 patients (group 1) had
annual exacerbations of DU, 8 patients had rare exacerbations (group 2). Group 1
was characterized by basal acid hyperproduction, hyperpepsinogenemia,
hypergastrinemia, marked contamination with Helicobacter pylori. Patients of
group 2 had normal basal and pentagastrin-stimulated acid production,
normopepsinogenemia, normogastrinemia, mild Helicobacter pylori infection.
CONCLUSION: The 7-year follow-up of new DU cases allowed demonstration of
functional-morphological prognostic criteria for frequently and rarely recurrent
DU courses.
PMID- 9551566
TI - [Gastroesophageal reflux combined with Helicobacter pylori infection].
AB - AIM: Investigation of the role of Helicobacter pylori infection of the low
esophagus in patients with duodenal ulcer (DU). MATERIALS AND METHODS: Endoscopic
examination was performed in 40 DU patients. All the biopsies were examined for
Helicobacter pylori and degree of relevant contamination. RESULTS: Helicobacter
pylori was present in all the patients' antral stomachs. It contaminated the low
part of the esophagus in 17 of 40 patients. Endoscopic changes were more severe
in those patients who had the infection both in the stomach and in the esophagus.
CONCLUSION: The presence of Helicobacter pylori in the lower esophagus and antral
stomach in DU patients may entail negative changes in the stomach and esophagus.
PMID- 9551567
TI - [Bicarbonate deficiency and duodenal peptic ulcer].
AB - AIM: The study of alkaline gastric secretion in health and disease and its
changes in response to blockers of H2-histamine receptors. MATERIALS AND METHODS:
The trial enrolled 74 patients with duodenal ulcer (DU), 28 patients with chronic
gastric (CG) and 16 healthy controls. The secretion was studied initially, in
administration of ranitidine, in stimulation with hydrochloric acid. RESULTS: DU
patients demonstrated a significant reduction of gastric secretion of
bicarbonates in the basal and stimulated phases and a 3-fold decrease in the
proportion alkaline/acid secretion. There was also a trend to acidosis.
Administration of H2-histamine receptors provided recovery of acid-alkaline
balance. CONCLUSION: Bicarbonate deficiency is an important element of duodenal
ulcer pathogenesis.
PMID- 9551568
TI - [The characteristics of the lipid peroxidation and antioxidant activity of the
duodenal mucosa in peptic ulcer patients].
AB - AIM: Lipid peroxidation (LPO) and antioxidant defense (AOD) in ulcer and
periulcer zones of duodenal mucosa were studied at different phases of ulcer.
MATERIALS AND METHODS: 111 patients with duodenal ulcer exacerbation before
treatment and in the course of the treatment were studied versus 23 healthy
volunteers. RESULTS: In active ulcer there was high activity of LPO and depressed
AOD. LPO may be initiated by Helicobacter pylori. Pathogenetic measures including
anti-Helicobacter ones decreased LPO hyperactivity and promoted AOD
normalization. CONCLUSION: In ulcer, optimal treatment is supposed to combine
antisecretory and antibacterial drugs adjusted to the activity of ulcer and
imbalance between LPO and AOD systems in gastric and duodenal mucosa.
PMID- 9551569
TI - [The results of a morphological study of the gastric and duodenal mucosae in
patients with vibration-induced disease].
AB - AIM: Morphological study of gastric and duodenal mucosa in patients with
vibration disease. MATERIALS AND METHODS: 64 patients with vibration disease
stage I and II were examined endoscopically, histologically, bacterioscopically
and morphometrically irrespective of the presence or absence of gastrointestinal
complaints. RESULTS: Erosive gastroduodenitis, non-erosive gastroduodenitis and
gastritis, polyps in the stomach and gastric ulcer were diagnosed in 19(29.7%),
40(62.5%), 2(3.2%) and 1(1.6%) patients, respectively. Small intestinal
metaplasia occurred in 22% of patients. Helicobacter pylori occurred most
frequently in the antral part of the stomach (90.24%). Advanced dissemination
often combined with metaplasia of the small bowel. Morphometrically, there were
slight differences from relevant values in patients with chronic gastroduodenitis
who were not exposed to occupational hazards. Vibration disease patients
exhibited impairment of duodenal vessels (large endothelial nuclei, thick
arteriolar walls) 2 times more frequently than controls. CONCLUSION: In vibration
disease, gastric and duodenal mucosa, as a rule, shows signs of chronic
gastroduodenitis.
PMID- 9551570
TI - [Chronic viral infection in patients with alcoholic liver involvement].
AB - AIM: Detection of viral hepatitides markers in patients with alcoholic damage to
the liver. MATERIALS AND METHODS: Virological, immunological and histochemical
tests were performed in 36 chronic alcoholics who had enlarged liver and/or
abnormal hepatic characteristics. RESULTS: 60% of the examinees carried chronic
HBV, HCV, HDV infection. The activity of chronic inflammation of hepatic
parenchyma was associated with biological phase of the viral infection
development. The degree of hepatic parenchyma morphological changes was unrelated
to the virus type. (HBV, HCV, HDV). CONCLUSION: Alcoholic hepatic damages often
combine with viral hepatitis.
PMID- 9551571
TI - [The bile acid and bile lipid spectrum of the migrant population of the Asian
North with biliary tract diseases].
AB - AIM: The study of biochemical bile composition in Asian North migrants with
biliary diseases (BD). MATERIALS AND METHODS: The diagnosis of BD was made upon
clinical examination, ultrasound scanning, duodenal intubation in 329 examinees.
The bile was examined for total bile acids, total cholesterol, total
phospholipids and bile acid spectrum. RESULTS: Cholelithiasis patients were found
to have high index of bile cholesterol saturation, high level of deoxycholic acid
and low ratio primary/secondary bile acids. CONCLUSION: Changes in bile lipid
spectrum are the leading cause of forming bile concrements in migrant population
of the high altitudes.
PMID- 9551572
TI - [The indices of lipid metabolism in the blood plasma of patients with chronic
calculous cholecystitis].
AB - AIM: The study of lipid fraction spectrum in plasma of patients with chronic
calculous cholecystitis (CCC) before and after the operative intervention.
MATERIALS AND METHODS: 28 female patients with CCC. Plasma lipids were measured
before the operation, 1 and 5 days after it, at the discharge from hospital and
in healthy donors. RESULTS: Before the operation blood concentrations of total
lipids, triacylglycerins, phosphatidylcholine and phosphatidylethanolamine were
elevated. Cholesterol, lisophosphatidylcholine and sphingomyelin,
cholesterol/phospholipids ratio were subnormal. The same changes of the lipids
persisted 1 and 5 days after the surgery and at discharge. CONCLUSION: Plasma
lipids in CCC patients are not corrected early after the surgery and require drug
correction.
PMID- 9551573
TI - [Current medical technologies in the treatment of cholelithiasis].
AB - AIM: Assessment of different approaches to treatment of cholelithiasis (CL).
MATERIALS AND METHODS: 245 CL patients were given a long-term treatment with
ursosan, laser lithotripsy and combined modalities. RESULTS: Ursosan promoted
dissolving of the stones in 56% of the patients. Laser lithotripsy destroyed the
stones in 74 from 91 patients. Ursosan and laser lithotripsy eliminated the
concrements in 59 of 67 patients. CONCLUSION: Efficacy of laser lithotripsy in CL
depends on valid selection of the patients. The combined therapy of CL is
preferable in patients who reject operative intervention and in those with severe
somatic complications.
PMID- 9551574
TI - [Antihypertensive therapy with doxazosin in patients with non-insulin-dependent
diabetes mellitus].
AB - AIM: Assessment of the antihypertensive effect of doxazosin, alpha-1 blocker, as
well as its action on lipid and carbohydrate metabolism, microcirculation and
platelet function in patients with non-insulin-dependent diabetes mellitus
(NIDDM). MATERIALS AND METHODS: Doxazosin (tonocardin) treatment was given for 11
weeks to 33 NIDDM patients with concomitant hypertension. The clinical
examination comprised evaluation of central hemodynamics, vessels of the fundus
of eye, lipid and carbohydrate metabolism, renal function, platelet aggregation.
RESULTS: Tonocardin produced a fall in the systolic blood pressure (BP) by 14%,
in the diastolic BP--by 17%. The 24-h profile of BP, lipid and purine metabolism,
microcirculation of the vessels of the fundus of eye also improved. Total
peripheral vascular resistance, left ventricular myocardial mass and platelet
aggregation. Carbohydrate metabolism remained unchanged. CONCLUSION: Monotherapy
with tonocardin (2-8 mg/day) is effective and safe in the treatment of arterial
hypertension in NIDDM patients.
PMID- 9551575
TI - [The treatment of peptic ulcer at a polyclinic day hospital].
PMID- 9551576
TI - [Life support on chronic hemodialysis over the course of 14-15 years (a report of
2 cases)].
PMID- 9551577
TI - [Glucagonoma as a tumor found by the therapist].
PMID- 9551578
TI - [The diagnosis of 3 cases of carcinoid].
PMID- 9551579
TI - [The efficacy of autofibronectin obtained by heparin cryofractionation in
patients with trophic ulcerative skin lesions].
PMID- 9551580
TI - [Prokinetic agents (prokinetics) in the treatment of motor disorders of the
gastrointestinal tract].
PMID- 9551581
TI - [The role of helicobacteriosis in stomach and duodenal lesions].
PMID- 9551582
TI - [Eosinophilic gastroenteritis].
PMID- 9551583
TI - [Chronic viral diseases of the liver--systemic infections?].
PMID- 9551584
TI - [Betaxolol (lokren) in arterial hypertension].
PMID- 9551585
TI - [Imidazoline receptor agonists in the practical treatment of hypertension].
PMID- 9551586
TI - Introduction. Forces of change in interventional vascular medicine: outlook for
the next millennium.
PMID- 9551587
TI - Pathobiologic responses to stenting.
AB - As the interventions available to treat obstructive coronary artery disease
become increasingly complex, our understanding of the vascular response to these
interventions requires greater sophistication. Molecular and cellular biologic
tools have now propelled us into another phase of work with vascular devices.
Initially, studies of endovascular implants such as stents focused on developing
models of vascular injury. With these models, we could then examine the designs
of individual stents and connect structure with performance. Now we are entering
a third phase in which stent manufacturers are looking to science to dictate
stent design.
PMID- 9551588
TI - In-stent restenosis: the Washington Hospital Center experience.
AB - In-stent restenosis has become a significant clinical problem. In 1997 alone, it
is estimated that up to 100,000 patients world-wide with in-stent restenosis were
treated. Serial intravascular ultrasound (IVUS) analysis has shown that tubular
slotted stents almost never chronically recoil and that neointimal hyperplasia is
responsible for in-stent restenosis. With the rapid recent explosion in stent
use, information about in-stent restenosis has lagged behind, especially on the
impact of new stent designs. For example, the true prevalence of in-stent
restenosis (1) varies with the lesion and patient subset, being much higher in
the "real world" than in the selected patients typically enrolled in many
studies; and (2) depends on its definition (i.e., clinical vs angiographic,
intralesion vs in-stent). "Conventional" catheter-based treatments have included
percutaneous transluminal coronary angioplasty (PTCA), rotational atherectomy,
excimer laser coronary angioplasty, directional coronary atherectomy, and
additional stent implantation. Rates of recurrence with these approaches are not
known and vary considerably among series; however, certain lesions seem likely to
recur regardless of the treatment modality. Recently, brachytherapy has emerged
as the most promising way to treat in-stent restenosis.
PMID- 9551589
TI - Pathophysiology of restenosis: interaction of thrombosis, hyperplasia, and/or
remodeling.
AB - In response to arterial injury, a series of intravascular changes take place that
lead to restenosis: thrombosis, neointimal hyperplasia, and remodeling of the
vessel. Neointima formation involves thrombosis, recruitment (migration), and
recruitment/cell proliferation. To determine the source of neointimal cells that
accumulate at the site of injury, pig models of stented and catheterized arteries
were examined. The phases of neointima formation can each be seen in the pig in
which neointimal cells come from nearby arterial tissue. The pig model was also
employed to assess the effect of different degrees of force exerted by self
expanding stents on the arterial wall. In this model, the luminal area increased
in response to chronic stent force. Slow expansion may help prevent neointimal
hyperplasia and maintain luminal patency without causing damage to the artery.
PMID- 9551590
TI - Radiation vascular therapy: a novel approach to preventing restenosis.
AB - In animal studies, beta and gamma radiation delivered via catheter-based systems
to sites of angioplasty after arterial injury has decreased the neointimal
proliferation that is a part of the restenotic process. Extending radiotherapy to
the clinical setting, results of the double-blind, placebo-controlled, randomized
Scripps Coronary Radiation to Inhibit Proliferation Post Stenting (SCRIPPS) study
showed dramatic reductions in the rate of restenosis after coronary stenting when
catheter-based gamma radiotherapy (with iridium-192) was used. In the Beta Energy
Restenosis Trial (BERT), angiographic, intravascular ultrasound, and clinical
outcomes were better than expected with beta brachytherapy. Strontium-90/yttrium
90 seeds were delivered via a unique catheter system in 35 patients who underwent
coronary angioplasty. Future trials are being planned to confirm these promising
results.
PMID- 9551591
TI - Endovascular brachytherapy: overcoming "practical" obstacles.
AB - Endovascular radiation therapy has proved to be safe and effective in preventing
restenosis after coronary intervention both in animal studies and in pilot
feasibility studies in humans. The rationale for such therapy is that radiation
prevents neointimal proliferation and vessel constriction after vascular injury.
Two forms of endovascular radiation therapy are available: catheter-based systems
and radioactive stenting. However, several practical issues related to this
technique still need to be addressed, such as questions about dosimetry,
shielding, expense, handling and disposal of radioisotopes, certification for
potential users, and-above all-safety and efficacy. In their pivotal studies,
investigators and industry need to focus on prioritizing the clinical
applications of this form of treatment. The clinical trials must attempt to
determine the cost-effectiveness of this therapy as well as its risk versus
benefit. For example, brachytherapy may prove to be of great benefit to patients
with in-stent restenosis, and favorable results of studies examining this
application should expedite the approval of endovascular radiation therapy for
clinical use.
PMID- 9551593
TI - Stent grafts for aortic aneurysms: the next interventional challenge.
AB - Stent grafts (endografts) have proved useful for the endoluminal exclusion of
peripheral and aortic aneurysms, both those in native arteries and those
resulting from prior surgery. In addition, their use may apply in some patients
with occlusive vascular disease. Various types of endografts are being evaluated
in clinical trials, including those that utilize unsupported grafts with
stentlike attachment mechanisms and those having a metallic endoskeleton or
exoskeleton. Relatively complex devices can be delivered through small
arteriotomies and in some cases percutaneous approaches. Unsupported grafts,
although more prone to kinking and incomplete expansion, appear to work well.
Some devices employ modularity, which involves separate placement of
contralateral limbs and, in some cases, extension devices. For performing
endovascular grafting, pretreatment planning is critical and requires
sophisticated imaging, including spiral computed tomography (CT) with 3
dimensional reconstruction and angiographic evaluation using catheters with
calibrated markers. Potential advantages of endovascular grafts include a
decreased hospital stay, a less invasive procedure, and lower morbidity and
mortality. Several issues remain unresolved and should be addressed by the newer
generation of these devices.
PMID- 9551592
TI - Intravascular ultrasound: state of the art and future directions.
AB - A variety of new devices in the field of intravascular ultrasound imaging are
being designed and tested. Mechanical intravascular ultrasound (IVUS) devices
with rotating transducers have been developed that allow transducer pullback with
integrated longitudinal 2-dimensional displays. Recent advances in the area of
imaging include (1) solid-state systems that combine ultrasound with balloon and
stent placement; (2) combined imaging atherectomy devices; (3) imaging cores or
guidewires; (4) forward-looking devices; (5) 3-dimensional reconstruction
techniques; (6) high-frequency imaging; and (7) improved methods for
characterizing tissue. Other promising approaches include magnetic resonance
imaging, thermography, and optical coherence tomography. An important goal for
long-term technologic improvement is visualization of lipid accumulations and
fibrous caps during their early stages of development.
PMID- 9551594
TI - Current perspectives on direct myocardial revascularization.
AB - Direct myocardial revascularization (DMR), either surgical or catheter-based,
uses lasers to create channels between ischemic myocardium and the left
ventricular cavity to improve perfusion and decrease angina. This technique can
also be used to deliver drugs to the damaged tissue. Candidates include patients
with chronic, severe, refractory angina and those unable to undergo conventional
surgical revascularization or angioplasty because remaining conduits or
acceptable target vessels are lacking. Although the mechanism of action of DMR is
still not known, several theories have been proposed, including stimulated
angiogenesis. Late sequelae also remain to be determined. Channel characteristics
differ depending on whether they were created by carbon dioxide or
holmium/yttrium-aluminum-garnet (Ho: YAG) lasers. Catheter-based DMR obviates
thoracotomy and anesthesia and, in systems that can create electromechanical
maps, fluoroscopy. Phase I clinical trials are now under way to evaluate catheter
based DMR, with endpoints that include improvement in symptoms of angina,
exercise capacity, and radionuclide myocardial perfusion.
PMID- 9551595
TI - Preferential benefit of platelet glycoprotein IIb/IIIa receptor blockade:
specific considerations by device and disease state.
AB - Several patient subgroups appear to benefit preferentially from inhibition of
platelet glycoprotein (GP) IIb/IIa receptors. In clinical trials the GP IIb/IIa
blocker abciximab (ReoPro; Lilly) proved both safe and effective in improving
outcomes after coronary interventions. Endpoints of death, myocardial infarction
(MI), and need for urgent intervention were significantly decreased in a
randomized placebo-controlled trial of patients treated with abciximab in
conjunction with either low-dose or standard-dose weight-adjusted heparin during
elective percutaneous coronary revascularization. In addition, studies have shown
that patients undergoing unplanned stent deployment or ablative technologies
benefit from GP IIb/IIa blockade. Patients undergoing saphenous vein graft
intervention also derive specific benefits. These agent--specifically abciximab,
eptifibatide (INTEGRILIN; Cor/Schering), and tirofiban--have also benefited
patients with the acute coronary syndromes (e.g., unstable angina) by decreasing
ischemic events.
PMID- 9551597
TI - Virus-cell interactions. Introduction.
PMID- 9551596
TI - Lipid-lowering therapy after coronary revascularization: the interventional
cardiologist's perspective.
AB - Despite the success of coronary interventions in the treatment of stenosis due to
coronary atherosclerosis, it behooves cardiologists to treat the underlying
disease by decreasing patients' cholesterol levels. Intravascular ultrasound has
made it possible to detect plaque accumulation not visible on angiography.
Although advanced lesions that are fibrous and calcific can be treated with
atherectomy and lasers, it is the soft, lipid-laden plaque that is particularly
vulnerable to rupture and leads to coronary events. Therefore, attention must
also focus on decreasing atherosclerotic progression in patients who have
undergone coronary interventions. Studies have clearly shown the value of
cholesterol reduction in decreasing coronary events. However, a review of
cardiologists' practices shows that more aggressive lipid-lowering therapy is
needed. One way to achieve this goal is to treat and monitor patients who have
undergone revascularization procedures and to encourage patients to become more
involved in their own care.
PMID- 9551598
TI - Cell cycle analysis of retroviral vector gene expression during early infection.
AB - To examine the pattern of retroviral vector gene expression during early stages
of infection, a Moloney murine leukemia virus (M-MuLV)-based vector that
transcribes the simian virus 40 (SV40) large T antigen (Tag) gene from the viral
long terminal repeat (LTR) was used to infect proliferating rodent fibroblasts.
At various times after infection, cells were fixed and stained for Tag by
indirect immunofluorescence, and for DNA using propidium iodide. Tag
immunofluorescence and DNA content were both quantified by flow cytometry. The
results showed that Tag expression was first detected exclusively in the late G1
and early S phases of the cell cycle, approximately 12 h postinfection. The
infection was synchronous in that Tag-expressing cells detected at 12 h, in late
G1 and early S, moved as a discrete population through S phase, into the G2 + M
phases of the cell cycle and then back into G1 during the next 8-10 h. The
presence of a synchronous Tag-expressing cell population suggests that, at time
of infection, cells in certain phases of the cell cycle were more susceptible to
infection than cells in other phases. This may be related to synchronizing events
that must occur before viral genes are expressed in infected cells; one such
event may be integration of viral DNA into cellular chromosomes (i.e., provirus
formation) that requires cells to pass through an M phase.
PMID- 9551599
TI - Identification of SV40 T-antigen mutants that alter T-antigen-induced chromosome
damage in human fibroblasts.
AB - The SV40 T antigen causes numerical (aneuploidy) and structural (aberrations)
chromosome damage when expressed in human diploid fibroblasts. This chromosome
damage precedes the acquisition of neoplastic traits such as anchorage
independence, colony formation in reduced serum growth factors, immortalization,
or tumorigenicity. Therefore, chromosome damage may be important in acquiring
these traits because it could provide a mutational mechanism. To determine how
the T antigen causes chromosome damage, point mutations were constructed that
altered previously defined biochemical functions of the T protein. Mutant T
antigen constructs were introduced into human diploid fibroblasts and selected by
using G418. Clones of G418r cells that expressed mutant T antigens were expanded
and scored for chromosome damage. Most of these mutant T antigens caused
[corrected] levels of chromosome damage similar to those caused by [corrected]
the wild-type T antigen. However, some T-antigen mutants induced fewer chromosome
changes. A subset of these clones that induced less chromosome damage than wild
type T were examined further. Mutant T-antigen protein levels from this subset
were quantified with flow cytometry and compared with wild-type protein
expression levels. Mutations of T antigen shown previously to form less stable
complexes with p53 caused less chromosome damage. A mutation in the zinc finger
domain of T antigen also caused less chromosome damage. Interestingly, a mutant
that caused loss of the ATPase activity of T antigen caused an increase in
endoreduplicated cells. Also, a correlation was noted between cells expressing
very low levels of T antigen (below detection limits when using flow cytometry)
and an undamaged karyotype. This correlation indicates that there is a threshold
level of T-antigen expression that induces chromosome damage and that expression
levels on a per-cell basis rather than on a population basis should be considered
in subsequent studies.
PMID- 9551600
TI - Activities of SV40 T antigen necessary for the induction of tetraploid DNA
content in permissive CV-1 cells.
AB - To determine the role of SV40 T antigen in stimulating multiple rounds of DNA
synthesis in permissive cells, CV-1 cells were transfected with plasmids
expressing mutant or wt T antigen in the presence or absence of the SV40 origin
of replication. Induction of cells with > G2 DNA content (tetraploid DNA content)
and levels of T antigen protein were detected and analyzed by flow cytometry. The
mutant T antigen proteins demonstrated the expected phenotypes as determined by
immunoprecipitation. Elevated levels of T antigen protein were detected in each
transfection, but full-length T antigen alone was responsible for the tetraploid
DNA content. The studies show that full-length T antigen with point mutations to
reduce binding to the cellular proteins p53 and/or Rb were capable of inducing >
G2 DNA content though the induction by these mutants was greatly enhanced by the
presence of the SV40 origin of replication. Truncated T antigen (aa 1-259) could
induce cells with tetraploid DNA content only in the presence of the SV40 origin
of replication and the absence of Rb binding. These studies suggest that multiple
functions of T antigen are involved in the stimulation of the second round of
cellular DNA synthesis.
PMID- 9551601
TI - Okadaic acid induces appearance of the mitotic epitope MPM-2 in SV40-infected CV
1 cells with a >G2-phase DNA content.
AB - Simian virus 40 (SV40) infection of quiescent monkey kidney cells stimulates two
successive rounds of cellular DNA synthesis without an intervening mitosis. This
uncoupling of S phase and mitosis indicates that SV40 modulates pathways
regulating the G2-to-M phase transition. To examine the integrity of mitotic
initiation pathways in infected cells that have bypassed mitosis, SV40-infected
CV-1 cells were treated with okadaic acid (OA), a known inducer of premature
mitosis in other cell types. OA treatment triggered the appearance of the mitotic
marker MPM-2 in SV40-infected CV-1 cells progressing through either the first
(diploid) or second (tetraploid) S phases. These results demonstrate that a
subset of mitotic pathways are intact but inactive in SV40-infected cells that
have bypassed mitosis and initiated tetraploid S phase.
PMID- 9551602
TI - Detection of HIV-RNA-positive monocytes in peripheral blood of HIV-positive
patients by simultaneous flow cytometric analysis of intracellular HIV RNA and
cellular immunophenotype.
AB - Determinations of plasma HIV viral RNA copy numbers help to define the kinetics
of HIV-1 infection in vivo and to monitor antiretroviral therapy. However,
questions remain regarding the identity of various infected cell types
contributing to this free virus pool and to the in vivo lifecycle of HIV during
disease progression. Characterization of a novel fluorescence in situ
hybridization (FISH) assay employing a pool of labeled oligonucleotide probes
directed against HIV RNA was done followed by coupling of the FISH assay with
simultaneous surface immunophenotyping to address these questions. In vitro
characterizations of this assay using tumor necrosis factor-alpha stimulated and
unstimulated ACH-2 cells demonstrated the ability to detect < 5% HIV RNA positive
cells with a sensitivity of < 30 RNA copies per cell. Peripheral blood
mononuclear cells from 39 HIV-seropositive patients on no, single, combination,
or triple drug therapy and 8 HIV-seronegative patients were examined. The
majority of HIV-positive patients (24/39) harbored monocytes positive for HIV RNA
and a significantly higher fraction of patients with high plasma viral load
carried positive monocytes (13/16) than did patients in the low plasma viral load
group (11/23). These results demonstrate the effectiveness of a novel FISH assay
for identifying and monitoring HIV-infected cell populations in the peripheral
blood of HIV-positive patients. In addition, monocytes are a major source of
cellular HIV virus in the peripheral blood of HIV patients, even with progression
of disease.
PMID- 9551604
TI - Automated image analysis system for detecting boundaries of live prostate cancer
cells.
AB - Image analysis provides a powerful tool for quantifying cell motility and has
been used to correlate motility with metastatic potential in an animal model of
prostate cancer. However, widespread use of this image analysis method has been
limited because earlier methods of quantitative analysis required time-intensive
and subjective manual tracing of cell contours. In this report, we describe a
fully automated image segmentation algorithm for detection and morphometric
description of prostatic cells. The segmentation system was tested on prostate
cell images generated from Hoffman modulation contrast microscopy (47 cells at 64
time points = 3,008 images) and differential interference contrast microscopy (29
cells at 64 times points plus 1 cell at 62 time points = 1,918 images).
Morphometric measurements were derived from computer-determined cell boundaries
and compared with the same measurements derived from manually traced cell
boundaries. Final correlation coefficients for area and perimeter measurements
for Hoffman and differential interference contrast microscopy were (0.76, 0.62)
and (0.93, 0.93), respectively. Results with our differential interference
contrast images demonstrate that our segmentation algorithm reliably and
efficiently replaces the need for manually traced cell boundaries in addition to
eliminating intraobserver variation. Our automated segmentation process will have
immediate utility in our motility analysis system that relates cell motility with
metastatic potential of prostate cancer.
PMID- 9551603
TI - Efficient, interactive, and three-dimensional segmentation of cell nuclei in
thick tissue sections.
AB - Segmentation of intact cell nuclei in three-dimensional (3D) images of thick
tissue sections is an important basic capability necessary for many biological
research studies. Because automatic algorithms do not correctly segment all
nuclei in tissue sections, interactive algorithms may be preferable for some
applications. Existing interactive segmentation algorithms require the analyst to
draw a border around the nucleus under consideration in all successive two
dimensional (2D) planes of the 3D image. The present paper describes an algorithm
with two main advantages over the existing method. First, the analyst draws
borders only in 2D planes that cut approximately through the center of the
nucleus under consideration so that the nuclear borders generally are most
distinct. Second, the analyst draws only five borders around each nucleus, and
then the algorithm interpolates the entire surface. The algorithm results in
segmented objects that correspond to individual, visually identifiable nuclei.
The segmented surfaces, however, may not exactly represent the true nuclear
surface. An optional, automatic surface optimization algorithm can be applied to
reduce this error.
PMID- 9551605
TI - Colcemid-induced apoptosis of cultured human glioma: electron microscopic and
confocal laser microscopic observation of cells sorted in different phases of
cell cycle.
AB - The effect of the antitubulin agent colcemid on human glioma cells was
investigated by sorting cells with different DNA content and subjecting them to
confocal laser microscopy and transmission electron microscopy. The human glioma
cell line U251MG was exposed to colcemid at a concentration of 0.05 microg for 16
h. Flow cytometric analysis revealed the accumulation of cells in S/G2M phase.
Cells harvested from each of G0/G1 and S/G2M peaks were then analyzed by confocal
laser microscopy and transmission electron microscopy. Confocal laser microscopy
revealed that colcemid-treated cells harvested from the G0/G1 peak contained
mitotic and apoptotic cells in addition to interphase cells. Electron microscopy
confirmed that colcemid-treated cells in the G0/G1 peak had fragmented nuclei
typical of apoptotic cells and mitotic cells with altered chromatin structure.
Some mitotic cells obtained by mitotic shake-off after treatment with colcemid
showed DNA strand breaks defined by in situ nick end labeling. The present study
indicates that mitotic as well as interphase apoptosis occurs in U251MG cells
following colcemid treatment.
PMID- 9551606
TI - Flow cytometric measurement of benzo[a]pyrene-diol-epoxide-DNA adducts in normal
human peripheral lymphocytes and cultured human lung cancer cells.
AB - DNA adducts are mainly detected by 32P-postlabeling and enzyme-linked
immunosorbent assays. We have established a method for detection of
benzo[a]pyrene-diol-epoxide (BPDE)-DNA adducts by flow cytometry, and have
clarified the effects of the DNA adducts on cell-cycle progression and the
relationship between cell-cycle phases and DNA adduct formation, using human
peripheral lymphocytes and three human lung cancer cell lines. We measured the
BPDE-DNA adduct levels in both lymphocytes and cancer cells by isolating nuclei,
using a nuclear isolation buffer containing Triton X-100 and staining with a BPDE
DNA-specific monoclonal antibody and biotin-streptavidin fluorescein conjugates.
BPDE did not affect cell-cycle progression in human peripheral lymphocytes.
However, in human lung cancer cells exposed to > 1 microg/ml BPDE, accumulation
of cells in the S phase was seen. Cells with DNA content greater than G2M
(aneuploid cells) or cells with less than G1 DNA content (apoptotic cells)
increased gradually with exposure to increasing BPDE concentrations, suggesting
that BPDE may affect cell-cycle progression through binding to DNA. Thus, the
measurement of DNA adducts by flow cytometry may provide new insights into
carcinogenesis.
PMID- 9551607
TI - Flow cytometric assessment of cell structural and functional changes induced by
acetic acid in the yeasts Zygosaccharomyces bailii and Saccharomyces cerevisiae.
AB - Flow cytometry (FCM) was used with different viability dyes to assess changes in
cell structure and function induced by acetic acid (AA) in populations of
Zygosaccharomyces bailii (AA resistant) and Saccharomyces cerevisiae (AA
sensitive). Kinetic changes in esterase activity, intracellular dye processing,
and membrane integrity were monitored, and to detect those changes we used three
assays involving fluorescein diacetate hydrolysis, FUN-1 processing, and
propidium iodide exclusion, respectively. In S. cerevisiae, the decrease in the
ability to process FUN-1 preceded the decrease in esterase activity, and there
was loss of cell membrane integrity after incubation with AA. In Z. bailii, with
higher AA concentrations, there was a similar decrease in the ability to process
FUN-1, which also preceded the loss of cell membrane integrity. Changes in
esterase activity in this yeast induced by AA treatment could not be monitored
because the changes occurred independently of the presence of the acid. For
control samples (untreated cells killed with 10% v/v of AA), the percentages of
nonaltered cells as estimated by FCM and percentages of viable cells as estimated
by colony forming unit (CFU) counts were identical. However, for cell samples
treated for short periods with 3% (v/v) or less of AA, none of the dyes produced
FCM results comparable to those produced by CFU counts.
PMID- 9551608
TI - Simian virus 40 as a vector for gene transfer to hematopoietic cells.
PMID- 9551609
TI - In vitro selection for K562 cells with higher retrovirally mediated copy number
of aldehyde dehydrogenase class-1 and higher resistance to 4
hydroperoxycyclophosphamide.
AB - Previously, we have reported the successful expression of human aldehyde
dehydrogenase class-1 (ALDH-1) in K562 leukemia cells using a retroviral vector
and demonstrated low expression that resulted in up to three-fold increase in
resistance to 4-hydroperoxycyclophosphamide (4-HC), an active derivative to
cyclophosphamide. The purpose of this study was to investigate whether in vitro
treatment with 4-HC will allow selection of K562 cells expressing higher levels
of ALDH-1, and whether these selected cells are more resistant to 4-HC. Stably
transfected or transduced K562 cells with retroviral pLXSN vector containing ALDH
1 cDNA (ALDH-1 cells) were treated repeatedly with 4-HC and then allowed to grow
to confluence in liquid culture. Subsequently, the resistance to 4-HC of ALDH-1
cells treated once (ALDH-1+) or twice (ALDH-1++) with 4-HC was compared to ALDH-1
cells or wild-type K562 cells (WT cells). The results show significant increase
in 4-HC resistance of ALDH-1+ (2- to 16-fold, p < 0.005) over ALDH-1 or WT cells.
No difference was detected between ALDH-1+ and ALDH-1++. In addition, higher ALDH
1 mRNA and enzyme activity were found in ALDH-1+ compared to ALDH-1 cells.
Southern analysis of DNA extracted from the different experimental groups
demonstrated an eight-fold increase in ALDH-1 cDNA in ALDH-1+ versus the ALDH-1
cells. This was confirmed by sequential FISH analysis using biotin labeled
pLXSN/ALDH-1 vector. Positive signals consistently localized to the centromeric
region of chromosome 9 and the long arm of chromosome 17 were demonstrated only
in the ALDH-1+ cells and represented a fusion product of multiple copies of the
pLXSN/ALDH-1 vector. In summary, we have demonstrated that in vitro treatment
with 4-HC results in the selection of K562 cells with multiple copies of ALDH-1
gene that are clustered in two main integration sites. These cells demonstrate
significantly higher resistance to 4-HC when compared to previously untreated
cells. Such successful in vitro selection could have significant implications for
future cancer gene therapy protocols.
PMID- 9551610
TI - Inhibition of human immunodeficiency virus type 1 replication by nuclear chimeric
anti-HIV ribozymes in a human T lymphoblastoid cell line.
AB - Human immunodeficiency virus (HIV) infection represents one of the most
challenging systems for gene therapy. Thanks to the extended knowledge of the
molecular biology of the HIV life cycle, many different strategies have been
developed including transdominant modifications of HIV proteins, RNA decoys,
antisense RNA, ribozymes, and intracellular antibody fragments. In this paper, we
have tested in a human T lymphoblastoid cell line the antiviral activity of
ribozymes specifically designed to co-localize inside the nucleus with the Rev
pre-mRNA before it is spliced and transported to the cytoplasm. This result was
obtained by inserting the ribozyme in the spliceosomal U1 small nuclear RNA
(snRNA) and in a derivative that has perfect complementarity with the 5' splice
site of the Rev pre-mRNA. These ribozymes were tested in human T cell clones and
were shown to be very efficient in inhibiting viral replication. Not only were
the p24 levels in the culture medium drastically reduced but so were the
intracellular HIV transcripts. Control disabled ribozymes enabled us to show the
specificity of the ribozyme activity. Therefore, these constructs have potential
utility for gene therapy of HIV-1 infection.
PMID- 9551611
TI - High-level dystrophin expression after adenovirus-mediated dystrophin minigene
transfer to skeletal muscle of dystrophic dogs: prolongation of expression with
immunosuppression.
AB - Replication-deficient adenovirus vectors (AdV) have been successfully used to
transfer a truncated human dystrophin cDNA to skeletal muscle of dystrophin
deficient mdx mice. A dystrophin-deficient golden retriever dog model (GRMD) has
been identified, which, unlike the mouse model, leads to a clinicopathological
phenotype similar to that of Duchenne muscular dystrophy (DMD). We show for the
first time that high-level dystrophin expression in skeletal muscle of GRMD dogs
can be achieved by AdV-mediated gene transfer. However, a humoral and cellular
immune response of the host against antigens of viral and transgene origin
(similar to that occurring in mdx mice after AdV-mediated dystrophin gene
transfer) leads to a decline of dystrophin expression over a 2-month period.
Immunosuppression by cyclosporin significantly prolonged transgene expression.
The GRMD model may help to solve the open questions pertaining to dystrophin gene
transfer such as systemic delivery and improvement of muscle function before
human trials for gene replacement therapy in DMD may be considered.
PMID- 9551612
TI - Vector-specific complementation profiles of two independent primary defects in
cystic fibrosis airways.
AB - Cystic fibrosis (CF) lung disease has been linked to multiple primary defects in
airway epithelia caused by a dysfunctional cystic fibrosis transmembrane
conductance regulator (CFTR) gene. These defects include altered Cl- and Na+
permeability as well as intracellular defects in glycoprotein processing. This
apparent diversity in CFTR function is reflected in the complex patterning of
CFTR expression in airway epithelia. Such complexities present challenges in the
design of CF gene therapies that are capable of reconstituting the endogenous
patterns of CFTR gene expression in appropriate target cells. Using a human
bronchial xenograft model of the CF airway, we have evaluated the efficacy of
recombinant adenoviral and cationic liposome-mediated gene transfer to correct Cl
permeability and mucous sulfation defects found in CF lung disease. Results from
these studies demonstrated a clear vector-specific complementation profile for
these two defects that was dependent on the type of cell transduced and the level
of transgene expression. Single-dose administration of recombinant adenovirus
effectively transduced high levels of CFTR transgene expression in 11 +/- 1% of
epithelial cells and was capable of correcting cAMP-induced changes in Cl-
permeability to 91 +/- 14% that seen in non-CF airways. However, this level of
transgene expression was incapable of reversing defects in mucous sulfation due
to the lack of efficient targeting to goblet cells. In contrast, cationic
liposome-mediated delivery of CFTR encoding plasmids to CF airways achieved
extremely low levels of transgene expression with insignificant correction (7.4
+/- 2.4%) of cAMP-induced Cl- permeability. This low level of transgene
expression, however, efficiently reduced mucous sulfation to levels seen in non
CF airways. Differences in the complementation profiles of these two vectors in
correcting Cl- permeability and mucous sulfation defects mirror the ability of
recombinant adenovirus and liposomes to reconstitute only certain features of the
endogenous distribution and abundance of CFTR protein expression. Such findings
suggest that the level of intracellular CFTR required to facilitate proper
glycoprotein processing may be much lower than that needed to mediate bulk Cl-
flow across the airway epithelium. In summary, these data present the first
example by which two different vector systems can efficiently complement
independent primary defects associated with a single dysfunctional gene.
PMID- 9551613
TI - Efficient transduction of human hematopoietic cells with the human multidrug
resistance gene 1 via SV40 pseudovirions.
AB - Transduction of MDR1 may be of use in chemoprotection of normal bone marrow (BM)
cells during treatment of malignancies, or as a selectable marker for the
transfer of other genes into the BM, a critical target for the cure of many
diseases. To that aim, the human multidrug resistance gene MDR1 was cloned into
an SV40 pseudoviral vector containing the SV40 origin of replication (ori) and
encapsidation signal (ses), and the plasmid was encapsidated in COS cells as
SV40/MDR1 pseudovirions. Expression of the human MDR1 gene was demonstrated in
murine MEL cells infected with SV40/MDR1 pseudovirions, using a monoclonal
antibody (MPK16) specific for the human 170-kD P-glycoprotein. Functional P
glycoprotein was demonstrated by resistance to colchicine in NIH-3T3 cells
infected with SV40/MDR1 pseudovirions. Activity of P-glycoprotein was assayed by
rhodamine-123 dye exclusion and fluorescence-activated cell sorter analysis
(FACS) in various cell types including hematopoietic cells. Highly efficient gene
transfer and expression was demonstrated in all murine and human cell types
tested, including primary human BM cells. Using multiplicities of infection (moi)
of 1-2, over 95% of cells were found to become MDR1+. The percent of MDR1+ cells
was proportional to the moi. We conclude that the SV40 pseudoviral vector is
efficient for gene transmission into human hematopoietic cells.
PMID- 9551614
TI - Systemic effect of human growth hormone after intramuscular injection of a single
dose of a muscle-specific gene medicine.
AB - A muscle-specific gene medicine is described that provides for long-term
secretion of biologically active human growth hormone (hGH) from skeletal muscle
into the systemic circulation. The hGH gene medicine is composed of a muscle
specific hGH plasmid expression system complexed with a protective, interactive,
non-condensing (PINC) delivery system. The muscle-specific gene expression
system, pSK-hGH-GH, was constructed by linking the promoter/enhancer regions of
chicken skeletal alpha-actin to hGH gene. C2C12 myoblast transfection with pSK
hGH-GH resulted in the synthesis of hGH in a muscle-specific manner. Direct
injection into rat tibialis cranialis muscle of pSK-hGH-GH complexed with a
polymeric PINC delivery system, polyvinylpyrrolidone (PVP), produced hGH levels
in muscle that were 10- to 15-fold higher compared with plasmid formulated in
saline at 14 days post-injection. Intratracheal instillation in rat lung of pSK
hGH-GH did not produce significantly detectable levels of hGH. In
hypophysectomized rats, a single intramuscular dose of the pSK-hGH-GH/PVP complex
resulted in hGH expression and a subsequent increase in serum levels of rat IGF-I
and growth. hGH expression and effects on rat serum IGF-I levels were detectable
up to 28 days after injection of formulated plasmid and effects on growth were
detectable unto 21 days. Anti-hGH antibodies were detectable in serum at 14 days
post-injection, reached a plateau at 21 days, and remained elevated through the
study period. Cyclosporin treatment of the pSK-hGH-GH/PVP-injected animals
completely inhibited the antibody response and resulted in increased hGH
expression.
PMID- 9551615
TI - Selective gene transfer into the liver of non-human primates with E1-deleted, E2A
defective, or E1-E4 deleted recombinant adenoviruses.
AB - Preclinical studies were designed to investigate the feasibility and safety of
recombinant adenoviruses transduced into the hepatic artery of nonhuman primates.
The vectors used are recombinant adenoviruses deleted in E1 and contain either a
temperature-sensitive mutation in the E2a gene, which encodes a defective DNA
binding protein at nonpermissive temperatures, or a deletion of the E4 region,
including open reading frame (ORF) 6. Six 8- to 10-kg baboons underwent femoral
artery cannulation, and angiographic techniques were used to introduce vector
selectively into either a portion of the right lobe of the liver via a branch of
the right hepatic artery or the common hepatic artery. Necropsies were performed
at 4, 29, or 61 days. Serial sequential liver biopsies were performed in the
baboons that survived 29 or 61 days. In the 2 baboons with vector transduction
into the right hepatic artery, X-Gal histochemical analysis of the liver showed
evidence of quantitatively increased gene transfer in the targeted lobe; however,
gene transfer was present throughout the liver. Quantitative analysis of
histopathology showed that portal inflammation was present throughout both livers
transduced with the highest dose of vector. No differences were seen in the level
of portal inflammation in targeted and untargeted lobes despite the observed
qualitative and quantitative differences in gene expression. Southern blot
analysis of total cellular DNA isolated from targeted and nontargeted lobes
showed similar levels of viral DNA throughout the liver. Polymerase chain
reaction (PCR) analysis was able to detect viral DNA sequence in gonads and brain
as well as many other tissues in baboons treated with high-dose vector. In
baboons treated with lower doses of an E1-E4 deleted vector expressing the human
ornithine transcarbamylase (OTC) gene, DNA was detectable by nested PCR in liver
but not gonads at days 29 and 61. The data suggest that intraarterial
administration of recombinant adenoviral E1-E4 deleted vector is feasible and
safe. At high doses of vector, widespread dissemination of vector DNA is seen. At
low doses, hepatic gene transfer is not associated with vector DNA dissemination
to gonads.
PMID- 9551616
TI - Recombinant E1-deleted adenovirus-mediated gene therapy for cancer: efficacy
studies with p53 tumor suppressor gene and liver histology in tumor xenograft
models.
AB - Type 5 adenoviral (Ad) vectors have been the "vector-of-choice" for preclinical
studies on p53 tumor suppressor gene therapy of cancer. Previous studies have
examined the in vivo efficacy of p53 Ad when given intratumorally. However
published information does little to guide clinicians in the design of
intraperitoneal (i.p.) dosing trials for i.p. tumors, e.g., ovarian, or clinical
trials using regional organ perfusion, e.g., for lung tumors. Therefore, we
examined several parameters with special significance for these routes of
administration. Lung metastases from p53mut MDA-MB-231 mammary xenografts were
treated with therapeutic levels of intravenous buffer, beta-galactosidase (beta
Gal) Ad, or p53 Ad. Treatment with intravenous p53 Ad significantly reduced the
number of metastases per lung and there was a dramatic reduction in the surface
area occupied by these tumors as compared to control groups. Two types of i.p.
tumor xenografts were used for preclinical modeling of i.p. gene therapy, the
p53null SK-OV-3 ovarian and the p53mut DU-145 prostate human cancers. In a study
examining the effect of different vehicle volumes on the efficacy of a constant
drug dose, all mice treated with p53 Ad had reduced tumor burden compared to
controls. Dosing volumes between 0.2 and 1 ml were equally effective and all were
more effective than a dosing volume of 0.1 ml. However, reduced efficacy was
observed when a volume of 1.5 ml was used. When the effect of dosing frequency on
antitumor efficacy was examined, fractionated doses of p53 Ad had somewhat
greater efficacy than fewer, bolus injections. One of the significant elements in
the emerging toxicology associated with recombinant adenoviruses is the
hepatocyte pathology caused by high systemic concentrations of adenovirus. For
recombinant Ad used in this study, there was a pronounced dose-dependence for the
liver response, with very high, repeated doses causing significant hepatocellular
insult. Expression of cytoplasmic beta-Gal protein coincided with areas of
greatest damage in mice treated with high doses of beta-Gal Ad. Ultrastructural
examination of hepatocyte intranuclear inclusions revealed moderately electron
dense, tightly packed granular material interspersed with more electron-dense
nuclear material. Human tumor xenografts, but not mouse tissues, expressed viral
hexon protein. In summary, hepatic toxicity caused by high concentrations of
recombinant adenovirus was observed in murine cancer models. However, therapeutic
levels of p53 Ad could be achieved which had dramatic efficacy without
significant pathology.
PMID- 9551617
TI - Factors influencing recombinant adeno-associated virus production.
AB - Recombinant adeno-associated virus (rAAV) is produced by transfecting cells with
two constructs: the rAAV vector plasmid and the rep-cap plasmid. After subsequent
adenoviral infection, needed for rAAV replication and assembly, the virus is
purified from total cell lysates through CsCl gradients. Because this is a long
and complex procedure, the precise titration of rAAV stocks, as well as the
measure of the level of contamination with adenovirus and rep-positive AAV, are
essential to evaluate the transduction efficiency of these vectors in vitro and
in vivo. Our vector core is in charge of producing rAAV for outside investigators
as part of a national network promoted by the Association Francaise contre les
Myopathies/Genethon. We report here the characterization of 18 large-scale rAAV
stocks produced during the past year. Three major improvements were introduced
and combined in the rAAV production procedure: (i) the titration and
characterization of rAAV stocks using a stable rep-cap HeLa cell line in a
modified Replication Center Assay (RCA); (ii) the use of different rep-cap
constructs to provide AAV regulatory and structural proteins; (iii) the use of an
adenoviral plasmid to provide helper functions needed for rAAV replication and
assembly. Our results indicate that: (i) rAAV yields ranged between 10(11) to 5 x
10(12) total particles; (ii) the physical particle to infectious particle
(measured by RCA) ratios were consistently below 50 when using a rep-cap plasmid
harboring an ITR-deleted AAV genome; the physical particle to transducing
particle ratios ranged between 400 and 600; (iii) the use of an adenoviral
plasmid instead of an infectious virion did not affect the particles or the
infectious particles yields nor the above ratio. Most of large-scale rAAV stocks
(7/9) produced using this plasmid were free of detectable infectious adenovirus
as determined by RCA; (iv) all the rAAV stocks were contaminated with rep
positive AAV as detected by RCA. In summary, this study describes a general
method to titrate rAAV, independently of the transgene and its expression, and to
measure the level of contamination with adenovirus and rep-positive AAV.
Furthermore, we report a new production procedure using adenoviral plasmids
instead of virions and resulting in rAAV stocks with undetectable adenovirus
contamination.
PMID- 9551618
TI - Combination therapy with interleukin-2 and wild-type p53 expressed by adenoviral
vectors potentiates tumor regression in a murine model of breast cancer.
AB - Although cytokine gene transfer for cancer treatment can stimulate immune
recognition and tumor regression in animal models, there is still a need for
improvements to these strategies. In this study, we examined the efficacy of a
combination gene therapy using adenovirus (Ad) 5 vectors expressing human
interleukin-2 and the wild-type (wt) human p53 gene under control of the human
cytomegalovirus immediate early promoter (AdIL-2 and Adp53wt, respectively).
Infected murine cell lines and primary mouse tumor cells secreted high levels of
IL-2 and over expressed the p53 protein for at least 9 days. After infection of
cells with Adp53wt, DNA synthesis was significantly inhibited and apoptosis was
induced within 3-5 days. Both vectors were tested in a transgenic mouse mammary
adenocarcinoma model for antitumor response. Following a single intratumoral
injection of mice bearing PyMT induced tumors, the combination of Adp53wt (1 x
10(9) pfu) plus a relatively low dose of AdIL-2 (1.5 x 10(8) pfu) caused
regressions in 65% of the treated tumors without toxicity. Fifty percent of the
treated mice remained tumor free and were immune to rechallenge with fresh tumor
cells. In contrast, injection of either vector alone at this does resulted in
only a delay in tumor growth. Only mice co-injected with Adp53wt and AdIL-2
showed specific antitumor cytolytic T lymphocyte (CTL) activity, indicating that
the immune response involved in tumor regression was promoted by the combination
therapy. These results suggest that cancer treatment strategies involving
combined delivery of immunomodulatory and antiproliferative genes may be highly
effective.
PMID- 9551619
TI - Intercellular communication mediates the bystander effect during herpes simplex
thymidine kinase/ganciclovir-based gene therapy of human gastrointestinal tumor
cells.
AB - A bystander effect is described when nontransduced or genetically unmodified
cells are killed during death of genetically modified tumor cells transduced with
a suicide gene. The "bystander effect" greatly enhances the efficacy of the
herpes simplex virus-thymidine kinase/ganciclovir (HSV-TK/GCV) gene therapy
approach for cancer. The mechanism of the bystander effect is controversial. In
this study, we examined the role of intercellular gap junction communication
(GJIC) for the bystander effect in human gastrointestinal tumor cells. Our
results show that the extent of the bystander effect varied amongst the tumor
cell lines; pancreatic cancer cells BXPC-3 exhibited excellent bystander effects
in vitro and in vivo studies whereas other gastrointestinal tumor cell lines such
as pancreatic cancer cells MIAPACA-2, and colon cancer cells HT-29 showed poor
bystander effects. Bystander effects were only found in the presence of cell-to
cell contact. The extent of the bystander effect was independent of the level of
HSV-TK activity in the transduced tumor cells and was correlated with GJIC as
demonstrated by an in vitro dye-transfer assay. Expression of the mRNA levels of
gap junction protein connexin 43 was 8- to 26-fold or greater and connexin 26
gene expression was 2- to 229-fold greater in BXPC-3 cells compared to HT-29,
MIAPACA-2, and PANC3 cells. Our results suggest that intercellular communication
is essential for the bystander effect. The correlation between GJIC and the
extent of the bystander effect suggest a role for GJIC in mediating the bystander
effect. Analysis of tumors for GJIC or expression of gap junction proteins may
identify the subset of patients suitable for gene therapy with the HSV-TK/GCV
approach.
PMID- 9551620
TI - Cancer gene therapy by direct tumor injections of a nonviral T7 vector encoding a
thymidine kinase gene.
AB - Previously, we described a nonviral cytoplasmic gene therapy vector system based
on the T7 autogene concept. This system has been shown to achieve rapid and high
levels of gene expression in a variety of animal cells and tissues. To test the
utility of the system in vivo tumor ablation, a T7 cancer gene therapy plasmid
vector, pT7T7/T7TK, was constructed. This nonviral vector contains a T7 autogene,
T7T7, and a human herpes simplex virus thymidine kinase (HSV-TK) gene driven by a
second T7 promoter (T7TK). When co-transfected with T7 RNA polymerase (T7 RNAP)
into cultured human osteosarcoma 143B cells, abut 10-20% of the cells were found
to express HSV-TK, and more than 90% of the cells were killed in the presence of
1 microM ganciclovir (GCV) within 4 days after DNA transfection. The increase in
killing above the transfection frequency is due to a "bystander" effect among
transfected and untransfected 143B cells. Direct injections of pT7T7/T7TK into
143B tumors grown in nude mice resulted in TK gene expression in tumor cells
located near the injection sites as revealed by the immunohistochemical staining.
Repeated tumor injections of the pT7T7/T7TK vector and intraperitoneal (i.p.)
injections of GCV resulted in inhibition of tumor growth and in tumor shrinkage
in 6 out of 10 treated nude mice. Three of those six tumors fully regressed
shortly after the end of the GCV injections. All of the full tumor regressions
were found to be permanent and no apparent tumor relapses were observed for the
rest of the lives of the treated nude mice after the initial tumor ablations.
These results, combined with the nonviral and rapid cytoplasmic gene expression
features, suggest that the T7 vector may be a good candidate for cancer gene
therapy and other medical and biological applications.
PMID- 9551621
TI - Retroviral vector targeting to melanoma cells by single-chain antibody
incorporation in envelope.
AB - Two strategies for targeting recombinant retroviruses to melanoma cells were
compared. One was to extend the tropism of an ecotropic envelope to human
melanoma cells, the other was to enhance the tropism of an amphotropic envelope
for melanoma cells. Chimeric retroviral envelopes, incorporating a single-chain
antibody (ScFv) directed against high-molecular-weight melanoma-associated
antigen (HMWMAA) at the amino terminus are correctly processed and incorporated
into virions. ScFv-ecotropic envelope chimeras allow specific, but low-titer,
targeting of HMWMAA-positive cells, when co-expressed with ecotropic envelopes.
ScFv-amphotropic envelope chimeras bind specifically to HMWMAA-positive cells and
allow preferential infection at high titer.
PMID- 9551622
TI - Antisense c-myc retroviral vector suppresses established human prostate cancer.
AB - Prostate cancer eventually becomes androgen resistant, resumes growth, and kills
the patient. Characterization of genetic events that lead to androgen refractory
prostatic neoplasia has revealed the frequent overexpression of c-myc and
uncontrolled prostate cancer proliferation. A novel strategy to combat advanced
prostate cancer utilized a replication incompetent retrovirus that contained the
mouse mammary tumor virus (MMTV) promoter within the retroviral vector to allow
transcription of antisense c-myc gene within target prostate tumor cells. The
transduction of cultured DU145 cells by XM6:MMTV-antisense c-myc RNA retrovirus
did not affect cell proliferation in culture, yet a single direct injection of
MMTV-antisense c-myc viral media into established DU145 tumors in nude mice
produced a 94.5% reduction in tumor size compared to tumors treated with control
virus MTMV sense fos and untreated tumor by 70 days. Two animals in the antisense
c-myc-treated group had complete regression of their tumors. Histopathological
examination of the tumors revealed that MMTV-antisense c-myc-transduced DU145
tumors had increased tumor cell differentiation, decreased invasion, and a marked
stromal response. The mechanism for the antitumor effect of MMTV-antisense c-myc
retrovirus appears to be suppression of c-myc mRNA and protein, and decreased bcl
2 protein. The in vivo transduction of prostate cancer cells with MMTV-antisense
c-myc retroviruses reduced tumor growth by suppressing c-myc, resulting in the
down-regulation of bcl-2 protein. Consequently, the MMTV-antisense c-myc
retrovirus may be useful for gene therapy against advanced, hormone-refractory
prostate cancer.
PMID- 9551623
TI - Microscopical localization on adenylate cyclase: a historical review of
methodologies.
AB - The histochemistry technique for localizing adenylate cyclase has been developed
over the past two decades. Early efforts were directed at overcoming the
criticism of the lead capture technique, the inhibition of the enzyme by
fixation, and problems associated with the substrate. The introduction of
alternative metal ions, strontium and cerium, offered solutions to the criticism
of the lead capture technique. The inhibition of the enzyme by the various
fixation methods used has been rarely overcome satisfactorily and the use of non
fixed material during incubation is one of the alternatives that has been
suggested. The introduction of adenylate (beta-gamma-methylene) diphosphate as an
alternative substrate offers a solution to the problems associated with
commercially available adenylyl imidodiphosphate. Although no standard medium or
method has been accepted by all researchers, the histochemical technique still
has a place in the arsenal of the modern cell biologist. The technique localizes
the active enzyme, as opposed to the protein, active and nonactive, by
immunocytochemistry and the precursors of the protein by in situ hybridization
methods.
PMID- 9551624
TI - Cerium ions in the histochemical demonstration of second-messenger enzymes.
AB - Second-messenger systems are involved in the regulation of numerous cellular
processes. Adenylate cyclase (AC) and guanylate cyclase (GC) enzymes are in key
positions in the regulation of these systems. The cerium method has been
successfully applied to demonstrate amine- and neuropeptide-stimulated AC in rat
nervous and adipose tissues and human sweat glands at the electron microscopic
level. AC was also localized in cultured neurons. Nitric oxide compounds
stimulated GC were demonstrated in rat hippocampal areas. Enzyme reactions were
located in neurons pre- and postsynaptically in synapses; in addition, GC
activity was seen intraneuronally and in glial cells. Adipocytes and eccrine
glandular cells exhibited reaction products in their plasmalemmas. Optimal
histochemical conditions are described, combined with control experiments. Some
handicaps, related to the sensitivity of the enzymes to the fixatives,
penetration problems of cerium salts, and especially the specificity of the
method in phosphatase enzyme histochemistry in general are discussed.
PMID- 9551625
TI - Cytochemical localization of adenylate cyclase in the limb buds of Bufo bufo.
AB - The importance of cyclic nucleotides in the regulation of the processes of
differentiation and embryonic development is known. The possible role that cyclic
adenosine monophosphate (cAMP) plays during the development of the posterior limb
of Bufo bufo is studied by the cytochemical localization of adenylate cyclase
(AC), an enzyme that catalyzes the synthesis of the cyclic nucleotide. The method
is based on the reaction between the enzyme AC and its specific substrate AMP-PNP
(5'-adenylylimidodiphosphate) in the presence of lead. The lead precipitates that
form as secondary reaction products are evidence of enzymatic activity. Reaction
products are present only at the epithelial level in the limb bud; initially,
such products are visible only at the base of the bud, particularly on the
epithelial fascia located at the boundary with the body. During successive
elongation and toe formation, AC activity is only present on the cells of the
proximal portion of each new segment. Enzymatic activity is never present in
correspondence to the ectodermal apical crest. cAMP is probably not involved in
the processes of cellular proliferation but, rather, in the processes of inducing
differentiation of the internal mesenchymal cells.
PMID- 9551626
TI - Cytochemical localization of adenylate cyclase in cultured renal epithelial (A6)
cells.
AB - To characterize the vasopressin-adenylate cyclase (AC) signaling pathway in
control of Na+ reabsorption in cultured renal (A6) cells, we determined the
distribution of AC with a cytochemical technique using 5'
adenylylimidodiphosphate as substrate and cerium chloride as capturing agent. The
addition of forskolin to the medium to stimulate AC activity increased the
production of reaction deposits at the enzyme sites. To ensure that the cells
were close to their physiological states, cytochemical reactions were performed
on unfixed tissues. Subsequent postfixation adequately preserved the
morphological features of the cells. AC was mainly restricted to the lateral
folds of the cells while the apical membranes were devoid of any deposits. This
result provided evidence that the V2-AC pathway is not present in the apical
membrane and, hence, any vasopressin action on apical Na+ channels from the
luminal side of the cell must involve other signaling pathways. The cytochemical
results provided further morphological evidence of the functional coupling
between the basolateral and apical membranes of renal cells. We examined the idea
that highly variable basal rates of Na+ transport in young differentiating cell
cultures may be related to the degree of AC activity. Cytochemical results
apparently revealed highly variable amounts of deposits in these cells, but by
quantitative analysis of AC activity we could find no significant differences
between cells of 6, 14, and 21 days.
PMID- 9551627
TI - Cytochemical and biochemical studies on adenylate cyclase activity in
preneoplastic and neoplastic liver tissue and cultured liver cells.
AB - The ATP-analogue adenylyl(beta,gamma-methylene)diphosphonate was chosen as
substrate for the cytochemical localization of adenylate cyclase (AC) activity.
The tissues investigated covered normal rat liver and liver from carcinogen
treated animals with preneoplastic lesions and hepatocellular neoplasms, as well
as cultured liver cells. The AC reaction product methylene diphosphonate was
precipitated with Pb2+ immediately at the place of production. This approach
permitted a precise localization of AC activity by light and electron microscopy.
The specificity of the AC reaction was demonstrated by control reactions,
including inhibition of AC with 2'5'-dideoxyadenosine and activation with
forskolin, glucagon, and cholera toxin. Endogenous phosphatases were inhibited
with tetramisole and NAD. In normal liver, AC activity was mainly localized in
the sinusoidal membrane of hepatocytes. A distinct gradient in activity was
observed within the liver lobule. Hepatocytes localized around the terminal
hepatic venule showed a significant higher AC activity compared to hepatocytes
near the portal tract. AC was clearly decreased in focal preneoplastic liver
lesions of the glycogenotic-basophilic cell lineage leading to hepatocellular
carcinomas. Cytochemically detected intensity of AC activity corresponded to data
obtained by microbiochemical assays in laser-dissected tissue samples. A
remarkable interdependence of AC activity and degree of differentiation was also
seen in epithelial rat liver cell lines: Highly differentiated cells show high
enzyme activity and vice versa, as shown by both cytochemical and biochemical
examinations. It is concluded that alterations in cellular signal transduction
caused by alterations in AC activity play an important role in
hepatocarcinogenesis.
PMID- 9551628
TI - Adenylyl cyclase in the heart: an enzymocytochemical and immunocytochemical
approach.
AB - This review provides a discussion of the localization of adenylyl cyclase (AC) in
normal mammalian heart tissue employing enzymocytochemistry (detection of the
catalytic activity of AC by a metal precipitation technique) and
immunocytochemistry (immunolabeling of the enzyme protein with antibodies against
AC subtypes). By the metal precipitation technique, AC activity was localized in
adult guinea pig cardiomyocytes along the sarcolemma and the T-tubule membranes.
This reaction can be enhanced by hormones and guanylyl imidodiphosphate,
fluoride, and forskolin. With this technique, no precipitates were detected at
the sarcoplasmic reticulum. However, under ischemic conditions, AC activity was
also found in the junctional sarcoplasmic reticulum of rat cardiomyocytes.
Immunocytochemistry revealed AC in the plasma membrane of rat cardiomyocytes.
Detection of AC in the perinuclear space of cardiomyocytes might reflect
initiation of synthesis and processing of the enzyme protein. Colocalization of
AC with cytoskeleton fibers of non-cardiomyocytes emerging in the cell culture of
neonatal rat cardiocytes imply a direct cytoskeletal-AC interaction. Finally, it
can be stated that the immunolabeling pattern of AC in cryosections of adult and
new-born rat hearts reveals a good correspondence with the localization of AC
activity in cardiomyocytes demonstrated by enzymocytochemistry.
PMID- 9551630
TI - Immunocytochemical localization of adenylyl cyclase in human myometrium.
AB - The enzyme adenylyl cyclase (AC) plays a pivotal role in smooth muscle
relaxation. Biochemical evidence suggests that AC is predominantly located in the
outer layers of the myometrium; however, neither immunocytochemical nor
histochemical studies have been undertaken to demonstrate the specific cellular
distribution of the enzyme in this tissue. As part of an ongoing study of the
human myometrium, a polyclonal antibody against types V and VI AC was used to
detect the presence of these isoforms in sections of formalin-fixed, wax-embedded
myometrial tissue. A positive reaction was seen in the cytoplasm of the smooth
muscle cells with the midmyometrial area having the greatest number of positive
cells, when compared to the subserosal and subendometrial areas. It is
hypothesized that AC isoform type VI is the predominant isoform present in the
myometrium and that the percentage distribution of positive cells reflects the
area of highest myometrial activity during parturition.
PMID- 9551629
TI - Intracellular distribution of adenylate cyclase in human cardiocytes determined
by electron microscopic cytochemistry.
AB - Subcellular localization of adenylate cyclase (AC) in human cardiocytes was
studied by electron microscopic cytochemistry using ventricular biopsies from
various diseased hearts. In addition to the weak enzyme activity on the
sarcolemma, the intense reaction products of AC were demonstrated within
distinctive morphologic components of sarcoplasmic reticulum, nuclear envelope,
and other internal membranes such as parallel lamellar structures and interlaced
tubular structures in the perinuclear regions and stacked membranous structures
beneath sarcolemma in cardiocytes. The distribution and intensity of cytochemical
activity within different organelles was variable among biopsy cases. The
reaction products of AC cytochemistry within the sarcoplasmic reticulum could be
related to signal transduction targeting Ca2+ handling by the organella.
Cytochemical activity within the nuclear envelope and perinuclear internal
membranes possibly reflects AC participation in a signal function to regulate
nuclear activity, such as gene expression. Cytochemical distribution of the
enzyme in membranous structures beneath the sarcolemma is most likely related to
hormone receptors and the linked activity of AC. The subcellular distribution of
AC on various internal membrane structures in cardiocytes may reflect
compartmentalization of the enzyme at individual intracellular sites to regulate
a preferential specific signal function among multiple potential signal
transductions by a cascade of AC, cyclic AMP, and cyclic AMP-dependent protein
kinase. Alternatively, subcellular localization of the reaction products may
reflect local enzyme synthesis or represent sites of enzyme transport, e.g., to
terminal localization beneath the sarcolemma.
PMID- 9551631
TI - Ultramicrotomy on fretting wear debris.
AB - A TEM-sample preparation method for small amounts of fretting wear debris is
presented. After embedding in a resin, the debris are ultramicrotomed to ultra
thin sections. In this way, valuable observation of nanocrystalline fretting wear
debris originating from TiN-coatings could be rapidly obtained.
PMID- 9551632
TI - Instrumental factors in infrared microspectroscopy.
AB - Instrumentation is the cornerstone of infrared microspectrometry (IMS) technology
and the foundation for all applications. The fundamental factors in IMS systems
are presented from the perspective of an instrument developer. While the current
state of instrument development is presented, speculation of future development
is also included. The goal of IMS instrumentation is to produce the highest
signal-to-noise ratio (SNR) spectrum with the highest spectral resolution from
the smallest sample area. Detector response, spectrometer efficiency, source
brightness, wavelength range, microscope optics and sample definition are factors
limiting IMS instrument performance. The current performance and future trends in
IMS instrumentation are presented in this work.
PMID- 9551633
TI - Chemical imaging of nucleic acids, proteins and lipids of a single living cell.
Application of synchrotron infrared microspectrometry in cell biology.
AB - Hybridoma B-cells have been used as models to evaluate the performance of
synchrotron infrared microscopy to obtain chemical images of a single living
cell. Chemical mapping of nucleic acids, proteins and lipids at a resolution of a
few microns, close to the diffraction limit in the mid-infrared region are shown.
PMID- 9551634
TI - FT-IR microspectroscopic detection of metabolically deuterated compounds in the
rat cerebellum: a novel approach for the study of brain metabolism.
AB - Deuteration provides a novel means for studying metabolism in biological
organisms and avoids the use of radioisotopes. Ingestion of D2O enriched drinking
water causes deuterium to be metabolically incorporated into molecules within
tissues. The incorporation of deuterium into various chemical functional groups
then can be monitored via infrared spectroscopy. The excellent spatial resolution
that can be achieved with Fourier transform infrared (FT-IR) microspectrometers
allows collection of infrared spectra from select microscopic regions of tissue
specimens. Thus, combining deuteration together with FT-IR microspectroscopy
enables analysis of metabolic activities by probing subregions within the
microscopic field. In the present study, adult rats were given drinking water
containing 30% or 40% D2O for 5 1/2 weeks. Frozen sections were prepared from the
cerebellum, and infrared spectra were collected from the molecular layer, granule
cell layer and white matter with FT-IR microspectrometers, using both
conventional and synchrotron sources. The CD:CH and ND,OD:NH,OH ratios were
highest in the molecular layer and lowest in the white matter. The high ratios in
the molecular layer are consistent with the active synthesis and recycling at
synapses, which are abundant structures in this layer. The low levels in the
white matter are consistent with radioactive measures that found slow turnovers
of proteins and lipids in myelin, which is the main constituent of white matter.
In addition to describing the metabolic incorporation of deuterium, a graphic
description of the distribution of chemical functional groups in the various
layers of the cerebellum is presented. In summary, this study demonstrates that
FT-IR microspectroscopy in conjunction with administration of D2O in drinking
water can be used to reveal relative metabolic activities in various layers of
the cerebellum. We predict that metabolic activities in other tissues and tissues
in different states, e.g., disease states, can be analyzed in a similar manner.
PMID- 9551635
TI - Infrared microspectroscopic imaging of the cerebellum of normal and cytarabine
treated rats.
AB - Conventionally, the diagnosis of neuropathology in a subject requires the
identification of a behavioral modification, which provides direction for
appropriate histological analyses. However, since the ultimate diagnosis of the
pathology largely depends on the initial choice of histological tests, the
opportunity exists for inaccurate or insensitive results. An innovative approach
using Fourier transform infrared (FT-IR) spectroscopic imaging to diagnose
neuropathology should prove useful. This novel method monitors and visualizes the
underlying chemistry of the tissue, based on hundreds of vibrational absorption
bands that are intrinsic to the sample. As such, it makes no prior assumptions as
to the type or degree of pathology. Using this technique, we have
spectroscopically imaged cerebellar tissue slices from rats [control subjects and
subjects treated with the antineoplastic drug, cytarabine (Ara-C)], and have been
able to correlate lipid and protein distributions within distinct cell types in
the cerebellum. A further benefit of the technique is that it simultaneously
records tens of thousands of independent spectra from different spatial locations
within the sample. Thus, a variety of statistical and multivariate techniques can
be exploited to characterize large sample areas and to provide robust
classification of individual spectral signatures. In comparison to standard
histological protocols, FT-IR spectroscopic imaging simultaneously analyzes cell
layers and identifies subtle structural and biochemical changes within the
sample. We suggest that FT-IR spectroscopic imaging should provide a highly
reliable, complementary tool for standard histological tier testing.
PMID- 9551636
TI - Infrared crystallographic investigation of T-state hemoglobin.
AB - Polarized IR measurements on single crystals of human hemoglobin, grown under low
salt conditions that stabilize the T quaternary structure, allow spectral
features to be associated with individual sites within the molecule. Differences
between the a- and c-polarized IR spectra in the sulfhydryl stretching region
distinguish the contributions of individual Cys residues to the S-H band and lead
to an evaluation of possible H-bonding partners for Cys beta-112. Successful
modelling of both crystal and solution S-H spectra with component bands having
identical frequencies and bandwidths, supports the use of the X-ray structure as
a model for the low affinity T-state in solution. Polarization analysis of a
crystal partially saturated with CO reveals comparable occupancy of the alpha-
and beta-hemes. In the T-state crystal, the C-O bands are broader and lower in
frequency than in the R-state solution, and 20% of the CO-ligated beta-subunits
adopt an alternate conformation with a 1967 cm(-1) C-O frequency. The latter
observation reflects an energetically significant disruption of the distal heme
pocket upon CO binding to beta-hemes in the low affinity T-state.
PMID- 9551637
TI - Near-IR and IR imaging in lipid metabolism and obesity.
AB - Approximately one-third of Americans are classified as obese. There has long been
an interest in drug therapies for obesity. Interest in obesity research and in
drug interventions in obesity has greatly increased since the discovery of a
protein named leptin, one of apparently many competing biological signals in
energy metabolism. The complexity of the obesity problem demands new non-invasive
and non-destructive methods for monitoring lipid metabolism and energy
expenditure to study the competing biological signals and their effects. A new
computer algorithm for spectrometric imaging of living subjects is used to remove
artifacts arising from subject motion from spectra and images. The algorithm is
sufficiently simple to be implemented easily in hardware for real-time video
processing. Because the algorithm can be applied to images, thermogenesis and
lipid metabolism in interscapular adipose tissue can be observed directly in
unrestrained and unanesthetized subjects using an InSb focal plane array video
camera. The accuracy and precision of temperature and spectral measurements are
established using laboratory references and prototype drugs in test subjects.
PMID- 9551638
TI - FT-Raman, FT-IR spectroscopy and PIXE analysis applied to gallstones specimens.
AB - Fourier transform Raman (FT-Raman) spectroscopy and Fourier transform infrared
spectroscopy (FT-IR) were used as the main analytical techniques for the
determination of human gallstone structural composition. These techniques provide
rapid, qualitative and quantitative information about stone structure. The
gallstones were obtained from. 40 patients during both surgical operations and
laparoscopy. The results of FT-Raman and FT-IR analysis allowed to distinguish of
four main groups of gallstones according their cholesterol and bilirubinate salt
content. Our studies were extended to trace element analysis by means of proton
induced X-ray emission (PIXE). On 14 elements detected, six elements Ca, Mn, Fe,
Cu, Zn and Br were chosen for quantitative analysis. The concentration levels of
these elements varied depending the chemical structure of the gallstones. The
relationship between Ca and Cu appears to be of particular significance. In this
paper a correlation between stone structure and trace element concentrations is
presented.
PMID- 9551639
TI - Characterization of silicone breast implant biopsies by Fourier transform
infrared mapping.
AB - Fourier transform infrared (FT-IR) spectral mapping was used to study polymers in
human tissue associated with silicone breast implants. Biomaterials such as
polyesters, polyurethanes and silicone were identified by FT-IR spectroscopy, and
their relative locations and distributions within tissue specimens were
characterized by three-dimensional (3D) spectral maps.
PMID- 9551640
TI - Drug distribution in human hair by infrared microscopy.
AB - Localization of drug metabolites within human hair is important in determining
the pharmacokinetics of drug incorporation in hair. This information is critical
to validate drug testing data from hair. Microspectroscopic probing of small
areas within longitudinally microtomed hair sections provides a profile of the
deposition of drug along a growth line and thus indicates localization as a
function of time. Probing across individual hairs may reveal the
hydrophobic/hydrophilic characteristics of the substance. Hydrophobic drugs tend
to bind to the central core or medulla of the hair while hydrophilic drugs tend
to be spread throughout the cortex of the hair and appear, generally, in lower
concentrations per dose. Profiles of distribution with high spatial resolutions
of the regions of the hair are necessary for these determinations. This
information is available to a certain extent in normal infrared microscopy and
enhanced in synchrotron powered infrared microscopy.
PMID- 9551641
TI - Infrared microscopic functional group mapping and spectral clustering analysis of
hypercholesterolemic rabbit liver.
AB - Fourier transform infrared microscopy has been applied to the characterization of
hypercholesterolemic rabbit liver. A combination of the traditional "group
frequency" approach to spectral interpretation and the technique of functional
group mapping was applied to aid understanding of the spectral changes observed
between normal and hypercholesterolemic liver. Using this approach, spectral
differences could be attributed to the accumulation of cholesterol esters (most
likely in the form of lipoprotein complexes) in the hypercholesterolemic liver. A
novel approach, spectral clustering, was used to identify regions of
hypercholesterolemic liver tissue which possessed similar spectral (and by
inference similar biochemical/histological) properties. Using this approach, a
complex data set consisting of 400 discrete spectra acquired from an area of
tissue approximately 1 x 1 mm could be reduced to five types of spectra, and the
distribution of each type of spectrum within the tissue analyzed.
PMID- 9551642
TI - FT-IR microspectroscopic imaging of flax (Linum usitatissimum L.) stems.
AB - Fourier transform infrared (FT-IR) microspectroscopy was used to image and
subsequently produce maps of the distribution chemical components in flax stem
tissue. Cross-sections of two flax cultivars, Ariane and Natasja, were examined.
The infrared maps produced were keyed to the visible images of the samples, thus
permitting superimposition of chemical composition onto anatomical structure. The
functional group frequencies utilized to produce chemical maps were based on
their diagnostic capability for indicating each component to the exclusion of
others in the matrix, by comparison of the spectra of "pure" components. Waxes
were best indicated by a sharp shoulder at 2850 cm(-1) and appeared primarily in
the cuticular and epidermal tissues. Pectins gave a band ca. 1615 cm(-1) for the
Ca2+ salt form that was primarily detected in tissue surrounding the fiber
bundles. Cellulose was the strongest contributor to the band located at ca. 1335
cm(-1) that showed its greatest intensity in the fiber cells. Aromatic compounds
were indicated most readily by the band at 1510 cm(-1) and were located primarily
in the core tissue. Acetyl groups, likely associated with hemicellulosic
polysaccharides, were indicated by a band centered at 1250 cm(-1) and found
within the fibers and core tissue.
PMID- 9551643
TI - Infrared microspectroscopic imaging of biomineralized tissues using a mercury
cadmium-telluride focal-plane array detector.
AB - A 64 x 64 mercury-cadmium-telluride focal-plane array detector attached to a
Fourier transform infrared microscope was used to spectroscopically image 5
microm sections of canine alveolar bone tissue in the fingerprint region of the
infrared spectrum. By ratioing the relative intensities of specific bands across
the images, it is possible to obtain spatial distributions of the mineral-to
matrix ratio and mineral maturity as a function of distance from an osteon.
PMID- 9551644
TI - A method for examining the chemical basis for bone disease: synchrotron infrared
microspectroscopy.
AB - Infrared microspectroscopy combines microscopy and spectroscopy for the purpose
of chemical microanalysis. Light microscopy provides a way to generate and record
magnified images and visibly resolve microstructural detail. Infrared
spectroscopy provides a means for analyzing the chemical makeup of materials.
Combining light microscopy and infrared spectroscopy permits the correlation of
microstructure with chemical composition. Inherently, the long wavelengths of
infrared radiation limit the spatial resolution of the technique. However,
synchrotron infrared radiation significantly improves both the spectral and
spatial resolution of an infrared microspectrometer, such that data can be
obtained with high signal-to-noise at the diffraction limit, which is 3-5 microm
in the mid-infrared region. In this study, we use infrared microspectroscopy to
study the chemical composition of bone using two mapping methods. In the osteon
method, linear maps are collected from the center of an osteon (newer bone) to
the periphery (older bone) and their chemical compositions are compared. In the
transverse method, applied specifically to subchondral bone, line maps are
collected from the edge of the articular cartilage (older bone) to the marrow
space (newer bone). A significant advantage of infrared microspectroscopy over
other chemical methods is that the bone does not need to be homogenized for
testing; we are able to study cross-sectional samples of bone in situ at a
resolution better than 5 microm and compare the results with morphological
findings on stained serial sections immediately adjacent to those examined by
infrared microspectroscopy. The infrared absorption bands of bone proteins and
mineral are sensitive to mineral content (i.e. carbonate, phosphate, acid
phosphate), mineral crystallinity and the content/nature of the organic matrix.
In this study, they are analyzed as a function of (1) age, i.e. distance with
respect to the center of an osteon, and (2) morphology, i.e. cortical versus
cancellous (notably subchondral) bone. Results show that the protein/mineral
ratio is higher in younger bone. As bone matures, mineralization increases, as
does carbonate substitution into the hydroxyapatite lattice. Finally, most of the
changes in chemical composition of bone occur within 20 microm of the site of new
bone growth, e.g. the center of an osteon, demonstrating the need for the high
spatial resolution achieved only with the use of a synchrotron infrared source.
PMID- 9551645
TI - An approach to the study of primitive thrombocythemia (PT) megakaryocytes by
means of Fourier transform infrared microspectroscopy (FT-IR-M).
AB - Chronic myeloid leukemia (CML), polycythemia vera (PV), idiopathic myelofibrosis
(IM) and primary thrombocythemia (PT) are myeloproliferative diseases of clonal
origin. Megakaryocyte series are commonly involved in these disorders. In a
previous paper of us, megakaryocytes (MKs) from PV and PT patients were shown to
be more pathological with respect to the MKs from CML. This paper describes a
Fourier transform infrared microspectroscopy (FT-IR-M) study analyzing the
cytoplasm and nucleus areas of MKs from thrombocythemic patients which exhibited
numerous giant cells (from 100 to 190 microm in diameter). The size of these
cells makes it possible to analyze the cell parts using FT-IR-M technique. The
infrared determinations on 10 single MKs for each case examined in these two
different cell regions revealed spectral differences with a high degree of
reproducibility. Finally, the spectra of whole MKs from normal donors and from
thrombocythemic patients were also compared.
PMID- 9551646
TI - Fourier transform infrared and Raman microspectroscopy of materials in tissue.
AB - Fourier transform infrared and Raman (FT-IR and FT-Raman) microspectroscopy were
used to study materials found in human tissue. Individual cases involving
cholesterol, calcium stearate, and a polystyrenesulfonate ion exchange resin
demonstrate the utility of the spectroscopic data. Characteristic spectral bands
for these materials were compared with those of authentic chemical species to
confirm their identities. The role of vibrational spectroscopy in pathologic
diagnoses is discussed.
PMID- 9551647
TI - Ultraspatially-resolved synchrotron infrared microspectroscopy of plant tissue in
situ.
AB - Routine use of 6 microm or 12 microm apertures with synchrotron microspectroscopy
provide good spectra without excessive co-addition of scans. 100% mapping by
stepping in pixel sized increments reveals chemical heterogeneity within cellular
dimensions. The brightness of the synchrotron source and the absence of thermal
noise compared to a conventional thermal (globar) source yields favorable signal
to-noise operation. The nondivergent characteristics of the source result in
minimal loss of radiation at the aperture, hence, spatial resolution approaches
the diffraction limit. Details of cellular dimensions are then localized within
any maps produced and individual spectra obtained from adjacent pixels clearly
shows the striking difference in chemistry even within a microscopic vicinity. In
this report the mapping of plant tissue with the synchrotron is contrasted to
previous lower spatial resolution mapping experiments done with the globar on
similar materials using interpolation between separated sampling spots and larger
apertures.
PMID- 9551648
TI - The analysis of exfoliated cervical cells by infrared microscopy.
AB - The screening technique developed by Dr. Papanicolau for cervical cancer has
significantly increased opportunities for early detection and treatment of this
disease. Recently there has been a great deal of concern related to the accuracy
of the Pap smear screening technique for cervical cancer and the need for highly
skilled technologists to reliably examine the prepared samples. The use of
infrared spectroscopy as a technique to discriminate between normal and malignant
cervical cell samples has been reported by several research groups. Samples of
cervical cells can be prepared for spectroscopic diagnosis by centrifuging cells
obtained by the normal Pap smear technique and applying them to an infrared
transparent window. A major concern with diagnosis by infrared spectroscopy is
the homogeneity of the sample and whether the spectral features used in the
analysis are caused by localized groups of cells or can be attributed to the
majority of the cells in the sample. In this paper we report on the use of
automated infrared microscopic mapping techniques to measure the infrared spectra
at fixed intervals across the sample covering a 5 mm spot. Various post
processing techniques have been applied to the spectral results to create images
revealing specific features of the sample. The techniques applied to the data
include: 1) Baseline corrected peak height; 2) Band ratioing to compensate for
thickness; 3) Correlation metrics; 4) Similarity matching, and 5) Mahalanobis
distance classification algorithm.
PMID- 9551649
TI - Infrared microspectroscopy and artificial neural networks in the diagnosis of
cervical cancer.
AB - Infrared spectra of 88 normal and 32 abnormal (mild to severe dysplasia) cervical
smear samples were used as a databank to investigate the usefulness of artificial
neural networks (ANN) in the diagnosis of cervical smears. The spectra were first
reduced, using principal component analysis (PCA), to seven wavenumber components
that are the major contributors to the variance. A number of different ANN
architectures were investigated that could differentiate between normal and
abnormal cervical smears. Although the ANNs were trained to differentiate only
normal from abnormal smears, the results using an independent test data set
indicated that within the abnormal category mild dysplasia could be distinguished
from severe dysplasia. The results using this restricted data set indicate that
neural networks coupled to infrared microspectroscopy could provide an
alternative automated means of screening for cervical cancer.
PMID- 9551650
TI - FT-IR microspectroscopic imaging of human carcinoma thin sections based on
pattern recognition techniques.
AB - FT-IR microspectroscopic maps of unstained thin sections from human melanoma and
colon carcinoma tissues were obtained on a conventional infrared microscope
equipped with an automatic x, y stage. Mapped infrared data were analyzed by
different image re-assembling techniques, namely functional group mapping
("chemical mapping") and, for the first time by cluster analysis, principal
component analysis and artificial neural networks. The output values of the
different classifiers were recombined with the original spatial information to
construct IR-images whose color or gray tones were based on the spatial
distribution of individual spectral patterns. While the functional group mapping
technique could not reliably differentiate between the different tissue regions,
the approach based on pattern recognition yielded images with a high contrast
that confirmed standard histopathological techniques. The new technique turned
out to be particularly helpful to improve discrimination between different types
of tissue structures in general, and to increase image contrast between normal
and cancerous regions of a given tissue sample.
PMID- 9551651
TI - Biochemical imaging and 2D classification of keratin pearl structures in oral
squamous cell carcinoma.
AB - Precise regulation of cell organization results in well-differentiated tissue
structures and continuous renewal of the oral epithelium maintaining a highly
ordered tissue architecture. Here we demonstrate that FT-IR microspectroscopy,
performed on sections of cancerous tissue biopsies, is capable of generating
biochemical maps that show the distribution and any abnormal concentration of
individual classes of biomolecules. Oral epithelia affected by cancer (squamous
cell carcinoma) show many abnormal changes in morphology, of which the formation
of keratin pearls is only one. Spectra from selected pearl areas demonstrate that
these structures contain not only abnormal keratin concentrations but also seem
to be stabilized by surrounding collagen fibers. Infrared image maps reveal that
in the center of keratin pearls the concentration of protein (cytokeratins) is
abnormally high, that DNA is absent and that the cell membrane fluidity is
reduced. This suggests that cells are structurally destroyed and transformed into
nuclei-free horny cells, simulating normal differentiation and epithelial growth.
We also introduce a new analysis modality, two-dimensional (2D) tissue
classification, and apply it to establish spectral similarities between different
tissue structures. A total of 315 spectra, recorded for the original map, were
analyzed by pattern recognition methods, classified and re-assembled into new
maps based on their spectral similarities. The re-assembled maps clearly indicate
significant tissue changes outside the pearls, suggesting early biochemical
changes that accompany abnormal growth. Employing this 2D analysis modality in
combination with infrared histopathology may be relevant to tumor diagnosis and
prognosis.
PMID- 9551652
TI - A new, non-destructive method for analysis of clinical samples with FT-IR
microspectroscopy. Breast cancer tissue as an example.
AB - A new method for infrared analysis of tissues and cells is presented. The method
is based on Fourier transform infrared microspectroscopy coupled with attenuated
total reflectance. The technique allows spectroscopic measurements on the same
samples used by pathologists for histopathological evaluation, e.g. stained
samples on plain glass slides. Since the same specimen can be used as for
histopathology, the method does not require sample preparation or modification.
Significantly, the sample is not damaged. Glass absorbs in the infrared and thus
has not been used previously in infrared analysis of tissues and cells.
Conventional infrared techniques utilize expensive substrates, such as BaF2
windows and gold coated slides which do not absorb infrared radiation. However,
these measurements require special preparation and result in the destruction of
the sample. Breast cancer tissues were examined to demonstrate the feasibility
and reproducibility of the new method. Linear discriminant analysis was used to
discriminate and classify three types of cells: benign, atypical hyperplasia and
malignant. It was demonstrated that benign vs. malignant cells were discriminated
with 100% accuracy, benign vs. atypical hyperplasia were discriminated with 100%
accuracy and malignant vs. atypical hyperplasia were discriminated with an
accuracy of 90% and higher.
PMID- 9551653
TI - Infrared spectroscopy of human tissue. IV. Detection of dysplastic and neoplastic
changes of human cervical tissue via infrared microscopy.
AB - Infrared absorption spectra of formalin-fixed, paraffin-embedded human cervical
tissue are reported for normal, dysplastic and neoplastic samples. The spectral
differences found in this study between these states of the tissues are far less
than those observed for single cells by us and others. Nevertheless, we find a
direct correspondence between spectral data from tissue sections, obtained from
biopsies, and individual exfoliated cells, typically obtained during a pap
procedure. We also find that spectra due to dysplastic samples fall about halfway
between the spectral features of normal and cancerous samples.
PMID- 9551654
TI - The in situ infrared microspectroscopy of bacterial colonies on agar plates.
AB - The specular reflectance infrared spectra of thirty species of bacteria were
obtained in situ, without their removal from the agar growth media, using the
infrared microscope. Compared to transmittance spectra obtained from dehydrated
films, the transformed reflectance spectra show significant band shifts which are
greater for gram positive bacteria. The most notable shift occurs in the v[a](PO2
) band which shifts 8 cm(-1) higher upon removal of water. In addition, some
measure of the differentiation potential of our in situ reflectance spectra was
gathered by using principal components regression as a method of discrimination.
We assigned a +1 for a gram positive property and a -1 to a gram negative
property for each different bacteria species. The prediction results from a cross
validation show that all the gram positive bacteria retain positive values for
Gram stain predictions while all the gram negative species retain their negative
values, suggesting a simple marker for differentiation. Overall, using
reflectance spectra from colonies directly on the agar requires no sample
preparation and provides slightly better differentiating spectral information
than the transmittance spectra of dehydrated films.
PMID- 9551655
TI - Raman spectroscopic analysis of Tet repressor-operator DNA interaction in
deuterium oxide.
AB - Tet repressor (TetR) plays a central role in the regulation of its own gene and
in that of TetA, a resistance protein against the antibiotic tetracycline (Tc).
In the absence of Tc, the TetR dimer binds with two alpha-helix-turn-alpha-helix
motifs to two successive major grooves of operator DNA. In order to elucidate
structural features of the TetR:operator complex, we measured the Raman spectra
of the TetR protein, a 18-mer oligonucleotide with sequence corresponding to TetR
operator DNA, and the TetR:operator complex in D2O. The spectra confirm and
extend previously obtained results in H2O: i) B-DNA conformation is conserved
with only small perturbations of the backbone geometry; ii) TetR and operator DNA
interact at major groove sites, as evident from intensity changes of thymine and
guanine bands; iii) Minor changes of TetR secondary structure are indicated upon
operator binding, and iv) Local environments of aromatic amino acids are altered
in the complex. These spectroscopic findings are consistent with a molecular
model proposed of the basis of genetic and biochemical studies.
PMID- 9551656
TI - Comparison of fresh and post-mortem human arterial tissue: an analysis using FT
IR microspectroscopy and chemometrics.
AB - Fourier transform infrared (FT-IR) microspectroscopy and chemometric methods have
been applied to the study of fresh and simulated post-mortem human arterial
tissue. The results have shown that although physical differences were observed
using light microscopy, no spectroscopic distinction could be made between these
groups. The presence of collagen throughout the artery wall results in
characteristic absorptions which may mask any biochemical changes that could
otherwise have been detected by the FT-IR technique. Because the structure of the
artery is unique, these findings should be regarded as tissue specific.
PMID- 9551657
TI - FT-IR spectroscopy as an emerging method for rapid characterization of
microorganisms.
AB - Statistical methods such as principal component analysis and cluster analysis
were used to analyze ATR-FT-IR spectra obtained from bacterial whole cells. Both
methods gave satisfactory results and are conclusive in showing that they can
discriminate and classify bacterial strains of clinical origin exhibiting
different resistance mechanisms. This approach places FT-IR spectroscopy at the
forefront of those new potential techniques that could be used in the rapid
screening of microorganisms.
PMID- 9551658
TI - Posttranslational changes in band 3 in aging and Alzheimer's disease: do anion
and glucose transport changes reflect or foreshadow the eventual metabolic
abnormalities?
PMID- 9551659
TI - Role of epidermal growth factor and insulin-like growth factor-I on porcine
oocyte maturation and embryonic development in vitro.
AB - The effects of epidermal growth factor (EGF) and insulin-like growth factor-I
(IGF-I) on the in vitro maturation of porcine oocytes were examined. Oocytes
obtained from the ovaries of slaughtered prepubertal gilts were matured in
modified Medium 199 supplemented with 25% porcine follicular fluid and
gonadotropins, and fertilized in vitro. Oocytes were either fixed 16 h later to
assess fertilization or cultured for 7 days to assess embryonic development. In
Experiment 1, the addition of EGF to maturation medium increased the percentage
of meiotically mature oocytes (88% v. 70%; P < 0.001) but did not affect the
proportion of fertilized or cleaved oocytes. Blastocysts derived from oocytes
matured in medium supplemented with 10 ng mL(-1) EGF had a greater number of
cells compared with those of control blastocysts (51.1+/-5.1 v. 36.0+/-3.1; P <
0.02). In Experiment 2, the addition of IGF-I to maturation medium had no effect
on meiotic maturation, fertilization or embryonic development. Our findings
demonstrate that EGF plays an important role in both the meiotic and cytoplasmic
maturation of porcine oocytes in vitro.
PMID- 9551660
TI - Triosephosphate metabolism by mature boar spermatozoa.
AB - Boar sperm rapidly interconverted dihydroxyacetone phosphate and glyceraldehyde 3
phosphate, produced fructose-1,6-bisphosphate, approximately equilibrium
concentrations of fructose 6-phosphate and glucose 6-phosphate but not glycerol
or glycerol 3-phosphate. In the presence of 3-chloro-1-hydroxypropanone, an
inhibitor of stage 2 of the glycolytic pathway, the triosephosphates were
metabolized faster, produced less fructose-1,6-bisphosphate, fructose 6-phosphate
and glucose 6-phosphate, but not glycerol or glycerol 3-phosphate. This suggests
that these cells may have the capacity to convert glycolytic intermediates into a
storage metabolite to conserve carbon atoms for the eventual synthesis of
lactate.
PMID- 9551661
TI - Metabolic activity of hypotonically treated mature boar spermatozoa.
AB - Treatment of washed boar sperm with hypotonic phosphate buffer removed the
acrosome, disrupted the cytoplasmic membrane and almost completely separated the
heads from the mid piece-tail segment. As assessed by oxygen uptake studies and
their ability to oxidize 14C-labelled substrates to 14CO2, hypotonically-treated
cells exhibit low glycolytic activity yet mitochondrial activity remains high.
Both lactate and glycerol 3-phosphate underwent oxidation and these substrates
continued to be metabolized by this preparation which had been stored for up to
10 days at 4 degrees C. Such preparations may be of assistance in the
investigation of the biochemistry of boar sperm mitochondria.
PMID- 9551662
TI - Seasonal patterns of luteal cyclicity in young red deer (Cervus elaphus) and
sambar deer (Cervus unicolor).
AB - Seasonal onset of pubertal ovulation and incidence of luteal cyclicity was
assessed from plasma progesterone profiles over 15 months for tame red deer (n =
7) and sambar deer (n = 7) hinds. Seasonal responses to photoperiod were
determined from plasma prolactin profiles. All red deer attained puberty at 17-18
months of age in May-June and expressed 3-6 luteal cycles of length 20.0+/-10.4
days (mean+/-s.e.m.) over 52-102 days. Six sambar deer attained puberty at 7-19
months of age, between August and December. Duration of luteal cyclicity was
variable. While one animal remained continuously cyclic for 13 months, most
entered anoestrus between November and February. The mean length of the luteal
cycle was 17.2+/-0.3 days. While red deer exhibited strongly seasonal patterns of
prolactin secretion, sambar deer showed no such seasonal trends. The data
collectively indicate that young sambar hinds at temperate latitudes exhibit
loosely defined patterns of reproductive seasonality that are 4-6 months out of
phase with those of red deer, although some individuals may be non-seasonal.
Failure to express seasonal patterns of prolactin secretion indicates that sambar
deer may not perceive photoperiodic cues to the same extent as do red deer.
PMID- 9551663
TI - A competitive enzyme immunoassay for follicle-stimulating hormone in ovine plasma
using biotin-streptavidin amplification.
AB - To determine follicle-stimulating hormone (FSH) concentration in ovine plasma, a
second-antibody enzyme immunoassay using biotin-streptavidin amplification (BS
EIA) was developed and was validated by comparison with a routine
radioimmunoassay (RIA). Ovine FSH was labelled with D-biotinyl-epsilon
aminocaproic acid-N-hydroxysuccinimide ester (biotin-7-NHS). The minimum and
maximum detection limits were 0.40 ng mL(-1) and 25.0 ng mL(-1) respectively in
the BS-EIA. Plasma samples from three superovulated ewes were measured for FSH by
both BS-EIA and RIA. Correlation between values obtained by BS-EIA and RIA was
0.86 (n = 106), and the linear regression had a slope of 0.88 and an intercept of
-0.07 (R2 = 0.74). The baseline of BS-EIA was slightly lower than that of RIA
(0.69 ng mL(-1) v. 1.10 ng mL(-1)). The intra-assay and inter-assay coefficients
of variation in BS-EIA were 13.8% and 16.7% (n = 106) respectively. The recovery
rates were 104.8+/-2.7% (mean+/-s.e.m., n = 14). Changes in plasma FSH
concentration from superovulated ewes evaluated by BS-EIA corresponded well with
the results of routine RIA.
PMID- 9551664
TI - Effect of enucleation on protein synthesis during maturation of bovine oocytes in
vitro.
AB - The role of the nucleus in protein synthesis reprogramming during oocyte
maturation was examined in immature or mature bovine oocytes, enucleated at the
germinal vesicle (GV) stage or the metaphase II (MII) stage. Cumulus-oocyte
complexes (COCs) were denuded before or after maturation in vitro. Denuded
oocytes were (i) enucleated at the GV or MII stage (after DNA staining and
ultraviolet (UV) exposure), (ii) stained and exposed to UV but not enucleated, or
(iii) used as controls. After treatment, oocytes were labelled for 4 h with 35S
methionine or were matured for 24 h before labelling. GV- or MII- karyoplasts and
small portions of cytoplasm (cytoplasts), removed during enucleation, were also
labelled. Labelled oocytes, karyoplasts or cytoplasts were prepared for one
dimensional polyacrylamide gel electrophoresis. Incorporation of labelled
methionine into oocyte protein was measured. Enucleation did not affect protein
synthesis reprogramming, but incorporation of 35S-methionine in immature UV
stained oocytes was high--possibly due to nuclear repair mechanisms. Protein
profiles of GV- and MII- karyoplasts differed from those of immature and mature
oocytes. In conclusion, normal protein synthesis reprogramming in the cytoplasm
can occur in the absence of the nucleus, and specific proteins are synthesized in
the nuclear region.
PMID- 9551665
TI - Effect of iron on transferrin receptor expression by human placental
syncytiotrophoblast cells.
AB - Transferrin receptor expression has been examined in primary cultures of
morphologically differentiated placental syncytiotrophoblast cells. More than 90%
of the cells were multinucleated. Incubation of syncytiotrophoblast for 4 days in
the presence of iron salts had no effect on receptor expression assessed by
measuring the binding of 125I-labelled transferrin. However, incubation of cells
in the presence of human diferric transferrin (10-100 microM) led to a 50%
decrease in surface and intracellular receptor expression. This down-regulation
was not accompanied by a significant decrease in receptor synthesis. In contrast
to syncytiotrophoblast, expression of intracellular transferrin receptors in non
differentiated cytotrophoblast cells decreased when cells were cultured with iron
salts; this was accompanied by decreased receptor synthesis. Addition of diferric
transferrin to cytotrophoblast cells led to a 50% reduction in surface and
intracellular receptor expression, similar to that seen in the
syncytiotrophoblast. This reduction was accompanied by a decrease in receptor
synthesis. In contrast to that of most cell types, the expression and
distribution of trophoblast transferrin receptors were not altered by insulin,
epidermal growth factor or hydrocortisone. These characteristics of
syncytiotrophoblast transferrin receptor expression may assist in ensuring a
supply of iron to the fetus regardless of the maternal iron status.
PMID- 9551666
TI - Homeobox gene HB24, a regulator of haematopoiesis, is a candidate for regulating
differentiation of the extra-embryonic trophoblast cell lineage.
AB - Expression of the human homeobox gene HB24 in the cytotrophoblast stem cell
population in first-trimester human placenta was investigated. HB24 expression
was downregulated after cytotrophoblast had differentiated into
syncytiotrophoblast. Expression of HB24 was also detected in first-trimester
invasive extravillous cytotrophoblast cells. In term placenta, HB24 expression
was detected in residual cytotrophoblast cells and in syncytiotrophoblast.
Northern analysis revealed two HB24 transcripts in first-trimester placenta of
approximately 2.5 kb and 5.3 kb. Ribonuclease protection assays were used to
confirm expression of HB24 in first-trimester and term placenta and also to
provide evidence that HB24 is downregulated in choriocarcinoma cell lines. In
addition to being required for differentiation of the haematopoietic cell
lineage, HB24 may be required for differentiation of the extra-embryonic
trophoblast cell lineage.
PMID- 9551667
TI - Effect of hormone pre-treatment of prepubertal sheep on the production and
developmental capacity of oocytes in vitro and in vivo.
AB - Twenty 3-6-week-old Merino lambs were given either 3, 1 or 0 treatments of 50
microg oestradiol benzoate and (48 h later) a 1.5 mg Norgestamet implant left in
situ for 9 days (3-, 1- and 0CYCLE+G). On Day 7 after the last implant insertion,
and on the same day for 0CYCLE+G, each lamb received 400 I.U. pregnant mare serum
gonadotrophin and 6 mg follicle-stimulating hormone (FSH). The reproductive
tracts were removed for oocyte collection 24 h after FSH. Reproductive tracts
were also collected from 16-24-week-old lambs (n = 31) (0CYCLE-G). The number of
antral follicles per ovary was similar for the 3-, 1- and 0CYCLE+G treatments.
Similar rates of in vitro maturation and monospermic fertilization were obtained
for all groups. The proportion of blastocysts per cleaved oocyte was higher for
1CYCLE+G (50.5%) than for 3CYCLE+G (32.9%), 0CYCLE+G (24.3%), and 0CYCLE-G
(11.8%) (P < 0.05). Viable fetuses were obtained at Day 93 of pregnancy after
transfer of embryos from all treatments. These results indicate that a single
treatment with oestrogen and progesterone, prior to gonadotrophin stimulation,
will increase the yield and developmental capacity of oocytes from prepubertal
sheep.
PMID- 9551668
TI - Possible involvement of placental proteases in bradykinin (BK) degradation.
AB - The hydrolysis of bradykinin (BK) by human placental subcellular fractions and
pregnancy sera was studied in the presence of inhibitors by measuring amino acids
liberated from BK by high-performance liquid chromatography. The effects of the
inhibitors DL-2-mercaptomethyl-3-guanidinoethylthiopropionic acid (MGTA, for
kininase I), phosphoramidon (for endopeptidase 24.11) and captopril and
rentiapril (for angiotensin-converting enzyme [ACE, kininase II]) suggested the
essential roles of the above three proteases in BK degradation: among the three
proteases, kininase I and endopeptidase 24.11 appeared to be the most important
in kininase action in the placenta microsomes, whereas kininase I and ACE
appeared to be the most important in kininase action in the placental cytosol,
lysosome and pregnancy serum. Measurements of BK concentrations in the umbilical
arterial blood, umbilical venous blood and maternal plasma revealed higher
concentrations in the mother than in the fetus. The present data suggest that
degradation of BK in the placenta and pregnancy serum might contribute to the
gradient of BK between mother and fetus.
PMID- 9551669
TI - Preliminary characterization of a placental factor inhibiting breathing in fetal
sheep.
AB - Previous studies have revealed a placental extract that inhibits breathing in
fetal sheep. In the present study of 29 chronically instrumented sheep at 132+/-1
days of gestation, infusion of the 1-10 kDa extract inhibited breathing in 76% of
the experiments whereas Krebs' solution inhibited it in 24%. It retained this
activity after 6 months of freezing, after lyophilization, and upon lowering the
pH during purification from 8.0 to 4.0, but it inhibited breathing in only 35%
when the pH was lowered to 2.0. A significant dose-dependent effect was observed
from a 16-fold dilution to a 4-fold concentration. Treatment of the extract with
proteinase K or boiling reduced the activity to 30% or 26% inhibition,
respectively. The activity was not adsorbed to an ion-exchange column at pH 7.0
or 8.0, but it was at pH 9.0 and it eluted with increasing NaCl concentrations.
On a polyacrylamide gel the activity was eluted at a K(av) of 0.66 (82%
inhibition), corresponding to between 2.5 and 4.5 kDa. These findings suggest
that a peptide produced by the placenta, with a molecular mass between 2.5 and
4.5 kDa, inhibits fetal breathing.
PMID- 9551670
TI - Prostaglandin and progesterone production by bovine luteal cells incubated in the
presence or absence of the accessory cells of the corpus luteum and treated with
interleukin-1beta, indomethacin and luteinizing hormone.
AB - This experiment examined production of prostaglandin (PG) F2alpha, PGE2 and
progesterone by bovine luteal cells incubated with or without the accessory cells
and treated with recombinant bovine interleukin-1beta (10 ng), indomethacin (5
microg) or luteinizing hormone (50 ng). During pretreatment, progesterone
production was similar in the luteal and luteal plus accessory cells, being
greater in either of these than in accessory cells; PGF2alpha was greatest in
luteal plus accessory, intermediate in accessory and lowest in the luteal cells;
PGE2 was similar among all cell arrangements. Luteinizing hormone or luteinizing
hormone plus indomethacin stimulated progesterone in the luteal and luteal plus
accessory cells, this being similar in these two cell arrangements. Interleukin
1beta stimulated PGF2alpha in luteal and luteal plus accessory cells, and tended
to elevate PGF2alpha in accessory cells. Interleukin-1beta stimulated PGE2 in all
cell arrangements. Indomethacin inhibited the interleukin-1beta-stimulated
PGF2alpha and PGE2 release. Indomethacin or indomethacin plus luteinizing hormone
inhibited basal PGE2 in luteal and luteal plus accessory cells. These data
suggest that progesterone production is not influenced by the presence of
accessory cells of the corpus luteum, that accessory and luteal cells produce
appreciable amounts of PG, and that recombinant bovine interleukin-1beta
stimulates PGE2 and PGF2alpha in the luteal and accessory cells.
PMID- 9551671
TI - Use of famciclovir to prevent HBV reactivation in HBsAg-positive recipients after
allogeneic bone marrow transplantation.
AB - BACKGROUND/AIMS: Reactivation of chronic hepatitis B viral infection causes
significant morbidity and mortality after bone marrow transplantation. Recently,
nucleoside analogues, such as famciclovir, were found to have a direct
suppressive effect on hepatitis B virus replication in both in vitro and in vivo
studies. We have studied the effect of famciclovir on the incidence of hepatitis
B virus reactivation and hepatitis after allogeneic bone marrow transplantation.
METHODS: Eight hepatitis B surface antigen (HBsAg)-positive patients who received
allogeneic bone marrow transplantation were given oral famciclovir 250 mg three
times daily, starting at least 1 week prior to bone marrow transplantation and
continuing for 24 weeks after transplantation. Clinical and serological outcomes
in these patients were compared with 24 HBsAg-positive recipients of allogeneic
bone marrow transplantation who did not receive famciclovir (historical
controls). RESULTS: After bone marrow transplantation, there were five patients
with hepatitis B virus reactivation among those who received famciclovir 250 mg
three times daily. Four of these patients responded to increased dosages of 500
mg three times daily and did not develop hepatitis. The remaining patient
suffered from hepatitis related to hepatitis B virus reactivation. Compared to
historical controls, there were fewer cases of hepatitis due to hepatitis B virus
reactivation and veno-occlusive disease. The median follow-up was 701.6 days
(range: 50-2346 days) with ten deaths (three due to hepatic failure related to
HBV reactivation) in those who did not receive famciclovir and one death (due to
hepatic failure related to graft-versus-host disease) in those who received
famciclovir. CONCLUSIONS: Use of famciclovir significantly reduced hepatitis due
to hepatitis B virus reactivation in HBsAg-positive recipients after allogeneic
bone marrow transplantation.
PMID- 9551672
TI - A pilot randomized, controlled trial of the effect of iron depletion on long-term
response to alpha-interferon in patients with chronic hepatitis C.
AB - BACKGROUND/AIMS: Some studies have suggested that hepatic iron may influence the
response to interferon therapy in chronic hepatitis C patients. We conducted this
randomized, controlled trial to evaluate the effect of iron depletion on: (1)
aminotransferase activity and hepatitis C RNA levels; and (2) response to
interferon therapy in 38 patients with elevated alanine aminotransferase levels
and who were HCV RNA positive. METHODS: Seventeen patients underwent a 500-ml
phlebotomy every 2 weeks until iron deficiency was achieved. Patients were then
started on a 6-month course of alpha-interferon 2b (3 mu tiw). Controls were 21
patients who were monitored for a 6- to 8-week period without phlebotomy prior to
interferon therapy. Response to interferon was defined as loss of serum HCV RNA
by reverse transcriptase-polymerase chain reaction. Serum HCV RNA was quantitated
by bDNA technique. RESULTS: Alanine aminotransferase levels decreased in 15/17
patients after phlebotomy. Mean alanine aminotransferase fell from 156.8 to 89.7
U/l (p=0.008). Changes in iron indices and alanine aminotransferase after
phlebotomy were not accompanied by changes in HCV RNA levels. In control
patients, neither alanine aminotransferase nor HCV RNA levels changed during the
observation period. At the end of 24 weeks of interferon therapy, 7/17
phlebotomized patients had a response, compared to 6/21 control patients (p=ns).
After 6 months of follow-up, 5/17 phlebotomized patients remained HCV RNA
negative, in contrast to only 1/21 controls (p=0.07). CONCLUSIONS: Iron depletion
led to a reduction in aminotransferase levels; this was not accompanied by
changes in levels of hepatitis C RNA. There may be an improvement in the
sustained response to interferon therapy, but this requires confirmation.
PMID- 9551674
TI - Use of granulocyte macrophage colony stimulating factor alone or in combination
with interferon-alpha-2b for treatment of chronic hepatitis C.
AB - BACKGROUND/AIMS: We have evaluated the effect of granulocyte macrophage colony
stimulating factor (GM-CSF) when utilized either alone or in combination with
interferon for treatment of chronic hepatitis C virus (HCV). METHODS: A total of
71 patients with chronic HCV, elevated alanine aminotransferase and normal
hepatic function were enrolled into these studies. Nineteen patients who had
previously failed to achieve both biochemical and virologic response during
interferon therapy were treated with increasing doses of GM-CSF alone (65-250
microg/m2 three times weekly) for 6 months. Another 52 patients who had not been
previously treated with interferon entered a randomized controlled trial; 25 were
treated with interferon alone (3 mU three times weekly) and 27 with a combination
of interferon+GM-CSF (3 mU+250 microg/m2 three times weekly). All patients were
treated for 6 months. Both groups were well matched for age, sex, race, serum
alanine aminotransferase, HCV-RNA titer, liver histology score and cirrhosis.
RESULTS: None of the patients treated with GM-CSF alone developed either
biochemical or virologic response at any of the treatment dosages and mean HCV
RNA titer remained unchanged from baseline during this therapy. For patients in
the randomized controlled trial, biochemical and virologic responses were
observed in 54% of interferon-treated patients compared to 31.8% for those
treated with interferon+GM-CSF. Long-term sustained virologic response was
observed in only one patient in each group. No significant differences were
observed in HCV-RNA titer during the course of treatment. GM-CSF treatment was
associated with a significant increase in total white blood cell count and
absolute eosinophil count, which peaked within the first month of therapy and
declined spontaneously during the remaining 5 months. CONCLUSION: GM-CSF either
alone or in combination with interferon does not appear to be effective for
treatment of chronic HCV.
PMID- 9551673
TI - Role of anti-interferon antibodies in breakthrough occurrence during alpha 2a and
2b therapy in patients with chronic hepatitis C.
AB - BACKGROUND/AIMS: Alpha interferon induces aminotransferase normalization in about
50% of patients with chronic viral hepatitis C. However, some patients who
initially respond experience a relapse during the treatment period (breakthrough
phenomenon). The aim of this study was to evaluate the prevalence of breakthrough
and its relationship with the emergence of neutralizing anti-interferon
antibodies. METHODS: We studied 172 patients with histologically proven chronic
hepatitis C, treated with interferon alpha 2a or 2b 3 mega units three times a
week for 6 months. For each patient, HCV RNA level (polymerase chain reaction and
bDNA) and anti-interferon antibodies dosage were determined during therapy.
RESULTS: Among 84 patients with initial response, 13 (15.5%) experienced
breakthrough. The kinetics of alanine aminotransferase and HCV RNA levels were
strongly correlated, suggesting that breakthrough is not due to a random alanine
aminotransferase fluctuation during treatment, but to the reappearance of viral
replication. Neutralizing anti-interferon antibodies emergence was observed in
38.5% in patients with breakthrough, as compared to 9.0% and 2.8% of non
responder and complete-responder patients, respectively (p<0.0005). By
multivariate analysis, the only factor predictive of breakthrough was the
emergence of neutralizing anti-interferon antibodies 3 months after the onset of
therapy. CONCLUSION: Our results suggest that the emergence of neutralizing anti
interferon antibodies during treatment may explain breakthrough in about one
third of cases. Other causes may also be responsible for this phenomenon and they
remain to be determined.
PMID- 9551675
TI - Alpha-glutathione transferases in HCV-related chronic hepatitis: a new predictive
index of response to interferon therapy?
AB - BACKGROUND/AIM: The aim of this study was to evaluate if plasma levels of alpha
glutathione-S-transferases (determined in basal conditions and monthly for 1 year
during and 1 year after interferon therapy) could characterize patients who show
only a primary response. METHODS: We studied 48 patients with biopsy-proven,
hepatitis C virus ribonucleic acid positive chronic hepatitis treated with
interferon: 18 were "Sustained Responders", 12 "Relapsers" and 18 "Non
Responders". RESULTS: Relapsers showed higher basal levels of alpha-glutathione-S
transferases, which remained higher than normal even when alanine
aminotransferases normalized. No correlation was documented between alpha
glutathione-S-transferase levels and all other parameters examined (alanine
aminotransferases, gamma-glutamyl-transpeptidase, viremia, and histological
activity index). CONCLUSIONS: These findings suggest that alpha-glutathione-S
transferase levels may be considered a predictive index of response to interferon
therapy in chronic hepatitis C patients.
PMID- 9551676
TI - Detection of squirrel monkey retroviral sequences in interferon samples.
AB - BACKGROUND/AIMS: Interferons have been used therapeutically in viral infections,
and as immunomodulants in the treatment of different types of cancers.
Interferons have been prepared from human lymphoid cell-lines, such as Namalwa,
that contain integrated copies of squirrel monkey retrovirus proviral DNA.
Squirrel monkey retrovirus is related to simian type D retroviruses, such as
Mason-Pfizer monkey virus. Thus it is important to determine if these retroviral
sequences are present in interferon preparations purified from human cell lines.
METHODS: DNA samples were prepared from 75 commercial interferon preparations and
analyzed for squirrel monkey retrovirus sequences by polymerase chain reaction
and DNA sequencing. Since single polymerase chain reaction is not as sensitive, a
nested polymerase chain reaction strategy was devised in order to detect squirrel
monkey retrovirus-pol sequences. Amplification of beta-actin (human) sequences
was used to confirm that samples contained human genomic DNA. To determine the
authenticity of squirrel monkey retrovirus sequences, we analyzed amplified
products by Southern blot hybridization and direct DNA sequencing.
RESULTS/CONCLUSIONS: Thirty-nine samples were positive for squirrel monkey
retrovirus-pol sequences by nested polymerase chain reaction. It is noteworthy
that 29 samples were either weakly or very weakly positive by single polymerase
chain reaction, thus stressing the importance of our sensitive polymerase chain
reaction assay. However, it remains to be determined whether the residual DNA
sequences detected by our sensitive nested polymerase chain reaction assay have
biological consequences.
PMID- 9551677
TI - The C282Y mutation in the haemochromatosis gene (HFE) and hepatitis C virus
infection are independent cofactors for porphyria cutanea tarda in Australian
patients.
AB - BACKGROUND/AIM: Whether mutations in the putative haemochromatosis gene (HFE) and
hepatitis C virus act independently to precipitate porphyria cutanea tarda is
unknown. The aim of the study was to investigate the relationship between
mutations in HFE, hepatitis C and porphyria cutanea tarda. METHODS: The
frequencies of the C282Y and H63D mutations in HFE were determined in 27 patients
with porphyria cutanea tarda and compared with the reported control frequencies.
In addition, the presence of hepatitis C virus infection was identified and
related to the patients' HFE status. RESULTS: The C282Y mutation was found in
44.4% of patients compared with the control frequency of 12% (p<0.001). Three
patients were homozygous for the C282Y mutation, two of whom did not meet current
clinical diagnostic criteria for expressed haemochromatosis. The proportion of
patients with the H63D mutation did not differ from the reported control
frequency. The mean transferrin saturation and serum ferritin concentration were
similar in porphyria cutanea tarda patients who were homozygous normal and
heterozygous for the C282Y mutation, but greater in both groups than previously
reported in healthy controls. Seven (25.9%) patients were anti-HCV IgG positive.
None of these patients carried the C282Y mutation. Porphyria cutanea tarda
patients heterozygous for the C282Y mutation and patients with anti-HCV
antibodies had elevated transferrin saturations and serum ferritin
concentrations. CONCLUSIONS: The raised frequency of the C282Y mutation in
porphyria cutanea tarda indicates that this mutation is likely to be a
predisposing factor. However, abnormalities of iron indices also exist in
porphyria cutanea tarda patients without mutations in HFE. Hepatitis C virus
infection is likely to be another common precipitating factor for porphyria
cutanea tarda which acts independently of the C282Y mutation.
PMID- 9551678
TI - Reduction in hepatic cytochrome P-450 is correlated to the degree of liver fat
content in animal models of steatosis in the absence of inflammation.
AB - BACKGROUND/AIM: Fatty liver has been associated with an increased risk of primary
graft non-function and drug toxicity. However, these effects have been observed
mainly in fatty liver with inflammation, a situation characterized by an overall
reduction in cytochrome P-450 (CYP)-dependent activities as well as a contrasting
increase in CYP2E1 activity. Our aim was to examine the impact of liver-fat
accumulation on CYP in two animal models of fatty liver without
necroinflammation. METHODS: Ducks were force-fed with a high-glucidic diet and
male Wistar rats, after 48 h fasting, were refed a high-glucidic, fat-free diet
for 48 h. Total CYP, aminopyrine- (AND), erythromycin-N-demethylase (END) and
chlorzoxazone hydroxylase (CZOHase) activities as well as CYP2E1 and CYP3A
proteins were quantified on microsomal proteins. RESULTS: Livers from force-fed
ducks exhibited significant decreases in total CYP, AND, END and CZOHase
activities, inversely correlated with fat-liver content. Refeeding male Wistar
rats a high-glucidic, fat-free diet after 48 h fasting, resulting in a 235%
increased liver fat content, was associated with a decrease in total CYP (55%),
AND (78%), END (55%) and CZOHase (62%) activities as well as in CYP3A (70%) and
CYP2E1 (80%) protein content. A significant inverse correlation was observed
between CYP and total lipid content. CONCLUSIONS: In these models of steatosis
induced by nutritional manipulations, fat liver accumulation was associated with
a significant decrease in CYP activities and in CYP protein expression.
Furthermore, the decreases in both CYP content and related activities were
correlated with the degree of liver fat content.
PMID- 9551679
TI - Rat liver transport and biotransformation of a cytostatic complex of bis
cholylglycinate and platinum (II).
AB - BACKGROUND/AIMS: Bile acids have previously been used as shuttles for directing
organic drugs to the liver. The aim of this study was to investigate liver
transport and biotransformation of a new cytostatic bioinorganic complex (Bamet
H2), that was obtained by binding platinum(II) to two cholylglycinate moieties.
METHODS: Using rat hepatocytes in primary culture, the kinetics of
cholylglycinate, cisplatin and Bamet-H2 uptake were studied. Sodium-dependency of
Bamet-H2 uptake was investigated by replacement of 116 mM NaCl by 116 mM choline
chloride. Liver biotransformation was investigated by HPLC analysis of bile
samples collected from anesthetized rats following intravenous Bamet-H2
administration. Using isolated rat liver preparations, which were perfused with
erythrocyte- and albumin-free Krebs-Henseleit solutions for 40 min, measurement
of cholylglycinate, cisplatin and Bamet-H2 uptake and bile output was carried
out. Interaction between Bamet-H2 and cholylglycinate for liver transport was
studied by co-administration of 1 microM Bamet-H2 plus 500 microM cholylglycinate
and 1 microM [14C]-cholylglycinate plus 500 microM Bamet-H2. RESULTS: Both
cholylglycinate and Bamet-H2 uptake by rat hepatocytes followed saturation
kinetics. Comparison between the two compounds indicated that the Vmax (22.2
versus 8.5 nmol.5 min(-1).mg protein(-1)), and Kt (365 versus 171 microM) were
higher for Bamet-H2 uptake. The efficiency of Bamet-H2 uptake (Vmax/Kt) was
significantly reduced (-35%) in the absence of sodium. Cisplatin uptake by rat
hepatocytes was approximately 10-fold lower than that for Bamet-H2 at any dose
used. Moreover, this was not saturable up to 400 microM cisplatin. Bamet-H2 was
not biotransformed during its intrahepatic residence in anesthetized rats. Bamet
H2 uptake and secretion into bile by isolated rat livers exceeded cisplatin but
were less than cholylglycinate. Differences between Bamet-H2 and cholylglycinate
were more marked for bile output than for liver uptake. Thus, higher drug liver
content was found after perfusion with Bamet-H2 than with cholylglycinate or
cisplatin. Co-administration of Bamet-H2 and cholylglycinate revealed the
existence of partial cross-inhibition in both liver uptake and bile output. Bamet
H2 induced a more profound alteration on cholylglycinate uptake and bile
secretion than cholylglycinate on both process for Bamet-H2. CONCLUSION: These
results suggest that in the transfer of Bamet-H2 from the sinusoids to the
canaliculi both bile acid and non-bile acid transport systems are involved.
PMID- 9551680
TI - Bile duct bacterial isolates in primary sclerosing cholangitis: a study of
explanted livers.
AB - BACKGROUND/AIMS: The pathogenesis of the inflammatory lesion in primary
sclerosing cholangitis is unknown. The clinical picture is characterized by i.a.
episodes of fever, the cause of which also remains speculative. Previous studies
of bacterial isolates in the liver or bile ducts in primary sclerosing
cholangitis have had the shortcoming of possible contamination associated with
the sampling. The aim of this study was to investigate whether bile and bile duct
tissue, obtained under sterile conditions in connection with liver
transplantation, contain bacteria. METHODS: We studied bile from bile duct walls
and bile collected from the explanted livers of 36 patients with primary
sclerosing cholangitis and 14 patients with primary biliary cirrhosis. RESULTS:
Positive cultures were obtained from 21 of 36 primary sclerosing cholangitis
patients, but from none of the primary biliary cirrhosis patients. The number of
bacterial strains was inversely related to the time after the last endoscopic
retrograde cholangiography. Treatment with antibiotics or intraductal stent, or
the occurrence of fever before liver transplantation did not seem to influence
the culture results, whereas antibiotic treatment in connection with endoscopic
retrograde cholangiography may possibly have reduced the number of isolates in
the cultures. Alpha-haemolytic Streptococci were retrieved as late as 4 years
after the last endoscopic retrograde cholangiography. Retrospective analysis of
liver laboratory tests after endoscopic retrograde cholangiography did not
indicate a deleterious effect of the investigation. CONCLUSIONS: The data suggest
that antibiotics should be given routinely in connection with endoscopic
retrograde cholangiography. They also raise the question of a possible role of
alpha-haemolytic Streptococci in the progression of primary sclerosing
cholangitis.
PMID- 9551681
TI - Mycobacterial DNA not detected in liver sections from patients with primary
biliary cirrhosis.
AB - BACKGROUND/AIMS: Recent studies in primary biliary cirrhosis have reported the
detection of serum antibodies against Mycobacterium gordonae and of mycobacterial
DNA in liver sections. The aim of this study was to investigate whether
mycobacterial DNA is present in liver biopsy material in primary biliary
cirrhosis. METHODS: Archival liver biopsy specimens from 11 patients with primary
biliary cirrhosis (10 female, mean age 52 years) and 11 patients with autoimmune
hepatitis (10 female, mean age 53 years) were identified. Positive control tissue
comprised five archival lymph node specimens from patients with tuberculous
lymphadenopathy, three of which had stained positive on ZN staining, and also a
liver biopsy specimen from a patient with tuberculous hepatitis (ZN positive).
Fixed sections were deparaffinised and DNA was extracted by mechanical disruption
with glass beads. DNA was purified by use of diatoms and lysis in guanidinium
thiocyanate in a technique previously validated for archival DNA. Primers were
directed to amplify a partial 16S ribosomal RNA gene yielding the species
specific character for mycobacteria, and also to amplify the constitutively
expressed human gene GAPDH. RESULTS: The polymerase chain reaction was shown to
be capable of detecting 1 fg of M. gordonae DNA in 'spiked' samples, equivalent
to 1-5 bacterial cells. No mycobacterial DNA was detected in liver biopsy samples
from either the primary biliary cirrhosis or autoimmune hepatitis groups. Of the
tuberculous control sections, mycobacterial DNA was detected in four of five
lymph nodes and the liver biopsy specimen. GAPDH amplification was detected in
all tested samples from liver disease and tuberculous control samples.
CONCLUSION: These data do not support a role for mycobacteria in the aetiology of
primary biliary cirrhosis.
PMID- 9551682
TI - Histopathological evaluation of liver fibrosis: quantitative image analysis vs
semi-quantitative scores. Comparison with serum markers.
AB - BACKGROUND/AIMS: Liver fibrosis is mainly evaluated by qualitative histological
examination. Although histological semi-quantitative scores and quantitative
determination with image analysis are now possible, these methods have not been
fully validated and compared. Therefore, we evaluated these two methods
prospectively in 243 patients with chronic liver disease. METHODS: The semi
quantitative fibrosis score was evaluated by two independent pathologists, using
the Knodell fibrosis score and a 6-grade score derived from the Metavir score;
the area of fibrosis was measured by image analysis. The serum levels of
hyaluronate, N-terminal peptide of procollagen III, laminin, transforming growth
factor-beta1, alpha2-macroglobulin, apolipoprotein A1, PGA score and prothrombin
index were measured. RESULTS: There was a good correlation between the semi
quantitative fibrosis score and the area of fibrosis (r=0.84, p<10(-4)). Using
multiple regression analysis, the semi-quantitative score was predicted by the 8
serum markers with R2=0.69 (R2=0.59 for hyaluronate at the 1st step) while the
area of fibrosis was predicted with R2=0.79 (R2=0.76 for hyaluronate at the 1st
step), and the Knodell fibrosis score was predicted with R2=0.65 (R2=0.31 for
hyaluronate at the 1st step). CONCLUSIONS: The area of fibrosis, as determined by
image analysis, and the semi-quantitative score are well correlated. However, for
serum markers the correlation is higher with the area of fibrosis than with the
semi-quantitative score. Other characteristics such as reproducibility, rapidity,
simplicity, adaptability, and exhaustiveness also favor image analysis.
PMID- 9551683
TI - Upright posture decreases esophageal varices flow velocity in patients with
cirrhosis.
AB - BACKGROUND/AIMS: Patients with cirrhosis tend to have esophageal variceal
bleeding episodes at night, rather than during the day time. Since human beings
carry on ordinary activities in the upright posture in the day time and are
recumbent at night, we hypothesized that posture may be a factor related to a
circadian variation of variceal bleeding. The aim of this study was to examine
the effect of upright posture on esophageal varices hemodynamics in patients with
cirrhosis. METHODS: Nine patients with cirrhosis and esophageal varices were
included in a crossover study performed on 2 separate days. On the non-endoscopic
day, cardiac output, portal vein flow velocity, and superior mesenteric artery
flow velocity were measured with percutaneous Doppler ultrasonography. Plasma
renin activity and plasma norepinephrine concentrations were also determined. On
the endoscopic day, in addition to the above measurements, esophageal varices
flow velocity was measured using transesophageal Doppler ultrasonography. These
measurements were performed in the supine position and 20 min after the
assumption of the upright position. RESULTS: On the non-endoscopic day, the
upright posture significantly decreased cardiac output, portal vein flow
velocity, and superior mesenteric artery flow velocity. Plasma renin activity and
plasma norepinephrine concentration were significantly increased after assumption
of the upright position. On the endoscopic day, similar hemodynamic and hormonal
changes were observed. In addition, the upright posture significantly decreased
esophageal varices flow velocity. Furthermore, the magnitude of the reduction in
esophageal varices flow velocity (-42%) was significantly greater than that in
portal vein flow velocity (-22%, p<0.01) and that in superior mesenteric artery
flow velocity (-25%, p<0.01). Although the change in esophageal varices flow
velocity was not significantly correlated with that in plasma renin activity (r=
0.28) and that in plasma norepinephrine concentration (r=-0.10), it was
significantly correlated with the change in superior mesenteric artery flow
velocity (r=0.73, p<0.05). CONCLUSIONS: The upright posture decreases esophageal
varices flow velocity mainly because of the reduction in splanchnic blood flow.
This effect may contribute to a low prevalence of esophageal variceal bleeding in
the day time in patients with cirrhosis.
PMID- 9551684
TI - Factors related to early mortality after transjugular intrahepatic portosystemic
shunt for failed endoscopic therapy in acute variceal bleeding.
AB - BACKGROUND: Uncontrolled variceal haemorrhage is the main indication for
transjugular intrahepatic portosystemic shunt. However, mortality is 50% for this
high-risk group. We have evaluated clinical and laboratory variables prior to
transjugular intrahepatic portosystemic shunt in order to establish predictors of
mortality, validated prospectively. METHOD: Over a 4-year period, 367 patients
were admitted with variceal bleeding. In 54 patients endoscopic therapy for acute
variceal bleeding failed and they had emergency transjugular intrahepatic
portosystemic shunt. Failure of therapy was defined as continued bleeding after 2
endoscopy sessions (n=39) or vasoconstrictor-resistant bleeding from
gastric/ectopic varices (n=15). Thirty-three variables were analysed from data
available immediately prior to transjugular intrahepatic portosystemic shunt.
RESULTS: Twenty-six patients died within 6 weeks. In a multivariate analysis, 6
factors had independent prognostic value: moderate/severe ascites, requirement
for ventilation, white cell blood count (WBC), platelet count (PLT), partial
thromboplastin time with kaolin (PTTK) and creatinine. A prognostic index (PI)
score was derived, in which presence of moderate/severe ascites, or need for
ventilation, scored 1: PI=1.54 (Ascites)+1.27 (Ventilation)+1.38 Ln (WBC)+2.48 ln
(PTTK)+1.55 Ln (Creat)-1.05 Ln (PLT). Using this equation, 42% (n=10) of deaths
occurred in the fifth quintile (PI > or = 18.52), where the mortality was 100%.
The score was prospectively validated in a further 31 patients, giving 100%
positive predictive value. Eleven further patients died, including all seven with
a PI >18.5. No survivors had a PI >18.3. CONCLUSION: Despite immediate control of
bleeding by transjugular intrahepatic portosystemic shunt, patients with
uncontrolled variceal haemorrhage have a high mortality, particularly when
associated with markers of advanced liver disease, sepsis and multi-organ
failure. The use of transjugular intrahepatic portosystemic shunt is probably not
justified in this subgroup. Our prognostic index can help identify such patients,
and, if validated elsewhere, will help in deciding when to use transjugular
intrahepatic portosystemic shunt.
PMID- 9551685
TI - Differential effects of exogenous and endogenously generated H2O2 on phagocytic
activity and glucose release of normal and cirrhotic livers.
AB - BACKGROUND/AIMS: Reactive oxygen species play an essential role in necro
inflammatory processes. Therefore, the aim of the present studies was to
investigate the effect of exogenous and endogenously produced H2O2 on the
phagocytic capacity and glucose release of perfused cirrhotic rat livers in
comparison with that on the controls. METHODS: Complete septal cirrhosis was
achieved by oral treatment of rats with thioacetamide for 6 months. The
phagocytic capacity of the perfused livers was measured by the uptake of
colloidal carbon. During the continuous perfusion with colloidal carbon, either
H2O2 or benzylamine was added to the perfusion medium for a limited time period.
The latter functioned as an endogenous H2O2 donor. RESULTS: In control rats
exogenous and endogenously produced H2O2 caused a transient stimulation of the
hepatic colloidal carbon uptake as well as of the glucose release. Inhibition of
the catalase by aminotriazol doubled the changes evoked by H2O2, whereas blockade
of the Kupffer cells by GdCl3 drastically reduced its stimulatory effect.
Cirrhotic livers took up less colloidal carbon and released lower amounts of
glucose than the controls when stimulated by exogenous H2O2. The inhibition of
the nitric oxide synthetase augmented the H2O2-induced effect in controls as well
as in the cirrhotic livers by 250% and 620% (colloidal carbon uptake) and 340%
and 760% (glucose release), respectively. The blockade of the eicosanoid
production by indomethacin and caffeic acid drastically increased the glucose
release and the colloidal carbon uptake in controls and, in absolute terms, to a
lesser extent in cirrhotic livers. Endogenous H2O2 produced by the addition of
benzylamine stimulated the colloidal carbon uptake and glucose release in livers
from both groups. The inhibition of the lipoxygenase increased both parameters,
whereas different effects were elicited by the addition of superoxide dismutase
in controls and cirrhotic livers. CONCLUSION: The maximum uptake of colloidal
carbon and glucose release, measured after stimulation by H2O2, was lower in
cirrhotic livers than in controls, thus indicating a lowered phagocytic capacity
of Kupffer cells and altered glycogenolytic response of the hepatocytes in
cirrhotic livers. The use of various effectors provided evidence that superoxide
anions, nitric oxide and, possibly, arachidonic acid are involved in the signal
transduction between Kupffer cells and hepatocytes when stimulated by exogenous
or endogenously produced H2O2. This signalling mechanism seems to be impaired in
cirrhotic livers.
PMID- 9551686
TI - Interferon gamma treatment prevents procollagen gene expression without affecting
transforming growth factor-beta1 expression in pig serum-induced rat liver
fibrosis in vivo.
AB - BACKGROUND/AIM: The aim of this study was to investigate the effect of interferon
gamma on the synthesis of matrix proteins such as collagens with the relation to
transforming growth factor-beta1 expression in vivo. METHODS: We investigated the
effects of interferon gamma in a model of liver fibrosis induced by pig serum in
male Wistar rats, which develops fibrosis without an increase in serum alanine
aminotransferase (i.e., without hepatocyte injury). Rats were injected with 0.5
ml of pig serum twice a week for 8 weeks with or without 20,000 or 50,000 U of
interferon gamma. RESULTS: Interferon gamma at doses up to 50,000 U/day prevented
fibrosis, as indicated by reduced hydroxyproline content in the liver. Interferon
gamma at 50,000 U/day also reduced expression of type I and III procollagen in
the liver. However, the expression of transforming growth factor-beta1 mRNA and
protein in the liver was not reduced by interferon gamma. Histologically,
interferon gamma at 50,000 U/day also reduced the number of myofibroblast-like
cells (activated stellate cells). CONCLUSIONS: These results indicate that
interferon gamma can prevent fibrosis by inhibiting the activation and
proliferation of stellate cells, resulting in reduced expression of procollagen
without affecting transforming growth factor-beta1 expression in pig serum
induced rat liver fibrosis in vivo.
PMID- 9551687
TI - Long-term cultures of human fetal liver cells: a three-dimensional experimental
model for monitoring liver tissue development.
AB - BACKGROUND/AIMS: The present study describes an embryonic-fetal liver culture
system which allows morphogenetic interactions consistent with the development of
the hepatocellular function. METHODS: Intact livers from 8-12-week embryos were
soaked in an extracellular matrix at 4 degrees C and gently dissociated without
any enzymatic treatment. The resulting spherical hepatic units were cultured in a
chemically defined serum-free medium and seeded into an extracellular matrix
layer. Adherent three-dimensional tissue specimens were examined at various times
by light and electron microscopy to evaluate the maintenance of hepatocyte
morphology. RESULTS: The liver cells were viable for over 4 months;
erythropoietic burst colonies were detected for longer than 6 weeks. Parallel
detection of bile salt production in the medium by high performance liquid
chromatography proved liver tissue functionality. Bile salt composition revealed
predominance of taurine-conjugates rather than glycine. Maximum bile salt
concentration (approximately 3 months) coincided with structural and
ultrastructural observations indicating a marked decline in hematopoiesis, well
defined biliary canaliculi and formation of an organ-like structure. CONCLUSIONS:
This three-dimensional culture system recapitulates fetal liver development with:
(i) initial proliferation of both fetal erythropoietic and hepatic cells and (ii)
subsequent shut-off of erythropoiesis and a shift to a more advanced stage of
hepatocyte function, such as bile salt secretion.
PMID- 9551688
TI - Diagnostic value and tolerance of Lipiodol-computed tomography for the detection
of small hepatocellular carcinoma: correlation with pathologic examination of
explanted livers.
AB - BACKGROUND/AIMS: This study aimed to assess the tolerance and the real
sensitivity of Lipiodol-computed tomography in the detection of small
hepatocellular carcinoma by comparison with pathological examination of the
explanted livers. METHODS: Seventy-two patients with cirrhosis (Child A=8, B=36,
C=28) awaiting orthotopic liver transplantation underwent Lipiodol-computed
tomography to determine the presence, number and location of possible
hepatocellular carcinoma nodules. Before liver transplantation six patients had a
presumed single hepatocellular carcinoma diagnosed by biopsy. Liver
transplantation was performed a mean of 6 months after Lipiodol-computed
tomography. Explanted livers were sectioned at 0.8- to 1-cm intervals. Lipiodol
computed tomography staging and pathologic findings were compared. RESULTS:
Pathologic studies showed 24 hepatocellular carcinoma nodules (diameter, 2-42 mm)
not diagnosed before liver transplantation in 14 of the 72 livers. Lipiodol
computed tomography detected 6 of these 24 nodules, but none of the daughter
lesions (n=9) in the six patients with a presumed single hepatocellular
carcinoma. Lesion-by-lesion analysis revealed a sensitivity of 37%. Lipiodol
computed tomography falsely detected three additional nodules not confirmed by
pathologic examination (1 haemangioma, 2 nondysplastic regenerating nodules). One
Child C patient developed variceal bleeding within 2 days after injection of
Lipiodol. CONCLUSIONS: Tolerance of this procedure was satisfactory, even in
Child C patients. Lipiodol-computed tomography has a low sensitivity in the
detection of small hapatocellular carcinoma. These results must be considered
when liver resection or liver transplantation is proposed for the treatment of
hepatocellular carcinoma.
PMID- 9551689
TI - Preoperative TNM-classification is a better prognostic indicator for recurrence
of hepatocellular carcinoma after liver transplantation than albumin mRNA in
peripheral blood. Liver Transplant Oncology Group.
AB - BACKGROUND/AIM: Survival after orthotopic liver transplantation for
hepatocellular carcinoma is limited by a high rate of tumor recurrence. A
polymerase chain reaction assay based on the detection of albumin mRNA expression
in peripheral blood for detection of hematogenous micrometastasis of
hepatocellular carcinoma has been described, which may help to select candidates
for orthotopic liver transplantation. METHODS: The prognostic value of a highly
sensitive nested reverse transcription-polymerase chain reaction assay was
evaluated in comparison with the TNM-classification of the International Union
against Cancer in a population of liver transplant candidates. RESULTS: Eighty
patients with liver disease and 42 control patients were evaluated. Six of 21
patients with hepatocellular carcinoma and 11 of 59 patients with other diseases
of the liver were positive for albumin reverse transcription-polymerase chain
reaction, making this assay an indicator of ongoing liver damage without absolute
specificity for hepatocellular carcinoma. Twelve patients with hepatoma were
followed after liver transplantation and seven of those patients had a tumor
recurrence within 12 months. Six of these patients with recurrence had
International Union against Cancer stage IV A tumors preoperatively, while only
one of them was positive for albumin reverse transcription-polymerase chain
reaction before transplantation. Only one patient with a stage I to III tumor had
a recurrence within 12 months. CONCLUSIONS: Detection of albumin mRNA in
peripheral blood by reverse transcription-polymerase chain reaction seems to be
an unreliable marker for assessing hematogenous spread of hepatocellular
carcinoma. With International Union against Cancer stage IV A being a much better
predictor of tumor recurrence, the practical value of albumin mRNA reverse
transcription-polymerase chain reaction for patient selection in liver transplant
candidates seems to be very limited.
PMID- 9551690
TI - Antitumor effect of the nucleoside analogs 2-chlorodeoxyadenosine and 2',2'
difluorodeoxycytidine on human hepatoma HepG2 cells.
AB - BACKGROUND/AIMS: Hepatocellular carcinoma is one of the most malignant tumors in
the world. Although a wide range of therapeutic options is available, the
efficacy of these methods and the prognosis of hepatocellular carcinoma are still
very poor. The nucleoside analogs 2-chlorodeoxyadenosine (Cladribine, 2-CdA) and
2',2'-difluorodeoxycytidine (Gemcitabine, dFdC) have shown potent cytotoxic
effects on various human tumor cell lines in vitro and marked therapeutic
efficacy in the treatment of lymphoproliferative disorders and several solid
tumors in vivo. In the present study we evaluated the antitumor effect of 2-CdA
and dFdC on human hepatoma HepG2 cells. METHODS: HepG2 cells were grown in the
absence and presence of increasing concentrations of 2-CdA and dFdC. Antitumor
activity was assessed by inhibition of cell growth, evaluated by counting cell
numbers in a hemocytometer and by 3H-thymidine uptake, and by reduction of cell
viability as determined by exclusion of 0.1% trypan blue. For rescue experiments,
the natural pyrimidine deoxycytidine (dCyd) was added simultaneously or delayed.
RESULTS: A strong antitumor activity was observed for both compounds. dFdC showed
a more pronounced effect with an inhibition constant (IC50) of 3.98+/-0.03 nM in
comparison to 2-CdA with an IC50 of 16.66+/-0.40 nM. Both drugs achieved their
half-maximal antitumor activity after 31 h. With respect to dFdC, fractionated
daily administrations showed a distinctly greater antitumor activity than a
single transient administration. The cytotoxic effects of 2-CdA and dFdC were
completely reversed by simultaneous addition of dCyd. CONCLUSION: In this paper
we show strong antitumor effects of the nucleoside analogs 2-CdA and dFdC on the
human hepatoma cell line HepG2. These findings suggest that both compounds, but
in particular dFdC, are promising substances for further evaluations in the
treatment of hepatocellular carcinoma.
PMID- 9551691
TI - Transient emergence of hepatitis B variants in a patient with chronic hepatitis B
resistant to lamivudine.
AB - BACKGROUND: Lamivudine is a cytosine nucleoside analogue that inhibits hepatitis
B virus replication. Resistance to lamivudine monotherapy has been reported in
patients who received lamivudine to prevent recurrent hepatitis B virus infection
after liver transplantation. No cases of resistance have been described in
patients who did not clear HBV DNA during lamivudine therapy. METHODS: We report
the case of an adult patient with chronic HBeAg-positive hepatitis B who had a
hepatitis flare during lamivudine therapy. The patient did not respond to
lamivudine and, at 4 months of treatment, developed a significant serum alanine
aminotransferase elevation. Alanine aminotransferase levels remained elevated for
4 months and returned to baseline spontaneously. Lamivudine therapy was
administered for 1 year (52 weeks) and after withdrawal, alanine aminotransferase
levels remained elevated. RESULTS: Sequencing studies of HBV DNA at week 52
showed the emergence of a lamivudine-resistant variant associated with two point
mutations in the hepatitis B virus polymerase gene: one mutation led to amino
acid substitution of methionine to valine at residue 552, in the highly conserved
tyrosine-methionineaspartate-aspartate motif, part of the active site of the
polymerase; the second mutation consisted of a substitution of leucine to
methionine at residue 528. At week 54 of follow-up, both mutations were
undetectable. CONCLUSION: This observation demonstrates the transient emergence
of HBV variants in the course of therapy in a patient resistant to lamivudine
therapy.
PMID- 9551692
TI - Insulin-dependent diabetes mellitus during alpha-interferon therapy for chronic
viral hepatitis.
AB - A 29-year-old man was observed to develop insulin-dependent diabetes mellitus
following a 5-month treatment with recombinant alpha-2b-interferon for chronic
hepatitis C. After the onset of the disease, serum samples that had,
respectively, been collected before therapy commencement, at month 3, and at the
onset of insulin-dependent diabetes mellitus were tested for islet-cell (ICA
IgG), glutamic acid decarboxylase (GAD-Abs), IA2 (IA2-Abs) and insulin (IA-Abs)
autoantibodies. The following results were obtained: ICA-IgG, 5, >80, and >80 JDF
U, respectively; GAD-Abs: >100 U/ml in all three measurements; IA2-Abs and IA
Abs: negative. During treatment, thyroid microsomal autoantibodies increased
markedly (from 1:100 to 25,600 titer); thyroid-stimulating hormone was
persistently normal. HLA class II typing revealed a genetic predisposition to
insulin-dependent diabetes mellitus as demonstrated by the presence of DRB1*
04/08, DQ A1 52 Arg+/Arg+, and DQB1 57 N-Asp/Asp alleles. One year after the
onset of insulin-dependent diabetes mellitus, the patient is still receiving 30
IU insulin daily; the liver function tests are normal and HCV-RNA is negative.
These data support the hypothesis that, in predisposed patients, alpha-interferon
therapy can enhance an ongoing autoimmune process against pancreatic beta-cells
and induce overt insulin-dependent diabetes mellitus. We therefore suggest that,
in patients with a documented predisposition to insulin-dependent diabetes
mellitus, alpha-IFN therapy should be administered with caution.
PMID- 9551693
TI - Cerebral aspergillosis in a liver transplant recipient: a case report of long
term survival after combined treatment with liposomal amphotericin B and surgery.
AB - Cerebral aspergillosis is a life-threatening complication in liver transplant
recipients, with mortality rates approaching 100%; treatment with amphotericin B
is of limited efficacy because of its poor distribution in the cerebrospinal
fluid and its systemic side effects. We report the case of a liver transplant
recipient who developed recurrent cerebral Aspergillus fumigatus infection, and
was successfully treated by combined surgical excision of the lesion and
administration of liposomal amphotericin B. This first report of long-term
complication-free survival in a liver transplant recipient suggests that therapy
with liposomal amphotericin B may reduce the risk of recurrence of cerebral
aspergillosis in these immunocompromised patients.
PMID- 9551694
TI - Images in hepatology: Hepatic iron in hemochromatosis enhances hepatocellular
carcinoma in magnetic resonance imaging.
PMID- 9551695
TI - Risk factors for acute hepatitis A in Italy: possible pitfalls of a disease
registry-based case-control study.
PMID- 9551696
TI - Successful treatment of polyarteritis nodosa related to hepatitis B virus with
interferon alpha as first-line therapy.
PMID- 9551697
TI - Ischaemic left ventricular dysfunction: a preventable precursor of heart failure?
PMID- 9551698
TI - Current therapeutic uses and potential of beta-adrenoceptor agonists and
antagonists.
AB - Beta-adrenoceptors are members of a large family of hormone and neurotransmitter
receptors that initiate their biological function by coupling to GTP-binding
regulatory proteins. beta-Adrenoceptors can be subdivided into two main
subgroups, designated beta1 and beta2. Atypical beta-adrenoceptors or beta3
adrenoceptors, which are present on adipocytes, have been demonstrated
pharmacologically. Their function in adipose tissue is currently being
investigated. Beta2-adrenoceptor agonists have played a key role in the treatment
of asthma for some 30 years, being used for the relief and prophylaxis of
symptoms. There is, however, no evidence that tolerance to the bronchodilator or
anti-bronchoconstrictor effects of these drugs is responsible for the deleterious
effects reported with the regular use of bronchodilators. In neuropsychiatry,
beta-adrenoceptor antagonists have been used for the treatment of acute stress
reactions and generalised anxiety, essential tremor and prophylaxis of migraine.
In general, they are effective in anxiety disorders if the somatic symptoms are
not extreme. For prophylactic treatment of migraine, beta-adrenoceptor
antagonists such as propranolol, metoprolol, nadolol and atenolol are the drugs
of first choice. In cardiology, beta-adrenoceptor antagonists are an important
class for the treatment of high blood pressure, arrhythmias and angina pectoris,
and for prevention of myocardial infarction. With chronic treatment, they reduce
mortality in hypertension and prolong survival in patients with coronary heart
disease.
PMID- 9551699
TI - The effect of Y-25510 injection on the serum levels of some cytokines in healthy
adult volunteers.
AB - OBJECTIVE: Y-25510 was administered by means of an intravenous drip infusion to
healthy adult male volunteers at a dose of 40, 80 or 160 mg in a single-dose
study, and at a dose of 160 mg once a day for 7 days in a multiple-dose study.
RESULTS: Serum levels of interleukin (IL)-1beta, IL-6 and IL-10 were
significantly increased, but there was no change in leukocyte and platelet
counts. The peak serum concentration of IL-1beta was nearly maximum at the single
doses of 40 and 80 mg, and at the multiple dose of 160 mg per day. The peak serum
concentration of IL-6 increased in a dose-dependent manner at a dose of 40 mg or
more. For the multiple-dose study, the serum level of IL-10, which remained
unchanged in the placebo group, began to increase in the Y-25510 group following
the maximum serum level of IL-1beta and IL-6. There were no clinically relevant
differences in body temperature and blood pressure after the administration of Y
25510. CONCLUSION: These findings that leukocyte and platelet counts never
increased, despite the increment of the IL-1beta and IL-6 production after the
administration of Y-25510, may be explained in part by the negative feedback
mechanism induced by IL-10.
PMID- 9551700
TI - Adjunctive lamotrigine therapy in patients with refractory seizures: a lifetime
cost-utility analysis.
AB - OBJECTIVE: Lamotrigine as add-on treatment (500 mg per day) is effective in
patients with refractory epilepsy, but its high cost requires a pharmacoeconomic
analysis. We conducted a retrospective lifetime cost utility study in which
clinical data were derived from a recent placebo-controlled clinical trial, cost
of-illness data were drawn from a previous ad-hoc study, and quality-of-life
values were obtained by prospectively interviewing a separate group of 81
patients referred to our institution with epilepsy. RESULTS: Our analysis showed
that chronic lamotrigine treatment implies an incremental lifetime cost of about
$1,600,000 for every 100 patients. Incremental lifetime utility was around 40
quality-adjusted life-years (QALYs) for every 100 patients. On the basis of these
data, adjunctive lamotrigine was estimated to cost approximately $41,000 per QALY
gained. Sensitivity testing suggested a range of $25,000-$85,000 per QALY gained.
CONCLUSION: Adjunctive lamotrigine (500 mg per day) in refractory epilepsy seems
to have a worse pharmacoeconomic profile than many pharmacological treatments
commonly used in areas other than epilepsy. Further data are needed to determine
if lamotrigine can be equally effective at lower (and less costly) daily doses
which could markedly improve its pharmacoeconomic characteristics.
PMID- 9551701
TI - Pharmacokinetics of glibenclamide and its metabolites in diabetic patients with
impaired renal function.
AB - BACKGROUND: Glibenclamide (Gb) may provoke long-lasting hypoglycaemic reactions,
and one of the known risk factors is impaired renal function. We have
demonstrated Gb to have a terminal elimination half-life of 15 h, and the main
metabolites have a hypoglycaemic effect. With few exceptions, detailed studies on
second generation sulphonylureas in diabetics with impaired renal function are
lacking. Therefore, we analysed the pharmacokinetics of Gb and its active
metabolites, 4-trans-hydroxyglibenclamide (M1) and 3-cis-hydroxy-glibenclamide
(M2) in this patient group. METHODS: Two groups of 11 diabetic patients with
impaired renal function (IRF, iohexol clearance range 7-42 ml.min(-1) . 1.73 m(
2)) or normal renal function (NRF, iohexol clearance range 75-140 ml.min(-1) .
1.73 m(-2)) were compared. A single oral 7-mg dose of Gb was administered after
overnight fasting. Serum samples and urine collections were obtained over 48 h
and 24 h, respectively. Concentrations of Gb, M1 and M2 were determined by a
sensitive and selective high-performance liquid chromatography assay. RESULTS:
Peak serum values of M1 (24-85 ng.ml(-1) vs 16-57 ng.ml(-1)), M2 (7-22 ng.ml(-1)
vs <5-18 ng.ml(-1)) and M1 + M2 (32-100 ng.ml(-1) vs 23-76 ng.ml(-1)) were higher
in the IRF group. AUC and Cmax of Gb were lower and the clearance to
bioavailability ratio (CL/f) was higher in the IRF group. AUC and Cmax of M1 were
higher and CL/f lower in the IRF group. Much lower amounts of M and M2 were
excreted in the urine in the IRF group (7.2% vs 26.4% in 24 h). The fraction of
the Gb dose excreted as metabolites (fe(met) 0-24 h), ranged between 0.005 and
0.36 and correlated significantly with renal function measured by iohexol
clearance. No other pharmacokinetic differences were found. CONCLUSION: The
differences in AUC, Cmax and CL/f of Gb may be explained by a higher free
fraction in the IRF group which would increase Gb metabolic clearance. The
inverse findings regarding M1 may be explained by the fact that the metabolites
are primarily eliminated by the kidneys. After a single dose of Gb, neither Gb,
M1 nor M2 seemed to accumulate in diabetic subjects with IRF. As only small
amounts of M1 and M2 were excreted in the urine, this indicates one or several
complementary non-renal elimination routes, e.g. shunting of metabolised Gb to
the biliary excretion route and/or enterohepatic recycling of both metabolites
and unmetabolised Gb.
PMID- 9551702
TI - Pharmacokinetics of low doses of methotrexate in patients with psoriasis over the
early period of treatment.
AB - OBJECTIVE: The aim of the present study was to investigate the pharmacokinetics
and pharmacodynamics of low-dose methotrexate (MTX) in the early phase (3 months)
after the start of antipsoriatic therapy. METHODS: Ten male and female psoriatic
patients who failed to respond to previous conventional therapy were treated with
15 mg oral MTX once per week. The pharmacokinetics in plasma and the urinary
excretion of MTX and 7-hydroxymethotrexate (7-OH MTX) were investigated after
doses 1, 5 and 13 (corresponding to phases I, II and III, respectively). On the
same occasions, MTX accumulation in erythrocytes obtained before MTX
administration was investigated. Pharmacodynamics of MTX were evaluated using the
psoriasis area and severity index (PASI) score. RESULTS: There were marked
intersubject differences (range of coefficients of variation 34.9-76.3%) in the
area under the curve (AUC), peak concentration (Cmax) and clearance (CL) of MTX.
Total CL was proportional to renal clearance (CLR) (r2 = 0.735, P < 0.0001) which
accounted for 73 (19)% of the former. There was a strong linear relationship (r2
= 0.819, P < 0.0001) between CL of MTX and creatinine clearance. Within 48 h of
drug administration, the urinary excretion of MTX was 46-99% of the dose, while
that of 7-OH MTX was 1.5-8.6%. In 8 of 10 patients, more than 70% of the MTX dose
was recovered. No intraindividual variations of MTX kinetic parameters during
treatment were observed. MTX concentrations in erythrocytes reached the steady
state concentration in the range 40.7-170 nmol.l(-1) after 2 months of therapy.
Pharmacodynamic measurement versus pharmacokinetics revealed a significant
inverse relationship between PASI score and MTX AUC (rs = -0.912, P < 0.002) and
between PASI score and erythrocytic MTX (rs = -0.988, P < 0.002). CONCLUSION: The
relationship between MTX pharmacokinetics (AUC or erythrocytic MTX) and
pharmacodynamics (PASI score) may exist. It is likely that the efficacy of
psoriasis therapy with MTX could be improved by adjusting the dose according to
plasma concentrations obtained after the first MTX administration.
PMID- 9551704
TI - An interaction study with cimetidine and the new angiotensin II antagonist
valsartan.
AB - OBJECTIVE: This was a randomised, open, three-way crossover study in 12 healthy
male volunteers to determine the effect of a single oral dose of cimetidine on
the pharmacokinetics of a single oral dose of the angiotensin II receptor
antagonist valsartan and vice versa. The volunteers received either valsartan
alone (160 mg), or cimetidine alone (800 mg), or valsartan 1 h after cimetidine.
The study was designed primarily to detect a possible influence of cimetidine on
the rate and extent of absorption of valsartan. METHODS: Plasma concentrations of
valsartan and cimetidine, measured by means of high-performance liquid
chromatography, were used to calculate pharmacokinetic parameters. The rate of
absorption of valsartan and the fraction of the dose absorbed and systemically
available after oral administration were calculated using data from an i.v. study
with valsartan in healthy young volunteers. RESULTS: The pharmacokinetics of
cimetidine area under curve (AUC0-48 h), maximum concentration (Cmax), time to
reach Cmax(tmax) and apparent terminal plasma half-life (t1/2) was not changed by
co-administration of valsartan. For valsartan, the AUC0-48 h increased by 7% and
the Cmax by 51% (ratio of geometric means) with co-administration of cimetidine.
The higher value for Cmax was attributed to the initial increase in the rate of
absorption of valsartan: ka was increased 2.7-fold and another indicator for the
rate of absorption, Cmax/tmax, 2.2-fold. This effect was ascribed to inhibition
of acid secretion by cimetidine, which leads to a higher gastric pH, thereby
increasing the solubility of valsartan; the t1/2 of valsartan was not changed.
After valsartan alone, 19% of the dose was absorbed, 23% with co-administration
of cimetidine. It was estimated that only 2.2% of the possible change in AUC
might be missed by giving a single high dose of cimetidine instead of multiple
doses, with the aim to optimally inhibit formation of the inactive metabolite of
valsartan. Cimetidine-related changes in the rate of elimination of valsartan
were not anticipated, since the clearance from plasma occurs mainly by biliary
excretion of unchanged valsartan; metabolism and renal excretion are only minor
contributors. Therefore, even in the clinically relevant situation with multiple
doses of valsartan and cimetidine, notable changes in the pharmacokinetics of
valsartan, except for an increase in Cmax, are not to be expected. This increase
in Cmax appears to be of no clinical significance. Valsartan alone and in
combination with cimetidine was well tolerated by healthy subjects.
PMID- 9551703
TI - Fluconazole but not itraconazole decreases the metabolism of losartan to E-3174.
AB - OBJECTIVE: Losartan is metabolised to its active metabolite E-3174 by CYP2C9 and
CYP3A4 in vitro. Itraconazole is an inhibitor of CYP3A4, whereas fluconazole
affects CYP2C9 more than CYP3A4. We wanted to study the possible interaction of
these antimycotics with losartan in healthy volunteers. METHODS: A randomised,
double-blind, three-phase crossover study design was used. Eleven healthy
volunteers ingested orally, once a day for 4 days, either itraconazole 200 mg,
fluconazole (400 mg on day 1 and 200 mg on days 2-4) or placebo (control). On day
4, a single 50-mg oral dose of losartan was ingested. Plasma concentrations of
losartan, E-3174, itraconazole, hydroxy-itraconazole and fluconazole were
determined over 24 h. The blood pressure and heart rate were also recorded over
24 h. RESULTS: The mean peak plasma concentration (Cmax) and area under the curve
[AUC(0-infinity)] of E-3174 were significantly decreased by fluconazole to 30%
and to 47% of their control values, respectively, and the t1/2 was increased to
167%. Fluconazole caused only a nonsignificant increase (23-41%) in the AUC and
t1/2 of the unchanged losartan. Itraconazole had no significant effect on the
pharmacokinetic variables of losartan or E-3174. The ratio AUC(0-infinity)(E
3174)/AUC(0-infinity)losartan was 60% smaller during the fluconazole than during
the placebo and itraconazole phases. No clinically significant changes in the
effects of losartan on blood pressure and heart rate were observed between
fluconazole, itraconazole and placebo phases. CONCLUSION: Fluconazole but not
itraconazole interacts with losartan by inhibiting its metabolism to the active
metabolite E-3174. This implicates that, in man, CYP2C9 is a major enzyme for the
formation of E-3174 from losartan. The clinical significance of the fluconazole
losartan interaction is unclear, but the possibility of a decreased therapeutic
effect of losartan should be kept in mind.
PMID- 9551705
TI - Pharmacokinetic and pharmacodynamic evaluation of fluticasone propionate after
inhaled administration.
AB - OBJECTIVE: To evaluate the pharmacokinetic and systemic pharmacodynamic
properties of inhaled fluticasone propionate (FP). METHODS: Single doses of 0.25,
0.5, 1.0 and 3.0 mg FP were administered to groups of six healthy subjects. Serum
concentration profiles of FP were monitored over 24 h by means of high
performance liquid chromatography/mass spectrometry (HPLC/MS-MS). Systemic
pharmacodynamic effects were evaluated by measuring endogenous serum cortisol and
circulating white blood cells, and analyzed with previously developed integrated
pharmacokinetic/pharmacodynamic (PK/PD) models. RESULTS: FP showed a dose
independent terminal half-life with a mean (SD) of 6.0 (0.7) h. Maximum serum
concentrations occurred 1.0 (0.5) h after administration, ranging from 90 pg.ml(
1) for the 0.25 mg dose to 400 pg.ml(-1) for the 3.0 mg dose. This, together with
an estimated mean absorption time of nearly 5 h and a known oral bioavailability
of less than 1%, indicates prolonged residence at and slow absorption from the
lungs. In the investigated dose range, the cumulative systemic effect was dose
dependent for both markers of pharmacodynamic activity. For doses of 0.25, 0.50,
1.0 and 3.0 mg FP, the PK/PD-based cumulative systemic-effect parameters were
159, 186, 257 and 372% .h for lymphocyte suppression, 107, 186, 202 and 348% .h
for granulocyte induction and 23.6%, 33.8%, 51.0% and 73.6% for cortisol
reduction, respectively. The time courses of lymphocytes, granulocytes and
endogenous cortisol could be sufficiently characterized with the applied PK/PD
models. The measured in vivo EC50 values, 30 pg.ml(-1) and 7.3 pg.ml(-1) for
white blood cells and cortisol, respectively, were in good agreement with
predictions based on the in vitro relative receptor affinity of FP. CONCLUSION:
After inhalation, FP follows linear pharmacokinetics and exhibits dose-dependent
systemic pharmacodynamic effects that can be described by PK/PD modeling.
PMID- 9551706
TI - Influence of erythromycin pre- and co-treatment on single-dose pharmacokinetics
of the HMG-CoA reductase inhibitor cerivastatin.
AB - OBJECTIVE: Cerivastatin is a novel, synthetic, highly potent 3-hydroxy-3
methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that effectively reduces
serum cholesterol levels at very low doses. It is exclusively cleared from humans
via cytochrome P450-mediated biotransformation (demethylation M1; hydroxylation
M23) and subsequent biliary/renal excretion of the metabolites. The influence of
concomitant administration of erythromycin, a potent CYP3A4 inhibitor, on
cerivastatin bioavailability and pharmacokinetics was investigated. METHODS:
Twelve healthy young male subjects received single oral doses of 300 microg
cerivastatin alone or on the 4th day of a 4-day pre- and co-treatment with
erythromycin 500 mg t.i.d. in a randomised, non-blind crossover study. Plasma and
urine samples were analysed for cerivastatin and its major metabolites by
validated specific high-performance liquid chromatography assays. RESULTS:
Cerivastatin was safe and well tolerated. No clinically relevant treatment
emergent changes in laboratory parameters were observed. The pre- and co
treatment with erythromycin 500 mg t.i.d. had a modest influence on cerivastatin
clearance, leading to a mean increase in the maximum plasma concentration (Cmax)
of 13% and a slightly increased terminal half-life (approximately 10%), resulting
in a mean elevation of the area under the curve (AUC) of 21%; time to peak (tmax)
remained unchanged. While the mean AUC of the metabolite M1 following the
combined dosing was decreased by 60% compared with mono-dosing, the mean AUC of
M23 exhibited an increase of approximately 60%. The respective Cmax results
paralleled these pronounced effects, whereas the influence on mean terminal half
lives was small (i.e. for M23, an approximate 20% increase) or not observable
(i.e. for M1). CONCLUSIONS: Concomitant administration of erythromycin 500 mg
t.i.d. affects, to a certain extent, the metabolism of cerivastatin, administered
as a single oral dose of 300 microg, resulting in a slightly increased exposure
of the parent drug and active metabolites which, however, does not need dose
adjustment. In addition, the small increase in cerivastatin half-life does not
predict an accumulation beyond steady state. The pharmacokinetic data for the
major metabolites suggest that the M1 metabolic pathway is more sensitive to
CYP3A4 inhibition than the parallel M23 pathway, supporting recent in vitro
findings that further cytochrome P450 isozymes are differently involved in the
metabolic pathways of cerivastatin.
PMID- 9551707
TI - Cimetidine does not alter atorvastatin pharmacokinetics or LDL-cholesterol
reduction.
AB - OBJECTIVE: To determine the effects of cimetidine on the steady-state
pharmacokinetics and pharmacodynamics of atorvastatin, a 3-hydroxymethyl-glutaryl
coenzyme A (HMG-CoA) reductase inhibitor. METHODS: Twelve healthy subjects
participated in a randomized two-way crossover study. Each subject received
atorvastatin 10 mg every morning for 2 weeks and atorvastatin 10 mg every morning
with cimetidine 300 mg four times a day for 2 weeks, separated by a 4-week
washout period. Steady-state pharmacokinetic parameters (based on an enzyme
inhibition assay) and lipid responses were compared. RESULTS: Pharmacokinetic
parameters and lipid responses were similar following administration of
atorvastatin alone and atorvastatin with cimetidine. Mean values for Cmax (the
maximum concentration) were 5.11 ng eq.ml(-1) and 4.54 ng eq.ml(-1), for tmax
(the time to reach maximum concentration) 2.2 h and 1.3 h, for AUC0-24 (area
under the concentration-time curve from time 0 h to 24 h) 58.6 ng eq.h.ml(-1) and
58.5 ng eq.h.ml(-1), and for t1/2 (terminal half-life) 10.1 h and 17.0 h,
respectively, following administration of atorvastatin alone and atorvastatin
with cimetidine. Following treatment with atorvastatin alone and atorvastatin
with cimetidine, mean values for the percentage change from baseline for total
cholesterol were -29.5% and -29.9%, for low-density lipoprotein (LDL) cholesterol
-41.0% and -42.6%, for high-density lipoprotein (HDL) cholesterol 6.3% and 5.8%,
and for triglycerides -33.8% and -25.8%, respectively. CONCLUSIONS: The rate and
extent of atorvastatin absorption and the effects of atorvastatin on LDL
cholesterol responses are not influenced by coadministration of cimetidine.
PMID- 9551708
TI - Effect of the serotonin4 receptor agonist cisapride on plasma aldosterone levels
in cirrhotic patients with secondary hyperaldosteronism.
PMID- 9551709
TI - The neuropharmacology of yawning.
AB - Yawning is a phylogenetically old, stereotyped event that occurs alone or
associated with stretching and/or penile erection in humans and in animals from
reptiles to birds and mammals under different conditions. Although its
physiological function is still unknown, yawning is under the control of several
neurotransmitters and neuropeptides at the central level as this short overview
of the literature on the neurochemistry of yawning shows. Among these substances,
the best known are dopamine, excitatory amino acids, acetylcholine, serotonin,
nitric oxide, adrenocorticotropic hormone-related peptides and oxytocin, that
facilitate yawning and opioid peptides that inhibit this behavioral response.
Some of the above compounds interact in the paraventricular nucleus of the
hypothalamus to control yawning. This hypothalamic nucleus contains the cell
bodies of oxytocinergic neurons projecting to extra-hypothalamic brain areas that
play a key role in the expression of this behavioral event. When activated by
dopamine, excitatory amino acids and oxytocin itself, these neurons facilitate
yawning by releasing oxytocin at sites distant form the paraventricular nucleus,
i.e. the hippocampus, the pons and/or the medulla oblongata. Conversely,
activation of these neurons by dopamine, oxytocin or excitatory amino acids, is
antagonized by opioid peptides, that, in turn, prevent the yawning response. The
activation and inhibition, respectively of these oxytocinergic neurons is related
to a concomitant increase and decrease, respectively, of paraventricular nitric
oxide synthase activity. However, other neuronal systems in addition to the
central paraventricular oxytocinergic neurons are involved in the control of
yawning, since they do not seem to be involved in the expression of yawning
induced by the stimulation of acetylcholine or serotoninergic receptors, nor by
adrenocorticotropic hormone (ACTH) and related peptides. Nitric oxide is also
involved in the induction of yawning by the latter compounds and neuronal links,
for instance between dopamine and acetylcholine and dopamine and serotonin, seem
to be involved in the yawning response. Finally, other neurotransmitters, i.e.
gamma-aminobutyric acid (GABA) and noradrenaline, and neuropeptides, i.e.
neurotensin and luteinizing hormone-releasing hormone (LH-RH), influence this
behavioral response. In conclusion, in spite of some recent progress, little is
known of, and more has to be done to identify, the neurochemical mechanisms
underlying yawning at the central level.
PMID- 9551710
TI - Role of corticotropin-releasing factor in forced swimming test.
AB - Several aspects of the role of corticotropin-releasing factor (CRF) in the forced
swimming test were investigated in this study by using two different
administration schedules. I.c.v. microinjection of CRF produced a dose-dependent
increase in swimming activity when the administration schedule originally
reported for this test to screen antidepressant drugs was followed. The most
effective doses were 1 and 3 microg of CRF. A lower dose of CRF (0.5 microg) was
also effective when repetitive experimental stress was present. CRF receptor
antagonist, alpha-helical CRF-(9-41) (alpha-helical CRF-(9-41)), was able to
block CRF-induced increases in swimming in all sessions of the forced swimming
test. However, the effects of CRF and CRF receptor antagonist depended on the
administration schedule. A decrease in swimming in the forced swimming test was
observed when CRF and CRF receptor antagonist were given together, using a
different administration schedule. I.c.v. CRF was ineffective and CRF receptor
antagonist alone produced an increase in swimming when administered according to
this schedule. These behavioural responses were maintained after twelve days
without any treatment. The results of the current study suggest that endogenous
CRF seems to play a determinant role in behavioural responses in the forced
swimming test. The involvement of the level of activation and memory processes in
these behavioural responses is discussed.
PMID- 9551711
TI - Involvement of endothelium in relaxant action of glibenclamide on the rat
mesenteric artery.
AB - The present report describes the complex effect of glibenclamide, an antidiabetic
sulfonylurea agent, on the rat isolated mesenteric artery. Although glibenclamide
concentration dependently reversed the relaxant effect of pinacidil, an activator
of ATP-sensitive K+ channels (the concentration for half-maximum reversal effect
was 0.56 microM with endothelium and 0.17 microM without endothelium), in the
artery precontracted with phenylephrine (1 microM), it relaxed phenylephrine
induced sustained contraction at higher concentrations (IC50: 4.4+/-1.1 microM
with endothelium and 226.1+/-44.2 microM without endothelium). The relaxant
effect of glibenclamide was partially inhibited by pretreatment of the artery
with either NG-nitro-L-arginine (10-100 microM) or methylene blue (1 microM).
Indomethacin (10 microM) had no effect. Moreover, glibenclamide also
concentration dependently (3-500 microM) reduced the sustained contraction
induced by 60 mM K+ (IC50: 99.5+/-16.1 microM). The relaxation induced by
glibenclamide was not affected by various putative K+ channel blockers such as
charybdotoxin (100 nM), tetraethylammonium ions (1 mM), apamin (100 nM) and 4
aminopyridine (1 mM). The results indicate an involvement of the endothelium,
probably of nitric oxide, in the relaxation induced by glibenclamide in the
endothelium-intact rat mesenteric arteries. The inhibitory effect of
glibenclamide on the high-K+-induced contraction suggests that glibenclamide may
interfere with Ca2+ influx, which in turn affects intracellular Ca2+ levels in
arterial smooth muscle, leading to reduction of muscle contractility. It is
suggested that two distinct pharmacological effects induced by glibenclamide may
be mediated through different glibenclamide binding sites, however, the data show
an overlap of concentrations of glibenclamide for producing the two effects in
rat isolated mesenteric arteries.
PMID- 9551712
TI - Characterization of oxytocin actions in guinea-pig isolated uterine artery: the
effect of pregnancy.
AB - While the contractile effect of oxytocin on uterine artery has been reported,
little is known about whether pregnancy affects the responsiveness of this artery
to oxytocin. If it does, is it a consequence of changed endothelial function, as
has been proposed for some other vasoconstrictors. Furthermore, the receptor
subtypes involved in oxytocin action on uterine artery has not been yet
determined. Therefore the purposes of this study were to (1) determine the
receptor subtypes involved in oxytocin action in non-pregnant and pregnant guinea
pig uterine artery and to (2) determine whether possible changes in uterine
artery sensitivity to oxytocin during pregnancy are due to altered endothelial
function. Therefore, the effect of oxytocin on non-pregnant and pregnant guinea
pig uterine arterial rings with and without endothelium was investigated. In non
pregnant guinea-pig uterine artery oxytocin induced contraction (pEC50 = 7.63)
with greater potency than in pregnant guinea-pig uterine artery (pEC50 = 7.17).
Removal of the endothelium did not affect oxytocin-induced contractions,
regardless of the pregnancy status. The uterine arteries did not respond to
[Thr4, Gly7]oxytocin. In the preparations studied, [d(CH2)5Tyr(Me)2]vasopressin
and [d(CH2)5, D-Ile2, Ile4]vasopressin antagonized oxytocin action with the
following pKB values ([d(CH2)5Tyr(Me)2]vasopressin versus [d(CH2)5, D-Ile2,
Ile4]vasopressin): 8.24 versus 7.29 and 8.11 versus 7.17 for non-pregnant guinea
pig uterine artery with and without endothelium, respectively; 8.39 versus 7.25
and 8.35 versus 7.25 for pregnant guinea-pig uterine artery with and without
endothelium, respectively. We suggest that, in uterine arteries, oxytocin induces
contraction by activation of vasopressin V1A receptors. The potency of oxytocin
in uterine artery is decreased during pregnancy and this is not associated with
altered endothelial function.
PMID- 9551713
TI - Myosin light chain phosphorylation and Mn2+ -dependent norepinephrine-induced
contractions in guinea-pig vas deferens.
AB - We have reported that norepinephrine but not K+ induced a sustained and dose
dependent contraction without extracellular Ca2+ and Mn2+ in Ca2+-depleted Mn2+
loaded vas deferens from the guinea-pig. In the present study, we determined the
phosphorylation of the 20-kDa myosin light chain and examined the effects of
inhibitors of calmodulin and myosin light chain kinase on the Mn2+-dependent
norepinephrine-induced contraction in order to evaluate the contribution of
phosphorylation to this contraction. W-7 [N-(6-aminohexyl)-5-chloro-1
naphthalenesulfonamide], ML-9 [1-(5-chloronaphthalene-1-sulfonyl)-homopiperazine]
and wortmannin inhibited this contraction. However, the Mn2+-dependent
norepinephrine-induced contraction developed without a significant increase in
the phosphorylation of the 20-kDa myosin light chain. In beta-escin-permeabilized
preparations, Mn2+ induced contractions that were inhibited by ML-9. These
results suggest that the activation of myosin light chain kinase is essential for
the development of Mn2+-dependent norepinephrine-induced contractions and that
the phosphorylation of myosin light chain may act as a trigger for these
contractions.
PMID- 9551714
TI - Studies on curare-like action of the tripeptide carbobenzoxy-Gly-Gly-Arg-beta
naphthylamide in mouse diaphragm.
AB - The effects of several protease substrates or protease inhibitors on
neuromuscular transmission in the isolated mouse phrenic nerve-diaphragm were
studied. N-Carbobenzoxy-Gly-Gly-Arg-beta-naphthylamide (Z-GGR-N) but none of the
other agents inhibited the nerve-evoked muscle contractions. By means of
electrophysiological studies, Z-GGR-N was found to inhibit the amplitudes of both
end-plate potentials (epps) (IC50 approximately 50 microM) and miniature end
plate potentials (mepps) but to increase the frequencies of mepps. This
tripeptide could protect the nicotinic acetylcholine receptor from the
irreversible inhibitory action of alpha-bungarotoxin on the mouse diaphragm.
Similar to D-tubocurarine, Z-GGR-N induced tetanic fading both of nerve-evoked
muscle contractions and of the amplitude of epps. Furthermore, Z-GGR-N exhibited
a greater depression of the amplitudes of train-epps than those of mepps, similar
to that of hexamethonium and D-tubocurarine, indicating an effect on presynaptic
autoreceptors. Suramin, which could competitively reverse the inhibitory effects
of non-depolarizing relaxants, acted in this study as an antagonist of all the
effects of Z-GGR-N, especially those at the presynaptic site. All of these
findings suggest that Z-GGR-N is a novel tripeptide possessing curare-like
actions at both presynaptic and postsynaptic sites and that these actions are
independent of its protease substrate property.
PMID- 9551715
TI - Comparison of in vitro effects of triflusal and acetysalicylic acid on nitric
oxide synthesis by human neutrophils.
AB - Recent studies have suggested that the protective anti-ischemic effects of
acetylsalicylic acid are stronger than the inhibition of platelet thromboxane A2
synthesis. Since ischemic events still occur in acetylsalicylic acid-treated
patients, the development of new drugs with more powerful protective effects is
needed. We compared the effects of a new platelet antiaggregating drug, 2-acetoxy
4-trifluoromethyl-benzoic acid (triflusal) and of acetylsalicylic acid on the
interaction between human neutrophils and platelets, examining the capability of
neutrophils to generate nitric oxide (NO). Triflusal, in the presence of
neutrophils, showed a greater antiplatelet potency than acetylsalicylic acid to
inhibit thrombin-induced platelet activation. Significant stimulation of NO
mediated mechanisms in the presence of acetylsalicylic acid or triflusal was
demonstrated by the following findings: (1) increased metabolism of arginine to
citrulline, (2) increase of cGMP in the platelet/neutrophil system and (3) the
inhibitory action of the L-arginine (L-Arg) competitive analogue, NG-nitro-L
arginine-methyl ester (L-NAME), which was reversed by L-Arg. Triflusal increased
the stimulation of NO synthesis by neutrophils more than did of acetylsalicylic
acid. The main metabolite of triflusal, 2-hydroxy-4-trifluoromethylbenzoic acid
(HTB), alone or in combination with acetylsalicylic acid, did not modify NO
production by neutrophils. Therefore, the whole molecule of triflusal is needed
to stimulate NO production by neutrophils. Our results show that, in the presence
of neutrophils, triflusal exerts an antiplatelet effect greater than that of
acetylsalicylic acid, demonstrating a more powerful stimulation of the NO/cGMP
system. The present results indicate that it is possible to develop new and more
potent acetylsalicylic acid-related antiplatelet drugs for the prevention of the
myocardial ischemic/reperfusion processes.
PMID- 9551717
TI - Magnolol inhibits Mac-1 (CD11b/CD18)-dependent neutrophil adhesion: relationship
with its antioxidant effect.
AB - Magnolol, a phenolic compound isolated from a Chinese herbal drug, Magnolia
officinalis, has been shown to protect rat heart from ischemia/reperfusion
injury. Neutrophil adhesion plays a crucial process during this inflammatory
response. To evaluate whether magnolol prevents ischemia/reperfusion injury by
inhibiting neutrophil adhesion, we determined whether magnolol can inhibit
adhesion of phorbol-12-myristate-13-acetate (PMA)-activated human neutrophils to
a fibrinogen-coated surface in a dose-dependent manner. Using flow cytometric
analysis, we observed that magnolol pretreatment (10 min at 37 degrees C)
diminished PMA (100 ng/ml)-induced Mac-1 upregulation. PMA also induced rapid
intracellular accumulation of superoxide (O2-.) and hydrogen peroxide (H2O2) in
neutrophils; magnolol pretreatment attenuated the accumulation of these two
substances. Inhibition of reactive oxygen species by superoxide dismutase and/or
catalase, which decompose O2-. and H2O2, respectively, also abolished Mac-1
upregulation and neutrophil adhesion. We conclude that magnolol inhibits
neutrophil adhesion and that this can account for its anti-ischemia/reperfusion
injury effect. We propose that the inhibitory effect of magnolol on neutrophil
adhesion to the extracellular matrix is mediated, at least in part, by inhibition
of the accumulation of reactive oxygen species, which in turn suppresses the
upregulation of Mac-1 that is essential for neutrophil adhesion.
PMID- 9551716
TI - Characterization of binding sites of a new neurotensin receptor antagonist,
[3H]SR 142948A, in the rat brain.
AB - The present study describes the characterization of the binding properties and
autoradiographic distribution of a new nonpeptide antagonist of neurotensin
receptors, [3H]SR 142948A (2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3
dimethylaminopropyl)-N-methyl carbamoyl)-2-isopropylphenyl)-1H-pyrazole-3
carbonyl]-amino]-ad amantane-2-carboxylic acid, hydrochloride), in the rat brain.
The binding of [3H]SR 142948A in brain membrane homogenates was specific, time
dependent, reversible and saturable. [3H]SR 142948A bound to an apparently
homogeneous population of sites, with a Kd of 3.5 nM and a Bmax value of 508
fmol/mg of protein, which was 80% higher than that observed in saturation
experiments with [3H]neurotensin. [3H]SR 142948A binding was inhibited by SR
142948A, the related nonpeptide receptor antagonist, SR 48692 (2-[[1-(7
chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole -3-carbonyl]amino]
adamantane-2-carboxylic acid) and neurotensin. Saturation and competition studies
in the presence or absence of the histamine H1 receptor antagonist,
levocabastine, revealed that [3H]SR 142948A bound with similar affinities to both
the levocabastine-insensitive neurotensin NT1 receptors (20% of the total binding
population) and the recently cloned levocabastine-sensitive neurotensin NT2
receptors (80% of the receptors) (Kd = 6.8 and 4.8 nM, respectively). The
regional distribution of [3H]SR 142948A binding in the rat brain closely matched
the distribution of [125I]neurotensin binding. In conclusion, these findings
indicate that [3H]SR 142948A is a new potent antagonist radioligand which
recognizes with high affinity both neurotensin NT1 and NT2 receptors and
represents thus an excellent tool to study neurotensin receptors in the rat
brain.
PMID- 9551718
TI - Necessity of interleukin-1beta converting enzyme cascade in taxotere-initiated
death signaling.
AB - Taxotere is a new type chemotherapeutic agent which targets tubulin. In the
present study, we investigated the molecular machinery of taxotere-initiated
death signaling. Taxotere induced cell death in mouse fibroblast L929 cells. Cell
morphological analysis revealed that this effect showed characteristics of
apoptotic and necrotic cell death. To further examine taxotere-induced cell
death, we investigated the direct involvement of caspase. When cells were
pretreated with the synthesized tetrapeptide inhibitor of caspase, YVAD-CHO (Ac
Tyr-Val-Ala-Asp-aldehyde: inhibitor of interleukin-1beta converting enzyme (ICE)
subfamily) or DEVD-CHO (Ac-Asp-Glu-Val-Asp-aldehyde: inhibitor of CPP32
subfamily), taxotere-induced cell death was prevented. In addition, time course
experiments demonstrated that activation of the ICE subfamily preceded activation
of the CPP32 subfamily in taxotere-initiated death signaling, suggesting the
direct involvement of the ICE cascade in taxotere-initiated death signaling. On
the basis of these results, we suggest that taxotere causes the initiation of ICE
cascade in its death signaling pathway and that the down-stream site of taxotere
initiated death signaling is the same as that of other chemotherapeutic agents.
PMID- 9551719
TI - [3H]RS79948-197 binding to human, rat, guinea pig and pig alpha2A-, alpha2B- and
alpha2C-adrenoceptors. Comparison with MK912, RX821002, rauwolscine and
yohimbine.
AB - The Kd values of the recently introduced radioligand [3H]RS79948-197 ((8a
R,12aS,13a-S)-5,8,8a,9,10,11,12,12a,13,13a-decahydro-3-metho xy-12
(ethylsulphonyl)-6H-isoquino[2,1-g][1,6]naphthyridine) were determined for the
recombinant human and rat alpha2A-, alpha2B- and alpha2C- as well as guinea pig
alpha2B- and alpha2c-adrenoceptors expressed in COS (CV-1 Origin, SV40) cells. In
addition, the Kd values were also determined for [3H]RS79948-197 for the guinea
pig spleen alpha2A-adrenoceptor and for pig alpha2A-, alpha2B- and alpha2C
adrenoceptors in membranes obtained from kidney and striatum. Available
radioligands for alpha2-adrenoceptors, besides [3H]RS79948-197 are the tritiated
forms of MK912 ((2S,12bS)1',3'-dimethylspiro(1,3,4,5',6,6',7,12b-octa hydro-2H
benzo[b]furo[2,3-a]quinazoline)-2,4'-pyrimidin-2'-one), RX821002 (2-methoxy
idazoxan), rauwolscine and yohimbine. In the present article the binding
constants of all these substances for the alpha2A-, alpha2B- and alpha2C
adrenoceptor subtypes in human, pig, rat and guinea pig are reviewed. In all
species tested MK912 was alpha2C-selective, RX821002 showed a minor alpha2A
selectivity, whereas [3H]RS79948-197 was non-selective among the alpha2
adrenoceptor subtypes, showing high affinity for all three subtypes. Rauwolscine
and yohimbine showed relatively low affinities for nmost of the alpha2
adrenoceptor subtypes investigated, the exception being rauwolscine having high
affinity for the human and porcine alpha2C-adrenoceptors.
PMID- 9551720
TI - Atypical effect of dopamine in modulating the functional inhibition of NMDA
receptors of cultured retina cells.
AB - Cultured retina cells released accumulated [3H]GABA (gamma-aminobutyric acid)
when stimulated by L-glutamate, N-methyl-D-aspartate (NMDA) and kainate. In the
absence of Mg2+, dopamine at 200 microM (IC50 60 microM), inhibited in more than
50% the release of [3H]GABA induced by L-glutamate and NMDA, but not by kainate.
This effect was not blocked by the D1-like dopamine receptor antagonist, R-(+)-7
chloro-8-hydroxy-3-methyl- -phenyl-2,3,4,5-tetrahydro- H-3-benzazepine
hydrochloride (SCH 23390), neither by haloperidol nor spiroperidol (dopamine D2
like receptor antagonists). The dopamine D1-like receptor agonist R(+)-1-phenyl
2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,diol hydrochloride (SKF 38393) at 50
microM, but not its enantiomer, also inhibited the release of [3H]GABA induced by
NMDA, but not by kainate; an effect that was not prevented by the antagonists
mentioned above. (+/-)-6-Chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3
benzazepin e hydrobromide (SKF 812497) had no effect. Neither 8BrcAMP (5 mM) nor
forskolin (10 microM) inhibited the release of [3H]GABA. Our results suggest that
dopamine and (+)-SKF 38393 inhibit the glutamate and NMDA-evoked [3H]GABA release
through mechanisms that seem not to involve known dopaminergic receptor systems.
PMID- 9551721
TI - A novel cause for bronchiolitis obliterans organizing pneumonia: exposure to
paint aerosols in textile workshops.
PMID- 9551722
TI - Reduced smoking--an acceptable goal for the hopeless heavy smoker?
PMID- 9551723
TI - Organizing pneumonia in textile printing workers: a clinical description.
AB - In April 1992 an outbreak of severe respiratory illness occurred among
aerographic textile workers in the area of Alcoi, Autonomous Community of
Valencia, Spain. An epidemiological study linked this outbreak to the use of a
reformulated aerosolized product, Acramin-FWN. We analyzed clinical, laboratory,
and pathological data of the first 14 patients with confirmed organizing
pneumonia (OP) secondary to this newly recognized occupational toxicant. The mean
age of the patients was 30 yrs. The most common clinical findings were cough
(86%), epistaxis (71%), dyspnoea (64%), oppressive chest pain (57%), and crackles
(50%). A restrictive functional pattern was evident in 64%. Radiographic findings
consisted predominantly of patchy infiltrates in 65% and a micronodular pattern
in 35%. Treatment with corticosteroids did not prevent initial progression in 11
of the 14 patients and development of irreversible respiratory failure in five
patients. At necropsy, besides features of OP, interstitial fibrosis and diffuse
alveolar damage were evident. A low total lung capacity, the presence of crackles
at admission, and increases in the alveolar-arterial oxygen difference were
predictive of death. The organizing pneumonia caused by the inhalation of Acramin
FWN is characterized by a tendency to evolve into progressive interstitial
fibrosis despite the use of corticosteroids. The illness is restricted to the
respiratory system and once respiratory failure has developed the prognosis is
poor.
PMID- 9551724
TI - Bronchial responsiveness in active steelworkers.
AB - Coke-oven workers are exposed to dust and irritant gases. Therefore they are at
risk of developing lung diseases including chronic bronchitis. Nonspecific
bronchial hyperresponsiveness (BHR) has been advocated as a potential risk factor
predisposing to the development of chronic bronchitis. In a previous study, we
showed that prevalence of BHR was higher in retired coke-oven workers than in
retired blast furnace workers. The present study was carried out to determine the
prevalence of BHR in active steelworkers. Thus, 137 coke-oven workers and 150
blast furnace workers underwent clinical examination, a standardized
questionnaire for the study of respiratory symptoms, pulmonary function testing
and methacholine aerosol challenge. The study demonstrates a higher prevalence
and degree of BHR [provocative concentration of methacholine causing a 20% fall
in forced expiratory volume in one second (PC20) < or = 8 mg x mL(-1)] in coke
oven workers than in blast furnace workers (31.4 versus 6.7%; p<0.001). Moreover,
the frequency of respiratory symptoms and basal bronchial obstruction were
greater among coke-oven workers with BHR in nonresponders. The basal maximum
expiratory flow from 25-75% of forced vital capacity and the respiratory symptoms
were correlated with bronchial responsiveness. The lack of correlation observed
between BHR and the intensity of smoking or years spent in coke-oven environment
may be explained by the high proportion of smokers, the worker turnover in the
steel plant, and the "healthy worker effect". In conclusion, the higher
prevalence and degree of bronchial hyperresponsiveness in coke-oven workers
suggests that coke-oven pollutants are more intense irritants than those that
escape from blast furnaces.
PMID- 9551725
TI - The Po River Delta Respiratory Epidemiological Survey: an analysis of factors
related to level of total serum IgE.
AB - The purpose of the present study was to analyse whether sex, age, skin test
reactivity, cigarette smoking and occupational exposure were related to the total
serum immunoglobulin (Ig)E concentrations (kU x L[-1]), in a general population
sample. We studied 1,905 subjects (915 males, 990 females) of a general
population sample (n=2,841, 8-73 yrs) participating in the second cross-sectional
respiratory epidemiological survey in the rural Po Delta area (near Venice, North
Italy). Distribution of total serum IgE concentrations was skewed, thus a log
transformation was performed to obtain a Gaussian shape. Significantly higher
values of IgE were found in males compared to females. In general, a peak of IgE
concentration was found at 8-14 yrs. IgE values tended to be lower in older than
younger adults. Significantly higher serum IgE levels were shown in subjects with
a positive skin-prick test index (ST+) than in those with a negative skin-prick
test index (ST-). There was a significant relationship of total IgE levels with
skin reactivity to pollens and house-dust mites. In both sexes higher values of
IgE were found in current smokers than in ex-nonsmokers, regardless of skin-test
reactivity. There was no significant difference in IgE values between ex- and
nonsmokers. Passive smoking and occupational exposure were significantly related
to increased IgE values. Our results confirm that in a general population sample
immunoglobulin E concentrations are related not only to skin-prick test
reactivity to common aeroallergens, but also to other risk factors for chronic
obstructive lung diseases, such as sex, active/ passive smoking and occupational
exposure.
PMID- 9551726
TI - Effectiveness of postal smoking cessation advice: a randomized controlled trial
in young men with reduced FEV1 and asbestos exposure.
AB - There have been few community-based randomized, controlled intervention trials
for cessation in high-risk smokers. In such a trial we evaluated the effects of
postal smoking cessation advice in smokers with asbestos exposure and/or reduced
forced expiratory volume in one second (FEV1). All men aged 30-45 yrs (n=22,392)
living in 34 municipalities in western Norway were invited to a cross-sectional
community survey. Information on smoking habits and occupational asbestos
exposure were obtained from self-administered questionnaires and measurements of
FEV1 were performed with dry-wedge bellow spirometers. Among 16,393 participants
we identified a group of 2,610 smokers with previous occupational asbestos
exposure and/or adjusted FEV1 in the lowest quartile. A random half (n=1,300)
received a mailed personal letter from a respiratory physician with a person
specific health advice to quit smoking and a pamphlet on smoking cessation. The
remaining smokers (n=1,310) acted as controls and did not receive any
information. Twelve months after the intervention, information on smoking habits
was re-examined using a postal questionnaire. Among the respondents (n=2,282),
smoking cessation was reported altogether by 13.7% in the intervention group
versus 9.9% in the control group (p<0.01). The 1 yr sustained quit rate (no
smoking at all during the last year) was 5.6 versus 35% (p<0.05), respectively.
Measurements of carbon monoxide in expired air (with < or = 10 parts per million)
confirmed self-reported nonsmoking in samples of the two groups. In a community
this simple postal smoking cessation advice from a respiratory physician based on
person-specific risk factors improved the 1 yr sustained success rate by 60% in
identified high-risk smokers.
PMID- 9551728
TI - Interleukin-8 plays a significant role in IgE-mediated lung inflammation.
AB - Interleukin (IL)-8 is a potentially important cytokine in allergic respiratory
responses since it is released by many resident lung cells, and it is a potent
granulocyte chemoattractant. Therefore, we induced an immunoglobulin (Ig)E
mediated response in human lung samples and studied whether IL-8 was produced in
sufficient quantities to promote human neutrophil and eosinophil migration across
naked filters and endothelial and pulmonary epithelial monolayers cultured on
these filters. Fresh human lung fragments from 16 thoracotomy specimens were
treated with either a 1:100 dilution of anti-IgE or buffer (control) for 30 min.
All anti-IgE treated lung samples had significant release of histamine and
neutrophil and eosinophil chemotactic activity. Fourteen of the 16 lung samples
had a significant increase in IL-8 subsequent to anti-IgE treatment (p<0.01).
Anti-IL-8 antibody (4 microg x mL[-1]) inhibited 42% and 53% of neutrophil and
eosinophil chemotactic activity respectively, contained in supernatants from anti
IgE-treated lung samples. Finally, we found that IL-8 at a concentration near
that measured after anti-IgE treatment of lung samples (2,000 pg x mL[-1])
induced neutrophil and eosinophil migration through naked filters and endothelial
and pulmonary epithelial cell monolayers. Thus, human lung IgE-mediated responses
in vitro results in the rapid release of interleukin-8 in amounts sufficient to
affect a biological response, granulocyte transcellular migration, indicating
that interleukin-8 may play a significant role in allergic respiratory diseases.
PMID- 9551727
TI - Murine strain differences in airway inflammation caused by diesel exhaust
particles.
AB - To elucidate whether immunoglobulin (Ig) E or IgG are involved in the murine
asthma model, we compared the pathogenic features of mice that were high IgG
responders (C3H/He) with mice that were high IgE responders (BALB/c) after
intratracheal instillation of diesel exhaust particles (DEP) and ovalbumin
sensitization. Both mouse strains received DEP intratracheally once a week for 5
weeks. After the second injection of DEP, ovalbumin and aluminium hydroxide were
injected intraperitoneally. After the last DEP administration, the mice were
challenged by exposure to an aerosol of ovalbumin. DEP caused increased IgG1
production and airway hyperresponsiveness after ovalbumin sensitization in C3H/He
mice, although IgE production did not change in either strain. Furthermore, in
C3H/He mice, the number of eosinophils and goblet cells in the bronchial
epithelium, and the expression of interleukin-5 and interleukin-2 were increased
by DEP and ovalbumin treatments. In contrast, the pathogenic changes in BALB/c
mice were weak, even though the same protocol was used. In conclusion, murine
strain differences in response to air pollutants and allergens seem to be related
to antigen-specific immunoglobulin G1 production and cytokine expression in the
lungs.
PMID- 9551729
TI - Role of leukotriene B4 in bronchial hyperresponsiveness induced by interleukin-8.
AB - Repeated intranasal administration of interleukin 8 (IL-8) induces bronchial
hyperresponsiveness (BHR) accompanied by lower airway neutrophil accumulation
(ANA) in guinea-pigs. Leukotriene B4 (LTB4) is a chemotactic factor for
neutrophils. To elucidate whether LTB4 and neutrophil elastase are involved in
the IL-8-induced BHR and ANA, the effects of a LTB4 antagonist (ONO-4057) and a
neutrophil elastase inhibitor (ONO-5046) on the responses were examined. IL-8 (5
microg x kg[-1]) was administered intranasally to guinea-pigs twice weekly for 3
weeks. One day after the last administration, animals were anaesthetized and
artificially ventilated through tracheal cannulae, and lateral pressure at the
tracheal cannula (Pao) was measured as an overall index of airway responses to
inhaled histamine. ONO-4057 (2 or 20 mg x kg[-1]) or ONO-5046 (30 or 300 mg x kg[
1]) was administered intraperitoneally 24 and 1 h before anaesthesia. ONO-4057,
but not ONO-5046, significantly inhibited the IL8-induced BHR and ANA, assessed
by bronchoalveolar lavage, in a dose-dependent manner. These findings suggest
that interleukin 8 causes bronchial hyperresponsiveness and airway neutrophil
accumulation in guinea-pigs in vivo. In part this appears to be due to release of
leukotriene B4, whereas it may not be mediated by neutrophil elastase.
PMID- 9551730
TI - Elevated serum interferon-gamma in atopic asthma correlates with increased
airways responsiveness and circadian peak expiratory flow variation.
AB - Interleukin (IL)-4, IL-5 and interferon (IFN)-gamma are thought to play an
important role in chronic airway inflammation in asthmatic subjects. Increased
airways responsiveness and nocturnal airway obstruction are important clinical
manifestations of asthma. The aim of this study was to investigate whether IL-4,
IL-5 and IFN-gamma values are elevated in atopic asthma and correlate with its
clinical manifestations. Serum IL-4, IL-5 and IFN-gamma levels of 17 atopic
asthmatics and eight nonatopic healthy subjects were determined at 16:00 and
04:00 h by a chemiluminescence enzyme-linked immunosorbent assay (ELISA) method.
The clinical manifestation of asthma was determined by assessment of the degree
of airway obstruction, airways responsiveness to methacholine and severity of
nocturnal airway obstruction, defined as the mean circadian (16:00-04:00 h) peak
expiratory flow (PEF) variation. Serum IL-4, IL-5 and IFN-gamma levels were
significantly higher in asthmatic subjects as compared to healthy controls, both
at 16:00 and 04:00 h. In asthmatic subjects serum IFN-gamma at both time points
correlated significantly with the provocative concentration of methacholine
causing a 20% fall in forced expiratory volume in one second (PC20,meth) (rho= -
0.55) and with the mean 16:00-04:00 h PEF variation (rho = 0.53). In contrast, no
relationship was found between the levels of IL-4 and IL-5 and the parameters of
clinical manifestation of asthma. The results suggest that the serum interferon
gamma level is a reflection of the severity of airway inflammation in atopic
asthma. More studies are needed to detect the cellular sources and to clarify the
exact roles of interferon-gamma and other pro-inflammatory cytokines in asthma.
PMID- 9551731
TI - CD14 expression and soluble CD14 after segmental allergen provocation in atopic
asthma.
AB - Allergic asthma is associated with the recruitment of activated inflammatory
cells after allergen challenge. Surface expression of CD14 has been proposed as a
marker of cell activation and differentiation. We therefore measured CD14
expression on activated macrophages and granulocytes as well as soluble CD14
(sCD14) concentrations in peripheral blood and bronchoalveolar lavage (BAL)
following segmental allergen provocation (SAP) with individually standardized
doses of allergen in eight patients with allergic asthma. Two segments of the
right lung were challenged with allergen. Two segments of the left lung, into
which saline was instilled, served as controls. CD14 expression on macrophages
and granulocytes was determined by flow-cytometry and concentrations of
interleukins and sCD14 were analysed by enzyme-linked immunosorbent assay (ELISA)
10 min and 18 h after challenge. Soluble CD14 concentrations remained unchanged
in BAL fluid after saline challenge and 10 min after SAP, but increased
significantly 18 h after SAP. Although macrophage numbers increased 18h after
SAP, CD14 expression on these cells did not change. Unlike macrophages,
granulocyte numbers correlated with sCD14 levels 18 h after SAP while their CD14
expression decreased significantly. Furthermore, sCD14 correlated with
interleukin (IL)-13 concentrations 18 h after SAP. An increase in soluble CD14
can be observed 18 h but not 10 min after segmental allergen provocation
suggesting local release of this surface antigen. Our findings imply that CD14
mediated cell activation following segmental allergen provocation could play a
role in asthmatic inflammation.
PMID- 9551732
TI - Attenuation of virus-induced airway dysfunction in rats treated with imiquimod.
AB - Viral respiratory infections cause acute airway abnormalities consisting of
inflammation and physiological dysfunction in both animals and humans. It is
likely that inflammatory cell products, such as cytokines, contribute
substantially to viral-induced airway dysfunction. We hypothesized that
imiquimod, an immune response enhancing agent that induces interferon-alpha,
would attenuate the development of airway dysfunction during acute viral illness
in rats. Adult Brown Norway rats were inoculated with parainfluenza type 1
(Sendai) virus or sterile vehicle, and treated with either imiquimod or water.
Respiratory system resistance (Rrs), arterial oxygen tension (Pa,O2), lung viral
titres and bronchoalveolar lavage (BAL) leucocyte counts were measured in
anaesthetized, paralysed, ventilated rats. Virus-infected, water-treated rats had
a significant decrease in Pa,O2 and had significant increases in leucocyte count
and Rrs when compared to both the virus-infected, imiquimod-treated, (Pa,O2, p =
0.03; leucocyte count, p = 0.02; and Rrs, p = 0.009) and noninfected, water
treated rats (Pa,O2, p = 0.007; leucocyte count, p = 0.001; and Rrs, p = 0.01).
In addition, imiquimod suppressed BAL eosinophils in both virus-infected (p =
0.02) and noninfected (p = 0.001) groups, and lowered overall virus titres (p =
0.03). Thus, both virus-induced airway inflammation and physiological dysfunction
were attenuated significantly by imiquimod treatment in this animal model. By
further delineating mechanisms by which infections induce airway dysfunction in
animal models, more specific pharmacological interventions can be developed for
the treatment of virus-induced asthma.
PMID- 9551733
TI - Influence of external pH on ciliary beat frequency in human bronchi and
bronchioles.
AB - Ciliated respiratory epithelial cells have to tolerate variations in local pH
caused by the respiratory cycle and potential ventilation-perfusion mismatches.
We showed previously that peripheral bronchiolar cilia beat at a lower frequency
than bronchial cilia, and have now investigated whether they show differences in
tolerance to changes in pH. Using the image analysis system applied in the
previous study, we compared variations in the ciliary beat frequencies (CBF) of
bronchi and bronchioles sampled from human lung resections at various pH in
vitro. Application of nonparametric tests (the variance of samples was not
similar) indicated that CBF was not significantly modified when pH was varied
between 7.5 and 10.5 for bronchi, and between 5.5 and 10.5 for bronchioles.
Reversible and significantly lower CBF were observed below pH 7.0 for bronchi and
below pH 5.0 for bronchioles. Extreme pH values such as 11.0 or 3.0 were lethal
within a few minutes. Thus, respiratory ciliary beating is able to tolerate
external pH variations between 3.5 and 10.5 without permanent impairment. In
addition we found that alkaline pH values are more favourable than acidic ones
and that bronchiolar ciliated cells are more tolerant to acidic pH than bronchial
cells.
PMID- 9551734
TI - Bronchial temperature reflects transcapillary heat transport of isolated blood
perfused rabbit lungs.
AB - The pulmonary capillaries are in such close proximity to the terminal airways
that changes in capillary blood temperature should also cause changes in
bronchial wall temperature. Therefore, we hypothesized that injection of cold
solutions into the pulmonary artery would yield bronchial temperature-time curves
similar to those in the pulmonary artery and left atrium. These bronchial curves
should mainly represent the capillary bed. Isolated rabbit lungs (n=8) were
ventilated (5% CO2 in air) and perfused (autologous blood, 37 degrees C) at
various flow rates (50-200 mL x min[-1]). Thermistor probes (diameter 0.46 mm)
registered temperature changes in the pulmonary artery, at the bronchial wall
(wedge position) and in the left atrium after injection of 0.8 mL Ringer's
lactate (0 degrees C) into the pulmonary artery. Bronchial temperature-time
curves were found to resemble "dilution" curves located between pulmonary
arterial and left atrial curves. Independent of flow rate, their appearance
times, peaks and calculated mean transit times were between those from the
pulmonary artery and the left atrium. We conclude that bronchial temperature-time
curves reflect transcapillary heat transport and that this approach might be
useful in gaining further information about vascular transport processes in the
interior of the lung.
PMID- 9551735
TI - Action of moguisteine on the activity of tracheobronchial rapidly adapting
receptors in the dog.
AB - We have studied the effects of moguisteine, a new non-narcotic, peripherally
acting antitussive compound, on tracheobronchial rapidly adapting irritant
receptors (RARs). Experiments were carried out on dogs anaesthetized with a
mixture of urethane and alpha-chloralose, paralysed with gallamine, vagotomized
and artificially ventilated. Single unit action potentials identified as
originating from tracheobronchial RARs were recorded from the peripheral cut end
of the right vagus nerve. The activity of these receptors was recorded together
with oesophageal pressure and arterial blood pressure. Fourteen RARs were
challenged with moguisteine (200 microg x kg[-1] i.v.) in 0.4% dimethylsulphoxide
(DMSO) or 0.4% DMSO alone (vehicle). Receptor activity was recorded before
(control) and at 2, 5, 10, 15, 20, 30 and 45 min after administration of the
challenging compounds. When the results at intervals of 2, 5, 10, 15 and 20 min
were averaged for each dog, it was found that moguisteine decreased the mean
activity of the 14 receptors to 75% of the control value (p<0.05); the greatest
inhibition occurred 10-20 min after moguisteine administration. DMSO did not
significantly affect the activity of these endings. Oesophageal pressure,
arterial blood pressure and cardiac frequency were not altered during the
experimental procedures. The overall results indicate the presence of an
inhibitory effect of moguisteine on rapidly adapting irritant receptors that
could account for the antitussigenic effect of this compound.
PMID- 9551736
TI - Chronic Chlamydia pneumoniae infection and asthma exacerbations in children.
AB - This study was undertaken to investigate the reported association between
Chlamydia pneumoniae and Mycoplasma pneumoniae infection and the expression of
asthma-related symptoms. One hundred and eight children with asthma symptoms,
aged 9-11 yrs, completed a 13 month longitudinal study. The children maintained a
daily diary of respiratory symptoms and peak flow rates. When respiratory
symptoms were reported an investigator was called and a nasal aspirate obtained.
In total 292 episodes were reported. After the study 65 children provided samples
when asymptomatic. The presence of infection was investigated by the polymerase
chain reaction for C. pneumoniae and M. pneumoniae and C. pneumoniae secretory
immunoglobulin A (IgA) was detected by amplified enzyme immunoassay. C.
pneumoniae detections were similar between the symptomatic and asymptomatic
episodes (23 versus 28%, respectively). Children who reported multiple episodes
also tended to remain PCR positive for C. pneumoniae suggesting chronic infection
(p< 0.02). C. pneumoniae-specific secretory-IgA antibodies were more than seven
times greater in subjects who reported four or more exacerbations in the study
compared to those who reported just one (p<0.02). M. pneumoniae was found in two
of 292 reports and in two of 65 asymptomatic samples. In conclusion, chronic
Chlamydia pneumoniae infection is common in schoolage children and immune
responses to C. pneumoniae are positively associated with frequency of asthma
exacerbations. We suggest that the immune response to chronic C. pneumoniae
infection may interact with allergic inflammation to increase asthma symptoms. In
contrast Mycoplasma pneumoniae was not found to be important in this study.
PMID- 9551737
TI - Clinical effect of Diskus dry-powder inhaler at low and high inspiratory flow
rates in asthmatic children.
AB - In vitro studies with the Diskus inhaler at low and high flow rates show
consistent doses of drug as fine particles <4.7 microm. The present study was
designed to ascertain whether this in vitro flow independency translates into
flow-independent clinical effect when the device is used by patients at low (30 L
x min[-1]) and high (90 L x min[-1]) flow rates. A pilot study in 129 children
aged 3-10 yrs demonstrated that 99% of children of 3 yrs and above can generate a
flow > or = 30 L x min(-1) through the device, while 26% performed > or = 90 L x
min(-1). Eighteen children aged 8-15 yrs with exercise induced asthma inhaled
placebo or salmeterol 50 microg at either 30 L x min(-1) or 90 L x min(-1).
Exercise challenges were carried out 1 h and 12 h after dosing. The maximum
percentage fall in forced expiratory volume in one second (FEVI) after exercise
12 h after treatment was significantly less after salmeterol at either flow rates
as compared to placebo. There was no significant difference in the protection
from salmeterol on the day of low-flow inhalation versus the day of high-flow
inhalation. Consistent in vitro fine particle dosing from the Diskus inhaler
translates into a consistent clinical effect at low and high flow rates in
children.
PMID- 9551738
TI - Prevalence of bronchial hyperresponsiveness to 4.5% saline and its relation to
asthma and allergy symptoms in Austrian children.
AB - The prevalence of asthma in school children has been reported to have increased,
with wide variations between countries. To allow comparison of prevalence data,
objective markers of asthma should be measured. Therefore, we assessed the
prevalence of bronchial hyperresponsiveness (BHR) to hypertonic saline and its
relation to asthma and allergy symptoms in 507 Austrian school children, aged 12
15 yrs in a cross-sectional, community based survey. These children were selected
from 3,371 children who had answered a self-administered written questionnaire on
asthma, hay fever, eczema and environmental factors. The prevalence of BHR to
hypertonic saline was 14% and the majority (70%) of the children had mild BHR.
The prevalence of wheeze in the last 12 months was 12% and of a diagnostic label
of asthma was 6%. Fifty three per cent of the children with symptoms in the last
12 months and a diagnostic label of asthma had BHR, and 33% of those with
symptoms in the last 12 months regardless of a diagnostic label of asthma showed
a positive response to hypertonic saline. Atopic dermatitis, a diagnostic label
of asthma, night cough apart from colds, wheeze in the past 12 months (but not
"former wheeze") and male gender were significantly associated with increased
response to 4.5% saline in the final logistic regression model. These results
show that the prevalence of asthma symptoms in the last 12 months and the
prevalence of bronchial hyperresponsiveness to hypertonic saline are twice that
of a diagnosis of asthma and that asthma might be underdiagnosed in the present
population. The response to hypertonic saline is most strongly associated with
current asthma and allergy symptoms. A combination of a "diagnostic label of
asthma" and "asthma symptoms in the last 12 months" might best reflect "current
asthma" in epidemiological studies in this population.
PMID- 9551739
TI - Effect of dietary intake of omega-3 and omega-6 fatty acids on severity of asthma
in children.
AB - We assessed the clinical and biochemical effects in asthmatic children of fish
oil supplementation and a diet that increases omega-3 and reduces omega-6 fatty
acids. Thirty nine asthmatic children aged 8-12 yrs participated in a double
blind, randomized, controlled trial for 6 months during which they received fish
oil capsules plus canola oil and margarine (omega-3 group) or safflower oil
capsules plus sunflower oil and margarine (omega-6 group). Plasma fatty acids,
stimulated tumour necrosis factor alpha (TNFalpha) production, circulating
eosinophil numbers and lung function were measured at baseline and after 3 and 6
months of dietary modification. Day and night symptoms, peak flow rates and
medication use were recorded for 1 week prior to laboratory visits. Plasma
phospholipid omega-3 fatty acids were significantly greater in the omega-3 group
at 3 and 6 months compared to the omega-6 group (p<0.001). In the omega-3 group
TNFalpha production fell significantly compared with baseline (p=0.026), but the
magnitude of change between groups did not reach significance (p=0.075). There
were no significant changes in clinical outcome measures. Dietary enrichment of
omega-3 fatty acids over 6 months increased plasma levels of these fatty acids,
reduced stimulated tumour necrosis factor alpha production, but had no effect on
the clinical severity of asthma in these children.
PMID- 9551740
TI - Hospitalization for lower respiratory disease during 20 yrs among under 5 yr old
children in Stockholm County: a population based survey.
AB - Lower respiratory disease (LRD) is a common cause of hospitalization in infants,
and episodes of obstructive LRD increase the risk for asthma later in life. The
purpose of this study was to assess time trends and geographical variation of
first time hospitalization for LRD among children in Stockholm County, Sweden.
Data on first time admittance for LRD among children aged up to 5 yrs from 1973
through 1992 were obtained from the Stockholm County Council hospital discharge
register, and population register data were used for estimation of the population
at risk. Municipal data were available for 1982-1992 on outbreaks of respiratory
syncytial virus (RSV) infections and socio-economic factors. A total of 12,450
children had been hospitalized for the first time with LRD. For children aged <2
yrs a 100% increase in the rate of first time hospitalization for LRD was
observed during the study period and children aged up to 1 yr predominated (50%).
The average yearly increase in the population based first time hospital admission
rate for LRD was 1.82%. Males constituted 65% of the cases. Of the diagnoses,
89.6% were consistent with obstructive LRD, e.g. asthma and obstructive
bronchitis. In children aged up to 1 yr, peaks in the rate of hospitalization
tended to coincide with outbreaks of RSV infections. Differences in
hospitalization between municipalities seemed to be partly explained by
differences in the admission practices of the four paediatric hospitals in the
area. We conclude that the increased rate of hospitalization for lower
respiratory disease in infants of Stockholm County may reflect a true increase in
the incidence of obstructive respiratory disease. However, several factors
determine admittance to hospital and the results need to be interpreted with
caution.
PMID- 9551741
TI - Inhaled nitric oxide in hypoxaemic newborns who are candidates for extracorporeal
life support.
AB - The aim of this study was to evaluate the effect of inhaled nitric oxide (NO) in
newborns with acute hypoxaemic respiratory failure and the impact of this NO
therapy on survival and the need for extracorporeal membrane oxygenation (ECMO).
A cohort of newborns with a gestational age of > or = 34 weeks and an oxygenation
index (OI) > 25 were prospectively evaluated. Patients were given NO at an
initial dose of 10 parts per million (ppm). Oxygenation parameters were evaluated
prior and during NO inhalation. From January 1994 to December 1996, 20 infants
were enrolled in the study. Based upon their outcome, patients were divided into
two groups: survivors with no need for ECMO, group A (n=8) and survivors
requiring ECMO or nonsurvivors, group B (n=12). All infants approached or met
ECMO criteria before NO inhalation. Eight patients (40%) were successfully
managed with NO and conventional treatment (group A). Newborns in this group
showed a rapid and sustained improvement of systemic oxygenation during NO
inhalation. Mean arterial oxygen tension (Pa,O2) increased significantly from 4.5
kPa (34 mmHg) (95% confidence interval (95% CI) 1.9-7.1 kPa (14.4-53.7 mmHg)) to
10.1 kPa (75.7 mmHg) (95% CI 6.5-13.6 kPa (49.1-1023 mmHg)) after 1 h and was 9.0
kPa (67.7 mmHg) (95% CI 7.1-11.0 kPa (53.1-82.4 mmHg)) at 24 h. Conversely, none
of the oxygenation parameters improved in the 12 patients who ultimately required
ECMO or died (group B). The results indicate that inhaled nitric oxide can
improve systemic oxygenation in newborns with acute respiratory failure and may
reduce the need for extracorporeal membrane oxygenation support in candidates.
Lack of a rapid response to nitric oxide may be an early predictor of
unfavourable short-term outcome, prompting a move towards alternative treatments.
PMID- 9551742
TI - Catalase, myeloperoxidase and hydrogen peroxide in cystic fibrosis.
AB - An oxidant-antioxidant imbalance with damaging consequences for the bronchial
epithelium has been hypothesized in the airways of patients with cystic fibrosis
(CF). It is based on the assumption that neutrophils entering the lumen of the
infected airways undergo activation and release toxic oxygen metabolites and
myeloperoxidase (MPO), an enzyme which transforms hydrogen peroxide (H2O2) into
highly toxic oxygen metabolites. Our aims were to substantiate this hypothesis.
H2O2 levels were measured in breath condensates of 63 CF patients and 51 normal
subjects. In CF sputum samples, activities and concentrations of MPO and catalase
(CAT) were determined. MPO/H2O2-mediated cytotoxicity of CF sputum was measured
in cell culture assays. H2O2 levels were similar in CF patients and normal
subjects (mean +/-SD) 0.97 +/- 0.69 versus 1.11+/-0.78 microM; p=0.427).
Concentrations and activities of CAT (0.31+/-0.18 microM; 105+/-69 units) and MPO
(5.93+/-4.8 microM; 87.8+/-75 units) were detectable in 38 CF sputa. Addition of
H2O2 to in vitro cells preincubated with CF sputum did not induce cytotoxicity
even when CAT was removed from sputum. Sputum MPO together with H2O2 did not
inactivate alpha-proteinase inhibitor. Preincubation of MPO with sulphated
glycoconjugates or deoxyribonucleic acid (DNA) totally inhibited its cytotoxic
effect. In conclusion, catalase, sulphated glycoconjugates and deoxyribonucleic
acid may prevent myeolperoxidase-mediated oxygen radical generation in cystic
fibrosis sputum.
PMID- 9551743
TI - Hydrogen peroxide-induced epithelial injury: the protective role of intracellular
nonprotein thiols (NPSH).
AB - Injury to the alveolar region is a hallmark of the adult respiratory distress
syndrome (ARDS) whereas injury to the epithelium of the conducting airways is a
characteristic of asthma. Reactive oxygen species have been implicated as
mediators of lung injury in both of these conditions. We have investigated the
relationship between intracellular nonprotein thiols (NPSH), and the release of
the cytosolic enzyme lactate dehydrogenase (LDH), as an index of cell injury,
following treatment of the human alveolar type II-like epithelial cell line (A549
cells) or the human bronchial epithelial cell line (16HBE140-) with hydrogen
peroxide (H2O2). We have also assessed the protective effects of pre-incubation
of both of these cells lines with H2O2 or enhancement of intracellular NPSH
against H2O2-induced cell injury. Exposure of A549 and 16HBE140- cells to H2O2
(0.1 mM and 1 mM respectively for 16 h) produced the release of 40% of the total
cellular LDH. H2O2 exposure produced an initial dose-dependent decrease in NPSH
in A549 cells, with a subsequent increase to above control values. 16HBE140-
cells also showed a dose-dependent decrease in NPSH following exposure to H2O2.
Pretreatment of A549 cells with 0.1 mM H2O2 followed by subsequent exposure to
H2O2 did not protect against H2O2-induced LDH release in this epithelial cell
line. Pre-incubation with 2 mM N-acetylcysteine (NAC) increased NPSH but not
intracellular reduced glutathione and resulted in total inhibition of H2O2
induced LDH release in both cell types. Pretreatment with reduced glutathione
protected both cell types against the injurious effects of H2O2, whereas
glutathione monethyl ester (GSHMEE) only partially protected A549 cells and had
no effect in 16HBE140- cells. Intracellular cysteine levels were increased in
both cell lines following NAC exposure but not sufficiently to account for the
increase in NPSH levels. These observations raise the possibility that a critical
concentration of nonprotein thiols may be necessary to protect pulmonary
epithelial cells against hydrogen peroxide-induced injury.
PMID- 9551744
TI - Hypoxia reduces endothelin production by rat alveolar type II cells in primary
culture.
AB - The purpose of the study was to describe endothelin (ET) production and to
characterize the effect of hypoxia on preproendothelin-1 (preproET-1) messenger
ribonucleic acid (mRNA) expression and ET secretion by rat type II pneumocytes in
vitro. Rat type II pneumocytes were incubated in a sealed chamber containing a
normoxic (21% O2) or hypoxic (1% O2) atmosphere for increasing durations.
Immunoreactive ET (irET) was measured in cell supernatants using a
radioimmunoassay. Rat preproET-1 mRNA was detected by Northern blot. Rat type II
pneumocytes expressed preproET-1 mRNA, contained irET and secreted irET in a time
dependent manner. ET secretion was dependent on de novo ribonucleic acid (RNA)
and protein synthesis. Hypoxia decreased irET secretion by 27% and reduced the
steady-state level of preproET-1 mRNA by 60% whereas intracellular irET
concentration was unchanged. Inhibition was partially reversible with the return
to a normoxic atmosphere. Inhibition of nitric oxide synthesis did not prevent
the inhibitory effect of hypoxia. In conclusion, rat type II pneumocytes in
primary culture secreted immunoreactive endothelin and expressed preproendothelin
1 messenger ribonucleic acid. Hypoxia reversibly reduced endothelin-1 production
through a reduction of the steady-state preproendothelin-1 messenger ribonucleic
acid level. Nitric oxide synthesis did not mediate the inhibitory effect of
hypoxia.
PMID- 9551745
TI - Integrin dependent migration of lung cancer cells to extracellular matrix
components.
AB - Since tumour progression is dependent on the ability of malignant cells to
interact with the extracellular matrix (ECM), we have investigated the
significance of beta1 and beta3 integrins for migration of lung cancer cells to
components of the ECM. In an in vitro hapto- and chemotactic assay system, five
cell lines representing the major types of lung cancer were examined:
adenocarcinoma (WART); squamous cell carcinoma (U-1752); small cell lung cancer
(SCLC) (U-1906, 054 A) and large cell lung cancer (LCLC) (U-1810). Flow
cytometric analyses were performed to characterize their integrin expression. U
1906, 054 A, WART and U-1752 all expressed beta1 integrins whereas U-1810 did
not. However, U-1810 and U-1752 expressed beta3 integrins. All cell lines except
U-1810 and U-1752 showed hapto- and chemotactic motility to fibronectin, laminin
and type IV collagen and this motility was beta1 integrin-dependent except in the
case of U-1810. However, the hapto- and chemotactic responses differed markedly
between the separate cell lines and there was no distinct pattern to separate non
small cell lung cancer (NSCLC) from SCLC. No or very little migration was seen in
control experiments with bovine serum albumin (BSA) or serum-free medium alone,
indicating that the migration of the lung cancer cells require adhesion
molecules, soluble or substratum bound. We have found the involvement of beta1
integrins in lung cancer cell migration in vitro towards fibronectin, laminin and
type IV collagen except in the case of U-1810. The U-1810 cell line clearly
differed from the rest of the cell lines by lacking expression of beta1
integrins.
PMID- 9551746
TI - Acute effects of deep diaphragmatic breathing in COPD patients with chronic
respiratory insufficiency.
AB - This study investigated the impact of deep diaphragmatic breathing (DB) on blood
gases, breathing pattern, pulmonary mechanics and dyspnoea in severe hypercapnic
chronic obstructive pulmonary disease (COPD) patients recovering from an acute
exacerbation. Transcutaneous partial pressure of carbon dioxide (Ptc,CO2) and
oxygen (Ptc,O2) and arterial oxygen saturation (Sa,O2), were continuously
monitored in 25 COPD patients with chronic hypercapnia, during natural breathing
and DB. In eight of these patients, breathing pattern and minute ventilation
(V'E) were also assessed by means of a respiratory inductance plethysmography. In
five tracheostomized patients, breathing pattern and mechanics were assessed by
means of a pneumotachograph/pressure transducer connected to an oesophageal
balloon. Subjective rating of dyspnoea was performed by means of a visual
analogue scale. In comparison to natural breathing deep DB was associated with a
significant increase in Ptc,O2 and a significant decrease in Ptc,CO2, with a
significant increase in tidal volume and a significant reduction in respiratory
rate resulting in increased V'E. During DB, dyspnoea worsened significantly and
inspiratory muscle effort increased, as demonstrated by an increase in
oesophageal pressure swings, pressure-time product and work of breathing. We
conclude that in severe chronic obstructive pulmonary disease patients with
chronic hypercapnia, deep diaphragmatic breathing is associated with improvement
of blood gases at the expense of a greater inspiratory muscle loading.
PMID- 9551747
TI - Partitioning of the elastic work of inspiration in patients with COPD during
exercise.
AB - During exercise, dynamic hyperinflation-induced intrinsic positive end-expiratory
pressure (PEEPi) and decreased dynamic lung compliance (CL,dyn) of patients with
chronic obstructive pulmonary disease (COPD) increase the elastic work of
inspiration (Wi) more than would be predicted from the increase in tidal volume
(VT). This contributes significantly to their exertional breathlessness. In 10
stable patients with COPD, the dynamic Wi was measured during incremental bicycle
exercise to exhaustion. The total Wi was then partitioned into the portion
required to overcome PEEPi (Wi,PEEPi) and nonPEEPi elastic load (Wi,nonPEEPi).
The latter is used to overcome the increase in the total respiratory system
elastance during inflation. From resting breathing to peak exercise, Wi more than
doubled (p<0.001). This increase was largely due to Wi,PEEPi, which significantly
rose from 1.7+/-0.3 to 5.3+/-0.8 L x cm H2O(-1) (p<0.001). In comparison,
Wi,nonPEEPi increased from only 3.0+/-0.4 to 5.1+/-0.5 L x cm H2O(-1) (p<0.01).
Consequently, Wi,PEEPi as a fraction of total Wi increased from 35.5+/-5.6 to
51.0+/-3.3% (p<0.02). In addition, the measured Wi,nonPEEPi at peak exercise,
when expressed as a percentage of its value during resting breathing, was 25%
more than that predicted from the increase in VT alone. Assuming a constant chest
wall compliance, this can be attributed to the exercise-induced decrease in
CL,dyn, which was 0.27+/-0.04 and 0.17+/-0.02 L x cm H2O(-1) (p<0.01),
respectively, during resting breathing and peak exercise. In conclusion, the
dynamic hyperinflation-induced intrinsic positive end-expiratory pressure is more
important than the increase in tidal volume in raising the work of inspiration
during exercise in patients with chronic obstructive pulmonary disease; the
decrease in dynamic lung compliance plays a definite but less important role.
PMID- 9551748
TI - Effects of proportional assist ventilation on exercise tolerance in COPD patients
with chronic hypercapnia.
AB - This study investigates the impact of proportional assist ventilation (PAV), a
new mode of partial ventilatory support, on exercise tolerance and breathlessness
in severe hypercapnic chronic obstructive pulmonary disease (COPD) patients. We
also examined the effects of continuous positive airway pressure (CPAP) and
pressure support ventilation (PSV). On two consecutive days, 15 stable
hypercapnic COPD patients underwent four endurance tests on a cycle ergometer at
80% of their maximal workrate, receiving, via a nasal mask in random order,
either: 1) sham ventilation (CPAP: 1 cmH2O); 2) CPAP (6 cmH2O); 3) PSV
(inspiratory pressure support: 12-16 cmH2O; expiratory positive airway pressure
(EPAP): 1 cmH2O); or 4) PAV (8.6+/-3.6 cmH2O x L(-1) and 3+/-1.3 cmH2O x L(-1)x
s(-1) of volume and flow assistance, respectively plus EPAP: 1 cmH2O). Oxygen
supply was standardized to maintain an arterial oxygen saturation (Sa,O2) of 92
93%. Breathing pattern and minute ventilation (by respiratory inductive
plethysmography), pulse oximetry, end tidal partial pressure of CO2, cardiac
frequency and sensations of dyspnoea and leg discomfort (by Borg scale) were
monitored. In comparison to sham ventilation, PAV, PSV and CPAP were able to
increase the endurance time (from 7.2+/-4.4 to 12+/-5.6, 10+/-5.2 and 9.6+/-4.6
min, respectively) and to reduce dyspnoea and oxygen flow to the nasal mask.
However, the greatest improvement was observed with PAV. We conclude that PAV
delivered by nasal mask can im-prove exercise tolerance and dyspnoea in stable
hypercapnic COPD patients and hence this mode of ventilatory support may be
useful in respiratory rehabilitation programmes.
PMID- 9551749
TI - Long-term treatment of alpha1-antitrypsin deficiency-related pulmonary emphysema
with human alpha1-antitrypsin. Wissenschaftliche Arbeitsgemeinschaft zur Therapie
von Lungenerkrankungen (WATL)-alpha1-AT-study group.
AB - Alpha1-antitrypsin (alpha1-AT) deficiency is a genetic disorder characterized by
low serum levels of alpha1-AT and a high risk of pulmonary emphysema at a young
age. The resulting surplus of proteases, mainly of neutrophil elastase, can be
balanced by i.v. augmentation with alpha1-AT. However, it is not clear if
affected patients benefit from long-term augmentation therapy and no long-term
safety data are available. We examined 443 patients with severe alpha1-AT
deficiency and pulmonary emphysema receiving weekly i.v. infusions of 60 mg x kg
body weight(-1) alpha1-AT in addition to their regular medication. The
progression of the disease was assessed by repeated lung function measurements,
particularly the decline in forced expiratory volume in one second (deltaFEV1).
Four hundred and forty three patients with alpha1-AT deficiency tolerated
augmentation therapy well with few adverse reactions. The deltaFEV1 in 287
patients with available follow-up data was 57.1+/-31.1 mL x yr(-1). Stratified
for baseline FEV1, the decline was 35.6+/-21.3 mL in the 108 patients with an
initial FEV1 <30% and 64.0+/-26.4 mL in the 164 with FEV1 30-65% of predicted
normal (p=0.0008). The remaining 15 patients had an initial FEV1 >65% pred. Long
term treatment with i.v. alpha1-antitrypsin in patients with severe alpha1
antitrypsin deficiency is feasible and safe. The decline in forced expiratory
volume in one second is related to the initial forced expiratory volume in one
second as in alpha1-antitrypsin deficient patients not receiving augmentation
therapy.
PMID- 9551750
TI - Heart block in patients with obstructive sleep apnoea: pathogenetic factors and
effects of treatment.
AB - Heart block during sleep has been described in up to 10% of patients with
obstructive sleep apnoea. The aim of this study was to determine the relationship
between sleep stage, oxygen desaturation and apnoea-associated bradyarrhythmias
as well as the effect of nasal continuous positive airway pressure (nCPAP)/nasal
bi-level positive airway pressure (nBiPAP) therapy on these arrhythmias in
patients without electrophysiological abnormalities. Sixteen patients (14 males
and two females, mean age 49.6+/-10.4 yrs) with sleep apnoea and nocturnal heart
block underwent polysomnography after exclusion of electrophysiological
abnormalities of the sinus node function and atrioventricular (AV) conduction
system by invasive electrophysiological evaluation. During sleep, 651 episodes of
heart block were recorded, 572 (87.9%) occurred during rapid eye movement (REM)
sleep and 79 (12.1%) during nonrapid eye movement (NREM) sleep stages 1 and 2.
During REM sleep, the frequency of heart block was significantly higher than
during NREM sleep: 0.69+/-0.99 versus 0.02+/-0.04 episodes of heart block x min(
1) of the respective sleep stage (p<0.001). During apnoeas or hypopnoeas, 609
bradyarrhythmias (93.5%) occurred with a desaturation of at least 4%. With nCPAP/
nBiPAP therapy, apnoea/hypopnoea index (AHI) decreased from 75.5+/-39.6 x h(-1)
to 3.0+/-6.6 x h(-1) (p<0.01) and the number of arrhythmias from 651 to 72
(p<0.01). We conclude that: 1) 87.9% of apnoea-associated bradyarrhythmias occur
during rapid eye movement sleep; 2) the vast majority of heart block episodes
occur during a desaturation of at least 4% without a previously described
threshold value of 72%; and 3) nasal continuous positive airway pressure or nasal
bi-level positive airway pressure is the therapy of choice in patients with
apnoea-associated bradyarrhythmias.
PMID- 9551751
TI - Time course of pulmonary artery pressure during sleep in sleep apnoea syndrome:
role of recurrent apnoeas.
AB - Recent results in animals have suggested that repetition of hypoxaemic stimuli
may result in a progressive increase in pulmonary arterial pressure (Ppa). The
purpose of the present study was to investigate the effects of recurrent
obstructive apnoeas on Ppa. We have, therefore, examined the nocturnal trend of
Ppa in seven obstructive sleep apnoea syndrome (OSAS) patients and in five
snorers. Mean Ppa was measured before, at the start, at the end and after the
selected apnoeas. The analysis was performed for each 1 h period for at least 7 h
throughout the night on at least 10 randomly selected apnoeas per hour. In
snorers, 100 randomly chosen values were measured during every hour of the night.
In the morning after the nocturnal study, the Ppa responses to acute hypoxia and
hypercapnia were measured. No Ppa changes throughout the 7 h were found during
sleep in snorers [Ppa slope:-0.002+/-0.10 mmHg x h(-1)]. In OSAS patients a small
but significant increase in Ppa throughout the night was noted, affecting the
values before [Ppa slope: 0.7+/-0.16 mmHg x h(-1)], at the start of apnoea [Ppa
slope: 0.530.1 mmHg x h(-1)] as well as at the end [Ppa slope: 0.44+/-0.08 mmHg x
h(-1)] and in the postapnoeic period [Ppa slope: 0.55+/-0.1 mmHg x h(-1)]. When
we limited the analysis to nonrapid eye movement (NREM) sleep, a trend in
progressive Ppa was also present, irrespective of changes in apnoea duration and
apnoea desaturation. The Ppa rise during the night was not affected by diurnal
Ppa pulmonary vascular response to hypoxia and hypercapnia or indices of sleep
apnoea severity. We conclude that in obstructive sleep apnoea, pulmonary artery
pressure progressively increases during the night, reflecting the cumulative
effects of apnoeas and nocturnal hypoxaemia.
PMID- 9551752
TI - Mandibular advancement devices for the control of snoring.
AB - Patients presenting with the complaint of antisocial snoring have very few
options available to them of proven efficiency. Mandibular advancement devices
worn intra-orally at night, have recently been shown in controlled trials to help
mild to moderate obstructive sleep apnoea. However, there are no properly
controlled studies with objective measurements on the use of such appliances for
the management of antisocial snoring. Fifteen patients, already established on
mandibular advancement devices for the control of snoring, were asked to
participate in this study. They were studied over two nights, using a portable
sleep monitoring device at home, both with and without their mandibular
advancement devices in place (in randomized order). Snoring was measured using a
surface throat microphone. In addition oxygen saturation and indirect beat to
beat blood pressure were measured. The latter (using pulse transit time) provided
an index of autonomic "arousals" and a measure of inspiratory effort. In nearly
all of these highly selected patients the mandibular advancement devices reduced
significantly the amount of snoring from a median of 193 to 20 snores x h(-1)
(p<0.0001). In addition there was a reduction in respiratory effort, implying
enlargement of the upper airway whilst wearing the appliance. These patients only
represent those who were able to tolerate the appliance. With such clear evidence
of their potential efficacy, and no suggestion from other studies of any harm, it
would seem reasonable to introduce this approach into the management of
antisocial snoring.
PMID- 9551753
TI - Normative data on snoring: a comparison between younger and older adults.
AB - Snoring is a common sleep-related behaviour. Increased body mass index (BMI),
cranio-facial anatomical features, and older age have been linked to the
occurrence of snoring. While mostly middle-aged populations have been studied for
the occurrence of snoring and sleep-related breathing abnormality, this study was
designed to assess the subjective report of snoring and the objective measurement
of snoring at the two extremes of human age. The study design called for
measurement of snoring in two age groups (college students; n=155 and older
subjects; mean age 64.1 yrs n=134) with a mean age difference of 45 yrs. Snoring
was assessed with a validated recording device. A validated questionnaire was
used to subjectively assess snoring and obtain relevant sleep-related
information. Students and older subjects differed in the self-report of snoring.
While 83% of students reported "never" or "rarely" snoring only 35% of older
subjects fell into these categories. Measurement of snoring during sleep revealed
that students spent more time during sleep with continuous snoring than older
subjects. In older subjects, a reduction in continuous snoring was accompanied by
an increase in apnoeic snoring. Subjective snoring frequency correlated with
continuous snoring in students only. A positive family history of snoring
increased the odds ratio for self-reported snoring but not for recorded snoring.
It has been shown that snoring frequency can vary depending on age and that the
congruency between perceived snoring frequency and recorded snoring is influenced
by the age of an individual.
PMID- 9551754
TI - Validation of automated sleep analysis in normal children.
AB - With the aim of determining normal reference values for our sleep laboratory and
evaluating the reliability of automated analysis for scoring polysomnographic
studies in children, we recorded polysomnograms in 16 healthy boarding-school
children. Sleep recordings were obtained with a computer system (Medilog SAC,
Oxford Instruments). Polysomnographic variables were monitored continuously on a
16-channel recorder equipped with a video. Data were acquired on optical disk for
computer-assisted data interpretation. Sleep stages and respiratory events were
also scored visually by operator. Comparison with visual scores showed that the
computer system significantly overscored wakefulness (W) (p<0.02) and stage IV
(p<0.001) and underscored stage II (p<0.001) and rapid eye movement (REM) sleep
(p<0.001). It also assigned respiratory events a higher score than did visual
scoring, as shown by the higher apnoea index (AI) and hypopnoea index (HI) (AI
p<0.03; HI p<0.001). Regression analysis showed a significant correlation between
visual and automated scores for central (r=0.679; p<0.004) and obstructive apnoea
(r=0.631; p<0.008). Computer apnoea scores did not correlate with visual scores.
Much remains to be done before computer-based scoring systems can be relied upon,
without visual scoring, for polysomnographic sleep studies in children. Their
main advantage at present is that they offer a convenient means of saving paper,
space and time.
PMID- 9551755
TI - Subjective scoring of cough in children: parent-completed vs child-completed
diary cards vs an objective method.
AB - Cough is often used as an outcome measure, although the reporting of cough is
unreliable. Using a 24 h ambulatory cough meter to measure cough frequency, the
aim of this study was to compare: 1) the correlation of child-completed diary
cards to the objective measurement, with that of parent-completed diary cards;
and 2) the visual analogue scale (VAS) to the verbal category descriptive (VCD)
score. The cough meter consisted of a previously validated Holter monitor and a
cough processor. Eighty four children (39 with recurrent cough and 45 controls,
aged 6-17 yrs) used a cough meter at least once. Thirty three subjects used the
cough meter twice. Parents and children completed separate diary cards using the
VAS and VCD scores. The strength of the relationship between the subjective
scores and the objective recordings was analysed by spearman's rank correlation
coefficient. For daytime cough, child-completed diary cards and the VCD
correlated better to the objective measurement than parent-completed diary cards
and the VAS, respectively. In subjects that used the cough meter twice, the
difference between the cough frequency correlated to the difference in the
subjective scores. The confidence intervals for the correlation coefficients were
wide. The agreement between the objective and subjective presence of daytime
cough was good but that for night-time cough was poor. We conclude that the
severity of cough defined on diary cards may not represent cough frequency.
Objective readings are first choice but currently not yet practical. The verbal
category descriptive diary card completed by children and assisted by parents has
the highest correlation to cough frequency measured objectively.
PMID- 9551756
TI - Exhaled single-breath nitric oxide measurements are reproducible, repeatable and
reflect levels of nitric oxide found in the lower airways.
AB - Measurement of exhaled nitric oxide (NO) may allow noninvasive assessment of
inflammatory disease in the lung. We determined immediate and day-to-day
reproducibility of single-breath NO measurements at different points on the
exhaled test, and whether levels recorded reflect levels of NO in the lower
airways. Using a rapid chemiluminescence analyser, 55 healthy control subjects
performed three sequential tests on each of two days. NO levels were compared at
the level corresponding with: 1) the time the mouth pressure fell below 4 cmH2O
(MP); 2) the plateau of end-exhaled CO2 (CO2); and 3) the NO plateau (NOp). NO
levels were measured directly from the lower airways of 15 lung transplant
recipients and compared with NO levels from a single-breath test performed in the
same cohort. For measurements performed at MP, CO2 and NOp, the mean +/- SD
differences between the two closest levels performed on the same day were 0.11+/
0.18, 0.095+/-0.16 and 0.094+/-0.13 parts per billion (ppb), respectively, and
between days were 0.18+/-0.76, 0.19+/-0.78 and 0.17+/-0.8 ppb, respectively. End
expiratory levels recorded at the mouth from a single-breath test and in the
lower airways were highly correlated (mouth versus trachea r2=0.95, p<0.0001,
mouth versus bronchus r2=0.92, p<0.0001). Single-breath exhaled nitric oxide
levels are a simple, reproducible and valid measure of nitric oxide production
from the lower respiratory tract.
PMID- 9551757
TI - Nicotine replacement: a new approach to reducing tobacco-related harm.
AB - Primary prevention is usually regarded as the most desirable goal in efforts to
control tobacco-related diseases. However, this has not been very effective so
far; moreover, it would take 30-40 yrs for primary prevention to translate into
major health benefits. Modification of tobacco products and/or reduction of
tobacco use may also have some impact on tobacco-related diseases. A tobacco dose
dependent risk has been observed in these diseases, including cancer,
cardiovascular diseases, chronic nonspecific respiratory disorders, and problems
during pregnancy. Reduced smoking (smoking fewer cigarettes, leading to a reduced
intake of toxic substances) may be indicated in individuals who: 1) are failing
in cessation attempts; 2) want to quit but are unable to do so; and 3) do not
want to quit but want to reduce smoking. Studies have shown that nicotine
replacement medications may be an untapped source in efforts to reduce smoking.
Based on Austrian data, it is estimated that, approximately 10 yrs after
implementation, a 1% reduction in smoking could save 14 male lung cancer deaths
each year, and a 50% reduction would save 700 male lives. Inclusion of females
and other tobacco-related diseases suggest that thousands of lives could be saved
if smoking could be reduced by 50%. In the European Union, such a reduction in
smoking could save > or = 100,000 lives annually. Even a 1% reduction would save
1,000 lives. In conclusion, reduced smoking should be explored as a valid method
of reducing tobacco-related harm in those unwilling or unable to quit smoking.
PMID- 9551758
TI - Current opinion of muco-active drug research: strategies and problems.
AB - In general, mucoactive drugs are classified into several groups. However, since
many drugs have overlapping effects, it is difficult to classify the drugs into
groups based on their major actions. It has been reported that many mucoactive
drugs have antioxidant effects. It is reasonable to suggest that an anti
inflammatory property is crucial to demonstrate effectiveness in a clinical
context. From this point of view, we have evaluated several mucoactive drugs over
two decades. Of these, we will consider the following drugs with anti
inflammatory properties: sodium aceneuramate; glucocorticoids; traditional
Chinese medicines; and new cysteine derivatives. On the basis of these findings,
we believe that the efforts to seek for compatible actions between
glucocorticoids and oriental medicines may provide new opportunities for
development of ideal mucoactive drugs with specified actions, i.e. suppression of
gene expression.
PMID- 9551759
TI - Respiratory muscles as a target for adenovirus-mediated gene therapy.
AB - The protein dystrophin is absent in the muscles of patients with Duchenne
muscular dystrophy (DMD) as well as dystrophin-deficient mice with muscular
dystrophy (mdx mice). The mdx mouse diaphragm closely resembles the human DMD
phenotype and thus provides a useful model for studies of dystrophin gene
replacement. Recombinant adenovirus vectors (AdVs) hold promise as a means for
delivering a functional dystrophin gene to muscle. As an initial step toward this
goal, we have determined the efficiency and functional consequences of AdV
mediated reporter gene transfer to the diaphragm in both normal and mdx adult
mice. At 1 week after AdV administration, there was a high level of transgene
expression in the diaphragm. One month later, however, elimination of transgene
expression was observed along with a significant decrease in force production by
both normal and mdx diaphragms. Immunosuppression with cyclosporine did not
augment the level of transgene expression, but a beneficial effect on diaphragm
force-generating capacity was observed in both groups of animals. In order to
further elucidate the cellular mechanisms underlying these findings, the effects
of AdV gene inactivation (by ultraviolet (UV) irradiation) and interference with
host T-lymphocyte subsets were examined. Both UV-inactivation of AdV and CD8+ T
cell deficiency were found to significantly alleviate AdV-induced reductions in
diaphragm force-generating capacity. Brief (2 day) administration of a
neutralizing antibody against host CD4+ T-cells also produced a trend towards
mitigation of AdV-induced contractile dysfunction. In addition, transgene
expression one month after AdV delivery was significantly enhanced with
inhibition of either CD4+ or CD8+ T-cell function. The data suggest two major
sources of reduced force generation after recombinant adenovirus vector-mediated
gene transfer to muscle: 1) a cytotoxic component associated with recombinant
adenovirus vector transcriptional activity; and 2) an immune-based component of
more delayed onset that is primarily dependent upon CD8+ T-cell activity. These
results have important implications for the design of future generation vectors
and the potential need for immunosuppressive therapy after recombinant adenovirus
vector mediated dystrophin gene transfer to Duchenne muscular dystrophy patients.
PMID- 9551760
TI - Functional upper airway obstruction and chronic irritation of the larynx.
AB - Wheezing and dyspnoea are typical symptoms of asthma but can also be found in
diseases of the extrathoracic airways. Functional upper airway obstruction may
imitate, as well as complicate asthma. Functional upper airway obstruction was
first described as a conversion disorder in young females with inspiratory
stridor. Subsequently, it was found that functional upper airway obstruction was
more often a secondary phenomenon in chronic asthma also involving the expiratory
laryngeal airflow. During a period of 15 months, we diagnosed six cases of
functional upper airway obstruction. Five patients were female and one male, and
four were also asthmatics. Three cases showed chronic sinusitis with postnasal
drip (PND) and/or gastro-oesophageal reflux. Both disorders may irritate the
larynx. Treatment of sinusitis and gastro-oesophageal reflux led to a significant
improvement of dyspnoea in all three of these patients. In asthma refractory to
treatment and in the case of an asthmatic exacerbation without obvious cause,
functional upper airway obstruction should be excluded to avoid unnecessary
treatment with systemic steroids. Some of the possible causative factors of
functional upper airway obstruction, such as postnasal drip and gastro
oesophageal reflux, are easily treatable.
PMID- 9551761
TI - Early-onset phenytoin toxicity mimicking a renopulmonary syndrome.
AB - Phenytoin is a commonly used anti-epileptic drug. Adverse reactions including
fever, skin reactions and lymphadenopathy are well known but atypical reactions
can also occur. A patient is described with a lag time of only 4 days between
onset of phenytoin and the development of a syndrome with acute lung injury and
renal failure. The symptoms mimicked a renopulmonary syndrome, and resolved
completely after cessation of phenytoin and addition of steroids.
PMID- 9551762
TI - Diffuse alveolar damage in a patient treated with gemcitabine.
AB - We present a case of diffuse alveolar damage (DAD) that occurred in a male aged
68 yrs treated with gemcitabine, a novel antineoplastic agent, that was given for
hepatic relapse of a previously resected non-small cell lung cancer. The patient
developed acute respiratory failure after the sixth drug dose, and died 4 days
after admission. Autopsy revealed a pattern of DAD. No evidence of infection or
other specific aetiologies could be found. To our knowledge, only three cases of
pulmonary toxicity resulting from treatment with gemcitabine have been published;
two of them were fatal and postmortem examination revealed a pattern consistent
with acute respiratory distress syndrome. A careful survey may determine the
incidence of pulmonary toxicity of this new drug in the future.
PMID- 9551763
TI - Rapidly progressing pulmonary nodules in a 14 yr old boy.
PMID- 9551764
TI - Treatment of spontaneous pneumothorax--an ongoing debate.
PMID- 9551765
TI - Deramciclane, a putative anxiolytic drug, is a serotonin 5-HT2C receptor inverse
agonist but fails to induce 5-HT2C receptor down-regulation.
AB - Deramciclane (EGIS-3886) is a novel anxiolytic agent that binds with high
affinity to 5-HT2A/2C receptors. The interactions of deramciclane with the
serotonin 5-HT2C receptor were characterized further using receptor
phosphoinositide hydrolysis assays and receptor autoradiography. Deramciclane
antagonized 5-HT2C receptor mediated 5-HT-stimulated phosphoinositide hydrolysis
with an IC50 value of 168 nM. Deramciclane also decreased basal phosphoinositide
hydrolysis by up to 33% (EC50 = 93 nM) in a physiological system in the choroid
plexus, suggesting that deramciclane possesses inverse agonist properties at this
receptor. Administration of single doses of 0.5 mg/kg and 10 mg/kg resulted in a
maximal 5-HT2C receptor occupancy of up to 45% and 79%, respectively, in the
choroid plexus. Chronic (14 days) treatment with 0.5 mg/kg or 10 mg/kg
deramciclane did not alter [125I]DOI (agonist) or [3H]mesulergine (antagonist)
binding to 5-HT2C receptors in the choroid plexus compared to saline-treated
controls, as determined by quantitative receptor autoradiography. In comparison,
the effects of deramciclane on 5-HT2A binding characteristics and receptor
occupancy were also studied. Deramciclane treatment resulted in 5-HT2A receptor
occupancy of up to 78%, but no significant effect of chronic treatment on 5-HT2A
receptor agonist binding levels was found. In conclusion, these data indicate
that deramciclane is a 5-HT2C receptor inverse agonist and occupies 5-HT2C
receptors during treatment, and that chronic treatment with deramciclane does not
lead to 5-HT2C receptor down-regulation.
PMID- 9551766
TI - Interactions between intra-perifornical region sulpiride and intra-ventral
tegmental area AP5 on measures of locomotor activity and conditioned place
preference.
AB - Infusions of sulpiride, a dopamine D2/D3 receptor antagonist within the
perifornical region of the lateral hypothalamus have been shown previously to
exhibit a behavioural profile generally attributed specifically to activation of
the mesoaccumbens dopamine projection. Experiment 1 confirmed previous work
showing that repeated homecage pretreatment with sulpiride (5 microg) in the
perifornical region of the lateral hypothalamus resulted subsequently in an
enhanced locomotor response to a d-amphetamine challenge. Experiment 2 examined
the possibility that the observed behavioural changes were due to stimulation of
the mesoaccumbens dopamine projection via the ventral tegmental area. Thus,
repeated intra-perifornical infusions with sulpiride were without effect
initially, but resulted in a gradual increase in locomotor activity during
subsequent sessions. Intra-ventral tegmental area infusions of the NMDA receptor
antagonist AP5 (0.3, 1.0 nmol) were without intrinsic effect upon locomotor
activity at any time. However, AP5 blocked the ability of repeated sulpiride
infusions to increase locomotor activity, and the ability of intra-perifornical
sulpiride to support the acquisition of a conditioned place preference. AP5
sulpiride co-infusions also increased locomotor activity in a non-incremental
manner. These data suggest there to be a functionally significant projection from
the perifornical region of the lateral hypothalamus to the ventral tegmental area
in the control over locomotor activity and rewarded behaviour.
PMID- 9551767
TI - The effects of selected antidepressant drugs on timing behaviour in rats.
AB - It has been suggested that the increased reinforcement rate on a differential
reinforcement-of-low-rate of responding (DRL) schedule observed following acute
antidepressant administration in the rat is due to an improvement in timing
accuracy. The aim of the present work was to evaluate the effects of
antidepressants in another schedule that requires accurate estimation of time
intervals, the peak procedure. Three antidepressant drugs were tested, the
tricyclic antidepressant imipramine (1.0-10.0 mg/kg, i.p.) and the 5-HT reuptake
inhibitors, zimelidine (10.0-40.0 mg/kg, i.p.) and clomipramine (1.0-10.0 mg/kg,
i.p.). For reference, the full benzodiazepine receptor agonist, diazepam (1.0-5.0
mg/kg, i.p.) and the psychomotor stimulant, d-amphetamine (0.5-1.5 mg/kg, s.c.)
were also tested. All doses of d-amphetamine tested significantly increased lever
pressing rates, whereas all the other compounds induced significant decreases in
lever-pressing rates. Overall, the time at which the maximal lever-pressing rate
occurred was not altered by any of the compounds, suggesting that timing accuracy
was not significantly affected by any of the compounds administered. The only
exception was zimelidine (40.0 mg/kg), which reduced the time at which the
maximal lever-pressing rate occurred, although lever-pressing rates were also
significantly reduced at this dose. These data suggest that previously reported
antidepressant-induced improvement in performance on the DRL schedule may not
have been due to improved timing accuracy per se but may have been due to a
decrease in lever-pressing rates.
PMID- 9551768
TI - Effects of AMPA receptor antagonists on dopamine-mediated behaviors in mice.
AB - Current data indicate that dopaminergic and glutamatergic neurotransmitter
systems interact. The role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic
acid (AMPA) glutamate receptor subtypes in modulating dopamine neurotransmission,
however, remains unclear. The noncompetitive AMPA antagonists, GYKI 52466 (5-40
mg/kg) and LY300164 (1-6 mg/kg), and the competitive AMPA antagonists, LY326325
(5-80 mg/kg) and NBQX (10-80 mg/kg), were compared to the dopamine antagonist,
haloperidol (0.03-1.0 mg/kg), for their ability to inhibit dopamine-mediated
behaviors after i.p. administration in mice. The behavioral paradigms included
amphetamine- or dizocilpine-induced hyperactivity, amphetamine-induced
stereotyped sniffing, and apomorphine-induced climbing and stereotyped sniffing.
All four AMPA antagonists and haloperidol attenuated amphetamine- and dizocilpine
induced hyperactivity and decreased spontaneous locomotion. Haloperidol and GYKI
52466 were more potent against amphetamine than against dizocilpine. In contrast,
LY326325 was more potent against dizocilpine than against amphetamine. The
hyperactivity decreases by LY300164 and NBQX were most likely due to non-specific
effects on motor behavior. The AMPA antagonists and haloperidol also attenuated
amphetamine- induced stereotypy. Unlike haloperidol, however, GYKI 52466,
LY300164, and NBQX failed to attenuate apomorphine-induced climbing and
stereotyped sniffing. LY326325, on the other hand, attenuated apomorphine-induced
stereotypy, but not climbing. These results indicate that AMPA receptor
antagonists can attenuate the behavioral effects of drugs, such as amphetamine
and dizocilpine, that increase dopamine neurotransmission. However, the
behavioral effects of the direct dopamine agonist apomorphine are not
consistently attenuated by AMPA antagonists. The competitive AMPA receptor
antagonist LY326325 appears to have a profile distinct from both haloperidol and
the other AMPA antagonists tested.
PMID- 9551769
TI - Methamphetamine modulates GABA-induced electrophysiological depression by
alternating noradrenergic actions in cerebellar Purkinje neurons.
AB - Previous studies have indicated that gamma-aminobutyric acid (GABA)-induced
electrophysiological responses can be enhanced by noradrenaline (NE) acting via
beta-adrenergic receptors. Methamphetamine (MA) has been reported to be a
noradrenergic releasing agent. In the present study, we examined the interaction
of MA and GABA in cerebellar Purkinje neurons of urethane-anesthetized rats. We
found that local application of MA did not potentiate GABA-induced
electrophysiological depressions in Purkinje neurons. Since MA may act indirectly
or directly on alpha or beta noradrenergic receptors, we further examined the
interactions of MA with selective noradrenergic antagonists. We found that after
blocking alpha-adrenergic receptors with prazocin, MA significantly facilitated
GABA responses. On the other hand, co-administration of timolol with MA did not
attenuate GABA-induced neuronal depressions. To examine further the interactions
between alpha and beta receptors in modulating GABA response, we found that
stimulation of alpha-adrenergic receptors in the absence of beta receptor
activation, such as by application of the alpha-agonist phenylephrine alone, did
not decrease GABA-induced inhibition. However, stimulation of alpha-adrenergic
receptors in the presence of beta-receptor activation, such as by co-application
of phenylephrine and the beta-agonist isoproterenol (ISO), attenuated ISO
facilitated GABA inhibition. Taken together, these data suggest that MA may
activate two noradrenergic modulatory mechanisms: beta-adrenergic receptor
induced GABA potentiation and alpha-adrenergic inhibition, which attenuates beta
mediated modulation. In conclusion, our data suggest that MA may regulate GABA
induced electrophysiological response by altering both the alpha- and beta
noradrenergic inputs in cerebellar Purkinje neurons.
PMID- 9551770
TI - Further evaluation of the reinforcing effects of the novel cocaine analog 2beta
propanoyl-3beta-(4-tolyl)-tropane (PTT) in rhesus monkeys.
AB - 2Beta-propanoyl-3beta-(4-tolyl)-tropane (PTT) is a cocaine analog which has been
shown in rhesus monkeys to have cocaine-like discriminative stimulus effects and
a long duration of action (>8 h), yet does not function as a reinforcer when
substituted for cocaine in monkeys responding under a fixed-interval 5-min
schedule (Nader et al. 1997). The purpose of the present study was to evaluate
the reinforcing effects of PTT under a fixed-ratio (FR) schedule and to determine
if decreasing the inter-injection interval would influence the reinforcing
effects of PTT. Male rhesus monkeys (n=3) were trained to respond under a
multiple FR 30 food-drug-food schedule. When responding was stable, cocaine
(0.003-0.3 mg/kg per injection) or PTT (0.001-0.03 mg/kg per injection) was
available during the drug component for at least five consecutive sessions and
until stable responding was observed. To investigate whether the inter-injection
interval would influence PTT-maintained response rates, the time-out (TO)
following PTT injections was reduced from 180 or 300 s to 10 s for at least five
consecutive sessions. Cocaine-maintained response rates were characterized as an
inverted-U shaped function of dose, with peak rates maintained by 0.03 mg/kg per
injection cocaine. PTT (0.001-0.03 mg/kg per injection) maintained response rates
significantly higher than rates maintained by the PTT vehicle, but significantly
lower than cocaine-maintained response rates; PTT intake increased with a dose. A
reduction of the TO following PTT injections to 10 s did not alter PTT-maintained
response rates or total session intake. Self-administered PTT was more potent
than cocaine at decreasing food-maintained responding. These results suggest that
for long-acting compounds like PTT, reinforcing effects are more likely to be
observed when the drug is available under a ratio-based schedule, compared to an
interval-based schedule.
PMID- 9551771
TI - Anxiolytic activity of ginkgolic acid conjugates from Indian Ginkgo biloba.
AB - Ginkgolic acid conjugates (GAC) (6-alkylsalicylates, namely n-tridecyl-, n
pentadecyl-, n-heptadecyl-, n-pentadecenyl- and n-heptadecenylsalicylates)
isolated from the leaves of Indian Ginkgo biloba Linn., (IGb) were tested for
their putative role in anxiety in rats. Elevated plus maze, open-field behaviour,
novelty-induced feeding latency and social interaction were the rodent
behavioural models used in this study. GAC (0.3 and 0.6 mg/kg, each, p.o.) on
single acute administration, showed dose-related changes in the behaviour. GAC
(0.6 mg/kg) and DZ augmented open arm entries, the open arm/closed arm entries
ratio and increased time spent in the open arm on the elevated plus maze. In the
open field, GAC (0.6 mg/kg) and DZ significantly increased ambulation and reduced
the immobility time. EGb 761 showed a similar profile. GAC (0.6 mg/kg) and DZ
significantly attenuated the increased latency to feed in novel environment. By
contrast, EGb 761 and Ginkocer further augmented feeding latency. None of the
drugs tested showed any significant effect in the social interaction test. GAC
showed consistent and significant anxiolytic activity in all the variables
investigated. By contrast, EGb 761 and Ginkocer, which are devoid of GAC, did not
evoke significant activity. However, increased rearing and decreased immobility
time only in open field behaviour shown by EGb 761 may be due to some antianxiety
activity of a lesser degree. Our observations suggest that GAC may be the active
constituents of Ginkgo biloba responsible for the anxiolytic activity.
PMID- 9551773
TI - Strychnine effects on ultrasound-elicited behaviours in Lister hooded rats.
AB - Previous studies have demonstrated that Lister hooded rats will exhibit
characteristic bursts of locomotion when exposed to a 20-kHz acoustic stimulus;
this ultrasound-induced locomotion has been suggested as a potential model for
panic attacks. Although ultrasound presentation rarely induces convulsions, the
locomotor bursts exhibited resemble pre-convulsant running. The present studies
examined the interactions between strychnine treatment and experimenter-presented
ultrasounds on behaviour in male Lister hooded rats. Strychnine was selected
because it is a potent and effective convulsion-inducing agent which is not known
to induce anxiety in humans. Behaviour in a circular arena (75 cm diameter) was
observed live, videotaped and traced electronically. In experiments 1 and 2,
moderate (60 s) or relatively brief (15 s) exposure to an ultrasound stimulus (20
kHz, 98 dB, SPL) typically resulted in 5- to 10-s bursts of locomotion in saline
treated subjects; strychnine treatment (0.5, 0.7, 1.0 mg/kg, injected i.p., 10
min prior to testing) significantly increased this ultrasound-induced locomotion
in a dose-dependent manner. Experiment 3 demonstrated that the strychnine
enhancement of the ultrasound response was not different in naive animals when
compared to those subjects which had received occasional strychnine and/or
ultrasound treatment previously. Experiment 3 also demonstrated that strychnine
treatment can cause at least modest running in subjects exposed to a 2 kHz tone
(96 dB SPL). In experiment 4, exposure to the 20 kHz, 98 dB ultrasound stimulus
for a much longer period, 9 min, resulted in irregular cycles of bursts of
locomotion, followed immediately by periods of relative inactivity in saline
treated animals; approximately 10% of these subjects exhibited tonic-clonic
convulsions. No convulsions occurred in strychnine-treated subjects during the
period 10-20 min post-injection in the absence of ultrasound exposure; in
contrast, the frequency of occurrence of convulsions in strychnine-treated
subjects (10-20 min post-injection) exposed to the ultrasound stimulus was
greater than 50%; these convulsions typically occurred at the end of a locomotor
burst. The results of the present studies suggest that there may be a
relationship between ultrasound-induced locomotor bursts and convulsant activity.
PMID- 9551772
TI - Olanzapine increases in vivo dopamine and norepinephrine release in rat
prefrontal cortex, nucleus accumbens and striatum.
AB - The in vivo effects of olanzapine on the extracellular monoamine levels in rat
prefrontal cortex (Pfc), nucleus accumbens (Acb) and striatum (Cpu) were
investigated by means of microdialysis. Sequential doses of olanzapine at 0.5, 3
and 10 mg/kg (s.c.) dose-dependently increased the extracellular dopamine (DA)
and norepinephrine (NE) levels in all three brain areas. The increases appeared
30 min after olanzapine administration, reached peaks around 60-90 min and lasted
for at least 2 h. The highest DA increases in the Acb and Cpu were induced by
olanzapine at 3 mg/kg but at 10 mg/kg in the Pfc. The peak DA increase in the Pfc
(421% +/- 46 of the baseline) was significantly larger than those in the Acb
(287% +/- 24) and Cpu (278% +/- 28). Similarly, the highest NE increase in the
Pfc (414% +/- 40) induced by 10 mg/kg olanzapine was larger than those in the Acb
(233% +/- 39) and Cpu (223% +/- 24). The DA and NE increases in the Pfc induced
by olanzapine at 3 and 10 mg/kg (s.c.) were slightly larger than those induced by
clozapine at the same doses. In contrast, haloperidol (0.5 and 2 mg/kg, s.c.) did
not change Pfc DA and NE levels. Extracellular levels of a DA metabolite, DOPAC,
and tissue concentrations of a released DA metabolite, 3-methoxytyramine, were
also increased by olanzapine, consistent with enhanced DA release. However,
olanzapine at the three sequential doses did not alter the extracellular levels
of either 5-HT or its metabolite, 5-HIAA, in any of the three brain areas. In
conclusion, the present studies demonstrate that in the case of sequential dosing
olanzapine more effectively enhances DA and NE release in the Pfc than in the
subcortical areas, which may have an impact on its atypical antipsychotic
actions.
PMID- 9551774
TI - The effects of cigarette smoking on overnight performance.
AB - Fifteen healthy smokers and 15 non-smokers were enrolled into this study
investigating the effects of smoking on overnight performance. Subjects arrived
at the test centre at 1930 hours and were assessed at baseline (2000 hours) and
at 2200, 0000, 0200, 0400, 0600, and 0800 hours on a battery of tests (including
Critical Flicker Fusion, CFF; Choice Reaction Time, CRT; Compensatory Tracking
Task, CTT; Short Term Memory Task, STM; and the Line Analogue Rating Scale,
LARS). Results showed that the performance of the smokers was more consistent
with baseline measures than that of the non-smokers, which became more impaired
throughout the night on a number of tasks [CFF (P < 0.005), Total Reaction Time
(TRT, P < 0.05), CTT (P < 0.05) and the Reaction Time (RT) aspect of the CTT task
(P < 0.0005)]. The Recognition Reaction Time (RRT) aspect of the CRT task showed
that the performance of the non-smokers became more impaired from baseline (P <
0.005), while that of the smokers remained at baseline levels until 0400 hours,
when it deteriorated to become comparable to that of the non-smoking controls.
Subjective sedation ratings (LARS) resulted in comparable levels of impairment
for both study groups (P < 0.00005). Findings from the STM task failed to reach
significance. These data suggest that when performance is being measured
overnight, smokers show little or no impairment, whilst the performance of non
smokers showed performance decrements.
PMID- 9551775
TI - Cerebral effects of nicotine during cognition in smokers and non-smokers.
AB - For the smoker, nicotine has a positive effect on attention, cognition and mood.
Conversely, nicotine abstinence is characterized by uncomfortable psychological
effects such as impaired attention, but also irritability. We postulated that
nicotine exerts an effect on cerebral areas important for attention and mood.
Regional cerebral blood flow (rCBF), as an index for cerebral activity, was
measured in both smokers and non-smokers. They were scanned during performance of
a psychometric task with and without i.v. infusion of nicotine (1-methyl-2-[3
pyridyll] pyrrolidine). Nicotine induced rCBF decreases in the anterior cingulate
cortex and the cerebellum, and concomitant increases in the occipital cortex. The
changes were similar in nature and magnitude in smokers and non-smokers. Thus,
specific changes were induced in areas pertaining to the anterior attention
system and to higher order visual cortex. We conclude that these effects on
cerebral activity provide insights into the desired positive effects of nicotine
on cognition as well as the negative effects experienced during nicotine
abstinence.
PMID- 9551776
TI - Antidepressant behavioral effects by dual inhibition of monoamine reuptake in the
rat forced swimming test.
AB - Because of clinical interest in the effects of antidepressant drugs that exert
their effects on multiple neurotransmitter systems, the behavioral effects
produced by combined treatment with an SSRI (fluoxetine) with a selective
norepinephrine (NE; desipramine) or dopamine (DA) reuptake inhibitor (buproprion)
were examined in the forced swimming test (FST), a behavioral test in rodents
that predicts the clinical activity of antidepressants. Three additional
compounds with mixed activity as NE-5-HT reuptake inhibitors, milnacipran,
duloxetine and venlafaxine, were also examined. Desipramine and fluoxetine both
reduced immobility in the FST, but desipramine increased only climbing behavior,
whereas fluoxetine increased only swimming behavior. The combination of
fluoxetine with desipramine or bupropion increased both climbing and swimming
behaviors at certain doses, but higher doses of desipramine when combined with
fluoxetine replaced swimming behavior with climbing behavior. The mixed NE-5-HT
reuptake inhibitors milnacipran and duloxetine reduced immobility and increased
climbing behavior, but did not alter swimming. Venlafaxine reduced immobility and
increased swimming behavior, except at the highest dose tested (80 mg/kg), which
increased both swimming and climbing behaviors. Thus, combining certain doses of
pharmacologically selective monoamine reuptake inhibitors, or the mixed reuptake
inhibitor venlafaxine, produced a pattern of mixed active behaviors in the FST
(climbing and swimming) that may reflect the activity of multiple
neurotransmitters, especially the combination of enhanced 5-HT and DA activity.
The combination of higher doses of desipramine with fluoxetine, or compounds with
mixed activity at inhibiting NE and 5-HT reuptake, demonstrated effects similar
to those of desipramine alone and may reflect inhibition of the expression of
serotonergic antidepressant behavioral effects by selective NE reuptake
inhibitors.
PMID- 9551777
TI - Lack of effect of hydrocortisone treatment on d-fenfluramine-mediated prolactin
release.
AB - The prolactin responses to the serotonin (5-HT) releasing agent d-fenfluramine
(30 mg orally) were studied in 11 male normal volunteers after administration of
hydrocortisone (20 mg orally, twice daily for 10 days) using a double-blind,
placebo-controlled, cross-over design. While hydrocortisone treatment
significantly elevated 24-h urinary cortisol excretion, it did not lower the
prolactin response to d-fenfluramine. Plasma levels of d-fenfluramine and d
norfenfluramine were not altered by hydrocortisone treatment. These findings show
that following 10 days administration of hydrocortisone, the prolactin responses
to d-fenfluramine are not changed.
PMID- 9551778
TI - Double-blind placebo controlled trial of dextrose tablets and nicotine patch in
smoking cessation.
AB - In a placebo-controlled double-blind trial 308 smokers were individually randomly
allocated to one of four groups: 1) 3 g dextrose tablets and 15 mg nicotine
transdermal patch; 2) dextrose and placebo patch; 3) placebo tablets and nicotine
patch; 4) placebo tablets and placebo patch. Patients were scheduled to attend
weekly smokers clinic sessions starting 1 week before the quit date and continue
for 4 weeks after that date. The primary outcome variable was biochemically
verified abstinence at the final session, four weeks after the scheduled quit
date. The proportion of smokers abstinent in the four groups was as follows: 49%
dextrose plus active patch; 44% - dextrose plus placebo patch; 36% - placebo
tablet plus active patch; 30% - placebo tablet plus placebo patch. The difference
between the dextrose and placebo tablets (13%) was statistically significant (P <
0.01, one-tailed); the difference between the active and placebo patches (6%) was
not. There was no significant difference between the effect of the dextrose when
accompanied by active versus placebo patches. There was no significant effect of
dextrose on weight. The results suggest that dextrose supplementation to the diet
may be a cheap and simple aid to giving up smoking. Further research is now
needed to establish its long-term efficacy.
PMID- 9551779
TI - Synergistic effect of status epilepticus and ischemic brain injury on mortality.
AB - Ischemic brain injury (stroke) is a major cause of status epilepticus (SE). In
our database of 529 adult SE cases, acute or remote cerebrovascular accidents
(CVA) were a primary cause of SE for 41% of the patients overall and for 61% of
the elderly patients. SE in the setting of acute CVA has a very high mortality,
approaching 35%. The degree to which mortality can be attributed to the severity
of the underlying CVA etiology vs. the effect of SE has not been evaluated. To
address this issue, we prospectively studied patients with SE and acute CVA and
compared them to control populations with acute CVA alone or with SE and remote
CVA. The groups did not significantly differ with regard to age, sex, or
radiographic lesion size. Mortality was unrelated to lesion size in the CVA and
SE group. Overall, acute CVA and SE patients had an almost three-fold increase in
mortality compared to the CVA group and an eight-fold increase compared to the SE
and the non acute (remote) CVA group. Logistic regression analysis demonstrated a
statistically significant synergistic effect of SE and CVA on mortality. This is
the first study to document that the high mortality of SE and acute CVA is not
solely due to the severity of the underlying CVA etiology, but due to the
synergistic effect of combined injuries from SE and cerebral vascular ischemia.
PMID- 9551780
TI - Multivariable prediction of seizure outcome one year after resective epilepsy
surgery: development of a model with independent validation.
AB - PURPOSE: To identify predictors of seizure-outcome after epilepsy surgery and
validate the findings in an independent series of patients. To use the results to
develop a predictive model. METHODS: Sequential patients undergoing resective
surgery for medically intractable epilepsy were identified at Yale New Haven
Hospital (1987-1990, group 1) and Columbia Presbyterian Hospital (1991-1994,
group 2). Information about seizure outcome and predictors of outcome was
obtained from medical chart review. Good seizure-outcome was defined as having
been seizure-free for one year beginning with discharge from the hospital.
Multiple logistic regression was used to develop a model of predictors in group
1. It was then validated in group 2. RESULTS: There were 133 patients in group 1
and 81 in group 2. In a multivariable analysis, independent predictors of outcome
in group 1 were presence of mesial temporal sclerosis based on postsurgical
pathological analysis (MTS) (relative risk (RR) = 1.47), having a known
underlying etiology (RR = 1.32), and partial seizures only (RR = 1.17). In group
2, the findings for each factor were similar to those in group 1: MTS, RR = 1.49;
etiology, RR = 1.32; and partial seizures, RR = 1.24. Used in combination, these
three factors can identify patients with nearly a 100% chance of being seizure
free (all three factors present) versus less than a 50% chance (none of the three
factors present). CONCLUSIONS: With independent validation of the findings, we
can be reasonably certain that the three factors identified in this analysis are
meaningful and generalizable predictors of seizure outcome following epilepsy
surgery. Use of predictive models should be considered in future studies to
convert study results into clinically relevant statements about a particular
patient's likelihood of surgical success.
PMID- 9551781
TI - Vigabatrin enhances promoted release of GABA in neonatal rat optic nerve.
AB - Vigabatrin (gamma-vinyl GABA) is an antiepileptic drug and blocks GABA
transaminase activity resulting in elevations in cellular GABA levels in the
brain. Nipecotic acid (NPA) promotes release of GABA from neonatal optic nerve
astrocytes, resulting in a bicuculline-sensitive depolarization of the optic
nerve axons. The NPA-induced depolarization of vigabatrin-treated rats (100
mg/kg, i.p.) more than doubled, suggesting an elevation in free GABA levels; the
GABA transporter inhibitor, NO-711 reduced the depolarization. These results are
consistent with the known ability of vigabatrin to block the GABA degradation
enzyme GABA-transaminase, suggesting that vigabatrin elevates astrocytic GABA
levels, thereby favoring greater release of GABA through the GABA transporter.
PMID- 9551782
TI - Quality of life in epilepsy: comparison of four preference measures.
AB - Several specific and general measures are available for the assessment of overall
health related quality of life in epilepsy. Few of the commonly used measures
provide utility weights for use in cost-utility analyses. This study compares
four methods for measuring utility weights: time trade-off (TTO), standard gamble
(SG), 15D, end the EuroQol visual analog scale. All patients aged 18-67 years
with a diagnosis of epilepsy, who had been admitted to or attended the outpatient
clinic at a large county hospital 1987-1994, received a comprehensive
questionnaire. From 397 respondents, 82 patients were randomly selected. Most of
the 57 patients completing the study generally had well-controlled epilepsy, but
were still on anti-epileptic medication. Mean age was 44 years. Fourty-one
percent were male and 59% female. The resulting utility weights differed
considerably between the measures, both with regard to central tendency and
dispersion. Median utility scores: EuroQol visual analog scale 0.75, 15D 0.90,
TTO 0.98, SG 0.99. There was a good association between the EuroQol rating scale
and the 15D, and a moderate association between SG and TTO. These preference
instruments measure different aspects of health-related quality of life and thus
yield different results. Caution should be taken when interpreting cost-utility
studies, as results will depend on the choice of utility instrument.
PMID- 9551783
TI - Attenuation of kindling-induced decreases in NT-3 mRNA by thyroid hormone
depletion.
AB - The expression of neurotrophins is altered by amygdala kindled seizures. Because
thyroid hormone can regulate the transcription of neurotrophins, we asked whether
thyroid hormone regulates neurotrophin mRNA expression following amygdala
kindling. Rats with electrodes implanted in the basolateral nucleus of the
amygdala were either depleted of thyroid hormone or given excess thyroid hormone.
The rats were then kindled daily until they had one generalized seizure. The
brains were removed 4 h after the seizure and processed for in situ hybridization
of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and
neurotrophin-3 (NT-3) mRNAs. In non-kindled rats, thyroid hormone depletion
increased the levels of BDNF mRNA in the paraventricular nucleus of the
hypothalamus and the pituitary gland. NGF and NT-3 mRNA expression was not
altered. In addition, thyroid hormone manipulations had no effect on kindling or
on kindling-induced BDNF and NGF mRNA. However, the kindling-induced decrease in
NT-3 mRNA expression in the dentate gyrus granule cell layer was significantly
attenuated by thyroid hormone depletion. These effects were reversed by thyroid
hormone replacement. The results indicate that thyroid hormone plays a modulatory
role in the seizure-induced changes of NT-3 mRNA expression found in the dentate
gyrus.
PMID- 9551784
TI - Electroencephalographic and histological characteristics of a model of limbic
status epilepticus permitting direct control over seizure duration.
AB - Status epilepticus is a neurological emergency associated with substantial
morbidity and mortality. Experimental and clinical investigations suggest that
prolonged seizure activity is associated with injury to vulnerable neurons.
Compounds with neuroprotective properties may minimize such injury. Existing
methods of inducing experimental status epilepticus result in seizure activity of
variable duration and neuronal injury of variable degree. To minimize such
variability, status epilepticus may be stopped with anticonvulsants, but this
limits the ability to screen for independent neuroprotective properties. We have
developed a simple and reliable non-pharmacological model of limbic status
epilepticus in which the duration of status epilepticus is under direct
experimental control. Status epilepticus is induced by continuous, unilateral
hippocampal stimulation. Using this model, the degree of hippocampal pyramidal
cell injury varies in direct proportion to status epilepticus duration across a
range of 15-140 min. A progressive sequence of EEG changes unfolds with
increasing status epilepticus duration, resembling that seen in other models.
This model may serve as a reference against which the effects of potential
neuroprotective compounds can be studied.
PMID- 9551785
TI - A summary of mechanistic hypotheses of gabapentin pharmacology.
AB - Although the cellular mechanisms of pharmacological actions of gabapentin
(Neurontin) remain incompletely described, several hypotheses have been proposed.
It is possible that different mechanisms account for anticonvulsant,
antinociceptive, anxiolytic and neuroprotective activity in animal models.
Gabapentin is an amino acid, with a mechanism that differs from those of other
anticonvulsant drugs such as phenytoin, carbamazepine or valproate. Radiotracer
studies with [14C]gabapentin suggest that gabapentin is rapidly accessible to
brain cell cytosol. Several hypotheses of cellular mechanisms have been proposed
to explain the pharmacology of gabapentin: 1. Gabapentin crosses several membrane
barriers in the body via a specific amino acid transporter (system L) and
competes with leucine, isoleucine, valine and phenylalanine for transport. 2.
Gabapentin increases the concentration and probably the rate of synthesis of GABA
in brain, which may enhance non-vesicular GABA release during seizures. 3.
Gabapentin binds with high affinity to a novel binding site in brain tissues that
is associated with an auxiliary subunit of voltage-sensitive Ca2+ channels.
Recent electrophysiology results suggest that gabapentin may modulate certain
types of Ca2+ current. 4. Gabapentin reduces the release of several monoamine
neurotransmitters. 5. Electrophysiology suggests that gabapentin inhibits voltage
activated Na+ channels, but other results contradict these findings. 6.
Gabapentin increases serotonin concentrations in human whole blood, which may be
relevant to neurobehavioral actions. 7. Gabapentin prevents neuronal death in
several models including those designed to mimic amyotrophic lateral sclerosis
(ALS). This may occur by inhibition of glutamate synthesis by branched-chain
amino acid aminotransferase (BCAA-t).
PMID- 9551786
TI - Comparison of EEG, MRI and PET in reading epilepsy: a case report.
AB - The pathophysiological and neuroanatomical bases of reading epilepsy (RE) are
unclear. We performed video-EEG, high quality MRI and [11C]diprenorphine PET in a
patient with RE to detect structural and functional abnormalities. EEG showed
multifocal seizure onset bilaterally in temporal and fronto-central regions. MRI
was normal, whereas [11C]diprenorphine PET revealed peri-ictal opioid binding
decreases in both temporal lobes and the left frontal lobe. These findings
confirm that RE is due to abnormal activity in the network subserving reading.
PMID- 9551787
TI - Proconvulsant effects induced by pyridoxine in young rats.
AB - High doses of pyridoxine (vitamin B6) can be neurotoxic in adults. Effects of
intraperitoneally administered B6 (100, 250 and 400 mg/kg) were studied in 7, 12,
18 and 60 day old rats. B6 elicited epileptiform EEG discharges without any motor
correlate in all age groups. In contrast, motor seizures were rare, seen only in
18 day old rats (250 mg/kg of B6). Data indicate that in young rats, B6 may have
proconvulsant effects in doses relevant to those sometimes used in pediatric
neurology.
PMID- 9551788
TI - Affinity capillary electrophoresis: a physical-organic tool for studying
interactions in biomolecular recognition.
AB - Affinity capillary electrophoresis (ACE) is a technique that is used to measure
the binding affinity of receptors to neutral and charged ligands. ACE experiments
are based on differences in the values of electrophoretic mobility of free and
bound receptor. Scatchard analysis of the fraction of bound receptor, at
equilibrium, as a function of the concentration of free ligand yields the
dissociation constant of the receptor-ligand complex. ACE experiments are most
conveniently performed on fused silica capillaries using a negatively charged
receptor (molecular mass < 50 kDa) and increasing concentrations of a low
molecular weight, charged ligand in the running buffer. ACE experiments that
involve high molecular weight receptors may require the use of running buffers
containing zwitterionic additives to prevent the receptors from adsorbing
appreciably to the wall of the capillary. This review emphasizes ACE experiments
performed with two model systems: bovine carbonic anhydrase II (BCA II) with
arylsulfonamide ligands and vancomycin (Van), a glycopeptide antibiotic, with D
Ala-D-Ala (DADA)-based peptidyl ligands. Dissociation constants determined from
ACE experiments performed with charged receptors and ligands can often be
rationalized using electrostatic arguments. The combination of differently
charged derivatives of proteins - protein charge ladders - and ACE is a physical
organic tool that is used to investigate electrostatic effects. Variations of ACE
experiments have been used to estimate the charge of Van and of proteins in
solution, and to determine the effect of the association of Van to Ac2KDADA on
the value of pKa of its N-terminal amino group.
PMID- 9551789
TI - Dynamic complexation of solutes in capillary electrophoresis.
AB - The analyte migration behavior in any chemical separation system can be described
using a single equation that unifies all areas of separation science. This
equation can be used in capillary electrophoresis (CE) to design separation
systems, and to study interactions between analytes and additives. By using
individual capacity factors for each analyte species present in the system, and
with the knowledge of the characteristics of each interaction, one can predict
the analyte migration behavior in complicated CE systems, including systems with
multiple 1:1 interactions and/or higher order interactions.
PMID- 9551790
TI - The effects of a mixture of charged and neutral additives on analyte migration
behavior in capillary electrophoresis.
AB - Multicomponent additives, such as derivatized cyclodextrins with various degrees
of substitution, can be considered single-component additives as long as the
fraction of each component remains constant. In this paper, equations are derived
describing the effect of such additives on the migration behavior of analytes.
These equations are used in the study of capillary electrophoresis (CE) systems
with differentially charged cyclodextrins as additives. For weakly acidic
analytes, the binding with highly negatively charged sulfobutyl ether beta
cyclodextrin (SBE-beta-CD) increases their negative electrophoretic mobility,
while the binding with neutral hydroxypropyl-beta-cyclodextrin (HP-beta-CD)
decreases their negative mobility. By obtaining the equilibrium constants and
mobilities for each additive with each analyte (in this case, phenol, 2-naphthol
and 1-naphthol), the migration behavior of these analytes in CE systems is
quantitatively predicted at various concentrations of mixtures of the two
additives. The properties of the contour lines in the binding isotherm surfaces
of such CE systems are discussed.
PMID- 9551791
TI - Capillary affinophoresis of pea lectin with polyliganded affinophores: a model
study of divalent-polyvalent interactions.
AB - Affinophoresis is a type of affinity electrophoresis using an affinophore, a
soluble ionic carrier bearing affinity ligand(s). It was reported previously that
an affinophore, prepared by coupling multiple p-aminophenyl alpha-D-mannoside
ligands to a part of the carboxyl groups of succinylated polylysine, specifically
changed the mobility of pea lectin in agarose gel. The affinophoresis of this
divalent lectin with the polyliganded affinophore was investigated by using
capillary electrophoresis. Analysis of the mobility change of the lectin in the
presence of differently modified affinophores showed that the affinity was larger
for affinophores having higher ligand density. Analysis of the inhibition of the
mobility change by a neutral ligand, with a known affinity constant for the
lectin, allowed estimation of the contributions of monovalent and divalent
interactions to the binding in the lectin-affinophore complex. The proportion of
divalent complexes was greater for affinophores having higher ligand density.
This approach to estimate the contribution of divalency in complex formation
should be generally applicable to the analysis of divalent interactions with
different techniques other than electrophoresis.
PMID- 9551792
TI - On-line competitive immunoassay based on capillary electrophoresis applied to
monitoring insulin secretion from single islets of Langerhans.
AB - An automated on-line competitive immunoassay based on capillary electrophoresis
(CE) was utilized to monitor secretion of insulin from single islets of
Langerhans stimulated by glucose and tolbutamide. In the instrument, fluorescein
isothiocyanate-labeled insulin (FITC-insulin), monoclonal anti-insulin and
perifusate of single islets were mixed on-line while islets were exposed to
different levels of glucose and tolbutamide. Insulin released from single islets
competed with FITC-insulin for antibody binding sites. Therefore, the amounts of
bound and free FITC-insulin were modulated by insulin released from islets. The
bound and the free FITC-insulin were separated by CE every 3 s and the bound over
free ratio (B/F) was measured. Insulin levels were obtained by comparing B/F with
calibration curves obtained under the same conditions except that the islet
perfusate was replaced with various concentrations of insulin. Patterns of
insulin secretion stimulated by glucose and tolbutamide observed were comparable
to what has been seen previously using radioimmunoassay or enzyme-linked
immunoassay. This on-line competitive immunoassay system provided a fast and
direct way to measure insulin release from single islets. The effects of
temperature on antibody-antigen reaction rate and binding equilibrium were also
studied.
PMID- 9551793
TI - A diagnostic test for scrapie-infected sheep using a capillary electrophoresis
immunoassay with fluorescent-labeled peptides.
AB - Scrapie in sheep and goats is the prototype of transmissible spongiform
encephalopathies found in humans and animals. A feature of these diseases is the
accumulation of rod-shaped fibrils in the brain that form from an aggregated
protein. This protein (PrPSC) is a protease-resistant form of a normal host cell
protein. When the aggregated protein is denatured in sodium dodecyl sulfate (SDS)
and beta-mercaptoethanol, a monomer form of approximately 27 kDa molecular mass
is observed. A competition immunoassay to detect PrPSC from scrapie-infected
sheep was developed using free zone capillary electrophoresis with laser-induced
fluorescence (LIF) for detection and flourescein-labeled synthetic peptides from
PrPSC. Antibodies were made to each respective peptide and used in the
competition assay. The fluorescent-labeled peptides bound to the antibody were
separated from the unbound peptides using 200 mM Tricine, pH 8.0, containing 0.1%
n-octylglucoside and 0.1% bovine serum albumin (BSA). The amount of antibody that
would bind approximately 50% of the fluorescent-labeled peptide was determined
for each peptide. When unlabeled peptide was added to the assay, approximately 2
fmoles of the peptide could be measured. When PrPSC extracted from infected sheep
brain was added to the assay, approximately 135 pg of PrPSC could be detected.
When preparations from normal sheep were assayed, there was little or no
competition for the bound peptides. Assays using two of the peptides, peptides
spanning amino acid positions 142-154 and 155-178, clearly differentiated scrapie
positive sheep from normal animals. This assay is a new method that can be used
to diagnose scrapie and, possibly, other transmissible spongiform
encephalopathies in animals and in humans.
PMID- 9551794
TI - Affinity capillary electrophoresis investigation of an epitope on human
immunodeficiency virus recognized by a monoclonal antibody.
AB - Affinity capillary electrophoresis (ACE) has been used to investigate the epitope
on the human immunodeficiency virus (HIV) core protein p24 recognized by the
monoclonal antibody (mAb) 13-102-100. The affinity of a series of peptides with N
and C-terminal truncations of the epitope sequence determined by mass
spectrometry was studied. The peak area change assay was used for the study of
the interactions of the mAb with those peptides, exhibiting tight binding to the
mAb, and the migration time shift assay was used to probe the relative affinities
of peptides showing weak binding to the mAb. The experimental results show that
the monoclonal antibody 13-102-100 recognizes the peptide VHPVHAGPIAP with
highest affinity. Smaller peptides incorporating only part of the epitope,
however, are recognized to some extent in the ACE experiments.
PMID- 9551795
TI - Double enzyme-catalyzed microreactors using capillary electrophoresis.
AB - This work evaluates the concept of a double enzyme-catalyzed microreactor using
capillary electrophoresis (CE). Migrating in a capillary under electrophoresis
conditions, plugs of substrate and two enzymes are injected separately in buffer
and allowed to react. Extent of reaction and product ratios were subsequently
determined by CE. This concept is demonstrated using two model systems: the
conversion of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) and
adenosine monophosphate (AMP) by hexokinase (HK, EC 2.7.1.1) and apyrase (APY, EC
3.6.1.5), respectively, in the conversion of glucose to glucose-6-phosphate and
inorganic phosphate, respectively, and the conversion of nicotinamide adenine
dinucleotide, reduced form (NADH), to nicotinamide adenine dinucleotide (NAD) and
back to NADH by lactate dehydrogenase (LDH, EC 1.1.1.27) and glucose-6-phosphate
dehydrogenase (G6PDH, EC 1.1.1.49), respectively, in the conversion of pyruvate
to lactate and glucose-6-phosphate (glc-6-P) to 6-phosphogluconate, respectively.
These procedures illustrate the use of the capillary as a double microreactor and
the ease of quantitation of reaction products under conditions of
electrophoresis.
PMID- 9551796
TI - Affinity mode of capillary isoelectric focusing for the characterization of the
biotin-binding protein actinavidin.
AB - Different modes of capillary isoelectric focusing (CIEF) with salt mobilization
and zwitterionic additive to cathodic mobilizer were applied to characterize the
biotin-binding protein actinavidin and its affinity properties. The analysis is
performed in a neutral coated capillary with completely eliminated electroosmotic
flow. Synthetic pI standards with absorption in the visible region were used in
all runs and pI determinations were based on a fitted nonlinear calibration
graph. CIEF of highly purified actinavidin in native conditions was revealed in
about 12 peaks in pI range 6.2-7.5, with three major forms having pI 6.80, 6.86,
6.90. CIEF of a mixture of actinavidin and increasing concentrations of two
affinity ligands (biotin and biotinylated oligonucleotide) demonstrated drastic
changes in the number of protein isoforms. In the latter case it resulted in only
one peak (pI 5.05) when the ligand was in excess. This method, which can be named
affinity CIEF, was found to be well-suited for studying structural changes,
occurring in receptor proteins upon binding with a ligand. CIEF of the protein,
performed under denaturing conditions (6 M urea in a solution of carrier
ampholytes) is also reported. It was revealed in three isoforms with a pI more
acidic than that of native actinavidin. It is demonstrated that careful selection
of denaturing conditions was necessary for the reproducible results.
PMID- 9551797
TI - Base-specific separation of oligodeoxynucleotides by capillary affinity gel
electrophoresis.
AB - Capillary affinity gel electrophoresis was applied to sequence-specific and base
composition-specific recognition of oligodeoxynucleotides, utilizing the
formation of heteroduplexes between a nucleic acid analogue immobilized into the
capillary gel and soluble oligodeoxynucleotides with different sequences.
Capillary affinity gel electrophoresis using capillaries filled with a conjugated
gel of polyacrylamide and a synthetic nucleic acid analogue [poly(9
vinyladenine)] was effective for the selective separation of hexathymidylic acid
from a mixture of four homopolymers of A6, C6, G6, and T6 and for the complete
resolution of five heteropolymers of hexadeoxynucleotides (TAAAAA, TTAAAA,
TTTAAA, TTTTAA, TTTTTA). We also demonstrated that capillary affinity gel
electrophoresis was useful for the selective and the sensitive sequence-specific
recognition of sequence isomers of DNA (TTTTAA, TTTTAAT, TTTATA, and TTTTAA).
PMID- 9551798
TI - Affinity capillary electrophoresis employing immobilized glycosaminoglycan to
resolve heparin-binding peptides.
AB - A new capillary electrophoresis technique has been developed for the affinity
resolution of synthetic heparin-binding peptides using an immobilized
glycosaminoglycan. Heparin and heparan sulfate were immobilized onto fused silica
capillaries using biotin-neutravidin conjugation. These capillaries exhibited
markedly reduced electroosmotic flow and were able to distinguish peptides based
on the heparin binding domain of acidic fibroblast growth factor (residues 125
144, GLKKNGSCKRGPRTHYGQKA) that differed only in the stereochemistry of the
proline amino acid residue. The peptide based on the native sequence was retarded
compared to the peptide having unnatural stereochemistry, consistent with its
stronger interaction for immobilized glycosaminoglycan. Improved resolution is
also obtained for additional arginine and lysine containing heparin-binding
peptides.
PMID- 9551799
TI - A heparin-binding peptide from human serum amyloid P component characterized by
affinity capillary electrophoresis.
AB - Affinity capillary electrophoresis (CE) was used for a detailed characterization
of the binding between heparin and a peptide isolated from the heparin-binding
serum protein amyloid P component (SAP). The peptide corresponds to a tryptic
fragment (T3) comprising amino acids 14-38 of SAP. By including ligands in the
electrophoresis buffer various glycosaminoglycans could be screened for binding
of T3 using one sample aliquot. The binding was found to be highly specific for
heparin and heparin fragments down to tetramers and appeared strongest at a
slightly alkaline pH while no binding could be demonstrated with heparan sulfate,
chondroitin sulfate, desulfated heparin, mannose 6-phosphate and phosphotyrosine.
The T3-heparin complexes were sufficiently stable to perform quantitative
measurements of the binding using preequilibration of samples prior to a CE
mediated separation of bound and free T3-peptide. Plots based on quantitation of
analyte peaks corresponding to free and complexed T3 yielded a dissociation
constant of 1.5 microM for the interaction with heparin. The results indicate
that a specific subfraction of the heparin molecules is active in binding
interactions with the peptide. The affinity CE approach proved to be useful for
these studies because of its sensitivity to complex formation involving charged
ligands and the possibility of achieving separations under native conditions.
Also advantageous is the low sample consumption and the ability to analyze
unlabeled reactants in solution.
PMID- 9551800
TI - Using capillary electrophoresis/frontal analysis to screen drugs interacting with
human serum proteins.
AB - We have used capillary electrophoresis in the frontal analysis mode (CE/FA) to
determine the binding capacity of beta-adrenoceptor blocking drugs to individual
serum proteins, serum protein mixtures and human serum. The free drug
concentration was directly measured from the height of the frontal peak and used
to calculate the bound drug concentration. From the bound drug concentration, the
percentage of drug bound to the serum proteins alpha1-acid glycoprotein (AGP) and
human serum albumin (HSA) was then determined. In addition to determining the
percent of a drug bound to a protein, the drug-protein association constant (Ka)
was determined for AGP binding to beta-blockers. The data-estimated association
constants were consistent with literature values. The CE/FA studies on the beta
adrenoceptor blocking drugs and the serum proteins indicated that HSA, AGP, high
density lipoprotein (HDL), and low density lipoprotein (LDL) were the main
contributors to serum binding for this series of compounds. The serum-drug
binding data sorted the beta-adrenoceptor blocking drugs into high and low
binding categories. The protein mixture (AGP + HSA + HDL + LDL) resulted in
dividing the beta-blockers into the same high/low rankings. The protein mixture
(AGP + HSA + HDL + LDL) was amenable to automation, did not autoaggregate, and
had constant concentrations for the proteins.
PMID- 9551801
TI - Separation of the enantiomers of ibuprofen and its major phase I metabolites in
urine using capillary electrophoresis.
AB - A capillary electrophoresis method for determination of the enantiomers of
ibuprofen and its major phase I metabolites: 2'-hydroxyibuprofen and 2'
carboxyibuprofen in urine samples have been developed. Cyclodextrins and linear
dextrins have been investigated as chiral selectors. Simultaneous chiral
separation of the enantiomers of ibuprofen, 2'-hydroxyibuprofen and 2'
carboxyibuprofen was obtained using a mixture of dextrin 10 and heptakis (2,3,6
tri-O-methyl)-beta-cyclodextrin in a 2-[N-morpholino]ethanesulphonic acid buffer,
pH 5.26. The electroosmotic flow was reversed using hexadimethrine bromide as a
buffer additive. The method can be used for the determination of the free
enantiomers of ibuprofen, 2'-hydroxyibuprofen and 2'-carboxyibuprofen as well as
for the indirect determination of their glucuronic acid conjugates in urine
samples.
PMID- 9551802
TI - Exploitation of a monoclonal antibody for weak affinity-based separation in
capillary gel electrophoresis.
AB - Weak biospecific recognition has been established for affinity separation in high
performance liquid chromatography (HPLC). The use of weak affinity chromatography
(WAC) has been limited previously by the insufficient separation efficiency
achieved, allowing only some 1000 plates/m to be obtained. However, it has been
shown that chiral drug separation can be performed with capillary affinity gel
electrophoresis (CAGE) at considerably improved efficiency as compared with
traditional chromatographic procedures. Our present study demonstrates the
potential of weak affinity monoclonal antibodies as a generic method for
immunologically based separations in capillary electrophoresis. Monoclonal
antibodies were polymerized within a silica capillary and were used for the
separation of structurally similar carbohydrate antigens. The results indicate
that weak biospecific interactions can be utilized in a CAGE format to produce
highly selective separation of the alpha- and beta-forms of p-nitrophenyl-labeled
maltose. It remains to be seen, however, how efficient weak affinity separation
in CAGE can be compared with affinity HPLC protocols. Details of typical
separations and of the preparation of the antibody gel are presented.
PMID- 9551803
TI - Determination of rat liver triglycerides by gas-liquid chromatography and
reversed-phase high-performance liquid chromatography.
AB - Rats fed with a fat-free or an olive oil-rich diet were employed to compare the
response of two chromatographic techniques in the determination of rat liver
triglyceride (TG) molecular species composition. Gas-liquid chromatography (GLC)
on polarizable liquid phase and reversed-phase high-performance liquid
chromatography (RP-HPLC) have been commonly employed for TG analysis, obtaining a
similar number of chromatographic peaks when used for animal tissue TG
determination. In the present study similar results were achieved with regard to
most relevant chromatographic peaks, however, important differences were found in
the content of minor TGs. Indeed, RP-HPLC permitted separation of long chain
polyunsaturated fatty acids, which were not detected by GLC, while the latter
technique reported a higher number of myristoyl-containing TG species. RP-HPLC
analysis reported a greater number of TGs, with more similarity to a random
composition, made up from the liver fatty acid composition. Therefore, it was
concluded that utilization of both techniques would be helpful for liver TG
analysis as the use of only one of them does not provide a complete profile of
liver TGs. Nevertheless RP-HPLC seems to be more useful for this purpose since
revealed a more extensive profile.
PMID- 9551804
TI - Simultaneous determination of tetrahydrocortisol and tetrahydrocortisone in human
plasma and urine by stable isotope dilution mass spectrometry.
AB - A capillary gas chromatographic-mass spectrometric method for the simultaneous
determination of tetrahydrocortisol (THF, 3alpha,11beta,17alpha,21-tetrahydroxy
5beta-preg nane-20-one), allo-tetrahydrocortisol (allo-THF,
3alpha,11beta,17alpha,21-tetrahydroxy-5alpha-pre gnane-20-one) and
tetrahydrocortisone (THE, 3alpha,17alpha,21-trihydroxy-5beta-pregnane-11,20-dion
e) in human plasma and urine is described. [1,2,3,4,5-2H5]THF (THF-d5), allo
[1,2,3,4,5-2H5]THF (allo-THF-d5) and [1,2,3,4,5-2H5]THE (THE-d5) were used as
internal standards. A double derivatization
(bismethylenedioxypentafluoropropionate, BMD-PFP) made possible the separation of
the three tetrahydrocorticoids with good gas chromatographic behavior.
Quantitation was carried out by selected-ion monitoring of the characteristic
fragment ions ([M-30]+) of the BMD-PFP derivatives of THF, allo-THF and THE. The
sensitivity, specificity, precision and accuracy of the method were demonstrated
to be satisfactory for measuring low concentrations of THF, allo-THF and THE in
human plasma and urine.
PMID- 9551805
TI - Simultaneous determination of glucocorticoids in plasma or urine by high
performance liquid chromatography with precolumn fluorimetric derivatization by 9
anthroyl nitrile.
AB - A new method for simultaneous determination of glucocorticoids (GCs) in plasma or
urine by high-performance liquid chromatography (HPLC) with fluorimetric
detection has been developed. Following extraction with ethyl acetate using a
reversed-phase disposable cartridge, the six GCs [cortisol (F), cortisone (E),
prednisolone (PL), prednisone (PN), 6beta-hydroxycortisol (6beta-OHF) and 6beta
hydroxyprednisolone (6beta-OHP)] and an internal standard (6beta
hydroxycotortisone) were derivatized by treatment with 9-anthroyl nitrile (9-AN)
in a mixture of basic catalysts (triethylamine and quinuclidine) to give the
fluorescent esters through the 21-hydroxyl group. The GC derivatives so obtained
were then cleaned by a straight-phase disposable cartridge and chromatographed on
a straight-phase column with an isocratic HPLC technique. The fluorescence
derivatives of the GCs, including the internal standard, were separated as clear
single peaks and no interfering peaks were observed on the chromatograms. The
lower limits of detection for F, E, PL and PN in plasma or urine were 0.1 ng/ml
and those for 6beta-OHF and 6beta-OHP in plasma or urine were 0.5 ng/ml, at a
signal-to-noise ratio of 3. The analytical recovery of known amounts of the GCs
added to plasma or urine were almost 100%. This method can be applied to the
determination of plasma or urinary F in renal transplant patients who received PL
and can be applied for other metabolic investigations in relation to the change
in blood pressure via 11beta-hydroxysteroid dehydrogenase or in hepatic
metabolizing via CYP3A4.
PMID- 9551806
TI - Ethyl acetate extraction procedure and isocratic high-performance liquid
chromatographic assay for testosterone metabolites in cell microsomes.
AB - An isocratic reversed-phase high-performance liquid chromatography (HPLC) method
was developed and validated for separation of testosterone and its main
metabolites over the nominal range 20 to 40 microg/ml and 280 to 4600 ng/ml,
respectively. Mobile phase composition (phosphate buffer-methanol-acetonitrile,
50:38.5:11.5) was optimised by studying the influence of numerous chromatographic
parameters. The most critical one was the ratio CH3CN/CH3OH. Good recoveries
(around 90% for all compounds) and an improved specificity were assessed by a
double ethyl acetate extraction of biological samples. According to the
performance criteria tested, the method could be applied to enzymatic inhibition
and induction in vitro studies.
PMID- 9551807
TI - Study of factors affecting the determination of total plasma 7-fluorobenzo-2-oxa
1,3-diazole-4-sulfonate (SBD)-thiol derivatives by liquid chromatography.
AB - A detailed investigation of the factors affecting the determination of total
plasma 7-fluorobenzo-2-oxa-1,3-diazole-4-sulfonate (SBD)-thiol derivatives (i.e.
cysteine, homocysteine and cysteinylglycine) is described. Essentially, this
assay entails extracting specific thiols by plasma disulphide bond reduction,
protein precipitation, sulphydryl compound derivatization with the thiol-specific
fluorogenic reagent ammonium 7-fluorobenzo-2-oxa-1,3-diazole-4-sulphonate (SBD
F), and subsequent separation with isocratic reversed-phase high-performance
liquid chromatography. By improving the reliability of several analytical
parameters (composition of the mobile phase, pretreatment of the sample using
different reducing and protein precipitation agents, and optimization of the
derivatization of thiols with SBD-F), a number of critical issues can be
identified and solved.
PMID- 9551808
TI - Mimetic ligand-based affinity purification of immune complexes and
immunoconjugates.
AB - We developed a simple purification method to purify alkaline phosphatase/anti
alkaline phosphatase IgG as immune complexes using mimetic affinity
chromatography wherein the antibody was either a monospecific antibody, a
bispecific antibody or a commercial polyclonal IgG conjugated with alkaline
phosphatase (AP-IgG) covalently. The immune complexes or conjugates were
efficiently bound on the mimetic Blue A6XL column and eluted under mild
conditions (5-20 mM phosphate buffer). A similar strategy of purifying
peroxidase/anti-peroxidase antibody complexes was also successfully demonstrated
using the mimetic Red 3 column. Mimetic affinity chromatography thus appears to
be a simple method to purify the desired monospecific or bispecific antibodies
from the respective hybridomas and quadromas.
PMID- 9551809
TI - Quantitative analysis of polychlorinated biphenyls, organochlorine insecticides,
polycyclic aromatic hydrocarbons, polychlorinated hydrocarbons and
polynitrohydrocarbons in spiked samples of soil, water and plasma by selected-ion
monitoring gas chromatography-mass spectrometry.
AB - A broad range of pollutants such as polycyclic aromatic hydrocarbons (PAHs),
polychlorinated hydrocarbons (PCHs), polynitrohydrocarbons (PNHs),
polychlorinated biphenyls (PCBs) and organochlorine (OCs) insecticides were
simultaneously analyzed in spiked soil, water or plasma samples by using gas
chromatography-mass spectrometry (GC-MS). Water and plasma samples containing the
pollutants were extracted by a solid-phase extraction (SPE) method using florisil
columns. The soil samples, fortified with the toxicants, were extracted with
water, methanol or dichloromethane (DCM). The water extract was processed by the
SPE method. The methanol and DCM samples were dried, dissolved in acetonitrile
and subjected to the SPE extraction. The extracted samples were analyzed by GC-MS
programmed to monitor selected ions. The deuterium labelled compounds were used
as the internal standards. The chromatographic profile of total ions indicated
complete separation of some compounds such as isophorone, naphthalene, all PCBs,
most OC insecticides and PNHs; high Mr PAHs and some PCHs were partially or
incompletely separated. The chromatographic profile of individual ion indicated
good separation of each ion. The minimum detection limit ranged from 1 to 4 pg
injected when 1 or 2 ions were monitored or from 20 to 200 pg injected when 20
ions were monitored. The SPE method that provided 60-105% recovery of pollutants
from water samples, provided only 2-60% recovery from plasma samples. This may be
due to the binding of pollutants to plasma proteins. Water recovered 1-30%, while
methanol or DCM recovered 65-100% of the pollutants added to the soil samples.
The use of internal standards corrected for the loss of pollutants from plasma or
soil.
PMID- 9551810
TI - Short column gas chromatography-mass spectrometry and principal component
analysis for the identification of coeluted substances in doping control
analysis.
AB - The identification of four doping control substances in an artificial mixture,
using short column gas chromatography-mass spectrometry (GC-MS) analysis was
examined. Two chromatographic peaks were recorded in the chromatogram, using a
short capillary column (1.8 m) at an oven temperature of 180 degrees C. The first
peak was associated with a mixture of a solvent derivative and an artifact. The
second one corresponded to the mixture of four control substances. Principal
component analysis was applied on a selected GC-MS data set of the latter peak to
determine clear full spectra of pure substances from mixture spectra. The time of
GC-MS analysis was significantly reduced to less than 1 min from 30 min which is
a typical GC-MS analysis time, using standard methods of doping control analysis.
PMID- 9551811
TI - Automated preparation and analysis of barbiturates in human urine using the
combined system of PrepStation and gas chromatography-mass spectrometry.
AB - A system for an automatic sample preparation procedure followed by on-line
injection of the sample extract into a gas chromatography-mass spectrometry (GC
MS) system was developed for the simultaneous analysis of seven barbiturates in
human urine. Sample clean-up was performed by a solid-phase extraction (SPE) on a
C18 disposable cartridge. A SPE cartridge was preconditioned with methanol and
0.1 M phosphate buffer. After loading a 1.5 ml volume of a urine sample into the
SPE cartridge, the cartridge was washed with 2.5 ml of methanol-water (1:9, v/v).
Barbiturates were eluted with 1.0 ml of chloroform-isopropanol (3:1, v/v) from
the cartridge. The eluate (1 microl) was injected into a GC-MS system. The
calibration curves, using an internal standard method, demonstrated a good
linearity throughout the concentration range from 0.02 to 10 microg/ml for all
barbiturates extracted. The proposed method was applied to several clinical
cases. The total analysis time for 20 samples was approximately 14 h.
PMID- 9551812
TI - Determination of 22-oxacalcitriol, a new analog of 1alpha,25-dihydroxyvitamin D3,
in human serum by liquid chromatography-mass spectrometry.
AB - A sensitive and specific liquid chromatographic-mass spectrometric assay has been
developed for the determination of 22-oxacalcitriol (OCT), which is a new analog
of 1alpha,25-dihydroxyvitamin D3. The analyte was isolated from serum by two
solid-phase extraction steps on a C18 cartridge and NH2 cartridge. The recovery
of OCT through two extraction steps was more than 90%. A related substance (ED
94), i.e. OCT with the side-chain shortened by one carbon, was used as an
internal standard. Extracts were chromatographed on a C18 reversed-phase column
interfaced to the electrospray ionization source. The mass spectrometer was
operated in the positive-ion mode of selected reaction monitoring. The
chromatographic run-time for one injection was less than 6 min. The intra- and
inter-assay coefficients of variation for the lowest concentration examined (30
pg ml[-1]) were 9.83 and 10.67, respectively. And the analytical recovery of OCT
added to serum was quantitative. Assay linearity was obtained in the range of 20
640 pg ml(-1).
PMID- 9551813
TI - Determination of sulfonamide antibiotics by gas chromatography coupled with
atomic emission detection.
AB - The paper describes the analysis of nine sulfonamides, chosen as the most widely
used representatives of an important class of antibacterial drugs. Atomic
emission detection has been found to allow simultaneous quantification and
identification of the N1-methylated derivatives, which are resolved efficiently
by conventional capillary gas chromatography. Results are given concerning the
linearity of the response and the characterization of the individual compounds by
the elemental ratio of their carbon, nitrogen and sulfur content. The method
looks promising for the quantitative analysis and confirmation of sulfonamide
residues in complex mixtures.
PMID- 9551814
TI - Reversed-phase ion-pair chromatographic analysis of tetracycline antibiotics.
Application to discolored teeth.
AB - A high-performance liquid chromatographic method with diode array detection was
developed to simultaneously separate tetracycline antibiotics and applied to the
analysis of discolored teeth. By a reversed-phase ion-pair chromatographic system
using pentanesulfonate as a counter ion, minocycline, oxytetracycline,
tetracycline and demeclocycline were eluted in this order, and they showed base
line separation within 9 min. When using oxytetracycline as an internal standard,
the quantitative ranges were between 2.5 ng/ml and 7.5 microg/ml. Powdered
dentine (10 mg) and enamel (40 mg) prepared from discolored primary teeth were
sonicated in 0.25 ml of 10 mM HCl containing oxytetracycline (0.75 microg/ml) and
50 mM EDTA-2Na, thereafter the supernatants were chromatographed. Eluates from
both discolored tooth samples were identified as minocycline based on diode array
spectra of their peaks, while minocycline was not detected in any samples from
nondiscolored normal teeth, indicating that discoloration of the tested teeth was
due to minocycline incorporated into dentine and enamel. Replicate quantitative
analyses of the identical tooth substances showed that intra- and inter-assay
C.V.s were 2.63 and 4.95% for dentine, and 5.42 and 10.88% for enamel.
Application of the developed method to nine discolored teeth revealed that the
incorporated minocycline ranged from 20.13 to 84.62 ng/mg of dentine and 0.89 to
7.87 ng/mg of enamel.
PMID- 9551815
TI - Quantitative analytical methods for the determination of a new hypertension drug,
CGS 25462, and its metabolites (CGS 25659 and CGS 24592) in human plasma by high
performance liquid chromatography.
AB - Two simple and sensitive reversed-phase high-performance liquid chromatography
(HPLC) methods were developed and validated for the quantitative determination of
a novel hypertension drug CGS 25462 and its major metabolites CGS 24592 and CGS
25659 in human plasma. CGS 25462 and CGS 25798 (internal standard) were purified
by one-step liquid-liquid extraction with methylene chloride. The metabolites
were analyzed on HPLC after plasma protein precipitation with 10% trichloroacetic
acid (TCA). Separations were achieved on a Zorbax RX C18 column. All compounds
were detected by using a fluorescence detector. The excitation wavelength was 254
nm, and emission was monitored at 325+/-12.5 nm. Assessment of recovery and
reproducibility indicated good accuracy and precision. Over the validation
concentration range of 10 to 1000 ng/ml for CGS 25462 and 25 to 5000 ng/ml for
both metabolites, overall mean relative recoveries were 96% for CGS 25462, 101%
for CGS 25659 and 107% for CGS 24592, and the coefficients of variation were 4.6
to 13% for CGS 25462, 9.5 to 13% for CGS 25659 and 7.7 to 15% for CGS 24592. The
limits of quantification (LOQs) were 10 ng/ml for CGS 25462 and 25 ng/ml for CGS
24592 and CGS 25659, which were of sufficient sensitivity to measure the
concentrations of CGS 25462, CGS 25659 and CGS 24592 in plasma samples from
normal volunteers following a single 800 mg oral dose.
PMID- 9551816
TI - High-performance liquid chromatographic determination of modafinil and its two
metabolites in human plasma using solid-phase extraction.
AB - A simple procedure for the simultaneous determination of modafinil, its acid and
sulfone metabolites in plasma is described. The assay involved an extraction of
the drug, metabolites and internal standard from plasma with a solid-phase
extraction using C18 cartridges. These compounds were eluted by methanol. The
extract was evaporated to dryness at 40 degrees C under a gentle stream of
nitrogen. The residue was redissolved in 250 microl of mobile-phase and a 30
microl aliquot was injected via an automatic sampler into the liquid
chromatograph and eluted with the mobile-phase (26%, v/v acetonitrile in 0.05 M
orthophosphoric acid buffer adjusted to pH 2.6) at a flow-rate of 1.1 ml/min on a
C8 Symmetry cartridge column (5 microm, 150 mm x 3.9 mm, Waters) at 25 degrees C.
The eluate was detected at 225 nm. Intra-day coefficients of variation ranged
from 1.0 to 2.9% and inter-day coefficients from 0.9 to 6.1%. The limits of
detection and quantitation of the assay were 0.01 microg/ml and 0.10 microg/ml
respectively.
PMID- 9551817
TI - Determination of propofol in low-volume samples by high-performance liquid
chromatography with fluorescence detection.
AB - In order to determine propofol in rat whole-blood samples of 50 microl, we
developed a rapid, simple and reliable method which is characterized by
precipitation of blood elements with acetonitrile and submission of the
supernatant to HPLC analysis with fluorescence detection. The method described is
linear from 0.4 to 40 mg/l and the relative standard deviations in this
concentration range are less than 10%. The limit of quantification proved to be
0.4 mg/l. Blood constituents do not interfere with the assay.
PMID- 9551818
TI - Development and validation of a sensitive method for the determination of
ganciclovir in human plasma samples by reversed-phase high-performance liquid
chromatography.
AB - A rapid, sensitive, specific liquid chromatographic method has been developed for
the determination of therapeutic levels of ganciclovir in human plasma. Plasma (1
ml) and acyclovir (I.S.) were treated with 50% trichloroacetic acid. The
supernatant was neutralized with 2 M NaOH and purified with chloroform. The
aqueous phase (80 microl) was analyzed by a 3-microm Hypersil ODS C18 column with
0.04 M triethylamine-0.1 M sodium dihydrogen phosphate monohydrate as the mobile
phase (1 ml/min) and ultraviolet detection at 254 nm. Calibration was linear from
50 to 10000 ng/ml. Intra- and inter-day C.V. did no exceed 6.65%. The detection
limit was about 10 ng/ml.
PMID- 9551819
TI - Quantification of pyrazinamide and its metabolites in plasma by ionic-pair high
performance liquid chromatography. Implications for the separation mechanism.
AB - Pyrazinamide, the amide of pyrazinoic acid, is one of the basic therapeutic
agents currently used in combination for chemotherapy of tuberculosis. A reversed
phase high-performance liquid chromatography method based on ionic pair
chromatography, was developed after solid-phase extraction of the analytes from
plasma with prior addition of internal standard. The main metabolites, pyrazinoic
acid, 5-hydroxypyrazinoic acid and 5-hydroxypyrazinamide, were included as well
as uric acid and other purine derivatives to allow detailed study of the
pharmacokinetics of the drug, especially in patients with impaired kidney
function. Some interesting features of the chromatographic system giving some
insight in the retention mechanism and of the solid-phase extraction are
discussed in detail.
PMID- 9551820
TI - Determination of salicylic acid in human serum with capillary zone
electrophoresis.
AB - The determination of salicylic acid (SA), a metabolite of aspirin, in human serum
was developed using capillary zone electrophoresis (CZE) with diode array
detection. The reproducibility of separation and quantification with CZE analysis
of the extract of SA from human serum was appropriate for the intra- and inter
day assay coefficients. A high correlation was revealed between the serum SA
levels in volunteers determined by CZE and those determined by a fluorescence
polarization immunoassay (r=0.973, n = 12), although the former values were
slightly higher than the latter. There were no peaks interfering with the assay
of SA by internal standard method. This CZE method could provide a simple and
efficient method for monitoring SA in patients.
PMID- 9551821
TI - Capillary gas chromatographic analysis of serum bile acids as the n-butyl ester
trimethylsilyl ether derivatives.
AB - Gas chromatographic separations of n-butyl ester-trimethylsilyl ether derivatives
of several common bile acids were compared with those of the corresponding methyl
ester-trimethylsilyl ether derivatives on a CP-Sil-5 CB capillary column. Both
types of derivatives were similarly resolved from each other. However, the n
butyl ester-trimethylsilyl ether derivatives of the bile acids showed longer
retention times than the corresponding methyl ester-trimethylsilyl ethers and
unlike the methyl ester-trimethylsilyl ether derivatives, were completely
resolved from and eluted later than the trimethylsilyl ethers of common plasma
sterols including sitosterol. A simplified method of plasma work-up for
quantitation of bile acids and application of the above method in quantification
of plasma bile acids in humans is described.
PMID- 9551822
TI - Determination of allantoin in bovine milk by high-performance liquid
chromatography.
AB - Determination of allantoin in bovine milk based on high-performance liquid
chromatography (HPLC) is described. Following dilution and filtration, milk
samples were analysed directly. Separation and quantification of allantoin was
achieved using a Spherisorb 5 NH2 column (250 x 4.6 mm ID), acetonitrile-water
(90:10, v/v) mobile phase at a flow-rate of 2.0 ml min(-1), temperature 20
degrees C and monitoring the effluent at 214 nm. Total analysis time was 10 min.
Recovery of allantoin added to milk was 97 (+/-3.7, n = 30)%. Lowest detectable
concentration was 1 micromol l(-1). Within-day and between-day variability were
less than 3%. Advantages of improved retention and separation of allantoin, and
less complicated sample preparation exist over current methods.
PMID- 9551823
TI - Measurement of serum nitrite/nitrate concentrations using high-performance liquid
chromatography.
AB - Previous studies have reported increased serum concentrations of nitrite/nitrate
the degradation products of nitric oxide - in Plasmodium vivax malaria and
uncomplicated Plasmodium falciparum malaria. In all these studies, however,
nitrite/nitrate has been measured spectrometrically using Griess reagent which
carries major disadvantages in the determination of serum nitrite/nitrate. The
method does not allow an exact differentiation of nitrite and biogenic amines
that are physiologically present in plasma. In the present study we introduce
high-performance liquid chromatography as a new, accurate and cost effective
method for determination of serum nitrite/nitrate levels. Significantly increased
nitrate concentrations were found in malaria patients and serum values remained
above normal levels for at least 21 days. It could be shown that our HPLC method
is a sensitive and cost-effective method for direct determination of
nitrite/nitrate in serum samples, which is not influenced by the presence of
biogenic amines.
PMID- 9551824
TI - Simultaneous determination of benzene, toluene, ethylbenzene, and xylenes in
urine by thermal desorption-gas chromatography.
AB - The determination of metabolites of benzene, toluene, ethylbenzene, and xylenes
in urine has been used to assess human exposure to these compounds. The analyses
of urine samples for these metabolites are tedious and time consuming. The
determination of unmetabolized individual compounds in urine has been studied
previously with some success. A simultaneous determination of several
unmetabolized VOC compounds in urine by thermal desorption-gas chromatography was
conducted to assess the exposure of smokers and nonsmokers to these compounds.
The method of thermal desorption-GC was sensitive enough to detect a significant
difference in exposure levels due to the contribution of light smoking in the
environmentally-exposed group.
PMID- 9551825
TI - Analysis of minocycline by high-performance liquid chromatography in tissue and
serum.
AB - A sensitive and rapid reversed-phase high-performance liquid chromatography assay
can be used to accurately determine serum and tissue minocycline concentrations.
Minocycline is a broad spectrum tetracycline derivative with many applications.
Tissue and serum samples were obtained from guinea pigs that had received either
topical or intravenous minocycline. Samples were extracted using a Sep-Pak C18
cartridge and were injected into a microBondapak C18 column with an isocratic
methanol mobile phase. Samples were analyzed using UV detection and produced
sharp peaks with a retention time of 2.5 min. The lower limit of detection was
100 ng and drug recovery was 61%. This method greatly facilitated the analysis of
minocycline while allowing for sensitivity.
PMID- 9551826
TI - High-performance thin-layer chromatographic determination of diltiazem
hydrochloride as bulk drug and in pharmaceutical preparations.
AB - A simple, rapid, selective and precise high-performance thin-layer
chromatographic method for the analysis of diltiazem hydrochloride both as a bulk
drug and in pharmaceuticals is reported. The mobile phase composition was ethyl
acetate-methanol-strong ammonia solution (80:10:10, v/v). Densitometric analysis
of diltiazem hydrochloride was carried out at 238 nm. The calibration curve of
diltiazem hydrochloride in distilled water was linear in the range 40-400 ng. The
mean value of correlation coefficient, slope and intercept were 0.997+/-0.0008,
0.0617+/-0.0012 and 7.16+/-0.2562, respectively. The limits of detection and
quantitation were 20 ng and 40 ng, respectively. The recovery of diltiazem
hydrochloride was about 99.5%. The method was utilized to analyse diltiazem
hydrochloride from conventional and sustained release tablets in the presence of
commonly used excipients.
PMID- 9551827
TI - Integration of somatic and visceral inputs by the brainstem: functional
considerations.
AB - Studies of the brainstem have traditionally either focused on mechanisms for the
control of limb or axial muscles or for the maintenance of homeostasis (e.g., the
circuitry for the regulation of respiration or blood pressure). However, recent
studies have demonstrated that movement and changes in cardiorespiratory activity
often are coordinated, indicating a linkage between the pathways that control
somatic motor activity and those that regulate respiration or circulation.
Neurons in regions such as nucleus tractus solitarius and the lateral medullary
reticular formation that regulate circulation and respiration have been shown to
receive somatic sensory signals (including those from the vestibular system)
indicating body position in space. In addition, somatic motor control may be
influenced by signals from visceral receptors that provide cues regarding body
position in space. Some areas of the brainstem may also participate directly in
both motor control and regulation of blood pressure and respiration. Thus, a
simple division of the brainstem into "somatic" and "autonomic" regions is no
longer possible.
PMID- 9551828
TI - Force sharing among fingers as a model of the redundancy problem.
AB - The aim of this study was to test Bernstein's idea that motor synergies provide
solutions to the motor redundancy problem. Forces produced by individual fingers
of one hand were recorded in one-, two-, three-, and four-finger tasks. The
subjects (n=10) were asked to produce maximal total force (maximal voluntary
contraction, MVC) and to match a ramp total force profile using different
combinations of fingers. We found that individual finger forces were smaller in
multifinger MVC tasks than in single-finger tasks. The deficit increased with the
number of fingers involved. A saturation effect was observed: when several
effectors were involved, adding a new effector did not significantly change the
total force output. The data confirmed the idea that the central neural drive
arriving at the level of synergies has a certain limit, a ceiling, that cannot be
exceeded. The central nervous system cannot maximally activate the muscles
serving all the fingers at the same time. Secondly, during the course of ramp
trials, forces produced by individual fingers were linearly related to each
other. Hence, a force sharing pattern was established at the beginning of the
trial and did not change during the ramp period. A hypothesis is suggested that
force distribution among fingers may be organized so as to minimize unnecessary
rotational moment with respect to the functional longitudinal axis of the hand.
Finally, in the four-finger trials, variance of the total maximal force output in
ten consecutive attempts was smaller than the sum of variances of the maximal
individual finger forces. The finding suggests that the control system of the
motor tasks studied involves at least two levels, a central neural drive level
and a synergy level. At the synergy level, an intercompensation in individual
finger force production is observed.
PMID- 9551829
TI - Intranigral ventral mesencephalic grafts and nigrostriatal injections of glial
cell line-derived neurotrophic factor restore dopamine release in the striatum of
6-hydroxydopamine-lesioned rats.
AB - We have previously reported that grafting of fetal ventral mesencephalic (VM)
tissue to the nigral region of unilaterally 6-hydroxydopamine (6-OHDA)-lesioned
rats, in conjunction with glial cell line-derived neurotrophic factor (GDNF)
injection between nigra and striatum, restores nigrostriatal tyrosine hydroxylase
(TH) immunoreactivity. In this study, we investigated the electrochemical indices
of dopamine (DA) release in these grafted animals in the striatum and nigra.
Adult Sprague-Dawley rats were anesthetized and unilaterally injected with 6-OHDA
into the medial forebrain bundle. The completeness of lesions was tested by
measuring methamphetamine-induced rotations. One to two months after 6-OHDA
administration, fetal VM tissues were grafted in the lesioned nigral area
followed by injection of GDNF, brain-derived neurotrophic factor (BDNF), or
phosphate-buffered saline (PBS), along a tract from nigra to striatum. Animals
receiving transplantation and GDNF, but not BDNF or PBS, injection showed a
significant decrease in rotation 1-3 months after grafting. High-speed
chronoamperometric recording techniques, using Nafion-coated carbon fiber
electrodes, were used to evaluate DA overflow in the striatum. We found that 6
OHDA lesions resulted in a loss of KCl-induced DA overflow in the urethane
anesthetized rats. Three months after GDNF-bridged grafting, application of KCl
elicited DA release both in nigra and striatum. The KCl-evoked DA release area
was limited to the GDNF-bridging tract in the striatum. On the other hand, KCl
did not induce DA release in the BDNF- or PBS-bridged grafts. Immunocytochemical
studies indicated that TH-positive neurons and fibers were found in the nigra and
striatum after GDNF-bridged grafting. Taken together, our data suggest that fetal
nigral transplantation and GDNF injection may restore the nigrostriatal DA
pathway and DA release in these hemiparkinsonian animals and support the
hypothesis of trophic activity of GDNF on fiber outgrowth from midbrain DA
neurons.
PMID- 9551830
TI - Evidence for a strychnine-sensitive mechanism and glycine receptors involved in
the control of urethral sphincter activity during micturition in the cat.
AB - Micturition in the decerebrate cat is characterized by a coordinated bladder
contraction and a simultaneous decrease in external urethral sphincter (EUS)
efferent activity. Without the suppression of EUS activity, voiding is
significantly impaired, resulting in a state sometimes referred to as bladder
sphincter dyssynergia. The aim of the present study was to determine whether
glycinergic inhibition contributes to the suppression of EUS activity during
micturition evoked by bladder distension or electrical stimulation of the pontine
micturition center (PMC) in decerebrate cats. Using subconvulsive intravenous
doses of strychnine (0.1-0.24 mg/kg), we examined changes in bladder and EUS
electroneurographic (ENG) activity during micturition. Following subconvulsive
doses of strychnine, tonic EUS ENG activity increased during bladder filling in
five of six animals. In the presence of strychnine, it was possible to evoke
reflex bladder contractions of similar duration and peak pressure to those
observed before strychnine administration. However, there was an absence of
suppression of EUS ENG activity during the bladder contractions in all the
animals. To determine whether the changes in sphincter activity could be due to
strychnine acting at glycine receptors on EUS motoneurons, sacral spinal tissue
was processed for a structural protein (gephyrin) associated with the glycine
receptor. Motoneurons in Onufs nucleus in S1 were identified using choline
acetyltransferase immunohistochemistry and subsequently processed with a gephyrin
monoclonal antibody. Abundant gephyrin labeling was evident throughout Onufs
nucleus. Since Onufs nucleus is made up of EUS and other motoneuron populations,
a sample of antidromically identified urethral and anal sphincter motoneurons
were intracellularly labeled with tetramethylrhodamine dextran (TMR-D) and then
processed with the gephyrin antibody. Using dual-beam confocal microscopy,
gephyrin immunoreactivity was observed on the soma and proximal processes of
individual EUS motoneurons in both male and female animals. It was concluded that
a strychnine-sensitive mechanism contributes to the suppression of sphincter
activity normally observed during voiding. Although glycinergic inhibition may
affect several components of the circuitry responsible for micturition, it
appears that the suppression of EUS motoneurons during micturition may be partly
due to a direct glycinergic inhibition of the EUS motoneurons.
PMID- 9551831
TI - Tilt perception during dynamic linear acceleration.
AB - Head tilt is a rotation of the head relative to gravity, as exemplified by head
roll or pitch from the natural upright orientation. Tilt stimulates both the
otolith organs, owing to shifts in gravitational orientation, and the
semicircular canals in response to head rotation, which in turn drive a variety
of behavioral and perceptual responses. Studies of tilt perception typically have
not adequately isolated otolith and canal inputs or their dynamic contributions.
True tilt cannot readily dissociate otolith from canal influences. Alternatively,
centrifugation generates centripetal accelerations that simulate tilt, but still
entails a rotatory (canal) stimulus during important periods of the stimulus
profiles. We reevaluated the perception of head tilt in humans, but limited the
stimulus to linear forces alone, thus isolating the influence of otolith inputs.
This was accomplished by employing a centrifugation technique with a variable
radius spinning sled. This allowed us to accelerate the sled to a constant
angular velocity (128 degrees/s), with the subject centered, and then apply
dynamic centripetal accelerations after all rotatory perceptions were
extinguished. These stimuli were presented in the subjects' naso-occipital axis
by translating the subjects 50 cm eccentrically either forward or backward.
Centripetal accelerations were thus induced (0.25 g), which combined with gravity
to yield a dynamically shifting gravitoinertial force simulating pitch-tilt, but
without actually rotating the head. A magnitude-estimation task was employed to
characterize the dynamic perception of pitch-tilt. Tilt perception responded
sluggishly to linear acceleration, typically reaching a peak after 10-30 s. Tilt
perception also displayed an adaptation phenomenon. Adaptation was manifested as
a per-stimulus decline in perceived tilt during prolonged stimulation and a
reversal aftereffect upon return to zero acceleration (i.e., recentering the
subject). We conclude that otolith inputs can produce tilt perception in the
absence of canal stimulation, and that this perception is subject to an
adaptation phenomenon and low-pass filtering of its otolith input.
PMID- 9551832
TI - Activity of thoracic and lumbar epaxial extensors during postural responses in
the cat.
AB - This study examined the role of trunk extensor muscles in the thoracic and lumbar
regions during postural adjustments in the freely standing cat. The epaxial
extensor muscles participate in the rapid postural responses evoked by horizontal
translation of the support surface. The muscles segregate into two regional
groups separated by a short transition zone, according to the spatial pattern of
the electromyographic (EMG) responses. The upper thoracic muscles (T5-9) respond
best to posteriorly directed translations, whereas the lumbar muscles (T13 to L7)
respond best to anterior translations. The transition group muscles (T10-12)
respond to almost all translations. Muscles group according to vertebral level
rather than muscle species. The upper thoracic muscles change little in their
response with changes in stance distance (fore-hindpaw separation) and may act to
stabilize the intervertebral angles of the thoracic curvature. Activity in the
lumbar muscles increases along with upward rotation of the pelvis (iliac crest)
as stance distance decreases. Lumbar muscles appear to stabilize the pelvis with
respect to the lumbar vertebrae (L7-sacral joint). The transition zone muscles
display a change in spatial tuning with stance distance, responding to many
directions of translation at short distances and focusing to respond best to
contralateral translations at the long stance distance.
PMID- 9551833
TI - The cat vertebral column: stance configuration and range of motion.
AB - This study examined the configuration of the vertebral column of the cat during
independent stance and in various flexed positions. The range of motion in the
sagittal plane is similar across most thoracic and lumbar joints, with the
exception of a lesser range at the transition region from thoracic-type to lumbar
type vertebrae. The upper thoracic column exhibits most of its range in
dorsiflexion and the lower thoracic and lumbar in ventroflexion. Lateral flexion
is limited to less than 5 degrees at all segments. The range in torsion is almost
180 degrees and occurs primarily in the midthoracic region, T4-T11. Contrary to
the depiction in most atlases, the standing cat exhibits several curvatures,
including a mild dorsiflexion in the lower lumbar segments, a marked
ventroflexion in the lower thoracic and upper lumbar segments, and a profound
dorsiflexion in the upper thoracic (above T9) and cervical segments. The
curvatures are not significantly changed by altering stance distance but are
affected by head posture. During stance, the top of the scapula lies well above
the spines of the thoracic vertebrae, and the glenohumeral joint is just below
the bodies of vertebrae T3-T5. Using a simple static model of the vertebral
column in the sagittal plane, it was estimated that the bending moment due to
gravity is bimodal with a dorsiflexion moment in the lower thoracic and lumbar
region and a ventroflexion moment in the upper thoracic and cervical region.
Given the bending moments and the position of the scapula during stance, it is
proposed that two groups of scapular muscles provide the major antigravity
support for the head and anterior trunk. Levator scapulae and serratus ventralis
form the lateral group, inserting on the lateral processes of cervical vertebrae
and on the ribs. The major and minor rhomboids form the medial group, inserting
on the spinous tips of vertebrae from C4 to T4. It is also proposed that the
hypaxial muscles, psoas major, minor, and quadratus lumborum could support the
lumbar trunk during stance.
PMID- 9551834
TI - Spatial disparity coding in the superior colliculus of the cat.
AB - Cells in the superficial layers of the superior colliculus of the cat have mainly
binocular receptive fields. The aim of the present experiment was to investigate
the sensitivity of these cells to horizontal spatial disparity. Unit recordings
were carried out in the superficial layers of the superior colliculus of
paralyzed and anesthetized cats. Centrally located receptive fields were mapped,
separated using prisms, and then stimulated simultaneously using two luminous
bars optimally adjusted to the size of the excitatory region of the receptive
fields. Only binocular cells were tested, and 65% of these units were found to be
sensitive to spatial disparities. Some cells (20%) were clearly insensitive to
spatial disparity and the remaining 15% showed complex, unclassifiable
interactions. The sensitive cells could be divided into four classes based on
their disparity-sensitivity profiles: 38% showed excitatory interactions, whereas
9% showed inhibitory interactions. Moreover, 11% and 7% of the cells responded,
respectively, to crossed or uncrossed disparities, and were classified as near
cells and far cells. Whereas the general shapes of the sensitivity profiles were
similar to those of cells in areas 17-18, selectivity in the superior colliculus
was significantly coarser. The superficial layers of the superior colliculus
project topographically to the deep layers of the superior colliculus, which are
known to contain circuits involved in the control of ocular movements. The
results thus suggest that disparity-sensitive cells of the superior colliculus
could feed information to these oculomotor neurons, allowing for the localization
and fixation of objects on the appropriate plane of vision.
PMID- 9551836
TI - Ascending propriospinal afferents to area X (substantia grisea centralis) of the
spinal cord in the rat.
AB - Area X (the tenth area) of the spinal cord is a region surrounding the central
canal and extending throughout the spinal cord length. Using anterograde and
retrograde labeling techniques, ascending propriospinal projections to area X
were examined in the rat. For anterograde tracing of axons, biotinylated dextran
was injected into middle-thoracic, lumbar, or sacral-caudal segments. Unilateral
injections resulted in bilateral labeling of terminals in area X of all segments
rostral to the injections. The distribution of labeled terminals was conspicuous
in regions dorsal and lateral to the central canal. The labeled axons were
derived from the ventrolateral and the lateral cord. They coursed through lamina
VII, giving off terminal axons. While giving off terminal axons in area X, they
coursed further rostrally or caudally along the central canal or crossed over the
central canal to terminate in the contralateral area X. Possible cells of origin
of these ascending afferents were examined after injections of wheat germ
agglutinin-horseradish peroxidase into regions surrounding the central canal
(area X) at the cervical or thoracic level. Retrogradely labeled neurons were
consistently seen in area X, and laminae VII and VIII of the thoracic and lumbar
segments. The present study shows that ascending propriospinal axons project to
area X of all spinal levels rostral to the cells of origin and suggests that some
of these afferents may originate from neurons in area X and laminae VII and VIII.
Based on previous data, it is surmised that area X functions, through these
intricate interconnections, as a site for integration or modulation of somatic or
nociceptive and visceroceptive sensation.
PMID- 9551835
TI - Comparison of mesencephalic free-floating tissue culture grafts and cell
suspension grafts in the 6-hydroxydopamine-lesioned rat.
AB - Ventral mesencephalon (VM) of fetal rat and human origin grown as free-floating
roller-tube (FFRT) cultures can survive subsequent grafting to the adult rat
striatum. To further explore the functional efficacy of such grafts, embryonic
day 13 ventral mesencephalic tissue was grafted either after 7 days in culture or
directly as dissociated cell suspensions, and compared with regard to neuronal
survival and ability to normalize rotational behavior in adult rats with
unilateral 6-hydroxydopamine (6-OHDA) lesions. Other lesioned rats received
injections of cell-free medium and served as controls. The amphetamine-induced
rotational behavior of all 6-OHDA-lesioned animals was monitored at various time
points from 18 days before transplantation and up to 80 days after
transplantation. Tyrosine hydroxylase (TH) immunostaining of the histologically
processed brains served to assess the long-term survival of grafted dopaminergic
neurons and to correlate that with the behavioral effects. Additional cultures
and acutely prepared explants were also fixed and stored for histological
investigation in order to estimate the loss of dopaminergic neurons in culture
and after transplantation. Similar behavioral improvements in terms of
significant reductions in amphetamine-induced rotations were observed in rats
grafted with FFRT cultures (127%) and rats grafted with cell suspensions (122%),
while control animals showed no normalization of rotational behavior. At 84 days
after transplantation, there were similar numbers of TH-immunoreactive (TH-ir)
neurons in grafts of cultured tissue (775 +/- 98, mean +/- SEM) and grafts of
fresh, dissociated cell suspension (806 +/- 105, mean +/- SEM). Cell counts in
fresh explants, 7-day-old cultures, and grafted cultures revealed a 68.2% loss of
TH-ir cells 7 days after explantation, with an additional 23.1% loss after
grafting, leaving 8.7% of the original number of TH-ir cells in the intracerebral
grafts. This is to be compared with a survival rate of 9.1% for the TH-ir cells
in the cell-suspension grafts. Immunostaining for the calcium-binding proteins
calretinin, calbindin, and parvalbumin showed no differences in the neuronal
expression of these proteins between the two graft types. In conclusion, we found
comparable dopaminergic cell survival and functional effects of tissue-culture
grafts and cell-suspension grafts, which currently is the type of graft most
commonly used for experimental and clinical grafting. In this sense the result is
promising for the development of an effective in vitro storage of fetal nigral
tissue, which at the same time would allow neuroprotective and neurotrophic
treatment prior to intracerebral transplantation.
PMID- 9551838
TI - Correlation of electrophysiology, morphology, and functions in corticotectal and
corticopretectal projection neurons in rat visual cortex.
AB - In most mammals the superior colliculus (SC) and the pretectal nucleus of the
optic tract (NOT) receive direct input from the ipsilateral visual cortex via
projection neurons from infragranular layer V. We examined whether these
projection neurons belong to different populations and, if so, whether it is
possible to correlate the electrophysiological features with the suggested
function of these neurons. Projection cells were retrogradely labeled in vivo by
rhodamine-coupled latex beads or fast blue injections into the SC or the NOT 2-5
days prior to the electrophysiological experiment. Intracellular recordings of
prelabeled neurons were made from standard slice preparations and cells were
filled with biocytin in order to reveal their morphology. Both cell populations
consist of layer V pyramids with long apical dendrites that form terminal tufts
in layer I. In electrophysiological terms, 12 of the corticotectal cells could be
classified as intrinsically bursting (IB), while two neurons showed a doublet
firing characteristic and one neuron was classified as regular-spiking (RS).
Intracortical microstimulation of cortical layer II/III revealed that SC
projecting neurons responded optimally to stimulation sites up to a distance of
1000 microm from the recorded cell. The morphological features of the SC
projecting cells reveal an apical dendritic tuft in layer I with a lateral
extension of 300 microm, a mean spine density of 65 spines per 40 microm on the
apical dendrites located in layer II/III, and a bouton density of 13 boutons per
100 microm on the intracortical axons. Sixteen NOT-projecting neurons exhibited
an IB and five cells an RS characteristic. Intracortical microstimulation of
cortical layer II/III showed that NOT-projecting neurons responded optimally to
stimulation sites up to a distance of 1500 microm. Their morphological features
consist of an apical dendritic tuft with a lateral extension of 500 microm, a
mean spine density of 25 spines per 40 microm on the apical dendrites located in
layer II/III, and a bouton density of 6 boutons per 100 microm on the
intracortical axons. When the passive membrane parameters, responses to
intracortical microstimulation in layer V, the extension of the basal dendritic
field, and spine densities in layers I or V were compared between SC- and NOT
projecting cells, no differences were revealed. Differences were only
consistently found in the supragranular layers, either for morphological
parameters or for intracortical microstimulation. The results suggest that NOT
projecting and SC-projecting neurons, although biophysically similar, could
integrate and transmit different spatial aspects of cortical visual information
to their target structures.
PMID- 9551837
TI - Differential localisation of the metabotropic glutamate receptor mGluR1a and the
ionotropic glutamate receptor GluR2/3 in neurons of the human cerebral cortex.
AB - Specimens of human cerebral cortex were obtained during neurosurgical operations
and studied by immunocytochemistry and electron microscopy, using antibodies to
the metabotropic glutamate receptor subunit mGluR1a and the ionotropic glutamate
receptor GluR2/3. A small number of non-pyramidal neuronal cell bodies were
labelled for mGluR1a. Double immunolabelling with mGluR1a and GluR2/3 showed that
most pyramidal cell bodies were labelled for GluR2/3 but not for mGluR1a. Despite
the non-colocalisation of these two receptor subtypes in cell bodies, however,
many dendrites and dendritic spines were double-labelled for mGluR1a and GluR2/3
at electron microscopy. As there is evidence that most neurons positive for
GluR2/3 are pyramidal cells, this suggests that mGluR1a is present in dendrites
of pyramidal neurons, despite absent or low levels of immunoreactivity in their
cell bodies.
PMID- 9551839
TI - Mechanical sensitivity of muscle afferents in a nerve treated with colchicine.
AB - The experiments reported here demonstrate that the mechanical sensitivity of
peripheral nerve fibres typically seen after injury can be induced without
overtly injuring the nerve, but by simply applying colchicine topically to the
nerve. In cats anaesthetised with pentobarbitone sodium, the medial gastrocnemius
nerve was exposed and 10 mM colchicine applied topically for 15 min. The animals
recovered from the operation normally and showed no subsequent motor deficit. Six
days later animals were re-anaesthetised, a laminectomy carried out and responses
recorded in single afferents at the level of the dorsal root. It was found that
many afferents, particularly those with conduction velocities in the group II-III
range, had become sensitive to local mechanical stimulation of the nerve in the
region treated with colchicine and showed slowly adapting responses to stretch of
the nerve. Many of the smaller fibres exhibited spontaneous activity.
Mechanically sensitive afferents exhibited impulse conduction blocks at the
colchicine-treated site. Some afferents, which appeared to conduct impulses
normally through the treated region, were associated with muscle receptors having
normal response properties. However, other muscle receptors were clearly abnormal
and were insensitive to muscle stretch or contraction or exhibited only phasic
responses. When the nerve was cut proximal to the colchicine-treated site, some,
but not all, spontaneous activity was abolished. It was subsequently shown using
a collision technique that the activity in some axons had its origin in the cell
body in the dorsal root ganglion. In one experiment, it was shown that after
nerve section proximal to the colchicine-treated region three of five axons
switched their activity from a peripheral to a central origin. It is postulated
that colchicine disrupts fast axonal transport of mechanically sensitive or
voltage-sensitive ion channels, from the cell body to the peripheral terminals of
the axons, leading to an accumulation of these channels at the treated site. This
induces mechanical sensitivity and spontaneous activity. It is postulated that
interruption of a retrogradely transported signal induces the spontaneous
activity in the cell body. These experiments suggest that an important influence
is exerted by the cell body on the peripheral terminals of mechanoreceptors to
confer on them their normal response properties.
PMID- 9551840
TI - Complex partial and secondarily generalized seizure patients: cognitive
functioning prior to treatment with antiepileptic medication. VA Epilepsy
Cooperative Study 264 Group.
AB - This investigation of cognitive functioning in patients with symptomatic
localization-related (partial) epilepsy prior to administration of antiepileptic
medication is part of a nationwide prospective, double-blind study of drug
efficacy and longitudinal changes in cognition associated with seizure disorders.
Recently-diagnosed patients with complex partial or secondarily generalized tonic
clonic seizures, equated for age, education and IQ, were compared with normal
controls on a battery of neuropsychological tests: verbal and figural memory
measures (Rey auditory verbal learning test, Rey Osterrieth complex figure), and
a brief behavioral toxicity battery comprising measures of motor function,
concentration and mental flexibility (Lafayette grooved pegboard, controlled word
association test, Stroop, paced auditory serial addition test [PASAT]). Control
subjects perform significantly better than both groups of seizure patients on
several measures of motor speed/integration and memory, specifically the pegboard
and the RAVLT learning (3-5) and recall trials. Secondarily generalized seizure
patients show greatest impairment. They perform significantly worse than patients
with complex partial seizures and control subjects on the controlled word
association test and the most demanding Stroop color word trial, both measures of
concentration and mental flexibility. These findings document deficits in memory
as well as concentration and motor function in complex partial and in secondarily
generalized seizure patients prior to treatment with antiepileptic medication.
PMID- 9551841
TI - Transcranial magnetic stimulation: its current role in epilepsy research.
AB - This paper reviews the current role of transcranial magnetic stimulation (TMS) in
epilepsy research. After a brief introduction to the technical principles, the
physiology and the safety aspects of TMS, emphasis is put on how human cortex
excitability can be assessed by TMS and how this may improve our understanding of
pathophysiological mechanisms in epilepsy and the mode of action of antiepileptic
drugs (AEDs). Also, potential therapeutical applications of TMS are reviewed. For
all aspects of this paper, a clear distinction was made between single-/paired
pulse TMS and repetitive TMS, since these two techniques have fundamentally
different scopes and applications.
PMID- 9551842
TI - A double-blind, placebo-controlled trial of tiagabine given three-times daily as
add-on therapy for refractory partial seizures. Northern European Tiagabine Study
Group.
AB - In a multicentre, double-blind, parallel-group, placebo-controlled trial, a three
times daily regimen of tiagabine was evaluated as add-on therapy in 154 adult
patients with refractory partial seizures. A total of 77 patients were randomised
to treatment in each arm. Tiagabine HCl was titrated from an initial dose of 12
30 mg/day over 4 weeks. During the 12-week fixed-dose period, there was a
significant reduction in the median 4-weekly seizure rate for all partial
seizures and simple partial seizures (P < 0.05 in each case). Furthermore, the
proportion of patients with a reduction of 50% or more in all partial seizures
was higher in the tiagabine group than in the placebo group (14 versus 6%),
though the difference did not achieve statistical significance. The difference
with respect to simple partial seizures was significant (21 versus 6%, P < 0.01).
The percentage of patients achieving an increase of at least 50% in the
proportion of days free of all partial seizures was significantly greater in the
tiagabine group compared to placebo (14 versus 4%, P<0.01). Tiagabine did not
appear to influence the plasma concentrations of other concomitant antiepileptic
drugs and was generally well tolerated, with most drug-related adverse events
being mild or moderate in severity. The most common adverse events were
dizziness, asthenia, headache and somnolence. Adverse event incidence was similar
between tiagabine and placebo groups, except for dizziness which was more common
with tiagabine (29 versus 10%, P < 0.01). Tiagabine had no significant effects on
laboratory tests or vital signs. The present study shows that tiagabine, at a
dose of 10 mg administered three-times daily, which is at the lower end of the
usual recommended dose range (30-50 mg/day, tiagabine base), is generally well
tolerated and demonstrates efficacy for the treatment of refractory partial
seizures.
PMID- 9551843
TI - Valnoctamide, valpromide and valnoctic acid are much less teratogenic in mice
than valproic acid.
AB - The teratogenic properties of valproic acid (VPA) and its analogues depend to a
great extent on their chemical structure. We investigated the structure
teratogenicity relationships of VPA, its structural isomer, valnoctic acid (VCA),
and their two amide analogues, valpromide (VPD) and valnoctamide (VCD),
respectively. Each substance was injected (3 mmol/kg) in NMRI-mice on the morning
of day 8 of gestation. Embryolethality, fetal weight and exencephaly rates were
recorded on day 18 of gestation. VPA caused 53% exencephaly, VPD induced 6%, VCA
and VCD produced only 1% exencephaly (control values between 0 and 1%). VPA
treated mice also had increased embryolethality rates (52%). There was no
significant change of embryolethality in the other treatment groups.
Pharmacokinetic studies showed that VCD was eliminated from plasma at a slower
rate than VPA. Also, the residual teratogenic activity of VPD was not accounted
for by the relatively small amounts of its hydrolysis product VPA. This study
indicates that VPD, VCA and VCD were distinctly less teratogenic than VPA.
Apparently the amidation of the free carboxylic group and/or methyl-substitution
at the beta-position of the carbon chain greatly decreased the teratogenic
activity of VPA.
PMID- 9551844
TI - Decreased brainstem seizure thresholds and facilitated seizure propagation in
mice exposed to repeated flurothyl-induced generalized forebrain seizures.
AB - We recently have described a novel model of epileptogenesis utilizing the
inhalant chemoconvulsant, flurothyl (Applegate et al., 1997; Samoriski and
Applegate, 1997). The hallmark feature of this model is a change in behavioral
seizure phenotype from a forebrain seizure, observed during the initial flurothyl
exposures, to a brainstem seizure, elicited by flurothyl, after a 28-day
stimulation free incubation period. In this study, we sought to establish the
basis for this change in behavioral seizure response. To this end, we examined
the effects of exposure to this paradigm on the generalized brainstem seizure
threshold and on the propagation of forebrain seizures onto the brainstem seizure
substrate. Ten mice were given flurothyl-induced generalized forebrain seizures
on 8 consecutive days (induction phase). The other ten mice were not exposed to
the flurothyl induction paradigm and served as controls. Minimal corneal
electroconvulsive shock (mECS--20 mA) was used to assay whether there was any
change in the animals' generalized brainstem seizure thresholds at 3, 14 and 28
days following the last flurothyl seizure trial. Mice that were exposed to
flurothyl exhibited a progressive increase in the percentage of animals having a
mECS-induced brainstem seizure when tested at 3 (40%), 14 (70%) and 28 (90%) days
following the last flurothyl seizure. Control mice rarely had a brainstem seizure
at any of the three time points tested, mostly forebrain seizures were observed.
These results suggest that there is a significant progressive lowering of the
brainstem seizure threshold, during the incubation phase of the flurothyl
paradigm, which is coincident with the previously reported time course of change
in the behavioral seizure phenotype observed using this flurothyl model
(Applegate et al., 1997; Samoriski and Applegate, 1997). Following mECS testing,
mice were implanted with bipolar electrodes and kindled from the olfactory bulb
(OB). Mice exposed to the flurothyl paradigm demonstrated significantly faster
kindling rates, longer afterdischarge durations. and longer durations of and
latencies to stage 5 seizures compared to controls. Furthermore, animals exposed
to the flurothyl protocol demonstrated an increase in the expression of brainstem
seizures after focally-elicited OB afterdischarges. These results suggest that
there is an increased interaction between the forebrain and brainstem seizure
systems after exposure to this model of epileptogenesis. Together, results
indicate that the change in behavioral seizure phenotype observed following
exposure to our flurothyl paradigm are promoted by both decreases in brainstem
seizure thresholds and facilitated forebrain seizure propagation onto the
brainstem seizure system.
PMID- 9551845
TI - Inhibition of pentylenetetrazol-induced seizures in rats by prostaglandin D2.
AB - This study was undertaken to evaluate the role of brain PGD2 activity during PTZ
induced seizures in rats. Potentiation of endogenous PGD2 activity caused an anti
convulsant effect. Thus, after PGD2 injection (5 microg/icv) the latency of
generalized tonic clonic convulsions was prolonged. ZK 118.182, a stable analogue
of PGD2, dose-dependently inhibited the incidence and the intensity of seizures
when injected at doses of 1-100 ng/icv. But on the other hand, inhibition of PGD2
activity either by a D-type PG receptor antagonist (AH 6809; 50 ng/icv) or by a
PGD synthase inhibitor (sodium selenite; 0.2 microg/icv) produced a proconvulsant
effect by increasing the incidence and the intensity of the seizures. These
findings indicate that endogenous PGD2 activity in the brain may have a specific
inhibitory role for the initiation and propagation of PTZ induced seizures in
rats.
PMID- 9551846
TI - Anticonvulsant effect of fosphenytoin in amygdala-kindled rats: comparison with
phenytoin.
AB - Phenytoin has been reported to exert variable anticonvulsant effects in the
kindling model of complex partial seizures. Phenytoin is only water soluble at a
pH of more than 10, and it has been suspected that poor absorption of the drug is
responsible for its lack of effect in some experiments. Recently, fosphenytoin, a
prodrug of phenytoin, has been developed by phosphorylating phenytoin which makes
the drug water soluble at physiological pH while it is rapidly transformed to
phenytoin after injection. This study examined the anticonvulsant profile and the
absorption after intraperitoneal injection of fosphenytoin, compared to its
parental drug phenytoin. The pharmacokinetic parameters of phenytoin and
fosphenytoin were compared by determining plasma levels of phenytoin after i.p.
injection of 50 mg/kg phenytoin or the equivalent dose of 84 mg/kg of
fosphenytoin in non-kindled female Wistar rats. After both injections the maximal
plasma concentration of phenytoin was about 30 microg/ml. The relative
bioavailability of fosphenytoin was 83%. In contrast to phenytoin, failed
injections resulting in non-detectable plasma concentration of phenytoin were
almost absent after fosphenytoin. In fully kindled female Wistar rats,
fosphenytoin dose-dependently increased the focal seizure (afterdischarge)
threshold. Seizure severity and duration at threshold were reduced only after the
highest does of fosphenytoin tested (84 mg/kg). Thus, fosphenytoin showed
anticonvulsant properties similar to phenytoin in amygdala kindled rats. We
conclude that fosphenytoin is an adequate and reliable substitute for the
parenteral injection of phenytoin in experimental seizure models of rats.
PMID- 9551847
TI - Heart rate variability in patients with epilepsy.
AB - Autonomic function was studied by the use of spectral analysis of heart-rate
variability in patients with epilepsy in relation to type of epilepsy and anti
epileptic drug therapy. A total of 21 patients with juvenile myoclonic epilepsy
(JME) and 21 with temporal lobe epilepsy (TLE) were included; 18 patients were
treated with carbamazepine (CBZ), 16 with valproate (VPA) and seven with
phenytoin (PHT). One healthy drug free control, matched for age and sex, was
selected for each patient. Patients and controls underwent an ambulatory 24 h
EKG. Heart-rate variability was analyzed in time and frequency domains. Patients
with TLE had significantly lower S.D. of the RR-intervals, lower low frequency
power and a lower low frequency/high frequency power ratio than their controls. A
lower low frequency/high frequency power ratio was the only significant
difference between the JME patient group and their controls. Treatment, however,
may have had a considerable influence on the heart rate variability in the
epilepsy patients. Patients on CBZ had significantly lower S.D. of RR-intervals,
low frequency power and a low frequency/ high frequency power ratio than did
their matched healthy drug free controls. The ratio of low frequency/high
frequency power was also lower in patients on VPA compared with their controls,
but apart from that no differences could be demonstrated between this treatment
group and the controls. In conclusion, patients with epilepsy appear to have an
altered autonomic control of the heart, with a reduction in some heart-rate
variability measures, suggesting a decreased sympathetic tone, which may be
related to the drug therapy or the epilepsy as such. Further studies are
warranted to explore these changes and their possible relevance for sudden death
in epilepsy.
PMID- 9551848
TI - Delta-aminolevulinic acid-induced lipid peroxidation in rat kidney and liver is
attenuated by melatonin: an in vitro and in vivo study.
AB - Acute intermittent porphyria (AIP) is a genetically inherited disease
characterized by a partial block in liver heme biosynthesis and by increased
urinary excretion of the delta-aminolevulinic acid (ALA). Recently, it has been
proposed that the toxic effects of ALA are related to the generation of free
radicals. In the present study the in vitro and in vivo effect of melatonin, a
recently described antioxidative agent, on ALA-induced lipid peroxidation in rat
liver and kidney was determined. The concentration of malonaldehyde (MDA) and 4
hydroxyalkenals (4-HDA) was assayed as an index of induced membrane oxidative
damage. In vitro melatonin protected, in a concentration-dependent manner,
against ALA-induced lipid peroxidation in liver and kidney homogenates. In in
vivo experiments as well, it was demonstrated that ALA (40 mg/kg)-induced lipid
peroxidation in liver and kidney was reduced by acute melatonin (10 mg/kg)
treatment. The results support the involvement of free radicals in ALA toxicity
and show that in vitro and in vivo melatonin confers protection against this
toxicity, likely due to the antioxidative capability of the indole.
PMID- 9551849
TI - Stimulatory effect of melatonin on the 5'-monodeiodinase activity in the liver,
kidney, and brown adipose tissue during the early neonatal period of the rabbit.
AB - The response of type I 5'-monodeiodinase activity (5'-MD) to a s.c. injection or
oral administration of melatonin was studied in 3-, 5-, and 7-day-old rabbits.
Melatonin-treated animals showed higher activity of the type I 5'-MD in the liver
and kidney and of type II 5'-MD in brown adipose tissue (BAT). This respond to
melatonin treatment was age dependent. The stimulatory effect of melatonin on
renal 5'-MD activity was observed only in 3- and 5-day-old rabbits and in the
liver and BAT during the first week of life. Oral melatonin administration tended
to exert a more marked effect on enzyme activity than s.c. injection of the
hormone. Changes in 5'-MD activities were accompanied by an increase in serum
iodothyronine (T4, T3, and rT3) concentrations. The T3 and rT3 increases may
result from the deiodinating processes by the type I 5'-MD and 5-MD,
respectively, whereas the rise in the serum T4 was probably due to the
stimulatory effect of melatonin on the secretory activity of the thyroid gland
itself. These results are the first description of the effects evoked by
melatonin treatment during the early neonatal period in newborns of the altricial
type.
PMID- 9551850
TI - Melatonin excretion is not related to sleep in the elderly.
AB - We examined the association between 6-sulphatoxymelatonin (6-SMT) excretion and
sleep in 68 volunteers 60-79 years of age who complained of insomnia or
depression. An Actillume wrist monitor was worn for 5-7 consecutive days and
nights in home-living conditions. Activity was used to estimate total sleep time
(TST) and wake after sleep onset (WASO). Throughout two 24 hr periods, urine was
collected approximately every 2 hr during the day and after any voidings during
the sleep period. During the next week, subjects spent 5 nights and 4 days in the
laboratory. Sleep was measured and scored with standard polysomnographic
techniques. Urine was collected, as for home recording, on days 1 and 4. Urinary
concentrations of 6-SMT were assayed. Cosine-fitting of urine data across both
days at home and both laboratory collections established the mesors and
amplitudes of 24 hr 6-SMT excretion rhythms, but neither was significantly
correlated with sleep. Mean and peak 6-SMT excretion during the sleep period was
also determined. Significant correlations were found between mean 6-SMT during
the laboratory sleep period and TST and WASO. However, these associations were
not independent of circadian timing: sleep was better when sleep occurred near
the circadian acrophase of 6-SMT excretion. These data indicate that low
melatonin production may not be an important factor in insomnia among the
elderly.
PMID- 9551851
TI - Effect of continuous melatonin infusions on steady-state plasma melatonin levels
in rats under near physiological conditions.
AB - It was the aim of this study to measure the actual amount of melatonin required
for elevating the circulating hormone from low daytime levels to the 10-fold
higher nocturnal steady-state concentrations in rats. For this purpose,
escalating doses of melatonin were continuously infused into the right jugular
vein and blood samples were repeatedly drawn from the left jugular vein for a
period of 2 hr in freely moving catheterized rats. In order to achieve an about
10-fold elevation of the plasma melatonin concentration, 500 ng melatonin/hr had
to be infused, i.e., about 300 times the normal nocturnal melatonin content of
the pineal. Infusions of up to 61 ng melatonin/hr (equivalent to the melatonin
content of 40 pineals at darkness) failed to cause a significant rise of the low
daytime steady-state concentrations in the blood. If the dose of 500 ng
melatonin/h was infused at night, a less-pronounced rise of the blood levels was
observed, as compared to that caused by the infusion of the same dose during
daytime. No differences were found in the rate of metabolism between daytime and
nighttime. The results of this study indicate 1) that the low basal
concentrations of melatonin in the blood are not affected by an increased
melatonin supply up to a certain critical threshold, 2) that the rat pineal gland
would have to release all its melatonin content almost every 10 sec in order to
sustain the elevated steady-state level of melatonin in the circulation during
the dark period, and 3) that significant day/night differences exist in the
disposition of circulating melatonin if administered in near physiological
amounts and under near physiological conditions.
PMID- 9551852
TI - Regulation of calcium influx and phospholipase C activity by indoleamines in
dinoflagellate Crypthecodinium cohnii.
AB - Exogenous indoleamines such as melatonin and 5-methoxytryptamine have been shown
to induce cyst formation (encystment) in many species of dinoflagellate.
Induction of inositol phosphates formation by indoleamine has previously been
demonstrated in Crypthecodinium cohnii. In addition, depletion of extracellular
Ca2+ blocks the indoleamine-induced encystment. In the present study, 12
indoleamines (including melatonin and related compounds) were examined for their
abilities to induce Ca2+ influx, inositol phosphates formation, and encystment in
C. cohnii. The results showed that melatonin, 5-methoxytryptamine, and the
peptide toxin mastoparan stimulated 45Ca2+ influxes in dose- and time-dependent
manners. The EC50 values of 5-methoxytrypramine and mastoparan to stimulate
45Ca2+ uptake were 2 mM and 35 microM, respectively. The 5-methoxytryptamine- and
mastoparan-induced 45Ca2+ influx were partially attenuated by the calcium channel
blockers, verapamil and ruthenium red. A series of indoleamines were examined for
their structure-activity relationship on the induction of encystment and
formation of inositol phosphates. Melatonin-induced inositol phosphates formation
was completely blocked by U73122, indicating the possible involvement of
phospholipase C. Taken together, we conclude that indoleamines may induce
encystment of the dinoflagellate C. cohnii via parallel activation of
phospholipase C and Ca2+ influx signaling pathways. However, activation of
phospholipase C and Ca2+ influx are not always necessary or sufficient for
inducing encystment. Also, these data provided the first direct evidence of a
Ca2+ influx regulating mechanism in dinoflagellate C. cohnii.
PMID- 9551853
TI - Daily and photoperiodic 2-125I-melatonin binding changes in the pars tuberalis of
the Syrian hamster (Mesocricetus auratus): effect of constant light exposure and
pinealectomy.
AB - Using quantitative autoradiography, 2-125I-melatonin binding was investigated
throughout the light/dark cycle in the pars tuberalis (PT) of the pituitary of
adult Syrian hamsters kept for 8 weeks either in long or short photoperiod (LP or
SP, respectively). Melatonin receptor density in the PT displayed photoperiod
dependent daily variations (maximal values in LP). Indeed, in LP, melatonin
receptor density underwent strong daily variations with maximal values during the
first half of the light period and minimal values at the end of the night. These
variations depended on changes in the maximal binding (Bmax) without differences
in the dissociation constant (Kd). In contrast, PT melatonin receptor density was
constant and at a very low level throughout the light:dark cycle in SP exposed
animals. Daily PT melatonin receptor density variations of LP exposed animals
were abolished by pinealectomy or continuous light exposure. These results show
clearly that both at the daily and at the seasonal level the regulation of PT
melatonin receptors is strongly dependent on circulating melatonin concentrations
in the Syrian hamster, but that other regulatory factors, yet unclarified, might
also play a role.
PMID- 9551855
TI - Melatonin prevents apoptosis induced by 6-hydroxydopamine in neuronal cells:
implications for Parkinson's disease.
AB - It was recently reported that low doses of 6-hydroxydopamine (6-OHDA) induce
apoptosis of naive (undifferentiated) and neuronal (differentiated) PC12 cells,
and this system has been proposed as an adequate experimental model for the study
of Parkinson's disease. The mechanism by which this neurotoxin damages cells is
via the production of free radicals. Given that the neurohormone melatonin has
been reported 1) to be a highly effective endogenous free radical scavenger, 2)
to increase the mRNA levels and the activity of several antioxidant enzymes, and
3) to inhibit apoptosis in other tissues, we have studied the ability of
melatonin to prevent the programmed cell death induced by 6-OHDA in PC12 cells.
We found that melatonin prevents the apoptosis caused by 6-OHDA in naive and
neuronal PC12 cells as estimated by 1) cell viability assays, 2) counting of the
number of apoptotic cells, and 3) analysis and quantification of DNA
fragmentation. Exploration of the mechanisms used by melatonin to reduce
programmed cell death revealed that this chemical mediator prevents the 6-OHDA
induced reduction of mRNAs for several antioxidant enzymes. The possibility that
melatonin utilized additional mechanisms to prevent apoptosis of these cells is
also discussed. Since this endogenous agent has no known side effects and readily
crosses the blood-brain-barrier, we consider melatonin to have a high clinical
potential in the treatment of Parkinson's disease and possibly other
neurodegenerative diseases, although more research on the mechanisms is yet to be
done.
PMID- 9551854
TI - N-acetyl-serotonin (normelatonin) and melatonin protect neurons against oxidative
challenges and suppress the activity of the transcription factor NF-kappaB.
AB - It is now well established that the formation of free radicals and oxidative
stress-induced neuronal cell death can be involved in various neurodegenerative
disorders, including Alzheimer's disease and Parkinson's disease. The pineal
hormone melatonin has been suggested to be a neuroprotective antioxidant. To
better understand the molecular mechanism of this activity, we compared the
ability of melatonin and its precursor, N-acetyl-serotonin (normelatonin), to
protect human neuroblastoma SK-N-MC cells and primary cerebellar granular neurons
against oxidative stress. We found that normelatonin and melatonin have
differential neuroprotective effects depending on the neuronal cell type.
Normelatonin was more protective against hydrogen peroxide (H2O2) and glutamate
induced cell death in SK-N-MC cells compared to melatonin which was more
effective to protect primary cerebellar granular neurons against the toxicity of
H2O2, glutamate and N-methyl-D-aspartate when compared to normelatonin. At the
molecular level, we tested the capacity of normelatonin and melatonin to inhibit
the oxidative stress-induced NF-kappaB activation in both neuronal systems.
Whereas normelatonin was more potent in the suppression of the activation of NF
kappaB by H2O2 in SK-N-MC cells compared to melatonin, no apparent differences in
the extent of suppression could be detected in primary neurons. Normelatonin's
and melatonin's neuroprotective activity in SK-N-MC neuroblastoma cells may be
mediated by the suppression of NF-kappaB activation.
PMID- 9551856
TI - Auto-regulation of thyroid hormone receptor genes during metamorphosis: roles in
apoptosis and cell proliferation.
AB - Amphibian metamorphosis is an excellent model system for studying postembryonic
development in vertebrates. It involves specific degeneration of larval cells
through programmed cell death with apoptotic morphology and selective
proliferation and differentiation of adult cell types. Thyroid hormone (T3) plays
a causative role in this process and the effects of T3 is presumed to be mediated
by T3 receptors (TRs). Studies in other systems have suggested that TRs function
as heterodimers formed with RXRs (9-cis retinoic acid receptors) and require the
presence of various cofactor in transcriptional activation and repression in the
presence and absence of T3, respectively. The T3-induced transcriptional
activation leads to chromatin remodeling which may involve some of the cofactors.
Recent investigation on receptor expression has implicated a role of TRs in T3
induced apoptosis in larval tissues and proliferation of adult cell types.
Functional studies in tadpoles and developing embryos have provide strong support
for such a role and further demonstrate the importance of RXR in mediating the
effect of T3.
PMID- 9551857
TI - The generation of fiber diversity during myogenesis.
AB - Adult muscle is composed of different fiber types distinguished by their speed of
contraction and metabolism. The generation of these differences is related both
to the sequence in which muscle fibers form and to differences between the
myogenic cells involved. Fibers form in two successive waves (primary and
secondary) whose time of appearance can be correlated with the existence of
successive populations of myogenic cells (embryonic and fetal). The differences
between fibers arise through an interplay between heritable cellular commitment,
where cells are preprogrammed to produce particular types of fiber and influences
from the limb environment. The techniques of genetically marking cells and clonal
analysis in vivo and in vitro are starting to reveal the relationship between
these different influences. Although the process of myogenesis is similar in
birds and mammals it is likely that cell autonomous behaviour plays a more
important role during avian development as compared to mammals. The
identification of muscle specific transcription factors has provided some clues
to the mechanisms by which development is controlled but the expression of
relatively few of these has been correlated with the sequence of events seen in
myogenesis.
PMID- 9551858
TI - Cell-cell signaling during neurogenesis: some answers and many questions.
AB - Development of a multicellular organism requires that cells communicate with each
other in order to regulate their growth, organize into tissues and coordinate
their function. This cell-cell communication is mediated by signals cells receive
(or send) between each other and from the environment. The signaling can be a
short range remote signaling (through secreted signaling molecules), contact
signaling (via plasma membrane bound molecules, gap junctions) or a long range
signaling (through hormones). In this article, I have reviewed the recent
advances on the role of cell-cell signaling in the development of the embryonic
nervous system of the fruitfly Drosophila melanogaster and discussed some of the
open questions raised by these studies. It discusses the contributions of the
neurogenic genes Notch and Delta and the signaling pathways controlled by
wingless, patched and hedgehog in neuroblast formation, neuroblast identity
specification and neuroblast lineage elaboration.
PMID- 9551859
TI - Tissue and developmental distribution of Six family gene products.
AB - To examine the presence and distribution of Six family gene products in a variety
of tissues at various developmental stages and in various cell types, we prepared
specific antibodies against recombinant Six gene products. The distribution of
Six2 and Six4 was examined by immunostaining in the developing mouse embryo.
Production of Six2 was detected at E8.5 mainly in the mesenchyme, while Six4 was
present in nuclei of neuronal cells in the peripheral region of the mantle layer
of developing brain and spinal cord and in various ganglia at E10.5 and E11.5.
Specific DNA binding activities of the Six proteins were analyzed by gel
retardation super-shift assays using nuclear extracts from different rat tissues
and cell lines. Six5 was the dominant isoform observed in the adult kidney, liver
and lung but not in the brain. Six4 was not detected in all tested adult tissues,
however, it was present in embryonic (FD21) lung nuclear extracts. In contrast,
Six4 was detected in a variety of cultured cell lines, including HeLa, 3T3, MDCK
and C2C12. Our results suggest that Six4 plays a specific role in the
differentiation or maturation of neuronal cells, while Six5 is an adult type Six
gene isoform product and is distributed in the kidney, liver and lung.
PMID- 9551860
TI - Formation of polar cytoplasmic domains (teloplasms) in the leech egg is a three
step segregation process.
AB - Segregation and proliferation of mitochondria, leading to formation of the
teloplasms (pole plasms), were studied in eggs of the leech T. rude by
immunocytochemistry, fluorescent time lapse video imaging, confocal and electron
microscopy. The translocation of mitochondria was analyzed after loading the egg
with either Rhodamine 123 or a Mitotracker. Mitochondrial proliferation was
assessed after pulse labeling with BrdU. The involvement of the cytoskeleton in
the segregation process was determined by drug action. The teloplasms form during
the first interphase as consequence of a 3-step sequential process of
mitochondrial redistribution throughout the egg cytoplasm. The first step is a
microtubule dependent process of ectoplasm thickening due to centrifugal
mitochondrial transportation from the neighboring endoplasm. During the second
step mitochondria move in the plane of the ectoplasm to become concentrated at
the wall of rings (polar rings) and bands of contraction. This process appears to
mostly depend on actin. The furrowing pattern of the egg during this step can be
modified by cold treatment and seems to be determined during oogenesis. During
the third step the ectoplasm flows to either of the poles in conjunction with
bipolar displacement of the polar rings and shortening of the contraction bands.
This step depends on both microtubules and microfilaments. Mitochondria of first
interphase eggs have three special features: (1) they move in clusters, (2) their
movement depends on both microtubules and microfilaments and (3) they proliferate
continuously. During the first interphase the polarized meiotic egg becomes a
bipolar cell.
PMID- 9551861
TI - Expression and function of tap in the gustatory and olfactory organs of
Drosophila.
AB - We have recently described the identification of a gene, tap, which encodes a
bHLH protein expressed in one neuron of each larval chemosensory organ. Here we
show that tap is expressed at a late stage in the development of one type of
adult chemosensory organ, the gustatory bristles of the leg, wing and proboscis.
We also show that tap is expressed very early in the development of a second type
of chemosensory receptors, the olfactory organs of the antenna. The results of
behavioral experiments suggest that the ectopic expression of tap affects the
response to sugar and salt.
PMID- 9551862
TI - Cloning of the Xenopus integrin alpha(v) subunit and analysis of its distribution
during early development.
AB - One striking feature of the integrin alpha(v) subunit is its ability to associate
with at least five different beta subunits (beta1, beta3, beta5, beta6 and beta8)
to form functional receptors. These receptors are involved in diverse biological
processes, such as differentiation, cell adhesion and migration. Here we report
the cloning of the Xenopus homolog of the integrin alpha(v) subunit. Integrin
alpha(v) mRNA and protein are maternally supplied and present throughout
development. During gastrulation and neurulation alpha(v) protein appears on cell
membranes of all three germ layers. In tailbud stage embryos great amounts of the
alpha(v) protein can be observed in the inner layer of the ectoderm and in the
endothelial cells lining the pharynx and gut.
PMID- 9551863
TI - Blastomeres and cells with mesendodermal fates of carp embryos express cth1, a
member of the TIS11 family of primary response genes.
AB - The carp cth1 gene, related to the mammalian TIS11 family of primary response
genes, encodes a novel fish protein with two putative CCCH zinc fingers. This
report describes the RNA expression of this gene during cleavage, blastula and
gastrula stages of carp embryos. Cth1 mRNA is present in all cleavage stage
blastomeres as a maternal message. After the late blastula stage, the maternal
expression decreases, revealing a spot of higher expression at the margin of the
blastoderm of the dome stage embryo. Further decrease of the maternal message
reveals a ring of cth1 expressing cells at the blastoderm margin from the stage
of 40% epiboly onwards. By alpha-amanitin treatment we established that this
local cth1 expression is of zygotic origin. At the onset of gastrulation the
cells of the cth1 ring involute, starting with those in the shield region, and at
approximately 60% epiboly the ring is fully involuted and occupies the hypoblast
layer. All cth1 transcripts have disappeared at completion of epiboly. We discuss
a possible role for the putative cth1 protein during cleavage and gastrulation.
PMID- 9551864
TI - HB-GAM/pleiotrophin: localization of mRNA and protein in the chicken developing
leg.
AB - The heparin-binding growth-associated molecule HB-GAM (also named pleiotrophin)
is a developmentally-regulated protein that belongs to a new family of heparin
binding molecules with putative functions during cell growth and differentiation.
In order to study the localization of HB-GAM during chicken embryogenesis, we
produced specific monoclonal antibodies to this factor. HB-GAM protein is first
observed at stage 23 in the developing nervous system and later in the forming
cartilage. We present an investigation of the HB-GAM mRNA expression and HB-GAM
protein distribution in the developing leg by in situ hybridization and
immunocytochemical studies. We focused our attention on the development of the
tibia, where the HB-GAM protein appears at stage 27-28, i.e., just after the
condensation of the mesodermal precursor cells of the chondrocytes. The protein
then progressively accumulates in the central part of the embryonic cartilage
(diaphysis). It persists until stage 42-44 in the regions where hypertrophic
cartilage is being replaced by bone marrow. In contrast to the protein, the
transcript is first detected at stage 26-27 and later expressed essentially in
the epiphysis until stage 37. Therefore the localization of the mRNA does not
parallel that of the protein and our data suggest a long half-life of the protein
in the hypertrophic cartilage. In addition, the layer of stacked cells
surrounding the cartilage core (usually considered as the osteoprogenitor cells)
clearly expresses the HB-GAM message between stages 30-37 whereas differentiated
osteoblasts do not. Furthermore, the distribution of HB-GAM protein in the
osteoblast/osteoid layer suggests an involvement of this protein in early steps
of osteogenesis. HB-GAM is absent from the newly formed bone.
PMID- 9551865
TI - Direct transdifferentiation in the vertebrate retina.
AB - Transdifferentiation is the process by which differentiated cells alter their
identity to become other, distinct cell types. The conversion of neural retina
into lens epithelium is one of the most spectacular examples of
transdifferentiation. We show that the redirection of cell fate from neural
retina to lens and subsequent transdifferentiation is independent of cell
replication as it occurs in growth-arrested cell populations. Using DNA
ratiometry of individual cells in these cultures we show that, indeed, individual
amitotic cells do transdifferentiate. Hence, choice of fate in
transdifferentiating cells does not rely on a "community effect" but instead can
be categorized as a <> For lack of overt lens progenitors, and
most importantly, for its mitotic independence, we conclude that lens colony
formation in vitro does occur by direct transdifferentiation and not by clonal
proliferation of progenitor cells.
PMID- 9551866
TI - Local increase level of chondroitin sulfate induces changes in the
rhombencephalic neural crest migration.
AB - Numerous studies suggest that chondroitin sulfate proteoglycan (CSPG) inhibits
neural crest cells (NCC) migration at the trunk level. However, its action on the
cephalic neural crest is not clear. To determine this action, we have
microinjected 0.5 nl of different concentrations of chondroitin sulfate (CS) at
the anterior rhombencephalon level in 9 stage chick embryos, as well as
subgerminally administering beta-D-xyloside to 8 stage chick embryos. Beta-D
xyloside disrupts CSPG synthesis, producing an increase in CS free chains in
several embryonal anlages. Chondroitin sulfate microinjected embryos and beta-D
xyloside treated embryos were reincubated until attaining 12 stage. Results
obtained for both experimental groups were similar. Immunoreactivity with HNK-1
antibody revealed that NCC did not migrate, remaining near the rhombencephalon
dorsal wall; in addition, several NCC did not separate from the neural fold,
becoming invaginated towards the rhombencephalon cavity. Our findings indicate
that an increase in CS free chains in cephalic neural crest migratory routes not
only disrupts their migration, but also impedes delamination and detachment of
the rhombencephalic neuroepithelium NCC. These data suggest that the inhibitory
action upon the neural crest migration attributed to CSPG may rest on its
glycosaminoglycan (GAG). We cannot, however, rule out the possibility that
increases in other GAGs apart from CS, may produce similar effects on neural
crest migration.
PMID- 9551867
TI - Laminin fragment E4 inhibition studies: basement membrane assembly and embryonic
lung epithelial cell polarization requires laminin polymerization.
AB - Laminins (LMs), the main constituents of basement membranes (BMs), are
heterotrimeric glycoproteins composed of alpha, beta, and gamma chains held
together by disulfide bonds. In the presence of Ca2+, some laminins, such as
laminin-1 self-assemble into a polymer through the interaction of their three NH2
termini. Here we exposed lung organotypic cultures to a proteolytic fragment of
laminin-1 that blocks laminin polymerization. This fragment, referred as E4,
comprises the outer globular region of laminin beta1 chain. Inhibition of laminin
polymerization in lung organotypic cultures resulted in impaired basement
membrane assembly and failure of epithelial cells to polarize. In addition, we
found that in control organotypic cultures, the bronchial smooth muscle cells
were arranged in concentric layers around the newly formed epithelium. However,
in E4-treated cultures, the smooth muscle cells were in disarray. Exposure of
organotypic cultures to laminin-1 proteolytic fragment P1', that comprises part
of alpha1, beta1, and gamma1 chains, but does not overlap with fragment E4, had
no effect in basement membrane assembly. Exposure to fragment E4 also caused an
increased release of laminin-1 into the culture medium, suggesting a failure to
retain laminin at the epithelial-mesenchymal interface. These studies provide the
first direct evidence linking epithelial cell polarization to laminin
polymerization at the epithelial-mesenchymal interface and assign a key role to
the outer globular region of laminin beta1 chain.
PMID- 9551868
TI - Identification of elf1, a beta-spectrin, in early mouse liver development.
AB - Beta-spectrins play essential roles in cell-cell interactions and in the
maintenance of cell polarity. Our aim was to identify beta-spectrin genes
important for the establishment of hepatocyte polarity and differentiation. Using
subtractive screening of cDNA libraries from early embryonic mouse livers (post
coital days 10, 11, and 12), we have isolated elf1 (embryonic liver fodrin 1), a
differentially expressed beta-spectrin or fodrin (betaSpIIsigmaI). Elf1 encodes a
220-amino acid protein with an NH2 terminal actin-binding domain. In situ
hybridization studies demonstrate elf1 expression initially in day 10 embryonic
heart tissue, then in day 11-11.5 hepatic tissue. These studies suggest that elf1
may play a role in the emergence of hepatocyte polarity during liver development.
PMID- 9551869
TI - Differentiation of the mouse embryoid bodies grafted on the chorioallantoic
membrane of the chick embryo.
AB - In order to test the developmental potential of the mouse embryonic-stem-cell
derived embryoid bodies as chorioallantoic grafts, the embryoid bodies were
transplanted to the chorioallantoic membrane (CAM) of the chick embryo. The graft
implantation was achieved if the embryoid bodies were transferred to the CAM into
the blood drop created by gentle laceration of a CAM blood vessel. The resulting
tumors were recovered after 10 days, when they were rounded white elevations, up
to 1 mm big. Histological analysis showed that they were made of groups of
compacted epithelial-like cells and fibroblast-like spindle shaped cells divided
by the CAM mesenchyme. The grafting caused angiogenic response of the CAM. Blood
vessels converged toward the tumor and spread through the CAM mesenchyme among
the groups of condensed cells. Although the embryonic bodies were able to implant
to the CAM of the chick, their differentiation did not result in a wide variety
of differentiated cell types or in the formation of complex structures resembling
morphogenesis. Thus in comparison with in vitro differentiation of embryoid
bodies on an adhesive substrate, or in vivo differentiation under the mouse
kidney capsule, the differentiation potential of embryoid bodies as
chorioallantoic grafts appeared restricted. However, we suggest that the
accessibility of the chorioallantoic graft can be an advantage for future
experiments.
PMID- 9551870
TI - Break-through for calcium antagonists in the treatment of hypertension based on
the Syst-Eur results.
PMID- 9551871
TI - Normotensive offspring of hypertensive parents: no evidence of left ventricular
diastolic dysfunction in a cross-sectional study.
AB - Left ventricular filling alterations occur early in the development of systemic
hypertension. We tested the hypothesis that alteration of diastolic filling might
be present in a normotensive population with increased genetic risk for
hypertension in the absence of increased left ventricular mass. In a blinded
study we compared 31 lean, normotensive offspring of hypertensive parents having
normal left ventricular mass (risk group) with 30 matched individuals without
family history of hypertension (control group). Left ventricular diastolic
function was assessed using Doppler echocardiography. Transmitral flow velocities
showed no significant differences between the two groups. Peak early diastolic
flow was 0.79+/-0.12 m/s and 0.79+/-0.13 m/s in the risk group and control group,
respectively. Peak late diastolic flow was 0.44+/-0.08 in the risk group and
0.42+/-0.11 m/s in the control group. The ratio of early to late diastolic
velocity was 1.85+/-0.32 and 1.94+/-0.37. The deceleration time of the early
diastolic flow was identical in both groups: 138+/-24 ms and 138+/-23 ms. There
was no significant prolongation of the isovolumic relaxation time in the risk
group: 75+/-17 compared to 73+/-17 ms in the control group. Doppler measurements
showed no correlation with left ventricular mass. We conclude that, in this cross
sectional study, young normotensive offspring of hypertensive parents do not
exhibit Doppler echocardiographic signs of diastolic filling alteration in the
absence of increased left ventricular mass.
PMID- 9551872
TI - Gender and the systemic hypertension-snoring association: a questionnaire-based
case-control study.
AB - Since the role of gender in the association between hypertension and snoring is
unknown, we studied it while accounting for age and body mass index (BMI) as
confounding variables. A questionnaire on snoring was administered to 90
hypertensive (HT) subjects (45 men and 45 women) and to 90 normotensive (NT)
subjects matched for gender, age and BMI. As expected, snoring was more commonly
reported by men than by women, but no significant difference was found between HT
and NT men, irrespective of age. Conversely, heavy snoring was more frequently
reported by HT than NT women; habitual snoring was more common among young (age <
50 years) HT than NT women; and heavy snoring was more common among older (age >
50 years) HT than NT women. These data suggest an effect of gender on the
hypertension-snoring association: in men, snoring may be accounted for by age and
BMI whether or not hypertension is present, whereas in women the natural history
of snoring appears different and more severe in HT than in NT. Although the
mechanism(s) responsible for the differences between men and women are obscure at
present, gender may be an important variable in the systemic hypertension-snoring
association.
PMID- 9551873
TI - Adrenomedullin levels are high in primary aldosteronism due to adenoma and
decline after surgical cure.
AB - The aim of the study was to evaluate the possible changes in plasma
adrenomedullin (AM) levels in patients with primary aldosteronism before and
after surgical resection. The study included 13 patients affected by aldosterone
producing adenoma (9 women, 4 men; mean age 36.2+/-14.2 years) and 20 healthy
control subjects (7 women, 13 M; mean age 31.8+/-12.4 years). Unilateral
adrenalectomy was performed in all patients and adrenal mass consisted of a
benign adrenal cortical adenoma. The mean plasma AM concentrations in patients
with primary aldosteronism (36.2+/-19.3 pg/ml) were significantly (p < 0.0001)
higher than those of normal subjects (13.2+/-6.2 pg/ml). In these patients the
plasma AM levels significantly (p < 0.0001) reduced after surgical removal of the
tumours (14.9+/-7.6 pg/ml). In all patients with aldosterone-producing adenoma,
tumour diameter correlated with the plasma AM concentrations (r=0.631; p <
0.021). In conclusion, the present investigation shows that in primary
aldosteronism due to adrenal adenoma plasma AM levels are higher at the moment of
diagnosis and decline after successful adrenal operation.
PMID- 9551874
TI - A placebo-controlled comparison of diltiazem and amlodipine monotherapy in
essential hypertension using 24-h ambulatory monitoring.
AB - Thirty patients (17 females, median age 55 years) with mild/moderate hypertension
(sitting diastolic blood pressure 95-110 mmHg over 2 consecutive weeks)
participated in a study of the efficacy and tolerability of once-daily diltiazem
"controlled delivery" 180 mg-360 mg and amlodipine 5-10 mg compared with placebo
(using clinic and 24-h ambulatory blood pressure measurement (Accutraker II). The
study was conducted in a general practice setting using a randomized double-blind
crossover design with Latin square allocation of treatment order within subjects.
During each phase, doses were titrated to achieve a predose clinic sitting
diastolic blood pressure of 90 mmHg. Three patients withdrew while taking
amlodipine and 3 while taking placebo. The numbers of patients receiving the
higher dose in each phase were as follows: placebo 22, diltiazem 12 and
amlodipine 19. End-of-phase mean clinic sitting blood pressures were as follows:
placebo 152/100, diltiazem 146/95 and amlodipine 140/93. End-of-phase mean 24-h
ambulatory blood pressures were as follows: placebo 151/93, diltiazem 143/86 and
amlodipine 137/84. Both clinic and ambulatory blood pressures were therefore
significantly reduced (p < 0.01) in both active phases compared with placebo, and
systolic blood pressure was also significantly lower with amlodipine compared
with diltiazem. Heart rate was increased with amlodipine. Both drugs were well
tolerated, and adverse events were predictable for each agent, with amlodipine
causing more vasodilator side effects. Thus both amlodipine and diltiazem once
daily are effective in reducing blood pressure. While amlodipine is more potent
than diltiazem in reducing systolic blood pressure, it causes more vasodilator
side effects.
PMID- 9551875
TI - Comparison of the angiotensin II receptor antagonist irbesartan with atenolol for
treatment of hypertension.
AB - In this multicenter, double-blind study, the antihypertensive efficacy and safety
of irbesartan were compared with those of atenolol in patients with mild-to
moderate hypertension. Following a 4- to 5-week placebo lead-in period, 231
patients with seated diastolic blood pressure (SeDBP) 95-110 mmHg were randomized
to irbesartan 75 mg or atenolol 50 mg once daily for 24 weeks. Doses were doubled
at Week 6 for SeDBP > or = 90 mmHg. At Week 12, or anytime thereafter, doses were
doubled for SeDBP > or = 90 mmHg if not done at Week 6, and hydrochlorothiazide
and then nifedipine were added. Efficacy was determined by change from baseline
in blood pressure and by therapeutic response rates. Safety was assessed by
monitoring adverse events (AEs). Both treatments significantly lowered blood
pressure from baseline. There were no significant differences between treatment
groups with respect to blood pressure changes or therapeutic response. Atenolol
significantly reduced seated heart rate compared with irbesartan at Week 12. The
incidences of serious AEs and discontinuations due to AEs were approximately
twice as high in the atenolol group compared with the irbesartan group. Thus, in
comparison to atenolol, irbesartan < or = 150 mg provided at least equivalent
blood pressure control while demonstrating an excellent safety and tolerability
profile.
PMID- 9551876
TI - A 5-year comparison of doxazosin and atenolol in patients with mild-to-moderate
hypertension: effects on blood pressure, serum lipids, and coronary heart disease
risk.
AB - The long-term efficacy and safety of once-daily treatment with doxazosin or
atenolol were compared in a 5-year study in patients with mild-to-moderate
hypertension. The study consisted of a 1-year, multicenter, double-blind,
parallel-group phase, followed by a 4-year, open-label extension phase. Of the
228 patients enrolled, 100 patients (54/111 doxazosin and 46/117 atenolol)
completed the 5-year study. Both treatments were similarly efficacious in
controlling blood pressure. As assessed by the Framingham risk equation, which
incorporates lipid parameter values, patients receiving doxazosin had
significantly less chance of developing coronary heart disease (CHD) within 10
years compared with those patients receiving atenolol (p < 0.05). Doxazosin
significantly (p=0.0005) reduced the mean CHD risk from baseline to final visit
by 12.3%; whereas, atenolol produced essentially no change in mean risk (0.2%
increase). In patients receiving doxazosin, statistically significant (p < 0.05)
increases from baseline were observed in serum concentrations of high-density
lipoprotein (HDL) cholesterol and the HDL/total cholesterol ratio during the
first 2 and 3 years of treatment, respectively. In contrast, significant (p <
0.05) percent reductions from baseline in both these lipid parameters were seen
in atenolol-treated patients during most of the 5-year trial. Between-group
differences were statistically significant (p < 0.01) at all time points.
Decreases in total cholesterol were similar between the two treatment groups.
Triglycerides, however, significantly increased with atenolol treatment (p <
0.0001 vs baseline) while remaining essentially unchanged with doxazosin
treatment. The safety profiles of doxazosin and atenolol were comparable. Thus,
while demonstrating similar antihypertensive efficacy and safety during this 5
year study, once-daily treatment with doxazosin produced a significantly greater
beneficial effect on both 10-year CHD risk and serum lipid parameters compared
with atenolol.
PMID- 9551878
TI - The antihypertensive effect and tolerability of candesartan cilexetil, a new
generation angiotensin II antagonist, in comparison with losartan.
AB - This multicentre study compared the antihypertensive effect and tolerability of
the novel angiotensin II antagonist candesartan cilexetil with those of losartan
and placebo. Men and women aged 20-80 years, with primary hypertension and
sitting diastolic blood pressure (DBP) 95-114 mm Hg after a 4-week placebo run-in
period, were randomized to once daily double-blind treatment with candesartan
cilexetil 8 mg (n=82), candesartan cilexetil 16 mg (n=84), losartan 50 mg (n=83)
or placebo (n=85) for 8 weeks. Blood pressure was measured 6 and 24 h after dose,
i.e. at peak and trough. Differences between treatments were analysed by analysis
of covariance, and the primary effect variable was reduction in trough sitting
DBP. Compared with placebo treatment, trough DBP was significantly reduced by a
mean (95% CI) of 8.9 (6.0; 11.8) mm Hg with 8 mg and 10.3 (7.4; 13.2) mm Hg with
16 mg candesartan cilexetil. The 8 mg dose was as effective as losartan 50 mg,
while 16 mg candesartan cilexetil was significantly more effective, with a
difference between treatments of 3.7 (0.8; 6.7) mm Hg (p=0.013). The placebo
corrected trough/peak ratio was 0.9-1.1 with candesartan cilexetil and 0.7 with
losartan. Candesartan cilexetil was similarly well tolerated as placebo. In
conclusion, candesartan cilexetil 8 mg or 16 mg once daily is an effective and
well tolerated antihypertensive treatment. Candesartan cilexetil 16 mg is
significantly more effective than losartan 50 mg once daily.
PMID- 9551877
TI - Relationship between salt and blood pressure in hypertensive patients on chronic
ACE-inhibition.
AB - We investigated the effect of a 4-day oral salt load (150 mmol NaCl extra per
day) on blood pressure, erythrocyte sodium transport and the activity in the
renin-angiotensin system in six males with primary hypertension, who had attained
normotension on chronic enalapril treatment for 4 years. The design was a placebo
controlled, randomized, two-way cross over, double-blind study, i.e. each patient
served as his own control. Intracellular erythrocyte sodium and potassium content
were measured by flame photomometry. The increase in the intracellular sodium
concentration during 1 h in 37 degrees C incubation of whole-blood with ouabain
(compared with no-ouabain) was measured to determine the rate of active sodium
efflux. 24-h blood pressure registration was performed with Space-lab equipment
(SL 90202) before and at the end of the salt load. Left ventricular morphology
was evaluated with echocardiography and the minimal vascular resistance of the
hand vascular bed with water plethysmography at baseline and after 4 years on
enalapril. Four years' enalapril treatment caused a significant decrease in blood
pressure, left ventricular mass and minimal vascular resistance. During the 4-day
salt load average 24-h blood pressure was significantly elevated, 129+/-3/85+/-2
mmHg as compared to 124+/-2/82+/-2 mmHg during placebo treatment (p=0.025). The
change (delta) in MAP during high salt intake showed a negative relationship to
delta-sodium efflux rate constant (r=-0.65, p=0.047). No significant relationship
was found between the blood pressure response to the salt load and structural
cardiovascular changes. In conclusion, a short-term oral salt load in
hypertensive patients on chronic enalapril treatment caused a blood pressure
rise, which was related to cellular sodium transport but not to structural
cardiovascular changes.
PMID- 9551880
TI - Imported dracunculiasis--United States, 1995 and 1997.
AB - Dracunculiasis is a parasitic infection caused by a filarial worm (Dracunculus
medinensis [i.e., Guinea worm]) that is transmitted through contaminated drinking
water. Approximately 1 year after a person is infected, one or more meter-long
adult female worms begin to emerge through the skin, often incapacitating the
patient for > or =2 months. Despite a dramatic decrease in cases worldwide,
dracunculiasis is still occasionally imported into the United States. Since 1995,
two cases of dracunculiasis have been reported in the United States, both
imported from Sudan. This report summarizes the investigation of these cases.
PMID- 9551879
TI - Tissue angiotensin II concentration in the heart and kidneys in transgenic
Tsukuba hypertensive mice.
AB - Tsukuba hypertensive mice (THM) are transgenic mice carrying both human renin and
angiotensinogen genes, and possessing an overexpressing human renin-angiotensin
system. The aim of this study is to evaluate the angiotensin II concentration in
the heart and kidney in THM. Twenty-week-old male THM and control C57BL/6 mice
(C57) were used. Each group consisted of 3 mice. For each mouse, systolic blood
pressure, heart to body weight ratio, renal glomerular sclerosis index and
angiotensin II concentration in the heart and kidney were measured. Systolic
blood pressure of THM was about 40 mmHg higher than that of C57. Heart to body
weight ratio and renal glomerular sclerosis index were significantly higher in
THM than those in C57. The angiotensin II concentration in THM was about 4 times
higher in the heart and about 5 times higher in the kidney compared with that in
C57. These results suggest that accelerated tissue angiotensin II production,
significant cardiac hypertrophy and renal glomerular sclerosis all occur because
of hypertension.
PMID- 9551881
TI - Update: HIV counseling and testing using rapid tests--United States, 1995.
AB - Approximately 25 million persons each year in the United States are tested for
antibody to human immunodeficiency virus (HIV). Publicly funded counseling and
testing (CT) programs conduct approximately 2.5 million of these tests each year.
CT can have important prevention benefits; however, in 1995, 25% of persons
testing HIV-positive and 33% of persons testing HIV-negative at publicly funded
clinics did not return for their test results. Rapid tests to detect HIV antibody
can be performed in an average of 10 minutes, enabling health-care providers to
supply definitive negative and preliminary positive results to patients at the
time of testing, potentially increasing the overall effectiveness of CT. In
comparison, results from enzyme immunoassays (EIAs) currently used for HIV
screening often are not available for 1-2 weeks. To quantify the potential
advantages and disadvantages of using rapid tests for CT, CDC estimated the
potential impact on the number of persons who would learn their HIV-test results.
This report summarizes the results of the analysis and provides the basis for
changing the Public Health Service (PHS) recommendations for providing HIV-test
results.
PMID- 9551882
TI - Strategies for providing follow-up and treatment services in the National Breast
and Cervical Cancer Early Detection Program--United States, 1997.
AB - The Breast and Cervical Cancer Mortality Prevention Act of 1990 authorized CDC to
establish the National Breast and Cervical Cancer Early Detection Program
(NBCCEDP) to increase screening services for women at low income levels who are
uninsured or underinsured. Although the NBCCEDP covers most diagnostic services
that women need after receiving an abnormal mammography or Papanicolaou (Pap)
test result, the program does not reimburse for breast biopsies. In addition, the
Act prohibits the use of NBCCEDP funds for cancer treatment. Participating health
agencies must ensure that NBCCEDP clients receive timely, appropriate diagnostic
and treatment services. In 1996, CDC began a case study to determine how early
detection programs in seven participating states (California, Michigan,
Minnesota, New Mexico, New York, North Carolina, and Texas) identified resources
and obtained diagnostic and treatment services. This report summarizes the
results of the study, which indicate that respondents in these states reported
that treatment had been initiated for almost all NBCCEDP clients in whom cancer
was diagnosed. However, respondents also considered the strategies used to obtain
these services as short-term solutions that were labor-intensive and diverted
resources away from screening activities.
PMID- 9551883
TI - Differential TCR signaling and the generation of memory T cells.
AB - There are currently two models for the generation of memory T cells: 1) memory T
cells arise directly from activated effector T cells that have reverted to the
resting state via an unknown mechanism; and 2) memory T cells are generated
directly from naive T cells, bypassing an effector stage. I discuss here how
recent results on the activation and signaling requirements of naive vs memory
CD4 T cells favor the second model and how differential signaling of naive T
cells may direct their developmental outcome.
PMID- 9551884
TI - A critical, invariant chain-independent role for H2-M in antigen presentation.
AB - Antigen presentation by MHC class II (class II) is facilitated by the accessory
molecules, invariant chain (Ii) and H2-M. Ii associates with class II during
biosynthesis and promotes transport of class II to Ag-loading compartments. One
function of H2-M is the removal of Ii fragments from MHC class II. We have
previously demonstrated that Ii-deficient mice, unlike class II-deficient mice,
are resistant to L. major infection. In the present study, we found that H2-M
deficient (H2-M0) mice were susceptible to progressive infection with L. major.
The dispensability of Ii for control of L. major allowed genetic analysis of
whether H2-M functions by association with or independently of Ii. In contrast to
Ii-deficient (Ii0) mice, Ii0H2-M0 mice were as susceptible to L. major as H2-M0
mice. Thus, H2-M has an essential, Ii-independent function during presentation of
microbial pathogens.
PMID- 9551885
TI - Cytokine-dependent abortion in CBA x DBA/2 mice is mediated by the procoagulant
fgl2 prothrombinase [correction of prothombinase].
AB - Spontaneous resorption in the CBA x DBA/2 model is attributed to NK cells,
macrophages, and Th1-type cytokines. In vivo depletion of NK cells by anti
asialoGM1 Ab or macrophage depletion by silicon dioxide treatment reduced
abortion rates, which could no longer be boosted by injecting TNF-alpha (which
activates NK cells) or IFN-gamma (which activates macrophages). TNF-alpha + gamma
IFN coadministration aborted >80% of the embryos whether or not NK cells or
macrophages had been depleted or estradiol + progesterone was injected to correct
potential reduction in ovarian function by cytokines. The cytokines also aborted
IRF1+/+ C57BL/6 but not IRF1-/- females pregnant by IRF1+/+ DBA/2. Both
spontaneous and cytokine-boosted abortions in CBA x DBA/2 were blocked by Ab to
fgl2 prothrombinase [corrected] expressed by cytokine-stimulated vascular
endothelial cells and monocytes; in vivo Ab depletion of granulocytes also
prevented TNF-alpha + IFN-gamma-induced abortions. Cytokine-triggered
thrombotic/inflammatory processes in maternal uteroplacental blood vessels causes
abortion.
PMID- 9551886
TI - T helper 1 and T helper 2 cells respond differentially to chemokines.
AB - T effector subsets, such as Th1 or Th2 cells, are key players in inflammatory
reactions. It is not known whether chemokines are able to recruit these subsets
differentially, as has been shown for memory vs naive T cells. Here we
demonstrate that Th1 and Th2 cells differ in their intrinsic migratory properties
and their chemotactic responsiveness toward distinct chemokines. While the CC
chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES
were efficient chemoattractants for Th1 cells, inducing a dose-dependent
transmigration, Th2 cells were not attracted by these chemokines. Another CC
chemokine, JE/monocyte chemoattractant protein (MCP)-1, and a CXC-chemokine,
stromal cell-derived factor (SDF)-1alpha, exerted chemotactic effects on both Th1
and Th2 cells, but differences in sensitivity and the percentage of responding
cells were recorded between both subsets. These results indicate that chemokines
play a distinct role in the regulation of local immune reactions by influencing
the local balance between proinflammatory and antiinflammatory T cell subsets.
PMID- 9551887
TI - Detection of MCP-4 in dermal fibroblasts and its activation of the respiratory
burst in human eosinophils.
AB - CC-chemokines are an important family of proinflammatory mediators that promote
the recruitment and activation of human eosinophils in chronic inflammatory
diseases. Recently, a novel human CC-chemokine, monocyte chemotactic protein 4
(MCP-4), has been reported that shows amino acid sequence similarities with
eotaxin and RANTES, induces chemotaxis of eosinophils, and signals through
specific chemokine receptors. In this study, we investigated the effect of MCP-4
on different eosinophil effector functions leading to the activation of the
respiratory burst. In human eosinophils, MCP-4 dose dependently induced the
production of reactive oxygen species and actin polymerization as a related
event. Pretreatment of eosinophils with different enzyme inhibitors interacting
with the signal transduction cascade revealed that Gi protein, protein kinase C,
tyrosine kinase, and phosphatidylinositol-3-kinase are involved in the signaling
following stimulation with MCP-4. In addition, cytokine-stimulated human dermal
fibroblasts expressed high levels of MCP-4 mRNA, suggesting that fibroblasts are
a physiologic source of MCP-4. Therefore, this study demonstrates that there is
an important role of MCP-4 in the activation of eosinophils and that the
interaction between dermal fibroblasts and human eosinophils may play an
important role within the cytokine network.
PMID- 9551888
TI - Suppression of immune responses by CD8 cells. I. Superantigen-activated CD8 cells
induce unidirectional Fas-mediated apoptosis of antigen-activated CD4 cells.
AB - Stimulation of mature CD4 cells through the TCR induces cellular activation and
expansion that are often followed by clonal elimination by a form of apoptosis
termed activation-induced cell death. This process of CD4 cell apoptosis is
generally thought to reflect clonal suicide and to be independent of other cell
types. Here we show that during the response to the superantigen Staphylococcal
enterotoxin A, activated CD8 cells, but not activated CD4 cells, suppress the CD4
proliferative response. Suppression by CD8 cells reflects their ability to induce
CD4 cell apoptosis via ligation of Fas. Moreover, although activated CD8 cells
that express Fas ligand and Fas eliminate CD4 cells through a Fas-dependent
mechanism, they are themselves resistant to Fas-dependent apoptosis. These
findings indicate a fundamental difference between the two major T cell subsets
with regard to sensitivity to Fas-dependent apoptosis, expression of Fas ligand,
and mediation of suppressive activity following immunization with superantigen.
PMID- 9551889
TI - Suppression of immune responses by CD8 cells. II. Qa-1 on activated B cells
stimulates CD8 cell suppression of T helper 2 responses.
AB - We have investigated the role of MHC class I products and CD8 T cells in
regulating Ab responses using beta2-microglobulin deficient (beta2m-/-) mice.
Beta2m-/- mice produced stronger IgM and IgG responses than did control beta2m+/+
mice to both cellular and viral Ags. These Ab responses could be suppressed by
infusion of activated B cells from beta2m+/+ mice. Further investigation showed
that the beta2m-associated molecule on activated B cells that induced CD8
suppression was Qa-1 and that the Th2 component of CD4 cells was most affected by
CD8-suppressive activity. Our findings suggest a novel pathway of Th inhibition
in which B cell presentation of Qa-1-associated peptides stimulates CD8
suppressive activity.
PMID- 9551890
TI - Rejection of allogeneic and syngeneic but not MHC class I-deficient tumor grafts
by MHC class I-deficient mice.
AB - The ability of TAP1-/-, beta2m-/-, and TAP1/beta2m-/- mice to mount rejection
responses against allogeneic, syngeneic, and MHC class I-deficient tumor grafts
was examined. The results demonstrate a potent ability of TAP1-/- and beta2m-/-
as well as TAP1/beta2m-/- mice to reject allogeneic tumors. In contrast to
published data, rejection of syngeneic MHC class I-expressing tumors was also
observed. This response was specific for the MHC class I-deficient mice, since
wild-type mice did not reject syngeneic MHC class I-positive tumors under
identical experimental conditions. The rejection response of syngeneic tumors
required preimmunization of the mice and was MHC class I specific at the level of
priming as well as at the level of the tumor target. Finally, MHC class I
deficient tumor grafts were accepted in MHC class I-deficient mice while similar
grafts were rejected in wild-type mice. In summary, while MHC class I-deficient
mice have retained a capacity to reject allogeneic tumors. they have gained an
ability to reject syngeneic MHC class I-positive tumors and lost the ability to
reject MHC class I-negative tumors. The present results are discussed in relation
to the role of MHC class I molecules in selecting functional CD8+ T and NK cell
repertoires, and the development of cell-mediated immunity.
PMID- 9551891
TI - Ovalbumin-specific, MHC class I-restricted, alpha beta-positive, Tc1 and Tc0 CD8+
T cell clones mediate the in vivo inhibition of rat IgE.
AB - In the following study, we demonstrate that medium responder PVG rats immunized
i.p. with OVA complexed to the adjuvant aluminum hydroxide exhibit a moderate IgE
response (400-1000 ng/ml). In these rats, we demonstrate that underlying the MHC
class II-restricted CD4+ T cell response, there is an MHC class I-restricted CD8+
T cell component that plays an important role in restricting the magnitude and
duration of the IgE response. We show that in vivo depletion of CD8+ T cells
effects a massive increase in IgE (20-fold), and that they are MHC class I
restricted, OVA-specific, cytolytic cells that universally produce IFN-gamma (25
69 ng/ml) and IL-2 (7.6-22 U/ml), and occasionally secrete IL-4 (68-81 U/ml IL
4), and when adoptively transferred into CD8-depleted recipients, can effect a
significant reduction in IgE (3- to 50-fold). We also demonstrate that this in
vivo inhibition of IgE is dependent on the Ag-specific activation of the CD8+ T
cells, and that the activated CD8+ T cells will suppress total/bystander IgE in
an Ag-nonspecific manner. These data are consistent with a growing literature
demonstrating sensitization of MHC class I-restricted CD8+ T cells by exogenous
protein Ags delivered to mucosal sites, and may represent a mechanism whereby a
selective pressure can be applied on the functional outcome of an immunoglobulin
response to environmental allergens.
PMID- 9551892
TI - Reduced T helper 1 responses in IL-12 p40 transgenic mice.
AB - To investigate the antagonistic effect of IL-12 p40 on IL-12 activity in vivo, we
generated transgenic (Tg) mice in which p40 gene was regulated by a liver
specific promoter. Three Tg mouse lines were generated, and they expressed the
p40 transgene predominantly in liver. Serum p40 level was extremely high, and it
consisted of mainly monomer and homodimer and also of higher m.w. complexes.
These Tg mice did not show any apparent phenotypic difference from control
littermates in lymphoid cells. Enhancement of NK cell lytic activity in spleen by
administration of rIL-12 to these mice was greatly diminished. Ag induced
cytokine production was impaired: decreased production of IFN-gamma and increased
production of IL-4 and IL-10. Delayed-type hypersensitivity response was also
significantly reduced. Moreover, these Tg mice showed increased susceptibility to
the infection with an intracellular pathogen, blood-stage Plasmodium berghei XAT,
which is an irradiation-induced attenuated substrain of P. berghei NK65,
presumably due to the decreased IFN-gamma production. These results suggest that
p40 functions as an IL-12 antagonist in vivo, and that Th1 responses in p40 Tg
mice are significantly reduced. Thus, these Tg mice could be a useful model to
evaluate the inhibitory effect of p40 on IL-12-mediated various immune responses
in vivo.
PMID- 9551893
TI - CD40 ligand exerts differential effects on the expression of I gamma transcripts
in subclones of an IgM+ human B cell lymphoma line.
AB - The CD40:CD40 ligand (CD40L) interaction plays a critical role in T cell
dependent isotype switching. To elucidate the role of CD40 signaling in the
activation of gamma germline transcription and as an extension, in targeting
Cgamma regions for isotype switching, an IgM+ Burkitt lymphoma cell line (Ramos
2G6) was assayed for the up-regulation of germline gamma transcripts after CD40L
stimulation. Independent Ramos 2G6 subclones that either expressed (Igamma+) or
did not express (Igamma-) basal levels of Igamma transcripts were assessed for
their transcriptional response to CD40L signaling by contact with either a Jurkat
T cell line (D1.1) or a transfected CD40L-expressing epithelial cell line
(293/CD40L) in the presence or absence of IL-4. Both Igamma- and Igamma+ Ramos
2G6 subclones cultured with IL-4 and CD40L markedly up-regulated germline
transcription predominantly from the gamma1, gamma2, and gamma3 subclasses over
levels obtained with IL-4 alone. In addition, these two signals were required to
obtain de novo switch recombination. However, incubation with CD40L alone
resulted in a substantial increase in germline transcription only in the Igamma+
and not the Igamma- subclones. Observed basal transcription at the gamma1 locus
also correlated with the ability of not only the gamma1 locus, but also the
gamma2 and gamma3 loci, to up-regulate germline transcripts in response to CD40
signaling. These data are consistent with CD40:CD40L contact up-regulating
germline transcription only after the B cell has received a signal that alters
the transcriptional state of the heavy chain locus.
PMID- 9551894
TI - MHC class II expression in double mutant mice lacking invariant chain and DM
functions.
AB - Invariant (Ii) chain and DM functions are required at distinct stages during
class II maturation to promote occupancy by diverse peptide ligands. The class II
molecules expressed by mutant mouse strains lacking Ii chain or DM activities
display discrete structural and functional abnormalities. The present report
describes the cellular and biochemical characteristics of Ii-DM- doubly deficient
mice. As for Ii chain mutants, their mature Aalphab Abetab dimers similarly
exhibit reduced mobilities in SDS-PAGE, and in functional assays these molecules
behave as if empty or occupied by an easily displaced peptide. Additionally, the
present experiments demonstrate that the production of floppy Aalphab Abetab
dimers is TAP independent. In comparison with Ii chain mutants, Ii-DM- doubly
deficient cell populations exhibit increased peptide binding activities and
consistently greater presentation abilities in T cell stimulation assays. These
functional differences appear to reflect higher class II surface expression
associated with their increased representation of B lymphocytes. We also observe
defective B cell maturation in mice lacking Ii chain or DM expression, and
interestingly, B cell development appears more severely compromised in Ii-DM-
double mutants. These mutant mice lacking both Ii chain and DM activities should
prove useful for analyzing nonconventional class II Ag presentation under normal
physiological conditions in the intact animal.
PMID- 9551895
TI - Intercellular adhesion molecule-1 and leukocyte function-associated antigen-3
provide costimulation for superantigen-induced T lymphocyte proliferation in the
absence of a specific presenting molecule.
AB - Bacterial superantigens can bind TCR in the absence of MHC class II molecules and
activate T lymphocytes when cocultured with certain class II-deficient accessory
cells. It has not been determined, however, whether these accessory cells provide
direct costimulation to the T cell or serve to present superantigens via a
nonconventional ligand. We have identified a human adenocarcinoma cell line,
SW480, that assists in the activation of human T cells by the staphylococcal
enterotoxins B (SEB), C1 (SEC1), and D (SED), but not SEA, SEC2, SEC3, or SEE.
SW480 cells did not express class II molecules, and anti-class II mAbs did not
inhibit T cell proliferation, supporting the hypothesis that class II is not
absolutely required for enterotoxin-mediated T cell activation. The TCR Vbeta
profile of T cells stimulated by SEB plus SW480 cells was similar to that of T
cells stimulated by SEB plus class II+ APC, indicating that TCR-SEB interactions
were preserved in the absence of class II molecules. Binding studies failed to
detect specific association of SEB with SW480 cells, suggesting that SW480 cells
do not express receptors for enterotoxin. SEB coupled to beads, however,
stimulated T cell proliferation, but only in the presence of SW480 cells. SW480
cells express both ICAM-1 and LFA-3 molecules, and the addition of Abs to these
receptors inhibited T cell proliferation. These findings support a model in which
certain enterotoxins engage the TCR independent of MHC class II or other specific
presenting molecules and induce T cell proliferation with signals provided by
nonconventional accessory cells.
PMID- 9551896
TI - Blockade of chemokine activity by a soluble chemokine binding protein from
vaccinia virus.
AB - Chemokines direct migration of immune cells into sites of inflammation and
infection. Chemokine receptors are seven-transmembrane domain proteins that, in
contrast to other cytokine receptors, cannot be easily engineered as soluble
chemokine inhibitors. Poxviruses encode several soluble cytokine receptors to
evade immune surveillance, providing new strategies for immune modulation. Here
we show that vaccinia virus and other orthopoxviruses (cowpox and camelpox)
express a secreted 35-kDa chemokine binding protein (vCKBP) with no sequence
similarity to known cellular chemokine receptors. The vCKBP binds CC, but not CXC
or C, chemokines with high affinity (Kd = 0.1-15 nM for different CC chemokines),
blocks the interaction of chemokines with cellular receptors, and inhibits
chemokine-induced elevation of intracellular calcium levels and cell migration in
vitro, thus representing a soluble inhibitor that binds and sequesters
chemokines. The potential of vCKBP as a therapeutic agent in vivo was illustrated
in a guinea pig skin model by the blockade of eotaxin-induced eosinophil
infiltration. a feature of allergic inflammatory reactions. Furthermore, vCKBP
may enable the rational design of antagonists to neutralize pathogens that use
chemokine receptors to initiate infection, such as HIV or the malarial parasite.
PMID- 9551897
TI - The level of CD4 surface protein influences T cell selection in the thymus.
AB - During T cell development thymocytes are subjected to positive and negative
selection criteria to ensure that the mature T cell repertoire is MHC restricted,
yet self tolerant at the same time. The CD4 and CD8 coreceptors are thought to
play a crucial role in this developmental process. To elucidate the role of CD4
in T cell selection, we have produced a mouse strain that expresses CD4 at a
reduced level. We used homologous recombination in embryonic stem cells to insert
neo into the 3' untranslated region of CD4. The resulting mice have a reduction
in the percentage of CD4+ cells in the thymus and a concomitant increase in CD8+
cells. In addition, breeding two individual class II-restricted TCR transgenic
mice onto the CD4low (low level of CD4) mutant background affects the selection
of each TCR differentially. In one case (AND TCR transgenic), significantly fewer
CD4+ cells with the transgenic TCR develop on the CD4low mutant background,
whereas in the other (5C.C7 TCR transgenic), selection to the CD4 lineage is only
slightly reduced. These data support the differential avidity model of positive
and negative selection. With little or no avidity, the cell succumbs to
programmed cell death, low to moderate avidity leads to positive selection, and
an avidity above a certain threshold, presumably above one that would lead to
autoreactivity in the periphery results in clonal deletion. These data also
support the idea that a minimum avidity threshold for selection exists and that
CD4 plays a crucial role in determining this avidity.
PMID- 9551899
TI - Perforin protects against autoimmunity in lupus-prone mice.
AB - The roles of cytolytic regulatory mechanisms in the immune system of lupus-prone
mice were examined in perforin-deficient animals bearing functional or defective
(lpr) Fas Ag (CD95). Perforin-deficient Fas+ animals developed accelerated
autoimmunity, characterized by increased hypergammaglobulinemia, autoantibody
production, and immune deposit-related end-organ disease compared with perforin
intact counterparts. In comparison, perforin-deficient lpr animals had
accelerated mortality compared with perforin-intact lpr mice, associated with the
abnormal accumulation of CD3+CD4-CD8- alphabeta T cells in conjunction with
unaltered hypergammaglobulinemia, autoantibody production, and immune complex
renal disease. These results indicate that cytolytic lymphoid regulation plays
critical roles in the immune homeostasis of lupus-prone animals, and identify
perforin-mediated cytotoxicity as a specific mechanism in the regulation of
systemic autoimmunity.
PMID- 9551898
TI - Activation of low avidity CTL specific for a self epitope results in tumor
rejection but not autoimmunity.
AB - To determine how self-tolerance can alter the ability of the immune system to
respond against tumor-associated Ags that are also expressed by normal tissue, we
designed experiments in which the same protein was expressed both as a tumor Ag
and as a transgene product. Unlike conventional BALB/c mice that rejected renal
carcinoma cells transfected with the influenza virus hemagglutinin (Renca-HA),
transgenic mice that are tolerant of HA due to its expression as a self-Ag on
pancreatic islet beta cells, (Ins-HA mice) supported progressive growth of these
tumor cells. However, when Ins-HA mice were immunized with a recombinant strain
of vaccinia virus expressing the dominant H-2Kd peptide epitope of HA before
receiving Renca-HA cells, they too were able to reject the tumor cells. Rejection
of Renca-HA cells by immunized Ins-HA mice was found to be associated with the
generation of CTL having much lower avidity for target cells presenting the KdHA
epitope than CTL from immunized conventional BALB/c mice. Significantly, we show
that self-tolerance to the HA Ag is quantitative rather then absolute, and that
vaccination of Ins-HA mice can activate low avidity KdHA-specific CD8+ T cells
that are able to reject tumor cells expressing high levels of HA, yet these mice
remain tolerant of pancreatic islet beta cells expressing HA.
PMID- 9551900
TI - MHC class II-transfected tumor cells directly present antigen to tumor-specific
CD4+ T lymphocytes.
AB - We have developed and shown to be efficacious an immunotherapeutic strategy to
enhance the generation of tumor-specific CD4+ T helper lymphocytes. The approach
uses autologous tumor cells genetically modified to express syngeneic MHC class
II genes as cell-based immunogens and is based on the hypothesis that tumor cells
directly present tumor Ags to CD4+ T cells. Since the conventional pathway for
CD4+ T cell activation is indirect via professional APC, induction of immunity
following immunization with class II-transfected tumor cells was examined in bone
marrow chimeric mice. Both tumor and host-derived cells are APC for tumor Ags,
suggesting that the efficacy of tumor cell vaccines can be significantly improved
by genetic modifications that enhance tumor cell Ag presentation.
PMID- 9551901
TI - Induction of tyrosine phosphorylation in human MHC class II-positive antigen
presenting cells by stimulation with contact sensitizers.
AB - To investigate the intracellular signaling mechanisms involved in the activation
of APC by contact sensitizers, we studied the induction of tyrosine
phosphorylation by these agents. Selective analysis of phosphotyrosine (p-tyr) in
human Langerhans cells and different mononuclear cell types was achieved using a
multicolor flow-cytometric technique. Stimulation with contact sensitizers
revealed a distinct increase in p-tyr exclusively for MHC class II-positive
cells. For different haptens, irritants, as well as activators of distinct signal
transduction pathways, it was demonstrated that only strong sensitizers or the
protein tyrosine phosphatase inhibitor sodium orthovanadate or cross-linking of
MHC class II molecules were able to induce formation of p-tyr in human blood
derived dendritic cells serving as model for the dendritic cell family. This
event required physiologic cell culture conditions and was blocked by specific
inhibitors of protein tyrosine kinases. No evidence for the inhibition of protein
tyrosine phosphatases by haptens was found. Western blot analysis of monocyte
enriched populations revealed an augmented phosphorylation of distinct proteins
after hapten stimulation partly resembling the pattern noticed after cross
linking of HLA-DR molecules. In dendritic cells generated from mononuclear
progenitors, the protein tyrosine kinase inhibitor genistein was able to block
tyrosine phosphorylation as well as production of IL-1beta mRNA transcripts. Our
data underline the unique capacity of haptens to activate APC and the important
role of tyrosine phosphorylation for this process.
PMID- 9551902
TI - NK cells from human MHC class I (HLA-B) transgenic mice do not mediate hybrid
resistance killing against parental nontransgenic cells.
AB - We have investigated the capacity of human MHC class I HLA-B gene products, HLA
B27, -B7 (fully human), and -B7kb (human-mouse hybrid consisting of the alpha1
and alpha2 domains of HLA-B7, and the alpha3 and cytoplasmic domains of mouse H
2Kb), expressed on mouse NK cells during ontogeny to influence NK recognition of
otherwise syngeneic mouse target cells. Despite a high level of surface
expression of the transgene (comparable to that of endogeneous H-2DbKb
molecules), the direct killing of YAC-1 targets, and the killing of P815 targets
in a redirected lysis assay, the NK effectors of these transgenic mice could not
mediate hybrid resistance-like killing of nontransgenic C57BL/6 target cells
either in vitro or in vivo. Splenocytes from B6-B27 mice could be used to
generate CTL lines against a B27-binding peptide, implying that T cells
restricted by HLA-B27 developed during ontogeny. NK cells from B6-B27 could lyse
B6-B27 Con A lymphoblasts pulsed with Db-binding peptide but not B27-binding
peptides. Taken together, our results show that these human HLA-B transgene
products cannot function as class I MHC "self" elements for mouse NK cells, even
when present throughout ontogeny.
PMID- 9551903
TI - Molecular and genetic requirements for preferential recruitment of TCRBV8S2+ T
cells in Lewis rat experimental autoimmune encephalomyelitis.
AB - The underlying mechanisms behind the preferential expression of select TCRBV
products in certain autoimmune illnesses, such as multiple sclerosis and some
models of experimental autoimmune encephalomyelitis (EAE), have principally
remained enigmatic. In this study, we examined the mutual role of nonself- vs
self-origin of antigenic myelin basic protein (MBP) peptides and given MHC
haplotypes in relation to the relative frequency of activated TCRBV8S2+ T
lymphocytes in the Lewis (LEW) rat EAE model. Inbred MHC (RT1) congenic LEW rats
(LEW (RT1l), LEW.1AV1 (RT1av1), and LEW.1W (RT1u)) were immunized with the 63 to
88 peptide of the guinea pig MBP (MBPGP63-88). Additionally, LEW rats were
immunized with the corresponding autologous rat sequence (MBPRAT63-88). Although
EAE ensued in all MBP peptide/LEW rat strain combinations, only LEW rats
immunized with the heterologous MBPGP63-88 peptide elicited T cell responses
encompassing a bias toward TCRBV8S2 expression, as determined by flow cytometric
analyses. Reduction of TCRBV8S2+ T cells led to mitigation of disease severity in
LEW rats immunized with MBPGP63-88, but not with MBPRAT63-88, indicating that
critical encephalitogenic characteristics are associated with this T cell subset.
We conclude that the preferential recruitment of TCRBV8S2+ T cells in the LEW rat
EAE model is due to selective, high-avidity recognition of the nonself-MBPGP63-88
in the context of the RT1.Bl molecule. This inference lends support to the notion
that the highly restricted TCR repertoire of the self-MBP-reactive T cells in
certain genetically predisposed multiple sclerosis patients may have its source
in a multistep molecular mimicry event.
PMID- 9551904
TI - Adenovector-mediated expression of human thrombopoietin cDNA in immune
compromised mice: insights into the pathophysiology of osteomyelofibrosis.
AB - Thrombopoietin (TPO) cDNA can be effectively delivered in vivo by adenovectors.
Immune normal mice (BALB/c) and syngeneic mice with variable degrees of immune
dysfunction nu, SCID, and NOD-SCID) were treated with an adenovirus vector
expressing the human TPO cDNA (AdTPO). Platelet peaks were significantly higher
in SCID and NOD-SCID mice compared with BALB/c and nu mice. Human plasma TPO
concentration correlated with the platelet counts. SCID and NOD-SCID mice
exhibited also granulocytosis and increased numbers of hemopoietic progenitors in
bone marrow. Following platelet peak, BALB/c mice developed autoantibodies
against murine TPO leading to thrombocytopenia and depletion of megakaryocytes
and hemopoietic progenitors in bone marrow. AdTPO-treated SCID mice developed
osteomyelofibrosis and extramedullary/extrasplenal hemopoiesis. In contrast, NOD
SCID mice with a similar magnitude of TPO overexpression did not show fibrotic
changes in bone marrow. We conclude, first, that a chronic high level of TPO
overexpression stimulates megakaryocytopoiesis and myelopoiesis leading to
thrombocytosis and granulocytosis. Second, increased megakaryocytopoiesis is not
sufficient for development of secondary osteomyelofibrosis. The functionally
deficient monocytes and macrophages of NOD-SCID mice probably prevented fibrotic
marrow changes. Third, immune deficiency enhances expression of adenovirally
mediated transgenes, and fourth, xenogeneic transgene delivered by adenovector to
a host with normal immune functions may induce loss of immune tolerance and
autoimmune phenomenon.
PMID- 9551905
TI - Opposite CD4/CD8 lineage decisions of CD4+8+ mouse and rat thymocytes to
equivalent triggering signals: correlation with thymic expression of a truncated
CD8 alpha chain in mice but not rats.
AB - Unselected CD4+8+ rat thymocytes, generated in vitro from their direct
precursors, are readily converted to functional TCRhigh T cells by stimulation
with immobilized TCR-specific mAb plus IL-2. Lineage decision invariably occurs
toward CD4-8+, regardless of the timing of TCR stimulation after entry into the
CD4+8+ compartment or the concentration of TCR-specific mAb used for stimulation.
CD4-specific mAb synergizes with suboptimal TCR-specific mAb in inducing T cell
maturation, but lineage decision remains exclusively CD4-8+. These results
contrast with those obtained in mice, in which Abs to the TCR complex were shown
to promote CD4+8- T cell maturation from CD4+8+ thymocytes. Surprisingly, when
rat and mouse CD4+8+ thymocytes were stimulated with PMA/ionomycin under
identical conditions, the opposite lineage commitment was observed, i.e., mouse
thymocytes responded with the generation of CD4+8- and rat thymocytes with the
generation of CD4-8+ cells. It thus seems that CD4+8+ thymocytes of the two
species respond with opposite lineage decisions to strong activating signals such
as given by TCR-specific mAb or PMA/ionomycin. A possible key to this difference
lies in the availability of p56lck for coreceptor. supported signaling. We show
that in contrast to mouse CD4+8+ thymocytes, which express both a complete and a
truncated CD8 alpha-chain (CD8 alpha') unable to bind p56lck, rat thymocytes only
express full-length CD8 alpha molecules. Mice, but not rats, therefore may use
CD8 alpha' as a "dominant negative" coreceptor chain to attenuate the CD8 signal,
thereby facilitating MHC class II recognition through the higher amount of p56lck
delivered, and rats may use a different mechanism for MHC class distinction
during positive selection.
PMID- 9551906
TI - Three populations of mouse lymph node dendritic cells with different origins and
dynamics.
AB - We have identified three distinct populations of mouse lymph node dendritic cells
(DC) that differ in their capacity to uptake Ag delivered by different routes,
and in their dynamics. The "I-DCs" are large cells that resemble the
interdigitating cells and have a mature phenotype and a slow turnover. They
derive from the regional tissues. The "sm-DCs" and "sI-DCs" are smaller (hence s
DC), have a more immature phenotype and a rapid turnover. The sI-DC phenotype,
including CD8alpha expression suggests a lymphoid-related origin. The sI-DC
population is expanded 100-fold after an in vivo flt3 ligand treatment. The sm-DC
phenotype suggests a myeloid-related origin. Interestingly, sm-DCs can acquire
i.v. injected macromolecules in less than 30 min after injection. They may,
therefore, play an important role in the immune response against blood Ags.
PMID- 9551907
TI - Positive selection of thymocytes expressing the same TCR by different MHC ligands
results in the production of functionally distinct thymocytes distinguished by
differential expression of the heat stable antigen.
AB - The issue of whether the signaling process during positive selection can affect
the efficiency by which the positively selected T cells respond to antigenic
stimulation has not been addressed. We approached this question by determining
the consequences of positive selection of a particular transgenic TCR (2C TCR) in
the H-2b and the H-2k thymus. The H-2b thymus provides a strong positive
selecting environment for the 2C TCR, whereas the H-2k thymus selects weakly for
the 2C TCR. Although the positively selected CD8 thymocytes from the H-2b or H-2k
thymus expressed similar levels of the CD8 coreceptor molecule, those for the H
2k thymus expressed a slightly lower level of the 2C TCR. This lower level of 2C
TCR expression by H-2k CD8 thymocytes was not a result of coexpression of
endogenous TCRs. Interestingly, CD8 thymocytes from H-2k mice were hyporesponsive
to Ag stimulation compared with those from the H-2b mice. The functional maturity
of positively selected CD8 thymocytes from the H-2b or H-2k thymus was inversely
correlated with the level of heat stable Ag expressed by these cells.
Furthermore, TCR-derived signals appear to be more efficiently coupled to
downstream pathways leading to proliferation and cytokine production in CD8
thymocytes from H-2b 2C mice than those derived from H-2k 2C mice. These results
provide the first demonstration that the intensity of the signaling process
during positive selection affects the efficiency by which TCR-derived signals in
positively selected thymocytes are coupled to downstream effector pathways.
PMID- 9551908
TI - A periarteriolar lymphoid sheath-associated B cell focus response is not observed
during the development of the anti-arsonate germinal center reaction.
AB - The behavior of p-azophenylarsonate (Ars)-specific B cell clones during the
primary T cell-dependent splenic response of A/J mice was investigated using an
immunohistochemical approach. The earliest Ars-specific B cells were observed as
isolated cells in the red pulp by day 3 after immunization with Ars-keyhole
limpet hemocyanin, (KLH) and at day 6, large clusters of Ars-specific B cells
were first detected in germinal centers, which continued to be observed for an
additional 8 to 15 days. Surprisingly, no Ars-specific B cell foci were observed
in or near the CD4 T cell-rich periarteriolar lymphoid sheath (PALS) during the
entire primary response. Nevertheless, A/J mice immunized with (4-hydroxy-3
nitrophenyl)acetyl-chicken gamma globulin (NP-CGG) or Ars-CGG mounted robust
splenic (4-hydroxy-3-nitrophenyl)acetyl or CGG-specific PALS-associated focus
reactions, respectively. In contrast, no Ars-specific PALS B cell foci were
detected in A/J mice immunized with Ars-CGG. These data add to a growing body of
evidence indicating that B cell proliferation and differentiation in CD4 T cell
rich microenvironments are not prerequisites for the GC reaction. Taken together
with previous results obtained using other model Ags, the data suggest that the
specificity of the B cell Ag receptor may strongly influence the lymphoid
microenvironment in which a B cell clone first undergoes Ag-driven clonal
expansion and differentiation.
PMID- 9551909
TI - Aberrant intermolecular disulfide bonding in a mutant HLA-DM molecule:
implications for assembly, maturation, and function.
AB - HLA-DM (abbreviated DM) is an MHC-encoded glycoprotein that catalyzes the
selective release of peptides, including class II-associated invariant chain
peptides, from MHC class II molecules. To perform its function, DM must assemble
in the endoplasmic reticulum (ER), travel to endosomes, and interact productively
with class II molecules. We have described previously an EBV-transformed B cell
line, 7.12.6, which displays a partial Ag presentation defect and expresses a
mutated DM beta-chain with Cys79 replaced by Tyr. In this study, we show that HLA
DR molecules in 7.12.6 have a defect in peptide loading and accumulate class II
associated invariant chain peptides (CLIP). Peptide loading is restored by
transfection of wild-type DMB. The mutant DM molecules exit the ER slowly and are
degraded rapidly, resulting in greatly reduced levels of mutant DM in post-Golgi
compartments. Whereas wild-type DM forms noncovalent alphabeta dimers, such
dimers form inefficiently in 7.12.6; many mutant DM beta-chains instead form a
disulfide-bonded dimer with DM alpha. Homodimers of DM beta are also detected in
7.12.6 and in the alpha-chain defective mutant, 2.2.93. We conclude that during
folding of wild-type DM, the native conformation is stabilized by a conserved
disulfide bond involving Cys79beta and by noncovalent contacts with DM alpha.
Without these interactions, DM beta can form malfolded structures containing
interchain disulfide bonds; malfolding is correlated with ER retention and
accelerated degradation.
PMID- 9551910
TI - Lack of local suppression in orally tolerant CD8-deficient mice reveals a
critical regulatory role of CD8+ T cells in the normal gut mucosa.
AB - We found that feeding keyhole limpet hemocyanin (KLH) to CD8-deficient (CD8-/-)
mice induced oral tolerance that was comparable in both magnitude and quality to
that induced in wild-type (wt) mice. The tolerance was dose dependent, and only
higher doses of KLH caused significant reduction in specific Ab and T cell
responses. Both Th1 and Th2 CD4+ T cell functions were affected. Feeding KLH
together with cholera toxin (CT) adjuvant, however, abrogated the induction of
oral tolerance equally well in CD8-/- and wt mice. On the contrary, CT adjuvant
was unable to abrogate already established oral tolerance in both CD8-/- and wt
mice. Most importantly, whereas Ag feeding induced hyporesponsiveness in systemic
as well as in local gut IgA responses in wt mice, a lack of local suppression was
evident in orally tolerant CD8-/- mice following oral immunizations. Thus,
contrary to the situation in wt mice, Ag feeding induces systemic, but not local,
gut IgA hyporesponsiveness in CD8-/- mice, suggesting that CD8+ T cells in the
normal gut mucosa exert an important down-regulatory function. In wt mice the
local suppression extended to an unrelated Ag, OVA, given together with KLH and
CT adjuvant, i.e., bystander suppression. Based on these results we propose that
tolerance induced by feeding Ag is highly compartmentalized, requiring CD8+ T
cells for local suppression of IgA responses, whereas systemic tolerance may
affect CD4+ T cells of both Th1 and Th2 types independently of CD8+ T cells.
Finally, the adjuvant effect of CT abrogates induction, but not established, oral
tolerance through a mechanism that does not require CD8+ T cells.
PMID- 9551911
TI - T cell growth cytokines cause the superinduction of molecules mediating antigen
induced T lymphocyte death.
AB - TCR stimulation of T lymphocytes that are activated and cycling in the presence
of IL-2 leads to programmed cell death. We now show that this effect is at least
partly attributable to the ability of IL-2 to dramatically increase the
expression of mRNAs encoding ligands and receptors that mediate apoptosis. We
also found that cyclosporin was not able to fully inhibit the TCR induction of
death molecule mRNAs or TCR-induced apoptosis, although it could completely turn
off IL-2 expression. The effect growth cytokines was further explored in T cells
derived from mice bearing a homozygous deficiency of the IL-2R alpha-chain. We
found that IL-2Ralpha-/- cells were resistant to death if IL-2 was used to induce
apoptosis susceptibility, but that large amounts of other T cell growth
cytokines, such as IL-4 and IL-7, could induce cell cycle progression and promote
TCR-induced apoptosis. However, our findings suggest that autoimmunity and
lymphoproliferation in IL-2Ralpha-/- mice can result from the loss of IL-2
stimulated feedback apoptosis and that other growth cytokines are not produced at
levels sufficient to compensate for this deficit.
PMID- 9551913
TI - Presence of activated antigen-binding B cells during immunization enhances
relative levels of IFN-gamma in T cell responses.
AB - To examine the influence of Ag presentation by B cells on immune responses, we
have used mice transgenic for an Ig heavy chain from a monoclonal anti
azobenzenearsonate (Ars) Ab to deliver Ag to B cells during immunization. A large
proportion of transgene-expressing B cells in these mice binds Ars, while
transgenic serum Ig shows poor Ars binding. Transgenic B cells present Ars
proteins better than their nonhaptenated counterparts. This is associated with an
increase in the proliferative responses of transgenic T cells to Ars protein
immunization. Although B cell numbers in the transgenic mice are lower, many B
cells in them show an activated phenotype, as identified by altered surface
levels of peanut agglutinin reactivity, CD23, CD24, CD44, CD62L, and CD86. Even
against nonhaptenated immunogens, transgenic responses show significant
enhancement in the relative proportions of the Th1 cytokine IFN-gamma over the
Th2 cytokines IL-4 and IL-10. Haptenated immunogens further enhance the
predilection of transgenic mice to produce relatively more IFN-gamma. Consistent
with this, there is an increase in IgG2a/IgG1 ratios in serum Abs in response to
haptenated immunogens in transgenic mice. Adoptive transfer of primed hapten
specific secondary B cells into nontransgenic mice also induces an increase in
relative levels of IFN-gamma in response to haptenated immunogens. Thus,
presentation of immunogen in vivo by activated Ag-binding B cells contributes to
enhanced immunogenicity and a Th1 cytokine bias.
PMID- 9551912
TI - TGF-beta 1 induces the cyclin-dependent kinase inhibitor p27Kip1 mRNA and protein
in murine B cells.
AB - TGF-beta1 inhibits the cell cycle progression of many types of cells by arresting
them in the G1 phase. This cell cycle arrest has been attributed to the
regulatory effects of TGF-beta1 on both the levels and the activities of the G1
cyclins and their kinase partners. The activities of these kinases are negatively
regulated by a number of proteins, such as p15INK4b, p21WAF1/Cip1, and p27Kip1,
that physically associate with cyclins, cyclin-dependent kinases (Cdk), or cyclin
Cdk complexes. In epithelial cell lines, TGF-beta1 was previously shown to
inhibit cell cycle progression through down-regulation of Cdk4 and/or up
regulation of p15INK4b and/or p21WAF1/Cip1. However, TGF-beta1 had little or no
effect on the p27Kip1 mRNA and protein levels. In this report, we show that, in
contrast to observations in epithelial cell lines, TGF-beta1 increased the
p27Kip1 mRNA and protein levels in the murine B cell lines CH31 and WEHI231. This
TGF-beta1-mediated induction of p27Kip1 also resulted in an increased association
of p27Kip1 with Cdk2 and a decreased Cdk2 kinase activity. In contrast to
epithelial cells, however, TGF-beta1 had little or no effect on the Cdk4 and
p21WAF1/Cip1 protein levels in these B cells. Finally, although several studies
suggested a direct role of p53 in TGF-beta1-mediated cell cycle arrest in
epithelial cells, TGF-beta1 inhibited cell cycle progression in CH31 even in the
absence of wild-type p53. Taken together, these results suggest that TGF-beta1
induces G1 arrest in B cells primarily through a p53-independent up-regulation of
p27Kip1 protein.
PMID- 9551914
TI - Role of proteasomes in T cell activation and proliferation.
AB - The role of proteasomes in T cell activation, proliferation, and apoptosis was
investigated using a proteasome-specific inhibitor lactacystin (LAC). Inhibition
of the proteasome activity by LAC repressed the mitogen-induced T cell
proliferation. The proteasome activity was definitively required for the T cells
to progress from the G0 to S phase. It was necessary to optimize the progress
from the G1/S boundary to the G2/M phase, but not for the progress from the G2/M
phase to the next G1 phase. Probably as a result of a blockage of cell cycle
progress, the cycling, but not the resting, T cells underwent apoptosis when
treated with LAC. Mechanistically, we have found that cyclin-dependent kinase-2
(CDK2) and the cyclin E-associated kinase (largely CDK2), but not CDK4, in the G1
phase were strongly inhibited by LAC. This could be an important mechanism for
the proteasome to regulate the cell cycle. The degradation of cyclin E in the
late G1 and early S phases was dependent on the proteasome, although it was
unlikely that this accounted for the observed inhibition of T cell proliferation.
There was a reduced decay of p27Kip1 in the late G1 phase when the proteasome
activity was suppressed, and this might be a contributing mechanism for the
observed inhibition of CDK2 activity. Interestingly, p21Cip1 was up-regulated
during the G1 phase, and the up-regulation was inhibited by LAC. Our study shows
that the proteasome plays pivotal roles in regulating T cell activation and
proliferation, and its effect is probably exerted through multiple mechanisms.
PMID- 9551915
TI - Degenerate recognition of alloantigenic peptides on a positive-selecting class I
molecule.
AB - The well-defined 2C T cell was used to investigate alloreactive degeneracy. A
panel of class I molecules that are known ligands for the 2C TCR were sensitized
with three known peptide ligands, p2Ca (LSPFPFDL), dEV-8 (EQYKFYSV), and SIYR-8
(SIYRYYGL). The peptide p2Ca was originally identified as the allopeptide seen in
the Ld class I molecule by 2C T cells, 2C recognizes the dEV-8 peptide as the
ligand in the Kbm3 class I molecule, and SIYR-8 was recently identified as a
peptide ligand for 2C in the context of the Kb class I molecule. Strong
recognition of all three Ag-presenting molecules occurred in the context of their
respective allopeptides, but 2C recognized all three peptides to a measurable
extent in the context of Kb. Molecular modeling of these Kb/peptide complexes
revealed a high degree of similarity between dEV-8 and SIYR-8, but very little
conformational similarity of either of these peptides with p2Ca. Furthermore, the
structural changes in the mutant Kbm3 binding site resulted in generalized
changes in the conformation of each of five bound peptides compared with those of
the same peptides bound to Kb. The finding that degenerate recognition occurs on
Kb, the restriction element responsible for selecting 2C T cells, suggests a
unique relationship between a TCR and the Ag-presenting molecule that mediates
its positive selection.
PMID- 9551916
TI - Nuclear targeted suppression of NF-kappa B activity by the novel quinone
derivative E3330.
AB - The activation of NF-kappa B consists of at least three steps: degradation of I
kappa B alpha, translocation of NF-kappa B into the nucleus, ai post
translational modification of NF-kappa B (e.g., phosphorylation of p65). In the
present study, we found that a novel quinone derivative E3330 selectively
inhibited NF-kappa B-mediated gene expression without affecting any of these
steps. E3330, when included in the culture medium, suppressed NF-kappa B DNA
binding activity in PMA-induced Jurkat cell nuclear extracts, suggesting that the
inhibition by E3330 of NF-kappa B-mediated gene expression was due to its ability
to suppress NF-kappa B DNA-binding activity. Fractionation of the nuclear
extracts by column chromatography revealed that a nuclear factor enhanced NF
kappa B DNA-binding activity and that this enhancing activity was interrupted
after treatment with E3330. Moreover, a major polypeptide with a molecular mass
of 40 kDa was found to be in the highly purified fraction containing the NF-kappa
B-enhancing activity and predominantly bind E3330. Taken together, these results
suggest that the NF-kappa B activity, after dissociation from I kappa B, is
enhanced by a nuclear factor that is active irrespective of PMA treatment, and
the nuclear factor-mediated enhancement is selectively inhibited by E3330. Thus,
we conclude that E3330 may belong to a novel class of anti-NF-kappa B drugs.
PMID- 9551918
TI - Distinct patterns of folding and interactions with calnexin and calreticulin in
human class I MHC proteins with altered N-glycosylation.
AB - Calnexin is a lectin-like chaperone that binds to class I MHC molecules soon
after their synthesis, retaining unassembled heavy chains and also assisting
their folding. Following association with beta2-microglobulin (beta2m) in the
endoplasmic reticulum, a large proportion of human class I molecules release from
calnexin, whereas mouse class I molecules do not. We asked whether addition of a
second N-glycan to the human class I molecule A*0201 at position 176, a site
present in mouse, would affect its binding to calnexin. The 176dg mutant with N
glycans at positions 86 and 176, when transfected into CIR cells, demonstrated
increased binding to calnexin, detectable both before and after association with
beta2m, and reduced interaction with calreticulin and TAP relative to wild-type
protein bearing a single N-glycan at position 86. Cell surface levels of the
mutant were decreased only slightly relative to the wild type, suggesting that
the protein is not misfolded or grossly altered structurally. A subpopulation of
mutant molecules was retained in the endoplasmic reticulum, and surprisingly,
these molecules reacted with w6/32, which recognizes an epitope present on
transport-competent class I HLA complexes. Transfection into Daudi cells
demonstrated that 176dg reacts with w6/32 in the absence of beta2m, suggesting
that the Ab epitope can be induced by binding of calnexin. These data may explain
previously noted differences between mouse and human class I MHC proteins and
demonstrate that the location of N-oligosaccharides within proteins can influence
their folding and interactions with chaperones such as calnexin and calreticulin.
PMID- 9551917
TI - Lack of intraclonal diversification in Ig heavy and light chain V region genes
expressed by CD5+IgM+ chronic lymphocytic leukemia B cells: a multiple time point
analysis.
AB - To analyze the modalities of clonal expansion of chronic lymphocytic leukemia
(CLL) cells, we sequenced at multiple time points the V(D)J genes expressed by
CD5+IgM+CLL B cells in three patients. All three V(D)J gene sequences were found
to be point mutated. The mutation frequency in the Ig VH (3.96 x 10(-2) and 2.41
x 10(-2) change/bp) and Vkappa and Vlambda (6.67 x 10(-2) and 1.74 x 10(-2)
change/bp) genes of two CLLs (1.19 and 1.32, respectively) was similar, and
higher than that in the corresponding gene segments of the third CLL (1.69; 3.4 x
10(-3) and 6.67 x 10(-3) change/bp). In all three CLLs, there was no preferential
representation of nucleotide changes yielding amino acid replacement (R
mutations), nor was there any preferential segregation of R mutations within the
Ig V gene complementarity-determining regions. In all three CLLs, the somatic
mutations were all identical in multiple Ig VHDJH transcripts at any given time
point, and were all conserved at multiple time points throughout a 2-yr period.
The lack of concentration of R mutations in the complementarity-determining
regions and the lack of intraclonal heterogeneity suggest that Ag may no longer
be able to play a significant role in the clonal expansion of these cells. This
conclusion would be strengthened further by the germline configuration of the bcl
1 and bcl-2 proto-oncogenes that are translocated in neoplastic B cells that
display significant traces of intraclonal diversification and Ag-dependent
selection, such as B-prolymphocytic leukemia and low grade follicular non-Hodgkin
lymphoma.
PMID- 9551919
TI - Activation of STAT5 by lipopolysaccharide through granulocyte-macrophage colony
stimulating factor production in human monocytes.
AB - LPS is a potent stimulator of monocytes, inducing many of their functions.
Although the details of how LPS exerts such functions remain largely unknown,
transcription factors such as nuclear factor-kappaB, nuclear factor-IL-6, and
activator protein-1 have been shown to be involved in this process. However, to
date it has been thought that no known STAT molecule plays a role in the
activation of monocytes by LPS. In this study we examined whether some known STAT
molecule is stimulated by LPS, based on the finding that a GAS motif sequence is
conserved in the promoter regions of human, mouse, and rat cyclo-oxygenase-2 (COX
2) genes. Consequently, LPS induced activation of STAT5 in human monocytes, and
this STAT5 activation occurred in an indirect way via granulocyte-macrophage CSF
(GM-CSF) secreted by LPS-stimulated monocytes. Expression of COX-2 protein was
partially reduced by treatment of anti-human GM-CSF Ab. Activation of STAT5 was
inhibited by either IL-10 or dexamethasone (Dex), but not by aspirin. IL-10
blocked activation of STAT5 indirectly by suppressing GM-CSF production, while
Dex inhibited this activation both directly and indirectly. Taken together, these
results suggest that in addition to other transcription factors, STAT5 plays an
important role in activation of monocytes by LPS, and that STAT5 is another
target for IL-10 and Dex to inhibit COX-2 expression in activated monocytes.
PMID- 9551920
TI - In vitro and in vivo mechanisms of action of the antiproliferative and
immunosuppressive agent, brequinar sodium.
AB - Intracellular pyrimidine nucleotides (PyN) can be synthesized de novo from
glutamine, CO2, and ATP, or they can be salvaged from preformed pyrimidine
nucleosides. The antiproliferative and immunosuppressive activities of brequinar
sodium (BQR) are thought to be due to the inhibition of the activity of
dihydroorotate dehydrogenase, which results in a suppression of de novo
pyrimidine synthesis. Here we describe the effects of the pyrimidine nucleoSide,
uridine, on the antiproliferative and immunosuppressive activities of BQR. In
vitro reduction of PyN levels in Con A-stimulated T cells and inhibition of cell
proliferation by low concentrations of BQR (< or =65 microM) are reversed by
uridine. However, uridine is unable to reverse the effects of high concentrations
of BQR (> or =65 microM). The ability of BQR to induce anemia in BALB/c mice is
prevented by the coadministration of uridine. In contrast, the immunosuppressive
activity of BQR is unaffected by similar doses of uridine. PyN levels in the bone
marrow, but not in the spleen, are depressed in mice treated with BQR. These
observations suggest that the induction of anemia by BQR is due to depletion of
intracellular PyN in hemopoietic stem cells located in the bone marrow. They also
suggest that the mechanism of immunosuppression by BQR may be only marginally
dependent on depletion of intracellular PyN in lymphocytes located in the
periphery. We report a novel activity of BQR: inhibition of tyrosine
phosphorylation, and hypothesize that the immunosuppressive activity may be due,
in part, to this unsuspected ability of BQR to inhibit tyrosine phosphorylation
in lymphocytes.
PMID- 9551921
TI - Separation of function between the domains of toxic shock syndrome toxin-1.
AB - Toxic shock syndrome toxin-1 (TSST1) is a superantigenic exotoxin produced by
certain strains of Staphylococcus aureus Structurally, TSST1 is composed of two
domains: residues determined by crystallography to directly interact with MHC II
molecules reside within the N-terminal domain, while TSST1 residues critical for
superantigenicity are within the C-terminal domain. In this study, we expressed
the individual N- and C-terminal domains of TSST1 in Escherichia coli and studied
their biologic activities. The TSST1 N-terminal domain (TSST(1-87)) did not
induce proliferation of human PBLs or release of TNF-beta, but did induce TNF
alpha release. However, TSST1-elicited proliferation and release of both TNF
isoforms were inhibited by a molar excess of TSST(1-87). The TSST1 C-terminal
domain (TSST(88-194)) did not bind MHC II molecules, yet it elicited production
of TNF-alpha and TNF-beta, and induced TCR Vbeta-specific proliferation similarly
to intact TSST1. When covalently cross-linked to tumor cells, TSST(88-194)
elicited a local in vivo antitumor response indistinguishable from TSST1.
Although intact TSST1 causes lethal shock in vivo, the individual domains of this
molecule may have therapeutic potential: the N-terminal domain to antagonize
lymphocyte activation and TNF release during acute TSST1-precipitated toxic shock
syndrome, and the C-terminal domain to stimulate antitumor responses without MHC
II binding.
PMID- 9551922
TI - Expression of two different antiphagocytic M proteins by Streptococcus pyogenes
of the OF+ lineage.
AB - All clinical isolates of Streptococcus pyogenes (group A streptococcus) share the
ability to resist phagocytosis and grow in human blood. In many strains, this
property is due to the expression of a single antiphagocytic M protein, while
other strains express more than one M-like molecule, of which the role in
phagocytosis resistance is unclear. In particular, all S. pyogenes strains of the
OF+ lineage, representing approximately half of all isolates, express two M-like
proteins, Mrp and Emm, which are immunologically unrelated. These two proteins
bind different ligands that have been implicated in phagocytosis resistance: Mrp
binds fibrinogen and Emm binds the complement inhibitor C4BP. Using a clinical
isolate of the common serotype 22, we created mutants affected in the mrp and emm
genes and characterized them in phagocytosis experiments and by electron
microscopy. A double mutant mrp-emm- showed strongly decreased resistance to
phagocytosis, while mrp- and emm- single mutants grew well in blood. However,
optimal growth required the expression of both Mrp and Emm. Experiments in which
coagulation was inhibited using the specific thrombin inhibitor, hirudin, rather
than heparin, indicated that Emm is more important than Mrp for resistance to
phagocytosis. Tuftlike surface structures typical for S. pyogenes were still
present in the mrp-emm- double mutant, but not in a mutant affected in the
regulatory gene mga, indicating that the presence of these surface structures is
not directly correlated to phagocytosis resistance. Our data imply that OF+
strains of S. pyogenes express two antiphagocytic M proteins with different
ligand-binding properties.
PMID- 9551923
TI - CpG DNA is a potent enhancer of specific immunity in mice immunized with
recombinant hepatitis B surface antigen.
AB - Unmethylated CpG dinucleotides in bacterial DNA or synthetic
oligodeoxynucleotides (ODN) cause B cell proliferation and Ig secretion, monocyte
cytokine secretion, and activation of NK cell lytic activity and IFN-gamma
secretion in vivo and in vitro. The potent immune activation by CpG ODN suggests
possible utility for enhancing immune responses to vaccines. Mice immunized with
recombinant hepatitis B virus surface Ag and a CpG ODN as an immune enhancer have
titers of Abs against HBsAg (anti-HBs) that are five times higher than those of
mice immunized with HBsAg and the standard adjuvant, aluminum hydroxide (alum).
Ab titers in mice immunized with HBsAg and both CpG ODN plus alum were 35 times
higher than the titers in mice immunized with alum alone, indicating a strong
synergistic interaction between the CpG ODN and alum. ODN without CpG motifs had
little or no immune-enhancing activity at the doses used herein. Alum induces a
Th2 humoral response (mostly IgG1) and no CTL. In contrast, CpG ODN gives a
strong Thl response with predominantly IgG2a Abs and CTL, even when mixed with
alum. In vitro studies to determine possible mechanisms of CpG immune-enhancing
effects show that CpG ODN induce expression of costimulatory molecules on Ag
presenting cells and drive B cell isotype switching in the appropriate cytokine
milieu. These studies demonstrate that CpG ODN are promising new immune enhancers
for vaccination applications.
PMID- 9551924
TI - Identification and characterization of the CXCR4 chemokine receptor in human T
cell lines: ligand binding, biological activity, and HIV-1 infectivity.
AB - The CXCR4 chemokine receptor has been shown to respond to the C-X-C chemokine
stromal-derived factor (SDF-1) and has recently been shown to be an important
coreceptor for HIV-1 infection. In the present paper we have tested a number of
human lymphocyte cell lines, including Jurkat, HUT78, CEM, and Sup-T1 for the
presence of CXCR4 receptors. We found that these T cell lines bind SDF-1alpha and
SDF-1beta with high affinity. The CXCR4 Ab 12G5 inhibited both SDF-1 binding and
HIV-1LAI-mediated fusion of CEM. Scatchard analysis revealed the presence of
approximately 150,000 SDF-1alpha-binding sites per cell with a Kd between 5 and
10 nM. Cross-competition experiments using unlabeled SDF-1alpha and SDF-1beta
revealed that both chemokines are equally capable of displacing their
radiolabeled counterparts. Internalization studies with [125]I-SDF-1alpha
revealed that Jurkat cells internalized greater than 90% of the ligand by 2 h at
37 degrees C. SDF-1alpha was also chemotactic for Jurkat cells and caused an
increase in the rate of extracellular acidification that was half-maximal at 18
nM SDF-1alpha and could be inhibited by pretreatment with the SDF-1 proteins,
pertussis toxin, or the Ab 12G5. Finally, SDF-1alpha also caused an increase in
the cytosolic Ca2+ concentration in Sup-T1 cells that was abolished by
preincubating the cells with pertussis toxin or PMA and inhibited by the Ab 12G5.
This molecular characterization of CXCR4 receptors should prove useful in
clarifying receptor interaction with SDF-1 proteins and with HIV-1 glycoprotein,
with the ultimate aim of targeting the viral interaction for therapeutic
intervention.
PMID- 9551925
TI - Control of Leishmania major by a monoclonal alpha beta T cell repertoire.
AB - Little is known regarding the diversity of the host T cell response that is
required to maintain immunologic control of microbial pathogens. Leishmania major
persist as obligate intracellular parasites within macrophages of the mammalian
host. Immunity is dependent upon activation of MHC class II-restricted T cells to
an effector state capable of restricting growth and dissemination of the
organisms. We generated alpha-beta Leishmania-specific (ABLE) TCR transgenic mice
with MHC class II-restricted T cells that recognized an immunodominant Leishmania
Ag designated LACK. Naive T cells from ABLE mice proliferated in vitro after
incubation with recombinant LACK or with Leishmania-parasitized macrophages and
in vivo after injection into infected mice. Infected ABLE mice controlled
Leishmania infection almost as well as wild-type mice despite a drastic reduction
in the T cell repertoire. ABLE mice were crossed to mice with disruption of the
TCR constant region alpha gene to create animals with a single alpha beta T cell
repertoire. Although mice deficient in all alpha beta T cells (TCR-C alpha 0
mice) failed to control L. major, mice with a monoclonal alpha beta T cell
repertoire (ABLE TCR-C alpha 0 mice) displayed substantial control. The immune
system is capable of remarkable efficiency even when constrained to recognition
of a single epitope from a complex organism.
PMID- 9551926
TI - Recognition of an antigenic peptide derived from tyrosinase-related protein-2 by
CTL in the context of HLA-A31 and -A33.
AB - Tumor-infiltrating lymphocytes (TILs) derived from tumor-bearing patients
recognize tumor-associated Ags presented by MHC class I molecules. The infusion
of TIL586 along with IL-2 into the autologous patient with metastatic melanoma
resulted in the objective regression of tumor. Two T cell epitopes derived from
tumor Ags, tyrosinase-related protein (TRP)-1 and TRP-2, were shown to be
recognized by HLA-A31 restricted TIL586 and its T cell clones. In this study we
tested the hypothesis that these two peptides can be recognized by CTL from non
HLA-A31 patients with melanoma. It was found that both peptides were capable of
binding to HLA-A3, -A11, -A31, -A33, and -A68 of the HLA-A3 supertype.
Importantly, we found that HLA-A33-positive TIL1244 and its T cell clones can
recognize TRP197-205 presented by both HLA-A31 and -A33 molecules, suggesting
that a single TCR can recognize peptide/A31 and peptide/A33 complexes. However,
peptide titration experiments showed that the affinity of TCR receptor to
peptide/A33 could be higher than that to the peptide/A31. These studies have
important implications for the development of peptide-based cancer vaccines.
PMID- 9551927
TI - Perforin-deficient CD8+ T cells provide immunity to Listeria monocytogenes by a
mechanism that is independent of CD95 and IFN-gamma but requires TNF-alpha.
AB - CD8+ T cells are effective mediators of immunity against Listeria monocytogenes,
but the mechanisms by which they provide antilisterial immunity are poorly
understood. CD8+ T cells efficiently lyse target cells in vitro by at least two
independent pathways. To test the hypothesis that CD8+ T cell-mediated immunity
to L. monocytogenes is dependent on perforin or CD95 (Fas, Apo-1), we used
C57BI/6 (B6) and perforin-deficient (PO) mice to generate CD8+ T cell lines
specific for the L. mono cytogenes-encoded Ag listeriolysin O (LLO). Both lines
specifically produce IFN-gamma and TNF-alpha, and mediate target cell lysis in
vitro. Cytolysis mediated by the PO-derived CD8+ T cell line is delayed relative
to the B6-derived line and is completely inhibited by anti-CD95 Abs. In vivo, PO
derived CD8+ T cells provide specific antilisterial immunity in B6 hosts, CD95
deficient hosts, and IFN-gamma-depleted hosts. However, PO-derived CD8+ T cells
fail to provide antilisterial immunity in hosts depleted of TNF-alpha. These
results indicate that single Ag-specific CD8+ T cells derived from PO mice can
mediate antilisterial immunity by a mechanism that is independent of CD95 or IFN
gamma, but requires TNF-alpha.
PMID- 9551928
TI - CXC chemokines suppress proliferation of myeloid progenitor cells by activation
of the CXC chemokine receptor 2.
AB - IL-8 is one of the major mediators of the transendothelial migration of
neutrophils from the circulation to the site of injury and infection. In this
work we demonstrate that the CXC or alpha-chemokines, IL-8 and melanoma growth
stimulatory activity (MGSA) induce myeloid suppression via direct action on
progenitor cells, mediated by activation of the murine homologue of the CXC
chemokine receptor-2 (CXCR2) or IL-8R B. We first show that proliferation of the
IL-3-dependent murine myeloid progenitor cell line 32D is suppressed by human IL
8 and the functionally and structurally related peptide, MGSA. Second, we show
for the first time the high endogenous expression of the murine CXCR2 in 32D
cells, as demonstrated by Northern blot analysis, binding to [125I]macrophage
inflammatory protein-2, and macrophage inflammatory protein-2-induced calcium
responses in 32D cells. Third, we demonstrate that IL-8 and MGSA induce a rise in
intracellular calcium in 32D cells. The IL-8-induced Ca2+ response is
desensitizing, since a second dose of IL-8 did not trigger a second calcium
response. Other chemokines, including neutrophil-activating protein-2, platelet
factor-4, RANTES, and macrophage chemotactic protein-1, neither suppressed the
proliferation of 32D cells nor induced a rise in intracellular calcium. Finally,
the IC50 of IL-8- and MGSA-dependent suppression of proliferation of 32D cells is
in good agreement with the EC50 of IL-8- and MGSA-dependent activation of
neutrophil Mac-1 up-regulation and chemotaxis. Our studies are consistent with
the idea that IL-8 and MGSA suppress the proliferation of 32D cells by activation
of murine CXCR2.
PMID- 9551929
TI - High affinity receptor for IgG (Fc gamma RI/CD64) gene and STAT protein binding
to the IFN-gamma response region (GRR) are regulated differentially in human
neutrophils and monocytes by IL-10.
AB - Since IL-10 has been shown to up-regulate the expression of the high affinity
receptor for IgG (FcgammaRI/CD64) in human monocytes, we examined whether the
cytokine exerts a similar action toward polymorphonuclear neutrophils (PMN).
Unexpectedly, we found that in neutrophils, IL-10 failed to induce either the
mRNA accumulation or the surface expression of FcgammaRI. Consistent with these
findings, stimulation of PMN with IFN-gamma, but not with IL-10, resulted in the
induction of specific DNA-binding activities to the IFN-gamma response region
(GRR), a regulatory element located in the FcgammaRI gene promoter, required for
transcriptional activation. In electrophoretic mobility shift assays (EMSAs), we
confirmed that in PBMC, IL-10 induces the binding to the GRR of both STAT1 and
STAT3, two members of the STAT family. In neutrophils, however, these activators
did not bind to the GRR in response to IL-10, despite the fact that both STAT1
and STAT3 are expressed in these cells. On the other hand, IFN-gamma was an
efficient inducer of STAT1 binding to the GRR in both PMN and PBMC. The lack of
inducible GRR-binding activity in IL-10-treated PMN could not be ascribed to a
lack of IL-10R, and did not appear to reflect an inhibitory effect of the
cytokine. Taken together, our data suggest that IL-10 is unable to induce
FcgammaRI gene expression in neutrophils because the intracellular signaling
pathway triggered by the cytokine is impaired at the level of, or upstream of,
STAT1 and/or STAT3 activation.
PMID- 9551930
TI - Regulation of monocyte IL-10 synthesis by endogenous IL-1 and TNF-alpha: role of
the p38 and p42/44 mitogen-activated protein kinases.
AB - IL-10 is an anti-inflammatory cytokine with potent immunomodulatory effects,
including inhibition of cytokine production. However, regulation of monocyte IL
10 production is poorly understood. In this report we have investigated the
mechanisms of LPS-induced IL-10 production by human peripheral blood monocytes
and demonstrate that IL-10 synthesis is uniquely dependent on the endogenous
proinflammatory cytokines IL-1 and/or TNF-alpha. LPS signal transduction in
monocytes has been shown to involve activation of the p38 and p42 mitogen
activated protein kinase (MAPK) cascades. The results in this paper indicate that
inhibition of p38 MAPK potently inhibited the production of IL-10, IL-1beta, and
TNF-alpha, whereas blockade of the p42/44 MAPK pathway, while partially
inhibiting TNF-alpha and IL-1beta production, had no effect on monocyte secretion
of IL-10. Furthermore, neither the inhibition of monocyte TNF-alpha induced by IL
10 nor the stimulation of soluble TNF receptor production was affected by
inhibition of the p42/44 MAPK pathway, suggesting that this signaling event is
not involved in either monocyte production of or anti-inflammatory responses to
IL-10. These data raise the interesting possibility that proinflammatory TNF
alpha-mediated effects may be selectively blocked without modulating the
induction or the response to IL-10, whereas the signaling events associated with
the anti-inflammatory events induced by IL-10 remain to be elucidated.
PMID- 9551931
TI - Prostaglandin E2 modulation of p59fyn tyrosine kinase in T lymphocytes during
sepsis.
AB - Prostaglandin E2 (PGE2) has been implicated in the suppression of T cell IL-2
production and proliferation during burn and sepsis. The present study evaluated
the potential intracellular mechanism of suppressed T cell responses by assessing
the activation of p59fyn kinase in T cells from septic rats as well as the T
cells incubated with PGE2. p59fyn is known to regulate T cell functions. Sepsis
was induced in rats by implanting fecal pellets containing Escherichia coli (150
CFU) and Bacteroides fragilis (10(4) CFU) into the abdominal cavity. For the
assessment of PGE2 role in sepsis, a group of septic rats were treated with
indomethacin, which inhibits endogenous PGE2 synthesis. As assessed by
immunoblotting or in vitro kinase assay, a more than 40% inhibition of p59fyn
phosphorylation and kinase activity was observed in septic rat T cells compared
with the T cells from sterile or control rats. A similar inhibition in p59fyn
phosphorylation and kinase activity was observed in PGE2-treated T cells compared
with the T cells incubated in the absence of PGE2. The septic-related suppression
in p59fyn phosphorylation and kinase activity in T cells was prevented in rats
treated with indomethacin. We observed that the inhibition in p59fyn activation
in septic or PGE2-treated T cells was due primarily to a suppression in p59fyn
phosphorylation and not due to alterations in p59fyn protein expression. These
findings suggest that PGE2 released during sepsis could contribute to the sepsis
related suppression in T cell proliferation by attenuating p59fyn phosphorylation
and its kinase activity.
PMID- 9551932
TI - Translational efficiency is up-regulated by alternative exon in murine IL-15
mRNA.
AB - IL-15 promotes the growth of T cells and shares properties of IL-2. IL-2 is
produced exclusively by T cells, while IL-15 message is expressed by a variety of
tissues. However, it has been difficult to demonstrate IL-15 in the supernatants
of many cells that express message for this cytokine. This suggests that IL-15
production is regulated by post-transcriptional controls. In this study, we
cloned three types of murine IL-15 cDNA isoforms generated by alternative
splicing and compared the translational efficiency among these isoforms. The
translational efficiency of isoforms with alternative exon 5 containing another
3' splice site was significantly higher than that of IL-15 cDNA with originally
described exon 5, which is generated by internal splicing of alternative exon 5.
The translation product of the isoform containing alternative exon 5 has a
shorter open reading frame due to stop codons in additional sequence, followed by
a new AUG codon, and displays a shorter leader sequence. The shorter isoform of
the IL-15 was detected in peritoneal macrophages stimulated with IFN-gamma and
LPS, which expressed an abundant level of alternative exon 5. These results
suggest that normal IL-15 production in stimulated macrophages is regulated by
splicing of alternative exon 5.
PMID- 9551933
TI - TNF receptor-deficient mice reveal divergent roles for p55 and p75 in several
models of inflammation.
AB - The pleiotropic activities of the potent proinflammatory cytokine TNF are
mediated by two structurally related, but functionally distinct, receptors, p55
and p75, that are coexpressed on most cell types. The majority of biologic
responses classically attributed to TNF are mediated by p55. In contrast, p75 has
been proposed to function as both a TNF antagonist by neutralizing TNF and as a
TNF agonist by facilitating the interaction between TNF and p55 at the cell
surface. We have examined the roles of p55 and p75 in mediating and modulating
the activity of TNF in vivo by generating and examining mice genetically
deficient in these receptors. Selective deficits in several host defense and
inflammatory responses are observed in mice lacking p55 or both p55 and p75, but
not in mice lacking p75. In these models, the activity of p55 is not impaired by
the absence of p75, arguing against a physiologic role for p75 as an essential
element of p55-mediated signaling. In contrast, exacerbated pulmonary
inflammation and dramatically increased endotoxin induced serum TNF levels in
mice lacking p75 suggest a dominant role for p75 in suppressing TNF-mediated
inflammatory responses. In summary, these data help clarify the biologic roles of
p55 and p75 in mediating and modulating the biologic activity of TNF and provide
genetic evidence for an antagonistic role of p75 in vivo.
PMID- 9551934
TI - Distinct phospholipases A2 regulate the release of arachidonic acid for
eicosanoid production and superoxide anion generation in neutrophils.
AB - Arachidonic acid (AA) released from membrane phospholipids by phospholipase A2
(PLA2) is important as a substrate for eicosanoid formation and as a second
messenger for superoxide anion (O2-) generation in neutrophils. Different
isoforms of PLA2 in neutrophils might mobilize AA for different functions. To
test this possibility, we sought to characterize the PLA2s that are activated by
the neutrophil stimuli, Aroclor 1242, a mixture of polychlorinated biphenyls, and
A23187, a calcium ionophore. Both Aroclor 1242 and A23187 caused release of
[3H]AA; however, O2- production was seen only in response to Aroclor 1242.
Eicosanoids accounted for >85% of the radioactivity recovered in the supernatant
of A23187-stimulated cells but <20% of the radioactivity recovered from cells
exposed to Aroclor 1242. Omission or chelation of calcium abolished A23187
induced AA release, but did not alter AA release in Aroclor 1242-stimulated
neutrophils. AA release and O2- production in response to Aroclor 1242 were
inhibited by bromoenol lactone (BEL), an inhibitor of calcium-independent PLA2.
BEL, however, did not alter Calcium-independent activity was inhibited >80% by
BEL, whereas calcium-dependent activity was inhibited <5%. Furthermore, calcium
independent, but not calcium-dependent, PLA2 activity was significantly enhanced
by Aroclor 1242. These data suggest that Aroclor 1242 and A23187 activate
distinct isoforms of PLA2 that are linked to different functions: Aroclor 1242
activates a calcium-independent PLA2 that releases AA for the generation of O2-,
and A23187 activates a calcium-dependent PLA2 that mobilizes AA for eicosanoid
production.
PMID- 9551935
TI - Fever-range hyperthermia enhances L-selectin-dependent adhesion of lymphocytes to
vascular endothelium.
AB - The L-selectin leukocyte adhesion molecule plays an important role in controlling
leukocyte extravasation in peripheral lymph nodes and at sites of tissue injury
or infection. Although febrile responses during infection and inflammation are
associated with enhanced immune activity, the contribution of fever-range
temperatures to controlling lymphocyte recruitment to tissues has not been
previously examined. In this report we provide evidence that direct exposure of
lymphocytes to fever-range temperatures (38-41 degrees C) in vitro for 9 to 24 h
resulted in a >100% increase in L-selectin-dependent adhesion of these cells to
lymph node high endothelial venules (HEV). Moreover, culture of lymphocytes under
hyperthermia conditions markedly enhanced the ability of these cells to traffic
in an L-selectin-dependent manner to peripheral lymph nodes, mesenteric lymph
nodes, and Peyer's patches. In contrast, febrile temperatures did not increase
LFA-1 function as assessed by measuring lymphocyte adhesion to ICAM-1-3T3
transfectants. Fever-range hyperthermia further did not increase L-selectin
surface density on lymphocytes or L-selectin-dependent recognition of soluble
carbohydrate substrates; however, a marked increase in ultrastructural immunogold
labeling of L-selectin was observed in response to thermal stimuli. These results
suggest that elevated temperatures enhance L-selectin adhesion and/or avidity
through the regulation of L-selectin conformation or organization in the plasma
membrane. Finally, the observed thermal effects on L-selectin adhesion were
attributed to soluble factors in the conditioned medium of heat-treated cells.
Taken together, these data provide new insight into the potential physiologic
role of the febrile response in enhancing lymphocyte recruitment to tissues
through the regulation of L-selectin adhesion.
PMID- 9551936
TI - Dynamic regulation of alpha- and beta-chemokine expression in the central nervous
system during mouse hepatitis virus-induced demyelinating disease.
AB - Infection of C57BL/6 mice with the V5A13.1 strain of mouse hepatitis virus (MHV
V5A13.1) results in an acute encephalomyelitis and chronic demyelinating disease
with features similar to the human demyelinating disease multiple sclerosis.
Chemokines are a family of proinflammatory cytokines associated with inflammatory
pathology in various diseases. The kinetics and histologic localization of
chemokine production in the central nervous system of MHV-infected mice were
examined to identify chemokines that contribute to inflammation and
demyelination. Transcripts for the chemokines cytokine-response gene-2 (CRG-2),
regulated on activation, normal T cell expressed and secreted (RANTES),
macrophage-chemoattractant protein-1 and protein-3 (MCP-1, MCP-3), macrophage
inflammatory protein-1beta (MIP-1beta), and MIP-2 were detected in the brains of
MHV-infected mice at 3 days postinfection (p.i.), and these transcripts were
increased markedly in brains and spinal cords at day 7 p.i., which coincides with
the occurrence of acute viral encephalomyelitis. By day 35 p.i., RANTES, CRG-2,
and MIP-1beta were detected in brains and spinal cords of mice with chronic
demyelination. CRG-2 mRNA expression colocalized with viral RNA and was
associated with demyelinating lesions. Astrocytes were the predominant cell type
expressing CRG-2 mRNA. These observations suggest a role for chemokines, notably
CRG-2, in the initiation and maintenance of an inflammatory response following
infection with MHV, which is important in contributing to demyelination.
PMID- 9551938
TI - Gene organization and promoter function for CC chemokine receptor 5 (CCR5).
AB - CC chemokine receptor 5 (CCR5) functions physiologically as a receptor for the
leukocyte chemoattractants macrophage inflammatory protein-1alpha, macrophage
inflammatory protein-1beta, and RANTES, and functions pathologically as a key
cell entry coreceptor for HIV-1. The factors that regulate CCR5 expression may be
useful therapeutic targets for HIV-1 infection. To identify nuclear regulatory
factors, we have located and functionally characterized the CCR5 gene promoter.
The gene consists of two exons separated by a 1.9-kb intron. Exon 1 contains 43
bp of the 5'-untranslated region; exon 2 contains 11 bp of the 5'-untranslated
region and the complete open reading frame. Primer extension analysis identified
two adjacent transcriptional start points (tsp) that map to the first 2 bp found
in the longest known CCR5 cDNA sequence. A TATA box is present 31 bp upstream
from the first tsp. CCR5 mRNA was detected constitutively in both primary human
myeloid and lymphoid cells by Northern blot hybridization. Consistent with this,
transcription of a chloramphenicol acetyltransferase reporter gene was
constitutively activated in both transiently transfected myeloid and lymphoid
cell lines by the 80-bp gene fragment located immediately upstream of the tsp.
Deletion analysis located a strong silencer element between nucleotides -244 and
80, and a strong enhancer element between -486 and -244. These results suggest
that the gene region between -486 and -1 may regulate the expression of CCR5 in
monocyte/macrophages and T lymphocytes.
PMID- 9551937
TI - IL-4 is an endogenous inhibitor of neutrophil influx and subsequent pathology in
acute antibody-mediated inflammation.
AB - IL-4 is an immunoregulatory cytokine that has in vitro and in vivo anti
inflammatory actions. In this study we investigated whether endogenously produced
IL-4 modulates inflammatory processes that occur after Abs bind to target tissue
by comparing the severity of glomerulonephritis induced by heterologous anti
glomerular basement membrane Abs in wild-type (IL-4+/+) mice to that of
glomerulonephritis induced in homozygous IL-4 gene knockout (IL-4-/-) mice. Two
hours after Ab injection, IL-4-/- mice had significantly higher intrarenal
intercellular adhesion molecule-1 mRNA expression and intraglomerular neutrophil
accumulation than the IL-4+/+ group. Treatment of IL-4-/- mice with recombinant
murine IL-4 at the time of disease induction reduced intercellular adhesion
molecule-1 expression and neutrophil influx to levels observed in IL-4+/+
kidneys. Four days after Ab administration, untreated IL-4-/- mice developed
significantly greater urinary protein excretion, intracapillary fibrinogen
deposits, and glomerular hypercellularity than IL-4+/+ mice. These results
demonstrate that endogenous IL-4 suppresses neutrophil influx and limits tissue
damage in Ab-induced glomerulonephritis, suggesting that IL-4 is an important
regulator of acute inflammatory processes.
PMID- 9551940
TI - Thymosin alpha 1 stimulates endothelial cell migration, angiogenesis, and wound
healing.
AB - In wound healing, lymphoid cells release soluble factors that attract fibroblasts
and macrophages, initiating repair, endothelial cell migration, angiogenesis, and
matrix production. We analyzed the effect of thymosin alpha1 (Talpha1) on
endothelial cell migration, angiogenesis, and wound healing. Talpha1, a 28 amino
acid peptide initially isolated from the thymus, enhanced the morphologic
differentiation of endothelial cells and was a potent chemoattractant for
endothelial cells and monocytes in vitro. In vivo, Talpha1 stimulated
angiogenesis in a subcutaneous model. When given either topically or i.p., it
accelerated wound healing in a punch model, demonstrating that Talpha1 promotes
angiogenesis and wound healing.
PMID- 9551939
TI - Neuropeptides, via specific receptors, regulate T cell adhesion to fibronectin.
AB - The ability of T cells to adhere to and interact with components of the blood
vessel walls and the extracellular matrix is essential for their extravasation
and migration into inflamed sites. We have found that the beta1 integrin-mediated
adhesion of resting human T cells to fibronectin, a major glycoprotein component
of the extracellular matrix, is induced by physiologic concentrations of three
neuropeptides: calcitonin gene-related protein (CGRP), neuropeptide Y, and
somatostatin; each acts via its own specific receptor on the T cell membrane. In
contrast, substance P (SP), which coexists with CGRP in the majority of
peripheral endings of sensory nerves, including those innervating the lymphoid
organs, blocks T cell adhesion to fibronectin when induced by CGRP, neuropeptide
Y, somatostatin, macrophage inflammatory protein-1beta, and PMA. Inhibition of T
cell adhesion was obtained both by the intact SP peptide and by its 1-4 N
terminal and its 4-11, 5-11, and 6-11 C-terminal fragments, used at similar
nanomolar concentrations. The inhibitory effects of the parent SP peptide and its
fragments were abrogated by an SP NK-1 receptor antagonist, suggesting they all
act through the same SP NK-1 receptor. These findings suggest that neuropeptides,
by activating their specific T cell-expressed receptors, can provide the T cells
with both positive (proadhesive) and negative (antiadhesive) signals and thereby
regulate their function. Thus, neuropeptides may influence diverse physiologic
processes involving integrins, including leukocyte-mediated migration and
inflammation.
PMID- 9551941
TI - Neutrophils are major contributors to intraparenchymal lung IL-1 beta expression
after hemorrhage and endotoxemia.
AB - Acute lung injury and the acute respiratory distress syndrome (ARDS) are
significant causes of morbidity and mortality following sepsis and hemorrhage.
Increased IL-1beta production in the lung is important in the development of
acute inflammatory lung injury. Although neutrophils are an important component
of the inflammatory response that characterizes acute lung injury, there is
little information to suggest that they are capable of initiating cytokine
mediated immune responses in the lung. To explore the role of neutrophils in the
early stages of acute lung injury, we examined IL-1beta production by mouse lung
neutrophils after hemorrhage and endotoxemia. There was a significant increase in
IL-1beta expression among intraparenchymal pulmonary neutrophil/mononuclear cells
(IPNMC) 1 h after hemorrhage or endotoxemia. IL-1beta was detected only in a
neutrophil-rich fraction of the IPNMC, but not in T and B lymphocytes positively
selected from the IPNMC. Cyclophosphamide (CTX)-treated neutropenic mice
expressed significantly less IL-1beta in IPNMC after hemorrhage or endotoxemia
compared with CTX-untreated controls. Immunohistochemical analysis of lung
sections from mice after hemorrhage or endotoxemia revealed IL-1beta expression
in infiltrating neutrophils. These data indicate that IL-1beta-producing
neutrophils traffic to the lungs rapidly in response to hemorrhage or endotoxemia
and support the concept that proinflammatory cytokine production by lung
neutrophils may contribute to the development of lung injury after blood loss and
sepsis.
PMID- 9551942
TI - Requirements for alpha d in IgG immune complex-induced rat lung injury.
AB - Alpha d is a newly cloned adhesion molecule that forms a heterodimer with CD18.
The requirement for alpha d in IgG immune complex-induced lung injury in rats has
been evaluated by the use of blocking polyclonal and monoclonal antibodies to rat
alpha d. Using whole lung extracts, Northern and Western blot analyses have
revealed up-regulation of mRNA and alpha d protein in inflamed lungs.
Immunostaining has revealed the presence of alpha d in lung tissue and in
alveolar macrophages as early as 1 h after initiation of the inflammatory
reaction. When polyclonal rabbit Ab to rat alpha d was coinstilled into lung
together with Ab to BSA, lung injury (as determined by leakage of [125I]albumin
into lung parenchyma) was significantly diminished. In parallel, there was
reduced accumulation of neutrophils recoverable in bronchoalveolar lavage (BAL)
fluids. These findings were associated with reduced levels of TNF-alpha as well
as NO2-/NO3- in BAL fluids. A hamster mAb to rat alpha d was also protective in
this lung injury model. Anti-alpha d inhibited in vitro production of NO2-/NO3-
by rat alveolar macrophages (stimulated with LPS and IFN-gamma) by approximately
60%. These data suggest that, in the lung inflammatory model employed, alpha d up
regulation occurs in lung macrophages and is necessary for expression of TNF
alpha, recruitment of neutrophils, and full development of lung injury.
PMID- 9551943
TI - T helper 1 response is dominant and localized to the synovial fluid in patients
with Lyme arthritis.
AB - Cytokines produced by subsets of CD4+ T helper cells responding to an infection
influences the efficiency with which the host is able to mount a protective
immune response. In an attempt to elucidate the population of active cells
involved in the propagation of Lyme arthritis we have utilized intracellular
cytokine staining to analyze the polyclonal immune response at the single cell
level. We have determined the Th phenotype in the synovial fluid of patients with
a variety of chronic inflammatory arthritides, including patients representative
of the spectrum of Lyme arthritis. Th1 cells dominate the immune response in the
synovial fluid of patients with Lyme as well as those with rheumatoid or other
types of chronic inflammatory arthritis. In addition, the severity of Lyme
arthritis directly correlates with the ratio of Th1 to Th2 cells in the synovial
fluid, such that the larger the effusion, the higher the ratio (r = 0.67, p <
0.05). These results suggest that Th1 cells play a direct role in the
pathogenesis of the inflammatory process seen in Lyme arthritis, and that Th2
cells modulate the pro-inflammatory response generated by Th1 cells in the joint.
Finally, we identify Th1 cells specific for outer surface protein A of Borrelia
burgdorferi, the agent of Lyme disease. These cells are restricted to patients
with Lyme arthritis and are localized to the joint. Furthermore, they persist in
patients with prolonged antibiotic treatment-resistant Lyme arthritis, suggesting
the possibility of an autoimmune process.
PMID- 9551944
TI - Humanization and pharmacokinetics of a monoclonal antibody with specificity for
both E- and P-selectin.
AB - E- and P-selectin (CD62E and CD62P) are cell adhesion molecules that mediate
leukocyte-endothelial cell and leukocyte-platelet interactions and are involved
in leukocyte recruitment during inflammation. We previously developed a murine
mAb, EP-5C7 (or mEP-5C7), that binds and blocks both E- and P-selectin. When used
in humans, murine mAbs have short circulating half-lives and generally induce
potent human anti-mouse Ab responses. We therefore engineered a humanized,
complementarity determining region-grafted version of mEP-5C7 incorporating human
gamma4 heavy and kappa light chain constant regions (HuEP5C7.g4). HuEP5C7.g4
retains the specificity and avidity of mEP-5C7, binding to human E- and P
selectin but not to human L-selectin, and blocking E- and P-selectin-mediated
adhesion. Surprisingly, when administered to rhesus monkeys, HuEP5C7.g4 was
eliminated from the circulation very rapidly, even faster than the original
murine Ab. To isolate the cause of the short serum half-life of HuEP5C7.g4,
several Ab variants were constructed. A chimeric IgG4 Ab was made by replacing
the humanized V regions with murine V regions. A humanized IgG2 Ab, HuEP5C7.g2,
was also made by replacing the human gamma4 with a gamma2 constant region.
Results from pharmacokinetic studies in rhesus monkeys demonstrated that the
chimeric IgG4 is also rapidly eliminated rapidly from serum, similar to the
humanized IgG4 Ab, while the humanized IgG2 Ab displays a long circulation half
life, typical of human Abs.
PMID- 9551945
TI - Development of murine allergic asthma is dependent upon B7-2 costimulation.
AB - Allergic asthma is thought to be mediated by CD4+ T lymphocytes producing the Th2
associated cytokines, IL-4, and IL-5. Recently, the costimulatory molecules B7-1
and B7-2, which are expressed on the surface of APC, have been suggested to
influence the development of Th1 vs Th2 immune responses. We examined the in vivo
role of these costimulatory molecules in the pathogenesis of Th2-mediated
allergen-induced airway hyperresponsiveness in a murine model of asthma. In this
model, OVA-sensitized A/J mice develop significant increases in airway
responsiveness, pulmonary eosinophilia, and pulmonary Th2 cytokine expression
following aspiration challenge with OVA as compared with PBS-control animals.
Strikingly, administration of anti-B7-2 mAb to OVA-treated mice abolished
allergen-induced airway hyperresponsiveness, pulmonary eosinophilia, and
elevations in serum IgG1 and IgE levels. Anti-B7-2 treatment of OVA-treated mice
reduced both total lung IL-4 and IL-5 mRNA and bronchoalveolar lavage fluid IL-4
and IL-5 protein levels, with no significant changes in IFN-gamma message or
protein levels. In contrast, treatment with anti-B7-1 mAbs had no effect on
allergen-induced airway hyperresponsiveness, IgE production, or cytokine
production, however, it significantly suppressed pulmonary eosinophilia. We
conclude that B7-2 provides the necessary costimulatory signal required for the
development of in vivo allergic responses to inhaled allergen exposure.
PMID- 9551946
TI - Lymphocyte inhibitor of TRAIL (TNF-related apoptosis-inducing ligand): a new
receptor protecting lymphocytes from the death ligand TRAIL.
AB - Apoptosis can be triggered by the engagement of cell surface receptors by their
ligands. A growing number of receptors belonging to the TNF receptor family have
been identified that contain a conserved cytoplasmic death domain. These include
Fas, TNF-R1, lymphocyte-associated receptor of death (LARD), DR4, and TNF-related
apoptosis-inducing ligand receptor inducer of cell killing-2 (TRICK2). The latter
two are receptors for the cytotoxic ligand TNF-related apoptosis-inducing ligand
(TRAIL), and one of the paradoxes raised by the cloning of these molecules was
why do most cells not die upon contact with the widely expressed TRAIL molecule?
This is a particular problem for lymphocytes that express DR4 and TRICK2 and are
in constant circulation through TRAIL-expressing tissues. We have cloned LIT
(lymphocyte inhibitor of TRAIL), which lacks a death domain. LIT is expressed
predominantly on PBL, where it can competitively inhibit TRAIL-induced apoptosis
through DR4/TRICK2, and may function to modulate lymphocyte sensitivity to TRAIL.
PMID- 9551947
TI - p21-activated kinase (PAK) is required for Fas-induced JNK activation in Jurkat
cells.
AB - The process of apoptosis is a critical component of normal immune system
development and homeostasis, and in many cells this involves signaling through
the c-Jun amino terminal kinase (JNK) pathway. In Jurkat T cells, Fas-induced JNK
activity is dependent upon activation of the caspase cascades known to be central
components of the apoptotic program. We show in Jurkat cell lines expressing a
dominant negative PAK construct that PAK signaling is necessary for JNK
activation in response to Fas receptor cross-linking. Inhibition of JNK
activation induced by Fas does not impair cell death as assessed by DNA
fragmentation. However, expression of the catalytically active C terminus of
PAK2, which is generated through caspase action during Fas-mediated apoptosis,
induces Jurkat cell apoptosis. We conclude that PAK activity resulting from
caspase-mediated cleavage is a necessary component of JNK activation induced by
Fas receptor signaling and that PAK2 can contribute to the induction of cell
death.
PMID- 9551948
TI - CTLA-4 ligation delivers a unique signal to resting human CD4 T cells that
inhibits interleukin-2 secretion but allows Bcl-X(L) induction.
AB - We have assessed the functional effects of a panel of CTLA-4 mAbs on resting
human CD4+ T cells. Our results demonstrate that some CTLA-4 mAbs can inhibit
proliferative responses of resting CD4+ cells and cell cycle transition from G0
to G1. The inhibitory effects of CTLA-4 were evident within 4 h, at a time when
cell surface CTLA-4 expression remained undetectable. Other CTLA-4 mAbs had no
detectable inhibitory effects, indicating that binding of Ab to CTLA-4 alone is
not sufficient to mediate down-regulation of T cell responses. Interestingly,
while IL-2 production was shut off, inhibitory anti-CTLA-4 mAbs permitted
induction and expression of the cell survival gene bcl-X(L). Consistent with this
observation, cells remained viable and apoptosis was not detected after CTLA-4
ligation.
PMID- 9551949
TI - Critical role of NK1+ T cells in IL-12-induced immune responses in vivo.
AB - CD1-dependent NK1+ T cells rapidly produce IL-4 upon stimulation through the TCR.
These cells may therefore play an important role in the initiation of Th2
responses. Here, we show that NK1+ T cells constitutively express receptors for
IL-12 and IFN-gamma, and that IL-12 induces production of perforin in these
cells. Moreover, while IL-12 induces high levels of IFN-gamma and cytotoxic
activity of hepatic or splenic mononuclear cells against tumor cells, this effect
of IL-12 is significantly reduced in CD1-deficient mice with impaired NK1+ T
cells development. These results indicate that NK1+ T cells play a critical role
in IL-12-induced production of IFN-gamma to initiate Th1 immune responses and as
IL-12-induced cytotoxic effector cells to initiate antitumor immunity.
PMID- 9551950
TI - Identification of the mouse IgG3 receptor: implications for antibody effector
function at the interface between innate and adaptive immunity.
AB - Mouse IgG3 appears early in immune responses independently of T cell help and, as
such, is an early effector molecule of the immune system. Yet, a specific IgG3
cellular receptor remains undefined. In transfection experiments, mouse Fc
gammaRI was clearly able to bind immune complexes of IgG3, whereas mouse Fc
gammaRII could not. Furthermore, macrophages from mice expressing Fc gammaRII and
Fc gammaRIII but lacking Fc gammaRI were unable to phagocytose IgG3 immune
complexes, thus identifying mouse Fc gammaRI as the sole receptor for IgG3 immune
complexes. Competition studies demonstrated that monomeric mouse IgG3 could
inhibit IgG2a binding to mouse Fc gammaRI with an ID50 approximately 10(-7) M
(fivefold lower than IgG2a). The identification of mouse Fc gammaRI as the IgG3
receptor establishes Fc gammaRI as a participant in events at the interface
between innate and adaptive immunity, implying a greater role for this receptor
in the development of normal and pathologic immune responses than previously
recognized.
PMID- 9551951
TI - Stimulation of CD28 with B7-2 promotes focal adhesion-like cell contacts where
Rho family small G proteins accumulate in T cells.
AB - Unless a costimulatory signal is provided, TCR recognition of Ag bound to the MHC
is insufficient to induce optimal T cell proliferation or the production of IL-2.
Here we show that the stimulation of CD28, a T cell costimulatory receptor, by a
specific Ab increases F-actin contents in T cells. The interaction between T
cells and B7-2-transfected Chinese hamster ovary cells expressing the CD28 ligand
leads to the rearrangement of the actin cytoskelton in the region of cell-cell
contact. Within the Rho family of G proteins, Rac1, but not Rho, translocates to
the sites of cell-cell contact where Tailin also accumulates. These results
indicate that the interaction between B7-2 and CD28 establishes a focal adhesion
like cell contact between T cell and APCs. The results also suggest that CD28
signaling is primarily transduced by a cytoskeletal rearrangement/signaling
pathway mediated by the Rho family G proteins.
PMID- 9551952
TI - HIV-1 infection induces a selective reduction in STAT5 protein expression.
AB - HIV-1 infection is accompanied by qualitative and quantitative defects in CD4+ T
lymphocytes. Loss of immune function in HIV patients is usually associated with a
profound dysregulation of cytokine production. To investigate whether cytokine
signaling defects occur during HIV infection, PHA blasts from healthy human
donors were infected with two strains of HIV-1 and screened for the expression of
STAT proteins used in cytokine signaling. A selective decrease in STAT5B was seen
8 days after infection with the BZ167 dual-tropic HIV isolate, but not with the
Ba-L, M-tropic strain. Based on these findings, purified T cells from HIV
infected patients in different stages of disease were also tested for STAT
expression; decreases in STAT5A, STAT5B, and STAT1alpha were observed in all
patients. The reduction in STATs seen in vivo and in vitro after HIV infection
may contribute to the loss of T cell function in HIV disease.
PMID- 9551953
TI - Differences between responses of naive and activated T cells to anergy induction.
AB - T cell unresponsiveness to Ag stimulation can be induced by several means. The
precise mechanism by which this process occurs remains poorly understood.
Preincubating T cells with either EDCI-fixed APC or ionomycin is a proven means
of inducing T cell anergy with reduced IL-2 production in response to Ag
stimulation. Using T cells from mice expressing the TCR transgene DO11.10, which
is specific for a peptide (323-339) derived from hen egg OVA, we demonstrate that
naive cells obtained directly from the host are resistant to the anergy induction
by either fixed APC or ionomycin. TCR transgenic mice also deficient in the
recombination-activating gene-2 (RAG-2(-/-)), preventing the formation of T cells
with endogenous TCRs, were immunized with OVA, and in vivo activated T cells with
low expression of CD62 were isolated. These primed cells possess the same
sensitivity to ionomycin-induced anergy as in vitro activated cell lines. This
unresponsive state most profoundly affects Ag-induced IL-2 production, with IFN
gamma and IL-3 affected to a lesser degree and no effect observed on IL-4
production. Thus, T cells in vivo can be distinguished phenotypically by their
susceptibility to anergic stimuli. Anergy so induced affects selected T cell
functions.
PMID- 9551954
TI - An alternative translational reading frame encodes an immunodominant retroviral
CTL determinant expressed by an immunodeficiency-causing retrovirus.
AB - Recognition of virus-infected or transformed cells by CD8+ CTL requires a
trimolecular complex composed of MHC class I, beta2-microglobulin, and a specific
foreign peptide composed of 8 to 10 linear amino acids. The generation of such
CTL epitopes has traditionally been thought to be from the primary open reading
frame encoding the viral or tumor-associated proteins. In this report it is
demonstrated that a viral CTL epitope can also be generated from an alternative
reading frame. Using a combination of synthetic peptides and Sindbis or vaccinia
expression systems, MHC class I Kd-restricted BALB/cByJ CTL directed against
defective gag gene constructs of the LP-BM5 virus complex that causes murine AIDS
were shown to have specificity for the antigenic peptide SYNTGRFPPL. This epitope
is generated in a novel fashion from the second open reading frame (ORF2) of both
the defective and ecotropic helper virus components of LP-BM5. Importantly, lysis
of target cells expressing BM5 ecotropic helper, and/or defective viral gag,
demonstrated that the SYNTGRFPPL epitope is generated during the course of a
normal retroviral infection. Furthermore, MAIDS-resistant BALB/cByJ mice also
generated secondary restimulated CTL specific for SYNTGRFPPL following in vivo
priming with the LP-BM5 retroviral complex. These data suggest that retroviruses,
and potentially other viruses and foreign genes, are capable of expressing T cell
epitopes from alternative open reading frames. If one considers the influence of
self peptides on T cell development, these "alternative reading frame-derived"
peptides could provide an important additional influence on the functional T cell
repertoire.
PMID- 9551955
TI - A new role for B cells in systemic autoimmunity: B cells promote spontaneous T
cell activation in MRL-lpr/lpr mice.
AB - A conventional view of the pathogenesis of systemic lupus erythematosus has
emerged. The role of B cells is to secrete pathogenic autoantibodies, while the
role of T cells is to provide help for autoantibody-producing B cells. A problem
with this view is that spontaneous T cell activation as well as T cell
infiltration of organs such as kidney and skin are prominent features in systemic
lupus erythematosus patients and murine models of lupus. The identification of T
cell infiltrates, in particular, suggests that autoantibody-mediated damage may
be only part of the story and that T cells could also play a primary role in
immune-mediated pathology. To test the role of B cells directly, we previously
generated autoimmune-prone MRL-lpr/lpr mice that lack B cells. The complete
absence of T cell infiltrates in these mice was surprising, and it prompted us to
examine whether a key role of B cells in disease evolution is to prime
autoreactive T cells. Here we demonstrate, by comparing B cell-deficient and
control mice, that the expansion of activated and memory T cells in the MRL
lpr/lpr mouse is indeed highly dependent on B cells. These results suggest a
novel role for B cells in autoimmune disregulation.
PMID- 9551956
TI - IL-4 induces eotaxin: a possible mechanism of selective eosinophil recruitment in
helminth infection and atopy.
AB - A common feature of some parasitic infections and allergic and atopic skin
diseases is the involvement of Th2 lymphocytes and the dermal appearance of
eosinophils (Eos). Because Th2 lymphocytes apparently do not release Eo
attractants, we addressed the question of whether the Th2 cytokine IL-4 induces
its production in dermal fibroblasts. We therefore stimulated fibroblasts with IL
4. HPLC investigation of supernatants revealed a single Eo chemotactic protein,
which was purified to homogeneity giving a single 13-kDa band upon SDS-PAGE
analyses. Peptide mapping with subsequent amino acid sequencing revealed an Eo
selective chemotaxin, which consists of a mixture of N-terminally truncated and O
glycosylated forms of the chemokine eotaxin. Other chemokines such as RANTES, MCP
3, MCP-4, or MIP-1alpha were not detected as Eo chemotaxins under these
conditions. Using reverse transcriptase-PCR techniques, we found that IL-4 dose
and time dependently induces eotaxin mRNA in dermal fibroblasts. Stimulation with
IL-4 and TNF-alpha caused a 10- to 20-fold increase of the release of three
biochemically different eotaxin forms, each consisting of a mixture of N
terminally truncated and O-glycosylated variants having the same backbone amino
acid sequence but different specific activities. Our findings support the
hypothesis that eosinophil recruitment seen in IL-4-mediated skin reactions, at
least in part, may be due to Th2 cytokine-mediated induction of eotaxin in dermal
fibroblasts.
PMID- 9551957
TI - In SCID-hu mice, passive transfer of a humanized antibody prevents infection and
atrophic change of medulla in human thymic implant due to intravenous inoculation
of primary HIV-1 isolate.
AB - Using SCID-hu mice, it was tested whether humanized mAb Rmu5.5 could prevent
infection by HIV-1 i.v. inoculation. The Ab that recognizes the IHIGPGRAFYT motif
in the principal neutralizing determinant (PND) of HIV(MN), as well as the
original mouse mAb mu5.5, neutralized HIV(MN) with high activity. Seven primary
field isolates from Japanese hemophiliacs seropositive for HIV-1 clade B were
compared for their reactivities to Rmu5.5. Rmu5.5 was effective, particularly
against the viruses that matched amino acid sequences of the PND region of HIV-1,
and it completely neutralized primary isolates. Moreover, the passive transfer of
the Ab elicited protection against challenge by the primary isolates in SCID-hu
or hu-PBL-SCID mice after i.v. inoculation with the virus by both quantitative
PCR and PBMC-based virus isolation in vitro. Further, inoculation with the Ab
also prevented the atrophic change in the medulla of the thymic transplant that
was induced by i.v. inoculation of the virus. Thus, the humanized neutralizing Ab
Rmu5.5 appears to protect SCID-hu mice from infection by primary field isolates.
PMID- 9551958
TI - Naturally occurring low affinity peptide/MHC class I ligands can mediate negative
selection and T cell activation.
AB - The affinity/avidity model for T cell development postulates that ligands with
high affinity for the TCR are efficient in negative selection, whereas those with
lower affinity/avidity favor positive selection. Using the 2C TCR transgenic
model, we evaluated the efficacy of ligands with widely differing affinity for
the TCR (3 x 10(3) to 2 x 10(6) M(-1)) in mediating thymocyte deletion. The
relative affinities of the 2C TCR for the p2Ca/Ld, dEV-8/Kb, p2Ca-A3/Ld, and
p2Ca/Kb ligands are approximately 1000:50:10:1, respectively. Here we show, using
an in vitro assay, that the deletion of 2C CD4+ CD8+ thymocytes is mediated not
only by p2Ca/Ld, but also by the lower affinity ligands dEV-8/Kb, p2Ca-A3/Ld, and
p2Ca/Kb, albeit at relatively higher peptide concentrations. Deletion mediated by
low affinity ligands required CD8, whereas high affinity ligand-mediated deletion
was CD8 independent. The p2Ca/Kb and dEV-8/Kb ligands are naturally occurring in
H-2b mice, and others have shown that p2Ca/Kb can induce the maturation of CD4-
CD8+ 2C-TCR(high) thymocytes in fetal thymic organ culture. In this study we
showed that in addition to deletion, the p2Ca/Kb and dEV-8/Kb ligands, in the
presence of exogenous IL-2, induced mature 2C T cell proliferation, albeit at a
lower level than that induced by the high affinity p2Ca/Ld ligand. Thus, the same
low affinity ligands that can effect negative selection and, in the case of
p2Ca/Kb, the maturation of CD8 single-positive thymocytes can also induce the
activation of mature CD8 T cells.
PMID- 9551959
TI - Differential effects of the rejection of bone marrow allografts by the depletion
of activating versus inhibiting Ly-49 natural killer cell subsets.
AB - Natural killer cells mediate the specific rejection of bone marrow cell (BMC)
allografts in lethally irradiated mice. The Ly-49 family of molecules present on
subsets of murine NK cells appears capable of binding class I MHC molecules,
resulting in transmission of an inhibitory signal to the NK cell. These Ly-49
family members have been shown to have an immunoreceptor tyrosine-based
inhibitory motif that is responsible for the inhibitory signal. However, a new Ly
49 family member was found that lacks this motif, Ly-49D, and evidence suggests
that this may be an activating receptor. We therefore compared the role of the
activating Ly-49 member with NK cells bearing inhibitory Ly-49 receptors in BMC
rejection. Depletion of Ly-49D+ NK cells in H-2b mice abrogated their ability to
reject H-2d BMC allografts. Similarly, Ly-49C+ NK cells also were shown to
mediate the specific rejection of H-2d BMC. When both subsets were depleted, an
additive enhancement of BMC engraftment was observed, indicating that both
subsets play a role in the rejection of allogeneic H-2-homozygous H-2d BMC.
However, rejection of H-2(b x d) or D8 (H-2b, Dd transgene) BMC allografts was
unaffected by Ly-49C+ NK cell depletion in H-2b mice. In marked contrast,
depletion of Ly-49D+ NK cells in H-2b mice totally abrogated the rejection of H
2(b x d) heterozygous BMC in support of in vitro data suggesting that Ly-49D+ NK
cells receive activating signals. Therefore, NK subsets demonstrate a
differential ability to reject H-2 homozygous and heterozygous BMC.
PMID- 9551960
TI - Normal responsiveness of CTLA-4-deficient anti-viral cytotoxic T cells.
AB - CTLA-4 has been proposed to negatively regulate immune responses, and mice
deficient for CTLA-4 expression succumb to a lymphoproliferative disorder within
a few weeks after birth. This study assessed the responsiveness of CTLA-4
deficient T cells expressing a class I-restricted TCR specific for lymphocytic
choriomeningitis virus (LCMV). The kinetics of T cell proliferation were studied
in vitro after stimulation of T cells with full and partial T cell agonists. No
gross abnormalities in CTLA-4-deficient T cells could be detected. Using adoptive
transfer experiments, T cell responses were also measured in vivo after infection
with LCMV. Low dose infection with LCMV leads to strong expansion of specific T
cells followed by a reduction in T cells that parallels the elimination of Ag.
The kinetics of T cell expansion and elimination after low dose LCMV infection
were not affected by the absence of CTLA-4. High dose infection of mice with LCMV
leads to a transient expansion of T cells followed by T cell exhaustion, where
all specific T cells are eliminated. T cell exhaustion also occurred in the
absence of CTLA-4. Thus, surprisingly, the absence of CTLA-4 did not interfere
with T cell activation, down-regulation of ongoing T cell responses after the
elimination of Ag, or the exhaustion of T cell responses in the presence of
excessive amounts of Ag.
PMID- 9551961
TI - Spontaneous inflammatory disease in HLA-B27 transgenic mice is independent of MHC
class II molecules: a direct role for B27 heavy chains and not B27-derived
peptides.
AB - Although association of HLA-B27 with human spondyloarthropathies has been known
for several years, its role in disease pathogenesis is not understood. Recently,
a few investigators have proposed that presentation of B27-derived peptides by
MHC class II molecules may be the underlying mechanism. HLA-B27 transgenic rat
and mouse models have provided a new tool for understanding the exact role of B27
in disease pathogenesis. HLA-B27 mice lacking endogenous beta2-microglobulin
(B27+ beta2m(o)) develop disease after they are transferred from the barrier
facility to the conventional colony. This model was utilized to test the
hypothesis that B27-derived peptide presented by MHC class II molecules is the
cause of the disease. The MHC class II knockout gene, A beta(o), was bred into
our B27+ beta2m(o) mice, and disease manifestation was monitored. These mice
develop spontaneous disease, demonstrating that MHC class II molecules do not
play a major role in B27-related disease. Thus, the disease is not manifested by
presentation of B27-derived peptides by class II molecules, since these mice are
devoid of H2-A and H2-E molecules. Furthermore, in vivo treatment with mAb
against the heavy chain of B27 reduced the incidence of disease in B27+ beta2m(o)
mice. Our results clearly demonstrate that B27 heavy chains are directly involved
in the disease process.
PMID- 9551962
TI - Long-lived B cells are distinguished by elevated expression of A1.
AB - Only 5% of the 15 million B cells formed daily reach the long-lived peripheral B
cell pool, presumably reflecting both negative and positive selection. These
selective events occur primarily during late stages of differentiation in the
marrow and periphery, when newly formed B cells bear surface IgM (sIgM), but
differ from mature B cells in their expression of heat-stable Ag (CD24), B220
(CD45), and sIgD. Because genes of the Bcl-2 family influence longevity, we
compared the expression of Bcl-2, Bax, and A1 among immature vs mature peripheral
B cells using semiquantitative reverse-transcriptase PCR. While the levels of
both Bcl-2 and Bax mRNA remain constant in these two populations, A1 expression
is strikingly up-regulated among mature B cells. In addition, A1 expression is
low among pro- and pre-B cells, as well as in immature (sIgM+) marrow B cells.
Together, these data indicate that A1 mRNA expression is low at all stages of B
cell development before final maturation in the periphery and, unlike other Bcl-2
family members whose expression changes little after marrow egress, A1 is up
regulated 10-fold as cells are recruited into the long-lived peripheral B cell
pool.
PMID- 9551963
TI - Post-thymic maturation of migrating human thymic single-positive T cells: thymic
CD1a- CD4+ T cells are more susceptible to anergy induction by toxic shock
syndrome toxin-1 than cord blood CD4+ T cells.
AB - To determine whether human CD4+ T cells undergo post-thymic maturation, we
compared the susceptibility to anergy induction in human thymic CD1a- CD4+ single
positive (CD4+), cord blood (CB) CD4+, and adult peripheral blood (APB) CD4+ T
cells by stimulation with toxic shock syndrome toxin-1 (TSST-1). Most TSST-1
induced T cell blasts derived from either T cell preparation expressed TCR
Vbeta2, which determines the potential reactivity to TSST-1. Most thymic CD4+ T
cell blast preparations exhibited little or no production of IL-2 and IL-4 after
restimulation with TSST-1 and only marginal responses after stimulation with rIL
2 or a combination of PMA and calcium ionophore, while the APB CD4+ T cell blasts
showed high responses to these stimuli. The responses of CB CD4+ T cell blasts to
these stimuli varied, ranging from minimal to relatively high. Studies of DNA
fragmentation showed that there was no significant cell death of thymic CD4+ T
cell blasts. Most thymic CD1a- CD4+ and CB CD4+ T cells were CD38 positive. APB
CD4+ T cell blasts derived from the CD38+ fraction and from the CD38- fraction
exhibited equally high responses to restimulation with TSST-1. These results
indicate that thymic CD1a- CD4+ and CB CD4+ T cells are inherently highly
susceptible to anergy induction by bacterial superantigens and that thymic CD1a-
CD4+ T cells are less mature than CB CD4+ T cells, suggesting that post-thymic
maturation in thymic T cells migrating to the periphery is required for
acquisition of full reactivity to antigenic stimulation.
PMID- 9551964
TI - TNF receptor-deficient mice reveal striking differences between several models of
thymocyte negative selection.
AB - Central tolerance depends upon Ag-mediated cell death in developing thymocytes.
However, the mechanism of induced death is poorly understood. Among the known
death-inducing proteins, TNF was previously found to be constitutively expressed
in the thymus. The role of TNF in thymocyte negative selection was therefore
investigated using TNF receptor (TNFR)-deficient mice containing a TCR transgene.
TNFR-deficient mice displayed aberrant negative selection in two models: an in
vitro system in which APC are cultured with thymocytes, and a popular in vivo
system in which mice are treated with anti-CD3 Abs. In contrast, TNFR-deficient
mice displayed normal thymocyte deletion in two Ag-induced in vivo models of
negative selection. Current models of negative selection and the role of TNFR
family members in this process are discussed in light of these results.
PMID- 9551965
TI - The c-Jun N-terminal kinase cascade plays a role in stress-induced apoptosis in
Jurkat cells by up-regulating Fas ligand expression.
AB - T lymphocytes undergo apoptosis in response to cellular stress, including UV
exposure and gamma irradiation. However, the mechanism by which stress stimuli
induce apoptosis is not well understood. While stress stimuli induce the
activation of the c-Jun N-terminal kinase (JNK) pathway, it is not clear whether
the JNK cascade is activated as a result of cell death or whether the cascade
participates in inducing apoptosis. Using a Jurkat T cell line transfected with
dominant active (DA)-mitogen-activated protein kinase kinase kinase (MEKK1) in a
tetracycline-regulated expression system, we found that expression of DA-MEKK1
results in the apoptosis of Jurkat cells in parallel with prolonged JNK
activation. Moreover, DA-MEKK1 induced Fas ligand (FasL) cell surface and mRNA
expression, as well as FasL promoter activation. Interference with Fas/FasL
interaction prevented DA-MEKK1-mediated apoptosis. In comparing the effect of
different stress stimuli to DA-MEKK1, we found that UV, gamma irradiation, and
anisomycin prolonged JNK activation in parallel with FasL expression and onset of
cell death. In addition, these stimuli also enhance cell surface expression of
FasL. Interference with Fas/FasL interactions inhibited anisomycin but not UV- or
gamma irradiation-induced apoptosis. Our data show that while the JNK pathway
contributes to stress-induced apoptosis in T lymphocytes by regulating FasL
expression, not all stress stimuli use the same cell death pathway.
PMID- 9551966
TI - Harnessing Syk family tyrosine kinases as signaling domains for chimeric single
chain of the variable domain receptors: optimal design for T cell activation.
AB - T cells of tumor bearers often show defective TCR-mediated signaling events and,
therefore, exhibit impaired immune responses. As such, patients with heavy tumor
burden are often not amenable to adoptive T cell therapy. To overcome this
limitation, we have developed a chimeric receptor that joins an extracellular
single chain Fv (scFv) of a specific Ab for Ag recognition to an intracellular
protein tyrosine kinase (PTK) for signal propagation. Stimulation through the
scFv-PTK receptor should bypass defective TCR-proximal events and directly access
the T cell's effector mechanisms. In this study we describe the optimization of a
scFv-PTK configuration, leading to complete T cell activation. The cytosolic PTK
Syk is superior to its family member, Zap-70, for intracellular signaling. As a
transmembrane (TM) domain, CD4 performs better than CD8 when plastic-immobilized
Ag serves as a stimulator. However, when APC are used to trigger chimeric
receptors, the need for a flexible spacer between the scFv and TM domains becomes
apparent. The CD8alpha-derived hinge successfully performs this task in chimeric
scFv-Syk receptors regardless of its cysteine content. A cytotoxic T cell
hybridoma expressing chimeric receptor genes composed of scFv-CD8(hinge)-CD8(TM)
Syk or scFv-CD8(hinge)-CD4(TM)-Syk is efficiently stimulated to produce IL-2 upon
interaction with APC and specifically lyses appropriate target cells in a non-MHC
restricted manner.
PMID- 9551967
TI - Induction of granulomatous experimental autoimmune thyroiditis in IL-4 gene
disrupted mice.
AB - To study the role of IL-4 in development of granulomatous experimental autoimmune
thyroiditis (EAT), IL-4 gene-disrupted mice expressing the EAT-susceptible H-2k
haplotype were generated and used for EAT induction. Spleen cells from mouse
thyroglobulin (MTg) and LPS-primed IL-4(+/+) and IL-4(-/-) donors could induce
severe granulomatous EAT when spleen cells were activated with MTg and anti-IL-2R
mAb in the presence of IL-12. Thyroid lesions had extensive follicular cell
proliferation, large numbers of histiocytes, polymorphonuclear leukocytes, and
multinucleated giant cells, in addition to lymphocytes and other mononuclear
cells. Expression of IFN-gamma gene mRNA and production of IFN-gamma by effector
spleen cells stimulated with MTg and IL-12 were similar for both IL-4(+/+) and IL
4(-/-) mice. Although IL-4 was undetectable in IL-4(-/-) mice, expression of mRNA
for IL-5, IL-10, and IL-13 and production of IL-5 by both MTg-activated spleen
cells and anti-CD3-activated CD4+ T cells were comparable for cells from IL
4(+/+) and IL-4(-/-) mice, indicating that the absence of IL-4 did not prevent
production of other Th2 cytokines. Production of MTg-specific IgG1 was very low
or undetectable in IL-4(-/-) mice. IL-4 gene mRNA and MTg-specific IgG1 could be
detected in IL-4(+/+) or IL-4(-/-) recipients only when they received effector
cells from IL-4(+/+) donor mice, indicating that IL-4- and IgG1-secreting cells
are of donor origin. These results demonstrate that IL-4 is not essential for
development of granulomatous EAT.
PMID- 9551968
TI - Regulation of TCR signal transduction in murine thymocytes by multiple TCR zeta
chain signaling motifs.
AB - The alphabeta TCR is a multimeric protein complex comprising ligand-binding and
signal-transducing subunits. The signal transduction processes are mediated by
the immunoreceptor tyrosine-based activation motifs (ITAMs), and up to 10 ITAMs
are present within a single TCR complex. This multiplicity may allow for signal
amplification and/or the formation of qualitatively distinct intracellular
signals. Notably, the TCR-zeta subunit contains three ITAMs, and exists as a
disulfide-linked homodimer in the TCR complex. In normal murine thymocytes and
peripheral T cells, a proportion of TCR-zeta molecules is constitutively tyrosine
phosphorylated and associated with the ZAP-70 protein tyrosine kinase. We
examined the contribution of the different TCR-zeta ITAMs in regulating the
constitutive phosphorylation of the TCR-zeta subunit in thymocytes by analyzing
TCR-zeta-deficient mice that had been reconstituted with either full-length or
single ITAM-containing TCR-zeta subunits. We report in this work that in the
absence of a full-length TCR-zeta subunit, there is no apparent constitutive
phosphorylation of the remaining TCR/CD3 ITAMs. Following TCR ligation, all of
the CD3 ITAMs become inducibly phosphorylated and associate with the ZAP-70
protein tyrosine kinase. Regardless of the number of TCR-zeta ITAMs present in
the TCR complex, we report that a number of molecules involved in downstream
signaling events, such as ZAP-70, SLP-76, and pp36, are all inducibly tyrosine
phosphorylated following TCR ligation. These results support the notion that the
different TCR ITAMs function in a quantitative rather than qualitative manner.
PMID- 9551969
TI - Reduced cell surface expression of HLA-C molecules correlates with restricted
peptide binding and stable TAP interaction.
AB - HLA-C molecules are poorly expressed at the cell surface compared with HLA-A and
HLA-B locus products. The reason for the low surface expression and the
underlying mechanism is unclear. We show that the HLA-C4 allele is expressed
intracellularly in amounts similar to HLA-A and HLA-B alleles. However, the
majority of the HLA-C4 molecules is not transported, but is retained in the
endoplasmic reticulum by stable interaction with TAP. This pool does not appear
to participate in the formation of HLA-C4/peptide complexes, but is degraded in
the endoplasmic reticulum. HLA-C4 molecules can dissociate from TAP upon binding
of specific peptide. However, they require a 10-fold higher concentration of a
completely degenerated 9-mer peptide mixture for release from TAP than the HLA-A
and HLA-B alleles. Our data show that the HLA-C molecules tested are more
selective in their peptide binding than HLA-A and HLA-B molecules, resulting in
prolonged association with TAP and a reduced formation of intracellular HLA
C/peptide complexes. The restricted peptide binding of certain HLA-C alleles
provides one explanation for the reduced expression of HLA-C molecules at the
cell surface. Other mechanisms will be discussed.
PMID- 9551970
TI - Detection and delineation of CXCR-4 (fusin) as an entry and fusion cofactor for T
tropic [correction of T cell-tropic] HIV-1 by three different monoclonal
antibodies.
AB - A chemokine receptor, CXCR-4, has been identified as an entry cofactor for T cell
line-tropic (T-tropic) HIV-1. To detect expression of CXCR-4 at the single cell
level and dissect postbinding events of HIV-1 infection, we generated three mAbs
against human CXCR-4. These mAbs inhibited SDF-1-induced intracellular Ca2+
mobilization, and one of the mAbs immunoprecipitated a specific 47-kDa component
from CXCR-4+ cells. Flow cytometric analysis showed that most human cell lines
examined expressed CXCR-4. A fraction of normal PBMC expressed CXCR-4, but
neutrophils were negative. Two-color analysis revealed that the majority of T
cells, virtually all B cells, and all monocytes expressed CXCR-4, while it was
only weakly present on NK cells. Thus, expression of CXCR-4 is not ubiquitous but
cell type specific in hemopoietic cells. The three mAbs were shown to suppress
cell fusion mediated by envelope proteins of a T-tropic NL432 virus but not by
those of an M-tropic JRCSF virus Likewise, they suppressed infection of NL432 but
not that of an M-tropic NL162 virus. In both cases it was noted that the
suppressive activity varied considerably among the mAbs. These data confirmed
that CXCR-4 is directly involved in env-mediated entry and fusion of T-tropic HIV
1 and suggest that the epitopes on CXCR-4 recognized by the three mAbs may have
different roles in interaction with the envelope proteins of T-tropic HIV-1.
PMID- 9551971
TI - The MHC-E locus is the most well conserved of all known primate class I
histocompatibility genes.
AB - The HLA-E locus is characterized by limited polymorphism and low levels of cell
surface expression. However, the function of the products of this nonclassical
MHC class I gene remains unknown. To evaluate the conservation of the MHC-E locus
throughout anthropoid primate evolution, we identified the homologue of the HLA-E
locus in six different New World monkey species. Full-length sequencing of MHC
EcDNAs in four unrelated cotton-top tamarins (Saguinus oedipus) revealed no
evidence for polymorphism. Using the PCR, denaturing gradient gel
electrophoresis, and direct sequencing, we also identified MHC-E alleles in five
other New World monkey species, representing all extant platyrrhine families. In
contrast to all other classical and nonclassical MHC class I genes in primates,
the rate of synonymous nucleotide substitution is much greater than the rate of
nonsynonymous nucleotide substitution within exons 2 and 3 encoding the peptide
binding region (PBR) in MHC-E genes. The PBR of the MHC-E molecule, therefore,
has evolved under purifying selective pressures, and the very unusual
evolutionary history of this ancient gene provides further evidence that the
products of the HLA-E locus serve a critical immunological function. Given the
remarkable conservation of the PBR during primate evolution, this critical
immunological function is probably related to the peptide binding ability of the
MHC-E protein.
PMID- 9551972
TI - Characterization and mapping to human chromosome 8q24.3 of Ly-6-related gene 9804
encoding an apparent homologue of mouse TSA-1.
AB - The 9804 gene, which encodes a human Ly-6 protein most similar to mouse
differentiation Ag TSA-1/Sca-2, has also been called RIG-E. Like mouse TSA-1, it
has a broad tissue distribution with varied expression levels in normal human
tissues and tumor cell lines. Like some members of the murine Ly-6 family, the
9804 gene is responsive to IFNs, particularly IFN-alpha. Overlapping genomic
fragments spanning the 9804 gene (5543 bp) have been isolated and characterized.
The gene organization is analogous to that of known mouse Ly-6 genes. The first
exon, 2296 bp upstream from exon II, is entirely untranslated. The three coding
exons (II, III, and IV) are separated by short introns of 321 and 131 bp,
respectively. Primers were developed for specific amplification of 9804 gene
fragments. Screening of human-hamster somatic cell hybrids and yeast artificial
chromosomes (YACs) indicated that the gene is distal to c-Myc, located in the q
arm of human chromosome 8. No positives were detected from the Centre d'Etude du
Polymorphisme Humain mega-YAC A or B panels, nor from bacterial artificial
chromosome libraries; two positive cosmids (c101F1 and c157F6) were isolated from
a human chromosome 8 cosmid library (LA08NC01). Fluorescence in situ
hybridization of metaphase spreads of chromosome 8, containing hybrid cell line
706-B6 clone 17 (CL-17) with cosmid c101F1, placed the 9804 gene close to the
telomere at 8q24.3. This mapping is significant, since the region shares a
homology with a portion of mouse chromosome 15, which extends into band E where
Ly-6 genes reside. Moreover, the gene encoding E48, the homologue of mouse Ly-6
molecule ThB, has also been mapped to 8q24.
PMID- 9551973
TI - Nuclear factor of activated T cells (NFAT) as a molecular target for 1alpha,25
dihydroxyvitamin D3-mediated effects.
AB - The molecular basis of the immunomodulatory properties of 1alpha,25
dihydroxyvitamin D3 (1alpha,25(OH)2D3) remains elusive. We demonstrate here that
1alpha,25(OH)2D3-mediated suppressive effects on the inducible expression of
cytokine genes in human T cells may, in part, be due to diminished activity of
the transcription factor NFAT. The vitamin D3 receptor (VDR) and its
heterodimeric partner retinoid X receptor alpha (RXR alpha) specifically bound to
the distal NFAT site in the human IL-2 promoter, and this binding was abolished
by mutating unique regions in the NFAT oligonucleotide. In vitro inhibition of
NFAT complex formation was noted when VDR-RXR alpha heterodimers were added to
DNA binding reactions containing nuclear extracts from activated B or T cells,
whereas in vitro NFkappaB complex formation was not significantly influenced.
Furthermore, 1alpha,25(OH)2D3 treatment of activated T cells resulted in
decreased formation of NFAT complexes detected upon incubation of nuclear
extracts from these cells with 32P-labeled probe. Transient expression of both
VDR and RXR alpha, but not of a single component, was capable of inhibiting
expression of a NFAT-driven reporter gene in stimulated jurkat cells in a ligand
dependent manner. These results suggest that NFAT plays a crucial role in
1alpha,25(OH)2D3-mediated immunosuppressive activity.
PMID- 9551974
TI - Identification of an inhibitory MHC receptor on alloreactive rat natural killer
cells.
AB - Studies of allogeneic lymphocyte cytotoxicity have shown that the rat NK
allorecognition repertoire is controlled by genetic elements in both the MHC
(RT1) and the NK gene complex (NKC). DA rats, possessing NK cells that are unable
to lyse allogeneic lymphoblasts, were immunized with alloreactive NK cells from
MHC-matched PVG.1AV1 rats, and two mAb, STOK1 and STOK2, were generated. STOK1
and STOK2 stained identical subsets of NKR-P1+ T and NK cells from certain
strains of rats. Relative numbers varied markedly in a panel of MHC congenic
strains, however, implicating a role for self MHC genes in their development.
Both STOK1 and STOK2 immunoprecipitated a 110-kDa disulfide-linked homodimeric
molecule, with extensive N-linked glycosylations, encoded by a gene that mapped
to the NKC. NK cells expressing this glycoprotein displayed an increased ability
to lyse allogeneic lymphoblasts, while syngeneic targets were spared. However,
blockade of the STOK2 Ag with F(ab')2 of STOK2 permitted the NK lysis of
syngeneic targets, but did not affect NK allorecognition. These results indicate
that mAb STOK1 and STOK2 identify an NKC-encoded MHC receptor in the rat that
acts as a negative regulator of cytotoxicity.
PMID- 9551975
TI - Staphylococcal enterotoxin D is a promiscuous superantigen offering multiple
modes of interactions with the MHC class II receptors.
AB - Dimerization of MHC class II molecules on the cell surface of human THP-1
monocytic cell line is a requirement for staphylococcal superantigen (SAG)
induced cytokine gene expression. The capacities of various SAG to induce this
response are governed by their modes of interaction with MHC class II molecules.
Staphylococcal enterotoxin A (SEA), with its two binding sites, dimerizes MHC
class II molecules and subsequently induces cytokine gene expression in THP-1
cells. Here, we demonstrate that staphylococcal enterotoxin D (SED) and
staphylococcal enterotoxin E (SEE) induce, similarly, IL-1beta and TNF-alpha gene
expression in these cells. Using mutated toxins that lost their binding site with
the MHC class II alpha- or beta-chain, we demonstrate that this response is also
mediated by the dimerization of MHC class II molecules through two binding sites.
Furthermore, SED forms Zn2+-dependent homodimers that allow multiple modes of MHC
class II clustering, including ligation of alpha-chains (alpha/alpha), beta
chains (beta/beta), or the alpha- and beta-chains of two different class II
molecules. The beta/beta interaction following Zn2+-dependent SED/SED homodimer
formation seems to be mediated by the appearance of a novel binding site on SED
that interacts with histidine 81 of the MHC class II beta-chain. The different
modes of SED interactions also influence SED-induced T cell activation where
simultaneous ligation of the alpha- and beta-chains is essential for optimal
response. These various modes of SED binding may be used to preserve bivalency
regardless of variability in the MHC class II alpha/beta/peptide complexes.
PMID- 9551976
TI - Identification of distinct regions of 5' flanking DNA that mediate constitutive,
IFN-gamma, STAT1, and TGF-beta-regulated expression of the class II
transactivator gene.
AB - Class II transactivator (CIITA) is a master regulator required for constitutive
and IFN-gamma-inducible expression of class II MHC genes. Although the role of
CIITA is greatly appreciated, the mechanisms underlying constitutive and IFN
gamma-induced expression of CIITA are not understood. The study of CIITA
induction is extremely important, but has been fraught with difficulty. This
study describes for the first time a large (7-kb) fragment of 5' flanking
sequences that mediates the B cell-specific, IFN-gamma-induced, and TGF-beta
suppressed expression of CIITA. This pattern of expression matches the authentic
expression of the endogenous gene. Within the 7-kb fragment, sequences that lie
between nucleotides -545 and -113 relative to the transcriptional start site are
critical for constitutive promoter expression in B cells. In contrast, inducible
activation of CIITA by IFN-gamma requires sequences contained in an additional 4
kb of upstream DNA. This region mediates an IFN-gamma response when linked to
either the endogenous CIITA promoter or a heterologous promoter. A role for STAT1
in regulation of the CIITA promoter is shown by the rescue of IFN-gamma induction
by expression of STAT1 in STAT1-defective U3A cells. TGF-beta significantly
inhibits IFN-gamma-mediated induction of the CIITA promoter in 2fTGH fibroblasts,
which indicates that the promoter is a target for TGF-beta. This inhibition is
achieved by suppression of the basal promoter. This study provides a focal point
for understanding the mechanism of B cell-specific, IFN-gamma-induced, and TGF
beta-suppressed expression of CIITA.
PMID- 9551977
TI - A two-step mechanism for recruitment of Pip by PU.1.
AB - Transcription of the Ig kappa light chain gene is controlled in part by the 3'
kappa enhancer. Two of the proteins that bind to the 3' enhancer, PU.1 and Pip,
show tissue-restricted expression and may be responsible for the tissue
specificity of 3' enhancer activity. PU.1 alone can bind to DNA; however, Pip
cannot bind to its 3' enhancer site in electrophoretic mobility shift assays,
unless recruited by PU.1. Previously, we showed that the PU.1 PEST domain (rich
in the amino acids proline, glutamate, serine, and threonine; sequences 118-160)
is necessary for Pip recruitment to DNA. Here we used detailed mutagenic analyzes
of PU.1 to more precisely identify sequences required for Pip recruitment by
electrophoretic mobility shift assay. We found that mutation of three segments
within the PU.1 PEST domain (118-125, 133-139, and 141-147) modulated the
efficiency of Pip recruitment, while mutation of sequences between residues 88
118 and 154-168 had no effect. Interestingly, we found that the PU.1 ETS domain
(residues 170 to 255) is both necessary and sufficient for Pip interaction in
solution and that other ETS domain proteins can physically interact with Pip as
well. Our results suggest that Pip recruitment to DNA by PU.1 occurs via a two
step mechanism. First, a physical interaction that is not sufficient to recruit
Pip occurs via the PU.1 ETS domain. Second, a conformational change in the PU.1
PEST domain, apparently mediated by serine phosphorylation, induces a
conformational change in Pip enabling it to bind to DNA. We also show that the
PU.1 PEST domain does not target PU.1 for rapid turnover.
PMID- 9551978
TI - Monoclonal anti-cardiolipin antibodies from New Zealand Black x New Zealand White
F1 mice react to thrombomodulin.
AB - The reactivity with and affinity for thrombomodulin (TM) of monoclonal anti
cardiolipin Abs (MoaCL), derived from a New Zealand Black x New Zealand White F1
(NZB/W F1) mouse, were studied to investigate the pathogenicity of anti
cardiolipin Abs (aCL). Four of eighteen MoaCL were found to react with rabbit TM
when examined using ELISA. These four MoaCL also reacted with synthetic peptide
that included the epidermal growth factor-like domain of human TM, a binding site
for thrombin. The reaction with TM of these four MoaCL was inhibited by bovine
thrombin. When the affinity for TM of the MoaCL was determined, the dissociation
constants (Kd) ranged from 4.8 x 10(-9) to 4.7 x 10(-8) M. By contrast,
examination of the affinity for cardiolipin (CL) gave values from 8.3 x 10(-6) to
7.4 x 10(-5) M. Thus, these MoaCL reacted to TM with a higher affinity than to
CL. Moreover, these MoaCL also bound to TM on HUVEC and down-regulated the
expression level of TM on the surface of HUVEC due to internalization of TM. The
binding of thrombin to TM is known to initiate rapid protein C activation, and
complexes of activated protein C and protein S show anticoagulatory activity.
Thus, the present studies suggest that certain pathogenic aCL cross-react with TM
and induce down-regulation of TM on endothelial cells, followed by induction of
thrombosis.
PMID- 9551979
TI - V(H) repertoire of a marsupial (Monodelphis domestica).
AB - When contrasted with information available for placental mammals, very little is
known about the development of immunocompetence in marsupials. Marsupials,
however, provide interesting immunology problems, since most appear to be born at
a stage of development much less mature than that of placental mammals. To
further understand the marsupial immune system, the Ig repertoire of the short
tailed opossum, Monodelphis domestica, was characterized. The majority of the
V(H) clones were isolated in an unbiased manner by screening a spleen cDNA phage
library, using C region probes, or anchored PCR, using C region-specific primers
paired with vector specific primers. Analysis of 54 unique V(H) sequences from
this marsupial revealed the presence of two V(H) families in the expressed Ig
repertoire. The larger family, which contributed the majority of the clones
identified, appears to be derived from 10 to 12 germline V(H) segments. The
second family of clones is derived from a single germline V(H). Both V(H)
families are related to the group III sequences described in other vertebrates.
Unusual codon bias differences between the two families may result in very
different patterns of somatic mutation within the opossum Ig repertoire.
PMID- 9551980
TI - Molecular analysis of the major MHC recombinational hot spot located within the
G7c gene of the murine class III region that is involved in disease
susceptibility.
AB - Recombination within the MHC does not occur at random, but crossovers are
clustered in hot spots. We previously described a recombinational hotspot within
the 50-kb Hsp70.3-G7 interval in the class III region of the mouse MHC. The
parental haplotypes of recombinants with crossovers in this region represent the
majority of the laboratory haplotypes (a, b, d, dx, k, m, p, px, q, s, and u).
Using microsatellite markers and sequence-based nucleotide polymorphisms, the
breakpoint intervals of 30 recombinants were mapped to a 5-kb-long interval
within the G7c gene adjacent to G7a. Recombination within the G7c hot spot does
not appear to be restricted to certain haplotypes. Sequence motifs that had been
suggested to be associated with site-restricted meiotic recombination were absent
in the vicinity of the G7c hot spot, and hence, these sequence motifs are no
prerequisite for meiotic recombination. The G7c hot spot resides in a region to
which a number of disease susceptibility loci have been mapped, including
susceptibility to cleft palate, experimental autoimmune allergic orchitis, and
chemically induced alveolar lung tumors. The exact localization of crossovers in
recombinants that have been used in functional studies is important for mapping
susceptibility genes and limits the number of candidate genes.
PMID- 9551981
TI - Common and distinct signaling pathways mediate the induction of TNF-alpha and IL
5 in IgE plus antigen-stimulated mast cells.
AB - A small number of signaling cascades represented by mitogen-activated protein
kinases, phosphoinositol-3-kinase, protein kinase C, signal transducers and
activators of transcription, Ca2+/calcineurin, and a few other molecules are
linked to an incomparably large number of surface receptors. Parallel activation
of several of these pathways and the existence of isozymes for a number of signal
transmitting molecules generate the required complexity and specificity matching
the receptor variety. Here we show that the proinflammatory mediator TNF-alpha
and the growth factor IL-5 are activated along common and distinct signaling
cascades in allergically stimulated murine mast cells. Both of them are dependent
on Ca2+ influx, activation of calcineurin and nuclear factor of activated T cells
as well as a member of the atypical PKC family, most likely PKCmu. Additionally,
mitogen-activated protein kinases for TNF-alpha and members of the classical or
nonclassical PKCs for IL-5, respectively, were identified as additional required
pathways. Inhibition of the classical and nonclassical PKCs, however, does not
abrogate IL-5 induction but instead leads to a switch to mitogen-activated
protein kinases, which then become essential. The activated branches of this
"salvage" signaling cascade are represented by extracellular signal-regulated
kinase 1/2 and c-jun NH2 terminal kinase 1 in allergically stimulated mast cells.
PMID- 9551982
TI - The role of recombinant murine IL-12 and IFN-gamma in the pathogenesis of a
murine systemic Candida albicans infection.
AB - Studies on murine candidiasis suggest that resistance to disease is linked to a
Th1 response and production of IFN-gamma, while failure to elicit protection is
associated with a Th2 response and production of IL-4 and IL-10. Experimental
infection of C57BL/6 mice, IL-12 treatment of these mice, or both infection and
IL-12 treatment resulted in a characteristic Th1 cytokine mRNA profile as
measured by quantitative competitive PCR. Specifically, little or no IL-4
transcripts were detected, while IFN-gamma message was elevated, particularly
with IL-12 treatment. Despite its role in driving increased IFN-gamma expression
and production, IL-12 treatment, paradoxically, promoted disease progression in
our model. Therefore, we examined the effect of IFN-gamma neutralization on IL-12
induced susceptibility to infection. None of the systemically infected mice
receiving IL-12 alone survived, while IL-12- and anti-IFN-gamma-treated mice had
a 70% survival rate, similar to that after infection alone. These results
suggested that IFN-gamma induced by IL-12 treatment contributed to lethality.
However, in separate studies, IFN-gamma knockout mice were more susceptible to
infection than their wild-type counterparts, suggesting that IFN-gamma is
required for resistance. Nonetheless, infected IFN-gamma knockout mice treated
with recombinant murine IL-12 exhibited enhanced resistance, suggesting that the
toxicities observed with IL-12 are directly attributable to IFN-gamma and that an
optimal immune response to Candida infections necessitates a finely tuned balance
of IFN-gamma production. Thus, we propose that although IFN-gamma can drive
resistance, the overproduction of IFN-gamma during candidiasis, mediated by IL-12
administration, leads to enhanced susceptibility.
PMID- 9551983
TI - Peptides that mimic the group B streptococcal type III capsular polysaccharide
antigen.
AB - Microbial polysaccharides are notably poor immunogens. We have developed an
alternate route for the production of Abs to important carbohydrate epitopes. mAb
S9, a protective mAb against the type III capsular polysaccharide of group B
streptococci (GBS), was used to select epitope analogues from a peptide display
phage library. Depending upon desorption conditions, two populations of phage
were identified with displayed sequences of WENWMMGNA and FDTGAFDPDWPA. ELISA
results demonstrated that these phage bound to S9 and no other Abs. Phage blocked
the binding of S9 to type III GBS, but did not block binding by another anti-GBS
mAb. Phage displaying the latter peptide sequence showed greater inhibition. Ab
S9 and other monoclonal and polyclonal anti-GBS type III antisera bound the
synthetic peptide FDTGAFDPDWPAC. The binding of S9 to GBS was inhibited by the
free peptide with an IC50 of 30 microg/ml. The binding of polyclonal anti-GBS
antibodies to peptide could be blocked by intact GBS as well as purified capsular
polysaccharide. The peptide was conjugated to three different carriers and was
used to immunize mice. All mice produced a significant antibody response to GBS
and to the purified capsular polysaccharide following a single immunization.
These data demonstrate that a peptide mimetic of the GBS capsular polysaccharide
is both antigenic and immunogenic. The incorporation of such peptides into
vaccine preparations may enhance the efficacy of vaccines in inducing Ab
responses to important carbohydrate epitopes.
PMID- 9551984
TI - IL-18 (IFN-gamma-inducing factor) regulates early cytokine production in, and
promotes resolution of, bacterial infection in mice.
AB - IL-12-induced IFN-gamma production is essential for clearance of Yersinia
enterocolitica infection. Similar to IL-12, the recently described cytokine IL-18
(IFN-gamma-inducing factor) is produced by macrophages and induces IFN-gamma
production in spleen cells. Therefore, we have investigated the role of IL-18 in
Yersinia infection of mice. Heat-killed yersinia-triggered IL-18-promoted IFN
gamma production of splenocytes was predominantly dependent on endogenous IL-12
production, whereas IL-12-promoted IFN-gamma production was not IL-18 dependent.
IL-18-induced IFN-gamma production was to a higher degree dependent on IFN-gammaR
mediated mechanisms and in synergism with IL-2 resulted in at least fivefold
higher IFN-gamma levels as compared with the combination of IL-12 plus IL-2.
Analysis of the effect of IL-18 on IL-12 production of LPS-stimulated peritoneal
macrophages revealed that IL-18 decreased LPS-induced IL-12 production,
indicating that IL-18 might be involved in negative regulation of IL-12
production. In vivo studies revealed that Yersinia-resistant C57BL/6 mice
expressed fourfold higher IL-18 mRNA levels than did susceptible BALB/c mice.
Administration of anti-IL-18 Abs caused a 100- to 1000-fold increase in bacterial
counts in the spleen of infected mice but did not change IFN-gamma production
levels. Taken together, our data demonstrate that IL-18 is involved in regulation
of cytokine production during the early phase of bacterial infections as well as
in clearance of Yersinia infection.
PMID- 9551985
TI - Septic arthritis following Staphylococcus aureus infection in mice lacking
inducible nitric oxide synthase.
AB - Nitric oxide (NO), produced in large amounts by inducible NO synthase (iNOS), has
emerged recently as an important microbicidal and immunomodulatory mediator. We
have investigated its role in bacterial septic arthritis caused by Staphylococcus
aureus infection using iNOS-deficient mice. The incidence, rate of development,
and severity of arthritis were greater in iNOS-deficient than in heterozygous or
wild-type control mice. Similarly, the incidence and severity of septicemia and
mortality were significantly higher in iNOS-deficient mice compared with
controls. Increased TNF-alpha synthesis in vivo and in vitro and enhanced IFN
gamma compared with IL-4 production in vitro in iNOS-mutant mice demonstrated
exaggerated Th1 polarization of the host response. These data indicate that high
output NO production is not a prerequisite for severe articular destruction and
imply that NO is of importance in synovial defense against staphylococcal
infection.
PMID- 9551986
TI - Legionella pneumophila infection in intratracheally inoculated T cell-depleted or
-nondepleted A/J mice.
AB - The inflammatory response and influence of T cell depletion on the pathogenesis
of an experimental Legionella infection were studied. A/J mice were infected with
10(6) CFU of Legionella pneumophila intratracheally. With this dose all infected
animals survived the infection and bacteria were cleared from lung, spleen,
liver, and kidney within 10 to 11 days, leaving no residual changes in the
affected organs. Inflammatory cells were recruited into the lung on the second
day of infection, reaching a maximum on the third day and filling out
predominantly the interstitial areas. During the first 3 days after inoculation,
mainly macrophages, B cells, NK cells, and large mononuclear cells of an unknown
phenotype were attracted into the lung interstitium, whereas T lymphocytes
infiltrated subsequently. During the early phase of infection, serum
concentrations of IFN-gamma, TNF-alpha, IL-1beta, IL-4, and IL-6 but not IL-2
increased dramatically. The cytokine secretion decreased on the third day after
infection although bacteria were still present in the lung or even disseminated
in different organs. Successful clearance of bacteria from the lung was not
observed before recruitment of T cells into the lung. In mice depleted of both
CD4+ and CD8+ T cells, control of infection was impaired and lethality of
infection increased. Depletion of either subset left residual antibacterial
mechanisms, which, however, were not sufficient to clear the Legionella as
rapidly as in undepleted mice.
PMID- 9551987
TI - Mechanism of protective immunity against influenza virus infection in mice
without antibodies.
AB - There is considerable interest in developing viral vaccines intended to induce T
cell immunity, especially cytotoxic CD8+ T lymphocytes, when Abs are not
protective or are too narrow in viral strain specificity. We have studied
protective immunity in doubly inactivated (DI) mice devoid of Abs and mature B
cells. When infected with influenza B virus, these mice cleared the virus in a
process dependent upon CD8+ T lymphocytes. Cytotoxic activity was detected in
lung lymphocytes of DI mice after primary or secondary infection, and was
abrogated by depletion of CD8+ cells in vivo. Challenge experiments showed that
DI mice could be protected by immunization against reinfection 1 mo later, and
protection was virus specific. Depletion of CD4+ or CD8+ T cells in vivo during
the challenge period partially abrogated, and depletion of both subsets
completely abrogated, the protection. This indicates that both CD4+ and CD8+ T
cells are required effectors in the optimal control of virus replication. Thus,
when Abs fail to protect against varying challenge viruses, as is the case with
variant strains of influenza and HIV, there is hope that T cells might be able to
act alone.
PMID- 9551988
TI - Accumulation of the p53 protein allows recognition by human CTL of a wild-type
p53 epitope presented by breast carcinomas and melanomas.
AB - The p53 protein is accumulated in tumor cells of many human cancers and can
elicit in vivo humoral and proliferative responses. Rare reports about p53
mediated tumor recognition by CTLs have remained questioned. We therefore studied
a panel of breast tumor and melanoma cell lines that we assayed for the presence
of accumulated p53 and surface HLA-A2 and for the presentation of p53 epitopes.
From PBMC of a healthy donor, we have generated a CTL line, D5/L9V, directed
against HLA-A2-restricted peptide 264-272 from wild-type p53. It efficiently
lysed breast adenocarcinomas MCF-7, MCF7/RA1, and MDA-MB-231, and melanoma M8,
which all accumulate the p53 protein. Using competition assays, we made sure that
tumor lysis by D5/L9V was due to recognition of endogenously produced p53 peptide
264-272 associated with the HLA-A2.1 molecule on the surface of these tumor
cells. Cells with undetectable levels of wild-type p53, such as lymphoblastoid
cells and melanoma M74, were not recognized by D5/L9V. Neither were breast tumor
cell line MCF7/ADR nor melanoma line M44 because of HLA loss. This study
therefore shows that it is possible to obtain in vitro CTL lines that
specifically recognize a p53 epitope spontaneously presented by a variety of HLA
A2+ transformed cell lines provided they display abnormal patterns of p53
expression. This work points out that breast tumors and melanomas share a p53
epitope, and raises hopes for future immunotherapeutic approaches.
PMID- 9551989
TI - Successful adoptive cellular immunotherapy is dependent on induction of a host
immune response triggered by cytokine (IFN-gamma and granulocyte/macrophage
colony-stimulating factor) producing donor tumor-infiltrating lymphocytes.
AB - Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) and systemic low
dose rIL-2 effectively eradicates pulmonary metastases of the murine MCA-105
sarcoma. We described earlier that host CD8+ T cells are critical for tumor
eradication and that successful treatment is associated with production of high
levels of IFN-gamma and granulocyte/macrophage (GM)-CSF by donor TIL in vitro.
Here, we propose the mechanism through which adoptively transferred Thy-1.1+ TIL
induce a host antitumor response in congenic Thy-1.2+ tumor-bearing mice. Donor
Thy-1.1+ TIL were detected at the tumor site 12 h after transfer. These Thy-1.1+
cells produced IFN-gamma and GM-CSF in situ. The percentage of Thy-1.1+ TIL at
the tumor site increased up to 16.4 +/- 4.9% 24 h after transfer but decreased to
undetectable levels thereafter. In contrast, the percentages of host cells
producing IFN-gamma and GM-CSF continued to increase at the tumor site. These
increases were significantly higher in TIL + rIL-2-treated mice compared with
untreated mice and rIL-2-treated mice 48 h after TIL transfer. The appearance of
IFN-gamma+ and GM-CSF+ cells was followed by a large influx of host CD4+, CD8+,
and Thy-1.2+ TIL and eventually by tumor eradication. This response was tumor
specific since TIL obtained from MCA-205 did not induce high levels of IFN-gamma
and GM-CSF and did not induce tumor eradication of MCA-105 tumor. Coinjection of
Thy-1.1+ TIL and anti-IFN-gamma or anti-GM-CSF mAb significantly inhibited
antitumor efficacy of the TIL + rIL-2 treatment. We conclude that successful
adoptive immunotherapy in this model is mediated through cytokine production by
adoptively transferred TIL that induce a host T cell-dependent antitumor
response.
PMID- 9551990
TI - Neutrophils but not eosinophils are involved in growth suppression of IL-4
secreting tumors.
AB - Local expression of IL-4 by gene-modified tumor cells increases their
immunogenicity by inducing an inflammatory response that is dominated by
eosinophils. Eosinophils have been implicated as antitumor effector cells because
the application of a granulocyte-depleting Ab inhibited rejection of IL-4
transfected tumors. This Ab did not discriminate between eosinophils and
neutrophils and, therefore, this experiment could not exclude neutrophils as
primary effector cells, whereas eosinophils were innocent bystander cells in IL-4
transfected tumors. We analyzed tumor growth suppression and granulocyte
infiltration in IL-5-deficient (IL-5(-/-)) mice that had a deficiency of
eosinophils, using two tumor lines (B16-F10 and MCA205) transfected to secrete IL
4. IL-4-expressing tumors were at least as efficiently rejected in IL-5(-/-) mice
as in wild-type mice, despite an almost complete absence of tumor-infiltrating
eosinophils. However, neutrophils were present in undiminished amounts and their
depletion partially restored tumor growth. Furthermore, the growth of IL-5
secreting tumors was not impaired in either wild-type or IL-5(-/-) mice, even
though it induced eosinophilia in both mouse strains. These findings demonstrate
that eosinophils can be induced in IL-5(-/-) mice by exogenous IL-5 and argue
against a compensatory effect of neutrophils in the absence of eosinophils. We
conclude that 1) infiltration of IL-4 transfected tumors by eosinophils is
completely IL-5 dependent, 2) eosinophils have no tumoricidal activity, and 3)
neutrophils are responsible, at least in part, for tumor suppression.
PMID- 9551991
TI - Helminth antigens selectively differentiate unsensitized CD45RA+ CD4+ human T
cells in vitro.
AB - Human filarial helminth infections are characterized by type 2 immune responses
to parasite Ag that can persist for the life of the individual; one possible
cause for this may be prenatal exposure to the blood-borne microfilarial (Mf)
stage of the parasite. To examine the relationship between early exposure to
filarial Ag and subsequent immune responsiveness, CD45RA+ CD4+ cells frp, normal
unsensitized donors were stimulated in vitro with soluble microfilarial Ag (MfAg)
from the filarial parasite Brugia malayi in the presence of APCs. MfAg alone
induced proliferation and IFN-gamma and IL-5 production in unsensitized CD45RA+
CD4+ cells, demonstrating the ability of filarial Ags to prime naive T cells in
the absence of exogenous cytokines and dendritic cells. Adding exogenous
cytokine(s) (particularly IL-12 and IL-4) during priming was able to alter the
MfAg-specific responses of CD45RA+ CD4+ cells as well as subsequent responses to
Ag. Interestingly, priming solely with MfAg led to enhanced IL-5 production
following Ag restimulation, suggesting that MfAg preferentially primes for type 2
responses. These data demonstrate that filarial Ags by themselves can
specifically prime CD45RA+ CD4+ cells in vitro and do so in such a way as to
deviate the immune response.
PMID- 9551992
TI - Macrophages kill T9 glioma tumor cells bearing the membrane isoform of macrophage
colony stimulating factor through a phagocytosis-dependent pathway.
AB - Rat T9 glioma cells transfected with the gene for the membrane isoform of
macrophage-CSF (mM-CSF) but not for the secreted isoform of M-CSF were directly
killed by bone marrow-derived macrophages. Macrophage-mediated cytolysis of the
mM-CSF-transfected clone was blocked by using chemical inhibitors of phagocytosis
such as iodoacetate, 2-deoxyglucose, gadolinium chloride, and cytochalasin B. In
contrast, macrophage-mediated killing of mM-CSF-expressing tumor cells was
augmented by the microtubule inhibitor, colchicine. Use of nitric oxide and
reactive oxygen intermediate inhibitors failed to alter the macrophage-mediated
killing of the mM-CSF-transfected tumor cells. Photomicroscopy, using
immunohistochemical staining with the anti-Hck Ab to distinguish macrophages from
tumor cells, revealed that phagocytosis began within 2 h after addition of the mM
CSF-bearing tumor cells. Photocinematography confirmed that macrophages first
phagocytosized and then lysed the internalized mM-CSF transfectant cells. Using
annexin V and acridine orange staining techniques, macrophages phagocytosized
living mM-CSF-transfected tumor cells.
PMID- 9551993
TI - Accommodation and T-independent B cell tolerance in rats with long term surviving
hamster heart xenografts.
AB - It was previously reported that treatment with leflunomide (LF; 10 mg/kg/day)
together with cyclosporine (CsA; 10 mg/kg/day) resulted in long term survival of
hamster heart xenografts (Xg) in rats and that LF could be withdrawn 2 to 4 wk
after transplantation. To study the mechanisms allowing withdrawal of LF, second
hamster heart Xgs were transplanted 6 wk after the first xenograft. Only the rats
that received LF for 4 wk accepted second Xgs (>30 days; n = 5). Hence, after 4
wk of LF, the rats developed partial B cell tolerance, as they were unable to
produce T-independent (CsA-resistant) XAbs. Rejection of second Xgs (2-4 days; n
= 5) in the 2-wk LF group resulted in the formation of IgM xenoantibodies (XAbs)
localizing together with complement within rejected grafts. However, these XAbs
did not affect first Xgs, suggesting that the latter Xgs became resistant to this
IgM XAb-mediated rejection, a phenomenon referred to as accommodation.
Accommodation was further confirmed as adoptive transfer of IgM XAbs, which
resulted in hyperacute Xg rejection in naive rats (<1 h; n = 5), did not cause
rejection in long term survivors (>30 days; n = 4). This was associated with a
down-regulation of the expression on the graft endothelial cells of adhesion
molecules (believed to be important expressers of xenogeneic epitopes), such as P
and E-selectins. Interestingly, these adhesion molecules reappeared after
retransplanting the accommodated Xgs to naive recipients. In conclusion,
depending on the duration of the LF treatment, long term survival of hamster
hearts in CsA-treated rats is based in part on accommodation and in part on T
independent B cell tolerance.
PMID- 9551994
TI - Chronic Listeria infection in SCID mice: requirements for the carrier state and
the dual role of T cells in transferring protection or suppression.
AB - Listeriosis in mice with the SCID mutation results in a chronic infection. The
chronic infection is characterized by abundant granulomas and neutrophil
infiltrates. Both lesions were particularly noticeable in the liver. In the
liver, about 95% are granulomas with 5% microabscesses involving intrahepatic
infection. The majority of Listeria resided in membrane-bound vacuolar structures
of the macrophages and not in the cytosol. Three manipulations resulted in
alterations in the equilibrium between granulomas and liver microabscesses, with
massive transfer of the infection to the hepatocyte and dissolution of the
granulomas: depletion of neutrophils and neutralization of IFN-gamma and TNF
alpha. We did not find a role for IL-12, IL-10, or nitric oxide. Adoptive
transfer studies showed a decisive role for both CD4+ and CD8+ T cells for an
effective immune response, i.e., clearance of bacteria, granuloma formation with
lymphocytes, and disappearance of microabscess. Clearance of Listeria was induced
by transfer of CD8+ T cells from mice with targeted disruption of the IFN-gamma
structural gene (IfgTM1KO), even in the presence of neutralizing mAb to IFN
gamma. In marked contrast, transfer of CD4+ T cells from IfgTM1KO mice
exacerbated the infection in the chronically infected SCID mice, resulting in
increased mortality with dissolution of the granulomas and severe hepatic
infection with neutrophil infiltration. Thus, these data indicate that both IFN
gamma-dependent and -independent mechanisms are operative in the context of a
chronic listerial infection.
PMID- 9551995
TI - Lymphoid hyperplasia, autoimmunity, and compromised intestinal intraepithelial
lymphocyte development in colitis-free gnotobiotic IL-2-deficient mice.
AB - IL-2-deficient (IL-2(-/-)) mice develop disorders of the hemopoietic and immune
systems characterized by anemia, lymphocytic hyperplasia, and colitis. The
mechanisms responsible for these abnormalities remain unclear. To investigate the
underlying basis of autoimmunity, the particular role of commensal gut flora in
the initiation of colitis, and the role of IL-2 in the development of intestinal
intraepithelial lymphocytes (iIEL), we evaluated IL-2(-/-) mice reared and
maintained under gnotobiotic (germfree) conditions. By 8 wk of age, 80% (20 of
25) of germfree IL-2(-/-) mice show signs of disease, including anemia,
disturbances in bone marrow hemopoietic cells, lymphocytic hyperplasia, and
generalized autoimmunity, similar to those seen in specific pathogen-free (SPF)
IL-2(-/-) mice. In striking contrast to SPF IL-2(-/-) mice, germfree IL-2(-/-)
mice do not develop colitis. However, the numbers of gammadelta+ and TCR
alphabeta+ CD8 alphaalpha+ iIELs are reduced, and in lethally irradiated SPF IL
2(+/+) mice, reconstituted with IL-2(-/-) bone marrow TCR gammadelta+ iIELs fail
to develop, consistent with an important role of IL-2/IL-2R signaling in the
development of gammadelta iIELs. Consequently, our findings demonstrate that the
colitis seen in SPF IL-2(-/-) mice depends upon the presence of intestinal
bacterial flora and that environmental Ags are not responsible for the anemia and
extraintestinal lymphoid hyperplasia that occur in IL-2(-/-) mice. Thus, germfree
IL-2(-/-) mice represent a unique system in which the role of IL-2 deficiency in
hemopoietic and immune system disorders can be investigated in dissociation from
complications that may arise due to colitis.
PMID- 9551996
TI - Human CD38 (ADP-ribosyl cyclase) is a counter-receptor of CD31, an Ig superfamily
member.
AB - Human CD38 is a cell surface molecule involved in the regulation of lymphocyte
adhesion to endothelial cells. This suggests that HUVEC bear a ligand(s) for CD38
on the cell surface. By means of the mAb Moon-1, which specifically inhibits CD38
mediated cell adhesion, we have identified a trans-membrane 130-kDa molecule
acting as a ligand for CD38. Here, we report that the molecule recognized by the
Moon-1 mAb is CD31, a member of the Ig superfamily. This conclusion is based on
1) cross-inhibition assays between Moon-1 and reference anti-CD31 mAbs; 2)
sequential immunoprecipitation experiments using Moon-1 and known anti-CD31 mAbs,
and 3) reactivity of the Moon-1 mAb with CD31 transfectants. Further, CD31 and
CD38 cognate interactions were found to modulate heterotypic adhesion as well as
to implement cytoplasmic calcium fluxes identical to those obtained by means of
agonistic anti-CD38 mAbs. Other effects tested included the synthesis of messages
for a panel of cytokines, markedly increased upon receptor-ligand interactions.
These results suggest that the interplay between CD38 and its ligand CD31 is an
important step in the regulation of cell life and of the migration of leukocytes
(and CD38+ cancer cells) through the endothelial cell wall.
PMID- 9551997
TI - IL-1 and TNF antagonists inhibit the inflammatory response and bone loss in
experimental periodontitis.
AB - Periodontal disease is the most frequent cause of tooth loss in humans and is the
most prevalent disease associated with bone loss, including osteoporosis.
Periodontal destruction is initiated by bacteria that colonize the tooth surface,
leading to inflammation and bone resorption. To assess the roles of IL-1 and TNF
in this process, studies were conducted in a Macaca fascicularis primate model of
experimental periodontitis. Function-blocking soluble receptors to IL-1 and TNF
were applied by local injection to sites with induced periodontal destruction and
compared with similar sites injected with vehicle alone. The results indicate
that injection of soluble receptors to IL-1 and TNF inhibited by approximately
80% the recruitment of inflammatory cells in close proximity to bone. The
formation of osteoclasts was reduced by 67% at the experimental sites compared
with that at the control sites, and the amount of bone loss was reduced by 60%.
All results were statistically significant (p < 0.01). These findings indicate
that a significant component of the pathologic process of periodontitis is due to
IL-1/TNF activity, since inhibiting IL-1/TNF reduces both inflammatory cell
recruitment and bone loss. The data also suggest that inflammation associated
with gingivitis is actively protective, since blocking further up-regulation of
the host response with IL-1/TNF inhibitors does not cause periodontal damage.
Furthermore, these results coupled with recent evidence that IL-1 and TNF
participate in endocrine-associated osteoporosis suggest that multiple
pathologies involving excessive loss of bone may operate through a common
mechanism involving IL-1 and/or TNF.
PMID- 9551998
TI - Inhibition of proinflammatory molecule production by adenovirus-mediated
expression of a nuclear factor kappaB super-repressor in human intestinal
epithelial cells.
AB - NF-kappaB plays a major role in the transcriptional regulation of many
proinflammatory genes in multiple cell lineages, including intestinal epithelial
cells (IEC). Activation of NF-kappaB requires both phosphorylation and
degradation of its natural cytoplasmic inhibitor, IkappaB. We tested whether a
super-repressor of NF-kappaB activity, which is a mutated nondegradable IkappaB
alpha resistant to phosphorylation and degradation, could be delivered into IEC
using an adenoviral vector (Ad5 IkappaB) and determined the antiinflammatory
potential of this inhibitor following different stimuli. We showed for the first
time that recombinant adenovirus efficiently infected (>80%) transformed as well
as primary IEC. Cytoplasmic levels of the NF-kappaB super-repressor protein were
more than 50-fold higher than those of endogenous IkappaB, and this mutated
IkappaB was resistant to IL-1beta-induced degradation. Immunofluorescent RelA
nuclear staining was strongly inhibited in Ad5 IkappaB-infected IEC compared with
control Ad5LacZ and NF-kappaB, but not AP-1 binding activity, was reduced by more
than 70% as measured by electrophoretic mobility shift assay (EMSA). Induction of
inducible nitric-oxide synthase (iNOS), IL-1beta, and IL-8 genes by IL-1beta, TNF
alpha, or PMA was blocked in Ad5 IkappaB-infected cells but not in Ad5 LacZ
controls as assayed by RT-PCR and ELISA. In addition, IL-1beta-induced IL-8
secretion was totally inhibited by Ad5 IkappaB in primary colonic IEC. We
conclude that an adenoviral vector efficiently transfers a nondegradable IkappaB
in both transformed and native IEC. The strong inhibition of NF-kappaB activity
and the resulting down-regulation of multiple proinflammatory molecules by Ad5
IkappaB suggests an exciting approach for in vivo intestinal gene therapy and
illustrates the key role of NF-kappaB in transcriptional regulation of the
inflammatory phenotype of IEC.
PMID- 9551999
TI - Regulated production of type I collagen and inflammatory cytokines by peripheral
blood fibrocytes.
AB - We recently described a novel population of blood-borne cells, termed fibrocytes,
that display a distinct cell surface phenotype (collagen+/CD13+/CD34+/CD45+),
rapidly enter sites of tissue injury, and contribute to scar formation. To
further characterize the role of these cells in vivo, we examined the expression
of type I collagen and cytokine mRNAs by cells isolated from wound chambers
implanted into mice. Five days after chamber implantation, CD34+ fibrocytes but
not CD14+ monocytes or CD90+ T cells expressed mRNA for type I collagen.
Fibrocytes purified from wound chambers also were found to express mRNA for IL
1beta, IL-10, TNF-alpha, JE/MCP, MIP-1alpha, MIP-1beta, MIP-2, PDGF-A, TGF-beta1,
and M-CSF. The addition of IL-1beta (1-100 ng/ml), a critical mediator in wound
healing, to fibrocytes isolated from human peripheral blood induced the secretion
of chemokines (MIP-1alpha, MIP-1beta, MCP-1, IL-8, and GRO alpha), hemopoietic
growth factors (IL-6, IL-10, and macrophage-CSF), and the fibrogenic cytokine TNF
alpha. By contrast, IL-1beta decreased the constitutive secretion of type I
collagen as measured by ELISA. Additional evidence for a role for fibrocytes in
collagen production in vivo was obtained in studies of livers obtained from
Schistosoma japonicum-infected mice. Mouse fibrocytes localized to areas of
granuloma formation and connective matrix deposition. We conclude that fibrocytes
are an important source of cytokines and type I collagen during both the
inflammatory and the repair phase of the wound healing response. Furthermore, IL
1beta may act on fibrocytes to effect a phenotypic transition between a
repair/remodeling and a proinflammatory mode.
PMID- 9552000
TI - RANTES-induced T cell activation correlates with CD3 expression.
AB - The chemokine RANTES induces a unique biphasic cytoplasmic Ca2+ signal in T
cells. The first phase of this signal, similar to that of other chemokines, is G
protein mediated and chemotaxis associated. The second phase of this signal,
unique to RANTES and evident at concentrations greater than 100 nM, is tyrosine
kinase linked and results in a spectrum of responses similar to those seen with
antigenic stimulation of T cells. We show here that certain jurkat T cells
responded to RANTES solely through this latter pathway. A direct correlation
between the RANTES-induced second phase response and CD3 expression was
demonstrated in these cells. Sorting the Jurkat cells into CD3(high) and CD3(low)
populations revealed that only the CD3(high) cells were responsive to RANTES.
Furthermore, stimulation of these Jurkat cells with anti-CD3 mAb significantly
depresses their subsequent response to RANTES. While a RANTES-specific chemokine
receptor is expressed at a low level on these Jurkat cells, the RANTES-induced
activation is dependent on the presence of the TCR. Thus, stimulation through TCR
may partially account for RANTES' unique pattern of signaling in T cells.
PMID- 9552002
TI - CD8+ myelin peptide-specific T cells can chemoattract CD4+ myelin peptide
specific T cells: importance of IFN-inducible protein 10.
AB - The demyelination process that occurs in the central nervous system (CNS) of
patients with multiple sclerosis (MS) is due, in part, to an inflammatory
response in which CD4+ and CD8+ T cells and macrophages infiltrate white matter.
While it is thought that the inflammatory and demyelination process in MS is the
product of Th1-associated cytokines secreted by CD4+ myelin protein-specific T
cells present in the CNS, the mechanisms that are responsible for the recruitment
and maintenance of these myelin-reactive CD4+ T cells in the CNS have not been
elucidated. We have shown previously that CD8+ CTL that recognize peptides
derived from sequences of the myelin proteolipid protein (PLP) presented by HLA
class I molecules can be generated in vitro, and that these PLP-specific CD8+ CTL
secrete the proinflammatory chemokines macrophage-inflammatory protein-1alpha and
-1beta, IL-16, and IP-10. In this study, we demonstrate that soluble products of
these PLP-specific CD8+ CTL can chemoattract CD4+ T cells that are specific for a
myelin basic protein peptide and a PLP peptide, and that the majority of this
chemotactic activity is mediated by IFN-inducible protein 10. These results
demonstrate that PLP-specific CD8+ T cells can play a role in the recruitment and
retention of myelin-derived peptide-specific CD4+ T cells, and indicate that they
may play a proinflammatory role in the pathogenesis of MS.
PMID- 9552001
TI - Importance of MEK in neutrophil microbicidal responsiveness.
AB - Exposure of neutrophils to inflammatory stimuli such as the chemoattractant FMLP
leads to activation of responses including cell motility, the oxidative burst,
and secretion of proteolytic enzymes. A signaling cascade involving sequential
activation of Raf-1, mitogen-activated protein kinase (MEK), and extracellular
signal regulated kinase (ERK) is also rapidly activated after agonist exposure.
The temporal relationship between these events suggests that the kinases may be
involved in triggering the effector functions, but direct evidence of a causal
relationship is lacking. To assess the role of the MEK/ERK pathway in the
activation of neutrophil responses, we studied the effects of PD098059, a potent
and selective inhibitor of MEK. Preincubation of human neutrophils with 50 microM
PD098059 almost completely (>90%) inhibited the FMLP-induced activation of MEK-1
and MEK-2, the isoforms expressed by neutrophils. This dose of PD098059 virtually
abrogated chemoattractant-induced tyrosine phosphorylation and activation of ERK
1 and ERK-2, implying that MEKs are the predominant upstream activators of these
mitogen-activated protein kinases. Pretreatment of neutrophils with the MEK
antagonist inhibited the oxidative burst substantially and phagocytosis only
moderately. In addition, PD098059 antagonized the delay of apoptosis induced by
exposure to granulocyte-macrophage CSF. However, the effects of PD098059 were
selective, as it failed to inhibit other responses, including chemoattractant
induced exocytosis of primary and secondary granules, polymerization of F-actin,
chemotaxis, or activation of phospholipase A2. We conclude that MEK and ERK
contribute to the activation of the oxidative burst and phagocytosis, and
participate in cytokine regulation of apoptosis.
PMID- 9552003
TI - Regulation of chemokine gene expression in human peripheral blood neutrophils
phagocytosing microbial pathogens.
AB - Production of chemokines (chemotactic cytokines) by neutrophils is likely to be
important in the regulation of inflammation and the control of infection. In this
study we show that exposure of human neutrophils to various microbial pathogens
leads to the production of both macrophage inflammatory protein 1alpha (MIP
1alpha) and IL-8. The bacterial microbes, Salmonella typhimurium and Pseudomonas
aeruginosa, and Staphylococcus aureus all strongly induced both IL-8 and MIP
1alpha secretion, whereas Streptococcus pneumoniae, Staphylococcus epidermidis,
and the opportunistic yeast Candida albicans were less potent. Saccharomyces
cerevisiae and zymosan both induced IL-8 secretion but failed to stimulate that
of MIP-1alpha. Coincubation of neutrophils with the proinflammatory cytokine TNF
alpha and the micro-organisms also led to differential expression of MIP-1alpha
and IL-8. Significant enhancement of the induction of both MIP-1alpha and IL-8 by
S. typhimurium, P. aeruginosa, and S. pneumoniae as well as by C. albicans was
observed. In contrast, while IL-8 production in response to S. cerevisiae and
zymosan was enhanced in the presence of TNF-alpha, no MIP-1alpha was produced.
These combined results indicate that while neutrophils exposed to some micro
organisms alone or in the presence of inflammatory cytokines such as TNF-alpha
will produce both MIP-1alpha and IL-8, resulting in generation of signals for the
recruitment of mononuclear leukocytes and neutrophils, respectively, certain
types of microorganisms can skew this response toward synthesis of IL-8.
PMID- 9552004
TI - Apical secretion of a pathogen-elicited epithelial chemoattractant activity in
response to surface colonization of intestinal epithelia by Salmonella
typhimurium.
AB - Modeling Salmonella-epithelial cell interaction in vitro has led to the
realization that epithelial cells are crucial in orchestrating neutrophil (PMN)
responses, in part by stimulating basolateral release of epithelial chemokines,
including IL-8. However, such basolaterally released chemokines, while likely
important in orchestration of PMN movement across the subepithelial matrix, are
unlikely to be responsible for the final step of transepithelial migration of PMN
and entry into the apical compartment. We now show that S. typhimurium attachment
to T84 cell apical epithelial membranes induces polarized apical secretion of a
pathogen-elicited epithelial chemoattractant (PEEC) bioactivity. Experiments
employing semipurified PEEC indicate that it is released in a polarized apical
fashion and is sufficient to explain the observed final step of transepithelial
migration of PMN induced by Salmonella-apical membrane interaction. By
preliminary physical characterization and profiles of PMN activation, PEEC
appears to be a novel PMN chemotactic bioactivity. This 1- to 3-kDa nominal
molecular mass chemokine-like bioactivity directly stimulates PMN via a pertussis
toxin-sensitive receptor and elicits a Ca2+ signal. While these latter features
are shared by most other chemokines, analysis of PEEC-elicited PMN activation
reveals that, unlike these other agonists, PEEC, even at saturating
concentrations, elicits chemotactic activity in the absence of stimulation of
superoxide production and/or release of primary and/or secondary granules. These
data suggest that the apically released PEEC activity appears to represent a
novel epithelial-derived chemoattractant that directs PMN movement across
epithelial monolayers.
PMID- 9552005
TI - Adhesion molecule mechanisms mediating monocyte migration through synovial
fibroblast and endothelium barriers: role for CD11/CD18, very late antigen-4
(CD49d/CD29), very late antigen-5 (CD49e/CD29), and vascular cell adhesion
molecule-1 (CD106).
AB - Monocytes migrate through vascular endothelium, and then in connective tissue. As
a model of this process, we investigated adhesion molecules involved in monocyte
migration through HUVEC and a barrier of human synovial fibroblasts (HSF).
Minimal spontaneous monocyte migration (6-7%) occurred through either cell
barrier, but this increased markedly (27-35% of added monocytes) when a C5a
chemotactic gradient was present. Migration across unstimulated HUVEC was
partially inhibited (40%) by mAb to CD18 (beta2 integrin) and completely blocked
by anti-CD18 plus anti-alpha4 (CD49d; very late Ag-4 (VLA-4)) mAbs. In contrast,
migration across HSF induced by C5a or monocyte chemoattractant protein-1 was not
inhibited by mAb to CD18 and was only partially inhibited (33%) in combination
with anti-alpha4 mAb. The CD18- and VLA-4-independent migration across HSF was
completely inhibited by mAb to alpha5 of VLA-5. The inhibitory effect of mAbs to
VLA-4 and VLA-5 was on the monocyte and required blockade of CD11/CD18 to be
observed. In contrast to HSF, no role for VLA-5 in monocyte transendothelial
migration was detected. Both HSF and IL-1-stimulated HUVEC expressed vascular
cell adhesion molecule-1 (VCAM-1). However, VLA-4-mediated monocyte migration
across HSF was only partially dependent on VCAM-1, in contrast to
transendothelial migration, which was completely blocked by anti-VCAM-1 mAbs. In
conclusion, unlike transendothelial migration, for which VLA-4 is the alternative
mechanism to CD11/CD18 on monocytes, both VLA-4 and VLA-5 can mediate monocyte
migration through fibroblast barriers. In addition to VCAM-1, other ligand(s) on
HSF are also involved in the VLA-4-mediated migration.
PMID- 9552006
TI - Effect of C1 inhibitor on inflammatory and physiologic response patterns in
primates suffering from lethal septic shock.
AB - We evaluated the effect of C1 inhibitor (C1-inh), an inhibitor of the classical
pathway of complement and the contact system, on the physiologic and inflammatory
response in baboons suffering from lethal Escherichia coli sepsis. Five animals
pretreated with 500 U/kg C1-inh (treatment group; n = 5), followed by a 9-h
continuous infusion of 200 U/kg C1-inh subsequent to bacterial challenge, were
compared with five controls receiving E. coli alone. Of the treatment group, one
animal survived and another lived beyond 48 h, whereas all control animals died
within 27 h. In four of five treated animals, less severe pathology was observed
in various target organs. C1-inh administration did not prevent the hemodynamic
or hematologic changes observed upon E. coli infusion. The activation of
fibrinolysis and the development of disseminated intravascular coagulation were
essentially unaffected by C1-inh. However, C1-inh supplementation significantly
reduced decreases in plasma levels of factor XII and prekallikrein and abrogated
the systemic appearance of C4b/c, indicating substantial inhibition of activation
of the contact system and the classical complement pathway, respectively.
Furthermore, treated animals displayed a reduced elaboration of various cytokines
including TNF, IL-10, IL-6, and IL-8. Thus, the administration of C1-inh may have
a beneficial but modest effect on the clinical course and outcome of severe
sepsis in nonhuman primates. We suggest that activated complement and/or contact
system proteases may, at least in part, contribute to the attendant
manifestations of septic shock through an augmentation of the cytokine response.
PMID- 9552007
TI - Differential activities of secreted lymphotoxin-alpha3 and membrane lymphotoxin
alpha1beta2 in lymphotoxin-induced inflammation: critical role of TNF receptor 1
signaling.
AB - Lymphotoxin (LT, LT alpha, TNF beta) is a member of the immediate TNF family that
also includes TNF-alpha and lymphotoxin-beta (LT beta). LT is produced by
activated lymphocytes and functions as either a secreted homotrimer or a membrane
associated heterotrimer that includes the transmembrane protein LT beta. Secreted
LT alpha3 can bind to two cell surface receptors, TNFR1 and TNFR2, while the
membrane-bound heterotrimer LT alpha1beta2 has been shown to interact with a
distinct receptor, LT betaR. LT alpha induces inflammation at the sites of
expression of a rat insulin promoter-driven lymphotoxin (RIPLT) transgene in the
pancreas and kidney. To determine the role of the various ligands and their
receptors in LT-induced inflammation, mice deficient in either TNFR1, TNFR2, or
LT beta were crossed to RIPLT-transgenic mice. Our results indicate that LT alpha
induced inflammation is dependent on the interaction of LT alpha3 with TNFR1, and
there is no obvious role for TNFR2, since in its absence, LT alpha-induced
inflammation is quantitatively and qualitatively similar to that seen in the wild
type. However, the absence of LT beta results in accentuated infiltration of the
kidney with an increase in the proportion of memory cells in the infiltrate.
These data show a crucial role for the secreted LT alpha3 signaling via TNFR1 in
LT alpha-induced inflammation, and a separate and distinct role for the membrane
LT alpha1beta2 form in this inflammatory process.
PMID- 9552008
TI - Distinct classes of chaperoned IL-6 in human blood: differential immunological
and biological availability.
AB - Transport of IL-6 in blood is fundamental to the biology of this cytokine. In the
present study, IL-6 transport, immunological reactivity, and biological
availability were investigated in blood from melanoma patients subjected to
different active specific immunization regimens (an anti-idiotypic mAb
immunization protocol (mAb-keyhole limpet hemocyanin (KLH)-Calmette-Guerin
bacillus (BCG), an autologous anti-cancer vaccine protocol (AAAP), or both). Sera
were subjected to Sephadex G-200 gel filtration chromatography, and the structure
and biological activity of IL-6 complexes in the eluate fractions were probed
using five IL-6 ELISAs and two bioassays. Sera from patients administered mAb
KLH+BCG followed by AAAP contained three distinct classes of IL-6 eluting at 30,
200, and 450 kDa, each with its characteristic ELISA reactivity and bioactivity:
the 30- and 450-kDa complexes were bioactive in the B9 and Hep3B assays, but the
200-kDa complex was not. The 30- and 450-kDa IL-6 complexes were preferentially
reactive in the 7IL6/5IL6 ELISA, the 200-kDa IL-6 complexes were preferentially
reactive in the 4IL6/5IL6 ELISA, while the three commercial ELISAs (R&D, Endogen,
and Genzyme) detected essentially only the 30-kDa IL-6. In contrast, 1) sera from
AAAP patients contained biologically active 30- and 450-kDa IL-6 complexes, while
2) sera from mAb-KLH+BCG patients contained 200-kDa IL-6 complexes inactive in ex
vivo bioassays. Both the 450- and 200-kDa complexes included soluble IL-6R, with
the 200-kDa complexes additionally containing ligand-occupied anti-IL-6 and anti
soluble IL-6R IgG. The data indicate the existence of specific mechanisms that
regulate the transport and function of IL-6 in vivo.
PMID- 9552010
TI - CDR3 size spectratyping and sequencing of spectratype-derived TCR of spinal cord
T cells in autoimmune encephalomyelitis.
AB - To characterize the nature of autoimmune disease-inducing T cells in the target
organ, oligoclonal expansion of spinal cord T cells of Lewis rats with
experimental autoimmune encephalomyelitis (EAE) was examined by complementarity
determining region 3 (CDR3) size spectratyping. It is known that TCR of in vitro
established myelin basic protein-specific T cell clones and lines have a short
CDR3 and that the amino acid sequence in this region is highly preserved. On the
basis of these findings, we analyzed 22 spectratypes of the TCR beta-chain
(Vbeta1-20). Among them, only Vbeta8.2 and Vbeta17 showed oligoclonal expansion
of TCR with a short CDR3 at the early stage of EAE. More interestingly, the
spectratype profile of Vbeta8.2 seen at the early stage was preserved throughout
the course of EAE, whereas that of Vbeta17 became more diverse at the peak stage
of the disease. Analysis of nucleotide and predicted amino acid sequences of
Vbeta8.2 CDR3 derived from the spectratypes revealed that the clones with
CASSDSSYEQYFGPG, which is one of the representative sequences of encephalitogenic
T cell clones, constituted the predominant population not only at the early stage
but also at the peak and recovery stages (71, 71, and 60%, respectively). These
findings imply that although the phenotype of T cells in the target organ
diversifies as the autoimmune disease progresses, disease-associated TCR
spectratype(s) are preserved throughout the course of the disease. Thus, CDR3
size spectratyping is a powerful tool for the screening of disease-inducing T
cells in an autoimmune disease of unknown pathomechanism.
PMID- 9552009
TI - A model of peptide-induced lupus autoimmune B cell epitope spreading is strain
specific and is not H-2 restricted in mice.
AB - Anti-Sm is a common and specific autoantibody found in systemic lupus
erythematosus. The peptide PPPGMRPP from Sm B/B' is an early target of the
autoimmune response in some anti-Sm-positive human patients. After immunization
with this peptide on a MAP backbone, rabbits develop anti-Sm autoantibodies with
B cell epitope spreading of the autoimmune response as well as other features of
lupus autoimmunity. Various strains of inbred mice have been immunized with
peptide PPPGMRPP or PSQQVMTP (nonantigenic region of Sm B/B') in Freund's
adjuvant or with no peptide. All peptide-immunized mouse strains eventually
develop high titers of specific anti-peptide of immunization Abs. Mice immunized
with Freund's adjuvant alone have no measurable Ab binding to the PPPGMRPP
peptide. With time, nearly half the mouse strains tested develop Abs that react
with additional regions of Sm B/B' and Sm D. All the regions bound by mouse serum
are major epitopes of the human systemic lupus erythematosus anti-Sm response.
These same strains also develop significant anti-Sm and anti-nuclear
ribonucleoprotein titers. In addition, some of these strains demonstrate positive
anti-nuclear Abs and anti-dsDNA Abs. Experiments with congenic H-2 mice
demonstrate that the H-2 region does not play a role in spreading the immune
response from the peptide of immunization to other epitopes of the spliceosome.
These results present a new murine model of B cell epitope spreading and lupus
autoimmunity induced by peptide immunization that is strain specific and not
apparently dependent upon the loci at H-2.
PMID- 9552011
TI - Introduction: mechanisms and management of COPD: we can do better--it's time for
a re-evaluation.
PMID- 9552012
TI - COPD: overview of definitions, epidemiology, and factors influencing its
development.
AB - COPD is a heterogeneous collection of conditions that can affect various
structures within the lung in a number of different ways. These various processes
can all result in limitation of expiratory airflow. If severe enough, this
physiologic abnormality defines COPD. The various conditions that can lead to
this syndrome are prevalent and often relentlessly progressive. In aggregate,
they represent an important public health problem. This supplement outlines
diagnostic and therapeutic strategies by which the practitioner can assist
patients suffering from this condition.
PMID- 9552013
TI - The role of infection in COPD.
AB - Clinical studies of acute exacerbations of COPD are difficult because of the
heterogeneous nature of COPD, diffuse symptoms that can vary spontaneously, and
difficulties in defining clinical response both in the short and long term. The
role of bacterial infection, and thus use of antibiotics, in COPD is
controversial. The available evidence shows that bacterial infection has a
significant role in acute exacerbations, but its role in disease progression is
less certain. Upper respiratory tract commensals, such as nontypable Haemophilus
influenzae, cause most bronchial infections by exploiting deficiencies in the
host defenses. Some COPD patients are chronically colonized by bacteria between
exacerbations, which represents an equilibrium in which the numbers of bacteria
are contained by the host defenses but not eliminated. When an exacerbation
occurs, this equilibrium is upset and bacterial numbers increase, which incites
an inflammatory response. Neutrophil products can further impair the mucosal
defenses, favoring the bacteria, but if the infection is overcome, symptoms
resolve. However, if the infection persists, chronic inflammation may cause lung
damage. About half of exacerbations involve bacterial infection, but these
patients are not easy to differentiate from those who are uninfected, which means
that antibiotics have to be given more often than is strictly necessary. Further
research is needed to characterize those patients in whom bacterial infection has
a more important role.
PMID- 9552014
TI - The value of antibiotics and the outcomes of antibiotic therapy in exacerbations
of COPD.
AB - COPD is the fifth leading cause of death in the United States, and acute
respiratory infections account for a significant proportion of all primary care
visits. Approximately one half of all exacerbations of COPD can be attributed to
bacterial infection, and antibiotic therapy has been demonstrated to improve
clinical outcomes and hasten clinical and physiologic recovery. The major
pathogen continues to be Haemophilus influenzae, and resistance to beta-lactam
antibiotics such as ampicillin can be expected in 20 to 40% of isolated strains.
Certain high-risk patients, in whom the cost of clinical treatment failure is
high, can be identified by simple clinical criteria. Patients with significant
cardiopulmonary comorbidity, frequent purulent exacerbations of COPD, advanced
age, generalized debility, malnutrition, chronic corticosteroid administration,
long duration of COPD, and severe underlying lung function tend to fail therapy
with older drugs, such as ampicillin, and early relapse can be expected.
Treatment directed toward resistant pathogens with potent bactericidal drugs may
be expected to lead to improved clinical outcomes and overall lower costs,
particularly if hospital admissions and respiratory failure can be prevented.
Future studies examining the role of antibiotics should enroll these high-risk
patients to determine if new therapies have significant clinical, quality-of
life, and economic advantages over older agents.
PMID- 9552015
TI - Supportive therapy in COPD.
AB - Supportive therapy in COPD includes long-term oxygen therapy (LTOT) and patient
support groups as two cornerstones in a comprehensive program of care known as
pulmonary rehabilitation. The rich history of LTOT dating to the early 1960s and
bolstered by excellent controlled clinical trials of the 1970s, along with
additional advances, provided an effective therapy which improved both the
quality and length of life in patients with COPD. Many patients with oxygen gain
insight into coping with advanced COPD through patient support groups. The need
for more cosmetically pleasing oxygen delivery systems to the nose, and future
directions in providing oxygen in the home, remain challenges.
PMID- 9552016
TI - Pulmonary rehabilitation.
AB - There has been a resurgence of interest in pulmonary rehabilitation mainly
because the prevalence of COPD has increased, scientific studies document
consistent benefits (increased exercise endurance and reduced dyspnea), and
thoracic surgeons recognize that preoperative and postoperative conditioning
enhances the results of lung volume reduction surgery and lung transplantation.
Although education and psychosocial/behavioral interventions are important
components of a multidimensional program, exercise training of the upper and
lower extremities is essential to achieve the described improvements. Current
programs vary considerably in the frequency, intensity, and duration of exercise
reconditioning. Two "key" questions relating to pulmonary rehabilitation are as
follows. What is an appropriate training intensity? How should patients monitor
the training intensity? Maintenance exercise programs and the development of home
or community-based programs will be important future developments.
PMID- 9552017
TI - Lung Transplantation for COPD.
AB - In appropriately selected patients with COPD and alpha1-antitrypsin deficiency
emphysema, lung transplantation prolongs life, improves functional capacity, and
enhances quality of life. However, rejection remains an obstacle to better medium
term results, and lung transplantation is a treatment, not a cure and not a
panacea.
PMID- 9552018
TI - Lung volume reduction surgery: answering the crucial questions.
AB - Emphysema and other forms of COPD are not only common, but also have a poor
prognosis. Mortality with severe COPD may be as high as 60% at 5 years and is
associated with a significant degree of disability and cost to the health-care
system. Building on Dr. Otto Brantigan's experience in the 1950s, when multiple
wedge resections of emphysematous lung were performed to decrease lung volume,
thereby improving airflow and reducing hyperinflation, recent investigators,
utilizing improved surgical and anesthetic technique, have redeveloped a surgical
approach to the treatment of emphysema. The operations used to treat emphysema
include excision of large bullae (bullectomy) and resection of diffusely
emphysematous lung and are variously known as lung volume reduction surgery
(LVRS), pneumectomy, and reduction pneumoplasty. These operations aim for a 20 to
30% reduction in lung volume and may be performed by stapler or laser resection,
or both. The mechanisms of benefit have been attributed to enhanced elastic
recoil, correction of ventilation perfusion mismatch, improved efficiency of
respiratory musculature, and improved right ventricular filling. Questions that
remain to be answered include duration of benefits, safety, and cost of LVRS. The
National Heart, Lung, and Blood Institute and the Health Care Financing
Administration have responded to the demand for more access to and information
about LVRS by organizing both a national registry and controlled clinical trial
of these procedures over a 7-year period. This multicenter trial intends to
enroll patients with end-stage emphysema to compare methods of bilateral LVRS to
maximal medical therapy.
PMID- 9552019
TI - Standards for the optimal management of COPD: a summary.
AB - Tobacco smoking is the main cause of COPD, and encouragement and support in
smoking cessation is the best way to help the patient with COPD. The three major
goals of COPD management are to lessen airflow limitation, to prevent and treat
secondary medical complications, and to decrease respiratory symptoms and improve
quality of life. Outpatient pharmacotherapy should be organized in a stepwise
manner according the severity of disease, the aims being to induce
bronchodilation, reduce inflammation, and facilitate expectoration, although the
role of anti-inflammatory and mucolytic treatment of COPD has not been clearly
established. Patients whose conditions are not well controlled with optimal
pharmacotherapy are candidates for enrollment in a pulmonary rehabilitation
program. Correction or prevention of hypoxemia is a priority, and long-term
oxygen therapy supplementation prolongs survival in hypoxemic patients. With only
limited data on criteria for hospital admission and the objectives of
hospitalization, the published standards on the management of COPD include an
expert consensus statement on these aspects of hospital care. Surgery, special
considerations such as sleep, nutrition, and air travel, and ethical issues are
discussed.
PMID- 9552020
TI - Ewing's sarcoma oncogene structure: a novel prognostic marker?
PMID- 9552021
TI - Germ cell tumors: there is still plenty to learn.
PMID- 9552022
TI - EWS-FLI1 fusion transcript structure is an independent determinant of prognosis
in Ewing's sarcoma.
AB - PURPOSE: More than 90% of Ewing's sarcomas (ES) contain a fusion of the EWS and
FLI1 genes, due to the t(11;22)(q24;q12) translocation. At the molecular level,
the EWS-FLI1 rearrangements show great diversity. Specifically, many different
combinations of exons from EWS and FLI1 encode in-frame fusion transcripts and
result in differences in the length and composition of the chimeric protein,
which functions as an oncogenic aberrant transcription factor. In the most common
fusion type (type 1), EWS exon 7 is linked in frame with exon 6 of FLI1. As the
fundamental pathogenetic lesion in ES, the molecular heterogeneity of these
fusion transcripts may have functional and clinical significance. PATIENTS AND
METHODS: We performed a clinical and pathologic analysis of 112 patients with ES
in which EWS-FLI1 fusion transcripts were identified by reverse-transcriptase
polymerase chain reaction (RT-PCR). Adequate treatment and follow-up data were
available in 99 patients treated with curative intent. Median follow-up in these
99 patients was 26 months (range, 1 to 140 months). Univariate and multivariate
survival analyses were performed that included other prognostic factors, such as
age, tumor location, size, and stage. RESULTS: Among the 99 patients suitable for
survival analysis, the tumors in 64 patients contained the type 1 fusion and in
35 patients contained less common fusion types. Stage at presentation was
localized in 74 patients and metastatic in 25. Metastases (relative risk [RR] =
2.6; P = .008), and type 1 EWS-FLI1 fusion (RR = 0.37; P = .014) were,
respectively, independent negative and positive prognostic factors for overall
survival by multivariate analysis. Among 74 patients with localized tumors, the
type 1 EWS-FLI1 fusion was also a significant positive predictor of overall
survival (RR = 0.32; P = .034) by multivariate analysis. CONCLUSION: EWS-FLI1
fusion type appears to be prognostically relevant in ES, independent of tumor
site, stage, and size. Further studies are needed to clarify the biologic basis
of this phenomenon.
PMID- 9552023
TI - Successful treatment of stage III neuroblastoma based on prospective biologic
staging: a Children's Cancer Group study.
AB - PURPOSE: To identify a biologically favorable and unfavorable subset of patients
with Evans stage III neuroblastoma and to determine whether treatment
stratification would improve the event-free survival (EFS) for high-risk patients
and maintain excellent EFS for the lower-risk patients. PATIENTS AND METHODS:
Risk stratification was performed by age, MYCN gene copy number, Shimada
histopathologic classification, and serum ferritin level. Lower-risk patients
were treated on the less intensive Children's Cancer Group (CCG)-3881, whereas
high-risk patients were treated on CCG-3891, which included more intensive
multimodality therapy and, in some cases, autologous bone marrow transplantation
(ABMT). RESULTS: Of 228 Evans stage III patients entered onto the study, 92% also
met the definition of International Neuroblastoma Staging System (INSS) stage 3.
One hundred forty-three patients met the lower-risk criteria, which included 89
patients less than 1 year of age and 54 patients 1 year of age or greater, and
favorable biology, whereas 85 patients were 1 year of age or greater and
biologically unfavorable. Biologically unfavorable patients 1 year of age or
greater who underwent gross surgical resection had improved survival, whereas the
outcome of infants or biologically favorable older patients did not change
according to resection. The EFS rate at 4 years was 100% for the patients with
favorable biology of any age, 90% for those less than 1 year of age but with at
least one unfavorable characteristic, and 54% for Evans stage III patients 1 year
of age or greater with unfavorable biology. Age, ferritin level, MYCN copy
number, Shimada histopathology, primary site, and intraspinal extension were
significant univariate prognostic factors for all patients, but only MYCN copy
number and age were independent factors in multivariate analyses. CONCLUSION: The
excellent survival of the biologically favorable group and the historically
improved EFS of the biologically unfavorable group suggest that biologic staging
should be used to define the prognosis and treatment of stage III neuroblastoma.
PMID- 9552024
TI - Spontaneous regression of localized neuroblastoma detected by mass screening.
AB - PURPOSE: To clarify whether and when neuroblastomas identified through screening
do regress, and to ascertain how to treat them appropriately, we observed
screened patients who had localized tumors, without any therapeutic intervention.
PATIENTS AND METHODS: The criteria for the observation program were as follows:
disease stage I or II; tumor less than 5 cm in diameter; no invasion to the
intraspinal canal or growth to the great vessels; urinary vanillylmandelic acid
(VMA) and homovanillic acid (HVA) less than 50 microg/mg creatinine; and informed
consent. Of 25 patients identified through screening for 6-month-old infants in
Saitama Prefecture, Japan between April 1994 and March 1996, 11 patients who met
the criteria and one other patient with stage III tumor were enrolled onto the
program. They were examined by abdominal ultrasonography (US) and their urinary
VMA and HVA levels were assessed approximately once per month. The observation
periods ranged from 4 to 27 months. RESULTS: The 11 tumors decreased in size,
although one of these 11 tumors initially enlarged until the patient was 12
months of age and decreased in size thereafter. One other tumor slightly
increased in size. Urinary VMA levels decreased in all patients. None of the
tumors had completely disappeared by the last observation day. CONCLUSION: Our
results suggest that regression of screened neuroblastoma is not a rare
phenomenon. At present, it seems reasonable to adopt a wait-and-see strategy,
with careful observation, for selected stage I or II tumors identified in infants
screened at 6 months of age.
PMID- 9552025
TI - Frequency and clinical significance of cytogenetic abnormalities in pediatric T
lineage acute lymphoblastic leukemia: a report from the Children's Cancer Group.
AB - PURPOSE: Nonrandom chromosomal translocations are frequently observed in
pediatric patients with acute lymphoblastic leukemia (ALL). Specific
translocations, such as t(4;11) and t(9;22), identify subgroups of B-lineage ALL
patients who have an increased risk of treatment failure. The current study was
conducted to determine the prognostic significance of chromosomal translocations
in T-lineage ALL patients. MATERIALS AND METHODS: The study included 169 children
with newly diagnosed T-lineage ALL enrolled between 1988 and 1995 on risk
adjusted protocols of the Children's Cancer Group (CCG) who had centrally
reviewed cytogenetics data. Outcome analyses used standard life-table methods.
RESULTS: Presenting features for the current cohort were similar to those of
concurrently enrolled patients for whom cytogenetic data were not accepted on
central review. The majority of patients (80.5%) were assigned to CCG protocols
for high-risk ALL and 86.4% had pseudodiploid (n = 80) or normal diploid (n = 66)
karyotypes; modal chromosome number was not a significant prognostic factor.
Overall, 103 of 169 (61%) patients had an abnormal karyotype, including 31 with
del(6q), 29 with 14q11 breakpoints, 15 with del(9p), 11 with trisomy 8, nine with
11q23 breakpoints, nine with 14q32 translocations, and eight with 7q32-q36
breakpoints. Thirteen patients had the specific 14q11 translocation
t(11;14)(p13;q11) and all were classified as poor risk. Patients with any of
these translocations had outcomes similar to those with normal diploid
karyotypes. CONCLUSION: Chromosomal abnormalities, including specific nonrandom
translocations, were frequently observed in a large group of children with T
lineage ALL, but were not significant prognostic factors for this cohort. Thus,
contemporary intensive treatment programs result in favorable outcomes for the
majority of T-lineage ALL patients, regardless of karyotypic abnormalities, and
such features do not identify patients at higher risk for relapse.
PMID- 9552026
TI - Alternative and complementary therapy use in pediatric oncology patients in
British Columbia: prevalence and reasons for use and nonuse.
AB - PURPOSE: Alternative and complementary therapies are infrequently studied in
pediatric populations. We performed a population-based survey to aid health care
workers in identifying and counseling parents who may use these remedies.
PATIENTS AND METHODS: We retrospectively surveyed the parents of 583 pediatric
patients diagnosed with cancer in British Columbia between 1989 and 1995.
Prevalence and factors that influence the use and nonuse of alternative and
complementary therapies were estimated. RESULTS: Alternative and complementary
therapies were used by 42% of 366 respondents. Herbal teas, plant extracts, and
therapeutic vitamins were the most commonly used alternative therapies.
Relaxation/imagery strategies, massage, and therapeutic touch were the most
commonly used complementary techniques. Factors that influenced the use of
alternative/complementary therapies were prior use (chi2 = 60.0, P < .0001),
prior positive attitude towards these remedies (chi2 = 41.6, P < .0001),
soliciting information from family and friends (chi2 = 70.5, P < .0001) or from
alternative care givers (chi2 = 58.7, P < .0001), high risk of death at diagnosis
(chi2 = 9.6, P < .002), and advanced education of the father (chi2 = 7.4, P <
.006) or mother (chi2 = 8.6, P < .003). Parents who used
alternative/complementary therapies did so in conjunction with conventional
medicine (98%). Lack of knowledge and fear of interference with conventional
therapies were the most common reasons cited for nonuse. No parent believed that
the quality of life of their child deteriorated due to the use of
alternative/complementary therapies. CONCLUSION: Alternative and complementary
therapy use in pediatric oncology patients is common. Factors have been
identified that may be associated with undertaking their use.
PMID- 9552027
TI - Randomized comparison of cisplatin and etoposide and either bleomycin or
ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern
Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia
Group B Study.
AB - PURPOSE: To compare standard therapy with bleomycin, etoposide, and cisplatin
(BEP) to experimental therapy with etoposide, ifosfamide, and cisplatin (VIP) as
primary treatment of men with advanced, disseminated germ cell tumors. PATIENTS
AND METHODS: A total of 304 men with advanced disseminated germ cell tumors were
randomly allocated to receive four courses of BEP or VIP. Two hundred ninety-nine
patients were assessable for toxicity and 286 were assessable for response.
Complete response rates, favorable response (complete remission, surgical free of
disease, continuous partial remission for 2+ years), time to treatment failure,
and overall survival were assessed. RESULTS: Overall complete remission rate
(VIP, 37%; BEP, 31%), favorable response rate (VIP, 63%; BEP, 60%), failure-free
at 2 years (VIP, 64%; BEP, 60%), and 2-year overall survival (VIP, 74%; BEP, 71%)
were not significantly different between the two treatments. Grade 3 or worse
toxicity, particularly hematologic and genitourinary toxicity, was significantly
more common in patients who received VIP. CONCLUSION: BEP and VIP produce
comparable favorable response rate and survival in patients with poor-risk germ
cell tumors. The substitution of ifosfamide for bleomycin, however, was
associated with significantly greater toxicity. Four courses of BEP remain the
standard treatment for advanced disseminated germ cell tumors.
PMID- 9552028
TI - Management strategies and outcomes of germ cell tumor patients with very high
human chorionic gonadotropin levels.
AB - PURPOSE: To determine the therapeutic results in advanced germ cell tumor (GCT)
patients with initial human chorionic gonadotropin (hCG) elevation greater than
50,000 mIU/mL and to document the levels of hCG decline and subsequent plateau
and outcome of this patient population. PATIENTS AND METHODS: We conducted a
retrospective review of 41 patients who presented to Indiana University (IU) with
hCG levels greater than 50,000 mIU/mL between December 1976 and August 1996. All
patients had received cisplatin-containing regimens and were monitored with
serial hCG levels. RESULTS: Twenty-two of 41 (53.7%) patients continuously show
no evidence of disease (NED) and eight additional patients (19.5%) are currently
NED with salvage therapy. Only two of 41 patients had a normal hCG level at the
start of the fourth and final course of cisplatin combination chemotherapy. Eight
additional patients showed normalized hCG levels 1 month later. Seven of these 10
are continuously NED and three are currently NED with salvage therapy. Thirty-one
patients had an abnormal hCG greater than 1 month after they completed primary
chemotherapy; 15 of these patients (48%) are continuously NED despite no further
therapy and five additional patients (16%) are currently NED with salvage
therapy. Overall, there was an initial rapid decline in hCG followed by a plateau
after the first two courses of therapy. CONCLUSION: Less than 10% of patients who
present with hCG levels greater than 50,000 mIU/mL will have a normal hCG at the
institution of the fourth and final course of chemotherapy. However, 22 of 41
(53.7%) are continuously NED despite no further therapy. We feel that the optimal
strategy for such patients is monthly observation with initiation of salvage
therapy if and when there is serologic progression.
PMID- 9552029
TI - Neoadjuvant chemotherapy and bladder-sparing surgery for invasive bladder cancer:
ten-year outcome.
AB - PURPOSE: To evaluate the 10-year outcome of patients with invasive (T2-3N0M0,
staged according to the tumor, node, metastasis system) bladder cancer who
responded completely to a combination of methotrexate, vinblastine, adriamycin,
and cisplatin (MVAC) chemotherapy followed by bladder-sparing surgery. PATIENTS
AND METHODS: Of 111 surgical candidates who received neoadjuvant MVAC, 60 (54%)
achieved a complete clinical response (T0) on transurethral resection (TUR) of
the primary tumor site. Of these, 28 requested follow-up with TUR alone, 15 had a
partial cystectomy, and 17 elected a radical cystectomy. The patients were
followed up for a median of 10 years (range, 8 to 13 years). RESULTS: Of 43
patients who had bladder-sparing surgery, 32 (74%) are alive, which includes 25
(58%) with an intact functioning bladder. Twenty-four patients (56%) developed
bladder tumor recurrences from 5 to 96 months, which were invasive in 13 (30%)
and superficial in 11 (26%). Thirteen patients required a salvage cystectomy, of
whom 6 died, which includes 4 (9%) from a new invasive neoplasm. Of the 17
patients who had radical cystectomy, 11 (65%) are alive. CONCLUSION: The majority
of patients with invasive bladder tumors who achieve T0 status after neoadjuvant
MVAC chemotherapy preserve their bladders for up to 10 years with bladder-sparing
surgery. The bladder remains at risk for new invasive tumors. Cystectomy salvages
the majority, but not all, of relapsing patients.
PMID- 9552030
TI - Correlation of p34cdc2 cyclin-dependent kinase overexpression, CD44s
downregulation, and HER-2/neu oncogene amplification with recurrence in prostatic
adenocarcinomas.
AB - PURPOSE: To test whether p34cdc2 overexpression, CD44s downregulation, and HER
2/neu amplification correlate with disease recurrence after radical
prostatectomy, and to evaluate a possible biologic association between p34cdc2
and HER-2/neu expression. MATERIALS AND METHODS: Immunohistochemical (IHC)
detection of both p34cdc2 cyclin-dependent kinase (CDK) and CD44s expression and
fluorescence in situ hybridization (FISH)-based analysis of HER-2/neu gene status
were performed on formalin-fixed, paraffin-embedded sections of 106 prostatic
adenocarcinomas (PACs). Findings were correlated with Gleason grade, pathologic
stage, DNA ploidy, and postsurgical biochemical disease recurrence. RESULTS: CDK
overexpression correlated with tumor grade (P = .001), DNA ploidy (P = .001),
pathologic stage (P = .04), and disease recurrence (P = .01). CD44s
downregulation correlated with grade (P = .03), ploidy (P = .01), and recurrence
(P = .02). HER-2/neu amplification correlated with grade (P = .001), ploidy (P =
.001), and recurrence (P = .01). On multivariate analysis, CDK overexpression
independently predicted recurrence (P = .001) after prostatectomy. CDK expression
correlated with HER-2/neu status with 32 of 65 (49%) tumors that overexpressed
CDK and showed concomitant HER-2/neu amplification (P = .04). CONCLUSION: This
study showed that p34cdc2, CD44s, and HER-2/neu are variably expressed or
amplified in prostatic carcinoma and that such alteration may affect tumor
behavior. In addition, CDK overexpression and HER-2/neu amplification may be
biologically related.
PMID- 9552031
TI - Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal
cancer: phase III randomized Intergroup study 0099.
AB - PURPOSE: The Southwest Oncology Group (SWOG) coordinated an Intergroup study with
the participation of Radiation Therapy Oncology Group (RTOG), and Eastern
Cooperative Oncology Group (ECOG). This randomized phase III trial compared
chemoradiotherapy versus radiotherapy alone in patients with nasopharyngeal
cancers. MATERIALS AND METHODS: Radiotherapy was administered in both arms: 1.8-
to 2.0-Gy/d fractions Monday to Friday for 35 to 39 fractions for a total dose of
70 Gy. The investigational arm received chemotherapy with cisplatin 100 mg/m2 on
days 1, 22, and 43 during radiotherapy; postradiotherapy, chemotherapy with
cisplatin 80 mg/m2 on day 1 and fluorouracil 1,000 mg/m2/d on days 1 to 4 was
administered every 4 weeks for three courses. Patients were stratified by tumor
stage, nodal stage, performance status, and histology. RESULTS: Of 193 patients
registered, 147 (69 radiotherapy and 78 chemoradiotherapy) were eligible for
primary analysis for survival and toxicity. The median progression-free survival
(PFS) time was 15 months for eligible patients on the radiotherapy arm and was
not reached for the chemo-radiotherapy group. The 3-year PFS rate was 24% versus
69%, respectively (P < .001). The median survival time was 34 months for the
radiotherapy group and not reached for the chemo-radiotherapy group, and the 3
year survival rate was 47% versus 78%, respectively (P = .005). One hundred
eighty-five patients were included in a secondary analysis for survival. The 3
year survival rate for patients randomized to radiotherapy was 46%, and for the
chemoradiotherapy group was 76% (P < .001). CONCLUSION: We conclude that
chemoradiotherapy is superior to radiotherapy alone for patients with advanced
nasopharyngeal cancers with respect to PFS and overall survival.
PMID- 9552032
TI - Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and
neck cancer: a randomized multicenter study.
AB - PURPOSE: A prospective randomized multicenter trial was performed to evaluate the
contribution of simultaneously administered chemotherapy (CT) and radiotherapy
(RT) in previously untreated patients with unresectable stage III/IV head and
neck cancer. PATIENTS AND METHODS: Patients with locoregionally advanced head and
neck cancer were treated either with RT alone (arm A) or simultaneous RT plus CT
(RCT; arm B). RT was identical in both arms and administered in three courses
with 13 fractions of 1.8 Gy each twice daily. During one course, from day 3 to
11, 23.4 Gy was delivered. In arm B, cisplatin (CDDP) 60 mg/m2, fluorouracil (5
FU) 350 mg/m2 by intravenous (i.v.) bolus, and leucovorin (LV) 50 mg/m2 by i.v.
bolus were given on day 2, and 5-FU 350 mg/m2/24 hour by continuous infusion and
LV 100 mg/m2/24 hours by continuous infusion were given from day 2 to 5.
Treatment was repeated on days 22 and 44; a total RT dose of 70.2 Gy was
administered. Treatment breaks were scheduled from days 12 to 21 and days 34 to
43. RESULTS: From 1989 to 1993, 298 patients were enrolled and 270 patients were
assessable. Acute mucositis grade 3 or 4 was more frequent in arm B (38%) than in
arm A (16%) (P < .001). Total treatment time was significantly longer in arm B
than in arm A (P < .001) due to prolonged breaks. According to hematologic
toxicity, scheduled drug doses were given in 74% of patients for the second
course and 46% for the third course. The 3-year overall survival rate was 24% in
arm A and 48% in arm B (P < .0003). The 3-year locoregional control rate was 17%
in arm A and 36% in arm B (P < .004). Both arms showed similar distant failure
patterns (arm A, 13 of 140; arm B, 12 of 130). Serious late side effects were not
significantly different between treatment arms (arm A, 6.4%; arm B, 10%; not
significant). CONCLUSION: Concomitant CT offered improved disease control and
survival in advanced head and neck cancer patients. Due to increased acute
toxicity, more supportive care is demanded when CT is given simultaneously.
Increased total treatment time does not exert a negative impact on outcome in
this combined modality regimen.
PMID- 9552033
TI - Phase II trial of paclitaxel, ifosfamide, and cisplatin in patients with
recurrent head and neck squamous cell carcinoma.
AB - PURPOSE: To assess the activity and toxicity profile of combined taxol
(paclitaxel), ifosfamide, and platinum (cisplatin) (TIP) in patients with
recurrent or metastatic squamous cell carcinoma (SCC) of the head and neck.
PATIENTS AND METHODS: Recurrent or metastatic head and neck SCC patients received
paclitaxel 175 mg/m2 in a 3-hour infusion on day 1; ifosfamide 1,000 mg/m2 in a 2
hour infusion on days 1 through 3; mesna 600 mg/m2 on days 1 through 3; and
cisplatin 60 mg/m2 on day 1, repeated every 3 to 4 weeks. All were premedicated
with dexamethasone, diphenhydramine, and cimetidine. Prophylactic hematopoietic
growth factors were not permitted. RESULTS: Fifty-two patients were assessable
for response and toxicity; 53 for survival (local-regional recurrence alone in
57% and distant metastasis with or without local-regional recurrence in 43%).
Overall response rate was 58% (30 of 52) of patients; complete response rate was
17% (nine of 52) of patients, with six complete responses that continued for a
median 15.7+ months. Median follow-up of all patients was 17.7 months. Median
survival was 8.8 months (95% confidence interval [CI] 8.1 to 17.5 months).
Toxicity was relatively well tolerated and caused no deaths. The most frequent
moderate-to-severe toxicity (90% of patients) was transient grades 3 to 4
neutropenia; neutropenic fever occurred in 27%. Grade 3 peripheral neuropathy
occurred in three patients, none had grade 4. Grade 3 mucositis occurred in only
one patient, none had grade 4. CONCLUSION: TIP had major activity in this
setting, with a 58% objective response rate, 17% complete response rate, durable
complete responses (six of nine persisting), and relatively well-tolerated
toxicity, with no toxic deaths. The activity of TIP, a novel taxol-cisplatin
based regimen, in recurrent or metastatic head and neck SCC should be confirmed
in a phase III trial.
PMID- 9552034
TI - Induction chemotherapy with docetaxel, cisplatin, fluorouracil, and leucovorin
for squamous cell carcinoma of the head and neck: a phase I/II trial.
AB - PURPOSE: A phase I/II trial of docetaxel, cisplatin, fluorouracil (5-FU), and
leucovorin (TPFL5) induction chemotherapy for patients with locally advanced
squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS:
Twenty-three previously untreated patients with stage III or IV SCCHN and Eastern
Cooperative Oncology Group functional status less than or equal to 2 were treated
with TPFL5. Postchemotherapy home support included intravenous fluids,
prophylactic antibiotics, and granulocyte colony-stimulating factor (G-CSF).
Docetaxel dose was escalated to determine the maximum-tolerated dose (MTD).
Fifteen patients were treated with three cycles of TPFL5 at MTD. Patients who
achieved either a partial response (PR) or complete response (CR) to three cycles
of TPFL5 then received definitive twice-daily radiation therapy. Toxicity and
clinical and pathologic response to TPFL5 were assessed. RESULTS: Twenty-three
patients received a total of 69 cycles of TPFL5. The MTD was determined to be
docetaxel 60 mg/m2. Dose-limiting toxicity (DLT) was neutropenia. Additional
significant toxicities at MTD were nausea, mucositis, diarrhea, peripheral
neuropathy, and sodium-wasting nephropathy. The overall response rate to TPFL5
was 100%, which included 14 of 23 (61%) clinical CRs and nine of 23 (39%)
clinical PRs. Primary-site clinical and pathologic CR rates were 19 of 22 (86%)
CRs and 20 of 22 (91%) CRs, respectively. Eight patients had less than a CR in
the neck to chemotherapy and, therefore, had postradiation neck dissections, four
of which were positive for residual tumor. CONCLUSION: TPFL5 is a tolerable
induction regimen in patients with good performance status. The DLT is
neutropenia with significant mucositis, diarrhea, peripheral neuropathy, and
sodium-wasting nephropathy. The high response rates to TPFL5 justify further
evaluation of this combination of agents in the context of formal clinical
trials.
PMID- 9552035
TI - neu/erbB-2 amplification identifies a poor-prognosis group of women with node
negative breast cancer. Toronto Breast Cancer Study Group.
AB - PURPOSE: It remains a challenge to predict which women with axillary node
negative (ANN) breast cancer at greatest risk of relapse may benefit most from
adjuvant therapy. Increases in neu/erbB-2 have been implicated in breast cancer
prognosis. Although overexpression has been investigated extensively, this study
represents the first prospective assessment of the prognostic value of neu/erbB-2
DNA amplification in a cohort of women with newly diagnosed ANN. METHODS: A
consecutive series of women was monitored for recurrence (median follow-up
duration, 36 months) and tumors from 580 individuals were analyzed for
amplification. The association of amplification with risk of recurrence was
examined in survival analyses with traditional and histologic markers as
prognostic factors. RESULTS: Neu/erbB-2 was amplified in 20% of cases. We found
an increased risk of disease recurrence when neu/erbB-2 was amplified > or =
twofold that persisted with adjustment for other prognostic factors (relative
risk, 2.36; P = .002). We found some evidence that amplification was more
important in patients who received chemotherapy compared with untreated patients.
CONCLUSION: neu/erbB-2 amplification is an independent prognostic factor for risk
of recurrence in ANN breast cancer. Women with tumors without neu/erbB-2
amplification have a good prognosis; aggressive therapy in this group is
therefore difficult to justify. On the other hand, even with adjuvant
chemotherapeutic treatment, women whose tumors exhibit neu/erbB-2 amplification
have an increased risk of recurrence. We encourage a randomized trial to compare
more aggressive adjuvant chemotherapy versus standard chemotherapy for ANN women
whose tumors exhibit neu/erbB-2 amplification.
PMID- 9552036
TI - Randomized phase II trial of infusional fluorouracil, epirubicin, and
cyclophosphamide versus infusional fluorouracil, epirubicin, and cisplatin in
patients with advanced breast cancer.
AB - PURPOSE: We previously developed an inpatient regimen that consisted of
infusional fluorouracil (5-FU), epirubicin, and cisplatin (ECisF), with a
response rate of 86% in advanced breast cancer. The current phase II 2:1
randomized study investigated whether cyclophosphamide can be substituted for
cisplatin (ECycloF) to reduce toxicity and allow the regimen to be administered
on an outpatient basis without loss of efficacy. PATIENTS AND METHODS: Ninety-six
women (median age, 49 years; range, 28 to 73) with breast cancer (59 metastatic,
37 locally advanced) received continuous infusional 5-FU (200 mg/m2/d via Hickman
line) and six cycles of epirubicin (60 mg/m2 every 21 days) with either
cyclophosphamide 600 mg/m2 every 21 days (38 metastatic, 24 locally advanced) or
cisplatin 60 mg/m2 every 21 days (21 metastatic, 13 locally advanced). There were
no significant differences in patient characteristics between these groups.
RESULTS: ECycloF was better tolerated than ECisF in terms of lethargy (P = .005),
stomatitis (P = .008), plantar palmar erythema (P = .02), constipation (P <
.001), thrombosis (P = .0014), and nausea and vomiting (P = .05). Although there
was a trend toward more anemia and leukopenia with ECisF (P =. 1), there was no
significant difference in the rates of infection. Efficacy was comparable in
terms of overall response (69% v 68%), complete response (CR; 13% v 15%), and
median progression-free survival (9 v 8 months). CONCLUSION: ECycloF is an
outpatient regimen with a lower incidence of severe nonhematologic toxicity than
inpatient ECisF; it has comparable efficacy and is considerably more economical.
PMID- 9552037
TI - Adjuvant chemoendocrine therapy in postmenopausal breast cancer:
cyclophosphamide, methotrexate, and fluorouracil dose and schedule may make a
difference. International Breast Cancer Study Group.
AB - PURPOSE: Adjuvant cytotoxics prolong disease-free survival (DFS) and overall
survival (OS) in patients with operable breast cancer. The first reported
effective adjuvant combination regimen consisted of oral cyclophosphamide on days
1 to 14 with intravenous methotrexate and fluorouracil on days 1 and 8, repeated
every 28 days (classical CMF). These drugs have since been extensively used with
or without endocrine therapies and/or other cytotoxic agents. Although doses and
schedules have varied widely, the combination of these three drugs is generically
referred to as CMF. RESULTS: Reducing the dose and/or altering the schedule of
CMF have compromised its efficacy in metastatic breast cancer. Reduction below
standard dose of a similar regimen also gave inferior results in the adjuvant
setting. CONCLUSION: Details of dose and schedule may therefore explain part of
the heterogeneity of results observed with CMF. Particular controversy surrounds
the contribution of CMF in postmenopausal women who are also receiving tamoxifen
(TAM). However, the trials that demonstrated a significant benefit for the
addition of CMF to TAM, even in postmenopausal women with estrogen receptor
positive tumors, used classical CMF. Therefore, adherence to the classical dose
and schedule is recommended when CMF is used in adjuvant therapy.
PMID- 9552038
TI - Early breast cancer: evaluation of the prognostic role of the site of the primary
tumor.
AB - PURPOSE: The prognostic role of the site of the primary breast cancer has not
been clarified. This study aimed to gather more information about this issue from
a large series of patients with long-term follow-up data. PATIENTS AND METHODS:
Data from 2,396 patients treated for early breast cancer with a conservative
approach were reviewed (1973 to 1989). In 1,619 patients, the tumor had a lateral
site, while in 777 cases, it was situated in the internal/central quadrants. The
characteristics of the two groups were well balanced, apart from axillary nodal
metastases, which were more frequent for lateral tumors (38.1% v 26.3%). RESULTS:
Analysis of distant metastases indicated that the regression coefficient
associated with tumor site was significant and the hazards ratio estimate was
1.291, which indicates the risk of distant metastases was increased by
approximately 30% for internal/central tumors. The analysis of overall survival
yielded a significant coefficient and a hazards ratio of 1.192, which indicates
an approximately 20% increase of mortality for internal/central tumors.
CONCLUSION: Early breast cancers situated in central/ internal quadrants have a
worse prognosis compared with those in lateral quadrants, in terms of distant
metastases and survival. Irradiation of the internal mammary chain for
internal/medial tumors could be suggested, but, to date, the therapeutic strategy
is still controversial.
PMID- 9552039
TI - Outcome after invasive local recurrence in patients with ductal carcinoma in situ
of the breast.
AB - PURPOSE: To detail the outcome, in terms of local recurrence, local invasive
recurrence, distant recurrence, and breast cancer mortality for patients
previously treated for ductal carcinoma in situ (DCIS). PATIENTS AND METHODS:
Clinical, pathologic, and outcome data were collected prospectively for 707
patients with DCIS accrued from 1972 through June 1997. RESULTS: There were 74
local recurrences; 39 were noninvasive (DCIS) and 35 were invasive. Fifty-one
percent of patients with invasive recurrences presented with stage 1 disease; the
remainder presented with more advanced disease. Invasive local recurrence after
mastectomy was a rare event that occurred in 0.8% of patients. Invasive
recurrence after breast preservation was more common and occurred in 7.4% of
patients. The 8-year probability of breast cancer mortality after breast
preservation was 2.1%, a number that is likely to increase with longer follow-up.
The 8-year breast cancer-specific mortality and distant-disease probability for
the subgroup of 74 patients with locally recurrent disease was 8.8% and 20.8%,
respectively. If only the 35 invasive recurrences are considered as events, the 8
year breast cancer-specific mortality and distant-disease probability was 14.4%
and 27.1%, respectively. CONCLUSION: Invasive local recurrence after breast
preservation treatment for patients with DCIS is a serious event that converts
patients with previous stage 0 disease to patients with disease that ranges from
stage I to stage IV. These results, however, indicate that most DCIS patients
with local recurrence can be salvaged.
PMID- 9552040
TI - No long-term increase in cardiac-related mortality after breast-conserving
surgery and radiation therapy using modern techniques.
AB - PURPOSE: To determine whether left-breast irradiation using modern techniques
after breast-conserving surgery leads to an increased risk of cardiac-related
mortality. METHODS: Between 1968 and 1986, 1,624 patients were treated for
unilateral stage I or II breast cancer at the Joint Center for Radiation Therapy,
Harvard Medical School, Boston, MA, with conservative surgery and breast
irradiation. Seven hundred forty-five patients with a potential follow-up of at
least 12 years were analyzed. Clinical, pathologic, and treatment characteristics
were compared between the 365 patients (49%) who received left-sided irradiation
and the 380 patients (51%) who received right-sided irradiation. The relationship
between left-sided breast irradiation and the risk of nonbreast cancer- and
cardiac-related mortality was examined. RESULTS: There was no significant
difference in the distribution of clinical, pathologic, or treatment
characteristics between the two groups, with the exception of a small difference
in pathologic tumor size (medians, left, 2.0 cm, right, 1.5 cm; P = .007). At 12
years, a majority of patients still were alive. Slightly more patients with left
sided tumors had died of breast cancer (31% v 27%; P = NS). Equivalent
proportions from each group died of nonbreast cancer causes (11%), including nine
patients (2%) from each group who died from cardiac causes. The risk of cardiac
mortality did not increase as time after treatment increased for patients who
received left-sided irradiation compared with right-sided irradiation. A model
that controlled for clinical, pathologic, and treatment differences showed no
significant increase in any category of cause of death (breast, cardiac, or
other) for patients who received left-sided irradiation. CONCLUSION: These
results suggest that modern breast radiotherapy is not associated with an
increased risk of cardiac-related mortality within at least the first 12 years
after treatment.
PMID- 9552041
TI - Quality of life and preferences for treatment following systemic adjuvant therapy
for early-stage breast cancer.
AB - PURPOSE: To evaluate the quality of life (QOL) of breast cancer patients who
survived 2 to 5 years following initiation of adjuvant cytotoxic and/or hormonal
therapy and to characterize relationships between QOL and patient physical
symptoms, sexual function, and preferences regarding adjuvant treatment. PATIENTS
AND METHODS: Eighty-six patients who had completed systemic adjuvant therapy for
early-stage breast cancer between 1988 and 1991 were surveyed by written
questionnaire and telephone interview. Sociodemographic information was obtained
for each patient, and patients were asked to complete the Functional Living Index
Cancer (FLIC), the Symptom Distress Scale (SDS), the Medical Outcomes Study (MOS)
Short Form 36 (SF-36), a series of questions regarding sexual function, and a
survey about preferences for adjuvant therapy in relation to possible benefit.
RESULTS: The mean FLIC score among all patients was 138.3 (+/- 12.2), which
suggests a high level of QOL. The reported frequency of moderate to severe
symptoms was generally low (ie, < 15%), with fatigue (31.4%), insomnia (23.3%),
and local numbness at the site of surgery (22.1%) occurring with greatest
frequency. Patients reported a wide range of sexual difficulties. Preference
assessment showed that more than 65% of patients were willing to undergo 6 months
of chemotherapy for a 5% increase in likelihood of cancer cure. CONCLUSION: Self
rated QOL in breast cancer patients 2 to 5 years following adjuvant therapy was
generally favorable. Less than one third of patients reported moderate to severe
symptoms. Selected aspects of sexual function appeared to be compromised. The
majority of patients indicated a willingness to accept 6 months of chemotherapy
for small to modest potential benefit.
PMID- 9552042
TI - Phase III randomized trial comparing cisplatin and carboplatin with or without
ifosfamide in patients with advanced non-small-cell lung cancer. European Lung
Cancer Working Party.
AB - PURPOSE: A phase III randomized trial in patients with advanced non-small-cell
lung cancer (NSCLC) was performed to determine if the addition of ifosfamide to
moderate-dose cisplatin and carboplatin improved response rate (primary end
point) and survival. PATIENTS AND METHODS: A total of 529 patients were
randomized to receive a combination of moderate-dose carboplatin (200 mg/m2
intravenously [i.v.] on day 1) and cisplatin (30 mg/m2 i.v. on days 2 and 3) with
(CCI arm) or without (CC arm) ifosfamide (1.5 g/m2 i.v. on days 1 to 3). There
were 248 eligible patients on the CC arm and 257 on the CCI arm, with 220 and 238
patients assessable for response, respectively. All but 23 had stage IV disease
with pleural effusion. RESULTS: There was a 16% objective response (OR) rate to
CC and a 31% OR rate to CCI. That observed difference was highly statistically
significant (P < 0.001). Duration of response and survival were not statistically
different between arms. The CCI regimen was associated with significantly more
acute toxicities: emesis, alopecia, leukopenia, and thrombocytopenia. The
frequency of chronic renal, auditive, and peripheral neurologic toxicity was low
in both arms (4.6% and 6.6%, respectively, after six courses of chemotherapy).
The relative dose-intensity (RDI) of the CCI arm was significantly lower than
that of the CC arm. CONCLUSION: The addition of ifosfamide to moderate-dose
cisplatin and carboplatin significantly improves the antitumoral response rate,
but has no apparent effect an survival in advanced NSCLC.
PMID- 9552043
TI - Novel staging protocol for non-small-cell lung cancers according to MRP-1/CD9 and
KAI1/CD82 gene expression.
AB - PURPOSE: The transmembrane-4 superfamily (TM4SF) is a recently discovered family
of genes. Of the TM4SF members, MRP-1/CD9, KAI1/CD82, and ME491/CD63 have been
reported to modulate tumor progression or metastasis. In this study, we
investigated the relationships between these three genes, MRP-1, KAI1, and ME491,
in patients with non-small-cell lung cancers (NSCLCs). Moreover, we assessed the
prognostic value of evaluating the expressions of MRP-1, KAI1, and ME491
simultaneously in NSCLCs. PATIENTS AND METHODS: One hundred seventy-two patients
up to stage IIIB NSCLC underwent radical surgery during the period of January
1991 through June 1994. Using a quantitative reverse-transcriptase polymerase
chain reaction (RT-PCR) analysis, we studied the expression of MRP-1, KAI1, and
ME491 genes in these patients. RESULTS: We found that 109 patients (63.4%) had
MRP-1-positive tumors and 42 patients (24.4%) had KAl1-positive tumors.
Conversely, all 172 patients expressed ME491. No relationship was found between
MRP-1 expression and KAI1 expression. We classified these patients into three
groups. The 36 patients who were positive for both MRP-1 and KAI1 were defined as
group A; the 79 patients with reduced expression of either MRP-1 or KAI1 were
defined as group B, and the remaining 57 patients with reduced expression of both
MRP-1 and KAI1 were defined as group C. This new classification was correlated
with nodal status, tumor status, and pathologic stage (P = .0056, P = .0003, and
P < .0001, respectively). In NSCLC patients, the 5-year survival rate of group A
patients was significantly better than that of group B patients and much better
than that of group C patients (86.8%, 53.9%, and 31.5%, respectively; P < .0001).
Cox multivariate regression analysis showed that this new classification in
NSCLCs was a significant prognostic factor, as was the nodal status (P < .0001).
CONCLUSION: Our results suggest that a low MRP-1 and KAI1 expression by tumors of
the lung may be associated with poor prognosis. It is conceivable that the
evaluation for MRP-1 and KAI1 expression may identify node-negative lung cancer
patients who are at high risk for early disease recurrence, and thus need
intensive adjuvant therapy.
PMID- 9552044
TI - Reduced expression of plakoglobin indicates an unfavorable prognosis in subsets
of patients with non-small-cell lung cancer.
AB - PURPOSE: Plakoglobin is thought to play a key role in cadherin-mediated
epithelial cell adhesion, because it is a common component of desmosomal and
nondesmosomal adherens junctions. Because loss of homotypic cell adhesion is an
important early step in invasion and metastasis of solid tumors, we evaluated the
frequency and prognostic significance of a deficient expression of plakoglobin in
human lung cancer. PATIENTS AND METHODS: At primary surgery, representative
specimens of the primary tumor were obtained from 96 consecutive patients with
completely resected non-small-cell lung carcinoma (NSCLC) without overt distant
metastases. Cryostat sections of these specimens and metastatic lymph nodes were
stained with monoclonal antibody (mAb) PG 5.1 against plakoglobin, using an
immunoperoxidase technique. Patients were monitored for a median of 39 months
(range, 12 to 56) after surgery. RESULTS: Absent or severely reduced expression
of plakoglobin (ie, < 30% positive tumor cells) was observed in 39 patients
(40.6%). There was no significant correlation to established risk factors, such
as the histology, extension, and histologic grade of the primary tumor and
metastatic lymph node involvement, or expression of alpha-catenin. Expression of
plakoglobin in lymph node metastases ranged from 0% to greater than 60% positive
tumor cells. Deficient plakoglobin expression on the primary tumor was
significantly correlated to a shortened disease-free and overall survival in
patients with adenocarcinomas, pT1-2 tumors, or negative lymph nodes (pN0). In
patients with pT1-2 tumors, the independence of this prognostic influence from
established risk factors was demonstrated by Cox regression analyses (disease
free survival, P = .002; overall survival, P = .038). CONCLUSION: Deficient
expression of plakoglobin appears to be an important event in the progression of
NSCLC.
PMID- 9552045
TI - Carboplatin plus vinorelbine, a new well-tolerated and active regimen for the
treatment of extensive-stage small-cell lung cancer: a phase II study. Gruppo
Oncologico Centro-Sud-Isole.
AB - PURPOSE: To evaluate the activity and toxicity of the combination carboplatin
plus vinorelbine in extensive small-cell lung cancer (SCLC). PATIENTS AND
METHODS: A two-stage optimal Simon design was applied. To proceed after the first
stage, responses from 8 of 11 treated patients were needed. Overall, 31 responses
of 43 treated patients were required to comply with the design parameters.
Inclusion criteria were cytohistologically proven SCLC; extensive disease; age of
70 years or less; Eastern Cooperative Oncology group performance status (ps ECOG)
of 2 or less; normal cardiac, hepatic, renal, and bone marrow functions; and no
previous chemotherapy. Patients were staged by physical examination;
biochemistry; chest radiograph; brain, thoracic; and abdominal computed
tomographic (CT) scans, and bone scan. All patients received carboplatin 300
mg/m2 intravenously (i.v.) day 1 and vinorelbine 25 mg/m2 i.v. on days 1 and 8
every 4 weeks up to six cycles. Of 43 enrolled patients, 36 were men and 7 women,
with a median age of 63 years (range, 46 to 70 years). RESULTS: All patients were
assessable for response and toxicity. We observed 32 (74%) objective responses,
with 23% complete responses. Median time to progression was 25 weeks, and median
survival was 37 weeks. The treatment was well tolerated. The reported main
toxicities were leukopenia grade 3 in 21% of patients and grade 4 in 5% of
patients, anemia grade 2 in 11% of patients and grade 3 in 2% of patients, and
thrombocytopenia grade 3 in 7% of patients. CONCLUSION: These data show that
carboplatin plus vinorelbine is an active and well-tolerated regimen in extensive
SCLC. In view of the activity, low toxicity, and ease of administration, it may
be a reasonable alternative to more toxic cisplatin-containing regimens.
PMID- 9552046
TI - Costs of care associated with non-small-cell lung cancer in a commercially
insured cohort.
AB - PURPOSE: To examine the cost of incident cases of non-small-cell lung cancer
(NSCLC) in a commercially insured cohort. METHODS: Claims from Virginia Blue
Cross and Blue Shield (BCBS) beneficiaries with lung cancer from 1989 to 1991
were merged with records from the Virginia Cancer Registry (VCR). Data from the
VCR identified incident cases, stage, and type of cancer at diagnosis. Costs for
all medical care included insurance payment, copayments, and deductibles for 2
years after diagnosis or until death. RESULTS: Three hundred forty-nine incident
NSCLC patients were evaluated. The mean 2-year cost for each patient after
diagnosis or until death was $47,941 (95% confidence interval, $43,758 to
$52,124). Total average costs and hospital days were significantly lower for
local disease ($37,514, 21.2 days), but were similar for regional ($52,797, 30.0
days) and distant ($49,382, 33.0 days) disease. Hospital days accounted for 48%
and hospital-based claims for 70% of costs. Initial treatments, which included
radiation, unadjusted for stage, had the lowest survival rates and the highest
costs, and were associated with the most hospital days. Initial stage, race,
gender, and age were not predictors of total 2-year costs. The independent
predictors of total 2-year costs were type of treatment: any radiation therapy,
any surgery, or any chemotherapy (all, P < .001). Inpatient hospital days was
only a modest predictor of costs after adjusting for type of treatment. Patients
who survived less than 1 year spent 30.5 days in hospital and had an average cost
of $47,280. CONCLUSION: The direct health care costs of younger NSCLC patients
care are substantial. These results should serve as a benchmark for future
comparisons as the United States market shifts to managed care.
PMID- 9552047
TI - Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous
melanoma. Austrian Malignant Melanoma Cooperative Group.
AB - PURPOSE: Patients with primary cutaneous melanoma with a Breslow thickness > or =
1.5 mm have only a 30% to 70% probability of survival after surgery, and no
adjuvant therapy has so far improved this outcome. Since interferon alfa-2a
(IFNalpha2a) exhibits antitumor activity in metastatic melanoma, we investigated
whether adjuvant IFNalpha2a diminishes the occurrence of metastases and thus
prolongs disease-free survival in melanoma patients after excision of the primary
tumor. PATIENTS AND METHODS: In a prospective randomized study, 311 melanoma
patients with a Breslow thickness > or = 1.5 mm were assigned to either adjuvant
IFNalpha2a treatment (n = 154) or observation (n = 157) after excision of the
primary tumor. IFNalpha2a was given daily at a dose of 3 mIU subcutaneously
(s.c.) for 3 weeks (induction phase), after which a dose of 3 mIU s.c. three
times per week was given over 1 year (maintenance phase). RESULTS: Prolonged
disease-free survival was observed in patients treated with IFNalpha2a versus
those who underwent surgery alone. This difference was significant (P = .02) for
all patients enrolled onto the study (intention-to-treat analysis) at a mean
observation time of 41 months. Subgroup analysis showed that Breslow tumor
thickness had no influence on treatment results in the groups of patients
investigated. CONCLUSION: Adjuvant IFNalpha2a treatment diminishes the occurrence
of metastases and thus prolongs disease-free survival in resected primary stage
II cutaneous melanoma patients.
PMID- 9552048
TI - Is the survival of melanoma patients receiving polyvalent melanoma cell vaccine
linked to the human leukocyte antigen phenotype of patients?
AB - PURPOSE: An allogeneic polyvalent melanoma cell vaccine (PMCV) has been shown to
be efficacious in improving overall survival of patients with malignant melanoma
in a phase II clinical setting. The PMCV consists of three allogeneic melanoma
cell lines. The objectives of the study were to determine (1) whether the
survival of melanoma patients who received PMCV was related to the patient's
human leukocyte antigen (HLA) class I phenotype matching the HLA class I
phenotype of the PMCV, and (2) whether PMCV clinical efficacy was correlated to
melanoma patients with a particular HLA phenotype(s). MATERIALS AND METHODS: PMCV
was given to 69 melanoma patients with American Joint Committee on Cancer (AJCC)
stage I to IV disease status. The PMCV and patients lymphocytes were typed for
HLA-A and -B. A correlation was made between the HLA expression of PMCV lines and
the HLA of patients to their survival status. A second correlation was made
between the HLA of patients and survival independent of the PMCV HLA phenotype.
RESULTS: Patients whose HLA phenotype (A3/11 and B7/44) matched the PMCV lines
had a better overall survival (P < .029). Analysis of HLA expression of patients
independent of PMCV HLA to survival showed that HLA-A25 phenotype patients had a
significantly better overall survival (P = .006). HLA-B35 patients had a poorer
survival outcome (P = .019). CONCLUSION: The studies indicate that overall
survival following PMCV treatment in melanoma patients significantly correlates
with their HLA phenotypes. These correlations may be related to the host immune
response to the PMCV or due to differences in the clinical course of melanoma in
patients with different HLA types.
PMID- 9552049
TI - Dose-intensive chemotherapy with ifosfamide, epirubicin, and filgrastim for adult
patients with metastatic or locally advanced soft tissue sarcoma: a phase II
study.
AB - PURPOSE: To evaluate the feasibility and toxicity of the combination of full-dose
epirubicin (EPI) and high-dose ifosfamide (IFO) with granulocyte colony
stimulating factor (G-CSF) support and to determine the clinical efficacy in
terms of response and impact on survival. PATIENTS AND METHODS: Forty-six
consecutive, previously untreated patients with locally advanced or metastatic
high-grade soft tissue sarcomas were treated with IFO 2.5 g/m2/d as a continuous
infusion on days 1 to 5 and EPI 45 mg/m2/d as a continuous infusion on days 2 and
3 every 3 weeks. G-CSF 5 microg/kg/d subcutaneously (s.c.) was given on days 6 to
15 or until recovery of leukocytes after all cycles. Response evaluation was
performed every two cycles and responding patients were treated with up to six
cycles. All patients were evaluated for resectability of residual local or
metastatic disease and underwent surgery if possible. RESULTS: All patients
experienced grade 3 or 4 myelosuppression. Other toxicities were mild. The
overall response rate was 52%, with a complete remission (CR) rate of 22% after
chemotherapy alone. Eight additional patients were rendered free of tumor (no
evidence of disease [NED]) by surgical procedures. The median overall survival of
all patients is 24 months. The CR/NED patients (39%) have a significantly
superior survival time compared with all other patients. Thirteen of these 18
patients (72%) are alive, nine free of tumor, with a median follow-up time of 33
months. CONCLUSION: This dose-intensive combination chemotherapy is toxic but
feasible and produced a high number of partial remissions (PRs) and especially
CRs, which resulted in prolonged survival.
PMID- 9552050
TI - Fumagillin analog in the treatment of Kaposi's sarcoma: a phase I AIDS Clinical
Trial Group study. AIDS Clinical Trial Group No. 215 Team.
AB - PURPOSE: Angiogenesis is a major component of Kaposi's sarcoma (KS) and a
critical process in tumor growth. The present study was designed primarily to
test the toxicity and pharmacokinetics (PK) of the angiogenesis inhibitor TNP-470
and secondarily to evaluate tumor response in patients with early AIDS-related
KS. PATIENTS AND METHODS: Patients with AIDS-related KS were required to have
cutaneous disease with > or = 5 measurable lesions and no evidence of pulmonary,
symptomatic gastrointestinal, or acutely life-threatening KS. Thirty-eight
patients received TNP-470 by weekly intravenous infusion over 1 hour at one of
six dose levels for up to 24 weeks. RESULTS: The dose levels tested included 10,
20, 30, 40, 50 and 70 mg/m2. Median CD4 count was 24 cells/microl (range, 0 to
460). Fourteen patients (36%) had > or = 50 cutaneous lesions and 19 (49%) had
oral lesions. Adverse events included neutropenia (n = 2), hemorrhage (n = 3),
and urticaria (n = 1). PK studies showed wide interpatient and intrapatient
variability. Elimination half-life values were short (range, 0.01 to 0.61 hours).
Seven patients (18%) achieved a partial response. The median time to partial
response was 4 weeks (range, 2 to 25), and the median duration of response was 11
weeks (range, 3 to 26+). CONCLUSION: TNP-470, administered as a weekly, 1-hour
infusion to patients with early AIDS-KS is well-tolerated at doses up to and
including the highest dose tested. Tumor responses were observed in a substantial
number of cases and occurred at various dose levels. TNP-470 should be evaluated
further in patients with AIDS-KS as a single agent and in combination with other
biologic response modifiers in early disease or after initial response to
cytotoxic chemotherapy.
PMID- 9552051
TI - Phase I clinical and pharmacologic study of eniluracil plus fluorouracil in
patients with advanced cancer.
AB - PURPOSE: To determine the highest dose of fluorouracil (5-FU) that could be
safely administered with Eniluracil (776C85; Glaxo Wellcome Inc, Research
Triangle Park, NC), an inactivator of dihydropyrimidine dehydrogenase (DPD), on a
daily schedule for 5 days, and to define the toxicities of the combination and
the pharmacokinetics of 5-FU when administered with 776C85. PATIENTS AND METHODS:
Patients with advanced solid tumors refractory to standard therapy were enrolled
at two institutions. The study consisted of three periods designed to evaluate
the safety, pharmacokinetics, and pharmacodynamics of 776C85 alone (period 1);
the effects of 776C85 on the pharmacokinetics of 5-FU (period 2); and the maximum
tolerated dose (MTD) of 5-FU, with or without leucovorin, that could be safely
administered with 776C85 (period 3). Cohorts of at least three patients each
received oral 776C85 alone at doses of 3.7 mg/m2/d, 18.5 mg/m2/d and 0.74
mg/m2/d. After a 14-day washout period, each patient then received 776C85 daily
for 3 days, with a single intravenous (i.v.) bolus dose of 5-FU 10 mg/m2 on day
2. After a second washout period, patients were treated with 776C85 daily for 7
days and 5-FU i.v. bolus on days 2 through 6. The starting dose of 5-FU 10
mg/m2/d was escalated until the MTD was determined. After determination of the
MTD of 5-FU given with 776C85, oral leucovorin 50 mg/d on days 2 through 6 was
added to determine the MTD of 5-FU with leucovorin in the presence of 776C85.
Near the completion of the study, additional cohorts of patients were treated
with 776C85 at 50 mg/d and oral 5-FU with or without leucovorin. RESULTS: Sixty
five patients were enrolled onto the study and 60 were assessable for toxicity
and response. Bone marrow suppression was the primary and dose-limiting toxicity
of this regimen. Other toxicities included diarrhea, mucositis, anemia, anorexia,
nausea, vomiting, and fatigue. 776C85 suppressed DPD activity in peripheral-blood
mononuclear cells (PBMCs) by at least 90% for at least 24 hours at all dose
levels tested. In the presence of 776C85, 5-FU half-life was prolonged, clearance
was reduced, and the drug displayed linear pharmacokinetics. Recommended doses
for further testing on a daily for 5-day schedule are 776C85 10 mg/d with i.v. 5
FU 25 mg/m2/d; 776C85 10 mg/d with i.v. 5-FU 20 mg/m2/d plus leucovorin 50 mg/d;
776C85 50 mg/d with 5-FU given orally at 15 mg/m2/d with leucovorin at 50 mg/d.
CONCLUSION: 5-FU can be safely administered with 776C85; however, the MTDs are
considerably lower than those conventionally used, caused, at least in part, by
marked alterations in 5-FU plasma pharmacokinetics.
PMID- 9552052
TI - Phase I and pharmacokinetic trial of aminopterin in patients with refractory
malignancies.
AB - PURPOSE: Aminopterin (AMT) is a potent folate analog that is no longer in routine
clinical use. Because of laboratory data that suggests improved metabolism of AMT
versus methotrexate (MTX) in lymphoblasts, we developed a phase I trial to
determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and
pharmacokinetic profile of AMT. PATIENTS AND METHODS: Twenty patients with
refractory malignancies were treated. The starting dose of AMT was 2.5 mg/m2
every 12 hours for two doses weekly: the dose of AMT was decreased and leucovorin
(LV) rescue was added after the DLT was observed. Pharmacokinetics were performed
after both intravenous (i.v.) and oral AMT administration. RESULTS: Mucosal
toxicity was dose-limiting and resulted in the need for a dose reduction (dose
level 2: AMT 2 mg/m2 every 12 hours for two doses weekly) and, subsequently, the
addition of scheduled LV rescue (dose level 3: AMT 2 mg/m2 every 12 hours for two
doses followed by LV 5 mg/m2 orally every 12 hours for two doses, starting 24
hours after the second dose of AMT). The mean areas under the curve (AUC) for the
i.v. (n = 14) and oral (n = 13) doses were 1.20 +/- 0.09 (SE) and 1.05 +/- 0.14
micromol x h/L respectively. The half-life was 3.64 +/- 0.28 hours and the oral
bioavailability in 12 matched subjects was 83.5% +/- 8.3%. One patient with
endometrial adenocarcinoma achieved a complete response (CR) and remains on
therapy at 11+ months. Seven patients had stable disease (SD) for 8 weeks or
greater, which included one patient with a metastatic nerve sheath tumor who was
stable for 9 months. CONCLUSION: We conclude that AMT has good oral
bioavailability and that, when given on a q12 hour x two weekly schedule, the MTD
is 2 mg/m2 with delayed LV rescue.
PMID- 9552053
TI - Higher levels of thymidylate synthase gene expression are observed in pulmonary
as compared with hepatic metastases of colorectal adenocarcinoma.
AB - PURPOSE: It has been observed previously that the pulmonary metastases of
colorectal adenocarcinoma are less responsive to therapy with fluorouracil (FUra)
as compared with other sites of metastasis (liver, local). To investigate the
basis of this chemoresistance, the levels of thymidylate synthase (TS) mRNA and
protein were measured, as TS expression has been shown to be predictive of
response to therapy in colorectal cancer. MATERIALS AND METHODS: Tumors were
obtained from 19 patients with metastatic colorectal cancer (12 hepatic and seven
pulmonary). TS expression was measured by quantitative reverse-transcriptase
polymerase chain reaction (RT-PCR) and TS protein levels were measured by Western
blotting. The presence of TS amplification was assessed by Southern blotting.
Levels of p53 protein were determined using immunohistochemistry. RESULTS: TS
mRNA expression was shown to be significantly higher in the pulmonary metastases
(mean TS/beta-actin ratio, 19.7; n = 7) as compared with the hepatic metastases
(mean TS/beta-actin ratio, 4.7; n = 11) of colorectal cancer. Lower TS expression
was observed in patients with hepatic metastases who had received prior FUra
versus patients who had not been treated. High levels of TS expression in some
samples was associated with low-level (two to three gene copies) increases in TS
gene copy numbers and this was observed more frequently in the pulmonary
metastatic samples. The increased gene copy numbers occurred both in samples with
wild-type p53 and those with mutant p53 tumor-suppressor gene as determined by
immunohistochemistry. CONCLUSION: High levels of TS enzyme may be the basis of
the lack of response of pulmonary metastases to FUra treatment.
PMID- 9552054
TI - Long-term weekly treatment of colorectal metastatic cancer with fluorouracil and
leucovorin: results of a multicentric prospective trial of fluorouracil dosage
optimization by pharmacokinetic monitoring in 152 patients.
AB - PURPOSE: A relationship between fluorouracil (5-FU) dose and response has been
previously shown in advanced colorectal cancer. In a previous study with 5-FU
stepwise dose escalation in a weekly regimen, and pharmacokinetic monitoring, we
defined a therapeutic range for 5-FU plasma levels: 2,000 to 3,000 microg/L (area
under the concentration-time curve at 0 to 8 hours [AUC0-8], 16 to 24 mg x h/L).
The current study investigated 5-FU therapeutic intensification with individual
dose adjustment in a multicentric phase II prospective trial. PATIENTS AND
METHODS: Weekly high-dose 5-FU was administered by 8-hour infusion with 400 mg/m2
leucovorin. The initial dose of 5-FU (1,300 mg/m2) was adapted weekly according
to 5-FU plasma levels, to reach the therapeutic range previously determined.
RESULTS: A total of 152 patients entered the study from December 1991 to December
1994: 117 patients with measurable metastatic disease and 35 with assessable
disease. Toxicity was mainly diarrhea (39%, with 5% grade 3) and hand-foot
syndrome (30%, with 2% grade 3). Among 117 patients with measurable disease, 18
had a complete response (CR), 48 a partial response (PR), 35 a minor response
(MR) and stable disease (SD), and 16 progressive disease (PD). Median overall
survival time was 19 months. The 5-FU therapeutic plasma range was rapidly
reached with a variable 5-FU dose in the patient population: mean, 1,803 +/- 386
mg/m2/wk (range, 950 to 3,396). Thirteen patients were immediately in the toxic
zone, whereas 51 required a > or = 50% dose increase. CONCLUSION: Individual 5-FU
dose adjustment with pharmacokinetic monitoring provided a high survival rate and
percentage of responses, with good tolerance.
PMID- 9552055
TI - Isolated hepatic perfusion with tumor necrosis factor and melphalan for
unresectable cancers confined to the liver.
AB - PURPOSE: To evaluate the efficacy and systemic and regional toxicities of
hyperthermic isolated hepatic perfusion (IHP) using tumor necrosis factor (TNF)
and melphalan for the treatment of unresectable primary or metastatic cancers
confined to the liver. PATIENTS AND METHODS: Thirty-four patients (18 men and 16
women; mean age, 49 years) underwent a 60-minute hyperthermic (39.5 degrees to
40.0 degrees C) IHP performed by laparotomy that used TNF 1.0 mg and melphalan
1.5 mg/kg. Perfusion inflow was through the gastroduodenal artery and outflow was
from a cannula positioned in an isolated segment of retrohepatic inferior vena
cava (IVC). Infrahepatic IVC and portal venous blood flow were shunted to the
axillary vein using an external venoveno bypass circuit. Complete vascular
isolation of the liver was confirmed by an I-131-labelled human serum albumin
monitoring technique. RESULTS: There was no operative mortality. Seventy-five
percent of patients had reversible grade III or IV (National Cancer Institute
Common Toxicity Criteria) hepatic toxicity with one treatment-related mortality
(3%) because of hepatic venoocclusive disease. In 33 assessable patients, the
overall response rate was 75% (complete response, one patient [3%]; partial
response, 26 patients [72%]). With a median potential follow-up of 15 months, the
mean duration of response was 9 months (range, 2 to 30 months). CONCLUSION: IHP
with TNF and melphalan results in significant regression of bulky hepatic cancers
confined to the liver in the majority of patients. Based on these initial
results, further refinement of this treatment technique is warranted; perhaps by
the combination of IHP with other regional treatment strategies to provide long
term control of unresectable cancers confined to liver.
PMID- 9552056
TI - Morbidity and mortality after D2 gastrectomy for gastric cancer: results of the
Italian Gastric Cancer Study Group prospective multicenter surgical study.
AB - PURPOSE: To investigate whether pancreas preservation together with a strict
quality-control system could ameliorate the outcome of D2 resections for gastric
cancer in Western patients. PATIENTS AND METHODS: Italian patients with
potentially curable proven adenocarcinoma of the stomach were registered from
nine general and/or university hospitals in the area of Turin, Northern Italy.
The study was performed according to the guidelines of the Japanese Research
Society for Gastric Cancer (JRSGC). A strict quality-control system was
guaranteed by a supervising surgeon of the reference center, who had stayed at
the National Cancer Center Hospital, Tokyo, to learn the standard D2 gastrectomy.
The standard procedure entailed removal of the level 1 and 2 lymph nodes. During
total gastrectomy, the pancreas was preserved according to the Maruyama
technique. RESULTS: Between May 1994 and December 1996, 191 eligible patients
were entered onto the study. The mean number of lymph nodes removed was 39. The
overall morbidity rate was 20.9%. Surgical complications were observed in 16.7%
of patients. Reoperation was necessary in six patients and was always successful.
The overall hospital mortality rate was 3.1%; it was higher after total
gastrectomy (7.46%) than after distal gastrectomy (0.8%). The average length of
hospital stay was 17 days. CONCLUSION: Given that postoperative morbidity and
mortality rates are favorably comparable with those reported after the Western
standard gastrectomy, the more extensive Japanese procedure with pancreas
preservation can be regarded as a safe radical treatment of gastric cancer for
selected Western patients treated in experienced centers.
PMID- 9552057
TI - Second-line therapy with paclitaxel and carboplatin for recurrent disease
following first-line therapy with paclitaxel and platinum in ovarian or
peritoneal carcinoma.
AB - PURPOSE: The combination of paclitaxel and a platinum compound is the most active
first-line regimen for advanced ovarian carcinoma. The current study was
undertaken to evaluate this combination in the re-treatment of patients with
ovarian or peritoneal carcinoma who had disease recurrence > or = 6 months
following this combination. METHODS: Twenty-five patients with recurrent ovarian
or peritoneal carcinoma > or = 6 months after a complete clinical response with
first-line paclitaxel and platinum chemotherapy were studied. Recurrent disease
was documented by computed tomography (CT), elevated CA 125 level, or surgical
findings. Second-line chemotherapy consisted of paclitaxel 135 mg/m2 as a 24 hour
infusion and carboplatin at an area under the concentration-time curve (AUC) of 5
to 6 every 21 days. Response to therapy was classified as measurable or
assessable. RESULTS: The median time to recurrence after first-line therapy was
10 months (range, 6 to 30). Among 20 measurable and assessable patients, 14 (70%)
demonstrated a complete clinical response and four (20%) a partial clinical
response. The response rate with measurable disease was 91% and with assessable
disease was 89%. The median progression-free interval for all patients was 9.0+
months (range, 2 to 15). The median progression-free interval for patients with
measurable or assessable disease was 9.0+ months and for nonassessable disease
was 7.0+ months. Fifteen patients (60%) have developed recurrence after secondary
therapy at a median interval of 9.0 months (range, 2 to 15). Only two patients
have died with a median survival after secondary therapy of 10.0+ months (range,
2.0 to 21.0+). CONCLUSION: The use of this combination, in this sensitive
population, has a high response rate and long progression-free interval. In a
chemotherapy-sensitive population, the activity of alternative second-line agents
must be interpreted with this perspective.
PMID- 9552058
TI - High-dose cladribine therapy for chronic myelogenous leukemia in the accelerated
or blast phase.
AB - PURPOSE: A phase II clinical trial was performed to evaluate the effectiveness of
high-dose cladribine (2CDA) for treatment of chronic myelogenous leukemia (CML)
in the accelerated or blast phase. PATIENTS AND METHODS: Nineteen patients were
treated. The median age was 55 years (range, 30 to 73). Six were older than 60
years. Eight had progressed after intensive combination chemotherapy and three
after allogeneic or autologous transplantation. For the first course, 16 patients
received 2CDA at 15 mg/m2/d intravenously (i.v.) over 1 hour for 5 days. Two
received 18 mg/m2 and one received 21.5 mg/m2 daily. The second course was
escalated to 20 mg/m2/d in five patients. RESULTS: Rapid cytoreduction of
leukemia occurred in the blood, with the nadir at 10 to 12 days. The median WBC
count decreased from 36,900/microL before treatment to 500/microL at the nadir
and recovered to 5,200/microL at day 30. The median platelet count changed from
113,000/microL to 24,000/microL at the nadir and 71,000/microL at day 30. The
complete remission (CR) plus partial remission (PR) rate was 47% (95% confidence
interval [CI], 23% to 72%). One 64-year-old man with lymphoid blast phase of CML
had a morphologic and cytogenetic CR that lasted 9 months. The median survival
for all patients was 34 weeks, and the median survival for the eight responders
was 56 weeks (range, 11 to 167). The median number of days spent in hospital over
the entire treatment period was 19 (range, 4 to 60). CONCLUSION: High-dose 2CDA
therapy provides effective palliation for CML in accelerated or blast phases,
even for heavily pretreated patients.
PMID- 9552059
TI - Demyelination and single-carbon transfer pathway metabolites during the treatment
of acute lymphoblastic leukemia: CSF studies.
AB - PURPOSE: To investigate the hypothesis that methotrexate causes demyelination due
to a deficiency in S-adenosylmethionine (SAM) during the treatment of acute
lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Twenty-four patients treated
on the Medical Research Council United Kingdom ALL trial no. 11 (MRC UKALL XI)
were studied. The trial randomized patients at the presymptomatic CNS treatment
(PCNS) phase to receive (1) intrathecal methotrexate and cranial radiotherapy
(CRTX); (2) high-dose intravenous methotrexate with folinic acid rescue and
continuing intrathecal methotrexate (HDMTX); and (3) continuing intrathecal
methotrexate alone (ITMTX). Serial CSF samples were collected throughout
treatment and concentrations of 5-methyltetrahydrofolate (MTF), methionine (MET),
SAM, and myelin basic protein (MBP) were measured. The results were grouped into
treatment milestones and compared with an age-matched reference population.
RESULTS: There was a highly significant effect of both treatment milestones and
trial arm on the metabolite and MBP concentrations. CSF MTF reached a nadir
during the induction phase of treatment, while SAM and MET reached their nadir
during the consolidation phase. CSF MBP mirrored SAM concentration and there was
a significant inverse relationship between the two. MTF, SAM, and MBP returned to
normal values by the end of treatment, while MET was increased significantly. The
effect of treatment was decremental across the ITMTX, HDMTX, and CRTX groups.
CONCLUSION: Treatment of ALL causes marked abnormalities in the single-carbon
transfer pathway and subclinical demyelination. Methotrexate is one cause of
this. Whether these abnormalities contribute to the late cognitive deficits
requires further study.
PMID- 9552060
TI - Nucleolar organizer region counts predict complete remission, remission duration,
and survival in adult acute myelogenous leukemia patients.
AB - PURPOSE: The analysis of the nucleolar organizer regions (AgNORs) was performed
in patients with acute myelogenous leukemia (AML) to verify the role of cell
proliferation in predicting complete remission (CR) and survival. MATERIALS AND
METHODS: Bone marrow biopsies from 40 adult patients with AML were stained with
the argyrophilic method. The mean AgNOR number (AgNOR count) was calculated for
each case. After induction therapy, patients who achieved CR received intensive
consolidation; two underwent autologous and four allogeneic bone marrow
transplantations (BMT). RESULTS: The mean AgNOR count for the whole series was
6.6 (SD = 1.35); it was higher in CR patients than in resistant ones (P = .02).
The median duration of CR was 26 months for patients with an AgNOR count greater
than 6.6, but only 6 months for those with lower counts (P = .01). Sixteen
patients who achieved a CR relapsed and 14 reached a second CR; the median
duration of second CR was 16 months for patients with AgNOR count greater than
6.6, but only 5 months for those with lower counts (P = .01). The median survival
time for the whole series was 14 months, with 30% of patients alive and in
continuous CR at 103 months. Survival was longer for patients with an AgNOR count
greater than 6.6 (33 months) than for those with lower counts (6 months; P =
.0009). In multivariate analysis, when CR was excluded from the model, AgNOR
count appeared as an independent prognostic variable (P = .005). CONCLUSION:
AgNOR analysis is a suitable method to assess cell proliferation in bone marrow
biopsies and can predict CR, remission duration, and survival in AML patients.
PMID- 9552061
TI - Competitive CBFbeta/MYH11 reverse-transcriptase polymerase chain reaction for
quantitative assessment of minimal residual disease during postremission therapy
in acute myeloid leukemia with inversion(16): a pilot study.
AB - PURPOSE: (1) Quantification of minimal residual disease (MRD) by competitive
CBFbeta/MYH11 reverse-transcriptase polymerase chain reaction (RT-PCR) in
patients with acute myeloid leukemia (AML) and inversion(16) [inv(16)] during
postremission therapy, (2) comparison of this method with conventional two-step
RT-PCR, and (3) evaluation of a potential prognostic value. PATIENTS AND METHODS:
MRD of six consecutive adult patients with AML and inv(16)(p13;q22) or
t(16;16)(p13;q22) who entered complete remission (CR) was monitored by
competitive CBFbeta/MYH11 RT-PCR in their bone marrow (BM) during postremission
therapy with high-dose cytarabine (HiDAC) or after BM transplantation with a
matched unrelated-donor marrow (MUD-BMT) during an observation period of 4.5 to
27 months after initiation of treatment. RESULTS: Competitive PCR showed a
gradual decline by at least 4 orders of magnitude after 7 to 9 months in patients
in continuous CR (CCR), while one patient who relapsed after 13.5 months only
achieved a reduction by 2 orders of magnitude at the end of consolidation
therapy. A rapid decrease below the detection limit was observed within 1 month
in two patients after MUD-BMT. A temporary reappearance of molecular MRD was
observed in these patients during immunosuppression for graft-versus-host disease
(GvHD). After reduction of immunosuppression, the level of MRD dropped again
below the PCR detection limit. Molecular monitoring by conventional two-step RT
PCR yielded comparable results only when multiple assays per time point were
performed, while single-assay RT-PCR gave misleading results. CONCLUSION:
Competitive RT-PCR is a valuable tool for molecular monitoring during
postremission chemotherapy, as well as after BMT.
PMID- 9552062
TI - Conversion of interferon-induced, long-term cytogenetic remissions in chronic
myelogenous leukemia to polymerase chain reaction negativity.
AB - PURPOSE: Interferon alfa (IFN-alpha) induces complete cytogenetic remission in a
significant minority of patients with chronic myelogenous leukemia (CML). To
date, use of the polymerase chain reaction (PCR) has suggested that residual
disease is present in virtually all these individuals at median follow-up
intervals of approximately 1 year after initial achievement of cytogenetic
remission. We sought to determine the PCR status of CML patients with very long
continuous complete cytogenetic remissions on IFN-alpha. PATIENTS AND METHODS:
Blood and/or bone marrow samples from 18 CML patients maintained in continuous
cytogenetic remission by IFN-alpha for at least 1 year were studied for residual
BCR-ABL mRNA by single-step reverse-transcriptase (RT)-PCR methodology, followed
by detection of the amplification product by the hybridization protection assay
(HPA). RESULTS: Ten of 18 patients showed RT-PCR negativity for BCR-ABL. The
median duration of continuous complete cytogenetic remission at the time of
sample collection for the negative patients was 42 months versus 21 months for
the patients whose tests remained positive (P = .05). CONCLUSION: Very long-term
follow-up of IFN-alpha-treated CML patients in continuous complete cytogenetic
remission is associated with a decrease in the number of BCR-ABL transcripts to a
level below that detectable by the RT-PCR assay used in this study.
PMID- 9552063
TI - Clinical implications of serum levels of soluble CD30 in 70 adult anaplastic
large-cell lymphoma patients.
AB - PURPOSE: In the last few years, the search for new biologic markers in high-grade
non-Hodgkin's lymphomas has provided important results. In particular, soluble
CD30 (sCD30) levels were elevated in most patients with Hodgkin's disease (HD)
and anaplastic large-cell lymphoma (ALCL). PATIENTS AND METHODS: From September
1988 to October 1993, treatment was completed in 70 previously untreated patients
with ALCL, of whom 38 had the common type (ALCL-CT) and 32 had the Hodgkin's-like
subtype (ALCL-HL). Serum sCD30 levels were measured at the time of diagnosis and
after induction polychemotherapy in all patients; in addition, the initial sCD30
levels were compared with those obtained from 50 stage-matched patients with HD.
RESULTS: Pretreatment levels of sCD30 were highly elevated in the stage-matched
group of HD patients compared with healthy controls; median sCD30 levels in
patients with ALCL-CT and ALCL-HL were 18 and seven times higher, respectively,
than in patients with HD. The sCD30 level normalized on achievement of complete
response (CR). The risk of lower relapse-free survival was associated with bulky
disease, advanced stage, and high pretreatment sCD30 levels; the risk of lower
overall survival was associated with advanced stage and pretreatment levels of
sCD30 in both univariate and multivariate analysis. CONCLUSION: The results of
this study suggest that sCD30 is a specific prognostic indicator of the risk for
lower complete response rate and relapse-free expectancy for patients with ALCL.
PMID- 9552064
TI - Comparable engraftment kinetics following peripheral-blood stem-cell infusion
mobilized with granulocyte colony-stimulating factor with or without
cyclophosphamide in multiple myeloma.
AB - PURPOSE: To compare, in the setting of tandem autotransplantations for multiple
myeloma (MM), two established methods of peripheral-blood stem-cell (PBSC)
procurement with chemotherapy or hematopoietic growth factor alone. PATIENTS AND
METHODS: Between June 1994 and July 1995, 44 patients with MM were randomized to
PBSC mobilization with either granulocyte colony-stimulating factor (G-CSF) 16
microg/kg (group 1; n = 22) or high-dose cyclophosphamide (HDCTX) 6 g/m2 plus G
CSF 5 microg/kg (group 2; n = 22). All 44 patients received melphalan 200 mg/m2
with their first autograft and 32 patients proceeded to a second transplantation.
RESULTS: Group 2 required a significantly longer time interval for completion of
PBSC collection than group 1 (median, 22 v 8 days; P = .0001), greater frequency
of hospitalization (100% v 32%; P = .0001), and increased transfusion of
platelets (86% v 18%; P = .0001) and packed RBCs (86% v 55%; P = .02). Likewise,
the incidence of fever and pneumonia/sepsis were higher in group 2 (P = .02 and P
= .04, respectively). Surprisingly, despite greater CD34 cell quantities infused
in group 2, median recovery times of granulocytes (both > 500/microL and
2,500/microL) and platelets (both > 50,000/microL and > 100,000/microL) were
similar (all P > .7). Posttransplant toxicities were also similar. CONCLUSION:
Compared with HDCTX plus G-CSF, high-dose G-CSF alone is associated with lower
morbidity, shorter duration of PBSC mobilization, and comparable hematopoietic
recovery after transplantation, which should result in significant cost
reduction. Considering the relatively limited antitumor activity of HDCTX (10%
with > or = 50% tumor cytoreduction), PBSC mobilization with HDCTX should be
limited to selected patients with persistent MM despite induction chemotherapy.
PMID- 9552065
TI - Back-up bone marrow is frequently ineffective in patients with poor peripheral
blood stem-cell mobilization.
AB - PURPOSE: To assess hematologic recovery and procedure-related mortality in
patients who received high-dose therapy with stem-cell support, in whom the
peripheral-blood stem-cell (PBSC) collection fails (CD34+ cells < 1 x 10(6)/kg).
The predictive value of granulocyte-monocyte colony-forming cell (GM-CFC)
measurements and the value of bone marrow obtained after PBSC collection failure
was assessed. PATIENTS AND METHODS: The study group comprised 324 consecutive
patients mobilized with granulocyte colony-stimulating factor (G-CSF) and
cyclophosphamide (273 patients), G-CSF with other chemotherapy (37 patients), and
G-CSF alone (14 patients). Between one and four aphereses were performed.
RESULTS: In 51 of 324 patients, there was failure to obtain 1 x 10(6)/kg CD34+
cells. Twenty-three patients had greater than 1 x 10(5)/kg GM-CFC; 22 patients
proceeded to high-dose therapy. Neutrophil recovery occurred within 21 days, but
platelet independence was delayed (> 28 days) in eight patients. Of 28 patients
with less than 1 x 10(5)/kg GM-CFC, six received high-dose therapy with PBSC
alone and five had delayed engraftment. Twelve patients with less than 1 x
10(5)/kg GM-CFC received high-dose therapy supported by bone marrow collected
after PBSC collection failure. Eleven patients were assessable for engraftment;
four patients had slow (> 21 days) or delayed (> 28 days) neutrophil recovery and
eight patients had delayed platelet recovery. In the group of patients who
received less than 1 x 10(5)/kg GM-CFC, there were five procedure-related deaths.
CONCLUSION: This study shows that delayed hematologic recovery is frequent if
less than 1 x 10(6)/kg CD34+ cells are infused after high-dose therapy,
particularly with GM-CFC less than 1 x 10(5)/kg. The procedure-related mortality
in this latter group is high. In most patients whose PBSC collection contains
less than 1 x 10(5)/kg GM-CFC, the use of bone marrow cells does not improve
engraftment, which suggests that poor PBSC mobilization usually indicates poor
marrow function.
PMID- 9552066
TI - High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal
cancer: is intrathecal chemotherapy necessary?
AB - PURPOSE: Standard treatments for neoplastic meningitis are only modestly
effective and are associated with significant morbidity. Isolated reports suggest
that concurrent systemic and intrathecal (i.t.) therapy may be more effective
than i.t. therapy alone. We present our experience, which includes CSF and serum
pharmacokinetic data, on the use of high-dose (HD) intravenous (i.v.)
methotrexate (MTX) as the sole treatment for neoplastic meningitis. PATIENTS AND
METHODS: Sixteen patients with solid-tumor neoplastic meningitis received one to
four courses (mean, 2.3 courses) of HD (8 g/m2 over 4 hours) i.v. MTX and
leucovorin rescue. Serum and CSF MTX concentrations were measured daily.
Toxicity, response, and survival were retrospectively compared with a reference
group of 15 patients treated with standard i.t. MTX during the same time
interval. RESULTS: Peak methotrexate concentrations ranged from 3.7 to 55
micromol/L (mean, 17.1 micromol/L) in CSF and 178 to 1,700 micromol/L (mean, 779
micromol/L) in serum. Cytotoxic CSF and serum MTX concentrations were maintained
much longer than with i.t. dosing. Toxicity was minimal. Cytologic clearing was
seen in 81% of patients compared with 60% of patients treated intrathecally (P =
.3). Median survival in the HD i.v. MTX group was 13.8 months versus 2.3 months
in the i.t. MTX group (P = .003). CONCLUSION: HD i.v. MTX is easily administered
and well tolerated. This regimen achieves prolonged cytotoxic serum MTX
concentrations and CSF concentrations at least comparable to those achieved with
standard i.t. therapy. Cytologic clearing and survival may be superior in
patients treated with HD i.v. MTX. Prospective studies and a reconsideration of
the use of i.t. chemotherapy for patients with neoplastic meningitis are
warranted.
PMID- 9552067
TI - Single-dose oral granisetron has equivalent antiemetic efficacy to intravenous
ondansetron for highly emetogenic cisplatin-based chemotherapy.
AB - PURPOSE: To compare the antiemetic efficacy of a single dose of an oral
antiemetic (granisetron 2 mg) with a single dose of an intravenous (i.v.)
antiemetic (ondansetron 32 mg) given before cisplatin-based chemotherapy.
PATIENTS AND METHODS: This was a multicenter, randomized, double-blind, parallel
group study. Patients (N = 1,054) scheduled to receive cisplatin (> or = 60
mg/m2)-based chemotherapy were randomized to receive either 2 mg of oral
granisetron tablets 1 hour before chemotherapy (n = 534) or i.v. ondansetron (32
mg) 30 minutes before chemotherapy (n = 520). The primary efficacy end point was
total control (no emesis, no nausea, and no use of antiemetic rescue medication)
over the initial 24 hours after the start of chemotherapy. Dexamethasone or
methylprednisolone were permitted, but not required, as concomitant prophylactic
antiemetics. RESULTS: Total control was equivalent 24 hours after cisplatin
chemotherapy for single-dose oral granisetron (54.7%) and i.v. ondansetron
(58.3%) (95% confidence interval [CI], -9.6 to 2.4). Similar proportions of
patients remained nausea-free in the granisetron group (55.4%) and the
ondansetron group (59%) (95% CI, -9.6 to 2.4). The rate of complete control of
emesis was 61.2% in the granisetron group and 67.1% in the ondansetron group (95%
CI, -11.7 to -0.1). Both treatment regimens were well tolerated, with similar
patterns of adverse reactions, generally of a mild degree. The most common side
effects included constipation (14%), headache (15%), and diarrhea (10%).
CONCLUSION: Oral granisetron, administered as a single 2-mg dose, provided
equivalent total antiemetic control when compared with i.v. ondansetron (32 mg)
in patients who received highly emetogenic, cisplatin-based chemotherapy.
PMID- 9552068
TI - Palliation of pain associated with metastatic bone cancer using samarium-153
lexidronam: a double-blind placebo-controlled clinical trial.
AB - PURPOSE: To evaluate the effectiveness and safety of samarium-153 (153Sm)
lexidronam (EDTMP) in a double-blind, placebo-controlled study. PATIENTS AND
METHODS: Patients with painful bone metastases secondary to a variety of primary
malignancies were randomized to receive 153Sm-EDTMP 0.5 or 1.0 mCi/kg, or
placebo. Treatment was unblinded for patients who did not respond by week 4, with
those who had received placebo eligible to receive 1.0 mCi/kg of active drug in
an open-label manner. Patient and physician evaluations were used to assess pain
relief, as was concurrent change in opioid analgesia. RESULTS: One hundred
eighteen patients were enrolled onto the study. Patients who received 1.0 mCi/kg
of active drug had significant reductions in pain during each of the first 4
weeks in both patient-rated and physician-rated evaluations. Pain relief was
observed in 62% to 72% of those who received the 1.O-mCi/kg dose during the first
4 weeks, with marked or complete relief noted in 31% by week 4. Persistence of
pain relief was seen through week 16 in 43% of patients who received 1.0 mCi/kg,
of active drug. A significant correlation (P = .01) was observed between
reductions in opioid analgesic use and pain scores only for those patients who
received 1.0 mCi/kg 153Sm-EDTMP. Bone marrow suppression was mild, reversible,
and not associated with grade 4 toxicity. CONCLUSION: A single dose of 1.0 mCi/kg
of 153Sm-EDTMP provided relief from pain associated with bone metastases. Pain
relief was observed within 1 week of administration and persisted until at least
week 16 in the majority of patients who responded.
PMID- 9552069
TI - Comorbidity and functional status are independent in older cancer patients.
AB - PURPOSE: Comorbidity is a frequent and often therapeutically limiting problem in
older cancer patients. However, to date, there is no standard measure of the
comorbidity burden available for these patients. We tested the performance of two
comorbidity scales and their relationship with functional status. PATIENTS AND
METHODS: The Cumulative Illness Rating Scale-Geriatric (CIRS-G) was compared with
the Charlson scale in 203 patients who received a comprehensive geriatric
assessment (CGA) in our Senior Adult Oncology Program (SAOP). Study end points
were variability, reliability, correlation with Eastern Cooperative Oncology
Group (ECOG) performance status (PS), Activities of Daily Living (ADL), and
Instrumental Activities of Daily Living (IADL). The relative weight of
comorbidity versus tumor stage in the correlations with functional status was
assessed. RESULTS: Median age was 75 years (range, 63 to 91). Sixty-four percent
of patients scored 0 on the Charlson scale versus 6% on the CIRS-G. The
correlation between the Charlson and CIRS-G was fair (p = 0.25 to 0.39). CIRS-G
grade 3/4 had a fair correlation with ADL (p = 0.27). Otherwise, there was low or
no correlation between comorbidity and functional status across the measures.
Tumor stage was not correlated with functional status either. Correlation of ECOG
PS with ADL (p = 0.51)c and IADL (p = 0.61) was moderate. Interrater and test
retest correlations were good or very good for both the Charlson and CIRS-G.
CONCLUSION: Comorbidity needs to be assessed independently from functional
status. Both the Charlson and CIRS-G scales are reliable tools for use in trials
of older cancer patients. Both can be tested in further studies as predictors of
outcomes such as toxicity of treatment, changes in functional status, or
survival.
PMID- 9552070
TI - Quality of life and cancer pain: satisfaction and side effects with transdermal
fentanyl versus oral morphine.
AB - PURPOSE: To compare pain-related treatment satisfaction, patient-perceived side
effects, functioning, and well-being in patients with advanced cancer who were
receiving either transdermal fentanyl (Duragesic, Janssen Pharmaceuticals,
Titusville, NJ) or sustained-release oral forms of morphine (MS Contin, Perdue
Frederick Co, Norwalk, CT, or Oramorph SR, Roxanne Laboratories, Columbus, OH).
PATIENTS AND METHODS: A total of 504 assessable cancer patients participated in
this cross-sectional, quality-of-life study. Relevant elements of four validated
scales were used--the Functional Assessment of Cancer Therapy-General (FACT-G)
scale, the Brief Pain Inventory (BPI), the Medical Outcomes Study (MOS)
questionnaire, and the Memorial Symptom Assessment Scale (MSAS)--as well as
original scales that were developed and validated for this study. RESULTS: The
majority of patients in both treatment groups had late-stage (IV/D) cancer.
Patients who received transdermal fentanyl were more satisfied overall with their
pain medication than those who received sustained-release oral forms of morphine
(P = .035). Fentanyl patients also experienced a significantly lower frequency (P
< .002) and impact (P < .001) of pain medication side effects. These results
occurred despite the fact that cancer patients who received fentanyl were
significantly older (P < .001) and had significantly lower functioning and well
being scores (P = .001). Measures of pain intensity, sleep adequacy, and symptoms
demonstrated no significant differences between treatment groups. CONCLUSION:
These data suggest that patients are more satisfied with transdermal fentanyl
compared with sustained-release oral forms of morphine. A lower frequency and
reduced impact of side effects with transdermal fentanyl may be one reason cancer
patients who receive fentanyl are more satisfied with their pain management.
PMID- 9552071
TI - Oncologists' recognition of depression in their patients with cancer.
AB - PURPOSE: This study was performed as part of a large depression screening project
in cancer patients to determine the degree of physician recognition of levels of
depressive symptoms in cancer patients and to describe patient characteristics
that influence the accuracy of physician perception of depressive symptoms.
METHODS: Twenty-five ambulatory oncology clinics affiliated with Community Cancer
Care, Inc of Indiana enrolled and surveyed 1,109 subjects treated by 12
oncologists. Subjects completed the Zung Self-Rating Depression Scale (ZSDS) and
physicians were asked to rate their patients' level of depressive symptoms,
anxiety, and pain using numerical rating scales. Subjects' sex, age, primary
tumor type, medications, primary caregiver, and disease stage at diagnosis were
also recorded. RESULTS: Physician ratings of depression were significantly
associated with their patients' levels of endorsement of depressive symptoms on
the ZSDS. However, agreement between physicians and patients is most frequently
clustered when patients report little or no depressive symptoms. While physician
ratings are concordant with patient endorsement of no significant depressive
symptomatology 79% of the time, they are only concordant 33% and 13% of the time
in the mild-to-moderate/severe ranges, respectively. Physician ratings were most
influenced by patient endorsement of frequent and obvious mood symptoms, ie,
sadness, crying, and irritability. Physician ratings also appeared to be
influenced by medical correlates of patients' level of depressive symptoms
(functional status, stage of disease, and site of tumor). Additionally, patients
whose depression was inaccurately classified reported significantly higher levels
of pain and had higher levels of disability. Physicians' ratings of depression
were most highly correlated with physicians' ratings of patients' anxiety and
pain. CONCLUSION: Physicians' perceptions of depressive symptoms in their
patients are correlated with patient's ratings, but there is a marked tendency to
underestimate the level of depressive symptoms in patients who are more
depressed. They are most influenced by symptoms such as crying and depressed
mood, and medical factors that are useful, but not the most reliable, indicators
of depression in this population. Physicians' ratings of their patients' distress
symptoms seem to be global in nature--they are highly correlated with anxiety,
pain, and global dysfunction. Physician assessment might be improved if they were
instructed to assess and probe for the more reliable cognitive symptoms such as
anhedonia, guilt, suicidal thinking, and hopelessness. Screening instruments and
the use of brief follow-up interviews would help to identify patients who are
depressed.
PMID- 9552072
TI - Role of adjuvant chemotherapy in the treatment of invasive carcinoma of the
urinary bladder.
AB - PURPOSE: The standard treatment for patients with muscle-invasive carcinoma of
the urinary bladder is radical cystectomy. While radical cystectomy cures many
patients with this tumor, almost 50% of them will develop metastatic disease.
Adjuvant chemotherapy has been proposed for these patients in an attempt to
reduce the probability of relapse and to improve survival. To assess whether
adjuvant chemotherapy does benefit patients with muscle-invasive bladder cancer,
we reviewed all phase II and III studies published in the English literature over
the last 20 years. METHODS: A review of all published reports was facilitated by
the use of Medline computer search and by manual search of the Index Medicus.
RESULTS: Several comparative, nonrandomized studies have indicated that adjuvant
chemotherapy may prolong disease-free survival. Four randomized studies have been
conducted and all had a suboptimal patient accrual. Three studies used a
cisplatin-containing combination chemotherapy and included primarily patients
with non-organ-confined transitional-cell carcinoma (TCC) of the bladder. All
three studies indicated that adjuvant chemotherapy improved disease-free survival
and two of them also showed improvement in event-free survival and overall
survival, respectively. CONCLUSION: Published series have been unable to
establish an undisputed benefit of adjuvant chemotherapy over radical cystectomy
alone for muscle-invasive bladder cancer. The interpretation of the available
data is compromised by several methodologic and statistical problems. Thus,
adjuvant chemotherapy cannot be considered as a standard treatment for all
patients with muscle-invasive carcinoma of the bladder. Well-designed prospective
randomized studies are needed to clarify the role of adjuvant chemotherapy in
this disease. However, outside a protocol setting, there is some evidence that
patients with extravesical disease or with lymph node involvement may benefit
from adjuvant treatment with cisplatin-based combination chemotherapy. No data
support such an approach for patients with muscle-invasive but organ-confined
bladder cancer.
PMID- 9552073
TI - Emergency treatment of malignant extradural spinal cord compression: an evidence
based guideline.
AB - PURPOSE: To review the literature for malignant extradural spinal cord
compression (MSCC), produce evidence-based recommendations based on the criteria
used by the Canadian Task Force on the Periodic Health Examination, and make
suggestions regarding future research directives. METHODS: A systematic review of
the literature with explicit study selection and evaluation criteria was
performed. Primary outcome measure was posttreatment ambulation rate. RESULTS:
There is good evidence to support the use of high-dose dexamethasone (96 mg/d),
but inconclusive evidence for the use of moderate-dose steroids (16 mg/d) in
conjunction with radiotherapy (RT) for the treatment of MSCC. Fair evidence
exists for not using steroids in patients who are nonparetic and ambulatory
pretreatment, and to give radiation to patients with subclinical spinal cord
compression (SCC). The remainder of the recommendations are based on inconclusive
evidence: RT alone should be the first-line treatment for ambulatory patients
except when there is spinal instability, bony compression, or paraplegia on
presentation, in which case surgery should be performed. Either modality can be
used for paraparetic patients who are nonambulatory. Postoperative RT should be
considered for tumor in residua. Ambulatory, undiagnosed patients should have
needle biopsy attempted first. Patients should be aggressively screened and
educated about SCC. CONCLUSION: In general, there were very few papers of high
methodologic quality found in the literature. More studies are needed to satisfy
the validity of many of the clinical decisions that are made today with regard to
the management of MSCC.
PMID- 9552074
TI - Case one. Bleomycin cutaneous toxicity.
PMID- 9552075
TI - Case two. Bleomycin cutaneous toxicity.
PMID- 9552076
TI - Access to quality cancer care: consensus statement. American Federation of
Clinical Oncologic Societies.
AB - In his Presidential address on May 17, 1996, Dr John Glick proposed the formation
of the American Federation of Clinical Oncologic Societies (AFCOS), a coalition
of all professional clinical oncology societies. AFCOS was intended to address
heightened concerns about changes in the health care delivery system and the
impact that they may have on quality patient care. AFCOS places primary emphasis
on educating patients, their families, health care providers, payors,
legislators, regulators, and the general public about what constitutes quality
care, advocating access to and coverage for such care, including clinical trials,
and supporting and promoting patient-oriented research. Several meetings of the
coalition have resulted in the development of a consensus statement on quality
cancer care, which the Journal of Clinical Oncology is pleased to publish in this
edition. The consensus statement was the product of collaboration among the
Federation's nine member societies as well as national patient advocacy groups
represented by the Cancer Leadership Council.
PMID- 9552077
TI - Concurrent is the key: combined modality small-cell lung cancer.
PMID- 9552078
TI - Don't be mis-guided when the data are silent and the editorial misses the mark.
PMID- 9552079
TI - Timing of thoracic irradiation for limited small-cell lung cancer.
PMID- 9552080
TI - Peripheral T-cell lymphoma after anti-CD20 antibody therapy.
PMID- 9552081
TI - Ethics of off-label treatment.
PMID- 9552082
TI - Approaches to primary care: current realities and future visions.
PMID- 9552083
TI - A four-year randomized controlled trial of hormone replacement and
bisphosphonate, alone or in combination, in women with postmenopausal
osteoporosis.
AB - PURPOSE: Hormone replacement therapy (HRT) with estrogen and treatment with
bisphosphonates have been shown to increase bone mineral density (BMD) in
postmenopausal women. This 4-year prospective randomized study was carried out to
assess the effectiveness of the combined HRT plus etidronate on BMD in
postmenopausal women with established osteoporosis. PATIENTS AND METHODS: Seventy
two postmenopausal women (mean age 64.9+/-0.5 years) attending metabolic bone
disease outpatient clinics with established osteoporosis were randomly allocated
into one of four treatment groups and monitored for 4 years. All patients
enrolled in this study including the control group (n=18) received 1.0 g
elemental calcium and 400 units vitamin D per day. The HRT group (n=18) received
cyclical estrogen and progesterone; the etidronate group (n=17) received
intermittent cyclical etidronate; and the combined therapy group (n=19) received
both HRT and etidronate. BMD was measured in the lumbar spine and the hip before
treatment and at 2 and 4 years after treatment. Changes in height were recorded,
and the occurrence of new vertebral fractures were documented in comparison with
the baseline radiographic evaluation. In 40 patients (10 patients per group),
analysis of bone histomorphometry was carried out after 4 years of treatment.
RESULTS: In patients who received the combined therapy, BMD increased in the
lumbar spine by 10.4% (P <0.001) and in the hip by 7.0% (P <0.001) at 4 years.
For patients treated with ICE, these increases were 7.3% (P <0.001) and 0.9% (P
<0.05), and with HRT, the increases were 7.0% (P <0.001) and 4.8% (P <0.01) in
the vertebrae and femora, respectively. The group treated with calcium and
vitamin D lost 2.5% (P <0.05) and 4.4% (P <0.01) of BMD in the vertebrae and
femora, respectively, after 4 years. Patients who received combined therapy had
significantly higher BMD in both the vertebrae and in the femora (P <0.05) in
comparison with patients who were treated with HRT or etidronate alone after 4
years. In comparison with patients in the control group, there was a trend toward
a lower rate of new vertebral fractures in the treatment groups. Height loss was
significantly less in all three active treatment groups (HRT [P <0.001],
etidronate [P <0.02], and combined therapy group [P <0.0001]), in comparison with
the control group. The combined therapy group did not have a significant height
loss, in comparison with the HRT (P <0.02) and the etidronate (P <0.001) groups.
None of the patients had histomorphometric evidence of osteomalacia. CONCLUSION:
This 4-year randomized study showed an additive effect of etidronate and HRT on
hip and spine BMD in postmenopausal women with established osteoporosis.
PMID- 9552084
TI - A randomized, double-blind, placebo-controlled study of growth hormone in the
treatment of fibromyalgia.
AB - PURPOSE: The cause of fibromyalgia (FM) is not known. Low levels of insulin-like
growth factor 1 (IGF-1), a surrogate marker for low growth hormone (GH)
secretion, occur in about one third of patients who have many clinical features
of growth hormone deficiency, such as diminished energy, dysphoria, impaired
cognition, poor general health, reduced exercise capacity, muscle weakness, and
cold intolerance. To determine whether suboptimal growth hormone production could
be relevant to the symptomatology of fibromyalgia, we assessed the clinical
effects of treatment with growth hormone. METHODS: Fifty women with fibromyalgia
and low IGF-1 levels were enrolled in a randomized, placebo-controlled, double
blind study of 9 months' duration. They gave themselves daily subcutaneous
injections of growth hormone or placebo. Two outcome measures--the Fibromyalgia
Impact Questionnaire and the number of fibromyalgia tender points-were evaluated
at 3-monthly intervals by a blinded investigator. An unblinded investigator
reviewed the IGF-1 results monthly and adjusted the growth hormone dose to
achieve an IGF-1 level of about 250 ng/mL. RESULTS: Daily growth hormone
injections resulted in a prompt and sustained increase in IGF-1 levels. The
treatment (n=22) group showed a significant improvement over the placebo group
(n=23) at 9 months in both the Fibromyalgia Impact Questionnaire score (P <0.04)
and the tender point score (P <0.03). Fifteen subjects in the growth hormone
group and 6 subjects in the control group experienced a global improvement (P
<0.02). There was a delayed response to therapy, with most patients experiencing
improvement at the 6-month mark. After discontinuing growth hormone, patients
experienced a worsening of symptoms. Carpal tunnel symptoms were more prevalent
in the growth hormone group (7 versus 1); no other adverse events were more
common in this group. CONCLUSIONS: Women with fibromyalgia and low IGF-1 levels
experienced an improvement in their overall symptomatology and number of tender
points after 9 months of daily growth hormone therapy. This suggests that a
secondary growth hormone deficiency may be responsible for some of the symptoms
of fibromyalgia.
PMID- 9552085
TI - Prognosis of patients with primary systemic amyloidosis who present with dominant
neuropathy.
AB - BACKGROUND: Primary systemic amyloidosis is an uncommon disorder associated with
the desposition of fragments of immunoglobulin light chains in a variety of
tissues. Some patients present with peripheral neuropathy. The prognosis of these
patients is not clear. METHODS: We searched the medical records of all patients
seen at the Mayo Clinic between January 1, 1978 and December 31, 1994 with the
diagnosis of amyloidosis. Twenty-six patients with sural nerve biopsy-proven
amyloid neuropathy and a documented monoclonal protein in the serum or urine were
studied. RESULTS: The most common symptoms that led to the diagnosis of primary
amyloid neuropathy were paresthesias (81%), muscle weakness (65%), and numbness
(58%). The median duration of symptoms before diagnosis was 29 months. Symptoms
of autonomic neuropathy were present at diagnosis in 17 patients (65%). Other
organs were involved in most patients. The monoclonal light chain protein
detected was lambda in 18 patients (69%) and kappa in 8 (31%). The neuropathy was
chronic, debilitating, and showed relentless progression. Twenty-two patients
(85%) died (median survival 25 months) and 4 patients were alive at a median
follow-up of 4.5 years. Progressive amyloidosis was the cause of death in most
patients. Survival was significantly better in the patients with a serum albumin
level >3 g/dL (median survival 31 months compared with 18 months; P <0.01, log
rank test). CONCLUSIONS: Patients with primary systemic amyloidosis in whom
neuropathy is the dominant clinical manifestation often do not receive a
diagnosis until years after the onset of symptoms. The prognosis is worse than
previously indicated. Neuropathy does not improve with therapy.
PMID- 9552086
TI - Predictors of adverse outcome in cancer patients with candidemia.
AB - BACKGROUND: Many factors, including severity of illness, neutropenia, intravenous
catheter management, and drug therapy may affect the outcome of candidemia in
cancer patients. METHODS: The records of all patients at M. D. Anderson Cancer
Center who developed one or more positive blood cultures for Candida spp between
January 1, 1988, and December 31, 1992, were retrospectively reviewed. Four
hundred ninety-one episodes of candidemia were identified, for which 476 had
complete medical records, which were reviewed in detail. RESULTS: By 3-month
follow-up, 52% of the patients had died. Neutropenia, higher APACHE III score,
and visceral dissemination were associated with poor prognosis. Cure rates,
adjusted for severity of illness, were similar for fluconazole and amphotericin B
treatment. Exchange of central venous catheters was associated with a modest
improvement in prognosis. CONCLUSION: Several factors that influence the outcome
of candidemia in cancer patients have been identified. These factors may be
relevant for the clinical management of cancer patients with candidemia, and for
the design of therapeutic trials.
PMID- 9552087
TI - Comparison of referring and tertiary cancer center physician's diagnoses in
patients with leukemia.
AB - PURPOSE: To analyze the rates of concordance in the diagnosis of various
hematological malignancies among patients referred to a tertiary cancer center,
comparing the referring diagnosis with the final diagnosis at the M.D. Anderson
Cancer Center. PATIENTS AND METHODS: This was a cross-sectional study analyzing
the 409 patients referred to the M.D. Anderson Leukemia Service in 1995 in whom a
bone marrow examination was performed by the referring physician and in whom this
examination was repeated at our institution. We also analyzed 100 cases,
including 84 of the 409 referred patients for whom the diagnostic outside bone
marrow slide had been sent for review. RESULTS: The overall concordance rate was
73%. In 18% discordances were present and considered of major importance
(affecting treatment and/or prognosis) while in 9% there were minor discordances.
Major discordance rates were 2% for chronic lymphocytic leukemic leukemia and 5%
for chronic myelogenous leukemia, but 29% for acute myelogenous leukemia (79
patients), 43% for acute promyelocytic leukemia (7 patients), 19% for acute
lymphocytic leukemia (42 patients), 57% for hairy cell leukemia (7 patients), and
23% for the myelodysplastic syndromes (75 patients). The concordance rate was 76%
in the 100 cases in which bone marrow specimens permitted comparison of the
morphologic diagnosis made by M.D. Anderson and the referring physician using the
same slide, with a rate of 75% in the acute leukemias as finally diagnosed at our
institution. CONCLUSION: Although in the majority of cases the referring
physicians and the specialty service agreed on diagnosis, major discordance
occurs in a significant number of cases, including highly treatable diseases such
as acute promyelocystic leukemia and hairy cell leukemia.
PMID- 9552088
TI - The impact of gastroesophageal reflux disease on health-related quality of life.
AB - BACKGROUND: Gastroesophageal reflux disease (GERD) affects health-related quality
of life. METHODS: We enrolled 533 adults with a history of heartburn symptoms for
at least 6 months of moderate to severe heartburn in 4 of the 7 days before study
entry. Patients were treated with ranitidine 150 mg twice a day for 6 weeks and
Gelusil antacid tablets as needed. We measured physician-rated symptoms and the
Medical Outcomes Study short-form 36 (SF-36) Health Survey at baseline and after
6 weeks of treatment. Baseline results were compared with normative data for the
US population and for patients with selected chronic diseases. Treatment response
was defined as no episode of moderate to severe heartburn for 7 days. Statistical
significance was set at P <0.001. RESULTS: GERD patients reported significantly
worse scores on all 8 SF-36 scales, physical function and well-being, and
emotional well-being compared with the general population. Patients with GERD
reported worse emotional well-being than patients with diabetes or hypertension.
Treatment responders demonstrated significantly less pain and better physical
function, social function, vitality, and emotional well-being compared with
nonresponders. CONCLUSIONS: Patients with GERD experience decrements in health
related quality of life compared with the general population. The impact of GERD
is most striking on measures of pain, mental health, and social function.
Successful treatment for GERD results in improvements in health-related quality
of life.
PMID- 9552089
TI - Resolving the conflicts between general and subspecialty medicine: the internist
as consulting physician-scientist.
AB - Internal medicine is confronting a conflict between its generalist and specialty
roles, coupled with a conflict between the needs of academic internal medicine in
contrast to those of private practice. The historical origins of these conflicts
are explored. To resolve these conflicts, internal medicine must rediscover the
common ground shared by the general internist and specialist, academician and
practitioner. This common ground is best found in the role of internist as
physician-scientist. In the future, specialists and general internists will need
to emphasize their roles as consultants. In the process, internal medicine will
become smaller and more "academic." The benefits of this role for internal
medicine should be rapidly demonstrated through outcomes based research in order
to win over skeptical payors, peers, and the public at large.
PMID- 9552090
TI - Clinical research: assessing the future in a changing environment; summary report
of conference sponsored by the American Medical Association Council on Scientific
Affairs, Washington, DC, March 1996.
AB - Concerns about funding of clinical research underlie all other problems
identified at the Council on Scientific Affairs conference. Future National
Institutes of Health (NIH) budgets are likely to be constant at best, and the
general public expects cost containment to be an ongoing goal; this is
exacerbated by the impending Medicare Trust Fund crisis. Meanwhile, traditional
financial support of clinical research in academic medical centers (AMCs) through
cross-subsidization is imperiled by competitive pressures largely caused by
managed care. Although managed care organizations (MCOs) are potentially rich
sources of funding and other resources, and some not-for-profit companies are
conducting some research, for-profit MCOs have not demonstrated an understanding
of the importance of clinical research. Young physicians are being discouraged
from careers as clinical researchers and established investigators are "dropping
out" because of demands for clinical productivity and competition for research
grants, loss of patients/research subjects to managed care, perceived lack of
status and compensation, and overall uncertainty about continued financial
support. Efforts to assist current and potential clinical investigators are
discussed in this report. Loss of patients, denial of reimbursement, and
competition with MCOs and contract research organizations (CROs) have placed AMCs
under unprecedented pressure. However, research centers located in AMCs have
allowed investigators to conduct clinical research by providing a "protected
environment." Furthermore, many AMCs are determined to continue conducting
clinical research and are addressing related problems. Although the NIH will
continue to be a major source of funding for clinical research, partnerships
between various private and public entities provide important opportunities to
maximize the productivity of all individuals and institutions involved. Potential
partnerships include MCOs, AMCs, CROs, pharmaceutical companies and other
industry, the Department of Defense, the Veterans Health Administration, practice
based physicians, and private foundations and patient support groups.
"Partnerships in advocacy" for clinical research will be essential. Efforts to
recruit for-profit MCOs to the clinical research endeavor identified in this
report include (1) emphasizing issues of interest to them (eg, outcomes
research); (2) stressing the significance of some research to the marketplace;
(3) developing criteria to distinguish individual MCOs on the basis of their
contribution to the public interest; (4) equating money spent on research with
"R&D dollars" spent in nonmedical business enterprises; and (5) educating
purchasers of health care (eg, corporate health plan directors) about clinical
research. Conducting clinical research in all managed care settings requires
leadership, the understanding and cooperation of physicians and support staff,
wise use of limited resources (ie, funding only the best research projects),
sound methodology, and above all, the perception that the research will
ultimately improve patient care.
PMID- 9552091
TI - Treatment strategies for atrial fibrillation.
AB - Atrial fibrillation is the most common arrhythmia observed in clinical practice,
occurring in 0.4% of the general population and in up to 4% of people greater
than 60 years old. It is often associated with other cardiovascular disorders,
such as hypertension, coronary artery disease, or cardiomyopathy. Critical
evaluation and management of patients with atrial fibrillation requires knowledge
of etiology, prognosis, and treatment options of this arrhythmia. On initial
presentation, emergency electrical cardioversion should be performed if the
patient is hemodynamically unstable. If the patient is stable, initial rate
control is recommended, using atrioventricular nodal blocking agents. Further
treatment mainly depends upon the duration of the episode. Patients who are in
atrial fibrillation <48 hours can be safely cardioverted. Patients who are in
atrial fibrillation for >48 hours are commonly anticoagulated for 3 to 4 weeks
before and after cardioversion because of the risk of thromboembolism formation
in the left atrial appendage. An alternate strategy, which is especially
attractive when immediate cardioversion is desired, is transesophageal
echocardiography to exclude left atrial thrombus followed by prompt
cardioversion. After cardioversion, sinus rhythm can be maintained with class I
and III drugs, such as flecainide and propafenone or amiodarone and sotalol. New
treatment options, such as atrial defibrillation, atrioventricular junctional
ablation, or modification of atrial pacing to prevent atrial fibrillation, are
currently under investigation. Although atrial fibrillation is so common in
clinical practice, it still remains difficult to treat. Conversion and
maintenance to sinus rhythm with antiarrhythmic drug therapy has not shown any
improvement in mortality, and some patients may benefit more from ventricular
rate control. This review article discusses different treatment strategies for
patients with atrial fibrillation.
PMID- 9552092
TI - New approaches to anti-inflammatory therapy for asthma.
AB - Currently, corticosteroids are the therapy of choice for the inflammatory
component of asthma. This class of drug provides powerful anti-inflammatory
effects in most patients; however, these effects are not specific and in some
cases may result in serious side effects. Also, many patients have difficulty
adhering to therapy with inhaled forms of these drugs, which are administered by
metered-dose inhalers up to several times per day. There are several other
therapies that provide potential anti-inflammatory effects, but they are of low
efficacy, with little definitive anti-inflammatory effect. While efforts are
currently under way to improve corticosteroid therapy, other directions include
the development of targeted anti-inflammatory agents. For example, the
leukotrienes, a family of inflammatory mediators that have been shown to enhance
bronchoconstriction and airway mucus secretion, have been the focus of numerous
investigations. Specific leukotriene receptor antagonists and synthesis
inhibitors have been developed and are currently showing promise in clinical
trials; one leukotriene receptor antagonist (zafirlukast) and one 5-lipoxygenase
inhibitor (zileuton) were recently approved by the United States Food and Drug
Administration for the treatment of asthma.
PMID- 9552093
TI - Liddle's syndrome.
PMID- 9552094
TI - Depression, palpitations, and unilateral pulsatile tinnitus due to a dopamine
secreting glomus jugulare tumor.
PMID- 9552095
TI - Bigger is still better for internal medicine: keeping the family under the tent.
PMID- 9552096
TI - Back to the future for internal medicine?
PMID- 9552097
TI - My vocation.
PMID- 9552098
TI - When housestaff die: musings of a program director.
PMID- 9552099
TI - Sister Elizabeth Kenny revisited.
PMID- 9552100
TI - The contribution of job satisfaction to the transition from acute to chronic low
back pain.
AB - OBJECTIVE: To determine the extent to which job satisfaction predicts pain,
psychological distress, and disability 6 months after an initial episode of low
back pain (LBP). DESIGN: A longitudinal design was used to follow an inception
cohort experiencing first-episode low back pain with assessment at 2 and 6 months
after pain onset. SETTING: Urban medical center outpatient orthopedic clinic.
PATIENTS: The consecutive sample was comprised of 82 men with initial-onset acute
LBP (T6 or below, daily pain for 6 to 10 weeks). INTERVENTION: Usual orthopedic
care. MAIN OUTCOME MEASURES: The primary study outcomes were pain (Descriptor
Differential Scale, Visual Analog Scales); disability (Sickness Impact Profile,
Quality of Well-Being); and psychological distress (Beck Depression Inventory,
Hamilton Rating Scale for Depression, Automatic Thoughts Questionnaire);
predictor variables were orthopedic impairment (Waddell Physical Impairment
Index) and job satisfaction (Job Descriptive Index, Work APGAR). RESULTS:
Measures of job satisfaction, pain, disability, and psychological distress at
baseline and 6 months after pain onset were separately reduced into factors using
principle components factor analysis. In hierarchical multiple regression
analyses, baseline job satisfaction significantly predicted variance in outcome
scores at 6 months after pain onset, beyond the variance explained by control
factors (demographics; baseline pain, mood, and disability; orthopedic
impairment). Zero-order correlations between job satisfaction and orthopedic
impairment were small and nonsignificant, suggesting that these two variables act
independently in predicting outcome. Although type of work performed (desk work
or work requiring light, moderate, or heavy lifting) and social position were
correlated with job satisfaction at baseline, neither contributed to the
prediction of outcome at 6 months. CONCLUSIONS: Satisfaction with one's job may
protect against development of chronic pain and disability after acute onset back
pain and, alternatively, dissatisfaction may heighten risk of chronicity.
Vocational factors should be considered in the rehabilitation of acute back
injury.
PMID- 9552101
TI - Immunizing against depression and anxiety after spinal cord injury.
AB - OBJECTIVE: To further report on the effectiveness of early psychological
intervention in reducing anxiety and depressive mood in persons with spinal cord
injury 2 years after injury. DESIGN: A nonrandomized, longitudinal, controlled
trial. SETTING, OUTCOME MEASURES, AND INTERVENTION: Twenty-eight spinal cord
injured persons participated in group cognitive behavior therapy during hospital
rehabilitation. They were assessed for depressive mood and anxiety before,
immediately after, and 12 and 24 months after treatment. The intervention group's
responses on the measures were compared with a control group of 31 spinal cord
injured persons who only received traditional rehabilitation services during
their hospitalization. RESULTS: Subjects in the treatment group with high
depression and anxiety scores before treatment were significantly less depressed
and reduced their anxiety to a greater extent 2 years after the injury in
comparison with similar persons in the control group. CONCLUSIONS: Group
cognitive behavior therapy for spinal cord injured persons who are abnormally
depressed and anxious appears to reduce depressive mood and anxiety in the short
and long term.
PMID- 9552102
TI - The reliability of a self-reported measure of disease, impairment, and function
in persons with spinal cord dysfunction.
AB - OBJECTIVE: To develop a self-report instrument that would provide information
about the different levels of the disablement process, and that (1) was suitable
for persons with spinal cord disease (SCD), (2) could be completed quickly, (3)
could be mailed, (4) had acceptable reliability, and (5) would be clinically
useful. STUDY DESIGN: Test-retest using a convenience sample. METHODS: Review of
the literature and an expert panel were used to develop the instrument. It was
mailed to 49,458 individuals in June 1995 and a second mailing was done in August
1995. A subset of 725 individuals who responded to both mailings was used to
examine the instrument's test-retest reliability. RESULTS: The instrument has a
4th grade reading level and has questions on causal disease, disease severity,
impairment, activities of daily living (including a self-reported version of the
Functional Independence Measure, the SRFM), and resource utilization. Individual
item test-retest reliability was high for a mailed questionnaire; all kappa
coefficients were near or above .60 and most were over .70. Intraclass
correlation coefficient for the SRFM was .90 and internal consistency
(Chronbach's alpha) was .96. CONCLUSION: This instrument provides a new, rapid
way to obtain information relative to the differing levels of the disablement
process.
PMID- 9552103
TI - Seat cushion optimization: a comparison of interface pressure and tissue
stiffness characteristics for spinal cord injured and elderly patients.
AB - OBJECTIVE: A method for designing tissue deformation minimizing seat surfaces was
evaluated. Pressure and stiffness criteria were used to optimize surface shape.
The method's efficacy for patients with spinal cord injuries (SCI) and a
comparison of cushion performance and interface characteristics with a group of
30 elderly patients are presented. DESIGN: Repeated measures, prospective study.
SETTING: University medical center. PATIENTS: SCI (n=12), elderly (age 65 +
years) [n=30]. INTERVENTIONS: One flat and two custom foam seat cushions. MAIN
OUTCOME MEASURES: Interface pressure measured using a pressure sensing pad;
tissue stiffness and pressure recorded on a rigid programmable seat surface.
RESULTS: Pressure distributions on contoured cushions for the SCI group contained
lower values than distributions on flat cushions. A comparison of the pressure
data between the elderly and SCI showed that significant differences exist
between interface characteristics. The SCI group had higher peak interface
pressures for all cushions tested. Tissue stiffness measurements were similar for
each group. CONCLUSIONS: Results showed improved effectiveness of custom
contoured foam seat cushions versus flat foam cushions. The results suggest that
pressure distributions for SCI are more sensitive to support cushion
characteristics than for the elderly. Further research is needed to determine the
extent of the difference between the populations represented by these groups.
PMID- 9552104
TI - Predictors of health status and life satisfaction in spinal cord injury.
AB - OBJECTIVE: To analyze relationships between injury-related variables, demographic
variables, functional health status, and life satisfaction of people with spinal
cord injury (SCI). DESIGN: Cross-sectional survey. SETTING: A community in the
Netherlands. SUBJECTS: Three hundred eighteen people with SCI, aged 18 to 65
years. Mean age was 39.4 years and mean time after injury was 3.6 years. MAIN
OUTCOME MEASURES: Health status was measured with the SIP68. Its six scales were
aggregated to three dimensions, measuring physical, psychologic, and social
functioning. Life satisfaction was measured with the Life Satisfaction
Questionnaire. Data were analyzed by path analysis using LISREL V8. RESULTS:
Obtained scores showed that respondents suffered from serious limitations in
physical functioning and social functioning, had only a few limitations in
psychologic functioning, and were satisfied with their lives in general and with
most life domains. Physical functioning was accurately predicted by injury
related variables, but psychologic functioning was not. Next to level and
completeness of the injury, the number of secondary complications turned out to
be a predictor of functional health. In a path model that had a close fit with
the data, injury-related variables were related to health status but not to life
satisfaction. Social functioning (-.48), marital status (-.38), psychologic
functioning (-.19), and age (-.16) were significant predictors of life
satisfaction (total R2=.44). CONCLUSIONS: This study points out the high
prevalence of secondary complications and their importance to the health status
of people with SCI. Level of social and psychologic functioning are more
important predictors of life satisfaction than the seriousness of the injury.
PMID- 9552105
TI - Catecholamine assays in a rat model for autonomic dysreflexia.
AB - OBJECTIVE: To determine if norepinephrine (NE) levels increased during autonomic
dysreflexia (AD) hypertension in spinal cord injured rats. DESIGN: Prospective,
randomized study of three groups of eight rats that underwent C8 spinal cord
transection. Two days postoperatively, catecholamine samples were collected from
the animals as follows: group 1 without preoperative chemical sympathectomy using
6-hydroxydopamine (6-OH DA) or induced AD; group 2 with induced AD; and group 3,
preoperative chemical sympathectomy with 6-OH DA and induced AD. SETTING: Basic
science research laboratory in an academic institution. PARTICIPANTS: Sprague
Dawley male rats weighing 300g. INTERVENTION: Three episodes of induced AD
hypertension with bowel distension for 1 minute. RESULTS: Results showed a
significant difference between groups 1 and 2, 2 and 3, and 1 and 3 (p=.0002,
ANOVA, Y1/2, post hoc Tukey). The mean NE levels in groups 1, 2, and 3 were 465+/
400 ng/mL, 1,328+/-1,116 ng/mL, and 31+/-61 ng/mL, respectively. CONCLUSION: NE
increased during AD in the spinal cord injured rat. NE levels were effectively
blocked by 6-OH DA when AD was induced. Knowledge of catecholamine levels in this
process may assist in determining both pathophysiology and potential
pharmacologic treatment options in future human studies.
PMID- 9552106
TI - Functional status in limb deficiency: development of an outcome measure for
preschool children.
AB - OBJECTIVE: To develop an outcome measure of functional status in preschool
children with limb deficiency. DESIGN: Parents of preschool children with limb
deficiency completed self-report measures during a routine medical clinic visit.
SETTING: Outpatient pediatric clinic. PARTICIPANTS: Fifty-two parents of children
(ages 4 to 7) with acquired or congenital limb deficiency. MAIN OUTCOME MEASURE:
The newly developed Child Amputee Prosthetics Project-Functional Status Inventory
for Preschool children (CAPP-FSIP). RESULTS: Initial psychometric studies
indicate high internal consistency reliability of the new instrument. Content
validity was established through expert clinician review. Initial construct
validity analyses confirm that the CAPP-FSIP discriminates between children with
upper and lower deficiency and their prosthesis use for functional activities.
CONCLUSION: The CAPP-FSIP is a promising new measure for evaluating preschool age
children with limb deficiency.
PMID- 9552107
TI - Back and hip extensor fatigability in chronic low back pain patients and
controls.
AB - OBJECTIVE: To compare the lumbar paraspinal and gluteus maximus muscle
fatigability between chronic low back pain patients and healthy controls by using
electromyographic (EMG) spectral analysis during a maximal isometric endurance
task. DESIGN: A cross-sectional comparative study between chronic low back pain
patients and healthy control subjects. SETTING: Physical medicine and
rehabilitation clinic in Finland. SUBJECTS: Twenty women with nonspecific chronic
low back pain (longer than 3 months) and 15 healthy controls. INTERVENTION:
Subjects performed maximal voluntary isometric back extensions (MVC) at 30
degrees forward flexion in a specially designed measurement unit. A 50% MVC load
was used in isometric endurance test. OUTCOME MEASURES: Low back pain intensity
was assessed by using the visual analogue scale and functional disability by the
Oswestry disability index. Time to endurance was measured. Bipolar surface EMG
recordings were made over the lumbar paraspinal muscles (L3-L4, L5-S1) and over
the gluteus maximus muscles. Average EMG (aEMG%), and initial spectral median
frequency (MFinit) and change over time (MFslope) were computed. RESULTS: Pain
intensity and functional disability were higher and MVC and time to endurance
were lower in the chronic low back pain group (p < .05). Similar muscle activity
levels (aEMG%) and MFinit indicated similar muscle loading in both groups at the
beginning of the endurance test. EMG spectral decreases (MFslope) indicated that
lumbar paraspinal muscle fatigability was similar in both groups. In the chronic
low back pain group, the gluteus maximus fatigued faster than in the control
group (greater MFslope, p < .05). However, the shorter endurance time indicated
greater fatigability in the chronic low back pain group in general (p < .05).
CONCLUSIONS: The chronic low back pain patients were weaker and fatigued faster
than the healthy controls. The EMG fatigue analysis results suggest that the
gluteus maximus muscles are more fatigable in chronic low back pain patients than
in healthy control subjects during a sustained back extension endurance test.
PMID- 9552108
TI - Environment effect of functional task performance in adults with acquired brain
injuries: use of the assessment of motor and process skills.
AB - OBJECTIVE: To examine household task performance in both familiar (home) and
unfamiliar (clinic) environments in adults with acquired brain injuries. DESIGN:
The research performed was a comparison study examining the effect of the
environment on functional task performance. Individuals were evaluated using the
Assessment of Motor and Process Skills both in their homes and in an unfamiliar
clinic setting. PARTICIPANTS: Twenty individuals with acquired brain injuries
living in the community. MAIN OUTCOME MEASURES: The Assessment of Motor and
Process Skills, an observational, standardized, occupational therapy assessment
tool, was used to evaluate household task performance. RESULTS: Paired one-tailed
t tests indicated a significant difference between home and clinic performance
measures in process ability (t=-4.28, p=.00), but no significant difference in
motor ability performance measures (t=-1.84, p=.410). Scatter plot analyses
showed that performance scores of 6 of the 20 subjects differed in a clinically
meaningful way, and that instrumental activities of daily living motor
performance scores for 3 of the 20 differed in a clinically meaningful way.
CONCLUSIONS: Individuals with acquired brain injuries may be influenced by their
environment when performing household tasks, although further study is necessary
to determine the extent of the environmental effect.
PMID- 9552109
TI - Severe complications of reflex sympathetic dystrophy: infection, ulcers, chronic
edema, dystonia, and myoclonus.
AB - OBJECTIVE: To determine the prevalence, type of complication, predisposing
factors, and treatment for severe complications in a population of reflex
sympathetic dystrophy (RSD) patients. DESIGN: Retrospective analysis of the data
from RSD patients collected over a 12-year period, to investigate the involvement
of predisposing factors in an RSD population without severe complications
compared with an RSD population with severe complications. SETTING: Outpatient
clinic of a department of surgery of a university hospital. PATIENTS: A total of
1,006 patients with the diagnosis of RSD established according to prospectively
defined criteria. MAIN OUTCOME MEASURES: The signs and symptoms of every RSD
patient who visited the department were prospectively documented in the medical
history; these data were retrospectively analyzed with special regard to RSD with
severe complications-infection, ulcers, chronic edema, dystonia, and/or myoclonus
for prevalence, type of complication, and treatment. RESULTS: Seventy-four RSD
patients who were mostly young and female developed severe complications. More
than one complication occurred in 91% of the affected extremities. Severe
complications developed more frequently in the lower extremity (65%). In patients
in whom the acute RSD started with a decreased skin temperature of the affected
extremity, severe complications developed significantly more often than in acute
RSD patients with a warm skin temperature of the extremity from the onset of the
disease (p < .001). CONCLUSIONS: It is important to recognize "cold" RSD
immediately at the onset of the disease because this group of RSD patients has a
higher risk of developing a severe complication, mostly followed by a severe
disability that is resistant to therapy.
PMID- 9552110
TI - Team approaches to treating children with disabilities: a comparison.
AB - OBJECTIVE: To investigate differences in team functioning between the
multidisciplinary and transdisciplinary models when treating children with
disabilities. DESIGN: A crossover trial. SETTING: An outpatient educational and
rehabilitation program in a rehabilitation institute based at a university
medical center. PARTICIPANTS: A population-based sample of 19 rehabilitation
specialists and educators. INTERVENTION: Participants attended four team meetings
using the multidisciplinary approach and then attended four team meetings using
the transdisciplinary approach. OUTCOME MEASURES: Behavioral ratings of team
participation (Transdisciplinary Team Rating Scale) and self-report instruments
of team development (Team Assessment Questionnaire) and treatment planning and
goal development (Staff Perception Questionnaire). RESULTS: Results of t tests
confirmed the hypothesis that there was more team member participation during
transdisciplinary meetings than during multidisciplinary meetings (p=.027). There
were no differences in levels of team development (p=.329); however, staff
members favored the transdisciplinary model for treatment planning and goal
development (p < .001). CONCLUSION: This study provides evidence of the
effectiveness of the transdisciplinary model. Further research is now needed to
investigate outcome variables such as rate of success in attaining treatment
goals when using this model.
PMID- 9552111
TI - Tracking control in the nonparetic hand of subjects with stroke.
AB - OBJECTIVE: To examine in subjects with stroke using their nonparetic side how
different levels of stimulus-response (S-R) compatibility, which require
different levels of information processing, affect manual tracking control.
DESIGN: Descriptive study comparing finger movement tracking performance under S
R-compatible and S-R-incompatible conditions between subjects with stroke and
healthy controls. Four two-factor analysis of variance tests with one independent
factor (group, gender, laterality, or order) and one repeated measures factor
(position) comprised the data analysis. SETTING: University-based research
setting. PATIENTS: Forty subjects with chronic stroke: 20 right hemiplegia
(average age, 65.2+/-2.3 yrs); 20 left hemiplegia (average age, 68.6+/-2.3 yrs).
Fifty-one healthy controls: 24 using nondominant hand (average age, 68.6+/-2.1
yrs); 27 using dominant hand (average age, 68.7+/-2.0 yrs). All were right
handed. MAIN OUTCOME MEASURE: Tracking accuracy index (AI), based on root-mean
square error normalized to scale of each subject's tracking target. RESULTS: In S
R-incompatible condition, AI of subjects with stroke was not significantly
different from controls (F[1, 89]=1.73, p=.19). In S-R-compatible condition, AI
of control subjects was significantly better than subjects with stroke (F[1,
89]=14.3, p=.0003). CONCLUSION: Manual tracking is impaired in nonparetic hand of
subjects with stroke, suggesting that information processing, distinctly separate
from motor weakness, may be an underestimated problem impairing controlled
movements in individuals with stroke.
PMID- 9552112
TI - Reliability assessment of isometric knee extension measurements with a computer
assisted hand-held dynamometer.
AB - OBJECTIVE: To assess clinically relevant indexes of measurement error of hand
held dynamometer measurements using a computer-assisted hand-held dynamometer
(CAHN-DY). DESIGN: In separate sessions, different physical therapists performed
repeated measurements of maximal isometric knee extension. SETTING: Four physical
therapy practices and outpatient departments. PATIENTS: Consecutive samples of 30
male and 28 female patients aged 13 to 77 years, with isolated orthopedic knee
disorders participated in this study. MAIN OUTCOME MEASURES: For intrarater and
interrater applications, the standard error of measurement (SEM) and related 95%
confidence intervals and minimal detectable changes were assessed. RESULTS: Sixty
percent of the patients performed within the therapist's upper force limit.
Variance between sessions performed by the same or different therapists accounted
for a large percentage of the measurement error (70% to 81%). For single
measurements, the standard error of measurement was assessed not to exceed 10N x
m. Minimal detectable changes for different designs varied from 13.8 to 28.2N x
m. CONCLUSIONS: The CAHN-DY facilitated standardization of test performance in a
satisfactory manner, resulting in less measurement error compared with simple
hand-held dynamometry.
PMID- 9552113
TI - Avascular necrosis of bilateral knees secondary to corticosteroid enemas.
AB - Avascular necrosis (AVN) is a devastating adverse effect of corticosteroid
therapy rarely reported in the setting of inflammatory bowel disease. We describe
a 48-year-old woman with 6 weeks of progressive bilateral knee pain resulting in
the inability to ambulate. Her symptoms developed suddenly, 9 months after
treatment with hydrocortisone enemas for ulcerative proctitis. On physical
examination, the patient had knee tenderness, decreased range of motion, and
flexion contractures. Magnetic resonance imaging showed multiple bony infarcts in
bilateral distal femora and proximal tibias, consistent with advanced AVN.
Initial therapy included pain management, serial casting, gentle flexibility and
strengthening, and limited mobility training. The rehabilitation efforts led to
functional improvement. Ultimately, bilateral total knee arthroplasties were
recommended to treat her advanced AVN. This is the first reported case of AVN
secondary to hydrocortisone enemas. We review the literature and discuss the
pathophysiology and management of corticosteroid-induced AVN.
PMID- 9552114
TI - Jejunostomy tube failure: malnutrition caused by intraluminal antegrade
jejunostomy tube migration.
AB - Complications occurring with jejunostomy feeding tubes are common and sometimes
life-threatening. We describe a case of peristalsis-induced intraluminal
antegrade migration of a jejunostomy tube's distal end with concomitant
retrograde movement of the small bowel over the tube, which was first discovered
at autopsy. This ultimately resulted in the jejunostomy feedings entering the
distal ileum, therefore bypassing most of the small intestine. Subsequent
malnutrition was a contributing factor in the death of the patient, who had
required tube feedings after suffering severe head trauma in a motor vehicle
accident 29 months earlier. The only nutritional interventions attempted before
death involved various attempts at controlling diarrhea. We discuss the
incidence, cause, recognition, and prevention of this rarely reported
complication of a "functioning" jejunostomy feeding tube.
PMID- 9552115
TI - Three women with lupus transverse myelitis: case reports and differential
diagnosis.
AB - Although the association between transverse myelitis (TM) and systemic lupus
erythematosus (SLE) has been reported previously, it remains a rare clinical
condition. Our experience treating three women with lupus TM within a few months
is presented. In each patient, spinal cord dysfunction was accompanied by
laboratory or clinical evidence of SLE. Further neurologic manifestations, such
as optic neuritis, developed in all patients, suggesting other diagnoses,
including multiple sclerosis (MS), Devic's syndrome, and lupoid sclerosis. The
outcomes for these three women were severe disability, death, and moderate
disability, respectively. The severity of outcome did not seem to correlate with
the timing or intensity of treatment. Physiatrists should be aware of the
potential for neurologic progression in lupus TM, because patients with this
condition invariably require rehabilitation.
PMID- 9552116
TI - Outcome after spontaneous spinal epidural hematoma in children: case report and
review of the literature.
AB - OBJECTIVE: Spontaneous spinal epidural hematoma (SSEH) is an idiopathic
accumulation of blood in the vertebral epidural space without identifiable
predisposing factors. First reported in 1869, the clinical outcome in children
younger than 18 years old has not been clearly delineated. DESIGN: A
comprehensive review of the English language literature revealed 26 patients
younger than 18 years old with reported clinical outcomes. The 27th case is
presented. RESULTS: Complete neurologic recovery occurred in 14 of 27 (52%)
patients, partial recovery in 12 of 27 (44%) patients, and death in 1 of 27 (4%)
patients. CONCLUSION: There is an overall good prognosis for neurologic recovery
in children who experience SSEH.
PMID- 9552117
TI - Hemicorporectomy: a case study from a physical therapy perspective.
AB - Hemicorporectomy, literally translated, means half (hemi), body (corpus), removal
(ectomy). The procedure is indicated as a last resort measure for patients with
life-threatening conditions such as advanced pelvic tumors, pelvic osteomyelitis,
crushing pelvic trauma, or intractable decubiti in the pelvic region. We report a
case in which this mutilating procedure was performed on a 49-year-old man with
extensive perineal and sacral sores. Squamous cell carcinoma was detected and
isolated to the pelvic region. His medical history was significant for paraplegia
secondary to a gunshot wound in 1966. The literature has documented fewer than 45
procedures of this radical nature. Few of the case studies specifically address
the rehabilitation of this patient population and none of the articles researched
were written from a physical therapy standpoint. Articles that addressed the
concept of rehabilitation comment only that the course of rehabilitation was
extensive and prolonged. This report provides an overview of the surgical
procedures and specifically addresses the physical rehabilitation of this patient
after his hemicorporectomy from a physical therapy perspective. This patient's
physical therapy was accomplished over a time span of less than 1 month.
PMID- 9552118
TI - Neuropsychological deficits after whiplash.
PMID- 9552119
TI - Magnetotherapy: a new intervention?
PMID- 9552120
TI - Systemic sclerosis.
PMID- 9552121
TI - Tai-Chi Chuan.
PMID- 9552122
TI - Identification and localization of neurohypophysial peptides in the brain of a
caecilian amphibian, Typhlonectes natans (Amphibia: Gymnophiona).
AB - The amphibian order Gymnophiona contains more than 150 different species of
caecilians. The characterization and distribution of neurohypophysial peptides,
however, has not been described for any member of this order. By using high
performance liquid chromatography, radioimmunoassay, and mass spectrometry, we
identified the peptide arginine vasotocin (AVT) in brain and pituitary extracts
from the caecilian Typhlonectes natans. By using immunocytochemistry, we found
five populations of AVT-immunoreactive (AVT-ir) cells in the brain of T. natans.
AVT-ir cell bodies were located in the preoptic area, amygdala pars medialis,
ventral thalamus, dorsal hypothalamic nucleus, and nucleus of the solitary tract.
AVT-ir fibers and terminal fields were widespread. We also identified a mesotocin
like peptide. The distribution of this peptide in the brain of T. natans was more
restricted than the distribution of AVT. Mesotocin-like-immunoreactive cell
bodies were located almost exclusively in the preoptic area, with only a few
other cells located in the amygdala pars medialis. This caecilian species,
therefore, possesses neurohypophysial peptides that are similar in their
structure and distribution to the peptides found in anuran and urodele amphibian
orders.
PMID- 9552123
TI - Some forebrain connections of the gustatory system in the goldfish Carassius
auratus visualized by separate DiI application to the hypothalamic inferior lobe
and the torus lateralis.
AB - The neuroanatomical connections of the diencephalic torus lateralis and inferior
lobe of the goldfish (Carassius auratus) were studied by retrograde and
anterograde labeling with the carbocyanine dye DiI. Both structures have
afferents originating in the central zone of the dorsal telencephalic area as
well as in the supracommissural nucleus of the ventral telencephalic area, and in
the secondary gustatory, tertiary gustatory, and posterior thalamic nuclei. Both
structures investigated have efferents to the tertiary gustatory and posterior
thalamic nuclei, as well as to the dorsal hypothalamus (dorsal hypothalamic
neuropil) and superior reticular formation. The torus lateralis receives
additional afferents from the secondary general visceral nucleus and, sparsely,
from the dorsal tegmental nucleus. The inferior lobe receives additional
afferents from the medial zone of the dorsal telencephalic area, as well as from
the suprachiasmatic, posterior pretectal, central posterior thalamic, caudal
preglomerular, two tegmental nuclei (T1 and T2), corpus mamillare, and, sparsely,
from the cerebellar valvula. The inferior lobe has additional efferents to the
dorsal and ventral thalamus and subglomerular nucleus. The lateral torus and
inferior lobe are also mutually interconnected. The lateral torus and inferior
lobe map topographically onto the vagal-related (intraoral) or onto the facial
related (extraoral) portions, respectively, of both the secondary and tertiary
gustatory nuclei. Because the posterior thalamic nucleus is reciprocally
connected with the lateral torus and inferior lobe and is further known to
project in turn to the area doralis telencephali, it likely represents a
quaternary gustatory projection nucleus to the telencephalon in cyprinids.
Whereas the lateral torus seems to be exclusively involved with gustatory and
general visceral systems, the inferior lobe has inputs from additional sensory
(e.g., octavolateralis, visual) systems, and, thus, likely represents a
multisensory integration center.
PMID- 9552124
TI - Organisation of the tectorotundal and SP/IPS-rotundal projections in the chick.
AB - The organisation of the neural projections from the optic tectum and pretectal
nuclei complex, n. subpretectalis / n. interstitio-pretecto-subpretectalis
(SP/IPS), to the nucleus rotundus (Rt) in chicks was studied by using retrograde
tracing techniques. After the injection of fluorescent retrograde tracers,
rhodamine-conjugated latex microspheres, fluorescein-conjugated latex
microspheres, True Blue, Fluoro-Gold, or rhodamine B isothiocyanate, into
different regions of Rt and its middorsal extension, the nucleus triangularis
(T), the distribution of retrogradely labelled neuronal cell bodies in the tectum
and pretectal nuclei was assessed. Both the ipsilateral and contralateral
tectorotundal projections were found to be organised topographically in as much
as different sublaminas of the stratum griseum centrale (SGC) project in an
orderly manner to Rt and T. The deepest stratum of SGC overlapping into the
stratum album centrale projects to T. Deep SGC projects to the dorsal Rt and
superficial SGC to the ventral Rt. A band running through the centre of Rt
receives input from the central sublamina of SGC, and the caudal central Rt
receives input from a deeper sublamina than does the rostral central Rt. The
SP/IPS projects to the ipsilateral Rt only and the projection order is dorsal SP
to dorsal Rt, ventral SP to ventral Rt and middle SP to the central band of Rt.
The neurones in IPS and the nucleus of the tractus tectothalamicus project to T.
Thus, Rt and T receive topographically both tecto- (excitatory) and SP/IPS-
(inhibitory) projections. The possible functional implications for parallel
information processing in these projections are discussed.
PMID- 9552125
TI - Morphological and electrophysiological characteristics of noncholinergic basal
forebrain neurons.
AB - Cholinergic neurons in the basal forebrain are the focus of considerable interest
because they are severely affected in Alzheimer's disease. However, both
cholinergic and noncholinergic neurons are intermingled in this region. The goal
of the present study was to characterize the morphology and in vivo
electrophysiology of noncholinergic basal forebrain neurons. Neurons in the
ventral pallidum and substantia innominata were recorded extracellularly, labeled
juxtacellularly with biocytin and characterized for the presence of choline
acetyltransferase immunoreactivity. Two types of ventral pallidal cells were
observed. Type I ventral pallidal neurons had axons that rarely branched near the
cell body and tended to have smaller somata and lower spontaneous firing rates
than did type II ventral pallidal neurons, which displayed extensive local axonal
arborizations. Subtypes of substantia innominata neurons could not be
distinguished based on axonal morphology. These noncholineregic neurons exhibited
local axon arborizations along a continuum that varied from no local collaterals
to quite extensive arbors. Substantia innominata neurons had lower spontaneous
firing rates, more variable interspike intervals, and different spontaneous
firing patterns than did type II ventral pallidal neurons and could be
antidromically activated from cortex or substantia nigra, indicating that they
were projection neurons. Ventral pallidal neurons resemble, both morphologically
and electrophysiologically, previously described neurons in the globus pallidus,
whereas the substantia innominata neurons bore similarities to isodendritic
neurons of the reticular formation. These results demonstrate the heterogeneous
nature of noncholinergic neurons in the basal forebrain.
PMID- 9552126
TI - CalbindinD28k- and parvalbumin-immunoreactive neurons form complementary
sublaminae in the rat superior colliculus.
AB - By using light microscopic immunocytochemistry and computer analysis, we have
mapped the distributions of two calcium-binding proteins (CaBPs), calbindinD28k
(CB) and parvalbumin (PV), in the rat superior colliculus (SC). The patterns of
CaBP expression were complementary. A band of heavily labeled, medium-sized CB
immunoreactive cells (CB-cells) was centered in the optic layer (OL), whereas PV
immunoreactive cells (PV-cells) were found predominantly in the intermediate gray
layer (IGL), where they were clustered within patches of PV-labeled fibers. The
superficial gray layer (SGL) could be divided into two sublaminae. CB-cells were
found mostly in the dorsal half of the SGL, whereas PV-cells were scattered
throughout the ventral SGL and the dorsal OL. Most of the CaBP-immunoreactive
cells in the SGL were small bipolar cells with vertically oriented dendrites;
however, there were also some PV-cells with horizontally oriented dendrites.
Quantitative analysis of the CaBP distributions reinforced our observations that
these cells are distributed in complementary tiers that are not restricted to the
traditional laminae. The size and shape of some of these tiers were determined
from a three-dimensional reconstruction of serial sections. The complementarity
of the CaBP-immunoreactive tiers was also confirmed by fluorescence microscopy of
double-labeled sections, in which few if any double-labeled neurons were
observed. Complementary tiers of CB-cells and PV-cells have been observed
previously in the SC of the cat. The present results demonstrate them in another
species and further suggest that there are functional sublaminae in the SC that
can be distinguished by CaBP content.
PMID- 9552127
TI - Ultrastructural evidence for prominent postsynaptic localization of alpha2C
adrenergic receptors in catecholaminergic dendrites in the rat nucleus locus
coeruleus.
AB - Alpha-2-adrenergic receptor (alpha2-AR) agonists potently inhibit the activity of
noradrenergic neurons of the locus coeruleus (LC), an effect that may be mediated
by the A- and/ or C-subtypes of alpha2-AR (alpha2A- and alpha2C-AR). To gain
insight into the functional significance of these alpha2-AR subtypes in the LC,
we have examined their ultrastructural localization by using subtype-specific
antibodies. We recently demonstrated that alpha2A-ARs are localized prominently
in axon terminals and catecholaminergic dendrites in the LC. In the present
study, we sought to identify the subcellular substrates underlying alpha2C-AR
actions in the LC by analyzing the ultrastructural distribution of alpha2C-AR
immunoreactivity (alpha2C-AR-IR) in sections that were dually labeled for the
catecholamine-synthesizing enzyme tyrosine hydroxylase (TH). Alpha-2C-AR-IR was
predominantly localized in dendrites, most of which also contained immunolabeling
for TH. Within such dendrites, alpha2C-AR-IR was associated with the plasma
membrane and occasionally Golgi cisternae and tubulovesicles. The vast majority
of dendrites containing alpha2C-AR-IR received asymmetric (excitatory) contacts
from unlabeled axon terminals that often contained dense core vesicles. Alpha-2C
AR-IR was observed in some unmyelinated axons and astrocytic processes that were
apposed to TH-immunoreactive dendrites but was rarely associated with axon
terminals. These results provide the first ultrastructural evidence that alpha2C
ARs (1) are localized postsynaptically in catecholaminergic neurons of the LC and
(2) may be strategically situated to modulate the activation of LC neurons by
excitatory inputs.
PMID- 9552128
TI - Neurogenic role of the neural gland in the development of the ascidian, Botryllus
schlosseri (Tunicata, Urochordata).
AB - In adult ascidians, the neural complex consists of a cerebral ganglion (the
brain) and the associated neural gland. We have studied the development of the
neural complex during the vegetative reproduction of the colonial ascidian
Botryllus schlosseri, the buds of which arise from the atrial mantle of the
parental zooid. Each bud develops into a new organism within which a neural
complex becomes differentiated. We found that the presumptive (pioneer) nerve
cells that ultimately form the cerebral ganglion of the adult arise as migratory
cells from a primordial cluster of rudimentary gland cells. Hence, the neural
gland appears to be neurogenic in that it serves as the cellular source of
components that differentiate into conventional nerve cells. In the adult, these
cells take on the form of a typical invertebrate ganglion with an outer cortex of
nerve cell bodies and an internal medulla. This medulla consists of a neuropile
of neuronal processes making classical synaptic contacts. The adult neural gland
differentiates into a structure with a ciliated duct that opens into the
branchial chamber, the body of the gland, and the dorsal organ, which is quite
distinct from the dorsal strand of other ascidians. The rudimentary neural gland
cells, therefore, differentiate into one of two distinct pathways: the first,
glandular, is possibly involved in the evaluation of environmental signals, and
the other, nervous, leads to brain formation. This compares with the vertebrate
situation in which the olfactory-pituitary placodes are thought to originate from
a common cellular source. Thus, these data support the earlier contention of a
homology between the tunicate neural gland and the vertebrate adenohypophysis.
PMID- 9552129
TI - Interleukin-1beta and its type 1 receptor are expressed in developing neural
circuits in the frog, Xenopus laevis.
AB - The cytokine interleukin-1 beta (IL-1beta) is an evolutionarily conserved
molecule that was originally identified in the immune system. In addition to
regulating peripheral immune responses, IL-1beta plays an important role in
mediating neural-immune interactions and regulating glial activities during
healing and repair in the damaged nervous system. Active IL-1beta is produced by
interleukin-converting enzyme (ICE), a caspase thought to be involved in the
induction of apoptosis. We report that, in the developing frog, Xenopus laevis,
IL-1beta and the IL-1 type 1 receptor proteins are coexpressed in specific
neurons that comprise early sensory-motor circuits. IL-1beta and IL-1 type 1
receptor proteins are colocalized in specific midbrain and hindbrain reticular
cells, including Mauthner's neuron; specific cells in the trigeminal (fifth),
lateral line (seventh), and vestibular (eighth) cranial ganglia; oculomotor
neurons; and the primordial Purkinje cells of the lateral cerebellar auricle. In
the spinal cord, Rohon-Beard sensory neurons, dorsal root ganglion cells, and
primary motoneurons are immunopositive. Anteriorly, the olfactory pits, olfactory
nerves, and olfactory bulbs are labeled, as are retinal cells, especially
photoreceptor inner segments. With regard to the function of IL-1beta during
neural development, IL-1beta and its type 1 receptor are present throughout the
course of neural development in identifiable, long-lived neurons, such as
Mauthner's neuron. These and other data suggest that IL-1beta and its type 1
receptor may be involved in the maintenance of cell survival rather than
induction of neuronal death.
PMID- 9552130
TI - Hippocampal interneurons expressing glutamic acid decarboxylase and calcium
binding proteins decrease with aging in Fischer 344 rats.
AB - Aging leads to alterations in the function and plasticity of hippocampal
circuitry in addition to behavioral changes. To identify critical alterations in
the substrate for inhibitory circuitry as a function of aging, we evaluated the
numbers of hippocampal interneurons that were positive for glutamic acid
decarboxylase and those that expressed calcium-binding proteins (parvalbumin,
calbindin, and calretinin) in young adult (4-5 months old) and aged (23-25 months
old) male Fischer 344 rats. Both the overall interneuron population and specific
subpopulations of interneurons demonstrated a commensurate decline in numbers
throughout the hippocampus with aging. Interneurons positive for glutamic acid
decarboxylase were significantly depleted in the stratum radiatum of CA1, the
strata oriens, radiatum and pyramidale of CA3, the dentate molecular layer, and
the dentate hilus. Parvalbumin interneurons showed significant reductions in the
strata oriens and pyramidale of CA1, the stratum pyramidale of CA3, and the
dentate hilus. The reductions in calbindin interneurons were more pronounced than
other calcium-binding protein-positive interneurons and were highly significant
in the strata oriens and radiatum of both CA1 and CA3 subfields and in the
dentate hilus. Calretinin interneurons were decreased significantly in the strata
oriens and radiatum of CA3, in the dentate granule cell and molecular layers, and
in the dentate hilus. However, the relative ratio of parvalbumin-, calbindin-,
and calretinin-positive interneurons compared with glutamic acid decarboxylase
positive interneurons remained constant with aging, suggesting actual loss of
interneurons expressing calcium-binding proteins with age. This loss contrasts
with the reported preservation of pyramidal neurons with aging in the
hippocampus. Functional decreases in inhibitory drive throughout the hippocampus
may occur due to this loss, particularly alterations in the processing of feed
forward information through the hippocampus. In addition, such a profound
alteration in interneuron number will likely alter inhibitory control of
excitability and neuronal synchrony with behavioral states.
PMID- 9552131
TI - The Shwachman Award of the North American Society for Pediatric Gastroenterology
and Nutrition presentation.
PMID- 9552132
TI - Primary eosinophilic esophagitis in children: successful treatment with oral
corticosteroids.
AB - BACKGROUND: The histologic appearance of esophageal eosinophils has been
correlated with esophagitis and gastroesophageal reflux disease in children.
Esophageal eosinophilia that persists despite traditional antireflux therapy may
not represent treatment failure, but instead may portray early eosinophilic
gastroenteritis or allergic esophagitis. In this study, a series of pediatric
patients with severe esophageal eosinophilia who were unresponsive to aggressive
antireflux therapy were examined and their clinical and histologic response to
oral corticosteroid therapy assessed. METHODS: Of 1809 patients evaluated
prospectively over 2.5 years for symptoms of gastroesophageal reflux, 20 had
persistent symptoms and esophageal eosinophilia, despite aggressive therapy with
omeprazole and cisapride. These patients were treated with 1.5 mg/kg oral
methylprednisolone per day, divided into twice-daily doses for 4 weeks. All
patients underwent clinical, laboratory, and histologic evaluation before and
after treatment. RESULTS: Histologic findings in examination of specimens
obtained in pretreatment esophageal biopsies in children with primary
eosinophilic esophagitis indicated significantly greater eosinophilia (34.2+/-9.6
eosinophils/high-power field [HPF]) compared with that in children with
gastroesophageal reflux disease who responded to medical therapy (2.26+/-1.16
eosinophils/HPF; p < 0.001). After corticosteroid therapy, all but one patient
with primary eosinophilic esophagitis had dramatic clinical improvement,
supported by histologic examination (1.5 +/-0.9 eosinophils/HPF, p < 0.0001).
CONCLUSIONS: Pediatric patients in a series with marked esophageal eosinophilia
and chronic symptoms of gastroesophageal reflux disease unresponsive to
aggressive medical antire-flux therapy had both clinical and histologic
improvement after oral corticosteroid therapy.
PMID- 9552133
TI - Antineutrophil cytoplasmic antibody subtypes in children and adolescents after
ileal pouch-anal anastomosis for ulcerative colitis.
AB - BACKGROUND: Perinuclear antineutrophil cytoplasmic antibodies occur frequently in
adult patients with chronic pouchitis after colectomy and ileal pouch-anal
anastomosis for ulcerative colitis. The purpose of the study was to determine the
prevalence of perinuclear antineutrophil cytoplasmic antibodies and cytoplasmic
antineutrophil cytoplasmic antibody in children and adolescents who undergo
colectomy and ileal pouch-anal anastomosis for ulcerative colitis and familial
adenomatous polyposis. METHODS: Five groups of children and adolescents (age, <20
years) were studied, with the following histories: acute pouchitis and history of
ulcerative colitis; chronic pouchitis and history of ulcerative colitis;
pouchitis with Crohn's disease features and a history of ulcerative colitis; no
pouchitis and a history of ulcerative colitis; and familial adenomatous
polyposis, with or without pouchitis. Antineutrophil cytoplasmic antibody levels
and titers were detected in postoperative sera by enzyme-linked immunosorbent
assay, and positive results were subtyped by indirect immunofluorescence.
RESULTS: The frequency of perinuclear antineutrophil cytoplasmic antibodies and
cytoplasmic antineutrophil cytoplasmic antibody in patients with a history of
ulcerative colitis were 67% and 15%, compared with a 0% presence in patients with
familial adenomatous polyposis (p < 0.001). There was no significant correlation
between the frequency of perinuclear antineutrophil cytoplasmic antibodies and
ulcerative colitis patient subgroups (patients with and without pouchitis, 66%
and 75%). Similarly, there was no significant correlation between the frequency
of cytoplasmic antineutrophil cytoplasmic antibodies among ulcerative colitis
patient subgroups (patients with and without pouchitis, 19% and 8%). The
frequency of cytoplasmic antineutrophil cytoplasmic antibody in patients with
Crohn's disease features (50%), was increased, but this difference was not
significant. CONCLUSIONS: There is a high frequency of perinuclear antineutrophil
cytoplasmic antibodies in children and adolescents who undergo ileal pouch-anal
anastomosis for ulcerative colitis, whether or not they have pouchitis. The
frequency of cytoplasmic antineutrophil cytoplasmic antibody is lower in this
patient population. Additional studies will be required to determine whether the
presence of cytoplasmic antineutrophil cytoplasmic antibody is associated with
the postoperative development of features of Crohn's disease.
PMID- 9552134
TI - Helicobacter pylori infection, gastric acid secretion, and infant growth.
AB - BACKGROUND: Helicobacter pylori infection is very common in Gambian infants and
children, who are also at risk of chronic diarrhoea and undernutrition. Acute H.
pylori infection is associated with depressed gastric acid secretion, and loss of
the gastric acid barrier may predispose to enteric infections. METHODS: In a
prospective study a noninvasive test of gastric acid output (measurement of
change in urine acid output before and after a feed) was performed on a
population of Gambian infants at high risk of H. pylori infection. The 13C urea
breath tests was used to measure the prevalence of H. pylori infection and growth
was measured by serial anthropometry. RESULTS: In 101 infants aged 3 to 12
months, there was a significant relation between H. pylori infection and
depressed urine acid output in those aged 6 months, during weaning when growth
failure and malnutrition begin. Those infants with sustained H. pylori infection
grew less well than those without. CONCLUSIONS: We speculate that H. pylori,
acquired in infancy, could be a "key that opens the door" to enteric infection in
childhood, leading to recurrent diarrhoea, malnutrition, and growth failure.
PMID- 9552135
TI - Persistent hepatitis G virus infection after neonatal transfusion.
AB - BACKGROUND: Recently two Flaviviridae-like viruses have been discovered and named
GB virus C and hepatitis G virus. Molecular characterization showed them to be
different subtypes of the same virus. An association with posttransfusion
hepatitis and with sporadic and fulminant hepatitis was reported, but most
infected people remain asymptomatic. Data concerning hepatitis G virus infection
in infants and children have not been reported to date. The prevalence of
hepatitis G virus infection in children after transfusion of blood products in
the neonatal period was studied. METHODS: Serum samples from 251 children, who
had received blood products in the first 4 weeks of life and who had been
reexamined as part of another study at a mean interval of 37 months (range, 10
70) after last transfusion, were analyzed for hepatitis G virus infection. Follow
up examinations were performed in 14 of 19 hepatitis G virus-positive children 12
to 17 years after the last transfusion. Presence of hepatitis G virus RNA in
serum was determined by a reverse transcription polymerase chain reaction assay
with nested primers from the helicase region of the hepatitis G virus. To prove
specificity of the hepatitis G virus, reverse transcription polymerase chain
reaction assay and compare follow-ups with initial sequences, direct sequencing
of the NS3 and NS5 regions of the hepatitis G virus was performed. RESULTS:
Hepatitis G virus RNA was detected in 19 of 251 patients (7.6%); sequence
analysis showed the isolates to be of hepatitis G virus type. None of the
patients with hepatitis G virus infection had evidence of liver disease, although
3 patients were coinfected with hepatitis C virus. Four of 14 patients who were
reinvestigated after a mean of 15 years showed persistent hepatitis G virus
infection. Each of the 4 children was healthy. In none were clinical signs of
liver disease observed; liver function test results were within the normal range.
CONCLUSIONS: Children receiving blood transfusions in the neonatal period are at
increased risk of hepatitis G virus infection with a high rate of chronic
infection. However, as in the findings in several studies of adult transfusion
recipients, in the current results, no association between hepatitis G virus
infection and clinical or biochemical signs of hepatitis or extrahepatic disease
could be seen.
PMID- 9552136
TI - Lipid digestion in cystic fibrosis: comparison of conventional and high-lipase
enzyme therapy using the mixed-triglyceride breath test.
AB - BACKGROUND: Fat maldigestion occurs in most patients with cystic fibrosis.
Conventional pancreatic enzyme replacement therapy partially corrects this
defect. In this study, the mixed-triglyceride breath test was used to evaluate
whether high-lipase enzymes are equivalent to conventional enzymes in improving
fat maldigestion in children with cystic fibrosis. METHODS: Fat digestion was
studied in 11 patients with a mean age of 10.5 years. The mean intake of
conventional enzyme capsules a day was 19. Four 13C mixed-triglyceride tests were
performed on separate days and in random order. One test was taken without enzyme
substitution, one with three capsules of 8,000 FIP units Creon (pancreatinum,
Kali-chemie Pharma, Hannover, Germany) and one with one capsule of 25,000 FIP
units. The fourth test was made with 13C octanoic acid to study gastric emptying
time. RESULTS: Without enzyme intake, the mean cumulative percentage of 13C dose
exhaled after 6 hours was 7.2+/-3.7%. This increased to 14.4+/-4% with intake of
conventional pancreatinum and to 14.3+/-5.1% with intake of high-lipase
pancreatinum (p = 0.0008 for both; paired t-test). There was no difference
between both treatments. Also, the time course of 13C exhalation measured by
percentage of 13CO2 exhaled per hour did not differ between enzyme treatments.
CONCLUSIONS: The 13C mixed-triglyceride test is noninvasive and documents
improved lipid digestion with pancreatic enzyme replacement therapy. If the
lipase dose is kept constant, results obtained with high-lipase preparations are
equivalent to those obtained with conventional preparations.
PMID- 9552137
TI - Effect of formula supplemented with docosahexaenoic acid and gamma-linolenic acid
on fatty acid status and visual acuity in term infants.
AB - BACKGROUND: Docosahexaenoic acid is present in high concentration in retina and
does not influence visual development in preterm infants. It is still under
discussion whether docosahexaenoic acid is important for visual development in
term infants. METHODS: Thirty-seven infants fed formula for a median of 14 days
were randomized at median age of 25 days to three formulas: a) DHAGF: 0.3 wt%
docosahexaenoic acid and 0.5 wt% gamma-linolenic acid; b) DHAF 0.3 wt%
docosahexaenoic acid; or c) STF: standard formula without long-chain
polyunsaturated fatty acids and 17 breast-fed infants were observed, using blood
samples and anthropometric measurements from 1 to 4 months of age. At 4 months,
visual acuity was measured by swept steady-state visual evoked potential. A cross
sectional study on 25 breast-fed infants was carried out as a reference group for
the analyses. RESULTS: Infants fed the two docosahexaenoic acid-supplemented
formula had relative docosahexaenoic acid concentrations in red blood cell
phospholipids almost as high as those in breast-fed infants, whereas infants in
the standard formula group had significantly lower levels. The addition of gamma
linolenic acid to the formula had a positive effect on red blood cell arachidonic
acid levels, compared with levels obtained using fish oil only. Visual acuity was
significantly different among all feeding groups (analysis of variance; p = 0.05,
means +/- standard deviation: breast-fed, 0.37+/-0.06 logMAR; DHAF and DHAGF
combined, 0.40+/-0.07 logMAR; and standard formula 0.44+/-0.07 logMAR. However,
there was no statistical difference among the formula groups. In a multiple
regression analysis including all formula-fed infants, weight at delivery (p =
0.002), but not type of formula, was significantly associated with visual acuity
at 4 months of age. CONCLUSIONS: The addition of docosahexaenoic acid resulted in
concentrations in red blood cells at similar levels as those in breast-fed
infants, whereas the increase in visual acuity did not reach significance. The
addition of gamma-linolenic acid resulted in higher arachidonic acid
concentrations in red blood cells.
PMID- 9552139
TI - Functional results of laparoscopic fundoplication in children.
AB - BACKGROUND: There is no evidence that the results of laparoscopic fundoplication
in children match those of the open procedure. In the current report, pre- and
postoperative function of the antireflux barrier is examined in children having
laparoscopic fundoplication for gastroesophageal reflux. METHODS: Twenty-seven
patients with gastroesophageal reflux, aged 7.2+/-4.5 years, were operated on for
unremitting gastrointestinal symptoms (n = 24), with respiratory tract disease (n
= 11), cystic fibrosis (n = 2), or brain damage (n = 11). Gastrostomy was added
in 5 cases. Barium contrast study, pH-metering, endoscopic examination, and
biopsy were performed before and after a median of 19 months (range, 8 to 46)
after operation. RESULTS: At diagnosis, 15 of 21 patients had esophagitis that
was moderate or severe in 11 (1 with Barrett's esophagus). Symptoms disappeared
after fundoplication in all but 2 patients, in whom they became milder. The
reflux index decreased from 20.2+/-20% to 4.9+/-9% and became normal in all
except 4 children (2 with brain damage and 1 with cystic fibrosis). Open repair
of the failed wrap was considered necessary in only 1 of them. CONCLUSIONS:
Laparoscopic fundoplication is as effective as the open procedure (14% overall
failure rate). However, the failure rate in neurologic patients (18%) suggests
that before reaching conclusions on the benefits of this approach, careful long
term assessment of the functional results is necessary.
PMID- 9552138
TI - T-cells and HLA-class II expression in the large intestine of infants in the
early postnatal period.
AB - BACKGROUND: There is only limited knowledge of the development of the immune
responses of the gut in very young infants after exposure to bacterial and food
antigens at birth. METHODS: In this study, 49 large intestinal biopsy specimens,
which were judged to have normal morphology, were taken from 49 young infants.
Eleven patients had Hirschsprung's disease (group 1) and 38 had miscellaneous
conditions (group 2). The densities of T cells, their subsets expressing surface
antigens CD8 and CD4, and T-cell receptors alpha/beta or gamma/beta were
measured, as well as densities of mononuclear and epithelial cells expressing HLA
class II antigens. RESULTS: T-cell densities in groups 1 and 2 were similar.
Patients with Hirschsprung's disease had significantly more HLA-DR (p = 0.006)
and HLA-DP-expressing cells (p = 0.003) in the lamina propria than did the
patients in group 2. In group 1, HLA-DR- (r = 0.58; p = 0.46) and HLA-DP
expressing cells (r = 0.66; p = 0.03) showed a significant positive regression
with age in the lamina propria, whereas in group 2, HLA-DR+ cells in the lamina
propria showed marked (r = -0.9; p = 0.006) negative regression during the first
1.5 months of life. In contrast to results in previous reports, in the current
results, HLA-D region antigens were present in the epithelium in a considerable
proportion (up to one fourth) of specimens from the large intestine in both
groups. CD3+ (r = -0.59; p = 0.006) and CD4+ (r = -0.64; p = 0.002) cells showed
a strong negative regression with age in the lamina propria during the first 2.5
months; and thereafter, there was a weak, insignificant rise in the numbers of
these cells. The distribution of CD4+, CD8+, and TCR alpha/beta or gamma/beta T
cells of the epithelium of the young infants did not differ significantly from
that in the epithelium of adults. CONCLUSIONS: These results show that several
significant changes occur in the mucosal immune system during the first few weeks
of life.
PMID- 9552140
TI - Butyrate and glucose metabolism in isolated colonocytes in the developing rat
colon.
AB - BACKGROUND: The newborn colon is devoid of microflora, in that bacterial
colonization is established after birth. Short chain fatty acids, products of
bacterial fermentation, are the major energy source for colonocytes. Because it
is not known whether colonocytes in the newborn can metabolize butyrate, this was
examined in newborn and infant rat colon. METHODS: Isolated colonocytes from rats
of different perinatal ages were incubated with 14C-labeled butyrate or glucose
in vitro. Complete oxidation was estimated by the production of 14C-labeled
carbon dioxide, whereas intermediate metabolites were measured enzymatically.
RESULTS: Oxidation of butyrate (in micromoles per hour per milligram of protein)
was highest in newborns (5.83+/-1.76), declining to 1.32+/-0.28 at day 10 and to
0.34+/-0.04 in adult rats. Glucose oxidation was also highest at birth (0.39+/
0.23), with a minor increase at approximately day 20 (weaning period) before
decreasing to adult levels (0.05+/-0). Butyrate oxidation was substantially
higher than was glucose oxidation in all age groups. Production of metabolic
intermediates paralleled substrate oxidation. Acetoacetate production was 4.35+/
2.68, 2.07+/-1.29, and 0.27+/-0.09 nmol/hr per milligram of protein in newborns,
at postnatal day 10, and in adults, respectively. The corresponding values for
beta-hydroxybutyrate were 3.62+/-3.35, 0.2+/-0.07, and 0.09+/-0.03 nmol/hr per
milligram of protein; and L-lactate production was 0.54+/-0.52, 0.06+/-0.04, and
0.02+/-0 micromol/hr per milligram of protein respectively. CONCLUSIONS: Neonatal
rat colon epithelial cells resemble adult colonocytes in their preference for
butyrate as a metabolic substrate, indicating a constitutive expression of this
property.
PMID- 9552141
TI - Clinical quiz. Trichobezoar, a rare and unique form of gastrointestinal foreign
body.
PMID- 9552142
TI - The biology of inherited disorders of the gastrointestinal tract--part II:
pancreatic and hepatobiliary disorders.
PMID- 9552143
TI - The role of zinc and vitamin A in persistent diarrhea among infants and young
children.
PMID- 9552144
TI - Diffuse microcystic pancreatic enlargement in a cystic fibrosis patient causing
severe gastrointestinal symptoms and successfully treated by total
pancreatectomy.
PMID- 9552145
TI - Epilepsy and Crohn's disease in children.
PMID- 9552146
TI - Spontaneous perforation of the cystic duct.
PMID- 9552147
TI - Superior mesenteric artery syndrome complicating mitochondrial encephalopathy.
PMID- 9552148
TI - Eosinophils in the esophagus: acid is not the only cause.
PMID- 9552149
TI - The difficulty with rapid communication: fulminant hepatic failure in infancy.
PMID- 9552150
TI - The use of antineutrophil cytoplasmic antibodies to determine clinical patterns
of ulcerative colitis in children.
PMID- 9552151
TI - Generalised mitochondrial cytopathy is an absolute contraindication to orthotopic
liver transplant in childhood.
PMID- 9552152
TI - Site-directed gene therapy: a goal for the 21st century.
PMID- 9552153
TI - Nutrition in children with cerebral palsy.
PMID- 9552154
TI - A phosphoinositide-binding sequence is shared by PH domain target molecules--a
model for the binding of PH domains to proteins.
AB - Pleckstrin homology (PH) domains have been proven to bind phosphoinositides (PI)
and inositolphosphates (IP). On the other hand, a binding of PH domains to
proteins is still a matter of debate. The goal of this work was to identify
potential PH domain protein target sites and to build a model for PH domain
protein binding. A candidate sequence, called HIKE, was identified by sequence
homology analysis of the proteins that are considered the strongest PH binding
candidates, i.e., Gbeta, PKC, and Akt. HIKE contains a PI binding sequence and
fulfills several criteria for a potential PH-binding site, i.e., it is present in
other PH-binding candidates, lies in regulatory regions independently predicted
to bind PH domains, and is conserved in 3-D structure among different molecules.
These findings and the similarities with the mode of binding of PTB and PDZ
domains suggest a beta strand-beta strand coordination model for PH-protein
binding. The HIKE model predicts that membrane anchoring of PH domains and their
targets could be a critical step in their interaction, which would consistently
explain why PH-protein binding has only been detected in the presence of PI.
PMID- 9552155
TI - Structure-based design of model proteins.
AB - A structure-based, sequence-design procedure is proposed in which one considers a
set of decoy structures that compete significantly with the target structure in
being low energy conformations. The decoy structures are chosen to have strong
overlaps in contacts with the putative native state. The procedure allows the
design of sequences with large and small stability gaps in a random-bond
heteropolymer model in both two and three dimensions by an appropriate assignment
of the contact energies to both the native and nonnative contacts. The design
procedure is also successfully applied to the two-dimensional HP model.
PMID- 9552156
TI - Crystal structure of calcium-independent subtilisin BPN' with restored thermal
stability folded without the prodomain.
AB - The three-dimensional structure of a subtilisin BPN' construct that was produced
and folded without its prodomain shows the tertiary structure is nearly identical
to the wild-type enzyme and not a folding intermediate. The subtilisin BPN'
variant, Sbt70, was cloned and expressed in Escherichia coli without the
prodomain, the 77-residue N-terminal domain that catalyzes the folding of the
enzyme into its native tertiary structure. Sbt70 has the high-affinity calcium
binding loop, residues 75 to 83, deleted. Such calcium-independent forms of
subtilisin BPN' refold independently while retaining high levels of activity
[Bryan et al., Biochemistry, 31:4937-4945, 1992]. Sbt70 has, in addition, seven
stabilizing mutations, K43N, M50F, A73L, Q206V, Y217K, N218S, Q271E, and the
active site serine has been replaced with alanine to prevent autolysis. The
purified Sbt70 folded spontaneously without the prodomain and crystallized at
room temperature. Crystals of Sbt70 belong to space group P2(1)2(1)2(1) with unit
cell parameters a = 53.5 A, b = 60.3 A, and c = 83.4 A. Comparison of the refined
structure with other high-resolution structures of subtilisin BPN' establishes
that the conformation of Sbt70 is essentially the same as that previously
determined for other calcium-independent forms and that of other wild-type
subtilisin BPN' structures, all folded in the presence of the prodomain. These
findings confirm the results of previous solution studies that showed subtilisin
BPN' can be refolded into a native conformation without the presence of the
prodomain [Bryan et al., Biochemistry 31:4937-4945, 1992]. The structure analysis
also provides the first descriptions of four stabilizing mutations, K43N, A73L,
Q206V, and Q271E, and provides details of the interaction between the enzyme and
the Ala-Leu-Ala-Leu tetrapeptide found in the active-site cleft.
PMID- 9552157
TI - Recognition and interaction of small rings with the ricin A-chain binding site.
AB - Ricin A-chain is an N-glucosidase that attacks ribosomal RNA at a highly
conserved adenine residue. Our recent crystallographic studies show that not only
adenine and formycin, but also pterin-based rings can bind in the active site of
ricin. For a better understanding of the means by which ricin recognizes adenine
rings, the geometries and interaction energies were calculated for a number of
complexes between ricin and tautomeric modifications of formycin, adenine,
pterin, and guanine. These were studied by molecular mechanics, semi-empirical
quantum mechanics, and ab initio quantum mechanical methods. The calculations
indicate that the formycin ring binds better than adenine and pterin better than
formycin, a result that is consistent with the crystallographic data. A tautomer
of pterin that is not in the low energy form in either the gas phase or in
aqueous solution has the best interaction with the enzyme. The net interaction
energy, defined as the interaction energy calculated in vacuo between the
receptor and an inhibitor minus the solvation energy of the inhibitor, provides a
good prediction of the ability of the inhibitor to bind to the receptor. The
results from experimental and molecular modeling work suggest that the ricin
binding site is not flexible and may only recognize a limited range of adenine
like rings.
PMID- 9552158
TI - Modeling of inhibitor-metalloenzyme interactions and selectivity using molecular
mechanics grounded in quantum chemistry.
AB - We investigated the binding properties of the metalloprotease inhibitors
hydroxamate, methanethiolate, and methylphosphoramidate to a model coordination
site occurring in several Zn2+ metalloproteases, including thermolysin. This was
carried out using both the SIBFA (sum of interactions between fragments ab initio
computed) molecular mechanics and the SCF/MP2 procedures for the purpose of
evaluating SIBFA as a metalloenzyme modeling tool. The energy-minimized
structures were closely similar to the X-ray crystallographic structures of
related thermolysin-inhibitor complexes. We found that selectivity between
alternative geometries and between inhibitors usually stemmed from multiple
interaction components included in SIBFA. The binding strength sequence is
hydroxamate > methanethiolate > or = methylphosphoramidate from multiple
interaction components included in SIBFA. The trends in interaction energy
components, rankings, and preferences for mono- or bidentate binding were
consistent in both computational procedures. We also compared the Zn2+ vs. Mg2+
selectivities in several other polycoordinated sites having various "hard" and
"soft" qualities. This included a hexahydrate, a model representing Mg2+/Ca2+
binding sites, a chlorophyll-like structure, and a zinc finger model. The latter
three favor Zn2+ over Mg2+ by a greater degree than the hydrated state, but the
selectivity varies widely according to the ligand "softness." SIBFA was able to
match the ab initio binding energies by < 2%, with the SIBFA terms representing
dispersion and charge-transfer contributing the most to Zn2+/Mg2+ selectivity.
These results showed this procedure to be a very capable modeling tool for
metalloenzyme problems, in this case giving valuable information about details
and limitations of "hard" and "soft" selectivity trends.
PMID- 9552160
TI - Prediction of the three-dimensional structure of proteins using the electrostatic
screening model and hierarchic condensation.
AB - We describe a method for predicting the three-dimensional (3-D) structure of
proteins from their sequence alone. The method is based on the electrostatic
screening model for the stability of the protein main-chain conformation. The
free energy of a protein as a function of its conformation is obtained from the
potentials of mean force analysis of high-resolution x-ray protein structures.
The free energy function is simple and contains only 44 fitted coefficients. The
minimization of the free energy is performed by the torsion space Monte Carlo
procedure using the concept of hierarchic condensation. The Monte Carlo
minimization procedure is applied to predict the secondary, super-secondary, and
native 3-D structures of 12 proteins with 28-110 amino acids. The 3-D structures
of the majority of local secondary and super-secondary structures are predicted
accurately. This result suggests that control in forming the native-like local
structure is distributed along the entire protein sequence. The native 3-D
structure is predicted correctly for 3 of 12 proteins composed mainly from the
alpha-helices. The method fails to predict the native 3-D structure of proteins
with a predominantly beta secondary structure. We suggest that the hierarchic
condensation is not an appropriate procedure for simulating the folding of
proteins made up primarily from beta-strands. The method has been proved accurate
in predicting the local secondary and super-secondary structures in the blind ab
initio 3-D prediction experiment.
PMID- 9552159
TI - Engineering of a stable mutant malic enzyme by introducing an extra ion-pair to
the protein.
AB - A double mutant (R9E/M17K) of pigeon liver malic enzyme with glutamate and lysine
replaced for arginine and methionine at positions 9 and 17, respectively, was
found to be much more stable in urea and thermal denaturation, but was
enzymatically less active than the wild-type enzyme (WT). Unfolding of the enzyme
by urea produced a large red shifting of the protein fluorescence maximum from
320 to 360 nm, which was completely reversible upon dilution. Analysis of the
denaturation curves monitored by enzyme activity lost suggested that a putative
intermediate was involved in the denaturation process. The half unfolding urea
concentration, measured by fluorescence spectral changes, increased from 2.24 M
for WT to 3.13 M for R9E/M17K. The melting temperature increased by approximately
10 degrees C for R9E/M17K compared with that for WT. Kinetic analysis of the
thermal inactivation at 58 degrees C also conformed to a three-state model with
the rate constant for the intermediate state of R9E/M17K (k2 = 0.03 min(-1))
being much smaller than the WT value (k2 = 2.39 min(-1)). Results obtained from
single mutants indicated that the decreasing enzyme activity of R9E/M17K was
exclusively due to R9 mutation, which increased the K(mMn) and K(mMal) by at
least one order of magnitude compared with WT. Consequently, a decrease occurred
in the specificity constant [k(cat)/(K(mMm)K(mNADP)K(mMal))] for the R9 mutants
at least four orders of magnitude smaller than the WT. M17K has similar
properties to the WT, while R9E is more labile than the WT enzyme. The above
results indicate that the extra stability gained by the double mutant possibly
occurs through the introduction of an extra ion-pair between E9 and K17, which
freezes the double mutant in the putative intermediate state. Examination of the
N-terminal amino acid sequence of pigeon liver malic enzyme reveals that position
15 is also a lysine residue. Since the R9E mutant, which has an extra Glu9-Lys15
ion-pair, is less stable than the WT, we conclude that the contribution to malic
enzyme stability is specific for the Glu9-Lys17 ion-pair.
PMID- 9552161
TI - Prediction and classification of domain structural classes.
AB - Can the coupling effect among different amino acid components be used to improve
the prediction of protein structural classes? The answer is yes according to the
study by Chou and Zhang (Crit. Rev. Biochem. Mol. Biol. 30:275-349, 1995), but a
completely opposite conclusion was drawn by Eisenhaber et al. when using a
different dataset constructed by themselves (Proteins 25:169-179, 1996). To
resolve such a perplexing problem, predictions were performed by various
approaches for the datasets from an objective database, the SCOP database
(Murzin, Brenner, Hubbard, and Chothia. J. Mol. Biol. 247:536-540, 1995).
According to SCOP, the classification of structural classes for protein domains
is based on the evolutionary relationship and on the principles that govern the
3D structure of proteins, and hence is more natural and reliable. The results
from both resubstitution tests and jackknife tests indicate that the overall
rates of correct prediction by the algorithm incorporated with the coupling
effect among different amino acid components are significantly higher than those
by the algorithms without using such an effect. It is elucidated through an
analysis that the main reasons for Eisenhaber et al. to have reached an opposite
conclusion are the result of (1) misusing the component-coupled algorithm, and
(2) using a conceptually incorrect rule to classify protein structural classes.
The formulation and analysis presented in this article are conducive to clarify
these problems, helping correctly to apply the prediction algorithm and interpret
the results.
PMID- 9552162
TI - Zebrafish tenascin-W, a new member of the tenascin family.
AB - A cDNA clone encoding tenascin-W, a novel member of the tenascin family, was
isolated from a 20- to 28-h postfertilization (hpf) zebrafish cDNA library on the
basis of the conserved epidermal growth factor-like domains represented in all
tenascin molecules. An open reading frame of 2796 base pairs encodes a mature
protein consisting of heptad repeats, a cysteine-rich amino terminal region, 3.5
epidermal growth factor-like repeats, five fibronectin type III homologous
repeats, and a domain homologous to fibrinogen. These domains are the typical
modular elements of molecules of the tenascin family. Sequence comparison
demonstrated that TN-W shares homologies with the members of the tenascin family
but is not a species homolog of any identified tenascin. The expression pattern
of tn-w was analyzed by in situ hybridization in 1-day-old embryos, in 3-day-old
larvae, and in juvenile zebrafish. At 24-25 hpf, tn-w mRNA was expressed in the
lateral plate mesoderm, most conspicuously in the presumptive sclerotome.
Migrating cells of sclerotomal and neural crest origins also showed high levels
of expression. At 3 days, expression by sclerotomal and neural crest cells
continued to be observed while expression in the somitic mesoderm was decreased.
In juvenile fish, tn-w was expressed weakly by cells in the myosepta and, more
strongly, by presumably nonneuronal cells in the dorsal root ganglia. In these
tissues and at the same developmental stages, the expression of tn-w partially
overlapped with the distribution of tn-c mRNA. In addition, tn-c was expressed in
the central nervous system (CNS) and in the axial mesoderm, neither of which
expressed tn-w at any of the age stages examined. The expression pattern of tn-w
suggests an involvement in neural crest and sclerotome cell migration and in the
formation of the skeleton. Similar and possibly overlapping functions could also
be performed by tn-c, which appears to have additional functions during the
development of the CNS.
PMID- 9552163
TI - Selective blockade of axonogenesis in cultured hippocampal neurons by the
tyrosine phosphatase inhibitor orthovanadate.
AB - Protein tyrosine phosphorylation has been implicated in several aspects of
neurite outgrowth regulation. To address specific roles in early neuronal
morphogenesis, hippocampal neurons in culture were treated with the tyrosine
phosphatase inhibitor orthovanadate. This treatment completely suppressed axon
formation, yet enhanced formation of minor neurites. The inhibition of
axonogenesis was dose dependent and occurred in parallel with a marked increase
in cellular phosphotyrosine immunoreactivity, which was especially concentrated
within neuritic growth cones and showed partial colocalization with f-actin. Both
the blockade of axonogenesis and the elevation of phosphotyrosine were completely
reversible. An additional and unexpected effect of orthovanadate was the
appearance of many binucleate neurons. Immunoblotting experiments using a
phosphotyrosine-specific antibody revealed an orthovanadate-induced reversible
hyperphosphorylation of several protein bands, especially of two at 115 and 125
kD. These data suggest a potentially important role for tyrosine phosphatases and
their phosphoprotein substrates in axonogenesis.
PMID- 9552164
TI - Nicotine blocks TNF-alpha-mediated neuroprotection to NMDA by an alpha
bungarotoxin-sensitive pathway.
AB - Excitotoxic neuronal death mediated by N-methyl-D-aspartate (NMDA) glutamate
receptors can contribute to the extended brain damage that often accompanies
trauma or disease. Both the inflammatory cytokine tumor necrosis factor-alpha
(TNF-alpha) and nicotine have been identified as possible neuroprotective agents
to NMDA assault. We find that TNF-alpha protection of a subpopulation of cultured
cortical neurons to chronic NMDA-mediated excitotoxic death requires both the
activation of the p55/TNFRI, but not p75/TNFRII, and the release of endogenous
TNF-alpha. Nicotine protection to NMDA was mediated through an alpha-bungarotoxin
sensitive receptor. When coapplied, neuroprotection to NMDA by either TNF-alpha
or nicotine was abolished but could be recovered with alpha-bungarotoxin. These
results suggest that the cytokine TNF-alpha and alpha-bungarotoxin-sensitive
nicotinic neurotransmitter receptors confer neuroprotection through potentially
antagonistic pathways.
PMID- 9552165
TI - Neurite outgrowth, RGD-dependent, and RGD-independent adhesion of identified
molluscan motoneurons on selected substrates.
AB - The extracellular matrix (ECM) provides structural support to cells and tissues
and is involved in the regulation of various essential physiological processes,
including neurite outgrowth. Most of the adhesive interactions between cells and
ECM proteins are mediated by integrins. Integrins typically recognize short
linear amino acid sequences in ECM proteins, one of the most common being
Arginine-Glycine-Aspartate (RGD). The present study investigated neurite
outgrowth and adhesion of identified molluscan neurons on a selection of
substrates in vitro. Involvement of RGD binding sites in adhesion to the
different substrates was investigated using soluble synthetic RGD peptides. The
cells adhered to native (i.e., nondenatured) laminin and type IV collagen, but
not to native plasma fibronectin. Denaturation of fibronectin dramatically
enhanced cell adhesion. Only the adhesion to denatured fibronectin was inhibited
by RGD peptides, indicating that denaturation uncovers a RGD binding site in the
protein. Laminin as well as denatured fibronectin, but not type IV collagen,
induced neurite outgrowth from a percentage of the RPA neurons. These results
demonstrate that molluscan neurons can attach to various substrates using both
RGD-dependent and RGD-independent adhesion mechanisms. This suggests that at
least two different cell adhesion receptors, possibly belonging to the integrin
family, are expressed in these neurons. Moreover, the results show that
vertebrate ECM proteins can induce outgrowth from these neurons, suggesting that
the mechanisms involved in adhesion as well as outgrowth promoting are
evolutionarily well conserved.
PMID- 9552166
TI - A detached branch stops being recognized as self by other branches of a neuron.
AB - The multiple peripheral projections of a single leech mechanosensory neuron form
individual arbors that do not overlap at all with each other, a phenomenon that
has been termed "self-avoidance" (Yau, 1976; Kramer and Stent, 1985). This is in
marked contrast to the peripheral arbors of adjacent segmental homologues, which
partially overlap with each other at their boundaries in target areas of the body
wall (Nicholls and Baylor, 1968; Gan and Macagno, 1995). How a neurite
differentiates between sibling neurites of the same cell and those of a homologue
is not known, but possible mechanisms include the recognition of surface markers
of neuronal identity or the detection of cell-specific patterns of activity. In
order to test whether this self-recognition requires a neurite to be in direct
communication with its soma, we used a laser microbeam to sever a branch of a dye
filled pressure-sensitive (P) neuron in an intact leech embryo. Time-lapse
observations of the P cell arbor in the living, unanesthetized, animal for up to
24 h following the surgery showed that the detached branch continued to show
dynamic growth behavior throughout the period of observation. However, the
detached branch ceased being avoided by the rest of the cell within a few hours,
other, attached branches of the neuron overgrowing its territory and directly
overlapping with it. Our experiments provide direct evidence for the existence of
strong growth-inhibiting interactions between sibling processes, and indicate
that self-avoidance by the growing neurites of a cell requires physical
continuity between these neurites.
PMID- 9552167
TI - Molecular characterization of NOS in a mollusc: expression in a giant modulatory
neuron.
AB - Here we report on the molecular characterization of the first molluscan NOS in
the CNS of the pond snail Lymnaea stagnalis. This Lymnaea NOS (Lym-nNOS) which is
expressed preferentially in the CNS is most similar to mammalian neuronal NOS but
contains tandem repeats of a seven amino acid motif not found in any other known
NOS. We have localized Lym-nNOS to the serotonergic cerebral giant cells (CGCs)
which modulate synaptic transmission within a neural network that generates
feeding behavior. Our results suggest that the CGCs employ both NO and serotonin
in the modulation of the central neural network underlying feeding.
PMID- 9552168
TI - Midline Fasciclin: a Drosophila Fasciclin-I-related membrane protein localized to
the CNS midline cells and trachea.
AB - Drosophila Fasciclin I is the prototype of a family of vertebrate and
invertebrate proteins that mediate cell adhesion and signaling. The midline
fasciclin gene encodes a second Drosophila member of the Fasciclin I family.
Midline Fasciclin largely consists of four 150 amino acid repeats characteristic
of the Fasciclin I family of proteins. Immunostaining and biochemical analysis
using Midline Fasciclin antibodies indicates that it is a membrane-associated
protein, although the sequence does not reveal a transmembrane domain. The gene
is expressed in a dynamic fashion during embryogenesis in the blastoderm, central
nervous system midline cells, and trachea, suggesting it plays multiple
developmental roles. Protein localization studies indicate that Midline Fasciclin
is found within cell bodies of midline neurons and glia, and on midline axons.
Initial cellular analysis of a midline fasciclin loss-of-function mutation
reveals only weak defects in axonogenesis. However, embryos mutant for both
midline fasciclin and the abelson nonreceptor tyrosine kinase, show more severe
defects in axonogenesis that resemble fasciclin I abelson double mutant
phenotypes.
PMID- 9552169
TI - Metabotropic glutamate receptor expression in olfactory receptor neurons from the
channel catfish, Ictalurus punctatus.
AB - Metabotropic glutamate receptors (mGluRs) were identified in olfactory receptor
neurons of the channel catfish, Ictalurus punctatus, by polymerase chain
reaction. DNA sequence analysis confirmed the presence of two subtypes, mGluR1
and mGluR3, that were coexpressed with each other and with the putative odorant
receptors within single olfactory receptor neurons. Immunocytochemical data
showed that both mGluR subtypes were expressed in the apical dendrites and some
cilia of olfactory neurons. Pharmacological analysis showed that antagonists to
each mGluR subtype significantly decreased the electrophysiological response to
odorant amino acids. alpha-Methyl-L-CCG1/(2S,3S,4S)-2-methyl-2
(carboxycyclopropyl++ +)glycine (MCCG), a known antagonist to mGluR3, and (S)-4
carboxyphenylglycine (S-4CPG), a specific antagonist to mGluR1, each
significantly reduced olfactory receptor responses to L-glutamate. S-4CPG and
MCCG reduced the glutamate response to 54% and 56% of control, respectively,
which was significantly greater than their effect on a neutral amino acid
odorant, methionine. These significant reductions of odorant response by the
antagonists, taken with the expression of these receptors throughout the
dendritic and ciliated portions of some olfactory receptor neurons, suggest that
these mGluRs may be involved in olfactory reception and signal transduction.
PMID- 9552170
TI - The shaking B gene in Drosophila regulates the number of gap junctions between
photoreceptor terminals in the lamina.
AB - The molecular structure of insect gap junctions differs from that in vertebrates,
and in Drosophila is possibly encoded by the shaking B (= Passover) locus.
shaking B2 is a null allele that acts in the nervous system. In the shakB2
mutant, one site of action are gap junctions between photoreceptor terminals in
the cartridges of the lamina, beneath the compound eye, which we assayed from the
number of close-apposition profiles in thin-section EM. The number of profiles in
the Canton-S (C-S) wild type is about 0.5 per cartridge per section in distal and
mid-lamina depths, and significantly less, about one quarter this value, closer
to the brain, in the proximal lamina. In shakB2, there are fewer profiles,
approximately one quarter the number of appositions in distal and mid-lamina
depths as in C-S, and their number does not differ significantly from those at
the proximal depth in either the mutant or wild type. Thus mutant action is
associated with a reduced number of appositions at distal and mid-lamina depths.
We propose that R1-R6 gap junctions are partitioned into at least two strata,
proximal and distal, and that two populations of gap junctions exist, one
extending throughout the lamina that does not require shakB, and a second at
distal and mid-depth levels, which does. The number of gap junctions is reduced
in mutant shakB2, and surviving appositions at distal and middle lamina depths
possibly have wider clefts than in C-S. Gap junctions are reduced equally between
all R1-R6 terminals, so the two different types of junction proposed, shakB2- and
non-shakB2-dependent, can apparently express in a single receptor terminal.
PMID- 9552171
TI - Synaptic connections between GABA-immunoreactive neurons and uniglomerular
projection neurons within the antennal lobe of the cockroach, Periplaneta
americana.
AB - Synapses within deutocerebral glomeruli between GABA-immunoreactive, putatively
inhibitory local interneurons and uniglomerular projection (output) neurons were
demonstrated by means of a combination of GABA-immunogold labeling and
intracellular HRP injection. The following connections were identified. 1) GABA
immunoreactive (GABAir) neurons form output synapses in a dyadic fashion onto a
uniglomerular projection neuron and, in addition, a second GABAir neuron. A
uniglomerular projection neuron in turn forms dyadic output synapses onto two
GABAir neurons. Several examples of reciprocal connections have been identified
between, first, GABAir neurons and uniglomerular projection neurons, and, second,
GABAir neurons themselves. 2) GABAir neurons are serially connected with
uniglomerular projection neurons via interposed GABAir processes. In some cases,
also the first GABAir process of such a polysynaptic connection formed an output
synapse onto the projection neuron. Such serial connections may form the
structural basis for both, the feedforward inhibition as well as the feedforward
disinhibition of uniglomerular projection neurons by GABAergic neurons. The
reciprocal contacts may serve as control devices that modulate the output
activity of the projection neurons.
PMID- 9552172
TI - Phencyclidine (PCP) and dizocilpine (MK801) exert time-dependent effects on the
expression of immediate early genes in rat brain.
AB - The mRNA expression pattern for four different immediate early genes was examined
dynamically in rat brain after administration of phencyclidine (PCP; 0.86 or 8.6
mg/kg) or MK801 (0.1 or 1.0 mg/kg). Following each treatment, the expression of
cfos, cjun, junB, and zif268 mRNA changed distinctively and dynamically between 1
and 48 hours. cfos mRNA was induced in cortical areas at early times after either
dose of PCP or of MK801; the change was especially prominent in cingulate and
auditory cortices. zif268 mRNA showed an early (1 hour) activation and a delayed
(24-48 hour) suppression after PCP and MK801 in neocortical areas. PCP also
caused cjun and junB mRNA induction in cortical areas at early times, with a
distribution and time course similar to its effects on cfos mRNA. No alterations
in cfos, cjun, or junB mRNA were found in neocortical or hippocampal areas at any
delayed time (>6 hours) after PCP treatment, whereas suppression of zif268
expression was prominent even at 48 hours post-treatment. CPP, a competitive NMDA
antagonist, showed a similar pattern of effects on cfos and zif268 mRNA
expression. These functional consequences of a PCP- or MK801-induced reduction in
NMDA-sensitive glutamate transmission may be relevant to an understanding of
animal NMDA pharmacology and/or to clinical psychotomimetic side effects of
antiglutamatergic treatments.
PMID- 9552173
TI - Neurotransmitter regulation of MAP kinase signaling in striatal neurons in
primary culture.
AB - Glutamate and dopamine are important neurotransmitters in the basal ganglia.
Dopamine can act via D1 receptors to activate adenylyl cyclase in striatal
neurons, while glutamate stimulation of NMDA receptors leads to an increase in
intracellular calcium. Increases in intracellular calcium or cAMP can induce
immediate early gene expression in striatal neurons. In the present study, NMDA
receptor stimulation or adenylyl cyclase activation resulted in the activation of
MAP kinase in striatal neurons in primary culture. The effect of cAMP appeared to
involve cAMP-dependent protein kinase, in addition to a tyrosine kinase and MEK.
NMDA-induced MAP kinase activation was also dependent on a tyrosine kinase and
MEK. The EGF receptor, which has been implicated in calcium- and G protein
induced MAP kinase activation, did not mediate the effects of NMDA or forskolin
on MAP kinase. Furthermore, the src kinase inhibitor, herbimycin A, and the
phosphoinositol-3-kinase inhibitor, wortmannin, did not prevent MAP kinase
activation by these stimuli. However, the ability of both NMDA and forskolin to
activate MAP kinase in striatal neurons was blocked by SB 203580, an inhibitor of
p38 reactivating kinase. These results indicate that both NMDA receptor
activation and elevations in cAMP can result in MEK-induced MAP kinase activation
in striatal neurons. However, the signal transduction pathways mediating these
responses appear to be distinct from those known to mediate MAP kinase activation
by other stimuli.
PMID- 9552174
TI - Compartmental analysis of dopa decarboxylation in living brain from dynamic
positron emission tomograms.
AB - The trapping of decarboxylation products of radiolabelled dopa analogs in living
human brain occurs as a function of the activity of dopa decarboxylase. This
enzyme is now understood to regulate, with tyrosine hydroxylase, cerebral
dopamine synthesis. Influx into brain of dopa decarboxylase substrates such as 6
[18F]fluorodopa and beta-[11C]dopa measured by positron emission tomography can
be analyzed by solution of linear differential equations, assuming irreversible
trapping of the decarboxylated products in brain. The isolation of specific
physiological steps in the pathway for catecholamine synthesis requires
compartmental modelling of the observed dynamic time-activity curves in plasma
and in brain. The several approaches to the compartmental modelling of the
kinetics of labelled substrates of dopa decarboxylase are now systematically and
critically reviewed. Labelled catechols are extensively metabolized by hepatic
catechol-O-methyltransferase yielding brain-penetrating metabolites. The
assumption of a fixed blood-brain permeability ratio for O-methyl-6
[18F]fluorodopa or O-methyl-beta-[11C]dopa to the parent compounds eliminates
several parameters from compartmental models. However, catechol-O
methyltransferase activity within brain remains a possible factor in
underestimation of cerebral dopa decarboxylase activity. The O-methylation of
labelled catechols is blocked with specific enzyme inhibitors, but dopa
decarboxylase substrates derived from m-tyrosine may supplant the catechol
tracers. The elimination from brain of decarboxylated tracer metabolites can be
neglected without great prejudice to the estimation of dopa decarboxylase
activity when tracer circulation is less than 60 minutes. However, elimination of
dopamine metabolites from brain occurs at a rate close to that observed
previously for metabolites of glucose labelled in the 6-position. This phenomenon
can cause systematic underestimation of the rate of dopa decarboxylation in
brain. The spillover of radioactivity due to the limited spatial resolution of
tomographs also results in underestimation of dopa decarboxylase activity, but
correction for partial volume effects is now possible. Estimates of dopa
decarboxylase activity in human brain are increased several-fold by this
correction. Abnormally low influx of dopa decarboxylase tracers in the basal
ganglia is characteristic of Parkinson's disease and other movement disorders.
Consistent with postmortem results, the impaired retention of labelled dopa is
more pronounced in the putamen than in the caudate nucleus of patients with
Parkinson's disease; this heterogeneity persists after correction for spillover.
Current in vivo assays of dopa decarboxylase activity fail to discriminate
clinically distinct stages in the progression of Parkinson's disease and are, by
themselves, insufficient for differential diagnosis of Parkinson's disease and
other subcortical movement disorders. However, potential new avenues for
therapeutics can be tested by quantifying the rate of metabolism of exogenous
dopa in living human brain.
PMID- 9552175
TI - Modulation of the neuronal response to N-methyl-D-aspartate by selective sigma2
ligands.
AB - It has now been accepted for several years that sigma (sigma) receptors exist in,
at least, two distinct entities denoted sigma1 and sigma2. Previous
electrophysiological studies from our laboratory have demonstrated that several
selective sigma1 ligands potentiate the neuronal response to NMDA. The
nonselective sigma1/sigma2 ligand DTG also potentiates the NMDA response.
However, when DTG is administered at doses between 3 and 40 microg/kg, the
increase of NMDA-induced activation turns to an epileptoid activity. Until
recently, the physiological role of sigma2 receptors had been less studied due to
the lack of selective sigma2 ligands. The goal of the present
electrophysiological studies was to assess the effect of the intravenous
administration of new selective sigma2 ligands on the neuronal response to NMDA
in the CA3 region of the rat dorsal hippocampus. Lu 28-179 and BD 1008
potentiated dose-dependently the NMDA response and generated bell-shaped dose
response curves. These ligands failed to generate any epileptoid activity on
their own but the subsequent administration of a low dose of a sigma1 agonist (JO
1784) induced an epileptoid activity. Interestingly, the potentiations of the
NMDA response induced by Lu 28-179 or BD 1008 were not reversed by haloperidol,
by the neurosteroid progesterone, nor by the selective sigma1 antagonist NE-100.
Ibogaine, a high affinity sigma2 ligand, slightly increases the NMDA response,
which was reversed by progesterone. These data suggest that, similarly to sigma1
ligands, sigma2 agonists potentiate the NMDA response and that the coactivation
of sigma1 and sigma2 receptors could be necessary to induce an epileptoid
activity. They also suggest that haloperidol may not act as a sigma2 antagonist
and that several subtypes of sigma2 receptors could exist.
PMID- 9552176
TI - Blockade of the reward-potentiating effects of nicotine on lateral hypothalamic
brain stimulation by chlorisondamine.
AB - Chlorisondamine, a quarternary nicotinic antagonist, was given in a dose that
crosses the blood-brain barrier, is taken up and concentrated intracellularly by
dopaminergic neurons, and induces long-term blockade of the locomotor stimulant
and rewarding effects of nicotine. This treatment had no effect on the rewarding
effects of lateral hypothalamic brain stimulation, failing to shift the function
that relates reward strength to rate of responding (rate-frequency function).
That the treatment regimen was sufficient to block nicotinic receptors in the
reward system was confirmed by the fact that it completely blocked the ability of
normally effective nicotine to potentiate the rewarding effects of stimulation
(shift this function to the left). These data add evidence that the direct,
endogenous cholinergic contribution to brain stimulation reward is muscarinic and
fit with other evidence that the potentiation of brain stimulation reward by
exogenous nicotine involves actions on nicotinic receptors native to dopaminergic
neurons.
PMID- 9552177
TI - Effect of social status on striatal dopamine D2 receptor binding characteristics
in cynomolgus monkeys assessed with positron emission tomography.
PMID- 9552178
TI - Human influenza viral infection in utero increases nNOS expression in hippocampi
of neonatal mice.
AB - We investigated the role of maternal exposure to human influenza virus (HI) in
C57BL/6 mice on day 9 of pregnancy on hippocampal expression of nNOS in day 0
neonates and compared that to sham-infected pups. Qualitative analysis using
polyclonal antibody to nNOS showed overall increases in immunoreactivity (IR) in
hippocampal and dentate layers of day 0 infected neonates when compared to sham
infected animals. These increases in nNOS immunoreactivity were pronounced in
hippocampal plate, intermediate, molecular, subplate, and dentate areas.
Quantitative analysis of specific immunogold silver-enhanced nNOS IR via
densitometry showed nNOS IR increases of 26-71.6% in all layers, i.e.,
hippocampal plate (35.1%), dentate area (71.6%), molecular area (43.75%),
subplate (45.7%), and intermediate zone (26%) in infected neonatal brains vs.
controls. The changes in levels of nNOS expression in hippocampi of neonates born
to mothers exposed to HI virus during the second trimester of pregnancy may
reflect the potential for glutamatergic excitotoxicity via activation of NMDA
receptors in the developing brains of these neonatal mice.
PMID- 9552179
TI - The developing prefrontal cortex: is there a transient interneuron that
stimulates catecholamine terminals?
PMID- 9552180
TI - Classifying waste by reducing its generation.
PMID- 9552181
TI - Biohazardous waste: risk assessment, policy, and management.
PMID- 9552182
TI - Bacillus of Calmette and Guerin vaccination for tuberculosis prevention in
healthcare workers: how good is good enough?
PMID- 9552183
TI - A viral gastroenteritis outbreak associated with person-to-person spread among
hospital staff.
AB - OBJECTIVE: To identify the etiologic agent and risk factors associated with a
hospital ward outbreak of gastroenteritis. SETTING: A regional referral hospital
in upstate South Carolina. METHODS: We reviewed patient charts, surveyed staff,
and tested stool from acutely ill persons. A case was defined as diarrhea and
vomiting in a staff member or patient from January 5 to 13, 1996. RESULTS: The
initial case occurred on January 5 in a staff nurse who subsequently was
hospitalized on the ward and visited by many staff colleagues. The staff were at
a significantly greater risk for gastroenteritis than were patients (28/89 [31%]
vs 10/91 [11%]; relative risk [RR], 2.9; 95% confidence interval [CI95], 1.5
5.5). All 10 case-patients had been exposed to case-nurses (assigned nurses who
were primary caretakers), and eight had documented exposure to case-nurses 1 to 2
days before their illness. Patients exposed to case-nurses had a significantly
increased risk of illness (8/57 [14%] vs 0/32; RR, >4.5; CI95, undefined).
Neither staff nor patients had significantly increased risk from food, water,
ice, or exposure to case-patients. Electron microscopy identified small round
structured viruses (SRSVs) in nine of nine stool samples. CONCLUSION: This
nosocomial outbreak of gastroenteritis was likely caused by SRSVs introduced by a
staff member and spread via person-to-person transmission from and among staff.
The potential for spread of SRSV-associated gastroenteritis from and among staff
should be considered in developing strategies to prevent similar outbreaks in
hospital settings.
PMID- 9552184
TI - Low risk for tuberculosis in a regional pediatric hospital: nine-year study of
community rates and the mandatory employee tuberculin skin-test program.
AB - OBJECTIVE: To assess the risk of Mycobacterium tuberculosis infection and disease
among patients and workers in a regional pediatric hospital. DESIGN: Descriptive
epidemiological study of the mandatory tuberculin skin testing program of
hospital employees at hire and during annual reevaluation, pediatric patients
with tuberculosis (TB), efficacy of hospital infection control measures, and
community rates of TB. SETTING: 361-bed, university, pediatric hospital serving
Cincinnati (1.7 million population). RESULTS: During 1986 through 1994, 2,275 to
4,356 employees were compliant with Mantoux skin testing and screening each year.
This represented >97% of the population who were eligible for screening. The
cumulative rate of M tuberculosis infection from a previous positive tuberculin
skin test was 10% to 12% per year during 1986 through 1994. Among new Mantoux
skin-test converters in employees at annual reevaluation, the risk of TB
infection was 0.3% in 1993 and 1994. There were no active cases of TB identified
during new employee screening or annual reevaluation. Of 62 new Mantoux skin-test
converters in 9 years, 23% were foreign-born, 13% were Asian, 23% were African
American, 11% received the bacillus of Calmette-Guerin vaccine, and 60% had
direct patient care or indirect patient contact. A cluster of five converters
occurred in a department with no patient care or contact. Mantoux conversion
rates were 1.9 per 1,000 employee patient-care or contact-years and 2.2 per 1,000
employee non-patient-contact years. Twenty pediatric patients with active TB were
identified during 1991 to 1994, with < or =6 cases per year, placing this
hospital in the low-risk category for M tuberculosis disease. Three children with
pulmonary TB were admitted without immediate respiratory isolation, possibly
exposing 9 patients and 42 employees; none converted their Mantoux skin tests on
retesting. Rates of active TB in Cincinnati were stable during the period (eg,
8/100,000 population in 1994). CONCLUSIONS: Despite intense active surveillance
among thousands of hospital employees with >97% annual compliance, tuberculin
conversion rates were low, and no cases of active TB were identified during 9
years of follow-up. There was no evidence of transmission of M tuberculosis from
infected patients to employees during uncontrolled exposures. Rates of TB in the
community were low. These data suggest that rigorous application of the Centers
for Disease Control and Prevention guidelines and Occupation Safety and Health
Administration regulations for preventing nosocomial TB in pediatric hospitals
may be excessive and costly. Special provisions should be made for pediatric
hospitals with a proven low risk of transmission of M tuberculosis.
PMID- 9552185
TI - Can hospital discharge diagnosis be used for surveillance of bacteremia? A data
quality study of a Danish hospital discharge registry.
AB - OBJECTIVE: To assess the data quality of septicemia and sepsis registration in a
hospital discharge registry in the County of Northern Jutland, Denmark. DESIGN:
Comparison of data from the discharge registry of an 880-bed, public, urban
hospital in the County of Northern Jutland with data from a computerized
bacteremia database at the regional department of clinical microbiology. SETTING:
Urban hospital with approximately 45,000 admissions per year. PATIENTS: The study
included 406 episodes of bacteremia in the bacteremia database and 83 discharges
with the diagnosis of septicemia registered in the hospital discharge registry
between January 1, 1994, and December 31, 1994. INTERVENTIONS: None. RESULTS:
Eighteen episodes were registered in both the hospital discharge registry and the
bacteremia database. Using the bacteremia database as reference standard, the
sensitivity for the diagnosis of septicemia in the hospital discharge registry
was 4.4% (18/406; 95% confidence intervals [CI95, 2.4%-6.4%]). By review of
hospital records, we estimated the positive predictive value of septicemia
registration in the hospital discharge registry as 21.7% (18/83; CI95, 12.8%
30.5%). No blood culture had been obtained in 44.4% (36/81; CI95, 33.6%-55.3%) of
the cases with a discharge diagnosis of septicemia. In 33.3% (27/81; CI95, 23.1%
43.6%), the discharge diagnosis of septicemia was given, although blood cultures
were negative. CONCLUSIONS: The hospital discharge registry revealed numerous
misclassifications, and the system was found not suited for surveillance of, or
research in, bacteremia at present.
PMID- 9552186
TI - Carriage of methicillin-resistant Staphylococcus aureus at hospital admission.
AB - OBJECTIVES: To measure the prevalence of, and to establish predictors for, the
nasal carriage of methicillin-resistant Staphylococcus aureus (MRSA) at hospital
admission. To evaluate mannitol-salt agar with oxacillin for the simultaneous
detection and identification of MRSA from nasal swabs. DESIGN: Three-month
prospective case-control survey, with data collected from interviews and
computerized databases. The criterion standard for MRSA detection was culture on
Mueller-Hinton agar with oxacillin 6 microg/mL (National Committee for Clinical
Laboratory Standards method). SETTING: 320-bed tertiary-care hospital. PATIENTS:
387 patients screened within 24 hours after admission, including 10 MRSA carriers
(cases), 291 patients with no S aureus, and 86 patients with methicillin
susceptible S aureus. RESULTS: The prevalence of MRSA nasal carriage was 2.6%,
whereas the prevalence of carriage was 3.1% when both nasal and wound cultures
were performed. The significant predictors of carriage were a prior detection of
MRSA, open wounds, diabetes mellitus, treatments by injection, prior nursing home
stays, visits at home by a nurse, and prior antibiotic treatments. Cases had
stayed for longer periods in hospitals and had received longer antibiotic
treatments within a year. Eighty patients (including the 10 cases) had diabetes,
had been exposed to healthcare facilities within a year, and had antibiotics
within 6 months. The sensitivity and negative predictive value of nasal swabs on
mannitol-salt agar with oxacillin were 60% and 71%, respectively. CONCLUSION:
MRSA carriage on admission to the hospital may be an increasing and
underestimated problem. Further studies are needed to develop and validate a
sensitive and specific prediction rule.
PMID- 9552187
TI - Risk factors associated with the acquisition of amikacin-resistant gram-negative
bacilli in central New Jersey hospitals.
AB - A case-control study was performed in central New Jersey hospitals to evaluate
the potential patient factors associated with the acquisition of amikacin
resistant gram-negative bacilli (ARGNB). Univariate analysis revealed an
association between numerous patient factors, and multivariate analysis revealed
four factors to be associated independently with ARGNB: the number of hospital
admissions during the prior year, previous aminoglycoside exposure, intubation,
and intensive-care-unit admission.
PMID- 9552188
TI - Colonization by Acinetobacter baumanii in intensive-care-unit patients.
AB - We prospectively studied the value of systematic rectal swabs performed for the
detection of colonization and the prediction of infections by Acinetobacter
baumanii in 751 consecutive patients admitted to five intensive-care units (ICUs)
over an 8-month period. Gastrointestinal tract colonization was found in 8.7% of
ICU admissions. The positive and negative predictive values of rectal swabs for
the detection of subsequent infection were 17% and 99%, respectively. Sensitivity
and specificity were 55% and 93%, respectively. We also determined the
comparative values of rectal or nasal swabs and skin cultures for the detection
of A baumanii colonization in 25 patients already colonized or infected with A
baumanii. The combination of rectal and nasal swabs was positive in 20 (80%) of
25. The results of the present study suggest that detection of gastrointestinal
tract A baumanii colonization is not an accurate predictor of subsequent A
baumanii infection and that combined rectal and nasal swabs might be used for the
detection of A baumanii colonization in ICU patients.
PMID- 9552189
TI - In support of bacillus of Calmette and Guerin for healthcare workers.
AB - Although widely used outside the United States, bacillus of Calmette and Guerin
(BCG) immunization generally is given scant consideration in the US literature.
We believe that the recent resurgence of tuberculosis, including multidrug
resistant tuberculosis, is a compelling argument for the use of BCG in healthcare
workers and that BCG given to those at risk of exposure could be more effective
than routine tuberculin skin testing and isoniazid prophylaxis
PMID- 9552190
TI - Statistical quality control methods in infection control and hospital
epidemiology, part I: Introduction and basic theory.
AB - This article is the first in a two-part series discussing and illustrating the
application of statistical process control (SPC) to processes often examined by
hospital epidemiologists. The basic philosophical and theoretical foundations of
statistical quality control and their relation to epidemiology are emphasized in
order to expand mutual understanding and cross-fertilization between these two
disciplines. Part I provides an overview of quality engineering and SPC,
illustrates common types of control charts, and provides references for further
information or statistical formulae. Part II discusses statistical properties of
control charts, issues of chart design and optimal control limit widths,
alternate possible SPC approaches to infection control, some common
misunderstandings, and more advanced issues. The focus of both articles is mostly
non-mathematical, emphasizing important concepts and practical examples rather
than academic theory and exhaustive calculations.
PMID- 9552191
TI - Guidelines for antiretrovirals in pediatric HIV.
PMID- 9552193
TI - How fat is too fat?
PMID- 9552192
TI - FDA approves new sterilants.
PMID- 9552194
TI - More ways to stay dry.
PMID- 9552195
TI - Psoriasis.
PMID- 9552196
TI - Dietary fat reconsidered.
PMID- 9552197
TI - I am 70 and have a cholesterol level of 250 mg/dl. Am I right to be concerned?
PMID- 9552199
TI - Back in August 1996 you ran an article about an outpatient alternative to
hysterectomy called balloon ablation. When I called the number you gave to enroll
in a clinical trial of this procedure, I found that the number had been
disconnected. What's going on?
PMID- 9552198
TI - I have found vaginal estrogen cream to be very effective for vaginal dryness but
am concerned about the long-term effects of using it. Are there any other
treatments that work well for this?
PMID- 9552221
TI - Antiinflammatory effects of enterically coated amoxicillin-clavulanic acid in
active ulcerative colitis.
AB - The inflammatory activity of colonic mucosal lesions may be stimulated by
intraluminal bacteria. Our aim was to investigate whether administration of broad
spectrum antibiotics decreases inflammatory activity in ulcerative colitis. To
this end, we performed a randomized, 5-day study with either oral enterically
coated amoxicillin-clavulanic acid (1 g + 250 mg, t.i.d.); i.v.
methylprednisolone (40 mg/day) and oral placebo (t.i.d.); or both i.v.
methylprednisolone and oral amoxicillin-clavulanic acid as above, in 30 patients
with clinically active ulcerative colitis. Before and after 5 days of treatment,
intestinal inflammation was assessed by the quantification of mucosal release of
eicosanoids and interleukin-8 by rectal dialysis in each patient. Breath H2
excretion after oral lactulose was determined as an index of metabolic activity
of colonic flora. The total release of (IL-8) interleukin-8 and eicosanoids
significantly decreased in patients treated with antibiotic or steroids and
antibiotic. Antibiotic treatment, but not steroids, markedly inhibited breath H2
excretion. In conclusion, short-term treatment with enteric-coated amoxicillin
clavulanic acid decreases the intraluminal release of IL-8 and other inflammatory
mediators.
PMID- 9552222
TI - Quality-of-life factors in adolescent inflammatory bowel disease.
AB - Little is known about the specific psychosocial factors that influence quality of
life in adolescents with newly diagnosed inflammatory bowel disease (IBD). We
adapted a model by Garrett and Drossman to assess adolescent adjustment to recent
onset IBD. Thirty adolescent-parent pairs completed a set of standardized
questionnaires. The inclusion criteria were adolescents 12-18 years of age with
Crohn's disease or ulcerative colitis of < 5 years' duration. Adolescents' health
related quality-of-life scores significantly correlated with satisfaction and
degree of closeness with their social support members, such as parents. An
unexpected finding was that the adolescents included more extended family than
peers in their social support networks. Also of note was that parental coping
styles rather than adolescent coping styles significantly correlated with
adolescents' quality-of-life health scores. Severity of illness did not correlate
with adolescent quality-of-life health scores. There was significant agreement
between adolescent and parental quality-of-life health scores and stressful event
ratings. Adolescents with recent-onset IBD rely more on family members than their
peers for emotional support, and they depend more on their parents' coping skills
than their own. These findings may indicate lags in normal adolescent
development. Adolescents and parents do communicate and share concerns with each
other. Support programs for adolescents with IBD should reinforce existing coping
skills and parent-adolescent communication while promoting normative development.
PMID- 9552223
TI - Mucin secretion in inflammatory bowel disease: comparison of a macrophage-derived
mucin secretagogue (MMS-68) to conventional secretagogues.
AB - We have described a novel macrophage-derived mucin secretagogue (MMS-68) that
mediates mucin secretion in colon cancer cell lines and explants of normal and
inflammatory bowel disease (IBD) mucosa. We compared MMS-68 induced mucin release
with other known intestinal mucin secretagogues in normal colon explants and in
the HT-29 colon cancer cell line, and to study the effects of MMS-68 on mucin
release from inflamed and uninflamed ulcerative colitis (UC) and Crohn's disease
(CD) mucosa. In normal colonic explants and HT-29 cells, each of the
secretagogues including, MMS-68-induced mucin release two- to fivefold more than
culture medium alone. In HT-29 cells, MMS-68 plus leukotriene C4 (LTC4) induced a
50% increase in mucin release over either secretagogue alone, and MMS-68 plus
platelet-activating factor (PAF) markedly enhanced mucin release by eightfold
over either secretagogue. In colonic explants from patients with UC and CD, the
mucin release in response to MMS-68 was similar to that of normal colonic
explants. Likewise, in isolated epithelial cells from CD and UC (whether involved
or uninvolved), MMS-68-induced release was similar to that of epithelial cells
isolated from normal colonic mucosa. The number of MMS-68-producing macrophages
was lower in uninflamed UC mucosa compared with inflamed UC mucosa and CD mucosa.
The mucin secretagogue activity of MMS-68 is comparable to that of other known
secretagogues, and PAF can have a synergistic effect on this activity. Whole
tissue explants and isolated colonic epithelial cells from patients with IBD
respond at least as well as their normal counterparts to MMS-68. MMS-68 may play
a role in mucin secretion in normal and inflamed colonic tissue.
PMID- 9552224
TI - The presence of anti-neutrophil antibodies reflects clinical and genetic
heterogeneity within inflammatory bowel disease.
AB - A detailed investigation of the relationship between anti-neutrophil cytoplasmic
antibodies (ANCA) status, HLA genotype, and clinical patterns of inflammatory
bowel disease was carried out, involving 236 European patients resident in the
United Kingdom [120 had ulcerative colitis (UC), 116 had Crohn's disease (CD)].
ANCA status was determined on coded plasma samples in Los Angeles using a two
stage assay [fixed neutrophil enzyme-linked immunosorbent assay (ELISA) and
indirect immunofluorescence], and HLA genotyping was carried out by polymerase
chain reaction. The results provide evidence that ANCA reflect clinical and
genetic heterogeneity within the inflammatory bowel diseases. In the UC patients,
78.3% were ANCA positive [64.2 perinuclear (pANCA)], but only 46.5% CD patients
were ANCA positive (19.3% pANCA). Furthermore, mean ELISA binding was
significantly lower in CD (14.5% +/- 18.8% versus 40.5% +/- 41.0% in UC, p = 2.31
x 10(-9)). Only 15 CD samples, all from patients with colonic disease, displayed
ELISA > 20%; and the six CD patients with highest ELISA binding had clinical
features very similar to ulcerative colitis. Moreover, in UC, significant
relationships between ANCA status and genotype were noted. Thus, 92.7% of
patients with the DR3 DQ2 TNF2 haplotype were ANCA positive [p = 0.03 versus DR3
DQ2 TNF2-negative patients (73.9%)]. ELISA binding was increased in DR3 DQ2 TNF2
positive patients (56.0 versus 35.7%, p = 0.02). In this population of UC, ANCA
was not associated with DR2, DR4, or clinical pattern. These data emphasize the
many factors that need to be considered in genetic marker studies in inflammatory
bowel disease. Extensive disease heterogeneity, ethnicity, and methodological
differences in ANCA detection are all pertinent.
PMID- 9552225
TI - Severe knee pain as the single symptom of CMV infection in acute ulcerative
colitis treated with cyclosporine.
AB - We describe a case of systemic cytomegalovirus (CMV) infection in an ulcerative
colitis patient admitted to the hospital for an acute flare-up of his colitis. He
was treated with combination immunosuppressive therapy including i.v.
cyclosporine and corticosteroids and PO azathioprine. Severe bilateral stabbing
knee pain was the only manifestation of CMV disease, which quickly responded to
adequate antiviral therapy.
PMID- 9552226
TI - The role of the fecal stream in Crohn's disease: an historical and analytic
review.
AB - Since 1939, a series of clinical reports and laboratory investigations have
suggested that the intestinal fecal stream may play a significant part in the
pathogenesis of Crohn's disease (CD). The beneficial effect of exclusion of the
stream by ileostomy was followed by improvement in patients with CD of the ileum
and colon despite little change in the histopathology of the excluded loop, even
to the point of allowing restoration of intestinal continuity in some patients.
End ileostomy lowers the risk of recurrence of CD compared with anastomotic
operations. Ileostomy effluent can reactivate the clinical activity of quiescent
bypassed bowel and some of its biochemical processes, and may be related to an
ultrafilterable constituent > 5 microns. Experimental models of inflammatory
bowel disorders in immunologically altered rodents (transgenic, knockout, or
spontaneous) require the presence of normal luminal bacteria, especially of the
Bacteroides species, and respond to antibiotic (metronidazole) therapy. Thus,
many but not all of the well-recognized clinical features of CD are compatible
with a pathogenetic role of the fecal stream. Although difficult to quantitate,
this concept opens the way to a variety of testable research lines, and allows
some speculation regarding its clinical implications.
PMID- 9552227
TI - Economic evaluation: an ethical imperative?
PMID- 9552228
TI - Nutritional therapy in Crohn's disease.
AB - The value of nutritional support in the prevention and treatment of malnutrition
in Crohn's disease is undisputed but its role in primary therapy continues to be
debated. Controlled trials have demonstrated that enteral nutrition induces
remission rates comparable to that of corticosteroid therapy in Crohn's disease
and remains the treatment of choice for specific subgroups such as children with
signs of growth impairment and patients with intolerable steroid-induced side
effects. The mechanism by which an enteral diet induces remission in Crohn's
disease is unclear. Bowel rest, reduced antigenic load, nutritional effects, the
provision of trophic amino acids, modification of gut flora, intestinal
permeability, or fecal pH have been proposed. Equally, the fat profile of the
feed may reduce pro-inflammatory ecosanoid synthesis and thus modify disease
activity. Maintaining long-term remission remains a challenge in the management
of this disease. Cyclic administration of enteral diets, maintenance drug
therapy, fat manipulated formulas, or fish oil therapy may be strategies to
prolong diet-induced remission. In the future, nutrient derivatives that play a
role in the protective processes of the intestinal mucosa may have application in
nutritional therapy in Crohn's disease.
PMID- 9552229
TI - The central role of chemokines (chemotactic cytokines) in the immunopathogenesis
of ulcerative colitis and Crohn's disease.
AB - The final composition of leukocytes present in a site of inflammation in response
to chemokine stimulation and activation may depend on both the nature of the
secreted chemokines as well as the relative expression of the multitude of
specific chemokine cell surface receptors on many different cell types. Because
related receptors with different affinities and cross-reactive binding
capabilities are present on each type of leukocyte, relative differences in
receptor distribution and receptor affinity for specific chemokines may
significantly influence which cells are ultimately attracted to and activated by
each individual chemokine. Production of IL-8, MCP-1, and ENA-78 by endothelial
cells, LPMNC, and epithelial cells in IBD could establish a chemotactic gradient
capable of influencing the increased migration of monocytes/macrophages,
granulocytes, and lymphocytes from the blood stream through the endothelium into
both the mucosa and submucosa during chronic IBD. The ability of chemokines to
induce chemotaxis, leukocyte activation, granule exocytosis, increased production
of metalloenzymes, and up-regulation of respiratory burst activity indicates that
there may be a variety of different mechanisms by which chemokines could markedly
increase chronic inflammation and chronic intestinal tissue destruction in IBD.
PMID- 9552230
TI - Treatment of erythema nodosum, aphthous stomatitis, and pyoderma gangrenosum in
patients with IBD.
PMID- 9552231
TI - How do I treat erythema nodosum, aphthous ulcerations, and pyoderma gangrenosum?
PMID- 9552232
TI - Treatment of pyoderma gangrenosum, erythema nodosum, and aphthous ulcerations.
PMID- 9552233
TI - Treatment of extraintestinal manifestations of inflammatory bowel disease.
PMID- 9552267
TI - Sexual harassment at work. Introduction.
AB - This article introduces the special section on sexual harassment at work. It
discusses the importance of sexual harassment as a continuing, chronic
occupational health psychology problem to which the public health and preventive
medicine notions of prevention may be applied. The article discusses the dilemmas
in conducting and reviewing research on harassment, briefly examining some
alternative methods of inquiry. The three articles in this section are introduced
and the contrasting legal views of the problems in Europe and the United States
are addressed. The preventive management of sexual harassment is suggested.
PMID- 9552268
TI - Personal and organizational predictors of workplace sexual harassment of women by
men.
AB - The authors investigated the predictors of workplace sexual harassment in 278
male university faculty and staff (M age = 45 years). Workplace variables
(perceptions of organizational sanctions against harassment and perceptions of a
sexualized workplace) and personal variables (adversarial sexual beliefs, sexual
harassment beliefs, perspective taking, and self-esteem) were studied as
predictors of sexualized and gender harassment. Social desirability was
controlled. Both organizational variables and beliefs about sexual harassment
predicted gender harassment and sexualized harassment. Perspective taking,
adversarial sexual beliefs, and sexual harassment beliefs moderated the effects
of perceived organizational sanctions against harassment on sexualized
harassment. Findings are discussed as they relate to organizational efforts to
reduce or prevent sexual harassment.
PMID- 9552269
TI - Stressors and adverse outcomes for female construction workers.
AB - The authors examined the impact of a number of job stressors, including sexual
harassment and gender-based discrimination, on female construction workers' level
of job satisfaction and psychological and physical health. Results from a
telephone survey with 211 female laborers indicated that having responsibility
for others' safety and having support from supervisors and male coworkers was
related to greater job satisfaction. Increased reported psychological symptoms
were also related to increased responsibility, as well as skill underutilization,
experiencing sexual harassment and gender-based discrimination from supervisors
and coworkers, and having to overcompensate at work. Perceptions of
overcompensation at work and job uncertainty were positively associated with self
reports of insomnia. Finally, sexual harassment and gender discrimination were
positively related to reports of increased nausea and headaches.
PMID- 9552270
TI - Gender harassment, job satisfaction, and distress among employed white and
minority women.
AB - This study tested the hypotheses that gender harassment is related to decreased
job satisfaction and increased distress, and that White and minority women differ
in their responses to it, in a sample of 385 women office workers. Over 70%
reported exposure to gender harassment at work. As predicted, frequency of
harassment was negatively correlated with job satisfaction and positively
associated with an index of distress, assessed by self-reported somatic
complaints, the Center for Epidemiological Studies Depression Scale (L. S.
Radloff, 1997), and the reported use of alcohol for palliative coping. Minority
status was unrelated to frequency of reported harassment or to responses to it.
The tendency to focus on negative aspects of self and environment (negative
affectivity) was statistically controlled. Findings indicate that gender
harassment is a commonplace workplace stressor that warrants serious attention.
PMID- 9552271
TI - Gender, employment, and retirement quality: a life course approach to the
differential experiences of men and women.
AB - Using a life course perspective in integrating 2 theories of retirement
satisfaction--role theory and continuity theory--this study draws on a sample of
retired men (n = 244) and women (n = 214), ages 50-72, to investigate factors
contributing to the quality of their retirement experience. Overall, we find that
men report greater retirement satisfaction than women, although the difference is
small. For women, increased retirement quality is associated with good health, a
continuous career (fewer years spent in part-time employment), an early
retirement (though not earlier than anticipated), and a good postretirement
income. For men, the key correlates with retirement quality are good health, an
enjoyable preretirement job, low work-role salience, substantial preretirement
planning, and retiring for internally motivated reasons (e.g., to do other
things). These results underscore the importance of a life course focus on
gendered pathways to and through life transitions such as retirement.
PMID- 9552272
TI - Temporal architecture of violent incidents.
AB - Five hundred five reports of violent incidents in British pubs and bars were
studied by using logical pathway modeling to provide information on the processes
underlying work-related violence. Logical pathway modeling is innovative in
examining and mapping sequences in real incidents at a population level. The data
reveal the most common pathway to be misbehavior by customers, intervention by
staff (before any physically violent act), physical attack on staff, and injury
to staff. The data also highlight the likelihood of further action after
assailants have exited and identify stages in incidents at which most staff and
customer injuries and damage to property occur. Results assist in the design of
strategies to reduce the risk from future violence, particularly by training
staff to recognize and to handle potentially violent situations and to maintain
vigilance and security following problem incidents.
PMID- 9552273
TI - An exploration into occupational stress experienced by HIV health care
professionals who work within genitourinary medicine settings.
AB - The present study investigates the occupational stress of health care workers
involved with HIV care in genitourinary medicine (GUM) outpatient departments.
Sixteen nursing and 14 medical staff completed the P. Gray-Toft and J. G.
Anderson (1981) occupational stress inventory. This assesses 7 potential sources
of stress (death and dying, uncertainty regarding treatment, inadequate
preparation, lack of support, conflict with others, conflict with physicians, and
workload). The mean scores obtained revealed a preponderance of low-stress scores
for both medical and nursing staff. Analyses of variance and covariance further
demonstrated that, in general, levels of stress did not differ within or between
the occupational groups. However, sources and characteristics of stress were
different between nurses and doctors. In this group of health care professionals,
their work with HIV-positive patients within the GUM outpatient setting may be
instrumental in limiting levels of stress.
PMID- 9552274
TI - Creating healthier workplaces: The American Psychological Association/National
Institute of Occupational Safety and Health cooperative agreement. Introduction
and historical overview.
AB - This article introduces the special section on the American Psychological
Association/National Institute for Occupational Safety and Health (APA/NIOSH)
collaboration. The section includes an overview statement of National Institute
for Occupational Safety and Health research by Linda Rosenstock and 5
competitively peer-reviewed articles submitted to the Journal of Occupational
Health Psychology following their presentation in an earlier form at the 3rd
APA/NIOSH conference in September 1995. This article provides a brief history of
the APA/NIOSH collaboration forged at the turn of this decade.
PMID- 9552275
TI - Work organization research at the National Institute for Occupational Safety and
Health.
AB - For 25 years, the National Institute for Occupational Safety and Health (NIOSH)
has conducted and sponsored laboratory, field, and epidemiological studies that
have helped define the role of work organization factors in occupational safety
and health. Research has focused on the health effects of specific job
conditions, occupational stressors in specific occupations, occupational
difference in the incidence of stressors and stress-related disorders, and
intervention strategies. NIOSH and the American Psychological Association have
formalized the concept of occupational health psychology and developed a
postdoctoral training program. The National Occupational Research Agenda
recognizes organization of work as one of 21 national occupational safety and
health research priority areas. Future research should focus on industries,
occupations, and populations at special risk; the impact of work organization on
overall health; the identification of healthy organization characteristics; and
the development of intervention strategies.
PMID- 9552276
TI - Employee reactions to ergonomic job design: the moderating effects of health
locus of control and self-efficacy.
AB - A field survey of 180 municipal government office employees (82% women, 21-75
years old) investigated the potential moderating effects of internal health locus
of control (HLOC) and self-efficacy on employees' reactions to ergonomic job
design. Internal HLOC moderated the associations between ergonomic job design and
somatic complaints and turnover intentions, and, to a lesser extent, job
satisfaction. Self-efficacy moderated the associations between job design and job
satisfaction, somatic complaints, and, to a lesser extent, persistent pain.
Employees with low self-efficacy or low internal HLOC were influenced more by
their physical job conditions than those with high self-efficacy or high internal
HLOC. Implications for the ergonomic design of offices are discussed.
PMID- 9552277
TI - Evaluation of a worksite injury and illness prevention program: do the effects of
the REACH OUT training program reach the employees?
AB - In this article the authors report the findings of a 2-year study evaluating the
effectiveness of REACH OUT, a train-the-trainer program developed to assist small
businesses comply with California legislation, Senate Bill 198 (1989), requiring
employees to implement a worksite Injury and Illness Prevention Program. Data
from a case study sample of 8 companies, drawn from 151 Southern California small
businesses participating in the larger study, are reported. Diagnostic walk
throughs were performed, and employee surveys collected at the case study
companies approximately 2 months before the treatment group received the
intervention and again 1 year later. Results indicate that greater corporate
compliance led to employees' perceptions of increased health and safety meetings
and training sessions, which led to greater employee health and safety knowledge
and improved employee health outcomes.
PMID- 9552278
TI - Relationships of occupational hazards with burnout: an assessment of measures and
models.
AB - A survey of aircraft maintenance technicians with the Canadian Forces (N = 157)
found support for a model of burnout and occupational risk assessment. The model
depicted employees' assessment of occupational risk as a function of the
prevalence and lethalness of workplace hazards, as well as of the amount of
control employees experience over their interactions with these hazards. A
confirmatory factor analysis, in which LISREL analysis was used, supported an
integrated model of risk perception and burnout. In this model, the employee's
sense of control in managing occupational hazards was pivotal in both the
experience of exhaustion and being at risk at work. Safety training contributed
to perceived control and technicians' sense of effectiveness at work. The
extension of the burnout construct beyond the human service domain was considered
by using the Maslach Burnout Inventory-General Survey.
PMID- 9552279
TI - The 120-S minute: using analysis of work activity to prevent psychological
distress among elementary school teachers.
AB - Primary school teachers in Quebec suffer psychological distress, as shown by the
Quebec Health Survey (M. Gervais, 1993; Sante Quebec, 1995). The authors applied
and extended the French model (F. Guerin, A. Laville, F. Daniellou, J.
Duraffourg, & A. Kerguelen, 1991) of analysis of work activity to observing
classroom teaching (14 women in 10 classrooms for a total of 48 hr 24 min) to
identify stressful elements. The authors observed a rapid sequence of actions,
eye fixations of short duration, little physical or mental relaxation, multiple
simultaneous activities, and uncomfortable temperature and humidity levels.
Teachers use many strategies to teach, to create a learning environment, and to
maintain attention in classrooms under adverse conditions. Examination of these
strategies led to recommendations to improve relations between the teachers and
their supervisors and to make the classroom an easier place to teach.
PMID- 9552280
TI - Violence at work: personal and organizational outcomes.
AB - To date, little empirical research has examined the personal and organizational
outcomes associated with exposure to workplace violence. On the basis of data
from 194 bank tellers, the authors evaluated, and supported, a model suggesting
that fear of future violence mediates the relationships between exposure to
workplace violence and negative outcomes. Specifically, exposure to workplace
violence predicted fear of future violence that, in turn, predicted psychological
well-being, somatic symptoms, and intent to leave the organization. These effects
emerged after controlling for self-report bias. The mediating role of fear was
supported, and implications for future research and practice are discussed.
PMID- 9552281
TI - Responses to an in-basket activity: the role of work stress, behavioral control,
and informational control.
AB - This study was undertaken to examine the main and interactive effects of work
stress and work control on levels of adjustment. Work stress, behavioral control,
and informational control were manipulated in an experimental setting in which
participants (N = 192) completed an in-basket activity. Although minimal support
was found for the main and interactive effects of objective work stress,
behavioral control, and informational control on adjustment, analyses involving
the subjective measures of these variables revealed strong support for the
proposal that work stress, behavioral control, and informational control would
exert main effects on adjustment. There was also evidence that subjective levels
of behavioral control buffered the negative effects of subjective work stress on
positive mood, subjective task performance, and task satisfaction.
PMID- 9552282
TI - Child-care satisfaction: linkages to work attitudes, interrole conflict, and
maternal separation anxiety.
AB - Analysis of a 20-item measure of child-care satisfaction (CCS) revealed 3
interpretable factors: Caregiver Communication, Dependability, and Attentiveness.
These CCS factors were used, along with employer sensitivity to child-care needs
and spousal support, in hierarchical multiple regressions to predict various
measures of work attitudes and role strain. Replicated across 2 samples of
employed women, the CCS factors demonstrated differential patterns of
relationships in which Caregiver Attentiveness was associated with lower
professional-self role conflict and higher levels of affective organizational
commitment and job satisfaction, whereas Caregiver Communication was associated
with lower levels of both professional-parent conflict and maternal separation
anxiety. These findings support the position that CCS is central to the
functioning of employed mothers in both work and family domains.
PMID- 9552283
TI - The changing workforce, job stress, and psychological distress.
AB - The change in the United States from a manufacturing economy to a service economy
has important implications for theoretical models of the relationships between
job characteristics and workers' psychological distress. A sample of 600 men and
women employed full-time were recruited to test 2 theoretical models. The job
demand-control model posits that jobs that are both high in job demands and low
in decision latitude are associated with greater psychological distress. The job
demand-service model posits that jobs that are high in job demands and low in
service to others are associated with greater psychological distress. Results
show that the job demand-control model is a significant predictor of
psychological distress among employees in the manufacturing industry, whereas the
job demand-service model is a significant predictor of psychological distress
among employees in the services industries.
PMID- 9552284
TI - Worker social identity and health-related costs for organizations: a comparative
study between ethnic groups.
AB - Health implications of value conflicts at work and 3 coping resources (self
esteem, collective esteem, and social support at work) were examined for 38
African American and 64 European American workers. Comparisons indicated that the
African American participants reported higher levels of value conflicts and
collective esteem, but lower levels of social support. They also reported more
health actions (i.e., absenteeism and doctor visits) likely to create
organizational costs. Value conflicts and the 3 coping resources predicted health
related behavior. Collective esteem predicted health only for African American
workers, though social support was a significant predictor only for European
American workers. The study findings are integrated with existing literature on
social identity at work, social support, and work influences on health.
PMID- 9552285
TI - Do resources bolster coping and does coping buffer stress? An organizational
study with longitudinal aspect and control for negative affectivity.
AB - Psychiatric workers facing redeployment completed questionnaire measures of
stressors, resources (locus of control and perceived social support), coping,
well-being, and negative affectivity, at baseline (N = 109) and 1 year later
(loss of 7 participants). Regression analyses of the baseline data suggested that
as stressors increased, so did avoidance coping, but less so for those high in
internality or perceived social support. Problem-focused coping was bolstered by
internality and emotion-focused coping by perceived social support. Other
regression analyses, with a longitudinal aspect, suggested that stressors had a
deleterious effect on well-being. Problem- and emotion-focused coping had
beneficial effects, whereas avoidance coping had a (delayed) deleterious effect.
These effects of coping were predominantly main and not buffering effects.
PMID- 9552286
TI - A cognitive-affective approach to understanding individual differences in stress
propensity and resultant strain.
AB - The cognitive-affective model of the stress response provides a framework for
making inferences about individual differences in stress propensity and levels of
resultant strain. A new cognitive-affective conceptualization provides a means of
analyzing mediating processes affecting psychological and physiological reactions
to stressors. The model also facilitates examination and understanding of a
latent cognitive-affective stress propensity construct that moderates the
relationships between stressors and strain. Propositions are presented with the
intention of stimulating further research.
PMID- 9552287
TI - Noise, physiology, and human performance: the potential role of effort.
AB - Thirty-three male college students ages 18-31 were assigned to 2 levels of noise
exposure and worked at 2 levels of effort while calculating the Norinder
arithmetic task (M. Frankenhaeuser & U. Lundberg, 1977). As hypothesized, noise
increased heart rate, norepinephrine, and cortisol only under high effort. Blood
pressure did not change significantly. Reaction time slowed significantly under
noise only when effort was low. Both self-report and epinephrine level confirmed
the effort manipulation and showed that it was orthogonal to noise levels. These
data support the adaptive costs hypothesis and have practical implications for
industry. These implications include trade-offs of productivity and worker
health, which may be dependent on management style.
PMID- 9552288
TI - Stressors, locus of control, and social support as consequences of affective
psychological well-being.
AB - Tests of the influence of affective psychological well-being on stressors, locus
of control, and social support in a 1-month follow-up study of 210 male and 34
female British accountants is reported. There was a marginally significant
association between the level of psychological symptoms and subsequent reports of
intensity of quantitative workload stressors. A significant interaction between
psychological symptoms and a measure of depression-enthusiasm was found to
predict subsequent locus of control. The results indicate a differential pattern
of associations between aspects of affective well-being and subsequent reports of
social support. The results also indicate that initially more frequent stressors
are associated with subsequently less intense stressors of the same type. The
findings highlight the dynamic and reciprocal nature of the occupational stress
process.
PMID- 9552289
TI - Hostility, social support, and perceptions of work.
AB - The aim of this study was to determine whether hostility and perceived
availability of social support are related to perceptions of the work
environment. The W.W. Cook and D.M. Medley (1954) Hostility (Ho) scale; the
Interpersonal Support Evaluation List (S. Cohen, R. Mermelstein, T. Kamarck, & H.
Hoberman, 1985); and measures of collegiality, time pressure, and job
dissatisfaction were completed by 204 attorneys (159 men and 45 women). After
controlling for age, gender, and other job characteristics, high Ho scores were
related to lower perceived supportive collegiality at work. Low perceived
availability of social support was related to greater job dissatisfaction.
Neither hostility nor social support was associated with perceptions of time
pressure at work. These findings suggest that hostility and availability of
social support may be an important pathway linking certain job characteristics to
cardiovascular disease and other illnesses.
PMID- 9552290
TI - Job control and job strain: a test of three models.
AB - The relationship between job control and job strain is examined. Three models of
that relationship provide a framework for the study hypotheses: (H1) Control is
inversely related to job strain, (H2) job demands interact with job control such
that job strain will be highest when job demands are high and job control is low,
and (H3) strain increases as the discrepancy between actual and desired levels of
job control increases. Study participants (N = 316) were health care workers in 2
hospitals in the northeastern United States. Objective measures of job control
and job demands were obtained through supervisor evaluations of incumbents' job
characteristics, and perceptual measures were obtained through incumbents' self
reports. Results provide support for Hypotheses 1 and 3; little support was found
for an interaction between job control and job demands.
PMID- 9552292
TI - Balancing elder care responsibilities and work: two empirical studies.
AB - It was hypothesized that workers with elder care responsibilities, compared with
noncaregiving workers, would be more likely to suffer physical symptoms of stress
and to be absent more days. In Study 1, 67 (32 noncaregivers, 35 caregivers)
employees of a financial institution were interviewed. In Study 2, 169 (118
noncaregivers, 51 caregivers) employees of a health care institution completed a
questionnaire. In Study 1, caregivers were absent more days than noncaregivers,
and caregiver status was related to the incidence of weight loss or gain,
drowsiness, and inability to sleep. In Study 2, caregiver status was related to
the incidence of weight loss or gain, drowsiness, inability to sleep, frequent
headaches, and nervousness. Caregivers were not significantly different from
noncaregivers in absenteeism. Results indicate that caregivers' responsibilities
may negatively affect work performance.
PMID- 9552291
TI - The role of pleasantness and activation-based well-being in performance
prediction.
AB - This study examined the relationships between 2 measures of psychological well
being and work performance using the circumplex model of emotion as the
theoretical framework. Although the pleasantness-based measure of well-being
predicted subsequent work performance, the results failed to establish a
relationship between the activation-based measure of well-being and work
performance. Future directions and implications of the findings regarding the
further refinement of the role of psychological well-being in performance
prediction are introduced.
PMID- 9552293
TI - Measuring psychosocial work quality and health: development of health care
measures of measurement.
AB - Demands on workload and work efficiency have increased because of ongoing global
changes in health care organizations. Assessing and evaluating effects of changes
on organizational and individual well-being require valid and reliable methods.
Questionnaires from 3 large health care studies were used to develop instruments
for work quality and health. Variable fields of work quality, health and well
being, and modifying factors were factor analyzed with replicated structures in
new samples, including 6 factors of work quality, 5 health factors, and 2
modifying factors. All except 2 factors had high internal consistency (Cronbach's
alpha = .69-.84) and low factor intercorrelations within areas. Social climate
(but not individual resources) had, according to our model, a modifying effect on
the work-health interaction.
PMID- 9552294
TI - Dependency and self-criticism as predictors of depression in young doctors.
AB - Brief measures of depression and of dependency and self-criticism, personality
factors believed to convey vulnerability to depression, were administered to 318
medical students. Depression was subsequently measured 2 years later (in the
highly stressful 1st postgraduate year) and 10 years later when careers were
established. When initial symptom levels and concurrent workload were controlled,
dependency and, more particularly, self-criticism were significant predictors of
depression for male doctors in the 1st postgraduate year. For female doctors,
self-criticism was the only significant predictor. Ten years later, the
predictive effects for male doctors were similar, but rather weaker, whereas none
of the variables predicted depression in female doctors. Implications for
preventive interventions are discussed.
PMID- 9552295
TI - The effectiveness and practicality of occupational stress management
interventions: a survey of subject matter expert opinions.
AB - Stress management (SM) subject matter experts (SMEs) evaluated 6 widely used
occupational SM interventions (relaxation, physical fitness, cognitive
restructuring, meditation, assertiveness training, and stress inoculation) on the
basis of 10 practicality criteria and 7 effectiveness objectives. Relaxation was
evaluated overall as the most practical intervention, while meditation and stress
inoculation were judged as the least practical. Physical fitness was chosen to be
the most effective intervention, while both meditation and assertiveness training
were rated overall as the least effective. The findings also revealed that the
SMEs considered history of success and duration of effect, rather than "relevance
to program objectives," as the most important factors when selecting SM
interventions. Incongruence between effectiveness ratings and actual choices of
interventions are discussed.
PMID- 9552296
TI - Combined somatic and psychiatric care--effects on personnel treating drug addicts
with infectious diseases.
AB - Infectious disease care, psychiatric care of drug addicts, and social care were
combined in a ward for drug addicts with infectious diseases. The aim of this
study was to evaluate the effects on the personnel (n = 22). One ward with
infectious disease care of HIV and AIDS patients (n = 24) and another with
nonsomatic care of drug addicts (n = 18) were selected to make comparisons
possible. The questionnaire concerned psychosocial work environment and health.
The personnel at the new ward also participated in a semistructured interview.
The personnel at the special ward experienced a significantly higher degree of
emotional exhaustion and lack of ability to concentrate than the comparison
groups. They also reported a higher degree of lack of clarity, more job strain,
and more difficulties due to demands from patients. The combined care is probably
associated with heavier psychological burdens than other forms of care. In spite
of this, the personnel experienced their work as meaningful and mentally
stimulating.
PMID- 9552297
TI - Effects of work overload and burnout on cholesterol and triglycerides levels: the
moderating effects of emotional reactivity among male and female employees.
AB - The effects of objective and subjective overload, and of physical and emotional
burnout, on cholesterol and triglycerides levels were studied in a
quasiprospective design. The possible moderating effects of emotional reactivity
on these relationships were also investigated. The study's hypotheses were tested
separately for male and female employees. Time 1 (T1) data were collected from
665 healthy employees (30% women) while they were undergoing periodic health
examinations in a health-screening center. Time 2 (T2) measures of cholesterol
and triglycerides were collected 2 to 3 years after T1. The hypotheses were
tested by regressing each T2 criterion on its T1 level; the control variables of
age, obesity, diet, alcohol consumption, and smoking; and the other predictors.
For female employees, the T2-T1 changes in the serum lipids were positively
predicted by emotional burnout, as expected, but negatively predicted by physical
fatigue. For male employees, both types of T1 burnout were positive predictors of
the T2-T1 change in total cholesterol.
PMID- 9552298
TI - Work characteristics and employee well-being within a context of strategic
downsizing.
AB - Findings from this 4-year longitudinal study of strategic downsizing suggest that
introducing deliberate work organization and change management strategies can
combat the negative effects of reduced head count. Results showed that there was
no overall decrease in well-being from before to after downsizing for the 139
employees remaining in an organization, despite an increase in work demands. The
potential detrimental effect of demands appears to have been offset by
improvement in work characteristics arising from initiatives introduced as part
of the downsizing strategy. This interpretation is consistent with analyses at
the individual level, which showed that high demands were associated with poorer
well-being but that increases in control, clarity, and participation were
associated with improved well-being.
PMID- 9552299
TI - Responses to occupational hazards: exit and participation.
AB - The authors developed and tested a model linking subjective risk perceptions to
both turnover intentions and employees' willingness to participate in health and
safety programs. On the basis of data from 130 employees of a manufacturing firm,
the model was supported. Risk perceptions were predicted by employees' accident
history and perceptions of others' commitment to health and safety. In turn, risk
perceptions predicted both turnover intentions and willingness to participate.
These effects emerged after controlling for monomethod bias.
PMID- 9552300
TI - Factors that influence the use and perceptions of employee assistance programs at
six worksites.
AB - Employee assistance programs (EAPs) have gained significant importance in
contemporary worksites. This article uses data from 6 case studies to examine
several research questions regarding the relationship between worker demographic
(e.g., gender, job tenure, and marital status), substance use, and workplace
policies and the actual and potential use of the company EAP. Unlike in most of
the existing literature, the authors did not find that gender, marital status, or
job dissatisfaction are statistically related to actual or potential EAP use at
most worksites. However, job tenure and some substance use behaviors were related
to actual EAP use in a positive and statistically significant way. Another
important finding, underlying the credible integration of EAPs into worksite
culture, is the positive and robust relationship between employee trust and
confidence in the EAP and actual use. The results of our study both reinforce
some long-established principles in the EAP field and encourage further
consideration of other beliefs.
PMID- 9552301
TI - Objective measurement of occupational stress factors--an example with San
Francisco urban transit operators.
AB - Eighty-one observational work analyses were conducted to measure stressors
independently of worker appraisal in the San Francisco transit system. On the
basis of action regulation theory, stress factors were defined as hindrances for
task performance due to poor work organization or technological design. Stressors
included (a) work barriers, defined as obstacles that cause extra work or unsafe
behavior; (b) time pressure; (c) monotonous conditions; and (d) time binding,
defined as control over timing. Reliability, measured as interrater agreement,
ranged between 80 and 97%, with kappas of .46-.70. Validity analyses were done
with 71 transit operators who participated in the observations and 177 operators
who were assigned mean line-specific observational stressor measures. High odds
ratios (ORs) were found for barriers and psychosomatic complaints (OR = 3.8, p =
.00), time pressure and relaxation time needed after work (OR = 3.1, p = .05),
and barriers and smoking to cope (OR = 3.8, p = .02). Using observational data in
conjunction with self-report data can reduce confounding and improve
interpretability of stress and health studies.
PMID- 9552302
TI - Correspondence of supervisor and subordinate perspectives during major
organizational change.
AB - Staff members (N = 2,605) and supervisors (N = 55) of 39 administrative units in
2 healthcare organizations completed a survey measuring confidence in the
organization, engagement with their work, and occupational hazards. A
correlational analysis determined correspondence between the perspectives of
supervisors with those of staff reporting to them as their facilities adjusted to
major organizational changes. Supervisors' scores were significantly and
positively correlated with the corresponding scores of staff members on cynicism,
meaningfulness, acceptance of change, goals, hospital reputation, and health
risks. Regression analysis found that relationships were relatively domain
specific: Supervisor engagement with work was positively related to that of their
staff members, and supervisors evaluations of the organization were positively
related to those of their staff members. Supervisor assessment of occupational
hazards was related to all 3 areas of staff perception.
PMID- 9552303
TI - Pregnancy planning and the impact on work climate, psychological well-being, and
work effort in the military.
AB - This study examined the joint effects of demographics and pregnancy planning and
timing on work climate, psychological well-being, and work effort among 345
pregnant U.S. military women from the Army, Navy, Air Force, and Marines. Rank
predicted both pregnancy planning and career timing. Pregnancy planning was
positively associated with support from coworkers and supervisors and with
enhanced work effort and psychological well-being. Pregnancy timing was
positively associated with support from supervisors, reduced harassment, and
increased psychological well-being. Rank interacted with the planning and timing
measures. Junior officers and enlisted participants reported reduced command and
pregnancy support and increased harassment in conjunction with poorly timed
pregnancies.
PMID- 9552304
TI - Novel methods of microparticulate production: application to drug delivery.
AB - The purpose of this paper is to present two novel techniques, electrostatic
spraying and oscillating capillary nebulization, for the production of
microspheres of uniform reproducible particle size distribution. Cholesterol was
chosen as a model compound to show the utility of both procedures. The processes
for each method are described, illustrating their simplicity and absence of an
external detrimental phase. Scanning electron microscopy was used to assess
morphology while laser diffraction analysis was used to determine particle size.
Electrostatic spraying of cholesterol yielded particles of round shape, smooth
surface, and uniform distribution of particle size ranging between 10-30 microns
and 100-300 microns. Oscillating capillary nebulization of cholesterol molten at
170 degrees C produced microspheres with an average diameter ranging from 22
microns to 30 microns when gas back pressures controlling the vibration of the
capillary ranged from 60 to 90 psi. Electrostatic spraying and oscillating
capillary nebulization are one-step procedures that result in high production
yields. Both techniques are easy to set up and afford both production speed and
reproducibility. The absence of a detrimental external phase makes them
particularly appealing for the microencapsulation of proteins and polynucleotides
in polymers with low melting temperatures. The feasibility of production of
cholesterol microspheres can be extrapolated to the production of excipient-free
microspheres of steroids.
PMID- 9552305
TI - Solubility enhancement of a bisnaphthalimide tumoricidal agent, DMP 840, through
complexation.
AB - The purpose of this research was to enhance the aqueous solubility of DMP 840 by
complexation with water-soluble and nontoxic agents, and to understand the nature
of the interactions involved in complex formation using nuclear magnetic
resonance (1H-NMR). The solubility of DMP 840 in water, saline, acetate buffers,
and cosolvent mixtures was determined by high-performance liquid chromatography,
and the effect of nicotinamide and pyridoxine concentrations on the solubility of
DMP 840 was examined by the phase solubility method. 1H-NMR spectra were acquired
in deuterated acetate buffer at 400 MHz on a Varian Unity-400 spectrometer. The
aqueous solubility of DMP 840 was sensitive to the presence of chloride and
acetate anions in solution, and did not improve in the presence of cosolvents.
The use of the nontoxic and water-soluble complex-forming agents nicotinamide and
pyridoxine, however, resulted in a linear increase in the aqueous solubility of
DMP 840 with both ligands. The solubilization appears to be due to formation of
1:1 complexes between DMP 840 and the bioorganic ligands. The complexation
constants were 15.57 M-1 for the DMP 840:nicotinamide complex and 13.36 M-1 for
the DMP 840:pyridoxine complex. The NMR results indicate that the interaction is
a result of vertical or plane-to-plane stacking and the complexation constants
were in agreement with that obtained by phase solubility. The results suggest
that the aqueous solubility of a poorly water soluble drug substance such as DMP
840 can be significantly enhanced by its complexation with water-soluble and
nontoxic agents.
PMID- 9552306
TI - Differences in the mechanical strength of dried microcrystalline cellulose
pellets are not due to significant changes in the degree of hydrogen bonding.
AB - The mechanical strengths of oven-dried pellets of microcrystalline cellulose,
MCC, prepared by extruder/marumerizer technology are weaker when ethanol/water
mixtures are used as granulating solutions than when granulated with water.
Previously, the difference in the strengths of these pellet systems were thought
to be due to changes in the degree of hydrogen bonding within these systems. This
work reports the results of studies using magic-angle-spin nuclear magnetic
resonance (NMR), x-ray diffraction and degree of crystallinity, and oxygen
combustion calorimetry studies of various MCC systems developed to test this
hypothesis. Carbon-13 cross polarization magic-angle spin NMR studies of MCC
pellets with and without 10% theophylline showed no differences in the spectra of
these systems. X-ray diffraction studies and heats of combustion data obtained
from oxygen combustion calorimetry of oven-dried pellets of MCC granulated with
either water, deuterated water, or a 70/30 ethanol/water mixture were found to
have no significant differences in their diffraction patterns, degree of
crystallinity, or internal energies. None of these results provide any evidence
that a significant net change in the degree of hydrogen bonding is responsible
for the observed changes in the strengths of these systems. It is hypothesized
that the strength of these dried pellets may, in part, be due to the conversion
of some of the intramolecular hydrogen bonded amorphous fibrils at the surface of
the MCC particles to intermolecular hydrogen bonded fibrils with other MCC
particles.
PMID- 9552307
TI - Oramucosal delivery of LHRH: pharmacokinetic studies of controlled and enhanced
transmucosal permeation.
AB - Several transmucosal therapeutic systems (TmTs) were developed to study the
enhanced/controlled delivery of luteinizing hormone-releasing hormone (LHRH)
through oral mucosae for prolonged periods. TmTs is a track field-shaped bilayer
mucoadhesive device consisting of fast-release and sustained-release layers. In
vivo evaluations were performed in beagle dogs, and pharmacokinetic profiles were
monitored to characterize the transmucosal permeation kinetics of LHRH delivered
by the various TmTs formulations containing a stabilizer, cetylpyridinium
chloride, and a permeation enhancer, such as bile salts, to enhance the stability
and permeability of LHRH. The plasma LHRH concentrations were observed to reach
the plateau level within 30 min and were maintained for 2 hr following
application of TmTs, in contrast to a rapid elimination profile observed after IV
administration. Addition of 5% bile salt into the fast-release layer was observed
to produce an enhancement in the absorption rate, higher plateau plasma levels,
and greater systemic bioavailability. Addition of pH modifiers was noted to
affect the bile salt enhanced transmucosal delivery of LHRH. To prolong the
plasma LHRH level, several loading doses of LHRH were incorporated into the
sustained-release layer. The plasma levels were sustained and the area under the
curve (AUC) values were found to be linearly dependent upon the combined loading
doses of LHRH in the fast-release and sustained-release layers. Mucosal
irritation was also measured, using buccal mucosa, and results were observed to
be low and reversible for the single application. The results indicated that TmTs
is relatively safe and capable of achieving enhanced and controlled transmucosal
delivery of peptide drugs.
PMID- 9552308
TI - Comparison of a respiratory suspension aerosolized by an air-jet and an
ultrasonic nebulizer.
AB - In the absence of USP standards and performance monographs, this research sought
to determine if differences in the aerosolization mechanism (air-jet vs.
ultrasonic) affected droplet and insoluble particle deposition of a nebulized
model respiratory suspension. Five milliliters of a model suspension containing
0.1% w/v fluorescein (to estimate droplet deposition) and known quantities of 1,
3, and 6 microns latex spheres (representing insoluble drug particles) was
aerosolized from an air-jet and an ultrasonic nebulizer. Nebulized output was
collected in a modified Andersen impactor. Samples were analyzed
spectrophotometrically (490.5 nm) and by a Coulter Counter to estimate droplet
and sphere deposition, respectively. The distribution of droplets throughout the
modified impactor for both nebulizers suggested that both the air-jet and the
ultrasonic nebulizer produced droplets (0.4 to 10 microns in aerodynamic
diameter) large enough to incorporate 1, 3, and 6 microns insoluble spheres.
However, Coulter Counter analysis of the sphere distribution revealed that while
the air-jet nebulized output contained spheres of all sizes, this was not true
for the ultrasonic nebulizer. In the ultrasonic nebulizer, 99% of the spheres
(irrespective of size) were not aerosolized and were recovered from the nebulizer
reservoir at the aerosolization end point. The results highlight the importance
of evaluating performance of a respiratory suspension in combination with a
specific nebulizer. When conducting in vitro inertial deposition testing of a
respiratory suspension, it is inappropriate to assume that deposition trends of
droplets will predict the deposition of the insoluble dispersed phase.
PMID- 9552309
TI - The physical state of nafcillin sodium in frozen aqueous solutions and freeze
dried powders.
AB - The purpose of this study was to develop a better understanding of the physical
chemistry of freeze drying of lyotropic liquid crystals using nafcillin sodium as
a model solute. Solutions and freeze-dried powders of nafcillin sodium were
studied by polarized light microscopy, differential scanning calorimetry, x-ray
powder diffraction, and water vapor adsorption. Differential scanning calorimetry
thermograms of nafcillin sodium solutions contain a melting endotherm at
approximately -5.5 degrees C and, depending on the concentration and heating
rate, a crystallization exotherm immediately after this endotherm followed by the
melting endotherm of ice. When the sample is annealed at -4 degrees C, both the
endotherm and exotherm are eliminated, and a new endotherm appears at
approximately -1 degree C on the shoulder of the ice-melting endotherm. The data
are interpreted as melting of a liquid crystalline phase, followed by
crystallization. X-ray powder diffractograms of unannealed freeze-dried nafcillin
sodium are consistent with a lamellar liquid crystal. Diffractograms of annealed
freeze-dried nafcillin sodium indicate crystalline material which is a different
crystal form than the monohydrate starting material. Moisture adsorption
isotherms of the freeze-dried annealed (crystalline) and unannealed (liquid
crystalline) nafcillin sodium show different affinities for moisture compared to
the crystalline starting material. Solid-state stability data demonstrate that
the freeze-dried liquid crystalline form of nafcillin sodium is much less stable
than the freeze-dried crystal-line material. The literature recognizes two types
of solute behavior on freezing, where the solute either crystallizes from the
freeze concentrate or remains amorphous. Lyotropic liquid crystal formation
during freezing represents a separate category of freezing behavior, the physical
chemistry of which is worthy of further investigation.
PMID- 9552310
TI - Evaluation of PLGA microsphere size effect on myotoxicity using the isolated
rodent skeletal muscle model.
AB - The present work investigated the magnitude of microsphere-induced acute
myotoxicity and determined whether this myotoxicity is related to microsphere
size and/or reconstitution solvent. Using a high molecular weight poly(dl-lactide
co-glycolide) copolymer, the myotoxicity of two different size microsphere
formulations (3.6 microns and 19 microns) in normal saline or distilled water was
quantified using a previously validated isolated rat muscle system. Overall,
microspheres were found to be relatively nontoxic compared to known myotoxic
agents (e.g., phenytoin) and control muscles. The smaller microspheres were found
to be significantly more myotoxic than larger microspheres. Furthermore, the
myotoxicity was lower in large microspheres reconstituted with normal saline or
normal saline with 0.5% (w/v) carboxymethylcellulose (to prevent aggregation)
compared to those reconstituted with distilled water. Smaller microspheres were
found to be extremely difficult to inject, due to aggregation, which could not be
prevented by the addition of carboxymethylcellulose. This study suggests that
larger microspheres are less myotoxic than smaller microspheres.
PMID- 9552311
TI - Development of a transdermal patch of methadone: in vitro evaluation across
hairless mouse and human cadaver skin.
AB - A 3-day monolithic polyacrylate adhesive dispersion type delivery system
containing methadone was fabricated and in vitro permeation through hairless
mouse and human cadaver skins was conducted. The effect of skin permeation
enhancers was also investigated. Skin permeation rate across human cadaver skin
was found to be lower than that of hairless mouse. Skin permeation profiles
across both types of skins showed a membrane permeation controlled cumulative
amount permeated (Q) versus time (t) relationship. Skin permeation rate was found
to be dependent on both adhesive film thickness and loading dose of the drug in
the matrix. Effective skin permeation rate across the hairless mouse skin was
obtained from a patch with 1.5 mm thickness and 15% w/w loading dose. n
Decylmethyl sulfoxide and Azone were found to produce an effective skin
permeation rate of methadone through human cadaver skin at a 5% w/w
concentration. These initial studies demonstrated the feasibility of methadone
administration through intact skin from a transdermal patch.
PMID- 9552312
TI - In vitro release of betamethasone dipropionate from petrolatum-based ointments.
AB - The purpose of this research was to develop new in vitro methodology for
measuring release from petrolatum-based semisolids and to determine whether two
ointments, both of which contained betamethasone dipropionate, 0.05%, but with
different formulations, could be distinguished by release measurements. Several
receptor media were explored to optimize the procedure utilizing Franz-type
cells. Analysis was by HPLC. The release slope was 1.5 to 6 times greater from
the ointment than the "augmented" ointment (which had greater clinical potency).
Release was highest with a receptor consisting of a 5% solution of hexane in
acetonitrile. Even so, it was necessary to subject samples of receptor from the
augmented ointment to evaporation followed by reconstitution with a smaller
volume of mobile phase to bring corticosteroid concentrations up to quantifiable
levels. In another series of experiments, the HPLC mobile phase was used as the
receptor and a relatively large volume (100 microliters) was injected onto the
column. With the second approach, measured concentrations were lower but more
reproducible. Quantifiable levels of betamethasone dipropionate were obtained for
both formulations beginning from the first data point (at 1 hr), with
satisfactory linearity of plots of amount released per unit area of membrane
versus the square root of time. Using this methodology, it was possible to
distinguish the effect of formulation differences in two ointments containing the
same drug in the same concentration.
PMID- 9552313
TI - An investigation into the use of thermorheology and texture analysis in the
evaluation of W/O creams stabilized with a silicone emulsifier.
AB - The aim of the study was to evaluate a range of W/O semisolid emulsion systems
(creams) containing white soft paraffin (petrolatum) and a new type of nonionic
lipophilic silicone emulsifier (Abil EM 90) using a novel combination of
rheological tests. Emulsifier concentrations from 1.5% to 3.0% w/w were used with
two manufacturing procedures, cold (25 degrees C) and warm (70 degrees C)
emulsification, to determine whether and to what extent these variables alter the
structure and consistency of the creams. The techniques comprised linear
(continuous flow) and dynamic (oscillatory) rheometry at 25 degrees C, thermal
flow experiments (from 10 degrees to 90 degrees C and back to 10 degrees C), and
penetrometry studies. The differences in emulsifier concentration produced
effects on the rheological properties of the W/ O creams, although the
manufacturing process was much more influential. Cold emulsification led to
creams with higher viscosity, lower thixotropy, and better elastic properties.
The results of penetration tests on creams correlated with those of the
rheological studies. The flow properties of white soft paraffin at 25 degrees C
were comparable with the creams obtained by cold emulsification, while the
elasticity was considerably lower. Thermorheological studies showed evidence for
transitional behavior for white soft paraffin on heating, but not for the creams.
White soft paraffin showed a higher viscosity (and resistance to the penetrating
force) when melted at 70 degrees C and left to solidify at room temperature,
compared to the "unmelted" sample. This was the opposite trend to that found with
warm and cold emulsified creams. The input of heat during the emulsification
process showed a strong effect on the structure and consistency of the W/O creams
containing petrolatum and silicone emulsifier, resulting in a less viscous
product. The use of the aforementioned techniques represents a useful and novel
approach to the evaluation of cream consistency.
PMID- 9552315
TI - Tuning in society to science and technology.
PMID- 9552314
TI - Dissolution properties of praziquantel-beta-cyclodextrin systems.
AB - The purpose of this study was to characterize the dissolution behavior of a
poorly water-soluble antischistosomal agent, praziquantel (PZQ), from PZQ-beta
cyclodextrin systems containing 20-100% w/w of drug. Dissolution parameters
obtained from the release data of simple physical mixtures and inclusion
compounds prepared by the solvent method were employed to characterize the effect
of drug loading on the release kinetics of PZQ. All the systems investigated
showed improved dissolution in comparison with the free drug due to the ability
to form a complex in solution. The systems prepared by the solvent method showed
different characteristics and mechanism of dissolution than the physical
mixtures: At low beta-cyclodextrin (beta-CD) weight fractions (high drug loading)
their dissolution profiles were higher than those of the physical mixtures. At
high polymer weight fractions (low drug loading and equimolar ratio) the physical
mixtures exhibited a 7-fold higher dissolution rate than the pure drug. The
inclusion systems, on the other hand, showed an improvement in the dissolution
rate, but to a lesser degree than the physical mixtures. The observed changes in
the mechanism of release kinetics of the different PZQ-beta-CD systems were
interpreted using the principles of percolation theory and the results of thermal
analysis of the physical mixtures and the inclusion compounds.
PMID- 9552316
TI - Extrusion/spheronization--effect of moisture content and spheronization time on
pellet characteristics.
AB - As part of a larger effort aimed at optimizing the properties of pellets produced
by spheronization of extruded masses, the effect of the moisture content of wet
masses on extrusion force and torque was studied. The wet masses were composed of
either microcrystalline cellulose (MCC) or mixtures of MCC with lactose or
dicalcium phosphate. Based on the force and torque data, a moisture content
"window" was defined for consistent extrusion. Moisture exerts a lubricant
effect, and a moisture level of 100-120% w/w dry solid seemed necessary for the
extrusion of MCC into rod-shaped, discrete pieces. Screen force clearly depended
on the moisture content but was relatively insensitive to extruder speed,
especially at 80% and 100% moisture content. The physical properties of pellets
as a function of spheronization time were studied by sampling the material at
known intervals. The percent yield, tapped density, and a two-dimensional
sphericity index of an 18/20 mesh fraction of pellets were measured. Maximum
yield, tapped density, and sphericity were achieved within 60 sec in the
spheronizer. With increasing residence time, the shape and density were unchanged
while the yield was severely reduced. Among the formulations studied, pellets
with equal amounts of lactose and MCC were superior to those of pure MCC in
yield, density, and sphericity. Based on these results, an outline to optimize
the endpoint of the spheronization process for formulations containing MCC is
suggested.
PMID- 9552317
TI - Interfacial properties as stability predictors of lecithin-stabilized
perfluorocarbon emulsions.
AB - The purpose of this study was to determine whether the addition of small
quantities of minor lecithin components (phosphatidylinositol, phosphatidic acid,
lysophosphatidylethanolamine, and cholesterol) and Pluronic F68 to lecithin could
improve the stability of lecithin-stabilized perfluorocarbon emulsions. Attempts
were made to correlate emulsion stability with interfacial properties (tension
and charge). Dynamic interfacial tension was determined using a Teflon Wilhelmy
plate method [reported previously (1)]. Emulsions were prepared by
microfluidization. Microelectrophoresis was used to measure emulsion droplet
charge, and photon correlation spectroscopy and Coulter analysis were used to
determine emulsion stability as a function of droplet size. Thermal kinetic
accelerated stability testing was conducted. Various droplet size parameters were
used to compare emulsion stabilities, and an overall stability ranking, based on
these parameters, was obtained for each emulsion. Small quantities of additives
altered emulsion stability and these data were correlated with interfacial
properties and initial droplet diameters. The addition of cholesterol to lecithin
resulted in the most stable perfluorocarbon emulsion.
PMID- 9552318
TI - The role of intra- and extragranular microcrystalline cellulose in tablet
dissolution.
AB - The objective of this study was to examine the influence of intra- and
extragranular microcrystalline cellulose (MCC) on drug dissolution from tablets
made by high-shear granulation. Granulations were made in a Littleford Model W-10
B (10-liter) mixer and dried in a fluid bed dryer (Niro Inc.). A Plackett-Burman
screening design and 2(3) factorial design were employed to study how drug type,
MCC (intra- or extra-), filler type (lactose or dicalcium phosphate),
disintegrant type (sodium starch glycolate or croscarmellose sodium) and level,
proportion of magnesium stearate, and impeller speed affect tablet hardness,
disintegration time, and dissolution. Two model drugs were chosen based on their
solubility: metoprolol tartrate (solubility > 1000 mg/ml) and hydrochlorothiazide
(solubility = 1.05 mg/ml). Tablets were compressed to the same target weight
(dose) and similar tablet hardness. In some cases, dissolution testing was also
carried out on the loose granules. The intra-extragranular distribution of MCC
was found critical to the compactibility and initial dissolution rates from these
tablets. Intragranular MCC reduced drug dissolution, the effect being most marked
in the case of the slightly soluble hydrochlorothiazide. For formulations
containing intragranular MCC, the granulating fluid level on tablet dissolution
was also important, since an increase in fluid level resulted in slower drug
dissolution from both the loose granules and the tablets compressed from them.
Conversely, extragranular MCC tended to increase both dissolution rates and
compactibility. It may be concluded that the appropriate distribution of MCC
between and within granules may optimize both dissolution and compactibility
without changing overall tablet composition.
PMID- 9552319
TI - In vitro release and permeation of oxytocin from a mucoadhesive buccal patch.
AB - A biocompatible, mucoadhesive patch was evaluated for potential use in the
delivery of peptides. The model peptide oxytocin was incorporated into the
polymeric patch matrix and the diffusion of oxytocin across excised rabbit buccal
epithelium was studied following patch application. Penetration of oxytocin
across excised mucosa from an applied patch did not exhibit a characteristic lag
time for diffusion, with the steady-state flux of oxytocin being 0.062 +/- 0.019
microgram/cm2/hr. However, when finite-dose diffusion studies were conducted to
quantitate transport of oxytocin across rabbit buccal mucosa, the mean apparent
permeability coefficient (P), diffusion coefficient (D), partition coefficient
(K), and lag time (tlag) were (1.94 +/- 0.74) x 10(-7) cm/sec, (9.20 +/- 1.65) x
10(-8) cm2/sec, 0.13 +/- 0.05 and 1.86 +/- 0.31 hr, respectively. The release of
oxytocin from the mucoadhesive buccal patches in vitro proceeded very rapidly
during the first 2 hr, with 72% of the amount initially incorporated into the
patches released at 24 hr. The disappearance rate of intact, parent oxytocin when
an oxytocin solution was placed in direct contact with the serosal and mucosal
sides of freshly excised rabbit buccal mucosa was 0.74 +/- 0.34 microgram/cm2/hr
and 3.38 +/- 1.07 micrograms/cm2/hr, respectively. Thus, the buccal patch
evaluated in these studies appears to be suitable for transmucosal delivery of
peptides.
PMID- 9552320
TI - Improvement of the material motion in a rotary processor.
AB - The purpose of this paper is to reject or to confirm the hypothesis that the
influence of the water addition rate on the size and size distribution of pellets
is caused by insufficient spreading of the added water at higher water addition
rates. To overcome insufficient spreading of the added water, the agitation in
the rotary processor is intensified by improving the spiral, rope-like movement
by means of two baffles and a permanent PTFE coating, and by installing a
chopper. Improvement of the spiral, rope-like movement moderates the influence of
the water addition rate on the pellet size. The chopper has no significant
influence on pellet size, pellet size distribution, or percentage of agglomerates
for the pellets, which are investigated in this study. Furthermore, the
implementation of the technical modifications does not influence the dissolution
characteristics of the pellets directly. It is therefore concluded that the water
added is well spread over the mass by ensuring an optimal spiral, rope-like
movement, so that incorporation of a chopper is superfluous. The remaining
influence of the water addition rate on the pellet size can most probably be
explained by differences in processing time, resulting in different volumes of
air capable of extracting water from the powder mass.
PMID- 9552321
TI - Solubility and intrinsic dissolution rate of alprazolam crystal modifications.
AB - The purpose of the study was to determine the solubility and the intrinsic rates
of dissolution of three crystal modifications, two anhydrate, and one dihydrate
of alprazolam, a 1,4-benzodiazepine derivative. Solubility was determined by
ultraviolet spectrophotometry at different levels of pH, and intrinsic
dissolution rates were determined by a rotating disk method. The apparent
solubility of alprazolam crystal modifications was dependent on pH, being 8-10
mg/ml at pH 1.6 and 0.1 mg/ml at pH 5.0. The apparent solubility values for the
anhydrate forms were similar, whereas the hydrate form showed lower apparent
solubility at each pH. The mean intrinsic rates of dissolution for the anhydrate
forms were 16 and 18 micrograms cm-2 min-1, and for the dihydrate modification 21
micrograms cm-2 min-1 at 50 rpm, respectively. At 75 rpm, the corresponding
values were 22, 22, and 27 micrograms cm-2 min-1. The rate of intrinsic
dissolution was also dependent on the pH. It can be concluded that the apparent
solubility and the intrinsic dissolution rate of the anhydrate and hydrate forms
were different. The obtained apparent solubility values at different levels of pH
for the water-solvated crystal modification were evidently lower than those of
the two anhydrate forms studied. Furthermore, the intrinsic rate of dissolution
was significantly (p < 0.05) higher for the hydrate form of alprazolam.
PMID- 9552322
TI - Influence of tablet hardness and hydrophobicity on the adhesive properties of an
acrylic resin copolymer.
AB - The adhesive properties--including the force of adhesion, elongation at adhesive
failure, the modulus of adhesion, and the adhesive toughness--of an acrylic resin
copolymer were determined using the butt adhesion technique. Flat-faced tablets
containing up to 30% hydrogenated castor oil were coated with an aqueous
dispersion of Eudragit L30D-55. Using data obtained from a Chatillon digital
force gauge attached to a motorized test stand, force-deflection profiles,
similar to stress-strain curves generated in the tensile testing of free films,
were constructed. The surface characteristics of the tablets significantly
influenced polymer-substrate interaction. The force of adhesion, the elongation
at adhesive failure, and the adhesive toughness decreased as the surface of the
tablet became more hydrophobic through the addition of wax to the tablet
formulation. Lower adhesive properties were found with increasing tablet
hardness, due to a decrease in the effective area of contact between the film
coating and the tablet surface. Increased polymer loading resulted in stronger
adhesion, indicating a relationship between the mechanical and adhesive
properties of the polymer. The present study demonstrated that the area under the
force-deflection profile in conjunction with the force of adhesion was more
representative of the adhesive properties of the polymer.
PMID- 9552323
TI - Pharmaceutical granulation and tablet formulation using neural networks.
AB - Current-day pharmaceutical formulation may be trial and error in nature due to
the absence of a clear relationship between the formulation characteristics
(output variables) and the material and process variables (input variables).
Neural networks are networks of adaptable nodes, which through a process of
learning from task examples, store experiential knowledge and make it available
for prediction. Prediction of a model granulation and tablet system
characteristics from the knowledge of material and process variables utilizing
neural networks is the basis of this presentation. The formulation design
contained the following variables: granulation equipment, diluent, method of
binder addition, and the binder concentration. The material, process, granulation
evaluation, and tablet evaluation data of the formulations were used as the data
set for training and testing of the neural network models. A comparison of the
neural network prediction performance with that of regression models was also
done. Both the granulation model and the tablet model converged fairly rapidly in
the training step. In the testing step, the predictions for all granulation model
variables (geometric mean particle size, flow value, bulk density, and tap
density) were satisfactory. In the tablet model, the predictions for
disintegration and thickness were also satisfactory. The predictions for hardness
and friability were less than satisfactory. Two situations where the neural
network may not perform adequately are discussed. The neural network prediction
is better or comparable for all the predicted variables in this study compared to
regression methods. The results clearly show the applicability of neural networks
to formulation modeling.
PMID- 9552324
TI - Optima: a windows-based program for computer-aided optimization of controlled
release dosage forms.
AB - The purpose of this work was to develop a computer program that assists
optimization of controlled-release devices, both visually and mathematically,
using response surface methodology (RSM). A Windows-based computer program,
Optima, which interactively implemented a number of subroutines for the
optimization procedure, was developed. Optima is an integrated, user-friendly,
and graphically oriented program for pharmaceutical dosage form optimization.
Central composite design is implemented in the program. First- and second-order
models containing up to five variables can be fitted to the data. The user can
also choose between linear and exponential individual desirability functions, and
use them to construct an overall desirability function that combines all the
response variables in a single response. The program can predict the optimum
levels of experimental variables, with respect to individual responses and/or the
overall desirability. Optima has been successfully used in the development of
sustained-release AZT-loaded microspheres. During the optimization process, three
experimental variables were investigated and four responses were measured. The
experimental design was a central composite design that was generated by the
program. The response values were used by the program to calculate the individual
desirability functions, which were then combined into an overall desirability
function. The individual responses as well as the overall desirability function
were optimized by fitting to a second-order polynomial equation. The response
surfaces were generated and optimum levels of the experimental variables were
predicted. The observed responses of the optimized formulation were very close to
those predicted by Optima. The program proved to be a very useful, integrated
tool for optimization of the controlled-release microspheres.
PMID- 9552325
TI - Dual-controlled drug delivery across biodegradable copolymer. I. Delivery
kinetics of levonorgestrel and estradiol through (caprolactone/lactide) block
copolymer.
AB - Four block copolymers of caprolactone (CL) and dl-lactide (LA) with varying
weight fractions were synthesized by living polymerization in the presence of
Al/Zn bimetallic alkoxide complex. The solubility of levonorgestrel (LNG) and
estradiol (E2) in the copolymers was evaluated and found to increase
exponentially with CL mole fraction. Their aqueous solubilities were also studied
and observed to increase linearly with the concentration of benzalkonium chloride
(BAC), a solubilizer. The kinetics of LNG and E2 permeation through the copolymer
membranes were studied and observed to follow a zero-order kinetics, and the
permeation rates obtained were noted to be a function of copolymer composition.
The release kinetics through the copolymer matrix were also studied and noted to
follow a matrix-diffusion process, and the release flux was found to be dependent
on copolymer composition. Permeation rates and release fluxes at steady state as
well as the permeability and solubility of LNG and E2 in the copolymers suggest
that these permeation parameters are affected by copolymer composition, which
increase as the CL/LA ratio in the copolymer was increased.
PMID- 9552326
TI - Interaction of recombinant human bone morphogenetic protein-2 with poly(d,l
lactide-co-glycolide) microspheres.
AB - The combination of recombinant human bone morphogenetic protein-2 (rhBMP-2) with
poly(d,l lactide-co-glycolide) (PLGA) porous microspheres provided for "sustained
release" of the protein from the microspheres. Soaking 50:50 PLGA microspheres in
a buffered rhBMP-2 solution for a sufficient period of time to permit equilibrium
binding enabled quantification of "free" and "bound" protein. "Free" protein is
defined as protein present within the porous matrix of the microspheres, whereas
"bound" refers to protein adsorbed to PLGA surfaces. Kinetics of the rhBMP-2
microsphere association revealed that equilibrium was attained within 8 hr for
two buffer systems (arginine/histidine, pH 6.50; and glutamic acid/sodium
glutamate, pH 4.50). Increasing the concentration of the rhBMP-2 stock solution
used for the interaction studies from 0.025 to 1.0 mg/ml increased the amount of
rhBMP-2 adsorbed and the concentration of free rhBMP-2. Beyond a 1.0 mg/mL
concentration, only free rhBMP-2 levels increased. Linearized Langmuir treatment
of the adsorption data yielded values corresponding to monolayer coverage of the
microspheres (Cm) and the equilibrium adsorption constant (K) of 0.17
microgram/cm2 and 7.57 ml/mg, respectively. Studies performed to determine the
effect of ionic strength revealed that increasing NaCl and buffer concentration
decreased the amount of protein adsorbed. rhBMP-2 release studies, conducted in
an isotonic phosphate buffered saline, pH 7.4 vehicle, revealed that free rhBMP-2
was released during an initial period of 72-96 hr. Following this period, there
was no discernible release of rhBMP-2 from the microspheres for up to 7 days,
suggesting that the bound protein would remain at a defect site and release
slowly upon erosion of the polymer. Mass balances performed by using an
extraction buffer of high ionic strength confirmed this prediction.
PMID- 9552327
TI - Studies on the influence of pH and pancreatin on 13C-formaldehyde-induced gelatin
cross-links using nuclear magnetic resonance.
AB - Carbon-13 nuclear magnetic resonance (13C-NMR) and 13C-enriched formaldehyde
(13CH2O) were utilized to observe cross-linking in gelatin. Thus, when a 6%
solution of gelatin in water was treated with 2000 ppm 13CH2O at 20 degrees C,
the 15 hr 13C-NMR spectrum of the crosslinked gel showed peaks representing
carbinolamines (methylols) of arginine and lysine, as well as a peak ascribed to
a methylene cross-link between arginine and lysine. Similar results were obtained
when these cross-linking reactions were conducted using only 100 ppm 13CH2O. When
pancreatin (1% w/v) was added to the solution of 6% gelatin cross-linked with
2000 ppm 13CH2O, the gel began to revert to a clear fluid solution. After
incubation for 24 hr at 37 degrees C, the 13C-NMR spectrum of this solution
confirmed the presence of the methylols of lysine and arginine, and the lysine
arginine cross-link. When 13CH2O (2000 ppm) was added to a 6% solution of gelatin
at pH 13.0, the arginine methylol and the lysine-arginine crosslinks were
produced. The 13CH2O-induced crosslinking of gelatin at pH 2.0, however, yielded
the lysine methylol as the sole product.
PMID- 9552328
TI - Micellization and solubilization behavior of sucrose laurate, a new
pharmaceutical excipient.
AB - The micellization and solubilization properties of sucrose laurate have been
investigated. Solubilization experiments showed that numerous poorly water
soluble drug substances could be solubilized by aqueous sucrose laurate
solutions; the solubilization was uncomplicated and the maximum solubilizate
concentration was high. Laser light scattering investigations proved that
solutions containing pure sucrose monolaurate formed spheroidally shaped micelles
with a hydrodynamic radius of 29.2 A, which behaved like ideal particles, showing
no solute-solute interactions. Surprisingly, the hydrodynamic radii of the
sucrose monolaurate micelles were hardly changed by the introduction of 0.20%
cyclosporin-A. The addition of sucrose dilaurate, the main impurity of the
sucrose laurate product, however, resulted in large and polydisperse structures.
Considering the critical packing parameters, the light scattering results could
be explained by assuming a transformation of the spherical micelle into a disk
with rounded edge.
PMID- 9552329
TI - Drug release from a multiparticulate pellet system.
AB - Multiparticulate pellet systems are used as both immediate and modified release
dosage forms. Previous work has classified uncoated pellet systems prepared from
microcrystalline cellulose as an inert matrix. The Higuchi square root of time
equation, derived to describe drug release from a single planar system, is the
accepted method to evaluate drug release from both planar and spherical
heterogeneous inert granular matrices. A second equation of interest, the Higuchi
cubic equation, was derived to describe drug release from a spherical pellet.
Both equations predict a linear relationship between drug release and the square
root of time or time. The purpose of the present study was to evaluate drug
release from a multiparticulate pellet system using both equations and to study
any differences when both equations are used to describe the same drug release
data. By evaluating dissolution data from various pellet mesh cuts representing
different bead radii and surface areas, changes in the slopes of both plots would
be expected. Pellets were manufactured using extrusion/spheronization technology
and consisted of 90% microcrystalline cellulose and 10% acetaminophen.
Statistical comparison indicates that the Higuchi cubic equation seems to be more
sensitive to changes in pellet size. While the square root of time equation
describes the drug release data from granular, inert, spherical pellets, it may
be better to utilize the Higuchi cubic equation because it is more sensitive to
changes in particle size.
PMID- 9552330
TI - The impact of crystallinity on Brequinar sodium hygroscopicity.
AB - The hygroscopicity of Brequinar sodium, an organ transplant immunosuppressant, at
75% relative humidity highly depends on the crystal form or crystallinity of the
drug substance. Hygroscopicity and ease of water uptake of three lots of
Brequinar sodium were investigated. Those lots contained different impurities at
levels ranging from 0.26% to 0.5%. DSC thermograms of the hydrated samples
suggest that unbound/loosely bound water was released around 90 degrees C and
water of hydration was released at 175 degrees C. At equilibrium, 2% of the water
was tightly bound. Stoichiometry suggests that this is a hemihydrate.
Unbound/loosely bound water has no impact on the hemihydrate crystal structure as
indicated by x-ray powder diffraction patterns. The results suggest that the less
perfect crystals exhibited a faster water uptake and converted to a stable
hemihydrate when stored at 75% relative humidity. Both the anhydrous and the
hemihydrate forms of Brequinar sodium exhibited rapid dissolution rate and
comparable water solubility.
PMID- 9552331
TI - Development and optimization of a solid dispersion hot-melt fluid bed coating
method.
AB - A new hot-melt fluid bed coating process has been developed, characterized, and
optimized. Polyethylene glycol served as the model coating agent and was charged
with substrate into the fluid bed chamber in the solid state. The processing
stages included: (A) warm-up, (B) preheating, (C) melting-spreading, and (D)
cooling-congealing. A central composite design was utilized to characterize and
optimize the process. Substrate porosity and density evaluations were conducted
by mercury intrusion. The method proved capable of coating nonpareils from 10 to
35 mesh (0.500 to 2.00 mm) and tablets up to 1 g. The nonpareils were coated as
individual particles, while particle sizes significantly smaller than 40 mesh
(0.420 mm) tended to agglomerate. The porosity and density values of dissimilar
nonpareil batches showed a large degree of variation, affecting the method's
reproducibility. Additive coatings were achieved by sequential runs using coating
agents of diminishing melting points. The method is a viable alternative to hot
melt spray-coating processes. Organic solvents, spraying equipment, steam
jackets, and/or heating tape are eliminated from the process.
PMID- 9552332
TI - Novel technology for the preparation of sterile alginate-poly-l-lysine
microcapsules in a bioreactor.
AB - The purpose of this study was to develop a method that may be suitable for the
commercial manufacture of sterile alginate-polylysine-alginate microcapsules in a
bioreactor. A Turbotak atomizing device in conjunction with a Bellco Bioreactor
was used to prepare sterile microcapsules. Aseptic procedures were followed using
sterilized equipment and materials. Sodium alginate solution was sprayed into
calcium chloride solution using the Turbotak, with nitrogen as the atomizing gas.
The resultant gelled alginate microcapsules were coated with polylysine and
alginate to produce alginate-poly-l-lysine microcapsules. In-process
contamination of the atomizing gas and microcapsules was investigated using
modified USP sterility tests. Microcapsule size was determined using a light
blockage technique (Accusizer) which measures both number and volume weighted
mean diameters. The microcapsules prepared passed a modified USP sterility test,
and the Bellco Bioreactor was found to minimize the possibilities of
environmental contamination and therefore enhanced operator safety. The flow rate
of the atomizing gas was determined to significantly alter number and volume
weighted mean microcapsule diameters. Statistical analysis indicated that the
number weighted mean diameters in conjunction with the volume weighted mean
diameters can be used to detect batch-to-batch changes in microcapsule diameters.
In conclusion, the modified Bellco Bioreactor offers a novel approach for
producing sterile alginate-polylysine microcapsules on a laboratory scale.
PMID- 9552334
TI - Determination of intraparticulate mass transfer coefficients via permeation
measurements: theory and experimental validation.
AB - A mathematical model of mass transfer through a heterogeneous, multiphase barrier
has been developed where the dispersed phase is capable of uptake of the
diffusant according to a linear relationship. The model was used to describe the
penetration of drugs through dispersions of permeable globules in media of known
diffusional properties. Water-in-oil-in-water (W/O/W) multiple emulsions have
been studied by this method. When used to analyze data obtained with a simple
diffusion cell, the model allows the calculation of the mass transfer coefficient
which characterizes the diffusional mass transfer across oil-water interfaces
within the emulsions. The mass transfer coefficient is directly related to the
drug release rate from the internal phases of multiple emulsions. Those cases
where instantaneous equilibria are established or where impermeable globules are
present can be treated as special limiting cases. Differential equations which
express diffusant concentrations as functions of time, space, and dispersion
system parameters have been solved by Laplace transformation without recourse to
numerical methods. The values of the mass transfer coefficient are shown to
reflect the physical characteristics of multiple emulsion systems.
PMID- 9552333
TI - Validation of cleaning procedures for highly potent drugs. I. Losoxantrone.
AB - The validation of a procedure designed to clean glass and stainless steel
surfaces after exposure to the experimental anticancer drug losoxantrone is
described. The cleaning procedure, using water and hypochlorite bleach, was
validated using a wipe test and a high-performance liquid chromatography (HPLC)
method developed to quantitate low levels of losoxantrone. The HPLC method is
shown to be linear and reproducible (relative standard deviation (RSD): 7.1% or
less), with a detection limit of 2 ng/ml. Recoveries of 71.0%, 50.1%, and 57.6%
were reproducibly obtained from the wipe pads, glass plates, and stainless steel
plates, respectively, at levels of 70-140 ng per 100 cm2. The cleaning procedure
is shown to clean glass and stainless steel plates to less than 20 ng and 17 ng
losoxantrone per 100 cm2, respectively. These results demonstrate the need to
fully characterize the recovery of drugs from surfaces and swabs in order to
properly validate cleaning procedures.
PMID- 9552335
TI - Determination of the pKa and pH-solubility behavior of an ionizable cyclic
carbamate, (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4- (trifluoromethyl)
2H-3,1-benzoxazin-2-one (DMP 266).
AB - The solubility of a nonnucleoside reverse transcriptase inhibitor, (S)-6-chloro-4
(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl )- 2H-3,1-benzoxazin-2-one
(DMP 266), was investigated as a function of pH. A dramatic increase in the
aqueous solubility was observed at pH > or = 10, which was consistent with going
from a neutral to a charged species. The ionization of the proton positioned on
the carbamate functionality was confirmed spectrophotometrically (pKa = 10.1).
The spectrophotometric result was in excellent agreement with that obtained from
the solubility studies (pKa = 10.2). The ionization behavior of DMP 266
represents a unique case in which the pKa for a carbamate functional group is
quite low. The anomalous pKa value may be attributed to stabilization of the
negatively charged species through inductive effects, which originate from the
surrounding substituents and delocalization of the negative charge via resonance
effects.
PMID- 9552336
TI - Sequential statistical optimization of a positively-charged submicron emulsion of
miconazole.
AB - A positively charged oil/water (O/W) emulsion containing an antifungal agent was
developed for ophthalmic use. An attempt was made using a sequential statistical
methodology to optimize the O/W emulsion by varying both formulation and process
parameters to obtain the smallest droplet size emulsion that can remain stable
for a long period of time. During the first step of the study, not less than 7
parameters were found to be important--drug content, amount of lipophilic phase,
poloxamer concentration, quantity of the phospholipids-stearylamine couple, pH
adjustment, time of coarse emulsification and time of high pressure
homogenization. A screening approach based on Hadamard's matrix was used to
select the parameters displaying the most significant effects on response
parameters. A first set of 8 experiments proved efficient enough to define the
concentration of poloxamer and the quantity of the couple phospholipids
stearylamine, which confer the overall positive charge to the emulsified droplet,
as the most significant parameters affecting the final droplet size of the
emulsions formed. A 2k-type experimental design was then built with the two main
factors in order to evaluate a first-order polynomial model with interaction.
Poor analysis of variance results after an additional center experiment was
performed revealed the lack of fit of the linear model as well as the importance
of the response surface curvature due to a close optimum location. To find the
optimal operating conditions the design was sequentially completed with 4 more
experiments according to the Box and Wilson method. The response surfaces in 3
dimensional representation and their corresponding contour plots proved helpful
in analyzing the validated models and in highlighting the precise optimum
location. The optimized positive submicron emulsion is now under in vivo
investigation.
PMID- 9552337
TI - Blending validation of low drug content dosage forms.
PMID- 9552338
TI - Compaction simulator studies of a new drug substance: effect of particle size and
shape, and its binary mixtures with microcrystalline cellulose.
AB - The compaction characteristics of a new drug substance with two crystal habits
and particle size fractions as well as its binary mixtures with microcrystalline
cellulose were studied using an integrated compaction research system under 300
and 450 MPa pressures. The results indicate that the drug substance has poor
intrinsic compaction properties. The three-dimensional hexagonal crystal habit or
smaller particle size consistently produced a slightly higher total work of
compaction as compared with the cubic brick habit or larger particle size,
respectively. However, neither crystal habit produced a coherent compact. The
compactability of the drug substance was improved by the inclusion of
microcrystalline cellulose, and the crushing strength of the compacts increased
as the amount of microcrystalline cellulose in the binary mixture was increased.
Such correlation was not observed when the compaction data were evaluated using
either the Heckel equation or the percentage porosity change as a function of
applied pressure.
PMID- 9552339
TI - beta-D(+) glucose-glucose oxidase-catalase for use as an antioxidant system.
AB - The purpose of this study was to investigate the use of beta-D(+) glucose-glucose
oxidase (EC 1.1.3.4)-catalase (EC 1.11.1.6) (BDG-GO-CAT) as a new antioxidant
system in solutions. A novel method for estimation of activity of the system was
developed using a dissolved oxygen (DO) meter and an oxygen probe. The method can
be used to determine the enzymatic activity of the system at GO concentrations of
0.005 to 0.030 unit/ml, with an r2 of 0.995 for the linearity of the standard
curve, and can be adapted for analysis in any solution. At room temperature of
23.0 degrees +/- 2.0 degrees C, the maximum activity of the BDG-GO-CAT system was
found to occur at pH 5.40. The half-life values for the stability of GO-CAT in
0.10 M phosphate buffer solutions of pH 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, and 10.0
were 9.78, 49.43, 53.46, 36.51, 12.68, 1.84, and 0.80 weeks, respectively.
Dextrose was used in place of beta-D(+) glucose for cost-saving purposes, and a
standard curve for the activity of GO-CAT was obtained using 20 mg/ml dextrose.
The BDG-GO-CAT was effective as a DO-scavenger in closed containers, when the
containers were opened and exposed to atmosphere for 2 days between tests, and
upon reclosing them. Pharmaceutical excipients such as ethanol, glycerin,
propylene glycol, methylparaben, propylparaben, artificial strawberry flavor, and
sodium benzoate did not show any adverse effect on the activity of BDG-GO-CAT.
Sorbitol, high-fructose corn syrup, sucrose, and polyethylene glycol 3350
increased the rate of DO removal. Sodium carboxymethyl-cellulose (CMC) at 2.0%
w/v decreased the rate of DO removal. These studies indicate that the
BDG(dextrose)-GO-CAT system warrants serious consideration for use an antioxidant
system in aqueous formulations.
PMID- 9552341
TI - Positively charged self-emulsifying oil formulation for improving oral
bioavailability of progesterone.
AB - A self-emulsifying oil formulation (SEOF) comprised of Tween 80, benzyl alcohol
(BA), ethyl oleate (EO), and oleylamine (OA), able to produce positively charged
submicron emulsions upon aqueous or buffer dilution, was developed and
characterized. The positive charge of the formulation was attributed to the
localization of the cationic lipid, OA, at the oil/water interface of the diluted
SEOFs. Binary phase diagram analysis of the basic lipophilic system showed that
the SEOF elicited progressive inverse phase behavior under continuous aqueous
phase dilution. At infinite dilution fine submicron o/w emulsions were formed
only when BA concentrations did not exceed 50% in the formulation. The self
emulsification process was not markedly affected by the variation in pH over the
entire physiological range. The neurotoxic effects observed in acute toxicity
studies with the concentrated emulsion containing 3% BA obtained from the
dilution of the SEOF vehicle were attributed to the BA since a simple aqueous
solution at the same BA dose caused similar adverse effects. However, no toxic
effects were noticed when the dose administered was 30 times the potential dose
that could probably be administered to humans. Comparative oral bioavailability
studies in young female rats using several different liquid dosage forms of
progesterone indicated that of those studied, only the positively charged SEOF
could be considered a potential effective dosage form for oral administration of
progesterone since it elicited the highest and most satisfactory absorption
profile.
PMID- 9552340
TI - In vitro permeation study of a mucoadhesive drug delivery system for controlled
delivery of nonoxynol-9.
AB - A carbopol 934P-based drug delivery system (AmDDS) was developed to achieve the
dual-controlled delivery of Nonoxynol-9 (N-9), a spermicidal agent, and EDTA, a
potentiator of spermicidal activity. This gel-type system made intimate contact
with vaginal mucosa and maintained an effective drug concentration within the
vagina for a prolonged period of time. An existing mathematical model, based on a
unilayer diffusion membrane, was applied for describing permeation of N-9 through
vaginal mucosa. Vaginal permeation of N-9 from AmDDS was negligible over the
initial 5 hr, then increased in a Q versus t pattern, but remained low. A
relationship was observed between the permeation rate (Js) of drug through
vaginal mucosa and the release flux (Q/t1/2) from AmDDS, which showed that the
permeation rate (Js) increased with increased square of the release flux
[(Q/t1/2)2] in a hyperbolic manner. This result indicated that release of N-9
from AmDDS is still the rate-limiting step at doses within the tested range.
EDTA, at concentration of up to 0.32%, did not change the permeation rate of N-9
through vaginal mucosa. It is thus concluded that the developed AmDDS can control
the intravaginal delivery of N-9 as well as its permeation through vaginal
mucosa.
PMID- 9552342
TI - Dissolution enhancement of an insoluble drug by physical mixture with a
superdisintegrant: optimization with a simplex lattice design.
AB - The aim of the present work was to optimize a tablet formulation containing a
physical mixture of a practically insoluble drug (prednisone) with a
superdisintegrant (croscarmellose sodium) and two filler-binders characterized by
differing water solubility (dicalcium phosphate dihydrate and anhydrous beta
lactose). Crushing strength, disintegration, and dissolution were measured for 10
formulations distributed over a factor space according to a simplex lattice
design for a special cubic model. Multiple linear regression analysis was used to
assess the best fit for each variable. The model predicted that increasing the
amount of disintegrant to a critical amount (50%) would result in reduced
disintegration time for dicalcium phosphate/beta-lactose ratios > 0.3, no changes
in disintegration time for ratios < 0.3, and for all ratios an improvement in
dissolution at 10 min. Crushing strength values of dicalcium phosphate increased
with increasing disintegration concentration but not for beta-lactose tablets.
The physical mixture of a practically insoluble drug with a superdisintegrant was
confirmed as a valid approach to the improvement of dissolution, even in presence
of other components. The solubility of the filler-binders influenced the minimum
amount of disintegrant needed; when a soluble diluent was used, the amount of
disintegrant required was reduced.
PMID- 9552343
TI - The evaluation of lyophilized polymer matrices for administering recombinant
human bone morphogenetic protein-2.
AB - Novel unitary devices, prepared by lyophilization of viscous solutions of sodium
carboxymethylcellulose (CMC) and methylcellulose (MC), were evaluated as
sustained-release delivery systems for recombinant human bone morphogenetic
protein-2 (rhBMP-2). In vitro characterization of the unitary devices, which
contained rhBMP-2-loaded poly (d,l lactide-co-glycolide) (PLGA) bioerodible
particles (BEPs), was conducted over a 2-month period. Determinations included
buffer uptake, mass and molecular weight loss and rhBMP-2 release from the
unitary devices. CMC devices imbibed approximately 16 times their weight of
buffer, while with MC, equilibrium uptake was approximately 6 times the dry
weight of the devices. Overall mass loss percentages were approximately 55 and
35%, respectively, for CMC and MC devices. rhBMP-2 release from the devices was
essentially a triphasic process: an initial phase during which "free" protein
(rhBMP-2 present on the surface and within the pores of the PLGA BEPs) was
released, a lag period during which no release was discerned, and then release of
"bound" rhBMP-2 (protein adsorbed to the BEPs). The release of bound protein
correlated with the mass loss of the polymer which began after 3 weeks. Release
from the unitary devices was lower than that from the BEPs alone, due to a
retardation effect of the gelled CMC/MC polymers. In rabbits in which full
thickness cranial bone defects were created, the implants were well tolerated and
induced significant new bone growth during an 8-week evaluation period. The CMC
devices appear to have induced bone earlier (at 2 weeks), but this did not affect
eventual 8-week results. CMC devices without rhBMP-2 appeared to provide some
bone conduction, in contrast to the blank MC devices.
PMID- 9552344
TI - Phenytoin sodium microcapsules: bench scale formulation, process characterization
and release kinetics.
AB - The objective of this investigation was to formulate and prepare sustained-action
microcapsules of phenytoin sodium (diphenyl hydantoin sodium salt). Using
ethylcellulose and methyl acrylic acid copolymers (Eudragit S-100 and L-100) as
coating materials, microcapsules of phenytoin sodium were formulated by an
organic phase separation and a granule coating method. The phase diagrams were
used to study the phase separation in an ethylcellulose-petroleum ether-toluene
system, and the effect of temperature and amount of petroleum ether on the
ethylcellulose left in the organic solvent mixture was investigated. The phase
diagrams showed that increase in temperature did not significantly affect the
ethylcellulose residue, and 60 ml of nonsolvent was found adequate for
microencapsulation. In vitro release of the formulated microcapsules and the
commercially available preparations was performed in CO2-free distilled water
using the USP XXIII rotating basket method, and the profiles were evaluated by
Higuchi kinetics. Geometric mean diameters of the microparticles prepared by two
different methods showed differences due to different core:wall ratios. A 4 x 5
factorial design was utilized and multiple regression was applied to the
dependent variables (ethylcellulose content, percent dissolved) against the
independent variables (amount of nonsolvent, temperature, core:wall ratio); the
optimum phenytoin sodium-to-ethylcellulose ratio was 1:2.3. Utilizing second
order polynomial equations, response-surface graphs and contour plots pointed out
the time necessary for 40%, 55%, and 70% release of phenytoin sodium. The desired
release profiles were obtained with formulations E-5, ES-2 and ESL-2.
PMID- 9552345
TI - Insoluble collagen matrices for prolonged delivery of proteins.
AB - The purpose of this investigation was to evaluate the application of high
molecular weight, insoluble collagen as a carrier material for proteins. Matrices
were formulated and their behavior in buffer solution was investigated with focus
on swelling and inner structure. Cross-linking with glutaraldehyde was introduced
prior to the formation of the devices and its influence characterized. In
addition, the enzymatic degradation process was studied and release experiments
with systems loaded with fluorescent-labeled bovine serum albumin were carried
out. Insoluble collagen matrices were characterized by intensive swelling in
buffer resulting in development of a coarse porous character. Cross-linking
strongly reduced the water penetration, leading to denser structures of the
swollen devices. The continuous enzymatic degradation of the disk-shaped matrices
by collagenase followed the kinetics of an heterogeneous enzymatic process with
hindrance of proteolysis by the addition of glutaraldehyde. Release studies
demonstrated that large amounts of model protein were held in the matrices with
increased cross-linking degree. In presence of collagenase a prolonged release of
the trapped protein over several days by matrix cleavage could be achieved.
Insoluble collagen can be effective as a carrier material for proteins with an in
vitro release characteristic by both diffusion-controlled and enzymatic
degradation mechanisms. Cross-linking at the stage of preparing the aqueous
dispersion offers an alternative to subsequent cross-linking processes.
PMID- 9552346
TI - Water-solid interactions. III. Effect of glass transition temperature, Tg, and
processing on tensile strength of compacts of lactose and lactose/polyvinyl
pyrrolidone.
AB - The effect of moisture sorption at different relative humidities on the tensile
strength and the physical stability of compacts of crystalline and partly
amorphous lactose, alone and in binary mixtures with PVP, has been studied.
Furthermore, the role of moisture as a plasticizer and its effect on the glass
transition temperature, Tg, are related to the compactibiltiy. Samples were
conditioned for 2 hr using a climate test chamber at different relative
humidities. Moisture sorption was determined, the radial crushing strength for
compacts was measured immediately and after storage, and the tensile strength was
calculated. The glass transition temperature, Tg, was determined using DSC. The
tensile strength of the compacts was found to depend on both the conditioning
humidity and the humidity during storage. An increase in humidity to a level at
which the glass transition temperature, Tg, fell below the operating temperature,
T, resulted in transition from a rigid glassy state to a mobile rubbery state.
For compacts of partly amorphous lactose, an increase in the tensile strength was
observed during storage of tablets, due to recrystallization of the amorphous
regions above Tg. Tablets of mixtures of lactose and PVP exhibit a sharp decrease
in tensile strength at humidities above 70% RH, due to the glass-to-rubber
transition of PVP.
PMID- 9552347
TI - Dilution potential: a new perspective.
AB - The objective of this work was to develop a method to assess the dilution
capacity of direct compression excipients based on a technique previously
proposed by Minchom and Armstrong (MA). The technique involves the addition of
increasing quantities of a poorly compactible (compressible) material to the
excipient and measuring the resultant decrease in the AUC of the tensile strength
versus compaction force profiles. The AUC of each mixture is divided by the AUC
of the "0% mixture" to obtain MA's "work potential," called "area ratios" in the
present study. The applicability of this approach was tested using three
excipients differing in their deformation mechanisms: microcrystalline cellulose
(Avicel PH 101, 102, 200, 301, 302) representing a plastic material; dibasic
calcium phosphate (Cal-Star) representing a brittle material, and anhydrous
lactose, which exhibits both brittle and plastic properties. Ascorbic acid or
acetaminophen was the poorly compactible challenge material. In the first study,
the MA method was found to apply only to Avicel PH 101, since the area ratios for
mixtures containing different compositions of acetaminophen with either Cal-Star
or anhydrous lactose remain constant until a certain percentage of drug is
exceeded, after which a decline starts to be observed. Further work carried out
on mixtures of different grades of Avicel with ascorbic acid revealed that MA's
approach reflects only the ability of the excipient to handle internal stress
induced by the drug and does not take into account the intrinsic ability of the
drug-free excipient to form strong compacts. A new index was thus proposed,
called the dilution capacity index (DCI), which weights the MA index by the AUC
of the drug-free excipient. The results suggest that DCI can be used to compare
different grades of microcrystalline cellulose and provide in-house quality
control for microcrystalline cellulose suppliers.
PMID- 9552348
TI - Mechanical properties of single pellets containing acrylic polymers.
AB - Three aqueous-based acrylic latex dispersions, Eudragit L 30 D, NE 30 D, and RS
30 D, were incorporated as granulating binders into a powder blend of
microcrystalline cellulose and anhydrous lactose by wet massing. Spheronized
pellets were prepared by extrusion-spheronization and the mechanical properties
of single pellets, including the tensile strength at break and the Young's
modulus were determined from the stress-strain profiles using a Chatillon TCD-200
tension/compression digital test gauge. The influence of particle size and
plasticizer on the mechanical properties of pellets containing Eudragit RS 30 D
was investigated. All bead formulations deformed by brittle fracture under a
diametral compression force. The mechanical strength was found to be influenced
by the adhesive strength between the polymers and the powder particles instead of
the cohesive strength of each polymer. The Young's modulus and the tensile
strength were also significantly influenced by the type and concentration of
polymer, the presence of plasticizer, and the particle size of the beads. The
results were related to the properties of the polymers and the fracture
mechanisms of the beads. Furthermore, the polymer type and the incorporation of
plasticizer influenced the susceptibility of the moistened extruded granules to
the shearing forces during the spheronization process, which influenced the
surface morphological properties of the pellets.
PMID- 9552349
TI - Checkpoints in the cell cycle from a modeler's perspective.
AB - The cell division cycle is a complex process by which cells grow and divide into
two viable daughter cells. So that mistakes are not made in this crucial
replication process, cells stop at one or more "checkpoints" in the cycle to
query their internal state and external conditions, before proceeding to the next
stage of the cycle. In this paper we study some simple mathematical models of
cell cycle arrest in G1 ("Start") and G2. Our models help to relate the molecular
mechanisms of these checkpoints with physiological properties of the cell cycle.
PMID- 9552350
TI - The role of RB in cell cycle control.
AB - The retinoblastoma protein is an inhibitor of cell cycle progression from the G1
to the S phase of the cell cycle. It acts through its ability to interact with
cellular target molecules such as E2F transcription factors. The function of pRB
is negatively regulated by a cell-cycle dependent phosphorylation catalyzed by
cyclin-dependent kinases in the late G1 cell cycle phase. Recent evidence
indicates that this pRB inactivation is a key molecular event leading to the S
phase commitment at the G1 restriction point in the cell cycle. Deregulated
inactivation of pRB in G1 phase may be a universal mechanism underlying cellular
transformation.
PMID- 9552351
TI - Regulation of p70s6k/p85s6k and its role in the cell cycle.
AB - Two to three-fold increases in the rate of protein synthesis are required both to
enter the G1 phase of the cell cycle from G0 and to proceed to S phase in
response to growth factors and mitogens. This increase is in part regulated via
multiple phosphorylation of the 40S ribosomal protein S6 by the mitogen
stimulated p70s6k/p85s6k. At the protein synthesis level this event appears to be
involved in specifically increasing the efficiency of translation of a family of
essential mRNAs containing a polypyrimidine tract at their 5' transcriptional
start site. The activation of p70s6k/p85s6k and maintenance of its activity
throughout G1 is controlled via multiple phosphorylation events mediated by a
complex signalling network acting on distinct sets of phosphorylation sites.
PMID- 9552352
TI - MAP kinase-dependent pathways in cell cycle control.
AB - Mitogen-activated protein kinases such as Erk1 and Erk2 serve as a paradigm for a
growing family of proline-directed protein kinases that mediate entry,
progression and exit from the cell cycle in diverse eukaryotic cells. These
enzymes function within highly conserved modules of sequentially activating
protein kinases that transduce signals from diverse extracellular stimuli. In
vertebrates, at least three distinct kinases modules have been characterized.
Mitogens induce the sequential activation of the kinases Raf1-->Mek1-->Erk2-->Rsk
via the G-protein Ras. Stress factors stimulate c-Jun activation through a
related kinase pathway involving Mekk-->Sek-->SAPK c-Jun, and hsp27
phosphorylation via the MKK3-->Hog-->MAPKAPK-2 hsp27 route. Genetic and
biochemical studies, for example from budding yeast, imply the existence of
several related protein kinase modules that can operate in parallel or within
integrated systems.
PMID- 9552354
TI - Cell cycle control of DNA replication.
AB - The cell cycle is driven by the sequential activation of a family of cyclin
dependent kinases (cdk), which phosphorylate and activate proteins that execute
events critical to cell cycle progression. In mammalian cells cdk2-cyclin A has a
role in S phase. Many replication proteins are potential substrates for this cdk
kinase, suggesting that initiation, elongation and checkpoint control of
replication could all be regulated by cdk2. The association of PCNA, a
replication protein, with cdk-cyclins during G-1 to S phase transition and with
cdk-cyclin inhibitors, adds an interesting complexity to regulation of DNA
replication.
PMID- 9552355
TI - Cell cycle-regulated transcription in mammalian cells.
AB - The periodic, phase-specific transcription of defined sets of genes is a hallmark
of cell cycle progression in all organisms (1-3). In this article, we will
summarise our current knowledge and views of the mechanisms governing the cross
coupling of cell cycle control and transcriptional regulation in mammalian cells,
with particular emphasis on the transcription factor E2F and the retinoblastoma
protein pRb (1-3). Excluded from this review will be the genomic response to
mitogenic stimulation, which is part of the mitogen-triggered signal transduction
cascades rather than a reflection of cell cycle regulation (4).
PMID- 9552356
TI - The CLN gene family: central regulators of cell cycle Start in budding yeast.
AB - The Start transition in the budding yeast cell cycle is the point of most
physiological regulation of cell cycle commitment. This transition is controlled
by the CLN1,2,3 gene family. We review what is known about the regulation, inter
regulation and function of these genes in controlling the Start transition.
PMID- 9552353
TI - Mechanism of action of rapamycin: new insights into the regulation of G1-phase
progression in eukaryotic cells.
AB - The immunosuppressant drug, rapamycin (RAP), is a potent inhibitor of IL-2
dependent T-cell proliferation. The antiproliferative effect of RAP is mediated
through the formation of an active complex with its cytosolic receptor protein,
FKBP12. The molecular target of the FKBP12.RAP complex is a putative lipid kinase
termed the mammalian Target Of Rapamycin (mTOR). This review will discuss recent
findings suggesting that mTOR is a novel regulator of G1- to S-phase progression
in eukaryotic cells.
PMID- 9552357
TI - Cyclin A: function and expression during cell proliferation.
AB - Cyclin A is a key regulatory protein which, in mammalian cells, is involved in
both S phase and the G2/M transition of the cell cycle through its association
with distinct cdks. Several lines of evidence have also implicated cyclin A in
carcinogenesis. Our review concentrates on the role of cyclin A in S phase, in
the S/G2 transition and in human carcinogenesis; it will also discuss the
transcriptional regulation of cyclin A gene.
PMID- 9552358
TI - The role of cyclin E in the regulation of entry into S phase.
AB - Cyclin E is a crucial regulator of entry into S phase in higher eukaryotes and
acts in association with the protein kinase cdk2. Cyclin E expression is
transcriptionally controlled in mammalian cells resulting in a maximum just
before entry into S phase. Premature expression of cyclin E advances entry into S
phase, while lack of cyclin E prevents entry into S phase. Cyclin E/cdk2 activity
is regulated at multiple levels (by transcription, phosphorylation and inhibitor
proteins) and appears to be involved in triggering initiation of DNA replication
and in regulating genes important for proliferation and progression through S
phase.
PMID- 9552359
TI - p27KIP1, an inhibitor of cyclin-dependent kinases.
AB - The identification of a family of proteins that stoichiometrically regulate the
activation of the G1 cyclin-dependent kinases has added to our understanding of
the process of commitment to the mitotic cycle. The properties of p27 as a CDK
binding protein, the ability of environmental signals to regulate the expression
of p27, and the observation that p27 may link the accumulation of G1 CDK
complexes with activation of the CDK2 kinase, suggest it may have a critical role
in establishing a threshold for G1 cyclin/CDK accumulation prior to activation of
CDK2 kinase and entry into the mitotic cycle.
PMID- 9552360
TI - Regulation of cell cycle progression following DNA damage.
AB - DNA damage causes an arrest in cell cycle progression. Checkpoints, which monitor
the state of the DNA, exist throughout the cycle and negatively regulate cell
cycle transitions when damage is detected. The molecular basis of how these
checkpoints are activated, and interact with the cell cycle machinery, is just
beginning to be understood. Studies in yeast have identified a number of genes
involved in a G2 DNA damage checkpoint, while in mammalian cells a G1 checkpoint
has been extensively studied.
PMID- 9552361
TI - The role of the Ran GTPase pathway in cell cycle control and interphase nuclear
functions.
AB - Ran is a small, highly abundant, nuclear GTPase. Mutants in Ran and in proteins
that interact with it disrupt the normal checkpoint control of mitosis with
respect to the completion of DNA synthesis. Ran and other components of this
pathway are also required for numerous nuclear functions such as RNA export,
protein import, RNA processing and DNA replication. It will be important to
understand how these facets of Ran's activities are linked and how they promote
correct control of the cell cycle. This review examines recent progress in
discovering other components of the Ran GTPase pathway and considers how this
pathway may be required for the control of the cell cycle.
PMID- 9552362
TI - The Cdc28 inhibitor p40SIC1.
AB - Sic1 inhibits the activity of Cdc28.Clb5 complexes in late G1, creating a delay
between cell cycle commitment and S phase initiation. The ultimate purpose of
this delay is unknown but loss of Sic1 activity negatively affects genomic
stability and cellular viability. Sic1 levels are controlled by periodic changes
in transcription rates and protein stability. The latter control is mediated
through the Cdc34 ubiquitin transferase and, possibly, Cdc28.Cln activity.
Possible roles of Sic1 in the G1/S and the M/G1 transitions are discussed.
PMID- 9552363
TI - The NIMA kinase: a mitotic regulator in Aspergillus nidulans and vertebrate
cells.
AB - CDC2 has been shown to regulate entry into mitosis in eukaryotic cells. However,
in Aspergillus nidulans, activation of CDC2 itself is not sufficient to trigger
mitosis if another mitotic protein kinase, NIMA, is not activated. Superficially,
NIMA and CDC2 have analogous functions and are regulated in a similar manner.
NIMA activity is tightly regulated during the cell cycle. Overexpression of NIMA
induces germinal vesicle breakdown in Xenopus oocytes and promotes premature
entry into mitosis in all eukaryotic cells examined, whereas dominant-negative
mutant NIMA causes a specific G2 arrest in Aspergillus nidulans and human cells,
as is the case for CDC2. However, NIMA and CDC2 have quite distinct primary
sequence substrate specificities. Furthermore, the regulatory mechanisms that
govern the cell cycle-dependent abundance, activity and localization are largely
intramolecular for NIMA but intermolecular for CDC2. More importantly, a NIMA
like pathway is also required for the G2/M transition in vertebrate cells. Thus,
NIMA may represent a new essential eukaryotic cell cycle regulator, although its
homologues in other species are yet to be identified.
PMID- 9552364
TI - The fission yeast Nim1/Cdr1 kinase: a link between nutritional state and cell
cycle control.
AB - Close connections appear to exist between extra-cellular signals that regulate
cell proliferation and the protein kinases that control the cell cycle machinery.
The fission yeast nim1 kinase is an inducer of cdc2 kinase activity acting
through the inhibition of wee1 kinase. Nim1 function is required for a correct
cellular response to nutritional starvation. In the absence of nim1, starved
cells are unable to decrease their size at mitosis, to arrest their cycle in G1
and to enter G0. Here, we review our current knowledge on the role and the
regulation of nim1 in connecting cell cycle and nutritional pathways.
PMID- 9552365
TI - Function and regulation of cdc25 protein phosphate through mitosis and meiosis.
AB - Activation of the cyclin B-cdc2 kinase mitotic inducer involves dephosphorylation
of two inhibitory residues, tyrosine 15 and threonine 14, cdc25 is the specific
phosphatase that directly dephosphorylates and activates the cdc2 kinase, cdc25
activity is regulated by phosphorylation. Both phosphatases 1 and 2A could act as
cdc25-specific inhibitory phosphatases. Although the cyclin B-cdc2 complex plays
a role in activating cdc25, it is highly probable that a distinct protein kinase
is involved as a trigger in cdc25 activation. The implication of raf kinase as a
cdc25-specific activating kinase in human cells and Xenopus oocytes is discussed.
PMID- 9552366
TI - The regulation and functions of cdk7.
AB - cdk7 started its life rather anonymously as a kinase called MO15, identified
during a search for cDNA's which encode protein kinases related to cdc2. For
several years its function remained obscure, but during the last 18 months MO15
has revealed itself as the catalytic subunit of cdk activating kinase,
associating with at least two other subunits including a new cyclin, cyclin H.
MO15(cdk7) has therefore been established paradoxically as both a new member and
a regulator of the cyclin dependent kinase family. New evidence now suggests that
cdk7 is also involved in the processes of transcription initiation and DNA
repair, associating with the general transcription factor TFIIH. The engima of
cdk7 is likely to remain for a while yet, and perhaps even more surprises are in
store.
PMID- 9552367
TI - Implications for cAMP-dependent protein kinase in the maintenance of the
interphase state.
AB - The cAMP dependent protein kinase (A-kinase) is one of the first and best studied
kinases in mammalian cells. There is extensive evidence that A-kinase activity
acts antagonistically toward mitotic entry both in oocyte and somatic cells.
Firstly, A-kinase seems to directly compromise the activation process of the cdc2
cyclin B mitotic kinase. Secondly, as shown by specific in vivo inhibition of A
kinase using microinjection of a stable form of its inhibitor peptide PKI, A
kinase modulates several key interphase cellular processes including cytoskeletal
dynamics, transcription, chromatin structure and nuclear localization. We discuss
the potential mechanisms involved in the down regulation of A-kinase activity at
the interphase/mitosis transition.
PMID- 9552368
TI - G-protein-mediated signal transduction for meiosis reinitiation in starfish
oocyte.
AB - Starfish oocyte maturation is induced by 1-methyladenine. There were apparently
two forms of 1-methyladenine receptor affected by GTP gamma S. Pertussis toxin
ADP-ribosylated the 39-kDa alpha subunit of a G protein and inhibited maturation.
Also, the G protein was ADP-ribosylated by cholera toxin only when 1
methyladenine was added. The purified G protein had an heterotrimeric structure
consisting of 39 kDa alpha, 37 kDa beta, and 8 kDa gamma subunits. The deduced
amino acid sequence of the cDNA of starfish G alpha was 89% identical to
mammalian Gi-1 alpha. The purified starfish beta gamma-subunits induced
maturation when they were microinjected into oocytes.
PMID- 9552369
TI - Phosphorylation of elongation factor-1 (EF-1) by cdc2 kinase.
AB - Elongation factor-1 (EF-1) is a major substrate for cdc2 kinase in Xenopus
oocytes. The guanine-nucleotide exchange factor EF-1 beta gamma delta, appears to
have a highly complex macromolecular structure containing several GTP/GDP
exchange proteins, valyl-tRNA synthetase, and a putative anchoring protein EF-1
gamma. During meiotic cell division, the factor becomes phosphorylated by cdc2
kinase, not only on EF-1 gamma, but also on two different phospho-acceptors on EF
1 delta. Phosphorylation is concomitant with changes in protein synthesis in
vivo. Xenopus oocytes, and potentially all cells, contain a multitude of
heteromeric forms of the complex which postulates that EF-1 beta gamma delta is
not a "house keeping" factor but a sophisticated regulatory element.
PMID- 9552370
TI - The regulation of mitotic nuclear envelope breakdown: a role for multiple lamin
kinases.
AB - The chapter reviews the structure and function of the nuclear envelope and
describes its dynamic structural changes during cell cycle. Particular emphasis
is placed on the regulation of mitotic nuclear envelope breakdown (NEBD), the
process by which the physical barrier between cytoplasm and nucleus is dissolved
to allow for cell division. The literature suggesting the involvement of multiple
protein kinases in NEBD is reviewed and evidence is presented that multiple
mitotic lamin kinases, including p34cdc2/cyclin B kinase and protein kinase C,
play key roles in mitotic nuclear lamina disassembly. Finally, a model for
regulation of mitotic nuclear lamina disassembly by multi-site phosphorylation is
described.
PMID- 9552371
TI - The MAP kinase cascade: its role in Xenopus oocytes, eggs and embryos.
AB - Mitogen-activated protein kinase (MAPK) was originally identified as a
serine/threonine kinase that is activated by mitogens. Now MAPK and its
activator, MAPK kinase (MAPKK), are thought to function in a wide variety of
intracellular signalling pathways from yeast to vertebrate. We describe here a
brief summary of the dissection of the MAPK cascade and its possible functions,
especially in Xenopus oocytes and embryos.
PMID- 9552372
TI - The oocyte metaphase arrest.
AB - Usually, oocyte meiosis reinitiation appears as a two step process during which
release from the prophase block is followed by a second arrest in metaphase I or
II. In this review, we will examine the mechanisms required to maintain the
metaphase arrest and stabilize MPF activity at this stage. Then, we will analyse
the processes required to exit from the metaphase block. These may drive the
cells forward to the metaphase-anaphase transition, as a result of fertilization,
activation or protein synthesis inhibition. Instead, inhibiting protein
phosphorylation drives the oocyte back to interphase. All these treatments result
in derepression of DNA synthesis.
PMID- 9552373
TI - Onset of chromosome segregation at the metaphase to anaphase transition of the
cell cycle.
AB - Chromosome segregation is one of the most important acts in the life of the cell.
Unequal inheritance of chromosomes (aneuploidy) is a cause of a number of
disorders, particularly in humans, even though eukaryotic cells can arrest or
delay the transition from metaphase to anaphase if an event critical to the
completion of metaphase is impaired. In this report, we review recent advances in
our knowledge of how the complex process of chromosome segregation is coupled
with cell cycle progression, and starts at onset of anaphase with sister
chromatids separation of the replicated chromosomes.
PMID- 9552374
TI - Mechanisms of chromosome segregation in metazoan cells.
AB - Despite over 100 year of research, the mechanisms that cells use to ensure the
proper segregation of chromosomes during mitosis are still surprisingly obscure.
However, recent high resolution video light microscopic studies of dividing cells
are telling us new and important information about chromosome behavior. Molecular
genetics is enabling us to build a more complete list of the components involved
in chromosome segregation. And in vitro assays for chromosome segregation are
providing information about the signals that control the equipartitioning of
sister chromatids during cell division.
PMID- 9552375
TI - The PITSLRE protein kinase family.
AB - A family of p34Cdc2 related protein kinases, the PITSLRE kinases, is generated by
alternative splicing and promoter utilization from three duplicated and tandemly
linked genes on human chromosome 1p36.3, which is frequently deleted during the
late stages of tumorigenesis. PITSLRE mRNA, protein, and enzyme activity are
induced during Fas receptor- and glucocorticoid-mediated apoptosis of human T
cells. Several PITSLRE isoforms are specific targets of proteolysis during
apoptosis, generating an enzymatically active 50 kDa isoform. Inhibition of this
protease activity blocks PITSLRE processing and enzyme activation, as well as
apoptosis. Thus, PITSLRE kinases may be integral downstream components of
apoptotic signal transduction pathway(s). Furthermore, PITSLRE genes, and their
products, are physically altered in human neuroblastoma tumors, suggesting that
they may be tumor suppressors.
PMID- 9552376
TI - Cell cycle regulation and functions of HMG-I(Y).
AB - Members of the HMG-I(Y) family of "high mobility group" (HMG) proteins are
distinguished from other nonhistone chromatin proteins by their ability to
preferentially recognize the structure of the narrow minor groove of A.T
sequences of B-form DNA. In vivo the HMG-I(Y) proteins are localized in the A.T
rich G/Q bands and in the "scaffold-associated regions" (SARs) of metaphase
chromosomes. These proteins also share with some of the other "HMG box" proteins
the ability to recognize non-B-form structures, such as cruciforms (four-way
junctions), as well as the possessing the capacity to introduce both bends and
supercoils in substrate DNAs. These characteristics, along with their ability to
specifically interact with a number of known transcription factors, enable the
HMG-I(Y) proteins to function in vivo as structural transcription factors for a
number mammalian genes. The HMG-I(Y) proteins are also in vivo substrates for the
cell cycle regulated Cdc2 kinase which phosphorylates the DNA-binding domain(s)
of the protein and, as a result, decreases their substrate binding affinity. This
reversible in vivo pattern of Cdc2 kinase phosphorylations during the cell cycle
is likely to play a major role in mediating the biological function(s) of the HMG
I(Y) proteins.
PMID- 9552377
TI - Chemical inhibitors of cyclin-dependent kinases.
AB - The eukaryotic cell division cycle is regulated by a family of protein kinases,
the cyclin-dependent kinases (cdk's), constituted of at least two subunits, a
catalytic subunit (cdk1-7) associated with a regulatory subunit (cyclin A-H).
Transient activation of cdk's is responsible for transition through the different
phases of the cell cycle. Major abnormalities of cdk's expression and regulation
have been described in human tumours. Enzymatic screening is starting to uncover
chemical inhibitors of cdk's with anti-mitotic activities. This review summarizes
our knowledge of these first inhibitors, their mechanism of action, their effects
on the cell cycle, and discusses the potential of such type of inhibitors as anti
tumour agents.
PMID- 9552378
TI - A quest for cytoplasmic factors that control the cell cycle.
AB - Between 1966 and 1986 the author and his former students carried out an
investigation into the cytoplasmic factors that regulate nuclear behaviour during
meiotic maturation of oocytes. This anecdotal chronicle traces the development of
the problems and the direction in which their solutions were attempted in the
course of this investigation. The author examines why he decided to study oocyte
maturation, how he discovered progesterone as a maturation-inducing hormone and
maturation promoting factor (MPF) and cytostatic factor (CSF) as meiosis
controlling factors, how the idea of the cell cycle without the cell occurred to
him, and how it was materialised by invention of a cell-free system.
PMID- 9552379
TI - G1/S regulatory mechanisms from yeast to man.
AB - Cyclin-dependent kinases play a key role in promoting and regulating the
transition from G1 to S phase in all eukaryotic organisms. The kinase activities
involved are distinguished from those participating in other cell cycle phase
transitions in that they are driven by a class of specialised G1-specific
cyclins. Although the G1 regulatory components have diverged structurally in the
course of evolution, the regulatory mechanisms and principles remain highly
conserved from yeast to vertebrates. An important issue that remains is that of
identifying the principal targets phosphorylated by G1 cyclin-dependent kinases.
PMID- 9552380
TI - Regulation of G1 progression in fission yeast by the rum1+ gene product.
AB - Recently it has been found that B-type cyclins in fission yeast regulate the
activation of the cdc2 kinase to promote the onset of both DNA replication and
mitosis. cig2 is the major G1 cyclin while cdc13 is the principal mitotic cyclin.
cdc13 also has an additional function in G2 phase, preventing more than one round
of DNA replication per cell cycle. In opposition to these cyclins the rum1
inhibitor, a protein present exclusively in G1, prevents premature activation of
the cdc2/cig2 and the cdc2/cdc13 complexes until cells have reached the critical
cell size required to pass Start and initiate a new cell cycle.
PMID- 9552381
TI - Progression through G1 and S phases of adult rat hepatocytes.
AB - Regenerating liver, hepatocyte primary cultures and differentiated hepatoma cell
lines are widely used to study the proliferation/differentiation/apoptosis
equilibrium in liver. In hepatocytes, priming factors (TNF alpha, IL6) target
G0/G1 transition while growth factors (HGF, EGF, TGF alpha) control a mid-late G1
restriction point. A characteristic pattern of cdk/cyclin expression is observed
in hepatocytes, presumably related to their ability to proliferate a limited
number of times and to undergo a reversible differentiation. Interestingly, cell
cell interactions between hepatocytes and liver biliary cells in co-cultures,
result in a cell cycle arrest in mid G1 of hepatocytes which are insensitive to
mitogens. Apoptosis exists in hepatocytes but is still poorly documented.
However, hepatoma cell lines stimulated by TGF beta undergo cell death in a p53
independent pathway. In conclusion, the interplay of growth and apoptosis
regulators and cell-cell interactions control the
proliferation/differentiation/apoptosis balance which is a specific feature of
hepatocytes.
PMID- 9552382
TI - A temporal and biochemical link between growth factor-activated MAP kinases,
cyclin D1 induction and cell cycle entry.
AB - Cell cycle re-entry requires the growth factor-stimulation of at least two
distinct classes of protein kinases: (i) the p42/p44 MAP kinases activated by the
Ras > Raf > MKK cascade and (ii) the G1 cyclin-dependent protein kinases (CDKs).
Specific inactivation of either class of kinase arrests fibroblasts in G1. Growth
factors promote nuclear translocation and persistent activation of p42/p44 MAP
kinases during the entire G0/G1 period. Here, we demonstrate that induction of
cyclin D1, and therefore cdk4/6 activity associated with, is positively
controlled by the p42/p44 MAP kinase cascade whereas the parallel
cytokines/stress-activated p38MAP kinase cascade is antagonistic. Finally, using
an antisense approach we demonstrate that p27Kip1 plays a key role in setting the
growth factor-dependency of the G0 state.
PMID- 9552383
TI - The plant cell cycle: conserved and unique features in mitotic control.
AB - Somatic plant cells can use a hormone checkpoint in late G2 phase. Here cytokinin
stimulates removal of phosphotyrosine from p34cdc2 kinase and concurrently
capacity for activation of the kinase by Cdc25 phosphatase declines while
activity of the kinase increases and cells enter mitosis. Processes unique to
plant mitosis are driven by the mitotically active kinase since the enzyme taken
from plant cells in metaphase, when injected, can disassemble the preprophase
band microtubules that form in G2 phase at the site of the future cross wall.
This action is specific, since microtubules are not depolymerised when in
interphase cytoplasmic array, or spindle, or phragmoplast. Plant metaphase kinase
acts as MPF by accelerating chromosome condensation and nuclear envelope
breakdown.
PMID- 9552384
TI - The functions of Myc in cell cycle progression and apoptosis.
AB - c-myc has emerged as one of the central regulators of mammalian cell
proliferation. The gene encodes a transcription factor of the HLH/leucine zipper
family of proteins that activates transcription as part of a heteromeric complex
with a protein termed Max. In mammalian fibroblasts, Myc acts as an upstream
regulator of cyclin-dependent kinases and functionally antagonises the action of
at least one cdk inhibitor, p27. Myc also induces cells to undergo apoptosis, and
the relationship between Myc-induced cell cycle entry and apoptosis is discussed.
PMID- 9552385
TI - DNA replication licensing factor.
AB - DNA Replication Licensing Factor (RLF) is an essential activity required to
restrict the duplication of genomic DNA to precisely once per cell cycle. Recent
fractionation of RLF activity from Xenopus egg extracts has resulted in the
identification of two essential components, RLF-B and RLF-M. RLF-M has been
purified to homogeneity and has been shown to consist of a complex of proteins in
the MCM/P1 family. RLF-B is still unidentified, but possible candidates for this
activity have been identified in yeast. Elucidation of the RLF mechanism will
provide important insights into the way that chromosome replication is
controlled.
PMID- 9552386
TI - Tyrosine kinases wee1 and mik1 as effectors of DNA replication checkpoint
control.
AB - Cell cycle studies have revealed mechanisms that prevent cell division if DNA
fails to be completely replicated or sustains damage. Here we focus on the
evidence from yeast genetics that the wee1 and mik1 tyrosine kinases cooperate in
the inhibitory phosphorylation of cdc2p, and the possibility that these kinases
function in pathways that ensure the integrity of the genome prior to cell
division. We also review the progress in cloning and analysing wee1-like tyrosine
kinases from higher eukaryotes, and the evidence for and against their
functioning in ensuring DNA replication prior to mitosis. Finally, we discuss the
genes involved in these feedback controls and suggest that wee1p and mik1p might
be the ultimate effectors that prevent mitosis when a checkpoint is triggered.
PMID- 9552387
TI - Regulation of Cdc2 activity by phosphorylation at T14/Y15.
AB - The highly conserved Cdc2 serine/threonine kinase plays a central role in cell
cycle progression. Although Cdc2 levels remain constant throughout the cell
cycle, Cdc2 kinase activity peaks at the G2/M boundary, in order to drive entry
into mitosis. In the model organism Schizosaccharomysces pombe, potentially
active Cdc2/Cdc13 kinase complex accumulates throughout the S and G2 phases of
the cell cycle. This complex, however, is maintained in an active state by
Wee1/Mik1-mediated phosphorylation at Y15 (and, possibly, T14). At the G2/M
boundary, the Cdc25 protein phosphatase is activated to dephosphorylate the
Cdc2/Cdc13 complex, resulting in abrupt activation of Cdc2 kinase activity and
entry into mitosis.
PMID- 9552388
TI - The family of polo-like kinases.
AB - Here we discuss members of a new family of serine/threonine protein kinases with
a likely role in cell cycle control. These kinases are referred to as polo-like
kinases, after the prototypic founding member of the family, the polo gene
product of Drosophila melanogaster. The polo kinase was originally identified in
mutants that display abnormal mitotic spindle organization. Subsequently,
potential homologues of Drosophila polo have been identified in yeasts (Cdc5p in
Saccharomyces cerevisiae; plo1+ in Schizosaccharmoyces pombe) and in mammals
(polo-like kinase 1; Plk1). Genetic and biochemical studies suggest that polo,
Cdc5p and plo1+ may be required for mitotic spindle organization and, possibly,
for cytokinesis. Likewise, the patterns of expression, activity and subcellular
localization of Plk1 strongly suggest that this mammalian kinase functions also
during mitosis, possibly in spindle assembly and function. In addition to Plk1,
however, more distantly related members of the polo-like kinase family have been
identified in mammalian cells, and the available data are consistent with the
idea that some of these may act earlier in the cell cycle, possibly during G1. If
this hypothesis is correct, different members of the polo-like kinase family
would act at several points during the cell cycle, reminiscent of the behaviour
of Cdk/cyclin complexes.
PMID- 9552389
TI - Ubiquitin-dependent proteolysis and cell cycle control in yeast.
AB - Genetic and biochemical data indicate that ubiquitin-mediated proteolysis is
involved in the regulated turnover of proteins required for controlling cell
cycle progression. In general, mutations in some genes that encode proteins
involved in the ubiquitin pathway cause cell cycle defects and affect the
turnover of cell cycle regulatory proteins. Furthermore, some cell cycle
regulatory proteins are short-lived, ubiquitinated, and degraded by the ubiquitin
pathway. This review will examine how the ubiquitin pathway plays a role in
regulating progression from the G1 to the S phase of the cell cycle, as well as
the G2 to M phase transition.
PMID- 9552390
TI - Suc1: cdc2 affinity reagent or essential cdk adaptor protein?
AB - CKS proteins, for which the original member, p13suc1, was identified as a
suppressor of cdc2 alleles in S. Pombe, have long served as a reagent for the
purification of p34cdc2, whereas their biological function has remained elusive.
Apparently conflicting data derived from different model systems may indicate a
diversity of function for these proteins. Several new observations in yeast and
Xenopus egg extracts together with new structural information tends to enhance
the hypothesis that CKS proteins function to alter the activity of cdc2 at
several important points in the cell cycle. Here we review previous observations
and recent data that suggest CKS proteins serve as adaptor proteins that modify
the functions of cdc2 throughout the cell cycle.
PMID- 9552391
TI - Structural basis for chemical inhibition of CDK2.
AB - The central role of cyclin-dependent kinases (CDKs) in cell cycle regulation
makes them a promising target for discovering small inhibitory molecules that can
modify the degree of cell proliferation. The three-dimensional structure of CDK2
provides a structural foundation for understanding the mechanisms of activation
and inhibition of CDK2 and for the discovery of inhibitors. In this article five
structures of human CDK2 are summarised: apoprotein, ATP complex, olomoucine
complex, isopentenyladenine complex, and des-chloro-flavopiridol complex.
PMID- 9552393
TI - DNA damage checkpoints: implications for cancer therapy.
AB - DNA damage evokes a complex array of cellular responses, including cycle arrest
in late G1 and/or G2 phases, and delayed progression through S phase. Arrest at
these points in the cell cycle is governed, in large part, by a series of control
systems, commonly termed "checkpoints". Activation of these checkpoints tends to
protect cells from DNA damage by providing cells additional time to complete DNA
repair. We discuss the impact of these DNA damage checkpoints on the
chemosensitivity of human cancer cells. We focus on some of the complexities of
the p53-dependent G1 checkpoint and review some recently discovered
vulnerabilities in p53 disrupted cells that might be pharmacologically exploited
for cancer treatment.
PMID- 9552392
TI - Apoptosis and the cell cycle.
AB - Apoptosis is a genetically controlled response by which eukaryotic cells undergo
programmed cell death. This phenomenon plays a major role in developmental
pathways (1), provides a homeostatic balance of cell populations, and is
deregulated in many diseases including cancer. Control of cell number is
determined by an intricate balance of cell death and cell proliferation.
Accumulation of cells through suppression of death can contribute to cancer and
to persistent viral infections, while excessive death can result in impaired
development and in degenerative diseases. Identification of genes that control
cell death, and understanding of the impact of apoptosis in both development and
disease has advanced our knowledge of apoptosis in the past few years. There
appears to be a linkage between apoptosis and cell cycle control mechanisms.
Elucidating the mechanisms that link cell cycle control with apoptosis will be of
key importance in understanding tumour progression and designing new models of
effective tumour therapy.
PMID- 9552395
TI - Telomeres, telomerase, and the cell cycle.
AB - Telomeres protect the ends of chromosomes from degradation and fusion. In most
eukaryotes telomeres are replicated by a specialised polymerase, telomerase.
Telomerase synthesises one strand of the telomere; while conventional DNA
polymerases synthesise the complementary strand. Additional processing of
telomeres occurs in ciliates and yeast during each cell cycle. Telomerase
activity and RNA levels change as cells enter and exit the cell cycle. Gradual
telomere shortening in the absence of telomerase does not immediately affect cell
cycling; however, "critically" short telomeres are hypothesised to play a role in
senescence and the triggering of DNA damage checkpoints.
PMID- 9552394
TI - Cellular responses to antimetabolite anticancer agents: cytostasis versus
cytotoxicity.
AB - Thymineless death is an important cytotoxic response to several classes of
antimetabolite agents used in the treatment of patients with carcinomas and
hematopoeitic malignancies. Cell death induced by lack of dThd results in the
formation of DNA nucleosomal ladders, and hence would be defined as a form of
apoptosis. Although drug resistance to these agents has been extensively studied,
relatively little attention has been focused on events downstream of dTTP
depletion that determine the ultimate fate of the cancer cell. In this article we
review some of the emerging data that suggests the role of p53 in determining
whether the cellular response to dThd deprivation is cytostasis or cytotoxicity
(apoptosis).
PMID- 9552396
TI - The cyclin C/Cdk8 kinase.
AB - Cyclin C was originally identified in a genetic screen for metazoan cDNAs that
complement a triple knock-out of the CLN genes, involved in G1/S progression in
S. cerevisiae. Unlike cyclin Ds and cyclin E, also identified in this screen,
cyclin C has not been found to have a cell-cycle role in metazoa. Identified as
the catalytic partner of cyclin C, Cdk8 is a novel protein-kinase of the Cdk
family structurally related to the yeast Srb10 kinase. Cyclin C, Cdk8 and RNA
polymerase II are found in a large multi-protein complex that shows structural as
well as functional homologies with the yeast polymerase II holoenzyme. These
observations and the sequence similarity to the kinase/cyclin pair Srb10/Srb11 in
S. cerevisiae, suggest that cyclin C and Cdk8 control RNA polymerase II function.
PMID- 9552397
TI - Cyclin-dependent kinase 5 (Cdk5) and neuron-specific Cdk5 activators.
AB - While cyclin-dependent kinase 5 (Cdk5) is widely distributed in mammalian tissues
and in cultured cell lines, Cdk5-associated kinase activity has been demonstrated
only in mammalian brains. An active form of Cdk5, called neuronal cdc2-like
kinase (Nclk) has been purified from mammalian brain and shown to be a
heterodimer of Cdk5 and a 25 kDa protein, which is derived proteolytically from a
35 kDa brain and neuron-specific protein. The protein is essential for the kinase
activity of Cdk5 and is therefore designated neuronal Cdk5 activator,
p25/35Nck5a. Nclk appears to have important neuronal functions. The changes in
Cdk5 and Nck5a expression appear to correlate with the terminal differentiation
of neurons of the mouse embryonic brain. Transfection of cultured cortical
neurons with dominant negative cdk5 mutants or Nck5a antisense DNA may reduce
neurite growth, suggesting that Nclk plays an active role in neuron
differentiation. A number of cytoskeletal proteins including neurofilament
proteins, the neuron-specific microtubule associated protein tau, and the actin
binding protein caldesmon are in vitro substrates of Nclk. Although Nck5a has
cyclin-like activity, it shows minimal amino acid sequence identity to members of
cyclin family proteins. The mechanism of activation of Cdk5 by Nck5a differs from
that of cyclin activation of Cdks in that full Cdk5 kinase activity can be
achieved in the absence of phosphorylation of Cdk5. An isoform of Nck5a, a 39 kDa
protein has been cloned and shown to share extensive amino acid identity and the
mechanism of Cdk5 activation with Nck5a. These proteins may represent a subfamily
of Cdk activators distinct from cyclins.
PMID- 9552398
TI - Role of Ca++/calmodulin binding proteins in Aspergillus nidulans cell cycle
regulation.
AB - The goal of this review is to summarise the current knowledge concerning the
targets of Ca++/calmodulin that are essential for cell cycle progression in lower
eukaryotes. Emphasis is placed on Aspergillus nidulans since this is the only
organism to date shown to posses essential Ca++ dependent calmodulin activated
enzymes. Two such enzymes are the calmodulin activated protein phosphatase,
calcineurin and the calmodulin dependent protein kinase. These proteins, each the
product of a unique gene, are required for progression of quiescent spores into
the proliferative cycle and also for execution of the nuclear division cycle in
exponentially growing germlings.
PMID- 9552399
TI - The roles of DNA topoisomerase II during the cell cycle.
AB - DNA topoisomerase II (topo II) is essential for survival of all eukaryotic cells.
Topo II is both an enzyme and a structural component of the nuclear matrix. It
regulates the topological states of DNA by transient cleavage, strand passing and
re-ligation of double-stranded DNA resulting in decatenation of intertwined DNA
molecules and relaxation of supercoiled DNA. Topo II plays an important role in
DNA replication and is required for condensation and segregation of chromosomes.
The expression of topo II is cell cycle dependent with both protein levels and
catalytic activity peaking at G2/M. Phosphorylation/dephosphorylation of topo II
may be a part of regulatory checkpoints at the entry and progression of mitosis.
PMID- 9552400
TI - Circadian rhythm of cell division.
AB - The existence of circadian oscillations in the level of hormones, in numerous
physiological parameters, in toxicity and in behavior is now fully recognized in
all living organisms. In contrast, the synchronisation and regulation of cell
proliferation by circadian rhythms in vivo is only starting to be appreciated.
This article reviews the experimental evidence for circadian synchronisation of
cell division in different mammalian tissues (mainly the gastro-intestinal tract
and hemapoietic system), including tumoral tissues. The possible causes of this
coupling of the cell cycle phases to the circadian rhythm are discussed. Testing
of novel antitumour agents using murine models should take into consideration the
temporal difference between murine and human circadian control of proliferation
(the peak of DNA synthesis occurs during the activity period, i.e. during daytime
in man, and at night-time in mice and rats). Experimental and clinical data
clearly support the important implications of the circadian control of the cell
cycle in the optimisation of cancer chemotherapy, both for reducing toxicity and
increasing the antitumour effects.
PMID- 9552401
TI - The mammalian Golgi apparatus during M-phase.
AB - The Golgi apparatus in mammalian cells disassembles into several thousand
vesicles as cells enter M-phase. Disassembly is dependent on the action of cdc2
kinase and at least two pathways contribute to the fragmentation: One involves
the budding of COP-coated vesicles from Golgi cisternae with concomitant
inhibition of fusion with their target membranes, the other is a less well
characterised COP-independent pathway. During telophase, the Golgi fragments
reassemble and fuse into a fully functional Golgi stack, using at least two
distinct fusion pathways. The morphological changes of the Golgi apparatus during
M-phase offer an ideal system to study how cellular organelles are generated and
how their structure is maintained during interphase.
PMID- 9552402
TI - Viruses and the cell cycle.
AB - Viruses depend on the host's machineries to replicate and express their genome.
Actively replicating cells have large pools of deoxynucleotides and high levels
of key enzyme activities that viruses exploit to their own needs. Some viruses
have developed strategies for driving quiescent cells into the S phase of the
cell cycle, e.g. adenovirus, others, such as parvovirus, wait until the host
itself begins to replicate. Viruses may also force the host cell to stay in a
favourable phase, e.g. Epstein-Barr virus, or, if necessary, they may inhibit
apoptotic cell death, e.g. human cytomegalovirus. In this review, we focus on the
different strategies that viruses use to create in infected cells an environment
favourable to the accomplishment of the viral life cycle through acting on cell
cycle regulators.
PMID- 9552403
TI - HIV-1 Vpr: G2 cell cycle arrest, macrophages and nuclear transport.
AB - HIV-1 possesses six open reading frames in addition to the gag, pol, and env
shared by all retroviruses. One of these accessory genes, vpr, is required for
maximal viral replication in macrophages. The molecular mechanism underlying this
effect may be related to one of the unusual properties of the encoded protein:
some believe Vpr promotes nuclear translocation of preintegration complexes in
non-dividing cells; also, Vpr arrests the cell cycle in G2 by inhibiting an
upstream activator of p34cdc2-cyclin B. Elucidation of Vpr-cell cycle
interactions may provide insight into both HIV-1 and basic cell biology.
PMID- 9552404
TI - Regulation of cell division in plants: an Arabidopsis perspective.
AB - Considerable progress has been achieved in the identification and molecular
characterisation of genes and/or cDNAs coding for cyclin-dependent kinases (CDK)
as well as cyclins in diverse plant species including Arabidopsis thaliana. Their
transcriptional control during the cell cycle progression and the response to
developmental cues and environmental signals has been studied in much detail,
although the transcription factors mediating this regulation have yet to be
identified. Experimental evidence has validated the involvement of CDKs and
cyclins in cell division control in Arabidopsis and has revealed differential
activation of two Arabidopsis CDKs in the course of the cell cycle. Finally, the
first active CDK/cyclin pairs are being characterised, providing the basis for
elucidation of their specific functions in cell cycle control and for unravelling
the mechanisms that control their activity.
PMID- 9552406
TI - Coordinate regulation of cell cycle and apoptosis during myogenesis.
AB - During myogenesis, precursor cells irreversibly withdraw from the cell cycle as
they differentiate into mature myotubes. The state of myocyte differentiation
also influences the propensity of these cells to undergo apoptosis. Proliferative
precursor cells are far more susceptible to apoptotic cell death than are
terminally differentiated myotubes. The upregulation of the cdk inhibitor p21 and
the dephosphorylation of pRb are critical regulatory events that establish both
the post-mitotic and apoptosis-resistant states. The coordinate regulation of
cell proliferation and death provides the organism with a mechanism to control
the deposition of muscle mass during embryonic development.
PMID- 9552405
TI - Intestinal cell cycle regulation.
AB - The intestinal epithelium is maintained by a balance between proliferation,
differentiation and death that occurs as cells migrate up the crypt-villus axis.
Cell cycle regulators such as cyclins, cyclin-dependent kinases (Cdks) and Cdk
inhibitory proteins are expressed in a distinct pattern along the crypt-villus
structure, suggesting their role in controlling intestinal cells. This is
supported by observations that these cell cycle proteins are regulated by growth
factors, nutrients and cell-cell contact in cultured intestinal epithelial cells.
One of the key regulators of intestinal cell proliferation and differentiation is
transforming growth factor-beta, which is expressed in the gut epithelium.
PMID- 9552407
TI - Cell cycle regulation of organelle transport.
AB - Microtubule- and actin-based motors play a wide range of vital roles in the
organisation and function of cells during both interphase and mitosis, all of
which are likely to be under strict control. Here, we describe how one of these
roles--the movement of membranes--is regulated through the cell cycle. Organelle
movement in many species is greatly reduced in mitosis as compared to interphase,
and this change occurs concomitantly with an inhibition of most membrane traffic
functions. Data from in vitro studies is shedding light on how microtubule motor
regulation may be achieved.
PMID- 9552408
TI - Protein kinase CK2 ("casein kinase-2") and its implication in cell division and
proliferation.
AB - Protein kinase CK2 (also termed casein kinase-2 or -II) is a ubiquitous Ser/Thr
specific protein kinase required for viability and for cell cycle progression.
CK2 is especially elevated in proliferating tissues, either normal or
transformed, and the expression of its catalytic subunit in transgenic mice is
causative of lymphomas. CK2 is highly pleiotropic: more than 160 proteins
phosphorylated by it at sites specified by multiple acidic residues are known.
Despite its heterotetrameric structure generally composed by two catalytic (alpha
and/or alpha') and two non catalytic beta-subunits, the regulation of CK2 is
still enigmatic. A number of functional features of the beta-subunit which could
cooperate to the modulation of CK2 targeting/activity will be discussed.
PMID- 9552409
TI - The regulation of cyclin-dependent kinase inhibitors (CKIs).
AB - Inhibitors of cyclin-dependent kinases (CKIs) play key roles in coordinating cell
proliferation and development. They also function to control critical cell cycle
transitions and as effectors of checkpoint pathways. The activity of CKIs is
tightly controlled through the cell cycle and in response to various signals.
Regulation generally affects the levels or availability of the CKIs rather than
changing their intrinsic activities. Mechanisms controlling CKI function include
the regulation of transcription, translation and proteolysis. In addition some
signals appear to induce sequestration of CKIs within the cells, thereby changing
their ability to interact with specific targets.
PMID- 9552410
TI - Contribution of the dual coding capacity of the p16INK4a/MTS1/CDKN2 locus to
human malignancies.
AB - During the three last years, the so-called p16 locus on human chromosome band
9p21 has been increasingly implicated in different cancers by a variety of
alterations abolishing both copies of the p16INK4a/MTS1/CDKN2 gene and the
adjacent p15INK4b gene, two members of a family of specific inhibitors of the
cyclin D 1-3-CDK4/6 complexes that control cell cycle progression of the G1 to S
phase. While these properties are characteristic of tumor suppressor genes,
abundant experimental data have clearly identified a link between the loss of
function of p16INK4a and tumorigenic processes. The role of p15INK4b alterations
in the onset of natural and experimental tumors is less obvious. New light may be
shed on the role of the p16 locus in tumor development by the recent finding that
an alternative transcript from the p16INK4a gene encodes p19ARF, a negative
regulator of cell cycle progression which is unrelated to p16 and p15 and does
not act by binding any CDK. Hence, this protein appears to be an element of a
novel negative cell cycle control mechanism, whose impairing might be involved in
tumorigenesis.
PMID- 9552411
TI - p21: structure and functions associated with cyclin-CDK binding.
AB - The cyclin dependent kinase inhibitor, p21, is a multifunctional protein involved
in coordinating the cellular response to negative growth signals. Induced by
cellular damage under the transcriptional control of the p53 tumour suppressor
protein, p21 interfaces with a number of cellular proteins involved in growth
control. Although p21 has a diverse range of activities, from assembly factor to
transcriptional modulator, its ability to interact with and regulate the activity
of the cyclin dependent protein kinases is paramount to many of these functions.
PMID- 9552412
TI - The cdc18 protein initiates DNA replication in fission yeast.
AB - Recent work has demonstrated that cdc18p plays a crucial role in regulating the
onset of S phase in fission yeast. cdc18p is a major product of START specific
transcription and associates with ORC and MCM proteins which are required for the
initiation of DNA replication. High expression of cdc18p induces continuing DNA
synthesis and is thought to drive the assembly of initiation complexes. In
addition to its role in bringing about DNA replication, cdc18p participates in
the cell cycle checkpoint control linking S phase to START and mitosis. We
propose that cdc18p is central to the molecular mechanism co-ordinating S phase
and M phase in concert with changes in activity of the master cell cycle
regulator, the cdc2 protein kinase.
PMID- 9552413
TI - Cell cycle regulation of S phase entry in Saccharomyces cerevisiae.
AB - Eukaryotic DNA replication is restricted to a narrow window of the cell cycle
called S phase, and occurs once and only once during each cell cycle. The
combination of genetic and biochemical approaches in the budding yeast
Saccharomyces cerevisiae has proven extremely helpful for studying the cell cycle
regulation of S phase entry. This review will try to summarise the most recent
discoveries which led to a new model to explain how entry into S phase is
regulated in eukaryotic cells.
PMID- 9552414
TI - The role of cyclin E in cell proliferation, development and cancer.
AB - Normal cell proliferation is under strict regulation governed by checkpoints
located at distinct points in the cell cycle. The deregulation of these
checkpoint events and the molecules associated with them may transform a normal
cell into a cancer cell. One of these checkpoints whose deregulation results in
transformation occurs at the Restriction point, near the G1/S boundary. The
periodic appearance of one of the recently identified regulatory cyclins, cyclin
E, coincides precisely with the timing of the Restriction point. The deregulation
in the expression and activity of cyclin E has been associated with a number of
cancers and is thought to be involved in the process of oncogenesis. In this
chapter, we summarise the current knowledge on the regulation and apparent
function of cyclin E in normal proliferating cells and in developing tissue and
alterations of these processes in cancer.
PMID- 9552415
TI - Multiple roles of the proliferating cell nuclear antigen: DNA replication, repair
and cell cycle control.
AB - The proliferating cell nuclear antigen (PCNA), the auxiliary protein of DNA
polymerase delta and epsilon, is involved in DNA replication and repair. This
protein forms a homotrimeric structure which, encircling DNA, loads the
polymerase on the DNA template. A role for PCNA in the cell cycle control is
recognised on the basis of the interaction with cyclins, cyclin-dependent kinases
(cdks) and the cdk-inhibitor p21 waf1/cip1/sdi1 protein. Association with the
growth-arrest and DNA-damage inducible proteins gadd45 and MyD118, further
demonstrates the role of PCNA as a component of the cell cycle control apparatus.
PMID- 9552416
TI - Aberrations of the G1- and G1/S-regulating genes in human cancer.
AB - Deregulated cell proliferation is the hallmark of cancer, and convergent data
from the fields of cell-cycle research and molecular oncology have revealed the
key role played by abnormalities of the cell-cycle control genes in multistep
tumorigenesis. Along with the p53-mediated DNA damage checkpoint, the G1
governing pathway of D-type cyclins, their partner cyclin-dependent kinases
(Cdk), Cdk inhibitors, and the retinoblastoma protein constitute a functional
unit and prominent oncogenic target. We have learned a great deal about the
molecular basis of G1 phase progression and G1/S transition, their proto
oncogenic defects, and potential clinical significance including diagnostic and
prognostic applications and new approaches to gene therapy of cancer.
PMID- 9552417
TI - Regulation of p34cdc2/cyclinB H1 and NIMA kinases during the G2/M transition and
checkpoint responses in Aspergillus nidulans.
AB - In A. nidulans, activation of both p34cdc2/cyclinB H1 and NIMA kinases is
required to initiate mitosis. These two kinases are regulated at several levels
during interphase and are activated independently as protein kinases during G2.
They are also targeted for negative regulation, to prevent mitosis by mitotic
entry checkpoint controls, when DNA is not replicated or is damaged. Then, to
initiate mitosis, they promote each other's mitotic functions to coordinately
promote mitosis upon completion of interphase events. In addition, inactivation
of both kinases by mitotic specific proteolysis is also required for progression
through mitosis into G1.
PMID- 9552418
TI - Myt1: a Wee1-type kinase that phosphorylates Cdc2 on residue Thr14.
AB - Most somatic cell division cycles contain a gap period (G2 phase) between the
completion of DNA synthesis and the initiation of mitosis. This delay of mitotic
entry is controlled, at least in part, by the repression of Cdc2 kinase activity
by the phosphorylation of two conserved residues (Thr14 and Tyr15) within the ATP
binding pocket of the Cdc2 catalytic subunit. The kinases responsible for these
two phosphorylation events include the Myt1 and Wee1 kinases, which phosphorylate
Cdc2 on Thr14 and Tyr15, respectively. In this discussion, we summarise our
current knowledge of the Myt1 kinase and its regulation of Cdc2 kinase activity
during the G2-to -M phase transition.
PMID- 9552419
TI - In vivo regulation of the entry into M-phase: initial activation and nuclear
translocation of cyclin B/Cdc2.
AB - The cyclin B/Cdc2 complex, Cdc2 kinase governs M-phase. Although the intracomplex
modification for its activation in vitro has been described extensively, its
regulation in vivo is not so well explained so far. In this article, we will
focus on the intracellular regulation of the cyclin B/Cdc2 activity, in
particular, how it is initially activated in vivo, how its nuclear translocation
is executed specifically at the onset of M-phase, and how the activation and the
nuclear translocation are coordinated in the cell. These concerted regulations
may determine the appropriate timing for the initiation of M-phase.
PMID- 9552420
TI - Mos and the cell cycle.
AB - The mos proto-oncogene-encoded serine/threonine protein kinase plays a key cell
cycle-regulatory role during meiosis. The Mos protein is required for the
activation and stabilisation of M phase-promoting factor MPF. As a component of a
large multiprotein complex known as the cytostatic factor (CSF), Mos is involved
in causing metaphase II arrest of eggs in vertebrates. Upon expression in somatic
cells, Mos causes cell cycle perturbations resulting in cytotoxicity and
neoplastic transformation. All the known biological activities of Mos are
mediated through activation of the mitogen activated protein (MAP) kinase
pathway. Here we discuss the interrelationship between Mos and other cell cycle
regulators.
PMID- 9552421
TI - Calcium and mitosis.
AB - Calcium signals often accompany mitosis. The most obvious example of calcium as a
mitotic signal is at fertilization in vertebrate eggs, where the calcium
transient induces anaphase onset. New imaging methods have demonstrated smaller
calcium signals that control mitosis entry and mitosis exit in sea urchin
embryos. Other experiments in mouse and frog embryos indicate that similar
signals with similar function may play a part in these embryos, too. The links
between these calcium control signals and mitotic kinase activation are
adumbrated. It appears that calcium oscillations are a property of the mitotic
state. A case is made that calcium may be a universal mitotic signal, with the
possible exception of early meiotic events in oocytes.
PMID- 9552422
TI - Role of chromosomes in assembly of meiotic and mitotic spindles.
AB - The assembly of a mitotic spindle requires the interaction of microtubules with
chromosomes. As a cell enters mitosis, long microtubules are converted to short
ones, as microtubules become unstable. Dynamic microtubules are then stabilised
by chromosomes, forming a bipolar spindle. In this review, we discuss the
different roles of kinetochores and chromosome arms during spindle assembly.
Kinetochores, required for proper chromosomes segregation, capture microtubules
and maintain attachment. Chromosome arms greatly enhance microtubule stability,
and alone can be sufficient for spindle assembly.
PMID- 9552423
TI - Organisation and functional regulation of the centrosome in animal cells.
AB - Molecular characterisation of centrosomal components is slowly progressing.
Recent results indicate that the major aspects of centrosome-mediated microtubule
nucleation may soon be understood at the molecular level. In contrast, centrosome
reproduction, which is an important aspect of animal cell division, remains terra
incognita. The most challenging issue for the future is to understand the
molecular mechanisms which control centrosome biogenesis. There is a urgent need
to identify with certainty proteins implicated in this process. Comparison
between organisms with structurally different centrosomes might be critical for a
better understanding of centrosome duplication if a general mechanism has been
conserved throughout evolution.
PMID- 9552424
TI - Mitosis and checkpoints that control progression through mitosis in vertebrate
somatic cells.
AB - During mitosis in vertebrates the sister kinetochores on each replicated
chromosome interact with two separating arrays of astral microtubules to form a
bipolar spindle that produces and/or directs the forces for chromosome motion. In
order to ensure faithful chromosome segregation cells have evolved mechanisms
that delay progress into and out of mitosis until certain events are completed.
At least two of these mitotic "checkpoint controls" can be identified in
vertebrates. The first prevents nuclear envelope breakdown, and thus spindle
formation, when the integrity of some nuclear component(s) is compromised. The
second prevents chromosome disjunction and exit from mitosis until all of the
kinetochores are attached to the spindle.
PMID- 9552425
TI - Will the Pharm.D. Make the pharmaceutics Ph.D. an endangered species?
PMID- 9552426
TI - An in vitro method to investigate food effects on drug release from film-coated
beads.
AB - The influence of simulated high-fat meals on drug release from beads coated with
modified-release ethylcellulose coating formulations was investigated as a
function of plasticizer type and concentration, and coating level. Ethylcellulose
coated beads were soaked in peanut oil prior to testing to simulate the influence
of concomitant administration of the dosage form with ingestion of fatty meals.
The USP apparatus 3 dissolution procedure was employed to study the drug release
properties of the beads. It was found that the ethylcellulose-coated beads
plasticized with either triethyl citrate (TEC) or dibutyl sebacate (DBS) had
faster drug release rates after the peanut oil treatment. Scanning electron
microscopy (SEM) revealed that the peanut oil soak caused the polymeric films to
detach from the surface of the bead, producing a series of uneven ridges and
cracks in the coating. Modulated differential scanning calorimetry (DSC)
demonstrated that the glass transition temperature was increased for DBS
plasticized films soaked in peanut oil, and that it was not influenced for TEC
plasticized films. Similar results were found for the puncture strength, percent
elongation, and modulus of elasticity for the DBS- and TEC-plasticized films
soaked in peanut oil. The results verified that the DBS was solubilized and
extracted from the plasticized film during the peanut oil soak, and that the film
plasticized with the TEC was not significantly affected by the peanut oil soak.
Drug release was influenced by the plasticizer type and concentration, and
coating level applied to the beads.
PMID- 9552427
TI - Evaluation of in vitro release rate and in vivo absorption characteristics of
four metoprolol tartrate immediate-release tablet formulations.
AB - The purpose of this investigation was to examine the impact of formulation and
process changes on dissolution and bioavailability/bioequivalency of metoprolol
tartrate tablets manufactured using a high-shear granulation process. A half
factorial (2(4-1), Res IV) design was undertaken to study the selected
formulation and processing variables during scale-up. Levels and ranges for
excipients and processing changes studied represented level 2 or greater changes
as indicated by the SUPAC-IR Guidance. Blend and tableting properties were
evaluated. Changes in sodium starch glycolate and magnesium stearate levels, and
the order of addition microcrystalline cellulose (intra- vs. extragranular) were
significant only in affecting percent drug released (Q) in 5, 10, and 15 min.
Statistical analysis of data showed no significant curvature. No interaction
effects were found to be statistically significant. To examine the impact of
formulation and processing variables on in vivo absorption, three batches were
selected for a bioavailability study based on their dissolution profiles.
Subjects received four metoprolol treatments (Lopressor, slow-, medium-, and fast
dissolving formulations) separated by 1 week according to a randomized crossover
design. After an overnight fast, subjects were administered one tablet (100 mg),
blood samples were collected over 24 hr and plasma samples were analyzed. The
formulations were found to be bioequivalent with respect to the log Cmax and log
AUC0-infinity. The results of this study suggest that: (i)
bioavailability/bioequivalency studies may not be necessary for metoprolol
tartrate and perhaps other class 1 drugs after level 2 type changes and (ii) in
vitro dissolution tests may be used to show bioequivalence of metoprolol
formulations with processing or formulation changes within the specified level 2
ranges for the equipment examined.
PMID- 9552428
TI - Optimization and characterization of a pH-independent extended-release
hydrophilic matrix tablet.
AB - A simple systematic optimization approach was applied to tailor the drug release
profile from a hydrophilic matrix extended-release tablet. When the ratio of
anionic and nonionic polymers was optimized, pH-independent in vitro release of
the model drug verapamil hydrochloride was obtained. The mechanisms of drug
release at the pH extremes were evaluated by graphical analysis of the
dissolution data and direct examination of the tablets during dissolution.
Graphical evaluation did not completely clarify the release control mechanisms
involved. Direct examination of tablets during dissolution, with estimation of
amounts of drug and excipients dissolved at different times, gave further insight
into relative contribution of mechanisms at different pH values. The change from
predominantly diffusional to predominantly erosional mechanisms as pH is
increased provides for the pH-independent release observed. This understanding
should help model the application of this approach to other drugs.
PMID- 9552429
TI - Reduced transdermal absorption of N,N-diethyl-m-toluamide from a new topical
insect repellent formulation.
AB - Extensive absorption of the topical insect repellent N, N-diethyl-m-toluamide
(DEET) causes systemic and local toxicities. This report describes the
preparation and characterization of a new insect repellent formulation (FA), a
PEG-polyacrylic acid polymer system, for its DEET release, in vitro skin
permeation, and in vivo transdermal absorption properties; and for its relative
repellency against Aedes aegypti mosquitoes. DEET release and skin permeation
were studied in Franz diffusion cells. DEET transdermal absorption and relative
repellency of FA were assessed in beagle dogs. A commercial DEET lotion (FB) and
technical DEET (FC) were used as references. FA exhibited 19.5% and 61.7%
decrease in DEET steady-state skin flux compared with FB and FC, respectively. At
15 mg DEET/kg, the absolute DEET transdermal bioavailability and Cmax were 13.4%
and 154.3 ng/ml, respectively, for FA; and were 17.5% and 196.5 ng/ml,
respectively, for FB. DEET half-lives (t1/2) for FA (2.52 hr) and FB (2.73 hr)
were similar, while MRT for FA (4.99 hr) was significantly greater (p < 0.05)
than that for FB (4.38 hr). FA showed lower mosquito biting rates at 1, 2, 3, 4,
5, and 6 hr postdose at 0.5 mg DEET/cm2. FA exhibited reduced in vitro skin
permeation and in vivo transdermal absorption of DEET as well as superior
repellency compared with FB. The PEG-polyacrylic acid polymer system is of value
in the formulation of DEET lotions.
PMID- 9552430
TI - Drug solubility effects on predicting optimum conditions for extrusion and
spheronization of pellets.
AB - This paper explores the utility of aqueous solubility of structurally similar
drugs in predicting optimum conditions for extrusion and spheronization of
pellets using response surface methodology. Pharmacologically active xanthine
derivatives exhibiting widely varying aqueous solubility were used to determine
optimum conditions for pelletization. The amount of water added to the
formulation, wet mixing time, and spheronizing time were explored in a series of
central composite experimental designs to exhaustively explore and mathematically
model the response surfaces for each drug. Using a marketed microcrystalline
cellulose excipient, optimum extrusion and spheronization conditions for less
soluble drugs required more water, a longer wet mixing time, and prolonged
spheronizing times. Results were similar when a new microcrystalline cellulose
was substituted, except that more water was required. When comparing results for
different drugs, a strong linear relationship was observed between the aqueous
solubility of the drug and the water content required for optimum pellet
production. The water content range over which quality pellets could be produced
was much broader for poorly soluble drugs. Aqueous solubility of the active
component appears to be a good predictor for the water requirements for optimum
extrusion and spheronization of pellets for pharmaceutical applications.
PMID- 9552431
TI - Biodegradable cisplatin microspheres for direct brain injection: preparation and
characterization.
AB - The objectives of the present study were to prepare cisplatin loaded-PLGA
microspheres that are suitable for direct brain injection and to characterize
them in terms of their physicochemical properties, in vitro drug release, and
self-removal mechanism. The microspheres were prepared by emulsification/solvent
evaporation method using PLGA (50:50) as the biodegradable matrix forming
polymer. The physicochemical characterization encompassed the following: surface
morphology, particle size, entrapment efficiency, surface area, and density. The
in vitro release and in vitro degradation studies were performed in phosphate
buffer and in 10% rat brain preparation. SEM micrographs revealed that the
microspheres have a rough porous surface and a smooth interior. Particle size
typically ranged from 180 to 250 microns with an average of 230 T microns.
Entrapment efficiency was approximately 70% and was found to be dependent on the
particle size. Surface area and density ranged from 0.038 to 0.025 m2/g and from
1.44 to 1.39 g/cm3, respectively. Both were also dependent on particle size. In
the in vitro release study in phosphate buffer, approximately 80% of cisplatin
was released over 30 days, after which the release rate plateaued. The release
profile in 10% rat brain preparation was comparable in shape to that obtained in
phosphate buffer. However, the release rate was lower and the total amount
released by the end of the study was only 55% of the total cisplatin content. The
degradation of PLGA microspheres in phosphate buffer and in rat brain homogenate
correlated well with the respective release profiles. Based on the evidence of
self-removal and the sustained release of cisplatin for over a month, cisplatin
loaded PLGA microspheres may be useful for local delivery to brain tumors.
PMID- 9552432
TI - Effect of particle morphology on emitted dose of fatty acid-treated disodium
cromoglycate powder aerosols.
AB - These studies assess the quantity and morphology of the emitted aerosolized dose
of irregularly shaped disodium cromoglycate particles in the fine particle
fraction using in vitro methods. Disodium cromoglycate was treated with a
homologous series of saturated fatty acids, between C8 and C18, in a range of
concentrations. The products of these treatments were powders with a variety of
particle size, shape, and aggregation characteristics. Samples of these powders
were loaded in gelatin capsules, generated as aerosols from a Rotahaler and
collected in a two-stage liquid impinger or eight-stage inertial impactor.
Particles were examined directly by scanning electron microscopy and subsequently
the images were analyzed to define morphology. The aerodynamic fine-particle
fraction determined by the two-stage impinger increased approximately twofold
with lauric acid treatment (0.0317 g/g, 6.7%) and threefold with stearic acid
treatment (0.58 g/g; 9.7%) compared with disodium cromoglycate alone (0 g/g,
3.56%). The lauric acid formulation appeared to alter deposition primarily by
changing particle morphology. Stearic acid altered particle shape to some extent
and the increase in the fine-particle fraction appeared to be attributable to
improved particle dispersion properties. The uncontrolled presence of irregular
shaped particles can introduce dosing errors due to effects on dispersion and
aerodynamic behavior. Conversely, controlled particle morphology and size may be
employed to optimize the dose delivered to the lungs particularly if particle
particle and particle-surface interactions can be minimized.
PMID- 9552433
TI - Effect of sorbitol on the phosphate adsorptive capacity of ferrihydrite
suspensions.
AB - The purpose of this study was to stabilize the phosphate adsorptive capacity of
aqueous suspensions of ferrihydrite, a potential phosphate binder. Ferrihydrite
was precipitated by the addition of 1 N NaOH to 1 M FeCl3 until pH 8.0 was
reached. The ferrihydrite suspension was divided into three portions and an
amount of sorbitol was added to produce sorbitol concentrations of 0, 1, or 5%
w/v, respectively. The phosphate adsorptive capacity and X-ray diffraction
pattern were periodically determined during aging at room temperature. The
phosphate adsorptive capacity of the ferrihydrite suspension containing 0%
sorbitol decreased steadily from 0.012 mgP/mg to 0.007 mgP/mg during the 1-year
aging period. In contrast, suspensions containing 1 or 5% sorbitol exhibited
constant phosphate adsorptive capacities during this period. X-ray diffraction
patterns revealed that ferrihydrite transformed to hematite and goethite during
aging of the control suspension. The presence of 1 or 5% sorbitol prevented the
transformation of ferrihydrite to more crystalline iron oxides. This study
suggests that the phosphate adsorptive capacity of ferrihydrite suspensions can
be stabilized by the incorporation of small amounts of sorbitol into the
formulation.
PMID- 9552434
TI - Calculation of intensified sampling plans in blending validation.
PMID- 9552435
TI - Industrial scientists and engineers: an underutilized academic resource.
PMID- 9552436
TI - Basic concepts of artificial neural networks (ANN) modeling in the application to
pharmaceutical development.
AB - Artificial neural networks (ANN) methodology is a new modeling method that has
not been broadly applied to pharmaceutical sciences up to now. The aim of this
paper is to give a detailed description of the associating networks as well as a
description of less well-known networks (i.e., feature-extracting and nonadaptive
networks) and their scope of application in pharmaceutical sciences. The
descriptions include the historical origin and the basic concepts behind the
computing. ANN are based on the attempt to model the neural networks of the
brain. Learning algorithms for associating ANN use mathematical procedures
usually derived from the gradient descent method whereas feature-extracting ANN
map multidimensional input data sets onto two-dimensional spaces. Nonadaptive ANN
map data sets and are able to reconstruct their patterns when presented with
corrupted or noisy samples. Associating networks can typically be applied in the
pharmaceutical field as an alternative to traditional response surface
methodology, feature-extracting networks as alternative to principal component
analysis, and nonadaptive networks for image recognition. Based on these
abilities, the potential application fields of the ANN methodology in the
pharmaceutical sciences is broad, ranging from clinical pharmacy through
biopharmacy, drug and dosage form design, to interpretation of analytical data.
The few applications presented in the pharmaceutical technology area seem
promising and should be investigated in more detail.
PMID- 9552437
TI - Application of artificial neural networks (ANN) in the development of solid
dosage forms.
AB - The application of ANN in pharmaceutical development has been assessed using
theoretical as well as typical pharmaceutical technology examples. The aim was to
quantitatively describe the achieved data fitting and predicting abilities of the
models developed with a view to using ANN in the development of solid dosage
forms. The comparison between the ANN and a traditional statistical (i.e.,
response surface methodology, RSM) modeling technique was carried out using the
squared correlation coefficient R2. Using a highly nonlinear arbitrary function
the ANN models showed better fitting (R2 = 0.931 vs. R2 = 0.424) as well as
predicting (R2 = 0.810 vs. R2 = 0.547) abilities. Experimental data from a tablet
compression study were fitted using two types of ANN models (i.e., multilayer
perceptrons and a hybrid network composed of a self-organising feature map joined
to a multilayer perception). The achieved data fitting was comparable for the
three methods (MLP R2 = 0.911, SOFM-MLP R2 = 0.850, and RSM R2 = 0.897). ANN
methodology represents a promising modeling technique when applied to
pharmaceutical technology data sets.
PMID- 9552438
TI - Determination of (pseudo)plastic flow properties of pharmaceutical semisolids
using rheological AUC parameters.
AB - The purpose of this study was to develop a simple and unique method of data
reduction for pharmaceutical semisolids. Application and accuracy of different
regression models for rate-controlled rotating cylinder and T-shaped spindle data
was compared in a conventional analysis of variance. Methods employed to
determine area under the flow curve (AUC) parameters included integration of
fitting function, planimetration, and calculation of trapezoids. Complex
rheological behavior such as structure breakdown at low rates of shear (D) and
deflocculation of particle aggregates at high values for D is not sufficiently
described by conventional fitting functions. Iterating the nonlinear power law
function tau = tau 0 + k2. Dn0, however, gives the best fit of data for
pharmaceutical samples, estimating a yield value, tau 0.1 calculated for D = 0.1
s-1 following double logarithmic transformation. Alternatively, rheological AUC
parameters are determined for D: 0 < or = D < or = 98 s-1. Validating models,
maximum deviation for different methods of determination is smaller than Srel of
5 consecutive planimetration experiments. In case of sufficient fit of
experimental data, integration of a nonlinear power law function is acceptable.
Convenient fitting parameters tau and n0 can be substituted by area parameters
such as AT, Arel, or R for all liquids, and hydrophilic and lipophilic gels, as
well as o/w and w/o emulsions being investigated. The new AUC method offers
robust data reduction and universal pharmaceutical application for different
Newtonian and (pseudo)plastic materials. The approach is, however, limited to
instrumental conditions and the range of D.
PMID- 9552439
TI - Preparation and characterization of agarose hydrogel nanoparticles for protein
and peptide drug delivery.
AB - The purpose of this work was to develop and characterize a protein and peptide
injectable drug delivery system in agarose hydrogel nanoparticles. The
nanoparticles were prepared by using a new emulsion-converted-to-suspension in
situ method. This is an emulsifier-free method that has advantages for protein
and peptide drug encapsulations. Ovalbumin, used as a model protein drug, was
successfully encapsulated into nearly spherical agarose hydrogel nanoparticles
under mild conditions. The nanoparticles possessed a log-normal size distribution
with an average size of 504 nm. They imbibed a large amount of water (66.85% to
84.33%) and the water content was a function of temperature; the water content
increased with increase in temperature. Release studies of the ovalbumin from the
agarose hydrogel nanoparticles revealed a diffusion-controlled release mechanism
with a temperature dependence; the ovalbumin release rate was higher at 37
degrees C than that at room temperature. The great biocompatibility of agarose
hydrogel, plus the mild conditions for drug encapsulation, make the agarose
hydrogel nanoparticles a potential system for protein and peptide drug delivery.
PMID- 9552440
TI - Use of poloxamer polymers to stabilize recombinant human growth hormone against
various processing stresses.
AB - Several processing and shipping stresses were investigated for their effect on
the physical stability of recombinant human growth hormone (rhGH). These included
exposure to air/water interfaces, adsorption to hydrophobic surfaces, freeze-thaw
cycles, and temperature. The interfacially and thermally denatured hormone was
evaluated for the presence of insoluble and soluble aggregates by
spectrophotometry and by size-exclusion chromatography, respectively. Noncovalent
aggregates were generated by either vortexing or multiple passages through a
hypodermic needle, processes which exposed the protein to air/water interfaces.
Thermal stress also resulted in the generation of aggregates. This aggregation
was reduced or eliminated by the use of poloxamer polymers. Under the conditions
employed, filtration through some commercially available filters, exposure to
hydrophobic beads, or multiple freeze-thaw cycles did not produce any aggregates
within the limitations of the analytical procedures used. Based on this study,
Poloxamer 407 was found to be the most effective stabilizer for rhGH for
protection against interfacial and thermal stress.
PMID- 9552441
TI - Solid tumor chemotherapy and in vivo distribution of fluorouracil following
administration in poly(L-lactic acid) microspheres.
AB - The physicochemical properties and in vivo distribution of poly(L-lactide) (L
PLA) microspheres containing 5-fluorouracil (5-FU) prepared by a solvent
evaporation method were evaluated for potential use in the treatment of liver
cancers. Two different molecular weight polymers of L-PLA [L-PLA1 (152,500 Da)
and L-PLA2 (52,000 Da)] were used to prepare 5-FU-loaded microspheres. The mean
particle size of the microspheres was 3-6 microns, and there was a direct
relationship between the mean particle size and the molecular weight of the
polymers. The drug release behavior from microspheres exhibited a diffusion
mechanism in different dissolution media, with the molecular weight of the
polymer being a major factor in controlling the drug release and degradation
rates. Following intravenous injection of 99mTc-labeled L-PLA microspheres, with
or without 5-FU, or free 5-FU into mice, L-PLA2 microspheres localized mainly in
the liver. The disappearance rate of radioactivity from the tissue was very slow
in comparison to that of free 5-FU. The results were confirmed by histological
examination of liver tissue following administration of fluorescein particles. In
addition, growth of a human liver tumor as first transplant generation under the
renal capsule of immunocompetent rats and antitumor activity of L-PLA2
microspheres were investigated. Histological examination by optical microscopy
showed that there was no neoplastic tissue of the kidney or in other tissues
examined after treatment.
PMID- 9552442
TI - Sustained release of acetaminophen from heterogeneous matrix tablets: influence
of polymer ratio, polymer loading, and co-active on drug release.
AB - The aim of this research was to investigate the effect of pseudoephedrine (PE),
polymer ratio, and polymer loading on the release of acetaminophen (APAP) from
hydroxypropyl methyl cellulose (HPMC)/polyvinylpyrrolidone (PVP) matrices.
Granules formulated with APAP or both APAP and PE, and various blends of HPMC and
PVP were compressed into tablets at varying compression forces ranging from 2000
to 6000 Ib. In vitro drug release from the matrix tablets was determined and the
results correlated with those of tablet water uptake and erosion studies. Drug
release from the formulations containing both APAP and PE was slower than those
containing only APAP (P < 0.05, F = 3.10). Drug release from tablets formulated
with APAP only showed an initial burst at pH 1.16 or 7.45, and at high total
polymer loading (> or = 9.6%). Formulations containing both APAP and PE showed
slower drug release at pH 1.16 than at pH 7.45. At pH 1.16, a decline in the
percentage of APAP released occurred after 18 hours. This was due to the
hydrolysis of APAP to p-aminophenol. The drug dissolution data showed good fit to
the Korsmeyer and Peppas model, and the values of the release exponents ranged
from 0.20 to 0.62, indicating a complex drug release pattern. Tablet erosion
studies indicated that the amount of APAP released was linearly related to the
percentage of tablet weight loss. The kinetics of tablet water uptake was
consistent with a diffusion and stress relaxation controlled mechanism. Overall,
the results of this study indicated that PE, as a co-active in the formulation,
modified the matrix, and hence retarded APAP release.
PMID- 9552443
TI - In vivo evaluation for rhGM-CSF wound-healing efficacy in topical vehicles.
AB - The wound-healing efficacy of recombinant human granulocyte-macrophage colony
stimulating factor (rhGM-CSF) was studied in a mouse model. Full-thickness wounds
were treated with liquid crystalline, emulsion, and niosome vehicles alone and
with rhGM-CSF. The control group was non-medicated. Observation of the vehicle
groups with and without the rhGM-CSF displayed better healing profiles than the
control group. The vehicles were also evaluated among themselves and it was noted
that emulsion base and niosome base groups gave significantly better healing
profiles and histological results than the liquid crystalline base group. Among
the rhGM-CSF containing groups, emulsion formulation displayed a stronger wound
healing effectiveness compared to the other formulations. In vitro release
characteristics of the recombinant protein from the three vehicle formulations
were demonstrated with diffusion cells. Histological and immunohistochemical
evaluation was performed on biopsies taken on the last day of the experiment.
PMID- 9552445
TI - A relationship between screen opening and mesh size for standard sieves.
PMID- 9552444
TI - Cosolvent effects on the gel formation and gel melting transitions of Pluronic
F127 gels.
PMID- 9552446
TI - Research in solid dosage forms--an obsolete topic?
PMID- 9552447
TI - Formulation development of sustained-release hydrophilic matrix tablets of
zileuton.
AB - The purpose of this paper was to develop a hydrophilic matrix system for extended
oral delivery of zileuton, and study the effects of certain formulation,
processing, and dissolution variables on in vitro drug release. Tablet
formulations with 60-70% drug and varying release rates were prepared by wet
granulation using low and medium viscosity grades of hydroxypropylmethocellulose.
In vitro drug release was evaluated using USP apparatus 1. The in vitro drug
release from all formulations followed zero-order kinetics and was independent of
compression force. In general, the release rate decreased with increasing drug
load and higher polymer concentration or viscosity. High-shear granulation also
resulted in lower release rate. Accelerated release was observed with increased
agitation as well as in the dissolution media with higher surfactant
concentration and/or ionic strength. No stereoselective release from the matrix
system was observed. The hydrophilic matrix system effectively controlled the in
vitro release of zileuton. Matrix tablets with desired release rates can be
prepared by adjusting various formulation and processing parameters. The matrix
system also has the advantage of simple processing and relatively low cost.
PMID- 9552448
TI - Preliminary assessment of an image analysis method for the evaluation of
pharmaceutical coatings.
AB - This article describes the development and preliminary assessment of an
innovative image analysis method for the evaluation of pharmaceutical coatings.
Nonpareils previously hot-melt coated with a red water-soluble dye incorporated
into polyethylene glycol were employed to develop and evaluate the new method.
Digital images of batch samples were acquired and transferred to a PC for
evaluation by image analysis software. Standard deviations generated for the
optical densities of individual nonpareils in each batch sample were utilized to
evaluate coating uniformity. Mean optical densities generated for each batch
sample were used to evaluate the mean coating thickness. Method precision
determinations, using an average sample size of 221 nonpareils, returned a
relative standard deviation of 2.47% for coating uniformity and 1.71% for coating
thickness. The new method is rapid, objective, and relatively inexpensive. It
proved to be both qualitative and quantitative for coating uniformity,
qualitative for coating thickness, and maintained a high degree of precision. The
method can be used independently or in conjunction with other methods to
eliminate their subjective aspects regarding sample selection.
PMID- 9552449
TI - The effect of operating and formulation variables on the morphology of spray
dried protein particles.
AB - The purpose of this research was to investigate the shape and morphology of
various spray-dried protein powders as a function of spray-drying conditions and
protein formulations. A benchtop spray dryer was used to spray dry three model
proteins in formulation with a sugar or a surfactant. Physical characterizations
of the powder included morphology (scanning electron microscopy), particle size,
residual moisture, and X-ray powder diffraction analyses. A significant change in
particle shape from irregular (e.g., "donut") to spherical was observed as the
outlet temperature of the dryer was decreased. The drying air outlet temperature
was shown to depend on various operating parameters and was found to correlate
with the drying rate of atomized droplets in the drying chamber. The morphology
of spray-dried protein particles was also affected by formulation. In
protein:sugar formulations, spray-dried particles exhibited a smooth surface
regardless of the protein-to-lactose ratio, whereas roughness was observed when
mannitol was present at > 30% of total solids, due to recrystallization. Protein
particles containing trehalose at concentrations > 50% were highly agglomerated.
The presence of surfactant resulted in noticeably smoother, more spherical
particles. The shape and the morphology of spray-dried powders are affected by
spray drying conditions and protein formulation. This study provides information
useful for development of dry proteins for fine powder (e.g., aerosol)
applications.
PMID- 9552450
TI - Relating formulation variables to in vitro dissolution using an artificial neural
network.
AB - The purpose of this paper was to investigate the effect of several experimental
variables on the ability of a neural network to predict in vitro dissolution rate
as a function of product formulation changes. Neural network software was trained
with sets of hypothetical and experimental data consisting of 4-15 formulations
with known in vitro drug dissolution profiles and the ability of the trained
model to recognize patterns was validated against similar formations not used to
train the neural network. The effect of selected variables, e.g., number of
hidden-layer nodes and iterations, as well as the use of replicate or mean data
on the accuracy of the predictions was investigated. The importance of optimizing
the number of hidden-layer nodes and iterations was demonstrated. The prediction
error increased for validation data sets that were outside the range of the
training data set. Accurate predictions were obtained with as few as four
formulations in the training set, provided the formulations were carefully
chosen, and the number of formulation variables were small. Also, limiting the
validation set to one formulation was not sufficient to validate the neural
network model. Increasing the size of the training set, or replication of the
input and output data, also provided more accurate predictions. The neural
network accurately predicted in vitro drug release provided the neural network
variables were optimized, and the training and validation data sets were
appropriately selected.
PMID- 9552451
TI - Physical and chemical properties of DMP 504, a polyalkylammonium-based bile acid
sequestrant.
AB - The purpose of this study was to characterize the physicochemical properties of
DMP 504 and lay the foundation for formulation development. Thermal properties
were characterized by DSC and TGA and moisture sorption and desorption by TGA.
The association rate and equilibrium binding capacity of the polymer for a
prototype bile acid was evaluated using cholic acid, and solid state stability
was examined at 25 degrees C, 40 degrees C (with and without 5% added water), 60
degrees C, and 600 foot candles/25 degrees C. The solid state excipient
compatibility of binary mixtures of DMP 504 and several commonly used
pharmaceutical excipients was also evaluated. Thermal analysis of the polymer
showed a glass transition temperature at approximately 95 degrees C and no
melting point, indicating a highly amorphous macromolecular structure with
thermal stability up to 250 degrees C. Moisture sorption and desorption isotherms
at controlled humidity ranging from 11% to 97% RH did not display hysteresis.
Cholic acid associated with DMP 504 extremely rapidly so that binding was
essentially complete within 5 min. Scatchard analysis of the equilibrium binding
of cholic acid to DMP 504 was unconventional, and indicated that the system was
exhibiting positive cooperative behavior. Modeling the binding curve for a system
exhibiting cooperative behavior indicated a maximum binding capacity of DMP 504
for cholic acid in phosphate buffered saline (pH 7.0) of 4.9 mumol/mg, and a
cooperativity value, P, of 2.2 implying that binding of one molecule promotes the
binding of additional molecules. DMP 504, a hygroscopic, amorphous cross-linked
polymer with a tendency to gain or lose moisture with ease, is stable in the
solid state, either drug substance alone or in presence of excipients, at normal
storage temperatures and light, and under controlled conditions of humidity.
PMID- 9552452
TI - Use of chitosan in compressed tablets of diclofenac sodium: inhibition of drug
release in an acidic environment.
AB - The purpose of this study was to evaluate the potential utility of chitosan (I)
in inhibiting diclofenac sodium (II) release in the gastric environment from a
directly compressible tablet formulation. I, subjected to depolymerization to
improve its microcrystallinity and subsequent compressibility, was then used to
prepare tablets of II. A full-factorial design was employed to evaluate the
effects of degree of N-deacetylation of I, and the pH and ionic strengths, mu, of
the dissolution media on drug release. Directly compressible tablets were
prepared from admixtures of 25 mg of II, 174 mg of I of various degrees of N
deacetylation (74, 87, and 92%), and 1 mg of magnesium stearate. The in vitro
dissolution studies were performed using aqueous buffers (pHs 1.2, 3.8, and 6.8,
and mu of approximately 1.0 and 0.1). The slopes of logarithmically transformed
cumulative percent released-time curves (from t = 0 to t = 5 hr) were compared.
Analyses of variance performed using SAS indicated that the degree of N
deacetylation of chitosan significantly affected drug release at pHs 1.2 and 6.8
(p < 0.0001). An increase in the pH of the dissolution medium resulted in an
increase in drug release (p < 0.0001). The ionic strength of the dissolution
medium did not significantly affect drug release at any of the pHs studied (p >
0.198). Besides the poor aqueous solubility of II, the two factors possibly
affecting the drug release in the acidic environment were (a) the formation of a
rate-limiting chitosan gel barrier; and (b) the ionic interaction of II with
ionized amino groups of I.
PMID- 9552453
TI - Glass fragility and the stability of pharmaceutical preparations--excipient
selection.
AB - The objectives of this study were, first, to calculate the zero mobility
temperatures, T0, of trehalose and sucrose by the Pikal method from the width of
the glass transition and compare these to the literature, obtained by enthalpy
relaxation measurement, and second, to compare the T0 values and physicochemical
properties of trehalose to those of sucrose in terms of potential to stabilize
labile actives in the glassy state. Differential scanning calorimetry and
coulometric Karl-Fischer analysis were used. The glass transition temperatures,
Tg, for the two carbohydrates at circa 0.7% moisture were 101 degrees C and 64
degrees C for trehalose and sucrose, respectively. Anhydrous amorphous trehalose
had a Tg of 116 degrees C. The T0 values were found to be 44 and 3.5 degrees C
for trehalose and sucrose, respectively. The Tg-T0 value for sucrose was
compared, and found to be in good agreement with that found by enthalpy
relaxation measurements. Trehalose was found to be resistant to crystallization
above the glass temperature. The study supports the validity of the calculation
method proposed by Pikal for T0. It has been proposed in the literature that T0
is a better measure of stability than Tg. Trehalose has a significantly higher T0
than sucrose and thus would work more effectively in stabilizing a labile active.
PMID- 9552454
TI - Transmucosal delivery of oxytocin to rabbits using a mucoadhesive buccal patch.
AB - A biocompatible, mucoadhesive buccal patch was evaluated in rabbits for
transmucosal delivery of peptides. Oxytocin (OT) was incorporated into custom
coformulations of Carbopol 974P and silicone polymer and the resulting plasma OT
concentration versus time profiles determined following patch application. For
comparative purposes, the mean values determined for the elimination half-life
(t1/2), volume of distribution (Vd), and the total body clearance (CL) following
intravenous injection of OT were 2.9 +/- 0.2 min, 85.3 +/- 6.7 ml, and 20.4 +/-
2.03 ml/min, respectively. Following application of oxytocin-loaded mucoadhesive
patches, plasma OT concentrations remained 20- to 28-fold greater from 0.5 to 3.0
hr than control animals administered placebo patches. The steady-state plasma OT
concentration (Css) following application of the buccal patches was 80.6 +/- 15.9
pg/ml. The lag-time associated with attainment of the Css was 0.45 +/- 0.18 hr.
Steady-state flux (Jss) of oxytocin in vivo was 139 +/- 36.8 ng/hr/cm2. Based on
the amount of OT remaining in the patches following removal, the average dose of
OT released in vivo was 0.27 +/- 0.024 mg with a bioavailability of 0.1%. No
significant alterations in mucosal histology were observed when underlying mucosa
to which OT patches had been applied were compared to either control (no patch)
mucosa or mucosa underneath placebo patches. The mucoadhesive buccal patches were
easy to apply and remove, nonirritating to tissue, and able to continuously
deliver a nonapeptide over 3 hr. Based on these preliminary studies, the
mucoadhesive buccal patches evaluated may represent an improved transmucosal drug
delivery system for peptides and conventional drug substances.
PMID- 9552455
TI - Hemolytic and antifungal activity of liposome-entrapped amphotericin B prepared
by the precipitation method.
AB - A new method of preparing liposomes containing amphotericin B (AmB) was developed
with the purpose of reducing the toxicity of AmB without causing a loss in its
antifungal activity. The procedure involved the precipitation of AmB and egg
phosphatidylcholine (PC) in phosphate buffered saline (PBS, pH 7.4) or tris
buffered saline (TBS, pH 7.4) by evaporating methanol and chloroform, which had
been previously mixed in the buffer solution, at 4 degrees C and 600 mm Hg. The
in vitro toxicity of the precipitated liposomes containing 3, 6, 9, 12, and 15
wt% AmB was compared with that of the film-swollen liposomes containing the
equivalent contents of the drug. The hemolytic ability of the precipitated
liposomes at 37 degrees C was 50.3% at maximum of the film-swollen liposomes at a
dose of 30 micrograms AmB/ml, as measured after 17-hr incubation. The significant
reduction in the hemolysis effect may in fact be attributed to the reduced rate
of drug release from the precipitated liposomes. The precipitated liposomes were
multilayered and aggregates of AmB were embedded in the bilayers. These
aggregates of AmB would be responsible for an intensive positive peak around 330
nm and reduced toxicity. Despite the decrease in toxicity, the activity of the
precipitated liposomes against Candida albicans remained almost equipotent to
that of the film-swollen liposomes. Therefore, liposomes prepared by the
precipitation method are less toxic but equally as active.
PMID- 9552456
TI - Studies on diffusion in alginate gels. II. Effect of acid and subsequent re
exposure to calcium on the diffusion of caffeine and theophylline in alginate gel
films.
AB - The aim of this research was to investigate the effect of acid exposure and
calcium re-exposure on the diffusion of caffeine and theophylline through calcium
alginate gel films. Diffusion was measured using side-by-side glass cells, before
and after the films were exposed to simulated gastric fluid (SGF) USP minus
pepsin. The permeability increased by about 15-fold for theophylline and 48-fold
for caffeine after 5 min SGF exposure. There was no significant further increase
by prolonging the exposure time to 4 hr. The diffusion of both drugs was less
than through alginate gel films that were not cross-linked with calcium but were
gelled in SGF. Treatment of the calcium alginate gel films with SGF depleted the
films of all of their calcium content. Calcium alginate gel films that were
exposed to SGF for a constant period of 15 min, were re-exposed to 0.34 M calcium
chloride solution for periods up to 24 hr. The calcium content returned to 80% of
the level in the original calcium alginate films and diffusion was reduced, but
not to the level that was observed in the original calcium alginate films. It was
concluded that the effect of SGF on calcium alginate was very rapid and that the
increase in drug diffusion observed was probably due to removal of calcium from
the gel. It was also concluded that the original diffusion properties and calcium
content could only be partially regenerated by re-exposing the acid-exposed films
to calcium chloride.
PMID- 9552457
TI - Solubilization of various benzodiazepines for intranasal administration, a pilot
study.
PMID- 9552458
TI - Is it necessary to take small blend samples to assess drug uniformity?
PMID- 9552459
TI - Accelerated conditions for stability assessment of bulk and formulated cefaclor
monohydrate.
AB - The stability of cefaclor monohydrate drug substance and formulated products was
studied under accelerated conditions in order to provide a rapid indication of
differences that might result from a change in manufacturing process or source of
the sample. The USP stability-indicating related substances assay was used to
assess the extent of sample degradation. An Arrhenius study of drug substance
stability from 45 to 70 degrees C predicted a degradation rate consistent with
that observed in room-temperature studies. Qualitative degradation profiles of
samples held at 65 degrees C for 2 weeks were also very similar to those of
samples held at room temperature for 2 years. Based on these results, additional
studies were conducted at 65 degrees C for 2 weeks on drug substance and
formulated product samples. Stability differences were observed among some
capsule formulations that had also exhibited real time differences. In some
studies, rapid degradation after 5 days was observed at 65 degrees C followed by
a slower rate from 5 to 15 days. Similar behavior was observed for cefaclor
monohydrate containing high amounts of amorphous cefaclor, suggesting that
differences in amorphous content could be an explanation for stability
differences observed in various samples. The accelerated conditions were shown to
differentiate samples and can provide a rapid indication of relative stability.
PMID- 9552460
TI - The effect of composition on the tableting indices of binary powder mixtures.
AB - The purpose of this study was to investigate the effect of the composition of a
binary powder mixture on the bonding index, the brittle fracture index, and the
strain index, as defined by Hiestand. The studies involved tensile strength and
dynamic indentation hardness determinations of square compacts, the solid
fractions of which were 0.83. The mixtures were such that both components
consolidated by plastic deformation, both components consolidated by brittle
fracture, or one component was brittle while the other was plastic. The measured
quantities were then used to compute the bonding index, the brittle fracture
index, and the strain index. The bonding indices and tensile strengths of the
individual plastic materials were greater than those of the individual brittle
materials. It was concluded that the bonding indices were linearly related to
composition when both materials consolidated by the same mechanism. It was
further concluded that the bonding indices were related to compact composition by
a second-degree polynomial equation for mixtures with one brittle and one plastic
component. This latter relationship was consistent for four pairs of components.
PMID- 9552461
TI - Microencapsulation of antimicrobial ceftiofur drugs.
AB - Polymeric microparticles containing two ceftiofur salts as antimicrobial agents
for intramammary application in dry cows were prepared by modified o/w-solvent
evaporation methods (dispersion or cosolvent method) or by a w/o/w-multiple
emulsion solvent evaporation method. The microspheres were characterized with
respect to drug loading, drug release, and morphological properties. The three
methods resulted in high encapsulation efficiencies. The choice of organic
solvent/solvent mixture strongly affected the structure of the microparticles;
both matrix and reservoir-type structures with different porosities were
obtained. Scaling up to larger batch sizes resulted in microspheres with a faster
drug release. The addition of water-miscible cosolvents to the water-immiscible
polymer solution allowed the preparation of microparticles from a drug solution
rather than a drug dispersion. Microparticles prepared by the cosolvent method
could be separated after shorter time intervals from the aqueous phase; the
microspheres had a denser matrix with finely dispersed drug crystals and a slower
drug release when compared with microspheres prepared by the dispersion method,
which had a more porous structure with larger embedded drug crystals. The
cosolvent and dispersion methods present a simple alternative to the w/o/w
solvent evaporation method for the encapsulation of water-soluble drugs with an
external water phase.
PMID- 9552462
TI - The formation of lactose plugs for hard shell capsule fills.
AB - The purpose of this investigation was to study the effects of lubricant
concentration, dosator pressure, and dosator piston height on the properties of
lactose plugs. An apparatus designed to simulate Macofar 13/2 capsule filling
equipment was used, and the relationship between the variables and the responses
was established using a Box-Behnken three-factor, three-level experimental design
followed by multiple regression. Plug porosity, both under compression and after
ejection, was found to be dependent on dosator pressure. Plug weight and length
were dependent on dosator piston height, and uniformity of plug weight was
independent of all the factors studied. Plug ejection pressure was dependent on
dosator pressure and dosator piston height, even when ejection pressure was
corrected for changes in plug length. Lubricant concentration had no significant
effect on any plug property, and it must be concluded that 0.5% magnesium
stearate provides adequate lubrication for lactose plugs. No interaction between
variables was noted, and values of the variables raised to the power 2 had no
significant effect, permitting a simplified experimental design to be adopted for
future work.
PMID- 9552463
TI - The effect of polyvinylpyrrolidine on the stability of taurolidine.
AB - In an aqueous solution, taurolidine reversibly degrades to taurultam,
hydroxymethyltaurultam, taurineamide, and formaldehyde. The objectives of this
research were to investigate the mechanism of polyvinylpyrrolidine (PVP)-induced
taurolidine stabilization by measuring the effect of PVP on the rate and extent
of formaldehyde release from taurolidine and its decomposition products, the
ionization of taurineamide, and the NMR and FT-IR spectra of taurineamide. PVP
was found to a) increase the rate constant for taurultam formation from
taurineamide and formaldehyde, b) decrease the apparent pKa of taurineamide, and
c) alter the NMR and FT-IR taurineamide spectra. The effect of PVP on the
stability of taurolidine was to increase the stability of its primary degradation
product, taurultam, which, in turn increased taurolidine stability because
taurultam was reversibly formed from taurolidine. Furthermore, the increased
stability of taurultam in acidic, aqueous PVP solutions was due to an increased
rate of taurultam formation from its primary degradation products: taurineamide
and formaldehyde. The rate constant for taurultam formation increased three-fold
in the presence of 5% PVP. The rate increase was caused by the interaction of
unprotonated taurineamide with PVP. The estimated taurineamide-PVP association
constant was 1800 M-1. This interaction decreased the concentration of
unreactive/protonated taurineamide while increasing the concentration of
unprotonated/associated substrate which was found to be fivefold less reactive
than the free/unprotonated amine.
PMID- 9552464
TI - Optimization of aqueous-based film coating of tablets performed by a side-vented
pan-coating system.
AB - The purpose of this research was to characterize the aqueous-based
hydroxypropylmethylcellulose (HPMC) film coating of tablets utilizing a
laboratory-scale side-vented pan-coating apparatus (Thai coater). The process and
apparatus parameters of potential importance with respect to the final film
quality were evaluated by using fractional factorial design (2(6-2)IV) and the
process was optimized using response surface methodology (central composite
design). Rotating speed of the pan was identified as a major parameter with
respect to film thickness (weight increase; p < 0.05) and breaking strength (p <
0.05) of the aqueous HPMC film-coated tablets. Increasing the rotating speed from
5 rpm to 10 rpm resulted in a mean relative change of -43.9% and 2.4% of film
thickness (weight increase) and breaking strength, respectively. As expected,
inlet air temperature significantly affected the moisture content of the final
film-coated tablets (p < 0.01) and the film thickness (weight increase; p <
0.05), but the effects on the other responses studied were minimal or negligible.
Pneumatic spraying pressure and position of the spray gun (excluding angle of the
gun) did not affect the responses studied. The process parameters relevant to a
side-vented pan-coating process can be identified (by fractional factorial
design) and, consequently, optimized (by central composite design) by using the
factorial design approach.
PMID- 9552465
TI - Optimization of sustained-release tablet formulations: a four-component mixture
experiment.
AB - Sustained-release tablet formulations containing chlorpheniramine maleate were
prepared using a mixture of two hydrophilic gums, gamma-carrageenan and cross
linked carboxymethylcellulose sodium, and two filler materials, alpha-lactose
monohydrate and dibasic calcium phosphate in different ratios. The objective of
the experiment was to find an optimum formulation with the most desirable
properties. In order to achieve this, the matrices were evaluated for the time
taken to release 80% drug (t80), the release exponent (n), and the crushing
strength (h). Several formulations produced near zero-order release of the model
drug over a time period of up to 10 hr. Response surface plots for the three
dependent variables were generated over the experimental region. the effect of
different levels of the components on the response variables was thus visualized.
Upon superimposition of the plots it was possible to graphically find a region
where the responses were in an optimum range of values. To pinpoint the best
formulation, a simultaneous optimum point within this region was located by
arbitrarily defining optimum values for each of the responses and using a multi
objective function that combined the three response variables. The observed
response variables of the optimum formulation were in good agreement with the
predicted values.
PMID- 9552466
TI - Enhancement and modification of etoposide release from crospovidone particles
loaded with oil-surfactant blends.
AB - A novel solid formulation for oral delivery of pH-sensitive, scarcely water
soluble etoposide has been designed, characterized, and tested in vitro. The
purpose of this study was to assess the performance of the new dosage forms, in
comparison to marketed, liquid-filled capsules. The solid formulation was
developed by grinding the drug with a cross-linked polymeric carrier
(crospovidone) under controlled process conditions (mechano-physical drug
activation), and subsequently incorporating selected oil/surfactant (o/s) blends
into the polymer particles. Physicochemical characterization (thermal analysis,
drug dissolution kinetics, drug o/w partition studies) provided information on
drug-polymer interaction at the solid state, and on the formulation performance
in vitro, resulting in the enhancement and modification of the etoposide
solubilization process. DSC thermograms showed the amorphous or nanocrystalline
state of etoposide within the carrier, as indicated by the shifting of DSC peaks
(delta T > -10 degrees C). Solubility kinetics of etoposide in oversaturation
conditions were strongly affected by the chemical nature of the vehicle used:
short-chain triglycerides afforded drug concentrations well above 600 micrograms
ml-1 for more than 3 hr, versus a drug equilibrium solubility of approximately
150 micrograms ml-1. Drug dissolution curves under sink conditions were
superimposable to those of liquid-filled capsules available on the market
(Vepesid 50, Bristol-Myers Squibb), yielding 100% drug release in 10 min. The oil
phase/water partition coefficient of etoposide (P) was affected by the surfactant
concentration. The biphasic trend observed in P values suggested a dual mechanism
in drug release from polymeric particles: the presence of oily vehicles and
surfactants in the formulation could create, upon release, a favorable
environment to sustain etoposide dissolution, slowing down drug reprecipitation.
Such solid formulation could be considered equivalent, in vitro, to the current
marketed product.
PMID- 9552467
TI - Controlled-release tablet matrices from carrageenans: compression and dissolution
studies.
AB - This study investigates the potential of two commercial carrageenans, Gelcarin GP
379 (iota-carrageenan) and Viscarin GP-209 (lambda-carrageenan) to be used for
the preparation of controlled-release tablet matrices. Tablets were compressed on
an instrumented Stokes single punch machine and compression characteristics of
the carrageenans were analyzed. Heckel plots using out-of-die tablet densities
were linear with calculated yield pressures of 81.3 MPa and 105.2 MPa for iota-
and lambda-carrageenan, respectively. Drug release from tablet formulations that
contained equal amounts of the two carrageenans had near zero-order release
profiles. There was little or no effect of tablet compression pressure on the
drug release profiles from 70 to 175 MPa. As drug loading was increased from 5 to
20%, the diffusional exponent decreased from 1.056 to 0.678. Thirty percent drug
loading resulted in breakup of tablets during dissolution and departure from zero
order release. Multiple regression analysis was used to predict the time for 50%
release as a function of the concentration of the two carrageenans and a third
filler material, microcrystalline cellulose. Predicted values were in good
agreement with observed values and R2 for the final cubic model was 0.9984.
PMID- 9552468
TI - Characterization of frozen glucose solutions.
AB - Reducing sugars may be used as additives in freeze-dried formulations. The
purpose of this study is to examine the effect of freezing on nonequilibrated
glucose solutions using FT-Raman spectroscopy. The methods used solutions freshly
prepared from either alpha- or beta-crystalline glucose, frozen at different time
intervals after dissolution. Solutions frozen immediately after dissolution
showed peaks in the anomeric region of the spectrum characteristic of those
observed for the parent crystalline form. No change occurred in these spectra
after 24 hr in the frozen state. Solutions prepared from either alpha- or beta
crystalline glucose and left for 24 hr at room temperature before freezing showed
the presence of both anomers. The glass transition temperature of maximally
freeze-concentrated solutions of beta-glucose, frozen immediately after
dissolution, was found to be approximately 3 degrees C lower than for solutions
prepared from alpha-glucose. Freezing appears to halt the interconversion of
glucose anomers, enabling the formation of predominantly alpha- or beta-frozen
solutions which exhibit different properties. Freezing of nonequilibrated
solutions of reducing sugars may lead to variation in the properties of freeze
dried formulations.
PMID- 9552469
TI - Physicochemical characterizations of piroxicam-poloxamer solid dispersion.
AB - To develop an efficient topical delivery system for piroxicam using poloxamer gel
formulation, physicochemical behavior of piroxicam in poloxamer was studied. The
gelling property of poloxamer and the solubility of piroxicam in the poloxamer
were investigated. The interaction between piroxicam and poloxamer was studied by
x-ray diffractometry (XRD), infrared (IR) spectroscopy and differential thermal
analysis (DTA) with a solid dispersion, coprecipitate, or physical mixture.
Poloxamer 407 solutions showed the property of a gel when the concentration was
higher than 15% (w/w) and poloxamer 407 increased the aqueous solubility of
piroxicam by about 11-fold at the concentration of 22.5% (w/w). The results of
XRD did not show the crystalline from of piroxicam in the solid dispersion and
results of IR spectroscopic analysis showed an association between functional
groups of piroxicam and poloxamer.
PMID- 9552470
TI - Stability of Octastatin, a somatostatin analog cyclic octapeptide, in aqueous
solution.
AB - In this study, the degradation of Octastatin, a cyclic octapeptide analog of
somatostatin, was examined as a function of pH, temperature, buffer, and ionic
strength by reversed-phase gradient high-performance liquid chromatography.
Degradation of Octastatin followed a first-order kinetics. Various buffer species
such as acetate, ammonium acetate, citrate, glutamate, phosphate, and borate
showed differing effects on the degradation of the octapeptide. Good stability
was found in glutamate and acetate buffer of pH 4.0. Degradation of Octastatin
was greater in citrate- or phosphate-containing buffers than in glutamate or
acetate buffers. With phosphate buffer, higher buffer concentration caused
greater degradation, while in acetate buffer, the effect of buffer concentration
and ionic strength was negligible. In addition, the degradation of Octastatin was
markedly inhibited by increasing the concentration of glutamate buffer. This
study allows the prediction of good stability in acetate buffer (0.01 M, pH 4.0)
with a t90% of 84.1 days at 20 degrees C.
PMID- 9552471
TI - Need for polishing of new sets of tooling.
PMID- 9552472
TI - Chitosan-mediated transfection of HeLa cells.
PMID- 9552479
TI - Historical perspective.
AB - Development of the first percutaneous catheters for local delivery is described.
Understanding of the mechanisms by which circulating materials gain entrance to
the artery wall, and the importance of hypertension in accelerating that process
were crucial to the conceptual basis of these devices. The double balloon
catheter and the porous balloon catheter were systematically studied to quantify
the local pressure-wall penetration relationship. Designs for many new catheters
that claim advantage over early models require similar systematic demonstration
of their performance with normal and diseased arteries. Only in this way can this
promising new technique become a clinical advance against human vascular disease.
PMID- 9552480
TI - Rationale for local drug delivery.
AB - Although advances during the last decade have transformed the management of
coronary artery disease, deficiencies in our understanding of the basic processes
of arterial thrombosis and restenosis after percutaneous intervention continue to
present major challenges to their prevention. While coronary stenting has in
selected cases provided the first effective approach to the problem of
restenosis, new devices such as atherectomy have largely proven ineffective in
this field. Similarly, despite evidence that many pharmacological agents reduce
neointimal hyperplasia in experimental models, in clinical trials these agents
have failed to attenuate the restenotic process. This may reflect patients'
inability to tolerate the high systemic drug concentrations required to achieve
adequate levels for sufficient time at the target site, necessitating a shift in
the focus of therapeutic agents for the prevention of thrombosis and restenosis
to local or site-specific delivery. The major advantage that local drug delivery
may potentially provide is the ability to achieve high and sustained local
concentrations of drug without large systemic doses, thus minimizing systemic
toxicity.
PMID- 9552481
TI - Mechanisms of delivery and local drug delivery technologies.
AB - Therapy of atherosclerotic vascular disease and neointimal hyperplasia after
percutaneous interventions remain enigmatic. Despite new interventional devices,
we have not altered the underlying pathological process. New devices are under
development that offer the opportunity to deliver high concentrations of
therapeutic agents directly to the diseased segment. The devices fall into three
major mechanisms of delivery (1) diffusion, (2) infusion under pressure and (3)
mechanical delivery. Diffusion catheters are atraumatic but require prolonged
exposures in excess of 20 min while the pressurized infusion and mechanical
catheters are more traumatic. Additionally, each system will need to be
characterized with respect to efficiency of delivery with each agent used. The
clinical opportunity for site-specific treatment of vascular disease is rapidly
approaching. In the near future we will be able to open a narrowed vessel and
also apply some agent into the lesion to facilitate healing.
PMID- 9552482
TI - Double balloon catheter.
PMID- 9552483
TI - Microporous infusion catheter.
PMID- 9552484
TI - Dual balloon catheter.
PMID- 9552485
TI - Multichannel balloon catheter.
PMID- 9552486
TI - Infusion sleeve catheter.
PMID- 9552487
TI - Coil balloon catheter.
PMID- 9552488
TI - Iontophoretic drug delivery system.
PMID- 9552489
TI - Nipple balloon catheter.
PMID- 9552490
TI - Needle injection catheter.
PMID- 9552491
TI - Hydrogel-coated balloon catheter.
PMID- 9552492
TI - A polymer-metal composite stent.
PMID- 9552493
TI - Microspheres.
PMID- 9552494
TI - Use of local drug delivery for treating intracoronary thrombus and thrombus
containing stenoses.
AB - The local delivery of thrombolytic agents directly to the site of intracoronary
thrombus using catheter-based technology is a new technique for treating
intraluminal clot and thrombus-containing stenoses that is currently under active
investigation. The theoretic mechanism of thrombolysis underlying this approach
involves the 'trapping' of thrombus in an environment of high thrombolytic drug
concentration, mechanical disruption of intraluminal clot by the drug delivery
catheter itself, and intramural deposition of lytic agents with the creation of a
drug reservoir that may provide for prolonged local thrombolysis. To date, animal
studies with five local drug delivery catheters have documented successful
intramural deposition of thrombolytic agents at balloon angioplasty sites. Three
of these devices have also been successfully used in patients to treat
intracoronary thrombus, with preliminary results suggesting that thrombolysis can
be achieved using much lower doses of lytic agents than are employed in standard
infusion protocols and with low complication rates. These preliminary
observations will be studied further in two multicentre randomized protocols
comparing local thrombolysis with standard techniques for treating intracoronary
thrombus.
PMID- 9552495
TI - Wall passivation for unstable angina.
AB - The disruption of an atherosclerotic plaque in a coronary artery, appears to be
fundamental for the development of arterial thrombosis and resultant ischaemia.
Platelets play a central role in the pathogenesis of unstable angina; they can
aggregate and cause mechanical obstruction if large enough. In addition, they can
lead to fibrin deposition and extension of the thrombus. The fundamental goal in
the treatment of unstable angina is to control the acute disease process that
leads to vascular occlusion. In addition to the currently available
pharmacological agents used to treat unstable angina, newer agents such as the
direct thrombin inhibitors and the glycoprotein IIb/IIIa receptor antagonists may
be more effective in achieving 'passivation'. This article summarizes the role of
the vessel wall and its interaction with platelets in arterial thrombosis. The
different pharmacological approaches used in achieving passivation of platelets
in unstable angina are described.
PMID- 9552496
TI - Use of locally delivered conventional drug therapies.
AB - Coronary artery restenosis remains the major limitation of balloon angioplasty
and occurs in 30-50% of initially successful procedures. Our current
understanding of pathophysiology of restenosis suggests that it involves three
inter-related phases; (1) acute effects of thrombosis, (2) neointimal
proliferation, and (3) acute recoil and chronic remodelling. In an attempt to
prevent vessel restenosis both systemic and site-specific pharmacotherapy have
been investigated. Although successful in animal models, systemically
administered pharmacological agents for the prevention of restenosis in humans
have not been effective. The local administration of compounds such as heparin,
anti-thrombin agents, colchicine, angiopeptin, antineoplastic agents, calcium
antagonists, nitrates, forskolin, cytochalasin B, protein kinase inhibitors and
dexamethasone have been shown to reduce neointimal formation in animal models of
restenosis. Clinical trials have demonstrated the feasibility of the local
administration of heparin using both InfusaSleeve and Dispatch drug delivery
catheters. Preliminary results on long-term prevention of restenosis by heparin
appear promising using the Dispatch delivery device. In addition, a multicentre
trial investigating the effectiveness of cytochalasin B delivered using the
Microporous Infusion Catheter for the prevention of restenosis is currently
underway. Rapid progress in our understanding of the complex pathophysiology of
restenosis and the development of more effective pharmacological agents and
atraumatic site specific delivery modalities ensure a promising future for local
delivery strategies.
PMID- 9552497
TI - Genetic therapy.
AB - Vascular gene transfer is the introduction of foreign DNA into host cells within
the vessel wall. Expression of recombinant genes within vascular cells has been
demonstrated in normal, injured and atherosclerotic arteries. Transfer of genes
with biological activity has provided insights into the role of specific genes in
normal and pathological states. The development of gene transfer as a form of
vascular therapy will require safe and effective vectors and intravascular
delivery systems. Viral and non-viral vectors and several delivery catheters are
being evaluated to determine their clinical applicability. The current
applications of vascular gene transfer to cardiovascular diseases are the
prevention of restenosis following arterial injury and induction of angiogenesis
in occlusive vascular disease.
PMID- 9552498
TI - Vascular applications of human gene therapy.
AB - Complexing recombinant DNA with cationic liposomes is a convenient means of
introducing foreign genes into cells (lipofection) and could potentially form the
basis for genetically modifying diseased blood vessels in patients. The mechanism
of lipofection is incompletely understood but it is recognized that the degree of
successful gene transfer is highly dependent on cell type. We have transfected
primary cultures of human vascular smooth muscle cells with a plasmid expressing
either firefly luciferase (Luc) or nuclear-localized beta-galactosidase (NL-beta
gal). Cells were derived from either normal human internal mammary arteries,
fragments of primary atherosclerotic plaque, or fragments of restenotic lesion.
Concurrent lipofection of rabbit vascular smooth muscle cells and NIH 3T3 cells
was performed as well. Compared to NIH 3T3 cells, expression in human vascular
smooth muscle cells was markedly reduced: in cells derived from internal mammary
artery, Luc expression, normalized for protein content, was 123-fold lower than
in NIH 3T3 cells, while the proportion of cells expressing NL-beta-gal was 30
fold lower. Luc expression in cells derived from restenotic tissue was
significantly greater than from cells derived from primary plaque. Within a given
population of cells, the mitotic index of cells expressing the recombinant gene
was significantly higher than the mitotic index for the total population of cells
(p < 0.05). Finally, cotransfection experiments, in which lipofection of smooth
muscle cells was performed using genes for NL-beta-gal and for human growth
hormone, showed that among positive transfectants, a high proportion of cells (23
36%) co-expressed both genes. Thus, the efficiency of successful lipofection in
human vascular smooth muscle cells in vitro is low. Transfection appears to be
preferentially facilitated in cells derived from restenotic tissue and specific
properties of smooth muscle cells, including growth rates, appear to be critical
for successful transfection. Further elucidation of cell properties that promote
transfection is required to augment the efficiency of liposome-mediated gene
transfer in human vascular cells.
PMID- 9552499
TI - Electro-encapsulating drugs within blood platelets: local delivery to injured
arteries during angioplasty.
AB - Prostacyclins (PGl2) inhibit platelet-platelet interactions at concentrations
that do not affect platelet adhesion to collagen and other arterial
subendothelial structures exposed during injury. Such compounds can be
encapsulated within platelets by reversible electroporation and, using the
platelet's natural haemostatic propensity, they can be targeted to injured
vessels in vivo. In rat (aorta), rabbit (ileofemoral) and pig (carotid)
angioplasty models, autologous platelets, electro-loaded with the stable
prostacyclin iloprost and given intravenously after balloon overstretch injury,
substantially reduced platelet deposition at the lesion site as compared with
control platelets. In the pig model, when the drug-loaded platelets were
delivered directly to the injury site during angioplasty via a double balloon
delivery catheter, platelet deposition was restricted to monolayer coverage (>
80% reduction compared with controls). Candidate antiproliferative drugs (for co
encapsulating with iloprost) are being investigated in order to develop a
combined antithrombotic/antirestenosis strategy for use during angioplasty and
thrombolysis procedures. Autologous platelets as drug-targeting vehicles should
obviate many of the immunological, toxicological and biodegradability concerns
inherent in the use of other drug transport vectors such as antibodies, viruses,
liposomes and synthetic polymer microcapsules.
PMID- 9552500
TI - Polymeric endoluminal gel paving: therapeutic hydrogel barriers and sustained
drug delivery depots for local arterial wall biomanipulation.
AB - Polymeric endoluminal paving is a process in which biodegradable polymers may be
locally applied percutaneously to blood vessels as endoluminal liners,
resurfacing or 'paving', the underlying vascular wall. Depending upon the type of
polymer selected, endoluminal polymer layers may function as wall supports,
barriers, therapeutic biomaterials or depots for local sustained drug delivery.
In the original description of the paving process, that is solid paving,
structural polymers were utilized. In this article a second form of paving--gel
paving is described. In this process, hydrogel polymers are locally applied or
polymerized on vascular endoluminal surfaces. Endoluminal hydrogel layers have
been demonstrated to function as physical non-pharmacological barriers limiting
cell and protein deposition and effectively reducing underlying arterial wall
thrombogenicity. Hydrogel paving layers also provide a means for prolonged local
arterial wall drug delivery. In this report an update on gel paving is provided.
The overall process of polymeric endoluminal paving is initially reviewed. Gel
paving and the rationale for this approach is described. Both thermoreversible as
well as photopolymerizable PEG-lactide hydrogel paving systems are outlined.
Recent experimental studies with gel paving examining polymer application,
haemocompatability and endoluminal surface thromboprotection, effects on post
injury neointimal thickening and local drug delivery, are then reviewed. Finally,
the role of gel paving in future approaches to vascular therapy is discussed.
PMID- 9552501
TI - Laser angioplasty: historical perspective.
AB - Serious interest in laser angioplasty began in the early 1980s in an attempt to
solve two of the primary limitations of balloon angioplasty, recanalization and
restenosis. By demonstrating the ability of laser irradiation to vaporize
atherosclerotic tissue, it was logical to hypothesize that this powerful tool may
allow recanalization of lesions that could not be crossed by conventional
guidewire and balloon technology. With refinements in laser fibreoptics and
catheter delivery systems, several laser systems were approved for clinical use
as recanalization devices in both peripheral and coronary arteries. However, the
requirement to follow laser angioplasty with conventional balloon angioplasty in
the majority of cases and the lack of an effect of laser tissue removal
(debulking) on restenosis has limited a broader acceptance of this technology.
Perhaps improved techniques discussed later in this series such as saline
infusion and better fibreoptic-lens systems will allow laser angioplasty to offer
a true niche in interventional cardiology.
PMID- 9552502
TI - Fundamental laser-tissue interactions.
AB - Pulsed xenon chloride excimer and holmium laser-tissue interaction is primarily
based on tissue water vaporization. Consequently, each ablative laser pulse
produces a rapidly expanding and imploding vapour bubble in blood or the target
tissue. In experimental studies, explosive water vaporization is the major
mechanical cause of observed tissue dissections. By reduction of the induced
bubble volume, a reduction in experimentally and clinically observed dissections
after coronary excimer laser angioplasty is to be expected. This reduction of
mechanical damage, however, in combination with efficient and substantial plaque
debulking is the major challenge in the development of laser angioplasty.
PMID- 9552503
TI - Clinical results with excimer laser coronary angioplasty.
AB - This comprehensive review of randomized trials and registry reports makes several
assertions about the clinical usefulness of excimer laser angioplasty. First,
refinements in patient selection and excimer laser technique have resulted in
improved procedural outcome. Second, the overall rates of clinical success for
excimer laser angioplasty are approximately 90%, major and minor complications
6%, and vessel perforation 1%. Third, superior success rates are achieved for
saphenous vein graft lesions, ostial stenoses and total occlusions, but decreased
success rates are obtained for bifurcation, calcified and thrombus-containing
lesions. The routine use of saline infusion during excimer laser angioplasty and
careful evaluation of this therapy for new indications such as in-stent
restenosis will increase the usefulness of excimer laser angioplasty in
interventional cardiovascular medicine.
PMID- 9552504
TI - Saline infusion in excimer laser coronary angioplasty.
AB - While the effects of high-intensity laser energy on tissue were studied early in
the development of the laser, the interactions of laser radiation with immersion
media have been the subject of more recent investigations. Prompted by reports of
severe, morphologically unusual dissections occurring during 308 nm excimer laser
angioplasty, several investigators have now demonstrated that both blood
(haemoglobin) and angiographic contrast media strongly absorb excimer laser light
at 308 nm. Upon absorption, this light energy is converted into rapidly expanding
and imploding cavitation bubbles that generate intense pressure pulses.
Subsequently, several techniques to remove contrast and dilute blood in the
ablation field were evaluated. The application of saline infusion has resulted in
improvements in both angiographic and clinical outcomes. The purpose of this
paper is to review the development and application of the technique of saline
infusion in the clinical practice of excimer laser coronary angioplasty.
PMID- 9552505
TI - Homogeneous light distribution to reduce vessel trauma during excimer laser
angioplasty.
AB - Excimer laser coronary angioplasty (ELCA) is associated with vascular damage,
caused by rapidly expanding water vapour bubbles and accumulation of insoluble
gas. The size of the rapidly expanding bubbles and the volume of gas can be
reduced by decreasing the laser pulse energy density. However, using current
multifibre catheters, penetration through porcine aortic tissue was found to be
impossible at energy densities < or = 45 mJ/mm2. By contrast, by employing a 660
microns bare fibre it was observed that efficient tissue crossing was possible at
12 mJ/mm2, with considerable reduction of the rapidly expanding bubble volume and
insoluble gas production. We attribute this efficient tissue penetration at low
energy densities to the absence of 'dead space' in the homogeneous light
distribution (HLD) at the fibre tip. Accordingly we hypothesize the ELCA
performed at lower energy densities may result in less mechanical trauma to the
vessel wall when compared with ELCA using current multifibre catheters.
PMID- 9552506
TI - Holmium laser angioplasty.
AB - The investigational solid-state, pulsed-wave, mid-infrared (2.1 microns)
holmium:YAG laser can be applied for plaque ablation and thrombus dissolution. A
multicentre study reports 87% laser success and 94% final procedural success. It
has established the safety and efficacy of this laser in ischaemic syndromes and
acute myocardial infarction treating lesions considered 'not ideal' for balloon
angioplasty. These include thrombotic occlusions, total occlusions, calcified
obstructions, de novo and restenosis lesions within native coronary arteries and
saphenous vein grafts. Unfortunately, the laser does not significantly reduce
restenosis rate. Processes related to laser-tissue interactions such as gas
vapour formation and generation of acoustic waves with tremendous intraplaque
pressures mandate application of appropriate lasing technique to ensure clinical
success.
PMID- 9552507
TI - The laser guidewire experience: 'crossing the Rubicon'.
AB - Despite continued improvements in mechanical hardware for coronary angioplasty,
chronic total occlusions (CTO) remain a true challenge in the field of
interventional cardiology. Therefore, new guidewire technology, which made use of
the unique forward debulking properties of excimer laser light, was designed and
introduced into clinical practice in 1993. After an initial pilot-study phase, a
European Multicenter Surveillance Study was initiated to evaluate the performance
of the new laser guidewire. A short overview is given of the incidence of CTO.
The limitations of the percutaneous treatment with various mechanical guidewires
and the clinical and angiographic follow-up of CTO are discussed. Furthermore,
the initial experience with the laser guidewire during the pilot-phase and
preliminary results of the European Multicenter Surveillance Study are presented.
At the introduction of yet another new (and costly) device, the key question is:
'Yes, but does it allow us to expand the battle field of interventional
cardiology?'
PMID- 9552508
TI - Molecular strategies to inhibit restenosis: modulation of the vascular myocyte
phenotype.
AB - The transduction of vascular myocytes with exogenous genetic material will be a
common feature of many gene-based therapies for cardiovascular disorders.
Therefore, the successful application of cardiovascular gene therapy will require
a thorough understanding of the molecular biology of the smooth muscle cell. Of
key importance are the transcriptional regulatory events that coordinate the de
differentiation and proliferation of myocytes in response to vascular injury. The
goal of this review is to highlight what is known about the regulators of
vascular myocyte transcription that may serve as candidate genes for the
development of genetic strategies to manage postinterventional restenosis.
PMID- 9552509
TI - Gene transfer approaches to the regulation of vascular cell proliferation.
AB - Considerable progress has been made in identifying potential targets for treating
vascular proliferative diseases. In this review, we discuss gene transfer
approaches to regulating smooth muscle cell proliferation after vascular injury
using the cell cycle specific proteins, p21, delta Rb and HSV-tk. Results from
these studies suggest that replicating smooth muscle cells and macrophages are
inhibited in vivo in several animal models of restenosis, including
hyperlipidaemic vessels. Identification of appropriate vascular diseases and
improvements in gene delivery and vectors will require careful optimization in
order to develop effective molecular therapies for human vascular diseases.
PMID- 9552510
TI - Gene therapy for vascular proliferative disorders.
AB - Despite major advances in interventional techniques in recent years, restenosis
remains an important late complication of percutaneous revascularization
procedures. Vascular smooth muscle cell proliferation after arterial injury plays
an important role in the pathogenesis of restenosis. Major progress has been made
recently in elucidating the cellular and molecular mechanisms underlying this
proliferative response. This in turn has led to the development of novel, gene
based approaches for the treatment and prevention of restenosis as well as other
vascular proliferative disorders. Included among these are somatic gene therapy
the ability to introduce and express recombinant genes in non-germ-line cells of
a recipient organism in vivo. This article reviews specific genetic approaches
that have recently been developed for the treatment of vascular proliferative
disorders such as restenosis, focusing on the use of adenovirus-mediated arterial
gene transfer strategies designed to suppress the vascular smooth muscle cell
proliferative response associated with these diseases.
PMID- 9552511
TI - Apoptosis in vascular disease: opportunities for genetic therapeutic
intervention.
AB - Apoptosis functions to efficiently eliminate normal cells no longer required in
remodelling tissues, and abnormal cells exhibiting neoplastic phenotypes. Since
injury is an important trigger to the development of vascular lesions, the
balance of proliferation and apoptosis during the healing response, and
aberrations of this process, may be important factors in lesion progression. The
expression of genes that regulate this process, including c-myc and members of
the bcl-2 and lce gene families, has been detected in the normal vasculature, and
in atheromatous tissues. These observations suggest that the transfer of
apoptosis-inducing genes into vascular lesions may be a feasible, non
inflammatory strategy to eliminate the cellular components of restenotic and
atherosclerotic plaques.
PMID- 9552512
TI - Adenovirus-mediated arterial gene therapy for restenosis: problems and
perspectives.
AB - Restenosis remains the main limitation of interventional cardiology. Restenosis
occurs when angioplasty-induced intimal hyperplasia as well as arterial
remodelling result in flow-limiting renarrowing of the arterial lumen at the
angioplasty site. Intimal hyperplasia is an important candidate for gene therapy
since it is related to smooth muscle cell proliferation, which is an inviting
target for molecular antiproliferative strategies. To date, adenoviral vectors
are, by far, the most efficient vectors to perform in vivo arterial gene
transfer. These vectors, as well as others, have been recently used to
demonstrate that therapeutic genes encoding cytotoxic (herpes virus thymidine
kinase) or cytostatic (hypophosphorylatable Rb, Gax, endothelial nitric oxide
synthase) products successfully inhibit smooth muscle cell proliferation and
related intimal hyperplasia. Despite substantial progress, major technical
issues, including the toxicity of first-generation adenoviral vectors,
inefficient transduction of atherosclerotic arteries, and the risk of extra
arterial transfection remain to be addressed before gene therapy is applied to
clinical restenosis.
PMID- 9552513
TI - Gene inhibition and gene augmentation for the treatment of vascular proliferative
disorders.
AB - Gene therapy is emerging as a potential strategy for the treatment of
vasculoproliferative diseases such as restenosis after angioplasty, vascular
bypass graft occlusion and transplant coronary vasculopathy for which no known
effective therapy exists. Our laboratory has demonstrated that vascular smooth
muscle proliferation and lesion formation can be prevented by the blockade of
genes regulating cell cycle progression. With this approach it was also shown
that genetically engineered bioprostheses can be developed that are resistant to
accelerated atherosclerosis and thus to graft failure. We have also reported that
the direct in vivo transfer of a cDNA encoding endothelial nitric oxide synthase
resulted in inhibition of neointimal lesion formation and improvement of vascular
reactivity, demonstrating that therapeutic effects can also be achieved by the in
vivo transfer of gene(s) whose product(s) exert a paracrine effect on the vessel
wall.
PMID- 9552514
TI - Methods of local gene delivery to vascular tissues.
AB - The development of methods employing the introduction of new genetic material for
therapeutic applications in the cardiovascular system is dependent not only on
the evolution of molecular vectors, but also 'mechanical vectors' encompassing a
variety of mechanisms and approaches for the delivery of vectors or vector
modified cells to anatomical regions of interest. A significant challenge lies in
the evolution of mechanical devices capable of highly efficient, localized and
homogeneous delivery. Each of these three characteristics, though very desirable,
remains generally elusive for several kinetic and physical reasons. Recently
developed devices which render possible minimally-invasive peri- or epivascular
delivery may provide advances in these aspects of delivery.
PMID- 9552515
TI - Naked cDNA encoding secreted proteins for intra-arterial and intramuscular gene
transfer.
AB - Experience with intra-arterial and intramuscular gene transfer of VEGF
illustrates in prototypical fashion how features of the gene, protein, and target
tissue may all contribute to phenotypic modulation of the host despite the low
transfection efficiency typical of naked plasmid DNA. These features include the
fact that VEGF is naturally secreted, binds to cell-surface heparan sulfates, is
generated by hypoxic endothelial cells, reduces apoptosis, and binds to high
affinity receptors that are upregulated by hypoxia. Thus the success of gene
therapy is not solely a function of vectors or transfection efficiency.
PMID- 9552516
TI - Coronary stenting.
PMID- 9552517
TI - Clinical trials on intracoronary stenting.
AB - The stent is currently taking the lead in the treatment of obstructive coronary
artery disease. The interest in this device is not only reflected by the relative
number of patients referred for angioplasty and treated with a stent but also by
the large number of clinical trials. These can be divided into trials assessing
the safety and feasibility of the implantation of second generation or new
stents, studies assessing novel treatment strategies and randomized clinical
trials. With respect to the latter, they all compare stent implantation with
balloon angioplasty. Of major importance will be the comparison of stent
implantation with surgical revascularization of obstructive coronary artery
disease. The increasing number of therapeutic options, however, confront the
physician with the difficult choice and responsibility of selecting the most
appropriate treatment. Therefore, systematic and objective evaluation of the
available therapeutic approaches by means of appropriately designed trials is
imperative. The purpose of this paper is to summarize and to put into perspective
the various studies on intracoronary stenting. Distinction is made between
observational studies testing a device or evaluating a new concept in
intracoronary stenting and randomized clinical trials.
PMID- 9552518
TI - An overview of US coronary stent trials.
AB - Since the introduction of coronary stent procedures in the US there has been a
determined effort to understand appropriate clinical applications better through
the use of carefully designed prospective clinical trials. These studies fall
into the general categories of efficacy studies, pharmacology, studies,
intravascular ultrasound studies, adjuvant stent therapy studies, stent versus
stent studies and new stent registries. Most of the pivotal clinical trials have
been randomized controlled studies, but there have also been several carefully
performed registry analyses which have provided useful insights. There are ample
data to support the use of stents for abrupt and threatened closure syndrome.
STRESS (the STent REStenosis Study) helped to establish the 'anti-restenosis'
efficacy of elective Palmaz-Schatz coronary stent placement in native coronary
arteries, although secondary complications (subacute stent thrombosis, bleeding
and vascular events) were disturbing owing to excessive systemic anticoagulation
regimens. Subsequent studies, often using intravascular ultrasound guidance, have
clearly indicated that optimal stent implantation requiring post-stent high
pressure dilatations combined with aggressive antiplatelet therapy (aspirin plus
ticlopidine) provides the best early and late clinical outcomes. Many of these
observations have now been extended to other lesion subsets including saphenous
vein grafts. In the future, stent adjuvant therapies will be carefully evaluated,
including pharmacological agents, intravascular irradiation, and pre-stent
atheroablation. Finally, interstent comparisons of randomized clinical trials are
ongoing and there are several new stent registries which will help to extend the
frontiers of clinical applications and operator technique.
PMID- 9552519
TI - Clinical and angiographic outcome of elective stent implantation in small
coronary vessels: an analysis of the BENESTENT trial.
AB - We examined the influence of vessel size using an intention-to-treat approach in
259 patients who underwent stent implantation and in 257 patients who underwent
balloon angioplasty alone in the BENESTENT trial. In the stented population,
smaller vessel size was associated with a higher stent:vessel ratio, a greater
relative gain and a greater subsequent loss index, and a higher risk of adverse
cardiac events. In the balloon angioplasty population small vessel size conveyed
an increased requirement for revascularization but did not increase the risk of
procedural failure or myocardial infarction during follow-up. Logistic regression
indicated that decreasing vessel size (as a continous variable) was associated
with an increasing risk of a cardiac event for both the stent and balloon
angioplasty populations.
PMID- 9552520
TI - Cost effectiveness of stent implantation versus PTCA: the BENESTENT experience.
AB - The aim of this paper is to assess the costs and effects of stent implantation
versus percutaneous transluminal coronary angioplasty (PTCA). Data have been
taken from both the BENESTENT-I and BENESTENT-II pilot study. Effects are
expressed in terms of event-free survival and costs include those of the initial
hospitalization and those during follow-up. The costs per additional event-free
survivor after 7 months are estimated at Dfl 88,315, Dfl 28,127 and Dfl 6747
using respectively the results from the BENSTENT-I study, the BENESTENT-II pilot
study and phase IV of the BENESTENT-II pilot study. Significant decreases in
complications and ischaemic events have made stent implantation not only the most
favourable in terms of event-free survival but also in terms of cost
effectiveness.
PMID- 9552521
TI - Provisional stenting--stent-like balloon angioplasty: evidence to define the
continuing role of balloon angioplasty for percutaneous coronary
revascularization.
AB - To clarify the current role of balloon angioplasty in interventional cardiology,
in an era of increasing development of new devices, especially stents, we
performed a retrospective comparative evaluation within the well-known BENESTENT
trial. We defined a balloon angioplasty result of diameter stenosis less than 30%
by quantitative angiography a 'stent-like' result and compared 6-month
angiographic and 1-year clinical outcome with patients undergoing Palmaz-Schatz
stent implantation. Patients having a so-defined 'stent-like' result had similar
angiographic and clinical outcomes to patients receiving a stent. It is concluded
that achievement of a postangioplasty diameter stenosis less than 30% may be
considered clinically equivalent to the average result of Palmaz-Schatz stent
implantation.
PMID- 9552522
TI - 'Bail out' stenting: case closed.
AB - Since the first description of percutaneous transluminal coronary angioplasty
(PTCA), the number of patients who have undergone this procedure has rapidly
increased. Two problems have plagued PTCA: acute vessel closure and restenosis.
Acute vessel closure following PTCA increases the incidence of in-hospital death,
myocardial infarction and coronary bypass grafting. The advent of intracoronary
stenting for acute closure has had a profound impact on these complications.
Complications following intracoronary stenting have declined with modification of
anticoagulation post-stenting and an improved understanding of stent mechanics.
Further refinement of these devices and continued improvement in our
understanding of them should lead to further reduction of post-stent
complications and improved patient outcomes.
PMID- 9552578
TI - Changes in energy metabolism of calf muscle in patients with intermittent
claudication assessed by 31P magnetic resonance spectroscopy: a phase II open
study.
AB - Energy status and metabolism in skeletal muscle of nine patients with peripheral
arterial disease and suffering from intermittent claudication were evaluated
using 31phosphorus magnetic resonance spectroscopy (MRS) before and after
treatment for 3 months with propionyl-L-carnitine (PLC; 2 g/day p.o.). Maximum
walking distance (MWD) was assessed on a standard treadmill (4 km/h, zero
incline). For the group as a whole 31P MRS results did not change significantly
with PLC. Although MWD increased by a mean of 36%, this change did not reach
significance. However, when these variables were assessed with respect to the
change in MWD, there were significant differences between those who increased MWD
by > 30% (responders, R; n = 5) and those who did not (nonresponders, NR; n = 4).
Compared with pretreatment values, during exercise the decrease in muscle pH in R
relative to the decrease in phosphocreatine was less after PLC (p = 0.04). After
exercise there was a significant inverse correlation between the changes in
recovery half-time (t1/2) for phosphocreatine and in MWD (r = -0.91, p = 0.01).
With PLC, Vmax increased in R (p = 0.04), but not in NR. For the patient group as
a whole, the changes in Vmax and MWD correlated positively (r = 0.90, p = 0.01).
This study helps to identify the changes in muscle metabolism that correlate with
changes in exercise performance, and may accompany treatment with PLC.
PMID- 9552579
TI - A novel therapy for lymphedema complicated by lymphorrhea.
AB - Lymphorrhea is a rarely described complication of chronic lymphedema, in which
the disrupted flow through diseased lymphatic channels gives rise to the external
drainage of lymph, often heralded by the presence of an enlarging lymphocele.
This report documents the applicability of the Reid sleeve, a novel, conservative
form of therapy, in an unusually severe and protracted example of lymphorrhea.
PMID- 9552580
TI - Vascular permeability/vascular endothelial growth factors: a potential role in
the pathogenesis and treatment of vascular diseases.
PMID- 9552581
TI - Positive and negative regulation of angiogenesis: from cell biology to the
clinic.
AB - Virtually every subspecialty in medicine in one way or another deals with
angiogenesis-associated physiological or pathological processes and, without
exception, every organ system in the body has many diseases in which angiogenesis
is an important component. This in itself makes the study of angiogenesis
mandatory, in both basic science and clinical settings. Yet the study of
angiogenesis does not require this justification. As a biological process it is
extraordinarily rich, touching on virtually every aspect of modern cell biology,
making it almost impossible for molecular biologists, biochemists and
morphologists to ignore. Considerable therapeutic benefit can now be obtained
through positive or negative manipulation of the angiogenic process, and this is
due in large part to the rapid transfer to the clinical setting of knowledge
acquired through a cell biological approach.
PMID- 9552582
TI - Atheromatous embolism.
PMID- 9552583
TI - The diagnosis and clinical manifestations of activated protein C resistance: a
case report and review of the literature.
AB - Activated protein C resistance (APCR) is a recently discovered, medically
important cause of venous thrombosis. More than 95% of cases are due to factor V
Leiden (FVL), a mutated form of factor V that is resistant to degradation by
activated protein C. The prevalence of this disorder, which is inherited in an
autosomal dominant fashion, is approximately 5% among asymptomatic people of
European heritage. In addition, 20 to 60% of patient cohorts with previous
thrombosis demonstrate APCR, making it the most common known genetic cause of
abnormal thrombophilia. Current laboratory techniques available for diagnosis
include functional assays, such as the APC ratio, as well as DNA-based tests that
detect the specific genetic anomaly responsible for FVL. A case report is
presented, along with a review of the literature highlighting epidemiology,
pathogenesis, clinical features and methods for laboratory diagnosis.
PMID- 9552584
TI - Dermatologic findings associated with antiphospholipid antibody syndrome.
PMID- 9552585
TI - The treatment of iliac artery atherosclerosis with angioplasty and intravascular
stents.
PMID- 9552586
TI - Images in vascular medicine. Giant cell arteritis of axillary artery.
PMID- 9552622
TI - A clinical method to determine the effectiveness of dental handpiece
sterilization.
PMID- 9552623
TI - Beyond referrals: a smart Yellow Pages investment can bolster your bottom line.
PMID- 9552624
TI - Peer review in the 90's.
PMID- 9552625
TI - Treat patients with respect.
PMID- 9552626
TI - Through an eyeglass darkly.
PMID- 9552627
TI - The field of implantology--an overview.
PMID- 9552629
TI - Hiring and keeping good people--a guide to office organization (Part 3--The
compensation package).
PMID- 9552628
TI - The effects of lisinopril and nifedipine on parotid function: two case reports.
PMID- 9552630
TI - Using comprehensive examinations to build productive dental practices.
PMID- 9552631
TI - Health care, medical care and dental care--a comparative analysis.
PMID- 9552632
TI - Marketing the dental practice.
AB - Marketing is a system. While it is key and the scope of this article to offer 40
internal/customer service, external/community marketing strategies, this is your
goal. The combination of programs consistently applied, analyzed and modified
makes a difference. Start with your internal/customer service program. Once that
is in place you can expand to external/community marketing programs. Creativity
and persistence are how strong dental practices are built!
PMID- 9552633
TI - Valuing a practice for a partnership.
PMID- 9552634
TI - Redefining our understanding of misbehaving child patients.
PMID- 9552635
TI - Isolation of the field more important than ever.
PMID- 9552637
TI - HMO dentistry (capitation): how to profit and be ethical at the same time.
PMID- 9552636
TI - Clinical pathology case conference. Verrucous carcinoma.
PMID- 9552638
TI - Direct metallic amalgam alternative: a research update.
AB - Discussions between two group leaders at the National Institute of Standards and
Technology (NIST) led to the suggestion that a mercury-free, silver-based
material could be used for dental direct-filling applications. This concept
brought about a new approach that, nonetheless, is still based on powder
technology such as amalgams. The resulting material also retains the tin and
silver components of conventional amalgams. The condensation of a loose powder
mixture into a cohesive solid relies, however, on cold-welding across atomically
clean silver-silver interfaces after a mild acid treatment of the surfaces. The
National Institute of Dental Research (NIDR) and American Dental Association
Health Foundation (ADAHF) became involved in the research in 1992, and ADAHF
scientists continue to collaborate with NIST metallurgists and electrochemists
toward the further development of this promising new technology.
PMID- 9552650
TI - Rubber dam isolation of cervical lesions. Part 1: Alternative techniques which
avoid injury to the periodontium.
AB - While it is arguable that the operative procedures depicted in this article could
have been done equally well with alternative forms of isolation, it is
indisputable that rubber dam provides for the most thorough 'isolation' in the
comprehensive sense of the term. It allows for the finite control over peripheral
variables such as access and controlled gingival retraction. This in turn permits
meticulous execution of restorative procedures within the luxury of 'true four
handed dentistry'. Most operative procedures are done within the limitations of
single handed dentistry as the other 'three hands' are involved with retraction,
fluid evacuation and access control. The rubber dam is indeed indispensable and
with the increased awareness of infection control it is conceivable that rubber
dam isolation will continue to be associated with quality patient care. Part 2 of
this article will detail the application of the 'Modified Gingival Retractor' in
the isolation of cervical lesions.
PMID- 9552651
TI - Additional precautions to prevent transmission of Creutzfeldt-Jakob disease and
other prion diseases.
PMID- 9552652
TI - Posterior composite resin restorations: assuring restorative integrity.
AB - Vancouver practitioner William Liebenberg, with whose work FDI World readers will
be familiar, here describes the techniques be applies to the creation of direct
composite resin restorations. Sharing a number of his solutions to attaining
adhesive excellence with posterior, tooth coloured restorations, Dr. Liebenberg
uses a case study to illustrate the quest for aesthetically pleasing anatomical
form, minimal postoperative sensitivity, and a durable bond.
PMID- 9552653
TI - Periodontology matters.
PMID- 9552654
TI - The Cambodian dental bus.
PMID- 9552655
TI - Rubber dam isolation of cervical lesions. Part 2: Application of the 'modified
gingival retractor'.
PMID- 9552656
TI - Atraumatic restorative treatment technique.
PMID- 9552657
TI - Cleft lip and palate surgery in Cambodia.
PMID- 9552658
TI - Universal precautions and pathways of infection.
PMID- 9552659
TI - Sterilisation: Part 1. Instrument preparation.
PMID- 9552660
TI - Working together in Peru--language needn't be a problem!
AB - International, co-operative links between dental schools are an increasingly
common occurrence, especially in relation to elective visits for under-graduates.
However, in this feature for FDI World Norman Whitehouse and Gillian Jones from
the Cardiff Dental School in Wales, UK, describe how they came to meet and assist
Teresa Rios Caro in Peru, in rather different circumstances, and how language
need not be a barrier when goodwill prevails.
PMID- 9552661
TI - Sterilisation: Part 2. Heat and chemical sterilisation.
PMID- 9552662
TI - The World Health Organisation's Oral Health Programme (ORH).
AB - FDI and WHO have recently negotiated an agreement which will enable enhanced co
operation in the future. In this article, written especially for FDI World, Dr.
Pakhomov describes how oral health fits into the overall WHO programme. The
article describes the way in which communicable and non-communicable diseases
have an impact on the world's population and how WHO has rationalised its
resources to cope with the consequent demands.
PMID- 9552663
TI - FDI World Dental Federation. Position statement on tobacco.
PMID- 9552664
TI - The collection of the dental school in Berlin--a creation of Friedrich Busch.
PMID- 9552665
TI - What causes oral cancer?
PMID- 9552666
TI - Working together as a team.
PMID- 9552667
TI - The single incisor.
PMID- 9552668
TI - 1994--the World Year of Oral Health.
AB - The FDI has declared 1994 the World Year of Oral Health--the WHO's World Health
Day, 7 April 1994, is dedicated to Oral Health. This makes 1994 a unique year,
during which the dental profession and organised dentistry worldwide will focus
on the promotion and further development of oral health and oral health care-
throughout the year.
PMID- 9552669
TI - Caries world-wide.
PMID- 9552670
TI - Dentistry at the grassroots in Trinidad and Tobago.
PMID- 9552671
TI - Gallium alloys in dentistry.
PMID- 9552672
TI - The green journal of Victor R. Pointer.
PMID- 9552673
TI - The aesthetic harmony of upper incisors.
PMID- 9552674
TI - FDI World Dental Federation. Policy statement on dental amalgam. Approved by the
FDI's General Assembly, 7 October 1994.
PMID- 9552675
TI - Mahlon Loomis, DDS, inventor of wireless telegraphy.
PMID- 9552676
TI - The diagnosis and treatment of precancerous lesions.
AB - Leukoplakia is the most common premalignant lesion of the oral mucosa. The term
should be used only for white lesions that cannot be characterised as any other
definable lesion. The chance of malignant transformation can to some extent be
predicted on the basis of the clinical appearance, the oral subsite, and the
histopathological findings in the biopsy. The management of patients with oral
leukoplakia is primarily directed towards elimination of possible causative
factors. If the lesion persists, treatment is recommended in most cases. Of the
various available treatment modalities no one is superior to the others. Both
treated and untreated patients should be scheduled for long term follow-up,
probably life long, with 6-12 month intervals in order to he able to detect
possible recurrences in an early stage. Erythroplakia is less common than
leukoplakia, but carries a considerably higher risk of malignant transformation.
Therefore, erythroplakias should always be removed and subsequently, followed up.
PMID- 9552677
TI - Self-responsibility comes first--a Swiss perspective.
PMID- 9552679
TI - Tooth numbering systems.
PMID- 9552678
TI - The future is now! Five steps for making it happen.
AB - In today's market, dentists need to be open to using different approaches for
increasing patient awareness of how dentistry can benefit them. The five key
areas of practice management addressed here are just a few of the many ways to
keep your practice healthy in our changing profession. Dentists who are committed
to improving patient communication and accommodating the needs of their patients
will be the ones for whom the future is bright.
PMID- 9552680
TI - Swiss mission for dental prevention in Peru.
PMID- 9552681
TI - Oral health in Oman.
PMID- 9552683
TI - FDI World Dental Federation. Policy statement on the equivalency of dental
diplomas.
PMID- 9552682
TI - Operation smile Kenya 1994: oro-facial cleft surgery.
PMID- 9552684
TI - Smile Alaska style.
PMID- 9552685
TI - The International Milk Fluoridation Programme.
PMID- 9552686
TI - Disinfection. Testing and validating sterilisation procedures and health and
immunisation for clinicians.
PMID- 9552687
TI - Challenges of dentistry in Africa.
PMID- 9552688
TI - The amalgam debate worldwide: science versus emotion, plus environment.
PMID- 9552690
TI - Volunteer dentists--an update.
PMID- 9552689
TI - The poor dental health of children in Pakistan.
PMID- 9552691
TI - Additional precautions for tuberculosis and a self assessment checklist.
PMID- 9552692
TI - Oral cancer--a worldwide problem.
PMID- 9552693
TI - The Netherlands into Africa, Malta into Albania and Spain into Central America-
worldwide dental aid.
PMID- 9552694
TI - How do we recognise and treat oral cancer and potentially malignant lesions?
PMID- 9552695
TI - Tonga dental health programme.
PMID- 9552696
TI - FDI Infection Control Checklist.
PMID- 9552697
TI - Using technology to reduce the costs of dentistry.
PMID- 9552698
TI - The amalgam story continues. Interview by Stephen Hancocks.
PMID- 9552699
TI - Dentistry in Sri Lanka.
PMID- 9552700
TI - Rebuilding dental health in The Lebanon.
PMID- 9552701
TI - The miswak as an aid in oral hygiene.
PMID- 9552702
TI - FDI World Dental Federation. World Health Organization. Consensus statement on
dental amalgam.
PMID- 9552703
TI - The atraumatic restorative treatment (ART) technique in the English-speaking
Caribbean.
PMID- 9552704
TI - Hygienic maintenance of dental handpieces and turbines.
PMID- 9552705
TI - FDI World Dental Federation. Position statement on fluorides and dental caries.
PMID- 9552706
TI - Leadership skills for the dentist.
PMID- 9552707
TI - Mercy ships.
PMID- 9552708
TI - Update on tooth numbering.
PMID- 9552709
TI - A short (3-day) course of azithromycin tablets versus a 10-day course of
amoxycillin-clavulanic acid (co-amoxiclav) in the treatment of adults with lower
respiratory tract infections and effects on long-term outcome.
AB - The efficacy and safety of a 3-day regimen of azithromycin prescribed in the new
tablet form and of a 10-day regimen of amoxycillin clavulanic acid (co-amoxiclav,
Augmentin) were compared in patients with acute lower respiratory tract
infections. Of the 144 enrolled patients, 123 had a Type 1 acute exacerbation of
chronic bronchitis (AECB), three patients had pneumonia, and 18 had purulent
bronchitis. Treatment was successful, defined as cure or major improvement on day
14, in 59/62 (95%) patients in the azithromycin treatment group compared with
54/61 (90%) patients in the co-amoxiclav. At 30 days, the incidence of success
was 77% (48/62) in the azithromycin treated group, compared with 66% (40/61) of
co-amoxiclav-treated patients. At 60 days, incidences were 66% (41/62) and 59%
(36/61), respectively. Several pathogens were isolated: Haemophilus influenzae in
21 patients (minimum inhibitory concentration (MIC) range for azithromycin 0.12-4
mg/l; co-amoxiclav 0.25-4 mg/l); Streptococcus pneumoniae in nine (MIC
azithromycin < or = 0.06 > or = 256 mg/l; co-amoxiclav < or = 0.06-1 mg/l); and
Moraxella catarrhalis in 11 (MIC azithromycin < or =0.06-2 mg/l; co-amoxiclav <
or = 0.06-0.5 mg/l). Microbiological response rates were comparable. A
significant correlation between clinical and microbiological cure was found (p =
0.02, power 0.6). In 15 (10%) patients, positive serology for viruses or atypical
pathogens was found. In the co-amoxiclav-treatment group, 24 patients had mild
adverse events (12 diarrhoea), compared with 27 treated with azithromycin (p =
0.47). It is concluded that a 3-day regimen of azithromycin prescribed as tablets
is as clinically and microbiologically effective as a 10-day regimen of co
amoxiclav in the treatment of acute lower respiratory tract infections. Moreover,
since the percentage of viral infections was low and a significant correlation
between microbiological and clinical cure was found, this study shows that
clinical symptoms can be used to establish which patients with AECB (Type 1)
should be treated with antimicrobial agents.
PMID- 9552710
TI - A broad-spectrum antifungal from the marine sponge Hyrtios erecta.
AB - Spongistatin 1, a macrocyclic lactone polyether from the marine sponge Hyrtios
erecta, was fungicidal for a variety of opportunistic yeasts and filamentous
fungi, including strains resistant to amphotericin B, ketoconazole and
flucytosine. In broth macrodilution assays, MICs ranged from 0.195 to 12.5
microg/ml, and minimum fungicidal concentrations ranged from 3.12 to 25
microg/ml. Initial disk diffusion screens with six related macrocyclic lactone
polyethers from H. erecta and Spirastrella spinispirulifera, revealed that these
polyethers were also antifungal. The fungicidal activity of spongistatin 1 was
confirmed in killing kinetics studies, where killing of Candida albicans and
Cryptococcus neoformans occurred within 6 and 12 h, respectively. During the
killing kinetics experiments, non-treated C. albicans maintained the yeast
morphology. However, elongated forms resembling germ tubes were the predominant
morphologic form in spongistatin 1-treated C. albicans cultures. The
spongistatins show promise as potential antifungal agents and as probes to study
fungal morphogenesis and nuclear division.
PMID- 9552711
TI - Quality assessment of glycopeptide susceptibility tests: a European collaborative
study. European Glycopeptide Resistance Group.
AB - The ability of seventy clinical laboratories in nine European countries to detect
glycopeptide resistance in Gram-positive bacteria was investigated. Results of
routine tests were compared with those on the same strains by a reference method
in national co-ordinating laboratories. In addition, control strains were tested
by some of the participants. Errors in reporting susceptibility of Staphylococcus
aureus to teicoplanin and vancomycin and coagulase-negative staphylococci to
vancomycin were < 1%. With coagulase-negative staphylococci however, 44 (3.4%)
teicoplanin susceptible isolates were reported intermediate and six (0.4%)
resistant; 18 (58.1%) of 31 teicoplanin intermediate isolates were reported
susceptible and five (16.1%) resistant; and six of nine teicoplanin resistant
isolates were reported susceptible and two intermediate. All seven isolates of
enterococci intermediate to vancomycin were reported susceptible. Distribution of
a known vancomycin intermediate strain of E. gallinarum indicated problems with
vancomycin susceptibility testing (44.4% reported susceptible, 32.7%
intermediate, 32.1% resistant) and identification (only 34.1% correct) of this
organism. Two of 28 teicoplanin resistant enterococci and three of 30 vancomycin
resistant isolates were reported susceptible. Among other organisms, one
resistant Lactobacillus sp. was reported susceptible to teicoplanin and
vancomycin. In reporting teicoplanin susceptible organisms, there were fewer
errors with comparative/Stokes methods than with most other methods and more
errors with the ATB and Sceptor methods than most other methods. None of the
methods used were reliable for testing teicoplanin intermediate and resistant
coagulase-negative staphylococci or low-level vancomycin resistant enterococci.
Alternative methods, such as breakpoint screening, should be considered for
detecting glycopeptide resistance.
PMID- 9552712
TI - ERIC-PCR typing profiles of Enterobacter cloacae are stable after development of
advanced cephalosporin resistance.
AB - Enterobacterial repetitive intergenic consensus (ERIC) sequence polymerase chain
reaction genotype profiles of Enterobacter cloacae were prepared for paired
isolates which were obtained before and after the high level expression of the
chromosomal cephalosporinase. These profiles were homologous within strain pairs
which suggests that the acquired resistance does not lead to major chromosomal
alterations. ERIC genotypes are therefore reliable markers in epidemiological
investigations where antibiogram modifications may arise as a consequence of
antibiotic exposure and beta-lactamase over-production..
PMID- 9552713
TI - The activity of rifabutin against Mycobacterium leprae in armadillos.
AB - The activity of rifabutin (LM 427) against Mycobacterium leprae was evaluated in
armadillos inoculated earlier with human-derived M. leprae. Rifabutin was
administered daily at a dose of 6 mg/kg body weight/day. The effect of rifabutin
on M. leprae harvested from armadillos was determined by measuring the
intracellular levels of ATP (an indicator of metabolic activity) of M. leprae and
also their ability to multiply in the mouse footpads and in vitro in DH medium.
Within 2 weeks of initiating the treatment, ATP levels declined to 21% of the
original (pre-treatment level) and these M. leprae failed to multiply in the
footpads of mice as well as in the in vitro culture system. This suggests that
rifabutin was able to kill all M. leprae within 2 weeks. After 8 weeks the
treatment was terminated and results showed that M. leprae from the treated
armadillos remained non-viable in the mouse footpad system as well as in the in
vitro system, indicating bactericidal action of rifabutin. The results suggest
that rifabutin can be a substitute for rifampin in the leprosy multi-drug therapy
regimen.
PMID- 9552714
TI - Antimicrobial resistance in gonococci isolated from patients and from commercial
sex workers in Harare, Zimbabwe.
AB - The objective is to compare antibiotic resistance amongst gonococci isolated from
different patient groups in Harare, Zimbabwe. Antimicrobial susceptibilities of
Neisseria. gonorrhoeae were determined by disc sensitivity tests. The MICs for
penicillin, kanamycin, ceftriaxone, norfloxacin and ciprofloxacin were determined
using E-test strips. There were 147 isolates from symptomatic men, 47 isolates
from symptomatic women, 29 isolates from asymptomatic women and 41 isolates from
female commercial sex workers. A total of 119 (45%) isolates were PPNG and 23
(16%) non-PPNG isolates had a penicillin MIC > 0.64 mg/l. Over 90% of isolates
were resistant to TMP/SMX and 16% were resistant to tetracycline. Resistance was
uncommon against kanamycin (6%), erythromycin (2%) or ceftriaxone ( < 1%). For
kanamycin, the MIC90 was 32 mg/l, for ceftriaxone the MIC90 was < 0.032 mg/l for
non-PPNG and < 0.064 mg/l for PPNG. For norfloxacin and ciprofloxacin the MIC90
was < 0.064 mg/l for both PPNG and non-PPNG. Isolates from the commercial sex
workers showed a significantly increased prevalence of PPNG, of penicillin
tolerant non-PPNG and of tetracycline resistance. Four of the 41 isolates from
sex workers showed multiple resistance (to penicillin, TMP/SMX, tetracycline and
kanamycin) compared to 1/223 isolates from other groups (OR = 24.0).
Antimicrobial resistance is common amongst gonococci in Harare, especially with
isolates from commercial sex workers. In order for STD treatment to be
implemented as an effective strategy in HIV control, continued monitoring of
resistance patterns is essential.
PMID- 9552715
TI - Gastric diffusion of antibiotics used against Helicobacter pylori.
AB - Only a few pharmacological studies have been carried out on men and guinea pigs
to determine the gastric diffusion of antibiotics, which are active against
Helicobacter pylori. The results of these studies have been analysed in
considering the physicochemical nature, the mode of administration, the way of
gastric diffusion (topic and/or systemic) and the pharmacological interactions.
The correlation of these pharmacokinetic results with those obtained in clinical
trials is difficult because of the heterogeneity of the pharmacological and
pharmacodynamic data. The absence of a convenient and suitable animal or in vitro
study model renders further standardized pharmacokinetic studies in infected man
and at steady state necessary.
PMID- 9552716
TI - Inhibition of Listeria monocytogenes and Salmonella enteriditis by combinations
of plant oils and derivatives of benzoic acid: the development of synergistic
antimicrobial combinations.
AB - This study describes inhibitory properties of combinations of oil of fennel, oil
of anise or oil of basil with either benzoic acid or methyl-paraben against
Listeria monocytogenes and Salmonella enteriditis. Micro-organisms were cultured
at 37 degrees C in broth and viable counts measured over a 48-h period. S.
enteriditis was particularly sensitive to inhibition by a combination of oil of
anise, fennel or basil with methyl-paraben where there was < 10 CFU/ml after 1 h.
L. monocytogenes was less sensitive to inhibition by each combination however
there was a significant reduction in growth of 4-8 log by combinations of all
oils and methyl-paraben at 8, 24 and 48 h. Synergistic inhibition by one or more
combinations was evident against each micro-organism.
PMID- 9552717
TI - Antibiotic resistance in Escherichia coli isolated from blood and cerebrospinal
fluid: a 6-year study of isolates from patients in England and Wales.
AB - A study of the incidence of resistance to antimicrobial drugs in Escherichia coli
from blood and CSF made in England and Wales in the 6-year period 1991 1996 has
demonstrated a significant increase in the incidence of strains resistant to
ampicillin and ciprofloxacin, two antibiotics used for first-line therapy of
invasive disease. In particular, there has been a dramatic change in the
occurrence of isolates with low level or high level resistance to ciprofloxacin;
over 90% of isolates in the high level group were also resistant to at least four
other antimicrobials. Physicians in England and Wales should be aware that there
is now an increasing possibility of treatment failures when ciprofloxacin is used
for the treatment of invasive E. coli infections.
PMID- 9552718
TI - Pharmacokinetics of miconazole in serum and exudate of pelvic retroperitoneal
space after radical hysterectomy and pelvic lymphadenectomy.
AB - Due to the increased number of compromised hosts with fungal infections, doctors
have recently started prescribing antifungal agents. In the field of gynecology,
however, the choice of which drug to use has been difficult. The efficacies of
these drugs depend on their antifungal spectra, potencies and concentrations in
tissues. The present study was designed to investigate the pharmacokinetics of
miconazole in the exudate of the retroperitoneal space that is formed after
radical hysterectomy and pelvic lymphadenectomy. A total of 600 mg of miconazole
was administered to the patients for exactly 60 min using an automatic drip
infusion pump. The parameters of the formulas analyzed by the two-compartment
model were determined using the least-squares method, and a simulation curve was
made. The maximum drug concentration (Cmax) of miconazole in serum was 6.26 mg/l
1 h after drip infusion commencement and the t1/2 in serum was 8.86 h. The value
of the area under the time-serum concentration curve (AUC) in serum was 19.13
mg/h per l. The Cmax of miconazole in the exudate of the retroperitoneal space
was 0.13 mg/l 2.48 h after the drip infusion was started. The value of AUC in the
exudate was 2.52 mg/h per l.
PMID- 9552751
TI - EEMCO guidance for the assessment of skin colour.
AB - GENERAL DESCRIPTION: Colour assessment of skin by visual inspection alone may be
precise for a given individual although comparison between colours is only
possible when they are viewed simultaneously. Subjective colour expression is
also difficult to communicate with consistency. The limitations of visual
observations may be overcome by colour-order systems and by instrumental
measurements using either reflectance spectrophotometry or reflectance
colorimetry following the CIE (Commission Internationale de l'Eclariage)
recommendations. Image analysis using sensitive colour video cameras is another
accurate method to record and compare skin colours. The current instrumental
methods have proven both sensitive and reliable. Numerical colour communication
expresses colours more precisely than words and allows exact analysis of skin
pigmentation and skin colour changes. LEARNING OBJECTIVE: The reader will be
introduced to the origins of skin colours and with basic principles of their
measurements. Methods of colour reading are reviewed with particular insight into
practical procedures, pitfalls and correct interpretation of data.
PMID- 9552752
TI - Skin diseases associated with hepatitis C virus infection.
AB - Hepatitis C virus (HCV) is a bloodborne agent transmitted by apparent and
inapparent parenteral procedures representing a frequent cause of liver disease
world-wide. Both acute and chronic HCV infection may affect the liver as well as
various non-hepatic tissues. Numerous extrahepatic disorders have been recognised
in association with HCV infection among which dermatological diseases occupy a
central part. Cutaneous necrotising vasculitis, mixed cryoglobulinemia, porphyria
cutanea tarda and lichen planus are the major skin diseases frequently associated
with HCV infection, but other skin disorders, such as Adamantiadis-Behcet
syndrome, erythema multiforme and nodosum, malacoplakia, urticaria and pruritus,
may also be linked to hepatitis C. Further studies are necessary to establish or
refute an aetiopathogenetic role of HCV in these conditions. Skin manifestations
are also part of the clinical picture of other extrahepatic disorders associated
with HCV infection, such as thyroid dysfunction and HCV-related thrombocytopenia.
The response to interferon alpha (alpha-IFN) therapy in skin diseases is
unpredictable with some patients ameliorating, others remaining stationary and
others deteriorating.
PMID- 9552753
TI - Duodenal ulcer patients exhibit a greater skin response to histamine.
AB - BACKGROUND: Histamine is considered a major mediator in the process of gastric
acid secretion. When acid peptic activity overpowers the mucosal defense
mechanism, peptic ulceration may develop. Is the hyperreactivity of patients with
duodenal ulcer to histamine also expressed in the skin? OBJECTIVE: The aim of the
present study was to assess the reactivity of patients with duodenal ulcer to
histamine as reflected in the skin, by comparing the erythema and the cutaneous
blood flow response to histamine in duodenal ulcer patients and healthy controls.
METHODS: Twenty volunteers participated in the study: 10 duodenal ulcer patients
and 10 age and gender matched healthy controls. Histamine was topically
administered to the back and to the volar side of the forearm, and the induced
response was quantified by spectrophotometry and laser Doppler flowmetry (LDF).
The extent of the response and time parameters were compared. RESULTS: The
maximum response, as measured by LDF, was greater in the peptic ulcer patients (P
< 0.05) compared to healthy controls. Aging was accompanied by decreased
responsiveness in both groups. CONCLUSION: The results suggest that some peptic
ulcer patients exhibit a greater cutaneous response to topical application of
histamine than healthy controls. As the methods used are non-invasive, simple and
rapid, they might be useful in preclinical ulcer diagnosis and detection of
patients at risk.
PMID- 9552754
TI - Use of recombinant pemphigus vulgaris antigen in development of ELISA and IB
assays to detect pemphigus vulgaris autoantibodies.
AB - AIM/OBJECTIVE: The objectives of this study are: (1) to measure the titers of
pemphigus vulgaris (PV) autoantibody in the sera of patients with active disease,
using three different assays: (a) Indirect immunofluorescence (IIF) using monkey
esophagus as a substrate, (b) immunoblot (IB) and, (c) enzyme-linked
immunosorbent assay (ELISA) using recombinant PV antigen (rPVA). (2) To compare
the sensitivity of these three assays. BACKGROUND: The titer of PV autoantibodies
and disease severity and extent do not always correlate. This could be due to the
lack of consistency and specificity of the substrate. Different results are
obtained using different substrates. A standard substrate with uniformly
controlled source of antigen would be more useful and clinically beneficial.
METHODS: In this study we studied 25 PV patients, six each with bullous
pemphigoid (BP), ocular cicatricial pemphigoid (OCP), mucous membrane pemphigoid
(MMP), and herpes gestationis (HG), and sera from 16 normal subjects. IIF was
used to determine the PV autoantibody using monkey esophagus. IB assay was used
according to standard protocol using normal human epidermis and rPVA as
substrates. ELISA was performed using rPVA as antigens expressed in E. coli.
RESULTS: Sera of all 25 PV patients showed binding to the rPVA, normal human sera
and the sera from the six BP, six OCP, six MMP, and six HG patients did not show
any binding. In addition, we used antisera from rabbits immunized with PVA
peptides (Bos-1, Bos-6) which also showed binding to rPVA, whereas normal rabbit
sera did not show any reactivity. ELISA and IB titers in all the patients were
2.5 to 160 times higher than with the conventionally used IIF assay. The titers
of the PV specific autoantibody measured using the rPVA did not show
statistically significant differences between the ELISA and IB assays.
CONCLUSIONS: IB and ELISA are superior to IIF in evaluating the antibody levels
in PV patients. ELISA is more practical and is preferable to IB and is
recommended for clinical use.
PMID- 9552755
TI - Generalized pustular drug eruptions: confirmation by in vitro tests.
AB - BACKGROUND: Generalized pustular eruptions are characterized by acute onset of
aseptic pustules in febrile patients with leukocytosis after exposure to the
offending drug. They have been regarded as uncommon manifestations of adverse
drug reactions. Until now few confirmation studies have been carried out.
OBJECTIVE: Our purpose was to describe a series of patients with generalized
pustular drug eruption. The diagnosis and etiological role of drugs in these
cases was confirmed by two in vitro tests, namely the macrophage migration
inhibitory factor (MIF) and the mast cell degranulation (MCD) tests. METHODS: The
clinical, pathological and laboratory findings in six patients with generalized
pustular eruption were studied prospectively. The MIF and MCD tests were
performed with the drugs taken by the patients. RESULTS: The dermatological
manifestations included numerous pustules on large erythematous areas, papules
and erythema multiforme-like lesions. The pustular eruption developed between 12
h and 5 days after the administration of the provoking drug. The
histopathological changes were characterized by subcorneal pustules, papillary
edema and mixed cell inflammatory infiltrate. In two biopsies the infiltrate
displayed numerous eosinophils. Laboratory investigations revealed leukocytosis
with neutrophilia (4 of 6 patients) and eosinophilia and hyperimmunoglobulinemia
E (2 of 6 patients). MCD tests with the suspected drugs (Ampicillin, Cefazolin,
Tetracycline, Griseofulvin, Enalapril Maleate) were positive in all patients.
Positive MIF results were seen in five of the six patients. Withdrawal of the
drug led to fast recovery. CONCLUSION: The diagnosis of pustular drug eruptions
depends on circumstantial evidence, some characteristic clinicopathological
findings and exclusion of alternative diagnoses of other disseminated pustular
eruptions. In vitro tests, namely MIF and MCD tests, are a useful diagnostic aid
in the identification of the offending drugs.
PMID- 9552756
TI - Low-dose retinoid therapy for chemoprophylaxis of skin cancer in renal transplant
recipients.
AB - BACKGROUND: Renal transplant recipients have an increased incidence of skin
cancers, which may be multiple and aggressive. OBJECTIVES: The purpose of this
study was to examine the chemoprophylactic effects of low-dose etretinate (0.3
mg/kg/day) on skin cancer development in renal transplant recipients and to
monitor retinoid toxic effects at this dose. METHODS: All skin lesions were
counted and photographed prior to therapy with etretinate. Patients were assessed
at monthly intervals for new skin lesions and for retinoid toxicity. RESULTS:
Eleven renal transplant recipients participated. There was a significant
reduction in the number of skin cancers which occurred during etretinate therapy
compared with pre-treatment for 3 and 6 months of treatment, and a trend towards
fewer skin cancers in the 12 and 18 month treatment periods. Side-effects were
well-tolerated and no significant biochemical effects were observed. CONCLUSION:
Low dose etretinate is safe, well-tolerated and partially effective in
chemoprophylaxis of skin cancer in renal transplant recipients.
PMID- 9552757
TI - Classic Kaposi's sarcoma in two young heterosexual men.
AB - Classic Kaposi's sarcoma is primarily a skin disease of the lower extremities
affecting predominantly elderly men of Mediterranean origin. We report classic
Kaposi's sarcoma first presenting in the third decade in two heterosexual, HIV
negative, males of Greek origin from Albania. Ten years after onset, the disease
became aggressive with unusual clinical features that included exophytic tumors,
extensive lesions on the hands as well as the legs, and prominent leg edema. One
of the patients also presented lesions on the face, trunk and palate, and bubonic
lymphadenopathy. In both cases, CD4 counts were normal and HLA-DR5 was positive.
Treatment included radiation therapy, subcutaneous interferon (alpha-2b) and
combined chemotherapy (ABV). At follow up 1 and 2 years later, both patients
remain in partial remission with significant improvement in clinical disease, on
maintenance interferon.
PMID- 9552758
TI - An unusual case of primary systemic amyloidosis.
AB - Here we report an unusual case of primary systemic amyloidosis. The cutaneous
lesions were polymorphic and included involvement of both external auditory
canals. The visceral involvement was covert. Mapping of amyloid deposits was
performed using scintigraphy with technetium-99m (V) dimercaptosuccinic acid
([99mTc (V)] DMSA). Therapy with melphalan, prednisone and colchicine resulted in
considerable improvement.
PMID- 9552759
TI - Cutaneous infection due to acremonium.
AB - We report an immunocompromised patient who developed a cutaneous infection caused
by acremonium which is a rare opportunistic fungi. With the increasing number of
immunocompromised patients opportunistic fungal infection can cause serious
diseases and early recognition is mandatory.
PMID- 9552760
TI - Subcutaneous T-cell lymphoma: report of two cases.
AB - We have seen two patients, a 24-year-old man and a 15-year-old girl, with
subcutaneous nodules and fever. The histopathological findings in both cases
showed a lobular, histiocytic panniculitis with 'bean bag' cells and lymphoid
cells identified as immature T-cells. This picture was consistent with
subcutaneous T-cell lymphoma associated with cytophagic histiocytic panniculitis.
The girl died after 5 months of disease with florid hemophagocytic syndrome; the
man was subjected to a course of treatment (CHOP;
cyclophosphamide/doxorubicin/vincristine/prednisone) and after 6 months
observation his symptoms of nodules and fever disappeared.
PMID- 9552761
TI - Juvenile acute cutaneous leishmaniasis: the first case report from north
Scandinavia.
AB - A case of juvenile acute cutaneous leishmaniasis is reported. Treatment with
freezing with CO2 snow was beneficial in healing of cutaneous lesions and no
relapses have occurred.
PMID- 9552762
TI - Linear IgA bullous dermatosis induced by piroxicam.
AB - Linear IgA bullous dermatosis (LABD) is an acquired, autoimmune, heterogeneous
subepidermal blistering disorder usually idiopathic in nature, but in recent
years a variety of drugs have been reported to induce this disorder. We describe
the first reported patient who developed LABD after ingestion of the non
steroidal anti-inflammatory agent (NSAID) piroxicam.
PMID- 9552763
TI - Hypomelanosis of Ito: a case report with clinical and ultrastructural data.
AB - Hypomelanosis of Ito (HI) is an uncommon skin disorder characterized by the
presence of hypochromic areas associated with visceral abnormalities, the most
common being neurological, muscular, skeletal and ocular. The authors describe a
typical case of hypomelanosis of Ito in a 7-year-old child. The patient was
obese, suffered from scoliosis, flat feet and had a bilateral genu valgus. No
neurological, ophthalmological or dental malformations were noted. An electron
microscopic study of a hypomelanotic area showed decreased functional activity in
the melanocytes, which contained only a few rudimentary cytoplasmatic projections
and poorly developed organelles. In addition, there was a reduction in the number
of mature melanosomes.
PMID- 9552764
TI - African histoplasmosis: therapeutic efficacy of itraconazole.
AB - A patient with African form of histoplasmosis was treated for 7 years with
ketoconazole, with no response; after a 9-month daily treatment with 100 mg of
itraconazole the patient was successfully cured. No evidence of relapse was
observed during the 3-year follow-up period.
PMID- 9552765
TI - Leukocytoclastic vasculitis induced by low-dose methotrexate: in vitro evidence
for an immunologic mechanism.
AB - The rare occurrence of methotrexate (MTX)-induced vasculitis has been associated
mainly with high or intermediate MTX doses. We report herein a case of cutaneous
leukocytoclastic vasculitis (LCV) following treatment with low-dose oral MTX (7.5
mg/week) for rheumatoid arthritis. The histological findings of a cutaneous
lesion were consistent with drug-induced vasculitis. The clinical and
histological findings, including the temporal relationship between MTX intake and
the onset of vasculitis, and the results of withdrawal and rechallenge tests,
suggest a causal relationship, and indicate a drug-induced LCV due to MTX. The
role of MTX in the induction of the vasculitis was further supported by a
positive mast cell degranulation (MCD) test.
PMID- 9552766
TI - Lyme borreliosis in the Emilia-Romagna region (Italy): identification of the
etiological agent.
PMID- 9552767
TI - Irritant contact dermatitis due to Dieffenbachia s.p.p.
PMID- 9552768
TI - Randomised double blind controlled trial of 2% ketoconazole cream versus 0.05%
clobetasol 17-butyrate cream in seborrhoeic dermatitis.
PMID- 9552769
TI - Pemphigus vulgaris exhibiting Koebner phenomenon.
PMID- 9552771
TI - The American Society of Regional Anesthesia: a founding partner of the American
Board of Anesthesiology.
PMID- 9552770
TI - Every problem is an opportunity, or one person's poison is another person's
remedy.
PMID- 9552772
TI - 2-Chloroprocaine and bupivacaine are unreliable indicators of intravascular
injection in the premedicated patient.
AB - BACKGROUND AND OBJECTIVES: Epinephrine-containing test doses for detection of
intravascular injection during epidural anesthesia may be unreliable or hazardous
in beta-blocked, elderly, or pregnant patients. Subtoxic injections of lidocaine
have been used as an alternative marker of intravascular injection in
unpremedicated patients. We studied two groups of premedicated patients and
unpremedicated subjects to evaluate the reliability of the local anesthetics
bupivacaine (B) and 2-chloroprocaine (2-CP) as test dose injections. METHODS:
Thirty ASA I and II subjects received blinded randomized injections of 2-CP, B,
or normal saline via a peripheral vein. RESULTS: In group I, 10 healthy
unpremedicated volunteers universally recognized injection of 90 mg 2-CP or 25 mg
B, but did not reliably detect the injection of 60 mg 2-CP. In group II, 20
patients premedicated with 1 microg/kg fentanyl and 30 microg/kg midazolam could
not reliably detect similar injections. Sixteen responded to the injection of 90
mg 2-CP, while 13 detected the 25 mg B test dose. A blinded observer rated only
12 of the subjective reports as conclusive of detection of intravascular
injection after each drug. There were no false-positive reports in any group.
CONCLUSIONS: While 90 mg 2-CP or 25 mg B may be reliable alternatives to
epinephrine test doses in unpremedicated subjects, they are unreliable indicators
of intravascular injection in the premedicated patient.
PMID- 9552773
TI - Epidural pressures and spread of 2% lidocaine in the epidural space: influence of
volume and speed of injection of the local anesthetic solution.
AB - BACKGROUND AND OBJECTIVES: The impact of epidural pressures on the spread of
epidural block is controversial. This study examined the effect of volume and
speed of injection of local anesthetics on epidural pressures and the spread of
anesthesia. METHODS: Twenty women undergoing epidural anesthesia received a test
dose of 3 mL of 2% lidocaine with epinephrine 1:200,000 over 6 seconds and
subsequently the main dose of 15 mL of the solution over 30 seconds (group I) or
3 minutes (group II). Variables studied included epidural pressures and the
extent and duration of thermal and sensory block. RESULTS: Peak epidural pressure
following the main dose was significantly higher in group I as compared to group
II. All other epidural pressures and the extent and duration of sensory and
thermal block were similar in both groups. The peak epidural pressure in group II
and the pressures obtained at 3 minutes after the main dose in both groups were
inversely correlated with the extent of the thermal block and directly correlated
with its regression time. CONCLUSIONS: The peak epidural pressures correlated
with the speed of injection of the lidocaine solution and not with its volume,
whereas the remaining epidural pressures correlated with its volume and not with
the speed of injection. The extent and duration of the thermal block exhibited a
more consistent correlation (inverse and direct, respectively) with the epidural
pressures than those of the sensory block.
PMID- 9552774
TI - Time course of the effects of cervical epidural anesthesia on pulmonary function.
AB - BACKGROUND AND OBJECTIVES: During cervical epidural anesthesia the C4, C5, and
sometimes C3 nerve roots are anesthetized. One might therefore expect pulmonary
compromise due to the block of the phrenic nerve if anesthesia extends to C3.
This study was conducted to measure the effects of cervical epidural anesthesia
using 2% lidocaine on pulmonary function, with specific attention given to the
time course of pulmonary changes in relation to spread of analgesia. METHODS:
Fifteen adult patients without preexisting lung disease undergoing carotid
endarterectomy, breast surgery, or cervical epidural steroid injection were
enrolled. Cervical epidural anesthesia was performed at the C7-T1 interspace
using 300 mg lidocaine with epinephrine. Pulmonary function, including forced
expiratory volume in one second (FEV1), forced vital capacity (FVC), maximum
inspiratory pressure (MIP), and SpO2 while breathing room air were measured prior
to and 5, 10, 20, and 40 minutes after lidocaine injection. RESULTS: Analgesia to
pinprick reached median dermatomes of C3 to T8 (range: C2-T12) by 20 minutes
after lidocaine injection. FEV1 and FVC decreased approximately 12-16% between 20
and 40 minutes after injection. Maximum inspiratory pressure and SpO2 did not
significantly change. CONCLUSIONS: Cervical epidural anesthesia using 300 mg
lidocaine results in measurable reduction in bedside pulmonary functions
concomitant with the spread of analgesia to the C3 dermatome. These changes were
complete 20 minutes after lidocaine injection. In patients without preexisting
lung disease, these changes were not clinically significant, except in one
patient. We conclude that motor block of the phrenic nerve is incomplete under
the conditions of this study.
PMID- 9552775
TI - High thoracic epidural block relieves acute herpetic pain involving the
trigeminal and cervical regions: comparison with effects of stellate ganglion
block.
AB - BACKGROUND AND OBJECTIVES: Stellate ganglion block can promptly relieve acute
herpetic pain (AHP) involving the trigeminal and cervical regions. However,
repeated blocks are needed to maintain pain relief in most patients with severe
AHP. Because continuous epidural block is easily performed using an indwelling
catheter, we compared the effect of high thoracic epidural block with that of
stellate ganglion block to relieve moderate-to-severe AHP involving these
regions. METHODS: Six patients received stellate ganglion blocks and seven
patients received high thoracic epidural blocks. Six milliliters 1% of
mepivacaine was given to each patient. Acute herpetic pain was evaluated before
and up to 60 minutes after the blocks, using a visual analog scale (VAS) of pain.
RESULTS: There was no significant difference in VAS pain scores before the blocks
between the groups, but there were significant (P < .05) decreases in VAS pain
scores for both groups between 10 and 60 minutes after the blocks. There were no
significant differences in VAS pain scores between the groups after the blocks.
CONCLUSIONS: High thoracic epidural block was as effective as stellate ganglion
block in relieving moderate-to-severe AHP involving the trigeminal and cervical
regions.
PMID- 9552776
TI - Sphenopalatine ganglion block for the treatment of myofascial pain of the head,
neck, and shoulders.
AB - BACKGROUND AND OBJECTIVES: This study examined the effectiveness of
sphenopalatine ganglion block (SPGB) for myofascial pain syndrome of the head,
neck, and shoulders using a double-blind, placebo-controlled, crossover study
design with comparison to an internal standard consisting of trigger point
injections (TPI). METHODS: Patients (n = 23) were randomly assigned to receive
either: (1) SPGB with 4% lidocaine, then TPI with 1% lidocaine, and finally SPGB
with saline placebo or (2) SPGB with saline placebo, then TPI with 1% lidocaine,
and finally SPGB with 4% lidocaine. Each respective treatment within each
protocol was given sequentially at 1-week intervals for both groups. Prior to the
first treatment, all patients assessed their average intensity of pain and pain
at that particular moment using a visual analog pain scale. Pain intensity and
pain relief were reassessed 30 minutes after each treatment and at 6 hours, 24
hours and 1 week using visual analog pain and pain relief scales. Pain intensity
and pain relief data were transformed into natural logarithm units, and the
statistical significance of SPGB with 4% lidocaine versus SPGB with placebo, SPGB
with 4% lidocaine versus TPI, and TPI versus SPGB with placebo were tested by
mixed-model analysis of variance. The magnitude of the differences in pain
intensity and pain relief ratings were also compared via computation of 95%
confidence intervals. RESULTS: The analgesic effect of SPGB with 4% lidocaine was
no better than placebo. Mixed-model analysis of variance revealed improved
analgesia with administration of TPIs as compared to SPGB with 4% lidocaine and
placebo over the entire week of observations (pain relief scores). CONCLUSIONS:
This study suggests that SPGB with 4% lidocaine is no more efficacious than
placebo and less efficacious than administration of standard trigger point
injections in the treatment of myofascial pain of the head, neck, and shoulders.
PMID- 9552777
TI - Celiac plexus block: a reappraisal.
AB - BACKGROUND AND OBJECTIVES: The neurolytic celiac plexus block is an established,
well-developed procedure and the most widely applicable of all the neurolytic
pain blocks. It optimizes palliative treatment for cancer of the upper abdominal
viscera. Several techniques have been proposed in an attempt to increase success
rates, reduce morbidity, and enhance technical accuracy. However, the assessment
of the results and effectiveness of the block have been controversial. METHODS: A
survey was made of pertinent English language literature on the anatomic and
technical problems, indications, advantages, complications, and outcomes related
to the neurolytic celiac plexus block as well as the neurolytic solutions and
radiologic guidance used. RESULTS: The successful relief of the pain of
pancreatic cancer and other abdominal malignancies can be expected in 85% and 73%
of patients, respectively. Following the block, many patients can be weaned from
opioids or at least have their dose reduced. The half-life of the celiac plexus
block seems to be more than 4 weeks. The probability of patients remaining
completely pain-free diminishes with increases survival time. The technique
selected should be appropriate to the available and the extent of malignancy,
since the analgesic results seem to be independent of the principal techniques
used. Serious complications are extremely rare. However, critical analysis
revealed major deficiencies in all of the reports reviewed. CONCLUSION:
Neurolytic celiac plexus block alone is capable of providing complete pain relief
until death in a few cases and, therefore, should be considered as an adjuvant
treatment in the analgesic strategy. Combination palliative therapy is necessary
in most cases. Failure of the block may be attributed to tumor metastasizing
beyond the nerves that conduct pain via the celiac plexus and the component
nerves that form it. Concomitant pain of somatic origin (frequently observed in
upper gastrointestinal cancer because of significant peritoneal involvement)
requires other therapeutic measures.
PMID- 9552778
TI - Enhancement of analgesic effect of intrathecal neostigmine and clonidine on
bupivacaine spinal anesthesia.
AB - BACKGROUND AND OBJECTIVES: Intrathecal administration of neostigmine has been
shown to produce analgesia in both animals and humans. The concurrent
administration of intrathecal neostigmine and clonidine has been reported to
produce no neurotoxicity in sheep. The purpose of the present study was to
evaluate the efficacy and safety of the combining intrathecal neostigmine and
clonidine for the relief of pain in patients after cesarean delivery. METHODS:
After giving their consents, 80 parturients who were scheduled for cesarean
delivery during spinal anesthesia were enrolled by a double-blind randomized
design into four groups: bupivacaine group (n = 20) received intrathecal (i.t.)
10 mg bupivacaine; bupivacaine + neostigmine group (n = 19) received i.t. 10 mg
bupivacaine + 50 microg neostigmine; bupivacaine + clonidine group (n = 20)
received i.t. 10 mg bupivacaine + 150 microg clonidine; and bupivacaine + both (n
= 21) received i.t. 10 mg bupivacaine + 50 microg neostigmine + 150 microg
clonidine. The maximum spread of anesthesia, duration of analgesia and motor
block, vital signs, and incidence of adverse effects were recorded for 14 hours
postinjection. Fifty milligrams intramuscular meperidine was given as a rescue
analgesic whenever patient's pain score was greater than 5/10 by the visual
analog scale. RESULTS: The demographic data were similar for all four groups.
Bupivacaine + both group had a significantly higher maximum spread of anesthesia
of 23.3 +/- 2.9 segments than bupivacaine group of 20.5 +/- 2.9 segment.
Bupivacaine + both group showed a later onset of postsurgical pain of 6.5 +/- 1.5
hours as compared to bupivacaine group of 1.3 +/- 0.6 hours. The pain score in
bupivacaine + both group was significantly lower than that of bupivacaine group
during the first 10 hours. The 24-hour meperidine consumption also was lower in
bupivacaine + both group than that of bupivacaine group. However, motor block was
significantly prolonged from 3.5 +/- 1.1 hours in bupivacaine group to 7.1 +/-
1.6 hours in bupivacaine + both group. In addition, other side effects such as
nausea and vomiting and dizziness were significantly increased in bupivacaine +
both group. CONCLUSION: Our study showed that the combination of 150 microg i.t.
clonidine and 50 microg neostigmine provided longer postsurgical analgesia than
with either drug used alone. However, this combination also produced
significantly more adverse effects of prolonged motor block and nausea and
vomiting. A further study combining the two study drugs but using a lower dose of
i.t. neostigmine (e.g., 25 microg) is recommended.
PMID- 9552779
TI - Incisional morphine has no analgesic effect on postoperative pain following
inguinal herniotomy.
AB - BACKGROUND AND OBJECTIVES: Opioids induce antinociceptive effects after
peripheral administration in experimental and clinical studies. The results of
the clinical studies are conflicting. The objective of this study was to examine
a possible analgesic effect of incisionally administered morphine on
postoperative pain in patients undergoing inguinal herniotomy during general
anesthesia. METHODS: Forty-six consecutive outpatients were included in a double
blind, randomized, placebo-controlled study. At conclusion of herniotomy 5 mg
morphine was injected incisionally in 11 patients, intravenously in 10, and
subcutaneously in 13. The placebo group of 12 had saline injected in the
incision. Postoperative pain at rest and during mobilization was assessed with a
visual analog scale. Assessments were made immediately before and after
herniotomy, at 2, 4, and 6 hours after surgery, and on the second and seventh
postoperative day. Postoperative morphine and acetaminophen consumptions were
recorded within the same period. RESULTS: There were no significant differences
in visual analog scores between the groups at any time during the study. Overall
differences in postoperative acetaminophen and morphine consumptions were
insignificant. CONCLUSIONS: The analgesic effect of a single 5 mg dose of
morphine injected in a herniotomy wound is not superior to saline or to morphine
given subcutaneously or intravenously.
PMID- 9552780
TI - Comparison of remifentanil and propofol infusions for sedation during regional
anesthesia.
AB - BACKGROUND AND OBJECTIVES: Patients treated with regional anesthesia often
require concomitant medication for comfort and sedation. Propofol is widely used
for this purpose. Remifentanil, a new ultra-short-acting opioid, exhibits at low
doses distinct sedative properties that may be useful for supplementation of
regional anesthesia. This study compared the effectiveness of remifentanil and
propofol infusions for providing sedation during regional block placement and
surgery. METHODS: In an open, prospective trial, 28 patients were randomly
allocated to receive continuous infusions of remifentanil (6 microg/kg/h) or
propofol (3 mg/kg/h) for sedation during spinal or axillary regional anesthesia.
Infusion rates were titrated to maintain a sedation level > or = 2 as assessed
with the Observer's Assessment of Alertness Scale. Vital signs were measured
continuously, during and for 2 hours after ending study drug infusion. RESULTS:
Similar scores for comfort and sedation were obtained in both groups during
placement of the regional block and during surgery. Degree of sedation correlated
with drug infusion rate of remifentanil (P < .002) but not for propofol.
Respiratory rate decreased in the remifentanil group in absence of surgery (P <
.05). Mean arterial pressure and heart rate were 20% lower in the propofol group
(P < .05). Return to alertness occurred after 10 +/- 6 minutes in the
remifentanil group and after 16 +/- 15 minutes in the propofol group. Similar
incidences of hypotension, bradycardia, and nausea and vomiting were found in
both groups, but intraoperative respiratory depression and nausea were more
prominent in the remifentanil group. CONCLUSIONS: When titrated to the same
sedation level, remifentanil provided a smoother hemodynamic profile than
propofol during regional anesthesia. The frequent occurrence of remifentanil
induced respiratory depression requires cautious administration of this agent.
The incidence of adverse reactions seen with both agents during and after their
administration makes the management of such sedative infusion techniques
difficult.
PMID- 9552781
TI - Bupivacaine-induced convulsion is suppressed by MK-801.
AB - BACKGROUND AND OBJECTIVES: Not only the facilitation of inhibitory synapses but
also the suppression of excitatory synapses may be effective in treating
convulsion induced by local anesthetics. The effects of MK-801, a N-methyl-D
aspartate (NMDA) receptor antagonist, on bupivacaine-induced convulsion and
hemodynamic changes were studied. METHODS: Cortex and hippocampal (A4; L5.5; H8)
electroencephalogram (EEG), heart rate, and mean arterial pressure were measured
in 21 cats anesthetized with urethane. Blood samples were obtained when cats
demonstrated arrhythmias, convulsed, and became hypotensive. In the control group
(n = 7), bupivacaine was continuously infused until a hypotensive state of 40
mm/Hg was reached. In the MK-801 pretreated group (n = 7), MK-801 (0.5 mg/kg) was
injected intravenously 15 minutes before the bupivacaine injection. In the MK-801
treatment group (n = 7), MK-801 (0.5 mg/kg) was injected intravenously at the
appearance of convulsive EEG after the bupivacaine injection. RESULTS:
Bupivacaine produced convulsion in the control group (17.1 +/- 2.4 microg/mL),
but not in the MK-801 pretreated group. In the treatment group, convulsive EEG
was suppressed gradually after injection of MK-801. The mean plasma bupivacaine
concentrations (microg/mL) reaching arrhythmia and hypotension were 9.5 +/- 2.9
and 23.0 +/- 3.0, respectively, in the control group; 10.9 +/- 3.5 and 22.5 +/-
4.9, respectively, in the MK-801 pretreated group; and 7.5 +/- 1.6 and 21.0 +/-
3.0, respectively, in the MK-801 treatment groups. The mean arterial pressure and
heart rate did not differ among the three groups. CONCLUSIONS: These results
demonstrated that one mechanism of bupivacaine-induced convulsion is the
excitatory neurotransmitter system in central nervous system and that MK-801 is
effective in suppressing the convulsion without any effects on hemodynamics.
PMID- 9552782
TI - Defining the cross-sectional anatomy important to interscalene brachial plexus
block with magnetic resonance imaging.
AB - BACKGROUND AND OBJECTIVES: Interscalene brachial plexus block is a useful
technique to provide anesthesia and analgesia for the shoulder and proximal upper
extremity. The initial needle direction at the interscalene groove has been
described as being "perpendicular to the skin in every plane" (1). A cross
sectional (axial) approach may offer a more easily conceptualized directed needle
placement. The purpose of this study is to define the cross-sectional anatomy and
idealized needle angles important to interscalene brachial plexus block. METHODS:
Following IRB approval, 50 patients were studied. Cross-sectional volume coil T1
weighted magnetic resonance images (MRI) were obtained from 50 patients
undergoing cervical region imaging for other reasons. At the interscalene groove,
a simulated needle path to contact the ventral rami or trunks of the brachial
plexus was approximated at the level of C6 or C6-C7 interspace. The angle of this
needle path intersecting the sagittal plane was recorded for each patient.
RESULTS: The mean angle of the simulated needle path relative to sagittal plane
was determined to be 61.1 +/- 6.1 degrees (range, 50-78 degrees). In 13 of 50
(26%) MRI scans, the cervical nerve roots were not visualized at the level of C6
and were measured at the C6-C7 level. CONCLUSIONS: These findings suggest initial
needle placement at the interscalene groove should be angled less perpendicularly
relative to the sagittal plane than is often observed. A cross-sectional approach
enables more practical visualization of initial needle placement. A more accurate
initial needle placement may minimize the number of needle passes necessary to
contact the nerve roots, thereby more efficiently obtaining a successful block.
PMID- 9552783
TI - Intrathecal addition of morphine to bupivacaine is not the cause of postoperative
nausea and vomiting.
AB - BACKGROUND AND OBJECTIVES: Postoperative nausea and vomiting after anesthesia is
an distressing side effect. This study was undertaken to determine to what extent
spinal opioids contribute to postoperative nausea and vomiting (PONV) and
secondly to how effectively metoclopramide can reduce the incidence of PONV after
intrathecal administration of morphine. METHODS: Patients were allocated to three
groups all undergoing major joint surgery of the lower limb. In group 1 (n =
200), intrathecal anesthesia was assessed by administration of 20 mg bupivacaine
and 0.2 mg morphine. In Group 2 (n = 100) intrathecal anesthesia was assessed in
the same way and in addition, 20 mg metoclopramide intramuscular during
maintenance of anesthesia and a second dose of 20 mg metoclopramide was
administered intramuscular after arrival at the recovery room. Finally, in group
3 (n = 100), intrathecal anesthesia was assessed after administration of 20 mg
bupivacaine. RESULTS: The maximum PONV percentages were 41.1%, 32.7%, and 37% in
groups 1, 2, and 3, respectively. The consumption of antiemetics was similar in
all groups. The number of patients who needed one or more additional antiemetics
during the first 24 hours after surgery was 112 (56.6%), 57 (58%), and 60 (60%)
in groups 1, 2, and 3, respectively. CONCLUSIONS: Administration of
metoclopramide did not reduce the overall incidence of PONV. Our study shows no
relationship between the use of intrathecal morphine and the incidence of PONV
during the first 24 hours postoperative.
PMID- 9552784
TI - The effects and side effects of interscalene brachial plexus block by posterior
approach.
AB - BACKGROUND AND OBJECTIVES: To investigate the use of interscalene block by
posterior approach in upper extremity surgery and its effects on routine
pulmonary function tests. METHODS: Interscalene block by posterior approach was
performed with a peripheral nerve stimulator localization in 29 ASA Physical
Status I and II patients undergoing upper extremity surgery. All patients were
given 20 mL of 1% lidocaine and 20 mL of 0.5% bupivacaine. Modified Bromage Scale
for motor block and pinprick test for sensory anesthesia was used. Pulmonary
function, measurements [forced vital capacity (FVC), forced expiratory volume in
1 second (FEV1), and VC (vital capacity)] were done in all patients just before
and 2, 5, 10, 15, and 30 minutes after the block. RESULTS: Surgery location was
the arm in four cases, and the forearm in 25 cases. General anesthesia was added
in nine patients. Intravenous analgesics or sedatives were needed in four cases.
Ulnar nerve was missed in 13 patients. FEV1 decreased 11.5% in 2 minutes (P >
.05), 19.7% in 5 minutes (P = .0525), and FVC decreased 16.6% in 2 minutes (P >
.05), 24.5% in 5 minutes after block (P < .05). CONCLUSIONS: Interscalene block
by posterior approach did not provide a satisfactory anesthesia for forearm and
hand surgery. This method also caused hemidiaphragmetic paresis and a reduction
in pulmonary function tests as in the lateral approach of Winnie. We believe
limitations and relative contraindications for interscalene block by lateral
approach are the same for posterior approach.
PMID- 9552785
TI - Sensory block extension during combined spinal and epidural.
AB - BACKGROUND AND OBJECTIVES: During a combined spinal and epidural technique,
extension of sensory block by epidural injection of saline or bupivacaine has
been demonstrated and attributed to a volume effect or to the combination of a
volume effect with a local anesthetic effect. This two-part study was designed to
evaluate the time dependency of the volume effect and the local anesthetic effect
on the mechanism of spinal block extension. METHODS: We performed two prospective
studies. Thirty patients were randomized in each study. A combined spinal and
epidural was performed in a sitting position in all groups. The patients in the
first study received 15 mg hyperbaric bupivacaine intrathecally and were placed
supine 2 minutes after spinal injection. They received 10 mL epidural saline
either 5 minutes after spinal (group A) or 20 minutes after spinal (group B)
compared to a control group (group C). The patients in the second study received
12.5 mg hyperbaric bupivacaine intrathecally and were placed supine 5 minutes
after spinal injection. They then received epidurally either 10 mL saline 7
minutes after spinal (group D) or 10 mL bupivacaine 7 minutes after spinal (group
E) or nothing (group F). Sensory block levels were assessed by a loss of
sensation to cold using ether. RESULTS: In the first portion of this study, in
group A, area under the curve of sensory block levels by time from 10 to 40
minutes after spinal injection, and maximum sensory block levels were
significantly higher (P < .05) compared to groups B and C. In the second portion
of the study, sensory block levels were comparable at all times in the three
groups. CONCLUSIONS: During a combined spinal and epidural technique with the use
of hyperbaric bupivacaine, the volume effect is time dependent and is seen when
epidural top up is done soon after spinal injection. This volume effect is
abolished when patients are left seated for 5 minutes after spinal injection. The
local anesthetic effect is not demonstrated when high sensory block levels are
achieved by spinal injection.
PMID- 9552786
TI - The use of 5% lidocaine for prolonged analgesia in chronic pain patients: a new
technique.
AB - BACKGROUND AND OBJECTIVES: It has been found that 5% lidocaine with 7.5% dextrose
causes irreversible conduction block in animal studies. Our case report subjects
allowed us to observe the efficacy of 5% lidocaine for a prolonged analgesia in
vivo. METHOD: After performing a diagnostic nerve block with 1% lidocaine, 5%
lidocaine with 7.5% dextrose was injected into three patients with trigeminal
neuralgia, post-herpetic occipital neuralgia, and intercostal neuralgia,
respectively. The patients were followed for one and a half years. Visual Analog
Scale (VAS) scores and the side effects were recorded for each patient. RESULTS:
One patient received a trigeminal block and one patient received an occipital
nerve block. Both patients reported immediate and complete pain relief lasting 14
and 8 months, respectively. One patient, given an intercostal nerve block,
received immediate pain relief lasting 5 weeks. None of these patients exhibited
any appreciable side effects or complications. CONCLUSIONS: Our observations
suggest that 5% lidocaine may be used safely and effectively for the purpose of
prolonged analgesia in selected patients with intractable chronic pain syndromes.
PMID- 9552787
TI - An unusual cause of acute chest pain during epidural anesthesia.
AB - BACKGROUND AND OBJECTIVES: Selective sympathetic denervation during epidural
anesthesia results in a small, active gut. These changes can also result in
selective activity in one segment of the gut that is absent in other segments.
CASE REPORT: A 61-year-old male was scheduled for bilateral total knee
replacement during epidural anesthesia. Following onset of the epidural block, he
experienced severe left-sided chest pain. Surgery was canceled. A portable chest
radiograph revealed a widened mediastinum, and he underwent angiography to rule
out a dissecting thoracic aortic aneurysm. The left subclavian artery could not
be visualized, and an MRI was obtained, which was normal. After his return to the
intensive care unit, he had a large bowel movement and his chest pain resolved.
CONCLUSION: Selective activity of the gastrointestinal tract during the onset of
epidural anesthesia created a visceral pain, which effectively simulated pain
with a cardiovascular origin.
PMID- 9552788
TI - Paraplegia following intracord injection during attempted epidural anesthesia
under general anesthesia.
AB - BACKGROUND AND OBJECTIVES: A case of permanent paraplegia is reported following
attempted epidural anesthesia for a total knee replacement in a 62-year-old woman
with a history of lumbar laminectomy for a prolapsed intervertebral disc.
METHODS: Epidural puncture was attempted during general anesthesia and
neuromuscular block. RESULTS: After four unsuccessful attempts, an epidural
catheter was inserted above the upper end of the laminectomy scar. Several
episodes of arterial hypotension occurred intraoperative and postoperative.
Operative blood loss was minimal, and no bone glue was used. The patient awoke
paraparetic with a sensory level of anesthesia to T5 bilaterally. MRI revealed an
air bubble in the cord at T10 and a region of increased T2-weighted signal in the
anterior aspect of the spinal cord between T4 and T5, consistent with infarction.
CONCLUSION: Standards of management are discussed in relation to this case.
PMID- 9552789
TI - The posterior epidural space depth.
PMID- 9552790
TI - Regarding axillary and supraclavicular techniques of nerve block being described
as approaches to brachial plexus.
PMID- 9552791
TI - Case report on gabapentin.
PMID- 9552792
TI - Combined spinal epidural (CSE) analgesia, fetal bradycardia, and uterine
hypertonus.
PMID- 9552793
TI - Regarding Dr. Steven's editorial.
PMID- 9552794
TI - New treatments for schizophrenia--Part I.
PMID- 9552795
TI - The many uses of interpersonal therapy.
PMID- 9552796
TI - The seriousness of child's play.
PMID- 9552797
TI - Breath of panic.
PMID- 9552798
TI - Aggressive children and their self-esteem.
PMID- 9552799
TI - Attention deficit and bad behavior.
PMID- 9552800
TI - What becomes of aggressive school-children?
PMID- 9552801
TI - A new take on prostate drugs.
PMID- 9552802
TI - High-tech aid for your hearing.
PMID- 9552803
TI - Outwitting three leading travel-health problems.
PMID- 9552804
TI - Treating an underdiagnosed cause of headaches.
PMID- 9552805
TI - Restoring sexuality after cancer.
PMID- 9552807
TI - It is true that drinking soda increases my risk of osteoporosis?
PMID- 9552806
TI - Is the new anti-obesity drug Meridia safer than fen-phen?
PMID- 9552808
TI - Direct veneers: the clinical technique.
PMID- 9552809
TI - Chewing gum and the dental health balance.
PMID- 9552810
TI - Disinfection of impressions.
PMID- 9552811
TI - Biological aspects of root canal filling materials-
histocompatibility,cytotoxicity, and mutagenicity.
AB - In order to minimize the incidence of local and/or systemic side effects, the
biocompatibility of all endodontic materials should be investigated by various in
vitro and in vivo tests prior to clinical application. The battery of in vitro
tests includes determinations of mutagenicity, cytotoxicity, and antibacterial
effects. Several reports have shown that paraformaldehyde-containing ZnO-eugenol
cements in particular, such as Endomethasone and N2, are antibacterial. On the
other hand, it has been found that endodontic materials with strong antimicrobial
activity are frequently mutagenic, i.e., primarily those which release
formaldehyde. Cell culture tests clearly show significantly different
cytocompatibility of the various types of endodontic sealers: in general,
formaldehyde-containing ZnO-eugenol cements are classified as highly/extremely
cytotoxic, whereas most Ca(OH)2-based sealers are rated as possessing good or
excellent cytocompatibility. These results were confirmed by numerous
histological studies in vivo. Sealers with inferior biocompatibility, such as
formaldehyde-releasing materials, should no longer be applied in practice because
safer alternatives are available.
PMID- 9552812
TI - The 5-year clinical performance of direct composite additions to correct tooth
form and position. I. Esthetic qualities.
AB - The aim of the study was to evaluate the esthetic performance of direct composite
additions in correcting tooth form and position at 5 years. Composite additions
were directly placed using the acid-etch technique and enamel bonding on 87
intact maxillary anterior teeth in 23 young patients (12-19 years old). The
restorations were made by one operator using an ultrafine midway-filled densified
restorative composite. Color slides were made at baseline and 5 years. At the 5
year recall, esthetic performance was assessed clinically by two evaluators at
chair-side in subterms of color match, translucency/opacity, surface roughness,
and anatomical form. Five additional examiners scored esthetics on the 5-year
slides. Of the restorations, 89% were still esthetically satisfactory after 5
years of clinical service. The remaining restorations needed replacement, mainly
because of severe loss of anatomical form, to a lesser degree because of severe
color mismatch. Central incisors and small unilateral restorations generally
showed the best results concerning color match (68% and 74%, respectively) and
surface smoothness (84% and 100%, respectively). The slide scores on color match
and translucency/opacity were generally similar or somewhat better than the
direct clinical scores; however, the difference were not statistically
significant (P > 0.05). As far as surface roughness is concerned, the results
were significantly better (P < 0.05) when recorded indirectly than by direct
clinical evaluation. In conclusion, direct composite additions are a valuable and
effective procedure for esthetic and conservative treatment of malformed and
misaligned anterior teeth. Loss of anatomical form due to wear points to a
shortcoming of the composite material used, with which a durable esthetic result
cannot always be guaranteed in the long term.
PMID- 9552813
TI - The 5-year clinical performance of direct composite additions to correct tooth
form and position. II. Marginal qualities.
AB - The aim of the study was to evaluate the marginal performance of direct composite
additions for the correction of tooth form and position at 5 years. Composite
additions were directly placed using the acid-etch technique and enamel bonding
on 87 intact maxillary anterior teeth in 23 young patients (12-19 years old). The
restorations were made by one operator using an ultrafine midway-filled densified
restorative composite. Color slides were made at baseline and 5 years. At the 5
year recall, marginal performance was assessed by two evaluators in terms of
marginal adaptation and retention, clinical microleakage, and caries recurrence.
Marginal adaptation and clinical microleakage were judged on the vestibular,
palatal, and proximal planes. In addition, these planes were divided into a
cervical and an incisal part. No caries recurrence was noted at 5 years and no
restoration was lost. Concerning marginal adaptation, only four restorations (5%)
presented a severe incisal chipping and needed replacement. The restorations
showed a significantly (P < 0.05) higher percentage of perfect margins incisally
(37%) than cervically (15%). Canines showed the best cervical marginal adaptation
(29% with perfect margins), the best results being with small unilateral
restorations. Concerning clinical microleakage, 7% of the restorations were rated
as clinically unacceptable due to severe marginal discoloration. Clinical
microleakage was significantly more often (P < 0.05) found among smokers. In
conclusion, an ultrafine midway-filled densified composite is indicated for use
in stress-bearing areas in the anterior region. The type and location of the
restoration are determining factors for marginal integrity.
PMID- 9552814
TI - Clinical evaluation of heat-pressed glass-ceramic inlays in vivo: 2-year results.
AB - In the present study, the 2-year clinical and scanning electron microscope (SEM)
results for heat-pressed ceramic inlays are reported. In a selected patient
population, 51 cavities were restored with all-ceramic inlays. All margins were
located within the enamel. The inlays were luted to the cavities with a high
viscosity, dual-cure luting composite. After 2 days, 1 year, and 2 years, the
restorations were evaluated clinically, using the modified USPHS criteria.
Quantitative margin analysis was performed in the SEM on the replicas fabricated
at the recall times. The data were tested for significant differences, using the
chi-square test for the clinical evaluation and the Mann-Whitney U-test for the
margin analysis. After 2 years, the clinical evaluation of the margin adaptation
revealed Bravo ratings for 14 restorations (27.5%); 37 restorations (72.5%) were
rated Alfa. Compared to the baseline data, this difference was statistically
significant (p < or = 0.5). SEM analysis revealed that the ceramic-composite
interface exhibited significantly (p < or = 0.01) more gap formation than the
enamel-composite interface at all times of evaluation. Wear of the luting
composite could be determined along 50% of the restoration interface during the
first year, 53% during the second year. The inlay restorations controlled in this
study perform well after a period of 2 years.
PMID- 9552815
TI - Nifedipine pharmacological variables as risk factors for gingival overgrowth in
organ-transplant patients.
AB - The prevalence and severity of gingival overgrowth in organ-transplant patients
medicated with cyclosporin are greater in patients concomitantly medicated with
nifedipine; however, no relationship between the gingival overgrowth and any of
the nifedipine pharmacological variables has been demonstrated. The study
examined the effect of five nifedipine pharmacological variables (nifedipine
dosage, plasma concentration and gingival crevicular fluid concentration, M1
metabolite plasma concentration and the nifedipine: M1 ratio). The effect of the
nifedipine variables on the gingival overgrowth score were examined using
univariate and multivariate regression analysis. Adjustment for the effect of
other risk factors was made by adding the distribution of each of the nifedipine
variables in turn to a stepwise regression model containing previously identified
risk factors for this condition. Despite the high levels of nifedipine
sequestered in the GCF, only the plasma concentration of nifedipine was
identified as a risk factor for the severity of gingival overgrowth in these
patients (P = 0.01) once adjusted for other known risk factors (R2 for the model
= 55%).
PMID- 9552816
TI - Longevity of glass ceramic inlays and amalgam--results up to 6 years.
AB - Ceramic inlays are discussed as one option for the substitution of amalgam
restorations. The purpose of this study was to determine the longevity of glass
ceramic inlays and amalgam restorations placed by the author: 123 class I and
class II Dicor inlays placed with adhesive techniques and 163 amalgam class I and
class II restorations were investigated. The observation time for the inlays
varied from 4 to 82 months. The inlays were clinically investigated using
modified USPHS criteria and documented photographically. Kaplan-Meier statistics
were used to calculate the survival rate. From the 123 evaluated inlays 12 inlays
(9.7%) failed: 7 due to fractures, 4 because of endodontic problems and 1 inlay
was replaced due to persisting postoperative pain. All fractures could be
explained by case selection errors. According to the Kaplan-Meier method, the
estimated success rate after 6 years was 76% for the Dicor inlays and 87% for the
amalgam restorations (control group). The difference was not statistically
significant. It was concluded that Dicor inlays may be used as a successful
alternative to amalgam.
PMID- 9552817
TI - Miconazole lacquer in the treatment of denture stomatitis: clinical and
microbiological findings in Chinese patients.
AB - OBJECTIVE: To investigate the efficacy of a miconazole lacquer in producing
mycological and clinical cure of Candida-associated denture stomatitis in a
Chinese cohort and to study the microbiology of the conditions. DESIGN: A cross
sectional study of the clinical and microbiological features of the condition and
its response to treatment with the lacquer. SUBJECTS AND METHOD: Twenty-one
Chinese adults with palatal erythema; 15 denture wearers matched for age and sex
as controls for microbiology. Clinical examination, impression for culture,
photograph of palate to monitor response to treatment, and lacquer application on
upper denture base on days 0, 7 and 14. Impression and photograph repeated on day
21; impression cultures quantified by image analysis. Palatal impression in
controls; dummy impression as control for impression culture procedures. MAIN
OUTCOME MEASURES: Severity of lesion, incidence and type of microorganism at
presentation and during treatment; qualitative and quantitative assessment of
yeast growth; the latter by statistical analysis of pixel units of yeast
colonies; correlation of clinical and mycological cure. RESULTS: Out of the 21
lesions (16 Newton's stage I and 5 stage II), 57% had yeasts at presentation, 10%
coliforms and 33% no significant growth. Clinical cure in 3 weeks in 71%,
mycological cure in 75% in 7 days; clinical and mycological cure coincided only
in 43%. Polymicrobial growth of yeasts and coliforms throughout the course in
some. CONCLUSIONS: Miconazole lacquer was a viable treatment option for Candida
associated denture stomatitis in this adult, Chinese cohort; microbiology
comprised yeasts, mainly C. albicans and coliforms, especially Klebsiella and
Enterobacter species; the pathogenic role of the latter is questionable.
PMID- 9552818
TI - Working parameters of a sonic scaler influencing root substance removal in vitro.
AB - This study assessed defect depth and volume resulting from root instrumentation
using a KaVo Sonic-flex Lux 2000 L sonic scaler with a slim scaling tip (Perio
Tip no. 8) in vitro. Combinations of the following working parameters were
analyzed: lateral forces of 0.5 N, 1 N, and 2 N; tip angulations of 0 degree, 45
degrees, and 90 degrees; and instrumentation time of 10 s, 20 s, 40 s, and 80 s.
Defects were quantified using a three-dimensional optical laser scanner.
Instrumentation time had an almost linear impact on defect depth and volume.
Although lateral force (beta-weight 0.55 +/- 0.062) had a greater influence on
defect volume than tip angulation (beta-weight 0.29 +/- 0.062), their effects on
defect depth were similar (beta-weight 0.43 +/- 0.052 and 0.50 +/- 0.052,
respectively). The combination of force and angulation showed synergistic effects
resulting in a wide range of defect depths (21.9 +/- 0.96 microns to 174 +/- 28.8
microns, at 40 s) and volumes (0.056 +/- 0.019 mm3 to 0.68 +/- 0.10 mm3 at 40 s).
Severe root damage (> 50 microns/40 s) did not occur at any combination of 0.5 N
lateral force and/or 0 degree tip angulation. By adjusting lateral force and tip
angulation, the efficacy of the assessed sonic scaler may be adapted to various
clinical needs.
PMID- 9552819
TI - Short-term assessment of leakage of Class V composite restorations placed in
vivo.
AB - The purpose of this study was to investigate the effectiveness of two dentin
bonding systems, one of which was also in combination with a self-curing resin,
when applied in V-shaped circular cavities cut in anterior teeth crossing the
cementum-enamel junction. Twenty-seven teeth scheduled for extraction for
periodontal reasons were treated in vivo. The sample teeth were divided at random
into three groups. Group 1 was treated with All Bond 2 (AB2) + Z-100 composite,
group 2 with Scotchbond Multipurpose Plus (SMPP) + Z-100, and group 3 with AB2 in
conjunction with Bisfil 2B as liner and Z-100. The in vivo restored teeth were
extracted after 2-3 months of clinical service. They were then immersed in a dye
solution for 24 h, sectioned, and scored for marginal leakage. Analysis of
variance revealed no significant differences between the three groups both at
cervical and incisal sites. The enamel sites were free from any leakage. Only two
cervical sites of groups 1 and 2 and one of group 3 showed a score 1 for leakage.
The results of the short-term clinical performance of the three systems were
promising.
PMID- 9552820
TI - One-year clinical evaluation of composite fillings and inlays in posterior teeth.
AB - In the course of a prospectively designed long-term clinical trial, composite
fillings and inlays were evaluated for clinical acceptability as restorative
materials in one, two or more surface cavities of posterior teeth over a 1-year
period. In 45 patients, 88 restorations were placed by nine student operators,
under the supervision of an experienced dentist, to compare the two half sides
using the composite resins Tetric (Vivadent), blend-a-lux (Blend-a-med), and
Pertac-Hybrid Unifil (Espe). The first clinical follow-up check took place within
a time period of 11-13 months after placement of the restorations using modified
USPHS criteria. The interpretation of the clinical criteria showed satisfactory
results over this time period: more than 85% of the inlays and direct fillings
were rated "alpha" or "bravo", using the parameters of assessment defined in this
study. Only three restorations (two fillings, one inlay), all in molars, were
rated "delta", i.e., unacceptable. The reasons for their replacement were
marginal opening, secondary caries, and loss of sensitivity. For the criteria
"surface texture", "anatomical form of the surface", and "occlusion", composite
inlays were significantly better than composite fillings. These results indicate
that posterior composite restorations provide acceptable and excellent clinical
service, even if they are placed by relatively inexperienced student operators.
PMID- 9552821
TI - Effectiveness of diamond-impregnated felt wheels for polishing a hybrid
composite.
AB - The effectiveness of diamond-impregnated felt wheels for polishing the surfaces
of a fine-particle hybrid composite was studied in relation to different
finishing methods. Standardised composite specimens were finished with one or a
series of two or three finishing diamonds (particle size 30, 15 and 8 microns),
one or two tungsten carbide finishing burs (12- and 30-fluted) or with a
finishing diamond followed by a tungsten carbide bur. The final polishing of all
specimens was done with the diamond-impregnated felt wheel Diafix alpha.
Treatment with Sof-Lex discs after the use of a finishing diamond served as a
polishing standard for comparison. Evaluation of the final surfaces was done with
profilometry and by scanning electron microscopy. The profilometric results
showed that the type of pretreatment was decisive for the quality of the final
polishing. Nearly all surfaces polished by the diamond-impregnated felt wheels
were smoother than those treated by the flexible discs (P < 0.01). The lowest
roughness data were recorded following a pretreatment with a finishing diamond
and a tungsten carbide finishing bur. After appropriate pretreatment, the hybrid
composite surface was sufficiently polished with the diamond-impregnated felt
wheels.
PMID- 9552822
TI - A microbiological study of pre- and postoperative apicoectomy sites.
AB - There is little information on the microbiology of periapical lesions, and no
data on the residual microbial flora in the periapex, if any, after apicoectomy
procedures. Hence, 64 patients treated by apicoectomy procedures were
prospectively studied to assess the bacterial flora in the periapex and to
evaluate the residual bacteria in postoperative apicoectomy sites. Of the 64
lesions studied, 14 (22%) were sterile and 50 (78%) yielded bacteria
preoperatively. Bacteria could be recovered from 28 (56%) of the latter lesions
after apicoectomy and curettage. A total of 105 bacterial strains was isolated
from 50 lesions, yielding a range of 1-4 (mean 2.1) species per sample. The
isolates comprised 84 (80%) facultative anaerobes and 21 (20%) strict anaerobes.
A polymicrobial growth was obtained from 39 lesions whilst 11 lesions yielded
pure cultures. On detailed microbiological analyses of 29 lesions, 40% of the
isolates were identified as alpha-haemolytic streptococci, half of which were
Streptococcus sanguis; anaerobic streptococci were the predominant anaerobes.
None of the organisms or group(s) of organisms emerged as recalcitrant colonisers
which were difficult to dislodge after surgical debridement. These data indicate
that the majority of periapical lesions harbour a variety of flora which cannot
be eradicated despite thorough apicoectomy procedures.
PMID- 9552823
TI - A randomised clinical trial on the influence of splinted and unsplinted oral
implants in mandibular overdenture therapy. A 3-year report.
AB - A randomised clinical trial was performed to investigate whether there is a need
or advantage to splint two implants in the mandible retaining a hinging
overdenture. Furthermore, patient satisfaction was evaluated for different
attachment systems retaining the overdenture. Thirty-six edentulous patients were
randomised into three groups of equal size and treated with either magnets, ball
attachments or straight bars (reference group). After 3 years of observation no
implants were lost in any of the groups. Besides, no statistically significant
differences were noted for the peri-implant outcome. Although the bar group
presented the highest retention force, the general satisfaction of the patients
in the three groups did not differ. The patients with bar retentions showed less
prosthetic complications of the retention elements but more at the level of the
denture-supporting mucosa. Finally, the clinical outcome of all groups confirms
that overdenture treatment demands regular controls with limited time intervals.
PMID- 9552824
TI - The stereognostic ability of natural dentitions versus implant-supported fixed
prostheses or overdentures.
AB - A stereognostic ability test was performed in 60 patients. Forty patients were
rehabilitated by means of osseointegrated implants. One group consisted of 20
patients with fixed prostheses on implants in both the upper and lower jaws. The
other 20 patients had a maxillary denture while in the mandible an overdenture
was retained by means of two implants connected by a bar. They were compared to a
group of 20 subjects (controls) with a non-restored natural dentition. For the
stereognostic ability test, subjects had to recognise ten different test pieces
by manipulating them with two antagonistic incisor teeth, avoiding any contact
with other oral structures. Both response time and percentage accuracy of
recognition were evaluated. The present findings indicated that subjects with an
overdenture on implants did not score significantly different from those with an
implant-supported fixed prosthesis. In contrast, subjects with teeth had a
significantly better stereognostic ability. The percentage of correct responses
was 52% for overdentures, 56% for fixed prostheses on implants and 75% for
natural dentitions. From these results, it could be concluded that the
stereognostic ability is impaired in subjects rehabilitated with osseointegrated
implants by about one-third to one-quarter compared to subjects with natural
teeth.
PMID- 9552825
TI - In vivo study on the effectiveness of a lacquer containing CaF2/NaF in treating
dentine hypersensitivity.
AB - The purpose of this double-blind study was to evaluate the effectiveness of a
commercially available fluoride lacquer (Bifluorid 12) containing CaF2 (6%) and
NaF (6%) in reducing dentine hypersensitivity. A fluoride lacquer containing only
NaF (6%) served as a control. Twenty-five adult patients complaining about at
least two hypersensitive teeth participated in this study. In each patient and at
each appointment, one tooth was treated with Bifluorid 12, while the other was
treated with the control substance. Sensitivity levels were determined before and
after the application of each lacquer at baseline as well as at 1, 2 and 3 weeks
after the start of study. The final evaluation of hypersensitivity was performed
at 4 weeks, and follow-ups were undertaken at 6 and 12 months. A reproducible air
blast stimulus and a visual analogue scale were used for evaluation. Results
demonstrated a distinct reduction of hypersensitivity after 1, 2 and 3 weeks in
the Bifluorid 12 group. Initially, no obvious effects could be observed in the
control group. However, a clear alleviation could be observed after 2 and 3 weeks
with the control. After 4 weeks, the overall sensitivity scores were comparably
low, without any significant differences between the two fluoride lacquers. In
both groups, the effects of treatment were seen over the 12-month observation
period. Bifluorid 12 was considered at least comparable to the control. It is
concluded from this study that Bifluorid 12 is effective in the initial reduction
of dentine hypersensitivity. The combination of CaF2/NaF can be recommended for
clinical use.
PMID- 9552827
TI - Effects of 15% oxygen on breathing patterns and oxygenation in infants.
PMID- 9552828
TI - Children in the mountains.
PMID- 9552829
TI - Why doesn't audit work?
PMID- 9552830
TI - Collapse reactions after whole cell pertussis vaccination.
PMID- 9552831
TI - Simian virus 40 and human malignancy.
PMID- 9552832
TI - Training in advanced trauma life support.
PMID- 9552833
TI - Tackling violence.
PMID- 9552834
TI - Cancer in parents: telling children.
PMID- 9552835
TI - Effect of exposure to 15% oxygen on breathing patterns and oxygen saturation in
infants: interventional study.
AB - OBJECTIVE: To assess the response of healthy infants to airway hypoxia (15%
oxygen in nitrogen). DESIGN: Interventional study. SETTINGS: Infants' homes and
paediatric ward. SUBJECTS: 34 healthy infants (20 boys) born at term; mean age at
study 3.1 months. 13 of the infants had siblings whose deaths had been ascribed
to the sudden infant death syndrome. INTERVENTION: Respiratory variables were
measured in room air (pre-challenge), while infants were exposed to 15% oxygen
(challenge), and after infants were returned to room air (post-challenge). MAIN
OUTCOME MEASURES: Baseline oxygen saturation as measured by pulse oximetry,
frequency of isolated and periodic apnoea, and frequency of desaturation (oxygen
saturation < or = 80% for > or = 4 s). Exposure to 15% oxygen was terminated if
oxygen saturation fell to < or = 80% for > or = 1 min. RESULTS: Mean duration of
exposure to 15% oxygen was 6.3 (SD 2.9) hours. Baseline oxygen saturation fell
from a median of 97.6% (range 94.0% to 100%) in room air to 92.8% (84.7% to 100%)
in 15% oxygen. There was no correlation between baseline oxygen saturation in
room air and the extent of the fall in baseline oxygen saturation on exposure to
15% oxygen. During exposure to 15% oxygen there was a reduction in the proportion
of time spent in regular breathing pattern and a 3.5-fold increase in the
proportion of time spent in periodic apnoea (P < 0.001). There was an increase in
the frequency of desaturation from 0 episodes per hour (range 0 to 0.2) to 0.4
episodes per hour (0 to 35) (P < 0.001). In 4 infants exposure to hypoxic
conditions was ended early because of prolonged and severe falls in oxygen
saturation. CONCLUSIONS: A proportion of infants had episodes of prolonged (< or
= 80% for > or = 1 min) or recurrent shorter (< or = 80% for > or = 4 s)
desaturation, or both, when exposed to airway hypoxia. The quality and quantity
of this response was unpredictable. These findings may explain why some infants
with airway hypoxia caused by respiratory infection develop more severe
hypoxaemia than others. Exposure to airway hypoxia similar to that experienced
during air travel or on holiday at high altitude may be harmful to some infants.
PMID- 9552837
TI - Mental health problems of homeless children and families: longitudinal study.
AB - OBJECTIVE: To establish the mental health needs of homeless children and families
before and after rehousing. DESIGN: Cross sectional, longitudinal study. SETTING:
City of Birmingham. SUBJECTS: 58 rehoused families with 103 children aged 2-16
years and 21 comparison families of low socioeconomic status in stable housing,
with 54 children. MAIN OUTCOME MEASURES: Children's mental health problems and
level of communication; mothers' mental health problems and social support one
year after rehousing. RESULTS: Mental health problems remained significantly
higher in rehoused mothers and their children than in the comparison group
(mothers 26% v 5%, P = 0.04; children 39% v 11%, P = 0.0003). Homeless mothers
continued to have significantly less social support at follow up. Mothers with a
history of abuse and poor social integration were more likely to have children
with persistent mental health problems. CONCLUSIONS: Homeless families have a
high level of complex needs that cannot be met by conventional health services
and arrangements. Local strategies for rapid rehousing into permanent
accommodation, effective social support and health care for parents and children,
and protection from violence and intimidation should be developed and
implemented.
PMID- 9552838
TI - Rate of recurrent collapse after vaccination with whole cell pertussis vaccine:
follow up study.
PMID- 9552839
TI - Phantom pain, anxiety, depression, and their relation in consecutive patients
with amputated limbs: case reports.
PMID- 9552841
TI - What's a network?
PMID- 9552840
TI - Influence of travel patterns on mortality from injury among teenagers in England
and Wales, 1985-95: trend analysis.
PMID- 9552842
TI - Quantitative systematic review of randomised controlled trials comparing
antibiotic with placebo for acute cough in adults.
AB - OBJECTIVES: To assess whether antibiotic treatment for acute cough is effective
and to measure the side effects of such treatment. DESIGN: Quantitative
systematic review of randomised placebo controlled trials. DATA SOURCES: Nine
trials (8 published, 1 unpublished) retrieved from a systematic search
(electronic databases, contact with authors, contact with drug manufacturers,
reference lists); no restriction on language. MAIN OUTCOME MEASURES: Proportion
of subjects with productive cough at follow up (7-11 days after consultation with
general practitioner); proportion of subjects who had not improved clinically at
follow up; proportion of subjects who reported side effects from taking
antibiotic or placebo. RESULTS: Eight trials contributed to the meta-analysis.
Resolution of cough was not affected by antibiotic treatment (relative risk 0.85
(95% confidence interval 0.73 to 1.00)), neither was clinical improvement at re
examination (relative risk 0.62 (0.36 to 1.09)). The side effects of antibiotic
were more common in the antibiotic group when compared to placebo (relative risk
1.51 (0.86 to 2.64)). CONCLUSIONS: Treatment with antibiotic does not affect the
resolution of cough or alter the course of illness. The benefits of antibiotic
treatment are marginal for most patients with acute cough and may be outweighed
by the side effects of treatment.
PMID- 9552843
TI - Recent advances. Cardiology.
PMID- 9552844
TI - Haemochromatosis as an endocrine cause of subfertility.
PMID- 9552845
TI - Caffeine and canine
PMID- 9552847
TI - Unequal encounter
PMID- 9552846
TI - ABC of allergies. Perennial rhinitis.
PMID- 9552848
TI - Sex, drugs, and the invasion of privacy
PMID- 9552850
TI - Supermarket cigarettes: the brands that dare not speak their name.
PMID- 9552849
TI - Urgency and priority for cardiac surgery: a clinical judgment analysis.
PMID- 9552851
TI - Coping with loss. Bereavement in childhood.
PMID- 9552852
TI - Fast track admission for children with sickle cell crises. Should morphine or
pethidine be given?
PMID- 9552854
TI - Management of aseptic meningitis secondary to intravenous immunoglobulin.
PMID- 9552853
TI - Management of sickle cell disease. Non-addictive analgesics can be as effective
as morphine and pethidine.
PMID- 9552855
TI - Coordinated neonatal screening programme for haemoglobin disorders is needed.
PMID- 9552857
TI - Doctors are not pressured into giving prescriptions.
PMID- 9552858
TI - Article showed how not to read economic evaluations.
PMID- 9552859
TI - Use of lasers can cause visual impairment
PMID- 9552861
TI - Resource allocation to health authorities. Expenditure on private health care
must be taken into account
PMID- 9552860
TI - Separate R&D budget is needed for monitoring effects of new drugs
PMID- 9552863
TI - BMA cannot bring proceedings arising out of incidents in other countries
PMID- 9552862
TI - New biomolecular assays must be tested by direct study in the developing world.
PMID- 9552865
TI - Health secretary wants to work with clinicians
PMID- 9552864
TI - Isidor ("Okkie") Gordon
PMID- 9552866
TI - Selling out
PMID- 9552867
TI - Just another Sunday
PMID- 9552868
TI - The hot air on passive smoking
PMID- 9552869
TI - Developing Professional Judgement in Health Care
PMID- 9552870
TI - Mass Listeria: The Meaning of Health Scares
PMID- 9552872
TI - Folic acid and vitamin B-12 and B-6 supplements reduce blood homocysteine
concentrations
PMID- 9552871
TI - Some infants develop hypoxaemia when breathing 15% oxygen
PMID- 9552874
TI - "Collapse" after pertussis vaccination does not recur after subsequent doses
PMID- 9552873
TI - Psychosocial problems continue in homeless families after rehousing
PMID- 9552875
TI - Phantom limb pain is not a sign of grief
PMID- 9552876
TI - Antibiotics are unlikely to alter clinical course of acute cough
PMID- 9552878
TI - Good engineering is not good medicine
PMID- 9552877
TI - Good engineering is not good medicine
PMID- 9552879
TI - Blood products produced from plasma from donors in UK are still being made
PMID- 9552880
TI - Patients offered treatment for CHD need full information to make decision
PMID- 9552881
TI - Publication of pictures of patient on BMJ's website was mistake
PMID- 9552883
TI - Task force will involve NHS staff
PMID- 9552882
TI - Flora Bridge
PMID- 9552884
TI - Mistakes
PMID- 9552885
TI - Most patients don't read the BMJ Editorial by Smith and Education and debate pp
1000-11
PMID- 9552886
TI - Nuchal translucency-screening without consent
PMID- 9552887
TI - What Are Doctors For?
PMID- 9552888
TI - Specialist Outreach Clinics in General Practice
PMID- 9552889
TI - The Pocket Guide to Grant Applications
PMID- 9552890
TI - The Mad Cow Crisis: Health and the Public Good
PMID- 9552891
TI - Colloids no better than crystalloids for fluid replacement in hypovolaemic
patients
PMID- 9552893
TI - Heparin (1 U/ml) flushes of peripheral venous catheters prolongs their potency
PMID- 9552892
TI - Inpatient and day care are equally good in acute rheumatoid arthritis
PMID- 9552894
TI - Use of magnesium in pre-eclampsia is growing
PMID- 9552895
TI - Understanding patients' cultural beliefs helps health providers serve them better
PMID- 9552896
TI - Epidemiological data are of little use in guiding clinical practice
PMID- 9552897
TI - Cardiac arrests outside hospital.
PMID- 9552898
TI - Shifts in opportunities for doctors in training.
PMID- 9552899
TI - Protecting the public from risk of harm.
PMID- 9552900
TI - Cannabis as medicine: time for the phoenix to rise?
PMID- 9552901
TI - Equity on both the scientific and the policy agendas.
PMID- 9552902
TI - Unscientific practice flourishes in science.
PMID- 9552903
TI - Smoking and risk of myocardial infarction in women and men: longitudinal
population study.
AB - OBJECTIVE: To compare risk of myocardial infarction associated with smoking in
men and women, taking into consideration differences in smoking behaviour and a
number of potential confounding variables. DESIGN: Prospective cohort study with
follow up of myocardial infarction. SETTING: Pooled data from three population
studies conducted in Copenhagen. SUBJECTS: 11,472 women and 13,191 men followed
for a mean of 12.3 years. MAIN OUTCOME MEASURES: First admission to hospital or
death caused by myocardial infarction. RESULTS: 1251 men and 512 women had a
myocardial infarction during follow up. Compared with non-smokers, female current
smokers had a relative risk of myocardial infarction of 2.24 (range 1.85-2.71)
and male smokers 1.43 (1.26-1.62); ratio 1.57 (1.25-1.97). Relative risk of
myocardial infarction increased with tobacco consumption in both men and women
and was higher in inhalers than in non-inhalers. The risks associated with
smoking, measured by both current and accumulated tobacco exposure, were
consistently higher in women than in men and did not depend on age. This sex
difference was not affected by adjustment for arterial blood pressure, total and
high density lipoprotein cholesterol concentrations, triglyceride concentrations,
diabetes, body mass index, height, alcohol intake, physical activity, and level
of education. CONCLUSION: Women may be more sensitive than men to some of the
harmful effects of smoking. Interactions between components of smoke and hormonal
factors that may be involved in development of ischaemic heart disease should be
examined further.
PMID- 9552904
TI - Ecological study of reasons for sharp decline in mortality from ischaemic heart
disease in Poland since 1991.
AB - OBJECTIVE: To investigate the reasons for the decline in deaths attributed to
ischaemic heart disease in Poland since 1991 after two decades of rising rates.
DESIGN: Recent changes in mortality were measured as percentage deviations in
1994 from rates predicted by extrapolation of sex and age specific death rates
for 1980-91 for diseases of the circulatory system and selected other categories.
Available data on national and household food availability, alcohol consumption,
cigarette smoking, socioeconomic indices, and medical services over time were
reviewed. MAIN OUTCOME MEASURES: Age specific and age standardised rates of death
attributed to ischaemic heart disease and related causes. RESULTS: The change in
trend in mortality attributed to diseases of the circulatory system was similar
in men and women and most marked (> 20%) in early middle age. For ages 45 to 64
the decrease was greatest for deaths attributed to ischaemic heart disease and
atherosclerosis (around 25%) and less for stroke (< 10%). For most of the
potentially explanatory variables considered, there were no corresponding changes
in trend. However, between 1986-90 and 1994 there was a marked switch from animal
fats (estimated availability down 23%) to vegetable fats (up 48%) and increased
imports of fruit. CONCLUSION: Reporting biases are unlikely to have exaggerated
the true fall in ischaemic heart disease; neither is it likely to be mainly due
to changes in smoking, drinking, stress, or medical care. Changes in type of
dietary fat and increased supplies of fresh fruit and vegetables seem to be the
best candidates.
PMID- 9552905
TI - Point of care testing: randomised controlled trial of clinical outcome.
AB - OBJECTIVES: To describe the proportion of patients attending an accident and
emergency department for whom blood analysis at the point of care brought about a
change in management; to measure the extent to which point of care testing
resulted in differences in clinical outcome for these patients when compared with
patients whose samples were tested by the hospital laboratory. DESIGN: Open,
single centre, randomised controlled trial. Blood samples were randomly allocated
to point of care testing or testing by the hospital's central laboratory.
SETTING: The accident and emergency department of the Bristol Royal Infirmary, a
large teaching hospital which cares for an inner city population. SUBJECTS:
Representative sample of patients who attended the department between April 1996
and April 1997 and who required blood tests. Data collection was structured in 8
hour blocks so that all hours of the day and all days of the week were equally
represented. MAIN OUTCOME MEASURES: The proportion of patients for whom point of
care testing brought about a change in treatment in which timing was considered
to be critical to clinical outcome. Mortality, the length of stay in hospital,
admission rate, the amount of time spent waiting for results of blood tests, the
amount of time taken to decide on management plans, and the amount of time
patients spent in the department were compared between patients whose samples
were tested at the point of care and those whose samples were sent to the
laboratory. RESULTS: Samples were obtained from 1728 patients. Changes in
management in which timing was considered to be critical occurred in 59 out of
859 (6.9%, 95% confidence interval 5.3% to 8.8%) patients in the point of care
arm of the trial. Decisions were made 74 minutes earlier (68 min to 80 min, P <
0.0001) when point of care testing was used for haematological tests as compared
to central laboratory testing, 86 minutes earlier (80 min to 92 min, P < 0.0001)
for biochemical tests, and 21 minutes earlier (-3 min to 44 min, P = 0.09) for
analyses of arterial blood gases. There were no differences between the groups in
the amount of time spent in the department, length of stay in hospital, admission
rates, or mortality. CONCLUSION: Point of care testing reduced the time taken to
make decisions on patient management that were dependent on the results of blood
tests. It also brought about faster changes in treatment for which timing was
considered to be critical in about 7% of patients. These changes did not affect
clinical outcome or the amount of time patients spent in the department.
PMID- 9552906
TI - Aspirin for prophylaxis against headache at high altitudes: randomised, double
blind, placebo controlled trial.
PMID- 9552907
TI - Prevalence of inflammatory bowel disease in British 26 year olds: national
longitudinal birth cohort.
PMID- 9552908
TI - Alternative definitions
PMID- 9552909
TI - Patients' action during their cardiac event: qualitative study exploring
differences and modifiable factors.
AB - OBJECTIVES: To explore the circumstances and factors that explain variations in
response to a cardiac event and to identify potentially modifiable factors.
DESIGN: Qualitative analysis of semistructured, face to face interviews with
patients admitted to two district hospitals for a cardiac event and with other
people present at the time of the event. Patients were divided into three groups
according to the length of delay between onset of symptoms and calling for
medical help. SUBJECTS: 43 patients and 21 other people present at the time of
the cardiac event. Patients were divided into three groups according to the
length of time between onset of symptoms and seeking medical help: non-delayers
(< 4 h; n = 21), delayers (4-12 h; n = 12), and extended delayers (> 12 h; n =
10). MAIN OUTCOME MEASURES: Decision making process, strategies for dealing with
symptoms, and perception of risk and of heart attacks before the event according
to delay in seeking help. RESULTS: The illness and help seeking behaviour of
informants had several components, including warning, interpretation, preliminary
action, re-evaluation, and final action stages. The length of each stage was
variable and depended on the extent to which informants mobilised and integrated
resources into a strategy to bring their symptoms under control. There were
obvious differences in informants' knowledge of the symptoms that they associated
with a heart attack before the event. Non-delayers described a wider range of
symptoms before their heart attack and twice as many (13) considered themselves
to be potentially at risk of a heart attack compared with the other two groups.
For most informants the heart attack differed considerably from their concept of
a heart attack. CONCLUSION: The most critical factor influencing the time between
onset of symptoms and calling for professional medical help is that patients and
others recognise their symptoms as cardiac in origin. This study suggests that
various points of intervention in the decision making process could assist
symptom recognition and therefore faster access to effective treatment.
PMID- 9552911
TI - The Nobel prizes
PMID- 9552910
TI - Fatality outside hospital from acute coronary events in three British health
districts, 1994-5. United Kingdom Heart Attack Study Collaborative Group.
AB - OBJECTIVES: To provide a contemporary account of the treatment and outcomes of
acute coronary attacks in England and Wales and to identify strategies that might
improve the outcome. DESIGN: Two year community and hospital based study in three
British health districts. SETTING: Health districts of Brighton (population
282,000), South Glamorgan (408,000), and York (264,000). SUBJECTS: 3523 men and
women under 75 years of age who died outside hospital from acute coronary causes,
who were admitted to hospital with acute myocardial infarction, or who developed
acute infarction or died unexpectedly from acute coronary causes while they were
already in hospital. INTERVENTIONS: Attempted resuscitation in people having a
cardiac arrest outside hospital. MAIN OUTCOME MEASURES: Total case fatality, case
fatality outside and inside hospital, and the effect of resuscitation on case
fatality outside hospital. RESULTS: 1589 patients died within 30 days of the
acute event. Case fatality was 45% (95% confidence interval 43% to 47%), rising
from 27% (160/595) (23% to 31%) at age < 55 years to 53% (1019/1916) (51% to 55%)
at 65-74 years. Overall, 74% (1172/1589) (72% to 76%) of fatal events happened
outside hospital, and there was a negative age gradient (P < 0.001) such that 91%
(145/160) (87% to 95%) of fatalities occurred outside hospital at age < 55
compared with 70% (710/1019) (67% to 73%) at 65-74 years. Without successful
resuscitation of 55 patients outside hospital, total case fatality at 30 days
would have risen from 45% to 46.7%. CONCLUSION: Opportunities for reducing
fatality from acute coronary attacks lie mainly outside hospital. These results
and others imply that survival from cardiac arrest outside hospital might be
trebled by improved ambulance and patient response. Proper application of
secondary preventive measures for patients with coronary disease could have an
even larger impact.
PMID- 9552913
TI - ABC of allergies. Avoiding exposure to indoor allergens.
PMID- 9552912
TI - Accident and emergency medicine.
PMID- 9552914
TI - The accurate use of language
PMID- 9552915
TI - Misleading, unscientific, and unjust: the United Kingdom's research assessment
exercise.
PMID- 9552916
TI - Cambodia--after the killing fields.
PMID- 9552918
TI - Reserve may be just another word for cowardice.
PMID- 9552917
TI - Surgery and loss of body parts.
PMID- 9552919
TI - Intravascular volume optimisation during repair of proximal femoral fracture.
Intravascular volume was depleted perioperatively in control group
PMID- 9552921
TI - Working in management. NHS managers have fundamental duty to put patients first.
PMID- 9552920
TI - Oral contraception was not associated with venous thromboembolic disease in
recent study.
PMID- 9552922
TI - New method of expressing survival in cancer is popular.
PMID- 9552923
TI - Drug and Therapeutics Bulletin defends its stance over donepezil
PMID- 9552924
TI - Rationing health care. Patients need to be prioritised
PMID- 9552925
TI - Breast feeding does not always work. Author should have felt angry rather than
guilty.
PMID- 9552926
TI - Human Fertility and Embryology Act 1990 discriminates against children. Children
must not be denied future choice of using their gametes.
PMID- 9552928
TI - James Seeds Naunton Briggs
PMID- 9552927
TI - Refugee doctors face enormous difficulty.
PMID- 9552929
TI - Doctors should have more input into merit award system
PMID- 9552930
TI - Pray silence
PMID- 9552931
TI - Painful decisions
PMID- 9552932
TI - Death on camera.
PMID- 9552934
TI - The Progress of Experiment: Science and Therapeutic Reform in the United States,
1900-1990
PMID- 9552933
TI - Principles and Practice of Critical Care
PMID- 9552935
TI - Women who smoke have a greater risk of myocardial infarction than men who smoke
PMID- 9552936
TI - Fall in coronary deaths in Poland may be linked to lower meat and butter intake
PMID- 9552937
TI - Point of care testing improves process but not outcome in patients in A and E
PMID- 9552938
TI - People need to recognise cardiac symptoms to reduce delay in receiving
thrombolysis
PMID- 9552939
TI - Death rates from heart attacks continue to be high outside hospital
PMID- 9552940
TI - Prevalence of inflammatory bowel disease is rising in Britain
PMID- 9552941
TI - Protecting breast feeding from breast milk substitutes.
PMID- 9552942
TI - Neurological channelopathies.
PMID- 9552943
TI - Antidepressant discontinuation reactions.
PMID- 9552944
TI - Doctors in training: wasteful and inefficient?
PMID- 9552945
TI - Rehabilitation for older people.
PMID- 9552946
TI - The BMJ's website scales up.
PMID- 9552947
TI - Violations of the international code of marketing of breast milk substitutes:
prevalence in four countries.
PMID- 9552948
TI - Open randomised study of use of levonorgestrel releasing intrauterine system as
alternative to hysterectomy.
AB - OBJECTIVES: To assess whether the levonorgestrel intrauterine system could
provide a conservative alternative to hysterectomy in the treatment of excessive
uterine bleeding. DESIGN: Open randomised multicentre study with two parallel
groups: a levonorgestrel intrauterine system group and a control group. SETTING:
Gynaecology departments of three hospitals in Finland. SUBJECTS: Fifty six women
aged 33-49 years scheduled to undergo hysterectomy for treatment of excessive
uterine bleeding. INTERVENTIONS: Women were randomised either to continue with
their current medical treatment or to have a levonorgestrel intrauterine system
inserted. MAIN OUTCOME MEASURE: Proportion of women cancelling their decision to
undergo hysterectomy. RESULTS: At 6 months, 64.3% (95% confidence interval 44.1
to 81.4%) of the women in the levonorgestrel intrauterine system group and 14.3%
(4.0 to 32.7%) in the control group had cancelled their decision to undergo
hysterectomy (P < 0.001). CONCLUSIONS: The use of the levonorgestrel intrauterine
system is a good conservative alternative to hysterectomy in the treatment of
menorrhagia and should be considered before hysterectomy or other invasive
treatments.
PMID- 9552949
TI - Baseline serum cholestanol as predictor of recurrent coronary events in subgroup
of Scandinavian simvastatin survival study. Finnish 4S Investigators.
PMID- 9552950
TI - Risk factors for coronary heart disease and infection with Helicobacter pylori:
meta-analysis of 18 studies.
PMID- 9552951
TI - Growth hormone as a risk for premature mortality in healthy subjects: data from
the Paris prospective study.
PMID- 9552953
TI - Randomised controlled trial of the READER method of critical appraisal in general
practice.
AB - OBJECTIVE: To evaluate the READER model for critical reading by comparing it with
a free appraisal, and to explore what factors influence different components of
the model. DESIGN: A randomised controlled trial in which two groups of general
practitioners assessed three papers from the general practice section of the BMJ.
SETTING: Northern Ireland. SUBJECTS: 243 general practitioners. MAIN OUTCOME
MEASURES: Scores given using the READER model (Relevance, Education,
Applicability, Discrimination, overall Evaluation) and scores given using a free
appraisal for scientific quality and an overall total. RESULTS: The hierarchical
order for the three papers was different for the two groups, according to the
total scores. Participants using the READER method (intervention group) gave a
significantly lower total score (P < or = 0.01) and a lower score for the
scientific quality (P < or = 0.0001) for all three papers. Overall more than one
in five (22%), and more men than women, read more than 5 articles a month (P < or
= 0.05). Those who were trainers tended to read more articles (P < or = 0.05),
and no trainers admitted to reading none. Overall, 58% (135/234) (68% (76/112) of
the intervention group) believed that taking part in the exercise would encourage
them to be more critical of published articles in the future (P < or = 0.01).
CONCLUSION: Participants using the READER model gave a consistently lower overall
score and applied a more appropriate appraisal to the methodology of the studies.
The method was both accurate and repeatable. No intrinsic factors influenced the
scores, so the model is appropriate for use by all general practitioners
regardless of their seniority, location, teaching or training experience, and the
number of articles they read regularly.
PMID- 9552954
TI - Randomised comparison of cost effectiveness of guided self management and
traditional treatment of asthma in Finland.
PMID- 9552957
TI - ABC of allergies. Allergy and the skin. I--Urticaria.
PMID- 9552956
TI - The role of nuclear medicine in clinical investigation.
PMID- 9552959
TI - Ethics and evidence based medicine.
PMID- 9552960
TI - Framework for analysing risk and safety in clinical medicine.
PMID- 9552961
TI - Reducing the risk of nosocomial HIV infection in British health workers working
overseas: role of post-exposure prophylaxis.
PMID- 9552962
TI - Blindness and loss of other sensory and cognitive functions.
PMID- 9552965
TI - Many climate change scientists do not agree that global warming is happening.
PMID- 9552970
TI - Culyer reforms will create new opportunities for research.
PMID- 9552968
TI - Medline and Embase complement each other in literature searches.
PMID- 9552973
TI - Basing resource allocation formulas on standardised mortality ratios would be
wrong.
PMID- 9552975
TI - More patients should be excluded from being tissue donors.
PMID- 9552976
TI - Acute excited states and sudden death. Death after restraint can be avoided.
PMID- 9552989
TI - Routine episiotomy in developing countries. Time to change a harmful practice.
PMID- 9552990
TI - Long term pharmacotherapy of depression. Can reduce relapses and recurrences in
major depression.
PMID- 9552991
TI - Tamoxifen for the prevention of breast cancer. Important questions remain
unanswered, and existing trials should continue.
PMID- 9552992
TI - Selegiline, or the problem of early termination of clinical trials. The clinical
questions are not well answered, and probably never will be.
PMID- 9552993
TI - Monitoring randomised controlled trials. Parkinson's disease trial illustrates
the dangers of stopping early.
PMID- 9552994
TI - Why do children have chronic abdominal pain, and what happens to them when they
grow up? Population based cohort study.
AB - OBJECTIVE: To test the hypotheses that children with abdominal pain have anxious
parents and come from families with high rates of physical illness and that they
grow up to suffer from high rates of medically unexplained symptoms and
psychiatric disorders. DESIGN: Population based birth cohort study. SETTING:
General population. SUBJECTS: Participants in the Medical Research Council (MRC)
national survey of health and development, a population based birth cohort study
established in 1946. MAIN OUTCOME MEASURES: Abdominal pain present throughout
childhood in the absence of defined organic disease, and measures of physical
symptoms and psychiatric disorder at age 36 years. RESULTS: There were high rates
of complaints about physical health among the parents of children with persistent
abdominal pain, and the mothers had higher neuroticism scores. Children with
persistent abdominal pain were more likely to suffer from psychiatric disorders
in adulthood (odds ratio 2.72 (95% confidence interval 1.65 to 4.49)) but were
not especially prone to physical symptoms once psychiatric disorder was
controlled for (odds ratio 1. 39 (0.83 to 2.36)). CONCLUSIONS: Persistent
abdominal pain is associated with poor health and emotional disorder in the
parents. Children with abdominal pain do not necessarily continue to experience
physical symptoms into adulthood but are at increased risk of adult psychiatric
disorders.
PMID- 9552996
TI - Asherisms
PMID- 9552995
TI - Effect of electrical cardioversion on myocardial cells in patients in intensive
care.
PMID- 9552997
TI - Who's out there?
PMID- 9552998
TI - Screening for hypercholesterolaemia in primary care: randomised controlled trial
of postal questionnaire appraising risk of coronary heart disease.
AB - OBJECTIVES: To validate a self administered postal questionnaire appraising risk
of coronary heart disease. To determine whether use of this questionnaire
increased the percentage of people at high risk of coronary heart disease and
decreased the percentage of people at low risk who had their cholesterol
concentration measured. DESIGN: Validation was by review of medical records and
clinical assessment. The questionnaire appraising risk of coronary heart disease
encouraged those meeting criteria for cholesterol measurement to have a
cholesterol test and was tested in a randomised controlled trial. The
intervention group was sent the risk appraisal questionnaire with a health
questionnaire that determined risk of coronary heart disease without identifying
the risk factors as related to coronary heart disease; the control group was sent
the health questionnaire alone. SETTING: One capitation funded primary care
practice in Canada with an enrolled patient population of about 12 000. SUBJECTS:
Random sample of 100 participants in the intervention and control groups were
included in the validation exercise. 5686 contactable patients aged 20 to 69
years who on the basis of practice records had not had a cholesterol test
performed during the preceding 5 years were included in the randomised controlled
trial. 2837 were in the intervention group and 2849 were in the control group.
MAIN OUTCOME MEASURES: Sensitivity and specificity of assessment of risk of
coronary heart disease with risk appraisal questionnaire. Rate of cholesterol
testing during three months of follow up. RESULTS: Sensitivity of questionnaire
appraising coronary risk was 87.5% (95% confidence interval 73.2% to 95.8%) and
specificity 91.7% (81.6% to 97.2%). Of the patients without pre-existing coronary
heart disease who met predefined screening criteria based on risk, 45 out of 421
in the intervention group (10.7%) and 9 out of 504 in the control group (1.8%)
had a cholesterol test performed during follow up (P<0.0001). Of the patients
without a history of coronary heart disease who did not meet criteria for
cholesterol testing, 30 out of 1128 in the intervention group (2.7%) and 18 out
of 1099 in the control group (1.6%) had a cholesterol test (P=0.175). Of the
patients with pre-existing coronary heart disease, 1 out of 15 in the
intervention group (6.7%) and 1 out of 23 in the control group (4.3%) were tested
during follow up (P=0.851, one tailed Fisher's exact test). CONCLUSIONS: Although
the questionnaire appraising coronary risk increased the percentage of people at
high risk who obtained cholesterol testing, the effect was small. Most patients
at risk who received the questionnaire did not respond by having a test.
PMID- 9553000
TI - The new NHS: medical students say no
PMID- 9552999
TI - Systematic review of dietary intervention trials to lower blood total cholesterol
in free-living subjects.
AB - OBJECTIVES: To estimate the efficacy of dietary advice to lower blood total
cholesterol concentration in free-living subjects and to investigate the efficacy
of different dietary recommendations. DESIGN: Systematic overview of 19
randomised controlled trials including 28 comparisons. SUBJECTS: Free-living
subjects. INTERVENTIONS: Individualised dietary advice to modify fat intake. MAIN
OUTCOME MEASURE: Percentage difference in blood total cholesterol concentration
between the intervention and control groups. RESULTS: The percentage reduction in
blood total cholesterol attributable to dietary advice after at least six months
of intervention was 5.3% (95% confidence interval 4.7% to 5.9%). Including both
short and long duration studies, the effect was 8.5% at 3 months and 5.5% at 12
months. Diets equivalent to the step 2 diet of the American Heart Association
were of similar efficacy to diets that aimed to lower total fat intake or to
raise the polyunsaturated to saturated fatty acid ratio. These diets were
moderately more effective than the step 1 diet of the American Heart Association
(6.1% v 3.0% reduction in blood total cholesterol concentration; P<0.0001). On
the basis of reported food intake, the targets for dietary change were seldom
achieved. The observed reductions in blood total cholesterol concentrations in
the individual trials were consistent with those predicted from dietary intake on
the basis of the Keys equation. CONCLUSIONS: Individualised dietary advice for
reducing cholesterol concentration is modestly effective in free-living subjects.
More intensive diets achieve a greater reduction in serum cholesterol
concentration. Failure to comply fully with dietary recommendations is the likely
explanation for this limited efficacy.
PMID- 9553002
TI - A victorian polymath
PMID- 9553003
TI - Allergy and the skin. II--Contact and atopic eczema.
PMID- 9553001
TI - Diabetes.
PMID- 9553005
TI - I saved my father's life
PMID- 9553004
TI - North of England evidence based guidelines development project: methods of
developing guidelines for efficient drug use in primary care.
PMID- 9553006
TI - What's wrong with Bonferroni adjustments.
PMID- 9553007
TI - The doctor's losses: ideals versus realities.
PMID- 9553008
TI - Old remedy effective
PMID- 9553009
TI - Economic benefit analysis of primary prevention with pravastatin. Modelling
economic benefits after such long term treatment is inappropriate.
PMID- 9553010
TI - Day case surgery has benefited patients with cataract in North Gwent.
PMID- 9553011
TI - Article about mental health law gave practical guidance.
PMID- 9553012
TI - Risk language and dialects. Expressing risk in relative rather than absolute
terms is important.
PMID- 9553013
TI - Fate of special hospitals in england has not yet been decided
PMID- 9553014
TI - Sexual abuse is not the only childhood adversity that may lead to later
depression.
PMID- 9553015
TI - Training in plastic surgery is being set up in The Gambia.
PMID- 9553016
TI - Management of Helicobacter pylori infection. Eradication treatment should be
limited to patients with proved peptic ulceration.
PMID- 9553017
TI - Patients with implants should be given implant cards. Intraocular lens implant
cards contain inadequate clinical data.
PMID- 9553018
TI - General practice must decide on its own education system.
PMID- 9553019
TI - Regulation of body weight is social skill.
PMID- 9553020
TI - Mouth care and skin care in palliative medicine. Chlorhexidine mouth washes are
important in mouth care.
PMID- 9553021
TI - Possible association between low birth weight and later heart disease needs to be
investigated further.
PMID- 9553022
TI - BMA must voice its opposition to Cuban embargo.
PMID- 9553023
TI - Punishment of doctors must fit their crime.
PMID- 9553025
TI - BMA's counselling service takes over 6000 calls
PMID- 9553024
TI - William louis murray bigby
PMID- 9553027
TI - Is rationing down under upside down?
PMID- 9553026
TI - Patients not paper?
PMID- 9553028
TI - Listen to the patient
PMID- 9553030
TI - Rationing: talk and action in health care
PMID- 9553029
TI - Genetics of common diseases
PMID- 9553031
TI - Early selegiline treatment in Parkinson's disease may not be advantageous
PMID- 9553032
TI - Abdominal pain in childhood is linked with psychiatric disorders in adulthood
PMID- 9553033
TI - Aminosidine is more effective than sodium stibogluconate in visceral
leishmaniasis
PMID- 9553034
TI - Suicide risk is increased in stroke
PMID- 9553035
TI - Postal risk appraisal questionnaire slightly increases cholesterol testing in
high risk patients
PMID- 9553036
TI - Individual dietary advice has modest effects on cholesterol
PMID- 9553037
TI - The telomerase reverse transcriptase: components and regulation.
PMID- 9553039
TI - A specific, nonproliferative role for E2F-5 in choroid plexus function revealed
by gene targeting.
AB - Homozygous E2F-5 knockout embryos and mice have been generated. Although
embryonic development appeared normal, newborn mice developed nonobstructive
hydrocephalus, suggesting excessive cerebrospinal fluid (CSF) production.
Although the CSF-producing choroid plexus displayed normal cellular organization,
it contained abundant electron-lucent epithelial cells, consistent with excessive
CSF secretory activity. Moreover, E2F-5 CNS expression in normal animals was
largely confined to the choroid plexus. Cell cycle kinetics were not perturbed in
homozygous knockout embryo fibroblasts. Thus, E2F-5 is not essential for cell
proliferation. Rather, it affects the secretory behavior of a differentiated
neural tissue.
PMID- 9553038
TI - Delta and Serrate are redundant Notch ligands required for asymmetric cell
divisions within the Drosophila sensory organ lineage.
AB - Asymmetric divisions allow a precursor to produce four distinct cells of a
Drosophila sensory organ lineage (SOL). Whereas this process requires cell-cell
communication via Notch (N) receptor, mitotic recombination that removes the N
ligand Delta (Dl) or Serrate (Ser) in the SOL had mild or no effect. Removal of
both Dl and Ser, however, led to cell fate transformations similar to the N
phenotype. Cell fate transformation occurred even when a single SOL cell lost
both Dl and Ser. Thus, Dl and Ser are redundant in mediating signaling between
daughter cells to specify their distinct cell fates.
PMID- 9553040
TI - Cytokine rescue of p53-dependent apoptosis and cell cycle arrest is mediated by
distinct Jak kinase signaling pathways.
AB - Exposure of hematopoietic progenitors to gamma-irradiation (IR) induces p53
dependent apoptosis and a p53-independent G2/M cell cycle arrest. These responses
to DNA-damage can be inhibited by treatment with cytokine growth factors. Here we
report that gamma-IR-induced apoptosis and cell cycle arrest are suppressed by
specific cytokines (e.g., erythropoietin and interleukin-3) and that activation
of the Jak kinase is necessary and sufficient for these effects. Using myleoid
cells expressing a series of erythropoietin receptor (EpoR) mutants, we have
demonstrated that Jak kinase-dependent signals initiated from the membrane
proximal domain of EpoR were sufficient to prevent IR-induced apoptotic cell
death, but failed to prevent cell cycle arrest. Cell survival by Epo did not
require activation of other known signaling pathways including PI-3 kinase, PLC
gamma, Ras or Stats. Signaling targets of Jak kinase pathways included members of
the Bcl-2 family of anti-apoptotic proteins, and enforced expression of Bcl-2 or
Bcl-xL was as effective as cytokine treatment in blocking IR-induced apoptosis
but did not prevent growth arrest. A distinct signal derived from a membrane
distal domain of EpoR is required to overcome growth arrest associated with DNA
damage. These findings functionally link the Jak signaling pathway to suppression
of p53-mediated cell death by cytokines and demonstrate that the apoptotic and
growth arrest responses to DNA damage in hematopoietic cells are modulated by
distinct, cytokine specific signal transduction pathways.
PMID- 9553041
TI - Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires
association with the inducible chaperone Hsp70.
AB - The Wilms tumor suppressor WT1 encodes a zinc finger transcription factor that is
expressed in glomerular podocytes during a narrow window in kidney development.
By immunoprecipitation and protein microsequencing analysis, we have identified a
major cellular protein associated with endogenous WT1 to be the inducible
chaperone Hsp70. WT1 and Hsp70 are physically associated in embryonic rat kidney
cells, in primary Wilms tumor specimens and in cultured cells with inducible
expression of WT1. Colocalization of WT1 and Hsp70 is evident within podocytes of
the developing kidney, and Hsp70 is recruited to the characteristic subnuclear
clusters that contain WT1. The amino-terminal transactivation domain of WT1 is
required for binding to Hsp70, and expression of that domain itself is sufficient
to induce expression of Hsp70 through the heat shock element (HSE). Substitution
of a heterologous Hsp70-binding domain derived from human DNAJ is sufficient to
restore the functional properties of a WT1 protein with an amino-terminal
deletion, an effect that is abrogated by a point mutation in DNAJ that reduces
binding to Hsp70. These observations indicate that Hsp70 is an important cofactor
for the function of WT1, and suggest a potential role for this chaperone during
kidney differentiation.
PMID- 9553042
TI - Mice heterozygous for a mutation at the Nf2 tumor suppressor locus develop a
range of highly metastatic tumors.
AB - A role for the membrane/cytoskeleton interface in the development and progression
of cancer is established, yet poorly understood. The neurofibromatosis type II
(NF2) tumor suppressor gene encodes a member of the ezrin/radixin/moesin (ERM)
family of membrane/cytoskeleton linker proteins thought to be important for cell
adhesion and motility. We report that in contrast to the narrow spectrum of
benign tumors in human NF2 patients, Nf2 heterozygous mice develop a variety of
malignant tumors. Using the fact that Nf2 is linked to the p53 tumor suppressor
locus in the mouse we have also investigated the effects of genetic linkage of
cancer-predisposing mutations on tumorigenesis and examined the genetic pathway
to tumor formation involving Nf2 loss. Importantly, we observed a very high rate
of metastasis associated with Nf2 deficiency, with or without loss of p53
function, and we provide experimental evidence supporting a role for Nf2 loss in
metastatic potential. Together, our results suggest an important role for the NF2
tumor suppressor, and perhaps the ERM family in tumor formation and metastasis.
PMID- 9553043
TI - RecQ helicase, in concert with RecA and SSB proteins, initiates and disrupts DNA
recombination.
AB - RecQ helicase is important to homologous recombination and DNA repair in
Escherichia coli. We demonstrate that RecQ helicase, in conjunction with RecA and
SSB proteins, can initiate recombination events in vitro. In addition, RecQ
protein is capable of unwinding a wide variety of DNA substrates, including joint
molecules formed by RecA protein. These data are consistent with RecQ helicase
assuming two roles in the cell; it can be (1) an initiator of homologous
recombination, or (2) a disrupter of joint molecules formed by aberrant
recombination. These findings also shed light on the function of the eukaryotic
homologs of RecQ helicase, the Sgs1, Blm, and Wrn helicases.
PMID- 9553044
TI - The control of maize spikelet meristem fate by the APETALA2-like gene
indeterminate spikelet1.
AB - The orderly production of meristems with specific fates is crucial for the proper
elaboration of plant architecture. The maize inflorescence meristem branches
several times to produce lateral meristems with determinate fates. The first
meristem formed, the spikelet pair meristem, produces two spikelet meristems,
each of which produces two floral meristems. We have identified a gene called
indeterminate spikelet1 (ids1) that specifies a determinate spikelet meristem
fate and thereby limits the number of floral meristems produced. In the absence
of ids1 gene function, the spikelet meristem becomes indeterminate and produces
additional florets. Members of the grass family vary in the number of florets
within their spikelets, suggesting that ids1 may play a role in inflorescence
architecture in other grass species. ids1 is a member of the APETALA2 (AP2) gene
family of transcription factors that has been implicated in a wide range of plant
development roles. Expression of ids1 was detected in many types of lateral organ
primordia as well as spikelet meristems. Our analysis of the ids1 mutant
phenotype and expression pattern indicates that ids1 specifies determinate fates
by suppressing indeterminate growth within the spikelet meristem.
PMID- 9553045
TI - DWnt-2, a Drosophila Wnt gene required for the development of the male
reproductive tract, specifies a sexually dimorphic cell fate.
AB - The sexually dimorphic characteristics of the reproductive tract in Drosophila
require that cells of the gonad and the genital disc be assigned sex-specific
fates. We report here that DWnt-2, a secreted glycoprotein related to wingless,
is a signal required for cell fate determination and morphogenesis in the
developing male reproductive tract. Testes from DWnt-2 null mutant flies lack the
male-specific pigment cells of the reproductive tract sheath and the muscle
precursors of the sheath fail to migrate normally. However, other cell types of
the testis are unaffected. DWnt-2 is expressed in somatic cells of the gonad
throughout development, implicating it as a signal that can influence pigment
cell fate directly. Indeed, the ectopic expression of DWnt-2 in females results
in the appearance of male-specific pigment cells in otherwise morphologically
normal ovaries. Thus, the presence of pigment cells is a sexually dimorphic trait
that is controlled by DWnt-2 expression. DWnt-2 is also expressed in regions of
the male genital disc and gonad, which we have identified as sites of contact
with muscle precursor cells, suggesting that secreted DWnt-2 protein is a signal
for the migration or attachment of these cells.
PMID- 9553046
TI - Down-regulation of transcription factor CF2 by Drosophila Ras/MAP kinase
signaling in oogenesis: cytoplasmic retention and degradation.
AB - Dorsoventral (D/V) patterning in Drosophila oogenesis is initiated by the
transmission of a TGF-alpha-like ligand, Gurken (Grk), from the oocyte to the
anterodorsal follicle cells, activating the EGF receptor (Egfr) signaling
pathway. The zinc-finger transcription factor CF2 is a negative regulator of the
rhomboid (rho) gene that encodes an essential membrane-bound component of the
dorsalizing pathway. Expression of CF2 itself is negatively regulated by the
activated Egfr. In this report, we demonstrate that CF2 is the target of down
regulation by the MAPK kinase cascade, and that this down-regulation is
independent of the Rho function. These results suggest that D/V patterning
involves a two-step signaling process: the initial Egfr signal, which represses
CF2 and induces rho expression; and the subsequent Egfr + Rho signal, which
determines the dorsal cell fates. Furthermore, we show that CF2 down-regulation
occurs at the post-translational level through a mechanism involving coupled
cytoplasmic retention and degradation.
PMID- 9553047
TI - Failure of megakaryopoiesis and arrested erythropoiesis in mice lacking the GATA
1 transcriptional cofactor FOG.
AB - GATA transcription factors are required for the differentiation of diverse cell
types in several species. Recent evidence suggests that their biologic activities
may be modulated through interaction with multitype zinc finger proteins, such as
Friend of GATA-1 (FOG) and U-shaped (Ush). In cell culture, FOG cooperates with
the hematopoietic transcription factor GATA-1 to promote erythroid and
megakaryocytic differentiation. We show here that mice lacking FOG die during mid
embryonic development with severe anemia. FOG-/- erythroid cells display a
marked, but partial, blockage of maturation, reminiscent of GATA-1- erythroid
precursors. In contrast to GATA-1 deficiency, however, megakaryocytes fail to
develop in the absence of FOG. Although the FOG-/- erythroid phenotype supports
the proposed role of FOG as a GATA-1 cofactor in vivo, the latter finding points
to a pivotal, GATA-1-independent requirement for FOG in megakaryocyte development
from the bipotential erythroid/megakaryocytic progenitor. We speculate that FOG
and other FOG-like proteins serve as complex cofactors that act through both GATA
dependent and GATA-independent mechanisms.
PMID- 9553048
TI - Defective peroxisomal catabolism of branched fatty acyl coenzyme A in mice
lacking the sterol carrier protein-2/sterol carrier protein-x gene function.
AB - Gene targeting in mice was used to investigate the unknown function of Scp2,
encoding sterol carrier protein-2 (SCP2; a peroxisomal lipid carrier) and sterol
carrier protein-x (SCPx; a fusion protein between SCP2 and a peroxisomal
thiolase). Complete deficiency of SCP2 and SCPx was associated with marked
alterations in gene expression, peroxisome proliferation, hypolipidemia, impaired
body weight control, and neuropathy. Along with these abnormalities, catabolism
of methyl-branched fatty acyl CoAs was impaired. The defect became evident from
up to 10-fold accumulation of the tetramethyl-branched fatty acid phytanic acid
in Scp2(-/-) mice. Further characterization supported that the gene disruption
led to inefficient import of phytanoyl-CoA into peroxisomes and to defective
thiolytic cleavage of 3-ketopristanoyl-CoA. These results corresponded to high
affinity binding of phytanoyl-CoA to the recombinant rat SCP2 protein, as well as
high 3-ketopristanoyl-CoA thiolase activity of the recombinant rat SCPx protein.
PMID- 9553049
TI - Knockout and knockin of the beta1 exon D define distinct roles for integrin
splice variants in heart function and embryonic development.
AB - The beta1D integrin is a recently characterized isoform of the beta1 subunit that
is specifically expressed in heart and skeletal muscle. In this study we have
assessed the function of the beta1D integrin splice variant in mice by
generating, for the first time, Cre-mediated exon-specific knockout and knockin
strains for this splice variant. We show that removal of the exon for beta1D
leads to a mildly disturbed heart phenotype, whereas replacement of beta1A by
beta1D results in embryonic lethality with a plethora of developmental defects,
in part caused by the abnormal migration of neuroepithelial cells. Our data
demonstrate that the splice variants A and D are not functionally equivalent. We
propose that beta1D is less efficient than beta1A in mediating the signaling that
regulates cell motility and responses of the cells to mechanical stress.
PMID- 9553052
TI - Complex, two-way traffic of molecules across the membrane of the endoplasmic
reticulum.
PMID- 9553050
TI - pX, the HBV-encoded coactivator, suppresses the phenotypes of TBP and TAFII250
mutants.
AB - Hepatitis B virus (HBV) infects humans and causes a wide range of clinical
manifestations, from acute hepatitis to hepatocellular carcinoma (HCC). The HBV
genome contains multiple promoters with gene expression regulated predominantly
by the cellular transcription initiation machinery. Accordingly, the HBV-encoded
pX, the only known viral regulator, is a potent transcription coactivator. We
investigated the relationship between pX and cellular coactivators. We show that
pX restores wild-type activity to inactive TBPAS mutants with poor TAFII250 and
activator-binding activity. This pX-mediated recovery, however, is not obtained
with inactive TBPAS mutants in binding of other general transcription factors.
Remarkably, ts13, a cell line temperature sensitive for TAFII250 function,
exhibiting growth arrest and apoptosis at the restrictive temperature, is rescued
partially by pX expression, thus generating a pX-dependent cell growth.
Collectively, our results suggest that pX suppresses some of the phenotypes of
TBP and TAFII250 mutations, implying that pX circumvents the need for a holo
TFIID complex for transcription activation to proceed.
PMID- 9553053
TI - Catalytic domain of the p120 Ras GAP binds to RAb5 and stimulates its GTPase
activity.
AB - Ras is a master GTPase switch controlling multiple signal transduction cascades
in the regulation of cell proliferation and differentiation. Rab5 is a local
GTPase switch that is localized on early endosomes and controls early endosome
fusion. This study demonstrates that the catalytic domain of p120 GTPase
activating protein (GAP), a well known Ras GAP, is able to interact physically
with Rab5 and stimulate its GTPase activity. This GAP activity toward Rab5,
however, cannot be extended to other Rab GTPases such as Rab3, Rab4, and Rab6,
indicating that it is not a generic GAP for the Rab family of GTPases that
regulate intracellular membrane fusion during endocytosis and exocytosis. The
findings indicate a level of structural similarity between Ras and Rab5
unexpected from their primary sequences. They also suggest a possible signal
transduction regulation of the Rab5-dependent endosome fusion via the Ras GAP.
PMID- 9553051
TI - Autocrine growth and anchorage independence: two complementing Jun-controlled
genetic programs of cellular transformation.
AB - Cellular transformation can be achieved by constitutive activation of growth
regulatory signaling pathways, which, in turn, activate nuclear transcription
factors thought to execute a transformation-specific program of gene expression.
Members of the dimeric transcription factor family AP-1 are at the receiving end
of such growth-regulating pathways and the viral form of the AP-1 subunit Jun
establishes one important aspect of transformation in chick embryo fibroblasts
(CEFs): enhanced growth in agar and in low serum. Enhanced Jun activity is likely
to target several different genetic programs as Jun forms heterodimers with one
of several members of the Fos and ATF2 subfamilies, resulting in transcription
factors with different sequence specificities. To identify the programs relevant
for transformation, we have reduced the complexity of AP-1 factors by
constructing Jun bZip mutants that can efficiently dimerize and transactivate
with only a restricted set of partner subunits. Upon introduction into CEFs, a
Jun mutant selective for the Fos family induced anchorage-independent growth but
no growth factor-independence. In contrast, a c-Jun mutant with preference for
ATF2-like proteins caused growth factor-independence, but no growth in agar.
Coexpression of both mutants reestablished the combined transformation program as
induced by wild-type Jun. These data show that Jun-dependent cell transformation
can be resolved into at least two distinct and independent processes, anchorage
and growth factor independence, obviously triggered by two classes of Jun
heterodimers likely regulating different sets of target genes.
PMID- 9553054
TI - ATP binding induces large conformational changes in the apical and equatorial
domains of the eukaryotic chaperonin containing TCP-1 complex.
AB - The chaperonin-containing TCP-1 complex (CCT) is a heteromeric particle composed
of eight different subunits arranged in two back-to-back 8-fold pseudo-symmetric
rings. The structural and functional implications of nucleotide binding to the
CCT complex was addressed by electron microscopy and image processing. Whereas
ADP binding to CCT does not reveal major conformational differences when compared
with nucleotide-free CCT, ATP binding induces large conformational changes in the
apical and equatorial domains, shifting the latter domains up to 40 degrees (with
respect to the inter-ring plane) compared with 10 degrees for nucleotide-free CCT
or ADP-CCT. This equatorial ATP-induced shift has no counterpart in GroEL, its
prokaryotic homologue, which suggests differences in the folding mechanism for
CCT.
PMID- 9553055
TI - Identification of a potent, selective non-peptide CXCR2 antagonist that inhibits
interleukin-8-induced neutrophil migration.
AB - Interleukin-8 (IL-8) and closely related Glu-Leu-Arg (ELR) containing CXC
chemokines, including growth-related oncogene (GRO)alpha, GRObeta, GROgamma, and
epithelial cell-derived neutrophil-activating peptide-78 (ENA-78), are potent
neutrophil chemotactic and activating peptides, which are proposed to be major
mediators of inflammation. IL-8 activates neutrophils by binding to two distinct
seven-transmembrane (7-TMR) G-protein coupled receptors CXCR1 (IL-8RA) and CXCR2
(IL-8RB), while GROalpha, GRObeta, GROgamma, and ENA-78 bind to and activate only
CXCR2. A chemical lead, which selectively inhibited CXCR2 was discovered by high
throughput screening and chemically optimized. SB 225002 (N-(2-hydroxy-4
nitrophenyl)-N'-(2-bromophenyl)urea) is the first reported potent and selective
non-peptide inhibitor of a chemokine receptor. It is an antagonist of 125I-IL-8
binding to CXCR2 with an IC50 = 22 nM. SB 225002 showed >150-fold selectivity
over CXCR1 and four other 7-TMRs tested. In vitro, SB 225002 potently inhibited
human and rabbit neutrophil chemotaxis induced by both IL-8 and GROalpha. In
vivo, SB 225002 selectively blocked IL-8-induced neutrophil margination in
rabbits. The present findings suggest that CXCR2 is responsible for neutrophil
chemotaxis and margination induced by IL-8. This selective antagonist will be a
useful tool compound to define the role of CXCR2 in inflammatory diseases where
neutrophils play a major role.
PMID- 9553056
TI - Requirement for Rho-mediated myosin light chain phosphorylation in thrombin
stimulated cell rounding and its dissociation from mitogenesis.
AB - Thrombin treatment causes a dose-dependent rounding of 1321N1 astrocytoma cells.
This cytoskeletal response is rapid, peaking 2 h after thrombin stimulation, and
reverses by 50% after 24 h. The thrombin receptor peptide SFLLRNP also induces
cell rounding, whereas other G protein-linked receptor agonists such as
carbachol, lysophosphatidic acid, or bradykinin fail to do so. Results of studies
using pharmacological inhibitors do not support a requirement for
phosphatidylinositol 3-kinase, mitogen-activated protein kinase, or Ca2+
mobilization in this response. Inhibition of protein kinase C or tyrosine kinase
produces minimal blockade. Pertussis toxin treatment is also without effect.
However, thrombin-induced rounding is fully blocked by the C3 toxin from
Clostridium botulinum, which specifically ADP-ribosylates and inactivates the
small G protein Rho. Thrombin also leads to a rapid, 2.4-fold increase in 32P
incorporation into myosin light chain while carbachol does not. Myosin
phosphorylation, like cell rounding is inhibited by inactivation of Rho with C3
exoenzyme, suggesting that myosin phosphorylation is necessary for this
cytoskeletal response. This is supported by the observation that thrombin-induced
rounding is also blocked by the myosin light chain kinase inhibitor KT5926.
However, treatment with KT5926 fails to inhibit mitogenesis. Thus, cell rounding
is not prerequisite to thrombin-induced DNA synthesis. We conclude that
stimulation of the heterotrimeric G protein-coupled thrombin receptor in 1321N1
cells activates Rho-dependent pathways for both DNA synthesis and cell rounding,
the cytoskeletal response being mediated in part through increases in myosin
phosphorylation.
PMID- 9553057
TI - Generation of constitutively active recombinant caspases-3 and -6 by
rearrangement of their subunits.
AB - Caspases play a major role in the transduction of the apoptotic signal and
execution of apoptosis in mammalian cells. Ectopic overexpression of the short
prodomain caspases-3 and -6 precursors in mammalian cells does not induce
apoptosis. This is due to their inability to undergo autocatalytic
processing/activation and suggests that they depend on the long prodomain
caspases for activation. To investigate directly the apoptotic activity of these
two caspases in vivo, we engineered constitutively active recombinant caspases-3
and -6 precursors. This was achieved by making contiguous precursor caspases-3
and -6 molecules, which have their small subunits preceding their large subunits.
Unlike their wild type counterparts, these recombinant molecules were capable of
autocatalytic processing in an in vitro translation reaction, suggesting that
they are catalytically active. They were also capable of autoprocessing and
inducing apoptosis in vivo independent of the upstream caspases. Furthermore,
their autocatalytic and apoptotic activities were inhibited by the pancaspase
inhibitor z-VAD-fluoromethylketone, but not by CrmA or Bcl-2, thus directly
demonstrating that the targets of inhibition of apoptosis by CrmA and Bcl-2 are
upstream of caspases-3 and -6. Since caspases-3 and -6 are the most downstream
executioners of apoptosis, the constitutively active versions of these caspases
could be used at very low concentrations in gene therapy model systems to induce
apoptosis in target tissues or tumors.
PMID- 9553058
TI - The GABP-responsive element of the interleukin-2 enhancer is regulated by
JNK/SAPK-activating pathways in T lymphocytes.
AB - T cell activation leads via multiple intracellular signaling pathways to rapid
induction of interleukin-2 (IL-2) expression, which can be mimicked by
costimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA) and ionomycin. We
have identified a distal IL-2 enhancer regulated by the Raf-MEK-ERK signaling
pathway, which can be induced by TPA/ionomycin treatment. It contains a dyad
symmetry element (DSE) controlled by the Ets-like transcription factor GA-binding
protein (GABP), a target of activated ERK. TPA/ionomycin treatment of T cells
stimulates both mitogen-activated ERK, as well as the stress-activated mitogen
activated protein kinase family members JNK/SAPK and p38. In this study, we
investigated the contribution of the stress-activated pathways to the induction
of the distal IL-2 enhancer. We show that JNK- but not p38-activating pathways
regulate the DSE activity. Furthermore, the JNK/SAPK signaling pathway cooperates
with the Raf-MEK-ERK cascade in TPA/ionomycin-induced DSE activity. In T cells,
overexpression of SPRK/MLK3, an activator of JNK/SAPK, strongly induces DSE
dependent transcription and dominant negative kinases of SEK and SAPK impair
TPA/ionomycin-induced DSE activity. Blocking both ERK and JNK/SAPK pathways
abolishes the DSE induction. The inducibility of the DSE is strongly dependent on
the Ets-core motifs, which are bound by GABP. Both subunits of GABP are
phosphorylated upon JNK activation in vivo and three different isoforms of
JNK/SAPK, but not p38, in vitro. Our data suggest that GABP is targeted by
signaling events from both ERK and JNK/SAPK pathways. GABP therefore is a
candidate for signal integration and regulation of IL-2 transcription in T
lymphocytes.
PMID- 9553059
TI - Sugar response sequence in the promoter of a rice alpha-amylase gene serves as a
transcriptional enhancer.
AB - Expression of alpha-amylase genes in both rice suspension cells and germinating
embryos is repressed by sugars and the mechanism involves transcriptional
regulation. The promoter of a rice alpha-amylase gene alphaAmy3 was analyzed by
both loss- and gain-of-function studies and the major sugar response sequence
(SRS) was located between 186 and 82 base pairs upstream of the transcription
start site. The SRS conferred sugar responsiveness to a minimal promoter in an
orientation-independent manner. It also converted a sugar-insensitive rice actin
gene promoter into a sugar-sensitive promoter in a dose-dependent manner. Linker
scan mutation studies identified three essential motifs: the GC box, the G box,
and the TATCCA element, within the SRS. Sequences containing either the GC box
plus G box or the TATCCA element each mediated sugar response, however, they
acted synergistically to give a high level glucose starvation-induced expression.
Nuclear proteins from rice suspension cells binding to the TATCCA element in a
sequence-specific and sugar-dependent manner were identified. The TATCCA element
is also an important component of the gibberellin response complex of the alpha
amylase genes in germinating cereal grains, suggesting that the regulation of
alpha-amylase gene expression by sugar and hormone signals may share common
regulatory machinery.
PMID- 9553060
TI - Drug-stimulated nucleotide trapping in the human multidrug transporter MDR1.
Cooperation of the nucleotide binding domains.
AB - The human multidrug transporter (MDR1 or P-glycoprotein) is an ATP-dependent
cellular drug extrusion pump, and its function involves a drug-stimulated,
vanadate-inhibited ATPase activity. In the presence of vanadate and MgATP, a
nucleotide (ADP) is trapped in MDR1, which alters the drug binding properties of
the protein. Here, we demonstrate that the rate of vanadate-dependent nucleotide
trapping by MDR1 is significantly stimulated by the transported drug substrates
in a concentration-dependent manner closely resembling the drug stimulation of
MDR1-ATPase. Non-MDR1 substrates do not modulate, whereas N-ethylmaleimide, a
covalent inhibitor of the ATPase activity, eliminates vanadate-dependent
nucleotide trapping. A deletion in MDR1 (Delta amino acids 78-97), which alters
the substrate stimulation of its ATPase activity, similarly alters the drug
dependence of nucleotide trapping. MDR1 variants with mutations of key lysine
residues to methionines in the N-terminal or C-terminal nucleotide binding
domains (K433M, K1076M, and K433M/K1076M), which bind but do not hydrolyze ATP,
do not show nucleotide trapping either with or without the transported drug
substrates. These data indicate that vanadate-dependent nucleotide trapping
reflects a drug-stimulated partial reaction of ATP hydrolysis by MDR1, which
involves the cooperation of the two nucleotide binding domains. The analysis of
this drug-dependent partial reaction may significantly help to characterize the
substrate recognition and the ATP-dependent transport mechanism of the MDR1 pump
protein.
PMID- 9553061
TI - Localization of the active site of HIV-1 reverse transcriptase-associated RNase H
domain on a DNA template using site-specific generated hydroxyl radicals.
AB - Reverse transcriptase (RT)-associated ribonuclease H (RNase H) can cleave both
the RNA template of DNA/RNA hybrids as well as double-stranded (ds) RNA. This
report shows that human immunodeficiency virus (HIV)-RT can also cleave the
template strand of dsDNA when Mg2+ is replaced by Fe2+ in the RNase H active site
of HIV-RT. The cleavage mechanisms as well as the positions of the cut vary
depending on whether RNA or DNA is used. While DNA is cleaved 17 base positions
upstream of the primer 3'-end, RNA is cleaved 18 base positions upstream.
Competition experiments show that Fe2+ replaces the catalytically active Mg2+ of
RT-associated RNase H. The bound Fe2+ is the source of locally generated OH
radicals that cleave the most proximate base in the DNA. Electrophoretic mobility
studies of the cleaved fragments suggest that DNA is cleaved by an oxidative
mechanism, while RNA is cleaved by an enzymatic mechanism which is
indistinguishable from the Mg2+-dependent cleavage. The Fe2+-dependent cuts can
be used to trace the active site of RT-associated RNase H on dsDNA as well as on
dsRNA and DNA/RNA hybrids. The observed 1 base difference in the cleavage
positions on DNA and RNA templates can be attributed to conformational
differences of the bound nucleic acids. We suggest that the lower pitch of dsRNA
and DNA/RNA hybrids compared with dsDNA permits accommodation of an additional
base pair in the region between the primer 3'-end and the Fe2+-dependent cleavage
position at the RNase H active site.
PMID- 9553062
TI - Prothymosin alpha stimulates Ca2+-dependent phosphorylation of elongation factor
2 in cellular extracts.
AB - Prothymosin alpha (PTA) stimulates in a dose-dependent manner the phosphorylation
of a 105-kDa protein (p105) in cell extracts from different cell types. Protein
sequencing and immunological analysis indicated that this protein is elongation
factor 2 (EF-2). We propose that calcium/calmodulin-dependent protein kinase III
is responsible for the PTA-dependent EF-2 phosphorylation based on the following
lines of evidence: (a) Ca2+ is required for the effect; (b) calmodulin enhances
the reaction, and calmodulin inhibitors block the phosphorylation; and (c) no
phosphorylation is seen in cell extracts depleted of calmodulin-binding proteins.
To obtain a strong phosphorylated EF-2 band, we found it necessary to add PTA to
cytosolic extracts from synchronized dividing cells in various phases of the cell
cycle except in mitosis. Since PTA is a nuclear protein everywhere in the cell
cycle except in mitosis, when it is found in the cytoplasm, we hypothesize that,
if PTA activates EF-2 phosphorylation in vivo, as present data suggest, its
presence in the cytoplasm during mitosis could explain why EF-2 phosphorylation
is mainly restricted to that phase of the cell cycle. Moreover, other bands in
addition to EF-2 were phosphorylated in a calmodulin- and PTA-dependent manner,
and several of them (in a range between 50 and 60 kDa) have similar Mr to those
that conform to the holoenzyme calcium/calmodulin dependent protein kinase II,
suggesting that PTA could have a more general function modulating the activity of
various Ca2+/CaM-dependent enzymes along the cell cycle.
PMID- 9553063
TI - The crk3 gene of Leishmania mexicana encodes a stage-regulated cdc2-related
histone H1 kinase that associates with p12.
AB - A cdc2-related protein kinase gene, crk3, has been isolated from the parasitic
protozoan Leishmania mexicana. Data presented here suggests that crk3 is a good
candidate to be the leishmanial cdc2 homologue but that the parasite protein has
some characteristics which distinguish it from mammalian cdc2. crk3 is predicted
to encode a 35.6-kDa protein with 54% sequence identity with the human cyclin
dependent kinase cdc2 and 78% identity with the Trypanosoma brucei CRK3. The
trypanosomatid CRK3 proteins have an unusual, poorly conserved 19-amino acid N
terminal extension not present in human cdc2. crk3 is single copy, and there is 5
fold higher mRNA in the replicative promastigote life-cycle stage than in the non
dividing metacyclic form or mammalian amastigote form. A leishmanial suc-binding
cdc2-related kinase (SBCRK) histone H1 kinase, has previously been described
which binds the yeast protein, p13(suc1), and that has stage-regulated activity
(Mottram J. C., Kinnaird, J., Shiels, B. R., Tait, A., and Barry, J. D. (1993) J.
Biol. Chem. 268, 21044-21051). CRK3 from cell extracts of the three life-cycle
stages was found to bind p13(suc1) and the leishmanial homologue p12(cks1). CRK3
fused with six histidines at the C terminus was expressed in L. mexicana and
shown to have SBCRK histone H1 kinase activity. Depletion of histidine-tagged
CRK3 from L. mexicana cell extracts, by Ni-nitrilotriacetic acid agarose
selection, reduced histone H1 kinase activity binding to p13(suc1). These data
imply that crk3 encodes the kinase subunit of SBCRK. SBCRK and histidine-tagged
CRK3 activities were inhibited by the purine analogue olomoucine with an IC50 of
28 and 42 microM, respectively, 5-6-fold higher than human p34(cdc2)/cyclinB.
PMID- 9553064
TI - Heparinase II from Flavobacterium heparinum. Role of histidine residues in
enzymatic activity as probed by chemical modification and site-directed
mutagenesis.
AB - The three heparinases derived from Flavobacterium heparinum are powerful tools
for studying heparin-like glycosaminoglycans in major biological processes,
including angiogenesis and development. Heparinase II is unique among the three
enzymes because it is able to catalytically cleave both heparin and heparan
sulfate-like regions of heparin-like glycosaminoglycans. Toward understanding the
catalytic mechanism of heparin-like glycosaminoglycan degradation by heparinase
II, we set out to investigate the role of the histidines of heparinase II in
catalysis. We observe concentration-dependent inactivation of heparinase II in
the presence of the reversible histidine-modifying reagent diethylpyrocarbonate
(DEPC). With heparin as the substrate, the rate constant of inactivation was
found to be 0.16 min-1 mM-1; with heparan sulfate as the substrate, the rate
constant was determined to be 0.24 min-1 mM-1. Heparinase II activity is restored
following hydroxylamine treatment. This, along with other experiments, strongly
suggests that the inactivation of heparinase II by DEPC is specific for histidine
residues and that three histidines are modified by DEPC. Substrate protection
experiments show that heparinase II preincubation with heparin followed by the
addition of DEPC resulted in a loss of enzymatic activity toward heparan sulfate
but not heparin. However, heparinase II preincubation with heparan sulfate was
unable to protect heparinase II from DEPC inactivation for either of the
substrates. Proteolytic mapping studies with Lys-C were consistent with the
chemical modification experiments and identified histidines 238, 451, and 579 as
being important for heparinase II activity. Further mapping studies identified
histidine 451 as being essential for heparin degradation. Site-directed
mutagenesis experiments on the 13 histidines of heparinase II corroborated the
chemical modification and the peptide mapping studies, establishing the
importance of histidines 238, 451 and 579 in heparinase II activity.
PMID- 9553065
TI - Type I protein C deficiency caused by disruption of a hepatocyte nuclear factor
(HNF)-6/HNF-1 binding site in the human protein C gene promoter.
AB - Protein C is a vitamin K-dependent zymogen of a serine protease that inhibits
blood coagulation by proteolytic inactivation of factors Va and VIIIa.
Individuals affected by protein C deficiency are at risk for venous thrombosis.
One such affected individual was shown earlier to carry a -14 T --> C mutation in
the promoter region of the protein C gene. It is shown here that the region
around this mutation corresponds to a binding site for the transcription factor
hepatocyte nuclear factor (HNF)-6 and that this site completely overlaps an HNF-1
binding site. HNF-6 and HNF-1 bound in a mutually exclusive manner. The -14 T -->
C mutation reduced HNF-6 binding. In transient transfection experiments, HNF-6
transactivated the wild-type protein C promoter and introduction of the mutation
abolished transactivation by HNF-6. Similar experiments showed that wild-type
protein C promoter activity was reduced by cotransfection of an HNF-1 expression
vector. This inhibiting effect of HNF-1 was reversed to a stimulatory effect when
promoter sequences either upstream or downstream of the HNF-6/HNF-1 site were
deleted. It is concluded that HNF-6 is a major determinant of protein C gene
activity. Moreover, this is the first report describing the putative involvement
of HNF-6 and of an HNF-6 binding site in human pathology.
PMID- 9553066
TI - Electron partitioning between the two branching quinol-oxidizing pathways in
Acanthamoeba castellanii mitochondria during steady-state state 3 respiration.
AB - Amoeba mitochondria possess a respiratory chain with two quinol-oxidizing
pathways: the cytochrome pathway and the cyanide-resistant alternative oxidase
pathway. The ADP/O method, based on the non-phosphorylating property of
alternative oxidase, was used to determine contributions of both pathways in
overall state 3 respiration in the presence of GMP (an activator of the
alternative oxidase in amoeba) and succinate as oxidizable substrate. This method
involves pair measurements of ADP/O ratios plus and minus benzohydroxamate (an
inhibitor of the alternative oxidase). The requirements of the method are listed
and verified. When overall state 3 respiration was decreased by increasing
concentrations of n-butyl malonate (a non-penetrating inhibitor of succinate
uptake), the quinone reduction level declined. At the same time, the alternative
pathway contribution decreased sharply and became negligible when quinone redox
state was lower than 50%, whereas the cytochrome pathway contribution first
increased and then passed through a maximum at a quinone redox state of 58% and
sharply decreased at a lower level of quinone reduction. This study is the first
attempt to examine the steady-state kinetics of the two quinol-oxidizing pathways
when both are active and to describe electron partitioning between them when the
steady-state rate of the quinone-reducing pathway is varied.
PMID- 9553067
TI - Events in the kinetic folding pathway of a small, all beta-sheet protein.
AB - The folding of cardiotoxin analogue III (CTX III), a small (60 amino acids), all
beta-sheet protein from the venom of the Taiwan Cobra (Naja naja atra) is here
investigated. The folding kinetics is monitored by using a variety of techniques
such as NMR, fluorescence, and circular dichroism spectroscopy. The folding of
the protein is complete within a time scale of 200 ms. The earliest detectable
event in the folding pathway of CTX III is the formation of a hydrophobic
cluster, which possess strong affinity to bind to nonpolar dye such as 1-anilino
8-napthalene-sulfonic acid. Quenched-flow deuterium-hydrogen exchange experiments
indicate that the segment spanning residues 51-55 along with Lys23, Ile39, Val49,
Tyr51 and Val52 could constitute the "hydrophobic cluster." Folding kinetics of
CTX III based on the amide-protection data reveals that the triple-stranded,
antiparallel beta-sheet segment, which is located in the central core of the
molecule, appears to fold faster than the double-stranded beta-sheet segment.
PMID- 9553068
TI - Transport and metabolism of the essential vitamin pantothenic acid in human
erythrocytes infected with the malaria parasite Plasmodium falciparum.
AB - The growth of the human malaria parasite, Plasmodium falciparum, within its host
erythrocyte is reliant on the uptake of a number of essential nutrients from the
extracellular medium. One of these is pantothenic acid, a water-soluble vitamin
that is a precursor of coenzyme A. In this study we show that normal uninfected
erythrocytes are impermeable to pantothenate but that the vitamin is taken up
rapidly into malaria-infected cells via a transport pathway that has the
characteristics (furosemide sensitivity, nonsaturability) of previously
characterized, broad specificity permeation pathways induced by the intracellular
parasite in the host cell membrane. The transport of pantothenate therefore
constitutes a critical physiological role for these pathways. Inside the
parasitized cell pantothenate undergoes phosphorylation, the first step in its
conversion to coenzyme A. Parasites within saponin-permeabilized erythrocytes
were shown to take up and phosphorylate pantothenate, consistent with the
intracellular parasite having both a pantothenate transporter and a pantothenate
kinase. Comparisons of the rate of phosphorylation of pantothenate by lysates
prepared from uninfected and infected erythrocytes revealed that the pantothenate
kinase activity of the P. falciparum trophozoite is some 10-fold higher than that
of its host cell and that most, if not all, of the phosphorylation of
pantothenate within the malaria-infected cell occurs within the intracellular
parasite. These results contrast with those of previous studies in which it was
proposed that the avian malaria parasite Plasmodium lophurae lacks pantothenate
kinase (as well as the other enzymes for the synthesis of coenzyme A) and is
reliant upon the uptake of preformed coenzyme A from the host cell cytosol.
PMID- 9553069
TI - Human tyrosine hydroxylase isoforms. Inhibition by excess tetrahydropterin and
unusual behavior of isoform 3 after camp-dependent protein kinase
phosphorylation.
AB - Human tyrosine hydroxylase exists as four isoforms (hTH1-4), generated by
alternative splicing of pre-mRNA, with tissue-specific distribution.
Unphosphorylated hTH3 and hTH1 were produced in large amounts in Escherichia coli
and purified to homogeneity. The phosphorylation sites were determined after
labeling with [32P]phosphate in the presence of cAMP-dependent protein kinase
(PKA) and calmodulin-dependent protein kinase II (CaM-PKII). Ser40 was
phosphorylated by PKA, and both Ser19 and Ser40 were phosphorylated by CaM-PKII.
The enzyme kinetics of hTH3 were determined in the presence of various
concentrations of the natural co-substrate (6R)-tetrahydrobiopterin and compared
with those of recombinant hTH1 (similar to rat TH). We show that, under initial
velocity conditions, excess (6R)-tetrahydrobiopterin inhibits hTH3 and hTH1. The
TH catalytic constants (kcat) were determined for each of the two isoenzymes:
hTH3 is about five times more active than hTH1. Phosphorylation by CaM-PKII did
not affect the kinetic parameters of hTH3. The classical activation of TH by PKA
phosphorylation, demonstrated for hTH1, was not observed with hTH3. Furthermore,
hTH3 escapes activity regulation by phosphorylation and is always more active
than phosphorylated hTH1. The properties of the hTH3 enzyme may be relevant to
diseases affecting dopaminergic cells.
PMID- 9553070
TI - Multiple regulatory elements in the 5'-flanking sequence of the human epsilon
globin gene.
AB - We have previously reported, on the basis of transfection experiments, the
existence of a silencer element in the 5'-flanking region of the human embryonic
(epsilon) globin gene, located at -270 base pairs 5' to the cap site, which
provides negative regulation for this gene. Experiments in transgenic mice
suggest the physiological importance of this epsilon-globin silencer, but also
suggest that down-regulation of epsilon-globin gene expression may involve other
negative elements flanking the epsilon-globin gene. We have now extended the
analysis of epsilon-globin gene regulation to include the flanking region
spanning up to 6 kilobase pairs 5' to the locus control region using reporter
gene constructs with deletion mutations and transient transfection assays. We
have identified and characterized other strong negative regulatory regions, as
well as several positive regions that affect transcription activation. The
negative regulatory regions at -3 kilobase pairs (epsilonNRA-I and epsilonNRA
II), flanked by a positive control element, has a strong effect on the epsilon
globin promoter both in erythroid K562 and nonerythroid HeLa cells and contains
several binding sites for transcription factor GATA-1, as evidenced from DNA
protein binding assays. The GATA-1 sites within epsilonNRA-II are directly needed
for negative control. Both epsilonNRA-I and epsilonNRA-II are active on a
heterologous promoter and hence appear to act as transcription silencers. Another
negative control region located at -1.7 kilobase pairs (epsilonNRB) does not
exhibit general silencer activity as epsilonNRB does not affect transcription
activity when used in conjunction with an epsilon-globin minimal promoter. The
negative effect of epsilonNRB is erythroid specific, but not stage-specific as it
can repress transcription activity in both K562 erythroid cells as well as in
primary cultures of adult erythroid cells. Phylogenetic DNA sequence comparisons
with other primate and other mammalian species show unusual degree of flanking
sequence homology for the epsilon-globin gene, including in several of the
regions identified in these functional and DNA-protein binding analyses,
providing alternate evidence for their potential importance. We suggest that the
down-regulation of epsilon-globin gene expression as development progresses
involves complex, cooperative interactions of these negative regulatory elements,
epsilonNRA-I/epsilonNRA-II, epsilonNRB, the epsilon-globin silencer and probably
other negative and positive elements in the 5'-flanking region of the epsilon
globin gene.
PMID- 9553071
TI - Selective inhibition of Ras interaction with its particular effector by synthetic
peptides corresponding to the Ras effector region.
AB - Ras proteins possess multiple downstream effectors of distinct structures. We and
others demonstrated that Ha-Ras carrying certain effector region mutations could
interact differentially with its effectors, implying that significant differences
exist in their Ras recognition mechanisms. Here, by employing the fluorescence
polarization method, we measured the activity of effector region synthetic
peptides bearing various amino acid substitutions to inhibit association of Ras
with the effectors human Raf-1 and Schizosaccharomyces pombe Byr2. The effect of
these peptides on association with another effector Saccharomyces cerevisiae
adenylyl cyclase was also examined by measuring inhibition of the Ras-dependent
adenylyl cyclase activity. The peptide corresponding to the residues 17-44
competitively inhibited Ras association with all the three effectors at the Ki
values of 1 approximately 10 microM, and the inhibition was considerably
attenuated by the D38A mutation. The peptide with the D38N mutation inhibited
association of Ha-Ras with Byr2 but not with the others, whereas that with the
P34G mutation inhibited association of Ha-Ras with Raf-1 and Byr2 but not with
adenylyl cyclase. Thus, the specificity observed with the whole Ras protein was
retained in the effector region peptide. These results suggest that the effector
region residues constitute a major determinant for differential recognition of
the effector molecules, raising a possibility for selective inhibition of a
particular Ras function.
PMID- 9553072
TI - Inhibition of assembly of bacterial cell division protein FtsZ by the hydrophobic
dye 5,5'-bis-(8-anilino-1-naphthalenesulfonate).
AB - To gain further insight into the structural relatedness of tubulin and FtsZ, the
tubulin-like prokaryotic cell division protein, we tested the effect of tubulin
assembly inhibitors on FtsZ assembly. Common tubulin inhibitors, such as
colchicine, colcemid, benomyl, and vinblastine, had no effect on Ca2+-promoted
GTP-dependent assembly of FtsZ into polymers. However, the hydrophobic probe 5,
5'-bis-(8-anilino-1-naphthalenesulfonate) (bis-ANS) inhibited FtsZ assembly. The
potential mechanisms for inhibition are discussed. Titrations of FtsZ with bis
ANS indicated that FtsZ has one high affinity binding site and multiple low
affinity binding sites. ANS (8-anilino-1-naphthalenesulfonate), a hydrophobic
probe similar to bis-ANS, had no inhibitory effect on FtsZ assembly. Because
tubulin assembly has also been shown to be inhibited by bis-ANS but not by ANS,
it supports the idea that FtsZ and tubulin share similar conformational
properties. Ca2+, which promotes GTP-dependent FtsZ assembly, stimulated binding
of bis-ANS or ANS to FtsZ, suggesting that Ca2+ binding induces changes in the
hydrophobic conformation of the protein. Interestingly, depletion of bound Ca2+
with EGTA further enhanced bis-ANS fluorescence. These findings suggest that both
binding and dissociation of Ca2+ are capable of inducing FtsZ conformational
changes, and these changes could promote the GTP-dependent assembly of FtsZ.
PMID- 9553073
TI - Oxygen-bridged dinuclear ruthenium amine complex specifically inhibits Ca2+
uptake into mitochondria in vitro and in situ in single cardiac myocytes.
AB - Ruthenium red is a well known inhibitor of Ca2+ uptake into mitochondria in
vitro. However, its utility as an inhibitor of Ca2+ uptake into mitochondria in
vivo or in situ in intact cells is limited because of its inhibitory effects on
sarcoplasmic reticulum Ca2+ release channel and other cellular processes. We have
synthesized a ruthenium derivative and found it to be an oxygen-bridged dinuclear
ruthenium amine complex. It has the same chemical structure as Ru360 reported
previously (Emerson, J., Clarke, M. J., Ying, W-L., and Sanadi, D. R. (1993) J.
Am. Chem. Soc. 115, 11799-11805). Ru360 has been shown to be a potent inhibitor
of Ca2+-stimulated respiration of liver mitochondria in vitro. However, the
specificity of Ru360 on Ca2+ uptake into mitochondria in vitro or in intact cells
has not been determined. The present study reports in detail the potency, the
effectiveness, and the mechanism of inhibition of mitochondrial Ca2+ uptake by
Ru360 and its specificity in vitro in isolated mitochondria and in situ in
isolated cardiac myocytes. Ru360 was more potent (IC50 = 0.184 nM) than ruthenium
red (IC50 = 6.85 nM) in inhibiting Ca2+ uptake into mitochondria. 103Ru360 was
found to bind to isolated mitochondria with high affinity (Kd = 0.34 nM, Bmax =
80 fmol/mg of mitochondrial protein). The IC50 of 103Ru360 for the inhibition of
Ca2+ uptake into mitochondria was also 0.2 nM, indicating that saturation of a
specific binding site is responsible for the inhibition of Ca2+ uptake. Ru360, as
high as 10 microM, produced no effect on sarcoplasmic reticulum Ca2+ uptake or
release, sarcolemmal Na+/Ca2+ exchange, actomyosin ATPase activity, L-type Ca2+
channel current, cytosolic Ca2+ transients, or cell shortening. 103Ru360 was
taken up by isolated myocytes in a time-dependent biphasic manner. Ru360 (10
microM) applied outside intact voltage-clamped ventricular myocytes prevented
Ca2+ uptake into mitochondria in situ where the cells were progressively loaded
with Ca2+ via sarcolemmal Na+/Ca2+ exchange by depolarization to +110 mV. We
conclude that Ru360 specifically blocks Ca2+ uptake into mitochondria and can be
used in intact cells.
PMID- 9553074
TI - Early activation of c-Jun N-terminal kinase and p38 kinase regulate cell survival
in response to tumor necrosis factor alpha.
AB - Fas ligand and tumor necrosis factor alpha (TNF) bind to members of the TNF
receptor superfamily. Stimulation by Fas ligand results in apoptosis, whereas TNF
induces multiple effects including proliferation, differentiation, and apoptosis.
Activation of the c-Jun N-terminal kinase (JNK) and p38 kinase pathways is common
to Fas and TNF signaling; however, their role in apoptosis is controversial. Fas
receptor cross-linking induces apoptosis in the absence of actinomycin D and
activates JNK in a caspase-dependent manner. In contrast, TNF requires
actinomycin D for apoptosis and activates JNK and p38 kinase with biphasic
kinetics. The first phase is transient, precedes apoptosis, and is caspase
independent, whereas the second phase is coincident with apoptosis and is caspase
dependent. Inhibition of early TNF-induced JNK and p38 kinases using MKK4/MKK6
mutants or the p38 inhibitor SB203580 increases TNF-induced apoptosis, whereas
expression of wild type MKK4/MKK6 enhances survival. In contrast, the Mek
inhibitor PD098059 has no effect on survival. These results demonstrate that
early activation of p38 kinase (but not Mek) are necessary to protect cells from
TNF-mediated cytotoxicity. Thus, early stress kinase activation initiated by TNF
plays a key role in regulating apoptosis.
PMID- 9553075
TI - The C2 domains of Rabphilin3A specifically bind phosphatidylinositol 4,5
bisphosphate containing vesicles in a Ca2+-dependent manner. In vitro
characteristics and possible significance.
AB - In the present study we investigated the lipid binding characteristics of the C2
domains of Rabphilin3a. We found that the tandem C2 domain of Rabphilin3a
specifically bound lipid vesicles containing phosphatidylinositol 4,5
bisphosphate (PtdIns(4,5)P2) in a Ca2+-dependent manner. There was little binding
to vesicles containing PtdIns(3,4)P2 in the presence or absence of Ca2+. Binding
to phosphatidylinositol 3,4,5-triphosphate-containing vesicles was similar to
binding to PtdIns(4,5)P2-containing vesicles. The presence of physiological
amounts of phosphatidylserine (PS) greatly potentiated the ability of
PtdIns(4,5)P2 to cause vesicle binding. As with the C2 domains together, the
binding of individual C2 domain of Rabphilin3a was much greater to PtdIns(4,5)P2
containing vesicles than PtdIns(3,4)P2-containing vesicles. Both C2 domains also
bound 29 mol % PS-containing vesicles in a Ca2+-dependent manner. Because of the
importance of the C2B domain in the enhancement of secretion from chromaffin
cells by Rabphilin3a, its biochemistry was further investigated. The mutation of
aspartates 657 and 659 to asparagines in C2B decreased Ca2+-dependent and
increased Ca2+-independent vesicle binding, indicating the Ca2+ dependence of the
domain is provided by aspartic acid residues in the putative Ca2+-binding pocket.
A peptide from the COOH-terminal region of the C2B domain specifically inhibited
ATP-dependent secretion from permeabilized chromaffin cells and the binding of
Rabphilin3a to phosphatidylcholine/PS/PtdIns(4,5)P2-containing lipid vesicles,
suggesting a role of this sequence in secretion through its ability to interact
with acidic lipid vesicles.
PMID- 9553076
TI - The N terminus of eukaryotic translation elongation factor 3 interacts with 18 S
rRNA and 80 S ribosomes.
AB - Elongation factor-3 (EF-3) is an essential fungal-specific translation factor
which exhibits a strong ribosome-dependent ATPase activity and has sequence
homologies that may predict domains critical for its role in protein synthesis,
including a domain at the N terminus, which exhibits sequence homology with
Escherichia coli ribosomal protein S5. A portion of the N terminus of
Saccharomyces cerevisiae EF-3 (spanning the S5 homology region) has been cloned,
expressed, and purified from E. coli. UV cross-linking experiments revealed that
the N-terminal EF-3 protein (N-term EF-3) can be specifically cross-linked to 18
S rRNA. Filter-binding assays confirmed these data, and also established that the
interaction has a Kd approximately 238 nM. Additional evidence shows that N-term
EF-3 is able to associate with yeast ribosomes and inhibit the ribosome-dependent
ATPase activity of native EF-3. These data taken together suggest that at least
one of the ribosome-binding sites of EF-3 is located at the N terminus.
PMID- 9553077
TI - Template strand switching by T7 RNA polymerase.
AB - T7 RNA polymerase (RNAP) is able to traverse a variety of discontinuities in the
template (T) strand of duplex DNA, including nicks, gaps, and branched junctions
in which the 3' end of the T strand is not complementary to the non-template (NT)
strand. The products represent a faithful copy of the T strand, with no
insertions or deletions. On double-stranded templates having protruding 3' ends
the polymerase is able to insert the free 3' end of the NT strand and to utilize
this as a new T strand ("turn around transcription"), resulting in the anomalous
production of high molecular weight transcripts. The capacity of T7 RNAP to
bypass interruptions in the T strand depends upon the stability of the elongation
complex. Sequences that are expected to stabilize a local RNA:DNA hybrid (such as
the presence of a C6 tract in the T strand) dramatically reduce dissociation of
the RNAP while still allowing the enzyme to insert a new 3' end. Similar effects
on RNAP release are observed when the enzyme reaches the end of a template (i.e.
when synthesizing runoff products), resulting in markedly different yields of RNA
product during multiple rounds of transcription.
PMID- 9553078
TI - Neuregulins promote survival and growth of cardiac myocytes. Persistence of ErbB2
and ErbB4 expression in neonatal and adult ventricular myocytes.
AB - Neuregulins (i.e. neuregulin-1 (NRG1), also called neu differentiation factor,
heregulin, glial growth factor, and acetylcholine receptor-inducing activity) are
known to induce growth and differentiation of epithelial, glial, neuronal, and
skeletal muscle cells. Unexpectedly, mice with loss of function mutations of NRG1
or of either of two of their cognate receptors, ErbB2 and ErbB4, die during
midembryogenesis due to the aborted development of myocardial trabeculae in
ventricular muscle. To examine the role of NRG and their receptors in developing
and postnatal myocardium, we studied the ability of a soluble NRG1 (recombinant
human glial growth factor 2) to promote proliferation, survival, and growth of
isolated neonatal and adult rat cardiac myocytes. Both ErbB2 and ErbB4 receptors
were found to be expressed by neonatal and adult ventricular myocytes and
activated by rhGGF2. rhGGF2 (30 ng/ml) provoked an approximate 2-fold increase in
embryonic cardiac myocyte proliferation. rhGGF2 also promoted survival and
inhibited apoptosis of subconfluent, serum-deprived myocyte primary cultures and
also induced hypertrophic growth in both neonatal and adult ventricular myocytes,
which was accompanied by enhanced expression of prepro-atrial natriuretic factor
and skeletal alpha-actin. Moreover, NRG1 mRNA could be detected in coronary
microvascular endothelial cell primary cultures prepared from adult rat
ventricular muscle. NRG1 expression in these cells was increased by endothelin-1,
another locally acting cardiotropic peptide within the heart. The persistent
expression of both a neuregulin and its cognate receptors in the postnatal and
adult heart suggests a continuing role for neuregulins in the myocardial adaption
to physiologic stress or injury.
PMID- 9553079
TI - A novel multifunctional motif in the amino-terminal A/B domain of T3Ralpha
modulates DNA binding and receptor dimerization.
AB - We reported previously that deletion of the 50-amino acid NH2-terminal A/B domain
of the chicken (c) or rat thyroid hormone (T3) receptor-alpha (T3Ralpha)
decreased the T3-dependent stimulation of genes regulated by native thyroid
hormone response elements (TREs). This requirement of the NH2-terminal A/B domain
for transcriptional activation was mapped to amino acids 21-30 of cT3Ralpha.
Expression of transcription factor IIB (TFIIB) in cells was shown to enhance T3
dependent transcriptional activation by cT3Ralpha, and this enhancement by TFIIB
was dependent on the same 10-amino acid sequence. In vitro binding studies
indicated that cT3Ralpha interacts efficiently with TFIIB, and this interaction
requires amino acids 23KRKRK27 in the A/B domain. In this study we document the
functional importance of these five basic residues in transcriptional activation
by cT3Ralpha, further supporting the biological significance of these residues
and their interaction with TFIIB. Interestingly, we also find that the same amino
acids also affect DNA binding and dimerization of cT3Ralpha. Gel mobility shift
assays reveal that a cT3Ralpha mutant that has all five basic amino acids changed
from 23KRKRK27 to 23TITIT27 binds to a palindromic TRE predominantly as a
homodimer, whereas cT3Ralpha with the wild-type 23KRKRK27 sequence binds
predominantly as a monomer. This results from both a marked decrease in the
ability of the cT3Ralpha mutant to bind as a monomer and from an enhanced ability
to dimerize as reflected by an increase in DNA-bound T3R-retinoic X receptor
heterodimers. These effects of 23KRKRK27 on DNA binding, dimerization,
transcriptional activation, and the association of T3Ralpha with TFIIB support
the notion that this basic amino acid motif may influence the overall structure
and function of T3Ralpha and, thus, play a role in determining the distinct
context-dependent transactivation potentials of the individual T3R isoforms.
PMID- 9553080
TI - Molecular cloning and functional characterization of a novel receptor-activated
TRP Ca2+ channel from mouse brain.
AB - Characterization of mammalian homologues of Drosophila TRP proteins, which induce
light-activated Ca2+ conductance in photoreceptors, has been an important clue to
understand molecular mechanisms underlying receptor-activated Ca2+ influx in
vertebrate cells. We have here isolated cDNA that encodes a novel TRP homologue,
TRP5, predominantly expressed in the brain. Recombinant expression of the TRP5
cDNA in human embryonic kidney cells dramatically potentiated extracellular Ca2+
dependent rises of intracellular Ca2+ concentration ([Ca2+]i) evoked by ATP.
These [Ca2+]i transients were inhibited by SK&F96365, a blocker of receptor
activated Ca2+ entry, and by La3+. Expression of the TRP5 cDNA, however, did not
significantly affect [Ca2+]i transients induced by thapsigargin, an inhibitor of
endoplasmic reticulum Ca2+-ATPases. ATP stimulation of TRP5-transfected cells
pretreated with thapsigargin to deplete internal Ca2+ stores caused intact
extracellular Ca2+-dependent [Ca2+]i transients, whereas ATP suppressed [Ca2+]i
in thapsigargin-pretreated control cells. Furthermore, in ATP-stimulated, TRP5
expressing cells, there was no significant correlation between Ca2+ release from
the internal Ca2+ store and influx of extracellular Ca2+. Whole-cell mode of
patch-clamp recording from TRP5-expressing cells demonstrated that ATP
application induced a large inward current in the presence of extracellular Ca2+.
Omission of Ca2+ from intrapipette solution abolished the current in TRP5
expressing cells, whereas 10 nM intrapipette Ca2+ was sufficient to support TRP5
activity triggered by ATP receptor stimulation. Permeability ratios estimated
from the zero-current potentials of this current were PCa:PNa:PCs = 14.3:1. 5:1.
Our findings suggest that TRP5 directs the formation of a Ca2+-selective ion
channel activated by receptor stimulation through a pathway that involves Ca2+
but not depletion of Ca2+ store in mammalian cells.
PMID- 9553081
TI - The effect of F-actin on the binding and hydrolysis of guanine nucleotide by
Dictyostelium elongation factor 1A.
AB - Indirect evidence implicates actin as a cofactor in eukaryotic protein synthesis.
The present study directly examines the effects of F-actin on the biochemical
properties of eukaryotic elongation factor 1A (eEF1A, formerly EF1alpha), a major
actin-binding protein. The basal mechanism of eEF1A alone is determined under
physiological conditions with the critical finding that glycerol and guanine
nucleotide are required to prevent protein aggregation and loss of enzymatic
activity. The dissociation constants (Kd) for GDP and GTP are 2.5 microM and 0.6
microM, respectively, and the kcat of GTP hydrolysis is 1.0 x 10(-3) s-1. When
eEF1A binds to F-actin, there is a 7-fold decrease in the affinity for guanine
nucleotide and an increase of 35% in the rate of GTP hydrolysis. Based upon our
results and the relevant cellular concentrations, the predominant form of
cellular eEF1A is calculated to be GTP.eEF1A.F-actin. We conclude that F-actin
does not significantly modulate the basal enzymatic properties of eEF1A; however,
actin may still influence protein synthesis by sequestering GTP.eEF1A away from
interactions with its known translational ligands, e.g. aminoacyl-tRNA and
ribosomes.
PMID- 9553082
TI - Alkyl-dihydroxyacetonephosphate synthase. Fate in peroxisome biogenesis disorders
and identification of the point mutation underlying a single enzyme deficiency.
AB - Peroxisomes play an indispensible role in ether lipid biosynthesis as evidenced
by the deficiency of ether phospholipids in fibroblasts and tissues from patients
suffering from a number of peroxisomal disorders. Alkyl-dihydroxyacetonephosphate
synthase, a peroxisomal enzyme playing a key role in the biosynthesis of ether
phospholipids, contains the peroxisomal targeting signal type 2 in a N-terminal
cleavable presequence. Using a polyclonal antiserum raised against alkyl
dihydroxyacetonephosphate synthase, levels of this enzyme were examined in
fibroblast cell lines from patients affected by peroxisomal disorders. Strongly
reduced levels were found in fibroblasts of Zellweger syndrome and rhizomelic
chondrodysplasia punctata patients, indicating that the enzyme is not stable in
the cytoplasm as a result of defective import into peroxisomes. In a neonatal
adrenoleukodystrophy patient with an isolated import deficiency of proteins
carrying the peroxisomal targeting signal type 1, the precursor form of alkyl
dihydroxyacetonephosphate synthase was detected at a level comparable to that of
the mature form in control fibroblasts, in line with an intraperoxisomal
localization. A patient with an isolated deficiency in alkyl
dihydroxyacetonephosphate (DHAP) synthase activity had normal levels of this
protein. Analysis at the cDNA level revealed a missense mutation leading to a
R419H substitution in the enzyme of this patient. Expression of a recombinant
protein carrying this mutation in Escherichia coli yielded an inactive enzyme,
whereas a comparable control recombinant enzyme was active, providing further
proof that this substitution is responsible for the inactivity of the enzyme and
the phenotype. In line with this result is the observation that wild-type alkyl
DHAP synthase activity can be inactivated by the arginine-modifying agent
phenylglyoxal. The enzyme is efficiently protected against this inactivation when
the substrate palmitoyl-DHAP is present at a saturating concentration. The gene
encoding human alkyl-dihydroxyacetonephosphate synthase was mapped on chromosome
2q31.
PMID- 9553083
TI - Reconstitution of a protein disulfide catalytic system.
AB - Disulfide bonds are important for the structure and stability of many proteins.
In prokaryotes their formation is catalyzed by the Dsb proteins. The DsbA protein
acts as a direct donor of disulfides to newly synthesized periplasmic proteins.
Genetic evidence suggests that a second protein called DsbB acts to specifically
reoxidize DsbA. Here we demonstrate the direct reoxidation of DsbA by DsbB. We
have developed a fluorescence assay that allows us to directly follow the
reoxidation of DsbA. We show that membranes containing catalytic amounts of DsbB
can rapidly reoxidize DsbA to completion. The reaction strongly depends on the
presence of oxygen, implying that oxygen serves as the final electron acceptor
for this disulfide bond formation reaction. Membranes from a dsbB null mutant
display no DsbA reoxidation activity. The ability of DsbB to reoxidize DsbA fits
Michaelis-Menten behavior with DsbA acting as a high affinity substrate for DsbB
with a Km = 10 microM. The in vitro reconstitution described here is the first
biochemical analysis of DsbB and allows us to study the major pathway of
disulfide bond formation in Escherichia coli.
PMID- 9553084
TI - Positively charged residues at positions 12, 17, and 18 of glucagon ensure
maximum biological potency.
AB - Glucagon is a peptide hormone that plays a central role in the maintenance of
normal circulating glucose levels. Structure-activity studies have previously
demonstrated the importance of histidine at position 1 and the absolute
requirement for aspartic acid at position 9 for transduction of the hormonal
signal. Site-directed mutagenesis of the receptor protein identified Asp64 on the
extracellular N-terminal tail to be crucial for the recognition function of the
receptor. In addition, antibodies generated against aspartic acid-rich epitopes
from the extracellular region competed effectively with glucagon for receptor
sites, which suggested that negative charges may line the putative glucagon
binding pocket in the receptor. These observations led to the idea that
positively charged residues on the hormone may act as counterions to these sites.
Based on these initial findings, we synthesized glucagon analogs in which basic
residues at positions 12, 17, and 18 were replaced with neutral or acidic
residues to examine the effect of altering the positive charge on those sites on
binding and adenylyl cyclase activity. The results indicate that unlike N
terminal histidine, Lys12, Arg17, and Arg18 of glucagon have very large effects
on receptor binding and transduction of the hormonal signal, although they are
not absolutely critical. They contribute strongly to the stabilization of the
binding interaction with the glucagon receptor that leads to maximum biological
potency.
PMID- 9553085
TI - Growth in iron-enriched medium partially compensates Escherichia coli for the
lack of manganese and iron superoxide dismutase.
AB - Enrichment of the growth medium with iron partially relieves the phenotypic
deficits imposed on Escherichia coli by lack of both manganese and iron
superoxide dismutases. Thus iron supplementation increased the aerobic growth
rate, decreased the leakage of sulfite, and diminished sensitivity toward
paraquat. Iron supplementation increased the activities of several [4Fe-4S]
containing dehydratases, and this was seen even in the presence of 50 microg/ml
of rifampicin, an amount which completely inhibited growth. Assessing the O-2
scavenging activity by means of lucigenin luminescence indicated that the iron
enriched sodAsodB cells had gained some means of eliminating O-2, which was not
detectable as superoxide dismutase activity in cell extracts. It is noteworthy
that iron-enriched cells were not more sensitive toward the lethality of H2O2
despite having the usual amount of catalase activity. This indicates that iron
taken into the cells from the medium is not available for Fenton chemistry, but
is available for reconstitution of iron-sulfur clusters. We suppose that
oxidation of the [4Fe-4S] clusters of dehydratases by O-2 and their subsequent
reductive reconstitution provides a mechanism for scavenging O-2 and that
speeding this reductive reconstitution by iron enrichment both spared other
targets from O-2 attack and maintained adequate levels of these enzymes to meet
the metabolic needs of the cells.
PMID- 9553086
TI - Seven novel mammalian SNARE proteins localize to distinct membrane compartments.
AB - Soluble N-ethylmaleimide-sensitive factor-attachment protein receptor (SNARE)
proteins of the vesicle-associated membrane protein (VAMP) and syntaxin families
play a central role in vesicular trafficking through the formation of complexes
between proteins present on vesicle and target membranes. Formation of these
complexes is proposed to mediate aspects of the specificity of vesicle
trafficking and to promote fusion of the lipid bilayers. In order to further
understand the molecular mechanisms that organize membrane compartments, we have
characterized seven new mammalian proteins of the VAMP and syntaxin families. The
proteins are broadly expressed; however, syntaxin 13 is enriched in brain and
VAMP 8 in kidney. The seven novel SNAREs localize in distinct patterns
overlapping with Golgi, endosomal, or lysosomal markers. Our studies support the
hypothesis that evolutionary radiation of these two gene families gave rise to
sets of proteins whose differential expression and combinatorial associations
define and organize the membrane compartments of cells.
PMID- 9553087
TI - Identification and characterization of a novel cap-binding protein from
Arabidopsis thaliana.
AB - Cap-binding proteins specifically bind to the 7-methyl guanosine (m7G) functional
group at the 5' end of eukaryotic mRNAs. A novel Arabidopsis thaliana protein has
been identified that has sequence similarity to cap-binding proteins but is
clearly a different form of the protein. The most obvious primary sequence
difference is the substitution of two of the eight conserved tryptophan residues
with other aromatic amino acids in the novel protein. Analogous forms of this
novel protein appear to be present in other higher eukaryotes but not in yeast.
Analysis of the native and recombinant forms of the novel protein by retention on
m7GTP-Sepharose indicate that it is a functional cap-binding protein.
Measurements of the dissociation constant for this protein indicate that it binds
m7GTP 5-20-fold tighter than eukaryotic initiation factor (eIF)(iso)4E. The novel
protein also supports the initiation of translation of capped mRNA in vitro.
Biochemical analysis and yeast two-hybrid data indicate that it interacts with
eIF(iso)4G to form a complex. Based on these observations, this protein appears
to be able to function as a cap-binding protein and is given the designation of
novel cap-binding protein (nCBP).
PMID- 9553088
TI - Identification of intron and exon sequences involved in alternative splicing of
insulin receptor pre-mRNA.
AB - The insulin receptor exists as two isoforms, A and B, that result from
alternative splicing of exon 11 in the primary transcript. We have shown
previously that the alternative splicing is developmentally and hormonally
regulated. Consequently, these studies were instigated to identify sequences
within the primary RNA transcript that regulate the alternative splicing.
Minigenes containing exons 10, 11, and 12 and the intervening introns were
constructed and transfected into HepG2 cells, which contain both isoforms of the
insulin receptor. The cells were able to splice the minigene transcript to give
both A (- exon 11) and B-like (+ exon 11) RNAs. A series of internal deletions
within intron 10 were tested for their ability to give A and B RNAs. Intron 10
contained two sequences that modulated exon 11 inclusion; a 48-nucleotide purine
rich sequence at the 5' end of intron 10 that functions as a splicing enhancer
and causes an increase in exon 11 inclusion, and a 43-nucleotide sequence at the
3' end of intron 10 upstream of the branch point sequence that favors skipping of
exon 11. Increasing the length of the polypyrimidine tract at the 3' end of
intron 10 caused exon 11 to be spliced constitutively, indicating that a weak
splice site is required for alternative splicing. Finally, point mutations,
insertions, and deletions within exon 11 itself were able to regulate inclusion
of the exon both positively and negatively.
PMID- 9553089
TI - Granulocyte-macrophage colony-stimulating factor gene transcription is directly
repressed by the vitamin D3 receptor. Implications for allosteric influences on
nuclear receptor structure and function by a DNA element.
AB - The primary function of activated T lymphocytes is to produce various cytokines
necessary to elicit an immune response; these cytokines include interleukin-2 (IL
2), interleukin-4, and granulocyte-macrophage colony-stimulating factor (GMCSF).
Steroid hormones and vitamin A and D3 metabolites act to repress the expression
of cytokines. 1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) down-modulates activated IL
2 expression at the level transcription, through direct antagonism of the
transactivating complex NFAT-1/AP-1 by the vitamin D3 receptor (VDR). We report
here that GMCSF transcription in Jurkat T cells is also directly repressed by 1,
25-(OH)2D3 and VDR. Among four NFAT/AP-1 elements in the GMCSF enhancer, we have
focused on one such element that when multimerized, is sufficient in mediating
both activation by NFAT-1 and AP-1 and repression in response to 1,25-(OH)2D3.
Although this element does not contain any recognizable vitamin D response
elements (VDREs), high affinity DNA binding by recombinant VDR is observed. In
contrast to VDR interactions with positive VDREs, this binding is independent of
VDR's heterodimeric partner, the retinoid X receptor. Moreover, VDR appears to
bind the GMCSF element as an apparent monomer in vitro. Protease digestion
patterns of bound VDR, and receptor mutations affecting DNA binding and
dimerization, demonstrate that the receptor binds to the negative site in a
distinct conformation relative to a positive VDRE, suggesting that the DNA
element itself acts as an allosteric effector of VDR function. This altered
conformation may account for VDR's action as a repressing rather than activating
factor at this locus.
PMID- 9553090
TI - A phosphatidylinositol 3-kinase and phosphatidylinositol transfer protein act
synergistically in formation of constitutive transport vesicles from the trans
Golgi network.
AB - Current evidence suggests that phosphatidylinositol (PI) kinases and
phosphatidylinositol transfer protein (PITP) are involved in driving vesicular
traffic from yeast and mammalian trans-Golgi network (TGN). We have tested the
interaction between these cytosolic proteins in an assay that measures the
formation of constitutive transport vesicles from the TGN in a hepatocyte cell
free system. This reaction is dependent on a novel PI 3-kinase, and we now report
that, under conditions of limiting cytosol, purified PI 3-kinase and PITP
functionally cooperate to drive exocytic vesicle formation. This synergy was
observed with both yeast and mammalian PITPs, and it also extended to the
formation of PI 3-phosphate. These collective findings indicate that the PI 3
kinase and PITP synergize to form a pool of PI 3-phosphate that is essential for
formation of exocytic vesicles from the hepatocyte TGN.
PMID- 9553091
TI - DNA bending by the chromosomal protein HMG1 and its high mobility group box
domains. Effect of flanking sequences.
AB - HMG1 is an evolutionarily highly conserved chromosomal protein consisting of two
folded DNA-binding domains, A and B ("high mobility group (HMG) boxes"), and an
acidic C-terminal domain. Several lines of evidence suggest that previously
reported sequence-independent DNA bending and looping by HMG1 and its HMG box
domains might be important for the proposed role of the protein in transcription
and recombination. We have used ligase-mediated circularization assays to
investigate the contribution of the individual A and B HMG1 box domains and of
the linker region between A/B- and B/C-domains, which flank the "minimal" B
domain (residues 92-162), to the ability of the HMG1 protein (residues 1-215) to
bend DNA. Neither the minimal B-domain nor the minimal B-domain with a 7-residue
N-terminal extension (85TKKKFKD91) bent the DNA. The attachment of an extra 18
residue C-terminal additional extension (residues 163-180) to the minimal B
domain had only a small effect on the ability of the HMG box to bend DNA. On the
other hand, circularization assay with a B-domain having both 7-residue N
terminal and 18-residue C-terminal flanking sequences (residues 85-180) revealed
a strong bending of the DNA, suggesting that both extensions are a prerequisite
for efficient DNA bending by the B-domain. We have also shown that a single
lysine residue (Lys90) in a short N-terminal sequence 90KD91 attached to the B
domain is sufficient for strong distortion of DNA by bending, provided that the B
domain is flanked by the 18-residue C-terminal flanking sequence. Although the
DNA bending potential of HMG1 seems to be predominantly due to the B-domain
flanked by basic sequences, covalent attachment of the A- and B-domains is
necessary for efficient DNA flexure and the ability of the (A+B)-bidomain to bend
DNA is further modulated in the native HMG1 protein by its acidic C-domain.
PMID- 9553092
TI - Inhibition of the expression of mitogen-activated protein phosphatase-1
potentiates apoptosis induced by tumor necrosis factor-alpha in rat mesangial
cells.
AB - Previously we showed that rat mesangial cells are normally resistant to tumor
necrosis factor-alpha (TNF-alpha)-induced apoptosis. They are made susceptible to
the apoptotic effect of TNF-alpha when pretreated with actinomycin D,
cycloheximide or vanadate. A sustained c-Jun N-terminal protein kinase (JNK)
activation was closely correlated with the initiation of apoptosis under these
conditions. We proposed that a TNF-alpha-inducible phosphatase was responsible
for preventing a sustained activation of JNK and consequent apoptosis in these
cells (Guo, Y.-L., Baysal, K., Kang, B. , Yang, L.-J., and Williamson, J. R.
(1998) J. Biol. Chem. 273, 4027-4034). In the present study we provide further
evidence to support this hypothesis. Ro318220, although originally identified as
a specific inhibitor of protein kinase C, was subsequently found to be a strong
inhibitor of MKP-1 expression. In rat mesangial cells, pretreatment of the cells
with Ro318220 blocked expression of MKP-1 induced by TNF-alpha. This treatment
also prolonged JNK activation and caused apoptosis. Taken together, our results
support the currently controversial hypothesis that the JNK pathway is involved
in TNF-alpha-induced apoptosis. In addition, we provide a mechanistic explanation
for how mesangial cells in primary culture achieve resistance to TNF-alpha
cytotoxicity. Specifically, induction of MKP-1 by TNF-alpha appears to be
responsible for protection of the cells from apoptosis by preventing a prolonged
activation of JNK.
PMID- 9553093
TI - Agonist occupation of an alpha2A-adrenoreceptor-Gi1alpha fusion protein results
in activation of both receptor-linked and endogenous Gi proteins. Comparisons of
their contributions to GTPase activity and signal transduction and analysis of
receptor-G protein activation stoichiometry.
AB - A fusion protein between a pertussis toxin-resistant (C351G) mutant of the alpha
subunit of the G protein Gi1 and the porcine alpha2A-adrenoreceptor was stably
expressed in Rat 1 fibroblasts. Agonists caused stimulation of high affinity
GTPase activity, which was partially prevented by pertussis toxin treatment,
demonstrating that the toxin-resistant component of the GTPase activity was
derived from the receptor-fused G protein and the remainder from endogenous
Gialpha. Half-maximal stimulation of the GTPase activity of endogenous Gi was
achieved with lower concentrations of agonist. Although the Km for GTP of the
fusion protein-linked Gi was lower than for the endogenous G protein, Vmax
measurements demonstrated that adrenaline activated some 5 mol of endogenous
Gi/mol of fusion protein-linked Gi. The isolated alpha2A-adrenoreceptor could
activate Gs; however, the fusion protein did not. Compared with adrenaline, the
efficacy of a range of partial agonists to stimulate endogenous Gialpha was
greater than for the fusion protein-constrained C351G Gi1alpha. alpha2A
Adrenoreceptor agonists could stimulate both p44 mitogen-activated protein kinase
and p70 S6 kinase and inhibit forskolin-amplified adenylyl cyclase activity in
untreated alpha2A-adrenoreceptor-C351G Gi1alpha fusion protein-expressing cells,
but these signals were abolished following pertussis toxin treatment. These
results demonstrate conclusively, and for the first time, that agonist occupancy
of a receptor-G protein fusion protein can result in activation of G proteins
other than that physically linked to the receptor. This was selective between G
protein classes. Analysis of the contributions of fusion protein-linked and
endogenous G proteins to agonist-stimulated GTPase activity provided a direct and
original measure of receptor-G protein activation stoichiometry.
PMID- 9553094
TI - The baculovirus anti-apoptotic p35 protein promotes transformation of mouse
embryo fibroblasts.
AB - The baculovirus p35 protein is a potent inhibitor of programmed cell death
induced by a variety of stimuli in insects, nematodes, and mammalian cell lines.
The broad ability of p35 in preventing apoptosis has led us to investigate its
effect on mouse embryo fibroblasts in vitro and in vivo. For this purpose, we
have used R- cells (3T3-like fibroblasts derived from mouse embryos with a
targeted disruption of the insulin-like growth factor I receptor (IGF-IR) genes)
and R508 cells (derived from R- and with 15 x 10(3) IGF-IRs per cell). Both cell
lines grow normally in monolayer, but they do not form colonies in soft agar, and
they are non-tumorigenic in nude mice. We show here that, in addition to its anti
apoptotic effect, p35 causes transformation of R508 cells, as evidenced by the
following: 1) decreased growth factor requirements, 2) ability to form foci in
monolayer and colonies in soft agar, and 3) ability to form tumors in nude mice.
Since R- cells stably transfected with p35 do not transform, our observations
suggest that in addition to its effect as an inhibitor of apoptosis, the
baculovirus p35 protein has transforming potential that requires the presence of
the IGF-IR. The possibility that these two properties could be separated was
confirmed by demonstrating that R508 cells expressing another anti-apoptotic
protein, Bcl-2, could not form tumors in nude mice.
PMID- 9553095
TI - Functional analysis of the Numb phosphotyrosine-binding domain using site
directed mutagenesis.
AB - The Numb protein is involved in cell fate determination during Drosophila neural
development. Numb has a protein domain homologous to the phosphotyrosine-binding
domain (PTB) in the adaptor protein Shc. In Shc, this domain interacts with
specific phosphotyrosine containing motifs on receptor tyrosine kinases and other
signaling molecules. Residues N-terminal to the phosphotyrosine are also crucial
for phosphopeptide binding to the Shc PTB domain. Several amino acid residues in
Shc have been implicated by site-directed mutagenesis to be critical for Shc
binding to receptor tyrosine kinases. We have generated homologous mutations in
Numb to test whether, in vivo, these changes affect Numb function during
Drosophila sensory organ development. Two independent amino acid changes that
interfere with Shc binding to phosphotyrosine residues do not affect Numb
activity in vivo. In contrast, a mutation shown to abrogate the ability of the
Shc PTB domain to bind residues upstream of the phosphotyrosine virtually
eliminates Numb function. Similar results were observed in vitro by examining the
binding of the Numb PTB domain to proteins from Schneider S2 cells. Our data
confirm the importance of the PTB domain for Numb function but strongly suggest
that the Numb PTB domain is not involved in phosphotyrosine-dependent
interactions.
PMID- 9553096
TI - Synchronized spontaneous Ca2+ transients in acute anterior pituitary slices.
AB - We investigated the organization of spontaneous rises in cytosolic free Ca2+
concentration ([Ca2+]i) due to electrical activity in acute pituitary slices.
Real time confocal imaging revealed that 73% of the cells generated fast peaking
spontaneous [Ca2+]i transients. Strikingly, groups of apposing cells enhanced
their [Ca2+]i in synchrony with a speed of coactivation >1,000 microm/s. Single
cell injection of Neurobiotin or Lucifer yellow labeled clusters of cells, which
corresponded to coactive cells. Halothane, a gap junction blocker, markedly
reduced the spread of tracers. Coupling between excitable cells was mainly
homologous in nature, with a prevalence of growth hormone-containing cells. We
conclude that spontaneously active endocrine cells are either single units or
arranged in synchronized gap junction-coupled assemblies scattered throughout the
anterior pituitary gland. Synchrony between spontaneously excitable cells may
help shape the patterns of basal secretion.
PMID- 9553097
TI - Crystal structure of the von Willebrand Factor A1 domain and implications for the
binding of platelet glycoprotein Ib.
AB - von Willebrand Factor (vWF) is a multimeric protein that mediates platelet
adhesion to exposed subendothelium at sites of vascular injury under conditions
of high flow/shear. The A1 domain of vWF (vWF-A1) forms the principal binding
site for platelet glycoprotein Ib (GpIb), an interaction that is tightly
regulated. We report here the crystal structure of the vWF-A1 domain at 2.3-A
resolution. As expected, the overall fold is similar to that of the vWF-A3 and
integrin I domains. However, the structure also contains N- and C-terminal arms
that wrap across the lower surface of the domain. Unlike the integrin I domains,
vWF-A1 does not contain a metal ion-dependent adhesion site motif. Analysis of
the available mutagenesis data suggests that the activator botrocetin binds to
the right-hand face of the domain containing helices alpha5 and alpha6. Possible
binding sites for GpIb are the front and upper surfaces of the domain. Natural
mutations that lead to constitutive GpIb binding (von Willebrand type IIb
disease) cluster in a different site, at the interface between the lower surface
and the terminal arms, suggesting that they disrupt a regulatory region rather
than forming part of the primary GpIb binding site. A possible pathway for
propagating structural changes from the regulatory region to the ligand-binding
surface is discussed.
PMID- 9553098
TI - Characterization of a Ca2+ release-activated nonselective cation current
regulating membrane potential and [Ca2+]i oscillations in transgenically derived
beta-cells.
AB - Although stimulation of insulin secretion by glucose is regulated by coupled
oscillations of membrane potential and intracellular Ca2+ ([Ca2+]i), the membrane
events regulating these oscillations are incompletely understood. In the presence
of glucose and tetraethylammonium, transgenically derived beta-cells (betaTC3
neo) exhibit coupled voltage and [Ca2+]i oscillations strikingly similar to those
observed in normal islets in response to glucose. Using these cells as a model
system, we investigated the membrane conductance underlying these oscillations.
Alterations in delayed rectifier or Ca2+-activated K+ channels were excluded as a
source of the conductance oscillations, as they are completely blocked by
tetraethylammonium. ATP-sensitive K+ channels were also excluded, since the ATP
sensitive K+ channel blocker tolbutamide substituted for glucose in inducing
[Ca2+]i oscillations. Thapsigargin, which depletes intracellular Ca2+ stores, and
maitotoxin, an activator of nonselective cation channels, both converted the
glucose-dependent [Ca2+]i oscillations into a sustained elevation. On the other
hand, both SKF 96365, a blocker of Ca2+ store-operated channels, and external Na+
removal suppressed the glucose-stimulated [Ca2+]i oscillations. Maitotoxin
activated a nonselective cation current in betaTC3 cells that was attenuated by
removal of extracellular Na+ and by SKF 96365, in the same manner to a current
activated in mouse beta-cells following depletion of intracellular Ca2+ stores.
Currents similar to these are produced by the mammalian trp-related channels, a
gene family that includes Ca2+ store-operated channels and inositol 1,4,5
trisphosphate-activated channels. We found several of the trp family genes were
expressed in betaTC3 cells by reverse transcriptase polymerase chain reaction
using specific primers, but by Northern blot analysis, mtrp-4 was the predominant
message expressed. We conclude that a conductance underlying glucose-stimulated
oscillations in beta-cells is provided by a Ca2+ store depletion-activated
nonselective cation current, which is plausibly encoded by homologs of trp genes.
PMID- 9553099
TI - Residues 21-30 within the extracellular N-terminal region of the C5a receptor
represent a binding domain for the C5a anaphylatoxin.
AB - The functions of the C5a anaphylatoxin are expressed through its interaction with
a cell-surface receptor with seven transmembrane helices. The interaction of C5a
with the receptor has been explained by a two-site model whereby recognition and
effector sites on C5a bind, respectively, to recognition and effector domains on
the receptor, leading to receptor activation (Chenoweth, D. E., and Hugli, T. E.
(1980) Mol. Immunol. 17, 151-161. In addition, the extracellular N-terminal
region of the C5a receptor has been implicated as the recognition domain for C5a,
responsible for approximately 50% of the binding energy of the C5a-receptor
complex (Mery, L., and Boulay, F. (1994) J. Biol. Chem. 269, 3457-3463;
DeMartino, J. A., Van Riper, G., Siciliano, S. J., Molineaux, C. J., Konteatis,
Z. D., Rosen, H., and Springer, M. S. (1994) J. Biol. Chem. 269, 14446-14450). In
this work, the interactions of C5a with the N-terminal domain of the C5a receptor
were examined by use of recombinant human C5a molecules and peptide fragments
M1NSFN5YTTPD10YGHYD15DKDTL20DLNTP25VDKTS30NTLR(hC5aRF-1-34), acetyl
HYD15DKDTL20DLNTP25VDKTS30NTLR (hC5aRF-13-34), and acetyl-TL20DLNTP25VDKTS30N
amide (hC5aRF-19-31) derived from human C5a receptor. Binding induced resonance
perturbations in the NMR spectra of the receptor fragments and the C5a molecules
indicated that the isolated Nterminal domain or residues 1-34 of the C5a receptor
retain specific binding to C5a and to a C5a analog devoid of the agonistic C
terminal tail in the intact C5a. Residues of C5a perturbed by the binding of the
receptor peptides are localized within the helical core of the C5a structure, in
agreement with the results from functional studies employing mutated C5a and
intact receptor molecules. All three receptor peptides, hC5aRF-1-34, hC5aRF-13
34, and hC5aRF-19-31, responded to the binding of C5a through the 21-30 region
containing either hydrophobic, polar, or positively charged residues such as
Thr24, Pro25, Val26, Lys28, Thr29, and Ser30. The 21-30 segment of all three
receptor fragments was found to have a partially folded conformation in solution,
independent of residues 1-18. These results indicate that a short peptide
sequence, or residues 21-30, of the C5a receptor N terminus may constitute the
binding domain for the recognition site on C5a.
PMID- 9553100
TI - Addressing the tertiary structure of human parathyroid hormone-(1-34).
AB - Parathyroid hormone (PTH) regulates mineral metabolism and bone turnover by
activating specific receptors located on osteoblastic and renal tubular cells and
is fully functional as the N-terminal 1-34 fragment, PTH-(1-34). Previously, a "U
shaped" conformation with N- and C-terminal helices brought in close proximity by
a turn has been postulated. The general acceptance of this hypothesis, despite
limited experimental evidence, has altered the direction of the design of PTH
analogs. Examining the structure of human PTH-(1-34) under conditions that
encompass the different environments the hormone may experience in the approach
to and interaction with the G-protein-coupled receptor (including benign aqueous
and saline solutions and in the presence of dodecylphosphocholine), we observe no
evidence for a U-shape conformation or any tertiary structure. Instead, the N-
and C-terminal helical domains, which vary in length and stability depending on
the conditions, are separated by a highly flexible region of undefined
conformation. These observations are in complete accord with recent
conformational studies of PTH-related protein analogs containing lactams (Mierke,
D. F., Maretto, S., Schievano, E. , DeLuca, D., Bisello, A., Mammi, S.,
Rosenblatt, M., Peggion, E., and Chorev, M. (1997) Biochemistry 36, 10372-10383)
or a model amphiphilic alpha-helix (Pellegrini, M., Bisello, A., Rosenblatt, M.,
Chorev, M., and Mierke, D. F. (1997) J. Med. Chem. 40, 3025-3031). Reliable
structural data from different environmental conditions are absolutely requisite
for the next step in the design of non-peptide PTH analogs.
PMID- 9553101
TI - Identification of a ligand binding site in the human neutrophil formyl peptide
receptor using a site-specific fluorescent photoaffinity label and mass
spectrometry.
AB - A novel fluorescent photoaffinity cross-linking probe, formyl-Met-p-benzoyl-L
phenylalanine-Phe-Tyr-Lys-epsilon-N-fluorescei n (fMBpaFYK-fl), was synthesized
and used to identify binding site residues in recombinant human phagocyte
chemoattractant formyl peptide receptor (FPR). After photoactivation, fluorescein
labeled membranes from Chinese hamster ovary cells were solubilized in
octylglucoside and separated by tandem anion exchange and gel filtration
chromatography. A single peak of fluorescence was observed in extracts of FPR
expressing cells that was absent in extracts from wild type controls.
Photolabeled Chinese hamster ovary membranes were cleaved with CNBr, and the
fluorescent fragments were isolated on an antifluorescein immunoaffinity matrix.
Matrix-assisted laser desorption ionization mass spectrometry identified a major
species with mass = 1754, consistent with the CNBr fragment of fMBpaFYK-fl cross
linked to Val-Arg-Lys-Ala-Hse (an expected CNBr fragment of FPR, residues 83-87).
This peptide was further cleaved with trypsin, repurified by antifluorescein
immunoaffinity, and subjected to matrix-assisted laser desorption ionization mass
spectrometry. A tryptic fragment with mass = 1582 was observed, which is the mass
of fMBpaFYK-fl cross-linked to Val-Arg-Lys (FPR residues 83-85), an expected
trypsin cleavage product of Val-Arg-Lys-Ala-Hse. Residues 83-85 lie within the
putative second transmembrane-spanning region of FPR near the extracellular
surface. A 3D model of FPR is presented, which accounts for intramembrane, site
directed mutagenesis results (Miettinen, H. M., Mills, J., Gripentrog, J., Dratz,
E. A., Granger, B. L., and Jesaitis, A. J. (1997) J. Immunol. 159, 4045-4054) and
the photochemical cross-linking data.
PMID- 9553102
TI - Mitogen-activated protein kinase pathway is involved in the differentiation of
muscle cells.
AB - The differentiation of muscle cells is controlled by the MyoD family of
transcription factors. This family is regulated by extracellular growth factors
that transmit largely unknown signals into the cells. Here we show that the
activity of extracellular signal-regulated protein kinase (ERK), a kinase that is
part of the mitogen-activated protein kinase (MAPK) cascade, is low in myoblasts
and is induced with the onset of terminal differentiation of C2 cells. ERK
activity is also induced in fibroblasts that were modified to express MyoD, but
not in the parental fibroblast cells. Thus, ERK induction is an intrinsic
property of muscle cells. A specific MAPK kinase inhibitor (PD098059) that was
added to C2 cells partially inhibited the fusion of myoblasts to multinucleated
myotubes without affecting the expression of muscle-specific markers. This
inhibitor blocked the induction of MyoD expression that normally takes place
during terminal differentiation. Two lines of evidence suggest that the MAPK
cascade induces the activity of MyoD: 1) the expression of constitutively
activated forms of MEK1 or Raf1 enhanced the transcriptional activity of MyoD in
10T1/2 fibroblasts; and 2) the addition of PD098059 to fibroblast cells
expressing a conditional MyoD-estrogen fusion protein significantly inhibited the
expression of MyoD-responsive genes. Our results indicate that the MAPK pathway
is activated in differentiating muscle cells and that it positively regulates the
expression and activity of MyoD protein.
PMID- 9553103
TI - Functional microdomains in G-protein-coupled receptors. The conserved arginine
cage motif in the gonadotropin-releasing hormone receptor.
AB - An Arg present in the third transmembrane domain of all rhodopsin-like G-protein
coupled receptors is required for efficient signal transduction. Mutation of this
Arg in the gonadotropin-releasing hormone receptor to Gln, His, or Lys abolished
or severely impaired agonist-stimulated inositol phosphate generation, consistent
with Arg having a role in receptor activation. To investigate the contribution of
the surrounding structural domain in the actions of the conserved Arg, an
integrated microdomain modeling and mutagenesis approach has been utilized. Two
conserved residues that constrain the Arg side chain to a limited number of
conformations have been identified. In the inactive wild-type receptor, the Arg
side chain is proposed to form an ionic interaction with Asp3.49(138).
Experimental results for the Asp3. 49(138) --> Asn mutant receptor show a
modestly enhanced receptor efficiency, consistent with the hypothesis that
weakening the Asp3. 49(138)-Arg3.50(139) interaction by protonation of the Asp or
by the mutation to Asn favors activation. With activation, the Asp3. 49(138)
Arg3.50(139) ionic bond would break, and the unrestrained Arg would be prevented
from orienting itself toward the water phase by a steric clash with Ile3.54(143).
The mutation Ile3.54(143) --> Ala, which eliminates this clash in simulations,
causes a marked reduction in measured receptor signaling efficiency, implying
that solvation of Arg3.50(139) prevents it from functioning in the activation of
the receptor. These data are consistent with residues Asp3.49(138) and
Ile3.54(143) forming a structural motif, which helps position Arg in its
appropriate inactive and active receptor conformations.
PMID- 9553104
TI - Visualization of the cysteinyl-phosphate intermediate of a protein-tyrosine
phosphatase by x-ray crystallography.
AB - Protein-tyrosine phosphatases (PTPs) are signal transduction enzymes that
catalyze the dephosphorylation of phosphotyrosine residues via the formation of a
transient cysteinyl-phosphate intermediate. The mechanism of hydrolysis of this
intermediate has been examined by generating a Gln-262 --> Ala mutant of PTP1B,
which allows the accumulation and trapping of the intermediate within a PTP1B
crystal. The structure of the intermediate at 2.5-A resolution reveals that a
conformationally flexible loop (the WPD loop) is closed over the entrance to the
catalytic site, sequestering the phosphocysteine intermediate and catalytic site
water molecules and preventing nonspecific phosphoryltransfer reactions to
extraneous phosphoryl acceptors. One of the catalytic site water molecules, the
likely nucleophile, forms a hydrogen bond to the putative catalytic base, Asp
181. In the wild-type enzyme, the nucleophilic water molecule would be
coordinated by the side chain of Gln-262. In combination with our previous
structural data, we can now visualize each of the reaction steps of the PTP
catalytic pathway. The hydrolysis of the cysteinyl-phosphate intermediate of PTPs
is reminiscent of GTP hydrolysis by the GTPases, in that both families of enzymes
utilize an invariant Gln residue to coordinate the attacking nucleophilic water
molecule.
PMID- 9553105
TI - In vivo regulation of the IkappaB homologue cactus during the immune response of
Drosophila.
AB - The dorsoventral regulatory gene pathway (spatzle/Toll/cactus) controls the
expression of several antimicrobial genes during the immune response of
Drosophila. This regulatory cascade shows striking similarities with the cytokine
induced activation cascade of NF-kappaB during the inflammatory response in
mammals. Here, we have studied the regulation of the IkappaB homologue Cactus in
the fat body during the immune response. We observe that the cactus gene is up
regulated in response to immune challenge. Interestingly, the expression of the
cactus gene is controlled by the spatzle/Toll/cactus gene pathway, indicating
that the cactus gene is autoregulated. We also show that two Cactus isoforms are
expressed in the cytoplasm of fat body cells and that they are rapidly degraded
and resynthesized after immune challenge. This degradation is also dependent on
the Toll signaling pathway. Altogether, our results underline the striking
similarities between the regulation of IkappaB and cactus during the immune
response.
PMID- 9553106
TI - Acrosin accelerates the dispersal of sperm acrosomal proteins during acrosome
reaction.
AB - Using homologous recombination, we have previously produced male mice carrying a
disruptive mutation (Acr-/-) in the acrosin gene. Although Acr-/- mouse sperm
lacking the acrosin protease activity still penetrated the zona pellucida and
fertilized the egg, the mutant sperm exhibited a delay in penetration of the zona
pellucida solely at the early stages after insemination. To further elucidate the
role of acrosin in fertilization, we have examined the involvement of acrosin in
the acrosome reaction of sperm using the Acr-/- mutant mice. When the ability of
sperm to adhere (attach) and bind to the zona pellucida of cumulus-free eggs was
assessed in vitro, no significant difference was observed among Acr+/+, Acr+/-,
and Acr-/- mouse sperm. Immunocytochemical analysis demonstrated that the release
of several acrosomal proteins from the acrosome of Acr-/- mouse sperm was
significantly delayed during the calcium ionophore- and solubilized zona
pellucida-induced acrosome reaction, despite normal membrane vesiculation. These
data indicate that the delayed sperm penetration of the zona pellucida in the Acr
/- mouse results from the altered rate of protein dispersal from the acrosome and
provide the first evidence that the major role of acrosin is to accelerate the
dispersal of acrosomal components during acrosome reaction.
PMID- 9553107
TI - Interaction of the Grb10 adapter protein with the Raf1 and MEK1 kinases.
AB - Grb10 and its close homologues Grb7 and Grb14, belong to a family of adapter
proteins characterized by a proline-rich region, a central PH domain, and a
carboxyl-terminal Src homology 2 (SH2) domain. Their interaction with a variety
of activated tyrosine kinase receptors is well documented, but their actual
function remains a mystery. The Grb10 SH2 domain was isolated from a two-hybrid
screen using the MEK1 kinase as a bait. We show that this unusual SH2 domain
interacts, in a phosphotyrosine-independent manner, with both the Raf1 and MEK1
kinases. Mutation of the MEK1 Thr-386 residue, which is phosphorylated by mitogen
activated protein kinase in vitro, reduces binding to Grb10 in a two-hybrid
assay. Interaction of Grb10 with Raf1 is constitutive, while interaction between
Grb10 and MEK1 needs insulin treatment of the cells and follows mitogen-activated
protein kinase activation. Random mutagenesis of the SH2 domain demonstrated that
the Arg-betaB5 and Asp-EF2 residues are necessary for binding to the epidermal
growth factor and insulin receptors as well as to the two kinases. In addition,
we show that a mutation in Ser-betaB7 affects binding only to the receptors,
while a mutation in Thr-betaC5 abrogates binding only to MEK1. Finally,
transfection of Grb10 genes with specific mutations in their SH2 domains induces
apoptosis in HTC-IR and COS-7 cells. These effects can be competed by co
expression of the wild type protein, suggesting that these mutants act by
sequestering necessary signaling components.
PMID- 9553108
TI - Caveolae, plasma membrane microdomains for alpha-secretase-mediated processing of
the amyloid precursor protein.
AB - Caveolae are plasma membrane invaginations where key signaling elements are
concentrated. In this report, both biochemical and histochemical analyses
demonstrate that the amyloid precursor protein (APP), a source of Abeta amyloid
peptide, is enriched within caveolae. Caveolin-1, a principal component of
caveolae, is physically associated with APP, and the cytoplasmic domain of APP
directly participates in this binding. The characteristic C-terminal fragment
that results from APP processing by alpha-secretase, an as yet unidentified
enzyme that cleaves APP within the Abeta amyloid sequence, was also localized
within these caveolae-enriched fractions. Further analysis by cell surface
biotinylation revealed that this cleavage event occurs at the cell surface.
Importantly, alpha-secretase processing was significantly promoted by recombinant
overexpression of caveolin in intact cells, resulting in increased secretion of
the soluble extracellular domain of APP. Conversely, caveolin depletion using
antisense oligonucletotides prevented this cleavage event. Our current results
indicate that caveolae and caveolins may play a pivotal role in the alpha
secretase-mediated proteolysis of APP in vivo.
PMID- 9553109
TI - Epiregulin is a potent pan-ErbB ligand that preferentially activates
heterodimeric receptor complexes.
AB - The ErbB signaling network consists of four transmembrane receptor tyrosine
kinases and more than a dozen ligands sharing an epidermal growth factor (EGF)
motif. The multiplicity of ErbB-specific ligands is incompletely understood in
terms of signal specificity because all ErbB molecules signal through partially
overlapping pathways. Here we addressed the action of epiregulin, a recently
isolated ligand of ErbB-1. By employing a set of factor-dependent cell lines
engineered to express individual ErbBs or their combinations, we found that
epiregulin is the broadest specificity EGF-like ligand so far characterized: not
only does it stimulate homodimers of both ErbB-1 and ErbB-4, it also activates
all possible heterodimeric ErbB complexes. Consistent with its relaxed
selectivity, epiregulin binds the various receptor combinations with an affinity
that is approximately 100-fold lower than the affinity of ligands with more
stringent selectivity, including EGF. Nevertheless, epiregulin's action upon most
receptor combinations transmits a more potent mitogenic signal than does EGF.
This remarkable discrepancy between binding affinity and bioactivity is permitted
by a mechanism that prevents receptor down-regulation, and results in a weak, but
prolonged, state of receptor activation.
PMID- 9553110
TI - Interaction of transcription factors with serum response factor. Identification
of the Elk-1 binding surface.
AB - Serum response elements (SREs) play important roles in transforming extracellular
signals into specific nuclear responses. The SRE-binding protein, serum response
factor (SRF), plays a pivotal role in this process. Several transcription factors
have been shown to interact with SRF and thereby create distinct complexes with
different regulatory potentials. The ETS domain transcription factor Elk-1 is one
such protein and serves to integrate distinct mitogen-activated protein kinase
cascades at SREs. Elk-1 uses a short hydrophobic surface presented on the surface
of an alpha-helix to interact with SRF. In this study we have used site-directed
mutagenesis to identify residues in SRF that comprise the Elk-1 binding surface.
The Elk-1 binding surface is composed of residues that lie on a hydrophobic
surface-exposed groove located at the junction of the MADS box and C-terminal SAM
motif. Different residues are implicated in interactions between SRF and the
transcription factor Fli-1, indicating that although some overlap with the Elk-1
binding surface occurs, their interaction surfaces on SRF are distinct. Our data
are consistent with the hypothesis that the SRF DNA-binding domain acts as
docking site for multiple transcription factors that can bind to small surface
exposed patches within this domain.
PMID- 9553111
TI - Does single-stranded DNA pass through the inner channel of the protein hexamer in
the complex with the Escherichia coli DnaB Helicase? Fluorescence energy transfer
studies.
AB - The structure of the complex of the Escherichia coli primary replicative helicase
DnaB protein with single-stranded (ss) DNA and replication fork substrates has
been examined using the fluorescence energy transfer method. In these
experiments, we used the DnaB protein variant, R14C, which has arginine 14
replaced by cysteine in the small 12-kDa domain of the protein using site
directed mutagenesis. The cysteine residues have been modified with a fluorescent
marker which serves as a donor or an acceptor to another fluorescence label
placed in different locations on the DNA substrates. Using the multiple
fluorescence donor-acceptor approach, we provide evidence that, in the complex
with the enzyme, ssDNA passes through the inner channel of the DnaB hexamer. This
is the first evidence of the existence of such a structure of a hexameric
helicase-ssDNA complex in solution. In the stationary complex with the 5' arm of
the replication fork, without ATP hydrolysis, the distance between the 5' end of
the arm and the 12-kDa domains of the hexamer (R = 47 A) is the same as in the
complex with the isolated ssDNA oligomer (R = 47 A) having the same length as the
arm of the fork. These data indicate that both ssDNA and the 5' arm of the fork
bind in the same manner to the DNA binding site. Moreover, in the complex with
the helicase, the length of the ssDNA is similar to the length of the ssDNA
strand in the double-stranded DNA conformation. In the stationary complex, the
helicase does not invade the duplex part of the fork beyond the first 2-3 base
pairs. This result corroborates the quantitative thermodynamic data which showed
that the duplex part of the fork does not contribute to the free energy of
binding of the enzyme to the fork. Implications of these results for the
mechanism of a hexameric helicase binding to DNA are discussed.
PMID- 9553112
TI - Molecular cloning, characterization, and promoter analysis of the mouse
Crp2/SmLim gene. Preferential expression of its promoter in the vascular smooth
muscle cells of transgenic mice.
AB - Several members of the LIM protein family have important roles in development and
differentiation. We recently isolated a rat cDNA encoding a new member of this
family, CRP2/SmLIM, that contains two LIM domains and is expressed preferentially
in vascular smooth muscle cells (VSMC). To study the molecular mechanisms that
regulate VSMC-specific transcription of the Crp2/SmLim gene, we cloned the cDNA
and gene of mouse Crp2/SmLim. Mouse Crp2/SmLim is a single copy gene of six exons
and five introns spanning approximately 20 kilobases of genomic DNA. By 5'-rapid
amplification of cDNA ends and S1 nuclease protection assay, we determined that
the transcription start site is an A residue 80 base pairs 5' of the translation
initiation codon. A TATA-like sequence is located 27 base pairs 5' of the
transcription start site, and there are potential cis-acting elements (GATA, Sp1,
AP-2, E box, CCAC box, and GArC motif) in the 5'-flanking sequence. In transient
transfection assays in rat aortic smooth muscle cells in primary culture, 5
kilobases of the Crp2/SmLim 5'-flanking sequence generated a high level of
luciferase reporter gene activity. By deletion analysis and gel mobility shift
assay, we found that the region between bases -74 and -39 of this 5 kilobase DNA
fragment binds Sp1 and confers basal promoter activity in the Crp2/SmLim gene. In
vitro, the 5-kilobase fragment was active in multiple cell types. In vivo,
however, the 5-kilobase fragment directed high level expression of the lacZ
reporter gene preferentially in the VSMC of transgenic mice, indicating the
presence of VSMC-specific element(s) in this fragment.
PMID- 9553113
TI - Multiple isoforms of eukaryotic protein synthesis initiation factor 4E in
Caenorhabditis elegans can distinguish between mono- and trimethylated mRNA cap
structures.
AB - The rate-limiting step for cap-dependent translation initiation in eukaryotes is
recruitment of mRNA to the ribosome. An early event in this process is
recognition of the m7GTP-containing cap structure at the 5'-end of the mRNA by
initiation factor eIF4E. In the nematode Caenorhabditis elegans, mRNAs from 70%
of the genes contain a different cap structure, m32,2,7GTP. This cap structure is
poorly recognized by mammalian elF4E, suggesting that C. elegans may possess a
specialized form of elF4E that can recognize m32,2,7GTP. Analysis of the C.
elegans genomic sequence data base revealed the presence of three elF4E-like
genes, here named ife-1, ife-2, and ife-3. cDNAs for these three eIF4E isoforms
were cloned and sequenced. Isoform-specific antibodies were prepared from
synthetic peptides based on nonhomologous regions of the three proteins. All
three eIF4E isoforms were detected in extracts of C. elegans and were retained on
m7GTP-Sepharose. One eIF4E isoform, IFE-1, was also retained on m32,2,7GTP
Sepharose. Furthermore, binding of IFE-1 and IFE-2 to m7GTP-Sepharose was
inhibited by m32,2,7GTP. These results suggest that IFE-1 and IFE-2 bind both
m7GTP- and m32,2, 7GTP-containing mRNA cap structures, although with different
affinities. In conjunction with IFE-3, these eIF4E isoforms would permit cap
dependent recruitment of all C. elegans mRNAs to the ribosome.
PMID- 9553115
TI - The role of an inverted CCAAT element in transcriptional activation of the human
DNA topoisomerase IIalpha gene by heat shock.
AB - Expression of the DNA topoisomerase IIalpha (topoIIalpha) gene is highly
sensitive to various environmental stimuli including heat shock. The amount of
topoIIalpha mRNA was increased 1.5-3-fold 6-24 h after exposure of T24 human
urinary bladder cancer cells to heat shock stress at 43 degreesC for 1 h. The
effect of heat shock on the transcriptional activity of the human topoIIalpha
gene promoter was investigated by transient transfection of T24 cells with
luciferase reporter plasmids containing various lengths of the promoter sequence.
The transcriptional activity of the full-length promoter (nucleotides (nt) -295
to +85) and of three deletion constructs (nt -197 to +85, -154 to +85, and -74 to
+85) was increased approximately 3-fold 24 h after heat shock stress. In
contrast, the transcriptional activity of the minimal promoter (nt -20 to +85),
which lacks the first inverted CCAAT element (ICE1), the GC box, and the heat
shock element located between nt -74 and -21, was not increased by heat shock.
Furthermore, the transcriptional activity of promoter constructs containing
mutations in the GC box or heat shock element, but not that of a construct
containing mutations in ICE1, was significantly increased by heat shock.
Electrophoretic mobility shift assays revealed reduced binding of a nuclear
factor to an oligonucleotide containing ICE1 when nuclear extracts were derived
from cells cultured for 3-24 h after heat shock. No such change in factor binding
was apparent with an oligonucleotide containing the heat shock element of the
topoIIalpha gene promoter. Finally, in vivo footprint analysis of the topoIIalpha
gene promoter revealed that two G residues of ICE1 that were protected in control
cells became sensitive to dimethyl sulfate modification after heat shock. These
results suggest that transcriptional activation of the topoIIalpha gene by heat
shock requires the release of a negative regulatory factor from ICE1.
PMID- 9553114
TI - Expression and conservation of apolipoprotein AIV in an avian species.
AB - In birds, intestinally derived lipoproteins are thought to be secreted directly
into the portal vein rather than to enter the circulation via the lymphatic
system as in mammals. Hepatic clearance of these so-called portomicrons must be
rapid, but the protein(s) mediating their catabolism, presumably analogues of the
36-kDa mammalian apolipoprotein E, have not been identified. In searching for
such a mediator(s), we have isolated a hitherto unknown 38-kDa protein from
chicken serum, which we identified by microsequencing and molecular cloning as a
counterpart to mammalian apolipoprotein AIV (apoAIV). Mature chicken apoAIV
consists of 347 amino acids, lacks cysteine residues, and displays 57% sequence
identity with human apoAIV and, to a significantly lesser extent, with apoAIVs of
rodents. This first nonmammalian apoAIV characterized is the smallest homologue
reported so far, because of the lack of repeated motifs at the carboxyl terminus
with the consensus sequence Glu-Gln-Glu/Ala-Gln, a hallmark of mammalian apoAIVs.
Chicken apoAIV (isoelectric point, 4.65) is also considerably more acidic than
its human counterpart. Agarose gel electrophoresis revealed that unlike human
apoAIV, which migrates to a pre-alpha-position, chicken apoAIV shows fast alpha
migration. Functional characterization demonstrated that the avian protein is
able to activate the enzyme lecithin:cholesterol acyltransferase. Roosters and
hens express apoAIV predominantly in the gut, one-fifth as much in the liver, and
no other sites of expression are identifiable by Northern blot analysis. Although
pronounced intestinal synthesis is common to apoAIVs, the features of the avian
protein support the notion that it represents a prototype of an apoprotein that
evolved to acquire possibly distinct functions in mammals and birds.
PMID- 9553116
TI - Two signaling mechanisms for activation of alphaM beta2 avidity in
polymorphonuclear neutrophils.
AB - Circulating polymorphonuclear neutrophils (PMN) are quiescent, nonadherent cells
that rapidly activate at sites of inflammation, where they develop the capacity
to perform a repertoire of functions that are essential for host defense.
Induction of integrin-mediated adhesion, which requires an increase in integrin
avidity, is critical for the development of these effector functions. Although a
variety of stimuli can activate integrins in PMN, the signaling cascades involved
are unclear. Phosphatidylinositol (PI) 3-kinase has been implicated in integrin
activation in a variety of cells, including PMN. In this work, we have examined
activation of the PMN integrin alphaM beta2, assessing both adhesion and
generation of the epitope recognized by the activation-specific antibody CBRM1/5.
We have found that PI 3-kinase has a role in activation of alphaM beta2 by immune
complexes, but we have found no role for it in alphaM beta2 activation by ligands
for trimeric G protein-coupled receptors, including
formylmethionylleucylphenylalanine (fMLP), interleukin-8, and C5a. Cytochalasin D
inhibition suggests a role for the actin cytoskeleton in immune complex
activation of alphaM beta2, but cytochalasin has no effect on fMLP-induced
activation. Similarly, immune complex activation of the Rac/Cdc42-dependent
serine/threonine kinase Pak1 is blocked by PI 3-kinase inhibitors, but fMLP
induced activation is not. These results demonstrate that two signaling pathways
exist in PMN for activation of alphaM beta2. One, induced by FcgammaR ligation,
is PI 3-kinase-dependent and requires the actin cytoskeleton. The second,
initiated by G protein-linked receptors, is PI 3-kinase-independent and
cytochalasin-insensitive. Pak1 may be in a final common pathway leading to
activation of alphaM beta2.
PMID- 9553117
TI - Modulation of protein splicing of the Saccharomyces cerevisiae vacuolar membrane
ATPase intein.
AB - Protein splicing of the Saccharomyces cerevisiae vacuolar membrane ATPase intein
involves four highly coordinated reactions that result in precise cleavage and
formation of peptide bonds. In this study, we investigated the roles of the last
N-extein residue (-1 residue) and the intein penultimate residue in modulating
splicing reactions. Most of the 20 amino acid substitutions at the -1 position
had no effect on overall protein splicing but could lead to significant
accumulation of thioester intermediates when splicing was blocked by mutation. A
subset of -1 substitutions attenuated the initiation of protein splicing and
enabled us to demonstrate in vitro splicing of a mesophilic intein containing all
wild-type catalytic residues. Substitutions involving the intein penultimate
residue allowed modulation of the branch resolution and C-terminal cleavage
reaction. Our data suggest that the N-S acyl rearrangement, which initiates
splicing, may also serve as the rate-limiting step. Through appropriate amino
acid substitutions, we were able to modulate splicing reactions in vitro by
change in pH or temperature or addition of thiol reagents. Both insertion and
deletion were tolerated in the central region of the intein although splicing or
structure of the intein may have been affected.
PMID- 9553118
TI - The M4M5 cytoplasmic loop of the Na,K-ATPase, overexpressed in Escherichia coli,
binds nucleoside triphosphates with the same selectivity as the intact native
protein.
AB - Escherichia coli was used to overexpress the large cytoplasmic loop of the rat
Na,K-ATPase. A 1260-base DNA segment encoding Lys354-Lys774 of the rat alpha1
subunit was constructed via polymerase chain reaction. The polymerase chain
reaction product was successfully subcloned into the expression vector pET-28
(Novagen), which produces an N-terminal 6-histidine-tagged fusion protein. The
pET-28 vector containing rat alpha-loop, i.e. pAN, was used to transform calcium
competent E. coli BL21(DE3) cells, and positive clones were selected by kanamycin
resistance. Bacterial cultures were grown, and protein synthesis was induced with
isopropyl beta-D-thiogalactoside. Cells were harvested and lysed, revealing
production of the His-tagged fusion protein ( approximately 46 kDa). The fusion
protein was affinity-purified from other soluble cellular proteins via a Ni-NTA
column, which routinely yielded approximately 20 mg of soluble His6-alpha-loop/L
cell culture. The His6-alpha-loop retained significant native structure, as
evidenced by the ability of ATP and ADP (but not AMP, CTP, GTP, or UTP) to
protect against chemical modification by either fluorescein isothiocyanate or
maleimidylanilinonapthalene sulfonic acid. More specifically, circular dichroism
spectroscopy was used to estimate the secondary structure of the His6 loop,
revealing an ordered folding composed of 23% alpha-helix, 23% antiparallel beta
sheet, 4% parallel beta-sheet, 19% beta-turn, and 32% random coil. The 6
histidine loop bound the fluorescent ATP analog trinitrophenyl-ATP with high
affinity, as determined by measuring the fluorescence changes associated with
binding. Affinities for ATP ( approximately 350 microM) and ADP ( approximately
550 microM) were determined by their ability to compete with and displace 2',3'-O
[2,4,6,-trinitrophenyl]-ATP. These nucleotide affinities are similar to those
observed for the E2 conformation of the intact Na,K-ATPase.
PMID- 9553119
TI - Transcriptional regulation of insulin-like growth factor-II gene expression by
cortisol in fetal sheep during late gestation.
AB - The objective of this study was to determine the mechanisms by which cortisol
down-regulates hepatic insulin-like growth factor-II (IGF-II) gene expression in
late gestation. Leader exons 6 and 7 of the ovine IGF-II gene, with their 5'
flanking regions, were first isolated. Characterization of transcription start
sites revealed a unique site for exon 6 and three dispersed sites for exon 7.
Nuclear run-on assays showed a 5-fold higher transcription rate of the IGF-II
gene in liver of adrenalectomized fetuses compared with control animals,
suggesting that regulation of IGF-II gene expression by cortisol is at the
transcriptional level. RNase protection assays demonstrated hepatic leader exon 7
expression in adrenalectomized fetuses to be more than 2-fold higher than in
controls, whereas it was reduced by 50% in cortisol-infused fetuses compared with
controls. There was no effect on the expression of other leader exons. Functions
of the upstream regulatory region of leader exon 7 (i.e. promoter P4) were
investigated by luciferase transient expression. A region of -172 bases
downstream relative to the first transcription site of leader exon 7 was shown to
retain basal promoter activity and respond to cortisol. These results suggest
that cortisol may induce the prenatal decline in ovine hepatic IGF-II expression
by suppressing promoter P4 of the IGF-II gene.
PMID- 9553120
TI - Regulatory properties of the NH2- and COOH-terminal domains of troponin T. ATPase
activation and binding to troponin I and troponin C.
AB - The contraction of skeletal muscle is regulated by Ca2+ binding to troponin C,
which results in an internal reorganization of the interactions within the
troponin-tropomyosin complex. Troponin T is necessary for Ca2+-dependent
inhibition and activation of actomyosin. Troponin T consists of an extended NH2
terminal domain that interacts with tropomyosin and a globular COOH-terminal
domain that interacts with tropomyosin, troponin I, and troponin C. In this study
we used recombinant troponin T and troponin I fragments to delimit further the
structural and regulatory interactions with the thin filament. Our results show
the following: (i) the NH2-terminal region of troponin T activates the actomyosin
ATPase in the presence of tropomyosin; (ii) the interaction of the globular
domain of troponin T with the thin filament blocks ATPase activation in the
absence of Ca2+; and (iii) the COOH-terminal region of the globular domain
anchors the troponin C-troponin I binary complex to troponin T through a direct
Ca2+-independent interaction with the NH2-terminal region of troponin I. This
interaction is required for Ca2+-dependent activation of the actomyosin ATPase
activity. Based on these results we propose a refined model for the troponin
complex and its interaction with the thin filament.
PMID- 9553121
TI - Tenascin-C hexabrachion assembly is a sequential two-step process initiated by
coiled-coil alpha-helices.
AB - We have investigated the oligomerization process of tenascin-C using a variety of
recombinant wild-type and mutant polypeptide chain fragments produced by
heterologous gene expression in Escherichia coli. Biochemical and biophysical
analyses of the structures and assemblies of these fragments indicated a
sequential two-step oligomerization mechanism of tenascin-C involving the
concerted interaction of two distinct domains and cysteines 64, 111, and 113.
First, the sequence between alanine 114 and glutamine 139 initiates hexabrachion
formation via a parallel three-stranded coiled coil. Subsequently, the tenascin
assembly domain, which is unique to the tenascins, is responsible for the
connection of two triplets to a hexamer. The oligomerization of the tenascin
assembly domains by the three-stranded coiled coil increases their homophilic
binding affinity and is an important prerequisite for tenascin-C hexamerization.
Although formation of the characteristic hexabrachion structure involves the
covalent linkage of the six subunits by cysteine residues, mutational analysis
indicates that hexamer formation is not dependent on intermolecular disulfide
bonds. Most interestingly, substitution of glutamate 130 within the coiled-coil
domain by leucine or alanine resulted in the formation of parallel four-stranded
helix structures, which further associated to dodecamers. Aside from supporting a
sequential process of tenascin-C assembly, this finding provides experimental
evidence that non-core residues can have profound effects on the oligomerization
states of coiled coils.
PMID- 9553122
TI - Importance of glucose-6-phosphate dehydrogenase activity for cell growth.
AB - The intracellular redox potential, which is determined by the level of oxidants
and reductants, has been shown to play an important role in the regulation of
cell growth. The principal intracellular reductant is NADPH, which is mainly
produced by the pentose phosphate pathway through the actions of glucose-6
phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate
pathway, and by 6-phosphogluconate dehydrogenase. Previous research has suggested
that an increase in G6PD activity is important for cell growth. In this article,
we suggest that G6PD activity plays a critical role in cell growth by providing
NADPH for redox regulation. The results show the following: 1) inhibition of G6PD
activity abrogated growth factor stimulation of [3H]thymidine incorporation in
all cell lines tested; 2) overexpression of G6PD stimulated cell growth, as
measured by an increase in [3H]thymidine incorporations as compared with cells
transfected with vector alone; 3) inhibition of G6PD caused cells to be more
susceptible to the growth inhibitory effects of H2O2; 4) inhibition of G6PD led
to a 30-40% decrease in the NADPH/NADP ratio; and 5) inhibition of G6PD inhibited
cell anchorage and significantly decreased the growth-related stimulation of
tyrosine phosphorylation.
PMID- 9553124
TI - Syndecan-4 proteoglycan cytoplasmic domain and phosphatidylinositol 4,5
bisphosphate coordinately regulate protein kinase C activity.
AB - Phosphatidylinositol 4,5-bisphosphate (PIP2) is involved in the organization of
the actin cytoskeleton by regulating actin-associated proteins. The transmembrane
heparan sulfate proteoglycan syndecan-4 also plays a critical role in protein
kinase C (PKC) signaling in the formation of focal adhesions and actin stress
fibers. The cytoplasmic domain of syndecan-4 core protein directly interacts with
and potentiates PKCalpha activity, and it can directly interact with the phos-
phoinositide PIP2. We, therefore, investigated whether the interaction of
inositol phosphates and inositol phospholipids with syndecan-4 could regulate PKC
activity. Data from in vitro kinase assays using purified PKCalpha beta gamma
show that in the absence of phosphatidylserine and diolein, PIP2 increased the
extent of autophosphorylation of PKCalpha beta gamma and partially activated it
to phosphorylate both histone III-S and an epidermal growth factor receptor
peptide. This activity was dose-dependent, and its calcium dependence varied with
PKC isotype/source. Addition of the cytoplasmic syndecan-4 peptide, but not
equivalent syndecan-1 or syndecan-2 peptides, potentiated the partial activation
of PKCalpha beta gamma by PIP2, resulting in activity greater than that observed
with phosphatidylserine, diolein, and calcium. This study indicates that syndecan
4 cytoplasmic domain may bind both PIP2 and PKCalpha, localize them to forming
focal adhesions, and potentiate PKCalpha activity there.
PMID- 9553123
TI - Inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase pathway induces
p53-independent transcriptional regulation of p21(WAF1/CIP1) in human prostate
carcinoma cells.
AB - Progression through the cell cycle is controlled by the induction of cyclins and
the activation of cognate cyclin-dependent kinases. The 3-hydroxy-3
methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor lovastatin induces growth
arrest and cell death in certain cancer cell types. We have pursued the mechanism
of growth arrest in PC-3-M cells, a p53-null human prostate carcinoma cell line.
Lovastatin treatment increased protein and mRNA levels of the cyclin-dependent
kinase inhibitor p21(WAF1/CIP1), increased binding of p21 with Cdk2, markedly
inhibited cyclin E- and Cdk2-associated phosphorylation of histone H1 or GST
retinoblastoma protein, enhanced binding of the retinoblastoma protein to the
transcription factor E2F-1 in vivo, and induced the activation of a p21 promoter
reporter construct. By using p21 promoter deletion constructs, the lovastatin
responsive element was mapped to a region between -93 and -64 relative to the
transcription start site. Promoter mutation analysis indicated that the
lovastatin-responsive site coincided with the previously identified transforming
growth factor-beta-responsive element. These data indicate that in human prostate
carcinoma cells an inhibitor of the HMG-CoA reductase pathway can circumvent the
loss of wild-type p53 function and induce critical downstream regulatory events
leading to transcriptional activation of p21.
PMID- 9553125
TI - Oxidation of catalase by singlet oxygen.
AB - Different bands of catalase activity in zymograms (Cat-1a-Cat-1e) appear during
Neurospora crassa development and under stress conditions. Here we demonstrate
that singlet oxygen modifies Cat-1a, giving rise to a sequential shift in
electrophoretic mobility, similar to the one observed in vivo. Purified Cat-1a
was modified with singlet oxygen generated from a photosensitization reaction;
even when the reaction was separated from the enzyme by an air barrier, a
condition in which only singlet oxygen can reach the enzyme by diffusion.
Modification of Cat-1a was hindered when reducing agents or singlet oxygen
scavengers were present in the photosensitization reaction. The sequential
modification of the four monomers gave rise to five active catalase conformers
with more acidic isoelectric points. The pI of purified Cat-1a-Cat-1e decreased
progressively, and a similar shift in pI was observed as Cat-1a was modified by
singlet oxygen. No further change was detected once Cat-1e was reached. Catalase
modification was traced to a three-step reaction of the heme. The heme of Cat-1a
gave rise to three additional heme peaks in a high performance liquid
chromatography when modified to Cat-1c. Full oxidation to Cat-1e shifted all
peaks into a single one. Absorbance spectra were consistent with an increase in
asymmetry as heme was modified. Bacterial, fungal, plant, and animal catalases
were all susceptible to modification by singlet oxygen, indicating that this is a
general feature of the enzyme that could explain in part the variety of catalases
seen in several organisms and the modifications observed in some catalases.
Modification of catalases during development and under stress could indicate in
vivo generation of singlet oxygen.
PMID- 9553126
TI - Identification of a vitamin D response element in the proximal promoter of the
chicken carbonic anhydrase II gene.
AB - The carbonic anhydrase II gene, whose transcription is enhanced by 1, 25
dihydroxyvitamin D3 (1,25-(OH)2D3), encodes an important enzyme in bone-resorbing
cells derived from the fusion of monocytic progenitors. We analyzed the 1,25
(OH)2D3-mediated activation of the avian gene by transient transfection assays
with promoter/reporter constructs into HD11 chicken macrophages and by DNA
mobility shift assays. Deletion and mobility shift analyses indicated that the
62/-29 region confers 1,25-(OH)2D3 responsiveness and forms DNA-protein
complexes. The addition of an anti-vitamin D receptor (VDR) antibody inhibited
binding to this sequence, whereas anti-retinoid X receptor (RXR) antibody
generated a lower mobility complex. Therefore, we concluded that this element
binds a VDR.RXR heterodimer, but the addition of extra 1,25-(OH)2D3 had no effect
on the formation of this complex. Moreover, the use of nuclear extracts from 1,25
(OH)2D3-treated macrophages led to the formation of an additional high mobility
complex also composed of VDR.RXR heterodimer. Mutations provided evidence that
the 1, 25-(OH)2D3-mediated activation of the carbonic anhydrase II gene is
mediated by VDR.RXR heterodimers bound to a DR3-type vitamin D response element
with sequence AGGGCAtggAGTTCG. This vitamin D response element is also functional
in the ROS 17/2.8 osteoblasts.
PMID- 9553127
TI - Parathyroid hormone regulates the rat collagenase-3 promoter in osteoblastic
cells through the cooperative interaction of the activator protein-1 site and the
runt domain binding sequence.
AB - Parathyroid hormone induces collagenase-3 gene transcription in rat osteoblastic
cells. Here, we characterized the basal, parathyroid hormone regulatory regions
of the rat collagenase-3 gene and the proteins involved in this regulation. The
minimal parathyroid hormone-responsive region was observed to be between base
pairs -38 and -148. Deleted and mutated constructs showed that the activator
protein-1 and the runt domain binding sites are both required for basal
expression and parathyroid hormone activation of this gene. The runt domain site
is identical to an osteoblast-specific element-2 or acute myelogenous leukemia
binding sequence in the mouse and rat osteocalcin genes, respectively.
Overexpression of an acute myelogenous leukemia-1 repressor protein inhibited
parathyroid hormone activation of the promoter, indicating a requirement of acute
myelogenous leukemia-related factor(s) for this activity. Overexpression of c
Fos, c-Jun, osteoblast-specific factor-2, and core binding factor-beta increased
the response to parathyroid hormone of the wild type (-148) promoter but not with
mutation of either or both the activator protein-1 and runt domain binding sites.
In summary, we conclude that there is a cooperative interaction of acute
myelogenous leukemia/polyomavirus enhancer-binding protein-2-related factor(s)
binding to the runt domain binding site with members of the activator protein-1
transcription factor family binding to the activator protein-1 site in the rat
collagenase-3 gene in response to parathyroid hormone in osteoblastic cells.
PMID- 9553128
TI - Identification of a hormonally regulated luteinizing hormone/human chorionic
gonadotropin receptor mRNA binding protein. Increased mrna binding during
receptor down-regulation.
AB - To elucidate the molecular events associated with the regulation of luteinizing
hormone/human chorionic gonadotropin (LH/hCG) receptor mRNA stability during hCG
induced receptor down-regulation, we have identified an LH/hCG receptor-specific
mRNA binding protein. Proteins were isolated from control and down-regulated rat
ovary and were incubated with in vitro transcribed RNAs corresponding to the full
length LH/hCG receptor, as well as 5'- and 3'-truncated receptor forms. Resultant
ribonucleoprotein complexes were analyzed by RNA gel mobility shift. A prominent
Mr 50,000 ribonucleoprotein complex was identified with the following
characteristics: 1) specificity for LH/hCG receptor open reading frame sequences
located between nucleotides 102 and 282; 2) lack of competition by nonspecific
RNAs; 3) a 3-fold increase in RNA binding activity during hCG-induced receptor
down-regulation; and 4) limited tissue expression. This report describes the
first evidence of an LH/hCG receptor mRNA binding protein, which we term LRBP-1,
for luteinizing hormone receptor RNA binding protein-1. This protein is a
candidate for a trans-acting factor involved in the hormonal regulation of LH/hCG
receptor mRNA stability in rat ovary.
PMID- 9553129
TI - Identity of the residues responsible for the species-restricted complement
inhibitory function of human CD59.
AB - The membrane-anchored glycoprotein CD59 inhibits assembly of the C5b-9 membrane
attack complex (MAC) of human complement. This inhibitory function of CD59 is
markedly selective for MAC assembled from human complement components C8 and C9,
and CD59 shows little inhibitory function toward MAC assembled from rabbit and
many other non-primate species. We have used this species selectivity of CD59 to
identify the residues regulating its complement inhibitory function: cDNA of
rabbit CD59 was cloned and used to express human/rabbit CD59 chimeras in murine
SV-T2 cells. Plasma membrane expression of each CD59 chimera was quantified by
use of a 5'-TAG peptide epitope, and each construct was tested for its ability to
inhibit assembly of functional MAC from human versus rabbit C8 and C9. These
experiments revealed that the species selectivity of CD59 is entirely determined
by sequence contained between residues 42 and 58 of the human CD59 polypeptide,
whereas chimeric substitution outside this peptide segment has little effect on
the MAC inhibitory function of CD59. Substitution of human CD59 residues 42-58
into rabbit CD59 resulted in a molecule that was functionally indistinguishable
from native human CD59, whereas the complementary construct (corresponding
residues of rabbit CD59 substituted into human CD59) was functionally
indistinguishable from rabbit CD59. Based on the solved solution structure of
CD59, these data suggest that selectivity for human C8 and C9 resides in a
cluster of closely spaced side chains on the surface of CD59 contributed by
His44, Asn48, Asp49, Thr51, Thr52, Arg55, and Glu58 of the polypeptide.
PMID- 9553130
TI - High affinity binding of latent matrix metalloproteinase-9 to the alpha2(IV)
chain of collagen IV.
AB - Association of matrix metalloproteinases (MMPs) with the cell surface and with
areas of cell-matrix contacts is critical for extracellular matrix degradation.
Previously, we showed the surface association of pro-MMP-9 in human breast
epithelial MCF10A cells. Here, we have characterized the binding parameters of
pro-MMP-9 and show that the enzyme binds with high affinity (Kd approximately 22
nM) to MCF10A cells and other cell lines. Binding of pro-MMP-9 to MCF10A cells
does not result in zymogen activation and is not followed by ligand
internalization, even after complex formation with tissue inhibitor of
metalloproteinase-1 (TIMP-1). A 190-kDa cell surface protein was identified by
ligand blot analysis and affinity purification with immobilized pro-MMP-9.
Microsequencing and immunoblot analysis revealed that the 190-kDa protein is the
alpha2(IV) chain of collagen IV. Specific pro-MMP-9 surface binding was competed
with purified alpha2(IV) and was significantly reduced after treatment of the
cells with active MMP-9 before the binding assay since alpha2(IV) is hydrolyzed
by MMP-9. A pro-MMP-9.TIMP-1 complex and MMP-9 bind to alpha2(IV), suggesting
that neither the C-terminal nor the N-terminal domain of the enzyme is directly
involved in alpha2(IV) binding. The closely related pro-MMP-2 exhibits a weaker
affinity for alpha2(IV) compared with that of pro-MMP-9, suggesting that sites
other than the gelatin-binding domain may be involved in the binding of
alpha2(IV) to pro-MMP-9. Although pro-MMP-9 forms a complex with alpha2(IV), the
proenzyme does not bind to triple-helical collagen IV. These studies suggest a
unique interaction between pro-MMP-9 and alpha2(IV) that may play a role in
targeting the zymogen to cell-matrix contacts and in the degradation of the
collagen IV network.
PMID- 9553131
TI - Growth hormone stimulates the tyrosine phosphorylation and association of p125
focal adhesion kinase (FAK) with JAK2. Fak is not required for stat-mediated
transcription.
AB - We have demonstrated that growth hormone (GH) activates focal adhesion kinase
(FAK), and this activation results in the tyrosine phosphorylation of two FAK
substrates, paxillin and tensin. The activation of FAK is time-dependent (maximal
activation at 5-15 min) and dose-dependent (maximal activation at 0.05 nM). FAK
and paxillin are constitutively associated in the unstimulated state, remain
associated during the stimulation phase, and recruit tyrosine-phosphorylated
tensin to the complex after GH stimulation. Half of the carboxyl-terminal region
of the GH receptor is dispensable for FAK activation, but FAK activation does
require the proline-rich box 1 region of the GH receptor, indicative that FAK is
downstream of JAK2. FAK associates with JAK2 but not JAK1 after GH stimulation of
cells. Using FAK-replete and FAK-deficient cells, we also show that FAK is not
required for STAT-mediated transcriptional activation by GH. The use of FAK in
the signal transduction pathway utilized by GH may be central to many of the
pleiotropic effects of GH, including cytoskeletal reorganization, cell migration,
chemotaxis, mitogenesis, and/or prevention of apoptosis and gene transcription.
PMID- 9553132
TI - Multiple signaling pathways of human interleukin-8 receptor A. Independent
regulation by phosphorylation.
AB - Interleukin-8 (IL-8) receptor A (CXCR1) couples to a pertussis toxin-sensitive G
protein to mediate phospholipase Cbeta (PLCbeta) activation and cellular
responses. Responses to CXCR1 are attenuated by prior exposure of neutrophils to
either IL-8, a cleavage product of the fifth component of complement (C5a) or n
formylated peptides (formylmethionylleucylphenylalanine, fMLP). To characterize
the role of receptor phosphorylation in the regulation of the CXCR1, a
phosphorylation-deficient mutant, M2CXCR1, was constructed. This receptor, stably
expressed in RBL-2H3 cells, coupled more efficiently to G protein and stimulated
enhanced phosphoinositide hydrolysis, cAMP production, exocytosis, and
phospholipase D activation, and was resistant to IL-8-induced receptor
internalization. The rate and total amount of ligand stimulated actin
polymerization remained unchanged, but interestingly, chemotaxis was decreased by
approximately 30% compared with the wild type receptor. To study the role of
receptor phosphorylation in cross-desensitization of chemoattractant receptors,
M2CXCR1 was coexpressed with cDNAs encoding receptors for either fMLP (FR), C5a
(C5aR), or platelet-activating factor (PAFR). Both C5aR and PAFR were cross
phosphorylated upon M2CXCR1 activation, resulting in attenuated guanosine 5'-3'-O
(thio)triphosphate (GTPgammaS) binding in membranes. In contrast, FR and M2CXCR1
were resistant to cross-phosphorylation and cross-inhibition of GTPgammaS binding
by other receptors. Despite the resistance of M2CXCR1 to cross-phosphorylation
and receptor/G protein uncoupling, its susceptibility to cross-desensitization of
its Ca2+ response by fMLP and C5a, was equivalent to CXCR1. Regardless of the
enhancement in certain receptor functions in M2CXCR1 compared with the wild type
CXCR1, the mutated receptors mediated equivalent PLCbeta3 phosphorylation and
cross-desensitization of Ca2+ mobilization by FR, C5aR, and PAFR. The results
herein indicate that phosphorylation of CXCR1 regulates some, but not all of the
receptors functions. While receptor phosphorylation inhibits G protein turnover,
PLC activation, Ca2+ mobilization and secretion, it is required for normal
chemotaxis and receptor internalization. Since phosphorylation of CXCR1 had no
effect on its ability to induce phosphorylation of PLCbeta3 or to mediate class
desensitization, these activities may be mediated by independently regulated
pathways.
PMID- 9553133
TI - Progesterone regulates transcription of the p21(WAF1) cyclin- dependent kinase
inhibitor gene through Sp1 and CBP/p300.
AB - Progesterone has biphasic effects on proliferation of breast cancer cells; it
stimulates growth in the first cell cycle, then arrests cells at G1/S of the
second cycle accompanied by up-regulation of the cyclin-dependent kinase
inhibitor, p21. We now show that progesterone regulates transcription of the p21
promoter by an unusual mechanism. This promoter lacks a canonical progesterone
response element. Instead, progesterone receptors (PRs) interact with the
promoter through the transcription factor Sp1 at the third and fourth of six Sp1
binding sites located downstream of nucleotide 154. Mutation of Sp1 site 3
eliminates basal transcription, and mutation of sites 3 and 4 eliminates
transcriptional up-regulation by progesterone. Progesterone-mediated
transcription is further prevented by overexpression of E1A, suggesting that
CBP/p300 is required. Indeed, in HeLa cells, Sp1 and CBP/p300 associate with
stably integrated flag-tagged PRs in a multiprotein complex. Since many signals
converge on p21, cross-talk between PRs and other factors co-localized on the p21
promoter, may explain how progesterone can be either proliferative or
differentiative in different target cells.
PMID- 9553134
TI - Cortactin-Src kinase signaling pathway is involved in N-syndecan-dependent
neurite outgrowth.
AB - N-syndecan (syndecan-3) was previously isolated as a cell surface receptor for
heparin-binding growth-associated molecule (HB-GAM) and suggested to mediate the
neurite growth-promoting signal from cell matrix-bound HB-GAM to the cytoskeleton
of neurites. However, it is unclear whether N-syndecan would possess independent
signaling capacity in neurite growth or in related cell differentiation
phenomena. In the present study, we have transfected N18 neuroblastoma cells with
a rat N-syndecan cDNA and show that N-syndecan transfection clearly enhances HB
GAM-dependent neurite growth and that the transfected N-syndecan distributes to
the growth cones and the filopodia of the neurites. The N-syndecan-dependent
neurite outgrowth is inhibited by the tyrosine kinase inhibitors herbimycin A and
PP1. Biochemical studies show that a kinase activity, together with its
substrate(s), binds specifically to the cytosolic moiety of N-syndecan
immobilized to an affinity column. Western blotting reveals both c-Src and Fyn in
the active fractions. In addition, cortactin, tubulin, and a 30-kDa protein are
identified in the kinase-active fractions that bind to the cytosolic moiety of N
syndecan. Ligation of N-syndecan in the transfected cells by HB-GAM increases
phosphorylation of c-Src and cortactin. We suggest that N-syndecan binds a
protein complex containing Src family tyrosine kinases and their substrates and
that N-syndecan acts as a neurite outgrowth receptor via the Src kinase-cortactin
pathway.
PMID- 9553135
TI - Regions remote from the site of cleavage determine macromolecular substrate
recognition by the prothrombinase complex.
AB - The proteolytic formation of thrombin is catalyzed by the prothrombinase complex
of blood coagulation. The kinetics of prethrombin 2 cleavage was studied to
delineate macromolecular substrate structures necessary for recognition at the
exosite(s) of prothrombinase. The product, alpha-thrombin, was a linear
competitive inhibitor of prethrombin 2 activation without significantly
inhibiting peptidyl substrate cleavage by prothrombinase. Prethrombin 2 and alpha
thrombin compete for binding to the exosite without restricting access to the
active site of factor Xa within prothrombinase. Inhibition by alpha-thrombin was
not altered by saturating concentrations of low molecular weight heparin.
Furthermore, proteolytic removal of the fibrinogen recognition site in alpha
thrombin only had a modest effect on its inhibitory properties. Both alpha
thrombin and prethrombin 2 were cleaved with chymotrypsin at Trp148 and separated
into component domains. The C-terminal-derived zeta2 fragment retained the
ability to selectively inhibit macromolecular substrate cleavage by
prothrombinase, while the zeta1 fragment was without effect. As the zeta2
fragment lacks the fibrinogen recognition site, the P1-P3 residues or the intact
cleavage site, specific recognition of the macromolecular substrate by the
exosite in prothrombinase is achieved through substrate regions, distinct from
the fibrinogen recognition or heparin-binding sites, and spatially removed from
structures surrounding the scissile bond.
PMID- 9553136
TI - Delineation of the regions of interleukin-2 (IL-2) receptor beta chain important
for association of Jak1 and Jak3. Jak1-independent functional recruitment of Jak3
to Il-2Rbeta.
AB - Interleukin-2 (IL-2) induces heterodimerization of the IL-2 receptor beta (IL
2Rbeta) and gammac chains of its receptor and activates the Janus family tyrosine
kinases, Jak1 and Jak3. Whereas Jak1 associates with IL-2Rbeta, Jak3 associates
primarily with gammac but also with IL-2Rbeta. We analyzed four IL-2Rbeta
mutations that diminish IL-2-induced proliferation and found that each also
decreased IL-2-induced signal transducer and activator of transcription (STAT)
activation. For this reason, and because the mutations were in the IL-2Rbeta
membrane-proximal region, we investigated and found that each mutation diminished
IL-2Rbeta association with both Jak1 and Jak3. This suggested that these Jaks
might interact with the same region of IL-2Rbeta; however, certain IL-2Rbeta
internal deletions and C-terminal truncations differentially affected the
association of Jak1 and Jak3. Interestingly, just as Jak1-IL-2Rbeta association
is Jak3-independent and functionally important, we show that Jak3-IL-2Rbeta
association is Jak1-independent and implicate this association as being important
for IL-2-induced Stat5 activation. Moreover, Jak1 and Jak3 could associate only
in the presence of IL-2Rbeta, suggesting that these kinases can simultaneously
bind to IL-2Rbeta. Thus, our data not only demonstrate that somewhat more distal
as well as membrane-proximal cytoplasmic regions of a type I cytokine receptor
are important for Jak kinase association but also suggest that two IL-2Rbeta-Jak
kinase interactions are important for IL-2 signaling.
PMID- 9553138
TI - Multidrug resistance protein. Identification of regions required for active
transport of leukotriene C4.
AB - Multidrug resistance protein (MRP) is a broad specificity, primary active
transporter of organic anion conjugates that confers a multidrug resistance
phenotype when transfected into drug-sensitive cells. The protein was the first
example of a subgroup of the ATP-binding cassette superfamily whose members have
three membrane-spanning domains (MSDs) and two nucleotide binding domains. The
role(s) of the third MSD of MRP and its related transporters is not known. To
begin to address this question, we examined the ability of various MRP fragments,
expressed individually and in combination, to transport the MRP substrate,
leukotriene C4 (LTC4). We found that elimination of the entire NH2-terminal MSD
or just the first putative transmembrane helix, or substitution of the MSD with
the comparable region of the functionally and structurally related transporter,
the canalicular multispecific organic anion transporter (cMOAT/MRP2), had little
effect on protein accumulation in the membrane. However, all three modifications
decreased LTC4 transport activity by at least 90%. Transport activity could be
reconstituted by co-expression of the NH2-terminal MSD with a fragment
corresponding to the remainder of the MRP molecule, but this required both the
region encoding the transmembrane helices of the NH2-terminal MSD and the
cytoplasmic region linking it to the next MSD. In contrast, a major part of the
cytoplasmic region linking the NH2-proximal nucleotide binding domain of the
protein to the COOH-proximal MSD was not required for active transport of LTC4.
PMID- 9553137
TI - Characterization of insulin receptor substrate 4 in human embryonic kidney 293
cells.
AB - We recently cloned IRS-4, a new member of the insulin receptor substrate (IRS)
family. In this study we have characterized IRS-4 in human embryonic kidney 293
cells, where it was originally discovered. IRS-4 was the predominant insulin
elicited phosphotyrosine protein in these cells. Subcellular fractionation
revealed that about 50% of IRS-4 was located in cellular membranes, and
immunofluorescence indicated that IRS-4 was concentrated at the plasma membrane.
Immunoelectron microscopy conclusively established that a large portion of the
IRS-4 was located at the cytoplasmic surface of the plasma membrane in both the
unstimulated and insulin-treated states. IRS-4 was found to be associated with
two src homology 2 (SH2) domain-containing proteins, phosphatidylinositol 3
kinase and Grb2, the adaptor to the guanine nucleotide exchange factor for Ras.
On the other hand, no significant association was detected with two other SH2
domain proteins, the SH2-containing protein tyrosine phosphatase 2 and
phospholipase Cgamma. Insulin-like growth factor I acting through its receptor
was as effective as insulin in eliciting tyrosine phosphorylation of IRS-4, but
interleukin 4 and epidermal growth factor were ineffective.
PMID- 9553139
TI - A human brain L-3-hydroxyacyl-coenzyme A dehydrogenase is identical to an amyloid
beta-peptide-binding protein involved in Alzheimer's disease.
AB - A novel L-3-hydroxyacyl-CoA dehydrogenase from human brain has been cloned,
expressed, purified, and characterized. This enzyme is a homotetramer with a
molecular mass of 108 kDa. Its subunit consists of 261 amino acid residues and
has structural features characteristic of short chain dehydrogenases. It was
found that the amino acid sequence of this human brain enzyme is identical to
that of an endoplasmic reticulum amyloid beta-peptide-binding protein (ERAB),
which mediates neurotoxicity in Alzheimer's disease (Yan, S. D., Fu, J., Soto,
C., Chen, X., Zhu, H., Al-Mohanna, F., Collison, K., Zhu, A., Stern, E., Saido,
T., Tohyama, M., Ogawa, S., Roher, A., and Stern, D. (1997) Nature 389, 689-695).
The purification of human brain short chain L-3-hydroxyacyl-CoA dehydrogenase
made it possible to characterize the structural and catalytic properties of ERAB.
This NAD+-dependent dehydrogenase catalyzes the reversible oxidation of L-3
hydroxyacyl-CoAs to form 3-ketoacyl-CoAs, but it does not act on the D-isomers.
The catalytic rate constant of the purified enzyme was estimated to be 37 s-1
with apparent Km values of 89 and 20 microM for acetoacetyl-CoA and NADH,
respectively. The activity ratio of this enzyme for substrates with chain lengths
of C4, C8, and C16 was approximately 1:2:2. The human short chain L-3-hydroxyacyl
CoA dehydrogenase gene is organized into six exons and five introns and maps to
chromosome Xp11.2. The amino-terminal NAD-binding region of the dehydrogenase is
encoded by the first three exons, whereas the other exons code for the carboxyl
terminal substrate-binding region harboring putative catalytic residues. The
results of this study lead to the conclusion that ERAB involved in neuronal
dysfunction is encoded by the human short chain L-3-hydroxyacyl-CoA dehydrogenase
gene.
PMID- 9553140
TI - Transactivation of the human keratin 4 and Epstein-Barr virus ED-L2 promoters by
gut-enriched Kruppel-like factor.
AB - The Kruppel-like family of transcription factors comprises genes that appear to
have tissue-restricted functions. Expression of gut-enriched Kruppel-like factor
(GKLF) may be important in the switch from proliferation to differentiation in
the squamous epithelium. We sought to determine transcriptionally mediated
effects of GKLF on two promoters active in the esophageal squamous epithelium,
namely the Epstein-Barr virus ED-L2 and human keratin 4 promoters. Both promoters
contain a CACCC-like motif previously shown to bind GKLF. To determine whether
GKLF regulates genes containing this element, we first demonstrated expression
and then cloned the full-length human GKLF from an esophageal squamous carcinoma
cell line. In a transient transfection system, GKLF increased the activity of
both promoters >25-fold, localized to regions containing the CACCC-like element.
Recombinant GKLF specifically binds the CACCC-like motif in both promoters. GKLF
epitope-tagged protein leads to the formation of two proteins of 65 and 34 kDa.
The chromatographically purified 65-kDa protein binds the CACCC-like element from
both Epstein-Barr virus ED-L2 and keratin 4 promoters, which is not attenuated by
the 34-kDa protein. In summary, GKLF is expressed in esophageal squamous
epithelial cells and transcriptionally activates two esophageal epithelial
promoters important at the transition toward differentiation.
PMID- 9553141
TI - Visualization of dynamic trafficking of a protein kinase C betaII/green
fluorescent protein conjugate reveals differences in G protein-coupled receptor
activation and desensitization.
AB - Protein kinase C (PKC) links various extracellular signals to intracellular
responses and is activated by diverse intracellular factors including
diacylglycerol, Ca2+, and arachidonic acid. In this study, using a fully
functional green fluorescent protein conjugated PKCbetaII (GFP-PKCbetaII), we
demonstrate a novel approach to study the dynamic redistribution of PKC in live
cells in response to G protein-coupled receptor activation. Agonist-induced PKC
translocation was rapid, transient, and selectively mediated by the activation of
Gqalpha- but not Gsalpha- or Gialpha-coupled receptors. Interestingly, although
the stimuli were continuously present, only one brief peak of PKC membrane
translocation was observed, consistent with rapid desensitization of the
signaling pathway. Moreover, when GFP-PKCbetaII was used to examine cross-talk
between two Gqalpha-coupled receptors, angiotensin II type 1A receptor (AT1AR)
and endothelin A receptor (ETAR), activation of ETARs resulted in a subsequent
loss of AT1AR responsiveness, whereas stimulation of AT1ARs did not cause
desensitization of the ETAR signaling. The development of GFP-PKCbetaII has
allowed not only the real time visualization of the dynamic PKC trafficking in
live cells in response to physiological stimuli but has also provided a direct
and sensitive means in the assessment of activation and desensitization of
receptors implicated in the phospholipase C signaling pathway.
PMID- 9553142
TI - Mechanisms in the transcriptional regulation of bradykinin B1 receptor gene
expression. Identification of a minimum cell-type specific enhancer.
AB - To investigate the mechanisms of bradykinin B1 (BKB1) receptor gene expression,
transient DNA transfection analyses of human BKB1 receptor gene promoter were
performed in SV-40 transformed IMR90 cells. A positive regulatory element (PRE)
located at position -604 to -448 base pair (bp) upstream of the transcription
start site consistently exhibited, by far, the highest level of relative
luciferase activity. A negative regulatory element, at position -682 to -604 bp,
was able to completely ablate the function of the PRE. Transfection combined with
deletion and mutation analyses illustrated that the PRE contains a classic,
powerful enhancer. This enhancer was minimized to a 100-bp element at position
548 to -448 bp. A 78-bp fragment of negative regulatory element functioned as a
silencer. Transient transfection of the enhancer construct, driven by
heterologous herpes simplex thymidine kinase promoter, into a variety of cell
types, showed that this enhancer presents a cell-type specific feature. In the
characterization of the enhancer, motifs A (-548 to -532) and B (-483 to -477)
were found to be essential for full enhancer activity. Motif D (-472 to -467)
played a smaller role in enhancer activation. Gel shift and antibody supershift
assays determined that an AP-1 factor binds with motif B. The nuclear protein
which binds to motif A has yet to be identified. Both factors are the critical
regulators for this enhancer activation.
PMID- 9553143
TI - ZAP-70-dependent and -independent activation of Erk in Jurkat T cells.
Differences in signaling induced by H2o2 and Cd3 cross-linking.
AB - Oxidative stress in T cells induces signaling events similar to those initiated
by T cell antigen receptor engagement, including tyrosine phosphorylation and
activation of the critical protein-tyrosine kinase ZAP-70. Distal signaling
events such as the activation of mitogen-activated protein kinases and downstream
transcription factors are also initiated by oxidative stimuli. In this study
P116, a ZAP-70-negative Jurkat T cell line, was used to investigate the role of
ZAP-70 in mediating activation of Erk in response to H2O2. Consistent with the
hypothesis that ZAP-70 is required for activation of Erk in response to an
oxidative stimulus, Erk1 and Erk2 could be rapidly activated in Jurkat cells but
not in P116 cells upon addition of H2O2. P116 cells became competent for H2O2
induced Erk activation upon stable transfection with wild-type ZAP-70. An in vivo
ZAP-70 substrate, SLP-76, implicated in Erk activation, also became rapidly
tyrosine-phosphorylated in Jurkat cells, but not in P116 cells, upon treatment
with H2O2. Surprisingly, although ZAP-70 was required for H2O2-mediated Erk
activation, Erk activation in response to T cell antigen receptor engagement did
not require ZAP-70. In addition to demonstrating a requirement for ZAP-70 in H2O2
stimulated Erk activation, these results provide the first evidence for the
existence of a ZAP-70-independent pathway for Erk activation in T cells.
PMID- 9553144
TI - Bax in murine thymus is a soluble monomeric protein that displays differential
detergent-induced conformations.
AB - Bcl-2, Bcl-XL, and Bax are members of the Bcl-2 family that play important roles
in apoptosis regulation. These proteins are believed to be membrane-bound and to
regulate apoptosis through formation of homo- and heterodimers. However, we
recently found by subcellular fractionation that whereas Bcl-2 is predominantly a
membrane protein as previously reported, Bax and a significant fraction of Bcl-XL
are soluble in thymocyte and splenocyte extracts. In addition, we have
demonstrated that the ability of Bax to form dimers appears to be a detergent
induced phenomenon that coincides with a detergent-induced conformational change.
We have further investigated the tertiary and quaternary states of Bax in the
presence of various detergents. Detergents such as Triton X-100 and Triton X-114
readily enable Bax hetero- and homodimerization. However, other detergents such
as polydocanol, W-1, octyl glucoside, dodecyl maltoside, Tween 20, and sodium
cholate allow varying degrees of Bax hetero- and homodimerization. Detergents
such as 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid (Chaps) and
Brij 35 allow neither hetero- nor homodimer formation. Immunoprecipitation
analysis with the conformation-sensitive antibody uBax 6A7 revealed that whereas
Triton X-100 readily exposes the N-terminal Bax epitope (amino acid 13-19), only
limited exposure of the epitope occurs in Triton X-114, polydocanol, dodecyl
maltoside, and sodium cholate, and no exposure of this epitope was observed in W
1, Chaps, octyl glucoside, Tween 20, and Brij 35. Moreover, we could not detect
any proteins associated with the cytosolic form of Bax based on
immunopurification of this protein. Sephacryl S-100 gel filtration chromatography
analysis of the cytosolic Bax indicated that this protein is monomeric and
displays an apparent molecular mass of 25 kDa. Induction of apo-ptosis which
causes the insertion of the soluble form of Bax into membranes did not result in
appreciable Bax/Bcl-XL, Bax/Bcl-2 or Bax/Bax dimer formation as determined by
cross-linking studies. Further analysis of Bax after apoptosis induction by
immunoprecipitation in the presence of Chaps also revealed no significant
heterodimer formation. In conclusion, Bax displays several distinct states in
different detergents that expose defined regions of the protein. In addition,
these results suggest that mechanisms other than the simple dimerization among
members of the Bcl-2 family may be required for the regulation of apoptosis.
PMID- 9553145
TI - Identification of heterogeneous nuclear ribonucleoprotein K (hnRNP K) as a
repressor of C/EBPbeta-mediated gene activation.
AB - Transcription factor C/EBPbeta has been known to regulate a wide array of genes
including those involved in the acute-phase response. One of the molecular
mechanisms underlying transcription activation by C/EBPbeta is through protein
protein interaction with other transcription factors. Here we report the
identification and characterization of physical and functional interactions
between C/EBPbeta and heterogeneous nuclear ribonucleoprotein (hnRNP) K. This
interaction results in the repression of C/EBPbeta-dependent trans-activation of
the agp gene. Footprinting assays indicate that hnRNP K cannot bind to the
promoter region of agp gene or interfere with the binding of C/EBPbeta to its
cognate DNA site. Furthermore, agp gene activation by the synergistic interaction
of Nopp140 and C/EBPbeta is abolished by hnRNP K. The kinetics of appearance of
C/EBPbeta-hnRNP K complex in the nuclear extract after initiation of acute-phase
reaction indicates that hnRNP K functions as a negative regulator of C/EBPbeta
mediated activation of agp gene.
PMID- 9553146
TI - The activation of p38 and apoptosis by the inhibition of Erk is antagonized by
the phosphoinositide 3-kinase/Akt pathway.
AB - Considerable attention has recently been focused on the role played by different
kinase cascades in the control of apoptosis. The triggering of stress-activated
kinases concomitant with the inhibition of the extracellular signal-regulated
kinase (ERK) pathway has been observed in a number of cell systems undergoing
programmed cell death. In addition, the activation of the phosphoinositide 3
kinase (PI 3-kinase)-Akt signaling cascade has been shown to protect from
apoptosis. Here we have explored the potential role played by the inhibition of
ERK in the activation of the stress kinases as well as the possible cross-talk
with the PI 3-kinase pathway in HeLa cells. We show that the simple inhibition of
ERK basal activity is sufficient to trigger apoptosis and p38 activation with no
changes in Jun N-terminal kinase/stress-activated protein kinase. This is a
process dependent on the caspases and is completely abrogated by serum. The
incubation with wortmannin or the transfection of dominant negative mutants of
p85 or Akt block the inhibitory function of serum, suggesting the involvement of
the PI 3-kinase-Akt system. Consistent with this, expression of active mutants of
PI 3-kinase and Akt inhibits p38 activation and apoptosis. We also show here that
the inhibition of ERK triggers the caspase system, which is abolished by serum in
a wortmannin-dependent manner. Collectively, these results demonstrate a link
between ERK and the p38 apoptotic pathway that is modulated by the survival PI 3
kinase-Akt module, acting upstream the caspase system.
PMID- 9553147
TI - Identification and characterization of two distinct truncated forms of gp130 and
a soluble form of leukemia inhibitory factor receptor alpha-chain in normal human
urine and plasma.
AB - Leukemia inhibitory factor (LIF) is a polyfunctional cytokine known to require at
least two distinct receptor components (LIF receptor alpha-chain and gp130) in
order to form a high affinity, functional receptor complex. In this report, we
present evidence that there are two distinct truncated forms of gp130 in normal
human urine and plasma: a large form with a molecular weight of approximately
100, 000, which is similar to a previously described form of soluble gp130 in
human serum, and a previously undescribed small form with a molecular weight of
approximately 50,000. Using a panel of monoclonal antibodies raised against the
extracellular domain of human gp130, we were able to show that the small form of
the urinary gp130 probably contained only the hemopoietin domain. Both forms of
gp130 bound LIF specifically and were capable of forming heterotrimeric complexes
with soluble human LIF receptor alpha-chain in the presence of human LIF. In
addition to the soluble forms of gp130, a soluble form of LIF receptor alpha
chain was also detected in human urine and plasma.
PMID- 9553148
TI - Evolutionary history and mechanism of the Drosophila cecropin gene family.
AB - Upon bacterial infection, insects secrete a set of synthesized antibacterial
proteins into the hemolymph and initiate synergistic destruction of invaders.
Cecropin is one such antibacterial protein which is also found in vertebrates. To
study the evolutionary history and mechanism of the Cecropin gene family, we
determined DNA sequences of one isogenic In(3R)C and six isofemale lines of
Drosophila melanogaster as well as one line of D. simulans and of D. yakuba. The
phylogenetic analysis of these sequences together with those published for D.
virilis and Sarcophaga peregrina reveals frequent gene re-organization. It was
also found that silent nucleotide differences within D. melanogaster are quite
heterogeneous across the gene region of approximately 3 kilobases and the extent
of polymorphism is unusually usually high. These data suggest that the Cecropin
gene region of D. melanogaster underwent intragenic recombination as well as
introgression from a closely related sibling species, D. simulans.
PMID- 9553149
TI - Footprints of intragenic recombination at HLA loci.
AB - To evaluate the effect of balancing selection and intragenic recombination (or
gene conversion) at six individual HLA loci, synonymous nucleotide diversity in
different exon groups is examined within (pi w) and between (pi b) allelic
lineages that may be defined by either serological or DNA sequence differences.
Both pi values are high in exons which encode for the peptide binding region
(PBR) and tend to decrease in other exons. The value of pi w is significantly
smaller than that of pib in any exon of any locus. However, even pi w is much
greater than nucleotide diversity at non-HLA loci. These observations provide
additional strong evidence for the operation of balancing selection in PBR
encoding exons and its indirect effects on polymorphism at linked neighboring
regions. It appears that allelic lineages have generally evolved in isolation but
the linkage relationships within and between exons are incomplete throughout the
long evolutionary history. To quantify intragenic recombination and account for
the large discrepancy between the HLA and non-HLA diversity, a population
genetics model is analyzed with special reference to the evolution of modern
humans. The analysis suggests that the recombination rate between two sites 1000
base pairs apart is about 10(-5) per generation and that the effective size of
human populations (equivalent roughly to the number of breeding individuals in a
randomly mating population) has dropped from 10(5) to 10(4) in most of the
Quaternary. One possibility for this reduction is discussed.
PMID- 9553151
TI - HLA-DRB1*03, but not the TNFA -308 promoter gene polymorphism, confers protection
against fistulising Crohn's disease.
AB - Crohn's disease (CD) appears in forms so diverse that it has been hypothesized CD
might be a syndrome, with different pathogenic mechanisms leading to the various
clinical phenotypes. This may plausibly explain the conflicting and inconclusive
results with regard to HLA associations in unselected groups of patients. The
power of these association studies may increase when disease heterogeneity is
taken into account. As fistulising CD has been proposed as a separate subgroup of
patients with CD, we studied the carrier frequencies (CF) of the DRB1 alleles in
35 unrelated Caucasian Dutch CD patients with proven peri-anal fistulas. A
striking decrease in the frequency of the DRB1(*)03 allele was found in those
patients with peri-anal fistulas when compared with a panel of 2400 healthy
controls (HC) (3% vs 25%; P = 0.005; Odds Ratio [OR] = 0.09). The DRB1(*)03
allele is in strong linkage disequilibrium with a polymorphism at position -308
in the promoter region of the gene encoding TNFalpha (TNFA-308(*)2). We
investigated whether this allele frequency was decreased as well. Surprisingly,
the CF of TNFA-308(*)2 was 29%, not different from the CF of 98 HC (34%; P = 0.
7; OR = 0.8). This study is the first showing a significant negative association
between DRB1(*)03 and a particular subgroup of CD patients. Thus, patient
selection may largely determine the outcome of genetic association studies in CD,
as we previously observed no association with this allele in an unselected
population of CD patients. As DRB1(*)03 frequency, but not the closely linked
TNFA-308(*)2, was decreased, this suggests recombination between the DRB1 and
TNFA loci in this group of patients, and may help to define the biological basis
of fistula formation.
PMID- 9553150
TI - cDNA cloning of human DEC-205, a putative antigen-uptake receptor on dendritic
cells.
AB - Dendritic cells (DC) are specialist antigen presenting cells which capture
antigens in the periphery, migrate centrally, and present the processed antigens
in the context of major histocompatibility complex and appropriate co-stimulatory
molecules to T lymphocytes for the initiation of an immune response. DEC-205 has
been identified as a putative antigen-uptake receptor, which is expressed
abundantly on mouse DC. The recently cloned mouse DEC-205 cDNA predicts a
molecular structure which has a marked similarity to the macrophage mannose
receptor. Using reverse transcriptase-polymerase chain reaction (RT-PCR) and cDNA
library screening, we obtained the full coding region of human DEC-205 cDNA from
the Hodgkin's disease-derived L428 cell line. The predicted protein structure is
a type I transmembrane protein of 1722 amino acids consisting of a signal
peptide, cysteine-rich domain, fibronectin type II domain, ten carbohydrate
recognition-like domains, transmembrane domain, and a cytoplasmic tail. Human DEC
205 is 77% identical to the mouse protein with completely conserved cysteines.
The DEC-205 gene (LY75) was mapped to chromosome band 2q24 by somatic cell hybrid
panel analysis and fluorescent in situ hybridization. Northern blot analysis
detected 7.8 and 9.5 kilobase DEC-205 transcripts in myeloid, B lymphoid, and
Hodgkin's disease-derived cell lines. RT-PCR analysis indicated that immature
blood DC contain a barely detectable amount of DEC-205 transcripts but these were
markedly increased upon differentiation/activation.
PMID- 9553152
TI - Analysis of polymorphisms in the major expressed class I locus (B-FIV) of the
chicken.
AB - We analyzed the polymorphic nature of eleven alleles expressed by the major class
I locus (B-FIV) in chickens. Similar to mammalian class I loci, the nucleotide
substitutions with high variability occur in exons 2 and 3 encoding the alpha1
and alpha2 domains. However, the nonsynonymous to synonymous ratio of nucleotide
substitutions in exon 3 encoding the alpha helix and beta sheets is reversed
compared with HLA. The region of exon 3 encoding the alpha2 helix demonstrates a
much lower nonsynonymous to synonymous ratio, suggesting evolutionary selection
of a more conserved alpha2 helix in B-FIV compared with HLA. Amino acid residues
with high Wu-Kabat variability are typically located in positions predicted to
impact antigen presentation. B-FIV amino acid residues predicted to interact with
the CDR1alpha region of the T-cell receptor (Tcr) demonstrate less variability
than in mouse and human class I alleles. The combination of a reduced
nonsynonymous to synonymous ratio in exon 3 encoding the alpha2 helix and the
limited variability in CDR1alpha contact residues is discussed with regard to
concerted evolution between a minimal major histocompatibility complex and
compaction of Tcr variable gene segments in the chicken.
PMID- 9553153
TI - Linkage analysis of HSP70 genes and historecognition locus in botryllus
schlosseri.
AB - The protochordate allorecognition system has long invited comparison with the
vertebrate major histocompatibility complex (MHC). In the colonial species
Botryllus schlosseri, a rapid fusion or rejection response resembling graft
acceptance or rejection in vertebrates is controlled by a single highly
polymorphic genetic region. Because linkage between heat shock protein 70 (HSP70)
genes and the MHC appears to be conserved within the vertebrate lineage, linkage
relationships between two HSP70 genes (HSP70.1 and HSP70.2) and the
historecognition locus (FuHC) have been analyzed in B. schlosseri. Segregation
patterns of restriction fragment length polymorphisms located in the 3' flanking
regions of HSP70.1 and HSP70.2 were determined for progeny of defined crosses.
These progeny were also analyzed for fusibility type by an in vivo cut colony
assay. No close linkage was detected between any of the three loci. These results
do not support the hypothesis that the allorecognition response in B. schlosseri
is determined by an MHC homologue. However, it remains a possibility that
orthologues of other MHC-linked genes will be linked to the B. schlosseri FuHC.
PMID- 9553154
TI - Isolation and molecular characterization of the rat MR1 homologue, a non-MHC
linked class I-related gene.
AB - We isolated and analyzed a new rat gene which is homologous to the recently
described human major histocompatibility complex class I-related gene MR1. The
deduced amino acid sequence of the rat Mr1 gene shows conserved cysteine residues
typical of class I genes as well as conserved beta2-microglobulin and CD8 contact
sites. Analysis of partial DNA sequences and restriction fragment length
polymorphism patterns of several inbred rat strains indicate that Mr1 is not
polymorphic. Mr1 is a single-copy gene, which could be mapped to rat chromosome
13 by co-segregation analysis of Mr1 and a microsatellite marker in the renin
(Ren) gene in double-backcross hybrids. The recombination frequency between both
genes was determined to be 14.7% (4.9-31.1, 95% confidence limits). Expression
analysis revealed various Mr1 transcripts in each organ tested and occurrence of
alternative splicing.
PMID- 9553155
TI - Opossum (Monodelphis domestica) terminal deoxynucleotidyl transferase gene.
PMID- 9553156
TI - Polymorphism and multiple loci for the horse DQA gene.
PMID- 9553157
TI - HTEX4, a new human gene in the MHC class I region, undergoes alternative splicing
and polyadenylation processes in testis.
PMID- 9553158
TI - Polymorphism of the tumor necrosis factor A gene in Melanesian and East-Asian
populations.
PMID- 9553159
TI - A polymorphic dinucleotide repeat in the 5' flanking region of the human
interleukin 11 (IL11) gene.
PMID- 9553160
TI - Complete coding sequence of a serologically undefined HLA-B antigen: HLA-B*1537.
PMID- 9553161
TI - Characterization of 12 microsatellite loci of the human MHC in a panel of
reference cell lines
PMID- 9553162
TI - [carbonyl-11C]Desmethyl-WAY-100635 (DWAY) is a potent and selective radioligand
for central 5-HT1A receptors in vitro and in vivo.
AB - [carbonyl-11C]Desmethyl-WAY-100635 (DWAY) is possibly a low-level metabolite
appearing in plasma after intravenous administration of [carbonyl-11C]WAY-100635
to human subjects for positron emission tomographic (PET) imaging of brain 5-HT1A
receptors. In this study we set out to assess the ability of DWAY to enter brain
in vivo and to elucidate its possible interaction with 5-HT1A receptors.
Desmethyl-WAY-100635 was labelled efficiently with carbon-11 (t1/2 = 20.4 min) in
high specific radioactivity by reaction of its descyclohexanecarbonyl analogue
with [carbonyl-11C]cyclohexanecarbonyl chloride. The product was separated in
high radiochemical purity by high-performance liquid chromatography (HPLC) and
formulated for intravenous injection. Rats were injected intravenously with DWAY,
sacrificed at known times and dissected to establish radioactivity content in
brain tissues. At 60 min after injection, the ratios of radioactivity
concentration in each brain region to that in cerebellum correlated with previous
in vitro and in vivo measures of 5-HT1A receptor density. The highest ratio was
about 22 in hippocampus. Radioactivity cleared rapidly from plasma; HPLC analysis
revealed that DWAY represented 55% of the radioactivity in plasma at 5 min and
33% at 30 min. Only polar radioactive metabolites were detected. Subsequently, a
cynomolgus monkey was injected intravenously with DWAY and examined by PET.
Maximal whole brain uptake of radioactivity was 5.7% of the administered dose at
5 min after injection. The image acquired between 9 and 90 min showed high
radioactivity uptake in brain regions rich in 5-HT1A receptors (e.g. frontal
cortex and neocortex), moderate uptake in raphe nuclei and low uptake in
cerebellum. A transient equilibrium was achieved in cortical regions at about 60
min, when the ratio of radioactivity concentration in frontal cortex to that in
cerebellum reached 6. The corresponding ratio for raphe nuclei was about 3.
Radioactive metabolites appeared rapidly in plasma, but these were all more polar
than DWAY, which represented 52% of the radioactivity in plasma at 4 min and 20%
at 55 min. In a second PET experiment, in which a cynomolgus monkey was
pretreated with the selective 5-HT1A receptor antagonist, WAY-100635, at 25 min
before DWAY injection, radioactivity in all brain regions was reduced to that in
cerebellum. Autoradiography of post mortem human brain cryosections after
incubation with DWAY successfully delineated 5-HT1A receptor distribution.
Receptor-specific binding was eliminated in the presence of the selective 5-HT1A
receptor agonist, 8-OH-DPAT [(+/-)-8-hydroxy-2-dipropylaminotetralin]. These
findings show that: (a) intravenously administered DWAY is well able to penetrate
brain in rat and monkey, (b) DWAY is a highly effective radioligand for brain 5
HT1A receptors in rat and monkey in vivo and for human brain in vitro, and (c)
the metabolism and kinetics of DWAY appear favourable to successful
biomathematical modelling of acquired PET data. Thus, DWAY warrants further
evaluation as a radioligand for PET studies of 5-HT1A receptors in human brain.
PMID- 9553164
TI - Technetium-99m Q4: a prototype cationic perfusion radiotracer with myocardial
washout.
AB - Technetium-99m Q4 is derived from an existing mixed ligand myocardial tracer
(99mTc-Q3) by the addition of an ester group to promote myocardial washout. Six
subjects with single-vessel coronary disease documented by angiography and/or Q
wave myocardial infarction documented by electrocardiography were studied with
99mTc-Q4 injection during exercise and with comparative thallium-201 tomography.
Six healthy volunteers were also studied with 99mTc-Q4 imaging following
injection at peak exercise. Tomographic images with 99mTc-Q4 and 201Tl each
provided correct assessment of the presence or absence of coronary disease in 22
of 30 myocardial segments (73.3%). Six myocardial segments showed defect
reversibility with 99mTc-Q4, whereas 14 segments showed reversibility with 201Tl,
but the latter included three segments with no angiographic or
electrocardiographic evidence of disease. In both normals and subjects with
coronary artery disease, significant global washout of 99mTc-Q4 was observed over
4 h. For five patients with angiographic evidence of unrevascularized coronary
artery stenosis, the ischemic to normal zone count ratio increased from 0. 782+/
0.107 at 45 min postexercise to 0.891+/-0.115 at 4 h postexercise (P = 0.016),
suggesting occurrence of differential washout. It is concluded that addition of
an ester group functionality to a previously studied mixed ligand cardiac tracer
promotes global and regional myocardial tracer washout. Nevertheless,
demonstration of perfusion defect reversibility with comparable frequency to that
observed with 201Tl stress and reinjection images, required separate injections
of 99mTc-Q4 at peak stress and at rest.
PMID- 9553163
TI - Imaging of infection in rabbits with radioiodinated interleukin-1 (alpha and
beta), its receptor antagonist and a chemotactic peptide: a comparative study.
AB - Previous studies have reported the favourable characteristics of chemotactic
peptides and interleukins for imaging of infection and inflammation. In the
present study, the potential of two species of interleukin 1 (IL-1), IL-1alpha
and IL-1beta, the IL-1 receptor antagonist (IL-1ra) and the synthetic chemotactic
peptide N-formyl-methionyl-leucyl-phenylalanyl-lysine (fMLFK) were directly
compared in a rabbit model of infection. IL-1alpha, IL-1beta, IL-1ra and fMLFK
were labelled with iodine-123 according to the Bolton-Hunter method. Twenty-four
hours after induction of Escherichia coli abscesses in the left thigh muscle,
rabbits were injected intravenously with 0.5 mCi of 123I-labelled agent. Gamma
camera images were obtained at 5 min and 1, 4, 8 and 20 h p.i. Biodistribution
was determined at 20 h p.i. Although all agents rapidly cleared from the blood,
at 20 h p.i. blood levels and the levels in most organs of 123I-fMLFK were
significantly lower than those of the other three agents (P<0.05). The abscesses
were clearly visualized with all agents from 4 h p.i. onwards. After 1 h p.i.,
the abscess uptake of 123I-IL-1beta was significantly higher than that of the
other agents (P<0.05), with the highest uptake observed at 8 h p.i. (1.3%+/
0.3%). After 20 h p.i., the highest abscess-to-contralateral muscle ratios were
obtained with 123I-IL-1beta, i.e. 39.0+/-11.5 vs 18.7+/-5.4, 18.1+/-2.3 and 29.
9+/-7.0 for 123I-IL-1alpha, 123I-IL-1ra and 123I-fMLFK, respectively. In
conclusion, all agents localized in the infectious focus. The potential of
radiolabelled IL-1beta for imaging of infection was better than that of the other
agents: higher absolute uptake in the infection and higher abscess-to
contralateral muscle ratios were obtained. The observation of localization of
radiolabelled IL-1ra in infection was important since this protein can be
administered to humans without any side-effects.
PMID- 9553165
TI - Assessment of reperfused myocardium using a new ischaemia-avid imaging agent,
technetium-99m HL91: comparison with myocardial glucose uptake.
AB - We evaluated the efficacy of a new ischae-mia-avid imaging agent, technetium-99m
labelled 4,9-diaza-3,3,10,10-tetramethyldodecan-2,11-dione dioxime (99mTc- HL91)
as a marker of myocardial viability in ischaemic and reperfused myocardium. The
left coronary artery of rats was ligated for 15 or 60 min and released. The
myocardium was reperfused for 60 min [stunned myocardium, or acute myocardial
infarction (MI)] or 7 days (subacute MI). Thereafter, 99mTc-HL91 and carbon-14 2
deoxyglucose (DG) were co-injected 30 min before sacrifice. We evaluated the
myocardial accumulation of 99mTc-HL91 and DG by dual-tracer ex vivo
autoradiography. The uptake of each tracer in the myocardial region was
normalized by that in the septum (control), and expressed as percent uptake (%HL
or %DG, respectively). Individual hearts were also histopathologically examined.
The %HL in the stunned myocardium (n = 8) and in the septum were identical
(101%+/-15%, mean+/-SD, P = ns), whereas the %DG was significantly increased
(149%+/-27%, P<0.05) compared with that in the septum. These results suggest that
99mTc-HL91 cannot visualize stunned myocardium, whereas DG can. In acute MI (n =
7), the %HL (423%+/-96%, P<0.005) and the %DG (318%+/-91%, P<0.001) in the non
infarcted area at risk were significantly augmented compared with those in the
septum. The %DG (181%+/-17%) in the infarcted area was also augmented (P<0.001),
whereas the %HL (106%+/-25%) in the infarcted area was identical to that in the
septum (P = ns). These results indicate that 99mTc-HL91 detected viable
myocardium in the area at risk. In subacute MI (n = 8), the%HL in the infarcted
area (101%+/-45%) and in the septum was identical, whereas %DG (292%+/-57%) was
significantly higher than that in the non-infarcted risk area or the septum
(P<0.0001). These findings suggest that DG detected viable myocardium in the area
at risk, but that 99mTc-HL91 was not retained. We conclude that 99mTc-HL91 is a
potent marker of myocardial viability when used during the early acute phase
after reperfusion.
PMID- 9553167
TI - Scintimammography with technetium-99m methoxyisobutylisonitrile: results of a
prospective European multicentre trial.
AB - The aim of the trial was to determine the diagnostic accuracy of
scintimmammography with technetium-99m methoxyisobutylisonitrile (99mTc-MIBI) in
the detection of primary breast cancer and to verify its clinical usefulness. A
total of 246 patients with a suspicious breast mass or positive mammogram were
included in this prospective European multicentre trial. At 5 min and 60 min
(optional) p.i. two lateral prone images were acquired for 10 min each; 30 min
p.i. one anterior image was acquired for 10 min. There were 253 lesions (195
palpable and 58 non-palpable), in respect of which histology revealed 165 cancers
and 88 benign lesions. Institutional and blinded read results were correlated to
core laboratory histopathology results obtained during excisional biopsy.
Diagnostic accuracy for the detection of breast cancer was calculated per lesion.
The overall sensitivity and specificity of blinded read scintimammography were
71% and 69%, respectively. For palpable lesions, the sensitivity of blinded read
and institutional read scintimammography was 83% and 91%, respectively.
Sensitivity was not dependent on the density of the breast tissue. Invasive
ductal and invasive lobular cancers showed similar sensitivity. The sensitivity
and specificity of mammography were 91% and 42%, respectively, and did not depend
on the tumour size. In 60% of false-negative mammograms, 99mTc-MIBI was able to
diagnose malignancy (true-positive). High-quality imaging with 99mTc-MIBI has a
high diagnostic accuracy for the detection of primary breast cancer. Used as a
complementary method, scintimammography with 99mTc-MIBI can help to diagnose
breast cancer at an earlier stage in patients with dense breasts.
PMID- 9553166
TI - The incidence of hyperthyroidism in Austria from 1987 to 1995 before and after an
increase in salt iodization in 1990.
AB - Between 1963 and 1990, Austria had iodized salt prophylaxis of endemic goitre
with 10 mg KI (7.5 mg I) per kg. This was obviously insufficient, as urinary
iodine excretion ranged from 42 to 78 microg I per g of creatinine and goitre in
adults remained in the endemic range of 15%-30%. Therefore salt iodization was
doubled in 1990. The aim of this study was to assess the annual incidence of
different types of hyperthyroidism (HT) before and after this increase in salt
iodization. The incidence of HT was recorded in 14 nuclear medicine centres from
1987 to 1995. In five additional centres data were available from 1992 onwards.
Data prior to 1992 were documented retrospectively, while those after 1992 were
recorded prospectively. The 14 centres drew patients from an area with a
population of approximately 4.23 million while all 19 institutes were estimated
to cover an area with a population of 5.4 million (the total population of
Austria is 7.86 million). A total of 414232 persons were examined for the first
time in the participating centres. HT and the type of HT were defined by clinical
examination, serum TSH, thyroid hormone levels in blood, ultrasonography,
scintigraphy and serum autoantibody titres. HT was classified into immunogenic HT
(Graves' or Basedow's disease, GD) and HT with intrinsic thyroid autonomy (uni-,
multinodular or disseminated Plummers' disease, PD). HT was also divided into
overt (o) or subclinical (sc) disease. The following data were calculated: annual
incidence per 100000 and the relative risk (RR) for HT with 95% confidence
intervals (CI). In addition, linear trends were calculated for each type of HT by
means of logistic regressions. In the 19 centres a total of 47834 patients with
HT were registered from 1987 to 1995. PD accounted for 75% of all cases of HT and
GD for 19%, while other types of HT were present in 6%. From 1987 to 1989 (time
period T0), the annual incidence of oPD was 30.5 (95% CI 29.6-31.5) per 100000.
The RR compared to the baseline period T0 was highest in 1992 (1.37; 1.3-1.45)
and decreased to 1.17 (1.1-1.24) in 1995. The annual incidence of scPD in T0 was
27.4 (26.5-28.3) per 100000. The RR was highest in 1991 (1.64; 1.56-1.73) and was
1.60 (1. 51-1.69) in 1995. In oPD and scPD a higher RR was observed in persons
older than 50 years of age, particularly in men. The incidence of oGD in T0 was
10.4 (9.8-10.9) per 100000; the maximum RR increased to 2.19 (2.01-2.38) in 1993
and decreased to 1.95 (1.78-2.13) in 1995. The incidence of scGD was 1.9 (1.6
2.1) in T0. The maximum RR was observed in 1994 (2.47; 2.04-3.0) and it was still
2.26 (1.85-2.77) in 1995. The increased incidence of oGD and scGD was evenly
distributed in all ages and both sexes. The time course of different types of HT
following the increase in salt iodization could be divided into two phases: an
increase in the incidences of HT with peaks after 1-4 years and a subsequent
decrease, the only exception being scGD. The effect was more pronounced in GD
than in PD. PD showed an age and gender dependency over time, while GD did not.
PMID- 9553168
TI - Intraindividual comparison of 99mTc-labelled anti-SSEA-1 antigranulocyte antibody
and 99mTc-HMPAO labelled white blood cells for the imaging of infection.
AB - Technetium-99m labelled antigranulocyte antibodies are ready to use and are
sensitive and specific in the diagnosis of infectious diseases. 99mTc-SSEA
antigranulocyte antibodies have a very high affinity constant (Kd 10(-12) M) for
human neutrophils (PMNs), and excellent imaging qualities with high
target/background ratios. The aim of this study was to compare the diagnostic
accuracy of the 99mTc-anti-SSEA-1 monoclonal antibody (Mab) with that of 99mTc
hexamethylpropylene amine oxime (HMPAO)-labelled white blood cells (WBCs). To
this end, 17 patients with 23 proven infectious foci were examined with 555 MBq
99mTc-anti-SSEA-1 MAb and with 370 MBq 99mTc-HMPAO labelled autologous leucocytes
within a period of 7 days. All the infections were confirmed by culture, biopsy,
surgery and follow-up. Whole-body images and planar spot views with the antibody
were performed at 1-h, 4-h and 24-h post injection; the biodistribution of the
antibody was quantified, absorbed radiation doses were calculated and the
diagnostic results were compared with the 99mTc-HMPAO WBC images. Human anti
mouse antibody (HAMA) evaluation was performed in all patients before and 3
months after antibody injection. Blood was drawn at different times after 99mTc
anti-SSEA-1 MAb injection to determine the amount of granulocyte-associated
radioactivity and to calculate recovery. 99mTc-anti-SSEA-1 MAb scintigraphy
detected all 23 lesions, while 21 were detected with 99mTc-HMPAO WBC scan. In
this small group of patients, the sensitivity and specificity of 99mTc-anti-SSEA
1 MAb scintigraphy were 95% and 96% respectively, as compared with 91% and 82%
respectively for 99mTc-HMPAO WBC scan. An increasing uptake of the injected
activity in the lesion at different time points was indicative of high affinity
and of specific PMN binding. There was no HAMA formation. In four of five
patients investigated, a transient mild leukopenia was found at 15 min p.i..
There was increased uptake of the antibody in liver and spleen and normal uptake
in kidneys and bone marrow. The estimated radiation doses for the whole body and
the red bone marrow were 1.1x10(-2) cGy/37 MBq and 5.3x10(-2) cGy/37 MBq,
respectively. The activity associated to the PMNs in vivo was 33.5%, 30.6%, 21.3%
and 9% at 5, 15, 30 and 45 min. post-injection, respectively. It is councluded
that use of 99mTc-anti-SSEA-1 antigranulocyte antibodies demonstrates promising
results comparable to those obtained with 99mTc-labelled autologous WBCs. The
99mTc-labelled MAb is ready to use, has excellent image qualities and a high
target/background ratio.
PMID- 9553169
TI - A comparison of adenosine and arbutamine for myocardial perfusion imaging.
AB - We have compared our standard stress protocol (adenosine combined with exercise)
with the new stress agent arbutamine, for thallium-201 myocardial perfusion
imaging (MPI) in order to assess the comparative value of arbutamine. We studied
23 patients referred for MPI, and each patient had two studies (18 males, median
age 66 years, five with previous myocardial infarction). Uptake scores were
assigned to each of nine segments, and the extent and severity of defects were
measured using a polar plot. Haemodynamic changes were greater with arbutamine
(rate-pressure product increase 78% vs 51%, P = 0.003). Symptoms were experienced
by 21 patients with arbutamine and 16 with adenosine (P = 0.07). Agreement
between the techniques for classification of patients as normal or as having
reversible, fixed or mixed defects was good (19 of 23 studies, 83%, kappa =
0.76). Agreement for similar classification of segments was also good (82%, kappa
= 0.71). Segmental agreement for stress scores was good (86%, kappa = 0.77).
However, mean size of stress defect was larger with adenosine (83+/-52 pixels vs
65+/-48 pixels, P<0.05), though severity and reversibility were similar (P = NS).
We conclude that arbutamine provides comparable results to those obtained with
adenosine and exercise and that the observed differences are not clinically
significant.
PMID- 9553170
TI - Application of SPET using technetium-99m sestamibi in brain tumours and
comparison with expression of the MDR-1 gene: is it possible to predict the
response to chemotherapy in patients with gliomas by means of 99mTc-sestamibi
SPET?
AB - Technetium-99m sestamibi (MIBI) is thought to be passively taken up by
metabolically active tumour cells and effluxed from them by P-glycoprotein (Pgp).
This 170-kDa membrane-bound protein, encoded by the MDR-1 gene, acts as an energy
dependent efflux pump for several antineoplastic agents, resulting in multidrug
resistance. For this reason, it is of interest whether the tumour's response to
chemotherapy can be predicted by MIBI single-photon emission tomography (SPET).
In this study, MIBI SPET was compared with thallium-201 (Tl) SPET using magnetic
resonance imaging as a guide in 16 patients with untreated brain tumours [ten
glioblastomas (GBs), two anaplastic astrocytomas (AAs), two low-grade gliomas
(LGASs) and two metastatic brain tumours) and in four patients who had received
treatment for with brain tumours (two GBs, two AAs). In addition, we investigated
the expression of the MDR-1 gene and its product Pgp in the same patients, and
compared the results with MIBI SPET findings. MIBI, as well as Tl, was highly
accumulated and retained in the enhanced region of malignant gliomas. In
addition, MIBI SPET yielded sharp and well-contrasted images, and the margin of
the tumour was more clearly defined than with Tl SPET due to a good signal-to
noise ratio. Follow-up MIBI SPET in patients who had received therapy showed
marked uptake in a patient with malignant transformation, who deteriorated
clinically. Patients with no uptake on MIBI SPET showed no sign of recurrence.
Semiquantitative analysis of untreated patients showed a relationship between the
early uptake index (UI, ratio of average count/pixel in the lesion to that in the
contralateral area on early images) and the degree of malignancy (early UI =
1.08+/-0.06 in LGASs, 4.10+/-0.84 in AAs, 5.71+/-3.47 in GBs, and 7.52+/-1.52 in
metastatic brain tumours). The retention index (RI, ratio of delayed to early UI)
of MIBI was significantly lower than that of Tl in metastatic brain tumours
(P<0.05), but not in malignant gliomas. Histological and biological investigation
of gliomas showed that the MDR-1 gene and its product Pgp were expressed only in
normal endothelial cells and not in tumour cells or proliferating endothelial
cells; Pgp tended to decrease as the degree of malignancy rose. Hence, the
presence of Pgp and the grade of malignancy were inversely related in gliomas. By
contrast, immunohistochemical study showed strong accumulation of Pgp in
metastatic brain tumour cells. These histopathological findings and MIBI SPET
findings are compatible with experimental data; MIBI was washed out by Pgp. The
main cause of chemoresistance is probably not an increasing drug efflux by Pgp in
gliomas. Thus, MIBI SPET is useful for detecting the active lesions, but may not
be useful for predicting the response to chemotherapy in gliomas.
PMID- 9553171
TI - Preliminary application of dynamic pulmonary xenon-133 single-photon emission
tomography in the evaluation of patients with pulmonary emphysema for
thoracoscopic lung volume reduction surgery.
AB - Dynamic pulmonary xenon-133 single-photon emission tomography (SPET) with three
dimensional (3D) displays was preliminarily applied to select resection targets
for thoracoscopic lung volume reduction surgery (LVRS) and to assess regional
ventilatory changes following surgery. Dynamic SPET was performed using a triple
detector SPET system in 14 patients with pulmonary emphysema before and after
LVRS. After reconstructing colour-illuminated, surface-rendered 3D images of
equilibrium (EQ) and 3-min washout (WO3), a single 3D fusion display was created
from these two different time-course image sets, in which the 3D WO3 image
indicating 133Xe retention was visible through the overlying 3D EQ image
delineating lung contours. Volumetric extent of retention on this display was
quantified by a 133Xe retention index, defined as the ratio (%) of total pixel
numbers of segmented 3-min WO data to those of EQ data. 133Xe SPET and
appropriately thresholded 3D displays efficiently localized a total of 36
retention sites; 19 (52.7%) of these sites were not localized by CT because they
were within the widely or homogeneously spreading non-bullous emphysematous lung
tissues. The 3D displays enhanced the perception of anatomical configurations and
the extent of 133Xe retention compared with multislice tomograms.
Postoperatively, 3D fusion display visualized the details of regional changes in
retention, and changes in the retention index on the 3D display with a
standardized threshold correlated well with changes in 133Xe clearance time
(T1/2) and %FEV1 (r = 0.881 and 0. 856, respectively; P<0.0001). This preliminary
study indicates that 133Xe SPET and appropriately thresholded, topographic 3D
displays are of potential use in selecting resection targets for LVRS, and in
evaluating the treatment effects on regional ventilation.
PMID- 9553172
TI - A clinical evaluation of the quantitative accuracy of simultaneous
emission/transmission scanning in whole-body positron emission tomography.
AB - We present a clinical evaluation of the quantitative bias which is introduced
during simultaneous emission/transmission (SET) acquisition for the application
of whole-body positron emission tomography (PET) with fluorine-18 2-fluoro-2
deoxy-d-glucose. The quantitative accuracy of the SET technique was assessed by
means of a clinical study involving 28 patients and a realistic phantom
experiment. In the clinical study, SET overestimated the activity concentration
in the tumours by a factor of approximately 1.10, but in the phantom study, where
the tumours were smaller, the bias was found to increase to a value of 1.39. The
bias in the soft tissue regions of the patient studies varied between 1.03 and
1.36, and close agreement was observed with the corresponding phantom results.
The extent of the bias increased as the local activity concentration decreased
and we attribute the effect to scattered photons from the transmission source
which are detected in the emission window during SET.
PMID- 9553173
TI - Targeting of cholecystokinin-B/gastrin receptors in vivo: preclinical and initial
clinical evaluation of the diagnostic and therapeutic potential of radiolabelled
gastrin.
AB - The outstanding sensitivity of pentagastrin in detecting the presence of primary,
recurrent or metastatic medullary thyroid cancer (MTC) suggests widespread
expression of the corresponding receptor type in human MTC. Indeed, recent
autoradiographic studies have demonstrated the presence of cholecystokinin (CCK)
B (= gastrin) receptors not only in more than 90% of MTCs but also in a high
percentage of small cell lung cancers, stromal ovarian cancers, astrocytomas and
several other tumour types. The aim of this study was to evaluate whether
radiolabelled gastrin may be suitable for targeting CCK-B receptor-expressing
tumours in vivo. For this purpose, the biodistribution of the radioiodinated
human heptadecapeptide gastrin-I was studied in nude mice bearing subcutaneous
xenografts of the human MTC cell line, TT. Initial therapy experiments were
undertaken. Finally, the biodistribution of iodine-131- labelled gastrin-I was
studied in a patient with metastatic MTC. At a peptide amount of approximately 1
microg, maximum tumour uptake (8.9+/-2.9%ID/g) was observed in animals at 1 h
post injection, with tumour-to-blood ratios as high as 6.3+/-1.9. Physiological
CCK-B receptors in the stomach, gallbladder and pancreas of the mice were
targeted as well. The major route of excretion was renal, but strong evidence for
a biliary excretion pathway also exists. Pilot therapy studies with 131I-labelled
gastrin showed significant anti-tumour efficacy as compared with untreated
controls. In accordance with the preclinical data, good receptor targeting was
observed in the tumour sites, stomach, gallbladder and pancreas of a patient with
metastatic MTC. These data suggest that gastrin and its analogues may represent a
useful new class of receptor binding peptides for diagnosis and therapy of a
variety of tumour types, including MTC and small cell lung cancer. Future
preclinical and clinical studies will address in more detail the molecular
features that render CCK-B receptor binding agents potentially useful candidates
for in vivo scintigraphy and radionuclide therapy.
PMID- 9553174
TI - Value of thallium-201 scintigraphy for primary tumour detection in patients with
malignant neck masses.
AB - The aim of this study was to assess the contribution of thallium-201 scintigraphy
to primary tumour detection in patients with malignant neck masses and to
evaluate its sensitivity and specificity. A total of 30 patients with
histopathologically proven malignant tumours were included in the study. The
sensitivity, specificity and accuracy of 201Tl scintigraphy were found to be 54%,
75% and 57% respectively. These results suggest that 201Tl scintigraphy has a
limited value in the detection of the primary tumour in patients with malignant
masses of the neck.
PMID- 9553175
TI - Cardiac sympathetic neurotransmission scintigraphy.
PMID- 9553178
TI - Prenatal and neonatal intussusception.
AB - Intussusception found in the 1st month of life is rare and usually discussed as
one entity, neonatal intussusception, but in fact, includes the intussusceptions
occurring both prenatally and neonatally, of which the clinical presentations and
results are different. Four full-term babies with prenatal intussusception
presenting as intestinal atresia (IA) and three premature babies with neonatal
intussusception mimicking necrotizing enterocolitis (NEC) are presented. Prenatal
intussusception, as one of the causes of IA produces prominent signs of
intestinal obstruction immediately after birth. Preoperative evaluation usually
fails to yield a definitive diagnosis, but surgery is usually performed in time
and is successful. In neonatal intussusception, full-term infants usually have a
pathological lead point and the colon is almost always involved. A barium enema
is thus useful in diagnosis. Premature babies, on the other hand, rarely have a
colonic component, and the clinical features are insidious and similar to NEC.
This results in diagnostic confusion that may lead to a dangerous delay in
appropriate surgical correction. A high level of suspicion about this condition
in cases diagnosed presumptively with NEC is important. Serial abdominal
sonograms may be helpful in the early diagnosis of neonatal intussusception.
PMID- 9553179
TI - Active collagen synthesis in infantile hypertrophic pyloric stenosis.
AB - M-57 antibody, which is capable of distinguishing newly-synthesized type I
procollagen from fully-processed, mature collagen, was used to examine the
expression of collagen synthesis in hypertrophic pyloric muscle from patients
with infantile hypertrophic pyloric stenosis (IHPS). Seven specimens from IHPS
patients were removed at the time of operation; age-matched normal pyloric tissue
of 5 post-mortem cases was obtained as controls. Immunohistochemistry was
performed using antibody of the amino-terminal end of the procollagen type I
propeptide (M-57). Newly-synthesized procollagen (M-57) was strongly detected in
both the connective tissue septa between circular muscle bundles, and among the
circular-muscle fibers in patients with IHPS. No M-57 staining was observed among
the circular-muscle fibers in controls. Our findings show that the hypertrophic
circular muscle in IHPS is actively synthesizing collagen, and this may be
responsible for the characteristic "firm" nature of the pyloric tumor.
PMID- 9553180
TI - Laparoscopic pyloromyotomy: a safer technique.
AB - A modified technique of laparoscopic pyloromyotomy was used to treat infantile
hypertrophic pyloric stenosis. Introducing a 5-mm periumbilical port for
visualization, two stab wounds are made on either side laterally to directly
insert 2.7-mm instruments for manipulation. From the left, the stomach is grasped
- not the duodenum! From the right, an inexpensive disposable arthroscopy knife
is used to incise the serosa and begin the myotomy, which is completed with a
laparoscopic spreader until the muscle is separated sufficiently to relieve the
obstruction. Twenty-nine children treated with laparoscopic pyloromyotomy were
compared to 125 children treated with the conventional open Ramstedt
pyloromyotomy. There were no statistically significant differences in the
presentation or results between groups, suggesting that the laparoscopic
technique is a safe and equal alternative.
PMID- 9553181
TI - Pathogenesis of infantile hypertrophic pyloric stenosis: recent progress.
AB - Although infantile hypertrophic pyloric stenosis (IHPS) is the most common
condition requiring surgery in the first few months of life, its pathogenesis is
not fully understood. Reviews of the recent progress in the pathogenesis of IHPS
show: (1) there is increasing evidence to suggest that smooth-muscle cells in
IHPS are not properly innervated; (2) because non-adrenergic, non-cholinergic
nerves are mediators of smooth-muscle relaxation, it is likely that the absence
of these nerves in pyloric muscle is the cause of excessively contracted
hypertrophic circular pyloric muscle; (3) there are abnormal amounts of
extracellular matrix proteins in hypertrophic pyloric muscle. Circular muscle
cells in IHPS are actively synthesizing collagen, and this may be responsible for
the characteristic "firm" nature of the pyloric tumor; and (4) the increased
expression of insulin-like growth factor-I, transforming growth factor-beta 1,
and platelet-derived growth factor-BB and their receptors in hypertrophic pyloric
muscle suggests that increased local synthesis of growth factors may play an
important role in smooth-muscle hypertrophy in IHPS.
PMID- 9553182
TI - Increased insulin-like growth factor-I mRNA expression in pyloric muscle in
infantile hypertrophic pyloric stenosis.
AB - The etiology of infantile hypertrophic pyloric stenosis (IHPS) is unknown.
Insulin-like growth factor-I (IGF-I) is a polypeptide hormone that elicits
various biological activities (cellular growth, replication, and differentiation)
by binding to its receptors. IGF-I has been suggested to play an important role
in both gastrointestinal (GI) maturation and smooth-muscle-cell (SMC)
hypertrophy. Full-thickness muscle biopsy specimens were obtained from 8 IHPS
patients (age range 14-64 days, mean 28.1 days) at pyloromyotomy and from 8 age
matched controls (15-60 days, mean 33.8 days) without GI disease at autopsy. In
situ hybridization was performed using an IGF-I-specific and digoxigenin (DIG)
labeled oligonucleotide probe and visualized by nitroblue tetrazolium staining.
In normal controls, IGF-I mRNA expression was absent or weak in both circular and
longitudinal smooth-muscle layers of pyloric muscle. In contrast, the pyloric
muscle in IHPS patients demonstrated strong IGF-I mRNA expression in the circular
smooth-muscle layer and moderate expression in the longitudinal smooth-muscle
layer. The increase in IGF-I mRNA in pyloric muscle in IHPS suggests that SMCs
are actively synthesizing IGF-I, contributing to the development of pyloric
muscle hypertrophy.
PMID- 9553183
TI - Endoscopic treatment of recurrent tracheo-oesophageal fistulae: long-term
results.
AB - Recurrent tracheo-oesophageal fistula (RTOF) occurs in 5%-15% of patients
following oesophageal atresia repair. Re-thoracotomy is technically challenging
and associated with significant morbidity, including a re-fistulation rate of 10%
22%. Endoscopic occlusion of the RTOF with tissue adhesives (fibrin glue,
Histoacryl) is reported to be safe and highly effective. However, long-term
results of such therapy are absent from the literature. A postal survey of 13
institutions reporting the use of such treatment regimes for RTOF in the
literature between 1974 and 1995 was performed, and data collected concerning the
long-term outcomes of their reported patients. Eleven institutions responded to
the request for data, providing 22 patients (age range 1 month to 12 years) for
review. All had undergone initially successful RTOF closure by endoscopic methods
and had been followed up for a median of 107 months (range 3-264 months). There
was no morbidity or mortality directly related to the procedure. Overall, only
55% of these endoscopically treated fistulas remained closed long-term. Fistula
recurrence invariably occurred within 12 months of successful therapy (median 46
days, range 9-335). Most patients required multiple endoscopic procedures to
achieve successful RTOF closure (median 2.0, range 1-4 attempts), although
significantly fewer attempts were required with fibrin glue therapy. Surgical re
exploration remains the treatment of choice in the fit child. Endoscopic therapy
offers a safe and elegant alternative to high-risk surgery in the sick child,
although repeated treatments may be required for successful RTOF closure.
PMID- 9553184
TI - Gastrointestinal tract perforation due to blunt abdominal trauma.
AB - A retrospective clinical study was performed to evaluate the etiology, diagnosis,
and management of gastrointestinal tract perforation (GITP) due to blunt
abdominal trauma (BAT) in order to find a predictor to avoid delay in diagnosis.
Thirty-five children with GITP out of 805 BAT victims (4.3%) over a 21-year
period formed the study group. Different parameters including preoperative
(mechanism of injury, abdominal and X- ray findings at presentation, diagnostic
modalities), operative (type and site of GITP, intra-abdominal associated
injuries, surgical method), and postoperative (complications, mortality) status
were analyzed. The patients were subdivided according to their initial clinical
presentation as group I: evidence of peritonitis (n = 19, 54%); group II:
abdominal findings such as distension, minimal tenderness, and guarding (n = 10,
29%); and group III: normal abdominal findings (n = 6, 26%). These groups were
also statistically compared to each other with regard to the parameters mentioned
above. The Mann-Whitney U, Wilcoxon rank-sum, and Kruskal-Wallis tests were used
for statistical analysis. P < 0.05 was considered to be statistically
significant. There were 28 boys and 7 girls; the mean age was 8.2 +/- 2.4 years.
Mechanisms of injury were motor vehicle accidents (MVA) (60%), falls (26%), and
bicycle accidents (BA) (14%). Group I patients presented with significantly
higher transaminase levels and white blood cell counts than groups II and III.
Group I patients and MVA victims were operated upon significantly earlier than
group III patients and BA victims because of significantly earlier development of
clinical signs of peritonitis. A significantly higher number of multiple
perforations was encountered in Group I and MVA victims than in groups II and III
and BA victims. The presence of multiple perforations correlated significantly
with the earlier development of clinical signs of peritonitis. The analysis of
site of perforation with regard to the other parameters did not differ
significantly. Fifty-four percent (n = 19) of the patients presented with
peritonitis; a pneumoperitoneum was detected in 46% (n = 16). Diagnosis was
accomplished by plain radiographs, ultrasound, computed tomography, and, most
importantly, frequent abdominal examination of the patient. The sites of
perforation were the stomach (4), duodenum (2), jejunum (11), ileum (12), jejunum
and ileum (3), colon (2), and ileum and colon (1). Simple closure was the most
common surgical procedure (n = 21), followed by resection and anastomosis (n =
12) and simple closure plus creation of a proximal ostomy (n = 2). Two deaths
(5.7%) were directly due to head injuries. Our experience revealed that in spite
of advanced imaging and laboratory modalities, frequent evaluation of the patient
by an experienced surgeon is still the most important tool for early diagnosis
and appropriate treatment. A child with BAT should be an inpatient and a high
index of suspicion is always required, even in the presence of normal abdominal
findings.
PMID- 9553185
TI - Is acute appendicitis different in patients with sickle cell disease?
AB - Nine patients with sickle cell disease (SCD) were operated upon at our hospital
for acute appendicitis, comprising only 0.43% of the total appendicectomies
performed at our institution. Three appendices were acutely inflamed and six
(66.7%) were perforated. Histologic evaluation of the six perforated specimens
revealed congestion and haemorrhage by sickled erythrocytes (RBCs) in addition to
acute transmural inflammatory cell infiltrates. The mucosa was extensively
ulcerated, with haemorrhage both within the lumen and in the appendiceal wall.
The blood vessels were dilated and packed with sickled RBCs. Two of the three
acutely inflamed appendices showed features of acute transmural appendicitis,
with marked congestion and haemorrhage by sickled RBCs. The third did not show
any acute inflammatory cell infiltrate, however, the mucosa was partly ulcerated
with both mucosal and intraluminal haemorrhage. These findings suggest that acute
appendicitis is different in patients with SCD: while it is not common, when it
does develop it has a rapid course with a high incidence of perforation due to
blockage of appendiceal vessels by sickled RBCs, leading to transmural necrosis.
PMID- 9553186
TI - Timing of colonic necrosis in hemolytic uremic syndrome.
AB - Hemolytic uremic syndrome (HUS) consists of an acute onset of microangiopathic
hemolytic anemia, thrombocytopenia, and renal dysfunction. HUS-associated colitis
can be seen in up to 100% of patients and is usually associated with severe
abdominal pain and distention. Colonic perforation is a complication of HUS that
has a reported incidence of 1%-2%, and although there are several case reports in
the literature describing perforation of the colon, it is still very difficult to
discern the abdominal symptoms associated with HUS colitis from perforation. Four
cases of colonic perforation are reported here from a consecutive series of 57
patients, in which a trend in the length of time from the onset of symptoms of
HUS to colonic perforation was determined. A review of the literature for cases
of HUS-associated colonic perforation was also performed. The time from the onset
of HUS symptoms to colonic perforation in our series was similar to that found in
the literature review (11 +/- 5 vs 14 +/- 8 days). Awareness that this
complication has a tendency to occur towards the end of the 2nd week during the
course of HUS is essential to avoid an unnecessary and untimely surgical
intervention.
PMID- 9553187
TI - Fetal adrenal transplants respond to ACTH and prevent addisonian crisis in
adrenalectomized rats.
AB - The present study investigates whether fetal adrenal transplants into the omentum
of adrenalectomized rats will be integrated into the recipient's endocrine system
to provide competent adrenocortical function. The results demonstrate that fetal
adrenals graft with a rich vascular supply, mature histologically, and produce
increasing levels of corticosterone. When bilateral adrenalectomy is performed in
the recipient, survival is prolonged and addisonian crisis can be prevented.
Moreover, adrenocorticotrophic hormone levels decrease with increasing levels of
corticosterone, indicating that the fetal grafts are integrated into the
physiological pituitary-adrenocortical feedback system.
PMID- 9553188
TI - Conservative management of fistula in ano in infants.
AB - We analyzed the natural course of fistula in ano (FIA) and/or perianal abscess
(PAA) in 97 children (male: 90, female: 7) and recommend conservative management
in infants. Nearly one-half of these children had no recurrent episodes, and 80%
of the infants recovered spontaneously within their 1st year of life. A radical
operation was required in only 6 children after 2 years of age. Two-thirds of the
children with a PAA did not develop fistula. Of the children who developed FIA,
42% had no recurrence. Although the duration of FIA was relatively longer than
that of PAA, 55% of the children were cured within 1 year. PAA and/or FIA in
infants is likely to be a period-limited disorder that occurs mainly in infancy
and spontaneously resolves within 1 year of life. Fistulotomy or fistulectomy
should be avoided in infants.
PMID- 9553189
TI - Endoscopic and minimal open surgical incision of ureteroceles.
AB - Ureterocele decompression by endoscopic or open incision was the primary
treatment in 59 children with 63 ureteroceles. Of these, 18 were intravesical and
45 were ectopic. The endoscopic or open incision adequately decompressed all
intravesical ureteroceles and 37 of 45 ectopic ureteroceles (82%). After
incision, the secondary operation rate was 17% for intravesical and 62% for
ectopic ureteroceles. In our opinion, endoscopic or open incision must be
considered a definitive treatment in the large majority of intravesical
ureteroceles and is also valid in ectopic ureteroceles. In these cases, the early
decompression obtained by this approach produced significant functional recovery,
fewer urinary tract infections, and facilitated subsequent surgery in those
patients requiring complete surgical reconstruction.
PMID- 9553190
TI - Management of nocturnal enuresis in children with desmopressin and bladder
physiotherapy.
AB - In the last 2 years, 29 children with nocturnal enuresis were treated in the
outpatient departments of the Departments of Urology and Pediatric Surgery of the
Aristotle University, Thessaloniki. There were 22 boys and 7 girls aged 7 to 12
years. The clinical examination was normal in all cases. All children had
undergone various treatments with no beneficial effect, and relapses had
occurred. The patients were given desmopressin (DDAVP) nasal drops in combination
with bladder physiotherapy; 77% were cured after 12 months. Physiotherapy
improves the percentage of cures as the functional capacity of the bladder
increases.
PMID- 9553192
TI - Antenatal rupture of a diverticular rectal duplication with neonatal perineal
fistulization.
AB - A cystic pelvic malformation was found in a fetus on antenatal sonography (US) at
26 weeks of gestational age that was no longer present 3 weeks later on control
US. The male child presented at birth with a right-sided perineal mass that
fistulized with meconial drainage. A radiopaque enema showed a low posterior
rectal fistula filling a poorly delineated pouch. Surgery performed through a
posterior sagittal approach allowed identification and closure of the fistula and
pouch drainage. The diagnosis of a diverticular rectal duplication was
considered, although no intestinal lining was observed macroscopically or
histologically. The child's anorectal function was normal after a 20-month follow
up. Labeling of the malformation and embryological hypotheses are discussed since
the case does not fulfill all the criteria of an intestinal duplication. Surgical
techniques are discussed, with an emphasis on the sagittal posterior approach.
PMID- 9553191
TI - Coeliac axis thrombosis associated with the combined oral contraceptive pill: a
rare cause of an acute abdomen.
AB - We report a case of coeliac axis thrombosis and splenic infarction presenting in
a girl of 14 years who had been on the oral contraceptive pill (OCP), Marvelon
(ethinyloestradiol 30 microg plus desogestrel 150 microg, Organon, Cambridge,
UK), for 3 weeks. She had no other risk factors for thrombo-embolism. Diagnosis
was made with duplex Doppler ultrasound and confirmed with dynamically-enhanced
comput-ed tomography and magnetic resonance angiography, thus avoiding the need
for percutaneous arteriography. Though mesenteric thrombo-embolic disease is
recognised in association with use of the combined OCP, it has not previously
been reported to affect the coeliac axis. Paediatricians and surgeons should be
aware of the risks to young girls on the OCP, and consider it in their
differential diagnosis of the acute abdomen.
PMID- 9553193
TI - Upper pole pelviureteric junction obstruction.
AB - A case of neonatal hydronephrosis affecting the upper moiety of a duplex kidney
is presented. In addition to the ectopic insertion of the upper-pole ureter into
the urethra, the ureter was obstructed by the lower pole at its pelviureteric
junction.
PMID- 9553194
TI - Wilms' tumor presenting as Cushing's syndrome.
AB - We report a 2-year-old boy presenting with Cushing's syndrome caused by a Wilms'
tumor. This is the fifth such case reported in the English literature.
PMID- 9553195
TI - Juvenile (calcifying) aponeurotic fibroma of the neck.
AB - A case of juvenile (calcifying) aponeurotic fibroma (JAF) arising in the neck of
a 5-year-old female is presented. The lesion was misdiagnosed as fibrous
hamartoma of infancy (FHI) on a superficial biopsy prior to total excision of the
mass. Only one instance of JAF of the neck has previously been reported; the
tumor is usually located in the distal extremities and often recurs following
excision. FHI occurs most frequently at and about the axilla and shoulder, and
does not recur in most instances.
PMID- 9553196
TI - The doughnut sign: an ultrasound finding in pediatric intestinal Burkitt's
lymphoma.
AB - This paper describes a doughnut-like ultrasound (US) finding in pediatric
intestinal Burkitt's lymphoma. A 9-year-old boy had a fist-sized, hard, non
movable mass in the lower abdomen. US showed a thickened, layered ring like a
doughnut. The outer, low-level echoes seemed to be consistent with mucosa and
muscle layers and the inner, high-level echoes seemed to be intraluminal air or
mucus. The serum lactic dehydrogenase level was high. At surgery, a solid, hard
tumor 15 x 10 cm in size was found in the jejunum. The intestinal wall was
diffusely thickened with an intact mucosa. From this experience, the US doughnut
sign may be a helpful diagnostic finding in pediatric intestinal Burkitt's
lymphoma.
PMID- 9553197
TI - Two children with xeroderma pigmentosum developing two different types of
malignancies simultaneously.
AB - Patients with xeroderma pigmentosum (XP) are highly sensitive to ultraviolet
radiation and prone to develop multiple skin malignancies. We report two children
under 6 years of age with XP who each developed two histologically different
types of malignancies simultaneously. We conclude that it is of importance to be
aware of the possibility of multiple malignancies of different types, even in
young children.
PMID- 9553198
TI - Papillomavirus-induced genital warts in a girl--management by surgery and
immunomodulating therapy.
AB - A 4-year-old girl with condylomata acuminata of the vulva and papular warts of
the surrounding skin is presented. The lesions were removed by surgery.
Histologic investigation showed koilocytosis of the squamous epithelium and in
situ hybridization revealed human papilloma virus type 6 infection. There were no
signs of sexual abuse or sexual transmission of the virus. After ablation, an
interferon-containing ointment was applied. In order to prevent recurrence, a low
molecular-weight immunomodulating leucocyte fraction was given for more than 1
year, during which time no relapse was observed.
PMID- 9553199
TI - Cutaneous angiosarcoma of the distal extremity.
AB - A case of childhood cutaneous angiosarcoma is presented to emphasize the
importance of accurate histological diagnosis in lymphovascular malformations
that behave atypically and to review the natural history, aetiology, and
differential diagnosis of this condition.
PMID- 9553200
TI - [The heart and kidney].
PMID- 9553201
TI - [The intestine as an immunological organ].
AB - The intestinal mucosa is in close contact with a large number of foreign antigens
and mitogenic substances in the gut lumen. To protect the host against invasion
of potential pathogens or an inappropriate immune response to the enormous number
of antigens, a highly specialized immune system in the intestinal mucosa has
developed, the so-called gut-associated lymphoid tissue (GALT). The passage of
viable bacteria from the gastrointestinal tract through the epithelial mucosa is
called bacterial translocation. Bacterial translocation in critically ill
patients may lead to a significant incidence of systemic sepsis. This has
attracted much clinical interest, as it has been shown that disturbances of the
GALT and malnutrition itself, impair various aspects of barrier function. Enteral
nutrition seems to be superior to parenteral nutrition in maintaining the
functional barrier of the gut. Defined dietary variable (fibre, glutamine)
influence bacterial translocation. Future therapeutic strategies should therefore
concentrate on early enteral feeding in traumatised patients to reduce the
incidence of bacterial translocation and septic complications.
PMID- 9553202
TI - Detection of mi transcription factor (MITF) mRNA in a case of myelodysplastic
syndrome and bone marrow mastocytosis.
AB - Myelodysplastic syndromes (MDS) may be accompanied by systemic mastocytosis. The
mechanisms which play a role in the evolution of mastocytosis, however, are not
well understood. We report on a case of refractory and anemia with ringed
sideroblasts (RARS), and co-existing bone marrow mastocytosis. Compact mast cell
(MC) infiltrates were detected in bone marrow sections by immunohistochemistry
using an antibody to tryptase. In addition, the MC were found to express c-kit,
the tyrosine kinase receptor for MGF (mast cell growth factor = stem cell factor,
SCF). Activating point mutations in the kinase domain of c-kit (often found in
mastocytosis) were not detectable. However, the mononuclear cells (MNC) of the
bone marrow expressed mRNA specific for MITF, a transcription factor that
regulates expression of c-kit and differentiation of MC. Surprisingly, the c-kit
ligand SCF was found to augment expression of MITF mRNA in bone marrow MNC.
Whether this augmentation represents a general response (preventing loss of
growth factor receptor expression during cell maturation) common to all types of
hemopoietic progenitors, or is confined to (some forms of) mastocytosis, remains
unknown.
PMID- 9553203
TI - Relationship between kidney function, hemodynamic variables and circulating big
endothelin levels in patients with severe refractory heart failure.
AB - Fluid retention is a major characteristic of symptomatic, progressive heart
failure when a main factor implicated in the pathogenesis of renal dysfunction is
renal hypoperfusion. This may be a consequence of forward cardiac failure,
resulting in a low cardiac output integrating poor left ventricular function
secondary to myocardial impairment and increased resistance in the regional renal
vasculature secondary to locally released vasoconstrictors, e.g. endothelin. So
far, the role of the pulmonary circulation in perpetuating renal dysfunction in
heart failure is unclear. METHODS: We investigated the relationship of
hemodynamic variables obtained during right heart catheterization and plasma big
endothelin levels to renal function variables in 18 male patients aged 52 +/- 3
years, with heart failure in the NYHA function class III-IV, based on idiopathic
causes in 8 and ischemic causes in 10 patients. Renal plasma flow (RPF) was
established by paraaminohippurate (PAH) clearance and the glomerular filtration
rate (GFR) was measured by iothalamate clearance. RESULTS: Plasma big endothelin
(ET) levels were increased above the upper normal range (1.8 fmol/ml) in 16 out
of 18 patients, averaging 5.0 +/- 0.8 fmol/ml (1.7-11.9 fmol/ml). Positive
correlations to big ET plasma levels were detected with mean pulmonary pressure
(r = 0.73, p < 0.001) pulmonary capillary wedge pressure (r = 0.56, p < 0.05) and
pulmonary vascular resistance index (r = 0.69, p < 0.01). Glomerular filtration
rate (70 +/- 7 ml/min) and renal plasma flow (358 +/- 36 ml/min) were
considerably reduced and exhibited a tendency to correlate inversely with big ET
levels (r = -0.46, p = 0.056 and r = -0.44, p = 0.069, respectively). Contrary to
expectations, RPF did not correlate significantly with cardiac index, systemic
vascular resistance index or arterial blood pressure. In contrast, significant
correlations were detected of RPF with pulmonary capillary wedge pressure (r =
0.69, p < 0.01), mean pulmonary artery pressure (r = -0.65, p < 0.01), right
atrial pressure (r = -0.47, p < 0.05) and right ventricular ejection fraction (r
= 0.49, p < 0.05). CONCLUSION: The findings suggest a role for endothelin in
renal vasoconstriction and accord well with the concept that in severe heart
failure renal hypoperfusion--by volume retention--as well as increased endothelin
synthesis--by pulmonary vasoconstriction--play a part in the increased pulmonary
filling pressures.
PMID- 9553204
TI - Protective effects of sucralfate and omeprazole on gastric mucosal damage induced
by ethanol in rats.
AB - Studies on the protective effect of omeprazole, a proton-pump inhibitor, against
damage to the rat gastric mucosa induced by strong irritants, are few and
contradictory. We have investigated the protective effects of omeprazole and
sucralfate against gastric mucosal damage induced by ethanol in rats. The study
was performed on 4 groups of 10 rats each. Group A received omeprazole 7
mg/kg/day intraperitoneally (i.p.) for 7 days. Group B received an equivalent
volume of 0.9% sodium chloride i.p. for 7 days, while no drugs were given to
groups C and D. After 1 week, following 24 hours of fasting, group A received
omeprazole 7 mg/kg, group B received an equivalent volume of 0.9% sodium chloride
group C received omeprazole 7 mg/kg i.p. and group D received sucralfate, 100
mg/kg intragastrically (i.g.). 4 hours after groups A, B and C received the last
medication and 30 minutes after group D received sucralfate, ethanol 95% was
given i.g. All rats were sacrificed 1 hour after ethanol application and their
stomachs were removed for macroscopic and microscopic examination. It was found
that sucralfate was effective in preventing gastric lesions induced by ethanol.
There was a significant difference between the sucralfate group and the other
group (p < 0.001). Omeprazole was ineffective in preventing gastric lesions,
either given as a single dose or after administration for 7 days. Our results
indicate that sucralfate has a protective effect on gastric lesions induced by
ethanol and omeprazole applied i.p. has no protective effect.
PMID- 9553206
TI - [Pain therapy only for specialists or general responsibility?].
PMID- 9553205
TI - [Gastrointestinal hemorrhage after operation for dissecting aneurysm of the
thoracic aorta].
AB - We present the case of a 45-year-old man who underwent surgical repair of a
dissecting aneurysm of the descending thoracic aorta. 25 days postoperatively,
the patient unexpectedly developed hematemesis and hypovolemic shock. Emergency
gastroscopy was performed and a suspected aortoesophageal fistula was diagnosed.
Unfortunately, the patient died prior to emergency surgery. Aneurysms of the
aorta or of aortic grafts occasionally lead to the development of fistulae to the
upper gastrointestinal tract. Once this rare, but life-threatening complication
is suspected, endoscopy must be performed immediately. Emergency surgery is
associated with a high risk, but represents the only possibly chance of survival
for the patient.
PMID- 9553207
TI - [Headache--differential diagnosis and therapy].
AB - Only few guidelines exist for the therapy of chronic pain syndromes but are
available for headache. It is important to know the therapeutic principles and
apply them to the patients. The education of a patient suffering from headache is
a main factor for a successful therapy. Physician and psychologist together in
cooperation with the patient can achieve a better quality of life for the
patient. New developments of the medication used for the therapy of chronic
headache will result in a better symptom control in the next years.
PMID- 9553208
TI - [Backache--diagnosis, therapy and prognosis].
AB - Back pain is a common disease causing tremendous costs for treatment,
rehabilitation, pension payments and work-loss. The reasons of back pain vary
considerably and often remain doubtful. The effectiveness of current treatment
concepts has not yet been proven significantly. In accordance with the
literature, in chronic pain only multimodal concepts of treatment seem to be
successful as far as they take care about somatic, psycho-social, and sport
physiological aspects.
PMID- 9553209
TI - [Therapy of tumor pain].
AB - The incidence of cancer pain is about 90%. The first step in the treatment
strategy is a causal therapy, including tumor mass reduction. An adequate pain
management should start sometimes before the onset of a causal treatment. A good
pain relief in cancer patients is mostly possible by the consequent application
of the World Health Organisation 3 step analgesic ladder for the treatment of
cancer. Pain management has become more comfortable since the development of new
ways of applications e.g. transdermal fentanyl, water soluble morphine granulate
and retarded drugs. With those new preparations, we got new possibilities and a
bigger variety in the practical use of the WHO analgesic ladder. Basics for a
good social integration of the patient are treatment of side effects, periodic
consultations and a professional psychological support.
PMID- 9553210
TI - [Indications and limits of nerve block techniques].
AB - Repetitive nerve blocks as a monotherapeutic treatment are loosing importance in
the therapy of chronic pain. Such invasive methods for pain reduction are just
one strategy in the interdisciplinary and multimodal planning of pain therapy.
They are mostly used in special indications, e.g. reflex sympathetic dystrophy
neurolysis in S3-S5 localized cancer pain. Premises for an invasive pain therapy
are the patient's knowledge and agreement concerning this method. Furthermore, it
is necessary for the physician to know the typical complications of the invasive
treatment and to be able to manage them. It is recommended to document the pain
course.
PMID- 9553211
TI - [Sympathetic reflex dystrophy and phantom pain. Diagnosis, therapy and
prognosis].
AB - The incidence of phantom limb pain has been significantly underestimated for many
years. However, studies published during the recent decade indicate that the real
incidence of phantom limb pain may be between 60% and 90%. Reflex sympathetic
dystrophy (RSD) occurs with an incidence of about 15.000 new cases every year in
Germany. Both diseases show early centralisation and chronification. Hence, only
early diagnosis and onset of correct therapy in time provide significant pain
reduction. When therapy is started too late, prognosis in regard to sufficient
pain reduction is poor. Phantom limb pain can be prevented by proper anaesthesia.
Several studies could show the benefit of perioperative continuous regional
anaesthesia . None of the patients treated with a combination of local
anaesthetics and low dose morphine developed phantom limb pain. Therapy of choice
for RSD is the sympathetic blockade. The most suitable method is intravenous
regional sympathetic blockade (IVRSB) with guanethidine (2).
PMID- 9553212
TI - [Non-opioid analgesics and co-analgesics in therapy of chronic pain].
AB - Efficacy and side effects of non-opioid-analgesics were analysed in a
standardized review of placebo-controlled or double-blind studies. In rheumatoid
arthritis, ibuprofen showed the best ratio of effectiveness and side-effects.
Naproxen, diclofenac and meloxicam may serve as alternatives. In osteoarthritis,
naproxen seems to be superior to diflunisal, meloxicam and diclofenac. In cancer
pain, ibuprofen is the treatment of the first choice followed by naproxen and
diclofenac. No sufficient data on non-opioids in neuropathic pain were available.
The dose administered in the management of chronic pain should be low in order to
reduce the incidence of side-effects. The frequency of side-effect-related
discontinuation of chronic pain medication was calculated as follows: ibuprofen
3.8%, aspirin 4.7%, piroxicam 4.8%, naproxen 7.4%, meloxicam 13.0% and diclofenac
17.8%. Since differences in efficacy were not clinically relevant, the indication
for a special non-opioid-analgesic medication should focus on the prevention of
side-effects.
PMID- 9553214
TI - [Palliative medicine].
AB - Palliative medicine is the care and the study of that care for patients, with an
active, progressive, and advanced disease, where life expectancy is relatively
short. The goal is achievement of the best possible quality of life for patients
and their families. Pain therapy, control of other physical symptoms and of
psychological, social and spiritual problems are cornerstones of palliative
medicine. Skilled empathetic communication and ethical issues are essential to
many of the aspects of palliative care. Education and training of professional
health workers involved in the care of dying patients is important.
PMID- 9553213
TI - [Paraspinal opioids and pump systems].
AB - The regional application of opioids close to the spinal cord by using pumps
induces a pain reduction comparable to the systemic medication of the WHO
analgesic ladder. However, this method does not reduce the side effects of these
drugs, e.g. nausea, vomiting, dysfunctional bladder emptying, and obstipation.
Problems and complications leading to revision surgery and system explantation,
respectively, are of more severe importance. Pump explantation occurs in a
frequency of 7.3% and revision surgery in a frequency of 6.2%. Catheters and port
systems have to be revised in 15% of all cases. Therefore, the indication for
this method has to be considered carefully and includes the following criteria:
pain of somatic origin, exclusion of mental diseases and psychogenic causes of
pain, causal therapy is exhausted, insufficient effects of peripheral analgesics
and co-analgesics, oral or transdermal opioids are insufficient despite dosages
resulting in side-effects, pain is sensible to opioids, regional application of
opioids has been tested effective before implantation.
PMID- 9553215
TI - [Psychological pain therapy].
AB - Psychologic strategies for the treatment of chronic pain are an important
component of the necessary multidimensional treatment for patients in chronic
pain. These techniques including relaxation training, biofeedback, hypnosis and
cognitive-behavioral therapy have demonstrated efficacy. The impact of these
techniques is on the sensory aspect of pain and the psychologic distress and on
the maladaptive coping mechanism people develop in response to pain. In Germany
there are still several impediments for the consequent application of psychologic
strategies for patients with chronic pain. These impediments and possible
solutions are discussed.
PMID- 9553216
TI - [Economic aspects of pain therapy].
AB - Chronic pain has an economic impact for the society and the patients suffering
from chronic pain. The indirect costs of chronic pain (loss of productivity,
social security payments) are higher than the direct costs (prevention, diagnosis
and therapy). The indirect costs in the family are often underestimated. It is
proven that in-patient and out-patient treatment in multidisciplinary pain
centers are effective. In-patient treatment is more expensive. Multidisciplinary
pain programmes increase the return-to-work-rate significantly. Further
investigations are requested to uncover costs and outcome of different pain
treatment methods.
PMID- 9553217
TI - [Suicide in the elderly: collapse of value orientation?].
AB - Suicide of the aged has often been understood as a careful deliberation of the
quintessence of life. Nevertheless, it displays the breakdown or the entire lack
of value orientation. Some gerontologists have come to terms with the fact that
the ideal of value-free living results in the suicidality of the aged. Suicide
seems to be a probable solution of their problems. But values regulate the social
existence of humans. Accordingly, this paper considers suicide of the aged to be
a result of this disorientation. Thus, it demands first of all that a rich set of
values has to be developed, and secondly, that adequate resources of values have
to be proposed. This can be achieved by four steps: 1) distance from the critical
situation, 2) combination of interaction and mutual appreciation, 3) analyzing
the reduced set of values, and 4) opening new priorities and preferences.
PMID- 9553218
TI - [Stages in coping after stroke].
AB - People who suffer a stroke most often experience a major crisis in their lives.
This leads to psychological problems which are likely to influence the patient's
life satisfaction, long-term rehabilitation outcome, and quality of life as much
as the physical consequences caused by the stroke, The patient's ability to
accept the new reality created by a disability as a part of their future life is
therefore essential. This necessitates an individual coping strategy in the
center of which is a mourning process, which unfolds in the same way as other
experiences of vital threat, e.g. confrontation with one's own dying. Different
stages of mourning that can also be found in stroke patients are nonacceptance of
the facts, erupting emotions, parting with the former and finding of a new self
as well as new perspectives for one's future. Whether a coping process is
successful does not depend on the type of the defense mechanisms or stages, but
essentially on their persistence. It is the task of the therapeutical team to
support this process by applying a basic therapeutic behavior, stage-consistent
interventions and a positive feedback. A failed process of coping may be one of
the causes of the high prevalence of psychological disorders like depression and
anxiety disorders in patients having suffered a stroke.
PMID- 9553219
TI - [Clostridium difficile toxin-associated diarrhea in geriatrics].
AB - In the course of 1 year, Clostridium difficile-associated diarrhea, which may
lead to pseudomembranous colitis and therefore may be very harmful in frail
elderly people, was diagnosed in six patients of a geriatric clinic. The disease
is associated with antibiotic therapy, due to an overgrowth of the intestinal
flora with Clostridium difficile. Symptoms varied from a state of asymptomatic
carriage or benign diarrhea to acute stages of the disease with severe diarrhea,
abdominal pain, fever and acute phase response. Diagnosis of Clostridium
difficile associated diarrhea was established when, in addition to typical
clinical symptoms, a toxin-positive stool specimen was found. Oral vancomycin was
effective in all cases, leading to a stop in the diarrhea and an amelioration of
systemic inflammatory parameters. According to recent results, in order to
prevent the induction of vancomycin-resistance and in view of higher treatment
costs, metronidazole is considered as the drug of choice in mildly and moderately
ill patients.
PMID- 9553220
TI - [Gerontologic studies in South Africa--a report].
AB - The paper reviews the present state of gerontological research in South Africa
and provides examples of relevant studies. So far, most of the research has
focused on socioeconomic conditions, e.g, financial status, living arrangements,
and intergeneration family relations. During recent years another topic has
gained prominence, e.g., the subjective well-being of the elderly. Another aspect
of research in this area is its inter- and multidisciplinary nature and its
concern with practical relevance. Terms often used in new research on aging are
"empowerment of the elderly" and "self-care strategies". In this context, the
elderly are beginning to be considered as significant brokers in development
planning. In the last part of the paper, the trend to qualitative methods is
discussed.
PMID- 9553221
TI - [How does subjective well-being of elderly patients during inpatient geriatric
rehabilitation change?].
AB - During rehabilitation of patients suffering from a recent hip fracture, we
evaluated the development of several aspects of their subjective well-being (n =
87, age: 70 to 94)). In most cases, a deterioration of subjective well-being due
to the consequences of the hip fracture could be prevented; the well-being
improved in most cases. When discharged, the subjective well-being of our
patients was comparable to the well-being of similar-aged people living at home.
PMID- 9553223
TI - [Management of treatment omission. Ethical problems in terminal care].
AB - Causes and courses of the diseases are subjected to a change of an increasing
life expectancy on the one hand and technically highly developed medicine on the
other hand. Since a growing number of elderly people is denying intensive medical
interventions which serve the purpose of keeping them alive despite severe
diseases, the problem of euthanasia imposes direct questions. A central role is
played by the active-passive difference and its moralistic legitimacy. The
difficulties of this difference are discussed below on the applicable level of
ethical discussions. At the same time, knowledge of the danger is being made
aware that in a maximal therapeutical orientated medical care system the desire
for euthanasia may become identical with the reverse side of this care system.
PMID- 9553222
TI - [Vascular dementia--a concise concept?].
AB - Although cerebrovascular disease are the most common causes of dementia after
Alzheimer's disease, vascular dementia (VD) has remained so far an ill-defined
term. The main problems in the definition of VD arise from finding criteria for
both terms "vascular" and "dementia". The detailed criteria for the diagnosis of
VD proposed by several groups or institutions (ADDTC, DSM-IV, ICD-10, NINDS
ARIEN) are critically reviewed. The diagnostic value of some clinical findings,
especially the very frequent white matter luciencies in CT (leuko-araiosis), are
discussed. The available studies suggest a differentiation of VD into some
subtypes (listed according to the frequency): subcortical VD, VD with acute
onset, multi-infarct-dementia, mixed types, and specific forms. Nevertheless,
these subtypes give only little information about the etiology of the underlying
vascular process and, therefore, no clear indication for specific therapeutic
strategies.
PMID- 9553224
TI - [Home care of demented and non-demented patients. I: Utilization of professional
home care services].
AB - 1911 informal caregivers from the Federal Republic of Germany who care for
someone with a chronic, non-congenital condition rendering them in need of
physical "hands-on" nursing completed a standardized questionnaire on their
situation as caregivers. The informants were found through magazine
advertisements as well as through dissemination of the questionnaires via contact
persons in the social services. Predictors of whether use is made of professional
help or not (in-home respite and/or day-care and/or temporary institutional
respite) are--independent of the reasons why help is necessary--the extent of the
help that is needed and the absence of support with the family. Sociodemographic
variables, that are age, sex, income, and education have no influence.
PMID- 9553225
TI - [Home care of demented and non-demented patients. II: Health and burden of
caregivers].
AB - 1911 informal caregivers from the Federal Republic of Germany who care for
someone with a chronic, non-congenital condition rendering them in need of
physical "hands-on" nursing completed a standardized questionnaire on their
situation as caregivers. The questionnaire was pertinent in particular to their
own somatic symptoms (Giessen Symptom List, GSL) as well as their subjective
burden (Burden Scale for Family Caregivers, BSFC). Eight out of ten caregivers in
Germany are women. The home care of a dementia patient or of a distant or non
related person is taken on significantly more frequently by female caregivers.
Somatic symptoms covering the spectrum of exhaustion, aching limbs, and heart and
stomach complaints are in greater evidence amongst caregivers of dementia
patients than amongst those caring for elderly people with relatively unimpaired
cognitive performance. In all, the average extent of the somatic symptoms lies
significantly above the age and gender specific value for the general population.
The increased subjective burden of caregivers caring for a dementia patient
expresses itself particularly in more interpersonal conflicts and clashes of
interest between the care given and other areas of activity.
PMID- 9553226
TI - [Dissertation criteria].
PMID- 9553227
TI - [Risks and protective factors in early childhood development: empirical
findings].
AB - A common result of many studies of children at risk for developmental disorder is
the heterogeneity of individual reactions to adversity. One attempt to explain
the differential outcome of children at risk lies in the assumption of protective
factors. In a prospective study of 362 infants the significance of pre- and
perinatal complications (early biological risks) and of adverse family living
circumstances (early psychosocial risks) on child development at 4 1/2 years was
examined. Additionally, to study the interplay between risk and protective
factors a number of mother-child and family characteristics potentially
favourable to early development were assessed. Results indicated that early risk
factors made a significant contribution to child development at preschool age.
Using multiple risk indices, between 10 and 20% of the variance of the
developmental outcome at 4 1/2 years was explained. Significant predictors of
later developmental disorders were neonatal seizures and very low birth weight
among the biological risks and low educational level of the parents, early
parenthood and unwanted pregnancy among the psychosocial risks. The contribution
of early protective factors to developmental outcome, however, was only limited.
The high overlap with risk factors, the low specific predictive power and the
lack of a moderator effect question the theoretical usefulness of a global
concept of protective factors. However, when interactions between specific risk
and protective factors were studied, there was evidence of a buffer effect of a
successful early mother child interaction.
PMID- 9553228
TI - [Eating before of an unselected student population of the 7th to 10th grade in a
Berlin school].
AB - In 1990 a study of 32 girls and 44 boys in Grades 7 to 10 in a former "East
Berlin" school in the borough of Prenzlauer Berg was carried out in continuation
of an "East-West Berlin Study on Eating Disorders in Adolescents" which we had
initiated in the mid-eighties. The Eating Attitudes Test (EAT), Eating Disorder
Inventory (EDI), State of Comfort Scale (SCS) were used in a one-step study
design together with complementary clinical and sociodemographic data, including
body weight, height and BMI. On the whole, all students were well aware of their
own body measurements and had definite ideas about their ideal body weight. Boys
were less sure about their real weight, while girls showed some insecurity in
defining their ideal weight. Regardless of weight parameters, girls were more
strongly preoccupied with issues specific to eating disorders, such as
dissatisfaction with their own body, the quest for a slim figure and diet. They
were more severely affected by perceptions of insufficiency. 44% of all girls and
4% of the boys said they had problems with their body weight. These students'
intensive preoccupation with issues specific to eating disorders was dependent on
their actual body weight. They exhibited more clearly pronounced psychological
characteristics of eating disorders. Eating-related and psychological
characteristics of eating disorders were significantly more pronounced in girls
with irregular menstruation. The correlation between irregular menstruation and
individually perceived weight problems was significant. These results are
discussed in greater detail with due consideration of the need for understanding
the specific dynamics of eating attitudes in the general population.
PMID- 9553229
TI - [Tradition and development in child and adolescent psychiatry].
PMID- 9553231
TI - [Dyssocial behavior and aggression: knowledge, management and knowledge gaps].
PMID- 9553230
TI - [Biological correlates of aggressive behavior].
PMID- 9553233
TI - Is the perception of laparoscopic technique for minor surgery such that of
cholecystectomy right?
PMID- 9553232
TI - [Outcome of adolescent treatment measures in dyssocial disorders].
PMID- 9553235
TI - Patient barriers to cancer pain management: from the viewpoint of the cancer
patients receiving analgesics in a teaching hospital of Taiwan.
AB - BACKGROUND: The purpose of this study was to investigate the barriers to
receiving analgesics for cancer pain in Taiwanese patients. METHODS: The sample
consisted of 128 hospitalized patients. All of the subjects were receiving
analgesics. Three questionnaires entitled "Barriers Questionnaire-Taiwan Form
(BQT)", "Brief Pain Inventory Short Form", and "Pain Management Index (PMI)" were
used in this study. Data were analyzed using Student's t-test and Pearson
correlation. RESULTS: The results showed that most of BQT subscales including
disease progression, time interval, tolerance, injection, addiction, fatalism and
side effects were approaching toward the moderate or high end of the scale. 42.1%
(n = 54) of the patients had negative PMI scores indicating that they were using
less than adequate analgesics for pain. There was a significant difference
between those who had adequate medication and those who did not, in terms of
disease progression score and the total BQT score. CONCLUSIONS: Overall the
result revealed that pain management in these cancer patients was inadequate.
Misconceptions on the part of patients still exist. Educational intervention
could be an effective means for overcoming such barriers in Taiwanese patients
who received analgesics for cancer pain.
PMID- 9553234
TI - The analgesic effect of PCA buprenorphine in Taiwan's gynecologic patients.
AB - BACKGROUND: The aim of this study was to evaluate the analgesic effect of PCA
buprenorphine (intravenous) on postoperative pain in gynecologic patients of
Taiwan and the potency ratio of buprenorphine versus morphine, a commonly used
potent analgesic. METHODS: Fifty women undergoing abdominal total hysterectomy
under spinal anesthesia were enrolled into the investigation. Patients were
randomly divided into 2 groups (n = 25 each). Group 1 received intravenous
buprenorphine using PCA device for the management of postoperative pain, whereas
Group 2 received PCA morphine for the same purpose. During the first 48 hours
postoperatively, we collected the following data: demand and delivery of
analgesics, pain scores, vital signs, nausea, vomiting and pruritus. RESULTS:
Despite different treatments, we found that pain scores on day 1 and day 2
postoperatively were low and were not significantly different between groups.
Also, times of demand for delivery of PCA medication were not significantly
different between groups. The cumulative consumption of buprenorphine and
morphine within 48 h were 1.5 +/- 0.6 mg and 36 +/- 7 mg, respectively. The
potency ratio between buprenorphine and morphine was 24:1. Both treatments showed
only minor side effects. CONCLUSIONS: We found that PCA buprenorphine
(intravenous) could be effective in the treatment of postoperative pain in the
gynecologic patients in Taiwan and the potency ratio of buprenorphine versus
morphine appeared to be 24:1.
PMID- 9553236
TI - The efficacy of intrathecal coadministration of morphine and bupivacaine for
labor analgesia.
AB - BACKGROUND: Intrathecal (i.t.) opioids can provide labor analgesia, but the onset
of pain relief is slow. Bupivacaine has the beneficial property of less motor
blockade than other local anesthetics. This study retrospectively examined the
efficacy of concomitant use of i.t. morphine and bupivacaine for labor pain
relief. METHODS: Fifty five nulliparas who requested analgesia in the active
phase (IA group) prior to a cervical dilation 3.9 +/- 0.6 cm and received i.t.
morphine 0.5 mg and 0.1% bupivacaine 2.5 mg served as the treatment group, and 88
similar nulliparas who did not request and receive analgesia served as the
control group. RESULTS: The mean onset time of analgesia was 2.6 +/- 0.5 min, the
duration was 4-12 h and 93% of parturients did not request additional analgesia
after a single injection of i.t. morphine and bupivacaine. The active phase of
the first and second stages of labor in the treatment group were significantly
longer [318 +/- 214 min vs. 176 +/- 120 min; 74 +/- 29 min vs. 37 +/- 26 min].
Frequency of instrument-assisted vaginal delivery was higher compared with the
control group (30.9% vs. 14.1%). However, there were no significant differences
in the rate of cesarean section and the Apgar scores of newborns at 1 min and 5
min between the treatment and control group. The major side effects of the
treatment group included pruritus (48%), nausea (40%), vomiting (37%), somnolence
(27%), shivering (27%), urinary retention (21%), hypotension (15%), and
bradycardia (13%). Most of the side effects were mild and could be alleviated by
naloxone. Neither post-spinal headache nor respiratory depression was noted.
CONCLUSIONS: Our results showed that a single injection of i.t. morphine and
bupivacaine provided rapid onset and effective analgesia with manageable side
effects and without major complications. Thus, i.t. morphine and bupivacaine
provides an alternative to epidural analgesia for most women in labor.
PMID- 9553237
TI - Comparison of intravenous retention of fentanyl and lidocaine on local analgesia
in propofol injection pain.
AB - BACKGROUND: With a tourniquet on arm for arresting venous blood flow, we
evaluated the efficacy of intravenous (i.v.) retention of fentanyl and lidocaine
in reducing the pain on i.v. propofol injection during general anesthesia.
METHODS: One hundred and twelve patients were studied. Following a venous
occlusion by a tourniquet inflated to 70 mmHg, patients in Group A (n = 38)
received normal saline (NS) 3 ml, while those in Group B (n = 37) and in Group C
(n = 37) respectively received fentanyl 150 micrograms or 3 ml and 2% lidocaine 3
ml (60 mg). The venous retention of drug was maintained for 1 min, followed
immediately by tourniquet release and propofol 100 mg i.v. injection over 20 s.
RESULTS: Both fentanyl and lidocaine treatments (Groups B and C) were
significantly better than placebo (Group A) in reducing pain on propofol
injection (p < 0.005). Lidocaine 60 mg was more effective than fentanyl 150
micrograms in reduction of pain associated with i.v. propofol (p < 0.001).
Injection of fentanyl itself caused pain in 28% of patients as compared to 2% in
the lidocaine group. Mild local skin erythema was noted in 14% of patients with
fentanyl venous retention versus 0% of patients with lidocaine venous retention.
CONCLUSIONS: Intravenous retention of fentanyl 150 micrograms, although less
effective than that of lidocaine (p < 0.001), showed local analgesic effect in
reducing the pain on propofol injection. The hypothetic mechanisms of action were
speculated.
PMID- 9553238
TI - Thromboelastographic study of thrombosis in the implantable central venous access
device.
AB - BACKGROUND: In the present study thromboelastography (TEG) was to study whether
or not hypercoagulopathy might contribute to the thrombosis of implantable
central venous access device (Port-A-Cath, Pharmacia) in cancer patients.
METHODS: All 76 oncological patients who were enrolled in this study had their R
time, alpha angle and MA value measured before Port-A-Cath implantation, of whom
11 patients received re-implantation because of thrombotic device. We compared
the measurements of these 11 patients (thrombotic group) with that of 65 patients
(control group) who received Port-A-Cath implantation for the first time.
According to TEG values the hemostatic status in these patients was classified as
hypercoagulable, normal or hypocoagulable for comparison. All patients in the
control group were followed up for 3 months for occurrence of thrombosis.
RESULTS: It was found that no patient in the thrombotic group was associated with
hypercoagulopathy. Five patients (7.5%) in the control group was found in
hypercoagulable status at the time of catheter insertion but none of them
developed clinical thrombosis during three months of observation. There was no
significant difference between the two groups for R time, alpha angle but a
higher MA value was found in the control group (p < 0.05). Furthermore, the
hypercoagulability (7.5% for the control vs. none for the thrombotic group),
hypocoagulability (1.5% vs. 9.1%) and normocoagulability (91.0% vs. 90.9%) were
not statistically different between the two groups (Fisher exact test, P =
0.229). CONCLUSIONS: We conclude that hypercoagulopathy in cancer patients has
little, if any, contribution in thrombosis of the implantable central venous
access device.
PMID- 9553239
TI - Low-flow anesthesia in adult orthotopic liver transplantation: a preliminary
clinical experience.
AB - BACKGROUND: Anesthesia in orthotopic liver transplantation (OLT) may carry with
complex hemodynamic, body temperature, and metabolic alterations. Although OLT
cases increased in recent years in Taiwan, experiences remained limited. Notable
advantage of low flow anesthesia may include reduced consumption of anesthetic
gases and vapors, reduced environmental pollution and cost-saving. This study
investigated patient profiles and the feasibility of low-flow rebreathing
technique for adult orthotopic liver transplantation. METHODS: Since June 1996,
there were six OLT patients who received low flow anesthesia with isoflurane. All
patients received hepatic veno-venal anastmosis (so-called piggy back procedure).
Two patients were excluded from this study because of different surgical
procedure (total occlusion of inferior vena cava and inferior vena cava veno
venal anastmosis). During maintenance of anesthesia, isoflurane was carried by a
mixture of oxygen and air at a total fresh gas flow of 0.6 L/min. Alongside with
the standard anesthesia machine and physiologic monitors, a newly designed Swan
Ganz catheter was introduced to measure and record cardiac output, systemic
vascular resistance, pulmonary artery pressure, central venous pressure, and core
temperature in a real-time manner. Blood samples were collected at 6
predetermined time-points in each patient for analysis of arterial blood gases,
electrolytes, lactate and glucose concentrations. RESULTS: The anesthetic time
was 916 +/- 26 min (900 to 930 min). All patients regained their consciousness
within 30 min after completion of surgery. The hemodynamics were relatively
stable except after reperfusion of the liver. There was a significant decrease in
mean arterial blood pressure, which occurred with accompaniment of a reduction of
systemic vascular resistance and increased cardiac output. Arterial blood gas,
electrolyte, and glucose were, however, maintained within acceptable limits.
Blood lactate was progressively increased and reached its peak after reperfusion
of the liver until the end of surgery. The core temperature was well maintained
above 34 degrees C. No patient developed hypoxia or hypercapnia. CONCLUSIONS: Low
flow rebreathing anesthetic technique maintained acceptable patient profiles and
good body temperature preservation in orthotopic liver transplantation. These
characteristics make it a promising method in maintenance of anesthesia for OLT.
PMID- 9553240
TI - Induction of tolerance to intrathecal butorphanol in rats.
AB - BACKGROUND: Butorphanol, an opioid agonist/antagonist, has been administered
spinally and epidurally in humans for moderate to severe pain. However, unlike
intrathecal (i.t.) morphine, virtually no information is available regarding
butorphanol's ability to induce analgesic tolerance at the spinal cord level upon
chronic i.t. administration. METHODS: Continuous infusion of i.t. butorphanol was
given via an osmotic minipump. Rats were randomly assigned to four groups (n = 7
each) to receive i.t. infusion (1 microliter/h) consisting of saline, or
butorphanol (13, 26, or 52 nmol/h) for 96 h. Tail-flick (TF) latencies were
measured during the period of i.t. infusion. RESULTS: A dose-dependent
antinociceptive effect, as measured by TF latency, was demonstrated in the groups
receiving i.t. butorphanol as compared to the saline group. The overall
antinociceptive effects calculated from the areas under the curve (AUC's) were
372 +/- 3.0, 394 +/- 7.5, and 433 +/- 20 for the 13, 26, and 52 nmol/h
butorphanol-infused groups, respectively; the AUC's of the 26 and 52 nmol/h
groups were significantly different from the AUC of 356 +/- 3.4 for the saline
infused group (p < 0.01, one way ANOVA; p < 0.05, post hoc Dunnett's test). The
TF latencies of the 26 and 52 nmol/h groups were 3.77 +/- 0.05 and 3.73 +/- 0.03
s at the baseline (before the i.t. infusion), respectively; and gradually
increased significantly (p < 0.01, two way repeated measure ANOVA; p < 0.05, post
hoc Student-Newman-Keuls or SNK test) to the peak values of 4.31 +/- 0.14 and
4.90 +/- 0.28 s, respectively; then decreased significantly from the peaks (p <
0.05, post hoc SNK test) to the final values of 3.87 +/- 0.06 and 4.10 +/- 0.13 s
at the end of the 96-h infusion, respectively. The TF values of the saline and
the 13 nmol/h groups did not show statistically significant differences
throughout the 96-h infusion period. CONCLUSIONS: Therefore, continuous infusion
of i.t. butorphanol at the rate of 26 and 52 nmol/h induced tolerance to tail
flick analgesia within 96 h.
PMID- 9553241
TI - Propofol anesthesia in a patient with Isaacs syndrome--report of a case and
literature review.
AB - Isaacs syndrome is an unusual lower motor neuron disease characterized by
myokymia (muscle twitching), muscular stiffness, and decreased tendon reflexes.
We reported a patient who was affected with this rare disease, with manifestation
of involuntary muscular contractions and required general anesthesia for
bilateral tonsillectomies. Understanding the presentation and characterization of
this unusual disease may be helpful in making choice of anesthetics or anesthetic
techniques. Its possible mechanisms of action and its specific considerations in
anesthesia in the literature are reviewed and discussed.
PMID- 9553242
TI - Hypovolemic shock induced by laparoscopic cholecystectomy--a case report.
AB - Since its introduction and development in the 1960s, laparoscopic cholecystectomy
has become widely accepted by the medical community and the public as the
treatment of choice for various gallbladder disorders. We present a 46-year-old
male who underwent laparoscopic cholecystectomy, during which inadvertent
penetration of the first trocar resulted in injury of the abdominal aorta and
then hypovolemic shock ensured. The time from notification of shock by the
anesthesiologist to switch of procedure to exploratory laparotomy for stanching
hemorrhage was twenty minutes. During the intervention, blood loss was over 3,000
ml and despite rapid infusion of plasma expander, blood pressure could only be
maintained between 40/18 to 60/20 mmHg. After the patient became stabilized and
blood pressure was elevated to acceptable levels, conventional cholecystectomy
was performed instead. Perioperative blood loss of 7,300 ml was estimated. In
total, the patient received 24 units of packed red blood cells, 12 units of fresh
frozen plasma, and 12 units of platelets. After the operation, the patient was
transferred to the surgical ICU for further observation. For 24 h at the ICU,
blood pressure remained unstable, urine output decreased gradually, and scrotal
and leg edema developed. Forty-four h after admission to the surgical ICU,
arrhythmia and profound hypotension were noted and cardiac arrest ensued. After
resuscitation for 2 h, the patient could not be revived and succumbed to
cardiovascular decompensation secondary to acute renal shutdown and continuous
retroperitoneal hemorrhage.
PMID- 9553243
TI - Unexpected left endobronchial intubation in a case of Turner's syndrome.
AB - Patients with Turner's syndrome present a multiplicity of cardiovascular and
airway abnormalities. We describe a case of Turner's syndrome with pericardial
effusion who experienced an inadvertent endobronchial intubation due to
displacement of the endotracheal tube immediately after the pericardial drainage.
A sudden increase of airway pressure and decrease of oxygen saturation in the
presence of breathing sound audible via the chest piece placed on the left
hemithorax first misled us to call our attention to sputum impaction. No sputum
was obtainable from airway suction. Inadvertent bronchial intubation was highly
suspected at the post-anesthesia room when a decrease of right side breathing
sound was noted together with a progressive fall of oxygen saturation. Emergent
chest x-ray confirmed the diagnosis. It was thought that the mishap took place
early in the act of or following the pericardial drainage. Our case serves as
evidence once again to emphasize the possibility of endobronchial intubation due
to displacement of endotracheal tube during anesthesia and the importance of
monitoring to guard against inadvertent bronchial intubation, particularly in
patients with associated problems such as Turner's syndrome with huge pericardial
effusion.
PMID- 9553244
TI - A new device: Tube Securer. An endotracheal tube holder with integrated bite
block.
AB - Endotracheal intubation is the most commonly employed technique in airway
management. Having an endotracheal tube (ETT) in place, however, does not
guarantee a patent airway. Tube obstruction due to kinking, blood
clots/secretion, dislodgment, or patient's biting can occur. These complications
are life-threatening or even fatal. Employing a Guedel oral airway (OA) to act as
a bite-block is a current common practice. However, with an OA in place does not
necessarily prevent patient biting on the ETT. The author therefore proposed that
this practice should have room for improvement and has made effort to design a
new device for the purpose. The new dual function endotracheal tube holder with
integrated bite-block as described can firmly secure the ETT in place and
effectively prevent patient's biting on the tube. Therefore, it helps prevent the
most serious complication of endotracheal intubation and subsequently improves
patient safety.
PMID- 9553245
TI - [Hydroxyethyl starch--an interim report].
AB - Since the beginning of this century, a few biopolymers have been used as basic
materials for volume substitution. Aside from gelatin and dextran, modified
starch (hydroxyethyl starch, HES) is currently the first-choice means. Due to
special manufacturing processes, different hydroxyethyl starches are now
available. They have several different characteristics and produce different
clinical effects. These clinical properties depend on the average molecular
weight and the distribution of molecular weight as well as on the degree and
pattern of substitution. The duration of volume effect, one of the most important
parameters for the effectiveness of a volume substitute, depends to a large
degree on the substitution. Elimination of HES from serum is delayed by a high
degree of substitution and a high C2/C6 ratio of the substitution pattern. The
molecular parameters of HES also influence other effects, such as cumulation in
various organs and hemostasis. Critical reading of current HES literature shows
that many questions still have to be answered. At the same time ways and means of
optimizing differential volume substitution therapy and hemodilution therapy are
emerging.
PMID- 9553246
TI - [Introduction of patient-controlled analgesia--an interim report].
AB - In spite of improved therapeutic methods, the number of patients who suffer from
moderate or severe postoperative pain remains high at 30 to 70%. It is accepted
that improvement of the organization of postoperative pain therapy is a necessary
precondition for changing this situation. Therefore, patient-controlled analgesia
(PCA) using pain-pumps should be recognized and the effect on the whole
postoperative pain therapy of a university clinic observed. The authors report on
the introduction of general therapeutic guidelines for the use of patient
controlled pain-pumps. The recovery ward takes on a central role for both the
beginning of pain therapy and the further care of the patient in various
peripheral wards. It proved to be advantageous to use a bed-side protocol to
document the programming of the pain-pumps and to register the pain-scores and
side-effects. Because of these fundamental changes, the frequency of the
application of pain-pumps increased six-fold within one year. Additionally, rapid
pain treatment based on patients' needs increased clearly from 9.2 to 30.8%. The
standardized introduction of PCA had an extremely favourable effect on the whole
postoperative pain therapy and can thus be wholeheartedly recommended.
PMID- 9553247
TI - [Ethics in preclinical emergency medicine--on the topic of medical futility and
resuscitation efforts].
AB - In prehospital emergency medicine, physicians are repeatedly faced with the
question of when cardiopulmonary resuscitation (CPR) efforts should be withheld
or terminated since they are clearly futile. Here, futile means the goal of
saving life cannot be achieved. Determining futility involves qualitative und
quantitative aspects. Does the possibility of simply restoring circulatory
function justify the decision to initiate resuscitation or must the prospect of a
prolonged meaningful life exist? The question of futility arises for the entire
life-saving team during resuscitation efforts, for example, after traumatic
cardiopulmonary arrest, prolonged down time, collapses in chronically-sick
nursing home residents or during transport to hospital when prehospital CPR
failed to restore spontaneous circulation. Possible solutions to this problem lie
in restricting the objective of resuscitation to achieving a physiological effect
in an organ system, i.e. regaining the cardiac pumping function, and in taking
into account the chance of long-term survival and quality of life of the patient.
Basically speaking, general ethical principles must be adhered to and these
include consideration of a patient's right to self-determination. In the
prehospital setting, however, the emergency physician is usually confronted with
an unknown and unconscious patient and has no information about his preferences.
In general, the patient's will to live and his desire for every effort to be made
to save him can be assumed, even when there is only a slight chance of survival.
Thus, unilateral decisions by emergency physicians to withhold CPR are only
justified in special cases when it is obvious that CPR and preservation of life
would not be in the patient's interest. When in doubt, resuscitation attempts
must be made. The futility of these efforts may emerge later in hospital, or
information becomes available regarding the patient's will which justifies an end
to therapy.
PMID- 9553248
TI - [Oxygen delivery, consumption and extraction in the acute period of burns in
children].
AB - Eighty-six children with burn injuries hospitalized in intensive care wards
during the acute period of burn disease were examined. They were divided into 3
groups: with involvement of up to 30%, 31-60%, and more than 61% of body surface.
The children were examined during and after shock. The study was aimed at
investigating the delivery, consumption, and extraction of oxygen in order to
assess the criteria of disorders in the blood gas transporting system. In group 1
these parameters were higher than normally during the acute period, reflecting
the adequate reaction to burn injury. Therapeutic measures required volume
support with infusion media. In the second and third groups these parameters were
increased both during and after shock; for increasing oxygen transport, inotropic
support was administered. In the third group oxygen delivery was within the norm
which did not correspond to its consumption and, hence, respiratory support was
needed.
PMID- 9553249
TI - [The causes of and methods for correcting kidney functional disorders in newborns
with surgical pathology].
PMID- 9553250
TI - [General anesthesia using diprivan in patients with lesions of the locomotor
system in a day hospital].
AB - The study is aimed at investigating the possibility of using diprivan in total
anesthesia of patients with consequences of infantile cerebral paralysis (ICP)
during orthopedic surgery in an outpatient setting. The study was carried out at
the Institute of Clinical Rehabilitology in the town of Tula. Ninety-two patients
aged 4 to 15 years were examined. Hemodynamics was assessed by tetrapolar
thoracic rheography after Kubecik. The patients were divided into 3 groups with
disorders of static kinetic functions of different severity: I) walk-in patients,
29.3%; II) patients walking with difficulty, 59.7; III) patients incapable to
walk by themselves, 9.2%. The autonomic status was studied using clino
orthostatic tests and cardiointervalography. Characteristic changes of the
hemodynamics under conditions of narcosis and surgery were revealed in the
patients with locomotor disorders of different severity. Diprivan can be used as
the basic hypnotic component of anesthesia in orthopedic operations in patients
with ICP consequences with locomotor disorders of different severity. It meets
the requirements to the adequacy of anesthesiological protection in an outpatient
setting. Assessment of the autonomic status in patients with ICP consequences
permits a differentiated approach to total anesthesia with diprivan.
Premedication with ketamine prevents the hypotensive effect of diprivan and
ensures hemodynamic stability in the course of anesthesia and surgery.
PMID- 9553251
TI - [Diprivan as a component of the anesthesia in emergency surgical interventions in
children].
AB - Sixty-seven children aged 5-15 years were induced to narcosis and narcotized with
diprivan. The patients were operated on for appendicitis, peritonitis,
osteomyelitis, phlegmons of different localization, and craniocerebral injuries.
For induction, diprivan was intravenously injected in a dose of 3-4 mg/kg. During
the main narcosis (central analgesia with fentanyl in a total dose of 0.008
mg/kg/h) diprivan was infused by microjets in a dose of 6-9 mg/kg/h in
combination with nitrogen oxide and oxygen in 1:1 ratio. Control group consisted
of similar age-matched patients, to whom central analgesia without diprivan was
administered. Respiration rate, heart rate, systolic and diastolic arterial
pressure, mean arterial pressure (MAP), SaO2, and clinical course of anesthesia
were examined at different stages of analgesia and surgery. During induction
anesthesia the respiratory rate decreased by 27% and SaO2 decreased to 92.75 +/-
1.2% due to the specific effect of diprivan. MAP decreased by 4.8%. During the
traumatic moment of surgery, respiratory rate increased by 20.1%, SaO2 was 98.25
+/- 0.24%, and heart rate increased by 22.6%. In the controls this period of
surgery was associated with a more expressed reaction of the cardiovascular
system, presenting as tachycardia (114.5 +/- 3.6) and increase of MAP by 10.1%.
After anesthesia pain sensitivity returned earlier, due to which tachycardia and
negligible hypertension were observed.
PMID- 9553252
TI - [High epidural anesthesia in the correction of congenital heart defects with
artificial circulation in children].
AB - Effects of high thoracic epidural anesthesia (TEA) on hemodynamics were studied
in patients undergoing cardiopulmonary bypass (CPB) surgery. In 7 patients aged 3
7 years, TEA was used as an adjunct to standard oxygen-air-isoflurane anesthesia.
We prefer using a combination of lidocaine with fentanyl for epidural anesthesia.
Usually we take a loading dose of 4.5 mg/kg of lidocaine and 1 microgram/kg of
fentanyl, which is followed after 40-50 min by 3.5 mg/kg lidocaine and 1
microgram/kg fentanyl. TEA ensures good pain relief and hemodynamic stability and
can be accepted as a safe and effective anesthetic technique in combination with
inhalation anesthesia in children subjected to CPB.
PMID- 9553253
TI - [Caudal epidural anesthesia in children operated on in the area of the
lumbosacral segments].
AB - Analgesia of children operated on the lumbosacral segments is discussed. Balanced
total anesthesia was used with caudal epidural blocking by a combination of alpha
2-agonist clofelin, local amide anesthetic bupivacaine, and narcotic analgesic
promedol. Injection of a combination of clofelin (0.01% solution) in a dose of 1
microgram/kg, standard dose of 0.25% bupivacaine solution with adrenaline
(1:200,000) in a dose of 0.3 ml/kg, and promedol in a dose of 0.2 mg/kg into the
epidural space via the caudal approach in the presence of superficial anesthesia
with halothane (0.2-0.4 vol/%), nitrogen oxide and oxygen in 2:1 ratio ensured
adequate analgesia and effective neurovegetative protection both during the
operation and the first 25 h after it.
PMID- 9553254
TI - [Regional anesthesias in children--the concept, advantages and general
principles].
AB - Validates the concept and discusses the advantages of central and peripheral
regional anesthesias in children in combination with superficial narcosis during
the stage of analgesia in surgical interventions of any severity. Emphasizes the
efficacy of regional blocking, including prolonged ones, for postoperative
analgesia. Presents the fundamentals of regional anesthesias in children.
PMID- 9553255
TI - [Tracheal intubation in children using the benzyl isoquinoline-series
nondepolarizing relaxants atracurium and mivacurium].
PMID- 9553256
TI - [The characteristics of the action of nondepolarizing myorelaxants during
operations on children with thermal injuries].
AB - Effects of nondepolarizing myorelaxants pancuronium, arduan, and tracrium were
studied during surgery in 347 children with thermal injuries aged from several
months to 15 years. Nondepolarizing myorelaxants are drugs of choice for
providing myoplegia in children operated on for thermal injuries. The optimal
initial dose of these agents in children with burns is 30-50% higher than the
recommended dose and depends on the size of the lesion. For controllable
myoplegia, the doses of subsequent injections are to be 1.-5-2 times lowered in
comparison with the initial dose. The effects of pancuronium and arduan depend on
the hepatorenal function. Tracrium ensures sufficient controllable myorelaxation
in children with burns even in cases with hepatorenal dysfunction.
PMID- 9553258
TI - [Etran anesthesia in minor surgical interventions in children].
PMID- 9553257
TI - [Central hemodynamic changes in children with locomotor system diseases during
surgery and anesthesia].
AB - Various neurovegetative reactions and disorders of circulation are observed in
children with consequences of infantile cerebral paralysis (ICP). The
manifestation of these reactions depends on the severity of motor disorders and
the local painful syndrome. This study was aimed at detecting the changes in the
central hemodynamics and development of measures preventing these changes during
narcosis in patients with orthopedic consequences of ICP subjected to surgical
treatment in an outpatient setting. In addition, we studied the possibility of
wide use of calypsol in this category of patients in a one-day hospital.
Autonomic reactivity was studied by cardiointervalography after Baevskii. The
stroke and minute volume were assessed by tetrapolar thoracic rheography after
Kubecik. A total of 120 patients aged 7-14 years with ICP consequences were
divided into 3 groups with motor disorders of different severity. Examinations
during preparation to narcosis and narcosis revealed a relationship between
autonomic and hemodynamic disorders and the severity of motor disorders. An
optimal method for preventing hemodynamic changes associated with narcosis in an
outpatient setting is proposed.
PMID- 9553259
TI - [The carbohydrate-energy metabolic and hemodynamic status of children with
diffuse suppurative peritonitis in the early postoperative period].
AB - Thirty-three children with grave peritonitis were examined 16-24 h after
operation. The groups were matched for the hemodynamic status. Group 1 were
patients with moderate hyperdynamic status, group 2 those with the extreme
hyperdynamic status, and group 3--patients with hypodynamic status. The control
group consisted of 36 healthy children subjected to herniotomy. Moderate
hyperdynamic status was associated with balanced carbohydrate-energy metabolism.
In the second group high levels of ATP+ADP+AMP and G6-PDH+6-PGDH activities and a
decrease of ATP/ADP ratio and hypophosphatemia were observed. In the third group,
low activity of the direct oxidative pathway and high activity of plasma LDH and
hypophosphatemia were observed.
PMID- 9553260
TI - [The effect of hemodilution on the indices of aerobic metabolism and water
metabolism in children with congenital heart defects operated on under artificial
circulation].
AB - The majority of pediatric cardiosurgery centers make use of cardiopulmonary
bypass (CPB) with low hematocrit, and therefore we deemed it interesting to
investigate the pathological effects of hemodilution on patients. Specifically,
we studied the effect of hemodilution on aerobic and water metabolism in children
with congenital heart disease subjected to CPB. Two groups of patients were
examined. In the studied group (n = 12, mean age 7.1 +/- 1.1 years) the blood
fluid ratio in primary filling of the CPB device was 1:6.2 +/- 0.7 and minimal
hematocrit during myocardial ischemia 18 +/- 0.7%. Control group consisted of 7
patients aged 8.3 +/- 0.6 years, with the above values 1:2.8 +/- 0.4 and 22 +/-
1.6%, respectively. The groups were similar as regards the initial status of
patients, level of hypothermia, and duration of myocardial ischemia. Gas content
in venous blood was the criterion of aerobic metabolism. Fluid accumulation in
the extravasal space during and after surgery was assessed by bioelectroimpedance
measurements of the total extracellular extravasal fluid (EEF). Monitoring showed
a decrease of hematocrit during CPB to 18 +/- 0.7%, saturation of venous blood
with oxygen within 70-75%, and oxygen content 37-43 mm Hg. In the main group a
manifest increase of EEF was observed as early as during the early postperfusion
period; this increase is probably one of the main components in the detrimental
effect of hemodilution. Redistribution of fluid after CPB leads to expressed
interstitial edemas and impairs the function of vital organs. That is why signs
of cardiorespiratory failure were observed in the main group. Thus, one of the
main problems in CPB with low hematocrit is fluid accumulation in the extravasal
space.
PMID- 9553261
TI - [The use of modified ultrafiltration in correcting complex congenital heart
defects in newborn and nursing infants].
AB - Modified ultrafiltration (MUF) was used in radical correction of complex
congenital heart disease in 61 newborns and infants. The children were divided
into 2 groups: group 1, 46 patients subjected to MUF, and group 2, 15 children
operated on without MUF. Hemodynamic, hematological, biochemical, and
immunological parameters were monitored. MUF in the newborns and infants helped
adequately correct the hemohydrobalance due to ultrafiltration in the patient and
hemoconcentration of the remaining volume in artificial ventilation device; it
normalized the hematocrit values without additional infusion of donor blood.
Elimination of inflammation mediators and cytokines recommends MUF for the
treatment of newborns and infants.
PMID- 9553262
TI - [The cardiac index dynamics of patients after the radical correction of tetralogy
of Fallot depending on the level of the pressure-support ventilation (PSV)
regimen].
AB - Seventeen patients were examined, reoperated on for correction of Fallot's
tetralogy on the open heart after a previous aortopulmonary anastomosis. Pressure
support ventilation (PSV) was used in all patients during transfer to spontaneous
pressure, making use of different levels of pressure support (20, 15, 13, 10, and
8 mm H2O). Decrease of pressure support from 20-15 mm H2O to 13 mm H2O resulted
in a sharp increase of cardiac index. We explain this phenomenon by a drastic
increase of the respiratory volume during the use of high PSV levels (20-15 mm
H2O), surpassing 1.5-2 times the physiological and age-specific norm; this leads
to a sharp increase of the mean intrathoracic pressure, disturbing the
cardiovascular function.
PMID- 9553263
TI - [New potentials for monitoring the temperature and the relative and absolute
humidity of the air-oxygen mixture during the prolonged artificial ventilation of
newborn infants].
AB - A new HTM-902 monitor (UCCP, Germany/Serviceinstrument, Russia) was used for
continuous measurements of the temperature and relative and absolute humidity of
inspired gas during prolonged mechanical ventilation in 86 neonates with
respiratory failure caused by the respiratory distress syndrome (n = 42),
meconium aspiration syndrome (n = 28), and congenital pneumonia (n = 16). All
measurements were performed with a special probe connected to the inspiratory
contour through a standard adapter close to the patient's T-piece. The monitor
helped maintain the optimal values of the inspired gas conditioning during
assisted ventilation of the neonates. The optimal relationships between gas
temperature and humidity can be attained only with humidifiers with a
servocontrol of temperature and heated wire inside the inspiratory circle tube.
For maintaining adequate humidity of inspired gas after any changes in the
ventilator flow rate or in the temperature inside the incubator, the heating
power of the humidifier had to be corrected. However, even with servocontrolled
humidifiers and humidity regulation, an increase of temperature inside the
incubator over 35 degrees C made impossible the maintenance of the inspired gas
humidity at the level of 96-100% with its temperature at the level of the
patient's T-piece no higher than 37 degrees C.
PMID- 9553264
TI - [The use of methods of assisted pulmonary ventilation in the weaning of children
from ventilator breathing].
PMID- 9553265
TI - [Parenteral nutrition: current concepts and methodological procedures].
PMID- 9553266
TI - [Problems in the diagnosis of myocardial infarct in a newborn infant after acute
severe intranatal asphyxia with the development of an organic CNS lesion].
PMID- 9553267
TI - [A case of the successful treatment of subtotal pancreonecrosis in a 14-year-old
child].
PMID- 9553268
TI - [A case of the successful treatment of drug-induced toxic hepatitis in a child
with tuberculous meningoencephalitis].
PMID- 9553269
TI - [A case of severe poisoning by a methemoglobin-forming poison (saltpeter) in a 1
month-old child].
PMID- 9553271
TI - [Undesirable effects and complications after propofol anesthesia].
PMID- 9553270
TI - [A case of the intravital diagnosis of a developmental defect of the
bronchopulmonary system].
PMID- 9553272
TI - Cultural divergence: Elie Metchnikoff's Bacillus bulgaricus therapy and his
underlying concept of health.
PMID- 9553273
TI - Kupat Holim, Dr. Isaac Max Rubinow, and the American Zionist Medical Unit's
experiment to establish health care services in Palestine, 1918-1923.
PMID- 9553274
TI - "Repeated disappointment": the Rockefeller Foundation and the reform of the Greek
public health system, 1929-1940.
PMID- 9553275
TI - The manuscript consultation reports of Francesco Torti.
PMID- 9553276
TI - New approaches to the history of health and welfare.
PMID- 9553277
TI - Looking for the answer.
PMID- 9553278
TI - Influenza A outbreak on a cruise ship.
PMID- 9553279
TI - A summary of the 1996-1997 Canadian FluWatch program.
PMID- 9553280
TI - Verocytotoxigenic Escherichia coli infection in dairy farm families.
PMID- 9553281
TI - Human isolates of Salmonella Typhimurium DT104 in Ontario.
PMID- 9553282
TI - Influenza in Canada--1996-1997 season.
PMID- 9553283
TI - Protocol for the investigation of acute flaccid paralysis and suspected paralytic
poliomyelitis.
PMID- 9553284
TI - Cytokine--intestinal epithelial cell interactions: implications for immune
mediated bowel disorders.
AB - The intestinal epithelial cell population is comprised of a dynamic continuum,
ranging from undifferentiated, actively proliferating crypt cells, to mature
absorptive villus enterocytes, lacking mitotic capacity. Under normal conditions,
the constant loss of differentiated villus tip cells via apoptosis leads to a
complete renewal of the epithelial cell population every few days. The
physiological factors regulating enterocyte proliferation, maturation and
apoptosis in health, as well as those that modulate these events in disease
states remain largely unknown. It has been demonstrated in vitro that immature
crypt cell proliferation is stimulated by factors such as TGF alpha and TNF
alpha, whereas TFG beta and IFN gamma inhibit mitotic activity. Further studies
showed that intestinal epithelial cells are able to produce and secrete several
cytokines such as IL6, IL8, TNF alpha, TGF alpha and TGF beta, indicating the
potential for autocrine and paracrine responses. A variety of immune mediated
bowel disorders, including celiac disease, Crohn's disease and ulcerative
colitis, are characterized by accelerated epithelial cell turnover and apoptosis,
leading to altered crypt/villus morphology. There is increasing evidence that
these changes, and the accompanying functional alterations of the bowel
epithelium, are mediated by the cytokines released from infiltrating inflammatory
cells, as well as from enterocytes themselves in an autocrine fashion.
PMID- 9553285
TI - Gastrointestinal uptake of macromolecules.
AB - Although the majority of dietary proteins undergo extensive digestion, small,
nutritionally insignificant amounts of food proteins appear to cross the
gastrointestinal mucosa intact. Experiments in a variety of allergic models has
demonstrated that exposure of the gastrointestinal mucosa to the intact allergen
leads to an anaphylactoid reaction. To examine the uptake of immunologically
intact protein across the gastrointestinal epithelium, the mucosal to serosal
movement of bovine serum albumin was measured in stripped gastric and intestinal
mucosa mounted in modified Ussing-type chambers. Studies demonstrated that both
gastric and intestinal mucosa are capable of actively transporting intact dietary
proteins. In the intestine, the transport of intact molecules across the
epithelium is a saturable, energy dependent process which utilizes the
microtubular network and is regulated by the enteric nervous system. Transport
across gastric mucosa is also dependent upon the microtubular network and is
energy dependent.
PMID- 9553287
TI - Rotavirus vaccines.
AB - Encouraging results have been reported from several large trials of tetravalent
rhesus rotavirus vaccine, with efficacy of 70-80% against severe disease. A
recent Venezuelan study showed similar results to trials in USA and Europe. The
vaccine may soon be licensed in USA. It provides the exciting prospect of a
strategy to prevent one of the world's major child killers. Other candidate
vaccines are under development including human-bovine reassortants, neonatal
strains, non-replicating rotaviruses, vector vaccines and other genetically
engineered products. Second and third generation rotavirus vaccines are on the
horizon. The need for a rotavirus vaccine is well accepted by paediatricians, but
public health authorities need to be lobbied. Other issues which need to be
addressed include relative importance of non-group A rotaviruses, possible
administration with OPV, the influence of breast feeding, and most importantly,
cost. It is essential that rotavirus vaccine is somehow made available to all of
the world's children, not just those in developed countries.
PMID- 9553286
TI - Management of gastrointestinal food allergy in childhood.
AB - Gastrointestinal food allergy in childhood is characterised by onset of
gastrointestinal symptoms following food ingestion where the underlying mechanism
is an immunologically mediated reaction within gastrointestinal tract.
Presentation may be quick, slow or quick and slow after food ingestion. Diagnosis
depends on response to food elimination, response to food challenge and analysis
of response to food elimination. Management centres upon an elimination diet, the
need for this is temporary. Cow's milk protein hydrolysates or amino acid
formulae are preferred to soy formulae.
PMID- 9553288
TI - Pathophysiology of growth retardation in chronic renal failure.
AB - Data concerning the transcription of growth hormone and the various interactions
between growth hormone/insulin-like growth factor (IGF) axis in uremia, acidosis
and nutrition are presented. The recent evidence of tissue resistance to growth
hormone in uremia provided the medical rationale for the use of growth hormone in
chronic renal failure. The growth hormone receptor resistance in uremia and the
decreased IGF-I by acidosis are additional rationale for the use of growth
hormone. New findings of how acidosis causes the reduction of IGF-I expression at
the growth plate of the long bone and the significant proteolysis after even
small changes in serum bicarbonate content are presented to provide the
pediatrician with an overview of these recent advances.
PMID- 9553289
TI - Serum HDL level at acute stage of Kawasaki disease.
AB - Kawasaki disease is a disease of acute vascular inflammation of unknown etiology
and HDL is a known risk factor of vascular damage. So far, there is no specific
serum marker for KD. The previous study has shown a remarkable change of serum
HDL in the patients with KD. To find whether changes in serum HDL level is a
specific serum marker for early diagnosis of KD, we measured the concentration of
HDL, LDL, TC, TG and CRP immediately after admission and one week later in three
groups of patients (56 patients with KD, 38 patients with clinical viral
infection, and 42 patients with bacterial infection). There was a significant
decrease of HDL and increase of TG immediately after admission in three groups of
patients. HDL and TG did not return to normal one week later. HDL level is more
adversely affected in severe diseases than in mild diseases. Our results
indicated that low HDL level is noted in various acute infection and is not a
specific serum marker in the early stage of Kawasaki disease. It is interesting
that low HDL is a universal phenomenon in this series. Further research is needed
to explain the mechanism of lipid alterations and its consequences.
PMID- 9553290
TI - A survey on the treatment strategy of patent ductus arteriosus in very low-birth
weight infants.
AB - This study is a retrospective analysis of the clinical data of 67 very low birth
weight infants (VLBWI) with symptomatic patent ductus arteriosus (PDA); all were
admitted to four neonatal intensive care units (NICU) from January 1, 1996
through December 31, 1996. The mean gestational age was 27.9 +/- 2.4 weeks, the
mean birth weight was 1078 +/- 193 g. Fifty-six infants (83.6%) had RDS, and 53
infants (79%) received artificial surfactant. The NICU at a regional hospital
used CVD score > or =3 as the sole criteria and the remaining three NICUs used
color Doppler echocardiogram to confirm a symptomatic PDA and to treat it;
sometimes LA/AO > or = 1.3 was used as the criteria for indomethacin treatment.
Two of these three hospitals sometimes used the pulsed Doppler echocardiogram as
well as color Doppler examination as the treatment criteria. Seven infants
(10.5%) had contraindication for indomethacin treatment; four of them closed
after conservative treatment, and another three were subjected to surgical
ligation. Of the remaining 60 infants, 3 were treated with oral indomethacin and
57 were treated with intravenous indomethacin. The mean age when initial
treatment given was 3.8 +/- 1.5 days (range, 8 hours approximately 20 days).
Among them 10 (16.7%) were within 24 hours after birth, 25 (41.7%) were between
24 and 48 hours, and 25 (41.7%) were beyond 48 hours. The dosage of indomethacin
was 0.2 mg/kg per dose intravenously every 12 to 24 hours for three doses as a
full course, if not contraindicated. The mean dose of indomethacin was 2.8 +/-
1.5; 10 infants (16.7%) received 1 dose, 15 (25%) received 2 doses, 27 (45%)
received 3 doses, 3 (5%) received 4 doses and 5 (8.3%) received 6 doses. Among
them, 51 infants (85%) PDA closed (including 2 treated with oral indomethacin), 9
(15%) failed to close and 6 of them received surgical ligation (including 1
treated with oral indomethacin). The complications associated with indomethacin
treatment were hypoglycemia (52%), decreased urine output (42%) and
gastrointestinal hemorrhage (32%). The infants with RDS had an earlier mean age
of initial treatment than non-RDS infants (3.3 +/- 2.5 vs. 7.6 +/- 5.6 days; p <
0.05), and also had a higher closure rate (89% vs. 57%; p < 0.05). There was a
closure rate of 85% in this multicenter retrospective analysis. Even though the
infants received only one or two doses, they still had a good chance of ductal
closure (21/25, 84%). To minimize the complications associated with indomethacin
treatment in VLBWI, the protocol of indomethacin treatment should be re
evaluated.
PMID- 9553292
TI - The role of percutaneous renal biopsy in the diagnosis and management of renal
diseases in children.
AB - We undertook a retrospective study to determine the proportion of patients in
whom diagnostic and therapeutic changes were made as a result of renal biopsy.
From April 1992 to March 1997, 111 renal biopsies were performed on 109 children
aged 11 months to 18 years at our hospital. Adequate renal tissue was obtained in
106 cases (95.3%). Gross hematuria was observed in 12 cases (10.8%). Perirenal
hematoma was found in 8 cases (7.2%) by ultrasound. A scoring system was designed
to assess if diagnosis and therapy are affected as a result of renal biopsy. For
diagnosis, the score was 0 when no additional information was obtained; 1 when
the diagnosis was confirmed or ruled out; and 2 when the diagnosis was changed
after biopsy or the pathologic findings provided a definite prognosis. For
therapy, the score was 0 when the management was not changed after biopsy; 1 when
the clinical diagnosis was confirmed and yielded a change in management; and 2
when the diagnosis and management were changed after biopsy. We found the benefit
score for diagnosis was 0 in 2 (1.9%) of the 106 biopsied cases; 1 in 78 (73.6%),
and 2 in 26 (24.5%). The benefit score for therapy was 0 in 62 (58.5%); 1 in 24
(22.6%); and 2 in 20 (18.9%). Therapeutic change always occurred in the biopsied
patients with steroid resistant nephrotic syndrome and systemic diseases with
renal involvement, and occasionally occurred in frequent relapsing nephrotic
syndrome, steroid dependent nephrotic syndrome and asymptomatic proteinuria plus
hematuria. It never occurred in patients with acute or chronic renal failure and
hematuria. We conclude that renal biopsy is a safe and efficient procedure in
pediatric patients. It can markedly change diagnosis and therapy, and can
increase the likelihood for a more rational management of children with renal
disease.
PMID- 9553291
TI - Evaluation of a live attenuated varicella vaccine in 15- to 18-month-old healthy
children.
AB - A clinical trial was conducted in Taiwan in 15- to 18- month-old healthy children
to study the reactogenicity and immunogenicity of live varicella vaccine combined
with standard measles-mumps-rubella vaccine. A total of 118 varicella antibody
negative children were enrolled. They received one dose of varicella vaccine and
one dose of measles-mumps-rubella vaccine at the same time. The vaccines were
well tolerated; adverse reactions were mild and infrequent, with 2% of vaccines
developed skin rash. No vesicular rash was seen. Concomitant varicella
vaccination did not significantly increase the incidences of reactions associated
with MMR vaccine. The seroconversion rates to varicella, measles, mumps and
rubella all approached 100%. This study confirmed that simultaneous
administration of live attenuated varicella vaccine and MMR vaccine was safe and
immunogenic in healthy young children in Taiwan.
PMID- 9553293
TI - Holocord intramedullary spinal cord astrocytoma: report of one case.
AB - Intramedullary spinal cord astrocytoma in infants is relatively uncommon. Its
occurrence is usually confined to the cervical and cervicothoracic regions. In
this paper, we report on the case of a 4-month old male infant with low grade
holocord intramedullary spinal cord astrocytoma. He had developed progressive
weakness of the lower extremities over a month period. Neurological examination
revealed flaccid paraplegia as well as complete loss of all modalities of
sensation below the T10 level. MRI revealed a large intramedullary mass which was
found to be an intramedullary astrocytoma at surgery. This case report presents
the clinical features, radiographic findings, and treatment and outcome for this
patient together with a review of relevant literature.
PMID- 9553294
TI - Absolute ethanol embolotherapy for hemangioma with Kasabach-Merritt syndrome.
AB - This report describes a female baby having a hemangioma over the right thigh that
had appeared as an irregular bruise since two days old. Severe thrombocytopenia,
consumptive coagulopathy, anemia, and heart failure developed at three months
old. With a diagnosis of Kasabach-Merritt syndrome, systemic corticosteroid,
vincristine, subcutaneous alpha-interferon, and massive plate transfusion were
given. However, the platelet count remained low and the skin lesion enlarged
gradually. Trans-feeding-arterial embolotherapy with a 5 ml pure ethanol (1
ml/kg) injection was performed at four months of age. Thirty days later, her
platelet count recovered and the hemangioma shrunk in size. This case illustrates
that absolute ethanol embolotherapy is an effective treatment for hemangioma with
Kasabach-Merritt syndrome and may be life-saving for those with lesions
refractory to medical therapy.
PMID- 9553295
TI - Pneumonia with pneumatocele formation caused by Mycobacterium tuberculosis:
report of one case.
AB - Pneumatoceles are usually characteristic of staphylococcal pneumonia. They are
rarely formed as one of the complications of Mycobacterium tuberculosis
pneumonia. We report a 1-year-and-5-month old male child with pneumonia who was
confirmed to have the rare complication, pneumatocele formation, by chest
radiography and computed tomography. Since the patient did not respond to empiric
antibiotic therapy, gastric larvage through a nasogastric tube was performed on
three consecutive mornings and, as a result, acid fast rods were found on the
three specimens. The cultures subsequently yielded M. tuberculosis. He was
finally cured with a 6-month course of antituberculous chemotherapy. We conclude
that tuberculosis should be considered in infants or young children with
pneumonia that presents radiologically as pneumatocele formation, especially in
whom there has been no response to empiric antibiotic therapy.
PMID- 9553296
TI - Pneumococcal meningitis complicated with hemolytic uremic syndrome: report of two
cases.
AB - Hemolytic uremic syndrome (HUS) in associated with infections of neuraminidase
producing streptococcus pneumoniae was rarely reported in the literature. We
report two infants with proven pneumococcal meningitis associated with anemia,
thrombocytopenia, renal failure, and T-antigen activation characteristic of
neuraminidase activity. This supports a common pathogenesis in HUS following
infection of neuraminidase-producing strains of S. pneumoniae. One infant
complicated with status epilepticus died, and the other infant survived without
sequelae. We recommend that neuraminidase production should be considered in case
of pneumococcal meningitis associated with anemia and thrombocytopenia without
diffuse bleeding tendency. Early recognition of HUS associated S. pneumoniae
neuraminidase production is vital. The use of compatible washed red blood cells,
meticulous supportive care and appropriate use of dialysis will improve survival.
PMID- 9553297
TI - Congenital myopathy with uniform type 1 fiber predominance and type 2 fiber
hypoplasia: report of one case.
AB - A 2-month-old female infant, presented with frequent choking and cyanosis during
feeding, and poor sucking capability since the age of 45 days. Growth retardation
with body weight and length below the third percentile, and head girth below the
tenth percentile, were noted on admission. Generalized hypotonia, mild proximal
muscle weakness and diminished tendon reflex were also noted. A biopsy from the
left quadriceps femoralis showed uniform type 1 fiber (90%) predominance, and a
decrease in fiber size and number of type 2 fibers. A biopsy from her father
revealed uniform type 1 predominance (99.8%) and 30% central nuclei change. The
course of her illness was rather short, and the patient has developed normally
since the age of 4 months. Significant improvement in muscle strength and normal
intelligence were observed after 3 years of clinical follow-up.
PMID- 9553298
TI - [Anaphylactic shock. Diagnosis-therapy--emergency measures].
AB - Anaphylaxis is an immediate, life-threatening, general allergic reaction mediated
by bioactive substances released by mast cells. Symptoms include diffuse
urticaria, gastrointestinal disorders (sensation of fullness, diarrhea and
abdominal cramps), bronchospasm, edema, airway obstruction, hypotension,
cardiovascular collapse, and even death. The present review discusses the
adequate diagnostic and therapeutic management based on our own experience.
PMID- 9553300
TI - [Hand on the heart: adequate experience is mostly absent. "Dry runs" are still
not real emergencies].
PMID- 9553299
TI - [Allergy test in general practice--yes or no?. Interview by Beatrice Wagner].
PMID- 9553302
TI - [Skin manifestations in Lyme borreliosis. 6: Acrodermatitis chronica atrophicans
(ACA)].
PMID- 9553301
TI - [Allergies in general practice are too infrequently diagnosed].
PMID- 9553303
TI - [New herpesviruses HHV 6, 7 and 8 and their clinical significance].
PMID- 9553304
TI - [Amantadine--a new option in chronic hepatitis C?].
PMID- 9553305
TI - [Recommendation for rehabilitation measures of elderly disabled patients by the
medical service of hospital insurance in Berlin and Brandenburg].
AB - According to the German Nursing Care insurance law (Pflegeversicherungsgesetz)
experts of the Medical Advisory Board of the statutory sickness funds
(Medizinischer Dienst der Krankenversicherung, MDK) must consider recommending
rehabilitative measures for persons in need of nursing care. This study measures
the proportion of proposed rehabilitative therapies (physiotherapy, ergotherapy,
speech therapy) as well as clinical and non-clinical predictors for these
recommendations. The study population of the cross-sectional study consisted of
all persons aged 60 years and older in Berlin and Brandenburg for whom the MDK
experts had diagnosed a need for nursing care (stages I to III) by means of home
visits in the second half of 1995. Data on recommendations and potential
predictors were taken from the expert records. Recommendation rates were 6.6%
(physiotherapy), 0.7% (ergotherapy) and 0.8% (speech therapy) respectively, for
Berlin and Brandenburg taken together. While clinical variables (impairments and
disabilities) had a considerable impact on the recommendations, also non-clinical
variations were noted. Physiotherapy recommendation rates differed 3-fold by
region (Brandenburg: 10.3%; Berlin: 3.4%). Variations also existed for age (60-70
years: 10.7%; > 90 years: 2.5%) and the presence of a professional care
institution (present: 8.6%; not present: 5.4%). The strongest effect had an
already existing prescription of physiotherapy from the patient's physician
(current physiotherapy: 23.5%, no current physiotherapy: 4.6%). Multiple logistic
regression demonstrated that these variables had independent effects after
accounting for their overlapping influences and clinical characteristics.
Variations of physiotherapy recommendation rates were also found for profession
of the MDK experts (physician: 5.9%; nurse: 9.2%; physician and nurse together:
7%), but the effects were only partially independent. The observed low rates of
recommended physiotherapy, ergotherapy and speech therapy as well as the non
clinical variations question the appropriateness of current recommendation
practices.
PMID- 9553306
TI - [Patient satisfaction after inpatient rehabilitation: different results at
different follow-up times?].
AB - Different Results at Different Times of Questioning? In 1994 a quality assurance
programme for the German medical rehabilitation system was introduced by the
national association of pension funds. One of its five parts focussed on
patients' satisfaction and health effects. Both domains were to be assessed by
postal questionnaires. The first section of the instrument enquired about
patients' perceptions and evaluations of both rehabilitation structures and
processes. It is well known that satisfaction surveys tend to underestimate the
true level of criticism due to social desirability bias. This is especially
problematic in the context of quality assurance programmes where criticism can be
seen as one driving force of improvement. The magnitude of the bias depends on
many factors. In this study we tested the influence of different time intervals
between discharge from rehabilitation clinic and first postal contact. DESIGN: We
conducted an experimentally varied satisfaction survey among four groups of
rehabilitands. If necessary, the first postal questionnaire was followed by two
reminders. SETTING: One Bavarian pension fund for blue collar workers. PATIENTS:
520 rehabilitands were recruited from various rehabilitation clinics specialized
in muskuloskeletal disorders. About 70% suffered from nonspecific back pain. They
were randomly allocated to one of the following time intervals between discharge
and postal questionnaire: one, four, eight and twelve weeks. INSTRUMENTS AND
TARGET VARIABLES: All patients received an identical questionnaire with 67 items
and several subscales. We compared the extent of dissatisfaction between the four
groups. RESULTS: The response rate (after two reminders) showed a linear decrease
from 97% (postal questionnaire after one week) to 83% (12 weeks). The extent of
dissatisfaction did not change systematically though there was a (statistically
nonsignificant) tendency towards higher levels of criticism at week twelve.
CONCLUSIONS: An experimental variation of time intervals between discharge from
rehabilitation and first postal contact does not seem to influence the extent of
reported dissatisfaction though it clearly influences the response rate: The
later the sending out the lower the response rate. Taking into account additional
administrative and organisational aspects of the programme we propose to send out
satisfaction questionnaires between 8 and 10 weeks after rehabilitation.
PMID- 9553307
TI - [Significance of social medicine in the medical contract office].
AB - In the German statutory social security system, the necessity of long-term care
for chronically ill persons with multi-morbidity and reduced performance has made
the socio-medical management of illness and its consequences an important
characteristic of primary medical activity. In routine practice a discrepancy
between the practical demands and social-medical insights has often been
observed. With this in mind, the aim of our pilot study was to systematically
collect data on the state of the art and attitudes towards the relevant spheres
of work in a defined group of physicians and analyse this data. The study was
carried out in the form of a voluntary questionnaire within the medical
association (Arztlicher Kreisverband-AKV) in the area of Erlangen-Hochstadt. The
database was a computer-processible, anonymous questionnaire with which first of
all general socio-demographic and activity-related data was collected. The
following 10 questions included, in addition to an estimation of the
participants' own socio-medical knowledge, questions on the general status of
socio-medical knowledge and how the individual gained this knowledge and the
importance of socio-medical themes in routine practice. The data was evaluated
using descriptive statistics in the form of exploratory data analysis. Of the 320
physicians registered at the time of the investigation (4/96), 89 (31 female
doctors, 58 male doctors) sent back a questionnaire that proved useful (returns:
approx. 28%). Significant sex-related or specialisation-related differences with
regard to participation in the study were not observed. The ratio of female to
male doctors and of general practitioners to specialists in the study collective
corresponded more or less to the distribution in the total group. The
participants had a median age of 41 years (minimum 31, maximum 71) and had been
in practice for a median of 11 years (maximum 43 years, minimum 1 year). 36% were
general practitioners, 64% specialists. 97% regarded sound knowledge in socio
medicine as essential for doctors wishing to set up practice. 70% regarded their
own knowledge of socio-medicine as being in need of improvement. 85% regarded
their knowledge as having been insufficient at the start of their medical
careers. With regard to doctors gaining socio-medical competence, routine
practice and their own autodidactic capabilities played an important role. 84%
would like to see increased teaching of socio-medical themes during specialist
training courses. For over 70% socio-medicine is a part of medical studies as a
subject in its own right. The content and aims of New Public Health were known to
45%. Among the areas of socio-medical work the care of chronically ill persons
was given highest priority. Preventive measures were also accorded high relevance
by the participants, and they were particularly interested in preventive
medicine. Taking into consideration conceptional problems (e.g. the size of the
random sample/selection effects) it was found that: despite many years of
practice in some cases, doctors feel there is a deficit in their socio-medical
knowledge--prcctical knowledge is mainly gained autodidactically during routine
practice ("learning by doing"). There is a clear wish for increased consideration
of socio-medical themes in specialist training courses. The great importance of
socio-medical tasks as part of medical practice is undeniable to the study
collective. The results underline the necessity for improved communication and co
operation between doctors involved in primary medical activity and in socio
medicine.
PMID- 9553308
TI - [Social psychiatry aspects of alcoholism: epidemiology, treatment structures and
recent results of therapy research].
AB - In Germany the per capita consumption of alcohol has tripled since World War II
with a slight decrease in recent years. The number of alcoholics has been
estimated between 2.5 mill. and 10 mill. Epidemiological studies suggest a 6
month prevalence rate of 3.1% (USA 2.9%): 10.4% in males, 0.8% in females; Life
time prevalence estimates range up to 13%. More recent findings also suggest that
alcoholism in adolescents is an increasing problem. The resources for treatment
of alcoholism are limited: Only 1% of all alcoholics are treated in special
addiction rehabilitation programmes, whereas the majority of patients are treated
by their physician, in a general hospital or not at all. Approximately 30,000
patients are treated in special clinical rehabilitation programmes per year.
Socioeconomic consequences of alcoholism have not been evaluated in detail; some
cast models are discussed. In recent years both day-hospital and outpatient
rehabilitation programmes for alcoholics have been established but few
catamnestic studies have been conducted so far. The possible benefit of new
antidipsotropic agents (so-called anticraving drugs) must also be examined in
greater detail. Catamnestic findings and the outcome of treatment studies are
discussed.
PMID- 9553309
TI - [Pyrethroids in house dust of the German housing population--results of 2
nationwide cross-sectional studies].
AB - As a part of the German Environmental Surveys performed in 1985/86 (West
Germany), 1990/91 (West Germany) and 1991/92 (East Germany), dust samples were
collected in the households of about 1600 randomly selected adults (25 to 69
years) and an analysis of these samples was performed in respect of their content
of 8 different pyrethroids and of the synergist piperonyl butoxide (PBO). In the
1990-92 survey about 90% of the samples contained permethrin in concentrations
above the limit of quantification. This showed permethrin to be the most
widespread of the 8 compounds investigated. The geometric mean of the permethrin
content in domestic dust was 0.22 mg/kg. Only about 8% of the samples contained
one or more of the other investigated substances (cyfluthrin, lambda-cyhalothrin,
cypermethrin, alpha-cypermethrin, deltamethrin, empenthrin, d-phenothrin) in
quantifiable amounts. About 76% of the samples contained quantifiable amounts of
PBO. In East Germany the geometric mean of the PBO content (0.21 mg/kg) was
significantly higher than in West Germany (0.07 mg/kg), but no difference for
permethrin was found. Significant associations could be shown for the permethrin
content and the application of biocides as well as for the PBO content and
regional factors (size of community, type of dwelling area). Samples collected in
1985/86 (West Germany) showed a geometric mean for permethrin of 0.06 mg/kg and
for PBO of 0.07 mg/kg. Comparing the values of 1985/86 and 1990/91, a significant
increase can be observed for permethrin, whereas the PBO concentration remained
constant.
PMID- 9553310
TI - [Snack breaks in primary and vocational schools of the Rems-Murr district].
AB - The aim of this study was to collect data on catering at break in primary schools
as a basis for planning health promotion activities. To meet this aim the
principals of all schools were interviewed and the snacks and drinks that were
sold at break were recorded in a checklist. The results show, that in 27.4% of
the schools snacks or drinks were sold that cause damage to dental health or are
not recommended for general health. Moreover nutritious products as school milk,
wholemeal bread and fruits were frequently not available. In 55.8% of the schools
no snacks and in 37.3% of them no drinks were sold at all. In 51% of the schools
the children had the opportunity to have breakfast together in the classroom. The
selling of not recommended snacks and drinks should be banned from schools,
because they rather make healthy choices more difficult than easier and therefore
undermine the effectiveness of health education. To change eating habits
continuous and long-standing activities concerning breakfast at school are
recommended.
PMID- 9553311
TI - [Thyroid hormone level in children in the area of a toxic waste incinerator in
South Essen].
AB - As part of an environmental epidemiological study on potential exposure to a
toxic waste incineration we investigated whether children in an area with a toxic
waste incinerator (TWI) have different levels of thyroid hormones than children
in two comparative regions. The TWI region is situated in the Rhine valley (about
30 km across) with low mountains on both sides. Other industries such as a
chemical plant are nearby, and several municipalities are located in the
environment of these. One comparative area 20 km north is also industrially and
agriculturally used, but has no incinerator (Rhine Valley comparison group, RVC
group). South-East of the incinerator region in an area of low mountains (about
400 m high) we investigated the second comparison group (Odenwald comparison
group, OWC group). Altogether 671 children from 18 municipalities participated in
1994/95 (participation 61.5%). Blood samples were taken from 341 children, aged 7
to 10 years, living in non-smoking households or in households with only light
smokers. Serum levels of thyrotropin stimulating hormone (TSH), free thyroxine
(FT4), and free triiodothyronine (FT3) were analysed. In a self-administered
questionnaire for the parents, which was checked during the medical examination,
we gathered information on age, gender, passive smoking, consumption of fish, as
well as use of wood preservatives and pesticides at home. By means of adjusted
regression analysis the first step was to check whether the TWI group had means
of TSH, FT4 and FT3 that differed from the OWC group and the RVC group. If
differences were at least marginally significant, the second step was to analyse
whether children from different municipalities had statistically different mean
values and if the pattern of these municipalities fitted into the three regions.
For the latter, children from a town in the Odenwald served as comparison group.
The TWI group had statistically significantly (p < or = 0.05) reduced FT3 and FT4
values with a higher prevalence of FT3 values below clinical references (TWI
group: 7.7%, RVC group: 3.2%, OWC group: 1.2%). Children from four out of nine
TWI municipalities showed statistically significantly lower FT3 means than
children from the reference town, and one of the seven municipalities from the
comparative areas. The mean FT4 was significantly lower in four municipalities of
the TWI area and in one of the two other areas. The mean TSH was only marginally
different, mainly influenced by gender differences with boys having higher TSH
levels. Comparison of the municipalities did not reveal a consistent pattern.
Industrial pollution might influence the regulatory system of the pituitary
thyroid axis. Reduced peripheral thyroid hormones associated with exposure to
polychlorinated biphenyls (PCB) and dioxins/furans (PCDD/F) were found in
previous studies. Our results suggest that children exposed to toxic waste
incineration in their environment have lower thyroxine and triiodothyronine
levels.
PMID- 9553312
TI - [Evaluation of scientific publication: a recommendation (not only) for general
medicine].
AB - A Proposal (not only) for General Practice/Family Medicine: Medical faculties and
other institutions increase their pressure on scientific societies and colleges
to present and set standards to evaluate publications from their discipline.
After discussing the quality of different literature and publication indices the
authors take a critical look at the impact factor which arouses much controversy
among medical faculties. The evaluation standard presented for general practice
comprises three categories of quality to which (A) Top Journals, (B) Standard
Journals and (C) other Journals (but also books and book contributions) are
allocated. Assessment criteria are mainly based on indexation (Index Medicus) and
independent peer review. Within that system original papers are valued higher
than reviews and editorials or comments. The impact factor is not considered to
be helpful for judgement. The authors are convinced that any numerical point
system would not be likely to lead to a reasonable assessment of an individual
publication. Furthermore, there could be an increased risk that members of
committees would prefer the point system for their judgement rather than to read
papers in detail. The suggested standard could serve as an aid for referees from
disciplines other than general practice. However, their expert decision regarding
the quality of publications could not be replaced by even the most sophisticated
valuation system.
PMID- 9553313
TI - [Excessive reactions in Mendel-Mantoux tuberculin tests].
PMID- 9553314
TI - [Infiltrating lobular carcinoma of the breast. Clinical picture, treatment and
prognosis].
AB - An analysis of 80 patients with infiltrating lobular carcinoma of the breast
treated at Center of Oncology in Krakow is presented. All patients underwent
radical mastectomy. The evaluation of treatment results showed stage,
pathological tumor size, and involvement of axillary nodes as the prognostic
factors. The ten-year survival rate NED in all group was 38.8%; for stage I, II,
and III it was 62.5%, 48.8%, and 19.4% respectively.
PMID- 9553315
TI - [Suture of the episiotomy wound--comparison of two techniques from clinical and
cosmetic aspects].
AB - The use of an episiotomy for vaginal delivery is a controversial topic in modern
obstetrics. If one is done, however, correct technique of perineal trauma repair
is important. The usual episiotomy has traditionally been closed with interrupted
suture. The use of a less reactive material, e.g. polyglycolic acid (Dexon), seem
to be suitable for subcutaneous skin closure and beneficial in terms of acute
postpartum discomfort and healing. The comparison of healing and patient comfort
parameters between interrupted and subcutis polyglycolic acid suture used for
episiotomy repair after delivery was done. Patients had follow-up during hospital
stay, and two months after delivery a self administered questionnaire was sent to
all women who participated, enquiring about perineal pain, resumption of sexual
intercourse and cosmetics of suture line. Of 52 patients who had repair with
interrupted suture, 21 were lost to follow-up. Of 65 gravidas who had repair with
subcutis suture, 23 were lost to follow-up. At the 3rd day postpartum
examination, patients with subcutis sutures had significantly better healing. An
inflammatory process was present in 2 of 52 patients with interrupted sutures
comparable with 1 of 65 in the subcutis group, and a gaping wound in 0 of 52 and
1 of 65, respectively. Recovery of function, measured by resumption of sexual
activity by 8 weeks, was demonstrated in 5 of 31 patients with interrupted
sutures versus 24 of 42 patients who had subcutis sutures. Episiotomy repair with
subcutis polyglycolic acid (Dexon) offers significant advantages over traditional
interrupted suture, both in terms of wound healing and resumption of sexual
activity.
PMID- 9553316
TI - [Glycosaminoglycans in uterine leiomyoma].
AB - During development of leiomyoma, a reorganisation of main components of
connective tissue has been found. All types of glycosaminoglycans are present in
this tissue. Among them the heparan sulphate is the most abundant. Its content
was found to increase with uterine myoma weight. It is worthy of note that the
increase of keratan sulphate is observed in big leiomyoma.
PMID- 9553317
TI - [Creatine kinase activity ec 2.7.3.2 in blood serum of women during pregnancy and
during delivery].
AB - In the serum of women during the pregnancy and during the stages of the delivery
the activity of creatine kinase (CK) was measured using the test by Fermognost.
The investigations were led in three 20-personal groups of women: non-pregnant,
pregnant examined three times, in each trimester of pregnancy, and labored women
examined three times, one time in each stage of delivery. The age of investigated
women was between 18-39 years. According to obtained results, it was noticed
statistically significant increase in the activity of this enzyme during the
pregnancy. Measuring the activity of creatine kinase in three stages of delivery,
the highest increase in this enzyme activity was observed in the third stage.
PMID- 9553318
TI - [Estimated levels of fructosamine in venous blood of pregnant women and in cord
blood].
AB - In the study there was estimated maternal (Fm) and cord blood (Fc) fructosamine
levels in 151 diabetic (58 PGDM and 93 GDM) and 100 control subjects on the day
of delivery. It was found that Fm and Fc levels in PGDM and GDM groups were
significantly higher than in the control group. It was also found the
significantly positive correlation between Fm and Fc levels in all study groups.
It leads to the conclusion that pregnant diabetic women and their fetuses were
hyperglycemic during the last 2 weeks of pregnancy. Our results indicate that on
the basis of maternal fructosamine levels it is possible to apply on indirect
estimation of metabolic status of the fetus.
PMID- 9553319
TI - The application of GnRH analogues in the treatment of uterine myomas in
perimenopausal women.
AB - Our objective was to determine whether long GnRH agonists induce effective and
persistent shrinkage of uterine myomas in perimenopausal women, as well as to
determine the usefulness of Doppler sonography study in evaluating the therapy
benefit. The study covers 30 patients with symptomatic myomas in perimenopausal
period. We used long GnRH agonist-Decapeptyl (Ferring) at 28 days intervals in
the course of 4 months. After discontinuing the application of Decapeptyl,
medroxyprogesterone acetate was introduced for 6 months. The GnRH/gestagens
therapy is useful and effective in treatment of symptomatic myomas in
perimenopausal patients, and may be a valid alternative to hysterectomy. Doppler
sonography is reliable in monitoring of uterine circulation in patients under
GnRH therapy.
PMID- 9553320
TI - [Stromal sarcoma of the uterus in an 18-year old girl].
AB - The authors describe diagnostic difficulties connected with proper estimation of
stromal sarcoma biological activities, which developed in uterus corpus in 18
year old girl previously treated with hormones, because of irregular painful
menses. Macroscopic and microscopic investigations of postoperative specimen
allowed to set final diagnosis: stromal sarcoma with intermediate grade of
malignancy, which showed an aggressive growth in the surrounding tissue and
demonstrated moderate, focal polymorphism and different amounts of the mitoses in
different areas.
PMID- 9553321
TI - [Spontaneous tumor regression].
AB - Spontaneous remission of cancer is a rare but definitely observed phenomenon.
Spontaneous remission is defined by partial or total disappearance of a proven
malignant tumor, without adequate medical treatment. It has been estimated that
it occurs no more than once in 60,000 to 100,000. The cause of phenomenon is
multifold: immunologic, hormonal and psychological mechanism as well as
elimination of carcinogen (action of oncogenes, growth factors, cytokines) and
apoptosis are postulated. In gynecological malignancies, excluding
chorionepithelioma and breast cancer, spontaneous remission is rare.
PMID- 9553322
TI - Current status of vitrification of embryos and oocytes in domestic animals:
ethylene glycol as an emerging cryoprotectant of choice.
AB - The cryopreservation of mammalian embryos has become an integral part of methods
to control animal reproduction. Numerous vitrification solutions have been
formulated with ethylene glycol in combination with macromolecules, sugars and
other cryoprotective agents. These indicate that a study of ethylene glycol as a
cryoprotectant of choice in vitrification studies would be promising. To
understand the cryobiology of ethylene glycol, several factors have to be
studied. These are: cryoprotectant toxicity, osmotic stress and temperature at
exposure. Understanding these factors could lead to the formulation of
vitrification protocols that would lead to higher viability rates after cooling.
First, ethylene glycol must be used as the sole cryoprotectant in a solution
without macromolecules and sugars. Second, partial dehydration and permeation
prior to cooling to subzero temperatures must be studied to achieve accurate
exposure and a one-step dilution method. Third, the toxic effects of ethylene
glycol must be overcome without sacrificing its vitrification properties by
combining step-wise exposure at appropriate temperatures, low concentration and
decreased volume. Fourth, the long-term effects of ethylene glycol on exposed or
vitrified embryos must be determined. Lastly, the influence of culture on the
viability of vitrified embryos must be studied to improve viability rates after
warming.
PMID- 9553323
TI - In vitro viability of mouse zygotes vitrified in ethylene glycol.
AB - A study was made to determine if mouse zygotes can be effectively vitrified in 7
M ethylene glycol in modified Dulbecco's phosphate buffered saline (PB1) and to
find out if the development of vitrified-warmed zygotes in vitro can be improved
by renewing the culture medium. The results showed that without medium change,
vitrification reduced the development of zygotes to the expanded blastocyst stage
(p < 0.01). With medium change, the development rate of vitrified-warmed zygotes
exposed in 7 M ethylene glycol for 1 or 2 min was similar to that of unvitrified
zygotes. However, prolonged exposure (5 min) markedly reduced the development
rates of vitrified-warmed zygotes to the expanded blastocyst stage (p < 0.05).
When the zygotes were vitrified in 7 M ethylene glycol and diluted at 18 degrees
C to 22 degrees C, a slower efflux of ethylene glycol from the cell might have
occurred, leading to a toxic effect of ethylene glycol in culture. The
development rates of vitrified embryos cultured with medium change at 24 hr did
not significantly differ from the untreated control (89.0% vs 96.5%). In
conclusion, this study showed that mouse zygotes can be vitrified in 7 M ethylene
glycol in PB1 and that changing the culture medium can improve the in vitro
development rates of vitrified-warmed zygotes to the expanded blastocyst stage.
PMID- 9553324
TI - Ultrasonographic evaluation of portal vein hemodynamics in experimentally bile
duct ligated dogs.
AB - The purpose of this study was to evaluate the relationship between the results of
laboratory examinations and ultrasonographic findings, especially portal vein
hemodynamics in experimentally bile duct ligated dogs. Biliary obstruction was
accomplished by surgically occluding the common bile duct in five dogs. All the
dogs became visibly jaundiced within 24 hours after surgery. The total protein
and albumin/globulin ratio showed a gradual decrease throughout the examination
period, while blood urea nitrogen reached its peak in the 6th week and decreased
to pre ligation values by the 10th week. Similar trends were noted in the
alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and
direct and total bilirubin. Total cholesterol and fasting serum bile acid levels
rapidly increased after surgery to peak values between the 2nd and 4th week, and
then gradually decreased, but still remained high throughout the experiment
period. The portal flow volume and velocity significantly (p < 0.05) decreased
while only a slight increase was noted in the congestion index after bile duct
ligation. The cross sectional area of the portal vein changed insignificantly.
Bile duct and gallbladder distention was evident within the 1st week after
ligation but there was little change in the echogenicity of the liver parenchyma.
The results of this study suggest that the determination of Doppler ultrasound
parameters of hepatic hemodynamics, especially the portal vein flow indices, may
contribute to a better noninvasive assessment of the canine patient with biliary
obstructive disease.
PMID- 9553326
TI - Functional enucleation of mouse metaphase II oocytes with etoposide.
AB - Mouse metaphase II (M II) oocytes were exposed to 50 micrograms/microliters
etoposide (ETO) before and after parthenogenetic activation with 7% ethanol and
they were washed with 0.75 M sucrose. The ETO treated parthenogenetically
activated oocytes were cultured or fused to single blastomeres of late 2-cell
stage mouse embryo to test their ability to support development in vitro. In
parallel untreated parthenogenetically activated oocytes were cultured to serve
as control. None of ETO treated oocytes developed beyond the 2-cell stage,
whereas 4% of the reconstituted embryos and 35% of control developed to
blastocysts. It is concluded that mouse M II oocytes can be functionally
enucleated by ETO treatment and can be used for nuclear transfer experiments.
PMID- 9553325
TI - Potentially virulent Newcastle disease viruses are maintained in migratory
waterfowl populations.
AB - Forty-seven Newcastle disease virus (NDV) strains isolated from fecal samples of
waterfowls in Alaska and Siberia from 1991 to 1996 were analyzed for their
virulence. None of the viruses formed plaques on MDBK cells in the absence of
trypsin. Of these, 29 strains showed virulent character by the mean death time
with the minimum lethal dose in chicken embryos comparable to velogenic NDV
strains. Of the 29 strains, 11 were sequenced for their fusion protein (F) gene.
The results showed that 5 of them contained a pair of dibasic amino acids at the
cleavage site of the F, which is of a virulent type. The present results suggest
that potentially virulent strains of NDV are maintained in migratory waterfowl
populations in nature, and that some of those may be transmitted to domestic
poultry and acquire pathogenicity during passages in chicken population.
PMID- 9553327
TI - [The effect of the formulation of a skin cream with a procyanidin polymer base
and its effect on skin lesions caused by herpesviruses].
AB - Procyanidin polymers are reported to be virostatic and virucidal in vitro. In
this experiment we showed, on a hairless mouse model, biological effects of these
agents, already demonstrated in vitro on cell cultures. Several dermic cream
compositions have been tested and compared for reduction of HSV1 cutaneous
lesions. In this study, it appeared clearly that active principle dosage form is
as important as the biological effect of the agent. Composition and water content
influence permeation speed, contact time with surface skin layers and
consequently the pharmacological effect on herpetic skin injuries.
PMID- 9553328
TI - Interpreting the standard of care.
PMID- 9553329
TI - Clinical application of the new civil airman vision standards and certification
procedures.
AB - INTRODUCTION: The final rule revising the civil airman medical standards became
effective September 16, 1996. The purpose of this study was to review changes in
the vision standards and procedures and how they relate to the clinical
optometrist. METHODS: Revision of Airman Medical Standards and Certification
Procedures and Duration of Medical Certificates; Final Rule, (14 CFR, Parts 61
and 67) and the Guide for Aviation Medical Examiners, published by the Federal
Aviation Administration's Office of Aviation Medicine, were reviewed, and those
parts pertaining to the clinical optometrist were summarized. DISCUSSION: The
uncorrected distance visual acuity standards for first- and second-class airmen
have been deleted. New equivalent near-vision standards were established for all
classes of airmen. A major change--for pilots > or = 50 years of age--was the
addition of an intermediate vision requirement of 20/40 or better at 32 inches
for both first- and second-class medical certificate holders. Although the third
class medical certificate is still valid for 24 months after the date of
examination for those > or = 40 years of age, the certificate is now valid for 36
months for those < 40 years of age. CONCLUSION: The new vision standards
primarily affect the elderly pilot. Ophthalmic considerations in the application
of the new vision standards are reviewed.
PMID- 9553330
TI - Ocular cicatricial pemphigoid: case report.
AB - BACKGROUND: The main characteristic of ocular cicatricial pemphigoid is
subepithelial conjunctival fibrosis, which, if progressive, can lead to
conjunctival shrinkage and symblepharon formation. Other characteristics include
entropion, trichiasis, dry eye, cornea ulceration, neovascularization, and
keratinization. Ultimately, blindness may occur. Cicatricial pemphigoid may also
affect the skin and mucous membranes, including the nose, oral cavity, pharynx,
esophagus, anus, and vagina. Treatment involves systemic immunosuppressants and
corticosteroids to suppress active inflammation. CASE REPORT: A 69-year-old man
had symblephara, conjunctival shortening, and extraocular manifestations, and was
diagnosed with ocular cicatricial pemphigoid on the basis of clinical appearance
and immunofluorescent studies. Treatment included oral Dapsone, prednisone, and
azathioprine to stabilize the condition. CONCLUSION: Close monitoring of ocular
cicatricial pemphigoid is imperative for ocular manifestations and for
extraocular complications occurring with this progressive autoimmune disease and
its treatment.
PMID- 9553331
TI - Optometric manpower in the Commonwealth of Puerto Rico: estimates and
projections, 1982-2025.
AB - BACKGROUND: The 1982 study investigated the potential impact of the IAUPR School
of Optometry on the adequacy of supply of optometrists in Puerto Rico for the
years of 1980-2000. This article is designed to: (1) update the 1982 study; (2)
appraise the accuracy of the 1982 projections; (3) re-evaluate the status of
optometric manpower in Puerto Rico through the year 2025; and (4) provide the
School of Optometry with information necessary to make informed judgments about
future enrollments. METHODS: Estimates of supply are based on data from the
Colegio de Optometras de Puerto Rico, the Seccion de Oftalmologia de la
Asociacion Medica de Puerto Rico, and the enrollment and graduation registries
from the School of Optometry. Requirements are based on estimates of annual
effective demand, provider-to-population ratios, per capita demand, and
optometric productivity. RESULTS: Optometrists comprised 52.2% of Puerto Rico's
actively practicing vision care manpower in 1995, with a mean optometrist-to
population ratio of 8.2 per 100,000. The number ranged from 28 in Mayaguez to 107
in San Juan. Under different assumptions regarding supply, productivity, and
demand, surpluses and deficits are estimated and projected for the years 1995 to
2025. CONCLUSIONS: Depending on the assumptions used, an undersupply or an
oversupply of optometrists may be found in Puerto Rico, currently and in the
future. Projections of supply and demand predict a considerable range--from a
surplus of 961 optometrists to a deficit of 2,085 optometrists in the year 2025.
PMID- 9553332
TI - Keratocytes: no more the quiet cells.
AB - BACKGROUND: In the past, the keratocytes of the adult cornea have been
characterized as quiescent cells populating the stroma. Recent research and the
introduction of laser refractive procedures have forced us to reassess this
notion. METHODS: By reviewing recent, pertinent papers, an attempt was made to
give an overview of the new information the scientific community is learning
about keratocytes. This overview assesses the heightened interest in the
keratocytes, while maintaining a clinical perspective. Where applicable, this
information was tied in with our own laboratory observations. RESULTS: It is
becoming increasingly clear that keratocytes may play a vital role in regulating
the stromal constituents, while also providing structural stability in
maintaining the interlamellar organization and, thus, promote corneal
transparency. Keratocytes form a communicating network of cells linked in a
anterior-posterior fashion, as well as laterally. This ability to communicate
appears instrumental in triggering and orchestrating the corneal response in
wound healing. External corneal injury, such as epithelial debridement and
excimer laser exposure, can cause profound anterior keratocyte loss. These cells
are replaced by aggressive stromal cells, which may play an important role in the
formation of scar tissue and corneal haze. CONCLUSION: Keratocytes play an
important role in both the healthy and the injured cornea. It appears that the
improved outcomes of laser refractive procedures will--to a large extent--depend
on our ability to maintain keratocyte health, while also controlling the negative
effects of cells replacing injured or dead keratocytes.
PMID- 9553333
TI - Optometry's first drug law: a personal memoir.
PMID- 9553334
TI - [Analysis of cytological values of bronchoalveolar lavage in allergic
inflammation of the bronchopulmonary system].
PMID- 9553335
TI - [Problems of cytological diagnosis of some tumors of the anterior mediastinum].
PMID- 9553336
TI - [Clinical value of total and free prostatic specific antigen in prostatic
cancer].
PMID- 9553338
TI - [Fluorescent microscopy in studies of microbiopsy specimens of the lung and
bronchoalveolar lavage].
PMID- 9553337
TI - [Epidermal growth factor receptors and their ligands as molecular markers of
breast cancer prognosis and hormone sensitivity].
PMID- 9553339
TI - [Spermoplasma protein markers in laboratory diagnosis of male sterility in
diseases of male reproductive system].
PMID- 9553340
TI - [Cytomegalovirus infection--modern diagnosis].
PMID- 9553341
TI - [Modern aspects of automation in microbiology, epidemiology and chemotherapy].
PMID- 9553342
TI - [On the diagnosis of Chlamydia infections].
PMID- 9553343
TI - [PCR diagnosis of sexually transmitted diseases].
PMID- 9553344
TI - [Agents of opportunistic infections--role in human infectious pathology and
methods of laboratory diagnosis].
PMID- 9553346
TI - [Polymerase chain reaction in diagnosis and treatment control of infectious
diseases].
PMID- 9553345
TI - [Laboratory assessment of tissue oxygen intake: blood gases and CO-oximetry
(lecture)].
PMID- 9553347
TI - [Experience gained in applying the expert approach to assessing the result of
patient's analyses made in chemical plants laboratories].
PMID- 9553348
TI - [Enzyme immunoassay in the laboratory diagnosis of human immunological
disorders].
PMID- 9553349
TI - [A variant of radioimmunoassay of alpha-fetoprotein].
AB - A variant of liquid-phase radioimmunoassay (RIA) with murine monoclonal
antibodies E7(B2-1) to human alpha-fetoprotein (AFP) is described. AFP levels
were measured by RIA with a commercial DIAplus kit in the sera of patients with
germinogenic tumors and of pregnant women.
PMID- 9553350
TI - [Efficiency of a laboratory: opinions and evaluations of clinical physicians].
AB - The opinions of 356 clinicists on the priority functions of a biochemical
laboratory are analyzed and the efficiency of these functions performed by
laboratories of a diagnostic center evaluated. The main laboratory functions were
rated in accordance with the results of analysis. Besides the accuracy of the
results, the respondents named time needed to obtain the results, the possibility
of urgent information on the presence of manifest abnormalities, etc., as the
most important factors. The author comes to a conclusion that other than
analytical functions of laboratories are to be strictly defined and described as
standards.
PMID- 9553351
TI - [Antiphospholipid syndrome (Hughes syndrome): 10 years of study in Russia].
PMID- 9553352
TI - [Arterial hypotension in the elderly].
PMID- 9553353
TI - [Variability of heart rate in postmyocardial infarction patients: clinical
implications, problems and prospects].
PMID- 9553354
TI - [Pulmonary lesion in polymyositis and dermatomyositis].
PMID- 9553355
TI - [Clinicofunctional and psychological characteristics of patients on
rehabilitation and aortocoronary bypass].
PMID- 9553356
TI - [Hepatolienal syndrome in patients with chronic lymphoid leukemia and liver
cirrhosis: similarities and differences of macrophagal function].
AB - Macrophagal function of the liver and spleen was studied using 99mTc dynamic
scintigraphy in 31 patients with chronic lymphoid leukemia (CLL) and 11 patients
with hepatic cirrhosis (HC). Total accumulation of the radionuclide in the above
patients took place with more active participation of the spleen and less active-
of the liver. Macrophagal function of the spleen and the liver was activated in
CLL patients, whereas hepatic cirrhosis was accompanied by enhanced splenic
function and diminished capacity of the liver for phagocytosis. Mechanisms of
such phenomena are discussed.
PMID- 9553357
TI - [Rheological and hydrodynamic properties of blood from patients with stable
angina pectoris: correction with high molecular polyethylene oxide].
AB - Rheological and hydrodynamic properties of blood taken from patients with stable
angina pectoris were investigated in different periods (1, 7 and 28 days) of
combined treatment (calcium antagonists, nitrates, beta-blockers, aspirin). The
high viscosity syndrome (elevated blood viscosity, red cell aggregation,
hyperfibrinogenemia) was registered before treatment, 1, 7 and 28 days after
beginning of the treatment. Low hydrodynamic index (the speed of blood flow in
turbulent regimen) reflected insufficiency of endogenic antiturbulent factor in
the blood. The addition of high-molecular-weight polyethylene oxide to blood
samples in concentration 2 x 10(-6) promoted normalization of the hydrodynamic
index and decline of red cell hyperaggregation.
PMID- 9553358
TI - [Antigliadin antibodies in the absence of celiac disease].
AB - Antigliadin antibodies (AGA) mark celiac disease, but AGA are also encountered in
IgA-nephritis, psoriasis, sickle-cell anemia, hepatic disorders, juvenile
rheumatoid arthritis, autoimmune thyroidism and in persons who occupationally
contact great amounts of wheat. AGA IgA and/or IgG were registered in 19 of 60
subjects (51 adults and 9 children) with various immunomediated diseases without
symptoms of celiac disease: in 4 cases of chronic active hepatitis, in 2 of 4
cases of chronic persistent hepatitis, in 4 of 16 cases of rheumatoid arthritis,
in 3 of 19 cases of IgA-deficiency, in 1 of 8 cases of SLE, in 2 cases of
postvaccine reaction, in all the single cases of juvenile rheumatoid arthritis,
focal scleroderma, macroglobulinemia. IgA only occurred in in 6 patients, IgG- in
6 patients, both IgA and IgG in 7 patients. The most pronounced positive reaction
to AGA was recorded in 8-year-old girl with juvenile rheumatoid arthritis. The
emergence of AGA in immunomediated diseases may be attributed to the response to
food protein in pathological conditions and is often unrelated closely with
celiac disease.
PMID- 9553359
TI - [Hemocarboperfusion in combined treatment of leptospirosis].
PMID- 9553360
TI - [Platelet hemostatic changes in patients with chronic alcoholism stage II in rest
and exercise].
AB - Platelet hemostasis was studied in 23 patients with chronic alcoholism (CA) stage
II at rest and under muscular exercise. At rest, the patients had elevated
spontaneous aggregation of platelets and more active start of adrenaline and
ristomycin aggregation. Exercise stimulated spontaneous platelet aggregation,
enhances adrenaline and ristomycin aggregation. According to adrenalin test 32%
of the examinees had platelet dysfunction. According to ristomycin aggregation,
vascular endothelium was impaired in 95.7%of the patients. Thus, it is evident
that CA stage II patients develop disorder of platelet hemostasis and vascular
endothelium. Such patients are at high risk of thrombogenesis.
PMID- 9553361
TI - [Urinary excretion of glycosaminoglycans in patients with chronic pyelonephritis
and chronic glomerulonephritis].
AB - Glycosaminoglycanes (GAG) were measured in 24-h urine of patients with chronic
pyelonephritis (CP) and chronic glomerulonephritis (CGN) at different stages of
nephrosclerosis. These patients developed hyperglycosaminoglycanuria at early
stages of nephrosclerosis before establishment of chronic renal failure. There is
a positive correlation between the severity of excretion of GAG and leukocyturia
in CP patients (p < 0.05). Estimation of GAG 24-h urinary excretion can help
evaluate metabolism of connective tissue of the kidneys in CP and CGN patients
for early diagnosis of nephrosclerosis, control of the treatment efficacy and the
disease prognosis. It can also serve as additional criterion for rating of
inflammation. The method is non-invasive, informative, available for clinical
diagnostic laboratories.
PMID- 9553362
TI - [Ecological zones of Dagestan territory and epidemiology od acute leukemia in
older age groups].
AB - The authors report annual acute leukemia incidence through 1980 to 1995 in
Dagestan in respect of implications of of environmental factors. The highest
leukemia incidence rate was in the age group over 50 years. Acute leukemia
incidence varied with years, sex and territory zones. Active utilization of
chemical fertilizers in agriculture proved a contributing factor in the onset of
acute leukemia, especially in persons older than 50 years.
PMID- 9553363
TI - [Long-term subfebrility].
PMID- 9553364
TI - [A case of allergic eosinophilic granulomatous angiitis (Churg-Strauss
syndrome)].
PMID- 9553365
TI - [Syndrome of functional dyspepsia: disputable and unsolved problems].
PMID- 9553366
TI - [History of teaching clinical medicine: leiden advance].
PMID- 9553367
TI - [Current objectives for the improvement of work conditions and prevention of
occupational diseases among miners].
AB - Workers engaged into deep mining are subjected to occupational factors intensity
of which is significantly higher than the allowable. Changing the mining
enterprises involves deterioration of the working environment, increase in
occupational morbidity. Features of the working environment, parameters of main
occupational entities, recent social instability at mining enterprises
necessitate further investigations on the problem.
PMID- 9553368
TI - [Medical and social problems related to cardiovascular diseases among the miners
of the Donbass coal mines].
AB - Occurrence and course of cardiovascular diseases in miners of Donbass is due to
social and occupational factors that should be considered in early diagnosis and
prophylaxis. Sudden coronary death of miners at the workplace or after leaving
the mine is associated with triggering of occupational factors and now is legally
appreciated as an occupational accident.
PMID- 9553369
TI - [The influence of dust and heating microclimate on lipid peroxidation].
AB - In experimental pneumoconiosis both under normal and heating ambient temperature
lipid peroxidation is not activated, although heating microclimate increases
alteration of lung tissue and induces rapid and intensive pulmonary fibrosis.
Association of dust and heating microclimate prolongs a period of "stress"
myocardial affliction due to intensified lipid peroxidation and exhausted
endogenous glutathione peroxidase, afterwards lipid peroxidation decreases with
progressing sclerosis and fat degeneration in heart.
PMID- 9553370
TI - [Irregular heart rate correction among miners with early signs of pulmonary
diseases by the method of alternative biocontrol of the heart contraction
frequency].
AB - The study covered 45 miners having anthracosilicosis and dust bronchitis. The
registered signs were lower spectral intensity of high-frequency waves
(oscillations period 3 to 36 s) and higher spectral intensity of low-frequency
waves (oscillations period 36 s), asymmetry of blood pressure, higher systolic
and diastolic BP before stress period of adaptation. Adequate therapy associated
with biologic regulation of cardiac rhythm restores normal regulation.
PMID- 9553371
TI - [Morbidity with temporary disability among miners of underground and surface
mines].
AB - The authors studied morbidity with transitory disablement among miners of open
and deep mines. The morbidity parameters appeared to differ reliably between deep
miners and open-cut miners. The morbidity structure is demonstrated. The authors
revealed strong direct correlation between the morbidity parameters and intensity
of occupational hazards in the mine.
PMID- 9553372
TI - [The impact of trinitrotoluene on eyes in miners].
AB - Trinitrotoluene (TNT) effect on the eyes of 250 miners was studied. The length of
service of the investigated group varied from one to twenty years. The specific
trinitrotoluene cataract of various stages was observed in 54.7% of the
examinees. The authors assume that the lens changes depend on the length of
service and on the TNT concentrations in the body after predominant skin
penetration.
PMID- 9553373
TI - [Data on occupational diseases among health personnel and workers of medicine
related industry in St. Petersburg].
AB - A total of 105 occupational morbidity cases in health service workers were
analyzed among 2914 occupational morbidity cases in St. Petersburg. Most of those
cases among health service workers were drug allergies, tuberculosis was
relatively rare. The study revealed low efficiency of periodic medical
examinations conducted for early diagnosis of occupational diseases. Alarming
evidence is rare diagnosis such occupational diseases as hands overstrain,
strained working posture, disorders due to physical factors, viral B hepatitis.
PMID- 9553374
TI - [Occupational environment and health status among workers at the enterprises of
"Sibtechspetsmontazh++" trust].
PMID- 9553375
TI - [Common shortcomings and mistakes in monographs and textbooks on industrial
ecology].
PMID- 9553377
TI - Births, marriages, divorces, and deaths for July 1997.
PMID- 9553378
TI - [How should the tuberculosis control activities of health center be?].
PMID- 9553379
TI - [Factors affecting active-life orientation among the elderly in a community in
Japan and its relationship to social activities].
AB - We surveyed a stratified random sample of 205 person from 45,500 residents, aged
65 years or older, in a city of Japan using an interview schedule including
scales of active-life orientation, social activities and other covariates. A
total of 157 (77%) participated in the study. The main results were as follows:
1) Significantly higher scores of active-life orientation were observed in those
who currently worked, than in those who did not work in males and females (p <
0.05). In males, scores of active-life orientation were significantly higher in
those who had hobbies than in those who did not (p < 0.05); in those who traveled
during the past year than in those who did not (p < 0.05). 2) In multiple linear
regression analysis, PGC scale scores positively and significantly correlated
with score of active orientation in males and females (p < 0.05). Age negatively
correlated with the scores in males. Scores of affiliation orientation positively
correlated with scores of active orientation, and satisfaction with available
social support negatively correlated with the scores in females (p < 0.05).
PMID- 9553381
TI - [The evolution of the thought of "Yojo" and its function as a theoretical bases
for development of health culture].
AB - The purpose of this monograph is to clarify the role of "Yojo" on public health
in Japan. Yojo is a traditional concept which has been used for the nourishment
of life in Eastern cultures. These thoughts on Yojo were published under the
title of Yojoron in ancient China. Yojoron was imported into Japan somewhere from
the 7th to 10th centuries. In ancient and medievel Japan, there were few writings
about Yojoron. However during the Edo period, Yojoron suddenly flourished.
Dominant in Yojoron was diet. Issues such as exercise, mental control, and sexual
restraint were also considered in the Bunka, Bunsei, and Tenpo periods (the first
half of 19th century). Yojoron included not only matters of physical and mental
health but various other matters regarding the general quality of life such as
morality, domestic economy, culture and education. However other health-related
issues such as longevity and absence of diseases, showed a simultaneous decrease
in the importance. Also principles of Yojoron such as restraint and austerity in
behaviour were liberalized. These trends indicated the basic shift in Yojoron
from personal health care to self-culture for the entire quality of life.
Writings on Yojoron were still published after the Meiji restoration (1868). The
principle of Yojoron in the Meiji period was based on both social Darwinism and
social revolution theories. The primary concerns of Yojoron were consolidated
into achieving health and longevity by personal effort. Therefore Yojoron can be
seen as the theory of lifestyle and quality of life in traditional societies in
Japan. The public saw in Yojoron a design for living through improved health.
This meant the Yojoron was a very refined art of living, and therefore, implies
that health care should be integrated with entire self-development. The principle
of Yojo offers the ideal foundation of 'health culture' in modern societies.
PMID- 9553380
TI - [Effectiveness of a health education class to increase fish intake evaluated by
serum fatty acid compositions].
AB - For prevention of cardiovascular disease, we recommended increased fish intake
for 50 middle-aged women and men of 40-83 years old at a three-month community
based health education program in an inland farming community. The effectiveness
of the education program was evaluated by examining changes in serum lipids and
serum fatty acid compositions. For comparison, we selected 48 men and women of 38
82 years old did not participated in the program. Before education, there was no
significant difference in the dietary frequency of fish, meat, egg and dishes
prepared with oil, mean values of serum lipids or serum fatty acid compositions
except for saturated fatty acid, gamma-linolenic acid, dihomo-gamma-linolenic
acid and alpha-linolenic acid. After three months, the frequency of fish intake
of one or more times per day increased from 33% to 43% in the education group
while the frequency of fish intake did not change in the control group. In the
education group, serum n3 polyunsaturated fatty acid composition increased from
8.8% to 10.6%. This fatty acid increase was primarily observed in
eicosapentaenoic acid and docosahexaenoic acid. The n3/n6 ratio increased from
0.21 to 0.31. In the control group, no change was observed in n3 polyunsaturated
fatty acids. This study suggests that the community-based dietary education
increased fish intake and serum n3 polyunsaturated fatty acids in women and men
of 40 years old or older.
PMID- 9553382
TI - [Relationship between subjective cognition and observed life-style in nursing
students].
AB - Complex interactions between long-standing lifestyles and genetic factors are
strongly involved in the pathologenesis of adult diseases or chronic degenerative
diseases. We usually use a questionnaire to obtain life-style information from
subjects in a health survey. However, the response to questionnaires is a
subjective recognition, therefore, it does not always precisely correspond to the
actual situation. The purpose of this research is to compare the response to the
questionnaire about life-styles with facts that can be objectively observed.
Furthermore, each aspect of life-styles was examined on a mutual influence grade.
The subjects were ninety-eight nursing college students aged from 18 to 23 years
old, in good health. Subjective symptoms and daily life practices were
investigated by a 15-item questionnaire, as the first step. Therefore, we asked
them to record their behavior on a time chart, everyday for ten days. Seven days
of serial records were obtained from sixty-four subjects (65.3% of 98 persons).
1) The response "yes" to the questionnaire "Do you sleep well?" and "Do you fall
asleep, easily?" was influenced by the hours of sleep, rather than what time the
subjects "go-to-bed" or "get-up". The response to "Do you wake up often during
the night?" expressed an actual situation, well. 2) For subjective cognition
regarding excretion, the answer for "constipation" was associated with the number
of defecation per week, though the answer for "diarrhea" was not. 3) The answer
to "Do you eat breakfast?" reflected the actual situation. However, the answer
for "Do you eat between meals?" did not express the actual situation, that is,
even the subjects who answered "occasionally" or "I don't eat between meals" had
eaten between meals 6.1 times per week, on average. 4) There were mutual
influences among sleeping, eating breakfast and excretion.
PMID- 9553383
TI - [Trend of aging on the number of teeth investigated through a survey of dental
health representation in a simple equation by using a kinetic method and its
application].
AB - A survey of dental health was conducted on 6,933 residents (aged 61.8 +/- 11.1)
in 4 villages Nara Prefectural Uchiyoshino Health Center administers. Examinees
were divided into 7 ages groups. The mean value of present teeth at each age
group was calculated. Age dependency of number of teeth was investigated with a
kinetic model based on the following premise. 1. Changes between age groups can
be treated as a time series occurrence. 2. Number of missing teeth can be
estimated as 29 - that of present teeth. Results show that the rate of decrease
of the number of present teeth is of a first order in itself and the number of
missing teeth. It can be mathematically expressed as follows: -dX/dt = k.X.(29 -
X).......eq. (1). in which X = number of present teeth, 29 - x = number of
missing teeth k = rate constant, t = time. From this simple relationship the
following are suggested 1. Tooth loss is caused by the interaction of present
teeth and sites where teeth are lost. 2. Integration of eq. (1) yields ln?(29 -
X)/X? = 29.k.t + a.......eq. (2). in which 0 < X < 29, t = time from the youngest
age group (20-29), a = constant. It appears that, from eq. (2), the dental health
of a community is determined by two coefficients, 29.k and a. 3. Helping a person
realize his present and future dental state and to motivate action for prevention
of tooth loss by showing him his rate of decrease, "tooth age" and the predicted
number of teeth a certain years later calculated from eq. (1) and eq. (2), can be
of great value. 4. Eq. (2) is transformed to X = 29/?exp(29.k.t + a) + 1?, which
represents the reverse S-shaped curve of the age dependency of the number of
teeth. 5. Applying this method to cohort analysis will enable forecast of the
trend of the number of teeth.
PMID- 9553384
TI - [A study of the association between the aortic pulse wave velocity and
atherosclerotic risk factors among Japanese Americans in Seattle, U.S.A].
AB - Cardiovascular disease prevention screening was conducted among 1389 Japanese
Americans in Seattle, Washington, U.S.A. from 1989 to 1994. The association
between atherosclerotic risk factors and the aortic pulse wave velocity (PWV), an
indicator of atherosclerosis, was examined by using multiple logistic regression
method. Based on a study in 1996 by Suzuki et al. on the association between PWV
and atherosclerotic indicators, abnormally high PWV was defined as 8.0 m/sec. and
over for those less than 60 years of age and 9.0 m/sec. and over for those 60
years of age and older Significant odds ratios to estimate the risk for the
presence of abnormally high PWV were found in age >or= 60 years (4.31, p <
0.001), hypertension (2.00, p < 0.001), diabetes (5.65, p < 0.001), current
drinker (0.44, p < 0.001), ex-drinker (0.49, p < 0.05), and ex-smoker (1.82, p <
0.01) among men. Women showed a similar association: age > or = 60 years (3.03, p
< 0.001), hypertension (1.94, p < 0.01), diabetes (2.47, p < 0.05), TC/HDL-C >or=
4.5 (1.98, p < 0.001), current drinker (0.47, p < 0.001), and ex-drinker (0.45, p
< 0.05). Our findings are almost identical to those from other studies showing
the association between coronary heart disease and its risk factors. The question
of whether PWV can be a predictor of atherosclerotic diseases, particularly
coronary heart disease, remains to be answered by additional studies. However,
PWV may serve as a simple and valuable indicator to estimate the extent and
severity of asymptomatic atherosclerosis in the large artery.
PMID- 9553385
TI - [Changes in knowledge of HIV/AIDS and attitudes for PWA in Tokyo: 1992-1995].
AB - In order to assess changes in knowledge of HIV/AIDS and attitude for People With
HIV/AIDS (PWA), interview surveys (Dec. 1992, Jan. 1994, Jan. 1995) were carried
out annually on random samples of the general public in Tokyo, age between 15-69
years. In total, 4,270 individuals were sampled, with an average response rate of
63.2%. Answers were scored and classified in 12 sex and age sub-groups.
Additionally, correlations between scores of questions and social indices were
analyzed. The results of the study are as follows: 1) The 15-19, 20-29 and 30-39
age groups showed higher scores on knowledge about HIV transmission modes. During
the entire study period, the score increased in 7 groups, but decreased in 5
groups. 2) The 30-39 and 40-49 age groups showed higher scores on knowledge about
HIV antibody test. During the period, the score increased in 11 groups, and among
them 6 groups showed statistically significant (p < 0.05) increases. However, the
score decreased in 9 groups at the third survey. 3) The 15-19, 20-29 and 30-39
age groups showed higher scores on acceptable attitudes for PWA. During the
period, the score increased in all groups, and among them 3 groups showed
statistically significant (p < 0.05) increases. 4) Rank correlations between two
scores-knowledge quantity about the transmission modes and acceptable attitudes
for PWA-were positive (0.2 < R) and statistically significant (p < 0.05) in 11
groups at the first survey, 9 groups at the second, and 6 groups at the third. 5)
During the entire study period, 6 groups showed positive correlations (0.7 < R)
between two changes: (1) score of knowledge about the transmission modes and (2)
score of acceptable attitudes. 6) During the entire study period, 10 groups
showed positive correlations (0.7 < R) between two changes: (1) score of
acceptable attitudes and (2) number of newspaper articles regarding acceptance or
discrimination of the PWA. 7) Knowledge about HIV/AIDS in the general public in
Tokyo showed increase in younger generation, but there is concern of decrease in
the older generation. These result indicate that acceptable attitude forward PWA
are affected by related knowledge about the transmission modes and mass-media
information, and must be considered in HIV/AIDS programs.
PMID- 9553386
TI - [Follow up study of community-based group education for body weight reduction].
PMID- 9553387
TI - [A support system after the health examination for the aged].
PMID- 9553388
TI - [An analysis of factors associated with the increase of in-patient medical
expenditures for the elderly in Fukuoka Prefecture].
AB - In order to evaluate factors associated with the increase in the in-patient
medical expenditures for the elderly in Fukuoka prefecture during the period from
1987 to 1991, an analysis was conducted based on the data of 10 Health Care
Regions. According to the results, there were two patterns in the increase. The
first was the pattern observed in the southern part of the prefecture, where most
of the increase in the in-patient medical expenditures for the elderly was
explained by the increase of medical expenditures per capita. Furthermore, this
increase per capita was due to the increase in utilization rate. This pattern is
considered to be associated with the increase of general hospital beds as well as
with the increase of the dependent elderly in the regions. The second pattern was
observed in urban regions, such as Fukuoka and Kitakyushu, where the increase of
in-patient medical expenditures for the elderly was mainly due to the increase in
the number of elderly in the regions. This pattern is considered to be associated
with the increase in the population categorized as the aged household. The
present result suggests that in order to control the medical expenditures for the
elderly, different service-mix strategies will be necessary, respecting the socio
economic characteristics of each region.
PMID- 9553389
TI - [A comparative study of local mental health and welfare policies in Japan: Cases
of Tokyo Metropolitan Government and Yamaguchi Prefecture].
AB - In this article the mental health and welfare policies of the Tokyo Metropolitan
Government and Yamaguchi Prefecture were analyzed, and the features of their
development and problems were discussed. The results are as follows: a) The
emphasis of the mental health and welfare policies both of Tokyo and Yamaguchi
experienced changes according to national policies and is to be divided into the
following four periods and key concepts. The 1st period (1950-1964): no policy or
increase of psychiatric beds The 2nd period (1965-1975): dawn of "from hospital
to community" The 3rd period (1976-1987): workplace for the mentally ill The 4th
period (1988-present): accommodation for the mentally ill b) During the 2nd
period, in terms of increase in psychiatric beds, the Tokyo Metropolitan
Government tried to limit increase, whereas Yamaguchi Prefecture accommodated it.
c) In the field of community mental health, the most remarkable development in
Tokyo in recent years is that the number of workshops and group homes grew
dramatically. The original policy of the Tokyo Metropolitan Government to
subsidize such small institutions was recommended in the report of Local Advisory
Council on Mental Health and Welfare (Chiho-Seishinhokenhukushi-shingikai). As a
result many voluntary groups operate those institutions with help of subsidy. On
the contrary the development in Yamaguchi is slow, because the establishment of
institutions for rehabilitation was mainly implemented by the regulation of
national law which demands high costs for its building and land. d) The original
policies of the Tokyo Metropolitan Government, however, is based on the premise
that a shortage exists of institutions for rehabilitation regulated by Mental
Health and Law. In this situation, therefore, the development of community mental
health depends on a subsidy from local government, development of community
mental health depends on a subsidy from local government, development of
voluntary groups, and accessibility to social services.
PMID- 9553390
TI - [Exposure to tobacco smoke in a Japanese urban population. An analysis using
biochemical markers of smoking].
AB - An epidemiological study in an urban population was conducted to investigate
exposure to tobacco smoke using two biochemical markers of smoking. In 1993 and
1994, expired air carbon monoxide (EACO) concentrations were determined with a
small portable CO monitor for 4,619 subjects aged 30 and over, who had been
randomly selected from residents of S-city in Osaka Pref, and who had received a
health examination for cardiovascular disease at the National Cardiovascular
Center. Urinary cotinine (UCOT) concentrations were determined using gas
chromatography for 480 subjects, who were nonsmokers, and who had received a
health examination during Sep. and Nov. in 1994. They also completed a
questionnaire about smoking habits and potential of passive smoking. In this
study smoking prevalences were 45% in men and 11% in women according to the
questionnaire. Among nonsmokers 55% of men and 46% of women reported some degree
of exposure to tobacco smoke. The EACO levels were related to the number of
cigarettes smoked per day in a dose-response fashion. The time elapsed since last
smoked and the usual depth of inhalation, in addition to the number of
cigarettes, had effects to EACO level. The optimal EACO cut-off points selected
to differentiate smokers and nonsmokers were between 6 and 7 ppm for men, and 5
and 6 ppm for women with a sensitivity and a specificity of about 90%. The hours
spent with tobacco smoke at home, whether there was a smoking spouse or not, and
the time elapsed since last inhalation of smoke affected EACO level in
nonsmokers. The frequency of going to an amusement place, a bar or a restaurant,
and the hours spent with tobacco smoke in a work place had effects on UCOT level
in non-smokers. The proper use of biochemical markers for tobacco smoke may be of
value in developing more effective strategies for smoking problems control.
PMID- 9553391
TI - [The relationship between smoking behavior and self-esteem among elementary and
junior high school students].
AB - OBJECT: This study examined the relationship between smoking behavior and self
esteem among Japanese early adolescents. METHOD: The study sample comprised 1,486
fourth through ninth grade students from 10 elementary schools and six junior
high schools throughout nine prefectures. Data were collected using an anonymous
self-administered questionnaire which included items measuring smoking behavior,
self-esteem, intention to smoke in the future, self-efficacy to refuse peer
pressure to smoke, the smoking behaviors of their parents, siblings and friends.
Self-esteem was measured using the Harter Perceived Competence Scale which
includes four areas: cognitive, social, physical, and general. RESULTS: The main
results were as follows: 1) Ever smokers had lower cognitive and general
competence scores, but a higher physical competence score than never smokers,
especially among males. 2) Ever smokers had more smoking parents, siblings and
friends than never smokers. 3) Ever smokers had stronger intention to smoke in
the future than never smokers. 4) Ever smokers had lower self-efficacy to refuse
peer pressure to smoke than never smokers. CONCLUSION: The results of this study
about the relationship between smoking behavior and self-esteem were consistent
with those of some previous studies in the U.S. Therefore, it is suggested that
effective smoking prevention programs for Japanese early adolescents should
include strategies to enhance self-esteem.
PMID- 9553392
TI - [Effects of pregnancy and lifestyles including food intake on bone density of
pregnant women].
AB - Bone densities measured by ultrasound at the calcaneus, and urinary
hydroxyproline (H.P) and calcium (Ca) concentrations adjusted for creatinine
(Cre) were measured in 79 pregnant women, aged 20 to 38 years, at 5-40 weeks of
gestation. Stiffness calculated from the combined value of speed of sound and
broadband ultrasound attenuation was used as an index of bone density. The
relationships between Stiffness and period of gestation, urinary H.P/Cre and
Ca/Cre, and such lifestyles as current and past food intake frequency, physical
activity and history of participating in sports obtained by questionnaire were
examined using stepwise multiple regression analysis, including age and weight as
independent variables. 1) The means of Stiffness in women with the gestation
period of more than 20 weeks (primipara 79.6, multipara 83.4) are a little lower
than those of non-pregnant and healthy women within the same age range. 2) Period
of gestation showed a significant negative correlation to Stiffness. Significant
positive correlations were found between urinary H.P/Cre and period of gestation.
These results suggest that bone resorption increases with stage of gestation and
causes bone loss in pregnant women. 3) Significant relationships with Stiffness
was found only in frequency of cow's milk intake before pregnancy among various
lifestyle factors. Stiffness of the subjects who took cow's milk every day before
pregnancy was significantly higher than those who took less than 2-3 times per
week or none. This result indicates that cow's milk and dairy products intake
before pregnancy may be important for bone mineral maintenance during pregnancy.
PMID- 9553393
TI - [Factors influencing admission to nursing homes among frail and bedridden elderly
persons receiving public health and welfare services].
AB - A prospective study was conducted to elucidate the factors influencing admission
to nursing homes among frail and bedridden elderly persons. The subjects were 149
persons, 70 years of age and above, who were living in Goshiki-cho, Hyogo
prefecture and were receiving services from public health and welfare
organizations. All of the subjects had a family physician and their own residence
or own room at home. A follow-up study of admissions to nursing homes was
performed from 1991 to 1996. The main results were as follows: 1. During the
study (about 5 years), 42.9% (N = 64) of subjects were staying at home, 38.9% (N
= 58) died at home, and 16.8% (N = 25) were admitted to nursing homes. 2. To find
factors influencing admission to nursing homes, an analysis using Cox
proportional, hazard model was conducted. Major factors found were high age,
women, disabilities of hearing and eyesight, and difficulty in communication. The
admission rate to nursing homes was especially high among patients 90 years of
age or greater. 3. The admission rate to nursing homes was higher in subjects
receiving home help services compared to the rest of the group. 4. Remarkable
differences in household composition were observed between those who continued to
stay at home and those admitted to nursing homes. Among the subjects living alone
or living with a spouse, the mean age was significantly higher in the group who
were admitted to nursing homes than those staying at home. In the case of two or
three-generation households, the admission rate to nursing homes was high when
the household lacked caregivers.
PMID- 9553394
TI - [State of bullying in a geriatric hospital].
AB - Recently, reports of bullying and beatings among school children has brought
these problems to the public attention. Unfortunately similar problems exist
among the aged and institutionalized patients in geriatric hospitals, e.g.,
covert teasing and bullying of the weak. Therefore, the present status of
bullying or being bullied in our geriatric hospital was analyzed and their
backgrounds studied to develop clinical countermeasures against bullying. Results
of this study were as follows; 1. Nineteen percent of patients were victims of
bullying, and patients who had performed the bullying were 3.0%. 2. Of those who
were bullied 20.0% wanted to change hospitals, while 60.0% felt they could
tolerate the situation or suppress their anger, and 13.3% of the patients who had
exhausted their patience took revenge on the bully. 3. Patients who had been
bullied tended to be more tenacious and had a high level of depression by Self
rating Depression Scale (SDS). The apparent error rate in these results was
22.5%.
PMID- 9553395
TI - [An experience of smoking cessation supports for officials of a village as a
beginning of tobacco control activities in the village].
PMID- 9553397
TI - [A research on the present and the future of managial attitude toward
contingencies in the assisted living residency for the elderly].
PMID- 9553396
TI - [Preventive measures against hepatitis B virus infection in nursing schools in
Japan].
AB - To clarify the use of preventive measures against Hepatitis B Virus infection
among nursing students, questionnaires were mailed to 488 nursing schools
throughout Japan (including colleges and junior colleges). Two hundred and sixty
eight nursing schools answered our questionnaire. The results are summarized as
follows: 1. Eighty percent of the nursing schools that responded, regularly
perform the HBs antigen test, and 70% conduct the HBs antibody test. However,
only 29% carry out HB vaccinations. 2. Of the 172 schools (71%) that do not
actually perform HB vaccinations, only 4% have a HB vaccination plan for the
future. 3. The main reasons why the schools do not carry out HB vaccinations are:
1) high cost (48%), 2) low risk of HBV infection among students (34%), 3) the
students are thought to be themselves capable of preventing HBV infection (31%).
4. Eighty percent of the nursing schools conduct an orientation program for their
nursing students on how to prevent infection before their practical training at
school as well as during their practical training at the hospital. 5. Thirty-five
percent of the nursing schools have their own "Prevention of HBV Infection
Manual", while some of the others use a manual provided by their training
hospital. 6. In answer to the question "Do the instructors ask the students to
report any potential risk of infection they encounter during their training in
the hospital?", 88 approximately 89% of the schools said that they instruct their
students to report all injuries involving a needle stick. Other questions
relative to various circumstances were also asked. To the question of whether the
school requires the students to report any wounds to their fingers or hands, the
rate of "yes" answers was only 33%, although this information is essential to
prevent avoidable risk. Conclusion In our investigation we found that the HBs
antigen and the HBs antibody tests are both performed in a high proportion in
nursing schools. Orientation concerning students' training at the hospital to
prevent infection is also provided at a high rate. On the other hand, HB
vaccinations are not widely performed. Manuals on the prevention of HBV infection
are not used at a high proportion either. Also, the reporting system for students
encountering any potential risks of infection is insufficient. We think that a
more active prevention system for HBV infection should be organized in every
nursing school.
PMID- 9553398
TI - [Relationship between obesity level and subjective symptoms in junior high school
students. Comparison between method of standard body weight and body mass index].
PMID- 9553399
TI - [Endothelin and arterial hypertension].
AB - Endothelins (ETs) are peptides of 21 amino acids synthesized and released by
variety of cells. Endothelin (now this peptide is called endothelin-1 (ET-1)) was
isolated and identified in 1988 by Yanagisawa et al. Following studies revealed
two other isoforms of endothelin': Endothelin-2 (ET-2) and endothelin-3 (ET-3).
All of them bind to two types of receptors (A and B (ET-A r, ET-Br). ET-A r are
responsible for concentration mediating. Two subtypes of ET-B r are known. ET-B1
r mediates vasorelaxation; ET-B2 vasoconstriction. ETs (especially ET-1) have
variety of biological actions but the most important are vasoconstrictor and
mitogenic action. Through these two mechanism ETs may participate in the
pathogenesis and/or in the maintenance of hypertension in both experimental
animal models and human essential hypertension. The intravenous infusion of
synthetic ET induces a long-lasting elevation of blood pressure in experimental
animals and in healthy humans. Number of studies have shown enhanced responses to
ET in hypertensive subjects but decreased responses have also been reported.
Similarly, plasma levels of ET-1 are either normal or elevated in experimental
and human essential hypertension. Numerous investigators have suggested an
interaction between ET and angiotensin-converting enzyme inhibitors through the
renin-angiotensin system or through the accumulation of endogenous bradykinin.
Also calcium antagonists of different classes prevent endothelin-induced
contractions. Endothelin- converting enzyme inhibitor (phosphoramidon) and ET-A/B
r antagonists (bosentan, BQ-123, FR139317) may have potential role as
vasodilators in the treatment of hypertension.
PMID- 9553400
TI - [Magnetic resonance arteriography as a method for diagnosing arteriosclerosis of
the lower extremities].
AB - The purpose of our study was the evaluation of usefulness of Magnetic Resonance
Angiography in diagnostic process in patients with arteriosclerosis of lower
extremities and complications such as aneurysms and pseudoaneurysms. 105 patients
were examined using 2D TOF method. We concluded the results were very similar as
in radiological examinations. The MRA is a very helpful method in evaluation of
constriction and occlusion of iliac and femoral arteries and aorta.
PMID- 9553401
TI - [Examination of veins with magnetic resonance imaging and it's place in the
diagnostic algorithm of patients with deep venous thrombophlebitis].
AB - The aim of our study was to show the results of the Magnetic Resonance
Angiography of pelvis and lower extremities. 21 patients with clinical signs of
venous thrombosis were examined. The obtained results show the MRA is very useful
in evaluation of venous flow.
PMID- 9553402
TI - [The influence of vitamin C and e or beta-carotene on peroxidative processes in
persons with myocardial ischemia].
AB - An increasing body of evidence suggests that beside hypercholesterolemia
peroxidative processes and natural antioxidant defence system play important role
in the development of atherosclerosis. Our earlier investigation showed the
increased intensity of the peroxidative processes in the course of the acute
myocardial infarction and unsatisfactory tocopherol, ascorbic acid and retinol
status. The purpose of the present study was the evaluation of the effect of
antioxidant vitamins supplementation by the period of 21 days on the peroxidative
processes in patients after heart attack or after "bypass" admitted to the
cardiological rehabilitation centre. Daily oral supplementation with vitamin C, E
and beta-carotene decreased significantly plasma lipid peroxide concentration
(TBARS). The highest drop in TBARS activity was found in the group after bypass.
No significant effect of vitamin supplementation was observed on antioxidant
enzymes activity.
PMID- 9553404
TI - [Resumption of professional work after cerebral aneurysm surgery].
AB - The influence of various factors upon the resumption of professional work was
examined in the group of 87 patients, who had undergone an operation of single
cerebral aneurysms. Professional activity was resumed by 59.9% members of the
examined group. The age and the level of education or professional training were
found to be the most influential factor. The location of aneurysms and sex of
patients was found to have no influence. The fact that greater percent of those
living in the country resumed their professional activities than those living in
towns or cities can be explained by greater difficulty in to suffering was a
quite frequent factor which can be overcome due to proper information given to
the patients, thereby the greater number of patients can resume their
professional career.
PMID- 9553403
TI - [The influence of ischemia provoked by dobutamine and exercise on presence of
late potentials in patients after myocardial infarction].
AB - The aim of this study was to examine the influence of transient exercise- and
dobutamine-induced myocardial ischemia on time domain parameters of signal
averaged ECG (SAECG) and presence of late potentials (LP) in patients after
myocardial infarction (MI). The investigation covered 85 patients after healing
of MI, divided into two groups. Group I (24 males and 2 females, mean age 56.8 +/
6.4 yrs) had exercise-induced ischemia and group II consisted of 59 patients (51
males and 8 females, mean age 58.3 +/- 8.5 years) with ischemia provoked by the
intravenous dobutamine stress-testing. In each patient 2-D echocardiography, 24-h
ambulatory Holter ECG, coronary arteriography were performed before stress
testing. The ischemia was proven by using Tc-99m MIBI myocardial perfusion and
standard 12-lead ECG monitoring. Recordings of SAECG were registered at rest and
during ischemia under influence of stress-testing. The following time-domain
parameters of SAECG were analysed: the root-mean-square voltage of the last 40
and 50 ms of the filtered QRS complex (RMS40, 50), total time duration of
filtered QRS (t-QRS) and duration of signal lower than 40 muV (LPD). LP were
detected when two or three of following criteria's had been registered: RMS 40 <
20 muV, t-QRS > 114ms, LPD > 38s. There was no statistically significant
differences in all time domain parameters of SAECG between records at the
baseline and during ischemia in each study group. At the baseline LP have been
registered in 11.5% and in 15% patients, respectively of group I and group II. On
the top of ischemia during treadmill exercise stress-testing LP have been
recorded in 27% subjects. Under influence of dobutamine-provoked ischemia LP have
been registered in 25% patients. CONCLUSIONS: Exercise- and dobutamine-induced
ischemia triggers development of LP in small grade in post-infarction patients.
PMID- 9553405
TI - [Coronary disease and hormonal treatment during the perimenopausal period].
AB - Hormone replacement therapy (HRT) is widely recognized as probably most advisable
treatment of perimenopausal women with cardiovascular disorders. Whenever HRT is
administered for gynecological reasons, special attention should be paid to the
presence of cardiological risk factors as these may be potentiated by high doses
of gestogens. The authors undertake this problem inspired by a cases of a 53
years old patient (given oral lynestrol fair persisting uterine bleedings) who
suffered from several complications, including venous thrombosis and myocardial
infarction.
PMID- 9553407
TI - [The significance of converting enzyme inhibitor angiotensin I to angiotensin II
in treatment of patients with coronary disease].
AB - Angiotensin-converting enzyme (ACE) inhibitors are now established drugs in the
treatment of hypertension and heart failure. The renin-angiotensin-aldosterone
system is complex and acts as a circulating hormonal system, a local endogenous
tissue system and neuromodular. Current experimental evidence suggests that ACE
inhibitors reduce the risk associated with atherosclerotic cardiovascular
disease. The antiatherogenic action of ACE inhibitors is related to complex
effects mediated by these agent, including an antiproliferative and antimitotic
action, beneficial effects on endothelial function, plaque-stabilizing effects
and the action of these agents on the sympathetic nervous system. The role of ACE
inhibitors in preventing the clinical sequale of atherosclerotic cardiac disease
has been evaluated in various patient populations. Several small trial assess the
effects of ACE inhibitors in severity of angina pectoris have reported
conflicting results, with benefit is some patients and no benefit or even
exacerbation of angina in others, indicating that ACE inhibitors do not have
consistent antianginal effects in short-term study. ACE inhibitors have the
theoretical potential to prevent restenosis after PTCA but they do not prevent
restenosis and has no effect on overall clinical outcome. New data suggest that
ACE inhibitors may be effective therapy fir patients following acute myocardial
infarction. The renin-angiotensin system, is activated during new myocardial
infarction and has an impact on the process of remodeling of the left ventricle
which causes ist dysfunction and heart failure. In most of the large mortality
trials the rationale for early treatment with ACE inhibitors after myocardial
infarction was stated. ACE inhibitors have a positive effect in preventing the
ventricular dilatation and they reduce the rate of reinfarctions and the
mortality rate.
PMID- 9553406
TI - [A case of centroblastic lymphoma of the thyroid gland].
AB - A case of a 49-year male patient with centroblastic lymphoma of the thyroid gland
is presented. Centroblastic lymphoma was diagnosed with cytological and
immunocytochemical examination of the biopsy specimen, and verified with
histological examination of tumor section collector intraoperationally. Diagnosed
tumor was classified as II AE degree. No signs of lymphocytic thyroiditis co
existing with centroblastic lymphoma were noted. The patient was treated
chemically with CBVPM/AVBP regimens for 8 months. Complete remission still
lasting, i.e. 96 months after completion of chemotherapy, was achieved.
PMID- 9553408
TI - [Combination therapy in primary hypertension].
AB - Hypertension is an important risk factor for vascular disease. Primary goal of
hypertension treatment is to prevent or delay the onset of blood pressure-related
morbidity and mortality. It has been well demonstrated that the responses rate to
any single class of antihypertensive agent, give as monotherapy is approximately
45% to 55%, and in half of hypertensive population a second will be required. The
data from clinical trials clearly demonstrate that two-drug combination, usually
with low-dose diuretics with any one of the other first-line agents increases the
response rate to about 80% to 85% and reduces the likelihood of adverse events
and alteration in lipid, carbohydrate and electrolyte metabolism. Of the various
combinations being given that of an diuretic and ACE inhibitor, and ACE inhibitor
and non-dihydropyridine calcium channel blockers seems particularly attractive.
Some combinations are inappropriate, such as diuretic and calcium channel
blockers, and beta-blocker with verapamil and diltiazem. Combination of ACE
inhibitor and a non-dihydropyridine calcium channel blockers may provide benefit
in regression left ventricular hypertrophy diabetic nephropathy, and post
myocardial infarction.
PMID- 9553409
TI - [Use of beta-adrenoreceptor antagonists in treatment of patients with chronic
heart failure].
AB - Chronic heart failure (CHF) is present in 1-10% of the whole population. From the
drugs used in CHF so far only angiotensin converting enzyme inhibitors and
nitrate with hydralazine improved the survival which was caused by beneficial
influence of these drugs on neurohormonal factors. There is growing interest in
beta-blockers which are believed to stop the progress of CHF. Although the first
attempts of using beta-blockers in the treatment of CHF took place in 70-ties,
only recent years brought better understanding of mechanisms of their action. The
beneficial effect of beta-blockers in CHF is related to their protective
influence on myocardium and to hampering of apoptosis--programmed cell death--the
phenomenon which is exaggerated in CHF. The investigations carried out in last
years proved that carvedilol which is beta 1-, beta 2- and alpha 1-blocker and
has antioxidant properties improved clinical status and reduced mortality in the
cohorts of patients with all-cause CHF. At present great trials estimating
various beta-blockers and comparing these drug among themselves are being
conducted.
PMID- 9553410
TI - [The influence of digitalis glycosides on certain neural and hormonal functions
in patients with chronic heart failure].
AB - Digitalis works not only as a positive agent in congestive heart but as a
modulator of neurosecretion as well. Opposite to its positive inotropic activity
the latter refers to small doses. It leads to restoring of the autonomic balance.
Its effect is resulted from the increased vagal activity that suppresses the
adrenergic tone. Disregulating of the neurosecreting system may occur in patients
with left ventricular impairment even without symptoms of left ventricular
failure. Digitalis then besides stimulating contractility stops the
neurosecretion and may be used not only to improve hemodynamics but also to slow
the process of progressive deterioration of cardiac function.
PMID- 9553411
TI - [Right ventricular infarction].
AB - Right ventricle infarction (RVI) is not a rare clinical entity. It complicates
approximately half of inferolateral myocardial infarctions. Under the term RVI we
can find mild, asymptomatic dysfunction of right ventricle and cardiogenic shock
as well. RVI is associated with increased mortality and its presence obliged us
to qualify patient to a high risk group. Diagnosis is based on clinical signs,
electrocardiographic findings, hemodynamic measurements and echographic
evaluations. The proper treatment of RVI requires support of right ventricle
preload with fluid administration, maintainance of atrio-ventricular synchrony,
reduction of right ventricle afterload. Early reperfusion with fibrinolytic
therapy and coronary angioplasty should be regarded as the prior methods of
treatment RVI. Patients who survive RVI have complete resolution of hemodynamic
abnormalities with restoration of proper right ventricle function.
PMID- 9553412
TI - [Retroperitoneal fibrosis and chronic peri-aortitis--new hypothesis].
AB - Retroperitoneal fibrosis is characterised by the development of fibrotic mass
surrounding the abdominal aorta and its branches. In the one third of cases, the
causes of this disease include ergot-derivative drugs, retoperitoneal haemorrhage
or urine extravasation and desmoplastic response to a variety of tumours.
Retroperitoneal fibrosis is idiopathic in two thirds of cases and is found most
commonly as an isolated fibrotic plague centered over the lumbar spine and
entrapping one or both ureters. It has been postulated that fibrosis in
idiopathic cases is caused by a chronic inflammatory or autoimmune response to
antigens leaking into retroperitoneum from atheromatous plagues in the aorta or
common iliac arteries. Many findings indicate the active nature of aortic
adventitial chronic inflammation associated with human advanced atherosclerosis
("chronic periaortitis") and show its possible progressive potential to the
clinically important disease termed "idiopathic retroperitoneal fibrosis" and
"inflammatory aneurysm". A definitive differential diagnosis requires not only CT
and NMR but also histologic confirmation. Treatment may be surgical or medical,
with the best outcome observed in patient receiving both.
PMID- 9553413
TI - [Axiomatic space of the physician's office].
AB - Doctor's surgery is a space containing a number of meanings which are
deliberately or unconsciously interpreted by the patient. Organization of that
space, its material shape, affect a successful contact between the doctor and the
patient, thanks to which a therapeutic aim is achieved.
PMID- 9553414
TI - [Polish army hospital in Zeithain].
AB - Polish Military Hospital in Zeithain was a prisoner-of-war hospital of Warsaw
Insurgents. In the period from 13 October 1944 until 23 April 1945, in the
hospital there were 1572 war prisoners, including 1029 sick and wounded. The
hospital consisted of all wards, the operating theatre, X-rays unit and the
laboratory. In August 1945 the hospital got repatriated.
PMID- 9553415
TI - [Obsessive-compulsive disorders in childhood and adolescence].
PMID- 9553416
TI - [Therefore force, when obsession is present?].
AB - To force somebody means inflict pressure on him. Obsessive-compulsive behaviour
(OCB) is a feature of relationships. In early infancy, repetitive biological
functions rapidly become automatic psychic functions. Small children often try to
relate to their surrounding in a constrained manner in order to re-establish
their omnipotence. Play and transitional space are opposites of OCB. Anxiety and
constraints show an inverse relation to each other. In many cases, OCB in infants
and small children has no clinical relevance. OCB is characterised by a high
intrapsychic persistence during the whole period of psychophysic development.
Obsessive-compulsive diseases (OCD) may serve as defence against oedipal
strivings or against psychotic functioning. It is addressed against the self, an
inner object or a relevant person of the surrounding. OCD correspond to a
relational illness. In this situation an involved person becomes rapidly involved
in the constraint problem. To maintain an adequate form of relationship within
such transferential movements, a continuous "unchaining" is necessary. During
transference, regressive anxieties and rages are expressed in a personalised
form. Verbalised by the therapist, they become ready for transformation. The
relationship may now open up to allow the inclusion of a third person.
PMID- 9553417
TI - [Obsessive-compulsive disorders in childhood and adolescence--recent
psychoanalytic views and treatment approaches].
AB - Based on neurobiological and development-psychological findings psychodynamic
concepts for understanding compulsive disorders are supplemented and extended. A
stimulus barrier impaired during development which in the early mother-child
system normally develops into an autonomous and self-regulating ability has the
consequence in compulsive disorders that the ability of drawing limits between
reality and phantasy has only poor success. Based on case examples the function
of the situation triggering the compulsive symptoms and the foreseeable
relationship quality are examined on the different levels of development. Then it
becomes clear how complex the originating conditions for compulsive disorders
are, and under which conditions a primary object fails as original external
psycho-neurobiological regulator in the development of autonomous self
regulation.
PMID- 9553418
TI - [Countertransference in psychoanalytic therapy of children and adolescents with
obsessive-compulsive disorders].
AB - Understanding countertransference in dynamic therapy of children and adolescents
is important for the clarification of unconscious conflicts because of the
frequent absence of dreams and free association in the analytic process. When
compulsions determine the course of the psychic disorder countertransference
becomes an important landmark for comprehending and resolving the affect-loaded
sadomasochistic collusion as an externalization of intrapsychic conflicts.
Compulsive acts and thoughts helping to preserve seriously threatened structures
of the self and the ego engender different countertransference reactions in the
analyst than the ego-superego-conflicts of compulsion neurosis. This makes them
essential for diagnosis and therapeutic interventions.
PMID- 9553419
TI - [Tuberculosis morbidity among children and adolescents in Udmurt Republic].
PMID- 9553420
TI - [Tuberculosis as hospital acquired infection].
AB - Tuberculosis morbidity rates were analyzed in the staff of antituberculosis
dispensaries and institutions of the general therapeutical network. There were 74
cases of tuberculosis among the medical workers in 1993-1996. The sociomedical
characteristics of the medical staff suffering from tuberculosis are given. The
findings show it necessary to refer tuberculosis to a group of hospital-acquired
infections and to implement a package of prophylactic measures to reduce
tuberculosis morbidity rates among medical workers, as well as to timely detect
patients with tuberculosis at general hospitals. Measures for preventing
tuberculosis are proposed for the personnel of therapeutical institutions.
PMID- 9553421
TI - [Role of general somatic hospitals in replenishment of contingents of
antituberculosis dispensaries].
AB - The patients whom tuberculosis was detected at general somatic hospitals form 28%
in the make-up of dispensary registry group IA. In these hospitals BC are found
in those with suspected tuberculosis and even in its destructive forms (4-5.7%).
Activization of explanatory work with physicians and nurses at a hospital has
caused an increase in positive sputum tests for BC and favoured a 7-fold increase
in their detection by bacterioscopy after Ziehl-Neelsen.
PMID- 9553422
TI - [Detection of tuberculosis in infants and preschool children].
AB - The paper analyzes 367 case histories of babies, infants and preschool children
treated for local tuberculosis at a specialized pediatric unit in 1977-1996. It
is ascertained that tuberculosis was detected in 55% of children on their
referral for medical aid and in 45% on prophylactic examinations. Prophylactic
examinations detected tuberculosis of the intrathoracic lymph nodes more
frequently (72.7%) and primary tuberculosis less frequently (26.7%). On
referrals, tuberculosis of the intrathoracic lymph nodes, primary tuberculosis,
and other forms of pulmonary tuberculosis were diagnosed in 68.8, 25.0, 6.2%,
respectively. When tuberculosis was identified on referrals, pulmonary
tuberculosis was much more commonly complicated. To form a tuberculosis risk
group and to make prophylactic antituberculosis measures are an inherent
condition for early detection of tuberculosis.
PMID- 9553423
TI - [Characteristics of tuberculosis process in new cases of pulmonary tuberculosis
from different social groups of patients in relation to methods of disease
detection].
AB - Three hundred and eighty new cases of pulmonary tuberculosis were examined and
the characteristics of a tuberculous process studied in different social groups
(industrial and office workers, unemployed) in relation to methods of detection
of the disease: on referrals or prophylactic examinations. There was a
considerable reduction in the proportion of patients whose disease was detected
on prophylactic examinations, and in the families of patients with tuberculosis.
The tuberculous process detected on referrals was characterized by its higher
prevalence and a qualitatively more severe form (caseous pneumonia, fibrinous
cavernous, and cavernous processes). A decay phase and bacterial isolation were
more frequently noted.
PMID- 9553424
TI - [Spread of drug-resistant strains of mycobacterium tuberculosis among patients
with isolated bacteria].
AB - The paper provides the data on the spread of drug-resistant strains of
Mycobacterium tuberculosis (MBT) among contingents of patients with pulmonary
tuberculosis who have been registered at a dispensary and new cases. The spread
was 42.5 and 20.0%, respectively. In the past 3 decades, the spread of primary
(baseline) drug resistance of MBT has increased from 6.5 to 22.0%.
PMID- 9553425
TI - [Diagnosis of tuberculosis in patients of pulmonological hospital].
AB - Analysis of clinical forms of tuberculosis in patients of a pulmonological showed
that 65.5% of them had infiltrative tuberculosis, 13.8% fibrocavernous
tuberculosis, 10.4% disseminated tuberculosis, 6.9% focal tuberculosis, and 1.7%
tuberculoma. It was ascertained that in these patients destructive tuberculous
changes were common and occurred in 67.2% and tuberculosis was concurrent with
other lung diseases in 70.7%. This follows that special attention should be given
to the patients of pulmonological hospitals and sputum tests for mycobacteria are
to be performed 3 times.
PMID- 9553426
TI - [Potentialities of x-ray computed tomography in diagnosis and treatment by
transthoracic paracentesis of caverns in tuberculosis].
AB - The paper presents data on the use of computed tomography in transthoracic
paracentesis of tuberculous caverns for diagnostic and therapeutical purposes.
The topography of caverns, their size, the pattern of the cavernous wall, the
degree of development and intensity of a fibrous layer were assessed from
computed tomographic findings, which was a guide in choosing the procedure of
paracentesis of the lung and topical treatment. The patency of draining bronchi
was determined by computed tomography to choose instillations or spraying of
antibiotics into the cavern. The possibility to determine the presence of
intracavernous timbers, the extent of vessels in the adjacent tissue, that of
pericavitary fibrosis and pleural commissures made it possible to locate the
optimal point of paracentesis and to avoid possible complications, such as
hemorrhage and pneumothorax. It is pointed out that computed tomography is shown
in the first paracentesis of a cavern to determine its topography and at the end
of treatment of establish the outcome of a cavernous process.
PMID- 9553428
TI - [Clinical and laboratory diagnosis of primary tuberculosis of respiratory organs
in adults].
AB - Comprehensive clinical, X-ray, and laboratory studies were made of 495 patients
with primary tuberculosis of respiratory tuberculosis whose age was over 18
years. Tuberculosis of intrathoracic lymph nodes (a tumorous form), infiltrative
tuberculosis at preroot and lower lobar sites), and exudative pleurisy were
prevalent in the clinical structure of primary forms of a specific process. The
highest morbidity was observed in the age group of 20-25 years. Tuberculin tests
were positive in 95.1% of cases, they being hyperergic in 10.9% and negative and
nuclear only in 4.9%. Sputum tests for altered forms of tuberculosis agents
enhance diagnostic verification by 16%. The informative value of a complex of
clinical and X-ray examinations in the diagnosis of primary respiratory
tuberculosis in adults ranges from 47.4 to 79.6% with immunoassay, and 28.3 to
77.5 with biochemical tests.
PMID- 9553427
TI - [Difficulties in diagnosing pulmonary visceral forms of rheumatoid arthritis in
tuberculous hospital].
AB - The articulovisceral form of rheumatoid arthritis is severe, which creates
difficulties in its diagnosis as it is characterized by polymorphism and atypical
features. This type concurrent with pulmonary manifestations should be
differentiated from inflammatory lung diseases, including tuberculosis.
PMID- 9553429
TI - [Some problems in diagnosis of peripheral lymph nodes tuberculosis].
AB - The structure of lymphadenopathies has been determined by biopsies of peripheral
lymph nodes. The parameters are different in general and specialized
prosectorship. Malignant diseases (34.0%), reactive hyperplasias (24.3%), and
tuberculosis (only in 6.0%) were verified in the general prosectorship.
Tuberculosis was detected in 61.3% at the phthisiological center. The problems of
diagnosis of lymphadenopathies of various etiology are discussed.
PMID- 9553430
TI - [Complications of polychemotherapy for renal tuberculosis].
AB - The paper analyzes the incidence of adverse reactions caused by tuberculostatics
used in the treatment of renal tuberculosis by follow-ups of 117 patients.
Current polychemotherapy for renal tuberculosis has been found to be complicated
by drug intolerance in 40.1% of cases. Intermittent intravenous injection of
tuberculostatics causes side effects in 36.8% of patients while conventional
treatment does in 59.1%. Pyrazinamide, streptomycin, and ethambutol are most
toxic to patients with renal tuberculosis. There is a higher likelihood of drug
intolerance in females with bilateral nephrotuberculosis complicated by chronic
renal failure.
PMID- 9553432
TI - [Endobronchial laser therapy in the surgery of pulmonary tuberculosis].
AB - Endobronchial helium-neon laser therapy was used in 80 patients to undergo
surgical intervention. For evaluation of the efficiency of laser therapy, the
patients were divided into 2 groups: 1) 50 patients with chronic destructive
pulmonary tuberculosis and 2) 30 with postoperative bronchopulmonary
complications. A control group included 80 patients with the similar processes.
Laser therapy used Group 1 patients expanded indications for surgical
intervention. The resections of the lung made in led to postoperative
complications in 32% of Group 1 patients and in 63% of the controls. Laser
therapy in Group 2 patients promotes sanitation of the bronchial tree by
enhancing the efficiency of reoperations by 18% than in the control group.
PMID- 9553431
TI - [Blood ozonation in the treatment of patients with progressive pulmonary
tuberculosis concurrent with diabetes mellitus].
AB - Twenty nine patients with progressive pulmonary tuberculosis in the presence of
diabetes mellitus were examined. Fifteen of them (a main group) had an additional
course of intravenous dissolved ozone once 6-8 days (4 mg/ml per 400 ml of
isotonic sodium chloride). By the end of month 2, 7 patients stopped massive
bacterial expiration, which correlated with clinical improvement while a control
group (n = 14) showed no clinical and laboratory changes. Following 3 months, 3
control patients stopped massive bacterial expiration. At month 6, 11 patients of
the main group also did this, decay cavities became close in 8 patients while in
the controls, these figures were 8 and 7, respectively. The use of systemic blood
ozoning eliminated chemotherapy resistance and accelerated abacillation and
healing in the decay cavities. The mechanism of action of dissolved ozone is
discussed.
PMID- 9553433
TI - [Surgical treatment of bilateral pulmonary tuberculosis].
AB - Two hundred and eighty two patients with different types of bilateral tuberculous
lesion of the lung were operated on. Most (n = 124) patients underwent
consecutive operations, 106 one-stage resections of the lung through transsternal
access on the one side and video thoracoscopic resections on the other. One-stage
bilateral video thoracoscopic operations were made in 52 cases. The greatest
number of postoperative complications was noted with multistage operations, which
is accounted for a critically ill patient group, advanced processes, concurrent
pyoseptic infection. The patients undergone-transsternal resections showed
minimum mortality rates with a rather low incidence of postoperative
complications.
PMID- 9553434
TI - [Use of antiseptic myramistin in the multimodality treatment of nonspecific
suppurative pleuropulmonary diseases].
AB - To treat patients with suppurative diseases of the bronchi, lung, and pleura, the
new aseptic myramistine was topically applied as 0.005% myramistine solution in
isotonic sodium chloride solution in 28 patients with acute and chronic pleural
empyema, acute abscess of the lung, and suppurative endobronchitis-complicated
bronchoectatic disease. The therapy made it possible to arrest the intoxication
syndrome, to achieve abacillation of contents in the cavities of empyema,
abscesses, and bronchoectases, to cure endobronchitis, to obliterate destructive
cavities in the lung more rapidly and to prepare patients for a planned surgical
intervention more valuably and to improve the results of surgical treatment. The
studies allow the antiseptic myramistine to be recommended for topical treatment
of pyodestructive diseases of the lung.
PMID- 9553435
TI - [Effectiveness of extracorporeal ultraviolet blood irradiation in patients with
chronic obstructive bronchitis].
AB - The use of extracorporeal ultraviolet blood radiation (EUVBR) in the treatment of
67 patients with chronic obstructive bronchitis (COB) showed some specific
features of the clinical course of bacterial complications of the basic process.
With EUVBR, most patients exhibited normal temperatures, less signs of
intoxication and coughing, and rare rale in the lung than in the controls. A most
objective criterion for the efficiency of EUVBR was a marked increase in the
forced expiratory volume per sec after the first 3 procedures, which improved the
patients' condition, diminished exercise-induced dyspnea. The hemogram of the
patients undergone EUVBR in combination with antibiotic therapy indicated a
substantial drop in erythrocyte sedimentation rates following the first 3
procedures. The growth of pathogenic and opportunistic microbes from the sputum
showed a great (10-fold) reduction when EUVBR and antibiotic therapy were
concurrently used. The findings suggest that EUVBR has high therapeutical
benefits in the treatment of COB.
PMID- 9553436
TI - [Plasmid profile of mycobacteria spread on the territory of the Russian
Federation].
AB - The plasmid profile of different species of mycobacteria vegetating in the
Russian Federation was first studied. All the drug-resistant mycobacterial
strains of tuberculosis were found to be truly polyresistant. There was a certain
association between the plasmid carriage and the high viability of the
mycobacterial population in nontuberculous mycobacteria.
PMID- 9553437
TI - [Diagnostic values of polymerase chain reaction test in females with genital
tuberculosis].
AB - The previously offered procedure for detecting. Mycobacterium tuberculosis, which
is based on the polymerase chain reaction (PCR), has been tested for diagnosing
genital tuberculosis in females. PCR was used to examine endometrial curettage
specimens in 44 patients with different nosological entities, which showed a high
sensitivity (80%) and a high specificity in the diagnosis of genital
tuberculosis.
PMID- 9553438
TI - [Method of resection and spondylocorporoplasty of lumbar and sacral vertebrates
in experiments].
AB - For a considerable reduction of injuries caused by resection and spondylodesis of
the lumbosacral region of the spine, the authors have developed a procedure of
conservation of vascular extravertebra and neural nets by employing 10 cadavers.
With this the transabdominal approach is used to form an aperture in SI and
partially LV corpus vertebralis, by removing all pathological substances of the
healthy spongious substance of the bone. The formed cavity is filled by two
autografts, bone bits, antibiotics and hemostatic sponge. The two autografts are
formed as a cross and their ends are clung to the edge of the entrance aperture
of the bone. Stitches are placed to the periosteum and the strata of the
abdominal wall.
PMID- 9553439
TI - [Detection rate of organochlorine pesticides and viral hepatitis B markers in
patients with pulmonary tuberculosis].
AB - Three hundred and fifty six patients with active forms of pulmonary tuberculosis
were studied for organochlorine pesticides (OCP) and viral hepatitis B markers
(VHBM) in their body. A combination of OCP and VHBM was detected in 37.4%, 63.2
and 61.5% had OCP and VHBM, respectively. Detection rates for pesticides and VHBM
were not related to the place of residence (town or village) or the clinical type
of pulmonary tuberculosis. However, the blood levels of OCP were significantly
higher in rural patients and in patients with advanced pulmonary tuberculosis
than in urban patients and in patients with restrictive pulmonary tuberculosis.
PMID- 9553440
TI - [Influence of mycobacterium on adaptive rearrangement in guinea pigs long exposed
to polycystic aromatic hydrocarbon-containing agents].
AB - Experiments on different groups of guinea pigs inoculated with Mycobacterium
tuberculosis (MBT) and intact guinea pigs who received coal refining products and
control ones indicated that long exposure to coal-tar resin enhanced mobilization
of methionine from the liver with its accumulation in the lung and hematopoietic
organs, increased the biosynthesis of arginine in the liver and its accumulation
in the lung and hematopoietic organs. MBT drastically enhanced the exchange of
the metabolites accumulated in the organs and prevented the formation of adaptive
reactions to long-term exposure to polycyclic aromatic hydrocarbons at the level
of membranous metabolism.
PMID- 9553441
TI - [Laparoscopic diagnosis of abdominal organs tuberculosis].
PMID- 9553442
TI - [A case of breast tuberculosis in patients with disseminated pulmonary
tuberculosis].
PMID- 9553443
TI - [Difficulties and errors in diagnosing of tuberculous meningitis and
meningoencephalitis].
PMID- 9553444
TI - [Contribution of Aspergillus fungi to the development of bronchopulmonary
pathology (literature review)].
PMID- 9553445
TI - Evolution, growth, and status of managed care in the United States.
AB - While under attack in the United States, managed care/competition is being viewed
by a number of European and other countries as a remedy in their struggle to
control rising health care costs. While many fundamentals of American managed
care have their roots in the British health system, significant differences exist
between the two systems. While managed care, which can be loosely defined as any
system of delivering health services in which care is delivered by a specified
network of providers who agree to comply with the care approaches established
through a case management process, has had a 100-year history in the United
States, it wasn't until the mid-1970's that it began to gain national
recognition. All health maintenance organizations (HMOs) are managed care
organizations (MCOs) but not all MCOs are HMOs. The two other categories of MCOs
are, preferred provider organizations (PPOs) and point of service plans (POS).
Currently, three-quarters of Americans with health insurance are enrolled in
managed care plans and there are 160 million Americans enrolled in such plans. A
major on-going debate occurring in the United States is in regard to the
comparative quality of care provided by MCOs and traditional fee-for-service
plans. The study results to date have been equivocal. Another controversial
managed care issue is the use of gag clauses in contracts between the MCOs and
their providers. These clauses limit providers from being totally open and honest
with patients about, for example, alternative treatment possibilities or the
details of provider reimbursement. Since the failure of U.S. health care reform
in 1994, there has been a more focused turn to the marketplace to provide the
impetus for reducing costs. As a result, health care plans and providers have
become more like traditional businesses which must focus on the bottom line to
survive. In a marketplace where purchasers of care look for low bidders, it
should be remembered that the level and quality of care a society receives is
usually commensurate with the level of resources that it is willing to expend.
PMID- 9553446
TI - Systematic review of case-control studies: oral contraceptives show no effect on
melanoma risk.
AB - BACKGROUND: Parallel to the rising incidence of malignant melanoma in fair
skinned populations, intensive efforts are currently devoted to identifying risk
factors for melanoma in addition to the well-known cutaneous factors and those
variables related to UV-exposure. OBJECTIVE: Systematic review of published
results to elucidate the role of oral contraceptives in the development of
malignant melanoma. DATA SOURCES: Literature retrieval systems MEDLINE and
CANCERLIT as well as reference lists of already collected studies. STUDY
SELECTION: All 18 (non-duplicate) case-control studies on the above relationship.
DATA EXTRACTION: From the published data, study-specific odds ratios (OR) and
accompanying confidence intervals (CI) were recalculated. For a quantitative meta
analytical summarisation two different models have been applied: a "fixed
effects" (FE) and a "random effects" (RE) model. DATA SYNTHESIS: Study-specific
ORs ranged from 0.13 up to 1.85; however, the majority of studies (14 of 18)
yielded similar ORs within the interval [0.82, 1.15]. The summary ORs estimated
from FE- and RE-models were both 0.95 (95% CI: [0.87, 1.04] for the FE-model,
[0.87, 1.05] for the RE-model). CONCLUSION: The systematic review of case-control
studies revealed no evidence for an aetiological role of oral contraceptives in
the development of malignant melanoma.
PMID- 9553447
TI - Blood pressure among immigrants to Israel from areas affected by the Chernobyl
disaster.
AB - OBJECTIVES: To validate and analyze apparent association of hypertension with
exposures to radiation at Chernobyl among immigrants to Israel from the
contaminated areas. METHODS: Data were collected in 1991 and 1994 from two
samples of persons who immigrated to Israel from the contaminated zone around the
Chernobyl nuclear power plant. The first sample were self-referred for evaluation
in a clinic by whole-body cesium measurement, physical examination, and
questionnaire (N = 756, 328 from less exposed and 438 from more exposed areas).
The second wave data were collected in 1994 during home interviews for evaluation
of psychosocial factors associated with their experience (N = 708, 121 from more
exposed and 253 from less exposed areas). In the second study a referent group
was included (n = 334) who were matched by age, sex, and year of immigration who
immigrated from other areas outside of the contaminated zone. Estimates of
exposure were based on the IAEA map of ground-level cesium isotope (137Cs)
contamination. RESULTS: In the 1991 sample, 21% from high exposure areas and 16%
from less exposed areas had elevated systolic blood pressure (> 140 mmHg).
Elevated diastolic blood pressure (> 90 mmHg) had a similar difference between
more and less exposed groups (21% and 16%). Age- and sex-specific analyses showed
that statistically different levels were found in the older age groups. In the
1994 sample, we confirmed a relationship between exposure and elevated blood
pressure. 33% of those from the more exposed areas and 34% of those from less
exposed areas had elevated systolic blood pressure, compared with 23% of the
comparison group, with a similar trend found in diastolic blood pressure. The
relationship between exposure and blood pressure was accentuated in the group of
respondents who had high scores on PTSD symptoms. Of the psychological variables
analyzed, systolic blood pressure was most strongly related to cancer-related
anxiety and somatization. A discriminant function analysis showed that three
variables: age, reporting a significant loss from the Chernobyl accident, and
fear of cancer correctly differentiated 72% of those with normal and high blood
pressure. CONCLUSIONS: There is a relationship between exposure to Chernobyl and
high blood pressure, partly due to the psychological reactions to the accident.
PMID- 9553448
TI - [Septic thrombophlebitis of the internal jugular vein and Lemierre syndrome].
AB - The authors report a case of Lemierre's syndrome. This uncommon clinical entity
is characterized by a septic internal jugular vein thrombosis with secondary
metastatic abscesses and Fusobacterium necrophorum septicemia, following an acute
oropharyngeal infection. The diagnosis is primarily clinical and it should be
suspected when a severe septicaemic illness, with pulmonary symptoms, occurs
after an acute pharyngotonsillar infection. This article reviews the clinical
picture, microbiology and treatment of this forgotten complication of acute
tonsillitis.
PMID- 9553449
TI - [The focus in neonatology].
AB - During the last years, neonatology has greatly improved. In the last decade,
mortality and morbidity have decreased: mortality from respiratory failure of
prematurity has decreased from 22% to 12%, mortality of the very low birthweight
infants under 1000 g fell from 56% to 35% and mortalities related to asphyxia
have diminished from 21% to 12% and to malformations from 33% to 28%. Prematurity
is now the first cause of neonatal mortality. During this period, the number of
babies under 1000 g has increased 4-fold and the number of multiple births
increased more than 2-fold from 3% to 7% of the live births of our hospital.
Attitudes towards the premature infant have changed, especially towards the
extremely small (called the micropremies). The number of disabled children has
increased in parallel with the better survival of the very immature newborns who
till recently were not resuscitated.
PMID- 9553450
TI - [Treatment of shoulder dislocation and the prevention of its recurrence].
AB - Shoulder dislocation is a frequent pathology with a high level of recurrences
especially in young patients. One week immobilization in a Dessault dressing is
sufficient if it is followed by free mobilization avoiding external rotation and
abduction. A 6 weeks rehabilitation program seems to prevent recurrences.
PMID- 9553451
TI - [The role of apoptosis during craniofacial development: concepts and importance
in pathology].
AB - Apoptosis is an essential common final pathway in numerous pathological
conditions such as malignant tumors, HIV-related CD4 lymphocytes degeneration,
neurodegenerative disorders, and in programmed cell death events during normal
embryogenesis. Some teratogenic substances for man and laboratory mammals induce
an increase of the apoptotic phenomenon, responsible for the occurrence of some
precise cranio-maxillo-facial malformations. The study of cell death during
normal or teratogenic embryonic development allows to analyse the cellular
mechanisms implied in the control of the apoptotic phenomenon, together with its
dysregulation ending in pathological processes. We review the cell death
phenomenon during cephalogenesis, both during normal embryogenesis, or in
teratogenic conditions known to induce cranio-maxillo-facial malformations.
PMID- 9553452
TI - [Meloxicam].
AB - NSAID's are currently medications widely prescribed. Meloxicam is a new oxicam
which has a low COX-2/COX-1 ratio, i.e. it has an inhibitory effect focused on
the inflammatory proteins (COX-2) with relative saving of the homeostatic
proteins (COX-1). This molecule has been studied in three rheumatic diseases, the
acute flare-up of osteoarthritis, rheumatoid arthritis, and ankylosing
spondylitis. The results show that meloxicam is as effective as comparative
NSAID's. A global analysis of the data from more than 5000 patients included in
clinical trials showed that gastro-intestinal tolerance of meloxicam was better
than that of comparative NSAID'S. Nevertheless, the clinical translation of the
anti-COX-2 selectivity concept is currently debated.
PMID- 9553453
TI - [Requested euthanasia].
PMID- 9553454
TI - [Death with dignity in cancer patients].
PMID- 9553455
TI - [Death and HIV infection].
PMID- 9553456
TI - [3 problem areas for the treating physician].
PMID- 9553457
TI - [Therapeutic compliance].
PMID- 9553458
TI - [Coronary stents].
PMID- 9553459
TI - [Recent chest pain].
PMID- 9553461
TI - [Why a burn center at the Vaud University Hospital Center?].
PMID- 9553462
TI - [Initial resuscitation of the severely burned adult].
PMID- 9553464
TI - [Metabolic and nutritional support of the adult burned patient].
PMID- 9553463
TI - [Burns: etiology, diagnosis and surgical treatment].
PMID- 9553465
TI - [Particularities of resuscitation in the burned child].
PMID- 9553466
TI - [Burns of the hand].
PMID- 9553467
TI - [Treatment of the severely burned patient with cultured autologous epidermis: the
experience at Lausanne].
PMID- 9553468
TI - [Living epidermal and dermal substitutes for treatment of severely burned
patients].
AB - Epidermal and dermal cells can be multiplied in vitro using different techniques.
Under particular conditions, the structure and the function of the original
tissues are partly recreated. Autologous epidermal substitutes for wound coverage
in deep burns are prepared in less than three weeks. Bilayered skin equivalents
containing a dermal component are obtained by growing epidermal cells on a
reconstructed dermal substitute or by juxtaposing stratified cultures of
keratinocytes and fibroblasts. New technologies are required to optimise the
nutrition of three-dimensional cultures of skin cells, which should lead to
further progress in the area of skin reconstruction.
PMID- 9553469
TI - [Basic principles for correcting late burn sequelae].
PMID- 9553470
TI - [Psychology of the severely burned patient].
PMID- 9553471
TI - [Psychiatric approach to the severely burned patient].
PMID- 9553472
TI - [Degree 3: a new association].
PMID- 9553473
TI - [The misunderstanding of the diagnosis somatoform pain: a plea for a
phenomenologic approach to pain].
PMID- 9553474
TI - [Abdominal trauma].
PMID- 9553475
TI - [Abdominal trauma].
AB - While a great part of the Anglo-American medical literature addresses the topic
of penetrating trauma the German speaking countries rather publish on blunt
abdominal injury. The presented paper discusses the strategic principles of acute
clinical management of abdominal trauma on the combined basis of own research
results and a comprehensive review of the literature. Blunt abdominal injuries in
most cases from a part in the pattern of multiple trauma. The early, first-hours
mortality is most often caused by severe traumatic brain injury or abdominal
trauma with massive hemorrhage. The prehospital management of penetrating
injuries is characterized rather by the concept of 'load and go', whereas the
onscene stabilization of the patient with blunt abdominal injury should precede
transport to the adequate hospital. On arrival in the accident and emergency room
an immediate blood transfusion is recommended for hemodynamically unstable
patients. If then a stabilization is not achieved, an emergency laparotomy should
follow. Abdominal stab injuries should be explored by laparoscopy if an
intraperitoneal lesion is suspected. If then the possibility of an intestinal
lesion is present a laparotomy should be performed directly thereafter. Firearm
injuries require open revision in almost all cases. The standard diagnostic
technique in blunt abdominal trauma is sonography, assisted by computed
tomography and, if indicated, angiography in hemodynamically stable patients.
Isolated abdominal injuries without hemodynamic or coagulation disorders allow
conservative treatment in the intensive care setting. In severe multiple trauma
as well as in manifest shock even the smallest fluid detection should lead to
laparotomy. The surgical treatment of splenic rupture is still a matter of
discussion. Splenectomy is indicated in patients with severe concomitating
injuries or shock whereas in the remainder of cases the total or partial
preservation of the spleen should be pursued. Hepatic injuries offer a broad
spectrum of operative interventions, ranging from superficial hemostatic measures
over compression techniques like 'packing' and 'mesh-wrapping' to atypical and
anatomical resections and to liver transplantation in exceptional cases. Lesions
of tubular organs and the pancreas pose especially difficult diagnostical
problems but regularly allow a rather easy operative treatment.
PMID- 9553476
TI - [Late outcome of severed extensor tendons in the area of the hand and fingers].
AB - In the care and further treatment of patients with hand injuries, a necessary
requirement of the hand surgeon is that he be able to cope with the interlocking
factors that are no longer influential, for example, the type and extent of the
trauma or the age of the patient; the influential factors are a thought-out care
plan, atraumatic action with regard to optimal restoration of the hand. This also
showed a retrospective analysis of results and post-examination from flexor
tendon injuries in the hand of 298 patients, who were surgically cared for from
1984 to 1994 at the surgical clinic of the University of Jena. Of the 298
patients 119 patients with 198 flexor tendon injuries (165 fingers and 33 thumbs)
were followed up. For objective assessment of the treatment results, the
assessment scheme Buck-Gramcko was used.
PMID- 9553477
TI - [Os odontoideum. Etiology, clinical aspects, therapy].
AB - The etiology of os odontoideum is still controversial. In most patients, it is
found by accident because of neurological symptoms and/or painful range of motion
of the cervical spine. Upon recognition of the os odontoideum, it is unknown
whether or not immediate surgery is beneficial. This is in contrast to an
"unstable" os odontoideum, which could result in atlantoaxial instability or
compression of the myelon. In this study, we present the results of our treatment
of four patients with an unstable os odontoideum. In all four cases, a C1-2
fusion was performed (3 x Magerl/Seemann, 1 GallieBrooks). Postoperatively, we
found a complete regression of neurological symptoms in three patients and one
was significantly improved. The range of motion of the cervical spine was free of
pain in all patients. As a result, we strongly support immediate surgical
treatment of an unstable os odontoideum in order to prevent severe and life
threatening neurological complications.
PMID- 9553479
TI - [Epiperiostal, percutaneous plate osteosynthesis. A new minimally invasive
technique with reference to "biological osteosynthesis"].
AB - Conservation of bone perfusion, protection of the soft tissue envelope and
reduction of systemic stress by strengthening the host defence mechanism are
general and essential aspects of a biological osteosynthesis. The minimal
invasive operating techniques with the use of technical aids and tricks form the
necessary presupposition for successful bone healing with a low complication
rate. For an epiperiosteal, percutaneous plate osteosynthesis, the technique
using a sliding tip and a manipulation handle is demonstrated.
PMID- 9553478
TI - [Clinical effects of supplemental enteral nutrition solution in severe
polytrauma].
AB - Previous studies in critically ill patients have shown the beneficial effects of
early enteral nutrition supplemented with arginine, omega-3 fatty acids and
nucleotides (Impact) on immunological response, infection rate and length of stay
in hospital. No specific data exist for patients with severe multiple injury, who
represent a high risk group for systemic inflammatory response syndrome (SIRS),
septic complications and multiple organ failure (MOF). In this prospective,
randomized, double-blind controlled clinical study on patients after severe
trauma (ISS ca. 40) the primary study endpoints were incidence of SIRS and MOF
[definitions according to Am Soc Crit Care Med (5) and Goris (23), Sauaia (43)].
Thirty-two patients enrolled in the study, and 29 were eligible for analysis:
test (Impact) (n = 16), control (n = 13). Both groups were comparable according
to age, body mass index and severity of trauma (PTS-test: 38.8 +/- 12.5, PTS
control: 40.8 +/- 15.5, ISS-test: 39.6 +/- 11.4, ISS-control: 40.5 +/- 9.2).
Patients were randomized to receive either Impact (test) or an isonitrogenous
isocaloric diet (control). Feeding was started on the 2nd day after trauma via
endoscopically placed nasoduodenal or jejunal feeding tubes. The experimental
diet was safe and well tolerated. During the 1st week the enteral feeding amount
was about 2000 ml without significant difference. Test-fed patients developed
SIRS significantly less frequently between day 1 and day 28 (8 vs 13.3; P < 0.05)
and especially between day 8 and day 14 (3 vs 6.2; P < 0.001). In the control
group the Goris score was significantly worse (P < 0.05) on days 3, 4, 6, 7, 10,
11, 16 and 17 and the Sauaia score on days 8, 9, 10 and 11 (P < 0.05; P < 0.01).
Mortality rate did not significantly differ (test 2/16, control 4/13), nor did
length of ICU or hospital stay. With regard to the acute-phase response, C
reactive protein was significantly lower on day 4 in the test group (test: 131 +/
67 mg/l, control: 221 +/- 110 mg/l) as was fibrinogen on day 12 (6.6 +/- 1.4 vs
7.5 +/- 1.4 g/l) and day 14 (7.1 +/- 1.3 vs 7.8 +/- 0.8 g/l). No significant
difference could be observed for CD4/CD8 ratio, CD45 isotope on activated T-cells
and lymphocytic interleukin (II)-2-receptor- and II-6 level. However, HLA-DR
antigen presentation on peripheral monocytes was significantly elevated on day 7
in the test group (P < 0.05). According to the results, arginine, omega-3 fatty
acids and nucleotides-enriched diet during early enteral feeding leads to
reduction of SIRS after severe multiple injury. There is evidence for improvement
of post-traumatic immunological response which helps to overcome the
immunological depression after trauma.
PMID- 9553480
TI - [Riding injuries and injuries due to handling horses in experienced riders].
AB - A group of experienced riders who qualified for the German riding badge 9.5 years
ago answered a questionnaire pertaining to injuries during jumping, dressage and
cross-country riding, as well as handling the horse. During riding 69% of the
persons had had 187 injuries and while handling the horse 52% had had 124
injuries. Fractures and contusions were the most-frequent injuries; most riding
injuries were located in the upper extremities and shoulder while handling mainly
in the hands and feet. The number of injuries was comparable in jumping, dressage
or cross-country riding. The time engaged in jumping was about one-third of the
other types of riding, but the injuries were more severe. While handling the
horse the number of injuries relative to the time spent during the activity were
higher but less complicated. No change in safety precautions had been implemented
by 67% of the persons injured. The injury rate for equestrians is relatively low
both in handling the horse and during riding. The frequent fractures and
contusions may be reduced by following the required safety regulations.
PMID- 9553481
TI - [Traumatologic emergency in the shock department. Analysis of the spectrum and
temporal aspects of diagnostic imaging].
AB - With a prospective assessment of 140 emergency-room patients, we registered the
conventional radiological examinations (CR), ultrasound (US) and computer
tomographies (CT), including the duration of the examinations, transportation and
diagnostic free time. RESULTS: CR: 98.6% (average 8.5 radiographs per patient),
US 78.6%, CT 67.8%. DURATION: CR average 20.3 min (range 1-80 min), US average
6.5 min (range 2-15 min), CT average 16.9 min (range 12-135 min). The entire time
spent in the primary diagnostic work-up, including CT: average 79.4 min (only CR
and US average 49.1 min). Diagnostic free time, including CT: average 31.9 min,
without CT average 19.2 min. Time for transportation and repositioning: average
14.5 min. When a CT is indicated, the radiological diagnostic work-up will
increase as a result of waiting and transportation. The patient also suffers
because of more repositioning procedures.
PMID- 9553482
TI - [Diagnosis and therapy of ligament injuries of the foot].
PMID- 9553483
TI - [Performance-related income budget. A means for reorganizing hospital financing].
AB - Performance-related budgets are the result of negotiated performance units per
hospital multiplied by state-wide negotiated prices. Such hospital budgets
contain profit chances and loss risks. Exceeding the contractual fixed amount
leads to price reductions, falling below that amount leads to lower
reimbursement. A consistent pricing system for basic and department performance
units could solve the present problem of cost separation in Germany. A step in
this direction is the definition of hospital department groups and the
construction of an average department treatment case, which could be priced on an
average cost base. In the long run, more flexibility according to pricing and
budgeting can be developed. Competitive insurance companies should be free to
find their own budgets so that a hospital can have several independent
contractors.
PMID- 9553484
TI - [Considerations of biomechanics after clavicular resection. Case report of rower
with Ewing sarcoma].
AB - Because of poorly compartmentalized paraclavicular soft tissues, total
extraperiostal claviculectomy in cases of malignoma with cortical destruction is
always marginal. Due to different muscular compensation in the patients examined,
literature disagrees on the biomechanical consequences of claviculectomy for the
shoulder girdle. We present a case of total clavicula resection including
chemotherapy and radiation in an 18-year-old rower with Ewing's sarcoma. Sixteen
month postoperative radiological and clinical examination revealed an excellent
result. Thirty-six months postoperatively the patients is able to row symptom
free without any evidence of the disease. Biomechanical reflections on the
significance of the trapezius muscle in compensating thoracoscapular instability
provide information for rehabilitation.
PMID- 9553485
TI - Quantifying HIV-1 RNA without amplification.
PMID- 9553486
TI - The nanoliter niche. NMR detection for trace analysis and capillary separations.
PMID- 9553487
TI - Keeping U.S. water programs in check.
PMID- 9553488
TI - Microminiaturized immunoassays using atomic force microscopy and compositionally
patterned antigen arrays.
AB - This paper combines the topographic imaging capability of the atomic force
microscope (AFM) with a compositionally patterned array of immobilized antigenic
rabbit IgG on gold as an approach to performing immunoassays. The substrates are
composed of micrometer-sized domains of IgG that are covalently linked to a
photolithographically patterned array of a monolayer-based coupling agent. The
immobilized coupling agent, which is prepared by the chemisorption of
dithiobis(succinimidyl undecanoate) on gold, is separated by micrometer-sized
grids of a monolayer formed from octadecanethiol (ODT). The strong hydrophobicity
of the ODT adlayer, combined with the addition of the surfactant Tween 80 to the
buffer solution that is used in forming the antibody-antigen pairs, minimizes the
nonspecific adsorption of proteinaceous materials to the grid regions. This
minimization allows the grids to function as a reference plane for the AFM
detection of the height increase when a complementary antibody-antigen pair is
formed. The advantageous features of this strategy, which include ease of sample
preparation, an internal reference plane for the detection of topographic
changes, and the potential for regeneration and reuse, are demonstrated using
rabbit IgG as an immobilized antigen and goat anti-rabbit IgG as the
complementary antibody. The prospects for further miniaturization are discussed.
PMID- 9553489
TI - Randomly ordered addressable high-density optical sensor arrays.
AB - Array-based sensors provide an architecture for multianalyte sensing. In this
paper, we report a new approach for array fabrication. Sensors are made by
immobilizing different reactive chemistries on the surfaces of microspheres.
Sensor arrays are prepared by randomly distributing a mixture of microsphere
sensors on an optical substrate containing thousands of micrometer-scale wells.
The sensors occupy a different location from array to array; thus the identity of
each sensor is ascertained and registered on the detector using encoding schemes,
rather than by a predetermined location in the array. The approach thereby shifts
the demand from fabrication to signal processing. The availability of commercial
image analysis software makes such a shift both cost-effective and time
efficient.
PMID- 9553490
TI - Classification and quantitation of 1H NMR spectra of alditols binary mixtures
using artificial neural networks.
AB - A pattern recognition method based on artificial neural networks (ANNs) to
analyze and quantify the components of six alditol binary mixtures is presented.
This method is suitable to classify the spectra of the 15 mixtures obtained from
the six alditols and to produce quantitative estimates of the component
concentrations. The system is user-friendly and is helpful in solving the problem
of greatly overlapping signals, often encountered in NMR spectroscopy of
carbohydrates. A "classification" ANN uses 200 intensity values of the 1H NMR
spectrum in the range 3.5-4 ppm. When the correct mixture is identified, the
quantification is solved by assigning a specific ANN to each mixture. These ANNs
use the same 200 values of the spectrum and output the values of the two
concentrations. The error in the ANN responses is studied, and a method is
developed to estimate the accuracy in determining the concentrations. The
networks' abilities to recognize previously unseen mixtures are tested. When the
classification ANN (trained on the 15 binary mixtures) is exposed to complex
(i.e., more than binary) mixtures of the six known alditols, it successfully
identifies the components if their minimum concentration is 10%. Given the
precision of the results and the small number of errors reported, we believe that
the method can be used in all fields in which the recognition and quantification
of components are necessary.
PMID- 9553491
TI - Screening ligands for membrane protein receptors by total internal reflection
fluorescence: the 5-HT3 serotonin receptor.
AB - The screening of ligands for membrane receptor proteins is central to the
discovery of new pharmaceutical drugs. We present a general method to reversibly
attach receptor proteins via an affinity tag to a quartz surface and subsequently
detect with high sensitivity the real-time binding of ligands by total internal
reflection fluorescence. A serotonin-gated ion channel protein was immobilized,
and the binding of a fluorescent ligand was investigated. The affinity and the
kinetic parameters of binding were measured, and the effect of unlabeled
compounds was determined by competition. The pharmacology of the immobilized
receptor was identical to that of the native receptor. The affinity of unlabeled
ligands was rapidly and effectively determined. The method described here is
generally applicable for membrane proteins and opens new ways for the discovery
of pharmacologically active compounds.
PMID- 9553492
TI - Surface-enhanced Raman gene probe for HIV detection.
AB - We report, for the first time, the use of surface-enhanced Raman (SERS)-active
labels for primers used in polymerase chain reaction amplification of specific
target DNA sequences. This method has the potential for combining the spectral
selectivity and high sensitivity of the SERS technique with the inherent
molecular specificity offered by DNA sequence hybridization. The effectiveness of
the detection scheme is demonstrated using the gag gene sequence of the human
immunodeficiency virus. The potential use of multiple probes for simultaneous
detection of multiple biological targets is discussed.
PMID- 9553493
TI - The potential of restricted access media columns as applied in coupled-column
LC/LC-TSP/MS/MS for the high-speed determination of target compounds in serum.
Application to the direct trace analysis of salbutamol and clenbuterol.
AB - This study investigated the potential of restricted access media (RAM) columns
used as a first column in coupled-column LC hyphenated to thermospray tandem mass
spectrometry (LC/LC-TSP/MS/MS) for the fast, selective, and sensitive
determination of target drugs in serum samples. Because of their wide range in
polarity, salbutamol and clenbuterol were chosen as model compounds and
representatives of the class of beta 2-agonists. Three types of RAM columns were
tested: (i) Pinkerton ISRP (internal surface reversed phase, 5 microns), (ii) SPS
(semipermeable surface, 5 microns C18), and (iii) RP-18 ADS (alkyl-diol silica,
25 microns). A 3-micron C18 column (50 mm x 4.6 mm i.d.) was chosen as the second
column. Tandem mass spectrometric detection was carried out in the selected
reaction monitoring (one parent-->one daughter) mode. With regard to retention
and, moreover, the peak elution volume of the analytes, the ISRP material was
found to perform best: a 50-mm x 4.6-mm i.d. ISRP column in combination with a
100% aqueous buffer (pH of 7.0 +/- 0.2) allowed the injection of large volumes
(up to 200 microL) of sample without additional band broadening of the analytes
and provided sufficient preseparation between analytes and large-molecule serum
constituents. Under the selected conditions, both analytes could be determined in
serum samples up to a limit of quantification (LOQ) of 0.5 ng/mL, with a sample
throughput of 7 and 5 h-1 for salbutamol and clenbuterol, respectively. Method
validation was carried out by analyzing, in the course of several days, calf and
human serum samples spiked with the analytes. In the case of salbutamol, the
overall recovery from serum samples spiked at levels between 0.5 and 50 ppb (n =
33) was 103.4%, with a repeatability of 12.7% and reproducibility of 14.3%. The
overall recovery for clenbuterol was 99.6% (n = 15, spiked level 0.5-5 ppb), with
a repeatability of 15.2% and reproducibility of 16.4%. The adopted LC/LC-TSP/MS/
MS analyzer appeared to be very robust under the selected conditions, and, after
the period of analysis involving the processing of more than 100 mL of serum,
neither loss of chromatographic performance nor pressure increase of columns or
of the interface was observed.
PMID- 9553494
TI - Ion trap mass spectrometry for kinetic studies of stable isotope labeled vitamin
A at low enrichments.
AB - The role of beta-carotene in chemoprevention of cancers and other chronic
diseases generated controversy when subpopulations taking beta-carotene
supplements showed increased mortality in clinical trials. Determination of the
dynamics of beta-carotene in individual human subjects has emerged as a high
priority. Stable isotope labeled beta-carotene tracers can be employed to
determine rates of conversion to retinol (vitamin A), but tracer doses must be
small to minimize perturbation of endogenous retinoid and carotenoid pools. In
such cases, ratios of labeled tracer/endogenous retinol are often low, and
quantitative analysis at enrichments of < 1 mol% are unreliable owing to ion
molecule reactions that generate ions at the same mass as the labeled tracer even
when no tracer is present. The current study demonstrates improved gas
chromatography/mass spectrometry quantification of retinol-d4 and unlabeled
retinol, as their tert-butyldimethylsilyl ethers, at low enrichments using an ion
trap mass spectrometer operated in selected ion storage mode. Electron ionization
of analyte takes place in the ion trap using conditions that eject ions outside
the range m/z 390-420, and molecular ions at m/z 400 and 404 from retinol and
retinol-d4 are quantified. Using this approach, unlabeled retinol yields a signal
close to values calculated from natural isotopic abundances (approximately
0.13%), whereas several quadrupole instruments operated using selected ion
monitoring yielded 2-5 times greater signal when no labeled retinol was present.
PMID- 9553495
TI - Chiral separations using dipeptide polymerized surfactants: effect of amino acid
order.
AB - Chiral separations using various polymerized dipeptide surfactants in
electrokinetic capillary chromatography (EKC) are investigated. The two main
dipeptide surfactants used in this study were sodium N-undecylenyl-L-valine-L
leucine (L-SUVL), and sodium N-undecylenyl-L-leucine-L-valine (L-SULV). These
studies were performed in order to determine if the order of amino acids in
dipeptide surfactants is important in terms of chiral recognition and
separations. Both the monomer and the polymer of these two surfactants were
compared for the separation of two model atropisomers, (+/-)-1,1-bi-2-naphtol
(BOH) and (+/-)-1,1'-bi-2-naphthyl-2,2'-diyl hydrogen phosphate (BNP). Some
advantages and disadvantages of the polymer relative to the monomer are
discussed. Four other surfactants, the polymers of sodium N-undecylenyl-L-leucine
L-leucine (L-SULL), sodium N-undecylenyl-L-valine-L-valine (L-SUVV), sodium N
undecylenyl-L-valine (L-SUV), and sodium N-undecylenyl-L-leucine (L-SUL), were
also used in this study, and their performance was compared to that of poly(L
SULV). These data show conclusively that the order of amino acids in dipeptide
surfactants has a dramatic effect on chiral recognition. Our investigations
indicate that poly-(L-SULV) provides the best enantioselectivity among the four
dipeptide and two single amino acid surfactants for the separation of BNP and
BOH. The advantages of poly-(L-SULV) are demonstrated via the ultrafast
separation of the enantiomers of BNP and BOH in less than 1 min.
PMID- 9553496
TI - A matrix for DNA separation: genotyping and sequencing using
poly(vinylpyrrolidone) solution in uncoated capillaries.
AB - We report a new sieving matrix for DNA separation based on commercially available
poly(vinylpyrrolidone). The new sieving matrix has a very low viscosity at
moderate concentrations, e.g., 27 cP at 4.5%. Its excellent self-coating property
can reduce electroosmotic flow to a negligible level. Column regeneration between
runs is very simple and effective. Successful separations were achieved in
uncoated capillaries. For genotyping, we show that D1S80 and amelogenin sex
determination system can be baseline separated as double-stranded DNA, and vWF,
TH01, TPOX, and CSF1PO short tandem repeats can be separated with single-base
resolution as single-stranded DNA in this new matrix. Sequencing of M13mp18
showed good resolution up to 500 bases in a solution of high-molecular-weight
fraction extracted from commercially available PVP. The feasibility of adaptation
to a multicapillary array system is discussed.
PMID- 9553497
TI - Capillary zone electrophoresis of bile acids with indirect photometric detection.
AB - Investigations in our laboratory have demonstrated that capillary zone
electrophoresis (CZE) with indirect photometric detection is a viable approach to
the separation and identification of free bile acids along with their taurine and
glycine derivatives. Various parameters such as pH, organic solvent
concentrations, column temperature, and type of chromophore electrolyte were
investigated to optimize the electrophoretic separation and to maximize the peak
capacity. The quality of separation of bile acids can be dramatically improved by
incorporating gamma-cyclodextrin (gamma-CD) in the running electrolyte. This
improvement in resolution is accompanied by a decreased migration time,
suggestive of an increase in association of gamma-CD with bile acids. As a
result, a CZE separation of all 15 bile acids was possible in approximately 30
min using 5 mM adenosine 5'-monophosphate, 7 mM gamma-CD in 75% (v/v) methanol at
pH 7.0.
PMID- 9553498
TI - Evaluation of association constants between drug enantiomers and human alpha 1
acid glycoprotein by applying a partial-filling technique in affinity capillary
electrophoresis.
AB - The principles for evaluation of conditional association constants between drug
enantiomers and proteins, exemplified here by alpha 1-acid glycoprotein (AGP),
using capillary zone electrophoresis employing a partial filling technique, is
presented. In the partial filling technique only the first part of the capillary
is filled with the selector, and this selector zone (plug) length can be varied
by introducing the selector solution at different times at constant pressure. An
important feature of the technique is the low consumption of selector solution in
this study only 40-290 nL is used per run, of special importance when the
availability of the selector is limited, and also in case it is expensive.
Conditions are chosen so that the protein has a net negative charge and migrates
toward the anode, while the analytes migrate toward the detector at the cathodic
side. The resolution is linearly related to the effective plug length, as shown
in separations of the enantiomers of disopyramide and remoxipride. The effective
plug length can be calculated, which forms the basis to apply this technique for
determinations of association constants. The association between the enantiomers
of the solutes and AGP varied with increasing temperature, as shown by determined
association constants. It was found that the association between the enantiomers
and AGP was strongest at 25 degrees C and decreased at both lower and higher
temperatures. This unexpected finding may indicate conformational changes of the
protein with temperature variations.
PMID- 9553499
TI - Aesthetic considerations for maxillary obturators retained by implants.
AB - Maxillary obturators are prostheses used to replace maxillary tissues, missing
congenitally or removed by trauma or tumor ablative surgery. These prostheses are
used to restore function (speech, swallowing, and mastication) and aesthetics. A
considerable number of edentulous patients have difficulty in retaining this type
of prosthesis. Utilization of osseointegrated dental implants is a significant
adjunct in treating these cases, but it must be undertaken with careful planning
to ensure predictable aesthetic results. The learning objective of this article
is to discuss the technique of designing aesthetic maxillary prostheses supported
by osseointegrated dental implants. The discussion includes indications and
contraindications, and a postcarcinoma surgery case is used to illustrate the
clinical procedure.
PMID- 9553500
TI - Search for metal-free restorations: a combination of ceramic optimized polymer
and a fiber-reinforced composite.
PMID- 9553501
TI - The aesthetic and endodontic dilemmas of calcific metamorphosis.
AB - Traumatic injuries to dentition can initiate either a resorptive or calcific
pulpal response. In the sequelae of calcific degeneration, the clinical crown
frequently becomes discolored, requiring an aesthetic correction to restore the
tooth to its natural color. Four potential solutions are currently available to
achieve this goal. The learning objective of this article is to describe the
etiology of calcific metamorphosis, discuss the four potential solutions, and
present the responses of endodontists polled as to the treatment indications.
While the posterior dentition may experience the identical pathologic response to
trauma and crown discoloration, this article focuses on the restoration of the
anterior dentition. Several cases are presented to illustrate the four treatment
modalities, and recommendations for follow-up of traumatic injuries are
indicated.
PMID- 9553502
TI - Management of temporomandibular disorders in a restorative practice.
AB - Various disorders related to the masticatory muscles or to the temporomandibular
joints may be encountered in a restorative dental practice. Most of them can be
managed by the restorative dentist whose primary interest may not lie in the area
of temporomandibular disorders. The term temporomandibular disorders is used in
this discussion to denote the group of diseases of the masticatory system that
involves primarily the temporomandibular joints, the masticatory muscles, and the
occlusion of the teeth. The learning objective of this article is to describe
temporomandibular disorders encountered in general practice. Managing these
disorders in the general practice of restorative dentistry is not difficult and
adds to the comfort of the patient and possibly to the success of the
restorations.
PMID- 9553503
TI - Myofascial trigger points of pain.
PMID- 9553504
TI - The milled implant-supported prosthesis: a treatment alternative for the
edentulous mandible.
AB - The milled implant-supported prosthesis offers the benefits of fixed and
removable restorations. Its infrastructure provides the same rigidity as the
fixed restoration, due to the precise fit to the superstructure that is removable
to promote adequate access for hygiene, yet provides lip support and maintains
close contact with the soft tissues. These advantages enhance phonetics,
aesthetics, correct lip support, and maintenance. The learning objective of this
article is to discuss the indications for milled implant-supported restorations,
review the scientific background of materials and techniques utilized, and
describe the clinical and laboratory procedures involved. An uncomplicated and
cost-effective impression technique is outlined, and the numerous steps of infra-
and superstructure fabrication are presented.
PMID- 9553505
TI - Functional versus aesthetic articulation of maxillary anterior restorations.
AB - The correct orientation of the master model is a frequently overlooked aspect of
communication between the clinician and the ceramist. The master model must
provide the ceramist with the same perspective of the patient as is seen by the
clinician--facing the viewer. Unless precise information is transferred to the
laboratory, the ceramist can only estimate horizontal and vertical alignment of
the working cast from landmarks taken from the cast itself. It is unwise to leave
such appraisal to chance, especially when restoring multiple anterior
preparations, where the potential for misalignment of the cast increases with the
number of restorations involved. The learning objective of this article is to
discuss communication techniques between the clinician and the ceramist for
achieving precise and predictable orientation in the treatment of aesthetic
anterior restorations.
PMID- 9553508
TI - Payment. Capitation is catching.
PMID- 9553506
TI - Rehabilitation of an edentulous mandible with an implant-supported prosthesis.
AB - The advances in osseointegration have resulted in an increased utilization of
implants for restoration of the edentulous jaw. The success of osseointegrated
implants supporting full arch prostheses has become more predictable. All implant
restorations require a thorough diagnosis and a definitive treatment plan.
Following a diagnostic wax-up, an optimal surgical implant template must be
fabricated; it serves as a guide or prescription for placement of implants in an
optimal anatomic location. The slightest misangulation of an implant may create
restorative limitations. In such circumstances, alteration of the restorative
design or selection of alternate materials may be required. The learning
objective of this article is to review the fabrication of a combined ceramometal
and resin-metal fixed/removable implant-supported mandibular hybrid prosthesis.
Diagnosis, surgical template fabrication, vertical dimensions, buccal/lingual
space limitations, and aesthetics are discussed.
PMID- 9553509
TI - Finance. Some gains, some pains.
PMID- 9553510
TI - Consumer polls. Another break with tradition.
PMID- 9553511
TI - AIDS Czarina. Interview by Theresa Hudson.
PMID- 9553512
TI - Fraud storm surges toward HMOs.
PMID- 9553513
TI - 6 new buying rules.
AB - Times change--and so does software purchasing. Buying in bulk, paying top dollar
for what a system does, trusting a vendor to watch out for you--that's old input.
Here are six fresh rules for the buying game.
PMID- 9553514
TI - 3 forces for change.
AB - For decades, health care has nursed a distrust of comparative clinical data. But
what the market wants, it gets. Economics, technology, and the spirit of the
times call for computer systems that measure quality.
PMID- 9553515
TI - 10 CEO resources.
AB - With computer woes marching into the front office and onto the front page these
days, it's time to bone up. This guide to books, Web sites, and other executive
resources will get you started.
PMID- 9553516
TI - It's worth the ... risk.
AB - Sharing risk with HMOs requires the patience of a kindergarten teacher, the
finesse of a U.N. negotiator, and the agility of a fighter pilot. Intimidated
yet? Neither are these executives. Our exclusive data show how hospitals handle
risk contracts.
PMID- 9553517
TI - Answers from the audit trail.
AB - It's a lot cheaper to develop a compliance plan than fight fraud charges. Trouble
is, off-the-shelf wisdom is hard to come by. Here's sage advice from compliance
pros on how to put your plan in motion.
PMID- 9553518
TI - A fight for poor eyes ... and other battles for the outpatient market.
PMID- 9553519
TI - Can mergers save these markets?
PMID- 9553520
TI - Managed care. Sierra's military maneuver.
PMID- 9553521
TI - Medical devices. Label fable?
PMID- 9553522
TI - End-of-life care. Plan B for pain code.
PMID- 9553523
TI - Rural health care. Wheeling and healing.
PMID- 9553524
TI - Phen-fen fallout. Financial side effects.
PMID- 9553525
TI - Hip fractures are an increasingly important public health problem.
PMID- 9553526
TI - The effects of adduction and abduction on the length of the limb in fractures of
the neck of the femur. 1884.
PMID- 9553527
TI - Circumstances of falls causing hip fractures in the elderly.
AB - A prospective analysis was performed on 832 patients to determine the
circumstances surrounding falls leading to hip fracture within a homogeneous,
elderly urban population. Special emphasis was placed on the season of year, time
of day, location of fall, and other circumstances in which the fracture occurred.
All patients were community dwelling, cognitively intact, previously ambulatory
elderly who sustained a femoral neck or intertrochanteric fracture. Most
fractures occurred at home, particularly in patients who were older, less
healthy, and poorer ambulators. More than 75% of fractures resulted from a fall
while the patient was standing or walking. Most falls occurred during daylight
hours with a peak seen in the afternoon. No seasonal variation in the incidence
of hip fractures was observed.
PMID- 9553528
TI - Medical management of osteoporosis. Fracture prevention.
AB - The current medical treatment for the prevention of fractures in patients with
osteoporotic bone, in particular, in patients with fractures involving the hip is
discussed. Four drugs, calcium, calcitonin, estrogen, and alendronate have been
approved for marketing by the Food and Drug Administration for the treatment of
osteoporosis. Each of these drugs has a different mode of action to prevent bone
loss and each carries its own side effects which must be weighed against the
benefits. The future of medical management of osteoporosis involves designing new
drugs that will reduce bone loss, potentially restore bone mass, and show proven
efficacy in preventing fractures.
PMID- 9553529
TI - Predictors of functional recovery after hip fracture in the elderly.
AB - Three hundred thirty-eight community dwelling, ambulatory, elderly patients who
sustained a hip fracture were observed prospectively to determine which patient
and fracture characteristics at hospital admission predicted functional recovery
at 3, 6, and 12 months. Multiple logistic regression was performed to estimate
the simultaneous contributions of the predictor variables to failure of
functional recovery. Before sustaining a fracture, 16% of patients were dependent
on basic activities of daily living and 46% were dependent on instrumental
activities of daily living. By 1 year after fracture, 73% of the patients had
recovered to their basic activities of daily living status before fracture
whereas only 48% had recovered to their instrumental activities of daily living
status before fracture. Patients who were age 85 years or older, who lived alone
before sustaining a fracture, and who had one or more comorbidities were at
increased risk of delay or failure in recovering basic activities of daily
living. Only instrumental activities of daily living independence before fracture
predicted failure to recover instrumental activities of daily living function by
3 and 6 months after fracture. At 1 year, patient age 85 years or older was the
only predictor of failure to recover instrumental activities of daily living
function that existed before fracture. Based on characteristics at admission, a
group of patients at high risk for failure to recover basic activities of daily
living function within 1 year of sustaining a hip fracture can be identified.
PMID- 9553530
TI - Functional outcome after hip fracture in Japan.
AB - One thousand one hundred sixty-nine elderly Japanese patients who sustained a hip
fracture were observed prospectively. Ninety-two percent had operative fracture
treatment. Hospital length of stay averaged 67 days; 81% of patients were
discharged to their place of residence where they resided before sustaining the
fracture. Mortality rates at 120 days, 1 year, and 2 years after injury were 6%,
11%, and 19%, respectively. At 1-year followup, ambulatory status was recovered
to that of the level experienced before injury in 67% of patients.
PMID- 9553531
TI - Functional outcome after hip fracture. Effect of general versus regional
anesthesia.
AB - The effect of anesthetic technique on ambulation and functional recovery after
hip fracture was studied in a series of 631 community dwelling, elderly patients.
Functional recovery at followup was determined by an 11-item functional rating
scale. In univariate analysis, recovery of ambulatory ability and percent
functional recovery were significantly higher at 6 months for patients who had
general anesthesia. When controlling for potential confounding variables,
however, no differences were observed in recovery of ambulatory ability or
percent functional recovery between the two groups at 3, 6, or 12 months after
hip fracture.
PMID- 9553532
TI - Norian SRS cement augmentation in hip fracture treatment. Laboratory and initial
clinical results.
AB - Bone quality, initial fracture displacement, severity of fracture comminution,
accuracy of fracture reduction, and the placement of the internal fixation device
are important factors that affect fixation stability. New high strength cements
that are susceptible to remodeling and replacement for fracture fixation may lead
to improved clinical outcome in the treatment of hip fractures. Norian SRS is an
injectable, fast setting cement that cures in vivo to form an osteoconductive
carbonated apatite of high compressive strength (55 MPa) with chemical and
physical characteristics similar to the mineral phase of bone. It can be used as
a space filling internal fixation device to facilitate the geometric
reconstruction, load transfer, and healing of bone with defects and/or fractures
in regions of cancellous bone. Furthermore, this cement can improve the
mechanical holding strength of conventional fixation devices. Use of this
material potentially could improve fracture stability, retain anatomy during
fracture healing and improve hip function, thus achieving better clinical
outcomes. In vivo animal studies have shown the material's biocompatibility, and
cadaveric studies have shown the biomechanical advantage of its use in hip
fractures. Initial clinical experience (in 52 femoral neck fractures and 39
intertrochanteric fractures) showed the potential clinical use of this innovative
cement in the treatment of hip fractures.
PMID- 9553533
TI - Outcome after hemiarthroplasty for femoral neck fractures in the elderly.
AB - A prospective outcome study was performed on 270 patients, 65 years of age and
older, who sustained a femoral neck fracture and underwent hemiarthroplasty. The
treatment compared was the use of a noncemented unipolar versus either a cemented
or a press fit bipolar prosthesis. The outcome variables assessed included the
occurrence of a postoperative complication, length and cost of hospitalization,
and function in various quality of life measurements. Patients who underwent
bipolar hemiarthroplasty with either a cemented or a press fit prosthesis had
better pain relief and function than patients who had a noncemented unipolar
prosthesis at a minimum of 24 months after surgery. However, the mean
hospitalization cost for patients who had a bipolar prosthesis was $12,290
compared with $8876 for a unipolar prosthesis.
PMID- 9553534
TI - Eight-year outcome associated with clinical options in the management of femoral
neck fractures.
AB - This study involved a review of the medical records of 367 patients treated
surgically after femoral neck fracture. Linkage of these records with claims
files from the Health Care Financing Administration allowed as many as 8 years of
followup to analyze the rates of hospital readmission rates for revision, other
postoperative complications and mortality. The results revealed: (1) a
significantly higher revision rate was associated with internal fixation for the
treatment of displaced femoral neck fractures in patients older than 80 years of
age; no differences in revision rates were seen between internal fixation or
hemiarthroplasty for the treatment of nondisplaced femoral neck fractures in this
patient age group; (2) no differences in revision rates were found between
internal fixation or hemiarthroplasty for the treatment of displaced femoral neck
fractures in patients between the ages of 65 to 80 years; (3) a significantly
higher mortality rate was associated with internal fixation than hemiarthroplasty
for patients who were between the ages of 65 and 80 years; and (4) no differences
in medical or surgical complications, revision rates, or other outcomes were
found between unipolar and bipolar prostheses, or between anterior and posterior
surgical approaches for hemiarthroplasty in patients who were age 65 years or
older.
PMID- 9553535
TI - Unipolar versus bipolar hemiarthroplasty for the treatment of femoral neck
fractures in the elderly.
AB - This paper presents the short term results of an ongoing prospective randomized
trial comparing a cemented unipolar with a cemented bipolar hemiarthroplasty for
the treatment of displaced femoral neck fractures in the elderly. Forty-seven
patients with an average age of 77 years completed 6-month followup. Outcomes at
6 weeks, 3 months and 6 months were assessed by completion of a patient oriented
hip outcome instrument and by functional tests of walking speed and endurance. No
differences in the postoperative complication rates or lengths of hospitalization
were seen between the two groups. Patients treated with a bipolar
hemiarthroplasty had greater range of hip motion in rotation and abduction and
had faster walking speeds. However, no differences in hip rating outcomes were
found. These early results suggest that use of the less expensive unipolar
prosthesis for hemiarthroplasty after femoral neck fracture may be justified in
the elderly.
PMID- 9553536
TI - Stress fractures of the femoral neck.
AB - Stress fractures of the femoral neck are uncommon injuries. In general these
injuries are seen in two distinct populations: (1) young, healthy, active
individuals such as recreational runners, endurance athletes, or military
recruits; and (2) the elderly who have osteoporosis. Stress fractures can be
classified as either fatigue or insufficiency fractures and result from untoward
cyclic loading or impaired bone quality. The key to treatment is early diagnosis,
which may require scintigraphy or magnetic resonance imaging. Nondisplaced
compression type stress fractures can be treated nonoperatively with protected
weight-bearing and frequent radiographic followup. Tension type stress fractures
should be stabilized internally to prevent the adverse consequences of fracture
displacement.
PMID- 9553538
TI - Intramedullary versus extramedullary fixation for the treatment of
intertrochanteric hip fractures.
AB - One hundred thirty-one patients (135 fractures) who sustained an
intertrochanteric fracture were assigned randomly to treatment with either a
sliding hip screw or an intramedullary hip screw and followed up prospectively.
In patients with unstable intertrochanteric fractures, the intramedullary device
was associated with 23% less surgical time and 44% less blood loss; however, use
of the intramedullary hip screw in patients who had a stable fracture pattern
required 70% greater fluoroscopic time. Intraoperative complications occurred
exclusively in patients in the intramedullary hip screw group. There were no
differences in the rates of functional recovery between the two fixation groups.
PMID- 9553537
TI - Comparison of the compression hip screw with the Medoff sliding plate for
intertrochanteric fractures.
AB - The Medoff sliding plate was designed to achieve compression along the femoral
neck and the longitudinal axis of the femoral shaft theoretically to improve the
treatment of intertrochanteric hip fractures. The Medoff sliding plate was
compared with a standard compression hip screw in a randomized, prospective study
for the fixation of 160 stable and unstable intertrochanteric fractures with an
average followup of 9.5 months (range, 6-26 months). Overall, 91 fractures were
treated using the compression hip screw and 69 were treated with the Medoff
sliding plate. Stable fracture patterns (46) united without complication in both
treatment groups. Unstable fractures (114) had an overall failure rate of 9.6%,
14% (nine patients) with the compression hip screw and 3% (two patients) with the
Medoff plate; this difference was significantly different. The time to union for
the 114 unstable fractures was not significantly different between the two
devices. For all patients, no differences in lengths of hospitalization, return
to ambulatory status before fracture, postoperative living status, or
postoperative pain was observed between the two device groups. Use of the Medoff
plate for all fracture types was associated with a significantly higher amount of
blood loss and operating time.
PMID- 9553539
TI - Use of an interlocked cephalomedullary nail for subtrochanteric fracture
stabilization.
AB - Forty-five Russell-Taylor Type 1B subtrochanteric femoral fractures were
stabilized using an interlocked cephalomedullary nail. The intraoperative
complication rate was 13.5%; the most frequent complication was a varus
malreduction. The union rate was 100% at an average of 13.5 weeks after surgery;
there were no implant failures. Forty-three of 45 (96%) patients regained greater
than 120 degrees knee motion. Based on these results it is thought that an
interlocked cephalomedullary nail may be the implant of choice for stabilization
of Russell-Taylor Type 1B fractures; however, its proper use requires careful
intraoperative technique, with particular attention given to avoid a varus
malreduction.
PMID- 9553541
TI - Magnetic resonance imaging of the shoulder in abduction.
AB - To simulate the painful arm position in subacromial impingement syndrome,
magnetic resonance imaging of the shoulder was done with the arms at the sides
and at 80 degrees abduction in two groups of patients. Group A had 20 shoulders
in 20 patients with subacromial impingement syndrome and Group B had 19 shoulders
in 19 patients without impingement syndrome. When arm position was changed from
adduction to abduction, an increase in signal intensity of the rotator cuff
tendon was seen more often in Group A (45%) than in Group B (26%). Group A
shoulders showed encroachment of the acromion or the acromioclavicular joint to
the rotator cuff in 25% of the shoulders with the arms at the sides, and in 75%
with the arms in abduction. Similar findings were observed in only 14% and 21% of
Group B shoulders in the respective arm positions. Abduction of the arms seemed
to cause encroachment of the overlying structure, especially of the
acromioclavicular joint, to the rotator cuff in patients with subacromial
impingement syndrome, even if there were no such findings in the images with the
arms at the sides.
PMID- 9553540
TI - Different ways to treat subtrochanteric fractures with the Medoff sliding plate.
AB - Thirty-two consecutive subtrochanteric fractures in 32 patients were stabilized
using the Medoff sliding plate and were followed up prospectively for 1 year. Two
patients died during the first postoperative year. Twenty-nine of the remaining
30 (97%) fractures united by 1-year followup. Two types of plate dynamization
schema were used: uniaxial (17 patients) and biaxial (15 patients). With uniaxial
dynamization, plate sliding averaged 12 mm along the femoral shaft without
medialization of the femoral shaft. With biaxial dynamization along the femoral
shaft and the neck, plate sliding averaged 11 mm and screw in barrel sliding
averaged 9 mm; medialization of the femoral shaft ranged from 0% to 35% of the
femoral shaft diameter. Three fractures treated with uniaxial dynamization had
migration of the lag screw within the femoral head; all three fractures united
without additional screw migration after secondary or staged biaxial plate
dynamization.
PMID- 9553542
TI - Anteroposterior instability of the distal clavicle after distal clavicle
resection.
AB - Resection of the lateral end of the clavicle disrupts the acromioclavicular
articulation and creates the potential for abnormal postoperative motion.
Seventeen isolated distal clavicle resections were reviewed to assess translation
of the acromioclavicular articulation in the anteroposterior plane and its
relationship to patient outcome. Stress radiographs were used to quantitate the
translation of the distal clavicle and the amount of bone resected. Radiographs
of the contralateral shoulder served as a control. Patients completed a
questionnaire on shoulder function and pain and were examined preoperatively and
postoperatively. The total translation (anterior plus posterior) in the
anteroposterior plane averaged 8.7 mm (range, 3-21 mm) for surgically treated
shoulders and was significantly greater than that for the contralateral shoulders
(mean, 3.2 mm; range, 1-6 mm). Patients' postoperative visual analog pain scales
correlated with the magnitude of anteroposterior translation. The amount of
translation and the postoperative pain scores did not correlate with the apparent
joint space seen on radiographs after surgery. The correlation of pain scores
with the amount of translation shows that excessive anteroposterior instability
of the distal clavicle can cause postoperative shoulder pain and poor surgical
outcome.
PMID- 9553543
TI - Subcoracoid dislocation of the distal end of the clavicle. A case report.
AB - Subcoracoid dislocation of the outer end of the clavicle in association with an
acromial fracture is a rare injury usually produced by high energy trauma that
moves the clavicle posterior to the conjoined tendon and inferior to the coracoid
process. To restore the acromioclavicular joint, open reduction is needed. After
the reduction is accomplished, the clavicle has to be stabilized with a
coracoclavicular screw. The acromial fracture can be reduced and held with
nonabsorbable sutures placed through the bone. To avoid osteolysis of the distal
end of the clavicle and to be able to repair the torn ligaments, treatment should
not be delayed.
PMID- 9553545
TI - Assessment of neuroforaminal decompression in degenerative spinal stenosis.
AB - Surgical decompression of spinal stenosis is a balance between adequate removal
of bone and soft tissue for an effective decompression of neural structures and a
sufficient retention of bone to maintain mechanical stability of the spine. To
develop an objective, reproducible technique for the assessment of neuroforaminal
decompression in the adult lumbar spine, facet sparing laminectomies were
performed from L1-S1 on the lumbar spines of 59 human cadavers. A series of
semirigid probes in 0.5-mm increments were passed into each successive
intervertebral foramen bilaterally, beginning at L2-L3. The minimum space
available for the nerve root within the foramen of the lumbar spine is 3.5 mm at
L2-L3, 3.9 mm at L3-L4, 4.3 mm at L4-L5 and 5.1 mm at L5-S1, as determined by
three independent observers. There were no significant differences in
interobserver or intraobserver measurements. There were no complications related
to passage of the probes. This study provides a method for the intraoperative
determination of the adequacy of neuroforaminal decompression.
PMID- 9553544
TI - Functional laboratory assessment after oncologic shoulder joint resections.
AB - A laboratory evaluation was undertaken to assess the shoulder range of motion and
distal strength after oncologic resection and reconstruction involving the
shoulder joint and to compare these functional parameters based on potentially
important variables. Inclusion in the study was limited to 32 patients with bone
tumors of the proximal humerus or scapula treated surgically by resection of the
shoulder joint including the proximal humerus from 1976 through 1992. Active
shoulder range of motion and isometric elbow extension and forearm supination
strength are significantly less after surgery in patients with greater amounts of
bony resection and with resection of the deltoid. Patients who had a modified
Tikhoff-Linberg resection were able to achieve 10 degrees to 15 degrees greater
shoulder motion in each direction than were patients who had the classic
procedure including complete scapulectomy. However, elbow flexion and extension
strength and forearm pronation strength were greater for the patients with the
classic resection. Osteoarticular allografts as a reconstructive alternative
provide as a group the best shoulder motion and overall distal upper extremity
strength, but these reconstructions were performed only when the rotator cuff
muscles and deltoid were able to be reconstructed. Diminishing elbow strength was
seen with longer followup in the patients with osteoarticular reconstructions,
corresponding temporally to subchondral collapse observed on radiographs. Range
of shoulder motion except rotation was just as good for allograft vascularized
fibular arthrodeses as for the osteoarticular allografts, but strength was
significantly less with the arthrodeses.
PMID- 9553546
TI - 100 cemented versus 100 noncemented stems with comparison of 25 matched pairs.
AB - Two series of 100 consecutive primary total hip arthroplasties, each using a
single design of noncemented or cemented femoral component (all 28 mm heads),
were compared. One cemented and two noncemented stems underwent revision for
aseptic loosening. Of unrevised hips, outcome data statistically favored
cemented, rather than noncemented, stems. The data for cemented and noncemented
stems, respectively, were: An excellent to good result in 97% versus 88%; thigh
pain in 3% versus 40%; subsidence in 0% versus 22%; and endosteal cavitation in
6% versus 12%. For patients with 25 unrevised matched pairs, selected by gender,
age, diagnosis, and weight, outcome data also statistically favored cemented over
noncemented stems, respectively: an excellent or good result in 25 versus 20
hips; thigh pain in two versus eight hips; and subsidence in none versus six
hips. Midterm followup data for these concurrent total hip arthroplasty series of
a mid 1980s design revealed prevalence of mechanical failure of 1% for cemented
stems and 4% for noncemented stems. Corroborating matched pair comparison
neutralized selection bias as a causative factor for these differences. These
data indicate contemporary cemented femoral stem fixation is superior to second
generation noncemented femoral stem fixation. Controlled comparative studies at
midterm to long term followup, such as in this report, are needed to define
outcome and indications for current third generation noncemented stem fixation.
PMID- 9553547
TI - Results of total hip arthroplasty for Crowe Type III developmental hip dysplasia.
AB - From 1969 through 1980, 90 hips in 82 patients had cemented total hip
arthroplasty for Type III developmental hip dysplasia. Seventy hips were reviewed
at an average of 16.6 years (range, 5-23 years) after operation. Aseptic
loosening developed in 53% of acetabular cups and 40% of femoral stems. Despite
attempts to place acetabular components in the anatomic center, 18 cups (25.7%)
were placed outside that area. Using a measurement method to determine the true
acetabular region and approximate femoral head center, final acetabular loosening
strongly correlated with initial cup placement. Loosening occurred in 15 of 18
cups (83.3%) initially positioned outside of the true acetabular region compared
with loosening in 22 of 52 cups (42.3%) initially positioned within the true
acetabular region. Acetabular loosening also correlated with initial lateral
displacement or initial superior displacement of the hip center from the
approximate femoral head center. Initial cup placement medial to the approximate
femoral head center was predictive of successful long term acetabular component
fixation. The method of acetabular reconstruction did not affect eventual cup
loosening. Placement of the hip arthroplasty center of rotation in or near the
true acetabular region is recommended.
PMID- 9553548
TI - 4- to 10-year results with the anatomic modular total knee.
AB - The outcome of 186 consecutive total knee arthroplasties performed with the
Anatomic Modular Knee is reported. One hundred forty-two knees had followup of 4
to 10 years (mean, 6.9 years). Two knees required revision of all components, one
because of infection and the other for instability. Seven patients underwent
exchange of the modular tibial polyethylene insert at an average of 84 months
postoperatively. The mean age of these seven patients at primary arthroplasty was
54 years. No implant showed clinical or radiographic evidence of loosening and
there were no complications related to patellofemoral articulation. The revision
rate of the femoral, tibial, and patellar components was two of 142 or 1.4%. The
revision rate including exchange of the polyethylene insert was nine of 142 or
6.3%. This minimally constrained posterior cruciate retaining modular design
performed well at intermediate followup. The absence of patellofemoral
complications and aseptic loosening was notable. Wear related phenomena were the
most common indications for reoperation and these occurred in younger, active
individuals with relatively thin polyethylene bearings. The relative value of
modular tibial inserts and the outcome of isolated polyethylene exchanges warrant
additional study.
PMID- 9553550
TI - Posterior medial meniscus-femoral insertion into the anterior cruciate ligament.
A case report.
AB - Medial meniscal anomalies are rare. The anterior horn insertion into the anterior
cruciate ligament is the most common. In the course of an arthroscopy for torn
lateral meniscus, an anomalous band in continuity with the posterior horn of the
medial meniscus was observed to insert into the anterior cruciate ligament.
Although the tibial portion of the anterior cruciate was redundant, the anomalous
band provided tension to the anterior cruciate ligament and a negative pivot
shift. A previously unreported posterior medial meniscal femoral insertion is
described.
PMID- 9553549
TI - Functional gait adaptations in patients with anterior cruciate ligament
deficiency over time.
AB - Functional adaptations in knee kinematics and kinetics during level walking in 30
patients with unilateral anterior cruciate ligament deficiency and 30 healthy
control subjects were studied. To examine the impact of time after injury on the
functional adaptations, patients were placed into three time interval groups:
early, intermediate, and chronic. The patients with anterior cruciate ligament
deficiency had significantly decreased external knee flexion moments (balanced by
net quadriceps contraction) and significantly increased external knee extension
moments (balanced by net knee flexors contraction) as compared with the control
subjects. As time after the injury increased, changes in the sagittal plane knee
moments were more pronounced. A significant linear relationship (positive
correlation) was found between the midstance knee flexion moment and the
corresponding knee flexion angle. The patients with anterior cruciate deficiency
had a greater knee flexion angle when generating a comparable midstance knee
flexion moment as compared to the control subjects. The identification of gait
adaptations over time provides additional information on the natural history of
anterior cruciate ligament deficiency and may have implications regarding
conservative rehabilitation, evaluation of outcomes, progression of meniscal
injury, and the development of degenerative arthritis of the knee.
PMID- 9553551
TI - Thromboembolism after foot and ankle surgery. A multicenter study.
AB - Thromboembolic disease presents a potentially fatal complication to patients
undergoing orthopaedic surgery. Although the incidence after hip and knee surgery
has been studied and documented, its incidence after surgery of the foot and
ankle is unknown. For this reason, a prospective multicenter study was undertaken
to identify patients with clinically evident thromboembolic disease to evaluate
potential risk factors. Two thousand seven hundred thirty-three patients were
evaluated for preoperative risk factors and postoperative thromboembolic events.
There were six clinically significant thromboembolic events, including four
nonfatal pulmonary emboli, after foot and ankle surgery. The incidence of deep
vein thrombosis was six of 2733 (0.22%) and that of nonfatal pulmonary emboli was
four of 2733 (0.15%). Factors found to correlate with an increased incidence of
deep vein thrombosis were nonweightbearing status and immobilization after
surgery. On the basis of these results, routine prophylaxis for thromboembolic
disease after foot and ankle surgery probably is not warranted.
PMID- 9553552
TI - Complications in the use of the Bailey-Dubow extensible nail.
AB - The results of 40 extensible intramedullary nailing procedures in 15 children who
had osteogenesis imperfecta were reviewed to identify risk factors leading to
complications of this method of treatment. There were 40 complications, 17 major
and 23 minor. The 17 major complications led to 15 additional procedures, 10 of
which were to remove or replace the implant. The prevalence of major
complications was highest in patients who were younger than 5 years when the nail
was inserted. Nails placed in the tibia tended to produce a higher incidence of
major complications than did those placed in the femur, but this difference was
not statistically significant. By survivorship analysis, patients had a greater
risk of requiring a revision procedure when a technical error occurred at the
time the nail was inserted. Patients who had nails placed in the femur tended to
have a lower risk of needing revision surgery than did those who had nails placed
in the tibia, but this difference was not statistically significant. The results
suggested that the extensible nail is most advantageous in the femur and in
patients older than 5 years. Avoiding technical errors when inserting the nail
may improve the longevity of the device.
PMID- 9553553
TI - Osteosarcoma of the pelvis. Oncologic results of 40 patients.
AB - The cases of 40 patients with osteosarcoma of the pelvis treated between 1977 and
1994 were reviewed. The location of the tumor was ilium in 30 patients, ischium
in four, pubis in one, and sacrum in five. Most (58%) of the tumors were of the
chondroblastic subtype. Thirty patients had surgical excision of the tumors: 10
with hemipelvectomies and 20 with limb sparing procedures. A wide margin was
achieved in 16 of 30 (53%) patients, including 12 of 14 who had no sacral tumor
involvement. Positive margins occurred at the sacrum in 11 patients, lumbar
vertebra in one, perirectal space in one, and contralateral pubic body in one.
Macroscopic tumor emboli within the regional large vessels were found in seven
patients. The incidence of local recurrence was 32%: 13% in wide excisions, 38%
in marginal excisions, and 80% in intralesional excisions. The 1- and 5-year
overall patient survivals were 73% and 34%, respectively. Patients who had a
surgical excision of the primary tumor had a significantly better survival than
did those treated without surgery (5-year survival; 41% and 10%, respectively).
Tumor size, surgical excision of the primary tumor, surgical margin, and type of
surgical procedure were the prognostic factors for patients with Stage IIB
tumors.
PMID- 9553554
TI - Polyarticular pigmented villonodular synovitis in a child.
AB - Pigmented villonodular synovitis is rare in the younger child. Polyarticular
involvement in this condition, regardless of patient age, is distinctly uncommon.
The authors describe a case of pigmented villonodular synovitis involving
multiple joints in a young boy who also had congenital anomalies of the
genitourinary tract. Although rare, pigmented villonodular synovitis should be
considered in the differential diagnosis of multiple joint swellings in children
with congenital anomalies.
PMID- 9553555
TI - Limb threatening neuropathic complications from ankle fractures in patients with
diabetes.
AB - Although less common than neuropathic (Charcot) deformities in feet, ankle
deformities can occur and produce significant limb threatening complications
after injury in patients with longstanding diabetes. A series of six such
complications, including one that resulted in amputation and several near
amputations, are presented. The authors' primary purpose is to alert or remind
physicians and orthopaedic surgeons of the often unanticipated but significant
complications of these rare and seemingly mild ankle injuries. A secondary
purpose is to point out that complications may be avoided or mitigated with early
stabilization and possibly with treatment of bone resorbing, inflammatory
processes characteristic of neuroarthropathies.
PMID- 9553556
TI - Function of stiff joints may be restored by Ilizarov joint distraction.
AB - Three patients with joint stiffness caused by trauma or infection are reported.
The involved joints are the interphalangeal joint of the thumb, patellofemoral
joint, and ankle joint. As an alternative for the indicated arthrodesis in these
patients, treatment with articulating joint distraction was performed. By use of
adapted Ilizarov external ring fixators, gradual distraction was applied to
loosen the joint, followed after loosening by a period of exercise during
distraction. In all three patients this experimental approach led to a decrease
in pain and improvement of joint function that persisted for at least 2 years
after treatment. With the use of Ilizarov joint distraction, joint function in
cases of joint stiffness may be restored, and the need for an arthrodesis can be
postponed.
PMID- 9553557
TI - Telemedicine and orthopaedic care. A review of 2 years of experience.
AB - The objective of this study was to study the delivery of orthopaedic care via a
telemedicine network. This study is a descriptive analysis of orthopaedic
teleconsultations done during a 2-year period by three orthopaedic surgeons. Four
hundred ten teleconsultations were done during the study period from February 1,
1995, to December 31, 1996. Orthopaedic surgeons engaged in 91 teleconsultations
(22% of all teleconsultations). Reasons for orthopaedic teleconsultations were:
evaluation and treatment of fracture care (39 cases; 43%); evaluation and
treatment of ligamentous injury, joint swelling and infection (32 cases; 35%);
postoperative evaluation (16 cases; 18%); and evaluation and treatment of
dislocations (four cases; 4%). Sixty-two (68%) of the patients remained in the
rural community. Twenty-one (23%) of the orthopaedic teleconsultations were
classified as emergent (done immediately). Thirty-five (38%) were urgent (done
within 1 to 2 hours of provider request), and 35 (38%) were scheduled. The mean
duration of time for teleconsultations was 12.8 minutes. Eighty-seven (96%) of
the teleconsultations occurred Monday through Friday. Outcome data were collected
on all patients involved in teleconsultations. No adverse patient outcomes
occurred. This study suggests telemedicine may be an avenue for the delivery of
orthopaedic care to patients residing in areas where orthopaedic specialists are
not available.
PMID- 9553558
TI - Tibiofemoral contact pressures in degenerative joint disease.
AB - Using tibiofemoral joints from older (age, 53-80 years) human cadavers with
articular cartilage degeneration, contact pressures and contact areas were
measured in the extended knee in four conditions: (1) neutral alignment; (2) 5
degrees varus (simulating single limb stance of gait); (3) 5 degrees valgus; and
(4) after a 5 degrees proximal tibial closing wedge valgus osteotomy. In
degenerated cartilage, contact pressures were reduced at the lesion sites and
were high on the borders of the lesions. No statistically significant changes
occurred in contact pressures and areas when values from neutral loading were
compared with values during loading in each of the other three conditions.
Lateral average and maximum contact pressures were less in varus loading than in
valgus loading. Equal medial and lateral contact pressures during varus loading,
in contrast to lower medial than lateral contact pressures in the other three
loading, supports the theory that the varus moment imposed on the knee in single
limb stance could be a mechanism causing medial tibiofemoral osteoarthritis. The
5 degrees valgus osteotomy resulted in contact pressures similar to those in
neutral loading. These experiments do not support the value of the 5 degrees
valgus osteotomy in reducing contact pressures on the medial tibial plateau.
PMID- 9553559
TI - Healing of the anterior attachment of the rabbit meniscus to bone.
AB - In a rabbit model the healing process of the anterior attachment of the medical
meniscus was observed during the first 12 weeks after sharp transection and
refixation in a tibial bone channel. Evaluations of the healing tissue were
histologic analysis, application of immunohistochemical methods to show collagen
types and nerve regeneration, and mechanical load to failure tests. Secondary
changes to knee joint cartilage, as signs of eventual dysfunction of the refixed
meniscus, were evaluated by analysis of proteoglycan fragment concentration in
joint fluid and histologic analysis of knee joint articular cartilage and
synovium. The healing tissue between the refixed attachment and bone matured from
highly cellular, nonspecific granulation tissue at 1 week, to bone,
fibrocartilaginous, and fibrous tissues, which at some sites developed an
insertion specific tissue arrangement within a 12-week period. However, the
irregular interface between the fibrocartilaginous tissue and the underlying
bone, which is typical for a normal insertion, was not reestablished. Labeling
for collagen Types I and II in the newly formed insertion did not return to
normal. In addition a few collagen fibers connected the refixed attachment tissue
to bone. New bone formation turned the initially cancellous bone tunnel walls
into more solid cortical bone. However, new bone formation did not fill the
distal part of the channel. The refixed meniscal attachment underwent necrosis
and was revitalized by cell ingrowth from the periphery. Nerve fibers were found
in the newly formed insertion by 12 weeks. The failure load at tensile testing
never reached more than 20% that of a normal attachment. Degeneration of
articular cartilage and increased proteoglycan fragment in the joint fluid were
common after this procedure. These data suggest that, despite the focal
appearance of insertion specific tissues and healing of collagen fibers to bone,
the tissue architecture of a normal meniscal insertion and a normal meniscal
joint protective function were not reestablished.
PMID- 9553560
TI - Osteogenesis of electrically stimulated bone cells mediated in part by calcium
ions.
AB - Culture selected and expanded osteoblastic cells may be able to be reintroduced
into massive skeletal defects to accelerate cell mediated regeneration of
skeletal tissues, especially in bone ingrowth in total joint replacement,
fracture healing, and osteoporosis. In vitro osteogenic cell culture is a useful
model in studying the mechanism of bone metabolism under direct current
stimulation. In this study, an osteoblastlike cell line was isolated from newborn
rat calvaria. The osteogenic processes of the in vitro cultured cell line were
studied by cytochemical, electron microscopic, and energy dispersive x-ray
analysis techniques that resembled those observed in membrane bone ossification
centers in vivo. Direct current stimulation of 100 microA/cm2 accelerated greatly
the proliferation and calcification of the in vitro cultured cells. Intracellular
free calcium ion metabolism was measured with an Adherent Cell Analysis and
Sorting Machine. Under direct current stimulation, intracellular free calcium ion
concentration increased an average of 2.3 times of the original level, which may
play a key role in regulating osteogenesis and bone metabolism.
PMID- 9553561
TI - Biomechanical topography of human articular cartilage in the first
metatarsophalangeal joint.
AB - The objective of this study was to provide a map of cartilage biomechanical
properties, thickness, and histomorphometric characteristics in the human,
cadaveric first metatarsophangeal joint, to determine if normal articular
cartilage was predisposed topographically to biomechanical mismatches in
articulating surfaces. Cartilage intrinsic material properties and thickness were
obtained from seven pairs of human, freshly frozen, cadaveric,
metatarsophalangeal joints using an automated creep indentation apparatus under
conditions of biphasic creep. Eight sites were tested: four on the metatarsal
head, two on the proximal phalanx base, and one on each sesamoid bone to obtain
the aggregate modulus, Poisson's ratio, permeability, shear modulus, and
thickness. Cartilage in the lateral phalanx site of the left metatarsal head had
the largest aggregate modulus (1.34 MPa), whereas the softest tissue was found in
the right medial sesamoid (0.63 MPa). The medial phalanx region of the right
joint was the most permeable (4.56 x 10(-15) meter4/Newton-second), whereas the
medial sesamoid articulation of the metatarsal head of the left joint was the
least permeable (1.26 x 10(-15) meter4/Newton-second). Material properties and
thickness are indicative of the tissue's functional environment. The lack of
mismatches in cartilage biomechanical properties of the articulating surfaces
found in this study may be supportive of clinical observations that early
degenerative changes, in the absence of traumatic events, do not occur at the
selected test sites in the human first metatarsophalangeal joint.
PMID- 9553562
TI - Ankle pain and swelling in a 10-year-old girl.
PMID- 9553563
TI - Pathogenesis of bone loss after total hip arthroplasty.
AB - Bone loss with or without evidence of aseptic loosening is a long term
complication after total hip arthroplasty (THA). It occurs with all materials and
in all prosthetic systems in use or that have been used to date. Bone loss after
THA can be a serious problem in revision surgery because bone deficiencies may
limit reconstructive options, increase the difficulty of surgery, and necessitate
autogenous or allogenic bone grafting. There are three factors adversely
affecting maintenance of bone mass after THA: (1) bone loss secondary to
particulate debris; (2) adaptive bone remodeling and stress shielding secondary
to size, material properties, and surface characteristics of contemporary
prostheses; and (3) bone loss as a consequence of natural aging. This chapter
reviews the mechanisms of the primary causes of bone loss after THA.
PMID- 9553564
TI - The pathogenesis of bone loss following total knee arthroplasty.
AB - Bone loss following total knee arthroplasty (TKA) may be focal or diffuse. It may
be caused mechanically, either by unloading of the bone leading to disuse
osteoporosis, or by overloading of the bone leading to trabecular fractures and
bone destruction. Osteolysis, instigated by an inflammatory reaction to
particulate wear debris, is an important and common cause of bone loss after TKA.
Less common, though sometimes dramatic, causes of bone loss are infection and
osteonecrosis.
PMID- 9553565
TI - Biology of allografting.
AB - Allograft bone continues to play an important role in revision hip and knee
arthroplasty. A basic understanding of allograft biology and immunology is
important in order to increase the success of allografting. Although the
literature has a wealth of knowledge on the subject there are still many
unknowns. The role of immunology in bone transplantation has been known for a
long time, but only recently has it become apparent that the bone remodeling
system and the immunologic system interact to affect the clinical success of bone
transplantation. Neither of these two systems are completely understood nor is
their interaction. Future research in the field of bone transplantation will be
aimed at a better understanding of these systems individually but, more
important, how they interact in humans. Until that time, allografting still can
be used with success if one understands the role of allograft biology,
immunology, and the important role of the host environment in bone
transplantation.
PMID- 9553566
TI - Classification and preoperative radiographic evaluation: knee.
AB - Preoperative radiographic planning for revision total knee arthroplasty begins
with obtaining excellent quality AP and lateral radiographs that permit: 1.
Evaluation of the extent of bone loss in the metaphyseal region of the femur and
tibia. 2. Full visualization of the patient's intramedullary canal for
determining appropriate stem size and length. The surgeon should then determine
the appropriate bone defect classification, keeping in mind the provisions needed
to address Type 2 and 3 defects. These provisions include any augments or
allografts, stemmed components, and the degree of component constraint needed in
the patient's revision surgery. Through preoperative templating, the surgeon can
determine whether a particular implant system provides the options necessary to
achieve an optimal surgical result. Whenever templating leaves unanswered
questions regarding the extent of bone damage or the degree of knee instability,
the surgeon must prepare for the worst case scenario to ensure that the
appropriate components and graft material are made available.
PMID- 9553567
TI - The classification and radiographic evaluation of bone loss in revision hip
arthroplasty.
AB - Many classification systems have been described over the past 10 years for bone
loss that is found in association with the failed hip arthroplasty. Most are
based on assessments of bone stock that are made intraoperatively. Good-quality
plain radiography is the most useful preoperative investigation and provides
important information regarding the residual bone stock. There is a need for
critical appraisal of the validity of classification systems currently in use and
the development of a consensus system that will permit comparison between the
published results of different techniques.
PMID- 9553568
TI - Seven specialized exposures for revision hip and knee replacement.
AB - With the increasing rates and complexity of revision hip and knee arthroplasty,
it has become more important than ever to approach the joint in a safe and
rational manner. The development of extensile approaches have significantly
simplified the removal of solidly fixed components without compromising bone
stock. The extended trochanteric osteotomy enables controlled access to the
femoral component and is a useful technique for revision of solidly-fixed femoral
components. The trochanteric slide allows comprehensive exposure of the
acetabulum and femur comparable to trochanteric osteotomy with a diminished risk
of trochanteric escape. The vastus slide allows wide exposure of the femoral
shaft when using an anterolateral approach. In revision total knee arthroplasty,
the extensor mechanism is often at risk of disruption or avulsion, and in most
cases, maneuvers that allow wide exposure of the femur and tibia while preserving
the extensor mechanism are essential. Such exposures include one of the extensor
mechanism reflecting techniques either proximally by rectus snip or patellar
turndown, or distally by tibial tubercle osteotomy. Occasionally a femoral peel
or epicondylar osteotomy is required. There should be a low threshold to consider
one of these specialized approaches during revision hip and knee arthroplasty.
PMID- 9553569
TI - Role and results of the high hip center.
AB - Anatomic placement of the acetabular component should be the surgeon's goal at
the time of revision THA. However, Acetabular loosening with subsequent implant
migration, progressive superior acetabular bone destruction or severe pelvic
osteolysis, may prevent the surgeon from obtaining adequate host bone-implant
contact needed for a successful reconstruction while maintaining a normal hip
center. The high hip center offers a technique for reconstruction of an
acetabulum with severe bony deficiency and where the majority of the remaining
host bone is superior to the anatomic hip centre.
PMID- 9553570
TI - Jumbo cups and morsalized graft.
AB - Revision of failed acetabular components presents a formidable problem due to
associated loss of bone and sclerosis of the remaining bone. Uncemented
acetabular components with porous surfaces have revolutionized acetabular
revision surgery. They can be stabilized into the existing host bone with
supplemental screws even in the face of major bone loss. Nonstructural
particulate bone grafts can then be used to supplement the bone stock. With large
defects, jumbo acetabular components ranging in sizes from 70 to 80 millimeter
outer diameters can be stabilized on the acetabular rim while the defects can be
grafted with morsalized bone. Nineteen of such revisions performed for major bone
loss without pelvic discontinuity between February 1986 and December 1988 were
evaluated at a mean follow-up period of ten years (range eight to eleven years).
One component had been revised for sepsis. None of the others had been revised.
Definite radiographic failure of fixation of the acetabular component was not
seen on any of the other hips. These results strongly support the use of jumbo
uncemented acetabular components with morsalized bone grafts even in the face of
major acetabular bone loss.
PMID- 9553571
TI - Reconstruction rings and bone graft in total hip revision surgery.
AB - This article deals with the design and indications of use of reconstruction rings
and cages plus bone graft for acetabular revision. Details of the technique and
the available results are presented and the advantages and disadvantages of
current designs are discussed.
PMID- 9553572
TI - Role and results of segmental allografts for acetabular segmental bone
deficiency.
AB - Acetabular reconstruction in both primary and revision hip arthroplasty often
requires reconstruction of deficient acetabular bone stock. The exact role of
allografts remains controversial. Published results of structural allografting
are presented. Recent literature supports the use of segmental allografts for
reconstruction of large segmental and combined defects.
PMID- 9553573
TI - Modified cups.
AB - Late results of structural allografting of the acetabulum are quite variable. In
order to reduce or avoid the necessity for bone grafting, some modified cups have
been developed. The deep cup with or without a lateralized polyethylene liner
reduces the problem of the protrusio socket. Oblong or bilobed ingrowth cups
significantly reduce the need for grafting of the roof-deficient acetabulum.
Constrained or capture polyethylene liners are useful in the unstable hip.
PMID- 9553574
TI - Impaction allografting with cement for the management of femoral bone loss.
AB - Impaction allografting with cement is the only technique currently available
which reverses the diminution of bone stock that occurs in a revision hip
arthroplasty, and as such, has great potential. It is particularly appropriate in
the younger patient, though older patients may also benefit from the technique.
Although the short term results are encouraging, there is a need for further
basic science research to determine the optimal graft material and prosthesis
design. Refinements in surgical instrumentation and technique will continue to
improve the predictability of the clinical result and expand the indications for
this important addition to the available options in revision hip arthroplasty.
PMID- 9553575
TI - Onlay cortical allografting for the femur.
AB - Failed femoral total hip replacement components are frequently associated with
bone loss. At the time of revision surgery, the goals are to create a construct
that relieves pain, is stable, and preserves and enhances bone stock. This
article discusses Materials and Methods, Indications, Operative Technique, and
Results regarding onlay cortical allografting for the femur.
PMID- 9553576
TI - Proximal femoral allografts for reconstruction of bone stock in revision
arthroplasty of the hip.
AB - Full circumferential bone loss of the proximal femur can be managed by segmental
allografts. The use of these grafts is indicated for uncontained defects longer
than five cm in length. The femoral implant is cemented into the allograft but
not into the host. The allograft host junction is stabilized by a step cut or
oblique osteotomy and autografted with residual host femur. The results at five
and nine years support this kind of reconstruction as a good alternative for this
difficult problem.
PMID- 9553578
TI - Principles of revision total knee arthroplasty.
AB - Revision total knee replacement is a demanding surgical exercise that requires
close adherence to a number of guiding principles if clinical results are to be
maximized and complications avoided. To achieve consistently good results in
revision total knee replacement, considerable emphasis has to be placed on
preoperative planning, surgical exposure, dealing with bone defects, and
selecting a proper revision implant.
PMID- 9553577
TI - Bypass fixation.
AB - Hip replacement has been a great achievement of orthopaedic surgery as it
reliably abolishes pain and restores function. The success of this operation has
lead to its use not only in the elderly, but increasingly, in the higher demand
that younger patients whose life expectancy is longer than the longevity of the
prostheses used to date. Thus, we are seeing a growing number of patients who
require a first or even repeat revision surgery, which is often complex and
technically demanding.
PMID- 9553579
TI - The role and results of bone grafting in revision total knee replacement.
AB - Failure in total knee replacement requiring revision surgery is often accompanied
by significant bone loss and soft tissue asymmetry. When embarking on these
complex reconstructions, careful preoperative planning is necessary to ensure
that these deficiencies will be corrected by surgical technique and implant
selection. This article discusses various techniques and results of bone grafting
in revision total knee arthroplasty.
PMID- 9553580
TI - Modular augments in revision total knee arthroplasty.
AB - Modularity in total knee arthroplasty is extremely helpful in the management of
patients with complex primary and revision total knee arthroplasties. Modularity
allows selective augmentation to deal with bone deficiencies on the distal and
posterior femur. The ability to selectively augment the femur is very helpful in
balancing the soft tissues and providing stability. Selective augmentation of the
femur allows restoration of the joint line and more normal patellar and
collateral ligament kinematics. Selective modular augments on the tibia allow
dealing with bone deficiency without the concerns of bone graft incorporation.
Modular extended intramedullary stems allow the option of either press-fit or
cement fixation of the stem, entailing the stem diameter length to the given
patient.
PMID- 9553581
TI - Management of the patella during revision total knee replacement arthroplasty.
AB - Managing the patella and balancing the patellofemoral joint space is one of the
most difficult aspects of performing a primary total knee replacement (TKR). The
situation is compounded in the revision situation. Unfortunately, an otherwise
well-performed TKR will fail because of problems with the patella or the extensor
mechanism. This article discusses various aspects of the management of the
patella and extensor mechanism during revision TKR with an objective of
minimizing complications and maximizing functional outcomes. The topics covered
include exposure of the patella and extensor mechanism during revision surgery,
whether or not to remove all prior patellar implants, the technique for removal
of a prior implant, the management of bone loss or fractures of the patella
during revision TKR, the insertion (or noninsertion) and fixation of a new
implant, and the balance of the patellofemoral joint space, including avoidance
of patella baja or patella alta. A compilation of scientific and "no-so"
scientific data and experience gleaned over the past 26 years of total knee
replacement surgery will be presented.
PMID- 9553583
TI - Medicine following the HCFA 'guidelines'.
PMID- 9553582
TI - Results of revision total knee arthroplasty in the face of significant bone
deficiency.
AB - The successful approach to the failed knee with bone deficiency is dependent upon
thorough planning prior to surgery in order to have the resources available in
terms of adequate bone allograft and suitable revision implants. The approximate
size of bone stock deficiency can be calculated from preoperative radiographs and
similarly ligamentous incompetence can often be diagnosed clinically prior to
surgery. Smaller defects of up to 1 to 1.5 cm in depth and localized in the main
to a single side of the tibial plateau or to a single femoral condyle can be
dealt with using smaller grafts that may be local autograft or allograft, or
modular wedges. Larger tibial defects can be compensated for using conventional
revision systems by thicker polyethylene and augmented baseplates, but once the
flexion-extension gap reaches approximately 40 mm this is no longer possible and
structural graft or customized componentry becomes necessary. Femoral defects
larger than about 1 cm that cannot be made up by augments necessitate grafting.
The need to use a large proximal tibial allograft also may dictate the operative
approach used to expose the joint, especially in the situation of a multiply
operated tight knee. In such cases the use of a quadriceps turndown may be more
advisable than the use of a tibial tubercle osteotomy as the osteotomy may well
not have an adequate bed to heal to following the reconstruction. Several series
have reported cases of patellar tendon avulsion and the clinical results
following this complication usually are not satisfactory. Preoperatively it is
important to identify, if possible, the case that is likely to require a more
extended approach because of a tight soft tissue envelope. The reports of results
of series of revision total knee arthroplasty in the setting of significant bone
loss are at present confined to short-term followup. The clinical results of
these series are satisfactory at this early point in time, but decision regarding
the durability of reconstructions requiring major structural allografting awaits
longer-term study. Of concern is the devastating complication of infection
following such revision surgery, the risk of which is amplified in the setting of
prior infection. In addition, the long-term viability of major structural grafts
in the setting of loading is uncertain as the risk of graft collapse in the
process of incorporation is not known. Notwithstanding these concerns, major
grafting is sometimes the only recourse to achieve satisfactory revision of a
failed arthroplasty. The use of such major grafts is therefore cautiously
supported and because of the risks inherent in such surgery we believe that such
surgery should be carried out in the setting of specialist interest units.
PMID- 9553584
TI - Cardiac arrhythmias set to music.
PMID- 9553585
TI - Which antibiotics for acute sinusitis?
PMID- 9553586
TI - What can I do for you today?
PMID- 9553587
TI - Detecting osteoporosis. Beyond the history and physical examination.
AB - A number of developments are contributing to clinicians' understanding of
osteoporosis as a clinical continuum characterized by low bone mass and increased
risk of fractures rather than as a disease characterized by fragility fractures.
With improved capability for accurate measurement of bone mass, the prevalence of
this disease has increased to include at least 25 million Americans. The
responsibility of primary care physicians to detect and treat osteoporosis has
increased accordingly. Parents should be counseled regarding their children's
diet and lifestyle to optimize peak adult bone mass and ensure adequate dietary
calcium intake. Adults should be counseled to minimize behaviors that result in
accelerated bone loss (e.g., smoking, alcohol use, anorexia, bulimia). Physicians
need to be aware of the serious potential complications of osteoporosis and offer
counseling to menopausal women about the disease and the benefits and risks of
hormone replacement and estrogen replacement therapy. Physicians should be
familiar with technologies available in their community for measuring bone mass
and recognize the need to consider prescribing pharmacologic and nonpharmacologic
therapies for patients with low bone mass or osteoporosis. Physicians also can
educate caregivers about prevention of falls and fractures in elderly patients
who are unsteady on their feet. Improved technologies for bone mass measurement
and fracture risk assessment, as well as expanded options for treatment and
prevention of osteoporosis, are likely to become available within the next 5 to
10 years, thereby increasing the wisdom of early detection and treatment of
osteoporosis.
PMID- 9553588
TI - Conservative management of lumbar spinal stenosis. Identifying patients likely to
do well without surgery.
AB - Lumbar spinal stenosis is a painful condition that often leads to irreversible
neurologic damage and functional disability. Thus, early diagnosis and management
are important. Conservative therapy, which is appropriate for many patients,
minimizes invasive intervention and decreases the risks of morbidity. As more
people live to older ages, the incidence of lumbar spinal stenosis will likely
increase. If results of a thorough history and physical examination suggest the
disorder, a course of appropriate physical therapy should be started promptly;
more expensive tests and treatments are reserved for patients whose pain is
refractory to early conservative intervention. However, if pain is severe, if the
origin is not clear, or if neurologic deficits quickly become worse, immediate
neuroradiologic studies should be considered, including timely EMG. Strong
guidance by the primary care physician is of paramount importance because the
therapeutic program is lengthy. Additional help from a physiatrist, neurologist,
or orthopedic surgeon may be indicated as treatment progresses.
PMID- 9553589
TI - Juvenile psoriasis. Early interventions can reduce risks for problems later.
AB - Psoriasis is a lifelong disease with genetic, systemic, and environmental roots
and an unpredictable course. In more than one third of patients, onset is in the
first two decades of life. Primary care physicians are in a unique position to
help these young patients by providing early treatment and education.
PMID- 9553590
TI - The blurred vision mystery. Idiopathic intracranial hypertension.
PMID- 9553592
TI - Management of COPD. Early identification and active intervention are crucial.
AB - Medical management of COPD begins with an awareness of risk factors and
identification of at-risk patients. Once disease is identified, patient and
family education, a smoking cessation program, and an appropriate bronchodilator
regimen should be initiated. Airway secretions and infections should be
minimized, hypoxemia corrected, and other secondary physiologic disturbances
evaluated when appropriate. Participation in a comprehensive pulmonary
rehabilitation program can markedly improve symptoms, function, exercise
performance, and quality of life. The results are a reduction in patient
limitations, medical expenses, and dependence on medical facilities and
caregivers.
PMID- 9553591
TI - Diagnosing chronic obstructive pulmonary disease. The importance of
differentiating asthma, emphysema, and chronic bronchitis.
AB - In patients with chronic obstructive pulmonary disease (COPD), a thorough
understanding on the clinician's part of the pathophysiologic basis of airflow
limitation greatly enhances decisions regarding care. Differences in prognosis
among the major types of COPD have become clear, and identification of airway
inflammation has dramatically altered medical therapy. Dr Martinez, who
coordinated this symposium, here explains the importance of judiciously applying
findings from history taking, physical examination, laboratory studies
(particularly pulmonary function testing), and radiographic studies to all
aspects of disease management. The remaining four symposium articles address
specific avenues for treatment of emphysema and chronic bronchitis.
PMID- 9553593
TI - Long-term oxygen therapy for COPD. Improving longevity and quality of life in
hypoxemic patients.
AB - Long-term oxygen therapy can increase life expectancy in hypoxemic patients with
COPD. Accurate identification of hypoxemia requires arterial blood gas
measurements. Pulse oximetry can be used to measure trends in oxygenation, oxygen
needs, and oxygen requirements during exercise and sleep. A detailed oxygen
prescription indicates: (1) the oxygen dose (L/min), (2) the number of hours per
day that oxygen therapy is required, (3) the dose required during exercise, (4)
the oxygen supply system: concentrator, compressed gas cylinder, or liquid oxygen
reservoir, and (5) the delivery device: nasal cannula, demand-flow device,
reservoir cannula, or transtracheal oxygen catheter.
PMID- 9553594
TI - Pulmonary rehabilitation for COPD. A practical approach for improving ventilatory
conditioning.
AB - Pulmonary rehabilitation has gradually become the "gold standard" for patients
with severe lung disease, especially chronic obstructive pulmonary disease
(COPD). Because some newer therapeutic strategies, such as lung volume reduction
surgery and lung transplantation, require well-conditioned patients, pulmonary
rehabilitation is now considered essential for many patients formerly deemed
untreatable. In this article, Dr Celli reviews the basic goals, components, and
benefits of pulmonary rehabilitation for COPD and other chronic respiratory
diseases.
PMID- 9553595
TI - Surgery for severe COPD. Lung volume reduction and lung transplantation.
AB - A management strategy for patients with severe emphysema is shown in figure 2 on
page 199. Although the reported physiologic improvements after LVRS are
significantly less than those seen after lung transplantation, LVRS has the
potential to improve functional performance in a larger number of patients
because of wider availability. Moreover, it accomplishes these goals without the
attendant risks associated with transplantation and immunosuppression. The
efficacy of LVRS over standard medical therapy in influencing survival and
favorably affecting physiologic variables at rest and during exercise remains to
be elucidated in NETT. Lung transplantation should be reserved for those patients
deemed unsuitable or too ill for LVRS. It is to be hoped that future developments
in organ preservation techniques and immunosuppressive regimens will expand the
donor pool and decrease the incidence of posttransplantation bronchiolitis.
PMID- 9553596
TI - Evaluation of bleeding disorders. A detailed history and laboratory tests provide
clues.
AB - A single, optimal screening laboratory test for hemostasis would evaluate
vascular, platelet, coagulation, and fibrinolytic functions. Unfortunately, such
a test does not exist. The key factor in determining the presence of a bleeding
diathesis is obtaining a detailed patient history. Results of coagulation tests
should always be interpreted in the context of such a history. Screening tests
include platelet count, PTT, and PT. Subsequent investigations depend on the
results of these tests.
PMID- 9553597
TI - Intravenous thrombolytic therapy for acute ischemic stroke. Weighing the risks
and benefits of tissue plasminogen activator.
AB - The use of intravenous tPA within 3 hours after acute ischemic stroke has been
proved to increase the number of good outcomes. However, tPA is a toxic therapy
that carries a substantial risk of intracerebral hemorrhage. To decrease the
risk, tPA use must be restricted to a carefully selected patient population.
Treatment must be administered in an intensive care setting and directed by
physicians with expertise in diagnosing and managing stroke.
PMID- 9553598
TI - When to worry about spider bites. Inaccurate diagnosis can have serious, even
fatal, consequences.
AB - Almost all species of spiders are capable of biting people, but the bites of only
a few are medically significant. Physicians need to be able to recognize the
clinical signs and symptoms of common venomous spider bites and administer
appropriate therapy. This may be difficult, since the offending spider is rarely
seen or recovered for identification. Knowledge of life cycles, habits, and
toxicity of venomous spiders enables physicians to provide more comprehensive
medical care of bite victims. It is hoped that study of immunologic mechanisms
and inflammation mediators will lead to the development of new treatments.
PMID- 9553599
TI - Hereditary angioedema. Complex symptoms can make diagnosis difficult.
AB - Although rare, hereditary angioedema is a potentially life-threatening disorder
that can be difficult to diagnose. It is characterized by a deficiency in C1
esterase inhibitor (C1 INH). Manifestations include gastrointestinal,
subcutaneous, and respiratory edema. Factors that trigger episodes vary. Symptoms
typically last 48 to 72 hours, but they can last 4 hours to 1 week. Treatment
includes prophylactic therapy with attenuated androgens or antifibrinolytic
agents. Acute episodes can be medical emergencies, and airway management is a
major concern. The treatment of choice in an acute episode is administration of
plasma concentrate of C1 INH.
PMID- 9553600
TI - Alcoholic liver disease. Treatment strategies for the potentially reversible
stages.
AB - Even modest alcohol ingestion can increase the risk of steatosis, and long-term,
excessive consumption can lead to alcoholic hepatitis and eventually cirrhosis.
Most patients with clinically significant alcoholic liver disease have histologic
findings typical of all three conditions. The only clearly beneficial treatment
is abstinence from alcohol. Abstinence in combination with proper nutrition and
general supportive care is state of the art. Steatosis is reversible upon
withdrawal of alcohol, but alcoholic hepatitis can persist even with abstinence
and may progress to cirrhosis. Corticosteroid therapy may reduce short-term
mortality rates in patients with moderate or severe alcoholic hepatitis who have
hepatic encephalopathy but no evidence of infection or gastrointestinal bleeding.
Treatment with colchicine may decrease the risk of cirrhosis; however, once
cirrhosis has developed, the liver damage is irreversible. The prognosis is
improved with abstinence, but complications (e.g., ascites, gastrointestinal
bleeding) often occur. Liver transplantation may be considered in patients with
severe complications.
PMID- 9553601
TI - Identifying and treating urinary incontinence. The crucial role of the primary
care physician.
AB - Urinary incontinence is a widespread problem that often goes undiagnosed and
untreated. Many patients are unwilling to discuss it with their physician because
of embarrassment or the belief that nothing can be done. Consequently, physicians
need to routinely inquire about symptoms so incontinent patients can be
identified. Physicians should reassure patients that urinary incontinence is
usually a symptom of a correctable problem. Careful evaluation and office tests
to determine the type and cause of urinary incontinence, together with
appropriate treatment, often lead to improvement in symptoms or return to
continence.
PMID- 9553602
TI - Cumulative indexes for volumes 230-241.
PMID- 9553603
TI - Alcohol and health.
PMID- 9553604
TI - Natural progesterone.
PMID- 9553605
TI - Wasting away: cancer cachexia.
PMID- 9553606
TI - Echocardiography stress tests.
PMID- 9553607
TI - Caution for new diet drug.
PMID- 9553609
TI - Minimizing migraines.
PMID- 9553608
TI - Genetic testing and Alzheimer's disease.
PMID- 9553610
TI - Drug therapy for prostate problems.
PMID- 9553611
TI - Narcolepsy.
PMID- 9553613
TI - More resistant bugs?
PMID- 9553612
TI - When to treat thyroid nodules.
PMID- 9553614
TI - Sunscreen & cancer.
PMID- 9553615
TI - On the biomechanical properties of the cornea with particular reference to
refractive surgery.
PMID- 9553616
TI - Therapeutic management of hematological malignancies in elderly patients.
Biological and clinical considerations. Part III: The chronic leukemias and
myelofibrosis.
AB - The different therapeutic options available for the treatment of chronic
leukemias and myelofibrosis are discussed. In reference to chronic myeloid
leukemia (CML), the choice of the most appropriate treatment must take into
account not only the clinical condition but also the age of the patient. While
subjects under 50 might benefit from the options offered by alpha-interferon,
bone marrow and peripheral stem cell transplant, in older age groups treatment of
the chronic phase must still rely on standard treatment. Chronic lymphocytic
leukemia (CLL) and its variants is a disease of mostly middle and late life, with
a variable clinical course. Patients show wide differences in morbidity and
mortality. Many features have been shown to influence the prognosis, and the most
important ones are incorporated into the staging systems currently in use. The
results obtained from the study of large trials support the concept that
treatment of patients with stable stage A CLL should be postponed until
progression of disease. Treatment relies principally on alkylating agents,
corticosteroids and radiation therapy; the new nucleoside analogues, such as
fludarabine and 2-chlorodeoxyadenosine, have recently acquired established value
in improving overall survival. With regard to myelofibrosis, the histological and
biological features that influence the natural course of the disease are
described, as well as the choice of the most appropriate treatment, which ranges
from the use of alkylating agents and androgens, to splenectomy and splenic
irradiation.
PMID- 9553618
TI - Age- and menopause-related changes in speed of sound and ultrasound attenuation
of the os calcis in a healthy Italian female population.
AB - This study assessed changes in ultrasonometric variables of bone (speed of sound,
broadband ultrasound attenuation and stiffness) related to age and years since
menopause in a normal Italian female population. Two hundred and thirty-one
healthy female subjects, age range 18-78 years, divided into two groups (113 pre
menopausal, age range 18-51 years, and 118 post-menopausal, age range 46-78
years), were investigated. The results obtained show that there was a linear
decrease in speed of sound, broadband ultrasound attenuation and stiffness with
age; a similar pattern was also observed in post-menopausal women as far as the
correlations between ultrasonometric variables and both age and years since
menopause were concerned. In particular, speed of sound declined at a rate of
0.86 m/s for each year post-menopause, while broadband ultrasound attenuation
declined at 0.4 dB/MHz, and stiffness at 0.5 units. These findings suggest that
ultrasound variables might be able to detect characteristics of bone that are
barely influenced by estrogen deficiency, and depend on other factors. Therefore,
ultrasound measurement should be considered as a possible alternative to x-ray
densitometry for the assessment of the skeleton.
PMID- 9553617
TI - Alterations in beta-adrenoceptor mechanisms in the aging heart. Relationship with
heart failure.
AB - In chronic heart failure substantial and characteristic changes occur in the
function of the adrenergic nervous system. Studies in isolated left ventricular
muscle and in single cardiomyocytes from experimental models of aging and,
recently, from humans show an age-related reduced contractile response to beta
adrenoceptor stimulation. "beta-adrenoceptor desensitization" is thought to be a
general and common mechanism to explain the age- and heart failure-related
decrease in beta-adrenoceptor response. The aim of this review is to compare
alterations in beta-adrenoceptor mechanisms in physiological cardiovascular aging
and chronic heart failure. From an analysis of the overall data on the role of
aging in beta-adrenoceptor regulation in human and animal hearts, it is possible
to conclude that the reduced response to beta-agonists is common to all species
and all cardiac tissues. Moreover, the age-related changes are limited to beta
adrenoceptor-G-protein (s)-adenylyl cyclase system abnormalities, while the type
and level of abnormalities change with species and tissues. The modifications
shown in the aging heart are not very different from some observed in heart
failure. In particular, both in aged and failing hearts we may see that the
decrease in beta-adrenoceptor responsiveness is related to changes in G-protein
function.
PMID- 9553619
TI - Autonomic nervous activity in elderly dipper and non-dipper patients with
essential hypertension.
AB - The pathogenetic mechanisms of the blunted nocturnal fall in blood pressure,
frequently observed in elderly patients with essential hypertension, are unclear.
The aim of this study was to evaluate the autonomic nervous system in elderly
dipper and non-dipper hypertensive subjects. The study group consisted of twelve
non-dipper and twelve dipper hypertensive patients (mean age 77.7 and 73.8 years,
respectively). Non-dippers were defined as subjects whose nocturnal fall in
systolic blood pressure (SBP), evaluated by means of Ambulatory Blood Pressure
Monitoring, was less than 10% of diurnal SBP. All the patients underwent the
following cardiovascular tests to explore autonomic function: Tilt Table,
Valsalva Maneuver, Deep Breathing, Cough. The tests were performed under standard
conditions, and heart rate and blood pressure were continuously recorded.
Valsalva ratio (VR), Expiration/Inspiration Ratio (E/IR) and Cough Test Ratio
(CTR) were calculated. Mann Whitney's and chi 2 tests were used for comparison
between groups. Relationships were assessed by univariate and multivariate
analyses. Non-dipper hypertensive subjects showed significantly lower scores in
VR (11.1 +/- 0.08 vs 1.28 +/- 0.14), E/IR (1.11 +/- 0.07 vs 1.21 +/- 0.10), and
CTR (1.07 +/- 0.02 vs 1.15 +/- 0.07). During the tilt test, a significant
decrease in SBP and a late increase in heart rate were observed in non-dippers.
The day-night difference in SBP was significantly related to VR, CTR and maximal
SBP drop during tilting. The findings confirm that non-dippers show an impairment
in autonomic nervous drive, which is characterized mainly by decreased
parasympathetic activity. These observations may explain the increase in
cardiovascular risk in non-dippers.
PMID- 9553620
TI - The relationship between premorbid life-style and wandering behaviors in
institutionalized people with dementia.
AB - Forty-nine ambulatory residents participated in a study conducted to determine
the relationship between premorbid life-style, work, and ways of handling stress,
and wandering in dementia units. The sample consisted of 23 males and 26 females
with a mean age of 79. Family members responded to open-ended questionnaires that
asked about premorbid leisure activities, hobbies, exercise, stress management,
type of employment and social interactions. Activities were ranked according to
energy expended on the Metabolic Cost of Activities (MET) Scale. No activity
equaled Inactive (0); 1.5-2 METS equaled Mildly Active (1), 2-3 METS equaled
Moderately Active (2), and 3-4 METS equaled Very Active (3). Subjects were
observed three times for one-hour intervals on each of three shifts (day,
evening, night) at randomly selected times to assess wandering behavior. Behavior
was logged every five minutes. The subjects' most frequent conditions were awake
(21%), alone (20%), and in their own rooms (17%). Twenty-four (50%) of the
subjects were observed pacing, and 16 (33%) were agitated/restless at some point
in time. Statistical analyses showed no significant correlations between
premorbid life-style variable rankings and the amount of time spent standing,
walking and pacing. The findings suggest that wandering behavior is not
influenced by premorbid life-styles.
PMID- 9553621
TI - Effects of age and food restriction on calcium signaling in parotid acinar cells
of Fischer 344 rats.
AB - In this study, we characterized alpha-adrenergic (alpha AR) and muscarinic
induced [Ca2+]i changes in individual parotid acinar cells from male Fischer 344
rats (6-24 month-old) fed ad libitum (AL) or 60% ad libitum intake (FR). Cells
were prepared by collagenase/hyaluronidase digestion. [Ca2+]i was measured by
video image, fluorescent microscopy in single acinar cells loaded with FURA2.
Neither age nor food restriction altered the peak [Ca2+]i achieved in response to
carbachol (100 microM). Similar results were obtained for epinephrine (Epi = 100
microM) stimulation in 6- and 12-month-old animals. However, the peak [Ca2+]i
response to Epi declined between 12 and 18 months in both dietary groups (e.g.,
AL: 12 months = 387 +/- 21 nM, 18 months = 253 +/- 10 nM; FR: 12 months = 430 +/-
22 nM, 18 months = 325 +/- 14 nM). The decline in response to Epi seen with age
was less in FR than in AL animals at 18 months, but not at 24 months. In
addition, db cAMP reduced the carbachol-stimulated [Ca2+]i response to levels
comparable to those observed with epinephrine. The results support the view that
calcium mobilization in parotid acinar cells from male Fischer 344 rats in
response to alpha AR, but not to muscarinic, stimulation is impaired with age.
Food restriction may slow down, but does not prevent, the functional decline.
Furthermore, cAMP appears to modulate the muscarinic response.
PMID- 9553622
TI - Theories of aging: a pathophysiological perspective.
PMID- 9553623
TI - Genetic theories on aging.
PMID- 9553624
TI - Molecular, cellular and genetic determinants of aging.
PMID- 9553625
TI - Intensive insulin treatment reduces the accumulation of oxidation and glycation
end-products in diabetic rat collagen.
PMID- 9553626
TI - Accumulation of dolichol and impaired signal transduction in aging.
PMID- 9553627
TI - From the kinetics of dying to the processes of aging.
PMID- 9553628
TI - Aging: current concepts.
PMID- 9553629
TI - Genetic mechanisms in aging and cancer.
PMID- 9553630
TI - Design and analysis of aging studies.
PMID- 9553631
TI - Animal models of aging.
PMID- 9553632
TI - Cell culture as a model for gerontological research.
PMID- 9553633
TI - Human studies: the longitudinal approach.
PMID- 9553634
TI - Geriatric pharmacology.
PMID- 9553635
TI - Grant application process in USA.
PMID- 9553636
TI - Transference and countertransference interpretations: harmful or helpful in short
term dynamic therapy?
AB - Finding effective and economical interventions in brief therapy has become a
challenge for therapists of all orientations needing to make noticeable progress
within a short period and to achieve positive, measurable outcomes. In this paper
three theoretical positions and the empirical data purporting to support them
were examined: (1) not using either transference or countertransference
interpretations; (2) using transference but not countertransference
interpretations; and (3) relying heavily on both kinds of interpretations. Though
limited research prevents firm conclusions, findings support infrequent, careful,
and cautious usage of transference and countertransference interpretations,
including crafting them to meet specific patient characteristics and reflect
presenting problems. If appropriately used, both interpretations can affect
outcome by contributing to alliance building, perseverance in therapy, and goal
attainment. If inappropriately used, however, both interpretations can cause
harm, even premature termination. Finally, research findings do not support the
theoretical position that positive outcome depends on transference and
countertransference interpretations.
PMID- 9553637
TI - Self-mutilation, substance abuse, and the psychoanalytic approach: four cases.
AB - While self-injury and substance abuse are difficult symptoms for both analyst and
patient to cope with, and relapses are frequent, the emphasis does not have to be
on managing crisis. The initial ego support and therapeutic boundary setting in
these difficult cases must be matched by psychoanalytic exploration. In working
with these patients, I find that, through mutual projective identification
processes, the analyst and the patient are frequently resurrecting certain
aspects of the patient's archaic phantasy life as defined by various self and
object representations. Therefore, the continuous analysis of the transference
and the countertransference is certainly essential. However, the additional
willingness on the part of the analyst and the patient to explore the frequent
and mutual interpersonal/intrapsychic acting out is paramount.
PMID- 9553638
TI - The evangelical Christian in psychotherapy.
AB - The history of the evangelical attitudes to therapy is complex. Several of the
historical roots to a general suspicion of psychological perceptive are explored.
Freudian psychoanalysis and fundamentalism were not compatible and for decades no
attempt at rapprochement developed. The liberal wing of Christianity made early
attempts with the religion/psychiatry dialogue of the 1960s. Drastic changes in
the youth of the evangelical, especially on the college campus in the 1960s,
broke through some of the resistance. A growing disillusionment on the part of
the evangelical in the pew concerning the efficacy of the traditional spiritual
approach to relational and emotional problems accompanied these changes. The
literalism and rigidity of a paranoid stance toward psychological insights has
given way to a kind of chaos. The evangelical person seeks outside the church
too. There is no consensus theoretically or practically among the many from
within the church who are therapists. There are many strengths in the
evangelical. These include family and developmental emphases in psychotherapy.
The effective therapist will comfortably explore the religious life of the
evangelical as it is relevant to the therapeutic task. Acceptance and elimination
of countertransferential bias will foster the honesty and mutual respect that are
essential for positive outcomes in therapy.
PMID- 9553639
TI - Engaging in psychotherapy with the Orthodox Jew: a critical review.
AB - A critical overview of the current knowledge of engaging in psychotherapy with a
cultural minority, Orthodox Jews, is provided. The various forms of psychotherapy
that have been utilized to engage Orthodox Jews in meaningful psychotherapeutic
encounters are discussed. Psychodynamic, cognitive, behavioral, couple, family,
and group therapies have all been employed with success. The first key in working
with cultural minorities, including Orthodox Jews, is patience. Patience is
required to allow a therapeutic alliance to develop in which the therapist, the
outsider, can be trusted. When patients are reluctant to accept the treatment
proposed, patience is necessary to give them the time required to verify the
treatment with someone they trust, often their rabbi in the case of the Orthodox
Jew. Patience is also valuable when patients request a change in the frame of
therapy, such as the use of a chaperon or leaving the door slightly ajar if being
treated by a member of the opposite sex. The second key in working with this or
any other cultural minority is flexibility. Flexibility is required, to chose
treatment modalities that best fit with the patient's beliefs, to respect the
patient's beliefs no matter the extent they deviate from the therapist's own, and
finally, to be critical of oneself when examining transference and
countertransference reactions.
PMID- 9553640
TI - Contemporary ethical dilemmas in psychotherapy: cosmetic psychopharmacology and
managed care.
AB - Two contemporary ethical dilemmas facing psychotherapists have been noted and
described: cosmetic psychopharmacology and the practice of psychotherapy in a
managed care environment. Regarding cosmetic psychopharmacology: It was noted
that whether a psychotherapist endorses the use of psychotropic agents for
cosmetic purposes, such as self-transformation, seems to be a function of the
severity of the client/patient symptoms as well as the psychotherapist's view of
human nature and the human condition. However, recent research indicates that
certain traits or reflections of the human condition, such as irritability, may
actually be neurotransmitter deficiencies that are responsive not only to
psychotropic agents but also to non-drug interventions. These findings add an
additional dimension to discussions of the ethics of cosmetic psychopharmacology.
Regarding psychotherapy in a managed care environment: Several ethical dilemmas,
including confidentiality, were discussed. These dilemmas were outlined rather
than analyzed in detail. Some of them will become major "thorns" of concern for
the practice of psychotherapy. Others will be less consequential. Of critical
concern is that limitations by managed care on the technique and optimal length
of treatment of psychotherapy can conceivably lessen its efficacy for some
patients and could possibly eliminate this powerful treatment procedure for
others.
PMID- 9553641
TI - Psychoanalytic psychotherapy with traumatized refugees: integration,
symbolization, and mourning.
AB - The author takes as a point of departure that severe trauma, such as torture, is
"unresolved" because it is not symbolized and is thus dissociated or existing as
warded-off parts of the personality. Depending on the severity and character of
the trauma, the depth of the regression experienced, and the age and life
circumstances of the patient at the moment of trauma, this can have more or less
severe impact on the personality structure. The consequences may at worst be
fragmentation and total lack of trust in others. In psychotherapy these patients
often fear retraumatization when narrating and working through their traumatic
experiences. This pinpoints the paradoxical nature of psychotherapy, where
painful aspects of the healing process are brought into focus. The totality of
the psychotherapeutic situation must then explicitly be taken into consideration.
The author discusses how different aspects of this address different aspects of
the psychopathology of the patient. Clinical vignettes illustrate some salient
points.
PMID- 9553642
TI - Therapeutic approaches to problems of meaninglessness.
AB - Paradigmatically, meaningful action, and by extension meaningful living, inhere
in immersed participation in activities from which one derives substantial
instrumental, intrinsic, and/or spiritual value. The greater the departure from
this paradigm (the existentialist's "absurd" being the extreme case), the more
meaningless will one's existence seem. Employing this paradigm case as a point of
departure, the job of the psychotherapist becomes that of (a) diagnosing
obstacles to clients securing such value in their behavior, and (b) assisting
them in the removal or diminution of these obstacles. The empirically most common
of these obstacles, as well as some therapeutic approaches to addressing them,
have been discussed in this article.
PMID- 9553644
TI - To a beginning psychotherapist: how to conduct individual psychotherapy.
AB - The paper presents a realistic orientation to the practice of primarily insight
psychotherapy. The principles, basic assumptions, and practical considerations
are nevertheless applicable to all serious psychotherapy. Therapy is here
understood not as a science or a matter of technique but as a collaborative and
uniquely personal exploration of the patient's difficulties in living.
Psychotherapy is thus seen as a search for meaning rather than for cure, with the
hope that knowing what they are doing with their lives will enhance the ability
of patients to live with more effectiveness and fulfillment. The limitations of
therapy and therapists are fully recognized. Specific guidelines for initiating
and conducting therapy are designed to promote genuine progress and reduce the
risk of errors that are so easily made even by the experienced. As the medium of
therapy, the patient-therapist interplay is presented from the perspective of
both patient and therapist. The intelligent use of empathy and interpretation and
the manifold forms of resistance all receive their share of attention. The paper
concludes with a consideration of values, morality, and the importance of
recognizing and respecting the spiritual dimension.
PMID- 9553643
TI - Disguised hysteria in a child psychosis?
AB - In this paper the stages are presented in the psychoanalysis of an eight-and-a
half-year-old boy consulting with a worsening symptomatology that has been
evolving for more than one year. The trigger element seems to have been the birth
of a brother. During the analysis the relation was clear between this brother's
birth, the mother's abortions, and the previous death of a brother. The
interpretation of the homicidal omnipotent fantasies and the analyst's reception
of projective identifications, destructive anxieties, and castrating anxieties of
the patient produced, apparently, an unimagined fast improvement of the psychotic
symptoms. This took the authors retrospectively to raise the hypothesis that this
patient's psychosis could be a disguised child hysteria.
PMID- 9553645
TI - The use of combined heparin/aspirin and immunoglobulin G therapy in the treatment
of in vitro fertilization patients with antithyroid antibodies.
AB - PROBLEM: To compare the effect of heparin/aspirin therapy alone vs.
heparin/aspirin in combination with intravenous immuno-globulin (IVIg)
immunotherapy on in vitro fertilization (IVF) outcome of patients who test
positive for antithyroid antibodies (ATAs). METHOD OF STUDY: Eighty-two women
younger than 40 years of age whose infertility was related exclusively to female
causes were evaluated. All tested positive for organ-specific antithyroid
antibodies (antimicrosomal and/or antithyroglobulin antibodies), but negative for
antiphospholipid antibodies. Thirty-seven of these women (group A) received H/A
alone, whereas 45 (group B) received heparin/aspirin in combination with IVIg.
RESULTS: Ten (27%) of women in group A and 23 (51%) of women in group B achieved
live births after completion of a single IVF/embryo transfer cycle (P = 0.027).
CONCLUSION: We conclude that IVIg therapy significantly improves IVF success
rates in ATA+ women.
PMID- 9553646
TI - Experimental autoimmune prostatitis: in vivo induction of the autoimmune response
to lymphocytic soluble factors. Alterations at the endocrine metabolism level.
AB - PROBLEM: In rats, immunization with male accessory gland (MAG) extract promotes
experimental autoimmune vesicle prostatitis. A specific mononuclear cell-mediated
immune response and prostate androgen metabolism impairment in MAG-immunized rats
were observed. The possibility that lymphocytic soluble factors (SoFs) can
regulate the local steroid metabolism in these rats directly was studied. We
investigated whether the SoFs released by MAG-sensitized lymphocytes are capable
of modifying the prostatic androgen metabolism and whether they induce histologic
lesions "in vivo" when they are inoculated, carried by liposomes, into untreated
rats. METHOD OF STUDY: "In vitro" enzymatic [3H]-5 alpha-dihydrotestosterone
bioconversion and histologic studies were performed with prostates from SoF
treated rats (LK rats). The obtained 3 alpha/beta-hydroxysteroid-oxidoreductase
activities showed that LK rat values were significantly lower than in controls:
79.0 +/- 2.5 vs 158.7 +/- 10.2 pmol/min/mg protein, respectively (P < 0.01).
RESULTS: In the histologic studies, LK rat prostates showed focalized mononuclear
infiltrates of various degrees, whereas control rats showed non-atypic
modification of the gland. CONCLUSION: These results indicate that SoFs (probably
total lymphokines) contribute significantly to the pathogenesis of experimental
autoimmune prostatitis, involving a biochemical relationship between immune
reaction and the androgenic enzymatic inhibition in the prostate.
PMID- 9553647
TI - Effects of antibodies to transferrin and alpha 2-HS glycoprotein on in vitro
sperm motion: implications in infertility associated with endometriosis.
AB - PROBLEM: Women with endometriosis have antibodies to endometrial transferrin and
alpha 2-HS glycoprotein in their serum and peritoneal fluid. The objective of
this study was to determine whether antibodies to transferrin and alpha 2-HS
glycoprotein adversely affect sperm motility and survival. METHOD OF STUDY:
Spermatozoa obtained from normal fertile donors and washed free of seminal plasma
were incubated with the medium (control), 1:2 and 1:100 dilutions of
antitransferrin, 1:4, 1:8 and 1:100 dilutions of anti-alpha 2-HS glycoprotein,
and a 1:2 dilution of antialbumin antiserum (negative control). Sperm motion
characteristics in 10 microliters aliquots were evaluated at 30 min, 1 hr, 2 hr,
4 hr, and 24 hr using computerized sperm motion analysis. A paired t-test was
done to analyze the effects of the various antibodies on sperm motion
characteristics. RESULTS: Antibodies to albumin failed to adversely affect sperm
motility in general or the several sperm motion characteristics in particular. In
contrast, antibodies to transferrin at the dilution of 1:2 adversely affected the
percentage of motile and rapid spermatozoa, progressive and path velocities,
straightness, linearity, track speed, and anterior-lateral head displacement (P <
0.001) at all the time intervals, whereas a 1:100 dilution of this antiserum
adversely affected these parameters only at 24 hr. Elongation and beat cross
frequency were significantly affected at 4 and 24 hr by a 1:2 dilution of
antitransferrin antiserum. The effects of anti-alpha 2-HS glycoprotein were more
pronounced than those of antitransferrin, but they were similar. Dilutions of 1:4
and 1:8 were effective at all time intervals, whereas a 1:100 dilution was
effective in reducing the track speed and the percentage of rapid cells at 24 hr
(P < 0.001). CONCLUSION: Antibodies to endometrial transferrin and alpha 2-HS
glycoprotein present in the peritoneal fluid, and possibly in the oviductal
fluid, of patients with endometriosis may adversely affect postcoital sperm
motility and sperm survival.
PMID- 9553648
TI - Complement regulatory proteins on the sperm surface: relevance to sperm motility.
AB - PROBLEM: To determine whether complement regulatory proteins are present on human
spermatozoa and whether antibodies to these proteins adversely affect sperm
motility. METHOD OF STUDY: Human sperm membrane proteins were solubilized and
subjected to polyacrylamide gel electrophoresis followed by Western blot analysis
against antibodies to complement component 1 inhibitor (C1-INH), decay-activating
factor (DAF; CD55), membrane cofactor protein (MCP; CD46), and homologous
restriction factor (HRF; CD59). Spermatozoa, obtained by a swim-up technique,
were incubated in medium (control 1) and medium supplemented with antibodies to
human albumin (control 2) and antibodies to these complement regulatory proteins.
We used a computerized sperm motion analysis to determine the effect of these
antibodies on sperm motion characteristics. RESULTS: Complement regulatory
proteins such as C1-INH, CD55, CD46, and CD59 were found in the sperm extracts as
shown by Western blot analysis. The heat-treated (56 degrees C, 30 min) IgG
fraction of antibodies to these proteins significantly reduced sperm motility in
general and other motion parameters. Addition of complement did not affect these
results except in the antibodies to CD46 in which the reducing action was further
amplified. CONCLUSIONS: Our data suggest that C1-INH, CD55, CD46, and CD59 are
present on the sperm surface. These proteins may have biological functions, such
as affecting sperm motility, besides the complement regulatory functions. In
infertile men and women with antibodies that recognize one or more of these
complement regulatory proteins, there may be problems related to poor sperm
motility and survival in the reproductive tracts.
PMID- 9553649
TI - The herbal medicine unkei-to stimulates cytokine-induced neutrophil
chemoattractant production in the pituitary folliculo-stellate-like cell line
(TtT/GF).
AB - PROBLEM: We previously reported that a cytokine-induced neutrophil
chemoattractant (CINC) was produced in the pituitary gland and that it influenced
anterior pituitary hormone release. In this study we investigated the effect of
Unkei-to, a Japanese herbal medicine, on CINC production in the rat anterior
pituitary gland and the pituitary folliculo-stellate-like cell line (TtT/GF).
METHOD OF STUDY: Dispersed normal anterior pituitary cells and the folliculo
stellate-like cell line TtT/GF were used to test the effect of Unkei-to on CINC
secretion and CINC mRNA accumulation. Concentrations of CINC in the conditioned
media were measured by an enzyme-linked immunosorbent assay, and levels of CINC
mRNA were analyzed by Northern blot analysis. RESULTS: Unkei-to (20
micrograms/ml) significantly increased the secretion of CINC by normal anterior
pituitary cells within 12 hr of incubation. Unkei-to also stimulated CINC
secretion from TtT/GF cells in a time- and dose-dependent manner. Unkei-to (20
micrograms/ml) increased CINC mRNA accumulation in TtT/GF cells within 3 hr of
incubation and also caused a 13-fold increase in the secretion of CINC from
TtT/GF cells compared with the vehicle group within 24 hr of incubation. Finally,
we found that some of the Unkei-to's ingredients, Evodiae fructus and Pinelliae
tuber, markedly stimulated CINC secretion from TtT/GF cells. CONCLUSIONS: Our
results will help to elucidate the mechanism behind the clinical effect of Unkei
to on the anterior pituitary gland. They also suggested the presence of special
substances, which stimulate CINC secretion, within Unkei-to's ingredients such as
E. fructus and P. tuber.
PMID- 9553650
TI - Changes in lymphoid tissue after treatment with a gonadotropin releasing hormone
antagonist in the neonatal marmoset (Callithrix jacchus).
AB - PROBLEM: The effect of neonatal treatment with a gonadotropin releasing hormone
(GnRH) antagonist on the morphology and distribution of lymphocytes in lymphoid
tissue of the infant marmoset was examined. METHOD OF STUDY: From a screened
panel of antihuman antibodies for specific immune cells, antibodies for the CD20
and CD3 antigens showed excellent reactivity with marmoset tissue. Five sets of
marmoset twins were treated with either the GnRH antagonist or a vehicle from
birth, and were euthanized at 7 to 9 (3 sets) or 16 to 20 weeks (2 sets) of age.
The spleen, thymus, and inguinal lymph nodes from each animal were processed for
immunocytochemistry, and the number of cells expressing the CD20 and CD3 antigens
were quantified. RESULTS: Control twins exhibited high plasma levels of
testosterone, characteristic of the neonatal period, whereas testosterone
concentrations were reduced (P = 0.001) to detection limits in the GnRH
antagonist-treated twins. Microscopic evaluation suggested that treatment reduced
the volume and cellularity of the thymic cortex, resulting in a decrease in the
cortical-to-medullary ratio. Treatment reduced (P = 0.046) the number of
thymocytes expressing the B-cell antigen (CD20) and marginally lowered (P =
0.067) the number expressing the T-cell antigen (CD3) in the thymic medulla. In
the spleens of treated animals, periarterial lymphatic sheaths were less
prominent on microscopic examination, and there were marginally fewer (P = 0.064)
CD3+ cells. Numbers of CD20+ lymphocytes in the peripheral white pulp of the
spleen and in the germinal centers of the lymph nodes, or CD3+ cells in the
paracortex and germinal centers of the lymph nodes, were not altered by
treatment. CONCLUSION: Neonatal treatment with a GnRH antagonist may alter
maturational processes for B and T cells in the thymus and spleen of the marmoset
and may deprive the immune system of its normal sensitivity to GnRH at a
potentially critical time in development.
PMID- 9553651
TI - Adenosine deaminase and human reproduction: a comparative study of fertile women
and women with recurrent spontaneous abortion.
AB - PROBLEM: We have investigated the possible role of adenosine deaminase (ADA)
genetic polymorphism in human fertility through a comparative study of couples
with recurrent spontaneous abortion (RSA) and healthy puerperae. METHOD OF STUDY:
Adenosine deaminase phenotype has been determined in 209 women with repeated
episodes of unexplained spontaneous abortion (RSA) and their husbands, as well as
in 115 healthy pregnant women from the population of Rome. An independent sample
of 286 puerperae along with their newborn infants in the population of Penne was
also studied. RESULTS: The proportion of carriers of ADA*2 allele, which is
associated with the lowest enzymatic activity, is lower among women with RSA than
among healthy pregnant women from the same population of Rome. Preliminary
observations suggest a protective effect of ADA*2 against the development of
autoantibodies in RSA. Such an effect seems to be mediated by an interaction with
AB0 blood groups. In the population of Penne the proportion of women carrying
ADA*2 allele is higher among those who have had two or more previously born
children than among women with only one or no children. CONCLUSIONS: The data
suggest that women carrying the ADA*2 allele are better protected against the
spontaneous loss of embryos and have a higher fertility rate.
PMID- 9553652
TI - Human lymphocytes obtained from decidual tissue express killer activatory
receptors as well as killer inhibitory receptors: analysis using a single strand
conformation polymorphism method.
AB - PROBLEM: The objective was to clarify whether lymphocytes in decidual tissue
express only killer inhibitory receptors (KIRs) or both KIRs and killer
activatory receptors (KARs). METHOD OF STUDY: A polymerase chain reaction (PCR)
single strand conformation polymorphism (SSCP) analysis method, using cDNA as a
template, was applied to detect as many natural killer receptors (NKRs) expressed
on natural killer (NK) cells as possible and to distinguish between KIRs and
KARs. Using this method, we analyzed NKRs on lymphocytes in decidual tissue and
maternal peripheral blood mononuclear cells (PBMCs) (n = 10) from the same
individuals. RESULTS: More than 20 SSCP bands were detected for NKRs on both the
lymphocytes in decidual tissue and the maternal PBMCs. The SSCP band patterns
were different for each individual. KARs mRNA was detected in lymphocytes in
decidual tissue according to the SSCP analysis results. CONCLUSION: Lymphocytes
in decidual tissue express not only KIRs but also KARs; this finding suggests
their roles in placentation and the maintenance of pregnancy.
PMID- 9553653
TI - How might pregnancy immunize against breast cancer?
AB - PROBLEM: This study investigated how pregnancy might protect against breast
cancer. METHOD OF STUDY: A critical review of the literature was done.
RESULTS/CONCLUSIONS: Support for an active role in pregnancy immunizing against
breast cancer comes from case studies demonstrating a reciprocal correlation
between pregnancy and breast cancer as well as recent experiments supporting the
fetal antigen hypothesis that confirms the presence of a tumor-specific antigen,
MUC1, on both fetal and breast cancer tissues. Multiparous women also generate
anti-MUC1 major histocompatibility complex-restricted cytotoxic T cell cytolytic
activity against MUC1-bearing tumor cell lines. Careful investigation of the
fetal antigen hypothesis and tolerogenic mechanisms may lead to effective
vaccination protocols against breast cancer and other cancers.
PMID- 9553654
TI - Transferrin receptor (CD71) expression in peritoneal macrophages from fertile and
infertile women with and without endometriosis.
PMID- 9553655
TI - Understanding and overcoming resistance to chemotherapy in acute myeloid
leukemia.
PMID- 9553656
TI - High-dose chemotherapy for chronic lymphocytic leukemia: eligibility, timing, and
benefit?
PMID- 9553657
TI - The changing landscape of breast cancer clinical research. ESMO-Award Lecture,
ECCO-9 Hamburg, 18 September 1997.
AB - Clinical research for breast cancer is moving in three new directions following:
1) a critical analysis of three decades of randomized clinical trials for early
disease; 2) increasing awareness of this lethal disease among women, generating
women's associations which are pressing for improved breast cancer education,
screening and treatment; 3) an exponential growth in our understanding of breast
cancer molecular biology, leading to a number of innovative therapies with new
targets in the cancer cell or its environment. It is the remarkable work of the
Oxford Group which has finally vindicated the use of our three main weapons
against breast cancer micro-metastases, namely tamoxifen, chemotherapy and
ovarian ablation. There is now consensus that clinical research in the adjuvant
setting may gain speed and efficiency through intergroup collaboration. Such an
'Intergroup' has been recently created in Europe and will collaborate with the
American-Canadian Intergroup. Women's associations have only recently stepped
forward to demand better care, and more effective therapies: they are becoming
new partners in identifying critical issues in breast cancer research. Medical
oncologists involved in breast cancer research are facing a new challenge: the
optimal integration of traditional breast cancer therapies, namely endocrine
treatments and chemotherapy, and entirely new strategies targeting signal
transduction, apoptosis or angiogenesis. In view of the above, there is no doubt
that we are entering a new and exciting era in breast cancer clinical research.
PMID- 9553658
TI - Malignant pleural mesothelioma.
PMID- 9553659
TI - Autologous peripheral blood progenitor cell transplantation mobilized with high
dose cytarabine in acute myeloid leukemia in first complete remission.
AB - BACKGROUND: The aim of this study was to increase disease-free survival (DFS) in
AML in CR1 using a high-dose cytarabine consolidation plus G-CSF as in vivo
purging and mobilization of CD34+ cells before ablative therapy and peripheral
blood autograft. PATIENTS AND METHODS: Fifty-six consecutive AML patients (pts)
(including 11 children < 15 years), with a median age of 32 years, were analyzed.
After achievement of CR with cytarabine-mitoxantrone (7 + 3) in adults and a BFM
like protocol in children, pts were intensified with cytarabine 2 g/m2 x six
doses plus mitoxantrone for adults, or, 3 g/m2 x six doses plus etoposide for
children, followed by G-CSF 5 micrograms/kg SC daily. The ablative regimens used
were busulfan and cyclophosphamide (Bu/Cy) in standard-risk pts plus etoposide
(2400 mg/m2) for high-risk pts. RESULTS: For the 54 pts who underwent autologous
transplant, the median time to reach > 1.0 x 10(9)/l neutrophils was 13 days (8
48), and to reach platelets > 25 x 10(9)/l 32 days (8-364), and the median
numbers of red blood cell and platelet units transfused were 3 and 5,
respectively. Six pts had treatment-related deaths (11%). The disease-free
survival and overall survival at 30 months (mos) for the 56 eligible pts were 61%
and 62%, respectively. Only two relapses were observed after 21 mos, while there
were 12 relapses within 12 mos. CONCLUSIONS: The above treatment results in a
similar DFS rate as does rescue with bone marrow cells, with faster neutrophil
and platelet recovery.
PMID- 9553660
TI - High expression of bcl-2 mRNA as a determinant of poor prognosis in acute myeloid
leukemia.
AB - BACKGROUND: The bcl-2 oncoprotein is suggested to be directly involved in the
emergence of drug resistance by disrupting or delaying the apoptotic program and
promoting tumor survival. PATIENTS AND METHODS: In order to define the clinical
relevance of the bcl-2 mRNA expression in acute myeloid leukemia (AML) and its
correlation to therapy outcome and prognosis, we analyzed 219 AML bone marrow
(BM) samples, including 119 patients with de novo AML at presentation, 37 with
AML following myelodysplastic syndrome (MDS), as well as 42 BM samples of AML in
relapse and 21 in complete remission (CR) using RT-PCR. For performing
quantitative measurements of bcl-2 mRNA, we developed a quantitative RT-PCR.
RESULTS: Bcl-2 mRNA was detectable in 133 of 156 (84%) patients at diagnosis and
40 of 42 (95%) at relapse. AML patients with high bcl-2 mRNA expression achieved
lower CR rates than those with no or low expression. Concerning the long-term
outcome, the overall (OS) and disease-free survival (DFS) was significantly worse
in AML patients with high expression levels of bcl-2 mRNA. The three-year OS for
all newly diagnosed AML patients was 49% and 10% (P = 0.028), respectively, and
71% and 15% (P = 0.0004) for patients < 60 years. Comparable significant
differences were observed for the DFS. In AML following MDS and patients > 60
years, the bcl-2 expression was not associated with remission rate or survival.
CONCLUSIONS: The expression of bcl-2 mRNA may serve as a prognostic factor
predicting remission outcome and long-term prognosis in AML.
PMID- 9553661
TI - Hematopoietic stem cell transplantation in chronic lymphocytic leukemia: a report
of 12 patients from a single institution.
AB - BACKGROUND: Stem-cell transplantation is a reasonable therapeutic approach for
younger patients with high-risk CLL. PATIENTS AND METHODS: Twelve patients (seven
males; median age 47 years, range 29-51) with high-risk CLL underwent
transplantation (allo, n = 7; auto, n = 5). The conditioning regimen consisted of
cyclophosphamide and total body irradiation in 11 patients, and BEAC in the
remaining one. Minimal residual disease (MRD) was assessed by cytofluorometry and
PCR. RESULTS: All 11 evaluable patients engrafted. Of the seven allografted
patients, two died of treatment-related causes; three patients developed acute
GVHD. No transplant-related mortality was observed in autografted patients. After
transplantation, 10 of 11 patients evaluable for response achieved CR (91%; 95%
CI 59%-100%) which was molecular in nine patients (82%; 95% CI 48%-98%). One
patient in CR but MRD+ relapsed nine months after transplantation and died. Seven
patients remain in molecular CR for a median of 16 months (range 1-58). Estimated
actuarial survival and disease-free survival at two years is 81% (95% CI 43%
100%) and 71% (95% CI 43%-99%), respectively. Relapse risk at two years is 12.5%
(95% CI 0%-35.5%). CONCLUSIONS: Patients with high-risk CLL can achieve long
lasting molecular CR after SCT. The role of transplants in CLL management
deserves investigation in controlled trials.
PMID- 9553662
TI - High-dose topotecan with granulocyte-colony stimulating factor in
fluoropyrimidine-refractory colorectal cancer: a phase II and pharmacodynamic
study.
AB - PURPOSE: The premise for this study was that topotecan (TPT) resistance in
preclinical studies is associated with low level expression of the p-glycoprotein
(Pgp) multi-drug transporter conferred by the multi-drug resistant (MDR)
phenotype, which might be overcome in clinical practice by administering
moderately (2.3-fold) higher doses of TPT that have shown to be feasible with
granulocyte colony-stimulating factor (G-CSF) support. This phase II study
evaluated the anti-tumor activity of TPT administered at its highest possible
solid tumor dose with G-SCF in patients with fluoropyrimidine-refractory advanced
colorectal carcinoma. The study also sought to identify pharmacodynamic (PD)
determinants of both activity and toxicity. PATIENTS AND METHODS: TPT was
administered as a 30-minute infusion daily for five days every three weeks at a
dose of 3.5 mg/m2/day to patients with advance colorectal carcinoma who developed
progressive disease either during treatment with fluoropyrimidine-based
chemotherapy for advanced disease or within six months after receiving
fluoropyrimidine-based adjuvant chemotherapy. This dose of TPT was previously
determined to be the maximal tolerated dose (MTD) with G-CSF support in a phase I
study involving solid tumor patients with similar risk factors for
myelosuppression. Plasma sampling with performed during course 1 to characterize
the pharmacokinetic (PK) and PD behavior of TPT. RESULTS: Seventeen patients who
received 89 courses of TPT and G-CSF were evaluable for toxicity; 16 patients
were evaluable for anti-tumor response. Toxicity, particularly myelosuppression,
was substantial. At the 3.5 mg/m2/day dose level, absolute neutrophil counts
(ANC) were less than 500/microliters for longer than 5 days in 17% of courses
involving seven of seventeen (41%) patients. Severe neutropenia associated with
fever occurred in 12.3% of courses; and platelet counts below 25,000/microliters
were noted in 26.9% of courses. These toxicities resulted in dose reductions in
seven of 17 (41%) patients. Nevertheless, 90% of the planned total dose of TPT
was administered. No major responses were observed, though minor activity was
noted in several patients. Both the median time to progression and the median
survival time were short--2.5 and 4 months respectively. Although interindividual
variability in the disposition of total TPT was observed, the lack of objective
responses precluded PD assessments related to disease activity. Total TPT
exposure was significantly higher than drug exposure achieved in similar patients
at an identical dose in a previous phase I study of TPT and G-CSF, which may
explain why more severe myelosuppressive effects occurred in the present study.
There were no PD relationships evident between relevant PK parameters and the
percent decrements in platelets and ANC's during course 1, although patients with
severe toxic effects (ANC below 500/microliters for more than five days and/or
platelets < 25,000/microliters) had higher drug exposure than patients with less
severe toxicity (P < 0.018 and P = 0.09, respectively). CONCLUSIONS: Based on
these results, the true response rate of TPT at its solid tumor MTD with G-CSF
support is unlikely to approach 20%. Although a response rate of less than 20%
might be viewed as significant in this disease setting and might be confirmed
with sufficient statistical certainty by treating additional patients, the
substantial toxicity, inconvenience, and cost associated with this high dose
TPT/G-CSF regimen does not warrant the acceptance of a lower level of anti-tumor
activity as a criterion for further development.
PMID- 9553663
TI - Positive immunostaining with MLuC1 of bone marrow aspirate predicts poor outcome
in patients with small-cell lung cancer.
AB - BACKGROUND: Immunocytochemistry has been proven able to identify tumor cells in
bone marrow aspirate (BMA) of patients with SCLC. However, few data exist about
the clinical significance of the procedure. PATIENTS AND METHODS: 108 BMA taken
from 60 patients were incubated with the MoAb MLuC1 (cluster 6) and stained by
the APAAP (alkaline phosphatase-antialkaline phosphatase) method. The serum
levels of LDH, TPA, NSE and CEA were also studied in relation to bone marrow
involvement by means of discriminant analysis. RESULTS: Immunocytochemistry of
the aspirate with MLuC1 detected positive cells in 23 patients (38%) (38 of 108
samples) vs. 13% of the conventional biopsies studied without MLuC1 (P < 0.001).
With respect to bone marrow positivity, three groups of patients were identified:
those with no positive cells in the aspirate and negative biopsy (group A); those
with less than 10 positive cells in the aspirate and negative biopsy (group B);
and those with more than 10 positive cells or clumps in the aspirate or positive
biopsy (group C). Group C patients had poorer median survivals than those in the
other two groups (5.5 vs. 11 months, respectively, P = 0.01). Discriminant
analysis showed that the four serum markers were poor discriminators of the
degree of bone marrow involvement, with only 55% of grouped cases being correctly
classified. CONCLUSIONS: These results show that detection of bone marrow
involvement i) can be improved by the use of MLuC1 ii) is not predictable by
conventional tumor markers, and iii) is related to poor outcome.
PMID- 9553664
TI - The role of pneumatic compression in the treatment of postmastectomy lymphedema.
A randomized phase III study.
AB - BACKGROUND: Pneumatic compression is a frequently prescribed physical therapy for
patients affected by postmastectomy lymphedema but, despite its wide use, its
efficacy has not been demonstrated in phase III studies. We performed a
randomized study comparing pneumatic compression versus no treatment in patients
with postmastectomy lymphedema. PATIENTS AND METHODS: Patients with monolateral
postmastectomy lymphedema were randomized to receive two cycles of intermittent
pneumatic compression (PC group), i.e., five two-hour sessions per week for two
weeks, to be repeated after a five-week interval, or to no treatment (control
group). The patients in both groups were instructed as to the prophylactic
hygienic care of the limb. Lymphedema was assessed by the sum of differences in
circumference measurements between affected and normal limbs ('delta'). Response
was defined as a > or = 25% reduction in delta value. RESULTS: Eighty patients
entered the study. No statistically significant differences in response rates
between the two groups were observed: 20% in the control group (95% CI: 9%-36%),
25% in the PC group (95% CI: 13%-41%, P = 0.59). The absolute mean decrease in
delta value was 1.9 +/- 3.7 cm in the PC group and 0.5 +/- 3.3 cm in the control
group. CONCLUSIONS: We demonstrated that intermittent pneumatic compression has a
limited clinical role in the treatment of postmastectomy lymphedema. Efforts to
prevent this complication should be undertaken.
PMID- 9553665
TI - For which patients with aggressive non-Hodgkin's lymphoma is prophylaxis for
central nervous system disease mandatory? Dutch HOVON Group.
AB - PURPOSE: Data of a multicenter study in non-Hodgkin's lymphoma (NHL) by the Dutch
Hovon Group were reanalyzed to assess the risk of relapse in the central nervous
system (CNS) related to the international risk index for NHL. In addition we
assessed the risk for CNS disease in relation to the presence of bone marrow
localisation at presentation. DESIGN: We focused our analysis on those patients
reaching a complete remission (CR). Two hundred eighty-six patients (histological
subtypes D-H Working Formulation) and with stages II-IV were analyzed. One
hundred ninety-three (67%) patients reached a CR. RESULTS: Relapse occurred in 78
patients of whom 10 patients with concomitant or isolated CNS disease. According
to the international risk index the following observations were made: low risk (n
= 38) nine out of 34 CR relapsed, none had CNS involvement; low-intermediate risk
(n = 115) 27 out of 83 CR relapsed, three had CNS involvement; high-intermediate
risk (n = 110) 37 out of 68 CR relapsed, six had CNS involvement; high risk (n =
22) four out of seven CR relapsed, one had CNS involvement. Two out of 10
developed isolated CNS disease and eight out of 10 patients developed CNS disease
with systemic relapse. CONCLUSION: Our data show that the number of CNS relapses
after CR is relatively low (10 out of 193 = 5%), with an increasing incidence in
the high-risk groups according to the international risk index. The occurrence of
CNS relapse seems to be related to the risk of systemic relapse after CR. No
subgroup could be discriminated in which prophylactic treatment would be of
substantial benefit.
PMID- 9553666
TI - Ten-year results of a strategy combining three cycles of ABVD and high-dose
extended irradiation for treating Hodgkin's disease at advanced stages.
AB - BACKGROUND: The treatment of Hodgkin's disease (HD) at advanced stages relies
mainly upon multi-agent chemotherapies (CT), while the role of radiation therapy
has not been definitely identified. The aim of this report is to analyze the 10
year results of a prospective study including 133 patients with HD clinical
stages (CS) IIIA to IVB treated by three monthly courses of ABVD (adriamycin,
bleomycin, vinblastin, and dacarbazine) followed by high-dose subtotal or total
lymphoid irradiation [(S)TLI]. PATIENTS AND METHODS: From 1 October 1981 to 30
September 1988, 133 adult patients with HD CS IIIA (45), IIIB (33), IVA (seven)
and IVB (48) were entered in the non-randomized multicentric prospective trial
POF81/34. The number of involved nodal areas (NINA), and the number of visceral
sites (NVIS) involved were registered in all patients; patients with bulky
mediastinal tumor (BuMT) (mediastinal mass ratio > or = 0.45) were also
identified. All patients received three monthly cycles of ABVD. Patients in
complete remission (CR) or partial remission (PR) after completion of CT received
a (S)TLI including the spleen (involved sites 40 Gy, non-involved 30 Gy);
initially involved lung(s) and liver received 18 and 20 Gy, respectively; and
patients not in CR or PR after CT or RT received salvage treatments. Univariate
and multivariate analyses were performed to identify the factors contributing
significantly to the prognosis; initial characteristics, as well as status after
the three cycles of CT, were entered in the model. RESULTS: Of the 133 patients,
74 (55.6%) entered in CR after CT and 116 (87.2%) after completion of radiation
therapy. Ten-year freedom from progression (FFP), freedom from tumor mortality
(FFTM) and survival rates were 70.4%, 78.9% and 70.6%, respectively. According to
univariate analysis the NVIS (< or = one vs. > or = two) was the only initial
factor simultaneously influencing 10-year FFP (73.9% vs. 38.2%) FFTM (82.5 vs.
34.1%) and survival (73.5% vs. 17.3%) rates; on the other hand, the NINA (< or =
four vs. > or = five) influenced FFP (81.4% vs. 60.7%) and FFTM rates (87.3% vs.
71.4%) while symptoms (A vs. B) influenced FFP (80.7% vs. 63.3%) and survival
(82.8% vs, 61.2%) rates. Finally, age (< 40 vs. > or = 40) influenced survival
rate only (79.2% vs. 50%). According to multivariate analysis, NVIS and NINA had
an independent impact on FFP and FFTM, while survival was modified by the NVIS
and age. The post-CT status (CR vs. no CR) had a major impact on FFP (85.3% vs.
64.9%) FFTM (92.1% vs. 63.3%) as well as on survival (78.6% vs. 54.7%) rates in
both univariate and multivariate analyses. Complications of therapy were mainly
due to RT: 11 patients acquired second malignancies, six developed lung fibrosis
or severe pulmonary infections, three developed intestinal obstructions and six
developed angina pectoris or carotid stenosis. CONCLUSIONS: Tumor burden
(identified by the number of involved nodal areas and the number of visceral
sites) and the response to initial CT were the two independent factors
influencing the outcome of this group of 133 patients with HD, CSIII and IV
treated by three cycles of ABVD followed by high-dose [(S)TLI].
PMID- 9553667
TI - The anti-proliferative effect of suramin towards tamoxifen-sensitive and
resistant human breast cancer cell lines in relation to expression of receptors
for epidermal growth factor and insulin-like growth factor-I: growth stimulation
in the presence of tamoxifen.
AB - BACKGROUND: A significant proportion of breast cancer patients receiving
tamoxifen therapy relapse during treatment following acquisition of tamoxifen
resistant or oestrogen-independent phenotypes. The mechanism behind this rapid
progression to oestrogen autonomy is at present unclear and further treatment
modalities are limited. Suramin represents a novel potential second line therapy.
The mechanism of the antineoplastic activity of suramin is not completely
understood, although the drug binds to many growth factors including epidermal
growth factor and insulin-like growth factors and can also dissociate growth
factors from their receptors. In this study we have related suramin sensitivity
to the expression of receptors for epidermal growth factor and insulin-like
growth factor-I in a number of breast cancer cell lines including lines resistant
to tamoxifen. MATERIALS AND METHODS: The anti-proliferative effects of suramin
were investigated in two oestrogen dependent breast cancer lines (ZR-75-1 and MCF
7), oestrogen independent (ZR-PR-LT) and tamoxifen resistant (ZR-75-9a1) variants
of ZR-75-1 and a tamoxifen resistant (LY2) variant of MCF-7. Full dose response
curves were constructed and IC50 values determined for each cell line.
Sensitivity to suramin was correlated with the level of expression of receptors
for epidermal growth factor (EGFR) and insulin-like growth factor-I (IGFR). On
observing stimulation of cell proliferation by suramin in the tamoxifen resistant
cell lines in the presence of tamoxifen we also investigated the possible role of
suramin sequestration of transforming growth factor-beta in mediating this
effect. RESULTS: All cell lines exhibited a dose- and time-dependent response to
suramin treatment. Tamoxifen resistant ZR-75-9a1 cells (day 6 IC50 85 micrograms
ml-1) were more resistant to suramin than oestrogen independent ZR-PR-LT cells
(day 6 IC50 45 micrograms ml-1), and the parent ZR-75-1 line (day 6 IC50 56
micrograms ml-1). Increased sensitivity to suramin was associated with increased
expression of IGFR and decreased expression of EGFR. Tamoxifen resistant LY2
cells were significantly more sensitive to suramin (day 6 IC50 70 micrograms ml
1) than MCF-7 cells (day 6 IC50 350 micrograms ml-1). Both IGFR and EGFR
expression by LY2 cells was lower than in the parent line. The antioestrogen
resistant ZR-75-9a1 and LY2 lines grown in the presence of 8 microM tamoxifen
were growth stimulated by concentrations of the drug below 100 micrograms/ml. As
growth stimulation observed in the presence of tamoxifen may have been due to
suramin sequestration of tamoxifen induced TGF-beta 1 secretion we also
investigated the response of the cells to this peptide in the presence and
absence of suramin. All cell lines were growth inhibited by TGF-beta 1 except ZR
75-9a1 which was unresponsive. Responses to TGF-beta 1 were modified in the
presence of 100 micrograms suramin ml-1 although TGF-beta 1 was unable to mimic
the ability of tamoxifen to stimulate proliferation in the presence of suramin.
CONCLUSIONS: These results suggest that for ZR-75-1 cells and variants, increased
sensitivity to suramin is associated with an increase in expression of IGFR and a
decrease in EGFR numbers. However, tamoxifen resistant LY2 cells, in which both
IGFR and EGFR expression is reduced were considerably more sensitive than
parental MCF-7 cells suggesting that there is no clear relationship between EGFR
and IGFR expression and suramin sensitivity. The unexpected stimulation of cell
proliferation of the tamoxifen resistant variants by suramin in the presence of
tamoxifen could not be explained by suramin sequestration of transforming growth
factor-beta and the mechanism of this interaction remains unclear.
PMID- 9553668
TI - Detection of primary breast cancer presenting as metastatic carcinoma of unknown
primary origin by 111In-pentetreotide scan.
AB - Women with isolated metastatic carcinoma or adenocarcinoma involving axillary
lymph nodes are a well-recognized group of unknown primary carcinoma (UPC)
patients with a favorable prognosis. This group of patients are generally treated
based on the assumption that they have occult breast cancer. However, to
facilitate patient access to the whole spectrum of therapies available for
patients with breast cancer, including strategies involving the use of high-dose
chemotherapy, a precise diagnosis is increasingly important. In this clinical
case we report the detection of a primary breast cancer by 111In-pentetreotide
scanning in a woman who presented with metastatic carcinoma in axillary nodes, no
palpable breast lesion, a nondiagnostic mammogram, and negative breast
ultrasonography. Previous outcomes analysis of patients with UPC have emphasized
the value of identifying women with breast cancer. This report suggests that the
111In-pentetreotide scan can contribute specific, clinically useful information
in the evaluation of women presenting with metastatic carcinoma in axillary nodes
and an occult primary and deserves prospective study in women with UPC presenting
with isolated axillary metastases.
PMID- 9553669
TI - A phase II study of oral clofazimine in unresectable and metastatic
hepatocellular carcinoma.
AB - BACKGROUND: Hepatocellular carcinoma is highly refractory to most
chemotherapeutic agents. Clofazimine, a riminophenazine compound used to treat
leprosy since 1962, inhibits various cancer cell lines, including hepatocellular
carcinoma cell lines, via phospholipase A2 dependant processes. Clofazimine also
inhibits p170-glycoprotein, the mdr1 gene product. PATIENTS AND METHODS: Thirty
patients (26 males and four females) with unresectable (25) or metastatic (5)
hepatocellular carcinoma received oral clofazimine 600 mg daily for two weeks,
followed by 400 mg daily until progression or death. RESULTS: There were three
responses (10%)--one of a soft tissue metastasis, and two of local disease, with
13 patients disease stabilizing for up to 20 months. The overall median survival
was 13 weeks. Adverse events included hyperpigmentation, eczematous skin rashes
and palpitations. CONCLUSIONS: Although only three patients had an objective
response (10%), the 13 patients with stable disease for up to 20 months, and an
overall median survival of 13 weeks, suggest that clofazimine, or other
riminophenazine compounds may prove to be of value in hepatocellular carcinoma.
PMID- 9553670
TI - Cytosine arabinoside, etoposide and aclarubicin (AVA) for the treatment of acute
myeloid leukemia (AML) in elderly patients.
AB - BACKGROUND: Elderly patients (age > or = 60 years) with acute myeloid leukemia
(AML) have unfavourable prognoses when polychemotherapy regimens are used,
because therapy response is characterized by low remission rates, short remission
duration and high toxicity. PATIENTS AND METHODS: A phase II trial in elderly AML
patients was conducted to determine the efficacy of two induction courses of a
moderately-dosed combination of aclarubicin (25 mg/m2, 30 min i.v., days 1-4),
etoposide (100 mg/m2, 30 min i.v., days 1-3) and conventional-dose cytosine
arabinoside (ara-C, 100 mg/m2, c.i.v., days 1-3 and 30 min i.v., q 12 hours, days
4-7) (AVA-7), followed by one consolidation treatment using a reduced-dose
schedule over five days (AVA-5) after three months in CR. RESULTS: Thirty-two AML
patients with a median age of 66.2 years (range 60-76) were included in the
study: three of them had histories of preexisting myelodysplasia and one of
polycythemia vera. Following 1-2 courses of AVA-7 17 patients (53%) achieved CR,
two PR (6%), and nine had resistant disease (28%); the overall response rate was
thus 59%. Toxicity was significant but acceptable, with an overall treatment
related death rate of five of 32 patients (16%) after 63 courses of AVA. The
median disease-free survival (DFS) was 12 months, and the median survival of all
patients was 16.6 months. CONCLUSIONS: These results indicate that the
combination of aclarubicin, etoposide and conventional-dose ara-C is effective in
elderly AML patients. The relatively brief remission duration requires new
consolidation and maintenance therapy approaches.
PMID- 9553671
TI - Vinorelbine, bleomycin and methotrexate as a salvage therapy for patients with
head and neck squamous carcinoma in relapse after cisplatin/fluorouracil.
AB - BACKGROUND: Cisplatin (CDDP) and 5-fluorouracil (5-FU) represent the standard
chemotherapy for advanced/recurrent head and neck squamous carcinoma (HNSC);
however, the duration of response is often short, with a median survival of only
five to six months. PATIENTS AND METHODS: Patients with HNSC were treated with
vinorelbine 20 mg/m2 and methotrexate 50 mg/m2 every week and bleomycin 15 mg/m2
every two weeks. All patients were previously treated with a CDDP/5-FU regimen.
RESULTS: Forty-eight patients were evaluable for response and toxicity. After a
median follow-up of 15 months, 16 patients are still alive and 32 have died. We
had one complete response (2%), 12 partial responses (25%) (overall response rate
27%; 95% CI: 14%-39%), 11 stabilizations (23%) and 24 progressions (50%) of
disease. Neutropenia grade 3-4 was seen in 12 patients; peripheral neurotoxicity
in two patients. There were no toxic deaths. CONCLUSIONS: This regimen,
administered in an outpatient setting, revealed some activity as a second-line
treatment in patients with HNSC, with acceptable toxicity.
PMID- 9553672
TI - Consolidation therapy for advanced ovarian cancer.
PMID- 9553673
TI - 5-Fluorouracil and mitomycin-C in colorectal cancer: unacceptable conclusion.
PMID- 9553674
TI - Onycholysis in patients treated with docetaxel.
PMID- 9553675
TI - [Leukotriene receptor antagonists and bronchial asthma].
AB - Leukotrienes play an important role in the pathogenesis of the allergic bronchial
asthma. The cysteinyl-leukotrienes C4, D4 and E4 (formerly known as slow reacting
substance of anaphylaxis, SRS-A) are able to induce all components of the
asthmatic reaction. The synthesis of adequate receptor antagonists stimulated
expectations to develop on this way new and especially effective antiasthmatic
drugs. The results of the first generation was disappointing. Newer compounds are
able to protect from bronchoconstriction-inducing noxes (especially in analgesic
intolerance), to improve chronic asthma (symptoms scores, long-time resp. rescue
medication). Especially remarkable are recent data which prove antiinflammatory
activities. Studies are underway to define the position of these drugs in
generally accepted recommendations on asthma therapy. This group of drugs is the
first one with a defined action.
PMID- 9553676
TI - Characterisation of furoxancarbonitriles as a new class of vasodilators.
AB - The synthesis, structural characterization, NO-donor properties, and in vitro
vasodilating activities of a series of furoxancarbonitriles 2, 17-22a, b are
reported. Some derivatives (2b, 2a, 18b, 21b, 22b) are more potent vasodilating
agents than sodium nitroprusside (SNP), the reference compound, some others
display similar potency (17b, 19b, 20b). Log EC50 values fit well on the linear
correlation log EC50 versus log C0.1(1 min) (namely the logarithm of the
concentration able to release 2.6 mumol l-1 min-1 of NO) found in a previous
work. The haemodynamic profile in anaesthetised pigs for some selected
derivatives (2a, b, 19a, b) is also presented. These profiles are consistent with
that known for another furoxan NO-donor (4-hydroxymethyl-3-furoxancarboxamide,
CAS 1609) and suggest similar characteristic of in vivo NO-release.
PMID- 9553677
TI - Cardiovascular effects of (2RS,3SR)- 2-aminomethyl-2,3,7,8-tetrahydro-2,3,5,8,8
pentamethyl-6H-furo- [2,3-e]indol-7-one hydrochloride (UK-1745), a novel
cardiotonic agent with vasodilatory and antiarrhythmic properties.
AB - The cardiovascular effects of (2RS,3SR)-2-aminomethyl-2,3,7,8- tetrahydro
2,3,5,8,8-pentamethyl-6H-furo[2,3-e]indol-7-one hydrochloride (CAS 170684-14-7,
UK-1745), a novel cardiotonic agent, were investigated using in vitro and in vivo
preparations. In paced left atria isolated from guinea pigs, both UK-1745 and
vesnarinone (CAS 81840-15-5) showed a concentration-dependent positive inotropic
effect. In spontaneously beating guinea pig right atria, both agents caused only
a minimal chronotropic effect. In isolated, blood-perfused canine papillary
muscle preparations, UK-1745 and vesnarinone injected intra-arterially into the
anterior septal artery (ASA) increased the developed tension in a dose-dependent
manner. In isolated, blood-perfused canine sinoatrial node preparations, both
agents injected into the right coronary artery (RCA) did not cause any
appreciable changes in the sinus rate. UK-1745 increased the blood flow through
the ASA and the RCA in a dose-dependent manner, whereas vesnarinone did not. In
anesthetized open-chest dogs, UK-1745 injected intravenously increased cardiac
contractility and cardiac output, and decreased left ventricular end-diastolic
pressure, systemic vascular resistance and heart rate. In experimentally induced
acute heart failure in anesthetized open-chest dogs, intravenously injected UK
1745 effectively improved hemodynamic functions. In conscious instrumented dogs,
orally administered UK-1745 increased LV dP/dtmax with insignificant changes in
systemic blood pressure and heart rate. In mice, orally administered UK-1745
protected the development of ventricular fibrillation induced by chloroform
inhalation, whereas vesnarinone did not. Thus, in respect of inotropic and
chronotropic effects, UK-1745 closely resembled vesnarinone, but differed from
vesnarinone in respect of coronary vasodilating and antiarrhythmic effects. The
results suggest that UK-1745 is a novel positive inotropic agent with
vasodilatory and antiarrhythmic properties, without significant chronotropic
action, and may be beneficial for the treatment of congestive heart failure.
PMID- 9553678
TI - In vivo cardiotonic activity of aryl- and pyridyl-substituted fused imidazoles.
AB - Two new imidazo[2,1-b]thiazoles related to sulmazole were synthesized and
subjected to an in vivo cardiotonic assay with 14 analog compounds which gave the
best results in previously reported in vitro tests. The data obtained show that
three substituents (3-pyridyl, 4-pyridyl and 2,5-dimethoxyphenyl group) are
useful pharmacophoric groups in modulating the in vivo cardiotonic activity of
the fused imidazoles considered.
PMID- 9553679
TI - Inhibitory action of silibinin on low density lipoprotein oxidation.
AB - Low density lipoprotein (LDL) oxidation and smooth muscle cell growth represent
key events in atherogenesis. Any mean to reduce these two phenomena may decrease
the risk of coronary artery disease and atherosclerosis in general. The effects
of silibinin (CAS 22888-70-6) on LDL oxidation and proliferation of vascular
smooth muscle cells were evaluated in vitro. Silibinin (50-200 mumol/l) prolonged
the lag times of both LDL autooxidation and oxidation by copper by > 50%, as
assessed by recordings of diene formation. However, silibinin (up to 500 mumol/l)
did not interfere with LDL-stimulated radiolabeled thymidine incorporation. These
findings indicate that silibinin, apart from its hepatoprotective effects, has
inhibitory properties on LDL oxidation in vitro. Therefore silibinin might
represent a novel tool in the prevention and therapy of atherosclerosis.
PMID- 9553680
TI - [Antihypertensive action of various talinolol dosages after four week's treatment
in comparison with placebo].
AB - The dose dependence of the antihypertensive effect of the beta 1 selective
blocker talinolol (CAS 57460-41-0, Cordanum) was investigated in 97 essential
hypertensive patients (mild to moderate) using the ambulatory blood pressure
monitoring (ABPM) in a single-centre, double-blind, randomized parallel-group
study. After 4 weeks of treatment a comparison was made between the once daily
administered doses of 50, 100 and 200 mg as well as with placebo. The primary
parameter was the mean diastolic blood pressure between 8.00 and 22.00 (dTMW).
Furthermore, the duration of action of the once daily administration of 200 mg
talinolol was compared with the twice daily application of 100 mg each. With
regard to dTMW an increasing antihypertensive effect was determined for the
dosage step from 50 mg to 100 mg talinolol/d. No further increase in the blood
pressure lowering effect was observed with 200 mg talinolol/d. The highest
frequency of therapy responders was found in the 100 mg group with 72.2%.
Moreover it could be demonstrated, that within the dosage range of 1 x 100-200 mg
Talinolol/d a significant and 24 h lasting reduction of blood pressure and pulse
rate was achieved, including the early morning period. There were no differences
between the blood pressure profile of the 200 mg group and the 2 x 100 mg group
at the end of the 4 weeks treatment. All talinolol dosages investigated in this
study were proved to be safe and well tolerated. The observed complaints
classified as adverse drug reactions represented typical side effects of beta
blockers of mild to moderate intensity. It can be concluded from the results that
the once daily intake of talinolol in the dosage range of 100-200 mg/d shows a
reliable efficacy in the treatment of essential hypertension accompanied by a
noncritical safety profile.
PMID- 9553681
TI - Effects of the novel oral antidiabetic agent HQL-975 on glucose and lipid
metabolism in diabetic db/db mice.
AB - The antidiabetic effects of 3-?4-[2-(5-methyl-2-phenyl-oxazol-4-
yl)ethoxy]phenyl?-2S-propylamino-propionic acid (CAS 185679-16-7, HQL-975), a
novel oral agent, on a genetically obese non-insulin-dependent diabetes mellitus
(NIDDM) model (db/db mice) were examined. HQL-975 administration (3.7-34.1
mg/kg/d for 7 days) decreased the levels of plasma glucose, triglyceride, total
cholesterol, non-esterified fatty acid and insulin in the mice. In an
intraperitoneal glucose tolerance test (IPGTT), HQL-975 administration decreased
the fasting plasma glucose level and improved the glucose tolerance in the mice.
The HQL-975 administration also significantly increased the glycogenesis and
lipogenesis from 14C-glucose in liver, but did not alter the glycogenesis in the
diaphragm or the lipogenesis in adipose tissues at 2 h after the glucose loading.
In the HQL-975-treated db/db mice, the radioactivity of 14C-glucose incorporated
into hepatic glycogen was higher than that incorporated into hepatic total
lipids. After the administration of HQL-975 (34.1 mg/kg/d for 7 days) to db/db
mice, the hepatic hexokinase and fatty acid synthetase activities were
significantly increased, the glycogen synthase I activity was increased but not
significantly, and the glucose-6-phosphatase and the phosphoenolpyruvate
carboxykinase activities were decreased. These results suggest that HQL-975
increases the hepatic glucose utilization and decreases the hepatic glucose
production. Since hepatic glycogenesis is regulated by glucose itself but not by
insulin in normoglycemic ICR mice, HQL-975 is thought to enhance the effect of
glucose on the stimulation of hepatic glycogenesis. It is concluded that the
enhancement of the hepatic glucose utilization played an important role in the
hypoglycemic action of HQL-975.
PMID- 9553682
TI - Comparison of the effects of ularitide acetate and other bronchorelaxing
substances on the thrombin-induced permeability raise of human endothelial cell
monolayers.
AB - Endothelial cell contraction plays a pivotal role in vascular leakage. It
increases the extravasation of fluid and macromolecules from the lumen into the
interstitium. This is also true for bronchial edema. Previous studies have
indicated that an elevation of intracellular adenosine-3',5'-cyclic monophosphate
(cAMP) or guanosine-3',5'-cyclic monophosphate (cGMP), respectively, can
counteract this vascular leakage by improving the endothelial barrier function in
analogy to the relaxation of smooth muscle cells. To investigate the potential
antiedemateous effects of ularitide acetate (CAS 115966-23-9), isoproterenol
hemisulfate (CAS 6078-56-4), sodium nitroprusside (CAS 13755-38-9, SNP),
aminophylline (CAS 317-34-0), and combinations of these compounds, their effects
on thrombin-induced macromolecular permeability raise in relation to cGMP- or
cAMP-levels, respectively, in a model of human umbilical vein endothelial cells
(HUVECs) were examined. Ularitide acetate, isoproterenol hemisulfate, and SNP all
increased the amount of cyclic nucleotides and decreased the raise in
permeability in the following order of potency: isoproterenol hemisulfate >
ularitide acetate > SNP. Aminophylline raised both cGMP- and cAMP-levels in a
weaker amount and was not able to decrease the thrombin-induced permeability
raise on its own. By way of contrast, preincubation of HUVECs with aminophylline
resulted in a more than additive potentiation of the cGMP-levels and the
permeability lowering induced by ularitide-acetate. These in vitro-data indicate
that ularitide-acetate, especially in combination with phosphodiesterase (PDE)
inhibitors, could probably have beneficial effects in bronchial permeability
edema.
PMID- 9553683
TI - Single dose study of the bioequivalence of two sustained-release theophylline
formulations.
AB - The relative bioavailability of theophylline (CAS 58-55-9) was evaluated after a
single dose administration of two sustained-release theophylline tablet
formulations: Controfilina-200 as test preparation (test) and a commonly used
reference preparation (reference). The design of the study was crossover in
twelve healthy volunteers, with a series of two experimental sessions. The two
sessions were carried out at weekly intervals. Theophylline concentrations were
measured by HPLC (high performance liquid chromatography). The bioavailability
was compared using the parameters: AUC0-infinity (area under the concentration
time curve), Cmax (maximal theophylline concentration), tmax (time after drug
intake at which the maximal concentration is reached) and Cmax/AUC0-infinity. The
results of this study indicated that the new generic sustained-release tablet and
the reference are bioequivalent when the same dosage is administered.
PMID- 9553684
TI - Synthesis of some new aroyl/aryloxy-2-amino-1,3-thiazole derivatives with anti
inflammatory activity.
AB - The synthesis of some novel aroyl/aryloxy aminothiazoles from the appropriate
gamma-chloro-butyrophenones, gamma-chloro-butyrothienones, gamma-chloro
aryloxypropanes with the corresponding substituted 2-amino-1,3-thiazoles is
described. The spectroscopical data (UV, IR, 1H-NMR and MS) of the derivatives
are presented.
PMID- 9553685
TI - Disposition of a new nonsteroidal anti-inflammatory agent, S-2-[4-(3-methyl-2
thienyl)phenyl]propionic acid, in rats, dogs and monkeys.
AB - The disposition of S-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid (CAS 155680
07-2, S-MTPPA, code: M-5011) was studied after oral administration to rats, dogs
and monkeys using the 14C-labeled drug. After oral dosing, S-MTPPA was well
absorbed from the gastrointestinal tract, to the extent of 97.7% in rats. The
concentration of S-MTPPA in rat plasma reached a peak (Cmax: 13.07 micrograms/ml)
at 15 min (tmax) after dosing and declined with a half-life (t1/2) of 2.5 h. The
values of the parameters tmax, Cmax and t1/2 for dogs were 30 min, 26.2
micrograms/ml and 7.0 h, and those for monkeys were 15 min, 12.8 micrograms/ml
and 3.0 h, respectively. The radioactivity was widely distributed in tissues and
almost completely excreted in urine and feces within 48 h after oral
administration to rats. The excretion of radioactivity in bile, urine and feces
within 48 h after oral administration of 14C-S-MTPPA to bile duct-cannulated rats
amounted to 75.0, 18.6 and 1.4% of the dose, respectively. The drug was
metabolized mainly by oxidation of the thiophenyl moiety and by glucuronidation
of the carboxyl group in rats and monkeys. The major urinary and fecal metabolite
in dogs was identified as the taurine conjugate of MTPPA.
PMID- 9553686
TI - Pharmacokinetics of estradiol and of estrone during application of a new 7-day
estradiol transdermal patch with active matrix.
AB - The pharmacokinetic patterns of estradiol (CAS 50-28-2) and of estrone (CAS 53-16
7) were investigated in 18 women in natural or surgical menopause during the
application of a new estradiol transdermal patch with active matrix and without
absorption enhancers designed for epicutaneous applications of 7 days
(hereinafter called "patch 7D"). The study was made with randomized and balanced
sequences of applications in cross-over of either patch 7D or of an authorized
estradiol transdermal patch with a nominal release rate of 50 micrograms/day
estradiol designed for a twice-a-week epicutaneous application (hereinafter
called "patch 50"). The sequences consisted of applications for 3 weeks either of
3 patches 7D or of 6 patches 50. The patches were applied on the skin of the hips
or upper buttocks. The serum samples were obtained during the 1st and during the
last week of application of the patches. Estradiol (E2) was assayed in serum by a
double-antibody RIA method selective for free estradiol. Estrone (E1) was assayed
in serum using a 3H-estrone RIA method. The steady state with regard to E2 and E1
was achieved already during the application of the 2nd patch. Patch 7D provided
within 6 h an increase of the E2 concentrations in serum from the basal
postmenopausal level of less than 3 pg/ml to therapeutically effective
concentrations. The Cmax of E2 of 45 pg/ml was reached on average after 25 h, the
concentrations of E2 remaining at sustained and therapeutically effective levels
during the whole application of patch 7D. At steady state, during the 3rd week of
application, the Cav was on average 31 pg/ml. With a small delay, E1 also
increased from the basal 15 pg/ml to a Cmax of 41 pg/ml after 44 h. At steady
state, during the 3rd week of application, the Cav was on average 38 pg/ml. Patch
7D provided a similar bioavailability as patch 50 with regard to the rate and the
extent of absorption of E2, as shown by the AUCs during the 7-day applications of
one patch 7D compared to those during the 7-day applications of 2 patches 50. The
release of E2 from patch 7D is therefore similar to that of patch 50, i.e. on an
average of 50 micrograms/day over a 7-day period of application. The E2/E1 ratio
increased from the postmenopausal values lower than 0.2 found before the
application of patch 7D to average values of 0.67, i.e., to values that are
normally found during the fertile life of the woman. The improvement of the E2/E1
ratio occurred already in the first 6-12 h of application of patch 7D. The E2/E1
ratio returned rapidly to the initial low postmenopausal levels after removal of
the patch. Patch 7D was well tolerated by the skin, probably because it does not
contain absorption enhancers. It provoked, however, some systemic adverse
reactions typical of E2 overdosing. In the therapeutic practice these adverse
reactions can easily be avoided using patches 7D of lower strength. No drop-out
due to systemic or local intolerance occurred. The adhesion of patch 7D on the
skin was good. During the application of a total of 54 patches, only in one
occasion one patch became partially detached (about 40% of the total area) from
the 3rd to the 7th day during the first 7-day period of application.
PMID- 9553687
TI - "Resultant bond moment" as a newly developed electronic parameter in the design
of antibacterial, antiprotozoal nitroimidazole derivatives.
AB - Nineteen nitroimidazole derivatives have been reported to be effective
antibacterial against one strain each of Bacteroides fragilis and Clostridium
perfringens. The negative logarithms of minimum inhibitory concentrations (MICs)
of these nitroimidazoles were fitted by a biostatistical relation involving a
newly designed structural descriptor, the Resultant Bond Moment (RBM). RBM was
developed on the basis of the chemical attribute of bond moments of heteroatoms.
RBM reflects the electronic characteristic of the molecule. Apart from this,
steric, electronic, and hydrophobic parameters were also utilised in the search
of a best fit regression equation. On the basis of these equations new
investigative nitroimidazole derivatives have been predicted concerning their
antibacterial and antiprotozoal efficacy.
PMID- 9553688
TI - Antibacterial activity of rhodium, iridium, and ruthenium tripodal phosphine
complexes.
AB - Twenty-eight rhodium, iridium, or ruthenium complexes were evaluated for their in
vitro antibacterial activity against Enterococcus faecalis ATCC 29212,
Staphylococcus aureus ATCC 29213, Escherichia coli ATCC 25922 and Pseudomonaa
aeruginosa ATCC 27853. Ten compounds showed an antibacterial activity against
Enterococcus faecalis ATCC 29212 and Staphylococcus aureus ATCC 29213 with a
range of the minimum inhibitory concentrations (MICs) between 16 and 125
micrograms/ml. None of the compounds exhibited antimicrobial activity against the
gram-negative strains E. coli ATCC 25922 or Pseudomonas aeruginosa ATCC 29213
with a concentration range between 4 and 500 micrograms/ml.
PMID- 9553689
TI - Epoxyethane-/ethynesulfonamides with antifilarial activities. Degradation
kinetics and inhibitory effect on filarial malate dehydrogenase and lactate
dehydrogenase.
AB - Some epoxyethane-/ethynesulfonamides had shown strong filaricidal activity with
inconstant reproducibility as a result of a lack of stability in aqueous
solution. The degradation in hydroxylic and aprotic solutions of two
epoxyethanesulfonamides and one ethynesulfonamide was investigated using TLC,
HPLC, GC and mass spectrometry. For both epoxydes, the degradation rate followed
first-order kinetics and was more rapid in hydroxylic than in aprotic solutions.
The degradation increased with the temperature whereas it was not modified with
and without light exposure. Four kinds of degradation products were found: the
first one involved the oxidation of the epoxyde bond, the second the breaking of
the N-S bond, the third a desulfonation product and the fourth was not
identified. In contrast, the stability of ethynesulfonamide was better than those
of epoxyethanesulfonamide. These results suggest that epoxyethanesulfonamides
should be kept at +4 degrees C before being injected to animals during the study
of biological activity. Since epoxyde compounds are known to have inhibitory
effects on parasite energy metabolism enzymes, the compunds were evaluated on two
major filarial enzymes: lactate dehydrogenase (LDH) and cytoplasmic malate
dehydrogenase (MDH). Both epoxyethanesulfonamides showed only a slight inhibitory
effect on filarial LDH and MDH confirming the evidence that the main mode of
action of these compounds remains to discover. Moreover, ethynesulfonamide and
the degradation products of both epoxyethane-sulfonamides had no effect on LDH
and MDH.
PMID- 9553690
TI - Toxicities of 166Holmium-chitosan in mice.
AB - 166Holmium (166Ho) is a radionuclide of rare earth chemical and is known to have
antitumor activity. Several chemicals were complexed with 166Ho to facilitate the
transport of this radionuclide to the site of action. In this study, 166Ho was
complexed to chitosan (Chit) which decreases the distribution of Ho into other
tissues when applied intrahepatically. To investigate the single dose toxicity,
mice were administered intravenously with 1 mCi/kg body weight of 166Ho-Chit (DW
166HC), Chit or nothing. Organ weights, hematological and histopathological
studies were performed in 6 animals per group at 1, 3 and 14 days after
administration. In 166Ho-Chit treated animals, a slight decrease of erythrocyte
number was observed at day 14 and increases of relative liver and lung weights
were found at day 3. Although marked multiple necrotic foci in the white pulp and
depletion of marginal zone in the spleen were noted at day 1, these findings were
decreased in severity and fully recovered at day 3 and day 14, respectively.
Slightly decreased kidney weights were observed both in Chit and in 166Ho-Chit
treated groups without histological alterations. Thus it is suggested that most
effects of 166Ho-Chit observed at an early stage after administration are limited
to rapidly dividing cells and reversible within 14 days.
PMID- 9553691
TI - Antiviral potential of interferon-omega on hepatitis B virus replication in human
hepatoma cells.
AB - Interferon-alpha (IFN-alpha) and other cytokines are able to interfere with
hepatitis B virus (HBV) replication. However, a sustained antiviral effect is
achieved only in 25% to 40% of the patients with chronic HBV infection and
clearance of the virus rarely occurs, stressing the need for developing
therapeutic alternatives. In this study the antiviral potential of a new
recombinant interferon, IFN-omega was investigated. IFN-omega was assessed in
comparison with IFN-alpha 2c, IFN-gamma, and TNF-alpha with respect to production
of HBV proteins and DNA in HepG2.2.15 cells, a HBV-DNA transfected hepatoma cell
line which produces infectious viral particles. Cells were seeded at different
states of confluence (20%-90%) and treated with increasing concentrations of
interferons (5 to 5,000 U/ml), TNF-alpha (5 to 500 ng/ml), or combinations of
both for one to three days. IFN-omega reduced the production of HBsAg down to 59%
of the untreated controls, which was comparable to the reduction obtained by
treatment with IFN-alpha (60%), the standard interferon used for the treatment of
chronic HBV infections. The strongest inhibition, however, was achieved by
treatment with 500 ng/ml TNF-alpha (42%). Likewise, production of HBeAg and
synthesis of HBV DNA were inhibited to similar degrees by the different
interferons. In non-replicating high-density cultures only TNF-alpha was
effective. IFN-omega is of similar antiviral potential as IFN-alpha in this in
vitro experimental system.
PMID- 9553692
TI - Central trigeminal and posterior eighth nerve projections in the turtle Chrysemys
picta studied in vitro.
AB - Recent electrophysiological studies in the turtle Chrysemys picta have suggested
that a neural correlate of the eye-blink reflex can be evoked in an in vitro
brain-stem-cerebellum preparation by electrical rather than natural stimulation
of the cranial nerves. Discharge recorded in the abducens nerve, which is similar
to EMG recordings from extraocular muscles during eye retraction, is triggered by
a brief electrical stimulus applied to the ipsilateral trigeminal nerve. Evidence
also suggests that pairing a one-second electrical stimulus applied to the
posterior eighth nerve immediately prior to a single shock to the trigeminal
nerve results in classically conditioned abducens nerve discharge in response to
the previously neutral eighth nerve stimulus. In view of these physiological
findings, the aim of the present study was to examine the central projections of
trigeminal and posterior eighth nerve inputs to elucidate the anatomical
substrates that may underlie the in vitro eye-blink reflex and possible pathways
involved in reflex conditioning. Neurobiotin (NB) or fluorescein dextran (FD) was
pressure injected into the cut end of either the trigeminal or posterior eighth
nerve of the in vitro brainstem-cerebellum. Following trigeminal nerve
injections, both tracers showed label in the ipsilateral trigeminal nuclear
complex. Direct projections to the ipsilateral principal and accessory abducens
motor nuclei were observed, suggesting that the eye-blink reflex is monosynaptic.
Trigeminal nerve axons were also observed to terminate in the ipsilateral
cerebellar cortex. The results of the posterior eighth nerve injections showed
axonal projections and terminals in the cochlear, vestibular and principal
sensory trigeminal nuclei. Terminal label was also observed in the ipsilateral
cerebellar cortex, deep cerebellar nuclei, and in the principal and accessory
abducens motor nuclei. Results from the NB cases suggested transneuronal
transport of this tracer substance, whereas the FD cases did not. The present
findings suggest that convergence of trigeminal and posterior eighth nerve inputs
occurs in the ipsilateral cerebellar cortex, the principal sensory trigeminal
nucleus, and the principal and accessory abducens motor nuclei. These regions of
convergence may therefore be considered as potential sites of synaptic
modification during in vitro studies of the conditioned abducens nerve reflex.
PMID- 9553693
TI - Afferent and efferent connections of nucleus praeeminentialis in the channel
catfish: a reevaluation.
AB - Nucleus praeeminentialis (nPr) is an isthmic nucleus that has been described in
the brains of electrosensory teleost fishes and a single non-electrosensory
species. The nucleus receives axon collaterals of ascending medullary sensory
lemniscal neurons. Axons of nPr neurons project in turn back down onto those same
populations of medullary projection neurons via a descending parallel fiber
system (the molecular layer or cerebellar crest). Thus nPr forms a link in a
sensory feedback loop that modulates the activity of neurons that relay
information from medulla to midbrain. The purpose of this study is to investigate
the nature of the afferent and efferent connections of the nPr with the specific
aim of investigating other sources of input into this modulatory circuit.
Transport of neuronal tracers (horseradish peroxidase, DiI and dextran amines)
revealed that nPr has extensive interconnections with nuclei in the basal
metencephalon, cerebellum, octavolateralis column and basal medulla. A previously
described source of afference, the torus semicircularis in the mesencephalon, was
not indicated by our studies. Our studies suggest that in addition to regulating
the sensitivity and resolution of electrosensory and mechanosensory lateral line
systems, the nPr may play a role in the resolution of signal ambiguities posed by
auditory or vestibular stimulation of the saccular endorgan of the inner ear.
PMID- 9553694
TI - Role of the archistriatal nucleus taeniae in the sexual behavior of male Japanese
quail (Coturnix japonica): a comparison of function with the medial nucleus of
the amygdala in mammals.
AB - Nucleus taeniae (Tn) is a prominent cell group within the medial archistriatum of
birds. Based upon similarities in sex-steroid binding sites, this nucleus has
been hypothesized to be homologous to the medial nucleus of the amygdala (Me) in
mammals, which is known to modulate the expression of sexual behavior in rodents.
We therefore tested whether or not Tn likewise plays a role in the expression of
sexual behavior in male Japanese quail. We found that bilateral damage to Tn
produced deficits in several components of male responses toward female stimuli
that were indicative of decreased sexual arousal, including goal-oriented
responses, vocalizations associated with courtship, and motor reflexes that
precede copulation. Our results suggest that Tn influences a wide range of
behavioral functions in response to sexual stimuli, and they indicate a function
for this nucleus similar to that subserved by the Me in mammals. These results
strengthen the argument that these sex-steroid accumulating cell groups are
homologous and suggest a conservation of function for them despite the vastly
divergent evolutionary histories separating birds and mammals.
PMID- 9553695
TI - A comparison of encephalization between odontocete cetaceans and anthropoid
primates.
AB - There have been very few studies of brain size and encephalization in cetaceans
and essentially none that have made direct quantitative comparisons of cetaceans
and another mammalian group using large normative samples. In the present study
two different measures of encephalization were calculated and used to rank and
compare 21 odontocete species and 60 anthropoid primate species. Comparisons were
made both within and between the two groups. Results show that the
encephalization level of Homo sapiens is still extraordinary relative to that of
nonhuman species. Nevertheless, a subset of delphinid odontocetes are
significantly more highly encephalized than the most highly encephalized
anthropoid primates and narrow the gap in encephalization between humans and
nonhumans substantially. These findings may have implications for comparative
models of the relative importance of brain size versus brain organization for the
evolution of intelligence.
PMID- 9553696
TI - Giant cell tumor of bone.
AB - Giant cell tumor of bone is an unusual neoplasm and treatment commonly leads to
local recurrence. This can be related to the aggressiveness of the tumor or to
the incompleteness of its removal. This study includes 27 cases that presented to
our institution between the 1984 and 1994. One case was as a consultation only
and 9 cases, either Campanacci Grade 3 or patients with considerable joint
destruction, were treated by resection and reconstruction. One case was treated
by curettage and cementation. Sixteen cases were treated with a combination of
radical curettage, high speed burring, pulsatile lavage, and bone graft (either
autograft or allograft mixed with autograft). No other adjuvant therapy was used.
All of these 16 cases had a minimum follow-up of 5 years and none had a local
recurrence. This study demonstrates that local control of giant cell tumors can
be obtained by appropriate staging, resection of aggressive tumors, and by
conservative management of the others. Such conservative management provides a
bony matrix for the subchondral bone that is preferable to other treatments that
have become popular in recent years, including cementation. This should provide
better joint function in the longer term. High local recurrence rates have been
reported in other series, but by a combination of appropriate selection of cases
and by careful treatment of the Campanacci Grade 1 and 2 cases, these patients
can have an uncomplicated outcome.
PMID- 9553697
TI - Outcomes following treatment of metastatic spine tumors.
AB - Fifty seven consecutive patients with metastatic spine tumors were assessed for
their suitability for operative treatment or radiotherapy and/or chemotherapy
using a modified version of the Nihon University scoring system. Using this
scoring system 29 patients underwent surgery and 28 received
radiotherapy/chemotherapy. The outcomes were assessed to determine if a modified
scoring had any effect on patient survival. No statistical difference was found
between the two groups, though a trend was noted--the group receiving surgery had
a mean survival of 30 weeks compared to a mean survival of 16 weeks found in the
non-surgical group.
PMID- 9553698
TI - The surgical management of degenerative lumbar scoliosis. Posterior
instrumentation alone versus two stage surgery.
AB - Twenty-one patients who underwent surgery for degenerative scoliosis were
retrospectively reviewed. Eleven patients underwent staged anterior and posterior
surgery. Ten patients had a single posterior procedure. Posterior instrumentation
to the sacrum was done in all cases. Average length of follow-up was 3.8 years
(range: 2 to 7 years). All patients were assessed by the Oswestry Disability
Questionnaire and Low-Back Outcome Score. Additional questions included analogue
scales for pain and quality of life, and self-rating of the outcome of treatment.
Nine patients that had two stage surgery and 4 patients that had single posterior
surgery considered their outcome to be good or excellent (p = 0.13). This
correlated with better functional tolerance, specifically sleep, lifting,
sitting, and social life. Although pain intensity was the same for both groups,
only the staged group reported significant reduction in analgesic intake.
Significant correction in scoliosis and the lumbosacral fractional curve was
noted only following staged surgery. A solid spinal fusion determined a
satisfactory outcome irrespective of the method of treatment. Staged anterior and
posterior surgery for degenerative lumbar scoliosis resulted in a better fusion
rate, greater correction of deformity, and more improvement in function than did
posterior surgery alone.
PMID- 9553699
TI - Cytokines and matrix metalloproteinases mRNA expression in archival human tissues
from failed total hip arthroplasty using in situ hybridization and color video
image analysis.
AB - Reports on the histological and biochemical nature of periprosthetic
fibrous/granulomatous tissue has, to date, been largely limited to frozen tissue
sections. This study reports the cytokine and matrix metalloproteinase profiles
found in periprosthetic interface tissues in THA which have failed due to aseptic
loosening and in capsular tissues obtained at primary surgery. The study employs
immunohistochemistry, in situ hybridization, and color video image analysis on
formalin fixed and paraffin embedded sections.
PMID- 9553700
TI - A quantitative analysis of knee joint kinematics during the sidestep cutting
maneuver. Implications for non-contact anterior cruciate ligament injury.
AB - This study accurately quantifies the knee joint kinematics associated with
sidestep cutting maneuvers in vivo. These data were subsequently evaluated to
determine the relationship between sidestep cutting and non-contact anterior
cruciate ligament (ACL) injury. Sixteen male subjects, proficient in the sidestep
cutting maneuver, had knee joint kinematic data recorded during the stance phase
of straight line running and sidestep cutting. Cutting speeds (5.5 msec-1 to 7.0
msec-1) and angles (30 degrees to 55 degrees) were chosen to reflect the sporting
context. All subjects underwent medical screening prior to testing to ensure data
represented joint biomechanics of healthy, ACL intact individuals. The temporal
three dimensional positions of externally mounted (skin) markers were submitted
to a custom software package (JTMOTION), which described in clinically meaningful
terms, movements for the three rotational degrees of freedom at the knee joint.
While mean patterns of motion for the three clinical knee rotations compared
favorably between running and cutting data, sidestepping induced significantly (p
< 0.01) greater maximum knee joint rotations during stance. Knee joint rotational
ranges were also found to be significantly (p < 0.01) larger during cutting when
compared to running. Increases in knee joint kinematics during cutting however,
were not of a great enough magnitude to alone elicit spontaneous non-contact ACL
injury, falling well within "safe" ranges of knee motion. Significant increases
in inter-trial variability for the three rotations were observed in some subjects
for sidestepping compared to running. It was concluded that a lack of consistency
in knee joint biomechanics between cutting maneuvers increased the risk of ACL
injury with the performance of an abnormal and potentially hazardous sidestep
being more likely. The risk of non-contact ACL injury during cutting maneuvers
was suggested to increase further when an individual displayed these "atypical"
joint biomechanics in conjunction with specific joint structures, levels of
experience and conditioning, and ligament morphologies.
PMID- 9553701
TI - The current state of bone and tissue banking in Australia.
AB - The development of bone and tissue banking in Australia over the last decade is
described and details of the administrative structure, donor and recipient
testing protocols, allograft segment processing procedures, and internal audit
safety arrangements are also provided. Demographic data concerning both the
retrieval and dispersal of musculoskeletal allograft materials in Australia are
also discussed. Current price schedules for a variety of allograft materials
available in Australia are made available for international comparison.
PMID- 9553702
TI - Orthopaedic education in Australia.
PMID- 9553703
TI - Simultaneous bilateral total hip arthroplasty with hydroxyapatite coated
implants.
AB - Thirty patients (60 hips) who underwent simultaneous bilateral total hip
arthroplasty with hydroxyapatite components were followed from 24 to 78 months
(mean: 49 months). All patients showed improvement in postoperative hip score
rating compared to preoperative for pain, function, and range of motion.
Postoperative complications were minimal compared to other series. There were no
thromboembolic complications. Heterotopic bone was noted in 18 hips (30%). At
latest follow up no patients had radiographic evidence of component loosening.
PMID- 9553704
TI - Reconstruction using implants compatible with MRI for malignant spine tumors.
AB - It is necessary to resect malignant spine tumors aggressively and to subsequently
reconstruct the spinal column. The Diapason screw and hook system, which is
compatible with magnetic resonance imaging, has been used recently for
reconstruction. This study included 17 patients (5 with primary tumors and 12
with metastatic tumors) who underwent excision and reconstruction with the
Diapason screw and hook system. The surgical procedures performed were circum
spinal decompression by posterior extensive curettage in 12 cases, and en bloc
total spondylectomy in 5. The follow-up periods ranged from 6 to 28 months.
Though paralyses of Frankel grade B in 2 patients were not improved, paralyses of
Frankel grade C in 10 cases and Frankel grade D in 4 cases improved to Frankel
grade D or better postoperatively. MRI was performed to detect recurrences during
the follow-up period. Recurrence of paralysis occurred in 5 patients. MRI could
disclose recurrences of tumors in these patients because there were fewer signal
loss artifacts in these implants than are found in those made of stainless steel
alloy. For detecting recurrences, the Diapason system was satisfactory in the MRI
follow-ups.
PMID- 9553706
TI - A case-control study of verocytotoxigenic Escherichia coli infection in cats with
diarrhea.
AB - The objectives of this study were to determine the prevalence of enteric
verocytotoxigenic E. coli (VTEC) infection in a population of cats in Ontario,
and to determine whether an association exists between the presence of VTEC and
feline diarrhea. Fecal samples from 179 cats, representing 113 cats with diarrhea
and 66 cats with normal feces, were cultured for E. coli. The fecal cultures were
screened for verocytotoxin activity with a Vero cell assay. Confirmation of the
presence of verocytotoxin (VT) genes was done with polymerase chain reaction
(PCR) amplification; the frequency of occurrence of the genes for generic VT,
VT1, and VT2 was determined. VTEC-positive samples were defined as those that
demonstrated cytotoxicity on the Vero cell assay and yielded E. coli possessing
one or more of the VT genes. All VTEC-positive isolates were serotyped. The
overall prevalence of enteric VTEC infection in the cats was 12.3% (22/179).
Statistical analysis of the case-control data showed no significant association
between VTEC infection and diarrheal illness. The majority of the cats with VT
positive E. coli were positive for the presence of the generic VT, rather than
for VT1 or VT2; it is therefore possible that a novel verocytotoxin gene may
exist in E. coli isolated from cats. Eight VTEC strains were identified by
serotyping; 4 of these serotypes have previously been isolated from humans, and 2
from cattle, suggesting that cats may be capable of acting as reservoirs for
human and bovine VTEC serotypes.
PMID- 9553705
TI - Localization of potential binding sites for the edema disease verotoxin (VT2e) in
pigs.
AB - The purpose of this study was to identify organs and cells to which the edema
disease verotoxin (VT2e) could bind in pigs. Frozen 4-5 microns thick sections of
organs usually affected in edema disease (colon, spinal cord, cerebellum and
eyelid) and organs not usually affected (liver, ileum) from two 5- to 6-week-old
weaned pigs were permeabilized with acetone, then exposed to VT2e. Unbound VT2e
was removed by washing and bound VT2e was detected by immunohistochemistry. In
the eyelid, double-label immunofluorescence was used to identify the cells to
which VT2e bound. VT2e was shown to bind to all six organs that were examined.
The toxin bound to arteries in all organs, to veins in all organs except the
liver, and to enterocytes in the ileal crypts. Double labelling of eyelid with
monoclonal antibodies specific for von Willebrand factor or alpha-smooth actin
and VT2e showed that the toxin bound to endothelial and vascular smooth muscle
cells. The binding of VT2e to endothelium is consistent with findings for other
verotoxins but binding to vascular smooth muscle has not been reported for other
verotoxins. It is concluded that i) factors other than the presence of receptors
for VT2e influence the development of lesions in edema disease, and ii) smooth
muscle necrosis, which is characteristic of the vascular lesions in edema
disease, may be due to a direct action of toxin on smooth muscle cells.
PMID- 9553707
TI - Pathogenesis of porcine Actinobacillus pleuropneumonia: Part I. Effects of
surface components of Actinobacillus pleuropneumoniae in vitro and in vivo.
AB - To understand the role of non-secreted components of Actinobacillus
pleuropneumoniae in virulence, we investigated in vitro cytotoxicity and in vivo
pulmonary changes in pigs due to various A. pleuropneumoniae (serotype 1)
fractions. Following 1.5 h incubation, lipopolysaccharide (LPS), 2 crude extracts
and bacterial culture supernatant (BCS) at high concentrations were cytotoxic to
porcine pulmonary alveolar macrophages (PAM), peripheral blood mononuclear
leucocytes, neutrophils and a cultured porcine bone marrow cell line. Heat-killed
bacteria were cytotoxic to PAM after 24 h incubation. The 2 crude extracts were
prepared by shaking either intact bacteria after removing culture supernatants
(crude surface extract, CSE), or whole bacterial culture (crude surface plus
culture supernatant extract, CSSE) with glass beads in saline at 60 degrees C.
Further experiments showed that proteins from the bacterial membrane were
partially involved in cytotoxicities of these 2 extracts. Both BCS and CSSE
caused multivocal hemorrhage and neutrophil infiltration when inoculated into
porcine lungs, but CSE did not. The lung:whole body weight ratios of the pigs
treated with CSSE were significantly higher (P < 0.05) than those of pigs treated
with BCS, CSE, or control solution. It is concluded that beside the secreted
proteins, bacterial surface components including LPS and non-secreted proteins
were cytotoxic in vitro; and secreted and non-secreted components act
synergistically to cause lung lesions.
PMID- 9553708
TI - The immunological response of llamas (Lama glama) following experimental
infection with Mycobacterium bovis.
AB - Llamas were experimentally infected with Mycobacterium bovis in order to evaluate
the axillary skin test and the ELISA as diagnostic procedures for tuberculosis in
llamas (Lama glama). Six llamas were given a single intratracheal challenge with
1 of 2 doses of a recent field isolate of M. bovis and 2 llamas were left as
noninfected controls. This resulted in a progressive disease in some animals with
1 mortality as early as 68 d post-infection (PI). The tuberculin skin test, at
the axillary site, was positive in 4 of 5 infected llamas at 80 d PI. At 143 d
PI, all 3 surviving lamas were positive, including the one which had not
responded at 80 d PI. The application of skin and serological tests throughout
the course of this experiment adds support for the need to further evaluate the
skin test and its anamnestic effect on serodiagnosis since serological responses
were generally not observed in the absence of skin testing or antibiotic
treatment. The wide variation in M. bovis antigens recognized by the serological
response would indicate that a diagnostic panel should include multiple antigens
such as MPB70 and lipoarabinomannan (LAM). While skin testing or serology alone
may be of limited value to diagnose tuberculosis in llamas, together they may
offer an enhanced potential for immunodiagnosis of tuberculosis.
PMID- 9553709
TI - Differentiation between porcine reproductive and respiratory syndrome virus
isolates by restriction fragment length polymorphism of their ORFs 6 and 7 genes.
AB - Three distinct antigenic profiles were identified by comparing the reactivities
of 15 Canadian field isolates, the attenuated U.S. vaccine (Ingelvac MLV) strain
and 2 European reference strains (Lelystad and Weybridge) of the porcine
reproductive and respiratory syndrome virus (PRRSV) by indirect
immunofluorescence with a set of 4 monoclonal antibodies to the nucleocapsid (N)
protein and 2 other to the matrix (M) protein. In the present study, 9 Canadian
isolates for which the sequences were determined appeared closely related to 2
U.S. reference strains (ATCC VR-2332 and ATCC VR-2385) with amino acid identities
varying between 90 to 98% for the M and N proteins; substitutions in the
nucleotide sequences were distributed randomly throughout the ORFs 6 and 7 genes,
and most were 3rd base silent mutations. In comparison, more than 30% divergence
was demonstrated with the Lelystad virus. Furthermore, differentiation between
North American and European isolates, and between field isolates and the MLV
strain could be achieved by cutting PCR-amplified products encompassing both ORFs
6 and 7 genes with 4 restriction endonucleases. When taken individually, BsaJI
and AluI were the more appropriate restriction enzymes for distinguishing the
vaccine strain from field isolates. The results obtained suggest that the
restriction fragment length polymorphism of the genomic region covering the ORFs
6 and 7 genes may be a valuable tool to differentiate among PRRSV isolates.
PMID- 9553710
TI - A bovine mammary endothelial/epithelial cell culture model of the blood/milk
barrier.
AB - The complex nature of the mammary gland has hampered in-depth studies of the
relationship of the circulatory system to cells lining the teat ducts and alveoli
of the gland. This study reports an in vitro model of endothelial and epithelial
cells separated by a subcellular matrix that simulates the blood milk barrier of
the bovine mammary gland. Dual chamber culture dishes with a porous membrane
separating the upper and lower chamber were used. Endothelial and epithelial
cells were cultured on opposite sides of the porous membrane. A collagen and
fibroblast subcellular matrix, separating the 2 cell layers, simulated the in
vivo interstitial tissue. Changes in surface binding of anti-bodies to
polymorphonuclear neutrophils (PMN) following their migration from the upper to
the lower chamber simulated the passage of PMN from blood to milk. Changes in the
binding of antibodies to PMN agreed with results observed following the migration
of PMN from blood to milk in vivo. This gives credence to the model's potential
value for studies where more direct observation of the blood/milk barrier is
required. The model will be further tested for its usefulness as an assay for
determining: 1) antibiotic diffusion from milk to blood and from blood to milk,
2) cytotoxicity of prophylactic and therapeutic mammary infusion products, 3)
factors affecting bacterial adhesion and penetration of mammary epithelial
tissue, 4) effectiveness of antibodies present in lacteal secretions in
preventing bacterial adhesion, and 5) the feasibility of gene constructs to
induce synthesis and secretion of mastitis-preventing compounds and prophylactic
and therapeutic compounds for treatment of human disorders.
PMID- 9553712
TI - Purification of myeloperoxidase from equine polymorphonuclear leucocytes.
AB - Increases of plasma concentrations of neutrophil myeloperoxidase (MPO) can be
used as markers of polymorphonuclear leucocytes (PMN) activation in pathological
situations (sepsis, acute lung injury, acute inflammation). To develop an assay
for measurement of plasma MPO in horses during the above-mentioned infectious and
inflammatory conditions, MPO was purified from equine PMN isolated from blood
anticoagulated with citrate. PMN were extracted in a saline milieu (0.2 M Na
acetate, 1 M NaCl, pH 4.7) to eliminate most of cellular proteins. Pellets were
then extracted in the same buffer containing cationic detergent (1%
cetyltrimethyl ammonium bromide). The supernatant was further purified by ion
exchange chromatography (Hiload S Sepharose HP column 0.5 x 26 cm, equilibrated
with 25 mM Na acetate, 0.2 M NaCl, pH 4.7) with a NaCl gradient (until 1 M). Most
of the peroxidase activity of MPO (spectrophotometrically measured by the
oxidation of orthodianisidine by hydrogen peroxide) was eluted at 0.65 M NaCl.
MPO was further purified by gel filtration chromatography (Sephacryl S 200 column
2.6 x 42 cm with 25 mM Na acetate, 0.2 M NaCl, pH 4.7). MPO (specific activity:
74.3 U/mg) was obtained with a yield of 30% from the detergent extraction
supernatant. Electrophoresis (non-reducing conditions) showed 3 bands identified,
by comparison with human MPO, (i) the mature tetrameric enzyme (150 kDa) with 2
light and 2 heavy subunits, (ii) the precursor form (88 kDa) and (iii) a form of
the heavy subunit without the prosthetic heme group (40 kDa). The mature enzyme
and its precursor were glycosylated and possessed peroxidase activity. Equine MPO
showed strong similarities with human and bovine MPO, with an absorption peak at
430 nm (Soret peak) characteristic of ferrimyeloperoxidase. Enzymatic activity
was pH dependent (optimal value at pH 5.5).
PMID- 9553713
TI - Evaluation of an in vitro degranulation challenge procedure for equine pulmonary
mast cells.
AB - Pulmonary mast cells (PMC) are important components of the inflammatory process
in equine allergic lung diseases such as heaves. Very little, however, is known
of the degranulation kinetics of these cells and thus, their pathophysiologic
role remains largely speculative. The purpose of this study was to develop a
repeatable protocol for in vitro equine PMC degranulation. Five mature horses
(sex: 2 M, 3 F; age: 8.8 +/- 6.5 y), historically free of pulmonary disease and
normal on clinical respiratory examination, arterial blood gas analysis,
pulmonary mechanics testing and histamine inhalation challenge, were studied.
Bronchoalveolar lavage was performed on 4 separate occasions, at least 2 d apart,
in a different lung lobe on each occasion. The lavage fluid was concentrated by
centrifugation. Cells were resuspended in modified HEPES/Tyrode, assessed for
viability by Trypan blue exclusion, and PMC concentration determined. Cell
inocula containing 30,000 PMC were incubated with 10(-8) to 6 x 10(-5) M A23187.
Cells were then separated by centrifugation and histamine release (HR) was
determined by fluorometric assay. The procedure was readily performed and yielded
sufficient PMC for 30 to 60 inocula per lavage. Maximal HR (34.4 +/- 16.1%) was
obtained with 10(-5) M A23187. The degranulation process was largely complete by
20 min but cell lysis was negligible. The challenge was repeatable within horse
and produced a mean coefficient of variability of 23.0% following 20 min
incubation with 10(-5) M A23187. We conclude that equine PMC degranulation can be
repeatably performed in vitro and speculate that this protocol may be useful in
further studies on the pathophysiology and treatment of equine allergic lung
diseases.
PMID- 9553711
TI - Serum copper and ceruloplasmin activity at the early growing stage in foals.
AB - Serum concentrations of copper (Cu), zinc (Zn), manganese (Mn), calcium (Ca) and
inorganic phosphorus (P), as well as antigenic ceruloplasmin (Cp) and oxidase
activity as a functional index for copper metabolism, were measured in 10 foals
(5 males and 5 females) and their dams. Samples were harvested from the foals
within 1 wk after birth and monthly from 1 to 17 mo of age. Samples were
collected from their dams in the perinatal period (monthly from 2 mo before
delivery to 5 mo postpartum). Serum oxidase activity, antigenic Cp and Cu in
foals were extremely low at 1 wk. Serum Cp had the lowest value of 17.0 +/- 8.0
(mean +/- SD) mg/dL within the 1st wk, then increased rapidly up to 43.7 +/- 5.8
mg/dL at 1 mo, and maintained this level until the 17th mo. Serum Zn in foals had
the highest value of 73.2 +/- 13.1 micrograms/dL within 1 wk, then decreased to
38.3 +/- 5.9 micrograms/dL by 17 mo. Serum Mn, Ca and P in mares were almost
stable and within established reference ranges for our laboratory in the
perinatal period, and these values in foals were also in the normal range. Even
on appropriate feeding, serum Cu, Cp and oxidase activity were quite low a few
weeks after birth, while a higher proportion of Cp-binding copper was found in
the foals. This might be caused by the limited synthesis of ceruloplasmin in this
period. These data suggest that newborn foals are in a critical situation of
marginal copper status in the early stage of growth.
PMID- 9553714
TI - An evaluation of the clinical pathologic findings in experimentally induced
urinary bladder rupture in pre-ruminant calves.
AB - The purpose of this project was to study the biochemical abnormalities that
develop over time in preruminant calves with experimentally induced
uroperitoneum. Uroperitoneum was produced by incising the bladder via a standing
left flank laparotomy. Serum and peritoneal concentrations sodium, chloride,
potassium, phosphate and creatinine were determined at 0, 2, 4, 8, 24, and 40 h.
Serum creatinine concentration was increased by 8 h post-bladder rupture.
Peritoneal concentrations of potassium and phosphate were significantly elevated
2 h after bladder rupture and peritoneal creatinine was significantly elevated by
4 h. Serum to peritoneal fluid ratios for potassium, phosphate and creatinine
exceeded 2:1 within 2 h of bladder rupture. Pre-ruminant calves with
experimentally induced uroperitoneum did not become hyperkalemic during the 40 h
experiment.
PMID- 9553715
TI - An evaluation of protein/fat ratio in first DHI test milk for prediction of
subsequent displaced abomasum in dairy cows.
AB - First DHI test milk that was sampled prior to displaced abomasum (DA) diagnosis
was used to evaluate milk protein/fat ratio (PFR) for prediction of subsequent DA
in dairy cows. Odds ratio, sensitivity, specificity, and likelihood ratio were
determined. Twenty-seven DA cases were matched to 3 controls per case by herd and
calving date. Milk was tested at a median of 19 d after calving, which was 8 d
prior to the median time of DA diagnosis. Adjusted for parity and days in milk, a
protein/fat ratio < or = 0.72 was 8.2 times more likely to come from a cow
subsequently diagnosed with DA than a protein/fat ratio > 0.72. Using the cut off
value of 0.72, the sensitivity of PFR for DA was 80% and the specificity was 68%.
A receiver operating characteristics curve indicated that the minimum sum of
false negative and false positive results was at a PFR cut off value of 0.72. The
likelihood ratio indicated that protein/fat ratios < or = 0.62 are 3.8 times more
likely to come from cows that are diagnosed subsequently with DA than from cows
without DA. The protein/fat ratio in 1st DHI test milk may predict subsequent DA
in dairy cows.
PMID- 9553716
TI - Molecular cloning and expression of the canine metallothionein-III gene.
AB - We have isolated and determined the complete nucleotide sequence of canine
metallothionein-III (MT-III) cDNA. The predicted amino acid sequence of the
canine MT-III showed a high homology (93%, 87% identity) to that of human and
mouse MT-III. The canine MT-III had 2 insertions relative to known mammalian MT-I
and MT-II: a threonine after the 4th amino acid and a block of 6 amino acids near
the carboxyl terminus. Expression of the canine MT-III mRNA was found exclusively
in the central nervous system, where neurons in the olfactory bulb, hippocampus
and cerebral cortex showed predominant signals.
PMID- 9553717
TI - A monoclonal antibody-based immunoperoxidase monolayer (micro-isolation) assay
for detection of type 1 and type 2 bovine viral diarrhea viruses.
AB - A monoclonal antibody (mAb)-based immunoperoxidase monolayer assay (IPMA) for
detection of bovine viral diarrhea virus (BVDV) was developed and compared with
an existing bovine polyclonal antibody (pAb)-based IPMA. A pool of 5 mAbs, 4 mAbs
produced to a type 1 BVDV and 1 mAb produced to a type 2 BVDV, was utilized in
the mAb-IPMA. The mAbs were chosen for inclusion in the pool because of their
broad cross-reactivities with type 1 and/or type 2 BVDV, their apparent avidities
for antigen, their reactivity to different BVDV proteins, and their lack of
competition for binding sites or their binding to unusual BVDV isolates. The mAb
IPMA outperformed the pAb-IPMA in staining, ease of reading test results, and
relative sensitivity with a panel of known BVDV positive and negative sera. The
relative sensitivities of the mAb-IPMA and pAb-IPMA were 100% and 93.5%,
respectively, for 62 positive samples including several that were known to
contain type 2 BVDV. With retesting, the pAb-IPMA gave a similar level of
sensitivity as that of the mAb-IPMA. Both tests gave a specificity of 100% for 40
negative serum samples obtained from a BVDV-free herd.
PMID- 9553718
TI - Expression of a 50 kDa putative receptor for bovine viral diarrhea virus in
bovine fetal tissues.
AB - The expression of a 50 kDa bovine viral diarrhea virus putative receptor in
different bovine fetal tissues from 3-month old fetuses was studied. The receptor
expression was examined by immunocytochemical staining and by immunoblotting
using antiidiotypic probe (anti-D89). Intense specific staining in enterocytes of
the small and large intestines, cortical tubular epithelial cells of kidneys,
respiratory epithelial cells of the trachea and esophageal mucosal epithelial
cells was observed, demonstrating the strong expression of bovine viral diarrhea
virus receptor in the tissues. Weak staining was found in cerebellum, thymus,
spleen, liver, cerebrum, and lung tissues; however, heart tissues were negative.
Immunoblotting results correlated with the immunoperoxidase staining assays.
Thus, the expression levels of the receptor are variable in different tissues.
This pattern of expression may provide clues to the pathogenic potential of
bovine viral diarrhea virus in the bovine fetus.
PMID- 9553719
TI - Transcriptional modulation of foreign gene expression in engineered somatic
tissues.
AB - Many diseases that are candidates for gene therapy require that the therapeutic
gene expression level be controlled to ensure biological efficacy and to prevent
toxic effects. Various systems have been described that allow transcriptional
regulation by artificial chimeric transactivators in mammalian cells. This paper
describes these various systems and discusses their interests for gene therapy.
PMID- 9553720
TI - Cationic lipid-mediated gene transfer: analysis of cellular uptake and nuclear
import of plasmid DNA.
AB - Cationic lipids are widely used for gene transfer in vitro and show promise as
vectors for in vivo gene therapy applications. However, there is limited
understanding of the cellular mechanisms involved in nonviral gene transfer. We
investigated two major steps that could be limiting barriers to cationic lipid
mediated gene transfer in vitro. We used a fluorescent plasmid to study the
cellular uptake and the intracellular fate of lipoplexes during in vitro
transfection of fibroblast cells and found that 100% of the cells take up
lipoplexes. The intracellular staining observed with lipoplexes was clearly
different from that obtained with endocytosed fluorescent dextran. This suggests
that cells readily take up lipoplexes by a mechanism that could be different from
endocytosis in our conditions. However, the escape of DNA from intracellular
vesicles could be a major limiting barrier to gene transfer. Direct injection of
plasmid DNA into the nucleus and cytoplasm of cells indicated that DNA traffic
from the cytoplasm to the nucleus might be also an important limiting step.
PMID- 9553721
TI - Retrovirus-mediated DNA repair gene transfer into xeroderma pigmentosum cells:
perspectives for a gene therapy.
AB - The rare hereditary disease xeroderma pigmentosum (XP) is clinically
characterized by extreme sun sensitivity and an increased predisposition for
developing skin cancer. Cultured cells from XP patients exhibit hypersensitivity
to ultraviolet (UV) radiation due to the defect in nucleotide excision repair
(NER), and other cellular abnormalities. Seven genes identified in the classical
XP forms, XPA to XPG, are involved in the NER pathway. In view of developing a
strategy of gene therapy for XP, we devised recombinant retrovirus-carrying DNA
repair genes for transfer and stable expression of these genes in cells from XP
patients. Results showed that these retroviruses are efficient tools for
transducing XP fibroblasts and correcting repair-defective cellular phenotypes by
recovering normal UV survival, unscheduled DNA synthesis, and RNA synthesis after
UV irradiation, and also other cellular abnormalities resulting from NER defects.
These results imply that the first step of cellular gene therapy might be
accomplished successfully.
PMID- 9553722
TI - Apoptosis: identification of dying cells.
AB - Cell death is usually classified into two broad categories: apoptosis and
necrosis. Necrosis is a passive, catabolic process, always pathological, that
represents a cell's response to extreme accidental or toxic insults. Apoptosis,
in contrast, occurs under normal physiological conditions and is an active
process requiring energy. However, apoptosis can also be elicited in a
pathological way by toxic injury or during disease processes. In these
nonphysiological conditions, both types of cell death can be encountered
following the same initial insult and the balance between death by apoptosis and
by necrosis appears to depend upon the intensity of the injury and the level of
available intracellular ATP. It is important, however, to discriminate between
apoptosis and necrosis in pathological conditions, as therapeutic intervention
could be considered in apoptotic cell death with putative new pharmacological
agents aimed at interfering with the key molecular events involved. In most
cases, none of the current laboratory techniques used alone allows for
unambiguous identification of apoptotic cells. Some of the most common methods
based on morphology, biochemistry, and plasma membrane changes are discussed in
terms of specificity and possible sources of error in data interpretation. As a
rule, classification of cell death in a given model should always include
morphological examination coupled with at least one of the other assays.
PMID- 9553723
TI - Proteases, proteolysis, and apoptosis.
AB - Proteolytic cleavage of a limited number of cellular proteins is a central
biochemical feature of apoptosis. Aspartate-specific cysteine proteases, the so
called 'caspases', are the main enzymes involved in this process. At least ten
homologues of interleukin-1 beta converting enzyme (ICE), the first described
human caspase, have been identified so far. The purified active proteins are
heterodimers with a long and a short subunit derived from a common inactive
precursor. Crystallized ICE has an original tetrameric structure. The various
caspases tend to show high degrees of homology around the active site Cys.
Proteolysis by caspases minimally requires a tetrapeptide substrate in which Asp
is an absolute requirement in P1 position, the P4 substrate residue is unique to
each homologue, and much more widespread amino acid substitution is observed in
P2 and P3. Caspase activation might involve a proteolytic cascade similar to that
of the coagulation cascade but the molecular ordering of these proteases in vivo
remains to be established clearly. Calpains, serine proteases, granzymes and the
proteasome-ubiquitin pathway of protein degradation are other proteolytic
pathways that have been suggested to play a role in apoptosis. Substrate proteins
can be either activated or degraded during cell death and the consequences of
their cleavage remains mostly ill-understood. Nevertheless, the recent
demonstration that protease inhibitors can rescue mice undergoing acute liver
destruction indicates the accuracy of therapeutic strategies aiming to inhibit
cell death-associated proteolysis.
PMID- 9553725
TI - Mitochondrial permeability transition in apoptosis and necrosis.
AB - Apoptosis has classically been viewed as a process not involving mitochondria,
whereas the implication of mitochondrial dysfunction in necrosis has been
recognized for several decades. Recently, it has become clear that apoptosis
implies a disruption of mitochondrial membrane intregrity that is decisive for
the cell death process. Cytofluorometric methods assessing the mitochondrial
membrane function and structure can be employed to demonstrate that, at least in
most models of apoptosis, mitochondrial changes precede caspase and nuclease
activation. Moreover, pharmacological and genetic experiments suggest that the
loss of mitochondrial membrane integrity is a critical event of the apoptotic
process, beyond or at the point of no return of programmed cell death. Inhibitors
of the mitochondrial megachannel (= permeability transition pore) can prevent
both the mitochondrial and the post-mitochondrial manifestations of apoptosis.
PMID- 9553724
TI - Proteolytic cleavage of retinoblastoma protein upon DNA damage and Fas-mediated
apoptosis.
AB - Proteolytic cleavage of key cellular proteins by caspases (ICE, CPP32, and Ich
1/Nedd2) may be crucial to the apoptotic process. The retinoblastoma tumor
suppressor gene is a negative regulator of cell growth and the retinoblastoma
protein (pRb) exhibits anti-apoptotic function. We show that pRb is cleaved
during apoptosis induced by either UV irradiation or anti-Fas antibody. Our
studies implicate CPP32-like activity in the proteolytic cleavage of pRb. The
kinetics of proteolytic cleavage of pRb during apoptosis differ from that
observed for other cellular proteins, suggesting that the specific cleavage of
pRb during apoptosis may be an important event.
PMID- 9553726
TI - Out of otherness: characters and narrators in the Dutch venereal diseases debates
1850-1990.
PMID- 9553728
TI - Intrauterine position, parenting, and nest-site attachment in male Mongolian
gerbils.
AB - We housed male Mongolian gerbils, their mates, and foster litters of standardized
size and sex ratio in enclosures that provided cover in two locations. Males had
been gestated in known intrauterine positions: either between two females (2F
males) or between two males (2M males). From Days 1 to 20 postpartum, we examined
the frequency with which both males and females were in contact with the pups
they were rearing. We found that 2F males spent more time with pups than did 2M
males both during entire observation periods and when females were away from the
nest. Further, when pups were moved from the nest site. 2M males spent more time
than did 2F males in the vacated nest site. We concluded that 2F male gerbils
spent more time with pups than 2M males not because of a greater attachment of 2F
than 2M males to places of concealment, their male, or their nest site. Rather,
2F males were more attracted to pups than were 2M males.
PMID- 9553727
TI - Maintenance of arterial pressure in infant rats during moderate and extreme
thermal challenge.
AB - It has recently been demonstrated in week-old rats that extreme cold challenges
that lead to significant bodily cooling result in decreased cardiac rate. To
determine whether pups are able to maintain arterial pressure in the face of
decreasing cardiac rate in extreme cold, we measured blood pressure in
unanesthetized week-old rats. Instrumented pups were thermally challenged and
thermoregulatory and cardiovascular responses were monitored. Despite pronounced
decreases in cardiac rate in the cold, pups were able to maintain mean arterial
pressure (MAP), presumably by increasing peripheral resistance. At the lowest air
temperature (17 degrees C) pups emitted ultrasonic vocalizations, and these
emissions were accompanied by pulsatile increases in intraabdominal pressure
(IAP) and MAP. We hypothesize that these pulsatile increases in IAP during
extreme cooling reflect the use of the abdominal compression reaction to increase
venous return during periods of diminished cardiac output.
PMID- 9553729
TI - The timing of food availability affects growth in chicks.
AB - Three experiments challenged the ability of domestic chicks to grow normally by
differentially restricting when and for how long food was available. In
Experiments 1 and 2, food was available for six 1-hr, three 2-hr, two 3-hr, or
one 6-hr (a.m., p.m.) periods/day over the first 3 posthatch weeks. Control
groups received continuous access to food. In Experiment 3, different amounts of
light surrounded the 6-hr feeding period. In Experiments 2 and 3, chicks composed
their own diets from separate sources high in protein or carbohydrate. Except for
the single 6-hr meal preceding dark, large meals at other times of day impaired
growth--primarily because chicks consumed insufficient dietary protein and ate
less earlier in the light phase. We conclude that both the amount eaten and the
proportion of the diet consumed as protein at given times of the day are
phylogenetically acquired strategies that fit the omnivorous, diurnal chicken to
its niche, independent of its momentary requirements, and appear early in
development.
PMID- 9553730
TI - Stimulus intensity modulates associative and nonassociative responding in
preweanling rats.
AB - The purpose of the present study was to determine whether preweanling rats
respond differentially to the intensity and energy source of a stimulus. Previous
studies have suggested that infants process compound stimuli based on net
stimulus intensity regardless of the energy source of the compound's elements,
but more direct tests have been needed of the infant's response to the stimulus
attributes of intensity and energy source. This response was tested for auditory
and visual stimuli that had been equated (Experiment 1) in terms of perceived
intensity (low and high). Intensity level and energy source of the stimuli were
varied independently within nonassociative (Experiment 2) and associative
(Experiment 3) procedures. The overall results indicate that stimuli of a low
perceived intensity were processed in terms of their intensity, whereas high
intensity stimuli were processed on the basis of energy source. These results are
relevant to contemporary issues of cognitive development in humans and animals.
PMID- 9553731
TI - Primacy and recency effects in rhesus monkeys (Macaca mulatta) using a serial
probe recognition task. III. A developmental analysis.
AB - In children, the recency effect emerges prior to the primacy effect. To determine
whether this dissociation is also seen in nonhuman primates, we evaluated the
development of the primacy and recency effect in 3 young adult (35 months) and 4
adolescent (21 months) male rhesus monkeys (Macaca mulatta) using a six-item
serial probe recognition (SPR) task. As predicted, the young adult monkeys
displayed both effects, while the adolescent monkeys only displayed the recency
effect. Not until after 26 months of training on the SPR task did the adolescent
monkeys exhibit both the primacy and recency effect. Interference and strategy
differences are discussed in terms of the results along with an interpretation of
Rudy's (1992) configural association theory of cognitive development. Additional
possible explanations for this developmental dissociation include the delayed
maturation of the neocortical, hippocampal, and/or cholinergic systems, the
latter two having been shown to be important in the expression of the primacy but
not the recency effect.
PMID- 9553732
TI - Long-term effects of postnatal manipulation on emotionality are prevented by
maternal anxiolytic treatment in mice.
AB - This study investigated the role of maternal behavior on the long-term effects of
postnatal manipulation (15 min of daily separation from the dam and exposure to
clean bedding from Day 1 to Day 14 of postnatal life) on emotionality in the
mouse. Mothers were treated with an antianxiety agent (Chlordiazepoxide: 5
mg/kg), daily upon removal of the litter from the nest. Emotionality in adult
offspring was tested in the elevated plus maze. Mice manipulated during postnatal
development were more explorative and less anxious than unhandled mice, but this
effect was not observable in the offspring of Chlordiazepoxide-treated dams. No
effect of maternal Chlordiazepoxide was observed in unhandled offspring. The
pharmacological treatment of the mother did not affect either pups' ultrasonic
calling during separation, or maternal behavior far apart from the daily
manipulation sessions. By contrast, Chlordiazepoxide-treated dams were less
responsive toward pups upon reunion following daily separation. This alteration
of dams' behavior was not related to alterations in the amount of ultrasonic
calls emitted by pups during reunion. Finally, when dams were daily injected with
Chlordiazepoxide far apart from pups' removal, the pharmacological treatment was
devoid of effects. These results support the view that the mother-infant
interaction which follows separation plays a major role in determining the
effects of postnatal manipulations on adult emotionality.
PMID- 9553733
TI - Evidence for a phase transition in the early development of prehension.
AB - A longitudinal study was conducted to examine the hypothesis that the development
of prehension during the first 5 months of life is characterized by the presence
of a discontinuous phase transition. Ten infants were observed weekly from 8 to
24 weeks of age. Video recordings were made of movements toward an attractive
object which were classified according to two behavioral categories: reaching
without grasping and reaching with grasping. The time evolution of the relative
incidence of these behavioral categories was analyzed statistically. Evidence was
found for a sudden jump from a (developmental) state in which reaching without
grasping is predominant to a state in which reaching with grasping is
predominant. Evidence was also found for bimodality, inaccessibility, and
anomalous variance. In combination, these findings support the hypothesis that
the investigated behavioral change constitutes a discontinuous phase transition.
The behavioral change in question occurred at the moment in developmental time at
which the attractor strength of reaching for objects as such relative to that of
other behavioral activities appeared to be increased.
PMID- 9553734
TI - Psychotropic drugs in breast milk: no evidence for adverse effects on prepulse
modulation of startle reflex or on cognitive level in infants.
AB - Reversals in modulation of the startle reflex probably reflect maturational
processes in the central nervous system. This study has investigated the
longitudinal changes in prepulse modulation of the blink reflex in three groups
of individual infants: (a) breast-fed infants of mentally ill mothers who were
prescribed selected psychotropic drugs, (b) bottle-fed infants of similarly ill
and medicated mothers, and (c) breast-fed infants of healthy control mothers. The
acoustic stimulation paradigm and neurophysiological methods were similar to
those used in previous studies and, in addition, the infants' development was
simultaneously assessed using the Bayley Scales of Infant Development. All the
infants were found to be developing normally and across all three groups we
observed a clear transition in prepulse modulation of the eye-blink reflex from
small inhibition or facilitation in early infancy (1-4 months) to a robust
facilitation in middle infancy (5-8 months). This reversal probably reflects the
changing balance of developing neural function in normal infants. There were,
therefore, no discernible effects in breast-fed infants of exposure to small
doses of antidepressant or neuroleptic drugs.
PMID- 9553735
TI - Detection of the low density lipoprotein receptor gene PvuII intron 15
polymorphism using the polymerase chain reaction: association with plasma lipid
traits in healthy men and women.
AB - We have used anchored PCR to amplify and sequence 1400 bp of the 15th intron of
the Low Density Lipoprotein (LDL) receptor gene, and have determined
oligonucleotides and conditions for the genotyping of the previously reported
PvuII polymorphism. The cutting site (CAGCTG) is created by the transition of a
CpG to a TpG within the sequence CAGCCG at a position roughly 600 bp 5' from the
splice acceptor site of exon 16. Genotype was determined in three population
based samples of healthy individuals. In a group of 318 men and women from
Iceland the frequencies of the Intron-15 T (cutting) allele was 0.23 (95% CI,
0.19-0.28) and was similar in men and women. In two groups of men from England (n
= 385) and Scotland (n = 320), the frequency was similar, being 0.23 (0.19-0.27)
and 0.25 (0.22-0.28) respectively. Individuals who were homozygous for the T
allele had lower levels of total-cholesterol triglycerides and apolipoprotein B,
than those with other genotypes, and in the combined group of UK men this effect
reached statistical significance; compared to the C/C group, the T/T group had 6%
lower cholesterol (p = 0.02) and 15% lower triglycerides (p = 0.03). The lowering
effect associated with the T/T genotype was greater in men who were in the lowest
tertile of body mass index (< 25 kg/m2) and for the trait of apoB levels, this
genotype x obesity interaction was statistically significant (p = 0.01). We thus
confirm the association between this allele and lower levels of plasma lipid
levels previously reported. The availability of a PCR-based method to detect this
polymorphism will facilitate further investigation of the impact of LDL-receptor
gene variation in determining lipid levels.
PMID- 9553736
TI - Fas gene polymorphisms are not associated with systemic lupus erythematosus,
multiple sclerosis and HIV infection.
PMID- 9553738
TI - A strategy and demonstration for integrated biotechnology information.
AB - Bioinformatics has developed as a key discipline to support science. Integrated
access to the various new and established information resources is a key
requirement for their future utility. A strategy for this integration has been
developed and is being demonstrated to a core group of European users.
PMID- 9553737
TI - Analysis of the association of a heat shock protein70-1 gene promoter
polymorphism with myocardial infarction and coronary risk traits.
AB - Heat shock proteins (HSP) are induced during coronary ischaemia, and abnormal
expression of one HSP gene may cause hypertension in rats. We examined
association of a promoter polymorphism in the major stress-inducible hsp70 gene
(hsp70-1 or HSP70A1) on chromosome 6 (p21.3) with coronary disease traits. This C
->A base substitution (AAACCCC) is at nucleotide position-110 in the heat shock
transcription factor binding site (heat shock element, HSE). The first study
sample (ECTIM), recruited from Belfast and three centers in France, consisted of
578 myocardial infarction cases and 698 age-matched controls. The frequency of
the A-110 allele was 0.381 (95% CI = 0.35-0.41) and 0.384 (95% CI = 0.36-0.41) in
cases and controls respectively. Homozygotes for the rarer A-110 allele had a
higher BMI (27.3 kg/m2 +/- 3.9) compared with homozygotes for the common C-110
allele (26.3 kg/m2 +/- 3.3). The rarer homozygotes were shorter and heavier than
the common homozygotes. A follow-up study involved 1431 healthy, middle aged men
from the UK (NPHS II group). The frequency of the A-110 allele was 0.385 (95% CI
= 0.37-0.40), and there was no association of genotype with BMI. Thus there
appears to be no strong association of the Hsp70-1 promoter polymorphism with
risk of myocardial infarction, BMI or any coronary disease traits analysed here.
PMID- 9553739
TI - Comparison of commercial ELISA for detection of antibodies to the viral capsid
antigen (VCA) of Epstein-Barr virus (EBV).
PMID- 9553740
TI - Haplotypes of the endogenous retrovirus HRES-1 in multiple sclerosis patients and
healthy control subjects of Shanghai Chinese origin.
PMID- 9553741
TI - Alpha 1-antichymotrypsin mutations in patients with chronic obstructive pulmonary
disease.
AB - Mutations in the alpha 1-antichymotrypsin gene have been described which result
in reduced levels of alpha 1-antichymotrypsin in the serum. Previous studies have
suggested that two of these mutations (Pro227-->Ala and Leu55-->Pro) predispose
to chronic obstructive pulmonary disease (COPD). We have investigated the
prevalence of these mutations in 168 COPD patients and 61 controls without
airflow obstruction. The prevalence of the Pro227-->Ala mutation was 0.9% and it
was not associated with impaired lung function. None of the subjects had the
Leu55-->Pro mutation.
PMID- 9553742
TI - BRCA1: a review of structure and putative functions.
AB - BRCA1 is a complex gene implicated in familial breast and ovarian cancer.
Although it is almost certainly a tumour suppressor, it is also essential for the
normal growth and development of embryonic cells. BRCA1 is probably involved in
DNA damage and repair, in cell cycle regulation, and in differentiation of cells.
It remains to be established whether all these functions are subserved by single
mechanism or pathway. Since the cloning of BRCA1 in 1994, much has been learned
about the function of the gene. However, a great deal more still has to be
uncovered. The size of the protein coded by the BRCA1 gene and the variety of
transcripts argues for a complexity of function and regulation that will provide
intellectual and technical challenges for years to come.
PMID- 9553743
TI - Effects of muscle fatigue and temperature on electromechanical delay.
AB - The effect of repeated maximal isometric knee extensions on electromechanical
delay (EMD) and associated muscle temperature changes were investigated on seven
college aged subjects. The exercise produced a significant reduction in muscle
contraction force, rate of force development and muscle conduction velocity,
whilst the muscle temperature increased by 2.1 degrees C. The EMD increased from
a pre-exercise value of 38.4 (SEM 3.4) ms to 55.7 (SEM 3.4) ms post-exercise. In
an attempt to evaluate the effect of muscle temperature on EMD, hot and ice-water
bags were placed on the quadriceps muscle to alter muscle temperature. The EMD in
isometric maximal knee extension was measured at 38, 36, 34, 32 and 30 degrees C.
The results showed that the EMD elongated at muscle temperatures either lower or
higher than 36 degrees C. It was speculated that the increased muscle temperature
might contribute to 20-25% of the EMD elongation found during the fatiguing
intermittent exercise. The information of the effects of muscle temperature on
EMD could be useful when evaluating the effects of strenuous exercise, in which a
substantial muscle temperature change might occur, on the time delay between
myoelectrical activity and force generation.
PMID- 9553744
TI - Quantitative electromyographical changes in cervical dystonia after treatment
with botulinum toxin.
AB - Injection of botulinum toxin (BT) into affected neck muscles gives symptomatic
relief to patients with cervical dystonia by causing a presynaptic block of
acetylcholine release. In a retrospective study of 19 patients, we used the turns
amplitude analysis of the EMG interference pattern for the evaluation of
electrophysiological changes as a function of time after BT treatment. EMG was
performed immediately before and during injection, and muscles showing abnormally
increased activity (> 100 turns/s at rest) were given botulinum toxin A (Oculinum
(= Botox)) 40-120 units. A second EMG was done 6-30 weeks later. At attempted
rest, the sternocleidomastoid muscle contralateral to the involuntary head
rotation showed the most pronounced changes, possibly due to relatively large
doses of BT, and the EMG changes were related to the time after BT treatment. Six
weeks after treatment the muscle showed decreased turns/s, mean amplitude and
ratio (turns/amplitude) at rest. At 30 weeks, turns and mean amplitude reached
values as before treatment, while ratio was increased to 175% of the pre
treatment value. This pattern may reflect a reversible and random loss of muscles
fibres, due to presynaptic denervation. At maximal voluntary contractions, no
correlation was seen between time after BT treatment and quantitative EMG.
PMID- 9553745
TI - Cortical representation of proximal and distal arm muscles as assessed by focal
transcranial magnetic stimulation.
AB - In 21 healthy volunteers, a mapping of cortical areas from which motor evoked
potentials in deltoid muscle and first dorsal interosseal muscle (FDI) could be
elicited by focal transcranial magnetic stimulation was performed. For this
purpose, magnetic stimuli were applied using a figure-of-eight shaped magnetic
coil and a Magstim 200 stimulator at an intensity of 15% above motor threshold
for the deltoid muscle. There was a considerable overlap between the cortical
areas from which motor responses of the two muscles could be evoked with the FDI
represented more laterally than the deltoid muscle. The cortical location from
which maximal amplitudes of motor evoked potentials were elicited was 4-8 cm
lateral of Cz with the FDI and 2-6 cm lateral of Cz with the deltoid muscle.
Calculated centres of cortical points with maximal muscle responses were
significantly separated with the FDI represented 5.7 cm lateral of Cz and deltoid
muscle 4.3 cm lateral of Cz. The anterior-posterior extension of the cortical
maps did not show significant differences between the proximal and distal arm
muscle. In no subject an ipsilateral representation of either muscle could be
found even when stimulating at maximal intensity.
PMID- 9553746
TI - Inhibitory influence of soleus massage onto the medial gastrocnemius H-reflex.
AB - It has previously been reported that the soleus Hoffmann (H-)reflex is diminished
in amplitude during a massage of the ipsilateral triceps surae. A question arises
as to the origin of this decrease. The purpose of this study was to determine
whether massage does indeed diminish motoneuronal excitability or whether the
decrease is an artefact associated with the experimental procedures, i.e.
saturation of the transmission capacity of the afferent pathway. H-reflexes and
the corresponding muscle (m-)responses were recorded from the medial
gastrocnemius (MG) muscle during a 3-minute massage of the ipsilateral soleus
muscle in 12 neurologically healthy adults during 4 control conditions (C1, C2,
C4, C5) and 1 experimental (C3-massage) condition. Peak-to-peak mean amplitudes
of the MG H-reflex obtained during massage were significantly reduced in
comparison to all control values recorded while the subjects were at rest. These
results suggest that massage does indeed diminish motoneuronal excitability,
since these effects were not restricted to the homonymous motoneurone pool, but
could also be demonstrated for a close synergistic muscle, uninvolved in the
massage.
PMID- 9553747
TI - Electrophysiological findings in hereditary motor and sensory neuropathy type I
and II--a conduction velocity study.
AB - We performed clinical and electrophysiological studies in 42 children with
hereditary motor and sensory neuropathy type I and II (HMSN I and HMSN II) and in
103 members of their families. In 24 families with HMSN I the conduction velocity
and the latency were markedly changed in the nerves innervating the distal
muscles (median, peroneal nerves), as well as proximal muscles (facial, axillary,
and musculocutaneous nerves). The changes were uniform in all motor and sensory
nerves studied in the particular patient. No nerve conduction worsening with age
has been found in cross-sectional analysis. In patients with HMSN I the
conduction velocity was impaired even when the clinical abnormalities were
minimal. The degree of the conduction velocity slowing was uniform within
majority of the families. Homogeneity of conduction velocity slowing in
individuals with HMSN I regardless of clinical expression suggests a primary
myelin defect as an underlying cause. In patients from 18 families with HMSN II
slight changes in conduction velocity were found only in the nerves innervating
the distal muscles, the latency of axillary and facial nerves was within normal
range. We recommend examining conduction time in facial and axillary nerves as a
useful procedure for differentiation between HMSN I and II, especially in
families with borderline conduction values in the long nerves.
PMID- 9553748
TI - Analysis of interaction of spinal and supraspinal reflex pathways involved in
physiological tremor.
AB - A model of feedback type in which physiological tremor are produced by both
muscular skeletal system and reflex action is described. Analysis of this model
shows that the interaction between the spinal and the supraspinal reflex pathways
is important in responsible for low and high frequency oscillations of
physiological tremor. Particularly the effect of gain ratio of the two pathways
is studied in order to examine the role for the two reflex pathways in
controlling neuromuscular oscillations. The existence of a critical point of the
gain ratio at which one oscillating frequency transitions to two ones is
predicted theoretically. A shift of the critical point with variations of weight
load is found and suggests a changeable correlation relation between the spinal
and the supraspinal pathways due to loading conditions. Our computations for
physiological tremor demonstrate the results that the high frequency component of
about 25 Hz is produced by the muscle-spinal reflex loop, and the low frequency
component of about 10 Hz originates from the central nervous system or from
supraspinal reflex loop. Several relations derived in this study are described,
and they can be compared with experimental observations. Our model sheds
considerable light on the details of the possible mechanism for physiological
tremor. In addition, a possibility arising from our study is that the tremulous
oscillation associated with some pathological states, say Parkinson's disease,
may arise from modified gains in one or more of the reflex pathways.
PMID- 9553749
TI - Double crush syndrome in lower extremities.
AB - Retrospective analysis of results of electromyography and nerve conduction
velocity was performed in 169 patients with lower back pain, mostly caused by
trauma. A total 289 peroneal, 280 posterior tibial and 301 sural nerves were
included in statistical analysis. Peripheral entrapment of nerves (tarsal tunnel
syndrome and anterior tarsal tunnel syndrome) were found in 5.3% of patients,
signs of acute or chronic partial muscle denervation of corresponding muscles of
lower extremities in 21.8% of patients, and abnormally prolonged F-wave latency
in 12.5% of patients. Combined partial denervation and abnormally prolonged F
wave latency were found in 6.2% of patients, combined partial denervation and
peripheral entrapment of nerves in 4.4% of patients, combined abnormally
prolonged F-wave latency and peripheral entrapment of nerves in 2.4% of patients
and combined partial denervation, abnormally prolonged F-wave latency and
peripheral entrapment of nerves in 3.5% of patients. Statistical analysis of
these data showed significantly higher than random overlap of peripheral
entrapment syndromes and signs of proximal nerve damage of the corresponding
nerves (partial muscle denervation or abnormalities of F-wave). This higher than
random coincidence of the two conditions strongly suggests cause-and-effect
relationship of damage of the proximal stretch of motor nerve fibers and
development of peripheral entrapment syndromes in the same nerves rather than a
random coincidence of two independent pathologies. Appreciation of this causal
relationship is important in the development of comprehensive approach to
treatment of peripheral entrapment syndromes. In appropriate cases, simultaneous
treatment of the lower back problem should be considered as well.
PMID- 9553750
TI - Continuous muscle fibre activity: description of neuroelectromyographic findings
including single fibre EMG.
AB - Four patients with continuous muscle fibre activity (Isaacs-Mertens syndrome) are
reported in this communication. Electrophysiological evidence of peripheral
neuropathy was present in two patients. Impulse induced repetitive CMAPs were
noted in two patients. In one case the repetitive activity increased upon
proximal stimulation. Single fibre EMG recordings of the spontaneous activity
revealed pathological discharges with variable frequencies. Each pathological
discharge comprised of a primary discharge and 1-4 extradischarges. There was
marked variability of the interval between the primary discharge and subsequent
extradischarges.
PMID- 9553751
TI - Distribution and functional significance of angiotensin-II AT1- and AT2-receptor
subtypes in the rat adrenal gland.
AB - The distribution and the functional significance of angiotensin-II (ANG-II)
receptor subtypes, AT1 and AT2, in the rat adrenal gland has been investigated in
vitro. Autoradiographic assessment of the selective displacement of [125I]ANG-II
binding by selective ligands of the two receptor subtypes indicated that zona
glomerulosa (ZG) was provided with both AT1 and AT2, and adrenal medulla (AM)
almost exclusively with AT2 receptors. ANG-II (10(-9) M) evoked a marked rise in
the secretion of aldosterone by dispersed ZG cells and catecholamines by AM
fragments. The selective AT1-receptor antagonist DuP753 blocked aldosterone
response to ANG-II, while the selective AT2-receptor antagonist PD123319 was
ineffective. Catecholamine response to ANG-II was inhibited by PD123319 and only
moderately affected by high concentrations of DuP753. The selective AT2-receptor
agonist CGP42112 did not change basal aldosterone release of ZG cells, but
concentration-dependently enhanced basal catecholamine release by AM fragments.
In light of these findings the conclusion is drawn that in the rat the
aldosterone secretagogue effect of ANG-II is exclusively mediated by the AT1
receptors present in the ZG, while the catecholamine secretagogue action
preminently involves the activation of AT2 receptor located on medullary
chromaffin cells.
PMID- 9553753
TI - Castration differentially regulates nitric oxide synthase in the hypothalamus and
pituitary.
AB - Mammalian reproductive function is under control of the integrated hypothalamic
pituitary-gonadal (HPG) axis. Castration in male rats has been utilized as an
effective tool to investigate hormonal interactions in the mammalian HPG axis.
Recently, nitric oxide (NO) has been suggested to play a role in HPG hormonal
regulation. In order to gain further insight into the function of the NO-NOS
system in reproductive neuroendocrine control, particularly in the gonadal
feedback regulation of the hypothalamic-pituitary unit, we examined steady state
levels of nNOS mRNA, nNOS protein, and the important physiological index, NOS
enzyme activity, of the intrinsic NOergic system in both hypothalamus and
pituitary in castrated male rats and their sham-operated counterparts one week
after surgery. In the pituitary, we found a significant four-fold increase in
nNOS mRNA, p < 0.0003 compared to sham. Castration also resulted in a four-fold
rise in pituitary nNOS protein, p < 0.02 compared to sham. Pituitary NOS enzyme
activity was stimulated 2 fold, p < 0.003 after castration. In the hypothalamus,
conversely, we observed no significant castration-modulated difference in either
nNOS mRNA, nNOS protein or NOS enzyme activity. Thus, it appears that the
hypothalamic NO-NOS system is either not required for hypothalamic adaptations to
castration, although important in the release of LHRH under normal physiological
conditions, or alternatively, the hypothalamus may become more sensitive to the
effects of NO in the castrated state. In the pituitary, NO may attenuate the
gonadotropin response to castration as a local balancing mediator.
PMID- 9553752
TI - The AT2 receptor-mediated stimulation of adrenal catecholamine release may
potentiate the AT1 receptor-mediated aldosterone secretagogue action of
angiotensin-II in rats.
AB - The role played by AT1 and AT2 receptors in the mediation of angiotensin-II (ANG
II) aldosterone secretagogue action has been investigated in vitro using
different types of rat adrenal preparations. ANG-II enhanced aldosterone
secretion of dispersed zona glomerulosa (ZG) cells in a concentration-dependent
manner (EC50, 3 x 10(-10) M), and its effect was annulled by the AT1-receptor
antagonist DuP753 and unaffected by the AT2-receptor antagonist PD123319. ANG-II
was significantly more effective in stimulating aldosterone secretion when
capsule-ZG and adrenal slices containing medullary chromaffin cells were used
(EC50, 1 x 10(-11) M and 7 x 10(-12) M, respectively); moreover, both DuP753 and
PD123319 caused partial reversals (intense and moderate, respectively) of the
responses to ANG-II, and when added together annulled them. The beta-adrenoceptor
antagonist l-alprenolol did not affect aldosterone response to ANG-II of
dispersed ZG cells, but exerted a PD123319-like effect on the responses of
capsule-ZG and adrenal slices. In light of these findings we conclude that, when
the integrity of adrenal tissue is preserved, ANG-II stimulates aldosterone
secretion by activating both AT1 and AT2 receptors, the major role being played
by AT1 receptors located on ZG cells. The activation of AT2 receptors probably
elicits the local release of catecholamines, which in turn enhance aldosterone
secretion in a paracrine manner acting through the beta-adrenoceptors with which
ZG cells are provided.
PMID- 9553754
TI - Characteristics of biochemical markers in patients with metabolic bone disorders.
AB - Biochemical markers of bone turnover are expected to have some different
characteristics among bone metabolic disorders. We compared bone formation
markers: serum total alkaline phosphatase (s-Alp), serum osteocalcin (s-OC) and
serum carboxy-terminal propeptide of type I collagen (s-PICP); and bone
resorption markers: serum carboxy-terminal telopeptide of type I collagen (s
ICTP), urinary pyridinoline (u-Pyr) and urinary deoxypyridinoline (u-Dpyr) to
examine which marker is the most suitable and reliable to evaluate bone turnover
in patients with osteoporosis (n = 29), osteomalacia (n = 10), primary
hyperparathyroidism (n = 6) and renal osteodystrophy (n = 21). The value of s-Alp
in the osteomalacia group was significantly higher than those in the normal
control group and the osteoporosis group (p < 0.001), and T-score of s-Alp was
significantly higher than those of s-OC and s-PICP in the osteomalacia group. The
values of u-Pyr and u-Dpyr in the primary hyperparathyroidism group were
significantly higher than those in the other groups (p < 0.001). S-PICP, which
are not dependent upon renal function, was much higher in the renal
osteodystrophy group than in all other groups. In the osteoporosis group, T-score
of s-ICTP was significantly higher than those of s-OC. Thus, s-Alp was a good
marker in osteomalacia, u-Pyr and u-Dpyr in primary hyperparathyroidism, s-PICP
in renal osteodystrophy, and s-ICTP in osteoporosis.
PMID- 9553755
TI - Pretreatment with glucocorticoid is essential for lactogenic induction of the
bovine beta-casein/CAT expression in HC11 cells.
AB - Hormonal regulation of the bovine beta-casein gene expression was studied in a
murine mammary epithelial HC11 cells and compared with that of the rat beta
casein gene expression. CAT expression vectors driven by their promoter sequences
were transfected into HC11 cells. Stable transfectents were treated with
lactogenic hormones, dexamethasone and prolactin for 2 days in confluent
cultures. While the lactogenic hormones synergistically induced a strong
activation of the rat beta-casein/CAT expression, neither a single or combined
treatment of dexamethasone and prolactin induced the bovine beta-casein/CAT
expression. To test a sequential treatment effect of lactogenic hormones on the
bovine beta-casein/CAT expression, cells were first treated with either
dexamethasone or prolactin for various days and then subjected to the second
treatment with both hormones for 2 days. Only dexamethasone-, but not prolactin
pretreated cells showed a strong lactogenic induction. Moreover, the fold
induction of dexamethasone-pretreated cells increased gradually as a function of
duration of dexamethasone pretreatment. A series of the bovine beta-casein/CAT
constructs with different length of the bovine beta-casein 5' flanking region
ranged from 0.3 kb to about 15 kb was analyzed in 12-days dexamethasone
pretreated cultures. CAT expression was increased even in 0.3 kb-containing
construct, but prominent induction was seen in more than 1.8 kb-containing
constructs. Therefore, it could be concluded that a long-term dexamethasone
pretreatment is essential for lactogenic induction of the bovine beta-casein
expression and the 0.3 kb proximal promoter region is important, but more distal
promoter element(s) is necessary for mediating the coordinated action of
lactogenic hormones to the bovine beta-casein expression.
PMID- 9553756
TI - Catalase transfection decreases hydrogen peroxide toxicity in a pancreatic beta
cell line.
AB - BetaTC6-F7 cells like normal Beta cells were found to be highly sensitive to
hydrogen peroxide and to possess very low levels of catalase. Therefore we tested
whether overexpression of catalase could enhance resistance to hydrogen peroxide.
Enzyme activity was increased forty fold by transient transfection of a catalase
transgene. To assess protection from hydrogen peroxide a cotransfection method
using a human growth hormone reporter gene was developed. Human growth hormone
secretion was shown to be a suitable marker for insulin secretion since both
hormones demonstrated virtually identical glucose dose response curves. Catalase
transfection was found to provide significant protection against hydrogen
peroxide indicating that low catalase may contribute to the sensitivity of cells
to hydrogen peroxide.
PMID- 9553757
TI - Interaction of estradiol, progesterone and corticosterone on uterine connective
tissue degrading enzymes.
AB - The impact of ovarian hormones and corticosterone acetate on uterine connective
tissue degrading enzymes were studied in mature albino rats. Ovariectomy resulted
in a significant increase in the activities of alpha- and beta-galactosidases and
glucosidases in the uterus. Administration of estradiol to ovariectomized rats
brought back the activities of alpha-galactosidase and alpha-glucosidase to
normalcy. While beta-galactosidase and beta-glucosidase were significantly
decreased. Administration of progesterone to ovariectomized rats resulted in the
increase of alpha- and beta-galactosidases and glucosidases. Administration of
corticosterone to ovariectomized rats produced a further increase in alpha- and
beta-galactosidases and glucosidases in the uterus. Adrenalectomy in ovary intact
rats produced a decrease in alpha-galactosidase however, beta-glucosidase was
significantly increased. Administration of corticosterone to ovary intact rats
significantly increased the activities of alpha- and beta-galactosidases, while
alpha- and beta-glucosidases were found to be decreased. Ovariectomy resulted in
a significant increase in the activities of cathepsin-D and cathepsin-E.
Administration of estradiol to ovariectomized rats brought back the activity of
cathepsin-D to normalcy, whereas cathepsin-E was significantly increased.
Administration of progesterone as well as estradiol to ovariectomized rats
significantly increased the levels of cathepsin-E, however, cathepsin-D was
brought back to normalcy. Administration of corticosterone to ovariectomized rats
as well as ovariectomy + adrenalectomy significantly increased the activity of
cathepsin-D and cathepsin-E. Adrenalectomy significantly decreased the activity
of cathepsin-D, while administration of corticosterone increased the cathepsin-D
and cathepsin-E in the uterus. Therefore, these results suggest that estradiol is
a potent ovarian steroid protecting the extra cellular matrix components. The
effect of progesterone appears to modulate and act hand in hand with estradiol.
Corticosterone appears to have an opposite effect to that of estradiol.
PMID- 9553759
TI - [Schizophrenia and quality of life--therapeutic aims to be re-interpreted].
PMID- 9553760
TI - Ecto-enzymes of lymphoid cells.
PMID- 9553758
TI - Plasma atrial natriuretic hormone in hyperthyroidism.
AB - In 22 hyperthyroid patients, atrial natriuretic hormone (ANH) levels (71.91 +/-
21.03 pg/ml), measured during a 3-h-Holter, were found to be significantly higher
(p < 0.001) than those in 20 age-matched normal subjects (37.22 +/- 8.73 pg/ml).
We have demonstrated that the presence of tachiarrhythmias does not influence ANH
release. The positive and significant correlation of FT3 with both ANH and heart
rate confirms the hypothesis of a direct action of thyroid hormones on ANH
release.
PMID- 9553761
TI - Ecto-phosphodiesterase/pyrophosphatase of lymphocytes and non-lymphoid cells:
structure and function of the PC-1 family.
AB - Many developmentally regulated membrane proteins of lymphocytes are ecto-enzymes,
with their active sites on the external surface of the cell. These enzymes
commonly have peptidase, phosphodiesterase or nucleotidase activity. Their
biological roles are just beginning to be discovered. Although their expression
is usually associated with particular stages of lymphoid differentiation, the
same gene products are often expressed on the surface of certain non-lymphoid
cell types outside the immune system, indicating that their functions cannot be
unique to lymphocytes, nor can they be ubiquitous. The plasma cell membrane
protein PC-1 (phosphodiesterase I; EC 3.1.4.1/nucleotide pyrophosphatase; EC
3.6.1.9), which was one of the first serological markers for lymphocyte subsets
to be discovered, is a typical example. Within the immune system, PC-1 is
confined to plasma cells, which represent about 0.1% of lymphocytes. However, PC
1 is also expressed on cells of the distal convoluted tubule of the kidney,
chondrocytes, osteoblasts, epididymis and hepatocytes. Recent work has shown that
PC-1 is a member of a multigene family of ecto-phosphodiesterases that currently
has two other members, PD-1 alpha (autotaxin) and PD-1 beta (B10). Within this
family, the extracellular domains are highly conserved, especially around the
active site. In contrast, the transmembrane and cytoplasmic domains are highly
divergent. Individual members of the eco-phosphodiesterase family have distinct
patterns of distribution in different cell types, and even within the same cell.
For example, PC-1 is present only on the basolateral surface of hepatocytes,
while B10 (PD-1 beta) is confined to the apical surface. Analysis of conservation
and differences in the sequence of their cytoplasmic tails may illuminate
intracellular targetting signals. Ecto-phosphodiesterases may play a part in
diverse activities in different tissues, including recycling of nucleotides. They
may also regulate the concentration of pharmacologically active extracellular
compounds such as adenosine or its derivatives and cell motility. Some members
may modulate local concentrations of pyrophosphate, and hence influence
calcification in bone and cartilage.
PMID- 9553762
TI - Enzymatic and extraenzymatic role of ecto-adenosine deaminase in lymphocytes.
AB - Adenosine deaminase (ADA, EC 3.5.4.4) is an enzyme of the purine metabolism which
has been the object of considerable interest mainly because the congenital defect
causes severe combined immunodeficiency (SCID). In the last 10 years, ADA, which
was considered to be cytosolic, has been found on the cell surface of many cells
and, therefore, it can be considered an ecto-enzyme. There is recent evidence
about a specific role of ecto-ADA, which is different from that of intracellular
ADA. Apart from degrading extracellular adenosine (Ado) or 2'-deoxyadenosine
(dAdo), which are toxic for lymphocytes, ecto-ADA has an extraenzymatic function
via its interaction with CD26. ADA/CD26 interaction results in co-stimulatory
signals in T cells. This co-stimulation is blocked by HIV-1, thus evidencing a
role for ecto-ADA in the pathophysiology of AIDS. The fact that, besides CD26,
ADA can interact with different cell-surface proteins opens new perspectives in
the research for a role of ecto-ADA in the function of the immune system and in
the interactions that take place between different cells in the development of
the immune system. The most interesting aspect is the possible participation of
the ecto-enzyme in cell-to-cell contacts during ontogenesis and maturation of
immunocompetent cells.
PMID- 9553763
TI - Dipeptidyl-peptidase IV/CD26 on T cells: analysis of an alternative T-cell
activation pathway.
AB - CD26 is a proteolytic enzyme (dipeptidyl-peptidase IV) with a wide tissue
distribution and a unique specificity that was already described 27 years ago.
CD26 is expressed on a fraction of resting T cells at low density but is strongly
upregulated following T-cell activation. Recent results indicate that CD26 is a
multifunctional molecule that may have important functions on T cells and in the
immune system. It is associated with molecules of immunological importance such
as the protein tyrosine phosphatase CD45 and adenosine deaminase (ADA) on the
cell surface. Synthetic inhibitors of the enzymatic activity of CD26 have been
shown to suppress certain immune reactions in vitro and in vivo. An interesting
feature of CD26 is its ability to transmit a transmembrane signal to trigger
functional programs in T cells. This triggering requires crosslinking of CD26 on
a cell membrane. The enzymatic activity of CD26 is not obligatory for the
activation of T cells via CD26. Since CD26 is a type II membrane protein with
only six intracellular amino acids, it must deliver its signal via a signal
transducing molecule. Signaling is dependent on the expression of the T-cell
receptor (TCR) complex with a special need for a functional zeta-chain. In this
context the zeta-chain of the TCR complex is required for CD26-mediated signaling
but, in contrast to other co-stimulatory molecules such as the CD2 molecule, is
not sufficient for triggering the T cell.
PMID- 9553764
TI - The structure and function of CD26 in the T-cell immune response.
AB - CD26 is a widely distributed 110 kD cell-surface glycoprotein with known
dipeptidyl-peptidase IV (DPP-IV) activity in its extracellular domain. This ecto
enzyme is capable of cleaving amino terminal dipeptides from polypeptides with
either L-proline or L-alanine in the penultimate position. On human T cells, CD26
expression appears late in thymic differentiation and is preferentially
restricted to the CD4+ helper/memory population, and CD26 can deliver a potent co
stimulatory T-cell activation signal. The cDNA sequence of CD26 predicts a type
II membrane protein with only 6 amino acids in its cytoplasmic region, suggesting
that, in addition to DPP-IV enzyme activity, other signal-inducing molecules may
be associated with CD26. Considerable evidence exists that CD26 interacts,
presumably in its extracellular domain, with both CD45, a protein tyrosine
phosphatase, and adenosine deaminase (ADA), each of which is capable of
functioning in a signal transduction pathway. In addition, CD26 is the receptor
for ADA, and ADA on the cell surface is involved in an important immunoregulatory
mechanism by which released ADA binds to the cell-surface ADA. This
multifunctional molecule may be involved in cell migration and the HIV-1
associated loss of CD4+ cells through the process of programmed cell death. Thus,
CD26 appears to play a key role in a number of aspects of lymphocyte function.
PMID- 9553765
TI - The enigmatic role of glutamyl aminopeptidase (BP-1/6C3 antigen) in immune system
development.
AB - The murine B-lymphocyte differentiation antigen BP-1/6C3, a homodimeric integral
membrane protein composed of M, 140,000 subunits, has been identified as glutamyl
aminopeptidase (EAP, EC 3.4.11.7). This ecto-enzyme cleaves acidic amino acid
residues from the amino terminal of polypeptide substrates such as angiotensin II
and cholecystokinin-8. Although BP-1/6C3/EAP is expressed by cells in many
tissues, among hematopoietic cell lineages this ecto-enzyme is restricted to
immature B-lineage cells where its expression is upregulated by interleukin-7 and
viral transformation. BP-1/6C3/EAP thus serves as a valuable marker of
progression along the B-cell differentiation pathway, but a corresponding
biological role has not yet been established.
PMID- 9553766
TI - CD38: a new paradigm in lymphocyte activation and signal transduction.
AB - CD38 is a type II transmembrane glycoprotein that is extensively expressed on
cells of hematopoietic and non-hematopoietic lineage. Although the intracellular
domain of CD38 is not homologous to any known proteins, the extracellular domain
of CD38 is structurally related to enzymes in the ADP-ribosyl cyclase family. The
structural homology between CD38 and the cyclase family members extends to
functional homology, as the extracellular domain of CD38 can mediate the
catalysis of beta-NAD+ into nicotinamide, ADP-ribose (ADPR) and, to a lesser
extent, into cyclic ADPR-ribose (cADPR). Extensive investigation in other systems
has shown that cADPR is an important regulator of intracellular Ca2+ release.
Since engagement of CD38 on hematopoietic cells with anti-CD38 Abs has been shown
to have potent effects on a number of in vitro cellular responses, we have
speculated that cADPR might control CD38-mediated signal transduction. However,
it has been difficult to understand how a mediator which is typically an
intracellular signaling molecule could potentiate its effects from an
extracellular location, thus posing a dilemma which pertains to all ecto-enzymes
and the mechanisms by which they regulate signal transduction and cellular
processes. This review describes the biologic properties of murine CD38, its role
in humoral immunity, and its signal transduction properties in B lymphocytes. We
suggest that signaling through CD38 represents a new paradigm in lymphocyte
signal transduction and is predicated upon extracellular, rather than
intracellular, crosstalk.
PMID- 9553767
TI - Ecto-enzyme and signaling functions of lymphocyte CD73.
AB - CD73 or ecto-5'-nucleotidase (5'-NT) is a widely expressed ecto-enzyme which
catalyzes the dephosphorylation of AMP and other nucleoside monophosphates. CD73
participates in purine salvage through this enzymatic activity, supplying cells
with precursors for energy metabolism and nucleic acid biosynthesis. As an enzyme
that produces adenosine, CD73 can also regulate adenosine receptor engagement in
many tissues. However, CD73 also has functions independent of its enzyme
activity. Like many glycosyl phosphatidylinositol (GPI)-anchored molecules, it
transmits potent activation signals in T cells when ligated by antibodies. Less
compelling evidence suggests that CD73 may function as a cell adhesion molecule.
In the human immune system, CD73 is expressed on subsets of T and B cells, on
germinal center follicular dendritic cells, and on thymic medullary reticular
fibroblasts and epithelial cells. Many challenging areas remain to be explored
before the role of CD73 in the immune system will be fully understood. These
include an evaluation of the role of adenosine receptors in lymphoid development,
the identification of physiological CD73 ligands, a functional assessment of the
GPI anchor, and an analysis of the intricate cell-type-specific and developmental
regulation of CD73 expression.
PMID- 9553768
TI - Ecto-ATPase: an activation marker necessary for effector cell function.
AB - Ecto-ATPase, a transmembrane enzyme that catalyzes the hydrolysis of
extracellular ATP (ATPe) to ADP and inorganic phosphate, is expressed upon cell
activation. Ecto-ATPase is inhibited by non-hydrolyzable ATP analogues, which are
competitive inhibitors of the catalytic reaction, and the ATP analogue affinity
label. 5'-p-(fluorosulfonyl)benzoyl adenosine (5'-FSBA), which irreversibly
inhibits the catalytic activity. These nucleotide antagonists do not cross the
cell membrane and are specific for ecto-ATPase in T cells, B cells and NK cells.
Inhibition of ecto-ATPase by both reversible and irreversible nucleotide
antagonists results in the inhibition of antigen-induced cytokine secretion and
cytolytic activity of T cells. Likewise, granule release and cytolytic activity
of NK cells as well as antibody secretion and spontaneous proliferation by B-cell
hybridomas are inhibited. Inhibition of ecto-ATPase does not influence effector
cell-target cell conjugate formation, but acts, in part, by regulating the influx
of extracellular calcium that is necessary to maintain cellular activation. Thus,
further elucidation of ecto-ATPase regulation and expression and its interaction
with intracellular signal transduction events will provide a basis for
understanding the role of the hydrolysis of ATPe by ecto-ATPase in lymphocyte
effector function.
PMID- 9553769
TI - Carboxypeptidase M as a marker of macrophage maturation.
AB - During terminal maturation of blood monocytes (MO) into macrophages (MAC), a
multitude of phenotypic and functional changes occur: cells increase in size and
enhance their capacity for phagocytosis and tumor cytotoxicity, but decrease
their ability for T-lymphocyte stimulation. The pattern of secreted cytokines is
shifted as is the profile of surface antigens. The identity of the MAC maturation
associated antigen MAX.I/MAX.II with carboxypeptidase M (CPM), a phosphoinositol
linked endopeptidase, was recently described. CPM is able to process a multitude
of different substrates, among them immunologically important peptides such as
bradykinin, anaphylatoxins and enkephalins. It was previously shown to be
expressed in placenta, lung and kidney. CPM as detected by MAX.I/II shows a
strong expression on MO-derived MAC in vitro and on MAC in vivo accompanying T
lymphocyte activation such as during allogeneic transplant rejection or allergic
alveolitis. In contrast, its expression is suppressed on MAC by some types of
tumor cells. A synchronous expression of CPM together with MAC cytotoxic function
makes a functional relationship very well possible. However, the biological
importance of CPM expression on MAC in vivo is difficult to predict, since a wide
range of biologically active peptides are substrates for CPM, and the relevance
for most of those peptides to be processed by CPM during an immune reaction is
only poorly understood at present.
PMID- 9553770
TI - Cellular carboxypeptidases.
AB - This article focuses on four human carboxypeptidases (CPs): two metallo-CPs and
two serine CPs. The metallo-CPs are members of the so-called B-type regulatory CP
family, as they cleave only the C-terminal basic amino acids Arg or Lys. The
plasma membrane-bound CPM and the mainly, but not exclusively, intracellular CPD
are surveyed from this group of enzymes. These enzymes can regulate peptide
hormone activity at the cell surface and possibly intracellularly after receptor
mediated endocytosis and may also participate in peptide hormone processing. The
serine CPs, as their name indicates, contain a serine residue in the active
center essential for catalytic activity that reacts with organophosphorus
inhibitors. Prolylcarboxypeptidase (PRCP) (angiotensinase C) and deamidase
(cathepsin A, lysosomal protective protein) are discussed here. These two enzymes
are highly concentrated in lysosomes; however, they may also be active
extracellularly after their release from lysosomes in soluble form or in a plasma
membrane-bound complex. Whereas deamidase cleaves a variety of peptides with C
terminal or penultimate hydrophobic residues (e.g. substance P, angiotensin I,
bradykinin, endothelin, fMet-Leu-Phe). PRCP cleaves only peptides with a
penultimate Pro residue (e.g. des-Arg9-bradykinin, angiotensin II). These enzymes
may also be involved in terminating signal transduction by inactivating peptide
ligands after receptor endocytosis.
PMID- 9553771
TI - Deciphering the apoptotic pathway: all roads lead to death.
AB - Research into apoptosis is proceeding at such a fast and ferocious pace that
anyone who is not completely engrossed in the field has difficulty keeping track
of the constant stream of newly identified proteins involved in the process.
Apart from being an enticing concept, the process of cell suicide is an important
function with wide-reaching implications. Virologists, biologists, immunologists,
physiologists and oncologists alike have had to incorporate this phenomenon into
their disciplines. The purpose of this article is to provide a solid background
on which to further review recent advances in this exciting field. The Bcl-2 and
caspase family homologues are discussed in detail and various models are proposed
to explain how they function to regulate and execute the death programme.
Finally, the importance of programmed cell death with respect to immune function
is explored, emphasizing the targets of viral inhibitors of apoptosis.
PMID- 9553772
TI - Tumour surveillance: missing peptides and MHC molecules.
AB - Immunotherapy involving CTL is an attractive alternative for treatment of various
malignancies. One of the approaches currently being explored for immune targeting
of human cancers involves potentiation of immunogenicity of malignant cells by
gene transduction. This strategy is undoubtedly influenced by the ability of the
malignant cells to endogenously process and present target epitopes on their cell
surface for immune recognition by CTL. However, there is increasing evidence to
suggest that a large proportion of human cancers escape CTL-mediated immune
surveillance by selectively down-regulating the expression of MHC class I
molecules and peptide transporter genes. Understanding and molecular analysis of
these immunologically relevant genetic defects in tumours is very important
before translating preclinical studies of immunotherapy to rational clinical
trials. Careful consideration of these potential limitations may lead to the
development of novel immunotherapeutic strategies and, potentially, prevention of
tumour progression or development.
PMID- 9553773
TI - Second symmetry in the BALB/c-C57BL/6 (B6) system, and anti-antiself antibodies
in ageing B6 mice.
AB - Using an ELISA assay and inhibition of antibody mediated cytotoxicity we found
that there was a higher level of anti-antiself activity in B6 anti-BALB/c
alloimmune mice than in BALB/c anti-B6 mice. In contrast, when an inhibition of
cellular cytotoxicity assay was used to assay for the activity, similar levels of
anti-antiself antibodies were seen in B6 anti-BALB/c and BALB/c anti-B6 sera.
Anti-antiself antibodies in alloimmune sera are not absorbed by the cellular
immunogen as readily as are anti-foreign antibodies. These results are
interpreted in terms of anti-antiself antibodies being directed mainly against T
cell receptors specific for self. Anti-antiself antibodies are found also in old
B6 mice, that are also known to make autoantibodies.
PMID- 9553774
TI - Defective TCR expression in transgenic mice constructed using cDNA-based alpha-
and beta-chain genes under the control of heterologous regulatory elements.
AB - We describe the generation of ovalbumin (OVA)-specific, MHC class II-restricted
alpha beta T cell receptor (TCR) transgenic mice. Initial attempts at generating
these transgenic mice utilized heterologous regulatory elements to drive the
expression of cDNA genes encoding the separate alpha- and beta-chains of the TCR.
Unexpectedly, T cells bearing the transgenic alpha beta TCR failed to emerge from
the thymus in these mice, although the transgenes did modify endogenous TCR
expression. However, subsequent modification of the approach which enabled
expression of the TCR beta-chain under the control of its natural regulatory
elements generated mice whose peripheral T cells expressed the transgenic TCR and
were capable of antigen-dependent proliferation. These results show that
successful generation of MHC class II-restricted, OVA-specific alpha beta TCR
transgenic mice was dependent upon combining cDNA- and genomic DNA-based
constructs for expression of the respective alpha- and beta-chains of the TCR.
PMID- 9553775
TI - IL-4, IL-5 and IL-10 are not required for the control of M. bovis-BCG infection
in mice.
AB - Mycobacterial infections in mice are normally characterized by a profound Th1
cell-mediated immune response, in which T cells secrete large amounts of IFN
gamma. Recent evidence suggests that this response also includes a Th2 component.
In order to investigate whether production of IL-4, IL-5, or IL-10 influenced the
outcome of a Mycobacterium bovis-bacille Calmette-Guerin (BCG) infection, we
intranasally infected IL-4, IL-5, and IL-10 gene-deficient and control mice and
monitored the resulting immune response and bacterial clearance. IL-4, IL-5, and
IL-10 deficient mice cleared the mycobacteria with the same kinetics as control
mice. Furthermore, T cells of cytokine deficient and control mice produced
similar levels of IFN-gamma following in vitro stimulation with purified protein
derivative (PPD) from M. bovis. We conclude that the cytokines IL-4, IL-5 and IL
10 are not essential for and do not negatively influence the protective immune
response against M. bovis-BCG in the lung of mice.
PMID- 9553776
TI - Insights into the aetiology and pathogenesis of multiple sclerosis.
AB - Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central
nervous system, and the most common neurological disease affecting young adults.
Multiple sclerosis is a clinically heterogeneous disorder. It is believed to be
an autoimmune disease, with cell-mediated and humoral responses directed against
myelin proteins. This hypothesis largely comes from pathological parallels with
an animal model, experimental autoimmune encephalomyelitis (EAE). Autoimmunity to
myelin proteins in humans may be inadvertently triggered by microbes which have
structural homologies with myelin antigens (molecular mimicry). As with other
autoimmune diseases, susceptibility to MS is associated with certain MHC
genes/haplotypes. Full genomic screening of mutiplex families has underscored the
role for MHC genes as exerting moderate but the most significant effects in
susceptibility. The primary target autoantigen in MS has yet to be definitively
identified, but as well as the major myelin proteins, it is now clear that minor
myelin components, such as myelin oligodendrocyte glycoprotein (MOG) may play a
primary role in disease initiation. This review examines the current knowledge
about the aetiology and pathogenesis of MS, and the important similarities with
EAE. A better understanding of the molecular mechanisms of autoimmune pathology
will provide the basis for more rational immunotherapies to treat MS.
PMID- 9553777
TI - Current immunotherapy in multiple sclerosis.
AB - The underlying pathophysiology of multiple sclerosis is presumed to be autoimmune
in nature. Attempts to find an effective treatment for this common disease of the
central nervous system have primarily focused on immune-mediated therapies, both
immunosuppressive and immunomodulatory. The wide variety of immunological
abnormalities detected in multiple sclerosis and its animal model, experimental
allergic encephalomyelitis, has prompted the testing of a diverse array of drugs
to be used for treatment. Recent successes in the treatment of relapsing
remitting multiple sclerosis with interferon beta and glatiramer acetate have
renewed interest in and raised expectations for the effective control of this
neurological disorder. Improved methodology in clinical trials, the development
of surrogate markers and the availability of novel therapies bode well for more
rapid advances.
PMID- 9553778
TI - Cytokine-directed therapies in multiple sclerosis and experimental autoimmune
encephalomyelitis.
AB - Secreted and cell surface molecules that control the nature of immune responses
or directly mediate tissue damage are important targets for therapeutic
intervention of autoimmune inflammatory disorders. The precise aetiology of
multiple sclerosis (MS), an inflammatory demyelinating disease of the central
nervous system is unknown and therapeutic interventions for this disease are
limited. However, as it is believed that MS is autoimmune in nature, it seems
likely that targeting of the immune system, either to deviate it down a more
benign pathway or to directly block tissue damaging effector mechanisms, may
enable this disease to be controlled. In this overview we examine three
alternative approaches to therapy of MS: cytokine-directed immune deviation,
immunoregulation by type I interferons and blockade of TNF. Underlying rationales
for the application of these approaches to the treatment of MS are based largely
on studies in the disease model experimental autoimmune encephalomyelitis. These
studies are reviewed.
PMID- 9553779
TI - Oral tolerance as therapy for experimental autoimmune encephalomyelitis and
multiple sclerosis: demonstration of T cell anergy.
AB - Experimental autoimmune encephalomyelitis (EAE) is an important model for
developing therapies for multiple sclerosis (MS). The oral administration of the
central nervous system antigen, myelin basic protein (MBP), to Lewis rats and
susceptible mouse strains prior to MBP immunization prevents the induction of
EAE. Clinical trials administering myelin orally to MS patients have met with
only partial success, and thus require that oral tolerance be further studied to
improve this treatment strategy. Clonal anergy, clonal deletion, immune deviation
from Th1 to Th2 T cell subsets, and active suppression by TGF-beta-secreting T
cells have all been implicated as possible mechanisms in oral tolerance. Which
mechanism predominates depends on antigen dosage, frequency of feeding, and
timing of antigen administration. In this study, we have characterized T cells
derived from MBP-fed rats and determined the level of their unresponsiveness.
Myelin basic protein-specific T cells are indeed present although in reduced
numbers in lymphoid tissue of orally tolerized animals. Following several cell
divisions in the presence of IL-2, these MBP-specific T cells undergo a dramatic
reversal of unresponsiveness, proliferate in response to MBP and are capable of
transferring EAE. These results support clonal anergy as an important mechanism
for oral tolerance. Recent developments in clinical trials of oral tolerance are
described.
PMID- 9553780
TI - Effects of vaccination with T cell receptor peptides: epitope switching to a
possible disease-protective determinant of myelin basic protein that is cross
reactive with a TCR BV peptide.
AB - Immunization of Lewis rats with guinea-pig myelin basic protein (Gp-MBP) induced
T cell responses to primary and secondary encephalitogenic determinants, as well
as to a third non-encephalitogenic epitope, residues 55-69. This sequence is of
interest due to its protective activity against experimental autoimmune
encephalomyelitis. Protection involved induction of MBP-55-69-specific T cells
expressing cross-reactive TCR BV8S6 genes that activated regulatory T cells
specific for TCR BV8S2 determinants expressed on encephalitogenic T cells. We
here present and discuss new evidence suggesting a possible immunological cross
reactivity between the protective Gp-MBP-55-69 peptide and the regulatory BV8S2
39-59 peptide. This cross-reactivity, which may also occur between the human MBP
55-74 peptide and the BV12S2-38-58 sequence, has potentially important
implications for human diseases such as multiple sclerosis.
PMID- 9553781
TI - Approaches to the treatment of central nervous system autoimmune disease using
specific neuroantigen.
AB - The ultimate aim in the treatment of autoimmune disease is to restore self
tolerance to the autoantigen(s) in question. In lieu of this ideal result, the
conversion of a destructive or pathogenic autoimmune response into one of benign
autoimmunity would also be highly desirable. In either case the use of the
antigenic epitope, which is the target of the destructive immune response, would
ideally be employed so as to give specificity to the protection without the need
for long-term immunosuppression. This review describes a number of different
approaches using various forms, doses, and routes of injection of specific
neuroantigen to inhibit the different clinical varieties of autoimmune
encephalomyelitis in a number of animal models; all done with the view to
translating the findings into the clinic for the treatment of multiple sclerosis.
We conclude that any treatment strategy for multiple sclerosis (MS) must have a
number of features: it must be clinically acceptable, specific, long-lasting,
require only short-term treatment, able to shunt off ongoing disease, and have
the potential to prevent or deal with epitope spreading. Few of the approaches we
describe fulfill all of these criteria. We suggest that investigations of new
adjunctive agents to be used with a specific antigen be pursued, and that
currently the use of chimeric proteins or DNA vaccination with or without the new
adjunctives may hold the most hope for the future.
PMID- 9553782
TI - Treatment of central nervous system inflammation with inhibitors of basement
membrane degradation.
AB - Currently available anti-inflammatory drugs for the treatment of multiple
sclerosis (MS) and other inflammatory diseases are generally inadequate, with
disease progression not being arrested by the treatments and undesirable side
effects posing problems. In response to these deficiencies our laboratories have,
over the past 10 years, been developing novel drugs that interfere with the entry
of leucocytes into inflammatory sites by inhibiting their passage through the
subendothelial basement membrane (BM). This review initially summarizes evidence
supporting the hypothesis that the subendothelial BM is a major barrier to the
accumulation of leucocytes in inflammatory sites. An important point that has
emerged is that breaching of the BM is probably a cooperative process, involving
activation- and cytokine-induced degradative enzymes contributed by leucocytes,
endothelial cells and platelets. The review then discusses the properties of
three separate classes of anti-inflammatory compounds we have developed, namely
sulfated polysaccharides/oligosaccharides, phosphosugars, and castanospermine
(CS), which inhibit the passage of leukocytes through BM. Each drug type appears
to prevent BM degradation by a different mechanism. Sulfated
polysaccharides/oligosaccharides mediate their anti-inflammatory effect by
inhibiting the endoglycosidase, heparanase, which plays a key role in the
solubilization of BM by invading leucocytes. In fact, our studies have
highlighted the heparanase enzyme as a major target for future drug development.
Phosphosugars probably inhibit inflammation by displacing lysosomal enzymes,
which are involved in BM degradation, from cell surface mannose 6-phosphate
receptors. This mechanism of expressing degradative enzymes on the cell surface
is particularly evident with activated T lymphocytes. On the other hand, CS
interferes with appropriate targeting of lysosomal enzymes involved in BM
degradation. For reasons which are still unclear, CS specifically inhibits BM
degradation by endothelial cells, which results in a characteristic perivascular
arrest of leucocytes in inflammatory sites. Overall, our studies have established
that inhibitors of subendothelial BM degradation represent viable anti
inflammatory agents. It is hoped that future work will result in the development
of a totally new class of highly effective, subtle and non-toxic anti
inflammatory drugs for the treatment of MS and other inflammatory diseases.
PMID- 9553783
TI - Occupational medicine in China.
PMID- 9553784
TI - Exposure to carbon black: a cancer risk?
AB - Lung cancer is one of the most serious health problems in the industrial nations
and is therefore of great public and scientific interest. Although inhalative
cigarette smoking is without doubt the main cause for the increasing frequency of
lung cancer, during recent years there has been more and more public interest in
other substances in the environment or at the work place that are assumed to be
potentially carcinogenic especially due to experiences with fibrous particles
such as asbestos and their effects. Enhanced attention is also directed to inert
or nuisance dusts such as carbon black. Evaluation of the possibly increased risk
for humans should first be based on exact epidemiology data. In the absence of
those data--as in the case of carbon black--experimental data in animals serve as
the point of orientation, especially results gained in rats in long-term
inhalation studies. Pathologic anatomy investigations of human lungs under
similar exposure conditions, however, render results quite different from those
obtained in rats and, thus, preclude ready interpretation of animal results to
human risk assessment. This is particularly true for the development of lung
tumors in rats under overload conditions as well as for certain tumor types not
observed in human lung tissues. It is therefore quite understandable that many
researchers propose to interpret the changes observed in rat lung tissues after
inhalation of carbon black as rat-specific reaction mechanisms that cannot be
applied to human tissues, which in the past have led to the wrong conclusions
regarding human risk assessment due, among other factors, to incorrect
experimental design and inaccurate nomenclature of tumorous lesions in rats.
PMID- 9553785
TI - Urinary 2,5-hexanedione increases with potentiation of neurotoxicity in chronic
coexposure to n-hexane and methyl ethyl ketone.
AB - OBJECTIVE: MEK (methyl ethyl ketone) is widely and frequently used as an
ingredient of mixed solvents together with n-hexane. MEK is known to decrease
urinary levels of 2,5-hexanedione dose-dependently in an acute or chronic
coexposure with a constant level of n-hexane. This change in urinary 2,5
hexanedione appears to contradict the potentiation effect of MEK on n-hexane
induced neurotoxicity because it is believed that the toxicity of n-hexane is
activated through n-hexane metabolism. We aimed to clarify how the urinary level
of 2,5-hexanedione changes when MEK modifies the degree of n-hexane-induced
neurotoxicity. METHOD: A total of 32 male Wistar rats were divided into 4 groups
of 8 each and were then exposed to fresh air only, 2000 ppm n-hexane only, 2000
ppm n-hexane plus 200 ppm MEK, and 2000 ppm n-hexane plus 2000 ppm MEK,
respectively. Inhalation exposures were performed 12 h/day, 6 days/week, for 20
weeks. Motornerve conduction velocity (MCV), distal latency (DL), and urinary 2,5
hexanedione were measured every 4 weeks. RESULTS: The MCV decreased, the DL
increased, and urinary levels of 2,5-hexanedione increased in the 2000-ppm n
hexane plus 200 ppm MEK group in comparison with the 2000-ppm n-hexane only group
following 4 weeks' exposure. On the 1st day of exposure, however, coexposure to
MEK decreased urinary levels of 2,5-hexanedione dose-dependently. CONCLUSIONS:
The present study showed that urinary concentrations of 2,5-hexanedione increased
with potentiation of n-hexane neurotoxicity. Urinary 2,5-hexanedione
concentration does not necessarily reflect the exposure concentration of n-hexane
in coexposure to n-hexane along with MEK or other solvents, but it may be useful
as a marker in the assessment of neurotoxicity in coexposure to n-hexane and
other solvents.
PMID- 9553786
TI - Variation in the ratio of respirable particulates over inhalable particulates by
type of dust workplace.
AB - OBJECTIVE: The aim of the present study was to clarify the quantitative
relationship between respirable particulates and inhalable particulates in
various dust workplaces. METHODS: Both respirable particulate and inhalable
particulate concentrations were measured in 1644 dust workplaces by means of
elutriation, and the ratio of respirable particulate mass over that of inhalable
particulate (R/I ratio) was calculated for each workplace. RESULTS: Statistical
analyses showed that the R/I ratio varied substantially, depending on the type of
dust work. The ratio was highest in welding workplaces (mean +/- SD: 53 +/- 19%)
and lowest in foundries (23 +/- 16%); the former value suggests that respirable
particulate exposure may be underestimated in substantial parts of welding work
when only the occupational exposure limit for inhalable particulates is taken for
compliance testing. CONCLUSIONS: Simple compliance with the limit for inhalable
particulates is not sufficient, and the limit for respirable particulates should
also be simultaneously cleared.
PMID- 9553787
TI - Correspondence between occupational exposure limit and biological action level
values for alkoxyethanols and their acetates.
AB - OBJECTIVES: The Finnish occupational exposure limit (OEL) values for
alkoxyethanols and their acetates were lowered in 1996. A reevaluation of the
correspondence between the new OEL value and the biological action level (BAL)
was thus needed. This study was conducted in silkscreen printing enterprises,
where 2-alkoxyethanols and their acetates are mainly used as solvents. The
air/urine correlations between 2-methoxyethylacetate, 2-ethoxyethylacetate, 2
butoxyethanol, 2-butoxyethylacetate, and 2-methoxyacetic (MAA), 2-ethoxyacetic
(EAA), and 2-butoxyacetic acid (BAA) were evaluated on an individual and time
related basis at four different enterprises. METHODS: Inhalation exposure to
alkoxyalcohols and their acetates was monitored with diffusion badges (n = 38)
for an entire work week. Urinary excretion of alkoxyacetic acids immediatley
after the shift and at 14-16 h after exposure (n = 112) was analyzed by a gas
chromatograph equipped with a flame-ionization detector. RESULTS: Inhalation
exposure to 2-methoxyethylacetate at 0.5 cm3/m3 corresponded to MAA excretion of
3 mmol/mol creatinine in urine at 14 to 16 hours after exposure. The next-morning
urinary EAA excretion of 37 mmol/mol creatinine corresponded to an 8-h 2
ethoxyethylacetate exposure of 2 cm3/m3 when all collected data were included.
This average EAA excretion was 69% of the German BAT value and only 34% of the
American biological exposure index (BEI) value. Urinary EAA excretion was 30-40%
lower at the beginning of the work week than at the end of the work week. On the
other hand, EAA excretion was 10-20% higher than that measured at 14-16 h after
exposure. Urinary BAA excretion of 75 mmol/mol creatinine in postshift urine
corresponded to an 8-h 2-butoxyethanol and 2-butoxyethylacetate exposure of 5
cm3/m3. This BAA excretion was 87% of the German BAT value. CONCLUSION: According
to these results, it seems that the BAL for MAA and EAA should be 3 and 50
mmol/mol creatinine as measured at 14-16 h after exposure, respectively. The BAL
value for BAA seems to be 70 mmol/mol creatinine in postshift samples. These
recommendations are valid only if samples are collected at the end of the work
week.
PMID- 9553788
TI - Mortality by cancer in groups of the Belgian population with a moderately
increased intake of arsenic.
AB - OBJECT: The dose-response relationship for lung carcinoma and other cancers at
low doses of As is highly uncertain because it is based on modeling data
collected in populations with a high daily intake of the element. The finding of
a slightly increased exposure to arsenic in certain groups of the Belgian general
population prompted us to examine whether this had repercussions on the causes of
mortality. METHOD: Statistics of mortality by causes with a possible link to
exposure to the element (standardized mortality ratio) were analyzed in groups of
the Belgian population previously shown to have been exposed to As from natural
(drinking water) and/or industrial (nonferrous metal smelter emissions) sources.
RESULTS: A moderately increased absorption of As, leading to a 3- to 4- fold
higher urinary excretion (35 micrograms/day as compared with 6-10 micrograms
As/day in nonexposed subjects) did not enhance the mortality by diseases of the
nervous system, liver and heart, and cancers. An increase in mortality by lung
cancer, however, was observed in men but not women living around zinc smelters
and might be related to past occupational exposure and/or smoking habits.
CONCLUSION: A low to moderate level of environmental exposure to inorganic
arsenic (0.3 microgram As/m3 of air; 20-50 micrograms As/l of drinking water)
does not seem to affect the causes of mortality, suggesting in particular
nonlinearity of the dose-response relationship for arsenic and cancer.
PMID- 9553789
TI - Longitudinal changes in inflammatory markers in nasal lavage of cotton workers.
Relation to endotoxin exposure and lung function changes.
AB - OBJECTIVES: The aim of this study was to evaluate time-related changes in
inflammatory markers in nasal lavage (NAL) in relation to endotoxin exposure and
lung function changes. METHODS: Endotoxin in cotton dust is well known to elicit
proinflammatory mediators involved in acute or chronic respiratory inflammation
due to cotton dust. We applied nasal lavage as well as lung function and exposure
measurements in a small group (n = 11) of cotton workers during 6 weeks of
observation (after 2 weeks free of exposure). Several inflammatory markers in
NAL, such as interleukin 8 (IL-8), IL-6, and down-stream mediators, including
soluble tumor necrosis factor receptor 75 (sTNF-R75) and soluble intercellular
adhesion molecule 1 (ICAM-1), cell counts, marker of epithelial response (uric
acid), and marker of plasma exudation (albumin) were measured. RESULTS: At the
exposure levels examined in this study [cotton dust, geometric mean (GM) = 1.10
mg/m3; endotoxin, GM = 2,869 EU/m3], several inflammatory markers in NAL such as
IL-8, sTNF-R75, and albumin tended to increase through the measurement period
with increasing airborne endotoxin concentration (in six workers who had paired
measurements in weeks 1 and 6). Although no statistical significance was reached,
airborne endotoxin exposure and all inflammatory markers in NAL were relatively
higher in cotton workers with a 6-week lung function decrease. CONCLUSION: The
data suggest that inflammatory markers in NAL are associated with repeated
airborne endotoxin exposure.
PMID- 9553790
TI - Sister chromatid exchanges in rotogravure printing plant workers.
AB - OBJECTIVE: The individual burden of inhaled ambient-air toluene and its link to
genotoxic phenomena in exposed printing workers. METHOD: The influence of toluene
on sister chromatid exchange (SCE) was investigated by monitoring of the
individual toluene burden of 42 exposed printing workers. Therefore, the urinary
hippuric acid (HA) excretion was measured directly after the work shift. The
results were compared with those recorded for a control group consisting of 45
blood donors. SCE frequencies were determined from peripheral lymphocytes for
both groups. RESULTS: The median HA excretion of the exposed and nonexposed
groups amounted to 1.94 and 0.45 g/g creatinine, respectively. For both groups,
different SCE rates were detected: 10.13 and 6.84 counts/lymphocyte for exposed
and nonexposed persons, respectively. The independence of the measured values
proved to be significant at a high confidence level (P = 0.000) for both groups.
The influences of smoking and alcohol consumption on SCE as well as on HA values
could be clearly separated from those induced by toluene. CONCLUSIONS: The
results of our study indicate a strong relationship between the individual
toluene burden and the genotoxic risk of the exposed persons. Since toluene was
used for dilution of the letter-press ink, the influence of ink mist on the
genotoxic effects could not be completely excluded.
PMID- 9553791
TI - Exposure of gasoline road-tanker drivers to methyl tert-butyl ether and methyl
tert-amyl ether.
AB - Organic oxygenates, namely, methyl tert-butyl ether (MTBE) and methyl tert-amyl
ether (MTAE), are added to gasoline to reduce carbon monoxide in exhausts and to
enhance the octane number. The aim of this study was to investigate road-tanker
drivers' exposure to oxygenate vapors during road-tanker loading and unloading as
well as to evaluate the measurements of these ethers and their metabolites in the
urine as a means of assessing the uptake of the ethers. A total of 11 drivers in
different parts of Finland were trained to monitor their exposure with personal
samplers, to report their working conditions, and to collect their whole-day
urine samples. Charcoal tubes of the air samples were analyzed for MTBE, MTAE,
benzene, toluene, and aliphatic hydrocarbons. For biological monitoring purposes
the two main oxygenates, tertiary ethers MTBE and MTAE, as well as their main
metabolites, tertiary alcohols tert-butanol (TBA) and tert-amyl alcohol (TAA),
were determined in urine specimens. On average the drivers were exposed to vapors
for short periods (21 +/- 14 min) three times during a work shift. The mean
concentrations of MTBE and MTAE (mean +/- SD) were 8.1 +/- 8.4 and 0.3 +/- 0.4
mg/m3. The total MTBE uptake during the shift was calculated to be an average of
106 +/- 65 mumol. The mean concentrations of MTBE, TBA, MTAE and TAA detected in
the first urine after the work shift were 113 +/- 76, 461 +/- 337, 16 +/- 21, and
40 +/- 38 nmol/l, and those found the next morning, 16 h later, were 18 +/- 12,
322 +/- 213, 9 +/- 10, and 20 +/- 27 nmol/l. The good relationship (r = 0.84)
found between MTBE exposure and postshift excretion suggests that urinary MTBE
can be used for biological monitoring of exposure, but at the present low level
of exposure the corresponding metabolite TBA is not equally reliable. The
determination of MTAE and its metabolite TAA in urine is sensitive enough to
detect the low degree of exposure to MTAE, but in this study the data were too
scarce to allow calculation of the correlations due to very low levels of MTAE
exposure.
PMID- 9553792
TI - Occupational lead exposure and screening of glucose-6-phosphate dehydrogenase
polymorphism: useful prevention or nonvoluntary discrimination?
AB - OBJECTIVE: To discuss regulatory guidelines excluding subjects with erythrocyte
glucose-6-phosphate dehydrogenase (G6PD) deficiency from lead-exposed jobs in the
light of epidemiology findings on the mortality of these subjects. METHODS: Two
mortality follow-up studies were conducted. The first comprised 1979 male
subjects newly identified as G6PD-deficient during a 1981 screening of the G6PD
polymorphism among the general population in Sardinia, Italy. The second
comprised 1080 male workers employed in maintenance and production departments of
a lead smelting plant, who were divided into two subcohorts by erythrocyte G6PD
phenotype. RESULTS: As compared with the general male population, G6PD-deficient
subjects had significantly fewer deaths than expected from ischemic heart disease
(standardized mortality ratio (SMR) = 28; 95% CI 10-62), cerebrovascular diseases
(SMR = 22; 95% CI 6-55), and liver cirrhosis (SMR = 12; 95% CI 0-66). Among lead
smelters the standardized mortality rates from cardiovascular diseases and all
cancers observed among the G6PD-deficient subcohort were lower than those seen
among subjects with the wild-type G6PD. No death from disease of the blood and
hematopoietic system was observed among G6PD-deficient subjects in these two
follow-up studies. CONCLUSIONS: These studies did not provide evidence of
hypersensitivity to lead hematotoxicity among G6PD-deficient individuals at
exposure levels within the current standards. Provided that workplace exposure
complies with current standards, the hypothetical benefit of excluding G6PD
deficient individuals from lead-exposed jobs should be weighted against the loss
of personal abilities and the economic damage in a social environment with
diffuse unemployment.
PMID- 9553793
TI - The Service for the Organization of Postexposure Medical Examinations: ODIN.
AB - In Germany, occupational contact with carcinogenic substances is regulated by
very strict legislation. Thus, alongside strict implementation of agreement 139
of the International Labour Organization (ILO), legislation governing the medical
monitoring and care of employees in the form of specialist preventive medical
examinations is also in force. It is extremely important that medical preventive
care should continue after employment involving contact with carcinogenic
substances has ceased, since there is often a long delay before occupationally
induced carcinosis develops. The German Service for the Organization of
Postexposure Medical Examinations (ODIN) was established by the statutory German
accident insurance institutions to ensure that early detection examinations
continue to be performed into the employee's later life. Such preventive
examinations can significantly enhance the success of cancer treatment by
detecting malignancy in its early stages. The registration by ODIN of data
concerning exposure to hazardous substances also has the function of preserving
evidence required for possible compensation claims by victims of occupational
illnesses. In the longer term, ODIN data may help us to explain the relationship
between exposure to hazardous substances and the incidence of carcinosis.
PMID- 9553795
TI - Predictive modelling of inactivation of Listeria spp. in bovine milk during high
temperature short-time pasteurization.
AB - A linear model was derived to describe the thermal inactivation of Listeria
innocua in bovine whole milk in a high-temperature short-time pilot scale
pasteurizer. Integrated lethal effect, or pasteurization effect (PE), was
obtained by converting times at different temperatures in the various sections of
the pasteurizer to the equivalent time at the reference temperature (72 degrees
C). PE was then related by a simple linear function to the log10 of the % viable
counts with a power transformation of the PE values to improve the linear fit. R2
values for the five L. innocua trials varied from 0.728 to 0.974. Validation of
this model with Listeria monocytogenes confirmed that L. monocytogenes was more
heat sensitive. Inter-trial variation was incorporated into the model using the
@RISK simulation software. Output from simulations confirmed that pasteurization
at the IDF standard conditions of 72 degrees C for 15 sec can ensure at least an
11-log reduction of L. monocytogenes. The results showed that L. innocua may be
used as a model microorganism to assess the thermal inactivation of L.
monocytogenes, since its heat resistance is at least equal to or greater than
that of the pathogenic species.
PMID- 9553794
TI - Evaluation of the role of Carnobacterium piscicola in spoilage of vacuum- and
modified-atmosphere-packed cold-smoked salmon stored at 5 degrees C.
AB - The microflora on spoiled cold-smoked salmon often consists of a mixture of
lactic acid bacteria (LAB) and Gram-negative bacteria. To elucidate the role of
the different groups, a storage trial was carried out in which nisin and CO2 were
used for the selective inhibition of the two bacterial groups. The shelf-life of
vacuum-packed cold-smoked salmon, recorded by sensory evaluation, was four weeks
at 5 degrees C and the microflora was composed of LAB (10(6)-10(7) cfu/g) with an
associate Gram-negative flora in varying levels (10(5)-10(7) cfu/g). The addition
of nisin and/or a CO2-atmosphere increased the shelf-life to five or six weeks
and limited the level of LAB to about 10(4)-10(6), 10(3)-10(6) and 10(2)-10(4)
cfu/g, respectively. CO2-atmosphere +/- nisin inhibited the growth of Gram
negative bacteria, whereas nisin had no effect on these in vacuum packages. The
Gram-negative flora on vacuum-packed salmon was dominated by a Vibrio sp.,
resembling V. marinus, Enterobacteriaceae (Enterobacter agglomerans, Serratia
liquefaciens and Rahnella aquatilis) and occasionally Aeromonas hydrophila.
Irrespective of the addition of nisin and/or CO2-atmosphere, the LAB microflora
was dominated by Carnobacterium piscicola, which was found to account for 87% of
the 255 LAB isolates characterized. Whole-cell-protein patterns analysed by SDS
PAGE confirmed the Carnobacterium species identification. The spoilage potential
of C. piscicola isolates was further studied by inoculation of approx. 10(6)
cfu/g in cold-smoked salmon stored at 5 degrees C. The salmon did not spoil
within 4 weeks of storage in vacuum- or CO2-atmosphere, and it is concluded that
despite high levels (> 10(7) cfu/g) of C. piscicola, sensory rejection was caused
by autolytic changes. This was supported by the development of soft texture and
sour, rancid and bitter off-flavours at the point of spoilage, irrespective of
the length of shelf-life and low or high total counts of LAB and Gram-negative
bacteria.
PMID- 9553796
TI - Interaction of monolaurin, eugenol and sodium citrate on growth of common meat
spoilage and pathogenic organisms.
AB - Interactions of monolaurin, eugenol (phenolic compound) and sodium citrate
(chelator) on the growth of six organisms including common meat spoilage
(Lactobacillus curvatus, Lactobacillus sake, Leuconostoc mesenteroides,
Brochothrix thermosphacta) and pathogenic (Escherichia coli O157:H7 and Listeria
monocytogenes) organisms were investigated. The combinations of 100 to 250 ppm
monolaurin with 500 and 1000 ppm eugenol, and 0.2 and 0.4% sodium citrate were
more effective than each component separately. More than one combination
prevented detectable growth of each organism. Lactic acid bacteria (LAB) and E.
coli O157:H7 were most resistant and L. monocytogenes and B. thermosphacta most
sensitive to control by the chosen combinations. The presence of sodium citrate
was necessary to yield potent inhibition of Lb. curvatus and Lb. sake growth by
the monolaurin and eugenol combinations.
PMID- 9553797
TI - Identification of pseudomonads from fresh and chill-stored chicken carcasses.
AB - Results of carbon source assimilation tests (17 carbon compounds) led to 88% of
pseudomonads from cold-stored chicken carcasses being assigned to one of 17
groups. Of these groups, 13 had combinations of properties identical to, or with
readily recognizable degrees of similarity to those of published species/biovars.
Two of the four groups having carbon assimilation patterns dissimilar to any
known species had cellular fatty acid composition corresponding to Pseudomonas
fluorescens, and two to Pseudomonas lundensis or Pseudomonas fragi. The P.
fluorescens biovars all had higher amounts of 16:1 cis 9 (21-37%) and 18:1 cis 11
(10-19%), than of 17:0 cyclo (1-17%) and 19:0 cyclo (0-1%). In contrast, for P.
lundensis and P. fragi, the relative amounts of these unsaturated acids and
cyclopropane acids were reversed. Both the carbon source assimilation tests and
the cellular fatty acid composition led to the conclusion that none of the
species were dominant, although the P. fluorescens biovars constituted about 50%
of the isolated pseudomonads.
PMID- 9553798
TI - Rapid cooling, moderate heat treatment and nisin addition influence cell
homeostasis of Clostridium perfringens type A.
AB - Vegetative cells of Clostridium perfringens type A were exposed to heat shock (50
degrees C), cold shock (4 degrees C) and nisin, respectively. In all cases,
pronounced leaks of cellular K+ were observed. These losses were not
systematically related to cell death, as demonstrated by cell viability
measurement by the most probably number method. During heat shock treatment, a
90% decrease of initial population was measured within 15 min, and K+ leaks were
mainly associated to cell death. A cold shock induced a rapid and large K+ efflux
from the cells, at least 50% of the total potassium content. Potassium movements
were not associated with internal pH changes, or with cell death during cooling
at 4 degrees C. After nisin addition up to 70% of the cellular potassium was lost
within 5 min. These potassium losses led to a transmembrane pH gradient decrease,
but not to cell death at 50 IU ml-1 of nisin. Increasing the nisin concentration
to 200 IU ml-1 resulted in a decimal reduction of 2.62.
PMID- 9553799
TI - Characterization of Bifidobacterium strains for use in soymilk fermentation.
AB - Soybean milk, which serves as a base for a variety of beverages, contains
raffinose, stachyose, pentanal and n-hexanal; the former two may be responsible
for flatulence after fermentation, whilst the latter two for a beany flavour.
Twenty-seven strains of Bifidobacterium were analyzed for their alpha
galactosidase activity and the production of lactic and acetic acids to determine
their potential for use in the production of fermented soymilk. The behaviour of
three strains in soymilk was studied to determine their ability to reduce alpha-D
galactosyl oligosaccharides and produce lactic and acetic acids. They all were
able to reduce stachyose and raffinose. Pentanal and n-hexanal were metabolized
by Bifidobacterium breve MB233. These data indicate that bifidobacteria can be
used for biotechnological processes that employ soymilk as the substrate. A
product with low levels of alpha-D-galactosyl oligosaccharides and alkylic
aldehydes may be obtained.
PMID- 9553800
TI - A further review of the microbiological quality of bottled water sold in Canada:
1992-1997 survey results.
PMID- 9553801
TI - Amino acid decarboxylase capability of microorganisms isolated in Spanish
fermented meat products.
AB - Enterobacteria, lactic acid bacteria (LAB) and Gram-positive cocci were isolated
from Spanish meat products. The most frequent species in the meat products
studied were identified as Lactobacillus sake, Lactobacillus plantarum and
Lactobacillus curvatus from De Man-Rogosa-Sharpe agar; Staphylococcus xylosus,
Staphylococcus saprophyticus and Micrococcus varians from mannitol salt phenol
red agar; and Hafnia alvei, Escherichia coli, Pseudomonas fluorescens,
Enterobacter amnigenes and Enterobacter aerogenes from violet red bile dextrose
agar. The amino acid decarboxylase activity of the microorganisms isolated was
assayed. Enterobacteria had higher amino acid decarboxylase activity than the
other groups. LAB did not show any significant amino acid decarboxylase
capability in this study.
PMID- 9553802
TI - Characterization of plasmids from Listeria monocytogenes and Listeria innocua
strains isolated from short-ripened cheeses.
AB - The plasmid content of 30 isolates of Listeria monocytogenes and 18 isolates of
Listeria innocua obtained from short-ripened cheeses was analysed. The isolates
of L. monocytogenes serogroup 1 harboured a single plasmid, pLM33 (33.2 kbp),
whereas the serogroup 4 isolates did not contain plasmids. One group of L.
innocua strains harboured the plasmid pLI71 (71 kbp) and another one contained
two plasmids: pLI59 (59.5 kbp) and pLI56 (56.5 kbp). These plasmid groups were in
accordance with clusters previously defined by pulsed-field gel electrophoresis
analysis of the chromosomal DNA of Listeria isolates. Plasmids pLM33, pLI71 and
pLI59 shared homology regions of at least 20 kbp. Plasmid pLI56 did not encode
genes for any known character (such as carbohydrate fermentation, resistance to
antibiotics, heavy metals or disinfectants, growth at low pH, NaCl tolerance or
thermal inactivation by pasteurisation) and displayed different characteristics
to the other three plasmids. It was also the only one cured from the parent
strain and the sole plasmid not digested by the restriction enzyme PstI. In
addition, its lack of homology with pLM33, pLI71 and pLI59 enhanced the
possibility of a different origin for plasmid pLI56.
PMID- 9553803
TI - Probiotics.
PMID- 9553804
TI - The diagnostic utility of inhibin staining in ovarian neoplasms.
AB - Previous immunohistologic studies have suggested that the antibody to the alpha
subunit of inhibin is a sensitive marker of sex cord-stromal differentiation.
However, detection has also been reported within both ovarian epithelial and germ
cell tumors. To further study the normal tissue distribution of inhibin and the
utility of its detection for the differential diagnosis of ovarian sex cord
stromal neoplasms, normal tissues and 225 lesions including sex cord-stromal
lesions, ovarian epithelial and stromal cancers, ovarian and testicular germ cell
tumors, metastases to the ovary, and non-ovarian cancers were analyzed using semi
automated immunohistochemistry. In normal tissues, immunostaining was found in
cell subsets of the ovary, testis, adrenal gland, placenta, and kidney. All sex
cord-stromal tumors were inhibin-positive and 37 of 50 (74%) cases exhibited at
least moderate to strong immunostaining. Two cases originally diagnosed as adult
granulosa cell tumors that were inhibin-negative were reassessed; diagnoses of
endometrioid stromal sarcoma and endometrioid carcinoma with sertoliform features
were rendered. In other primary or metastatic ovarian lesions or metastases to
the ovary, weak to moderate immunostaining was found in only 4 of 84 (4.8%)
cases, including ovarian clear cell carcinoma (2/2), uterine clear cell
carcinomas metastatic to the ovary (1/3), and serous papillary carcinoma (1/2).
Similarly, only 4 of 66 (6.1%) non-ovarian neoplasms exhibited weak
immunostaining, including melanoma (1/5), uterine endometrioid carcinoma (1/2),
transitional cell carcinoma (1/3), and breast adenocarcinoma (1/8). Only one case
of a non-sex cord-stromal tumor had moderate or strong immunostaining. Based on
these results, immunohistologic detection of the alpha subunit of inhibin is a
useful adjunct in the differential diagnosis of sex cord-stromal neoplasms.
PMID- 9553805
TI - Frequent loss of chromosome 12 in human epithelial ovarian tumors: a chromosomal
in situ hybridization study.
AB - The short arm isochromosome of chromosome 12 and trisomy 12 are well-established
chromosomal alterations in human ovarian germ cell tumors. However, numerical
aberrations of chromosome 12 in epithelial ovarian tumors (EOTs) are highly
controversial; both trisomy 12 and monosomy 12 have been observed. We performed
chromosomal in situ hybridization in paraffin-embedded and formalin-fixed tissue
sections of 31 EOTs. Twenty-five EOTs could be evaluated statistically (2
mucinous, 11 serous, 5 endometrioid, 3 borderline, and 4 other epithelial-type
tumors) to examine the copy number of chromosome 12 and 15. The frequency
distribution of hybridization signals with alpha-satellite centromeric DNA probes
for chromosome 15 revealed disomy in all cases. However, we found the loss of
chromosome 12 in 16 of 25 tumor samples. No correlation was found between the
presence of monosomy 12 and the clinical stage of the tumors. Frequent loss of
chromosome 12 may indicate that this chromosome is involved in the tumorigenesis
of EOTs. Further studies are needed to clarify whether loss of chromosome 12 is
an early or late event in ovarian carcinogenesis.
PMID- 9553806
TI - Primary ovarian rhabdomyosarcoma: a report of 13 cases.
AB - Primary ovarian rhabdomyosarcomas were found in 13 patients aged 7 to 79 (mean
37) years who had reported abdominal pain and swelling. Six tumors involved the
right ovary, 3 involved the left, 1 involved both, and the laterality was unknown
in 3 cases. Four tumors were stage I, 2 were stage II, 4 were stage III, and 2
were stage IV; the stage of 1 tumor is not known. The tumors ranged from 10 to
19.5 (average 16) cm in diameter and had solid sectioned surfaces that varied
from yellow to white to pink and from gelatinous to hemorrhagic. Microscopically,
11 tumors were embryonal and 2 were alveolar rhabdomyosarcomas. Follow-up
information, available for 11 patients, revealed that 7 died of disease 10 days
to 26 months postoperatively; 2 of these patients had stage II disease, 3 had
stage III, and 2 had stage IV. Four patients were alive 2 to 9 months
postoperatively; 3 had stage I and 1 had stage III disease. These 13 tumors and
an additional 10 from the English-language literature are reviewed and the
differential diagnosis of ovarian rhabdomyosarcoma is discussed.
PMID- 9553807
TI - Membranous fat necrosis in mature cystic teratomas of the ovary.
AB - We identified and documented the occurrence of membranous fat necrosis (MFN) in
217 mature cystic teratomas (MCTs) of the ovary. Cysts lined by an eosinophilic
and scalloped membrane with pseudopapillary infoldings, the characteristic
histologic features of MFN, were identified in 9 tumors. The membranes had the
histochemical staining properties of ceroid, as evidenced by periodic acid
Schiff, sudan black, and long Ziehl Neelsen (ZN) positivity, diastase resistance,
and autofluorescence. The causes and pathogenesis of MFN are enigmatic, but
trauma, torsion, and ischemia are probable factors. MFN is a distinct entity in
ovarian MCTs and heightened awareness will increase its histopathologic
recognition.
PMID- 9553808
TI - Desmin expression in reactive mesothelium: a potential aid in evaluation of
gynecologic specimens.
AB - Desmin is a marker of smooth and striated muscle, but evidence is accumulating
that it may be expressed by human mesothelium. The aim of this study was to
describe desmin expression in normal, reactive, and hyperplastic peritoneal
mesothelium, and to evaluate its potential use as a marker for differentiating
between epithelial and mesothelial proliferations. We immunohistochemically
studied 27 tissue specimens (from 22 patients) with reactive mesothelium,
including omentum (n = 14), fallopian tubes (n = 7), ovaries (n = 3), ascitic
fluid (n = 1), and peritoneal washings (n = 2). Ovarian surface epithelium (OSE)
from 9 cases and 28 ovarian surface epithelial tumors was evaluated for
comparison. The desmin expression pattern in the mesothelium, which was similar
to but less consistent than that of cytokeratins, was evident in flat and
reactive mesothelium, including hyperplastic mesothelial sheets and mesothelium
entrapped in clefts. Mesothelial pseudoglandular structures, present in three
cases, were predominantly negative for desmin. Desmin expression was observed in
the OSE in 4 of 9 cases but not in any mullerian-derived epithelium or mullerian
type tumor. Thus, in contrast to cytokeratins, desmin discriminated mesothelial
cells from mullerian type epithelia. Compared with vimentin, desmin discriminated
mesothelial cells from other tissues except muscle cells. We conclude that desmin
may be used in addition to cytokeratins and vimentin as a marker of peritoneal
mesothelium.
PMID- 9553809
TI - Distinctive p53 and mdm2 immunohistochemical expression profiles suggest
different pathogenetic pathways in poorly differentiated endometrial carcinoma.
AB - Endometrial serous carcinoma (ESC) and FIGO (International Federation of
Gynecology and Obstetrics) grade 3 endometrioid adenocarcinoma (EC) are high
grade endometrial tumors that have different clinical and morphologic attributes.
Alteration of p53 tumor suppressor protein function has been implicated in the
pathogenesis of both tumors, although the mechanisms may differ. We sought to
investigate this difference by comparing immunohistochemical expression of p53
and mdm2. p53 immunoreactivity often correlates with gene mutation, whereas
increased mdm2 expression is linked to complex formation with wild-type p53
resulting in its inactivation. Twenty cases of ESC and 21 cases of EC were
evaluated and an immunoreactivity score (IRS) was assigned using both the
percentage of cells stained and the intensity of staining. The overall IRSs were
significantly different in ESCs versus ECs for both p53 and mdm2 (p < 0.001 and p
< 0.01, respectively). Strong mean immunoreactivity for p53 was detected in 15
(75%) ESCs as compared to only weak mean immunoreactivity in 17 (81%) ECs.
Conversely, for mdm2 expression, 17 (81%) ECs had moderate mean immunoreactivity
whereas 9 (45%) ESCs showed only weak mean immunoreactivity. mdm2 expression more
closely correlated with p53 expression in ECs than in ESCs. In ECs, mdm2 was
detected in 16 of 17 (94%) p53-positive tumors but in only 1 of 3 (33%) p53
negative tumors (p < 0.025). In ESCs, mdm2 was detected in 9 of 15 (60%) p53
positive tumors but in none of the 5 p53-negative tumors (p < 0.10). Overall, our
results demonstrate an inverse relationship between the expression of p53 and
mdm2 in ESC versus high-grade EC. Specifically, strong p53 immunoreactivity is
associated with weak mdm2 expression-in ESC and weak p53 expression is associated
with moderate mdm2 expression in EC. These results suggest different pathogenetic
pathways resulting in loss of normal p53 function in these two tumors: by p53
gene mutation (strong p53 overexpression) in ESCs, or by mdm2 complex formation
and inactivation of p53 in high-grade ECs.
PMID- 9553810
TI - Random nuclear p53 overexpression pattern in tamoxifen-mediated endometrial
carcinoma.
AB - In a previous paper, we suggested that tamoxifen (TAM)-mediated endometrial
carcinogenesis may not involve estrogenic pathways because of random estrogen
receptor positivity among endometrial carcinomas with and without TAM treatment
for breast cancer. DNA adduct formation (reported in rat liver and human
endometrium) was considered to be a more plausible mechanism for TAM-mediated
carcinogenesis. To examine the reported correlation between DNA adduct formation
and p53, the present study examined p53 expression in the endometrial carcinomas
reported in the previous study. Seven endometrial adenocarcinomas associated with
long-term TAM treatment for breast carcinoma and 4 carcinomas without TAM
treatment but with history of breast carcinoma were immunohistochemically
investigated for nuclear p53 expression. The bcl-2 product was also examined.
Diffuse and intense nuclear reactivity for p53 protein was present in only one
TAM-related case. Essentially, no differences were observed in the bcl-2 staining
patterns of TAM-treated and -untreated patients with cancer. Thus, p53
overexpression in endometrial carcinomas occurring in patients with breast cancer
seems to be not specific for TAM-treated patients, and, if DNA adduct formation
has any role in this type of endometrial carcinogenesis, it may not be related
preferentially to p53 gene alteration. Further studies are needed to understand
the precise mechanism(s) of the endometrial carcinogenesis.
PMID- 9553811
TI - Morphologic and immunophenotypic characterization of foam cells in endometrial
lesions.
AB - The detection of foam cells in cervicovaginal smears obtained from postmenopausal
women suggests the possibility of an endometrial lesion. Ultrastructural studies
have suggested that foam cells represent endometrial stromal cells but the
histogenesis of these cells has not been firmly established. To investigate the
origin and diagnostic significance of foam cells, we analyzed the morphology and
immunophenotype of these cells in endometrial tissue specimens and correlated the
findings with cervical smears obtained within the preceding 6 months. Selected
biopsies containing foam cells were evaluated using four well-characterized
macrophage markers: KP-1(CD68), HAM 56, MAC 387, and lysozyme. Foam cells were
found in 11 (38%) of 29 simple hyperplasias, 7 (50%) of 14 complex hyperplasias,
6 (50%) of 12 complex atypical hyperplasias, 21 (70%) of 30 adenocarcinomas, 1
(4%) of 25 samples with stromal breakdown, and 0 of 30 specimens showing normal
cycling endometrium. Foam cells were also found in smears preceding the
histologic diagnosis of 2 (13%) simple hyperplasias, 2 (25%) complex
hyperplasias, 3 (43%) complex atypical hyperplasias, 5 (28%) adenocarcinomas, 5
(28%) cases of stromal breakdown, and 0 of 8 normal tissue specimens examined.
Foam cells were immunoreactive with at least 2 of the 3 macrophage-specific
antibodies in all 21 biopsies studied. Our results suggest that foam cells
phenotypically represent macrophages and not endometrial stromal cells. Foam
cells are identified in a significant percentage of cervical smears and
endometrial tissue specimens obtained from women with endometrial pathology. The
morphology and immunophenotype of foam cells, however, does not appear to be
useful in distinguishing benign endometrial stromal breakdown, endometrial
hyperplasia, and endometrial adenocarcinoma.
PMID- 9553812
TI - Disruption of the E1 and E2 reading frames of HPV 16 in cervical carcinoma is
associated with poor prognosis.
AB - The E1 and E2 reading frames of 158 cervical carcinoma samples containing human
papillomavirus (HPV) 16 were mapped using polymerase chain reaction (PCR). The
reading frames were amplified using primers spanning the entire genes. Of the
analyzed samples, 23% showed no amplification with the E1 primers and 29% showed
no amplification with the E2 primers. There was an overlap, but not complete
identity, between the E1- and E2-disrupted groups. All E1- and E2-negative
samples were further analyzed with primers spanning subsections of the E1 and E2
reading frames, which together covered the entire genes. Of the 35 samples
negative for E1, 11 were positive in specific amplification of the 3' end of the
E1 gene. Several different subsections of E2 could be amplified from most samples
negative for the entire gene (37/46). Five classes of patterns were found, in
which either all subsections of the E2 gene or subsections in the 5', middle, or
3' end were disrupted. Although a variable pattern of disruption/deletion in the
E1-E2 area of the HPV 16 genome was found in cervical carcinoma, the 5' end
disruption was the most common one in both E1 and E2. Patients with carcinomas
showing disruptions in E1/E2 had a poorer survival than those without such
changes, and E1 disruptions were the most important prognostically.
PMID- 9553813
TI - Lectins in the vulva. I. Normal vulvar epithelium and epithelium adjacent to
vulvar intraepithelial neoplasia and squamous cell carcinoma.
AB - Lectins were used to investigate the cell surface oligosaccharide expression in
normal vulvar epithelium from premenopausal and postmenopausal volunteer women.
In addition, histologically normal epithelium adjacent to high-grade vulvar
intraepithelial neoplasia (VIN III) and adjacent to vulvar tumors was examined
with lectins for evidence of a possible "field change" surrounding these vulvar
lesions. Seventeen vulvar biopsies were obtained prospectively from volunteer
women, and 20 and 40 cases, respectively, of VIN III and vulvar squamous cell
carcinoma were randomly chosen from pathology archives. Thirteen of the 20 VIN
cases and all 40 vulvar carcinomas contained at least 2 cm of histologically
normal-appearing epithelium adjacent to the vulvar lesion suitable for analysis.
No alterations to lectin binding in normal vulvar epithelium with respect to
patient age, menopausal status, phase of menstrual cycle, estrogen therapy, or
history of cervical intraepithelial neoplasia were shown. ABO blood group antigen
status affected epithelial binding for lectins HPA and UEAI (p < 0.005 and p <
0.001, respectively). In addition, lectins SNA, MPA, and LCA identified markers
of cellular differentiation and maturation. T-antigen expression (as shown by the
lectin PNA) was almost universally present in histologically normal epithelium
adjacent to VIN and vulvar tumors, contrasting with the lack of PNA binding in
normal vulvar epithelium from volunteer women (p < 0.001 and p < 0.001), a
finding suggestive of a local "field change" surrounding preinvasive and invasive
vulvar lesions.
PMID- 9553814
TI - Lectins in the vulva. II. Vulvar intraepithelial neoplasia and squamous cell
carcinoma.
AB - This study used lectins as histologic probes to determine the cell surface
oligosaccharide expression in different grades and types of vulvar
intraepithelial neoplasia (VIN). Lectin binding patterns in metastasizing and non
metastasizing squamous cell carcinomas (SCCs) of the vulva were also compared to
correlate lectin binding patterns with metastatic potential and other
clinical/tumor characteristics. Twenty cases each of VIN epithelium,
metastasizing SCC, and non-metastasizing vulvar carcinoma were randomly chosen
from the pathology archives. Sixteen lectins were used to probe individual
terminal oligosaccharide residues in formalin-fixed, paraffin-embedded tissue
specimens from these cases through an indirect immunohistochemical technique.
There were no differences in lectin binding patterns between the different
histologic subtypes of VIN. In addition, there were no consistent differences
between metastasizing and non-metastasizing primary tumors and no major
differences in staining patterns between nodal metastases and the corresponding
primary tumors. Furthermore, there was no identifiable correlation between lectin
binding patterns and subsequent survival or local or regional recurrence;
however, lectin staining of invasive tumor cells did appear to be related to
local invasiveness. In addition, positive PNA binding was found to be a constant
finding in each of the VIN and invasive SCC cases, confirming that the T-antigen
becomes unmasked during the process of vulvar carcinogenesis. However, poorly
differentiated areas consistently showed absent lectin binding, suggesting loss
of specific glycosyl transferase activities. In addition, the blood group "A"
antigen appears to be lost during the process of tumorgenesis, although the blood
group "O" antigen appears to be preserved.
PMID- 9553815
TI - Fibroadenoma phyllodes arising in vulvar supernumerary breast tissue: report of
two cases.
AB - Ectopic breast tissue, found along the mammary line or sometimes outside it, can
exhibit pathologic changes similar to those of the eutopic mammary gland.
Fibroadenoma phyllodes, an unusual variant of mammary phyllodes tumor with
stromal cellularity similar to a conventional fibroadenoma, rarely arises outside
of breast. Its histogenesis is unclear; although some cases suggest an origin in
cutaneous adnexa, the presence of normal breast tissue surrounding other tumors
favors an ectopic mammary origin. Two cases of fibroadenoma phyllodes arising in
ectopic vulvar breast tissue are described.
PMID- 9553816
TI - Sarcomatoid squamous cell carcinoma of the uterine cervix with osteoclast-like
giant cells: report of two cases.
AB - Two postmenopausal women with sarcomatoid squamous cell carcinoma (SSCC) of the
uterine cervix are described. This report brings the total number of reported
SSCCs in the lower female genital tract to 11. The gross and microscopic features
of our SSCCs were similar to those of SSCCs in the digestive and upper
respiratory tracts with the additional finding of osteoclast-like giant cells in
each case. The behaviour and differential diagnosis of these tumors are briefly
discussed.
PMID- 9553817
TI - Leiomyomatosis peritonealis disseminata, endometriosis, and multicystic
mesothelioma: an unusual association.
AB - A 32-year-old, previously healthy woman with a diffuse, complex tumoral process
is described. While she was being evaluated for primary infertility, a
laparoscopic procedure revealed a disseminated peritoneal process associated with
bilateral ovarian lesions. A clinical diagnosis of stage III ovarian cancer was
made and total hysterectomy, bilateral salpingo-oophorectomy, and omentectomy
were performed. Pathologic studies showed an admixture of leiomyomatosis
peritonealis disseminata (LPD) endometriosis, and an extensive multicystic
mesothelial proliferation. Although endometriosis is known to occur in
conjunction with either LPD or multicystic mesothelioma, to our knowledge this is
the first report of all three lesions occurring simultaneously.
PMID- 9553818
TI - Dr. Arthur T. Hertig.
PMID- 9553819
TI - Gynandroblastoma with elements of juvenile granulosa cell tumor.
PMID- 9553820
TI - Connecting to Internet.
PMID- 9553821
TI - Advancing nursing ethics: time to set a new global agenda?
PMID- 9553822
TI - Marketing and nursing in a competitive environment.
AB - Marketing can no longer be considered vulgar commercialism. Ethically applied,
marketing is in fact one of the necessary building stones and development tools
for the future development of nursing. In the new competitive environment being
created in health sectors to improve efficiency and cost-effectiveness, the
nursing profession must learn to use marketing techniques to survey the needs,
identify gaps in services and develop products and services that will be relevant
for today's empowered consumer.
PMID- 9553823
TI - Sharing in practice: new partnerships for health.
AB - A vital part of health care, sharing in practice is not a vision for the future
but the reality of today. Below, the meaning and implications of sharing in
practice not just for nursing but for health care.
PMID- 9553824
TI - International partnerships in nursing education.
AB - As economies are shrinking, international partnerships in nursing education are
growing, with the more established educational institutions launching not only on
site internationally focused programmes but also educational partnerships that
cross borders, regions, societies, cultures, languages and educational and
nursing traditions. Below, some issues related to initiating and maintaining
partnerships, as well as the benefits and problems based on personal experience
with these partnerships in developing countries.
PMID- 9553826
TI - Nursing and home care in Europe.
AB - The demographic trend of a rapidly ageing society becomes increasingly
persuasive. More chronically ill patients will be discharged to home care. More
people with psychotic problems and debilitating diseases will be living in
communities. All require nursing care. This situation is recognized everywhere
and no boundaries can change this future.
PMID- 9553825
TI - An action approach to redesigning a patient-centred unit.
AB - Receptiveness to innovation is critical in orchestrating change and learning to
use new technology in a redesigned work environment. The patient-centred unit
redesign approach (PCURA) provides a guide for unit assessment in many healthcare
settings. The backbone of the PCURA approach: work excitement and unit culture
assessment.
PMID- 9553827
TI - The truth and nothing but the truth: objectivity in alternative and orthodox
biomedicine?
PMID- 9553828
TI - Topical progesterone cream application and overdosing.
PMID- 9553829
TI - Tobacco as a psychiatric remedy.
PMID- 9553830
TI - Misuse of herbal remedies: the case of an outbreak of terminal renal failure in
Belgium (Chinese herbs nephropathy)
AB - At least 100 cases of extensive interstitial fibrosis of the kidneys were
observed in Belgium in women who had followed a weight-loss regimen that included
the use of Chinese herbs. The possible relation between the renal disease and
these Chinese herbs was investigated. It was shown that the prescribed Chinese
herb called Stephania tetrandra was, in fact, inadvertently replaced by another
Chinese herb, namely Aristolochia fangchi in the powdered extracts delivered in
Belgium and in France. The development of renal disease in about 100 patients
exposed to the so-called Stephania tetrandra stresses the need for more stringent
control of herbal medicine.
PMID- 9553831
TI - Chinese herbs: risk, side effects, and poisoning: the case for objective
reporting and analysis reveals serious misrepresentation.
PMID- 9553832
TI - Chinese medicine users in the United States. Part I: Utilization, satisfaction,
medical plurality.
AB - OBJECTIVES: Chinese medicine is growing in popularity and offers an important
alternative or complement to biomedical care, but little is known of who uses it
or why they purchase it. This article reports the first in-depth, large-scale (n
= 575) survey of United States acupuncture users. DESIGN: An anonymous mixed
quantitative-qualitative survey questionnaire assessed user demographics, Chinese
medicine modalities used, complaints, response to care, other health-care used,
and satisfaction with care in six general-service clinics in five states. RESULTS
AND CONCLUSIONS: The user demographic picture was of mid-age, well-educated,
employed, mid-income patients. They sought care for a wide variety of conditions;
top uses were for relief of musculoskeletal dysfunction, mood care, and wellness
care. A large majority reported "disappearance" or "improvement" of symptoms,
improved quality of life, and reduced use of selected measures including
prescription drugs and surgery. Respondents reported utilizing a wide array of
practices in addition to Chinese medicine, while also expressing extremely high
satisfaction with Chinese medicine care. The evidence indicates that these
respondents behave as astute consumers within a plural health care system. Part
II (in press) details reasons given for satisfaction and situates respondent
attitudes within a larger sociocultural framework.
PMID- 9553833
TI - Effect of acupuncture stimulation of the auricular sympathetic point on evoked
sudomotor response.
AB - OBJECTIVES: To investigate whether stimulation of the auricular sympathetic
acupuncture point would affect the mean maximum amplitude of evoked sudomotor
responses. DESIGN: A placebo-controlled trial. Two types of controls were used:
no acupuncture and acupuncture of an alternate "non-sympathetic nervous system"
related (i.e., a non-sympathetic, placebo) point. Subjects were included in
either the placebo or the test group. Each subject would have one session of
acupuncture and one session without acupuncture, the acupuncture was applied in
either the first or the second session. Initially, each group was unaware in
which of the two sessions they would receive acupuncture (cross-over design).
Each individual was unaware of which group they were to participate in.
SETTINGS/LOCATION: A quiet, sealed room with a constant temperature, in the
research department of the Anglo-European College of Chiropractic. SUBJECTS:
Thirty-eight asymptomatic male, white volunteers (18 to 40 years old).
INTERVENTIONS: The two groups underwent two electrodermal response (EDR)
recording sessions, at an interval of 5 weeks. During each session, they were
also presented with eight stimuli, each of which was designed to stimulate the
sympathetic nervous system. In each session, subjects either received auricular
acupuncture (AA) or did not. OUTCOME MEASURES: The maximum amplitude of the EDR
for each stimulus. RESULTS: AA at the non-sympathetic, placebo point
significantly increased EDR both with respect to the individual stimuli (p < or =
0.05 to < or = 0.001) and for the pooled data (p = 0.0001). AA to the sympathetic
point produced no significant change in EDR for either individual stimuli (p
range > or = 0.8 to > or = 0.1) or for the pooled data (p > 0.8). A significant
difference was found between the results from placebo and sympathetic point
stimulated groups during AA for 2 of the 8 stimuli (p < 0.05), and for the pooled
data from all 8 stimuli (p = 0.0006). CONCLUSION: Stimulation of the sympathetic
AA point significantly decreased the stimulus-evoked EDR when compared with an AA
stimulation to a non-sympathetic (placebo) point. However, it did not
significantly alter EDR compared with no treatment. This implies that the
increase in response as a result of inserting the needles was negated by placing
the electrodes in the AA sympathetic point. Consequently, one might surmise that
there may be a specific action of AA in respect to hyperhidrosis resulting from
an increase in sympathetic activity.
PMID- 9553834
TI - Extraction, assay, and analysis of antimicrobials from plants with activity
against dental pathogens (Streptococcus sp.)
AB - Many dental and periodontal diseases are largely a question of bacterial
etiology. Dental caries develop due to an increase of strongly acidogenic and
aciduric gram-positive bacteria while common forms of periodontal disease are
linked to anaerobic gram-negative bacteria in subgingival plaque. Many plants and
plant-derived antimicrobial components are used in folklore therapeutics for the
treatment of periodontal disorders and for the purposes of oral hygiene. Some
have been evaluated for possible use in modern medicine, while thousands of other
potentially useful/plants have not been tested. In this study, we evaluated the
feasibility of screening for antibacterials isolated from plants with activity
against three representatives of oral streptococci. We developed and tested the
following methodologies: (1) Extraction of antibacterial components from plants;
(2) Assays for antibacterial activity; (3) Chromatographic methods for initial
analysis of compounds of interest. The screening process for plant antimicrobials
consisted of extraction of plant material and assay of antibacterial activity
using a spotting test with the selected oral streptococci as indicator strains.
In addition, we developed chromatographic procedures that allow characterization
and optimization of initial isolation steps. Depending on the indicator
microorganisms used, the screening assay can target additional pathogens
including other streptococci (group A and B, and pneumococci) and periodontal
pathogens such as Porphyromonas. Also, we noted that the activity of some
extracts varied against different oral bacteria. Our conclusion, supported by
extensive data, was that the screening for antimicrobials from plants is a
feasible approach to the identification of natural compounds with antimicrobial
properties against dental pathogens.
PMID- 9553835
TI - The problem of treating dental pathogens.
PMID- 9553836
TI - Can biological activity be maintained at ultra-high dilution? An overview of
homeopathy, evidence, and Bayesian philosophy.
AB - Forty percent of general practitioners in the Netherlands practice homeopathy.
With over 100 homeopathic medical schools, homeopathy is practiced in India along
with conventional Western medicine in government clinics. In Britain, 42% of
general practitioners refer patients to homeopaths. Two recent meta-analyses of
homeopathy both indicate that there is enough evidence to show that homeopathy
has added effects over placebo. Against this evidence is a backdrop of
considerable scientific scepticism. Homeopathic remedies are diluted substances-
some are so diluted that statistically there are no molecules present to explain
their proposed biological effects (ultra-high dilutions or UHDs). Without
knowledge of the evidence, most scientists would reject UHD effects because of
their intrinsic implausibility in the light of our current scientific
understanding. The objective of this article is to critically review the major
pieces of evidence on UHD effects and suggest how the scientific community should
respond to its challenge. Such evidence has been conducted on a diverse range of
assays--immunologic, physiological, behavioral, biochemical, and clinical in the
form of trials of homeopathic remedies. Evidence of UHD effects has attracted the
attention of physicists who have speculated on their physical mechanisms.
Included is a critique of several experiments that form the Benveniste affair
which was sparked by a publication in Nature that advocated the existence of UHD
effects of anti-immunoglobulin E (IgE) on human basophils, and is the paradigm
example of how a controversial phenomenon can split the scientific community. It
is argued that if the phenomenon was uncontroversial, the evidence suffices to
show that UHD effects exist. However, given that the observations contradict well
established theory, normal science has to be abandoned and scientists need to
decide for themselves what the likelihood of UHD effects are. Bayesian analysis
describes how scientists ought rationally to change their prior beliefs in the
light of evidence. Theories by Kuhn and Lakatos indicate that whether UHD effects
are proved or not depends on the beliefs and behaviors of scientists in their
communities. This article argues that there is as yet insufficient evidence to
drive rational scientists to a consensus over UHD effects, even if they possessed
knowledge of all the evidence. The difficulty in publishing high-quality UHD
research in conventional journals prevents a fair assessment of UHD effects.
Given that the existence of UHD effects would revolutionize science and medicine,
and given the considerable empirical evidence of them, the philosophies of
science tell us that possible UHD effects warrant serious investigation by
conventional scientists and serious attention by scientific journals.
PMID- 9553837
TI - Chemical sensitivity after intoxication at work with solvents: response to sauna
therapy.
AB - OBJECTIVES: The purpose of this case study is twofold. One, to illustrate a
simple method of detoxification using heat chamber depuration (sauna). Second, to
raise awareness in the practice of medicine of the importance of taking an
environmentally oriented history. SUBJECT: A patient with a chronic, debilitating
multisystem disorder of 20-years' duration related to a chemical sensitivity
resulting from low-level exposure to toxic chemicals (solvents) at work.
INTERVENTIONS: Detoxification treatment consisted of heat chamber depuration
(sauna) together with a specific protocol of oral and intravenous therapy.
Appropriate advice was offered related to choosing a safe and suitable workplace.
OUTCOME MEASURES: Observation of the dynamic interaction and elimination of
chlorinated and aromatic hydrocarbons (solvents) from the patient's bloodstream
and related clinical improvement during the course of treatment. RESULTS: The
patient was able to discontinue, without ill effect, all medications previously
prescribed to treat her symptoms. Heat chamber depuration (sauna) detoxification
treatment brought substantial release of symptoms and returned the individual to
gainful employment. CONCLUSION: The connection between symptoms of chronic
degenerative diseases and environmental and/or nutritional factors is missed in
many cases due to lack of obtaining an environmentally oriented medical history.
Taking such a history and dealing with the cause of illness using avoidance
and/or appropriate therapy is preventive and cost-effective for both the patient
and society.
PMID- 9553838
TI - Some biological actions of alkylglycerols from shark liver oil.
AB - Shark liver oil has been used for over 40 years as both a therapeutic and
preventive agent. The active ingredients in shark liver oil have been found to be
a group of ether-linked glycerols known as alkylglycerols. Initial clinical use
was for treating leukemias, and later to prevent radiation sickness from cancer x
ray therapy. Studies over the last 30 years have shown that alkylglycerols are
multifunctional. The level of natural alkylglycerols rises within tumor cells,
apparently in an effort to control cell growth. Recent studies indicate that the
activation of protein kinase C, an essential step in cell proliferation, can be
inhibited by alkylglycerols. This action suggests a competitive inhibition of 1.2
diacylglycerol by alkylglycerols. Further studies on the immunostimulatory action
of alkylglycerols suggest a primary action on the macrophage. The process of
macrophage activation has been demonstrated with both synthetic and natural
alkylglycerols. While the exact mechanism has not been found, both an autocrine
and paracrine system have been suggested. Shark liver is a major natural source
of alkylglycerols, which have no known side effects in dosages of 100 mg three
times a day. The information presented in this article suggests that
alkylglycerols may be used both as an adjunct therapy in the treatment of
neoplastic disorders and as an immune booster in infectious diseases.
PMID- 9553839
TI - Soul consciousness and human suffering: psychotherapeutic approaches to healing.
AB - A clinical approach to the understanding of disturbances of the psyche that
otherwise would be regarded as pathological states of mind is described. A
parallel is drawn between psychoanalytic object relations theory and "spiritual
object relations," working from the premise that mind comes before matter. A
number of clinical examples illustrate how both psychological and spiritual
interpretations may be applied and that highlight the need for psychiatrists to
be open to the transpersonal frame of reference.
PMID- 9553840
TI - Clinical management of brain metastasis.
AB - Brain metastasis is a common complication occurring in about 15-20% of all cancer
patients. For the initial management, distinguishing between three types of
presentation is essential: de novo brain metastasis, simultaneous presentation of
both brain metastasis and the primary tumour (usually lung carcinoma), and the
presentation of a patient known to have systemic cancer developing a brain
metastasis. For de novo brain metastasis, surgery is required, and detecting the
primary tumour is of limited value. For simultaneous presentation, both a
craniotomy and a thoracotomy may be indicated and may lead to cure in a number of
cases. For a sequential presentation, the outcome is determined by a number of
independent prognostic factors: age, performance status, and the extent of
metastatic disease. In relatively young patients with a single brain metastasis,
good performance status and no progression of systemic disease, treatment by
either surgery or radiosurgery in combination with whole brain radiation therapy
is indicated. Otherwise, as in multiple brain metastases, radiation therapy only
is the main treatment. For symptomatic therapy of brain oedema or increased
intracranial pressure, dexamethasone is administered. The standard doses of
dexamethasone may vary between 4 and 16 mg/day, depending on the severity of
symptoms.
PMID- 9553841
TI - Serum antibodies against membranous labyrinth in patients with "idiopathic"
bilateral vestibulopathy.
AB - To investigate the possibility of an autoimmune mechanism in idiopathic bilateral
vestibulopathy (IBV), we screened patients' sera for antibodies against inner ear
structures. IgG antibodies against membranous labyrinth (ampulla, semicircular
canals, saccule and utricle) were detected in 8 of 12 patients by
immunofluorescence on rat inner ear cryosections. All but one serum of 22 healthy
controls and the sera of 6 patients with known autoimmune disorders showed only
background staining. Low-titre anti-nuclear IgM antibodies were present in three
control sera and one IBV serum. High-titre anti-nuclear IgM was found in a
patient with lupus erythematosus and in one with scleroderma. Anti-nuclear IgM
was not organ-specific. No human serum used contained detectable anti-vascular
preformed antibodies. Cross-reactivity to sections of liver, kidney, cornea,
brain and skeletal muscle was absent. Double-staining for IgG and F-actin, the
primary constituent of hair cell cilia, did not show predominant Ig-coating of
sensory hair cells. Immunosuppressive therapy in 3 IBV patients did not improve
the disorder, probably owing to irreversible loss of sensory and neural
structures. These data suggest that the bulk of anti-labyrinthine autoantibodies
may be an epiphenomenon, yet a small subgroup of organ-specific autoantibodies
may synergize with a cellular response in the development of vestibular lesions.
PMID- 9553843
TI - Effect of transcutaneous electrical nerve stimulation (TENS) on central nervous
system amplification of somatosensory input.
AB - The effect of transcutaneous electrical nerve stimulation (TENS) on the central
nervous system amplification process was investigated focusing on the dorsal
column-medial lemniscal pathway, because the dorsal column nucleus was recently
shown to receive multiple sources of sensory information, including pain. Short
latency somatosensory evoked potentials (SSEPs) were recorded in ten healthy
normal volunteers. Amplitude changes in each SSEP component (the N9 brachial
plexus potential, the P14 potential that originates from the cervicomedullary
junction, spinal N13/P13 generated by the cervical dorsal horn and the cortical
N20/P25 potential) were studied at stimulus strengths ranging from the threshold
(40% maximum stimulus) to 2.5 times the threshold (maximum). The findings suggest
that sensory amplification begins at the P14 generator source near the cuneate
nucleus. There was no statistically significant difference in sensory
amplification between P14 and cortical N20/P25, indicating that the cuneate
nucleus is the main site of the central amplifying process. When TENS was applied
to the palm distal to the median nerve stimulation used for SSEP, cortical
N20/P25 amplification disappeared, evidence that TENS suppresses the central
amplification phenomenon, most probably at the level of the cuneate nucleus.
PMID- 9553842
TI - Pulsatile tinnitus--a review of 84 patients.
AB - Pulsatile tinnitus can be annoying for a patient and can also be the only clue to
a potentially devastating and life-threatening disease. In order to understand
its clinical spectrum and management better we analysed the files of 84 patients
seen at our institution over a 10-year period. Noninvasive techniques
(ultrasound, computed tomography, magnetic resonance imaging) and angiography
were employed as investigations tailored to the individual patient. A vascular
disorder [i.e. arteriovenous fistula, dissection of the internal carotid artery
(ICA), fibromuscular dysplasia, aneurysm of the ICA and sinus thrombosis] was
found in 36 patients (42%), most commonly a dural arteriovenous fistula or a
carotid-cavernous sinus fistula. In 26 patients with a vascular abnormality,
pulsatile tinnitus was the presenting symptom. In 12 patients (14%), nonvascular
disorders such as glomus tumour or intracranial hypertension with a variety of
causes explained the tinnitus. We conclude that patients with pulsatile tinnitus
should be investigated with noninvasive techniques. If these are negative or to
clarify abnormal findings of noninvasive techniques selective angiography is
needed for diagnosis and to guide treatment.
PMID- 9553844
TI - Increased rate of factor V Leiden mutation in patients with cerebral venous
thrombosis.
AB - We investigated the association between cerebral venous thrombosis and hereditary
resistance to activated protein C (APC) in 12 consecutive German patients with
non-fatal cerebral venous thrombosis and in 187 controls without a history of
thrombotic disorder. Three patients (25%) had a mutation in the factor V Leiden
gene against only one subject in the control group. This difference was
significant (P < 0.05), with an odds ratio of 11.7 (1.5-87; 95% confidence
interval). Two patients carrying the mutation had additional common risk factors
for thrombosis, and 2 had a positive family history of thromboembolism. We
conclude that inherited APC resistance by a mutation in factor V Leiden is an
important risk factor in non-fatal cerebral venous thrombosis. We recommend
testing for APC resistance and, if abnormal for factor V Leiden mutation in
patients with cerebral venous thrombosis.
PMID- 9553845
TI - Functional correlates of callosal atrophy in relapsing-remitting multiple
sclerosis patients. A preliminary MRI study.
AB - In multiple sclerosis (MS), periventricular lesions produce atrophy of the corpus
callosum (CC), as evidenced by magnetic resonance imaging (MRI). We investigated
whether CC atrophy in relapsing-remitting MS patients is related to functional
deficits. We compared 14 mildly disabled (mean Expanded Disability Status Scale
score 2.7) relapsing-remitting MS patients with 14 age- und sex-matched controls.
CC size was determined using sagittal T1-weighted MRI. The function of the CC was
studied using a neuropsychological battery and neurophysiological evaluation
based on visual stimulation using a divided visual field paradigm. The total area
of the CC in patients (mean 5.3 cm2) was significantly (P = 0.002) smaller than
in controls (mean 6.6 cm2). Patients showed left ear extinction using the
dichotic listening test and impaired name learning, which was correlated with
atrophy of the splenium. There were no differences in interhemispheric transfer
time between patients and controls. Marked atrophy of the CC can be encountered
in relapsing-remitting MS patients. The associated cerebral disconnection
correlated with atrophy of expected regions of the CC, thus supporting
topographical organization.
PMID- 9553846
TI - Epineurial microvasculitis in proximal diabetic neuropathy.
AB - Amongst the focal and multifocal neuropathies that are associated with diabetes
mellitus one of the most common is a proximal predominantly motor lower limb
neuropathy. Recent evidence has indicated that, at least in a proportion of
cases, this may have an inflammatory basis. We have examined a consecutive series
of 15 cases of proximal diabetic neuropathy (diabetic amyotrophy). These were
characterized by proximal pain and asymmetric proximal or generalized lower limb
muscle weakness, associated in some cases with radicular sensory involvement. Two
thirds of the patients had an accompanying distal symmetric sensory
polyneuropathy. Biopsy of the intermediate cutaneous nerve of the thigh, a
sensory branch of the femoral nerve, showed epineurial microvasculitis in 3
patients and nonvasculitic epineurial inflammatory infiltrates in another case.
In a further case, microvasculitis was found in both in the sural nerve and a
quadriceps muscle biopsy specimen. The detection of inflammatory changes appeared
to be correlated with the occurrence of sensory radicular involvement. Whether
similar changes are present in muscle nerves in this predominantly motor syndrome
requires further study. Nevertheless, the present observations confirm the view
that secondary vasculitic or other inflammatory reactions may contribute to some
forms of diabetic neuropathy.
PMID- 9553847
TI - Determinants of onset age in Friedreich's ataxia.
AB - We studied the factors that might influence onset age in Friedreich's ataxia in
41 cases (20 male, 21 female) homozygous for GAA expansion on the first intron of
X25 gene. Patients came from 18 multiplex families (13 couples, 5 triplets). Mean
age (SD) was 18.1 (8.9) years and did not differ by gender. Onset age and the
sizes of the smaller (GAA1) and the larger (GAA2) allele in each pair showed high
intrafamily correlation. We found an inverse correlation between age at onset and
GAA1 size, but not between age at onset and GAA2 size. Stepwise multiple
regression of onset age on GAA1 size, sibling onset age, and GAA2 size showed
that GAA1 accounts for 73% of onset age variance, and sibling onset age for an
additional 13%. The study demonstrates that, in addition to GAA expansion size,
other environmental or genetic familial factors influence disease expression.
PMID- 9553848
TI - Humoral immune response to p53 in malignant glioma.
AB - p53 immunoreactivity and humoral immune response to p53 were examined in 14
patients with malignant glioma, including 4 patients with leptomeningeal glioma
cell dissemination. Twelve patients expressed p53 protein within the tumour
tissue. p53 antibodies were detected in the serum in 2 of 14 patients but never
in the cerebrospinal fluid (CSF). Soluble p53 protein was detected neither in
serum nor in CSF of the glioma patients. CSF levels of the immunosuppressive
cytokine, transforming growth factor (TGF)-beta, were elevated in the glioma
patients, including those with a humoral response to p53. These preliminary
findings raise the possibility of systemic humoral immune responses to antigens,
including mutant p53, expressed by glioma cells in the central nervous system.
PMID- 9553849
TI - Disorders of micturition in neurological patients. A clinical study of 786
patients.
AB - Our aim was to evaluate the utility and effectiveness of a study protocol for
neurological involvement in neurological disorders. We studied a sample of 786
patients with neurological disorders followed by the Neurological Department of
Catania University and applied to them a four-step diagnostic protocol. Fifty-six
per cent of the sample showed urological functional abnormalities; only 78
patients (9.9%) presented with an organic urological disease. Among the
vesicosphincteric dysfunctions, bladder hyperreflexia was the most common pattern
with remarkable differences between diseases. The present study demonstrated the
utility of a standardized urological protocol in the screening and detection of
neurological involvement in neurological diseases. Our protocol showed good
specificity and reasonable low costs.
PMID- 9553850
TI - Diagnosis and treatment of intramedullary spinal cord sarcoidosis.
PMID- 9553851
TI - Hemiparkinsonism-hemiatrophy: a new observation.
PMID- 9553852
TI - Neuromyotonia, systemic lupus erythematosus and acetylcholine-receptor
antibodies.
PMID- 9553853
TI - Long-term functional prognosis of posterior injuries in high-energy pelvic
disruption.
AB - OBJECTIVE: This study sought to identify the long-term functional results of
various posterior pelvic lesions and to determine whether such injuries benefit
from exact reduction. DESIGN: Consecutive cohort of patients admitted for pelvic
disruption between 1980 and 1990. SETTING: University hospital. PATIENTS: Eighty
eight pelvic fractures in eighty-eight patients were classified according to the
instability and anatomy of the posterior injury. Simple fractures of the pubic
rami, minimally displaced fractures with pubic diastasis of less than 2.5
centimeters, and fractures without other pelvic lesions (type B1 lesions, stage 1
in the Tile classification) were all excluded. Patients with sequelae of
associated lesions that could render functional evaluation difficult were also
excluded. INTERVENTIONS: The initial status of the patient and the type of
fracture determined the treatment. In the anteroposterior compression injuries
group, an external fixator using the double-frame Hoffmann device was applied in
twenty-eight cases to reduce a large external horizontal displacement, either
immediately to control bleeding or later as definitive treatment when anterior
internal fixation was not possible. Anterior internal fixation with a plate was
used six times to repair a symphyseal disruption. In vertical shear injuries,
tibial skeletal traction was used for six weeks as an attempt to stabilize
vertical instability. In ten patients, traction alone was used. In other cases,
traction was used in conjunction with an external fixator or internal pubic
fixation. In impacted lateral compression injuries, simple bed rest for six weeks
was used in cases of stable lesions. Skeletal traction was applied in ten
patients of this group because of a potential vertical instability, particularly
in cases with a comminuted sacral lesion. MAIN OUTCOME MEASURES: Anatomic
diagnosis and evaluation of the reduction were made using anteroposterior, inlet,
and outlet radiographs of the pelvic ring. To assess reduction, vertical,
anteroposterior, and rotatory displacement was measured. Functional results were
qualified based on the injury pattern and the quality of the final reduction and
were then quantified according to the grading proposed by Majeed. RESULTS:
Functional results varied according to injury anatomy, with fractures of the
iliac wing and sacroiliac (SI) fracture-dislocations having the best prognosis.
The quality of reduction did not affect the functional results. Conservative
methods such as skeletal traction and external fixation generally gave
satisfactory functional results. Conversely, however, pure SI lesions were
associated with poor functional results, especially if reduction was not exact.
CONCLUSIONS: This study shows that when the posterior injury is a fracture of the
iliac wing or a mixed fracture with SI propagation, a long-term satisfactory
functional result can be obtained without an exact reduction even in cases of
vertical instability. Simple methods are usually sufficient, and it seems
unnecessary to propose more aggressive treatment. It is important, however, to
recognize that SI fracture-dislocations (17 percent in this series) seem to be
quite different from pure SI disruptions in terms of persistent pain. Moreover,
it appears that exact reduction of pure SI lesions is critical for good
functional results, something that is difficult to obtain with conservative
procedures. Sacral fractures represent a special problem for the surgeon because
of the frequency of fair results in which neurologic lesions whose
pathophysiology is poorly known seem to be responsible.
PMID- 9553854
TI - Biomechanical evaluation of a low anterior wall fracture: correlation with the CT
subchondral arc.
AB - OBJECTIVE: To measure the effect of a simulated low anterior wall fracture of the
acetabulum on load transmission in the hip joint. DESIGN: We measured the contact
areas and pressure between the acetabulum and the femoral head of cadaveric
pelves in three different conditions: intact, with an operatively created
fracture of the anterior wall, and after anatomic reduction and internal fixation
of the fracture. SETTING: Hips were loaded in simulated single-limb stance.
Pressure and area measurements were made with Fuji pressure-sensitive film.
SPECIMENS: Seven hip joints in seven whole pelves were tested. INTERVENTION:
Anterior wall fractures were anatomically reduced and fixed. MAIN OUTCOME
MEASUREMENTS: Contact area, load, and mean and maximum pressures were measured.
RESULTS: Anterior wall fractures in our specimens entered the hip joint an
average of 9.7 millimeters from the vertex of the acetabulum, corresponding to a
45-degree roof arc measurement. Peripheral loading seen in the intact acetabulum
was disrupted after fracture. The loading pattern was not restored to preinjury
levels with anatomic reduction and fixation. There was no significant change in
the contact area (p = 0.43), force (p = 0.06), or mean (p = 0.57) or maximum (p =
0.20) pressures in the superior aspect of the acetabulum after creation of the
anterior wall fracture. CONCLUSIONS: These results differ from those of previous
studies with posterior wall acetabulum fractures, where significant increases in
force and mean and maximum pressures were noted in the superior acetabulum after
fracture. The lack of significant increases in superior acetabular pressures is
discussed in relation to the mean computed tomographic subchondral arc of
approximately ten millimeters in our specimens.
PMID- 9553855
TI - Functional outcome of acromioclavicular joint injury in polytrauma patients.
AB - OBJECTIVE: To evaluate the functional outcome of displaced acromioclavicular (AC)
injuries in polytrauma patients. DESIGN: A matched, case-control study using a
prospectively gathered trauma database. METHODS: Twelve polytrauma patients with
a concomitant displaced acromioclavicular joint injury were matched to polytrauma
patients without an acromioclavicular joint injury and to patients with an
isolated displaced acromioclavicular joint injury. They were evaluated with a
series of five shoulder questionnaires and the SF-36 general health status
questionnaire. RESULTS: Shoulder function in polytrauma/acromioclavicular joint
injured patients was consistently worse than in control patients with an isolated
acromioclavicular joint injury. In addition, the presence of an acromioclavicular
joint injury in a polytrauma patient had a negative effect on several components
of the SF-36. CONCLUSIONS: A displaced acromioclavicular joint injury in a
polytrauma patient has a greater effect on shoulder function than isolated
acromioclavicular joint injuries when evaluated by both disease-specific and
general health outcomes. Standard treatment methods may be inadequate for this
group of patients.
PMID- 9553858
TI - Mechanical characteristics of eight femoral intramedullary nailing systems.
AB - OBJECTIVE: There are few nonproprietary papers addressing the mechanical strength
of intramedullary nails; none address the characteristics of the proximal and
distal ends of these devices. Our objective was to provide such data. DESIGN:
Independent testing of eight femoral intramedullary nail systems at the proximal,
middle, and distal regions was undertaken to evaluate strength and flexural
rigidity (stiffness). METHODS: Each device, usually a reconstruction nail, was
forty-two to forty-six centimeters in length. Four or five nails of each
available size (range 9 to 13 millimeters in diameter) were tested for each
system. The nails were cut into proximal, middle, and distal thirds. Each nail
section was loaded to failure using a four-point bend test on a custom fixture
(modification of the American Society of Testing Materials standard test).
RESULTS: Significant variations (p < 0.05) were found in strength and stiffness
between the middle and the proximal or distal aspects of some rods. A significant
difference (p < 0.05) was observed when comparing the properties of earlier
designs with the properties of more recent designs. Newer rod designs all
performed in a similar manner with regard to strength. Strength and rigidity
increased with increasing rod diameter in some but not all systems. CONCLUSIONS:
Although none of the newer designs appeared to have superior static strength, the
individual systems had significant variations in their mechanical properties
(bending rigidity), particularly in the proximal and distal sections. It is
important that the surgeon become familiar with the individual characteristics of
strength and rigidity for the particular devices available and how these might
impact fracture healing. Consideration of this information could alter the
decision to select one system over another in a complex fracture situation.
PMID- 9553857
TI - Reamed intramedullary femoral nailing after induction of an "ARDS-like" state in
sheep: effect on clinically applicable markers of pulmonary function.
AB - OBJECTIVES/HYPOTHESIS: At present, the optimal treatment for appropriately
resuscitated, multiply injured patients includes fixation of long bone fractures
within twenty-four hours of injury. This management approach has been shown to
decrease the incidence of pulmonary complications, multiple organ failure, and
death. Some investigators have hypothesized that acute reamed intramedullary
nailing of the femur (RIMNF) may result in pulmonary dysfunction as a result of
the pulmonary fat embolization generated during this procedure. Patients with
concomitant thoracic trauma may be at particular risk for this potentially severe
complication. In an attempt to determine whether RIMNF can be safely carried out
regardless of the severity of a pulmonary injury, we monitored the pulmonary
effects of RIMNF in sheep in which an acute respiratory disorder (ARDS)-like
state had been induced. Our hypothesis was that, if the pulmonary fat
embolization that occurs as a result of RIMNF has a clinically significant
effect, it would be detectable in an animal model in which a severe lung injury
had been induced prior to the start of RIMNF. STUDY DESIGN: This was an acute
experimental procedure performed on yearling sheep. METHODS: Reamed
intramedullary nailing of the femur was performed in two groups of instrumented
sheep. The first group had no pulmonary injuries. The second group had an ARDS
like state induced by intravenous infusion of perilla ketone prior to RIMNF.
Perilla ketone increases pulmonary microvascular permeability without changing
filling pressures and is used to induce a model of human ARDS. Hemodynamic and
oximetric parameters were measured or calculated, as was pulmonary dynamic
compliance during the experiment. RESULTS: Infusion of perilla ketone caused a
significant pulmonary injury. RIMNF caused no additional significant effect on
intrapulmonary shunt, mixed venous oxygen saturation, or dynamic compliance,
which are clinically used to assess the severity of pulmonary dysfunction in
injured patients. CONCLUSIONS: The fat embolization that occurs during RIMNF in
an appropriately resuscitated sheep has no clinically significant effect on
pulmonary function, even in the setting of a severe pulmonary dysfunction.
PMID- 9553856
TI - Femur fractures in chest-injured patients: is reaming contraindicated?
AB - OBJECTIVE: To determine if reamed femoral intramedullary nailing increases the
pulmonary complications seen in chest-injured patients. DESIGN: Retrospective
review of prospectively collected trauma database data from January 1991 to
October 1994. SETTING: Methodist Hospital, Indianapolis, Indiana, Level I Trauma
Center. PATIENTS: Group I: Chest-injured patients [chest Abbreviated Injury Score
(AIS) > or = 2] without femur or tibia fractures. Group II: Chest-injured
patients (chest AIS > or = 2) with femoral reamed intramedullary fixation. Group
III: Chest-injured patients (chest AIS > or = 2) with femoral shaft fixation
using nonreamed fixation (rush rods, plating, or external fixation). Group IV:
Non-chest-injured patients (chest AIS < 2) with femoral reamed intramedullary
fixation. MAIN OUTCOME MEASUREMENT/HYPOTHESIS: Reamed femoral intramedullary
nailing does not alter pulmonary outcomes, even in chest-injured patients.
RESULTS: Groups I and II had a very similar incidence of adult respiratory
distress syndrome (ARDS), pneumonia, and number of ventilator days. Group III had
a significantly higher incidence of ARDS and number of ventilator days than did
Group I or II. Group III did not have a chest AIS score significantly different
than Groups I and II. Group II had significantly higher ARDS and more ventilator
days than did Group IV when only analyzing raw data. When injury severity was
adjusted, there were no significant differences in pulmonary outcomes.
CONCLUSION: Reamed intramedullary femoral fixation did not increase pulmonary
morbidity in chest-injured patients.
PMID- 9553859
TI - Mechanical complications associated with the use of the unreamed AO femoral
intramedullary nail with spiral blade: first experiences with thirty-five
consecutive cases.
AB - OBJECTIVE: To evaluate the unreamed femoral nail with spiral blade (UFN-SB) in
the treatment of subtrochanteric femur fractures. DESIGN: Retrospective review of
a consecutive series of twenty-eight fractures. Sixteen patients had metastatic
disease. SETTING: Academic teaching hospital. MAIN OUTCOME MEASURES: Clinical and
radiographic examination. RESULTS: Five mechanical complications were observed in
four patients. In one patient with a metastastic fracture, we noted a breakage of
the SB twice. In patients with traumatic subtrochanteric fracture, migration of
the SB was observed three times, needing reintervention twice. CONCLUSIONS:
Although this implant is useful in the treatment of subtrochanteric femur
fractures, it is our contention that the problem of subtrochanteric fracture
fixation is not solved with this implant, especially in elderly osteoporotic
patients who require early weight bearing.
PMID- 9553860
TI - Removal of a broken Synthes proximal spiral blade.
AB - Use of cephalomedullary nails is an option for treatment of subtrochanteric femur
fractures. However, the magnitude of bending forces in this area of the femur
often can lead to implant failure before union. We report on a case of hardware
failure of a specific device (Synthes spiral blade) and a method for removal.
PMID- 9553861
TI - Effects of degrees of reaming on healing of segmental fractures in rats.
AB - OBJECTIVE: To assess the effects of graded intramedullary reaming and nailing on
the healing pattern of segmental diaphyseal fractures using male Wistar rats.
STUDY DESIGN: In male Wistar rats we produced two standardized, partial
osteotomies with an eight-millimeter intermediary fragment in the femoral
diaphysis. The osteotomies were subsequently manually broken. In Group A,
intramedullary reaming was performed to 1.6 millimeters, and the fracture was
stabilized with a 1.6-millimeter steel pin. In Group B, the femoral canal was
reamed to 2.0 millimeters, and a hollow steel tube of 2.0 millimeters was
installed. The rats were allowed free movement. After four, eight, and twelve
weeks, eight rats in each group were sacrificed and callus formation,
biomechanical properties, and bone blood flow were evaluated. RESULTS: The callus
area was relatively constant with time in Group B, whereas a reduction was
observed in Group A at twelve weeks. The biomechanical properties increased
throughout the experimental period in both groups, and no significant differences
between the groups were detected in bending moment, bending rigidity, or fracture
energy. Total bone blood flow was substantially increased at four weeks in both
groups and decreased throughout the experimental period. In addition, blood flow
of the segmental fractured area was substantially increased after four weeks and
decreased gradually thereafter. The increases in blood flow tended to be largest
in the moderately reamed group. CONCLUSION: This study indicates that the degree
of reaming does not significantly affect the healing pattern measured as
restoration of mechanical characteristics.
PMID- 9553862
TI - Ultrasound for the early diagnosis of tibial fracture healing after static
interlocked nailing without reaming: histologic correlation using a canine model.
AB - OBJECTIVE: Ultrasound is thought to be clinically useful in evaluating bone
formation through its presumed identification of fracture callus. However,
documentation of the actual histology of the tissue identified by ultrasound has
been lacking. The purpose of this study was to determine the histologic
composition of the hyperechoic tissue "seen" by ultrasound. STUDY DESIGN:
Unilateral fractures were created in eight canine tibias and then fixed by using
locked intramedullary nailing without reaming. The limbs were studied at two,
three, four, six, and eight weeks postoperatively with plain radiographs,
ultrasound, and ultrasound-directed needle biopsy. RESULTS: The presence of a
hyperechoic ultrasound signal was found to have a 100 percent correlation with
the presence of hard fracture callus biopsy tissue. In addition, fracture union
by ultrasound criteria significantly predated radiographic fracture union (5.6
vs. 7.3 weeks, p = 0.05). CONCLUSIONS: These results support and provide a
scientific basis for the clinical use of ultrasound to assess tibial fracture
healing following static interlocked nailing without reaming.
PMID- 9553863
TI - Ultrasound for the early diagnosis of tibial fracture healing after static
interlocked nailing without reaming: clinical results.
AB - OBJECTIVE: Based on the results of a pilot study indicating the potential value
of ultrasound (US) as a diagnostic tool for the early assessment of fracture
healing and the related need for secondary operative procedures in patients
treated by statically locked intramedullary (IM) nailing without reaming, a
protocol was established for a larger scale prospective trial. The purpose of
this study was to evaluate the outcome of this follow-up trial. DESIGN/METHODS:
All skeletally mature patients admitted to the Henry Ford Hospital (Detroit,
Michigan) from January 1993 to August 1994 who had sustained an acute fracture of
the tibial shaft and who were treated by statically locked IM nailing, without
reaming, were candidates for study. Forty-seven patients with fifty fractures
that could be evaluated by US were included. The adopted determinants for
fracture healing were complete disappearance of the IM nail on US examination
performed at six weeks postoperatively, or progressive disappearance of the nail
noted between the initial six-week study and a second nine-week US examination,
both in conjunction with periosteal callus formation. Radiographs were obtained
to monitor maintenance of reduction and to further evaluate fracture healing.
RESULTS: Of thirty-eight fractures with a positive US (thirty-two at six weeks,
six at nine weeks), thirty-seven healed uneventfully, a positive predictive value
of 97 percent. Radiographic fracture healing was not evident until, on average,
nineteen weeks after injury. The single false-positive fracture progressed to
nonunion. Of the twelve fractures with negative US studies, ten underwent
secondary procedures (nine dynamization, one bone graft), with four progressing
to nonunion. Two patients refused secondary surgery; screw failure occurred in
both. Otherwise, there were no hardware failures in this series. CONCLUSIONS: The
results of this study indicate that US may provide important prognostic
information concerning fracture healing after unreamed tibial nailing, upon which
subsequent treatment can be based.
PMID- 9553864
TI - Infections in periarticular fractures of the lower extremity treated with
tensioned wire hybrid fixators.
AB - OBJECTIVES: To observe the incidence and clinical presentation of infection in
periarticular fractures of the tibia and femur treated with tensioned wire
external fixators. DESIGN: Prospective cohort study. SETTING: Level One Trauma
Center in urban community. Single surgeon. PATIENTS: One hundred thirty-five
patients with 145 fractures: seventy tibial plateau, fifty-six pilon, and
nineteen distal femur. Five-year treatment period, 1991 to 1995. MAIN OUTCOME
MEASUREMENTS: The incidence of infection was evaluated. RESULTS: Nineteen of 145
fractures (13 percent) were complicated by infection. Infections presented as pin
tract inflammation requiring intravenous antibiotics (seven), deep infection
requiring debridement and removal (five), septic arthritis (three), deep fracture
infection (three), and necrotizing fasciitis (one). CONCLUSIONS: Infection is a
common complication of juxtaarticular fractures treated with tensioned wire
fixators. Excellent pin care is required. Aggressive management of infections
with intravenous antibiotics and debridement will resolve infections occurring in
patients treated with tensioned wire fixators. Septic arthritis is associated
with wires placed less than one centimeter from the subchondral bone. Deep
infection is associated with insidious swelling and excessive proliferative
callus. Wire infections increase with prolonged frame time.
PMID- 9553865
TI - Technical notes on a radiolucent distractor for indirect reduction and
intramedullary nailing.
PMID- 9553866
TI - Coordinate production of PGE2 and IL-1 beta in the gingival crevicular fluid of
adults with periodontitis: its relationship to alveolar bone loss and disruption
by twice daily treatment with ketorolac tromethamine oral rinse.
AB - The inflammatory mediators prostaglandin E2 (PGE2) and interleukin-1 beta (IL-1
beta) play critical roles in the inflammatory process leading to alveolar bone
and connective tissue loss in periodontal disease. Data from a previously
published 6-month clinical study demonstrated that twice daily use of 0.1%
ketorolac tromethamine oral rinse prevented alveolar bone loss in adults with
periodontitis. We further analyzed data from this study to examine the
relationship between PGE2. IL-1 beta and bone loss. Patient mean PGE2 and IL-1
beta levels in gingival crevicular fluid (M-GCF) measured throughout the course
of the study were directly compared to the maximum amount of alveolar bone height
loss observed at a single study site in each patient. The maximum amount of bone
loss measured was chosen for the analysis since the pattern of bone loss was
clearly episodic in nature. A statistically significant correlation (r = 0.73, p
= 0.001) exists between M-GCF PGE2 concentration and the maximum amount of bone
height lost at individual patient study sites. The correlation between M-GCF IL-1
beta concentration and maximum bone height lost is also statistically significant
(r = 0.66, p = 0.005). Over the 6-month duration of the study, both PGE2 and IL-1
beta were coordinately expressed in the placebo treatment group as reflected in
the significant correlation between M-GCF concentrations of the 2 mediators (r =
0.81, p < 0.001). Treatment of patients with 0.1% ketorolac tromethamine twice
daily for 6 months resulted in reductions of PGE2 in GCF and a negligible
correlation between M-GCF PGE2 and M-GCF IL-1 beta (r = 0.42, p = 0.088). This
lack of a strong association between the 2 mediators in the ketorolac treatment
group provides a direct biochemical readout of the anti-inflammatory efficacy of
ketorolac tromethamine oral rinse in patients with periodontitis. Further studies
are warranted to determine the full diagnostic potential of M-GCF levels of PGE2
and IL-1 beta for predicting risk of alveolar bone loss in patients with
periodontitis and monitoring periodontal therapy effectiveness.
PMID- 9553867
TI - The regulation of fiber arrangement in advanced cellular cementogenesis of human
teeth.
AB - This study observed cellular cementum in fully formed human premolars by light
and electron microscopy to elucidate how cementoblasts regulate the fiber
arrangement in cementum. Cementoblasts had wing-like processes encircling the
principal fibers, where Sharpey's fibers were dense. On the cementum-facing side,
wing-like processes were segmented into finger-like processes in parallel with
the cementum surface. Observations suggested that with the segmentation intrinsic
fibers appeared around principal fibers in close association with finger-like
processes. Where Sharpey's fibers were few or absent, where intrinsic fibers were
the main fibrous element of the cementum, cementoblasts had only few or no wing
like processes, but had finger-like processes not associated with the wing-like
processes on the cementum-facing side. On the basis of the origin of the finger
like processes the main results suggest that there are two kinds of
cementoblasts: one has finger-like processes associated with wing-like processes
and secretes intrinsic fibers from the finger-like processes to incorporate the
principal fibers for tooth support. The second type has finger-like processes not
associated with wing-like processes, this type secretes intrinsic fibers from the
finger-like processes to adjust the cementum thickness.
PMID- 9553869
TI - A comparison of stereological and computer-assisted histomorphometric analysis as
tools for histological quantification in regenerative studies.
AB - This study was designed to compare computer-assisted histomorphometric analysis
(CAHA) and stereology (STER) as measurement tools for evaluating the repair
response during periodontal wound healing. Thirty-six histological sections
derived from 4 surgically created defects in the furcation of mandibular second
premolars of sheep were measured by each technique to determine the furcation
area and volume, and the percentage of new bone formation at 7 wk
postoperatively. Slides were viewed in random order with the source unknown to
the examiner (JL). One section from each of the 4 specimens was flagged for
triplicate measurement by each technique. Intraexaminer error was determined to
be low as the coefficient of variation in each of the 2 techniques was between 1%
and 4%. A consistently higher percentage of bone was identified using stereology.
The coefficient of agreement was plotted to determine how closely these 2
techniques were matched in their respective estimations of bone fill in a
furcation defect. This analysis revealed statistical bias between the 2
techniques and a low degree of agreement between them. This study demonstrates
that the 2 techniques are not interchangeable. It also emphasizes that the reader
must be cautious when comparing results from studies in which different systems
of measurement and analysis have been used. Stereology was determined to be the
measurement tool of choice due to its high degree of reproducibility, ease of use
and efficient use of time.
PMID- 9553868
TI - Killing of Fusobacterium nucleatum, Porphyromonas gingivalis and Prevotella
intermedia by protegrins.
AB - Protegrins are broad spectrum antibiotic peptides isolated from porcine
leukocytes. In this study, we (i) examine the sensitivity of Gram-negative,
anaerobic periodontal pathogens to synthetic protegrins; (ii) determine the
relative potencies of protegrin congeners against these bacteria; and (iii)
compare the potency of protegrins with other antibiotic peptides, including
magainin MSI-78, tachyplesin I, cecropin P1, human defensins HNP-1-3, and
clavanin A. Synthetic L- and D-enantiomers of protegrin 1 (PG-1 and D-PG-1,
respectively), and L-enantiomers of protegrins 2, 3 and 5 (PG-2, PG-3 and PG-5)
were tested against Fusobacterium nucleatum, and black-pigmented organisms
including Porphyromonas gingivalis and Prevotella intermedia. Strains of both F.
nucleatum and the black-pigmented organisms were sensitive to PG-1, and exhibited
mean ED99 of 2.2-2.3 micrograms/ml and 3.4-9.9 micrograms/ml, respectively. The D
form was statistically more potent than the L-form against these oral anaerobes,
and although this difference in potency is unlikely to be of decisive therapeutic
significance, the D-form may be of value given ability to resist microbial and
host-derived proteases. PG-1 was more potent than magainin, tachyplesin,
cecropin, defensins and clavanin under test conditions. Hypertonic salt
concentrations and heat-inactivated serum were found to be inhibitory to the
bactericidal activity of PG-1. PG-1 was found to induce morphologic alterations
in the ultrastructural appearance of F. nucleatum consistent with damage to the
bacterial membranes. We conclude that protegrins may be useful antimicrobial
agents in therapy against Gram-negative anaerobic bacteria believed to be
involved in chronic, adult forms of periodontal infections.
PMID- 9553870
TI - Rapid chair-side DNA probe assay of Bacteroides forsythus and Porphyromonas
gingivalis.
AB - This study compared a rapid, colorimetric DNA probe assay designed to be
performed in a dental office within 40 min, with anaerobic culture and indirect
immunofluorescence microscopy (IFM) for detection of Bacteroides forsythus and
Porphyromonas gingivalis in subgingival plaque samples. The DNA probe assay used
the Periodontal Microbial Identification Test (Saigene Corporation, Bothell,
Washington, USA). B. forsythus was detected in 46 (52%), 49 (55%) and 39 (44%) of
the samples by DNA probe, culture (at levels > or = 10(5)) and IFM, respectively.
P. gingivalis was detected in 24 (27%), 18 (20%) and 29 (33%) of the samples by
DNA probe, culture (at levels > or = 10(5)) and IFM, respectively. Results from
the DNA probe assay were compared to culture. Culture negative, probe positive
samples were re-evaluated by IFM, and IFM positive samples were considered
positive in "resolved" data. Using resolved data. DNA probe detection sensitivity
and specificity values for B. forsythus were 81% and 91% and for P. gingivalis
were 80% and 95%, respectively. DNA probe test results were further compared with
culture and IFM. For samples negative by both culture and IFM, probe specificity
was 92% in 25 B. forsythus samples and 95% in 57 P. gingivalis samples. For
samples positive by both reference methods, probe sensitivity was 82% in 27 B.
forsythus samples and 73% in 15 P. gingivalis samples. B. forsythus was detected
more frequently by culture compared with IFM; the reverse was observed for P.
gingivalis. The rapid DNA probe assay for B. forsythus and P. gingivalis was
comparable to cultivable and IF analyses.
PMID- 9553872
TI - Differential chemotactic effect of cementum attachment protein on periodontal
cells.
AB - Selective re-population of the root surface by periodontal ligament cells is
considered a key factor in periodontal regeneration. A recently isolated cementum
attachment protein (CAP) has been shown to enhance fibroblast attachment. In the
present study the potential of CAP to selectively attract periodontal ligament
cells (PLC) was studied in vitro in a micro-chemotaxis system. Human periodontal
ligament cells and gingival fibroblasts (GF) were compared for their chemotactic
response to either cementum attachment protein or to fibronectin. Murine dermal
fibroblasts (MDF) served as control, irrelevant to the periodontium. The
chemotactic response of PLC to fibronectin at 10(-8) M was of a similar magnitude
as that of GF (16 +/- 5 and 11 +/- 3 cells/field, respectively), but both were
significantly lower than the response of MDF (28 +/- 3 cells/field). The
chemotactic response of periodontal ligament cells to the cementum attachment
protein at 10(-7) M was higher (36 +/- 5 cells/field) than that of gingival
fibroblasts or murine dermal fibroblasts (14 +/- 2 and 16 +/- 2 cells/field,
respectively). These results suggest that cementum attachment protein can
influence the selective re-population of root surfaces by periodontal ligament
cells.
PMID- 9553873
TI - Forced eruption technique: rationale and clinical report.
AB - This article describes a refined, simplified forced eruption technique, and
compared it with previous methods. This simplified method is easy to perform and
encourages the use of adjunctive orthodontics in general practice. This
relatively uncomplicated, quick, and cost-effective treatment can benefit
patients.
PMID- 9553871
TI - Type VI collagen is associated with microfibrils and oxytalan fibers in the
extracellular matrix of periodontium, mesenterium and periosteum.
AB - Type VI collagen was immunolocalized in several soft connective tissues at the
light and electron microscopic level. Positive labeling was found in all tissues
examined, periodontal ligament, gingiva, mesenterium and periosteum. The labeled
structures could be divided into 2 categories: microfibrils intermingling with
collagen fibrils, and those that formed bundles (oxytalan fibres and elastin
associated microfibrils). Control sections incubated with antibody preabsorbed to
purified type VI collagen, or with non-immune antibody, proved to be negative.
Our observations indicate that the structural organization of type VI collagen
varies from small microfibrillar structures associated with the collagen and
elastin fibre systems to highly ordered parallel arrays of oxytalan bundles.
PMID- 9553874
TI - An alternative treatment with the overlay removable partial denture: a clinical
report.
PMID- 9553875
TI - Acceptability of shade differences in metal ceramic crowns.
AB - STATEMENT OF PROBLEM: Application of technology that quantify color and color
differences is currently used in esthetic restorative materials research.
However, parameters for the size of perceptible and acceptable color differences
in metal ceramic crowns have not been determined. PURPOSE: The CIELAB
colorimetric system was used to study the relationship between instrumentally
measured color differences (delta E) and human observer assessment of color
differences in metal ceramic crowns. MATERIAL AND METHODS: Subjects were shown
pairs of metal ceramic crowns whose color difference varied from
indistinguishable to obvious. The subjects attempted to discern a difference in
each pair's color and indicated the clinical acceptability of the shade
difference between the crown pairs. RESULTS: Correlations between instrumental
and visual assessment of color differences in these crown pairs did not agree in
all dimensions of color space. Thresholds acceptability of color differences were
1.1 delta E units for red-varying crowns and 2.1 delta E units for yellow-varying
crowns. Thresholds for perceptibility judgments were significantly lower than
thresholds for acceptability judgments. CONCLUSIONS: Acceptability thresholds
were found to be dependent on chromaticity. Observers were more sensitive and
critical of crowns whose color differed in redness as opposed to crowns whose
color differed to the same extent in yellowness.
PMID- 9553876
TI - Microleakage of Class V compomer and light-cured glass ionomer restorations.
AB - STATEMENT OF PROBLEM: Resin-modified (light-cured) glass ionomer and polyacid
modified composite resin (compomer) restorations are popular choices for the
restoration of root caries and cervical abrasion/erosion lesions, but clinical
studies are relatively few and have been published primarily as abstracts.
PURPOSE: In the absence of adequate clinical data, the marginal integrity of
restorations of the above two types of material was compared in vitro. The
microleakage of restorations of two light-cured glass ionomer restorative
materials and of one compomer material was evaluated. METHODS AND MATERIAL:
Restorations of the three materials were placed in facial and lingual Class V
cavity preparations in bovine incisors. All preparations were centered on the
cementoenamel junction and were prepared with 45-degree enamel bevels. After
thermal cycling, teeth were immersed in methylene blue dye, then sections of the
restorations (n = 16) were visually evaluated. RESULTS: Dye penetration was
observed at approximately 20% of restoration margins for all three materials,
with the greatest incidence of severe leakage in the compomer restorations.
CONCLUSION: No significant difference in microleakage among the three materials
(ANOVA; p > 0.05) was found.
PMID- 9553877
TI - Microleakage along apical root fillings and cemented posts.
AB - STATEMENT OF PROBLEM: Coronal leakage of endodontically treated teeth has been
found to result in a high failure rate. PURPOSE: This study tested leakage along
apical root fillings remaining after post space preparation and cemented posts in
root canals. MATERIAL AND METHODS: A total of 120 human roots were used in the
study and divided into six groups, 20 roots for each group. By using a modified
fluid transport model, leakage (in microL/hr) along ParaPost dowels that were
cemented in the coronal 7 mm of root canals with Fuji Duet, Ketac Cem, Panavia
EX, or zinc phosphate cements was compared with that along the coronal 7 mm of
conventional root canal fillings. Leakage along the apical 4 mm of root filling
remaining after post space preparation was compared with that along the 11 mm
root filling before post space preparation. RESULTS: More leakage was recorded
along the apical 4 mm of root filling than along the 11 mm of original root
filling (p = 0.0325). ParaPost dowels cemented with any test cement did not
produce more leakage than the 7 mm coronal root filling (p = 0.2145).
CONCLUSIONS: The apical 4 mm of root canal filling remaining after post space
preparation leaks statistically significantly more than the original full-length
root canal filling. The leakage created by removal of the coronal part of root
canal filling during post space preparation may be compensated by the cemented
posts.
PMID- 9553878
TI - Resin to metal bond strengths using two commercial systems.
AB - STATEMENT OF PROBLEM: A secure bond between resin and an alloy framework is
necessary for clinical success in removable prosthodontics. PURPOSE: This study
compared the shear bond strength of composite to composite to metal with two
commercially available chemical bonding systems: a silicoating system
(Silicoater) and a nitrogenous heterocycle-acrylonitrile system (Kevloc).
MATERIAL AND METHODS: Fifty-two nickel-chromium cubes were cast and composite
resin was bonded to the alloy surfaces according to manufacturer's directions.
After storage at 35 degrees C for 15 days, and thermocycling at 5 degrees C and
55 degrees C for 1200 cycles, the bonds were fractured in shear on a universal
testing machine. RESULTS: Mean bond strength for the silicoated sample was 10.93
MPa and for the heterocycle-acrylnitrate system 11.44 MPa. An unpaired t test
revealed no difference between the groups (p = 0.60). Visual inspection of the
fracture surfaces revealed that failure was adhesive at the resin-to-metal
surface in almost all the specimens.
PMID- 9553879
TI - Comparison of a new autocuring temporary acrylic resin with some existing
products.
AB - STATEMENT OF PROBLEM: Some problems of the self-curing or autopolymerizing resins
may include color instability and dimensional inaccuracy. PURPOSE: This study
compared the color and dimensional stability of the new autopolymerizing resin
Unifast II, which combines a new activator with some existing products. RESULTS:
The change in color (delta E value) of Unifast II resin was less than that
demonstrated for four autopolymerizing resins (Unifast, Curefast, ADFA, and
MIKY). Unifast II did not exhibit color change when stored in conditions below 37
degrees C. Unifast II also had a significantly better fit than the other four
autopolymerizing resins (p < 0.01). No significant differences in transverse
strength were observed among Unifast II, Unifast, and ADFA, but the Unifast II
autopolymerizing resin maintained its color stability and dimensional accuracy
without sacrificing its transverse strength.
PMID- 9553880
TI - New acrylic resin composite with improved thermal diffusivity.
AB - STATEMENT OF PROBLEM: Studies have shown that physical characteristics of denture
base materials may affect patient acceptance of denture prostheses by altering
sensory experience of food during mastication. Thermal diffusivity is one
material property that has been cited as being important in determining gustatory
response, with denture base acrylic resins having low thermal diffusivity
compared with denture base metal alloys. PURPOSE: This study prepared and
characterized experimental acrylic resin composite material with increased
thermal diffusivity. MATERIAL AND METHODS: Sapphire (Al2O3) whiskers were added
to conventional denture base acrylic resin during processing to achieve loadings
of 9.35% and 15% by volume. Cylindrical test specimens containing an embedded
thermocouple were used to determine thermal diffusivity over a physiologic
temperature range (0 degree to 70 degrees C). RESULTS: Thermal diffusivities of
the sapphire containing composites were found to be significantly higher than the
unmodified acrylic resin. Thermal diffusivity was found to increase in proportion
to the volume percentage of sapphire filler, which suggested that the high aspect
ratio ceramic particles formed a pathway for heat conduction through the
insulating polymer matrix. CONCLUSION: The thermal diffusivity of denture base
acrylic resin was increased by the addition of thermally conducting sapphire
whiskers.
PMID- 9553881
TI - Laser welding of a cobalt-chromium removable partial denture alloy.
AB - STATEMENT OF PROBLEM: The electric alloy brazed joints of removable partial
denture alloys have failed frequently after routine usage. PURPOSE: A technique
providing higher joint strengths was investigated. This investigation compared
the tensile strengths of electric-brazed and laser-welded joints for a cobalt
chromium removable partial denture alloy. MATERIAL AND METHODS: Twenty-four
cobalt-chromium standard tensile testing rods were prepared and divided into
three groups of eight. All specimens in the control group (group 1) were left in
the as-cast condition. Groups 2 and 3 were the test specimens, which were
sectioned at the center of the rod. Eight specimens were joined by using electric
brazing, and the remaining specimens were joined by using laser welding. After
joining, each joint was ground to a uniform diameter, then tested to tensile
failure on an Instron universal testing machine. Failure loads were recorded and
fracture stress calculated. Statistical analysis was applied. RESULTS: The
student-Newman-Keuls test showed a highly significant difference between the
joint strengths of the as-cast control specimens, the electric-brazed and laser
welded joints. CONCLUSIONS: The tensile strengths of the as-cast joints were
higher than those for the laser-welded joints, and both were higher than the
electric-brazed joint strengths.
PMID- 9553882
TI - Effects of joint configuration for the arc welding of cast Ti-6Al-4V alloy rods
in argon.
AB - STATEMENT OF PROBLEM: Titanium and its alloys are more commonly used in
prosthodontics and welding has become the most common modality for their joining.
Studies on the welding of titanium and its alloys have not quantified this value,
though its importance has been suggested. PURPOSE: This study compared the
strength and properties of the joint achieved at various butt joint gaps by the
arc-welding of cast Ti-6Al-4V alloy tensile bars in an argon atmosphere. MATERIAL
AND METHODS: Forty of 50 specimens were sectioned and welded at four gaps. All
specimens underwent tensile testing to determine ultimate tensile strength and
percentage elongation, then oxygen analysis and scanning electron microscopy.
RESULTS: As no more than 3 samples in any group of 10 actually fractured in the
weld itself, a secondary analysis that involved fracture location was initiated.
There were no differences in ultimate tensile strength or percentage elongation
between specimens with weld gaps of 0.25, 0.50, 0.75, and 1.00 mm and the as-cast
specimens. There were no differences in ultimate tensile strength between
specimens fracturing in the weld and those fracturing in the gauge in welded
specimens; however, as-cast specimens demonstrated a higher ultimate tensile
strength than welded specimens that fractured in the weld. Specimens that
fractured in the weld site demonstrated less ductility than those that fractured
in the gauge in both welded and as-cast specimens, as confirmed by scanning
electron microscopy examination. The weld wire showed an oxygen scavenging effect
from the as-cast parent alloy. CONCLUSIONS: The effects of the joint gap were not
significant, whereas the characteristics of the joint itself were, which
displayed slightly lower strength and significantly lower ductility (and thus
decreased toughness). The arc-welding of cast titanium alloy in argon atmosphere
appears to be a reliable and efficient prosthodontic laboratory modality
producing predictable results, although titanium casting and joining procedures
must be closely controlled to minimize heat effects and oxygen contamination.
PMID- 9553883
TI - Radiographic verification of implant abutment seating.
AB - STATEMENT OF PROBLEM: It is possible to incorrectly seat an abutment on an
external hex implant. PURPOSE: This study investigated the theoretical and
practical limits of radiographic verification of the complete seating of implant
abutments on external hex implants. MATERIAL AND METHODS: A positioning device
that could accurately place the film and/or tube head in any vertical relation
desired relative to the implant and abutment was fabricated. For all records, a
standard abutment was secured to the implant in both a fully seated position
(closed) and with the abutment turned approximately 30 degrees and seated atop
the implant external hex (open). Digital radiographs were made with the tube head
fixed perpendicular to the implant and the film angled at 0, 5, 10, 15, 20, 25,
30, 35, 40, and 45 degrees. The film was then positioned parallel to the implant
and the tube head was angled at 0, 5, 10, 15, 20, 25, 30, 35, 40, and 45 degrees.
An image of each position was shown to 36 dentists and they were asked if the
image was diagnostic for determining the status of the implant/abutment
interface. RESULTS: The data were analyzed with a computer statistics program.
The group with the tube head changed was analyzed with the Cochran's Q test and
revealed a statistically significant (p < 0.0001) change in the diagnostic value
of radiographs beginning at 20 degrees. The group with the film angle changed was
analyzed with a Pearson chi-square and showed no statistical difference (p =
0.394) for the diagnostic value of any of the film angles. CONCLUSION:
Maintaining the tube head to less than 20 degrees from perpendicular to the long
axis of the implant resulted in a diagnostic radiograph, regardless of the angle
of the film.
PMID- 9553884
TI - Osseointegrated implants and orbital defects: U.C.L.A. experience.
AB - PURPOSE: A clinical study of 23 craniofacial implants placed in 8 irradiated and
nonirradiated orbital detects was conducted over a 7-year period. MATERIAL AND
METHODS: Implant-retained orbital prostheses were fabricated, implant success
rate was determined, and the soft tissue responses were recorded at 6-month
intervals. As a result of patient death, no data were gathered on three implants.
A five-point scale was used to record the health of the peri-implant soft tissues
and the patients were followed from 9 to 72 months. The unit of measure was a
visit/site that was assigned for each instance an implant site was evaluated.
Evaluations were conducted at 6-month intervals, and for the study period, there
were 80 visit/sites. RESULTS: The study revealed that 42.5% (34/80) of the
visit/sites demonstrated an absence of inflammation; 23.7% (19/80) of visit/sites
demonstrated slight redness; 13.8% (11/80) demonstrated peri-implant red and
moist tissues; 6.2% (5/80) demonstrated granulation tissue associated with the
implants; and 13.8% (11/80) infection of the peri-implant soft tissues was noted.
Implant success rate was 35% (7/20); implant success rate in the nonradiated
patients was 37.5% (3/8) and the success rate for radiated patients was 33.3%
(4/12). Implants placed in the orbital region demonstrated a high failure rate.
Most implant failures occurred late as opposed to early in the study period.
CONCLUSION: Orbital implants should be placed in patients who understand that
long-term success rates may be low and require meticulous hygiene maintenance.
PMID- 9553887
TI - A comparison of maxillary and mandibular bone mineral densities.
AB - STATEMENT OF PROBLEM: The success rate of implant osseointegration is dependent
on many factors such as bone mineral density, volume and vascularity of bone,
implant design, ridge shape, and patient selection criteria among others.
PURPOSE: This study examined whether a technique to measure differences in bone
mineral density in the maxilla and mandible might be useful to predict the
likelihood of successful osseointegration. MATERIAL AND METHODS: Bone
densitometry of the jaws was performed with a densitometer, and bone mineral
density was calculated at three regions of the maxilla and one site in the
mandibular body in 39 edentulous subjects. RESULTS: Significant differences were
found between the mean bone mineral density of each site when compared with the
three other locations. The mean bone mineral density for the mandible (mean =
1.11 g.cm-2), was twice that of the anterior maxilla (mean = 0.55 g.cm-2). Both
were significantly greater than the bone mineral density of the posterior maxilla
(mean = 0.31 g.cm-2; including the hard palate, mean = 0.45 g.cm-2). The bone
mineral densities at the three maxillary sites were all highly correlated (r > or
= 0.78, p < 0.001). CONCLUSION: The dissimilarity in bone mineral density at
different mandibular and maxillary sites may partly explain some variation in
previously reported osseointegration rates. The posterior maxilla had the lowest
bone mineral density and in certain circumstances before implant insertion, bone
augmentation, or guided tissue regeneration may be advisable to improve the rate
of osseointegration. Because the radiation dose is low, dual energy x-ray
absorptiometry may be a useful noninvasive technique for determining the bone
mineral density before implant insertion.
PMID- 9553886
TI - Dental extractions after radiation therapy in the head and neck area and hard
tissue replacement (HTR) therapy: a preliminary study.
AB - STATEMENT OF PROBLEM: Dental extractions in patients who had radiation therapy
for cancer in the head and neck region carry with them the risks of delayed
healing, prolonged alveolar bone exposure, infection, and osteoradionecrosis.
Among the precautions to minimize these risks are antibiotic coverage, limited
extractions at any one time, soft tissue closure, and hyperbaric oxygen
treatment. Rapid epithelization and minimal bone exposure are essential after
extractions in irradiated patients. PURPOSE: This study examined the effects of
hard tissue replacement on head and neck cancer patients who were treated with
radiation therapy. MATERIAL AND METHODS: In a series of eight patients who had
radiation doses from 4000 cGy to 7440 cGy in the head and neck area and who had
44 teeth extracted, hard tissue replacement material mixed with tetracycline
powder was placed in the extraction sites. RESULTS: Of the 44 teeth extracted, 19
mandibular molars and premolars were in the direct field of radiation in seven
patients. One patient also had 6 mandibular anterior teeth and 12 maxillary teeth
extracted that received minimal radiation exposure. One patient had 6 mandibular
anterior teeth extracted that were not in the area of direct exposure. One
patient had a mandibular first molar extracted in an area that received minimal
radiation exposure. Clinically, complete epithelization occurred in all patients.
No infections developed. Radiographically no bone dissolution could be identified
in the extraction area(s). The follow-up times ranged from 7 months to 18 months
when the patients were seen last. CONCLUSION: The hard tissue replacement
particles appears to provide a matrix for fibrous connective tissue formation.
PMID- 9553885
TI - Obturator prostheses after cancer surgery: an approach to speech outcome
assessment.
AB - PURPOSE: This article describes a speech assessment protocol for patients using
either obturator prostheses or speech aid prostheses for surgically acquired
defects due to cancer of the maxilla and/or soft palate. METHODS: This protocol
is structured according to the executive summary of "Disability in America:
Toward a National Agenda For Prevention" a report formulated by the Institute of
Medicine that describes four levels of disorder: (1) pathology, (2) impairment,
(3) functional limitation, and (4) disability. Assessment instruments included
(1) the Sentence Intelligibility Test to measure the rate and understandability
of speech, (2) a speech physiology system to measure appropriate separation of
the nasal/nasopharyngeal and oral compartments, (3) a 13-point interval scale to
rate speech nasality, and (4) a scale to rate self-perceptions of communication
effectiveness. RESULTS: The results from two patients are reported to illustrate
the outcome assessment protocol.
PMID- 9553888
TI - The influence of abutment angulation on strains and stresses along the
implant/bone interface: comparison between two experimental techniques.
AB - STATEMENT OF PROBLEM: Preangled abutments produce different stress distribution
compared to straight abutments. PURPOSE: The objectives of this study were to (1)
test the hypothesis that preangled abutments produce different stress
distribution than straight abutments by using strain gauges attached to implants
embedded in a medium simulating bone to determine strain distribution along the
implant/bone interface; (2) test this hypothesis by photoelastic method; and (3)
compare the two experimental techniques. MATERIALS AND METHODS: Five Integral
Omniloc cylindrical implants 13 x 4 mm were polished to remove the hydroxyapatite
coating, then six linear miniature strain gauges were attached, three on each
side of the implant's surface. Two similar implants were embedded in a
photoelastic material. Three abutments, straight, 15 degrees, and 25 degrees,
were connected to each implant; strain versus applied compressive forces were
recorded. Strain response to force parameter was defined as the slope of the
strain-force curve. Isochromatic fringe patterns were also recorded. RESULTS: The
strain gauge measurements showed higher, threefold and 4.4-fold, compressive
strain concentration in the coronal zone of the implant when 15-degree and 25
degree angulated abutments were used, respectively, compared with the straight
abutment; whereas the photoelastic method showed an increase of only 11% in
fringe order. Tensile strains were also measured from the coronal contralateral
position on the implant, where photoelastic models did not show a change in
stress type. CONCLUSIONS: Data obtained from strain gauges bonded to implants
embedded in a medium can represent a precise simulation of the clinical condition
when analyzing stress distribution along the implant/ bone interface.
Photoelasticity provides different information and therefore should be regarded
as a complementary method.
PMID- 9553889
TI - Thermal modeling of laser welding for titanium dental restorations.
AB - STATEMENT OF PROBLEM: Concerns of laser welding for titanium dental prostheses
are the limited depth of laser beam penetration and extensive surface damage.
PURPOSE: This study used numerical heat transfer simulation to explain this
behavior and offers an alternate multiple-pulsed method. MATERIAL AND METHODS: A
one-dimensional finite difference analysis was used to simulate heat transfer in
pure titanium and gold during laser welding with a custom-constructed software
program. RESULTS: The thermal gradient profiles revealed the problem to be
inherent in titanium's low thermal conductivity; gold did not have this problem.
Time-elapsed multiple pulses on titanium relieved this problem by giving the
energy time to diffuse into the depth of the material. CONCLUSIONS: With single
pulse laser irradiation on titanium, an increase in power could not greatly
increase melting depth. The excess energy only vaporized the material surface.
PMID- 9553891
TI - An esthetic and hygienic approach to the use of intracoronal attachments as
interlocks in fixed prosthodontics.
AB - This article describes a procedure that uses the Ney MS (Minimal Space)
intracoronal attachment as an interlock in a pontic. This procedure overcomes the
disadvantages associated with the use of the intracoronal attachments, which are
(1) excessive tooth reduction often required to place the attachment within the
contour of the crown; (2) compromised embrasures, which result in oral hygiene
and periodontal problems; and (3) poor esthetics.
PMID- 9553890
TI - A study of the classification and treatment of noncarious cervical lesions by
general practitioners.
AB - PURPOSE: This study presented a survey to determine what general practitioners in
Nova Scotia perceived to be the cause of noncarious cervical lesions, and to
ascertain their most frequent method of treatment. METHODS: The survey was
completed by 63% of the 343 dentists polled. RESULTS: Ninety-four percent
classified the lesion as abrasion, and 66% rated toothbrushing as the most likely
cause. Treatment methods were varied, with no clear preference. CONCLUSION: The
most frequently used restorative materials were GI/composites (29%) and
composites (27%). The results of the survey suggest that treatment provided for
noncarious cervical lesions may not be based on the correct diagnosis.
PMID- 9553893
TI - A device to prevent jaw clenching.
AB - This article describes a device that is intended to prevent the clenching of the
teeth. The principle involved is that to clench the teeth for an extended period,
an intraoral vacuum must be formed and maintained. A tube or drinking straw held
between the lips extending out of the mouth will prevent a vacuum. The article
explains and illustrates how such a device can be made that will exploit this
principle. Disadvantages and advantages are discussed.
PMID- 9553892
TI - Use of aluminum strips to fabricate verification jig for an implant-supported
fixed partial denture.
AB - Verification of the accuracy of the master cast for an implant-supported fixed
partial denture will reduce the chair time and laboratory costs of implant
prosthodontic treatment. A wire is usually luted in the mouth to machined
components that have been secured to the implants, and the luted assembly is then
transferred to the cast to evaluate the positional accuracy of the implant
analogs. Unless this wire is dead soft, inaccuracies as a result of elastic
memory of the wire can occur. Also, if the wire is not completely rigid, it can
be distorted during handling. This article describes a more reliable verification
jig for an implant-supported fixed partial denture that can be fabricated with
1.5 mm thick aluminum strips that are luted to the implant components. The use of
two aluminum strips creates a metal framework that is rigid and not easily
distorted. Also the aluminum pieces do not have elastic memory because they were
cut and not bent to shape.
PMID- 9553894
TI - A simple method for obtaining a uniform thickness for long-term soft denture
linings.
AB - The thickness of long-term soft denture linings influences both their compliance
and durability. Increasing the thickness of the lining material increases its
perceived softness but makes the restoration more likely to fail through
weakening of the acrylic resin denture base. Such effects have led to broad
recommendations as to an appropriate thickness, advice that assumes a constant
thickness of the lining material within the same denture. Several procedures used
to produce such a constant thickness have been described. The necessary spacer is
produced by manually adapting materials in their plastic state to the cast. Such
procedures are liable to distortion and variation in spacer thickness and can be
considered unreliable. This article describes a method for obtaining a uniform
thickness of soft denture lining through the use of a vacuum-formed,
thermoplastic blank as a spacer. The method is simple, applicable to all ridge
forms, and reliably results in a soft lining of a known, uniform thickness. The
method can be applied to long-term soft linings placed in both old and newly
fabricated dentures. The spacer can be modified to allow variations in the
prescribed extension of the soft lining within the denture base.
PMID- 9553895
TI - Provisional retention of a removable partial denture during fabrication of a root
retained overdenture.
PMID- 9553896
TI - Enhanced stability for implant-supported overdenture record bases.
PMID- 9553897
TI - Fabrication of an acrylic resin device used to increase the size of toothbrush
handles.
PMID- 9553898
TI - Computer-printer denture microlabeling system.
AB - This procedure is easy to use and is cost-effective because it uses equipment
that exist in any office or institution. The material used, transparency film for
use with plain paper copier, is less expensive than either photographic slide
film or normal slide films. Moreover, the transparency sheet can be used again
for photocopying until the sheet is fully used up. There is no added cost of
development of film, or is it necessary to wait for the whole roll of film to be
used before the label can be retrieved and used. The background of the label is
clear and only the black images of the characters of the label can be clearly
seen. The effect of the transparency film, photocopy ink, and adhesive glue is
not known. But no adverse effects have been noted. Microlabels have advantages
over conventional labels with characters in font size 8 to 12, because more
information, such as the full name of the patient, sex, country of origin, and
national identification number can be incorporated. With more detailed
information, quick identification of a deceased person can be made. Microlabels
with a clear background will have minimal esthetic impact on the patient. The
disadvantages of the technique is that it may not withstand a fire. In situations
where the deceased body is badly burned, the denture and its identification strip
may be burned, too. However, this risk can be minimized by placing the strip in
the most posterior part of the denture-palatal in the maxillary denture and
distal lingual in the mandibular denture. For testing of durability, dentures
with the labels were placed in water for up to 4 months. The labels showed no
sign of fading or deterioration.
PMID- 9553899
TI - Curriculum integration in nutrition and mathematics.
AB - Today's school-aged children face a multitude of health issues that affect their
well-being and academic performance. Partnerships have developed between health
and education agencies to help American children succeed at math and science and
to prepare them to make healthful, lifelong decisions. Curriculum integration
provides a framework for children to apply knowledge from several disciplines and
to use this knowledge to solve real-life problems at work and at play. Goals for
instruction focus on the needs not only of the individual but also of society.
Nutrition science and mathematics form a natural partnership. Nutrition science
incorporates numerous mathematical concepts and procedures such as sorting,
classifying, statistics, probability, estimation, and rates and proportion. In
preparation for participation in a global and technological society that will
require citizens to be quantitative thinkers, educators must endeavor to assist
all children in becoming adults who are mathematically literate and competent.
PMID- 9553900
TI - Gambling behavior of students in grades seven and eight in Alberta, Canada.
AB - This article reports results from a survey of gambling activities of seventh and
eighth grade students in northeastern Alberta, Canada. Results confirmed that
gambling practices are common among young adolescents. During the 12 months
preceding the survey, virtually all respondents (98%) had gambled. Playing
scratch tickets was the gambling activity most often played by young adolescents,
followed by bingo. Boys were more likely than girls to engage in all forms of
gambling activities. Sports betting and wagering on games of skill dimension were
mostly male domains, whereas games of chance were female pursuits. Survey
implications for public health officials are discussed.
PMID- 9553901
TI - School Health Nursing Services Progress Review: report of 1996 national meeting.
AB - This is a report of the outcomes of an invitational meeting convened in 1996 by
the Division of Adolescent and School Health at the Centers for Disease Control
and Prevention (DASH/CDC) and the National Center for School Health Nursing,
American Nurses Association, Participants reviewed progress made on seven
critical needs identified in 1994 at the School Health Nursing Services:
Exploring National Issues conference. Priority actions were updated, consensus
was reached for specific strategies to move towards achievement of goals and
organizations and agencies were suggested to assume leadership. Participants and
current membership of the National Nursing Coalition for School Health are listed
as well as examples of related activities occurring in the interim. Collaborative
partnerships are encouraged to assist school nurses in meeting the school-related
health needs of all students.
PMID- 9553902
TI - Health practices of educators participating in an Idaho wellness conference: one
year follow-up.
AB - The Great Potato Health Conference (GPHC), which convenes annually in Idaho, is
one of more than 25 statewide wellness conferences for K-12 school personnel.
This follow-up study assessed the health practices of conference participants one
year following the GPHC. A 25-item health behavior instrument was administered to
68 school district personnel prior to attending the GPHC and again three months,
six months, and one year following the conference. Data were analyzed using a
repeated measures one-way factorial analysis of variance to test for differences
in the health practices of participants over time. Results indicated
statistically significant main effects for both previous conference attendance
and time of measurement. No statistically significant interaction effect occurred
between previous conference attendance and time of measurement.
PMID- 9553903
TI - The School Health Innovative Programs: integrating school health and managed care
in San Diego.
AB - Managed care organizations (MCOs) are being recruited to support school health
services delivered in school clinics. Schools without clinics already provide
numerous health services and could provide more if they had support from managed
care organizations. This article describes the first two years of a San Diego
based collaborative consisting of MCOs, school districts, and other health care
agencies. By establishing trust, developing overriding principles, and creating
an interagency communication infrastructure, this collaborative has encouraged
shared management of many student health issues. Because the agreements apply to
all schools, programs can reduce high rates of absenteeism district-wide and
avoid unnecessary doctor appointments for common health problems. These
collaborative agreements are designed to be financially self-sustaining. However,
data collection, the logistics of obtaining parental consent, and getting health
professionals to communicate with each other in new ways remain to be significant
challenges.
PMID- 9553904
TI - Evaluation of a three-year urban elementary school tobacco prevention program.
AB - The longitudinal study compared effects of varying amounts of tobacco instruction
(one, two, and three years) on the knowledge, attitudes, and behavioral
intentions of urban elementary students. A three-year, fourth-through-sixth grade
tobacco prevention curriculum was developed based on the Centers for Disease
Control and Prevention's Guidelines for School Health Programs to Prevent Tobacco
Use and Addiction. The curriculum comprised five, 45-minute lessons per year. The
same trained instructor taught the curriculum all three years. Six intervention
schools were taught the curriculum, and two control schools were not. A 49-item
questionnaire was used to assess tobacco knowledge, attitudes, and behavioral
intentions. The experimental group's posttest knowledge and attitude scores were
significantly higher than the control group's posttest scores. No significant
differences occurred in posttest behavioral intention scores between the control
and intervention groups.
PMID- 9553905
TI - Should school uniforms be mandated in elementary schools?
PMID- 9553906
TI - Vitamin E: the radical protector.
AB - Since its discovery and isolation the importance of vitamin E in maintaining
normal physiologic processes and its value in treating various disease states
have been the subject of much controversy. It was our intention to review and
highlight some of the arguments and problems regarding the usefulness of vitamin
E and to try to put them into proper perspective. The major area of interest
concerning vitamin E lies essentially in its role in preventing damage caused by
free radicals. The latter are now known to play an important role in radiation
induced carcinogenesis, photoaging and photosensitization. The chemistry of
vitamin E, its physiological function as a major antioxidant and its interaction
with other antioxidants are described by the sum of animal studies, in vitro
research and epidemiological investigations. In preparing the current data, it
appeared that despite the controversy and conflicting results the body of
literature as a whole judges vitamin E to be useful as an antioxidant. Although,
in principle, the use of vitamin E can be quite advantageous, the manner of its
administration, especially regarding topical application, remains unclear.
PMID- 9553908
TI - A clinical survey of psoriasis in Italy: 1st AISP report. Interdisciplinary
Association for the Study of Psoriasis.
AB - BACKGROUND: Psoriasis is present all over the world and its prevalence varies in
the different populations and different geographical areas. For example, Northern
European countries seem to have rates of incidence which are greater than those
known for Southern Europe. However, today there is still a lack of adequate data
to allow comparisons at an international level. METHODS: In Italy in 1994 the
AISP (Interdisciplinary Association for the Study of Psoriasis) co-ordinated the
recording of monthly case histories and clinical results relating to psoriasis in
patients observed in dermatology centres homogeneously distributed throughout
Italy. The results were extrapolated from the overall case series. RESULTS: A
sample of nearly 8000 cases was collected, most presenting psoriasis vulgaris.
This pathology, prevalent in males, first appears at an age somewhere between the
teens and twenties. Numerous factors may be involved, and onset is mainly
attributed to stress, viral or bacterial infections and pharmacological therapy.
Over 90% of cases lost between 1 and 7 working days in the course of the year.
Local anti-psoriasis treatment in monotherapy was administered more frequently
than systemic therapy or combined therapy. CONCLUSIONS: The results of this first
Italian epidemiological study confirm that psoriasis is homogeneously distributed
throughout the country. About 50% of patients avail themselves of specialist
cures, even several times in the course of the year, and use a wide range of
therapies which may be more or less demanding. The internal socio-economic cost
of the disease is evident, particularly in terms of working days lost and/or
medical expenses.
PMID- 9553907
TI - Advances in the understanding of malignant transformation of keratinocytes: an
immunohistochemical study.
AB - AIM: We set out to investigate the interactions between malignant transformation
of keratinocytes, presence of oncoproteins and immunosurveillance in squamous
cell carcinoma (SCC) and in a preneoplastic lesion, actinic keratosis (AK).
METHODS: Samples of SCC, AK and normal skin (NS) were subjected to quantitative
analysis using the following antibodies: anti-p53, Ki67, OKT6, OK-DR, B7/BB1,
anti-CD54, anti-CD11, OKT3, OKT4, OKT8; positivity for ras-p21, EGFr and bcl-2
was evaluated by semiquantitative analysis. RESULTS: Oncoprotein alterations and
increased keratinocyte proliferative activity were observed both in AK and SCC.
The number of Langerhans cells (CD1a+ cells) was similar in the two lesions but
lower in SCC compared to AK. The proportion of CD1a(+)-B7/BB1+ cells was slightly
higher in AK and SCC than in NS. The Langerhans cells expressed the HLA-DR
antigen in all groups. Values were highest in AK and NS, and quite low in SCC.
Cytotoxic T lymphocytes were more numerous in SCC than in AK and NS.
Interestingly, the total CD4/CD8 ratio was much lower in SCC than in AK and NS,
which indicates an increase in the CD8+ subpopulation in samples of SCC. In the
epithelia of SCC samples there were a considerable number of B7/BB1+
keratinocytes. CONCLUSIONS: We suggest that alterations in the immunodefence
mechanisms have an important role in the transformation of AK into SCC, and that
these changes affect not only lymphocytes, but also professional (i.e.,
Langerhans cells) and non-professional (i.e., keratinocytes) antigen presenting
cells.
PMID- 9553910
TI - Comparison of skin atrophy and vasoconstriction due to mometasone furoate,
methylprednisolone and hydrocortisone.
AB - BACKGROUND/AIMS: Topical glucocorticoids with improved benefit/risk ratio are of
great interest in dermatology, but there are very few trials directly comparing
the efficacy and side-effects of these new preparations. In our study the
vasoconstrictor effect and side-effects of two of these new glucocorticoids were
evaluated and blanching effect was determined by two-dimensional laser scanning.
METHODS: In a randomised, double blind intra-individual comparative trial, 10
subjects were treated with various glucocorticoids or drug-free vehicle. The test
drugs were mometasone furoate (MF), methylprednisolone aceponate (MP) and
hydrocortisone (OH-C). The preparations were tested for a period of 3 weeks with
occlusion on the flexor side of the forearm. Skin thickness and vasoconstriction
were determined using 20 MHz ultrasound scanning, laser Doppler scanning (LDS)
and chromometry. RESULTS: No adverse effects were observed during the observation
period. Only partial vasoconstriction occurred in most cases during the
observation period. MP and MF produced maximal blanching between days 3 and 5 of
treatment, while with OH-C clinically visible blanching did not occur. Ultrasound
evaluation of skin thickness showed similar behaviour for all three steroids
tested: there were no signs of skin atrophy in any of the cases. LDS evidenced
hypoperfusion of a test area on the perfusion image in only a few patients and
there were no significant differences between the steroids tested. On evaluation
of vasoconstriction caused by the steroids tested using chromometry there was a
significant difference between MF and OH-C on the L*a*b* scale (P < 0.005). Only
at day 3 was a blanching effect caused by MP and MF demonstrable (a-value, P <
0.05). CONCLUSION: In summary, the synthetic steroids MF and MP presented side
effects similar to those of OH-C but much greater vasoconstrictor effect; after
an application period of over 5 days under occlusion a blanching effect in our
model was not demonstrable by means of chromometry. Two-dimensional laser
scanning offers no advantage in the evaluation of the blanching effect in
comparison to one-dimensional laser fluxmetry (LDF).
PMID- 9553909
TI - Langerhans cells in benign, premalignant and malignant skin lesions of renal
transplant recipients and the effect of retinoid therapy.
AB - BACKGROUND AND DESIGN: Langerhans cells (LC) are a unique population of antigen
presenting cells in the epidermis which may play a role in the defense mechanisms
against skin tumors. Renal transplant recipients (RTRs) have a significantly
increased incidence of premalignant and malignant skin lesions. Langerhans cells,
which are important for local immune surveillance, may be depleted or
downregulated in skin neoplasms of RTRs, facilitating their growth. We
investigated the Langerhans cell densities in 29 squamous cell carcinomas (SCCs),
five basal cell carcinomas (BCCs), four Bowen's disease, eight dysplastic lesions
(actinic keratoses), and three viral warts from 15 RTRs and compared these to the
Langerhans cell densities in normal control skin. Eleven RTRs were receiving low
dose etretinate as chemoprophylaxis for recurrent skin cancer and the effect of
low-dose retinoid therapy on Langerhans cell densities in SCCs from these
patients was also assessed. Langerhans cells in frozen tissue sections were
stained with the anti-human Leu-6 monoclonal antibody. RESULTS: There was no
significant difference in LC numbers between normal skin from RTRs and normal
skin from non-immunosuppressed individuals. There was a statistically significant
reduction in LC/mm2 and LC/1000 K (keratinocytes) for SCC, BCC, dysplastic
lesions and viral warts compared with normal skin (P < 0.001, P < 0.01, P <
0.001, P < 0.05, respectively). There was a trend for an increase in Langerhans
cell density in SCCs which developed during etretinate therapy compared with pre
etretinate but the difference was not statistically significant. CONCLUSIONS: In
this study of RTRs, a significant reduction in Langerhans cell densities was
observed in SCCs, BCCs and dysplastic lesions compared with normal skin. A
reduction in Langerhans cell density in viral warts from RTRs was also observed.
A working hypothesis may include a multifactorial etiology for this reduction in
Langerhans cell densities. It is possible that human papilloma virus (HPV)
infection, by reducing intraepidermal Langerhans cell density, may decrease local
immune surveillance and facilitate the development of skin cancers. Ultraviolet
radiation and immune suppression may also play a role. The marked depletion of
Langerhans cells in skin cancers, precursor lesions and viral warts suggests a
central role for Langerhans cells in skin cancer promotion in RTRs.
PMID- 9553911
TI - Calcipotriol improves the efficacy of cyclosporine in the treatment of psoriasis
vulgaris.
AB - OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of
the association of calcipotriol ointment (50 micrograms/g) plus cyclosporine
versus cyclosporine alone in the treatment of moderate psoriasis (mean PASI: 13).
METHODS: Twenty patients were enrolled in this right-left open study. All the
patients admitted were treated with cylosporine at an initial dose of 4.5
mg/kg/day; in case of clinical improvement this dosage was reduced by 0.5
mg/kg/day every 15 days. In each patient we chose two similar, symmetrical
lesions and calcipotriol ointment was applied only on the right lesion, twice a
day, until the healing of the lesion or for 1 month. Patients were checked at
baseline and every 15 days. RESULTS: Eighteen patients completed the study and 17
of the 18 presented more evident improvement on the side treated with combined
therapy, while only one patient showed a better result on the side treated with
cyclosporine alone. A significant difference of the total score was already
present after 15 days of therapy and was confirmed at the following check-ups.
CONCLUSIONS: These results underline the usefulness of the association of
calcipotriol and cyclosporine in order to decrease the total dosage of
cyclosporine.
PMID- 9553913
TI - Lichen striatus-like leukoderma.
AB - A particular pigmentary disorder develops on the skin of Chinese children. The
lesions are composed of whitish macules and patches arranged in linear bands on
the extremities unilaterally. Histologically these lesions are hypopigmented
chronic dermatitis. Although the lesions are arranged in a lichen striatus
pattern, they differ clinically from lichen striatus by the absence of papules
and plaques. These cases may represent a new entity. The differential diagnosis
includes lichen striatus, vitiligo, piebaldism, nevus depigmentosus, and
hypomelanosis of Ito. The differences between the disorder presented here and
those of different diagnosis are discussed.
PMID- 9553912
TI - Plasma concentrations of IFN-gamma and TNF-alpha in psoriatic patients before and
after local treatment with dithranol ointment.
AB - IFN-gamma and TNF-alpha plasma levels were measured before and after local
treatment in 27 patients. Twenty healthy subjects served as controls. Plasma
concentrations of IFN-gamma and TNF-alpha were significantly higher before
treatment (178.7 +/- 11.9 pg/ml and 31.9 +/- 11.6 pg/ml, respectively) compared
to the control group (139.6 +/- 7.86 pg/ml and 17.1 +/- 7.7 pg/ml, respectively).
After treatment IFN-gamma levels were significantly decreased (151.3 +/- 8.3
pg/ml) toward the control group values and TNF-alpha levels were observed even
lower than in the controls (11.48 +/- 6.8 pg/ml). No correlations were found
between age, duration of psoriasis and plasma levels of cytokines. However, IFN
gamma levels were related, although not significantly, to disease severity
(evidenced by the PASI score). The data support the important proinflammatory
role of IFN-gamma and TNF-alpha in the clinical manifestation of psoriasis.
PMID- 9553915
TI - Acquired ichthyosis, alopecia and loss of hair pigment associated with
leiomyosarcoma.
AB - Acquired ichthyosis is an important clinical finding; internal malignancy,
systemic disease and medication are recognised associations. We present a 70-year
old lady with acquired ichthyosis and leiomyosarcoma, one of the less frequently
associated malignancies. An additional unusual finding was generalised thinning
and loss of pigment affecting her hair. Scalp biopsy showed histological evidence
of ichthyosis. Following resection of the tumour the ichthyosis resolved and
there was regrowth of darker hair.
PMID- 9553914
TI - Lipodystrophia centrifugalis abdominalis infantilis.
AB - AIM: To describe the clinical features of lipodystrophia centrifugalis
abdominalis infantilis (LCAI) with special attention to the erythema which is
seen around the depressed lesion. BACKGROUND: LCAI is a rare disorder which
occurs mainly in Asian people, particularly in Japanese; it usually begins as an
erythematous macule which subsequently expands centrifugally and leaves a central
depression. However, the erythema has been seldom documented in detail. We here
report a case of LCAI observed from its early stage and review the literature.
CASE REPORT: A 2-year-old Japanese girl was brought to our out-patient clinic.
Clinical examination revealed a slight depression surrounded by faint erythema
that mimicked morphea on her left inguinum, but there was no hardening of the
skin. The erythema disappeared 5 months after onset. Thereafter, the
lipodystrophy expanded irrespective of the treatment to her right inguinum and
lower abdomen. CONCLUSIONS: The depression continues to grow without the erythema
in most patients. This suggests that the erythema is not necessary for
enlargement of the depression although it precedes the depression in most
patients.
PMID- 9553916
TI - Childhood cutaneous mucinosis.
AB - A case of childhood cutaneous mucinosis is described. This is a clinical
condition that is rarely seen and has only recently been included in the group of
primary mucinosis.
PMID- 9553917
TI - Primary cutaneous cryptococcosis in an immune competent patient.
AB - A 50-year-old female developed a swelling in the epigastrium which later ruptured
to form a sinus. A diagnosis of primary cutaneous cryptococcosis was made with
the help of histopathology and microbiological studies. Treatment with
amphotericin-B and 5-flucytosine gave a good therapeutic response and the sinus
healed within 2 months.
PMID- 9553918
TI - Sclerosing sweat duct carcinoma mimicking dermatofibroma.
AB - Sclerosing sweat duct carcinoma is an infrequent adnexal tumor, locally
aggressive and with a high incidence of local recurrences. Its location is
preferably cephalic and its clinical presentation often unspecific. We present a
new case with an atypical location and the clinical appearance of a benign
cutaneous lesion. Diagnosis was established after a histological and
immunohistochemical study. A terminological review was done.
PMID- 9553919
TI - Familial occurrence of pseudoxanthoma-elasticum-like papillary dermal
elastolysis.
AB - We report the morphological, immunohistochemical and ultrastructural cutaneous
findings of two sisters, aged 72-74, with pseudoxanthoma-elasticum-like papillary
dermal elastolysis (PDE), recently defined as an age-related condition. To our
knowledge, these are the first familial cases of PDE reported in the literature.
The lesions appeared as small, asymptomatic, soft papules around the neck and
axillary regions. The affected skin revealed a marked decrease of normal elastic
network of papillary dermis without alterations in either the relevant collagen
or reticular dermis. Ultrastructural and immunohistochemical examinations showed
activated dermal fibroblasts with abundant elongated dendritic cytoplasmic
processes and the absence of myofibroblasts. The well documented avoidance of sun
exposure (the patients are both nuns), the rare incidence of the disorder (only
six cases reported), and the familial occurrence suggest that genetic or
inherited predisposition should also be considered in the pathogenesis of PDE.
PMID- 9553920
TI - Balneophototherapy in small plaque parapsoriasis--four case reports.
AB - Four patients suffering from small plaque parapsoriasis were treated successfully
with balneophototherapy. Within 4 weeks salt-water baths and UV irradiation
resulted in clinical clearing of more than 90% of lesions with a duration of
total clinical response between 8 and 12 weeks without further maintenance
treatment.
PMID- 9553921
TI - Disseminated histoplasmosis presenting with cutaneous lesions in a patient with
acquired immunodeficiency syndrome.
AB - OBJECTIVE: Presentation of a case of disseminated histoplasmosis, observed in a
non-endemic area, in which cutaneous lesions and fever were the dominant clinical
signs of the infection. CASE: A 54-year-old homosexual man with acquired
immunodeficiency syndrome (AIDS) related Kaposi's sarcoma presented with
cutaneous lesions and fever due to disseminated histoplasmosis. The patient was
successfully treated with itraconazole 200 mg/day. He died after 8 months from
AIDS dementia complex: disseminated histoplasmosis relapse was not observed.
CONCLUSION: The case shows that infection with Histoplasma capsulatum must be
considered by dermatologists in HIV/AIDS patients, even in non-endemic areas.
PMID- 9553923
TI - Ulcerative lichen planus-like dermatitis due to long-term hydroxyurea therapy.
PMID- 9553924
TI - Nail changes in 1000 Indian patients with alopecia areata.
PMID- 9553925
TI - Effects of cyclosporin A on mycelial transformation of Candida albicans cells in
human serum.
PMID- 9553922
TI - An elderly man with vasculitis and IgA myeloma.
PMID- 9553926
TI - Lichen planus and hepatitis C-virus infection in Turkish patients.
PMID- 9553927
TI - The effects of various diets on glycogen, protein and lipid levels in the skin of
albino rats.
PMID- 9553929
TI - [Diagnosing and treating sinusitis. 8th Congress of the Association for
Phytotherapy. Symposium: "Phytotherapy in Sinusitis". Wurzburg, 27 November
1997].
PMID- 9553928
TI - Congenital angiokeratoma of Fordyce.
PMID- 9553930
TI - Mechanisms of secretion of toxic organic anions in mammalian kidneys.
AB - This short review considers the mechanisms of organic anion secretion in renal
proximal tubules. Particular attention is given to the energy coupling of p
aminohippurate transport to inorganic anion gradients generated across both
basolateral and brush-border membranes. The coupling is considered to be a
consequence of the combined operation of the co-transport and anion-exchange
mechanisms. A possible coexistence of several organic anion pathways with
overlapping substrate specificity and/or energetic dependence of the total ion
gradient are suggested. The problem of identification of transporters involved in
organic anion secretion is discussed.
PMID- 9553931
TI - Thermoluminescence in photosynthesis. 4. Influence of energy transfer processes.
AB - Thermoluminescence (TL) emission arising from charge recombination in
photosynthetic reaction centres was examined considering the energy transfer
between antenna chlorophylls and the reaction centre. The energy transfer
processes were shown to decrease the width and change the temperature of the
maximum glow of the TL band profiles when the rate constant of direct
recombination between the oxidized primary electron donor and reduced primary
acceptor (pheophytin or bacteriopheophytin) did not exceed 10(6) s-1. The primary
radical pair lifetime of 3.10(-9)-10(-8) s was shown to minimize the influence of
energy transfer on the TL band profiles and, therefore, the energy transfer can
be neglected when the TL band profiles are calculated. The profile of the TL band
arising from charge recombination in the photosystem 2 state S2QB.- was shown to
depend considerably on the temperature-dependent rate constant of direct
recombination between QB.- and S2 state of the photosystem 2 donor site.
PMID- 9553932
TI - Characterization of [3H]AMP binding to rat adipose plasma membranes and its
substrate specificity.
AB - We evaluated the binding of [3H]AMP to rat adipose plasma membranes and studied
the substrate specificity of the process. The [3H]AMP binding was investigated by
high-speed filtration under conditions of virtually complete inhibition of the 5'
nucleotidase activity by EDTA/Na. The Scatchard plot revealed the existence of a
single class of AMP-binding sites on the membrane surface with Kd of 2.14 +/-
0.210 microM and the binding capacity (Bmax) of 26.0 +/- 0.68 pmol per mg
protein. Addition of ATP (12.5 microM) or ADP (3.5 microM) to the incubation
medium resulted in a two-fold increase of Kd, whereas in the presence of
adenosine (400 microM) or its pharmacological antagonist theophylline (200
microM), the number of AMP-binding sites decreased. Therefore, ATP and ADP but
not adenosine compete with AMP for the same nucleotide-binding site. It is
suggested that the observed [3H]AMP binding may be primarily caused by the
interaction of AMP with a specific substrate-binding active centre of the
membrane ectoenzyme 5'-nucleotidase.
PMID- 9553933
TI - Spatial association of prekinetochores and chromocentres in the interphase nuclei
of mouse cultured fibroblasts.
AB - The structure and spatial distribution of prekinetochores and chromocentres
(centromeric heterochromatin) in the interphase nuclei of mouse fibroblasts were
studied by light and electron microscopy. Using the autoimmune serum GS reacting
with centromeric proteins CENP-A, B, C in mammalian cells, we showed that most
interphase prekinetochores were associated with chromocentres. During the
interphase S period, including DNA replication in chromocentres, the
macroorganization of chromocentres and their association with prekinetochores
were maintained. Using cryosections and the electron microscopy immunogold
technique, we found that centromeric proteins were mainly located at the
chromocentre periphery. Nevertheless, we failed to find any definite kinetochore
structures including those usually observed during mitosis at the sites of
protein binding. Only small associates of fibrous material, presumably,
corresponding to centromeric proteins, could be observed in association with the
interphase mouse chromocentres in both cryosections and conventionally fixed
sections.
PMID- 9553934
TI - Phorbol ester at concentrations 10(-18)-10(-7) M inhibits lipid peroxidation in
rat brain plasma membranes via activation of protein kinase C.
AB - We studied the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) and protein
kinase C (PKC) in a broad range of concentrations (10(-18)-10(-7) M) on lipid
peroxidation (LP) in rat brain plasma membranes. TPA and PKC were shown to
inhibit LP, the concentration curves had two maxima at 10(-15) M and 10(-12) M
for TPA and at 10(-16) M and 10(-13) M for PKC. The combined action of TPA (10(
12) M) and PKC (10(-16) M) resulted in a synergic inhibition of LP. These data
suggest PKC to have two (kinase and antioxidative) enzymatic activities. The
properties of TPA as an LP inhibitor (via activation of PKC) and tumour promoter
(inhibition of LP is a necessary step of tumour promotion) can be explained based
on this suggestion.
PMID- 9553935
TI - Erythrocyte hemolysis by detergents.
AB - The numbers of Triton X-100 and sodium dodecyl sulfate molecules required to form
respective pores were estimated from the relationship between the detergent
concentrations and the rates of fast and slow hemolysis components. It has been
found that the slow hemolysis component evoked by Triton X-100 is related to the
existence of two different pores. It is shown that the fast hemolysis component
induced by sodium dodecyl sulfate is associated with the modification of
phosphatidylcholine which determines the break in the Arrhenius plots of the
hemolysis rate within the range of 20 degrees C. The shape of hemolysis kinetic
curves and the dependence of hemolytic parameters on the detergent concentration
and temperature are discussed based on the concept of hemolysis caused by the
formation of pores in various membrane lipid regions and by releasing vesicles
from erythrocytes.
PMID- 9553937
TI - Effective diameters of ion channels formed by homologs of the antibiotic
chrysospermin.
AB - Radii of ion channels formed in the lipid bilayer by 4 homologs of the
alamethicin-like antibiotic, chrysospermin, were determined using hydrophilic
nonelectrolytes. It is shown that the replacement of isovaline amino acid at
position 15 of the polypeptide chain by alpha-aminoisobutyric acid results in the
decrease in the channel effective radius from 1.2 +/- 0.15 to 0.94 +/- 0.1 nm and
a respective 2.5-fold decrease in channel conductance.
PMID- 9553938
TI - Redox properties of benzocaine and its homologs.
AB - Redox properties of the local anesthetic benzocaine and its homologs were studied
by their reactions with free radical intermediates of dyes excited by the visible
light. Homologs with more hydrophobic substituents at the benzene ring appeared
to be better electron donors and facilitated photobleaching of the dye Methylene
Blue or photoreduction of hemin. The electron-donor properties decreased in the
same order as their blocking activities (C. Quan, W. M. Mok, and G. K. Wang,
Biophys. J. 70:194-201 (1996)). This correlation is considered as additional
evidence in favour of the ion channel redox model.
PMID- 9553936
TI - Kinetics of tert-butyl hydroperoxide decomposition in erythrocyte suspension.
AB - The kinetics of tert-butyl hydroperoxide (t-BHP) decomposition was examined in
erythrocyte suspension from C57B1/6 mice by the chemiluminescence method. The
reaction with horseradish peroxidase, t-BHP (20 nmol/ml), and luminol was
accompanied by a rapid chemiluminescence increase. The integral value of the
chemiluminescence signal correlated with the t-BHP concentration at every moment
of time. In the erythrocyte suspension, the half-life of t-BHP decomposition was
23.8 s. The decomposition rate significantly decreased after pretreatment of the
erythrocytes with o-phenanthroline (0.1 mM), EDTA (1 mM), benzohydroxamic acid
(0.1 mM) or adriamycin (30 microM). These effects were not associated with the
changes in the glutathione peroxidase activity and, more likely, could be related
to the modification of the membrane iron-binding sites. The influence of iron
chelators on the kinetics of t-BHP decomposition suggests the existence of
various Fe-binding sites, that can decompose organic hydroperoxides upon their
interaction with cell plasma membranes.
PMID- 9553940
TI - The effect of AC voltage on the ionophore-induced steady-state flux across the
bilayer lipid membrane.
AB - Application of an AC voltage to a model bilayer lipid membrane in the presence of
electrogenic ionophores (valinomycin, protonophores CCCP and TTFB) was shown to
change the steady-state current across the membrane induced by a DC voltage. The
change in the DC current was proportional to the magnitude of the DC voltage and
to the amplitude of the AC voltage and depended on both the AC frequency and the
ionophore used. Application of this new experimental approach to the estimation
of kinetic constants at individual stages of ionophore functioning is discussed.
PMID- 9553939
TI - Selective labeling of the inner liposome leaflet by fluorescent lipid probes, and
studies of liposome fusion with influenza virus.
AB - The inner leaflet of unilamellar lipid vesicles was labeled with fluorescent
lysophosphatidylcholines. The probes make a donor-acceptor pair in resonance
energy transfer (RET), being labeled with 9-anthrylvinyl (L-APC, donor) and 3
perylenoyl (L-PPC, acceptor) fluorophores. They migrate rapidly between bilayers
through the water phase: tau 1/2 of equilibration is approximately 5 min at 37
degrees C. The probe(s) can be removed from the outer leaflet of uniformly
labeled medium-size unilamellar vesicles (MUV) by repeated washings with excess
unlabeled large unilamellar vesicles (LUV) (separation by centrifugation). The
probes flip-flop across bilayers rather slowly. MUV containing the ganglioside
GT1b and labeled with the L-APC/L-PPC pair in the inner leaflet were fused with
an equal amount of influenza virus; the process was monitored by an increase of
the donor fluorescence in RET assay. If inner MUV leaflet was labeled with the
anthrylvinyl probe only, the probe fluorescence decreased by half when the probe
was removed from the outer leaflets of the fused membranes. This shows that the
lipids of the inner and outer leaflets of the MUV randomize in the process of
fusion.
PMID- 9553941
TI - Lipid and cell membranes in the presence of gadolinium and other ions with high
affinity to lipids. 1. Dipole and diffuse components of the boundary potential.
AB - Two methods were used for monitoring the changes in the boundary and surface
potentials induced by Gd3+ adsorption--the method of intramembranous field
compensation applied to planar BLM and electrophoresis of liposomes,
respectively. The data of both methods agree well in the case of membranes made
from phosphatidylcholine (PC), in contrast to those made from phosphatidylserine
(PS). In the latter case, they show a significant discrepancy between potential
amplitudes even within the micromolar range of Gd3+ concentrations because of
cation-induced changes in the dipole component of the boundary potential. The
adsorption of these cations with extremely high affinities to lipids was
described by the theory of diffuse double layer (Gouy-Chapman-Stern) combined
with the condition of mass balance, which is essential in the case of limited
volumes of real systems. The electrokinetic data for PS and PC liposomes are in
good agreement with the modified theory and correlate well with the Gd3+
association constants of 5.10(4) and 10(3) M-1, respectively. The same theory was
used to extract the changes in the dipole component from the measured changes in
the PS membrane boundary potential. The dependence of this component on the
number of binding sites occupied by cation was shown to be nonlinear but
cooperative with the step-like increase of dipole potential up to about 140 mV
(positive inside the membrane) at the Gd3+ concentration around the zero charge
point of the PS membranes. This potential corresponds to the structural changes
in the lipid bilayers which are discussed with respect to the Gd3+ blocking
effects on the mechanosensitive channels.
PMID- 9553942
TI - Clinical and genetic aspects of X-linked adrenoleukodystrophy.
AB - X-linked adrenoleukodystrophy (ALD), a leukodystrophy characterized by abnormal
accumulation of saturated very long chain fatty acids in brain white matter and
adrenal cortex, is the most common inherited peroxisomal disorder. The
biochemical defect is localized to the level of lignoceroyl-CoA synthesis, a step
in the peroxisomal beta-oxidation of very long chain fatty acids. The responsible
gene encodes a peroxisomal integral membrane protein of as yet unknown function
which is a member of the ATP-binding cassette transporter protein superfamily.
The patient gene mutations are heterogeneously distributed over the functional
protein domains with a tendency to clustering in the nucleotide-binding fold. The
mechanisms by which these mutations cause a loss of protein function is unknown.
Diagnosis of patients and carriers, including prenatal testing, is mainly based
on the clinical picture, the demonstration of increased levels of saturated very
long chain fatty acids in tissues and body fluids as well as on DNA mutation
analyses. There are at least six distinct clinical phenotypes ranging from the
severe childhood cerebral form to asymptomatic persons. The various phenotypes
commonly occur within the same kindred. Modifying genes and/or environmental
factors may contribute to this phenomenon. At present, there is no proven therapy
for the prevention or cure of the neurological disabilities. Several approaches
are under investigation including diets, immunosuppression, bone marrow
transplantation and gene therapy.
PMID- 9553943
TI - 4-Hydroxybutyric acid and the clinical phenotype of succinic semialdehyde
dehydrogenase deficiency, an inborn error of GABA metabolism.
AB - SSADH deficiency, a rare inborn error of human metabolism, disrupts the normal
metabolism of the inhibitory neurotransmitter GABA. In response to the defect,
physiologic fluids from patients accumulate GHB, a compound with numerous
neuromodulatory properties. Clinical and bio-chemical findings in patients are
contrasted with existing neuropharmacologic data on GHB in animals and men. We
conclude that GHB contributes to the pathogenesis of SSADH deficiency; whether
this effect is mediated by GHB, by GABA following metabolic interconversion, or
via synergistic mechanisms by both compounds, remains to be determined. An animal
model of SSADH deficiency should further define the role of GHB in the
pathogenesis of SSADH deficiency, and provide a useful vehicle for the evaluation
of new therapeutic intervention.
PMID- 9553944
TI - Guillain-Barre syndrome, case studies and questionnaire to illustrate junior
doctors' awareness of muscle strength testing.
AB - Three patients, aged 7-15 years, with Guillain-Barre syndrome presented with pain
as the primary complaint. Two did not complain of weakness and their progressive
loss of function was incorrectly ascribed to the pain. One did complain of
weakness, in association with flu-like symptoms, but the significance of the
complaint was not appreciated. At diagnosis all three had profound, predominantly
proximal weakness. We believe the delayed diagnosis relates to doctors' lack of
opportunity to examine patients with muscle weakness. We conducted a
questionnaire survey of junior hospital doctors asking them about their hands-on
experience of testing muscle strength and about their knowledge of the Medical
Research Council (MRC) Scale of muscle strength. Doctors who claimed most
experience did not have a better knowledge of the MRC scale. We recommend doctors
in-training should be given more opportunity to examine patients with muscle
weakness and should be made familiar with a clinical scale of muscle strength.
PMID- 9553946
TI - Dramatic effect of ethosuximide on epileptic negative myoclonus: implications for
the neurophysiological mechanism.
AB - Epileptic negative myoclonus (ENM) is a recently defined epileptic seizure type
seen in various epileptic syndromes. Although the long-term prognosis appears to
be favorable, the treatment of localization-related epilepsy (LRE) with ENM in
childhood is sometimes difficult due to the apparently pharmaco-resistant nature
of ENM. We evaluated the effects of antiepileptic drugs (AEDs) in 10 patients
with ENM. Carbamazepine was administered to eight patients, none of whom
improved. Responses to clonazepam and valproic acid were unpredictable, whereas
ethosuximide (ESM) achieved complete control of ENM in all six cases treated with
this drug as adjunctive therapy. The pharmacological responses of ENM to CBZ and
ESM were quite similar to those of absence seizures. According to the SPECT and
ictal EEG findings in addition to the pharmacological responses from this study,
we favor to postulate that ENM is produced by a direct inhibitory action on the
motor cortex resulting in the interruption of voluntary muscle contraction as
generated by sharp-slow wave complexes, compatible with the mechanism considered
to underlie absence seizures. ENM are refractory to treatment and persisting if
the wrong AEDs, such as PHT or CBZ, are selected at the diagnosis of LRE. We
recommended a trial of ESM when ENM develops during the clinical course of LRE
regardless of etiology.
PMID- 9553947
TI - Cerebrospinal fluid levels of amino acids in infants and young children with
chronic renal failure.
AB - Chronic renal failure (CRF) is associated, especially in young children, with
delayed cognitive development of unknown origin. As cerebrospinal fluid (CSF)
reflects the composition of the extracellular fluid of the brain, not only plasma
but also CSF amino acids concentrations were determined in 8 infants (age 2-8
months) and 3 children (age 26, 32 and 56 months) with CRF (creatinine clearance
13 +/- 9 ml/min/ 1.73 m2). In three of these children investigations were
repeated after six weeks of CAPD treatment. In the infants, a significant
decrease was found in CSF of alpha-aminobutyric acid, valine, isoleucine,
leucine, tyrosine, tryptophane, histidine and n-zeta-methyl-1-lysine, whereas
there was a significant increase of 3-methylhistidine. In plasma serine, valine,
leucine, tyrosine and histidine were significantly decreased, whereas there was a
significant increase of aspartic acid, citrulline, and 3-methylhistidine. These
abnormalities remained constant after the start of CAPD except for the
normalization in CSF and plasma of 3-methylhistidine. These data indicate a
generalized disturbance of amino acids in young children with CRF. An abnormal
substrate is offered to the neurons and astroglia in children with CRF.
PMID- 9553945
TI - Stopping antiepileptic therapy in mentally-retarded, epileptic children.
AB - It has, increasingly, become the practice to withdraw antiepileptic drugs (AEDs)
in epileptic patients, who have been seizure-free for two years. However, the
presence of mental retardation is frequently considered to be a markedly adverse
factor for stopping treatment. Many physicians are loth to phase out AEDs in
mentally retarded patients. In this study, 29 well-controlled epileptic, mentally
retarded children had their AEDs withdrawn. Seventeen have remained well and 12
have relapsed. IQ, neurological findings, EEGs, types of epilepsy, frequency of
attacks, age of onset, duration of the active disease and the fit-free period,
and antiepileptic drug (AED) levels did not predict the outcome. It is suggested
that consideration be given to withdrawing AEDs from well-controlled, mentally
retarded, epileptic children.
PMID- 9553948
TI - Detection of subclinical central nervous system abnormalities in two patients
with mucolipidosis III by the use of motor and somatosensory evoked potentials.
AB - We have studied motor, somatosensory, brainstem auditory and visual evoked
potentials in two patients with ML III without overt neurologic symptoms. Both
our patients showed abnormal central motor functions upon magnetic cortical
stimulation; in addition, in one of them, we observed a decreased conduction
velocity of the nervous impulse in the central tract of the upper limb
somatosensory pathway, from the cervical spinal cord to sensory cortex. Our
results suggest that central motor pathways are affected in both children and
also that the central somatosensory system is involved in one of them. We propose
that the electrophysiological techniques might be of help to detect, locate and
monitor minimal neurological lesions of mild lysosomal disorders like ML III.
PMID- 9553949
TI - Systemic infantile complex I deficiency with fatal outcome in two brothers.
AB - A male infant presented at 5 months of age with vomiting, developmental
stagnation and convulsions. Complex I activity was in skeletal muscle 0.025 mU/mU
CS (N 0.044-0.265) and in fibroblasts 0.046 mU/mU CS (N 0.100-0.307). Despite
riboflavine supplementation progressive neurological deterioration occurred and
he died at 14 months of age. During the mother's following pregnancy complex I
activity was measured in chorionic villi and found mildly reduced, pregnancy was
continued. A male infant was born who presented at 7 months of age with vomiting,
developmental stagnation and hypotonia. Complex I activity was in skeletal muscle
0.031 mU/mU CS and in fibroblasts 0.100 mU/mU CS. There was progressive
neurological deterioration and he died at 17 months of age. Complex I activity in
autopsy liver of both patients was normal. Apparently, complex I deficiency
presenting in infancy can have a fatal outcome despite only mild reduction of
enzyme activity in skeletal muscle and/or fibroblasts, and chorionic villi and
normal activity in liver.
PMID- 9553950
TI - Reversible palsy of the hypoglossal nerve complicating infectious mononucleosis
in a young child.
AB - We report a 7-year-old boy with serologic evidence of active Epstein-Barr virus
(EBV) infection who developed transient unilateral hypoglossal nerve palsy, with
complete recovery within 21 days. This is, to our knowledge, the youngest
reported patient with isolated hypoglossal nerve palsy in the context of EBV
infection. Acute EBV infection should be considered early in the evaluation of
children with twelfth nerve palsy in order to avoid extensive ancillary testing.
PMID- 9553951
TI - Infantile muscle phosphorylase-b-kinase deficiency. A case report.
AB - A Turkish girl is described who showed a severe floppy infant syndrome and
respiratory failure at birth. She suffered upper respiratory tract infections and
pneumonia. She was ventilated and had hypercapnoea secondary to bradypnoea.
Biochemical analysis of skeletal muscle revealed a slightly increased glycogen
content, and enzymatic analysis revealed a muscle phosphorylase-b-kinase
deficiency. The infant succumbed after 140 days due to persistent apnoea and
asystole. Isolated muscle phosphorylase-b-kinase deficiency should be considered
as a possible diagnosis in floppy infants.
PMID- 9553953
TI - 3-Methyl glutaconic aciduria in Iraqi Jewish children may be misdiagnosed as
cerebral palsy.
AB - It is generally accepted that patients with cerebral palsy suffer from a static
encephalopathy causing a non-progressive disorder of posture and/or movement. We
describe 7 patients from 5 families who were initially diagnosed with cerebral
palsy. Eventually, excessive excretion of urinary 3-methyl glutaconic acid (3
MGA) was found. The data of our 7 patients are quite similar to the clinical
description of Costeff et al (1989): Jewish-Iraqi origin (7/7), consanguinity
(2/7), involuntary movements (5/7), ataxia (6/7), pyramidal involvement (6/7) and
optic atrophy (6/7). The cognitive functions were intact in 5/7 and 2/7 showed
mild to moderate mental retardation. The mean delay in the definitive diagnosis
was 9 years. Cerebral palsy-like symptoms accompanied by optic atrophy and
extrapyramidal signs should call for extensive metabolic evaluation including the
determination of urinary 3-MGA.
PMID- 9553952
TI - Adenylosuccinase deficiency with neonatal onset severe epileptic seizures and
sudden death.
AB - We report a male infant with adenylosuccinase deficiency who developed epileptic
seizures on the second day of life. Growth was normal and seizures were well
controlled with anti-epileptic drugs. Despite axial hypotonia associated with
peripheral hypertonicity he presented some development until seven months of age,
when he developed high fever and died within a few hours. Although clinical
heterogeneity in this disorder of purine synthesis and interconversion is well
known, in 14 out of 17 cases who experienced epilepsy seizures started after the
first year of life. The early presentation in our index patient followed by his
sudden death at the age of 7 months has not been described before. A search for
disorders of purine metabolism should be included in the screening programme for
every child with severe neonatal convulsions.
PMID- 9553955
TI - Blood mercury and auditory neuro-sensory responses in children and adults in the
Nambija gold mining area of Ecuador.
AB - This study investigated blood mercury (B-Hg) levels and the auditory neuro
sensory status of children and adults in the remote Andean settlement of Nambija,
Ecuador where Hg is used in the extensive gold mining operations. The mean B-Hg
level in 75 Nambija (Study Area) inhabitants (36 children and 39 adults) was 17.5
micrograms/L (SD = 11.0) vs 3.0 micrograms/L (SD = 1.6) in a second group of 34
subjects (15 children and 19 adults) in a non-gold mining area (Reference Area),
the difference being statistically significant (p < 0.0001). Neuro-otological
examinations revealed 34 subjects (45%) with complaints of headaches and/or
memory loss, 3 cases of severe neurological impairment and 4 cases of middle ear
pathology. Audiological tests on 40 persons in the Study Area (21 children and 19
adults) showed hearing thresholds ranging from normal to mildly abnormal at 2, 3,
4, 6 and 8 kHz for children, and normal to severely abnormal for adults.
Correlation coefficients showed a significant relationship between B-Hg level and
hearing level in children at 3 kHz in the right ear, and at no frequency for
adults. Auditory brainstem evoked responses (ABR) on subjects in the Study Area
showed a significant correlation between B-Hg and the I-III interpeak latency on
the right side. The results indicated that the study population of the Nambija
gold mining area had abnormally elevated B-Hg levels, and may be at neurological
risk from exposure to methylmercury (MeHg) from the consumption of contaminated
food and possibly from elemental Hg vapors inhaled during amalgam burning in the
gold extraction process.
PMID- 9553954
TI - Interaction of phentermine plus fenfluramine: neurochemical and neurotoxic
effects.
AB - Previous studies have reported the use of combined serotonergic and dopaminergic
agonists in the treatment of obesity and alcoholism. Along these lines,
phentermine plus fenfluramine has been suggested as a possible clinical treatment
for alcohol craving. To determine the neurochemical effects of a combined
treatment of phentermine plus fenfluramine, animals were injected subcutaneously
with saline, phentermine 12 mg/kg, fenfluramine 16 mg/kg, or a combination of
phentermine plus fenfluramine. One hour after injection, animals were sacrificed
and neurochemical analysis performed. Furthermore, separate groups of animals
were given the same injections 8 times, 12 hours apart, to determine the effects
on body weight and to detect a possible exacerbation of fenfluramine induced
toxicity. The drug combination produced a significant rise in dopamine in the
striatum, greater than that seen with either drug alone. Furthermore, the
addition of phentermine reduced the fenfluramine induced rise in striatal 3,4
dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindolacetic acid (5
HIAA). Phentermine plus fenfluramine combination produced a greater weight loss
than either drug alone, however, it did not produce a significantly greater drop
in striatal serotonin or 5-HIAA levels above that induced by fenfluramine alone.
Thus, while previous studies report the potentiated neurotoxicity of phentermine
plus fenfluramine over fenfluramine alone, the present study does not indicate
that such an effect occurs following an administration regimen analogous to that
of patients treated with the drug combination.
PMID- 9553956
TI - Regional distribution of 203PbCl2 in the mouse after intravenous injection.
AB - Lead is a known neurotoxicant, and concentrations of lead in the CNS after acute
exposure to low doses have not been studied in detail. In this investigation, the
temporal distribution of lead ([203Pb]), injected intravenously at no-carrier
added (NCA) (0.6-0.7 mumol/kg) and at carrier-added (7.0-62.3 mumol/kg) levels
was determined in mice. Concentrations of [203Pb] were measured in major organs
and in different regions of the brain. Ex-vivo autoradiographic visualization was
used to confirm and extend the brain distribution findings. RESULTS: The highest
concentrations of NCA [203Pb] were observed initially in the kidneys (52% of the
injected dose (ID)/g at 1 hr) and liver (10.5% ID/g at 30 min). Uptake into bone
occurred gradually, reaching 25% ID/g at 24 hr. In accord with previous reports,
excretion of the tracer was very slow. Approximately 80% of total ID remained in
the body after 24 hr and 68% at 48 hr. Interestingly, in the mouse brain, the
highest levels of [203Pb] were noted in the area of the hypothalamus. At all
times between 30 min and 16 hr postinjection, and at all Pb dose levels injected,
the accumulation of [203Pb] in the hypothalamic region exceeded that in all other
brain regions examined. Autoradiography performed at the 16 hr time point
confirmed the high uptake and strong retention of [203Pb] by the hypothalamus.
These studies afford new insight into the distribution of acutely administered
lead in the brain, and may have implications for the understanding of some of the
neurotoxic effects of lead.
PMID- 9553957
TI - Reversal by desferrioxamine of tau protein aggregates following two days of
treatment in aluminum-induced neurofibrillary degeneration in rabbit:
implications for clinical trials in Alzheimer's disease.
AB - A clinical trial in patients with Alzheimer's disease has indicated that frequent
intramuscular (i.m.) treatment with desferrioxamine (DFO) slows progression of
the disease. Confirmatory trials have not been carried out, partly because of the
rigors of twice daily intramuscular injections over a period of 2 years, even
though the initial report gave promising results. The aim of the present study
was to determine an optimal DFO treatment protocol in an animal model exhibiting
Alzheimer's-like intraneuronal protein aggregates, previously shown to be
partially reversed by such treatment. New Zealand white rabbits were injected
intracisternally with either aluminum (Al) maltolate or with saline on day 0.
Intramuscular injections of DFO were given to selected rabbits for 2 days prior
to sacrifice on days 4, 6 or 8. Bielschowsky's silver impregnation demonstrated
widespread neurofibrillary degeneration (NFD) in neuronal cell bodies and
neurites of brain and spinal cord from Al-treated rabbits. Monoclonal antibodies
Tau-2, AT8, PHF-1 and Alz-50, all of which characteristically stain
neurofibrillary tangles associated with Alzheimer's disease, strongly labeled the
Al-induced NFD. The number of positive neurons and staining intensities were much
less in rabbits treated with Al and subsequently with DFO, than in animals only
given Al. Control rabbit receiving intracisternal saline were negative for NFD.
The results of quantitative immunohistochemistry using image analysis confirmed
that immunostaining densities with all tau mAbs were higher in Al-treated than in
Al-DFO-treated or in saline-treated controls. Furthermore, it appears that
hyperphosphorylation of tau does not make this protein resistant to degradation
once Al has been removed by DFO treatment. The effectiveness of only two days of
DFO treatment in reversing Al-induced neurofibrillary degeneration suggests that
further clinical trials of DFO for treatment of Alzheimer's disease should be
attempted using much less frequent administration of DFO than in the initial
study (Crapper McLachlan et al., 1991).
PMID- 9553958
TI - Trimethylolpropane phosphate (TMPP) perfusion into the nucleus accumbens of the
rat: electroencephalographic, behavioral and neurochemical correlates.
AB - The infusion (0.13 mumol/infusion) of the convulsant trimethylolpropane phosphate
(TMPP) into the nucleus accumbens (NA) of adults Sprague-Dawley rats reliably
induced subclinical seizures, hyperlocomotor activity, and integrated
stereotypies. Observation of these behaviors was temporally correlated with the
appearance of EEG paroxysms, as well as with significant decreases in
extracellular concentrations of both dopamine (DA) and norepinephrine (NE) in the
NA. Repeated perfusion of TMPP revealed significant increases in stereotypic
behavior during subsequent pre-drug baseline testing.
PMID- 9553959
TI - Acidosis-induced metallothionein (MT) mRNA expression in neonatal rat primary
astrocyte cultures.
AB - Metallothionein (MT) mRNA levels were determined following exposure of neonatal
rat primary astrocyte cultures to acidosis. Astrocyte total RNA was probed on
northern blots with [alpha 32 P]dCTP-labeled synthetic cDNA probes specific for
rat MT isoform mRNAs. The probe for MT-I mRNA hybridized to a single mRNA with a
size appropriate for MT, approximately 550 nucleotides. MT-I mRNA levels in
astrocyte monolayers exposed to pH 6.5 and 6.0 for 3 or 6 hours were unchanged
compared with MT-I mRNA levels in control cultures exposed to pH 7.4. In
contrast, 9 hour exposure of astrocytes to pH 6.5 and 6.0 led to a significant
increase in MT-I mRNA transcripts compared with controls maintained at pH 7.4 (p
< 0.001 and p < 0.02, respectively). A probe for MT-II mRNA that hybridizes to a
single mRNA (450 nucleotides) was also used to determine the effect of acidosis
on astrocyte MT-II mRNA transcripts. Although statistical significance was not
attained, a similar trend was noted, with a 9 hour exposure to pH of 6.5 and 6.0
resulting in increased astrocytic expression MT-II mRNA compared with control
cells maintained at pH 7.4. Acidosis was also associated with a pH-dependent
increase in astrocytic volume. Accordingly, acidosis is invoked as an added
stimulus to stress factors associated with the induction of astrocytic MT mRNA
transcripts.
PMID- 9553960
TI - Prosaptide prevents paclitaxel neurotoxicity.
AB - Paclitaxel (Taxol), a chemotherapeutic agent used to treat breast and ovarian
tumors, has been reported to induce a predominantly sensory neuropathy. Co
treatment with neurotrophic factors and paclitaxel has been proposed for
preventing or reversing paclitaxel-induced peripheral neuropathy. Prosaposin, the
precursor of saposins A, B, C and D was recently identified as a neurotrophic
factor and was reported to facilitate nerve regeneration in vivo. Peptides
(prosaptides) encompassing the neurotrophic sequence located in the saposin C
domain, have neurotrophic activity similar to the holoprotein (O'Brien et al.
1995). In the present study, we investigated the effect of a 14-mer prosaptide,
TX14(A), or a 22-mer prosaptide, 769P, on paclitaxel-induced neutrotoxicity in
vitro and in vivo. Paclitaxel treatment (1 microM) decreased cell viability of
both PC12 and Schwann cells. TX14(A) (10 nM) prevented paclitaxel-induced loss of
cell viability in PC12 cells but not in Schwann cells. Systemic injections (i.p.)
of paclitaxel (1.2 mg/kg/day) given five times per week for three weeks
(cumulative dose 18 mg/kg) or given every third day (25, 12.5 and 12.5 mg/kg) for
10 ten days (cumulative dose 50 mg/kg) in adult rats induced thermal hypoalgesia
that was not accompanied by morphological changes in the sciatic nerve or changes
of nerve conduction velocity. Co-administration of paclitaxel with prosaptides
(cumulative dose 3 or 10 mg/kg) prevented paclitaxel-induced thermal hypoalgesia.
In the short-term high dose study, paclitaxel treated rats lost 10% of their body
weight, had reduced erythrocyte counts, hematocrit and hemoglobin concentrations
which were not prevented by treatment with prosaptide. TX14(A) did not diminish
paclitaxel cytotoxicity of breast cancer cells in vitro. These findings suggest
that prosaptide prevents the neurotoxic effects of paclitaxel while not
interfering with its anti-tumor activity.
PMID- 9553961
TI - Block of neuronal voltage-dependent K+ channels by diacylhydrazine insecticides.
AB - RH-5849 (1,2-dibenzoyl-1-tert-butylhydrazine), a novel insect growth regulator,
also produces acute neurotoxic symptoms by selectively blocking the maintained
voltage-dependent K+ current (IK) in nerve and muscle Salgado (1992). The effects
of RH-5849 and an analog were examined on IK channels in internally-perfused
crayfish giant axons. For bilaterally applied RH-5849, the concentration needed
for 50% block (IC50) was 79 +/- 6 microM (mean +/- SEM, n = 3), with a Hill
coefficient near 2. Block was independent of membrane potential, but dependent on
time, with a speed proportional to concentration, suggesting an open channel
block mechanism. In addition to their effects on IK, both diacylhydrazines were
much weaker blockers of the voltage-dependent sodium current (INa). RH-5849
blocked IK from either side of the membrane, and was more potent when applied
bilaterally. When RH-5849 was introduced inside the axon and internal perfusion
was halted, IK increased within a few minutes to the control level, indicating
that the compound diffused freely through the membrane and bound to a receptor
within the plane of the membrane. The permeability coefficients measured in the
stopped-flow experiments indicate that diacylhydrazines can diffuse readily
throughout the body of a poisoned insect, consistent with the rapid onset of
central nervous system symptoms following injection. The octanol:water partition
coefficient of RH-5849 increased sharply from 145 to 258 at aqueous
concentrations between 5 and 10 microM, suggesting that a new phase, possibly
micellar, is formed in the octanol phase. This may be responsible for the
anomalously high Hill coefficients for the channel blocking activity of the
diacylhydrazines.
PMID- 9553962
TI - Chemical sensitivity and the immune system: a paradigm to approach potential
immune involvement.
AB - This paper approaches the issue of chemical sensitivity and the immune system
though a consideration of established environmentally-induced immune alterations
which have particular relevance to the broader topic of chemical sensitivity.
Additionally, the report discusses the potential problems associated with prior
narrow evaluation strategies for the assessment of environmentally-induced
inflammation. A combined approach to assessment drawing upon biomarkers of both
the immune and neurological systems is suggested. Such an approach recognizes the
key roles which mediators of these two systems play in facilitating host
inflammatory responses. The paper concludes with a discussion of the types of
specific immune alterations which, from a mechanistic perspective, are likely to
be involved with any linkage of chemical sensitivity to the immune system.
PMID- 9553963
TI - Neurobehavioral properties of chemical sensitivity syndromes.
AB - Chemical sensitivity Syndromes refers to aggregations of symptoms marked by
largely subjective neurobehavioral complaints and hypothesized links to immune
system dysfunction. The entities reviewed here consist of the Multiple Chemical
Sensitivity Syndrome, the Sick Building Syndrome, the Chronic Fatigue Syndrome,
and the Gulf War Syndrome. Except for the Chronic Fatigue Syndrome, toxic
chemical exposures are accorded a significant role in their etiology. The
connections are ambiguous because of the variety of chemical agents cited and,
for the most part, the relatively low levels at which exposures occur.
Conventional clinical signs are also typically lacking. Explanatory mechanisms
include psychiatric diagnoses such as somatization, behavioral mechanisms such as
conditioning and generalization, neuropharmacological mechanisms such as
sensitization, and psychoneuroimmunological mechanisms such as those involving
the hypothalamic-pituitary-adrenal axis. Laboratory animal experimentation and
controlled clinical trials, especially with inhaled material, provide the means
for exploring the proffered explanations.
PMID- 9553964
TI - Astrocytes as mediators of immune and inflammatory responses in the CNS.
AB - The long-standing view that the brain is isolated from the effects of the immune
system has recently been challenged, with experimental evidence suggesting that
in response to invasion by microorganisms, the CNS can mount its own defense by
resident cells, such as the microglia and astrocytes. Both cell types produce and
secrete a number of cytokines and therefore can potentially modulate and
integrate the communication between hematogenous cells and resident cells of the
CNS. This manuscript will commence with a brief overview of astrocytic functions
in the CNS, and proceed to discuss astrocytic responses that may regulate CNS
inflammation. Specifically, it will address (1) the function of astrocytes as the
antigen presenting cells (APCs) of the CNS, and (2) the role afforded by
astrocyte-derived cytokines, and astrocytic responses to cytokines secreted
elsewhere, in mediating and sustaining immune responses. Finally, some recent
experimental evidence on the possibility that astroglial impairment by pathogens
may contribute to the etiology of neurologic diseases will be highlighted.
PMID- 9553965
TI - Lead potentiates cytokine- and glutamate-mediated increases in permeability of
the blood-brain barrier.
AB - We have measured the transendothelial electrical resistance across the blood
brain barrier (BBB) with a microelectrode technique and determined the effects of
subcutaneous injections (five injections over ten days) of lipopolysaccharide
(LPS, 100 ng/g), recombinant mouse interleukin-6 (IL-6, 5 ng/g), and/or inorganic
lead (lead, 2.5 5 micrograms/g) on the ion permeability of arterioles in the
temporoparietal cortex of anaesthetized mice between 10 and 40 days of age. In
controls the electrical resistance increased with age. It was decreased in
animals treated with IL-6, but unaffected by lead at the different ages studied.
In IL-6 treated mice, repeated neonatal exposure to lead (five injections between
2 and 10 days after birth) caused a delay in the increase in arteriole resistance
with age. LPS injections caused a 36% increase in ion permeability of the BBB in
twenty-day-old mice, and lead potentiated this effect of LPS. Intra-arterial
injections of glutamate did not alter vascular resistance, but topical
applications of glutamate on the cerebrum caused a reversible decrease in the
resistance in mice not treated with lead, and an irreversible decrease in mice
treated with lead. Injections of glutamate in the lumen of arterial vessels in
the parietal and temporoparietal brain areas of mice pretreated with lead and
LPS, plus a topical application of glutamate, caused depolarization of neurons in
the temporoparietal cortex. These results suggest that disruption of the BBB can
allow serum glutamate to penetrate the brain, causing further disruption of the
BBB, and that lead irreversibly potentiates this cascade of harmful events.
PMID- 9553968
TI - A review of methylmercury and child development.
AB - Methylmercury (MeHg) is a neurotoxin present in both fresh and saltwater fish
throughout the world. Increased levels of MeHg can be found in individuals who
regularly consume fish. The developing brain is very sensitive to the deleterious
effects of MeHg, and prenatal exposure can occur when the mother has a diet high
in fish. If the level of MeHg exposure achieved by eating fish adversely affects
the fetus or child's neurological development it could have far reaching public
health implications. Studies of human prenatal MeHg poisoning in Iraq suggest
that MeHg levels achieved by eating fish may affect neurological development even
when the fish MeHg levels are not elevated by obvious pollution. Studies in fish
eating populations have identified adverse neurological and developmental
outcomes, but these findings have not been consistent. Additional studies are
presently underway to determine whether consistent adverse outcomes can be
identified using more sensitive testing methods and examining children older than
in previous studies. This review examines studies of human prenatal and postnatal
MeHg exposure. Studies of poisoning episodes where children are symptomatic and
studies of fish eating populations where no symptoms are apparent will be
addressed. Individuals around the world depend on fish as a protein source and
increasing evidence suggests that regular fish consumption has cardiovascular
benefits. It is not presently clear whether MeHg exposures from a high fish diet
adversely affect children's neurological development, but it is an important
question to answer.
PMID- 9553966
TI - Lipopolysaccharide and interleukin-6 enhance lead entry into cerebellar neurons:
application of a new and sensitive flow cytometric technique to measure
intracellular lead and calcium concentrations.
AB - The distribution of intracellular ionized lead (Pb) and calcium in dissociated
cerebellar cells of ten-day-old mice was measured by flow cytometry. There are no
fluorescent probes specific for lead, whereas commonly used fluorescent calcium
indicators bind heavy metals with greater affinity than they do calcium, which
impedes discrimination of lead- and calcium-induced fluorescence changes.
Therefore, we developed a method to determine [Pb2+]i and [Ca2+]i by employing a
combination of the calcium indicator fluo-3 and the heavy-metal chelator TPEN.
Using these methods, we studied the effects of multiple in vivo exposure (five
subcutaneous injections over 10 days) to lipopolysaccharide (LPS, 100 ng/g),
recombinant mouse interleukin-6 (IL-6, 5 ng/g) and/or inorganic lead (lead, 2.5
micrograms/g) on lead and calcium concentrations. Control cells had [Cai] of 112
nM. Lead exposure alone had little effect on [Ca2+]i and resulted in a mean
[Pb2+]i of about 7 pM, and did not alter cell volume. A significant fraction of
cells (about 44% of living cells) from animals treated with lead plus LPS were
swollen, as determined by analysis of the light scattering pattern, and there was
a small increase in the number of dead cells, identified with the nucleic acid
stain, 7-aminoactinomycin. While [Ca2+]i was not significantly increased in
animals treated with either only LPS or IL-6, lead and calcium concentrations
were increased in animals exposed to lead and LPS or IL-6 in both the non-swollen
and swollen cells, with a mean value of (Pb2+)i of 32 pM and (Ca2+)i of 155 nM in
cells not swollen. Electrophysiological analysis showed that LPS injections
caused decreases in the membrane potential of endothelial cells of the blood
brain barrier (BBB) and lead potentiated the effect of LPS. IL-6 mimicked the
effects of LPS, but was less potent. Thus these experiments indicate a
synergistic interaction between lead and cytokines on biophysical properties of
both neurons and endothelial cells of the BBB.
PMID- 9553967
TI - Developmental neurotoxicity and immunotoxicity of 2,4,6-tribromophenol in Wistar
rats.
AB - Pregnant Wistar rats were exposed to 2,4,6-Tribromophenol (TBP) by whole body
inhalation (0, 0.03, 0.1, 0.3, 1.0 mg/m3, 24 hr/day, 7 days/weeks, from day 1 to
21 of gestation). Significant decreases in orientation reactions were noted at
concentrations of 1.0 mg/m3 (p < 0.05) in the open field test. Nonsignificant
trends (p > 0.05) toward decreased horizontal movement and emotionality in the
open field and increased electrical impulse skin pain threshold (SPT) were
observed. No significant exposure-related differences in the nonspecific
immunological status (phagocytosis and blood anti-microbe activity) of pregnant
rats were seen after the exposure. Preimplantation and postimplantation embryo
losses were significantly increased in a dose-dependent manner and were seen in
all treated groups except the lowest concentration (0.03 mg/m3) group. Signs of
retarded fetal skeletal development and increased frequencies of visceral
abnormalities were found at concentrations of 0.1 and 1.0 mg/m3. Significant
effects were found for lower incisor eruption and ear unfolding at a
concentration of 0.3 mg/m3. The grooming behavior of 30-day old male progeny was
significantly less than control in all experimental groups. Grooming behavior in
female subjects exposed to a concentration of 0.3 mg/m3 and emotionality in
subjects exposed to a concentration of 1 mg/m3 were decreased significantly. At
60 days of age emotional reactions were significantly decreased in female
subjects from the 0.03, 0.3 and 1.0 mg/m3 groups. SPT was significantly increased
in the 1 mg/m3 group for both male and female pups. Thus, evidence of CNS
depression influence of TBP both in maternal and offspring groups was found. The
NOEL (No Observed Effect Level) for developmental neurotoxicity is thus < 0.03
mg/m3, and the NOEL for maternal neurotoxicity is 0.3 mg/m3. These results
suggest that exposure to TBP for 24 hr/day throughout gestation may cause
developmental neurotoxicity, embryotoxicity and fetotoxicity, but not
immunotoxicity.
PMID- 9553969
TI - A method for the induction of a cochlea-specific auditory deprivation in the
gerbil (Meriones unguiculatus).
AB - The neurophysiological effects of early electrical stimulation on the development
and neural plasticity of the central auditory system in prelingually deafened
children with cochlear implants are still unknown. Many of these basic questions
can be answered systematically only in animal experiments. Meriones unguiculatus
is a well-established animal model in hearing research. Deafening is produced by
a single intracochlear application of an ototoxic aminoglycoside antibiotic
(neomycin sulfate) on the 14th day after birth (DAB), i.e. before the late
natural onset of hearing on the 16th DAB. A single application of the antibiotic
abolishes auditory brainstem responses (ABR) to clicks completely and reduces
sensitivity to low frequency tonebursts by 50 dB SPL. Scanning electron
microscopy results show a destruction of the stereocilia of the inner and outer
hair cells of the basal and medial cochlear turn and a reduction of those in the
apical turn. Our method avoids a systemic application of antibiotics and can be
used in studies dealing with the consequences of different forms of auditory
deprivation, neuronal compensation processes or with ontogenetic studies and
chronic electrostimulation in an animal model.
PMID- 9553970
TI - Localization of nitric oxide synthase isoforms (NOS I, II and III) in the
vestibular end organs of the guinea pig.
AB - The localization of nitric oxide (NO) synthase (NOS) isoforms was investigated in
the vestibular organ of the pigmented guinea pig by indirect
immunohistochemistry. The cytoplasm of both type I and type II vestibular sensory
cells as well as vestibular ganglion cells showed both NOS I and III
immunoreactivity, whereas there was no reactivity in their nuclei and sensory
hairs. The afferent nerve chalices were usually not stained. NOS III staining was
also observed in the nerve fibers contacting type II cells and in the
subepithelial tissue. The endothelial lining of the blood vessels displayed
reactivity for NOS III. The cytoplasm of fluid transporting cells showed weak
staining for NOS I and moderate staining for NOS III. Immunostaining for NOS II
did not display any reactivity in general. These findings may suggest that NO is
a mediator of neurotransmission in the vestibular system in sensory cells and
ganglia. NO in the fluid transporting cells may play an important role for
maintaining the endolymph and ion homeostasis, and NOS III in vascular
endothelial cells implies regulatory effects of NO on vascular wall tonus and
vestibular blood supply.
PMID- 9553971
TI - Calcium mobilization in isolated epithelial cells of the endolymphatic sac.
AB - Endolymphatic sac epithelial cells were isolated from the endolymphatic sac of
the guinea pig by enzymatic and mechanical dissociation. The intracellular free
calcium ion concentrations ([Ca2+]i) of the isolated cells were determined using
the Ca(2+)-sensitive dye fura-2. The isolated cells were classified into two
types, i.e. light and dark cells. In the resting state, [Ca2+]i in the cells was
variable in both types of cells. In the presence of 200 microM ATP, there was a
rapid rise in [Ca2+]i. These findings suggest that endolymphatic sac epithelial
cells may have receptor-mediated Ca channels which may play an important role for
a nerve-mediated local feedback system of the endolymphatic sac to regulate
homeostasis of endolymph volume, pressure and electrolyte balance.
PMID- 9553972
TI - Vascular inner ear partition: a concept for some forms of sensorineural hearing
loss and vertigo.
AB - The results of a series of scanning electron microscopical studies were used to
construct a model for the vascular pathways in the inner ear. Corrosion cast
preparations of the vessels of the inner ear of the adult rat were used in this
study. The inner ear is, like a hand, an end organ containing four sense organs
(cochlea, saccule, utricle and the cristae ampullaris). All these specific inner
ear structures have their own vascular supply. We have developed a blood flow
diagram of the inner ear. This model was used for a classification of different
types of ischemia in the inner ear and forms a concept for some forms of
sensorineural hearing loss and vertigo. Four types of inner ear ischemia are
proposed. In type I (a or b) of inner ear ischemia only the vessels of the
cochlea are involved resulting in two types of hearing loss without vertigo. Type
II is characterized by ischemia of a part of the cochlea and a part of the
vestibular system. In type III (a or b) only the vestibular system is involved,
while in type IV no blood circulation will be present in the inner ear resulting
in total deafness and severe vertigo. Inner ear partition at ultramicroscopical
level of these structures may be possible in the future and new imaging
techniques will probably support the vascular schematic model presented in this
study.
PMID- 9553973
TI - Vestibular function and cochlear implant.
AB - The authors illustrate their personal experience relating to 32 patients, aged
between 12 and 74 years, undergoing cochlear implant, in whom vestibular reflexes
were evaluated before and after surgery. This series did not include cases of
areflexia, but only 1 case of reduced vestibular reflexia consequently to
surgery. In this case, owing to the probable intervention of central compensation
processes, labyrinthine hyporeflexia never became clinically significant. These
personal results enable the authors to affirm that preoperative vestibular
reflexes do not offer elements able to influence the choice of the ear in which
to perform the cochlear implant. In the series of patients reported by the
authors, a cochleostomy by removal of the floor of the round window niche,
following the suggestions of O'Leary et al., always headed the electrode implant.
This contrivance may reduce or eliminate the negative effects on vestibular
receptors indirectly caused by the consequent and inevitable alteration of
perilymph pressure produced by the implant.
PMID- 9553974
TI - The effect of ammonia on olfactory epithelium and vomeronasal organ
neuroepithelium of rabbits. A histological and histochemical study.
AB - In recent studies, the vomeronasal organ (VNO), although vestigial and with
unknown function in humans, was reported to be present in almost every person
examined. In rabbits, it is a well-developed organ, one lying on each side of the
nasal septum. Histologically it was found to contain neuroepithelium which is
considered an accessory olfactory system taking charge of an olfactory
discrimination different from that of olfactory epithelium. Experimental removal
of the VNO in male animals reduces reproductive performance and aggression. In
this study, the effects of prolonged exposure to ammonia vapor on the
histological pattern and enzymatic activity of the olfactory epithelium and the
VNO neuroepithelium of 30 adult male rabbits were investigated and compared with
a control group. In the exposed animals, the supporting cells in both types of
epithelia showed hyperplasia which was more marked in the olfactory epithelium.
Manifestations of cytotoxicity were found more in the bipolar cells of the
olfactory epithelium than in the VNO neuroepithelium. The enzymatic activity in
the exposed group supported the histological results. The presence of the VNO
neuroepithelium of the rabbit in a narrow duct with a minute nasal orifice could
have some protective effects on the cells.
PMID- 9553975
TI - Clinical-morphological correlation of nasal obstruction with skull base
development and otitis media. An experimental study.
AB - Morphological changes of the middle ear were investigated by means of
microotoscopy and scanning electron microscopy in 40 developing Albino rats. In
20 one nostril (group B) and in 20 both nostrils (group C) had been
experimentally obstructed. 20 rats were used as controls (group A). Microotoscopy
and scanning electron microscopy on the middle ear mucosa were performed when the
animals were 2 months old, i.e. at 90% of their development. At microotoscopy the
tympanic membranes, homolateral to the obstructed nostril, proved to be abnormal
in 81% of group B rats and in almost all rats belonging to group C. Scanning
electron microscopy, performed after the bullae had been removed, showed the
following epithelial surface changes of the middle ear homolaterally to the
obstructed nostril: (a) a significant increase of nonciliated elements with a
secretory behavior as compared to controls, even of the floor where normally a
large number of ciliated cells is present; (b) several ciliated cells were
destroyed and their cilia were irregular and untidy; (c) thick mucous secretions
covered the floor of the tympanic bulla; and (d) squamous metaplasia of the
hypotympanic epithelium. Extrarotation of the eustachian tubes and developmental
abnormalities of the skull base in growing rats, caused by nasal obstruction,
seem to be able to induce pathological events of the middle ear.
PMID- 9553976
TI - Effects of isoproterenol on the orbicularis oculi and stapedius muscles.
AB - The effect of the beta-adrenoceptor agonist, isoproterenol, on the orbicularis
oculi and stapedius muscles was studied. Rats were injected with isoproterenol (5
mg/kg) every day. The animals were sacrificed after 1 and 2 weeks, and the
orbicularis oculi muscle and stapedius muscle were removed. Muscle fibers were
separated into single fibers, and cytochrome oxidase enzyme staining was applied
with 1% MnCl2, DAB + H2O2. The density of cytochrome oxidase enzyme reaction
products and the diameter of individual muscle fibers were analyzed by computer
assisted measurement. The administration of isoproterenol increased the activity
of cytochrome oxidase as well as the diameter of muscle fibers in the orbicularis
oculi muscle and stapedius muscle. It was suggested that these muscle fibers
exhibited increases in functional activity after the administration. The results
showed that the diameter and cytochrome oxidase enzyme activity of the
orbicularis oculi and stapedius muscles increased. We conclude that isoproterenol
induces hypertrophy of the orbicularis oculi and the stapedius muscle fibers, and
promotes cytochrome oxidase enzyme activity.
PMID- 9553977
TI - Three-dimensional imaging of laryngeal cancers using high-speed helical CT
scanning.
AB - To evaluate the clinical usefulness and limitations of three-dimensional (3-D)
imaging of laryngeal cancers by high-speed helical (spiral) CT scanning, 3-D
images were reconstructed for one dissected human larynx and 10 patients with
laryngeal cancer. The larynges were scanned in 1- to 2-mm slices, and were
reconstructed using a slice thickness of 0.5-1.0 mm. The macroscopic (or
endoscopic) findings and the 3-D CT images of the larynx were compared. The
selected threshold CT values were -600 HU (Hounsfield units) to -100 HU for the
mucous membranes, and 250 HU for bone. Under these conditions, almost all of the
structures remained distinct. The 3-D images of the larynx obtained by helical CT
were very helpful in understanding laryngeal anatomy, especially in the
subglottic area, which cannot be seen clearly by endoscopy or conventional axial
CT. Clinically, this system would have advantages in the detection of subglottic
cancers, or the invasion of glottic or supraglottic cancers into the subglottic
area.
PMID- 9553978
TI - Carotid artery reconstruction following resection during radical neck dissection.
AB - From 1972 to 1991, 7 patients with advanced cancer of the head and neck and nodal
metastasis with capsular rupture underwent radical neck dissection and sacrifice
of the carotid artery. Vascular reconstruction was performed with either an
autologous venous (8 cases) or arterial (1 case) graft. In all patients, the
postoperative course was uneventful without neurologic complications. One patient
is alive 4 years after the procedure. Six patients expired after a mean survival
of 20 months. The indications for vascular reconstruction are discussed.
PMID- 9553979
TI - Advances in the use of glass-ionomeric cement. Part 1: Experimental results and
portrayal of a technique.
AB - The objective of this study was to develop a method of cement microapplication
using glass-ionomeric cement. The results of an experimental study to design a
microapplication method of glass-ionomeric cement (Ionocem) are presented.
Typical middle ear implant materials, as well as human temporal bones and middle
ear ossicles, were used to test the efficiency of this application method. Two
different versions of Ionocem, low and normal viscosity, were tested under
different temperatures and with several application tools. Sufficient processing
time could be achieved by cooling the cement down to 4 degrees C. A subcutaneous
insulin syringe with a milled-off tip proved to be cost-effective, efficient and
versatile. Using this instrument, durable and secure cementation between the
parts tested could be achieved. This method may be of significant importance in
otologic research and microsurgical routine. In part 2, experimental animal
results will follow, as the method portrayed was used to secure parts of a
totally implantable middle ear hearing device.
PMID- 9553980
TI - Advances in the use of glass-ionomeric cement. Part 2: Functional results of fine
application of low-viscosity glass-ionomeric cement: animal experimental results.
AB - An experimentally developed technique for microapplication of low-viscosity glass
ionomeric cement (see part 1) was tested in animals over a 6-month period. The
cement was used to firmly connect gold with titanium and gold with middle ear
ossicles in 22 adult foxhounds. After a 6-month period of acoustic stimulation
via parts of an implantable hearing aid, the finely applied glass-ionomeric
cement was integrated in situ, stable and caused no adverse reactions. The
microapplication technique used proved to be easy, effective and provided long
term stability.
PMID- 9553982
TI - Determinants of total and specific IgE in infants with atopic dermatitis. ETAC
Study Group. Early Treatment of the Atopic Child.
AB - ETAC (Early Treatment of the Atopic Child), a multi-centre predominantly European
study to investigate the potential for cetirizine to prevent the development of
asthma in infants with atopic dermatitis has completed enrollment: 817 children
have been randomised to 18 months' treatment with either active or placebo and a
subsequent 18 months of post-treatment follow-up. Results of the therapeutic
effects will not be available for some time, but the study has provided an
opportunity to investigate influences on sensitization to allergens in a large
cohort of 1-2 years olds with already established atopic dermatitis, resident in
different countries and in different environments. The study shows that in
infants with atopic dermatitis, raised serum total IgE has significantly
different determinants from that a specific allergen sensitization. In infancy,
increased total IgE is more affected by factors increasing risk of intercurrent
infection and non-specific airway inflammation, such as environmental tobacco
smoke exposure (p < 0.001) and the use of gas cookers (p = 0.02). Specific
allergen sensitization as represented by detectable IgE antibodies is influenced
primarily by allergen exposure. In Sweden, low level exposure to allergens is
associated with reduced specific allergen sensitization rates even though the
infants already have atopic dermatitis.
PMID- 9553983
TI - Serum specific-IgE antibodies to peptides detected in a casein hydrolysate
formula.
AB - Up to 2.5% of infants are affected by cow milk hypersensitivity in the first two
years of life, although most of these children will "outgrow" their reactivity
within 2-3 years. Extensively hydrolyzed ("hypoallergenic") cow milk-based
formulae are often recommended as a substitute formula and are generally well
tolerated. However, a small minority of cow milk-allergic children experience
allergic reactions to the hypoallergenic formulae as well. Utilizing inhibition
ELISAs and sera from patients with IgE-mediated cow milk allergy, we have
identified residual protein fractions less than 20 kD in several of the
extensively hydrolyzed cow milk-based formulae. Although many of the cow milk
allergic children had positive skin prick tests [SPT] to one of the hydrolysate
formulae (Nutramigen), the positive skin test result generally did not correlate
with clinical reactivity, although the negative predictive value of the negative
SPT was excellent. Children with IgE-mediated cow milk allergy and a positive
skin prick test to the hypoallergenic formula should probably receive their first
dose of the formula in a medical setting so that appropriate therapy can be
administered in the unlikely event of an allergic reaction.
PMID- 9553981
TI - Worldwide variations in prevalence of symptoms of allergic rhinoconjunctivitis in
children: the International Study of Asthma and Allergies in Childhood (ISAAC).
AB - BACKGROUND: As part of the International Study of Asthma and Allergies in
Childhood (ISAAC), prevalence surveys were conducted among representative samples
of school children from locations in Europe, Asia, Africa, Australia, North and
South America. SUBJECTS: 257,800 children aged 6-7 years from 91 centres in 38
countries, and 463,801 children aged 13-14 years from 155 centres in 56
countries. METHODS: Written symptom questionnaires were translated from English
into the local language for self-completion by the 13-14-year-olds and completion
by the parents of the 6-7-year-olds. Rhinitis was described as a problem with
sneezing, or a runny, or blocked nose when you (your child) DID NOT have a cold
or the flu. Additional questions were asked about rhinitis associated with itchy
watery eyes, interference with activities and a history of hay fever ever.
RESULTS: The prevalence of rhinitis with itchy-watery eyes
("rhinoconjunctivitis") in the past year varied across centres from 0.8% to 14.9%
in the 6-7-year-olds and from 1.4% to 39.7% in the 13-14-year-olds. Within each
age group, the global pattern was broadly consistent across each of the symptom
categories. In centres of higher prevalence there was great variability in the
proportion of rhinoconjunctivitis labelled as hay fever. The lowest prevalences
of rhinoconjunctivitis were found in parts of eastern Europe, south and central
Asia. High prevalences were reported from centres in several regions. CONCLUSION:
These results suggest substantial worldwide variations in the prevalence and
labelling of symptoms of allergic rhinoconjunctivitis which require further
study. These differences, if real, may offer important clues to environmental
influences on allergy.
PMID- 9553984
TI - Soy allergy is not common in atopic children: a multicenter study.
AB - The aim of the present study was to evaluate the prevalence of soy allergy
(positive skin test and positive challenge test) in a large cohort of atopic
children, many of them soy fed early in life for several months. In order to
investigate the prevalence of soy allergy, two groups of children were enrolled
into the study. The first group comprised a cohort of 505 children with personal
history suggestive of food allergy. The second group included 243 children born
of atopic parents, who had been soy protein formula fed for the first six months
of life for the prevention of cow's milk allergy and who had been prospectively
followed up, from birth to 5 years. As regards the prevalence of soy allergy in
the cohort of children suffering from allergic disease: 31/505 children (6%) had
positive skin prick test to soy, however only six of the 31 children with
positive skin prick test to soy had positive challenge test to soy. With regard
to the prevalence of soy allergy in the children who had been soy protein formula
fed in the first six months of life (second group): 14/243 children (6%) had
positive skin prick test to soy, but the double blind placebo control oral food
challenge to soy was positive in only one of these 14 children. In conclusion
documented soy allergy is not common in atopic children.
PMID- 9553985
TI - Lack of correlation between soluble CD14 and IL-6 in meningococcal septic shock.
AB - Meningococcal sepsis is a good model to study the dynamic response of cytokines
and other soluble factors in vivo in the early stages of the disease. Levels of
soluble CD14, interleukin-6 (IL-6), IL-6 receptor (IL-6R), and C-reactive protein
(CRP) have been measured in plasma from 26 children with septic shock (nine of
whom had disseminated intravascular coagulation) and from ten control children.
All samples were collected at the onset, before treatment, and, when possible, 24
and 48 hours later. At admission, patients had significantly higher levels of IL
6 (p < 0.001) and CRP (p < 0.001), and lower levels of IL-6R (p < 0.005) than
normal controls. After 24 hours, there was a significant increase of sCD24 (p <
0.05) and CRP (p < 0.001). Although IL-6 showed a progressive decline since the
onset, its levels were always higher than controls. There was an inverse
correlation between IL-6 and both IL-6R (p < 0.001) and CRP (p < 0.001), probably
due to the later increase of CRP. Nevertheless, sCD14 did not correlate with IL-6
levels. We have confirmed the finding of IL-6 as a sensitive and reliable
inflammatory marker in septic shock. Moreover, the ratio IL-6/IL-6R may have a
prognostic value, given a putative role of IL-6R in modulating the effects of IL
6 in meningococcal sepsis.
PMID- 9553986
TI - Is asthma an endocrine disease?
AB - The prevalence of pediatric asthma has increased in many parts of the world. This
increase started more than 30 years ago and is particularly obvious in studies
which document the onset of asthma in native populations when they change to a
"Western" lifestyle. Besides a genetic influence, numerous environmental factors
have been described for the development of asthma. Genetic factors are unlikely
to explain the sharp increase within the short time period and also allergen and
pollution exposure or any specific infection does not actually seem to be the
main cause for this phenomenon. Another factor, however, that fits well into the
geographical and temporal background of the asthma epidemic is the mother's oral
contraceptive use. We therefore review the epidemiological association with later
asthma in the children, give a summary of estrogen effects on immune function and
develop a preliminary theory how oral contraception could influence later
pregnancy.
PMID- 9553987
TI - Peroxynitrite: a putative cytotoxin.
AB - In recent years it has become apparent that peroxynitrite, which is one of the
toxic metabolites originating from the reaction of nitric oxide and superoxide
presents a number of pathologic states in which free radicals are thought to be
involved. Peroxynitrite is capable of oxidizing a wide variety of biomolecules
including plasma, proteins, lipids, carbohydrates and nucleic acids.
Peroxynitrite is involved in the hydroxylation of aromatic compounds and acts as
a nitrating agent. It modifies free or protein-associated tyrosine residues to
give nitrotyrosines, leaving a marker detectable in vivo. Peroxynitrite has been
implicated in the pathophysiology of a variety of diseases including
inflammation, atherosclerosis, arthritis, endotoxemia, ischaemia-reperfusion
injury, or acute respiratory distress syndrome. Development of specific
peroxynitrite scavengers may provide new approaches for the effective treatment
of these disease states.
PMID- 9553988
TI - The effect of 1,25-vitamin D3 on calbindin-D and calcium-metabolic variables in
the rat.
AB - Intraperitoneal injection of 1,25-(OH)2D3 4 micrograms/kg was given to 84 calcium
and vitamin D-repleted Wistar rats and samples of plasma, duodenal mucosa and
renal tissue were taken after 0, 3, 6, 12, 24, 48 and 96 hr (n = 12 at each time
interval). Plasma-ionized Ca increased after 6 hr, reached a maximum after 24 hr
and returned to the initial values after 96 hr. The concentrations of renal
calbindin-D28k and intestinal calbindin-D9k did not increase until 48 hr after
injection and remained elevated until 96 hr after. Therefore, significantly
elevated concentrations of the cytosolic calbindin-D were found at a time with
normal values of plasma Ca. The present data suggest that calbindin-D does not
alone increase the transcellular Ca transport and, therefore, supports the view
that calbindin-Ds may serve as Ca buffer proteins.
PMID- 9553989
TI - Evidence for functional interactions between 5-HT1A and 5-HT2A receptors in rat
thermoregulatory mechanisms.
AB - The present study was designed to examine 1) functional interactions between 5
HT1A and 5-HT2A/C receptors in thermoregulation in rats and 2) the specific
involvement of 5-HT2A and 5-HT2C receptors in such interactions. The 5-HT2A/C
receptor agonist DOI (0.025 1.6 mg kg-1, subcutaneously) produced a dose
dependent hyperthermia in rats, which was enhanced by addition of either of two 5
HT1A receptor antagonists, (-)-pindolol (0.5-1.0 mg kg-1, subcutaneously) or WAY
100,635 (0.1-0.4 mg kg-1, subcutaneously). Furthermore, the DOI-induced
hyperthermia was counteracted by pretreatment with the 5-HT1A receptor agonist 8
OH-DPAT (0.05 mg kg-1, subcutaneously). The hyperthermia produced by DOI, alone
or in combination with WAY-100,635, was fully antagonized by pretreatment with
the 5-HT2A/C receptor antagonist ritanserin (1.0 mg kg-1, subcutaneously), as
well as with the selective 5-HT2A receptor antagonist amperozide (2.0 mg kg-1,
subcutaneously). The present results provide evidence for functional interactions
between 5-HT1A and 5-HT2A receptors in temperature regulation in rats, and also
suggest an important role for postsynaptic 5-HT2A receptors in the mediation of
DOI-induced hyperthermia.
PMID- 9553990
TI - Acetaminophen protection against estramustine-induced cytotoxicity on cultured
fibroblasts.
AB - Two commonly used analgesics, ibuprofen and acetaminophen (paracetamol) were
investigated for possible influence on Chinese hamster fibroblast (V-79)
cytotoxicity (measured by cells cloning ability and 86Rb accumulation) of the
anti-neoplastic drugs estramustine and bleomycin in vitro. Fibroblast exposure to
estramustine (80 mg/l) or bleomycin (50 mg/l), for 1 or 24 hr, reduced the number
of surviving clones to approximately 35% and 50% respectively. Acetaminophen (10
or 100 mg/l), but not ibuprofen, significantly increased the number of surviving
clones with estramustine. The analgesics had no effect on bleomycin cytotoxicity.
The uptake of 86Rb+ (K+ analogue) by V-79 cells was reduced after incubation with
80 mg/l estramustine phosphate. Acetaminophen (30 mg/l) but not 10 mg/l
acetaminophen or ibuprofen (30 or 100 mg/l), significantly protected against
estramustine reduction of 86Rb accumulation. Acetaminophen inhibition of
estramustine cytotoxicity is suggested to be due to reversal of estramustine
induced inhibition of cellular potassium channel ion transport.
PMID- 9553991
TI - Cross-fostering study of methyl mercury retention, demethylation and excretion in
the neonatal hamster.
AB - The cross-fostering technique was used in order to compare methyl mercury (MeHg)
metabolism in hamsters following prenatal (in utero) and neonatal (lactational)
exposure. Pregnant Syrian golden hamsters were administered radiolabeled MeHg on
day 12 of gestation. The offspring was nursed by foster mothers unexposed to
MeHg, while the pups from the unexposed animals were nursed by the MeHg
administered animals. Under these conditions, each pup in the litter received a
dose of MeHg in utero corresponding to 0.9% of the maternal dose. The average
amount of mercury found in the pups exposed via milk corresponded to 4.5% of the
total body burden of the foster dam at the onset of lactation. This was about
half the amount received by the pups exposed in utero. The total body burden of
mercury, and the amount of mercury in the liver, brain and kidney of the pups
exposed in utero began to decrease at seven days of age. The rate of decrease
differed among the tissues and was lowest in the kidney. The amount of mercury in
pups exposed via milk reached a peak level when the pups were 10-15 days old. The
total body burden of mercury showed a slow decrease while the liver, brain and
kidney levels decreased rapidly. In both groups of animals, up to 80% of the
total body burden of mercury was found in the pelt. These data show that milk may
be a significant exposure route for mercury and that neonatal hamsters are unable
to demethylate MeHg and excrete mercury in urine and faeces.
PMID- 9553992
TI - Excitatory amino acid antagonists alleviate convulsive and toxic properties of
lindane in mice.
AB - Pesticides acting at GABAA receptors may induce convulsions in man and animals,
but the mechanisms responsible for their convulsant activity are not fully
explained. The following excitatory amino acid antagonists were studied for their
protective action in mice intoxicated with chlorinated hydrocarbon insecticide
lindane (gamma-hexachlorocyclohexane): the competitive NMDA antagonist: 3-(2
carboxypiperazine-4-yl)propenyl-1- phosphonic acid (D-CPPene, 20 mg/kg), the non
competitive NMDA antagonist: dizocilpine (MK-801, 0.4 mg/kg), the glycine site
antagonist of NMDA receptor: 2-phenyl-1,3-propane-diol dicarbamate (felbamate,
400 mg/kg) and the competitive AMPA antagonist: 2,3-dihydroxy-6-nitro-7-sulfamoyl
benzo(F)quinoxaline (NBQX, 100 mg/kg). Systemic administration of an antagonist
prior to lindane resulted in a strong anticonvulsant effect. D-CPPene, MK-801 and
NBQX produced a marked increase of CD50 values of lindane for clonic convulsions.
All the antagonists protected animals against tonic convulsions. Toxicity of
lindane was potently reduced, as assessed 2, 24 and 120 hr after administration
of the pesticide. Our results demonstrate that excitatory amino acid antagonists
reduce convulsant properties and toxicity of lindane, suggesting that excitatory
amino acid neurotransmission may be involved in its central action.
PMID- 9553993
TI - Optimization and application of the head space liver S9 equilibration technique
for metabolic studies of organic solvents.
AB - A head space liver S9 vial equilibration technique for qualitative and
quantitative metabolism of volatile organic solvents in vitro is described and
investigated for optimal experimental conditions with toluene and n-hexane as
model substrates. The method was also used for studying the metabolic interaction
between acetone and styrene. NADP+ was a critical cofactor in the system as
concentrations above 2.5 mM resulted in inhibition of metabolism. Induction of
cytochrome P450 by phenobarbital did not alter the observed cofactor dependency,
and addition of vehicles such as rat blood did not enhance metabolism. Acetone
induced liver S9 increased the primary oxidation of styrene and also the
formation of styrene oxide, but not significantly that of mandelic acid. Acetone
as such had no effect on the metabolic elimination of styrene, indicating that
the interaction is mainly on the level of enzyme induction occurring after long
term exposure to acetone. As earlier reports on styrene metabolism in vivo has
not been able to detect styrene oxide in toxicokinetic studies with a sufficient
degree of accuracy, the head space liver S9 vial equilibration technique may
offer a fast and sensitive tool for screening of metabolic interactions between
organic solvents when optimized for metabolic activity.
PMID- 9553994
TI - The effect of acute lithium and rubidium pretreatment on apomorphine-induced
pecking in pigeons.
AB - The effects of different doses of lithium (5-320 mg/kg intramuscularly) and
rubidium (0.25 32 mg/kg intramuscularly) on apomorphine-induced pecking were
investigated in pigeons. These two cations did not induce pecking by itself.
Intramuscular administration of apomorphine (a mixed D1/D2 dopamine receptors
agonist, 0.1-1.6 mg/kg) induced pecking in a dose-dependent manner. SCH 23390 (D1
dopamine receptor antagonist, 0.02-0.08 mg/kg) and sulpiride (D2 dopamine
receptor antagonist, 25-100 mg/kg) decreased apomorphine-induced pecking dose
dependently. Combination of SCH 23390 (0.04 mg/kg) with sulpiride (50 mg/kg)
caused a stronger inhibitory effect on apomorphine response. This indicates that
both D1 and D2 dopamine receptors are involved in apomorphine-induced pecking.
The response induced by apomorphine (0.2-0.8 mg/kg) was decreased in animals
pretreated with lithium and rubidium. In these conditions, SCH 23390 and
sulpiride produced a larger inhibitory effect on the apomorphine response,
suggesting that acute lithium and rubidium pretreatment inhibit pecking by
interfering with dopaminergic mechanisms.
PMID- 9553995
TI - Prolactin response to bromperidol treatment in schizophrenic patients.
AB - The prolactin response to an antipsychotic drug, bromperidol was studied in 24
schizophrenic in-patients (13 males. 11 females). Eight patients were given 6
mg/day, 8 were given 18 mg/day. Duration of treatment was 3 weeks. Plasma
concentrations of bromperidol and reduced bromperidol were measured by high
performance liquid chromatography, and that of prolactin was measured by
radioimmunoassay. Bromperidol treatment significantly (P < 0.01) increased plasma
concentration of prolactin each week. The mean +/- S.D. of the delta-prolactin
(the mean concentration during treatment minus the pretreatment concentration)
was 13.3 +/- 12.4 ng/ml. Multiple regression analysis showed that the delta
prolactin concentration was significantly greater in females than in males (P <
0.05) and correlated to plasma concentrations of bromperidol (P < 0.001) and
reduced bromperidol (P < 0.0001). These results suggest that the prolactin
response to bromperidol treatment depend on plasma concentrations of both
bromperidol and reduced bromperidol and gender, and that reduced bromperidol is
involved in the pharmacological effects during bromperidol treatment.
PMID- 9553997
TI - Chernobyl: a survivable ecological disaster?
AB - A study of events occurring after the Chernobyl accident until 1996 was funded by
the European Commission (EC). The study included work by hundreds of scientists
from the EC and the former Soviet Union. An overview of these studies is given
that puts the science into historical context and shows the effects of the
radioactive doses on the population and on the environment. The exposed
populations are considered in terms of the separate exposure subgroups (emergency
workers; inhabitants of settlements near the reactor; inhabitants of settlements
receiving high doses of condensation radionuclides; children in the deposition
areas; the general population). The scientific understanding of the natural and
anthropogenic countermeasures that reduced doses is presented, and the effects on
the human population are discussed.
PMID- 9553996
TI - Ketobemidone plus (RS)-3-dimethylamino-1,1-diphenylbut-1-ene (A29) is more potent
at NMDA receptors than ketobemidone alone: evidence for A29 as a non-competitive
NMDA receptor antagonist.
AB - The opioid, ketobemidone, has previously been shown to be a non-competitive N
methyl-D-aspartate (NMDA) receptor antagonist. In Denmark, ketobemidone is
available in a formulation which contains ketobemidone and a spasmolytic
compound, (RS)-3-dimethylamino-1,1-diphenylbut-1-ene, hydrochloride (A29), in a
one to five ratio. Using in vitro receptor binding techniques and an in vitro
electrophysiological preparation consisting of rat cerebral cortex, we have
characterized the interaction between A29 and the different glutamate receptor
subtypes. A29 selectively inhibited binding of the non-competitive NMDA receptor
antagonist 3H-MK-801 with a Ki value 16 +/- 4.5 microM, but was inactive in
assays measuring affinities for other glutamate receptors. In agreement with the
binding studies, A29 was found to selectively inhibit responses to NMDA in the
rat cortical wedge preparation, whereas responses to kainate and AMPA were
unaffected. Analysis of dose response curves showed A29 to be a NMDA receptor
antagonist with an IC50 value of 100 microM versus responses to 10 microM NMDA.
The inhibitory effects of ketobemidone and A29 on responses to 10 microM NMDA
were additive. These data show that the combination of A29 and ketobemidone exert
more potent antagonism at the NMDA receptor than does ketobemidone alone.
PMID- 9553998
TI - The toxicologic hazard of superfund hazardous-waste sites.
AB - Uncontrolled hazardous-waste sites are a major environmental and public health
concern in the United States and elsewhere. The remediation of and public health
responses to these sites is mandated by the federal Superfund statute.
Approximately 40,000 uncontrolled waste sites have been reported to U.S. federal
agencies. About 1,300 of these sites constitute the current National Priorities
List (NPL) of sites for remediation. Findings from a national database on NPL
sites show approximately 40% present completed exposure pathways, although this
figure rose to 80% in 1996. Data from 1992 through 1996 indicate that 46% of
sites are a hazard to public health. Thirty substances are found at 6% or more of
sites with completed pathways. Eighteen of the substances are known human
carcinogens or reasonably anticipated to be carcinogenic. Many of the 30
substances also possess systemic toxicity. The high percentage of sites with
completed exposure pathways and the toxicity potential of substances in these
pathways show that uncontrolled hazardous-waste sites are a major environmental
threat to human health. Findings from the United States' experience in responding
to uncontrolled waste sites are relevant to other countries as they address
similar environmental and public health concerns.
PMID- 9553999
TI - Antihypertensive treatment and serum cholesterol: results of population-based
surveys in the German Cardiovascular Prevention Study.
AB - We analyzed the data from three cross-sectional, population-based surveys in West
Germany to evaluate the effect of antihypertensive drug therapy on the level of
serum cholesterol in German residents (18,344 males; 19,137 females) aged 25-69
years, after excluding persons with missing values (N = 5529) for any study
variable. The data were obtained from the national and regional health surveys
that were conducted during the years 1984-1992, within the framework of the
German Cardiovascular Prevention Study (GCP). The response rates were between
66.0% and 71.4% for the national surveys and between 65.9% and 83.3% for the
regional surveys. Blood-pressure and non-fasting cholesterol measurements were
carried out under strictly standardized conditions. Multiple linear regression
analysis was used to compare the age-adjusted mean value and prevalence for each
of the following study variables: total serum cholesterol, HDL-cholesterol, non
HDL cholesterol, and the ratio of HDL cholesterol/total cholesterol for users and
non-users of antihypertensive medications. Antihypertensive medications were
reportedly taken during the seven days preceding the survey examination by 7.8%
of all males and 10.4% of all females. The beta-blocker type of medication was
prescribed most frequently for lowering high blood pressure. In both genders, the
strongest age-adjusted effect of an increase in cholesterol level was found for
beta-blockers. The difference in the age-adjusted means for non-HDL cholesterol
values between users and non-users of beta-blockers was 9.2 mg/dL (p < 0.001) in
males and 9.0 mg/dL (p < 0.001) in females. Regression analysis carried out to
control for several potential confounders confirmed the results. The findings
suggest that mass treatment of hypertension with beta-blockers may be associated
with reductions in benefit because of an increase in non-HDL and a decrease in
HDL cholesterol levels.
PMID- 9554000
TI - Molecular biomarkers of early responses to environmental stressors: implications
for risk assessment and public health.
PMID- 9554002
TI - Erdheim-Chester disease: radiographic findings in five patients.
AB - We present the case histories of five patients with Erdheim-Chester disease, a
rare lipoidosis that has several typical radiographic features. In all the
patients, the diaphyses and metaphyses of the extremities demonstrated a
symmetric pattern of diffuse or patchy increased density, a coarsened trabecular
pattern, medullary sclerosis, and cortical thickening. The epiphyses were spared
in four patients and partially involved in one. The axial skeleton was involved
in one patient. Radiotracer 99mTc accumulated in areas of radiographic
abnormalities in all patients. In one patient, MRI demonstrated an abnormal
signal, corresponding to radiographic abnormalities. The signal was hypointense
to muscle on T1-weighted sequences and heterogeneously hyperintense and
hypointense to normal bone marrow on T2-weighted sequences. Xanthogranulomatous
lesions infiltrated the retroperitoneum in one patient, the testes in one
patient, the eyelids in one patient, and the orbits in two patients.
PMID- 9554001
TI - Mastocytosis: magnetic resonance imaging patterns of marrow disease.
AB - OBJECTIVE: To report the bone marrow MRI findings of patients with mastocytosis
and correlate them with clinical, pathologic, and radiographic features. DESIGN
AND PATIENTS: Eighteen patients with mastocytosis had T1-weighted spin echo and
short tau inversion recovery MRI of the pelvis at 0.5 T. In each patient the MR
pattern of marrow disease was classified according to intensity and uniformity
and was correlated with the clinical category of mastocytosis, bone marrow biopsy
results, and radiographic findings. RESULTS: Two patients had normal MRI scans
and normal bone marrow biopsies. One patient had a normal MRI scan and a marrow
biopsy consistent with mastocytosis. Fifteen patients had abnormal MRI scans and
abnormal marrow biopsies. There were several different MR patterns of marrow
involvement; none was specifically associated with any given clinical category of
mastocytosis. Fifteen of the 18 patients had radiographs of the pelvis; of those,
13 with abnormal MRI scans and abnormal marrow biopsies had the following
radiographic findings: normal (nine); sclerosis (three); diffuse osteopenia
(one). CONCLUSION: While radiographs are very insensitive for the detection of
marrow abnormalities in mastocytosis, MRI is very sensitive and may display
several different patterns of marrow involvement.
PMID- 9554003
TI - MR imaging of epicondylitis.
AB - OBJECTIVE: To systematically evaluate the MR findings in patients with
epicondylitis compared with asymptomatic volunteers. DESIGN AND PATIENTS: We
imaged 43 elbows: 24 with epicondylitis (22 lateral, 2 medial) diagnosed by
clinical examination, and 19 in 16 normal volunteers. MRI was performed at 1.5 T
using axial T1-weighted, axial fat-saturated FSE, and coronal or sagittal Fast
STIR sequences. Two independent observers evaluated the images for intratendon
signal, tendon thickening, periosteal reaction, fluid in the radial head bursa,
and anconeus edema. RESULTS: All 24 patients with epicondylitis had increased
signal on fat-saturated FSE and Fast STIR images. Twenty-two of these patients
had increased intratendon T1 signal, and 19 had tendon thickening. No patient
demonstrated fluid in the radial head bursa or periosteal reaction. Only two
patients had subtle anconeus edema, while three patients unexpectedly had
increased T2 signal within the involved epicondyle. One asymptomatic volunteer
(high-performance athlete) had increased T1 and T2 signal with tendon thickening.
An additional two asymptomatic volunteers had increased T1 signal only.
CONCLUSION: MRI of epicondylitis demonstrates tendon thickening with increased T1
and T2 signal, but these findings may be seen in a small minority of asymptomatic
individuals. Anconeus edema, previously demonstrated on MRI in epicondylitis, was
only rarely found, and distension of the radial head bursa, surgically described,
was not seen. Increased marrow T2 signal within the involved epicondyle is
occasionally seen.
PMID- 9554004
TI - Slipped capital femoral epiphysis: a physeal lesion diagnosed by MRI, with
radiographic and CT correlation.
AB - OBJECTIVE: To define and compare early lesions associated with slipped capital
femoral epiphysis (SCFE) on magnetic resonance imaging (MRI), computed tomography
(CT) and radiography. DESIGN AND PATIENTS: Thirteen patients with 15 symptomatic
hips due to SCFE underwent radiography and MRI; CT was performed in 12 patients.
SCFE was graded on radiographs, head/neck angles and qualitative changes were
evaluated on CT, and morphologic/signal abnormalities were determined on MRI.
RESULTS: Physeal widening, apparent on T1-weighted MRI, was evident in every case
of SCFE, including one presumed "pre-slip." T2-weighted images demonstrated
synovitis and marrow edema but obscured physeal abnormalities. CT head/neck
angles ranged from 4-57 degrees for symptomatic to 0-14 degrees for asymptomatic
hips. Physeal and metaphyseal changes were variably identified on both
radiographs and CT in all cases of SCFE, but not in the pre-slip. CONCLUSION: MRI
clearly delineates physeal changes of both pre-slip and SCFE, and demonstrates
very early changes at a time when radiographs and CT may appear normal.
PMID- 9554005
TI - Chondroblastic osteosarcoma: characterisation by gadolinium-enhanced MR imaging
correlated with histopathology.
AB - OBJECTIVE: To identify specific features of chondroblastic osteosarcoma on
gadopentetate dimeglumine (Gd)-enhanced magnetic resonance (MR) imaging. DESIGN
AND PATIENTS: Nine patients with chondroblastic osteosarcoma and a control group
of 20 patients with conventional central osteosarcoma were included in this
study. The histopathological findings of the surgical specimens were compared
with enhancement patterns on static Gd-enhanced MR images. RESULTS: In
chondroblastic osteosarcoma septonodular and peripheral rim enhancement
represented tumour with a pure chondroid matrix. Non-enhancing and heterogeneous
enhancing areas represented tumour with both chondroid and osteoid matrix. In the
tumours in the control group enhancement was predominantly heterogeneous but in
one it was homogeneous. All these areas corresponded to necrotic or viable
osteoid tumour tissue or fibrovascular tissue in areas of necrosis. CONCLUSION:
Gd-enhanced MR imaging can assist in obtaining diagnostic biopsy material of
chondroblastic osteosarcoma by identifying both osteoid- and chondroid-forming
areas.
PMID- 9554006
TI - Bizarre parosteal osteochondromatous proliferation of bone.
AB - A 47-year-old man presented with a painless mass of 7 months' duration, on the
plantar aspect of the great toe of the right foot. Radiographs and CT images
initially suggested an osteochondroma arising from the proximal phalanx of the
great toe but there was no continuity between the medullary canal of the phalanx
and the lesion. The mass was excised and a histological diagnosis of bizarre
parosteal osteochondromatous proliferation of bone (Nora's disease) was made. The
aggressive growth of this lesion may clinically suggest a neoplasm. Histological
features, however, are those of a reactive lesion.
PMID- 9554008
TI - Parosteal osteoma of the iliac bone.
AB - A 33-year-old patient with a 2-year history of intermittent pain in the right
gluteal region and thigh presented with a large sclerotic lesion of the iliac
bone. From the findings on radiography, scintigraphy, CT and MRI, a giant
parosteal osteoma was suspected. The histological examination confirmed the
diagnosis. Since the lesion was extensive it was observed with periodic follow-up
examinations. At present, 5 years after the diagnosis, the patient is
asymptomatic and imaging studies show that the lesion persists with reduction of
sclerosis and size. The tumor was on the surface as well as intramedullary--only
one other case with such a distribution is known to us--and it was also in the
iliac bone.
PMID- 9554007
TI - Recurrent parosteal osteosarcoma of the talus in a 2-year-old child.
AB - Parosteal osteosarcoma is an uncommon, low-grade malignant bone tumor and is
found in an older age group than conventional osteosarcoma. We present a talar
parosteal osteosarcoma that recurred twice in a 2-year-old child. To our
knowledge, this is the youngest patient reported with a parosteal osteosarcoma.
The talus is an unusual site for parosteal osteosarcoma. Inadequate resection due
to a diagnosis of juxtacortical chondroma resulted in recurrence of the tumor.
The age of the patient, the thick cartilaginous cap, and well-differentiated
trabecular bone all contributed to the critical erroneous diagnosis.
PMID- 9554009
TI - Radiation-induced tibial sarcoma in a treated case of hind foot angiomatosis.
AB - Hemangiomatosis with osteolysis, osteosclerosis and loss of bony definition is an
uncommon disease entity. Many forms of treatment have been used, varying almost
from case to case. The use of radiation therapy has proved successful in the
control of the disease process in reported cases. The current case of hind foot
hemangiomatosis went on to develop sarcoma 17 years later in the uninvolved tibia
at the margin of the radiation field, which proved to be fatal to the patient.
Treatment by radiotherapy had permitted normal function for 15 years. This case
highlights the difficulties of management of skeletal angiomatosis based on
anatomic location and emphasizes the need for judicious planning and selection of
the mode of delivery of radiotherapy.
PMID- 9554011
TI - Light chain deposition disease in multiple myeloma: MR imaging features
correlated with histopathological findings.
AB - The clinical, histopathological, and imaging findings on MRI of a 56-year-old
woman with light chain deposition disease occurring in multiple myeloma are
presented. Light chain deposition disease is a variant of multiple myeloma with
distinct clinical and histological characteristics. MRI of this patient also
revealed an infiltration pattern in the bone marrow distinct from that of typical
multiple myeloma. Multiple small foci of low signal intensity were present on T1-
and T2-weighted spin echo and STIR images, corresponding to conglomerates of
light chains in bone marrow biopsy. Contrast-enhanced T1-weighted spin echo
images show diffuse enhancement of 51% over all vertebral bodies, with a minor
enhancement of the focal conglomerates of light chains. Light chain deposition
disease in multiple myeloma should be added to the list of those few entities
with normal radiographs and discrete low-signal marrow lesions on T1- and T2
weighted spin echo pulse sequences.
PMID- 9554010
TI - Spinal cord compression caused by thoracic vertebral hemangioma involving only
the posterior elements of two contiguous vertebrae.
AB - An unusual case of symptomatic thoracic vertebral hemangioma involving two
contiguous vertebrae but confined to the posterior elements is presented. The
lesion displaced and compressed the cord. The diagnosis was not considered prior
to biopsy. There was uncontrolled bleeding at biopsy. Only partial surgical
resection was performed, with incomplete relief of motor weakness after initial
surgery. The patient refused further surgical resection. Motor power was
gradually recovered after a course of postoperative radiotherapy.
PMID- 9554012
TI - Sustained improvements in neurological function in spinal cord injured patients
treated with oral 4-aminopyridine: three cases.
AB - Preclinical trials of intravenously administered 4-Aminopyridine (4-AP) have
demonstrated transient improvements in neurological function in patients with
longstanding spinal cord injury (SCI). The present report describes three
patients with SCI who responded favourably in preclinical trials and who were
subsequently administered oral (capsule) 4-AP (10 mg b.i.d. or t.i.d.) over a 4
month interval. The three patients (two male: 1 female) all had incomplete
tetraplegia (ASIA levels C and D) with the neurological level of the lesion
between C5-C7. Following the administration of 4-AP the patients demonstrated
marked and sustained reductions in upper (n = 1) or lower extremity (n = 2)
spasticity. Other clinical benefits of 4-AP were reduced pain (n = 1), restored
muscle strength (n = 3), improved sensation (n = 2), voluntary control of bowel
function (n = 1), and sustained penile tumescence (n = 2). The patients exhibited
improved hand function (n = 1), enhanced mobility in transfers and gait (n = 2),
with improved energy and endurance. Only trivial side effects (transient light
headedness) were observed. In one case, the enhanced neurological function
allowed the patient to stand with support for the first time post injury (16
years). The time course of therapeutic response to the initial dose matched the
pharmacokinetic elimination profile derived from serum and urine analysis. There
was no evidence of renal or hepatic toxicity with prolonged use. These results
indicate a therapeutic benefit of oral 4-Aminopyridine in the management of
various neurological deficits in a select group of SCI patients.
PMID- 9554014
TI - Medication usage in a spinal cord injured population.
AB - The patterns of medication usage in persons with a spinal cord injury (SCI) in a
residential facility have been studied. This population averaged over eight (8)
medications per person, took 70% of this medication from five (5) therapeutic
categories (MIMS) and thus took multiple medications from individual categories.
This level of medication usage is higher than what has been published for elderly
populations, who are considered 'at risk' of medication misadventure. The SCI
population was predominantly young and as yet, taking few medications for
treating age related conditions. Thus, the level of medication use might be
expected to increase further in this population.
PMID- 9554015
TI - Spinal hydatid disease.
AB - Vertebral hydatid cysts are rare and found in less than 1% of all the cases of
hydatidosis. Neural compression is common in vertebral hydatidosis. The prognosis
is generally regarded as very poor. This paper examines the natural history and
complications which may arise during the treatment of vertebral hydatid cyst, and
discusses their treatment. Thirteen cases of hydatid disease affecting the
vertebrae are presented. The patients were admitted with symptoms of spinal cord
compression. Twelve were treated by laminectomy and one by costotransversectomy.
Low back pain radiating to the legs and lower extremity weakness were the
predominant symptoms. Different degrees of pareses were present in 12 patients.
Nine patients had impaired sensation in lower extremities. In 13 patients, 27
operations were performed. The major complication of surgery was the death of one
patient due to the formaline irrigation. The surgical goal should be an extensive
removal of the cysts and affected bone. The surgical area needs to be irrigated
with hypertonic saline. Mebendazole or albendazole therapy seems to retard the
recurrences and control the disease.
PMID- 9554013
TI - Central cord syndrome: functional outcome after rehabilitation.
AB - Seventy-three spinal cord injured patients with central cord syndrome who had
undergone inpatient rehabilitation, were studied retrospectively with regard to
their demographic, neurologic and functional characteristics. There were 67 males
and six females with a mean age of 53.5 years. Falls was the commonest mechanism
of injury (54.8%) followed by motor vehicle accidents. Eleven patients sustained
cervical fractures and 41 had radiological evidence of cervical spondylosis.
Seventeen patients had sensory impairment and significant spasticity was present
in 14 patients. Significant improvements in the admission/discharge ASIA motor
scores and Modified Barthel Index (MBI) scores (P < 0.001) were noted after
rehabilitation. Ninety-two percent of patients were continent of bladder on
discharge compared to 64.4% on admission. Multiple regression analysis revealed
three factors associated with a better functional outcome, namely, higher
admission MBI scores, absence of spasticity and younger age (P < 0.05).
PMID- 9554017
TI - Iatrogenic hypospadias--a preventable injury?
AB - Iatrogenic hypospadias is a preventable injury to the ventral male urethra
produced by the downward pressure of an indwelling urethral catheter. In spite of
avoiding long-term urethral catheterisation, we have acquired 16 patients with
this injury in the last 9 years either in our unit or discovered in patients
referred to our unit. Although not a life endangering complication, the majority
of such patients find the penile appearance so produced unacceptable. We have
reconstructed any penis that has more than meatal cleavage in a total of six
patients, with good results. The majority of patients have been fully
investigated so that an alternative therapy to catheterisation may be provided.
Where possible a catheter free state has been achieved. If not, a suprapubic
catheter has been inserted. Those not reconstructed were due to reasons of ill
health, and in two instances, due to patient choice.
PMID- 9554018
TI - Alterations in self-perceptions following childhood onset of spinal cord injury.
AB - Most research into psychological aspects of spinal cord injury (SCI) has focused
on adult onset. This is a retrospective study of self-perceptions following a
childhood onset of SCI. Self-esteem, depression and self-perception were examined
in 86 people who had a traumatic SCI before the age of 16. Depression was
measured using the Beck Depression Inventory, and self-esteem using the Culture
Free Self-Esteem Inventory Self-perception was measured using a scale developed
for this study, consisting of 20 adjectives, with participants themselves on
dimensions of 'As I am', 'As I would be without the injury', and 'as I would be
ideally'. The participants' self perceptions of the injured self and the
uninjured self were found to be significantly different on only nine of the 20
adjectives. Low self-perception was found to be associated with low self-esteem
and high depression levels, but independent of age at injury, level of injury and
gender. The change noted by the participants between how they see themselves now
and how they would have been without the injury is not as great as might have
been expected.
PMID- 9554016
TI - Long-term suprapubic catheterisation: clinical outcome and satisfaction survey.
AB - We report on the clinical outcome and satisfaction survey of long-term suprapubic
catheterisation in patients with neuropathic bladder dysfunction. Between early
1988 and later 1995, 185 suprapubic catheters were inserted under direct
cystoscopic vision. Anti-cholinergic therapy was given to all patients with
significant detrusor hyper-reflexia; the catheters clamped daily for two hours
and changed every six weeks. Ultrasonography and assessment of the serum
creatinine were used to assess the upper renal tracts, and the results of the pre
and post-catheter video-cystometrography was used to evaluate bladder
morphology, cystometric capacity, maximum detrusor pressure and the presence of
vesico-ureteric reflux. There were equivalent numbers of males and females. The
follow-up ranges from 3-68 months. Following catheterisation, there was a 50%
reduction in the average maximum detrusor pressure, bladder morphology improved
in 85% of the cases; the bladder capacity and upper renal tracts remained
unchanged. Vesico-ureteric reflux was abolished in 33% of the cases. Complaints
were common consisting of recurrent catheter blockage, persistent urinary leakage
and recurrent urinary tract infections. There was a 2.7% incidence of small bowel
injury with one fatality. However, the general level of satisfaction was high. It
is concluded that suprapubic catheterisation is an effective and well tolerated
method of management in selected patients with neuropathic bladder dysfunction
for whom only major surgery would otherwise provide a solution to incontinence.
We are encouraged to find preservation of renal function with maintained bladder
volumes and reduced maximum detrusor pressures thus justifying the policy of
catheter clamping and anti-cholinergic therapy in the presence of significant
detrusor hyper-reflexia. However, even in expert hands this procedure is not
without hazards.
PMID- 9554019
TI - Premature degenerative shoulder changes in spinal cord injury patients.
AB - Shoulder pain and the resultant dysfunction is an expected problem in individuals
with spinal cord injury. But there is a remarkable lack of information about the
natural history, diagnosis, prevention and long term outcomes. Degenerative
changes may develop prematurely in their shoulders, due to overuse and altered
mechanical stresses, with or without symptoms was the hypothesis of this
prospective study. Information from this study is expected to assist in
identification of high risk SCI individuals, and ultimately in development of
preventive strategies. The shoulders of 53 spinal cord injury patients from the
onset of injury until 15 years duration were subjected to clinical and
radiological examination at the Rehabilitation Institute of Chicago. Thirty-eight
out of 53 (72%) patients demonstrated radiological evidence of degenerative
changes, but only six (11%) complained of pain in the shoulders. This study
demonstrated a correlation between individuals with higher level of wheelchair
activity (72%), higher age (92% above and 8% less than 30 years) and female
gender (89% females versus 65% males) more prone to develop degenerative changes
in the shoulders. Acromioclavicular joint was predominantly affected. Detailed
radiological findings, etiopathological factors and long term recommendations are
discussed. The need for further studies and consistent management strategies are
stressed.
PMID- 9554020
TI - Epidural spinal cord stimulation for the control of spasticity in spinal cord
injury patients lacks long-term efficacy and is not cost-effective.
AB - Epidural spinal cord stimulation has been used to decrease spasticity and spasms
in spinal cord injury patients. However, the long-term benefits of this procedure
have not been determined. We therefore conducted a retrospective study of the
possible long-term efficacy of the epidural spinal cord stimulator for the relief
of symptoms. Seventeen patients were identified who had undergone implantation of
an epidural spinal stimulator. The total number of implantations in these
seventeen patients was 24, (seven patients had undergone a second implantation)
costing a total of $566,400. In only one of the patients was the epidural
stimulator providing symptomatic relief. The epidural spinal cord stimulator
lacks long-term efficacy for the relief of spasticity and pain and is not cost
effective.
PMID- 9554021
TI - Comparison of health-related quality of life in three subgroups of spinal cord
injury patients.
AB - Health-related quality of life (HRQL) was evaluated in three subgroups of spinal
cord injury (SCI) patients: (1) persons who had sustained a pediatric SCI (mean
time from injury 20 years, age at injury 11.3 years, n = 36), (2) newly injured
patients at the beginning of acute rehabilitation (mean age 35.3 years, n = 31),
and (3) patients with a chronic SCI (mean time from injury 4.8 years, mean age at
injury 35.2 years, n = 34). All the patients were clinically examined and
structurally interviewed with a list of questions dealing with details of
anamnestic information about injury, its treatment, possible complications and
persons past and present psycho-social condition. HRQL was assessed by a generic
fifteen-dimensional self-administered instrument (15D). The relative importance
of the 15D dimensions and an overall judgement of health status were measured by
a 0-100 visual analogue scale. Average importance weights of the dimensions of
moving and working differed significantly in the three subgroups. Patients with
pediatric SCI assigned the lowest importance for moving. The newly injured
patients highly valued working capability. The HRQL scores of the patients who
had sustained their injury in childhood were significantly higher than those of
the newly injured patients or chronic patients. The tetraplegic patients
estimated their HRQL significantly lower than patients with incomplete
paraplegia. Of the three subgroups studied, those with pediatric SCI were well
adjusted on the basis of anamnestic information and scored high on HRQL when
compared with the other two subgroups. Patients injured in adulthood rated their
overall HRQL lower and were often unable to return to work. Patients injured in
childhood expressed better performance in physical functions than patients who
had sustained their injury in adulthood. The subgroups did not differ in
psychological functions.
PMID- 9554022
TI - Long-term follow up in lumbar spinal stenosis.
AB - In a retrospective study the charts of 72 patients who had decompressive surgery
for lumbar stenosis between 1987 and 1990 were evaluated. Mean first follow up
was 2.5 years (range 1.5 years to 3.5 years). A second follow up was done 8 years
after surgery via mail. The mean age was 59.7 years (females 63.7, males 55
years). The average interval between the onset of complaints to surgery was 6
years. Claudicatio intermittens was found in 34.7% of cases. Patients were
divided into four groups according to the classification by Arnoldi from 1976.
Laminectomy of hemilaminectomy was performed in 73.6% of cases. In 68.1%
nucleotomy was performed. In the first follow up outcome of patients was good in
73.6%. Complete recovery was noted in 61.1%. 11% were not satisfied with
operative results. Old patients especially benefitted from the operation. In the
second follow up after 8 years only 62.1% of the patients mentioned that their
results were unchanged, good or better than at the first evaluation. The other
37.9% complained of a poorer result.
PMID- 9554023
TI - Aerobic and anaerobic arm-cranking power outputs of males with lower limb
impairments: relationship with sport participation intensity, age, impairment and
functional classification.
AB - Fifty individuals with lower limb impairments including spinal cord injury, polio
and amputations underwent aerobic and anaerobic arm-cranking tests in a
standardized laboratory setting. Based on linear regression models applied with
age as dependent variable aerobic performance variable including HRmax (R =
0.395, P = 0.004), and POaer (R = 0.31, P = 0.021) were subjected to ANCOVA
adjusting for age in order to determine the significance of participation
intensity (competitive vs leisure) and type of physical impairment. Anaerobic
performance variables were not influenced by age and thereby subjected to 1-Way
ANOVA with the same independent variables. Participation intensity and type of
impairment significantly discriminated (P < 0.001) between athletes in all power
variables. Linear regression models have shown moderate but significant (P <
0.001) relationship with functional ability (bases on International Wheelchair
Basketball Federation classification system). In anaerobic mean power (MP)
classification accounted for 42% of the variance, while in anaerobic peak power
(PP) and aerobic Power (POaer) for 38% and 30% respectively. By means of a post
hoc Tukey analysis significant differences were observed between athletes with a
high level paraplegia (class 1) and those with one leg affected by polio or
amputations (classes 4, 4.5). Athletes with low level paraplegia and two legs
affected by polio (classes 2-3.5) had values in-between. Based on the descriptive
evaluation, a three group scheme was conceptualized and resubjected to ANOVA.
Significant intergroup differences were thus obtained only for PP. Descriptive PP
data for each group were transformed into a five category table in order to
provide reference values for fitness-estimation in males with lower limb
impairments of various etiologies.
PMID- 9554024
TI - Problems, struggles and some success with spinal cord injury in Zimbabwe.
AB - Spinal cord injury is a common occurrence in Zimbabwe and carries with it a high
morbidity and mortality. In the past almost all patients discharged from hospital
were dead within a year. Reasons for this high mortality are presented. The
establishment of the National Rehabilitation Centre has had a profound impact on
the survival of these individuals as well as on improving their quality of life.
The results of a retrospective survey on the mortality and life situation of
individuals with spinal cord injuries sustained through trauma are presented.
However major unresolved problems are inadequate housing, lack of financial
support, practically no prospect of employment and depression compounded by
boredom.
PMID- 9554025
TI - Electrocardiographic alterations associated with the hearts of athletes.
AB - Physical conditioning induces numerous cardiovascular adaptations, including
vagotonia and increased cardiac volume and mass. These adaptations characterise
the 'athletic heart' and account for most of the normal variants in the athlete's
electrocardiogram. Common alterations associated with vagotonia include sinus
bradycardia, sinus arrhythmia, junctional escape beats, first degree
atrioventricular block and second degree (Mobitz type I) atrioventricular block.
Common electrocardiographic variants associated with increased cardiac mass and
volume include increased voltage, prominent U waves, intraventricular conduction
delays, early repolarisation and increased QT intervals. It is sometimes
difficult to differentiate the healthy athlete with an athletic heart from the
athletic patient with a diseased heart. Thus, further evaluation may be
warranted, especially when the athlete also presents with hypertension and/or
abnormalities of the cardiovascular physical examination.
PMID- 9554026
TI - Proprioception of the ankle and knee.
AB - Proprioception and accompanying neuromuscular feedback mechanisms provide an
important component for the establishment and maintenance of functional joint
stability. Neuromuscular control and joint stabilisation is mediated primarily by
the central nervous system. Multisite sensory input, originating from the
somatosensory, visual and vestibular systems, is received and processed by the
brain and spinal cord. The culmination of gathered and processed information
results in conscious awareness of joint position and motion, unconscious joint
stabilisation through protective spinal-mediated reflexes and the maintenance of
posture and balance. Clinical research aimed at determining the effects of
articular musculoskeletal injury, surgery and rehabilitation, on joint
proprioception, neuromuscular control and balance has focused on the knee and
ankle joints. Such studies have demonstrated alterations in proprioception
subsequent to capsulo-ligamentous injury, partial restoration of proprioceptive
acuity following ligamentous reconstruction, and have suggested beneficial
proprioceptive changes resulting from comprehensive rehabilitation programmes.
PMID- 9554027
TI - Fluid and carbohydrate replacement during intermittent exercise.
AB - Most studies relating to fluid replacement have addressed the problem of drinking
during prolonged exercise. Fluid replacement is also very important for
intermittent exercise, although it has not been extensively studied. More studies
in this area would help coaches and athletes understand the importance of fluid
balance and carbohydrate supplementation during intermittent exercise. Based on
available data, it can be concluded that: (i) because of high exercise intensity,
sweat loss and glycogen depletion during intermittent exercise are at least
comparable with those during continuous exercise for a similar period of time.
Therefore, the need to ingest a sport drink or replacement beverage during
intermittent exercise may be greater than that during continuous exercise in
order to maintain a high level of performance and to help prevent the possibility
of thermal injury when such activity occurs in a warm environment; (ii) the
volume of ingested fluid is critical for both rapid gastric emptying and complete
rehydration; and (iii) osmolality (250 to 370 mOsm/kg), carbohydrate
concentration (5 to 7%), and carbohydrate type (multiple transportable
carbohydrates) should be considered when choosing an effective beverage for
rehydration and carbohydrate supplementation during intermittent exercise.
PMID- 9554032
TI - Use of the zebrafish (Danio rerio) to define hematopoiesis.
AB - Hematopoiesis in the vertebrate is characterized by the induction of ventral
mesoderm to form hematopoietic stem cells and the eventual differentiation of
these progenitors to form the peripheral blood lineages. Several genes have been
implicated in the differentiation and development of hematopoietic and vascular
progenitor cells, yet our understanding of the discrete steps involved in the
induction of these cells from the ventral mesoderm is still incomplete. One
method of delineating these processes is based on the use of lower vertebrates.
The zebrafish (Danio rerio) is an especially robust vertebrate system for both
isolating and characterizing genes involved in these processes. Hematopoietic
mutants have been generated with defects in many of the steps of both the
primitive and definitive hematopoietic programs. Cloning of the genes that
underlie these mutations should yield valuable details of hematopoiesis and may
have therapeutic implications for bone marrow transplantation and stem cell gene
therapy.
PMID- 9554030
TI - Shoulder injuries from alpine skiing and snowboarding. Aetiology, treatment and
prevention.
AB - There has been a decrease in the overall injury rate and the rate of lower
extremity injuries for alpine skiing, with a resultant increase in the ratio of
upper extremity to lower extremity injuries. Upper extremity injuries account for
20 to 35% of all injuries during alpine skiing and nearly 50% of all injuries
during snowboarding. The most common upper extremity injuries during skiing are
sprain of the thumb metacarpal-phalangeal joint ulnar collateral ligament, and
the most common in snowboarding is wrist fracture. Shoulder injuries from skiing
and snowboarding have been less well characterised. With the increased ratio of
upper to lower extremity injuries during alpine skiing and the boom in popularity
of snowboarding, shoulder injuries will be seen with increasing frequency by
those who care for alpine sport injuries. Shoulder injuries account for 4 to 11%
of all alpine skiing injuries and 22 to 41% of upper extremity injuries. The rate
of shoulder injuries during alpine skiing is 0.2 to 0.5 injuries per thousand
skier-days. During snowboarding, shoulder injuries account for 8 to 16% of all
injuries and 20 to 34% of upper extremity injuries. Falls are the most common
mechanism of shoulder injury, in addition to pole planting during skiing and
aerial manoeuvres during snowboarding. Common shoulder injuries during skiing and
snowboarding are glenohumeral instability, rotator cuff strains,
acromioclavicular separations and clavicle fractures. Less common shoulder
injuries include greater tuberosity fractures, trapezius strains, proximal
humerus fractures, biceps strains, glenoid fractures, scapula fractures, humeral
head fractures, sterno-clavicular separations, acromion fractures and biceps
tendon dislocation. Prevention of shoulder injuries during skiing and
snowboarding may be possible through interventions in education and technique,
conditioning and equipment and environment.
PMID- 9554031
TI - An intricate Web: chemokine receptors, HIV-1 and hematopoiesis.
AB - Cellular infection by the human immunodeficiency virus type 1 (HIV-1) requires
interaction of the viral envelope protein with CD4 and at least one additional
cell surface molecule, termed a "cofactor" or "coreceptor." Recent discoveries
have determined that macrophage-tropic strains of HIV-1 which are largely
responsible for sexual transmission require the beta-chemokine receptor CCR5 in
addition to CD4, while the T cell tropic viruses that emerge later after
infection use the alpha-chemokine receptor CXCR4. Thus, both CD4 and the
appropriate chemokine receptor must be expressed on the cell surface in order for
HIV-1 to enter the cell and establish an infection. The in vivo importance of
CCR5 for HIV-1 is demonstrated by the finding that individuals homozygous for a
32 bp deletion (delta 32) in the CCR5 gene that renders them effectively CCR5
negative are highly resistant to virus infection. In this review, the structure
function correlates of the chemokine receptors that serve as major coreceptors
for HIV-1 and simian immunodeficiency virus entry will be reviewed. Since certain
chemokines have been implicated as stem cell inhibitory factors, the biological
consequences of chemokine receptor expression as it relates to HIV-1-associated
hematodyspoiesis will also be discussed.
PMID- 9554029
TI - Impact of resistance training on endurance performance. A new form of cross
training?
AB - In accordance with the principles of training specificity, resistance and
endurance training induce distinct muscular adaptations. Endurance training, for
example, decreases the activity of the glycolytic enzymes, but increases
intramuscular substrate stores, oxidative enzyme activities, and capillary, as
well as mitochondrial, density. In contrast, resistance or strength training
reduces mitochondrial density, while marginally impacting capillary density,
metabolic enzyme activities and intramuscular substrate stores (except muscle
glycogen). The training modalities do induce one common muscular adaptation: they
transform type IIb myofibres into IIa myofibres. This transformation is coupled
with opposite changes in fibre size (resistance training increases, and endurance
training decreases, fibre size), and, in general, myofibre contractile
properties. As a result of these distinct muscular adaptations, endurance
training facilitates aerobic processes, whereas resistance training increases
muscular strength and anaerobic power. Exercise performance data do not fit this
paradigm, however, as they indicate that resistance training or the addition of
resistance training to an ongoing endurance exercise regimen, including running
or cycling, increases both short and long term endurance capacity in sedentary
and trained individuals. Resistance training also appears to improve lactate
threshold in untrained individuals during cycling. These improvements may be
linked to the capacity of resistance training to alter myofibre size and
contractile properties, adaptations that may increase muscular force production.
In contrast to running and cycling, traditional dry land resistance training or
combined swim and resistance training does not appear to enhance swimming
performance in untrained individuals or competitive swimmers, despite
substantially increasing upper body strength. Combined swim and swim-specific 'in
water' resistance training programmes, however, increase a competitive swimmer's
velocity over distances up to 200 m. Traditional resistance training may be a
valuable adjunct to the exercise programmes followed by endurance runners or
cyclists, but not swimmers; these latter athletes need more specific forms of
resistance training to realise performance improvement.
PMID- 9554033
TI - Characterization of natural suppressor cells in human bone marrow.
AB - Natural suppressor (NS) cells, which exert nonspecific suppressive activity in an
unprimed manner, have been found in mouse, rabbit and monkey bone marrow (BM). In
the present study, we characterize NS cells in human BM. NS activity was found in
a fraction of low density (1.055-1.065 g/ml) BM cells that had been depleted of T
cells, B cells, and monocytes. The NS activity was significantly decreased by the
depletion of CD34+ or CD33+ cells but not CD56+ cells. The NS activity was indeed
detected in isolated CD34+ cells and further enriched in CD34+CD33+ cells.
Hematopoietic progenitor cells committed to the myeloid lineage were also
enriched in the CD34+CD33+ cells, which significantly correlated to the NS
activity. From these findings, it is strongly suggested that NS activity in human
BM is exerted by the myeloid hematopoietic progenitors. Since cell-to-cell
contact was not necessary for the action, NS cells seemed to secrete soluble
mediator(s). Transforming growth factor-beta 1 and leukemia inhibitory factor
were, however, not the candidates, based on experiments using neutralizing
antibodies.
PMID- 9554028
TI - The effects of strength training and disuse on the mechanisms of fatigue.
AB - Increases in force, electromyography, reflex potentiation, muscle action
potential amplitude and protein synthesis occur with strength training. Training
induced increases in the efficiency of the neuromuscular system and capacity of
the muscle to generate force result in an improved ability to cope with a
submaximal load. There is also some evidence of improved fatigue resistance with
maximal contractions which could be attributed to a prolongation of membrane
excitation or decreased antagonist activity with training. On the other hand,
although a variety of factors including strength are diminished with disuse, a
number of studies have demonstrated no significant difference in the rate of
fatigue with maximal contractions (fatigue index) between trained, untrained and
disused muscle. Equivalent control and disuse fatigue indexes in some studies
might be attributed to decreased muscle activation resulting in a comparison of
maximal (control) and submaximal (disuse) efforts. Furthermore, increases in the
duration of muscle membrane electrical propagation with disuse may increase the
quantity of Ca++ released, augmenting force production. In addition, the smaller
volume of disused muscle may allow a more efficient diffusion of oxygen and
energy substrates in comparison with a hypertrophied muscle.
PMID- 9554034
TI - Estimation of extent of cell death in different stages of normal murine
hematopoiesis.
AB - Murine hematopoiesis has been analyzed by many authors, and available data allow
for quantitative evaluation of this dynamic process. In this study, the capacity
of several populations of the bone marrow clonogenic cells (progenitors) to
produce blood cells was compared with their actual production. The cell cycle
progression rate was directly measured in the following types of hematopoietic
progenitors: day 8 colony-forming units-spleen, GM-colony-forming cells, BFU-E,
and CFU-E in normal mice. The cell cycle progression rates of the individual
progenitors, together with their numbers in the whole hematopoietic tissue, were
used to calculate the absolute numbers produced daily in each population. The
data reviewed from literature were analyzed in parallel. The capacity of the
progenitors to produce mature blood cells were derived from the daily production
of progenitors multiplied by their clonogenic potential. This theoretical
capacity to produce blood cells was compared to the actual blood cell production
determined from the turnover of circulating blood elements. The comparison
strongly suggested an intensive cell death rate occurring at the early stages of
differentiation and its decline as the hematopoietic cells become more
differentiated and mature.
PMID- 9554035
TI - Stem cell factor improves the repopulating ability of primitive hematopoietic
stem cells after sublethal irradiation (and, to a lesser extent) after bone
marrow transplantation in mice.
AB - Bone marrow transplantation (BMT) and sublethal irradiation (XRT) cause profound
long-term damage to hematopoietic stem cells. We used the competitive
repopulation assay in mice to test the ability of granulocyte-macrophage colony
stimulating factor (GM-CSF) and stem cell factor (SCF), cytokines given in
clinical settings to enhance marrow recovery after XRT or BMT and to protect the
marrow repopulating ability of primitive hematopoietic stem cells (PHSC) after
these modalities. The repopulating ability of exhaustible multilineage
progenitors (EMP) was also tested after these modalities, with or without
cytokines. Repopulating abilities of EMP and PHSC were significantly reduced
after XRT or BMT; PHSC were preferentially affected. Administration of SCF to
C57B6/J mice after XRT resulted in improved EMP and PHSC repopulating ability,
although progenitor numbers--repopulating units--were not completely returned to
control levels. Whether given as a single dose or multiple doses, GM after XRT
did protect PHSC function from the deleterious effects of XRT, but this was not a
significant effect. SCF caused an increase in PHSC repopulating ability after
BMT, but this too was not a significant difference. GM after BMT had little
effect. SCF administration before XRT led to severe impairment of PHSC function
with very little or no stem cell activity observed. Therefore, timing of its
administration is an important consideration since preadministration of the
cytokine before XRT can be extremely harmful to PHSC function.
PMID- 9554036
TI - Cell adhesion molecule expression in cord blood CD34+ cells.
AB - Self-renewal, proliferation, differentiation, homing, and mobilization of
hematopoietic progenitor cells (HPCs) are regulated by a complex mechanism that
involves the bone marrow (BM) microenvironment. Cell adhesion molecules (CAMs)
expressed on HPCs and on endothelial and stromal cells play a pivotal role in
this process. In this study, we have used three-color cytofluorometric analysis
to compare CAM expression in the subsets of cord blood (CB) and BM HPCs and
examined the effect of a short exposure to various cytokines on L-selectin
expression. The study was carried out on unseparated samples to avoid any
possible bias from positive CD34 selection. CAMs were highly expressed in both CB
and BM CD34+CD38+ cells. In this population, L-selectin, H-CAM, and LFA-1 were
significantly more expressed in BM than in CB. With regard to the more immature
progenitors, the subsets of CD34+/CD38-/L-selectin+ and CD34+/CD38-/LFA1+ cells
were significantly larger in CB than in BM. Since the expression of such CAMs has
been related to the repopulating capacity of HPCs, our results suggest a possible
advantage in homing and engraftment of more undifferentiated CB as opposed to BM
HPCs. A 4/24-h exposure to various cytokines significantly increased the
percentage of CB CD34+/CD38+/L-selectin+ cells, while HPCs were differentiated
since the percentage of CD34+/CD38-/L-selectin+ cells was reduced. These data
show that a short exposure to cytokines increases L-selectin expression in the
more differentiated CB HPCs. This could improve their homing in a transplant
setting.
PMID- 9554037
TI - Kinetics of hematopoiesis in Dexter-type long-term cultures established from
human umbilical cord blood cells.
AB - In the present study, we have established Dexter-type long-term cultures (D-LTC)
from human umbilical cord blood (UCB) and followed the kinetics of different
hematopoietic progenitor cells (HPCs)--including multipotent (colony forming unit
[CFU]-Mixture), erythroid (CFU-erythroid, BFU-E), and myeloid (CFU-granulocyte,
CFU-macrophage, CFU-granulocyte/marcophage) progenitors as well as of
morphologically recognizable erythroid, myeloid and lymphoid cells--during a nine
week culture period. D-LTC were also established from adult bone marrow (BM) as
controls. On day 0, both UCB and BM showed similar total numbers of HPCs (about
310/10(5) cells), however, UCB showed a higher proportion of primitive HPCs
(i.e., CFU-Mixture, CFU-granulocyte/macrophage and BFU-E). A poor adherent cell
layer, consisting almost exclusively of macrophages, was developed in UCB D-LTC
and this correlated with a continuous decline in HPC numbers throughout the
culture period. In contrast, adherent cell numbers in BM D-LTC, including
fibroblasts and macrophages, were two- to fourfold higher than in UCB cultures,
and the numbers of HPCs were also significantly higher, reaching plateau levels
between weeks 6 and 9. In both types of cultures, erythroid and multipotent
progenitors declined relatively fast, reaching undetectable levels after five
weeks of culture. Myeloid progenitors, on the other hand, were sustained longer
(always at higher levels in BM cultures) and were still detected by week 9. Among
myeloid progenitors, a shift towards the predominance of macrophage HPCs was
observed, both in UCB and BM D-LTC, and this correlated with an increase in the
proportion of mature monocytes and macrophages. Taken together, our results
indicate that myeloid progenitor cell growth is deficient in UCB D-LTC and
suggest that this is due to the impaired development of an adherent cell layer,
unable to provide the factors and conditions required for their growth.
Interestingly, throughout the culture period the total numbers of multipotent and
erythroid progenitors were similar both in UCB and BM cultures regardless of the
number and types of adherent cells present; this suggests that the stroma
developed in D-LTC is not sufficient for the proliferation of these progenitor
cells.
PMID- 9554040
TI - Simplified retroperfusion system preserves the myocardial function during acute
coronary artery occlusion.
AB - It is known that coronary venous retroperfusion restores the blood flow to the
ischemic myocardium, resulting in reduction of infarct size and improvement in
left-ventricular pump function. In this study, we used an animal model to
investigate the effects of a simplified coronary venous retroperfusion system on
myocardial hemodynamics. Twenty dogs were entered in this study. All dogs
underwent fifteen minutes occlusion of the left anterior descending artery. For
the rest of the experiment the dogs were randomized into two groups: the control
group (n = 10) underwent a further 2 hours left anterior descending artery
occlusion, then clamps were released and the animals were observed for 6 hours.
In the retroperfusion group (n = 10) a simple aortocoronary sinus connection was
made and retrograde perfusion achieved with an outflow of 43 +/- 6 ml/min.
Retrograde coronary sinus perfusion was maintained for three hours and then the
dogs were observed for six hours. Tissue adenosine triphosphate levels were 6 +/-
3 mumol/g in the control group and 12 +/- 2 mumol/g in the retroperfusion group
(p < 0.05) 6 hours after reperfusion. Creatine phosphokinase levels were 99 +/-
11 IU/L in the control group and 42 +/- 8 IU/L in the retroperfusion group 6
hours after reperfusion (p < 0.05). Cardiac index was 63 +/- 4 ml/kg/min in the
control group and 79 +/- 2 ml/kg/min in the retroperfusion group 6 hours after
retroperfusion (p < 0.05). Left-ventricular stroke-work index at a pulmonary
capillary artery wedge pressure of 20 mmHg was 0.54 +/- 0.06 g.m/kg in the
retroperfusion group and 0.29 +/- 0.03 g.m/kg in the control group 6 hours after
reperfusion (p < 0.05). It is concluded that myocardial hemodynamic and
biochemical function can be preserved by simplified coronary sinus
retroperfusion.
PMID- 9554038
TI - Identification by differential display of transcripts regulated during
hematopoietic differentiation.
AB - The polymerase chain reaction-based differential display method (DDRT-PCR) was
used to identify mRNAs differentially expressed during the maturation of human
CD34+ progenitor cells stimulated to differentiate in vitro towards
granulomonocytic or erythroid lineages with a mixture of hemopoietins (kit ligand
+ interleukin 3 + GM-CSF in the absence or presence of erythropoietin,
respectively). Three cDNA transcripts (B32, B41, and B56) display differential
expression during cytokine-induced maturation of CD34+ cells. These clones have
no homology with already-described sequences. Primer extension cofirmed the
presence of the corresponding mRNA. The levels of mRNA corresponding to B32 are
enhanced in the later phases of the granulomonocytic as well as in the erythroid
differentiation of CD34+ cells. The mRNA identified by B41 was induced by a late
stage in only granulomonocytic differentiation of CD34+ cells. The mRNA
corresponding to B56 was instead present in nonstimulated CD34+ cells, declined
in the early stages of differentiation, and reappeared at later stages in cells
treated with both combinations of cytokines. Expression of these genes was
detected in a number of acute myelogenous leukemias, as well as in some leukemic
cell lines. B32 and B41 were downregulated in KG-1 cells induced to differentiate
towards the monocytic lineage, whereas the levels of B56 were unchanged. In K562
cells, clones B41 and B56 were downregulated only in the late phases of PMA
induced megakaryocytic differentiation and during erythroid differentiation. B32
was rapidly downregulated when K562 cells were induced to differentiate towards
either megakaryocytic or erythroid phenotypes. These transcripts represent novel
hematopoietic cDNAs that should prove of value for the study of human blood cells
and their disorders.
PMID- 9554039
TI - Influence of rhG-CSF scheduling on megakaryocytopoietic recovery following 5
fluorouracil-induced hematotoxicity in splenectomized B6D2F1 mice.
AB - Recombinant human granulocyte colony-stimulating factor, rhG-CSF, is widely
applied to ameliorate neutropenia following chemotherapy. However, rhG-CSF can
exert negative effects on megakaryocytopoiesis that might cause a delay of
megakaryocyte recovery. Therefore, the present study was designed to test
different rhG-CSF administration protocols with regard to their megakaryocytic
inhibitory potential in a 5-fluorouracil (5-FU)-induced experimental model
system. Splenectomized B6D2F1 mice received a single injection of 5-FU (150
mg/kg) on day 0 followed by 50 micrograms/kg/day rhG-CSF given daily for either
zero, four, or eight days. Five days after 5-FU, bone marrow and blood
hematopoiesis were reduced significantly when compared with controls, independent
of whether or not animals received rhG-CSF. However, nine days after 5-FU,
granulopoietic recovery from 5-FU-induced toxicity was faster for rhG-CSF-treated
versus untreated mice as demonstrated by higher values for colony forming unit
granulocyte macrophage (CFU-GM) and granulocytes (CFU-GM: 7.2 +/- 0.4 versus 5 +/
0.6 x 10(4)/femur, granulocytes: 4.3 +/- 2 versus 1.4 +/- 0.4 x 10(5)/ml,
respectively). Furthermore, significant mobilization of CFU-megakaryocyte (CFU
Meg) and CFU-GM into the peripheral blood was induced by the eight-day
administration of rhG-CSF following 5-FU (day 9: 911 +/- 102 CFU-Meg/ml, 2330 +/-
152 CFU-GM/ml). However, megakaryocytic cells in these same mice were
considerably lower when compared with those of animals receiving no rhG-CSF (CFU
Meg: 2.7 +/- 0.2 x 10(3) versus 4.2 +/- 0.2 x 10(3)/femur; small
acetylcholinesterase positive (SAChE+) cells: 4.9 +/- 0.3 x 10(3) versus 7.3 +/-
0.9 x 10(3)/femur; megakaryocytes: 2.5 +/- 0.2 x 10(3) versus 4.1 +/- 0.7 x
10(3)/femur; platelets: 2.67 +/- 0.5 x 10(9) versus 3.1 +/- 0.5 x 10(9)/ml,
respectively). On the other hand, the shortening of the rhG-CSF treatment from
eight to four days caused a rapid granulopoietic recovery comparable to animals
receiving eight days of G-CSF with no significant delay in megakaryocytic
recovery when compared with mice treated with 5-FU alone; however, with four days
of rhG-CSF, the mobilization of CFU into the peripheral blood was significantly
less effective. Taken together, the results showed that a shortening of rhG-CSF
treatment after chemotherapy is capable of ameliorating neutropenia without
negatively affecting megakaryocytopoietic recovery. If, however, maximum
recruitment of CFU into the peripheral blood circulation by rhG-CSF for
subsequent harvest and transplantation is needed, any shortening of rhG-CSF
administration is not advisable.
PMID- 9554041
TI - An assessment of selective cerebral perfusion via the innominate artery in aortic
arch replacement.
AB - Maintaining an adequate cerebral oxygen supply is a serious problem in aortic
arch surgery. Deep hypothermic circulatory arrest is the most common method used
for cerebral protection, but guarantees only a time-limited safety period. Based
on experimental investigations, we applied selective cerebral perfusion via the
innominate artery alone with only moderate hypothermia (28 degrees C) and without
circulatory arrest in 25 consecutive patients undergoing surgical treatment of an
aneurysm (n = 10) or acute type-A dissection (n = 15) involving the aortic valve
and arch. In every case a test perfusion was carried out to assess whether the
cerebral perfusion achieved would be adequate for the whole operation. In no case
was the perfusion inadequate. As a new perioperative monitoring system, we used
computer-aided topographical electroencephalometry (CATEEM). There were 18 male
and 7 female patients, their age was 47.0 +/- 15.1 years (mean +/- SD). Mean time
periods were 155.1 +/- 37.3 min for aortic cross-clamping, and 69.3 +/- 35 min
for selective cerebral perfusion. Postoperatively, two patients (8%) revealed a
temporary left-sided hemiparesis, and 4 patients (16%) died within 30 days. The
overall mortality rate was 16% in a follow-up period of 24.2 +/- 9.5 months. In
this small group the CATEEM monitoring enabled an intraoperative selection of
patients with sufficient bihemispheric collateral circulation and therefore
suitable for simple innominate artery perfusion.
PMID- 9554042
TI - Composite graft replacement of the aortic root in 335 patients with aneurysm or
dissection.
AB - The hypothesis that replacement of the aortic root with a valved composite graft
is a safe and effective therapy for aneurysms involving the sino-tubular segment
of the aorta was tested by a retrospective review. From September 1978 to January
1995, 335 consecutive patients underwent prosthetic aortic root replacement as
the primary operation for aneurysm (222) or dissection (acute 59, chronic 54).
There were 248 men (74%) and 87 women (26%) with a mean age of 50 +/- 14 years.
22 patients (6.6%) experienced hospital death primarily due to cardiac causes.
Mortality was significantly higher in patients with acute dissection versus those
with non-dissecting aneurysms and chronic dissection. Sex, Marfan syndrome (20.3%
of patients), mitral regurgitation, coronary artery disease, and era of operation
had no effect on early outcome. Mortality was significantly increased in patients
aged over 50 years, in those with circulatory compromise, and in patients
requiring emergency operation. Follow-up was complete in 313 survivors (97%) at a
mean of 61.3 +/- 44 months. Actuarial survival was 80% at 5 and 67% at 10 years.
There were no complications involving the coronary anastomoses, other than
infection-related, regardless of the mode of ostial reattachment.
PMID- 9554043
TI - Risk indicators for cerebrovascular complications after coronary artery bypass
grafting.
AB - All patients from western Sweden were retrospectively studied in whom CABG was
performed between June 1, 1988 and June 1, 1991 without simultaneous valve
surgery. The aim was to detect clinical factors prior to and at the time of
coronary artery bypass grafting (CABG) which were associated with the risk of
neurological complications during the postoperative hospital stay. A neurological
complication during the hospital stay was registered if a neurological
consultation was made and if this consultation diagnosed a neurological deficit.
In all, there were 2121 patients in the study, of whom 81 (3.8%) had a
neurological complication. 23 of the latter (28%) died before discharge. Among
preoperative factors the following appeared as significant independent predictors
of a neurological complication: a history of cerebrovascular disease (p < 0.001),
diabetes mellitus (p < 0.01), hypertension (p < 0.05), degree of urgency of the
operation (p < 0.01), and age (p < 0.01). Among pre- and post-operative events
the following predicted a neurological complication: intensive care unit
treatment for more than two days (p < 0.001) and respirator required for more
than 24 hours (p < 0.001).
PMID- 9554044
TI - An experimental approach to quantitative thermal coronary angiography.
AB - Thermal coronary angiography is a noninvasive but not yet quantitative method to
intraoperatively assess graft patency in CABG surgery. Aim of this study was to
quantify graft flow by measuring perfusion-induced myocardial temperature changes
over time. Saphenous vein grafts to the left anterior descending artery were
perfused at flow rates of 16-105 ml/min with warm saline. A thermal scanner with
a 256 x 256 focal-plane array detector providing a spatial resolution of 1.2 mrad
was used. The resulting temperature curves were averaged and a non-linear fit
procedure was performed to calculate the time constant (tau) at each flow rate.
An increase of myocardial temperature along the LAD with different flow rates
could be demonstrated. There was an excellent correlation between the calculated
time constant and actual flow (r = 0.96, p < 0.0002). By determining the time
constant for different flow rates an estimate of actual graft flow is possible
using thermal coronary angiography. Clinical studies have to show if the time
constant can be used as a predictor of graft flow in patients.
PMID- 9554045
TI - Preconditioning enhances myocardial protection in patients undergoing open heart
surgery.
AB - To date, ischemic preconditioning is regarded as the most powerful form of
endogenous myocardial protection. For the purpose of surgical myocardial
protection, a few clinical studies have investigated the effects of ischemic
preconditioning in conjunction with hypothermia or blood cardioplegia during open
heart surgery, but the results were controversial. We now tested the hypothesis
that preconditioning improves myocardial protection in patients undergoing cold
crystalloid cardioplegic arrest. 36 patients needing mitral prosthetic valve
replacement for rheumatic heart disease were studied. Patients were evenly
divided into two groups at random. Preconditioning was elicited by two cycles of
3 minutes ischemia by occlusion of vena cava and aortic cross-clamping followed
by 2 minutes reperfusion under cardiopulmonary bypass. All hearts were arrested
using 4 degrees C St. Thomas' Hospital solution before the intracardiac operative
program. Myocardial protective effects were mainly assessed by electrocardiac
activities, leakage of myocardial enzymes, myocardial contractility, and early
postoperative recovery. The results indicated that there was a significant
reduction of ST-segment shifting (ST-segment elevation, 0.07 +/- 0.02 vs 0.22 +/-
0.07 mV, p < 0.05, at 4 hours post reperfusion) and smaller release of creatine
kinase-MB (87 +/- 11.5 vs 143 +/- 17.2 IU/L, p < 0.05, at 12 hours post
reperfusion) in the preconditioning group. Preconditioning also enhanced
myocardial contractility (dp/dtmax = 1490 +/- 75 vs 1280 +/- 88 mmHg/sec, at 30
minutes post reperfusion, p < 0.05) and promoted early postoperative recovery.
The present study suggests that ischemic preconditioning reduces ischemia
reperfusion injury in human hearts even when combined with cold crystalloid
cardioplegia.
PMID- 9554046
TI - Everting closure for interrupted aortic arch, ventricular septal defect, and
severe subaortic stenosis.
AB - Interrupted aortic arch with ventricular septal defect in the neonate is
sometimes complicated by severe subaortic stenosis from posterior deviation of
the infundibular septum. We have developed a novel approach to the treatment of
this condition. The infundibular septum is penetrated from the right-ventricular
side to the left-ventricular outflow tract. It is compressed with patch fixation.
The lower margin of the infundibular septum is everted. Three consecutive
neonates were treated. The smallest diameters of the left-ventricular outflow
tract were 3,4, and 2.5 mm. All patients survived the operation and were
discharged from the hospital. They remained well 2 to 7 years after the repair
and were in normal sinus rhythm without a left bundle branch block or any
significant pressure gradient between the upper and lower extremities. Follow-up
two-dimensional and Doppler echocardiography demonstrated no residual shunt, no
left-ventricular outflow-tract pressure gradient, and no aortic regurgitation.
This technique provides effective widening of the left-ventricular outflow tract,
and is more safely and easily performed than conventional methods.
PMID- 9554047
TI - Morbidity after transsternal thymectomy for myasthenia gravis: a changing
perspective?
AB - A detailed assessment of recent changes in morbidity and mortality after
transsternal thymectomy for myasthenia gravis is pending. To this end, a
retrospective analysis was carried out of morbidity and mortality rates in 125
patients subjected to transsternal thymectomy for myasthenia gravis in the
periods 1976-85 (1st decade) and 1986-95 (2nd decade). Composition of patients
did not change much over time, except for more concomitant preoperative disease
in the second decade (p = 0.001). None the less, complication rates were not
higher, nor did the pattern of complications alter. Mortality was nil in both
decades. There was no difference over the decades as to length of ventilation,
intensive care treatment, or overall hospitalization. Most complications did not
reveal a monocausal relationship, suggesting that a combination of risk factors
was implicated. Further reductions in future morbidity rates after transsternal
thymectomy for myasthenia gravis seem unlikely as patient preoperative state is
unlikely to improve. In the light of the deteriorating preoperative patient
condition, constant postoperative morbidity rates indicate that patient care has
in fact improved.
PMID- 9554048
TI - 'No touch' technique for coronary anastomoses with arterial grafts.
AB - We describe a simple no-touch technique for facilitating coronary anastomosis
using different arterial grafts. To accomplish this technique it is necessary to
make a cut near the end of the graft creating a "cuff". Holding this cuff during
the anastomosis steadies the graft, which simplifies the suturing technique and
facilitates precise anastomosis.
PMID- 9554049
TI - Preoperative estimation of resectable trachea by the cervical approach in surgery
for tracheal stenosis.
PMID- 9554050
TI - Pulmonary artery trunk leiomyosarcoma.
AB - Pulmonary artery leiomyosarcomas are rare tumors. They cause symptoms suggestive
of recurrent pulmonary emboli. As in the case reported here, the diagnosis is
virtually never considered initially, despite modern diagnostic imaging methods,
but usually made at autopsy or at histologic examination of material removed from
the pulmonary artery at surgery. The prognosis remains poor and prolongation of
life up to 6 months has not been clearly demonstrated with radical excision in
conjunction with radiotherapy. The difficulty is the accurate diagnosis required
to consider these tumors for curative resection, which is the only hope for a
longer disease-free course.
PMID- 9554051
TI - Video-assisted thoracoscopy in single-stage resection of a para-aortic posterior
mediastinal dumbbell tumor.
AB - We report the successful single-stage thoracoscopic resection of a neurogenic
mediastinal dumbbell tumor close to the aortic arch, using a combined posterior
approach. A 63-year-old asymptomatic male was referred to our hospital for
evaluation of an abnormal round shadow in the left thoracic cavity on a chest
radiograph. He was diagnosed to have an intrathoracic and intraspinal neurogenic
dumbbell-shaped tumor close to the aortic arch. Surgery combined both a
laminectomy and thoracoscopic tumor resection. The tumor was lysed as deeply as
possible via a posterior approach, then with the patient in the right lateral
position the pleura around the tumor on the aortic side was clipped and
cauterized thorocoscopically, freeing the tumor completely and allowing it to be
extracted in toto.
PMID- 9554053
TI - Video-assisted thoracoscopic surgery in the management of acute purulent
mediastinitis and pleural empyema.
AB - Management of acute purulent mediastinitis requires broad-spectrum antibiotics
and proper surgical drainage-routine use of thoracotomy is recommended by several
authors. We describe two cases where video-assisted thoracoscopic surgery (VATS)
was used instead of thoracotomy. Etiology of mediastinitis in one patient was a
stab wound and in the other an iatrogenic esophageal perforation. In addition,
the first patient had purulent pericarditis and suppurated haemothorax and the
second a pleural empyema. In both cases VATS allowed debridement of the entire
thoracic cavity and subsequent drainage of the mediastinum. Continuous irrigation
was used postoperatively until pleural fluid became clear. Both patients
recovered without a need for further surgical treatment. They are doing well 8
and 9 months later. Adequate debridement and drainage of pleural empyema and
mediastinitis can be achieved using VATS instead of a thoracotomy approach.
PMID- 9554052
TI - Coronary artery bypass grafting by median sternotomy in patients with a
tracheostoma.
AB - The approach to the heart for open heart surgery in patients with a tracheostoma
requires careful consideration. The presence of a tracheostoma interferes with
the standard sternotomy and increases the risk of mediastinitis. We have
successfully performed coronary artery bypass grafting in two patients with a
tracheostoma using the limited median sternotomy and describe the surgical
procedure used in these patients.
PMID- 9554054
TI - Complete intercostal artery reimplantation using a method of aneurysmoplasty.
AB - We report the case of a 58-year-old woman who underwent repair of a chronic
dissecting thoracoabdominal aortic aneurysm. Using a method of aneurysmoplasty
under normothermic cardiopulmonary bypass, all intercostal arteries were quickly
reperfused, and the spinal cord ischemic time was minimized. No neurological
deficits developed in our patient using this method.
PMID- 9554055
TI - The skin sensitization potential of four alkylalkanolamines.
AB - The skin sensitization potential of 4 alkylalkanolamines (N-methylethanolamine,
N,N-dimethylethanolamine, N-methyldiethanolamine and N,N-diethylethanolamine),
was evaluated in a guinea pig maximation procedure by the method of Magnusson and
Kligman. While all 4 alkylalkanolamines tested were irritating to the guinea pig
skin, only N-methylethanolamine showed potential to induce allergic contact
dermatitis. None of the remaining 3 alkylalkanolamines exhibited clear skin
responses suggestive of sensitization.
PMID- 9554056
TI - Toxicity of Rhazya stricta to sheep.
AB - The toxicity of Rhazya stricta leaves for Najdi sheep is described in 9 sheep
assigned as untreated controls, Rhazya-treated at 0.25 g/kg/d and Rhazya-treated
at 1 g/kg/d. The oral use of 1 g/kg/d caused body weight depression, ruminal
bloat, diarrhea, dyspnea and weakness of the hind limbs. Enterohepatonephropathy,
pulmonary congestion, hemorrhage and emphysema, lymphocytes in vital organs, and
congestion of the blood vessels of the heart were associated with increases in
serum AST and LDH, in elevated bilirubin and urea concentrations, and decreased
total protein, albumin and calcium concentrations, and leucopenia and anemia.
PMID- 9554057
TI - Cytochrome P450 enzyme activities in the Australian brushtail possum trichosurus
vulpesula: a comparison with the rat, rabbit, sheep and chicken.
AB - A comparative study of cytochrome P450 phase 1 biotransformation enzyme
activities of the Australian brushtail possum was conducted. Since its
introduction to New Zealand this animal pest has caused considerable agricultural
and ecological problems. The objective of this work was to probe for potential
biochemical weaknesses that may be exploited for designing a more species
specific method of toxicological control of the possum population in New Zealand.
Liver microsomal enzyme content and the kinetics of in vitro biotransformation
reactions in the possum were quantified and compared with those of the rabbit,
rat, chicken and sheep. Significant (p > 0.05) species variations in the liver
cytochrome P450 enzyme content were observed. All mammals, including the possum,
had considerably higher cytochrome P450, cytochrome b5 and cytochrome reductase
levels than the chicken. The chicken had the highest specific phase 1
biotransformation activity (Vmax) for all except 1 of the 8 xenobiotics tested.
Among the mammals studied, P450 (Vmax) values in the possum were similar or
higher than in the rabbit, rat or sheep. The Km values varied significantly (p >
0.05) between species. The Km for 7-hydroxylation of coumarin was highest in the
rat. In comparison with other species, the possum had a lower Km for aromatic
hydroxylation of aniline, N-demethylation of N,N-dimethyl aniline, and N-dimethyl
aniline, but a higher Km for 0-demethylation of 7-methoxycoumarin, 7
hydroxylation of coumarin, and 0-deethylation of acetophenetidin. It was
concluded that phase 1 biotransformation of xenobiotics in the possum is similar
to or more efficient than in the other animals tested.
PMID- 9554058
TI - Effect of combined fenthion and cimetidine use in rats on lethality, blood
cholinesterase activities, and serum cholinesterase isoenzymes.
AB - H2-receptor antagonists inhibit cholinesterase (ChE) activity. We examined
perturbations in ChE isoenzyme patterns and ChE activities of rats from the
combined effects of fenthion (FEN) and cimetidine (CIM). Sixty-four female
Sprague-Dawley rats were divided into 8 groups. Four rat groups were given FEN or
gum arabic solution and each group divided into 2 small groups according to the
CIM or gum arabic administration. FEN was administered po at 12.3 mg/kg (1/20
LD50) or 24.5 mg/kg (1/10 LD50) for 14 days or 49 mg/kg (1/5 LD50) every 4 days.
CIM was given po at 1,500 mg/kg from days 7 to 13. Samples were collected 3 h
after CIM administration on days 8 and 13. CIM did not influence ChE isoenzyme
patterns or ChE activity. FEN inhibited both the ChE isoenzyme patterns and ChE
activities without producing clinical signs. Although 1 rat in the 12.5 mg FEN/kg
+ CIM group died on day 10, all rats in other FEN (24.5 mg/kg or 49 mg/kg) + CIM
groups died on days 8-10. Differences in suppression of ChE isoenzyme patterns
were detectable between the FEN-dosed and FEN + CIM-dosed groups. There were no
differences in ChE activities between the FEN-dosed and FEN + CIM-dosed groups.
The i.p. administration of 500 mg CIM/kg (LD50) did not suppress ChE activities.
PMID- 9554059
TI - Effects of phorbol esters in carp (Cyprinus carpio L).
AB - Carp (Cyprinus carpio L) were fed diets containing phorbol esters at
concentrations of 0, 3.75, 7.5, 15, 31, 62.5, 125, 250, 500 and 1,000
micrograms/g feed. Phorbol esters were from Jatropha curcas nuts. Jatropha curcas
toxicity has been reported in humans, rodents and livestock, and phorbol esters
have been identified as the main toxic agent. The adverse effects observed in
carp at phorbol esters concentrations of 31 micrograms/g or higher were lower
average metabolic growth rate, fecal mucus production and rejection of feed.
Average metabolic growth rates (g/kg 0.8/d) in a 7-d experimental period during
which diets containing phorbol esters were fed to carp (values with different
letters being significantly different) were 15.4a, 14.4a, 12.5ab, 12.4ab, 10.9b,
3.4c, 0.2c, -3.8d, -4.9d and -5.6d, respectively, at the above mentioned
concentrations. The values for the recovery phase of 9-d during which phorbol
esters were not included in the diet were 16.0a, 15.6a, 14.9a, 15.6a, 5.3b, 1.6b,
4.6bc, 6.3bc, 7.8c and 8.2c, respectively. The adverse effects of phorbol esters
were reversible since withdrawal of the esters from the diets led to gain in body
mass. None of the fish died at any of the concentrations studied. Incorporation
of vitamin C, an antioxidant, at levels of 0.4 and 2% in the feed did not prevent
occurrence of the adverse effects of the phorbol esters. The threshold level at
which phorbol esters appeared to cause adverse effects in carp was 15
micrograms/g feed or 15 ppm in the diet. Carp were highly sensitive to phorbol
esters, thus making them a useful species for bioassay of these compounds. This
bioassay together with other analytic procedures could be of immense use in the
development of detoxification processes for agro-industrial products containing
phorbol esters, such as jatropha meal or jatropha oil, and as a quality control
method to monitor successive stages in industrial detoxification processes.
PMID- 9554061
TI - A report of pediatric SUCCIMER overdose.
AB - A 3-y-old child ingested SUCCIMER capsules to receive a dose of 185 mg
dimercaptosuccinic acid/kg body weight. No adverse effects occurred.
PMID- 9554060
TI - Sulfhemoglobinemia after dermal application of DMSO.
AB - A 43-y-old Caucasian female applied 4 ounces of dimethyl sulfoxide (DMSO) to her
lower abdomen for treatment of interstitial cystitis. Within 24 h she developed
fatigue, cyanosis and dyspnea with mild exertion. She sought medical attention 10
d later, at which time initial laboratory tests revealed a methemoglobin level of
47%. Two doses of 1 mg methylene blue/kg i.v. were given without significant
improvement in either her cyanosis or methemoglobin level. Repeat analysis the
day following admission using an outside lab demonstrated a sulfhemoglobin level
of 6.2% and a methemoglobin level of < 0.1%. No prior reports have associated
sulfhemoglobin formation with DMSO application. Carbon monoxide-oximetry may
falsely identify sulfhemoglobin as methemoglobin; sulfhemoglobinemia should be
considered in cases of methemoglobinemia refractory to methylene blue therapy.
PMID- 9554062
TI - Lead toxicity in humans from contaminated flour in Albania.
AB - In April 1997, a severe lead poisoning in humans was reported in rural Albania
and a 30-y-old male and a 17-y-old female died. Twenty-three persons exhibiting
signs of lead intoxication recovered following intensive EDTA-Ca chelation
therapy. The poisoning resulted from lead contaminated flour originating from
repair of a mill's cracked grindstone with metallic lead. Lead levels in flour
samples averaged 325 +/- 18 ppm and in bran were 370 +/- 22 ppm. Blood lead
levels in intoxicated individuals averaged 0.42 +/- 0.05 ppm and were compatible
with their symptomatic status. Contaminated bran from the same mill was fed to
lactating cows as well. Lead levels in blood and milk of exposed cows averaged
0.27 +/- 0.06 and 0.61 +/- 0.04 ppm, respectively.
PMID- 9554063
TI - Calcium oxalate is the main toxic component in clinical presentations of alocasis
macrorrhiza (L) Schott and Endl poisonings.
AB - Alocasia macrorrhiza (L) Schott and Endl is called Hai Yu, Tien Ho, Shan Yu, Kuan
Yin Lien, Tu Chiao lien, Lao Hu Yu and Lang Du in Chinese. Its common English
name is Giant Elephant's Ear. The toxic effects of A macrorrhiza arise from
sapotoxin and include gastroenteritis and paralysis of the nerve centers. From
1985 to 1993 all individuals who called the Poison Control Center asking for
information regarding macrorrhiza were included in this retrospective study. A
questionnaire filled out by the Poison Control Center staff collected the
demographic data of the victim, the reason for consumption, the prescribed part,
clinical symptoms and signs of the victim, and medical outcome of poisonings.
Among 27 cases of A macrorrhiza poisoning, the age was 1.5 to 68 y with 12
females and 15 males. One had skin contact and 1 had eye contact. In the 25 cases
that consumed the plant leaf or tuber either raw or cooked, the primary symptom
was in injected sore throat and the secondary symptom was numbness of the oral
cavity. Some patients had salivation, dysphonia, abdominal pain, ulcers of the
oral cavity, difficulty in swallowing, thoracodynia, chest tightness and swollen
lips. We believe the presence of sapotoxin alone is not sufficient to explain the
injected swollen and ulcerative lesions. Calcium oxalate is reported distributed
in the entire plant and results in inflammation of the oral cavity and mucous
membranes just as our patients had.
PMID- 9554064
TI - Putaminal infarct in methanol intoxication: case report and role of brain imaging
studies.
AB - Methanol toxicity can cause severe central nervous system insult in which a
characteristic pattern of bilateral putaminal injury is noted on brain imaging
studies. We present a fatal case of subacute methanol toxicity with associated
diffuse brain involvement, including bilateral putaminal necrosis and cerebral
edema with ventricular compression. Theoretical basal ganglia toxicologic
mechanisms of methanol poisoning are reviewed, and the role of brain imaging
studies will regard to diagnosis, prognosis and impact on management is
discussed.
PMID- 9554065
TI - Copper toxicosis in sheep: a case report.
AB - Two ewes died after being fed rabbit ration and mineral salts designated for
cows. This food is known to contain copper levels above that indicated for sheep.
Blood counts revealed anemia, and serological tests showed high blood urea
nitrogen, glutamic pyruvic transaminase and glutamic oxalacetic transaminase
values. At necropsy, the animals had hepatopathy and nephropathy. Hepatic copper
levels were 414 ppm. Histological examination revealed chronic active hepatitis
with bile casts and tubular nephrosis. The liver, spleen and kidneys had
hemosiderosis. This was attributed to the massive hemolysis caused by the copper.
The liver failure and hemolytic anemia caused death in these sheep.
PMID- 9554066
TI - Those pesky berries ... are they a source of concern?
AB - Plant exposures constitute the 4th most common call to poison information
centers. Within the plant category, exposures to unidentified berries are common
and often create panic in the public and indecisiveness by health professionals.
Are exposures to unidentified berries associated with morbidity and mortality?
Can these berry exposures be managed at home or do they necessitate medical
evaluation? The AAPCC Toxic Exposure Surveillance System was queried to identify
exposures with the "unidentified berry" code for a 10-y period. Data parameters
included frequency, age, outcome, patient disposition, referral pattern, symptom
progression and therapeutic intervention. The data were analyzed using
descriptive statistics. Unidentified berry exposures included 11,237 incidents,
making it the 11th most common plant-related exposure. Children < 6 y-of-age
accounted for 88.5% of the exposures, and 88.5% occurred during June-October.
There were no fatalities, and morbidity included 1 major outcome in an infant and
26 exposures with moderate outcomes. In exposures with a known outcome, no
effects (86.0%) and minor effects (13.6%) accounted for 99.6% of exposures. When
a patient was initially asymptomatic, 89.7% did not develop symptoms and 10.2%
progressed to have minor symptoms, accounting for 99.9% of all exposures. Poison
centers referred 7.5% to a health care facility. There was no apparent benefit
conferred by decontamination therapy. Exposures to unidentified berries represent
common inquiries to poison information centers. They are associated with low
morbidity and no mortality. If no initial symptoms are present, it is unlikely
that the patient will develop clinically relevant effects.
PMID- 9554067
TI - Accidental ingestion of sustained release calcium channel blockers in children.
AB - We examined the effects of small ingestions of sustained release calcium channel
blockers (SR-CCBs) in young children and characterized current recommendations
regarding monitoring after a suspected ingestion. A 2-part study was performed of
pediatric calcium channel blocker (CCB) ingestion: first a telephone survey of 33
randomly selected Poison Control Centers (PCCs) from around the US concerning
their recommended management of a small ingestion of sustained release calcium
channel blocker in a child, and then a 5-y retrospective review of local cases of
CCB ingestions in children under 4 y-of-age. The number of hours of medical
observation recommended by the PCCs varied from > or = 24 h (n = 15, 45%) to < 6
h (n = 6, 18%). The retrospective chart review revealed that 19 of 29 local cases
involved a SR-CCB, and 6 of these were thought to have ingested only 1 tablet.
Observation time varied from > 24 h to < 6 h in the 17 cases seen in an emergency
department. No symptoms or vital sign abnormalities were reported in any case.
Recommendations regarding duration of observation varied from < 6 h to 24 h.
Ingestion of a few SR-CCB tablets was not associated with symptoms, suggesting
that admission and 24-h monitoring may not be necessary under those
circumstances.
PMID- 9554068
TI - "Acute poisonings due to alkalies used during industrial cleaning of soft drinks'
glass containers: a case report".
PMID- 9554070
TI - Human cryptosporidiosis: epidemiology, transmission, clinical disease, treatment,
and diagnosis.
AB - Cryptosporidiosis is now recognized as one of the most common human enteric
infections. In this critical review, relatively unexplored details of
transmission, the interaction with malnutrition and the development of chronic
diarrhea, and the need for effective treatment are highlighted. Our inability to
detect small numbers of foodborne oocysts limits our understanding of this
transmission route, and the possibility of respiratory transmission is yet to be
rigorously studied. The toll this disease imposes on children, especially the
malnourished, has not been fully appreciated. Indeed, the dynamics of the
progression from acute cryptosporidiosis to chronic diarrhea and death of
malnourished children is still enigmatic. Our knowledge of the intestinal
pathophysiology, while limited, is increasing. The lack of effective drug therapy
is both remarkable and sobering. Overall, these unknown areas demonstrate how
little we truly know about this parasite.
PMID- 9554069
TI - Natural history and biology of Cryptosporidium parvum.
AB - The taxonomy of the genus Cryptosporidium remains ambiguous, because the current
criteria for speciation are insufficient to validate the 6-8 named species. Cross
transmission experiments have shown varying and conflicting results, and the
limited genetic data available do not necessarily support currently proposed
species designations. The reasons for this ambiguity lie with the ubiquitous
nature of Cryptosporidium, probably infecting all vertebrates and variety of
tissues therein, and the absence of reference strains with defined virulence
attributes that can be linked to genetic markers for comparative analysis. The
inability to classify oocysts or confidently to identify their origin, implicate
oocysts from all sources as hazardous to humans. Another major issue is the
unusual degree of resistance that Cryptosporidium has shown to antiprotozoan and
antimicrobial agents. The intracellular but extracytoplasmic domain the parasite
occupies is in itself a significant barrier to drug entry. In support of this we
outline how the intracellular niche of this parasite differs from the related
Apicomplexans, Plasmodium and Toxoplasma, and delineate why the feeder organelle
membrane, rather than, or in addition to, the parasitophorous membrane, is the
major portal of nutrient entry for Cryptosporidium. The broad conclusion is that
anticryptosporidial agents will have to enter the parasite via the multiple
apical membranes that camouflage the parasite, or via the host cell, possibly
transported by vesicles to the feeder organelle membrane. This may have major
implications for rational drug discovery and design.
PMID- 9554071
TI - Innate and cell-mediated immune responses to Cryptosporidium parvum.
AB - Cryptosporidium parvum has gained much attention as a major cause of diarrhea in
the world. Knowledge of the host immune mechanisms responsible for the clearance
of this parasite from the gastrointestinal tract may prove to be vital for
successful therapeutic treatment of cryptosporidiosis, particularly in the
immunodeficient host. This chapter focuses on the innate and cell-mediated immune
mechanisms associated with resistance to and resolution of a C. parvum infection.
Much of the work in these areas is still in its infancy. Despite this, general
consensus supports a role for interferon-gamma (IFN gamma) in mediating the
initial resistance to C. parvum, although the mechanism by which this cytokine
imparts resistance is unclear. It is also generally agreed that CD4+ T
lymphocytes are required for the resolution of both acute and chronic
cryptosporidiosis. However, the effector mechanism is again unclear. Several
studies suggest that IFN gamma may also be involved in the resolution of
cryptosporidiosis. However, the extent to which this cytokine is involved in the
actual resolution of infection has been debated. Less extensive studies
investigating the participation of other cells and cytokines in the innate and
cell-mediated immune responses to C. parvum are also discussed.
PMID- 9554072
TI - Antibody-based immunotherapy of cryptosporidiosis.
AB - Passive antibody immunotherapy (PAI) for cryptosporidiosis is a treatment
strategy that has been actively pursued in laboratory studies and early-stage
clinical studies for the last decade. Several experimental approaches have been
initiated, including use of bovine colostrum and colostral antibodies
(hyperimmune and natural), monoclonal antibodies, chicken egg yolk antibodies,
and even orally administered human plasma antibodies. Most studies have employed
oral administration to treat or prevent this intestinal infection. The interest
in this treatment strategy has been sparked by the lack of an effective or
approved therapy, increased awareness of the widespread nature of this parasite,
epidemiological evidence that humoral immunity plays an important role in host
resistance, and several early case reports of antibody therapy in which
remarkable resolution of the disease was observed. Most studies using a variety
of preparations of antibodies administered to animals and humans have shown some
degree of efficacy, though the responses have been, for the most part, partial
rather than complete resolution of the disease. This chapter examines critically
the scientific rationale and the evidence for PAI for cryptosporidiosis,
including practical considerations and future approaches.
PMID- 9554073
TI - Cryptosporidium: molecular basis of host-parasite interaction.
AB - Host-parasite interactions occur at a number of stages during the process of
infection with Cryptosporidium. Until recently, very little was known about the
molecular basis of these interactions or of specific parasite and host molecules
involved in them. Within the past decade significant advances have been made in
our understanding of Cryptosporidium host-parasite interactions and in
identifying molecules involved in them. However, with most interactions the story
is far from complete and a number of gaps remain to be filled. This chapter
reviews the existing knowledge of the molecular basis of various host-parasite
interactions and of specific molecules that may be involved in them, and
identifies areas in which further investigation is necessary. Identification of
these molecules and elucidation of molecular mechanisms underlying the host
parasite interaction are of vital importance in developing strategies to combat
cryptosporidiosis by targeted chemo- and immunotherapy.
PMID- 9554075
TI - Genetic heterogeneity and PCR detection of Cryptosporidium parvum.
AB - A variety of methods have been applied to the study of genotypic and phenotypic
polymorphism in Cryptosporidium parvum. Results from these studies have
consistently shown the existence of different genotypes and phenotypes within the
species. A long-term goal of this work is the identification of markers for
virulence in humans and animals and the elucidation of transmission cycles of C.
parvum. Achievement of these goals will depend on the identification of highly
polymorphic loci. Of particular interest are polymorphisms amenable to typing by
polymerase chain reaction (PCR), as C. parvum cannot be expanded in vitro.
Fingerprinting of isolates by restriction of PCR fragments or allele-specific PCR
has given promising results. As originally observed by isoenzyme analysis,
genetic fingerprinting has confirmed the occurrence in humans of unique C. parvum
genotypes which are not found among calf isolates. This observation remains to be
reconciled with the cross-infectivity of C. parvum to ruminant and nonruminant
hosts and the important role that bovines play in the epidemiology of C. parvum
and human cryptosporidiosis. Although PCR detection of C. parvum DNA from
individual oocysts has been reported, the sensitivity of PCR detection when
working with environmental or fecal samples is significantly reduced. Therefore,
PCR is currently not used for routine diagnosis or environmental monitoring for
C. parvum. Inhibitors present in environmental samples, mainly in water and soil,
which can negatively affect PCR recoveries, have been identified, and several
methods have been proposed to circumvent these problems. The further refinement
of detection and genetic fingerprinting protocols will provide essential tools
for indentifying environmental sources of oocysts and elucidating transmission
cycles.
PMID- 9554074
TI - Cryptosporidiosis: laboratory investigations and chemotherapy.
AB - Much progress has been achieved in the last decade in terms of development of
laboratory techniques, reagents and in vivo models. They have undoubtedly
contributed to better and more accurate investigations. Despite a concerted
effort by many investigators, however, breakthroughs have been minimal. The
development of adequate in vitro and in vivo techniques for drug screening, and
the intensified and systematic screening, has so far not resulted in the
discovery of an effective therapy. The reason for the failure may well be due to
the unique biological niche the parasite occupies (discussed at length in the
first chapter in this volume). Its location beneath the cell membrane, but
outside the cell cytoplasm, may prove a crucial element that needs to be
considered when designing new therapeutic approaches. Laboratory investigations
on two drugs currently used against chronic Cryptosporidium parvum in acquired
immune deficiency syndrome (AIDS) are discussed. This chapter also provides
information and the rationale for work in progress in our laboratory that relates
to the development of novel approaches for control of the disease. This includes
the identification of molecular targets of parasite origin for drug design, and
studies on the structure-activity relationships of partially effective drugs with
a view to synthesize more effective derivatives. Other investigations attempt to
establish the role of secretory antibody, and the merit of repeated mucosal
immunizations as a means of providing protection to individuals with AIDS who are
at risk of developing chronic C. parvum infection.
PMID- 9554076
TI - Water-borne cryptosporidiosis: detection methods and treatment options.
AB - Since the infamous outbreak in Milwaukee, WI, USA, of water-borne
cryptosporidiosis affecting over 400,000 people, there have been at least 20
smaller outbreaks associated with this parasite in the UK and North America.
These events have led to an explosion of interest in and research on the nature
of cryptosporidiosis as a dangerous water-borne pathogen, particularly patients
with acquired immune deficiency syndrome (AIDS). In addition, several major
environmental laws and proposed regulations specifically address the control of
this parasite. The possible ramifications of these laws include billions of
dollars of modifications to water-treatment facilities in the USA. Unfortunately,
the methods used to gather the information on which these laws are based have
serious deficiencies that could lead to gross underestimation of the magnitude of
this problem. The present review considers gaps in our understanding of water
borne cryptosporidiosis, new methods under investigation that could improve our
ability to monitor water for the presence of this organism, and treatment and
control strategies to limit the threat to our water supplies.
PMID- 9554077
TI - Biology of microsporidian species infecting mammals.
AB - Microsporidia (phylum Microspora) are obligate intracellular protozoan parasites
that infect a wide range of vertebrate and invertebrate hosts. Over 1000 species
have been classified into approximately 100 genera, and at least 13 species have
been reported to infect mammals. Phylogenetically, the microsporidia are early
eukaryotes because they have a true nucleus, possess prokaryote-like ribosomes,
and lack mitochondria. The species that infect mammals are relatively small,
measuring 2.0-7.0 microns long and 1.5-5.0 microns wide. The mature organism is
the spore, which is enclosed by a chitinous coat, making it relatively resistant
to the environment. Infections often occur by fecal-oral or urinary-oral
transmission, although vertical transmission is quite common in the carnivores.
Host cells become infected through a process of germination in which the spore
propels its contents through the everting and unwinding polar filament into the
host cell. The polar filament is unique to the microsporidia. With a few
exceptions, microsporidiosis is typically chronic and subclinical in
immunologically competent hosts. Young carnivores infected with microsporidia,
however, develop severe and sometimes lethal renal disease, and immunodeficient
laboratory animals (e.g. athymic and SCID mice) develop ascites and die from
microsporidiosis. This review describes the morphology, life cycle, taxonomy, and
host-parasite relationships of the species of microsporidia that infect mammals.
PMID- 9554078
TI - Clinical syndromes associated with microsporidiosis.
AB - Microsporidia are ubiquitous in nature. Several clinical syndromes have been
associated with microsporidiosis, especially in HIV-infected individuals, and
include enteropathy, keratoconjunctivitis, sinusitis, tracheobronchitis,
encephalitis, interstitial nephritis, hepatitis, cholecystitis, osteomyelitis,
and myositis. Diarrhea and malabsorption are the most common clinical problems.
Enterocytozoon bieneusi is the most common microsporidial cause of intestinal
disease. A second species, Encephalitozoon intestinalis (originally named Septata
intestinalis) is associated with disseminated as well as intestinal disease.
Microsporidiosis has been seen worldwide, and is recognized as a frequent enteric
infection in patients with AIDS. The pathogenesis of intestinal disease is
related to excess death of enterocytes as a result of cellular infection.
Clinically, microsporidiosis most often presents with diarrhea and weight loss as
a result of small intestinal injury and malabsorption. However, microsporidia
have been detected in virtually all organs, and may provoke symptoms related to
their specific localization. The diagnosis of microsporidiosis is made
histologically, either from tissue biopsies or secretions. While transmission
electron microscopy was required for diagnosis in the past, special stains and
light microscopy, as well as immunohistochemical and molecular techniques are
capable of providing a firm diagnosis. Therapeutic options are limited. Enc.
intestinalis responds well to albendazole, while no antiparasitic therapy has
documented efficacy in Ent. bieneusi infections.
PMID- 9554079
TI - Microsporidiosis: molecular and diagnostic aspects.
AB - The term 'microsporidia' is a nontaxonomic designation which is used to refer to
a group of intracellular parasites belonging to the phylum Microspora. These
eukaryotic obligate intracellular protozoans have been described infecting every
major animal group, especially insects, fish and mammals. They are important
agricultural parasites in commercially important insects, fish, laboratory
rodents, rabbits, fur-bearing animals, and primates. There is now an increasing
recognition of microsporidia as important opportunistic pathogens in persons
infected with the human immunodeficiency virus (HIV). Microsporidia possess
ribosomes with features resembling prokaryotes. Phylogenetic analysis of the rRNA
sequence from several of the microsporidia suggests that these organisms were
early branches in the eukaryotic evolutionary line. The data on these molecular
phylogenetic relationships are reviewed in this paper. Inroads have recently been
made into the molecular biology of these organisms and these data are also
presented. Diagnosis of microsporidia infection from stool examination is
possible and has replaced biopsy as the initial diagnostic procedure in many
laboratories. These staining techniques can be difficult, however, due to the
small size of the spores. The specific identification of microsporidian species
has classically depended on ultrastructural examination. With the cloning of the
rRNA genes from the human pathogenic microsporidia it has been possible to apply
polymerase chain reaction (PCR) techniques for the diagnosis of microsporidial
infection at the species level. Both staining and PCR techniques for the
diagnosis of microsporidia are reviewed.
PMID- 9554080
TI - Cyclospora cayetanensis.
AB - Cyclospora cayetanensis is a coccidian pathogen in humans. Cyclosporiasis is
characterized by mild to severe nausea, anorexia, abdominal cramping, and watery
diarrhea. Cyclospora has now been described from patients with protracted
diarrheal illness in North, Central and South America, the Caribbean, Africa,
Bangladesh, south-east Asia, Australia, England, and eastern Europe, and is
characterized by marked seasonality. Routes of transmission are still unknown,
although the fecal-oral route, either directly or via water, is probably the
major one. A recent outbreak in the USA suggested transmission of Cyclospora by
ingestion of contaminated berries. Cyclospora oocysts can be detected by phase
contrast microscopy, modified acid-fast staining, autofluorescence, and
amplification by the polymerase chain reaction. Oocysts are not sporulated when
excreted in the feces, and sporulated oocysts are needed for infection. Each
sporulated oocyst contains two sporocysts and each sporocyst contains two
sporozoites. Humans seem to be the only host for this parasite. Histopathological
examination of jejunal biopsies from infected individuals showed mild to moderate
acute inflammation of the lamina propria and surface epithelial disarray.
Parasitophorous vacuoles containing sexual and asexual forms of Cycl.
cayetanensis were located in the cytoplasm of epithelial cells. Cyclospora
infections can be treated successfully with trimethoprim-sulfamethoxazole.
PMID- 9554083
TI - Saccharification and alcohol fermentation in starch solution of steam-exploded
potato.
AB - Steam explosion pretreatment of potato for the efficient production of alcohol
was experimentally studied. The amount of water-soluble starch increased with the
increase of steam pressure, but the amounts of methanol-soluble material and
Klason lignin remained insignificant, regardless of steam pressure. The potatoes
exploded at high pressure were hydrolyzed into a low molecular liquid starch, and
then easily converted into ethanol by simultaneous saccharification and
fermentation using mixed microorganisms: an amylolytic microorganism, Aspergillus
awamori, and a fermentation microorganism, Saccharomyces cerevisiae. The maximal
ethanol concentration was 4.2 g/L in a batch culture at 15 g/L starch
concentration, and 3.6 g/L in a continuous culture fed the same starch
concentration. In the fed-batch culture, the maximal ethanol concentration
increased more than twofold, compared to the batch culture.
PMID- 9554081
TI - Large-scale preparation of the delta10 form of staphylokinase by in vitro
processing of recombinant staphylokinase with purified human plasminogen.
AB - The authors have developed a rapid and convenient method for purification of a
low molecular weight form (delta 10) of the bacterial plasminogen activator,
staphylokinase. Recombinant staphylokinase is expressed in Escherichia coli, with
an amino terminal extension that facilitated purification by immobilized metal
affinity chromatography. Purified staphylokinase is treated with human
plasminogen, and the resulting truncated form is purified using a combination of
immobilized metal affinity chromatography and hydrophobic interaction
chromatography. Purified protein is characterized by amino terminal sequencing
and in vitro plasminogen activation assay.
PMID- 9554084
TI - Generation of carbohydrate-deficient transferrin by enzymatic deglycosylation of
human transferrin.
AB - Carbohydrate-deficient transferrin (CDT) molecules are transferrin isoforms that
lack one or both of the carbohydrate groups attached to a normal human
transferrin molecule. CDT has been reported to be a sensitive and specific marker
for diagnosing alcoholism. This report demonstrates the in vitro generation of
CDT molecules that can potentially be used as the standard in measuring CDT
concentrations. This was achieved by deglycosylation of human transferrin with
the enzyme Endo-beta-N-acetylglucosaminidase F2 (Endo-F2). The enzyme was
immobilized on sepharose beads, which were packed into a column. The
immobilization of the enzyme not only eliminated the Endo-F2 contamination of
CDT, but also rendered the enzyme suitable for repetitive use. In this manner, it
was possible to obtain at least 200 mg of CDT over a period of more than 3 mo,
without any noticeable decrease of enzyme activity, using only 3.0 micrograms of
enzyme. This proved to be an efficient method for generating CDT.
PMID- 9554087
TI - Performance deficits following failure: learned helplessness or self-esteem
protection?
AB - We report two laboratory experiments which compare two competing explanations of
performance deficits following failure: one based on Seligman's learned
helplessness theory (LHT), and the other, on self-esteem protection theory
(SEPT). In both studies, participants (Study 1: N = 40 pupils from secondary
schools in Walbrzych, Poland; Study 2: N = 45 students from the University of
Bielefeld, Germany) were confronted with either success or failure in a first
phase of the experiment. Then, in the second phase of the experiment the
participants had to work on a set of mathematical problems (Study 1) or a set of
tasks taken from Raven's Progressive Matrices (Study 2) either privately or in
public. In both studies failure in the first phase causes performance deficits in
the second phase only if the participants had to solve the test tasks in public.
These results were interpreted in line with SEPT and as incompatible with LHT.
PMID- 9554086
TI - Friends, lovers and spouses: intimacy in young adults.
AB - Intimacy in young heterosexual adults was studied as a function of their familial
roles. The 168 males and females employed represented four familial role groups:
late adolescents, single adults, married people and parents. Participants were
administered two forms of an Intimacy Scale (Sharabany, 1994) in which they
described their desired and their obtained intimacy with a same-sex and an
opposite-sex best friend. Results indicated that (a) intimacy of adults with
opposite-sex partner was higher than intimacy with same-sex friend. (b) Although
no direct effect of familial role on intimacy was found, the married and parent
groups displayed greater intimacy towards their spouses than late adolescents and
single adults towards their opposite-sex partners. (c) Women who were late
adolescents and women who were married scored significantly higher than men in
intimacy. However, single women expressed significantly lower intimacy than
single men. (d) Higher intimacy with opposite-sex partner was associated with a
concurrent lower same-sex intimacy. (e) Satisfaction with other-sex partner was
higher in the married group than in the other groups.
PMID- 9554085
TI - Some tests of the distinction between attitude and perceived behavioural control.
AB - Although perceived behavioural control has recently become a popular variable for
use in predicting behaviour or intention to behave, it is far from clear that
this variable is theoretically distinguishable from attitude. Consequently, we
performed some tests of the distinction between attitude and perceived
behavioural control. In Expt 1, using participants from an American university,
the semantic differential scales that have often been used to measure attitude
and perceived behavioural control were submitted to factor analyses. Consistent
with the distinction, a two-factor solution resulted in the attitude and
perceived behavioural control items clearly loading on different factors.
Further, Expt 2 demonstrated that the attitude factor predicts behavioural
beliefs and does not predict control beliefs, but the reverse is true concerning
the perceived behavioural control factor. Finally, in Expts 3-5, the beliefs
presumed to underlie these two variables were cluster analysed. Consistent with
the distinction, and paralleling findings obtained by Trafimow & Fishbein (1995),
the order in which participants wrote down their beliefs exhibited significant
clustering by belief type.
PMID- 9554088
TI - Gender solidarity in hierarchical organizations.
AB - Previous research has suggested that promotion decisions in hierarchical
organizations may vary as a function of the decision maker's sex. In particular,
it has been argued that women may be more likely to support a same-sex other than
men due to higher levels of identification with their gender in-group. This paper
reports findings from two experiments which examine gender identification and
candidate promotion strategies amongst university students (N = 116) and public
servants (N = 136) in hypothetical organizations which manipulated the
participants' personal status and that of their gender in-group. In the
university sample women did identify more strongly with their sex than men. This
was not generally the case in the public service sample, although here women with
high personal status tended to show greater identification than men in a similar
position. However, in both studies there was little evidence that gender
identification was associated with preferential treatment of in-group candidates
in promotion-related decisions. These decisions were generally influenced by
norms of fairness qualified by the participants' personal status. Implications
for the self-categorization process are discussed.
PMID- 9554089
TI - Inter-judge agreement in evaluation of adult attachment style: the impact of
acquaintanceship.
AB - Inter-judge agreement in the evaluation of attachment style was examined across
different levels of acquaintanceship. A self-rating scale on attachment style was
administered to 242 students. Then, 72 participants--25 avoidant, 25 secure, and
22 ambivalent--were invited to the laboratory in unacquainted same-sex pairs,
videotaped during a five-minute conversation, and asked to rate the attachment
style of their conversion partner. In addition, each participant asked four
friends to rate his/her attachment style and the videotaped interactions were
shown to a separate sample of strangers who rated participants' attachment
styles. The results showed high correlations between participants' self-reported
attachment styles and the manner in which they were perceived by their friends
and conversation partners. In contrast, correlations with ratings by strangers
based on videotaped interactions were low. This pattern of findings was observed
in both discrete and continuous measures of attachment. The findings suggest that
attachment style can be considered an observable interpresonal trait.
PMID- 9554090
TI - Habit versus planned behaviour: a field experiment.
AB - A field experiment investigated the prediction and change in repeated behaviour
in the domain of travel mode choices. Car use during seven days was predicted
from habit strength (measured by self-reported frequency of past behaviour, as
well as by a more covert measure based on personal scripts incorporating the
behaviour), and antecedents of behaviour as conceptualized in the theory of
planned behaviour (attitude, subjective norm, perceived behavioural control and
behavioural intention). Both habit measures predicted behaviour in addition to
intention and perceived control. Significant habit x intention interactions
indicated that intentions were only significantly related to behaviour when habit
was weak, whereas no intention-behaviour relation existed when habit was strong.
During the seven-day registration of behaviour, half of the respondents were
asked to think about the circumstances under which the behaviour was executed.
Compared to control participants, the behaviour of experimental participants was
more strongly related to their previously expressed intentions. However, the
habit-behaviour relation was unaffected. The results demonstrate that, although
external incentives may increase the enactment of intentions, habits set boundary
conditions for the applicability of the theory of planned behaviour.
PMID- 9554091
TI - Synchrony effects in inhibitory control over thought and action.
AB - Two experiments explore whether synchrony between peak circadian arousal periods
and time of testing influences inhibitory efficiency for younger and older
adults. Experiment 1 assesses inhibitory control over no-longer-relevant
thoughts, and Experiment 2 assesses control over unwanted but strong responses,
as well as performance on neuropsychological tasks that index frontal function.
Inhibitory control is greatest at optimal times for both age groups and is
generally greater for younger than for older adults. Performance on 2
neuropsychological measures (Stroop and Trails) also changes over the day, at
least for older adults, and is correlated with inhibitory indexes, suggesting
that for older adults changes in inhibition may be mediated by circadian
variations in frontal functioning. By contrast, access to well-learned responses
is not vulnerable to synchrony or age effects.
PMID- 9554092
TI - Mechanisms of phonological inference in speech perception.
AB - Cross-modal priming experiments have shown that surface variations in speech are
perceptually tolerated as long as they occur in phonologically viable contexts.
For example, [symbol: see text] (frayp) gains access to the mental representation
of freight when in the context of [symbol: see text] (frayp bearer) because the
change occurs in normal speech as a process of place assimilation. The locus of
these effects in the perceptual system was examined. Sentences containing surface
changes were created that either agreed with or violated assimilation rules. The
lexical status of the assimilated word also was manipulated, contrasting lexical
and nonlexical accounts. Two phoneme monitoring experiments showed strong effects
of phonological viability for words, with weaker effects for nonwords. It is
argued that the listener's percept of the form of speech is a product of a
phonological inference process that recovers the underlying form of speech. This
process can operate on both words and nonwords, although it interacts with the
retrieval of lexical information.
PMID- 9554093
TI - Figure-ground organization and object recognition processes: an interactive
account.
AB - Traditional bottom-up models of visual processing assume that figure-ground
organization precedes object recognition. This assumption seems logically
necessary: How can object recognition occur before a region is labeled as figure?
However, some behavioral studies find that familiar regions are more likely to be
labeled figure than less familiar regions, a problematic finding for bottom-up
models. An interactive account is proposed in which figure-ground processes
receive top-down input from object representations in a hierarchical system. A
graded, interactive computational model is presented that accounts for behavioral
results in which familiarity effects are found. The interactive model offers an
alternative conception of visual processing to bottom-up models.
PMID- 9554094
TI - The psychological refractory period effect following callosotomy: uncoupling of
lateralized response codes.
AB - A callosotomy patient was tested in 2 dual-task experiments requiring successive
speeded responses to lateralized stimuli. The patient showed a robust
psychological refractory period (PRP) effect. Three aspects of the data indicate
that, unlike for the control participants, the PRP effect for the split-brain
patient should not be attributed to a response selection bottleneck. First, the
patient did not show an increase in reaction time (RT) when the 2 tasks required
responses from a common output system compared with when different output systems
were used. Second, inconsistent stimulus-response mappings for the 2 tasks
increased RTs for the control participants but had minimal effect on the
performance of the split-brain patient. Third, the consistency manipulation was
underadditive with stimulus onset asynchrony but was additive or overadditive for
the normal participants. These results suggest that the persistent PRP effect
following callosotomy should be attributed to a bottleneck associated with
response initiation, a strategy adopted to comply with the task demands, or a
combination of these factors.
PMID- 9554095
TI - Multiple-location access in vision: evidence from illusory line motion.
AB - Four experiments with undergraduates used illusory line motion (ILM) to contrast
Z. W. Pylyshyn's (1989) FINST theory of spatial indexing with predictions made by
unitary attention models. Multiple-onset stimuli were able to cause ILM at
disparate, noncontiguous spatial locations. Consistent with gradient explanations
of ILM and with FINST theory predictions, varying line-drawing speed and the
number of stimuli revealed a decrease in ILM and a capacity limitation,
respectively. Modeling analyses suggested a limit in the number of locations (5
7) that could elicit the illusion. Requiring participants to report the locations
of all stimuli exhibiting illusory motion in a specified direction suggested
parallel access to between 2 and 5 display locations simultaneously. The results
of all 4 experiments were predicted by FINST theory but not by a broad class of
unitary attention hypotheses.
PMID- 9554096
TI - Higher order and lower order variables in the visual perception of relative
pulling force.
AB - In 7 experiments, undergraduates judged the force exerted by a videotaped
standing puller, a computer-generated (stick-figure) puller, or a computer
generated inverted pendulum. Single and stepwise multiple regression analyses
determined the kinematic variables exploited by the participants. Results show
that (a) judgments correlated highly with force and improved with feedback; (b)
judgments correlated more highly with lower order kinematic variables than with
force itself; (c) participants differed in the kinematic variables exploited; (d)
participants changed over blocks of trials in the variables exploited; (e) some
participants used compound kinematic variables; (f) the variables exploited
depended on the type of feedback; and (g) judgments to upright pullers, inverted
pullers, and simple pendula showed the same qualitative patterns. Implications
for theories of direct perception, directed perception, and heuristics are
considered.
PMID- 9554097
TI - Frames of reference and control parameters in visuomanual pointing.
AB - Three hypotheses concerning the control variables in visuomanual pointing were
tested. Participants pointed to a visual target presented briefly in total
darkness on the horizontal plane. The starting position of the hand alternated
randomly among 4 points arranged as a diamond. Results show that during the
experiment, movement drifted from hypometric to hypermetric. Final positions
depended on the starting position. Their average pattern reproduced the diamond
of the starting points, either in same orientation (hypometric trials), or with a
double inversion (hypermetric trials). The distribution of variable errors was
elliptical, with the major axis aligned with the direction of the movement.
Statistical analysis and Monte Carlo simulations showed that the results are
incompatible with the final point control hypothesis (A. Polit & E. Bizzi, 1979).
Better, but not fully satisfactory, agreement was found with the view that
pointing involves comparing initial and desired postures (J. F. Soechting & M.
Flanders, 1989a). The hypothesis that accounted best for the results is that
final hand position is coded as a vector represented in an extrinsic frame of
reference centered on the hand.
PMID- 9554098
TI - Processing of illegal consonant clusters: a case of perceptual assimilation?
AB - Evidence is presented for a perceptual shift affecting consonant clusters that
are phonotactically illegal, albeit pronounceable, in French. They are perceived
as phonetically close legal clusters. Specifically, word-initial /dl/ and /tl/
are heard as /gl/ and /kl/, respectively. In 2 phonemic gating experiments,
participants generally judged short gates--which did not yet contain information
about the 2nd consonant /l/--as being dental stops. However, as information for
the /l/ became available in larger gates, a perceptual shift developed in which
the initial stops were increasingly judged to be velars. A final phoneme
monitoring test suggested that this kind of shift took place on-line during
speech processing and with some extratemporal processing cost. These results
provide evidence for the automatic integration of low-level phonetic information
into a more abstract code determined by the native phonological system.
PMID- 9554099
TI - Perceived orientation of axis of rotation in structure-from-motion.
AB - Perceived orientation of axis of rotation and accuracy in discriminating fixed
axis from nonfixed-axis rotations were investigated for orthographic projections
of three-dimensional rotating objects. The principal findings were (a) the slant
of the axis of rotation was systematically misperceived; (b) in both two-view and
multiview displays, the perceived slant of the axis of rotation was well
predicted by the ratio between the deformation (a property of the first-order
optic flow) and the component parallel to the image plane of the global velocity
vector; (c) if this ratio was kept constant in each frame transition of the
stimulus sequence (or it was varied), then the stimuli tended to be judged as
fixed-axis rotations (or as nonfixed-axis rotations), regardless of whether they
simulated a fixed-axis rotation or not; and (d) the tilt of the axis of rotation
was perceived in two-view displays with a very small error.
PMID- 9554100
TI - Recognition by action: dissociating visual and semantic routes to action in
normal observers.
AB - In this article the operation of a direct visual route to action in response to
objects, in addition to a semantically mediated route, is demonstrated. Four
experiments were conducted in which participants made gesturing or naming
responses to pictures under deadline conditions. There was a cross-over
interaction in the number of visual errors relative to the number of semantic
plus semantic-visual errors in the two tasks: In gesturing, compared with naming,
participants made higher proportions of visual errors and lower proportions of
semantic plus semantic-visual errors (Experiments 1, 3, and 4). These results
suggest that naming and gesturing are dependent on separate information
processing routes from stimulus to response, with gesturing dependent on a visual
route in addition to a semantic route. Partial activation of competing responses
from the visual information present in objects (mediated by the visual route to
action) leads to high proportions of visual errors under deadline conditions.
Also, visual errors do not occur when gestures are made in response to words
under a deadline (Experiment 2), which indicates that the visual route is
specific to seen objects.
PMID- 9554101
TI - Investigating single-word syntactic primes in naming tasks: a recurrent network
approach.
AB - Three experiments compared the qualitative pattern of participants' word-naming
performance in a syntactic priming task with the qualitative pattern of
performance generated by a recurrent network model. Experiments 1 and 2
demonstrated that when participants had a 600-ms response deadline, the
appropriateness of a syntactic prime affected their naming times for high
frequency words but not low-frequency words. However, Experiment 2 also
demonstrated that participants made the most pronunciation errors when naming
inconsistent low-frequency words (e.g., pint) that were preceded by an
inappropriate prime. The results of Experiment 3 suggest that participants'
naming times to both high- and low-frequency words are affected by syntactic
primes when there is no response deadline. The implication of these findings for
the study of syntactic priming in English and other languages is discussed.
PMID- 9554102
TI - Object-based perceptual grouping affects negative priming.
AB - In 5 experiments the authors examine the role of object-based grouping on
negative priming. The experiments used a letter-matching task with multiple
letters presented in temporally separated prime and probe displays. On mismatch
trials, distractor letters in primes were repeated as targets in probes, or
distractor and target letters were completely different. Negative priming was
shown by slowed responses when distractors were repeated as targets relative to
when the stimuli differed. This occurred both when only letters were presented
(Experiments 1 and 4) and when letters were surrounded by boxes (Experiment 5).
Experiments 2, 3, and 4 showed that negative priming was affected by the grouping
of target and distractor letters in prime displays. Negative priming was reduced
when 1 of the distractor letters was placed in the target box and 1 was left
outside the box; facilitatory priming was observed when both distractor letters
appeared in the target box. The data were accounted for in terms of there being
(a) object-based competition for visual selection, (b) inhibition of distractor
objects that compete for selection with target objects, and (c) activation or
inhibition of the identities of all component elements within target or
distractor objects.
PMID- 9554103
TI - The contribution of covert attention to the set-size and eccentricity effects in
visual search.
AB - To reexamine the role of covert attention in visual search, the authors directly
manipulated attention by peripherally cueing the target location and analyzed its
effects on the set-size and the eccentricity effects. Observers participated in
feature and conjunction tasks. Experiment 1 used precues, and Experiment 2 used
postcues in a yes-no task under valid-, invalid-, and neutral-cueing conditions.
Experiments 3 and 4 used a 2-interval alternative forced-choice visual-search
task under cued and neutral conditions. Precueing the target location improved
performance in feature and conjunction searches; postcueing did not. For the cued
targets, the eccentricity effect for features and conjunctions was diminished,
suggesting that the attentional mechanism improves the quality of the sensory
representation of the attended location. The conjunction set-size effect was
reduced but not eliminated. This questions serial-search models that attribute a
major role to covert attention in visual search.
PMID- 9554104
TI - Quantitative information of specific diagnostic tests.
AB - The goal of diagnostic testing is to maximize information (I) of a specific
disease of interest (D) resulting from the performance of a specific diagnostic
test procedure (T). However, all tests suffer from errors which result in
incomplete information and inaccurate diagnostic conclusions. The methods of
Information Theory have successfully solved a range of signal transmission
problems involving physical systems operating under conditions of noise. Medical
testing procedures were found to be analogous to noisy systems; hence,
Information Theory methods were applied to minimize errors in diagnostic testing.
Prior to performing a diagnostic test, the quantity of information, Apriori
Information (ID), regarding the presence or absence of the disease was only a
function of the prevalence (P) of disease in the population. After performing a
diagnostic test, the quantity of information, Aposteriori Information (IDIT) was
a function of not only P but also the test sensitivity (A) and test specificity
(B). The quantity of information gained by test performance was computed from the
difference between aposteriori and apriori information. delta I = IDIT - ID To
illustrate the relationship between pretest, apriori, and post-test, aposteriori,
information the values of ID and IDIT were computed for five common
cardiovascular tests applied to populations with different coronary artery
disease prevalence. This cross-sectional analysis studied the quantitative
information obtained from Electrocardiography (ECG), Bicycle Ergometer Stress
Tests (BEST), Stress-Echo Ergometer Tests (SEET), Thallium 201 Stress Tests
(ThST), and Coronary Arteriography (CorA). Apriori information ranged from a
minimum of 0 (for prevalence = 0.5) to a maximum of 1.0 (for prevalence = 0 or
1.0) The aposteriori information was computed for all apriori information and
occupied the range between that of a "perfect" test (A = 1.0 and B = 1.0) and
that of a "worthless" test (A = 0.5 and B = 0.5). All tests demonstrated greater
information gain when apriori information was minimal; Little additional
information could be gained when the apriori information was close to certainty
(i.e., for prevalence near 0 or 1.0). Electrocardiography demonstrated little
significant IDIT at any value of ID. Thallium 201 stress tests provided similar
aposteriori information values to those of Stress-Echo Ergometer Stress and
either demonstrated greater information gain than Bicycle Ergometer Stress Tests.
Coronary Arteriography provided the maximum values of aposteriori information.
Information Theory methods provided an effective quantitative method to compare
the effectiveness of diagnostic tests over a wide range of disease prevalence.
PMID- 9554106
TI - Longitudinal studies to determine the effect of body fat rate reduction on blood
pressure.
AB - Body constitution is estimated by weight as a quantity index and percent body fat
(%BF) as a quality index. Obesity is one of the risk factors in hypertension.
High blood pressure drops by body weight reduction. The relationship between %BF
change and blood pressure change during 1 year, and whether blood pressure
changed in subjects whose %BF decreased without body weight reduction, were
investigated. %BF was measured with bioelectrical impedance analysis. The changes
of body weight, %BF and blood pressure in the decreased %BF group that decreased
more than 2 points of %BF, and in the no body weight change group which body
weight had not changed in the decreased %BF group, were studied. In the decreased
%BF group, average blood pressures fell significantly from 149/92 to 141/86 mm Hg
in the subjects in hypertensive state at baseline. In the no weight change group,
average blood pressures also fell significantly from 151/93 to 140/87 mm Hg. Even
if the body weight had not changed, blood pressure had decreased significantly
when %BF had decreased significantly.
PMID- 9554105
TI - Ultrasonographically assessed carotid intima-media thickness and risk for
asymptomatic cerebral infarction.
AB - Cerebral infarction (CI) is still a leading cause of death in Japan. Thus, the
management of risk factors for CI as primary prevention is one of the most
important tasks in multiphasic health testing and services. To determine whether
carotid intima-media thickness (IMT) is a risk for CI, ultrasonographically
assessed carotid IMT was compared between normal subjects (N) and subjects with
asymptomatic CI (ACI) in 243 subjects who underwent human brain dry dock. ACI was
found in 68 people (28.0%). Age, body mass index, and mean blood pressure were
higher in ACI than in N. Also, atherogenic index was higher in ACI than in N.
Carotid IMT was significantly thicker in ACI than in N. Furthermore, incidence of
atherogenic plaque in ACI was significantly higher than that in N. In conclusion,
not only aging, obesity, blood pressure, and plasma lipids, but also carotid IMT
may be a risk for ACI.
PMID- 9554107
TI - Health risk assessment for diabetes mellitus based on longitudinal analysis of
MHTS database.
AB - This study was designed with a follow up of 16 years to provide the
epidemiological model evaluating the risk of developing diabetes mellitus in
Japan. A cohort of 2573 subjects (1851 males and 722 females) from a MHTS in
Tokyo, who were nondiabetic (fasting blood glucose (FBS) less than 110 mg/dl) in
the initial year, were selected. This cohort was followed every year to identify
the occurrence of diabetes mellitus. Diabetes Mellitus was defined as fasting
blood glucose over 110 mg/dl, or the initiation of diabetic therapy. We compared
two prognosis groups (a normal group and a diabetic group) in terms of age,
examination findings, and prevalence of health risks (lifestyle, stress, and
working form). We also assessed family history of diabetes and past histories
including hypertension, hypercholesterolemia, and hyperuricemia. After assessing
each variable by univariate analysis (t-test, chi 2 test), we employed Cox's
proportional hazards model analysis. We used stepwise model adopting risk
factors. The diabetic group had significant differences compared to the normal
group in age, BMI (body mass index), FBS, smoking, drinking, not eating
breakfast, dairy intake, hypertension, hypercholesterolemia, hyperuricemia, and
family history by univariate analysis. According to proportional hazards model
analysis, FBS, age, family history, hypertension, smoking, and BMI were
incorporated into significant risk factors for diabetes in males, and not eating
breakfast, FBS, age, drinking, and hypertension were incorporated in females.
Diabetes seemed to be related to fixed factors (age), or genetic factors (family
history and FBS) in males. For females, lifestyle (not eating breakfast and
drinking habit) seemed to play an important role. It will be worthwhile to assess
the risks of developing diabetes mellitus by this epidemiological model.
PMID- 9554108
TI - The validity of cognitive testing in screening for dementia.
AB - The concept of "cognitive impairment," as an indicator of dementia, defined in
1980 as a loss of intellectual abilities of sufficient severity to interfere with
social or occupational functioning, is the model which has been adopted for a
condition, which has recently been reclassified from an "organic" to a "cognitive
disorder." Data derived from the assessment of a sample of older people
demonstrated the extreme sensitivity of a widely employed cognitive assessment
instrument to all levels of educational experience, and educational correlates,
notably level of physical disability, were identified as other independent
predictors of test performance. The analyses raise questions with regard to the
reinterpretation of "lack of education," from a confounding factor in prevalence
estimates of cognitive impairment to a "risk factor" for dementia, and support
those who have questioned the validity of the one-dimensional "cognitive
paradigm," and the trend to diagnosis based upon objective assessment with
standardized instruments.
PMID- 9554109
TI - Development of a health promotion system for the elderly: Committee of Health
Evaluation for Elderly Persons Council of Japan AMHTS Institutions.
AB - A new health promotion approach for elderly persons is required which maintains
not only their physical health but also their quality of life. We are developing
a health promotion system which makes use of questionnaires dealing with physical
conditions and quality of life, and makes health reports. Health evaluation is
carried out in three steps. First, detailed information about the physical health
of each client is collected. Second, quality of life is evaluated according to
five health indicators. Last, health recommendations are generated. An artificial
intelligence (AI) program produces detailed questions to collect necessary
information for the evaluation of a client's health. The information related to
quality of life is converted into five health indicators and presented as a radar
chart in documents and displays. The knowledge-based AI program automatically
generates the health recommendation documents. This information is available for
physicians and nurses for health counseling.
PMID- 9554110
TI - Driving safe & sober.
PMID- 9554111
TI - Fitness-for-duty testing.
PMID- 9554112
TI - First aid: medical or safety?
PMID- 9554113
TI - Medical miracles.
PMID- 9554114
TI - Quantitative evaluation of protein-protein and ligand-protein equilibria of a
large allosteric enzyme by electrospray ionization time-of-flight mass
spectrometry.
AB - A mass spectrometer coupling electrospray ionization with time-of-flight mass
spectrometry (ESI-TOFMS) has been used to investigate the oligomeric species of
Escherichia coli citrate synthase, and to determine the effect of nicotinamide
adenine dinucleotide (NADH), an allosteric inhibitor of this enzyme, on the
equilibrium between the oligomeric forms. An equilibrium mixture of dimers (M =
95,770 Da) and hexamers (M = 287,310 Da) was found under the conditions used (KA
= 6.9 x 10(10) M-2), and NADH was observed to bind selectively to the hexamer (KD
= 1.1 microM), shifting the equilibrium to the latter form. The power of ESI
TOFMS to measure ions of very large mass-to-charge ratio (up to m/z approximately
10,000 in this case) is shown to be a valuable tool for obtaining accurate
information about compositions of noncovalent complexes and equilibrium
constants. The measured constants agree with those determined by conventional
means.
PMID- 9554115
TI - [Eulogy of Mr. Andre Djourno (1904-1996)].
PMID- 9554116
TI - [Current issues in respiratory allergology].
AB - To summarise in a few lines our present understanding of respiratory allergies
necessarily limits the number of topics which can be addressed. The role of
aeroallergens in these diseases, both those which were previously unknown or non
existent and those which were well characterised (cypress, ambrosia) but which
are becoming more prevalent in the atmosphere has now been demonstrated. The
understanding of the mechanisms of respiratory allergies, which are essentially
derived from tissue inflammation, has undergone rapid progress and evolved
towards the identification of transcription factors which regulate the genes
coding for cytokines, enzymes and adhesion molecules. Specific immunotherapy
should be heralded as one of the key elements in the global therapeutic strategy
for respiratory allergies as long as the indications for it are rationally
discussed. Our increasing our knowledge of the genetics of respiratory allergies
should continue to stimulate research projects, but the results obtained so far
underline the complexity of this domain and diagnosis and treatment via genetics
remains in the future.
PMID- 9554117
TI - [New aero-allergens. Interaction between allergens and the environment].
AB - There is a qualitative as well as a quantitative change in allergen exposure.
From a qualitative viewpoint, the relevance of some allergens (domestic allergens
i.e. cockroaches, outdoor allergens i.e. plane tree, chestnut and ash tree
pollens) has been established. The role of some other allergens has been,
strictly speaking, discovered: latex from Hevea and ficus, trichophyton mold,
some occupational allergens and very recently transgenic allergens. From a
quantitative viewpoint, the concentration and/or distribution of some allergens
has increased. Plantation of numerous trees or fortuitous introduction of weeds
has led to an increased specific sensitization. In like manner, introduction of
new foods or food processing procedures has created new food allergens and
allergy. Besides, the distribution of some well-known aero-allergens is better
known since discovery of ELISA--technology allowing measurements of minute
amounts of these allergens. A burning issue today is to know whether irritant
factors could modify allergens. Few data, sometimes contradictory, are available
in the field of interaction between air pollutants and allergens.
PMID- 9554118
TI - [Recent data on the physiopathology of respiratory allergies].
AB - Mechanisms of the allergic inflammatory reaction in the respiratory tract, such
as those involved in chronic asthma and allergic rhinitis involve a complex and
integrated cellular cascade. After allergen inhalation, the response is initiated
by the airway epithelial dendritic cells which are responsible after
transportation to regional lymph nodes, for the presentation to naive CD4+ T
helper (Th0) cells. After the first phase of allergen sensitization, CD4+ T cells
give rise in atopic patients to lymphocytes CD4+ with a cytokine profile of Th2
type (secretion of IL-4, IL-5 and IL-13). Both cytokines IL-4 and IL-13 favor the
IgE antibody production towards inhaled allergens, while IL-5 allows the
differentiation, activation and survival of eosinophils. Among effector cells,
two are predominant: mast-cells and activated eosinophils. During the initiation
phase of the allergic reaction the dominant phenomena is represented by IgE
mediated mast cell/basophil activation which leads to the release of granular
mast cell mediators but also to the secretion by mast cells of cytokines also
offering a Th2 profile. Moreover in chronic asthma histopathological,
immunocytochemical studies and in situ hybridization techniques demonstrate a
large recruitment of inflammatory cells, mainly of activated eosinophils that
similarly produce Th2 type cytokines and participate in the development of the
local allergic inflammation. Several additive environmental factors such as
viruses or aeropollutants are susceptible to amplify the Th2 type response;
conversely specific immunotherapy has been shown to allow a shift from the Th2 to
Th1 profile, which explains at least for a part its therapeutic effects.
PMID- 9554119
TI - [Specific immunotherapy of respiratory allergies].
AB - Specific immunotherapy has been in routine use since 1911 for the treatment of
respiratory allergic diseases. There is however a certain amount of controversies
regarding its overall indications. Its efficacy has been demonstrated in double
blind placebo controlled studies in both allergic rhinoconjunctivitis and
allergic asthma. The improvement of allergenic extracts (in particular by
standardization), the better understanding of the mechanisms of action of
immunotherapy, the recently proposed use of other administration routes and the
publication of guidelines have legitimated its definite role to play in the
therapeutic management of allergic respiratory diseases.
PMID- 9554120
TI - [Recent advances in the genetics of respiratory allergies].
AB - The genetics of atopy and asthma is a fascinating area of research which has made
tremendous progresses over the last couple of years. It has been known for ages
that allergies and asthma are concentrating within families. Modern genetics has
pintpointed some gene areas such as 5q31.1, 6p21.3, 11q13, 12q15 and 14q11.1. To
do so, a crucial step is the definition of the phenotypes. Once the phenotype is
set up (which is not an easy task), familial aggregation and segregation studies
can be performed. These familial studies allow molecular genetics and linkage
analysis. Both candidate gene approach and genome-wide search have been utilized
in the genetic of atopy and asthma. Much of the information available today has
been fragmentary and not always confirmed. Alleles at multiple loci are likely to
be involved and the ultimate picture is most likely determined by many genetic
and environmental factors.
PMID- 9554121
TI - [A new concept in digestive surgery: the computer assisted surgical procedure,
from virtual reality to telemanipulation].
AB - Surgical simulation increasingly appears to be an essential aspect of tomorrow's
surgery. The development of a hepatic surgery simulator is an advanced concept
calling for a new writing system which will transform the medical world: virtual
reality. Virtual reality extends the perception of our five senses by
representing more than the real state of things by the means of computer sciences
and robotics. It consists of three concepts: immersion, navigation and
interaction. Three reasons have led us to develop this simulator: the first is to
provide the surgeon with a comprehensive visualisation of the organ. The second
reason is to allow for planning and surgical simulation that could be compared
with the detailed flight-plan for a commercial jet pilot. The third lies in the
fact that virtual reality is an integrated part of the concept of computer
assisted surgical procedure. The project consists of a sophisticated simulator
which has to include five requirements: visual fidelity, interactivity, physical
properties, physiological properties, sensory input and output. In this report we
will describe how to get a realistic 3D model of the liver from bi-dimensional 2D
medical images for anatomical and surgical training. The introduction of a tumor
and the consequent planning and virtual resection is also described, as are force
feedback and real-time interaction.
PMID- 9554122
TI - [The robotization of neurosurgery: state of the art and future outlook].
AB - Neurosurgery is by excellence a field of application for robots, based on
multimodal image guidance. Specific motorized tools have been already developed
and routinely applied in stereotaxy to position a probe holder or in conventional
neurosurgery to hold a microscope oriented towards a given target. The
potentialities of these approaches have triggered industrial developments
currently commercially available. These systems use data bases, primarily coming
from multimodal numerical images from X-ray radiology to magnetic resonance
imaging. These spatially encoded data are transferred through digital networks to
workstations where images can be processed and surgical procedures are
preplanned, then transferred to the robotic systems to which they are connected.
We have been using a stereotactic robot since 1989 and a microscope robot since
1995 in various surgical routine procedures. The future of these applications
mainly rely on the technical progress in informatics, about image recognition to
adapt the preplanning to the actual surgical situation, to correct brain shifts
for instance, about image fusion, integrated knowledge such such as brain
atlases, as well as virtual reality. The future developments, covering surgical
procedure, research and teaching, will sure be far beyond our wildest
expectations.
PMID- 9554123
TI - [Vaccination against malaria. Disappointments and hopes].
AB - After the first in vitro cultivation of Plasmodium falciparum 21 years ago, the
prospect of anti-malarial vaccination arose many hopes, but, in the end, it so
far has mainly given rise to doubts and disappointments. Technically, the problem
is particularly difficult. Plasmodium falciparum has a very complex antigenic
structure with several hundreds, if not several thousands, of different epitopes
for each of the four main evolutive stages of the parasite (sporozoites,
merozoites, gametocytes, ookinetes) which correspond to different phase of the
infection and could be a target for vaccination. Many of these epitopes are stage
specific and some of them vary from one strain to another. Adjuvants also play a
major role and can qualitatively modify the type of immune response. The immune
mechanisms also differ according to the final goal: anti-Plasmodium infection or
anti-disease vaccine. Over the last few years, the first clinical assays have
been carried out with the Spf66 vaccine, a synthetic complex protein directed
against sporozoites and merozoites. In adults and children, the first results in
South America and in East Africa were modest but encouraging. Unfortunately they
were not confirmed by further studies in West Africa and South-East Asia. Two new
types of vaccines are under preliminary clinical evaluation. One is directed
against ookinetes of Plasmodium falciparum (Pfs25 and Pfs28) and can stop the
transmission from the mosquito. The other is an anti-sporozoite vaccine with a
new immunogen (RTS,S) in which the circumsporozoite protein is fused to the
hepatitis B surface antigen and can protect against infestation. New prospects
and improvements are offered by the technique of DNA vaccines and will probably
also result from better knowledge of cellular and molecular biology of the
parasite which is being extensively studied (genomic structure). If new promising
perspectives exist, it is particularly important to be careful to avoid such
disappointments as those caused, in the past, by a too-optimistic and over
publicized presentation of some preliminary results. It is now certain that one
or several malaria-vaccines will be available, but no one can seriously say when,
for whom and how. In any case, it is unrealistic to hope that vaccine(s) alone
will be able to eradicate such an epidemiologically complex disease as malaria.
It is probable that only the coordinated use of all the techniques available
(anti-vectorial protection and fight, chemoprophylaxis and chemotherapy,
vaccination) will lead to success.
PMID- 9554124
TI - [Colorectal carcinogenesis, frequency and significance of genetic alterations:
deletion of the short arm of chromosome 1, and initiating event].
AB - Cytogenetic anomalies described in colo-rectal tumors are numerous. Despite the
complexity and the number of the anomalies observed, a combined study of their
frequency and of the stage of prognosis of the tumors suggests that the evolution
from colonic adenoma to carcinoma often follows a sequence of events comprising a
5q15-22 deletion (DCC), and a 17p deletion (P53). It even seems likely that in
many cases, these events are not constant and that others might lead to the same
phenotypic transformation. Chromosome 1 involvement in structural rearrangements
has been demonstrated in numerous forms of cancers, malignant blood disorders and
in solid tumors. In colorectal adenocarcinoma anomalies have been described on
short and/or long arms. In a case of adenoma with mild dysplasia a deletion of
the distal part of the short arm of chromosome 1 was observed as an isolated
cytogenetic anomaly, suggesting it would be an early, perhaps triggering, event
for the tumour development. A cytogenetic study in a series of colo-rectal
tumours, researches on loss of heterozygosity and microsatellite instability lead
to consider deletions at chromosome 1p as an early event in human colorectal
tumourigenesis.
PMID- 9554125
TI - [Examples of foreign countries].
AB - In France we are not well aware of the health of people in situation of poverty:
they have not resources enough to care of oneself, not knowing the services of
social welfare, and not identified by these services. 1) Some studies in Great
Britain and in U.S. have followed up some deprived groups with health index on a
long duration: life expectancy at birth, number of stillbirths in the group, low
birth weight, casualty during childhood, violent deaths among teen agers and
young men. Disparities between rich and poor are dramatic, unskilled men have a
mortality three times that of professional men; advantage is given to people who
had had some education and a steady family home during childhood, compared with
those who have not. 2) In France investigations have been more accurate on the
health of deprived individuals: where are they taken care of, who cures them for
which diseases? According to the results, they are not abandoned. Places for
reception and care are many, the public institutions welcome them even without
social security guarantee, almost a hundred non profit associations may help
them: these discreet institutions are poorly known even by the public
administration.
PMID- 9554126
TI - [Access to health care for the destitute].
AB - An increasing proportion of low income people, in spite of receiving mandatory
coverage, cannot afford supplementary insurance, and they cannot afford to
advance payment for care which will lately be reimbursed, nor can they afford
copayments. The results is that a growing proportion of French population is
unable to access common care. Faced with this deteriorating situation, parallel
delivery systems of care have been devised at a local level, facilities have been
created, and health care providers volunteers to deliver health care to
underserved populations. To estimate the extent of the phenomenon, CREDES carried
out a specific survey at the national level. First we identified all health care
providers or facilities accessible to the underserved. These include traditional
providers or facilities, such as private physicians and hospitals which agree to
provide "charity care". There are also new facilities created specifically to
provide health care to the underserved. The second part of the survey covered the
human resources, equipment and services offered at these specific facilities. It
revealed the extensive participation by physicians and nursing staff generally on
a voluntary basis and the special attention given to the reintegration of the
underserved into the standard health care system through assistance with the
necessary administrative procedures.
PMID- 9554127
TI - [Access to health care for destitute persons at Public Assistance Hospitals in
Paris].
AB - All legal French residents are entitled to health care. The 1992 regulatory
measures, which create a contractual agreement between the government and public
medical institutions, aim at facilitating access to health care by resolving the
financial obstacles to accessing health care. The Assistance Publique-Hopitaux de
Paris (AP-HP) has set up a medical reception center in several hospitals since
1993. This system is integrated in the general structure of each hospital: in
some cases, there is a single and centralized unit; in other cases, all
departments of the hospital, including the emergency room, are involved in caring
for destitute patients. Whatever the type of the structure may be, social workers
are a key element to helping the patients recover their social rights. Thirty to
seventy-percent of patients visiting these centers regain access to social and
health care coverage. The epidemiological survey of the active file of patients
revealed that 70% are male, more than 50% are non-French nationals, half of which
do not have legal immigration status in France. Homeless people represent 40 to
80% of the population. The average age is around 35. The number of medical visits
varies greatly from one hospital to another and range from 20 to 60 per month.
The reasons for visiting the center and the identified medical disorders are
strongly related to the patients' life conditions and vary significantly with the
risk factors related to the social and economic situation. The frequency of some
diseases (psychiatric disorders, tuberculosis, infections by the HIV and HCV) is
higher in this population than in general population. Delayed visits to the
medical center represents a severity factor. The hospitals' mission statement is
not only to ensure that patients facing a precarious social and professional
situation have equal access to health care, but also to help such patients
recover their social rights, facilitate their integration in the society and
fight against social exclusion.
PMID- 9554128
TI - [Evaluation of the population received and cared for in France in the "Doctors of
the World" Health Centers].
AB - For 11 years now, Medecins du Monde's Mission to France has tried to respond to
the needs of a part of marginalized population, which has no access to health
care. In 1996, 72,000 consultations have been given throughout the 31 free Health
centers based in 31 cities in France. Who is this population? Basically young
people (more than half are under the age of 30 and 10% are underaged), men in 213
of the cases, living alone, in 80% of the cases. How do they live? Almost 65%
live with less than 20 francs per day (given by social care); 54% are officially
jobless. As far as housing is concerned, only 1/4 have a home (women in
particular). The others live in hostels, self-made shelters, hotels, or with
relatives; 13% admit living on the street. Why do they come to health centers?
Almost all diseases observed are identical to the ones detected in regular Health
care centers, i.e., Ear--Nose and Throat, respiratory and gynecological
infections. What makes them particular is the fact they are diagnosed later than
usual, which makes them more serious than usual. The living conditions of this
marginalized population explain the high frequency of skin problems (12%) and
neuropsychologic disorders. Why do they come to Medecins du Monde? 1/4 of the
patients do benefit from social welfare, but are unable to advance the payment of
medical costs, or support the difference between the actual cost and the
reimbursement by the Social security. 40% have no social coverage whatsoever.
However, other motives (1 to 7%) such as administrative problems, rights outside
their district, refusal to start the administrative procedures, ignorance of
their rights ... are rarely put forward. The population with no access to health
care is still unknown. This is why the information gathered is so important. It
allows a better qualification of the patients' requests and, consequently, a
better comprehension of the social exclusion phenomenon, particularly in the area
of health.
PMID- 9554129
TI - [Recourse to care and morbidity of the homeless in the Paris district].
AB - The disparities of access to care and morbidity according to different socio
economic characteristics are highlighted over about thirty years; what is the
situation with regard to the homeless, the least provided for, who in some sense
lie at the limits of the social scale? We present data on hospitalizations,
ambulatory care and the morbidity declared by the homeless revealed in the INED
survey of February-March 1995 in the Paris region. We tried to compare
hospitalizations and physician care of the homeless with the population of
"ordinary households" in the same region on the basis of different statistical
sources. Hospitalizations are considerably more numerous in this group than in
the rest of the population which indicates that the homeless are more exposed to
diseases and accidents; on the other hand, taking into account any possible
errors of observation, the homeless and the general population seem to have the
same rate of recourse to outpatient doctor treatment. Is this also the case for
complementary examinations, biological tests and medical imagery?
PMID- 9554130
TI - [Toe transplantation in congenital malformations of the hand].
AB - Toe transfer is a well established procedure for thumb and finger reconstruction
after mutilation. The indications in congenital malformations are a mater of
controversy. Out of a personal series of 209 patients, 42 were children
presenting a congenital malformation. Thirty six, with 46 transfers were
available for review. There is only one failure at the beginning of our
experience. The main indication was absence of pinch either due to absence of
thumb (like in congenital band syndrome or some extreme cases of ulnar club hand
or cleft hand) or absence of long finger (like in symbrachydactyly monodactylous
type) or lack of both thumb and finger (like in peromelic type of
symbrachydactyly). In this last type, we have been disappointed by the functional
result of the distal implantation of two second toes taken from both feet; we
have proposed a "stub" operation consisting in a second toe transfer on the
anterior aspect of the radial epiphysis to take advantage of the mobility of the
wrist and the availability of plenty tendon transfer (in this proximal
situation). When planing to "built" an absent pincer, an early age is mandatory
for operation (mean 12 months), to ensure a good cortical integration. A less
frequent indication is a partial toe transfer with a vascularized epiphysis to
provide growth and mobility in some cases of thumb hypoplasia (like in
symbrachydactyly or Blauth and Manske type III b). Results are difficult to
assess due to the early operation but if the mobility has been disappointing
(mean 32 degrees), sensibility (mean 2PD 5 mm) and growth were excellent.
PMID- 9554131
TI - [Excimer laser: history, development and comparison of equipment].
AB - We first present the history of the Excimer Laser technological development which
began in 1975 with Velazco and Sester's research. We report various studies about
lasers conceiving, treatment parameters, laser-tissues interactions, and
treatments evolution. In the second part, we compare different Excimer laser
systems and their capacities. Three current technologies are used for clinical
application: the broad beam lasers, which use a diaphragm or a disc with multiple
apertures, the scanning slits and the flying spots. Advantages and disadvantages
of the various delivery systems are discussed.
PMID- 9554132
TI - [Laser and corneal surgery: pathological anatomy].
AB - The studies of the effects of different lasers on the cornea have usually been
done on animals. These studies show that ultra-violet lasers (Excimer 193 nm, 213
nm) have a pure photo-ablative effect, without distant lesions. The corneal
endothelium is always intact as long as the laser beam is acting at a distance of
more than 50 microns from the cells. The same findings after photo-ablation is
the presence of a fibroblastic scar after epithelial healing. This scar
correspond to the haze observed in clinical conditions. The infra-red lasers
(Intrastomal YAG) produce an important thermal effect the corneal stroma and a
destruction of the corneal endothelium if influence and frequency are increased.
In conclusion, the lasers used in corneal surgery appear to be safe for the
corneal structure but histological studies remain necessary for the new lasers in
order to be certain of their safety.
PMID- 9554133
TI - [Laser and corneal surgery: topography and preoperative evaluation].
AB - The purpose of preoperative clinical examination is to determine accurately the
refraction under cycloplegia. Operative techniques and protocols are chosen in
relation to the degree of ametropia. Computer assisted videokeratography allows
early keratoconus detection and gives reference quantitative datas for analysing
postoperative changes.
PMID- 9554134
TI - [Laser and corneal surgery: patient selection].
AB - The aim of refractive surgery is a good postoperative visual acuity and the
satisfaction of the patient. To reach this, a good selection of the patient is
important. Each patient has to be evaluated personally and individually at the
hand of the next criteria: A complete preoperative examination The motivation and
the expectations of each patient The possibilities and the complications of each
operative technique. the contra-indications of the refractive surgery and each
operative technique. In case of small and moderate myopia, the results of the
radial keratotomy and the excimer-laser are similar and comparable with each
other. In case of moderate and high myopia, the excimer-laser (PRK and LASIK) is
the only valuable operative technique.
PMID- 9554135
TI - [Treatment of severe myopia using the excimer laser].
PMID- 9554136
TI - Excimer laser correction of astigmatism using erodible masks.
AB - PURPOSE: The latest development in the erodible mask technology is an excimer
laser containing the mask in the laser optical pathway. This paper reports the
results of the first human series of consecutive treatments performed for the
correction of compound myopic astigmatism. METHODS: We have treated 83 eyes.
Spherical equivalent attempted correction ranged between -1.75 and -11.75 D (mean
-7.07 +/- 2.45 D), astigmatic attempted correction ranged between -1.00 and -5.00
D (mean -2.42 +/- 1.02 D). The sphere correction was made by diaphragm using a
multi-zone software with three ablation zones: 100% of the total attempted
correction for the central 5.0 mm zone, 70% for the second 6.0 mm zone, 30% for
the outer 6.5 mm zone. Cylinder correction was made sequentially after myopic
correction using the appropriate mask. RESULTS: One month after treatment, mean
refractive error was +1.07 +/- 1.24 D (range +4.50/-1.75 D) for spherical
equivalent, and -0.49 +/- 0.57 D (range +0.75/-2.00 D) for astigmatism. Forty
eight eyes (57.8%) had uncorrected visual acuity of 20/40 or better. At six
months, mean refractive error was +0.42 +/- 0.97 D (range +3.75/-1.00 D) for
spherical equivalent, and -0.44 +/- 0.51 D (range +0.25/-3.00 D) for astigmatism.
Vector analysis showed that 57 eyes (68.7%) had 5 or less degrees rotation.
Seventy-two (86.7%) and 54 eyes (65.1%) had uncorrected visual acuity equal or
better than 20.40 and 20/25 respectively. One eye (1.2%) showed a best corrected
visual acuity loss of more than one line, but 8 eyes (9.6%) had a gain of more
than one line. One-year results on a smaller series (33 eyes) overlap the six
month results. CONCLUSIONS: The mask in-the-rail excimer laser delivery system
appears to be effective and predictable in the correction of compound myopic
astigmatism. We observed no significant regression of the astigmatic correction
over time. Longer follow-up on larger series is necessary to draw final
conclusions.
PMID- 9554137
TI - [Treatment of hypermetropia using the Holmium laser--laser thermokeratoplasty
(LTK)].
AB - The results of two year follow-up after Holmium LTK are presented. The choice of
the technique was justified based on experimental, technical and anatomo
pathological data as well as on the property of the corneal collagen fibers to
shrink at a temperature of 60-70 degrees C. Although the immediate results were
encouraging, we found an important regression after two years follow-up,
resulting in a final correction of maximally 1.5 D, independent on the degree of
hypermetropia to be treated. These results were obtained with the "contact"
method, which is in our experience slightly superior to the "non-contact"
technique. The question is whether the regression will continue with time or will
stabilize and remain at 1.5 D of hyperopic correction.
PMID- 9554138
TI - [Surgery in myopic astigmatism: arciform keratotomy and PKR versus PARK].
AB - Two surgical techniques for treatment of myopic astigmatism are compared: One
technique is a combined procedure with relaxing incision and photorefractive
keratectomy (RI PRK), the other one is photoreactive keratectomy done for
correction of myopia and astigmatism (PARK). Fifty-nine eyes (42 patients) were
operated by IR PRK. The preoperative myopia was between -1.5 and -14 D and the
astigmatism between -0.75 and -6 diopters. Thirty-two eyes (20 patients) were
treated with the PARK. The preoperative myopia was between -1 and -15 D and the
astigmatism between -0.5 and -4. In 38 cases, relaxing incisions allowed to
correct astigmatism entirely. The mean preoperative sphere of -6.8 D before PRK
was 1.4 D and the spheres between -1 and -15 D. Twelve months after treatment, 26
eyes on 30 were spherical. The spherical equivalent varied between +0.75 and
1.50 D. Relaxing arciform incision presents the advantage to correct high
asymmetric astigmatism without corneal thinning, as well as mixed astigmatism. At
the present time, the PARK allows to correct only symmetrical myopic astigmatism.
CONCLUSION: The predictability of the results is high if the cylinder is less
than 3 D and the sphere less than 6 D. Beyond this limit, there is a higher risk
of regression, and haze related with the depth of photo-ablation and we prefer RI
PRK.
PMID- 9554139
TI - [Excimer laser phototherapeutic keratectomy].
PMID- 9554140
TI - [Complications in excimer laser photorefractive keratectomy].
AB - The complications of photorefractive keratectomy with excimer laser for myopia
depend on preoperative myopia and inter-individual variability in wound healing.
Loss of best corrected visual acuity is induced by Haze, irregular astigmatism
and decentration. Haze is more frequent after treatment of high myopia.
Decentration is a severe complication because its treatment is not well defined
and is difficult. Corneal ulcerations infectious and non-infectious have been
reported. Other complications are described: induced astigmatism, over and under
corrections, central islands, halos, loss of corneal sensitivity, abnormal
epithelial healing, recurrent epithelial breakdown, sterile corneal infiltrates,
elevated intraocular pressure, subretinal hemorrhage.
PMID- 9554141
TI - [Medical treatment in laser (PRK) photoretractive keratotomy].
AB - The need of medical treatment after photorefractive surgery has been studied by
reviewing the literature on the subject and comparing their conclusions with our
clinical experience. Considering the pre-operative and immediate post-operative
medical treatment, there is a large consensus since the aim is treatment of pain
and prevention of superinfection. The post-operative considerations for medical
treatment are more controversial and can be considered as to be useful or
possibly useful.
PMID- 9554142
TI - [Deamination of adenine and adenosine in staphylococci].
AB - Deaminations of adenine and adenosine by pattern strains of 24 staphylococcal
species, were tested. During 3 hours of incubation of the suspensions of 8
staphylococci with adenine the liberation of ammonia occurred. The same
staphylococci accumulated ammonia in the incubation medium with adenosine. The
Staphylococcus intermedius PCM 2405 strain as opposite to the Staphylococcus
aureus 536 strain in the media with adenine or adenosine accumulated hypoxanthine
or inosine, respectively and ammonia. These results indicated that adenine
deaminase (adenase) and adenosine deaminase activities were associated with the
cells of the Staphylococcus intermedius PCM 2405 strain. Staphylococci were
heterogeneous within three species groups with respect to adenine and adenosine
deaminations. Adenine and adenosine determinations were absent in staphylococci
belonging to the Staphylococcus simulans species group.
PMID- 9554143
TI - [The influence of temperature on culture of Staphylococcus aureus for cell
adhesion to collagen].
AB - The aim of this study was the investigation of adhesion of 88 S. aureus clinical
isolates to collagen. The experiments were extended to determine the influence of
growth temperature on collagen adhesin-collagen interaction. Bacterial adhesion
to collagen was estimated by using immunoenzymatic assay at absorbance of 492 nm
and compared with standard curves obtained for 8 different densities of each
strain. The amount of collagen adhesin was indicated by colour reaction intensity
measured by immunoenzymatic assay. Hydrophobicity of S. aureus strains was
measured by aggregation in (NH4)2SO4 test. Almost all S. aureus strains isolated
from bone and joint infections adhered to collagen whereas only a part of soft
tissue infections isolates showed this feature. The comparison of adhesive
properties of S. aureus cells cultured at 21 degrees C, 37 degrees C and 42
degrees C did not make it possible to indicate the optimal culture temperature
for S. aureus adhesion to collagen. However, the intensive colour reaction of
cells cultured at 37 degrees C with anti-collagen adhesin antibodies proves the
production of the highest amount of this adhesin under the mentioned conditions.
The influence of growth temperature as well as solid and/or liquid medium on the
change of S. aureus hydrophobic properties was not observed. The obtained results
show that the S. aureus growth temperature can be one of the factors influencing
the staphylococci cells adhesion to collagen.
PMID- 9554144
TI - [Utilization of Staphylococcus siderophores produced by Corynebacterium and
Coryneform bacteria].
AB - The ability of iron utilizing by means of siderophores produced by donor strains
Coryne-bacterium and coryneform organisms (8 strains) by 24 staphylococcal
strains was investigated. All the donor strains synthesized catecholate class
siderophores and two strains also hydroxamate class. The majority of
staphylococcal strain could utilize these siderophores. Most of strains utilized
siderophores from Corynebacterium pseudodiphtheriticum and Corynebacterium
aquaticum as well as chelators from plant pathogens-coryneform organisms. Only
two staphylococcal strains were not be able to utilize siderophores from all
donor strains.
PMID- 9554145
TI - [Susceptibility to antibiotics of Staphylococcus aureus strains].
AB - Staphylococcus aureus is a very important pathogen in humans about 20% of all
bacterial infections are caused by S. aureus. Because the staphylococcal
sensitivity patterns have changed, the aim of this study was to investigate the
current susceptibility of the S. aureus strains to 9 antibiotics: penicillin (P),
amoxacillin/clavulanic acid (AMC), erythromycin (E), cortimoxazole (SXT),
tetracycline (T), chloramphenicol (C), mupirocin (MUP), gentamicin (Ge) and
vancomycin (Va). Susceptibility testing was performed by disc diffusion
technique, by the procedure outlined by the National Committe for Clinical
Laboratory Standards (NCCLS). Susceptibility to methicillin was determined using
5 micrograms methicillin disks. beta-lactamase production in the penicillin
resistant strains was detected with nitrocefin impregnated disk (Cefinase, BBL
Microbiology system). The microbiological characteristics of the samples: 338 of
the isolates were derived, from noses and the throats 382--from surgical wound
secretions. The analysis of the results showed that most S. aureus strains
(82.8%) are penicillin resistant and beta-lactamase producing 13.5% of all
strains were methicillin-resistant. 16.5%--were erythromycin resistant; 3.2%-
were cotrimoxazole resistant; 51.4%--were mupirocin resistant; 20.6%--were
gentamicin resistant. All of the strains were vancomycin sensitive.
PMID- 9554146
TI - [Sensitivity to disinfectants of methicillin resistant Staphylococcus aureus
strains (MRSA) and gentamicin resistant strains].
AB - The aim of the study was to find out whether methicillin-resistant S. aureus
strains (MRSA) are tolerant in a higher degree to disinfectants, and whether a
correlation exists between lower sensitivity to these agents and resistance to
gentamicin. The study was carried out on 30 strains of MRSA and 20 of MSSA
isolated from various clinical materials in various regions of the country. Among
the studied MRSA 24 strains were resistant and 6 were sensitive to gentamicin,
and in MSSA 3 strains were resistant and 17 sensitive to this antibiotic. The
sensitivity to four disinfectants: Manusan, Sterinol, Septyl R and Lysoformin
Spezial was determined by measurement of MIC (minimal inhibitory concentration)
in agar medium. Most MRSA in Poland showed decreased sensitivity to these
disinfectants. Among gentamicin-sensitive and resistant MRSA strains the
proportions of strains with higher tolerance of three disinfectants (Manusan,
Sterinol and Lysoformin Spezial) were very similar. Reduced sensitivity to
disinfectants was found in all gentamicin-resistant MSSA. These data indicate
that S. aureus strains possess various mechanisms of tolerance of disinfectants.
Nearly half the studied strains (46%) had decreased sensitivity to all three
preparations (Manusan, Sterinol and Lysoformin Spezial) belonging to various
chemical groups this seems to indicate that increased tolerance to these
disinfectants is a non-specific feature of S. aureus strains.
PMID- 9554147
TI - [Production of enterotoxins by Bacteroids fragilis strains--effect of
clindamycin].
AB - Four B. fragilis strains were examined: one nonenterotoxigenic (NTBF) and three
producing enterotoxin (ETBF). The growth of cultures was determined and
enterotoxin, which is released to the culture medium during growth of strains,
was detected. BHI broth and BHI broth with addition of subinhibitory doses (sub
MIC) of clindamycin were applied. Bacterial cultures were incubated at 37 degrees
C for 48 hours. After 4, 8, 16, 24, 48 hours of cultivation, samples of bacterial
cultures were collected and the optical density was measured. Then the samples
were centrifuged, supernatants were filtered through 0.45 micron filters and
concentrated three times with 5000 D ultrafilters. Prepared samples were kept
frozen at -70 degrees C until used. The titre of enterotoxin in samples was
determined on human colon adenocarcinoma cell line HT 29/C1. Neutralization assay
was performed with culture filtrates, which were enterotoxin-positive and with
rabbit anti-enterotoxin serum. The results of the experiments indicate that
enterotoxin is detected after 16 hours of incubation of ETBF strains. Clindamycin
at subinhibitory concentrations (sub-MIC) inhibits the growth of B. fragilis
cultures. The antibiotic causes also delay and decrease in enterotoxin production
by ETBF strains.
PMID- 9554149
TI - [Establishing the types of Dienes compatibility in clinical Proteus mirabilis
strains].
AB - The aim of the study was to use the Dienes phenomenon for the differentiation of
Proteus mirabilis strains isolated from urine by the method of making possible
their typing. The subject of the study were 351 strains of Proteus mirabilis
obtained from the laboratory of the Institute of Pediatrics, Medical Academy in
Lodz. For establishing of the compatibility type 18 indicator strains were taken,
each of them had action antagonistic towards all other ones. The results were
read according to the presence or absence of the demarcation line between
indicator strains and the studied strain. Out of 351 strains in 190 (54%) the
reactions were compatible with one or more indicator strains. They were
classified into 30 Dienes compatibility types. In the view of the simplicity and
easy performance the method can be used in every microbiological laboratory.
PMID- 9554148
TI - [Use of the LAL test for quantitative determination of Bacteroids fragilis
endotoxin].
AB - The aim of this study was the evaluation of LAL test with chromogenic substrate
usefulness for the quantitative detection of B. fragilis endotoxin and the
determination of the amount of endotoxin in culture filtrates of the strains of
this species. Also, the trial was undertaken to determine the influence of
clindamycin on endotoxin release from B. fragilis rods to the culture medium.
Four B. fragilis strains were examined: one nonenterotoxigenic (NTBF) and three
enterotoxigenic (ETBF). The growth of cultures was determined and endotoxin
liberated to the culture medium during growth of strains was detected. BHI broth
and BHI broth with addition of sub inhibitory doses (sub-MIC) of clindamycin were
applied. Bacterial cultures were incubated for 48 hours at 37 degrees C. Samples
of bacterial cultures were collected after 4, 8, 16, 24 and 48 hours of
cultivation, and the optical density was measured. Then the samples were
centrifuged, supernatants were filtered through 0.45 micron filters and
concentrated three times with 5000 D ultrafilters. Prepared samples were kept
frozen at -70 degrees C until used. The amount of endotoxin in samples was
determined using quantitative LAL test with chromogenic substrate S-2423. The
results of the experiments indicate that LAL test is the useful method for
determination of B. fragilis endotoxin concentration. This endotoxin activates
the enzymatic system present in Limulus polyphemus amebocyte lysate. Endotoxin is
shed spontaneously by B. fragilis rods to the culture medium during growth.
Clindamycin at subinhibitory concentrations (sub-MIC) inhibits the growth of
cultures of examined strains. The antibiotic caused increase in endotoxin amount
in culture medium.
PMID- 9554150
TI - [Evaluation of the usefulness of the agglutination test with Mangifera indica
extract for the identification of pathogenic Yersinia enterocolitica strains].
AB - The study was performed on 137 Y. enterocolitica strains belonging to various
serological groups, including 75 03 group strains isolated form human clinical
material. The agglutination test on slides was carried out on this strains using
Mangifera indica extract of own production. Agglutinating preparation obtained
from the seeds of M. indica agglutinated Y. enterocolitica organisms possessing
the pVY plasmid and CRMOX+ phenotype in dilutions to 1.56 micrograms/ml. In
identification tests conducted parallelly agglutination solution was used in
concentrations of 100 and 10 micrograms/ml. All clones of Y. enterocolitica from
O3 group from cultures at 37 degrees C and with CRMOX+ phenotype possessing the
pVY plasmid were agglutinated by the extract. Agglutination failed to develop in
the cultures of these clones incubated at 25 degrees C. Yersinia clones not
containing the pVY plasmid with CRMOX- phenotype were resistant to agglutination.
The virulence plasmid was found in 44 out of 75 strains of Y. enterocolitica O3
and was identified by restriction analysis after plasmid DNA digestion with Eco
RI enzyme. The obtained results agreed with those of Wauters et al. in 1995 and
confirmed the opinion of these authors on the usefulness of the test with M.
indica agglutinin for the identification of virulent Y. enterocolitica strains.
PMID- 9554151
TI - [Hydrophobic properties of Pseudomonas aeruginosa strains].
AB - Hydrophobic properties are considered as a factor enhancing the adhesion of
bacteria to tissue cells. The strains of P. aeruginosa isolated from patients
with urinary tract infections (UTI), from feces and soil were investigated. It
shows that over 50% strains isolated from UTI had hydrophobic cell surface. Most
of all strain investigated (67.9%) is characterized by hydrophobicity what
probably favours their pathogenicity.
PMID- 9554152
TI - [Susceptibility of clinical strains of gram-negative rods to selected beta-lactam
antibiotics].
AB - The aim of the study was to determine the activity of four beta-lactam
antibiotics against nosocomial strains of gram-negative bacilli. Two antibiotics
combined with beta-lactamase inhibitors: timentin (TIC/CLAV) and tazocin
(PIP/TZB) and two carbapenems: imipenem and meropenem were applied. The clinical
strains were isolated from patients hospitalized in the following wards: surgery
and intensive care unit of State Clinical Hospital No 1 in Warsaw. The strains
were identified in the automatic ATB system using ID 32 E and ID 32 GN strips.
The susceptibility of isolates to antibacterial agents was determined in the
automatic ATB system using ATB G- and ATB PSE strips. The susceptibility of the
strains to imipenem, meropenem, timentin and tazocin was tested by disc-diffusion
method. 157 strains of gram-negative bacilli were cultured. 100 strains were
isolated from patients hospitalized in surgical ward and 57 strains from patients
hospitalized in ICU. Nonfermenting rods dominated among isolated strains-91. The
results obtained indicate that multiresistant gram-negative rods causing serious
therapeutic problems are often isolated from clinical specimens. The contribution
of nonfermenting rods, especially Pseudomonas spp. and Acinetobacter spp. to the
etiology of infections in hospitalized patients has increased. Infections caused
by these strains are difficult to cure. Tazocin and carbapenems (imipenem and
meropenem) are highly active in vitro against the examined strains of gram
negative bacilli.
PMID- 9554153
TI - [Breast feeding for prevention of viral acute respiratory diseases in infants].
AB - The incidence of acute viral respiratory diseases (confirmed by
immunofluorescence test) was compared in a group of 159 infants aged 0-9 months
breast-fed at least once daily and in a group of 608 infants of similar age and
hospitalization duration receiving only artificial food. The incidence was
significantly lower in breast-fed infants (p = 0.00057), especially in the first
trimester of life (p = 0.00039). This was valid of all RSV infections (p =
0.01854) and parainfluenza type 4 virus infections (p = 0.0846). The antibody
level against parainfluenza type 1 and 3 (HI) and against RSV in IgA class
(ELISA) was compared with that in mother's milk and serum. No significant
correlation was found for parainfluenza type 1 antibodies (r = 0.159) and 3 (r =
0.025), while for RSV the correlation was positive and statistically significant
though rather low (r = 0.234). No significant correlation was found between milk
antibody levels and the incidence of acute viral respiratory infections. Breast
feeding showed a significant influence on the lower incidence of these
infections, particularly in the first trimester of life. It seems that this was
associated with a non-specific mechanism rather than with the milk levels of
specific antibodies.
PMID- 9554154
TI - [Use of the western blot method for detecting antibodies against proteins of
various rotavirus strains].
AB - The aim of this work was to adapt the Western blot method to analyse the humoral
response to proteins of rotavirus strains having various antigens. 10 serum
samples from animals immunized with SA11, 18 serum samples from hospitalized
children with rotavirus infections and 17 serum samples from healthy adults were
examined for rotavirus antibodies using Western blot. Antibodies against all
structural rotavirus proteins were detected. The examined sera reacted
differently with rotavirus proteins depending on the strain used. The highest IgG
reactivity was observed for Wa and SA11, while the lowest was noted for DS-1. At
the same time a different level of cross-reactivity of human sera with specific
proteins of antigenically varying rotaviruses was observed. The sera taken from
adults showed a lower reactivity with proteins of antigens used compared with
sera from children. The exception was VP6 of the Ito strain for which the
reactivity of adult sera was statistically higher. Essential differences in the
reactivity of children's and adult sera were found mainly in the case of VP2 and
VP4 belonging to the SA11 strain and VP4 and VP7 of the Ito strain. From these
investigations we can conclude that the Western blot method may be useful in
assessing immune response caused by rotaviruses. The results of reactivity of
some human sera with proteins of strains used indicates that the persons had
previously been infected by antigenically varied rotaviruses.
PMID- 9554155
TI - [Use of western blot methods for serodiagnosis of hydatidosis in Poland].
AB - 46 sera and 1 cerebrospinal fluid samples from 47 patients suspected of
hydatidosis were examined by Western blot method, and the results were compared
with those of the indirect haemagglutination, immunoelectrophoresis and an enzyme
linked immunosorbent assay (ELISA). The examinations confirmed high sensitivity
and specificity of the reactions with 8 kDa antigenic fraction in the Western
blot. The above data supported the concept, that serological diagnosis of
hydatidosis should be carried out using a high sensitivity screening test, such
as ELISA, then the Western blot method to verify positive results.
PMID- 9554157
TI - [Clinical genetics in The Netherlands. I. Organization, activities and laboratory
diagnosis].
AB - There are seven centres for clinical genetics in the Netherlands. In 1996, some
63,000 persons (patients and possible carriers of hereditary diseases) were
tested. In centres for clinical genetics chromosomal studies, biochemical
diagnostics of hereditary metabolic diseases and DNA diagnostics are integrated
with genetic counseling and prenatal diagnosis. The borders between the three
different forms of laboratory testing for congenital anomalies and hereditary
diseases gradually diminish. The variations of the numbers of laboratory
examinations, genetic advices and prenatal diagnoses over the last ten years show
that there is no correlation between these activities and the method of funding.
Owing to the low prevalence of the diseases involved, the total number of DNA
diagnoses for monogenic diseases will not increase significantly. However, once
genetic risk factors of diseases such as cancer, cardiovascular diseases,
diabetes, asthma, rheumatism, some psychiatric disorders and Alzheimer dementia
will have been mapped, DNA diagnostics will greatly expand and will have
implications in a broad area of medicine.
PMID- 9554156
TI - [Detoxication in opiate addiction and prevention of recurrence: administration of
naltrexone and cognitive behavior therapy].
AB - Rapid opiate withdrawal and relapse prevention in opiate addicts are made
possible by naltrexone, clonidine and diazepam in combination with cognitive
behavioural therapy according to the Community Reinforcement Approach. In an open
pilot experiment 12 addicted patients achieved initial detoxification. At follow
up after a minimum of 6 months, 10 of these had not relapsed. Good results with
this detoxification method could be booked by selecting highly motivated opiate
addicts.
PMID- 9554158
TI - [Clinical genetics in The Netherlands. II. Genetic counseling and prenatal
diagnosis].
AB - The main feature of clinical genetics is the involvement of close relatives in
the diagnostics of a hereditary disorder, and the possible consequences of the
findings for future generations. Complex genetic counseling is required in cases
with different, possibly hereditary disorders or congenital anomalies in the
family or by a syndrome with variable risks of recurrence, depending on the exact
nature of the disorder; also the difficult, often emotionally charged choices
with which counselees are faced demands the expertise of a clinical genetic
centre. Results of follow-up studies after genetic counseling show that
experience with a handicap or disease in the own environment and the presence of
healthy issue are the main determinants for the decision about reproduction of
persons with an enhanced genetic risk who request counseling. Because of the
great variety in perception of risks and of the severity of a disorder, and
because of the marked clinical heterogeneity, rigid legislation should be avoided
in the field of prenatal diagnosis. In the future, the training of the clinical
geneticist has to be adapted to the rapid progress in human genetics.
Increasingly, the clinical geneticist will function in collaboration with other
disciplines such as oncology, obstetrics and gynaecology, paediatrics and
neurology; in connection with family testing and counseling, there will also be
more collaboration with primary health care.
PMID- 9554159
TI - [Current antimicrobial drugs].
AB - In the past few years several new antibiotics became available, but no major
inventions as to new treatment strategies were made. There are a few new broad
spectrum antibiotics for the intravenous route like piperacillin-tazobactam, the
carbapenem meropenem and the fourth-generation cephalosporins. cefepime and
cefpirome. New oral antibiotics include the third-generation cephalosporins
ceftibuten, cefetamet and cefpodoxime and the macrolides clarithromycin and
azithromycin. The last two have the great advantage of less frequent dosing and
fewer side effects than erythromycin. Of the two new quinolones, sparfloxacin and
trovafloxacin, trovafloxacin is the more promising. In the treatment of Gram
positive infections the glycopeptide teicoplanin became available and the
combined derivatives quinupristin-dalfopristin may prove valuable in the future.
PMID- 9554160
TI - [Consensus diagnosis and treatment of arterial intermittent claudication. Central
Guidance Organization for Peer Review].
AB - Intermittent claudication is an indicator of increased risk of cardiac and
cerebrovascular morbidity and mortality and as such a reason to look for
modifiable risk factors for atherosclerosis. A vascular anamnesis and physical
examination can reliably exclude presence of peripheral arterial occlusive
disease in the lower extremities, but cannot reliably demonstrate its presence.
Certainty about presence or absence of peripheral arterial occlusive disease can
be obtained by determination of an ankle-brachial blood pressure index. The main
method for the diagnosis of severity and localisation of stenoses and occlusions
in the arteries to the legs is the echo-Doppler (duplex) examination. With this
method the feasibility of percutaneous transluminal angioplasty (PTA) can also be
determined. Consequently, angiography has lost importance as a diagnostic method
and is only still indicated as part of an interventional treatment (operation or
PTA). Treatment should be aimed at both amelioration of symptoms and reduction of
risk factors for atherosclerosis. A key-stone of the treatment is cessation of
smoking. The role of pharmacotherapy in reducing symptomatology is only limited.
Walking exercise can have a positive effect on walking distance and should always
be tried. PTA is the treatment modality of first choice for stenoses in the
aortoiliac and femoropopliteal arteries. For segmental occlusions in the iliac
pathway, also recanalisation by means of PTA (in combination with stent
placement) is a justifiable treatment option. In all other cases operative
revascularisations give good functional results. Invasive treatments for patients
with intermittent claudication should be performed within a multidisciplinary
team.
PMID- 9554161
TI - [Decreased quality of cervix mucus under the influence of clomiphene: a meta
analysis].
AB - OBJECTIVE: To determine whether clomiphene (citrate) has a negative influence on
cervical mucus qualities and whether administration of exogenous oestrogens has a
favourable influence in that case. DESIGN: Meta-analysis. SETTING: Stichting
Gezondheidszorg Oostelijk Zuid-Limburg, Midwifery School, Kerkrade, the
Netherlands. METHOD: Relevant articles were searched using the Medline database
for the years 1980-1996 and the Knowledge Finder search system. The reference
lists of these articles were studied. All prospective, randomized and controlled
clinical trials mentioning detailed figures were selected and analysed. RESULTS:
Six articles met all criteria for analysis of the effect of clomiphene on
cervical mucus. Clomiphene 50 mg/day had an unfavourable influence on cervical
mucus (not significant), but clomiphene 100 and clomiphene 150 mg/day did have a
significant effect, the relative risk of unfavourable cervical mucus being more
than seven in comparison with women not using clomiphene (respective odds ratios
7.90 (95% confidence interval: 4.15-15.00) and 7.50 (1.97-28.60)). Four articles
met all criteria for analysis of the effect of exogenous oestrogens on cervical
mucus of women being treated with clomiphene. Exogenous oestrogens resulted in
improvement of the cervical mucus qualities in these women (odds ratio: 2.87
(1.76-4.69)). CONCLUSION: The influence of clomiphene 50 mg/day on cervical mucus
is not significantly unfavourable, unlike the influence of clomiphene 100 and 150
mg/day. Exogenous oestrogen administration improves this cervical mucus. In all
patients being treated with clomiphene the cervical mucus qualities should be
investigated.
PMID- 9554163
TI - [Lichen sclerosus et atrophicus as a cause of genital lesions in a girl].
AB - In a 10-year old girl with irritated vulva lichen sclerosus et atrophicus (LSA)
was diagnosed. She was successfully treated with local application of equal
amounts of a cortisol ointment and zinc oil. LSA is a disease of the skin
infrequently seen in children, and then mostly in girls. Diagnosis is based on
typical lesions in the anogenital region (sharply delineated ivory discoloration,
moderate sclerosis and atrophy, haemorrhagic erosions). Knowledge of this disease
is important in order to distinguish it from sexual abuse.
PMID- 9554164
TI - [Joint decision making, how? Physician-patient communication about palliative
treatment].
PMID- 9554165
TI - Extended-spectrum beta-lactamases: an actual problem of hospital microbiology (a
review).
AB - Although there is a variety of mechanisms of bacterial resistance to beta-lactam
antibiotics, the most important one is production of beta-lactamases inactivating
penicillins and cephalosporins. The classification of beta-lactamases is based on
biochemical, enzymological (i.e. molecular structure, inhibitory property,
substrate-profile, relative rate of hydrolysis) and immunological characters.
Extended-spectrum beta-lactamases (ESBLs) can be derived from TEM or SHV enzymes.
These enzymes have now been sequenced and it has been found that relatively few
point mutations have occurred in the gene of the TEM and SHV type enzymes. These
point mutations clustered in five areas of the gene. The amino acid mutations can
alter the conformation, the active site and change the hydrance of beta-lactamase
cephalosporin binding capacity. So the enzyme is able to bind and hydrolyse the
third generation cephalosporins. Successive mutation interacted radically
increasing the binding capacity of enzymes and confer resistance to newer
cephalosporins. The use of these drugs provides a strong selective pressure to
develop these mutations. Sporadic nosocomial outbreaks due to strains producing
an ESBL led to an epidemic problem in some hospitals resulting in a concurrent
dissemination of genes, plasmids or strains. Clinical epidemiological importance
and role of ESBLs and emergence of multiply resistance of bacteria of nosocomial
importance are discussed in this brief.
PMID- 9554166
TI - Clinical, laboratory, and serological findings of adult Hungarian hospitalized
acute hepatitis patients, and possible source of the infection.
AB - Clinical, epidemiological features of acute viral hepatitis of 331 hospitalized
adult patients were evaluated. HA, HB, HC, and non A-C H were diagnosed in 36.6%,
34.1%, 10.6%, and 18.7%, respectively. Age of HA cases was significantly lower
than that of other cases. Only HA showed seasonal variation. Acquisition of HA
was often associated with visits in endemic areas when compared with all other
types, while HB, HC, and non A-C H were rather associated with iatrogenic events
(blood transfusion, surgical procedures, and hospitalization). Symptoms of fever
and diarrhea, and high ESR were more frequent in HA than in other types, while
signs of weight loss and high levels of ALT, AST, and S.T.B, and decreased PT
index were significantly more frequent in HB. Cholestasis course was found in
1.7%, 0.9%, and 3.2% of patients with HA, HB, and non A-C H, respectively.
Fulminant course was found only in 0.9% of HB patients. Factors as sex and age
had no effect on severity of acute phase in HA, HC, and non A-C H, while only the
age of patients was inversely associated with severity of acute phase in H B.
PMID- 9554167
TI - Compact growth of Staphylococcus haemolyticus in soft agar is not due to
hydrophobic interaction between the cocci.
AB - It was hypothesized that the formation of compact colony in soft-agar both in the
presence and absence of serum, characteristic mainly for strains of the species
Staphylococcus haemolyticus among coagulase-negative staphylococci [Szucs et al.
Acta Microbiologica Hungarica 40:181-189 (1993)] was due to hydrophobic
interaction between cocci. The effect of a number of surface active agents on
this phenomenon was examined. Neither 0.1% and 1%. Tween-80 nor 5% and 10%
ethylene glycol and polyethylene glycol nor 0.1%-4% trypsin influenced the colony
morphology in soft-agar prepared in modified Staphylococcus 110 broth. Bovine
lactoferrin and apolactoferrin at concentrations of 0.1%-0.4% made compact
colonies transient to diffuse ones. Thus, cocci are not adhered to each other in
compact ball-like colonies by hydrophobic interaction or trypsin-sensitive
proteins. It is possible that still unknown polysaccharide-binding proteins or
other trypsin-resistant proteins are responsible for the formation of compact
colonies by Staphylococcus haemolyticus in soft-agar.
PMID- 9554169
TI - A new selective method for isolation of Haemophilus species.
AB - Chocolate agar with teicoplanin disk (30 micrograms) was used for the isolation
of Haemophilus strains. Fifty strains of 3 Haemophilus species grew as well in
the inhibition zones of teicoplanin disks as on teicoplanin containing selective
plates, whereas Gram-positive bacteria failed to form colonies. This selective
method proved especially advantageous when Haemophilus strains were isolated from
mixed bacterial cultures of 665 specimens.
PMID- 9554168
TI - Growth of microorganisms on rubbers and plastics. Medical aspects of
microbiological corrosion and the role of quality control.
AB - The cause of nosocomial infections and their possible solutions, according to the
chemical compounds of rubber and plastic equipments are shortly summarized.
Compounds of rubbers and plastics act as culture medium for bacteria and fungi
being causative agents in nosocomial infections and because of their long-term
persistence they can be source of such infections. This problem needs cooperation
between experts and specialists from different scientific fields working in both
industry and medicine. Only "united forces" can make steps in order to find
solutions to these emerging questions and problems.
PMID- 9554170
TI - Bacterial endotoxins and nonspecific resistance.
AB - The stress situations, including medical intervention (e.g. operations, antitumor
drugs, irradiation, etc.) decrease the nonspecific resistance of the body. In
these situations patients people have greater chance to get an opportunistic
infection than healthy ones. The restoration or elevation of the activity of
immune system in injured patients is a very important task of medicine. Minute
amounts of bacterial endotoxin (LPS)--given parenterally--can elevate the
nonspecific resistance. Unfortunately this beneficial influence is associated
with noxious properties. Irradiation (60 Co-gamma; 150 kGy) is a good technique
for the detoxification of LPS. The radiodetoxified endotoxin (RD-LPS) preparation
(so-called TOLERIN) is less toxic but its beneficial properties is preserved. On
the basis of animal experiments and clinical trials TOLERIN could be a suitable
preparation for regeneration of the lymphoreticular-immune system and elevation
of nonspecific resistance.
PMID- 9554171
TI - The role and importance of Endre Hogyes in the history of Hungarian microbiology.
PMID- 9554172
TI - Clinical significance of alimentary tract microbes in bone marrow transplant
recipients.
AB - A prospective study on the microbes isolated from the alimentary tract in 120
bone marrow transplant (BMT) recipients (1991-1993) was undertaken to define the
spectrum of organisms isolated under antimicrobial prophylaxis, their temporal
sequence of emergence, and the associated morbidity and mortality. Clostridium
difficile (n = 20), isolated in the pre-engraftment and early post-engraftment
periods (day 2-45 post-BMT), was the most common microbe recovered from stool of
patients with diarrhea. In contrast to previous reports, no significant
difference in mortality was observed between patients with and without C.
difficile isolated in stool. Two patients had neutropenic ileocecitis with
concomitant bacteremia due to Escherichia coli and Klebsiella pneumoniae. One
patient was found to have astrovirus gastroenteritis (day 7), and Giardia lamblia
was recovered from the stool of another (day -7). Heavy growth of Staphylococcus
aureus from direct smear-positive specimens was found from the upper airway of
two patients with severe mucositis and complete dysphagia (day 12 and 23).
Salmonella spp. of groups B and E were found in the stool of five asymptomatic
patients at the time of conditioning. No specific organisms was recovered from
the endoscopic brushing of two patients with lower end esophagitis, three
patients with upper gastrointestinal bleeding, and three patients with perirectal
cellulitis. During the post-engraftment period, five patients had documented
cytomegalovirus gastroenterocolitis (days 34-97), one had Mycobacterium chelonae
colitis (day 70), and another had nodular gastritis due to Acremonium falciforme
(day 270). Overall, only 28% of patients with alimentary tract symptoms/syndrome
had specific pathogens isolated from clinical specimens. Differentiation of the
causation of alimentary tract symptoms was often difficult because noninfectious
complications such as conditioning toxicity, graft-versus-host disease, and its
treatment often caused alimentary tract symptoms in addition to predisposed BMT
patient to infection. The reluctance of obtaining tissue biopsy for ascertaining
the importance of those potential alimentary tract pathogens often dictate the
use of empirical treatment.
PMID- 9554173
TI - The role of copper on ethambutol's antimicrobial action and implications for
ethambutol-induced optic neuropathy.
AB - The principal side effect of the antimycobacterial agent ethambutol (EMB) is an
optic neuropathy with clinical features very similar to a mitochondrial
hereditary optic neuropathy (Leber's). The mechanism of EMB-induced optic
neuropathy may be EMB's chelation of copper, thereby precluding normal cytochrome
c oxidase activity and mitochondrial metabolism in the optic nerve. Before
attempting to use therapeutic copper to replenish endogenous stores in an attempt
to preclude EMB-induced optic neuropathy, we wished to determine whether EMB is
still effective against mycobacteria in the presence of copper. EMB and copper,
alone and in combination, were tested against six strains of Mycobacterium
tuberculosis and five strains of Mycobacterium avium using a radiometric broth
macrodilution assay. Copper did not effect EMB's antimicrobial actions against
either species of mycobacteria. This in vitro study suggests that if copper were
given to patients to prevent EMB-induced optic neuropathy, it would not
compromise EMB's bacteriostatic properties.
PMID- 9554174
TI - In vitro activity of LY333328 against vancomycin-resistant enterococci,
methicillin-resistant Staphylococcus aureus, and penicillin-resistant
Streptococcus pneumoniae.
AB - We report the activity of LY333328 against 35 clinical isolates of vancomycin
resistant enterococci (including organisms carrying the vanA, vanB, vanC-1, and
vanC-2/3 genes, as determined by PCR), 33 clinical isolates of methicillin
resistant S. aureus, and 29 clinical isolates of high-level penicillin-resistant
S. pneumoniae. All isolates of vancomycin-resistant enterococci were inhibited by
2 micrograms/mL LY333328, and 8 micrograms/mL LY333328 was bactericidal against
all isolates tested. All isolates of methicillin-resistant S. aureus were
inhibited by 1 microgram/mL LY333328, and 4 micrograms/mL LY333328 was
bactericidal against all methicillin-resistant S. aureus isolates tested. All
isolates of penicillin-resistant S. pneumoniae were inhibited by < 0.125
microgram/mL LY333328, and 0.25 microgram/mL LY333328 was bactericidal against
all S. pneumoniae isolates tested. LY333328 is a promising new glycopeptide
antimicrobial agent.
PMID- 9554175
TI - In vitro assessment of the antimicrobial activity of a local sustained release
device containing amine fluoride for the treatment of oral infectious diseases.
AB - Dental caries and periodontal diseases are chronic infectious diseases caused by
oral bacteria. Local sustained release delivery systems extend the time in which
the drug is present in the oral cavity, thus enhancing its therapeutic potential
while reducing its side effects. Amine-fluorides (AmF) are known anticaries
agents and have recently been found to have an antibacterial effect against
periodontal pathogens and caries-associated bacteria. The purpose of this in
vitro study was to assess the antimicrobial activity of a local sustained release
device (LSRD) containing AmF on Streptococcus sobrinus 6715. LSRD was prepared
from an ethylcellulose matrix containing AmF. Release kinetics of AmF from the
LSRD was measured simultaneously with its antimicrobial activity. The organic
amine and the fluoride were released in different kinetics profiles: The fluoride
was released faster than the organic amine. The antimicrobial activity of AmF was
measured on planktonic bacteria in solution and on bacteria as part of
experimental dental plaque. During a 10-day period, the concentration of the
released AmF was above its MIC and no bacterial growth was observed. Bacterial
counts in the dental plaque were reduced by 1 to 2 log units. Hence, the LSRD
containing AmF has the potential to serve as a medicament in prevention and
treatment of dental caries and periodontal diseases.
PMID- 9554176
TI - In vitro activity of oral antimicrobial agents against clinical isolates of
Pasteurella multocida.
AB - Pasteurella multocida causes a wide variety of infections and is the most common
localized soft tissue infection after animal bite injuries. Penicillin or
amoxicillin has been considered agent of choice for therapy. Reported beta
lactamase production by some isolates, the therapeutic dilemma of the penicillin
allergic patient, and the polymicrobial nature of some infections led to this
study of alternate antimicrobial agents. The in vitro activity of ampicillin,
amoxicillin/clavulanate, cefprozil, cefuroxime, erythromycin, clarithromycin,
trimethoprim/sulfamethoxazole, ciprofloxacin, and tetracycline were compared to
penicillin against 73 geographically diverse isolates of P. multocida from human
infections collected since 1991. MIC90 (microgram/mL) were as follows: penicillin
< or = 0.06; ampicillin < or = 0.5; amoxicillin/clavulanate < or = 0.5; cefaclor
1.0; cefprozil 1.0; cefpodoxime 0.06; cephalothin 2.5; cefuroxime < or = 0.25;
erythromycin 2.0; azithromycin 1.0; clarithromycin 4.0;
trimethoprim/sulfamethoxazole < or = 0.5/9.5; ciprofloxacin < or 0.25;
tetracycline < or = 2.0. No beta-lactamase producing isolates were found in this
study. This in vitro study has identified alternate oral agents to penicillins
that may be appropriate for therapy of P. multocida infections.
PMID- 9554177
TI - Emergence of ciprofloxacin resistance in Escherichia coli isolates after
widespread use of fluoroquinolones.
AB - The evolution (from 1990 to 1996) of fluoroquinolone consumption and resistance
and the current patterns of fluoroquinolone usage were examined in a 250-bed
community hospital in Spain. Fluoroquinolone consumption increased from 1392 g in
1990 to 3203 g in 1996 (p < 0.05). A significant increase in ciprofloxacin
resistance was observed in Escherichia coli isolated from urine samples (from 3
to 20%, p < 0.00001), but not in those E. coli isolated from blood or other
sample cultures. In 69 randomly selected clinical charts, fluoroquinolone was
used as prophylaxis, empirical therapy, and specific directed therapy in 20%,
65%, and 15%, respectively. Evaluation of quinolone indication was: first choice
agents (29%), alternative agents (49%), experimental agents (4.3%) and, agents
with no role (1.4%). Our study shows that the increase in the use of
fluoroquinolones is associated with the emergence of ciprofloxacin-resistant E.
coli from urinary tract sources. Based on their indications, current quinolone
usage can be greatly reduced.
PMID- 9554178
TI - Comparative in vitro and bactericidal activity of oxazolidinone antibiotics
against multidrug-resistant enterococci.
AB - Increasing resistance among enterococci poses a considerable therapeutic problem.
In this study, we evaluated the comparative in vitro activity of two
investigational oxazolidinone antibiotics, eperezolid and linezolid, versus
clinical isolates of multidrug-resistant enterococci. One hundred isolates (16
Enterococcus faecalis, 69 E. faecium, 10 E. gallinarum, 2 E. casseliflavus, 1 E.
avium, 1 E. hirae, and 1 E. raffinosus) evaluated were collected from diverse
geographic areas in North America and Europe from 1991 to 1995. Eperezolid MIC50
and MIC90 were 1.0 microgram/mL and 2.0 micrograms/mL (1.0-2.0 micrograms/mL
range). Linezolid MIC50 and MIC90 were 2.0 micrograms/mL and 2.0 micrograms/mL
(0.5-2.0 micrograms/mL range), respectively. MICs were the same at 10(3) CFU/mL
and 10(8) CFU/mL initial inoculum. In time-kill experiments using 10 strains and
concentrations of 4 micrograms/mL, 8 micrograms/mL, and 16 micrograms/mL
(achievable serum concentrations) of eperezolid and linezolid there was a 2 log10
reduction of growth for 2 of 10 isolates tested using eperezolid and a 1 log10
reduction for 50% of isolates with both agents. There was indifferent
bactericidal killing when either oxazolidinone was combined with gentamicin,
ampicillin, or streptomycin for isolates lacking these resistances. This study
demonstrates these oxazolidinone agents to have excellent in vitro activity
versus multidrug-resistant enterococci.
PMID- 9554180
TI - National surveillance of nosocomial blood stream infection due to species of
Candida other than Candida albicans: frequency of occurrence and antifungal
susceptibility in the SCOPE Program. SCOPE Participant Group. Surveillance and
Control of Pathogens of Epidemiologic.
AB - A national surveillance program of nosocomial blood stream infections (BSI) in
the USA between April 1995 and June 1996 revealed that Candida was the fourth
leading cause of nosocomial BSI, accounting for 8% of all infections. Forty-eight
percent of 379 episodes of candidemia were due to species other than Candida
albicans. The rank order of non-C. albicans species was C. glabrata (20%) > C.
tropicalis (11%) > C. parapsilosis (8%) > C. krusei (5%) > other Candida spp.
(4%). The species distribution varied according to geographic region, with non-C.
albicans species predominating in the Northeast (54%) and Southeast (53%)
regions, and C. albicans predominating in the Northwest (60%) and Southwest (70%)
regions. In vitro susceptibility studies demonstrated that 95% of non-C. albicans
isolates were susceptible to 5-fluorocytosine, and 84% and 75% were susceptible
to fluconazole and itraconazole, respectively. Geographic variation in
susceptibility to itraconazole, but not other agents, was observed. Isolates from
the Northwest and Southeast regions were more frequently resistant to
itraconazole (29-30%) than those from the Northeast and Southwest regions (17
18%). Molecular epidemiologic studies revealed possible nosocomial transmission
(five medical centers). Continued surveillance for the presence of non-C.
albicans species among hospitalized patients is recommended.
PMID- 9554179
TI - Multicenter evaluation of the in vitro activity of six broad-spectrum beta-lactam
antimicrobial agents in Puerto Rico. The Puerto Rico Antimicrobial Resistance
Study Group.
AB - The minimum inhibitory concentrations of 6 broad-spectrum beta-lactam
antimicrobial agents were determined by use of the Etest versus a total of 569
bacteria in 7 Puerto Rican hospital laboratories. These included 342 recent
clinical isolates of Enterobacteriaceae, 63 Pseudomonas aeruginosa, 54
Acinetobacter species, and 110 oxacillin-susceptible staphylococci. Extended
spectrum beta-lactamase production was noted among 11% of Klebsiella pneumoniae
isolates. Hyperproduction of Amp C cephalosporinase was observed with > 20% of
isolates of Enterobacter spp., Serratia spp., and Citrobacter freundii. The
overall rank order of activity of the six beta-lactams examined in this study
versus all clinical isolates was imipenem (95.8% susceptible) > cefepime (91.1%)
> piperacillin/ tazobactam (82.3%) > cefotaxime (77.6%) > piperacillin (72.5%) >
ceftazidime (67.0%).
PMID- 9554181
TI - Identification of oxacillin-susceptible and oxacillin-resistant Staphylococcus
aureus using commercial latex agglutination tests.
AB - Four hundred thirteen Staphylococcus sp. were identified by Staphaurex,
Staphaurex Plus, and BACTiStaph kits using tube coagulase as reference. Among 222
coagulase-positive isolates, 56 were oxacillin-resistant Staphylococcus aureus.
All tests were accurate in distinguishing between coagulase-positive and
negative staphylococci with sensitivities and specificities > or = 97% and only
nine discrepancies.
PMID- 9554182
TI - Timed kill kinetic studies of levofloxacin, ofloxacin, and ciprofloxacin against
Moraxella catarrhalis.
AB - Levofloxacin bactericidal activity was compared to ciprofloxacin and ofloxacin
against 10 strains of Moraxella catarrhalis. The cidal action (by kill-curve
analysis) was slightly more rapid for levofloxacin, but all tested
fluoroquinolones were considered bactericidal for all strains tested, including
those producing BRO-1 and 2 beta-lactamases.
PMID- 9554183
TI - Individual differences in P300 amplitude: a genetic study in adolescent twins.
AB - Using quantitative genetic research designs, we decomposed phenotypic variance in
P300 parameters into genetic and environmental components. The twin method was
used to carry out this decomposition. Event related potentials (ERPs) were
measured during a visual oddball paradigm in a sample of 213 adolescent twin
pairs. The presence of male and female same-sex and opposite-sex twins in the
sample enabled us to study sex differences in the contributions of genetic and
environmental effects to P300 parameters. For targets and nontargets, half of the
variance in the P300 amplitude is attributable to factors shared by the family
members. However, it remains unclear whether this resemblance is attributable to
shared environmental or genetic influences. The same factors (genetic or shared
environmental) were found to contribute to the individual differences in males
and females. The contributions do, however, differ across gender. Multivariate
genetic analyses investigated the covariance among various brain areas to
determine whether the covariance between two or more leads is attributable to the
same genetic and/or the same environmental factors. The covariance of the P300
amplitude measured at different locations was attributable both to unshared
environmental and to shared factors. Again it was not possible to show that the
shared factors where either genetic or shared environmental.
PMID- 9554184
TI - Context effects in a category verification task as assessed by event-related
brain potential (ERP) measures.
AB - This study examined the extent to which decisions about category membership
(between category structure) are dependent on or dissociable from the typically
structure (within category structure) of categories. To this end, behavioral and
event-related brain potential (ERP) measurements were obtained in a category
verification task that incorporated a context manipulation (list composition
effect) that was previously shown to affect membership verification. In a German
and an American English version of the experiment, pairs of words were presented
and subjects were asked to decide whether or not the second word was an exemplar
of the superordinate indicated by the first word. Both versions yielded similar
results. The behavioral data showed that both typicality and context manipulation
affected the verification times for the true exemplars. Furthermore, atypical
true exemplars were affected more by context manipulation than mere typical ones.
By contrast, the N400 component of the ERPs elicited by the true exemplars was
influenced by typicality, but invariant in the face of the context manipulation.
These results underscore the previously shown dissociation between reaction times
and N400 changes and suggest that category membership decision (as reflected in
verification times) and semantic relatedness or typicality of an exemplar (as
reflected in N400 modulation) can vary independently from each other and,
therefore, likely index the activity of different brain systems.
PMID- 9554185
TI - ERP components elicited in response to warning stimuli: the influence of task
difficulty.
AB - A series of experiments were conducted to systematically evaluate the relative
contributions of task difficulty and stimulus probability to P300 amplitudes.
Scalp event-related potentials (ERPs) were recorded and the topographic
distributions were evaluated during a multi-level cognitive task with an
antecedent warning. In three separate studies, task difficulty (five levels),
probability or expectedness (10-60%), and randomness (random or blocked
presentation) were manipulated. Response accuracy, subjective ratings, and
reference-free averages of the P300 components elicited by the warning stimuli
were evaluated. Statistical analysis indicated that significantly larger P300s
were associated with the more difficult task warnings except when memory tasks
were presented in a blocked design, suggesting that neither task difficulty nor
probability alone can account for variations in the P300 in a multi-level task
scenario. Results are discussed with regard to adaptation-level theory.
PMID- 9554187
TI - EEG changes index camouflaged object identification: a pilot study.
AB - EEG correlates of camouflaged object identification were investigated in this
pilot study by recording 8-s epochs of scalp potentials under two conditions. In
the experimental condition subjects, three female and two male right-handers,
aged 23-47, viewed images depicting camouflaged target objects, and signalled
identification by blinking. In the control condition subjects viewed a neutral
screen and blinked at will. Theta band activity was analysed for linear
associations using cross-correlation. Correlation increased over a 1-s interval
preceding. Associations included, progressively, occipital and left temporal
regions, bilateral frontal and temporal areas, and bilateral occipital, temporal,
central, frontal and prefrontal regions. A descriptive model is presented,
according to which a unitary percept is the emergent result of a process of self
organisation of a network of interregional signalling.
PMID- 9554186
TI - Event-related potentials can reveal differences between two decision-making
groups.
AB - Previous research has shown that a complex decision is dependent on an underlying
utility metric that is used by decision making processes to accumulate preference
for one alternative. This study postulated that a state of indecision may arise
if this underlying metric is poorly organized. The underlying metric was examined
with a paired comparison task while measuring event-related potentials (ERP) for
subjects classified as 'career decided' and 'career undecided'. Stimuli for
comparison were presented either sequentially or simultaneously. The simultaneous
condition produced results consistent with the hypothesis that undecided subjects
have a poorly organized value metric as revealed in both the behavioral data and
the P3 component. A relationship between P3 amplitude and word distance on the
underlying metric was found only for the decided group. This was interpreted in
terms of the previously documented relationship between P3 and the constructs of
decision confidence and task difficulty.
PMID- 9554188
TI - BUN/creatinine ratios: aid to decision making about delayed imaging in Tc-99m red
blood cell scans for gastrointestinal hemorrhage.
AB - In patients with gastrointestinal hemorrhage, delayed or late scans with Tc-99m
labeled red blood cells are readily performed and have prognostic impact when
early images are negative. Nevertheless, there have been no indicators for the
likelihood of detecting bleeding on such images. In a review of all
gastrointestinal bleeding scans over an 8-year period, 73 patients had delayed
images (> 3 hours) following early negative exams. For these patients,
determinations of serum blood urea nitrogen (BUN) and creatinine (Cr) were
evaluated as the BUN/Cr ratio and were compared against delayed scan findings and
confirmed diagnoses. Patients with significant renal failure were excluded from
analysis. There were 34 late positive (46%) and 39 late negative (54%) studies.
Mean BUN/Cr was 26.5 and 20.0 in patients with late positive and late negative
scans, respectively (p < 0.05). Occurrence of late positive scans was 38% (19/50)
for BUN/Cr < 25.0 vs. 65% (15/23) for BUN/Cr > 25.0 (p < 0.05). Patients with
early negative images and a BUN/Cr ratio of 25 or greater have a greater
likelihood of a positive delayed image. Late imaging should be encouraged in
patients with elevated BUN/Cr and early negative scintigraphy.
PMID- 9554189
TI - Coexistent parathyroid adenomas and Hurthle cell tumors: failure of full
detection by subtraction method.
AB - Tc-99m sestamibi and I-123 sodium iodide studies were performed on two patients,
one with a neck mass and another with suspected hyperparathyroidism. Subtraction
images, detected what proved to be Hurthle cell tumors in each case, but
coexisting parathyroid adenomas, which were found at surgery, were not
visualized. The findings indicate that both types of lesions can occur
simultaneously, and that studies are needed to determine whether detailed assays
of rate of washout could distinguish between the lesions.
PMID- 9554190
TI - The diagnostic utility of dual phase Tc-99m sestamibi parathyroid imaging.
AB - PURPOSE: Primary hyperparathyroidism is a disease of uncertain etiology that
results from hypersecretion of parathyroid hormone (PTH) by the parathyroid
gland. In most institutions, the preferred imaging protocol utilizes a dual-phase
technique with Tc-99m sestamibi which is reported to be more sensitive than
earlier protocols involving TI-201 with Tc-99m pertechnetate subtraction. The
purpose of this study is to evaluate the accuracy and clinical utility of Tc-99m
sestamibi dual-phase scintigraphy for localizing hyperfunctioning parathyroid
tissue. MATERIALS AND METHODS: We retrospectively reviewed thirty-nine
consecutive hyperparathyroid patients who received a dual-phase Tc-99m sestamibi
parathyroid scan. Thirty-seven of the subjects subsequently underwent a bilateral
neck exploration and parathyroidectomy. Each scan interpretation was then
correlated with the histopathologic diagnosis and the patients' post-surgical
clinical course. RESULTS: The sestamibi dual-phase imaging protocol correctly
localized 21 of 25 parathyroid adenomas and identified 8 out of 10 cases of
hyperplasia. Our overall sensitivity and specificity were 83% and 75%,
respectively. In addition, four of the adenomas were successfully localized
intraoperatively using a gamma probe. CONCLUSION: Parathyroid imaging with
sestamibi appears to be superior to TI-201/Tc-99m pertechnetate subtraction based
on the reported results of both techniques at various institutions. Dual-phase
sestamibi imaging appears to be useful and cost-effective for presurgical
localization of hyperfunctioning parathyroid tissue. In addition, sestamibi
imaging in conjunction with an intraoperative probe is a very promising technique
that has the potential to provide both localization information of a suspected
parathyroid adenoma and to facilitate its surgical removal by reducing operation
time.
PMID- 9554191
TI - Postinfectious cerebellitis: clinical significance of Tc-99m HMPAO brain SPECT
compared with MRI.
AB - PURPOSE: We compared Tc-99m HMPAO brain SPECT and MRI with the clinical findings
in a case of a 14-year-old boy with post-infectious cerebellitis. RESULTS: Tc-99m
HMPAO brain SPECT scan showed marked reduction in perfusion to the left anterior
lobe, left lateral hemisphere, and left posterior lobe of the cerebellum. The MRI
showed a limited region of abnormal signal in the mid posterior left cerebellar
hemisphere. Since the patient's overall neurological deficit was characterized by
ataxia, nystagmus, head and body titubation, dysmetria, dysdiadochokinesia, loss
of normal check, and rebound testing attributed to the involvement of the
anterior, lateral, and posterior lobes of the left cerebellar hemisphere, the Tc
99m HMPAO brain SPECT finding correlated better with the extent of functional
neurological deficits. CONCLUSION: Tc-99m HMPAO brain SPECT may better assess
cerebellar signs and symptoms in cerebellitis since the blood flow abnormalities
correlated with dysfunction of the cerebellum, whereas the MRI abnormalities did
not encompass the scope of the neurological deficits.
PMID- 9554192
TI - Significance of early tubular extraction in the first minute of Tc-99m MAG3 renal
transplant scintigraphy.
AB - Renal transplant perfusion curves obtained using Tc-99m MAG3 differ from those
with Tc-99m DTPA. The perfusion curve can be divided into a first phase (up to
the first-pass peak) and a second phase (the curve after the initial peak). The
second phase of the MAG3 perfusion curve is usually ascending in contrast to the
descending Tc-99m DTPA curve. This ascending MAG3 curve reflects early tubular
extraction of MAG3. However, the second phase of the MAG3 curve is sometimes flat
or descending. We hypothesized that a flat or descending curve reflects poor
early tubular extraction and therefore graft dysfunction. Ninety-two studies of
59' renal transplant patients were retrospectively reviewed. The second phase of
the perfusion curve was visually classified as ascending, flat, or descending.
77.2% of studies had ascending curves, 16.3% flat curves, and 6.5% descending
curves. A descending curve had a positive predictive value (PPV) of 100% for
medical graft dysfunction, while a flat curve had a PPV of 93.3%. A nonascending
second phase curve was specific (96.4%) but not sensitive (33.9%) for graft
dysfunction. Patients with acute tubular necrosis were not significantly more
likely to have a nonascending curve than those with acute rejection. There was no
significant difference in creatinine level between patients with medical graft
dysfunction and ascending vs. nonascending curves. A nonascending second phase Tc
99m MAG3 perfusion curve is predictive for graft dysfunction. An ascending curve
is nonspecific and can be seen in both normally and poorly functioning grafts.
PMID- 9554193
TI - Demonstration of double-chambered right ventricle on myocardial perfusion SPECT.
AB - A 19-year-old man with a double-chambered right ventricle (DCRV) and an
associated ventricular septal defect was admitted to the hospital for surgical
correction. Preoperative study of myocardial perfusion with Tc-99m tetrofosmin
SPECT depicted the two chambers of the right ventricle. There was a substantial
differential in the radioactive uptake between these two chambers. The inflow and
outflow chambers with different peak-pressures (94 and 18 mm Hg) showed different
uptakes reflecting the pressure difference, which was intense in the inflow
chamber and weak in the outflow.
PMID- 9554195
TI - Thyroid hemiagenesis accompanying a thyroglossal duct cyst: a case report.
AB - A case of thyroid hemiagenesis discovered incidentally in a patient presenting
with a thyroglossal duct cyst is reported. Thyroid embryology is briefly
reviewed. Various characteristics of thyroid hemiagenesis and thyroglossal duct
cysts are explored.
PMID- 9554194
TI - Acute cholecystitis in AIDS patients: correlation of Tc-99m hepatobiliary
scintigraphy with histopathologic laboratory findings and CD4 counts.
AB - BACKGROUND: AIDS patients are susceptible to opportunistic gastrointestinal
infections including ascending cholangitis and cholecystitis, especially if CD4
count is < 200. Incidence of acalculous cholecystitis has not been reported
previously. PURPOSE: We aim to evaluate the incidence of acalculous cholecystitis
in AIDS patients and to identify causative organisms and mortality rate following
cholecystectomy. MATERIALS AND METHODS: We reviewed the files of 46 patients in
order to meet the objectives of this study. RESULTS: CD4 counts were < 200 in 31
patients and > 200 in 15 patients. HIDA imaging was performed in 31 patients; in
8, the CD4 count was > 200 and all had calculous cholecystitis. The gallbladder
was visualized in 3 patients for a sensitivity of 63% and no organisms were found
in the gallbladder specimens. In 23 patients, the CD4 count was < 200; the
gallbladder was visualized in 5 patients for a HIDA sensitivity of 78%; 16 (52%)
had acalculous cholecystitis; and 15 had calculous cholecystitis. In acalculous
cholecystitis, Cryptosporidium was found in six cases, cytomegalovirus (CMV) in
six cases, and fungus, yeast, tuberculosis, and mycobacterium avium intracellular
each in one case. The thirty day mortality rate was 18%; 5 of 28 who underwent
open cholecystectomy died within 30 days, 4 of them with a CD4 count < 200. There
was no mortality in the 26 patients who underwent laparoscopic cholecystectomy.
CONCLUSION AND RECOMMENDATIONS: (1) Because of the high incidence of 52% of
acalculous cholecystitis in AIDS patients with a CD4 count < 200, we recommend
using intravenous cholecystokinin if the gallbladder is visualized on
hepatobiliary scintigraphy in order to determine gallbladder ejection fraction
and exclude acalculous cholecystitis. (2) Laparoscopic rather than open
cholecystectomy should be the surgical procedure of choice in AIDS patients
especially if the CD4 count is < 200.
PMID- 9554196
TI - Tc-99m pertechnetate scintigraphy for the detection of ileal duplication.
PMID- 9554197
TI - Gardner's syndrome with bone scintigraphic and CT demonstration.
PMID- 9554198
TI - Lateral displacement of liver and bowel on renal imaging.
PMID- 9554199
TI - SPECT in the early diagnosis of Creutzfeldt-Jakob disease.
PMID- 9554200
TI - Retrocardiac uptake of Tc-99m sestamibi: manifestation of a hiatal hernia.
PMID- 9554201
TI - Hyperthyroidism: an underappreciated cause of diffuse bone disease.
PMID- 9554202
TI - Warthin's tumor demonstrated with Tc-99m pertechnetate SPECT and CT.
PMID- 9554203
TI - Ga-67 and Tc-99m HMPAO labeled WBC imaging in erythema nodosum leprosum reaction
of leprosy.
PMID- 9554204
TI - Tc-99m sestamibi planar and SPECT imaging of a retrotracheal parathyroid adenoma.
PMID- 9554205
TI - Extraskeletal accumulation of bone-seeking agent mimicking diaphragmatic uptake.
PMID- 9554206
TI - Tc-99m MDP scintigraphy of temporal bone metastasis from breast carcinoma.
PMID- 9554207
TI - Tc-99m DMSA and Tc-99m MAG3 findings in crossed renal ectopia.
PMID- 9554208
TI - Three phase bone imaging in a patient with fulminant meningococcemia.
PMID- 9554209
TI - False-positive I-131 deposition in a parotid gland duct ectasia.
PMID- 9554210
TI - Tc-99m sestamibi esophageal activity during myocardial imaging.
PMID- 9554211
TI - Bone scan in ossifying fibromyxoid tumor of soft parts.
PMID- 9554212
TI - Injection artifact on FDG PET imaging.
PMID- 9554213
TI - Current readings in nuclear medicine.
PMID- 9554214
TI - Recognition and consequences of obstructive sleep apnea hypopnea syndrome.
AB - There is a growing recognition of sleep-disordered breathing (SDB) in patient
groups and in the general population. This article reviews issues related to
recognizing the disorder, including the problems of relying on narrowly defined
polysomnographic data for case findings and for assessment of disease severity.
The distributions of symptoms and physiologic measurements of SDB in the
population and their inter-relationships are reviewed. The epidemiological data
that address risk factors and consequences of sleep apnea hypopnea syndrome
(SAHS) also are discussed, with recommendations regarding recognition priorities.
PMID- 9554215
TI - Pathophysiology of upper airway obstruction during sleep.
AB - Obstructive sleep apnea is a common medical disorder with significant adverse
health consequences. The pathogenesis of pharyngeal obstruction during sleep,
however, remains elusive. This article addresses the key mechanisms of upper
airway (UA) obstruction including the role of transmural pressure, pharyngeal
compliance, pharyngeal dilating muscle activity and non-neuromuscular factors. A
proposed scheme of the pathophysiology of UA obstruction is outlined.
PMID- 9554216
TI - Upper airway imaging.
AB - Upper airway imaging is a powerful technique to study the mechanisms underlying
the pathogenesis, biomechanics, and efficacy of treatment options in patients
with obstructive sleep apnea. Imaging studies have provided significant insight
into the static and dynamic structure, and function of the upper airway and
surrounding soft-tissue structure during wakefulness and sleep. Upper airway
imaging modalities primarily include nasopharyngoscopy, cephalometrics, computed
tomography (CT), and magnetic resonance (MR) scanning. These imaging modalities
have been used to study the effect of respiration, weight loss, dental
appliances, and upper airway surgery on the upper airway. MR imaging and CT have
allowed quantification of the airway and surrounding soft-tissue structures in
three dimensions. Clinical indications for upper airway imaging are evolving for
patients being treated with dental appliances and upper airway surgery.
PMID- 9554217
TI - Positive pressure therapy.
AB - Positive airway pressure in the treatment of obstructive sleep-disordered
breathing (OSDB) is reviewed. Continuous positive airway pressure (CPAP), bilevel
positive airway pressure, and variable (auto-CPAP) pressure, their mechanisms of
action, benefits, and complications are examined. A perspective on the future of
positive airway pressure therapy for OSDB is provided.
PMID- 9554218
TI - Oral appliances in the treatment of snoring and sleep apnea.
AB - Oral appliances have been developed that are effective in snoring patients and in
patients with mild to moderate sleep apnea. This article reviews the types of
appliances that are available, their possible modes of action, and their
efficacy. In addition, the clinician is provided with guidelines on how to choose
the appropriate patient for this therapy.
PMID- 9554219
TI - Surgical management of obstructive sleep apnea syndrome.
AB - This article discusses the history of operative management of obstructive sleep
apnea syndrome and reviews a protocol for surgical intervention. An overview of
diagnostic procedures and evaluation is also presented, and emerging technology
for the management of this disorder is touched on.
PMID- 9554220
TI - Decision making in obstructive sleep-disordered breathing. Putting it all
together.
AB - Obstructive sleep-disordered breathing consists of a spectrum ranging from the
upper airway resistance syndrome to complete apnea. Although this disorder is
relatively common, it is still under-recognized, resulting in a significant
increase in morbidity and mortality. In this article, we describe the rationale
for treating this disorder. Then, using the best available evidence, we try to
develop a systemic approach to the problem, covering recognition, diagnosis, and
treatment.
PMID- 9554221
TI - Sleep apnea in congestive heart failure.
AB - Sleep-related breathing disorders, including obstructive sleep apnea (OSA) and
Cheyne-Stokes respiration with central sleep apnea (CSR-CSA), commonly occur in
patients with congestive heart failure (CHF). In this setting they can have
adverse pathophysiologic effects on the cardiovascular system. OSA may lead to
development or progression of left ventricular (LV) dysfunction by increasing LV
afterload through the combined effects of elevations in systemic blood pressure
and a generation of exaggerated negative intrathoracic pressure, and by
activating the sympathetic nervous system through the influence of hypoxia and
arousals from sleep. Abolition of OSA by continuous positive airway pressure
(CPAP) can improve cardiac function in patients with CHF. In contrast to OSA, CSR
CSA is likely a consequence rather than a cause of CHF. Here, pulmonary
congestion causes hyperventilation by stimulating pulmonary irritant receptors.
This leads to reductions in PaCO2 below the apneic threshold during sleep,
precipitating posthyperventilatory central apneas. CSR-CSA is associated with
increased mortality in CHF, probably because of sympathetic nervous system
activation caused by recurrent apnea-induced hypoxia and arousals from sleep.
Treatment of CSR-CSA by supplemental O2, theophylline, and CPAP can alleviate
central apneas. Of these treatments, however, only CPAP has been shown to improve
cardiac function and symptoms of heart failure. We conclude that effective
treatments of OSA and CSR-CSA may prove to be useful adjuncts to the standard
pharmacologic therapy of patients with CHF.
PMID- 9554222
TI - Sleep in patients with chronic obstructive pulmonary disease.
AB - Patients with chronic obstructive pulmonary disease (COPD) become hypoxemic
during sleep, particularly during rapid eye movement (REM) sleep. Those who are
most hypoxemic when awake experience the most severe hypoxemia during sleep. The
major cause of REM hypoxemia is hypoventilation, with additional contributions
from alteration in ventilation/perfusion matching and functional residual
capacity (FRC) reduction. REM hypoxemia probably contributes to the development
of pulmonary hypertension and polycythemia and may predispose to cardiac
arrhythmias in some patients. The most effective form of therapy is nocturnal
oxygen therapy, but the indications for the use of nocturnal oxygen therapy are
entirely based on daytime oxygenation levels. Routine polysomnography is not
indicated in patients with COPD but should be performed in patients who have
symptoms suggestive of coexisting sleep apnea/ hypopnea syndrome.
PMID- 9554223
TI - Sleep in asthma.
AB - The nocturnal worsening of asthma is a major cause of morbidity and mortality
from this disease. The physiologic changes that occur during normal sleep can
have adverse effects on breathing patterns, arousal responses, and airway
clearance in asthmatics. Understanding of these alterations in airway mechanics
and airway inflammation may lead to better management of this disease.
PMID- 9554224
TI - Hypoventilation syndromes.
AB - In summary, alveolar hypoventilation can be associated with a diverse group of
disorders, collectively referred to as the hypoventilation syndromes. Most have
associated hypercapnia and hypoxemia while awake, with a significant worsening in
gas exchange during sleep. In some disorders, gas exchange abnormalities are
manifested only during periods of sleep. Signs and symptoms suggestive of the
underlying disorder leads one to investigate for associated hypoventilation.
Proper diagnosis allows the implementation of appropriate therapy, which may both
improve gas exchange and associated symptoms, and impact overall survival.
PMID- 9554225
TI - Insomnia.
AB - This article reviews issues involved in the diagnosis of insomnia and discusses
treatment options, including pharmacologic treatment, which is indicated mainly
in acute insomnia. Sleep hygiene is then discussed. Finally, the various
behavioral treatments are reviewed, including light therapy, relaxation training,
cognitive therapy, sleep curtailment, and stimulus control therapy.
PMID- 9554226
TI - Narcolepsy and idiopathic hypersomnolence.
AB - Narcolepsy is among the leading causes of excessive daytime sleepiness. Its
classic form associates daytime sleepiness with cataplexy, sleep paralysis,
hypnopompic hallucinations, and nocturnal disrupted sleep. This form is
associated with HLA DQ betal-0602 in about 85% to 90% of affected subjects,
independently of their ethnicity. But the definition of the variants of
narcolepsy remains controversial, despite the fact that, in some cases,
narcolepsy may be limited to daytime sleepiness. In its classic form, it is
associated with two or more sleep onset rapid eye movement periods at the
Multiple Sleep Latency Test. This test, performed after nocturnal
polysomnography, can be helpful in diagnosing narcolepsy, in the absence of a
convincing history of partial or complete attacks of cataplexy--a pathognomonic
symptom. Investigation of narcoleptic Dobermans has indicated that a muscarinic
cholinergic hypersensitivity exists in the brain of affected animals and
abnormalities involve also the dopaminergic system. Despite its prevalence of
0.03% to 0.05%, it is still a neurologic entity often missed. Investigations of
families of narcoleptics, including monozygotic twins, indicate that this
syndrome is polygenic in nature with association of environmental factors. As the
peak of onset of disabling symptoms occurs between 15 and 25 years of age, it is
important to improve the treatment of this lifelong, disabling illness.
Stimulants medications, independently of their mode of action, are prescribed to
help daytime sleepiness, and tricyclic antidepressant drugs or serotonergic
reuptake blockers are used on the other symptoms. But these medications have a
limited efficacy. Short naps at regular intervals during the day are a strong
therapeutic adjuvent.
PMID- 9554227
TI - Parasomnias including the restless legs syndrome.
AB - The three states of mammalian being, W, REM sleep, and NREM sleep, are not
mutually exclusive, and may occur simultaneously, oscillate rapidly, or appear in
dissociated or incomplete form to produce primary sleep parasomnias. In addition,
dysfunctions of a wide variety of organ systems may take adwide variety of organ
systems may take advantage of the sleeping state to declare themselves, resulting
in secondary sleep parasomnias. Contrary to popular opinion, the majority of the
often bizarre and frightening experiences are not the manifestation of underlying
psychological or psychiatric conditions. There is an interesting interaction
between sleep-disordered breathing and parasominas. Formal study in an
experienced sleep disorders center will usually reveal a diagnosable and
treatable condition that explains the spells. Continued study of unusual sleep
related events undoubtedly will reveal more fascinating conditions, expanding our
knowledge of sleep physiology, and strengthening the bonds between clinicians and
basic-science sleep researchers.
PMID- 9554228
TI - Monitoring sleep and breathing: methodology. Part I: Monitoring breathing.
AB - There is considerable variation in monitoring techniques and definitions of sleep
disordered breathing. Work underway in the Sleep Heart Health Study may help to
clarify these issues. Home and portable monitoring have the potential to improve
cost and convenience of diagnosis and treatment of sleep disorders but are
currently indicated only in specific instances. Detection and monitoring of
pediatric sleep-disoriented breathing varies considerably from that of adults.
PMID- 9554229
TI - Current and future methodology for monitoring sleep.
AB - Sleep is much more than simply decreased consciousness, and the distinctions
among the stages of nonREM and REM sleep are of significance for the
polysomnographer because of their implications for physiologic events. The rules
for staging sleep are essentially unchanged since their original description in
1968. This article describes this system for sleep staging, some of its
weaknesses, and potential new approaches.
PMID- 9554230
TI - A look toward the future.
AB - There will be many changes in the sleep field in the next 5 to 10 years. These
will include increments in our knowledge of the basic neurobiologic mechanisms
driving sleep and the impact of sleep loss on general health. The technology used
in the sleep laboratory will likely change as well, leading to a larger range of
available tests and new ways to conduct standard ones. Finally, as the knowledge
base in sleep increases, the expertise required to practice sleep medicine will
rise, leading to a better-trained, more focused practitioner.
PMID- 9554231
TI - The porphyrias. Commentary.
PMID- 9554232
TI - The porphyrias. Historical perspective.
PMID- 9554233
TI - Evolution of porphyrins.
PMID- 9554234
TI - The biochemistry of heme synthesis in porphyria and in the porphyrinurias.
PMID- 9554235
TI - Genetic defects in the porphyrias: types and significance.
PMID- 9554236
TI - How genetic defects are identified.
PMID- 9554237
TI - Enzyme assays and the porphyrias: which tissues and when indicated.
PMID- 9554238
TI - Clinical features of the porphyrias.
PMID- 9554239
TI - Porphyria cutanea tarda of the toxic and sporadic varieties.
PMID- 9554240
TI - Clinical laboratory methods for diagnosis of the porphyrias.
PMID- 9554241
TI - Treatment of the cutaneous porphyrias.
PMID- 9554242
TI - Management of acute attacks in the porphyrias.
PMID- 9554243
TI - Lessons from the porphyrias of animals.
PMID- 9554244
TI - Norplant consensus statement and background review.
AB - This review has highlighted the attributes of a very important new method of
contraception. The signatories to this document agree that, with the provision of
appropriate information and instruction for the user, Norplant is a good
contraceptive choice to be made available worldwide in family planning programs
that have the resources for appropriate training and counseling. The signatories
to this document are acting in their own personal capacity and not as
representatives of any particular organization.
PMID- 9554245
TI - Oral contraceptive use and benign gynecologic conditions. A review.
AB - The following review considers the main epidemiologic data on oral contraceptives
(OC) and the risk of major benign gynecologic diseases. Earlier studies
investigating the relationship between OC use and functional ovarian cysts
indicated that the use of high-dose combination OC have a protective effect,
whereas low-dose monophasic or multiphasic pills have little or no effect. With
regard to seromucinous cysts, the scanty data available are consistent with the
notion of some protection of OC in current but not in former users, although
possible effects of diagnostic and selection bias should be considered. Published
data on the relationship between fibroids and OC appear too scattered to allow a
precise quantification of risk. In any case, any relationship is moderate and,
hence, of limited clinical and public health relevance. The data on OC and benign
gynecologic conditions are reassuring in their absence of any consistent excess
risk.
PMID- 9554246
TI - Continuation rates of long-acting methods of contraception. A comparative study
of Norplant implants and intrauterine devices.
AB - Following adverse widespread publicity in the United Kingdom and the United
States, it is commonly believed that discontinuation rates for the contraceptive
implants Norplant in the UK are high. We have compared discontinuation rates
between new intrauterine device (IUD) users (253 women) and new Norplant implant
users (502 women) over 33 months following the introduction of Norplant implants
among a population of women attending the same clinic and counseled in the same
manner by the same group of providers. Women choosing the IUD were slightly older
and were more likely to be changing their contraceptive method because of
dissatisfaction with their current method. Nor plant implant users were more
likely to have completed their families. Continuation rates for Norplant implants
were significantly higher than for IUD at 12, 18, and 24 months after insertion.
At 24 months, continuation rates for Norplant implants were 72% compared with
rates of 55% for IUD users. Higher continuation rates may be related more to
factors associated with the providers than with the users of these two long
acting methods.
PMID- 9554248
TI - Thromboembolic stroke in young women. A European case-control study on oral
contraceptives. Transnational Research Group on Oral Contraceptives and the
Health of Young Women.
AB - A matched case-control study was performed between 1993 and 1996 in 16 centers in
the United Kingdom, Germany, France, Switzerland, and Austria. The objective was
to determine the influence of oral contraceptives (OC), particularly those
containing modern progestins, on the risk for ischemic stroke in women aged 16-44
years. A total of 220 women who had had an incident ischemic stroke and were
compared with 775 control subjects who were unaffected by stroke. At least one
hospital and one community control subject per patient was matched and
interviewed with the corresponding patient for 5-year age band and for area of
residence. Crude odds ratios (95% confidence intervals [CI]) for ischemic stroke
were as follows. For current use of any OC versus no use 2.3 (1.7-3.2), the
adjusted odds ratio (OR) 3.6 (2.4-5.4). The OC associated risk was higher for
first generation than for second or third generation OC. The risk estimates for
patients versus community control subjects were always lower than for hospital
control subjects. No major regional difference of the risk estimates was found.
Compared with nonusers of OC without hypertension, women with hypertension who
used OC had an almost 10-fold increased risk. However, OC users who had had a
blood pressure check before OC prescription had a lower risk than did those
without such a check. Smoking > 10 cigarettes/day is associated with higher risk
of stroke, particularly for OC users. No significant effect was found for
duration of OC use. We conclude that although there is a small relative risk of
occlusive stroke for healthy women currently using OC, the attributable risk is
very small because the incidence in this age group is very low. The small
increase in risk of OC use may be further reduced by preventive efforts for
cardiovascular risk factors, particularly hypertension and smoking.
PMID- 9554247
TI - Effectiveness of Cyclofem in the treatment of depot medroxyprogesterone acetate
induced amenorrhea.
AB - A total of 100 women who were using depot medroxyprogesterone acetate (DMPA) for
contraception and who had experienced at least 6 months of drug induced
amenorrhea, were randomized to either switching their method of contraception to
Cyclofem, or continuing with DMPA. At the end of 6 months, 82% of the Cyclofem
users had experienced some vaginal bleeding, compared with 10% of DMPA users.
Time to resumption of vaginal bleeding was related to the duration of DMPA use to
the duration of DMPA induced amenorrhea, and to the body mass index of the user.
Over the 6 months of follow-up, 94% of Cyclofem users complained of some side
effects, compared with 22% of DMPA users. The most frequently cited problems
among Cyclofem users included breast tenderness, abdominal pain, and
dysmenorrhea; yet a third of these women opted to stay on Cyclofem at the end of
the study. It is concluded that switching to Cyclofem is a new option for DMPA
users who are concerned about amenorrhea. Although using Cyclofem in this setting
will not meet the needs of all such women, its effectiveness in inducing vaginal
bleeding justifies a trial in those who have no contraindication to estrogen
treatment.
PMID- 9554249
TI - A regimen of oral contraceptives restricted to the periovulatory period may
permit folliculogenesis but inhibit ovulation.
AB - Increased safety of oral contraceptives (OC) has resulted from a reduction in the
estrogen and progestin content per tablet. A reduction in the number of
hormonally active pills and their placement at critical points within the cycle
may provide a novel regimen for further reducing the hormonal content of OC per
cycle and their attendant side effects without compromising efficacy. The
objective of this study was to determine the effectiveness of two OC regimens
that incorporate a delayed start and limited midcycle use of the combination of
ethinyl estradiol and norethindrone, and limited use of norethindrone only during
the second half of the cycle. Main outcome measures were defined as ovulation,
serum concentrations of estradiol (E2), luteinizing hormone (LH), follicle
stimulating hormone (FSH), progesterone (P), follicular diameters, and
endometrial thickness. Volunteers were issued blister packs containing 28 pills
and randomized to one of two groups. Group 1 used a combination of 50 micrograms
ethinyl estradiol and 1 mg norethindrone per tablet day 6-10, and 0.70 mg
norethindrone only day 11-19. Placebo tablets were used on days 1-5 and day 20
28. Group 2 used a combination of 50 micrograms ethinyl estradiol and 1 mg
norethindrone per tablet on day 8-12, and 0.70 mg norethindrone only on day 13
21. Placebo tablets were used on day 1-7 and day 22-28. A total of 20 cycles were
studied using 10 volunteers. To assess any possible carryover effect, two
successive cycles were studied for each subject. Serum sampling for E2, FSH, LH,
and P, and transvaginal ultrasound imaging to assess endometrial thickness and
follicle diameter were carried out at 4 day intervals throughout the cycle. One
ovulation occurred in 10 cycles in group 1. Five ovulations occurred in 10 cycles
in group 2. All ovulations, regardless of group, occurred in the second cycle.
Peak E2 concentrations were not significantly different between groups (152.04 +/
107.1 pg/mL vs 162.1 +/- 56.1 pg/mL [mean +/- SD] for groups 1 and 2,
respectively] but occurred earlier in the cycle in group 1. No differences were
noted between the groups in serum concentrations of FSH or LH for any given cycle
day. Maximum follicle diameters were not different between groups 1 and 2,
regardless of ovulatory status (20.5 +/- 8.1 mm2 vs 20.6 +/- 14.2 mm2,
respectively). Ultrasound imaging assessment of midcycle follicle growth revealed
diameters ranging from 18.5 mm2 to 34.0 mm2 with gradual resolution through the
second half of the cycle in anovulatory cycles, and 16.0 mm2 to 23.5 mm2 with
abrupt disappearance in ovulatory cycles. Endometrial thickness did not exceed 10
mm for any anovulatory cycle regardless of group, but ranged from 6 to 9 and 6 to
11 during the luteal phase of ovulatory cycles of groups 1 and 2, respectively.
Peak serum P concentrations at midluteal phase in ovulatory cycles ranged from
9.2 ng/ml to 18.2 ng/ml. Data from this preliminary study suggest that ovulation
may be prevented with a combination of ethinyl estradiol and norethindrone
started as late as cycle day 6 and limited to 5 days' duration using
norethindrone only for 9 days during the second half of the cycle. Such a
restricted regimen may offer both an effective method of contraception and a
means of further reducing both estrogen and progestin content per cycle and the
possible short and long term adverse side effects of these hormones.
PMID- 9554250
TI - Dimeric inhibin serum values as markers of ovarian activity in pill-free
intervals.
AB - Levels of inhibin A and B as well as other hormones in serum samples obtained
during the pill-free interval in women taking combined oral contraceptives (OC)
were measured to asses the extent of ovarian activity during that period. Type of
pill and day of pill-free interval were recorded during routine gynecologic check
ups, if patients were in the pill-free period and had taken their pills regularly
in the previous cycle. In addition to inhibin A and B, serum levels of follicle
stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and
progesterone were also quantified. Inhibin B levels rise significantly in
parallel with rising levels of FSH, LH, and E2. Progesterone levels were
completely suppressed and inhibin A levels rose slightly but insignificantly.
Inhibins are sensitive biochemical markers of ovarian activity in pill-free
intervals.
PMID- 9554251
TI - Corrosion behavior of copper in a copper bearing intrauterine device in the
presence of indomethacin.
AB - As an improvement to the use of the copper bearing intrauterine device,
indomethacin has been introduced to reduce the incidence of bleeding after
insertion of the device. The effects of indomethacin on copper corrosion were
studied in vitro in simulated uterine fluid. Electrochemical polarization
resistance measurements indicated that indomethacin powder slightly increased the
corrosion rate of copper if pH of the fluid was not under control and it did not
change the corrosion rate if pH was adjusted daily to maintain some constancy.
The experimental results for medication by indomethacin-releasing Silastic were
basically the same as those with powdered indomethacin. X-ray diffraction showed
that only cuprous oxide was formed on the copper substrated surface and that
indomethacin did not affect the corrosion products. As scanning electron
microscopy demonstrated, however, in the presence of indomethacin the oxide
particles formed were found to be more coarse and dense than in the absence of
indomethacin.
PMID- 9554253
TI - Oral contraceptives and risk of venous thromboembolism: impact of duration of
use.
PMID- 9554252
TI - Effect of inhibitors of enzymes involved in polyamine biosynthesis pathway on
pregnancy in mouse and hamster.
AB - The syntheses of polyamines, which play a definitive role in cell proliferation
and tissue growth during early embryogenesis, are believed to be principally
regulated by two enzymes: ornithine decarboxylase (ODC) and polyamine oxidase
(PAO). However, when the level of enzyme ODC goes down, another enzyme known as S
adenosyl methyl decarboxylase (SAMDC) is believed to up-regulate the biosynthetic
pathway. In the present study, the effects of inhibitors of enzymes SAMDC and PAO
were determined in mated hamster and mouse in peri-and immediate postimplantation
stages of pregnancy. It was noticed that, whereas the SAMDC inhibitor (MDL-73815)
failed to arrest the pregnancy in the hamster in spite of raising the dose to 100
mg/kg, the PAO inhibitor (MDL-72527DA) was found to be 100% effective at 75 mg/kg
in both species. The results confirmed the role of enzyme PAO in promoting early
development of the embryo.
PMID- 9554254
TI - The mode of action of immunological adjuvants.
AB - Adjuvants augment immune responses to antigens and influence the balance between
cell-mediated and humoral responses, as well as the isotypes of antibodies
formed. New adjuvant formulations include antigen-carrying vehicles and small
molecules with immunomodulating activity. Widely used two-phase vehicles comprise
liposomes and microfluidized squalene or squalane emulsions. These are believed
to target antigens to antigen-presenting cells, including dendritic cells (DC),
follicular dendritic cells (FDC) and B-lymphocytes. Activation of complement
generates C3d, which binds CR2 (CD21) on FDC and B-lymphocytes, thereby
stimulating the proliferation of the latter and the generation of B-memory.
Targeting of antigens to DC may favour cell-mediated immunity. Immunomodulating
agents induce the production of cytokine cascades. In a primary cascade at
injection sites TNF-alpha, GM-CSF and IL-1 are produced. TNF-alpha promotes
migration of DC to lymphoid tissues, while GM-CSF and IL-1 accelerate the
maturation of DC into efficient antigen-presenting cells for T-lymphocytes. In a
secondary cytokine cascade in draining lymph nodes, DC produce IL-12, which
induces Th1 responses with the production of IFN-gamma. The cytokines elicit cell
mediated immune responses and the formation of antibodies of protective isotypes,
such as IgG2a in the mouse and IgG1 in humans. Antibodies of these isotypes
activate complement and collaborate with antibody-dependent effector cells in
protective immune responses.
PMID- 9554255
TI - Will adjuvants be needed for vaccines of the future?
AB - Adjuvants improve the uptake of antigens by the immune system, and stimulate
antigen-presenting cells (APC) to express "danger signals" such as the secretion
of cytokines. The physical changes in antigen distribution can also be brought
about by DNA vaccines, which provide persistent antigenic stimulation, access to
the endogenous antigen processing pathway and, with the appropriate mode of
injection, targeting to APC; however the question of whether DNA vaccines induce
danger signals is unresolved. This presentation reviews the particular features
of the adjuvant action of Al(OH)3, muramyl dipeptides and saponins, and the
danger signals they induce in APC to ascertain whether they provide clues as to
how DNA vaccines might be improved. Three conclusions are drawn: (i) adjuvants
differ in the relative efficacy with which they stimulate Th1 and Th2 cells; (ii)
IL-1 is the only identified common danger signal induced by the three adjuvants;
(iii) in the case of both muramyl dipeptides and saponins there are toxic and
nontoxic analogues, and the adjuvant activity can be separated from the toxicity.
The basis of the difference between the toxic and non-toxic analogues is not
clear.
PMID- 9554256
TI - Adjuvants and delivery systems for viral vaccines--mechanisms and potential.
AB - Of the vaccines against viral diseases of man currently available, several are
less than satisfactory, and the present surge of interest in improving such
vaccines, and in developing new vaccines against viral diseases as yet
unchallenged, has led to major developments in three areas. The capacity to
identify the nature and form of antigenic epitopes in proteins allows the
specific design of molecular entities to promote relevant and protective immune
responses. Such entities, although ideal in terms of specificity and purity, may
not achieve their goals through failure to reach relevant cells of the immune
system due to simple dilution, elimination by host enzymes or lack of specific
targeting. Concomitant with the above there has been development of a plethora of
adjuvants aimed at enhancing immune responses to these 'new' immunogens,
paralleled by an almost equally rapid increase in understanding the complex
nature of the immune response, particularly with respect to antigen processing,
the nature and role of cytokines and the importance of T-cell subsets in
infection. These developments allow exploration of matching the properties and
mechanistic action of a given adjuvant to a defined immune response. Adjuvants
can be grouped according to their physical characteristics and mode of action.
They include particulate adjuvants, oil and emulsifier-based adjuvants, those
providing controlled antigen delivery, adjuvants based on specific targeting of
antigen, and gel-type adjuvants. They may act non-specifically in promoting an
immune response to an antigen through depot formation, or very specifically as in
a "delivery system" where an antigen is linked to a cellular protein, targeted to
a specific cell receptor. As adjuvant technology develops it is becoming
increasingly clear that these differing approaches may be combined, and an
adjuvant/delivery system designed, to provide slow release of a targeted antigen.
The role of adjuvants in modern viral vaccine technology and their influence on
the immune system are the subject of this review.
PMID- 9554257
TI - Iscom, a delivery system for parenteral and mucosal vaccination.
AB - The iscom is a supramolecular spherical structure, about 40nm in diameter, built
up by structure-forming and immunomodulating quillaja triterpenoids, lipids and
antigens. Iscoms with a defined quillaja triterpenoid formulation named QH 703
are in human trials. The advantages of using the particulate iscom form of
quillaja components are (i) that local reactions at the site of injection can be
avoided; a manifold higher dose of quillaja components in iscoms than in free
form can be injected without causing side effects; (ii) considerably lower doses
of both quillaja components and antigens are required to obtain a certain level
of immune response. The iscom particle targets the antigen and adjuvant
components to both the endosomal and cytosolic pathways for antigen presentation,
resulting in both MHC class I and class II restricted immune responses. Further,
iscoms induce APC to produce IL-1, IL-6 and IL-12 and a TH1 type of response with
enhanced IL-2 and IFN-gamma production. Iscoms are now constructed to target the
mucosal lymphatic systems. Iscoms administered intranasally induce secretory IgA
responses in lungs and distant mucosal membranes e.g. in the genital tract.
PMID- 9554258
TI - QS-21 and QS-7: purified saponin adjuvants.
AB - QS-21 and QS-7 are two adjuvant-active saponins that can be obtained in high
purity from Quillaja saponaria Molina extracts. QS-21 is a highly characterized
compound and is known to be a potent adjuvant for antibody and CD8+ CTL response
to subunit antigens. Less is known about the activity and structure of the
hydrophilic saponin QS-7. Hence, we have carried out a detailed structural and
immunological characterization. As with QS-21, QS-7 was shown to be a 3,28-O
bisglycoside quillaic acid, with some differences being a higher degree of
glycosylation and a considerably shorter fatty acyl unit in QS-7. These
differences were correlated to a lower lytic activity against sheep red blood
cells. Different doses of QS-7 were evaluated for stimulation of immune response
to the antigen ovalbumin, given three times by subcutaneous route to C57BL/6
mice. QS-7 doses of 40 micrograms or higher were shown to induce a strong CD8+
CTL response reproducibly against E. G7-OVA targets (similar to that induced by a
5-10 micrograms dose of QS-21). QS-7 (at doses above 5 micrograms) was also shown
to stimulate CTL against peptide 18 of HIV-1IIIB gp120 after three immunizations
of Balb/c mice with recombinant gp120 and different doses of QS-7. These data
suggest that a hydrophilic saponin with low lytic activity can stimulate MHC
Class I CTL responses although a higher minimum dose may be required for some
antigens.
PMID- 9554259
TI - Induction of virus-specific immunity by iscoms.
AB - Immune stimulating complexes (iscoms) are 30-40 nm cage-like structures, which
consist of glycoside molecules of the adjuvant Quil A, cholesterol and
phospholipids in which antigen can be integrated. Even in the presence of pre
existing antibodies they may function as a potent adjuvant system by inducing
high systemic and local long-lasting antibody and T cell responses. An additional
advantage is their capacity to induce MHC class I restricted CD8+ CTL responses.
This combination will in most cases, when the relevant antigens are incorporated,
lead to adequate protection against virus infection or disease. An overview is
given of the present data available on the use of iscoms in viral systems, and
some relevant examples are discussed to highlight general principles in the use
of iscoms as an adjuvant system.
PMID- 9554260
TI - Biodegradable polymer microspheres as vaccine adjuvants and delivery systems.
AB - Though vaccination has been the most cost-effective way of controlling infectious
diseases, the logistics of delivering at least two to three doses of conventional
vaccines for primary immunization to achieve protection are difficult and
compliance is frequently inadequate, particularly in developing countries. In
recent years biodegradable polymer microspheres have received much attention for
the purposes of controlled release of antigens, (i) to reduce the number of doses
needed for primary immunization to as few as a single dose and (ii) to target an
antigen to microfold cells on mucosal surfaces after oral administration or to
antigen-presenting cells after parenteral inoculations. A variety of vaccine
antigens have been encapsulated in microspheres usually composed of poly
(lactic/glycolic) acid (PLGA). Based on the size of the microspheres, molecular
weight of polymer and ratio of lactic to glycolic acid in the polymer, the
antigen may be targeted to various cells of the immune system or it may form a
depot at the site of injection, allowing the slow release of the antigen for
extended periods. Additionally, another adjuvant may be incorporated inside
microspheres together with the antigen, further enhancing or modulating the
immune response to the desired type. The major problems in developing controlled
release vaccines include instability of vaccine antigens during micro
encapsulation, storage and subsequent hydration. We encapsulated tetanus toxoid
(TT) and Haemophilus influenzae type b capsular polysaccharide conjugated to TT
(Hib-T) inside PLGA microspheres and evaluated the antibody levels in mice. A
single injection of these micro-encapsulated vaccines elicited high antibody
levels which persisted for several months. The antibody levels were similar or
superior to those elicited by conventional formulations of AIPO4-adsorbed TT or
soluble Hib-T conjugate vaccine.
PMID- 9554262
TI - Cellular and molecular mechanisms for induction of mucosal immunity.
AB - The epithelial glycoprotein called secretory component (SC) is quantitatively the
most important receptor of the immune system because it is responsible for
external transport of locally produced polymeric IgA (pIgA) to generate
remarkably large amounts of secretory IgA. Antibodies of this type constitute the
major mediators of specific humoral immunity. Transmembrane SC belongs to the Ig
supergene family and functions as a common pIg receptor, also translocating
pentameric IgM externally to form secretory IgM. The B cells responsible for
mucosal production of Ig polymers are initially stimulated in organized mucosa
associated lympho-epithelial structures, particularly the Peyer's patches in the
distal small intestine; from these inductive sites they migrate ("home") as
memory cells to exocrine tissues all over the body. Mucous membranes are thus
furnished with secretory antibodies in an integrated way, ensuring a variety of
specificities at every secretory effector site. There is currently great interest
in exploiting this integrated or "common" mucosal immune system for oral
vaccination against pathogenic infectious agents and also to induce tolerance in
T cell-mediated auto-immune diseases. However, much remains to be learned about
mechanisms for antigen uptake and processing necessary to elicit stimulatory or
suppressive mucosal immune responses in humans. Moreover, evidence is emerging
for the existence of considerable regionalization with regard to functional links
between inductive sites and effector sites of mucosal immunity.
PMID- 9554261
TI - PCPP as a parenteral adjuvant for diverse antigens.
AB - The adjuvanticity of the phosphazene polymer, poly[di(carboxylatophenoxy)
phosphazene] (PCPP) was examined with a diverse collection of immunogens. PCPP
proved to be a potent adjuvant for trivalent influenza virus vaccine, tetanus
toxoid, hepatitis B surface antigen, herpes simplex virus glycoprotein gD2 and
the capsular polysaccharide, polyribosylribitolphosphate, from Haemophilus
influenzae type b. Taken together these results clearly demonstrate the general
utility of PCPP as an adjuvant. Furthermore, PCPP was a superior adjuvant at
least with TT compared to similar negatively charged polyanions,
polymethylacrylic acid and polyacrylic acid.
PMID- 9554263
TI - Lipidation as a novel approach to mucosal immunization.
AB - We describe the design and development of a novel peptide-based approach for
mucosal immunization. The design contains an amplified peptide chain as multiple
antigen peptide (MAP) with a cluster of lipids. Such a design would confer on
lipidated MAP the ability to self-assemble in water, mimicking enveloped viral
particles. The importance of lipidation for mucosal immunization was confirmed by
oral immunization with lipidated MAP in phosphate-buffered saline (PBS), which
induced mucosal and systemic immune responses at local and distant sites,
including sera and vaginal IgG as well as secretory IgA in saliva, vaginal
secretions and fecal matter. T-cell proliferative responses were found in spleen,
Peyer's patches and genital lymph nodes. In addition, significant splenic
cytotoxic T-cell responses were also observed. No significant immune responses
were observed with non-lipidated MAPs by oral delivery in PBS. Furthermore, these
responses were selectively enhanced by different regimens, systemic priming and
microparticle delivery. These results demonstrate the effectiveness of lipidated
MAP for mucosal immunization to evoke both systemic and mucosal immune responses
without the use of carrier or extraneous adjuvant.
PMID- 9554264
TI - Systemic immunization with conserved pilus-associated adhesins protects against
mucosal infections.
AB - Colonization and infection of the bladder mucosa by Escherichia coli, the major
uropathogenic organism, is dependent on the expression of pilus organelles. Type
1 pili are expressed by the majority of E. coli strains derived from patients
with cystitis and pyelonephritis. FimH is the adhesin protein located at the
distal tip of the heteropolymeric type-1 pilus which mediates binding to bladder
cells through mannose receptors. We have shown that humoral antibody raised
against two forms of purified FimH adhesin inhibited 94% (49/52) of E. coli UTI
clinical isolates from binding to bladder tissue in vitro. Animals immunized with
FimH-containing vaccines by a systemic route reduced colonization of the bladder
mucosa in vivo in a murine cystitis model by > 99%. IgG antibody to FimH was
detected in urinary samples obtained from immunized, protected mice. Passive
systemic administration of immune sera from FimH-inoculated mice to naive animals
also resulted in reduced colonization of bladder mucosa by uropathogenic E. coli.
These studies demonstrate that systemic immunization with an anti-bacterial
vaccine targeting a highly conserved adhesin on uropathogenic E. coli can induce
IgG-mediated protection at a mucosal surface and may be a means of preventing
recurrent and acute infections of the urogenital tract mucosa.
PMID- 9554265
TI - Adjuvant effect of non-toxic mutants of E. coli heat-labile enterotoxin following
intranasal, oral and intravaginal immunization.
AB - Cholera toxin and Escherichia coli heat-labile enterotoxin (LT) are known to be
very effective mucosal adjuvants, but their toxicity limits their use in humans.
We genetically detoxified LT by substituting single residues in the active site
of the enzymatic A subunit and obtained mutant molecules that retain mucosal
adjuvant activity but are devoid of toxicity. These mutant LT molecules induce
mucosal and systemic responses to antigens delivered intranasally, orally and
intravaginally in mice. Furthermore, mucosal immunization with these molecules
confers protection against systemic challenge with tetanus toxin (TT) and mucosal
challenge with Helicobacter pylori.
PMID- 9554266
TI - Towards a nasal vaccine against meningococcal disease, and prospects for its use
as a mucosal adjuvant.
AB - A Norwegian outer membrane vesicle (OMV) vaccine against group B meningococcal
disease proved to be strongly immunogenic when administered intranasally in mice.
The OMV preparation, made from Neisseria meningitidis and intended for parenteral
use, was therefore given without adjuvant to human volunteers (n = 12) in the
form of nose drops or nasal spray. Such immunizations, which were carried out at
weekly intervals during a three-week period, were able to induce systemic
antibodies with bactericidal activity in more than half of the individuals. In
addition, all vaccinees developed marked increases in OMV-specific IgA antibodies
in nasal secretions. The potential of the OMV particles as carriers for other
less immunogenic antigens were elucidated in mice with use of whole inactivated
influenza virus. Even though influenza virus alone did induce some systemic and
salivary antibody responses after being administered intranasally, these
responses were greatly augmented when the virus was presented together with OMVs.
Thus, it is possible that a nasal OMV vaccine may induce protection against
invasive meningococcal disease, and also that it might be used as a vehicle for
nasal vaccines against other diseases.
PMID- 9554267
TI - The potential of retro-inverso peptides as synthetic vaccines.
AB - Retro-inverso (RI) peptides, also called all-D-retro peptides, have been shown to
mimic the antigenic and immunogenic properties of L-peptides successfully. RI
peptides corresponding to the loop 141-159 of the VP1 protein of foot-and-mouth
disease virus (FMDV) have been synthesized and used to immunize rabbits and
guinea pigs. These peptides induced longer-lasting and higher antibody titres in
immunized animals than did the corresponding L-peptides and the antibodies cross
reacted strongly with virus particles and with L-peptides. Antisera raised to RI
peptides had in vitro virus neutralization titres equal to or better than those
obtained after immunization with classical FMDV antigens and L-peptides. In view
of their increased stability, RI peptides may overcome some of the shortcomings
of synthetic viral vaccines based on L-peptides.
PMID- 9554268
TI - Protective immunity to intracellular parasites--a focus for vaccine research and
a challenge to immunization programmes.
AB - Protective immunity to intracellular parasites is mediated by T cells. This
response is complex, requiring activation of several subgroups of T cells and
production of a balanced blend of cytokines to obtain protection rather than
delayed hypersensitivity leading to tissue damage. To obtain additional, detailed
information, on the kind, proper localization and specificity of the required
immune response represents a major challenge in current vaccine research.
Insufficient knowledge of these features is the major constraint for development
as illustrated in tuberculosis and related mycobacterial infections.
PMID- 9554269
TI - Oral delivery of micro-encapsulated DNA vaccines.
AB - Oral delivery of vaccines is an attractive alternative to injection. It is a non
invasive procedure which allows access to the gut-associated lymphoid tissues
(GALT). Immunisation at GALT results in mucosal immune responses, which may be of
particular importance in protection against infection at mucosal surfaces, as
well as systemic immune responses. Vaccine antigens can be protected in the gut
by encapsulation in poly(DL-lactide-co-glycolide) (PLG) microparticles. Their
uptake into the immune inductive tissues of the GALT is mediated by M cells,
which selectively phagocytose particles less than 10 microns in diameter. We have
developed a method for the PLG encapsulation of plasmid DNA. Encapsulated DNA,
expressing the insect protein luciferase under the transcriptional control of the
human cytomegalovirus immediate early promoter, was administered to mice by
intraperitoneal injection or oral gavage. Intraperitoneal injection of
encapsulated DNA elicited good serum IgG and IgM responses and a modest IgA
response. Oral administration stimulated good serum antibody titres in all three
classes, and in addition, significant levels of mucosal IgA. PLG encapsulation
thus has the ability to protect plasmid DNA against degradation after
administration, and to facilitate its uptake into appropriate cells for the
subsequent expression and presentation of antigen, in such a way as to elicit
both systemic and mucosal antibody responses. This may have major implications
for the design of novel vaccines and delivery strategies.
PMID- 9554270
TI - Nucleic acid vaccines against hepatitis viruses.
AB - Direct DNA intramuscular or intradermal injection of plasmids containing viral
genes under the control of viral promoters is an efficient means of stimulating
both class I and class II-mediated antiviral responses. Viral hepatitis B and C
are suitable candidates for this approach, particularly as therapeutic immunogens
for chronically infected individuals. Several groups have shown that the S gene
of HBV is expressed in murine muscle and stimulates a high titre and long-lasting
anti-HBs response. Uniquely, CD8+ CTL responses are also induced to HBsAg. No
vaccine exists for HCV. Therefore the structural genes (C + E1 + E2) have been
cloned as a 2,831 bp fragment from a genotype la isolate into the vector pcDNA3.
The resulting plasmid DNA was injected directly into the quadriceps muscle of
three-week-old BALB/c mice. Intracellular-expressed E1 and E2 proteins thus
represent the complete spectrum of native structural epitopes, including those
dependent on glycosylation and protein folding. Mouse antisera were tested for
reactivity against conserved sequences using overlapping 7-mer peptides. Two
conserved, overlapping epitopes were identified in E2 spanning residues 581-591
and 590-603. This domain represents one of seven major E2 antigenic domains
recognized by HCV human antibodies, one of three with antigenic homologies to
related flavivirus proteins. Thus antigen is presented with high efficiency
following DNA injection and offers the potential of high rates of seroconversion
and virus clearance in those predisposed to virus-induced chronic liver disease.
PMID- 9554271
TI - Immune responses against hepatitis C virus structural proteins following genetic
immunisation.
AB - We have used direct DNA inoculation to study the in vivo induction of both
humoral and cellular immune responses to hepatitis C virus (HCV) encoded
structural antigens. Following immunisation of mice, immune responses were
compared using plasmids encoding full-length or partial HCV gene sequences for
the nucleocapsid and envelope E2 proteins. Plasmids encoding secreted or non
secreted forms of the immunogens, including constructs expressing HCV sequences
fused with the hepatitis B virus surface antigen (HCV-HBV chimeras), were
evaluated. Results indicate that: (i) all constructs induced specific anti-HCV
antibodies; (ii) antibody titres ranged from 1:100 to > 1:100,000; (iii) all HCV
DNA immunogens induced a predominant Th1 response with the induction of IgG2a
antibodies; (iv) the secretion level of the antigens and immune responses was not
always correlated and (v) CTL could be detected against both HCV and HBV
determinants.
PMID- 9554272
TI - Induction of a TH1 type cellular immune response to the human immunodeficiency
type 1 virus by in vivo DNA inoculation.
AB - DNA inoculation is capable of producing antigens intracellularly for ultimate
presentation to the cellular and humoral components of the immune system and has
potential for vaccine strategies against a number of infectious pathogens
including HIV-1. It is well documented that the antigenic diversity of HIV-1 and
its high level of nucleotide mutations during reverse transcription can lead to
escape from immune surveillance. However, data suggest that a CD8-mediated
cytotoxic T lymphocyte response may be less susceptible to escape mutants. We
have shown previously that in vivo inoculation of rodents and non-human primates
with plasmid expression vectors encoding HIV-1 gene products leads to production
of HIV-1 antigens and results in the production of both cellular and humoral
immune responses. In addition we have also demonstrated previously that these
responses lead to protection in several in vivo models. We further demonstrate
here that the cellular response induced is a type TH1 response and specific lysis
of HIV-infected targets is CD8-mediated.
PMID- 9554274
TI - Antigen-independent activation of resting T-cells in the liver of patients with
chronic hepatitis.
AB - Since the adult liver is an organ without constitutive lymphoid components, any
intra-hepatic T cell found in chronic viral hepatitis should have
compartmentalised to the liver after infection and inflammation. In liver
biopsies from patients with chronic hepatitis C there is a great discrepancy
between the percentage of activated T cells and the frequency of antigen-specific
T cells. Usually, 40 to 80% of the liver-infiltrating T cells express activation
markers, whereas only 0.5%, at best, of these cells are specific for any HCV
protein. This finding suggests that there may be antigen independent mechanisms
activating bystander T cells. We investigated whether human resting T cells could
be activated to proliferate and display effector function in the absence of TcR
occupancy. We have found that a combination of IL-2, TNF alpha and IL-6 could
activate highly purified naive and memory T cells to proliferate. Under these
conditions, resting memory T cells could also display effector function, as
assessed by cytokine synthesis and help for IgG production by B cells. This novel
antigen-independent pathway of T cell activation may play an important role in
vivo in activating effector T cells in the liver and in maintaining the clonal
size of peripheral memory T cells in the absence of antigenic stimulation.
PMID- 9554273
TI - The effect of IL-12 treatment on vaccine-enhanced illness during infection with
respiratory syncytial virus.
AB - In humans and mice, sensitisation to respiratory syncytial virus (RSV) antigens
can result in severe inflammatory lung disease during subsequent infection with
the virus. Although specific antiviral T cells are thought to be responsible for
this augmentation of disease, the precise role of different functional subsets is
unknown. BALB/c mice sensitised to the major surface glycoprotein (G) of RSV
expressed by recombinant vaccinia virus develop Th2-driven lung eosinophilia
after intranasal challenge with the virus. Mice treated with IL-12 at various
times during vaccination and challenge, had reduced vaccine-induced lung
eosinophilia but increased total pulmonary lymphoid cell infiltration.
Intracellular cytokine analysis showed that interferon-gamma production during
challenge was increased and IL-4 and IL-5 reduced by IL-12 treatment. Though IL
12 treatment reduced lung eosinophilia, illness (as assessed by weight loss) was
not eliminated and sometimes increased. Reversing Th2-associated pathology with
IL-12 does not necessarily benefit the host.
PMID- 9554275
TI - A novel method for enhancement of T independent responses.
AB - Bacterial capsular polysaccharides are the major targets for vaccination against
encapsulated bacteria but present problems when used for immunisation as they are
T cell independent antigens (TI-II). TI-II antigens do not induce a memory
response, but induce an antibody response which is of low magnitude and is
predominantly IgM, with little or no isotype switching to IgG isotypes. This is
because TI-II antigens do not induce T cell help. Such T cell help to B cells is
mediated through up regulation of the CD40 ligand (CD154) on the activated T
cell, which binds to CD40 inducing B cell activation, proliferation and isotype
switching in conjunction with cytokines produced by the T cell. We have
successfully mimicked this T cell help and induced very strong, isotype switched
antibody responses to TI-II antigens by the simple addition of agonistic anti
CD40 antibodies to pneumococcal polysaccharides before immunisation.
PMID- 9554276
TI - Cytotoxic activity induced by Mycobacterium Bovis BCG.
PMID- 9554277
TI - The role of cytotoxic T-cells in HIV infection.
AB - HIV-specific cytotoxic T lymphocytes (CTL) are believed to play a major role in
controlling virus levels through the asymptomatic period of HIV infection. For
the rational design of an HIV vaccine, we need to know whether protective
immunity can ever develop following HIV exposure in people who remain uninfected.
We have detected HIV-specific CTL in 5/6 repeatedly exposed, persistently
seronegative female sex-workers in The Gambia. Their CTL, repeatedly detected
over two years, recognise epitopes presented by HLA-B35 which are cross-reactive
between HIV-1 & HIV-2, suggesting they could have been primed first by HIV-2
exposure and subsequently boosted by exposure to HIV-1. Using previously
identified clade B HIV-1 epitope peptides, we have now detected HIV-specific CTL
in 6/15 highly exposed and apparently HIV-resistant Kenyan prostitutes,
predominantly towards epitopes highly conserved between B and the Kenyan A & D
clades of HIV-1. This CTL activity towards conserved virus epitopes may represent
protective immunity to HIV generated in response to repeated exposure, and
prophylactic HIV vaccines should aim to generate similar CTL responses.
PMID- 9554278
TI - Immunopotentiating reconstituted influenza virosomes as a novel antigen delivery
system.
AB - Using immunopotentiating, reconstituted influenza virosomes (IRIV) as a delivery
vehicle, a number of vaccines have been developed. In humans, IRIV-based vaccines
containing hepatitis A and influenza antigens have been found to possess enhanced
immunogenicity compared to alum-adsorbed vaccine for hepatitis A or commercial
subunits or whole virion influenza vaccines. These vaccines were safe and did not
engender any anti-phospholipid antibodies against the liposome components of the
IRIV. Hepatitis B, tetanus toxoid and diphtheria toxoid, and nucleic acids have
also been incorporated into IRIVs. These vaccines are now undergoing clinical
phase I testing. IRIVs are also being evaluated in phase I trials for their
ability to deliver antigens by the intranasal route.
PMID- 9554279
TI - Protective mucosal immunity elicited by targeted lymph node immunization with a
subunit SIV envelope and core vaccine in macaques.
AB - Prevention of sexually transmitted HIV infection was first investigated in non
human primates by mucosal immunization via the rectal, vaginal or male urethral
route. This was compared with subcutaneous targeted iliac lymph node (TILN) and
systemic intramuscular immunization in non-human primates. TILN immunization
elicited the most consistent mucosal sIgA and IgG antibody response in the
rectum, vagina, urine and seminal fluid, as well as in blood. Both mucosal and
TILN immunization induced a specific CD4+ T cell proliferative response in the
iliac lymph nodes which drain these mucosal surfaces, and in the splenic and
circulating T cells. In the next experiment macaques were immunized by the TILN
route with SIV gp120 and p27 in alum. Rectal mucosal challenge with SIVmac 32H J5
molecular clone (or cell-free virus) induced total protection in four out of
seven macaques, compared with infection in 13 of 14 unimmunized macaques or
immunized by other routes (p = 0.025). The remaining three macaques immunized by
the TILN route showed either decrease in viral load (> 90%) or transient
viraemia, indicating that all seven TILN immunized macaques showed total or
partial protection of rectal transmission by SIV (p = 0.001). Protection was
associated with significant increase in the iliac lymph nodes IgA antibody
secreting cells to p27 (p < 0.02), CD8-suppressor factor inhibiting replication
of SIV in CD4+ T cells (p < 0.01) and the chemokines RANTES and MIP-1 beta (p <
0.01). We suggest that administration of gp120 and p27 by the TILN route may
elicit protective B and T cell immunity which can significantly prevent rectal
transmission of SIV or HIV.
PMID- 9554280
TI - Adjuvants in perspective.
AB - Many vaccines currently under development and testing are composed of synthetic,
recombinant, or highly purified subunit antigens. Vaccines composed of these
subunit antigens are often considered to be safer than whole-inactivated or live
attenuated vaccines. However, vaccines containing purified subunit antigens are
often less immunogenic than traditional vaccines. Immunological adjuvants are
agents that enhance specific immune responses to vaccines. Formulation of
vaccines with potent adjuvants is an attractive approach for enhancing immune
responses to subunit antigens. Adjuvants have diverse mechanisms of action and
should be selected for use based on the route of administration and the type of
immune response (antibody, cell-mediated, or mucosal) desired for a particular
vaccine. Adjuvant mechanisms of action include: (i) increasing the biological or
immunological half-life of vaccine antigens; (ii) improving antigen delivery and
presentation; and (iii) inducing the production of immunomodulatory cytokines.
Through modulation of cytokine responses, adjuvant formulations can be designed
that favour the development of Th1 (type 1) or Th2 (type 2) immune responses to
vaccine antigens. Novel adjuvants are currently undergoing preclinical and
clinical testing with experimental vaccines, including vaccines against HIV-1.
Standardized preclinical adjuvant safety tests are also being developed.
PMID- 9554281
TI - Modulation of the immune response to tetanus toxoid by polylactide-polyglycolide
microspheres.
AB - The cellular and antibody responses in mice to tetanus toxoid (TT), alone or
adsorbed to aluminium hydroxide TT were compared to those obtained with TT
incorporated in polylactide-polyglycolide (PLGA) microspheres, a candidate single
dose vaccine. After subcutaneous injection, the serum IgM antibody to TT followed
similar overall patterns for all preparations although the highest levels were
achieved with the alum-adsorbed material. A similar pattern was observed with the
overall IgG antibody responses. The isotype distribution of antibodies was
broadly similar for all types of preparation although considerable qualitative
differences were observed. IgG1 antibodies predominated although IgG2a and IgG2b
made a substantial contribution, especially at three months in the case of the
two adjuvanted preparations. The IgG3 responses to each type of vaccine were very
low. Both alum and microsphere vaccines induced proliferative responses to TT in
splenic lymphocytes at three months after vaccination. Each type of vaccine was
much less effective in inducing proliferative responses in lymph node cells.
There was evidence of induction of IL2, IL4 and interferon-gamma genes by
microsphere vaccines in splenic but not lymph node cells. There were indications
that PLGA microspheres alone exerted a modulating effect on cellular responses
after immunization. These results suggest that TT encapsulated in microspheres
induces a pattern of cellular and antibody responses qualitatively similar to
those induced by conventional TT vaccines.
PMID- 9554282
TI - Development of an animal model to assess the immunogenicity of single-dose
tetanus and diphtheria vaccines based on controlled release from biodegradable
polymer microspheres.
AB - We have determined threshold doses of aluminium phosphate (AlPO4) adsorbed
tetanus toxoid (TT) and diphtheria toxoid (DT) in mice and guinea pigs with a
view to developing an animal model to assess the immunogenicity of controlled
release vaccines. A dose was sought (threshold dose) which produces little
antibody after primary injection and a moderate response after a booster
injection, thus mimicking the adult human response to TT and DT vaccines adsorbed
on to aluminium adjuvants. After the first injection, mice and guinea pigs showed
a dose response for both tetanus toxin IgG antibodies and tetanus antitoxin over
a wide range of doses of AlPO4-adsorbed TT (0.01 to 0.2 Lf). After the second and
third injections, there was no clear dose response for doses between 0.05 and 0.2
Lf However, doses between 0.01 and 0.04 Lf still showed a dose response after the
second injection. Dilution of AlPO4-adsorbed TT in saline just before injection
did not alter immunogenicity after the first injection, but stronger booster
responses were seen in mice to diluted versus undiluted vaccine after the second
and third injections. The threshold dose of AlPO4-adsorbed TT for both mice and
guinea pigs was 0.01 Lf given in 100 microliters. For AlPO4-adsorbed DT, three
strains of mice (inbred, Balb/c and C57/B6, and outbred, CD-1) showed a dose
response after the first injection for DT IgG antibodies and diphtheria antitoxin
at 0.1 and 0.2 Lf doses. Outbred CD-1 mice showed a dose response after the
second and third injections also, whereas inbred mice showed inconsistent dose
responses after the second injection and none after the third injection. In
contrast to AlPO4-adsorbed TT, mice injected with undiluted AlPO4-adsorbed DT
elicited significantly higher antibodies than those injected with diluted
formulations, particularly after the first injection. The threshold dose of AlPO4
adsorbed DT for mice was 0.1 Lf in a volume of 250 microliters. Lower doses did
not produce consistent antibody responses in mice. We propose that a single dose
of controlled release formulations at doses not greater than 1/10 of a single
human dose when injected into mice and guinea pigs should produce an antibody
response similar or higher than two to three threshold doses of AlPO4-adsorbed TT
or DT.
PMID- 9554283
TI - Kinetics, localization and characteristics of B- and T-cell responses to iscoms
containing human influenza virus glycoproteins.
AB - B- and T-cell responses have been studied after primary and secondary
immunizations of mice with iscoms containing influenza virus envelope
glycoproteins. After primary immunization both B- and T-cell responses were
initiated in the draining lymph nodes. T-cells showed peak activity with respect
to proliferation and cytokine production after five to eight days and the highest
number of IgG secreting cells (IgG-SC) was recorded at day seven. The responses
in the spleen developed slowly but were of longer duration. Cytokines produced by
spleen cells included high levels of IFN-gamma and IL-2. After a secondary
immunization the frequencies of IgG-SC were drastically increased in both LN and
spleen, but decreased rapidly with time. At day eight after the secondary
immunization high numbers of IgG-SC were detected in the bone marrow. High titres
of IgG1 and IgG2a and substantial titres of IgG2b and IgG3 were detected in
serum.
PMID- 9554284
TI - In vitro determination of antigen quality: biosensor analysis and fluorescence
spectroscopy.
AB - We are probing the potential of two techniques to monitor the quality of antigens
in vitro. Structural and conformational differences between diphtheria toxin and
toxoid are detected via biosensor analysis (BIA-core) and fluorescence
spectrometry. With BIA-core the interaction kinetics between toxin and toxoid and
a monoclonal antibody were established. The fluorescence properties of both
antigens were determined with respect to fluorescence intensity and emission
maximum as a function of guanidinium hydrochloride concentration. In all cases
clear differences were found between toxin and toxoid. Antibody affinity of the
toxoid was lower compared with toxin, caused by lower binding and higher release
rates. Fluorescence intensity of toxoid was reduced by about 50%. Toxoid was less
sensitive to guanidinium hydrochloride-induced denaturation, reflected in a
diminished shift of the emission maximum.
PMID- 9554285
TI - Immunity provided by haemorrhagic septicaemia-subunit vaccine in ruminants.
AB - A subunit vaccine against haemorrhagic septicaemia (HS), the principal killer
disease in ruminants, especially cattle and carabao, in the Philippines, has been
developed. Using capsules of Pasteurella multocida Group B as an active component
of the vaccine, it gave solid protection against challenge with live organism in
mice. An active calf protection test showed that in 24 hours, animals vaccinated
with plain saline died after challenge compared to those given the subunit
vaccine which survive the challenge dose. Using 104 cattle from a farm, the field
trial of the HS subunit vaccine showed that the antibody titre was high for up to
14 months. A high titer is an indication of protection.
PMID- 9554286
TI - Cellular immune responses of cattle to Cowdria ruminantium.
AB - Peripheral blood mononuclear cells (PBM) from cattle immunised against Cowdria
ruminantium infection (Heartwater), proliferated in vitro in the presence of
either infected autologous endothelial cells pre-treated with T cell growth
factors to induce MHC class II expression, or infected autologous monocytes.
Proliferation was not observed in PBM cultured with a soluble extract of the
agent, but PBM responded to two recombinant antigens of C. ruminantium, namely a
32 kDa (MAP1) and a 21 kDa antigen (MAP2). We hypothesize that infected
endothelial cells and monocytes present Cowdria antigens to specific lymphocytes
during infection and thereby play a role in the pathogenesis/immune response to
the pathogen.
PMID- 9554287
TI - Salivary immune responses after gingival immunization with tetravaccinal and
bivaccinal formulations of inactivated micro-organisms.
AB - Two groups of rats were treated separately, fourteen times during three months,
by rubbing at gingival mucosa with two antigenic mixtures: (i) Staph. aureus,
Str. faecalis, E. coli and Prot. vulgaris; (ii) Str. mutans and Act. viscosus. At
the end of the treatments the increases of specific salivary IgAGM ranged from
202.6% (Str. faecalis) to 312.7% (E. coli) in the case of tetravaccinal
association and from 123% (Act. viscosus) to 171.4% (Str. mutans) in the one of
bivaccinal formulation.
PMID- 9554289
TI - Humoral response to HSV-1 subunit vaccines--a statistical analysis.
AB - Following primary infection with HSV, the virus becomes latent in the local
sensory ganglia for the lifetime of the host. In some cases, periodic
reactivation may occur due to various stimuli and cause a recrudescent lesion at
or near the initial site of infection. As yet there is no suitable vaccine to
prevent its spread within the human population. We investigated the potential of
a large number of commercial and experimental adjuvant preparations to enhance
the immunogenicity of an HSV-1 glycoprotein subunit vaccine. Evaluation was based
on toxicity, total antibody titre, neutralizing antibody production and
protection against lethal challenge. All adjuvants tested increased the titre of
antigen specific total and neutralizing lg when compared to subunit vaccine
alone, although functional neutralising antibody was only detected in some cases.
Following challenge, a broad range of protective responses was noted but no
correlation between antibody levels and protection was observed. The results
emphasize the requirement of adjuvants when using subunit preparations as vaccine
formulations and demonstrate that the magnitude and effectiveness of the induced
immune response varies greatly with the choice of adjuvant.
PMID- 9554290
TI - Systematic development of a block copolymer adjuvant for trivalent influenza
virus vaccine.
AB - The current influenza virus vaccines induce systemic humoral immunity and short
lived cellular immunity in young adults. Unfortunately these vaccines are only
50% efficacious in the elderly (> 65 years) and high risk groups of the very
young. The use of a vaccine adjuvant to correct this deficit would therefore be
very beneficial to these population groups. We have developed high molecular
weight synthetic non-ionic block copolymers with adjuvant activity. These
copolymers are compatible with, and active in, aqueous, physiological
formulations in which they spontaneously assemble into 500-3000 nm particles. By
varying both the molecular weight and the proportions of hydrophilic and
hydrophobic components of the molecule, we have designed the optimal copolymer
adjuvant for use with influenza hemagglutinin. This copolymer, termed CRL-1005,
was investigated for its ability to augment the immune response of mice to the
commercially-available human influenza vaccine, Fluogen. Co-formulation of CRL
1005 with the vaccine resulted in markedly increased antibody titres measured by
both ELISA and the functional haemagglutination inhibition assay, indicating that
critical immunogen epitopes were not destroyed. A single dose of copolymer and
vaccine produced both long term rising antibody titres (six months) and primed
for a potent secondary response. This high molecular weight copolymer is non
toxic and should therefore be well suited for widespread use.
PMID- 9554288
TI - Effect of aluminium hydroxide and meningococcal serogroup C capsular
polysaccharide on the immunogenicity and reactogenicity of a group B Neisseria
meningitidis outer membrane vesicle vaccine.
AB - Three different formulations of an outer membrane vesicle (OMV) vaccine against
group B meningococcal disease have been prepared and tested for immunogenicity
and reactogenicity in adult volunteers. The vaccines were prepared with or
without aluminium hydroxide and serogroup C-polysaccharide (C-ps). Doses from
12.5 to 100 micrograms protein were given twice at a six weeks' interval. All
three formulations were well tolerated and highly immunogenic, inducing
bactericidal and opsonizing antibodies in humans. Adsorption of OMVs to aluminium
hydroxide reduced the pyrogenicity in rabbits. The differences in immunogenicity
between the formulations were relatively small, but after the second dose a
stronger booster response was observed when the vaccines were adsorbed. Thus, a
formulation with OMVs and C-ps represents a safe and highly immunogenic vaccine,
even without aluminium hydroxide.
PMID- 9554291
TI - Ovalbumin coupled either with murine red blood cells or liposome induces IgG but
not IgE antibody production.
AB - Ovalbumin (OVA) was coupled with murine red blood cells (MRBC) using
glutaraldehyde. The OVA-MRBC conjugate induced anti-OVA IgG antibody in mice at
almost the same level as OVA in alum. However, no IgE antibody production
specific for OVA was observed in OVA-MRBC-injected mice. A significant increase
in IGG2a production was obtained with OVA-MRBC immunization, whereas the
production of IgG1 predominated in OVA in alum immunization. Am OVA-liposome
conjugate induced IgE-specific unresponsiveness in mice in the same manner as OVA
MRBC. Similar results were obtained when antigens other than OVA, such as tetanus
toxoid or diphtheria toxoid, were coupled to liposome. These results show the
potential of antigen-liposome conjugates for the development of vaccine that
induces sufficient IgG antibody production without IgE synthesis.
PMID- 9554292
TI - Scleredema of Buschke successfully treated with electron beam therapy.
PMID- 9554293
TI - An infant with firm, fixed plaques.
PMID- 9554294
TI - The morality of cosmetic surgery for aging.
PMID- 9554295
TI - Clinical, pathologic, and immunologic features of human T-lymphotrophic virus
type I-associated infective dermatitis in children.
AB - OBJECTIVES: To define the clinical and laboratory features associated with
infective dermatitis (ID) and confirm its association with human T-lymphotrophic
virus type I (HTLV-I). DESIGN: A case series of patients with ID were compared
with patients with atopic dermatitis (AD), which is an important disease in the
differential diagnosis of ID. SETTING: Patients were recruited from dermatology
and pediatric clinics at the University Hospital of the West Indies and the
Bustamante Children's Hospital, Kingston, Jamaica. MAIN OUTCOME MEASURES:
Clinical and laboratory features of patients with AD were compared with those of
patients with ID. PATIENTS: Consecutive patients older than 1 1/2 years diagnosed
as having ID (n=50) and AD (n=35) were enrolled based on clinical findings.
RESULTS: The mean ages of patients with ID and AD were 6.9 and 7.8 years,
respectively. Histologically, both diseases were predominantly chronic dermatitis
with propensity for skin colonization with Staphylococcus aureus and beta
hemolytic streptococci; however, the distribution of sites of skin involvement
differed. Infection with HTLV-I was the most distinguishing feature among
patients with ID, with seropositive results in 100%; only 5 (14%) of the 35
patients with AD had results seropositive for HTLV-I. Infective dermatitis was
further characterized by dermatopathic lymphadenitis in 16 (67%) of 24 patients
with palpable nodes. Anemia, lymphocytosis, and low albumin and elevated serum
globulin levels were more prevalent among patients with ID. Significant
elevations of IgA, IgD, and IgG levels were observed among patients with ID
compared with those with AD. However, both patients with AD and those with ID had
levels of IgD and IgE elevated above the normal range. T-cell subsets among
patients with ID revealed T-cell activation with a high percentage of HLA-DR
antigen positivity, elevated CD4 (2.4 x 10(9)/L) and CD8 (1.4 x 10(9)/L) cell
counts, with an increased CD4/CD8 ratio of 1:73. CONCLUSION: Infective dermatitis
is a distinct clinical entity associated with HTLV-I, which plays a role in the
pathogenesis and immune perturbations observed.
PMID- 9554296
TI - Livedo vasculopathy vs small vessel cutaneous vasculitis: cytokine and platelet P
selectin studies.
AB - OBJECTIVE: To assess the role of platelets and lymphocyte-related immunological
mechanisms in livedo vasculopathy (LV) and cutaneous small vessel vasculitis
(CSVV). Livedo vasculopathy is thought to be related to the thrombotic occlusion
of small and medium-sized dermal vessels. Cutaneous small vessel vasculitis
comprises a heterogeneous group of disorders in which the main pathogenetic
events could be modulated by circulating cytokines. DESIGN: Case series study of
2 groups of patients affected respectively with LV and CSVV. SETTING: A large
clinical and research institute for the study and treatment of cutaneous
diseases. PATIENTS: Consecutive patients with clinically and histologically
proved idiopathic LV (n = 8) and CSVV (n = 20) were studied and compared with
healthy donors (n = 20). Patients with potentially correlated systemic diseases
were excluded. MAIN OUTCOME MEASURES: Surface expression of platelet P-selectin
and circulating level of interleukin (IL) 1beta, tumor necrosis factor alpha (TNF
alpha), IL-8, IL-2, and soluble IL-2 receptor. RESULTS: The IL-2 and soluble IL-2
receptor levels were significantly higher in serum samples from patients with
both LV (1.24 +/- 0.46 IU/mL [mean +/- SD] vs 0.46 +/- 0.24 IU/mL, P<.001; 899 +/
368 IU/mL vs 628 +/- 132 IU/mL, P<.02) and CSVV (0.91 +/- 0.57 IU/mL, P<.02;
1087 +/- 451 IU/mL, P<.001) than in those from the healthy controls. The serum
levels of IL-1beta, TNF-alpha, and IL-8 were higher in patients with CSVV than in
controls (7.53 +/- 6.7 pg/mL vs 4.58 +/- 2.72 pg/mL; 23.7 +/- 12.6 pg/mL vs 10.82
+/- 2.46 pg/mL, P<.001; 37.8 +/- 46 pg/mL vs 8.25 +/- 3.53 pg/mL, P<.02,
respectively). No significant difference in the serum levels of IL-1beta (7.2 +/-
4.9 pg/mL), TNF-alpha (12.9 +/- 3.47 pg/mL), and IL-8 (5.9 +/- 4.13 pg/mL) was
observed in patients with LV compared with controls. An increased expression of
platelet P-selectin was also detected in patients with LV in comparison with
controls and patients with CSVV. The mean +/- SD percentage of positive cells for
P-selectin was 43% +/- 5% in the patients with LV, 5.1% +/- 2% in the controls
(P<.001), and 5.3% +/- 2% in the patients with CSVV (P<.001). CONCLUSIONS: Taken
together, these data demonstrate that different pathogenetic mechanisms are
operative in LV and CSVV. In fact, platelet and lymphocyte activation is present
in LV, whereas the levels of inflammatory mediators are in a normal range. In
CSVV, the high serum levels of proinflammatory cytokines suggest that they are
actively involved in the pathogenesis of cutaneous vasculitis.
PMID- 9554297
TI - Acne vulgaris and the quality of life of adult dermatology patients.
AB - OBJECTIVE: To determine the effects of acne vulgaris on the quality of life of
adult dermatology patients. DESIGN: Cross-sectional and longitudinal
questionnaire study. PATIENTS: Sixty patients with acne vulgaris attending
appointments with their dermatologists. MAIN OUTCOME MEASURES: Findings using
Skindex, a validated 29-item instrument to measure the effects of skin disease on
patients' quality of life. Results are reported as 3 scale scores (functioning,
emotions, and symptoms) and a composite score (average scale score). In addition,
dermatologists rated the clinical severity of patients' skin disease, and
patients responded to a global question about how they are bothered by acne.
Higher Skindex scores indicate greater effects on quality of life. RESULTS:
Patients with acne experienced functioning and emotional effects from their skin
disease comparable with those of patients with psoriasis, but experienced fewer
symptoms (for patients with acne and psoriasis, respectively, Skindex functioning
scores of 14.9 and 22.8 [P=.08]; emotion scores, 39.2 and 38.9 [P=.95]; and
symptoms scores, 29.5 and 42.1 [P<.05]). Skindex scores were higher in older
patients than in younger patients, and patients aged 40 years or older were less
likely to report improvement in their acne after 3 months (43% vs 85%; P<.05).
Among patients reporting no improvement in their acne, older patients reported
greater effects of their acne on their quality of life. Furthermore, in
multivariate analyses, older adults reported more effects of acne on their
quality of life than younger adults, even after controlling for sex and acne
severity as judged by the dermatologist. CONCLUSIONS: Acne vulgaris significantly
affects patients' quality of life. Regardless of the severity of acne, older
adults were more affected by their acne.
PMID- 9554298
TI - Topical cyproterone acetate treatment in women with acne: a placebo-controlled
trial.
AB - OBJECTIVE: To evaluate the clinical and hormonal response of topically applied
cyproterone acetate, oral cyproterone acetate, and placebo lotion in women with
acne. DESIGN: Placebo-controlled, randomized study. SETTING: Patients were
recruited from the Institute of Endocrine Cosmetics, Vienna, Austria. PATIENTS:
Forty women with acne. INTERVENTIONS: Treatment with oral medication consisting
of 0.035 mg of ethinyl estradiol and 2 mg of cyproterone acetate (n=12), 20 mg of
topical cyproterone acetate lotion (n=12), and placebo lotion (n=16) was offered.
Patients were assessed monthly for 3 months. MAIN OUTCOME MEASURES: Clinical
grading according to acne severity and lesion counts as well as determinations of
serum cyproterone acetate concentrations. RESULTS: After 3 months of therapy with
topical cyproterone acetate, the decrease of mean facial acne grade from 1.57 to
0.67 was significantly better (P<.05) compared with placebo (which showed a
change from 1.57 to 1.25), but not compared with oral medication (1.56 to 0.75)
(P>.05). Lesion counts also decreased from 35.9 to 9.1 in the topical cyproterone
acetate group compared with oral medication (45.4 to 15.5) (P>.05) and placebo
(38.2 to 23.1) (P<.05). After topical cyproterone acetate treatment, serum
cyproterone acetate concentrations were 10 times lower than those found after
oral cyproterone acetate intake. CONCLUSIONS: The therapeutic effect of topically
applied cyproterone acetate for acne treatment was clearly demonstrated.
Topically applied sexual steroids in combination with liposomes are as effective
as oral antiandrogen medication in acne treatment, while reducing the risk of
adverse effects and avoiding high serum cyproterone acetate concentrations.
PMID- 9554299
TI - High risk of death in elderly patients with extensive bullous pemphigoid.
AB - OBJECTIVE: To evaluate survival and factors predicting death in bullous
pemphigoid. DESIGN: Retrospective analysis of cohort. SETTING: Three referral
centers (university hospitals). PATIENTS: Among 237 patients recruited between
January 1, 1985, and December 31, 1992, 20 were excluded because of doubtful
diagnosis. The 217 remaining patients were 79+/-11 years old (mean+/-SD); 120
were women and 97 were men; and 79% had been treated with oral corticosteroids,
40 to 90 mg/d. INTERVENTIONS: Missing information on follow-up was minimized by
letters and/or telephone calls to patients, families, nursing homes, and
physicians. MAIN OUTCOME MEASURES: Actuarial survival curve, compared with the
expected curve as derived from census data, and evaluation of prognostic factors
by comparing initial characteristics between patients alive at 6 months and these
who died before that point. RESULTS: Survival curve demonstrated an early
increased mortality: 17% at 3 months and 31% at 6 months, mainly from sepsis and
cardiovascular diseases. Of the factors related to bullous pemphigoid activity
(duration; pruritus; and number and extent of blisters, eosinophilia, and serum
antibodies) only generalized pemphigoid was predictive of death in comparison
with localized forms. In multivariate analysis, age of 86 years or more (relative
risk, 7.1; 95% confidence interval [CI], 2.0-25.4; P < or = .01), poor general
condition (relative risk, 8.2; 95% CI, 3.0-22.4; P < or = .001), female sex
(relative risk, 2.4; 95% CI, 1.1-5.4; P < or = .05), and generalized disease
(relative risk, 4.4; 95% CI, 1.4-13.7; P < or = .01) were associated with
increased risks of death at 6 months. CONCLUSION: In this series, generalized
bullous pemphigoid had a poor prognosis especially in older patients and those in
poor general condition.
PMID- 9554300
TI - Teledermatology and in-person examinations: a comparison of patient and physician
perceptions and diagnostic agreement.
AB - OBJECTIVE: To compare physician and patient impressions and interphysician
diagnostic agreement between live teledermatology and in-person examinations.
DESIGN: Paired video and in-person examinations with different dermatologists.
SETTING: An urban Veterans Affairs dermatology clinic. PATIENTS: One hundred
thirty-nine patients. MAIN OUTCOME MEASURES: Satisfaction questionnaires and
interphysician diagnostic agreement. RESULTS: Patient and physician satisfaction
was high. Agreement between video and in-person diagnoses was 80%. CONCLUSIONS:
Physicians and patients were satisfied with teledermatology examinations.
Diagnostic agreement between in-person and video dermatologists was high.
PMID- 9554301
TI - Differences in Epstein-Barr virus expression between primary and secondary
cutaneous angiocentric lymphomas. French Study Group of Cutaneous Lymphomas.
AB - BACKGROUND: Epstein-Barr virus (EBV) has been demonstrated in angiocentric
immunoproliferative lesions, suggesting that it could be a causative factor. We
investigated for the presence of EBV in 12 primary and 2 secondary cutaneous
angiocentric lymphomas (CALs). OBSERVATIONS: In the 2 secondary CALs, strong
reactivity for EBV RNAs and latent membrane protein 1 were detected on paraffin
embedded sections. In contrast, 10 of 12 primary CALs were completely negative
for EBV RNAs and latent membrane protein 1. In 2 primary CALs, EBV RNAs and
latent membrane protein 1 were detected in few tumor cells. In the group of
primary CALs, 8 of 12 were still alive at last follow-up, 3 died of systemic
lymphoma, and 1 died of another cause, whereas both patients with secondary CALs
died of disease within 1 year. CONCLUSION: Differences in the presence of EBV and
clinical behavior between primary and secondary CALs suggest that different
mechanisms are operative in the pathogenesis of these conditions, and indicate
that the 2 groups should be considered separately.
PMID- 9554302
TI - Infective dermatitis: a pabulum for human T-lymphotrophic virus type I
leukemogenesis?
PMID- 9554303
TI - Livedoid vasculopathy: what is it?
PMID- 9554304
TI - Persistent, solitary, erythematous, hyperkeratotic plaque.
PMID- 9554305
TI - Woman with new-onset boggy scalp.
PMID- 9554306
TI - An unusual papule.
PMID- 9554307
TI - Panniculitis and ulcers in a young man.
PMID- 9554308
TI - Interobserver variation in the assessment of rosacea.
PMID- 9554309
TI - Are we consultants or peddlers?
PMID- 9554310
TI - The case for sunscreens revisited.
PMID- 9554311
TI - Helicobacter pylori in rosacea: lack of an association.
PMID- 9554312
TI - Propolis-induced allergic contact dermatitis mimicking pemphigus vulgaris.
PMID- 9554313
TI - Localized bullous pemphigoid following radiotherapy for breast carcinoma.
PMID- 9554314
TI - Use of a topical fluorescent dye to evaluate effectiveness of sunscreen
application.
PMID- 9554315
TI - Skin involvement in male breast carcinoma.
PMID- 9554316
TI - Basic psychopharmacology of antidepressants, part 1: Antidepressants have seven
distinct mechanisms of action.
AB - Distinct pharmacologic mechanisms allow the antidepressants to be separated into
seven different classes. These basic pharmacologic concepts can explain not only
the therapeutic actions, but also the side effects of the wide range of
antidepressants currently available. The two classical mechanisms are those of
tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). The
most widely prescribed agents are the serotonin selective reuptake inhibitors
(SSRIs). Three other classes of antidepressants, like the SSRIs, increase
serotonergic neurotransmission, but they also have additional actions, namely
dual serotonin and norepinephrine reuptake inhibition (venlafaxine); serotonin-2
antagonism/reuptake inhibition (nefazodone); and alpha2 antagonism plus serotonin
2 and -3 antagonism (mirtazapine). The selective norepinephrine and dopamine
reuptake inhibitor bupropion defines a novel class of antidepressant that has no
direct actions on the serotonin system.
PMID- 9554317
TI - Basic psychopharmacology of antidepressants, part 2: Estrogen as an adjunct to
antidepressant treatment.
AB - Estrogen exerts profound effects upon behavior by interacting with neuronal
estrogen receptors. Changes in estrogen levels over a woman's life cycle are
linked not only to behavioral fluctuations, but potentially to the onset or
recurrence of mood disorders. The modern psychiatric evaluation of women requires
obtaining a complete reproductive history, including details of hormone
treatments, while identifying reproductive events as triggers of affective
disorder episodes. While guidelines for the use of reproductive hormones in
psychiatry are just evolving, administration of estrogen as an adjunct to
antidepressants is an exciting possibility for expanding the frontiers of
psychiatry into the field of women's health.
PMID- 9554318
TI - Bupropion sustained release: a therapeutic overview.
AB - Sustained-release bupropion (bupropion SR) represents a new form of an already
known effective antidepressant drug. Its pharmacokinetics, mechanism of action,
metabolism, and efficacy are reviewed. Benefit relative to placebo has been
demonstrated in two large multicenter trials, with low doses (100 or 150 mg)
having been shown to have therapeutic efficacy. An overview of all placebo
controlled trials of bupropion SR is given, and the differential properties of
bupropion and serotonergic drugs are described. The concept of a catecholamine
indolamine spectrum is presented, along with its implications for possible
differential therapeutics of selective antidepressants.
PMID- 9554320
TI - Drug interactions--friend or foe?
AB - An explosion of knowledge about interactions of drugs with other drugs and with
foods threatens to inundate clinicians. This review provides a better
understanding of the cytochrome P450 system with a focus on those enzymes most
involved in drug metabolism. Emphasis is placed on antidepressant medications,
how they are metabolized by the P450 system, and how they alter the metabolism of
other drugs. The role of antidepressants in precipitating the serotonin syndrome
is also discussed.
PMID- 9554319
TI - Bupropion sustained release: side effect profile.
AB - Bupropion IR (immediate release) has been on the market since 1988 and is an
effective and usually well-tolerated antidepressant. In late 1996, a new
sustained-release formulation, bupropion SR, was approved and is now available.
Compared with the IR formulation, the SR formulation demonstrates similar
efficacy and has been found to have similar, but to some degree fewer, side
effects. Its efficacy is similar to that of other newer antidepressants. Side
effects of bupropion SR are limited and are not dissimilar to those of the
serotonergic antidepressants; however, bupropion SR produces neither substantial
sexual side effects nor drug interactions. Study data demonstrate that seizure
incidence, which is a concern with high-dose IR, is substantially lower with the
new SR formulation.
PMID- 9554321
TI - Antidepressant-induced sexual dysfunction.
AB - This article reviews current evidence regarding sexual side effects of
antidepressant drugs. Controlled studies have demonstrated that some
antidepressant drugs have adverse effects on orgasm and libido. Orgasmic
dysfunction and ejaculatory delay appear to be common sexual side effects of the
serotonin selective reuptake inhibitors (SSRIs). A variety of treatment options
are available if a patient experiences antidepressant-induced sexual dysfunction.
Often, modification of the pharmacologic regimen will restore sexual function
while maintaining antidepressant activity. The frequency of sexual side effects
reported with the SSRIs mandates that the clinician inquire about sexual function
if these agents are used. Bupropion and nefazodone appear to have an unusually
low incidence of sexual side effects.
PMID- 9554322
TI - Depression, sleep, and antidepressants.
AB - Sleep disturbances are an integral feature of depressive disorders. Like the
disorders themselves, the sleep disturbances associated with depression are
heterogeneous, ranging from hypersomnia to marked difficulties maintaining sleep.
These difficulties are to some extent age dependent and reflect abnormalities of
central nervous system arousal. Moreover, the sleep disturbances associated with
depression have both reversible, or state-dependent, and more persistent trait
like characteristics. Polysomnographic recordings can be used to document sleep
maintenance difficulties, and they often also reveal reduced slow wave sleep, an
early onset of the first episode of rapid eye movement (REM) sleep, and increased
phasic REM sleep. A deficit of serotonergic neurotransmission, a relative
increase in pontine cholinergic activity, and, perhaps, an excess of
noradrenergic and corticotropin-releasing hormone activity have been implicated
in the pathogenesis of the sleep disturbances of more severe depressive
disorders. Antidepressant medications have class- and compound-specific effects
on polysomnographic profiles. Unlike other antidepressants, bupropion may
increase or intensify REM sleep. While no single effect of antidepressants on
sleep neurophysiology is necessary or sufficient for treatment efficacy,
differences in drug effects may provide important clues to selection of specific
medications for particular patients.
PMID- 9554323
TI - Bupropion sustained release and smoking cessation.
AB - The identification of nicotine dependence as a psychiatric disorder and increased
knowledge of nicotine's neuropharmacologic effects have stimulated researchers to
search for new pharmacologic interventions for smoking cessation. After reviewing
the efficacy and safety of bupropion sustained release (SR) as an agent for
treating smoking cessation, the Food and Drug Administration recently approved
the use of bupropion SR for this indication. This paper reviews nicotine's
pharmacologic effects and the factors contributing to the development of nicotine
dependence, the general principles and strategies for treating nicotine
dependence, and the evidence for the efficacy of bupropion SR as a treatment for
smoking cessation. The release of bupropion SR as a treatment for smoking
cessation may provide clinicians with additional opportunities to address smoking
cessation with their patients.
PMID- 9554324
TI - The Expert Consensus Guidelines for treating depression in bipolar disorder.
AB - We present expert consensus guideline recommendations for the treatment of
bipolar depression. These were arrived at through the statistical aggregation of
the survey responses of 61 leading clinical researchers to eight questions about
the key decision points in the management of bipolar depression. The experts'
first-line recommendation for treating psychotic depression in bipolar disorder
is to provide a combination of mood stabilizer, antidepressant, and neuroleptic
medication. For severe, but nonpsychotic bipolar depression, the experts
recommend the combination of a mood stabilizer and an antidepressant. For milder
bipolar depression, a mood stabilizer and an antidepressant together or a mood
stabilizer alone would be first line. The experts' antidepressant dose and dosing
schedule recommendations are equivalent for unipolar and bipolar depression, but
the experts recommend a faster discontinuation of antidepressants during the
maintenance phase in bipolar patients--probably to reduce the risk of rapid
cycling. Among the antidepressants, the experts prefer bupropion and the
serotonin reuptake inhibitors as first line. They also believe that bupropion is
least likely among antidepressants to cause switches to mania. Among mood
stabilizers, the experts rate lithium as most likely to have a direct
antidepressant effect.
PMID- 9554325
TI - Diagnosis and treatment of depression in late life.
AB - Major depression and dysthymia are common and often disabling disorders in late
life. Several features of late-life depression, such as its frequent association
with general medical conditions, polypharmacy, cognitive disturbances, and
adverse life events, make accurate diagnosis a substantial clinical challenge.
Yet, prompt diagnosis is an important component of implementing appropriate
treatment strategies. An ideal treatment program integrates patient and family
education, focused psychotherapy, and pharmacotherapy. Because of pharmacokinetic
and pharmacodynamic changes associated with aging, lower doses of medication and
more gradual dose increases than are required in younger adults are needed in the
treatment of elderly depressed patients. In addition, medications should be
selected that have minimal antihistaminic, anticholinergic, and antiadrenergic
effects, minimal cardiovascular risk, and minimal drug-drug interactions. Since
depression in late life tends to be at least as chronic and/or recurrent as
depression earlier in life, treatment for acute depressive episodes should last
at least 6-8 months, and long-term maintenance treatment should be considered in
selected individuals.
PMID- 9554326
TI - ADHD through the life span: the role of bupropion in treatment.
AB - Attention-deficit/hyperactivity disorder (ADHD) is a common problem that begins
early in life and in many cases persists through the life span. Psychostimulants
have been the psychopharmacologic treatment of choice. Not all patients respond
to psychostimulants, and some patients have significant side effects. This paper
reviews the use of a nonstimulant psychopharmacologic agent, bupropion, to treat
ADHD in both children and adults.
PMID- 9554327
TI - Surgical trauma on the tunica albuginea.
PMID- 9554328
TI - An analysis of watchful waiting for clinically localized prostate cancer.
AB - PURPOSE: We reviewed recent series of watchful waiting for prostate cancer to
place this management strategy in appropriate perspective MATERIALS AND METHODS:
We reviewed the literature and analyzed the 9 articles on watchful waiting
published in leading medical journals in the last decade. RESULTS: Watchful
waiting is probably the best treatment option for men with well and perhaps
moderately differentiated, low volume prostate cancer who have a life expectancy
of less than 10 years. However, the conclusions derived from watchful waiting
studies of older men cannot and should not be applied to younger, healthier men
or to those with more advanced or aggressive disease. If treated ineffectively,
many of these men will die of prostate cancer. CONCLUSIONS: Most men with
prostate cancer who have a life expectancy greater than 10 to 15 years should be
treated with curative intent.
PMID- 9554329
TI - Locally recurrent prostate tumors following either radiation therapy or radical
prostatectomy have changes in Ki-67 labeling index, p53 and bcl-2
immunoreactivity.
AB - PURPOSE: We compare the biological phenotype of recurrent prostatic tumors after
definitive local therapy (radiation or radical prostatectomy) with that of the
same tumors before treatment. MATERIALS AND METHODS: Cellular proliferation (Ki
67 labeling index), p53 nuclear reactivity and bcl-2 immunoreactivity were
determined in pretreatment and posttreatment tumor specimens from 13 patients
with local tumor recurrence following radiation, and in 18 patients with local
tumor recurrence following radical prostatectomy. RESULTS: Mean Ki-67 labeling
index increased approximately 2-fold in locally recurrent tumors after radiation
(10.5 versus 5.6%, p=0.0008) or surgery (6.0 versus 3.2%, p=0.0025) when compared
with pretreatment tumors. We noted p53 nuclear reactivity in a significantly
higher proportion of recurrences than in pretreatment tumors following radiation
(54 versus 8%, p=0.032) and surgery (39 versus 5%, p=0.022). Although bcl-2
immunoreactivity was also seen in a higher proportion of recurrent tumors, this
difference did not reach statistical significance for either radiation or
surgery. CONCLUSIONS: Recurrent tumors following either radiation or surgery
differ significantly from the corresponding pretreatment tumors with respect to
cellular proliferation and p53 nuclear reactivity.
PMID- 9554330
TI - Differential expression of urinary inter-alpha-trypsin inhibitor trimers and
dimers in normal compared to active calcium oxalate stone forming men.
AB - PURPOSE: We determine if the immunoreactive profile of urinary inter-alpha
trypsin inhibitor can be used to distinguish between normal individuals and
individuals with calcium oxalate stone disease. MATERIALS AND METHODS: Urinary
proteins were dialyzed against water (15 kDa. molecular weight cutoff),
lyophilized and resolved by sodium dodecyl sulfate-polyacrylamide gel
electrophoresis (6% acrylamide, reducing conditions) followed by Western blot.
Inter-alpha-trypsin immunoreactive proteins were detected by enhanced
chemiluminescence. Stone formation was confirmed to be active radiologically or
passed as stone or gravel within 12 months of the sample. Stone composition was
confirmed crystallographically. Normal individuals had no personal or familial
history of urolithiasis and matched stone forming patients regarding race (white)
and age (23 to 71 years old). Urine from a total of 101 individuals was analyzed.
RESULTS: The intact inter-alpha-trypsin trimer (approximately 220 to 240 kDa.)
and heavy chain (HC) 2-bikunin/HC1-bikunin dimers (approximately 115 to 130 kDa.)
were detected more often in stone forming men (23 of 26 [89%] and 26 of 26
[100%], respectively) than in normal individuals (6 of 26 [23%] and 5 of 26
[19%], respectively, p < 0.0001). In those normal individuals who expressed inter
alpha-trypsin trimer and HC-bikunins the relative intensities were 5.3+/-1.4% and
16.3+/-17.1% of the stone forming controls, respectively. The identity of high
molecular weight-inter-alpha-trypsin immunoreactive bands was confirmed using
antibodies against the individual subunits (HC1, HC2, HC3, bikunin). In contrast
to men high molecular weight-inter-alpha-trypsin's were readily detected in
normal and stone forming women with equal frequency (inter-alpha-trypsin-trimer
p=0.1337, HC-bikunins p=0.2836): inter-alpha-trypsin-trimer 17 of 18 [94%] and 9
of 13 [77%]; HC-bikunins 17 of 18 [94%] and 10 of 13 [85%]). Inter-alpha-trypsin
trimer and HC-bikunins, respectively, were detected in 2 and 5 of 10 patients
with chronic renal disease. Expression was not related to hematuria or
proteinuria. CONCLUSIONS: Immunoreactive profiles of urinary proteins may be able
to be developed into a useful diagnostic tool to identify active stone formation,
although a separate panel may be required for men and women. It is possible that
these differences may provide clues as to why the incidence of stone disease is
higher in men than women.
PMID- 9554331
TI - Sustained reduction in urinary calcium during long-term treatment with slow
release neutral potassium phosphate in absorptive hypercalciuria.
AB - PURPOSE: We tested whether UroPhos-K, a new slow release neutral form of
potassium phosphate (155 mg. phosphate, 8 mEq. potassium per tablet) in a dose of
4 tablets twice daily would produce a sustained hypocalciuric response and
maintain bone mass in patients with absorptive hypercalciuria, a major cause of
nephrolithiasis characterized by excessive intestinal calcium absorption
accompanied in some patients by excessive bone loss. MATERIALS AND METHODS: A
total of 25 patients with absorptive hypercalciuria were studied in a 4-year,
prospective, open trial with UroPhos-K at yearly intervals during a 4-day
inpatient physiological study with a constant metabolic diet containing 400 mg.
calcium, 100 mEq. sodium and 800 mg. phosphate daily. RESULTS: Treatment with
UroPhos-K caused a sustained, marked reduction in urinary calcium (264 to 181 mg.
daily). Fractional 47calcium absorption decreased modestly (74.0 to 64.6%)
commensurate with a reduction in serum 1,25-dihydroxyvitamin D (42 to 34
pg./ml.). Intact parathyroid hormone increased within the normal range (30 to 42
pg./ml.). Bone mineral density was stable at the lumbar spine, femoral neck and
distal third of the radius. CONCLUSIONS: UroPhos-K may provide a long-term
alternative for hypercalciuric patients in whom thiazide therapy fails.
PMID- 9554332
TI - Insights into the pathophysiology and treatment of patients with calcium oxalate
nephrolithiasis.
PMID- 9554333
TI - Cytokine levels in cystic renal masses associated with renal cell carcinoma.
AB - PURPOSE: We compared cytokine levels in fluid from renal cysts with and without
renal cell carcinoma. MATERIALS AND METHODS: Fluid was aspirated from 18 renal
cysts without (benign) and 21 with renal cell carcinoma (malignant). Serum from
patients with renal cell carcinoma and healthy controls was collected and
cytokines were measured by enzyme-linked immunosorbent assay. RESULTS:
Interleukin-6 (IL-6) and basic fibroblast growth factor concentrations were
higher in malignant than benign cysts or serum (p <0.006). Epidermal growth
factor levels were significantly higher in malignant cysts and serum than in
benign cysts (p <0.01). IL-6 levels in malignant cysts positively correlated with
the erythrocyte sedimentation rate (R=0.80) and C-reactive protein (R=0.86), and
they were higher in grade 3 than in grade 2 tumors. Basic fibroblast growth
factor levels were significantly higher in malignant cysts associated with
hypervascular than hypovascular tumors (p=0.029). CONCLUSIONS: Cytokine levels in
aspirated fluid may help to identify malignant renal cysts and indicate the
characteristics of coexisting tumors.
PMID- 9554335
TI - Bowel dysfunction after bladder reconstruction.
AB - PURPOSE: Bowel function may be disturbed after intestinal segments are used in
urinary reconstruction. The etiology of this condition and its incidence in
different patient groups is unclear. We studied the incidence of bowel
disturbance in patients who underwent bladder replacement, continent diversion,
enterocystoplasty for idiopathic detrusor instability and ileal conduit
diversion. MATERIALS AND METHODS: We evaluated 71 patients after ileal conduit
diversion and 82 after bladder reconstruction, including clam enterocystoplasty
for detrusor instability in 28, neurogenic bladder dysfunction in 26 and
nonneuropathic conditions in 28. We noted the severity of symptoms, such as
frequency of defecation, nocturnal diarrhea, flatus leakage, fecal urgency, fecal
incontinence and explosive diarrhea, as well as quality of life. RESULTS: Of the
patients who underwent bladder reconstruction 24% had symptoms of bowel
dysfunction preoperatively and 42% of those who were asymptomatic preoperatively
described new bowel symptoms postoperatively. These symptoms were most common and
severe in 54% of patients after clam enterocystoplasty for detrusor instability
compared to 26% with neuropathy, 14% with a nonneuropathic condition and 15% with
an ileal conduit. Compared to those in other groups patients who underwent
enterocystoplasty for detrusor instability had a significantly higher incidence
of nocturnal bowel movements (18 versus less than 4%, p <0.01), flatus leakage
(29 versus less than 8%, p <0.01), fecal urgency (39 versus less than 12%, p
<0.001) and fecal incontinence (32 versus less than 16%, p <0.001). The length of
ileum used for clam enterocystoplasty was only slightly greater than that used
for ileal conduit operations (25 versus 18 cm.). Of the patients who underwent
enterocystoplasty for detrusor instability 29% regretted undergoing the procedure
due to subsequent bowel symptoms. CONCLUSIONS: After enterocystoplasty for
detrusor instability patients are at risk of significant bowel symptoms. The
development of new bowel symptoms was associated with poor patient satisfaction.
PMID- 9554334
TI - Nephron sparing surgery for renal cell carcinoma 4 cm. or less in diameter:
indicated or under treated?
AB - PURPOSE: Although radical nephrectomy is the standard treatment for localized
unilateral renal cell carcinoma with a normal contralateral kidney, there is
ongoing interest in the use of nephron sparing surgery or partial nephrectomy in
such cases. The extent of radical surgery in such cases has also been
reconsidered in view of the uncertainty regarding the malignant or benign nature.
MATERIALS AND METHODS: Of 14,793 autopsies in Jena from 1985 until 1995 there
were 260 renal cell carcinomas. Of the 260 renal cell carcinomas the diameter was
40 mm. or less in 104. These 104 tumors were divided into group 1-20 mm. or less
(33 cases), group 2-21 to 30 mm. (28) and group 3-31 to 40 mm. (43). RESULTS:
Grade 1 renal cell carcinomas decreased in frequency with increasing tumor
diameter, while an opposite result was noted for grade 3. Lymph node and distant
metastases were well correlated with tumor size. With an increase in tumor size
the frequency of venous involvement increased as well. Significantly more
multifocal malignant renal cell carcinomas were seen in tumors between 21 and 40
mm. compared to those 20 mm. or less in diameter. CONCLUSIONS: The metastatic
potential and biology of these small nodules are not yet known. To lower the risk
of local recurrence the results of our study suggest that nephron sparing surgery
might be advisable in patients with renal cell carcinoma 20 mm. or less in
diameter.
PMID- 9554336
TI - Sacral root neuromodulation in idiopathic nonobstructive chronic urinary
retention.
AB - PURPOSE: Sacral root neuromodulation is becoming a superior alternative to the
standard treatment of idiopathic nonobstructive urinary retention. We report
results in 20 successive patients who underwent sacral foramen implantation to
restore bladder function. MATERIALS AND METHODS: After an initial, thorough
baseline assessment 20 patients 19.43 to 55.66 years old with idiopathic
nonobstructive urinary retention underwent percutaneous nerve evaluation.
Response was assessed by a detailed voiding diary. Responders underwent
implantation with an S3 foramen implant, and were followed 1, 3 and 6 months
postoperatively, and every 6 months thereafter. RESULTS: Sacral root
neuromodulation restored voiding capability in these patients. Bladders were
emptied with minimal post-void residual urine, which decreased from 78.3 to 5.5
to 10.2% of the total voided volume from baseline to postoperative followup.
These results were reflected in uroflowmetry and pressure-flow studies, which
were almost normal after implantation. Furthermore, the urinary tract infection
rate decreased significantly and associated pelvic pain improved substantially.
The Beck depression inventory and SF-36 quality of life questionnaire indicated
some improvement but reached significance in only 1 item. In addition,
cystometrography showed no significant difference after 6 months of implantation
compared with baseline values. Complications were minimal and within
expectations. CONCLUSIONS: Sacral root neuromodulation is an appealing,
successful modality for nonobstructive urinary retention. Only patients who have
a good response to percutaneous nerve evaluation are candidates for implantation.
The high efficacy in patients who undergo implantation, relative simplicity of
the procedure and low complication rate make this a treatment breakthrough in
this difficult group.
PMID- 9554337
TI - The treatment of interstitial cystitis with supratrigonal cystectomy and
ileocystoplasty: difference in outcome between classic and nonulcer disease.
AB - PURPOSE: Interstitial cystitis is a chronic debilitating condition that mainly
affects women. Accumulated evidence indicates that interstitial cystitis is a
heterogeneous syndrome. The nonulcer type seems to respond less favorably to
various conservative treatments than the classic type. Supratrigonal cystectomy
with ileocystoplasty is established treatment for interstitial cystitis
refractory to conservative treatment. We evaluate whether classic interstitial
cystitis responds differently than nonulcer disease to subtotal bladder resection
and ileocystoplasty. MATERIALS AND METHODS: We evaluated 13 patients 27 to 79
years old with interstitial cystitis who underwent supratrigonal cystectomy and
ileocystoplasty due to failure to respond to conservative treatment. RESULTS: In
all 10 patients with classic interstitial cystitis symptoms were relieved after
ileocystoplasty. In the 3 patients with nonulcer interstitial cystitis pain
remained, while the frequency of voiding somewhat decreased. In these patients
trigonal resection and urinary diversion with a Kock pouch resolved the symptoms.
CONCLUSIONS: Our study confirms that supratrigonal cystectomy with
ileocystoplasty results in a good outcome in classic interstitial cystitis.
However, this method seems to be unsuitable for nonulcer disease. Identification
of the relevant subtype of interstitial cystitis is of crucial importance for
selecting the appropriate method of lower urinary tract reconstruction.
PMID- 9554338
TI - The efficacy of intravesical bacillus Calmette-Guerin in the treatment of
interstitial cystitis: long-term followup.
AB - PURPOSE: Interstitial cystitis is a severe debilitating bladder disease
characterized by unrelenting pelvic pain and urinary frequency. A prospective,
double-blind, placebo controlled study of the use of intravesical bacillus
Calmette-Guerin (BCG) in the treatment of interstitial cystitis was recently
completed with a mean followup of 8 months. Results demonstrated a 60% BCG
response rate, compared to a 27% placebo response rate. We now report the long
term followup results of those patients who received intravesical BCG. MATERIALS
AND METHODS: Subjects randomized to receive BCG were followed at routine
intervals with questionnaires and voiding diaries identical to those in the
blinded study. Adverse events were closely monitored in the treatment and
followup phases of the study. Subject baseline values were compared to followup
data. RESULTS: Of the BCG responders mean followup was 27 months (range 24 to
33), and 8 of 9 (89%) continue to have an excellent response in all parameters
measured. The global interstitial cystitis survey improved 70%, daily voids
decreased 31%, nocturia improved 54%, mean voided volume increased 61%, pelvic
pain decreased 81%, vaginal pain decreased 71%, urgency decreased 71% and dysuria
decreased 82%. Overall well-being improved 54% and the Rand-36 quality of life
survey overall improved 64%. In 86% of the patients (6 of 7) dyspareunia
resolved. Of the initial BCG nonresponders there was no significant difference in
interstitial cystitis symptomatology from baseline to last followup, suggesting
that BCG does not worsen interstitial cystitis symptoms. No long-term adverse
events from BCG were noted. CONCLUSIONS: Intravesical Tice BCG is safe, effective
and durable in the treatment of interstitial cystitis. Of those patients who
received only 6 weekly treatments and responded favorably 89% continue to have an
excellent response with followup ranging from 24 to 33 months.
PMID- 9554339
TI - Activation of human dendritic cells by bacillus Calmette-Guerin.
AB - PURPOSE: Dendritic cells are the most potent antigen presenting cells capable of
initiating antitumor immune responses. We previously showed that bacillus
Calmette-Guerin (BCG) stimulates cultured human dendritic cells. We extended
these studies and tested the ability of cultured human dendritic cells to express
interleukin IL-8 in response to BCG. We also investigated the T cell stimulatory
potential of BCG treated dendritic cells in mixed leukocyte reactions. MATERIALS
AND METHODS: Dendritic cells were obtained by culturing plastic adherent
mononuclear cells from peripheral blood for 6 days in the presence of granulocyte
macrophage colony-stimulating factor and IL-4. Spontaneous and BCG stimulated IL
8 protein release into culture supernatants was measured by a quantitative
immunoassay. IL-8 gene transcription was assessed by reverse transcription
polymerase chain reaction. Untreated and BCG exposed dendritic cells were
compared as stimulators of allogeneic T cell proliferation, measured as
[3H]thymidine incorporation. RESULTS: BCG stimulated IL-8 messenger ribonucleic
acid expression and IL-8 protein release. IL-8 secretion occurred in a dose and
time dependent fashion. BCG induced IL-8 release was further enhanced in the
presence of indomethacin. BCG treated dendritic cells were much more potent T
cell stimulators than untreated dendritic cells. CONCLUSIONS: These data
demonstrate that BCG enhances the production of IL-8, a potent chemokine of T
cells and granulocytes, as well as the T cell stimulatory potential of human
dendritic cells.
PMID- 9554340
TI - The molecular characteristics of bladder cancer in young patients.
AB - PURPOSE: The molecular characteristics of bladder cancer in children and young
adults remain largely undefined. We sought to identify common molecular changes
in bladder tumors in young patients using standard immunohistochemical and
interphase cytogenetic methods. MATERIALS AND METHODS: We retrospectively
evaluated 73 bladder tumors removed from patients younger than 30 years for the
p53 tumor suppressor gene product using immunohistochemical techniques and
numerical aberrations of chromosomes 9, 17, X and Y. RESULTS: Regardless of
stage, immunohistochemical evidence of p53 gene product over expression was found
in the majority of tumors studied. Numerical aberrations (monosomy) of chromosome
9 were rare. Aneuploidy of chromosome 17 was common, particularly in carcinoma in
situ and invasive bladder cancer. CONCLUSIONS: These data suggest that
immunohistochemical evidence of p53 gene product over expression is common in
bladder cancer in young patients. Further prospective analysis of lesions in this
population may help to establish a comprehensive molecular progression model for
urothelial neoplasms.
PMID- 9554341
TI - Carcinosarcoma and sarcomatoid carcinoma of the bladder: clinicopathological
study of 41 cases.
AB - PURPOSE: Carcinosarcoma of the bladder is a rare neoplasm characterized by an
intimate admixture of carcinoma and malignant soft tissue neoplasm. The clinical
usefulness of separating carcinosarcoma (carcinoma with sarcomatous component)
from sarcomatoid carcinoma (carcinoma with spindle cell carcinomatous component)
is uncertain, and it comprises the subject of this report. MATERIALS AND METHODS:
We reviewed the clinical and pathological records of 10 men and 5 women a mean of
66 years old with carcinosarcoma, and 21 men and 5 women a mean of 66.5 years old
with sarcomatoid carcinoma of the bladder, as documented in the files of the Mayo
Clinic between 1936 and 1995. RESULTS: Of the 15 patients in the carcinosarcoma
group 9 had urothelial carcinoma, small cell carcinoma, 3 had squamous cell
carcinoma and 2 had more than 1 type. The sarcomatous component included
chondrosarcoma in 3 cases, leiomyosarcoma in 3, malignant fibrous histiocytoma in
3, osteosarcoma in 2, fibrosarcoma in 1, rhabdomyosarcoma in 1 and more than 1
type in 2. All disease was high stage at presentation. Treatment included
cystectomy in 11 patients with (4) and without (7) radiation therapy, and
transurethral resection in 4 with (1) and without (3) radiation therapy. Mean
followup available in 14 cases was 34 months (range 1 to 144). A total of 11
patients died of cancer at 1 to 48 months (mean 17.2) and 2 survived for 8 to 131
months. Of the 26 patients in the sarcomatoid carcinoma group 18 had urothelial
carcinoma, 1 had squamous carcinoma, 2 had urothelial carcinoma combined with
squamous cell carcinoma and 5 had spindle cells only with no recognizable
epithelium. All but 1 case was high stage at diagnosis. Treatment included
transurethral resection in 17 patients with (7) and without (10) radiation
therapy, including 1 who also received chemotherapy, and only cystectomy in 5,
including 2 who also underwent radiation therapy and 1 who also received
chemotherapy. Mean followup available in 21 cases was 49 months (range 1 to 420).
A total of 17 patients died of cancer at 1 to 73 months (mean 9.8), 1 was alive
at 140 months and 3 died of unrelated causes. CONCLUSIONS: Carcinosarcoma and
sarcomatoid carcinoma of the bladder are highly aggressive malignancies with a
similar outcome regardless of histological findings and treatment. Pathological
stage is the best predictor of survival.
PMID- 9554342
TI - Collagen injection for intrinsic sphincteric deficiency in men: a reasonable
option in selected patients.
AB - PURPOSE: We evaluate transurethral collagen injection as a minimally invasive
option in treating stress urinary incontinence in men and identify the prognostic
factors for success or failure. MATERIALS AND METHODS: Transurethral collagen was
injected in 35 men with grades III (22) and II (13) incontinence. RESULTS: Of the
patients 7 became dry (20%), 11 improved (31.4%) and 17 were considered failures
(48.6%). Abdominal leak point pressure increased and the number of pads needed
decreased. In the failed group 4 patients had a history of pelvic irradiation, 5
urethral stricture disease and 3 bladder instability before injection. There was
1 case of temporary urinary retention as a complication. CONCLUSIONS:
Transurethral collagen injection for male stress urinary incontinence is a
reasonable option in select patients.
PMID- 9554343
TI - Delayed hypersensitivity and systemic arthralgia following transurethral collagen
injection for stress urinary incontinence.
AB - PURPOSE: During a prospective cohort study to determine the effectiveness of and
adverse effects associated with transurethral collagen injection for treatment of
stress urinary incontinence in women, we observed 3 cases of delayed allergic
reaction at the skin test site associated with arthralgia. MATERIALS AND METHODS:
A total of 337 women with at least a 1-year history, physical findings and
urodynamic abnormalities consistent with stress urinary incontinence, who
required pads or protective clothing and who had no or only grade 1 cystocele
were enrolled in this prospective cohort study. Adverse effects were documented
by a third party at each followup. RESULTS: Delayed reaction at the skin test
site occurred in 3 patients (0.9%), and was associated with arthralgias in 2.
CONCLUSIONS: The incidence and systemic nature of this type of reaction suggest
that gluteraldehyde cross-linked collagen injection is not as innocuous as
previously believed. Patients should be counseled regarding the unknown long-term
outcome of this complication. Before treatment clinicians should consider double
skin testing.
PMID- 9554344
TI - The male bulbourethral sling procedure for post-radical prostatectomy
incontinence.
AB - PURPOSE: We evaluate the efficacy of the male bulbourethral sling procedure in
the treatment of post-radical prostatectomy urinary incontinence. MATERIALS AND
METHODS: We reviewed the records of 64 consecutive men with severe post
prostatectomy incontinence who underwent the male bulbourethral sling procedure
at Northwestern Memorial Hospital and Stanford University Hospital.
Preoperatively 50% of the patients were completely incontinent (diapers, clamps
or condom catheter), and the remainder required a mean of 4.7 pads per day. Data
were collected by chart review, patient interviews at followup appointments and
telephone interviews. Median followup was 18.1 months (mean 22.4, range 6.5 to
53.8). RESULTS: Following a single sling procedure 36 patients (56%) became dry,
and 5 (8%) were significantly improved. In 17 patients 23 retightening procedures
were performed, which decreased the median followup to 16 months and increased
the success rate to 75% (67% cured, 8% improved). The revision, erosion and
infection rates were 27, 6 and 3%, respectively. CONCLUSIONS: The male
bulbourethral sling procedure is effective treatment for post-radical
prostatectomy urinary incontinence. Patients who had received adjuvant radiation
therapy demonstrated a lower continence rate than those who had not. Further
followup is needed to assess long-term efficacy.
PMID- 9554345
TI - Sacral nerve root neuromodulation: an effective treatment for refractory urge
incontinence.
AB - PURPOSE: Sacral foramina implants have been recognized recently as a method for
treatment of refractory urinary urge incontinence. We study the outcome of the
procedure with in-depth analysis of the results of 18 implanted cases. MATERIALS
AND METHODS: Patients with urinary urge incontinence were subjected to
percutaneous nerve evaluation of the S3 roots as a temporary screening test to
determine response to neuromodulation. Satisfactory responders were implanted
with permanent sacral root neuroprosthesis. The study design included
comprehensive voiding diaries for 4 consecutive days twice as a baseline, 1 with
percutaneous nerve evaluation screening, 1 after the percutaneous nerve
evaluation, 1 at the 1, 3 and 6 post-implantation visits, and every 6 months
thereafter. Uroflowmetry and quality of life questionnaires were performed at the
same intervals. Urodynamic study was done as a baseline and 6 months after
implantation of the neuroprosthesis. RESULTS: All 18 patients (16 women and 2
men) with refractory urge incontinence received a sacral foramina neuroprosthesis
after demonstrating a good response to the percutaneous nerve evaluation. Average
patient age at presentation was 42.3+/-3.3 years (range 22 to 67) and duration of
urinary symptoms was 6.6+/-1.3 years (range 1.2 to 18.8). Average followup was
18.8 months (range 3 to 83). Neuromodulation in these patients showed a marked
reduction in leakage episodes from 6.49 to 1.98 times per 24 hours and in the
leakage severity score. Eight patients became completely dry and 4 had average
leakage episodes of 1 or less daily. Patients showed as well a decrease in
urinary frequency with an increase in functional bladder capacity. Associated
pelvic pain improved substantially. Cystometrograms demonstrated increased volume
at first sensation by 50% and increased cystometric capacity by 15% with the
disappearance of uninhibited contractions in 1 of the 4 patients who presented
with it preoperatively. There was also noticeable improvement in the quality of
life. Complication rate was low and none was life threatening. CONCLUSIONS:
Sacral root neuromodulation is an appealing modality for treatment of urge
incontinence refractory to conventional pharmacotherapy. The relative simplicity
of the technique, promising results and low complication rate make this therapy a
likely alternative.
PMID- 9554346
TI - Management of urinary incontinence--progress and innovative strategies.
PMID- 9554347
TI - Erectile response to transurethral alprostadil, prazosin and alprostadil-prazosin
combinations.
AB - PURPOSE: Transurethral alprostadil has been shown to be efficacious in many men
with erectile dysfunction. We compared transurethral alprostadil and prazosin
alone, and in combination to treat this disorder. MATERIALS AND METHODS: In this
double-blind, placebo controlled study the erectile responses to transurethral
alprostadil, prazosin and alprostadil-prazosin combinations were assessed in 234
men 26.8 to 81.5 years old with complete organic erectile dysfunction. Patients
self-administered a random sequence of 7 doses in the clinic in 4 weeks. The
erectile response was assessed using categorical and visual analog scales.
RESULTS: Full penile enlargement or rigidity was achieved by 165 of the 234 men
(70.5%) after at least 1 active dose of medication. The most effective
alprostadil dose (500 microg.) resulted in full penile enlargement or rigidity in
51.8% of administrations, whereas the most effective prazosin dose (2,000
microg.) and placebo resulted in a similar response in 12.7 and 2.7%,
respectively (p <0.001). The 500/2,000 microg. alprostadil/prazosin combination,
which resulted in full enlargement or rigidity in 58.9% of doses, was only
slightly better than the most effective dose of alprostadil alone (500 microg.).
However, combinations of 125/500 and 250/500 microg. alprostadil/prazosin were
more effective (p <0.01) than 125 and 250 microg. alprostadil given alone,
respectively. The most common side effect of therapy was penile pain, which
rarely led to study discontinuation. Hypotension most commonly developed at the
higher alprostadil-prazosin combination. CONCLUSIONS: Transurethral alprostadil
and alprostadil-prazosin combinations produced erections in men with complete
organic erectile dysfunction. This combination therapy may be an option in
patients who do not respond to transurethral alprostadil alone.
PMID- 9554348
TI - A possible mechanism for alteration of human erectile function by digoxin:
inhibition of corpus cavernosum sodium/potassium adenosine triphosphatase
activity.
AB - PURPOSE: Digoxin use has long been recognized to affect adversely male sexual
function but the underlying mechanism is poorly understood. Digoxin is a known
inhibitor of sodium/potassium adenosine triphosphatase (sodium pump), a plasma
membrane enzyme that has a role in the regulation of smooth muscle tone. We
investigated the effects of digoxin on human corpus cavernosum smooth muscle
contractility and overall erectile function. MATERIALS AND METHODS: In human
corporeal smooth muscle strips the in vitro effects of digoxin were assessed on
sodium pump activity as measured by digoxin inhibitable uptake of 86rubidium,
basal tone and endothelium dependent, neurogenic and nitric oxide donor induced
relaxation. An in vivo prospective double-blind, placebo controlled, crossover, 4
period investigation was performed in 6 healthy male volunteers. The effects of
digoxin on serum hormones, erectile function questionnaire, visual sexual
stimulation and nocturnal penile tumescence were recorded. RESULTS: In vitro
digoxin caused concentration dependent inhibition of 86rubidium uptake (half
maximum effect at 0.01 microM.) and contraction of corporeal smooth muscle (half
maximum effect at 0.8 microM.). Therapeutic concentrations of digoxin (2 nM.)
also inhibited relaxation induced by acetylcholine and electrical field
stimulation, which release nitric oxide from corpus cavernosum endothelial cells
and nonadrenergic noncholinergic nerves, respectively. In vivo digoxin diminished
penile rigidity during visual sexual stimulation and nocturnal penile tumescence
testing compared to placebo without influencing libido or serum testosterone,
estrogen or luteinizing hormone levels. CONCLUSIONS: Digoxin associated
alteration of human erectile function may be explained, in part, by inhibition of
corporeal smooth muscle sodium pump activity, which promotes contraction and
impedes nitric oxide induced relaxation. Such findings suggest therapeutic use of
digoxin for treatment of recurrent priapism states.
PMID- 9554349
TI - Quantifying risk of penile prosthesis infection with elevated glycosylated
hemoglobin.
AB - PURPOSE: Elevation of glycosylated hemoglobin above levels of 11.5 mg.% has been
considered a contraindication to penile prosthesis implantation in diabetic
patients. We determine the predictive value of glycosylated hemoglobin A1C in
penile prosthesis infections in diabetic and nondiabetic patients to confirm or
deny this prevalent opinion. MATERIALS AND METHODS: We conducted a 2-year
prospective study of 389 patients, including 114 diabetics, who underwent 3-piece
penile prosthesis implantation. All patients had similar preoperative preparation
without regard to diabetic status, control or glycosylated hemoglobin A1C level.
Risk of infection was statistically analyzed for diabetics versus nondiabetics,
glycosylated hemoglobin A1C values above and below 11.5 mg.%, insulin dependent
versus oral medication diabetics, and fasting blood sugars above and below 180
mg.%. RESULTS: Prosthesis infections developed in 10 diabetics (8.7%) and 11
nondiabetics (4.0%). No increased infection rate was observed in diabetics with
high fasting sugars or diabetics on insulin. There was no statistically
significant increased infection risk with increased levels of glycosylated
hemoglobin A1C among all patients or among only the diabetics. In fact, there was
no meaningful difference in the median or mean level of glycosylated hemoglobin
A1C in the infected and noninfected patients regardless of diabetes. CONCLUSIONS:
Use of glycosylated hemoglobin A1C values to identify and exclude surgical
candidates with increased risk of infections is not proved by this study.
Elevation of fasting sugar or insulin dependence also does not increase risk of
infection in diabetics undergoing prosthesis implantation.
PMID- 9554350
TI - Health outcomes variables important to patients in the treatment of erectile
dysfunction.
AB - PURPOSE: Erectile dysfunction is underreported and the rate of noncompliance with
therapy is high. The National Institutes of Health Consensus Conference on
Impotence endorsed the need for outcomes research of the various approaches to
treatment. The purpose of our exploratory study was to begin that process through
identification of erectile dysfunction treatment outcomes variables that are
important to men. MATERIALS AND METHODS: The study format consisted of focus
group meetings. The goal of the discussions was to identify variables that are
important to men when choosing among and judging the success of treatment
modalities for erectile dysfunction. After discussion participants were
individually asked to identify the 10 variables that they considered important
and rank the 5 most important variables. An importance score reflecting group
consensus was calculated for each variable. RESULTS: Success and negative
outcomes were identified as the 2 most important outcomes variables for all
treatment modalities. Participants defined success in several ways. The most
important measures of success were cure, pleasure and partner satisfaction.
Negative outcome was defined as negative consequences associated with treatment.
CONCLUSIONS: The focus group discussion assisted in identifying and defining
outcomes variables important to patients with erectile dysfunction. We believe
that understanding issues and outcomes important to such patients is necessary to
increase compliance with treatment and, thereby, increase the success of
treatment of this widespread condition.
PMID- 9554351
TI - Sperm pellet analysis: a technique to detect the presence of sperm in men
considered to have azoospermia by routine semen analysis.
AB - PURPOSE: In men considered to have azoospermia by routine semen analyses sperm
may be identified after centrifuging the semen. Because these sperm may be used
for intracytoplasmic sperm injection, we describe our technique and findings of
sperm pelleting. MATERIALS AND METHODS: Semen centrifugation for sperm pellet
analysis was performed in 140 consecutive men in whom no sperm was identified on
routine semen analysis and who were categorized as having obstructive or
nonobstructive azoospermia. Obstructive azoospermia was defined as failed
vasectomy reversal, failed reconstruction for congenital vasal or epididymal
occlusion, or an acquired obstruction unrelated to ejaculatory duct obstruction.
Patients with congenital absence of the vas deferens or who had undergone
vasectomy were not included in the study. Nonobstructive azoospermia was defined
as moderate to severe testicular atrophy with markedly elevated serum follicle
stimulating hormone (greater than 3 times normal), or a testicular biopsy that
revealed maturational arrest, severe hypospermatogenesis or the Sertoli-cell-only
pattern. Obstructive and nonobstructive azoospermia were present in 70 men who
provided 109 samples and 70 who provided 103, respectively. RESULTS: Motile and
nonmotile sperm was identified in 13 of the 70 patients (18.6%) with obstructive
and in 16 of the 70 (22.8%) with nonobstructive azoospermia. Pellet variability,
that is the absence of sperm in 1 specimen and its presence in another from the
same patient, was noted in 7 of the 17 men (41.2%) with obstructive and 2 of the
17 (11.8%) with nonobstructive azoospermia (not statistically significant).
Motile sperm was present in the pellets of 6 of the 70 men (8.6%) with
obstructive and 15 of the 70 (21.4%) with nonobstructive azoospermia. The median
number of motile sperm was lower in the obstructive than in the nonobstructive
group (0 sperm in 17 samples versus 5 sperm in 41 samples, p <0.001). The median
value of 0 in the obstructive azoospermia group reflects the finding that 9 of
the 17 samples did not contain motile sperm. Similarly the median number of
nonmotile sperm was lower in the obstructive than in the nonobstructive group (5
versus 8 sperm). CONCLUSIONS: We demonstrated the presence of motile and
nonmotile sperm in a significant number of men considered to have azoospermia by
routine semen analysis. Semen centrifugation (sperm pelleting) should be
performed in all men considered to have this condition by routine semen analysis,
especially those with testicular failure and those in whom intracytoplasmic sperm
injection is possible.
PMID- 9554352
TI - Experience with vasal sperm aspiration.
AB - PURPOSE: We describe our experience with vasal aspiration of sperm in patients
with azoospermia secondary to neurogenic anejaculation or obstruction of the vas
deferens. MATERIALS AND METHODS: We performed 15 vasal sperm aspirations on 11
patients with neurogenic anejaculation or vasal obstruction. RESULTS: Adequate
sperm was obtained from all 15 aspirations with an average sperm count of 42 x
10[6] (range 0.5 to 252 x 10[6]) and an average motility of 73.4% (range 16 to
100%). Aspirations were performed for use with assisted reproductive techniques
in 12 cases and for cryopreservation alone in 3. Following assisted reproductive
techniques 6 of the 12 aspirations (50%) resulted in pregnancy. CONCLUSIONS:
Vasal aspiration of sperm should be considered when electroejaculation fails, is
not available or is contraindicated. Although the overall sperm quality and
pregnancy rate are higher with vasal aspiration and in vitro fertilization than
electroejaculation and intrauterine insemination, vasal aspiration is a more
technically demanding and costly approach to conception.
PMID- 9554353
TI - Sperm acrosome status and sperm antibodies in infertility.
AB - PURPOSE: We studied whether the spermatozoa from sperm autoimmune infertile men
undergo premature acrosomal loss and whether this relates to the presence of
sperm antibodies in wives. MATERIALS AND METHODS: We evaluated acrosome status of
live washed native and overnight capacitated spermatozoa from 17 sperm
nonautoimmune fertile and 23 sperm autoimmune infertile men using an
immunofluorescent peanut lectin binding assay. We used cytotoxic and immunobead
binding assays to prescreen the serum and seminal plasma of these men, and serum
and cervical mucus of the wives for immunological infertility. We performed
immunofluorescent sperm antibody assays on all study samples to ascertain sperm
antibody isotype levels in each sample. Levels of acrosomal loss in husband
native and capacitated spermatozoa were correlated with levels of IgG, IgA and
IgM sperm antibodies in the study samples. RESULTS: Sperm autoimmune infertile
men had a significantly larger percentage of sperm (p <0.0001) that had lost the
acrosome and a lower percentage of sperm with intact acrosome (p <0.0001) in
native and capacitated preparations in contrast to those of fertile controls.
Levels of cytotoxic and IgA antibodies, especially in seminal plasma and cervical
mucus, correlated significantly with percentages of sperm with a total loss of
acrosome in native and capacitated sperm preparations (p < or = 0.01).
CONCLUSION: Infertile men with sperm antibodies in serum and seminal plasma
undergo premature acrosome loss. This loss may expose the reproductive tract
immune system, especially that involving IgA, in autoimmune infertile men and the
wives to high immunogenic levels of sperm acrosome membrane antigens, thereby
rendering them immunologically infertile.
PMID- 9554354
TI - Effects of alprostadil and prazosin on motility, viability and membrane integrity
of human sperm.
AB - PURPOSE: We evaluated the effects of alprostadil, prazosin hydrochloride, and
alprostadil/prazosin hydrochloride, agents used in the clinical treatment of male
erectile dysfunction, on the motility, viability and membrane integrity of human
sperm. MATERIALS AND METHODS: Ten healthy volunteers provided semen samples that
were incubated with 0.4 mg./ml. alprostadil, 0.1 and 0.2 mg./ml. prazosin
hydrochloride and 0.4 mg./ml. alprostadil plus 0.1 mg./ml. prazosin hydrochloride
for 2 hours. Control incubations included polyethylene glycol 1450, the
formulation vehicle for the clinical use of alprostadil and prazosin, and Ham's F
10 buffer. Serial evaluations of percent sperm motility, percent viability,
membrane function (by hypo-osmotic swelling test) and several computer generated
measurements of sperm motion, including straight line velocity, curvilinear
velocity, linearity and amplitude of lateral head displacement, were made.
RESULTS: None of the agents had a significant impact on the percentage of motile
or viable sperm or on sperm membrane function. Incubation with 0.2 mg./ml.
prazosin reduced straight line velocity and curvilinear velocity significantly
compared with the other agents. These changes were most likely a direct result of
the viscosity of the 0.2 mg./ml. prazosin solution and not a cellular or
metabolic effect on the sperm. CONCLUSIONS: Alprostadil and prazosin
hydrochloride at doses used in transurethral therapy for erectile dysfunction
have no effect on the motility, viability and membrane integrity of human sperm.
PMID- 9554355
TI - Breaking down the barriers to reproduction in male infertility.
PMID- 9554356
TI - Outcomes of varicocele ligation done for pain.
AB - PURPOSE: Surgical ligation is an option in the management of patients with
painful varicocele. Little objective data exist addressing the effectiveness of
this treatment. We reviewed records from 58 patients who underwent varicocele
ligation at our institution from January 1985 to May 1996 to establish success of
surgical ligation of the painful varicocele. MATERIALS AND METHODS: ICD-9 billing
codes were used to identify all patients who had undergone varicocele ligation
for pain since 1985. We documented patient age, grade and location of varicocele,
duration and quality of pain, response to conservative therapy and surgical
approach to ligation. Telephone interviews and chart reviews were conducted to
determine resolution of pain, complications of the procedure and if the patient
would choose surgery again. RESULTS: We obtained followup on 35 of the 58 painful
varicocele patients (60%). Average patient age was 25.7 years (range 15 to 65).
The varicocele was on the left side in 30 men and bilateral in 5. Of the patients
31 described the pain as a dull throbbing ache, 2 as sharp and 2 as a pulling
sensation. Initial conservative therapy failed in all 35 men. Varicocele was
grade III in 18 cases, grade II in 16 and grade I in 1. The inguinal or
subinguinal approach was used in 24 patients, high ligation in 10 and
laparoscopic repair in 1. In 30 patients there was (86%) complete resolution of
pain postoperatively and 1 had partial resolution. Only 4 patients (11%) had
persistent or worse symptoms. CONCLUSIONS: This retrospective review supports the
conclusion that varicocele ligation is an effective treatment for painful
varicocele in properly selected patients.
PMID- 9554357
TI - Transrectal ultrasound of the prostate: innovations and future applications.
AB - PURPOSE: We present a critical evaluation of the use of ultrasound for prostate
disease examination in urological practice, and provide perspectives on
ultrasound applications that may become important for the future evaluation of
prostate problems. MATERIALS AND METHODS: Based on an evaluation of clinical data
in cases suspicious for prostatic malignancy, we addressed the apparent
shortcomings of transrectal ultrasound for accurately diagnosing prostate cancer.
Future applications presented in the literature were noted. RESULTS: Evaluating
the ultrasound data in cases suspicious for malignancy indicated that imaging has
little advantage over digital rectal examination for detecting malignant areas.
The new applications of ultrasound that hold great promise for use in the urology
clinic include the injection of contrast agents to obtain information on blood
supply, temperature estimation for the noninvasive assessment of temperature
distributions during heat treatment and a therapeutic application for local
treatment of prostate cancer. CONCLUSIONS: While differential diagnosis with
ultrasound appears to result in disappointing sensitivity and specificity values,
its use in volume measurement and biopsy guidance is unquestioned. The
development of new applications may improve the clinical value of ultrasound in
urological practice. The application of ultrasound contrast agents for the
detection and clinical staging of prostate cancer is especially promising. Future
research will indicate whether the promise evolves in clinical applications.
PMID- 9554358
TI - Association of smoking with lower urinary tract symptoms.
AB - PURPOSE: We studied the association of smoking with lower urinary tract symptoms.
MATERIALS AND METHODS: In 1994 we performed a population based study by mailing a
questionnaire to all 3,143 men born in 1924, 1934 or 1944 who resided in Tampere,
or in 11 rural or semirural municipalities in the same county. Of this population
68% were ultimately included in the study. A modified Danish Prostate Symptom
Score-1 was used to assess urinary symptoms and associated bothersomeness. A
symptom index was created by multiplying the symptom and bothersomeness scores of
hesitancy, incomplete emptying, urge, urge incontinence, nocturia and daytime
frequency, and totaling the products. The index for lower urinary tract symptoms
was defined as positive when it reached 7 points. Subjects were also asked
whether they had smoked for at least a year, and they were defined as smoking
currently, formerly and never according to the response. RESULTS: Compared with
respondents who never smoked age adjusted odds ratios were 1.47 (95% confidence
interval 1.09 to 1.98) and 1.38 (1.08 to 1.78), respectively, for those who
currently and formerly smoked. After further adjusting for alcohol consumption,
body mass index, previous prostate surgery, pelvic area surgery, prostate cancer
and bladder cancer, the odds ratios for current and former smokers were 1.39 (95%
confidence interval 1.02 to 1.93) and 1.34 (1.03 to 1.75), respectively.
CONCLUSIONS: Smoking increases the prevalence of lower urinary tract symptoms.
The similarity in the odds ratios of these symptoms between current and former
smokers suggests that changes caused by smoking occur long term or the
pathological process resulting in symptoms starts early in smokers. The decreased
risk of lower urinary tract symptoms after the cessation of smoking suggests that
the process is reversible but recovery is a long-term process.
PMID- 9554359
TI - Intraprostatic temperature monitoring during transurethral microwave
thermotherapy for the treatment of benign prostatic hyperplasia.
AB - PURPOSE: We evaluated whether the results of transurethral microwave
thermotherapy improve using high intraprostatic temperatures of 55C or greater.
MATERIALS AND METHODS: We accrued 30 men 58 to 85 years old (mean age 69) from
the waiting list for transurethral prostatic resection in whom maximum urinary
flow was less than 13 ml. per second and Madsen score was greater than 8.
According to the Abrams-Griffith nomogram all but 1 patient had obstruction.
Before treatment 3 thin temperature probes, each containing 5 sensors in a row,
were introduced into the prostate from the perineum and positioned using
transurethral ultrasound guidance. The microwave power of the transurethral
microwave thermotherapy equipment was set based on the actual temperature in the
prostatic tissue. A temperature of at least 55C and often more than 60C was
reached at the hottest spot. Treatment duration was 1 hour. Postoperatively an
indwelling catheter remained in place for 2 weeks. Patients were followed for 6
months with the first followup after 3 months. RESULTS: At the 3-month followup
mean maximum urinary flow had increased from 7.4 to 12.5 ml. per second and the
mean Madsen score had decreased from 12.6 to 2.9. At the 6-month followup mean
maximum urinary flow was 12.2 ml. per second and the mean Madsen score was 3.4.
Using pressure-flow data we divided the patients into responders and
nonresponders. In the 18 responders maximum urinary flow had increased from 7.2
to 14.6 ml. per second (103%), the Madsen score had decreased from 12.5 to 1.4
(89%) and detrusor pressure had decreased from 9.2 to 6 kPa. (35%). CONCLUSIONS:
High energy transurethral microwave thermotherapy relieved bladder outlet
obstruction in 60% of the patients and had a good effect on symptoms. Compared
with a previous multicenter study with 40% responders, using the same criteria
there were 60% responders in our series. Our results indicate that better control
of intraprostatic temperature provides better results, approaching those after
transurethral prostatic resection.
PMID- 9554360
TI - A prospective, randomized 1-year clinical trial comparing transurethral needle
ablation to transurethral resection of the prostate for the treatment of
symptomatic benign prostatic hyperplasia.
AB - PURPOSE: We assess the 1-year efficacy and safety of transurethral needle
ablation of the prostate compared to transurethral resection of the prostate for
the treatment of symptomatic benign prostatic hyperplasia (BPH). MATERIALS AND
METHODS: A prospective, randomized clinical trial of 121 men 50 years old or
older with symptomatic BPH was performed at 7 medical centers across the United
States. Of the men 65 (54%) were treated with transurethral needle ablation of
the prostate and 56 (46%) underwent transurethral resection of the prostate. Mean
and percentage changes from baseline and between cohorts for American Urological
Association (AUA) symptom score, AUA bother score, quality of life score, peak
urinary flow rate and post-void residual urine volume were measured at 1, 3, 6
and 12 months following treatment. Length of procedure, hospitalization, type of
anesthesia, post-procedure catheterization, side effects and sexual function were
compared. RESULTS: Transurethral needle ablation and resection resulted in a
statistically significant improvement in AUA symptom, bother and quality of life
scores, peak urinary flow rate and post-void residual. At 1-year followup, needle
ablation and resection were equally effective in enhancing quality of life.
Needle ablation had less effect on sexual function, with resection being
associated with a greater incidence of retrograde ejaculation. Needle ablation
could be performed as an outpatient procedure with local anesthesia while
resection required anesthesia and hospitalization. Needle ablation was associated
with markedly fewer side effects than resection. CONCLUSIONS: Compared to
transurethral resection of the prostate, transurethral needle ablation of the
prostate is an efficacious, minimally invasive treatment for symptomatic BPH that
is associated with few side effects.
PMID- 9554361
TI - Ratio of free-to-total prostate specific antigen in serum cannot distinguish
patients with prostate cancer from those with chronic inflammation of the
prostate.
AB - PURPOSE: We demonstrate the effect of chronic inflammation of the prostate on the
ratio of free-to-total prostate specific antigen (PSA) in serum calculated as a
percentage of free PSA and, therefore, that percentage of free PSA is an
unspecific means to distinguish among prostate cancer, chronic prostatitis and
benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: Total, free and
percentage of free PSA was measured in 66 men with prostate cancer, 119 with BPH
and 17 with asymptomatic chronic prostatitis. In all patients the diagnosis was
histopathologically confirmed by microscopic examination of prostatic specimens
after sextant biopsy, transurethral prostatic resection or prostatectomy.
RESULTS: The median values of total, free and percentage of free PSA were 4.11
microg./l., 0.75 microg./l. and 20.4% in patients with BPH, 10.0 microg./l., 0.84
microg./l. and 8.5% in those with prostate cancer, and 7.60 microg./l., 1.23
microg./l. and 10.6% in those with chronic prostatitis. Patients with prostate
cancer and chronic prostatitis had a significantly lower percentage of free PSA
than those with BPH. Receiver operating characteristics curve analysis showed
that percentage of free PSA as a discriminator between prostate cancer and BPH
was not suitable for differentiating between prostate cancer and chronic
prostatitis. CONCLUSIONS: Chronic prostatitis is not characterized by elevated
total PSA concentrations alone but also by a decreased percentage of free PSA, a
tendency similar to that in prostate cancer. This unspecific change in percentage
of free PSA must be considered to interpret the percentage of free PSA correctly.
PMID- 9554362
TI - Stability of free and total prostate specific antigen in serum from patients with
prostate carcinoma and benign hyperplasia.
AB - PURPOSE: Instability of prostate specific antigen (PSA) in serum might complicate
the interpretation of the free-to-total PSA ratio. We studied the in vitro
stability of free PSA and total PSA in serum of patients with prostate cancer or
benign prostate hyperplasia (BPH), and of elderly men without known prostate
disease. Furthermore, we investigated conditions to stabilize the in vitro values
in serum. MATERIALS AND METHODS: The effects of storage at 4C on free and total
PSA were investigated in serum of 32 men with prostate cancer, 25 with BPH and 29
older than 70 years. All had total PSA less than 25 microg./l. The influence of
total PSA levels on in vitro changes in free-to-total PSA was studied in serum of
39 other prostate cancer patients (total PSA 1.7 to 298 microg./l.).
Stabilization studies were performed in yet another series of samples from 54
prostate cancer patients (total PSA 1.3 to 238 microg./l.) by adjustment of serum
pH to 5.5 before storage. Free and total PSA was measured by a commercial
immunofluorometric assay, as well as by in-house immunofluorometric assays.
Statistical analyses of the results were performed by analysis of variance with
repeated measures. RESULTS: We found no difference between the results obtained
by the 2 assay systems. After 7 days at 4C there was a slight decrease in total
PSA in sera of prostate cancer patients, BPH patients and men older than 70
years. A decrease in mean free PSA values occurred in all groups (21.3, 15.7 and
14.6%, respectively). The decrease of free PSA with time was significant (p
<0.0001) in all groups but there was no significant difference among the groups
(p=0.16). The concomitant decrease in free-to-total PSA ratio was significant in
all groups (p <0.0001). This change was group dependent (p=0.003), with the
largest decrease in the prostate cancer group. Large interindividual differences
were observed. Storage at 4C for 7 days of sera of 39 patients with localized and
disseminated prostate cancer (total PSA 1.7 to 298 microg./l.) gave a more
pronounced decrease in free PSA than in total PSA. Adjustment of serum pH to 5.5
had a stabilizing effect on free PSA and on the free-to-total PSA ratio, giving a
significantly smaller change in both values (p <0.0001). CONCLUSIONS: In vitro
instability of free PSA in serum and large interindividual differences should be
considered when using the ratio of free-to-total PSA in evaluation of patients
with suspected prostate cancer. Serum samples should be stored frozen if not
analyzed immediately or acidified to pH 5.5. Interpretation of data from
determination of free-to-total PSA ratio should be done with caution if the
sampling and storage conditions are not known.
PMID- 9554363
TI - Prostate rebiopsy is a poor surrogate of treatment efficacy in localized prostate
cancer.
AB - PURPOSE: Many investigators use prostate rebiopsy as an indicator of treatment
efficacy and tumor response of localized prostate cancer for therapies in which
the gland remains in situ. Because of the inherent sampling error of needle
directed biopsies, however, some men will have a false-negative rebiopsy even if
they have had no therapy or if the therapeutic intervention was unsuccessful in
eradicating the malignancy. We evaluate the risk of a false-negative biopsy and
the clinical factors that influence this risk. MATERIALS AND METHODS: A total of
90 patients undergoing radical prostatectomy for clinically localized disease
underwent sextant biopsy of the prostate immediately after removal of the gland.
Data collected included prostate specific antigen (PSA), hormonal status, age and
biopsy core status. RESULTS: Of the total study population 67.8% received
neoadjuvant hormonal therapy. While all patients had pathologically confirmed
adenocarcinoma within the prostatectomy specimen, 45.6% demonstrated a false
negative rebiopsy. Within a combined predictive model, PSA and hormonal status
demonstrated a statistically significant effect on the false-negative rebiopsy
rate. Predictive power of this combined model was high across the spectrum of
risk for a false-negative rebiopsy. CONCLUSIONS: This series demonstrates that
the risk of a false-negative sextant biopsy in the presence of documented
prostate cancer is high and is affected by several factors, including PSA and
hormonal status. These data suggest that prostate sextant rebiopsy is an
inaccurate method of assessing the therapeutic efficacy of treatments for
carcinoma of the prostate in which the gland remains in situ following therapy.
PMID- 9554364
TI - Tumor cell proliferation and survival in patients with prostate cancer followed
expectantly.
AB - PURPOSE: Prostate cancers have different biological potentials, and aggressive
tumors are difficult to identify when still localized. Tumor cell proliferation
determined by MIB-1 expression has been suggested as an important predictor for
outcome in several human cancers including the prostate. We test the possible
prognostic value of tumor cellular proliferation in prostate cancer patients
treated with no intent to cure. MATERIALS AND METHODS: Formalin fixed, paraffin
embedded tumor tissue obtained at the time of diagnosis from 221 patients
originating from a well known complete Danish prostate cancer population was
immunohistochemically investigated. The tumor cell proliferation rate was
determined using the MIB-1 antibody. Tumors were clinically localized in 57% of
the patients. RESULTS: Tumor cell proliferation rate expressed by the MIB-1 score
significantly correlated with tumor stage (p <0.001) and malignancy grade (p
<0.001). The MIB-1 score, divided into low and high by the median value, showed
significant association with disease specific survival in the entire study
population (p <0.0001), as well as in the 125 patients suffering from clinically
localized disease (p=0.018). Multivariate analyses showed that MIB-1 was a
significant (p=0.0003) prognostic factor in the entire population, including
advanced disease stages. However, in the theoretically curable clinically
localized subpopulation MIB-1 was not significant (p=0.08) contrary to
histopathological grade (p=0.02), erythrocyte sedimentation rate (p=0.02) and T
classification (p=0.035). CONCLUSIONS: Prostate tumor cell proliferation,
expressed by MIB-1 immunoreactivity, demonstrated significant association with
disease specific survival. However, MIB-1 is a close alternative to
histopathological grade in describing the natural history of clinically localized
prostate cancer. The additional prognostic value and the practical consequence of
tumor cell proliferation remain to be clarified.
PMID- 9554365
TI - Endoscopic treatment of refractory filarial chyluria: a preliminary report.
AB - PURPOSE: We report our experiences treating 5 patients who had filarial chyluria
using an endoscopic approach. MATERIALS AND METHODS: Two men and 3 women 47 to 83
years old with chyluria were treated with endoscopic coagulation using guide tube
methods. Intrarenal pelvic instillation of silver nitrate was not effective in 4
patients and catheterization was impossible in 1. RESULTS: The responsible lesion
was successfully coagulated in all 5 patients. Because the lesion was in the
ruptured portion of the caliceal fornix, we thought that chyluria had arisen in
the fragile portion of the fornix (fistulization). After endoscopic treatment
there was no recurrence in any patient. CONCLUSIONS: Endoscopy is effective and
minimally invasive therapy for filarial chyluria.
PMID- 9554366
TI - Back propagation neural network in the discrimination of benign from malignant
lower urinary tract lesions.
AB - PURPOSE: We investigated the potential value of morphometry and artificial
intelligence tools to discriminate between benign and malignant lower urinary
tract lesions. MATERIALS AND METHODS: The lesions included lithiasis in 50 cases,
inflammation in 61, benign prostatic hyperplasia in 99, carcinoma in situ in 5,
and grade I and grades II and III transitional cell carcinoma of the bladder in
71 and 184, respectively. Images of routine processed voided urine smears stained
by the Giemsa technique were analyzed using a custom image analysis system,
providing a data set of 45,452 cells. A neural net model of the back propagation
type was used to discriminate benign from malignant cells based on the extracted
morphometric and textural features. Data from 13,636 randomly selected cells (30%
of the total data) were used as a training set and the data from the remaining
31,816 cells comprised the test set. In a similar attempt to discriminate at the
patient level data on 30% of those randomly selected were used to train a back
propagation neural net and data on the remaining 329 were used for testing.
RESULTS: Application of the back propagation neural net enabled the correct
classification of 95.34% of benign and 86.71% of malignant cells with overall
90.57% accuracy. At the patient level the back propagation neural net enabled the
correct classification of 100% of those with benign and 94.51% of those with
malignant disease with overall 96.96% accuracy. CONCLUSIONS: The use of neural
nets and image morphometry may increase the speed of cytological diagnosis and
the diagnostic accuracy of voided urine cytology.
PMID- 9554367
TI - Genitourinary small cell carcinoma: determination of clinical and therapeutic
factors associated with survival.
AB - PURPOSE: We assessed the prognostic impact of genitourinary small cell carcinoma
tumor and patient characteristics, and therapy. MATERIALS AND METHODS: We
retrospectively reviewed the records of 180 patients with genitourinary small
cell carcinoma in which patient and tumor characteristics, therapy, followup
duration and survival status had been documented. Patient age, sex, primary site,
histological features, tumor size, stage, locoregional therapy, systemic
chemotherapy and hormonal manipulations were analyzed for association with
survival. RESULTS: There were 106 cases of bladder, 60 prostatic, 8 renal and 6
ureteral small cell carcinoma. Median survival was 10.5 months overall, and 7 and
13 months for prostatic and bladder small cell carcinoma, respectively (p <0.0001
log rank analysis). In all cases metastatic disease at presentation (p <0.008,
risk ratio 1.9) predicted poor survival on multivariate analysis. Radical surgery
(p <0.0001, risk ratio 0.34) and cisplatin chemotherapy (p <0.0001, risk ratio
0.20) were the only factors that predicted improved survival on multivariate
analysis. For prostatic small cell carcinoma primary surgical therapy (p <0.012,
risk ratio 0.46) was the only parameter that predicted survival on univariate
analysis. For bladder small cell carcinoma only cisplatin chemotherapy (p
<0.0001, risk ratio 0.15) predicted survival on multivariate analysis.
CONCLUSIONS: Genitourinary small cell carcinoma has a poor prognosis, which is
worse in prostatic than bladder disease. Patient and tumor characteristics were
not determinants of survival when prostatic and bladder small cell carcinoma were
analyzed individually. For prostatic disease only primary surgical therapy was
associated with prolonged survival, while for bladder disease cisplatin
chemotherapy was associated with a favorable prognosis. We recommend considering
primary surgical therapy for prostatic and cisplatin based chemotherapy for
bladder small cell carcinoma.
PMID- 9554368
TI - Preoperative hyperbaric oxygen therapy for radiation induced injuries.
AB - PURPOSE: We present our experience with preoperatively administered hyperbaric
oxygen therapy to patients who have sustained significant therapeutic radiation
induced soft tissue injuries and subsequently undergo planned abdominal
intervention/surgery. MATERIALS AND METHODS: From February 1993 to May 1997, 5
patients with a history of complications following therapeutic radiation were
prospectively treated with hyperbaric oxygen before a planned abdominal
operation. RESULTS: All patients had uneventful hospital courses. An additional
procedure was eventually necessary in 2 patients but with fewer radiation related
problems following hyperbaric oxygenation. CONCLUSIONS: Hyperbaric oxygenation
may improve postoperative outcomes when given before planned open operations in
patients with previous therapeutic pelvic irradiation and a history of radiation
related complications.
PMID- 9554369
TI - Bilateral emphysematous pyelonephritis with autosomal dominant polycystic kidney
disease.
PMID- 9554370
TI - Continent orthotopic ileal neobladder after kidney transplant in a female patient
with multifocal transitional cell carcinoma.
PMID- 9554371
TI - Filarial cystitis with ureteral obstruction.
PMID- 9554372
TI - Miliary tuberculosis of the lung in a patient treated with bacillus Calmette
Guerin for superficial bladder cancer.
PMID- 9554373
TI - Primary signet ring cell adenocarcinoma of the bladder with elevated serum
carbohydrate antigens 19-9 and 50.
PMID- 9554374
TI - Hydroxyurea in the treatment of sickle cell associated priapism.
PMID- 9554375
TI - Bilateral metachronous testicular seminoma associated with microlithiasis.
PMID- 9554376
TI - Re: floating kidneys: a century of nephroptosis and nephropexy.
PMID- 9554377
TI - Re: floating kidneys: a century of nephroptosis and nephropexy.
PMID- 9554378
TI - Re: the role of computerized tomography in the evaluation of complications after
laparoscopic urological surgery.
PMID- 9554379
TI - Re: Female Stress Urinary Incontinence Clinical Guidelines Panel summary report
on surgical management of female stress urinary incontinence.
PMID- 9554380
TI - Re: modified Nesbit procedure for the treatment of Peyronie's disease: a
comparative outcome analysis.
PMID- 9554381
TI - Re: leech therapy for massive scrotal hematoma following percutaneous
transluminal angioplasty.
PMID- 9554382
TI - Re: p53 protein and gene alterations in pathological stage C prostate carcinoma.
PMID- 9554383
TI - Re: reverse transcriptase polymerase chain reaction for prostate specific antigen
in the management of prostate cancer.
PMID- 9554384
TI - Re: recurrence patterns after radical retropubic prostatectomy: clinical
usefulness of prostate specific antigen doubling times and log slope prostate
specific antigen.
PMID- 9554385
TI - Can perinatal events cause neonatal urinary ascites?
PMID- 9554386
TI - Renal angiomyolipoma in children: diagnositc difficulty in 3 patients.
AB - PURPOSE: Because angiomyolipoma is less common in children than in adults, its
diagnosis can be difficult. We present 3 cases of pediatric angiomyolipoma in
which diagnostic problems resulted due to the presenting characteristics.
MATERIALS AND METHODS: We report on 3 children with unilateral renal
angiomyolipoma. Computerized tomography (CT) and ultrasonography revealed 3 large
renal masses, 20, 7 and 8 cm. in diameter, respectively. A correct diagnosis was
not made preoperatively in any case by CT, ultrasound or fine needle biopsy.
Wilms tumor was suspected in the first patient who received preoperative
chemotherapy. Imaging was inconclusive in the other 2 cases. RESULTS: All
patients underwent surgical exploration and subsequent nephrectomy due to the
large size of the tumor. At followup 33, 23 and 13 months postoperatively all
children were well without signs of recurrence. CONCLUSIONS: It has been reported
that the demonstration of fat on renal ultrasound and CT can diagnose
angiomyolipoma in 95% of the cases. Most radiologists rely solely on CT
demonstration of lipid density in the renal mass to diagnose angiomyolipoma but
the identification at imaging of lipid tissue may be difficult in small tumors.
In our cases the fat content of the tumors was less than 10% despite the large
size. This low fat content results in misdiagnosis, since fatty tissue is also
present in other renal tumors, such as lipoma, liposarcoma, teratoma and Wilms
tumors. We recommend conservative surgery when tumor size permits in pediatric
patients with angiomyolipoma to avoid chemotherapy.
PMID- 9554387
TI - Renal deterioration in myelodysplastic children: urodynamic evaluation and
clinical correlates.
AB - PURPOSE: We determined which factors portend a higher risk of renal deterioration
in the myelodysplastic child, and evaluated the sensitivity and predictive value.
MATERIALS AND METHODS: We retrospectively reviewed the medical history, imaging
studies and urodynamics of 90 children with spinal dysraphism. Median patient age
at initial evaluation was 3 months and average followup ranged between 2 and 25
years (average 11). We evaluated the relation of urodynamic parameters and sex to
upper tract changes and the resolution of these changes. RESULTS: Statistically
significant relationships were identified between the urodynamic parameters of
leak point pressure, compliance and detrusor-sphincter dyssynergia, and renal
deterioration but not with resolution of deterioration. Boys and girls did not
demonstrate a significant difference among urodynamic parameters. Female patients
had a higher incidence of reflux and parenchymal loss. CONCLUSIONS: With
knowledge of the inherent sensitivity, specificity and predictive value of
urodynamic parameters, selective use of urodynamics will assist in identifying
patients at risk of renal deterioration. Female patients with reflux are at
greatest risk of parenchymal loss. We advocate early institution of intermittent
catheterization in patients identified as high risk for deterioration by
urodynamics.
PMID- 9554388
TI - Modified Lich-Gregoir ureteral reimplantation: experience of a Canadian center.
AB - PURPOSE: Various techniques of ureteral reimplantation have been described for
correction of vesicoureteral reflux. We report our experience regarding the
safety and efficacy of a modified Lich-Gregoir extravesical approach. MATERIAL
AND METHODS: From January 1991 to January 1996 we evaluated prospectively 256
patients who underwent a modified Lich-Gregoir procedure for correction of
vesicoureteral reflux. A total of 385 vesicoureteral units were reimplanted,
including 41 duplex systems. The modification to the Lich-Gregoir technique we
used consists of ending the paraureteral myotomy with an inverted Y, which
permits easier detrusor muscle reapproximation. RESULTS: This procedure was
successful initially in 214 of 237 patients, as confirmed by a normal voiding
cystourethrogram 4 to 6 months postoperatively. Of the 237 cases persistent
vesicoureteral reflux developed in 13 patients, which resolved spontaneously in 9
after 1 year, contralateral reflux developed in 8, which was treated
conservatively, and ureteral obstruction developed in 2. Thus, the 1-year overall
success rate was 96%. Urinary retention developed in 12 children with bilateral
reimplantation (8.3%) with successful recovery in all after conservative
management with urethral catheter drainage of 1 week or less. The duration of
hospitalization after surgery ranged from 1 to 3 days. CONCLUSIONS: The modified
Lich-Gregoir technique of extravesical ureteral reimplantation is successful,
simple to perform, reproducible and associated with low morbidity. It also
requires minimal hospital stay. These results should encourage the use of this
technique when indicated to correct vesicoureteral reflux in children.
PMID- 9554389
TI - Ureteral tissue expansion for bladder augmentation.
AB - PURPOSE: Ureteral augmentation is an effective method of bladder reconstruction
using the native urothelium of a megaureter. Clinically this procedure is
contingent on the presence of an enlarged ureter. We have iatrogenically produced
a segmental megaureter, while preserving renal function in a pig model. The
urothelium of the enlarged ureter was then used for augmentation cystoplasty.
MATERIALS AND METHODS: A tissue expander suitable for insertion into the lumen of
the ureter was constructed. The tissue expander was passed antegrade through a
flank incision of 8 pigs, and a separate nephrostomy tube was left in place.
During the ensuing 1 to 4 weeks the pigs underwent daily dilation of the tissue
expander without anesthesia. After dilation the pigs underwent ureteral
augmentation of the bladder. The segment of expanded ureter was isolated from the
native ureter, opened and anastomosed to the bladder. The continuity of the left
ureter was restored by primary ureteroureterostomy. The animals underwent
cystograms at 1 and 4 weeks and were sacrificed 4 weeks after augmentation.
Tissue was harvested for gross and microscopic histology. RESULTS: Of the 8 pigs
starting the protocol 5 underwent successful ureteral tissue expansion followed
by bladder augmentation. Tissue expansion was performed from 1 to 4 weeks, and
volumes of 150 to 1,000 cc were obtained. Two to 3 weeks of dilation was optimal
to achieve ease of dilation, and no animal showed evidence of discomfort or
failure to thrive. All 5 animals underwent successful ureteral augmentation with
primary ureteroureterostomy. Tissue expansion volumes of approximately 250 cc
were optimal for tissue management and ease of augmentation. Cystograms of all
augmented animals showed increased bladder capacity with filling of the ureteral
segment. Histological examination of the ureteral augmentation revealed
preservation and regeneration of the urothelial mucosa. CONCLUSIONS: The use of a
tissue expander in the lumen of the ureter is a novel method of generating
urothelium for use in bladder augmentation. It may provide an alternative to
bowel in patients who require bladder augmentation. Long-term studies are
currently under way.
PMID- 9554390
TI - Diagnosis and grading of detrusor instability using a computerized algorithm.
AB - PURPOSE: Detrusor instability and hyperreflexia are characterized by involuntary
detrusor contractions in the filling phase of the voiding cycle. The diagnosis is
made when urodynamic evaluation reveals such contractions. To compare patients
and evaluate treatment a method is needed to quantify the degree of instability.
We developed an instability parameter based on the area under the curve of
involuntary detrusor contractions on conventional filling cystometry. MATERIALS
AND METHODS: We developed an automatic method to calculate the area under the
curve of involuntary detrusor contractions in conventional filling cystometry.
Logistic regression was used to construct decision rules to differentiate stable
from unstable bladders. These rules, derived from a group of 100 children, were
applied to a second group of 77 who were independently assessed by 3 urodynamics
experts. RESULTS: Typically 88% of the second group were correctly classified as
stable or unstable by the automatic procedure. In the unstable subgroup there was
poor correlation between the calculated instability parameter and the instability
score assigned by the experts. Most likely this difference occurred because the
experts based their opinion mainly on the amplitude of the highest unstable
contraction and the percentage of filling time that instability was found.
CONCLUSIONS: The proposed method of automatically grading detrusor instability
based on the area under detrusor contractions differs from the intuitive method
used by experts. Since no standard is available, it cannot be concluded which
method is better. Our proposed method is objective and it results in a single
physical value.
PMID- 9554392
TI - Lessons learned in 3 decades of managing the prune-belly syndrome.
PMID- 9554391
TI - Voiding function in patients with the prune-belly syndrome after Monfort
abdominoplasty.
AB - PURPOSE: We reviewed our experience with patients with the prune-belly syndrome
who had undergone Monfort abdominoplasty to assess whether our clinical
impression of improved voiding efficiency could be demonstrated objectively.
MATERIALS AND METHODS: From 1990 to 1993, 12 patients with the prune-belly
syndrome underwent Monfort abdominoplasty with or without concomitant
genitourinary reconstruction. All patients completed questionnaires on voiding
before and after abdominoplasty, incontinence, bladder sensation, urinary flow,
history of urinary tract infections and the ability to defecate. Urodynamic
testing was performed in 8 patients before and after abdominoplasty. RESULTS:
Subjective changes that occurred after abdominoplasty included resolution of or
less double voiding in 9 patients, improved urinary continence in 7, improved
bladder fullness sensation in 11, improved urinary flow in 10 and improved
defecation in 5. The incidence of urinary tract infections decreased from a
preoperative average of 5.7 per patient per year to 1.2 per patient per year
postoperatively. Urodynamics demonstrated no significant changes in the measured
urinary flow, capacity or maximal detrusor pressure. Compliance decreased on
average but it remained in the compliant range. However, post-void residual
volumes did significantly decrease from a preoperative average of 40.3% of
bladder capacity to 13% after abdominoplasty. If the 5 patients who underwent
concomitant urinary reconstruction were excluded, the reduction in average post
void residuals remained approximately the same, which was 40% of bladder capacity
preoperatively to 14.3% after abdominoplasty. These data suggest that
abdominoplasty alone was responsible for improved micturition. CONCLUSIONS: In
addition to the cosmetic benefits and exposure provided for genitourinary
reconstruction Monfort abdominoplasty seems to improve voiding efficiency.
PMID- 9554393
TI - The exstrophy-epispadias complex in the duplicated lower urinary tract.
AB - PURPOSE: The exstrophy-epispadias complex in combination with a duplicated lower
urinary tract is an extremely rare congenital malformation. We describe 2 cases
of bladder exstrophy in association with a duplicated lower urinary tract.
MATERIALS AND METHODS: We analyzed the case histories of 2 patients. The first
case had anteroposterior duplication of the bladder communicating through an
isthmus and a duplicate urethra. The anterior system was exstrophic and
epispadiac. The second case had a duplicate bladder without epispadias. There was
a communication between the anterior exstrophic and posterior normal bladders. No
other malformations were present. RESULTS: Both patients underwent excision of
the duplicate exstrophic bladder in conjunction with primary closure of the
abdominal wall. Postoperative continence was normal. Histological examination
confirmed the diagnosed bladder duplication. CONCLUSIONS: Although duplication of
the lower urinary tract in combination with the exstrophy-epispadias complex is
extremely rare, all children presenting with an exstrophic bladder and a normal
urethra alone or in association with an epispadiac anterior urethra should be
evaluated for a bladder duplication with possible isthmic communication.
PMID- 9554394
TI - Somatic function, mental health and psychosocial functioning in 22 adolescents
with bladder exstrophy and epispadias.
AB - PURPOSE: We report the long-term somatic outcome, mental health and psychosocial
adjustment in adolescents with bladder exstrophy and epispadias. MATERIALS AND
METHODS: A total of 22 adolescents 11 to 20 years old (median age 14.5),
including 19 with bladder exstrophy and 3 with epispadias, were assessed for
urogenital status, stoma, renal and bowel function, anorectal physiology, mental
health and psychosocial functioning by physical examinations, semistructured
interviews and standardized questionnaires. The parents of 21 patients were
interviewed and completed questionnaires. Information was also obtained on
control groups. RESULTS: Of the 22 patients 9 (41%) had no urinary diversion and
were urinary incontinent, 6 (27%) had persistent fecal staining and anal canal
pressures that were lower than the controls, 10 (59%) were dissatisfied with the
penile appearance and 11 (50%) met the criteria for psychiatric diagnoses. The
main predictors of mental health were parental warmth and patient genital
appraisal in the 11 to 14-year age group, and parental warmth and urinary
continence function in the 15 to 20-year age group. Psychosocial dysfunction was
predicted by fecal incontinence in the younger group and worries about future
sexual relationships in the older group. CONCLUSIONS: The present multimodal
outcome study revealed that adolescents with bladder exstrophy and epispadias had
significant physical and mental problems. Genital malformation, and urinary and
fecal incontinence may have a negative impact on mental health and psychosocial
functioning. Our findings emphasize the need to include psychosocial experts on
health care teams to reveal the amount of distress caused by these anomalies and
to offer psychosocial support.
PMID- 9554395
TI - A prospective randomized trial comparing 2 diuresis renography techniques for
evaluation of suspected upper urinary tract obstruction in children.
AB - PURPOSE: We compare the diagnostic impact of 2 diuresis renography techniques for
evaluation of suspected upper urinary tract obstruction in children. MATERIALS
AND METHODS: A total of 72 children were randomly assigned to 1 of 2 standardized
diuresis renography protocols. The protocols were identical, except for the time
of furosemide (F) injection. In the F+20 scans furosemide was given 20 minutes
after the 99mtechnetium pentetic acid radiopharmaceutical. With the modified F-15
scans furosemide was injected 15 minutes before renography. Hydration, bladder
catheterization, urine output determination, radiopharmaceutical injection and
scan acquisition were identical. Renography outcomes (obstructed, nonobstructed
or equivocal) were analyzed for the investigated side(s) and for the
contralateral side, which was used as a control in children with suspected
unilateral obstruction. Chi-square test was used to compare the percentage of
obstructed and nonobstructed scans of both protocols. Fisher's exact test was
used to compare the nonobstructed scans and equivocal results of both protocols.
RESULTS: Of the 96 scans performed 8 were excluded because of technical problems.
The remaining scans included 44 F+20 and 44 F-15. Of the 88 scans 10 were used to
evaluate possible bilateral obstruction. A total of 48 boys and 24 girls were
evaluated. Because 2 children had a solitary kidney each, the total number of
renal units studied for outcome was 174. The F-15 scan showed 7 times more
obstruction than the F+20 scan on the investigated side, and this difference was
statistically significant. No obstruction was diagnosed on the contralateral side
with either technique when used to investigate cases of suspected unilateral
obstruction. CONCLUSIONS: The timing of the furosemide injection (F-15 scan
versus F+20) has a significant impact on the obstructive versus nonobstructive
renography results when evaluating children with suspected upper urinary tract
obstruction.
PMID- 9554396
TI - Torsion in a triorchid testis.
PMID- 9554397
TI - The effect of surgical trauma on rat tunica albuginea.
AB - PURPOSE: Increased TGF-beta1 protein expression in tunica albuginea has been
found to be associated with Peyronie's disease. The present study is designed to
investigate whether surgical trauma induces TGF-beta up-regulation and
histological changes in rat penis. MATERIALS AND METHODS: Thirty-two adult male
Sprague-Dawley rats were divided into two groups. The first group (n=24)
underwent incision and suture repair of the tunica albuginea of the penis. The
second group (n=8) received sham surgery (incision of the penile skin and
underlying fascia) as the control group. The trauma-induced group was divided
into four subgroups in which the rats were euthanized at 6 hours (n=6), 1 day
(n=6), 3 days (n=6), and 8 weeks (n=6). Two sham-operated (control) animals were
also euthanized at each of the above time points. All tunical tissues from the
trauma-induced and sham-operated rats were collected and examined histologically
using Trichrome and Hart elastic fiber stain. Electron microscopy was used to
study the ultrastructural changes of both trauma induced and control specimens.
Western blotting technique was performed to study TGF-beta protein expression in
both experimental and sham-operated groups. RESULTS: Tissue edema and hemorrhage
between collagen bundles are noted in the experimental groups after 6 hours, 1
day and 3 days. At 8 weeks the most prominent changes observed were inflammatory
cellular infiltration and disorganization of the collagen bundles. In the control
group the tunica albuginea retains normal wavy regular appearance in all rats.
This histological analysis is similar to the reported description of histological
features of the acute phase of Peyronie's disease. Electron microscopy showed
packed collagen bundles in the trauma-induced group with normal appearing elastic
fibers. No abnormal change was detected in the control group. Immunoblot results
revealed remarkable TGF-beta1 protein expression in 1, 5, 3, and 0 rats of trauma
induced subgroups after 6 hours, 1 day, 3 days, and 8 weeks respectively. No TGF
beta1 protein expression in any rats in the control group was detected. No
significant TGF-beta2 or TGF-beta3 protein expression was observed either in the
trauma induced group or in the control group. CONCLUSION: Trauma can induce
histological changes similar to the acute phase of Peyronie's disease but not the
overt picture of the chronic phase of Peyronie's disease. It can also result in
an early but transient up-regulation of TGF-beta1 protein expression in the rat
penis. We conclude that surgical incisional trauma does not result in Peyronie's
disease-like changes in the tunica.
PMID- 9554398
TI - Urethral replacement with vascularized tunica vaginalis: defining the optimal
form of use.
AB - PURPOSE: Residual urethral defects after failed hypospadias surgery present
difficulties in reconstruction. In these situations, repair using vascularized
tissue flaps remains ideal, yet challenging. In order to offer more surgical
alternatives in these cases, the use of vascularized tunica vaginalis flaps as
urethral replacements has recently been established in an animal model. We
undertook the following studies to further define the role of tunica vaginalis in
urethral reconstruction. MATERIALS AND METHODS: A vascularized flap of tunica
vaginalis was used to replace an experimentally created 25-30 mm. gap in the
anterior urethra of 26 rabbits, either as an onlay or tube flap. A control group
consisting of 7 animals underwent only a segmental anterior urethral resection
and primary re-anastomosis. RESULTS: Satisfactory urethral healing occurred in
all control animals that survived the procedure. All 8 animals which had tunica
vaginalis tube flap reconstruction underwent contracture of the neourethra
probably secondary to the presence of striated cremasteric muscle elements
brought with the tunica during mobilization. All 16 animals available for long
term study in the onlay flap group had excellent flap viability and 100% urethral
patency rates. The mesothelial lining of the tunica was seen to be replaced by a
stratified epithelial lining similar to the urothelial lining of the native
urethra. CONCLUSION: The tunica vaginalis is a viable alternative to other
tissues presently used for urethral replacement and can be used successfully as a
vascularized onlay flap.
PMID- 9554399
TI - Innervation of the striated muscle of the membranous urethra of the male dog.
AB - PURPOSE: To identify the functional innervation of the striated muscle layer of
the post-prostatic urethra of male dogs. MATERIALS AND METHODS: Detailed anatomic
dissection of the pelvic and pudendal nerves was carried out. The pressure and
contractile responses to stimulation of these nerves were recorded in vivo and in
vitro. RESULTS: Small branches of the pelvic nerve entered the membranous urethra
but passed through the striated muscle to the inner smooth muscle layer.
Stimulation of the nerve with 1 msec pulses at 10 Hz produced a slow contraction
of the urethra which was unaffected by d-tubocurarine. Pudendal nerve branches
entered the striated layer from the caudal end. Stimulation produced a rapid,
visible contraction that was abolished by d-tubocurarine. Field stimulation of
isolated strips of striated muscle resulted only in rapid, d-tubocurarine
sensitive contractions. CONCLUSIONS: The striated muscle of the membranous
urethra is innervated exclusively by the pudendal nerve.
PMID- 9554400
TI - In vitro functional properties of the rat bladder regenerated by the bladder
acellular matrix graft.
AB - PURPOSE: To assess the response of rat urinary bladder regenerated by the
homologous bladder acellular matrix graft (BAMG) to in vitro electrical and
pharmacologic stimuli. MATERIALS AND METHODS: In Sprague-Dawley rats, partial
cystectomy (>50%) was performed, followed by BAMG augmentation cystoplasty. After
4 months, organ bath studies of tissue strips in 10 were used to compare the
contractility of the BAMG regenerates and the corresponding host detrusor smooth
muscle. RESULTS: The BAMG regenerates exhibited contractile activity to
electrical field stimulation and a qualitatively identical pattern of response to
muscarinic, purinergic, alpha- and beta-adrenergic drug administration and nitric
oxide. At 4 months after surgery, the maximum forces of contraction of the BAMG
regenerates to carbachol stimulation amounted to close to 80% of the host bladder
response. With electrical field stimulation, they equaled 44% and 62% of the host
bladder response after 2.5 and 4 months, respectively. Histological and
immunohistochemical studies confirmed the presence of receptors for
neurotransmitters that these functional in vitro studies implied. CONCLUSIONS:
The present study provides further evidence that augmentation cystoplasty with
the BAMG leads to functional regeneration of the rat bladder detrusor smooth
muscle.
PMID- 9554401
TI - Molecular analysis of P16(Ink4)/CDKN2 and P15(INK4B)/MTS2 genes in primary human
testicular germ cell tumors.
AB - PURPOSE: p16 (MTS 1) and p15 (MTS 2) are negative regulators of cell cycle
progression at the G1 cell cycle checkpoint and function as tumor suppressor
genes (TSG). Both p15 and p16 are located on chromosome 9p21 and alterations have
been demonstrated in a variety of human malignancies and human cancer cell lines.
In testicular germ cell tumors (TGCT) loss of heterozygosity of 9p21 to 23 has
been observed in 41% to 72% of informative cases. The aim of our study was to
examine TGCT and testicular cancer cell lines for deletions and mutations of the
p15 and p16 genes. MATERIALS AND METHODS: 24 testicular germ cell tumors, 4
testicular cancer cell lines (TERA I, TERA II, HTE, HTH), 8 benign testicular
tumors and 9 samples of normal testicular parenchyma were examined. Examinations
for loss of heterozygosity (LOH) on 9p21 were performed for IFNA, D9S171, D9S126,
D9S161, D9S1748 and PKY9 locus using Southern Blot analysis. Southern Blot
analysis of the p16 gene to examine gross alterations was done using random
primer labeled p16 cDNA. In addition all samples were examined for mutations of
exons 1 to 3 of p16 and exons 1 to 2 of p15 by polymerase chain reaction (PCR)
followed by single strand conformation polymorphism (SSCP) analysis on MDE-gels.
All observed band shifts on SSCP were further evaluated by direct DNA sequencing
techniques. RESULTS: No major deletions were detected for p16 and p15. 42% of all
TGCT demonstrated LOH of the IFNA locus, 16% of the D9S161 locus and 5.5% of the
D9S171 locus. No LOH was seen for the D9S126 locus. 5/24 TGCT (21%) and 1
testicular cancer cell line (TERA II) demonstrated band shifts for exon 2, 8/24
TGCT (33%) and 1 testicular cancer cell line (TERA I) showed band shifts for exon
3; 4 TGCT had an allelic loss for exon 3 on SSCP. DNA sequencing analysis for
exon 2 demonstrated a single base substitution (G-->A) in codon 140 resulting in
an amino acid exchange (ala-->thre) in 4 cases and a single base deletion with
frame shift mutation in codon 142 in 2 cases. DNA sequencing analysis for exon 3
demonstrated a polymorphism in intron 2 in all cases. For p15 no band shifts were
observed for exons 1 to 2 in TGCT or testicular cancer cell lines; none of benign
testicular tumors or normal control tissues demonstrated any band shifts for p15
or p16. DISCUSSION: We demonstrated a high frequency of mutations for exon 2 in
specimens of primary testicular germ cell tumors, but not in benign tumors or
normal controls. We therefore believe that p16 might be involved in the
pathogenesis of human TGCT. The polymorphisms described for exon 3 might be
utilized for further LOH studies. The absence of mutations in p15 gene in TGCT
specimens suggests that p15 might not play an important role in the pathogenesis
of testicular germ cell tumors.
PMID- 9554402
TI - Observations on seminal vesicle dynamics in an in vivo rat model.
AB - PURPOSE: To gain understanding of the seminal vesicle as a muscular organ,
seminal vesicle compliance and contractile properties were quantified with an in
vivo, microsurgical rat model. MATERIALS AND METHODS: Microsurgical dissection
was performed on anesthetized rats to enable simultaneous organ filling and
monitoring of intraluminal pressures. The reliability and reproducibility of post
ganglionic hypogastric nerve-induced ipsilateral (4 rats) and bilateral (5 rats)
seminal vesicle contractile responses were assessed during repeated nerve
stimulation. Seminal vesicle resting compliance was assessed during a constant
saline infusion (10 rats). Functional performance curves were obtained at fixed
fill-volumes by measuring organ contraction after nerve stimulation (4 rats).
RESULTS: A reproducible seminal vesicle contractile response was obtained with a
nerve stimulation interval > 15 minutes. Bilateral seminal vesicle responses were
observed with unilateral nerve stimulation. The resting organ compliance curve
with saline filling exhibited a characteristic, triphasic response. Functional
performance studies revealed that contractile performance improves as the fill
volume increases until the distensibility limit of the organ is reached.
CONCLUSIONS: A reliable, in vivo, rat model of seminal vesicle organ compliance
and contractility is described. The seminal vesicle is a highly contractile,
compliant smooth muscular organ with dynamic properties analogous to that of the
urinary bladder. This experimental system may allow for the investigation of
pharmacologic and other physiological influences on in vivo organ activity.
PMID- 9554403
TI - Cell-mediated autoimmune response to testis induced by bilateral testicular
injury can be suppressed by cyclosporin A.
AB - PURPOSE: Since the delayed type hypersensitivity (DTH) response to testis
antigens plays a key role in the induction and/or maintenance of experimental
autoimmune orchitis (EAO), an animal model for human immunological male
infertility or aspermatogenesis, we have investigated the immunosuppressive
effect of cyclosporin A (CsA) on the DTH response to autologous testicular cells
(TC). MATERIALS AND METHODS: A DTH response to autologous TC was induced in
C3H/HeN mice by bilateral testicular injury (trauma). CsA was administered
intraperitoneally for 10 consecutive days before and after injury. A DTH response
was assessed by measuring delayed footpad reaction (DFR) to autologous TC 9 days
after injury. RESULTS: When the mice were traumatized alone, 10 mg./kg. or more
of CsA suppressed the DTH response to autologous TC significantly. In mice
traumatized with 100 mg./kg. of cyclophosphamide (CY)-pretreatment, 30 mg./kg. or
more of CsA was needed to suppress the DTH response. In mice traumatized with 200
mg./kg. of CY-pretreatment, 50 mg./kg. of CsA was needed to suppress the
autoimmune response. CONCLUSIONS: The DTH response to autologous TC was
suppressed significantly by administration of CsA in a dose-dependent manner. We
have also shown the direct suppressive effect of CsA on effector cells for DTH by
means of local passive transfer of DTH. Administration of CsA had no augmenting
or suppressive effect on suppressor cells for DTH. CsA might be a significant
drug for the immunosuppression of EAO and possibly for immunological male
infertility.
PMID- 9554404
TI - Presence and biological activity of C-type natriuretic peptide-dependent
guanylate cyclase-coupled receptor in the penile corpus cavernosum.
AB - PURPOSE: To investigate the presence of C-type natriuretic peptide 1-22 (CNP)
dependent guanylyl cyclase (GC)-coupled receptor and its biological function in
the penile erectile smooth muscle. MATERIALS AND METHODS: Experiments have been
done in rabbit and rat to detect cyclic GMP (cGMP) generation by the activation
of particulate GC by natriuretic peptides (NPs) in cavernosal membrane, to
localize precise receptor using a quantitative in vitro autoradiography of the
snap frozen sections, to define natriuretic peptide receptor (NPR) mRNA using a
reverse transcriptase-polymerase chain reaction (RT-PCR) technique and to monitor
changes of erectile smooth muscle tone by NPs in the penile tissue strips.
RESULTS: Productions of cGMP by particulate GC in the corpus cavernosum membranes
of rabbit and rat were stimulated by CNP, atrial natriuretic peptide 1-28 (ANP)
and brain natriuretic peptide 1-26 (BNP) with a rank order of potency of CNP >
BNP > ANP. HS-142-1, a selective antagonist for the GC-coupled NPR, inhibited the
CNP-stimulated cGMP production in corpus cavernosal membrane of rabbit and rat.
Specific 125I-(Tyr[0])-CNP bindings were localized in the corpus cavernosal
smooth muscle of rabbit with Kd of 19.92+/-3.38 nM. and Bmax of 734.64+/-139.63
amol./mm2. B-subtype of NPR mRNA was detected in the penile corpus cavernosum of
rat using RT-PCR technique. CNP relaxed the smooth muscle contracted by Nomega
nitro-L-arginine methylester (L-NAME). CONCLUSIONS: These results suggest for the
first time that CNP modulates the erectile smooth muscle tone of penis by
predominant activation of B-subtype of NPR with augmentation of cGMP production
via particulate GC.
PMID- 9554405
TI - Alterations in constituent urinary proteins in response to bladder outlet
obstruction in rats.
AB - PURPOSE: Benign prostatic hyperplasia, resulting in bladder outflow obstruction,
induces well recognized clinical symptoms and morphologic bladder changes.
Despite these phenomenon, relatively little is known with regard to the precise
molecular events occurring in the bladder as a consequence of obstruction. In an
effort to screen for alterations in bladder gene expression induced by
obstruction, and/or alterations in uroepithelial integrity, this study compared
pre- and post-obstructive constituent urinary proteins in an animal model.
MATERIALS AND METHODS: Outlet obstruction was created using a previously
established model system. Experimental animals were surgically obstructed for
either 2 or 7 days, at which time the urine was aspirated and the bladders
removed and weighed. Urinary proteins were separated using 2-D PAGE. Following
comparison of sham versus experimental animals, microsequencing was performed on
proteins that were down regulated. RESULTS: Duplicate experiments confirmed the
presence of outflow obstruction. Statistically significant increases (p <0.01) in
bladder weights were seen at 2 and 7 days in the obstructed groups as compared
with both sham and control groups. 2-D PAGE demonstrated a down regulation of
three urinary proteins post-obstruction. Microsequencing identified these
proteins as prostatic steroid-binding protein C3 precursor (pI=5.5, MW=15000),
glandular kallikrein 9 (S3) precursor (pI=6.2, MW=19000), and glandular
kallikrein 8 (P1) precursor (pI=6.2, MW=33000). CONCLUSIONS: Bladder outflow
obstruction alters constituent urinary protein composition in an animal model
system. The precise etiology of these alterations remains to be defined.
PMID- 9554406
TI - Does intratesticular testosterone administration modify the evolution of
transitory testicular ischemia in pre-pubertal rats?
AB - PURPOSE: Testicular torsion followed by ischemia results in variable degrees of
infertility and until now there appears to be no effective way to recover it.
Testosterone participation in the maintenance of male sexual organs and
spermatogenesis led us to hypothesize that intratesticular administration could
recover ischemic injury. MATERIALS AND METHODS: We divided 40 Wistar rats in 2
groups, of 20 each. One group was control and the other underwent a 120-minute
testicular ischemia by means of a vascular clamp on the left spermatic cord. Each
group was further subdivided in 2 subgroups. The first one was observed and the
second received intratesticular testosterone 25 mg. starting on the third day
after injury and during the next 7 consecutive days. Half the animals were
sacrificed 30 days after injury and the remaining ones after 60 days. Weight,
volume, number of seminiferous tubules, histology and spermatogenesis of the same
side and contralateral testes were examined. For statistical analysis ANOVA and
Fisher's tests were applied. RESULTS: It was found that testosterone was capable
of acting upon volume and weight of the left testis (p=0.0001). The animals
receiving intratesticular testosterone showed lower testicular weight and volume
after 30 and 60 days, respectively. This subgroup also showed a higher number of
seminiferous tubules, modified histology and absent spermatogenesis suggesting
testicular atrophy. CONCLUSIONS: We concluded that intratesticular injection of
testosterone 25 mg. once a day during 7 consecutive days after transitory
testicular ischemia causes ipsilateral testis atrophy. The animals in control
group showed testicular histological recovery 60 days after injury. There were no
significant histological differences in the contralateral testes.
PMID- 9554407
TI - The inhibition of calcium oxalate monohydrate crystal growth by maleic acid
copolymers.
AB - The crystallization of calcium oxalate monohydrate (COM) was investigated at
conditions of constant supersaturation both in the absence and in the presence of
synthetic maleic acid copolymers at 37C, 0.15 M NaCl. The dependence of the rates
of COM crystallization in the absence of inhibitors was found to be second order
at low and first order at higher supersaturations suggesting a surface diffusion
controlled mechanism. The presence of all copolymers tested at concentration
levels up to 5 ppm retarded the rates of COM crystal growth up to 90%. The
decrease of the COM crystal growth rates by the polymers depended on the nature
of the comonomer polymerized with maleic acid and the order of inhibition was
found to be vinyl acetate > N-vinylpyrrolidone > styrene. Taking into
consideration kinetics data published in the literature concerning the inhibition
of COM crystal growth, it is suggested that molecular weight also plays a role,
with more inhibition at higher molecular weights. The morphology of the COM
crystals grown was unaffected yet the crystals growing at lower rates in the
presence of the copolymers were larger and their size more uniform. It is
concluded that maleic acid copolymers are strong inhibitors of the
crystallization of COM, the inhibitory activity being more pronounced in the case
of the linear copolymers.
PMID- 9554408
TI - Detection of oxidative DNA damage in human sperm and the association with
cigarette smoking.
PMID- 9554409
TI - Physiological consequences of testicular sperm extraction.
PMID- 9554410
TI - Local interferon-alpha2b is not an effective treatment in early-stage Peyronie's
disease.
PMID- 9554411
TI - The first use of meta-analysis?
PMID- 9554412
TI - Problems involved in including women with simple hysterectomy in epidemiologic
studies measuring the effects of hormone replacement therapy on breast cancer
risk.
PMID- 9554413
TI - Incidence of invasive cancers following basal cell skin cancer.
AB - To obtain quantitative information on the risk of invasive cancers following a
diagnosis of basal cell carcinoma (BCC) of the skin, patients with incident BCC
cases listed in the cancer registries of the Swiss cantons of Vaud and Neuchatel
between 1974 and 1994 were actively followed up through December 31, 1994, for
the occurrence of subsequent invasive neoplasms. Among 11,878 persons with
incident BCC who were followed for a total of 76,510 person-years at risk, 1,543
metachronous cancers were observed versus 1,397.9 expected, corresponding to a
standardized incidence ratio (SIR) of 1.1 (95% confidence interval (CI) 1.0-1.2).
However, after exclusion of skin cancers (mostly squamous cell carcinoma and
melanoma), 975 second primary cancers were observed versus 1,059 expected (SIR =
0.9, 95% CI 0.8-1.0). Significant excesses were registered for cancer of the lip
(SIR = 2.2), for squamous cell skin cancer (SIR = 4.5) and melanoma of the skin
(SIR = 2.5), and for non-Hodgkin's lymphoma (SIR = 1.9). The SIRs were also above
unity, though not significantly, for cancers of the salivary glands (SIR = 2.8)
and the small intestine (SIR = 2.1) and for soft-tissue sarcomas (SIR = 1.7). The
SIR for lung cancer was 0.9. The SIRs for salivary gland and skin cancer were
appreciably greater below age 70 years. For most sites, particularly for squamous
cell cancer and melanoma of the skin, the SIRs remained elevated 5 or more years
after BCC diagnosis. The cumulative incidence of squamous cell skin cancer was
13% at 19 years; this stresses the importance of carefully monitoring skin
lesions among persons previously diagnosed with BCC.
PMID- 9554414
TI - Nested case-control study of tumors of the hemopoietic and lymphatic systems
among workers in the meat industry.
AB - Workers in the meat industry are exposed to viruses that cause leukemia and
lymphoma in cattle and chickens, and also to carcinogenic chemical agents. This
case-control study, nested in a cohort of members of a meatcutters' union in
Baltimore, Maryland, investigated whether occupational exposures are associated
with death from tumors of the hemopoietic and lymphatic systems. Cases of these
tumors represent all deaths which occurred in the cohort between 1949 and 1980.
Excess risks of tumors of the hemopoietic and lymphatic systems were observed
throughout the meat industry, except in meatpacking plants. Slaughtering
activities involving heavy exposure to oncogenic viruses were strongly associated
with these tumors, especially with lymphomas. Thus, elevated risks were observed
for butchers who killed animals (odds ratio (OR) = 5.3, 95% confidence interval
(CI) 1.0-27.0); workers in chicken-slaughtering plants (OR = 3.3, 95% CI 0.8
13.1); and workers in cattle/sheep/pig abattoirs (OR = 2.8, 95% CI 0.8-9.5).
Among supermarket workers, wrapping meat (mainly a female activity) was
associated with increased risk of tumors of the hemopoietic and lymphatic systems
(OR = 3.8, 95% CI 1.0-14.3), with the odds of both lymphomas and tumors of the
myeloid stem cell being elevated. On the other hand, meatcutting in supermarkets
(almost exclusively a male activity) was associated with multiple myeloma; the
odds ratio for men was 18.0 (95% CI 1.6-207.5), with no myeloma cases being
recorded in women. These associations persisted after limited control for
exposures outside the industry that have also been observed to be associated with
excess risk, such as exposure to pesticides, working/living on pig farms, and
exposure to X-rays. The findings provide evidence that workers in the meat
industry may be at elevated risk of tumors of the hemopoietic and lymphatic
systems. Further studies with larger sample sizes are needed to identify more
conclusively which exposures play an etiologic role in the occurrence of the
different histologic types of these tumors.
PMID- 9554415
TI - Mortality and optimal body mass index in a sample of the US population.
AB - In this paper, the authors model the nonmonotonic relation between body mass
index (BMI) (weight (kg)/height2 (m2)) and mortality in 13,242 black and white
participants in the NHANES I Epidemiologic Follow-up Study in order to estimate
the BMI at which minimum mortality occurs. The BMI of minimum mortality was 27.1
for black men (95% confidence interval (CI) 24.8-29.4), 26.8 for black women (95%
CI 24.7-28.9), 24.8 for white men (95% CI 23.8-25.9), and 24.3 for white women
(95% CI 23.3-25.4). Each confidence interval included the group average. Analyses
conducted by smoking status and after exclusion of persons with baseline illness
and persons who died during the first 4 years of follow-up led to virtually
identical estimates. The authors determined the range of values over which risk
of all-cause mortality would increase no more than 20% in comparison with the
minimum. This interval was nine BMI units wide, and it included 70% of the
population. These results were confirmed by parallel analyses using quantiles.
The model used allowed the estimation of parameters in the BMI-mortality
relation. The resulting empirical findings from each of four race/sex groups,
which are representative of the US population, demonstrate a wide range of BMIs
consistent with minimum mortality and do not suggest that the optimal BMI is at
the lower end of the distribution for any subgroup.
PMID- 9554416
TI - Sex hormones and age: a cross-sectional study of testosterone and estradiol and
their bioavailable fractions in community-dwelling men.
AB - The role of endogenous sex hormones in many diseases makes understanding factors
that influence levels of these hormones increasingly important. This study
examined age-associated variations in total and bioavailable testosterone and
estradiol levels among community-dwelling Caucasian men in Rancho Bernardo,
California. Plasma samples obtained from 810 men aged 24-90 years in 1984-1987
were analyzed in 1993 using radioimmunoassay. Analyses of age-hormone
associations, adjusting for weight, body mass index, alcohol ingestion, smoking,
physical activity, caffeine intake, specimen storage time, and disease status,
were undertaken. Bioavailable testosterone and bioavailable estradiol levels
decreased significantly with age independently of covariates. Total testosterone
and estradiol levels decreased with age only when analyses were controlled for
confounders. The importance of the age-associated decline in endogenous sex
hormone levels, particularly levels of bioavailable testosterone and bioavailable
estradiol, and their relation to disease and function in men deserve further
research.
PMID- 9554418
TI - Short-term consistency in self-reported physical functioning among elderly women:
the Women's Health and Aging Study.
AB - The assessment of physical functioning and disability is integral to population
based and clinical research carried out among elderly people. Typically,
functional status is measured through self-reported responses to questions of the
form "Do you have difficulty [doing a specific task]?" Knowledge of the
reliability and validity of these self-report measures is key to the
interpretation of many research efforts, but data on these measurement parameters
are sparse. This paper addresses this deficiency through analyses of data from
the Weekly Substudy of the Women's Health and Aging Study, a cohort of Baltimore
area women aged > or =65 years with moderate to severe physical disability. Self
reported data on 20 activities, obtained weekly over a 6-month period in 1993 or
1994, were analyzed to investigate how time intervals between assessments and a
subject's age and baseline level of disability influenced the consistency of self
reports of disability at both the population level and the individual level. The
prevalence of self-reported difficulty increased with baseline disability and, to
a lesser extent, with age group. Consistency for all items was very high over
short time intervals, but it decreased substantially with increasing intervals
between responses (although associations between responses remained significant
at 24 weeks). Consistency did not vary with age or baseline disability. Graphic
techniques and statistical methods for use with repeated binary data are also
illustrated.
PMID- 9554417
TI - Epidemiology of sarcopenia among the elderly in New Mexico.
AB - Muscle mass decreases with age, leading to "sarcopenia," or low relative muscle
mass, in elderly people. Sarcopenia is believed to be associated with metabolic,
physiologic, and functional impairments and disability. Methods of estimating the
prevalence of sarcopenia and its associated risks in elderly populations are
lacking. Data from a population-based survey of 883 elderly Hispanic and non
Hispanic white men and women living in New Mexico (the New Mexico Elder Health
Survey, 1993-1995) were analyzed to develop a method for estimating the
prevalence of sarcopenia. An anthropometric equation for predicting appendicular
skeletal muscle mass was developed from a random subsample (n = 199) of
participants and was extended to the total sample. Sarcopenia was defined as
appendicular skeletal muscle mass (kg)/height2 (m2) being less than two standard
deviations below the mean of a young reference group. Prevalences increased from
13-24% in persons under 70 years of age to >50% in persons over 80 years of age,
and were slightly greater in Hispanics than in non-Hispanic whites. Sarcopenia
was significantly associated with self-reported physical disability in both men
and women, independent of ethnicity, age, morbidity, obesity, income, and health
behaviors. This study provides some of the first estimates of the extent of the
public health problem posed by sarcopenia.
PMID- 9554419
TI - Epidemiology of Salmonella typhimurium O:4-12 infection in Norway: evidence of
transmission from an avian wildlife reservoir.
AB - In 1987, a nationwide outbreak of Salmonella typhimurium O:4-12 infection traced
to contaminated chocolate bars occurred in Norway. In the 5 years after the
outbreak, elevated numbers of sporadic cases caused by the epidemic strain of
Salmonella were detected, followed by a decline in subsequent years. To
characterize the epidemiology of this infection, the authors analyzed information
concerning all sporadic cases reported in Norway from 1966 to 1996. Of the 153
patients infected by the outbreak strain, 43% were less than 5 years of age, and
only three persons had acquired the infection abroad. In contrast, 46% of the
cases attributable to other S. typhimurium O:4-12 variants and 90% of the total
number of Salmonella infections were related to foreign travel. A distinct
seasonality was observed: 76% of the cases appeared between January and April. At
the same time of year, the epidemic strain was regularly encountered as the
etiologic agent of fatal salmonellosis among wild passerine birds, suggesting an
epidemiologic link between the avian and human cases. The strain was rarely
isolated from other sources. From 1990 to 1992, the authors conducted a
prospective case-control study of sporadic indigenous infections to identify risk
factors and obtain guidance for preventive efforts. Forty-one case-patients, each
matched by age, sex, and geographic area with two population controls, were
enrolled. In conditional logistic regression analysis, the following
environmental factors were independently related to an increased risk of
infection: drinking untreated water, having direct contact with wild birds or
their droppings, and eating snow, sand, or soil. Cases were also more likely than
controls to report having antecedent or concurrent medical disorders. Forty-six
percent of the study patients were hospitalized for their salmonellosis.
PMID- 9554421
TI - Re: "Breast cancer and lactation history in Mexican women".
PMID- 9554420
TI - Confidence limits made easy: interval estimation using a substitution method.
AB - The use of confidence intervals has become standard in the presentation of
statistical results in medical journals. Calculation of confidence limits can be
straightforward using the normal approximation with an estimate of the standard
error, and in particular cases exact solutions can be obtained from published
tables. However, for a number of commonly used measures in epidemiology and
clinical research, formulae either are not available or are so complex that
calculation is tedious. The author describes how an approach to confidence
interval estimation which has been used in certain specific instances can be
generalized to obtain a simple and easily understood method that has wide
applicability. The technique is applicable as long as the measure for which a
confidence interval is required can be expressed as a monotonic function of a
single parameter for which the confidence limits are available. These known
confidence limits are substituted into the expression for the measure--giving the
required interval. This approach makes fewer distributional assumptions than the
use of the normal approximation and can be more accurate. The author illustrates
his technique by calculating confidence intervals for Levin's attributable risk,
some measures in population genetics, and the "number needed to be treated" in a
clinical trial. Hitherto the calculation of confidence intervals for these
measures was quite problematic. The substitution method can provide a practical
alternative to the use of complex formulae when performing interval estimation,
and even in simpler situations it has major advantages.
PMID- 9554422
TI - Re: "Temporal trends in diabetes mortality among American Indians and Hispanics
in New Mexico: birth cohort and period effects".
PMID- 9554423
TI - Proposals for funding graduate medical education: the Institute of Medicine
report in context.
AB - Federal support of graduate medical education (GME) has been accepted as an
intrinsic ingredient of the Medicare program since that program's inception.
Streams of clinical income generated by teaching hospitals, medical faculty
practice plans, Medicaid, and other state and federal sources have also made
important contributions to GME. Although it is difficult to ascribe legislative
intent precisely, Medicare funding seems to have been based on a 2-fold
assumption: that GME was socially beneficial and that there were legitimate costs
to teaching hospitals associated with their educational missions, even though
such costs were hard to identify specifically. The benefits and costs include the
high quality generally ascribed to a teaching hospital environment; extra
services and teaching costs; active, unsponsored research; a higher proportion of
complex medical conditions and care; and technology development and introduction.
The argument for Medicare support of GME is thus partly based on better service
to all Medicare beneficiaries, and partly on a broader social investment in
education and teaching hospitals, with benefits accruing to both present and
future Medicare participants. Teaching hospitals and their young physicians in
training are also important in providing care to underserved poor populations.
PMID- 9554425
TI - The Institute of Medicine report on graduate medical education.
PMID- 9554424
TI - Half a loaf: is compromise the best policy?
PMID- 9554426
TI - Antidepressant prescribing practices of outpatient psychiatrists.
AB - BACKGROUND: The authors examined recent changes in the number and proportion of
patients prescribed antidepressants by psychiatrists in outpatient private
practice and characterized antidepressant prescription patterns by patient age,
sex, race, payment source, and clinical diagnosis. METHODS: The authors analyzed
physician-reported data from the 1985 and 1993-1994 National Ambulatory Medical
Care Survey, focusing on visits to physicians specializing in psychiatry.
Logistic regressions were used to examine associations between survey year and
antidepressant prescription, adjusting for the presence of other variables.
RESULTS: The proportion of outpatient psychiatric visits in which an
antidepressant was prescribed increased from 23.1% (95% confidence interval [CI],
19.7%-26.5%) in 1985 to 48.6% (95% CI, 47.5%-49.7%) in 1993-1994. After
controlling for several patient variables, psychiatric patients were
approximately 2.3 (95% CI, 1.8-2.9) times more likely to receive an
antidepressant in 1993-1994 than in 1985. In 1993-1994, selective serotonin
reuptake inhibitors accounted for approximately half of the psychiatric visits
with an antidepressant prescription. Increases in the rate of antidepressant
prescription were particularly evident for children and young adults; whites; new
patients; and patients with adjustment disorders, personality disorders,
depression not otherwise specified or dysthymia, and some anxiety disorders.
CONCLUSIONS: During the late 1980s and early 1990s, there was a significant
increase in the prescription of antidepressants by office-based psychiatrists.
This increase was greatest for patients with less severe psychiatric disorders.
PMID- 9554427
TI - Treatment of posttraumatic stress disorder by exposure and/or cognitive
restructuring: a controlled study.
AB - BACKGROUND: Unanswered questions from controlled studies of posttraumatic stress
disorder concern the value of cognitive restructuring alone without prolonged
exposure therapy and whether its combination with prolonged exposure is
enhancing. METHODS: In a controlled study, 87 patients with posttraumatic stress
disorder of at least 6 months' duration were randomly assigned to have 10
sessions of 1 of 4 treatments: prolonged exposure (imaginal and live) alone;
cognitive restructuring alone; combined prolonged exposure and cognitive
restructuring; or relaxation without prolonged exposure or cognitive
restructuring. RESULTS: Integrity of audiotaped treatment sessions was
satisfactory when rated by an assessor unaware of the treatment assignment.
Seventy-seven patients completed treatment. The pattern of results was similar
regardless of rater, statistical method, measure, occasion, and therapist.
Exposure and cognitive restructuring, singly or combined, improved posttraumatic
stress disorder markedly on a broad front. Gains continued to 6-month follow-up
and were significantly greater than the moderate improvement from relaxation.
CONCLUSION: Both prolonged exposure and cognitive restructuring were each
therapeutic on their own, were not mutually enhancing when combined, and were
each superior to relaxation.
PMID- 9554428
TI - A functional magnetic resonance imaging study of tic suppression in Tourette
syndrome.
AB - BACKGROUND: The inability to inhibit unwanted behaviors and impulses produces
functional debility in a broad range of neuropsychiatric disorders. A potentially
important model of impulse control is volitional tic suppression in Tourette
syndrome. METHODS: Tic suppression was studied in 22 adult subjects with Tourette
syndrome by using functional magnetic resonance imaging. Images acquired during
periods of voluntary tic suppression were compared with images acquired when
subjects allowed the spontaneous expression of their tics. The magnitudes of
signal change in the images were then correlated with measures of the severity of
tic symptoms. CONCLUSIONS: Significant changes in signal intensity were seen in
the basal ganglia and thalamus and in anatomically connected cortical regions
believed to subserve attention-demanding tasks. The magnitudes of regional signal
change in the basal ganglia and thalamus correlated inversely with the severity
of tic symptoms. These findings suggest that the pathogenesis of tics involves an
impaired modulation of neuronal activity in subcortical neural circuits.
PMID- 9554429
TI - Use of pattern analysis to predict differential relapse of remitted patients with
major depression during 1 year of treatment with fluoxetine or placebo.
AB - BACKGROUND: Delayed and persistent ("true drug") improvement characterizes the
response to antidepressant medication. Early or nonpersistent ("placebo") benefit
is typical of a placebo response. The prediction was that patients with a true
drug response would sustain their benefit best if they continued to receive the
drug and that patients with a placebo response would have an equivalent prognosis
whether they continued to receive the drug or were switched to placebo. METHODS:
Patients with major depression who met the study's response criteria (a modified
Hamilton Depression Rating Scale score < or =7 and failure to meet major
depression criteria after each of the last 3 weeks following 12 to 14 weeks of
treatment with fluoxetine hydrochloride, 20 mg/d) were enrolled in a 50-week
randomized placebo substitution trial during which the return of depressive
symptoms defined relapse. The timing and persistency of response during initial
treatment defined true drug or placebo response patterns. RESULTS: Patients with
a true drug response pattern relapsed significantly more frequently if they were
switched to placebo than if they continued to receive fluoxetine (P<.001 for
weeks 12-26, P<.005 for weeks 26-50, and P<.41 for weeks 50-62). Patients with a
placebo response pattern had an equivalent outcome whether maintained on
fluoxetine therapy or placebo (P< .20 for weeks 12-26, test invalid for weeks 26
50, and P<.67 for weeks 50-62). Patients with a placebo response pattern relapsed
more often when they continued to receive fluoxetine than patients with a true
drug response pattern (P<.01 for weeks 12-26, P<.10 for weeks 26-50, and P<.36
for weeks 50-62). CONCLUSIONS: These findings confirm that pattern analysis
validly differentiates true drug from nonspecific initial responses and extend
its use to the continuation and maintenance phases of treatment for depression.
Investigations into the mechanisms of antidepressant activity might best be
limited to those that can account for delayed efficacy. Fluoxetine's efficacy
during the continuation and maintenance phases of treatment may be limited to
patients with a true drug pattern of initial response.
PMID- 9554430
TI - Proton magnetic resonance spectroscopic imaging of cortical gray and white matter
in schizophrenia.
AB - OBJECTIVE: To apply in vivo proton magnetic resonance spectroscopy imaging
estimates of N-acetylaspartate (NAA), a neuronal marker, to clarify the relative
contribution of neuronal and glial changes to the widespread volume deficit of
cortical gray matter seen in patients with schizophrenia with magnetic resonance
images. METHODS: Ten male veterans meeting criteria of the DSM-IV, for
schizophrenia and 9 healthy age-matched men for comparison were scanned using
spectroscopic, anatomical, and field-map sequences. Instrument and collection
variables were standardized to allow an estimation of comparable values for NAA,
choline, and creatine for all subjects. Metabolite values from each voxel on 3
upper cortical slices were regressed against the gray tissue proportion of that
voxel to derive estimates of gray and white matter NAA, creatine, and choline
concentrations. RESULTS: The volume of cortical gray matter was reduced in
patients with schizophrenia, but NAA signal intensity from a comparable region
was normal. In contrast, the volume of cortical white matter was normal in
patients with schizophrenia, but NAA signal intensity from a comparable region
was reduced. CONCLUSIONS: The lack of reduction in gray matter NAA signal
intensity suggests that the cortical gray matter deficit in these patients
involved both neuronal and glial compartments rather than a neurodegenerative
process in which there is a decrease in the neuronal relative to the glial
compartment. Reduced white matter NAA signal intensity without a white matter
volume deficit may reflect abnormal axonal connections.
PMID- 9554431
TI - Dose-related ethanol-like effects of the NMDA antagonist, ketamine, in recently
detoxified alcoholics.
AB - BACKGROUND: This study evaluated the dose-related ethanol-like subjective effects
of the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine
hydrochloride in recently detoxified alcoholics. METHODS: Twenty male inpatients
meeting DSM-III-R criteria for alcohol dependence and who had not consumed
alcohol for 10 to 27 days prior to the study completed 3 test days that involved
the intravenous infusion of ketamine hydrochloride (0.1 mg/kg or 0.5 mg/kg) or
saline solution under randomized double-blind conditions. Ethanol-like subjective
effects were assessed using the Sensation Scale; the Biphasic Alcohol Effects
Scale; visual analog scales to measure "high" and degree of similarity to
ethanol, cocaine, and marijuana; a scale assessing the number of standard alcohol
drinks producing similar subjective effects; and visual analog scales measuring
ethanol craving. RESULTS: Ketamine produced dose-related ethanol-like effects on
each scale measuring its similarity to ethanol. Its effects were more similar to
the sedative or descending limb effects of ethanol than to the stimulant or
ascending limb effects. Ketamine effects also were more like ethanol than
marijuana or cocaine. Ethanol-like effects were more prominent at the higher
ketamine dose, a dose rated as similar to greater levels of ethanol intoxication.
However, ketamine did not increase craving for ethanol. CONCLUSION: The
production of ethanol-like subjective effects by ketamine supports the potential
clinical importance of NMDA receptor antagonism among the mechanisms underlying
the subjective effects of ethanol in humans.
PMID- 9554433
TI - Ribozymes as therapeutic agents: are we getting closer?
PMID- 9554432
TI - Noise stress impairs prefrontal cortical cognitive function in monkeys: evidence
for a hyperdopaminergic mechanism.
AB - BACKGROUND: Stress can exacerbate a number of psychiatric disorders, many of
which are associated with prefrontal cortical (PFC) cognitive deficits.
Biochemical studies demonstrate that mild stress preferentially increases
dopamine turnover in the PFC. Our study examined the effects of acute, mild
stress exposure on higher cognitive function in monkeys and the role of
dopaminergic mechanisms in the stress response. METHODS: The effects of loud (105
dB) noise stress were examined on a spatial working memory task (delayed
response) dependent on the PFC, and on a reference memory task with similar motor
and motivational demands (visual pattern discrimination) dependent on the
inferior temporal cortex. The role of dopamine mechanisms was tested by
challenging the stress response with agents that decrease dopamine receptor
stimulation. RESULTS: Exposure to noise stress significantly impaired delayed
response performance. Stress did not impair performance on "0-second" delay
control trials and did not alter visual pattern discrimination performance, which
is consistent with impaired PFC cognitive function rather than nonspecific
changes in performance. Stress-induced deficits in delayed-response performance
were ameliorated by pretreatment with drugs that block dopamine receptors
(haloperidol, SCH 23390) or reduce stress-induced PFC dopamine turnover in
rodents (clonidine, naloxone hydrochloride). CONCLUSIONS: These results indicate
that stress impairs PFC cognitive function through a hyperdopaminergic mechanism.
Stress may take the PFC "off-line" to allow more habitual responses mediated by
posterior cortical and subcortical structures to regulate behavior. This
mechanism may have survival value, but may often be maladaptive in human society,
contributing to the vulnerability of the PFC in many neuropsychiatric disorders.
PMID- 9554434
TI - "Big Smoke" has big risks: daily cigar use causes cancer, heart disease.
PMID- 9554435
TI - Molecular diagnostics takes one small step forward.
PMID- 9554436
TI - Specialists help cancer survivors face unexpected challenges.
PMID- 9554437
TI - Non-physician providers may ease oncology work force crisis.
PMID- 9554438
TI - President heeds panel's call for increased research funding.
PMID- 9554439
TI - Transfusion-induced immunomodulation following cancer surgery: fact or fiction?
PMID- 9554440
TI - Inhibition of tumor growth by ribozyme-mediated suppression of aberrant epidermal
growth factor receptor gene expression.
AB - BACKGROUND: Amplification and rearrangement of the epidermal growth factor
receptor (EGFR) gene is frequently associated with malignant gliomas. One type of
EGFR mutation in primary gliomas results in overexpression of an aberrant EGFR
messenger RNA (mRNA) that lacks sequences of exons II through VI of the human
EGFR gene. We observed that the aberrantly spliced EGFR mRNA contains a ribozyme
cleavable sequence (5'-AAG GUA AUU-3') created by the joining of EGFR exon I to
exon VII. We hypothesized that an appropriately designed ribozyme RNA could
mediate site-specific cleavage of the aberrant EGFR mRNA and reduce the growth of
aberrant EGFR-producing tumor cells. METHODS: We synthesized aberrant EGFR mRNA
substrates and a sequence-specific hammerhead ribozyme (abEGFR-rib) to examine
the ribozyme's activity in vitro. We also constructed an abEGFR-rib plasmid and
introduced it into ERM5-1 cells, which are murine NIH3T3 cells transfected to
express an aberrant EGFR complementary DNA. We measured the growth potential of
the cotransfected cells in culture and in nude mice. RESULTS: The synthesized
abEGFR-rib efficiently and specifically cleaved aberrant EGFR mRNA substrates in
vitro. Expression of the transfected abEGFR-rib suppressed expression of aberrant
EGFR mRNA in ERM5-1 cells and reduced the growth of tumors formed by the
cotransfected cells in nude mice. Finally, the incorporation of
bromodeoxyuridine, a measure of mitotic activity, was also decreased in abEGFR
rib-producing ERM5-1 cells in vivo. CONCLUSION: Ribozymes targeted to aberrant
EGFR mRNA can inhibit the growth of tumors formed by cells that express this
mRNA.
PMID- 9554441
TI - Role of nitric oxide in angiogenesis and tumor progression in head and neck
cancer.
AB - BACKGROUND: Angiogenesis (formation of new blood vessels) is associated with
tumor growth and metastasis in patients with solid tumors, including those of the
head and neck. Nitric oxide (NO) production may contribute to these processes. We
assessed the role of the NO pathway in angiogenesis and tumor progression in
patients with head and neck cancer. METHODS: Biochemical assays were used to
measure NO synthase (NOS) activity and cyclic guanosine monophosphate (cGMP)
levels in specimens of tumor and normal mucosa obtained from 27 patients.
Microvessels in tumor specimens were identified by CD-31-specific
immunohistochemical staining. Associations between microvessel densities, levels
of NOS, and cGMP were examined by use of two-sided statistical tests. Tumor
specimens and human squamous carcinoma A-431 cells were grown as explants on the
corneas of rabbits, and the effect of the NOS inhibitor N(omega)-nitro-L-arginine
methyl ester (L-NAME) was tested. RESULTS: Levels of total NOS, inducible NOS,
and cGMP were higher in tumor specimens than in specimens of normal mucosa (all
P<.0001). Tumor specimens from patients with lymph node metastases presented a
higher total NOS activity (P = .005) and were markedly more vascularized than
tumor specimens from patients with no lymph node involvement (P = .0002).
Microvessel density at the tumor edge was an independent predictor of metastasis
for this series of patients (odds ratio = 1.19; 95% confidence interval = 1.07
2.89; P = .04). A-431 cells and tumor specimens exhibiting high levels of NOS
activity induced angiogenesis in the rabbit cornea assay; when NO production was
blocked, tumor angiogenesis and growth were repressed. CONCLUSIONS: The NO
pathway appears to play a key role in tumor angiogenesis and spread in patients
with head and neck cancer.
PMID- 9554442
TI - Retinoic acid receptor beta expression and growth inhibition of gynecologic
cancer cells by the synthetic retinoid N-(4-hydroxyphenyl) retinamide.
AB - BACKGROUND: The synthetic retinoid N-(4-hydroxyphenyl) retinamide (4HPR) can
inhibit the growth of tumor cells. Preliminary results from a clinical trial
suggest that 4HPR may reduce ovarian cancer incidence. We examined the growth
inhibitory effects of 4HPR on gynecologic cancer cell lines in vitro and the role
of retinoid receptors in modulating this effect. METHODS: Twelve human
gynecologic cancer cell lines (the ovarian cell lines--A224, AD10, UCI 101, UCI
107, SKOV3, 222, CP70, ML3B, and ML5; the cervical cell lines--HT3 and ME180; and
the endometrial cell line--Hec 1A were tested for sensitivity to 4HPR (by
assaying cell proliferation rates). Gel electrophoretic analysis of DNA
fragmentation was used to measure programmed cell death (apoptosis). Specific
retinoid receptor (retinoic acid receptor [RAR] and retinoid X receptor)
messenger RNA (mRNA) levels were measured by northern blot hybridization. AD10
cells were stably transfected with human RARbeta complementary DNA, and the
effect of 4HPR on cell proliferation was examined. RESULTS: 4HPR inhibited the
growth of all 12 cell lines, but to varying degrees; IC50 values (i.e.,
concentrations that inhibit proliferation by 50%) ranged from 0.3 to 9 microM.
Following 4HPR treatment, ovarian cancer cells that were sensitive to 4HPR (222,
CP70, and UCI 101; IC50 <3 microM) contained higher levels of RARbeta transcripts
than more resistant cells (AD10, ME180, Hec 1A, and A224; IC50 > or =3 microM)
(2.8-fold; two-sided P = .006). Anchorage-independent growth of transfected AD10
cells expressing high levels of RARbeta was totally abolished, even in the
absence of 4HPR; transfectants expressing low levels of RARbeta exhibited lower
levels of anchorage-independent growth and grew more slowly in the presence of
4HPR than control untransfected AD10 cells. CONCLUSION: 4HPR inhibited the
proliferation of ovarian cancer cells in vitro; RARbeta expression appeared to be
associated with this effect.
PMID- 9554443
TI - Multiple primary cancers in families with Li-Fraumeni syndrome.
AB - BACKGROUND: Li-Fraumeni syndrome is a dominantly inherited disorder characterized
by early-onset breast cancer, sarcomas, and other cancers in children and young
adults. Members of families with this syndrome also develop multiple primary
cancers, but the frequency is unknown. To approach this issue, we quantified the
incidence of second and third primary cancers in individuals from 24 Li-Fraumeni
kindreds originally diagnosed with cancer during the period from 1968 through
1986. METHODS: The relative risk (RR) of subsequent cancers and 95% confidence
intervals (CIs) were calculated by use of population-based incidence data from
the Connecticut Cancer Registry. Kaplan-Meier analysis was used to determine the
cumulative probability (+/- standard error) of subsequent cancers. RESULTS: Among
200 Li-Fraumeni syndrome family members diagnosed with cancer, 30 (15%) developed
a second cancer. Eight individuals (4%) had a third cancer, while four (2%)
eventually developed a fourth cancer. Overall, the RR of occurrence of a second
cancer was 5.3 (95% CI = 2.8-7.8), with a cumulative probability of second cancer
occurrence of 57% (+/- 10%) at 30 years after diagnosis of a first cancer. RRs of
second cancers occurring in families with this syndrome were 83.0 (95% CI = 36.9
187.6), 9.7 (95% CI = 4.9-19.2), and 1.5 (95% CI = 0.5-4.2) for individuals with
a first cancer at ages 0-19 years, 20-44 years, and 45 years or more,
respectively. Thirty (71%) of 42 subsequent cancers in this group were component
cancers of Li-Fraumeni syndrome. CONCLUSIONS: Compared with the general
population, members of Li-Fraumeni syndrome families have an exceptionally high
risk of developing multiple primary cancers. The excess risk of additional
primary cancers is mainly for cancers that are characteristic of Li-Fraumeni
syndrome, with the highest risk observed for survivors of childhood cancers.
Cancer survivors in these families should be closely monitored for early
manifestations of new cancers.
PMID- 9554444
TI - Oral transmucosal fentanyl citrate: randomized, double-blinded, placebo
controlled trial for treatment of breakthrough pain in cancer patients.
AB - BACKGROUND: Patients with cancer frequently experience episodes of acute pain,
i.e., breakthrough pain, superimposed on their chronic pain. Breakthrough pain is
usually treated with short-acting oral opioids, most of which provide some relief
after 15-20 minutes, with peak effects after 30-45 minutes. Oral transmucosal
fentanyl citrate (OTFC), a unique formulation of the opioid fentanyl, has been
shown to provide meaningful pain relief within 5 minutes in patients following
surgery. We conducted a multicenter, randomized, double-blinded, placebo
controlled trial of OTFC for cancer-related breakthrough pain. METHODS: Patients
who were 18 years of age or older, receiving the equivalent of at least 60 mg
oral morphine or at least 50 microg transdermal fentanyl per day for chronic
cancer-related pain, and experiencing at least one episode of breakthrough pain
per day were studied. After titration to an effective OTFC dose, subjects were
given 10 randomly ordered treatment units (seven OTFC units and three placebo
units) in the form of identical lozenges. If acceptable pain relief was not
achieved within 30 minutes, subjects were instructed to take their previous
breakthrough pain medication (i.e., rescue medication). Pain intensity, pain
relief, and use of rescue medication were evaluated at 15-minute intervals over a
60-minute period. RESULTS: Eighty-nine of 92 patients who received the randomized
treatment were assessable (i.e., treated with at least one unit of OTFC and one
unit of placebo). OTFC produced significantly larger changes in pain intensity
and better pain relief than placebo at all time points (two-sided P<.0001).
Episodes treated with placebo required the use of rescue medication more often
than episodes treated with OTFC (34% versus 15%; relative risk = 2.27; 95%
confidence interval = 1.51-3.26; two-sided P<.0001). CONCLUSIONS: OTFC appears
effective in the treatment of cancer-related breakthrough pain.
PMID- 9554445
TI - Human leukocyte antigen class II alleles associated with human T-cell
lymphotropic virus type I infection and adult T-cell leukemia/lymphoma in a Black
population.
AB - BACKGROUND: Human T-cell lymphotropic virus type I (HTLV-I) is linked to adult T
cell leukemia/lymphoma (ATL) and HTLV-I-associated myelopathy (HAM; also known as
tropical spastic paraparesis [TSP]), a chronic neurodegenerative disorder.
Worldwide, several million HTLV-I carriers are at risk for disease, with an
estimated lifetime cumulative risk of 1%-5%. However, the determinants of disease
progression are relatively unknown. We studied human leukocyte antigens (HLA
class II) that have been implicated in the pathogenesis of HTLV-I-related
diseases. METHODS: We analyzed HLA class II alleles among asymptomatic HTLV-I
carriers (n = 45), patients with ATL (n = 49) or HAM/TSP (n = 54), and HTLV-I
seronegative control subjects (n = 51). All participants were of African descent
and were enrolled in epidemiologic studies conducted at the University of the
West Indies, Kingston, Jamaica. We used standard microlymphocytotoxicity assays
for HLA antigen serotyping and polymerase chain reaction-based methods to examine
HLA class II DRB1 and DQB1 alleles. RESULTS: Two antigens determined by
serotyping, DR15 and DQ1, occurred at significantly increased frequency among
HTLV-I carriers compared with seronegative control subjects (42% versus 22% for
DR15 [odds ratio [OR] = 2.7; 95% confidence interval [CI] = 1.0-7.2] and 78%
versus 53% for DQ1 [OR = 3.1; 95% CI = 1.2-8.5]). Asymptomatic carriers were
shown to have an HLA class II allele distribution similar to that of patients
with ATL, and the frequencies of the alleles DRB1*1501, DRB1*1101, and DQB1*0602
were significantly greater in patients with ATL and asymptomatic carriers than in
patients with HAM/TSP. In addition, haplotypes DRB1*1101-DQB1*0301 and DRB1*1501
DQB1*0602 were significantly increased among patients with ATL compared with
patients with HAM/TSP. CONCLUSIONS: These data suggest that host genetic
background is an important factor in determining whether HTLV-I carriers develop
either ATL or HAM/TSP.
PMID- 9554446
TI - Detection of mutations associated with colorectal cancer in DNA from whole-gut
lavage fluid.
PMID- 9554447
TI - Re: Biology of cachexia.
PMID- 9554448
TI - Chemo-hormonal therapy of breast cancer: lack of interaction between lab and
clinic.
PMID- 9554449
TI - Re: Dietary modulation of omega-3/omega-6 polyunsaturated fatty acid ratios in
patients with breast cancer.
PMID- 9554450
TI - Angioimmunoblastic lymphadenopathy with dysproteinemia: emphasis on pathogenesis
and treatment.
AB - Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is a rare
lymphoproliferative disorder characterized by diffuse lymphadenopathy, fever,
hepatosplenomegaly, hemolytic anemia, and polyclonal hypergammaglobulinemia.
Morphologically, the involved lymph nodes demonstrate complete effacement of the
normal architecture, prominent neovascularization and infiltration by
immunoblasts and plasma cells. Other terms that have been used to describe this
entity include diffuse plasmacytic sarcomatosis, immunoblastic lymphadenopathy,
lymphogranulomatosis X, and immunologic aberrations in idiopathic reticulosis.
Initially, AILD was thought to be a disease of B-cell origin that represented
reactive immune response to unknown stimulus and high potential for malignant
transformation. It is now evident that AILD in 80% of cases follows an aggressive
course with short median survival, especially, if complete response with
chemotherapy is not achieved. Immunologic and molecular studies have demonstrated
that the majority of AILD cases are T-cell clonal disorders. Despite the numerous
reports on the role of Epstein-Barr virus in this disorder, it is unknown whether
the presence of this virus is associated with the immune defect that accompanies
AILD, or whether it is a pathogenetic factor. In contrast to non-Hodgkin's
lymphomas, a stage is not usually assigned to the patient since the disease is
systemic in nature, subsequently, parameters such as extent of disease and tumor
bulk used to identify high-risk patients with non-Hodgkin's lymphomas, do not
appear to correlate with disease activity or prognosis in AILD. Treatment of AILD
has been unsatisfactory, with approximately 25% of patients achieving complete
and sustained remission when combined chemotherapy agents are used. This article
is devoted to a discussion of the different manifestations, suggested
pathogenesis, and treatment of AILD.
PMID- 9554451
TI - Effects of oxygen and carbon dioxide on mean cell volume.
AB - Changes in mean cell volume (MCV) following addition of CO2, O2 or both to venous
blood treated with ethylenediaminetetraacetic acid were studied in an attempt to
evaluate the effects of saturation with these gases. The MCV before the addition
was taken to be 100%. When CO2 was mixed with each of 353 samples, the mean
increase (+/- SD) was 6.10 +/- 1.72%. When O2 was added to 335 specimens, the
mean decrease was 1.42 +/- 0.96%. When first CO2 and then O2 was added to 266
samples, the mean change (the sum for each sample of the absolute value of the
increase plus that of the decrease) was 7.39 +/- 1.90%. Results of samples of
venous and arterial blood from 15 subjects were compared to check these
observations in vivo. The MCV of venous blood was always larger than that of
arterial blood.
PMID- 9554452
TI - Comparison of progenitor cell content in sequential peripheral blood progenitor
collections after mobilization with chemotherapy and granulocyte macrophage
colony-stimulating factor.
AB - Optimal timing of peripheral blood progenitor cell (PBPC) harvest to collect
maximal stem cell numbers is unknown. We assessed the progenitor cell content in
128 PBPC harvests from 21 patients primed with chemotherapy and granulocyte
macrophage-colony stimulating factor (GM-CSF) in relation to absolute neutrophil
count (ANC) at collection time. Samples were obtained by leukapheresis during
rebound from chemotherapy-induced neutropenia while receiving GM-CSF, and assayed
by flow cytometry for CD34+ and by colony assays for CFU-GM and BFU-E. The CD34+
cell concentrations per sample tended to be greater at an ANC < 1,000 mm3 and
decreased with rising ANC (p = 0.001). The CFU-GM and BFU-E concentrations per
sample remained relatively constant with rising ANC (p = 0.72, p = 0.90,
respectively). Total CD34+ cell number per harvest per kg slightly increased with
ANC levels (p = 0.044) whereas the total CFU-GM and the total BFU-E per kilogram
increased more modestly with rising ANC (p < 0.001, p < 0.001, respectively). We
conclude that after priming with chemotherapy and GM-CSF, PBPC could be collected
at different absolute neutrophil counts without greatly affecting total CD34+
cell numbers. The greater concentration of CD34+ progenitor cells at a lower ANC
together with the CFU-GM and BFU-E peaking with higher ANC suggest a less mature
progenitor cell population at lower ANC levels.
PMID- 9554453
TI - Thromboembolic events in beta thalassemia major: an Italian multicenter study.
AB - Thromboembolic (TE) events have been frequently reported in beta-thalassemic
patients in association with known risk factors such as diabetes, complex
cardiopulmonary abnormalities, hypothyroidism, liver function anomalies, and
postsplenectomy thrombocytosis. In a recent survey involving 9 Italian
thalassemic centers, we identified 32 patients with TE episodes in a total of 735
subjects, of whom 683 had thalassemia major and 52 thalassemia intermedia,
corresponding to 3.95 and 9.61%, respectively. There was a great variation in
localization: the main one (16/32) was CNS, with a clinical picture of headache,
seizures and hemiparesis. Other localizations were the pulmonary (3 patients),
mesenteric (1 patient) and portal (2 patients) sites. There were 6 cases of deep
venous thrombosis (2 in the upper limbs, 4 in the lower ones). Intracardiac
thrombosis was found in 2 subjects and clinical and laboratory signs of DIC were
observed in 2 others during pregnancy. Since our patients with TE events present
a statistically significantly higher incidence of associated dysfunction
(cardiomyopathy, diabetes, liver function anomalies, hypothyroidism) than those
without TE events (50 vs. 13.8%), we suggest close monitoring of those patients
who are at higher risk of developing TE events because of the presence of one or
more of these predisposing factors.
PMID- 9554454
TI - Six new Gaucher disease mutations.
AB - Six previously undescribed mutations were identified in 6 unrelated Gaucher
disease patients: 437C-->T (107Ser-->Leu), 593C-->T (159Pro-->Leu), 604C-->T
(163Arg-->Stop), 1138G-->A (341Ala-->Thr), 1214G-->A (366Ser-->Asn), 1294T-->A
(393Trp-->Arg). Five patients were compound heterozygotes and 1 patient was a
593T/593T homozygote. Four patients had type I Gaucher disease with mild clinical
phenotypes. Two other patients manifested central nervous system involvement
(type II and type III).
PMID- 9554455
TI - Overproduction of antiplatelet antibody against glycoprotein IIb after
splenectomy in a patient with Evans syndrome resulting in acquired
thrombasthenia.
AB - We treated a 33-year-old female with Evans syndrome. She received high dose gamma
globulin, prednisolone, and azathioprine, and her platelet count transiently
increased. After splenectomy, the platelet count markedly increased. However, the
bleeding tendency worsened and the bleeding time was prolonged. A platelet
defect, characteristic of thrombasthenia, was found. Antigen-captured ELISA and
Western blotting revealed that the patient's serum had an IgG autoantibody
against platelet membrane glycoprotein IIb and the patient's plasma inhibited
normal platelet aggregation. These findings suggest that overproduction of the
antiplatelet antibody is triggered by platelet recovery due to splenectomy and
affects platelet function resulting in acquired thrombasthenia.
PMID- 9554456
TI - Therapeutic efficacy of recombinant interferon-alpha in polycythaemia vera.
AB - The therapeutic efficacy of recombinant interferon-alpha (rIFN-alpha) has been
evaluated in 7 patients with polycythaemia vera (PV), diagnosed according to the
criteria of the Polycythemia Vera Study Group. Six complete responses and one
partial response were achieved. Pruritus significantly improved in 80% (4/5) of
the cases. Recombinant interferon-alpha had to be discontinued in 1 patient
because of grade 3-4 nephrotoxicity according to WHO criteria. rIFN-alpha therapy
significantly decreased the phlebotomy requirements and improved the mean
corpuscular volume, erythrocyte and platelet counts, pruritus complaints and the
degree of splenomegaly (p < 0.05). rIFN-alpha seems to be an effective treatment
modality for the myeloproliferation of PV and pruritus complaints.
PMID- 9554457
TI - Translocation t(1;10) (q21;q26) in a case of acute nonlymphocytic leukemia.
AB - Chromosome banding studies carried out on bone marrow cells from a 16 year-old
boy with an M1 acute nonlymphocytic leukemia (ANLL) revealed an unbalanced
translocation involving chromosomes 1 and 10: der(10) t(1;10) (q21;q26) that
results in a partial trisomy 1q between bands 1q21-1qter. Marker del(6)(q21) and
trisomies of chromosomes 18, 21 and 22 were also observed. To our knowledge, this
der(10) is the first to be reported in a patient with ANLL.
PMID- 9554458
TI - Recurrent breast relapses in a patient with acute lymphoblastic leukaemia
following allogeneic bone marrow transplantation.
AB - Isolated extramedullary relapse is very rare after allogeneic bone marrow
transplantation (BMT) in acute lymphoblastic leukaemia (ALL) and continues to be
a therapeutic problem. We report recurrent breast relapses in a patient with ALL
after allogeneic BMT. On both occasions, bone marrow cells were shown to be of
donor origin and masses disappeared after systemic chemotherapy. Treatment of the
isolated extramedullary relapse after allogeneic BMT is discussed.
PMID- 9554459
TI - Bone marrow dysplasia with basophilic cells in a patient with angiocentric
lymphoma.
AB - We report a 46-year-old man suffering from angiocentric lymphoma of the skin. On
admission, he had atypical cells rich in basophilic granules in the bone marrow
and peripheral blood, in addition to skin eruptions and bone marrow dysplasia.
Immediately after diagnosis, the patient was treated with multidrug combination
chemotherapy. At first, the chemotherapy markedly relieved the skin eruption and
bone marrow dysplasia, and atypical cells in the bone marrow and peripheral blood
disappeared rapidly. However, the disease gradually became resistant to
chemotherapy, resulting in a gradual deterioration of the skin eruption and bone
marrow dysplasia, and reappearance of atypical cells. The levels of serum
cytokines such as interleukin-4 and interleukin-6, and of soluble interleukin-2
receptor correlated well with the disease states. These results suggest that the
lymphoma cells directly or indirectly induce the production of these cytokines
and that a dysregulated cytokine network, which might be caused by lymphoma
cells, induces an increase in atypical cells.
PMID- 9554460
TI - Atypical spontaneous factor VIII inhibitor: specific diagnostics and therapy of
acute bleeding.
AB - Differentiation of rapidly binding coagulation factor inhibitors from
antiphospholipid antibodies is a challenge for the hemostaseologic laboratory,
especially with respect to the different therapeutic consequences. Several
immunological and functional assays for the diagnosis of these disorders have
been proposed. Here we report the clinical and laboratory findings of a 65-year
old man who developed severe bleeding after a tooth extraction. The process
leading to the diagnosis of a spontaneous atypical factor VIII inhibitor and the
value of different laboratory tests are discussed.
PMID- 9554461
TI - Phase I study of taxol in refractory acute myelogenous leukemias using a weekly
schedule.
PMID- 9554462
TI - Usefulness of determining reticulated and large platelets in idiopathic
thrombocytopenic purpura.
PMID- 9554463
TI - Pediatric endocrinology update: an overview. The essential roles of estrogens in
pubertal growth, epiphyseal fusion and bone turnover: lessons from mutations in
the genes for aromatase and the estrogen receptor.
AB - The goals of this presentation are to review the essential roles of aromatase,
estrogens and the estrogen receptor in pubertal growth. Estrogen deficiency due
to mutations in the aromatase gene (CYP19) and estrogen resistance due to
disruptive mutations in the estrogen receptor gene have no effect on normal male
sexual maturation in puberty. However, they lead to absence of the pubertal
growth spurt, delayed bone maturation, unfused epiphyses, continued growth into
adulthood and very tall adult stature in both sexes. Gonadotropin and androgen
levels are elevated in patients with either estrogen deficiency (aromatase
deficiency) or estrogen resistance (estrogen receptor mutation). Glucose
intolerance, hyperinsulinemia and lipid abnormalities are also present. Skeletal
integrity is compromised. Increased bone turnover, reduced bone mineral density
and osteoporosis develop in both sexes. Sexual orientation is appropriate in
males and females. In females, aromatase deficiency in the ovary causes pubertal
virilization and multicystic ovaries because of elevated gonadotropins and
androgens. Simultaneously, secondary sexual maturation fails to occur. Placental
aromatase deficiency results in virilization of the mother and her female fetus
because of the accumulation of potent androgens which are not converted to
estrogens. The male fetus has normal genitalia. In conclusion, estrogens are
essential for normal female secondary sexual maturation, bone maturation,
epiphyseal fusion, pubertal growth spurt and achievement of normal bone mineral
mass. Estrogens also influence insulin sensitivity and lipid homeostasis.
However, estrogens do not appear to be essential for fetal survival, placental
growth, or female sexual differentiation.
PMID- 9554464
TI - Genetic defects in the control of growth hormone secretion.
AB - Since growth hormone deficiency (GHD) causes short stature and metabolic
derangements, the processes which control its release are important
physiologically. These processes can be illuminated by an understanding of
genetically determined GHD. In 2 Indian Moslem cousins from a consanguineous
family, GHD resistant to growth hormone releasing hormone (GHRH) stimulation was
found. No mutations were found in the growth hormone gene (GH1) (J. Phillips).
The receptor for GHRH (GHRHR), implicated in the dwarfism of the little mouse,
thus becomes a candidate gene to explain their GHD. Amplification and sequencing
a region of GHRHR homologous to that mutated in the little mouse showed a
mutation (265G*T) leading to a stop codon at position 72 which would completely
prevent GHRHR expression. Subsequently, Maheshwari et al. found an identical
mutation in a multiplex kindred from Sindh, Pakistan, about 800 km from the place
of origin of our patients. GHD is more commonly caused by recessive or dominant
mutations of GH1. The latter are of great interest in understanding the mechanism
of GH secretion. In a large kindred with dominant GHD we found a heterozygous
666G*A mutation replacing of Arg with His at amino acid 183. We speculate that
the introduced histidine interferes with interactions necessary for correct GH
secretion.
PMID- 9554465
TI - Growth hormone therapy update in Thailand.
AB - There were 841 children in Thailand with growth hormone deficiency (GHD) from
January 1992 to 1996. Idiopathic isolated GHD was the major diagnosis. Only
40.19% received recombinant DNA human growth hormone (rhGH) treatment. Also
reported here is a 1-2 year study of rhGH therapy in 30 GH-deficient children (21
males, 9 females), aged (mean +/- SD) 10.41+/-3.16 years, and bone age 7.37+/
3.34 years. The height velocity 1 and 2 years posttreatment were 8.17+/-1.9 and
7.36+/-2.8 cm/year respectively, which were statistically significant compared to
pretreatment values of 3.91+/-1.09 cm/ year. Improved height SDS was observed at
the end of each treatment period. Thyroid function and glycosylated hemoglobin
tests were normal during the treatment period. There were no reports of side
effects.
PMID- 9554466
TI - Review on the physical growth in primates.
AB - J.M. Tanner concluded in 1962 that the growth velocity curve in body weight shows
two peaks in primates but only one peak in the other mammals, and that the first
peak in primates corresponds phylogenetically to the peak in the other mammals.
Many reports on the physical growth of primates have been accumulated in the past
70 years. Using some of them as a basis, the author illustrated the normative
velocity curves (increment curves) of the weight of monkeys, chimpanzees and
humans, and reconsidered Tanner's conclusion. However, there are still some as
yet obscure aspects to be interpreted in future.
PMID- 9554467
TI - The molecular basis of hypopituitarism.
AB - Pit-1 is a pituitary-specific transcription factor responsible for pituitary
development and hormone expression in mammals. My laboratory and others have
recently described several patients with combined pituitary hormone deficiency
(CPHD) due to point mutations in the pit-1 gene. In addition to pit-1, other
nuclear factors appear to be necessary for full expression of pituitary genes. A
zinc finger transcription factor, Zn-15, is responsible with pit-1 for
synergistic activation of the GH gene. The Pr1 gene is regulated synergistically
by pit-1 and the estrogen receptor. Finally, the pit-1 gene itself is regulated
by an enhancer element located > 10 kb upstream of the transcriptional start.
This element contains several pit-1 DNA binding sites and retinoic acid response
elements (RAREs). On one of these elements, pit-1 and RAR interact functionally
to mediate a synergistic response to RA. Recent data from our laboratory suggests
that RA induction of the pit-1 gene can be impaired by pit-1 gene mutations.
Study of pit-1 mutations and their diverse pathophysiological mechanisms should
increase our understanding of anterior pituitary gland development and gene
regulation in normal and disease states.
PMID- 9554468
TI - The role of the insulin-like growth factor system in the developing brain.
AB - Insulin-like growth factors (IGFs) play a central role in brain growth and
development, with IGF-1, its receptors and binding proteins (IGFBPs) being highly
expressed, particularly in the olfactory bulb (OB), representing a local
paracrine system. A potential role of IGFBPs in transporting and targeting IGFs
to their receptors is supported by the finding that abundant IGFBP-2 is
associated with cell surface proteoglycans. An OB organ culture system expressing
IGF-1 and IGFBPs represents an in vitro injury model. Although IGF-1 is potently
antiapoptotic for neurons and oligodendrocytes, marked gliosis and IGFBP-3
expression are seen, similar to in vivo injury responses, where intraventricular
injection of IGF-1 postinjury enhances neuronal survival by blocking apoptosis.
In contrast, des (1-3) IGF-1, which has low affinity for IGFBPs, is ineffective,
supporting a transport or receptor targeting role for local IGFBPs. We conclude
that the IGF system plays a crucial cell survival and growth role in the
developing and injured brain and that IGFs have significant therapeutic
potential.
PMID- 9554470
TI - Growth hormone therapy: a survey.
PMID- 9554469
TI - Short stature caused by a natural growth hormone antagonist.
AB - Severe short stature in a male child due to a single mutation in the GH-1 gene
was first reported in 1996 by Takahashi et al. [N Engl J Med 1996;334:432-436].
This missense mutation was predicted to convert codon 77 from arginine (R) to
cysteine (C). The child's chronological age was 4 years and 11 months, and his
bone age 2 years and 6 months, i.e., equal to only 51% of his chronological age.
Body proportions were normal except for the prominent forehead and saddle nose.
Pituitary size was normal on magnetic resonance imaging examinations. Serum IGF
1, IGFBP-3 and GHBP were all decreased or at the lower limit of the normal range.
Nocturnal urinary growth hormone (GH) excretion was high. Isoelectric focusing
analysis revealed the presence of an abnormal GH peak in addition to the normal
one. The R77C mutant GH possessed a 6 times greater affinity to GHBP than the
wild-type GH, and inhibited tyrosine phosphorylation in IM-9 cells 10 times more
potently than the wild-type GH, showing an antagonistic or a dominant negative
action. In agreement with the antagonistic property of the mutant GH exhibited,
the child did not show any increase in serum IGF-1 levels after exogenous hGH
administration. It should be noted that the child in this study is not a typical
case of Kowarski syndrome in which endogenous GH is found to be simply
bioinactive, as in the patient we recently described elsewhere. Therefore, this
patient's condition should be categorized as a new syndrome of short stature
caused by a natural GH antagonist.
PMID- 9554471
TI - Growth hormone insensitivity syndrome (Laron dwarfism).
PMID- 9554472
TI - Recombinant human growth hormone therapy in infants with chronic renal failure.
PMID- 9554473
TI - Free form of insulin-like growth factor-I in circulation is normal in children
with simple obesity.
PMID- 9554474
TI - IGF-1 generation test in non-growth hormone-deficient short children.
PMID- 9554475
TI - Turner syndrome in Taiwan.
PMID- 9554476
TI - The role of the GH-N gene abnormality in the development of growth hormone
deficiency.
PMID- 9554477
TI - Final height after long-term growth hormone treatment in Thai children with
Turner syndrome.
PMID- 9554478
TI - Growth hormone deficiency associated with pituitary stalk interruption syndrome.
PMID- 9554479
TI - FGFR3 gene mutations in transmembrane domain in Chinese achondroplasia and
hypochondroplasia patients.
PMID- 9554480
TI - Determining gene dosage.
PMID- 9554481
TI - Growth factor involvement in progression of prostate cancer.
AB - Understanding how the regulation of growth factor pathways alters during prostate
cancer (PC) progression may enable researchers to develop targeted therapeutic
strategies for advanced disease. PC progression involves the shifting of cells
from androgen-dependent growth to an androgen-independent state, sometimes with
the loss or mutation of the androgen receptors in PC cells. Both autocrine and
paracrine pathways are up-regulated in androgen-independent tumors and may
replace androgens as primary growth stimulatory factors in cancer progression.
Our discussion focuses on growth factor families that maintain homeostasis
between epithelial and stromal cells in the normal prostate and that undergo
changes as PC progresses, often making stromal cells redundant. These growth
factors include fibroblast growth factor, insulin-like growth factors, epidermal
growth factor, transforming growth factor alpha, retinoic acid, vitamin D3, and
the transforming growth factor beta families. We review their role in normal
prostate development and in cancer progression, using evidence from clinical
specimens and models of PC cell growth.
PMID- 9554482
TI - Determination of gene dosage at the PMP22 and androgen receptor loci by
quantitative PCR.
AB - Although many genetic diseases are caused by the presence of point mutations in
respective genes, an increasing number of diseases are known to be caused by gene
copy number changes. We report the development of a rapid and reliable PCR-based
method for quantitation of gene copy number with sufficient sensitivity to detect
single copy changes without the use of radioactive or fluorescent labeling. The
sensitivity of this technique has been demonstrated by the detection of the DNA
duplication or deletion occurring in two inherited peripheral neuropathies,
Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to
pressure palsies (HNPP), that are caused by a reciprocal duplication or deletion
event on chromosome 17p11.2-12. This method relies on the comparison of the
amount of PCR product generated from a potentially duplicated or deleted target
sequence with the amount of product generated from a disomic reference gene. The
value of this ratio (target PCR product:reference PCR product) indicates whether
the target sequence is duplicated, deleted, or unchanged. Using primers from
within a duplicated or deleted region (PMP22 gene and EW401) and from within a
reference region (NF1 gene), we tested 50 CMT1A, 30 HNPP, and 50 unaffected
individuals for the presence of a DNA duplication or deletion. TARGET: reference
ratios of 1.58, 1.02, and 0.56 were detected for the CMT1A, unaffected, and HNPP
groups, respectively. Thus, differentiation of the three groups of individuals
was on the basis of gene copy number. This technique was successfully used to
detect the difference in the X chromosome copy number between males and females
(target:reference ratios of 1.1 and 2.3, respectively). This approach to the
detection of DNA duplications and deletions is sensitive, accurate, and has
potential applications in the quantitation of changes in gene copy number
associated with diseases characterized by such chromosomal alterations.
PMID- 9554483
TI - Automated fluorescent analysis procedure for enzymatic mutation detection.
AB - The Enzymatic Mutation Detection (EMD) assay detects mutations or polymorphisms
in DNA. The assay procedure takes <1 h and is followed by electrophoretic
detection. We report an automated procedure, using fluorescently labeled probe
and quantitative analysis on the ABI Prism 377 DNA Sequencer, that improves on
earlier methods (1, 2) by eliminating the need for sample purification,
shortening the hybridization time, and increasing the signal-to-noise ratio. The
EMD assay uses the bacteriophage resolvase T4 endonuclease VII, which cleaves the
heteroduplex molecules at the mismatch site, forming two shorter fragments that
are resolved by gel electrophoresis. Unlike existing mutation techniques, the EMD
method uses a single protocol to identify point mutations, deletions, and
insertions for all DNA fragments. Test DNA samples are assayed directly from PCR
reactions, and fragments up to 4 kb in size have been assayed successfully. A
independent analysis on the p53 tumor suppressor gene from clinical samples has
shown 100% sensitivity and 94% specificity. Because the fluorescent EMD assay has
been optimized for high signal-to-noise ratios, mutations can be identified in
mixed samples containing up to a 20-fold excess of normal DNA.
PMID- 9554484
TI - Prenatal and postnatal diagnoses of thalassemias and hemoglobinopathies by HPLC.
AB - The conventional approach to qualitative and quantitative analyses of hemoglobin
(Hb) molecules for the diagnoses of hemoglobinopathies requires a combination of
tests. We used an automated HPLC (VARIANT) system to study alpha-thalassemia and
beta-thalassemia syndromes in Thailand. The beta-thalassemia short program is
applicable to the diagnosis of alpha-thalassemia and beta-thalassemia disorders,
including Hb H, EA Bart's disease, and EF Bart's disease, in adults, newborns,
and fetuses. The system cannot quantify accurately certain Hb molecules, such as
Hb H and Hb Bart's. The alpha-thalassemia short program was therefore developed
and used to quantify Hb Bart's to detect alpha-thalassemia genotypes in cord
blood. This automated HPLC system is an alternative approach to the diagnosis of
complicated thalassemia syndromes in Thailand and Southeast Asia.
PMID- 9554485
TI - Serum protein electrophoresis by CZE 2000 clinical capillary electrophoresis
system.
AB - We compared the automated Paragon 2000 clinical capillary zone electrophoresis
(CZE) system with two manual methods, agarose electrophoresis (AGE) and cellulose
acetate electrophoresis (CAE). Reference intervals in healthy adults were
determined for each method. When compared with AGE and CAE, CZE gave
substantially higher reference values for the alpha1-globulin fraction. With CZE,
within-run precision for fraction quantitation was between 0.5% (albumin) and
4.1% (alpha1-globulin). Total precision was between 0.8% (albumin) and 5.3% (beta
globulin). Data obtained from CZE showed poor linear correlation with results
obtained by AGE but good linear correlation with data from CAE. Analysis of serum
from patients with inter alia inflammation, nephrotic syndrome, or polyclonal
gammopathy showed that clinical information obtained by CZE is comparable with
information obtained by AGE and CAE. We conclude that CZE offers a clinically
reliable alternative to AGE and CAE and has the advantages of automation, higher
precision, and faster turnaround time.
PMID- 9554486
TI - Detection and classification of paraproteins by capillary
immunofixation/subtraction.
AB - A selection of 58 specimens with a monoclonal component identified by
immunoelectrophoresis and/or immunofixation was analyzed with the
immunosubtraction procedure on the Paragon 2000 capillary electrophoresis system.
The capillary system detected 93% of the paraproteins and, using
immunosubtraction, correctly identified 91% of the paraproteins. Paraproteins
that were detected by immunofixation and/or immunoelectrophoresis but not by
capillary electrophoresis were also missed by agarose electrophoresis and
cellulose acetate electrophoresis. Cellulose acetate electrophoresis was the
least sensitive method for detection of paraproteins. Only 74% of the monoclonal
components were detected by this technique, whereas 86% were revealed by agarose
electrophoresis. In addition to monoclonal paraproteins, we also studied biclonal
paraproteins and oligoclonal banding. Capillary electrophoresis and
immunosubtraction correctly detected and identified three specimens containing
biclonal paraproteins. In one specimen, capillary zone electrophoresis detected
only one band, whereas agarose gel electrophoresis detected two bands. The
sensitivity for detection and identification of oligoclonal banding by capillary
electrophoresis was inferior to immunofixation.
PMID- 9554487
TI - Multicenter evaluation of the Bayer Immuno I CA 15-3 assay.
AB - We conducted a multicenter evaluation of the analytical and clinical features of
the automated Bayer Immuno 1 CA 15-3 assay and compared assay performance to two
manual tests. Results of the 10-day imprecision study of the Bayer Immuno 1 assay
pooled across four evaluation sites and three lots of reagent produced total CV <
or = 4%. Lot-to-lot reproducibility for 26 different lots of reagents and
calibrators manufactured over a 2-year period was demonstrated (CV, 1.1%).
Results for the Bayer Immuno 1 assay correlated well with the Biomira TRUQUANT BR
27.29 and Centocor CA 15-3 RIAs (r > or = 0.94). The upper limit of the reference
interval for the Bayer Immuno 1 assay was 35.9 kilounits/L (35.9 units/mL);
values were similar for all methods. Longitudinal monitoring of healthy women
yielded assay values with an average CV of 11% and 21% for the Bayer Immuno 1 and
Biomira assays, respectively. The Bayer Immuno 1 assay demonstrated the
analytical features, intermethod correlation, and long-term performance
characteristics that are essential for longitudinal monitoring of breast cancer
patients.
PMID- 9554488
TI - A competitive reverse transcription-PCR to study apolipoprotein epsilon gene
expression.
AB - We developed a rapid and simple competitive reverse transcription-polymerase
chain reaction for the quantification of apo epsilon mRNA in human monocyte
derived macrophages. The method was applied, and its reliability was shown in
patients with the familial lipoprotein disorder, type III hyperlipoproteinemia.
Type III hyperlipoproteinemic patients express markedly higher concentrations of
apo epsilon mRNA when compared with healthy controls. Patients with this disease
are usually (>90%) homozygous for a receptor binding-defective isoform of
apolipoprotein apo E (apo E2). The higher expression of apo epsilon mRNA in the
patients could, therefore, be a physiological mechanism to compensate for
functionally defective apo E. The developed procedure might be valuable in
assessment of apo epsilon gene expression in human disease.
PMID- 9554489
TI - Reference standardization and triglyceride interference of a new homogeneous HDL
cholesterol assay compared with a former chemical precipitation assay.
AB - A homogeneous HDL-c assay (HDL-H), which uses polyethylene glycol-modified
enzymes and sulfated alpha-cyclodextrin, was assessed for precision, accuracy,
and cholesterol and triglyceride interference. In addition, its analytical
performance was compared with that of a phosphotungstic acid (PTA)/MgCl2
precipitation method (HDL-P). Within-run CVs were < or = 1.87%; total CVs were <
or = 3.08%. Accuracy was evaluated in fresh normotriglyceridemic sera using the
Designated Comparison Method (HDL-H = 1.037 Designated Comparison Method + 4
mg/L; n = 63) and in moderately hypertriglyceridemic sera by using the Reference
Method (HDL-H = 1.068 Reference Method - 17 mg/L; n = 41). Mean biases were 4.5%
and 2.2%, respectively. In hypertriglyceridemic sera (n = 85), HDL-H
concentrations were increasingly positively biased with increasing triglyceride
concentrations. The method comparison between HDL-H and HDL-P yielded the
following equation: HDL-H = 1.037 HDL-P + 15 mg/L; n = 478. We conclude that HDL
H amply meets the 1998 NCEP recommendations for total error; its precision is
superior compared with that of HDL-P, and its average bias remains below +/-5% as
long as triglyceride concentrations are < or = 10 g/L and in case of moderate
hypercholesterolemia.
PMID- 9554490
TI - Analytical approaches of European Union laboratories to drugs of abuse analysis.
AB - We report a survey on urine drug testing within a total of 269 laboratories of
the European Union. Clinical laboratories predominated over forensic laboratories
(59.5% vs 28.5%). Screening without identification/quantification was the common
approach used by clinical laboratories, whereas screening with
identification/quantification was the approach used by almost all forensic
laboratories. Screening was primarily performed by immunoassay in both types of
laboratories. Gas chromatography coupled to mass spectrometry was the main
analytical method used for specific identification/quantification of drugs, but
other methods (including immunoassays) were also used. Cutoff values applied
varied by laboratory type, country, and method used. A high percentage of
laboratories did not use or report cutoff values. Overall, countries of the
European Union vary significantly in regards to drugs tested, analytical
approach, and screening and identification cutoff values. It is recommended to
clearly state the analytical method and the cutoff values used when reporting
results for drugs of abuse testing.
PMID- 9554491
TI - Zinc protoporphyrin as screening test in female blood donors.
AB - Erythrocyte zinc protoporphyrin (ZPP) was measured in 102 women blood donors to
evaluate its usefulness in screening for evolving iron deficiency anemia, a
reason for the deferral of donors. The results were compared with serum ferritin
determinations. Five women were deferred before their first donation and eight
women were deferred after one or two donations. Women with increased ZPP values
all had low serum ferritin concentrations, indicating iron-deficient
erythropoiesis that was caused by iron depletion. The positive predictive value
of an increased ZPP in predicting deferral of the donor after one or two
donations was 75%, whereas a serum ferritin concentration < or = 12 microg/L
predicted deferral in 26% of the donors. The results indicate that the ZPP test
can be recommended as a feasible and inexpensive predonation test to determine a
subset of donors with iron-deficient erythropoiesis at risk of developing iron
deficiency anemia.
PMID- 9554492
TI - A non-(1-84) circulating parathyroid hormone (PTH) fragment interferes
significantly with intact PTH commercial assay measurements in uremic samples.
AB - We have previously shown that the Nichols assay for intact parathyroid hormone (I
PTH) reacts with a non-(1-84) molecular form of PTH. This form behaves as a
carboxy-terminal fragment and accumulates in renal failure, accounting for 40-60%
of the measured immunoreactivity. We wanted to see whether this was a common
event with other commercial two-site I-PTH assays. We thus compared the ability
of three commercial kits [Nichols (NL), Incstar (IT), and Diagnostic System
Laboratories (DSL)] to measure I-PTH in 112 renal failure patients and to detect
hPTH(1-84) and non-(1-84)PTH on HPLC profiles of serum pools from uremic patients
with I-PTH concentrations of 10-100 pmol/L. The behavior of synthetic hPTH(7-84),
a fragment possibly related to non-(1-84)PTH was also compared with hPTH(1-84) in
the three assays. The I-PTH concentrations measured with the three assays in the
112 uremic samples were highly related (r2 > or = 0.89, P < 0.0001), and the
values measured with NL were, on average, 23% higher than IT. Values measured
with DSL were 23% and 56% higher than IT for values less than and more than 40
pmol/L, respectively. The three assays detected two HPLC peaks on four different
profiles corresponding to hPTH(1-84) and non-(1-84)PTH. This last peak
represented 36 +/- 8.4% of the immunoreactivity with NL, 24 +/- 5.5% with IT, and
25 +/- 2.8% with DSL (NL vs IT or DSL: P < 0.05). These differences were
confirmed by a 50% lower immunoreactivity to hPTH(7-84) compared with hPTH(1-84)
for IT and DSL but not for NL. These results suggest that most of the two-site I
PTH assays would cross-react with non-(1-84)PTH material, thus explaining about
one-half of the 2-2.5 x higher I-PTH concentrations reported in uremic patients
without bone involvement than in subjects without uremia.
PMID- 9554493
TI - Determination of free and total carnitine with a random-access chemistry
analyzer.
AB - Carnitine deficiency presents as a major problem in fatty acid oxidation. The use
of a plasma carnitine assay can rapidly help to describe this deficiency. The
method we describe here requires two simple steps of sample preparation, followed
by automated analysis with the Beckman Synchron CX4 random-access chemistry
analyzer. The goal of this method development was to reduce the cost of analysis
and to allow a greater number of laboratories to perform this assay on demand
within 1 h for both free and total carnitine. The method has a linearity of 0-150
micromol/L and a detection limit of 5 micromol/L. The inter- and intraday CVs are
<20%. The method agreed closely with both the widely used RIA and
spectrophotometric methods.
PMID- 9554494
TI - Direct determination of urinary iodine by inductively coupled plasma mass
spectrometry using isotope dilution with iodine-129.
AB - An inductively coupled mass spectrometric method was developed for the direct
determination of iodine in urine. The application of isotope dilution analysis
with added 129I offers new possibilities for automatic and accurate
determinations. The sample preparation consists of dilution with an ammonia
solution containing 129I. The validation was made by comparison with the results
obtained in another laboratory by a spectrophotometric method based on the
Sandell-Kolthoff reaction. Different regression models, including maximum
likelihood estimation, were used to compare the methods. None of the models
revealed analytical bias between the two methods. The urine samples analyzed for
validation were from three persons previously exposed to an iodine bath and
covered a concentration range of 0.2 to 2.8 micromol/L. A detection limit of 0.02
micromol/L, a within-run CV of 2.5%, and a between-run CV of 11.9% were estimated
for the proposed method.
PMID- 9554495
TI - Fully automated assay for total homocysteine, cysteine, cysteinylglycine,
glutathione, cysteamine, and 2-mercaptopropionylglycine in plasma and urine.
AB - We describe a 6-min HPLC method to measure the total concentrations of the most
important thiols in plasma and urine--cysteine, homocysteine, cysteinylglycine,
and glutathione--as well as the concentrations in plasma and urine, respectively,
of cysteamine and 2-mercaptopropionylglycine, two compounds used to treat
disorders of cysteine metabolism. Precolumn derivatization with bromobimane and
reversed-phase HPLC were performed automatically by a sample processor.
Throughput was up to 100 samples in 24 h. The within-run CV ranged from 0.9% to
3.4% and the between-run CV ranged from 1.5% to 6.1%. Analytical recovery was 97
107%, with little difference between plasma and urine samples. The detection
limit was approximately 50 nmol/L for all the analytes studied. Thiol
concentrations were determined in the plasma of 206 healthy donors and in the
urine of 318 healthy donors distributed for age and sex. Mean values of plasma
cysteine and homocysteine were significantly lower in infants (ages, <1 y)
compared with other age groups (P <0.005). In adults, mean plasma homocysteine
values were higher in males than in females (9.2 vs 6.7 micromol/L, P <0.0001)
and in the 6- to 10-year-old group (P <0.05). Mean values for glutathione and
cysteinylglycine were not sex- and age-dependent. In urine, both cysteine and
homocysteine showed a wide range of variation.
PMID- 9554496
TI - Clinical laboratory test menu changes in the Pacific Northwest: 1994 to 1996.
AB - Laboratory testing services are presently undergoing dynamic changes in response
to a wide range of external factors. Government regulations, reimbursement, and
managed care are only a few of the influences affecting the availability of
testing services and on-site testing capabilities in hospital, independent, and
physician office laboratories. Medical practice changes, marketplace influences,
test technologies, and costs also play a role in determining where testing is
being performed. To better understand the factors influencing clinical laboratory
test volumes and menus and to identify on-site testing deemed essential in
physician office laboratories, we gathered information from a network of clinical
laboratories in the Pacific Northwest. Questionnaires were sent to 257 Laboratory
Medicine Sentinel Monitoring Network participants in March 1996. In the past 2
years, changes in on-site test volumes and test menus have been primarily due to
medical practice changes and marketplace influences. When laboratories had a
decrease in test volumes or test menu choices, the size of the patient workload
and the volumes of test orders have had the greatest impact. Laboratory
regulations and managed care contracts have played a role in shifting on-site
testing to outside sources; however, these factors did not appear to be primary
influences. Only 5% of physician office laboratories identified tests that they
believed were essential for optimal patient care but did not perform on-site.
PMID- 9554497
TI - A stochastic approximation method for assigning values to calibrators.
AB - A new procedure is provided for transferring analyte concentration values from a
reference material to production calibrators. This method is robust to
calibration curve-fitting errors and can be accomplished using only one
instrument and one set of reagents. An easily implemented stochastic
approximation algorithm iteratively finds the appropriate analyte level of a
standard prepared from a reference material that will yield the same average
signal response as the new production calibrator. Alternatively, a production
bulk calibrator material can be iteratively adjusted to give the same average
signal response as some prespecified, fixed reference standard. In either case,
the outputted value assignment of the production calibrator is the analyte
concentration of the reference standard in the final iteration of the algorithm.
Sample sizes are statistically determined as functions of known within-run signal
response precisions and user-specified accuracy tolerances.
PMID- 9554498
TI - Intrinsic and routine quality of serum total potassium measurement as
investigated by split-sample measurement with an ion chromatography candidate
reference method.
AB - We evaluated the intrinsic quality of eight routine test systems for the
measurement of serum total potassium (K+), as well as the routine quality of four
of these systems, using a group of 60 single-donation serum samples that had been
certified with an ion chromatography reference method. The intrinsic quality of
the tests was evaluated by analysis of the sera in the manufacturers' application
laboratories under strict internal quality control. The routine quality was
evaluated by analysis of the same sera in five (per system) routine laboratories
under daily working conditions. The results of the study were interpreted in
light of the most stringent specifications derived from the biological variation
of K+, which require limits of 6.3% for total error and 1.6% for systematic
error. The study revealed that the intrinsic quality of all systems was
excellent. None of the test systems yielded a substantial number of results
outside the 6.3% total error limit, and only one test system exceeded the 1.6%
systematic error limit. The majority of the routine laboratories reproduced the
manufacturers' intrinsic quality. In particular, most laboratories satisfied the
6.3% total error limit. However, several laboratories exceeded the 1.6%
systematic error limit. Generally, there was a considerable difference in quality
between the participating laboratories. This showed that the major problems for
serum K+ analysis (for samples with no unusual matrices and with concentrations
within the reference interval) are at the routine laboratory.
PMID- 9554499
TI - Serum kynurenine-to-tryptophan ratio increases with progressive disease in HIV
infected patients.
AB - An alternative pathway of Trp metabolism involves the conversion of Trp to
kynurenine by indoleamine-2,3-dioxygenase, which leads to synthesis of the
neurotoxin, quinolinic acid. This study explores the relationship of indoleamine
2,3-dioxygenase activity with stages of HIV infection. Sera from 206 HIV-positive
and 72 seronegative subjects were analyzed for Trp and kynurenine. The kynurenine
to-Trp (KT) ratio was calculated. The mean KT ratio of seronegative controls was
36.6 +/- 10.9, and the median ratio was 34.9. The upper limit of the seronegative
KT ratio, defined as mean + 2 SD, was 58.4. Patients with HIV infection showed a
reciprocal relationship between the KT ratio, the CD4 count, and the stage of the
disease. The median KT ratios for asymptomatic and AIDS patients were 50.5 and
117.0, respectively. This study shows that the serum Trp concentration is
markedly decreased and that the kynurenine concentration is increased with immune
stimulation in HIV infection. This may lead to changes in quinolinic acid and
explain some of the pathogenesis of AIDS dementia.
PMID- 9554500
TI - Evaluation of an acidic deproteinization for the measurement of ascorbate and
dehydroascorbate in plasma samples.
AB - The most popular pretreatment method of plasma samples for the measurement of
ascorbate (AsA) and dehydroascorbate (DHA) has been an acidic deproteinization
via metaphosphoric acid or trichloroacetic acid. In general, DHA is absent in
plasma samples prepared from human blood in a conventional manner. However, when
these plasma samples were subjected to acidic deproteinization, DHA was detected
in the acidified sample solutions. In the present study, we demonstrate that the
oxidation of AsA to DHA in the solutions was promoted by at least two mechanisms,
one involving catalysis by ferric ion released from transferrin, and the other
involving catalysis by plasma hemoglobin. In the acidified transferrin solution
by trichloroacetic acid, an oxidation of AsA to DHA proceeded with standing time,
whereas the oxidation was not observed in that by metaphosphoric acid. This
oxidation appeared to be catalyzed by ferric ion released from transferrin. In
contrast, plasma hemoglobin functioned as a catalyst for AsA oxidation in both
metaphosphoric acid and trichloroacetic acid solutions. Therefore, DHA content in
the trichloroacetic acid-treated plasma sample was markedly higher than that in
the metaphosphoric acid-treated one. These results suggest that DHA detected in
acidified plasma samples is an artifact resulting from AsA oxidation.
PMID- 9554501
TI - Simple DNA probe assays based on particle agglutination.
PMID- 9554502
TI - Evaluation of proficiency survey results for serum immunoglobulins following the
introduction of a new international reference material for human serum proteins.
PMID- 9554503
TI - PCR conditions and DNA denaturants affect reproducibility of single-strand
conformation polymorphism patterns for BRCA1 mutations.
PMID- 9554504
TI - Measurements of total and desialylated sex hormone binding globulin in serum by
ELISA.
PMID- 9554505
TI - The use of a whole-blood benchtop analyzer (Nova 16) in a cardiac STAT intensive
care unit.
PMID- 9554506
TI - Rapid and sensitive gas chromatography-mass spectroscopy method for the detection
of mannitol and sorbitol in serum samples.
PMID- 9554507
TI - Measurement of the total antioxidant activity of human aqueous humor.
PMID- 9554508
TI - Cardiac troponin I in myocardial contusion.
PMID- 9554509
TI - Combined use of markers of muscle necrosis and fibrinogen conversion in the early
differentiation of myocardial infarction and unstable angina.
PMID- 9554510
TI - More on interference of N-acetylcysteine in measurement of acetaminophen.
PMID- 9554511
TI - Toxic levels of acetaminophen produce a major positive interference on Glucometer
Elite and Accu-chek Advantage glucose meters.
PMID- 9554512
TI - Why "urea nitrogen" when urea is measured?
PMID- 9554513
TI - Total and non-protein-bound fractions of 3,4-dihydroxyphenylalanine.
PMID- 9554514
TI - PSA concentrations in seminal plasma.
PMID- 9554515
TI - Inadequate laboratory technique for amino acid analysis resulting in missed
diagnoses of homocystinuria.
PMID- 9554516
TI - Early historical milestones in HDL-cholesterol assay.
PMID- 9554517
TI - Utilization of polymerase chain reaction technology in the detection of solid
tumors.
AB - BACKGROUND: Most cancer detection tests currently performed are based on either
antibody assays to a marker protein with altered expression in cancer patients or
on imaging studies to identify characteristic lesions. Generally, for a positive
result, these detection assays require that a tumor have a significant volume of
cancer cells. Advances in diagnostic techniques and technology may allow for
cancer detection at earlier stages, when the tumor burden is smaller and
potentially more curable. The molecular techniques of polymerase chain reaction
(PCR) and reverse transcriptase PCR (RT-PCR) are highly sensitive methods for
detecting a small number of cancer cells. Over the past few years, numerous
clinical studies have used PCR techniques to detect physical alterations of
genes, such as mutations, deletions, translocations and amplification, the
presence of oncogenic viruses, and the expression of genes specific to tissue,
cancer, and metastasis. The current status of PCR as a method for detecting
marker genes in the management of solid tumors is reviewed. METHODS: A review of
the literature on the clinical utility of PCR and RT-PCR in the detection of
solid tumor micrometastasis was conducted. RESULTS: Amplification by PCR is a
highly sensitive method to determine gene expression. A single cell expressing a
tumor marker among 10-100 million lymphocytes can be detected by the PCR assay.
This approach has been used to detect tumor cells in approximately 18 different
solid tumor types, with melanoma and carcinoma of the breast and prostate the
most widely investigated to date. PCR-based assays have been used to detect
cancer cells in biopsies of solid tissue, lymph nodes, bone marrow, peripheral
blood, and other body fluids. Several studies have reported a high specificity
and sensitivity of tumor marker detection and a high correlation between PCR
results and the presence of metastatic disease. However, in a few studies, PCR
assays have not consistently demonstrated a higher sensitivity and specificity of
detection than traditional modalities for many types of cancer. There has been a
wide range in sensitivity and specificity among the studies, which may be partly
attributed to the lack of uniformity among the PCR protocols used in different
studies. CONCLUSIONS: PCR can detect tumor marker-expressing cells that are
otherwise undetectable by other means in patients with localized or metastatic
cancer. Reports from various study groups have lacked uniformity in their
protocols, and this has prevented adequate comparison. The clinical utility of
this assay as a tool for the prognosis and management of cancer patients remains
and area of active investigation. PCR is a powerful tool in the study of the
biology of cancer metastasis and will likely serve as a useful adjunct to
clinical decision-making in the future.
PMID- 9554518
TI - Tumor thickness predicts cervical metastasis in patients with stage I/II
carcinoma of the tongue.
AB - BACKGROUND: The incidence of cervical metastases after surgery for Stages I/II
carcinoma of the tongue is 30-40%. Postoperative cervical metastases are an
adverse prognostic factor for patients with this malignancy. The purpose of this
study was to evaluate the clinicopathologic factors associated with late cervical
metastases in patients with carcinoma of the tongue. METHODS: The
clinicopathologic features of 44 patients with previously untreated Stage I/II
carcinoma of the tongue were reviewed. All patients were treated with partial
glossectomy only. RESULTS: Cervical metastases developed in 21 of 44 patients
within 5 years. Factors significantly associated with the development of cervical
metastases were invasive growth, differentiation, nuclear polymorphism in the
deep portion, tumor border, nest formation, infiltrative growth ratio, depth, and
thickness. No statistical correlations between cervical metastases and age,
gender, tumor location, clinical stage, Brinkman index, alcohol index, mitosis,
connective tissue, lymphocytic infiltration, or perineural invasion were found.
Multivariate analysis demonstrated that only tumor thickness > 4 mm had a
predictive value for cervical metastasis (risk ratio 9.4; 95% confidence
interval, 1.5-57.7). CONCLUSIONS: The current study data indicate that patients
with Stage I/II carcinoma of the tongue > 4 mm in thickness are at increased risk
for subsequent cervical metastasis. Thus, conservative supraomohyoid neck
dissection is indicated in patients with Stage I/II carcinoma of the tongue > 4
mm in thickness.
PMID- 9554519
TI - Epstein-Barr virus detection in nasopharyngeal tissues of patients with suspected
nasopharyngeal carcinoma.
AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) is strongly associated with Epstein
Barr virus (EBV). Detection of EBV in biopsy specimens may serve as a tumor
marker. METHODS: To assess the sensitivity and specificity of the polymerase
chain reaction (PCR) and in situ hybridization in the diagnosis of NPC, formalin
fixed, paraffin embedded nasopharyngeal biopsies from patients in Taiwan
suspected of having NPC were studied. RESULTS: In specimens from 107 patients
with NPC, EBV was detected by PCR in 97 cases (90.7%) and by EBER in situ
hybridization in 105 cases (98.1%). In specimens from 61 patients without
neoplasia, EBV was detected by PCR in 7 cases (11.5%) and by EBER in situ
hybridization in 0 cases. CONCLUSIONS: These results suggest that although EBV
DNA may occasionally be detected in nonneoplastic nasopharyngeal tissues, cells
expressing EBER are not. EBER in situ hybridization may therefore prove to be a
useful adjunct in the diagnosis of NPC.
PMID- 9554520
TI - The clinicopathologic significance of small areas unstained by Lugol's iodine in
the mucosa surrounding resected esophageal carcinoma: an analysis of 147 cases.
AB - BACKGROUND: Small areas unstained with Lugol's iodine are often observed in the
mucosa surrounding esophageal carcinomas. METHODS: For light microscopic
evaluation, the histologic features of 131 small areas unstained by Lugol's
iodine in 12 selected cases were investigated. For clinicopathologic evaluation,
the numbers of small areas unstained by Lugol's iodine in the mucosa surrounding
147 consecutively resected esophageal carcinomas, including these 12 cases, were
counted. The relation between the incidence of such areas and the development of
multiple primary cancers in the upper aerodigestive tract was examined together
with data on the patients' tobacco and alcohol consumption. RESULTS: Ninety-two
percent (131) of the small areas unstained by Lugol's iodine contained dysplastic
lesions. Seventeen (12%) of the 147 resected specimens contained fewer than 5
small unstained areas, whereas 52 (35%) had 6-10 and 78 (53%) had more than 11
such areas. The incidence of multicentric cancer in the upper aerodigestive tract
and the average alcohol index scores were significantly higher for patients who
had more than 11 unstained areas than for patients who had fewer than 5 such
areas (P < 0.01). CONCLUSIONS: Lugol's iodine staining method is useful for
detecting groups at high risk of multicentric cancer in the upper aerodigestive
tract.
PMID- 9554521
TI - Treatment of patients with advanced gastric carcinoma with a 5-fluorouracil-based
or a cisplatin-based regimen: two parallel randomized phase II studies.
AB - BACKGROUND: Although many drug combination therapies have been proposed, there is
no standard therapy for patients with advanced gastric carcinoma. The superiority
of combination therapy over monochemotherapy has not been demonstrated
convincingly. To explore the role of monochemotherapy, the authors evaluated 5
fluorouracil (5-FU), modulated by 6S-leucovorin (6S-LV) and a cisplatin
containing regimen, which was comprised of epirubicin, etoposide, and cisplatin
with the addition of the reversal agent lonidamine (EEP-L). METHODS: After
stratification according to performance status (PS) and resection of the primary
tumor, 72 patients with advanced gastric carcinoma were randomized to 2 parallel
Phase II trials with 5-FU/6S-LV and EEP-L, respectively. Thirty-six patients in
Study A received bolus 6S-LV, 100 mg/m2, followed by bolus 5-FU, 370 mg/m2, on
Days 1-5 and 36 others in Study B received epirubicin, 30 mg/m2, on Days 1 and 5;
etoposide, 100 mg/m2, on Days 1, 3, and 5; cisplatin, 30 mg/m2, on Days 2 and 4;
and lonidamine, 150 mg/day. RESULTS: There were 6 partial responses (18.2%) (95%
confidence interval [CI] +/- 13.2) in Study A and 7 partial responses (21.9%)
(95% CI +/- 14.3) in Study B. Partial responses were more frequent in patients
with resected tumors or with an Eastern Cooperative Oncology Group PS of 0-1. The
median duration of response was 8.8 and 8.3 months, respectively, in Study A and
Study B. The median survival reached 8 months in Study A and 9 months in Study B.
In the whole population of patients survival was significantly higher in patients
with a PS of 0-1 (P < 0.05). Patients with a PS of 0-1 and a resected tumor had
the significantly longest survival both in EEP-L treated patients and in all
evaluable patients in the two studies. The most frequent World Health
Organization Grade 3-4 toxic effects were gastrointestinal in Study A and
hematologic in Study B. No treatment-related death was observed. CONCLUSIONS: The
efficacy of 5-FU, modulated with 6S-LV, is moderate in patients with advanced
gastric carcinoma, similar to cisplatin-containing regimens. PS and other
prognostic factors could influence the response rate, which does not appear to be
a reliable parameter for evaluating the outcome of chemotherapy trials.
PMID- 9554522
TI - Interrelation between tumor-associated cell surface glycoprotein and host immune
response in gastric carcinoma patients.
AB - BACKGROUND: Expression of changes in cell surface glycoprotein may correlate with
the malignant potential and development of gastric carcinoma. Immunologic defense
mechanisms of the host against the tumor can be effective in preventing the
development of gastric carcinoma. The authors studied the effects of immunologic
defense of the host against the tumor, using infiltration of S-100 protein
positive dendritic cells (DC) as a marker. In cases with or without changes in
the surface glycoprotein of tumor cells, determinations were made by binding of
Helix pomatia agglutinin (HPA). METHODS: Paraffin blocks of 123 gastric carcinoma
specimens were prepared for immunohistochemical staining with the antibody
against HPA and S-100 protein. Clinicopathologic factors and patient prognosis
were examined for each indicator. RESULTS: Patients with HPA positive tumors had
a more aggressive character in several important prognostic aspects and poorer 5
year survival rates compared with patients with HPA negative tumors. The degree
of infiltration of DC had no particular correlation with pathologic factors, and
there was no significant difference between the prognosis of patients with slight
and marked DC infiltration. In the HPA negative patients there was no significant
difference in the 5-year survival rates between patients with slight and marked
DC infiltration; however, in the HPA positive patients the 5-year survival rates
of patients with marked infiltration of DC were higher. Further investigation
showed that patients with marked DC infiltration had better 5-year survival rates
than patients with slight DC infiltration, especially in patients with HPA
positive and histologically advanced disease. CONCLUSIONS: Patients with a higher
immunologic defense against cancer cells, as indicated by marked infiltration of
DC, had a better prognosis in cases of gastric carcinomas of highly malignant
potential, as indicated by a positive HPA.
PMID- 9554523
TI - Factors associated with the use of flexible sigmoidoscopy as a screening test for
the detection of colorectal carcinoma by primary care physicians.
AB - BACKGROUND: Despite current recommendations of flexible sigmoidoscopy as a
screening test for the detection of colorectal carcinoma, relatively few
asymptomatic patients undergo this procedure. To enhance the use of
sigmoidoscopy, differences in the use of screening, as well as barriers to
screening among specific physician groups, should be defined. METHODS: The
authors surveyed 1762 practicing primary care physicians to determine their self
reported ability to perform sigmoidoscopy and perceived obstacles to either
initiating or enhancing screening. RESULTS: A total of 884 physicians (50%)
responded. Ninety percent of primary care physicians reported that they offered
sigmoidoscopic screening to their patients, with 46% referring patients and 44%
performing the procedure themselves. Physician characteristics were not
associated with the overall use of sigmoidoscopy. In contrast, compared with
physicians who referred patients for the procedure, physicians who performed
sigmoidoscopy themselves were more often board certified, male, and graduated
from medical school after 1970 (P < 0.001). In a multivariate analysis, these
characteristics were also independently associated with the ability to perform
sigmoidoscopy. The barrier to sigmoidoscopy cited most often was poor patient
acceptance, whether or not the physician performed or referred patients for
sigmoidoscopic screening. Other barriers cited were lack of training, lack of
equipment, and time required, each of which was identified most often by
physicians who did not screen at all. CONCLUSIONS: Most physicians surveyed
reported using sigmoidoscopic screening to some degree in their practice,
although many did not perform the procedure themselves. Population-based
interventions to increase screening may benefit from targeting specific physician
subgroups and attempting to improve patient acceptance of the procedure.
PMID- 9554524
TI - Lymph node harvest reporting in patients with carcinoma of the large bowel: a
French population-based study.
AB - BACKGROUND: In patients with resected colorectal carcinoma, lymph node
involvement has particular importance for patient prognosis and adjuvant therapy.
The network of French cancer registries (FRANCIM) established a study aimed at
analyzing the validity of lymph node harvest reporting in a population-based
sample. METHODS: The study population was comprised of 1081 resected tumors
without distant visceral metastasis and classified using the TNM system.
Correlation between the number of examined lymph nodes and the staging of the
tumor was examined by logistic regression analysis to establish an estimate of
the minimum number of lymph nodes required to determine whether a tumor is lymph
node negative. RESULTS: An average of 7.7 +/- 0.2 lymph nodes were examined per
specimen in the 851 patients for whom the number of lymph nodes examined was
known. The proportion of cases classified as N+ increased significantly with the
number of examined lymph nodes (chi-square trend = 24.6; P < 0.0001). If the
probability of correct lymph node status assessment is 1 in the reference group
(comprised of pathology reports of specimens with > or = 16 examined lymph
nodes), the probability of correct N+/N- dichotomization was significantly < 1
for the 1 to 3 lymph nodes group and the 4 to 7 lymph nodes group (i.e., 53.7% of
cases). CONCLUSIONS: To comply with current rules for adjuvant chemotherapy,
surgeons must provide pathologists with at least eight lymph nodes for optimal
N+/N- dichotomization to reduce the risk of misclassification and understaging.
PMID- 9554525
TI - The establishment of a preoperative diagnosis of pancreatic carcinoma using cell
specimens from pancreatic duct brushing with special attention to p53 mutations.
AB - BACKGROUND: Previously, the authors reported that 82% of cases of pancreatic
carcinoma were positive for p53 in cytologic specimens obtained by selective
endoscopic pancreatic duct brushing (SEPB). However, there was an extreme
discrepancy between the authors' data of p53 overexpression using cytologic
specimens and other reports using surgically resected specimens. In this study,
the authors demonstrate that p53 positive cells precisely reflect its gene
mutations, and also establish systematic procedures for the preoperative
diagnosis of patients with pancreatic carcinoma. METHODS: The authors examined 44
cases of pancreatic carcinoma, 30 cases of chronic pancreatitis, and 9 cases of
papillary adenoma. In all cases, pathologic diagnosis was made by surgery or
autopsy. The conventional cytology and p53 immunocytology were performed
simultaneously in the cell specimens obtained by SEPB. In the cases immunostained
for p53, DNA was extracted selectively from p53 immunostained cells using a light
microscope. p53 mutations in exons 5 to 8 were examined by direct sequencing.
RESULTS: Forty of 44 pancreatic carcinomas (91%) were diagnosed correctly by the
methods of conventional cytology associated with p53 immunocytology. p53
mutations were detected in 12 of 14 cases that were positive for p53 (86%). Four
of six cases that were inoperable due to massive metastasis or invasion had the
mutation at codon 273 (CGT to CAT) in exon 8. CONCLUSIONS: These results suggest
that p53 immunocytology reflects its gene mutations precisely, and that the point
mutation at codon 273 (CGT to CAT) of p53 may play an important role in the
invasive potential and metastasis of pancreatic carcinoma.
PMID- 9554526
TI - Estrogen-receptor-related protein p29 in primary nonsmall cell lung carcinoma:
pathologic and prognostic correlations.
AB - BACKGROUND: Estrogen-dependent intracellular processes are important in the
growth regulation of normal tissue and may play a role in the regulation of
malignancies. Utilization of estrogen receptor assays in breast carcinoma is well
established, but the role of such evaluation in other cancers largely is unknown.
In this study, immunohistochemical expression of estrogen receptor (ER) and the
ER-related protein p29 was correlated with survival of patients with nonsmall
cell carcinoma of the lung. METHODS: All patients with a tissue diagnosis of
primary nonsmall cell bronchogenic carcinoma diagnosed over a 6-year period at
the Medical Center Hospital of Vermont were reviewed. Assays for p29 and ER using
a streptavidin-biotin immunoperoxidase method were performed on each tumor.
Results were correlated with clinical data, including survival. RESULTS: Of 111
tumors examined, 109 (98%) were positive for p29 whereas none of the tumors
reacted with ER (ER1D5). The relation between p29 expression and survival time
was different for men and women. A statistically significant negative relation
for women was observed; this relation was most pronounced in patients with Stage
I and II tumors. A positive but not statistically significant relation was
observed for men. CONCLUSIONS: The ER-related protein p29 commonly is expressed
in nonsmall cell carcinomas of the lung. The relation between p29 and survival
time is different for males and females, suggesting the presence of gender
specific factors that may influence tumor growth and overall patient survival,
especially in patients with early stage lung carcinoma.
PMID- 9554527
TI - Primary systemic amyloidosis with delayed progression to multiple myeloma.
AB - BACKGROUND: Primary systemic amyloidosis (AL) and multiple myeloma both are
clonal plasma cell proliferative disorders. Although 10-15% of patients with
myeloma have coexisting primary amyloidosis, it is unusual for patients with
primary amyloidosis to progress to myeloma at a later date. The authors describe
a case series of six patients in whom such progression occurred. METHODS: A
computerized search was done of the medical records of all patients seen at the
Mayo Clinic between January 1, 1960 and December 31, 1994 with a diagnosis of AL.
Of 1596 patients with AL, 6 patients (age range, 60-74 years; median age, 68
years) with biopsy-proven AL were reviewed in whom delayed (at least 6 months
after the diagnosis of AL) progression to multiple myeloma occurred. RESULTS: At
the time of the diagnosis of AL, none of the six patients had evidence of
multiple myeloma. The dominant manifestation of AL was peripheral neuropathy in
three patients and cutaneous AL, renal AL, and amyloid arthropathy in one patient
each. The diagnosis of multiple myeloma was made 10-81 months after the diagnosis
of AL, based on the demonstration of multiple osteolytic lesions (4 patients) or
marked bone marrow infiltration (> or = 50%) by plasma cells (5 patients). Two
patients had received chemotherapy (melphalan and prednisone) for AL. Five
patients received chemotherapy (four patients) or high dose methylprednisolone
(one patient) after the diagnosis of multiple myeloma. Five patients died, and
the median actuarial survival after the diagnosis of multiple myeloma was 20
months. Multiple myeloma was the cause of death in four patients; one patient
died of systemic amyloidosis. In 2 patients death occurred within 3 months.
CONCLUSIONS: AL occasionally progresses to overt multiple myeloma. These cases
usually occur in patients without significant cardiac or hepatic AL who live long
enough to develop multiple myeloma.
PMID- 9554528
TI - Assessment of pulmonary and cardiac function after high dose chemotherapy with
BEAM and peripheral blood progenitor cell transplantation.
AB - BACKGROUND: Limited information is available regarding the cardiac and pulmonary
effects of high dose chemotherapy (HDCT) and autologous peripheral blood
progenitor cell (PBPC) transplantation. METHODS: The authors evaluated cardiac
and pulmonary function after BEAM (BCNU 300 mg/m2, etoposide 400 mg/m2/day x 3
days, cytosine arabinoside 200 mg/m2/day x 4 days, and melphalan 140 mg/m2),
HDCT, and PBPC transplantation in 26 patients with non-Hodgkin's lymphoma or
Hodgkin's disease. Therapy prior to BEAM included doxorubicin (25 patients),
bleomycin (6 patients), and mediastinal irradiation (4 patients). All patients
had pulmonary function tests (PFTs) and equilibrium radionuclide angiography
before and at a median of 57 weeks after transplantation. RESULTS: Prior to high
dose therapy, 8 patients had abnormal PFTs, including 6 with a diffusing capacity
of the lung for carbon monoxide (DLCO) <70% of predicted value. At the time of
reevaluation after HDCT, all patients included in the study were in complete
remission, and none had received additional therapy after transplantation. At a
median of 77 weeks after transplantation, none of the patients had cardiac or
pulmonary symptoms. Moreover, there were no significant changes in total lung
capacity, forced vital capacity, forced expiratory volume in 1 second/forced
vital capacity, DLCO, or left ventricular ejection fraction values when compared
with baseline studies. CONCLUSIONS: The authors concluded that HDCT with BEAM and
PBPC transplantation did not result in significant cardiac or pulmonary toxicity,
even in patients with borderline pretransplantation PFT values. Further studies
of patients undergoing HDCT and PBPC transplantation are needed.
PMID- 9554529
TI - Expression of c-met is a strong independent prognostic factor in breast
carcinoma.
AB - BACKGROUND: The c-met protooncogene encodes the met protein, the receptor for
scatter factor/hepatocyte growth factor, a growth factor that modulates the
motility and stable interaction of the epithelial cells. This study assesses the
expression of met receptor in breast carcinoma and its prognostic value with
respect to survival. METHODS: Immunofluorescence was used to evaluate 91 archival
breast carcinoma specimens using a polyclonal antibody to the cytoplasmic domain
of the receptor. Cases were scored by two pathologists on a percentage basis and
then converted to binary scores (positive or negative) on the basis of a bimodal
distribution. RESULTS: Strong expression of met was found in 20 invasive ductal
breast tumor specimens (22%). The 5-year survival of patients whose tumors showed
decreased met expression was 89%, in contrast to a 52% 5-year survival rate in
patients whose tumors expressed met (P = 0.008). This trend also was observed in
patients without lymph node metastases at presentation, in whom met negative
patients had a 95% 5-year survival compared with only 62% for met positive
patients (P = 0.006) Multivariate analysis using the Cox proportional hazards
model showed met expression to be an independent predictor of survival, with a
predictive value nearly equivalent to that associated with lymph node status.
CONCLUSIONS: The authors conclude that expression of met in patients with
invasive ductal carcinoma of the breast is a strong, independent predictor of
decreased survival and may be a useful prognostic marker with which to identify a
subset of patients with more aggressive disease.
PMID- 9554530
TI - Results of intermediate measures from a population-based, randomized trial of
mammographic screening prevalence and detection of breast carcinoma among Asian
women: the Singapore Breast Screening Project.
AB - BACKGROUND: Although increasing rates of breast carcinoma incidence have been
observed in Asian countries, appropriate strategies for detecting early stage
breast carcinoma in such communities have been difficult to formulate,
particularly because no large population screening trial specifically involving
Asian women has been reported. The objective of this study was to evaluate the
effectiveness and quality of mammography as a screening technique for Singaporean
women, who are predominantly Chinese. METHODS: In this prospective study, 166,600
women in Singapore ages 50-64 years were randomized to either 2-view mammography
without physical examination (67,656) or observation (97,294, controls) over 2
years. RESULTS: Of these women, 28,231 (41.7%) responded and were screened; they
were more likely to be married, have more formal education, be working, be
Chinese, and be in a higher socioeconomic group (P < 0.001 for all variables). To
assess for response bias that could affect outcome, results were also evaluated
for nonrespondents (n = 39,425). The incidence rate of cancers among
nonrespondents (1 per 1000 woman-years) was less than the 1.3 in women not
invited to have screening (P = 0.03, relative risk [RR], 1.3; 95% confidence
interval [CI], 1.0-1.7). However, cancers arising from nonrespondents did not
differ significantly in stage distribution when compared with cancers within the
control group. For every 1000 women screened, 4.8 cancers were detected. The
prevalence ratio (the number of cancers detected per 1000 women at first
screening divided by the corresponding incidence rate in controls per year) was
3.6 for screened women and 2.4 for women invited to have screening. The majority
of cancers detected through screening were early stage, with 64% as either ductal
carcinoma in situ (26%) or Stage I disease (38%) and was significantly more than
the corresponding 26% in women not invited to have screening (P < 0.001). When
only invasive cancers were considered, screened women still had more early
cancers, with 65% having no lymph node involvement, compared with 47% in the
group not invited to have screening (P = 0.001; RR, 1.4; 95% CI, 1.2-1.7). Women
who were screened had half the risk of having Stage II or later cancers (P <
0.0001; RR, 0.5; 95% CI, 0.4-0.7) when compared with women not invited to have
screening. This higher detection rate of early cancers through screening was
accomplished with acceptable recall rates of 8% for further mammographic films or
physical examination and a biopsy rate of 1.0% (10 per 1000 women screened). The
interval cancer rate was 2.1 per 10,000 women screened in the first year of
follow-up. CONCLUSIONS: These positive results of intermediate measures suggest
that, in Asian communities, screening mammography could be an important modality
for detecting early stage breast carcinoma. However, the low compliance rates
suggest that health education efforts must focus on issues related to
acceptability if such programs are to succeed.
PMID- 9554532
TI - Primary heterologous carcinosarcoma (metaplastic carcinoma) of the urinary
bladder: a clinicopathologic, immunohistochemical, and ultrastructural analysis
of eight cases and a review of the literature.
AB - BACKGROUND: Heterologous carcinosarcomas of the urinary bladder are rare
neoplasms, the histogenesis of which is still disputed. METHODS: The
clinicopathologic, immunohistochemical, and ultrastructural features of eight
cases were analyzed. RESULTS: The patients, 5 males and 3 females, had a median
age of 70 years. Gross hematuria, dysuria, and urinary tract infections were the
main presenting symptoms. Tumors were solitary in all cases and located in the
right wall in six cases. Tumor size ranged from 2 to 12 cm (median, 5 cm). Four
patients died of disease 2, 6, 17, and 42 months postoperatively, respectively.
Microscopically, the tumors consisted mostly of a varied mixture of high grade
transitional cell carcinoma with chondrosarcoma, osteosarcoma, rhabdomyosarcoma,
and undifferentiated spindle cell (leiomyosarcoma-like) components with
occasional transitional features between one component and another. All tumors
but one invaded the muscularis propria or the perivesical fatty tissue.
Immunohistochemically, keratin expression was observed focally in the sarcoma
component as well as the carcinoma component. Reactivity for vimentin, desmin,
muscle specific actin, and S-100 protein was observed in poorly differentiated
areas in addition to the expected positivity of each histologic subtype of
sarcoma. Ultrastructurally, one tumor showed evidence of both epithelial and
chondrosarcomatous differentiation, whereas three contained rhabdomyosarcomatous
elements. CONCLUSIONS: On the basis of the current series and a review of 55
reports from the literature, primary heterologous carcinosarcoma of the urinary
bladder proved to be a highly malignant type of neoplasm occurring predominantly
in elderly males that was most often in an advanced stage at presentation and
rapidly became lethal. Histogenetically, some heterologous carcinosarcomas should
be regarded as a variant of sarcomatoid carcinoma (metaplastic carcinoma) that
shows prominent heterologous differentiation.
PMID- 9554531
TI - Neoadjuvant chemotherapy in the treatment of locally advanced cervical carcinoma
in pregnancy: a report of two cases and review of issues specific to the
management of cervical carcinoma in pregnancy including planned delay of therapy.
AB - BACKGROUND: Women diagnosed with invasive cervical carcinoma during pregnancy are
faced with difficult decisions regarding therapy and the fate of their unborn
child. A modest treatment delay for International Federation of Gynecology and
Obstetrics Stage I cervical lesions is considered acceptable in patients who wish
to continue their pregnancy. METHODS: Two patients with locally advanced cervical
carcinoma diagnosed early in the second trimester strongly desired continuation
of their pregnancies. They were treated with neoadjuvant chemotherapy until the
third trimester, and then underwent delivery and definitive surgical treatment.
The patients were evaluated during pregnancy for evidence of a clinical response
to chemotherapy. Intraoperative findings and pathologic analysis of the surgical
material provided further objective data regarding disease status. RESULTS: Both
patients experienced a dramatic reduction in tumor volume, rendering radical
hysterectomy feasible at the time of cesarean section. In addition, both patients
tolerated chemotherapy well and there were no adverse fetal effects. Favorable
neonatal outcomes were achieved. One patient experienced recurrence within 5
months of surgery, whereas the other patient remained without evidence of disease
for 2 years. CONCLUSIONS: To the authors' knowledge, these reports constitute the
first description of the use of neoadjuvant chemotherapy for invasive squamous
cell carcinoma of the cervix in pregnancy (MEDLINE 1966-1997). This therapeutic
option should be considered in selected women with locally advanced cervical
carcinoma who do not want termination of their pregnancy.
PMID- 9554533
TI - Mitosis identification in diffuse gliomas: implications for tumor grading.
AB - BACKGROUND: The histologic differentiation of mitotic figures is a cornerstone of
several highly predictive grading systems for gliomas. In some systems, the
presence of even a single mitotic figure is sufficient to classify an astrocytoma
as high grade. However, the extent of microscopic examination necessary to
exclude the presence of significant mitotic activity has not been determined.
METHODS: Hematoxylin and eosin-stained slides from 410 astrocytomas and 107
oligodendrogliomas/oligoastrocytomas were reviewed until the first mitosis was
identified or 100 400x fields had been reviewed without identification of a
mitosis. The number of the field in which the first mitosis was found was
correlated with diagnosis, grade, and survival. RESULTS: A review of 50 400x
fields was necessary to achieve a >90% sensitivity in identifying a mitosis in a
Grade 3 astrocytoma specimen, compared with 20 400x fields in anaplastic (Grade 3
and 4) oligodendroglioma specimens. For Grade 3 astrocytomas, there was a
significant independent correlation between survival and the field in which the
first mitosis was found (P = 0.02). For the oligodendroglial tumors, there was a
strong correlation between the number of fields counted until the first mitosis
was found and grade (P < 0.0001). CONCLUSIONS: The evaluation of mitotic activity
offers more prognostic information than can be obtained by the simple approach of
noting only their presence or absence. Data were acquired regarding the diligence
of the microscopic examination necessary to evaluate the presence or absence of
mitotic activity. A 1 cm x 0.1 cm needle biopsy contains adequate tissue to
evaluate mitotic activity for the purpose of histologic grading; however, this
adequacy is dependent on the sample's being representative and composed entirely
of cellular tumor.
PMID- 9554534
TI - Nonnasopharyngeal lymphoepithelioma of the head and neck.
AB - BACKGROUND: Lymphoepithelioma (squamous cell carcinoma with associated lymphoid
stroma) commonly occurs in the nasopharynx, rarely at other sites. As a result,
the clinical course and optimal treatment of nonnasopharyngeal lymphoepithelioma
of the head and neck have not been well described. This retrospective study was
undertaken to analyze the clinical course of the disease in patients treated at a
single institution and to formulate recommendations for treatment based on that
experience as well as results reported in the literature. METHODS: Between 1950
and 1994, 34 patients with nonnasopharyngeal lymphoepithelioma of the head and
neck were treated at the University of Texas M. D. Anderson Cancer Center. The
patients' medical records were reviewed and their pathologic specimens evaluated.
The primary tumor sites were: oropharynx (24 patients), salivary gland (4),
laryngohypopharynx (4), and the maxillary sinus/nasal cavity (2). Assessed in
accordance with the 1992 American Joint Committee Against Cancer TNM staging
system, T classifications were TX-2, T1-7, T2-8, T3-10, and T4-7, and N
classifications were N0-8, N1-5, N2-15, and N3-6. Treatment consisted of
radiotherapy for 24 patients, excisional biopsy of the primary tumor followed by
radiotherapy for 7 patients, and surgery for 3 patients. Of the patients treated
with radiotherapy, neck dissections were performed on only two, both of whom had
persistent lymph node masses after completing radiotherapy. The median dose
delivered to the primary tumor was 65 gray (Gy) (range, 46-78 Gy). The median
fraction size was 2.1 Gy (range, 1.6-3.2 Gy). RESULTS: The 5-year actuarial
disease specific survival and overall survival rates were 59% and 39%,
respectively. The 5-year actuarial local control rate for all patients was 94%.
For the irradiated patients, the 5-year regional control rates were 77% overall
and 83% within the radiation field. The 5-year actuarial rate of distant
metastasis for all patients was 30%. For patients who presented with and without
regional adenopathy, the 5-year rates of distant metastasis were 36% and 12%,
respectively (P = 0.27). CONCLUSIONS: Nonnasopharygeal lymphoepithelioma is a
radiosensitive disease. High rates of locoregional tumor control were achieved
with radiotherapy at all head and neck sites. The main cause of treatment failure
was distant metastasis, which occurred more frequently in patients with lymph
node involvement. Radiotherapy is appropriate initial locoregional therapy for
patients with this disease. Surgery should be reserved for patients who have
persistent disease after completing radiotherapy. Systemic therapy is a
reasonable approach for patients who present with regional adenopathy because
they have a relatively high rate of distant metastasis.
PMID- 9554535
TI - Generation of a monoclonal antibody that inhibits the procoagulant activity of
various cancer cell lines.
AB - BACKGROUND: Tumor procoagulant is one of the factors responsible for disseminated
intravascular coagulation and metastasis. The authors found procoagulant activity
in LK52 human squamous cell carcinoma cells, which they designated cancer cell
derived blood coagulating activity 1 (CCA-1). A monoclonal antibody (MoAb) was
generated to characterize this CCA-1 procoagulant activity. To date, antibodies
that show an inhibitory effect on procoagulant activity as well as high
reactivity in cancer cells are well known for their tissue factor specificity.
METHODS: Characterization of the procoagulant activity of CCA-1 was performed and
an anti-CCA-1 MoAb, FS01, was generated. CCA-1 expression on the cancer cell
surface was examined by flow cytometry. Procoagulant activity of various cancer
cell lines and the inhibitory effect of the FS01 MoAb on this procoagulant
activity was monitored by a clot timer. RESULTS: The enzymologic character
differed from that of cancer procoagulant (CP). The FS01 MoAb inhibited the
procoagulant activity of CCA-1, but did not inhibit that of tissue factor. A
positive correlation was observed between the expression intensity of CCA-1 and
the inhibitory effect of the FS01 MoAb on the procoagulant activity of cancer
cell lines. Expression of CCA-1 was observed more frequently than that of tissue
factor in human cancer cell lines. CONCLUSIONS: The FS01 MoAb generated in the
current study is a new antibody that reacts with various cancer cell lines, but
not with normal cells. FS01 inhibits cancer cell-derived procoagulant activity
and does not react with tissue factor and CP. CCA-1, which is recognized by the
FS01 MoAb, appears to play a major role in cancer cell-derived procoagulant
activity.
PMID- 9554536
TI - The cancer specific advance directive.
AB - BACKGROUND: Advance directives are an important part of end of life care, but
current advance directive documents do not address the specific issues facing
cancer patients. The authors' purpose was: 1) to develop a cancer specific
advance directive, 2) determine whether oncology outpatients find this directive
more acceptable than a generic advance directive, and 3) describe oncology
outpatient preferences for life-sustaining treatment. METHODS: A cancer specific
advance directive ("The Cancer Living Will"; the full text of the updated version
is available at the University of Toronto Joint Centre for Bioethics website
[URL: www.utoronto.ca/jcb]) was developed in four steps: 1) literature search, 2)
key informant interviews, 3) focus groups, and 4) evaluation of face and content
validity. Subsequently, 91 volunteer oncology patients were given copies of the
cancer specific advance directive and the generic advance directive ("The
University of Toronto Centre for Bioethics Living Will") from which it was
adapted. Acceptability of the advance directive was measured by determining the
participants' preferred directive. Participants recorded their treatment
preferences in both the cancer specific and generic advance directives. RESULTS:
Of 60 patients who returned their questionnaires, 50 expressed a preference for
the advance directive. Thirty-two patients (64%; 95% confidence interval (CI), 49
77%) preferred the disease specific Cancer Living Will and 18 patients (36%; 95%
CI, 23-51%) preferred the generic Centre for Bioethics Living Will. Most
participants who preferred the Cancer Living Will did so because it was more
specific and relevant to their situation. CONCLUSIONS: The authors have developed
and evaluated a cancer specific advance directive that they believe can be
recommended for clinical use with cancer patients.
PMID- 9554537
TI - Dihydro-5-azacytidine and cisplatin in the treatment of malignant mesothelioma: a
phase II study by the Cancer and Leukemia Group B.
AB - BACKGROUND: In a prior Cancer and Leukemia Group B (CALGB) Phase II trial of
patients with advanced, previously untreated mesothelioma, dihydro-5-azacytidine
(DHAC) demonstrated a 17% response rate, including 1 complete response, with only
mild myelosuppression. This Phase II study (CALGB 9031) was conducted to
determine the effectiveness of and toxicities that would result from adding
cisplatin to DHAC administered to the same patient population. METHODS: Thirty
six patients were treated with concurrent DHAC at 1500 mg/m2/day for 5 days by
continuous infusion and cisplatin 15 mg/m2 daily for 5 days. Therapy was repeated
every 3 weeks. Cisplatin was to be increased to 20 mg/m2 daily in subsequent
cycles if toxicity was minimal. Therapy was continued until disease progression
or excessive toxicity mandated discontinuation. RESULTS: Overall, 5 objective
responses were observed in 29 evaluated patients (objective response rate, 17%).
The median duration of response was 6.6 months. Median survival was 6.4 months,
with a median time to clinical failure of 2.7 months. The major toxicity noted
was significant chest/pericardial pain, as was observed with DHAC alone. There
were 2 early deaths of unknown cause on Days 9 and 17 of therapy, respectively.
Significant leukopenia was observed in 29% of patients, but there were no
neutropenic fevers. CONCLUSIONS: The addition of cisplatin to DHAC did not
increase the response rate over that observed with DHAC alone in patients with
mesothelioma; however, it did increase toxicity, especially leukopenia. This
combination is not recommended for further studies involving mesothelioma
patients.
PMID- 9554538
TI - The role of glucagon administration in the diagnosis and treatment of patients
with tumor hypoglycemia.
AB - BACKGROUND: Tumor hypoglycemia can be recurrent and severe enough to interfere
with definitive antineoplastic treatment. Therefore, rapid commencement of
effective therapy is essential. This is best accomplished by identifying which of
the hypoglycemic processes is involved, as treatments differ. Some patients
present with hypoglycemia and liver metastases; among them, only a few develop
hypoglycemia as a result of a failure of hepatic glucose production. Most develop
hypoglycemia as a result of an insulin-mediated process--either the secretion of
insulin by an islet-cell tumor or the secretion of insulin-like growth factor-II
by an extrapancreatic tumor. Administration of glucagon can rapidly make the two
groups distinguishable, thus allowing institution of therapy and prompt
symptomatic control of hypoglycemia. METHODS: The charts of seven patients with
tumor hypoglycemia and liver metastases who had a glucagon stimulation test
(serial glucose measurements after a 1 mg infusion of glucagon) as part of the
workup for hypoglycemia were retrospectively reviewed. Those patients whose test
revealed a rise in serum glucose of >30 mg/ dL were subsequently treated as
outpatients, with a continuous glucagon infusion delivered by a portable pump.
RESULTS: Three patients had an insulinoma and four had non-islet cell tumor
hypoglycemia (NICTH) due to hepatocellular carcinoma, colon carcinoma, meningeal
sarcoma, and hemangiopericytoma, respectively. All of the patients had liver
metastases. Evaluation of these patients included a glucagon stimulation test (1
mg intravenous push), which quickly provided information about the mechanism of
tumor hypoglycemia and the direction towards therapy. All patients with
insulinoma responded to glucagon with a rise in blood serum glucose levels,
indicating adequate glycogen stores. The four patients with NICTH had mixed
responses: in two patients, the response suggested that hypoglycemia was due to
an insulin-like tumor product; glucose levels did not rise in the other two
cases, indicating that hypoglycemia was due to poor hepatic glycogen
reserve/liver failure. In all cases, a glycemic response to glucagon predicted
good response to long term treatment with glucagon (0.06-0.3 mg/hour, via
intravenous infusion pump). CONCLUSIONS: The glucagon stimulation test is a
simple and fast approach that serves to clarify the etiology of hypoglycemia
(diagnostic use) and guide effective long term strategies for its control
(therapeutic use) in patients with neoplastic diseases and liver metastases.
PMID- 9554539
TI - Neuroblastoma screening in the United States: results of the Texas Outreach
Program for neuroblastoma screening.
AB - BACKGROUND: Mass screening of infants for neuroblastoma began in Japan after
studies suggested that survival rates could be improved by early detection. This
study was initiated in 1991 to test the methodology and feasibility of screening
for neuroblastoma within the U. S. health care system. METHODS: Infants ages 5-10
months (mean age, 9 months, 25 days) who were born in Texas were screened for
neuroblastoma. An enzyme-linked immunoadsorbent assay (ELISA) for homovanillic
acid (HVA) and vanillylmandelic acid (VMA) used to quantify the HVA and VMA was
performed on urine extracted from specimens dried on filter paper. Infants were
recruited to participate in the study by several methods, and the effectiveness
of each method was determined by calculating compliance rates. RESULTS: Between
February 1991 and June 1994 a total of 14,046 infants were recruited to
participate in neuroblastoma screening. Neuroblastoma was detected in 2 children
for an incidence rate of 1 in 7023. A total of 291,158 screening kits were
distributed to the parents of these infants, resulting in an overall compliance
rate of only 4.8%. Compliance rates varied by method of distribution of the test
kits: Houston Women, Infants, and Children (WIC) clinic (53%), volunteers (31%),
Rio Grande Valley WIC clinics (14.5%), the patient's private physician (9.9%),
and by mail (4.7%). CONCLUSIONS: Early detection of neuroblastoma in infants ages
5-10 months was achieved using ELISA. Compliance rates were poor, but clinics
with a preventive health focus, such as the WIC clinics, achieved higher
compliance rates than did private physicians.
PMID- 9554541
TI - Understanding and affirming the sexual/relationship realities of end-stage renal
disease patients and their significant others.
AB - End-stage renal disease (ESRD) frequently occurs within the social context of
relationships and has many predictable consequences in the experience of patients
and their significant others. Relationship and sexual issues and concerns must be
assessed early in the treatment process and be continually attended to as
patients seek new levels of coping. Sex-role conflicts, changes in sexual
functioning and sexual self-esteem, challenges to both physical and emotional
intimacy, and the life-altering consequences of chronic illness are all very real
for ESRD patients. If a holistic perspective on the health care needs of ESRD
patients is to be a reality, it will contain a concern for, active attention to,
and involvement in the relationship/sexual dimension of life.
PMID- 9554540
TI - Neurodevelopmental anomalies in children with neuroblastoma.
AB - BACKGROUND: Case reports have associated neuroblastoma, a cancer derived from the
embryonal neural crest, with aganglionosis coli and neurofibromatosis type I. The
aim of the current study was to test the hypothesis that neuroblastoma is part of
a global defect in neurodevelopment. METHODS: Neuropathologic findings from
autopsies of children who died of neuroblastoma during the period 1980-1995 at
the Children's Hospital of Pittsburgh were reviewed for macroscopic and
microscopic abnormalities. As controls, autopsies of children who had died of
other primary extracranial cancers over the same time period also were studied.
Medical records of neuroblastoma patients for whom autopsies were available were
reviewed for clinical evidence of preexisting nonmalignant neurologic disease.
RESULTS: Of 145 children diagnosed with neuroblastoma, 49 had died, and autopsies
not restricting examination of the brain had been performed on 13. Macroscopic
anatomic abnormalities (a small cerebellum and the absence of the corpus
callosum) were noted in one patient who was known to have been mentally retarded
without having a defined syndrome. Microscopic abnormalities of cytoarchitecture
were noted in that patient as well as 3 of the 12 other patients (focal cortical
dysplasia [fcd], n = 3; leptomeningeal heterotopia, n = 1; abortive sulcation or
flattened gyri, n = 2). None of 3 patients with only microscopic abnormalities
had clinical evidence of problems with neurodevelopment. Of the 26 children with
nonneuroblastoma cancers for whom complete autopsies were available, 1 infant had
major macroscopic structural abnormalities of the brain. None of these patients
had microscopic abnormalities (P < 0.01). CONCLUSIONS: Children with
neuroblastoma have an increased incidence of abnormalities of brain
cytoarchitecture, particularly fcd. These abnormalities are generally
asymptomatic and are diagnosed by histologic examination. Such abnormalities
cannot be attributed to chemotherapy and are not observed in other children with
non-central nervous system tumors. These findings are consistent with the concept
that neuroblastoma may occur in the setting of a more global defect in
neurodevelopment. A blinded review of larger numbers of cases will be needed to
verify these data.
PMID- 9554542
TI - Kidney transplants from living donors: how donation affects family dynamics.
AB - Living donors continue to provide the optimum outcome for kidney transplant
recipients, yet information is limited on how donation can affect the donor and
his or her family. Questionnaires returned by 524 donors whose donor
nephrectomies took place between August 1, 1985 and December 31, 1996 at the
University of Minnesota were analyzed to determine if perioperative complications
influence their quality of life, among other emotional and lifestyle areas.
Results showed that donors have a higher quality of life than the general
population, confirming they have an increased self-worth and positive self
esteem. An overwhelming 96% would donate again. However, donation was self
reported as more stressful when complications were experienced (P = .003) and
when donors were female (P = .041). Relatives other than immediate family members
(extended relatives) were more likely to be among the 4% who said they would not
donate again. Available support, financial impact, and relationship changes as a
result of donation also were revealed. Relevant results from this larger study
are discussed as they relate to how the renal donor and transplant family are
affected.
PMID- 9554543
TI - Family caregivers: caring for aging end-stage renal disease partners.
AB - With the rapid aging of end-stage renal disease patients have come increasing
burdens on families to provide care and support. This article focuses on the role
changes, strains, and burdens for family caregivers, particularly spouses.
Analysis is on the process of dramatic role changes and losses that occur within
families and the resulting risks to dialysis patients and caregivers. Importance
of constant assessment of caregivers by renal professionals is emphasized.
Suggestions for families and professionals coping with role change and care
burdens are offered. Concern is raised about American society shifting more care
burdens onto families at a time of cultural change and stress on families,
without enough societal support and programs to assist families adequately with
care burdens of aging members.
PMID- 9554544
TI - Advance directives in end-stage renal disease inherently involve family and
staff.
AB - Advance directives (ADs) have a pivotal role in the practice of clinical
nephrology. The following discussion reviews our own viewpoint, drawing on the
present literature and on many case anecdotes from our own practice. The review
focuses on (1) the intrinsic value of ADs; (2) the impact of family and staff on
clinical outcome in general; (3) family relationships and medical decision
making, especially in the area of ADs; (4) the importance of communication within
families and between families and staff, as characterized in "family meetings";
and (5) the power of reconciliation when family members and staff "let go." In
the final analysis, ADs present the opportunity for approaching medical decision
making in a manner that can lessen the stress of making difficult decisions for
the patient and even promote peace of mind for all concerned family and staff.
PMID- 9554545
TI - Adolescent issues in renal treatment.
AB - Everyone who helps to care for a growing and developing child has the potential
to impact the future. Families provide the greatest influence and bear the major
responsibility, but physicians, nurses, dietitians, social workers, teachers,
camp counselors, and others who work with children make a direct contribution
toward the development of the child's self image and image of the world around
them. At no other time in an individual's life do other people have such awesome
power and responsibility. Families and caregivers working together on behalf of a
child may be likened to an extended family; their combined efforts are needed to
help promote the resilience that children need to cope with serious chronic
illness.
PMID- 9554546
TI - Cultural basics and chronic illness.
AB - Cultural factors have significant impact on the clinical encounter between health
care professionals and their patient-families. A good continuing relationship is
essential for successful management of chronic disease. Misunderstandings
predicated on implicit cultural assumptions are a frequent potential hazard. This
review outlines some possible problems and concludes by making eight suggestions
for culturally sensitive and medically effective communication.
PMID- 9554547
TI - A team's three-dimensional approach to assisting the end-stage renal disease
family.
AB - This review will identify ways in which the interdisciplinary team assists a
family confronting end-stage renal disease (ESRD) for the first time. The
developmental models of the family life cycle and the ESRD life cycle are used to
understand the family's needs. The treatment team uses a three-dimensional
approach of education, support, and communication to enhance family coping.
PMID- 9554548
TI - Drug dosing in acute renal failure: the role of renal replacement therapy in
altering drug pharmacokinetics.
AB - The combination of multiple medical problems requiring complex drug therapy with
rapidly changing organ functions that lead to pharmacokinetic alterations makes
drug regimen design in the intensive care unit challenging. Acute renal failure
leads to even greater physiologic disturbances requiring additional
pharmacologic, nutritional, and dialytic support. A variety of renal replacement
modalities, both intermittent and continuous, are used to manage the solute,
volume, and acid-base derangements of patients with acute renal failure. Renal
replacement therapies differ in their impact on drug dosing. The clinician must
consider the impact of both disease and treatment if drug prescribing is to be
optimal. Principles of solute removal are reviewed and concepts of drug regimen
design are discussed. A practical approach to drug prescribing in this setting is
described. Examples of dose adjustments for intermittent and continuous renal
replacement therapies are provided.
PMID- 9554549
TI - Dialysis through a child's eye.
PMID- 9554550
TI - APO B 3' HVR polymorphism in healthy population: relationships to serum lipid
levels.
AB - We have analyzed allele frequency distribution at the hypervariable locus 3' to
the apolipoprotein B gene in a healthy population sample (241 women and 246 men)
from the Belgrade area. The bimodal distribution of sixteen different
hypervariable region (HVR) alleles and the heterozygosity index (average 0.76) in
both samples are similar to ones reported for other Caucasian populations.
However, we found the hypervariable element containing 34 repeats-HVE34 allele to
be the most common one in both female and male samples, and that there was a
lower frequency of the HVE>36 alleles. For further analysis of 3'HVR allele
frequency and its possible association with serum lipid levels, all HVR alleles
were grouped into five main types (HVE<32, HVE32, HVE34, HVE36, and HVE>36), and
the samples were divided into lipid quartiles. We found that (1) apo B gene 3'HVR
polymorphism is associated with variation of normal lipid levels in males, (2)
HVE32 alleles are associated with decreased serum levels of total cholesterol,
LDL cholesterol, and triglycerides, and (3) HVR genotypes containing HVE34 and
HVE36 alleles are associated with elevated serum levels of total cholesterol, low
density lipoprotein (LDL) cholesterol, and triglycerides.
PMID- 9554551
TI - Relative predispositional effects and mode of inheritance of HLA-DRB1 alleles
among community-based Caucasian females with rheumatoid arthritis.
AB - Multiple HLA-DRB1 alleles encoding a shared epitope (SE) at amino acid positions
70-74 are associated with susceptibility to rheumatoid arthritis (RA). However,
the nature of the association and the mode of inheritance differ depending upon
the source of RA patients and laboratory methodology. We studied the relative
predispositional effects (RPE) and mode of inheritance of DRB1 alleles among a
community-based sample of 180 RA patients and 116 healthy controls, all Caucasian
females. Polymerase chain reaction (PCR)-based assays were used for DRB1
genotyping, and the genotypic distributions were analyzed by both the RPE and
antigen genotype frequency among patients (AGFAP) methods. We examined the
evidence of synergy among DRB1 alleles for RA risk by comparing the observed DRB1
genotype distribution to that predicted under Hardy-Weinberg equilibrium. Fifty
six percent of RA cases were attributable to DRB1 alleles encoding the SE. The
RPEs of DRB1 alleles were *0401 > *0404 > *1001 > *0408 > *0101. The strength of
the RA association was not significantly different for these alleles. The AGFAP
analysis was consistent with a recessive mode of inheritance for DRB alleles,
while an additive (dominant) model was rejected. We found no evidence of synergy
for RA risk among individual DRB1 alleles based on comparison of the observed vs.
predicted genotype distributions. These results suggest that among community
based Caucasian females with RA, the DRB1 RA susceptibility gene influences
disease risk in a recessive fashion without synergy among individual DRB1
alleles.
PMID- 9554552
TI - Genotypic relative risks under ordered restriction.
AB - In mapping diseases of complex aetiology, conventional linkage approaches narrow
the location of the disease susceptibility locus to quite a large region so that
candidate gene association studies are then necessary to further isolate these
genes. However, even in the simplest scenario where the candidate locus is bi
allelic, two statistical tests with various correcting factors have been
proposed: a chi-square 1 df test (counting chromosomes) which may be slightly
conservative and a 2 df chi-square test (counting genotypes) which may lack power
because of the extra degree of freedom. This paper introduces a better and more
powerful alternative which turns out to be a compromise between the two existing
statistical tests. The asymptotic distribution of this test statistic is
determined and the efficacy of the 3 tests are compared under different genetic
models by simulation.
PMID- 9554553
TI - Modeling hazard functions in families.
AB - A genetic frailty model is presented for censored age of onset data in nuclear
families where individuals carrying a genetic susceptibility gene have an
increased risk of becoming affected. We use maximum likelihood via the EM
algorithm to estimate the genetic relative risk and the allele frequency under a
dominant susceptibility type and a proportional hazards model. When sampling is
from a disease registry, likelihood corrections are necessary for reducing bias
in the parameter estimates. In these biased samples, the full conditional
likelihood is approximated by a likelihood conditional on the proband's age of
onset. For unbiased samples, simulations show the distributions of the estimates
are similar under both a semiparametric and the correctly specified parametric
likelihoods. For biased samples, simulations under the approximate conditional
likelihood show the median estimates of the allele frequency and genetic relative
risk tend to under- and overestimate, respectively, the true values; however, the
approximation is better for rarer allele frequencies (0.0033 vs. 0.01). In
practice, large samples or more complex ascertainment corrections are
recommended. Using the approximate conditional likelihood on familial breast
cancer onset data collected as part of a case-control study at the Fred
Hutchinson Cancer Research Center in Seattle, Washington, we estimate an allele
frequency of 0.0009 (approximate 95% CI 0.0006-0.002) and a genetic relative risk
of 104 (approximate 95% CI 55-181).
PMID- 9554554
TI - Logistic regression model for analyzing extended haplotype data.
AB - Recently, there has been increased interest in evaluating extended haplotypes in
p53 as risk factors for cancer. An allele-specific polymerase chain reaction
(PCR) method, confirmed by restriction analysis, has been used to determine
absolute extended haplotypes in diploid genomes. We describe statistical analyses
for comparing cases and controls, or comparing different ethnic groups with
respect to haplotypes composed of several biallelic loci, especially in the
presence of other covariates. Tests based on cross-tabulating all possible
genotypes by disease state can have limited power due to the large number of
possible genotypes. Tests based simply on cross-tabulating all possible
haplotypes by disease state cannot be extended to account for other variables
measured on the individual. We propose imposing an assumption of additivity upon
the haplotype-based analysis. This yields a logistic regression in which the
outcome is case or control, and the predictor variables include the number of
copies (0, 1, or 2) of each haplotype, as well as other explanatory variables. In
a case-control study, the model can be constructed so that each coefficient gives
the log odds ratio for disease for an individual with a single copy of the
suspect haplotype and another copy of the most common haplotype, relative to an
individual with two copies of the most common haplotype. We illustrate the method
with published data on p53 and breast cancer. The method can also be applied to
any polymorphic system, whether multiple alleles at a single locus or multiple
haplotypes over several loci.
PMID- 9554555
TI - Using family history information to distinguish true and false positive model
free linkage results.
AB - Genome scans that test for increased marker identity-by-descent sharing between
pairs of affected siblings have become increasingly common. These methods do not
specify a priori a genetic model for the disease locus and as such lose the
ability to specify the parental source of the disease allele. We propose a method
that uses family history information to build a more complete model of disease
and marker inheritance, while still avoiding specification of the parameters of
the disease model of inheritance. One important use for such a model is to test
whether a positive linkage result obtained during the course of a genome scan is
a true or false positive result. The key to the new test statistics is the
interaction between gender-specific marker identity-by-descent sharing and gender
specific family history of disease. The method is useful when the disease locus
of interest has a dominant mode of inheritance and a sufficient number of parents
are genotyped at the marker locus. If these conditions are met, the proposed
tests have good power to differentiate between true and false positive linkage
results.
PMID- 9554556
TI - Using information from both parents when testing for association between marker
and disease loci.
AB - Several extensions of the transmission/disequilibrium test (TDT) to multi-allelic
markers now exist. In some of these, however, separate tests must be performed on
male and female parents because of the non-independence of parental transmission
patterns, reducing power, and complicating interpretation of the test results.
Here we show that this non-independence is asymptotically irrelevant when using
the allelic TDT of Bickeboller and Clerget-Darpoux [(1995) Genet Epidemiol 12:577
582], allowing the analysis of data from both parents simultaneously.
PMID- 9554557
TI - Analysis of Swedish male breast cancer family data: a simple way to incorporate a
common sibling effect.
AB - Based on a population-based cohort study, Olsson et al. [1993] found significant
evidence for elevated incidence of breast and ovarian cancers among female first
degree relatives of men with breast cancer. Using an extension of logistic
regressive models we investigate whether, after allowing for multifactorial
familial correlations, single locus segregation could be the cause of the
elevated incidence in these families. The logit for a given sib in the class D
logistic regressive model depends on the order in which affected sibs occur in a
sibship. That makes the model less appropriate for the situation where a
polygenic component or a common sibling environment may be present, as well as
being computationally cumbersome. In this paper, we propose to use the proportion
of siblings in a sibship who are affected to quantify a sibling correlation. That
not only relaxes the interchangeability problem but also makes the model
computationally efficient. We then use this modified class D logistic regressive
model for our segregation analysis. Using the proportion of siblings in a sibship
who are affected as a covariate resulted in a significantly higher likelihoods in
all the models we investigated. We found evidence for a dominant Mendelian gene
leading to early age of onset of breast and/or ovarian cancer. This could either
be a germline mutation of BRCA2 or a mutation in a gene different from BRCA2.
PMID- 9554558
TI - Laudatio Joel D. Kopple.
PMID- 9554559
TI - Mechanisms of insulin-like growth factor-I-induced accelerated recovery in
experimental ischemic acute renal failure.
AB - Exogenous administration of recombinant human insulin-like growth factor I (rhIGF
I) to normal rats or humans increases renal blood flow and glomerular filtration
rate (GFR). In rats with ischemic acute renal failure (iARF) the peptide
accelerates the recovery of renal function and tubular integrity. These latter
effects may be caused by renal hemodynamic actions of IGF-I or may result from
direct actions of IGF-I on injured tubular cells. To examine this hypothesis, in
vivo studies were performed in rats with iARF and in vitro experiments were
conducted using a model of anoxia/reoxygenation injury in primary cultures of rat
proximal tubular cells. In rats with iARF, IGF-I ameliorates the rise in serum
creatinine, improves GFR, increases the rate of bromodeoxyuridine (BrdU)
incorporation and the mitosis score, and reduces the number of apoptotic bodies.
In acutely injured proximal tubular cells, IGF-I receptor mRNA levels decrease,
but the remaining receptors are functional as indicated by ligand-induced
phosphorylation of the IGF-I receptor beta-subunit. In anoxia/reoxygenation
injured cells, exogenous rhIGF-I improves ATP repletion, increases 3H-thymidine
and BrdU incorporation and reduces the incidence of apoptosis as determined by
the TUNEL method. We conclude that rhIGF-I accelerates the recovery of renal
function in rats with iARF probably through hemodynamic effects, but in addition
through direct metabolic, mitogenic and antiapoptotic actions on injured tubules.
PMID- 9554560
TI - Fat-soluble vitamins in patients with acute renal failure.
AB - OBJECTIVE: Systematic investigations on the status of fat-soluble vitamins in
patients with acute renal failure (ARF) are lacking and hence no recommendations
for vitamin supply can be defined for these subjects. Thus we compared the status
of fat-soluble vitamins, of transport molecules and some vitamin-dependent
proteins in patients with ARF and healthy controls. SETTING: Nephrology unit of a
university hospital. PATIENTS AND METHODS: Eight patients with ARF requiring
hemodialysis therapy were investigated and 28 healthy volunteers served as
controls. Plasma concentrations of retinol (vitamin A) and retinol-binding
protein (RBP), 25-OH and 1,25-(OH)2 vitamin D3, of parathyroid hormone (PTH), of
alpha-tocopherol (vitamin E) and of phylloquinone (vitamin K), osteocalcin and
noncarboxylated osteocalcin, respectively, were measured and plasma lipoprotein
fractions (as vitamin transport vehicle) were evaluated. RESULTS: Vitamin A
levels were decreased (p < 0.001), but RBP levels were normal in ARF patients.
Vitamin D3 metabolites 25-OH and 1,25-(OH)2 vitamin D3 plasma levels were
profoundly depressed, and PTH was elevated (p < 0.001). Vitamin E plasma
concentration was reduced (p < 0.001) but this cannot be accounted for by
decreased LDL cholesterol or triglyceride levels. In contrast, vitamin K plasma
level was rather elevated in ARF patients with a broad range of individual
values. Blood coagulation was normal but total and carboxylated osteocalcin were
decreased. No correlation of vitamin K concentrations and any of the plasma
lipoprotein fractions could be identified. CONCLUSION: With the exception of
vitamin K, profound deficiencies of fat-soluble vitamins develop in patients with
ARF. Current recommendations for vitamin supplementation are inadequate and
should be reevaluated for these patients.
PMID- 9554561
TI - Osteopontin expression in the kidney during unilateral ureteral obstruction.
AB - Osteopontin is a bone protein also expressed in other tissues. Increased
osteopontin is thought to be associated with tissue inflammation. We used
immunocytochemical analyses and polymerase chain reaction amplification of mRNA
to examine osteopontin expression and regulation in unilateral ureteral
obstruction (UUO) in rats, a model of inflammatory kidney disease. In the
obstructed kidney, osteopontin mRNA and protein were significantly increased. The
increase reached 4-fold after 1 day of UUO and persisted at this level for the 5
day duration of UUO. Immunocytochemical analyses showed increased osteopontin
protein in tubular cells of the obstructed kidney cortex from days 1 through 5 of
UUO. No such significant increase was apparent in the glomerulus or interstitium.
Increased osteopontin mRNA and protein likewise occurred in the tubular cells of
the obstructed kidney of rats that had undergone whole-body irradiation to
eliminate macrophage infiltration into the experimental kidney. Purified
osteopontin was found to be a chemoattractant for macrophages isolated from the
rat peritoneum. Enalapril treatment, which decreases macrophage infiltration of
the obstructed kidney, had no effect on the increase in osteopontin mRNA but
significantly attenuated the increase in protein in tubular cells. Western blot
analysis of whole cortical homogenates revealed that the osteopontin antibody
recognized one protein of 67 kD. The amount of this protein was substantially
decreased in kidney homogenates obtained from enalapril-treated compared to
untreated animals. Increased osteopontin synthesis may, therefore, contribute in
part to the inflammatory response that characterizes obstructive nephropathy.
PMID- 9554562
TI - High-protein diets augment albuminuria in rats with Heymann nephritis by
angiotensin II-dependent and -independent mechanisms.
AB - Urinary albumin excretion (U(alb)V) increases following dietary protein
augmentation (DPA) in nephrotic humans and rats. Angiotensin-converting enzyme
inhibitors (ACEI) blunt, but do not entirely prevent, increased U(alb)V at doses
that reduce blood pressure and entirely block the pressor effect of exogenously
administered angiotensin I (Ang-I), suggesting that angiotensin II (Ang-II) might
not mediate the effect of DPA on U(alb)V. We determined the effect of losartan
(Los), a specific Ang-II receptor antagonist, and compared its effect to that of
enalapril (En), an ACEI, on DPA-induced increase in U(alb)V in rats with passive
Heymann nephritis (HN). When Los was administered to HN rats for 48 h prior to
DPA from 8.5 to 40% casein. U(alb)V increased in an identical fashion in treated
and untreated rats, even though Los caused hypotension and prevented the pressor
effect of infused Ang-II. Only on day 6 after DPA did U(alb)V decrease. We then
measured the effect of duration of pretreatment with Los on Ang-II binding to
isolated glomeruli. Maximal inhibition of Ang-II binding required treatment with
Los for 6 days. We then pretreated HN rats with either En or Los for 6 days prior
to DPA. In contrast to administration of Los for 2 days prior to DPA,
pretreatment with either Los or En for 6 days entirely prevented any increase in
U(alb)V. We then increased dietary NaCl from 0.2% to 2% (HS) to determine whether
En or Los would modulate U(alb)V after DPA when Ang-II activity was suppressed.
En reduced the DPA-mediated increase in U(alb)V regardless of dietary NaCl, while
Los was effective only in when dietary NaCl was reduced (0.2%), suggesting that
under these conditions ACEI reduces U(alb)V by a mechanism that is independent of
inhibition of Ang-II and that high protein diets augment U(alb)V by both Ang-II
independent and Ang-II-dependent mechanisms.
PMID- 9554563
TI - Corticomedullary procollagen alpha1(IV) mRNA levels and localization after
subtotal nephrectomy.
AB - The relationships between tubular hypertrophy/hyperplasia, procollagen alpha1(IV)
mRNA levels, and the development of tubular basement membrane thickening were
studied in male Sprague-Dawley rats subjected to subtotal renal ablation and
sacrificed 2 or 15 days later. Tubular hypertrophy and hyperplasia were
demonstrable at 2 days, however no increment in procollagen alpha1 (IV) mRNA
levels was discerned at that time, demonstrating a dissociation between mRNA
levels for classical type IV collagen and tubular enlargement. At 15 days,
tubular procollagen alpha1(IV) mRNA levels did increase approximately 2-fold (p <
0.002), localizing predominantly in proximal tubules in the deep cortex and outer
medullary stripe. At this time point, there was still no significant correlation
to tubular enlargement, but there was a significant correlation to tubular
basement membrane thickening (r = 0.89, p < 0.01). These studies demonstrated
that an increase in mRNA for classical type IV collagen is not required for the
development of hypertrophy, and that the increment is a better marker for matrix
expansion than it is for hypertrophy.
PMID- 9554564
TI - High-glucose media enhance the responsiveness of tubular cells to growth
promoters: effect on lysosomal cathepsins and protein degradation.
AB - Nephromegaly is a prominent feature of diabetic nephropathy and predominantly
reflects increased renal tubule mass, mostly due to hypertrophy. To elucidate
pathogenetic factors involved, we studied the effects of high glucose (HG) alone,
and in combination with hormones/growth promoters: angiotensin II (10(-7) M);
parathyroid hormone (10(-7) M); insulin-like growth factor-1 (10(-7) M), or
transforming growth factor-beta1 (TGF-beta1, 10 ng/ml) in a renal cell line (LLC
PK1) with many characteristics of the proximal tubule. Activities of lysosomal
cathepsins (B, L+B and H) and the protein turnover were investigated. Exposure to
HG (25 mM) for up to 48 h increased cellular protein content, due to enhanced
protein synthesis, while protein degradation rate and cathepsin activities tended
to lower values. Hyperosmotic mechanisms of glucose action were excluded, since
these effects were not induced by mannitol. In normoglycemic conditions only TGF
beta1 decreased cathepsin activities and protein degradation rate significantly.
However, in HG media all applied hormones/growth factors significantly lowered
the protein degradation rate, as well as lysosomal cathepsin activities. The
enhanced responsiveness could contribute to the impaired protein turnover, with
consequent hypertrophy of the tubulointerstitium in diabetic nephropathy.
PMID- 9554565
TI - Inhibition of protein synthesis by acid in L6 skeletal muscle cells: analogies
with the acute starvation response.
AB - Impaired protein synthesis (PS) occurs in skeletal muscle during acute
starvation. Even though it is well established that uraemic metabolic acidosis
(MA) stimulates protein degradation (PD) and is a major contributor to skeletal
muscle wasting in chronic renal failure, the accompanying effects of MA on PS are
much less clear. Previous work has shown that, in cultured L6 skeletal muscle
cells, PD and leucine oxidation are stimulated by acid. The aim of the present
study was to determine whether acid (like acute starvation) can also inhibit PS.
PS (14C-phenylalanine incorporation) was measured in L6 cells in MEM + 2% serum
at acid pH (7.1) or control pH (7.5). After 24 h, acid inhibited PS (7.7 +/- 0.2
vs. 8.9 +/- 0.1 nmol Phe/4 h/35-mm culture well in controls, p = 0.01) and this
was maintained at 72 h. In vitro this could arise because acid only inhibits the
rapid PS occurring in dividing cells. However, when division was abolished with
10(-5) mol/l cytosine arabinoside, PS inhibition by acid still occurred (6.9 +/-
0.1 vs. 8.3 +/- 0.2 at control pH, p < 0.05). Acid also had no effect on the
specific radioactivity of cellular phenylalanine, suggesting that the impaired PS
was not a consequence of inadequate labelling of this pool. Elevated PD and
impaired PS together led to loss of 7% of the total protein in only 28 h (-21 +/-
3 microg/well, p = 0.004). This combination of impaired PS with increased PD and
increased leucine oxidation in response to acid resembles the response of
skeletal muscle to acute starvation. These superficial similarities between the
starvation state and MA suggest that fundamental metabolic signals may occur
which are common to both states.
PMID- 9554566
TI - Relationship between whole-body protein turnover and serum creatinine in
chronically uremic patients.
AB - To investigate the relationship between decline in renal function and alterations
of protein metabolism we determined the rate of whole-body protein turnover in a
group of 15 postabsorptive chronically uremic patients (9 males and 6 females)
with different levels of serum creatinine concentrations (average 5.7 +/- 0.4
(SE) mg x dl(-1); range 3.3-9.1). Patients' age and body mass index were 53 +/- 4
years (range 26-73) and 24.7 +/- 0.6 kg/m2 (range 20.3-28.7), respectively.
Nutritional status (plasma albumin 3.6 +/- 0.4 g x dl[-1]) and acid-base
equilibrium (arterial pH 7.38 +/- 0.01) were fairly controlled by therapy. Whole
body leucine rate of appearance (Ra), an index of whole-body protein turnover,
was assessed using a stable isotope technique. L-[1-(13)C]leucine was
continuously infused and plasma [1-(13)C]alpha-ketoisocaproic acid enrichment was
determined in steady-state conditions as a marker of the intracellular leucine
enrichment. The average leucine Rawas 2.03 +/- 0.13 micromol x kg(-1) x min(-1)
(range 1.29-3.19). Using simple linear regression analysis, the coefficient of
correlation between the individual values of serum creatinine concentration and
leucine Ra was 0.59 (n = 15; p = 0.02). Leucine Ra did not significantly
correlate with blood pH or plasma albumin. In conclusion, we found a positive
linear relationship between the values of plasma creatinine concentration and the
rate of whole-body protein degradation. This correlation suggests that the
progression of renal insufficiency is associated with accelerated rates of
turnover of body proteins.
PMID- 9554567
TI - Effects of recombinant growth factors on energy expenditure in maintenance
hemodialysis patients.
AB - We compared the metabolic effects of recombinant human (rh) insulin-like growth
factor (IGF)-1 or a combination of rhIGF-1 + rh growth hormone (GH) on resting
energy expenditure (REE) in 8 maintenance hemodialysis (MHD) patients. Seven
males and 1 female (aged 41.6 +/- (SD) 12.4) with no evidence of malnutrition
(BMI 21.6 +/- 2.2 kg/m2, serum albumin 45 +/- 2 g/l, serum IGF-1 359 +/- 165
microg/l) received either rhIGF-1 (80 microg/kg/day) or rhIGF-1 (80
microg/kg/day) + rhGH (50 microg/kg/day) for 3 days in a random crossover design.
REE and the respiratory quotient (RQ) were measured at rest before and after the
3-day treatment. The results confirmed that MHD patients have a REE not different
from normal individuals. REE was strongly correlated with lean body mass but not
with fat mass. rhIGF-1 treatment did not modify REE despite doubling serum IGF-1
values, whereas a combined rhIGF1 + rhGH treatment significantly increased REE by
11% (p < 0.001). There was no change in RQ under both treatments, in response to
a proportionate increase in VCO2 and VO2. These results show that energy
expenditure is mainly dependent upon lean body mass in well-nourished MHD
patients. The metabolic effects of rhIGF-1 and rhGH on energy expenditure may
differ in response to their opposite effects on lipid oxidation and insulin
regulation.
PMID- 9554568
TI - Effects of a meat meal on renal sodium handling and sodium balance.
AB - Protein ingestion increases renal blood flow and glomerular filtration rate
(GFR). This study investigated in healthy adults if the renal response to protein
ingestion includes changes in urinary sodium (Na) excretion rate and Na balance.
Renal clearance of Na and inulin (used as index of GFR) were measured in 25
healthy adults before (90 min) and after (180 min) a standard meal and, as
control, before and after administration of water and Na-chloride (saline). The
meal consisted of red lean meat (2 g protein/kg body weight); in control
experiments, water and Na were given to match water and Na content of the meal.
ANOVA for repeated measures, Student's t-test, and linear regression were used
for statistical analysis. GFR and urinary Na excretion increased over baseline
after the meal (p < 0.001), not after saline. The post-meal natriuretic response
was accounted for an early (0-90 min) increase in glomerular filtered load of Na
(p < 0.001) and a late (90-180 min) reduction in tubular Na reabsorption (p <
0.02). Urine flow rate and plasma Na did not significantly change after the meal
and in control experiments. Analysis of Na balance showed that post-meal Na
excretion was significantly higher than baseline also after Na balance returned
to pre-meal values. In healthy individuals, a meat meal stimulates natriuresis
and causes a net decrease in Na balance. The renal natriuretic response to the
meal appears secondary to the meal-induced changes in renal hemodynamics. The
data are in keeping with the hypothesis that dietary protein intake affects also
renal Na handling.
PMID- 9554569
TI - Nutritional considerations in the treatment of patients with chronic uremia.
AB - Low-protein diets ameliorate uremic symptoms and some of its metabolic
complications. These diets can be used successfully to treat patients with
chronic renal failure (CRF) because they are able to activate normal compensatory
responses when protein intake is restricted and their protein and energy
requirements are similar to healthy subjects. However, there has been concern
that dietary therapy compromises the nutritional status of CRF patients and that
initiating dialysis would be preferable to this type of therapy. Kopple and co
workers have identified the requirements of CRF patients for protein and calories
and available evidence indicates that when properly implemented, low-protein
diets are safe and can maintain lean body mass even during long-term therapy.
Based on the information published by Kopple and co-workers, the strategies for
treating CRF patients should include careful analysis of the diet and the
nutritional status of the patient.
PMID- 9554570
TI - Intermittent calcitriol therapy and growth in children with chronic renal
failure.
AB - Intermittent calcitriol (1,25D) therapy has been used for the management of
secondary hyperparathyroidism in children with chronic renal failure; however,
the development of adynamic bone has been demonstrated in up to 40% of pediatric
patients after 12 months of intermittent 1,25D therapy. To assess its effect on
linear growth, we compared growth and biochemical data from 16 prepubertal
patients with biopsy-proven secondary hyperparathyroidism during 12 months of
intermittent 1,25D therapy and the preceding year of daily 1,25D therapy. While Z
scores for height remained stable during daily therapy, values decreased from
1.8 +/- 0.32 to -2.0 +/- 0.33, p < 0.01, during intermittent 1,25D therapy; the
largest reductions were seen in those who developed adynamic bone. Reductions in
growth may be due to the direct inhibitory effects of large intermittent doses of
calcitriol on chondrocyte activity.
PMID- 9554571
TI - Salt intake and renal outcome in patients with progressive renal disease.
AB - Experimental studies suggest that salt intake plays a critical role in the
progressive glomerular filtration rate (GFR) loss of established renal disease;
however, this issue has never been addressed in humans. To this aim, we have
retrospectively analyzed the clinical data of patients with chronic renal failure
(CRF), in whom a low-protein diet was prescribed, over a period of about 3 years.
On the basis of the daily urinary sodium output, the patients were divided into
two groups: a group of patients constantly ingesting > 200 mEq NaCl/day (high
sodium intake, HSD, n = 30) and a group in which salt intake was < 100 mEq/day
(low sodium intake, LSD, n = 27). Patients taking diuretics or ACE inhibitors
were excluded. At baseline, the LSD group, as compared to the HSD group, was
characterized by significantly lower creatinine clearance (24 +/- 2 vs. 28 +/- 2
ml/min) and higher proteinuria (2.9 +/- 0.3 vs. 1.5 +/- 0.2 g/day). Despite the
presence of these risk factors for progression, and a similar control of blood
pressure (the average of the mean arterial pressure during follow-up was 111 +/-
2 mm Hg in LSD and 107 +/- 2 mm Hg in HSD), the LSD patients showed a better
renal outcome: in this group, as compared to HSD, the GFR decline was lower (0.25
+/- 0.07 vs. 0.51 +/- 0.09 ml/min/month, p < 0.05), and proteinuria did not
change while it markedly increased in HSD. During follow-up, LSD patients also
ingested a significantly lower amount of protein. This study therefore suggests
that efficacious salt restriction in CRF patients improves the outcome of renal
disease independent from its antihypertensive effects.
PMID- 9554572
TI - The suprachiasmatic nucleus: a 25-year retrospective.
AB - The suprachiasmatic nuclei (SCN) of the anterior hypothalamus contain the master
circadian pacemaker in mammals. On the occasion of the 25th anniversary of the
discovery of the SCN as the circadian clock, Charles A. Czeisler and Steven M.
Reppert organized a meeting to review milestones and recent developments in the
study of the SCN. The discovery that the SCN contain tissue necessary for
generation of circadian rhythmicity was established by lesion studies published
in 1972. The second phase of study demonstrated unequivocally that the SCN
contain an autonomous circadian pacemaker. The principal studies in this period
showed the presence of metabolic and electrical activity rhythms in the SCN in
vivo and progressed to studies showing that the SCN maintain rhythmicity in
vitro, demonstrating that the transplanted SCN can restore circadian function
following destruction of the host SCN and ultimately showing that single SCN
"clock cells" exhibit independent rhythms in firing rate. The third phase of
study, aimed at identifying the biochemical and molecular mechanisms responsible
for rhythmicity within the SCN, has begun with the identification of circadian
mutants (tau mutant hamsters and Clock mutant mice) and the isolation of the
Clock gene. This report traces the important steps forward in our understanding
of the suprachiasmatic circadian clock by recounting the information presented at
the SCN Silver Anniversary Celebration.
PMID- 9554574
TI - Circadian parameters as individual characteristics.
AB - Human circadian rhythms that are free running in temporal isolation can show an
extreme variability of the sleep-wake cycle without the subject being aware of
it. This is due mainly to a systematic adjustment of certain circadian time
structures to the varying length of the "day": the perception of long time
intervals in the range of 1 h and the intervals between meals have a strong
positive correlation with the duration of wake time alpha, in contrast to the
amount of hourly locomotor activity that is negatively correlated with alpha. So
far, the dependence of locomotor activity, of the "1-h" intervals, and of the
intermeal intervals on alpha is well documented for the data sets of single
subjects. The present article demonstrates that the correlations found
intraindividually also apply if data from several subjects are compared. If
plotted as a function of the mean individual alpha, the individual means of "1-h"
intervals and of the intermeal intervals show the same positive correlation and
the means of locomotor activity show the same negative correlation with alpha as
known from single individuals. It is to be concluded that each individual has its
characteristic place on the regression lines that describe the dependence of the
three circadian parameters on the duration of wake time.
PMID- 9554573
TI - A parallelism between human body temperature and performance independent of the
endogenous circadian pacemaker.
AB - A battery of performance tests involving manual dexterity, serial search, and
verbal reasoning was given about seven times per day to 2 healthy young male
subjects (22 and 25 years of age) involved in separate forced desynchrony
studies, each involving several months of temporal isolation. In these studies,
the period lengths (denoted T) of the imposed day lengths (sleep/wake and
light/dark cycles) were 25.8 and 26.0 h for the 2 subjects. For each subject, the
endogenous circadian pacemaker (ECP) failed to entrain to a period of T and
instead free ran at a period length denoted tau (24.2 and 24.5 h). By educing
performance rhythms (and rectal temperature rhythms) separately at tau and at T
(after three complete beating cycles for the first subject and two complete
beating cycles for the second subject), the hypothesis could be tested as to
whether performance and temperature were parallel, both when educed at tau
(indicating ECP influence) and when educed at T (indicating sleep/wake cycle
influences). The hypothesis was consistently confirmed at tau and mostly
confirmed at T. For most variables, when educed at T, both performance speed and
body temperature showed an inverted V-shaped function, with a peak about 9 to 12
h after waking.
PMID- 9554575
TI - Testing the hypothesis of a circadian phase disturbance underlying depressive
mood in nonseasonal depression.
AB - In a crossover design, 8 nonseasonal depressed subjects, selected on the presence
of diurnal mood variations, and 8 sex- and age-matched controls were exposed to
dim light (< 10 lux) in the evening (18:00-21:00 h) and bright light (2500 lux)
in the morning (ML, 6:00-9:00 h), to dim light in the morning and bright light in
the evening (EL), or to dim light both in the evening and in the morning (DL)
during 3 consecutive days in each of these conditions. There were no initial
phase differences between depressed and healthy subjects in the timing of dim
light melatonin onset, sleep termination, and body temperature. The phase shifts
after EL and ML in both healthy and depressed subjects were as expected on the
basis of a human phase response curve. On average, there was no therapeutic
effect of the light exposure in the depressed patients. Two patients improved,
but these effects do not seem to be related to shifts in the circadian system.
PMID- 9554576
TI - Decreased light intensity alters the perception of day length by male European
starlings (Sturnus vulgaris).
AB - The breeding season of wild starlings is controlled by photoperiod. Full breeding
condition is attained during exposure to lengthening days in the spring, and
photorefractoriness ensues. The reproductive system of starlings will not
subsequently be stimulated by long day lengths until photorefractoriness is
dissipated by the short day lengths experienced in the autumn and winter. Unlike
most studies on avian photoperiodism, this investigation involved manipulation of
light intensity of a fixed photoperiod rather than of photoperiod itself.
Photosensitive starlings transferred from short days to long days of different
light intensities underwent graded reproductive responses according to the light
intensity they experienced. Testes size in the group in the lowest intensity (3
lux) increased faster than that in controls on short days of normal intensity,
but they did not become photorefractory. Testes size increased in the groups on
13, 45, and 108 lux and subsequently became photorefractory. However, the 13- and
45-lux groups required more time to become photorefractory than did the 108-lux
group. The responses observed were similar to those seen in starlings exposed to
different photoperiods (e.g., 11 h light:13 h dark [11L:13D], 13L:11D, 16L:8D,
18L:6D), even though all were on the same 18L:6D photoperiod. Initially, the
results appear to challenge the external coincidence model for photoperiodic time
measurement, but consideration of the phase response curve of the circadian
rhythm of photoinducibility in starlings and the way in which it might be
affected by low light intensities refute this challenge.
PMID- 9554577
TI - Photoreception in entrainment of rhythms and photoperiodic regulation of diapause
in a hemipteran, Graphosoma lineatum.
AB - The role of compound eyes in photoperiodic regulation of diapause and entrainment
of circadian rhythms was studied in a hemipteran, Graphosoma lineatum. Bilateral
removal of compound eyes resulted in the loss of locomotor rhythmicity under both
24-h light cycle and constant darkness. The arrhythmicity was associated with the
loss of photoperiodic regulation of diapause. Females with removed compound eyes
had similar incidence of oviposition under diapause preventing long-day
photoperiod (light:dark [LD] 18:6) and diapause inducing short-day photoperiod
(LD 12:12). By contrast, both locomotor rhythmicity and photoperiodic regulation
of diapause were maintained after unilateral removal of compound eyes. The
results suggest that the compound eye-optic lobe axis is involved in the
transmission of light signals for both entrainment of rhythms in locomotor
activity and photoperiodism. The compound eyes probably act as photoreceptors in
both transmission chains. Sites of the clocks for the two phenomena are
discussed.
PMID- 9554578
TI - Molecular circadian oscillators: an alternative hypothesis.
AB - Results from experiments in different organisms have shown that elements of input
pathways can themselves be under circadian control and that outputs might feed
back into the oscillator. In addition, it has become clear that there might be
redundancies in the generation of circadian rhythmicity, even within single
cells. In view of these results, it is worth reevaluating our current working
hypotheses about the pacemaker's molecular mechanisms and the involvement of
single autoregulatory genes. On one hand, redundancies in the generation of
circadian rhythmicity might make the approach of defining a discrete circadian
oscillator with the help of single gene mutations extremely difficult. On the
other hand, many examples show that components of signal transduction pathways
can indeed be encoded by single genes. The authors have constructed a model
placing an autoregulatory gene and its products on an input pathway feeding into
a separate oscillator. The behavior of this model can explain the majority of
results of molecular circadian biology published to date. In addition, it shows
that different qualities of the circadian system might be associated with
different cellular functions that can exist independently and, only if put
together, will lead to the known circadian phenotype.
PMID- 9554579
TI - Hematoxylin procedure for staining mature pollen grains in maize with
dimethylsulfoxide as a clearing agent.
AB - Observing nuclei of mature pollen grains in maize is extremely difficult because
the starch granules surrounding the nuclei are deeply stained. The cytoplasm of
hematoxylin stained pollen grains becomes clear when DMSO and gentle heating are
used. By separating the staining and clearing processes, uniformly stained pollen
grains were consistently obtained. Using this method, 2,000 pollen grains were
examined and it was determined that 99.5% were in the normal tricellular state,
while pentacellular pollen, bicellular pollen and pollen grains with two
vegetative nuclei were observed in the remaining 0.5%.
PMID- 9554580
TI - Fluorescence in situ hybridization (FISH): DNA probe production and hybridization
criteria.
AB - We describe methods for the production of fluorescence in situ hybridization
(FISH) probes and the utilization of these probes for the detection of
complementary DNA sequences with accuracy and sensitivity for application in both
basic research and clinical diagnosis. Due to the frequent use of FISH in many
laboratories, it is important to apply the most convenient and reproducible
approach. This review describes some of the most recent techniques, and includes
versatile, effective and simple methods of probe production and fluorescence in
situ hybridization. We also describe methods for the production of region
specific and chromosome-specific DNA probes and hybridization techniques for the
visualization of these probes.
PMID- 9554581
TI - Histochemical determination of stereoselectivity of esterases in normal pancreas
and pancreatic tubular adenocarcinoma of hamsters.
AB - Esterases in normal hamster pancreas and pancreatic tubular adenocarcinoma of
ductal origin induced by N-nitrosobis(2-oxopropyl)amine were stained in cryostat
sections with mixtures of a diazonium salt (fast blue RR) and with each of the
enantiomers of alpha-naphthyl N-methoxycarbonylalaninate, N
methoxycarbonylvalinate, and N-acetylprolinate. Azo coupling of alpha-naphthol
formed by enzymatic hydrolysis with the diazonium salt gives an azo dye that
indicates the presence and amount of the enzyme activity in situ. Comparison
between the color intensities obtained with each of the enantiomers of a chiral
alpha-naphthyl ester shows the stereoselectivity, or enantiomeric preference, of
the enzyme. Esterases in acinar cells of the normal pancreas showed slight
stereoselectivity for N-methoxycarbonylalaninate, while esterases in fat cells
scattered throughout the exocrine pancreas showed high stereoselectivity for (R)
N-acetylprolinate. These esterase activities were not found in the tumor, but
another prominent esterase activity with high stereoselectivity for (S)-N
methoxycarbonylvalinate was found. Similar results were obtained by staining
after polyacrylamide gel electrophoresis showing that the bands of esterases in
the adenocarcinoma stained only with the S enantiomer of the N
methoxycarbonylvalinate. The present method is a valuable tool for designing
anticancer prodrugs that are activated by tumor-specific esterases.
PMID- 9554582
TI - Cytological comparison of leaves and stems of Prunus avium L. shoots cultured on
a solid medium with agar or gelrite.
AB - An axillary proliferating clone of Prunus avium L. was subcultured every four
weeks on solid MS medium with agar as the gelling agent. Vitrification
(hyperhydricity) of shoots was induced in one four week cycle with the same
medium except that agar was replaced by gelrite. During culture on the vitrifying
medium, the water content of the shoots progressively increased with a parallel
decrease in chlorophyll content. Cytological differences between the leaves and
stems of the vitrified and normal shoots were detected by light and electron
(both transmission and scanning) microscopy. Leaves of vitrified shoots were
characterized by lower number of chloroplasts in the palisade parenchyma and by a
defective cuticle. The stems of vitrified shoots had a less developed and
lignifled xylem tissue, lacked sclerenchymatic areas and showed hypertrophy of
the cortical parenchyma. More intense vacuolar activity with evaginations of the
chloroplast envelope into the vacuole was noted in cells of vitrified leaves.
PMID- 9554583
TI - High contrast and homogeneous staining of paraffin sections of whole human brains
for three dimensional ultrahigh resolution image analysis.
AB - The gallocyanin chromalum stain belongs to the classical DNA-RNA staining
techniques in histochemistry. It has some important features for successful
object orientated image analysis of whole sections of the human brain. To obtain
reproducible staining results with these large sections, the method of Einarson
was adapted to image analytical requirements. We discuss staining in a warm
staining solution, pH adjustment, and optimal stain composition. The embedding
procedure for whole human brains is considered as well.
PMID- 9554584
TI - Improved osmication, dehydration and flat embedding of vibratome sections and
delicate whole mount preparations.
AB - A simple method for flat embedding vibratome sections or delicate whole mount
preparations in epoxy resin is described that allows thin layers of interest
within the specimen to be cut and studied as a whole in one plane. The fatal
curling that occurs during dehydration was avoided or at least minimized by
dehydrating the specimens in a layer of filter paper and a plastic meshwork under
permanent slight pressure. The flatness of the structures was maintained through
a graded series of ethanols followed by acetone. The specimens were transferred
to the resin and polymerized between two coated glass slides making it possible
to view and select the material without direct handling of the thin resin layer.
PMID- 9554586
TI - Preclinical in vivo antitumor activity of vinflunine, a novel fluorinated Vinca
alkaloid.
AB - Vinflunine, or 20',20'-difluoro-3',4'-dihydrovinorelbine, is a novel Vinca
alkaloid obtained by hemisynthesis using superacidic chemistry. The most
impressive structural modification of this vinorelbine derivative was the
selective introduction of two fluorine atoms at the 20' position, a part of the
molecule previously inaccessible by classic chemistry. The antitumor activity of
vinflunine was evaluated against a range of transplantable murine and human
tumors. Vinflunine exhibited marked activity against murine P388 leukemia grafted
i.v. when given i.p. in single or multiple doses according to various schedules
or in single i.v. or p.o. doses. Increases in life span achieved with vinflunine,
as assessed by T/C ratios, ranged from 200% to 457% and proved markedly superior
to those of 129-186% obtained with the other Vinca alkaloids tested. Against s.c.
implanted B16 melanoma, multiple i.p. administration of vinflunine proved active
in terms of both survival prolongation and tumor growth inhibition, with optimal
T/C values and relative areas under the tumor growth curves (rAUC) being 24% and
36%, respectively. The extent of this activity was superior to that noted for
vinorelbine under the same experimental conditions. Growth inhibition of human
tumor xenografts LX-1 (lung) and MX-1 (breast) was also observed following four
weekly i.p. injections of vinflunine as reflected by optimal T/C values of 23%
and 26%, respectively, and significant differences in the rAUCs noted for treated
versus control animals. It was also noticeable that vinflunine induced
considerably more prolonged inhibitory effects on tumor growth than did
vinorelbine. These results demonstrate that vinflunine is well tolerated and is
definitively active against a range of experimental animal tumor models.
Vinflunine activity has been documented in terms of both survival prolongation
and tumor growth inhibition, with definite superiority over vinorelbine being
shown in each tumor model evaluated.
PMID- 9554585
TI - Practical implementation of a modified continual reassessment method for dose
finding trials.
AB - PURPOSE: We describe a practical, reliable, efficient dose-finding design for
cytotoxic drugs applied in a multi-institutional setting. METHODS: The continual
reassessment method (CRM) was modified for use in phase I trials conducted
through the New Approaches to Brain Tumor Therapy (NABTT) Consortium. Our
implementation of the CRM uses (1) a simple dose-toxicity model to guide data
interpolation, (2) groups of three patients to minimize calculations and
stabilize estimates, (3) investigators' clinical knowledge or opinion in the form
of data to make the process easier to understand, and (4) a flexible computer
program and interface to facilitate calculations. RESULTS: The modified CRM was
used in two dose-finding trials of 9-aminocamptothecin in patients with newly
diagnosed and recurrent glioblastoma who were taking anticonvulsant medication.
The CRM located the maximum tolerated dose (MTD) efficiently in both trials.
Compared to conventional designs, the CRM required slightly more than half the
number of patients expected, did not greatly overshoot the MTD (i.e. no patients
were treated at dangerously high doses), and did not underestimate the MTD.
CONCLUSIONS: Our experience demonstrates the feasibility of implementing this
design in multi-institutional trials and the possibility of performing dose
finding studies that require fewer patients than conventional methods.
PMID- 9554587
TI - Sequence-dependent cytotoxicity of etoposide and paclitaxel in human breast and
lung cancer cell lines.
AB - PURPOSE: To evaluate the effect of schedule on the interaction of etoposide with
paclitaxel in vitro against the A549 human lung cancer cell line and the MDA-231
and MCF-7 human breast cancer cell lines. METHODS: Exposure schedules that were
24-h concurrent, 24-h sequential, and sequential 24-h with a 24-h intervening
drug-free period were quantitatively evaluated by the use of the median-effect
principle and the combination index. The clonogenic assay was used to assess
cytotoxicity, and calculations were done with computer software. RESULTS:
Concurrent exposures were less than additive in two of the three cell lines
tested. Sequential 24-hour and sequential 24-h with an intervening 24-h drug-free
period showed synergism at high effect levels in all three cell lines. Similar
synergistic interactions were found when either agent was administered first.
CONCLUSIONS: These results show a schedule-dependent cytotoxic interaction
between etoposide and paclitaxel in the human lung and breast cancer cell lines
evaluated, with optimal synergism occurring with sequential, but not with
concurrent, treatment.
PMID- 9554588
TI - Phase II trial of combination chemotherapy with cisplatin, carboplatin and
etoposide in stage IIIB and IV small-cell lung cancer. Fukuoka Lung Cancer Study
Group.
AB - PURPOSE: A phase II trial combining cisplatin, carboplatin and etoposide was
conducted in previously untreated patients with stage IIIB and IV small-cell lung
cancer, in an attempt to increase response rates and prolong survival. METHODS:
Previously untreated patients with small-cell lung cancer, with measurable
disease, aged < or = 72 years, performance status < or = 2, and adequate
hematologic, hepatic and renal function were enrolled in the study. They were
treated with 80 mg/m2 cisplatin on day 1, 100 mg/m2 carboplatin on days 2, 3 and
8, and 50 mg/m2 etoposide on days 1, 2, 3 and 8. RESULTS: A total of 46 patients
(20 with stage IIIB and 26 with stage IV disease) were enrolled in the study. A
total of 186 courses of chemotherapy were given, and the dose was reduced in 27
courses (15%). The chemotherapy was repeated for four or more courses in 30
patients. There were 10 complete responses and 32 partial responses, for a total
response rate of 91% (95% confidence interval, 79% to 98%). The median survival
time and 2-year survival rates were 18 months and 22% for stage IIIB disease, and
14 months and 15% for stage IV disease. Major side effects were hematologic:
leukopenia, anemia, and thrombocytopenia of grade 3 or more occurred in 48%, 46%,
and 43% of patients, respectively. CONCLUSIONS: The three-drug regimen of
cisplatin, carboplatin and etoposide is feasible and active against small-cell
lung cancer.
PMID- 9554589
TI - Expression of Bcl-2 in human epithelial tumor (HeLa) cells enhances clonogenic
survival following exposure to 5-fluoro-2'-deoxyuridine or staurosporine, but not
following exposure to etoposide or doxorubicin.
AB - A reduced capacity for apoptosis induction is considered to play a significant
role both in the development of malignancy and in tumor cell resistance to
chemotherapeutic drugs. The Bcl-2 oncoprotein inhibits apoptosis induced by
antitumor agents at a point downstream of drug-target interactions. Stable
expression of Bcl-2 in the human epithelial tumor (HeLa) cell line results in
inhibition of apoptosis following exposure to the topoisomerase II poison,
etoposide. However, Bcl-2 is unable to enhance clonogenic survival as a result of
alternate pathways to reproductive death induced by the drug. PURPOSE: The
purpose of this study was to further investigate the role of Bcl-2 in human
epithelial tumor cell drug resistance using 5-fluoro-2'-deoxyuridine,
staurosporine, and doxorubicin, in addition to etoposide. METHODS: The ability of
Bcl-2 to enhance clonogenic cell survival was studied by colony-forming assays,
while delay of cell death induction was assessed by trypan blue viability
measurements. The proportion of apoptotic cells was measured by morphological
criteria, as well as detection of apoptotic DNA fragmentation using the terminal
deoxynucleotidyl transferase assay. RESULTS: Despite profound inhibition to loss
of plasma membrane integrity for all agents tested, Bcl-2 was only able to
significantly increase clonogenic survival following exposure to 5-fluoro-2'
deoxyuridine and staurosporine, but not following exposure to etoposide or
doxorubicin. Furthermore, the time-course of apoptosis induction following
exposure of HeLa cells to equitoxic concentrations of staurosporine and etoposide
was profoundly different. CONCLUSIONS: These results indicate that Bcl-2 enhances
clonogenic survival of human epithelial tumor cells in an agent-specific fashion,
which may be determined by the initial cytotoxic lesion induced by a particular
drug.
PMID- 9554590
TI - Plasma and cerebrospinal fluid pharmacokinetics of 9-aminocamptothecin (9-AC),
irinotecan (CPT-11), and SN-38 in nonhuman primates.
AB - PURPOSE: The plasma and cerebrospinal fluid (CSF) pharmacokinetics of the
camptothecin analogs, 9-aminocamptothecin (9-AC) and irinotecan, were studied in
a nonhuman primate model to determine their CSF penetration. METHODS: 9-AC, 0.2
mg/kg (4 mg/m2) or 0.5 mg/kg (10 mg/m2), was infused intravenously over 15 min
and irinotecan, 4.8 mg/kg (96 mg/m2) or 11.6 mg/kg (225 mg/m2), was infused over
30 min. Plasma and CSF samples were obtained at frequent intervals over 24 h.
Lactone and total drug forms of 9-AC, irinotecan, and the active metabolite of
irinotecan, SN-38, were quantified by reverse-phase HPLC. RESULTS: 9-AC lactone
had a clearance (CL) of 2.1 +/- 0.9 l/kg per h, a volume of distribution at
steady state (Vd[ss]) of 1.6 +/- 0.7 l/kg and a half-life (t1/2) of 3.2 +/- 0.8
h. The lactone form of 9-AC accounted for 26 +/- 7% of the total drug in plasma.
The CSF penetration of 9-AC lactone was limited. CSF 9-AC lactone concentration
peaked 30 to 45 min after the dose at 11 to 21 nM (0.5 mg/kg dose), and the ratio
of the areas under the CSF and plasma concentration-time curves (AUC(CSF):AUC[P])
was only 3.5 +/- 2.1%. For irinotecan, the CL was 3.4 +/- 0.4 l/kg per h, the
Vd(ss) was 7.1 +/- 1.3 l/kg, and the t1/2 was 4.9 +/- 2.2 h. Plasma AUCs of the
lactone form of SN-38 were only 2.0% to 2.4% of the AUCs of irinotecan lactone.
The lactone form of irinotecan accounted for 26 +/- 5% of the total drug in
plasma, and the lactone form of SN-38 accounted for 55 +/- 6% of the total SN-38
in plasma. The AUC(CSF):AUC(P) ratio for irinotecan lactone was 14 +/- 3%. SN-38
lactone and carboxylate could not be measured (< 1.0 nM) in CSF. The
AUC(CSF):AUC(P) ratio for SN-38 lactone was estimated to be < or = 8%.
CONCLUSION: Despite their structural similarity, the CSF penetration of 9-AC and
SN-38 is substantially less than that of topotecan which we previously found to
have an AUC(CSF):AUC(P) ratio of 32%.
PMID- 9554591
TI - Differential effects of all-trans-retinoic acid, docosahexaenoic acid, and
hexadecylphosphocholine on cisplatin-induced cytotoxicity and apoptosis in a
cisplantin-sensitive and resistant human embryonal carcinoma cell line.
AB - Apart from modulation of tumor-cell drug sensitivity, induction of
differentiation might be an alternative in the treatment of tumors resistant to
cytotoxic drugs. In this report the capacity to induce differentiation and to
modulate the cis-diamminedichloroplatinum(II) (CDDP) sensitivity of all-trans
retinoic acid (RA), docosahexaenoic acid (DCHA), and hexadecylphosphocholine
(HePC) is examined in human germ-cell tumor cell lines. In the embryonal
carcinoma cell line Tera-2 and its 3.7-fold CDDP-resistant subline Tera2-CP, we
evaluated the effects of 96 h of pretreatment with RA (0.1 microM), DCHA (23
microM), and HePC (25 microM) on differentiation induction and on CDDP-induced
cytotoxicity, DNA platination (4-h incubation), and apoptosis (continuous
incubation). Without drug treatment, Tera2-CP showed less apoptosis than Tera-2.
Pretreatment with RA decreased the cytotoxicity and apoptosis induced by CDDP
without resulting in decreased DNA platination and increased differentiation in
both cell lines. DCHA enhanced CDDP-induced cytotoxicity and apoptosis and did
not affect the embryonal character of either cell line. HePC did not affect CDDP
cytotoxicity or differentiation in either cell lines. Effects of the modulators
on differentiation and on CDDP-induced cytotoxicity, DNA platination, and
apoptosis did not differ between Tera-2 and Tera2-CP. RA can be applied for
differentiation induction in CDDP-resistant germ-cell tumor models. However, in
this model, RA reduced the apoptotic susceptibility. DCHA potentiated CDDP
cytotoxicity in vitro; its in vivo modulatory capacity in germ-cell tumor cells
deserves further study.
PMID- 9554592
TI - Clinical and pharmacokinetic studies of high-dose levamisole in combination with
5-fluorouracil in patients with advanced cancer.
AB - PURPOSE: To determine the maximum tolerable dose (MTD) and activity of levamisole
administered concurrently with 5-fluorouracil (5-FU) in a standard 5-day course.
To determine the pharmacokinetics of levamisole during the course of treatment.
PATIENTS AND METHODS: Levamisole was administered to 38 patients orally three
times a day for 5 days concurrently with a course of 5-FU administered daily by
rapid intravenous injection for 5 days. Toxicity was evaluated in 20 patients who
received escalating doses of levamisole. The activity of the combination was
evaluated in 18 patients who received levamisole at the MTD with 5-FU. The
pharmacokinetics of levamisole were characterized in ten patients at the MTD
level. RESULTS: Intractable vomiting, confusion and vertigo were the major dose
limiting toxicities. The MTD of oral levamisole was 100 mg/m2 administered three
times a day concurrently with 450 mg/m2 per day intravenous 5-FU for 5
consecutive days. Partial responses lasting 5 and 11 months were observed in 2/18
patients with measurable disease at the MTD. Peak plasma concentrations of 1
microg/ml (range 0.6-1.3 microg/ml) were achieved 90 min (range 60-360 min) after
an oral dose of 100 mg/m2 levamisole with a 3.5-fold accumulation noted following
4 days of administration. Peak plasma concentrations of p-hydroxylevamisole were
about 5% of parent drug. Little parent drug (2-5%) was detected in urine.
CONCLUSIONS: Levamisole may be administered safely with 5-FU at doses which are
up to four to five times greater than those presently given in conventional
regimens. The recommended dose of levamisole combined with 5-FU for future
research protocols is 75 mg/m2 t.i.d for 5 days.
PMID- 9554593
TI - Enhancement of irinotecan (CPT-11) activity against central nervous system tumor
xenografts by alkylating agents.
AB - Two major obstacles in the treatment of patients with central nervous system
malignancies are drug resistance and host toxicity. The goal of combination
chemotherapy is to achieve therapeutic effects that are more favorable than using
a single drug alone, but without an increase in normal organ toxicity. The study
reported here examined the combination of a topoisomerase I inhibitor, irinotecan
(CPT-11), with three different alkylating agents: 1,3-bis(2-chloroethyl)-1
nitrosourea, busulfan, and cyclophosphamide. We evaluated the antitumor effects
of these three combinations against a panel of human tumor xenografts derived
from central nervous system malignancies, including adult high-grade gliomas (D
54 MG, D-245 MG) and a childhood ependymoma (D-612 EP). In replicate experiments,
the alkylating agents were given on day 1 in doses varying from 10% to 75% of the
dose lethal to 10% of the animals, and CPT-11 was given on days 1-5 and 8-12 in
doses varying from 10% to 100% of the dose lethal to 10% of the animals. The
antitumor effects of the various combinations ranged from less than additive
(7.61 days below additive with 0.5 CPT-11 + 0.75 cyclophosphamide in D-54 MG) to
statistically significant (P < 0.001) supraadditive effects (18.80 days above
additive with 0.5 CPT-11 + 0.5 1,3-bis(2-chloroethyl)-1-nitrosourea in D-54 MG).
These studies show that the combination of the topoisomerase inhibitor CPT-11 and
alkylating agents may increase the antitumor effect in some cases well above
additive with no increase in host toxicity (0/10 deaths in both experiments cited
above) and should be considered for combination chemotherapy of central nervous
system malignancies.
PMID- 9554594
TI - Interactions of mild hyperthermia, cisplatin and split dose irradiation in human
ovarian carcinoma cells.
AB - PURPOSE: Human ovarian cancer cells were evaluated to determine whether
combination treatment with mild hyperthermia and cisplatin could inhibit repair
of sublethal radiation damage. MATERIALS AND METHODS: Human ovarian carcinoma
cell lines A2780S (parental line) and A2780CP (cisplatin resistant variant) were
used in this study. Cisplatin at concentrations of 1 or 3 microg/ml was given
concomitantly with 1 h of heating at 40 degrees C either immediately before or
after irradiation. Survival was determined using a colony-forming assay. RESULTS:
Neither mild hyperthermia nor cisplatin treatments alone affected sublethal
damage repair. The combined treatment showed an effect in both cell lines and was
treatment sequence-dependent. The effect was greater in the parental cell line.
CONCLUSIONS: The data show that combined treatment of cisplatin and hyperthermia
may have clinical efficacy at cisplatin concentrations and hyperthermia
temperatures which by themselves have little to no effect.
PMID- 9554595
TI - Paclitaxel/carboplatin administration along with antiangiogenic therapy in non
small-cell lung and breast carcinoma models.
AB - INTRODUCTION: With the introduction of new drugs, the efficacy of chemotherapy in
non-small-cell lung cancer has been improving. The combination of paclitaxel and
carboplatin has shown activity in this disease but is far from curative. METHODS:
The antiangiogenic agent regimen of TNP-470/minocycline was added to treatment
with paclitaxel and carboplatin alone and in combination in animals bearing the
Lewis lung carcinoma. RESULTS: Administration of the antiangiogenic regimen prior
to, during and after the cytotoxic therapy increased the tumor growth delay 1.6
fold and decreased the number of lung metastases to 20% of the number observed in
the control animals. [14C]Paclitaxel, platinum from carboplatin and [14C]albumin
levels were determined over a 24-h time course in tumors and normal tissues of
animals bearing the Lewis lung carcinoma and pretreated with TNP-470/minocycline
or not pretreated. There were higher levels of [14C]paclitaxel, platinum from
carboplatin and [14C]albumin in the tumors and some normal tissues of the animals
that had received TNP-470/minocycline compared with those that had not received
TNP-470/minocycline, especially at the earlier time points. Administration of TNP
470/minocycline to animals bearing the EMT-6 mammary carcinoma increased the
cytotoxicity of high-dose paclitaxel toward EMT-6 tumor cells and toward bone
marrow CFU-GM. Administration of TNP-470/minocycline to animals bearing the EMT-6
mammary carcinoma also increased the cytotoxicity of carboplatin toward the EMT-6
tumor cells but did not affect the toxicity of carboplatin toward the bone marrow
CFU-GM. CONCLUSIONS: The addition of TNP-470/minocycline to treatment with
paclitaxel and carboplatin resulted in increased antitumor activity and efficacy
and further investigation of this combination is warranted.
PMID- 9554596
TI - Effects of polyamine analogues on prostatic adenocarcinoma cells in vitro and in
vivo.
AB - PURPOSE: The overall purpose of this study was to determine the potential
usefulness of 1,19-di-(ethylamino)-5,10,15-triazononadecane (BE-4-4-4-4) in the
treatment of prostate cancer using in vitro and in vivo models. More specifically
the objectives were: (1) to determine the in vitro and in vivo sensitivity of
human and rat prostate cancer cells to two polyamine analogues N1,N11
di(ethyl)norspermine (DENSPM) and BE-4-4-4-4; (2) to determine whether the
mechanism of cell kill occurred through an apoptotic pathway; and (3) to
determine the toxicity associated with therapeutic doses of BE-4-4-4-4 using an
animal model. METHODS: In order to determine the ability of these drugs to cause
in vitro cytotoxicity, colony-forming assays were performed utilizing the well
characterized Dunning rat prostate cancer cell lines AT3.1, AT6.1 and AT6.3, and
the androgen-insensitive human prostate cancer cell lines DU145, DuPro-1 and TSU
Pr1. Apoptotic cell death was determined using DNA laddering and DAPI staining of
nuclei. The antitumor activity of BE-4-4-4-4 was evaluated by treatment of DuPro-
and PC-3 xenograft tumors in nude mice. RESULTS: BE-4-4-4-4 was shown to be
approximately 4 to 86 times more cytotoxic in clonogenic assays than DENSPM in
both rat and human prostate carcinoma cell lines. Cells treated with cytotoxic
doses of DENSPM or BE-4-4-4-4 showed no signs of apoptosis using either DNA
laddering or DAPI staining of nuclei. There was a significant inhibition of DuPro
1 tumors for animals treated with BE-4-4-4-4 compared with control animals.
Equitoxic doses of BE-4-4-4-4 resulted in greater tumor inhibition than DENSPM,
although the difference was not significant. After treatment with therapeutic
doses of BE-4-4-4-4, histopathologic evaluation indicated minimal to mild
necrosis and inflammation in the kidneys on days 15 and 22 following treatment.
On day 35, there was no necrosis or regeneration present in the kidney,
indicating that the toxicity was transient and that regeneration of epithelial
cells was complete with apparent return to normalcy. CONCLUSIONS: These initial
studies demonstrate that BE-4-4-4-4 is cytotoxic against rat and human prostate
cancer cells in culture and effective against DuPro-1 xenografts in nude mice.
Polyamine analogues, such as DENSPM or BE-4-4-4-4, should be considered for
clinical use in the treatment of prostate adenocarcinomas.
PMID- 9554597
TI - High-dose-intensity combination chemotherapy for advanced sarcomas: a pilot
study.
AB - A new polychemotherapy schedule involving high dose intensity and shortened
intervals has been developed for patients with advanced sarcomas. Mesna at 2500
mg/m2 for 3 days, epidoxorubicin at 60 mg/m2 on day 1, ifosfamide at 2500 mg/m2
for 3 days, and dacarbazine at 450 mg/m2 for 2 days were given every 2 weeks to a
consecutive series of 20 patients. All patients received granulocyte colony
stimulating factor (G-CSF; Filgrastim) subcutaneously at 300 microg from day 5 to
day 12 of each cycle. The treatment was feasible and toxicity was acceptable,
with grade IV myelotoxicity being observed only in one case. In all, 6 of 14
evaluable patients had an objective response; the median survival was 12 months.
Toxicity was milder than that observed for the classic combination MAID, and the
planned dose intensity was maintained in the majority of cases.
PMID- 9554598
TI - Effect of the multidrug resistance modulator valspodar on serum cortisol levels
in rabbits.
AB - PURPOSE: To contribute to a better understanding of the physiological role of P
glycoprotein (P-gp) in the adrenal gland, we initiated our studies in rabbits.
The aim of our study was to explore the effect of the selective multidrug
resistance (MDR) modulator PSC 833 (valspodar) on serum cortisol in rabbits.
METHODS: Baseline and corticotropin-stimulated serum cortisol levels were
measured before and after valspodar treatment in adult male rabbits. Seven
rabbits were treated with 50 mg/kg per dose and seven, with 75 mg/kg per dose of
valspodar subcutaneously. Serum cortisol levels were determined by
radioimmunoassay adjusted for expected values. RESULTS: Serum cortisol levels
(baseline as well as corticotropin-stimulated) increased after both valspodar
treatment regimens. The increase was dose-dependent and was higher for the
baseline than for the corticotropin-stimulated values. Serum valspodar levels
exceeding 1000 ng/ml were achieved in all except one animal in each group. We
hypothesize that the increased serum cortisol levels were due to increased
adrenocorticotropic hormone (ACTH) secretion after valspodar treatment, but,
unfortunately, we could not measure ACTH properly in rabbits by means of the
commercially available kits. CONCLUSIONS: Our study indicates that P-gp is not
involved in steroid hormone secretion in the adrenal gland. This is evident from
observations that serum cortisol levels were found to have increased rather than
decreased in rabbits treated with a P-gp blocker and that the treated animals
appeared healthy and normal. Since P-gp was found to play an important role in
protection against xenobiotics in some other organs, further studies to explore
the protective role of P-gp in the adrenal gland are warranted.
PMID- 9554599
TI - Quantitative evaluation of multiplicity in epidemiology and public health
research.
AB - Epidemiologic and public health researchers frequently include several dependent
variables, repeated assessments, or subgroup analyses in their investigations.
These factors result in multiple tests of statistical significance and may
produce type 1 experimental errors. This study examined the type 1 error rate in
a sample of public health and epidemiologic research. A total of 173 articles
chosen at random from 1996 issues of the American Journal of Public Health and
the American Journal of Epidemiology were examined to determine the incidence of
type 1 errors. Three different methods of computing type 1 error rates were used:
experiment-wise error rate, error rate per experiment, and percent error rate.
The results indicate a type 1 error rate substantially higher than the
traditionally assumed level of 5% (p < 0.05). No practical or statistically
significant difference was found between type 1 error rates across the two
journals. Methods to determine and correct type 1 errors should be reported in
epidemiologic and public health research investigations that include multiple
statistical tests.
PMID- 9554600
TI - Caffeine intake and low birth weight: a population-based case-control study.
AB - The authors conducted a matched case-control study to investigate the effects of
caffeine intake during pregnancy on birth weight. From January to November 1992,
in the first 24 hours after delivery, 1,205 mothers (401 cases and 804 controls)
were interviewed and their newborns were examined to assess birth weight and
gestational age by means of the method of Capurro et al. (J Pediatr 1978;93:120
2). The cases were children with birth weight < 2,500 g and gestational age > or
= 28 weeks. Cases and controls were matched for time of birth and hospital of
delivery and were recruited from the four maternity hospitals in Pelotas,
southern Brazil. Daily maternal caffeine intake during pregnancy for each
trimester was estimated. To assess caffeine intake, 10% of the mothers were
reinterviewed at their households and samples of reported information on drip
coffee and mate (a caffeine-containing drink widely used in South America) were
collected and sent to the laboratory for caffeine determination through liquid
chromatography. When instant coffee was reported, the weight of powder was
measured using a portable scale, and caffeine intake was estimated from a
reference table. Caffeine intake from tea, chocolate, soft drinks, and medicines
was estimated from a reference table. Analyses were performed by conditional
logistic regression. Crude analyses showed no effect of caffeine on low birth
weight, preterm births or intrauterine growth retardation. The results did not
change after allowing for confounders.
PMID- 9554601
TI - Effects of physical activity on preterm birth.
AB - The authors conducted a cohort study of low income women to determine the effect
of physical activity on the risk of preterm birth. Women were sampled prenatally
from four clinic sites and were scheduled for delivery at the University of
Maryland Medical Systems (UMMS). Women who delivered infants at UMMS but who had
received no prenatal care were also eligible. Preterm delivery was defined as a
delivery prior to 37 completed weeks gestation. After adjusting for confounders,
the odds of preterm delivery were increased for women who climbed stairs > or =
10 times per day (odds ratio (OR) = 1.60, 95% confidence interval 1.05-2.46) and
for women who engaged in purposive walking > or = 4 days per week (OR = 2.10, 95%
CI 1.38-3.20). Leisure-time exercise (> or = 60 days in the first and second
trimesters combined) had a protective effect on preterm delivery (OR = 0.51, 95%
CI 0.27-0.95). Television viewing had a U-shaped relation with preterm delivery
(ORs (95% CI): < 15 hours, 2.09 (1.21-3.61); 29-42 hours, 1.50 (0.84-2.67); > 42
hours, 3.05 (1.75-5.40)). While the results support current recommendations
regarding leisure-time activities, activities of daily living appear to increase
risk of preterm delivery among low income women. These findings and those for
television watching warrant further investigation.
PMID- 9554602
TI - Menstrual cycle characteristics and history of ovulatory infertility in relation
to breast cancer risk in a large cohort of US women.
AB - Menstrual cycle characteristics and ovulatory infertility were evaluated in
relation to breast cancer risk among 116,678 women in the Nurses' Health Study
II, a prospective cohort study of female registered nurses who were aged 25-42
years and living in 14 US states at enrollment in 1989. During 396,299 person
years of follow-up between return of the baseline questionnaire and June 1993,
251 cases of breast cancer were identified in this cohort. The multivariate
relative risk (RR) associated with age at menarche > 13 years compared with age <
or = 12 years was 0.66 (95% confidence interval (CI) 0.44-0.99). Short and long
menstrual cycle lengths at ages 18-22 years were associated with reduced risk.
Compared with menstrual cycle length 26-31 days, the multivariate relative risks
(95% CIs) for more extreme cycle lengths were: < 26 days, 0.50 (0.25-0.98); 32-39
days, 0.81 (0.51-1.28); and > 39 days or too irregular for estimation of a usual
cycle length, 0.41 (0.18-0.94). The multivariate relative risk associated with a
history of ovulatory infertility, compared with no such history, was 0.41 (95% CI
0.18-0.93). These results are consistent with the hypothesis that reduced
exposure to ovulatory menstrual cycles provides a protective effect against
breast cancer.
PMID- 9554603
TI - Body mass index, cigarette smoking, and other characteristics as predictors of
self-reported, physician-diagnosed gallbladder disease in male college alumni.
AB - Despite the high prevalence of gallbladder disease in industrialized countries,
little is known about the predictors of the disease, especially in men. The
authors prospectively studied 16,785 alumni of Harvard University, aged 15-24
years, who were followed for up to 61 years. The health characteristics of these
men were ascertained from their college entrance physical examination done in
1916-1950, and updated via mailed questionnaires in 1962 or 1966 (1962/1966).
Alumni subsequently self-reported physician-diagnosed gallbladder disease on
further mailed questionnaires in 1972 or 1977. Between college time and
1962/1966, 371 gallbladder disease cases occurred. An additional 314 cases
occurred after 1962/1966. With respect to college characteristics, after
adjustment for potential confounders, the authors found that body mass index
(BMI), smoking, physical activity, blood pressure, and consumption of alcohol,
coffee, or tea were unrelated to risk. However, BMI in 1962/1966 was directly
related to risk of subsequent gallbladder disease, as was BMI gain since college
(p, trend = 0.002 and 0.013, respectively). Compared with men with BMI < 22.0,
men with BMI > or = 27.0 had a rate ratio of 2.71 (95% confidence interval (CI)
1.57-4.66) for risk of contracting the disease. Men who gained > or = 6.0 BMI
units since college had a rate ratio of 1.46 (95% CI 0.86-2.46) compared with men
who gained -0.9 to +0.9 BMI units. Compared with never smokers, men who smoked
pipes or cigars or < 1 pack of cigarettes daily in 1962/1966 had a rate ratio of
1.43 (95% CI 1.00-2.06), while heavier cigarette smokers had a rate ratio of 1.52
(95% CI 1.03-2.24). Neither physical activity nor physician-diagnosed
hypertension or diabetes mellitus in 1962/1966 predicted risk.
PMID- 9554604
TI - Family history score as a predictor of breast cancer mortality: prospective data
from the Cancer Prevention Study II, United States, 1982-1991.
AB - A consistent predictor of a woman's risk for breast cancer is a family history of
the disease. Most studies of family history and breast cancer have used the
number of affected relatives in the family to calculate relative risk, but they
have not considered the heterogeneity of the familial risk for breast cancer in a
systematic way. With the use of data from a large prospective mortality study of
US adults, the authors compared simple classification of family history of breast
cancer (yes/no) to the method of using a quantitative family history score
method, which takes into account the effects of family structure, age, and birth
cohort as predictors of breast cancer mortality. After 9 years of follow-up,
1,428 cases of fatal breast cancer were observed among 453,073 women with
complete information on number and age of siblings and family history. With the
use of the family history score, about one-third of women with a positive family
history of breast cancer were at no higher risk for breast cancer mortality than
those without a family history of the disease. As a quantitative measure of
relative risk for each family, family history score gave a better fit to the
data, and it provided an incremental improvement of predictive accuracy of
developing fatal breast cancer. Family history score can also be used as a
categorical variable to stratify families. This allows researchers to focus on
which risk groups would benefit from conducting further genetic analysis and to
test the effects of genetic factors, environmental exposure, and gene-environment
interactions on the etiology of the development of breast cancer.
PMID- 9554605
TI - Marked increase in bladder and lung cancer mortality in a region of Northern
Chile due to arsenic in drinking water.
AB - Studies in Taiwan and Argentina suggest that ingestion of inorganic arsenic from
drinking water results in increased risks of internal cancers, particularly
bladder and lung cancer. The authors investigated cancer mortality in a
population of around 400,000 people in a region of Northern Chile (Region II)
exposed to high arsenic levels in drinking water in past years. Arsenic
concentrations from 1950 to the present were obtained. Population-weighted
average arsenic levels reached 570 microg/liter between 1955 to 1969, and
decreased to less than 100 microg/liter by 1980. Standardized mortality ratios
(SMRs) were calculated for the years 1989 to 1993. Increased mortality was found
for bladder, lung, kidney, and skin cancer. Bladder cancer mortality was markedly
elevated (men, SMR = 6.0 (95% confidence interval (CI) 4.8-7.4); women, SMR = 8.2
(95% CI 6.3-10.5)) as was lung cancer mortality (men, SMR = 3.8 (95% CI 3.5-4.1);
women, SMR = 3.1 (95% CI 2.7-3.7)). Smoking survey data and mortality rates from
chronic obstructive pulmonary disease provided evidence that smoking did not
contribute to the increased mortality from these cancers. The findings provide
additional evidence that ingestion of inorganic arsenic in drinking water is
indeed a cause of bladder and lung cancer. It was estimated that arsenic might
account for 7% of all deaths among those aged 30 years and over. If so, the
impact of arsenic on the population mortality in Region II of Chile is greater
than that reported anywhere to date from environmental exposure to a carcinogen
in a major population.
PMID- 9554606
TI - Obesity, weight gain, large weight changes, and adenomatous polyps of the left
colon and rectum.
AB - Epidemiologic studies of colorectal neoplasia have usually examined body mass
index as a risk factor, but not other aspects of obesity. During 1991-1993, the
authors obtained weight histories and comprehensive covariate data from men and
women aged 50-75 years who underwent sigmoidoscopy at a health maintenance
organization in southern California. Using 483 cases with adenomas and 483
controls, measures of obesity (body mass index), positive energy balance (net
weight gain in the past 10 years), and weight variability (large weight changes)
were each independently related to adenoma prevalence. Compared with subjects in
the lowest quartile of body mass index, multivariate-adjusted odds ratios for
subjects in increasingly higher quartiles were 2.1 (95% confidence interval (CI)
1.4-2.3), 1.8 (1.1-2.9), and 1.7 (1.0-2.8), respectively. Compared with subjects
who reported a net weight loss during the 10 years before sigmoidoscopy, subjects
with net weight gains of 1.5-4.5 kg or > or = 4.5 kg had adjusted odds ratios
(95% CI) of 2.5 (1.2-5.6) and 1.8 (0.7-4.4), respectively. Compared with subjects
who had no large weight changes during adulthood, subjects with 1-2, 3, or > or =
4 changes had adjusted odds ratios (95% CI) of 2.0 (1.0-3.9), 2.5 (1.2-5.5), and
1.5 (0.6-3.6), respectively. Obesity, weight gain, and unstable adult weight may
be independently associated with colorectal carcinogenesis.
PMID- 9554607
TI - Selection bias in occupational sperm studies.
AB - Participation rates in sperm studies are typically 25-50%, and therefore it is a
matter of concern whether the men who provide semen samples truly reflect the
parent population. The authors analyzed data from three Danish occupational sperm
studies and evaluated the relation between age and occurrence of subfertility to
participation and provision of semen samples. Age and subfertility were found to
be rather strong determinants of participation. Willingness to provide semen
samples was greater among men aged <40 years (odds ratio (OR) = 1.8, 95%
confidence interval (CI) 1.3-2.6) and among men who had experienced an infertile
period (OR = 1.7, 95% CI 1.3-2.1). Furthermore, the effect of infertility was
modified by occupational exposure status, thus resulting in a tendency to
differential selection and possibly biased risk estimates. In a cross-sectional
study, the authors recommend that priority be given to a high participation rate
and that data on the basic variables be collected from the entire study
population, so that it is possible to make a nonresponder analysis and evaluate
bias. Such an analysis can be carried out by means of questions enquiring about
infertility, genital disorders, and earlier seminal examinations. Although the
longitudinal study design is without many of the limitations of the cross
sectional study, a longitudinal study is usually not feasible.
PMID- 9554608
TI - Association of a central pattern of body fat with blood pressure and lipoproteins
from adolescence into adulthood. The Amsterdam Growth and Health Study.
AB - The association between the change in a central pattern of body fat and blood
pressure and lipoprotein levels was investigated longitudinally in a healthy
population of young males and females over 15 years. The subjects (males, n = 84;
females, n = 98), participants in the Amsterdam Growth and Health Study, were
measured six times between the mean ages of 13 and 27 years. As an indicator of a
central pattern of body fat, subscapular/triceps skinfold ratio (S/T ratio) was
used as an independent variable. Systolic blood pressure (SBP), diastolic blood
pressure (DBP), total serum cholesterol (TC), high density lipoprotein
cholesterol (HDL-C), and TC/HDL-C ratio were used as dependent variables.
Longitudinal associations were analyzed by generalized estimating equations (GEE)
in which data of the six periods of measurement were included simultaneously.
Between ages 13 and 27 years, and after adjustment for the sum of four skinfolds,
physical activity, smoking, and alcohol intake, the increase of the S/T ratio was
significantly associated with an increase in SBP in males and females and with a
decrease in level of HDL-C in males only. The change in central pattern of body
fat negatively affects the change in established risk factors for cardiovascular
diseases early in life.
PMID- 9554609
TI - Comparison of population-averaged and subject-specific approaches for analyzing
repeated binary outcomes.
AB - Several approaches have been proposed to model binary outcomes that arise from
longitudinal studies. Most of the approaches can be grouped into two classes: the
population-averaged and subject-specific approaches. The generalized estimating
equations (GEE) method is commonly used to estimate population-averaged effects,
while random-effects logistic models can be used to estimate subject-specific
effects. However, it is not clear to many epidemiologists how these two methods
relate to one another or how these methods relate to more traditional stratified
analysis and standard logistic models. The authors address these issues in the
context of a longitudinal smoking prevention trial, the Midwestern Prevention
Project. In particular, the authors compare results from stratified analysis,
standard logistic models, conditional logistic models, the GEE models, and random
effects models by analyzing a binary outcome from two and seven repeated
measurements, respectively. In the comparison, the authors focus on the
interpretation of both time-varying and time-invariant covariates under different
models. Implications of these methods for epidemiologic research are discussed.
PMID- 9554610
TI - Adult female twins' recall of childhood social class and father's education: a
validation study for public health research.
AB - To assess recall of childhood socioeconomic position for public health research,
the authors conducted a cross-sectional study of 352 adult women twin pairs
enrolled in Examination II of the Kaiser Permanente Women Twins Study carried out
in 1989-1990 in Oakland, California. Among twin pairs, 91% (95% confidence
interval (CI) 89-94%) agreed on their father's educational level and 81% (95% CI
77-85%) on their childhood social class. Recall did not differ by adult
socioeconomic position, zygosity, race/ethnicity, or age. Thus, epidemiologic
studies can validly use retrospective data on childhood socioeconomic position to
study its relation to adult health status.
PMID- 9554611
TI - Geographic epidemiology of gonorrhea in Baltimore, Maryland, using a geographic
information system.
AB - The epidemiology of gonorrhea is characterized by geographically defined
hyperendemic areas, or "cores." Geographic information system (GIS) technology
offers new opportunities to evaluate these patterns. The authors developed a GIS
system linked to the disease surveillance database at the Baltimore Health
Department and used this system to evaluate the geographic epidemiology of
gonorrhea in Baltimore, Maryland, during 1994. There were 7,330 reported cases,
of which 87.4% were in persons aged 15-39 years; 56.6% were of the cases were in
males; and 60.5% of the cases were reported from the nonsexually transmitted
disease (STD) clinic sector. Valid residential addresses were available for 6,831
(93.5%) of cases. In the GIS system, gonorrhea cases were geocoded by reported
address using digitized maps, and assigned to census tract. Census tract-specific
rates for persons aged 15-39 years were calculated using 1990 census data.
Gonorrhea was reported from 196/202 (97%) of census tracts, of which 90 census
tracts had >30 cases. For these 90 census tracts, rates were ranked. The core was
considered as the top rate quartile, consisting of 13 geographically contiguous
census tracts with rates 4,370-6,370 per 100,000; adjacent areas were 19 census
tracts in the second quartile (rates: 3,730-4,370 per 100,000). As radial
distance from the core areas increased, incidence rates decreased and male/female
ratio increased, which is consistent with previous definitions of the core theory
of STD transmission. Mapping of cases by provider showed that cases reported from
STD clinics had similar geographic distribution to those from the non-STD clinic
sector. From an operational perspective, GIS can be effectively integrated with
clinical data systems to provide epidemiologic analysis.
PMID- 9554612
TI - Mechanisms of acute epicardial and myocardial injury in pericardial disease.
PMID- 9554613
TI - Preoperative smoking reduction: all or nothing at all?
PMID- 9554614
TI - Use of the breathing reserve to interpret submaximal exercise responses.
PMID- 9554615
TI - It's not "just a virus" anymore.
PMID- 9554616
TI - The acute effect of minocycline on the pericardium: experimental and clinical
findings.
AB - STUDY OBJECTIVES: To evaluate the acute effect of minocycline on the pericardium
in the experimental animal and in the human with malignant pericardial disease.
DESIGN: A prospective study in open-chest dogs and in humans. SETTING:
Experimental surgery laboratory, medical school; coronary care unit, university
hospital. METHODS: Twenty-three open-chest dogs were divided into four groups
according to the solution injected intrapericardially: (1) minocycline, 5 mg/kg;
(2) minocycline, 10 mg/kg; (3) normal saline solution, 100 mL, followed by
minocycline, 10 mg/kg; (4) a mixture of 50 mL of the dog's own blood mixed ex
vivo with minocycline, 10 mg/kg to evaluate the effect of rising pH of
minocycline solution. The extent of myocardial injury is evaluated by measuring
ST-T segment deviation in six standard bipolar leads and in three unipolar
electrograms recorded over the left ventricular pericardial surface. The pH of
the various minocycline solutions is measured. Nine consecutive patients with
malignant cardiac tamponade receiving minocycline intrapericardially are
evaluated for the appearance of chest pain and ECG changes. RESULTS: Minocycline
(5 and 10 mg/kg) caused marked, transient ST-T segment deviation in all dogs,
whether or not saline solution was previously injected into the pericardial sac.
Prior mixing of minocycline with blood markedly increased the acidic pH of the
minocycline solution and significantly reduced the extent of ST-T segment
deviation. Four of nine patients had chest pain during minocycline injection.
None had ST-T segment changes. CONCLUSION: Minocycline causes a marked, transient
injury to the epicardial-pericardial surface. Our animal and in vitro studies
indicate that this acute injury is probably partly related to the acidic pH of
the minocycline solution. Our experimental findings suggest that this minocycline
induced injury may be reduced by raising the pH of the solution either ex vivo
(eg, by mixing minocycline with previously withdrawn pericardial fluid) or in
vivo (eg, by leaving 200 to 300 mL of pericardial fluid prior to minocycline
injection). Limited experience in the human with malignant cardiac tamponade
indicates that intrapericardial minocycline is usually well tolerated, although
severe chest pain may appear.
PMID- 9554617
TI - Normal left ventricular ejection fraction in older persons with congestive heart
failure.
AB - STUDY OBJECTIVES: To investigate in older patients with congestive heart failure
(CHF) associated with prior myocardial infarction or hypertension the
relationship between normal left ventricular (LV) ejection fraction and age,
gender, hypertension, prior myocardial infarction, and atrial fibrillation.
DESIGN: A prospective study was performed in 572 older patients (age >60 years)
with CHF associated with prior myocardial infarction or hypertension and
technically adequate two-dimensional echocardiograms for measuring LV ejection
fraction. SETTING: A long-term health-care facility. PATIENTS: One hundred
seventy-seven men and 395 women, mean age 82+/-8 years, with CHF associated with
prior myocardial infarction or hypertension. MEASUREMENTS AND RESULTS: Normal LV
ejection fraction (> or = 50%) occurred in 66 of 177 men (37%) and in 221 of 395
women (56%) (p<0.0001). Multiple logistic regression analysis showed that
independent risk factors for normal LV ejection fraction in patients with CHF
were no prior myocardial infarction (p=0.0001; odds ratio=3.048), female gender
(p=0.0004; odds ratio=1.978), and age (p=0.016; odds ratio=1.029). CONCLUSIONS:
Normal LV ejection fraction occurred in 50% of 572 older patients with CHF
associated with prior myocardial infarction or hypertension. Independent risk
factors for normal LV ejection fraction in patients with CHF were no prior
myocardial infarction, female gender, and age.
PMID- 9554618
TI - Left ventricular-arterial system coupling at peak exercise in dilated nonischemic
cardiomyopathy.
AB - We assessed the ventricular-arterial coupling at peak exercise in 20 patients
with dilated cardiomyopathy (ejection fraction, 27+/-12%) and 7 normal subjects
by radionuclide ventriculography during exercise, coupled with respiratory gas
analysis. The end-systolic pressure-volume ratio, taken as an index of
contractility, and the effective arterial elastance were calculated at rest and
at peak exercise. The end-systolic pressure/volume ratio increased from 3.7+/-2.7
to 6.9+/-4.0 mm Hg/mL at peak exercise in the normal subjects, but did not change
significantly (from 0.9+/-0.5 to 1.0+/-0.6 mm Hg/mL) in the patients. Arterial
elastance did not change significantly in the patients (+17+/-32%, not
significant [NS] vs rest) or in the normal subjects (+22+/-28%, NS vs rest). The
change in ejection fraction during exercise correlated both with the end-systolic
pressure/volume ratio and with effective arterial elastance changes (r=0.60 and
0.68, respectively). We conclude that ventricular arterial coupling is further
altered at peak exercise in these patients because of the lack of increase in
contractility and not of altered effective arterial elastance response.
PMID- 9554619
TI - Coronary artery bypass grafting in patients with COPD.
AB - OBJECTIVE: To more fully define the influence of COPD in patients undergoing
coronary artery bypass grafting (CABG). METHODS: One hundred ninety-one patients
with COPD underwent CABG from March 1, 1995, to June 21, 1996. There were 129
male and 62 female patients. The mean age was 69 years (45 to 86 years). Patients
with COPD were defined according to the Summit Database definition: requires
therapy for the treatment of chronic pulmonary compromise or has an FEV1 <75% of
predicted value. RESULTS: Hospital mortality was 7%. Hospital morbidity was 50%.
Statistically significant (p<0.05) morbidity included general pulmonary
complications (12%) and atrial fibrillation (27%). Hospital mortality for COPD
patients with postoperative pneumonia was 11%. Hospital mortality for patients
with COPD receiving steroids was 19%. The hospital mortality for patients > or =
75 years of age was 17%. The combined mortality for patients with COPD who are >
or = 75 years of age and receiving steroid therapy was 50%. The mean length of
stay was 12 days. Late mortality was 1% at a mean of 1.5 years. CONCLUSIONS:
Hospital mortality in most patients with mild-to-moderate COPD undergoing CABG is
similar to those without COPD. In the minority of patients with severe COPD who
are receiving steroids and > 75 years, the hospital mortality is exceptionally
high. These findings support CABG in patients with mild-to-moderate COPD.
Nonsurgical therapy should be considered for elderly COPD patients with severe
disease taking steroids.
PMID- 9554620
TI - Preoperative smoking habits and postoperative pulmonary complications.
AB - OBJECTIVE: To examine the effect of preoperative smoking behavior on
postoperative pulmonary complications. DESIGN: Prospective cohort study. SETTING:
The Veterans Administration Medical Center, Syracuse, NY. PARTICIPANTS: Patients
scheduled for noncardiac elective surgery (n=410). MEASUREMENTS AND RESULTS:
Smoking status was determined by self-report. Postoperative pulmonary
complications were determined by systematic extraction of medical record data.
Postoperative pulmonary complications occurred in 31 of 141 (22.0%) current
smokers, 24 of 187 (12.8%) past smokers, and 4 of 82 (4.9%) never smokers. The
odds ratio (OR) for developing a postoperative pulmonary complication for current
smokers vs never smokers was 5.5 (95% confidence interval [CI], 1.9 to 16.2) and
4.2 (95% CI, 1.2 to 14.8) after adjustment for type of surgery, type of
anesthesia, abnormal chest radiograph, chronic cough, history of pulmonary
disease, history of cardiac disease, history of COPD, education level, pulmonary
function, body mass index, and age. Current smokers who reported reducing
cigarette consumption prior to surgery were more likely to develop a complication
compared with those who did not (adjusted OR=6.7, 95% CI, 2.6 to 17.1).
CONCLUSIONS: Current smoking was associated with a nearly sixfold increase in
risk for a postoperative pulmonary complication. Reduction in smoking within 1
month of surgery was not associated with a decreased risk of postoperative
pulmonary complications.
PMID- 9554621
TI - Comparison of short-term functional outcomes following unilateral and bilateral
lung volume reduction surgery.
AB - STUDY OBJECTIVES: To compare short-term functional outcomes following unilateral
and bilateral lung volume reduction surgery (LVRS) performed in patients with
advanced emphysema. METHODS: LVRS was performed unilaterally in 32 patients and
bilaterally in 119 patients. Pulmonary function testing and 6-min walk test
(6MWT) were performed preoperatively and repeated at 3 to 6 months
postoperatively. RESULTS: Bilateral LVRS was associated with increased in
hospital mortality (10% vs 0%, p<0.05) and a higher incidence of postoperative
respiratory failure (12.6% vs 0%; p<0.05) compared with unilateral LVRS. There
was no significant difference in duration of air leaks between unilateral and
bilateral groups, but the mean hospital stay was significantly longer following
bilateral LVRS (21.1+/-32.0 days vs 14.2+/-14.0 days; p<0.05). Preoperatively,
there was no significant difference between the unilateral and bilateral groups
with respect to FEV1, FVC, residual volume, or 6MWT distance. However, for all of
these parameters, the magnitude of improvement was significantly greater
following bilateral LVRS. Notably, the magnitude of improvement in each parameter
following unilateral LVRS exceeded half that following bilateral LVRS, suggesting
that functional outcomes after the unilateral procedure were disproportionate to
the amount of tissue resected. Serial functional assessment of seven patients
undergoing staged unilateral procedures (two unilateral procedures separated in
time by at least 3 months) demonstrated somewhat unpredictable responses; failure
to achieve a favorable response to the initial procedure did not necessarily
portend a similar outcome with the contralateral side, and vise versa.
CONCLUSIONS: Bilateral LVRS produces a greater magnitude of short-term functional
improvement than does the unilateral procedure and should be considered the
procedure of choice for most patients. Unilateral LVRS should be reserved for
patients in whom factors contraindicating entrance into one hemithorax exist.
PMID- 9554622
TI - Lung volume reduction surgery: an analysis of hospital costs.
AB - OBJECTIVE: Lung volume reduction surgery (LVRS) represents a potential
breakthrough in the management of advanced emphysema, although questions remain
about clinical and economic implications of widespread application of LVRS. In
this report, we describe hospital costs, excluding physicians' fees, for LVRS.
DESIGN: Hospital charges were obtained from billing records and converted to
costs by applying multiple cost-to-charge ratios. SETTING: A large, urban
academic medical center. PATIENTS: Fifty-two consecutive patients who received
bilateral LVRS through a median sternotomy between April 1995 and August 1996.
RESULTS: Median hospital stay was 10 days (mean= 14.8+/-12.8 days; range=3 to 48
days), including 2 days (mean=6+/-9.2 days; range=1 to 35 days) in the ICU. One
hospital death occurred. Hospital costs per case ranged from $11,712 to $121,829,
with mean costs of $30,976 and median costs of $19,771. Costs were related
significantly to duration of ICU stay and length of hospitalization. Patients who
accrued the highest costs were significantly older than the remainder of the
sample (69.3 years vs 62.4 years). CONCLUSIONS: Hospital costs of LVRS vary
significantly but are related directly to hospital stay. Identification of
factors associated with prolonged stays can be used in assessing benefits and
risks of LVRS against utilization of health-care dollars.
PMID- 9554623
TI - Impaired skeletal muscle endurance related to physical inactivity and altered
lung function in COPD patients.
AB - STUDY OBJECTIVE: The aims of this work were to determine (1) whether patients
with COPD have impaired skeletal muscle performance (ie, maximal strength and
endurance) compared with healthy subjects, and (2) whether the level of physical
activity, body composition, and lung function are related to skeletal muscle
performance in COPD patients. METHODS: Seventeen COPD patients and eight healthy
age-matched control subjects performed maximum voluntary contraction (MVC) of the
quadriceps and an endurance test consisting of dynamic contractions of the
quadriceps against 20% of MVC at an imposed regular pace until exhaustion. The
endurance test duration determined the muscle "limit time" (Tlim). A score of
physical activity (PA score) was obtained using an adapted physical activity
questionnaire for the elderly, and body composition was measured by the
bioelectrical impedance method. Symptom-limited oxygen uptake (VO2 sl) was also
assessed in COPD patients using a maximal incremental exercise test. RESULTS: The
results showed that Tlim and PA score were significantly decreased in COPD
patients (p<0.05). Significant positive correlations were found in the COPD group
between Tlim and the PA score (r=0.60; p<0.05), FEV1 (r=0.52; p<0.05), and PaO2
(r=0.63; p<0.05). The same results were found between the PA score and VO2 sl
(r=0.57; p<0.05) and FEV1 (r=0.63; p<0.05). CONCLUSION: These findings indicate
impaired skeletal muscle endurance in COPD patients related to altered lung
function and associated physical inactivity.
PMID- 9554624
TI - Aerobic endurance training program improves exercise performance in lung
transplant recipients.
AB - STUDY OBJECTIVE: To determine whether an aerobic endurance training program (AET)
in comparison to normal daily activities improves exercise capacity in lung
transplant recipients. PATIENTS AND STUDY DESIGN: Nine lung transplant recipients
(12+/-6 months after transplant) were examined. All patients underwent
incremental bicycle ergometry with the work rate increased in increments of 20 W
every 3 min. Identical exercise tests were performed after 11+/-5 weeks of normal
daily activities and then after a 6-week AET. The weekly aerobic training time
increased from 60 min at the beginning to 120 min during the last week. Training
intensity ranged from 30 to 60% of the maximum heart rate reserve. RESULTS:
Normal daily activities had no effect on exercise performance. The AET induced a
significant decrease in resting minute ventilation from 14+/-5 to 11+/-3 L/min.
At an identical, submaximal level of exercise, a significant decrease in minute
ventilation from 47+/-14 L/min to 39+/-13 L/min and heart rate from 144+/-12 to
133+/-17 beats/min, before and after the AET, was noted. The increase in peak
oxygen uptake after AET was statistically significant (1.13+/-0.32 to 1.26+/-0.27
L/min). CONCLUSIONS: These data demonstrate that normal daily activities do not
affect exercise performance in lung transplant recipients > or = 6 months after
lung transplantation. An AET improves submaximal and peak exercise performance
significantly.
PMID- 9554625
TI - Breathing reserve at the lactate threshold to differentiate a pulmonary
mechanical from cardiovascular limit to exercise.
AB - STUDY OBJECTIVES: Criteria used to define the respective roles of pulmonary
mechanics and cardiovascular disease in limiting exercise performance are usually
obtained at peak exercise, but are dependent on maximal patient effort. To
differentiate heart from lung disease during a less effort-dependent domain of
exercise, the predictive value of the breathing reserve index (BRI=minute
ventilation [VE]/maximal voluntary ventilation [MVV]) at the lactate threshold
(LT) was evaluated. DESIGN: Thirty-two patients with COPD and a pulmonary
mechanical limit (PML) to exercise defined by classic criteria at maximum oxygen
uptake (VO2max) were compared with 29 patients with a cardiovascular limit (CVL)
and 12 normal control subjects. Expired gases and VE were measured breath by
breath using a commercially available metabolic cart (Model 2001; MedGraphics
Corp; St. Paul, Minn). Arterial blood gases, pH, and lactate were sampled each
minute during exercise, and cardiac output (Q) was measured by first-pass
radionuclide ventriculography (System 77; Baird Corp; Bedford, Mass) at rest and
peak exercise. RESULTS: For all patients, the BRI at lactate threshold (BRILT)
correlated with the BRI at VO2max (BRIMAX) (r=0.85, p<0.0001). The BRILT was
higher for PML (0.73+/-0.03, mean+/-SEM) vs CVL (0.27+/-0.02, p<0.0001), and vs
control subjects (0.24+/-0.03, p<0.0001). A BRILT > or = 0.42 predicted a PML at
maximum exercise, with a sensitivity of 96.9%, a specificity of 95.1%, a positive
predictive value of 93.9%, and a negative predictive value of 97.5%. CONCLUSIONS:
The BRILT, a variable measured during the submaximal realm of exercise, can
distinguish a PML from CVL.
PMID- 9554626
TI - Cytomegalovirus pneumonia in AIDS patients: value of cytomegalovirus culture from
BAL fluid and correlation with lung disease.
AB - OBJECTIVES: To verify the value of cytomegalovirus (CMV) cultures of BAL fluid vs
postmortem lung histopathology in detecting CMV pneumonia, and to correlate the
BAL viral dose with the number of CMV inclusion bodies (CMV-IB) in the lung
tissue of AIDS patients. DESIGN: Retrospective analysis of 434 BALs and 40
autopsies involving 307 AIDS patients; clinical follow-up lasted 10 months.
PATIENTS AND METHODS: The 40 patients who died within 20 days of undergoing BAL
were divided on the basis of histopathologic findings into subjects with and
without CMV-IB in the lung tissue. The relationship between the BAL viral dose
and CMV lung infection was evaluated by counting the early antigen (CMV-EA)
positive cells/200 microL of BAL and the number of CMV-IB/mm2 of lung tissue.
RESULTS: The predictive value of BAL virus isolation for the diagnosis of CMV
pneumonia was 61% for positive and 100% for negative results. The patients with
the largest number of CMV-IB had CMV-EA counts from 2 to 840; in those with a
moderate and small number, the CMV-EA counts were, respectively, from 11 to 700
and 2 to 300. Among the patients surviving up to 10 months after the BAL index
sample, the frequency of recurrent extrapulmonary CMV abnormalities was 27% in
those with positive and 7% in those with negative cultures. CONCLUSIONS: BAL CMV
cultures from AIDS patients have a very high negative and relatively low positive
predictive value for CMV pneumonia. The presence and replication of CMV in the
lung may lead to systemic dissemination as suggested by the higher probability of
CMV extrapulmonary diseases. Viral titers do not seem to be related to the degree
of lung damage.
PMID- 9554627
TI - Cytomegalovirus viremia in lung transplant recipients receiving ganciclovir and
immune globulin.
AB - BACKGROUND: Cytomegalovirus (CMV) disease is an important cause of organ
transplant-related morbidity and mortality. During the last 5 years at our
institution, prophylactic ganciclovir and hyperimmune globulin have been
routinely administered to lung transplant recipients whenever the donor or the
recipient was CMV antibody-positive. We sought to assess the efficacy of
prophylaxis on viremia, CMV disease, and bronchiolitis obliterans syndrome (BOS).
METHODS: A retrospective chart review of 61 consecutive lung transplants
performed between recipients between January 1993 and August 1995 was performed.
Fifty-six patients who survived at least 1 month were analyzed. Patients were
considered at risk for CMV disease whenever pretransplant donor or recipient
serology was positive. RESULTS: Fourteen of the 39 patients at risk (36%) had
viremia while on prophylaxis. The rate of CMV disease was 13% during the first 6
months following transplantation. A donor whose CMV serology was positive
appeared to increase the risk of BOS in a Cox regression model (relative
risk=2.4; 95% confidence interval=0.86-6.74; p=0.0957). Neither age, CMV
infection (viremia or a positive specimen from BAL), recipient's serology at the
time of transplantation, or CMV disease was associated with BOS. None of these
variables was associated with mortality on Cox regression analysis or univariate
analysis. CONCLUSIONS: Administration of combination ganciclovir and hyperimmune
globulin prophylactic therapy to lung transplant recipients at risk for CMV
infection and disease is associated with a relatively low incidence of disease,
which appears only after prophylaxis treatment with ganciclovir is completed.
Ganciclovir prophylaxis does not prevent CMV viremia; however, viremia while on
prophylaxis is not predictive of disease.
PMID- 9554628
TI - Pulmonary tuberculosis treated with directly observed therapy: serial changes in
lung structure and function.
AB - OBJECTIVES: (1) To correlate structure (CT) with function in pulmonary
tuberculosis (TB), and (2) to describe the evolution of structural and functional
abnormalities when pulmonary TB is treated with directly observed therapy.
SUBJECTS AND METHODS: Twenty-five patients with drug-susceptible pulmonary TB, 15
cavitary and 10 noncavitary, were studied prospectively. Conventional CT and
pulmonary function testing (spirometry, diffusing capacity, and arterial blood
gases) were performed at baseline, and after 1 and 6 months of directly observed
therapy. RESULTS: All but one patient with noncavitary miliary TB had CT evidence
of endobronchial disease, and all patients with cavitary disease had coexistent
reduced lung attenuation, the latter presumably a result of gas trapping, hypoxic
vasoconstriction, and vascular injury. Functional impairment was minimal and in
proportion to the number of diseased segments and cavitary volume. Bronchiectasis
was significantly more likely to complicate cavitary than noncavitary disease (64
vs 11%; p<0.05). CONCLUSIONS: CT findings correlate well with function in
pulmonary TB. Physiologic data were consistent with the concept that pulmonary TB
is an endobronchial disease that causes parallel reductions in ventilation and
perfusion. This concurrent involvement of both airways and contiguous pulmonary
blood supply offers an explanation for the minimal respiratory limitation
experienced by these patients despite often extensive lung disease. Supervised
therapy of drug-susceptible disease results in minimal structural and functional
residua.
PMID- 9554629
TI - Community respiratory viral infection in adult lung transplant recipients.
AB - STUDY OBJECTIVE: To define the epidemiology, clinical manifestations, and long
term complications of respiratory viral infections in adult lung transplant
recipients. DESIGN: Retrospective review of the records of 122 adult lung
transplant recipients over a 5-year period at one institution. RESULTS: Ten
episodes of infection with respiratory syncytial virus, parainfluenza, influenza,
or adenovirus were identified. All patients presented with symptoms of
respiratory tract infection. Two patients died acutely and four patients
subsequently had development of obliterative bronchiolitis (OB). CONCLUSIONS:
These data suggest community respiratory viral infections cause significant
morbidity and mortality in lung transplant recipients. Further prospective
studies are warranted to clarify the relationship between respiratory viral
infection and OB and to define the optimal therapy for these viral infections.
PMID- 9554630
TI - A comparison of the availability of tobramycin for inhalation from vented vs
unvented nebulizers.
AB - STUDY OBJECTIVE: To compare drug output from a vented nebulizer (Pari LC Jet
Plus) with a traditional unvented nebulizer (Hudson 1730 T Up-Draft 11) using
aerosolized tobramycin, which is frequently used in the treatment of cystic
fibrosis. DESIGN: Six nebulizers of each type were filled with a 4 mL tobramycin
(80 mg) solution and were driven by a compressor (Pulmo-Aide). Various
inspiratory flows (VI) (0, 5, 10, 15, 20 L/min for the Pari LC Jet Plus and 0, 5,
and 10 L/min for the Hudson 1730, all at 40% relative humidity) were directed
through each nebulizer. Drug output was measured from changes in weight and
concentration (assessed by changes in osmometry) within the nebulizer. Particle
size distributions were determined by laser diffraction allowing the calculation
of the amount of aerosol output in the respirable range (<5 microm). The
nebulizers were first run until end-nebulization to establish total drug output
and then for either 4 or 5 min to determine the rate of drug output (mg/min)
before intermittent aerosol output. RESULTS: The total drug output without VI for
both the unvented and the vented nebulizers was not significantly different, 55
(51, 60) mg for the Hudson 1730 vs 51 (49, 53) mg for the Pari LC Jet Plus (mean
[95% confidence limits]). Inspiratory flow had no effect on the unvented Hudson
1730 nebulizer but significantly increased the rate of total drug output and the
rate of drug output in the respirable range for the vented Pari LC Jet Plus
nebulizer (VI=0, 3.35 [2.84, 3.85] and 1.72 [1.48, 1.96] compared with VI=20,
9.87 [9.03, 10.70] and 6.11 [5.33, 6.88] mg/min). CONCLUSIONS: These findings
indicate that the increase in the rate of drug output with VI for the vented
nebulizer would result in shorter nebulization times and a relative decrease in
drug loss during the expiratory phase.
PMID- 9554631
TI - Lung deposition of fenoterol and flunisolide delivered using a novel device for
inhaled medicines: comparison of RESPIMAT with conventional metered-dose inhalers
with and without spacer devices.
AB - STUDY OBJECTIVES: To compare lung deposition of fenoterol or flunisolide
administered from a novel, multidose inhalation device delivering liquid droplets
(RESPIMAT; Boehringer Ingelheim Ltd; Bracknell, UK) or from conventional metered
dose inhalers (MDIs) with and without spacers. DESIGN: Two randomized, three-way
crossover studies. SETTING: Clinical research laboratory. PARTICIPANTS: Healthy,
nonsmoking volunteers. INTERVENTIONS: In one study, radiolabeled aerosols of
fenoterol from the RESPIMAT device and from a conventional MDI with or without an
Aerochamber spacer (Trudell Medical; London, Ontario Canada). In the second
study, radiolabeled aerosols of flunisolide from a RESPIMAT device, from a
RESPIMAT device modified by inclusion of a baffle/impactor in the mouthpiece, and
from a conventional MDI with an Inhacort spacer (Boehringer Ingelheim; Ingelheim,
Germany). MEASUREMENTS AND RESULTS: Assessment of the deposition of fenoterol or
flunisolide in the lung and oropharynx using gamma scintigraphy. Safety was
assessed based on reported adverse effects and spirometry (FEV1, FVC, and peak
expiratory flow rate) to detect any paradoxical bronchoconstriction. The RESPIMAT
device delivered significantly more fenoterol to the lungs than either an MDI
alone or an MDI with Aerochamber (39.2% vs 11.0% and 9.9% of metered dose,
respectively; p<0.01). Oropharyngeal deposition of fenoterol from the new device
was lower than that from the MDI (37.1% vs 71.7%, respectively; p<0.01). The
RESPIMAT device deposited significantly more flunisolide in the lungs compared
with MDI plus spacer (44.6% vs 26.4%, respectively; p<0.01), while resulting in
similar oropharyngeal deposition (26.2% vs 31.2%, respectively). Introduction of
a baffle into the RESPIMAT system reduced lung deposition of flunisolide to
29.5%, and oropharyngeal deposition to 7.8% (p<0.01). CONCLUSION: The RESPIMAT
device may prove to be an effective alternative to MDIs for the administration of
inhaled bronchodilators and corticosteroids. The high lung deposition and low
oropharyngeal deposition may lead to improved efficacy and tolerability of
inhaled medications, especially corticosteroids.
PMID- 9554633
TI - Compliance with peak expiratory flow monitoring in home management of asthma.
AB - BACKGROUND: The recent consensus reports on asthma management emphasize the
importance of using peak flowmeters to accurately assess the degree of airflow
obstruction. However, the optimal way to use those devices has not yet been
determined. OBJECTIVES: To assess compliance with peak expiratory flow (PEF)
measurements in the long-term management of asthma, and identify the
characteristics of patients with poor compliance. SETTING: Asthma clinics from
three tertiary-care hospitals. DESIGN: A descriptive and prospective study of 1
year duration. PATIENTS: Twenty-six patients with moderate to severe asthma
taking part in an asthma education program. MAIN OUTCOME MEASURES: Patients were
asked to measure morning and evening PEF using an electronic peak flowmeter with
a 3-month memory; they were unaware that PEF values were being recorded by this
device. RESULTS: Compliance with PEF measurements was relatively good during the
first month (63% of the measurements done) but even with regular reinforcement,
fell to 50% at 6 months and to 33% at 12 months. Right from the beginning, 8 of
26 subjects (30%) never or almost never (<5% of the readings done) measured PEF,
with seven of these subjects writing fabricated results in their diaries most of
the time. At 12 months, 60% of the subjects were measuring PEF <25% of the time,
and most of them continued writing fabricated PEF values in their diaries. None
of the subjects' characteristics helped us to identify those who had poor
compliance with these measurements. CONCLUSIONS: While short-term compliance with
PEF measurements is fairly good, most patients with moderate to severe asthma are
not interested in measuring PEF twice daily over a prolonged period. In the
current management of asthma, PEF measurement devices can be suggested to those
showing a strong personal interest in using them, but should be limited to short
periods of time. Furthermore, this study outlines the usefulness of electronic
peak flowmeters when doing clinical research where PEF improvement is an
important outcome.
PMID- 9554632
TI - Is normal bronchial responsiveness in asthmatics a reliable index for withdrawing
inhaled corticosteroid treatment?
AB - STUDY OBJECTIVE: Inhaled corticosteroid (ICS) treatment is first-line maintenance
therapy in bronchial asthma. However, it is not clear whether and when ICS
treatment can be withdrawn. The aim of this open study was to assess whether
normalization of bronchial responsiveness could be used as a reliable index to
assess the opportunity of ICS treatment withdrawal. DESIGN: Open study at two
different points in time. SETTING: Outpatient pulmonary clinic. PATIENTS:
Eighteen asthmatic subjects. MEASUREMENTS AND RESULTS: ICS therapy was withdrawn
in subjects treated with beclomethasone dipropionate, at the maintenance dose of
889+/-246 microg/d for >3 months. Upon recruitment, all subjects were
asymptomatic, had FEV1 >70% of predicted value, and were in treatment with beta2
agonists on an as-needed basis. Eight subjects (group 1) had normal bronchial
responsiveness (methacholine provocative dose causing a 20% fall in FEV1 [PD20]
>2,000 microg) and 10 subjects (group 2) had bronchial hyperresponsiveness (BHR)
(PD20 < or = 2,000 microg). After withdrawal of ICS treatment, subjects were
followed up for 3 weeks and were asked to record their asthma symptoms (cough,
dyspnea, and wheezing) and their beta2-agonist use. At recruitment and at the end
of follow-up, subjects underwent spirometry and a methacholine challenge test.
Frequency of asthma exacerbation was similar in subjects with normal bronchial
responsiveness (NBR) and in subjects with BHR (50% vs 60%), but subjects with NBR
tended to remain asymptomatic for longer than those with BHR (mean+/-SD, 10.7+/
4.4 days vs 5.5+/-3.8 days) (p=0.08). None of the subjects reported any condition
that could have triggered exacerbation. Asthma exacerbation was associated with a
significant decrease in FEV1 (-105+/-107 mL; p<0.05) and in PD20 (-1,332+/-1,020
microg; p<0.001). CONCLUSIONS: Our study shows that the likelihood of asthma
exacerbation is not reduced if ICS treatment is withdrawn when the subjects have
NBR, but the exacerbation could be delayed. Further studies in larger populations
of asthmatics are needed to confirm these findings.
PMID- 9554634
TI - Longitudinal determinants of bronchial responsiveness to inhaled histamine.
AB - BACKGROUND AND STUDY OBJECTIVE: The point prevalence of bronchial
hyperresponsiveness (BHR) is imperfectly associated with current asthma, possibly
due to changes over time in bronchial responsiveness (BR). To evaluate cross
sectional and longitudinal determinants of BR, a population sample comprising 408
children and adolescents, aged 7 to 17 years at enrollment, was examined twice, 6
years apart. METHODS: Case history was obtained by interview and questionnaire.
BR to inhaled histamine, pulmonary function, and skin prick test reactivity were
measured using standard techniques. RESULTS: The point prevalence of BHR (the
concentration of histamine causing a 20% decline in FEV1 <8 mg/mL) declined from
childhood to early adulthood (25% and 6%, respectively; p<0.001); and similarly a
decline in histamine dose-response slope was observed. At both surveys,
prechallenge FEV1 percent predicted, asthma, and atopy, especially atopy to house
dust mite (HDM), were important determinants for the degree of BR. After
adjustment for prechallenge FEV1 percent predicted, no male-female difference was
observed in degree of BR. Lower FEV1 percent predicted (p=0.003), asthma
(p<0.001), higher degree of BR (p=0.003), and atopy to HDM (p=0.007) at
enrollment predicted a higher degree of BR at the second survey (degree of BR at
second survey adjusted for prechallenge FEV1). Furthermore, new asthma (p<0.001)
and/or atopy to HDM (p=0.003) were associated with higher BR at the second
survey. Confining the analysis to nonasthmatics showed that subjects with new or
persistent atopy to HDM had significantly increased BR compared with nonatopic
subjects; and, moreover, prechallenge FEV1 percent predicted was significantly
correlated with BR. CONCLUSIONS: BR declines from childhood to early adulthood,
possibly reflecting the increase in airway caliber. The level of FEV1 and atopy,
especially to HDM, are important determinants for changes over time in level of
BR, also in nonasthmatic subjects.
PMID- 9554635
TI - The relation between multiple sleep latency test findings and the frequency of
apneic events in REM and non-REM sleep.
AB - STUDY OBJECTIVES: A recent study of 34 patients with mild obstructive sleep apnea
syndrome (OSAS) suggested that the number of apneas and hypopneas per hour of
sleep (apnea/hypopnea index [AHI]) may show a stronger correlation with
sleepiness, as measured by the Multiple Sleep Latency Test (MSLT), when
calculated for rapid eye movement (REM) sleep alone (AHIR) as opposed to the
entire night. We sought to reexamine this possibility in a larger group of
similar patients and in patients who had a wider range of OSAS severity. DESIGN:
Retrospective and observational. SETTING: A large, accredited, academic sleep
disorders center where a database of sleep study results is maintained. PATIENTS:
We studied 1,146 persons who had polysomnography and MSLTs for clinical
indications. RESULTS: In linear regression models, the AHI explained 11.0% of the
variance in MSLT results, AHIN (AHI during non-REM sleep) explained 10.8%, and
AHIR explained only 6.0% (p < or = 0.0001 for each). Among subjects with AHI <
10, the AHI explained 3.1% of the variance (p=0.0012), the AHIN 2.3% (p=0.0049),
and the AHIR 0.2% (p=0.40). Among all subjects, the ratio AHIR/AHIN had no
influence on the overall relationship between AHI and sleepiness (p=0.23).
CONCLUSIONS: We conclude that apneic events during REM and non-REM sleep probably
contribute equally to sleepiness as measured by the MSLT.
PMID- 9554636
TI - Arterial blood pressure response to transient arousals from NREM sleep in
nonapneic snorers with sleep fragmentation.
AB - STUDY OBJECTIVES: To assess the hemodynamic effects of graded arousals during
nonrapid eye movement (NREM) sleep in patients with partial upper airway
obstruction during sleep without obstructive sleep apnea/hypopnea, overnight beat
to-beat BP was recorded in six patients. SETTING: At the end of each nonapneic
obstructive event, EEG responses were graded as follows: grade 2, grade 1, and
grade 0 were defined as increased high-frequency EEG lasting >15 s, 3 to 15 s,
and no EEG arousals according to the American Sleep Disorders Association,
respectively. MEASUREMENTS AND RESULTS: The following were observed during grade
0, 1, and 2 EEG patterns (mean+/-SD): systolic pressure increased by 7.1+/-1.5,
11.7+/-1.9, and 14.2+/-3.4 (p<0.005), respectively; diastolic pressure increased
by 4.6+/-0.6, 6.7+/-1.7, and 9.4+/-3.0 (p<0.005), respectively; heart rate
increased by 2.9+/-0.4, 3.9+/-2.2, and 8.6+/-4.6 (p<0.005), respectively.
CONCLUSIONS: We conclude that nonapneic-nonhypopneic obstructive events are
followed by arterial systemic pressure increases whose magnitude varies with the
grade of the arousal.
PMID- 9554637
TI - The efficacy of oral appliances in the treatment of persistent sleep apnea after
uvulopalatopharyngoplasty.
AB - Twenty-four patients who failed uvulopalatopharyngoplasty (UPPP) for obstructive
sleep apnea (OSA) had an adjustable oral (Herbst) appliance made to treat the
persistent apnea. Six patients discontinued the device prior to sleep evaluation.
Eighteen patients had polysomnographic evaluations at baseline, post-UPPP, and
with the Herbst appliance in place. The apnea-hypopnea index baseline (AHI) and
arterial oxygen saturation (SaO2) nadir were 42.3+/-6.1 and 83.6+/-1.8%,
respectively. There was no significant change in either parameter with surgery.
With the oral appliance, the AHI fell to 15.3+/-4.4 (p < or = 0.01) and the SaO2
nadir increased to 87.9+/-1.2% (p < or = 0.05). Ten of the patients had control
of the OSA with the Herbst appliance with a fall in the AHI to < 10. There were,
in addition, two partial responders as defined by an AHI of <20 and a >50% fall
in AHI compared with baseline and post-UPPP values. All but one of the responders
and partial responders had complete resolution of subjective symptoms of daytime
sleepiness with the appliance. An adjustable oral appliance appears to be an
effective mode of therapy to control OSA after an unsuccessful UPPP.
PMID- 9554638
TI - Analysis of cell type and radiographic presentation as predictors of the clinical
course of patients with bronchioalveolar cell carcinoma.
AB - STUDY OBJECTIVES: Bronchioloalveolar carcinoma is a primary lung neoplasm of
variable histopathologic, radiologic, and clinical expression. There are three
cell types described in bronchioloalveolar carcinoma: Clara cells, mucin
producing cells, and alveolar type II epithelial cells. It is unclear whether
these three tumor cell types are associated with a specific radiologic
presentation and clinical course. In this study, we investigated whether tumor
cell type, identified by transmission electron microscopy, correlated with a
specific radiologic pattern, and whether tumor cell type or radiologic
presentation correlated with the patient's clinical course and outcome. DESIGN:
Transmission electron microscopy was used to restudy tissue blocks from the
original surgical histopathologic specimens in 54 patients with primary
bronchioloalveolar carcinoma diagnosed over a 10-year period (1980 to 1990). The
pretreatment radiographs were reviewed in each case, and the first chest
radiograph obtained at the time of the discovery of the tumor in each patient was
compared with the results of the ultrastructural study. The medical records of
each patient were examined to obtain pertinent radiologic, clinical, and patient
outcome information. MEASUREMENT AND RESULTS: There were 32 Clara cell tumors, 10
mucin-producing cell tumors, and 1 alveolar type II epithelial cell tumor in this
series. Eleven additional tumors had mixtures of two or more cell types. No
statistically significant relationship was detected between tumor cell type and
radiologic presentation or patient mortality pattern. There was increased
mortality among patients who presented radiologically with segmental, lobar,
multifocal, or diffuse disease compared with those patients exhibiting a solitary
pulmonary nodule at presentation. CONCLUSION: Radiologic presentation, rather
than tumor cell type, provides prognostic information that aids in predicting
patient outcome.
PMID- 9554639
TI - Thoracoscopic talc poudrage in malignant pleural effusions: effective pleurodesis
despite low pleural pH.
AB - STUDY OBJECTIVE: To determine the effectiveness of pleurodesis by thoracoscopic
talc poudrage (TTP) in patients with low pH malignant pleural effusions. DESIGN:
Review of prospectively collected data on all thoracoscopic procedures performed
from 1982 to 1996. PATIENTS AND SETTING: Twenty-five members in a prepaid, closed
panel health maintenance organization, whose malignant pleural effusion pH was <
or = 7.30. INTERVENTIONS: Pleural fluid pH was measured prior to diagnostic and
therapeutic, single puncture, rigid thoracoscopy, under local anesthesia, in an
operating room. MEASUREMENTS AND RESULTS: Success of pleurodesis was determined
with serial radiographs at 10 days, 30 days, and frequent intervals until death
or up to 1 year following the procedure. Failure was indicated by evidence of
recurrent fluid or persistence of a space between the visceral and parietal
pleura. Morbidity of the procedure, days of chest tube drainage, and days of
hospitalization were recorded concurrently during hospitalization and outpatient
follow-up. Fifty of the 76 patients found to have a pleural pH measurement had a
pleural pH >7.30, averaging 7.37 (7.31 to 7.55). The other 26 patients (34%) with
pH < or = 7.30 (low pH) are the subjects of this study, of whom 25 were
evaluable. Pleurodesis was successful in 22 of 25 (88%), although 4 died prior to
30 days. The three failures all had trapped lung. Chest tube drainage averaged
3.2+/-1.3 days, which approximated the time of hospitalization (3.3+/-1.1 days).
There were no thoracoscopy-related deaths; significant morbidity occurred only in
one patient with trapped lung, who had prolonged chest tube drainage before and
after TTP, and eventually developed empyema. CONCLUSIONS: TTP is an effective
pleurodesis technique in malignant pleural effusions, even when the pleural pH is
low. The short hospital stay and high success rate make this approach a good
choice in palliating symptomatic malignant pleural effusions.
PMID- 9554640
TI - The acute effects of nasal positive pressure ventilation in patients with
advanced cystic fibrosis.
AB - OBJECTIVE: To evaluate the acute effects of noninvasive positive pressure
ventilation (NPPV) in patients with stable chronic respiratory failure secondary
to cystic fibrosis. PATIENTS: Eight patients (29+/-5 years of age) with severe
airflow limitation (mean FEV1, 24+/-3% predicted) and chronic respiratory failure
(PaO2=67+/-15 mm Hg and PaCO2=50+/-4 mm Hg) were evaluated. METHODS: Tidal
volume, respiratory rate, minute ventilation, oxygen saturation, and
transcutaneous CO2 (TcCO2) measurements were made over a 20-min period before and
after the application of NPPV (inspiratory pressure of 10 to 12 cm H2O and
expiratory pressure of 4 to 6 cm H2O). RESULTS: NPPV increased saturation from
88+/-2% to 90+/-1% (p<0.05) and decreased TcCO2 from 51+/-3 mm Hg to 50+/-2 mm Hg
(p<0.05). Tidal volume increased from 219+/-20 mL to 256+/-37 mL (p=not
significant [NS]) and respiratory rate decreased from 24+/-2 to 18+/-1 (p<0.01).
Minute ventilation decreased from 5.3+/-0.8 L/min to 4.6+/-0.6 L/min (p=0.08).
There was no change in duty cycle (32+/-5% to 34+/-5%, p=NS). In two patients,
esophageal pressure measurements were also recorded. There was a decrease in
pressure from -21+/-1 cm H2O to -11+/-2 cm H2O and -14+/-1 cm H2O to -7+/-1 cm
H2O. CONCLUSIONS: In patients with stable, severe cystic fibrosis, NPPV (1)
acutely improves gas exchange, (2) decreases minute ventilation, suggesting
either a reduction in CO2 production or an increase in alveolar ventilation, and
(3) reduces work of breathing.
PMID- 9554641
TI - Effect of high-frequency oral airway and chest wall oscillation and conventional
chest physical therapy on expectoration in patients with stable cystic fibrosis.
AB - STUDY OBJECTIVE: To compare the effect of high-frequency oral airway oscillation,
high-frequency chest wall oscillation, and conventional chest physical therapy
(CPT) on weight of expectorated sputum, pulmonary function, and oxygen saturation
in outpatients with stable cystic fibrosis (CF). DESIGN: Prospective randomized
trial. SETTING: Pediatric pulmonary division of a tertiary care center. PATIENTS:
Fourteen outpatients with stable CF recruited from the CF center. INTERVENTIONS:
Two modes of oral airway oscillation (1: frequency 8 Hz; inspiratory to
expiratory [I:E] ratio 9:1; 2: frequency 14 Hz; I:E ratio 8:1), two modes of
chest wall oscillation (1: frequency 3 Hz; I:E ratio 4:1; 2: frequency 16 Hz; I:E
ratio 1:1, alternating with frequency 1.5 Hz, I:E ratio 6:1), and CPT (clapping,
vibration, postural drainage, and encouraged coughing) were applied during the
first 20 min of 4 consecutive hours. MEASUREMENTS AND RESULTS: Sputum was
collected on an hourly basis for a total of 6 consecutive hours. During the first
and the last hour, patients collected sputum without having any treatment and
underwent pulmonary function tests (PFTs). Oxygen saturation was measured at 30
min intervals during hours 1 to 6. For the first 20 min of the second to the
fifth hour, patients received one of the treatments. To assess the effect of the
intervention, the weight of expectorated sputum during hours 2 to 6 was averaged
and expressed as percentage of the weight expectorated during the first hour
(baseline). For the five treatment modalities, mean sputum dry and wet weights
ranged between 122% and 185% of baseline. There was no statistically significant
difference among the treatment modalities. As measured by sputum wet weight, all
oscillatory devices tended to be less effective than CPT (p=0.15). As measured by
dry weight, oral airway oscillation at 8 Hz with an I:E ratio of 9:1 and CPT
tended to be more effective than the other treatment modalities (p=0.57). None of
the treatment modalities had an effect on PFTs and oxygen saturation and all were
well tolerated. CONCLUSION: In outpatients with stable CF, high-frequency
oscillation applied via the airway opening or via the chest wall and CPT have
comparable augmenting effects on expectorated sputum weight without changing PFTs
or oxygen saturation. In contrast to CPT, high-frequency oral airway and chest
wall oscillations are self-administered, thereby containing health-care expenses.
PMID- 9554642
TI - Effects of positive end-expiratory pressure on oscillated flow rate during high
frequency chest compression.
AB - OBJECTIVE: To investigate the effects of positive end-expiratory pressure (PEEP)
on end-expiratory lung volume (EELV) and mean oscillated flow rate (VOSC) during
high-frequency chest compression (HFCC) in normal subjects and patients with
severe COPD. DESIGN: Comparative study. SETTING: Pulmonary function and lung
mechanics laboratory, University of Alberta Hospitals. PARTICIPANTS: Six normal
subjects (five male; one female) and six patients with clinically stable COPD
(five male; one female) with hypercapnia. INTERVENTIONS: A pneumatic vest system
was operated at 10 Hz with a mean chest wall pressure of 16 cm H2O to provide the
HFCC. A closed-circuit spirometer system permitted measurement of HFCC- and PEEP
induced changes in EELV that were expressed as per cent baseline functional
residual capacity (FRC). An isothermic chamber connected near the mouthpiece
permitted measurement of VOSC. RESULTS: For the normal subjects, HFCC caused a
significant decrease in EELV to 82.0% of FRC (p < or = 0.01) and the addition of
4.8+/-0.5 cm H2O of PEEP during HFCC increased EELV to 97.5% FRC. In the COPD
patients, HFCC decreased EELV to 92.3% of FRC (p < or = 0.01), and the addition
of 3.7+/-1.0 cm H2O of PEEP increased EELV to 98.4% FRC. For the normal subjects,
increasing EELV to near FRC caused VOSC during expiration to increase 14.6% (p <
or = 0.01), but there was no significant effect on VOSC during inspiration (5.1%
increase). In the COPD patients, PEEP increased VOSC during both inspiration
(30.5%) and expiration (57.0%) (both, p < or = 0.01). CONCLUSIONS: Addition of a
modest amount of PEEP during HFCC prevents the decrease in EELV and increases
VOSC during both phases of spontaneous breathing in COPD patients. This higher
VOSC during HFCC+PEEP may improve the effectiveness of HFCC in clearing mucus
from the lungs of patients with airway disease.
PMID- 9554643
TI - Absence of left-sided predominance in asbestos-related pleural plaques: a CT
study.
AB - STUDY OBJECTIVES: Differences between the number and areas of pleural plaques in
every hemithorax could not be expected a priori. However, previous studies based
on chest radiographs reported an unexplained left-sided predominance. In this
paper, a comparison of summed surfaces and location of plaques calculated from CT
studies was performed. PATIENTS AND METHODS: Thoracic CT scans from 40 adults
with asbestos exposure and pleural plaques were analyzed. The surface area of
every plaque was calculated, and summed areas were recorded separately for every
hemithorax. The statistical analysis was performed with t-tests for paired
samples. Emphasis was placed on measurement differences. MEASUREMENTS AND
RESULTS: The results show lack of significant predominance for any hemithorax. A
total of 668 plaques (352 right and 316 left) were measured, with an average area
(+/-SD) of 47.81+/-47.72 cm2 for the right plaques and 45.34+/-67.32 cm2 for the
left. The mean of differences (left minus right areas) was -2.56+/-53.68 and
slightly statistically different from zero (p=0.652). CONCLUSIONS: Left-sided
predominance of asbestos-related pleural plaques is not supported by this study.
PMID- 9554644
TI - Transbronchial lung biopsy: can specimen quality be predicted at the time of
biopsy?
AB - STUDY OBJECTIVES: To determine the bronchoscopist's ability to predict specimen
quality at the time of transbronchial biopsy and to determine the influence of
biopsy specimen size and alveolar content on diagnostic value. DESIGN:
Prospective, blinded, observational analysis. SETTING: Tertiary care academic
hospital-based pulmonary practice. PATIENTS: Forty-three adult patients who
underwent transbronchial lung biopsy. INTERVENTIONS: Each of 170 biopsy specimens
was rated as to likelihood of containing diagnostic tissue, size and ability to
float, tissue types present, number of alveoli, and pathologic diagnosis.
RESULTS: Fifteen percent of biopsy specimens were small and 40% were large.
Seventy-six percent of specimens floated; 61.8% of the 170 biopsy specimens
contained abnormal lung tissue; and 14.7% of individual specimens were
diagnostic. Fifty-two percent of specimens contained >20 alveoli. Larger biopsy
specimens were more likely to contain diagnostic tissue (r=0.29, p=0.001). Cup
forceps retrieved smaller pieces of tissue (p=0.007) and were less likely to
obtain diagnostic tissue (p=0.06). Physician ratings of specimen quality (mean+/
SD) did not differ between specimens containing normal and abnormal tissue
(5.98+/-2.3 vs 5.46+/-5.5; p=0.24) or between specimens containing diagnostic vs
nondiagnostic tissue (5.56+/-2.5 vs 6.25+/-2.1; p=0.14). Specimens that floated
were no more likely to be diagnostic or abnormal than specimens that sank
(p<0.05). Diagnosis when established was made by the first biopsy specimen in
53.3% and the second in 33.3% CONCLUSIONS: Physician estimate of biopsy specimen
quality and the float sign are not helpful in predicting that the biopsy specimen
contains abnormal or diagnostic tissue. Diagnostic biopsy specimen will likely be
obtained if the size of the specimen fills the forceps, 2 to 4 biopsies are
performed, and toothed forceps are used.
PMID- 9554645
TI - Use of a pulse oximeter in an adult emergency department: impact on the number of
arterial blood gas analyses ordered.
AB - STUDY OBJECTIVES: To assess the impact of pulse oximetry (SpO2) on the
indications and the number of arterial blood gas (ABG) levels ordered in an adult
emergency department (ED). DESIGN: A prospective study during a 2-month period in
1993 with a pulse oximeter available and a comparison with the same period in
1992 without the oximeter. SETTING: An adult medical ED of a university hospital
in France. PATIENTS: All patients who underwent ABG or SpO2 measurements.
INTERVENTIONS: During the prospective study, residents ordered ABG or SpO2
measurements at their discretion. The reasons for their ordering were reviewed by
two independent experts who determined whether their choice was justified. The
data were compared with those for 184 consecutive patients who had ABG
measurements in 1992. MEASUREMENTS AND RESULTS: The study included 152 patients.
SpO2 alone was used in 33 patients; ABG levels were measured in 119 patients. The
use of SpO2 did not result in the ordering of fewer useful ABG determinations.
One hundred and five (88%) ABG measurements were justified. There were fewer
unjustified ABG determinations in 1993 when the pulse oximeter was available than
in 1992 when it was not (14 of 119 vs 54 of 184; p<0.001) mainly because fewer
ABG determinations were ordered for miscellaneous nonrespiratory indications (13
of 119 vs 43 of 184; p<0.01). CONCLUSION: The availability of a pulse oximeter
did not affect the ordering of useful ABG measurements but allowed a significant
reduction of unjustified ABG measurements. Substantial cost savings could be
achieved by using SpO2 in an ED.
PMID- 9554646
TI - Right ventricular end-diastolic volume as a predictor of the hemodynamic response
to a fluid challenge.
AB - OBJECTIVE: To compare thermodilution right ventricular end-diastolic volume index
(RVEDVI) and pulmonary artery occlusion pressure (Ppao) as predictors of the
hemodynamic response to a fluid challenge. DESIGN: Prospective cohort study.
SETTING: Medical ICU of a university-affiliated county hospital and medical
surgical ICU of a community hospital. PATIENTS: Twenty-five critically ill
patients who had one or more clinical conditions that suggested the possibility
of inadequate preload. INTERVENTIONS: Thirty-six fluid challenges. Fluid (saline
or colloid) was administered rapidly until the Ppao rose by at least 3 mm Hg.
When a patient underwent more than one fluid challenge, these were given on
separate days and for different clinical indications. MEASUREMENTS AND RESULTS:
Responders (n=20; > or = 10% increase in stroke volume [SV]) and nonresponders
(n=16; <10% increase in SV) differed with respect to baseline Ppao (10.0+/-3.4 vs
14.2+/-3.6 mm Hg; p=0.001), but not with respect to baseline RVEDVI (105+/-31 vs
119+/-33 mL/m2; p=0.22). There was a moderate correlation between RVEDVI and
fluid-induced change in SV (r=0.44); the relationship between Ppao and change in
SV was stronger (r=0.58). A positive response to fluid was observed in 4 of 9
cases in which RVEDVI exceeded 138 mL/m2, a threshold value that has been
suggested to reliably predict a poor response to fluid. CONCLUSION: RVEDVI was
not a reliable predictor of the response to fluid. As a predictor of fluid
responsiveness, Ppao was superior to RVEDVI. In an individual patient, adequacy
of preload is best assessed by an empiric fluid challenge.
PMID- 9554647
TI - Serum cardiac troponin T as a prognostic marker in early sepsis.
AB - STUDY OBJECTIVE: Sepsis is the leading cause of death in the noncardiologic ICU.
Maldistributed nutritive blood flow and altered convective and diffusive oxygen
transport during sepsis can lead to organ dysfunction and multiple organ failure.
One of the causes of myocardial dysfunction is thought to be myocardial ischemia
in sepsis; however, conventional biochemical parameters to detect myocardial
ischemia lack sensitivity and specificity. Serum cardiac troponin T (S-TnT) was
reported to have higher sensitivity and specificity in diagnosing minor
myocardial injury. The aim of this study was to investigate if and how often S
TnT is pathologically elevated in patients with sepsis and to evaluate whether S
TnT might be a prognostic marker in early sepsis. DESIGN: Prospective study.
SETTING: Surgical ICU. PATIENTS: Twenty-six patients with sepsis were included in
this study within 24 h of the onset of sepsis. The patients were allocated a
priori to a high S-TnT group (S-TnT > or = 0.2 microg/L) and a low S-TnT group (S
TnT<0.2 microg/L). MEASUREMENT: Blood samples for the determination of S-TnT and
conventional myocardial ischemia markers as well as for adhesion molecules were
drawn. Hemodynamic measurements were performed every 4 h during the first 24 h
and then once per day over 7 days. S-TnT was determined by enzyme-linked
immunosorbent sandwich assay. RESULTS: Eighteen patients had pathologically high
S-TnT values. High S-TnT values were associated with an increased mortality rate
(15/18 in the high S-TnT group vs 3/8 in the low S-TnT group; p=0.02).
Significant differences between the two groups were found in the norepinephrine
dosages at maximum values of S-TnT. Soluble intercellular adhesion molecule-1 was
significantly elevated in the high S-TnT group. CONCLUSIONS: As high S-TnT values
were associated with an increased mortality rate, it seems reasonable to further
evaluate S-TnT as a prognostic marker of myocardial ischemia in patients with
sepsis under different therapeutic regimens.
PMID- 9554648
TI - Failure of splanchnic resuscitation in the acutely injured trauma patient
correlates with multiple organ system failure and length of stay in the ICU.
AB - INTRODUCTION: The purpose of our study was to evaluate the relationship between
the state of splanchnic perfusion and morbidity and mortality in the
hemodynamically unstable trauma patient acutely resuscitated in the ICU. METHODS:
Gastric intramucosal pH (pHi) was monitored in a blinded fashion in 19
consecutive critically ill trauma patients with evidence of systemic
hypoperfusion (arterial pH [pHa] <7.35, base excess >2.3 mmol/L, lactic acid >2.3
mEq/L) who received right heart catheters to guide resuscitation and subsequent
hemodynamic monitoring. DESIGN: Prospective randomized consecutive series with
retrospective analysis of data. SETTING: University hospital, surgical ICU.
RESULTS: The mean values of APACHE II (acute physiology and chronic health
evaluation) Injury Severity Score, pHa, arterial base excess, cardiac index,
oxygen delivery index, and oxygen consumption index by 24 h were similar
(Student's t test, p>0.1) between survivors and nonsurvivors and between those
who developed at most a single (SOF) vs multiple organ system failure (MOSF).
Supranormal oxygen delivery and utilization parameters were evenly distributed
among survivors and nonsurvivors and patients with SOF and MOSF (chi2, p>0.5).
Ten patients had a pHi <7.32 and nine patients had a pHi > or = 7.32 by 24 h.
Fifty percent of patients with a pHi <7.32 died, compared with 11% of patients
with a pH > or = 7.32 (chi2, p=0.07). Sixty percent of patients with a pHi <7.32
developed MOSF compared with 11% of patients with a pHi > or = 7.32 (chi2,
p=0.03). The one patient who developed MOSF and died in the pHi > or = 7.32
cohort suffered from massive head trauma and had all futile medical interventions
halted. No other patients who achieved a pH > or = 7.32 by hour 24 developed
MOSF. Survivors with a pHi <7.32 at hour 24 had an increased ICU stay (pHi
<7.32=46+/-15 days, pHi > or = 7.32=13+/-9 days; p<0.01). A pHi <7.32 carried a
relative risk of 4.5 for death and 5.4 for the occurrence of MOSF. CONCLUSION:
Attainment of a pHi > or = 7.32 at hour 24 carried a significantly reduced
likelihood of MOSF. Being an inference of the state of regional perfusion, in a
high-risk microvascular bed, gastric intraluminal tonometry should identify
perfusion states of compensated or uncompensated shock during hemodynamic
resuscitation of the critically ill injury patient. A low pHi appears to be a
marker of postresuscitative morbidity and subsequent increased length of stay.
PMID- 9554649
TI - Reproducibility of double indicator dilution measurements of intrathoracic blood
volume compartments, extravascular lung water, and liver function.
AB - STUDY OBJECTIVE: Arterial thermal dye dilution (TDDart) with the COLD system
(Munich, Germany) allows measurement of cardiac index (CI), partial blood
volumes, lung water, and liver function. The aim of the study was to determine
agreement of TDDart measurements with pulmonary artery thermal dilution
measurements (TDpa) and to assess the reproducibility of TDDart parameters.
DESIGN: Prospective study. SETTING: ICU of a university hospital department of
cardiac surgery. PATIENTS: Thirty consecutive patients after coronary artery
bypass grafting. MEASUREMENTS AND RESULTS: Triplicate measurements of TDDart
parameters were performed 1, 3, 6, 12, and 24 h postoperatively and coefficients
of variation (CVs) were computed. At the 3-h point, additional fivefold TDDart
measurements were done and compared with TDpa measurements. The coefficient of
correlation for CI from TDDart vs TDpa was 0.96 (p<0.001), and the mean
difference was 0.16 L/min/m2 (2.4%). The CVs of the TDDart and TDpa CI
measurement were 7.2% and 5.9%; the CVs of other TDDart parameters were 4.6%
(cardiac function index), 8.3% (global end-diastolic volume), 7.0% (intrathoracic
blood volume), 7.6% (total blood volume), 7.4% (right ventricular end-diastolic
volume), 7.4% (right heart end-diastolic volume), 11.3% (left heart end-diastolic
volume [LHEDV]), 12.0% (right to left heart volume proportion [R/LHV]), 8.8%
(pulmonary blood volume), 10.8% (extravascular lung water), 16.4% (plasma
disappearance rate of dye), and 19.8% (dye clearance). The CV did not depend on
Glasgow coma scale or on body temperature. CONCLUSION: The CVs of LHEDV and R/LHV
are influenced by asynchronous TDDart and TDpa variation. The CVs of plasma
disappearance and dye clearance are increased as the half-life of the dye is
longer than the measurement sequence. All other parameters derived from TDDart
and TDpa show a clinically sufficient reproducibility.
PMID- 9554650
TI - Gastric and esophageal intramucosal PCO2 (PiCO2) during endotoxemia: assessment
of raw PiCO2 and PCO2 gradients as indicators of hypoperfusion in a canine model
of septic shock.
AB - STUDY OBJECTIVES: To validate capnometric recirculating gas tonometry (CRGT) for
continuously monitoring gut intramucosal PCO2 (PiCO2) in a septic shock model,
and to compare gastric vs esophageal PCO2 vs intramucosal-arterial PCO2
gradients. INTERVENTIONS: CRTG catheters were placed in the stomach and esophagus
of six anesthetized dogs. A saline solution filled balloon tonometry (ST)
catheter was also placed in the stomach. After equilibration, 3 mg/kg Escherichia
coli lipopolysaccharide (LPS) was administered IV. PiCO2 measurements were made
at 0, 45, and 90 min post-LPS by ST and continuously by CRGT. RESULTS: Baseline
PiCO2 was 41.5+/-1.9 (+/-SE) in the stomach by CRGT, 38.0+/-1.0 by ST, and 43.0+/
4.4 mm Hg in the esophagus (p=not significant). Gastric PiCO2 by CRGT increased
to 47.0+/-2.4 mm Hg by 25 min post-LPS (p<0.05), whereas gastric (ST) and
esophageal PiCO2 increased significantly by 45 min post-LPS. Good agreement was
observed between gastric CRGT and ST measurements (mean bias, 1.3 mm Hg). The
PiCO2-PaCO2 gradient increased post-LPS, but was significant only for gastric
CRGT measurements 90 min post-LPS infusion. CONCLUSION: CRGT provided continuous
gastric PiCO2 measurements that were in close agreement with ST but detected
changes earlier than the conventional technique. Continuous esophageal PiCO2
represents a valid alternative for assessing gastric PiCO2.
PMID- 9554651
TI - Optimizing standard cardiopulmonary resuscitation with an inspiratory impedance
threshold valve.
AB - OBJECTIVES: This study was designed to assess whether intermittent impedance of
inspiratory gas exchange improves the efficiency of standard cardiopulmonary
resuscitation (CPR). BACKGROUND: Standard CPR relies on the natural elastic
recoil of the chest to transiently decrease intrathoracic pressures and thereby
promote venous blood return to the heart. To further enhance the negative
intrathoracic pressures during the "relaxation" phase of CPR, we tested the
hypothesis that intermittent impedance to inspiratory gases during standard CPR
increases coronary perfusion pressures and vital organ perfusion. METHODS: CPR
was performed with a pneumatically driven automated device in a porcine model of
ventricular fibrillation. Eight pigs were randomized to initially receive
standard CPR alone, while seven pigs initially received standard CPR plus
intermittent impedance to inspiratory gas exchange with a threshold valve set to
40 cm H2O. The compression:ventilation ratio was 5:1 and the compression rate was
80/min. At 7-min intervals the impedance threshold valve (ITV) was either added
or removed from the ventilation circuit such that during the 28 min of CPR, each
animal received two 7-min periods of CPR with the ITV and two 7-min periods
without the valve. RESULTS: Vital organ blood flow was significantly higher
during CPR performed with the ITV than during CPR performed without the valve.
Total left ventricular blood flow (mean+/-SEM) (mL/min/g) was 0.32+/-0.04 vs
0.23+/-0.03 without the ITV (p<0.05). Cerebral blood flow (mL/min/g) was 20%
higher with the ITV (+ITV, 0.23+/-0.02; -ITV, 0.19+/-0.02; p<0.05). Each time the
ITV was removed, there was a statistically significant decrease in the vital
organ blood flow and coronary perfusion pressure. CONCLUSIONS: Intermittent
impedance to inspiratory flow of respiratory gases during standard CPR
significantly improves CPR efficiency during ventricular fibrillation. These
studies underscore the importance of lowering intrathoracic pressures during the
relaxation phase of CPR.
PMID- 9554652
TI - Microsatellite instability and loss of heterozygosity at chromosomes 9 and 17 in
non-small cell lung cancer.
AB - BACKGROUND: Microsatellite instability (MI) and loss of heterozygosity (LOH) are
described in lung cancer specimens. However, their importance in tumorigenesis
remains unknown. The aim of this study was to identify the presence of MI and LOH
in human tumor and normal bronchial mucosa DNA. METHODS: We performed biopsies
with fiberoptic bronchoscopy and took specimens from the tumor and from the
opposite site normal bronchial mucosa in 20 patients with non-small-cell lung
cancer (NSCLC). Four patients had an adenocarcinoma, while 16 had a squamous cell
carcinoma. Also, 6 patients had an early-stage disease (stages I and II), while
14 patients had an advanced-stage disease (stages III and IV). All paired
specimens were studied for MI and LOH on chromosome 17p, 17q, 9p, and 9q, with 10
polymorphic markers. RESULTS: Sixteen of 20 tumors displayed genetic alterations
(80%). Six tumors (30%) exhibited MI, five tumors (25%) exhibited LOH, while five
tumors exhibited MI and LOH concurrently. The marker HBX had the most frequent
incidence of LOH (4/20, 20%), indicating that the hbx gene becomes a strong
candidate tumor suppressor gene, whereas of MI it was D17S515 (4/20, 20%). No
relationship was observed between the presence of LOH or MI and the histologic
subtype of NSCLC or the stage of the disease. CONCLUSION: Results suggest that
genetic alterations exist in tumor, compared with the normal mucosa DNA. They may
have a role in carcinogenesis as they exist in all stages and in both NSCLC
histologic subtypes studied.
PMID- 9554653
TI - Long-acting inhaled beta2-agonists in asthma therapy.
AB - OBJECTIVE: To review the pharmacology of the long-acting inhaled beta2-agonists,
salmeterol and formoterol, summarize results of their clinical trials, evaluate
their safety records, and discuss their roles in the treatment of asthma. DATA
SOURCES: Preclinical and clinical studies involving salmeterol or formoterol were
identified by a MEDLINE search, weekly computerized literature updates, and
manual searches. Studies of satisfactory quality were chosen for review. DATA
SYNTHESIS: Salmeterol and formoterol are potent and selective beta2-adrenoceptor
agonists with durations of action >12 h. Their major differences are that
formoterol has a rapid onset of action and is a partial agonist of high intrinsic
efficacy, whereas salmeterol has a delayed onset and is a partial agonist of low
intrinsic efficacy. Twice daily use of either drug results in improved lung
function, reduced symptoms, and a better quality of life. These agents protect
against exercise-induced asthma for 12 h and eliminate nighttime awakening in
most patients. Limited tolerance develops, especially to their bronchoprotective
effects, but their improvement of lung function is sustained. CONCLUSIONS:
Regular use of salmeterol or formoterol provides subjective and objective
amelioration of asthma in patients experiencing excessive symptoms or physiologic
impairment despite the regular administration of low doses of inhaled
corticosteroids (equivalent to approximately 500 microg/d of beclomethasone).
Intermittent use of either long-acting beta2-agonist can provide prolonged
protection against exercise-induced asthma or nighttime symptoms. Patients should
be instructed to continue taking inhaled steroids when long-acting beta2-agonists
are administered on a regular schedule and to not take long-acting beta2-agonists
between regularly scheduled doses. Used properly, they are effective and safe
adjunctive agents in the treatment of asthma.
PMID- 9554654
TI - The natural history and rate of progression of aortic stenosis.
AB - One of the challenges in clinical cardiology is to determine the optimal time of
valve replacement surgery in patients with aortic stenosis. To meet this
challenge, one requires an accurate knowledge of the natural history and rate of
progression of the disease. This review will summarize the natural history of
aortic stenosis in terms of symptoms, mortality, and stenosis progression.
PMID- 9554655
TI - Controversies surrounding long-term anticoagulation of very elderly patients in
atrial fibrillation.
PMID- 9554656
TI - Ischemic heart disease with congestive heart failure--problems in clinical
management.
PMID- 9554657
TI - A man with dyspnea, productive cough, and chest radiograph showing hyperinflation
and a diffuse nodular pattern.
PMID- 9554658
TI - Hypoxic respiratory failure in a 30-year-old spelunker.
PMID- 9554659
TI - Acute pneumopathy in a nonsurgical transsexual.
PMID- 9554660
TI - Massive hemoptysis from a pulmonary artery aneurysm associated with an
emphysematous bulla.
AB - A 66-year-old man with a history of COPD and Aspergillus fumigatus infection
developed massive hemoptysis. Pulmonary artery angiography revealed an aneurysm
which was successfully treated with coil embolization. This is the first known
report of a pulmonary artery aneurysm causing massive hemoptysis in a patient
with bullous emphysema.
PMID- 9554661
TI - Venous and arterial gas embolism associated with positive pressure ventilation.
AB - We report a 53-year-old woman with ARDS who required positive pressure
ventilation with positive end-expiratory pressure. She sustained an acute right
ventricular myocardial infarction associated with cardiovascular instability. The
next day she sustained a fatal cerebral arterial gas embolism. Intravascular gas
was documented within the cerebral, coronary, and pulmonary arterial
circulations. Clinicians need to be aware of venous and arterial gas embolism as
a complication of mechanical ventilation.
PMID- 9554662
TI - Elevation of peak expiratory flow by a "spitting" maneuver: measured with five
peak flowmeters.
AB - STUDY OBJECTIVE: To determine if peak expiratory flow (PEF) is higher using
incorrect technique versus correct technique with five marketed peak flowmeters.
DESIGN: Randomized, nonblinded study. SETTING: University pulmonary medicine
clinic. PATIENTS: Twenty adults with clinically stable asthma. INTERVENTIONS:
After inhaling 2 puffs of albuterol via a valved aerosol holding chamber
(Aerochamber), patients were instructed over the next 15 min in correct and
incorrect (a "spitting" action) technique when using peak flowmeters. Order of
use of five peak flowmeters and correct vs incorrect technique was random.
MEASUREMENTS AND RESULTS: PEF (percentage of personal best) was recorded for best
of three attempts with correct and incorrect technique. Each peak flowmeter had a
statistically significant elevation in PEF with incorrect technique. The range
for elevation in PEF using incorrect technique was 12.4 to 68.2% above the PEF
with the subject using correct technique. CONCLUSION: Each of the five marketed
peak flowmeters had a significant elevation in PEF when a "spitting action" was
used. Clinicians need to instruct patients carefully regarding correct technique
when using peak flowmeters.
PMID- 9554663
TI - ARDS and adrenal insufficiency associated with the antiphospholipid antibody
syndrome.
AB - The antiphospholipid antibody syndrome (APS) is typically characterized by
recurrent arterial and/or venous thromboses, miscarriages, and thrombocytopenia.
There have been five reported cases of ARDS associated with primary APS. Adrenal
insufficiency has also been reported as a rare complication of APS. We report a
case of both ARDS and adrenal insufficiency associated with primary APS. Chest
radiographs and pulmonary angiography studies revealed findings consistent with
ARDS. CT scans confirmed the presence of bilateral adrenal hemorrhagic
infarction. Patients with APS are at an increased risk of widespread vascular
thrombosis due to the presence of circulating antiphospholipid antibodies. This
case emphasizes the importance of recognizing APS and its potential for multiple
organ system involvement.
PMID- 9554664
TI - Circumflex coronary artery dissection following waterskiing.
AB - A previously healthy 35-year-old woman experienced chest discomfort following
mild blunt chest trauma while waterskiing. During the following 48 h, she
underwent evaluation in two separate emergency departments (EDs) where she was
found to have normal ECGs and cardiac enzyme values. She was subsequently
discharged from both EDs. Twelve hours after the second ED visit, she was
discovered unconscious at home and was resuscitated from ventricular
fibrillation. Emergency cardiac catheterization demonstrated moderate circumflex
disease without angiographic evidence of a false lumen or intimal flap. Left
ventriculography demonstrated posterolateral wall hypokinesis. Eight days after
remaining ventilator-dependent and unconscious, the patient was declared brain
dead. At autopsy, the patient was found to have a dissection of the circumflex
artery. Waterskiing is an unusual source of cardiac trauma; however, we believe
this to be the first reported case of dissection in the circumflex artery
following blunt chest trauma.
PMID- 9554665
TI - Board review courses for critical care medicine.
PMID- 9554666
TI - Deciphering histoplasmosis, systemic noncaseating granuloma, and sarcoidosis in
the literature.
PMID- 9554667
TI - False-positive results of carcinoembryonic antigen in pleural effusions.
PMID- 9554668
TI - Tumor markers in sputum of patients with bronchioloalveolar carcinoma.
PMID- 9554669
TI - Intracavitary bleomycin vs interferon in the management of malignant pleural
effusions.
PMID- 9554670
TI - A case of systemic lupus erythematosus or hepatitis C virus?
PMID- 9554671
TI - Health-related quality of life: what is being measured?
PMID- 9554672
TI - Exercise testing in patients with interstitial lung disease.
PMID- 9554673
TI - Where have all the flowers gone: where is the joy in medicine?
PMID- 9554674
TI - Case of the month: Complications of therapy, nursing homes, and the elderly.
Autopsy Committee of the College of American Pathologists.
PMID- 9554675
TI - Lifestyle, stress, and genes in peptic ulcer disease: a nationwide twin cohort
study.
AB - BACKGROUND: The familial accumulation of peptic ulcer disease observed in several
studies may be attributable to genetic effects, aggregation of environmental
exposure (shared environment), or both. The intrafamilial spread of Helicobacter
pylori infection has raised the question whether shared environment could explain
the familial aggregation of peptic ulcer disease rather than genetic similarity
of family members. OBJECTIVE: To examine the contribution of genetic and
environmental factors to the pathogenesis of peptic ulcer disease in a nationwide
population-based cohort of adult twins. METHODS: The Finnish Twin Cohort consists
of all same-sexed twin pairs born before 1958 with both twins alive in 1975. The
total number of twin pairs is 13888, of whom 4307 are monozygotic (MZ) and 9581
are dizygotic (DZ) twins. Questionnaire surveys of twins were carried out in
1975, 1981, and 1990, including medical and psychosocial questions. One question
asked whether a physician had ever made a diagnosis of gastric or duodenal ulcer.
In addition, hospital discharge data from 1972 to 1991 were linked with the twin
cohort to obtain those twin individuals who had been treated for gastric or
duodenal ulcer. The prevalence of and concordance for peptic ulcer disease were
examined in MZ and DZ twins. Model-fitting analysis was used to specify the
relative roles of genetic and environmental factors. The contribution of
lifestyle factors and stress was examined prospectively in an incidence study and
by comparison of discordant pairs. RESULTS: The prevalence of peptic ulcer
disease was 6.2% in men and 2.8% in women in 1975. There were 63 MZ and 86 DZ
pairs concordant for peptic ulcer disease. Concordance for disease was
significantly higher in MZ than in DZ twin pairs; the probandwise concordance
rate was 23.6% (95% confidence interval [CI], 20.9%-26.3%) in MZ twins and 14.8%
(95% CI, 13.3%-16.3%) in DZ twins. In the model-fitting analysis, a model with
both additive genetic and unshared environmental effects had the best goodness-of
fit. Thirty-nine percent (95% CI, 32%-47%) of the liability to peptic ulcer
disease was explained by genetic factors and 61% (95% CI, 53%-68%) by individual
environmental factors. In the incidence study (logistic regression analysis of
the entire cohort initially free of peptic ulcer disease, with subjects diagnosed
as having peptic ulcer after 1975 as cases), current smoking (relative risk, 2.2;
95% CI, 1.5-3.2) and high stress levels (relative risk, 3.2; 95% CI, 1.4-7.6) in
men and regular use of analgesics (relative risk, 3.3; 95% CI, 1.3-8.1) in women
predicted peptic ulcer disease during the follow-up from 1976 to 1991. In the
analysis of discordant pairs, smoking in men and regular use of analgesics in
both sexes were predictors of peptic ulcer disease. CONCLUSIONS: The
questionnaire and hospital usage data on peptic ulcer disease in the population
based twin cohort suggest that the familial aggregation of the disease is modest,
and attributable almost solely to genetic factors. Environmental effects not
shared by family members were significant predictors of disease, and they were
attributable to smoking and stress in men and the use of analgesics in women. The
minor effects of shared environment to disease liability do not support the
concept that the clustering of risk factors, such as H pylori infection, would
explain the familial accumulation of peptic ulcer disease.
PMID- 9554676
TI - Effectiveness of treatments of depression in older ambulatory patients.
AB - OBJECTIVE: To determine the effectiveness of acute-phase pharmacological and
psychological treatments of depression in older ambulatory patients by
systematically reviewing original research relevant to this topic. METHODS:
Searches in MEDLINE and PsycINFO and manual reviews of bibliographies located 233
articles. Of these, 40 (37 different studies) met our 8 inclusion criteria:
original research, written in English or French, subjects 55 years and older,
diagnosis of depression, outpatient or community setting, prospective controlled
study design, acute-phase pharmacological or psychological treatment, and outcome
measure of depression. Two independent reviewers assessed the methodological
quality of each article using a standard form and a quality score was computed.
Quantitative data on levels of depression at the end of treatment were
abstracted. Results were grouped by specific treatment comparison (type of
treatment and type of control group). For comparisons that used the Hamilton
Depression Rating Scale, we computed mean posttreatment differences. Effect sizes
were computed from the Hamilton Depression Rating Scale or an alternative scale.
RESULTS: In studies that compared active drugs with placebo, the heterocyclic
drugs significantly reduced the posttreatment Hamilton Depression Rating Scale
score (mean difference, -5.78; 95% confidence interval, -8.31 to -3.25); other
drugs had smaller effects. In studies that compared active drugs, there were no
significant differences overall between different classes of drugs; selective
serotonin reuptake inhibitors appeared to be as effective as heterocyclic drugs.
Rational psychological treatments performed significantly better than no
treatment (mean posttreatment Hamilton Depression Rating Scale difference, -7.25;
95% confidence interval, -10.10 to -4.40) but not significantly better than that
for controls who received similar attention. Adjustment for the study quality
score did not affect these results. CONCLUSIONS: Based on comparisons with
untreated controls, heterocyclic antidepressants and rational psychological
therapies appear to be the most effective treatments for older ambulatory
patients with mild to moderate depression. Based on drug-drug comparisons,
selective serotonin reuptake inhibitors appear to be as effective as heterocyclic
drugs. However, overall, the magnitude of the treatment effects is modest.
Limitations in the quantity and quality of appropriate studies suggest a sober
approach to treatment in this population.
PMID- 9554677
TI - Accuracy of an automated blood pressure device in stable inpatients: optimum vs
routine use.
AB - BACKGROUND: Despite widespread use of the automated blood pressure (BP) device
(IVAC model 4200, IVAC Corporation, San Diego, Calif), there is little formal
validation in the literature on its accuracy. OBJECTIVE: To assess the accuracy
of the IVAC 4200 device, both under standardized conditions and as routinely used
by ward staff, compared with the true indirect BP measured by mercury manometer
(MM). METHODS: One hundred forty-five stable inpatients were randomly selected
for BP measurements by 3 randomly ordered protocols: (1) MM performed by
certified investigators, (2) IVAC 4200 BP performed by trained investigators
(research automated [RA]), and (3) IVAC 4200 BP performed by ward personnel (ward
automated [WA]). RESULTS: For RA compared with MM ("true" indirect BP), 59% of
systolic and 54% of diastolic readings were within 5 mm Hg and 83% of systolic
and 86% of diastolic were within 10 mm Hg for a British Hypertension Society
grade C for both. For WA compared with MM, 40% of systolic and 50% of diastolic
readings were within 5 mm Hg and 70% of systolic and 80% of diastolic readings
were within 10 mm Hg for British Hypertension Society grades D and C,
respectively. The presence of arrhythmias and/or low K5 values (fifth phase of
Korotkoff sounds <30 mm Hg) significantly increased the inaccuracy for diastolic
values. Inappropriate cuff selection significantly increased inaccuracy of
systolic BP (WA vs MM). CONCLUSIONS: The IVAC 4200 yields substandard estimates
of systolic and diastolic BP even under standardized, thus optimum conditions.
The presence of arrhythmias or low K5 values and the selection of inappropriate
cuff size by the ward staff also contributed to inaccuracy.
PMID- 9554678
TI - Most common dermatologic problems identified by internists, 1990-1994.
AB - BACKGROUND: Internists in all settings see many patients with skin conditions.
Thus, their education in dermatology is important. Information on which areas of
dermatology are most commonly seen in internal medicine practices is necessary
for designing effective educational programs on skin disease. OBJECTIVE: To
determine what types of dermatologic problems internists most commonly diagnose.
METHODS: National Ambulatory Medical Care Survey data from 1990 to 1994 were
analyzed for dermatologic diagnoses. Physicians specializing in internal medicine
and all its subspecialties were compared with dermatologists and with other
physicians. RESULTS: The most common skin disorders diagnosed by internists were
dermatitis (15.8% of all diagnoses) and bacterial skin infections (14.0% of all
diagnoses). Combined, bacterial, fungal, and viral infections included 28.3% of
the most common dermatologic diagnoses made by internists. The top 10 most common
diagnoses accounted for 57.9% of all skin-related diagnoses and the top 20 most
common diagnoses accounted for 72.8%. Internists were more likely to see patients
for bacterial skin infections, herpes infection, exanthem, urticaria, and insect
bites while dermatologists more commonly saw patients for actinic and seborrheic
keratoses, warts, benign and malignant skin tumors, and psoriasis. CONCLUSIONS:
The most common dermatologic diseases diagnosed by internists differ considerably
from those diagnosed by dermatologists. Because dermatologists do much of the
dermatology teaching of internal medicine residents, it is important to recognize
these differences to place emphasis on the proper areas of study. Some common or
serious skin conditions not often diagnosed by internists such as psoriasis and
melanoma also deserve attention in internal medicine training programs.
PMID- 9554679
TI - Trillion virion delay: time from testing positive for HIV to presentation for
primary care.
AB - BACKGROUND: Human immunodeficiency virus (HIV)-infected individuals' initial
presentation to medical care frequently occurs at a point of advanced
immunosuppression. OBJECTIVES: To investigate the time between HIV testing and
presentation to primary care. Also to examine factors associated with delayed
presentation. METHODS: One hundred eighty-nine consecutive outpatients without
prior primary care for HIV infection were assessed at 2 urban hospitals: Boston
City Hospital, Boston, Mass, and Rhode Island Hospital, Providence.
Sociodemographics, alcohol and drug use, social support, sexual beliefs and
practices, and HIV testing issues were examined in bivariate and multivariate
analyses for association with delay in presentation to primary care after
positive test results for HIV. RESULTS: Of 189 patients, 74 (39%) delayed seeking
primary care for more than 1 year, 61 (32%) delayed for more than 2 years, and 35
(18%) for more than 5 years after an initial positive HIV serologic evaluation.
The median CD4+ cell count of subjects was 0.28 x 10(9)/L (range, 0.001-1.71 x
10(9)/L). In multiple linear regression analysis the following characteristics
were found to be associated with delayed presentation to primary care after HIV
testing: history of injection drug use (P<.001); not having a living mother
(P=.01); not having a spouse or partner (P=.08); not being aware of HIV risk
before testing (P<.001); and being notified of HIV status by mail or telephone
(P=.002). An interaction effect between sex and screening for alcohol abuse was
significant (P=.03) and suggested longer delays for men with positive screening
test results (CAGE [an alcoholism screening questionnaire containing 4 structured
questions], 2+) compared with men without positive screening test results or
women. CONCLUSIONS: Patients with positive HIV test results often delay for more
than a year before establishing primary medical care. Information readily
available at the time of HIV testing concerning substance abuse, social support,
and awareness of personal HIV risk status is useful in identifying patients who
are at high risk of not linking with primary care. Patients who were notified of
their HIV status by mail or telephone delayed considerably longer than those
notified in person. Efforts to ensure primary care linkage at the time of
notification of positive HIV serostatus are necessary to maximize benefits for
both individual and public health and should be an explicit task of posttest
counseling.
PMID- 9554680
TI - Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on
glucose, lipid, uric acid, and potassium levels in older men and women with
isolated systolic hypertension: The Systolic Hypertension in the Elderly Program.
SHEP Cooperative Research Group.
AB - BACKGROUND: Previous studies often of short duration have raised concerns that
antihypertensive therapy with diuretics and beta-blockers adversely alters levels
of other cardiovascular disease risk factors. METHODS: The Systolic Hypertension
in the Elderly Program was a community-based, multicenter, randomized, double
blind, placebo-controlled clinical trial of treatment of isolated systolic
hypertension in men and women aged 60 years and older. This retrospective
analysis evaluated development of diabetes mellitus in all 4736 participants in
the Systolic Hypertension in the Elderly Program, including changes in serum
chemistry test results in a subgroup for 3 years. Patients were randomized to
receive placebo or treatment with active drugs, with the dose increased in
stepwise fashion if blood pressure control goals were not attained: step 1, 12.5
mg of chlorthalidone or 25.0 mg of chlorthalidone; and step 2, the addition of 25
mg of atenolol or 50 mg of atenolol or reserpine or matching placebo. RESULTS:
After 3 years, the active treatment group had a 13/4 mm Hg greater reduction in
systolic and diastolic blood pressure than the placebo group (both groups,
P<.001). New cases of diabetes were reported by 8.6% of the participants in the
active treatment group and 7.5% of the participants in the placebo group (P=.25).
Small effects of active treatment compared with placebo were observed with
fasting levels of glucose (+0.20 mmol/L [+3.6 mg/dL]; P<.01), total cholesterol
(+0.09 mmol/L [+3.5 mg/dL]; P<.01), high-density lipoprotein cholesterol (-0.02
mmol/L [-0.77 mg/dL]; P<.01) and creatinine (+2.8 micromol/L [+0.03 mg/dL];
P<.001). Larger effects were seen with fasting levels of triglycerides (+0.9
mmol/L [+17 mg/dL]; P<.001), uric acid (+35 micromol/L [+.06 mg/dL]; P<.001), and
potassium (-0.3 mmol/L; P<.001). No evidence was found for a subgroup at higher
risk of risk factor changes with active treatment. CONCLUSIONS: Antihypertensive
therapy with low-dose chlorthalidone (supplemented if necessary) for isolated
systolic hypertension lowers blood pressure and its cardiovascular disease
complications and has relatively mild effects on other cardiovascular disease
risk factor levels.
PMID- 9554681
TI - Tuberculosis among immigrants and refugees.
AB - BACKGROUND: Overseas screening of immigrants and refugees applying for a visa to
the United States identifies foreign-born individuals who are at high risk for
tuberculosis (TB) or who have active TB. The system's effectiveness relies on
further medical evaluation and follow-up of foreign-born individuals after their
arrival in the United States. METHODS: Retrospective cohort study of 893
immigrants and refugees who arrived in the United States from July 1, 1992,
through December 31, 1993, with a destination of San Francisco, Calif, and a
referral for further medical evaluation. MAIN OUTCOME MEASURES: Time to report to
the local health department after arrival and the yield of active and preventable
cases of TB from follow-up medical evaluations. RESULTS: Median time from arrival
in the United States to seeking care in San Francisco was 9 days (range, 1-920
days). Of 745 immigrants and refugees (83.4%) who sought further medical
evaluation, 51 (6.9%) had active TB and 296 (39.7%) were candidates for
preventive therapy. Being a refugee was an independent predictor of failure to
seek further medical evaluation in the United States. Class B-1 disease status
based on overseas TB screening (odds ratio, 3.5; 95% confidence interval, 2.0
6.2) and being from mainland China (odds ratio, 4.4; 95% confidence interval, 1.9
9.9) were independent predictors of TB diagnosed in San Francisco. CONCLUSIONS:
Timely, adequate medical evaluation and follow-up care of immigrants and refugees
has a relatively high yield and should be a high priority for TB prevention and
control programs.
PMID- 9554682
TI - Carotid and lower extremity arterial disease in patients with renal artery
atherosclerosis.
AB - BACKGROUND: Atherosclerotic lesions of the carotid and lower extremity arteries
may be associated with renal artery stenosis and influence the management of
patients with renal artery disease. OBJECTIVE: To document the prevalence and
clinical features of carotid and lower extremity arterial disease in patients
with renal artery atherosclerosis. METHODS: An analysis of baseline data on 149
patients enrolled in a prospective natural history study of atherosclerotic renal
artery stenosis. Patients with at least 1 abnormal renal artery by duplex
scanning were eligible. Carotid artery disease was evaluated by duplex scanning,
and ankle/brachial indices were used to assess the lower extremity arteries.
Disease at each of the 3 arterial sites was classified as mild, moderate, or
severe based on the extent of involvement on both sides. Serum urea nitrogen,
creatinine, and lipid levels were also measured. RESULTS: Severe renal, carotid,
or lower extremity arterial disease was present in 44%, 19%, and 21% of the
patients, respectively. There was a trend for patients with increasing degrees of
renal artery disease to have increasing degrees of carotid and lower extremity
arterial disease. The prevalence of severe carotid artery disease increased from
7% in the mild renal artery group to 28% in the severe renal artery group.
Clinical factors that were most predictive of severe disease were elevated
apolipoprotein B levels for the renal arteries, high serum urea nitrogen or
creatinine levels for the carotid arteries, and smoking for the lower extremity
arteries. CONCLUSIONS: There was a strong association between severe renal artery
atherosclerosis and severe carotid artery disease. Patients with renal artery
disease also had a high prevalence of lower extremity arterial disease. In this
patient population, screening for lower extremity arterial disease can be
reserved for those with signs or symptoms of peripheral ischemia. Noninvasive
carotid screening is justified in patients with renal artery disease to detect
asymptomatic lesions that require either immediate surgical treatment or serial
follow-up for disease progression.
PMID- 9554683
TI - Human granulocytic ehrlichiosis in New York.
AB - BACKGROUND: Human granulocytic ehrlichiosis (HGE), a potentially fatal tick-borne
disease, was first described in the upper Midwest in 1994. Following reports of
suspected cases of ehrlichiosis from New York physicians, descriptive and case
control studies were conducted to characterize the epidemiology and risk factors
for HGE in New York residents. METHODS: Descriptive data were gathered from
surveillance and laboratory reports and hospital records. A confirmed case was
defined as either (1) a 4-fold change in total antibody titer to Ehrlichia equi
by indirect immunofluorescence or (2) a polymerase chain reaction assay positive
for Ehrlichia phagocytophila/E equi group DNA. A probable case was defined as an
acute febrile illness and either (1) a single E equi titer greater than or equal
to 80 or (2) morulae on a peripheral blood smear. The case-control study included
patients with confirmed HGE 18 years of age or older with the onset of disease in
1995 and 2 to 3 neighborhood-matched controls. RESULTS: During 1994 and 1995, the
New York State Department of Health, Albany, received reports of 241 residents
who were tested for HGE; 30 met the confirmed case definition and 34 met the
probable case definition. The median age of patients was 46 years (age range, 9
90 years), 35 (55%) were male, and 25 (45%) were hospitalized. Fever, headache,
malaise, and myalgia were the most frequently reported symptoms. Fifty-six (88%)
of the 64 patients resided in areas in which Lyme disease is hyperendemic. In the
case-control analysis, cases were more likely than controls to have sustained a
tick bite during 1995 (matched odds ratio, 5.0; 95% confidence interval, 0.9
49.8). Cases and controls did not differ by occupational exposure to ticks,
underlying chronic diseases, or measures taken to prevent tick bites.
CONCLUSIONS: This study, which, to our knowledge, is the first population-based
study of HGE, demonstrates the recent recognition of HGE in the state of New
York. Control measures should be integrated with those for Lyme disease and
should focus on minimizing contact with ticks and obtaining early treatment for
infection.
PMID- 9554684
TI - Carrier screening for cystic fibrosis, Gaucher disease, and Tay-Sachs disease in
the Ashkenazi Jewish population: the first 1000 cases at New York University
Medical Center, New York, NY.
AB - BACKGROUND: By late 1993, the genes for cystic fibrosis and Gaucher disease and
the mutations common among Ashkenazi Jews had been identified. In response to
these advances, heterozygote screening for cystic fibrosis and Gaucher disease
was added to the more than 20-year-old Tay-Sachs disease screening program at New
York University Medical Center, New York, NY. OBJECTIVE: To review the outcomes
from the first 1000 patients screened through this program. METHODS: Patients and
their referring physicians were informed about the new carrier tests. At the time
of screening, patients could choose their tests (hexosaminidase A by enzyme
analysis for Tay-Sachs disease or mutation analysis for cystic fibrosis and
Gaucher disease). All partners of Tay-Sachs and cystic fibrosis carriers were
tested. Prenatal diagnosis was offered and performed for carrier couples or mixed
marriage couples in whom the Ashkenazi Jewish partner was a carrier of Gaucher
disease. Outcomes were measured by: (1) choice of tests, (2) decisions regarding
prenatal diagnosis, and (3) phenotypes of children born to patients who underwent
screening. RESULTS: The majority of Ashkenazi Jewish patients chose to have
testing for all 3 diseases. If they previously underwent screening for Tay-Sachs
disease, then they chose to undergo testing for cystic fibrosis and Gaucher
disease. All carrier couples for each of these diseases went on to have prenatal
testing. All mixed-marriage couples in whom the Jewish partner was found to be a
carrier for Gaucher disease chose to have prenatal diagnosis. One fetus was
identified as having cystic fibrosis. Since the program was initiated, no
Ashkenazi Jewish baby has been born with any of these diseases at New York
University Medical Center. CONCLUSIONS: New tests can be readily incorporated
into established heterozygote screening programs. The Ashkenazi Jewish population
described herein tends to choose testing for all conditions for which
heterozygote screening is available.
PMID- 9554685
TI - Member ratings of health care provided by 48 physician groups.
AB - BACKGROUND: Satisfaction with health plan performance has been assessed
frequently, but assessment of physician group performance is rare. OBJECTIVE: To
present ratings of the care provided by physician groups to enrollees in a
variety of capitated health maintenance organization plans. METHODS: A random
sample was drawn of adult enrollees receiving managed health care from 48
physician groups in a group practice association. Each individual in the sample
was mailed a 12-page questionnaire and 7093 were returned (59% response rate).
The mean age of those returning the questionnaire was 51 years; 65% were women.
RESULTS: Reliability estimates for 6 multi-item satisfaction scales were
excellent, and noteworthy differences in ratings among groups were observed. In
particular, ratings of overall quality ranged from a low of 28 to a high of 68
(mean, 50; SD, 10). Average scores for physician groups were strongly correlated
across all scales, but no single group scored consistently highest or lowest on
the different scales. Negative ratings of care were significantly related to the
following: intention to switch to another physician group, difficulty in getting
appointments, lengthy waiting periods in the reception area and examination room,
the inability to get consistent care from one physician for routine visits, and
not being informed by the office staff when there was a delay in seeing the
primary care provider. CONCLUSIONS: Monitoring of health care quality at the
physician group level is possible, and could be used for benchmarking, internal
quality improvement, and for providing information to the public about how these
physician groups will meet its needs.
PMID- 9554686
TI - End-stage renal disease in specific ethnic and racial groups: risk factors and
benefits of antihypertensive therapy.
AB - During the past few years, it has become apparent that there are factors that
place a person at greater risk for the development and progression of renal
failure. This has been documented since the early 1980s by the United States
Renal Data System that has collected data confirming that end-stage renal disease
occurs at a greater rate in certain subpopulations of Americans. It is evident
from an examination of the data that African Americans and American Indians have
an incidence of end-stage renal disease that is not proportional to their
percentage of the total population. In fact, African Americans and American
Indians are reported to have at least a 4-fold greater incidence of end-stage
renal disease than white Americans. There have been 5 factors identified:
hypertension, glucose intolerance, insulin resistance, salt sensitivity, and
hyperlipidemia, which may play a greater role in these subpopulations. In
addition, as with other populations, lifestyle issues may serve to alter these
primary risk factors or may act as direct modulators of renal disease
progression. There is also a possibility that interactions between risk factors
frequently occur that may modify the development or progression of the disease.
This article reviews these risk factors and emphasizes the interaction between
hypertension and the other factors. In addition, the effects of antihypertensive
agents on risk factors and on renal outcome are emphasized. Where possible,
issues specific to African Americans and American Indians are underscored;
however, one must accept that the database on these populations is only now
developing. This review should help the clinician make appropriate choices when
prescribing antihypertensive therapy for patients who may be at risk of
developing progressive renal failure.
PMID- 9554687
TI - Diagnostic utility of the polymerase chain reaction in 2 cases of suspected
Whipple disease.
AB - We describe 2 patients with a diagnosis of Whipple disease in whom the usual
antibiotic therapy failed. A polymerase chain reaction-based test was used to
identify the recently described Whipple bacillus, Tropheryma whippelii. In one
case, the diagnosis was confirmed, whereas in the second case, which had been
histologically diagnosed as Whipple disease of the brain, the process was
identified as a monocyte-derived histiocytosis. In conclusion, Whipple disease
can be distinguished from other diseases with similar histological features with
the use of a polymerase chain reaction-based test.
PMID- 9554689
TI - Depression, adherence behavior, and coronary disease outcomes.
PMID- 9554688
TI - More evidence on safety of intramuscular immune serum globulin produced from
plasma unscreened for anti-hepatitis C virus antibodies.
PMID- 9554690
TI - Intractable hiccups induced by the use of megestrol acetate.
PMID- 9554691
TI - Group A streptococcal meningitis.
PMID- 9554693
TI - Influence of extremely low frequency magnetic fields on chromosomes and the
mitotic cycle in Vicia faba L., the broad bean.
AB - Vicia faba seedlings were subjected to one of the following magnetic fields
continuously for 3 days: 0 Hz (DC) at 5 mT, 50 Hz at 1.5 mT, 60 Hz at 1.5 mT, and
75 Hz at 1.5 mT. The lengths of all the phases of mitosis differed from the
controls in all treatments using alternating magnetic fields and for prophase and
metaphase in the DC condition. In particular, all treatments increased the length
of prophase significantly in meristematic root-tip cells compared with the
controls. The implications of these results for chromosome coiling are discussed.
The length of prophase, however, did not vary significantly between any of the
treatments. Furthermore, none of the exposed seedlings had a greater frequency of
chromosome breakages above that of the control plants.
PMID- 9554692
TI - Alternate indices of electric and magnetic field exposures among Ontario
electrical utility workers.
AB - Epidemiologic studies examining the risk of cancer among occupational groups
exposed to electric fields (EF) and or magnetic fields (MF) have relied on
traditional summaries of exposure such as the time weighted arithmetic or
geometric mean exposure. Findings from animal and cellular studies support the
consideration of alternative measures of exposure capable of capturing threshold
and intermittent measures of field strength. The main objective of this study was
to identify a series of suitable exposure metrics for an ongoing cancer incidence
study in a cohort of Ontario electric utility workers. Principal components
analysis (PCA) and correlational analysis were used to explore the relationships
within and between series of EF and MF exposure indices. Exposure data were
collected using personal monitors worn by a sample of 820 workers which yielded
4247 worker days of measurement data. For both EF and MF, the first axis of the
PCA identified a series of intercorrelated indices that included the geometric
mean, median and arithmetic mean. A considerable portion of the variability in EF
and MF exposures were accounted for by two other principal component axes. The
second axes for EF and MF exposures were representative of the standard deviation
(standard deviation) and thresholds of field measures. To a lesser extent, the
variability in the exposure variable was explained by time dependent indices
which consisted of autocorrelations at 5 min lags and average transitions in
field strength. Our results suggest that the variability in exposure data can
only be accounted for by using several exposure indices, and consequently, a
series of metrics should be used when exploring the risk of cancer owing to MF
and EF exposure in this cohort. Furthermore, the poor correlations observed
between indices of MF and EF reinforce the need to be take both fields into
account when assessing the risk of cancer in this occupational group.
PMID- 9554694
TI - Evaluation of potential health effects of 10 kHz magnetic fields: a rodent
reproductive study.
AB - New technology involving the use of high-frequency inductive power distribution
(HID) has recently been developed for use in materials handling and personnel
transfer. Sinusoidal magnetic fields at a frequency of 10 kHz with field
intensities of approximately 0.2 mT are generated directly between the current
carrying coils of this equipment. Effects of 10 kHz magnetic fields on cell
division, migration, and differentiation have never been previously investigated.
To evaluate potential effects on these parameters, a rodent reproductive study
was undertaken using Wistar rats. Exposures were at 0.095, 0.24, and 0.95 mT with
a background exposure of 5-10 microT. Three sets of parental rats were exposed
continuously for 20-23.5 h/day to the fields: maternal rats during gestation,
paternal rats for at least 45 days prior to mating and maternal rats 1 month
prior to mating. Exposure phases thus covered spermatogenesis, maturation of the
ovum and ovulation, fertilization, implantation, embryogenesis, organogenesis,
and maturation of the fetus immediately prior to parturition. In all experiments
pregnancy outcome was assessed. These studies failed to demonstrate any
reproductive toxicity resulting from maternal or fetal exposure during gestation
or following paternal or maternal exposure for several weeks prior to mating. No
quantitative or qualitative effects on spermatogenesis occurred after exposure,
and no effects on the estrous cycle or ovulation could be demonstrably linked to
the 10 kHz magnetic field exposure at 0.095, 0.25, or 0.95 mT. Where possible,
parental clinical chemistry and hematology were also examined. As in mouse
toxicology studies previously reported, minor differences were observed between
control and treated groups. These were regarded as statistically, but not
biologically, significant and could not categorically be attributed to magnetic
field exposure.
PMID- 9554695
TI - 60 Hz magnetic field exposure and urinary 6-sulphatoxymelatonin levels in the
rat.
AB - Four separate experiments were carried out to investigate the effect of extremely
low frequency magnetic field (MF) exposure (60 Hz, 1 mT rms) on urinary 6
sulphatoxymelatonin (aMT6s) levels in Sprague-Dawley rats. In the first
experiment, immature male rats maintained under a regular 12 h daily photoperiod
(white fluorescent light) were exposed to a 20 h daily MF exposure for 6 weeks.
The second experiment was similar to the first, except that the MF exposure was
limited to 10 days. In the third experiment, adult male rats acclimated to a
combination of continuous dim red light and regular 12 h daily photoperiod (white
fluorescent) were subjected to a single 1 h exposure to intermittent MF (1 min on
and 1 min off cycles), 2 h before fluorescent lights went off. The fourth
experiment was similar to the third, except that the animals received 2
consecutive days of 20 h daily exposure to intermittent MF, beginning 1 h before
the fluorescent lights went off each day. In all four experiments, the circadian
profile of urinary aMT6s was examined before, during, and after the MF exposure.
No significant effect of 1 mT MF on indoleamine metabolism was observed in any of
the above experiments. However, in one of the experiments (no. 4), both the
control and the MF groups showed a lower aMT6s level during the exposure days,
when compared with that of pre- and post-exposure days, suggesting that the
existence of possible effects with lower field strengths at the range of stray
field cannot be ruled out.
PMID- 9554696
TI - A physical analysis of the ion parametric resonance model.
AB - We show, in elementary terms, using for the most part only elementary
mathematics, the physical bases for the ion parametric resonance model so as to
clarify the assumptions and consequences of the model. The analysis shows why,
contrary to earlier conclusions, no combination of weak DC and AC magnetic fields
can modify the transition rate to the ground state of excited ions. Although
reinterpretations of the biological consequences of the motion of the excited
ions circumvent that particular objection to the model, those changes introduce
other difficulties. Also, other objections to the mechanism still stand; hence
the model cannot account for any purported biological effects of weak extremely
low frequency magnetic fields.
PMID- 9554697
TI - Analysis of the effect of a 60 Hz AC field on histamine release by rat peritoneal
mast cells.
AB - Reports have indicated effects of electromagnetic fields on inflammatory
processes in vivo. To begin a systematic approach toward separating and examining
the many components of such responses, we created and tested a temperature
controlled device to develop 5 mT 60 Hz magnetic fields for studies of the
effects of fields on mast cells, a key component in acute inflammatory responses.
Such fields have been reported to modulate cell activity, including changes in
membrane function, in various systems. The magnetic field was generated using a
solenoid and calibrated with an induction probe. Tests of mast cell function were
determined by histamine release response to stimulation by compound 48/80, using
both an "expose then test" and a "test during exposure" protocol. Aliquots not
treated with 48/80 were used to evaluate field treatment effects on spontaneous
histamine release. Freshly harvested rat peritoneal mast cells were exposed to
the magnetic field for periods of 30 min to 2 h at 37 degrees C. They showed no
significant degranulation during treatment, nor did they show reduced sensitivity
to the degranulating agent 48/80. These observations are consistent with a model
in which such processes are exclusively reflexive by the cells using field
independent membrane systems. This observation is very useful and was needed
before examining longer term exposures in which gene expression in the cells
might be influenced; this is the first such report of in vitro exposure of
purified mast cells under these conditions and will further the study of the
effects of electromagnetic fields on cell types active in acute inflammation.
PMID- 9554698
TI - Human sleep under the influence of pulsed radiofrequency electromagnetic fields:
a polysomnographic study using standardized conditions.
AB - To investigate the influence of radiofrequency electromagnetic fields (EMFs) of
cellular phone GSM signals on human sleep electroencephalographic (EEG) pattern,
all-night polysomnographies of 24 healthy male subjects were recorded, both with
and without exposure to a circular polarized EMF (900 MHz, pulsed with a
frequency of 217 Hz, pulse width 577 micros, power flux density 0.2 W/m2.
Suppression of rapid eye movement (REM) sleep as well as a sleep-inducing effect
under field exposure did not reach statistical significance, so that previous
results indicating alterations of these sleep parameters could not be replicated.
Spectral power analysis also did not reveal any alterations of the EEG rhythms
during EMF exposure. The failure to confirm our previous results might be due to
dose-dependent effects of the EMF on the human sleep profile.
PMID- 9554699
TI - Acetylcholine release and the cholinergic genomic locus.
AB - Choline acetyltransferase and vesicular acetylcholine-transporter genes are
adjacent and coregulated. They define a cholinergic locus that can be turned on
under the control of several factors, including the neurotrophins and the
cytokines. Hirschprung's disease, or congenital megacolon, is characterized by
agenesis of intramural cholinergic ganglia in the colorectal region. It results
from mutations of the RET (GDNF-activated) and the endothelin-receptor genes,
causing a disregulation in the cholinergic locus. Using cultured cells, it was
shown that the cholinergic locus and the proteins involved in acetylcholine (ACh)
release can be expressed separately ACh release could be demonstrated by means of
biochemical and electrophysiological assays even in noncholinergic cells
following preloading with the transmitter. Some noncholinergic or even
nonneuronal cell types were found to be capable of releasing ACh quanta. In
contrast, other cells were incompetent for ACh release. Among them, neuroblastoma
N18TG-2 cells were rendered release-competent by transfection with the
mediatophore gene. Mediatophore is an ACh-translocating protein that has been
purified from plasma membranes of Torpedo nerve terminal; it confers a
specificity for ACh to the release process. The mediatophores are activated by
Ca2+; but with a slower time course, they can be desensitized by Ca2+. A strictly
regulated calcium microdomain controls the synchronized release of ACh quanta at
the active zone. In addition to ACh and ATP, synaptic vesicles have an ATP
dependent Ca2+ uptake system; they transiently accumulate Ca2+ after a brief
period of stimulation. Those vesicles that are docked close to Ca2+ channels are
therefore in the best position to control the profile and dynamics of the Ca2+
microdomains. Thus, vesicles and their whole set of associated proteins (SNAREs
and others) are essential for the regulation of the release mechanism in which
the mediatophore seems to play a key role.
PMID- 9554700
TI - Extracellular nucleotide signaling in the inner ear.
AB - Extracellular nucleotides, particularly adenosine 5'-triphosphate (ATP), act as
signaling molecules in the inner ear. Roles as neurotransmitters,
neuromodulators, and as autocrine or paracrine humoral factors are evident. The
diversity of the signaling pathways for nucleotides, which include a variety of
ATP-gated ion channels (assembled from different subtypes of P2X-receptor
subunit) and also different subtypes of G protein-coupled nucleotide receptors
(P2Y receptors) supports a major physiological role for ATP in the regulation of
hearing and balance. Almost invariably both P2X and P2Y receptor expression is
apparent in the complex tissue structures associated with the inner-ear
labyrinth. However P2X-receptor expression, commonly associated with fast
neurotransmission, is apparent not only with the cochlear and vestibular primary
afferent neurons, but also appears to mediate humoral signaling via ATP-gated ion
channel localization to the endolymphatic surface of the cochlear sensory
epithelium (organ of Corti). This is the site of the sound-transduction process
and recent data, including both electrophysiological, imaging, and
immunocytochemistry, has shown that the ATP-gated ion channels are colocalized
here with the mechano-electrical transduction channels of the cochlear hair
cells. In contrast to this direct action of extracellular ATP on the sound
transduction process, an indirect effect is apparent via P2Y-receptor expression,
prevalent on the marginal cells of the stria vascularis, a tissue that generates
the standing ionic and electrical gradients across the cochlear partition. The
site of generation of these gradients, including the dark-cell epithelium of the
vestibular labyrinth, may be under autocrine or paracrine regulation mediated by
P2Y receptors sensitive to both purines (ATP) and pyrimidines such as UTP. There
is also emerging evidence that the nucleoside adenosine, formed as a breakdown
product of ATP by the action of ectonucleotidases and acting via P1 receptors, is
also physiologically significant in the inner ear. P1-receptor expression
(including A1, A2, and A3 subtypes) appear to have roles associated with stress,
acting alongside P2Y receptors to enhance cochlear blood flow and to protect
against the action of free radicals and to modulate the activity of membrane
conductances. Given the positioning of a diverse range of purinergic-signaling
pathways within the inner ear, elevations of nucleotides and nucleosides are
clearly positioned to affect hearing and balance. Recent data clearly supports
endogenous ATP- and adenosine-mediated changes in sensory transduction via a
regulation of the electrochemical gradients in the cochlea, alterations in the
active and passive mechanical properties of the cells of the sensory epithelium,
effects on primary afferent neurons, and control of the blood supply. The field
now awaits conclusive evidence linking a physiologically-induced modulation of
extracellular nucleotide and nucleoside levels to altered inner ear function.
PMID- 9554701
TI - Age-related alteration of PKC, a key enzyme in memory processes: physiological
and pathological examples.
AB - Brain aging is characterized by a progressive decline of the cognitive and memory
functions. It is becoming increasingly clear that protein phosphorylation and, in
particular, the activity of the calcium-phospholipid-dependent protein kinase C
(PKC) may be one of the fundamental cellular changes associated with memory
function. PKC is a multigene family of enzymes highly expressed in brain tissues.
The activation of kinase C is coupled with its translocation from the cytosol to
different intracellular sites and recent studies have demonstrated the key role
played by several anchoring proteins in this mechanism. PKC-phosphorylating
activity appears to be impaired during senescence at brain level in a strain
dependent fashion in rodents. Whereas the levels of the various isoforms do not
show age-related alterations, the enzyme translocation upon phorbol-ester
treatment is deficitary among all strains investigated. Anchoring proteins may
contribute to this activation deficit. We discuss also modifications of the PKC
system in Alzheimer's disease that may be related to pathological alterations in
neurotransmission. A better insight of the different factors controlling brain
PKC activation may be important not only for elucidating the molecular basis of
neuronal transmission, but also for identifying new approaches for correcting or
even preventing age-dependent changes in brain function.
PMID- 9554702
TI - Gender specificity in the neural regulation of the response to stress: new leads
from classical paradigms.
AB - Pronounced gender-related differences are observable in the regulation of the
limbic-hypothalamic-pituitary-adrenal (LHPA) activity under basal and stress
related conditions, and by circulating glucocorticoid levels. This article
reviews recent studies that have unequivocally demonstrated that these
differences emerge from the organizational effects of gonadal steroids during
early brain development. Although largely masked by the dominating role of
glucocorticoids in maintaining feedback thresholds, gonadal steroids continue to
exert gender-specific activational effects on the LHPA axis through adulthood.
The importance of these modulatory effects of gonadal steroids may be reflected
in gender differences in the incidence of psychopathologies that are accompanied
by symptoms of LHPA dysregulation. One goal of this review is to highlight the
need for further investigations into the (still elusive) cellular and molecular
mechanisms underlying the activational effects of sex steroids, which may provide
leads for neuroprotective hormone replacement strategies.
PMID- 9554705
TI - Disabled doctors: the insurance industry seeks a second opinion.
AB - This article focuses on disability in the professional work force, especially
among physicians, and includes a background on private disability insurance in
the United States, a discussion of problems experienced by the insurance industry
over the past few years, a review of relevant case law on private disability, and
legal and clinical issues involved in performing independent medical evaluations.
PMID- 9554703
TI - Role of MAP kinase in neurons.
AB - Extracellular stimuli such as neurotransmitters, neurotrophins, and growth
factors in the brain regulate critical cellular events, including synaptic
transmission, neuronal plasticity, morphological differentiation and survival.
Although many such stimuli trigger Ser/Thr-kinase and tyrosine-kinase cascades,
the extracellular signal-regulated kinases, ERK1 and ERK2, prototypic members of
the mitogen-activated protein (MAP) kinase family, are most attractive candidates
among protein kinases that mediate morphological differentiation and promote
survival in neurons. ERK1 and ERK2 are abundant in the central nervous system
(CNS) and are activated during various physiological and pathological events such
as brain ischemia and epilepsy. In cultured hippocampal neurons, simulation of
glutamate receptors can activate ERK signaling, for which elevation of
intracellular Ca2+ is required. In addition, brain-derived neurotrophic factor
and growth factors also induce the ERK signaling and here, receptor-coupled
tyrosine kinase activation has an association. We describe herein intracellular
cascades of ERK signaling through neurotransmitters and neurotrophic factors.
Putative functional implications of ERK and other MAP-kinase family members in
the central nervous system are give attention.
PMID- 9554706
TI - Expert witness travel dilemmas: a pilot study of billing practices.
AB - A pilot study was performed, by questionnaire, on the strategies that expert
witnesses use in calculating billing for travel on forensic cases. The authors
tentatively conclude that as the complexity of the travel situation increases, a
tendency toward redundant billing emerges. The results--the first of their kind-
are presented with their implications for this and future studies.
PMID- 9554704
TI - Measuring human brain GABA in vivo: effects of GABA-transaminase inhibition with
vigabatrin.
AB - Gamma-aminobutyric acid (GABA) plays a pivotal role in suppressing the origin and
spread of seizure activity. Low occipital lobe GABA was associated with poor
seizure control in patients with complex partial seizures. Vigabatrin
irreversibly inhibits GABA-transaminase, raising brain and cerebrospinal fluid
(CSF) GABA concentrations. The effect of vigabatrin on occipital lobe GABA
concentrations was measured by in vivo nuclear magnetic-resonance spectroscopy.
Using a single oral dose of vigabatrin, the rate of GABA synthesis in human brain
was estimated at 17% of the Krebs cycle rate. As the daily dose of vigabatrin was
increased to up to 3 g, the fractional elevation of brain GABA was similar to CSF
increase. Doubling the daily dose from 3 to 6 g failed to increase brain GABA
further. Increased GABA concentrations appear to reduce GABA synthesis in humans
as it does in animals. With traditional antiepileptic drugs, remission of the
seizure disorder was associated with normal GABA levels. With vigabatrin,
elevated CSF and brain GABA was associated with improved seizure control.
Vigabatrin enhances the vesicular and nonvesicular release of GABA. The release
of GABA during seizures may be mediated in part by transporter reversal that may
serve as an important protective mechanism. During a seizure, this mechanism may
be critical in stopping the seizure or preventing its spread.
PMID- 9554707
TI - "Courtroom whores"?--or why do attorneys call us?: findings from a survey on
attorneys' use of mental health experts.
AB - Mental health professionals who serve as expert witnesses are repeatedly
characterized as (in the words of one recent author) "Whores of the Court."
However, scholars have published little systematically gathered data about why
attorneys seek mental health opinions and the criteria they use for selecting
experts. We investigated these issues using a mailed survey of attorneys and
judges. A slight majority of attorney respondents had requested mental health
professionals' opinion in the previous year. The most important factors in
selecting experts were their knowledge, ability to communicate, and local
reputation; national reputation and scholarly writings were least important.
Forty-nine percent of the responding attorneys said that receiving a favorable
opinion was a "very important" or "essential" consideration, although this did
not necessarily mean they wanted a dishonest opinion. Our findings suggest that
most forensic work is performed by mental health professionals who are chosen
because of their knowledge, communication skills, and local reputations.
PMID- 9554708
TI - Prototypes of intrafamily homicide and serious assault among insanity acquittees.
AB - Public concern with societal violence is intensified when persons who have been
found not guilty by reason of insanity (NGRI) of having committed a homicide or
serious assault are returned to the community. Successful management of such
acquittees in the community requires a sophisticated understanding of the person
and the illness within the larger context of the violent incident, the family,
the community, and the culture. In this article, we present an analysis of
psychotic violence within a family context. A qualitative study of 64 subjects
who were found NGRI of killing or seriously injuring a family member resulted in
four prototypes of intrafamilial homicide/assault: Till Death Us Do Part;
Overwhelming Burden, Elimination of the Limit Setter; and Family-Focused
Delusional Killing. The prototypes are presented as a model for developing
management strategies both for future risk assessment and for successful
transition of the insanity acquittee into the community.
PMID- 9554709
TI - Relating competency status to functional status at discharge in patients with
chronic mental illness.
AB - This study assessed performance on a screening test of competency to consent to
treatment, the Hopkins Competency Assessment Test (HCAT), in a population
diagnosed with chronic mental illness, and examined the relationship between HCAT
performance and functional status at discharge. We hypothesized that patients
with chronic mental illness who failed the HCAT would also have problems in
performing activities of daily living at the time of discharge. Forty-three
patients on a short-stay psychiatric service were administered the following
screening tests: (1) Mini-Mental State Exam (MMSE), on admission; (2) the HCAT,
approximately four to five days after admission; (3) At discharge, the Milwaukee
Evaluation of Daily Living Skills (MEDLS), and the Occupational Therapy Task
Observation Scale (OTTOS). Analyses included correlation between the competency
measure HCAT and the functional measures; sensitivity, specificity, and positive
and negative predictive values of the HCAT score; and odds ratio and chi-square
analysis. The HCAT was highly correlated with the MEDLS and OTTOS. The HCAT was
not sensitive in identifying impairment on either functional measure, but when
patients failed the HCAT, they were likely to be functionally impaired at
discharge. The negative predictive value of the HCAT was greater than the
positive predictive value. Patients who failed HCAT were significantly more
likely to have an MMSE score lower than 27 and less than 12 years of school.
Seven of forty-three (16.3%) patients failed a screening measure of competency,
indicating that there is a subgroup of chronically mentally ill patients who may
not understand issues of informed consent. Patients who failed the HCAT were more
likely to be functionally impaired at discharge. Cognitive impairment and low
education are important factors in failure to pass competency screening.
Competency screening along with screening for cognitive impairment can be useful
in identifying patients at risk for poor functional status at discharge.
PMID- 9554710
TI - Corruption in law enforcement: a paradigm of occupational stress and deviancy.
AB - In the closed society of a law enforcement agency, factors such as the conspiracy
of silence, authoritarian supervision, and police discretion contribute to
corruption. This article describes various types of corrupt behavior by police
officers, reports the incidence of corruption in law enforcement agencies,
discusses psychiatric conditions that may arise from corruption and also
contribute to further corruption, and reviews proposed remedies for corruption.
It also suggests that an understanding of corruption in law enforcement might be
helpful in understanding, correcting, and preventing corruption in other
professions, including medicine.
PMID- 9554711
TI - A comparison of youthful inmates who have committed violent versus nonviolent
crimes.
AB - The incidence of violent crimes committed by youthful offenders in the United
States is increasing. In this report, 150 inmates in a prison for youths (ages 14
to 24 years) who were treated by a psychiatrist were compared with 150 control
subjects on several parameters including those who had committed violent crimes
(V) versus those who had committed nonviolent crimes (NV). There were more
similarities than differences between those who had committed V versus NV crimes.
There was no statistically significant difference between the V and NV groups in
most diagnostic categories, the Beck Hopelessness Scale, the IQ scale, the MMPI
scores, job stability, and whether they were treated by a psychiatrist or not.
There were, however, some significant differences. The V group was younger than
the NV group; those with a diagnosis of paranoid schizophrenia disorder had
committed V crimes, while those with a diagnosis of dysthymic disorder had
committed NV crimes.
PMID- 9554713
TI - Competency to stand trial in preadjudicatory juveniles and adults.
AB - This study compared the competency to stand trial (CST) of 108 juveniles (ages 7
to 16 years) and 145 adults (17 years or older) undergoing pretrial, court
ordered forensic psychiatric evaluations. Adults were superior on both global and
specific competency abilities (p < .001). Clustered by age (<13, 13 and 14, 15
and 16 years old), preteens accused of crimes failed to meet a Dusky v. United
States standard, while 13- and 14-year-olds displayed an equal mix of abilities
and deficits. Mid-adolescents (ages 15 and 16) were equivalent to adults in CST
abilities except in their knowledge about plea bargaining elements. The
ramifications of CST in felony juvenile transfer to adult court as well as the
needs for ecologically valid, empirically based CST research on adolescents is
discussed.
PMID- 9554712
TI - Extended civil commitment for dangerous psychiatric patients.
AB - Mental health clinicians are increasingly held civilly liable for the dangerous
acts of their psychiatric patients. One area of liability is the negligent
release of involuntarily committed patients who engage in dangerous acts after
their hospital discharge. All states have provisions for extended involuntary
commitment for mentally ill dangerous patients. We examined extended civil
commitment petitions in Los Angeles County, California, and found that the great
majority were rejected. While the standard for extended civil commitment in
California includes verbal threats of substantial physical harm, deputy district
attorneys tended to reject petitions initiated by clinicians when verbal threats
were the sole criterion of dangerousness. This tendency by deputy district
attorneys can be quite confusing for clinicians. Mental health professionals'
liability has sensitized them to the legal implications of patients' verbal
threats of harm; attorneys do not incur the same legal liability and are not so
sensitized.
PMID- 9554714
TI - Stone walls do not a prison psychiatrist make.
PMID- 9554715
TI - An introduction to correctional psychiatry: Part III.
AB - This article, which is the last of three parts, provides an overview of relevant
national guidelines/standards for providing mental health services within a
correctional setting and describes essential characteristics of mental health
systems designed to meet constitutional standards. Part III addresses issues
pertinent to treatment programs for inmates with serious mental illnesses;
confidentiality; involuntary treatment; quality assurance; management information
systems; and research.
PMID- 9554716
TI - Disability discrimination and Parker v. Metropolitan Life: separate, but equal?
AB - In August 1997, the Sixth Circuit U.S. Court of Appeals ruled that disability
insurance obtained as an employment benefit is not a "physical place" protected
by Title III of the Americans With Disabilities Act (ADA). The majority held that
because benefits were obtained from an employer instead of from an insurance
office, the insurance plan's disparity between mental health benefits and
benefits for physical disabilities did not constitute "discrimination" as defined
by Title I of the ADA. Other circuit courts have held that illness-specific
discrimination in disability insurance coverage is indeed prohibited under Title
III. The conflict between the circuit courts may ultimately work its way to the
U.S. Supreme Court.
PMID- 9554717
TI - Privatized managed care and forensic mental health services.
AB - Managed care for mental health services, which began in the private, commercial
sector, has spread over the past few years to the public mental health sector as
well. Recently, states have begun considering whether to include the forensic
population within their privatized managed care systems. This article explores
some of the complexities and special challenges unique to forensic services and
notes some of the problems that might be incurred if the forensic population were
included in a managed care system.
PMID- 9554718
TI - A theory of ethics for forensic psychiatry.
PMID- 9554719
TI - How are neurons specified: master or positional control?
PMID- 9554720
TI - Getting the most out of noise in the central nervous system.
AB - Rather than merely a nuisance, noise in biological systems is a useful property.
Before patch-clamp methods were invented, analysis of membrane current noise
provided the first solid, if indirect, evidence for the existence of ion
conducting pores with discrete conductance levels. Although supplanted by single
channel recording techniques for most tasks, analysis of current membrane noise
remains useful for certain problems, such as determining the properties of
channels with rapid kinetics that open with a high probability and desensitize,
channels localized at synapses, channels with an unusually low unitary
conductance and open-channel noise. In addition, the role of noise in information
processing in the CNS is increasingly being recognized. In this article, we
summarize the analysis of current membrane noise with an emphasis on what the
technique is still useful for, and discuss the role for noise in information
processing.
PMID- 9554721
TI - Schizophrenia as failure of hemispheric dominance for language.
PMID- 9554722
TI - Schizophrenia as failure of hemispheric dominance for language.
PMID- 9554723
TI - Schizophrenia as failure of hemispheric dominance for language.
PMID- 9554724
TI - Subunit interaction sites in voltage-dependent Ca2+ channels: role in channel
function.
AB - Voltage-dependent Ca2+ channels are heteromeric complexes found in the plasma
membrane of virtually all cell types and show a high level of
electrophysiological and pharmacological diversity. Associated with the pore
forming alpha 1 subunit are the membrane anchored, largely extracellular alpha2
delta, the cytoplasmic beta and sometimes a transmembrane gamma subunit; these
subunits dramatically influence the properties and surface expression of these
channels. Effects vary depending on subunit isoforms, suggesting that functional
diversity of native channels reflects heterogeneity of combinations. Interaction
sites between subunits have been identified and advances have been made in our
understanding of the molecular basis of functional effects of the auxiliary
subunits, their capacity to be regulated by G proteins, and their interaction
with related cellular systems.
PMID- 9554725
TI - Do chemokines mediate leukocyte recruitment in post-traumatic CNS inflammation?
AB - Hematogenous leukocytes infiltrate the CNS after inflammatory stimuli, including
infection, mechanical trauma and excitotoxic neuronal necrosis. However,the role
of leukocytic inflammation in promoting or hindering tissue repair is poorly
understood. Identification of signals that lead to leukocyte recruitment and
activation is essential for the designing of interventions that modulate
inflammation, thus improving neurological outcome. Chemokines are small
pleiotropic chemoattractant cytokines whose target specificity suggests an
important role in determining the cellular composition of inflammatory
infiltrates. Chemokine expression profiles in the CNS during autoimmune and post
traumatic inflammation correlate well with the composition of leukocyte
infiltrates, and expression studies in systems such as transgenic mice, suggest
that chemokines have potent functional attributes in CNS physiology. We propose
that selective chemokine expression by CNS cells is crucial for post-traumatic
leukocyte accumulation.
PMID- 9554726
TI - How well do we understand the cochlea?
AB - As sensory cells, hair cells within the mammalian inner ear convert sounds into
receptor potentials when their projecting stereocilia are deflected. The organ of
Corti of the cochlea contains two types of hair cell, inner and outer hair cells,
which differ in function. It has been appreciated for over two decades that
although inner hair cells act as the primary receptor cell for the auditory
system, the outer hair cells can also act as motor cells. Outer hair cells
respond to variation in potential, and change length at rates unequalled by other
motile cells. The forces generated by outer hair cells are capable of altering
the delicate mechanics of the cochlear partition, increasing hearing sensitivity
and frequency selectivity. The discovery of such hair-cell motility has modified
the view of the cochlea as a simple frequency analyser into one where it is an
active non-linear filter that allows only the prominent features of acoustic
signals to be transmitted to the acoustic nerve by the inner hair cells. In this
view, such frequency selectivity arises through the suppression of adjacent
frequencies, a mechanical effect equivalent to lateral inhibition in neural
structures. These processes are explained by the interplay between the
hydrodynamic interactions among different parts of the cochlear partition and the
effective non-linear behaviour of the cell motor.
PMID- 9554727
TI - Pro-epileptic changes in synaptic function can be accompanied by pro-epileptic
changes in neuronal excitability.
AB - Repetitive sensory input, stroboscopic lights or repeated sounds can induce
epileptic seizures in susceptible individuals. In order to understand the process
we have to consider multiple factors. The output of a set of neurones is
determined by the amount of excitatory synaptic input, the degree of positive
feedback and their inherent electrical excitability, which can be modified by
synaptic inhibition. Recent research has shown that it is possible to separate
these phenomena, and that they do not always behave in unison.
PMID- 9554728
TI - Temporal stability of defibrillation thresholds with an active pectoral lead
system.
AB - INTRODUCTION: Monophasic defibrillation thresholds rise over time with a variety
of lead systems. These chronic changes are attenuated or eliminated by biphasic
waveforms, although the effect appears dependent upon the lead system. With the
downsizing of pulse generator size to allow for routine pectoral implantation,
active can lead systems have now become standard. However, the temporal stability
of such lead systems has not been evaluated previously. METHODS AND RESULTS: This
study was a prospective assessment of the changes of active pectoral
defibrillation thresholds over time. Thresholds were measured at implant,
predischarge, and at a mean follow-up of 50 days in 46 patients with a uniform
testing protocol and shock polarity. The lead system was a dual-coil Endotak DSP
lead with an active pectoral pulse generator. Defibrillation thresholds were
9.9+/-5.5 J at implantation, 8.5+/-6.0 J predischarge, and 7.6+/-5.5 J at follow
up (ANOVA, P = 0.007). Moreover, only two patients developed an increased
threshold > 5 J, and no patient had an inadequate safety margin at follow-up.
CONCLUSION: These results indicate that active pectoral defibrillation thresholds
are stable over the first 2 months postimplantation and question the need for
routine serial defibrillation threshold testing.
PMID- 9554729
TI - Intracardiac stimulation of human parasympathetic nerve fibers induces negative
dromotropic effects: implication with the lesions of radiofrequency catheter
ablation.
AB - INTRODUCTION: The dromotropic effects of intracardiac parasympathetic nerve
stimulation have not been well studied; furthermore, the effects of
radiofrequency ablation lesions on parasympathetic nerve stimulation are not
clear. METHODS AND RESULTS: Group I: intracardiac electrical stimulation in the
right posteroseptal and anteroseptal areas under different stimulation strengths;
group II: intracardiac electrical stimulation before and 10 minutes after
intravenous propranolol; group III: intracardiac electrical stimulation before
and 5 minutes after intravenous atropine. Among the 10 patients with AV nodal
reentrant tachycardia (group IV) and the 10 patients with atrial flutter (group
V), atrial fibrillation was induced before and after successful ablation, and
intracardiac electrical stimulation in the right posteroseptal area was performed
before and after successful ablation. The maximal response and complete decay of
the response occurred within 2 to 6 seconds of initiation or termination of
parasympathetic nerve stimulation. This negative dromotropic effect disappeared
after atropine was administered, but not after propranolol. After successful
ablation, parasympathetic stimulation still induced negative dromotropic effects.
CONCLUSION: Electrical stimulation of parasympathetic nerve fibers near the
posteroseptal and anteroseptal areas could induce a negative dromotropic effect,
and this effect was preserved after successful radiofrequency ablation of slow
pathway and isthmus conduction.
PMID- 9554730
TI - Influence of filtering techniques on the time-domain analysis of signal-averaged
P wave electrocardiogram.
AB - INTRODUCTION: The advent of signal-averaged ECG (SAECG) systems for P wave
analysis has made it important to determine if the use of different filtering
techniques in these systems is diagnostically equivalent. METHODS AND RESULTS:
Three different high-pass filtering techniques and two cutoff frequency values
were used: 29- and 40-Hz Butterworth bidirectional filter (BB29, BB40), 29- and
40-Hz Butterworth unidirectional filter (UB29, UB40), and 29- and 40-Hz least
mean square filter (LMS29, LMS40). Normal healthy volunteers (n = 36) and
patients with documented paroxysmal atrial fibrillation (n = 23) were analyzed. A
custom-built SAECG system and standard bipolar orthogonal leads were used. Noise
was reduced to < 0.3 microV. P wave total duration, root mean square voltage of
the terminal 20, 30, and 40 msec of the filtered vector magnitude, and the area
under the curve between the onset and offset of averaged unfiltered and filtered
P wave vector magnitude were analyzed. Only the duration of the P wave showed
statistically significant differences between groups, being longer in the PAF
group for all filters and cutoff frequencies studied. A bias increment of
approximately 20 msec was detected in unidirectional and least mean square
filters as compared to the bidirectional filter. Sensitivity, specificity, and
predictive accuracy were > 70% for all filters; the BB40 filter yielded the best
performance. CONCLUSION: The normality limits derived from one filter cannot be
applied directly to recordings obtained from the other filters. Critical limits
must be established individually for different software settings.
PMID- 9554731
TI - Enhanced detection criteria in implantable defibrillators.
AB - INTRODUCTION: Enhanced detection criteria in third-generation implantable
defibrillators have been implemented to avoid inappropriate therapy of fast
supraventricular arrhythmias. We prospectively analyzed the use of these criteria
in patients with an implantable defibrillator with electrogram storing
capability. METHODS AND RESULTS: In 82 consecutive patients with a Guidant-CPI
implantable defibrillator, sudden onset > 9% and stability < 40 msec were
systematically programmed in zone 1 of therapy together with a sustained rate
duration security mechanism. All detected tachycardia episodes were analyzed. The
study population consisted of 59 patients who had at least one episode of
tachycardia detected in zone 1 during follow-up. The tachycardia rate in zone 1
never exceeded 210 beats/min. Twenty patients had no episodes during follow-up,
and three patients had episodes detected exclusively in zone 2 of therapy.
Supraventricular arrhythmias were detected frequently in the ventricular
tachycardia zone (193 of 690 tachycardia episodes in 23 of 59 patients). Use of
sudden onset was very effective in detecting sinus tachycardias (65 of 67
episodes), and stability was very useful in detecting atrial fibrillation (31 of
32 episodes). However, sensitivity in detecting ventricular tachycardia was only
90% (451 of 497 episodes). Application of the sustained rate duration criterion
allowed appropriate treatment of all ventricular tachycardia episodes, increasing
sensitivity to 100%; however, specificity in appropriate nontreatment of
supraventricular decreased from 96% to 83%. Subsequent analysis of different
algorithms applied to our data showed that sudden onset > 9% and stability < 40
msec was the algorithm with the best specificity and sensitivity. CONCLUSION:
Programming sudden onset and stability detection criteria with a sustained rate
duration safety net for triggering tachycardia therapy results in appropriate
device management in most patients with supraventricular and slow (< 210
beats/min) ventricular tachycardias.
PMID- 9554732
TI - Changes in cardiac repolarization following short periods of ventricular pacing.
AB - INTRODUCTION: "Cardiac memory" (primary T wave change) is thought to occur after
15 minutes to several hours of right ventricular (RV) pacing. The two components
of the temporal change in repolarization are memory and accumulation. The purpose
of this study was to examine quantitatively the effect of short periods of
ventricular pacing on the human cardiac action potential, using monophasic action
potential (MAP) recordings. METHODS AND RESULTS: Thirty-one patients (ages 43+/
14 years) with structurally normal hearts undergoing a clinically indicated
electrophysiologic procedure were enrolled. Catheters were placed in the right
atrium (RA) and RV, and a MAP catheter was positioned at the RV septum. APD90 was
calculated from digitized MAP recordings. MAP morphology comparisons were
performed using the root mean square (RMS) of the difference between complexes.
All pacing was at 500-msec cycle length. There were four pacing protocols: (1) RA
pacing was performed for approximately 15 minutes to evaluate temporal stability
of the MAP recordings (5 pts); (2) to evaluate the memory phenomenon, four
successive 1-minute episodes of RV pacing were interspersed with 2 minutes of RA
pacing (5 pts); (3) the accumulation phenomenon was evaluated by assessing the
effects of 1, 5, 10, and 15 minutes of RV pacing on the MAP during RA pacing (16
pts); and (4) 20 minutes of RV pacing was followed by 10 minutes of RA pacing to
correlate visually apparent T wave changes with changes in MAP recordings (5
pts). In the control patients, no changes in APD90 or RMS analysis were noted
during 14.9+/-1.4 minutes of RA pacing. In the second protocol, RMS of the
difference between the baseline MAP complexes and the signal average of the first
50 beats following each of four 1-minute RV pacing trains demonstrated
progressively greater differences in morphology after successive episodes of RV
pacing. In protocol 3, RMS analysis identified a progressively greater difference
between the baseline MAP recording and the average of the first 50 beats after 1,
5, 10, and 15 minutes of RV pacing. In protocol 4, visually apparent changes in T
waves occurred in parallel with the RMS of the difference between the baseline
MAP recordings and the average of the first 50 beats after 20 minutes of RV
pacing. Similar changes also were demonstrated by APD90 analysis. CONCLUSION:
This study is the first to demonstrate that episodes of abnormal ventricular
activation as short as 1 minute in duration may exert lingering effects on the
repolarization process once normal ventricular activation resumes.
PMID- 9554733
TI - Mechanisms of induction of typical and reversed atrial flutter.
AB - INTRODUCTION: Typical flutter is due to reentry around caval veins and terminal
crest. In patients with typical flutter, reversed (clockwise) reentry can be
induced. We studied mechanisms of typical and reversed flutter induction. METHODS
AND RESULTS: Thirteen patients (11 men) underwent 16 radiofrequency (RF) ablation
procedures for typical (12) or reversed flutter (1). High right atrium (RA)
stimulation included 1 to 3 extrastimuli over cycle lengths 600 to 250 msec, and
burst. We recorded simultaneously from three levels of septal and anterior RA. RF
was delivered to the inferior vena cava-tricuspid isthmus (CTI). Of 25
inductions, 4 were a result of single, 9 double, and 11 triple extrastimuli, and
1 burst. Clinical basal flutter was induced (7 typical, 1 reversed). After RF,
typical flutter was reinduced in 9 cases and reversed flutter in 7, with only
typical flutter seen clinically. All flutters were interrupted by ablation or
catheter pressure on the CTI. Typical flutter began by low RA septal activation
block, preceded by repetitive responses in 12 instances, atypical flutter in 1,
and directly from stimuli in 4. Reversed flutter started in 8 instances by low RA
block of a stimulated front descending the anterior wall and in 1 by repetitive
responses. CONCLUSION: Septal activation block was the usual mechanism of typical
flutter induction by RA extrastimuli. Facilitation of reversed flutter after RF
application is probably due to a new area of block in the CTI. Flutter induction
without intermediate rhythms confirms the presence of block at the terminal crest
at baseline.
PMID- 9554735
TI - Reduced inward rectifying and increased E-4031-sensitive K+ current density in
arrhythmogenic subendocardial purkinje myocytes from the infarcted heart.
AB - INTRODUCTION: Subendocardial Purkinje myocytes from the 48-hour infarcted heart
(IZPCs) have reduced resting potentials, possibly due to altered inwardly
rectifying K+ currents IK1. Abnormal depolarization-activated outward K+ currents
could contribute to long triangularly shaped action potentials of IZPCs. METHODS
AND RESULTS: We used whole cell patch recordings to compare cesium-sensitive IK1
and 4-aminopyridine (4-AP)-resistant, noninactivating sustained IK between normal
Purkinje myocytes (NZPCs) and IZPCs. IZPCs showed decreased net membrane
currents. Two IZPC groups were distinguished, based on 4-AP-resistant outward K+
currents. IZPC-I had isochronal IK1 current-voltage relations similar to NZPCs
whereas IZPC-II showed significantly reduced IK1 and increased outward plateau
currents. To study the sustained IK in the presence of the Class III
antiarrhythmic agent E-4031, a two-pulse protocol was used to inactivate
transient outward currents, followed by step depolarizations. E-4031-sensitive
currents were significantly greater in IZPCs at depolarized potentials (> 0 mV).
Similar to NZPCs, IZPC E-4031 currents showed time dependence during
depolarization, lack of rectification at positive steps, and voltage-dependent
recovery from block. CONCLUSION: Decreased IK1 may account for reduced resting
potentials in IZPCs. E-4031-sensitive currents in NZPCs, unlike those in canine
ventricular myocytes, are sensitive to 4-AP and are larger in IZPCs.
PMID- 9554734
TI - Differential role of epicardial and endocardial K(ATP) channels in potassium
accumulation during regional ischemia induced by embolization of a coronary
artery with latex.
AB - INTRODUCTION: K(ATP) channels are activated predominantly in the epicardium
during regional ischemia. Therefore, the role of K(ATP) channels in ischemia
induced rise of extracellular potassium concentration ([K+]o) might be greater in
the epicardium. METHODS AND RESULTS: In 18 anesthetized dogs, the left anterior
descending coronary artery (LAD) was ligated, followed by injection of 23-microm
latex beads into the occluded artery to interrupt collateral flow, by which
accumulated [K+]o might wash out. Epicardial and endocardial [K+]o were measured
during a 20-minute period of ischemia using a valinomycin membrane. The dogs were
divided into three groups: 6 control dogs (CTRL); 7 dogs pretreated with
intravenous glibenclamide (0.3 mg/kg [GLIB]), a blocker of K(ATP) channels; and 5
dogs pretreated with intravenous nicorandil (0.2 to 0.25 mg/kg [NCR]), a K(ATP)
channel opener. Before LAD occlusion, there was no difference in [K+]o among the
three groups. In the control group, epicardial and endocardial [K+]o were
increased to a similar level as a function of time after occlusion (CTRL) at both
layers. Ischemia-induced epicardial [K+]o rise was suppressed by GLIB (8.4+/-0.4
vs 6.7+/-0.5 mM, P < 0.05) but augmented by NCR (12.9+/-2.0 mM, P < 0.05). In
contrast, endocardial [K+]o rise remained unaffected (7.6+/-0.2 mM CTRL, 7.6+/
1.3 mM GLIB, and 9.4+/-2.2 mM NCR, P = NS). CONCLUSION: Activation of K(ATP)
channels plays an important role in epicardial [K+]o rise, but not in endocardial
[K+]o rise, during regional ischemia. Another mechanism(s) may be important for
endocardial [K+]o accumulation.
PMID- 9554737
TI - AV nodal reentrant tachycardia with unusual characteristics: lessons from
radiofrequency catheter ablation.
AB - There are still some AV nodal reentrant tachycardias with unusual AV nodal
properties that need further study to understand these complexities. Accordingly,
the two-dimensional model with alpha and beta pathways in the AV nodal reentrant
tachycardia circuit certainly is an oversimplification and does not explain
adequately the anatomic and physiologic complexity of the AV junctional area. The
modern concept suggests that this arrhythmia takes place in a highly complex
three-dimensional model with nonuniform anisotropy and discontinuous conduction
property in the AV junctional area. Application of radiofrequency energy within
the AV junctional area should always be performed carefully to achieve a
successful ablation procedure and to minimize possible injury of AV nodal
conduction.
PMID- 9554736
TI - Lidocaine's effect on defibrillation threshold are dependent on the
defibrillation electrode system: epicardial versus endocardial.
AB - INTRODUCTION: Epicardial and endocardial defibrillation electrode systems affect
myocardial electrophysiology and sympathetic function differently. Thus, we
postulate that antiarrhythmic drugs will interact with these electrode systems
differently. METHODS AND RESULTS: Defibrillation energy requirements (DER) at 20%
(ED20), 50% (ED50), and 80% (ED80) success were measured at baseline and during
lidocaine (10 mg/kg per hour) or D5W treatment for epicardial and endocardial
electrodes. Pigs were randomized to treatment (lidocaine or D5W) and electrode
system, which resulted in four experimental groups: (1) epicardial electrode +
D5W; (2) epicardial electrode + lidocaine; (3) endocardial electrode + D5W; and
(4) endocardial electrode + lidocaine. ED50 DER (mean +/- SEM) values at baseline
for groups 1-4 were 10.6+/-1, 8.5+/-1, 12.6+/-1, and 12.3+/-1 J, respectively.
DER values for groups 1 and 3 during D5W were similar to baseline. Conversely,
lidocaine increased ED50 DER values from 8.5+/-1 to 13.5+/-2 J (P < 0.05) in
group 2 animals (epicardial electrodes). When lidocaine was administered to group
4 animals (endocardial electrodes), however, ED50 DER values remained similar to
baseline values (12.3+/-1 to 14.3+/-2 J, P = NS). Lidocaine increased ED50 DER
values by 59% with the epicardial electrode system, which was significantly
greater than the 16% increase with the endocardial electrode system (P < 0.05).
Electrophysiologic response and electrode impedance were similar between
electrode systems. CONCLUSION: Lidocaine increases DER values to a greater extent
when using epicardial versus endocardial electrode system. Thus, drug-device
interactions are dependent on the electrode system. These data suggest that the
electrophysiologic milieu created by endocardial defibrillation mitigates the
effects that lidocaine has on DER values.
PMID- 9554738
TI - Atrial tachycardia in a patient with tricuspid atresia and Fontan surgery.
PMID- 9554739
TI - The morphology of the atrial approaches to the AV node.
PMID- 9554740
TI - In vitro mutations in dihydrofolate reductase that confer resistance to
methotrexate: potential for clinical application.
AB - Mammalian cells cultured in the presence of the chemotherapeutic agent,
methotrexate, develop resistance to this drug. Sometimes this is due to mutations
in the gene for dihydrofolate reductase, the primary target of methotrexate.
However, it has not been possible to link such polymorphism to resistance of
neoplastic disease to therapy with methotrexate. Nevertheless, interest in this
possibility lead to the introduction of many mutations into the cDNA for human
DHFR by mutagenesis. Most of the corresponding enzyme variants have been
expressed in Escherichia coli and characterized. Many mutations in codons for
hydrophobic residues at the active site greatly decrease inhibition by
methotrexate, and by the related substrate analogue, trimetrexate, while allowing
the retention of considerable catalytic efficiency. Introduction of some of these
mutants into mammalian cells by retroviral transfer provides substantial
protection from toxic effects of the inhibitors, and has promise for the
myeloprotection of patients receiving therapy with methotrexate or trimetrexate.
Another potential use is in therapy for inherited disorders of hematopoiesis,
where genetic modification of enough cells is a perennial problem. After
transplantation of bone marrow that has been transduced with a bicistronic vector
encoding both the mutant DHFR and a therapeutic gene, subsequent administration
of methotrexate or trimetrexate should permit selection and enrichment of
genetically modified hematopoietic cells.
PMID- 9554741
TI - Common ancestral mutation in the MEN1 gene is likely responsible for the
prolactinoma variant of MEN1 (MEN1Burin) in four kindreds from Newfoundland.
AB - Familial multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant
disorder with affected individuals developing parathyroid, gastrointestinal (GI)
endocrine, and anterior pituitary tumors. Four large kindreds from the Burin
peninsula/Fortune Bay area of Newfoundland with prominent features of
prolactinomas, carcinoids, and parathyroid tumors (referred to as MEN1Burin) have
been described, and they show linkage to 11q13, the same locus as that of MEN1.
Haplotype analysis with 16 polymorphic markers now reveals that representative
affected individuals from all four families share a common haplotype over a 2.5
Mb region. A nonsense mutation in the MEN1 gene has been found to be responsible
for the disease in the affected members in all four of the MEN1Burin families,
providing convincing evidence of a common founder.
PMID- 9554742
TI - Seven novel mutations in mut methylmalonic aciduria.
AB - Methylmalonic aciduria (MMA) is an autosomal recessive inborn error of metabolism
that results from functional defects in methylmalonyl CoA mutase (MCM), a nuclear
encoded, mitochondrial enzyme that uses the vitamin B12 derivative,
adenosylcobalamin (AdoCbl) as a cofactor. To date, 23 mutations have been
identified at the MUT locus on the short arm of chromosome 6, causing the mut
forms of MMA (mut complementation group; mut MMA, McKusick #251000). We now
report seven novel mutations. Three were found inmut0 patients: R228Q (c759G-->A)
was found as a heterozygous change; G312V (c1011G-->T) and 346delL (c1112delCTT)
were both found as homozygous changes. Four mutations were found in mut patients:
A191E (c648C-->A) and V633G (c1974T-->G) were found in the same patient; 684insL
(c2128insCTC) and L685R (c2130T-->G) were both found as homozygous changes. The
recent modelling of the human methylmalonyl CoA mutase allowed for an
interpretation of the identified mutations.
PMID- 9554743
TI - Identification of three novel mutations and a high frequency of the Arg778Leu
mutation in Korean patients with Wilson disease.
AB - Four mutations--R778L, A874V, L1083F, and 2304delC--in the copper-transporting
enzyme, P-type ATPase (ATP7B), were identified in Korean Patients with Wilson
disease. Arg778Leu, the most frequently reported mutation of this enzyme, was
found in six of eight unrelated patients studied, an allele frequency of 37.5%,
which is considerably higher than those in other Asian populations. The novel
single nucleotide deletion, 2304delC, was found in one patient. Since a mutation
at cDNA nucleotide 2302 (2302insC) had been previously described, this region of
the ATP7B gene may be susceptible to gene rearrangements causing Wilson disease.
PMID- 9554744
TI - Homozygous nonsense mutation in helix 2 of K14 causes severe recessive
epidermolysis bullosa simplex.
AB - We have studied a consanguineous family containing two children with severe,
generalized epidermolysis bullosa simplex (EBS). Electron microscopy of skin
biopsies from the affected individuals showed that basal keratinocytes were
devoid of tonofilament bundles, although some single intermediate filament were
visible. Genetic linkage analysis with the microsatellite probe D12S96 excluded
the type II keratin gene cluster in this family. However, homozygosity by descent
was observed with the polymorphic probes KRT9, KRT10 Ava II, and D17S1787 in both
affected children, consistent with a recessive defect in a type I keratin.
Immunoreactivity to keratin K5 and K15 was normal, but monoclonal antibodies
LL001 and RCK107 against K14 showed no staining, suggesting a deficiency of K14
in these individuals. mRNA extracted from biopsy material was amplified by RT-PCR
to obtain full-length K14 cDNA. Direct automated sequencing identified a
homozygous nonsense mutation, W305X. A Hinf I restriction enzyme site is created
by this nucleotide transition, which was used to confirm the presence of the
mutation in this kindred and exclude it from 100 normal chromosomes. This is the
fourth kindred with severe recessive EBS for whom a mutation has been found in
the K14 gene. In this instance, the premature termination codon is the farthest
downstream of the reported cases, occurring in the helix 2 domain and so giving a
much longer translation product. Nevertheless, the heterozygous carriers are
unaffected by the disease and display no epidermal fragility. We postulate that
translation of the potentially dominant-negative truncated K14 might be down
regulated due to instability of the mutant mRNA, as observed in previous cases
with similar mutations.
PMID- 9554745
TI - Mutation and expression analysis of the endoglin gene in hereditary hemorrhagic
telangiectasia reveals null alleles.
AB - Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder
characterized by multisystemic vascular dysplasia and recurrent hemorrhage from
the sites of vascular lesions. Two genes have been identified for HHT. Endoglin,
a TGF-beta binding protein which maps to chromosome 9q3, is the gene for HHT1.
The type and location of most of the previously described mutations in the
endoglin (ENG) gene suggested a dominant-negative model of receptor-complex
dysfunction for the molecular basis of this disorder. In this article we describe
11 novel ENG mutations in HHT kindreds, which include missense and splice-site
mutations. Two identical missense mutations in unrelated families disrupt the
start codon of the gene. In addition, some frameshift and nonsense mutations lead
to very low or undetectable levels of transcript from the mutant allele. These
combined data suggest that the nature of most ENG mutations is to create a null
(nonfunctional) allele, and that there is no requirement for the synthesis of a
truncated endoglin protein in the pathogenesis of HHT.
PMID- 9554746
TI - Molecular analysis and clinical findings in the Spanish Gaucher disease
population: putative haplotype of the N370S ancestral chromosome.
AB - Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in
the lysosomal beta-glucocerebrosidase (GBA) gene. As the disease is particularly
prevalent among Ashkenazi Jews, most studies have been carried out on this ethnic
group. In the current study, we present a mutation analysis of the GBA gene in
Spanish patients together with the clinical findings. We conducted a systematic
analysis in 53 unrelated GD patients. The GBA gene was initially scanned for nine
previously described mutations by ASO hybridization or restriction analysis after
PCR amplification. The remaining unidentified alleles were screened by
nonisotopic PCR-SSCP analysis and sequenced. This approach allowed the
identification of 101 of 106 GD alleles (95.3%) involving 24 different mutations,
11 of which are described for the first time: G113E (455G-->A), T134P (517A-->C),
G389E (1283G-->A), P391L (1289C-->T), N392I (1292A-->T), Y412H (1351T-->G), W(
4)X (108G-->A), Q169X (662C-->T), R257X (886C-->T), 500insT, and IVS5+1G-->T.
Most mutations are present in one or few GD chromosomes. However, two mutations,
N370S (1226A-->G) and L444P (1448T-->C), are very frequent and account for 66.1%
of the total number of alleles. Linkage disequilibrium was detected between these
two mutations and an intragenic polymorphism, indicating that expansion of
founder alleles occurred in both cases. Analysis of several microsatellite
markers close to the GBA gene allowed us to establish the putative haplotype of
the ancestral N370S chromosome.
PMID- 9554747
TI - Frequent mutation in Chinese patients with infantile type of GSD II in Taiwan:
evidence for a founder effect.
AB - Glycogen storage disease type II (GSD II, Pompe's disease), an autosomal
recessive inherited disease, is caused by the deficiency of acid alpha-D
glucosidase, which results in the impaired glycogen degradation in lysosome and
causes excess glycogen accumulation in lysosome. In Taiwan, the infantile form of
GSD II is the most common type of glycogen storage diseases. The frequency of
C1935A mutant allele is 0.8 in these Chinese patients. In this study, we analyzed
four single point polymorphic markers (324, 1203, 2065, 2338) by ACRS-based RFLP
We observed that the alleles possessing the C1935A mutation in 19 of 25 Chinese
patients who were heterozygous or homozygous have conserved polymorphic markers,
and all of C1935A mutant alleles in these patients are linked to a specific
haplotype. The allele frequency of this specific haplotype in 19 Chinese patients
and in 42 normal individuals is 0.95 and 0.17, respectively (P<0.005, chi2 =
66.018). This result suggests that the C1935A mutation in Chinese patients with
infantile form of GSD II is due to the founder effect.
PMID- 9554748
TI - Identification of molecular defects in Italian Sanfilippo A patients including 13
novel mutations.
AB - Sanfilippo syndrome type A or mucopolysaccharidosis IIIA (MPS IIIA) is a
lysosomal storage disorder caused by the deficiency of the enzyme heparin
sulfamidase (EC 3.10.1.1), required for the degradation of the mucopolysaccharide
heparan sulfate. Patients develop central nervous system degeneration resulting
in progressive dementia, developmental delay, hyperactivity, and aggressive
behaviour; subjects may present a wide spectrum of clinical severity. Here, we
report the results from molecular analysis of 24 Italian MPS IIIA patients
diagnosed over the last 15 years in our laboratory. Altogether, we were able to
characterize 38 out of the 48 (79%) pathogenic alleles. We identified 16
molecular defects, 13 novel. The majority of alterations were missense mutations:
on exon two (Y40N; A44T; S66W; R74C), on exon four (G122R; P128L; L146P; R150Q),
on exon five (D179N; R182C), on exon six (P227R) and on exon eight (E369K;
R377C). Single base pair deletions: on exon two (A52nt-1) and on exon eight
(T360nt-1) and one base pair insertion on exon eight (V361nt+1) were also
identified. Restriction enzyme or ARMS analyses were used to confirm each
alteration. S66W represents the most common alteration in our patients population
accounting for 33% of the total alleles. Interestingly, all six patients from
Sardinia present this mutation, and five of them are homozygous for this change,
suggesting that these subjects may have been derived from a common founder.
PMID- 9554749
TI - Clustering of private mutations in the congenital chloride diarrhea/down
regulated in adenoma gene.
AB - An inherited defect in intestinal anion exchange, congenital chloride diarrhea
(CLD), was recently shown to be caused by mutations in the down-regulated in
adenoma (DRA) gene. A three base pair deletion resulting in the loss of an amino
acid valine (V317del) in the predicted CLD/DRA protein was shown to be
responsible for all CLD cases in a Finnish founder population. Two additional
mutations, H124L and 344delT, were found in Polish CLD patients. Here, we
screened for additional mutations in a set of 14 CLD families of Polish, Swedish,
North American, and Finnish origin using primers that allowed mutation searches
directly from genomic DNA samples. We found eight novel mutations in the CLD/DRA
gene. The mutations included two transversions, one transition, one insertion,
and four small deletions. Of 11 sequence alterations detected so far, nine lie
clustered in three short segments that are 49 bp, 39 bp, and 65 bp in size,
respectively. These short segments span only 6.7% of the total cDNA length,
suggesting functional importance or mutation-prone DNA regions of the
corresponding CLD/DRA protein domains.
PMID- 9554750
TI - Identification of a novel point mutation (S65T) in alpha-galactosidase A gene in
Chinese patients with Fabry disease. Mutations in brief no. 169. Online.
AB - Fabry disease is an X-linked inborn error of sphingolipid catabolism resulting
from deficient enzyme activity of alpha-galactosidase A. The molecular defects of
human alpha-galactosidase A gene causing Fabry disease have been characterized,
including gene rearrangement and point mutations, which show the genetic
heterogeneity in Fabry disease. To characterize the molecular defects of these
patients, each exon of alpha-galactosidase A gene including intron-exon junctions
were PCR amplified using biotin-labelled primer and sequenced using magnetic
beads solid-phase sequencing. A G to C transversion was identified in the last
nucleotide of exon 1 in two unrelated Chinese patients. This mutation obliterates
an EcoN1 restriction site. Family studies show close linkage with the affected
family members. Screening of 100 alleles (22 males, 39 females) of unrelated
normal Chinese can not find this mutation. This mutation not only changes the
amino acid from serine to threonine, but also likely cause splicing defects. To
our knowledge, this is the first report of mutation in Chinese patients with
Fabry disease, and a novel mutation causing Fabry disease not reported in
literature previously.
PMID- 9554751
TI - A novel lysosomal acid lipase gene mutation in a patient with cholesteryl ester
storage disease.
AB - The molecular defects in the gene encoding the lysosomal acid lipase (LAL) were
investigated in an adult male patient affected with cholesteryl ester storage
disease (CESD), an autosomal recessive disorder associated with LAL deficient
activity. Nucleotide sequencing of amplified LAL genomic DNA or reverse
transcribed mRNA demonstrated that this patient was a compound heterozygote for a
previously reported mutation, a G-->A transition at position -1 of the exon 8
splice donor site, resulting in skipping of the complete exon 8, and for a C-->T
substitution at position 233 (exon 3), which introduces a premature in-frame
termination codon. This yet undescribed mutation, which results in the loss of
89% of LAL amino acids, is very likely to abolish the LAL catalytic activity.
PMID- 9554752
TI - A novel single basepair insertion in exon 6 of the Bruton's tyrosine kinase (Btk)
gene from a Japanese X-linked agammaglobulinemia patient with growth hormone
insufficiency.
AB - A novel insertion mutation in exon 6 of the Btk gene was detected in a 17 year
old XLA patient with GH insufficiency. We synthesized cDNA from leukocyte total
RNA and amplified every region of the Btk-coding sequence. Sequencing of cDNA
fragments revealed a single basepair insertion mutation at codon 157 in exon 6
(CAG-->CAAG) which leads to premature termination at codon 193 in exon 7. To
confirm the results, we also performed a PCR-DdeI digestion analysis using
leukocyte genomic DNA. The PCR product from the patient's genomic DNA was
uncleaved with DdeI, as expected. PCR-DdeI digestion analysis of the family
members showed that the mother and elder sister were carriers with the mutation
and that the younger sister did not carry the mutation.
PMID- 9554753
TI - Identification of a novel mutation (S13F) in the CFTR gene in a CF patient of
Sardinian origin.
AB - In this paper, we describe a novel CF mutation consisting in a C-->T substitution
at nucleotide 170 in exon 1 of CFTR gene, converting a serine residue into
phenylalanine at position 12 (S13F) of the CFTR protein. This mutation was
detected in a single patient of Sardinian descent in compound heterozygosity with
T338I, who presented at 9 years of age with hyponatremic dehydration associated
with hypochloremia, hypokaliemia and metabolic alkalosis. Sweat chloride values
were 120 mmol/l. Now the patient is 11 years old and has not shown so far any
pancreatic or lung involvement. The serine to phenylalanine substitution is a non
conservative change, replacing a non polar for a polar amino acid residue and
therefore is most likely a disease-causing mutation.
PMID- 9554755
TI - An androgen receptor gene mutation (A645D) in a boy with a normal phenotype.
AB - Over 100 mutations have so far been published in the androgen receptor gene (AR)
in patients with different degrees of undervirilisation. The AR gene consists of
8 exons, exons 2-3 code for the DNA binding domain and exons 4-8 (codon 628-919)
for the steroid binding domain (codon 667-919). Only four mutations have been
published in the 5' end of exon 4, codons 628-667, that is in two PAIS cases and
two prostate tumours. In a set of phenotypically normal controls we observed one
mutation in exon 4, codon 645, in a 15 year old boy. He has a history of Wilms'
tumour but no undervirilisation and without a family history with intersex. Exon
4 was amplified from constitutional DNA and subject to DGGE with 35-65% of
denaturants. Aberrant fragments were subject to a new PCR and direct sequencing
was performed. This mutation changed Ala645-->Asp due to change of GCT-->GAT This
was not detected in 108 normal chromosomes. Interestingly, the same mutation was
recently reported in one PAIS case. This phenotypic discrepancy calls for
functional studies of this region. This is the first case of a normal phenotype
with an amino acid alteration in the AR gene.
PMID- 9554754
TI - A new missense substitution at a mutational hot spot of the androgen receptor in
siblings with complete androgen insensitivity syndrome.
AB - Several mutations have been described in the human androgen receptor gene
including constitutional mutations in androgen insensitivity syndrome, somatic
mutations in prostate cancer and triplet expansions in Kennedy's disease
(Gottlieb et al. 1997). Here we report on two siblings with complete androgen
insensitivity and a novel missense mutation, D695V, in their androgen receptor
gene. The two XY females are siblings of German descent and presented at the ages
of 23 and 19 years, respectively, with typical clinical features of complete
androgen insensitivity. We found both siblings to be hemizygous for a new adenine
to thymine transversion at the second nucleotide of codon 695 within the fourth
exon of the human androgen receptor gene. The resulting missense mutation D695V
is located at the amino-terminal border of the ligand-binding domain of the
androgen receptor. The aspartic acid residue at this position is highly conserved
in the steroid binding domains of other members of the nuclear receptor family
and has already been found to be the site of two other missense mutations
associated with androgen insensitivity syndrome (Ris Stalpers et al. 1991, Hiort
et al. 1996). Three of four reported subjects showed the complete androgen
insensitivity phenotype, in accordance with the two siblings in our study. We
suggest that the existence of three pathological amino acid substitutions for
aspartic acid 695 most likely reflects the essential role of this residue for
normal androgen receptor function in male sexual differentiation.
PMID- 9554757
TI - A Dde I RFLP in exon 21 of human EL1 gene, encoding protein 4.1, detectable by
SSCP.
AB - Protein 4.1 is a major component of the junctional complex at the red cell
skeleton. Genomic studies have recently evidenced that the encoding gene (EL1
locus) is present in a single copy per haploid genome. Several RFLPs have already
been characterized within intron sequences. Here, we describe the first RFLP
found within the coding sequence. This polymorphism (C or T at position 2723, in
exon 21) does not affect the amino acid sequence (Thr-->Thr). It can be detected
by either Dde I restriction digestion of an appropriate PCR product, or simply by
SSCP These findings should facilitate analysis of families with 4.1 deficiencies
causing hereditary elliptocytosis.
PMID- 9554756
TI - Familial Kallmann syndrome: a novel splice acceptor mutation in the KAL gene.
AB - Kallmann syndrome is an inherited disease which is characterised by anosmia
(inability to smell) and hypogonadotropic hypogonadism both of which are thought
to occur as a result of a failure of correct neuronal migration. To date the only
genetic lesions identified are mutations in the X-linked gene, KAL. We conducted
a mutation screen of the KAL gene in a family with Kallmann syndrome. This
identified a new mutation in the KAL gene which removed an acceptor site at the
junction of exon 6/intron 5. Exon 6 of the KAL gene encodes the C-terminal
portion of a fibronectin type III domain may be involved in axonal pathfinding.
We presume that the described mutation would result in the removal of exon 6
resulting in a frame shift which terminates the protein prematurely. It has been
proposed that both mental illness and vesico-ureteric reflux are associated with
mutations in the KAL gene. However, results from the family presented here do not
show an association between either trait and the KAL gene mutation.
PMID- 9554758
TI - Novel DNA sequence differences in the beta2-adrenergic receptor gene promoter
region.
PMID- 9554759
TI - Real-time measurement of skin radiation during cardiac catheterization.
AB - A novel skin dose monitor was used to measure radiation incident on maximal X-ray
exposed skin during 135 diagnostic and 65 interventional coronary procedures. For
the diagnostic studies (n = 135), mean skin dose was 180 +/- 64 mGy; for PTCA (n
= 35), it was 1021 +/- 674 mGy, single stents (n = 25) 1529 +/- 601 mGy, and
multiple stents with rotational atherectomy (n = 5) 2496 +/- 1028 mGy. The dose
independently increased with more cine runs, more fluoroscopy, and greater
patient weight. Physicians should consider the potential for adverse radiation
exposure when planning coronary interventional cases and deciding on the X-ray
mode and angles used.
PMID- 9554760
TI - Use of assumed versus measured oxygen consumption for the determination of
cardiac output using the Fick principle.
AB - Assumed oxygen consumption (VO2) is increasingly used as a convenient surrogate
for measured VO2 for calculation of cardiac output. This substitution is often
based on empirical formulae, previously validated only in relatively young
patients. To assess the inaccuracy introduced by extrapolating these formulae to
older patients, we compared measured VO2 with assumed VO2 in 57 patients. VO2 was
measured using an open circuit analyzer. Assumed VO2 was calculated according to
the LaFarge or Bergstra formulae. Agreement between both methods was assessed
according to the method of Bland and Altman. The mean difference of measured VO2
minus assumed VO2 was 7.9 ml/min/m2 (P < 0.02) using the LaFarge formula, and
15.6 ml/min/m2 (P < 0.0002) using the Bergstra formula across a range of measured
VO2 from 70 to 176 ml/min/m2. A systematic error was introduced by assumed VO2
from both formulae of underestimating higher and overestimating lower values of
VO2, resulting in poor overall agreement with measured VO2. The same error and
poor agreement was found when analyzing subgroups of patients > or =60 or <70
years of age. In summary, use of assumed VO2 introduces large, unpredictable
errors in adult patients, suggesting requirement for measurement of VO2 when
calculating cardiac output.
PMID- 9554761
TI - Efficacy and safety of early coronary stenting for unstable angina.
AB - To determine the efficacy and safety of early coronary stenting for unstable
angina, we studied 91 consecutive patients with unstable angina. Thirty-one
patients underwent stenting 72 h or more after admission, and another 60 patients
underwent stenting within 72 h of admission. The clinical and angiographic follow
up had been done for 6 mo. There were no differences between the baseline
clinical and angiographic characteristics of both groups. The maximum balloon
pressure was higher (14.1 +/- 1.2 vs. 12.6 +/- 0.9, P < 0.01) and the hospital
stay was shorter (9.7 +/- 2.7 vs. 18.7 +/- 5.8 d, P < 0.0001) in the early
stenting group. These two groups were similar in the clinical success rate (90.0%
vs. 93.5%), without any abrupt closure, subacute thrombosis, death, myocardial
infarction, or coronary bypass surgery. These findings indicate that early
stenting can be useful in patients with unstable angina.
PMID- 9554762
TI - Comparison of the sheath delivery system versus bare stenting for coronary stent
implantation.
AB - Outside the United States, Palmaz-Schatz coronary stents are implanted by hand
crimping the stent to a high pressure balloon without the use of a protective
sheath. This lowers the delivery profile, increases the ease of deployment, and
ensures that the postdilatation balloon is centered on the stent. To assess this
bare stenting technique, 209 patients were retrospectively analyzed: 92 patients
(107 lesions) with the sheath protected stent delivery system (SDS) and 117
patients (150 lesions) with the bare stent approach. The number of balloons used
per lesion in the bare stent group was significantly less than in the SDS group
(1.9 +/- 0.6 vs. 3.8 +/- 1.2, P < 0.0001). In addition, the procedure time in the
bare stent group was significantly shorter than in the SDS group (106 +/- 55 vs.
134 +/- 60 min, P = 0.001). There was no difference in frequency of adverse
events or stent displacement during the procedure. The bare stenting technique
decreases the procedure time, reduces the number of balloons used, and is as safe
as the SDS approach.
PMID- 9554763
TI - Long-term outcome of intracoronary microstent implantation: lesion matched
comparison with Palmaz-Schatz stent.
AB - We performed a lesion matched comparison of AVE Microstent and Palmaz-Schatz
stent implants with 6 month follow-up angiography to compare the occurrence of
restenosis. Thirty-three pairs of lesions were matched for lesion location,
ACC/AHA lesion type, reference diameter, lesion length, and angiographic
descriptors. Age, sex, clinical profile, and indication for stenting were
comparable. Quantitative coronary analysis before and after the procedure was
comparable in the two groups but minimum lumen diameter (MLD) at follow-up was
less with Microstent--2.01 +/- 1.01 mm than Palmaz-Schatz stent--2.43 +/- 0.96 mm
(P = 0.05). Binary restenosis was present in 33% and 21% and was diffuse in 55%
and 29% of the two groups, respectively. Typical angina at follow-up was more
frequent with Microstent (36%) than Palmaz-Schatz stent (15%; P = 0.038). When
implanted in lesions of similar complexity, Microstent yields similar post
procedure angiographic results but smaller MLD at follow-up and more frequent
angina than Palmaz-Schatz stent.
PMID- 9554764
TI - Garbage in, garbage out.
PMID- 9554765
TI - Randomised comparison of Micro Stent I with Palmaz-Schatz stent placement for the
elective treatment of short coronary stenoses.
AB - This randomised trial compared the Micro Stent I and the Palmaz-Schatz stent for
the elective treatment of short (<8 mm long), new-onset coronary stenoses. The
primary endpoints were restenosis rate and minimal luminal diameter at 6 mo
angiographic follow-up. The secondary endpoints were angiographic and procedural
success of stenting and a composite clinical endpoint at 6 mo (death, myocardial
infarction, and target site revascularisation). A total of 93 patients were
randomised. Clinical and angiographic characteristics of the two groups were
comparable. Angiographic success of stenting was 96% in both groups, and there
were no complications so that the procedural success was also 96% in both groups.
The restenosis rate was 29% for Micro Stent I and 27% for the Palmaz-Schatz stent
(P = NS). The minimal luminal diameter at 6 mo was 1.75 +/- 0.72 mm in the Micro
Stent I group and 1.84 +/- 0.59 in the Palmaz-Schatz group (P = NS). At 6 mo, a
clinical endpoint was reached by 21% of the patients in the Micro Stent I group
and by 11% in the Palmaz-Schatz group (P = NS). In conclusion, the elective
treatment of short coronary stenosis with the Micro Stent I or the Palmaz-Schatz
stent resulted in similar early and late outcomes. In particular, the late
angiographic results were very similar.
PMID- 9554766
TI - Percutaneous transvenous mitral commissurotomy using Inoue balloon in children
less than 12 years.
AB - Rheumatic mitral stenosis in some parts of the world afflicts even young
children. Percutaneous transvenous mitral commissurotomy (PTMC) using Inoue
balloon in these children is not well reported. Forty-five children (aged 7-12
years, mean 11.0 +/- 1.2 years) with severe rheumatic mitral stenosis (mitral
valve area [MVA] 0.64 +/- 0.14 cm2) underwent PTMC. The pulmonary artery wedge
pressure (PAW) decreased from 24.3 +/- 8.6 to 14.7 +/- 7.2 mmHg (P < 0.0001) and
mean diastolic gradient decreased from 24.3 +/- 7.7 to 7.9 +/- 5.9 mmHg with the
final MVA of 1.63 +/- 0.45 cm2 (P < 0.0001). Complications included significant
mitral regurgitation (MR) in three children and atrial shunting in two patients.
No procedural death, systemic embolism, and cardiac tamponade were encountered.
Twenty-four children had maximum balloon size (MBS) same as recommended balloon
size (RBS) derived according to the height (group I) and 21 children had MBS 1-3
mm less than RBS (group II). Despite the lesser maximum balloon size, the final
results were comparable in both groups (MVA group 1.66 +/- 0.44 vs. group II 1.61
+/- 0.48 P = NS). The incidence of significant MR (2 and 1 in group I and group
II, respectively) was similar. On follow-up of 20.4 +/- 16.3 months (range 3-56
months), one child developed restenosis. We conclude that PTMC is safe and
effective in children less than 12 years of age. However, the smaller balloon
size than the RBS derived from height may be equally effective and possibly
safer.
PMID- 9554767
TI - Percutaneous balloon mitral valvuloplasty with Inoue balloon is applicable to all
age groups.
PMID- 9554768
TI - Characterization of the atherosclerotic plaque in the internal mammary artery.
AB - The current study examines, at both structural and ultrastructural levels,
representative segments of internal mammary arteries obtained from 15 male
patients, ranging in age from 45 to 75 years, with signs or symptoms of coronary
heart disease. These segments were obtained at the time of coronary bypass
surgery. Of the 15 segments examined, only 2 were found to have atherosclerotic
plaques. In other segments, only an intimal thickening similar to that observed
during aging was found. There was evidence of endothelial cell loss and defects
of internal elastic lamina in the present study; however, there was no evidence
of lipid accumulation in the intimal region. This observation agrees with
previous findings that indicate that lipid accumulation is not a necessary factor
for the formation of atherosclerotic plaques. During the study microfilament
bundles, the so-called "stress fibers," were also observed in the cytoplasm of
the luminal side of endothelial cells. Stress fibers are known to be present in
some endothelial cells in some pathologies such as regeneration after injury or
hypertension. One of the features of the atherosclerotic plaques from an internal
mammary artery was the presence of cells with contractile and synthetic
phenotypes (contractile and synthetic smooth muscle cells), as well as cells with
intermediate features. Cells with similar characteristics have also been observed
during the development of the early stages of atherosclerosis, during
embryological development of vessels, after experimental excimer laser treatment,
and in primary cell culture. To our knowledge, this is the first report showing
the ultrastructural features of the atherosclerotic plaques in the internal
mammary artery.
PMID- 9554769
TI - Usefulness of collagen plugging with VasoSeal after PTCA as compared to manual
compression with identical sheath dwell times.
AB - This study investigated the usefulness of collagen plugging with VasoSeal in
patients after PTCA compared to a control group having identical sheath dwell
times and therefore comparable levels of anticoagulation. A total of 150 patients
were enrolled in this prospective and randomized study. Sheaths were pulled at
exactly 5 h after arterial puncture. Time to hemostasis and local complications
were determined. There were no statistical differences in baseline
characteristics. The mean time to hemostasis in the collagen group was
significantly shorter (3 +/- 3 min) than that of the control group (17.4 +/- 7
min). At 24 h, 23% of the collagen group patients had a small, 1% a medium and 4%
a large hematoma. In the control group, 32% had a small, 4% a medium sized, but
no patient a large hematoma. After collagen, one patient developed a
pseudoaneurysm needing vascular surgery. In the control group, no major
complication occurred. Compared to patients with manual compression at an
identical sheath dwell time and an identical level of anticoagulation, there was
a significant reduction in time to hemostasis but no statistical difference
regarding local complications. Although the incidence of medium or large hematoma
was low, the trend towards a decreased risk of smaller hematomas seemed to be
counterbalanced by an increased risk of larger hematomas.
PMID- 9554770
TI - Arterial sealing: we keep plugging away.
PMID- 9554771
TI - Transcatheter fenestration of hemi-Fontan baffles after completion of Fontan
physiology using balloon dilatation and stent placement.
AB - De novo transcatheter fenestration of hemi-Fontan baffles has not been previously
described. The purpose of this report is to present our experience in such de
novo transcatheter fenestration in two consecutive patients with absent
fenestration in whom the hemi-Fontan baffle was the only direct access to the
pulmonary venous atrium.
PMID- 9554772
TI - Stent fenestration of hemi-Fontan baffles: an intriguing addition to the
armamentarium.
PMID- 9554773
TI - Coil occlusion of arteriovenous fistula of the vertebral artery in a child.
AB - A 5-year-old boy with congenital fistula between the right vertebral artery and
concomitant veins underwent a successful transcatheter fistula occlusion with a
Gianturco coil.
PMID- 9554774
TI - Extramural vessel wall hematoma causing a reduced vessel diameter after coronary
stenting: diagnosis by intravascular ultrasound and treatment by stent
implantation.
AB - An extramural vessel wall hematoma occurred immediately after implanting a
coronary stent in an in-stent-restenosis of the intermedius branch. Angiography
showed a significant luminal reduction distal to the intervention site.
Intravascular ultrasound revealed an extramural echolucent zone compressing the
vessel lumen. Stent implantation compressed the hematoma and allowed adequate
myocardial perfusion. This demonstrates the value of intravascular ultrasound
(IVUS) in cases of unusual angiographic results which can help to manage
complications after coronary intervention.
PMID- 9554775
TI - Antegrade transseptal coronary angiography: an alternative technique in severe
vascular disease.
AB - We report the case of a patient with severe vascular disease in whom retrograde
access to the aortic root was not possible because of aortoiliac and axillary
vascular disease. Antegrade coronary angiography was performed through the
transseptal approach using standard catheters, although several technical
difficulties were encountered.
PMID- 9554776
TI - Rotational atherectomy for the treatment of restenotic ostial side branches
jailed by prior stent placement.
AB - This report describes the treatment by rotational atherectomy of three restenotic
ostial diagonal lesions that originated within stented segments of the left
anterior descending artery. Excellent results were obtained without complications
to stent architecture.
PMID- 9554777
TI - Case of tumor neovascularization demonstrated by cardiac catheterization.
AB - A 46-year-old man presented to his physician with nonspecific abdominal
complaints. CT of the abdomen was obtained to investigate his symptoms, which
showed significant pericardial effusion. One week after drainage of the
pericardial fluid, his symptoms recurred and a transesophageal echo showed a
right atrial tumor. Cardiac catheterization demonstrated right coronary artery
neovascularization. A nonresectable primary angiosarcoma was found following
median sternotomy and biopsy.
PMID- 9554778
TI - All coronary artery disease is not fatty.
PMID- 9554779
TI - A rare complication of coronary arteriography.
AB - We describe a 66-year-old man with acute mesenteric ischemia and myocardial
ischemia within 6 hr after coronary arteriography. He underwent successful
emergency surgery with embolectomy of the mesenteric artery and coronary artery
bypass grafting.
PMID- 9554780
TI - Coronary embolism following aortic and mitral valve replacement: successful
management with abciximab and urokinase.
AB - We report a case of coronary embolism in a 63-year-old woman with St. Jude aortic
and mitral valve replacements who presented with acute myocardial infarction.
Urgent catheterization revealed a saddle embolus in the proximal part of the
circumflex and ramus arteries and another embolus in a diagonal branch. After
employing angioplasty for the totally occluding diagonal embolus, a combined
regimen of intracoronary urokinase and intravenous abciximab was successful in
achieving complete resolution of the emboli.
PMID- 9554781
TI - Acute coronary artery occlusion likely due to thrombus occurring during coronary
angiography: report of a case.
AB - Twenty-five years ago, fatalities due to acute thrombotic coronary occlusion
occurring during coronary angiography were reported not infrequently, but are
thought to have been eliminated by changes in technique and equipment. We present
a case with documentation of a normal coronary arterial tree just before the time
of an abrupt occlusion, which had the angiographic features of clot. The likely
source of the thrombus was the arterial sheath. Measures for prevention of this
complication are discussed.
PMID- 9554782
TI - Spontaneous migration of a catheter embolus from the left inferior to the right
inferior pulmonary artery.
AB - This is the first reported case of a spontaneous migration of an embolized
catheter fragment from the left side of the pulmonary arterial system to the
right side.
PMID- 9554783
TI - Hemodynamic rounds series II: left ventricular puncture for hemodynamic
evaluation of double prosthetic valve stenosis.
PMID- 9554784
TI - Prevention of the inadvertent aspiration of air into 6 French guiding catheters
during Magic Wallstent implantation.
PMID- 9554785
TI - Coronary artery perforation repair using microcoil embolization.
AB - An 82-year-old woman undergoing percutaneous transluminal coronary angioplasty
experienced perforation of the terminal portion of the left anterior descending
coronary artery caused by guidewire trauma. The coronary artery perforation was
successfully closed using a vascular occlusion system consisting of individual
thrombogenic coils delivered to the site. Coronary artery perforation (CAP)
during percutaneous transluminal coronary angioplasty (PTCA) has been reported to
occur in less than 1% of cases. The incidence seems to be higher with the new
interventional devices, e.g., DCA, TEC, and laser CAP may result in pericardial
hemorrhage and cardiac tamponade or a coronary artery fistula to either the left
or right ventricle. The management of CAP may include prolonged balloon
inflations, reversal of anticoagulation, pericardiocentesis, and emergency
surgery. Proximal perforations sometimes can be managed with vein covered stents.
We describe another option in the treatment of distal CAP using a vascular
occlusion system.
PMID- 9554786
TI - Remote suturing for percutaneous closure of popliteal artery access.
AB - We present a case of balloon angioplasty of the superficial femoral artery via a
popliteal artery access with successful percutaneous vascular closure of the
vascular access site (6-F Techstar). A femoral arterial approach had not been
feasible due to previous aorto-femoral and femoro-femoral bypass operations.
Clinical and ultrasound follow-up showed no complications up to 3 months after
remote suturing.
PMID- 9554787
TI - Rheolytic thrombectomy of chronic coronary occlusion.
AB - Percutaneous intervention in patients with intracoronary thrombus continues to
pose a significant clinical challenge. In this report, we describe the successful
treatment of a 44-year-old patient with an extensive chronic thrombotic occlusion
of the right coronary artery using a rheolytic thrombectomy catheter. Despite
angiographic documentation of coronary thrombosis 104 days prior to treatment and
a voluminous thrombus burden (60 mm in length x 3 mm in diameter), rapid
recanalization was accomplished with this device without embolic complications.
At 1 year clinical follow-up, the patient has remained symptom free. The design
of this novel device and its mechanism of action are described.
PMID- 9554788
TI - Stent: the answer!
PMID- 9554789
TI - Left coronary artery to left ventricular fistula can result in a coronary steal:
reply to the letter to the editor by Cheng et al.:.
PMID- 9554790
TI - Management of aortic dissection complicating coronary intervention.
PMID- 9554791
TI - Closure of patent ductus arteriosus with detachable coils: easy is better than
hard.
PMID- 9554792
TI - Protective effects of ethynylestradiol on the hemodynamic changes induced by
lipopolysaccharide in anesthetized rats.
AB - Estrogen pretreatment has been reported to protect rats from death induced by
endotoxin. We investigated the effects of posttreatment with a synthetic
estrogen, ethynylestradiol, on arterial pressure and hemodynamics in
thiobutabarbitone-anesthetized rats challenged with Escherichia coli
lipopolysaccharide. Rats were i.v. injected with lipopolysaccharide (1 mg/kg)
followed by vehicle or a single dose of ethynylestradiol (0.25, 0.5, or 1 mg/kg)
1 h later. Another group (time-matched control) was given the vehicle. In the
time-control group, there was a slight decrease in mean arterial pressure (-10 +/
3 mm Hg) but no significant changes in cardiac output, total peripheral
resistance, or heart rate over the 6-h study period. Lipopolysaccharide
progressively reduced mean arterial pressure and cardiac output (-27 +/- 8 mm Hg
and -52 +/- 6 ml/min, after 6 h) and increased total peripheral resistance and
heart rate (+0.33 +/- 0.10 mm Hg/min/ml and +21 +/- 13 beats/min, after 6 h).
None of the time-control rats died, but 36% of the rats treated with
lipopolysaccharide died between 3 and 6 h after endotoxin challenge.
Ethynylestradiol, at 0.25 and 0.5 completely, and at 1 mg/kg partially, restored
mean arterial pressure and cardiac output at 6 h after injection of
lipopolysaccharide. Ethynylestradiol at 0.5 and 1 mg/kg, but not 0.25 mg/kg,
completely reversed the increase in total peripheral resistance at 6 h after
injection of lipopolysaccharide. Mortality was 14% in each of the three groups of
rats given ethynylestradiol 1 h after lipopolysaccharide. Therefore posttreatment
with ethynylestradiol attenuated hemodynamic changes in endotoxic shock.
PMID- 9554793
TI - Influence of myocardial ischemia and reperfusion on beta-adrenoceptor subtype
expression.
AB - The effects of ischemic injury and reperfusion on myocardial beta-adrenoceptor
expression were examined in dogs after 30 min of left anterior descending
coronary artery (LAD) ligation. Three sets of six dogs were allocated to either
sham ligation (group I), 30 min ischemia without reperfusion (group II), or
ischemia with 1 h of reperfusion (group III). The density of total beta
adrenoceptors along with beta1- and beta2-adrenoceptor subtypes were compared in
tissue from the ischemic LAD and nonischemic left lateral zones by using
radioligand binding with 125-labeled iodocyanopindolol (ICYP). In the control
animals, there was no difference between total beta-adrenoceptors (43.8 +/- 7.2
vs. 40.7 +/- 8.0 fmol/mg protein +/- SEM) or percentage beta-adrenoceptor
subtypes between the two zones. In group II, total beta-adrenoceptors increased
19.9% (p = 0.03) in the LAD compared with the lateral zone after 30 min of
ischemia. Both beta-adrenoceptor subtypes increased, but only the increase in
beta2-adrenoceptor was significant (39.8%; p = 0.02). Animals in group III
revealed no difference in total beta-adrenoceptors density between LAD and
lateral zones (48.3 +/- 13.4 vs. 55.2 +/- 8.5 fmol/mg protein). Brief myocardial
ischemia is associated with an increase in total beta-adrenoceptors, attributed
predominantly to increased beta2-adrenoceptors density. The increase in beta
adrenoceptor density is reversible after 1 h of reperfusion.
PMID- 9554794
TI - UL-FS 49 (zatebradine) does not affect arterial baroreflex in conscious normal or
aortic-constricted rats.
AB - Heart-rate reduction is an important element of patient management during cardiac
bypass surgery and in therapeutic measures for combating ischemia and relieving
pain in patients with angina. UL-FS 49 is a novel bradycardic agent that
purportedly acts solely on the sinoatrial node without potentially deleterious
effects on arterial pressure and cardiac inotropism. However, little is known
about influences of this agent on neuronal tissue and cardiovascular reflexes.
Moreover, left ventricular hypertrophy, which often accompanies cardiovascular
disease, is known to attenuate the arterial baroreflex and could have effects
interactive with those of UL-FS 49. In this study, the effects of UL-FS 49 on the
arterial baroreflex were tested in normal rats (N), rats with left ventricular
hypertrophy 14 days after abdominal aortic constriction (AC), and sham-operated
controls (SH). Arterial baroreflex sensitivity (BRS) was estimated as the slope
of the relation between mean arterial pressure (independent variable) and the RR
interval (dependent variable). At the time of study, the AC group had
significantly greater mean arterial pressure than either SH or N (159 +/- 2, 122
+/- 3, and 124 +/- 3 mm Hg, respectively; mean +/- SEM, p < 0.01) and
significantly greater left ventricular mass to body mass ratio than did SH (3.73
+/- 0.11, 2.33 +/- 0.11 mg/g; p < 0.01). As expected, BRS was significantly
depressed in AC, compared with either SH or N (0.52 +/- 0.16, 1.48 +/- 0.12, 1.69
+/- 0.25 ms/mm Hg, respectively; p < 0.01). Despite its potent dose-dependent
bradycardic effects in all three groups, UL-FS 49 did not affect BRS
significantly in any group. These results show that the arterial baroreflex is
largely unaffected by UL-FS 49 in both normal rats and rats with systemic
hypertension and left ventricular hypertrophy.
PMID- 9554795
TI - Reduced responsiveness of [Ca2+]i to adenosine A1- and A2-receptor stimulation in
the isoproterenol-stimulated ventricular myocytes of spontaneously hypertensive
rats.
AB - To determine the modulatory action of adenosine-receptor stimulation on [Ca2+]i
responses to beta-adrenoceptor stimulation in the heart of the spontaneously
hypertensive rat (SHR), the electrically induced [Ca2+]i transient in response to
isoproterenol (ISO) in single ventricular myocytes pretreated with adenosine
agonists in SHRs and its normotensive control Wistar-Kyoto (WKY) rats was
measured with a spectrofluorometric method by using fura-2/AM as the calcium
indicator. In both types of rat, ISO at 0.001-1 microM augmented the electrically
induced [Ca2+]i transient, and the effect was blocked by a beta-adrenoceptor
blocker, propranolol. In SHRs that did not exhibit cardiac hypertrophy, the
resting level of [Ca2+]i and the amplitude of the electrically induced [Ca2+]i
transient were the same as those in WKY rats, whereas the augmentation of the
electrically induced [Ca2+]i transient in response to ISO was significantly lower
than that in WKY rats. In WKY rats, the effects of ISO on the electrically
induced [Ca2+]i transient were inhibited by the adenosine A1-receptor agonist, R(
)-N6-(2-phenylisopropyl)adenosine (R-PIA) at 0.01-10 microM. In contrast, the
effects of ISO were further enhanced by the adenosine A2-receptor agonist, N6-[2
(3,5-dimethoxyphenyl)-2-(2-methylphenyl)-ethyl)]adenosine (DPMA) at 1-10 microM.
In SHRs, the inhibitory effect of R-PIA was significantly reduced, whereas the
excitatory effect of DPMA was absent. The effects of both adenosine-receptor
agonists in both types of rat were abolished by the respective adenosine-receptor
antagonists, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and 3,7-dimethyl-1
propargylxanthine (DMPX). The results indicate that the modulatory actions of
adenosine-receptor stimulation on [Ca2+]i response to beta-adrenoceptor
stimulation in the hearts of SHRs are reduced, which is independent of cardiac
hypertrophy.
PMID- 9554796
TI - Stereoisomer-specific inhibition of superoxide anion-induced rat aortic smooth
muscle cell proliferation by 17beta-estradiol is estrogen receptor dependent.
AB - An in vitro xanthine/xanthine oxidase reaction system was used to generate
superoxide anions that significantly stimulated tritiated [3H]thymidine
incorporation into endothelium-removed (denuded) male rat aortic explants.
Tritiated thymidine uptake was used as an index of vascular smooth-muscle cell
(VSMC) proliferation. Superoxide dismutase (SOD) significantly attenuated the
oxygen free radical-induced proliferative response of these cells. 17Beta
estradiol (17beta-E) significantly inhibited superoxide anion-induced VSMC
proliferation. In contrast, the growth-modifying effects of 17beta-E were not
mimicked by 17alpha-estradiol (17alpha-E), progesterone, or testosterone. The
pure estrogen receptor (ER) antagonist, ICI 164,384, reversed the growth
inhibitory effect of 17beta-E. 17Beta-estradiol failed directly to reduce in
vitro superoxide anion production or to modify xanthine oxidase activity.
Therefore, these data indicate that 17beta-E, through an ER-dependent mechanism,
specifically and significantly inhibited superoxide anion-mediated SMC
proliferation in denuded rat aortic explants.
PMID- 9554797
TI - Effects of epanolol, a selective beta1-blocker with intrinsic sympathomimetic
activity, in patients with ischemic left ventricular dysfunction.
AB - Recently, different beta-blockers have been shown to be effective in the
treatment of chronic heart failure (CHF), but the importance of their ancillary
properties is not clear. Epanolol is a selective beta1-blocker with intrinsic
sympathomimetic activity, which has been shown useful in angina pectoris, but its
value in patients with left ventricular (LV) dysfunction and CHF is unknown. We
examined the effects of epanolol in patients with LV dysfunction (n = 8; mean LV
ejection fraction, 0.33 +/- 0.08) and compared them with patients with normal LV
function (n = 8; mean LV ejection fraction, 0.52 +/- 0.04). Measurement of
invasive hemodynamics and neurohormones was performed at rest and during
myocardial ischemia, which was induced by atrial pacing. All measurements were
performed before and after epanolol. Before epanolol, pacing-induced ischemia led
to a similar increase in norepinephrine and coronary sinus blood flow in both
groups. After epanolol, the increase in neurohormones was more pronounced in the
group with LV dysfunction (norepinephrine, 1,130 +/- 164 pg/ml for patients with
LV dysfunction vs. 637 +/- 41 pg/ml for normal subjects; p < 0.05). A similar
effect was observed for angiotensin II. Further, in the LV-dysfunction group,
coronary sinus blood flow increased less, and coronary vascular resistance
decreased less (both values, p < 0.05). Despite the fact that the increase in
double product was decreased to a similar extent in both groups, ischemia was
reduced only in normal LV function (p < 0.05). In ischemic LV dysfunction,
neurohumoral activation after epanolol may impair adequate coronary flow
response, and this may limit its antiischemic properties. Because of the small
size of the study, no definitive inference on the clinical benefit of epanolol in
patients with ischemic LV function can be made from this study.
PMID- 9554799
TI - Effects of dantrolene sodium on progression of left ventricular hypertrophy
induced by pressure overload in rats.
AB - We studied the long-term effects of dantrolene sodium (D), a specific
sarcoplasmic reticulum (SR) Ca2+-release inhibitor, on the progression of left
ventricular pressure-overloaded hypertrophy in rats. We treated abdominal aorta
constricted rats with one of two doses of D for 4 weeks. The extent of
hypertrophy was expressed as the ratio of left ventricle to body weight.
Hemodynamic parameters were measured by using a microtip catheter manometer.
Although a low dose of D (500 mg/L in drinking water) decreased blood pressure to
normal levels, the progression of cardiac hypertrophy was not inhibited. In
contrast, a high dose of D (5 mg/kg, i.p.) also reduced blood pressure and
inhibited the progression of cardiac hypertrophy. Dantrolene sodium had no effect
on cardiac function in sham-operated rats. Thus control of Ca2+ release from the
SR might be crucial in regulating the progression of cardiac hypertrophy, the
final mediator possibly being intracellular Ca2+ concentration.
PMID- 9554798
TI - Intramural injection of biodegradable microspheres as a local drug-delivery
system to inhibit neointimal thickening in a rabbit model of balloon angioplasty.
AB - Restenosis remains the major limitation of coronary angioplasty. The objective of
this study was to develop microspheres able to be delivered at the angioplasty
site for long-term drug release and to test their effects in a model of balloon
angioplasty. Polylactic-co-glycolide acid microspheres (5-10 microm in diameter)
were prepared by using an oil-in-water emulsion-solvent evaporation method. In
vitro experiments with hydrocortisone-loaded microspheres revealed a
hydrocortisone release for 4 weeks. We studied the in vivo effect of injection of
microspheres into the arterial wall of New Zealand White rabbits by using a
perforated balloon. Deep penetration of microspheres in the arterial wall was
documented immediately after angioplasty. Intimal hyperplasia was assessed in
iliac arteries 4 weeks after angioplasty. The morphometric analysis was performed
in four groups of animals; the first group was subjected only to conventional
angioplasty (control, n = 10), whereas the other three groups after conventional
angioplasty were received perforated balloon angioplasty with saline (n = 10),
microspheres (n = 10), or hydrocortisone-loaded microspheres (n = 7). Intramural
injection of saline did not induce greater intimal hyperplasia compared with
control (0.17 +/- 0.03 vs. 0.18 +/- 0.03 mm2, respectively). Microspheres
injection was associated with a trend toward a greater degree of intimal
hyperplasia that did not reach statistical significance. Hydrocortisone-loaded
microspheres were associated with a significant reduction in intimal hyperplasia
compared with unloaded microspheres (0.16 +/- 0.02 vs. 0.26 +/- 0.03 mm2,
respectively). The polylactic-co-glycolide acid microspheres are well tolerated,
easily injected into the arterial wall, and the increase of intimal hyperplasia
is easily inhibited by release of hydrocortisone for 4 weeks after initial
injury.
PMID- 9554800
TI - Augmented endothelium-dependent contraction to angiotensin II in the SHR aorta:
role of an inducible cyclooxygenase metabolite.
AB - The purpose of this study was to investigate the mechanisms involved in the
angiotensin II-induced increase in the contractile response of the hypertensive
wall after prolonged incubation in the organ-bath buffer. In 5-h incubated rings,
the contractile response to angiotensin II in aortic rings with endothelium from
spontaneously hypertensive rats (SHRs) was markedly exaggerated in comparison to
2-h incubated rings. No such potentiation was observed in SHR rings after removal
of the endothelium or in intact and denuded Wistar-Kyoto (WKY) rat rings. Aspirin
and SQ29548 inhibited and cycloheximide and actinomycin D reduced the time
dependent enhanced response to angiotensin II in rings with endothelium from
SHRs. In SHR rings with endothelium incubated for 2 h, the contractions caused by
angiotensin II were potently inhibited by piroxicam but were unaffected by NS
398. Conversely, in rings incubated for 5 h, the hyperresponsiveness to
angiotensin II was inhibited to a greater extent by NS-398 than by piroxicam.
Piroxicam but not NS-398 had a further inhibitory effect on the residual
angiotensin II-induced contraction in actinomycin D-treated rings incubated for 5
h. In conclusion, our study shows that long-term incubation leads to
hyperresponsiveness to angiotensin II in SHR aorta with endothelium. The enhanced
response is associated with the induced release of vasoconstrictor prostanoids
sensitive to the inhibitory effect of NS-398, a preferential inhibitor of COX-2.
PMID- 9554801
TI - Chronotropic effects of cilostazol, a new antithrombotic agent, in patients with
bradyarrhythmias.
AB - Whether phosphodiesterase inhibitors increase the heart rate in patients with
bradyarrhythmias is not known. We attempted to determine whether the oral
phosphodiesterase inhibitor cilostazol exhibits beneficial chronotropic effects
in patients with symptomatic bradyarrhythmias. Twenty patients comprising eight
with bradycardic atrial fibrillation, eight with sick sinus syndrome, and four
with Wenckebach-type atrioventricular block, whose 24-h total heart-beat count
was < or =70,000 beats and whose maximal RR interval was > or =2.5 s, were
enrolled. Holter recordings (24-h) were made before and 2 weeks after oral daily
administration of 200 mg of cilostazol. Cilostazol increased the 24-h total heart
beat count from 77,429 +/- 11,168 to 107,981 +/- 13,536 (95% confidence interval,
24,605-36,497; p < 0.0001), the minimal heart rate from 33 +/- 9 47 +/- 13
beats/min (95% confidence interval, 9-19 beats/min; p < 0.0001), and the maximal
RR interval from 3,149 +/- 1,018 to 2,087 +/- 601 ms (95% confidence interval,
1,517 to -608 ms; p = 0.0001). Only two patients had headaches as adverse
effects. In conclusion, cilostazol had a beneficial positive chronotropic effect
in patients with bradyarrhythmias, especially with bradycardic atrial
fibrillation and sick sinus syndrome.
PMID- 9554802
TI - Antiatherosclerotic and antioxidative effects of captopril in apolipoprotein E
deficient mice.
AB - The effect of the angiotensin-converting enzyme (ACE) inhibitor, captopril, on
the development of atherosclerosis was determined in the apolipoprotein (apo) E
deficient mice. These mice develop severe hypercholesterolemia and extensive
atherosclerotic lesions on chow diet, similar to those found in humans.
Furthermore, in these mice, accelerated atherosclerosis is associated with
increased plasma lipid peroxidation, a phenomenon that may play a crucial role in
the buildup of the atherosclerotic lesions. Mice received either placebo or 50
mg/kg/day of captopril. After 12 weeks of treatment, captopril reduced the aortic
lesion area by 70% compared with that of the placebo-treated group. Captopril
also increased the resistance of low-density lipoprotein (LDL) to CuSO4-induced
oxidative stress, as shown by a significant reduction in the LDL content of
malondialdehyde (MDA) by 30%, as well as by the prolongation of the lag time
required for LDL oxidation from 55 min in the placebo-treated mice to 70 min in
the captopril-treated mice, and reduction of the maximum LDL oxidation at 150 min
by 35%. In vitro studies demonstrated that preincubation of LDL with captopril,
inhibited the onset of CuSO4-induced LDL peroxidation up to 120 min, and reduced
the LDL content of MDA by 90%. We conclude that captopril attenuates
atherosclerosis in the apo E-deficient mice, and this phenomenon may be related
to its inhibitory effect on the plasma LDL oxidation.
PMID- 9554803
TI - SR142948A is a potent antagonist of the cardiovascular effects of neurotensin.
AB - The novel compound SR142948A was compared with SR48692 as an antagonist of
neurotensin-induced cardiovascular effects both in vitro and in vivo. SR142948A
inhibited [125I]-neurotensin binding [median inhibitory concentration (IC50) =
0.24 +/- 0.01 nM], neurotensin-induced cytosolic free Ca2+ increase (IC50 = 19 +/
6 nM), and prostacyclin production in human umbilical vein endothelial cells
(IC50 = 17 +/- 3 nM) at much lower concentrations than did SR48692 (respective
IC50 values, 14 +/- 5, 41 +/- 16, and 86 +/- 16 nM). Oral administration of
SR142948A (10 microg/kg) resulted in significant inhibition of neurotensin
induced blood pressure changes, whereas SR48692 was active only at 10-fold higher
doses. Furthermore, SR142948A administered i.v. in microg/kg quantities in the
rat was as active as mg/kg doses of SR48692 on neurotensin-induced increase in
hematocrit. SR142948A injected intradermally also significantly inhibited
neurotensin-induced plasma extravasation at concentrations as low as 10
pmol/site, whereas 1,000 pmol/site of SR48692 were necessary to reach a
significant inhibition. These data show that SR142948A is a novel, extremely
potent antagonist of neurotensin-induced cardiovascular responses both in vitro
and in vivo. SR142948A and SR48692 constitute a pair of nonpeptide neurotensin
antagonists of different potency, which may be used to probe for the implication
of neurotensin receptors in physiologic or pathologic phenomena.
PMID- 9554804
TI - Comparative effects of glibenclamide, tedisamil, dofetilide, E-4031, and BRL
32872 on protein kinase A-activated chloride current in guinea pig ventricular
myocytes.
AB - The modulation of the protein kinase A-activated chloride current (PKA-I[Cl]) may
lead to modification of the cardiac action potential shape. The purpose of this
study was to evaluate the effects of glibenclamide, tedisamil, dofetilide, E
4031, and BRL-32872 on the PKA-I(Cl). Experiments were conducted by using the
patch-clamp technique in guinea pig ventricular myocytes. PKA-I(Cl) was activated
by application of 1 microM isoproterenol and was inhibited by 1 microM
propranolol, 10 microM acetylcholine, or 1 mM 4-acetamido-4'
isothiocyanatostilbene-2,2'-disulfonic acid (SITS). The sulfonylurea receptor
inhibitor, glibenclamide, inhibited PKA-I(Cl) at micromolar concentration. Among
class III antiarrhythmic agents, tedisamil induced a dose-dependent inhibition of
PKA-I(Cl) with a half effective concentration (EC50) of 7.15 microM (Hill
coefficient, 0.54). This effect may contribute to action potential widening
induced by tedisamil. In contrast, the selective inhibitors of the rapid
component of the delayed rectifier K current (I[Kr]), dofetilide, and E-4031, as
well as BRL-32872, that blocks I(Kr) and the L-type calcium current, did not
significantly affect the amplitude of PKA-I(Cl), even at high concentrations (10
30 microM). These results demonstrate that compounds such as glibenclamide and
tedisamil that are known to block the adenosine triphosphate (ATP)-sensitive K
current also affect PKA-I(Cl). Furthermore it appears that blockade of PKA-I(Cl)
is not a common feature for all class III antiarrhythmic agents.
PMID- 9554805
TI - Inhibition of sodium current by chloride channel blocker 4,4'
diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) in guinea pig cardiac
ventricular cells.
AB - The effects of 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), a
potent anion transport blocker, on transmembrane action potentials (APs) and the
sodium current (I[Na]) of guinea pig ventricular myocytes were examined by using
conventional microelectrode and whole-cell patch-clamp recording techniques. In
papillary muscle preparations, DIDS (> or =0.1 mM) suppressed the maximal
upstroke velocity (.v[max]) of the AP without significant changes in other AP
parameters. Extracellular application of DIDS on single cardiomyocytes isolated
from the guinea pig ventricle markedly reduced the peak amplitude of the
tetrodotoxin (TTX)-sensitive and voltage-activated sodium current. The
concentration-dependent block of DIDS could be expressed by the Hill equation
with a Hill coefficient of 0.97 and a dissociation constant of 0.15 mM at a
holding potential of (VH) -120 mV. DIDS (0.1 mM) shifted the steady-state
inactivation curve for I(Na) toward more negative potentials by 6.0 +/- 0.5 mV
and the activation curve to more positive potentials by 5.0 +/- 1.0 mV, although
the slope factors were unaffected. With repetitive depolarizing pulses from -120
mV, DIDS produced a use-dependent block on the I(Na). Recovery of I(Na) from
inactivation was slowed (time constant = 245 ms, compared with 10 ms of control)
in the presence of 0.1 mM DIDS. In the two-pulse experiments, DIDS produced two
distinct phases of development of I(Na) block, the rapid phase (tau = 5 ms)
caused by an open channel block, and the slower phase (tau = 382 ms) induced by
an inactivated channel block. These results suggest that the Cl- transport
blocker DIDS has a direct inhibitory effect on the cardiac sodium channel. DIDS
induced use dependence of I(Na) block may result from the interaction of the drug
with sodium channels in both the open and inactivated channel states.
PMID- 9554806
TI - Pharmacologic profile of TA-606, a novel angiotensin II-receptor antagonist in
the rat.
AB - This study was carried out to characterize a novel angiotensin II-receptor
antagonist, TA-606, (3-pentyloxy) carbonyloxymethyl-5-acetyl-2-n-propyl-3-[2'(1H
tetrazole-5-yl) biphenyl-4-yl]methyl-4,5,6,7-tetrahydro imidazo [4,5-c] pyridine
4-carboxylate hydrochloride, which is a newly synthesized prodrug of 606A. In
anesthetized rats, 606A inhibited angiotensin II-induced pressor response with a
median inhibitory concentration (IC50) of 6 microg/kg, i.v., and was 8 times more
potent than EXP3174, an active metabolite of losartan. Bioavailability of TA-606
was 11 times higher than that of 606A in Sprague-Dawley rats, with consistent
hypotensive potencies in spontaneously hypertensive rats (SHRs). In conscious
renal hypertensive rats (RHRs) and conscious SHRs, TA-606 lowered the blood
pressure without any effects on the heart rate, and its effective dose for 30 mm
Hg (ED30) values were 0.14 and 0.21 mg/kg, p.o., respectively. The effect of TA
606 lasted > 10 h in both models. Moreover, the effect of TA-606 was
approximately 30 and 10 times more potent than those of losartan in RHRs and
SHRs, respectively. TA-606 did not affect the blood pressure in
deoxycorticosterone acetate (DOCA)-salt hypertensive rats. TA-606 given for 12
weeks attenuated the development of hypertension in stroke-prone SHRs. These
results indicate that TA-606 is a potent angiotensin II-receptor antagonist with
antihypertensive efficacy. Thus TA-606 is suggested to be a possible useful agent
in the treatment of hypertension.
PMID- 9554807
TI - Effects of angiotensin II-receptor blockade with losartan on insulin sensitivity,
lipid profile, and endothelin in normotensive offspring of hypertensive parents.
AB - Humans genetically predisposed to hypertension tend to develop at a
prehypertensive stage subtle metabolic and hormonal dysregulations, and certain
of these could potentially be angiotensin II dependent. Therefore the aim of this
study was to investigate the effects of the angiotensin II-receptor antagonist
losartan on insulin sensitivity, lipid profile, and plasma endothelin-1 (ET-1)
levels in normotensive offspring of hypertensive parents with a randomized,
double-blind, placebo- controlled, crossover design. Insulin sensitivity index
(SI), determined by the Minimal Model Method of Bergman, fasting plasma insulin
and glucose concentrations, serum total and HDL cholesterol, serum triglycerides,
and plasma ET-1 levels were assessed in 19 young (26.2 +/- 0.7 years, mean +/-
SEM), healthy, lean [body mass index (BMI), 22.6 +/- 0.7 kg/m2] normotensive male
offspring of essential hypertensive parents after 14 days of losartan, 50 mg, and
14 days of placebo, respectively. Compared with placebo, losartan administration
did not significantly modify SI (12.2 +/- 1.7 vs. 12.7 +/- 1.5 x 10(
4)/min/microU/ml on placebo), fasting plasma insulin and glucose, as well as the
areas under the insulin and glucose curves. Plasma ET-1 levels also did not
differ significantly between the placebo and losartan administration phases (1.1
+/- 0.06 vs. 1.2 +/- 0.06 pg/ml). However, serum total cholesterol and
triglycerides decreased significantly with losartan treatment (3.8 +/- 0.2 vs.
4.1 +/- 0.2 mM and 0.9 +/- 0.1 vs. 1.1 +/- 0.1 mM, respectively; p < 0.01). Body
weight, BMI, heart rate (HR), blood pressure (BP), and 24-h urinary sodium,
potassium, and creatinine values were stable throughout the study. These findings
demonstrate that angiotensin II-receptor blockade with losartan, administered in
the therapeutic dose of 50 mg daily, does not alter insulin sensitivity
determined by the Minimal Model Method of Bergman and does not affect ET-1 in
normotensive offspring of essential hypertensive parents. The normal insulin
sensitivity in the subjects studied might explain why losartan did not improve
it. However, losartan significantly reduced serum total cholesterol and total
triglyceride levels.
PMID- 9554808
TI - Contribution of bradykinin to the beneficial effects of ramipril in the fructose
fed rat.
AB - The contribution of nondegraded bradykinin to the metabolic effects of the
angiotensin-converting enzyme (ACE)-kininase II inhibitor ramipril was evaluated
in rats rendered hypertensive, hyperinsulinemic, and hypertriglyceridemic by a
fructose-enriched diet. The response of blood pressure, insulin, and triglyceride
levels to concomitant administration of ramipril and the bradykinin antagonist
HOE 140 was studied. Rats that received ramipril, HOE 140, or not treated at all
served as controls. Treatment with ramipril reduced levels of both insulin (from
6.6 +/- 2.0 to 3.6 +/- 1.7 ng/ml; p < 0.05) and triglycerides (from 292 +/- 88 to
164 +/- 35 mg/dl; p < 0.001) as well as blood pressure (from 144 +/- 6 to 116 +/-
6 mm Hg; p < 0.001). In contrast, treatment with HOE 140 did not alter any of
these parameters. The combined treatment, however, blunted the beneficial
metabolic effects of ramipril on insulin (7.8 +/- 4.4 ng/ml before and 7.7 +/-
2.9 ng/ml after treatment) and triglycerides (290 +/- 135 mg/dl before and 285 +/
152 mg/dl after treatment), whereas the hypotensive effect of ramipril was
preserved (151 +/- 8 mm Hg before and 122 +/- 6 mm Hg after treatment (p <
0.001). The data suggest that whereas the hypotensive effect is mostly
angiotensin-II dependent, the advantageous metabolic affect of ramipril is highly
dependent on the accumulation of bradykinin.
PMID- 9554809
TI - Diminished responsiveness of Gs-coupled receptors in severely failing human
hearts: no difference in dilated versus ischemic cardiomyopathy.
AB - In end-stage heart failure, cardiac beta-adrenoceptors are decreased and cardiac
Gi protein is increased. We assessed beta-adrenoceptors, G proteins, and effects
of several beta-adrenoceptor agonists, histamine, and 5-HT on adenylyl cyclase
activity in right and left atria and left ventricles and on left ventricular
contractility in six potential heart transplant donors (nonfailing hearts; NFHs)
and in nine patients with end-stage dilated cardiomyopathy (DCM) and 11 patients
with end-stage ischemic cardiomyopathy (ICM) to establish whether the functional
responsiveness of all cardiac Gs-coupled receptors is reduced. Beta-adrenoceptors
were reduced in all three tissues; in DCM, beta1-adrenoceptors were more markedly
downregulated; in ICM, both beta1- and beta2-adrenoceptors were diminished. In
all three tissues, isoprenaline-, terbutaline-, histamine- and 5-HT-induced
adenylyl cyclase activation was reduced similarly in DCM and ICM. Moreover, in
DCM and ICM, guanosine triphosphate (GTP)- (involving Gs and Gi) activated
adenylyl cyclase was significantly diminished, whereas NaF-activated (involving
only Gs) and Mn2+-activated (acting at the catalytic unit of the enzyme) adenylyl
cyclase was unaltered. Left ventricular positive inotropic responses to beta1-
(noradrenaline, dopamine, and dobutamine), beta2- (terbutaline), and beta1- and
beta2-adrenoceptors (isoprenaline, adrenaline, and epinine), as well as H2
receptor (histamine) stimulation were significantly reduced. The extent of
reduction was not different for each agonist in ICM and DCM. We conclude that in
DCM and ICM, functional responsiveness of all cardiac Gs-coupled receptors is
similarly reduced.
PMID- 9554810
TI - Vascular levels and cGMP-increasing effects of nicorandil administered orally to
rats.
AB - We examined a relation between cyclic guanosine monophosphate (cGMP) production
in thoracic aorta, as an indicator probably reflecting the vascular response, and
the vascular as well as plasma levels of nicorandil administered orally to rats.
Nicorandil (3 mg/kg) given orally was rapidly absorbed, reaching the maximal
plasma (approximately 2,600 ng/ml) and vascular concentrations (approximately 176
ng/g) at 15 min after the dosing and thereafter decreased rapidly. Even 2 h after
the dosing, the level of the vascular cGMP formation in vivo remained
significantly higher (approximately 1,000 fmol/mg increase from the control
level) in the nicorandil-treated group, compared with the vehicle-treated one,
and was enough to develop pronounced muscle relaxation in in vitro aortic
preparations. However, it seems that the vascular cGMP increase in vivo was not
always correlated to the plasma concentration of nicorandil, because the plasma
concentration (approximately 750 ng/ml corresponding to 3.5 microM) at 2 h after
the dosing, caused only relatively low cGMP production (300-400 fmol/mg increase
from the control level), when tested in in vitro aortic preparations. Our study
may indicate, therefore, that the vascular cGMP elevation in vivo is due to the
content of nicorandil effectively remaining at its vascular targets of action as
well as the plasma nicorandil concentration.
PMID- 9554811
TI - Comparative efficacy of a DA2/alpha2 agonist and a beta-blocker in reducing
adrenergic drive and cardiac fibrosis in an experimental model of left
ventricular dysfunction after coronary artery occlusion.
AB - Attenuation of neuroendocrine activation may be beneficial in congestive heart
failure. Sympathetic nervous system overactivity can be reduced by receptors
blockade or by reducing norepinephrine (NE) spillover. This study evaluated and
compared the effects of a DA2-dopaminergic receptor/alpha2-adrenoceptor agonist
(CHF-1024) and a beta1-adrenoreceptor antagonist in terms of hemodynamics,
ventricular remodeling, beta-adrenergic drive, and cardiac fibrosis after
myocardial infarction (MI) in rats. MI was induced by left coronary artery
ligation in 213 rats, whereas 12 were left unoperated on. After 2 months, the
operated-on animals were treated for 1 more month with CHF-1024 at either 0.33
mg/kg/day (low dose) or 1 mg/kg/day (high dose) or with metoprolol (10
mg/kg/day), delivered through implanted osmotic minipumps. Plasma concentration
and urinary excretion of NE were measured before the rats were killed.
Hemodynamic variables were measured and morphometric analysis was done on the
diastole-arrested hearts to quantify left ventricular remodeling and interstitial
collagen density. Metoprolol treatment tended to normalize LV end-diastolic
pressure (LVEDP). CHF-1024 at either dose, and metoprolol, significantly reduced
collagen deposition in LV of infarcted animals (from 8.8 +/- 0.5% LV area in
vehicle-treated rats to 6.6 +/- 0.2% or 6.4 +/- 0.2% after the low or high dose
of CHF-1024, respectively; p < 0.05). Similarly, CHF-1024 at either dose reduced
the plasma concentration of NE (from 224 +/- 53 pg/ml to 60 +/- 7 pg/ml or 87 +/-
13 pg/ml; p < 0.05) and urinary excretion of NE in rats with MI, whereas beta
blockade did not affect these variables. In conclusion, CHF-1024 infused for 1
month to rats with LV dysfunction reduced heart rate, NE spillover, and collagen
deposition, without unwanted effects, only appearing at the higher dose.
Effective beta-blockade with metoprotol reduced LVEDP with no effects on heart
function. Neither DA2/alpha2 stimulation nor beta-blockade altered LV remodeling
after coronary artery ligation.
PMID- 9554812
TI - KCB-328: a novel class III antiarrhythmic agent with little reverse frequency
dependence in isolated guinea pig myocardium.
AB - The effects of 1-(2-amino-4-methanesulfonamidophenoxy)-2-[N-(3,4-dimethoxypheneth
yl)-N-methylamino] ethane hydrochloride (KCB-328), in comparison with those of
dofetilide, were studied on the action potentials (APs) of isolated guinea pig
papillary muscles. KCB-328 (0.003-3 microM) concentration-dependently prolonged
the AP duration at 90% repolarization (APD90) at 1- and 3-Hz pacing, and the
concentration-response relations at 1 and 3 Hz resemble each other. Dofetilide
(0.001-1 microM) also produced the concentration-dependent prolongation of APD90
but more pronouncedly at 1 than at 3 Hz, demonstrating the reverse frequency
dependent effect. KCB-328 at 0.03, 0.1, 0.3, and 1 microM increased APD90 by 11
+/- 1, 19 +/- 1, 25 +/- 1, and 29 +/- 1% at 3 Hz and by 9 +/- 1, 19 +/- 2, 27 +/-
2, and 33 +/- 2% at 1 Hz, respectively. Prolongation of the effective refractory
period (ERP) by each drug is parallel to those of APD90 at each pacing frequency.
KCB-328 modified neither the maximal velocity of depolarization, amplitude of AP,
and resting membrane potential in the fast APs, nor any parameters of the slow
APs. In a separate experiment, the effects of KCB-328 on the ERP of contractile
response (ERPc) of excised guinea-pig papillary muscles also were studied at 1
and 3 Hz. KCB-328 (0.01-10 microM) lengthened the ERPc in a concentration
dependent and frequency-independent manner as in the electrophysiologic results.
This frequency-independent ERPc prolongation by KCB-328 was not influenced by
increased extracellular K+ concentration from 4 to 10 mM. These results suggest
that KCB-328 might be a selective class III agent with effects that are
relatively frequency independent.
PMID- 9554813
TI - Contribution of endothelin to the acute pressor response of L-NAME in stroke
prone spontaneously hypertensive rats.
AB - In this study, we examined whether endothelin (ET) plays a role in the short-term
increase in mean arterial pressure (MAP) after nitric oxide synthase (NOS)
inhibition with N(omega)-nitro-L-arginine methyl ester (L-NAME) in stroke-prone
spontaneously hypertensive rats (SHRSPs). Experiments were performed by using
Inactin-anesthetized male SHRSPs that were pretreated with chlorisondamine to
block reflex autonomic cardiovascular effects. Injection of L-NAME (10 mg/kg,
i.v.), but not D-NAME, produced rapid and marked increases (74 +/- 3 mm Hg) in
MAP that were sustained for >1 h. In SHRSPs that were treated with the ET(A/B)
receptor antagonist, L-754,142 (15 mg/kg + 15 mg/kg/h), L-NAME increased MAP by
45 +/- 4 mm Hg (p < 0.0001 compared with L-NAME alone). L-754,142 blocked pressor
responses to big ET-1 by >90% but was without effect on pressor responses to
norepinephrine. Plasma levels of ET-1 averaged 5 +/- 1 pg/ml in animals given
vehicle and were slightly increased in animals given either L-NAME alone (7 +/- 2
pg/ml) or L-754,142 alone (7 +/- 2 pg/ml) but increased markedly when L-NAME and
L-754,142 were given together (114 +/- 18 pg/ml). This may relate to an effect of
L-754,142 to block ET-receptor-mediated clearance of ET-1. We conclude that ET
plays a role in the short-term pressor response after NOS inhibition in SHRSPs.
PMID- 9554814
TI - Neutral endopeptidase and angiotensin-converting enzyme inhibitors increase
nitric oxide production in isolated canine coronary microvessels by a kinin
dependent mechanism.
AB - Bradykinin is a substrate for both neutral endopeptidase 24.11 (NEP) and
angiotensin-converting enzyme (ACE). Our previous studies showed that ACE
inhibitors can stimulate nitric oxide production in coronary microvessels, which
is mediated by local kinins. Whether inhibition of NEP also can affect local
vascular NO production has not been established. To determine the role of NEP in
the control of NO production, coronary microvessels were isolated from seven
mongrel dogs. Two NEP inhibitors, phosphoramidon and thiorphan, and an ACE
inhibitor, ramiprilat, were used. Nitrite, the metabolite of NO in aqueous
solution, was measured by using the Griess reaction. Phosphoramidon and thiorphan
(10(-6) M) increased nitrite production from 80 +/- 6 to 136 +/- 6 and 144 +/- 7
pmol/mg, respectively. Ramiprilat (10(-8) M) increased nitrite production from 78
+/- 6 to 155 +/- 7 pmol/mg wet weight. The effect of these agents on nitrite
release was blocked by L-NAME, which inhibits NO synthase, HOE-140, which blocks
bradykinin B2-receptor, and dichloroisocoumarin, which blocks kinin-forming
enzymes. These results clearly indicate that inhibition of kinin metabolism by
using neutral endopeptidase inhibitors increases NO production from coronary
microvessels. Thus neutral endopeptidase plays an important role in local kinin
modulated NO production in the coronary microcirculation and NEP inhibitors may
be useful clinical tools in treatment of cardiovascular disease.
PMID- 9554815
TI - Effect of chronic blockade of angiotensin II-receptor subtypes on aortic
compliance in rats with myocardial infarction.
AB - This study was undertaken to investigate changes in aortic geometry and
compliance after long-term blockade of angiotensin receptors type 1 (AT1) and AT2
receptors under basal conditions and after myocardial infarction (MI). Sham
operated (sham) or MI rats received either no treatment, AT1 antagonist GR138950C
(GR; 2 mg/kg/day i.v.), or AT2 antagonist PD123319 (PD; 3 mg/kg/day s.c.). After
3 weeks, mean arterial blood pressure (MAP) was measured. Thoracic aorta
diastolic diameter (D[dia]), compliance coefficient (CC), and distensibility
coefficient (DC) were determined noninvasively in anesthetized rats by using
ultrasound and wall tracking. After the rats were killed, histologic measurements
were made on aortic cross sections. In sham rats, MAP was reduced by GR treatment
(76 +/- 6 vs. 106 +/- 5 mm Hg), but not by PD. D(dia) was reduced in both GR
treated (1.74 +/- 0.08 vs. 2.09 +/- 0.05 mm) and PD-treated (1.83 +/- 0.05 vs.
2.09 +/- 0.05 mm) sham rats. CC and DC were not modified by either treatment.
Although media cross-sectional area was not affected by either GR or PD treatment
in sham rats, media thickness and media/lumen ratio were increased in both cases.
Induction of MI had no effect on aortic structure, geometry, or mechanics;
however, treatment with either GR or PD improved DC versus untreated MI rats. We
conclude that AT1 and AT2 receptors are involved in angiotensin II-mediated
effects on aortic geometry and mechanics under both basal conditions and after
MI. Whereas blockade of AT1 receptors most likely influences vascular properties
through a depressor mechanism, AT2 receptors induce pressure-independent
remodeling.
PMID- 9554816
TI - Inhibitory effect of enalapril on neurally mediated syncope in elderly patients.
AB - A dramatic increase in catecholamine (CA) concentration is believed to be a
primary trigger of the neurally mediated syncope (NMS) in elderly subjects. The
hypercontractile state of the heart might be alleviated by angiotensin-converting
enzyme (ACE) inhibitor through depression of CA release from the sympathetic
nerve ending. Thus ACE inhibitor might have positive effect on the prevention of
NMS. In this study, 24 elderly subjects who had reproducible NMS induced with
head-up tilt test (HUT) were randomized and double-blind divided into placebo and
ACE-inhibitor groups. The plasma CA concentration [norepinephrine (NE) and
epinephrine (E)] were measured during HUT, and the effects of enalapril on NMS
were observed in the two groups. Before administration of enalapril, plasma CA
concentrations were significantly increased during HUT compared with those in the
supine position; In contrast, administration of the enalapril (10 mg/day) for >1
year inhibited the concentration of plasma CA increase and prevented syncope in
all 12 patients (p < 0.05); however, placebo had no effect on plasma CA
concentrations and syncope disappeared in only two of 12 patients after
administration of placebo. From this study, we conclude that enalapril can
prevent NMS in patients, presumably because of its part in the inhibition of CA
release from sympathetic nerve endings.
PMID- 9554817
TI - Influence of the renal endothelin A system on the autoregulation of renal
hemodynamics in SHRs and WKY rats.
AB - In this study, we investigated the influence of a short-term blockade of the
renal endothelin A system on the autoregulation of total renal blood flow,
cortical renal blood flow, and pressure-dependent plasma renin activity in
spontaneously hypertensive rats (SHRs) and normotensive controls [Wistar-Kyoto
(WKY) rats]. In anesthetized rats, renal blood flow was measured by a transit
time flow probe and cortical blood flow by a laser flow probe. Blood samples were
taken for measurement of plasma renin activity. Renal perfusion pressure was
reduced in 5-mm Hg steps by means of a servocontrolled electropneumatic device by
an inflatable suprarenal cuff. During the experiments, the rats (n = 6, each
group) received an intrarenal infusion of either the selective endothelin A
receptor antagonist BQ123 (3 mg/kg/h) or vehicle. We observed an improvement of
total and cortical blood flow autoregulation as indicated by a shift of lower
limits of autoregulation to lower threshold pressures [103 +/- 2 vs. 132 +/- 4 mm
Hg compared with 98 +/- 3 vs. 120 +/- 4 mm Hg (mean +/- SEM); p < 0.01 resp. p <
0.05] in BQ123-treated SHRs, whereas BQ123 had no influence on breakpoints of
autoregulation in WKY rats (p > 0.05). Pressure-dependent plasma renin activity
in SHRs was not influenced by BQ123. Renal blood flow autoregulation is improved
in SHRs after short-term blockade of the renal endothelin A system. This effect
is independent of the renin-angiotensin system. The endothelin A system does not
seem to play an important role in the autoregulation of renal blood flow in
normotensive WKY rats.
PMID- 9554818
TI - Intraoperative blood salvage (IOBS) for tumor surgery.
PMID- 9554819
TI - Cytokine production and nutritional status in hemodialysis patients.
AB - Malnutrition is an important predictor of mortality in patients on chronic
hemodialysis, however the pathogenesis of wasting in this population remains
unclear. Experimental data suggest that the dialysis procedure per se leads to
enhanced catabolism, as well as direct loss of plasma amino acids and proteins
into the dialysate. In the present study, the primary hypothesis examined is that
hemodialysis-induced cytokine production is associated with reductions in lean
body mass and other plasma markers of nutrition. We used the production of
interleukin-1 receptor antagonist (IL-1Ra) by peripheral blood mononuclear cells
(PBMC) as an indicator of cytokine production. PBMC were obtained pre-dialysis on
the first and second sessions of the week in a cohort of 16 patients on chronic
hemodialysis using reprocessed cellulose dialyzers who fulfilled rigorous entry
criteria designed to eliminate known etiologies of increased cytokine production,
e.g. chronic infections. PBMCs were either immediately frozen (cell content) or
incubated for 24 hours at 37 degrees C in the presence or absence of endotoxin 10
ng/ml and total IL-1Ra was measured by radioimmunoassay. Nutritional staus was
assessed using body mass index (BMI), total body potassium (TBK), anthropometry
derived arm muscle area (AMA), and measurements of plasma albumin, transferrin,
total cholesterol, and triglycerides. Over the subsequent 3 months, patients were
monitored carefully for pyrogen reactions, hemodynamic stability and intra
interdialytic symptoms. There was a direct correlation of cell content of IL-1Ra
with several indices of nutritional status including BMI (r = 0.90, p = 0.0001),
AMA (r = 0. 77, p = 0.0008), serum total cholesterol (r = 0.57, p = 0.03) and
serum triglycerides (r = 0. 73, p = 0.002). Endotoxin-stimulated IL-1Ra
production correlated directly with AMA (r = 0.59, p = 0.02), TBK (r = 0.71, p =
0.01) and serum triglycerides (r = 0.51, p = 0.05). These studies suggest a
direct correlation between nutrition and cytokine production, and that
malnutrition could depress cytokine production and potentially contribute to
reduced immune responsiveness in patients on chronic hemodialysis.
PMID- 9554820
TI - Efficacy and tolerability of recombinant human erythropoietin treatment in pre
dialysis patients: results of a multicenter study.
AB - Chronic renal failure is characterized by a normochromic normocytic anemia, the
severity of which generally increases during progression toward uremia. The
purpose of the study was to evaluate the efficacy and safety of recombinant human
erythropoietin (rHu-EPO) given subcutaneously (s.c.), the dose required to reach
and maintain Hb levels within 10 and 11 g% and its effects, if any, on the
progression of chronic renal failure. Eighty-four pre-dialysis patients (46 F,
38M, age 61.7+/-13.9 years) with Hb levels between 6 and 9 g% and serum
creatinine ranging from 3 to 9 mg/dl were treated with s.c. rHu-EPO (2000 U/twice
weekly). After 6 weeks, if Hb increase was below 1 g%, 1000 U of s.c. rHu-EPO
were added at each administration (3000 U twice weekly). Once the Hb target was
reached (10-11 g%), the rHu-EPO weekly dose was halved and administration reduced
to once weekly. The patients showed a significant rise in mean Hb values
(p<0.001) after 3 months. Mean Hb values were as follows: 8.00+/-0.77 g%
(pretreatment), 9.35+/-1.0 (3rd month), 10.06+/-1.04 (6th month), 10.25+/-0.62 g%
(12th month). The mean rHu-EPO doses were 4000 U/w (start of the study), 3592+/
1685 U/w (6th month), 2840-/+1178 U/w (12th month). Renal function was evaluated
by plotting the reciprocal of serum creatinine values vs time with a two period
comparison: period A (retrospective-8 mo); period B (prospective-12 mo). The
residual renal function was not impaired by rHu-EPO therapy. Meanwhile, no
relevant modifications were observed in mean blood pressure values. Low doses of
s.c. rHu-EPO were well tolerated, safe and effective; this therapeutic approach
should therefore be considered for the improvement of anemia in pre-dialysis
patients. A slow and gradual correction of anemia induces an improved sense of
well being and a more active of life style.
PMID- 9554821
TI - Phosphate-binding capacities of calcium and aluminum formulations.
AB - Calcium and aluminum phosphate binders are used to treat hyperphosphatemia which
is responsible for the development of osteodystrophy commonly seen in patients
with end-stage renal disease. The purpose of this study was to determine the
phosphate binding capacities of several frequently used calcium and aluminum
formulations. The effect of formulation types on phosphate binding was evaluated.
Calcium and aluminum phosphate binders were administered to six healthy
volunteers after phosphate load on separate study days. Total urine outflow was
collected afterwards to determine the amount of phosphate recovered, which
indicates the ability of the phosphate binder to reduce gastrointestinal
phosphate absorption. The amounts of urinary phosphate recovered were different
after administration of the phosphate binders. Calcium acetate resulted in the
least amount of phosphate excreted. Calcium carbonate suspension, when compared
with the tablet formulation, caused a smaller amount of phosphate excreted in the
urine. Different phosphate binders formulations were found to have different
phosphate binding capacities. Patients should therefore be closely monitored for
efficacy after switching from one phosphate binder to another.
PMID- 9554822
TI - Fatal hepatic failure caused by miliary tuberculosis in a hemodialysis patient:
case report.
AB - A 57 year-old male dialysis patient died soon after the onset of high fever,
hypoglycemia, and disturbance of consciousness. Autopsy revealed granulomatous
lesions associated with caseous necrosis mainly found in the liver, despite the
absence of pulmonary changes on chest radiographs performed during the patients
illness. It appears that tubercle bacilli were hematogenously disseminated mainly
to the liver causing miliary tuberculosis without producing typical diffuse
lesions in the lungs. Since tuberculosis is a common complication in hemodialysis
patients, the potential development of atypical miliary tuberculosis should
always be borne in mind.
PMID- 9554823
TI - A computer controlled mock circulatory system for mono- and biventricular assist
device testing.
AB - The clinical use of heart assist devices for heart recovery, implies the problem
of their in vitro testing and training to use. In a mock circulatory system
developed to this aim, the main problem is reproducing interaction among the
device, the ventricle and the circulatory network. This can be analysed by the
position, on the p-v plane, of the working point defined by the intersection
between end systolic ventricular (ESPVR) and arterial elastance lines. The system
developed on this basis, connectable to mono- and biventricular parallel assist
devices, was a closed loop model including systemic and pulmonary circulation.
The arterial trees were reproduced by two windkessels with adjustable peripheral
resistance, and the Starling's law of the heart by a variable elastance model.
The software controls and monitors circulatory parameters and variables. Results
showed the behavior of the system with preload or afterload changes. Further, the
reproduction of physiological, pathological (obtained by modifying slope and
volume intercept of the ESPVR line) and LVAD assisted circulatory conditions was
shown. The assistance effect was underlined by the changes in the ventricular
work cycle and in hemodynamics variables. The evaluation of the effect of device
control strategy on the ventricle and its energetics (on p-v plane) were among
the main characteristics of this system, which ought to be further improved to
test devices such as the IABP, which requires a different aortic model.
PMID- 9554824
TI - Test procedure for artificial mitral valves.
AB - The flow curve of a valve-tester has a great influence on the performance of a
valve. Usually the flow curve of the aorta is used. However, the mitral valve
flow curve differs greatly from the flow curve of the aortic valve. It varies
with the pulse rate and is further changed in patients with certain heart
diseases. To investigate the different mitral flow conditions, ultrasonic flow
curves from patients with a mechanical artificial mitral valve were analyzed. The
curves show that a mitral valve prosthesis has not only to work under
physiological flow conditions, but also in pathologically deviant flows.
According to these results three different characteristic flow curves were
selected and used to test several valves with a computer controlled valve-tester.
The mean diastolic pressure difference and the whole closing behavior were
influenced by the flow curve; and the differences in energy losses were
particularly great. This indicates, that the flow curve must be adjusted
appropriately.
PMID- 9554825
TI - Positive biochemical effects of a bioartificial liver support system (BALSS) in a
porcine fulminant hepatic failure (FHF) model.
AB - This study describes biochemical changes in the plasma and blood of pigs with
devascularised livers treated in a bioartificial liver support system (BALSS).
Porcine hepatic cells were incubated with collagen-coated dextran microspheres
(CDM) for 3 hours and the medium tested to determine cellular metabolic activity.
Incubation continued for a further 18 hours during which the hepatic cells attach
to the CDM. The CDM-attached cells were inoculated into a hollow fibre bioreactor
which was part of an extracorporeal support system. Hepatic cell content of the
bioreactor was 6 x 10(9) cells. The system was tested in a controlled trial in
pigs prepared in a surgical model of fulminant hepatic failure (FHF). When plasma
from FHF pigs was circulated through the device containing hepatic cells, there
was significantly less increase in the accumulation of ammonia and most amino
acids, together with a decrease in plasma lactate and of one amino acid, compared
to control experiments when hepatic cells were excluded. We conclude that primary
porcine hepatocytes can contribute beneficial metabolic function in a BALSS.
PMID- 9554826
TI - Gait restoration in a spinal cord injured subject via neuromuscular electrical
stimulation controlled by an artificial neural network.
AB - Attempts to restore gait in spinal cord injured subjects have stumbled on control
difficulties associated to the neuromuscular system's non-linearity and time
variance. Thus, a simple autoadaptive artificial neural network has been devised
to control gait swing generation by means of neuromuscular electrical
stimulation. Both theoretical and experimental approaches were taken. The
computer-based system consisted of a three-layer artificial neural network that
read angular data from the hip, knee and ankle joints. The output signal
consisted of variations on the applied stimulation pulse width. Surface
electrical stimulation was applied to the femoral and peroneal nerves of one leg.
Neural network training included off-line supervised learning schemes. The system
was tested on a male subject with an incomplete C6-level lesion. Several tests
were run to determine whether the off-line trained neural network could correctly
control the motion. The effect of on-line learning upon the control performance
was also evaluated. The system was found to control the motion with success only
at times. Control performance was found to improve in response to the application
of on-line learning. Learning stability following on-line learning was found to
be satisfactory. In a final test, the artificial neural system had appropriate
responses to an initial perturbation, which suggests that further research in
this area should be pursued.
PMID- 9554827
TI - Granulocyte transfusion in leukopenic children by simplified leukapheresis of
related donors.
PMID- 9554828
TI - Phagomimetic action of antimicrobial agents.
AB - A wide variety of extracted and synthesised drug molecules have electron transfer
capabilities which allow them to generate reactive oxygen species (ROS). In
particular, many antibiotics that kill or inhibit bacteria, yeasts and cancer
cells readily transfer electrons to oxygen making superoxide and hydrogen
peroxide in the process. When suitable redox active forms of iron are available,
Fenton chemistry occurs generating the highly damaging hydroxyl radical. This
type of chemistry is very similar to that which evolved within phagocytic cells
as part of their microbial killing armoury. Many antibiotics, when used in model
systems, have well defined pharmacological actions against key cellular
functions, but their clinical usefulness is also often demonstrable at
concentrations in vivo well below their in vitro minimum inhibitory
concentrations. These observations have led us to propose that a common mechanism
exists whereby phagocytic cells and antibiotics exploit the use of ROS for
microbial killing.
PMID- 9554829
TI - Plasma levels of antioxidant vitamins, selenium, total sulfhydryl groups and
oxidative products in ischemic-stroke patients as compared to matched controls in
Taiwan.
AB - The possible involvement of oxidative damage and antioxidant protection has been
suggested in the pathogenesis of stroke which is the second-leading cause of
death in Taiwan. In this study we investigated the relationship between ischemic
stroke and plasma status of antioxidants and oxidative products. Plasma levels of
vitamin A, alpha-tocopherol, carotenoids, selenium (Se), total SH groups (T-SH),
thiobarbituric acid-reactive substances (TBARS) and protein carbonyl, a marker of
protein damage, were determined in ischemic-stroke patients (n = 36, blood
sampled within 24 hrs after the clinical event) in comparison with 21 matched
controls. The cholesterol-adjusted carotenoids and vitamin E were significantly
lower (P < 0.05) in the plasma of ischemic-stroke patients than those of the
controls. TBARS were higher (P < 0.05) in the patients than in the controls but
Se, T-SH and protein carbonyls were not significantly different between the two
groups. Separation of the patients into small-artery ischemic stroke (SAIS, n =
17) and large-artery ischemic stroke (LAIS, n = 19) groups revealed that both
carotenoids/cholesterol and vitamin E/cholesterol ratios were significantly lower
in both LAIS and SAIS groups than the controls (n = 21) while vitamin
A/cholesterol was not different among the three groups. TBARS were only
significantly higher in the LAIS group. The results demonstrated that, within 24
hrs after the clinical event, the acute-ischemic stroke patients had lowered
levels of cholesterol-adjusted carotenoids and alpha-tocopherol but elevated
levels of TBARS in the plasma as compared to the matched controls. It remains to
be resolved as to whether enhanced lipid peroxidation is a cause or a result of
lowered antioxidants in ischemic stroke.
PMID- 9554830
TI - Lipid peroxidation, tissue necrosis, and metabolic and mechanical recovery of
isolated reperfused rat heart as a function of increasing ischemia.
AB - Isolated Langendorff-perfused rat hearts, after 30 min of preperfusion, were
submitted to increasing times of global normothermic ischemia (1, 2, 5, 10, 20
and 30 min) or to the same times of ischemia followed by 30 min of reperfusion.
Analysis of malondialdehyde, ascorbic acid, oxypurines, nucleosides, nicotinic
coenzymes and high-energy phosphates was carried out by HPLC on neutralized
perchloric acid extracts of freeze-clamped tissues. In addition, maximum rate of
intraventricular pressure development and cardiac output of malondialdehyde,
lactate dehydrogenase, oxypurines and nucleosides were monitored during both
preperfusion and reperfusion. Besides decreasing energy metabolites and nicotinic
coenzyme pool, prolonged ischemia produced oxidation of significant amounts of
hypoxanthine and xanthine to uric acid and generation of detectable levels of
malondialdehyde (0.002 micromol/g dry weight). After oxygen and substrate
readmission, tissue and perfusate malondialdehyde increased only if previous
ischemia was longer than 5 min, while lactate dehydrogenase was detected in
perfusate of reperfused hearts following 10, 20, and 30 min of ischemia. Highest
values of tissue malondialdehyde and total malondialdehyde output were recorded
in reperfused hearts subjected to 30 min of ischemia (0.043 micromol/g dry weight
and 0.069 micromol/30 min/g dry weight, respectively). Since tissue
malondialdehyde was observed without detectable lactate dehydrogenase release in
perfusate, it might be stated that malondialdehyde generation (i.e., lipid
peroxidation) temporally preceded lactate dehydrogenase release (i.e., tissue
necrosis). In reperfused hearts, evaluation of myocardial energy state and of
mechanical recovery allowed us to determine times of ischemia beyond which
reperfusion did not positively affect these metabolic and functional parameters.
Main findings are that, under these experimental conditions, lipid peroxidation
might be the cause and not the consequence of tissue necrosis and that duration
of ischemia might be the factor deciding effectiveness of reperfusion.
PMID- 9554831
TI - Serum of Behcet's disease enhances superoxide production of normal neutrophils.
AB - Using an MCLA-dependent chemiluminescence technique, we evaluated superoxide
production by neutrophils isolated from 7 patients with Behcet's disease. After
stimulation by phorbol myristate acetate, N-formyl-methionyl-leucyl-phenylalanine
or opsonized zymosan, neutrophils from the patients produced significantly more
superoxide than those from 20 controls. Pretreatment of control neutrophils with
serum prominently enhanced superoxide production, and serum from Behcet's disease
patients had a significantly greater effect than that from controls. These
findings suggest that serum from patients with Behcet disease contains the
priming factor(s) that can enhance enhanced superoxide production by neutrophils
in response to stimulation.
PMID- 9554832
TI - Generation of oxygen radicals from iron complex of orellanine, a mushroom
nephrotoxin; preliminary ESR and spin-trapping studies.
AB - Orellanine, [2,2'-bipyridine]-3,3',4,4'-tetrol-1,1'-dioxide, is the toxin
responsible for the lethal nephrotoxicity of some Cortinarius mushrooms. Our
present ESR and spin-trapping studies of the redox properties of the system of
non-illuminated orellanine, ferrous iron and dioxygen contribute to understanding
the molecular mechanism of its toxicity. UV-visible spectrophotometry, cyclic
voltammetry and ESR in frozen medium showed the formation of a wine-red tris
complex, Fe(III)Or3. This ferric complex is easily reducible (Ep = -565 mV vs
Ag/AgCl/3M KCl at pH 7), involving a one-electron reversible process. Spin
trapping using DMPO is employed to detect the generation of superoxide anion and
hydroxyl radicals. The instantaneous one-electron oxidation of ferrous ions in
the presence of the toxin under air is concomitant with dioxygen consumption as
supported by dioxygen consumption. GSH involves the toxin and ferrous ions under
air in a redox cycling process resulting in the production of glutathionyl and
oxygen free radicals, observed for the first time with an iron complex of a
mushroom toxin. In most cases, EDTA is not able to prevent the Fe(III)Or3 and
radical formation. The ortho-dihydroxylated groups borne by the di-N-oxidized
bipyridine structure and not the bipyridine structure itself, are responsible for
the formation of a stable ferric complex at pH 7, as they are for the generation
of an apparently stable ortho-semiquinone anion radical. These one-electron
mechanisms may play a major role in some of the known toxic effects of
orellanine.
PMID- 9554833
TI - Nasal cavity lining fluid ascorbic acid concentration increases in healthy human
volunteers following short term exposure to diesel exhaust.
AB - To determine if diesel exhaust (DE) exposure modifies the antioxidant defense
network within the respiratory tract lining fluids, a randomized, single blinded,
crossover control study using nasal lavage and flexible video bronchoscopy with
bronchial and bronchoalveolar lavage was performed. Fifteen healthy, non-smoking,
asymptomatic subjects were exposed to filtered air or diluted diesel exhaust
(300mg m(-3) particulates, 1.6ppm nitrogen dioxide) for one hour on 2 separate
occasions, at least three weeks apart. To examine the kinetics of any DE-induced
antioxidant reactions, nasal lavage fluid and blood samples were collected prior
to, immediately after, and 5 1/2 hours post exposure. Bronchoscopy was performed
6 hours after the end of DE exposure. Ascorbic acid, uric acid and reduced
glutathione (GSH) concentrations were determined in nasal, bronchial,
bronchoalveolar lavage and plasma samples. Malondialdehyde (MDA) and protein
carbonyl concentrations were determined in plasma and bronchoalveolar lavage
samples. Nasal lavage ascorbic acid concentration increased 10-fold during DE
exposure [1.02 (0.26-2.09) Vs 7.13 (4.66-10.79) micromol/L(-1)], but returned to
basal levels 5.5 hours post-exposure [0.75 (0.26-1.51) micromol/L(-1)]. There was
no significant effect of DE exposure on nasal lavage uric acid or GSH
concentration. DE exposure did not influence plasma, bronchial wash, or
bronchoalveolar lavage antioxidant concentrations and no change in MDA or protein
carbonyl concentrations were found. The physiological response to acute DE
exposure is an increase in the level of ascorbic acid in the nasal cavity. This
response appears to be sufficient to prevent further oxidant stress in the
respiratory tract of normal individuals.
PMID- 9554834
TI - Re-appraisal of the tocopheroxyl radical reaction with beta-carotene: evidence
for oxidation of vitamin E by the beta-carotene radical cation.
AB - Photobleached beta-carotene (Car) is regenerated in hexane on a microsecond
timescale in the presence of alpha-tocopherol (TOH) but not when alpha-tocopherol
is absent, as studied by laser flash photolysis. Beta-carotene radical cations
(Car.+) likewise react with (excess) alpha-tocopherol: Car.+ + TOH-->Car + TO. +
H+ (second-order rate constant of k = 1.7 +/- 0.1 x 10(7) M(-1) s(-1) in
homogeneous di-tert-butylperoxide/benzene at 20 degrees C) rather than alpha
tocopheroxyl radicals (TO.) reacting with beta-carotene. In hexane, hexane
radicals formed by pulse radiolysis react considerably faster with beta-carotene
(k = 2.1 +/- 0.1 x 10(9) M(-1) s(-1)) than with alpha-tocopherol (k = 4.9 +/- 0.1
x 10(6) M(-1) s(-1)). No evidence was obtained for a slower rate of beta-carotene
radical cation formation in beta-carotene/alpha-tocopherol mixtures resulting
from alpha-tocopheroxyl radical oxidation of beta-carotene. Steady-state
radiolysis experiments confirmed that alpha-tocopherol protects beta-carotene
from oxidation by hexane radicals. In both solvent systems, beta-carotene is
regenerated from the radical cation by alpha-tocopherol rather than alpha
tocopherol being regenerated by beta-carotene from the alpha-tocopheroxyl
radical.
PMID- 9554835
TI - Antioxidant vitamin levels in plasma and low density lipoprotein of obese girls.
AB - To investigate the antioxidant status of obese children, we analyzed beta
carotene and alpha-tocopherol levels in plasma and low density lipoprotein (LDL).
We also analyzed the fatty acid composition of LDL as a substrate for oxidative
stress. The plasma beta-carotene and alpha-tocopherol levels were relatively
lower in obese girls than in normal controls. However, the plasma alpha
tocopherol/lipids ratio was significantly lower in obese girls than in normal
controls. Both LDL beta-carotene and LDL alpha-tocopherol levels were
significantly lower in obese girls than in normal controls, although no obvious
differences were observed in plasma levels. In obese girls LDL contained more
polyunsaturated fatty acid (PUFA) compared with normal controls. When the
peroxidizability index (PI) was calculated to estimate the susceptibility of
lipids to oxidative stress, obese girls had significantly higher PI values than
normal controls. Both the LDL beta-carotene/PI ratio and the LDL alpha
tocopherol/PI ratio were significantly lower in obese girls than in normal
controls. These results indicate the increased susceptibility of LDL to oxidative
stress in obese girls which may promote atherosclerosis later in life.
PMID- 9554836
TI - Effect of alpha-tocopherol status on alpha-tocopherol transfer protein expression
and its messenger RNA level in rat liver.
AB - Studies were designed to explore the role of vitamin E nutritional status in
regulating the synthesis of alpha-tocopherol transfer protein (alphaTTP) in rat
liver. In vitamin E-replete rats, expression of this protein and its specific
messenger RNA (mRNA) was decreased by about 300% compared with rats with normal
vitamin E levels. In vitamin E-depleted rats, the alphaTTP-specific mRNA level
increased to about 150% of that in the normal vitamin E group. However, protein
expression remained constant. These findings indicate that the synthesis of
alphaTTP can be regulated by the vitamin E nutritional status.
PMID- 9554837
TI - In vivo dual effects of vitamin C on paraquat-induced lung damage: dependence on
released metals from the damaged tissue.
AB - Vitamin C, a potent antioxidant, can act as a pro-oxidant in the presence of free
transition metal ions by accelerating the Fenton reaction. An in vivo pro-oxidant
role of vitamin C has been suggested, but direct evidence for it is scant. Here,
we report the dual role of vitamin C on paraquat-induced lung injury, which
appears to depend on the metal ions released from damaged cells. Vitamin C (10
mg/kg) given at the time when the extensive tissue damage was in progress
aggravated the oxidative damage, while it protected against the damage when given
before the initiation of the damage. The extent of oxidative tissue damage was
monitored by measuring the expiratory ethane, one of the hydrocarbons produced
during lipid peroxidation. Deferoxamine, given intraperitoneally as a bolus dose
of 50 mg/kg, completely blocked the aggravation of oxidative damage by vitamin C.
Moreover, deferoxamine unmasked the antioxidant effect of vitamin C. The results
show that vitamin C can either aggravate or alleviate the oxidative tissue damage
depending on the presence of metal ions released from damaged cells.
PMID- 9554838
TI - Structure and function in the nucleus.
AB - Current evidence suggests that the nucleus has a distinct substructure, albeit
one that is dynamic rather than a rigid framework. Viral infection, oncogene
expression, and inherited human disorders can each cause profound and specific
changes in nuclear organization. This review summarizes recent progress in
understanding nuclear organization, highlighting in particular the dynamic
aspects of nuclear structure.
PMID- 9554839
TI - Intense sub-kilometer-scale boundary layer rolls observed in hurricane fran
AB - High-resolution observations obtained with the Doppler On Wheels (DOW) mobile
weather radar near the point of landfall of hurricane Fran (1996) revealed the
existence of intense, sub-kilometer-scale, boundary layer rolls that strongly
modulated the near-surface wind speed. It is proposed that these structures are
one cause of geographically varying surface damage patterns that have been
observed after some landfalling hurricanes and that they cause much of the
observed gustiness, bringing high-velocity air from aloft to the lowest
observable levels. High-resolution DOW radar observations are contrasted with
lower-resolution observations obtained with an operational weather radar, which
underestimated peak low-level wind speeds.
PMID- 9554840
TI - Switching supramolecular polymeric materials with multiple length scales
AB - It was demonstrated that polymeric supramolecular nanostructures with several
length scales allow straightforward tailoring of hierarchical order-disorder and
order-order transitions and the concurrent switching of functional properties.
Poly(4-vinyl pyridine) (P4VP) was stoichiometrically protonated with methane
sulfonic acid (MSA) to form P4VP(MSA)1.0, which was then hydrogen-bonded to
pentadecylphenol. Microphase separation, re-entrant closed-loop macrophase
separation, and high-temperature macrophase separation were observed. When MSA
and pentadecylphenol were complexed to the P4VP block of a microphase-separated
diblock copolymer poly[styrene-block-(4-vinyl pyridine)], self-organized
structures-in-structures were obtained whose hierarchical phase transitions can
be controlled systematically. This microstructural control on two different
length scales (in the present case, at 48 and 350 angstroms) was then used to
introduce temperature-dependent transitions in electrical conductivity.
PMID- 9554841
TI - Platinum catalysts for the high-yield oxidation of methane to a methanol
derivative
AB - Platinum catalysts are reported for the direct, low-temperature, oxidative
conversion of methane to a methanol derivative at greater than 70 percent one
pass yield based on methane. The catalysts are platinum complexes derived from
the bidiazine ligand family that are stable, active, and selective for the
oxidation of a carbon-hydrogen bond of methane to produce methyl esters.
Mechanistic studies show that platinum(II) is the most active oxidation state of
platinum for reaction with methane, and are consistent with reaction proceeding
through carbon-hydrogen bond activation of methane to generate a platinum-methyl
intermediate that is oxidized to generate the methyl ester product.
PMID- 9554842
TI - The Lost Colony and Jamestown droughts.
AB - Tree-ring data from Virginia indicate that the Lost Colony of Roanoke Island
disappeared during the most extreme drought in 800 years (1587-1589) and that the
alarming mortality and the near abandonment of Jamestown Colony occurred during
the driest 7-year episode in 770 years (1606-1612). These extraordinary droughts
can now be implicated in the fate of the Lost Colony and in the appalling death
rate during the early occupations at Jamestown, the first permanent English
settlement in America.
PMID- 9554843
TI - Tunneling into a single magnetic atom: spectroscopic evidence of the kondo
resonance
AB - The Kondo effect arises from the quantum mechanical interplay between the
electrons of a host metal and a magnetic impurity and is predicted to result in
local charge and spin variations around the magnetic impurity. A cryogenic
scanning tunneling microscope was used to spatially resolve the electronic
properties of individual magnetic atoms displaying the Kondo effect.
Spectroscopic measurements performed on individual cobalt atoms on the surface of
gold show an energetically narrow feature that is identified as the Kondo
resonance-the predicted response of a Kondo impurity. Unexpected structure in the
Kondo resonance is shown to arise from quantum mechanical interference between
the d orbital and conduction electron channels for an electron tunneling into a
magnetic atom in a metallic host.
PMID- 9554844
TI - Clouds of high contrast on Uranus.
AB - Near-infrared images of Uranus taken with the Hubble Space Telescope in July and
October 1997 revealed discrete clouds with contrasts exceeding 10 times the
highest contrast observed before with other techniques. At visible wavelengths,
these 10 clouds had lower contrasts than clouds seen by Voyager 2 in 1986.
Uranus' rotational rates for southern latitudes were identical in 1986 and 1997.
Clouds in northern latitudes rotate slightly more slowly than clouds in opposite
southern latitudes.
PMID- 9554845
TI - Brain activity during speaking: from syntax to phonology in 40 milliseconds.
AB - In normal conversation, speakers translate thoughts into words at high speed. To
enable this speed, the retrieval of distinct types of linguistic knowledge has to
be orchestrated with millisecond precision. The nature of this orchestration is
still largely unknown. This report presents dynamic measures of the real-time
activation of two basic types of linguistic knowledge, syntax and phonology.
Electrophysiological data demonstrate that during noun-phrase production speakers
retrieve the syntactic gender of a noun before its abstract phonological
properties. This two-step process operates at high speed: the data show that
phonological information is already available 40 milliseconds after syntactic
properties have been retrieved.
PMID- 9554846
TI - Targeting the receptor-Gq interface to inhibit in vivo pressure overload
myocardial hypertrophy.
AB - Hormones and neurotransmitters may mediate common responses through receptors
that couple to the same class of heterotrimeric guanine nucleotide-binding (G)
protein. For example, several receptors that couple to Gq class proteins can
induce cardiomyocyte hypertrophy. Class-specific inhibition of Gq-mediated
signaling was produced in the hearts of transgenic mice by targeted expression of
a carboxyl-terminal peptide of the alpha subunit Galphaq. When pressure overload
was surgically induced, the transgenic mice developed significantly less
ventricular hypertrophy than control animals. The data demonstrate the role of
myocardial Gq in the initiation of myocardial hypertrophy and indicate a possible
strategy for preventing pathophysiological signaling by simultaneously blocking
multiple receptors coupled to Gq.
PMID- 9554847
TI - Enzyme structure with two catalytic sites for double-sieve selection of
substrate.
AB - High-fidelity transfers of genetic information in the central dogma can be
achieved by a reaction called editing. The crystal structure of an enzyme with
editing activity in translation is presented here at 2.5 angstroms resolution.
The enzyme, isoleucyl-transfer RNA synthetase, activates not only the cognate
substrate L-isoleucine but also the minimally distinct L-valine in the first,
aminoacylation step. Then, in a second, "editing" step, the synthetase itself
rapidly hydrolyzes only the valylated products. For this two-step substrate
selection, a "double-sieve" mechanism has already been proposed. The present
crystal structures of the synthetase in complexes with L-isoleucine and L-valine
demonstrate that the first sieve is on the aminoacylation domain containing the
Rossmann fold, whereas the second, editing sieve exists on a globular beta-barrel
domain that protrudes from the aminoacylation domain.
PMID- 9554848
TI - Dependence of germinal center B cells on expression of CD21/CD35 for survival.
AB - Affinity-driven selection of B lymphocytes within germinal centers is critical
for the development of high-affinity memory cells and host protection. To
investigate the role of the CD21/CD35 coreceptor in B cell competition for
follicular retention and survival within the germinal center, either Cr2+ or
Cr2null lysozyme-specific transgenic B cells were adoptively transferred into
normal mice immunized with duck (DEL) or turkey (TEL) lysozyme, which bind with
different affinities. In mice injected with high-affinity turkey lysozyme,
Cr2null B cells responded by follicular retention; however, they could not
survive within germinal centers. This suggests that CD21 provides a signal
independent of antigen that is required for survival of B cells in the germinal
center.
PMID- 9554849
TI - Visualization of single RNA transcripts in situ.
AB - Fluorescence in situ hybridization (FISH) and digital imaging microscopy were
modified to allow detection of single RNA molecules. Oligodeoxynucleotide probes
were synthesized with five fluorochromes per molecule, and the light emitted by a
single probe was calibrated. Points of light in exhaustively deconvolved images
of hybridized cells gave fluorescent intensities and distances between probes
consistent with single messenger RNA molecules. Analysis of beta-actin
transcription sites after serum induction revealed synchronous and cyclical
transcription from single genes. The rates of transcription initiation and
termination and messenger RNA processing could be determined by positioning
probes along the transcription unit. This approach extends the power of FISH to
yield quantitative molecular information on a single cell.
PMID- 9554850
TI - In situ visualization of DNA double-strand break repair in human fibroblasts.
AB - A method was developed to examine DNA repair within the intact cell. Ultrasoft x
rays were used to induce DNA double-strand breaks (DSBs) in defined subnuclear
volumes of human fibroblasts and DNA repair was visualized at those sites. The
DSBs remained in a fixed position during the initial stages of DNA repair, and
the DSB repair protein hMre11 migrated to the sites of damage within 30 minutes.
In contrast, hRad51, a human RecA homolog, did not localize at sites of DNA
damage, a finding consistent with the distinct roles of these proteins in DNA
repair.
PMID- 9554851
TI - Formation of a preinitiation complex by S-phase cyclin CDK-dependent loading of
Cdc45p onto chromatin.
AB - Cdc45p, a protein essential for initiation of DNA replication, associates with
chromatin after "start" in late G1 and during the S phase of the cell cycle.
Binding of Cdc45p to chromatin depends on Clb-Cdc28 kinase activity as well as
functional Cdc6p and Mcm2p, which suggests that Cdc45p associates with the
prereplication complex after activation of S-phase cyclin-dependent kinases
(CDKs). As indicated by the timing and the CDK dependence, binding of Cdc45p to
chromatin is crucial for commitment to initiation of DNA replication. During S
phase, Cdc45p physically interacts with minichromosome maintenance (MCM) proteins
on chromatin; however, dissociation of Cdc45p from chromatin is slower than that
of MCMs, which indicates that the proteins are released by different mechanisms.
PMID- 9554852
TI - Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and
GSK3beta.
AB - Control of stability of beta-catenin is central in the wnt signaling pathway.
Here, the protein conductin was found to form a complex with both beta-catenin
and the tumor suppressor gene product adenomatous polyposis coli (APC). Conductin
induced beta-catenin degradation, whereas mutants of conductin that were
deficient in complex formation stabilized beta-catenin. Fragments of APC that
contained a conductin-binding domain also blocked beta-catenin degradation. Thus,
conductin is a component of the multiprotein complex that directs beta-catenin to
degradation and is located downstream of APC. In Xenopus embryos, conductin
interfered with wnt-induced axis formation.
PMID- 9554853
TI - Activation of the protein kinase p38 in the spindle assembly checkpoint and
mitotic arrest.
AB - The mitogen-activated protein kinase (MAPK) superfamily comprises classical MAPK
(also called ERK), c-Jun amino-terminal or stress-activated protein kinase (JNK
or SAPK), and p38. Although MAPK is essential for meiotic processes in Xenopus
oocytes and the spindle assembly checkpoint in Xenopus egg extracts, the role of
members of the MAPK superfamily in M phase or the spindle assembly checkpoint
during somatic cell cycles has not been elucidated. The kinase p38, but not MAPK
or JNK, was activated in mammalian cultured cells when the cells were arrested in
M phase by disruption of the spindle with nocodazole. Addition of activated
recombinant p38 to Xenopus cell-free extracts caused arrest of the extracts in M
phase, and injection of activated p38 into cleaving embryos induced mitotic
arrest. Treatment of NIH 3T3 cells with a specific inhibitor of p38 suppressed
activation of the checkpoint by nocodazole. Thus, p38 functions as a component of
the spindle assembly checkpoint in somatic cell cycles.
PMID- 9554854
TI - Supramolecular structure of the Salmonella typhimurium type III protein secretion
system.
AB - The type III secretion system of Salmonella typhimurium directs the translocation
of proteins into host cells. Evolutionarily related to the flagellar assembly
machinery, this system is also present in other pathogenic bacteria, but its
organization is unknown. Electron microscopy revealed supramolecular structures
spanning the inner and outer membranes of flagellated and nonflagellated strains;
such structures were not detected in strains carrying null mutations in
components of the type III apparatus. Isolated structures were found to contain
at least three proteins of this secretion system. Thus, the type III apparatus of
S. typhimurium, and presumably other bacteria, exists as a supramolecular
structure in the bacterial envelope.
PMID- 9554855
TI - A distinctive class of integron in the Vibrio cholerae genome.
AB - The ability of bacteria to acquire and disseminate heterologous genes has been a
major factor in the development of multiple drug resistance. A gene, intI4, was
identified that encodes a previously unknown integrase that is associated with a
"gene-VCR" organization (VCRs are Vibrio cholerae repeated sequences), similar to
that of the well-characterized antibiotic resistance integrons. The similarity
was confirmed by IntI1-mediated recombination of a gene-VCR cassette into a class
1 integron. VCR cassettes are found in a number of Vibrio species including a
strain of V. metschnikovii isolated in 1888, suggesting that this mechanism of
heterologous gene acquisition predated the antibiotic era.
PMID- 9554856
TI - The risk of a diagnosis of cancer after primary deep venous thrombosis or
pulmonary embolism.
AB - BACKGROUND: Several small studies have indicated an association between deep
venous thrombosis or pulmonary embolism and a subsequent diagnosis of cancer, but
the subject is controversial. METHODS: We conducted a nationwide study of a
cohort of patients with deep venous thrombosis or pulmonary embolism that was
drawn from the Danish National Registry of Patients for the years 1977 through
1992. The occurrence of cancer in the cohort was determined by linkage to the
Danish Cancer Registry. The expected number of cancer cases was estimated on the
basis of national age-, sex-, and site-specific incidence rates. RESULTS: A total
of 15,348 patients with deep venous thrombosis and 11,305 patients with pulmonary
embolism were identified. We observed 1737 cases of cancer in the cohort with
deep venous thrombosis, as compared with 1372 expected cases (standardized
incidence ratio, 1.3; 95 percent confidence interval, 1.21 to 1.33). Among the
patients with pulmonary embolism, the standardized incidence ratio was 1.3, with
a 95 percent confidence interval of 1.22 to 1.41. The risk was substantially
elevated only during the first six months of follow-up and declined rapidly
thereafter to a constant level slightly above 1.0 one year after the thrombotic
event. Forty percent of the patients given a diagnosis of cancer within one year
after hospitalization for thromboembolism had distant metastases at the time of
the diagnosis of cancer. There were strong associations with several cancers,
most pronounced for those of the pancreas, ovary, liver (primary hepatic cancer),
and brain. CONCLUSIONS: An aggressive search for a hidden cancer in a patient
with a primary deep venous thrombosis or pulmonary embolism is not warranted.
PMID- 9554857
TI - Topical treatment with nerve growth factor for corneal neurotrophic ulcers.
AB - BACKGROUND: Corneal neurotrophic ulcers associated with impairment of sensory
innervation of the cornea may lead to loss of vision, and there is no effective
treatment for these ulcers. We evaluated the effects of nerve growth factor in
patients with this disorder. METHODS: Twelve patients (14 eyes) with severe
neurotrophic corneal ulcers associated with corneal anesthesia were treated with
topical nerve growth factor 10 times daily for two days and then 6 times daily
until the ulcers healed. Treatment continued for 2 weeks after the ulcers healed,
and the patients were then followed for up to 12 months. The evolution of the
corneal disease during treatment and follow-up was evaluated by slit-lamp
examination, photography, fluorescein-dye testing, and tests of corneal
sensitivity and best corrected visual acuity. RESULTS: Corneal healing began 2 to
14 days after the initiation of treatment with nerve growth factor, and all
patients had complete healing of their corneal ulcers after 10 days to 6 weeks of
treatment. Corneal sensitivity improved in 13 eyes, and returned to normal in 2
of the 13 eyes. Corneal integrity and sensitivity were maintained during the
follow-up period (range, 3 to 12 months). Best corrected visual acuity increased
progressively during treatment and follow-up in all patients. There were no
systemic or local side effects of treatment. CONCLUSIONS: In this preliminary,
uncontrolled study, topically applied exogenous nerve growth factor restored
corneal integrity in patients with corneal neurotrophic ulcers.
PMID- 9554858
TI - Relation between preoperative inspiratory lung resistance and the outcome of lung
volume-reduction surgery for emphysema.
AB - BACKGROUND: Surgery to reduce lung volume has recently been reintroduced to
alleviate dyspnea and improve exercise tolerance in selected patients with
emphysema. A reliable means of identifying patients who are likely to benefit
from this surgery is needed. METHODS: We measured lung resistance during
inspiration, static recoil pressure at total lung capacity, static lung
compliance, expiratory flow rates, and lung volumes in 29 patients with chronic
obstructive lung disease before lung-volume-reduction surgery. The changes in the
forced expiratory volume in one second (FEV1) six months after surgery were
related to the preoperatively determined physiologic measures. A response to
surgery was defined as an increase in the FEV1 of at least 0.2 liter and of at
least 12 percent above base-line values. RESULTS: Of the 29 patients, 23 had some
improvement in FEV1 including 15 who met the criteria for a response to surgery.
Among the variables considered, only preoperative lung resistance during
inspiration predicted changes in expiratory flow rates after surgery. Inspiratory
lung resistance correlated significantly and inversely with improvement in FEV1
after surgery (r=-0.63, P<0.001). A preoperative criterion of an inspiratory
resistance of 10 cm of water per liter per second had a sensitivity of 88 percent
(14 of 16 patients) and a specificity of 92 percent (12 of 13 patients) in
identifying patients who were likely to have a response to surgery. CONCLUSIONS:
Preoperative lung resistance during inspiration appears to be a useful measure
for selecting patients with emphysema for lung-volume-reduction surgery.
PMID- 9554859
TI - Identification of fetal DNA and cells in skin lesions from women with systemic
sclerosis.
AB - BACKGROUND: Systemic sclerosis is a disease of unknown origin which often occurs
in women after their childbearing years. It has many clinical and
histopathological similarities to chronic graft-versus-host disease. Recent
studies indicate that fetal stem cells can survive in the maternal circulation
for many years post partum. This finding suggests that fetal cells persisting in
the maternal circulation or tissues could be involved in the pathogenesis of
systemic sclerosis by initiating a graft-versus-host reaction. METHODS: We used
the polymerase chain reaction (PCR) to identify Y-chromosome sequences in DNA
extracted from peripheral-blood cells and skin lesions from women with systemic
sclerosis of recent onset. To confirm the PCR findings, we used fluorescence in
situ hybridization of peripheral-blood cells and cells within chronic
inflammatory-cell infiltrates in biopsy specimens of affected skin. RESULTS: Y
chromosome sequences were found in DNA from peripheral-blood cells in 32 of 69
women with systemic sclerosis (46 percent), as compared with 1 of 25 normal women
(4 percent, P<0.001), and in T lymphocytes from 3 women with systemic sclerosis
who had male offspring. Furthermore, Y-chromosome sequences were identified in
skin-biopsy specimens from 11 of 19 women with systemic sclerosis (58 percent); 9
of the 11 were known to have carried male fetuses. Nucleated cells containing Y
chromosomes were detected by fluorescence in situ hybridization in paraffin
embedded sections of skin lesions from all seven women we tested whose skin
biopsy specimens contained Y-chromosome sequences. CONCLUSIONS: Fetal
antimaternal graft-versus-host reactions may be involved in the pathogenesis of
systemic sclerosis in some women.
PMID- 9554860
TI - Images in clinical medicine. The Gaudi-colon connection.
PMID- 9554861
TI - A national survey of physician-assisted suicide and euthanasia in the United
States.
AB - BACKGROUND: Although there have been many studies of physician-assisted suicide
and euthanasia in the United States, national data are lacking. METHODS: In 1996,
we mailed questionnaires to a stratified probability sample of 3102 physicians in
the 10 specialties in which doctors are most likely to receive requests from
patients for assistance with suicide or euthanasia. We weighted the results to
obtain nationally representative data. RESULTS: We received 1902 completed
questionnaires (response rate, 61 percent). Eleven percent of the physicians said
that under current legal constraints, there were circumstances in which they
would be willing to hasten a patient's death by prescribing medication, and 7
percent said that they would provide a lethal injection; 36 percent and 24
percent, respectively, said that they would do so if it were legal. Since
entering practice, 18.3 percent of the physicians (unweighted number, 320)
reported having received a request from a patient for assistance with suicide and
11.1 percent (unweighted number, 196) had received a request for a lethal
injection. Sixteen percent of the physicians receiving such requests (unweighted
number, 42), or 3.3 percent of the entire sample, reported that they had written
at least one prescription to be used to hasten death, and 4.7 percent (unweighted
number, 59), said that they had administered at least one lethal injection.
CONCLUSIONS: A substantial proportion of physicians in the United States report
that they receive requests for physician-assisted suicide and euthanasia, and
about 7 percent of those who responded to our survey have complied with such
requests at least once.
PMID- 9554862
TI - The nephrotic syndrome.
PMID- 9554864
TI - Primary venous thromboembolism and cancer screening.
PMID- 9554865
TI - Clearing the cornea with nerve growth factor.
PMID- 9554866
TI - Microchimerism and autoimmune disease.
PMID- 9554867
TI - (-)-6-Chloro-2-[(1-furo[2, 3-c]pyridin-5-ylethyl)thio]-4-pyrimidinamine, PNU
142721, a new broad spectrum HIV-1 non-nucleoside reverse transcriptase
inhibitor.
PMID- 9554868
TI - 2-Iminohomopiperidinium salts as selective inhibitors of inducible nitric oxide
synthase (iNOS).
AB - An attractive approach to the treatment of inflammatory conditions such as osteo-
and rheumatoid arthritis, inflammatory bowel disease, and sepsis is through the
selective inhibition of human inducible nitric oxide synthase (hiNOS) since
localized excess nitric oxide (NO) release has been implicated in the pathology
of these diseases. A series of monosubstituted iminohomopiperidinium salts
possessing lipophilic functionality at ring positions 3, 5, 6, and 7 has been
synthesized, and series members have demonstrated the ability to inhibit the
hiNOS isoform with an IC50 as low as 160 nM (7). Compounds were found that
selectively inhibit hiNOS over the human endothelial constitutive enzyme (heNOS)
with a heNOS/hiNOS IC50 ratio in excess of 100 and as high as 314 (9). Potencies
for inhibition of hiNOS and the human neuronal constitutive enzyme (hnNOS) are
comparable. Substitution in the 3 and 7 positions provides compounds that exhibit
the greatest degree of selectivity for hiNOS and hnNOS over heNOS. Submicromolar
potencies for 6 and 7 in a mouse RAW cell assay demonstrated the ability of these
compounds to inhibit iNOS in a cellular environment. These latter compounds were
also found to be orally bioavailable and efficacious due to their ability to
inhibit the increase in plasma nitrite/nitrate levels in a rat LPS model.
PMID- 9554869
TI - Rational drug design approach for overcoming drug resistance: application to
pyrimethamine resistance in malaria.
AB - Pyrimethamine acts by selectively inhibiting malarial dihydrofolate reductase
thymidylate synthase (DHFR-TS). Resistance in the most important human parasite,
Plasmodium falciparum, initially results from an S108N mutation in the DHFR
domain, with additional mutation (most commonly C59R or N51I or both) imparting
much greater resistance. From a homology model of the 3-D structure of DHFR-TS,
rational drug design techniques have been used to design and subsequently
synthesize inhibitors able to overcome malarial pyrimethamine resistance.
Compared to pyrimethamine (Ki 1.5 nM) with purified recombinant DHFR fromP.
falciparum, the Ki value of the m-methoxy analogue of pyrimethamine was 1.07 nM,
but against the DHFR bearing the double mutation (C59R + S108N), the Ki values
for pyrimethamine and the m-methoxy analogue were 71.7 and 14.0 nM, respectively.
The m-chloro analogue of pyrimethamine was a stronger inhibitor of both wild-type
DHFR (with Ki 0.30 nM) and the doubly mutant (C59R +S108N) purified enzyme (with
Ki 2.40 nM). Growth of parasite cultures of P. falciparum in vitro was also
strongly inhibited by these compounds with 50% inhibition of growth occurring at
3.7 microM for the m-methoxy and 0.6 microM for the m-chloro compounds with the
K1 parasite line bearing the double mutation (S108N + C59R), compared to 10.2
microM for pyrimethamine. These inhibitors were also found in preliminary studies
to retain antimalarial activity in vivo in P. berghei-infected mice.
PMID- 9554870
TI - Anti-HIV agents that selectively target retroviral nucleocapsid protein zinc
fingers without affecting cellular zinc finger proteins.
AB - Agents that target the two highly conserved Zn fingers of the human
immunodeficiency virus (HIV) nucleocapsid p7 (NCp7) protein are under development
as antivirals. These agents covalently modify Zn-coordinating cysteine thiolates
of the fingers, causing Zn ejection, loss of native protein structure and nucleic
acid binding capacity, and disruption of virus replication. Concentrations of
three antiviral agents that promoted in vitro Zn ejection from NCp7 and inhibited
HIV replication did not impact the functions of cellular Zn finger proteins,
including poly(ADP-ribose) polymerase and the Sp1 and GATA-1 transcription
factors, nor did the compounds inhibit HeLa nuclear extract mediated
transcription. Selectivity of interactions of these agents with NCp7 was
supported by molecular modeling analysis which (1) identified a common saddle
shaped nucleophilic region on the surfaces of both NCp7 Zn fingers, (2) indicated
a strong correspondence between computationally docked positions for the agents
tested and overlap of frontier orbitals within the nucleophilic loci of the NCp7
Zn fingers, and (3) revealed selective steric exclusion of the agents from the
core of the GATA-1 Zn finger. Further modeling analysis suggests that the
thiolate of Cys49 in the carboxy-terminal finger is the site most susceptible to
electrophilic attack. These data provide the first experimental evidence and
rationale for antiviral agents that selectively target retroviral nucleocapsid
protein Zn fingers.
PMID- 9554872
TI - Effect of steroids on DNA synthesis in an in vitro replication system: initial
quantitative structure-activity relationship studies and construction of a non
estrogen receptor pharmacophore.
AB - The molecular mechanism(s) by which steroids affect carcinogenesis is an active
area of investigation. Recent studies with a series of related steroids in an in
vitro DNA replication system produced a wide range of effects including
enhancement and inhibition of DNA synthesis. The HeLa cell-free system used in
these studies did not contain estrogen receptors. Since the majority of hormone
effects on cellular replication have been attributed to interactions with
estrogen receptors, an alternative description of the results was required.
Quantitative structure-activity relationships (QSARs) were used to relate the
observed bioactivity of these steroids with their structure. The results indicate
that the percentage of DNA replication could be related to three parameters
according to the following equation: %DNA = 23.9(+/-3.8)Xdipact + 57.8(+/
22.4)Hyd - 19.4(+/-10.4)Biophpi + 128.9, where Xdipact is the dipole moment on
the X-axis, Hyd is the atomic hydrophobicity index, and Biophpi is the atomic pi
population on the heteroatom found in the pharmacophore. For each molecule, the
orientation of the functional groups changed the dipole moment value, and this
descriptor was used as a selector of active conformations. A 3D-QSAR model was
then constructed combining pharmacophoric features and global properties, and the
active space and inactive space were defined using a Boolean volumetric
operation.
PMID- 9554871
TI - Modulation of receptor and receptor subtype affinities using diastereomeric and
enantiomeric monosaccharide scaffolds as a means to structural and biological
diversity. A new route to ether synthesis.
AB - We show that carbohydrates constitute an attractive source of readily available,
stereochemically defined scaffolds for the facile attachment of side chains
contained in genetically encoded and other amino acids. beta-D- and beta-L
glucose, L-mannose, and the 6-deoxy-6-N-analogue of beta-D-glucose have been
employed to synthesize peptidomimetics that bind the SRIF receptors on AtT-20
mouse pituitary cells, five cloned human receptor subtypes (hSSTRs), and the NK-1
receptor. The affinity profile of various sugar-based ligands at the hSSTRs is
compared with that of SRIF. Compound 19 bound hSSTR4 with a Ki of 100 nM. Subtle
structural changes affect affinities. Evidence is presented that suggests that
one compound (8) binds both the AtT-20 cell receptors and the five hSSTRs via a
unique mode. The SARs of the glycosides at SRIF receptors differ markedly from
those at the NK-1 receptor. For example a 4-benzyl substituent is important for
SRIF receptor binding, but the 4-desbenzyl analogue 27 was highly potent (IC50 of
27 nM) at the NK-1 receptor. A new, nonbasic method for the synthesis of base
sensitive ethers from primary and secondary alcohols is also described.
PMID- 9554873
TI - Novel tetranuclear orthometalated complexes of Pd(II) and Pt(II) derived from p
isopropylbenzaldehyde thiosemicarbazone with cytotoxic activity in cis-DDP
resistant tumor cell lines. Interaction of these complexes with DNA.
AB - The reaction of p-isopropylbenzaldehyde thiosemicarbazone [p-is.TSCN], 1, with
palladium(II) acetate and potassium tetrachloroplatinate yielded two tetrameric
orthopalladated isomers, [Pd(p-is.TSCN)]4 (complexes 2 and 3), and the platinum
analogue [Pt(p-is.TSCN)]4 (complex 4), respectively. All of these complexes
contain the thiosemicarbazone bonded as a terdentate ligand to the metallic atom,
through the thiol sulfur, the azomethinic nitrogen and the ortho carbon of the p
isopropylphenyl ring to which the imine group is attached to as deduced from the
study of the IR, NMR, and XRD spectra of complexes 2 and 4. Complexes 2 and 4
crystallize in the centrosymmetric monoclinic space group C2/c, with Z = 8. Unit
cell parameters for complex 2 are as follows: a = 25.742(5) A, b = 19.560(4) A, c
= 24.199(5) A, beta = 101.70(3)o. Unit cell parameters for complex 4 are as
follows: a = 25.8728(19) A, b = 19. 5053(14) A, c = 24.0899(16) A, beta =
101.305(2)o. As can be deduced from the NMR study, the palladated isomers 2 and 3
interconvert in DMSO which may be a consequence of the existence in both
complexes of a flexible eight-membered ring with alternating Pd-S atoms. The
testing of the cytotoxic activity of these compounds against several human and
murine cell lines sensitive and resistant to cisplatin (cis-DDP) suggests that
compounds 2, 3, and 4 may be endowed with important anticancer properties since
they elicit IC50 values in the microM range as does the clinically used drug cis
DDP, and, moreover, they display cytotoxic activity in tumor lines resistant to
cis-DDP. The analysis of the interaction of these novel tetrameric cyclometalated
compounds with DNA suggests that they form DNA interhelical cross-links.
PMID- 9554874
TI - Synthesis and biological activities of tricyclic conformationally restricted
tetrahydropyrido annulated furo[2,3-d]pyrimidines as inhibitors of dihydrofolate
reductases.
AB - The synthesis of seven 2,4-diamino-5,6,7,8-tetrahydro-7-substituted
pyrido[4',3':4,5]furo[2,3-d]pyrimidines 1-6 are reported as nonclassical
antifolate inhibitors of dihydrofolate reductase (DHFR) and compound 7 as a
classical antifolate inhibitor of tumor cells in culture. The compounds were
designed as conformationally restricted analogues of trimetrexate. The synthesis
was accomplished from the cyclocondensation of 3-bromo-4-piperidone with 2, 4
diamino-6-hydroxypyrimidine to afford regiospecifically 2, 4-diamino-5,6,7,8
tetrahydropyrido[4',3':4,5]furo[2, 3-d]pyrimidine-7-hydrobromide (16). This in
turn was alkylated with the appropriate benzyl halide to afford the target
compounds 1-6. The classical antifolate 7 utilized 4-(chloromethyl)benzoyl-l
glutamic acid diethyl ester (17) instead of the benzyl halide for alkylation,
followed by saponification to afford 7. Compounds 1-6 showed moderate inhibitory
potency against DHFR from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium
avium, and rat liver. The classical analogue 7 was 88-fold more potent against M.
avium DHFR than against rat liver DHFR. The classical analogue was also
inhibitory against the growth of tumor cells, CCRF-CEM, and FaDu, in culture.
PMID- 9554875
TI - cycloSal-2',3'-dideoxy-2',3'-didehydrothymidine monophosphate (cycloSal-d4TMP):
synthesis and antiviral evaluation of a new d4TMP delivery system.
AB - The synthesis, hydrolysis, and antiviral evaluation of novel, lipophilic cycloSal
d4TMP derivatives 3a-h of the anti-HIV dideoxynucleoside 2',3'-dideoxy-2',3'
didehydrothymidine (d4T, 1) are reported. This pro-nucleotide concept has been
designed to deliver d4TMP (2) by selective chemical hydrolysis. All compounds 3a
h were synthesized using phosphorus(III) chemistry in good yields and in somewhat
lower yields using phosphorus(V) chemistry starting from substituted salicyl
alcohols 6a-h. The phosphotriesters 3 were obtained without stereochemical
preference with respect to the configuration at the phosphorus center as 1:1
diastereomeric mixtures. However, a few of the triesters 3 could be separated
into the diastereomers by means of semipreparative HPLC. In a 1-octanol/phosphate
buffer mixture, all compounds 3 exhibited 9-100-fold higher lipophilicity as
judged from their Pa values as compared to d4T (1). Furthermore, in hydrolysis
studies 3 decomposed under mild aqueous basic conditions releasing solely d4TMP
(2) and the diols 6 following the designed tandem reaction sequence. A
correlation of the electronic properties introduced by the substituents and the
half-lives of triesters 3 was observed. Thus, by varying the substituent, the
half-lives of 3 could be adjusted over a wide range of compounds still delivering
d4TMP (2) selectively. Phosphotriesters 3 exhibited considerable activity against
HIV-1 and HIV-2 in wild-type human T-lymphocyte (CEM/O) cells as well as mutant
thymidine kinase-deficient (CEM/TK-) cells. Surprisingly, we observed a 3-80-fold
difference in antiviral activity between the two diastereomers. Our data clearly
prove that the cycloSal-d4TMPs deliver exclusively the nucleotide d4TMP not only
under simulated hydrolysis conditions but also under cellular conditions and thus
fulfill the thymidine kinase-bypass premise. Therefore, the cycloSal-nucleotide
concept is the first reported pro-nucleotide system that delivers the
dideoxynucleotide by a pH-driven, chemically activated, tandem reaction without
the requirement of an enzymatic contribution.
PMID- 9554876
TI - Synthesis and structure-activity relationships of carboxyflavones as structurally
rigid CysLT1 (LTD4) receptor antagonists.
AB - The synthesis and CysLT1 receptor affinities of a new series of highly rigid 3'-
and 4'-(2-quinolinylmethoxy)- or 3'- and 4'-[2-(2-quinolinyl)ethenyl]
substituted, 6-, 7-, or 8-carboxylated flavones are described. CysLT1 receptor
affinities of the flavones (down to 11 nM) were determined by their ability to
displace [3H]LTD4 from its receptor in guinea pig lung membranes. Structure
affinity relationship studies showed that the relative positions of the
carboxylic acid and the quinoline moiety were critical for CysLT1 affinities.
While the carboxyl is optimal in the 8 position but tolerated in the 6 position,
only the 6- and not the 8-tetrazole has significant activity. The quinoline
moiety may be connected to the flavone skeleton by an ethenyl or a methoxy
linker, but the substitution position is important for high affinity, especially
in the 6-carboxylated flavones. 4'-Substituted 6-carboxyflavones are essentially
inactive, whereas the 3'-substituted analogues have submicromolar CysLT1
affinity. Replacement of the quinoline by other heteroaromates generally leads to
decreased affinities, with the phenyl and naphthyl analogues displaying only
little or no affinity, while the 7-chloroquinoline analogue is comparable in
activity to the quinoline. Flavones having CysLT1 receptor affinities of 10-30 nM
were selected for determination of their inhibitory effects on the LTD4-induced
contraction of guinea pig ileum in vitro. The IC50 values ranged between 15 and
100 nM. Compound 5d (8-carboxy-6-chloro-3'-(2-quinolinylmethoxy)flavone, VUF
5087) was selected for further research because of its high potency in the
functional assay. This series contains the most rigid CysLT1 receptor antagonists
known to date, and they are useful in the development of a CysLT1 antagonist
model, which is discussed in the companion paper.
PMID- 9554877
TI - Development of a three-dimensional CysLT1 (LTD4) antagonist model with an
incorporated amino acid residue from the receptor.
AB - This paper describes the molecular modeling of leukotriene CysLT1 (or LTD4)
receptor antagonists. Several different structural classes of CysLT1 antagonists
were superimposed onto the new and highly rigid CysLT1 antagonist 8-carboxy-3'-[2
(2-quinolinyl)ethenyl]flavone (1, VUF 5017) to generate a common pharmacophoric
arrangement. On the basis of known structure-activity relationships of CysLT1
antagonists, the quinoline nitrogen (or a bioisosteric equivalent thereof) and an
acidic function were taken as the matching points. In order to optimize the
fitting of acidic moieties of all antagonists, an arginine residue from the
receptor was proposed as the interaction site for the acidic moieties.
Incorporation of this amino acid residue into the model revealed additional
interactions between the guanidine group and the nitrogen atoms of quinoline
containing CysLT1 antagonists. In some cases, the arginine may even interact with
pi-clouds of phenyl residues of CysLT1 antagonists. The alignment of Montelukast
(MK-476) suggests the presence of an additional pocket in the binding site for
CysLT1 antagonists. The derived model should be useful for a better understanding
of the molecular recognition of the leukotriene CysLT1 receptor.
PMID- 9554878
TI - Nonpeptide cyclic cyanoguanidines as HIV-1 protease inhibitors: synthesis,
structure-activity relationships, and X-ray crystal structure studies.
AB - Comparison of the high-resolution X-ray structures of the native HIV-1 protease
and its complexes with the inhibitors suggested that the enzyme flaps are
flexible. The movement at the tip of the flaps could be as large as 7 A. On the
basis of this observation, cyclic cyanoguanidines have been designed,
synthesized, and evaluated as HIV-1 protease (PR) inhibitors. Cyclic
cyanoguanidines were found to be very potent inhibitors of HIV-1 protease. The
choice of cyclic cyanoguanidines over cyclic guanidines was based on the reduced
basicity of the former. X-ray structure studies of the HIV PR complex with cyclic
cyanoguanidine demonstrated that in analogy to cyclic urea, cyclic
cyanoguanidines also displace the unique structural water molecule. The structure
activity relationship of the cyclic cyanoguanidines is compared with that of the
corresponding cyclic urea analogues. The differences in binding constants of the
two series of compounds have been rationalized using high-resolution X-ray
structure information.
PMID- 9554880
TI - Conformation-function relationship of vitamin D: conformational analysis predicts
potential side-chain structure.
AB - In previous studies, we have grouped regions in space occupied by the vitamin D
side chain into four: A, G, EA, and EG. We showed that the receptor (VDR)
affinity of 1alpha,25-dihydroxyvitamin D3 derivatives increases, in terms of side
chain region, in the order EG, G, A, and EA. We called this the active space
group concept. In the present study, we used this active space group concept to
analyze the conformation-activity relationship of about 40 representative potent
1alpha,25-dihydroxyvitamin D3 analogues. We initially listed structural
modifications in the side chain of potent vitamin D analogues and estimated their
potency factor. Possible side-chain conformations of representative analogues
were calculated by the molecular mechanics method and plotted on a dot map
compared with the regions A, G, EA, and EG. The cell-differentiating potency of
the analogues was correlated with our active space group concept with few
exceptions. Among potent analogues with a natural configuration at C(20), the
side chains of those with a 22-oxa, 22-ene, 16-ene, or a 18-nor modification were
located in front of region EA (termed F). The side chains of the most potent 20
epi-22-oxa-24-homovitamin D analogues were concentrated at the left side of the
EA region (L-EA). Thus, the side chains of almost all potent analogues were
distributed around the EA region, and potency increased in the order A, F, EA,
and L-EA.
PMID- 9554879
TI - Human P2Y1 receptor: molecular modeling and site-directed mutagenesis as tools to
identify agonist and antagonist recognition sites.
AB - The molecular basis for recognition by human P2Y1 receptors of the novel,
competitive antagonist 2'-deoxy-N6-methyladenosine 3', 5'-bisphosphate (MRS 2179)
was probed using site-directed mutagenesis and molecular modeling. The potency of
this antagonist was measured in mutant receptors in which key residues in the
transmembrane helical domains (TMs) 3, 5, 6, and 7 were replaced by Ala or other
amino acids. The capacity of MRS 2179 to block stimulation of phospholipase C
promoted by 2-methylthioadenosine 5'-diphosphate (2-MeSADP) was lost in P2Y1
receptors having F226A, K280A, or Q307A mutations, indicating that these residues
are critical for the binding of the antagonist molecule. Mutation of the residues
His132, Thr222, and Tyr136 had an intermediate effect on the capacity of MRS 2179
to block the P2Y1 receptor. These positions therefore appear to have a modulatory
role in recognition of this antagonist. F131A, H277A, T221A, R310K, or S317A
mutant receptors exhibited an apparent affinity for MRS 2179 that was similar to
that observed with the wild-type receptor. Thus, Phe131, Thr221, His277, and
Ser317 are not essential for antagonist recognition. A computer-generated model
of the human P2Y1 receptor was built and analyzed to help interpret these
results. The model was derived through primary sequence comparison, secondary
structure prediction, and three-dimensional homology building, using rhodopsin as
a template, and was consistent with data obtained from mutagenesis studies. We
have introduced a "cross-docking" procedure to obtain energetically refined 3D
structures of the ligand-receptor complexes. Cross-docking simulates the
reorganization of the native receptor structure induced by a ligand. A putative
nucleotide binding site was localized and used to predict which residues are
likely to be in proximity to agonists and antagonists. According to our model TM6
and TM7 are close to the adenine ring, TM3 and TM6 are close to the ribose
moiety, and TM3, TM6, and TM7 are near the triphosphate chain.
PMID- 9554881
TI - Clarification of the binding mode of teleocidin and benzolactams to the Cys2
domain of protein kinase Cdelta by synthesis of hydrophobically modified,
teleocidin-mimicking benzolactams and computational docking simulation.
AB - Phorbol esters (12-O-tetradecanoylphorbol 13-acetate; TPA) and teleocidins are
known to be potent tumor promoters and to activate protein kinase C (PKC) by
binding competitively to the enzyme. The relationship between the chemical
structures and the activities of these compounds has attracted much attention
because of the marked structural dissimilarities. The benzolactam 5, with an
eight-membered lactam ring and benzene ring instead of the nine-membered lactam
ring and indole ring of teleocidins, reproduces the active ring conformation and
biological activities of teleocidins. Herein we describe the synthesis of
benzolactams with hydrophobic substituents at various positions. Structure
activity data indicate that the existence of a hydrophobic region between C-2 and
C-9 and the steric factor at C-8 play critical roles in the appearance of
biological activities. We also computationally simulated the docking of
teleocidin and the modified benzolactam molecules to the Cys2 domain structure
observed in the crystalline complex of PKCdelta with phorbol 13-acetate.
Teleocidin and benzolactams fitted well into the same cavity as phorbol 13
acetate. Of the three functional groups hydrogen-bonding to the protein, two
hydrogen-bonded with protein atoms in common with phorbol 13-acetate, but the
third one hydrogen-bonded with a different protein atom from that in the case of
phorbol 13-acetate. The model explains well the remarkable difference in activity
between 5 and its analogue having a bulky substituent at C-8.
PMID- 9554882
TI - Membrane-induced secondary structures of neuropeptides: a comparison of the
solution conformations adopted by agonists and antagonists of the mammalian
tachykinin NK1 receptor.
AB - We present what we believe to be the first documented example of an inducement of
distinctly different secondary structure types onto agonists and antagonists
selective for the same G-coupled protein receptor using the same membrane-model
matrix wherein the induced structures are consistent with those suggested to be
biologically active by extensive analogue studies and conventional binding
assays. 1H NMR chemical shift assignments for the mammalian NK1 receptor
selective agonists alpha-neurokinin (NKA) and beta-neurokinin (NKB) as well as
the mammalian NK1 receptor-selective antagonists [d-Pro2,d-Phe7,d-Trp9]SP and [d
Arg1, d-Pro2,d-Phe7,d-His9]SP have been determined at 600 MHz in sodium dodecyl
sulfate (SDS) micelles. The SDS micelle system simulates the membrane-interface
environment the peptide experiences when in the proximity of the membrane
embedded receptor, allowing for conformational studies that are a rough
approximation of in vivo conditions. Two-dimensional NMR techniques were used to
assign proton resonances, and interproton distances were estimated from the
observed nuclear Overhauser effects (NOEs). The experimental distances were used
as constraints in a molecular dynamics and simulated annealing protocol using the
modeling package DISCOVER to generate three-dimensional structures of the two
agonists and two antagonists when present in a membrane-model environment to
determine possible prebinding ligand conformations. It was determined that (1)
NKA is helical from residues 6 to 9, with an extended N-terminus; (2) NKB is
helical from residues 4 to 10, with an extended N-terminus; (3) [d-Pro2,d-Phe7,d
Trp9]SP has poorly defined helical properties in the midregion and a beta-turn
structure in the C-terminus (residues 6-9); and (4) [d-Arg1,d-Pro2, d-Phe7,d
His9]SP has a helical structure in the midregion (residues 4-6) and a well
defined beta-turn structure in the C-terminus (residues 6-10). Attempts have been
made to correlate the observed conformational differences between the agonists
and antagonists to their binding potencies and biological activity.
PMID- 9554883
TI - Therapeutic effects of monoclonal antibody-beta-lactamase conjugates in
combination with a nitrogen mustard anticancer prodrug in models of human renal
cell carcinoma.
AB - A panel of 13 renal cell carcinoma cell lines was evaluated for the expression of
antigens recognized by the L6 and L49 monoclonal antibodies. All of the cell
lines were strongly positive for the L6 antigen, and 9/13 bound 96.5, which, like
the L49 monoclonal antibody, recognizes the p97 melanotransferrin antigen. The L6
and L49 antibodies were chemically conjugated to Enterobacter cloacae beta
lactamase (bL), and their abilities to effect site-selective anticancer prodrug
activation on two of the renal cell carcinoma cell lines (SN12P and 1934J) were
evaluated in vitro and in vivo. L49-bL was 10-90-fold more potent in vitro than
L6-bL for the activation of 7-(4-carboxybutanamido)cephalosporin mustard (CCM), a
cephalosporin prodrug of phenylenediamine mustard (PDM). In addition, L49-bL
showed higher degrees of specific SN12P and 1934J intratumoral uptake than L6-bL,
even though the expression of L6 antigen was 2-fold higher than that of p97.
These differences might be due to the high-affinity antigen binding of L49-bL
relative to L6-bL. In vivo studies utilizing nude mice with established
subcutaneous SN12P and 1934J tumor xenografts demonstrated that L49-bL/CCM
combinations led to regressions and cures at well-tolerated doses, while L6
bL/CCM and the nonbinding control conjugate P1.17-bL in combination with CCM were
ineffective. Conjugate localization in 1934J tumors was much lower than that
observed in SN12P tumors, a finding that might acount for the higher activities
of L49-bL/CCM in the latter model. These data show that the p97 antigen on renal
cell carcinomas can be exploited for selective prodrug activation, even on tumors
that localize very small amounts of the L49-bL conjugate.
PMID- 9554885
TI - Synthesis and biological activity of chimeric structures derived from the
cytotoxic natural compounds dolastatin 10 and dolastatin 15.
AB - The natural cytotoxic compounds dolastatins 10 and 15 exhibit great similarities
in structure and in their biological activity profiles. Two compounds (1 and 2)
formed by interchanging the dolaisoleuine residue of dolastatin 10 and the MeVal
Pro dipeptide of dolastatin 15 were synthesized in order to evaluate the possible
equivalence of these units. These compounds can be considered as chimeras of
dolastatins 10 and 15 formed by the N-terminal part of the former and the C
terminal part of the latter and vice versa. Both analogues exhibited a marked
decrease in their cytotoxic activity but showed similar differential cytotoxicity
with regard to the cell lines assayed compared with the parent compounds. HT-29
cell line was the least sensitive one. However, this activity was in the
nanomolar level and close to that of vincristine. The differences in their effect
on tubulin polymerization were less pronounced. We confirmed the already known
crucial role of the Dil residue in this assay. The nonequivalence of the Dil unit
and the MeVal-Pro dipeptide probably reflects modification in the relative
positions of the N-dimethylamino and the phenyl moieties.
PMID- 9554884
TI - Design and synthesis of potent, selective inhibitors of endothelin-converting
enzyme.
AB - Endothelin-1 is the most potent peptidic vasoconstrictor discovered to date. The
final step of posttranslational processing of this peptide is the conversion of
its precursor by endothelin-converting enzyme-1 (ECE-1), a metalloprotease which
displays high amino acid sequence identity with neutral endopeptidase 24.11 (NEP)
especially at the catalytic center. A series of potent and selective
arylacetylene-containing ECE-1 inhibitors have been prepared. (S, S)-3-Cyclohexyl
2-[[5-(2, 4-difluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]amino] propio
nic acid (47), an arylacetylene amino phosphonate dipeptide, was found to inhibit
ECE-1 and NEP with IC50 values of 14 nM and 2 microM, respectively. Similarly,
(S)-[[1-[(2-biphenyl-4-ylethyl)carbamoyl]-4-(2-fluorophenyl)but-3- yny
l]amino]methyl]phosphonic acid (56), an arylacetylene amino phosphonate amide,
had IC50's of 33 nM and 6.5 microM for ECE-1 and NEP, respectively. Slight
modification of the aryl moiety was found to have dramatic effects on ECE-1/NEP
selectivity. The 2-fluoro dipeptide analogue, (S, S)-2-[[5-(2-fluorophenyl)-2
[(phosphonomethyl)amino]pent-4-ynoyl]+ ++amin o]-4-methylpentanoic acid (40),
showed a 72-fold selectivity for ECE-1 over NEP, while the 3-fluoro dipeptide
analogue, (S, S)-2-[[5-(3-fluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]+
++amin o]-4-methylpentanoic acid (22), was equipotent for ECE-1 and NEP. Several
of these inhibitors were shown to be potent in blocking ET-1 production in vivo
as demonstrated by the big ET-1-induced pressor response in rats. These potent
inhibitors are the most selective for ECE-1 reported to date and are envisaged to
have a variety of therapeutic applications.
PMID- 9554886
TI - Nuclease-resistant composite 2',5'-oligoadenylate-3', 5'-oligonucleotides for the
targeted destruction of RNA: 2-5A-iso-antisense.
AB - A new modification of 2-5A-antisense, 2-5A-iso-antisense, has been developed
based on a reversal of the direction of the polarity of the antisense domain of a
2-5A-antisense composite nucleic acid. This modification was able to anneal with
its target RNA as well as the parental 2-5A-antisense chimera. The 2-5A-iso
antisense oligonucleotide displayed enhanced resistance to degradation by 3'
exonuclease enzyme activity such as that represented by snake venom
phosphodiesterase and by that found in human serum. 2-5A-Iso-antisense was able
to effect the degradation of a synthetic nontargeted substrate, [5'-32P]pC11U2C7,
and two targeted RNAs, PKR and BCR mRNAs, in a cell-free system containing
purified recombinant human 2-5A-dependent RNase L. These results demonstrated
that the novel structural modification represented by 2-5A-iso-antisense provided
a stabilized biologically active formulation of the 2-5A-antisense strategy.
PMID- 9554887
TI - Structure-activity relationship of new growth inhibitors of Trypanosoma cruzi.
AB - Several drugs bearing the 4-phenoxyphenoxy skeleton and other closely related
structures were designed, synthesized, and evaluated as antiproliferative agents
against Trypanosoma cruzi, the etiologic agent of Chagas' disease. The new class
of drugs was envisioned by modifying the nonpolar 4-phenoxyphenoxy moiety
replacing selected aromatic protons by different groups via electrophilic
aromatic substitution reactions as well as introducing a sulfur atom at the polar
extreme. Of the designed compounds, sulfur-containing derivatives were shown to
be potent antireplicative agents against T. cruzi. Among these drugs, 4
phenoxyphenoxyethyl thiocyanate (compound 56) proved to be an extremely active
growth inhibitor of the epimastigote forms of T. cruzi and displayed an IC50 of
2.2 microM. Under the same assay conditions, this drug was much more active than
Nifurtimox, one of the drugs currently in clinical use to control this disease.
This thiocyanate derivative was also a very active inhibitor against the
intracellular form of the parasite at the nanomolar level. Other sulfur
derivatives prepared also exhibited very potent antiproliferative action against
T. cruzi. The presence of a sulfur atom at the polar extreme for this family of
compounds seems to be very important for biological action because this atom was
always associated with high inhibition values. 4-Phenoxyphenoxyethyl thiocyanate
presents very good prospective not only as a lead drug but also as a potential
chemotherapeutic agent.
PMID- 9554890
TI - Antibiotic resistance: an increasing problem?. It always has been, but there are
things we can do.
PMID- 9554891
TI - Drugs in British prisons. Policies need outside scrutiny if they are to do more
good than harm.
PMID- 9554892
TI - Leukotriene modifiers in the treatment of asthma. Look promising across the board
of asthma severity.
PMID- 9554893
TI - Functional neurosurgery for Parkinson's disease. Has come a long way, though much
remains experimental.
PMID- 9554894
TI - Developing the BMJ's coverage of basic science. We are introducing science
commentaries
PMID- 9554895
TI - Medical and psychosocial effects of early discharge after surgery for breast
cancer: randomised trial.
AB - OBJECTIVE: To assess the medical and psychosocial effects of early hospital
discharge after surgery for breast cancer on complication rate, patient
satisfaction, and psychosocial outcomes. DESIGN: Randomised trial comparing
discharge from hospital 4 days after surgery (with drain in situ) with discharge
after drain removal (mean 9 days in hospital). Psychosocial measurements
performed before surgery and 1 and 4 months after. SETTING: General hospital and
cancer clinic in Rotterdam with a socioeconomically diverse population. SUBJECTS:
125 women with operable breast cancer. MAIN OUTCOME MEASURES: Incidence of
complications after surgery for breast cancer, patient satisfaction with
treatment, and psychosocial effects of short stay or long stay in hospital.
RESULTS: Patient satisfaction with the short stay in hospital was high; only 4%
(2/56 at 1 month after surgery and 2/52 at 4 months after surgery) of patients
indicated that they would have preferred a longer stay. There were no significant
differences in duration of drainage from the axilla between the short stay and
long stay groups (median 8 v 9 days respectively, P=0.45) or the incidence of
wound complications (10 patients v 9 patients). The median number of seroma
aspirations per patient was higher for the long stay group (1 v 3.5, P=0.04).
Leakage along the drain occurred more frequently in short stay patients (21 v 10
patients, P=0.04). The two groups did not differ in scores for psychosocial
problems (uncertainty, anxiety, loneliness, disturbed sleep, loss of control,
threat to self esteem), physical or psychological complaints, or in the coping
strategies used. Before surgery, short stay patients scored higher on scales of
depression (P=0.03) and after surgery they were more likely to discuss their
disease with their families (at 1 month P=0.004, at 4 months P=0.04).
CONCLUSIONS: Early discharge from hospital after surgery for breast cancer is
safe and is well received by patients. Early discharge seems to enhance the
opportunity for social support within the family.
PMID- 9554896
TI - Resolution of peanut allergy: case-control study.
AB - OBJECTIVES: To determine whether there are any differences between children who
remain mildly or moderately allergic to peanut and children with similar
histories but a negative reaction on challenge with peanut. DESIGN: Case-controls
matched for age and sex. SETTING: Children's day wards in two teaching hospitals.
INTERVENTION: Open food challenge with peanut. SUBJECTS: 15 children with
resolved peanut allergy (resolvers) and 15 with persistent allergy (persisters).
MAIN OUTCOME MEASURE: Reaction on challenge with peanut, serum total and peanut
specific IgE concentrations. RESULTS: The groups had a similar median age at
first reaction to peanut (11 months, range 5-38) and similar symptoms. Allergy to
other foods was less common in resolvers (2/15) than persisters (9/15) (P=0.02).
On skin prick testing with peanut all 13 resolvers tested but only 3/14
persisters had a weal of <6 mm (P<0.0001). Total and peanut specific IgE
concentrations did not differ much between the groups. CONCLUSION: Appropriately
trained clinicians must be prepared to challenge preschool children with peanut
as some will be tolerant despite a history of reactions to peanut and a positive
skin prick test with peanut. Preschool children whose apparent peanut allergy is
refuted by food challenge show allergy to other foods less often than those in
whom peanut allergy persists. The size of weal on skin prick testing to peanut
predicts reactivity but not severity on peanut challenge.
PMID- 9554898
TI - Alternative definitions
PMID- 9554900
TI - The new NHS: 38,534 doctors disapprove
PMID- 9554897
TI - Effectiveness of antibiotic prophylaxis in critically ill adult patients:
systematic review of randomised controlled trials.
AB - OBJECTIVE: To determine whether antibiotic prophylaxis reduces respiratory tract
infections and overall mortality in unselected critically ill adult patients.
DESIGN: Meta-analysis of randomised controlled trials from 1984 and 1996 that
compared different forms of antibiotic prophylaxis used to reduce respiratory
tract infections and mortality with aggregate data and, in a subset of trials,
data from individual patients. SUBJECTS: Unselected critically ill adult
patients; 5727 patients for aggregate data meta-analysis, 4343 for confirmatory
meta-analysis with data from individual patients. MAIN OUTCOME MEASURES:
Respiratory tract infections and total mortality. RESULTS: Two categories of
eligible trials were defined: topical plus systemic antibiotics versus no
treatment and topical preparation with or without a systemic antibiotic versus a
systemic agent or placebo. Estimates from aggregate data meta-analysis of 16
trials (3361 patients) that tested combined treatment indicated a strong
significant reduction in infection (odds ratio 0.35; 95% confidence interval 0.29
to 0.41) and total mortality (0.80; 0.69 to 0.93). With this treatment five and
23 patients would need to be treated to prevent one infection and one death,
respectively. Similar analysis of 17 trials (2366 patients) that tested only
topical antibiotics indicated a clear reduction in infection (0.56; 0.46 to 0.68)
without a significant effect on total mortality (1.01; 0.84 to 1.22). Analysis of
data from individual patients yielded similar results. No significant differences
in treatment effect by major subgroups of patients emerged from the analyses.
CONCLUSIONS: This meta-analysis of 15 years of clinical research suggests that
antibiotic prophylaxis with a combination of topical and systemic drugs can
reduce respiratory tract infections and overall mortality in critically ill
patients. This effect is significant and worth while, and it should be considered
when practice guidelines are defined.
PMID- 9554899
TI - Identifying asthma and chronic obstructive pulmonary disease in patients with
persistent cough presenting to general practitioners: descriptive study.
AB - OBJECTIVE: To determine the prevalence of asthma and chronic obstructive
pulmonary disease in patients not known to have these disorders, who present in
general practice with persistent cough, and to ascertain criteria to help general
practitioners in diagnosis. DESIGN: Descriptive study. SETTING: Primary
healthcare centre in the Netherlands. SUBJECTS: 192 patients aged 18-75 years,
not known to have asthma or chronic obstructive pulmonary disease, attending
their general practitioner with cough persisting for at least 2 weeks. : A
diagnosis of asthma or chronic obstructive pulmonary disease was based on the
recurrence of airway symptoms in the past year accompanied by spirometric
measurements (including bronchodilator testing) and methacholine provocation
tests. A scoring formula to estimate the probability of asthma or chronic
obstructive pulmonary disease, based on history and physical examination, was
generated by means of logistic regression. RESULTS: 74 patients (39%) were
classified as having asthma, 14 (7%) as having chronic obstructive pulmonary
disease. The best formula for predicting asthma or chronic obstructive pulmonary
disease used scores for three symptoms: (reported) wheeze, (reported) dyspnoea,
and allergen induced symptoms, together with prolonged expiration, pack years of
smoking, and female sex. Variables were scored 1 when present and 0 when absent,
except for allergen induced symptoms (1.5) and number of pack years of smoking
(n/25). With a cut off value of 3 on the scoring formula, 76% of the patients
could be classified correctly. CONCLUSIONS: About half of patients with
persistent cough who present to a general practitioner have asthma or chronic
obstructive pulmonary disease. With a simple formula based on three symptoms and
prolonged expiration, pack years of smoking, and female sex, most patients may be
identified correctly in general practice.
PMID- 9554901
TI - Rethinking NHS networking.
PMID- 9554903
TI - Food allergy.
PMID- 9554902
TI - Adverse drug reactions.
PMID- 9554905
TI - Truth drug
PMID- 9554906
TI - Development and importance of health needs assessment.
PMID- 9554907
TI - The dying adult.
PMID- 9554908
TI - How should different life expectancies be valued?
PMID- 9554904
TI - North of England evidence based guideline development project: guideline on the
use of aspirin as secondary prophylaxis for vascular disease in primary care.
North of England Aspirin Guideline Development Group.
PMID- 9554909
TI - Carers of patients receiving palliative care. Social workers bring specialist
skills to care of carers.
PMID- 9554910
TI - New combined hepatitis A and B vaccine. Risks Of viral hepatitis related to
travel.
PMID- 9554911
TI - Topical treatment of erectile dysfunction did not show results.
PMID- 9554912
TI - Authors defend their study to develop tool to predict falls in elderly people.
PMID- 9554913
TI - Deaths related to intrapartum asphyxia. Audit In one unit found neonatal care to
be suboptimal at weekends.
PMID- 9554914
TI - Second study shows that octreotide may prevent early rebleeding in cirrhosis.
PMID- 9554915
TI - New government, same narrow vision. How hospitals manage emergency admissions
needs to be examined.
PMID- 9554916
TI - Ways of assessing capacity to complete an advance directive should be developed.
PMID- 9554917
TI - All troops sent to gulf should be randomised to receive anthrax vaccination or
placebo.
PMID- 9554918
TI - Doctors should beware of asking for too high a salary. Scottish GPs earn less
than intended average net remuneration.
PMID- 9554919
TI - Britain needs 1000 more GPs
PMID- 9554920
TI - What rough beast?
PMID- 9554921
TI - Last on the list
PMID- 9554923
TI - Early discharge after surgery for breast cancer may be beneficial
PMID- 9554922
TI - Trust me, I'm a wreck doctors at large, an 11 part series on BBC2, looks at how a
group of doctors have fared 14 years on from their acceptance at medical school.
David fitzmaurice says future medics should be forced to watch the series in one
sitting
PMID- 9554924
TI - Peanut allergy may resolve in some young children
PMID- 9554925
TI - Antibiotic prophylaxis in critically ill patients is clinically effective
PMID- 9554926
TI - Scoring system identifies asthma in patients with persistent cough
PMID- 9554927
TI - NHS networking needs a new approach
PMID- 9554928
TI - Evidence for aspirin as secondary prophylaxis for vascular disease is strong
PMID- 9554929
TI - Prognostic significance of pathological response of primary tumor and metastatic
axillary lymph nodes after neoadjuvant chemotherapy for locally advanced breast
carcinoma.
AB - PURPOSE: The prognostic significance of pathological response of primary tumor
and metastatic axillary lymph nodes after neoadjuvant chemotherapy was assessed
in patients with noninflammatory locally advanced breast carcinoma. PATIENTS AND
METHODS: Between January 1989 and April 1995, 148 consecutive patients with
locally advanced breast carcinoma participated in the study. Of these, 140 fully
evaluable patients (67, stage IIIA; 73, stage IIIB) were treated with three
courses of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC), followed by
modified radical mastectomy when technically feasible or definitive radiation
therapy. The median age was 53 years (range, 26 to 75 years); 55% of patients
were postmenopausal. RESULTS: Objective response was recorded in 99 of 140
patients (71%; 95% confidence interval, 63% to 79%). Complete response occurred
in 11 patients (8%), and partial response occurred in 88 patients (63%). No
change was recorded in 37 patients (26%), and progressive disease occurred in 4
patients (3%). One hundred and thirty-six patients underwent the planned surgery.
Maximal pathological response of the primary tumor (in situ carcinoma or minimal
microscopic residual tumor) was observed in 24 (18%); 112 patients (82%)
presented minimal pathological response of the primary tumor (gross residual
tumor). The number of metastatic axillary nodes after neoadjuvant chemotherapy
was as follows: N0, 39 patients (29%); N1-N3, 35 patients (26%); > N3, 62
patients (45%). Considering the initial TNM status, 75% of the patients had
decreases in tumor compartment after neoadjuvant chemotherapy. Also, 31% and 23%
of patients with clinical N1 and N2, respectively, showed uninvolved axillary
lymph nodes. A significant correlation was noted between pathological response of
primary tumor and the number of metastatic axillary lymph nodes. Median disease
free survival was 34 months, whereas median overall survival was 66 months.
Pathological responses of both primary tumor and metastatic axillary lymph nodes
were strongly correlated with disease-free survival and overall survival in
univariate analyses. Additionally, in a proportional hazard regression model and
in an accelerated failure time model, metastatic axillary lymph nodes
significantly influenced both disease-free survival and overall survival, whereas
pathological response of primary tumor did so on disease-free survival only.
CONCLUSION: After neoadjuvant chemotherapy, pathological responses of both
primary tumor and metastatic axillary lymph nodes had a marked prognostic
significance and influenced outcome for patients with locally advanced breast
carcinoma. Our results suggest that maximal tumor shrinkage and sterilization of
potentially involved axillary nodes may represent a major goal of neoadjuvant
chemotherapy. Further studies are warranted to clarify whether these results
reflect the therapeutic effect or intrinsic biologic factors of the tumor.
PMID- 9554930
TI - The generation of proton electrochemical potential gradient by cytochrome c
oxidase.
AB - Cytochrome c oxidase, the terminal oxidase of mitochondria and some bacteria,
catalyzes the four electron reduction of oxygen, and generates a proton
electrochemical potential gradient (Delta microH). The recently determined
structures of the bacterial and the bovine enzymes, together with studies of site
directed mutants of a bacterial cytochrome c oxidase and a closely related
ubiquinol oxidase, have greatly advanced our understanding of the mechanism by
which oxygen reduction is coupled to the generation of Delta microH. Two
different mechanisms contribute to the generation of Delta microH: protons that
are consumed by the reduction of oxygen, are taken exclusively from the
mitochondrial matrix ('consumed' protons), while other protons are translocated
by the enzyme across the membrane ('pumped' protons). It is suggested that both
proton consumption and proton pumping are driven by the electrostatic charging of
the enzyme reaction center by the reducing electrons. Proton consumption is
suggested to result from the electrostatically driven ejection of hydroxyls into
the matrix that is catalyzed by a tyrosine residue in the reaction center. Proton
pumping is suggested to result from the electrostatically driven translocation of
a glutamate residue near the reaction center, and is assisted by secondary
acceptors that release the translocated protons.
PMID- 9554931
TI - Transient changes of electrical activity in the rat barrel cortex during
conditioning.
AB - To reveal the dynamics of neurophysiological changes in the rat barrel cortex
induced by conditioned stimulation we recorded the local micro
electroencephalographic (EEG) activity and evoked potentials (EPs) in barrel
cortex to stimulation of a single vibrissa before and after pairing it with a
mild electric shock applied to the rat's tail. Following the introduction of the
reinforcing stimulus, the amplitude of the first negative component of evoked
potentials in the cortex on the conditioned side grew in relation to the same
component of control potentials, evoked by stimulation of the opposite
symmetrical vibrissa. This change was accompanied by a latent decrease in
spectral power of the EEG within the alpha and beta frequency bands in both
hemispheres. The observed changes in both of these electrical manifestations of
enhanced neuronal activity reverted after two (EP) or three (EEG) days of
conditioning. These results are discussed in relation to the putative activity of
neuromodulatory systems.
PMID- 9554932
TI - Short-term and complete reversal of NGF effects in rats with lesions of the
nucleus basalis magnocellularis.
AB - Rats received bilateral quisqualic acid lesions of the nucleus basalis
magnocellularis. Three weeks after lesioning, osmotic minipumps were implanted
that released recombinant human nerve growth factor or cytochrome c at a dosage
of 5.0 microg rat-1 day-1 through intracerebroventricular cannulas for 7 weeks.
One quarter of the rats were sacrificed at the end of the treatment, while the
rest of the animals were sacrificed 2, 8, and 12 weeks after termination of
NGF/cc treatment. ICV administration of nerve growth factor (NGF) transiently
reduced weight gain. NGF maximally increased choline acetyltransferase activity
in all cortical regions, the olfactory bulb and the hippocampus between 20% and
56% at the end of the treatment. This increase linearly declined and completely
regressed during the 12-week withdrawal period both in regions affected and
unaffected by the lesion. Administration of NGF induced a short-lasting
hypertrophy of low affinity NGF receptor immunoreactive neurons within the
nucleus basalis magnocellularis (NBM), the horizontal limb of the diagonal band
of Broca, and the medial septum. In contrast, QUIS-induced NBM lesions
permanently reduced ChAT activity most pronounced in the frontal and parietal
cortex up to 45%. Furthermore, QUIS induced a permanent loss of p75NGFr
immunoreactive neurons within the NBM and the DB without affecting the MS. These
findings suggest that degenerating cholinergic neurons of the NBM and HDB do not
spontaneously recover after lesioning and may require continuous neurotrophic
support by NGF to ameliorate cholinergic hypofunctioning.
PMID- 9554933
TI - POU domain genes are differentially expressed in the early stages after lineage
commitment of the PNS-derived stem cell line, RT4-AC.
AB - RT4 is a family of cell lines derived from a rat peripheral neurotumor and
consists of a multipotential stem cell which spontaneously gives rise to a glial
derivative and two neuronal derivatives. To begin to understand the role(s) of
transcription factors in neural differentiation, we examined the expression of
ten transcription factor genes (MASH1, REST/NRSF, Oct-1, Oct-2, Tst-1/SCIP, Brn
1, Brn-2, Brn-3.0, Brn-4, Brn-5) in the RT4 cell lines. We report here that all
of the RT4 cells express REST/NRSF, Oct-1 and Brn-5, but do not express MASH1,
Brn-3.0 or Brn-4. Furthermore, Brn-2 and Tst-1/SCIP expression was restricted to
the RT4 stem cell line and glial derivative, while Oct-2 was expressed
predominantly by the RT4 stem cell line and neuronal derivatives. We propose that
the lack of expression of MASH1 (which is expressed relatively early in autonomic
neuron differentiation) and Brn-3.0 (which is expressed early in sensory neuron
differentiation), in combination with the presence of REST/NRSF (a repressor of
neuronal gene expression), in all of the RT4 cell lines, establishes the RT4
system as a unique model for examining very early events in neuronal versus glial
cell fate determination.
PMID- 9554934
TI - A role for brain glucocorticoid receptors in contextual fear conditioning:
dependence upon training intensity.
AB - We studied the possible involvement of corticosteroids in the establishment and
long-term expression of contextual fear conditioning and questioned whether a
corticosteroid action might be dependent upon stimulus intensity at training.
Experiments included: (i) the intracerebroventricular administration of specific
antagonists for the two types of intracellular corticosteroid receptors to rats
trained at either 1 mA or 0.4 mA shock intensity at conditioning; and (ii) the
administration of corticosterone after conditioning rats to 0.2 mA shocks. The
results showed that the administration of a type II glucocorticoid, but not a
type I mineralocorticoid, receptor antagonist before conditioning rats to the
intermediate shock condition attenuated long-term expression of contextual fear
conditioning. However, treatment with the antagonists before conditioning to the
high shock intensity failed to influence the extent of fear conditioning. In
addition, an intraperitoneal corticosterone injection, given immediately after
training rats at the low shock intensity, enhanced long-term expression of the
fear response. The results support the view that post-training levels of
circulating corticosterone, through an interaction with central type II
glucocorticoid receptors, modulate the strength to which memory for contextual
fear conditioning is established and maintained.
PMID- 9554935
TI - Distribution of somatostatin-like immunoreactivity in the brain of the frog, Rana
esculenta, during development.
AB - The anatomical distribution of somatostatin-like immunoreactivity in the central
nervous system of the frog, Rana esculenta, during development and in juvenile
specimens was investigated by indirect immunofluorescence. Soon after hatching,
at stages II-III, somatostatin-like immunoreactive structures were found in the
preoptic-median eminence complex. In stage VI tadpoles, new groups of
immunopositive perikarya and nerve fibers appeared in the diencephalon, within
the ventral infundibular nucleus and in the ventral area of the thalamus, as well
as in the medial pallium. In stages XII-XIV of development, immunopositive
perikarya were also present in the dorsal infundibular nucleus of the
hypothalamus and ventrolateral area of the thalamus. A small group of
somatostatin-like immunoreactive neurons appeared in the posteroventral nucleus
of the rhombencephalon. However, these neurons were not seen in later stages of
development. Tadpoles in stages XVIII, XXI-XXII and in juveniles were
characterized by a wider distribution of immunoreactive cell bodies and fibers in
the pallium. New groups of immunoreactive neurons were found in the dorsal and
lateral pallium. The presence of positive perikarya in the lateral pallium is a
transient expression found only in these stages. The organization of the
somatostatinergic system was most complex during the metamorphic climax, with the
appearance of positive cell bodies in the posterocentralis area of the thalamus,
and in juvenile animals with the presence of perikarya in the ventral part of the
medial pallium and within the central grey rhombencephali. In contrast to the
adult frog, somatostatin neurons were not observed in the mesencephalon of
tadpoles and juveniles.
PMID- 9554936
TI - Tactile hyperesthesia, altered epidermal innervation and plantar nerve injury in
the hindfeet of rats housed on wire grates.
AB - The effects of wire grates on nerve injury and recovery were examined in rats
housed in cages with sawdust-covered solid flooring. For the first 3 weeks of the
study, 20 rats were housed on sawdust alone and 20 rats were housed in cages with
wire grates placed over the sawdust. For the remaining 9 weeks, 10 animals housed
on sawdust had wire grates added to their cages, while grates were removed from
the cages of 10 animals. The effects of tactile stimulation on hindpaw plantar
skin was measured weekly using the Von Frey filament test. Intraepidermal
innervation using PGP 9.5 immunostaining and plantar nerve histology were
assessed at the end of the 12-week study. After just 1 week on grates, hindpaw
withdrawal thresholds were already markedly decreased and remained low until the
grates were removed at 3 weeks. Thresholds returned to normal by 4 weeks after
removal of the grates. Wire grates also induced increases in PGP 9.5
immunoreactive intraepidermal fine nerve endings that were normalized after grate
removal. Demyelination, Wallerian degeneration and Renaut bodies were induced in
the medial plantar nerve in rats housed in cages with wire-grate flooring. Nerve
injury was largely resolved after 9 weeks on sawdust flooring. These data
demonstrate that wire grates rapidly induce hindpaw tactile hyperesthesia and
plantar neuropathy in rats and emphasize a risk of using wire-grate cage flooring
in studies assessing hindlimb function and structure.
PMID- 9554937
TI - Photosynthetic rhizobia
PMID- 9554938
TI - Pitch vs. spectral encoding of harmonic complex tones in primary auditory cortex
of the awake monkey.
AB - Neuromagnetic studies in humans and single-unit studies in monkeys have provided
conflicting views regarding the role of primary auditory cortex (A1) in pitch
encoding. While the former support a topographic organization based on the pitch
of complex tones, single-unit studies support the classical tonotopic
organization of A1 defined by the spectral composition of the stimulus. It is
unclear whether the incongruity of these findings is due to limitations of
noninvasive recordings or whether the discrepancy genuinely reflects pitch
representation based on population encoding. To bridge these experimental
approaches, we examined neuronal ensemble responses in A1 of the awake monkey
using auditory evoked potential (AEP), multiple-unit activity (MUA) and current
source density (CSD) techniques. Macaque monkeys can perceive the missing
fundamental of harmonic complex tones and therefore serve as suitable animal
models for studying neural encoding of pitch. Pure tones and harmonic complex
tones missing the fundamental frequency (f0) were presented at 60 dB SPL to the
ear contralateral to the hemisphere from which recordings were obtained. Laminar
response profiles in A1 reflected the spectral content rather than the pitch
(missing f0) of the compound stimuli. These findings are consistent with single
unit data and indicate that the cochleotopic organization is preserved at the
level of A1. Thus, it appears that pitch encoding of multi-component sounds is
more complex than suggested by noninvasive studies, which are based on the
assumption of a single dipole generator within the superior temporal gyrus. These
results support a pattern recognition mechanism of pitch encoding based on a
topographic representation of stimulus spectral composition at the level of A1.
PMID- 9554939
TI - Antagonism of peripheral 5-HT4 receptors reduces visceral and cutaneous pain in
mice, and induces visceral analgesia after simultaneous inactivation of 5-HT3
receptors.
AB - The role of 5-HT4 receptors on cutaneous and visceral pain remains largely
unexplored. The objective of this study was to establish the activity profile of
SDZ 205-557, a 5-HT4 antagonist, on cutaneous (hotplate) and visceral (writhing)
models of pain, after peripheral administration. Since SDZ 205-557 possesses some
affinity for 5-HT3 receptors at high doses, nociceptive effects of a 1:1
combination of SDZ 205-557 and MDL 72222, a 5-HT3 antagonist, were also
evaluated. Drugs were injected 30 min before tests (0, 0.001, 0.01, 0.1 or 1
mg/kg IP). A hypoalgesic effect of SDZ 205-557 on cutaneous pain was found at 0.1
and 1 mg/kg doses, as revealed through an enhanced nociceptive threshold in rats
placed on the hotplate. This effect was likely mediated through inactivation of
peripheral 5-HT4 receptors. After the 1:1 combination, the hypoalgesic effect
disappeared, which indicates that simultaneous inactivation of 5-HT3 and 5-HT4
receptors antagonized peripherally 5-HT4-mediated hypoalgesia by an unknown
mechanism. SDZ 205-557 also induced hypoalgesia in the writhing test over the
entire dose range tested, and visceral hypoalgesia turned out to be analgesia
after 1:1 combination. In summary, findings of the present study imply that: i)
antagonism of 5-HT4 receptors mediates antinociception in enteric viscera and, to
a lesser extent, in cutaneous terminals, and ii) dual inactivation of both 5-HT4
and 5-HT3 receptors induces visceral analgesia, a fact which might have clinical
importance.
PMID- 9554940
TI - Onset of optic nerve conduction and synaptic potentials in superior colliculus of
fetal rats studied in vitro.
AB - This article describes the onset of electrical excitability and synaptic
transmission in the retinocollicular pathway of the fetal and early postnatal
rat, utilizing a novel in vitro preparation. Although the optic nerve is visible
in embryonic day (E) 14 brain, its stimulation produced no response in the
superior colliculus (SC) until E16 when a low voltage simple negative wave was
evoked. At E17 these potentials were blocked rapidly, completely, and reversibly
when choline was substituted for sodium or with the addition of cobalt ions. In
the course of establishing the block with either of the above agents the latency
of response increased, indicating an action on axonal transmission. By E20 the
collicular evoked potential showed a short followed by a longer latency wave. The
latter was blocked by the glutamate antagonist kynurenic acid, with latency
unaffected. Further examination of potentials with the addition of glutamatergic
receptor subtype blockers aminophosphonopentanoic acid (APV) and 6-cyano-7
nitroquinoxaline-2,3-dione/6,7-dinitroquinoxaline- 2,3-dione (CNQX/DNQX) showed a
clear abolition of the elicited potentials by E20 and older. Thus, fetal rat
optic nerve fibers are capable of conduction in response to electrical
stimulation as soon as they reach the SC at E16. Both sodium and calcium are
involved. GABA-mediated modulation of axonal conduction is evident by E18.
Glutaminergic synaptic transmission is established by E20. The timetable of fetal
onset of capability to conduct and support synaptic transmission in the
retinocollicular pathway is earlier than had previously been reported in vivo in
the rat in which the superior colliculus neurones are said not to be driven by
the optic nerve until 6 days post natal. This has relevance to the possible role
of impulse activity in development of the pathway.
PMID- 9554941
TI - Neutrophil inhibitory factor treatment of focal cerebral ischemia in the rat.
AB - The present study was designed to determine whether a hookworm-derived
recombinant neutrophil inhibitory factor (rNIF) is neuroprotective when
administered after initiation of focal cerebral ischemia in the rat. We measured
the rNIF dose-response on cerebral infarct volume, the therapeutic time window,
the therapeutic response to permanent ischemia, and whether rNIF treatment delays
the maturation of the ischemic lesion (2 days), or reduces cerebral infarct
volume at 7 days after middle cerebral artery occlusion (MCAO). MCAO was induced
by an insertion of intraluminal 4-0 monofilament nylon suture into internal
carotid artery (n=195). We demonstrate a significant neuroprotective effect of
rNIF administration 48 h after MCAO in a dose-dependent fashion when treatment
was initiated upon reperfusion after 2 h MCAO and maintained until 48 h after
MCAO. The beneficial effect was lost under conditions of permanent MCAO. The
therapeutic time window is 4 h after MCAO. Brief treatment (6 h) is not
sufficient to provide protection for the final ischemic damage. Continuous
treatment with a high dose of rNIF for a long duration (7 days) is necessary to
achieve maximum neuroprotection.
PMID- 9554943
TI - A re-estimation of the number of glomeruli and mitral cells in the olfactory bulb
of rabbit.
AB - Although morphological characteristics of mammalian olfactory bulb (OB) are well
documented in rodents (rat, mice), only one study has been performed in rabbit,
which is also commonly used in olfactory research. The study carried out by
Allison and Warwick in 1949 led to surprising results still quoted in recent
literature. The present study re-examined this question in young rabbit OB, while
it was also conducted with rat as control. In five animals of each species, areas
and coordinates of glomeruli and mitral profiles were measured in 10 coronal
sections uniformly distributed along the rostrocaudal axis of the OB, and a
distribution-free stereological method was used to compute values along this
axis. For glomeruli, the estimated number was 4200 in rat and 6300 in rabbit.
While this estimation matched with those found in literature in rat, it
strikingly differed from the Allison and Warwick's value of 1900 only. For mitral
cell number, we found 59,600 while the preceding study found 45,000 only. In
contrast to the number of glomeruli, the mitral cell number in rat and rabbit
were very close. Indeed, results showed 56, 200 in rat. The results suggest that
the numbers of olfactory glomeruli and mitral cells has been previously
underestimated in rabbit, and that the number of glomeruli changes as a function
of species. In addition, both the results of the present study and reports in the
literature suggest the number of mitral cells to be rather similar in mouse, rat
and rabbit. As a consequence, the glomerular/mitral cell ratio is likely to
varied in a wide range across species.
PMID- 9554942
TI - Behavioral inhibition of light-induced circadian phase resetting is phase and
serotonin dependent.
AB - Circadian rhythms in Syrian hamsters can be phase shifted by light exposure
during the subjective night and by a bout of wheel running induced during the
subjective day. Interactions between photic and behavioral stimuli were examined
by comparing phase shifts to 15 min, 50 lux light pulses with and without a bout
of running induced by confinement to a novel wheel 30 min prior to and extending
through light exposure. Light pulses 6 h after dark onset on the first night of
constant dark induced phase advance shifts averaging 80 min. Wheel running
attenuated these shifts by 45% on average (p<0.01). Light pulses 1 h or 2.25 h
after dark onset induced phase delay shifts averaging 50 min and 20 min,
respectively, that were not affected by stimulated running. A significant running
response to the novel wheel was evident at all 3 time points, but was greater to
wheel confinement at both times early in the night. Stimulated running alone
early or late in the night did not produce significant phase shifts. Behavioral
attenuation of phase advances to light late in the night was prevented by
pretreatment with the general 5HT1 antagonist metergoline (2 mg/kg i.p.).
Metergoline did not significantly attenuate running in novel wheels. These
results indicate that modulation of light-induced phase shifts by behavior is
phase dependent and may involve direct or indirect actions of serotonin within
the circadian system.
PMID- 9554944
TI - Roles of the bradyrhizobium japonicum terminal oxidase complexes in microaerobic
H2-dependent growth
AB - Spectral, inhibitor, and O2-consumption studies on membranes from free-living and
bacteroid forms of Bradyrhizobium japonicum have revealed the existence of a
number of terminal oxidases, and four terminal oxidase gene clusters within the
heme-copper cytochrome family have been cloned. Here the complexes encoded by
coxMNOP and coxWXYZ, genes with homology to CuA-containing cytochrome c oxidases
and b-type ubiquinol oxidases respectively, are studied by analysis of mutants in
each of the two oxidases and a double mutant in both of the terminal oxidase
genes. Membranes from microaerobically incubated strain JHK12 (which contains an
insertion in coxWXYZ) were deficient in levels of CO-reactive heme b, and both
strains JHK12 and Bj3430 (the latter lacks coxMNOP) were deficient in CN-
reactive cytochrome b. Membranes of the double mutant (strain JHKS4) retained
less than 7% of the cytochrome b3 and 25% of the total CN--reactive cytochrome b
of the wild type. Cyanide inhibition curves of oxygen uptake by wild-type
membranes were triphasic, and only the phases inhibited by the highest (at about
50 &mgr;M CN-, attributed to cytochrome aa3) and the lowest (at approximately 0.1
&mgr;M) CN- were identifiable in the membranes from the two individual oxidase
mutants. Membrane respiratory activity of the double mutant was resistant to CN-
over a broad inhibitor concentration in the micromolar range. Consistent with our
findings that these oxidases are expressed when cells are incubated in a low O2
environment, the double mutant was severely deficient in H2-dependent
chemolithotrophic growth. The latter growth condition requires prolonged
incubation in an atmosphere of H2, CO2, and a low (1% or less) partial pressure
of oxygen. The double mutant was also deficient in whole cell O2 dependent H2
oxidation, with H2 uptake rates 31% of the wild type. Copyright 1998 Elsevier
Science B.V.
PMID- 9554945
TI - Conditioned release of corticosterone by contextual stimuli associated with
cocaine is mediated by corticotropin-releasing factor.
AB - Elevated blood concentrations of corticosterone (CORT), an adrenal steroid
associated with stress responses, is one of the endocrine correlates of cocaine
treatment. Experiment 1 confirmed and extended previous findings that chronic
cocaine treatment does not alter corticosteroid responses to cocaine. In
Experiment 2, conditioned endocrine effects of cocaine were examined in three
groups of rats after 7 consecutive days of treatment. Cocaine-induced
conditioning was achieved using a simple contextual design. In group 1 (paired),
rats were injected with cocaine (30 mg/kg), then immediately placed into a
locomotor activity chamber for 30 min. One hour after the rats were returned to
their home cages, they received an injection of saline. In group 2 (unpaired),
rats were injected with saline, then immediately placed into a locomotor activity
chamber for 30 min. One hour after the rats were returned to their home cages,
they received an injection of cocaine (30 mg/kg). Rats in group 3 (control)
received only saline injections, but otherwise were treated as animals in the
other treatment groups. On the test day (Day 8), all rats were placed immediately
into the locomotor apparatus for 30 min prior to collection of a blood sample.
Blood CORT concentrations and locomotor activity in the paired group were
significantly higher than in the unpaired and control groups. However,
pretreatment of the rats in Experiment 3 with the corticotropin-releasing factor
(CRF) antagonist, alpha-helical CRF9-41 (1 microg, i.c.v.), on the test day,
prior to exposure to cocaine-associated contextual cues, attenuated the
subsequent conditioned increase in blood CORT concentrations. These data
represent the first demonstration of classical conditioning of a steroid hormone
response to stimuli associated with a psychoactive drug in rats and suggest that
the effect is mediated by endogenous CRF. Because the hypothalamic-pituitary
adrenal (HPA) axis has been implicated in modulating the actions of cocaine, it
is plausible that such conditioned increases in CORT release by cocaine
associated cues may further predispose an organism to the reinforcing effects of
the drug or enhance the susceptibility to drug-taking behavior. Alternatively,
such conditioned effects may be related to the anxiogenic properties of cocaine.
Further understanding of the conditioned effects of hormones in the development
and expression of addictive behaviors may provide new insights into treatment of
drug addiction.
PMID- 9554946
TI - Hippocampal nitric oxide synthase in the fetal guinea pig: effects of chronic
prenatal ethanol exposure.
AB - The effects of chronic maternal administration of ethanol on nitric oxide
synthase (NOS) activity and the numbers of NOS containing neurons, and CA1 and
CA3 pyramidal neurons in the hippocampus of the near term fetal guinea pig at
gestational day (GD) 62 were investigated. Pregnant guinea pigs received oral
administration of 4 g ethanol/kg maternal body weight (n = 5), isocaloric
sucrose/pair feeding (n = 5) or water (n = 5), or no treatment (NT; n = 5) from
GD 2 to GD 61. NOS activity in the 25,000 x g supernatant of hippocampal
homogenate was determined using a radiometric assay. The numbers of NOS
containing neurons, and CA1 and CA3 pyramidal neurons were determined using NADPH
diaphorase histochemistry and cresyl violet staining, respectively. The chronic
ethanol regimen produced a maternal blood ethanol concentration of 193 +/- 13
mg/dl at 1 h after the second divided dose on GD 57. Chronic ethanol exposure
produced fetal body, brain, and hippocampal growth restriction and decreased
fetal hippocampal NOS activity compared with the isocaloric sucrose/pair feeding,
water, and NT experimental groups, but did not affect the number of NOS
containing and CA1 or CA3 pyramidal neurons. These data demonstrate that, in the
near term fetus, chronic maternal administration of ethanol suppresses
hippocampal NOS activity and consequent formation of NO, without loss of NOS
containing neurons and prior to loss of CA1 pyramidal neurons that occurs in the
adult.
PMID- 9554948
TI - Thermoluminescence measurements on chloride-depleted and calcium-depleted
photosystem II
AB - Photosystem II (PSII) in which O2 evolution was inhibited by depletion of either
chloride or calcium ions was studied by thermoluminescence (TL) and luminescence
(L) measurements in the presence and absence of 3-(3',4'-dichlorophenyl)-1,1
dimethyl urea (DCMU). Cl--depleted PSII gives rise to TL and L signals which are
similar to those in untreated controls i.e., DCMU shifts the TL band from 30
degreesC to 8 degreesC and suppresses the L component with t1/2=10-15 s. In Ca2+
depleted PSII a TL-band at around 50 degreesC and a slow luminescence decay
(t1/2=60 s) is observed. Under these conditions, DCMU does not lead to a
downshift of the peak temperature of the TL-band nor does it accelerate the decay
kinetics of the luminescence. This indicates that in Ca2+-depleted PSII the QA/QB
electron transfer is inhibited prior to the addition of DCMU while in Cl-
depleted PSII QA/QB electron transfer seems unaffected. These results are
consistent with previous fluorescence measurements which showed that the midpoint
potential of the redox couple QA/QA- is unchanged in Cl--depleted PSII compared
to the control while in Ca2+-depleted PSII it is shifted towards a more positive
value [A. Krieger, A.W. Rutherford, Biochim. Biophys. Acta, 1319 (1997) 91-98].
In the literature there are several conflicting reports concerning the TL in Ca2+
and Cl--depleted material so we attempted to understand the origin of some of
these discrepancies. We find that in the absence of cryoprotectants, excitation
of TL at low temperatures leads to an upshift of TL-bands in Cl--depleted PSII,
both in the presence and absence of DCMU, while the peak temperature of TL-bands
in control and Ca2+-depleted PSII are downshifted. When TL is excited at 20
degreesC or at low temperature in the presence of a cryoprotectant then there was
no shift of the peak temperature of TL-bands. These unexpected results suggest
that the formation of the charge pair triggers modifications in its environment
and that the exact nature of these modifications differs depending on the
temperature of excitation. It seems that once these modifications have occurred
at a given temperature they remain 'locked in' being unaffected by subsequent
temperature changes until charge recombination has occurred. Copyright 1998
Elsevier Science B.V.
PMID- 9554947
TI - Distribution of the endothelial constitutive nitric oxide synthase in the
developing rat brain: an immunohistochemical study.
AB - The present study deals with the distribution of endothelial constitutive nitric
oxide synthase (ecNOS) in the developing rat brain using optimized protocols for
preparation and fixation and the tyramide-signal-amplification technique. The
immunostaining patterns of a monoclonal antibody against ecNOS are compared with
results obtained with a rat pan-endothelial marker, the monoclonal RECA-1
antibody. It is shown that ecNOS is present in the endothelial lining of all
types of blood vessels and the choroid plexuses of the rat brain from the
beginning of vasculogenesis at embryonic day 11 until adulthood (75 weeks). The
same is true for RECA-1 immunoreactivity, that was demonstrated in the
developmental brain vasculature for the first time. Both antigens expressed
identical immunostaining patterns. At all investigated stages of brain
development neither ecNOS negative blood vessels nor ecNOS positive non
endothelial cells, e.g., neurons, were found. The data indicate that ecNOS is
involved in the embryonic angiogenesis and the regulation of hemodynamic
functions of brain vasculature throughout the individual life.
PMID- 9554949
TI - Selective activation of carotid nerve fibers by acetylcholine applied to the cat
petrosal ganglion in vitro.
AB - The petrosal ganglion innervates carotid body chemoreceptors through the carotid
(sinus) nerve. These primary sensory neurons are activated by transmitters
released from receptor (glomus) cells, acetylcholine (ACh) having been proposed
as one of the transmitters involved in this process. Since the perikarya of
primary sensory neurons share several properties with peripheral sensory endings,
we studied the electrical responses of the carotid nerve and glossopharyngeal
branch to ACh locally applied to the cat petrosal ganglion superfused in vitro.
Ganglionar applications of AChCl (1 microg-1 mg) generated bursts of action
potentials conducted along the carotid nerve, while only a few spikes were
exceptionally recorded from the glossopharyngeal branch in response to the
largest doses. Carotid nerve responses to ACh were dose-dependent, the higher
doses inducing transient desensitization. Application of nicotine to the petrosal
ganglion also evoked dose-dependent excitatory responses in the carotid nerve.
Responses to ACh were reversibly antagonized by adding hexamethonium to the
superfusate, more intense and prolonged block of ACh responses being produced by
mecamylamine. Ganglionar applications of gamma-amino butyric acid and serotonin,
in doses of up to 5 mg, did not induce firing of action potentials in any of the
branches of the glossopharyngeal nerve. Our results indicate that petrosal
ganglion neurons projecting through the carotid nerve are selectively activated
by ACh acting on nicotinic ACh receptors located in the somata of these neurons.
Thus, cholinosensitivity would be shared by the membranes of peripheral endings
and perikarya of primary sensory neurons involved in arterial chemoreception.
PMID- 9554950
TI - Calcitonin gene-related peptide: distribution and effects on spontaneous rhythmic
activity in embryonic chick spinal cord.
AB - Immunohistochemical and in vitro electrophysiological techniques were utilized to
examine the distribution and possible role of calcitonin gene-related peptide
(CGRP) in the spinal cord of the developing chick. CGRP-like immunoreactivity
first appeared in the lateral motor column of the lumbosacral spinal cord at
embryonic day 6 followed by the emergence of fiber immunoreactivity in the dorsal
horn at embryonic day 11. A rostrocaudal survey of the cervical to lumbosacral
spinal cord in embryonic day 18 chick demonstrated robust CGRP-like
immunoreactivity at all levels in both putative motor neurons and dorsal horn
fibers. Additionally, small immunoreactive lamina VII neurons were observed in
sections of lumbosacral cord. In the embryonic day 10 (E10) in vitro reduced
spinal cord preparation, bath application of the calcitonin gene-related peptide
antagonist human alpha-CGRP fragment 8-37 decreased the frequency and increased
the duration of episodes of spontaneously occurring rhythmic activity.
Conversely, application of alpha or beta forms of calcitonin gene-related peptide
increased the frequency of the rhythmic episodes. The electrophysiological
results suggest there is a constitutive release of calcitonin gene-related
peptide contributing to the spontaneous rhythmic activity. Immunohistochemical
results from E10 animals suggest that CGRP-like immunoreactive putative
motoneurons may be the source of the released CGRP.
PMID- 9554951
TI - Selective chemokine mRNA expression following brain injury.
AB - Injury in non-neuronal tissues stimulates chemokine expression leading to
recruitment of inflammatory cells responsible for orchestration of repair
processes. The signals involved in directing repair of damage to the brain are
less well understood. We hypothesized that following brain injury, chemokines are
expressed and regulate the rate and pattern of inflammatory cell accumulation.
The two chemokine subfamilies are alpha(alpha)-chemokines, which primarily
function as neutrophil chemoattractants, and the beta(beta)-chemokines, which
function primarily as monocyte chemoattractants. We assessed alpha and beta
chemokine mRNA expression patterns and leukocyte accumulation following a
cerebral cortical lesion. Cortical lesions were produced with and without
addition of endotoxin, Escherichia coli lipopolysaccharide (LPS), which
stimulates cytokine expression. We studied the expression of the beta-chemokines:
monocyte chemoattractant protein (gene product JE; MCP-1/JE), macrophage
inflammatory protein-1 alpha and beta (MIP-1alpha and MIP-1beta), and the
regulated upon activation normal T expressed and secreted chemokine (RANTES) as
well as the alpha-chemokines: interferon-gamma-inducible protein (IP-10) and
N51/KC (KC; a murine homologue of MIP-2). Changes in gene expression were
analyzed by Northern analysis at different time points following injury.
Leukocyte and macrophage densities were analyzed by immunohistochemistry at the
same time intervals. All chemokines were elevated following cortical
injury/endotoxin. MCP-1 and MIP-1alpha were elevated at 2 h and peaked 6 h, MIP
1beta peaked at 6 h, but declined more rapidly than MCP-1 or MIP-1alpha, and IP
10 peaked at 6 h and showed the most rapid decline. KC was elevated at 1 h, and
peaked at 6 h following LPS. RANTES was elevated at 1 h and achieved a plateau
level between 6 and 18 h, then declined. In contrast, sterile injuries produced
in the absence of endotoxin only induced the mRNA of the beta-chemokine MCP-1,
and its expression was delayed compared to the cortical injury/endotoxin group.
The presence of chemokine message as early as 1 h indicates that expression of
this class of molecules is an early response in the repair process following
traumatic brain injury. Macrophage/microglia accumulation occurred more rapidly,
activated microglia further from the lesion border, and more cells accumulated in
cortical injury/endotoxin than in cortical lesions produced under sterile
conditions. Thus, there was a positive correlation between beta-chemokine
expression and the number of beta-chemokine responsive cells (i.e. microglia)
accumulating in injury sites. This is the first comprehensive study using a panel
of chemokine probes and specific marcophage/microglial markers to study in vivo
activation of the brain following injury. Our data show that the brain is capable
of expression of multiple chemokine genes upon appropriate stimulation (e.g. LPS
treatment). The gradient of microglial activation is consistent with physical
damage stimulating release of chemokines that diffuse from the injury site. These
data strongly suggest that chemokines are instrumental in the initiation of
repair processes following brain injury.
PMID- 9554952
TI - High-voltage electroencephalogram spindles in rats, aging and 5-HT2 antagonism.
AB - We examined the effects of serotonin-2 (5-hydroxytryptamine-2, 5-HT2) receptor
antagonists on the so-called high-voltage spindles (HVS, electroencephalographic
patterns, characterized by large amplitude rhythmic waves mainly in the alpha
band), recorded from the frontal cortex of young, middle-aged and old freely
moving rats during waking immobility. The study was based on the assumption that
the effects of 5-HT2 receptor antagonists on the HVS activity depend on the age
of rats, because there is evidence for an age-related decrease in the 5-HT2
binding sites density. Four parameters of the electroencephalogram (EEG) were
used to characterize the HVS activity: the square root-transformed EEG peak power
in the alpha band, the frequency corresponding to this peak (both measured from
the EEG power spectra using the fast Fourier transform), the HVS mean duration,
and the HVS incidence (both measured from the EEG records). The EEG parameters
were analyzed after i.p. administration of three 5-HT2 receptor antagonists:
ketanserin, ritanserin and cyproheptadine. In young rats, the three drugs
increased the alpha power, but did not change the alpha peak-corresponding
frequency. Ketanserin and ritanserin did not change the HVS mean duration and HVS
incidence, while cyproheptadine increased both these parameters in young rats. In
middle-aged and old untreated rats, the HVS activity was significantly increased.
The three 5-HT2 antagonists did not change the HVS activity in aged rats, which
could be due to age-related suppression of the 5-HT2 receptor functions.
PMID- 9554953
TI - Angular dependence of electron paramagnetic resonances of an azide-NO complex of
cytochrome c oxidase: orientation of the haem-copper axis in cytochrome aa3 from
ox heart.
AB - The orientation dependence of the EPR signals arising from the azide-nitric oxide
complex of cytochrome oxidase was investigated using oriented multilayers of
mitochondrial membranes from ox heart. Variations in line shape of the DeltaMS=1
signal of the triplet state were apparent, whilst the DeltaMS=2 transitions
between g=4.7 and 3.9 varied in intensity as the angle of the applied magnetic
field was varied. These half-field signals were maximal with the field parallel
to the membrane plane. A model of the bi-liganded azide-nitric oxide complex has
been constructed, in which the nitric oxide is bound to the high-spin haem in a
bent configuration, with the Fe-N=O plane at 60-90 degrees to the membrane plane
and the azide bound to the copper, distal from the haem. In addition, angular
variations of the signals at g'=11 and g' around 3.5, derived from an integer
spin complex, were also observed.
PMID- 9554954
TI - Hypoxia-tolerant neonatal CA1 neurons: relationship of survival to evoked
glutamate release and glutamate receptor-mediated calcium changes in hippocampal
slices.
AB - Neurons in the neonatal mammalian brain survive greater degrees of hypoxic stress
than those in the mature brain. To investigate how developmental changes in
glutamate receptor-mediated neurotoxicity contribute to this difference, we
measured hypoxia-evoked glutamate release, glutamate receptor contribution to
hypoxia-evoked intracellular calcium changes, and survival of hypoxia-/ischemia
sensitive CA1 neurons in rat hippocampus. Glutamate release was measured by a
fluorescence assay, calcium changes in CA1 neurons with fura-2, and cell
viability using Nissl and fluorescence staining with calcein-AM/ethidium
homodimer, all in 300-micron thick hippocampal slices from 3-30 post-natal day
(PND) rats. Glutamate released from PND 3-7 slices during hypoxia (PO2 = 5 mmHg)
was only one third that of PND 18-22 slices. In PND 3-7 slices, survival of CA1
neurons after 5 min of hypoxia and 6 h of recovery was significantly greater than
in PND 18-22 slices (viability indices 0.60 and 0.28, respectively, (p < 0.05).
Five min of anoxia significantly altered Nissl staining pattern and morphology of
CA1 neurons in PND 18-22 but not PND 3-7 slices. Hypoxia (PO2 = 5 mm Hg) caused
three to five times greater increases in [Ca2+]i in PND 18-22 slices than in PND
3-7 slices (p < 0.001). During re-oxygenation, [Ca2+]i returned to baseline in
PND 3-7 slices, but remained elevated in PND 18-22 slices. Glutamate receptor
mediated calcium changes in CA1 during hypoxia were 33% and 62% of the total
calcium change in PND 3-7 and PND 18-22 CA1, respectively. We conclude that
survival of CA1 neurons in PND 3-7 slices following hypoxic stress is associated
with smaller increases and enhanced recovery of [Ca2+]i, less accumulation of
glutamate, and less glutamate receptor-mediated calcium influx than in PND 18-22
slices.
PMID- 9554955
TI - Age-related changes in auditory spatial properties of the guinea pig superior
colliculus.
AB - The map of auditory space located in the deep layers of the guinea pig superior
colliculus (SC) is a complex computational representation of the auditory azimuth
surrounding the animal. The map undergoes a protracted developmental profile
during the first postnatal month and remains plastic until well into adulthood.
However, there are no data concerning the state of the collicular auditory space
map in much older animals. Multi-unit responses to broadband noise stimuli
presented around the azimuthal plane under anechoic conditions were recorded from
the deep SC of guinea pigs of a variety of ages, up to 44 months. The data
obtained show that the map remains stable up to the age of approximately 36
months. However, after this age, the map shows rapid deterioration and at 42
months, multi-unit responses did not show features consistent with a normal map.
It appears that deficits accruing within the central auditory system with
increasing age, combine to overcome the ability of the mechanisms of plasticity
responsible for space map maintenance to keep pace with the changes, resulting in
degraded SC spatial tuning with increasing age.
PMID- 9554956
TI - The 9-kDa phosphoprotein of photosystem II. Generation and characterisation of
Chlamydomonas mutants lacking PSII-H and a site-directed mutant lacking the
phosphorylation site.
AB - The chloroplast gene psbH encodes a 9-10 kDa thylakoid membrane protein (PSII-H)
that is associated with photosystem II and is subject to light-dependent
phosphorylation at a threonine residue located on the stromal side of the
membrane. The function of PSII-H is not known, neither is it clear what
regulatory role phosphorylation may play in the control of PSII activity. Using
particle gun-mediated transformation, we have created chloroplast transformants
of Chlamydomonas reinhardtii in which the synthesis of PSII-H is prevented by the
disruption of psbH, or in which the phosphorylatable threonine is replaced by
alanine through site-directed mutagenesis of the gene. The mutants lacking PSII-H
have a photosystem II-deficient phenotype, with no detectable functioning PSII
complex present in whole cells or isolated thylakoid membranes. In contrast, the
alanine mutant (T3A) grows photoautotrophically, and PSII activity is comparable
to wild-type cells as determined by various biochemical and biophysical assays.
PMID- 9554957
TI - Selective loss of hippocampal long-term potentiation, but not depression,
following fluid percussion injury.
AB - We investigated the early effects of in vivo fluid percussion injury (FPI) on
hippocampal synaptic potentials and excitability. In vitro field potential
recordings and immunocytochemistry were performed in the CA1 region in slices
from naive, post-FPI, or sham-operated rats. The following electrophysiological
and morphological parameters were affected following FPI: (1) threshold for
population spike generation was increased suggesting that post-FPI neurons were
hypoexcitable; (2) long-term potentiation (LTP) could not be induced in injured
hippocampi; (3) GFAP and inducible NO synthase (iNOS) immunoreactivity were
enhanced post-FPI; and (4) following injury, synaptophysin immunoreactivity was
enhanced in CA1 stratum radiatum. The effects of FPI on synaptic plasticity were
LTP-specific, since long-term depression (LTD) could be equally induced and
maintained in post-FPI, sham-operated and control slices. Sham-operated slices
were characterized by synaptic excitability indistinguishable from naive
controls, but displayed decreased ability for LTP production and expressed high
levels of iNOS. We conclude that FPI causes a selective loss of LTP, possibly due
to a previous potentiation induced by trauma as reflected by the increased
expression of synaptic proteins. Sham surgical procedures were, however, not
without effects on long-term potentiation itself; the latter effects appear to be
mediated by an increased production of NO. Our study demonstrates for the first
time that hippocampal slices can be used to investigate the correlates of in vivo
FPI. Furthermore, we describe LTP-specific deficits in post-traumatic brain
injury, suggesting that FPI can selectively erase one of the two main NMDA
dependent forms of synaptic plasticity in the hippocampus.
PMID- 9554958
TI - 2'-Deoxyadenosine selectively kills nonneuronal cells without affecting survival
and growth of chick dorsal root ganglion neurons.
AB - Recently, we have demonstrated that adenosine and 2'-deoxyadenosine are toxic to
embryonic sympathetic neurons and proposed that purine and pyrimidine metabolism
may play a critical role in the growth and development of sympathetic neurons. To
extend this hypothesis further, we examined the effects of these nucleosides on
two other neuronal populations in the chick embryo, sensory dorsal root ganglion
neurons and parasympathetic ciliary ganglion neurons. Now, we show that 2'
deoxyadenosine and adenosine have no visible adverse effect on the viability of
either sensory or parasympathetic neurons. Instead, 2'-deoxyadenosine proved to
be highly toxic to the nonneuronal cells. The toxic effects of 2'-deoxyadenosine
were markedly enhanced by inhibition of adenosine deaminase. In contrast,
adenosine was much less toxic to nonneuronal cells than 2'-deoxyadenosine and its
effect was not potentiated by inhibition of adenosine deaminase. Priming of
pyrimidine pools by exogenous uridine and the specific inhibitor of the
nucleoside transporter, nitrobenzylthioinosine, did not protect nonneuronal cells
from 2'-deoxyadenosine toxicity. Since phosphorylation of internalized
nucleosides was a key step in the initiation of toxicity in sympathetic neurons,
adenosine kinase activity was compared in sensory and sympathetic neuronal
cultures. The adenosine kinase activity in dorsal root ganglion cultures was only
20% of that in sympathetic ganglion cultures. Furthermore, inhibition of
phosphorylation by blocking 2'-deoxyadenosine kinase with iodotubercidin and 5'
amino-5'-deoxyadenosine had no protective effect against 2'-deoxyadenosine
toxicity. [3H]-thymidine incorporation was inhibited over 90% by 2'
deoxyadenosine as early as 6 h following its addition and for up to 4 days,
suggesting inhibition of proliferation of nonneuronal cells by 2'-deoxyadenosine.
The nucleoside was also able to wipe out already well established nonneuronal
cells, leaving behind an enriched population of sensory neurons. The selective
vulnerability of nonneuronal cells to 2'-deoxyadenosine offers a convenient and
effective tool for removing nonneuronal cells from neuronal cultures as well as
providing a new model for studying the mechanisms of nucleoside toxicity.
PMID- 9554959
TI - Early patterning of the rat cerebral wall for regional organization of a neuronal
population expressing latexin.
AB - The exact timing of regional patterning in the developing cerebral cortex and
other telencephalic structures remains to be elucidated. In the present study, we
addressed this issue by comparing the distribution and density of neuronal
population expressing latexin in the adult rat telencephalon, with the regional
pattern in the fetal cerebral wall as to the potential to generate latexin
expressing neurons. Immunohistochemical analyses on adult animals have shown that
latexin-expressing neurons are restricted to a lateral cortical field, within
which they are most abundant at the middle level, decreasing in number rostrally
and caudally. Substantial numbers of latexin-immunopositive neurons were recorded
in the claustrum and endopiriform nuclei, both of which are located from rostral
to middle level in the lateral telencephalon. By examining the number and density
of latexin-immunopositive neurons in organotypic slice cultures from various
portions of the developing rat cerebral wall, it has been shown that the regional
pattern within the early cerebral wall as to the potential to generate latexin
expressing neurons matches well the distribution and density of latexin
expressing neurons in the adult telencephalon. Thus, in cultures derived from
either embryonic day 13 or 16 fetuses, latexin-immunopositive neurons appeared
most prominently in those from rostral-to-middle portions of the lateral cerebral
wall, decreasing in number rostrally and caudally. In cultures from the dorsal
cerebral wall, the number was generally very low. In light of our previous
finding that most prospective latexin-expressing neurons are still dividing at
embryonic day 13, it can be concluded that some kind of pattern formation event
occurs within the early cerebral wall even prior to the genesis of the
postmitotic neurons that would be later allocated in a region-specific manner.
PMID- 9554960
TI - Isolation of mutants of the Arabidopsis thaliana alternative oxidase
(ubiquinol:oxygen oxidoreductase) resistant to salicylhydroxamic acid.
AB - The plant-type ubiquinol:oxygen oxidoreductase, commonly called the alternative
oxidase, is a respiratory enzyme thought to contain non-heme iron at its active
site. To explore the structure of the enzyme by identifying amino acids involved
in inhibitor-binding, a library of random mutants of the Arabidopsis thaliana
alternative oxidase was constructed using error-prone polymerase chain reaction
and expressed in the heme-deficient Escherichia coli SASX41B. Selection for
resistance to salicylhydroxamic acid (SHAM) resulted in the recovery of four
mutations. Three of these, F215L, M219I, and M219V, confer a small, but
measurable resistance to SHAM of between 1.4- and 1.7-fold relative to the wild
type alternative oxidase. These changes are located in a putative amphipathic
helix following the second transmembrane helix. The fourth mutation, G303E, is
found three residues from the C-terminus of the protein, and results in 4. 6-fold
resistance to SHAM. None of the mutations have any effect on the sensitivity of
the alternative oxidase to propyl gallate. The identification of distant residues
involved in SHAM resistance suggests that the poorly conserved C-terminal region
is in spatial proximity to the amphipathic helix, and thus located in the
vicinity of the iron-binding motif.
PMID- 9554961
TI - Development of muscle afferents in the spinal cord of the tammar wallaby.
AB - The development of muscle afferents in the tammar wallaby was examined to address
whether proprioceptive input contributes to the marked asymmetry of the fore and
hindlimb movement. Anatomical tracing with biocytin showed that the muscle
afferents had reached the brachial motor horn by postnatal day (P1), but were
less advanced in the lumbar region. Labelled cells lying outside the motor horn,
presumably filled via gap junctions, were evident in the neonatal lumbar cord. By
the 4th postnatal week, the afferent innervation of both brachial and lumbar
cords became similar. Afferent discharges from stretching the biceps muscle could
be recorded at birth, but not until P4 from the hindlimb gastrocnemius muscle.
The discharges were predominantly phasic until P35 when tonic activity could also
be recorded. Short latency spinal reflex responses superimposed upon a longer
lasting potential were present in the brachial cord at birth, appearing in the
lumbar cord at P4. By the 3rd postnatal week, spinal reflex became comparable in
both segmental levels. The time course of muscle afferent development was
compared to the progression of natural cell death in the lumbar cord.
Sensorimotor connections were established towards the end of the rapid phase cell
death as observed in other vertebrates.
PMID- 9554962
TI - Single and repeated episodes of ethanol withdrawal increase adenosine A1, but not
A2A, receptor density in mouse brain.
AB - A history of multiple ethanol withdrawal experiences has been shown to exacerbate
the severity of future withdrawal episodes, and this sensitization of the
withdrawal response has been hypothesized to represent a 'kindling' phenomenon.
Since adenosine functions as an inhibitory modulator of seizure activity and may
interact with ethanol to influence neuronal excitability, the present study was
conducted to examine the effects of single and repeated episodes of ethanol
withdrawal on adenosine A1 and A2A receptors in adult C3H/He mice. Mice were
chronically exposed to ethanol vapor in inhalation chambers and tested for
withdrawal seizures following multiple withdrawal (MW) experience (four cycles of
16 h ethanol intoxication interrupted by 8 h periods of abstinence), single
withdrawal experience following 16 h (SW) or 64 h (CE) continuous ethanol
intoxication, or no ethanol exposure (controls). Separate groups of mice from
each withdrawal condition were used to generate pooled cortical and striatal
tissue for ligand saturation experiments using [3H]cyclohexyladenosine to label
A1 receptors and [3H]CGS 21680 to label A2A receptors. Results indicated that
withdrawal seizures were significantly more severe in mice with multiple
withdrawal experience in comparison to animals that experienced only a single
withdrawal episode, even when total amount of ethanol exposure was equated among
groups. The density of A1 receptors in cerebral cortex was significantly
increased over controls 8 h following final ethanol withdrawal by approximately
35% in SW and CE groups, with the largest increase observed in the MW group
(56%). Withdrawal treatment groups did not differ in cortical A1 binding sites
immediately upon withdrawal from ethanol, and no significant differences in
binding of [3H]CGS 21680 to striatal A2A receptors were observed following
ethanol withdrawal. Ethanol exposure and withdrawal did not significantly alter
ligand affinity for either adenosine receptor. These results indicate that
adenosine A1 receptors are selectively upregulated during ethanol withdrawal and
that the degree of upregulation may be enhanced following multiple withdrawal
episodes. Further, these observations suggest that the upregulation of brain A1
receptors during ethanol withdrawal may represent a compensatory inhibitory
response to increased seizure severity associated with repeated episodes of
ethanol withdrawal.
PMID- 9554963
TI - Three classes of GABA-like immunoreactive neurons in the mushroom body of the
cockroach.
AB - The mushroom body (MB) is a higher center of the insect brain and is critical to
some forms of associative memory. Each MB consists of calyces connected to alpha
and beta lobes via pedunculus. In the calyces, input neurons make synaptic
connections with intrinsic neurons. In the pedunculus and lobes, intrinsic
neurons make synaptic connections with output neurons. Here, the distribution of
gamma-aminobutyric acid (GABA)-like immunoreactivity in the MB of the cockroach
Periplaneta americana was investigated, using an antiserum against a GABA-protein
conjugate, to elucidate inhibitory pathways of the MB. We report that three
classes of extrinsic neurons of the MB exhibit GABA-like immunoreactivity. The
first is four large neurons which arborize in a diffuse neuropil surrounding the
alpha lobe and project into whole areas of the calyces. Their cell bodies are 30
50 micron in diameter, among the largest in the brain. The second group is 7-9
neurons ascending from the circumesophageal connective and projecting into the
calyces, which probably represent inhibitory input neurons. The third group is
ca. 40 neurons with dendritic arborizations in the junction between the
pedunculus and the lobes, which probably represent inhibitory output neurons.
PMID- 9554964
TI - Permeability of the blood-brain barrier to neurotrophins.
AB - To evaluate the feasibility of applying blood-borne neurotrophins to promote
normal function of the central nervous system (CNS) and to rescue neuronal
degeneration, we characterized the permeability of the blood-brain barrier (BBB)
to neurotrophins. We report here that some members of the neurotrophin family
(NGF, betaNGF, NT3, and NT5) can cross the BBB of mice in vivo to arrive at the
brain parenchyma. BBB permeability differed among individual neurotrophins in
that NGF had the fastest influx rate (Ki) and NT3 the slowest, and that the entry
rate of NGF was twice that of its smaller bioactive subunit betaNGF. BBB
permeability also differed at various CNS regions in that the cervical spinal
cord had the greatest rate of influx, whereas brain had the lowest. Saturability
of influx was suggested by self-inhibition studies for NT3 in vivo, and for NGF
in an in situ brain perfusion system, indicating the presence of saturable
transport systems. The results suggest that peripheral administration of
neurotrophins could have therapeutic effects within the CNS.
PMID- 9554965
TI - Xanthine oxidase-derived superoxide causes reoxygenation injury of ischemic
cerebral endothelial cells.
AB - Oxygen free radicals, generated by cerebral ischemia, have been widely implicated
in the damage of vascular endothelium. Endothelial cells have been proposed as a
significant source of oxygen free radicals. In the present study, we developed an
anoxia-reoxygenation (AX/RO) model using pure cultures of cerebral endothelial
cells (CECs) isolated from piglet cortex to measure CEC oxygen free radical
production and determine its role in AX/RO-induced CEC injury. CEC injury, as
measured by lactate dehydrogenase efflux into the culture medium, increased
progressively with the duration of anoxic exposure, becoming significant after 10
h. Reoxygenation significantly increased CEC anoxic injury in a time-dependent
manner. A 55% increase in oxygen free radical production, determined by
fluorescence detection of dihydroethidium oxidation, was measured at the end of 4
h reoxygenation in CECs subjected to AX/RO conditions that killed 40% of the
cells. Blockade of oxygen free radical production with superoxide dismutase (SOD;
250 and 1000 U/ml) or oxypurinol (50 and 200 microM), a potent xanthine oxidase
inhibitor, reduced this injury by 32-36% and 30-39%, respectively. Results from
our in vitro model indicate that CECs produce significant amounts of oxygen free
radicals following ischemia, primarily from the xanthine oxidase pathway. These
radicals ultimately have a cytotoxic effect on the very cells that produced them.
Thus, reductions in oxygen free radical-mediated vascular injury may contribute
to improvements in neurophysiologic outcome following treatment with oxygen free
radical inhibitors and scavengers.
PMID- 9554966
TI - Effects of tetrodotoxin treatment in LGN on neuromodulatory receptor expression
in developing visual cortex.
AB - The expression and distribution patterns of transmitter receptors change
dramatically during pre- and post-natal development of the visual cortex, but the
factors that control these processes are largely unknown. We have tested the
hypothesis that input activity from the lateral geniculate nucleus (LGN), one
major input source to visual cortex, may contribute to the processes underlying
transmitter receptor redistributions in the visual cortex during development. We
found that a short period of tetrodotoxin (TTX) treatment in LGN retarded the
developmental expression and age-dependent reorganization of neuromodulatory
receptors, including muscarinic, serotonergic and adrenergic receptors, in kitten
primary visual cortex. The visual cortices ipsilateral to the TTX infusion site
displayed a 'younger' receptor pattern than that of their contralateral control
counterparts in the same animals. The results suggest that active input from LGN
regulates the expression profile of a broad range of receptors in the developing
visual cortex.
PMID- 9554967
TI - Altered distribution of Galphah/type 2 transglutaminase following catecholamine
deprivation is associated with depression of adrenoreceptor signal transduction
in cultured ventricular zone germinal cells.
AB - Type 2 transglutaminase (Tg), which catalyzes the covalent cross-linking of
cytoplasmic proteins during apoptosis, also functions as the alpha subunit of a
heterodimeric G-protein (Gh) which can activate phospholipase C-delta1 during the
signal transduction pathway linked to alpha1-adrenoreceptors. Continued
stimulation of rat forebrain ventricular zone (VZ) germinal cells with the alpha1
agonist phenylephrine during development in vitro suppresses apoptosis and
promotes DNA synthesis [Pabbathi et al., Brain Res., 760, 1997, 22-33].
Immunocytochemistry with a monoclonal antibody to Galphah/Tg reveals that alpha1
agonist deprivation during culture of VZ cells in the presence of a protein
synthesis inhibitor results after 20 h in a loss of peripheral distribution of
the protein and an increase in the reaction product of Tg in the cytoplasm of
cells undergoing apoptosis. Using photoaffinity labelling, we observed reduced
GTP binding to Galphah/Tg in phenylephrine-deprived cultures. Formation of
inositol triphosphate (IP3) and intracellular Ca2+ transients occurred in the
presence of phenylephrine. In cultures grown in phenylephrine-deprived conditions
in the presence of protein synthesis inhibitor, both the IP3 response and the
amplitude and duration of Ca2+ transients were reduced. These results show that
loss of signal transduction coincides with the onset of transglutaminase activity
in VZ cells during a period when cell survival is reduced following withdrawal of
alpha1-agonist, and support the hypothesis that Tg/Galphah could be implicated in
both signal transduction and programmed cell death.
PMID- 9554968
TI - Growth factors improve immediate survival of embryonic dopamine neurons after
transplantation into rats.
AB - Embryonic dopamine neurons survive poorly after transplant into models of
Parkinson's disease, possibly due to programmed cell death (apoptosis). Apoptosis
in cultured dopamine neurons can be reduced by growth factors such as glial cell
line-derived neurotrophic factor (GDNF) or a combination of insulin-like growth
factor-I (IGF-I) and basic fibroblast growth factor (bFGF). To improve the
survival of dopamine neurons in grafts, strands of E15 rat ventral mesencephalon
were pretreated with a combination of GDNF, IGF-I, and bFGF and then transplanted
into 6-hydroxydopamine-lesioned rats. In control animals, only 32% of dopamine
neuron profiles survived the first 24 h after transplant. Growth factor
pretreatment increased survival to 49% on day 1. Growth factors reduced the
apoptotic rate of transplanted cells, just as they had in the previous in vitro
experiments. Apoptotic nuclear morphology was observed in the transplanted
dopamine neurons. We conclude that the majority of transplanted dopamine neurons
die in grafts within the first 24 h after transplant, most likely by an apoptotic
mechanism. Prevention of apoptosis with anti-apoptotic agents may improve the
viability of dopamine neurons grafted for Parkinson's disease.
PMID- 9554969
TI - Ontogeny of calretinin expression in rat dorsal root ganglia.
AB - The relationship between the expression of calretinin and the maturation level of
peripheral sensory neurons was investigated by means of immunohistochemistry and
immunoblot analysis. Our immunohistochemical results show that calretinin is
expressed during two different developmental phases in rat dorsal root ganglia.
The early phase lasts between embryonic days 11 and 14, when calretinin is
detectable in the majority (75%) of the cells. A second phase starts at embryonic
day 17 and lasts throughout the whole postnatal life, when calretinin is
expressed only in a small proportion of the neurons (less than 8%). Between these
two periods no calretinin is found in the ganglia. These changes in calretinin
expression during embryonic development were confirmed by Western blot analysis.
The early expression of calretinin in dorsal root ganglion cells suggests that
calretinin may act as a calcium regulator until neurotrophins take over the
precise tuning of intracellular calcium concentration.
PMID- 9554970
TI - The effect of MK-801 and of brain-derived polypeptides on the development of
ischemic lesion induced by photothrombotic occlusion of the distal middle
cerebral artery in rats.
AB - The effect of neuroprotective drugs on the early and late electrophysiological
manifestations of photothrombotic occlusion of distal branches of middle cerebral
artery was studied in rats treated with MK-801 and Cerebrolysin (CL). DC
potentials were recorded from the irradiated cortex (ischemic core), from the
adjacent penumbra zone and from remote intact cortex. Irradiation elicited after
a few minutes of spontaneous spreading depression (SD) waves followed during 10
15 min by focal ischemic depolarization (FID) developing in the irradiated cortex
and spreading into the perifocal areas. While the core FID amplitude reached
about 30 mV and decayed during subsequent 2 h to 10-13 mV, FID in the penumbra
zone was broken by periods of partial repolarization and returned during 30-90
min almost to baseline. At the same time, generation of spontaneous SD waves
almost stopped. MK-801 (0.5 mg/kg, i.p., 45 min after ischemia) blocked SD waves,
but did not shorten penumbra FID, the decay of which was slowed down to the rate
found in the ischemic core. CL treatment (2.5 ml/kg, i.p. , 1 h after ischemia)
did not influence FID in the acute phase of the experiment, but its 10-day
administration facilitated post-ischemic recovery indicated by higher amplitude
of evoked SD waves penetrating into the former penumbra zone. Morphological
examination showed that the volume of total and partial necrosis was increased in
the MK-801 group and marginally reduced in the CL group. It is suggested that the
absence of the SD-induced hyperperfusion episodes in MK-801-treated rats may
accelerate perifocal thrombotization in this model of focal ischemia.
PMID- 9554971
TI - Regulation of G protein-mediated adenylyl cyclase in striatum and cortex of
opiate-dependent and opiate withdrawing mice.
AB - Previous research has demonstrated that acute and chronic opiate treatment alters
receptor- and postreceptor-mediated adenylyl cyclase activity. This study
examined the regulation of G protein- and forskolin-mediated adenylyl cyclase
activity in mouse striatum and cortex after short- and long-term opiate exposure.
To directly measure adenylyl cyclase enzymatic activity, assays were done in the
presence of catalytic site activator forskolin. To measure G protein-mediated
adenylyl cyclase activity, assays were performed in the presence of non
hydrolyzable guanosine 5'-triphosphate (GTP) analogue, 5'-guanylyl
imidodiphosphate. Short-term in vitro morphine exposure produced reductions in
forskolin-stimulated adenylyl cyclase activity in striatal and cortical tissues.
Long-term morphine treatment in mice was performed via morphine- or placebo
pellet implantation for 72 h; this treatment has been shown to produce opiate
dependence and withdrawal. In both opiate-dependent and opiate withdrawing mice
(1 h post-naloxone induction), there were significant increases in G protein
mediated adenylyl cyclase activity in the striatum (vs. controls). In opiate
dependent mice, there was an decrease in G protein-mediated adenylyl cyclase
activity in cortex. In opiate-dependent mice, there were no changes in forskolin
stimulated adenylyl cyclase in the striatum or cortex. Increases in striatal G
protein-mediated adenylyl cyclase could represent a compensatory adaptation that
opposes the persistent inhibition of adenylyl cyclase by chronic opiate treatment
contributing to the expression of opiate dependence and withdrawal.
PMID- 9554972
TI - Ontogeny of human brain dopamine receptors. I. Differential expression of [3H]
SCH23390 and [3H]-YM09151-2 specific binding.
AB - Dopamine receptor expression in human fetal forebrain (between 6 and 20 weeks of
gestation) was measured using tissue-slice receptor autoradiography with the D1
like and D2-like antagonists [3H]-SCH23390 and [3H]-YM09151-2, respectively.
Tissue sections were assayed in saturation studies and examined for age- and sex
related changes in Bmax. We made the following observations: (1) the ages at
which D1- and D2-like receptors were first expressed in whole forebrain sections
could be reliably identified but were not significantly different from one
another (gestational age 65 days for D1- vs. 72 days for D2-like receptors); (2)
age-related increases in both D1- and D2-like receptors were demonstrated in
forebrain and, from the middle of the first to the middle of the second
trimester, the Bmax for each ligand increased by an order of magnitude after the
onset of the specific binding site's expression; (3) age-related increases in D1
like receptors, but not D2-like receptors, could be demonstrated in cortex; and,
(4) in one case of trisomy 18, the Bmax for [3H]-SCH23390 was significantly
elevated above the 95% confidence interval when compared to an age-regressed
normal sample. Although D2-like receptor density significantly increased with age
in forebrain, age-regressed changes in D2-like receptor expression in cortex and
striatum did not reach statistical significance. Likewise, a comparison of the
mean Bmax's by sex for both ligands in midgestational striatum failed to reach
significance. These data corroborate the findings of other investigators who have
delineated the ontogeny of dopaminergic systems in other animal species. The
regional differences in the expression of dopamine receptor families may be
relevant to the role which dopamine may play during normal gestational brain
development. Moreover, significant deviations in dopamine receptor expression
during gestation (as seen in this one case of trisomy 18) may signify underlying
pathological processes that ultimately are manifested by abnormal psychological
development and/or cognitive functioning.
PMID- 9554973
TI - Dopaminergic agonists administered into the nucleus accumbens: effects on
extracellular glutamate and on locomotor activity.
AB - The hypothesis to be tested was that increased dopaminergic transmission induced
by amphetamine in the nucleus accumbens results in increased glutamatergic
neurotransmission in this brain area and that the increase in level of this
neurotransmitter contributes to behavioral effects of psychostimulant drugs.
Amphetamine (1 mg/kg, i. p.) increased the amount of extracellular glutamate in
the accumbens, as measured by in vivo dialysis, and stimulated locomotor
activity. Amphetamine (10 mM) infused into the accumbens by reverse dialysis
through the probe produced a similar stimulation of locomotor activity as
systemic amphetamine but a greater increase in extracellular glutamate levels.
Both of these responses to amphetamine were attenuated by either the selective D1
antagonist SCH23390 or the selective D2 antagonist eticlopride. The combination
of a D1 and D2 agonist, SKF38393 (20 mM) and quinpirole (50 mM), administered
into the accumbens by reverse dialysis also increased extracellular glutamate and
stimulated locomotor activity. Administration of a glutamate uptake inhibitor,
threo-beta-hydroxy-aspartate (50 mM), increased extracellular glutamate but did
not stimulate locomotor activity. Systemic administration of caffeine (15 mg/kg,
i.p.) increased locomotor activity but did not increase extracellular levels of
glutamate. These data suggest that activation of dopaminergic receptors in the
nucleus accumbens results in stimulation of locomotor activity and in activation
of glutamatergic transmission in this brain region. However, an increase in
glutamate levels in the nucleus accumbens is neither sufficient nor necessary to
produce a stimulation of locomotor activity.
PMID- 9554974
TI - Inhibitory neuronal activity can compensate for adverse effects of beta-amyloid
in hippocampal neurons.
AB - One of the most prominent effects of Alzheimer disease is the disruption of
finely tuned neuronal circuitry of discrete brain regions associated with
learning and memory. Results from the present study support a role for the
intrinsic inhibitory component of neuronal circuitry in determining the magnitude
of beta-amyloid peptide induced cell death in the highly vulnerable pyramidal
neurons of the hippocampus. Previous efforts have mostly focused on direct
effects on excitatory neurons. By contrast, less emphasis has been placed on
addressing a role for the intrinsic inhibitory component of cell-cell
interactions of neuronal networks in response to Abeta. The present study
provides evidence demonstrating that blockage of the intrinsic inhibitory
component between Abeta exposed neurons leads to destabilization of calcium
homeostasis and exacerbated neuronal death compared to Abeta treated cultures.
Neuronal electrical activity was first silenced by exposing cultures to
tetrodotoxin (TTX; 100 nM) plus Abeta, followed by survival counts. Cell death,
unexpectedly, did not significantly differ from Abeta-exposed neurons. The
intrinsic inhibition in Abeta-exposed cultures was then pharmacologically removed
with picrotoxin (40 microM) or bicuculline (25 microM) resulting in significantly
greater death than Abeta-exposed neurons alone. From these observations, it is
proposed that intrinsic functional inhibition in hippocampal circuits can reduce
adverse effects of Abeta on the excitatory component. By considering not just the
excitatory component of electrical activity, but the intrinsic balance between
excitation and inhibition, new strategies for the treatment of Alzheimer disease
may emerge.
PMID- 9554976
TI - Mecamylamine selectively blocks nicotinic receptors on vasomotor sympathetic C
neurons.
AB - Mecamylamine differentially blocked fast nicotinic transmission in two functional
subsets of sympathetic neurons within lumbar paravertebral ganglia of the
bullfrog. EC50s for inhibition of postsynaptic compound action potentials were
27.3+/-2.5 microM in the secretomotor B system and 5.7+/-0.7 microM in the
vasomotor C system. This 5.2:1 selectivity is 2.6 times greater than observed
previously with d-tubocurarine, a nonselective blocker of nicotinic receptors,
and it indicates that mecamylamine preferentially interacts with nicotinic
receptors on sympathetic C neurons. We tested this by analyzing the effect of
mecamylamine upon synaptic currents. In both cell types, the drug produced a
qualitatively similar picture of open-channel blockade. It reduced EPSC
amplitude, speeded EPSC decay, and became more effective with membrane
hyperpolarization and repetitive activity. Despite these similarities, 8 microM
mecamylamine reduced EPSC amplitude to a greater extent in C neurons, and the
rate constant for drug binding to open channels was 4.4 times greater in B cells,
irrespective of membrane potential. This implies that the unblocking rate for
mecamylamine is much slower in C cells than B cells, and it shows that the drug
recognizes a structural difference between nicotinic receptors on these two
populations of sympathetic neurons.
PMID- 9554975
TI - Elevation of cyclic AMP by iloprost and prostaglandin E1 increases cholesterol
efflux and the binding capacity for high-density lipoproteins in human
fibroblasts.
AB - Elevation of cAMP concurrently enhances cholesterol efflux and binding of HDL3 in
human skin fibroblasts. These effects were observed regardless of the route by
which cAMP levels were increased. Cholesterol efflux and HDL3 binding were
stimulated by the cAMP analogue CPT-cAMP, the adenylate cyclase activator
forskolin, and by iloprost and prostaglandin E1 (PGE1) (which elevate cAMP via
receptor-mediated processes). Dideoxyforskolin and PGF2alpha, which do not
elevate cAMP, altered neither cholesterol efflux nor binding of HDL3. Inhibition
of protein kinase A with H89 abolished the stimulatory effects of CPT-cAMP and
iloprost, suggesting protein kinase A involvement in enhancing cholesterol efflux
and HDL3 binding. Enhancement of HDL3 binding by iloprost was due to increased
maximal capacity of the cells to bind HDL3, i.e., a greater number of HDL3
binding sites. A positive correlation was demonstrated between changes in HDL3
binding and changes in [3H]cholesterol efflux. The data are compatible with a
model in which cholesterol efflux is partially dependent upon HDL binding to the
cells. A short exposure to iloprost was sufficient to stimulate cAMP synthesis,
triggering a chain of events leading to increased HDL3 binding and
[3H]cholesterol efflux 20-24 h later. We conclude that both cholesterol efflux
and the maximal capacity for HDL3 binding are enhanced by elevation of cellular
cAMP. Cyclic AMP-elevating prostanoids could initiate these responses in vivo.
PMID- 9554977
TI - The effects of fetal adrenalectomy at 110 days gestational age on AVP and CRH
mRNA expression in the hypothalamic paraventricular nucleus of the ovine fetus.
AB - AVP and CRH produced in the parvocellular neurons of the paraventricular nucleus
(PVN) have both been implicated in the regulation of anterior pituitary ACTH
synthesis and secretion. In sheep, fetal ACTH secretion increases around 120 days
gestational age (dGA). Little is known about adrenal regulation of AVP and CRH
immediately prior to this critical period. We investigated the effects of
adrenalectomy and subsequent cortisol (F) administration on PVN AVP and CRH mRNA
in the fetal sheep PVN at 109-125 dGA. At 109-113 dGA, fetal sheep adrenals were
removed (ADX)(n = 8); or sham surgery performed (CONT)(n = 4). From day 6 post
ADX, maternal plasma cortisol and fetal plasma ACTH and cortisol levels were
determined daily by radioimmunoassays. From day 7 post ADX, cortisol (4
micrograms/min) was continuously infused intravenously to four ADX fetuses (ADX +
F). Fetal hypothalami were collected at 123-125 dGA, and studied by in-situ
hybridization and quantitative autoradiography for AVP and CRH mRNA. Plasma
cortisol levels remained low in CONT and ADX fetuses (< 4.9 ng/ml), while during
cortisol infusion to ADX + F fetuses, plasma F increased to 16.4 +/- 2.2 and 22.3
+/- 3.2 ng/ml (mean +/- S.E.M.) on day 10 and 13, respectively. Plasma ACTH
levels increased significantly in ADX compared with CONT fetuses. This ACTH
increase was completely suppressed in ADX + F fetuses. AVP mRNA abundance in the
whole PVN was the same in all three groups, however, a separate analysis of AVP
mRNA abundance in parvocellular and magnocellular regions of the PVN revealed
that AVP mRNA in the parvocellular PVN showed a significant increase in ADX and
suppression in ADX + F fetuses when compared to CONT. AVP mRNA in the
magnocellular PVN remained unchanged. PVN CRH mRNA expression was augmented in
ADX and suppressed in ADX + F when compared to CONT fetuses. We conclude that in
fetal sheep at 109-125 dGA: AVP and CRH mRNA abundance in the parvocellular
region of the PVN are increased by adrenalectomy and that cortisol inhibits this
increase.
PMID- 9554978
TI - Simultaneous microdialysis in brain and blood of the mouse: extracellular and
intracellular brain colchicine disposition.
AB - A simultaneous brain and blood microdialysis system was developed to study the
passage of colchicine through the blood-brain barrier in the mouse. Colchicine
was administered as a bolus in the jugular vein (1.5 mg kg-1) and its hippocampal
extracellular fluid (ECF) and blood kinetics were determined over a 4 h period
using two microdialysis probes, one in the dorsal hippocampus, the other in the
inferior vena cava. Colchicine rapidly diffused into the hippocampus (maximum
concentration in the first dialysate sample) and brain and blood concentrations
declined in parallel, suggesting rapid equilibration between these two
compartments. However, only 6. 7% of total blood colchicine, 14% of unbound
colchicine was present in the hippocampus suggesting that the P-glycoprotein
efflux pump limits colchicine uptake by the brain. We also found, using
conventional tissue homogenate analysis in parallel, that the concentration of
colchicine in the hippocampal ECF was 10 times less than that in the
intracellular space and that the hippocampus colchicine concentration was 2.8
times higher than that of the rest of the brain. This study shows that the
simultaneous brain and blood microdialysis can be used to measure the passage of
colchicine through the blood-brain barrier and to estimate the brain extra- and
intracellular distribution of colchicine.
PMID- 9554979
TI - An in vitro model for analysis of oxidative death in primary mouse astrocytes.
AB - Astrocytes provide a vital protective function in the brain. These cells are also
vulnerable to oxidative stress, thus their loss of function could contribute to
neurodegeneration. The goal of this study is to develop a cell culture model to
study oxidative stress in astrocytes. Enriched astrocytic cultures were generated
from neonatal mice. tertiary-butyl hydroperoxide (t-bOOH) was used as an
exogenous peroxide and lactate dehydrogenase (LDH) release as a measure of loss
of viability. Exposure to t-bOOH resulted in a linear increase in astrocytic
death reaching 91.2% after 4 h exposure. That cell death was due to oxidative
injury, was shown by the ability of the antioxidant N,N'-diphenyl-1,4
phenylenediamine (DPPD) to protect the t-bOOH treated cells. The involvement of
iron in cell toxicity was demonstrated by the ability of the iron specific
chelator desferal (DF) to completely prevent t-bOOH induced LDH release. Cells
treated with a lipid soluble iron compound 3,5, 5-trimethyl (hexanoyl) ferrocene
(TMH-Ferrocene), were more vulnerable to t-bOOH whereas neither ferrous ammonium
sulfate (FAS) nor ferric ammonium citrate (FAC) had an effect. The increased
sensitivity of the cells exposed to TMHF was reversible with the iron chelator
desferal. Addition of recombinant human heavy chain ferritin or human apo
transferrin (Tf) did not alter LDH release. Electron microscopic analysis
indicated astrocytes exposed to t-bOOH exhibited mitochondrial swelling prior to
cell death (lactate dehydrogenase release). Additional increases in mitochondrial
swelling were seen when the astrocytes were exposed to the lipophilic iron
compound TMH-ferrocene and t-bOOH. These studies show that astrocytes are
exquisitely sensitive to oxidative stress and that their vulnerability is related
to and enhanced by iron. Decreased mitochondrial function in response to
oxidative stress may precede cell death.
PMID- 9554980
TI - The protective role of mild acidic pH shifts on synaptic NMDA current in
hippocampal slices.
AB - Glutamate is a major neurotransmitter in the CNS. Its release activates NMDA and
non-NMDA receptors on the postsynaptic membrane. NMDA receptor activation is
shown to be important in physiological and pathological events. The modulatory
sites on the NMDA receptor-channel ionophore complex are important in the
regulation of the channel's cation conductance. Regulation of the channel by
proton concentration may be important in the alkalinization that occurs during
the normal release of glutamate or in the acidification that occurs during
hypoxia/ischemia. In this study, the selective downregulation of the NMDA channel
with slight extracellular pH changes and reversibility of this modulation have
been shown in hippocampal slices. It has also been shown that hippocampal slices
are more responsive to pH changes than other experimental preparations. The
downregulation of the NMDA current may represent a native control mechanism.
Direct and indirect modulation caused by extracellular pH changes on the NMDA
receptor ionophore complex might be important in the overall response of the
neuron under pathophysiological changes.
PMID- 9554981
TI - Potassium chloride inhibits proliferation of cerebellar granule neuron
progenitors.
AB - CNS neurogenesis involves a critical transition where neuronal progenitors exit
the cell cycle and initiate terminal differentiation. Recent experiments have
suggested that depolarization inhibits DNA synthesis in cortical progenitors.
Depolarization of proliferating neuronal progenitors may thus activate mechanisms
that prevent proliferation and allow the initiation of terminal differentiation.
We present evidence that depolarizing concentrations of KCl (25-50 mM) reduce
proliferation of developing postnatal cerebellar granule cells in culture. These
studies show that KCl antagonizes the mitogenic response of granule cells to
insulin-like growth factor-I (IGF-I) and that this reduction in proliferating
cells is not the result of a selective cell death. We also examined the
differentiation of granule cell cultures using Brn-5 expression as an early
differentiation marker. In vivo Brn-5 expression occurs soon after developing
granule cells exit the cell cycle and begin their final differentiation. In
control cultures and cultures treated with high concentrations of KCl Brn-5
expression increased over 24-48 h of culture. Our results suggest depolarizing
concentrations of KCl antagonize proliferation of cerebellar granule neuron
progenitors however allow their continued differentiation.
PMID- 9554982
TI - A peptide from hog plasma that inhibits human cholesteryl ester transfer protein.
AB - A peptide that inhibits the human cholesteryl ester transfer protein (CETP) was
isolated from hog plasma by ultracentrifugation, two sequential column
chromatographies and electroelution from gels. Molecular weight of the peptide
was determined to be approximately 3 kDa on the SDS-PAGE. The peptide contained
28 amino acids with an identical sequence to the amino terminus of hog
apolipoprotein-CIII except two amino acid residues: -Pro-Glu- at the fifth and
sixth amino acids from the amino terminus in the isolated peptide, in contrast to
-Leu-Leu- in hog apo-CIII. A peptide synthesized chemically according to the
amino acid sequence of the peptide (designated P28) showed approximately the same
degree of CETP inhibitory activity as the isolated peptide. Synthetic peptides
with different number of amino acids were also tested for CETP inhibition. Among
the peptides, the one with 20 amino acid residues (P20) from the amino terminus
showed the highest inhibitory activity against the CETP. The peptide appeared to
be associated with the hog high-density lipoproteins (HDL), as determined by
immunoblot analysis using antibody against P28. The CETP-inhibitory activity of
the peptide was examined in vivo using diet-induced hypercholesterolemic rabbits.
When the peptide was injected into the rabbits (7-9 mg/kg body weight),
approximately 75% CETP activity disappeared from the plasma in 1 h after the
injection and the effect lasted up to 30 h. The inhibition of CETP in vivo led to
a concomitant decrease in total plasma cholesterol level up to 30% and an
increase in the level of HDL-cholesterol up to 32%. The cholesterol
concentrations in the rabbit plasma gradually recovered to the initial level
after 48 h.
PMID- 9554983
TI - Low dose MK-801 protects against iron-induced oxidative changes in a rat model of
focal epilepsy.
AB - We have used chemiluminescence measurements to examine the relationship between
free radical formation and excitotoxicity in a post-traumatic epilepsy model. For
this purpose, seven days after injecting iron in rat brain cortices, we measured
luminol- and lucigenin-enhanced chemiluminescence in different brain regions
(ipsilateral cortex, contralateral cortex, hypothalamus and hippocampus). In all
brain regions (except contralateral cortices) both luminol- and lucigenin
enhanced chemiluminescence were increased in iron-injected group compared to
saline-injected control group. These increases returned to control values in iron
injected rats pretreated with MK-801. Our results suggest that both free radicals
and excitatory amino acids play important roles in the development of post
traumatic epilepsy and that MK-801 has protective effects against iron-induced
chemiluminescence formation.
PMID- 9554984
TI - Effects of kappa and delta opioid agonists on activity and thermosensitivity of
rat hypothalamic neurons.
AB - Extracellular recordings were made from 161 warm-sensitive, six cold-sensitive
and 153 temperature-insensitive neurons in slices of the preoptic area/anterior
hypothalamus (PO/AH) of rats, to investigate the effects of the kappa-receptor
opioid agonist dynorphin A1-17 and the delta-receptor opioid agonist DPDPE on
neuronal response characteristics. While 61% of the neurons exhibited kappa
receptors, delta-receptors were only present in 37% of the neurons. No co
localization was observed between kappa- and delta-receptors, whereas mu
receptors could be co-localized with kappa- as well as delta-receptors.
Antagonistic effects on tonic activity were induced by different concentrations
of the kappa-agonist dynorphin A1-17. At 0.5 nM, the excitatory effect was
predominant, while 50% of the neurons were already inhibited at 5 nM and
inhibition was the major effect at 100 nM. A significant increase in temperature
sensitivity was observed in warm-sensitive neurons during administration of 0.5
nM dynorphin A1-17; in contrast, the temperature sensitivity was significantly
decreased at the high dose of 100 nM. In most of the neurons responding to the
delta-receptor agonist DPDPE (0.5-100 nM) the firing rate was decreased. The
temperature sensitivity was only affected in warm-sensitive neurons, and was
increased in the majority of neurons at 0.5 and 5 nM, but predominantly decreased
at higher concentrations. The effects of low concentrations of dynorphin A1-17
and DPDPE were prevented by pre- and co-perfusion of the appropriate antagonists.
The present results suggest that changes of the temperature sensitivity of warm
sensitive PO/AH neurons are an important mechanism for the effect of low doses of
opioids on body temperature.
PMID- 9554986
TI - The influence of preischemic hyperglycemia on acute changes in brain water ADCw
following focal ischemia in rats.
AB - The effect of preischemic hyperglycemia on the acute decline of brain apparent
diffusion coefficient of water (ADCw) following cerebral ischemia was studied in
a rat model of middle cerebral artery occlusion (MCAO). ADCw was measured by NMR
with a newly developed spin-echo line-scan protocol that provides for an ADCw
calculation every 15 s at a spatial resolution of 3.4 microl/pixel. A remote
controlled occluding device was used to initiate ischemia from outside the
magnet, allowing for continuous monitoring of ADCw before, during and after MCAO.
Preischemic hyperglycemia (25-30 mM) was achieved via i.v. infusion of 50%
glucose. The decline in ADCw following ischemia was analyzed to obtain three-time
constants: the time from onset of ischemia to initial significant ADCw decline
below baseline level (i.e., 20% of maximal decline, T0.20), the time to decline
by 50% (T0.50), and the time to decline by 95% (T0.95). Mean (+/-S.D.) values for
T0.20, T0.50, T0.95 were: 39.6+/-7.2, 54. 0+/-7.8, 105.0+/-15.0 s for the
normoglycemic group (n=7), and 49. 2+/-33.0, 116.4+/-2.4, 351.0+/-189.0 s for the
hyperglycemic group (n=6), respectively. Hyperglycemia significantly prolongs
T0.50 and T0.95 but does not affect T0.20. The temporal profiles of ADCw decline
following ischemia under normo- and hyperglycemia are distinctively different
from the known time course of membrane depolarization under similar experimental
conditions, suggesting that mechanisms other than membrane depolarization and
cell swelling may contribute to changes in ADCw in cerebral ischemia.
PMID- 9554985
TI - D1-dopamine receptor binding and tyrosine hydroxylase-immunoreactivity in the
fetal and neonatal hamster suprachiasmatic nucleus.
AB - The suprachiasmatic nucleus (SCN) of the anterior hypothalamus is the site of an
endogenous biological clock that regulates mammalian circadian rhythms. Circadian
rhythms, although endogenously driven, are synchronized or entrained to daily
environmental cues. Developmentally, the SCN begins to oscillate before birth and
is entrained to the maternal circadian rhythm by a mechanism that is still
unclear. Recent evidence in rats and hamsters suggests that a fetal dopaminergic
system and D1-dopamine receptors may be involved in the process of entraining the
fetal clock. The present study using [3H]SCH 23390 autoradiography and tyrosine
hydroxylase (TH) immunocytochemistry determined the developmental time courses of
the appearance of D1 receptor in, and catecholaminergic input to, the hamster
SCN. [3H]SCH 23390 binding to D1-dopamine receptors was first detected in the
fetal SCN on embryonic day (E) 15, the day before birth in this species, and
persisted through adulthood. The TH immunoreactive fibers were first observed on
day E15 coursing just ventral to the fetal SCN but TH-immunoreactive cells and
fibers were not seen within the SCN until postnatal day (P) 5. The presence of D1
dopamine receptor binding in the fetal hamster SCN is consistent with the role of
these receptors in entrainment of the fetal circadian pacemaker to maternal cues.
However, a receptor-transmitter mismatch exists between D1-dopamine receptors and
TH-immunoreactive fibers in the fetal SCN suggesting that the role of dopamine in
maternal-fetal entrainment may be as a paracrine or humoral signal.
PMID- 9554987
TI - Electrophysiological evidence that a subset of midbrain dopamine neurons
integrate the reward signal induced by electrical stimulation of the posterior
mesencephalon.
AB - This study was aimed at determining whether midbrain dopamine (DA) neurons are
trans-synaptically activated by rewarding electrical stimulation applied near the
midline in the posterior mesencephalon (PM), and in the affirmative, whether the
increase in firing was proportional to the rewarding effectiveness of the
stimulation. Experiments were performed on male Long-Evans rats trained to lever
press to obtain 400 ms trains of cathodal rectangular pulses. Following the
training period, curves relating the rates of responding to the stimulation
frequencies were determined at two current intensities and reward thresholds were
calculated for each animal. Each animal was then anesthetized with urethane (1.2
g/kg, i.p.) and firing rate of DA neurons were recorded before, during, and after
each of 50 trains (1 train/3 s) of stimulation to the PM using stimulation
parameters that either sustained near threshold responding (rewarding), or failed
to sustain responding (non-rewarding), in the behavioral tests. A total of 24 DA
cells were recorded from 13 behaviorally trained animals, and of these, 17 (71%)
responded to rewarding stimulation by an increase in firing, five (21%) were
unresponsive and two (8%) were inhibited. In 12 of the 17 cells that were
activated, the increase in firing was proportional to the rewarding effectiveness
of the stimulation rather than the total strength of the stimulation. These
results provide evidence that a subset of midbrain DA neurons are trans
synaptically activated by rewarding PM stimulation and constitute a second, or
subsequent, stage of the reward-relevant pathway that integrates the PM reward
signal.
PMID- 9554988
TI - The effects of glucose, mannose, fructose and lactate on the preservation of
neural activity in the hippocampal slices from the guinea pig.
AB - Using hippocampal slices from guinea pigs, we investigated the effect of
different concentrations of glucose and replacement of glucose with mannose,
fructose and lactate on neural activity. As an index of neural activity, the
population spikes (PS) were recorded in the granule cell layer of the dentate
gyrus (DG) and the pyramidal cell layer of the CA3 area in the hippocampal
slices. Lowering the concentration of glucose from 10 mM to 5, 3, 2, 1 and 0 mM
caused a reduction in the PS amplitude. There were differences in the decay times
of the PS evoked in these two regions. PS evoked in CA3 region decayed faster
even at a concentration of 3 mM glucose at which PS in granule cell layer was
well maintained. The decay time of the PS in the CA3 region in the presence of
glucose up to a concentration of 3 mM was shorter than that evoked in the DG.
After the replacement of glucose with mannose, fructose or lactate, the PS
disappeared within 35 min and there were no significant differences between the
decay times in the two regions of slices incubated in the same medium. ATP,
creatine phosphate (CrP) and lactate levels in each slice were determined. To
investigate whether mannose and fructose could be metabolized or not in the
tissue slice, anaerobic production of lactate from glucose, mannose and fructose
were measured during oxygen and glucose deprivation. Under anaerobic conditions
for 60 min, the levels of high-energy phosphates decreased to 50% of the initial
level and lactate was produced from glucose, mannose or fructose. However, there
were significant differences in the rate of lactate production between the DG and
CA3 areas during application of 3 mM glucose, 10 mM mannose and 10 mM fructose.
These results indicate that mannose, fructose and lactate can be metabolized and
are available for maintaining the levels of high-energy phosphates but not for
neural activity in the tissue slices and that the presence of glucose is
indispensable for the maintenance of neural activity.
PMID- 9554989
TI - Maturational changes in cell surface antigen expression in the mouse retina and
optic pathway.
AB - The distribution of the cell surface molecules M6 and L1 was studied using the
immunohistochemistry and in situ hybridization in the developing and adult mouse
retina and optic nerve. L1 is a cell adhesion molecule while M6 is a cell surface
molecule homologous to the myelin protein proteolipid protein (PLP/DM20).
Although both molecules were expressed in retina and optic nerves of embryonic
and neonatal mice, our studies show that their patterns of postnatal expression
are quite different. While L1 continues to be expressed in optic axons throughout
adulthood, expression of M6 on optic axons declines after birth and instead
becomes strongly expressed on Muller glial endfeet and in the inner plexiform
layer. The modulation of these molecules after birth could provide clues to
changing cell-cell interactions occurring in the proximal portion of the optic
pathway.
PMID- 9554990
TI - Stearoyl-CoA desaturase mRNA is transcribed from a single gene in the ovine
genome.
AB - Clones corresponding to ovine stearoyl-CoA desaturase (SCD) cDNA were isolated
from an adipose tissue cDNA library. All of these clones represented a single
mRNA species as judged by restriction fragment and DNA sequence analysis. RNase
protection analysis demonstrated that this SCD transcript is highly expressed in
adipose tissue and liver, and in the mammary gland of lactating animals. A lower
level of expression was detectable in a variety of other tissues including brain.
Levels of the SCD transcript were decreased in adipose tissue during lactation,
and this appears to be related to a marked decline in serum insulin and insulin
responsiveness of the tissue. Southern analysis of ovine and mouse genomic DNA
demonstrated that the ovine SCD cDNA hybridised in a manner consistent with a
single gene for SCD in ovine DNA; mouse genomic DNA produced a pattern of
hybridisation consistent with the previously characterised mouse SCD-1 and SCD-2
genes. Three ovine cosmids were isolated that comprised the restriction fragments
predicted by the genomic Southern analysis. The ovine SCD gene was predicted to
be encompassed within a 23 kbp region that was present in all three cosmids.
These results demonstrate that SCD is transcribed from a single gene in the ovine
genome and this gene is insulin-responsive in ovine adipose tissue.
PMID- 9554991
TI - Apolipoprotein-E deficiency results in an altered stress responsiveness in
addition to an impaired spatial memory in young mice.
AB - It has been suggested that Alzheimer's disease (AD) is associated with an altered
neurotrophic function of apolipoprotein-E (ApoE) and abnormal neuroendocrine
activities. In the present study we investigated stress responsiveness of ApoE
deficient mice. Firstly, two sessions of restraint were introduced, 20 min per
day for two (session 1) and three (session 2) consecutive days. In session 1,
there was no difference between genotypes in open-field activity in response to
restraint stress. In session 2, spatial memory was assessed in a Morris Water
Maze 'Place Learning Set' task immediately following stress. Restraint stress
caused a significant impairment of spatial memory in wild-type mice. The non
restraint ApoE-deficient mice showed a severe impairment of spatial memory
similar to that of the restrained wild-type mice. Restraint stress had no obvious
effect on spatial memory in ApoE-deficient mice until the third day of testing,
when there was a decrease in reference memory compared with their non-restraint
controls. In addition, the first session of restraint stress had an inhibitory
effect on food intake in wild-type but not ApoE-deficient mice, and a longer
lasting effect on body weight in the wild-type than ApoE-deficient mice. ApoE
deficient mice showed a weaker corticosterone response to the initial restraint
stress and a slower descending rate in serum corticosterone level during a 30-min
post-stress period than their wild-type controls. However, higher baseline levels
and stronger corticosterone responses were observed in ApoE-deficient mice than
in wild-type mice when exposed to repeated restraint stress. The expression of
ApoE mRNA was upregulated in the hypothalamus in wild-type mice exposed to
repeated restraint stress. Taken together, these results demonstrate that ApoE
deficiency causes a memory impairment and an altered stress responsiveness in
mice.
PMID- 9554992
TI - CNS cell groups projecting to sympathetic outflow of tail artery: neural circuits
involved in heat loss in the rat.
AB - In the rat, approximately 20% of total body heat-loss occurs by sympathetically
mediated increases in blood flow through an elaborate system of arteriovenous
anastomoses in the skin of its tail. In this study, the CNS cell groups that
regulate this sympathetic outflow were identified by the viral transneuronal
labeling method. Pseudorabies virus was injected into the wall of the ventral
tail artery in rats that had their cauda equina transected to eliminate the
somatic innervation of the tail. After 4-7 days survival, the pattern of CNS
transneuronal labeling was studied. Sympathetic preganglionic neurons in the T11
L2 (mainly L1) levels of the intermediolateral cell column (IML) were labeled by
4 days. After 5 days, sympathetic pre-motor neurons (i.e., supraspinal neurons
that project to the IML) were identified near the ventral medullary surface; some
of these contained serotonin immunoreactivity. Additional groups of the
sympathetic premotor areas were labeled by 6 days post-injection, including the
rostral ventrolateral medulla (C1 adrenergic neurons), rostral ventromedial
medulla, caudal raphe nuclei (serotonin neurons in the raphe pallidus and magnus
nuclei), A5 noradrenergic cell group, lateral hypothalamic area and
paraventricular hypothalamic area (oxytocin-immunoreactive neurons). Seven days
after the PRV injections, additional cell groups in the telencephalon (viz., bed
nucleus of the stria terminalis, medial and lateral preoptic areas and medial
preoptic nucleus), diencephalon (viz., subincertal nucleus, zona incerta as well
as dorsal, dorsomedial, parafascicular, posterior and ventromedial hypothalamic
nuclei) and midbrain (viz., periaqueductal gray matter, precommissural nucleus,
Edinger-Westphal nucleus and ventral tegmental area) were labeled. The discussion
is focused on the CNS cell groups involved in the control of body temperature and
fever.
PMID- 9554994
TI - Kinetic mechanism of glutathione conjugation to leukotriene A4 by leukotriene C4
synthase.
AB - The kinetic mechanism for human leukotriene (LT) C4 synthase, a membrane-bound
glutathione S-transferase, which catalyzes the conjugation of glutathione (GSH)
to 5,6-oxido-7,9,11, 14-eicosatetraenoic acid (LTA4), to form 5(S)-hydroxy-6(R)-S
glutathionyl-7,9,trans-11, 14-cis-eicosatetraenoic acid (LTC4) was investigated
by initial rate kinetic studies in which concentrations of both substrates and
the reversible dead-end inhibitor, 2-[2-[1-(4-chlorobenzyl)-4-methyl-6-[(5
phenylpyridin-2-yl)- methoxy]- 4,5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2
yl]ethoxy]butanoic acid (L-699,333) were varied. Analysis of the initial
velocities of LTC4 formation in the absence of the inhibitor using non-linear
regression fits of various models to the data favoured a random, rapid
equilibrium mechanism, with strong substrate inhibition by LTA4, over both a
compulsory ordered mechanism and a ping-pong mechanism. The estimated parameters
were calculated to be Vmax = 14 +/- 4 microM/min, KLTA4 = 40 +/- 18 microM, KGSH
= 0.4 +/- 0.2 mM, and a KiLTA4 = 2.3 +/- 1.7 microM for the rapid equilibrium
random model. Inhibition of enzymatic activity by L-699,333 was found to be
reversible as assessed by the ability of the enzyme to restore its activity by
95% upon dilution. L-699,333 was found to be a competitive inhibitor against GSH
and non-competitive against LTA4. Non-linear least squares regression analysis
yielded estimated parameters of Km = 0.7 +/- 0.1 mM, Vmax = 2.5 +/- 0.1
microM/min, and Ki = 0.7 +/- 0.1 microM for GSH at a fixed LTA4 concentration of
20 microM, and Km = 45 +/- 3 microM, Vmax = 4.9 +/- 0.2 microM/min, and a Ki =
5.8+/-0.4 microM for LTA4 at a fixed GSH concentration of 2 mM. The rate equation
for the random equilibrium mechanism accommodates the inhibition patterns
observed for L-699,333 against both substrates as revealed by kinetic fits of the
inhibition data to the overall rate equation.
PMID- 9554993
TI - Neuronal and glial epitopes and transmitter-synthesizing enzymes appear in
parallel with membrane excitability during neuroblastoma x glioma hybrid
differentiation.
AB - The membrane excitability and the presence of neural proteins, including neuronal
and glial markers and neurotransmitter-synthesizing enzymes, were examined in
parallel while the NG108-15 cell line was maintained in a serum-free medium.
Whole-cell recordings in voltage-clamp or current-clamp configurations were used
to evaluate the membrane excitability, and immunostaining was done with a panel
of well-characterized antibodies against NSE, NF150, S-100 beta, GFAP, ChAT and
TH. Culture for 4 to 10 days led to a striking rise in neurite outgrowth,
electrical excitability and expression of neural proteins in type I neuron-like
cells, which were of both neuronal and glial character, and expressed both
cholinergic and adrenergic traits. After about 2 weeks, type II cells which lack
neurite processes began to emerge. The type II cells proliferated, as revealed by
BrdU uptake, and gradually overgrew differentiated cell types. They exhibited
little or no membrane excitability and absence of immunoreactivity for the
neuronal and glial specific proteins tested. These measurements indicate that the
presence of these neural proteins at crucial stages of membrane excitability
development is an important characteristics of NG108-15 cell differentiation,
providing insights into the neural development and the reversible nature of
neoplasia in the nervous system.
PMID- 9554995
TI - Participation of hippocampal formation in negative feedback inhibition of penile
erection in the rat.
AB - Detailed information on how the central nervous system regulates penile erection,
particularly the inhibitory aspect, is sparse. We observed in Sprague-Dawley rats
anesthetized and maintained with chloral hydrate that administration of
papaverine (400 microg) directly into the corpora cavernosum of the penis
produced an increase in intracavernous pressure (ICP). This elicited experimental
index for penile erection was accompanied by a transient increase in the root
mean square values, concurrent with a shift in the contribution of Theta
(increase) and delta (decrease) power to the hippocampal electroencephalographic
(hEEG) activity. Reversal blockade of these hEEG responses with xylocaine, given
either intrathecally at the L6-S1 spinal levels or unilaterally to the
hippocampal formation, significantly heightened and prolonged the ICP response.
Pretreatment with xylocaine by itself, however, did not alter appreciably the
baseline ICP or hEEG activity. These results suggest the presence of a novel
negative feedback inhibitory mechanism in the hippocampal formation, which is
triggered by ascending sensory inputs initiated by tumescence of the penis during
normal erectile processes.
PMID- 9554996
TI - Prolonged anoxic depolarization exacerbates NADH hyperoxidation and promotes poor
electrical recovery after anoxia in hippocampal slices.
AB - Mitochondrial dysfunction appears to occur during brain ischemia and following
reperfusion. A characteristic event during reoxygenation after anoxia in
hippocampal slices is hyperoxidation of the electron carriers of the
mitochondrial respiratory chain. Earlier studies suggested that calcium influx
due to loss of ion homeostasis during anoxia was linked to neuronal damage. Since
a link between cytosolic calcium overload and post-anoxic hyperoxidation (PAMHo)
has been suggested in previous studies, present studies sought to test the
hypothesis that the length of anoxic depolarization can influence hyperoxidation
and electrical activity recovery following anoxia in hippocampal slices. Rat
hippocampal slices were made anoxic and then allowed to recover for 60 min. The
time of anoxia was defined by the time of anoxic depolarization (AD), and slices
were divided in five groups: 0.5, 1, 2, 5 and 10 min of AD. Reduction/oxidation
shifts of NADH were measured by rapid scanning spectrofluorometry. Synaptic
activity was indicated by population spike amplitudes in the CA1 pyramidal cell
subfield of the hippocampus in response to stimulation of the Schaffer
collaterals. We report here that mitochondrial hyperoxidation and synaptic
activity in hippocampal slices are highly sensitive to the time in which slices
remain depolarized (AD).
PMID- 9554997
TI - Development of dynorphin-like immunoreactive auditory nerve terminals in the
chick.
AB - The novel discovery that auditory nerve terminals in the chick cochlear nucleus
magnocellularis (NM) are immunoreactive for the opioid peptide dynorphin (DYN)
was recently reported [3]. The present study examines the development of DYN
immunoreactivity (DYN-I) in auditory nerve terminals in NM from embryos through
young post-hatch chicks. No DYN-I was observed in NM at embryonic day 13 (E13).
DYN-I first appeared at E16 as short flat structures partially surrounding NM
cell bodies. Around post-hatch day 1 (P1), these structures had a more rounded,
chalice-type of morphology reminiscent of the specialized auditory nerve
terminals found in birds, the end-bulbs of Held. At P6, most NM neurons were
circumscribed by a prominent DYN-I calyceal-type of ending. By P13, fewer NM
cells were ringed by this DYN-I and by the third post-hatch week, there was very
little DYN-I in NM. There were no obvious differences in the density of DYN-I
terminals across either the rostrocaudal length or the mediolateral width of NM
at any age examined. These results suggest that during a restricted time of
development, end-bulbs of Held in the chick NM contain DYN.
PMID- 9554998
TI - Phospholipases A2 of rod outer segment-free bovine retinae are different from
well-known phospholipases A2.
AB - We have recently demonstrated the presence of phospholipase A2 (PLA2) activity in
a rod outer segment-free retinal fraction which we called P200 and which contains
neuronal cells, Muller cells and rod inner segments. We report here our results
on the characterization of this P200-PLA2 activity. We show that P200 probably
contains more than one type of PLA2, as indicated by the results obtained with
different chromatographically eluted PLA2-active fractions which were treated
with either Ca2+, EGTA, dithiothreitol (DTT) or p-bromophenacyl bromide (pBPB),
or heated. Moreover, the results from PLA2 assays using different substrates, as
well as those obtained after treatment of the homogenate with H2SO4, guanosine 5'
O-(3-thio)triphosphate (GTPgammaS) and ATP, suggest that P200-PLA2 are different
from well-known secretory PLA2, cytosolic PLA2 and Ca2+-independent PLA2. Control
experiments using our 'back-and-forth'-thin layer chromatography (bf-TLC)
technique allowed us to confirm that, in our assay conditions, the release of
fatty acids was due to PLA2 enzymes. These results, which constitute the first
characterization of PLA2 of the neural retina, thus suggest that it contains
novel types of PLA2 enzyme, in contrast to well-known PLA2.
PMID- 9554999
TI - Microinjections of anisomycin into the intermediate cerebellum during learning
affect the acquisition of classically conditioned responses in the rabbit.
AB - The purpose of this study was to examine the effects of protein synthesis
inhibition in the intermediate cerebellum on the acquisition and expression of
classically conditioned nictitating membrane responses in the rabbit. Animals
were conditioned for three days in a standard delay paradigm. Before each
training session, either a solution of anisomycin (a protein synthesis inhibitor)
or vehicle was bilaterally injected into the interposed cerebellar nuclear.
Following these three training sessions, rabbits were tested to determine whether
the previous training under the influence of anisomycin or vehicle resulted in
the acquisition of conditioned responses. In this test, animals that were
injected previously with the protein synthesis inhibitor exhibited significantly
less retention of conditioned responses than rabbits injected with vehicle.
Additional experiments demonstrated that anisomycin does not block the expression
of conditioned responses during conditioning or in well-trained animals.
Microinjections of muscimol at the same sites of the previous drug infusions
suppressed the expression of conditioned responses, indicating that the protein
synthesis inhibitor was applied to the eyeblink-related parts of cerebellar
circuits. The obtained data are the first to demonstrate that a manipulation of
cerebellar circuits, which does not affect the performance of learned behavior,
can affect the process of learning. These results suggest that the synthesis of
new proteins in the intermediate cerebellum participates in the formation of
plastic changes responsible for eyeblink conditioning.
PMID- 9555000
TI - Parasympathetic varicosity proliferation and synaptogenesis in rat eyelid smooth
muscle after sympathectomy.
AB - Parasympathetic innervation to eyelid smooth muscle inhibits sympathetic
neurotransmission pre-junctionally without appreciable direct post-junctional
effects. However, 5 weeks after sympathectomy, parasympathetic stimulation
elicits substantial cholinergically mediated contractions. This study examined
ultrastructural changes accompanying the conversion to parasympathetic
excitation. In intact muscles, 64+/-9 nerve varicosities were encountered per 104
micron2. Most were close to muscle cells and not fully enclosed by supporting
cells. Axo-axonal synapses were observed occasionally. Two days following
sympathectomy, varicosity numbers were reduced by 97% and, relative to controls,
remaining varicosities were farther from muscle cells and more frequently fully
enclosed by supporting cells, but contained greater numbers of small spherical
and large dense vesicles. By 6 weeks post-sympathectomy, numbers of varicosities
per unit muscle volume increased to 14% of controls. These varicosities differed
from those at 2 days in being closer to smooth muscle cells, less frequently
enclosed, and having fewer small vesicles. These findings indicate that intact
eyelid smooth muscle varicosities are predominantly sympathetic, but a small
number of parasympathetic varicosities are present, some of which may form pre
junctional synapses with sympathetic nerves. Between 2 days and 6 weeks post
sympathectomy, varicosities increased in number and established appositions with
smooth muscle cells. This suggests that parasympathetic nerves are capable of re
innervating an atypical smooth muscle target after sympathectomy, and that
parasympathetic synaptogenesis is likely to contribute to conversion from pre
junctional inhibition to post-junctional excitation after sympathectomy.
PMID- 9555001
TI - NMDA receptor activation enhances the release of a cholinergic differentiation
peptide (HCNP) from hippocampal neurons in vitro.
AB - Hippocampal cholinergic neurostimulating peptide (HCNP) is a novel undecapeptide
purified from the hippocampus of young rats. The peptide stimulates cholinergic
phenotype development in the rat medial septal nucleus in vitro. Here, we have
focused on the mechanism of release of the peptide from the hippocampus, by
applying tissue culture techniques. Quantitation of HCNP in the culture
supernatant after chemical stimulation was carried out by RIA, and by a
combination of HPLC and RIA. We found that the N-methyl-D-aspartate (NMDA)
receptor specifically mediates release of the deacetylated form of HCNP from the
culture. Our results suggest that during the early development of hippocampal
neurons, the peptide is released by NMDA receptor activation, and that it may be
involved in mediating the effect of activity-dependent cues on developing septal
cholinergic neurons.
PMID- 9555002
TI - Pharmacological characterisation of the histamine H3 receptor in the rat
hippocampus.
AB - The purpose of this report was to pharmacologically characterise the histamine H3
in the rat hippocampus using radioligand binding studies with the H3 receptor
antagonist [125I]iodophenpropit and the H3 receptor mediated inhibition of
[3H]noradrenaline release. A dissociation constant of 0.33 nM and a maximal
number of binding sites of 125 fmol/mg protein were found for
[125I]iodophenpropit. Competition studies showed stereoselectivity for the (R)
and (S) enantiomers of alpha-methylhistamine and 10 microM of GTPgammaS shifted
the curve of (R)-alpha-methylhistamine rightwards. Up to 1 microM, (R)-alpha
methylhistamine displaced only 30% whereas the tested H3-antagonists displaced 50
60% of the total [125I]iodophenpropit bound. This indicates the presence of an
additional non-H3 receptor binding site(s) for [125I]iodophenpropit in the rat
hippocampus. This secondary site shows low affinity for H3 agonists, but high
affinity for the tested H3 antagonists. Electrically evoked [3H]acetylcholine
release was shown in slices of rat hippocampus. No H3 receptor modulation of
[3H]acetylcholine release from hippocampal slices was detectable. However, H3
receptor activation inhibited 42% of the electrically-evoked [3H]noradrenaline
release in rat hippocampal slices. The inhibition of [3H]noradrenaline release
was effectively antagonized by the H3 antagonists thioperamide and burimamide. We
describe the pharmacological identification of the histamine H3 receptor in the
rat hippocampus and its similarities and differences from the cortical H3
receptor. These studies enable us to investigate changes in density and
functionality of the hippocampal H3 receptor under (patho)physiological
conditions.
PMID- 9555003
TI - Vesicular amine transporter expression and isoform selection in developing brain,
peripheral nervous system and gut.
AB - The vesicular monoamine transporters VMAT1 and VMAT2 are essential components of
monoaminergic neurons and endocrine cells whose expression in development may
provide insight into lineage pathways for chemical coding in the diffuse
neuroendocrine system. Thus, the brain is a compartment in which only
monoaminergic neurons are generated, the gut epithelium generates only endocrine
monoamine-containing cells, and the neural crest produces both autonomic
monoaminergic neurons and endocrine/paracrine monoaminergic cells. Selection of
either the VMAT1 or VMAT2 isoform was examined in these three compartments during
development. In the central nervous system VMAT2, but not VMAT1, was expressed in
neuroepithelial cells by embryonic day 12 (E12), and all major monoaminergic cell
groups by E14. Thalamocortical and hypothalamic neurons that do not express VMAT2
in adulthood were transiently VMAT2-positive from E16 to postnatal day 6 (P6). EC
cells of the gut expressed exclusively VMAT1 from E19 on, while histamine
containing enterochromaffin-like (ECL) cells of the stomach expressed only VMAT2
by E19 and throughout postnatal development. VMAT2 and the vesicular
acetylcholine transporter VAChT were co-expressed in early development of the
primary sympathetic chain as well as in the cranial parasympathetic ganglia.
VAChT was progressively restricted to a small population of VMAT2-negative post
ganglionic neurons in the adult sympathetic chain, while VMAT2 expression
persisted in sympathetic principal ganglion and SIF cells but was eventually
extinguished in cranial parasympathetic ganglia. VMAT1 was co-expressed with
VAChT and VMAT2 mRNA in the primary sympathetic chain on E12, but progressively
restricted to small intensely fluorescent (SIF) and chromaffin cells thereafter.
Thus, expression of the vesicular amine transporters appropriate for chemical
coding of brain neurons and gut endocrine cells are pre-determined
developmentally. In contrast, the neural crest-derived sympathoadrenal and neural
crest-derived parasympathetic cell groups examined here initially co-express two
or more vesicular amine transporters, followed by extinction of the inappropriate
transporter(s) later in development. Some neural crest-derived neuroendocrine
cell populations continue to express both isoforms of VMAT even in adulthood.
Lineage distinctions in ontogeny of vesicular amine transporter expression in
brain, gut and autonomic nervous system make it likely that the same genes are
regulated differently in the autonomic nervous system compared to brain and gut.
PMID- 9555004
TI - Differential expression of calbindin and calmodulin in motoneurons after
hypoglossal axotomy.
AB - Axotomy induces a profound modification of Ca2+ homeostasis in injured neurons
which may lead to neuronal death. Remarkably, after axotomy and resection of the
hypoglossal nerve, 65-75% of the hypoglossal motoneurons survive in the long term
and this suggests some adaptive mechanisms compensating the massive calcium
influx. As potential components of this adaptation, we have examined calmodulin
and calbindin-D28k by in situ hybridisation and immunohistochemistry in
motoneurons of the rat after hypoglossal nerve transection. Neuronal calbindin
mRNA and protein content was low in normal state, transiently increased to 200%
of the basal expression at 8 days post-operation (dpo), then declined to normal
again until 28 dpo. Calmodulin mRNA was highly expressed in normal hypoglossal
motoneurons and remained constant after axotomy. Calmodulin protein
immunoreactivity, however, was transiently decreased in axotomised motoneurons
suggesting post-transcriptional modification. The upregulation of calbindin
expression may facilitate the survival of injured motoneurons.
PMID- 9555006
TI - Expression of substance P receptor in the substantia nigra.
AB - Since the substantia nigra receives abundant substance P innervations but lacks
clear evidences about a presence of substance P receptors, expressions for mRNA
and protein of substance P receptors were investigated in the rat to resolve this
mismatch. Expression levels of substance P receptors mRNA in the substantia nigra
pars compacta and reticulata were 37.7 and 24.1% of those in the striatum,
respectively, by reverse transcription-polymerase chain reaction (RT-PCR).
Substance P receptors mRNA was found in dopamine neurons of the substantia nigra
pars compacta by single cell RT-PCR. Ca. 90% of dopamine neurons in the
substantia nigra pars compacta were immunoreactive to anti-substance P receptor
antibody in the colchicine treated rats. These are the first direct evidence for
the existence of substance P receptors in dopamine neurons of the substantia
nigra pars compacta.
PMID- 9555005
TI - Oxidative modification of HDL3 in vitro and its effect on PLTP-mediated
phospholipid transfer.
AB - The oxidation of HDL3 by Cu(II) and its effect on the ability of these particles
to act as phospholipid acceptors in human plasma phospholipid transfer protein
(PLTP)-mediated lipid transfer were investigated. Oxidation of HDL3 was monitored
by measuring the following parameters: (i) formation of conjugated dienes, (ii)
production of thiobarbituric acid reactive substances (TBARS), (iii) decrease in
reactive lysine and (iv) tryptophan residues, (v) change in particle charge and
(vi) diameter, and (vii) oligomerisation of apoA-I and apoA-II. Formation of
conjugated dienes was the parameter responding to the oxidative treatment with
the fastest kinetics. The appearance of TBARS and modification of apolipoprotein
tryptophan residues were detected simultaneously but required higher Cu(II)
concentrations for maximal kinetics. Cross-linking of the major protein
constituents of HDL3, apoA-I and apoA-II, represented later steps of the
oxidation process. Further, the oxidative modification was accompanied by a
progressive change in HDL3 particle charge and a minor increase in particle
diameter. PLTP-mediated phospholipid transfer to the oxidized particles was
investigated using an assay measuring the transfer of fluorescent, pyrene-labeled
PC. The transfer was significantly inhibited, but only after extensive
modification of the HDL proteins, suggesting that the HDL oxidative modifications
occurring in vivo do not essentially impair its phospholipid acceptor function. A
similar but less pronounced inhibition was observed when two other phospholipid
transfer proteins, the nonspecific lipid transfer protein (ns-LTP) and the
phosphatidylcholine transfer protein (PC-TP), were studied in parallel. This
indicates that the inhibition was partly due to unspecific effects of the
modification on acceptor particle surface properties, but included an aspect
specific for PLTP.
PMID- 9555007
TI - Laminin inhibits Abeta42 fibril formation in vitro.
AB - In the present study, we investigated whether or not laminin inhibits Abeta42
fibril formation in the same manner as Abeta40. Both a thioflavine-T fluorometric
assay and electron microscopy by negative staining demonstrated laminin to have a
concentration-dependent inhibitory effect on Abeta42 fibril formation. The
amyloid fibril formation was inhibited approximately by 70% due to the presence
of 1.0 mg/ml laminin co-incubated with 1. 0 mg/ml Abeta42 peptide (molar ratio;
Abeta42 peptide:laminin=200:1). These results thus suggested that laminin or its
derivatives may be effective as therapeutic agents to either prevent or slow down
the progression of amyloidogenesis in Alzheimer's disease.
PMID- 9555008
TI - The 5-HT3 receptor agonist attenuates the action of antidepressants in the forced
swim test in rats.
AB - Involvement of 5-hydroxytryptamine (5-HT)3 receptors in action of antidepressants
was examined in the forced swim test in rats. Rats were forced to swim in a
cylinder for 15 min on day 1 and for 5 min on day 2. Imipramine, desipramine and
mianserin, administered after the 15-min swim session on day 1 and before the 5
min swim test on day 2, dose-dependently decreased the duration of immobility in
the swim test on day 2. 1-(m-Chlorophenyl)-biguanide (mCPBG) attenuated the
decreased duration of immobility induced by imipramine, desipramine and
mianserin, although mCPBG did not affect the duration of immobility when it was
given alone. ICS205-930 dose-dependently decreased the duration of immobility in
the swim test on day 2, and the effect of ICS205-930 was attenuated by mCPBG.
These results suggest that the suppression of 5-HT3 receptor activity may
contribute to the action of antidepressants.
PMID- 9555009
TI - Diffusion, perfusion, and T2 magnetic resonance imaging of anti-intercellular
adhesion molecule 1 antibody treatment of transient middle cerebral artery
occlusion in rat.
AB - The effect of anti-intercellular adhesion molecule-1 (anti-ICAM-1) antibody
treatment of transient (2 h) middle cerebral artery (MCA) occlusion in the rat
was measured using diffusion (DWI)-, T2 (T2I)- and perfusion (PWI)-weighted
magnetic resonance imaging. Rats were treated upon reperfusion with an anti-ICAM
1 monoclonal antibody (n=11) or a control antibody (n=7). DWI, T2I and PWI were
performed before, during, and after induction of focal cerebral ischemia from 1 h
to 7 days. In both groups, the apparent diffusion coefficient of water (ADCw) and
cerebral blood flow (CBF) values in the ischemic region significantly declined
from the preischemic ADCw values (p<0. 05). The post ischemic increase in T2 of
the control group was significantly higher at 48 h than in the anti-ICAM-1
treated group (p<0.05). CBF was not significantly different between the two
groups. The temporal profiles of MRI cluster analysis, which combines ADCw and T2
maps into a single image, was significantly different between groups. These data
suggest that the neuroprotective effect of anti-ICAM-1 antibody treatment is
reflected in reductions of T2 and lesion growth during reperfusion and may not be
associated with increased cerebral perfusion.
PMID- 9555010
TI - Molecular cloning, functional expression and tissue distribution of rat acyl
coenzyme A:cholesterol acyltransferase.
AB - Acyl-coenzyme A:cholesterol acyltransferase (ACAT) is an enzyme catalyzing the
intracellular formation of cholesteryl esters from free cholesterol and fatty
acyl-CoA. In the present study, we cloned rat ACAT cDNA and determined its tissue
distribution. Rat ACAT cDNA, having a coding region of 1635 bp with its deduced
protein sequence of 545 amino acids and two typical motifs such as signature
sequences and leucine heptad motif, showed 83, 92 and 90% identity with human,
mouse, and hamster ACAT, respectively. Expression of rat ACAT cDNA in A293 cells
and CHO cells resulted in a 3.0 to 3.5-fold increase in the enzyme activity.
Among twelve tissues examined, ACAT activity was highest in adrenal followed by
liver and intestine while that of aorta was extremely low. The mRNA level was
also the highest in adrenal among four tissues examined. However, in contrast to
its high ACAT activity, the liver mRNA level was extremely low (adrenal >>
intestine > aorta >> liver). Consistent with mRNA levels, immunohistochemical
analyses with a specific ACAT antibody detected significant ACAT signals in
adrenal and intestine but a negligible signal in liver. These results indicate
that adrenal most abundantly expresses ACAT in rat. Furthermore, rat liver showed
a high ACAT activity but an extremely low ACAT mRNA and negligible
immunohistochemical reactivity, suggesting the presence of a structurally
different ACAT protein(s) in rat liver.
PMID- 9555011
TI - Effects of extracellular calcium and magnesium on central respiratory control in
the brainstem-spinal cord of neonatal rat.
AB - The influence of extracellular Ca2+ and Mg2+ concentrations ([Ca2+]ECF and
[Mg2+]ECF, respectively) on central respiratory control was analyzed using the
isolated brainstem-spinal cord of the neonatal rat. Central respiratory activity
was recorded from the C4 ventral roots. The depth profile of [Ca2+]ECF below the
ventral medullary surface was measured with ion-sensitive electrodes. The
gradient in [Ca2+]ECF disappeared about 1 h after changing superfusate Ca2+
([Ca2+]CSF) from 2 to 0.5 mM, but not even in 2 h after switching to Ca2+-free
superfusate. High [Ca2+]CSF (4 mM) or high [Mg2+]CSF (4, 8 mM) decreased
respiratory frequency (fR), whereas low [Ca2+]CSF (0.5 mM) increased fR and
augmented the respiratory CO2 responsiveness. High [Ca2+]CSF as well as low
[Mg2+]CSF (0.5 mM) disturbed respiratory rhythm and pattern, which were markedly
restored by high CO2. The depressing effect of high [Ca2+]ECF and the stimulating
effect of low [Ca2+]ECF on the medullary neuronal activity were confirmed by
perforated patch recordings. These results suggest that [Ca2+]ECF and [Mg2+]ECF
determine the excitability of the respiratory neuron network by modulating the
neuronal surface potential, transmembrane Ca2+ influx, Ca2+-sensitive cation
channel gating, and synaptic transmission. Furthermore, some of these actions
appear to be antagonized by CO2/H+.
PMID- 9555012
TI - Localization of 5-HT2A receptor in rat cerebral cortex and olfactory system
revealed by immunohistochemistry using two antibodies raised in rabbit and
chicken.
AB - Serotonin 2A receptor (5-HT2A receptor) is widely distributed in the central
nervous system, and has been suggested to be involved in a variety of behavioral
conditions and neuropsychiatric disorders. Two polyclonal antibodies were raised
against the N-terminus peptide of rat 5-HT2A receptor in chickens (5-HT2A-N) and
a glutathione S-transferase fusion protein that contained the C-terminus of the
mouse 5-HT2A receptor in rabbits (5-HT2A-C). Affinity-purified 5-HT2A-N and -C
antibodies reacted strongly with a single band of 77-78 kDa in postsynaptic
density proteins prepared from the rat cortex. The distribution pattern of
immunoreactive structures in the rat brain was virtually the same for the two
antibodies. The highest levels of immunoreactivity were observed in the olfactory
bulb, neocortex, claustrum, piriform cortex, mamillary bodies, pontine nuclei,
red nucleus and cranial motor nuclei. In the olfactory bulb, mitral cells were
intensely labeled. In the neocortex, many immunoreactive neurons were found in
layers II-VI. In layer IV of the neocortex, strong neuropil labeling was
observed. In a double-labeling study using chicken 5-HT2A-N and rabbit anti-glial
fibrillary acidic protein (GFAP) antibody, a considerable number of GFAP positive
cells also showed 5-HT2A immunoreactivity. By using an immunoelectron microscopic
technique, 5-HT2A receptor immunoreaction was shown to be localized just beneath
the postsynaptic membrane thickening of asymmetric synapses.
PMID- 9555013
TI - Transplanted embryonic entorhinal neurons make functional synapses in adult host
hippocampus.
AB - Grafts of embryonic entorhinal cortex (EC) or non-entorhinal cortex (NEC) were
placed into the hippocampus of adult rats with transection of the perforant
paths. Graft-host connectivity was investigated at 4-6 months post
transplantation by recording extracellular evoked responses in hippocampal slice
preparations. Electrical stimulation of the grafts evoked excitatory postsynaptic
potentials (EPSPs) in the outer molecular layer of the dentate gyrus, and the
stratum lacunosum moleculare of CA1, CA3, and elicited population spikes in the
granule cell layer and the pyramidal cell layer of CA1, but not CA3. While the
latencies and the forms of these evoked response were similar to those in matched
control slices from the normal animals, the amplitudes were smaller than normal
controls. However, in the slices with NEC grafts, no such responses were recorded
when stimulus was applied in similar position in the grafts. The findings suggest
that grafted entorhinal neurons make viable synaptic connections with the host
hippocampus.
PMID- 9555014
TI - Indirect dexamethasone down-regulation of the liver fatty acid-binding protein
expression in rat liver.
AB - The effects of glucocorticoids on the regulation of the liver fatty acid-binding
protein (L-FABP) were studied in vivo and in primary culture of hepatocytes in
rats. No change in L-FABP cytosolic content and mRNA levels occurred after
adrenalectomy. By contrast, a twofold decrease in L-FABP expression was found in
dexamethasone (Dex) treated rats. In primary culture of rat hepatocytes, insulin
did not modify the L-FABP mRNA levels, whereas Dex produced a significant
decrease. This down-regulation was independent of specific glucocorticoid
receptors, of alteration in the turnover of L-FABP mRNA and did not require a de
novo protein synthesis. However, it was totally prevented when 320 microM oleic
acid was added in the culture medium. These findings show that the dex-mediated
down-regulation of the L-FABP expression found in vivo is not due to a direct
endocrine effect, but is likely secondary to changes in cellular lipid
metabolism.
PMID- 9555015
TI - Composition of ibotenic acid-induced calcifications in rat substantia nigra.
AB - Agonists of the excitatory neurotransmitter glutamate have neurotoxic properties
and are, therefore, frequently used to place locally circumscript brain lesions.
In certain vulnerable brain areas, especially the substantia nigra and globus
pallidus, the ensuing neurodegeneration is accompanied by the formation of
calcium deposits. In the present study, we investigated the structure and
chemical composition of calcium deposits formed in rat substantia nigra upon
local application of ibotenic acid. Using scanning and transmission electron
microscopy in combination with X-ray analysis and analysis of the electron
diffraction patterns, we demonstrate that the inorganic components of the
calcifications consist of calcium and phosphate. The calcium phosphate is
deposited in a polycrystalline manner in degenerating neurons and in a matrix
surrounding the degenerated complexes. New matrix is continuously added around
the enlarging calcium deposits. Content of inorganic material is always higher in
the center of the deposits than in the margin, but in every case the diffraction
pattern reveals that the calcium phosphates are present in the form of
hydroxyapatite. Thus, organic and inorganic components of the calcifications are
subject to a continuous process of growth and maturation. The ibotenic acid
induced calcium deposits in rat substantia nigra provide a reliable model system
to study the pathogenesis of non-arteriosclerotic calcifications.
PMID- 9555016
TI - Midkine exists in astrocytes in the early stage of cerebral infarction.
AB - Midkine (MK), a heparin-binding neurotrophic factor, is expressed in the early
stage of experimental cerebral infarction in the zone surrounding the infarct.
Double immunostaining with anti-MK and anti-glial fibrillary acidic protein
showed existence of MK in astrocytic cytoplasm on postoperative day 2.
Immunoelectron microscopic analysis revealed the presence of MK in the swollen
astrocytic processes on postoperative day 4.
PMID- 9555017
TI - Serotonergic activity in the rat striatum after intrastriatal transplantation of
fetal nigra as measured by microdialysis.
AB - In vivo microdialysis was used to examine the effects of dopaminergic transplants
on extracellular concentrations of dopamine (DA), serotonin (5-HT), and their
precursors and major metabolites in the denervated rat striatum. Dialysis
perfusates were collected from intact 6-hydroxydopamine (6-OHDA) lesion plus sham
grafted, and lesion plus fetal substantia nigra (SN) grafted striata. The SN
transplants ameliorated the reduction of striatal DA and dihydroxyphenylacetic
acid (DOPAC) levels in rats with unilateral 6-OHDA lesions of the mesostriatal
pathway. The transplants also increased extracellular levels of 5-HT and 5
hydroxyindoleacetic acid (5-HIAA) in the denervated striatum. In response to NSD
1015 (an inhibitor of aromatic L-amino acid decarboxylase, AADC), 5
hydroxytryptophan (5-HTP) levels were substantially elevated in the SN grafted
striata as compared with those in the sham grafted controls, which continued even
after subsequent administration of L-3,4-dihydroxyphenylalanine (L-DOPA, 100
mg/kg i.p.). Immunohistochemical analysis showed hyperinnervation of 5-HT fibers
in the grafted striatum, which was consistent with the results of microdialysis
experiments. These results indicated that implantation of SN grafts into the 6
OHDA-lesioned striatum of rats induces hyperactivity of 5-HT synthesis, release
and metabolism.
PMID- 9555018
TI - The development of synaptophysin-like immunoreactivity in the lumbosacral
enlargement of the spinal cord of the opossum Monodelphis domestica.
AB - The presence of synaptophysin in the lumbosacral enlargement of developing
opossums, Monodelphis domestica, was studied immunohistochemically at the light
microscopic level. In newborn, synaptophysin-labeling was observed in the
presumptive white matter, presumably in growing axons, and was scant in the
ventrolateral gray matter. Over the next 3 weeks the labeling filled the gray
matter following a general ventrodorsal gradient. Labeling was found in the white
matter until the fifth week. Synaptogenesis in the lumbosacral enlargement of the
opossum thus occurs mostly postnatally, when many descending axons have already
reached that level. It is particularly intense in the ventral horn when the
hindlimbs begin to move, and in the dorsal horn when sensorimotor reflexes can be
elicited.
PMID- 9555019
TI - Alzheimer-associated presenilin-1 gene is induced in gerbil hippocampus after
transient ischemia.
AB - To investigate the biological roles of the presenilin-1 (PS-1) gene after
neuronal injury, the changes of PS-1 mRNA expression in the gerbil hippocampus
after transient ischemia were examined. From 1 day to 3 day-reperfusion after 5
min-ischemia, PS-1 mRNA was induced in the hippocampus compared with the sham
operated control. The cells which induced the PS-1 genes were neurons of CA3 and
dentate gyrus, the region relatively resistant to ischemic stress. These findings
suggest that the induction of PS-1 genes may be associated with some responses of
neurons damaged by transient ischemia.
PMID- 9555021
TI - Effects of haloperidol metabolites on neurotransmitter uptake and release:
possible role in neurotoxicity and tardive dyskinesia.
AB - This research explored the effects of haloperidol (HP) metabolites on biogenic
amine uptake and release, and compared them to those of MPTP and its toxic
metabolite, MPP+. In synaptosome preparations from mouse striatum and cortex, the
HP metabolites haloperidol pyridinium (HPP+), reduced haloperidol pyridinium
(RHPP+), and haloperidol tetrahydropyridine (HPTP) inhibited the presynaptic
uptake of dopamine and serotonin, with greater affinity for the serotonin
transporter. HPP+ was the most potent inhibitor of dopamine uptake, and HPTP of
serotonin uptake, both with IC50 values in the low micromolar range. RHPP+ was
less active than the other metabolites, but was more active than the parent
compound, HP. Inhibition of uptake was reversed when free drug was removed by
centrifugation and then resuspension of the synaptosomes in fresh buffer,
suggesting that inhibition of uptake was due to interaction with the transporters
and was not due to irreversible cytotoxicity. HPP+ showed noncompetitive
inhibition of both serotonin and dopamine uptake, suggesting that it has a
relatively slow dissociation rate for its interaction with the transporter
proteins. In experiments on amine release, HPP+ and HPTP were four-fold less
potent than MPP+ for releasing preloaded dopamine from striatal synaptosomes, and
only MPP+-dependent release was antagonized by the uptake blocker, mazindol. In
contrast, RHPP+ displayed little ability to release either amine
neurotransmitter. HPTP was about two-fold more potent than MPP+ for releasing
serotonin from cortical synaptosomes, whereas HPP+ was less active than MPP+. The
specific serotonin transport blocker fluoxetine was only able to antagonize
release induced by MPP+. These results suggest that HP metabolites bind to the
transporters for dopamine and serotonin, but are not transporter substrates. In
contrast to their potent effects on amine release, HPP+ and HPTP were unable to
release preloaded GABA from cortical synaptosomes. The implications of these
results concerning a possible role of HP metabolites in the development of
tardive dyskinesia are discussed.
PMID- 9555020
TI - Platelet-derived growth factor and fibroblast growth factor differentially
regulate interleukin 1beta- and cAMP-induced group II phospholipase A2 expression
in rat renal mesangial cells.
AB - Expression of group II phospholipase A2 (PLA2; EC 3.1.1.4) in rat renal mesangial
cells is triggered in response to two principal classes of activating signals.
These two groups of activators comprise inflammatory cytokines such as
interleukin 1beta (IL-1beta) or tumor necrosis factor alpha and agents that
elevate cellular levels of cyclic AMP (cAMP) such as forskolin, an activator of
adenylate cyclase. Treatment of mesangial cells with IL-1beta or forskolin for 24
h induces group II PLA2 activity secreted into cell culture supernatants by about
15-fold and 11-fold, respectively. Platelet-derived growth factor (PDGF)-BB
potently inhibits secretion of IL-1beta- and forskolin-induced group II PLA2
activity. By Western and Northern blot analyses, we demonstrate that this is due
to a reduction of PLA2 protein levels and the corresponding PLA2 mRNA steady
state levels. Basic fibroblast growth factor (bFGF) virtually does not inhibit IL
1beta-stimulated group II PLA2 activity, but markedly inhibits forskolin-induced
expression of group II PLA2 activity. These effects are caused by changes in the
corresponding PLA2 protein and PLA2 mRNA steady-state levels. Inhibition of
protein kinase C (PKC) by the potent and selective PKC inhibitor calphostin C
converted the inhibitory action of PDGF into a bFGF-type of response thus
suggesting that PKC is a major effector in PDGF-induced inhibition of IL-1beta
stimulated group II sPLA2 expression. In summary, our data suggest that PDGF and
bFGF differentially modulate in a stimulus-specific manner the expression of
group II PLA2 in mesangial cells.
PMID- 9555022
TI - RU-486 blocks stress-induced enhancement of proenkephalin gene expression in the
paraventricular nucleus of rat hypothalamus.
AB - The purpose of this study was to investigate the glucocorticoid (GC) mediated
regulation of corticotropin-releasing hormone (CRH) and proenkephalin (PE) gene
expressions in the paraventricular nucleus (PVN) of the hypothalamus during
physical stress induced by a single intraperitoneal (i.p.) injection of
hypertonic saline (9% NaCl). Previous intracerebroventricular (i.c.v.)
administration of the type II glucocorticoid receptor (GR) antagonist RU-486 (20
ng/rat), increased the basal CRH mRNA levels in the PVN but had no effect on PE
gene expression. Stress induced by injection of hypertonic saline increased both
CRH and PE mRNA levels in PVN. Administration of RU-486 completely blocked the
stress-induced increase of PE mRNA levels, but failed to alter the CRH mRNA
levels in the PNV. These data suggests that, under these experimental conditions,
endogenous GC are necessary for a normal PE response to hypertonic saline stress.
PMID- 9555023
TI - Postnatal conditioning for spreading cortical depression in the rat brain.
AB - The cerebral cortex of anaesthetised 2- to 12-day-old rats was superfused with
artificial cerebrospinal fluid containing 100 mM acetate substituted for chloride
to condition the brain for spreading depression (SD). After such superfusion, the
earliest SD-like events were found at day 9 and full blown SD at day 10, whereas
in the unconditioned brain the first SD occurred between days 12 and 15. Acetate
conditioning of the cerebral cortex may be used to unmask neuronal and glial
properties that are hidden in early stages of development.
PMID- 9555024
TI - Altered number of diaphorase (NOS) positive neurons in the hypothalamus of rats
with heart failure.
AB - Recently, we have demonstrated a decreased neuronal isoform of nitric oxide
synthase (nNOS) message in the hypothalamus of rats with heart failure (HF). The
purpose of this study was to determine the changes in NADPH-diaphorase (a
commonly used marker for neuronal NOS activity) positive neurons in specific
hypothalamic sites of rats with HF. After a standard histochemical protocol, NOS
positive neurons were measured in paraventricular nucleus (PVN), supraoptic
nucleus (SON), median preoptic area (MePO), subfornical organ (SFO), organum
vasculosum of the lamina terminalis (OVLT) and lateral hypothalamus (LH) of rats
with coronary artery ligation (HF group; n=8) and sham-operated control rats
(n=9). A total of 4 months after coronary ligation, the rats in the HF group
displayed infarcts greater than at least 35% of the left ventricular wall (n =
8). Sham-operated rats had no observable damage to the myocardium. Rats with HF
had a significantly lower number of NOS positive cells in the PVN (36% less)
compared to sham rats. The number of NOS positive cells remained unaltered in the
SON, MePO and LH in rats with HF. Conversely there was an increased number of NOS
positive cells in the SFO (42% greater) and OVLT (100% greater). These data
support the conclusion that the NO system within the hypothalamus involved in
controlling autonomic outflow is altered during HF and may contribute to the
elevated levels of vasopressin and sympatho-excitation commonly observed in HF.
PMID- 9555025
TI - Isolation and characterization of a bovine neural specific protein (CRMP-2) cDNA
homologous to unc-33, a C. elegans gene implicated in axonal outgrowth and
guidance.
AB - We have cloned the cDNA encoding bovine CRMP-2 from bovine brains. A full length
cDNA encoding bovine CRMP-2 was isolated and sequenced. The deduced amino acid
sequence reveals that the gene encodes a protein of 572 amino acids and is highly
homologous to Caenorhabditis elegans unc-33, which controls the guidance and
outgrowth of neuronal axons. The CRMP-2 transcript was present in bovine brains
but not non-neural tissues, and its protein product existed in both soluble and
membrane-bound forms. The expression of CRMP-2 protein and mRNA was upregulated
during neuronal differentiation of rat PC12 cells. Immunoprecipitation of PC12
cell extracts shows that CRMP-2 was co-immunoprecipitated with a 190 kDa protein
(p190). Both CRMP-2 and p190 were phosphorylated on serine residues in vivo and
in vitro in a kinase assay of CRMP-2 immune complexes. Immunocytochemistry shows
that CRMP-2 was exclusively localized in both the central and peripheral nervous
systems in mouse embryos and detectable in the adult brain although the level of
CRMP-2 decreased. The protein was expressed in the axon, dendrite, and cytoplasm
of postmitotic neurons and in the cytoplasm of oligodendrocytes and astrocytes.
The CRMP-2 gene maps to the region of mouse chromosome 14 syntenic with human
chromosome 8p21. Taken together, these data suggest multi-functional roles for
CRMP-2 in developing and adult nervous systems, and the biological activity of
CRMP-2 could be regulated by phosphorylation reaction.
PMID- 9555026
TI - Squalene-hopene cyclase from Methylococcus capsulatus (Bath): a bacterium
producing hopanoids and steroids.
AB - We report the cloning and characterisation of the Methylococcus capsulatus shc
gene, which encodes the squalene-hopene cyclase (SHC). This enzyme catalyses the
complex cyclization of squalene to the pentacyclic triterpene skeleton of
hopanoids and represents the key reaction in this biosynthesis. Using a
combination of PCR amplification and DNA hybridization, two overlapping 2.6 kb
PstI and 3.3 kb SalI DNA fragments were cloned bearing a 1962 bp open reading
frame encoding a 74 kDa protein with 654 amino acids and a predicted isoelectric
point at about pH 6.3. The deduced amino acid sequence of the M. capsulatus shc
gene showed significant similarity to known prokaryotic SHCs and to a lesser
degree to the related eukaryotic oxidosqualene cyclases (OSCs). Like other
triterpene cyclases, the M. capsulatus SHC contains seven so-called QW-motifs as
well as an aspartate-rich domain. The recombinant M. capsulatus SHC was expressed
in Escherichia coli and in vitro activity of the recombinant cyclase was
demonstrated using crude cell-free lysate or solubilized membrane preparation.
The cyclization products hop-22-ene and hopan-22-ol (diplopterol) were identified
by GC and GC-MS.
PMID- 9555027
TI - A light and electron microscopic study of cytoplasmic phospholipase A2 and
cyclooxygenase-2 in the hippocampus after kainate lesions.
AB - The systemic administration of kainate (10 mg/ml) into adult Wistar rats produces
seizures and neurodegeneration. We have studied the effect of kainate
administration on cPLA2 and COX-2 immunoreactivities after 3 days and 1, 2, 4 and
11 weeks. The cPLA2 immunoreactivity was increased in hippocampal neurons at 1
and 3 days after kainate injection suggesting that PLA2 may be involved in
neurodegeneration. Increased cPLA2 and COX-2 immunoreactivities in astrocytes at
1, 2, 4 and 11 weeks after kainate injection indicate an adaptive astrocytic
response that may be associated with gliosis.
PMID- 9555028
TI - NMDA- and MK801-induced changes in dopamine release are attenuated in kainic acid
lesioned nucleus accumbens of conscious rats: an in vivo microdialysis study.
AB - Local application of N-methyl-d-aspartate (NMDA) and a NMDA receptor antagonist,
MK801 through the dialysis membrane into the nucleus accumbens (NAC) caused a
significant decrease and increase in extracellular dopamine (DA) in the NAC of
conscious rats, respectively. These neurochemical changes were significantly
smaller in the kainic acid (KA)-lesioned NAC than in the intact NAC. These
findings show that locally applied NMDA and MK801 into the NAC modulate DA
release mainly through indirect mechanism involving putative GABA neuron of the
NAC.
PMID- 9555029
TI - Adrenomedullin increases intracellular Ca2+ and inositol 1,4,5-trisphosphate in
human oligodendroglial cell line KG-1C.
AB - The effects of adrenomedullin (AM), a hypotensive peptide, were investigated in
cultured human oligodendroglial cell line KG-1C. Human AM increased the
intracellular Ca2+ concentration ([Ca2+]i) at concentrations greater than 10(-7)
M. Human calcitonin gene-related peptide (CGRP), a peptide structurally related
to AM, also increased [Ca2+]i with a potency similar to that of AM. AM increased
[Ca2+]i in the absence of extracellular Ca2+. Further, AM increased inositol
1,4,5-trisphosphate (Ins(1,4,5)P3) level in a concentration-dependent manner
similar to that of AM-induced [Ca2+]i, suggesting that AM-induced elevation of
[Ca2+]i is due to Ca2+ release from Ins(1,4,5)P3-sensitive stores. AM (10(-9) to
10(-6) M) increased cAMP in a concentration-dependent manner. Forskolin also
increased cAMP, but did not mimic the [Ca2+]i-raising effect of AM. These
findings suggest that functional AM receptors are present in oligodendroglial KG
1C cells and that AM increases [Ca2+]i through a mechanism independent of cAMP.
PMID- 9555030
TI - Abnormal localization of iron regulatory protein in Alzheimer's disease.
AB - A role for altered iron metabolism in the pathogenesis of Alzheimer's disease has
been suggested by several reports associating the cardinal neuropathologic
lesions with markers of free radical-induced damage and redox-active iron. We
hypothesized that the abnormal distribution of iron in Alzheimer brain might
result from alterations in iron regulatory proteins (IRP) such as IRP-1 and IRP
2, the main control elements of cellular iron homeostasis. Here, we report that
while IRP-1 is present at similar levels in both Alzheimer and control brain
tissue, IRP-2 shows striking differences and is associated with intraneuronal
lesions, including neurofibrillary tangles, senile plaque neurites and neuropil
threads. Since IRP-2 colocalizes with redox-active iron, our results suggest that
alterations in IRP-2 might be directly linked to impaired iron homeostasis in
Alzheimer's disease.
PMID- 9555031
TI - Reversible translocation of CTP:phosphocholine cytidylyltransferase from cytosol
to membranes in the adult bovine liver around parturition.
AB - The key regulatory enzyme of phosphatidylcholine (PC) synthesis,
CTP:phosphocholine cytidylyltransferase (CT), is known to be activated in vitro
by translocation from soluble to particulate fractions of the cell. In the
present study the periparturient cow was chosen as a model to investigate whether
translocation of CT can contribute to the regulation of PC synthesis in vivo.
Between parturition and 1.5 weeks post-partum, the cytosolic CT activity in the
liver of the adult animal decreased 1.9-fold, and this correlated with a 1.8-fold
increase in microsomal CT activity. At that time, microsomal CT activity started
to decline again whereas the cytosolic activity rose concomitantly until both
activities reached their pre-partum values at 8 weeks post-partum. The activities
of soluble and membrane-bound CTP:phosphoethanolamine cytidylyltransferase (ET),
the analogous enzyme in the CDP-ethanolamine pathway, did not change
significantly throughout this period. Whereas hepatic PC concentrations declined
until about 2 weeks post-partum and thereafter gradually returned to pre-partum
levels, the PC levels in very-low-density-lipoproteins, started to rise 2 weeks
after the partus reaching a maximum of 219% of the original value at 8 weeks post
partum. These results strongly suggest that there is a reversible redistribution
of CT between cytosol and membranes in a physiologically relevant animal model,
supporting the concept that translocation of CT is occurring in vivo.
PMID- 9555032
TI - SB209670, a potent endothelin receptor antagonist, prevents or delays axonal
degeneration after spinal cord injury.
AB - We developed a rat spinal cord transection injury model and investigated whether
endogenous endothelin takes part in axonal degeneration after injury, by using a
potent nonselective endothelin receptor antagonist, SB209670. Light microscopic
analysis showed that axonal degeneration of the spinal cord was clearly observed
one week after injury, supported by immunohistochemical study with anti
neurofilament antibody. Electron microscopic observation showed enlargement and
shrinking of spinal axons in the injured sites one week after injury. Application
of SB209670 to the lesion sites markedly inhibited axonal damage after injury.
These results suggest that endogenous endothelin plays a role in axonal
degeneration after spinal cord injury and that SB209670 prevents or delays the
axonal degeneration after CNS damage.
PMID- 9555033
TI - Locus coeruleus neurons from morphine-treated rats do not show opiate-withdrawal
hyperactivity in vitro.
AB - In vitro studies have not consistently demonstrated naloxone-precipitated opiate
withdrawal hyperactivity of locus coeruleus neurons. The reason for this
inconsistency may be because partial or complete withdrawal occurred during
preparation of the locus coeruleus slice. The aim of the present study was to
assay opiate withdrawal-related hyperactivity in neurons recorded from locus
coeruleus slices while ensuring the maintenance of dependence until naloxone
precipitated withdrawal. Extracellular recordings were obtained from individual
locus coeruleus neurons in slices from morphine-treated and drug-naive rats.
Morphine 1 microM was present in all solutions during preparation and recording
in slices from morphine-treated rats. The average firing rate of the drug-naive
controls was 0.93 Hz (+/-0.04 Hz). Bath application of morphine (1 microM) almost
completely suppressed firing in drug-naive controls (0.058 Hz, +/-0.04 Hz, n=12),
whereas in solutions containing 1 microM morphine, the firing rate of cells from
morphine-treated rats averaged 0.71 Hz (+/-0.05 Hz), indicating considerable, but
incomplete tolerance. In the same slices, naloxone increased the average
spontaneous firing of locus coeruleus cells to 0.96 Hz (+/-0. 04 Hz). Thus,
naloxone did not produce withdrawal hyperactivity, but returned the cells from
morphine-treated rats to control rates. We conclude that locus coeruleus cells in
locus coeruleus slice preparations from morphine-treated rats did not demonstrate
withdrawal-related hyperactivity even when dependence was maintained until
naloxone-precipitated withdrawal. Thus, our results do not support a role for
adaptations intrinsic to locus coeruleus neurons in withdrawal hyperexcitability,
but instead imply the necessity of functional afferent activity.
PMID- 9555034
TI - Local renin-angiotensin system in the pineal gland.
AB - Besides the classical endocrine renin-angiotensin system (RAS), a local RAS has
been described also in the brain. We attempted to clarify the existence of a
local RAS in the pineal gland. Through the use of a ribonuclease protection
assay, it proved possible to detect the mRNA for angiotensinogen (AOGEN), for the
angiotensin receptor type 1A (AT1a) and 1B (AT1b) and for the angiotensin
converting enzyme (ACE) in pineal glands from rats. Renin mRNA, however, could
not be found by this method. By in situ hybridization and immunocytochemistry,
AOGEN mRNA was co-localized with the astrocyte marker glial fibrillary acidic
protein. AT1b mRNA expression exceeded the expression of AT1a mRNA and was co
localized with the pinealocyte-specific tryptophan hydroxylase. Thus, in the
mammalian pineal gland there is a local formation of the components of the RAS.
The presence of angiotensin II receptors further substantiates a role for
angiotensins and the pineal RAS in the physiology of this gland.
PMID- 9555035
TI - Effects of toxic doses of methamphetamine (METH) on dopamine D1 receptors in the
mouse brain.
AB - Methamphetamine (METH) is a drug of abuse that causes marked DA depletion in the
mammalian dopaminergic systems. These are characterized by marked decreases in
presynaptic markers including dopamine (DA) levels and DA transporters. Very
little research has been carried out to evaluate possible postsynaptic effects of
this drug. In the present study, we assessed the status of METH on striatal DA D1
receptors labeled with [3H]SCH23390 after toxic doses of METH that were shown to
cause marked depletion of various markers of presynaptic DA systems in mice [J.
Neurochem. 69 (1997) 780]. Our results show that these doses of METH caused 30%
decrease in striatal DA D1 receptors. In contrast, p53 knockout mice that show
protection against the toxic effects of METH show no significant decreases in DA
D1 receptors. These results suggest that toxic doses of METH that cause loss of
presynaptic DA markers might also affect postsynaptic elements. We discuss the
possibility that these changes might be secondary to toxic effects of METH on
intrinsic striatal cell bodies.
PMID- 9555036
TI - Thyroxine stimulates the acylation of lysophosphatidylethanolamine in rat heart.
AB - The acylation of cardiac lysophosphatidylethanolamine (LPE) was examined in rats
treated with thyroid hormone. Rats were treated for five consecutive days with
thyroxine (250 microg/kg) and controls were treated with saline. On the sixth day
after an overnight fast, the hearts were removed and perfused in the Langendorff
mode with 0.1 mM [1-14C]oleic acid. Radioactivity incorporated into
phosphatidylethanolamine (PE) was increased 1.5-fold (P < 0.025) compared to
controls. Radioactivity incorporated into phosphatidylcholine was not effected.
The pool size of phosphatidylethanolamine and de novo biosynthesis of this
phospholipid from [3H(G)]serine or [1,2-14C]ethanolamine were unaltered by
thyroxine treatment. Treatment of rats with thyroxine resulted in a 1.5-fold (P <
0.025) increase in the relative percent of oleic acid in cardiac
phosphatidylethanolamine. Thyroxine treatment resulted in a 1.8-fold (P < 0.025)
increase in cardiac microsomal acyl-coenzyme A:1-acyl
glycerophosphorylethanolamine acyltransferase activity compared to controls
whereas, phospholipase A, acyl-coenzyme A hydrolase and fatty acyl-coenzyme A
synthase activities were unaltered. The results demonstrate that the reacylation
of cardiac LPE is regulated by thyroid hormone.
PMID- 9555037
TI - Evidence for Fos involvement in the regulation of proenkephalin and prodynorphin
gene expression in the rat hippocampus.
AB - For a long time Fos has been proposed to play some role in regulation of the
proenkephalin (PENK) and prodynorphin (PDYN) gene expression. In recent years,
however, evidence has accumulated that the transcription of both genes in several
brain regions in vivo is transactivated by the transcription factor CREB rather
than by Fos. In the present study, involvement of Fos in the mechanism of the
PENK and PDYN gene induction in the hippocampal dentate gyrus during seizures
elicited by kainic acid was studied using a knock-down technique. Pretreatment
with an antisense oligonucleotide complementary to c-fos mRNA did not influence
the kainic acid-elicited convulsions. It inhibited, by about 50%, the induction
of Fos protein in the dentate gyrus during seizures. The subsequent induction of
PENK and PDYN mRNAs was reduced by more than 60% by the c-fos antisense
oligonucleotide, while constitutive expression of three other genes (alpha
tubulin, NMDA receptor-1, and GS protein alpha-subunit) was not affected. The
obtained results support the view that Fos may be involved in regulation of the
PENK and PDYN gene expression in the dentate gyrus during seizures, which further
suggests that the mechanisms triggering the up-regulation of both these genes in
the dentate gyrus may differ from these working in other brain regions, such as
the striatum and hypothalamus.
PMID- 9555038
TI - Cyclosporine A modulation of Ca++ activated K+ channels in cardiac sensory
afferent neurons.
AB - Whole-cell and single channel recordings were used to characterize the effects of
the immunosuppressant cyclosporine A (CsA) on cardiac sensory neurons (CSN) of
the nodose ganglia. Application of 10 nM CsA resulted in a 29.1% decrease in CSN
input resistance and an average -8+/-3 mV hyperpolarization of membrane
potential. Application of 10 nM CsA had no effect on evoked Ca++ currents but
increased evoked K+ currents by 158.9+/-24%. Application of 10 nM CsA
significantly increased the open probability of KCa channels by 183+/-9%. These
results suggest that application of CsA results in the activation of KCa channels
in cardiac sensory neurons and this effect may contribute to the cellular
mechanisms underlying CsA modulation of vagal afferent neurons.
PMID- 9555039
TI - GABAB receptors in the dorsomedial hypothalamus and heart rate in anesthetized
rats.
AB - Previous studies have shown that: (1) activation of neurons in the dorsomedial
hypothalamus (DMH) of the rat by blockade of local GABAA receptors with
bicuculline methiodide (BMI) elicits cardiovascular changes resembling those seen
in experimental stress, including marked sympathetically-mediated tachycardia,
and (2) inhibition of neurons in the same region by local microinjection of the
GABAA receptor agonist muscimol can virtually abolish stress-induced tachycardia.
This study examined the possibility that GABAB receptors exist in the neural
circuitry of the DMH, and that stimulation of these receptors might suppress the
cardiovascular response to local disinhibition with BMI. Microinjection of BMI 10
pmol into the DMH in urethane-anesthetized rats resulted in marked tachycardia
with little or no effect on arterial pressure. Simultaneous injection of the
GABAB receptor agonist baclofen at doses of 2.5, 5.0 and 10 pmol produced dose
related suppression of BMI induced tachycardia. Coinjection of the GABAB receptor
antagonist 2-hydroxysaclofen 100 or 200 pmol had no significant effect on the
heart rate response to BMI, but reversed the suppression elicited in the presence
of baclofen. These findings indicate that (1) functional GABAB receptors exist in
the DMH, and (2) stimulation of these receptors inhibits the tachycardia
resulting from blockade of local GABAA receptors.
PMID- 9555040
TI - Ionophore A23187-induced leukotriene biosynthesis in equine granulocytes
neutrophils, but not eosinophils require exogenous arachidonic acid.
AB - Equine granulocyte suspensions, mainly consisting of neutrophils, failed to
produce detectable amounts of leukotrienes when stimulated with calcium ionophore
A23187 alone, whereas leukotrienes were dose-dependently formed in control
incubations with human granulocytes. In contrast, ionophore A23187 initiated
synthesis of leukotrienes B4 and C4 in equine granulocytes when added in
combination with low concentrations of exogenous arachidonic acid. Similarly,
ionophore A23187 provoked leukotriene biosynthesis when added alone to human
whole blood, whereas addition of exogenous arachidonic acid was a prerequisite
for ionophore A23187-induced leukotriene formation in equine whole blood.
Leukotriene biosynthesis was provoked by A23187 alone after addition of
homologous platelets to equine granulocyte suspensions. After separation of
equine neutrophils and eosinophils, purified eosinophil suspensions produced LTC4
after stimulation with ionophore A23187 alone, whereas exogenous arachidonic acid
was required for ionophore-induced LTB4 formation in purified neutrophil
suspensions. Leukotriene synthesis in both eosinophils and neutrophils was
suppressed by the 5-lipoxygenase activating protein (FLAP) inhibitor, MK-886.
Exogenous arachidonic acid was needed for ionophore-induced leukotriene synthesis
also in bovine granulocytes, but was not a prerequisite for the production of
leukotrienes in porcine granulocytes or in rat and rabbit white blood cell
suspensions. The results indicate differences in the mechanisms regulating
leukotriene synthesis in equine neutrophils, as compared to human granulocytes or
equine eosinophils, and suggest that elevation of intracellular calcium is an
insufficient stimulus to provoke utilisation of endogenous arachidonic acid for
leukotriene synthesis in equine neutrophils.
PMID- 9555041
TI - Alterations of substance P immunoreactivity in lumbar and thoracic segments of
rat spinal cord in ultraviolet irradiation induced hyperalgesia of the hindpaw.
AB - Substance P immunostaining was quantified on sections from the 4th-5th lumbar and
midthoracic spinal segments of rats at the peak of hyperalgesia following
ultraviolet irradiation-induced inflammation of one hindpaw. The area of the
immunostaining in the lumbar dorsal horn was significantly decreased on both
sides by 50%, while in the thoracic spinal cord, it was increased by 18% on the
contralateral and stayed unchanged on the ipsilateral side.
PMID- 9555042
TI - Immunological assessment of the distribution of type VII adenylyl cyclase in
brain.
AB - The localization of the nine identified isoforms of adenylyl cyclase in brain has
been largely based on determination of patterns of mRNA expression. A polyclonal
antibody has now been developed that specifically recognizes Type VII adenylyl
cyclase. This antibody was used for immunocytochemical analysis of the
distribution of Type VII adenylyl cyclase in rat brain. Labeling of Type VII
adenylyl cyclase was observed in several areas, including cerebellum, caudate
putamen, nucleus accumbens, hippocampus and cerebral cortex. In some of these
areas, the staining of the adenylyl cyclase protein suggested the possibility of
presynaptic localization. For example, in situ hybridization showed Type VII
adenylyl cyclase mRNA concentrated in cerebellar granule neurons. The cerebellar
granule cell layer, however, showed little immunostaining, while punctate
immunostaining was observed in the molecular layer. These results suggested that
protein synthesized in the granule neurons may be targeted to the neuron
terminals. Punctate staining in the caudate-putamen, globus pallidus and nucleus
accumbens also suggested the possibility of axonal and/or dendritic localization
of Type VII adenylyl cyclase in these regions. Labeling of the soma of cerebellar
Purkinje cells, cortical pyramidal and non-pyramidal cells and interneurons in
the cerebellum and hippocampus was also observed. Type VII adenylyl cyclase, like
the other adenylyl cyclase isoforms, has distinct regulatory characteristics,
including sensitivity to stimulation by Gsalpha and G protein betagamma subunits,
modulation by protein kinase C, and high sensitivity to stimulation by ethanol.
These characteristics, and the discrete localization of this enzyme, may
contribute to its ability to provide signal integration and/or control of
neurotransmitter release in particular neurons or brain areas.
PMID- 9555043
TI - Neuroprotective effects of 2,4-dimethoxybenzylidene anabaseine (DMXB) and
tetrahydroaminoacridine (THA) in neocortices of nucleus basalis lesioned rats.
AB - The nicotinic alpha7 agonist dimethoxybenzilidene anabaseine (DMXB) and
cholinesterase inhibitor tetrahydroaminoacridine (THA) were investigated in a
trans-synaptic model for neocortical atrophy and degeneration following nucleus
basalis lesions. Bilateral lesions reduced parietal neuronal density in layers II
V 8 months later. DMXB administered i.p. daily to rats for 3 months attenuated
this loss in layers II-V at a 1 mg/kg i.p. dose. A lower, 0.2 mg/kg i.p. dose,
was neuroprotective in layer IV only. THA (1 mg/kg i.p.) also protected against
neocortical Nissl-staining deficits.
PMID- 9555044
TI - Expression of the amino acid dimorphism in the small myelin-associated
glycoprotein cytoplasmic domain in rat peripheral nerves during postnatal
development.
AB - The myelin-associated glycoprotein (MAG) is one of the proteins expressed during
the period of myelin formation and is believed to play a major role in the
initiation of myelination. It exists as two differentially expressed isoforms, L-
and S-MAG, that are generated by alternative mRNA splicing. A nucleotide
dimorphism at the mRNA level resulting in an Arg/Pro dimorphism in the
cytoplasmic tail of the S-MAG protein has previously been detected in the rat
brain. In this study, we show that this dimorphism is detectable in the rat
peripheral nervous system. We propose an allelic origin for the dimorphism and
demonstrate the differential expression of the S-MAG alleles in the sciatic
nerves of heterozygous rats during the period of active myelination. We also
present data on the properties of the two S-MAG cytoplasmic domains produced as
GST fusion proteins. The importance of this differentially expressed amino acid
dimorphism is discussed, taking into account both its probable effect on the S
MAG cytoplasmic domain function and its significance in functional and structural
studies concerning the S-MAG protein.
PMID- 9555045
TI - Single-channel activity of the Ca2+-dependent K+ channel is modulated by FK506
and rapamycin.
AB - Single-channel patch clamp recordings were performed in primary cultured neurons
from rat dorsal hippocampi. Ca2+-dependent and TEA-sensitive K+ current was
recorded from the neurons. Application of immunosuppressants FK506 and rapamycin
to the channel inside the plasma membrane of the neurons significantly prolonged
the mean open time of the channel. Calcineurin autoinhibitory fragment and W-7
induced no significant alteration in the mean open time of the channel. These
results suggest that modulation of the activity of the Ca2+-dependent K+ channel
by FK506 and rapamycin is directly through association of immunosuppressants with
FKBP12.
PMID- 9555046
TI - T-->G or T-->A mutation introduced in the branchpoint consensus sequence of
intron 4 of lecithin:cholesterol acyltransferase (LCAT) gene: intron retention
causing LCAT deficiency.
AB - Previous mutations associated with lecithin:cholesteryl acyltransferase (LCAT)
deficiency syndromes have been identified in the coding regions of the LCAT gene.
However, recently, an intron mutation was found in a family in which three
sisters presented with fish-eye disease (FED). The probands were shown to be
heterozygotes for a mutation in intron 4. The respective T-->C nucleotide
substitution, 22 bases upstream of the 3'-splice site, causes a null allele as
the result of complete intron retention. Since the natural mutation occurs in a
putative branchpoint consensus sequence of the intron, it was hypothesized that
the point mutation may disrupt the splicing of the pre-mRNA. To further study the
functional significance of the above thymine residue in the branchpoint sequence,
we introduced other nucleotides at this position, i.e., LCAT Int-4 MUT-1 (T-->G)
and LCAT Int-4 MUT-2 (T-->A). After stable transfection of the mutated pNUT-LCAT
minigenes into BHK cells, we could detect neither LCAT activity nor LCAT protein
in the culture medium of the pNUT-LCAT Int-4 MUT-1 and pNUT-LCAT Int-4 MUT-2 cell
lines, as was previously described for the natural mutation. To determine the
effects of the introduced mutations on pre-mRNA splicing, total RNA from
transfected BHK cells was used for RT-PCR analysis. All BHK cell lines were shown
to transcribe the integrated LCAT minigenes. However, the sizes of these LCAT
messengers indicated that intron 4 was retained in the pNUT-LCAT Int-4 MUT-1 and
pNUT-LCAT Int-4 MUT-2 cell lines. Subsequent sequence analysis of the RT-PCR
products demonstrated that the unspliced intronic sequences contained the
introduced mutations. In conclusion, the observed retention of intron 4 of the
LCAT gene is the result of the specific loss of a thymine residue two bases
upstream of the branchpoint adenosine residue in the putative branchpoint
consensus sequence. The results confirm that a single base change in the
branchpoint consensus sequence of an intron can cause human disease although this
sequence is poorly conserved in mammals.
PMID- 9555047
TI - Distribution of substance P receptor binding in dorsal column nuclei of rat, cat,
monkey and human.
AB - In the present study, substance P receptor binding was localized in the dorsal
column nuclei (DCN) of the rat, cat, monkey, and human. Bolton-Hunter-labeled
[125I]substance P binding was most concentrated in the cell nests of the core
region, but was present throughout the DCN of each species. The distribution of
substance P receptors may reconcile apparent mismatches between the widespread
responsiveness of DCN neurons to substance P and the restricted distribution of
substance P containing afferents.
PMID- 9555049
TI - Electrophysiology of the neuromuscular junction of the laminin-2 (merosin)
deficient C57 BL/6J dy2J/dy2J dystrophic mouse.
AB - The C57 BL/6J dy2J/dy2J dystrophic mouse expresses an abnormal truncated form of
the alpha2 subunit of the protein laminin-2 (or merosin), which is unable to form
a stable link between the extracellular matrix and the dystrophin-associated
proteins, resulting in muscular dystrophy. Morphological abnormalities of the
peripheral nervous system and neuromuscular junction have also been reported. The
electrophysiological properties of the neuromuscular junctions of diaphragm,
extensor digitorum longus (EDL), and soleus from C57 BL/6J dy2J/dy2J mice and
controls are described. No evidence for the presence of denervated fibres were
found. Mean MEPP amplitudes were significantly increased in EDL and soleus but
reduced in the diaphragm from affected mice. Mean MEPP frequencies were raised in
all the dy2J/dy2J muscles studied. dy2J/dy2J muscles were paralysed by low
concentrations of mu-conotoxin suggesting that embryonic (tetrodotoxin and mu
conotoxin resistant) sodium channels are not widespread on dy2J/dy2J muscle as
has previously been reported. EPP latencies were significantly prolonged in the
diaphragm and EDL but not soleus from dy2J/dy2J mice. Quantal contents were
higher in all dy2J/dy2J muscles. In the dy2J/dy2J diaphragm failures in
neurotransmission occurred and a faster rate of rundown of EPPs were apparent.
Some changes appear from a direct effect of dystrophy, whilst increased MEPP
frequency and quantal content, and failures in neurotransmission indicate
neuronal abnormalities.
PMID- 9555048
TI - Metabotropic glutamate receptor agonist increases neuropeptide mRNA expression in
rat striatum.
AB - Metabotropic glutamate receptors (mGluR) are coupled to multiple intracellular
second messenger systems through G-proteins and densely expressed by medium spiny
projection neurons in the rat striatum. Unlike ionotropic glutamate receptors
which mediate rapid synaptic transmission, mGluRs are important for relatively
long-lasting modulation of neuronal metabotropic activity, possibly including
gene expression, in response to cellular stimulation. In this study, the effects
of acute injection of the selective mGluR agonist (1S,3R)-1-aminocyclopentane-1,3
dicarboxylic acid (ACPD) on behavior and striatal neuropeptide mRNA expression
were evaluated in chronically-cannulated rats. Unilateral injection of ACPD into
the dorsal striatum at doses of 0.8, 4, 20, 100, 500 and 1000 nmol had no
significant effect on spontaneous behavioral activity. However, intrastriatal
ACPD (0.8, 4, 20 and 100 nmol) dose-dependently elevated preprodynorphin (PPD),
substance P (SP) and preproenkephalin (PPE) mRNA expression in the dorsal
striatum as revealed by quantitative in situ hybridization. PPD/SP mRNAs showed a
biphasic response to a single injection of ACPD as the expression of these two
mRNAs was increased at 3 and 6 h, decreased at 11 h, and returned to normal 24 h
after ACPD administration. PPE induction in the dorsal striatum was significantly
elevated as early as 2 h and remained even 24 h after ACPD was injected. In
addition, the PPD and PPE mRNA induction by ACPD was blocked by intrastriatal
pretreatment with the selective mGluR antagonist, (+)-alpha-methyl-4
carboxyphenyl-glycine. These data demonstrate a facilitatory regulation of
constitutive expression of striatonigral PPD/SP, and striatopallidal PPE, mRNAs
by local mGluR-mediated glutamatergic transmission.
PMID- 9555050
TI - Comparison of [125I]-bolton-hunter substance P binding in young and aged rat
spinal cord.
AB - Binding of [125I]-labeled Bolton-Hunter substance P ([125I]-BHSP) to NK1
receptors was investigated in the spinal cord of young (3-4 month) and aged (14
16 month) rats. In homogenates of whole spinal cord, the affinity (equilibrium
dissociation constant, approximately 210 pM) and maximum density of [125I]-BHSP
binding sites ( approximately 0.25 fmol/mg wet weight) were similar for young and
aged rats. Autoradiographic studies revealed a similar distribution of [125I]
BHSP sites in both young and old rats at all spinal levels. Intense binding was
observed in the superficial dorsal horn (laminae I-III), grey commissure (lamina
X) and thoracic intermediolateral cell column (IML) with lower levels of binding
in the deeper dorsal horn (laminae IV-VI) and ventral horn (laminae VII-IX).
However, the density of [125I]-BHSP sites was significantly (P<0.05) lower in
lamina X of lumbar sections of aged rats compared with young controls. These
studies suggest that ageing is associated with a selective loss of NK1 receptors
in lamina X of the lumbar spinal cord, although the affinity of NK1 receptors in
aged rats is unchanged.
PMID- 9555051
TI - Hexadecylphosphocholine and 2-modified 1,3-diacylglycerols as effectors of
phospholipase D.
AB - The kinetic behaviour of phospholipase D (PLD) from cabbage has been studied in
the presence of several substrate-like compounds such as hexadecylphosphocholine
(HPC) and 1,3-didodecanoylglycero-2-phosphatides. 1,3-Didodecanoyl- glycero-2
phosphocholine (1,3-DiC12PC) was found being not cleft by PLD, whereas HPC is
hydrolyzed by PLD with small rate. The plot of initial velocity vs. substrate
concentration for HPC is more sigmoidal than those for the common substrate
phosphatidylcholine (PC)/sodium dodecylsulfate (SDS) (1:0.5) or the short-chain
1,2-dihexanoyl-sn-glycero-3-phosphocholine (DiC6PC). The anionic amphiphiles 1,3
didodecanoylglycero-2-sulfate and 1,3-didodecanoylglycero-2-phosphate act as
activators of PLD towards PC similar to SDS. In contrast, 1,3-DiC12PC shows
inhibitory properties with an increase in the sigmoidicity of the initial
velocity as a function of substrate concentration in the PC/SDS assay. Also HPC
inhibits the hydrolysis of PC/SDS, whereas it acts as activator or inhibitor in
the hydrolysis of DiC6PC. The results suggest that PLD possesses two substrate
binding sites, where one binds substrate in function of an effector without
catalytic activity while the other is the catalytic site. HPC and 1,3-DiC12PC are
assumed to compete with the substrate for both binding sites with effects
depending on the ratio of concentrations and affinities of substrates and
effectors.
PMID- 9555052
TI - Neuroprotection of mild hypothermia: differential effects.
AB - To estimate whether mild hypothermia during repetitive hypoxia provides a
neuroprotective effect on brain tissue, hippocampal slice preparations were
subjected to repetitive hypoxic episodes under different temperature conditions.
Slices of guinea pig hippocampus (n=40) were placed at the interface of
artificial cerebrospinal fluid (aCSF) and gas (normoxia: 95% O2, 5% CO2; hypoxia:
95% N2, 5% CO2). Evoked potentials (EP) and direct current (DC) potentials were
recorded from hippocampal CA1 region. Slices were subjected to two repetitive
hypoxic episodes under the following temperature conditions: (A) 34 degrees C/34
degrees C, (B) 30 degrees C/30 degrees C and (C) 34 degrees C/30 degrees C.
Hypoxic phases lasted until an anoxic terminal negativity (ATN) occurred. The
recovery after first hypoxia lasted 30 min. Tissue function was assessed
regarding the latency of ATN and the recovery of evoked potentials. The ATN
latencies with protocol A (n = 25) for the first and second hypoxia were 5.9+/
1.3 min (mean+/-S.E.M., 1st hypoxia) and 2.4+/-0.9 min (2nd hypoxia), with
protocol B the latencies (n = 7) were significantly longer: 25.2+/-7.1 min and
15.6+/-7.7 min. With protocol C (n=8), the latencies were 5.6+/-1.8 and 3.3+/-0.5
min. No differences were seen in the recovery of the EPs with protocols A-C. Our
results suggest that a mild hypothermia is only neuroprotective if applied from
an initial hypoxia onwards.
PMID- 9555053
TI - Effects of aniracetam after LTP induction are suggestive of interactions on the
kinetics of the AMPA receptor channel.
AB - The modulatory influence of aniracetam, a drug which reversibly modifies the
kinetic properties of AMPA-type glutamate receptors, on synaptic responses is
reported to be detectably changed by the induction of long-term potentiation
(LTP). The present study used hippocampal slices to examine three issues arising
from this result. First, possible contributions of inhibitory currents and
postsynaptic spiking to the aniracetam/LTP interaction were investigated with
infusions of GABA receptor antagonists and topical applications of tetrodotoxin.
Second, tests were carried out to determine if the altered response to aniracetam
is sufficiently persistent to be a plausible substrate for the extremely stable
LTP effect. Third, the nature of the change responsible for the aniracetam/LTP
interaction was explored with waveform analyses and a kinetic model of the AMPA
receptor. The following results were obtained. LTP reduced the effect of
aniracetam on the amplitude but increased its effect on the decay time constant
of field EPSPs recorded under conditions in which local spiking and inhibitory
responses were blocked. The LTP-induced change in the effect of aniracetam was
extremely stable in that it was still evident 75 min after induction of
potentiation. Finally, the waveform distortions introduced by LTP and aniracetam
could be corrected by uniform stretching of the responses, suggesting that the
changes introduced by each of the manipulations are unitary in nature. These
distortions and the interactions between them could be reproduced in the AMPA
receptor model by representing LTP as an acceleration of channel gating kinetics.
PMID- 9555054
TI - Vitamin E protects against Alzheimer's amyloid peptide (25-35)-induced changes in
neocortical synaptosomal membrane lipid structure and composition.
PMID- 9555055
TI - Caloric restriction retards the aging associated changes in gamma-aminobutyric
acidA receptor gene expression in rat cerebellum.
AB - It is widely accepted that calorie restriction is an effective way of delaying
the aging process. Also, there is an indication that the beneficial effects
exerted by dietary manipulation may be due to a direct effect at the molecular
level like gene expression. The studies were conducted to determine whether
calorie restriction prevents any age-related changes in the structural and
molecular aspects of the GABAA-BZ receptor. In aged (24-month old diet ad
libitum) rats, the binding of [35S]t-butyl-bicyclophosphorothionate (TBPS) was
significantly reduced in the cerebellum. In contrast, [35S]TBPS binding remained
unchanged in the cerebellum of calorie restricted old rats. In order to evaluate
the molecular basis of these changes, the alpha sub-unit mRNA levels were
measured. The GABAA receptor alpha1 sub-unit mRNA level remained unchanged in
both the old groups of rats. The alpha2 subunit mRNA level was significantly
decreased in the cerebellum of aged rats (24-month old ad libitum), whereas it
remained unchanged in the cerebellum of calorie restricted old animals. These
findings indicate a selective age and diet related modulation in the
stoichiometry of the GABAA receptor in aging.
PMID- 9555056
TI - Lipid metabolism in fibroblast growth factor-stimulated L6 myoblasts: a receptor
mutation (Y766F) abrogates phospholipase D and diacylglycerol kinase activities.
AB - Phosphatidylcholine (PC) hydrolysis induced by basic fibroblast growth factor
(bFGF) was studied in rat L6 myoblasts expressing the wild-type FGF receptor-1
(FGFR-1) or a mutant (Y766F) that is incapable of activating phospholipase C
gamma (PLCgamma). Stimulation of FGFR-1 activated phospholipase D (PLD) rapidly
and transiently, but did not induce PC-specific PLC activity. Downregulation of
protein kinase C blocked bFGF-induced PLD activation but not phosphatidic acid
formation by diacylglycerol (DG) kinase. Only phosphoinositide (PI)-derived DG,
not PC-derived DG, appeared to be a substrate for DG kinase. Stimulation of FGFR
1(Y766F) did not activate PLD or DG kinase, both of which apparently require
initial PLCgamma activation. The Y766F mutation reduced mitogen-activated protein
kinase activation but not cell proliferation. We conclude that both PI turnover
and PC hydrolysis are dispensable for bFGF-induced mitogenesis.
PMID- 9555057
TI - Molecular heterogeneity of Vicia villosa-recognized perineuronal nets surrounding
pyramidal and nonpyramidal neurons in the guinea pig cerebral cortex.
AB - Of three monoclonal antibodies (mAbs Cat 301, 1B5 and 473) which recognize
epitopes on perineuronal nets (PnNs), only mAb 473 displayed considerably varied
degrees of staining intensity on Vicia villosa-labeled pyramidal (P) neurons (5%,
intensely; 54%, very weakly; and 41%, unstained). These results indicate the
heterogeneity on molecular structure or composition of the terminal N
acetylgalactosamine-containing PnNs within P class as well as between P and
nonpyramidal classes.
PMID- 9555059
TI - A role for phospholipase D activation in the lipid signalling cascade generated
by bradykinin and thrombin in C2C12 myoblasts.
AB - In the present study evidence is provided for a rapid activation of lipid
signalling pathways induced by thrombin and bradykinin (BK) in C2C12 myoblasts.
Both agonists were able to increase [3H]inositol phosphates (InsP), 1,2
[3H]diacylglycerol (DAG) and [3H]phosphatidic acid (PtdOH) levels. In particular
[3H]PtdOH values were rapidly increased and maintained at significantly high
values at prolonged times of incubation. BK and thrombin were able to activate
phospholipase D (PLD) in vivo as demonstrated by the accumulation of
[3H]phosphatidylethanol (PtdEtOH) through the transphoshatidylation reaction
catalyzed by the enzyme in the presence of ethanol. The observation that ethanol
could significantly reduce [3H]PtdOH formation in myoblasts stimulated with BK
and thrombin indicates that stimulation of PLD has a major role. The two agonists
appear to stimulate PLD activity through a common molecular mechanism, involving
the activation of protein kinase C (PKC). In addition, BK and thrombin appear
able to activate DAG kinase at early times of incubation and also this pathway
may contribute to determine the increase in [3H]PtdOH levels. This is the first
report which describes activation of lipid signalling pathways by BK and thrombin
in myoblast cells and it is possible that these early signals may have an
important role in mediating the biological effects of the two agonists.
PMID- 9555058
TI - Abnormal properties of creatine kinase in Alzheimer's disease brain: correlation
of reduced enzyme activity and active site photolabeling with aberrant cytosol
membrane partitioning.
AB - The report shows that Alzheimer's disease (AD) brain creatine kinase (CK) is
modified such that the nucleotide binding site of CK is blocked and that abnormal
partitioning of CK between the soluble and pellet fractions occurs. First, CK
activity was 86% decreased in AD brain homogenates in comparison to age-matched
controls. Secondly, over a 23.5 fold greater 32P photoincorporation of [alpha
32P]8N3ATP was observed into CK of control vs. AD samples. Also, a 7.4-fold
increase of enzyme induced 32P incorporation was observed in controls vs. AD
samples by incubation with [gamma 32P]ATP. Thirdly, Western blot analysis showed
that CK copy numbers in the AD homogenate were decreased by less than 14% in
comparison to controls. However, analysis showed that control supernatant and
pellet fractions contained 10.3 and 0.4 times the CK copy number found in the
corresponding AD fractions. 32P incorporation by both photolabeling and enzyme
catalyzed incorporation of radiolabel followed CK activity and not CK copy
number. Further, [alpha 32P]ADP and [gamma 32P]ATP incorporated 32P into control
brain and purified brain CK equally well, indicating that a mechanism different
from gamma-phosphoryl transfer is involved in the enzymatic incorporation of
radiolabel. Also, the level of abnormal partitioning of CK into AD brain pellet
correlated with the decreased [32P]8N3GTP photolabeling and abnormal partitioning
of beta-tubulin, a protein known to be aberrantly modified in the AD brain. This
indicates that a common chemistry is affecting both CK and tubulin in AD.
PMID- 9555060
TI - Role of noradrenergic projections to the bed nucleus of the stria terminalis in
neuroendocrine and behavioral responses to fear-related stimuli in rats.
AB - The bed nucleus of the stria terminalis (BNST) receives dense noradrenergic
projections from the brainstem and has been claimed to play a role in expression
of a variety of stress responses. Fear-related stimuli suppress vasopressin and
facilitate oxytocin release from the neurohypophysis and induce behavioral
suppression. Here we investigated in male rats whether conditioned fear stimuli
increase noradrenergic activity in the BNST and whether depletion of epinephrine
content in the BNST prevents neuroendocrine and behavioral responses to fear
stimuli. Environmental stimuli previously paired with electric footshocks
increased the ratio of 3-methoxy-4-hydroxyphenylglycol to norepinephrine contents
in the BNST, suggesting that the stimuli activated noradrenergic projections to
the BNST. 5-Amino-2, 4-dihydroxy-alpha-methylphenylethylamine, a neurotoxin
relatively selective for noradrenergic fibers, when injected into the BNST 7 days
before measurement, decreased the content of norepinephrine by 95% and that of
dopamine or serotonin by about 50%. In the rats that received the neurotoxin, the
suppressive vasopressin but not the augmentative oxytocin response to
intermittent footshocks was abolished. In the experiments with conditioned fear
stimuli, the neurotoxin given before training partially but significantly
impaired the suppressive vasopressin and behavioral responses to testing stimuli.
The neurotoxin given after training, however, did not prevent the vasopressin,
oxytocin or behavioral responses. The results suggest that noradrenergic fibers
in the BNST mediate the suppressive vasopressin but not the augmentative oxytocin
response to nonassociatively applied fear stimuli and that they modulate, in a
facilitative fashion, acquisition but not retention or recall of the emotional
memory associated with the vasopressin and behavioral responses to conditioned
fear stimuli.
PMID- 9555061
TI - Physiological properties and functions of intracellular fatty acid-binding
proteins.
PMID- 9555062
TI - The stimulation of rat astrocytes with phorbol-12-myristate-13-acetate increases
the proenkephalin mRNA: involvement of proto-oncogenes.
AB - The effect of phorbol-12-myristate-13-acetate (PMA) on the regulation of
proenkephalin (proENK) mRNA level, ENKCRE-2 or AP-1 DNA binding activity, and the
mRNA and protein levels of proto-oncogenes (c-fos, fra-1, and c-jun) in primary
cultured rat astrocytes were studied. The proENK mRNA level was elevated at 4 h
after the treatment of PMA (2.5 microM) without altering the intracellular proENK
protein level, and this increase was attenuated by pre-treatment with
cycloheximide (CHX; 15 microM), a protein synthesis inhibitor. Both AP-1 and
ENKCRE-2 DNA binding activities were markedly increased at 1-4 h by PMA treatment
and these PMA-induced responses were inhibited by pre-treatment with CHX, showing
that the increase of proENK mRNA level was well correlated with the AP-1 and
ENKCRE-2 DNA binding activities. In contrast, although the phospho-CREBP level
was also increased by PMA at 0.5-1 h, the pre-treatment with CHX further
increased the PMA-induced phospho-CREBP level. In addition, PMA caused the
induction of c-fos, c-jun and fra-1 mRNA level and, especially, PMA-induced
increase of fra-1 mRNA level was further enhanced by CHX treatment at 4 h.
Furthermore, western immunoblot assay showed that PMA caused induction of c-Fos,
Fra-1, and c-Jun protein levels. PMA-induced increases of proto-oncoproteins
levels were also inhibited by CHX treatment. The results suggest that newly
synthesized AP-1 proteins, such as c-Fos, Fra-1, and c-Jun may play important
roles in the regulation of PMA-induced proENK gene expression in cultured rat
astrocytes. Phospho-CREB protein appears not to be involved in the regulation of
PMA-induced proENK gene expression.
PMID- 9555063
TI - Dopamine levels of two classes of vesicles are differentially depleted by
amphetamine.
AB - Differential depletion of neurotransmitter by amphetamine in two classes of
vesicles, termed large vesicles and small vesicles, has been studied with
amperometry. Carbon fiber microelectrodes have been used to monitor and quantify
exocytotic events. Current transients, corresponding to individual exocytotic
events, have been obtained from the cell body of the dopamine-containing neuron
of Planorbis corneus. The dopamine released from individual vesicles of these
cells has been compared for cells treated with D-amphetamine vs. control cells.
Our results show that amphetamine has differential effects on the release of
dopamine from the two classes of vesicles. Thus, it is concluded that at low
concentrations, amphetamine preferentially depletes the large vesicles with a
minimal effect on the small vesicles. At high concentrations, amphetamine
depletes small vesicles more strongly than large vesicles although amphetamine
continues to deplete the large vesicles in a dose-dependent manner. Our data
appear to indicate that the two classes of vesicles observed in the Planorbis
dopamine neuron might have different mechanisms associated with transmitter
depletion.
PMID- 9555064
TI - Differential catalytic properties in metabolism of endogenous and exogenous
substrates among CYP3A enzymes expressed in COS-7 cells.
AB - The catalytic properties of CYP3A7 in the metabolism of endogenous and exogenous
substrates were compared with those of CYP3A4 and CYP3A5 using COS-7 expressing
enzymes. The highest activities of dehydroepiandrosterone (DHEA) and
dehydroepiandrosterone 3-sulfate (DHEA-S) 16alpha-hydroxylase were observed in
COS-7 cells expressing CYP3A7. In contrast, the activity of testosterone 6beta
hydroxylase of CYP3A7 expressed in COS-7 cells was much less than that of CYP3A4
expressed in COS-7 cells. The rate of carbamazepine 10, 11-epoxidation was the
greatest in COS-7 cells expressing CYP3A4, followed by CYP3A5 and CYP3A7. On the
other hand, the formation of reductive metabolite of zonisamide was the highest
in COS-7 cells expressing CYP3A4, followed by CYP3A7 and CYP3A5. Furthermore, the
addition of triazolam resulted in a decrease in 6beta-hydroxylation catalyzed by
CYP3A7, but not by CYP3A4, whereas the pretreatment of microsomes with
triacetyloleandomycin (TAO) resulted in a decrease in the reaction catalyzed by
CYP3A4, but not by CYP3A7. Together with these results, it was suggested that
CYP3A7 exerts differential catalytic properties not only in metabolism of
endogenous substrates but also in drug metabolism compared to CYP3A4 and CYP3A5.
PMID- 9555065
TI - Differential localization of the mRNAs for the pertussis toxin insensitive G
protein alpha sub-units Gq, G11, and Gz in the rat brain, and regulation of their
expression after striatal deafferentation.
AB - The corticostriatal pathway is among the largest glutamatergic pathways in the
brain, and of particular interest to the study of glutamatergic transmission. The
metabotropic glutamate receptors (mGluRs) couple the actions of glutamate to
intracellular second messenger systems through G-proteins. The most prominent of
the mGluRs present in the target of this pathway, the striatum, is mGluR5. The
identity of the G-proteins mediating the actions of mGluR5 are unknown, but the
receptor is linked to stimulation of phosphoinositide (PI) turnover and largely
resistant to the effects of pertussis toxin, which inhibits some G-proteins. We
used in situ hybridization to examine the expression and regulation of three
pertussis toxin insensitive G-protein alpha sub-units: Gq, G11, and Gz. We found
that these mRNAs are differentially distributed in the rat brain, but all three
are expressed by striatal neurons. After glutamatergic deafferentation of the
striatum by decortication, there is a modest upregulation of G11 mRNA, while
expression of Gq and Gz are unchanged. Following dopaminergic deafferentation,
expression of Gq, G11, and Gz are not altered, although expression of the
pertussis-sensitive sub-unit Go is increased. Our data suggests that Gz, Gq, and
G11 are each expressed by striatal neurons, and therefore may be involved in
mediating the actions of mGluR5 in these cells. After decortication G11 is
upregulated, but the magnitude of this effect is small, and alone seems
insufficient to account for the marked biochemical supersensitivity of glutamate
stimulated PI turnover which is observed.
PMID- 9555066
TI - Effect of hyperglycemia on pyruvate dehydrogenase activity and energy metabolites
during ischemia and reperfusion in gerbil brain.
AB - The effects of hyperglycemia on brain pyruvate dehydrogenase (PDH) and
metabolites (ATP, PCr, and lactate) were investigated at 20 min ischemia, 0, 20,
and 60 min, and 4 h reperfusion. During reperfusion, PDH activities were
suppressed corresponding to the poor recovery of ATP and PCr concentrations and
the increase in lactate concentration in the hyperglycemic group, suggesting that
preischemic hyperglycemia may impair metabolism by suppressing PDH activity.
PMID- 9555067
TI - Rapid stress-induced elevations in corticotropin-releasing hormone mRNA in rat
central amygdala nucleus and hypothalamic paraventricular nucleus: an in situ
hybridization analysis.
AB - High densities of nerve cells containing corticotropin-releasing hormone (CRH)
are located in the central nucleus of the amygdala (CeA) and paraventricular
nucleus (PVN) of the hypothalamus. These brain regions play an important role in
activating autonomic, behavioral, and endocrine responses to stress. This study
was conducted to provide needed information concerning the acute effects of
stress on CeA and PVN CRH mRNA expression. Rats were exposed to restraint stress
for 1 h and brains collected after a 1-h post-stress interval. CRH mRNA
expression occurring in the CeA and PVN was examined using in situ hybridization
techniques. Densitometric analysis revealed that acute restraint stress produced
significant increases in CRH mRNA levels in the PVN and in the rostral CeA
region. In addition, the area in the rostral CeA encompassing high CRH mRNA
signals increased significantly after stress. Results provide clear evidence that
CRH neurons in the CeA and PVN exhibit rapid increases in CRH mRNA expression
after exposure to stress.
PMID- 9555068
TI - Tissue distributions of CYP2D1, 2D2, 2D3 and 2D4 mRNA in rats detected by RT-PCR.
AB - The tissue distributions of four isoforms (CYP2D1/5, 2D2, 2D3 and 2D4/18) in rat
CYP2D subfamily were investigated. Twelve kinds of tissue (liver, kidney, brain,
lung, heart, spleen, adrenal gland, small intestine mucosa, bladder, testis,
ovary and gonecystis) were removed from Sprague-Dawley male and female rats. The
expression of CYP2D mRNA in these tissues was detected by RT-PCR. Specific
primers were designed to recognize the four isoforms individually. In liver,
kidney and small intestine mucosa, the mRNA expression of all four CYP2D isoforms
was detected as high-intensity PCR products. mRNA of CYP2D1/5 was expressed in
all tissues used in this study except the brain, although the intensity of PCR
products varied among tissues. mRNAs of CYP2D2 and CYP2D3 were mainly expressed
in liver, kidney and small intestine mucosa, which were exposed to xenobiotics
such as drugs, food components and environmental contaminations. mRNA of
CYP2D4/18 was expressed in liver, kidney, small intestine mucosa and brain. In
brain, only mRNA of CYP2D4/18 was expressed. CYP2D4/18 mRNA was also expressed in
ovary, testis and gonecystis. The tissue distributions help to clarify the
differences in physiological and pharmacological functions between CYP2D
isoforms.
PMID- 9555069
TI - Studies on the regulation of CTP:phosphocholine cytidylyltransferase using
permeabilized HEP G2 cells: evidence that both active and inactive enzyme are
membrane-bound.
AB - To obtain more insight into the mechanisms regulating CTP:phosphocholine
cytidylyltransferase (CT), we determined the effect of oleate treatment on the
rate of CT release from permeabilized Hep G2 cells and the distribution of the CT
remaining in the permeabilized cells. When we permeabilized untreated cells in pH
7.5 buffer containing 0.15 M KCl, the rate of CT release was much slower than the
release of lactate dehydrogenase. Oleate treatment caused a further decrease in
CT release from cells. In untreated cells, 70-80% of the CT remaining in cells 10
min after permeabilization was recovered as soluble CT. Oleate treatment
increased the amount of bound CT but over 50% of the CT in cells 10 min after
permeabilization was recovered as soluble CT. In both control and oleate-treated
cells, the increase in CT release with time correlated with a decrease in the
amount of CT recovered from permeabilized cells as soluble CT. These results
suggested that CT existed in a form that was not immediately available for
release from permeabilized cells, but was recovered in the soluble fraction after
cell disruption. When cells were permeabilized in 10 mM imidazole-20% glycerol-5
mM Mg2+ pH 6.5, over 80% of CT in control and over 90% of CT in oleate-treated
cells was recovered bound to the particulate fraction. Essentially no CT was
released from the cells. The recovery of CT in the particulate fraction required
Mg2+ to be present when permeabilization was initiated. The addition of Mg2+,
after cells were disrupted, did not increase CT in the particulate fraction. In
untreated cells, 50% of bound CT was active. Oleate treatment increased the
amount of active CT in the particulate fraction to over 70% of total. About 50%
of particulate CT in untreated cells but only 15% in oleate-treated cells was
extracted with 0.15 M KCl. Inactive CT was preferentially extracted by KCl. The
bound CT was recovered in isolated nuclei. Overall, the results suggested that
both inactive and active CT are bound to nuclear membranes, and that the
activation of CT involves conversion of CT loosely bound to membrane to a form
more tightly bound to membranes perhaps by hydrophobic interaction with
phospholipids. This model does not involve translocation from a soluble pool.
PMID- 9555070
TI - Changes in presynaptic protein NACP/alpha-synuclein in an ischemic gerbil
hippocampus.
AB - We observed temporal changes in NACP (precursor protein of non-Abeta component of
Alzheimer's disease amyloid), a presynaptic protein a.k. a. alpha-synuclein, in
the hippocampus after 5 min ischemia. Intense NACP immunoreactivity was seen
transiently around cerebral blood vessels in the CA1 subfield on day 4, and NACP
positive unusual tubal and chain-like structures developed on month 6. We suggest
that the changes in NACP may play an important role in the ischemic pathogenesis.
PMID- 9555071
TI - Localization of the mRNAs for two isoforms of Ca2+/calmodulin-dependent protein
kinase kinases in the adult rat brain.
AB - Ca2+/calmodulin-dependent protein kinase (CaM kinase) I and IV are thought to be
activated by CaM kinase kinases (CaMKK). We examined the distribution of mRNAs
for two isoforms (alpha and beta) of CaMKKs in the brain by in situ hybridization
histochemistry. In the adult rat brain, CaMKK alpha mRNAs are widely distributed
throughout the brain, whereas CaMKK beta mRNAs are restricted to some neuronal
populations, particularly the cerebellar granule cells.
PMID- 9555072
TI - Irreversible phase transition of firefly luciferase: contrasting effects of
volatile anesthetics and myristic acid.
AB - Firefly luciferase (FFL) has been used as a lipid-free protein model to study
direct interaction of anesthetics with proteins. FFL emits a burst of light when
luciferin and ATP are added in the presence of oxygen. Volatile anesthetics
inhibited FFL at mM ranges, while myristic acid inhibited it at microM range.
Despite the large difference, octanol/water partition coefficients of both
myristic acid and halothane are 199. Differential scanning calorimetry (DSC)
showed that thermal transition occurred at 38.5 degreesC with excess enthalpy of
denaturation of 91.9 kcal mol-1. The transition, however, was irreversible.
According to the irreversible transition kinetics, the anesthetic effects were
evaluated by the temperature where the irreversible transition is half completed
(T1/2). Volatile anesthetics decreased T1/2 at mM ranges, while myristic acid and
oxyluciferyladenylate (luciferin competitor) increased it at microM ranges.
Luciferin is a heterocyclic carboxylate and acylates AMP. Carboxyl group of
myristic acid appears to make a high affinity contact to the luciferin
recognition sites. The induced-fit theory states that binding of substrates
induces the enzyme into high-energy transition state. Myristic acid stabilized
FFL at the transition state, which resisted thermal denaturation. Anesthetics
destabilized FFL by reversibly unfolding the protein into less active
intermediate states and promoted irreversible transition when the temperature is
elevated.
PMID- 9555073
TI - Striatal glutamate antagonism induces contralateral neglect.
AB - To assess the role of striatal glutamatergic synapses in mediating sensorimotor
orientation behavior, glutamate receptor antagonists were infused into the left
striatum of awake rats and behavioral orientation to contralateral and
ipsilateral stimuli were quantified. The AMPA-kainate antagonist, DNQX, and the
NMDA antagonist, CPP, both induced a large asymmetry in responding, such that the
rats oriented much less to stimuli presented contralateral to the antagonist
infusions. Furthermore, intrastriatal glutamate antagonist infusions increased
the occurrence of incorrect responses, or turning away from a contralaterally
presented stimulus. In a separate experiment, intrastriatal DNQX was shown to
block kainic acid (KA)-induced Fos expression in the striatum, but not in
adjacent cerebral cortex, suggesting that the diffusion of this drug is
restricted to the striatum.
PMID- 9555074
TI - Expression pattern of a novel death-promoting gene, DP5, in the developing murine
nervous system.
AB - We examined the expression patterns of the DP5 gene, which encodes a protein with
apoptosis-inducing activity, in the developing nervous system of mice. This gene
was primarily expressed in the spinal motor neurons and peripheral sensory
ganglia of mouse embryos and transiently in the postnatal brain, particularly in
the entorhinal cortex and hippocampus. These expression patterns suggest that the
DP5 gene may be involved in the apoptosis, if not all, of the developing nervous
system.
PMID- 9555075
TI - Proteolytic processing of a secreted glycoprotein and O-glycosylation of
mannoproteins are affected in the N-glycosylation mutant Saccharomyces cerevisiae
ldb1.
AB - In a previous work [P.I. Manas, I. Olivero, M. Avalos, L.M. Hernandez,
Glycobiology, 7 (1997) 487-497], we described the isolation and characterization
of the Saccharomyces cerevisiae ldb1 mutant which is affected in several steps of
the N-glycosylation of mannoproteins probably due to a malfunction of the Golgi
apparatus. Here, we found that two further functions assigned to the Golgi
cisternae are also affected in the mutant: proteolytic processing of a secreted
protein and O-glycosylation. We found that around 70% of the exoglucanase
activity that is secreted into the culture medium by ldb1 bears an extra
tetrapeptide in its NH2-terminus due to incomplete proteolytic processing. The O
linked oligosaccharides from ldb1 mnn1 were indistinguishable from those
synthesized by the parental strain mnn1. However, when the O-oligosaccharides
from the wild type and ldb1 were compared, we found a significant decrease in the
tetrasaccharide in the latter, as well as a concomitant increase in the
disaccharide, suggesting a defect in the Kre2p/Mnt1p involved in the transfer of
the third mannose of these residues.
PMID- 9555076
TI - Expression of estrogen receptor alpha and beta transcripts in female monkey
hippocampus and hypothalamus.
AB - Understanding mechanisms of estrogen effects on cognition is critical for
designing therapies for post-menopausal women and others with dementia.
Hippocampus, an area important to cognitive function, responds robustly on
estrogen. ERbeta and ERalpha transcripts were detected in the hippocampus and
hypothalamus of an ovariectomized female monkey at a relatively high
ERbeta/ERalpha ratio. These results suggest that ERbeta may play a role in
mediating estrogen effects in the primate hippocampus and hypothalamus.
PMID- 9555077
TI - Xanthophyll biosynthesis: molecular and functional characterization of carotenoid
hydroxylases from pepper fruits (Capsicum annuum L.).
AB - To dissect the mechanism by which carotenoid hydroxylases catalyze xanthophyll
formation, we have cloned two pepper cDNAs encoding beta-cryptoxanthin and
zeaxanthin biosynthetic enzymes. Using an in vitro system, we find that both
enzymes are ferredoxin dependent and that their activity is strongly inhibited by
iron chelators such as o-phenanthroline or 8-hydroxyquinoline. This suggests the
transfer of a reducing equivalent from NADPH to the hydroxylase via ferredoxin
and the involvement of an iron activated oxygen insertion process. Based on
sequence analysis, the putative histidine clusters involved in the iron
coordination were identified and their roles evaluated. Following site-directed
mutagenesis of the identified histidine residues hydroxylase activity was totally
inactivated. Collectively, our data indicate that carotenoid hydroxylases belong
to a new class of diiron proteins structurally related to membrane fatty acid
desaturases. Mechanistically, both types of enzymes exploit iron activated oxygen
to break the C-H bond with concomitant formation of double bond or oxygen
insertion. We propose that the same mechanism operates for beta-carotene ketolase
and probably for other carotenoid oxygenases as well.
PMID- 9555078
TI - mu Opioid receptor knockout in mice: effects on ligand-induced analgesia and
morphine lethality.
AB - The mu opioid receptor gene (MOR) was mutated in mice by a gene targeting
procedure. In these MOR-knockout mice, the analgesic effects of morphine, its
major metabolites, morphine-6-glucuronide (M-6-G) and morphine-6-ethereal sulfate
(M-6-S), and endomorphin-2, as well as morphine-induced lethality, were
drastically reduced, whereas the effects of DPDPE and U50488 remained unchanged.
It is concluded that analgesic effects of mu-specific opioid ligands and acute
morphine lethality are mediated by the mu receptor.
PMID- 9555079
TI - Muscarinic-receptor antagonist scopolamine rescues hippocampal neurons from death
induced by glutamate.
AB - Cultured hippocampal neurons were used to test the hypothesis that modulation of
muscarine receptors can modify glutamate-induced neurodegeneration. Treatment of
hippocampal cultures with scopolamine (1 nM to 1 mM) under glutamate incubation
had beneficial effect on neuronal viability. Thus, blockade of muscarinic
receptor sites increased the threshold for glutamate neurotoxicity. These data
show that interactions between the NMDA, muscarinic receptors and their
corresponding neurotransmitter inputs to hippocampal neurons may play a crucial
role in neurodegeneration.
PMID- 9555080
TI - Polysynaptic neuronal pathways from group I and group II afferents innervating
tail muscles to hindlimb motoneurons in the cat.
AB - Postsynaptic potentials evoked in motoneurons innervating m. posterior biceps and
semitendinosus (PBSt) and m. triceps surae (GS) by low threshold afferents from
various tail muscles located at the level of the second-third caudal vertebrae
were investigated in the non-anesthetized and spinalized cat. Afferent inputs
from tail muscles on both sides predominantly evoked depolarizing potential in
PBSt motoneurons and hyperpolarizing potential in GS motoneurons. The findings
suggest that in general, tail muscle afferents facilitate flexor and inhibit
extensor hindlimb motoneurons through polysynaptic pathways, so that the pelvic
girdle is kept in a low position to maintain the stability of the body
irrespective of different movements or posture of the tail.
PMID- 9555081
TI - Cloning of a cyclic GMP phosphodiesterase gamma subunit from the ground squirrel
retina.
AB - Recent evidence suggests that the two main classes of cones are not only equipped
with different photopigments, but also exhibit differences in their downstream
phototransduction cascade. An antibody against the gamma subunit of retinal cGMP
phosphodiesterase (PDE) had previously been found to label all photoreceptors in
the ground squirrel (Spermophilus tridecemlineatus). This property was utilized
for the cloning of a cDNA fragment encoding the corresponding polypeptide. A
lambda gt11 cDNA library was constructed and screened with the antibody. Positive
clones were isolated, subcloned, and sequenced. Clones were used as probes in RNA
blot hybridization, and the obtained sequence information was compared to other
available gamma-PDE sequences. Four virtually identical cDNA clones were
isolated. Both nucleic acid and amino acid sequence alignment placed this gene in
the same group as bovine and human cone gamma-phosphodiesterase subunits. The
predicted length of the translated protein was 84 amino acids, and its molecular
weight 11 kD. The cDNA hybridized with an 0.6-kb transcript in retinal RNA from
ground squirrel, Syrian golden hamster, and mouse, and also with a 1.4-kb
transcript in the ground squirrel. We conclude that the isolated cDNA fragment
encodes a gamma subunit of cone cGMP-PDE. This subunit is expressed in middle
wavelength sensitive cones (the predominant photoreceptor type in this species).
It remains to be determined if this subunit is expressed in short-wavelength
sensitive cones as well, or if these photoreceptors are equipped with another,
unique gamma-PDE subunit.
PMID- 9555082
TI - Cytotoxicity and DNA binding characteristics of dextran-conjugated doxorubicins.
AB - The antitumor antibiotic doxorubicin was conjugated with polymeric dextrans of
various molecular weights and the cytotoxicity of the conjugates against human
carcinoma KB-3-1 cells and its multidrug-resistant subclone KB-V-1 cells was
measured by tetrazolium salt MTT assay. The conjugates were much less toxic to
the KB-3-1 cells than the free doxorubicin but exhibited similar toxicity to the
KB-V-1 cells. The conjugate-DNA interactions were monitored in real-time using an
optical biosensor based on evanescent wave detection to obtain the association
(ka) and dissociation (kd) rate constants as well as the equilibrium binding
constants (KA) of the bindings. Both ka and kd values for the conjugates are more
than three magnitudes smaller than those for free doxorubicin, while the KA
values of the conjugate-DNA complexes are only about 10 times smaller than that
of the free doxorubicin-DNA complex. The results indicate that the cytotoxicity
and the DNA-binding kinetics of doxorubicin may be modified with dextran
conjugation. The KA values obtained from the biosensor measurements were in close
agreement with those determined in solution by fluorescent titration method,
verifying the utility of the label-free biosensing measurements as an efficient
method for studying ligand-DNA interactions.
PMID- 9555083
TI - Negative regulation of Apo A-I gene expression by retinoic acid in rat
hepatocytes maintained in a coculture system.
AB - Rat hepatocytes cocultured with rat liver epithelial cells (RLEC) were used to
investigate the influence of all-trans retinoic acid (RA) on the regulation of
apolipoproteins (Apo) A-I and A-II gene expression, the major protein constituent
of high-density lipoproteins. In contrast to rat hepatocytes in conventional
primary culture, Apo A-I and Apo A-II gene expression remained high and stable
for several days in parenchymal cells in coculture. Treatment of cocultured rat
hepatocytes with RA resulted in a specific decrease in Apo A-I mRNA levels
whereas no marked difference in Apo A-II mRNA levels was observed. Such a
negative effect of RA was already detected as early as 2 days of treatment and
was effective for the entire experimental period (6 days). As controls, RARbeta
mRNA levels increased whereas those of GAPDH mRNA were not affected by the RA
treatment. The decrease in Apo A-I mRNA levels was associated with lower amounts
of Apo A-I secreted in the culture medium within day 1 of treatment. This effect
required active transcription and protein synthesis. These results show that,
contrary to primary pure hepatocyte cultures and hepatoma cell lines, cocultures
of rat hepatocytes reproduce the in vivo results suggesting that only well
differentiated hepatocytes may correctly respond to RA. Furthermore, they
demonstrate that RA can directly act on hepatocytes and differently affect Apo A
I and Apo A-II gene expression.
PMID- 9555084
TI - Post-lesion up-regulation of 5-HT1B binding sites in the suprachiasmatic nucleus
may be reversed after spontaneous or graft-induced serotonin reinnervation.
AB - We have previously reported that selective axotomy of serotoninergic neurons
produced by an intraventricular injection of 5, 7-dihydroxytryptamine is followed
by an increase in 5-HT1B binding sites in the suprachiasmatic nucleus of the
hypothalamus. This post-lesion up-regulation is shown here to be spontaneously
reversed after long-term survival in spite of an incomplete reinnervation of the
nucleus. Recovery may be accelerated by fetal raphe transplants that produce more
rapid reinnervation.
PMID- 9555085
TI - Inhibition of cytochrome c oxidase activity by 4-hydroxynonenal (HNE). Role of
HNE adduct formation with the enzyme subunits.
AB - The role of 4-hydroxynonenal (HNE), a major lipid peroxidation product, in
oxidative damage to mitochondrial cytochrome c oxidase (COX) was examined.
Oxidative stress was induced in mitochondria isolated from livers of male Sprague
Dawley rats by tert-butylhydroperoxide (t-BHP). COX activity was inhibited, with
a concomitant increase in endogenous HNE level in mitochondria. COX activity was
also inhibited following incubation of mitochondria with 50-450 microM HNE.
Blocking HNE degradation intensified COX inhibition by HNE and by t-BHP-induced
oxidative stress, the latter accompanied by a simultaneous increase in endogenous
HNE production. On the other hand, COX inhibition by HNE was markedly reduced by
potentiating HNE degradation via enhancing conjugation of HNE with reduced
glutathione (GSH). Incubation of purified COX with 10-400 microM HNE resulted in
HNE adduct formation with specific subunits of COX, correlated with inhibition of
the enzyme activity. These data suggest that HNE may inhibit mitochondrial COX by
forming adducts with the enzyme, and that this could be one mechanism underlying
mitochondrial damage caused by oxidative stress. The findings also illustrate a
role for GSH in protecting mitochondria from the deleterious effects of HNE.
PMID- 9555087
TI - Noxious heat-evoked fos-like immunoreactivity in the rat lumbar dorsal horn is
inhibited by glutamate microinjections in the upper cervical spinal cord.
AB - Microinjections of glutamate into the upper cervical spinal cord significantly
reduced (to 57% of control) the total number of neurons demonstrating noxious
heat-evoked fos-like immunoreactivity in the lumbar spinal cord. Neurons in the
upper cervical spinal cord, with descending propriospinal projections to the
lumbar spinal cord, therefore, produce inhibitory effects on dorsal horn neurons
in the lumbar spinal cord that receive nociceptive input from cutaneous thermal
nociceptors.
PMID- 9555086
TI - Neuromedin B activates phospholipase D through both PKC-dependent and PKC
independent mechanisms.
AB - The actions of neuromedin B (NMB), a recently discovered mammalian bombesin
related peptide, are mediated by interacting with a distinct receptor; however,
little is known about its cellular basis of action. Recent studies show
activation of phospholipase D (PLD) is an important transduction cascade for a
number of GI hormones, especially for stimulation of growth and protein sorting.
The purpose of the present study was to determine whether activation of the NMB
receptor causes activation of PLD and to explore whether this activation was
coupled to PLC activation. Rat C6 glioblastoma cells (C6 cells), which contain a
low density of native NMB receptors and BALB 3T3 cells stably transfected with
rat NMB receptors, were used. NMB caused a 3-fold increase in C6 cells and an 11
fold increase in rNMB-R transfected cells in PLD activity. Increases in PLD
activity were rapid and NMB was 100-fold more potent than gastrin-releasing
peptide (GRP). NMB caused a half-maximal increase in [Ca2+]i at 0.2 nM, in [3H]IP
and PLD at 1 nM, and half-maximal receptor occupation at 1.2 nM. TPA increased
PLD dose-dependently with a half-maximal effect at 60 nM. The calcium ionophore
A23187 (1 microM) alone did not increase PLD activity but potentiated the effect
of TPA. The Ca2+-ATPase inhibitor, thapsigargin, did not affect NMB- or TPA
stimulated PLD activities, although it blocked completely the NMB-induced
increase in [Ca2+]i. The PKC inhibitor GF109203X completely abolished TPA-induced
PLD activity, however, it only inhibited NMB-induced PLD activity by 20%. The
combination of thapsigargin and GF109203X had the same effect as GF109203X alone.
These data indicate that NMB receptor activation is coupled to both PLC and PLD.
In contrast to a number of other phospholipase C-coupled receptors, NMB receptor
stimulated changes in [Ca2+]i do not contribute to PLD activation. Both PKC
dependent and PKC-independent mechanisms are involved in the NMB-stimulated PLD
activation with the PKC-independent pathway predominating.
PMID- 9555088
TI - Modification of dopamine release by nociceptin in conscious rat striatum.
AB - Nociceptin (NOC), an endogenous ligand for the orphan receptor ORL1, has recently
been recognized as a neuropeptide. We used brain microdialysis and on-line high
performance liquid chromatography to examine the effect of NOC on the basal
outflow of dopamine (DA) and its metabolite in the freely moving rat striatum in
vivo. The percent change of DA release induced by NOC at concentrations of 10-6
and 10-5 M were 383% and 398%, respectively. This effect of NOC was attenuated by
naloxone, suggesting that NOC activates classic (micro, delta, kappa) receptors
in a very little way. These data indicates that NOC may act as a neuropeptide
which enhances DA release from the striatum of rat brain via an opioid receptor.
PMID- 9555089
TI - Enhancement of intestinal UDP-glucuronosyltranferase activity in partially
hepatectomized rats.
AB - To evaluate whether a temporary hepatic insufficiency may affect intestinal
glucuronidation, we determined UDP-glucuronosyltransferase activity towards
bilirubin and p-nitrophenol in rat jejunum and liver after partial hepatectomy.
Enzyme assays were performed in native, and in UDP-N-acetylglucosamine- or
palmitoyl lysophosphatidylcholine-activated microsomes at different times post
hepatectomy. Content of enzyme was analyzed by Western blot. Microsomal
cholesterol/phospholipid ratio, phospholipid and total fatty acid classes were
also determined to evaluate the possible influence on enzyme activity. The
results show that while hepatic microsomes exhibited no change in UDP
glucuronosyltransferase activity (for both substrates) with respect to shams at
any time of study, intestinal activities increased significantly 48 h after
surgery, returning to sham values 96-h post-hepatectomy. Western blotting
confirmed the increase (about 50% for both substrates 48-h post-hepatectomy) in
intestinal UDP-glucuronosyltransferase activity. No variations were observed in
hepatic and intestinal microsomal lipid composition in agreement with the absence
of modification in the percent of activation by palmitoyl
lysophosphatidylcholine. In conclusion, jejunum but not liver, was able to
produce a compensatory increase in conjugation capacity during a transitory loss
of hepatic mass. The phenomenon is associated to a modification in the amount of
UDP-glucuronosyltransferase, rather than to changes in the characteristics of the
enzyme environment.
PMID- 9555090
TI - Anxiolytic-like effect of neuropeptide Y (NPY) and NPY13-36 microinjected into
vicinity of locus coeruleus in rats.
AB - Neuropeptide Y (NPY, 1 and 10 pmol), NPY Y1 receptor agonist [Leu31, Pro34]NPY
(10 pmol) and Y2 agonist NPY13-36 (100 pmol) were administered unilaterally into
the region of the nucleus locus coeruleus (LC) in rats. NPY (10 pmol) and NPY13
36 increased the percentage of open arm entries, the percentage of time spent on
open part, number of both open and closed arm entries and line crossings in the
open part while [Leu31,Pro34]NPY failed to modify elevated plus-maze behavior.
These data suggest that NPY applied close to LC has anxiolytic-like effects by
acting on NPY Y2, not on Y1 receptors. Thus, NPY Y2 receptors in the vicinity of
LC may be involved in the regulation of anxiety in rats.
PMID- 9555091
TI - Organization of quinto-frontal structures in hatchling ring doves (Streptopelia
risoria).
AB - Transganglionic and retrograde tracing procedures were applied to peripheral and
central trigeminal structures in hatchling ring doves. The organization of the
trigeminal ganglion, its somatotopic projections upon the principal sensory
nucleus (PrV), and the projections of PrV upon the telencephalon are similar in
adult and hatchling Columbiformes. The results suggest that development of
feeding patterns in these species involves experiential differentiation of
trigeminal sensorimotor circuits present at hatching.
PMID- 9555092
TI - Pristanic acid beta-oxidation in peroxisomal disorders: studies in cultured human
fibroblasts.
AB - To investigate the individual steps of peroxisomal beta-oxidation, human
fibroblasts from controls and patients affected by different peroxisomal
disorders were incubated for 96 h with pristanic acid. Hereafter, 2,3-pristenic
acid and 3-hydroxypristanic acid in the incubation medium were quantified by
stable isotope dilution gas chromatography mass spectrometry (GC-MS). In control
fibroblasts, both intermediates were formed and excreted into the medium in
significant amounts. In cells from patients affected with different types of
generalized peroxisomal disorders, the formation of both intermediates was absent
or low, depending on the clinical severity of the disorder. In fibroblasts from
patients affected with bifunctional protein deficiency, the concentrations of 2,3
pristenic acid and 3-hydroxypristanic acid in the medium were higher than in
control cell lines.
PMID- 9555093
TI - 7-Nitro indazole enhances methohexital anesthesia.
AB - 7-nitro indazole, a selective inhibitor of the neuronal nitric oxide (NO)
synthase dose-dependently prolongs the duration of methohexital narcosis in the
rat. This effect can be antagonized stereoselectively by the NO-synthase
substrate l-arginine (l-Arg). The results support the assumption that the
potentiation of the anesthetic state by NO-synthase inhibitors is due to a
specific effect on brain NO-synthase and a disruption of synaptic NO signalling
pathways. These results are also in accordance with predictions that follow from
recent hypotheses proposing that a modification of the NMDA receptor function is
the final common pathway of anesthetic action.
PMID- 9555094
TI - Novel vectors for gene delivery formed by self-assembly of DNA with poly(L
lysine) grafted with hydrophilic polymers.
AB - Complexes formed between DNA and cationic polymers are attracting increasing
attention as novel synthetic vectors for delivery of genes. We are trying to
improve biological properties of such complexes by oriented self-assembly of DNA
with cationic-hydrophilic block copolymers, designed to enshroud the complex
within a protective hydrophilic polymer corona. Poly(L-lysine) (pLL) grafted with
range of hydrophilic polymer blocks, including poly(ethylene glycol) (pEG),
dextran and poly[N-(2-hydroxypropyl)methacrylamide] (pHPMA), shows efficient
binding to DNA and mediates particle self-assembly and inhibition of ethidium
bromide/DNA fluorescence. The complexes formed are discrete and typically about
100 nm diameter, viewed by atomic force microscopy. Surface charges are slightly
shielded by the presence of the hydrophilic polymer, and complexes generally show
decreased cytotoxicity compared with simple pLL/DNA complexes. pEG-containing
complexes show increased transfection activity against cells in vitro. Complexes
formed with all polymer conjugates showed greater aqueous solubility than simple
pLL/DNA complexes, particularly at charge neutrality. These materials appear to
have the ability to regulate the physicochemical and biological properties of
polycation/DNA complexes, and should find important applications in packaging of
nucleic acids for specific biological applications.
PMID- 9555095
TI - Arginyl residues are involved in acyl-CoA binding to the elongase from etiolated
leek seedlings.
AB - The C18:0-CoA elongase from etiolated leek seedling microsomes was inactivated by
treatment with phenylglyoxal, a reagent which specifically modifies arginyl
residues. In the presence of 20 mM phenylglyoxal, 95% of the C18:0-CoA elongation
was inhibited. The condensation and dehydration reactions of the overall
elongation were totally inhibited, whereas enoyl-CoA reductase activity was
diminished by 75%, but the nature of the final elongation product was unchanged.
Phenylglyoxal did not modify the C18:0-CoA partition between membrane and aqueous
compartments; moreover, [1-14C]phenylglyoxal labeling experiments showed a
covalent binding of the inhibitor to membrane proteins. The ability of several
substrates to prevent the inactivation by phenylglyoxal was investigated. NADH
and NADPH had no effect. CoA led to a 75% protection, and the incorporation of
[14C]phenylglyoxal was strongly affected by 10 mM CoA. The acyl chain length of
the acyl-CoAs played also a crucial role in preventing the binding of
phenylglyoxal. The maximal prevention of phenylglyoxal inhibition was obtained
with C18:0-CoA. This suggests that arginyl residues could be present in the
vicinity of the acyl-CoA binding site of the subunits of C18:0-CoA elongase.
PMID- 9555096
TI - Inhibition of secreted phospholipases A2 by annexin V. Competition for anionic
phospholipid interfaces allows an assessment of the relative interfacial
affinities of secreted phospholipases A2.
AB - The ability of annexins, particularly annexin 1 (lipocortin 1), to inhibit
phospholipase A2 (PLA2) is well known and a substrate depletion mechanism is now
widely accepted as the explanation for most inhibitory studies. In this
investigation we have examined the substrate depletion mechanism of annexin V
using a variety of phospholipid substrates and secreted PLA2's (sPLA2). The
results suggest that the term interfacial competition best describes the
inhibitory effect of annexin V although the overall inhibitory process remains
one of substrate sequestration by the annexin. We have utilised the competitive
nature of the interaction of enzyme and annexin V for a phospholipid interface as
a means of quantifying the relative affinity of sPLA2's for anionic phospholipid
vesicles. The results highlight the very high affinity of the human non
pancreatic sPLA2 for such vesicles (Kd<<10-(10) M) while the Naja naja venom PLA2
and porcine pancreatic sPLA2 showed lower affinities. Hydrolysis of mixed
vesicles containing phosphatidylserine and phosphatidylcholine by the venom and
pancreatic enzymes were differentially inhibited by annexin V. This difference
must reflect the preference of both annexin V and the pancreatic enzyme for an
anionic phospholipid interface. In contrast, the venom enzyme is able to readily
hydrolyse phosphatidylcholine domains that would be minimally affected by annexin
V. Annexin V was an effective inhibitor of cardiolipin hydrolysis by the
pancreatic PLA2, however the inhibition was of a more complex nature than seen
with other phospholipids tested. Overall the results highlight the ability of
annexin V to inhibit phospholipid hydrolysis by sPLA2's by an interfacial
competition (substrate depletion) mechanism. The effectiveness of annexin V as an
apparent inhibitor depends on the nature of the enzyme and the phospholipid
substrate.
PMID- 9555097
TI - Serum DNA polymerase beta as an indicator for fatal liver injury of rat induced
by D-galactosamine hydrochloride and lipopolysaccharide.
AB - DNA polymerase beta (pol beta) is a nuclear enzyme that is tightly bound to
chromatin. Release of the pol beta activity into serum, therefore, may indicate
the occurrence of massive destruction of cell nuclei in organs or tissues. In the
present study, we made a liver injury model rat by the intraperitoneal injection
of D-galactosamine hydrochloride (GalN, 500 mg/kg) and lipopolysaccharide (LPS,
100 microg/kg). Serum from the GalN/LPS-treated rats showed a high level of pol
beta activity up to 118 pmol/0.5 microl serum (4700 cpm) at 12 h after the
treatment, while the control rat serum showed the back ground level (3.8 pmol/0.
5 microl, 150+/-70 cpm). The serum pol beta activity was sensitive to inhibition
by 2',3'-dideoxyTTP and by an anti-rat pol beta antibody. Among 30 rats treated
with GalN/LPS, 10 rats died within 120 h (dead group). Serum pol beta activity in
the dead group was as high as 23.0+/-19.5 pmol/0.5 microl (925+/-778 cpm) at 10 h
after the treatment, while in alive group (n=20), it was 3.7+/-3.2 pmol. Levels
of the serum pol beta activity correlated well with the prognosis of GalN/LPS
treated rats based on an analysis of the receiver-operator characteristic curves.
PMID- 9555098
TI - Characterization of hyaluronan synthase from a human glioma cell line.
AB - In the present study we describe a method to prepare membranes with high
hyaluronan synthase activity from human glioma cells by pretreatment of the cells
with both testicular hyaluronidase and 4-phorbol 12-myristate 13-acetate (PMA). A
23-fold increase in hyaluronan synthase activity was detected in comparison to
untreated cells. Using isolated membranes as a source of hyaluronan synthase
activity we demonstrate that chain elongation occurs at the reducing end of the
hyaluronan molecule. We also present a method to solubilize hyaluronan synthase
in active form with 1% digitonin. The solubilized synthase synthesized shorter
hyaluronan chains than the membrane bound enzyme. Partial purification of the
solubilized enzyme on a Superdex-200 column revealed a 12-fold increase in
specific activity. Affinity purified polyclonal antibodies, raised against a
synthetic peptide corresponding to the carboxy-terminus of the deduced protein
sequence of human hyaluronan synthase recognized a 66 kDa component in the
purified preparations. The elution position of the solubilized hyaluronan
synthesizing activity immediately after V0 corresponding to a molecular mass of
about 600 kDa, suggested that the 66 kDa enzyme forms a complex with other
components which may have accessory or regulatory roles during hyaluronan
synthesis.
PMID- 9555099
TI - Interaction of mercaptoundecahydrododecaborate (BSH) with phosphatidylcholine:
relevance to boron neutron capture therapy.
AB - The interaction of mercaptoundecahydrododecaborate (B12H11SH2-, BSH) with
phosphatidylcholine was investigated in this study in order to illuminate
possible uptake mechanisms of BSH in tumor cells. BSH has been used clinically in
Japan as a boron containing agent in patients with malignant brain tumors for
boron neutron capture therapy (BNCT). After infusion, BSH accumulates selectively
in tumor tissue. Little is known for the mechanism of boron uptake to tumor
cells. Fourier transform infrared (FTIR) spectrometry was used to quantify BSH
(at wavenumber 2490 cm-1) and phosphatidylcholine (at wavenumber 2850-2970 cm-1).
After extraction into carbon tetrachloride (CCl4), we could find an absorbance
maximum at 2490 cm-1 as a B-H band in the mixture of BSH with
phosphatidylcholine, which is attributed to a BSH-phosphatidylcholine complex,
which could dissolve well in CCl4. The molar ratio of BSH to phosphatidylcholine
in the CCl4 solution was at most one mole of BSH to two moles of
phosphatidylcholine independent of the excess BSH. The doubly negatively charged
BSH can interact with two phosphatidylcholine molecules through their singly
positively charged choline residues. These ion pairs could be responsible for
membrane binding and penetration, and for cell internalization.
PMID- 9555100
TI - Cloning and expression of a group IV cytosolic Ca2+-dependent phospholipase A2
from rat pancreatic islets. Comparison of the expressed activity with that of an
islet group VI cytosolic Ca2+-independent phospholipase A2.
AB - Stimulation of pancreatic islets with glucose induces phospholipid hydrolysis and
accumulation of nonesterified arachidonic acid, which may play signaling or
effector roles in insulin secretion. Of enzymes that catalyze phospholipid
hydrolysis, islet beta-cells express low molecular weight secretory
phospholipases A2 (PLA2) and a Group VI, Ca2+-independent PLA2 (iPLA2). Previous
studies indicate that islets also express a protein recognized by antibodies
against a Group IV, cytosolic, Ca2+-dependent PLA2 (cPLA2). To further examine
the possible expression of cPLA2 by islets, we screened a rat islet cDNA library
with a probe that recognizes cPLA2 sequence, and isolated a full-length cPLA2
cDNA. The rat islet cPLA2-deduced amino acid sequence is 96% identical to those
of human and mouse cPLA2. Transfection of COS-7 cells with cPLA2 cDNA in an
expression vector induced expression of Ca2+-dependent PLA2 activity and of a
protein recognized by anti-cPLA2 antibody. Comparison of recombinant islet cPLA2
and iPLA2 activities expressed in transfected COS-7 cells indicated that iPLA2
but not cPLA2 is stimulated by ATP. Both activities are similarly sensitive to
inhibition by arachidonyltrifluoromethyl ketone, but iPLA2 is more effectively
inhibited by a haloenol lactone suicide substrate than cPLA2. RT-PCR experiments
with RNA from purified islet beta-cells and from an alpha-cell-enriched
population prepared by fluorescence-activated cell-sorting indicated that cPLA2
mRNA is more abundant in the beta-cell population. Immunoblotting analyses
indicate that islets express cPLA2-immunoreactive protein, and that interleukin-1
does not affect its expression. The cPLA2 is thus one of at least three classes
of PLA2 enzymes with distinct properties expressed in beta-cells.
PMID- 9555101
TI - Erythrocyte defenses against hydrogen peroxide: the role of ascorbic acid.
AB - Ascorbate has been reported to increase intracellular hydrogen peroxide (H2O2)
generation in human erythrocytes. In the present work, the basis for this
prooxidant effect of the vitamin was investigated in the context of erythrocyte
defenses against H2O2. Ascorbate added to erythrocytes caused a dose-dependent
increase in intracellular H2O2, which was measured as inactivation of endogenous
catalase in the presence of 3-amino-1,2,4-triazole (aminotriazole). Ascorbate
induced catalase inactivation was not observed when only the intracellular
ascorbate concentration was increased, when cells were incubated with ascorbate
in plasma, or when extracellular Fe3+ was chelated. Together, these results
suggest that the observed ascorbate-induced H2O2 generation is due to Fe3+
catalyzed oxidation of extracellular, as opposed to intracellular, ascorbate by
molecular oxygen. Rather than generate an oxidant stress in erythrocytes,
ascorbate was one of the most sensitive intracellular antioxidants to H2O2 coming
from outside the cells. On the other hand, intracellular ascorbate contributed
little to the detoxification of H2O2, which was found to be mediated by both
catalase and by the GSH system.
PMID- 9555102
TI - Hypoxia and contractions do not utilize the same signaling mechanism in
stimulating skeletal muscle glucose transport.
AB - We have investigated whether hypoxia and muscle contractions stimulate glucose
transport in perfused rat muscle to the same extent, additively and with the same
sensitivity to the microbial products calphostin C and wortmannin. Hindlimb
glucose uptake increased gradually from 3.4+/-0.5 to a maximal level of 12.7+/
0.6 micromol g-1 h-1 (n=11) after 50 min of hypoxia. Compared with hypoxia, the
effect of maximal electrical stimulation of the sciatic nerve on muscle glucose
uptake was more than two-fold higher (27+/-2 micromol g-1 h-1 (n=14)). This was
due to a higher contraction- vs. hypoxia-induced glucose transport rate in
oxidative fibers. The stimulatory effect of hypoxia and electrical stimulation
was not additive. Contraction-induced muscle glucose transport was inhibitable by
both calphostin C and wortmannin in the micromolar range, whereas the effect of
hypoxia was totally insensitive to these drugs. Our data suggest that
diacylglycerol/phorbol ester-sensitive protein kinase C is involved in
stimulation of muscle glucose transport by contractions and that in contrast to
the prevailing concept, hypoxia and contractions do not stimulate muscle glucose
transport by the same signaling mechanism.
PMID- 9555103
TI - Distinctive inhibitory activity of docosahexaenoic acid against sphingosine
induced apoptosis.
AB - The effect of supplementation of docosahexaenoic acid (DHA) on the apoptosis of
HL60 cells was examined using N-acetyl sphingosine (C2-ceramide) and sphingosine
as apoptosis-inducing agents. Although C2-ceramide-induced apoptosis was not
affected by DHA supplementation, sphingosine-induced apoptosis was reduced almost
to the background level by preincubation with 10 microM DHA for 24 h. Among the
fatty acids, only DHA appeared to be endowed with the ability to reduce
sphingosine-induced apoptosis, whereas, other unsaturated fatty acids, such as
arachidonic acid (AA) and eicosapentaenoic acid (EPA), did not show this
activity. Incubation of HL60 with DHA within 6 h did not affect the apoptosis,
suggesting that DHA probably expressed the inhibitory activity after modulation
of the membrane fatty acid composition. DHA also attenuated the apoptosis induced
by dimethylsphingosine and H-7, but not by calphostin C, indicating that
enrichment of DHA in membranous phospholipid does not necessarily prevent all of
the apoptosis associated with the inhibition of protein kinase C. The mechanism
of the inhibition against sphingosine-induced apoptosis by DHA remains to be
further explored. However, the inhibition of cytosolic phospholipase A2 (cPLA2)
may be involved in the mechanism, because distinctive inhibitory activity of DHA
against cPLA2 has been demonstrated [M. Shikano, Y. Masuzawa, K. Yazawa, K.
Takayama, I. Kudo, K. Inoue, Biochim. Biophys. Acta, 1212, 1994, 211-216], and
arachidonyl trifluoromethylketone, a specific inhibitor of cPLA2, attenuated the
apoptosis induced by sphingosine.
PMID- 9555104
TI - Modular subdivisions of dolphin insular cortex: does evolutionary history repeat
itself?
AB - The structural organization of the insular cortex in the bottlenose dolphin was
investigated by examining Nissl- and myelin-stained tissue that was sectioned
coronally and tangentially. An uneven distribution of cell clusters that
coincided with myelin-light zones was observed in layer II. When the present
observations were compared to descriptions of modules in other animals, we found
that the range of module size is restricted, while the size of the brain,
particularly the neocortex, varies dramatically. Indeed, despite the tremendous
expansion of the cetacean neocortex, the size of the modules in the insular
cortex is similar to that described for small-brained mammals like the mouse,
suggesting that module size is evolutionarily stable across species. Selection
for optimal-size processing units, in terms of the lengths of connections within
and between them, is a likely source of this stability.
PMID- 9555105
TI - Contribution of human prefrontal cortex to delay performance.
AB - Neurological patients with focal lesions in the dorsolateral prefrontal cortex
and age-matched control subjects were tested on an auditory version of the
delayed-match-to-sample task employing environmental sounds. Subjects had to
indicate whether a cue (s/S1) and a subsequent target sound (S2) were identical.
On some trials, S1 and S2 were separated by a silent period of 5 sec. On other
trials, the 5-sec delay between S1 and S2 was filled with irrelevant tone pips
that served as distractors. Behaviorally, frontal patients were impaired by the
presence of distractors. Electrophysiologically, patients generated enhanced
primary auditory cortex-evoked responses to the tone pips, supporting a failure
in inhibitory control of sensory processing after prefrontal damage.
Intrahemispheric reductions of neural activity generated in the auditory
association cortex and additional intrahemispheric reductions of attention
related frontal activity were also observed in the prefrontal patients. Together,
these findings suggest that the dorsolateral prefrontal cortex is crucial for
gating distracting information as well as maintaining distributed
intrahemispheric neural activity during auditory working memory.
PMID- 9555106
TI - Toward a functional analysis of the basal ganglia.
AB - Parkinson patients were tested in two paradigms to test the hypothesis that the
basal ganglia are involved in the shifting of attentional set. Set shifting means
a respecification of the conditions that regulate responding, a process sometimes
referred to as an executive process. In one paradigm, upon the appearance of each
stimulus, subjects were instructed to respond either to its color or to its
shape. In a second paradigm, subjects learned to produce short sequences of three
keypresses in response to two arbitrary stimuli. Reaction times were compared for
the cases where set either remained the same or changed for two successive
stimuli. Parkinson patients were slow to change set compared to controls.
Parkinson patients were also less able to filter the competing but irrelevant set
than were control subjects. The switching deficit appears to be dopamine based;
the magnitude of the shifting deficit was related to the degree to which 1-dopa
based medication ameliorated patients' motor symptoms. Moreover, temporary
withholding of medication, a so-called off manipulation, increased the time to
switch. Using the framework of equilibrium point theory of movement, we discuss
how a set switching deficit may also underlie clinical motor disturbances seen in
Parkinson's disease.
PMID- 9555107
TI - Self-organization of binocular disparity tuning by reciprocal corticogeniculate
interactions.
AB - This article develops a neural model of how sharp disparity tuning can arise
through experience-dependent development of cortical complex cells. This learning
process clarifies how complex cells can binocularly match left and right eye
image features with the same contrast polarity, yet also pool signals with
opposite contrast polarities. Antagonistic rebounds between LGN ON and OFF cells
and cortical simple cells sensitive to opposite contrast polarities enable
anticorrelated simple cells to learn to activate a shared set of complex cells.
Feedback from binocularly tuned cortical cells to monocular LGN cells is proposed
to carry out a matching process that dynamically stabilizes the learning process.
This feedback represents a type of matching process that is elaborated at higher
visual processing areas into a volitionally controllable type of attention. We
show stable learning when both of these properties hold. Learning adjusts the
initially coarsely tuned disparity preference to match the disparities present in
the environment, and the tuning width decreases to yield high disparity
selectivity, which enables the model to quickly detect image disparities.
Learning is impaired in the absence of either antagonistic rebounds or
corticogeniculate feedback. The model also helps to explain psychophysical and
neurobiological data about adult 3-D vision.
PMID- 9555108
TI - Neural site of the redundant target effect electrophysiological evidence.
AB - The present study represents an attempt to find an electrophysiological correlate
of the redundant targets effect, or RTE (i.e., the speeding up of reaction time,
or RT, for redundant vs. single targets). Subjects made a speeded response either
to one small checkerboard presented to the left or right of fixation or to a pair
of identical checkerboards presented simultaneously to both hemifields. Both
single and double targets could appear either in the upper or lower visual
hemifield. The task required detection but not discrimination of the stimuli.
During task performance, we recorded the event-related potentials (ERPs) elicited
by the checkerboard targets. As in previous studies, we found that manual RTs to
bilateral stimuli were faster than those to unilateral stimuli. This effect was
more marked for lower- than for upper-field stimuli and could not be ascribed to
probability summation. In addition, we found that the P1 and N1 components of the
visual ERP had a shorter latency for bilateral than for summed unilateral stimuli
presented to the two hemifields. In parallel with the behavioral findings, the
latency values for the above components showed a larger RTE for lower-field
stimuli. These findings indicate that the RTE occurs at the level of early visual
processing, probably in the extrastriate visual cortex, rather than at late
decisional or pre-motor stages.
PMID- 9555109
TI - Cortical-hippocampal auditory processing identified by magnetoencephalography.
AB - We recorded magnetic and electrical responses simultaneously in an auditory
detection task to elucidate the brain areas involved in auditory processing.
Target stimuli evoked magnetic fields peaking at approximately the same latency
of around about 400 msec (M400) over the anterior temporal, superior temporal,
and parietal regions on each hemisphere. Equivalent current dipoles (ECDs) were
analyzed with a time-varying multidipole model and superimposed on each subject's
magnetic resonance image (MRI). Multiple independent dipoles located in the
superior temporal plane, inferior parietal lobe, and mesial temporal region best
accounted for the recorded M400 fields. These findings suggest that distributed
activity in multiple structures including the mesial temporal, superior temporal,
and inferior parietal regions on both hemispheres is engaged during auditory
attention and memory updating.
PMID- 9555110
TI - Encapsulation of implicit and explicit memory in sequence learning.
AB - Contrasts between implicit and explicit knowledge in the serial reaction time
(SJRT) paradigm have been challenged because they have depended on a single
dissociation; intact implicit knowledge in the absence of corresponding explicit
knowledge. In the SRT task, subjects respond with a corresponding keypress to a
cue that appears in one of four locations. The cue follows a repeating sequence
of locations, and subjects can exhibit knowledge of the repeating sequence
through increasingly rapid performance (an implicit test) or by being able to
recognize the sequence (an explicit test). In our study, amnesic patients were
given extensive SRT training. Their implicit and explicit test performance was
compared to the performance of control subjects who memorized the training
sequence. Compared with control subjects, amnesic patients exhibited superior
performance on the implicit task and impaired performance on the explicit task.
This crossover interaction suggests that implicit and explicit knowledge of the
embedded sequence are separate and encapsulated and that they presumably depend
on different brain systems.
PMID- 9555111
TI - Event-related brain potentials and case information in syntactic ambiguities.
AB - In an ERP study, German sentences were investigated that contain a case-ambiguous
NP that may be assigned accusative or dative case. Sentences were disambiguated
by the verb in final position of the sentence. As our data show, sentences ending
in a verb that assigns dative case to the ambiguous NP elicit a clear garden-path
effect. The garden-path effect was indicated by a broad centro-posterior negative
shift that occurred between 300 and 900 msec after the dative-assigning verb was
presented. No enhanced P600 following the misanalysis was observed. Noun phrases
whose case ambiguity was resolved in favor of accusative case and unambiguously
dative-marked NPs did not trigger significant ERP differences. We will discuss
the implications of our results for parsing and its neuropsychological
correlates. The results of this study support a parser design according to which
the so-called structural case (nominative or accusative) is assigned without any
delay in the absence of morpho-lexical counterevidence. It is argued that the
enhancement of a negative ERP component with a "classical" N400 topography
reflects the difficulty of reanalysis due to reaccessing morpho-lexical
information that lies outside the domain of the parsing module. Consequently, ERP
responses to garden-path effects are not confined to a late positivity but vary
depending on the level of processing involved in reanalysis. The fact that garden
path effects may also elicit an N400 can be linked to the nonhomogeneous
linguistic properties of the constructions from which they arise.
PMID- 9555112
TI - The neurology of empty categories aphasics' failure to detect ungrammaticality.
AB - A direct investigation into the grammatical abilities of Broca's and Wernicke's
aphasics sought to obtain critical evidence for a revised model of the functional
neuroanatomy of language. We examined aphasics' ability to make grammaticality
judgments on a set of theoretically selected, highly complex syntactic structures
that involve, most prominently, fine violations of constraints on syntactic
movement. Although both groups have been thought to possess intact abilities in
this domain, we discovered severe deficits; Broca's and Wernicke's aphasics
(whose performances differed) exhibited clear, delineated, and grammatically
characterizable deficits - they follow from the Trace-Deletion Hypothesis, which
is motivated by independent comprehension results. These conclusions have both
linguistic and neurological implications; Linguistically, they show that the
aphasic deficit interacts with more than one module of the grammar. Namely, it
manifests not only when the thematic module is called for in interpretive tasks
but also when constraints on syntactic movement are tapped in a study of
judgment. Neurologically, the results support a view of receptive grammatical
mechanisms in the left cortex, which is functionally more restrictive than
currently assumed; neuroanatomically, however, it is more distributed.
PMID- 9555113
TI - The complexity of the Epstein-Barr virus infection in humans.
AB - The Epstein-Barr virus (EBV) was isolated 40 years ago from cultures of Burkitt
lymphoma cells (BL). The tumor was encountered in Africa and exhibited
characteristical geographical, clinical and pathological features. Serological
studies revealed that the virus is ubiquitous in humans. The primary infection is
often accompanied by the syndrome of acute infectious mononucleosis (IM). It can
induce malignant proliferation of B lymphocytes in conditions of
immunodeficiency. EBV can immortalize B lymphocytes in culture. These cells carry
the virus as episomes and express 9 virally encoded proteins. Their immunological
recognition constitutes the surveillance which is responsible for the healthy
virus carrier state. The main virus reservoir is represented by a low number of
resting B lymphocyte which contain the viral genome but do not express its
transformation proteins. The viral genome is detectable in all African BLs, in
variable proportions of nasopharyngeal carcinoma, Hodgkin's disease, T cell
lymphoma, lymphoepithelial like carcinoma, gastric carcinoma and leiomyosarcoma
cases. The role of EBV in the genesis of these tumors is unknown.
PMID- 9555114
TI - P53 expression in stage I squamous cell lung cancer.
AB - P53 expression was studied using immunohistochemistry in patients (n=94) with
pathologic stage I squamous cell lung cancer treated surgically between 1991
1992. The overall p53 positivity ratio was 48/94. 83 of the cases proved to be
suitable for follow-up analysis carried out in November, 1995. 46/83 were p53
positive, and 25/46 patients were alive at the time of analysis. The patients who
died (21/46) had a mean survival time of 17.5 months. In p53 negative cases
(37/83), however, 29/37 patients were still alive at the time of follow-up, and
8/37 had died with a mean survival time of 23.1 months. A significant correlation
could be found between p53 immunopositivity and reduced survival time (p=0.0125).
Interestingly, out of 83 cases analyzed histologic evidence of tuberculous scar
tissue was present in 9 tumors with a p53 positivity ratio of only 1/9. When flow
cytometry was used to examine tumor samples from all subgroups mentioned above
(n=32), no correlation was found between the p53 immunopositivity or the
prognosis and the DNA content of tumor tissues. Our results suggest that in the
early stage of squamous cell lung cancer the p53 positivity may be an indicator
of a more aggressive tumor behavior and a shortened survival time.
PMID- 9555115
TI - Expression of invasion markers CD44v6/v3, NM23 and MMP2 in laryngeal and
hypopharyngeal carcinoma.
AB - Twelve laryngeal squamous cell carcinoma cases (7 laryngeal and 5 hypopharyngeal
cancer; 15 samples) were analysed by immunohistochemistry for the expression of
invasion markers CD44v6/v3, NM23 and matrix metalloproteinase, MMP2. The
laryngeal epithelium showed CD44v6+/v3+/NM23-/MMP2- phenotype. When tumors were
grouped into TNM categories the phenotype of the T2 and T3 tumors was similar,
characterised by decreased CD44v3+ and lack of MMP2 expressions. Meanwhile the
NM23 expression was more frequent in T3 tumors. In T4 stage the frequency of NM23
and MMP2 positive cases increased (5/6 and 4/6, respectively) but there was no
correlation with the appearence of lymph node metastasis. Comparison of the
phenotype of laryngeal and hypopharyngeal tumors, irrespective of the TNM stages,
revealed characteristic differences: T2 stage laryngeal tumors showed decreased
CD44v3 and occasional NM23 and MMP2 positivity, while in T3 stage these tumors
were characterised by increased frequency of NM23 positivity. The phenotype of
the hypopharyngeal tumors was significantly different with a high frequency of
MMP2 positive cases (5/6) and NM23+/low CD44v3+ phenotype. The sharp differences
in the phenotypes of laryngeal and hypopharyngeal carcinomas were connected to
the differences in their invasive capacity unlike to the size of the tumors,
since the T4 stage hypopharyngeal tumors had a significantly smaller size than
laryngeal ones, even at lower stages.
PMID- 9555116
TI - Cellular alterations upon IR-laser (890 nm) exposures, in vivo.
AB - Exposure of cultured cells and small animals to ionizing radiation as well as
irradiation of cultured cells with He-Ne laser can cause changes in the
functional condition of plasma membranes. The ionizing radiation-induced cell
membrane alterations have been determined after either partial or local
exposures. The aim of the present study was to reveal whether the local laser
treatments cause a general, distant, so called abscopal" effect measured at
cellular level, when the laser treatment is intended as a stimulatory procedure.
The biological effect of infrared laser (mean power of 5 Watts, 150 Hz frequency,
890 nm wavelength) was demonstrated through 3H-concanavalin A binding by blood
cells of daily irradiated (altogether 10 exposures) oncological and non
oncological patients as well as by changes in the proliferation of bone marrow
cells of whole body gamma-irradiated (4 Gy) rats, partially laser-treated. The
lectin binding of lymphocytes of oncological, as well as ischaemic heart disease
patients was increased immediately after the first laser treatment. However, it
was decreased after completion of the full course. In cases of inflammatory
diseases the test parameters were either unchanged or decreased as compared to
their self-control values. The platelets and erythrocytes did not react in any
group. Gamma irradiation caused a deep inhibition of proliferation of rat bone
marrow cells. The number of fibroblast colony-forming units (CFU-F) could be
increased again if the animals were partially exposed to laser. Laser irradiation
of one of the femurs led to some recovery of CFU-F values in the exposed as well
as unexposed femur. Thus, local infrared laser treatment induces abscopal effects
on the cell membrane and cell proliferation characteristics.
PMID- 9555117
TI - Embryotoxicity and teratogenicity of some derivatives of
chloroethylaminophenylacetic acid.
AB - Embryotoxic and teratogenic properties of Lophenal, Phenalon, Pharanox and
Pharanoxi selenate were investigated experimentally. All examined antitumour
agents showed embryotoxic effects. Lophenal, Phenalon and Pharanox had
teratogenic effects. By modifying the structure of Pharanox with selenium a
reduction in teratogenic effect was achieved.
PMID- 9555118
TI - Comparison of the effects of the antimetastatic compound ImH[trans-RuCl4(DMSO)Im]
(NAMI-A) on the arthritic rat and on MCa mammary carcinoma in mice.
AB - The effects of the new molecule ImH[trans-RuCl4(DMSO)Im] (NAMI-A), administered
orally or intraperitoneally to adjuvant-arthritic rats or orally to mice bearing
s.c. or i.m. implants of MCa mammary carcinoma, were studied. NAMI-A was not able
to modify the progression of chronic inflammation in the complete Freund-adjuvant
injected animals. Histology indicated a significant worsening of the inflammatory
process, characterised by an increased infiltration of inflammatory cells, as
well as by a remarkable deposition of connective tissue fibres around the blood
vessels and alveolar walls. NAMI-A had no effect on primary i.m. implanted MCa
mammary carcinoma growth and its lung metastasis formation, but significantly
interfered with the cell cycle of primary tumor cells following bolus oral
administration. On the contrary, NAMI-A caused a significant inhibition of lung
metastasis accompanied by a dramatic deposition of connective tissue fibres
around the primary tumor mass, when given as medicated food to mice implanted
s.c. with MCa tumor. These data indicated that NAMI-A is well absorbed after oral
administration although there is no connection between lung concentration and the
antimetastatic activity. Conversely, the marked deposition of connective tissues
in NAMI-A treated animals is in agreement with the reported effects of the
compound on extracellular matrix and tumor blood vessels.
PMID- 9555119
TI - Coronary vasculopathy in polycythemia vera.
AB - Thrombosis is a common complication in polycythemia often causing death. In
coronary artery occlusion, thrombosis due to hyperviscosity and thrombocytosis is
mostly discussed as the origin of the infarction. We discuss the case of a 30
year-old male patient, with polycythemia, who died of myocardial infarction. On
autopsy the vessels showed neither ateriosclerotic changes nor thrombotic
occlusions. Instead, a marked intima proliferation was found leading to multiple
occlusions whereas media and adventitia were unchanged. This pattern of a
coronary vasculopathy has not been described before, and can be interpreted as an
alternative mechanism for vascular occlusion in polycythemia. Similar
histopathological changes have already been found in skin lesions in
erythromelalgia, a common symptom in polycythemia.
PMID- 9555120
TI - Carcinoid tumor of the middle ear in a 28-year-old patient.
AB - Carcinoid tumor of the middle ear is an extremely rare condition. The origin of
the tumor cells is still speculative and the closeness of relationship to
adenomas of the middle ear has been a matter of discussion since the first
description of this tumor entity in 1980. In this study we report a case of a 28
year-old male patient with a carcinoid tumor of the middle ear. We present the
results of histomorphological, immunohistochemical and electron microscopic
examinations and compare our findings to those of previously published cases.
PMID- 9555121
TI - Intravenous leiomyomatosis of the uterus. A report of three cases.
AB - Three cases of intravenous leiomyomatosis (IVL) of the uterus, a rare benign
smooth-muscle tumor, are described. A preoperative diagnosis of IVL was not made
in any of the patients, all of which presented with a pelvic mass with the
presumptive diagnosis of leiomyoma. Surgical exploration confirmed the presence
of uterine mass and two of the three cases showed extra-uterine extension into
the ovarian or uterine veins. Histological examination demonstrated a fascicular
pattern of bland spindle-shaped smooth-muscle cells, which extended to veins
inside the myometrium or to extrauterine veins. This was confirmed by
immunohistochemical stain for desmin and factor VIII. Despite their histological
benignity, these lesions have a tendency to metastasize and are closely related
to the conditions called "benign metastasizing leiomyoma" and "intracaval mass
and cardiac extension". The primary treatment of IVL is hysterectomy and excision
of any extrauterine tumor, when technically feasible. Anti-estrogenic therapy has
been suggested as potentially useful in controlling of unresectable tumor.
According to the literature, the follow-up must be long and periodic
postoperative ultrasonic or magnetic nuclear resonance imaging studies may be
useful in detecting growth of residual intravascular tumor.
PMID- 9555122
TI - Plasma HIV-1 load and disease progression in HIV-infected patients in Hungary.
AB - Nucleic Acid Sequence Based Amplification (NASBA) is a suitable method for the
quantification of HIV-1 RNA in plasma and serum samples. Since determination of
the viral load appears to be a valuable marker for the prediction of disease
progression and for monitoring the efficiency of antiretroviral therapy, the
National AIDS Committee initiated the introduction of NASBA in Hungary at the end
of 1996. We obtained plasma samples from patients with ARC and AIDS of the Szt.
Laszlo Hospital, Budapest. We found an increased viral burden in untreated AIDS
(CDC group C) patients compared to untreated ARC (CDC group B) patients. In
plasma samples of clinically stable ARC and AIDS patients treated with
antiretroviral drugs we detected relatively low HIV-1 RNA copy levels while
similarly treated ARC and AIDS patients with progressive disease had high HIV-1
RNA copy numbers. The CD4+ T-cell count was lower in AIDS patients compared to
ARC patients, as expected. In general, there was an inverse correlation (r =
0.487, P < 0.0001) between CD4+ T-cell counts and HIV-1 RNA levels. We concluded
that measurement of HIV-1 RNA plasma level has an important role in assessing
prognosis and effects of antiretroviral therapy in HIV-infected patients.
PMID- 9555123
TI - Studies on the antibodies to human herpesvirus type 6 among Hungarian patients
with asymptomatic HIV infection.
AB - The occurrence and the possible role in promoting HIV infection by human
herpesvirus type 6 (HHV-6) have not yet been revealed in Hungary. In different
groups of patients, serum titre of IgM and IgG antibodies, as well as avidity of
IgG were quantitated by indirect immunofluorescence and an enzyme-linked
immunosorbent assay, using isolate U1102 of HHV-6 variant A as antigen. In 60% of
HIV-seronegative adult controls, high avidity IgG antibodies were found in low
titre suggesting childhood infection. In HIV-seronegative persons with high risk
behaviour for HIV-infection, both IgM and low avidity IgG were frequently found
in higher titre, representing either primary or frequent reinfections, or
reactivation of latent HHV-6. In asymptomatic HIV-seropositive patients, high
titre of high avidity IgG antibodies was predominant, proving virus infection in
the near past. These results indicate the contribution of HHV-6 to
immunosuppression prior to AIDS, predisposing the organism to HIV infection.
PMID- 9555125
TI - [Diabetic gastroparesis: is tube feeding an alternative?].
AB - A woman aged 26 with long-standing insulin-dependent diabetes mellitus displayed
recurrent periods of nausea, vomiting, abnormal blood sugar levels, weight loss
and poor physical condition in spite of a diet and use of propulsive agents.
Scintigraphy revealed decelerated gastric evacuation for solid and liquid
nutrients. The patient recovered after insertion of a percutaneous endoscopic
gastrostomy (PEG) catheter. Diabetic gastroparesis is associated with a vicious
circle in which delayed gastric emptying leads to poor glucose regulation with
frequent hyperglycaemia, which in its turn adversely affects gastric emptying.
Treatment should be aimed at improvement of the gastric motility (for instance by
propulsive agents), more accurate glucose regulation and nutritional counselling.
If this fails to produce improvement, tube feeding via a permanent nasoduodenal
tube or via a PEG catheter constitutes an acceptable alternative for oral
nutrition.
PMID- 9555124
TI - Current concepts of tumor-induced angiogenesis.
AB - Tumor induced angiogenesis is responsible for the nutrition of the growing tumor
and can also increase the probability of hematogenous tumor dissemination. Data
obtained from morphological analysis of tumor angiogenesis can contribute to the
development of new anti-angiogenic therapies. Based on in vitro and in vivo
observations several models of angiogenesis were introduced, explaining the
mechanism of lumen formation and the timing of basement membrane depositon. (1)
Lumen is formed either by cell body curving or by fusion of intracellular
vacuoles of nonpolarized endothelial cells. New basement membrane is deposited
after lumen formation. (2) Slit-like lumen is immediately formed by migrating
polarized endothelial cells. Basement membrane is continuously deposited during
endothelial cell migration, only cellular processes of the endothelial cell
migrating on the tip of the growing capillary are free of deposited basement
membrane material. (3) Development of transluminal bridges in larger vessels a
process called intussusceptive growth leads to the division of the vessels. These
models, however, describe angiogenesis in tissues rich in connective tissue.
Different processes of angiogenesis take place in organs such as liver, lungs,
adrenals, which are the most frequent sites of metastasis having high vessel
density without sufficient space for capillary sprouting. In the case of liver
metastases of Lewis lung carcinoma the proliferation of endothelial cells was
elicited only by direct contact between tumor and endothelial cells, leading to
the development of large convoluted vessels inside the metastases. These vessels
were continuous with the sinusoidal system, suggesting that these metastases have
dual blood supply. This observation, among others, is in contrast to the
generally accepted view that liver tumors have arterial blood supply. The
increasing number of data demonstrating the dual or venous blood supply of liver
metastases should be taken into consideration in the therapy of liver metastasis.
PMID- 9555126
TI - [Combination therapy in early rheumatoid arthritis: the COBRA study].
AB - The scheme 'Combination therapy in rheumatoid arthritis' (COBRA) in early
rheumatoid arthritis (RA) involves administration of not only sulfasalazine but
also prednisolone and methotrexate during the first six months. The trial showed
that the COBRA scheme over a period of 1.5 years was superior to sulfasalazine
alone: less disease activity in the major part of the year of treatment, less
articular damage on radiographs, fewer side effects and equal or reduced costs.
An 'aggressive' treatment in patients with early RA is indicated, with
(re)assessment of the use of corticosteroids.
PMID- 9555127
TI - [Future developments in genetic research. I. Technological possibilities].
AB - The attention in genetic research is shifting from the determination' of (rare)
monogenic disorders to identification of genetic risk factors for important
diseases at adult age. Mapping of all man's 80,000-100,000 genes will also
provide more insight into the gene polymorphisms and mutations that are
associated with various types of cancer, certain cardiovascular diseases,
diabetes and neurodegenerative disorders, including Alzheimer dementia. Apart
from new diagnostic possibilities, the DNA techniques create new prospects for
the study of the pathogenesis of diseases and the devising of new strategies for
treatment. Examples are familial hypercholesterolaemia, diabetes, breast cancer
and colorectal carcinoma.
PMID- 9555128
TI - [Future developments in genetic research. II. Psychological and social aspects].
AB - Regarding the determination of genetic risk factors for serious diseases, the
main question for a patient's young relatives is 'to know or not to know'. The
answer depends among other things on the assessment of the severity of the
disorder and the magnitude of the risk in relation to the population risk and on
the availability of therapeutic or preventive measures. Experience with the
requests for and the coping with results of the presymptomatic DNA test for
untreatable neurodegenerative chorea of Huntington show that expectations about
the effect of predictive DNA studies are often different from reality. A problem
of a different nature arises in multifactorial diseases such as mammary or
colonic carcinoma, because irrespective of the DNA study it remains uncertain
whether or not the disease will occur. Nevertheless more than half of the healthy
relatives of a patient with breast cancer requests DNA testing and a large
majority of the proven carriers of a BCRAI and BRCA2 mutation chose for bilateral
mastectomy and oophorectomy. Many questions about psychosocial consequences of
predictive DNA testing remain to be answered: what will be the effect of early
medicalization, how will relations be affected and which effect will carriership
of genetic risk factors have on behaviour? Dutch legislation provides adequate
guarantees against the use by third parties of results of genetic testing. The
question remains, however, how future internationalization will work out in this
respect. The possibly far-reaching social and psychological consequences of
genetic research make some people feel that restraints should be imposed on this
research. However, there are more grounds for curiosity and enthusiasm to
constantly find new solutions for the new problems.
PMID- 9555129
TI - [End of life and termination of life: opinions of elderly persons with health
problems].
AB - OBJECTIVE: To determine the views of elderly persons with physical limitations
about a number of aspects of the end stage of life and termination of life.
DESIGN: Enquiry. SETTING: University of Groningen, the Netherlands. METHOD: An
enquiry was conducted in 1995 among 575 elderly (429 females, 146 males; age 57
99 years; 281 living alone) with physical restrictions (mostly heart disease,
hypertension, rheumatism or other articular diseases). The group had been
selected from the 'Groningen longitudinal aging study'. The respondents were
asked (a) what they thought about euthanasia, (b) whether they worried about the
end stage of life, (c) whether they were afraid of death and how much they were
'preoccupied with death'. For the last-mentioned two questions a visual analogue
scale was used. RESULTS: Almost one-third of the elderly were not preoccupied
with death and over half were not afraid of death. Very few scored high on these
scales. Respondents' views about the acceptability of active termination of life
varied greatly: almost half were of the opinion that their life had to be
terminated once they themselves had developed complete dementia. Regarding the
end stage of life, respondents mostly worried about being a burden to others,
being completely dependent on others, having to say goodbye to their loved ones
and having to suffer greatly. Elderly persons with poorer health were more
preoccupied with death and worried more about the problems of the end stage of
life. CONCLUSION: Most of those interviewed were not greatly preoccupied with or
afraid of death. They did worry, however, about the problems that might be
associated with the end stage of life.
PMID- 9555130
TI - [Psychiatric morbidity among adults in The Netherlands: the NEMESIS-Study. I.
Objectives, design and methods. Netherlands Mental Health Survey and Incidence
Study].
AB - OBJECTIVE: To determine prevalence, incidence and course of psychiatric disorders
in non-institutionalised Dutch adults. DESIGN: Prospective and cross-sectional.
SETTING: Trimbos Institute, Utrecht, the Netherlands. METHOD: A multistage,
stratified random sampling procedure was used to obtain a sample of 7076 adults
(18-64 years). Respondents were interviewed throughout 1996 in their homes. The
main diagnostic instrument was the 'Composite international diagnostic interview'
(CIDI), designed to assess lifetime prevalence of mental disorders according to
Diagnostic and statistical manual of mental disorders, 3rd revised edition (DSM
III-R). The diagnostic categories were: affective disorders, anxiety disorders,
eating disorders, schizophrenia and other non-affective psychoses, and substance
use disorders (dependence and abuse). The sample was weighted towards national
census data on sex, age, marital status and urbanicity. RESULTS: The results of
the first measurement (1996) will be described in the next article (1997:2353
60). The response rate was 64.2%. There were no indications that the psychiatric
morbidity of non-respondents differed from respondents. The same respondents will
be interviewed again after 12 (1997) and after 36 months (1999).
PMID- 9555131
TI - [Psychiatric morbidity among adults in The Netherlands: the NEMESIS-Study. II.
Prevalence of psychiatric disorders. Netherlands Mental Health Survey and
Incidence Study].
AB - OBJECTIVE: To determine the prevalence of psychiatric disorders in non
institutionalised Dutch adults. DESIGN: Cross-sectional. SETTING: Trimbos
Institute, Utrecht, the Netherlands. METHODS: A representative sample of 7076
adults (18-64 years) in the Netherlands' population were interviewed in 1996 to
determine the prevalence of mental disorders ever, in the previous 12 months and
in the previous month. Objectives and study design are described in the previous
article (1997: 2448-52). The 'Composite international diagnostic interview'
(CIDI) was used to assess the following mental disorders according to Diagnostic
and statistical manual of mental disorders, 3rd revised edition (DSM-III-R):
affective disorders, anxiety disorders, eating disorders, schizophrenia and other
non-affective psychoses, substance dependence and substance abuse. RESULTS:
Mental disorders were common in the general population: the prevalence 'ever' of
all disorders was 41.2%, the 12-month prevalence 23.5%, without sex differences.
Depression, anxiety disorders and alcohol abuse and dependence showed high
prevalence and comorbidity. The prevalence 'ever' of schizophrenia and other non
affective psychoses was low (0.4%).
PMID- 9555132
TI - [Cerebral hyperperfusion syndrome following carotid endarterectomy].
AB - Three patients with a severe symptomatic carotid stenosis developed headache,
epileptic seizures and focal neurologic deficits several days after carotid
endarterectomy. CT of the brain revealed hypodensities, indicative of cerebral
oedema with haemorrhagic components. This is caused by cerebral hyperperfusion, a
complication after carotid endarterectomy as a result of increased cerebral
perfusion on the side of the operated carotid stenosis. Dysfunction of the
cerebral autoregulation believed to be the cause of this hyperperfusion.
Sometimes these complications are incorrectly attributed to one of the better
known types of stroke.
PMID- 9555133
TI - [Peritoneal pseudomyxoma].
PMID- 9555134
TI - [Current developments in preventive health care].
PMID- 9555135
TI - [Pain control in the end stage of life].
PMID- 9555136
TI - [Pain control in the end stage of life].
PMID- 9555137
TI - ['Tramps feet' in vagrants].
AB - The lifestyle of the homeless often implies lack of hygiene resulting in -
neglected - feet pathology. The Public Health department for the homeless (GG&GD)
was visited by a man aged 43 with drug addiction and schizophrenia who suffered
from severe 'tramp's feet' complicated by cellulitis of the right lower leg,
which had not been diagnosed adequately during a previous visit to an emergency
department. Adequate antibiotic treatment improved the condition in a few days.
'Maladjusted' presentation of the homeless may lead to hasty, inadequate
judgement and treatment by health care workers. These socially handicapped
patients need proper physical examination and efforts to realise shelter, care
and indicated treatment.
PMID- 9555138
TI - [Prasterone (dihydroepiandrosterone): a modern source of eternal youth?].
AB - The function of adrenal cortical hormone dihydroepiandrosterone (DHEA) is
currently unknown. The use of this hormone as a food supplement is widely
recommended in the USA for the elderly, as DHEA serum concentrations decrease
dramatically after the age of about fourty. DHEA is available without
prescription. Many sources suggest a causal relation between the decrease of DHEA
production during aging and the emergence of degenerative disorders. To
substantiate this relationship animal experimental and epidemiological literature
is cited. However, data from clinical trials are rare and neither the safety nor
the efficacy of DHEA is documented. Via the modern media such as the Internet the
consumer is stimulated to use and order DHEA, 'the fountain of youth'. Consumers
willing to follow this recommendation should be informed about the absence of
proof of safety and efficacy. However, the compelling suggestions from animal and
epidemiological literature of DHEA activity are intriguing, and further clinical
trials to document the efficacy and safety of DHEA are urgently needed.
PMID- 9555139
TI - [Prevalence of discrepant lipid levels in Curacao].
AB - OBJECTIVE: To assess the prevalence of lipid risk factors in Curacao and to
investigate possible interactions with socioeconomic and demographic variables.
DESIGN: Cross-sectional population-based study. SETTING: Public Health Laboratory
and Public Health Service, Curacao, Netherlands Antilles. METHODS: In a random
sample of persons aged 18 years and over from the population of Curaao, serum
levels were measured of total cholesterol, high-density lipoprotein (HDL)
cholesterol, triglycerides and, in a smaller number of samples, of lipoprotein(a)
(Lp(a)). The findings were in persons between 20 and 60 years compared with those
reported for a random sample from the Netherlands. Multiple regression analysis
was used to study the relationship between the total cholesterol values found and
various socio-economic variables (age, sex, education, place of residence, race).
RESULTS: Among persons aged 20-59 years serum cholesterol levels were > 6.5
mmol/l in 30 of the 288 male participants (11%) and in 42 of the 427 female
participants (10%). Fifty-three of the males (18%) had HDL cholesterol levels <
0.9 mmol/l as against 31 of the females (7%). The distributions of both total
cholesterol and HDL cholesterol levels was better in Curaao than in the
Netherlands, among males aged 20-29 years and males and females over 40 years of
age. The median Lp(a) concentration of the 225 participants of Curaao in whom it
was measured was 250 mg/l, as against 80 mg/l in the Dutch group. More advanced
age, female sex, higher educational level, negroid race and residence in the
'East District' were correlated with a higher serum level of total cholesterol.
CONCLUSIONS: Both total cholesterol and HDL cholesterol concentrations were
favourable in Curacao compared with the Netherlands, especially in the elderly
population.
PMID- 9555140
TI - [Risk factors for a complicated disease course in children with measles admitted
to a Philippine university hospital].
AB - OBJECTIVE: To analyse the correlation of specific risk factors and measles
complications in children admitted to a Philippine university medical centre.
DESIGN: Retrospective cross-sectional study. SETTING: Department of Pediatrics,
De La Salle University Medical Center at Dasmarinas, a suburb of Manila, the
Philippines. METHOD: Information was collected on patients under 16 admitted for
measles from January 1993 to May 1996, using a data collection form. RESULTS: Of
the 180 patients included in this study, 8 (4%) died during the hospital stay,
and 172 left the hospital in good condition. 61 Patients (34%) had complicated
measles (pneumonia, gastroenteritis, and (or) encephalitis). Age under 2 years
and stay in the service ward (as opposed to the private ward) were significantly
related to complicated measles. No significant relation was found for the
presence of associated illnesses or malnutrition. CONCLUSION: More severe
complications were seen at an early age than in industrialised countries where
the frequency appears to increase with age. Malnutrition possibly contributes
less to severity of the disease than environmental factors such as hygiene and
social class.
PMID- 9555141
TI - [Harlequin syndrome].
AB - Harlequin syndrome is an autonomic syndrome of heat, emotion and exercise induced
flushing and sweating limited to one side of the face in combination with
impairment of sweating and flushing on the contralateral side, Two women aged 32
and 39 years displayed this syndrome. In one patient no other neurological
symptoms were found; MRI of cervicothoracic spine failed to disclose a structural
lesion. The second patient had four years before presented with a Horner's
syndrome on the contralateral side, where MRI now disclosed a tumour located in
the paravertebral thoracic region at the apex of the lung.
PMID- 9555142
TI - [Toe tourniquet syndrome].
AB - In two boys aged 4 months and one girl aged 2 months one or two toes were red and
oedematous, while in one boy aged 3 weeks one toe had become necrotic. In the
first-mentioned three children the affected toes were encircled by a hair, the
hair was removed under anaesthesia, after which the children recovered. In the
last-mentioned child, amputation through the proximal phalanx was necessary. The
toe tourniquet syndrome occurs mainly in infants. Strangulation of the toes by
circular foreign material. such as hair or fibre, causes oedema and increasing
constriction. Timely treatment is followed by good recovery. Delayed or
incomplete treatment can lead to necrosis which may necessitate amputation.
PMID- 9555143
TI - [The first Nassaus in The Netherlands: identification of and paleopathological
findings in Willem van Oranje's ancestors, buried in the Grote Onze Lieve Vrouwe
Kerk in Breda].
AB - OBJECTIVE: Identification and paleopathological analysis of the remains of the
first members of the Nassau dynasty in the Netherlands. DESIGN: Descriptive.
SETTING: Centre for Physical Anthropology 'Barge's Anthropologica', Leiden
University. METHODS: In 1996, seven interments were discovered in situ in a tomb
under the Nassau monument of the so-called 'Grote' or 'Onze Lieve Vrouwe' Church
of the city of Breda. The interments were excavated and examined by osteological
analysis, X-ray analysis, accelerator mass spectrometry (AMS) 14C dating of bone
and dendrochronological dating. RESULTS: Evaluation of archaeological,
osteological, dendrochronological and AMS 14C-dating data resulted in
identification. in order of death, of: Engelbrecht I van Nassau (ca. 1370-1442
AD), Johanna van Polanen (1392-1445 AD), Jan IV van Nassau (1410-1475 AD),
Cimburga van Baden (1450-1501 AD), Maria van Loon (1425-1502 AD), Engelbrecht II
van Nassau (1451-1504 AD) and Francoise van Savoye ((1480-1486)-1511 AD).
Remarkable medical findings were: embalming procedures employed (skull cap
detachment, removal of viscera), treponematosis (Engelbrecht II), tumour
metastases (Jan IV) and scoliosis (Francoise van Savoye). CONCLUSION: The methods
employed resulted in positive identification of the first members of the Nassau
dynasty in the Netherlands and diagnoses of their paleopathological changes.
PMID- 9555144
TI - [Jan Steen's fire pot; pregnancy test or gynecological therapeutic method in the
17th century?].
AB - The doctor's visit is a frequently used subject in paintings from the 17th
century. Jan Steen made several paintings in this genre. He always used as a
medical attribute a fire pot with a burning lace. This lace can be explained as a
diagnostic tool for pregnancy, as a medium to bring round a fainting woman--or
(and most probably) as a scent therapy for a wandering womb. This therapy
originates from the Egyptians and antique Greek doctors.
PMID- 9555145
TI - [Penicillin: just in time].
AB - In the attic of his home the author found papers concerning the case history of a
woman who in the first days after the liberation, in April-May 1945, suffered
from a severe form of puerperal sepsis. The woman recovered completely after
treatment with a totally new drug: penicillin, obtained from the medical supplies
of the allied British forces. She probably was the first patient treated with
this antibiotic in the Netherlands.
PMID- 9555146
TI - [Stranger in Turkey].
AB - The author, a professor of nephrology, reports some impressions of his 7-year
stay in Turkey. He worked at the Ege University in Izmir, traditionally one of
the most 'western' cities. He and his wife, who gave unpaid assistance to
dialysis patients, attempted to integrate into Turkish society as fully as
possible. They traversed the country in weekends and holidays and introduced as
many Dutch guests as they could to the unique archeological treasures, the
magnificent nature and the extremely friendly population. Work at the university
focused increasingly on cultivating a critical attitude with regard to the self,
society and the trends and commercialization of medicine in Turkey and in the
rest of the world. Self-reliance, also, had to be strengthened. Although this
contravened the authority-based Turkish educational system, the efforts were
clearly appreciated and even stirred enthusiasm in many of the younger people.
There is no doubt that a foreign worker is regarded much more favourable in
Turkey than in the Netherlands.
PMID- 9555147
TI - [When is the morning-after pill indicated and which application is preferable?].
PMID- 9555148
TI - [Excessive terfenadine level caused by drinking grapefruit juice].
PMID- 9555149
TI - [Excessive terfenadine level caused by drinking grapefruit juice].
PMID- 9555150
TI - [Eye paralysis and confusion].
AB - Two patients, women of 85 and 76 years, presented with horizontal ocular paresis.
The first patient had a palliative ileocecal resection for adenocarcinoma with
metastases and developed the ocular paresis only after intravenous glucose
infusion. The second had chronic haemolytic anaemia and weight loss due to
malnutrition. The two women were also confused. In both patients acute Wernicke's
encephalopathy was diagnosed, caused by thiamine deficiency. The disorder could
easily have been missed because of confounding clinical problems. Early treatment
of Wernicke's encephalopathy (thiamine 100 mg/day intramuscularly for 3 days) is
of major importance in preventing permanent neurological damage or even death.
PMID- 9555151
TI - [A cholesterol reducing diet is not useful].
AB - In daily practice a cholesterol-lowering diet with intensive monitoring by
dieticians leads to a mean decrease of the serum cholesterol level by 2%. Once
the monitoring is discontinued, the serum cholesterol level as a rule returns to
baseline. Were it possible to maintain a 5% cholesterol reduction throughout
life, occurrence of coronary heart disease would in theory be postponed by one to
a few months. In diet studies, with observation lasting from 6 to 15 years, no
clear favourable effect on the development of coronary heart disease was
demonstrated. Prescription of a cholesterol-reducing diet and referral to a
dietician are therefore fairly useless.
PMID- 9555152
TI - [Cholesterol reducing food certainly is useful].
AB - The effect of a low-cholesterol diet in open intervention studies depends in the
long run on motivation, knowledge and dedication. The mean decrease of the serum
cholesterol level is 10% (range: 0-20). Epidemiological and cohort studies
clearly prove a connection between the intake of saturated fat, the serum
cholesterol level and the risk of coronary heart disease and death. High-fat food
slows down the clearance of the degradation products rich in cholesterol which
appear in the blood after a meal and which are highly atherogenic (these products
are not found at a fasting cholesterol assay). Cholesterol-reducing nutrition has
additional useful effects, for instance on the blood pressure and the
coagulation. The recommendations for healthy, low-cholesterol nutrition for the
population as a whole apply particularly to patients with a high risk of coronary
heart disease. Although advice given to individuals often has a disappointing
effect, influencing the life pattern should be included in the strategy to reduce
the risk of coronary heart disease.
PMID- 9555153
TI - [Value of determining serum cholesterol levels in patients with coronary heart
disease].
AB - Cholesterol synthesis (HMG-CoA reductase) inhibitors have proven their value in
preventing cardiovascular events, especially in patients with manifest coronary
heart disease. Besides cholesterol lowering a number of effects have been
described which may contribute to the beneficial influence of these agents on the
process of atherosclerosis. Measurement of serum lipids is still necessary for
various reasons, namely, to know the degree of elevation in serum cholesterol and
specific disturbances in lipid metabolism, the extent to which serum lipids must
be lowered and the compliance with cholesterol lowering therapy.
PMID- 9555154
TI - [Is detection and treatment of familial hypercholesterolemia indicated in
children?].
AB - Familial hypercholesterolaemia (FH) is a congenital metabolic disorder
predisposing to severe atherosclerosis resulting in coronary heart disease
sometimes even at early adult age. Children with FH lack the stigmata at physical
examination and measuring the cholesterol level does not always enable the
clinician to make the diagnosis. In about 70% of the cases, the diagnosis of FH
in childhood can be made by means of molecular-biological examination, by
demonstrating the underlying defect of the LDL cholesterol receptor gene. In the
remaining cases, the combination of the positive family history for
cardiovascular diseases and increased total cholesterol and LDL cholesterol
levels should suggest the diagnosis of FH. Pharmaceutical agents inhibiting the
cholesterol synthesis have been researched very little in children and are not
registered in the Netherlands. Nevertheless, drug treatment of children with FH
is advisable because of the better possibilities to make a definite diagnosis and
the early occurrence of coronary heart disease. If this treatment were indicated
before patients reach adult age, the question arises whether screening for FH of
children in families in which this disorder prevails, should not be promoted more
strongly.
PMID- 9555155
TI - [Is the detection of familial hypercholesterolemia in children indicated?
Occasionally, yes].
AB - Searching for familial hypercholesterolaemia (FH) in children is useful only if
efficacious treatment is to be administered shortly and if there are relatives
with ischaemic heart disease at very early ages. In all other cases, the
(psychological) drawbacks probably outweigh the doubtful benefit of early
intervention. The search for the major homozygous form of FH begins with
cholesterol assay in both parents, in the absence of FH in either of them, the
above-named restrictions apply.
PMID- 9555156
TI - [Nobel Prize of Medicine 1997 awarded for prion theory].
AB - The Nobel Prize 1997 for Medicine and Physiology was awarded to S.B. Prusiner,
who proposed the prion hypothesis. Prions are small 'proteinaceous infectious
particles' that lack nucleic acids and hence genetic information. Prions are
normal host encoded proteins but with an abnormal tertiary structure, which makes
them extremely resistant to chemical and physical inactivation that would modify
nucleic acids. They 'replicate' by forcing their conformation upon the normal
prion proteins. Recently it was demonstrated that the prion disease, bovine
spongiform encephalopathy (BSE) can be transmitted to man in whom it causes a new
variant of Creutzfeldt-Jakob disease.
PMID- 9555157
TI - [Molecular biology diagnosis of tumors of the musculoskeletal system].
AB - It is sometimes difficult to make an unequivocal diagnosis of tumours of bone and
soft tissue based upon classical morphology alone, which has led to an increased
use of additional diagnostic tools. In the past decade new techniques have become
available, based on tumour specific genetic alterations, for instance chromosomal
translocations. With the cloning of the translocation breakpoints and the
identification of the genes involved, the reverse transcriptase polymerase chain
reaction (RT-PCR) detection of the fusion gene has become an important diagnostic
test. Also, non-tumour specific genetic alterations with prognostic value can be
detected.
PMID- 9555158
TI - [Revision consensus hemophilia: treatment and responsibility. Nederlandse
Vereniging van Hemophilia Patients].
AB - Haemophilia is an X-linked clotting disease occurring in 1400 men in the
Netherlands. As the result of factor VIII or IX deficiency, haemophilia patients
suffer from severe bleedings, spontaneous or caused by trauma. Bleedings mostly
occur in major joints and muscles. Repeated bleedings can cause disability.
Treatment of haemophilia consists of replacement therapy with factor VIII or IX.
The first aim of treatment is to prevent bleedings (prophylaxis). The second aim
is to limit joint damage in case of bleeding by timely and adequate substitution
therapy. In addition, physical therapy and sports are used to keep patients in
shape. Until the introduction of recombinant factor VIII in 1992 only plasma
derived factor VIII and IX products were available. Substitution therapy has
caused various side effects, such as allergic reactions. Since the introduction
of ultra-pure concentrates, allergic reactions have grown rare. Viral infections
like HIV and hepatitis C, which were transmitted through blood products, have not
occurred in Dutch haemophilia patients since the introduction of adequate viral
inactivation steps. In case of development of antibodies against factor VIII or
IX, therapy with factor VIII or IX products is insufficient. Antibody formation
is more often seen in haemophilia A (25%) than in haemophilia B (2%). In most
cases antibodies disappear during so-called immune tolerance induction. This
therapy consists of regular infusion with factor VIII or IX. Once an inhibitor
has disappeared, patients can be treated normally once more. As haemophilia is a
rare and complex disease patients should be treated in specialized centres,
preferably by a comprehensive care team. This is even more justified because
treatment of haemophilia is costly. Over the last 20 years haemophilia treatment
has improved much. This has resulted in a decrease of the number and of the
duration of hospitalization, and a decrease in days lost at school or work. This
has led to great improvement of the social life of haemophilia patients.
PMID- 9555159
TI - [Hyperthyroidism due to contamination of the alternative drug Ader-Rein (Vascu
Vitaal)].
AB - A 52-year-old woman developed hyperthyroidism due to the alternative Vascu-Vitaal
pills. She was suffering from nephrotic syndrome due to membranoproliferative
glomerulonephritis and subclinical hypothyroidism, possibly due to renal loss of
thyroid hormone. For peripheral vascular disease she took the non-registered
Vascu-Vitaal pills on her own initiative. According to the product information,
these pills contain multiple vitamins, minerals, amino acids and tissue extracts
of bovine adrenals, hypophysis and thymus. The patient developed hyperthyroidism
after starting on a new batch of the preparation; it subsided after stopping the
treatment. A technetium thyroid scan showed decreased uptake and subsequently the
Vascu-Vitaal pills were found to contain both thyroxine and triiodothyronine. The
thyroid hormone contamination was probably caused by bovine thyroid tissue. It is
suggested to require a health warning statement on the package of alternative
therapeutics stating that production and contents are not subject to governmental
supervision.
PMID- 9555160
TI - [Medical education of tomorrow: a glance into the (near) future].
AB - Educational reform is a topical subject in Dutch medical schools. Public
visitation reports were issued in 1992 and 1997. In 1994 an 'outline plan' was
presented, setting forth communal training requirements (final results). An
important consequence will be reorganization of (assistant) housemanships.
Options are to start already in the 3rd- and 4th-year with a few (assistant)
housemanships, to reduce the number but increase the duration of the (assistant)
housemanships and to introduce a more comprehensive training (including elements
from several disciplines). Other areas for special attention are the insufficient
professionalization of teachers in medicine, the bureaucracy weighing down the
teaching and the continuing need of educational research. Regarding the future
doctors' image of their profession, emphasis should be placed on the
international trend toward more attention for prevention and cost control, apart
from the physician's traditional curative task. With respects to curriculum
reorganization, six items should be considered: the need of a basic philosophy
(per faculty), the priority to be given to the process of medical problem solving
over that of acquiring knowledge and information, the desirability of increasing
orientation to practice, the necessity of an integrated approach of medical
teaching (teaching elements to be deduced from the final terms, instead of vice
versa), development of a professional attitude and the realization of a master
apprentice relationship in medical education.
PMID- 9555161
TI - [Contemplating a university clinical department].
AB - University clinics combine teaching, research and patient care. Some think that
no single person (head of department) can perform all three tasks. Also, the head
has to have the political skills necessary to manage the faculty society. The
guidelines for university clinics, and for their heads in particular, are: (a)
conscious pursuit of optimal quality, (b) giving the highest priority to training
house staff and teaching students, (c) providing patient care and (d) ensuring
that clinical research should serve the purpose of inspiring scientific attitudes
in house staff. The 'product' of a university clinic is neither the sum of its
publications nor the cured patient, but the medical specialist delivered to
society.
PMID- 9555162
TI - [Multidisciplinary treatment of cerebral arteriovenous malformations: preliminary
results in 115 consecutive patients].
PMID- 9555163
TI - [Boron neutron capture a a new radiotherapy model].
AB - The boron neutron capture therapy is based on the reaction occurring with certain
probability, if a thermal neutron meets the boron 10 isotope. The low energy slow
neutron is captured by the nucleus and it disintegrates into Li-nucleus and He
nucleus (alpha particle). If this physical reaction occurs in a living cell that
will be destroyed. If the boron neutron capture reaction could be achieved
selectively in malignant cells of tumor patients, that could be an effective
therapeutical modality to treat the locally growing cancers. For boron neutron
capture therapy to be successful two basic conditions must be fulfilled, an
appropriate neutron source must be available and the sufficient number of 10B
must be delivered possibly selectively into the tumor cells by a boron compound.
At present both part of this binary system are under intensive investigation, the
development of the neutron source, the synthetisation and experimental testing of
boron delivery agents. The development of the dosimetry, microdosimetry, the work
out of the powerful tools of detection the cellular, subcellular 10B
distribution, the continuous improvement of the planning system and the
optimization of the boron neutron capture therapy are the main point of the
research area on boron neutron capture therapy. Clinical studies and clinical
application of boron neutron capture therapy are under way for the treatment of
melanoma malignum and for brain tumors, with the two boron compound has been
clinically tested up to now, in Japan, at two Centres in USA, and recently has
been started in Europe. The authors give an overview about the principles of
boron neutron capture therapy, about the result of the research on neutron
sources and boron compounds, moreover about the possible application area of this
new radiation modality.
PMID- 9555164
TI - [Incidence of septal aneurysm and its clinical significance].
AB - The authors performed 451 transesophageal echocardiographic (TEE) investigations
over a period of three years and four months. Atrial septal aneurysm (ASA) was
found in 40 cases. Of these, protrusion of the atrial septum towards the right
atrium was observed in 17 cases, whilst oscillation of the atrial septum was
noted in 23 cases. ASA was associated with patent foramen ovale (PFO) in ten
patients, with type II. ASD in nine patients, with other congenital heart disease
in six patients, and with other organic heart disease in eight patients. In three
cases either an embolus or a tumor was detected in the left atrium, whilst in
four cases with ASA there were no other organic cardiac disorders found. In ten
patients there was a history of cerebral embolisation. Of these two had chronic
atrial fibrillation, whilst the others had sinusrhythm. Of those who had cerebral
embolisation, four patients had PFO, one patient had left atrial and auricular
thrombi, whilst in four patients various organic heart problems (ischemic heart
disease, left ventricular hypertrophy) were detected. In one patient with ASA
there was no other cardiac abnormality detected. The authors conclude that ASA,
which is often associated with PFO and ASD (in 25.0% and 22.5% of their cases,
respectively) is detected in around eight percent of the patients who undergo
TEE. ASA particularly when associated with PFO should be considered as a
potential source of cerebral emboli. Indeed, cerebral embolisation occurred in
25% of their patients with ASA. It is recommended, that patients with ASA are
treated with acetyl salicylic acid, whilst in patients with ASA and PFO
anticoagulant therapy is the treatment of choice. In case of cerebral
embolisation, or repeated cerebral ischemic attacks, operative interventions
should be considered.
PMID- 9555165
TI - [Juvenile aneuploid papillary cancer of the thyroid with pulmonary metastasis].
AB - The long-term cause-specific survival results of papillary thyroid cancer
patients in Hungary are (78%) worse than the best international data (90%). The
authors have recited its causes through the case of a young papillary thyroid
cancer patient during the diagnostics (aspiration cytology, diagnostic imaging
technics, DNA-analysis) the treatment (surgery-external radiotherapy-radioiodine
treatment) and the follow-up (HTG, diagnostic imaging).
PMID- 9555166
TI - [The role of vaginal smears in the follow-up od menopausal symptoms].
AB - The author analyzed the data of 122 climacteric patients, getting a fix
combination, continuous hormone replacement therapy, having an initial, a 6 month
and a 12 month vaginal hormone smear and telling the opinion on the efficacy of
the treatment. According to the data, the author registered a significant
improvement of the climacteric complaints after a 6 month treatment period. The
author considers the vaginal hormone smear an easy and effective method to follow
the hormonal state of the climacteric patients. It is advisable to spread this
procedure more widely, than it is to day.
PMID- 9555168
TI - [Pal Salacz M.D., (1897-1971)].
PMID- 9555167
TI - [Angiolymphoid hyperplasia with eosinophilia].
AB - The authors describe the case of a 38-year-old female patient suffering from
angiolymphoid hyperplasia with eosinophilia. The symptoms, histopathology,
differential diagnostic relations and the therapeutic modalities of this disease
are discussed.
PMID- 9555169
TI - [Zsigmond Szerb, M.D., internist and dietitian].
PMID- 9555170
TI - [Conditions of public health during the 1848/49 War of Independence in Hungary].
PMID- 9555171
TI - [The Medical Review of Liege].
PMID- 9555172
TI - [The 1998 cover of the Medical Review of Liege: histoplasmosis in an AIDS
patient].
PMID- 9555173
TI - [Drug clinics. How I treat cutaneous melanoma].
AB - Skin melanoma is one of the rare cancers whose prevalence has increased over the
past decades. Its treatment is based on a classification into four
anatomoclinical stages. Surgical excision is the mainstay of therapy. However,
several protocols of chemotherapy, radiotherapy and immunotherapy also have
specific indications in the therapeutic or palliative approach to the disease.
PMID- 9555174
TI - [The clinical case of the month. Apropos of a case of unexplained fever].
AB - An episode of fever of prolonged duration and undetermined origin always remains
a difficult clinical problem. Several etiologies can indeed be responsible. If
one wishes to obtain a diagnosis of the origin of the fever, one should adopt a
well-structured strategy in which the various investigations are carried out in a
strictly determined hierarchical order. This is badly needed if one wishes to
reach a clue to the diagnosis and be able to implement an adequate therapy. In
spite of all this, some cases will remain without precise diagnosis. The
treatment of those cases will primary be empirical.
PMID- 9555175
TI - [Medical disorders which interfere with pregnancy].
AB - During pregnancy, the future mother can develop several different diseases. Most
of them have a benign prognosis. Cyanotic heart disease, at least when it is
accompanied by significant pulmonary hypertension or induces a functional class
IV represents a contra-indication to pregnancy. Pregnancy cardiomyopathy
generally carries a poor prognosis and may be responsible for the mother's death.
Herpes virus pneumopathy can also be extremely dangerous. Lupus erythematosus
represents a factor of guarded prognosis for the outcome of pregnancy;
discontinuation of the latter should be seriously considered. Hepatic steatosis
which is a rare diagnosis must be distinguished from Hellp syndrome in which the
maternal prognosis is much better. In this review, we shall briefly discuss
various medical diseases which may have a deleterious influence on the evolution
of pregnancy or on the foetus. These deleterious influences can be direct, i.e.
due to the disease, or indirect, i.e. due to the therapy. We shall successively
consider several neurological, cardiological, pulmonary, dermatological and
digestive diseases. We shall not take into account viral infections or infections
in general, diabetes mellitus or the various vasculo-renal syndromes.
PMID- 9555176
TI - [Implementation of oral rehydration in gastroenteritis in infants].
AB - The best treatment of the infant acute gastroenteritis, when it is applied at
home, is oral rehydration. The latter should be limited in duration (between 12
to 24 hours at the longest), should be performed with a specifically prepared
solution, should be administered in sufficient amount and should be followed with
an early realimentation.
PMID- 9555177
TI - [Drug clinics. Clinical drug trials: the importance and role of the general
practitioner].
AB - Clinical trials are an essential step in the development of a drug. They must be
conducted according to strict rules called "Good Clinical Practice" or GCP. GCP
requirements aim to guarantee a perfect methodology in the planning, realization
and interpretation of clinical trials. The latter can be divided in four phases:
phase 1 aiming to demonstrate the safety and to investigate the
pharmacokinetics/metabolism of the drug in healthy volunteers; phase 2 aiming to
study the intrinsic activity (generally versus a placebo) and safety of the
compound in a rather small number of (hospitalized) patients; phase 3 aiming to
confirm the comparative efficacy (versus a placebo or a reference drug) and
safety of the pharmacological agent in a quite large number of (ambulatory)
patients; and phase 4 carried out after commercialization, to verify the clinical
utility of the drug in conditions of daily practice. Because he/she occupies a
crucial position in the recruitment and follow-up of outpatients, the general
practitioner should play a more active role in clinical trials, provided that
he/she could work in collaboration with academic centers specialized in clinical
pharmacology which can help to perform studies in accordance with GCP
requirements.
PMID- 9555178
TI - [Lipoma, multiple lipomas and lipomatosis].
AB - Lipomatous tumors are very frequent; simple lipoma is the most common variety.
According to Enzinger, lipomatous tumors are classified into five different
groups: simple lipomas, variant lipomas forms, heterotopic lipomas, infiltrating
lipomas and lipomatosis, and finally hibernomas. Usually, lipomatous tumors are
characterized by a slow, unpainful, growth. Classical treatment includes surgical
resection. The clinical diagnosis is confirmed by histology. Liposucion can be a
therapeutic option in certain cases.
PMID- 9555179
TI - [Alcohol, drugs, medication and highway safety in Belgium. Belgian Toxicology and
Trauma Study Research Group].
AB - The BTTS study (Belgian Toxicology and Trauma Study) was performed in Belgium
between January 15th 1995 and June 15th 1996. The purpose was to investigate how
frequently the drivers involved in road accidents were driving under the
influence of psychotropic drugs. Two thousand fifty-three blood tests were
performed of which 207 in the Liege region. The results obtained at the national
level are compared to those obtained at the level of the Liege region. In both
cases, the BTTS study allows the conclusion that a considerable proportion of
drivers involved in road accidents resulting in significant traumatic
consequences were driving under the influence of substances with psychotropic
properties.
PMID- 9555180
TI - [Syndrome X, at the crossroads of metabolic and cardiovascular diseases].
AB - The relationships between metabolic disorders and cardiovascular diseases are
very strong. Hypercholesterolaemia and diabetes mellitus, for instance, are well
known risk factors. The multifaceted metabolic syndrome or syndrome X, originally
described by Reaven in 1988, comprises several abnormalities which are associated
to insulin resistance and compensatory hyperinsulinaemia. Syndrome X results in
an increased vascular risk by at least two mechanisms. On the one hand, it
favours atherosclerosis and is associated to angiographic lesions, especially in
the coronary arteries. On the other hand, it is associated to endothelial
dysfunction which may contribute to myocardial ischaemia even in presence of
angiographically normal arteries, a phenomenon named also syndrome X by the
cardiologists. Thus, metabolic syndrome X and cardiological syndrome X are very
close and syndrome X may be considered as a crossing between metabolic disorders
and cardiovascular diseases.
PMID- 9555181
TI - [Corticosteroid sensitivity, dependence and resistance in inflammatory and
immunologic diseases. Physiopathologic review].
AB - Patients suffering from inflammatory or dysimmunitary diseases may develop
various clinical responses to corticotherapy. This brief article describes the
various cellular and molecular mechanisms which underly the genetic, endocrine
and immunitary factors involved in corticosensitivity, corticoresistance and
corticodependence.
PMID- 9555182
TI - [How I study syncope].
AB - The diagnosis of the cause of a syncope is based, above all, on the basis of a
careful clinical history obtained from the patient or from persons who attended
one of the episodes of loss of consciousness. It should also include a careful
clinical examination comprising an electrocardiogram and, most often, an
echocardiogram. The selection of further investigations should be guided by the
existence or absence of an underlying cardiac disease. In the presence of a
patent cardiac disease, one should first try to detect a disorder of cardiac
rhythm (Holter, mini-Holter, possibly invasive electrophysiology); a dysfunction
of the autonomic regulation of the cardiovascular system should only be
considered in a second step (Tilt table test). The sequence of investigation
should be reversed when syncope occurs in a patient without underlying cardiac
disorder.
PMID- 9555183
TI - [Drug clinics. The drug of the month. Ranitidine bismuth citrate (Pylorid)].
AB - Ranitidine bismuth citrate (Pylorid, Glaxo-Wellcome) is a novel salt of
ranitidine which provides a unique combination of properties: inhibition of
secretion of gastric acid by competitive antagonism of the action of histamine at
the histamine H2-receptor on the gastric parietal cell, mucosal protective
effects and anti-Helicobacter pylori action. Ranitidine bismuth citrate provides
effective healing and symptom relief, both in duodenal ulcer disease and in
gastric ulcer disease. When coprescribed with certain antibiotics (clarithromycin
alone or combined with amoxicillin or nitro-imidazole), it heals ulcers,
eradicates Helicobacter pylori and prevents recurrence of the disease. Several
clinical studies demonstrated that ranitidine bismuth citrate is well-tolerated
and has quite similar efficacy as proton pump inhibitors.
PMID- 9555184
TI - [I have the hiccups].
PMID- 9555185
TI - Restoring Class III caries using a custom matrix.
PMID- 9555186
TI - Why direct reimbursement?
PMID- 9555187
TI - A simplified approach to DR. Direct reimbursement.
PMID- 9555188
TI - An introduction to ethics.
PMID- 9555189
TI - Dr. Pinkney Adams--a dentist before his time.
PMID- 9555190
TI - Interviewing the new dental client.
PMID- 9555191
TI - Dental Hygiene Education in Michigan.
PMID- 9555192
TI - Dental accreditation provides educational criteria for professional programs.
PMID- 9555193
TI - Volunteers answer the call.
PMID- 9555194
TI - Illinois Dental Sealant Program: 1986-1996.
AB - Dental sealants have been shown to be an effective means of preventing pit and
fissure caries. Despite more than 20 years of research and overwhelming evidence
in support of the use of sealants, the dental profession has been slow to make
use of them. This article explores the strategy used by the Illinois Dental
Sealant Program to increase dental sealant use.
PMID- 9555195
TI - Informed consent.
PMID- 9555196
TI - Take the guesswork out of software purchases.
PMID- 9555197
TI - A portrait of integrity: Arnold Bennett Donawa, DDS.
PMID- 9555198
TI - How long do you keep your documents?
PMID- 9555199
TI - Project Mouthguard: a survey of Illinois dentists' attitudes on mouthguards.
AB - A random sample survey of Illinois dentists was conducted to determine their
knowledge and experience in providing mouthguards for individuals and athletic
teams. This article offers information on their education and involvement in
mouthguard programs.
PMID- 9555200
TI - Survey sez: polls reveal how dental, public relations and journalism
professionals view each other.
PMID- 9555201
TI - Information you need to succeed.
PMID- 9555202
TI - Osseointegration enhanced by chemical etching of the titanium surface. A torque
removal study in the rabbit.
AB - Roughened implant surfaces are thought to enhance osseointegration. Torque
removal forces have been used as a biomechanical measure of anchorage or
osseointegration in which the greater forces required to remove implants may be
interpreted as an increase in the strength of osseointegration. The purpose of
this study was to compare the torque resistance to removal of screw shaped
titanium implants having an acid etched (HC1/H2SO4) surface (Osseotite) with
implants having a machined surface. Two custom screw shaped implants, 1 acid
etched and the other machined, were placed into the distal femurs of 10 adult New
Zealand White rabbits. These implants were 3.25 mm in diameter x 4.00 mm in
length without holes, grooves or slots to resist rotation. Following a 2 month
healing period, the implants were removed under reverse torque rotation with a
digital torque measuring device. Two implants with the machined surface
preparation failed to achieve osseointegration. All other implants were found to
be anchored to bone. Resistance to torque removal was found to be 4 x greater for
the implants with the acid etched surface as compared to the implants with the
machined surface. The mean torque values were 20.50 +/- 6.59 N cm and 4.95 +/-
1.61 N cm for the acid etched and machined surfaces respectively. The results of
this study suggest that chemical etching of the titanium implant surface
significantly increases the strength of osseointegration as determined by
resistance to reverse torque rotation.
PMID- 9555203
TI - Comparison of periodontal and peri-implant probing by depth-force pattern
analysis.
AB - The purpose of this study was to compare the tissue resistance to probing and the
accuracy of depth determination at different force levels around implants and
teeth. In 11 subjects 1 implant and 1 tooth at a comparable location and with
comparable probing depth were investigated. The sites were located on either the
mesial or distal aspect of the tooth and the implant. A probing device was used
which allowed simultaneous monitoring of probing force and probe penetration and
which standardized the insertion pathway for repeated measurements. The probing
instrument was fitted with an attachment for an aiming device to take a
radiograph with the probe tip in the sulcus, using a standardized projection
geometry. Probing depth values were determined at 0.25, 0.50, 0.75, 1.00 and 1.25
N probing force. The standard error of the individual measurement (Si), evaluated
by comparison of repeated measurements in the same session, was 0.2 mm on
implants and 0.1 mm on teeth. For implants there was a trend for slightly better
reproducibility at higher force levels. Curve analysis of depth force patterns
showed that a change in probing force had more impact on the depth reading in the
peri-implant than in the periodontal situation. The mean distance between the
probe tip and the peri-implant bone crest amounted to 0.75 +/- 0.60 mm at 0.25 N
probing force. It is concluded that peri-implant probing depth measurements are
more sensitive to force variation than periodontal pocket probing.
PMID- 9555204
TI - Reproducibility of automated periodontal probing around teeth and osseointegrated
oral implants.
AB - Three different probing devices (Audio-Probe, Florida-Probe, Peri-Probe) were
tested in order to determine the clinical probing depth (CPD) around clinically
stable oral implants and their homologous teeth and to evaluate their
reproducibility. In all 37 patients, in the age range of 24-80 years, who had
undergone periodontal therapy and placement of 1 or more oral implants (ITI),
were selected for the study. The CPD was determined on 75 oral implants in total
and at 4 sites of both the implants and the control teeth at 3 visits, each 1
week apart. At the 1st visit, the Florida-Probe and the Audio-Probe were used. At
the 2nd visit, the Florida-Probe and the Peri-Probe and, at the 3rd visit, again,
the Florida-Probe and the Audio-Probe were used. At each visit bleeding on
probing (BOP) was registered. A statistically significant (P < 0.05) difference
between the mean scores of implant and tooth sites was found showing slightly
higher values for implant sites. A tendency for the deeper pockets to bleed more
frequently than the shallow pockets was observed. The comparisons of differences
of the readings of the Audio-Probe on 2 different occasions were smaller than for
the Florida-Probe. However, comparisons between 2 different probes showed
significantly greater measurement errors than when comparing the probes alone.
There was a tendency for the Peri-Probe to yield the highest and the Audio-Probe
the lowest values in inflamed sites. It was concluded that all 3 probing devices
appeared to have adequate reproducibility both around teeth and oral implants.
For clinical use in daily practice, the Audio-Probe was found to be the most
simple device with the highest reproducibility.
PMID- 9555205
TI - Titanium implants and lateral forces. An experimental study with sheep.
AB - The purpose of this study was to investigate the resistance of titanium implants
to horizontal forces in a sheep model. Twenty implants were inserted into the
foreheads of 5 sheep, 4 implants on each animal. After a healing period of 3
months, abutments were mounted on the implants. After a further healing period of
3 weeks, the implants were loaded with a horizontal pull of orthodontic elastics.
The force varied between 250 and 350 grams. The duration of loading was 3 months.
After the loading period the animals were sacrificed and the forehead bones with
implants were fixed in formalin and evaluated histologically. In the histological
specimens no signs of infection or bone loss were found around the implants. The
results of the present study encourage the use of titanium implants also in cases
where constant lateral forces are present.
PMID- 9555206
TI - A 5-year prospective clinical study of Astra Tech dental implants supporting
fixed bridges or overdentures in the edentulous mandible.
AB - In a 5-year prospective clinical study, 155 endosseous implants were installed in
the mandible anterior to the mental foramina in 33 edentulous patients (13 males
and 20 females). Usually 6 implants were installed for fixed prostheses (FP), 13
patients with 77 implants, and 4 implants for overdentures (OD) with a Dolder
bar, 20 patients with 78 implants. At the time of abutment connection 1 implant
in 2 patients was found to be loose and removed. However, in both these patients
overdentures were successfully placed on the remaining 3 implants. Narrow-beam
radiography was used for radiological evaluation. The mean (SD) total marginal
bone loss in 5 years was 0.48 (0.38) mm (0.36 (0.22) mm in the FP group and 0.56
(0.45) mm in the OD group). Very few complications were reported during the 5
years, most of them being related to the superstructures. The overall cumulative
implant survival rate was 98.7% (100% in the FP group and 97.4% in the OD group).
The survival rate of the superstructures was 100%. The present study has
demonstrated that Astra Tech implants offer reliable and predictable medium-term
support for fixed prostheses and overdentures in the edentulous mandible.
PMID- 9555207
TI - The mini bottle brush--a new fastening device in cancellous bone.
AB - A new design for bone implants, the bottle brush, was recently presented in a
pilot study on marrow cavities in the femur of rabbits. In this study, the
concept is further evaluated on a mini bottle brush. The fixture, 5 x 7 mm, with
an implant shaft made of CP-titanium and bristles of nylon coated with sputtered
titanium, was inserted into the cancellous bone of the medial femoral condyle in
15 adult rabbits. The titanium fixture was compared with a similar brush without
the titanium sputtered surface. The animals were sacrificed after 4 months and
the quantity and quality of bone integration were evaluated with pull-out tests
and histological examination. In both parameters, the values were significantly
higher for the titanium-sputtered brushes, with removal forces similar to
titanium cylinders of the same size and with a bone-to-metal contact area of
about 50%.
PMID- 9555208
TI - Complete nose coverage to prevent airborne contamination via nostrils is
unnecessary.
AB - Besides an atraumatic procedure, aseptic techniques during surgery have been
suggested to have a positive impact on the predictability of osseointegration. To
avoid an infection of the surgical field, coverage of the face of the patient
(drapes) and nose (surgical mask, drape and plastic film) were advocated in order
to reduce airborne infections and to prevent a contact contamination of
instruments and gloves. Such a coverage, however, increases the feeling of
claustrophobia when local anaesthesia is used and can lead to hypoxemia. The aim
of the present study was to investigate whether the expired air via the nostrils
could contribute to the contamination of the oral surgical field. Test blood agar
plates were installed for 30 min under the nose of volunteers lying on a surgical
table; once with full coverage of their nostrils, as indicated above, and once
without. Simultaneously, control plates were installed on a table besides the
patient to measure the basic contamination from the environment. All plates were
incubated both aerobically and anaerobically. The number of colony forming units
(c.f.u.) recorded on test plates after aerobic and anaerobic incubation were
surprisingly low, with a mean score of 2.7 and 5.0 c.f.u. for the uncovered
situation, and 2.5 and 3.3 c.f.u. for the covered situation, respectively. The
control plates were infected by a nearly comparable number of bacteria (means
ranging from 2.2 to 3.2). These findings indicate that covering nostrils by a
mask and sterile adhesive plastic film is not essential in avoiding airborne
microbial contamination. However, the use of a meshed nose guard to prevent
contact with the highly contaminated nasal skin is highly recommended.
PMID- 9555209
TI - Treatment of severe peri-implant bone loss using autogenous bone and a resorbable
membrane. Case report and literature review.
AB - Clinical case reports and animal studies have demonstrated that the principle of
guided bone regeneration can be applied for surgical treatment of moderate to
profound peri-implant bone loss (peri-implantitis). However, the degree of bone
regeneration within the peri-implant osseous defect was reported to be variable
depending on different clinical factors and on the postoperative course. Most
papers dealing with surgical treatment of peri-implantitis advocate the use of a
non-resorbable ePTFE membrane for secluding the peri-implant bone defect enabling
bone regeneration. Additionally some surgeons fill the defects with allografts or
alloplasts. The present case report demonstrates another surgical approach by
using autogenous cancellous bone for grafting into the peri-implant bone defect
and placing a bioresorbable polylactide membrane as a matrix barrier. The
successful outcome of this modified surgical approach enabled the patient to
maintain the implant for prosthetic reconstruction after early but severe bone
loss.
PMID- 9555210
TI - Endoscopically controlled sinus floor augmentation. A preliminary report.
AB - Sinus augmentation has been advocated to be a surgical technique with predictable
results in peri-implant surgery. Endoscopic surgery of the maxillary sinus so far
has been used as diagnostic procedure. In this paper, the use of endoscopy is
described as a low invasive adjunctive technique in sinus floor augmentation.
After preparation of the mucoperiosteum, bone grafts can be placed under
endoscopic control between sinus floor and mucoperiosteum. A laterobasal approach
via a small osteotomy and a transalveolar approach are possible for mucosal
elevation and graft placement. First clinical results are reported. Endoscopic
sinus lift may contribute to a reduction of perioperative morbidity, reduction of
oroantral fistulae and control of graft position. The less invasive technique may
allow to extend the indication for sinus augmentation.
PMID- 9555211
TI - Concepts in biocompatibility testing of dental restorative materials.
AB - Due to the diversity of adverse biological effects which might be caused by
dental restorative materials, biocompatibility assessment cannot rely on a single
test but has to be based on a planned and structured approach (concept). First,
the possible harm evoked by the material, the known data, and suitable biological
and other test methods available must be taken into consideration. Modern
regulatory concepts require for this purpose the services of experts to propose
the appropriate set of required tests for a given material. The use of standards
is generally emphasized because of better comparability of the data. Other tests
may be chosen if more appropriate. Modern scientific concepts of biocompatibility
testing are based on the need for rapid and cost-effective test methods, avoiding
animal tests whenever possible. While formerly in vitro experiments did not take
into account the special clinical situation in which the material would be used,
modern concepts try to simulate important parameters of the in vivo situation as
closely as possible. This may be achieved, for example, by including suitable
barriers between the material and the target cells, by constructing appropriate
target cells, and by choosing clinically relevant markers for measuring the
biological effects caused by the material. There are indications so far that
through this approach the number of animal tests can be reduced. The use of these
methods may also lead to a better understanding of the mechanisms behind the
biological reactions (mechanistic approach) in describing the biocompatibility of
dental restorative materials.
PMID- 9555212
TI - Clinical and quantitative marginal analysis of feldspathic ceramic inlays at 4
years.
AB - The aim of this clinical study was to evaluate feldspathic ceramic inlays both by
clinical criteria and quantitative margin analysis in continuation of an earlier,
identically conducted 2-year study. Fifty feldspathic ceramic inlays were
adhesively luted in Class II preparations with all margins located in enamel. The
inlays were evaluated clinically according to modified USPHS criteria after 3 and
4 years. Quantitative margin analysis was performed with a scanning electron
microscope (SEM). Clinically, the inlays showed no recurrent caries and no
changes in colour, but superficial marginal discolouration (6%) was apparent
after 4 years. Margins were perceptible clinically in 64% of the cases after 4
years. Quantitative margin analysis showed significantly more marginal gaps at
the composite/ceramic interface than at the enamel/composite interface, There was
neither a significant decrease in perfect margins nor a significant increase in
marginal gaps and marginal imperfections at both interfaces between the third and
fourth year. Clinically, the inlays performed very well up to 4 years. Clinical
evaluation using an explorer only detected substance loss in the cementation gap.
The SEM evaluation showed significantly higher changes in marginal qualities
during the first 2-year interval of clinical service compared to the second 2
year interval following an exponential mathematical regularity. Quantitative
margin analysis should be included in clinical long-term trials to detect early
marginal deficiencies at the luting interfaces.
PMID- 9555213
TI - The role of alveolar ridge width in dental implantology.
AB - Sometimes, preoperative planning in dental implantology, based on sufficient
alveolar height, cannot be verified due to transversal deficiencies. A total of
102 bony mandibles and 95 maxillae were analysed after classification of atrophy,
simulating implant insertion at 518 standardised edentulous cross sections with
regard to anterior/posterior, mandible/maxilla and class of atrophy. Furthermore,
the relation of alveolar height to possible implant length in 86 patients was
evaluated retrospectively. Implant length reduction compared with alveolar height
was necessary in 10% (mandibles) and 7.5% (maxillae) of the bony-jaw sections and
52.5% (mandibles) and 41.5% (maxillae) of the patients' implant regions. In this
respect, the class of atrophy of the bony jaws was more important than the region
of simulation. However, the highest differences were observed between mandibles
and maxillae, both clinically and experimentally: simulation was possible in all
mandibles and 42.5% of the maxillae, but clinical implantation was only possible
in 86% of 62 mandibles and 0% of 24 maxillae, mostly due to reduced alveolar
height. Alveolar ridge width primarily affected the possible implant lengths.
Nevertheless, in four (two mandibular and two maxillary cases) of 58 patients
(7%) with sufficient height, a surgical procedure that had already been started
had to be stopped. It is expected that cross-sectional radiographical techniques
of implantation planning, including ridge-width determination, will gain
importance in the future.
PMID- 9555214
TI - A thin-plate spline analysis of the face and tongue in obstructive sleep apnea
patients.
AB - The shape characteristics of the face and tongue in obstructive sleep apnea (OSA)
patients were investigated using thin-plate (TP) splines. A relatively new
analytic tool, the TP spline method, provides a means of size normalization and
image analysis. When shape is one's main concern, various sizes of a biologic
structure may be a source of statistical noise. More seriously, the strong size
effect could mask underlying, actual attributes of the disease. A set of size
normalized data in the form of coordinates was generated from cephalograms of 80
male subjects. The TP spline method envisioned the differences in the shape of
the face and tongue between OSA patients and nonapneic subjects and those between
the upright and supine body positions. In accordance with OSA severity, the hyoid
bone and the submental region positioned inferiorly and the fourth vertebra
relocated posteriorly with respect to the mandible. This caused a fanlike
configuration of the lower part of the face and neck in the sagittal plane in
both upright and supine body positions. TP splines revealed tongue deformations
caused by a body position change. Overall, the new morphometric tool adopted here
was found to be viable in the analysis of morphologic changes.
PMID- 9555216
TI - Erosion on abraded dental hard tissues by acid lozenges: an in situ study.
AB - The aim of this study was to analyse the erosive effect of acidic lozenges and to
compare it with that of orange juice, known to have the capacity to cause
erosion. Two acidic, sugar-free lozenges and orange juice were tested in situ in
nine patients. Changes in surface Knoop microhardness and change in the surface
texture were assessed. The results revealed that orange juice and one acidic
lozenge were--under the conditions of this experiment--capable of significantly
softening abraded enamel (P < or = 0.017). It was concluded that excessive
consumption of acidic lozenges could have the potential to enhance existing
dental erosion.
PMID- 9555215
TI - Marginal adaptation to enamel of a polyacid-modified resin composite (compomer)
and a resin-modified glass ionomer cement in vivo.
AB - Recently, new restoratives, such as resin-modified glass ionomer cements (RMGIC)
and polyacid-modified resin composites (PMC) were introduced for class III and
class V cavities. Both materials use simplified cavity conditioning methods. The
well-established treatment of enamel with phosphoric acid has been replaced with
treatment using weaker acids. The purpose of this study was to investigate in
vivo the quality and durability of the marginal bond to enamel of these
restorative system and compare it with a resin composite restorative, Seventeen
patients received class III restorations of each of the three restoratives. At
baseline and after 1 year replica impressions were made for investigation of the
vestibular margins with the scanning electron microscope. Semi-quantitative
analysis of the enamel-restorative interfaces was performed at x200 and x1000
magnifications. The three restorative systems showed good marginal adaptation and
high percentages of the length of the margins investigated at baseline were gap
free (82%-92%). The resin composite showed significantly better adaptation than
the other materials. The marginal quality decreased significantly after 1 year
for the resin composite and the polyacid-modified resin composite. The RMGIC
showed improved sealing after 1 year in vivo, probably due to continuing water
uptake. The percentages of gap-free margins of the total marginal length observed
at 1 year were 73%, 90%, and 84%, respectively, for the PMC, the RMGIC and the
resin composite. The difference between the PMC and the RMGIC was significant. In
conclusion, a good marginal quality was seen for all three restorative systems in
class III cavities after a period of 1 year.
PMID- 9555217
TI - Comparing dental utilization of United States of America military recruits with
their employed civilian cohorts.
AB - This study compares the dental utilization of United States of America (USA)
military recruits with that of their employed civilian cohorts. Military data
were collected between February and June 1994 at one recruit in processing site
per service, using self-administered questionnaires on a prestratified,
systematic, random sample of 2369 Army, Air Force, Navy, and Marine recruits.
Women and blacks were oversampled. Civilian data come from the most recent oral
health survey of working adults in the USA. Results show that annual dental
utilization rates of military recruits equal or are less than those of their
employed civilian cohorts. Overall, 38% of recruits have seen a dentist in the
past year, while 30% have not seen a dentist in 3 or more years. Such low
consumption of dental care suggests that dental utilization habits prior to
service entry do not contribute appreciably to the high dental utilization rates
seen among active duty US military personnel.
PMID- 9555218
TI - Clinical evaluation of Helioseal F fissure sealant.
AB - Unfilled resins are commonly in use as sealant material. In addition, there are
filled sealants available. Helioseal F is a newly developed filled material with
fluoride release. In this clinical trial, Helioseal F has been evaluated in one
lower molar versus Delton opaque as an unfilled control in lower molars. After 12
months there were no significant differences in retention, porosities, and the
number of clinically unacceptable margins between the materials. The complete
retention was 30 out of 31 examined teeth for Delton and 28 out of 31 for
Helioseal F. After 1 year of clinical testing, these results indicate that a
sealant containing fluoride-releasing particles did not show a significant
difference in retention rate compared to an unfilled conventional sealant.
However, long-term results concerning marginal adaptation should be evaluated.
PMID- 9555219
TI - Who we are. Highlights of the 1997 ADAA Demographics Survey.
PMID- 9555220
TI - Current prosthodontic perspectives of implant dentistry: focusing on age
guidelines.
PMID- 9555221
TI - Team approach to implant dentistry: how should it work? (Part II)
PMID- 9555222
TI - Bone expansion techniques reduce need for grafting.
PMID- 9555223
TI - Dual templates for effective placement of root-form implants.
PMID- 9555224
TI - Current implantology affects traditional perio-prosthetics.
PMID- 9555225
TI - Ascending ramus offered as alternate harvest site for onlay bone grafting.
PMID- 9555226
TI - Calcium sulfate: a valuable addition to the implant/bone regeneration complex.
PMID- 9555227
TI - Preferred designs for mandibular implant overdentures.
PMID- 9555228
TI - Reduce bone loss, enhance outcomes with immediate implant placement.
PMID- 9555229
TI - Safeguards and precautions for risk management in implant dentistry.
PMID- 9555230
TI - The key to peri-implant esthetics: hard- and soft-tissue management.
PMID- 9555231
TI - Occlusal fulfillment for today's implant restorative/prosthetic dentist.
PMID- 9555232
TI - Nasal sinus lift: an innovative technique for implant insertions.
PMID- 9555233
TI - How to insert the mixed tooth/implant arch fixed prosthesis using cement and
screw fixation.
PMID- 9555234
TI - Perfection in emergence profiles: a road map for ideal placement of the single
tooth implant.
PMID- 9555235
TI - The regional acceleratory phenomenon: an up-to-date rationale for bone
decortication.
PMID- 9555236
TI - How to achieve anterior symmetry in implant prosthodontics with single-tooth
replacements.
PMID- 9555237
TI - Sinus lift complications: avoiding problems and finding solutions.
PMID- 9555238
TI - Proper restoration-generated site development leads to exemplary implantations.
PMID- 9555239
TI - How to combine cementation and retrievability of implant prostheses: why access
should be attainable.
PMID- 9555240
TI - Harvesting autogenous cancellous bone from the cranium for oral placement of
implants.
PMID- 9555241
TI - A regeneration update: resorbable and non-resorbable membranes.
PMID- 9555242
TI - Double guidance approach for the improvement of the single-tooth implant
replacement.
PMID- 9555243
TI - High-tech case presentations in implant dentistry foster value-based decisions.
PMID- 9555244
TI - Sinus lift revisited: an update on current implant-related procedures.
PMID- 9555245
TI - Harvesting autogenous cancellous bone from the tibia for enhanced oral implant
placements.
PMID- 9555247
TI - Flap designs and suturing techniques related to anterior single-tooth implant
placement.
PMID- 9555246
TI - Current usage of bone fill as an adjunct in implant dentistry.
PMID- 9555248
TI - Loss of vertical dimension, tooth loss, and migration: treatment planning for
implant prosthodontics.
PMID- 9555249
TI - An innovation in implant template design allows more accuracy during placement.
PMID- 9555250
TI - Characterization of 50wt%SiO2-20wt%P2O5-30wt%CaO glass-ceramic powders prepared
by the sol-gel process.
AB - Glass-ceramic powders with the oxide batch formulation 50wt%SiO2, 20wt%P2O5 and
30wt%CaO were prepared by the sol-gel process using tetraethoxysilane, calcium
nitrate and phosphoric acid as raw materials. The obtained gels and powders were
characterized by TG-DTA thermal analysis, FTIR analyses and XRD measurements. The
results indicated that (1) heating to more than 600 degrees C brought about
elimination of -OC2H5 side chains from gels, and formation of a SiO2-based glass
network, (2) crystallization such as Ca3(PO4)2 notably occurred in the SiO2-based
glass matrix when heated to more than 900 degrees C, (3) -OH groups existed on
SiO2-based glass-ceramic surfaces in the temperature region less than 900 degrees
C, and (4) the melting point of this composition was more than 1400 degrees C.
This study suggests that sol-gel-derived SiO2-based glass-ceramic powder
containing P and Ca might be useful as bioactive implant materials.
PMID- 9555251
TI - Glass transition temperatures of dental porcelains determined by DSC measurement.
AB - The differential scanning calorimetry (DSC) curves for three commercial dentin
and incisal porcelains fused-to metal were measured using high-temperature DSC.
The glass transition temperatures (Tg) were determined from the DSC curves at
heating rates of 7-20 degrees C/min, and the activation energy was derived from
an Arrhenius plot of negative reciprocal Tg vs. logarithm of heating rate. The Tg
of the dental porcelains depended on the content of aluminum oxide, whereas the
activation energy depended on the content of sodium oxide. The ultra-low fusing
type porcelains had a low activation energy due to the higher content of sodium
oxide than the other porcelains.
PMID- 9555252
TI - Influence of modification of Na2O in a glass matrix on the strength of leucite
containing porcelains.
AB - The desirable thermal properties of matrix glass to the strength of feldspar
porcelain with leucite crystal were investigated. Five kinds of feldspar glasses,
each with different a content of Na2O, were prepared for the matrix glasses of
the leucite-containing porcelains. The specimens were arranged by mixing each
glass powder with high-purity natural leucite crystals (0, 20 and 40%) followed
by firing. The thermal properties of the glass and the transformation temperature
of the leucite were measured. A three-point bending test was performed to measure
the flexural strength of the porcelains. The glass transition temperature and
deformation temperature of the glass-only porcelains were decreased as the Na2O
content increased. The Na2O-modified glasses were substantially strengthened by
the leucite dispersion. However, the strength of the porcelains was affected by
the relation between the transformation temperature of the leucite and the
thermal properties of the glass matrix. It was concluded that control of the
residual stress in the composite porcelain is an important factor in developing
high strength porcelain containing leucite.
PMID- 9555253
TI - A coherent phase diagram of the [(AuCu)0.86Ag0.14]1-XPtX pseudobinary section in
Au-Cu-Ag-Pt quaternary system.
AB - In order to determine a coherent phase diagram of the [(AuCu)0.86Ag0.14]1-XPtX
pseudobinary system, phase identifications and analyses of the microstructural
configurations were performed by means of transmission electron microscopy.
Various phase regions were detected in the coherent phase diagram as follows; (1)
alpha 0 (fcc) single phase region, (2) two-phase region (alpha 1 + alpha 2), (3)
AuCu I (L10) + alpha 0, (4) AuCu I + alpha 2, (5) AuCu II (L10-S) + alpha 2, (6)
AuCu I + AuCu II + alpha 2, (7) AuCu I single phase region. Microstructural
features of these regions relating to the phase transformations were described.
PMID- 9555254
TI - Effects of aging on tensile fatigue strength of bovine dentin.
AB - The effects of aging on the tensile fatigue strength of bovine dentin were
investigated. Tensile tests and tensile fatigue tests were performed in 37
degrees C water with bovine dentin specimens of two different age groups. The
tensile strengths of the young group and the adult group were 74.0 MPa and 72.7
MPa, respectively; there was no significant difference between the young and the
adult group. However, the tensile fatigue strength of the adult group, 46.9 MPa,
was significantly weaker than that of the young group, 51.0 MPa. There was a
obvious difference between the tensile fracture surface and the tensile fatigue
fracture surface; a smooth surface of the peritubular dentin and an uneven
surface of the intertubular dentin were clearly distinct in the fatigue fracture
surface. Plugged dentinal tubules and narrower dentin tubules were commonly
observed in the adult group. These morphological changes were suggested to be the
reason for the decrease in the tensile fatigue strength with aging.
PMID- 9555255
TI - Erosion process of light-cured and conventional glass ionomer cements in citrate
buffer solution.
AB - The aim of this study was to clarify the erosion behavior of light-cured glass
ionomer cement. One light-cured glass ionomer cement and two conventional
chemically-cured glass ionomer cements were immersed in citric acid buffer
solutions of pH 4 and pH 6. Fluoride release was almost the same in both types of
cements, irrespective of pH. The amounts of other species eluted, such as Al, Sr,
Si and P2O5 were smaller in the light-cured glass ionomer cement than in the
conventional ones at pH 4. The amounts of species eluted at pH 6 were almost the
same in both types of cement. Dissolution of the light-cured cement in pH 4
solution was controlled by the diffusion of the eluted species in the cement
matrix. On the other hand, dissolution of the conventional cements was controlled
by both diffusion and surface reaction. The surface features of the cements after
erosion corresponded well to the dissolution mechanism. In pH 6 solution,
dissolution of the cements was mainly controlled by diffusion of the species in
the cement.
PMID- 9555256
TI - Development of the computerized dental cast form analyzing system--three
dimensional diagnosis of dental arch form and the investigation of measuring
condition.
AB - To analyze the functional and morphological harmonies of the tooth and dental
arch, a computerized system to measure a dental cast and to detect the apex of
dental cusps and angle points of incisors was developed. Detailed morphology in
the measured dental cast could be displayed distinctively by computer graphics
(CG) with a surface model. Accuracy in determining the position of the apex of
the dental cusp was examined by increasing the measuring pitch from 50 microns to
400 microns, the error increased gradually with increased measuring pitch. Taking
the measuring error, the time for measurement and the memory size for analysis
into account, a measuring pitch of 200 microns was determined to be reasonable.
Three-dimensional data measurements from the apex of the dental cusp in molar,
and the mesial and distal angles in canine and incisor were fitted to a
polynomial formula. In the present measured model, the 4th order polynomial
formula was used for the dental arch, and the 2nd order polynomial formula was
used for the anteroposterior and lateral occlusal curves. These formulae could be
simultaneously superimposed on the surface model of the dental cast, and
displayed using CG.
PMID- 9555257
TI - Effect of Pd and In on mercury evaporation from amalgams.
AB - The amount of Hg vapor released from "synthesized" gamma 1 with 1% (wt) Pd was
reported to be less than 30% of that from gamma 1 with no Pd. This study tested
the hypothesis that Hg evaporation from Pd-containing amalgams decreases with Pd
concentration and that In also reduces Hg vapor. Specimens (4 mm dia, 8 mm long)
were prepared by triturating Ag-Sn(25%)-Cu(12%) alloy powder containing 0.5-9.0%
Pd with pure Hg and by triturating 3% Pd alloy powder with Hg containing 1-5% In
(all residual Hg approximately equal to 62%). The total amount (ng/mm2) of Hg
vapor released at 37 degrees C from freshly prepared amalgams was measured. Pd (3
9%) in the powder significantly (p < 0.05) decreased Hg vapor release from
amalgams during setting. Use of In-containing Hg also reduced Hg vapor release
(5% In, p < 0.05). The reduction in the Hg vapor pressure by adding Pd and the
rapid oxide film formation on the In-containing amalgam appear to work together
to reduce Hg vaporization from these amalgams.
PMID- 9555258
TI - Behavior of pure gallium in water and various saline solutions.
AB - This study investigated the chemical stability of pure gallium in water and
saline solutions in order to obtain fundamental knowledge about the corrosion
mechanism of gallium-based alloys. A pure gallium plate (99.999%) was suspended
in 50 mL of deionized water, 0.01%, 0.1% or 1% NaCl solution at 24 +/- 2 degrees
C for 1, 7, or 28 days. The amounts of gallium released into the solutions were
determined by atomic absorption spectrophotometry. The surfaces of the specimens
were examined after immersion by x-ray diffractometry (XRD) and x-ray
photoelectron spectroscopy (XPS). In the solutions containing 0.1% or more NaCl,
the release of gallium ions into the solution was lowered when compared to
deionized water after 28-day immersion. Gallium oxide monohydroxide was found by
XRD on the specimens immersed in deionized water after 28-day immersion. XPS
indicated the formation of gallium oxide/hydroxide on the specimens immersed in
water or 0.01% NaCl solution. The chemical stability of pure solid gallium was
strongly affected by the presence of Cl- ions in the aqueous solution.
PMID- 9555259
TI - Want to go with the flow? A state-side ride with the tide might spell disaster
for your Canadian practice.
PMID- 9555260
TI - Building a successful dental partnership.
PMID- 9555261
TI - Getting rich from scratch: a twelve point checklist.
PMID- 9555262
TI - What do you really want from your practice?
PMID- 9555263
TI - Enhance scheduling: give the patient a reason to come back.
PMID- 9555264
TI - From mediocrity to mastery: a practice case study.
PMID- 9555265
TI - Sound advice to build success.
PMID- 9555266
TI - How to make your hygiene department more profitable.
PMID- 9555267
TI - From concept to reality ... it's leading edge dentistry.
PMID- 9555268
TI - Building partnerships with your dental suppliers & laboratories.
PMID- 9555269
TI - Get your lab fit for profits. Experience the benefit$ of bringing back their
smiles.
PMID- 9555270
TI - Not just another pretty place.
PMID- 9555271
TI - Laboratory lotto? Are you gambling with your success?
PMID- 9555272
TI - The benefits of using an employment contract.
PMID- 9555273
TI - Choosing the right partner for your practice.
PMID- 9555274
TI - Ethics, anyone? Ethics, everyone!
PMID- 9555276
TI - Legislative change--discussions are heating up.
PMID- 9555277
TI - Responsibility and the practice environment.
PMID- 9555278
TI - Off-label prescribing for infants.
PMID- 9555279
TI - For your patients: when your child has an ear infection.
PMID- 9555280
TI - Asthma in adolescents.
PMID- 9555281
TI - A flexible option for adolescents with diabetes. Insulin pump therapy.
PMID- 9555282
TI - Protecting young athletes. Achieving injury prevention and health maintenance.
PMID- 9555283
TI - Attention-deficit hyperactivity disorder. The psychostimulants and beyond.
PMID- 9555284
TI - Respiratory syncytial virus. Understanding this pediatric threat.
PMID- 9555285
TI - Otitis media with effusion. Outlining strategies and controversies.
PMID- 9555286
TI - Environmental tobacco smoke.
PMID- 9555287
TI - The challenge of chickenpox. Vaccine is best bet against this childhood illness.
PMID- 9555288
TI - Responding to pediatric pain. A new way of thinking.
PMID- 9555289
TI - What we give to, and receive from, our patients.
PMID- 9555291
TI - Carol Bradley, MSN, RN, president-elect for AONE.
PMID- 9555290
TI - Managing ICU bed changes to match patient acuity.
PMID- 9555292
TI - Implementing best practices.
PMID- 9555293
TI - Ten steps to a patient-driven interdisciplinary care plan.
PMID- 9555294
TI - Spirituality in the health care workplace.
PMID- 9555295
TI - Building a values-driven, visionary organization.
PMID- 9555296
TI - Transforming knowledge to a healing environment.
PMID- 9555297
TI - We've all been there...
PMID- 9555298
TI - Are we doing enough to protect our children on the roads?
PMID- 9555299
TI - The principles of mixing and handling to minimise potential hazards of methyl
methacrylate bone cement.
PMID- 9555301
TI - The Protection From Harassment Act.
PMID- 9555300
TI - Teamwork in the operating department.
AB - The Gynaecology theatre team of the Leicester Royal Infirmary NHS Trust were
runners-up in the 1997 3M/NATN joint award. This article is a report of their
work on the concept of teamwork and its benefits to the organisation and delivery
of patient care in the operating department.
PMID- 9555302
TI - Workplace bullying--the abuse of power.
PMID- 9555303
TI - Shared governance--a personal view.
PMID- 9555304
TI - Education in the workplace.
AB - Other parts of the portfolio included sections for their six monthly appraisals,
reports on objectives and other projects. At this point fifteen D grade nurses
have subscribed to the PDP and an average of two per month are being added to it.
It is hoped that the PDP will lead to the increased motivation of all staff and
increased promotion prospects for the D grade nurses and thus have an impact on
the recruitment and retention of staff.
PMID- 9555305
TI - 'Green door, what's that secret you're keeping'!
PMID- 9555306
TI - Adding degrees C to old shouldn't read cold.
PMID- 9555307
TI - Surfing the "Net".
PMID- 9555310
TI - [Systemic nursing intervention in couples in which one member has cardiac
insufficiency].
AB - Chronic heart failure is a family affair since the spouse's quality of life is
affected as much as that of the patient. This article deals with three clinical
cases exploring the couple's perceptions of how the illness affected their
marital relationship and how helpful the family systems nursing interventions
have been. Three themes emerged from the analysis of the relationship between the
evolution of the illness and the marital dynamics, and these are: a search for a
balance between protectiveness/overprotectiveness, a reassessment of the marital
relationship, and the adoption of new coping strategies. The family systems
nursing interventions that were perceived as the most helpful were the systemic
questionf1p4++ and the exploration of the couple's strengths and resources. These
interventions allowed the couple to: 1) share their illness experience; 2)
increase their understanding of the relationship between the illness and their
marital dynamics, and 3) reflect on different ways to enhance their competence
and resources in meeting with the challenges of this type of cardiac health
problem.
PMID- 9555308
TI - [Is the family important in cardiovascular care?].
AB - Family care is an increasingly important component of nursing practice. A
systemic perspective on a cardiac health problem compels nurses to consider the
reciprocal relationship between the evolution of the illness and the patient's
family dynamics. An increasing number of studies focus on how an illness impacts
on the family and how the family can be either a source of stress for the patient
or a welcome support. Based on various studies and on clinical examples from the
authors' practice, this article stresses the importance for nurses to include the
family in their cardiovascular nursing care whatever the clinical context or
their expertise in family nursing. Systemic questioning that facilitates the
sharing of the illness experience between family members and the exploration of
the family's strengths and resources are nursing interventions that can be
practiced in all clinical contexts. These interventions are important because
they can considerably alleviate the patient's as well as and the family's
suffering.
PMID- 9555311
TI - Family partnership in care: integrating families into the coronary intensive care
unit.
AB - Since the introduction of Family Partnership in Care in the CICU and other pilot
units, many changes have been made. Education sessions are now unit specific
rather than in groups with multiple units. This facilitates the discussion of
unit-specific educational and implementation needs. In addition, unit-specific
sessions allow for some case scenario/role playing activities to facilitate
learning and application of the FPCP elements to the unique culture of the unit.
Finally, less emphasis is placed on the documentation, while greater emphasis is
placed on the philosophy behind the program and the nurses values and attitudes
towards families. Overall, the implementation of the FPCP in CICU has had a
positive impact on staff and patients. Staff awareness regarding the importance
of involving family in the patient's care and the benefits of this has been
heightened. Staff who were initially very skeptical have become strong advocates
for the program. The successful shift with families in "doing for" to "working
with" has enhanced the professional practice of many nursing staff and
contributed to the overall unit functioning. Finally, the feedback from patients
and their care partners and the independence and informed decision-making
fostered by designing a plan of care with staff validates the importance of this
program in a critical care area.
PMID- 9555313
TI - From loss to action.
PMID- 9555314
TI - Seeking to prevent further tragedy.
PMID- 9555315
TI - Pharmaceuticals and osteoporosis.
PMID- 9555316
TI - Cancelling immunization program a bad idea.
PMID- 9555317
TI - Article on physical punishment biased.
PMID- 9555318
TI - Hamelin responds to feedback.
PMID- 9555319
TI - The future supply of registered nurses in Canada.
PMID- 9555321
TI - How men learn about health.
PMID- 9555320
TI - Patterns of renewal in mothers who are nurses.
PMID- 9555322
TI - [Urinary function integrity in the elderly person].
AB - How can nurses help preserve the integrity of elimination in the elderly?
Further, what new perspectives must they bring to practice? First, health
professionals must rid themselves of their misconceptions, especially the belief
that incontinence is "normal" in the aging process. The authors provide avenues
for reflection and action, with a view to arriving at a dynamic clinical practice
focusing on quality of life and the well-being of the individual. In terms of new
perspectives, nurses are encouraged to stop limiting themselves to assisting with
personal hygiene because this deprives the client of possible recourse to a
better adaptation. Nurses must no longer dispense comfort by reassuring the
incontinent person that "there's no harm done". This message ignores the real
life experience associated with the problem and reinforces the idea of normality.
Assessment of the client's condition must go beyond the superficial and instead
target interventions that lead to a resolution. Updating the caregiver's and the
client's knowledge, enhancing the nurse's role in prevention and treatment,
combining various approaches to care and improving communication are good places
to start.
PMID- 9555323
TI - Home phototherapy for uncomplicated neonatal jaundice.
PMID- 9555324
TI - The ten worst and best days of my career.
PMID- 9555325
TI - Who decides what's in the public interest?
PMID- 9555326
TI - Your role in giving weight-control advice.
PMID- 9555327
TI - Depot injections at home or clinic? Letting clients choose.
PMID- 9555328
TI - Exercising for better health and mobility.
PMID- 9555330
TI - Treating eczema in ethnic minority groups.
PMID- 9555329
TI - Dilemmas in moving and handling patients.
PMID- 9555331
TI - The role of the papillomavirus in cervical changes.
PMID- 9555332
TI - The menopause without HRT.
PMID- 9555333
TI - Role of immunisation in the care of the chronically sick.
PMID- 9555334
TI - Using alginate dressings: a cost-effective option.
PMID- 9555335
TI - Pressure relief seating: are your patients comfortable?
PMID- 9555337
TI - Putting food scares into perspective.
PMID- 9555336
TI - Night nurses provide vital service.
PMID- 9555338
TI - The role of skin-prick testing in asthma care.
PMID- 9555339
TI - Role of diet in the management of diabetes.
PMID- 9555341
TI - Can HRT help in Alzheimer's disease?
PMID- 9555340
TI - Treating rashes in the groin.
PMID- 9555342
TI - A tale of the unexpected.
PMID- 9555343
TI - Management of constipation in children.
PMID- 9555344
TI - Accountability in prescribing.
PMID- 9555345
TI - Management of paediatric pain 1: Non-drug approaches.
PMID- 9555346
TI - Management of paediatric pain 2: Drug therapies.
PMID- 9555347
TI - A multidisciplinary approach to foot care in diabetes.
PMID- 9555348
TI - Choosing antiseptic dressings for infected wounds.
PMID- 9555349
TI - Effective communication in continuity of stoma care.
PMID- 9555350
TI - Reflections on scholarship in diabetes education.
PMID- 9555351
TI - Education--a lifelong process.
PMID- 9555352
TI - Mini-residency on diabetes care for healthcare providers: enhanced knowledge and
attitudes with unexpected challenges to assessing behavior change.
PMID- 9555353
TI - "Learn, taste, and share": a diabetes nutrition education program developed,
marketed, and presented by the community.
PMID- 9555354
TI - Participation in a diabetes education and care program: experience from the
diabetes care for older adults project.
AB - There is very little reported information concerning the participation of older
adults in diabetes education and care programs, factors related to their
attendance, and the influence of attendance on program outcomes. In this study,
which was part of a larger study of insulin therapy, subjects (> or = 65 years
old) assigned to the intensive management group (n = 53) were provided with
educational sessions during the 18-month study period. Data for this group were
examined to determine factors that influenced enrollment and attendance.
Attendance rates for individual participants averaged 72% during the first 6
months and 68% during the subsequent 12 months. Demographic factors, baseline
knowledge test scores, and baseline glycosylated hemoglobin levels did not
significantly influence participation. Greater distance from the clinic and
shorter time using insulin were significantly related (P = .05) to attendance.
Perceived benefits of the program included diabetes education (45%), glucose
control (23%), and interacting with others who have diabetes (23%).
PMID- 9555355
TI - Greatest fears of type 1 and type 2 patients about having diabetes: implications
for diabetes educators.
AB - This exploratory study was undertaken to describe the differences in the greatest
fears about having diabetes between type 1 and type 2 patients. Frequency
distributions, measures of central tendency, and nonparametric statistics were
employed to examine the traits of the sample and to make comparisons between type
1 and type 2 patients. Content analysis was used to describe and analyze the
subjects' responses to the question, What is your greatest fear about having
diabetes? Subjects' answers to this question were categorized and scored as
representing fear of either a long-term or acute complication based on the
clinical judgment of the authors. Results revealed that both type 1 and type 2
patients were likely to have given responses that were suggestive of fear of long
term complications. The major fears concerned amputation, cardiovascular disease,
nephropathy, neuropathy, retinopathy, and stroke. The findings of the present
investigation suggest that diabetes educators may need to address patients' fears
of long-term complications directly and effectively. Several areas of research
that grew out of this exploratory study were recommended for future
consideration.
PMID- 9555356
TI - Feasibility and use of an Internet support service for diabetes self-management.
AB - Diabetes self-management is a challenging task due to its complexity and ever
present barriers to self-care. A key issue for patients, providers, and
healthcare systems is how to deliver personalized behavioral support in ways that
are affordable and can reach most patients. The Internet offers several
advantages in this regard because it is available 24 hours a day, low cost, and
capable of reaching thousands of patients. Although Internet sites for diabetes
support are popular, they have not been evaluated. For this study, a Web site for
diabetes self-management that emphasized personalized goal setting, feedback, and
social support was developed. Over a 10-week period, 111 different persons logged
onto D-NET for a total of 21,046 accesses. Users included persons across a broad
age range (up to age 77 years) and duration of diabetes. The most popular areas
of the site were the Social Support Conference and the Diabetes Information
Pages. User ratings revealed high satisfaction with the service. The Internet has
great potential for providing needed support and services for patients with
diabetes and other chronic illnesses.
PMID- 9555357
TI - A primary intervention program (pilot study) for Mexican American children at
risk for type 2 diabetes.
AB - Many chronic diseases that are leading causes of morbidity and mortality can be
prevented or controlled by primary or secondary interventions. Type 2 diabetes
with its complications constitutes a major health problem, especially among
Mexican Americans. The purpose of this pilot study was to develop an age- and
culturally appropriate primary intervention program for Mexican American children
at risk of type 2 diabetes. The sample included 37 Mexican American children ages
7 to 12 years who had at least one parent or grandparent with type 2 diabetes. A
health screen of physiologic risk factors, a nutritional assessment, and a
diabetes knowledge test were administered before and after the program. The eight
session activity oriented educational program focused on nutrition, exercise, and
diabetes knowledge. Due to small sample size and limited study time, changes in
physiologic factors and diet were not analyzed for statistical significance.
Analysis of individual factors showed a trend toward more normal values. Results
of this pilot program indicated that health intervention projects may be
effective in helping children at risk of type 2 diabetes adopt healthier
lifestyles.
PMID- 9555359
TI - Natural products and diabetes treatment.
AB - Many natural products are promoted to improve the health status of patients with
diabetes by people making a profit on these products. Few of these claims have
any scientific basis. Certain natural products are potentially damaging to
patients with chronic diseases, especially if the products are used instead of
proven scientific treatment regimens. Many individuals believe that if a product
is natural it must be effective and safe. What is ironic is that if the products
were safe and effective, and if studies would have been done on humans to prove
safety and effectiveness, the sales of the products would greatly increase (as
opposed to present limited sales as herbs from health food stores). Some of the
products do have a beneficial effect, especially as a placebo if the patient
believes that the product is going to work. As can be seen from the summary of
products that are listed here that claim to improve the treatment of patients
with diabetes, very few are available in a standard form that would produce a
known positive effect. The few products that do have a mild impact on lowering
blood glucose levels are much less effective than standard treatments. In a
recent review of the role of plant-derived drugs and herbal medicines in
healthcare, no natural products were listed as having a beneficial effect on
diabetes. Diabetes care providers need to confront the issue of the use of
natural products with their patients. Patients should be taught the importance of
using proven, effective treatment regimens. Any patient who decides to use a
natural product should be followed closely to make sure that no toxic effects
occur and that treatment objectives are achieved.
PMID- 9555358
TI - Focus on insulin resistance in type 2 diabetes: therapeutic implications.
AB - Type 2 diabetes is extremely common and increasing in the United States. The
pathophysiology of type 2 diabetes is a combination of increased insulin
resistance and inadequate secretion. The main risk factors for diabetes are
family history, obesity, sedentary lifestyle, ethnic background, age, and a
history of gestational diabetes. Diet and exercise, the cornerstones of diabetes
management, will improve insulin sensitivity and indirectly augment insulin
secretion. Until recently, the only pharmacological approaches to diabetes were
sulfonylureas and insulin, which either augment insulin secretion or replace
insulin, thus acting only on the insulin side of the equation. Recently, a series
of new drugs have become available that are capable of decreasing hepatic glucose
output (metformin), slowing postprandial glucose absorption (acarbose), and
improving peripheral insulin sensitivity (troglitazone). With these drugs, either
alone or in combination, and behavioral therapies, it is now feasible to achieve
good to outstanding glycemic control in most individuals with type 2 diabetes.
PMID- 9555360
TI - Esophageal varices: treatment and implications.
AB - The purpose of this article is to present an overview of esophageal varices. The
causes of esophageal varices and the current treatments are examined. Information
is provided regarding surgical and nonsurgical forms of treatment. Various
aspects of nursing care are discussed, including the implications involved in the
emergency setting, psychological needs, and education for patients and their
families.
PMID- 9555361
TI - The hidden illness of endoscopy patients: mental health disorders, Part III.
PMID- 9555362
TI - Understanding pediatric intestinal pseudo-obstruction: implications for nurses.
AB - Pseudo-obstruction is actually a group of disorders resulting in bowel
dysmotility in the absence of anatomic obstruction. Because of varied pathologic
abnormalities of the GI tract involved in the disorder, pseudo-obstruction has
been reported in the literature under different names, including
hypoganglionosis, chronic adynamic ileus, pseudo-Hirschprung's disease, visceral
neuropathy, visceral myopathy, and megacystis-microcolon-intestinal
hypoperistalsis syndrome. Although a rare condition, its effects are severe,
disabling, and life-threatening in pediatric clients. Prognosis is inversely
correlated with age and is especially poor in those children with symptoms as
newborns. Management involves promoting nutrition adequate for growth, treating
symptoms, and preventing complications. Total parenteral nutrition is almost
always required, and its long-term use is associated with chronic cholestasis and
potential hepatic failure. Nurses may encounter pediatric clients with this
disorder and their families in many different healthcare arenas, such as in
radiology departments, ambulatory care, and acute and home care settings. The
purpose of this article is to review current literature on this disease and
summarize information useful to nurses.
PMID- 9555363
TI - The nurse endoscopist: reality or fiction?
AB - In this article, the author describes a study conducted to determine whether
advanced practice registered nurses (APRNs) should perform endoscopic procedures,
such as colonoscopy and esophagogastroduodenoscopy. Questionnaires were mailed to
APRNs belonging to the Society of Gastroenterology Nurses and Associates.
Questionnaire items pertained to demographics, current activities, interest in
performing GI endoscopic procedures, and barriers to performing GI endoscopic
procedures. Over 70% of respondents approved of nurses performing diagnostic
endoscopic procedures, yet 80.6% did not think that nurses should perform
therapeutic endoscopic procedures. Training opportunities were limited. The
barriers to performing endoscopic procedures included liability, third-party
reimbursement, lack of physician support, lack of policies, and lack of
education. APRNs should develop policies and establish acceptable training
guidelines and competency rates in performing GI endoscopic procedures.
PMID- 9555364
TI - Medication history and Helicobacter pylori testing.
PMID- 9555365
TI - Camp Magic: a GI camp.
PMID- 9555366
TI - Infergen (interferon alfacon-1).
PMID- 9555367
TI - The more things change, the more they stay the same: whither midwifery?
AB - The pace of change is said to increase over the next few years. One of the most
significant recent changes has been the "McDonaldization of Society". The notion
of "fastness" is permeating all society, including health and education. The
concentration of rationalization through the principles of efficiency,
calculability predictability and control, when extended to its logical
conclusion, results in irrationality or dehumanization. Childbirth has been
"McDonaldized" by the medical profession, but modern midwifery, is leading the
way in an anti McDonald's movement to rehumanize it. Returning to past values
contained in aesthetics, use of the partnership model, different forms of
research and political action, midwifery is taking control of childbirth away
from the rationalists and returning it to women. It is reclaiming childbirth by
placing value on women and empowering them to take control of their own
childbirth.
PMID- 9555368
TI - Women have innate knowledge and wisdom to birth.
PMID- 9555369
TI - Re: Women have the innate knowledge and wisdom to birth.
PMID- 9555371
TI - Re: Letter to the editor, Dr Nick Silberstein ACMI Journal Sept 1997, Vol 10, No.
3, p5.
PMID- 9555370
TI - Collecting the Newborn Screening Test (NST), via the heel prick.
PMID- 9555372
TI - Childbirth and the illness focus.
AB - Childbirth is essentially women's business, a natural female act being performed
since the beginning of mankind. However, as Western society has evolved, so too
has the management of childbirth. It is the medical profession that has gained
control of providing care for childbearing women, to the detriment of many
women's experiences. The societal expectations on childbearing women, the
iatrogenic effects of pregnancy being treated as an illness under the medical
model, and the implications for the profession of midwifery will be discussed.
PMID- 9555373
TI - Midwifery negligence: a case study.
AB - A professional health practitioner can be found in law to be liable to compensate
clients when the practitioner causes harm to the client through a negligent act
or omission. To date, most health-related litigation has been directed toward the
medical profession. A minority of cases are taken against health institutions
with respect to nursing and midwifery practice. In recent years there have been a
few cases in England in which midwifery practice has been an issue. The purpose
of this article is to report on one such case. It is important for all midwifery
practitioners to be aware of the facts and circumstances in which midwives have
been found to be negligent, and the way in which the courts have dealt with the
matters in dispute.
PMID- 9555374
TI - Reforms affecting diverse populations.
PMID- 9555375
TI - Family member discrepancies in report of a child's race.
AB - This paper describes the types of discrepancies in self report of a child's race
in a research study of cardiovascular health in school age children. Researchers
sometimes make conclusions based on the percentage of subjects from each racial
group included in the study. This is particular concern because in intervention
studies researchers may report differing responses to treatment based on the race
variable. This study increases awareness of issues surrounding assigning race of
children participating in research studies.
PMID- 9555376
TI - Protective factors within the family, and their role in fostering resiliency in
African American adolescents.
AB - Violence has reached epidemic proportions in the United States, with African
American males residing in urban areas bearing the brunt of this epidemic. The
violence permeating our society emanates from a variety of societal ills,
including poverty, racism, substance abuse and exposure to violence.
Traditionally, methods of research on adolescent violence have focused on an
identification of associated risk factors. The majority of African American
adolescents living in communities with widespread and chronic violence grow up to
be law-abiding citizens. The reason for this may be due to resiliency within
these adolescents. Resiliency has been defined as the ability to experience
adverse circumstances and successfully overcome them. Resiliency is enhanced
through three mechanisms identified as protective factors: individual
characteristics/traits; familial traits; and extrafamilial relationships. The
risks faced may be altered, and even ameliorated, through the presence of these
protective factors. The purpose of this paper is to identify protective factors
within the family that foster resiliency. Protective factors within the family
may be categorized as having three broad characteristics: caring and support,
high expectations, and encouragement of participation and involvement for the
adolescent.
PMID- 9555377
TI - Cultural implications for nursing care of the Amish.
AB - The Amish are a conservative Protestant religious sect with a unique set of
culture and traditions. In order to provide culturally appropriate and sensitive
health care, it is imperative for nurses and other health care providers to have
a basic understanding of variations of Amish lifestyle from other cultural
groups. Application of Giger and Davidhizar's Transcultural Assessment Model
provides information and nursing implications to assist nurses and other health
care personnel when caring for Amish clients.
PMID- 9555378
TI - A glance at Appalachia.
AB - Appalachia is usually written about in romantic terms; rarely are the citizens of
Appalachia portrayed as contributors to society. Appalachia is made up of many
cultures--African American, European American, Melungeon, Native American and
others. Appalachian cultures are not locked in a fixed state; one needs only to
review the history of Appalachia to understand this concept (Tice & Billings,
1991). Appalachian cultures are fluid and ever-changing. The cultures are
expressed in literature, oral histories, music and regional history.
PMID- 9555379
TI - Understanding the process.
AB - The overall goal of the editors of the Journal of Holistic Nursing was to enhance
the link between the professional literature and holistic nursing practice. To
accomplish this goal, strategies were developed/refined that would increase the
journal's acceptance into the clinical/academic marketplace. The purpose of this
article is to produce a concise document that describes the publication process.
The following topics are addressed: (a) the rationale for writing, (b) the
publication requirements, (c) selecting a journal, (d) the peer review/evaluation
process, and (e) the essential components of an article. The purpose of this
editorial effort was to assist manuscript writers to become published authors.
Hopefully, the activities of the editors and the contents of this article will
facilitate the efforts of many aspiring authors.
PMID- 9555380
TI - Inventory of professional activities and knowledge of a holistic nurse (IPAKHN).
AB - In the development and administration of a certification examination in holistic
nursing, an important issue is to ensure adequate content validity. Thus, the
American Holistic Nurses' Association (AHNA) and the American Holistic Nurses'
Certification Corporation (AHNCC), with the assistance of the National League for
Nursing, conducted a practice analysis study to generate empirical data on the
professional activities and knowledge required to practice holistic nursing on a
day-to-day basis.
PMID- 9555381
TI - Differentiating holistic practice and speculations for future directions.
AB - Technological advances and economic, social, and cultural conditions have created
a climate of change in health care. New roles and approaches are developing in
relation to the holistic health movement. Within the holistic nursing community,
three concepts of holistic practice have emerged. Differentiations among (a)
certified holistic nurses, (b) practitioners of a healing modality, and (c)
healers are presented to promote future discussion. As new roles must match a
social need and become institutionalized to secure a professional role,
speculations on possible directions for the certification in holistic nursing are
presented.
PMID- 9555382
TI - Humor and pain management. A review of current literature.
AB - The purpose of this article is to provide a review of current literature related
to humor and pain management. A brief review of the benefits of humor on the body
is followed by a literature review of articles on humor and pain management,
including research articles and scholarly articles on the topic. Research studies
on the use of humor with both acute and chronic pain will be reported. The review
of scholarly unresearched articles will include articles giving guidelines for
humor use, suggested humor assessment guidelines, discussion of the nurse's role
with humor use, and implementation strategies via humor carts and rooms.
PMID- 9555383
TI - The meaning of diabetes. Significance for holistic nursing practice.
AB - Recent research has raised questions about the validity and relevance of health
practitioners' perspectives of diabetes and diabetes care. This article describes
a qualitative research study that was undertaken to illuminate an insider's
perspective of how Type I diabetes is meaningfully experienced. The results of
this study reveal that although people with diabetes share a common disease, the
meaning of that disease in people's lives is unique and varied. To provide
holistic care, nurses must assist people in discovering and articulating the
meaning of diabetes in their lives as well as acknowledging and attending to the
significant elements within their experiences.
PMID- 9555384
TI - [Respiratory therapy (physical therapy) in children with heart disease].
PMID- 9555385
TI - [Long-term electrocardiography for the diagnosis of congenital and postoperative
arrhythmias].
PMID- 9555386
TI - [Temporary pacemaker therapy after heart surgery].
PMID- 9555387
TI - [Psychosocial care of parents of children with heart disease].
PMID- 9555388
TI - [The counseling team of the St. Anna Pediatric Hospital nursing service--a center
for pediatric and adolescent care].
PMID- 9555389
TI - [Giving competent care--where does one learn that?].
PMID- 9555390
TI - [Practical training from the viewpoint of nursing students in Austria and
Germany].
PMID- 9555391
TI - [Integration of parents into German pediatric units--current problems and
strategies for their management].
PMID- 9555392
TI - [Transplantation legislation is now in force].
PMID- 9555393
TI - [Basal stimulation in the premature].
PMID- 9555394
TI - [More and less toxic plants. 36].
PMID- 9555395
TI - [Nursing legislation--presentation report and commentary on the opinion "Public
legal basis for the nursing profession in view of their range of duties"].
PMID- 9555396
TI - A framework for managing risk.
AB - Supervision aims to maintain standards, thereby reducing clinical risk. Katrina
Neal warns that supervision records could be used in a court of law, so should
not be written simply to let off steam.
PMID- 9555397
TI - Lecturer-practitioners: serving two masters for a common cause.
AB - Is the theory-practice gap being bridged now that lecturer-practitioner posts
exist in many parts of the country? Jenine Willis finds out how some
practitioners are coping with the demands of the job.
PMID- 9555398
TI - Designing learning activities.
AB - In the fifth part of this series on teaching skills, Dai Hall suggests some ways
of organising your material when imparting information or when organising a
discussion.
PMID- 9555399
TI - Freedom and free will.
PMID- 9555400
TI - What are 'rights'?
PMID- 9555401
TI - Using technology for distance.
AB - Internet-based distance education is in its infancy. As technology continues to
develop and accessibility to the Internet grows, so, too, will delivery of
educational materials via the Internet. In the meantime, the Wolfson Institute is
taking the opportunity to learn how to harness this technology for educational
purposes and to prepare for a future where education and technology move even
closer together.
PMID- 9555402
TI - What's the point of ... public health?
PMID- 9555403
TI - Cervical screening programme omitted from article.
PMID- 9555404
TI - Towards a national paediatric service.
PMID- 9555405
TI - Grateful for help given, not disempowered.
PMID- 9555406
TI - Workplace relations bill is anti worker.
PMID- 9555407
TI - Nurses should speak in plain language.
PMID- 9555408
TI - Blueprint lacks social analysis.
PMID- 9555410
TI - Caring for the mentally ill.
PMID- 9555409
TI - A tribute to Tama.
PMID- 9555411
TI - Leading from behind.
PMID- 9555412
TI - Seeing the whole picture. A gift from the sea.
PMID- 9555413
TI - Seeing makes the difference.
PMID- 9555414
TI - Seeing beyond.
PMID- 9555415
TI - When I'm ok is not ok.
PMID- 9555416
TI - Guiding the way.
PMID- 9555417
TI - The gift of life.
PMID- 9555418
TI - Administering drugs.
PMID- 9555419
TI - Raising Te Runanga's profile.
PMID- 9555420
TI - Will nursing exist tomorrow? A reprise.
PMID- 9555421
TI - Ontology, epistemology, and methodology: a clarification.
AB - The vistas of scholarly discourse in nursing are open to philosophical as well as
scientific exploration. Careful attention to intersubjectivity in the use of
language shared with other fields will continue to be a mark of nursing's
rightful presence in an intellectual community committed to the pursuit of
knowledge in the interest of advancing human welfare.
PMID- 9555422
TI - Grounded theory research: its value for nursing.
PMID- 9555423
TI - A nursing theory-guided model of health ministry: human becoming in parish
nursing.
PMID- 9555424
TI - A review of the power as knowing participation in change literature.
AB - In the 15 years since the introduction of Barrett's theory of power as knowing
participation in change and its accompanying measurement instrument, a rapidly
growing number of research studies have been conducted using the theory and
instrument. This article presents a critical review of this literature, as well
as recommendations for further research.
PMID- 9555425
TI - Methodological ponderings related to the power as knowing participation in change
tool.
AB - Based on 15 years of research using the Power as Knowing Participation in Change
Tool, the authors summarize tool development, including reliability and validity,
and discuss specific methodological issues and insights. These include clarity of
instructions and complexity of language used in the PKPCT along with response
set, norms, and sensitivity of the instrument to detect differences between
groups. Problems of linear measurement are discussed along with the
appropriateness of both qualitative and quantitative methods of studying power
from the view of the science of unitary human beings. Recommendations for further
psychometric studies of power are proposed.
PMID- 9555426
TI - Evaluation of the human becoming theory in practice in an acute care psychiatric
setting.
AB - Using a descriptive evaluation research method, this study evaluated Parse's
theory of human becoming in practice in the psychiatric setting. A pre- mid- post
implementation design served to generate qualitative data from nurses, patients,
unit nurse managers, hospital nurse supervisors, and nurse documentation that
illuminated changes in the quality of nursing care on three diverse pilot units.
Major themes of change supported by all data sources were shifting views of human
beings, altered ways of listening, altered foci of nurse-person discussions, and
personal transformations. Identified themes surfaced strikingly different
qualities of change for each pilot unit. Recommendations related to the
successful implementation of Parse theory-based practice are presented.
PMID- 9555427
TI - Empirical verification of a theoretical model derived from the Roy adaptation
model: findings from five studies.
AB - This article presents a theoretical model derived from the Roy adaptation model
and the findings of an empirical verification of this model from five studies.
Four groups of subjects were included in the studies: informal caregivers of
demented relatives at home, informal caregivers of psychiatrically ill relatives
at home, professional caregivers of elderly institutionalized patients, and aged
spouses in the community. In at least three studies, a number of theoretical
propositions derived from the Roy adaptation model were supported using LISREL
VIII, thus adding credence to some tenets of Roy's model. Particularly, the focal
stimulus of perceived stress, the contextual stimulus of conflicts in the
exchange of social support, and one component of the coping mechanisms (the
passive/avoidance coping strategies) were positively linked directly or
indirectly with psychological distress, which is an indicator of adaptation in
the self-concept mode. Given their importance, these elements should be
considered in the development of a middle-range theory of psychological
adaptation derived from the Roy adaptation model.
PMID- 9555428
TI - Homecare nurses face unique challenges in caring for patients with cancer.
AB - Oncology care is going home. The changes in health care that have occurred during
the past decade have significantly impacted the growth of home care. Factors that
have contributed to this growth include prospective payments for hospital
services to Medicare patients leading to a decreased length of stay, advances in
the development of equipment for providing high-tech treatments in the home,
changes in reimbursement from fee-for-service to managed care and capitation, an
aging population, and improved survival rates for patients with chronic
illnesses, including cancer.
PMID- 9555429
TI - Leadership is about ordinary people doing extraordinary things.
PMID- 9555430
TI - Describe a unique accommodation or creative solution you have used in caring for
a patient at home.
PMID- 9555431
TI - Can homecare services adequately address end-of-life issues?
PMID- 9555432
TI - Immediate call to action: proposed regulation threatens cancer care delivery.
PMID- 9555433
TI - Let's rediscover the joy of nursing.
PMID- 9555434
TI - Highlights from the states: 1997.
PMID- 9555436
TI - The personal and professional benefits of the ENT Nursing Foundation.
AB - SOHN created the ENT Nursing Foundation at the 21st Annual Congress. This article
describes the Foundation, the basics of its operation, and the benefits to SOHN
and donors.
PMID- 9555435
TI - Otorhinolaryngology nursing research priorities: results of the 1996/1997 SOHN
Delphi survey.
AB - This study was initiated by the Society of Otorhinolaryngology and Head-Neck
Nurses, Inc. (SOHN) to establish research priorities for the specialty.
Otorhinolaryngology (ORL) Nurses were asked to identify, rate, and rank
priorities for ORL nursing research. The survey sample was gleaned from attendees
at the 20th Annual SOHN Congress and Nursing Symposium plus a follow-up mailing
to active SOHN members who did not attend. A decision-making method, the reactive
delphi technique, was employed. Four rounds of soliciting opinions by
questionnaires were completed. Data from each round were reviewed and analyzed by
three ORL nurse investigators. The respondents were largely actively employed,
female SOHN members who were seasoned nurses, experienced in ORL nursing. The
majority were Registered Nurses (RN) or held Bachelor of Science (BSN) degrees.
They were primarily employed as staff nurses in outpatient settings and working
with a general otorhinolaryngology patient population of all ages. The fourteen
priorities identified fall in the areas of patient outcomes (three), patient
education (three), symptom management (two), patient self-care (two),
psychosocial issues (two), and nursing care delivery (two), spanning the practice
spectra of all ORL nurse generalists and subspecialists. The top five research
priorities identified are; care of neck stomas and related equipment, quality of
life in head and neck cancer patients, impact of managed care on ORL nursing care
delivery, value of ORL specialty nurses/nursing units, and effective techniques
to promote cessation of substance abuse in adolescents. This priority
identification provides a baseline for the newly forming SOHN Foundation.
PMID- 9555437
TI - The 21st annual SOHN congress.
AB - In a recent Presidential Perspectives column (see ORL-Head and Neck Nursing, Vol.
15, No. 3, Fall 1997, p. 4), Mary LeGrand described the impact that volunteerism
can have on the success of an organization. The following article lends a prime
example of how one SOHN member volunteers her services at both the local and
national levels, donating her time and talents, reaping the rewards of her
experiences, and ultimately sharing her thoughts in the following article.
PMID- 9555438
TI - Who are pediatric nurse case managers ... and what are the hot issues?
PMID- 9555439
TI - Little women: early menarche in rural girls.
AB - Menarche, the first menstrual period, is a significant life event with important
cultural, social, and personal implications. After noticing that several girls in
a rural pediatric practice reached menarche at young ages, the researchers
conducted a qualitative case study to investigate when menarche occurs and
factors that may be associated with menarche onset. Four of the total of seven
cases reached menarche before the average age of 12.8 years and had mothers who
started at later ages. All four also experienced significant stressors just prior
to onset. Lack of generalizability and the small sample disallow for any
significant findings. However, the findings do indicate that menarche occurs in
rural girls as young as age 9, creating implications for nurses in the areas of
assessment, client teaching/counseling, and future research.
PMID- 9555440
TI - Teaching and communication strategies: working with the hospitalized adolescent
with pelvic inflammatory disease.
AB - The increased incidence of sexually transmitted disease (STD) in the adolescent
population has led the Centers for Disease Control and Prevention to highly
recommend inpatient therapy for all adolescents with pelvic inflammatory disease
(PID). This in turn has led to an increased need for nurses in inpatient settings
to be skilled at providing sexuality education to adolescents with PID. The nurse
needs a clear understanding of STD and PID, and the ability to communicate
effectively with adolescents to help them make healthy decisions about their
sexual behavior.
PMID- 9555441
TI - Adolescent transitions: a nursing concern.
AB - Adolescents with chronic conditions face unique challenges as they approach
adulthood. Statistics on adults with disabilities indicate high rates of
unemployment, few with college degrees, and limited options for community living.
Until recently, efforts to facilitate successful transitions for adolescents with
chronic conditions to adulthood have been limited. An awareness of some of the
pertinent issues pertaining to adolescent transitions, especially those
pertaining to health care, can assist the pediatric nurse in facilitating the
transition to adult health care, career, employment, and community living.
PMID- 9555442
TI - Impact of research on pediatric pain assessment and outcomes.
AB - PURPOSE: Pediatric nurses from varied practice and educational backgrounds
learned about research by doing a ward-based study. The aim of the study was to
determine if regular assessment of children's pain would improve their pain
management and postoperative progress. METHOD: Children, ages 5 to 17 years (n =
36), measured their pain every 4 hours postoperatively using the Wong-Baker Faces
Pain Rating Scale. Outcomes regarding amount of analgesic given, subjective pain
reports, time and progress of ambulation, and length of hospital stay were
compared with data from a retrospective chart-review of a control group (n = 50).
FINDINGS: No statistically significant differences in these variables were found.
An important clinical finding was that despite all children having prescribed PRN
analgesic orders, one quarter of the children received no pain relief
intervention. Also, one quarter of the children stated that their pain control
was only partially effective. CONCLUSIONS: Study results reinforce findings
reported in the literature regarding ineffective pain management in children, and
highlight a need for improved nursing practice. Clinical significance was
achieved in terms of staff learning of the research process, increased awareness
of pediatric pain management practices, improved ward morale, and inter-agency
sharing of resources.
PMID- 9555443
TI - Public policy and child lead poisoning: implementation of Title X.
AB - Nurses who care for pediatric patients in all settings must be aware of the
critical effects of lead poisoning in children. Lead causes toxic effects in the
human body, especially in children. These hazards have led to government
involvement related to the issues of lead poisoning. Currently, governmental
programs are set up under Title X: The Residential Lead Based Paint Hazard
Reduction Act of 1992. However, the political changes and potential cuts in
government spending may affect programs such as Title X. Because of this and
their important role in child health, pediatric nurses should understand the
political process, the implementation of such programs, and effects of potential
funding cuts.
PMID- 9555444
TI - Language development in bilingual children.
AB - Bilingual language ability in children includes a wide range of verbal, written,
and comprehension skills. Assessment of language development in bilingual
children that is not individualized may yield inaccurate information and result
in unnecessary referrals. Primary care nurses need to be aware of differences in
language development between mono- and bilingual children in order to accurately
assess their language skills.
PMID- 9555445
TI - Effects of relaxation on anxiety in primary caregivers of chronically ill
children.
AB - PURPOSE: To evaluate the effects of self-applied breathing and guided imagery
relaxation techniques, separately and in combination, and a reinforcement tool on
primary caregivers (PCGs) coping with anxiety when caring for a chronically ill
child. METHOD: Twenty PCGs, aged 25-57, of chronically ill children were randomly
assigned to an experimental or control group. The State Anxiety Scale of the
State-Trait Anxiety Inventory (Form Y) was used to measure state anxiety across
three test administrations. FINDINGS: While there were no statistically
significant changes in state anxiety, behavioral evaluations indicated that PCGs
used both the self-applied relaxation techniques and the reinforcement tool more
than twice daily. CONCLUSIONS: Relaxation techniques may be useful for those
people caring for chronically ill children.
PMID- 9555446
TI - Gender reassignment in children: ethical conflicts in surrogate decision making.
AB - Parents, as surrogate decision makers for their infants, are generally expected
by health care providers to act in the child's "best interest." However, when the
wishes of the parents are contrary to those of the medical profession, an ethical
dilemma occurs. Whose decisions are best for the infant? Whose recommendations
are in the child's best interest? This article explores an issue that may not
involve a life and death decision, but one in which the parents clearly refuse
expert medical recommendations for what the providers believe are in the best
interest of the infant. Specifically, the case study explores the parents'
refusal to proceed with gender reassignment to female for their genetic XY baby
born with micropenis and nonpalpable testes. The issue calls into question the
possible limits of surrogate decision making. The ethical principles of
beneficence, respect for persons, nonmaleficence, and justice are addressed in
relation to this particular case.
PMID- 9555447
TI - Ethical commentary on gender reassignment: a complex and provocative modern
issue.
PMID- 9555448
TI - Helping families mobilize their personal resources.
AB - With changes in delivery of and payment for health care, hospital stays may be
shorter and children may be going home sooner and sicker. Therefore, more care
may be required at home. Even with access to a variety of services and resources
in the community, families of medically fragile or chronically ill children can
be overwhelmed and stressed. Relief can be provided to some degree if families
creatively mobilize their own personal resources. However, for a variety of
reasons, families may find it difficult to do this. While nurses and other health
care professionals are accustomed to helping families find professional services
and resources in the community, they can also be invaluable before discharge by
assisting families with their personal resources--from giving encouragement and
motivation to outlining practical planning steps. Pediatric nurses can use
guidelines and a checklist to assist families with mobilizing their resources to
ease the transition from hospital to home for the whole family.
PMID- 9555449
TI - Consumer Bill of Rights: family-centered care.
PMID- 9555450
TI - Changes proposed for RN licenses.
PMID- 9555451
TI - Pediatric management problems. Plagiocephaly.
PMID- 9555452
TI - Beyond hospital walls: educating pediatric nurses for the next millennium.
AB - As pediatric units in acute care hospitals close, as lengths of stay shorten, and
as increasing numbers of procedures are completed on an outpatient basis, faculty
must find different learning experiences for their prelicensure students. Some
programs have discontinued pediatric rotations, others are seeking clinical
experiences in community settings. These community experiences hopefully produce
a more well-rounded, globally thinking nurse to practice in the 21st century, yet
they also raise a number of concerns.
PMID- 9555453
TI - [Effects of nursing insurance on institutional care for the elderly].
PMID- 9555454
TI - [Negative quality assurance by nursing insurances and social security].
PMID- 9555455
TI - [Dynamic propositions in geriatric care].
PMID- 9555456
TI - [Latex allergies as a problem in the health professions].
PMID- 9555457
TI - [Transplantation legislation].
PMID- 9555458
TI - [A glance into the European office of the World Health Organization].
PMID- 9555459
TI - [Prevention of decubitus ulcers].
PMID- 9555460
TI - [Specified tasks in nursing].
PMID- 9555462
TI - [Three steps forward and two back].
PMID- 9555463
TI - [Legal foundations for the health care market].
PMID- 9555464
TI - [Quality assurance in operating room nursing].
PMID- 9555465
TI - [Fed, clean and quiet in the nursing home. Effects of the 2. step in nursing
insurance on geriatric care].
PMID- 9555466
TI - [The limits of bearable treatment. May life-preserving measures be abandoned in
terminal coma?].
PMID- 9555467
TI - [Health care in Finnish schools].
PMID- 9555468
TI - Covenant of caring.
PMID- 9555469
TI - Succeeding against the odds. Interview by Nancy Evans.
PMID- 9555471
TI - Research awards.
PMID- 9555470
TI - Founders awards.
PMID- 9555472
TI - Social action.
PMID- 9555473
TI - A lot of care but little credit.
PMID- 9555474
TI - [Public health: stakes in the changes in the 21st century].
PMID- 9555475
TI - [The historical path of occupational health].
PMID- 9555476
TI - [Tattooing in adolescence: using one's skin as parchment].
PMID- 9555477
TI - [Refusal or impossibility to communicate?].
PMID- 9555478
TI - [The kangaroo method: a bond in caring for prematures].
PMID- 9555479
TI - [Dr. Pierre Balde, pediatrician. The Kangaroo method. Interview by Anne-Claire
Delval-Motro].
PMID- 9555480
TI - [Professor Jean-Pierre Relier, pediatrician. The Kangaroo method. Interview by
Anne-Claire Delval-Motro].
PMID- 9555481
TI - [A kit for scabies].
PMID- 9555482
TI - [Hirschsprung's disease with all its features].
PMID- 9555483
TI - [The story of Arthur ... or a mother's experience].
PMID- 9555484
TI - [The reading lure or the book, the child and the hospital].
PMID- 9555485
TI - [From the studio to the hospital].
PMID- 9555486
TI - [A very specific nursing activity...].
PMID- 9555487
TI - [End of a taboo: migraine is a very specific disorder].
PMID- 9555488
TI - [The pluridisciplinary team: a complex requirement].
PMID- 9555489
TI - [Ethics of care].
PMID- 9555490
TI - [We like to talk a lot about health].
PMID- 9555491
TI - [Health between dream and reality].
PMID- 9555492
TI - [Cardiac insufficiency in the aged].
PMID- 9555493
TI - [Prevention of malnutrition].
PMID- 9555494
TI - [The dysharmonies of aging. A therapeutic place in a long-term facility].
PMID- 9555495
TI - [Touch in nursing care].
PMID- 9555496
TI - [Entering an institution. Anxieties of the elderly].
PMID- 9555497
TI - [Self-help groups among nursing staff].
PMID- 9555498
TI - [Wheelchair standards. How to choose one].
PMID- 9555499
TI - [The Liliane Plaa Gerontology School].
PMID- 9555500
TI - [The music therapist and the elderly].
PMID- 9555501
TI - [The specific dependency allowance].
PMID- 9555502
TI - [Sudden loss of autonomy. How to discuss the future of a patient with a
cerebrovascular accident with his family].
PMID- 9555503
TI - [The hairdresser].
PMID- 9555504
TI - [Adolescent psychiatry. 40 years already...].
PMID- 9555505
TI - [Adolescents and nursing care. Are there specific forms of care?].
PMID- 9555506
TI - [A history of the nurses at the Clinique Dupre. 40 years already...].
PMID- 9555507
TI - [Adolescent emergency and intensive care units. 10 years already...].
PMID- 9555508
TI - [The role of the psychiatric nurse in the day hospital].
PMID- 9555509
TI - [To be an actor in ones own life].
PMID- 9555510
TI - [Counseling services in high schools and colleges].
PMID- 9555511
TI - [Clinical nursing approach, beginning with daily discussions].
PMID- 9555512
TI - [Adolescence, a special age. Summary of interventions].
PMID- 9555513
TI - [Nursing care within the hospital unit].
PMID- 9555514
TI - [ Emilio has hung himself...].
PMID- 9555515
TI - [Prevention of drug dependence: how to do it].
PMID- 9555516
TI - [Experience of pregnancy, delivery, motherhood and knowledge transfer in 3
generations of mothers].
AB - The purpose of the study was to describe how three generations of mothers have
reacted to their pregnancies and deliveries and also how they feel about their
maternity. Furthermore, the purpose was to illustrate the transfer of knowledge
from one generation to another. Interviews have been made with three triads of
generations, in all nine mothers. A phenomenological-hermeneutic onset has been
chosen in order to analyse the narratives of the mothers. In the structural
analyses the following themes came to hand: positive experiences/feelings,
negative experiences/feelings, internal and external network and knowledge. The
life-experiences of the maternity of the mothers were chiefly positive while
experiences from pregnancy and childbirth were positive as well as negative. The
knowledge of the mothers regarding childbirth and the bringing up of children
were mostly conveyed in the everyday-contact during their early years, amongst
mother-daughter-granddaughter. For the feeling of a successful experience during
pregnancy, delivery and maternity, the internal network as well as the external
turned out to be of great importance. In order to even better be able to provide
for the needs of the expectant mothers or of those who have recently become
mothers, an individual planning of care of both in- and out-patients within
maternity- and childwelfare can be valuable.
PMID- 9555517
TI - A follow-up study of the learning transfer process in further training of nursing
staff.
AB - The purpose of the study was to investigate whether the human and economic
investment of resources in the further training of nursing and nursing assistants
is justified. The study focused in particular on the transfer of knowledge from
training course to working practice. It was carried out as a case study in
Ringkobing County, Denmark, during 1993/94. The population consisted of 49 nurses
and 49 nursing assistants. The study showed that the participants took a keen
interest in the courses. The learning process was found relevant by the nurses,
but not by the nursing assistants. Neither group found that their expectations of
getting more knowledge were satisfied. With respect to job-behaviour, the study
confirmed the hypothesis that the practising of the content of the course will
depend on the support and interest of the head of the department towards a goal
oriented development of competence and structure. If such support and interest is
lacking, the course-participant will only change her own working practices,
independent of the organizational structure.
PMID- 9555518
TI - [Expectations and satisfaction of patients in home care--a qualitative study].
AB - The purpose of this study was to illuminate the following questions, What do the
district nurses think about the expectations of the patients during a home-visit?
Which are the expectations of the patients concerning the home-visit done by a
district nurse? The district nurses in a primary health care-centre and the
patients that received home nursing in the primary health care district
constituted the population. Ten nurses and twenty patients participated in the
study. The method was qualitative with a hermeneutical approach. The tape
recorded interviews were transcribed verbatim to constitute the empirical
material for analysis and interpretation. The theoretical starting point was the
concept of patient satisfaction. In the analysis and interpretation the following
dimensions appeared; knowledge--professionalism, art of care--patient-district
nurse relationship, participation and responsibility, continuity and
availability. The result shows that the patients' expectations of the district
nurses were extensively met and that they were satisfied with the home nursing
care. The patients expected to meet a skilled district nurse who was kind, able
to listen and reassuring. The district nurses think that the patients expect to
meet a skilled person whose judgements are correct, who listens, shows respect
and keeps her appointments.
PMID- 9555519
TI - [The qualitative research interview as a method of approach to psychiatric
nurses' professional life-world in community health services].
AB - In the last decade the qualitative research interview, based on hermeneutic
phenomenological understanding, has become a successfully used method in the
Nordic countries, in the study of how persons experience their life-world (Ger.
Lebenswelt) in social interaction and or in relation to their professions. The
essential features of the qualitative research interview and its structural
components have been quite well developed in these countries. Various aspects of
the interpretation of interview texts have been theoretically analyzed from the
hermeneutic-phenomenological viewpoint, and also its validity, reliability and
fruitfullness have been carefully and constructively scrutinized. Necessary
conditions to stimulate the 'right' use of qualitative research interview are,
e.g., scientific articles which clearly describe how the method has been
successfully applied on, inter alia, mental health and research dealing with
public health. In this respect it is desireable to describe 1) how the choice of
different strategies and techniques within the domain of qualitative approach are
made and and illustrated, by means of concrete examples, and 2) to show how they
are systematically and effectively applied in the research process. The purpose
of this article should be seen against the background of 1) and 2), i.e., the
article purports to show how the qualitative research interview was
systematically used in studying psychiatric nurses' professional thoughts,
experiences and practices in community psychiatric nursing, a study which
attempted to do justice to the attainment of both goals 1) and 2).
PMID- 9555520
TI - [Their own science? Analysis and discussion of Ingrid Heyman's thesis "Gange hatt
till ..." nursing research comes of age in Sweden--nurses' papers 1974-1991].
PMID- 9555522
TI - [Field study of nursing care quality. Interaction and asepsis in clinical
practice].
AB - Competence as communication skills and as skilled practice of asepsis were
studied by observing four nurses while interacting with patients and performing
intravenous procedures. Nurses were observed using sterile equipment for methods
of intravenous therapy. Asepsis is performed frequently, but through
misunderstanding in the learning of asepsis or improper model learning the nurses
may establish incorrect routines. When performing procedures, unexpected factors
can distract both the expert and the inexperienced, resulting in a failure to
apply basic aseptic techniques. The nurses showed an interest in the patient by
listening and giving responses. Nurses may control interactions with the patient
by using undesirable communication skills which include incomplete sentences,
incomplete explanations and closed questions. Asked to evaluate their own
behavior, the nurses did not estimate whether or not the appropriate skills were
applied in observed situations. To improve the quality of nursing care
performance it is recommended to further develop and apply skill training
programs.
PMID- 9555521
TI - [Quality assurance in nursing in acute care using a Swedish modified version of
the Rush-Medicus instrument].
AB - The aim of the article is to describe experiences from a project on quality
assurance of nursing care in a county hospital. Assessment and improvement of the
quality of care were mainly based on an earlier developed modified Swedish
version of the Rush Medicus Nursing Process Quality Monitoring Instrument (RMI
MSV). Two hundred and forty patients and 57 registered nurses (RNs) representing
surgical, medical and orthopaedic care units participated in the study, which was
divided into two quality assessment occasions. An experiment-control design was
used with intervention to the experiment units after the first quality assessment
occasion. All the E-units improved their quality levels in almost all main areas
in the second assessment occasion. The E-units together in relation to the C
units together obtained statistically significant improvements (p < 0.05) in the
main area concerning documentation (E-units minus C-units occasion 2 minus
occasion 1). The overall experience is that the RMI-MSV can be used for quality
assurance of nursing care in a Swedish acute hospital, but needs to be further
refined.
PMID- 9555523
TI - Nurses' perceptions of the content, relevance and usefulness of the quality of
life concept in relation to nursing practice.
AB - The aim of this study was to investigate how nurses define the quality of life
concept and if they find it relevant and useful for their daily practice.
Eighteen nurses recruited from a neurological and rheumatologic unit at a
Norwegian University Hospital filled in a questionnaire consisting of four open
ended questions in relation to the definition of quality of life, the concept's
relevance for their daily practice, characteristics of a patient experiencing
good vs. bad quality of life and ways to improve quality of life. The findings
showed that nurses associated quality of life with the individual's experience of
meaning in life. Meaning in life was associated with good mood, positive self
concept, being solution-oriented, initiative to self-care and having a close
relationship to significant others. Further, the nurses expressed that their way
of being towards the patients in terms of give time, encourage, inspire
confidence, be present and listen was the most important intervention to maintain
or increase patients' quality of life.
PMID- 9555524
TI - Parents' skin to skin holding of small premature infants: differences between
fathers and mothers.
AB - AIM: Both mothers and fathers should achieve early skin to skin holding of their
small premature infants, despite the infants' need for breathing equipment,
including respirator. If the mother needs to wait to hold her newborn due to her
medical condition, this is not reason enough for the father also to wait.
PURPOSE/QUESTION: Do fathers wait significantly longer post delivery to hold
their small premature infants skin to skin (kangaroo) than mothers do? METHODS:
Registration-schedule, existing sources of data, and interviews were used.
FINDING/CONCLUSION: The time from birth (hours) until fathers held their small
premature infants skin to skin was significantly different (p = 0.0004) compared
to mothers. Fathers held their infants later than did mothers, despite the fact
that fathers saw their infants before the mothers did. Compared to the mothers
the average waiting time before fathers first held their infants skin to skin
showed a difference of 120.9% (difference of the median).
PMID- 9555525
TI - [Salutogenic model and utilization of the KASAM form (Sense of Coherence) in
nursing research--a methodological report].
AB - This paper presents psychometrical properties of the Swedish version of the Sense
of Coherence (SOC) scale. The concept sense of coherence is proposed to explain
successful coping with stressors and as being a stable trait of the individual.
The stronger the SOC, the more successful coping and the more likely one is to
have better health and quality of life. The data in this study has been obtained
from five groups of healthy individuals and eight patient groups. The scores of
the SOC scale did not change over time when studied after two, 12 and 18 months
respectively. Weaker sense coherence was correlated to more self-rated anxiety,
functional limitations especially those of a psychosocial character, and severe
perception of symptoms, and to worse self-rated general health, and less
motivation. It is suggested that the SOC scale could be of clinical use in
assessing the need for nursing care.
PMID- 9555526
TI - [Critical reflections on the uncritical use of measuring instruments: Example
Sense of Coherence questionnaire].
AB - This article presents a critical discussion of Antonovsky's salutogenic model,
focusing on its instrumentalisation in the Sense of Coherence questionnaire and
implications for health care research. The critical discussion is related to
three themes: a. The divorce between theory and method, b. The Sense of Coherence
questionnaire: a "supra-cultural instrument"? and c. Numbers, normality and the
social construction of reality. The author concludes that extreme cautiousness
and further study is necessary before the Sense of Coherence questionnaire should
be considered adequate for use in applied clinical research.
PMID- 9555528
TI - Transplantation.
PMID- 9555527
TI - [Stigmatization, coping and handicap experience: interviews with middle-aged
persons with progressive hearing impairment].
PMID- 9555529
TI - Biology and management of acquired severe aplastic anemia.
AB - Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder
characterized by pancytopenia and a hypocellular marrow. Drugs, chemical
exposure, radiation, and viruses are implicated as etiologic agents, although the
majority of community-acquired SAA is idiopathic. Regardless of the inciting
event, most cases of SAA result from immune-mediated destruction of bone marrow
progenitor cells, which spares pluripotent hematopoietic stem cells. SAA is
treated by either allogeneic bone marrow transplantation (BMT) or
immunosuppressive therapy. BMT restores normal hematopoiesis and cures the
disease in 60% to 80% cases, with the major causes of failure being graft
rejection and graft-versus-host disease. Most patients treated with
immunosuppressive therapy recover hematopoiesis sufficiently to not require
transfusions and are free of infection, although in many, recovery is incomplete.
Moreover, up to 50% of SAA patients successfully treated with immunosuppressive
therapy relapse or develop a secondary clonal disorder, such as paroxysmal
nocturnal hemoglobinuria, myelodysplastic syndrome, or leukemia. High-dose
cyclophosphamide without BMT is capable of restoring normal hematopoiesis with
little or no risk of relapse or secondary clonal disorders. A number of effective
treatment options for the treatment of SAA are now available. The optimal
approach for definitive management of SAA continues to evolve.
PMID- 9555530
TI - Bone marrow transplantation for chronic myelogenous leukemia.
AB - Chronic myelogenous leukemia (CML) is a hematologic malignancy characterized by
an initial chronic phase of expanded clonal myelopoiesis followed by inevitable
progression to accelerated phase and finally to fatal blast crisis. Although
interferon therapy results in hematologic control of disease in most patients and
major cytogenetic responses in 30% to 35%, resulting in better survival than with
conventional therapy with hydroxyurea or busulfan, most patients have residual
disease detectable by molecular methods. Allogeneic bone marrow transplantation
may cure selected patients with CML and should be considered early in the course
of disease. Newer approaches to therapy include autografting using mobilized
peripheral blood stem cells. Selection and expansion of nonleukemic progenitors
may improve outcome following autologous transplantation. Advances in
understanding of mechanisms of action of antisense oligonucleotides, ribozymes,
and tyrosine kinase inhibitors and the immunologic responses to CML cells are
also likely to lead to novel approaches to therapy.
PMID- 9555531
TI - Quality of life following bone marrow transplantation.
AB - Quality of life (QOL) studies in bone marrow transplantation (BMT) recipients are
increasingly regarded as one of the ways to evaluate the outcome of BMT. Recent
reports continue to detail acute and late psychosocial problems in BMT
recipients. More and more longitudinal studies of QOL and comparisons of QOL
outcomes after BMT or alternative nontransplant treatments are appearing in the
literature. Several interventions that may promote positive effects on
psychosocial adjustment are suggested: attention to patients' coping styles by
the healthcare team, encouragement of aerobic exercise, attempts to lessen
patients' levels of anxiety, and the presence of at least one staff member
identified by the patient as an important source of support over time--all may
have positive influences on QOL.
PMID- 9555532
TI - Peripheral blood versus bone marrow for hematopoietic cell transplantation.
AB - Peripheral blood stem cell transplantation is being used more frequently in both
the autologous and allogeneic setting. The use of cytokines either alone or in
conjunction with chemotherapy priming has made peripheral procurement of the stem
cells through apheresis possible. Differences exist both in the composition of
the graft and in subsequent posttransplantation immune reconstitution between
peripheral blood stem cells and bone marrow. Reliable estimates of the
comparative incidence of acute and chronic graft-versus-host disease following
blood or marrow allogeneic transplantation are not yet available.
PMID- 9555533
TI - Slow but real progress in the treatment of thoracic malignancies.
PMID- 9555534
TI - Prevention of lung cancer.
AB - Lung cancer chemoprevention continued to make progress in 1997. The incidence of
tobacco abuse continues to slowly fall in the United States, and paralleling it,
lung cancer incidence. Biomarkers of carcinogenesis and susceptibility continue
to be an important area in identifying high-risk patients. The analyses of two
major lung cancer prevention trials, beta-Carotene and Retinol Efficacy Trial
(CARET) and Alpha-Tocopherol Beta-Carotene (ATBC), were also published this past
year. Both found an increased incidence of lung cancer in individuals receiving
beta-carotene. In both trials, heavy smokers seem to be the most adversely
affected group. The mechanism of this increased incidence of cancer and total
deaths still eludes investigators.
PMID- 9555535
TI - Gene replacement strategies for lung cancer.
AB - Considerable evidence has accumulated that cancer has a genetic origin based on
the development of somatic mutations in families of genes responsible for
critical functions of cellular DNA repair, growth control, and division.
Restoration of the function of a single pivotal gene product appears sufficient
to mediate antitumor effects that are potentially clinically significant. For
example, restoration of wild-type p53 function in the cancer cell by gene
transfer is sufficient to cause either cell-cycle arrest or apoptosis. This
effect is not restricted to p53 but has been observed for oncogenes and other
tumor suppressor genes as well. Genes can be delivered with sufficient efficiency
by direct intratumoral injection to mediate tumor regression as shown in
preclinical studies and phase I clinical trials in non-small cell lung cancer.
Although clinical trials of gene replacement are in the earliest stages, this
treatment offers a unique mechanism of action with a potentially high therapeutic
index.
PMID- 9555536
TI - Current therapy of small cell lung cancer.
AB - This article reviews the most important recent clinical trials on the treatment
of small cell lung cancer (SCLC). Two randomized studies addressing the timing of
thoracic radiotherapy in limited stage SCLC are discussed. In the smaller of the
two studies (n = 103), a survival benefit was associated with initial versus
delayed radiotherapy. No survival differences in the larger study of the two
studies were detected, which compared alternating with sequential delivery of
radiotherapy (n = 335). The optimal way to deliver radiotherapy still must be
defined. Two small, randomized studies on dose intensity with the use of growth
factor support in patients with extensive disease reached conflicting results.
Two randomized trials including patients with poor prognosis were discontinued
prematurely, owing to interim analyses reporting a significant disadvantage in
survival associated with oral single-agent etoposide compared with intravenous
multiagent treatment. Thus, oral etoposide has a very limited role as single
agent treatment in the palliative setting. Convincing data have emerged regarding
the camptothecins. Randomized studies of both the camptothecins and the taxanes
in combination with established drugs are awaited with interest. Unfortunately,
too many studies still lack sufficient statistical power, and large randomized
studies are needed.
PMID- 9555537
TI - Enhancing the role of radiotherapy in non-small cell lung cancer.
AB - Radiation therapy plays an important role in the treatment of patients with
unresectable non-small cell lung cancer. Local control rates with past radiation
therapy techniques have been poor, in the range of 10% to 15%. Recent advances in
dose planning and delivery, as well as radiation biology, offer the promise of
improved control and better protection of dose limiting normal tissues.
PMID- 9555539
TI - Melanoma and other skin neoplasms.
PMID- 9555538
TI - Surgical management of pulmonary metastases.
AB - The management of pulmonary metastases remains controversial. More information is
available, however, on outcomes in larger series of patients undergoing
metastasectomy as well as the indications for the procedure. The role of video
assisted thoracic surgery for the diagnosis and management of these patients is
being scrutinized carefully. Isolated perfusion techniques for treating patients
with unresectable pulmonary metastases have been applied in phase I and II trials
at selected institutions. More data regarding clinical outcomes are necessary,
however, before widespread adaptation of this experimental form of treatment is
accepted as standard practice.
PMID- 9555540
TI - Modifying the criteria of the American Joint Commission on Cancer staging system
in melanoma.
AB - The currently used staging system in melanoma has not been significantly modified
since 1988. While this four-stage system effectively stratifies patients into
prognostic groups, additional discriminating criteria have been reported that is
not presently incorporated in the staging system. The following additions and
modifications are suggested based on a review of the recent literature: 1) for
stage I and II patients, Clark's level of invasion is only predictive in patients
with melanomas less than 1 mm, the best statistical fit for tumor thickness
cutoffs are less than 1 mm, 1 to 2 mm, 2 to 4 mm, and greater than 4 mm, and
ulceration should be included as part of the staging system; 2) in stage III
patients, the presently used criteria of 3 cm in size needs to abandoned and
replaced by the number of lymph nodes involved and the number of lymph node
basins involved; and 3) local recurrence presenting as local metastases and
satellite disease represent a biologic continuum of regional lymphatic
dissemination and should both be classified in the stage III prognostic groups.
These modifications, if accepted, should provide the ability to better stratify
patients for future adjuvant therapy trials.
PMID- 9555541
TI - The role of the pathologist in the diagnosis of melanoma.
AB - The pathologist plays a vital role in patients with malignant melanoma.
Dermatologists, surgeons, and oncologists must rely on the pathologist for
accurate and complete diagnoses. Although most melanomas can be easily recognized
with routine histopathology, special stains, including immunohistochemistry, may
be necessary to differentiate melanoma from other cutaneous malignancies.
Likewise, there are benign entities that can mimic melanoma microscopically,
including Spitz nevi, pigmented spindle cell nevi, deep-penetrating nevi, and
Monsel's reaction. Recognition of these entities is important to avoid
unnecessary surgery, testing, adjuvant therapy, and unnecessary concern by the
patients and their families. In addition to making an accurate diagnosis, the
pathologist should report prognostic histologic attributes that may influence
therapy and follow-up care for these patients. These histologic features should
be recorded in the pathology report. This chapter provides a brief review of the
most important histologic attributes that should be identified and reported by
the pathologist.
PMID- 9555542
TI - Use of biological response modifiers in the treatment of cutaneous T-cell
lymphoma.
AB - Cutaneous T-cell lymphoma (CTCL) is typically a skin-infiltrating, clonal
proliferative disorder of CD4+ T cells that exhibit a T-helper type 2 cytokine
phenotype. Therapeutic decisions are based on the extent of disease and the
observations that host-antitumor responses occur and that these responses may be
blunted by the immunosuppressive cytokines produced by the malignant T cells.
Biologic response modifiers, which may enhance cell-mediated immunity and
antitumor responses, are active agents in the treatment of CTCL. The rationale
and use of biologic response modifiers to treat CTCL are reviewed in this
article.
PMID- 9555543
TI - Transplantation.
PMID- 9555545
TI - Melanoma and other skin neoplasms.
PMID- 9555544
TI - Lung and mediastinum.
PMID- 9555546
TI - Urinary incontinence in elderly women.
PMID- 9555547
TI - The need for an international classification of benign prostatic hyperplasia.
AB - An international classification of patients suffering from benign prostatic
hyperplasia is essential, as we are currently unable to categorize patients there
by allowing application of the most appropriate treatment as a function of
selected items. We have adopted 4 items: weight of the prostate (P); quality of
life index (Q); international prostatic symptom score (S), and maximum flow rate
(F). 112 patients were analyzed according to this classification and the results
are presented. We have tried to develop a simple, easy to remember classification
in order to easily allocate a given patient to a particular category. This
proposed classification corresponds to a real 'Prostate Who's Who', which should
be evaluated and improved to act as a working basis for an international
classification of benign prostatic hyperplasia.
PMID- 9555548
TI - Clearance of free and total serum PSA after prostatic surgery.
AB - INTRODUCTION: Although the biology and sites of secretion of PSA are well known,
its pharmacokinetics are still unclear. This study analyzes the differences
between the clearance of total and free serum PSA following open surgery for BPH
and radical prostatectomy. METHODS: Free and total PSA were measured in 27
patients submitted to radical prostatectomy for clinically localized prostate
cancer (group I) and in 27 patients submitted to open surgery for BPH (group II).
In both groups, the clearance of free and total PSA was studied. RESULTS: Group I
the mean half-life was 1.416 +/- 0.723 days for free PSA and 2.43 +/- 0.688 days
for total PSA. After prostate removal, free PSA showed a marked increase. Group
II-the mean half-life of free PSA was 2.157 +/- 1.792 days and 3.391 +/- 2.337
days for total PSA. CONCLUSIONS: The increase in free PSA shortly after
manipulative procedures of the prostate was higher than the increase in total
PSA. Serum clearance of free PSA after eradicative prostatic surgery was related
to the indication and type of procedure used.
PMID- 9555549
TI - Effect of digital rectal examination and flexible cystoscopy on free and total
prostate-specific antigen, and the percentage of free prostate-specific antigen.
Differences between two PSA assays.
AB - OBJECTIVE: To determine the effect of prostate manipulations on free PSA, total
PSA and the percentage of free PSA using an equimolar and nonequimolar PSA
assays. METHOD: A total of 67 men were studied. Blood samples were obtained
before and 45-60 min after two different prostatic manipulations: DRE from 45
patients and flexible cystoscopy from 22 patients. Total PSA (t-PSA) was assayed
with a non equimolar method using the Cobas Core PSA kit from Roche (Cobas Core
PSA) and an equimolar method using the Immulite 3rd-generation PSA kit from DPC
(Immulite-PSA). Free PSA (f-PSA) was quantified with an Immulite free PSA kit. We
obtained two f-PSA/t-PSA ratios dividing the f-PSA by both t-PSA (Cobas Core-PSA)
and t-PSA (Immulite-PSA). RESULTS: The Cobas Core-PSA yielded higher values than
Immulite-PSA and the baseline percentages of free PSA were different depending on
the method used. Both t-PSA values were increased after DRE and flexible
cystoscopy from the baseline although the increase of Cobas Core-PSA was much
higher than Immulite-PSA. Also the f-PSA was increased after the two
manipulations. The f-PSA/t-PSA ratio (Cobas Core-PSA) remains at the baseline
whereas the f-PSA/t-PSA ratio (Immulite-PSA) had an important increase from the
baseline. CONCLUSION: The effect of DRE and flexible cystoscopy is different
depending on the PSA assay used. The data from studies which are carried out in
relation with the molecular forms of the PSA are not interchangeable if they are
performed with different PSA methods (equimolar and nonequimolar). The serum
samples should precede any prostate manipulation in all investigations related to
PSA molecular forms.
PMID- 9555550
TI - Gleason scores from prostate biopsies obtained with 18-gauge biopsy needles
poorly predict Gleason scores of radical prostatectomy specimens.
AB - OBJECTIVES: Prostate cancer is the most frequent cancer among men in the US.
Histological grading is an important part of the diagnostic evaluation aside from
clinical staging and serum PSA. The most commonly used grading system is the one
described by Gleason. From a prognostic point of view, it is of considerable
interest to know how accurate the needle biopsy Gleason score is in predicting
the final score of the radical prostatectomy specimen. From an outcome research
point of view, it is important to recognize that a stratification of patients by
Gleason score may prove correct in patients undergoing radical prostatectomy,
while in patients undergoing radiation or conservative management some of the
well-differentiated cancers could actually be moderately and poorly
differentiated, and some of the moderately differentiated might be poorly
differentiated, thus favoring radical prostatectomy in a direct comparison of
treatment efficacy. We aimed to determine (1) whether such undergrading exists,
(2) what the magnitude of the bias is, and (3) whether it is common and similar
in different institutions. MATERIALS AND METHODS: We retrospectively reviewed the
records of 415 patients who underwent radical prostatectomy in three Dallas area
hospitals, excluding patients who received neoadjuvant therapy prior to surgery.
Data of Gleason grades and score were collected from the needle biopsy and the
radical prostatectomy specimen. Analysis was done using three categorization
schemes for mild, moderate and poor differentiation for the three individual
hospitals and the entire group. RESULTS: The most common Gleason score by needle
biopsy and prostatectomy was five. 37.2% of all patients had no change in score
assignment, while 12.7% were 'overgraded' and 50.1% 'undergraded' by needle
biopsy. The most common undergrading was by 1 or 2 score points. Only 23.7% of
the category 'well' cancers remained so after surgery. Between 65.0 and 88.4% of
the category 'moderate' cancers remained so after surgery. To determine the
degree of agreement between needle biopsy and surgery category, kappa statistics
were employed. The kappa value ranged from 0.148 to 0.328 for all categories and
classification schemes indicating poor reproducibility. Serum prostate-specific
antigen was not helpful in predicting Gleason score upgrading. CONCLUSIONS:
Independent of the setting, about 50% of all Gleason score assignments made on
needle biopsy specimen are revised in the direction of a worse score/category. It
is important for clinicians to realize this phenomenon when consulting with
patients regarding treatment choices if the grade is taken into consideration.
For outcome research purposes, it is important to realize that this introduces a
bias into direct comparisons between surgical and nonsurgical (radiation and
watchful waiting) series favoring the outcomes of surgical series as the
nonsurgical series suffer from a less favorable patient mix.
PMID- 9555551
TI - Prognostic significance of seminal vesicle invasion on the radical prostatectomy
specimen. Rationale for seminal vesicle biopsies.
AB - OBJECTIVE: The prognostic significance of seminal vesicle invasion on the radical
prostatectomy specimen was evaluated according to the proximal or distal site of
this invasion. MATERIALS AND METHODS: 52 consecutive patients undergoing radical
prostatectomy for stage pT3b N0 M0 prostatic cancer were classified into two
groups: group A (18 patients): patients with invasion limited to the proximal
part of the seminal vesicles (stage T3b limited); group B (34 patients): patients
with invasion extending to the free part of the seminal vesicles (stage T3b
extensive). The PSA progression-free curves were compared between the two groups.
A multivariable regression model was performed to determine independent
prognostic factors. RESULTS: Overall, the 5-year PSA progression free rate of the
52 patients was 14.4%. The 5-year PSA progression-free rate of the patients in
group A was 45.4 vs. 4.2% at 4 years in group B (p = 0.0004). The stage of
seminal vesicle invasion and the Gleason score were the only independent
predictive factors of PSA progression (p = 0.02 and p = 0.04, respectively).
CONCLUSIONS: The prognostic significance of seminal vesicle invasion is not
constant and depends on the site of invasion. Preoperative seminal vesicles
biopsies can select patients with invasion extending to the free part of seminal
vesicles and who have a poor prognosis in terms of PSA progression after radical
prostatectomy.
PMID- 9555552
TI - Comparative analysis of MiB1 and p53 expression in human bladder tumors and their
correlation with cancer progression.
AB - Expression of p53 and MiB1, markers of tumor proliferation, was evaluated in
human bladder tumors, and correlated with ploidy and cancer progression in 83
consecutive patients. Transurethral resection of a newly diagnosed bladder tumor
was performed in 73 cases, and systematic bladder biopsies were performed in 10
cases after bacillus Calmette-Guerin (BCG) treatment. p53 and MiB1 expression
were performed by an immunohistochemical technique and the ploidy was determined
on a frozen fragment of the tumor. p53 expression was correlated in relation to
grade, stage and combination of grade and stage. MiB1 expression was correlated
with cytological grade, and a significant difference was demonstrated between pT0
and pTa, pTa, and pT1, pTa and pT2 tumors but not between pT1 and > or = pT2
tumors. A discordance was observed for the comparison of p53 and MiB1 values,
stage by stage, suggesting that these two techniques are independent of each
other. A larger proportion of aneuploid tumors were positive for p53 and MiB1
(64.8 vs. 86.5%, respectively), but p53 and MiB1 immunostaining were not better
indicators than ploidy alone to predict cancer progression.
PMID- 9555553
TI - A randomized study of short-versus long-term intravesical epirubicin instillation
for superficial bladder cancer. Nagoya University Urological Oncology Group.
AB - OBJECTIVE: A prospective randomized study was undertaken to determine whether
prophylactic maintenance instillation of epirubicin following induction treatment
is beneficial in patients with superficial bladder cancer. PATIENTS AND METHODS:
One hundred and forty-eight patients with resectable superficial bladder cancer
(Ta-1, single, multiple, primary or recurrent with, however, no recurrence during
the last year) were enrolled in this study. In both arms, epirubicin (40 mg/ml in
normal saline) was administered six times within 4 weeks after a transurethral
resection of the bladder tumor(s). In arm A, the patients received 11 additional
monthly instillations of epirubicin. RESULTS: Of the 148 patients, 138 (93.2%)
were eligible and followed for an average of 29.6 months. 93 (67.4%) had a
solitary tumor. No significant difference in the recurrence-free curve was
observed between the two arms (p = 0.62). The recurrence rate per year was 0.16
in arm A and 0.17 in arm B. Toxicity included vesical irritability in 10 (7.2%)
and hematuria in 1 patient. No significant difference in the frequency or degree
of toxicity was observed between the two arms. CONCLUSION: These data suggest
that maintenance instillation of epirubicin does not reduce superficial bladder
cancer recurrence.
PMID- 9555554
TI - Changes in erectile response to repeated audiovisual sexual stimulation.
AB - OBJECTIVES: To determine changes in erectile response to repeated audiovisual
sexual stimulation in patients with psychogenic impotence and normal men.
METHODS: The same erotic video was shown to 45 men (20 patients with psychogenic
impotence and 25 normal men) for 3 consecutive days. Their erectile responses
during the audiovisual stimulation were monitored using RigiScan (Dacomed,
Minneapolis, Minn., USA), and the maximal rigidity of erection, sustained for
more than 5 min, was measured. The rigidities on the first, second and third days
were comparatively analyzed. Whether previous multiple viewings of the erotic
movie and previous exposure to the same or a similar movie influenced the
erectile response were also evaluated. RESULTS: Rigidity on the third day was
significantly decreased compared to that on the first day in both patients with
psychogenic impotence and normal controls (p < 0.05), regardless of the frequency
of previous viewings and the previous exposure to a similar movie. Rigidity on
the first day was significantly lower in the group with multiple viewings than in
the group with fewer viewings (p < 0.05). CONCLUSIONS: Real-time monitoring of
penile erection during audiovisual sexual stimulation may result in false
negative responses when patients are repeatedly exposed to the stimulation.
PMID- 9555555
TI - The effect of re-dosing of vasodilators on the intracavernosal pressure and on
the penile rigidity.
AB - PURPOSE: To study the effect of re-dosing of vasodilators on cavernous smooth
muscle relaxation. METHODS: The intracavernosal pressure (ICP) was measured in 48
patients undergoing an intracavernosal injection test followed by gravity
cavernosometry before and after administration of 1 or 2 booster injections with
20 micrograms prostaglandin E1 after an initial injection of a trimix of
vasodilators. When submitted to Duplex scanning on another occasion, the
injection of the trimix was followed by squeeze of the corpora. The occurrence of
clinical full erection during the examinations was registered. RESULTS: The mean
values of the ICP changed little, albeit statistically significant, after the
first booster injection (+3.47 mm Hg) but not after the second one. With
cavernosometry, a false diagnosis of cavernous leakage was made in at least 14
patients. During Duplex scanning, after the corpora were squeezed, 12 patients
developed a clinical full erection, but none did during the intracavernosal
injection test, even after re-dosing. A minimal drop in blood pressure was
observed in 15 subjects after a booster injection. CONCLUSIONS: Administration of
booster injections of 20 micrograms prostaglandin E1 after an initial injection
of trimix did not induce sufficient cavernous smooth muscle relaxation. Squeezing
of the corpora after injection of trimix was more successful.
PMID- 9555556
TI - Comparative analysis of bladder neck suspension using Raz, Burch and transvaginal
Burch procedures. A 3-year randomized prospective study.
AB - PURPOSE: Ever since Pereyra described needle suspension of the bladder neck for
the treatment of stress urinary incontinence in women, numerous modifications
have been presented. There were variations in the success reported by different
authors. We report 3-year follow-up results in 146 women operated on for stress
urinary incontinence using Raz, Burch and our own new procedures. MATERIALS AND
METHODS: During a 5-year period, 146 women were operated on for genuine stress
urinary incontinence. Using the method of Raz, and transvaginal Burch as well as
the Burch retropubic urethropexy, a modified bladder neck suspension was
performed in 46 (32%), 44 (30%) and 56 (38%) patients, respectively. In all
patients a prior gynecological or urological operation for urinary incontinence
and a clear neuropathic condition had been excluded before surgery. The routine
diagnostic procedure consisted of multichannel cystometry, voiding
cystourethrography, infusion urography and cystoscopy. A pressure-flow
electromyography study was done in patients with a residual volume greater than
50 ml following voiding. The operations were performed by the same surgeon
(I.G.). Initial follow-up was done after 12 months and then every year. RESULTS:
Urodynamic testing did not reveal significant differences between Burch and Raz
(p = 0.2652), Raz and transvaginal Burch (p = 0.5745) as well as between Burch
and transvaginal Burch procedures (p = 0.7602; Fisher's exact test). Three years
after surgery, 50 of 56 (89.3%; Burch procedure), 37 of 46 (80.4%; Raz
modification) and 38 of 44 patients (86.4%; transvaginal Burch) were continent.
CONCLUSIONS: There is no reason (except patient condition) to prefer any of the
numerous modifications of bladder neck suspension. We believe that the success of
the operation lies in adequate mobilization of the bladder neck and urethra as
well as in a surgeon's familiarity with the procedure.
PMID- 9555557
TI - Laparoscopic adrenalectomy. Comparison of the transperitoneal and retroperitoneal
approach.
AB - OBJECTIVES: The efficacy of transperitoneal (TP) and retroperitoneal (RP)
laparoscopic adrenalectomy was compared. METHODS: Twenty-nine patients (male: 13;
female: 16) with benign adrenal tumor were evaluated in this study. Seventeen
were treated with the TP, and 12 with the RP approach. RESULTS: Convalescence for
the TP group took longer than that for the RP group and postoperative pain was
stronger for the TP than the RP group, although the difference was not
significant. In addition, the amount of blood loss was larger for the TP than the
RP group. When the cases were divided according to site of disease, the operating
time for the right side was 351 min for the TP group and 347 min for the RP
group, while that for the left side was 528 min for the TP group and 267 min for
the RP group. CONCLUSIONS: Therefore, we recently prefer the RP approach for left
adrenalectomy, but consider either approach suitable for the right side. The
reason for this preference is that shortening the operating time is most
important, also in the case of laparoscopic adrenalectomy because of the
resulting reduced blood loss and the patients' early convalescence.
PMID- 9555558
TI - Rotundovaginopexy in orthotopic ileal neobladder following radical cystectomy in
women.
AB - PURPOSE: The technique of rotundovaginopexy after cystectomy in females is
described. MATERIALS AND METHODS: Four cases, two of them with over 12 months of
follow-up are presented in whom this technique was used. RESULTS:
Rotundovaginopexy stabilizes the vagina and thus prevents descent of the
neobladder. Therefore the position of the neobladder is truly orthotopic. Thus
continence and micturition are optimized. CONCLUSIONS: With this technique a
truly orthotopic neobladder position can be achieved. The technique is simple to
accomplish, even if hysterectomy has been performed long before. Pouchocele with
possible complications such as secondary increased post-void residuals or
incontinence may be avoided.
PMID- 9555559
TI - Maximum efficacy of finasteride is obtained within 6 months and maintained over 6
years. Follow-up of the Scandinavian Open-Extension Study. The Scandinavian
Finasteride Study Group.
AB - OBJECTIVES: To study the long-term efficacy and safety of the drug finasteride
(Proscar) for benign prostatic hyperplasia and to evaluate whether an improved
effect beyond 1 year was due to continuous selection of 'responders'. We also
wanted to investigate whether drop-outs differed in short-term responses to those
completing the trial. METHODS: A total of 182 patients were enrolled in a double
blind randomized multicenter study with the drug finasteride. After 6 months, all
patients were treated with active drug for up to 6 years. Ninety-nine of the
patients (54.5%) were still in the trial at its closure. RESULTS: Patients
treated with active drug had a decrease in prostate size of around 27% at 6
months, a figure reached by the ex-placebo group at 12 months. At 6 years, both
groups had a reduction in prostate size of 21% as measured from baseline. At 6
months, urinary flow had improved by a mean of 2.4 ml/s in the finasteride group
and reached an improvement of 2.8 ml/s in the ex-placebo group at 12 months. At 6
years, the flow had improved by 2.2 ml/s in both groups combined as compared to
baseline data. The symptom score was improved by 3.4 points in the finasteride
group at 6 months and by 2.6 points in the ex-placebo group at 12 months; both
values were then maintained over 6 years. CONCLUSION: In responders (those
completing the 6-year trial), finasteride appeared to be a safe drug which
reduced the prostate size by 20-25% within 6 months, with a simultaneous 30%
improvement of objective and subjective symptoms and a 2.2 ml/s improvement in
urinary flow rate. The improvements were maintained for at least 6 years;
however, further improvement beyond 6 months of therapy was not likely to occur.
PMID- 9555560
TI - Vasal reanastomosis using fibrin glue combined with sutures: which combination of
sutures in a delayed protocol? Experimental study in rats.
AB - OBJECTIVES: The actual number of transmural sutures needed to ensure a successful
fibrin-glued vasovasostomy is a key study parameter of the few experimental works
already published. The present work was done to evaluate fibrin-glued
vasovasostomy in rats in combination with only 2 transmural sutures. We compared
the results to our previous study in which we demonstrated the efficiency of a
combination of the use of fibrin glue with 3 sutures in comparison with a
conventional microsurgical technique. MATERIALS AND METHODS: Twenty Sprague
Dawley rats underwent bilateral vasectomy followed 2 weeks later by bilateral
vasovasostomy using fibrin glue combined with 2 transmural sutures. Each animal
was sacrificed 7 weeks postoperatively after a 3-week mating period with a
Sprague-Dawley female rat, the vasal specimens were evaluated for sperm granuloma
formation. Mean operative time and fertility rates were recorded. RESULTS: The
combination of fibrin glue with 2 transmural sutures gave evidence of less
successful performances than the combination with 3 transmural sutures and the
conventional microsurgical technique for all parameters evaluated but the mean
operative time. CONCLUSION: Our study underlines the need for a third transmural
suture placed 120 degrees apart from the others when performing a fibrin glue
delayed vasovasostomy. This allows a better vas lumen opening at the anastomotic
site and therefore a more efficient vasal anastomosis in a delayed protocol.
PMID- 9555561
TI - Repeated urine analysis in patients with calcium stone disease.
AB - OBJECTIVE: To study the variability in urine composition with respect to factors
of importance for the calcium salt crystallization process and to test the
reliability of using one or several urine samples in the clinical evaluation.
PATIENTS AND METHODS: Twelve patients collected 16-hour daytime and 8-hour night
urine samples during 4 days of the same week. The urine was analysed for calcium,
oxalate, phosphate, magnesium, citrate and pH, and the ion activity products of
CaOx [AP(CaOx) index] and CaP were calculated. The risk of CaOx crystallization,
as well as the inhibition of CaOx crystal growth and aggregation, were assessed.
RESULTS: There was a good correlation between estimates of the AP(CaOx) index in
the different samples, as well as between the AP(CaOx) index and the direct
assessment of the risk of CaOx crystallization in the night and daytime urine
samples. There was, however, a pronounced intra-individual variation of all
variables and parameters. With the assumption that an abnormality would appear in
at least one of the four samples, we found that in more than 80% of the cases,
two 24-hour (16 + 8 h) urine samples were sufficient to establish whether the
patient had a normal or an abnormal urine composition. CONCLUSION: Urine samples
collected during two 24-, 16- or 8-hour periods appear to be useful for detecting
biochemical abnormalities considered of importance for CaOx stone formation.
PMID- 9555562
TI - Results of extracorporeal shock wave lithotripsy in the pediatric age group.
AB - OBJECTIVE: In this study we aimed to show the efficacy of extracorporeal shock
wave lithotripsy (ESWL) for urinary stone disease in the pediatric age group and
to evaluate the complications encountered after the treatment. METHODS: 67
children with 109 stones underwent ESWL, using a Dornier MPL 9000 lithotriptor.
Styrofoam boards were used to protect the lungs. KUB and chest radiographs were
taken on the day after treatment. If stone-free status was achieved, the patient
was followed with ultrasonography and urine analysis every 6 months for 2 years.
If fragments < 4 mm were present, follow-up was repeated every 3 months. RESULTS:
Stone size ranged from 0.5 to 3.5 cm. 71 renoureteral units underwent a total of
129 ESWL sessions. Retreatment was required in 28 patients. The mean number of
sessions per unit was 1.8. A stone-free status was achieved in 60 renoureteral
units. The overall success rate was 88.6%. The composition of the stone was mixed
calcium oxalate and phosphate in the majority of the patients. Auxiliary
procedures used were push-back, ureteroscopic stone removal, and open surgery.
Hematuria, colics and fever over 38 degrees C were the complications encountered
after the treatment. CONCLUSIONS: ESWL is the first-line treatment for renal and
upper ureteral calculi. However, larger stones which will require several ESWL
sessions and consecutively increased number of shock waves are best treated with
percutaneous nephrolithotomy plus ESWL. Patients with congenital anomalies
necessitating surgical reconstruction are the best candidates for operation.
PMID- 9555563
TI - Posttraumatic high-flow priapism in a 10-year-old boy: superselective
embolization of the arteriovenous fistula.
AB - We report on a 10-year-old boy who presented with painless priapism 11 days after
blunt perineal trauma. Examination by color flow Doppler sonography demonstrated
an arteriovenous fistula, which was confirmed by penile arteriography. Complete
detumescence of the penis developed following superselective embolization with
Ethibloc.
PMID- 9555564
TI - Effect of the lipidosterolic extract of Serenoa repens (Permixon) and its major
components on basic fibroblast growth factor-induced proliferation of cultures of
human prostate biopsies.
AB - OBJECTIVE: To assess the effect of the lipidosterolic extract of Serenoa repens
(LSESr) on in vitro cell proliferation in biopsies of human prostate MATERIAL AND
METHODS: Cell proliferation was assessed by incorporation of [3H]thymidine
followed by historadiography. RESULTS: Basic fibroblast growth factor (b-FGF)
induced a considerable increase in human prostate cell proliferation (from +100
to +250%); the glandular epithelium was mainly affected, minimal labeling being
recorded in the other regions of the prostate. Similar results were observed with
epidermal growth factor (EGF), although the increase in cell proliferation was
not recorded in some cases. Lovastatin, an inhibitor of hydroxymethylglutaryl
coenzyme A, antagonized both the basal proliferation and the growth factor
stimulated proliferation of human prostate epithelium (EGF, mean inhibition
approximately 80-95%; b-FGF, mean inhibition approximately 40-90%). Geraniol, a
precursor of both farnesyl pyrophosphate and geranylgeranyl pyrophosphate, and
farnesol, the precursor of farnesyl pyrophosphate, increased cell proliferation
only in some prostate specimens, this effect being antagonized by lovastatin.
LSESr did not affect basal prostate cell proliferation, with the exception of two
prostate specimens in which a significant inhibition of basal proliferation was
observed with the highest concentration of LSESr (30 micrograms/ ml). In
contrast, LSESr inhibited b-FGF-induced proliferation of human prostate cell
cultures; this effect was significant for the highest concentration of LSESr (30
micrograms/ml). In some prostate samples, a similar inhibition was also noted
with lower concentrations. Unsaturated fatty acids (UFA), in the range 1-30
ng/ml), did not affect the basal prostate cell proliferation, only a slight
increase in cell proliferation was noted in 1 prostate specimen. UFA (1, 10 or 30
micrograms/ml) markedly inhibited the b-FGF-induced cell proliferation down to
the basal value. Lupenone, hexacosanol and the unsaponified fraction of LSESr
markedly inhibited the b-FGF-induced cell proliferation, whereas a minimal effect
on basal cell proliferation was noted. CONCLUSIONS: Despite the large variability
in the response of the prostate samples to b-FGF, these results indicate that
LSESr and its components affect the proliferative response of prostate cells to b
FGF more than their basal proliferation.
PMID- 9555565
TI - Urinary N-acetyl-beta-N-glucosaminidase in patients with urinary tract infection.
AB - N-acetyl-beta-glucosaminidase (NAG, EC 3.2.1.30) is a lysosomal enzyme present in
the proximal convoluted tubule. Increased urinary excretion of NAG has been shown
in urinary tract infections. Our results have confirmed that urinary excretion of
NAG is significantly higher (33.70 +/- 8.75 U/g Cr) in patients with upper
urinary tract infection than in patients with lower urinary tract infection
(14.10 +/- 6.80 U/g Cr) and healthy adults.
PMID- 9555566
TI - Numerical cognition: age-related differences in the speed of executing
biologically primary and biologically secondary processes.
AB - Groups of younger and older adults were administered numerical and arithmetical
tasks that varied in the extent to which they assess evolved versus culturally
specific forms of cognition, termed biologically primary and biologically
secondary abilities, respectively. Componential analyses of solution times
suggested that younger adults are faster than older adults in the execution of
biologically primary processes. For biologically secondary competencies, a
pattern of no age-related differences or an advantage for older adults in speed
of processing was found. The results are consistent with the view that there has
been a cross-generational decline in arithmetical competencies in the United
States and are discussed in terms of models of age-related change in cognitive
performance.
PMID- 9555567
TI - Impact of knowledge and age on tip-of-the-tongue rates.
AB - Older (50-82), middle age (30-49), and younger (17-29) adults were asked to
answer 57 general knowledge questions about words, objects, and people that were
used to generate tip-of-the-tongue (TOT) experiences; none required a proper name
answer. Middle age and older participants correctly answered more of the general
knowledge questions and received higher scores on a vocabulary test than the
younger participants. An analysis of variance of the number of positive TOTs
indicated a significant main effect of age; older adults experienced more TOTs
than younger and middle aged adults, but an analysis of covariance conducted to
statistically control for the level of knowledge showed no significant
differences between the age groups. Level of knowledge, and not age, contributed
to the amount of TOTs experienced; those people with higher levels of knowledge
experienced more TOTs. The implications of these results for the transmission
deficit hypothesis are discussed.
PMID- 9555568
TI - Aging and rapid aiming arm movement control.
AB - The authors explored the motor control of target-oriented arm movements across 3
age groups: 20 20- to 30-year-olds, 2 groups (n = 38) of older adults (54 to 64,
and 65 to 80). Each individual completed 2 arm movement tasks that had the same
movement difficulty but different movement directions. A mixed design was used to
examine the differences among age groups and movement directions in reaction time
(RT), variability in RT, movement time (MT), timing variability, and inter
segment-interval (ISI). Comparing to the young participants, the senior adults
initiated movement tasks slower (RT) and with more RT variability, and executed
the arm movements slower and less consistently. The two older groups had greater
timing variability in their movements, showed more delays (longer ISI) when
reversing arm movement direction, and had lower correlations among segments of
the movements than the younger group. The quality of the elderly's control of
rapid aiming arm movements showed a regression, which suggests a lack of movement
planning, resulting in greater use of visual feedback during movement execution.
PMID- 9555569
TI - Serum cholesterol levels as a measure of frailty in elderly patients.
AB - The authors evaluated the association between serum cholesterol levels and
social, clinical, and functional characteristics in 637 elderly hospitalized
patients (mean age = 79.1 years, range = 65-97) from the Geriatric Evaluation and
Rehabilitation Unit (GERU) at P. Richiedei Hospital in Gussago, Brescia (Italy).
Patients consecutively admitted to the GERU during an 18-month period underwent a
multidimensional evaluation including information on demographics, cognitive
status, physical health (number of chronic diseases and administered drugs),
functional disability, and nutritional status. Mean cholesterol levels were
significantly lower in men; persons living with others; older individuals; and
individuals with cognitive impairment, poorer somatic health, higher disability,
and a higher level of malnutrition. Lower serum cholesterol levels may be
considered an independent hematologic marker of frailty in elderly hospitalized
patients.
PMID- 9555570
TI - Aging and scanning of imagined and perceived visual images.
AB - The authors examined adult age differences in the proficiency of visually
scanning across perceived and imagined displays. Participants were asked to
indicate whether an arrow in the central region of a square grid ring pointed to
a target square. The distance between arrow and target was varied, and all
participants showed the expected increase in response times and error rates as
scanning distance increased. The arrow and grid display either remained visible
until the participant responded (perceptual condition) or disappeared after 50 ms
(imagery condition). In both conditions, older participants required more time to
scan and made more errors as distance increased than did younger participants.
These findings conflict with previous studies showing that perceptual and imagery
scanning are preserved with aging. Although methodological factors may have
contributed to these differences, further research is needed to elucidate effects
of aging on visual scanning.
PMID- 9555571
TI - Memory for activities for young, young-old, and old adults.
AB - Adult age differences in memory for activities have frequently been reported.
However, the age range of the older sample has varied from as young as 56 to as
old as 89. The present memory for activities study distinguished between the
performance of young-old adults (60 to 70) and old adults (71 to 82) in
comparison to young adults (18 to 34). Nineteen tasks were administered over a 2
day period, and individuals were asked to recall them immediately or after a 24-h
delay. Young-old adults' memory for activities was comparable to the young
adults' for both immediate and delayed recall. Both the young and the young-old
groups outperformed the old adults. The results suggest that researchers must
consider the age of the individuals in the "old" group before drawing conclusions
about adult age differences in memory for activities.
PMID- 9555572
TI - Radiological and functional assessment of radiation-induced lung injury in the
rat.
AB - The purpose of this study is to develop an experimental model to measure
localized radiation-induced lung injury using multiple end-points including
breathing frequency, high-resolution computed tomography (CT), and radionuclide
perfusion. The rats were anesthetized and the right lung irradiated with a single
dose of 18 Gy using 200-kVp x-rays. The lung function of the animals was measured
every 2 weeks after irradiation with the breathing rate assay. CT scanning and
radionuclide lung perfusion assay were performed prior to and 2, 4, 10, 16, and
34 weeks after irradiation. Significant elevation in breathing rate occurred
after 16 weeks, with a maximal increase between 22 and 28 weeks. An increase in
the right lung density started 4 weeks after irradiation. Regional measurements
indicated a relatively uniform increase in density at 4 and 10 weeks, while foci
of high-density areas were observed at the later time points. Changes in rat lung
volume indicated shrinkage of the irradiated right lung and accompanying
compensatory hypertrophy of the shielded left lung. Radionuclide perfusion assay
showed significant decrease in relative blood flow in the irradiated right lung 4
weeks after hemithoracic irradiation. Changes in breathing rate provide an index
of overall lung function while changes in lung density, volume, and perfusion are
of particular importance for evaluating loco-regional differences in lung
sensitivity. This study is the first demonstration that CT can be used to measure
volume changes after thoracic irradiation in rats.
PMID- 9555573
TI - Effect of adrenergic stimulation on clearance from small ciliated airways in
healthy subjects.
AB - Mucociliary transport is an important clearance mechanism of larger airways, but
in the smallest ciliated airways (bronchioles) it may be less effective. The
present study aimed at investigating whether clearance from the bronchioles in
subjects with healthy airways was stimulated by an adrenergic agonist
(terbutaline sulphate). Tracheobronchial clearance was studied twice in 10
healthy subjects after inhalation of 6-micron (aerodynamic diameter) monodisperse
Teflon particles labeled with 111In. At one exposure, oral treatment with
terbutaline sulphate, known to stimulate clearance in large airways, began
immediately after inhalation of the particles. The other exposure was a control
measurement. The particles were inhaled at an extremely slow flow, 0.05 L/s,
which gave deposition mainly in the small ciliated airways (bronchioles). Lung
retention was measured at 0, 24, 48, and 72 h. Clearance was significant every 24
h for both exposures (p < .05, two-tailed paired t-test), with similar fractions
of retained particles at all time points. During treatment with terbutaline
sulphate, the subjects' pulse rates tended to be higher, but clearance rates did
not increase. We found, as expected, no significant correlation between lung
retention and lung function in either exposure. This study shows that an
adrenergic agonist does not significantly influence overall clearance from the
bronchiolar region in healthy subjects. This suggests that mucociliary transport
does not significantly contribute to clearance from the smallest ciliated
airways. Other mechanisms may be more important for the transportation of mucus
from these airways.
PMID- 9555574
TI - Regional deposition of inhaled Evans blue dye in mechanically ventilated rabbits
with air or helium oxygen mixture.
AB - An animal model has been used and further developed to examine and evaluate
differences in regional deposition patterns of an Evans Blue dye (EB) tracer
aerosol. This was done by using different carrier gas composition of either He-O2
(80% helium, 20% oxygen) or air (79% nitrogen, 21% oxygen) in histamine-provoked
and nonprovoked rabbits. The ratio of peripheral deposition to total deposition
(central + peripheral), in relation to percentage increase in intratracheal
pressure (ITP delta %), was used as an evaluation tool. The animals were
tracheostomized, cannulated, and ventilated in a volume-controlled mode until
they were stable. Saline or histamine was then administrated for 2 min before the
tracer aerosol EB was given. The percentage increase in intratracheal pressure
before and after provocation was calculated (ITP delta %) and was, on average, 51
+/- 20% for air and 51 +/- 20% for He-O2. EB was extracted from lung tissues and
measured with a spectrophotometer. The absorbance in different lung regions was
used as a measure of the distribution of aerosol. Bronchial provocation gave a
central deposition 0.55 +/- 0.11 (mean +/- SD, ratio = peripheral
deposition/central + peripheral deposition) compared to 0.80 +/- 0.09 in the
control group. He-O2-ventilated rabbits showed significantly higher peripheral
deposition ratio (0.67 +/- 0.12) compared with air-ventilated rabbits (0.55 +/-
0.11). The latter finding may be due to the difference in the degree of turbulent
flow. There were significant correlations between intratracheal peak pressure and
peripheral deposition, r = -.60 and r = -.71 for air and He-O2, respectively.
This study demonstrates the possibility of using a rabbit model and different
carrier gases for evaluation of effects of bronchial provocation.
PMID- 9555575
TI - Modulation of rat lung Na+,K(+)-ATPase gene expression by hyperoxia.
AB - Rats exposed to 85% O2 for 5-7 days develop tolerance to otherwise lethal
hyperoxia (100% O2). The rate of alveolar fluid clearance increases during
adaptation to hyperoxia, due in part to increased alveolar epithelial sodium
channel activity. In these studies, we have investigated molecular mechanisms
leading to increased lung Na+,K(+)-ATPase activity in hyperoxia. We exposed adult
rats to 85% O2 (sublethal hyperoxia) for 7 days, followed by 2, 3, or 4 days in
100% O2. Steady-state levels of the Na+,K(+)-ATPase alpha 1 and beta 1 subunit
mRNAs increased in whole lung tissue during hyperoxia exposures. Stability of the
Na+,K(+)-ATPase alpha 1 and beta 1 subunit mRNA messages in whole lung RNA did
not change significantly. Thus, lung Na+,K(+)-ATPase gene expression in sublethal
hyperoxia appears to be regulated in part at the transcriptional level. Alveolar
epithelial type II (ATII) cell Na+,K(+)-ATPase alpha 1 and beta 1 subunit
proteins, measured by quantitative immunofluorescence, increased significantly
after sublethal hyperoxia and 100% O2 exposures. Increases in lung fluid
clearance after sublethal hyperoxia are associated with increased ATII cell
Na+,K(+)-ATPase protein and whole lung Na+,K(+)-ATPase mRNA expression, which
correspond to previously described increases in epithelial sodium channel
expression under these conditions.
PMID- 9555576
TI - Inflammatory and epithelial responses in mouse strains that differ in sensitivity
to hyperoxic injury.
AB - The pulmonary response to various toxicants including bleomycin, ozone, ionizing
radiation, and hyperoxia is highly variable among mouse strains. The current
study tests the hypothesis that at a similar stage of injury, regardless of
strain, expression of inflammatory cytokine and epithelial marker genes would be
similar, indicating a common pathway of injury progression. Three strains of
mice, C57B1/6J, 129/J, and C3H/HeJ, ranging from sensitive to resistant, were
exposed to > 95% O2 for varying times. Ribonuclease protection was used to
quantify changes in cytokine mRNA. Despite differences in the kinetics, each
strain demonstrated similar hyperoxia-induced changes in the abundance of
interleukin (IL)-6, IL-1 beta, IL-3, and tumor neucrosis factor (TNF)-alpha. For
each strain, death was accompanied by similar increases in cytokine mRNAs above
steady-state control levels. Other inflammatory cytokines, including IL-1 alpha,
IL-4, and interferon (IFN)-gamma, were unaltered in all strains at all times. In
situ hybridization analysis of the epithelial markers, surfactant protein B
(SPB), and clara cell secretory protein (CCSP) at the time of proinflammatory
induction showed a similar pattern of expression in all strains. Increased SPB
was detected in bronchiolar epithelium, while the number of type II cells
expressing this message declined. Both the number of cells expressing CCSP as
well as abundance per cell declined. These results suggest that although
differences in acute sensitivity to hyperoxia exist between mouse strains, once
initiated, acute epithelial cell injury and associated inflammatory changes
follow the same pattern in all strains.
PMID- 9555577
TI - Expression of the insulin-like growth factor system in postpneumonectomy lung
growth.
AB - The insulin-like growth factors (IGF-I and IGF-II) may play an important role in
postpneumonectomy compensatory lung growth by translating hormonal inputs and
mechanical forces into cellular proliferation signals. We examined the mRNA
abundance of IGF-I, IGF-II, and IGF binding proteins (IGFBPs) in lungs of rats on
postoperative days 1, 2, 3, 5, and 7 following left pneumonectomy (PNX) or
shamoperation (SC) and in normal animals (CON). There was no difference in the
abundance of lung IGF-I mRNA (measured by Northern analysis) or serum IGF-I
(measured by radioimmunoassay (RIA)) between SC and PNX animals. IGF-II mRNA
abundance was initially decreased following PNX (73% decrease compared to SC
animals on day 1, p < .05) and then rose to approach SC group values on
subsequent days. Transcripts for IGFBP-2, -3, -4, -5, and -6 were decreased in
both the SC and PNX groups compared to CON animals on the day following
pneumonectomy, then rose back to baseline by postoperative day 2-3. Tissue
IGFBPs, measured by ligand blot analyses, were not different in either the SC or
PNX groups. In contrast, all serum IGFBP bands were increased on postoperative
day 1 following either sham or PNX surgery. In addition, serum IGFBP-4 was
increased in PNX animals compared to the SC group on days 1 and 2 (increase of
38% and 78%, respectively, p < .05). We conclude that the changes observed in
lung IGF and IGFBP expression following pneumonectomy do not represent major.
PMID- 9555578
TI - Depletion of iron and ascorbate in rodents diminishes lung injury after silica.
AB - Exposures of the lung to iron chelates can be associated with an injury. The
catalysis of oxygen-based free radicals is postulated to participate in this
injury. Such oxidant generation by mineral oxide particles can be dependent on
availability of both iron and a reductant. We tested the study hypothesis that
lung injury after silica is associated with the availability of both iron and
ascorbate in the host by depleting this metal and reductant in the lungs of rats
and guinea pigs, respectively. Rats were fed either a normal diet or a diet
deficient of iron. After 30 days, animals were instilled with either saline or
1.0 mg Minusil-5 silica. Relative to saline, silica significantly increased
neutrophils and lavage protein. Iron depletion significantly diminished both the
cellular influx and injury but only at 1 week after silica exposure. Guinea pigs
were provided either a normal diet supplemented with 1,000 ppm vitamin C or a
diet deficient in ascorbate. After 14 days, the guinea pigs were instilled with
either saline or 1.0 mg silica. Silica exposure significantly increased
neutrophils and lavage protein. Ascorbate depletion significantly diminished the
influx of inflammatory cells and injury at both 1 day and 1 week after silica
exposure. We conclude that host concentrations of both iron and ascorbate can
affect lung injury after silica exposure.
PMID- 9555580
TI - Strong variable clinical presentation in 3 patients with 7q terminal deletion.
AB - We report 3 patients with a 7q terminal deletion. The first, a 7 weeks old
female, with a de novo 7q36-->qter deletion, was microcephalic and had a partial
hypoplasia of the corpus callosum on the MRI-scan of the brain. The second, a 3
months old male, showed microcephaly, disproportionate growth retardation,
truncal obesity and facial dysmorfism giving the clinical impression of a
"microcephalic primordial dwarfism (osteodysplastic type)". At the age of 6
months he had developed a single maxillary central incisor suggesting a minimal
form of holoprosencephaly (HPE). Additional FISH-studies showed a 7q36.1-->qter
deletion, as the unbalanced product of a t(5;7)(q35.2;q36.1)pat. The de novo 7q36
->qter deletion in the third patient, a 5 years old female, was associated with
borderline intelligence, mild microcephaly, small midface, choanal narrowing and
a single maxillary central incisor as a minimal form of HPE. CT- and MRI-scan of
the brain were normal. In these 3 patients extensive FISH analysis was performed
to investigate the possible involvement of the HPE gene region on chromosome
7q36. The target gene for HPE, the Sonic hedgehog gene (SHH) as well as several
other genes important for normal brain development (En2;HOX1,HTR5A) were found to
be deleted in all three patients. Our findings stress the importance of 7q36
microdeletion studies in patients with even minimal signs of HPE, as relative
microcephaly with small midface (choanal narrowing), agenesis/hypoplasia of the
corpus callosum/septum pellucidum, thalamic fusion or a single maxillary central
incisor.
PMID- 9555581
TI - Neonatal death in Marshall-Smith syndrome.
AB - Marshall-Smith syndrome is characterized by accelerated skeletal maturation,
failure to thrive and dysmorphic features. Since 1971, twenty cases of MSS have
been reported. We describe another patient with a very early death demonstrating
the clinical variability of the syndrome and the importance of systematic X rays
of the skeleton for determining the causes of fetal or neonatal death.
PMID- 9555582
TI - Congenital camptodactyly associated with the 48,XXYY syndrome.
AB - A male premature infant presented with slow development and congenital
camptodactyly of both hands. Chromosome analysis showed a 48,XXYY karyotype. As
far as we know, this is the first report describing congenital camptodactyly
associated with the 48,XXYY syndrome.
PMID- 9555583
TI - Symbrachydactyly involving hands and feet.
AB - Two patients are described with a symbrachydactyly of the hand and foot. This is
a rare combination which cannot be explained by the subclavian artery supply
disruption sequence.
PMID- 9555584
TI - Oligodontia, microcephaly and facial dysmorphia syndrome.
AB - Congenital absence of third molars is common. However absence of the other
permanent teeth is relatively rare. Absence of teeth may be isolated or
associated to other features. We had the opportunity to examine a girl with
oligodontia associated to microcephaly, to facial dysmorphia and to short
stature.
PMID- 9555585
TI - Lymphedema combined with brachydactyly and tachycardia.
AB - Hereditary lymphedema can appear at birth or later up to adulthood. It may be
seen in connection with diverse symptoms forming various syndromes. The authors
report a family with hereditary lymphedema, brachydactyly, syndactyly and
tachycardia. Lymphedema and tachycardia could appear together by chance. However
this combination could also be a syndrome.
PMID- 9555586
TI - Oral-facial-digital syndrome type IV (Mohr-Majewski syndrome): a fetopathological
study.
AB - We present a 22-week male fetus with cleft lip and palate, lobulated tongue,
talipes equinovarus, and polysyndactyly. In addition there was skeletal dysplasia
with micromelia and short ribs. Autopsy revealed a cardiac anomaly
(perimembranous VSD), very incomplete lobation of the lungs, mild congenital
hepatic fibrosis, and segmental renal cystic dysplasia. Brain anomalies included
internal hydrocephalus, olfactory aplasia, and agenesis of the corpus callosum.
This constellation of multiple congenital anomalies is consistent with the oral
facial-digital syndrome (OFDS) type IV. OFDS type IV may be a heterogeneous
condition. Our pathological findings confirm that at least some of these cases a
transitional phenotype between OFDS type II (Mohr syndrome) and short rib
polydactyly syndrome type II (Majewski syndrome).
PMID- 9555587
TI - Diaphragmatic hernia in the Coffin-Siris syndrome.
AB - At 32 weeks of gestation, delivery of a female fetus was induced because of
severe malformations seen on ultrasonogram: congenital diaphragmatic hernia and
cerebellar hypoplasia. The diagnosis of Coffin-Siris syndrome was based on the
physical examination: coarse face with low-set ears, low nuchal hairline, scalp
hypotrichosis and hypoplasia of the nails of fingers and toes with absence of the
right fifth fingernail. Autopsy confirmed the prenatally diagnosed major
associated abnormalities: hypoplasia of the cerebellum and congenital
diaphragmatic hernia. Various clinical entities are included in the differential
diagnosis.
PMID- 9555588
TI - Distinct familial syndrome of severe to profound mental retardation, spastic
paraplegia with contrasting axial hypotonia, short stature and distinct
craniofacial appearance with nasal hypoplasia.
PMID- 9555589
TI - Brachydactyly and fragile site at 16q22: a chance association.
PMID- 9555590
TI - Hypoplastic claviculae in the Kabuki (Niikawa-Kuroki) syndrome.
PMID- 9555591
TI - Trisomy 21 in a second trimester male hydropic fetus with "Noonan-syndrome
phenotype": nuchal and thoracic lymphangiomatosis, oedema of the dorsum of hands
and feet, and bicuspid pulmonary valve.
PMID- 9555592
TI - A lethal, unclassifiable form of micromelic dwarfism with posterior cleft palate,
multiple cervicothoracal vertebral anomalies and iliac hypoplasia: evidence for
autosomal recessive inheritance.
PMID- 9555593
TI - Preaxial polydactyly in the 4p- syndrome.
PMID- 9555594
TI - Clozapine and fluvoxamine, a curious complexity.
PMID- 9555595
TI - Therapeutic equivalence of risperidone given once daily and twice daily in
patients with schizophrenia. The Risperidone Study Group.
AB - A study was conducted to determine whether once-daily administration of
risperidone was as effective and safe as twice-daily administration. In a double
blind 6-week trial, 211 patients with acute exacerbation according to DSM-III-R
criteria were randomly assigned to receive risperidone at 8 mg once daily or 4 mg
twice daily. The primary efficacy measure was the treatment response rate,
defined as a 20% or greater reduction in total Positive and Negative Syndrome
Scale (PANSS) scores. Severity of extrapyramidal symptoms was assessed by the
Extrapyramidal Symptom Rating Scale. The percentage of patients who showed a
treatment response at endpoint was not significantly different between groups
(76%, once-daily; 72%, twice-daily), nor was the median time to first treatment
response (14 days, both groups). Significant reductions in PANSS total and
subscale scores and PANSS-derived Brief Psychiatric Rating Scale were observed in
both groups, with no significant between-group differences. Extrapyramidal
Symptom Rating Scale scores did not differ significantly between groups. There
were no clinically relevant changes in vital signs, electrocardiograms, or
clinical laboratory test results in either group. Gradual dosage titration over
the first 3 days of treatment was well-tolerated in both groups. The median
trough plasma concentrations of risperidone, 9-hydroxyrisperidone, and
risperidone plus 9-hydroxyrisperidone were significantly lower with once-daily
than with twice-daily administration; median plasma concentrations measured
within the first 8 hours after administration tended to be higher with once-daily
administration. These differences did not affect the safety and efficacy of
risperidone. Risperidone given once daily at 8 mg is as effective as twice-daily
administration of 4 mg in the treatment of acute exacerbations of schizophrenia.
Both regimens were equally well-tolerated.
PMID- 9555597
TI - A controlled trial of ondansetron, a 5-HT3 antagonist, in benzodiazepine
discontinuation.
AB - Serotonin is implicated in the etiology of anxiety disorders and in the
anxiolytic actions of benzodiazepines. Preclinical studies with 5-HT3 receptor
antagonists, including ondansetron, show they have anxiolytic properties and that
ondansetron suppresses withdrawal anxiety after abrupt discontinuation of chronic
benzodiazepine treatment. We evaluated the efficacy of ondansetron as an
adjunctive medication in the discontinuation of benzodiazepines in long-term
users. One hundred eight patients who had used alprazolam or lorazepam regularly
for > 3 months entered, and 97 completed a randomized double-blind
discontinuation treatment program during which they received either ondansetron 2
mg twice daily or placebo and flexibly tapered their benzodiazepine over a 6-week
period. There were no significant differences between the patients who had
entered and completed treatment. Three weeks postmedication, 63% of the patients
discontinued use of benzodiazepine. The percentage of reduction of benzodiazepine
daily dosage at all time points in the treatment trial was similar for the
ondansetron and placebo groups. Ondansetron had no significant effects on
severity of withdrawal symptoms or levels of anxiety. High placebo response may
have prevented detection of an ondansetron effect. At 1 year follow-up, 68% of
patients reported that they stopped using benzodiazepine. Patient characteristics
were more important than ondansetron in tapered benzodiazepine discontinuation.
PMID- 9555596
TI - Risperidone versus haloperidol and amitriptyline in the treatment of patients
with a combined psychotic and depressive syndrome.
AB - In a multicenter, double-blind, parallel group trial, the efficacy of risperidone
(RIS) was compared with a combination of haloperidol and amitriptyline (HAL/AMI)
over 6 weeks in patients with coexisting psychotic and depressive symptoms with
either a schizoaffective disorder, depressive type, a major depression with
psychotic features, or a nonresidual schizophrenia with major depressive symptoms
according to DSM-III-R criteria. A total of 123 patients (62 RIS; 61 HAL/AMI)
were included; the mean daily dosage at endpoint was 6.9 mg RIS versus 9 mg HAL
combined with 180 mg AMI. Efficacy results for those 98 patients (47 RIS; 51
HAL/AMI) who completed at least 3 weeks of double-blind treatment revealed in
both treatment groups large reductions in the Positive and Negative Syndrome
Scale-derived Brief Psychiatric Rating Scale (RIS 37%; HAL/AMI 51%) and the Bech
Rafaelsen Melancholia Scale total scores (RIS 51%; HAL/AMI 70%). The reductions
in the Brief Psychiatric Rating Scale and the Bech-Rafaelsen Melancholia Scale
scores in the total group were significantly larger in the HAL/AMI group than in
the RIS group (p < 0.01), mostly because of significant differences in the
subgroup of patients suffering from depression with psychotic features, whereas
treatment differences in the other diagnostic subgroups were not significant. The
incidence of extrapyramidal side effects as assessed by the Extrapyramidal
Symptom Rating Scale was slightly higher under RIS (37%) than under HAL/AMI
(31%). Adverse events were reported by 66% of RIS and 75% of HAL/AMI patients.
The results of this trial suggest that the therapeutic effect of HAL/AMI is
superior to RIS in the total group of patients with combined psychotic and
depressive symptoms. However, subgroup differences have to be considered.
PMID- 9555598
TI - Imipramine in the treatment of social phobia.
AB - We report the results of an 8-week open trial of imipramine in 15 patients with
social phobia. Nine patients completed the trial; six dropped out early because
of adverse effects. The mean reduction in the Liebowitz Social Anxiety Scale was
15% and 18% for the intent-to-treat and completer groups, respectively; the
overall response rate (based on the Clinical Global Impression Scale of 1 or 2,
very much or much improved) was 20% (3/15) and 22% (2/9), respectively. The
results from this open trial do not support the efficacy of imipramine as a
treatment for social phobia.
PMID- 9555599
TI - A meta-analysis of the effects of venlafaxine on anxiety associated with
depression.
AB - Venlafaxine is the first member of a novel class of antidepressants that inhibits
the reuptake of both serotonin and norepinephrine. Clinical trials of venlafaxine
have demonstrated its efficacy and safety in the treatment of patients diagnosed
with major depression. Because patients who have depression also often have
anxiety, recent investigations have focused on determining whether venlafaxine
can relieve symptoms of anxiety in depressed patients. We performed a pooled
analysis of six short-term trials of venlafaxine, retrospectively measuring
anxiety in anxious depressed patients using the Hamilton Rating Scale for
Depression (HAM-D), Anxiety/Somatization factor and Anxiety Psychic item scores.
Three studies were placebo-controlled, and three were placebo- and active-drug
controlled; active controls were imipramine in two trials and trazodone in the
third trial. Patients were categorized as having anxiety accompanying depression
if baseline HAM-D Anxiety Psychic item scores were 2 or greater. Anxious
depressed patients treated with venlafaxine showed greater improvement than those
treated with placebo beginning at week 3, according to the HAM-D
Anxiety/Somatization factor score, and beginning at week 1, according to the
Anxiety Psychic item score. Both effects were maintained at week 6 of treatment
(and at week 12 in the one study of longer duration). Finally, treatment with
venlafaxine resulted in a highly significant (p < or = 0.001) improvement in
depression scores in patients who were anxious at baseline, compared with placebo
treated patients. The results of this analysis demonstrate that venlafaxine is
more effective than placebo in reducing symptoms of anxiety in depressed patients
and suggest that venlafaxine may afford a monotherapy option for treating
patients who have a comorbid diagnosis of depression with anxiety.
PMID- 9555600
TI - Benzodiazepine-receptor ligands in humans: acute performance-impairing, subject
rated and observer-rated effects.
AB - The study presented here compared the acute performance-impairing, subject-rated,
and observer-rated effects of quazepam (15, 30, and 45 mg), triazolam (0.1875,
0.375, and 0.5625 mg), zolpidem (7.5, 15, and 22.5 mg), and placebo in nine
healthy, non-drug-abusing humans. Quazepam, a trifluoroethylbenzodiazepine, was
chosen for study because, when compared with triazolam, a triazolobenzodiazepine,
it is a relatively weak benzodiazepine-receptor ligand, and it may bind
selectively to the BZ1 benzodiazepine-receptor subtype. Zolpidem, an
imidazopyridine, is the most commonly prescribed hypnotic and was chosen for
study because it is biochemically distinct from benzodiazepine hypnotics and also
purportedly binds selectively to the BZ1 benzodiazepine-receptor subtype.
Triazolam was chosen as the reference compound because it binds nonselectively to
BZ1 and BZ2 benzodiazepine-receptor subtypes. Triazolam, zolpidem, quazepam, and
placebo were administered orally in a double-blind, crossover design. Triazolam
and zolpidem produced orderly dose- and time-related impairment of learning,
performance, and recall, and produced sedative-like subject- and observer-rated
drug effects. The behavioral pharmacologic profile of zolpidem and triazolam was
indistinguishable in that at peak effect, the absolute magnitude of drug effect
was comparable across the various measures. Quazepam, by contrast, did not impair
performance on any task to a statistically significant degree, nor did it produce
significant sedation as measured by subject- and observer-rated drug-effect
questionnaires. Whether these effects are a result of the unique benzodiazepine
receptor binding profile of quazepam or the testing of insufficient dosages is
unknown. Future research could extend the findings presented here by testing
higher dosages of quazepam.
PMID- 9555602
TI - Clozapine induced atrial fibrillation.
PMID- 9555601
TI - Serum levels of valproate and carbamazepine in breastfeeding mother-infant pairs.
AB - Few data are available about the use of anti-convulsants during breastfeeding. In
this article, three women with bipolar disorder who insisted upon breastfeeding
their infants were studied. One mother was treated with carbamazepine (CBZ) and
two were treated with valproate (VLP) monotherapy. Mother and infant serum levels
were assessed when maternal steady-state was reached. The infant whose mother
took CBZ developed a serum level that was 15% of the total maternal CBZ. Free CBZ
was 20% of maternal values. The two infants whose mothers took VLP developed low
serum levels (1.5 and 6.0% of maternal values). In the series, the serum levels
of both CBZ and VLP were lower than previously reported values. However,
information is limited and careful monitoring is recommended.
PMID- 9555603
TI - Delirium in elderly patients treated with risperidone: a report of three cases.
PMID- 9555604
TI - Treatment of refractory rapid cycling bipolar disorder with risperidone.
PMID- 9555605
TI - Comments on article by Tran and colleagues, "Double-blind comparison of
olanzapine versus risperidone in treatment of schizophrenia and other psychotic
disorders".
PMID- 9555606
TI - Comments on article by Tran and associates, "Double-blind comparison of
olanzapine versus risperidone in treatment of schizophrenia and other psychotic
disorders".
PMID- 9555608
TI - Treatment-resistant schizophrenia: the importance of early detection and
treatment. Introduction.
PMID- 9555607
TI - ApoE-epsilon 4 allele and susceptibility to drug-induced memory impairment in the
elderly.
PMID- 9555609
TI - Predictors of outcome in schizophrenia.
AB - Several factors have been reported to be associated with poor outcome in
psychosis. A prospective study was conducted to identify and subsequently assess
the relative prognostic value of factors that might assist in the earlier
identification of patients likely to have a poor outcome. The results confirmed
that certain factors, including male gender, family history of schizophrenia,
structural brain abnormalities, absence of adverse life events, and tardive
dyskinesia, were indeed associated with poor outcome.
PMID- 9555610
TI - The evolution of treatment resistance: biologic implications.
AB - The evolution of resistance of positive symptoms to antipsychotic therapy may
represent a valuable means of subtyping schizophrenia. In contrast, resistance of
negative symptoms and cognitive function to antipsychotic agents seems to be
present from the first episode of psychotic symptoms and does not evolve over
time to the same extent. If these findings are validated, this clearly points
toward differences in the etiology of these components of schizophrenia. Data
from a cohort of 223 patients with unsatisfactory responses to classical
antipsychotic therapy are evaluated, at least 60% of whom responded to subsequent
treatment with clozapine. Comparisons were made between the subgroups of patients
with primary and delayed onset treatment resistance. Both subgroups responded to
clozapine therapy, although better response was evident for patients with delayed
resistance. The withdrawal of clozapine from patients who had previously been
responsive to classical antipsychotic therapy was capable of inducing treatment
resistance.
PMID- 9555611
TI - The cognitive efficacy of atypical antipsychotics in schizophrenia.
AB - Cognitive dysfunction, a symptom of schizophrenia, has been recently identified
as an important measure of outcome in the treatment of this disorder. Drug
mediated symptom improvement, the traditional measure of treatment success for
schizophrenia, typically fails to associate with modifications of cognitive
dysfunction, resulting in a failure of the patient to reintegrate into society. A
paradigm shift is now required in the conceptualization of treatment success away
from symptom decrement and towards treatments that improve cognitive function.
Clozapine treatment has been shown to provide a significantly greater improvement
in several domains of cognitive function, especially attention and verbal
fluency, compared with conventional neuroleptics, whereas risperidone appears to
have a beneficial effect on working memory. These results may be because of the
normalization of dopamine function by clozapine and antagonism of 5HT2 receptors.
PMID- 9555612
TI - The development of treatment resistance in patients with schizophrenia: a
clinical and pathophysiologic perspective.
AB - The pathophysiologic process and clinical factors that contribute to the
development of treatment resistance in schizophrenia are not well defined. This
article describes data indicating that treatment resistance may evolve over the
course of the patients' illness and maturational development. Data from
multiepisode patients suggest that early effective intervention with clozapine
can prevent treatment resistance. Early identification of patients with signs of
treatment resistance is vital. Treatments must be effective and prevent relapse.
At the first indication that a patient may be developing resistance (e.g., the
emergence of extrapyramidal symptoms or increases in negative symptomatology) or
may not be complying with treatment, clozapine therapy should be considered.
PMID- 9555613
TI - Association between pollen hypersensitivity and edible vegetable allergy: a
review.
AB - Over the last three decades several authors have described the existence of an
association between sensitivity to different pollens and sensitivity to diverse
edible vegetables. An association between ragweed pollinosis and hypersensitivity
to Cucurbitaceae vegetables (e.g., watermelon, melon, cucumber) and banana has
been reported. Other authors have found a relationship between birch pollinosis
and sensitization to hazelnut, apple, carrot, potato, kiwi and other vegetables.
Additionally, several papers have shown the association between mugwort
pollinosis and sensitization to celery, carrot, spices, nuts, mustard and
Leguminoseae vegetables. Later, some studies showed association between grass
pollinosis and sensitization to tomato, potato, green- pea, peanut, watermelon,
melon, apple, orange and kiwi. Finally, an association between sensitization to
plantain pollen and melon hypersensitivity was also described. The association
between pollinosis and edible vegetable sensitization has been explained by the
combination of different hypotheses, such as the following: 1) presence of
lectins in edible vegetables; 2) existence of IgE to carbohydrates of the
glycoproteins (cross-reactive carbohydrate determinants); and, 3) existence of
common allergens between pollens and edible vegetables. Up to now three allergens
have been identified as responsible for cross-reactivity in these associations:
profilin, a 14 kd protein that regulates actin; Bet v 1, the 18 kd birch pollen
allergen; and a 60-69 kd allergen. It is important to study in depth these
associated sensitizations and the common allergens responsible for them in order
to improve diagnostic methods and treatment of these syndromes.
PMID- 9555614
TI - Study of IgE-dependent sulphidoleukotriene cellular releasability.
AB - Cellular releasability of mediators, as termed by Lichtenstein and Conroy (1),
can be triggered by interaction with allergens, anti-IgE antibodies or other
agonists. Genetic factors can also influence the cell releasability. We studied
104 subjects, including 92 atopic patients (62 sensitive to D. pteronyssinus and
54 sensitive to Lolium perenne) and 12 healthy controls. Sulphidoleukotriene
(sLT) production was measured after allergen and anti-IgE stimulus with CAST
ELISA, and histamine release using a fluorometric method. We found a significant
sLT production after anti-IgE stimulation, higher than in basal conditions with
medium alone. The sLT production was also significantly higher in sensitive
patients than in healthy controls. We found 14.5% of healthy and atopic subjects
to be non-responders to anti-IgE stimulus. We also found a positive and
significant correlation between sLT production and histamine release. Moreover,
we observed a significant positive correlation between IgE-dependent and antigen
specific sLT release. We also noticed a decrease in sLT production and a decrease
in histamine release with aging. Male patients had a sLT production significantly
higher than female patients. With respect to clinical diagnosis, the group of
patients with rhinitis had the highest mediator production. Finally, pollinic
patients studied during the spring had a higher sLT production to anti-IgE than
those studied out of this season. We conclude that quantification of sLT
production after anti-IgE stimulation is a useful method to study cell
releasability of mediators and that such releasability is higher in atopic
patients than in healthy donors. We must emphasize the usefulness in allergy
diagnosis of relying not only on the use of methods demonstrating the existence
of sensitization to an allergen, but also of techniques able to quantify the
ability to respond to that allergen. In this way we would be able to evaluate the
clinical and immunological evolution of patients and to follow up the efficacy of
their treatment.
PMID- 9555615
TI - Cetirizine reduces conjunctival nonspecific hyperreactivity in children with mite
allergy.
AB - As mite allergy is characterized by a continuous allergen exposure, persistent
inflammation is always detectable even during symptomless periods. It has been
reported that mite allergic patients present a nonspecific hyperreactivity to
different stimuli, including hyperosmolar solution. Since it has been reported
previously that cetirizine is able to reduce minimal persistent inflammation due
to mite allergy, the aim of the study was to investigate the effect of cetirizine
on nonspecific conjunctival hyperreactivity. Twenty children with mite allergy
were studied; two hyperosmolar conjunctival challenges were performed before and
after cetirizine or placebo treatment, lasting one week. Patients treated with
cetirizine showed a significant reduction in nonspecific conjunctival
hyperreactivity compared to the placebo group (p < 0.05). In conclusion,
cetirizine was able to reduce nonspecific hyperreactivity related to allergic
inflammation.
PMID- 9555616
TI - Serial determinations of Der p 1 and Der f 1 show predominance of one
Dermatophagoides species.
AB - One dust sample each month was collected for an average of 11 months throughout
the year from the bedroom carpet of 39 mite allergic, asthmatic individuals
living in the Tampa Bay area of Florida. Dust samples were collected from a
square meter area from the bedroom carpet for 2 min using a portable vacuum
cleaner and analyzed using two-site monoclonal antibody assays. The geometric
mean of Dermatophagoides allergens Der p 1 and Der f 1 levels measured in each
individual home was used in the statistical analysis of the results and reflects
the average allergen level per year per home. Der p 1 levels were greater than
Der f 1 in 21 homes; five homes had between 1.1 and 5 times more; one home had
between 5 and 10; and 15 had between 10 and 175. Der f 1 levels were greater than
Der p 1 in 18 homes; seven homes had between 1.1 and 5 times more; four had
between 5 and 10; and seven homes had between 10 and 44. Spearman rank analysis
of the results yielded a negative correlation coefficient (Rho) = -0.213 (p =
0.19) between Der p 1 and Der f 1 levels. These data suggest that when mite
allergen levels reach a geometric mean value of approximately 2 micrograms/gram
of dust throughout a year, one mite species predominates over the other.
PMID- 9555618
TI - Late onset asthma clinical and immunological data: importance of allergy.
AB - In people over 65 years of age (mean age 72) late onset asthma (LOA) is often
mistaken for chronic obstructive pulmonary disease (COPD). Furthermore, it is
generally believed that true allergic asthma starts very seldom in old age and
that, in this case, it is actually intrinsic asthma i.e., without any
sensitization to aeroallergens. The aim of this study was to show that LOA is not
an uncommon entity and is often allergic. Among a population of 1,888 subjects
(over 65 years of age) in a general medicine ward we found 21 patients (1.1%)
corresponding to this entity. The diagnosis of asthma was assessed according to
clinical data, pulmonary function and nasal provocation tests, and blood
eosinophilia. The diagnosis of atopy was assessed on total IgE, prick tests and
RAST for the commonest allergens of our area. This group of 21 patients was
compared to three groups of age-matched subjects including: 68 patients afflicted
with chronic bronchitis, a group of 14 patients who had asthma before the age of
65 (presenile asthma), and 20 normal controls. A group of 15 asthmatics under age
65 was also included (young asthma mean age 37). We found a rather high incidence
of allergy (72%), mostly to Dermatophagoides pteronyssinus, but also to the
pollens Parietaria judaica, grasses and Olea europea. Although the average age
(except in the young asthma group) and the severity of symptoms were the same in
the four groups, unexpectedly mean RAST and skin test values were higher in LOA
than in the two groups of young asthmatics and presenile asthmatics. It was
concluded that LOA is not uncommon among elderly patients over 65, which is in
contrast with most previous studies; 72% of our cases were allergic, the main
allergens being mite, and Parietaria judaica pollen.
PMID- 9555617
TI - Is it useful to add an anticholinergic treatment to beta 2-adrenergic medication
in acute asthma attack?
AB - The aim of our study was to determine whether the combination of an
anticholinergic treatment with a beta 2-adrenergic medication is a more effective
treatment for acute asthma attack than the two treatments individually. The
association of salbutamol-ipratropium was compared to treatment with salbutamol
and ipratropium alone. It was a prospective double-blind study in children with
acute asthma attack, participating as outpatients. Their clinical history and
characteristics of bronchial obstruction were recorded on a standard form.
Afterwards, they were included in one of the three following study groups: group
one, 100 micrograms/inh salbutamol; group two, 20 micrograms/inh ipratropium;
group three, 100 micrograms/inh of salbutamol plus 20 micrograms/inh ipratropium.
There were 40 patients in each group, with Tal score +/- 5 and PEF < 80% of the
predicted value. They were evaluated at the beginning (0 min), and at 15, 30, 45,
60, 80, 100 and 120 min. Each patient was treated with two inhalations of the
study medication and was then evaluated for variations in Tal score. The mean age
was 7.3 years; Tal score was 5.6, 5.6 and 6.0 at 0 min (p > 0.05). Decrease in
Tal score after 15 min meant p < 0.01 for salbutamol-ipratropium and salbutamol
vs. ipratropium. At 30 min p < 0.05 for salbutamol-ipratropium vs. salbutamol,
and at 45 min p < 0.01 for salbutamol-ipratropium vs. salbutamol. PEF at 0 min
was 70.9%, 71.3% and 68.6% (p > 0.05) increasing after 15 min. At 30 min p < 0.05
for salbutamol-ipratropium vs. salbutamol, and p < 0.01 vs. ipratropium. At 45
min p < 0.01 for salbutamol-ipratropium vs. salbutamol and ipratropium. A total
4.7 doses of salbutamol were needed to improve the asthma attack, 5.3 of
ipratropium and 3.7 of salbutamol-ipratropium, with p < 0.01 for salbutamol
ipratropium vs. salbutamol and ipratropium. We conclude that the combination of
salbutamol and ipratropium is more effective than each medication alone in
treating acute asthma attacks in pediatric patients.
PMID- 9555619
TI - Different responses of lymphocyte to human placenta conditioned medium in vitro.
AB - Several cytokines appear to be implicated in peri-implantation events and in
maternal-fetal interaction. The majority of these molecules appear in
supernatants or in extracts of placental origin. The purpose of this study was to
investigate the action of human placenta conditioned medium (HPCM) on peripheral
lymphocytes in vitro. Peripheral lymphocytes of women with different numbers of
deliveries, of nulliparous and pregnant women, as well as of men, were cultivated
in their own plasma with and without HPCM at 5%, 10% and 20%. The index of
lymphocyte blast transformation (ILBT) was determined (values of > or = 0.5
indicated stimulation). In women who had had children, the highest lymphocyte
blastogenesis was observed with HPCM at 10%, this finding being correlated to the
numbers of deliveries (r = 0.828). In pregnant women, even though the highest
answer was also obtained with HPCM at 10%, the addition of suboptimal
concentration of HPCM (5%) produced blastic transformation (IBLT: x = 0.54 +/-
0.05), which was not observed in women who had had children. Lymphocytes of men
and nulliparous women did not respond to any of the HPCM concentrations tested.
In conclusion, HPCM at 10% was still the best concentration to produce lymphocyte
blastogenesis. In addition, in the plasma of pregnant women, there may be some
substance that enhanced the action in vitro of the extract, thus permitting
threshold reduction necessary for lymphocyte stimulation.
PMID- 9555620
TI - Honeybee venom specific IgG subclass antibodies in Brazilian beekeepers and in
patients allergic to bee stings.
AB - Fifty-nine beekeepers who had been practicing apiculture for more than 2 years
were selected in order to determine the distribution of bee venom specific IgG
subclasses using ELISA. The assays were standardized into arbitrary units. For
comparison, IgG subclasses were determined in eight individuals allergic to bee
stings who did not receive specific treatment. No correlation was detected
between beekeeping time and specific IgG1, IgG2 or IgG4 levels. There was a
correlation between IgG2 levels and mean number of stings per month received by
the beekeepers. Twenty-five percent of the beekeepers presented bee venom
specific IgE class II or more in an ELISA assay. The IgG1 levels detected in
beekeepers were similar to those detected in allergic individuals. IgG2 and IgG4
levels were significantly higher in beekeepers than in allergic individuals. IgG3
was not detected in any group studied. In conclusion, the maintenance of high
levels of bee venom specific IgG2 and IgG4 represents a characteristic of
beekeepers. These subclasses may be related to a modulatory effect of IgG on
allergic reactions.
PMID- 9555621
TI - Severe allergic conjunctivitis and chemosis caused by disodium cromoglycate.
AB - A 63-year-old man with chronic, nonallergic rhinoconjunctivitis presented
immediate adverse reactions, such as intense itching, burning, redness and severe
swelling of both conjunctivae after using disodium cromoglycate eye drops. Skin
prick tests and conjunctival provocation tests were positive with pure disodium
cromoglycate. Circulating IgE-specific antibodies to disodium cromoglycate in
serum were demonstrated by RAST. We suggest that the acute ocular reaction was
caused by disodium cromoglycate and that the underlying mechanism was probably an
IgE-mediated immunological reaction.
PMID- 9555623
TI - A support system for content-based medical image retrieval in object oriented
databases.
AB - This work describes both the concepts used in an Object Manager for storage of
medical images as one more data type associated to objects, and a support system
developed to offer this kind of tool to medical application developers. The
purpose of this work is to support the retrieval of images through queries based
on the graphical contents of the stored images. The usual approach uses icons and
textual attributes stored with the images to specify the queries. This work uses
a novel modeling technique to define the "image data type," by means of which it
is possible to decide, before the query itself, the key data of each image that
must be extracted from the image when it is stored in the database, so the search
can be accelerated when queries are issued. This approach enables building of
expansible systems, where new image processing algorithms can be added easily,
using its syntactic representation stored through an Image Meta-schema into the
application database schema. This work shows how such a system has been
implemented, and also provides a query language used to refer and execute these
algorithms from inside the database management system.
PMID- 9555622
TI - Anisakis, anisakiasis and IgE-mediated immunity to Anisakis simplex.
AB - Anisakis simplex is a common parasite in fish and cephalopods and is not only
capable of causing anisakiasis in humans through visceral invasion of the third
stage larvae but can also cause anaphylactic reactions, as has recently been
demonstrated. We present the clinical case of a 56-year-old man who initially
presented anaphylactic reactions related to eating fish. Shortly afterwards, he
began to experience self-limiting recurrences of very intense epigastric pain,
nausea and vomiting. Skin tests for immediate hypersensitivity (prick tests) with
a commercial extract as well as the determination of specific IgE in the
patient's serum were clearly positive for A. simplex. The hemogram did not show
eosinophilia. Copro-cultures and parasites in the patient's feces were repeatedly
negative. Gastroscopy was normal. The intestinal tract showed contrast
flocculation and dilation of ansas in the distal duodenum and proximal jejunum.
Biopsy samples of gastric and distal duodenum mucous showed an active process of
chronic inflammation with a predominance of eosinophils in the lamina propria.
After subjecting the patient to a fish and cephalopod-free diet and treating him
with thiabendazole 350 mg every 12 hours for 6 days, he showed no sign of
symptoms while awaiting new tests. Even though the diagnosis of IgE-mediated
allergy caused by A. simplex offers no room for doubt, we are unable to present a
firm diagnosis of anisakiasis as no larva has been seen. Nevertheless, the
clinical pattern, the image of the intestinal tract, the eosinophilic infiltrate
in the biopsies and the good response to thiabendazole all lead to the suspected
existence of anisakiasis in this patient coexisting with IgE-mediated allergy to
this parasite.
PMID- 9555624
TI - 3D reconstruction of tomographic images applied to largely spaced slices.
AB - This paper presents a full reconstruction process of magnetic resonance images.
The first step is to bring the acquired data from the frequency domain, using a
Fast Fourier Transform algorithm. A Tomographic Image Interpolation is then used
to transform a sequence of tomographic slices in an isotropic volume data set, a
process also called 3D Reconstruction. This work describes an automatic method
whose interpolation stage is based on a previous matching stage using Delaunay
Triangulation. The reconstruction approach uses an extrapolation procedure that
permits appropriate treatment of the boundaries of the object under analysis.
PMID- 9555625
TI - LEMMA: a language for easy medical models analysis.
AB - The quality of health care systems and processes is becoming a prominent problem
and more and more efforts are devoted to define methodologies and tools to
measure and assure quality of care. New methods are required to optimize health
care processes to guarantee high quality standards within (limited) available
resources. Resource optimizations able to preserve the quality of treatments
require good models of medical processes. This paper presents LEMMA, a new
notation to model medical processes. LEMMA provides physicians with intuitive
graphical elements to design their models. At the same time a high level timed
Petri net corresponding to the designed model is built automatically. In this
way, LEMMA models are ascribed formal semantics and can be executed and analyzed
automatically. The dual language approach followed in this paper allows
physicians to gain all the benefits of formal methods without being proficient in
them. Medical users manage simple graphical elements, while Petri nets ensure
formality and validation capabilities. In this way LEMMA mixes formal and
informal notations, overcoming the problems of both the approaches. The
definition of the notation has been supported by the development of an
environment to design LEMMA models. The environment, besides letting us
experiment with the notation, has been employed to define and analyze real case
studies.
PMID- 9555626
TI - Using an artificial neural network to define the planning target volume in
radiotherapy.
AB - A neural network for predicting the planning target volume in radiotherapy from
the shape of the detected tumor is designed and tested in this research project.
The proposed neural network is able to generalize expert medical knowledge and
predict the planning target volume from a three-dimensional image of the detected
tumor. Initial results for simple shaped brain tumors are presented in this
paper.
PMID- 9555627
TI - The limitations of decision trees and automatic learning in real world medical
decision making.
AB - The decision tree approach is one of the most common approaches in automatic
learning and decision making. The automatic learning of decision trees and their
use usually show very good results in various "theoretical" environments. But in
real life it is often impossible to find the desired number of representative
training objects for various reasons. The lack of possibilities to measure
attribute values, high cost and complexity of such measurements, and
unavailability of all attributes at the same time are the typical
representatives. For this reason we decided to use the decision trees not for
their primary task--the decision making--but for outlining the most important
attributes. This was possible by using a well-known property of the decision
trees--their knowledge representation, which can be easily understood by humans.
In a delicate field of medical decision making, we cannot allow ourselves to make
any inaccurate decisions and the "tips," provided by the decision trees, can be
of a great assistance. Our main interest was to discover a predisposition to two
forms of acidosis: the metabolic acidosis and respiratory acidosis, which can
both have serious effects on child's health. We decided to construct different
decision trees from a set of training objects. Instead of using a test set for
evaluation of a decision tree, we asked medical experts to take a closer look at
the generated trees. They examined and evaluated the decision trees branch by
branch. Their comments show that trees generated from the available training set
mainly have surprisingly good branches, but on the other hand, for some, no
medical explanation could be found.
PMID- 9555628
TI - Genetic algorithm based system for patient scheduling in highly constrained
situations.
AB - In medicine and health care there are a lot of situations when patients have to
be scheduled on different devices and/or with different physicians or therapists.
It may concern preventive examinations, laboratory tests or convalescent
therapies, therefore we are always looking for an optimal schedule that would
result in finishing all the activities scheduled as soon as possible, with the
least patient waiting time and maximum device utilization. Since patient
scheduling is a highly complex problem, it is impossible to make a qualitative
schedule by hand or even with exact heuristic methods. Therefore we developed a
powerful automated scheduling method for highly constrained situations based on
genetic algorithms and machine learning. In this paper we present the method,
together with the whole process of schedule generation, the important parameters
to direct the evolution and how the algorithm is guaranteed to produce only
feasible solutions, not breaking any of the required constraints. We applied the
described method to a problem of scheduling patients with different therapy needs
to a limited number of therapeutic devices, but the algorithm can be easily
modified for use in similar situations. The results are quite encouraging and
since all the solutions are feasible, the method can be easily incorporated into
an interactive user interface, which can be of major importance when scheduling
patients, and human resources in general, is considered.
PMID- 9555629
TI - Induction of decision trees and Bayesian classification applied to diagnosis of
sport injuries.
AB - Machine learning techniques can be used to extract knowledge from data stored in
medical databases. In our application, various machine learning algorithms were
used to extract diagnostic knowledge which may be used to support the diagnosis
of sport injuries. The applied methods include variants of the Assistant
algorithm for top-down induction of decision trees, and variants of the Bayesian
classifier. The available dataset was insufficient for reliable diagnosis of all
sport injuries considered by the system. Consequently, expert-defined diagnostic
rules were added and used as pre-classifiers or as generators of additional
training instances for diagnoses for which only few training examples were
available. Experimental results show that the classification accuracy and the
explanation capability of the naive Bayesian classifier with the fuzzy
discretization of numerical attributes were superior to other methods and
estimated as the most appropriate for practical use.
PMID- 9555630
TI - Automated computer-assisted detection of follicles in ultrasound images of ovary.
AB - Monitoring the follicles in women's ovaries is especially important in human
reproduction. Today, the monitoring of follicles is done with human interaction.
Such monitoring can be very demanding and inaccurate, and in most cases signifies
additional burdens for the experts. In this paper, a new algorithm for automated
computer-assisted detection of follicles in the ultrasound images of the ovary is
proposed. It has a typical object recognition scheme (preprocessing,
segmentation, and classification). The algorithm is based on the following idea:
first, the ovary is estimated (coarsely) and then follicles are searched for. The
methods used are known from literature (despeckle filter, Kirsch's operator,
optimal thresholding, thinning, shape descriptions, classification), and the
majority of our work was done experimenting with these methods and selecting the
appropriate thresholds. The algorithm's computational complexity is of order of
O(n2), which means about 6 min of processing time per an ultrasound image of
dimensions of 768 x 576 pixels on HP 715 machines. It has been tested on a set of
20 real ultrasound images of the ovary. The recognition rate of follicles with
these procedures was around 62%. The algorithm is not perfect, but it will be
further modified and improved, as indicated in our conclusions.
PMID- 9555631
TI - Molecular medicine, managed care, and the moral responsibilities of patients and
physicians.
PMID- 9555632
TI - Genetic links, family ties, and social bonds: rights and responsibilities in the
face of genetic knowledge.
AB - Currently, some of the most significant moral issues involving genetic links
relate to genetic knowledge. In this paper, instead of looking at the frequently
addressed issues of responsibilities professionals or institutions have to
individuals, I take up the question of what responsibilities individuals have to
one another with respect to genetic knowledge. I address the questions of whether
individuals have a moral right to pursue their own goals without contributing to
society's knowledge of population genetics, without adding to their family's
knowledge of its genetic history, and without discovering genetic information
about themselves and their offspring. These questions lead to an examination of
the presumed right to genetic ignorance and an exploration of a variety of social
bonds. Analyzing cases in light of these considerations leads to a surprising
conclusion about a widely accepted precept of genetic counseling, to some ethical
insights into typical problems, and to some further unanswered questions about
personal responsibility in the face of genetic knowledge.
PMID- 9555633
TI - Responsibility, alcoholism, and liver transplantation.
AB - Many believe that it is morally wrong to give lower priority for a liver
transplant to alcoholics with end-stage liver disease than to patients whose
disease is not alcohol-related. Presumably, alcoholism is a disease that results
from factors beyond one's control and therefore one cannot be causally or morally
responsible for alcoholism or the liver failure that results from it. Moreover,
giving lower priority to alcoholics unfairly singles them out for the moral vice
of heavy drinking. I argue that the etiology of alcoholism may involve enough
control for the alcoholic to be responsible for his condition and accordingly
have a weaker claim to receive a new liver than someone who acquires the disease
through no fault of his own. In addition, I show why it is more plausible to
reframe the question of priority in terms of control and responsibility rather
than virtue and vice. Given that medical resources like livers are scarce, some
people may justifiably be given lower priority than others in receiving these
resources.
PMID- 9555634
TI - Selection of recipients for donor organs in transplant medicine.
AB - This paper deals with a problem which has received a great deal of attention in
the ethical literature, but about which very little is known empirically: the
selection of recipients for organs in transplant medicine. Based on a larger
study, it is shown how this problem is practically resolved in one European
country, Germany. It is demonstrated that most of the criteria used to determine
recipients are non-medical in nature, even though they generally tend to be
rationalized in medical terms. Moreover, the choice of criteria depends as much
on prognostic considerations as on personal indiosyncrasies and values held by
individual physicians who are in charge at the various programs. Several examples
of the extremely diverse policies in which this results are presented.
PMID- 9555635
TI - Patenting medical and surgical techniques: an ethical-legal analysis.
AB - Considerable controversy has recently arisen regarding the patenting of medical
and surgical processes in the United States. One such patent, viz. for a
"chevron" incision used in ophthalmologic surgery, has especially occasioned
heated response including a major, condemnatory ethics policy statement from the
American Medical Association as well as federal legislation denying patent
protection for most uses of a patented medical or surgical procedure. This
article identifies and discusses the major legal, ethical and public policy
considerations offered by proponents and opponents of such patents. The existing
literature divides up into those who favor such patents essentially without
qualification, and those who condemn and wish to outlaw them. We advance a
compromise position where administrative and legislative action is called for to
provide more specific guidelines regarding the patentability of such processes by
the Patent and Trademark Office. Our position, in sum, will be that too much is
at stake in this complicated area for either the blanket prohibition, or
wholesale, uncritical acceptance, of the patenting of medical and surgical
processes or techniques.
PMID- 9555636
TI - A radical rupture in the paradigm of modern medicine: conflicts of interest,
fiduciary obligations, and the scientific ideal.
AB - Conflicts of interest serve as a cipher for a radical rupture in the Flexnerian
paradigm of medicine, and they can only be addressed if we recognize that health
care is now practiced by institutions, not just individual physicians. By showing
how "appropriate utilization of services" or "that which is medically indicated"
is a function of socioeconomic factors related to institutional responsibilities,
I point toward an administrative and organizational ethic as a needed component
for addressing conflicts of interest. The argument is developed by reviewing
three important books. First, I consider Mark Rodwin's attempt to configure the
economic structures of medicine so that classical fiduciary and scientific ideals
can be fostered. Second, I consider E. Haavi Morreim's attempt to modify the
classical ideals in order to account for new economic realities. Finally, by
considering essays in a recent volume on conflicts of interest edited by Spece,
Shimm, and Buchanan, I argue for a constructive dialectic between the approaches
of Rodwin and Morreim. In order to properly address conflicts of interest, there
must be a radical reassessment of medicine that accounts for the interrelation
between scientific, ethical, and economic concerns. Until institutions come into
view and professional ethics is developed to account for their role, legitimate
interests and obligations of diverse parties cannot be harmonized.
PMID- 9555637
TI - Combined management of intracranial vascular malformations in children.
AB - We have reviewed 39 cases of intracranial vascular malformations, observed in the
Section of Paediatric Neurosurgery of the Catholic University of Rome between
1980 and 1995 (age 1-15 years). Diagnosis was of parenchimal AVM in 26 cases, in
7 cases of AVM of the Galen region, in 5 cases of dural AVM and in 1 case of
venous angioma. RESULTS AND CONCLUSIONS: Haemorrhage was the prevalent clinical
onset in patients with parenchimal AVMs (57.7% of cases). Only one patient with a
Galen region AVM presented cardiovascular symptoms, while 2/5 children observed
for a dural AVM complained a congestive heart failure. Total surgical excision
was performed in 17 of the 26 patients with parenchimal AVMs; moreover surgery
was combined with preoperative endovascular embolization in 2 cases and with
radiosurgery in 1 patient; we think that surgery is still the treatment of choice
in patients with parenchimal AVMs. Endovascular treatment and radiosurgery have
mainly an adjuvant role; nevertheless we agree that a preoperative endovascular
management of parenchimal AVMs reduces the surgical risk, especially in cases of
huge AVMs or AVMs localized in eloquent areas of the brain. Radiosurgery may be
an alternative choice for complex or deeply sited AVMs; however in most cases, a
combination with surgery or endovascular treatment is necessary to reduce the
"target" size. AVM embolization was the only treatment in 2 of the 6 cases of
dural AVMs; dural AVM embolization was combined with surgery in 1 case.
Endovascular AVM exclusion is the treatment of choice in these patients. Surgery
may be combined with endovascular treatment in case of a partial persistence of
the AVM, or if signs of revascularization are present on control angiography. A
conservative management is justified in patients with carotido-cavernous
fistulae; in fact a complete spontaneous thrombosis is very frequent in these
cases. A high rate of cardiovascular symptoms is reported in patients with Galen
region AVMs diagnosed in the 1st year of life, but only 1 of our patients
complained of congestive cardiac symptoms. Surgical treatment of Galen region
AVMs is associated with a high morbidity and mortality. Actually a transarterial
embolization of afferent vessels represents the treatment of choice in these
patients; it can be combined with transvenous approach in case of complex AVMs
and/or a non complete AVM exclusion.
PMID- 9555638
TI - Endovascular treatment of pial AVMs: technical options, indications and limits in
pediatric age patients.
AB - Our study group consisted of 29 patients who underwent endovascular treatment for
the presence of pial AVMs. The patients were treated with various embolization
methods including "-free flow" embolization (2 cases); embolization with suture
threads (2 mm long micro-emboli: 17 cases) and embolization with acrylic glue (10
cases). There were significant angio-architectural and AVM location differences
between the pediatric and the adult patient groups. In pediatric patients, the
more frequent AVMs were of the mono or few-pedunculated type, then simple direct
fistulas and high-flow fistulous-plexiform AVMs and giant infra-tentorial or deep
seated malformations. In mono or few-pedunculated AVMs, the elected treatment was
acrylic glue followed by radio-surgery achieving definitive cure in 3 cases. In
direct AVFs and elevated flow AVMs, embolization with suture and acrylic glue
offered definitive results. Treatment for infra-tentorial and deep-seated AVMs
presented the greatest difficulty in pediatric patients. In two of them,
embolization with glue enabled radiosurgery (giant cerebellar AVMs). Our
experience did not confirm that current endovascular techniques provide
definitive treatment in extensive, deep-seated AVMs. Each treatment, in children
more so than in adults, requires a risk/benefit evaluation of the method taking
into account the natural history data.
PMID- 9555639
TI - Comparison of pediatric and adult cerebral arteriovenous malformations.
AB - The authors report 19 consecutive children with cerebral arteriovenous
malformations over the period 1978-1992. These patients are compared with a
series of 120 consecutive adult patients with the same pathology, managed during
the same period. The main clinical and angiographic features, as well as the
treatment modalities and outcome are reviewed and compared. Children seem to
harbour smaller and simpler lesions than adults. Furthermore, despite a more
severe clinical presentation, children appears to fare better than adults. The
possibility of evolution of brain arteriovenous malformations is discussed.
PMID- 9555640
TI - Complex arteriovenous fistula of the brain in an infant. Case report.
AB - A rare case of complex cerebral arteriovenous fistula in an infant is reported.
An 8-month-old boy first presented with a syndrome of increased intracranial
pressure. Neuroradiological assessment showed a direct intracerebral
arteriovenous shunt with marked venous engorgement. No hemorrhage was evident.
Direct surgical treatment was decided. Clinical and radioanatomical cure was
achieved. The main angiographic and pathophysiologic features of this unusual
entity, as well as the available therapeutic options, are reviewed and discussed.
PMID- 9555641
TI - Surgical management of paediatric cerebral cavernomas.
AB - Over the past 15 years (1981-1995) 24 children with cerebral cavernous angiomas
have been treated surgically at the Section of Pediatric Neurosurgery of the
Catholic University of Rome. The most common symptoms at presentation were
epilepsy (13 children) and intracranial hypertension (9 children). None of these
patients had a family history of cerebro-vascular malformations. Multiple lesions
were detected in two subjects. In 19 cases, radiological signs of significant
acute and subacute hemorrhage were present at the radiological examinations. The
supratentorial compartment was the most frequent localization of the lesions,
with only four cavernomas observed in the subtentorial space. The post-surgical
results were good: only nine children had a persistence of the presurgical
neurological signs, although ameliorated by the treatment; no patient showed a
progression of pre-operative neurological signs, neither the onset of new
deficits; only one child died, but his clinical conditions were very critical
before surgery. Our results suggest that the youngest children present with
evidence of significant hemorrhages more frequently than their older counterpart.
In our series, the removal of cavernomas allowed to control the seizure disorders
in all the case, thus suggesting that in this type of malformative lesion,
lesionectomy alone may be sufficient to resolve epilepsy.
PMID- 9555642
TI - Giant intracavernous carotid aneurysm in a child. Case report.
AB - The occurrence of intracranial aneurysm in the pediatric population is a rare
phenomenon. A case of giant aneurysm of the intracavernous carotid artery in a
child is reported. Clinicoradiological findings are presented and the surgical
procedure is illustrated. Authors stress the value of monitoring the cerebral
collateral blood flow before and during the operation.
PMID- 9555643
TI - Cerebral cavernous angiomas in critical areas. Reports of three cases in
children.
AB - Cerebral cavernous angiomas are congenital malformations usually presenting with
symptomatic hemorrhages or seizures. The advent of MRI has allowed to detect
asymptomatic, "cryptic" brain cavernomas. They can occur in a sporadic, isolated
form and in a familial form characterized by multiple lesions. Surgical treatment
is recommended by most authors in symptomatic cases when the lesion is isolated
and readily accessible. Treatment is more controversial when the vascular
malformation is located in critical brain region. On the other hand the increased
risk of rebleeding after a prior hemorrhage and the decreased effectiveness of
lesionectomy in patients with a long seizure history could lead to perform an
early surgical excision also for cavernous angiomas located in those areas. We
report three cases of symptomatic cerebral cavernomas located in critical areas,
in children. In all cases the surgical removal of the lesions was successfully
performed. The two cases presented with seizures are seizure-free in spite of the
interruption of the antiepileptic therapy. The patient presented with
neurological deficit due to intraparenchymal hemorrhage progressively recovered
his motor function. Our experience seems to confirm the value of surgical removal
regardless of where the cavernoma is located.
PMID- 9555644
TI - Stereotactic radiosurgery for the treatment of arteriovenous malformations in
childhood.
AB - BACKGROUND: The main techniques and results in stereotactic radiosurgical
treatment of endocranial AVM's are described and compared. The authors also
report their preliminary experience in the treatment of 6 consecutive pediatric
patients with intracerebral vascular malformations using gamma knife (GK)
radiosurgery. METHODS: The various stereotactic radiosurgery methods currently
used (charged-particle beam, modified linear accelerator, and GK) are described.
At the Department of Neurosurgery in Verona, from February 1993 to February 1996,
stereotactic GK radiosurgery was performed on 721 patients, including 20 of
pediatric age (3%). Of the 78 AVMs, 7 (9%) were diagnosed in children. One
patient was lost at follow-up. Among the remaining 6 children, there were 3 males
and 3 females with a mean age of 12.3 years (range, 5-16 years). Treatment
general anesthesia was needed only in 1 case. The AVM volume was always less than
10 cc. After completion of the procedure, children were discharged from the
hospital the following day. RESULTS: The follow-up period ranged from 4 months to
29 months (median 18.8 months). The angiographic confirmed total obliteration is
used as the end point of an AVM treated radiosurgically, and usually requires 2
to 3 years. All the patients are alive; four of the treated children are
neurologically normal and one patient has clinically improved to a normal
neurological status. The sixth patient has fixed neurological deficits that
existed prior to treatment. Among the three cases with a follow-up period of over
2 years, complete obliteration has been angiographically confirmed in 2 patients
and subtotal in 1 patient. In the three remaining patients with follow-up periods
less than 2 years, serial MR images suggest subtotal obliteration in 2 cases and
no significant change in one patient who had undergone treatment within the
current year. To date, neither persistent GK radiosurgery-related complications
nor bleeding following stereotactic radiosurgery has been described. CONCLUSIONS:
The review of literature and our preliminary results suggest that also in
children, as in adults, the use of stereotactically delivered irradiation
represents a safe and effective technique obtaining complete obliteration of AVMs
previously considered surgically inaccessible due to their location and poor
response to resection and/or embolization.
PMID- 9555645
TI - Activated protein C resistance due to a factor V mutation associated with
familial ischemic stroke.
AB - Recent findings have indicated the association between activated protein C (APC)
resistance and cerebrovascular disease. These reports prompted us to investigate
whether resistance to APC could be found in patients suffering from transient
ischaemic attacks or stroke. Therefore, we studied APC-resistance in 14 young
adults belonging to three different families with a history of transient ischemic
attacks (TIAs) and stroke. Nine out of fourteen subjects showed APC-resistance
but no deficiencies in the anticoagulant proteins AT III, PC and PS. The family
history demonstrated a distribution of APC-resistance compatible with dominant
autosomal inheritance. A rapid screening method to detect factor V R506Q (Leiden)
mutation without sequencing or restriction enzyme digestion has been set-up after
biochemical analyses. DNA analysis showed a guanine to adenine transition at
nucleotide 1,691 in patients and their relatives with poor response to activated
protein C detected by APTT tests. Of 14 investigated subjects and their family
members, 5 were normals, 6 were heterozygotes and 3 were homozygotes for factor V
mutation. The mutation, in heterozygous form, was also found in 1.3% of our
normal population (n = 75). Our findings indicate a possible involvement of APC
resistance in the pathogenesis of arterial thrombosis in young adults.
PMID- 9555646
TI - Blood degradation products play a role in cerebral ischemia caused by acute
subdural hematoma.
AB - The pathogenesis of ischemic brain lesions with traumatic hematoma is
multifactorial. It has been suggested that the presence of subdural hematoma in
patients with severe head injury is associated with elevated intracranial
pressure and higher mortality. In this study we created acute subdural mass in
the rats by injecting 250 microliters of autologous blood and silicone oil into
the subdural space. The goal of this study was to determine the effect of
subdural hematoma versus silicone oil on the adjacent brain parenchyma. Twenty
four hours after the injection, of the hematoma in the subdural space in rats
produced an extensive zone of underlying ischemic damage but silicone oil did
not. This study has shown that pressure alone caused by silicone oil is
insufficient to cause significant neuronal damage or loss.
PMID- 9555647
TI - The postero-lateral approach in the treatment of post-traumatic canalar stenosis
of the thoraco-lumbar spine.
AB - METHODS: Twenty-four cases of unstable thoraco-lumbar fractures with significant
canalar stenosis were operated in the Emergency Neurosurgical Unit of the
Cardarelli Hospital from November 1989 to October 1991. The surgical technique
was the combined transpedicular (TPA) and transarticular (TAA) postero-lateral
approach, posterior osteosynthesis and arthrodesis. The average follow-up was 20
months. RESULTS: No evidence of implant breakage or pseudoarthrosis was detected.
CONCLUSIONS: The authors affirm recalibration of the posterior wall by direct
impaction, epidural hemostasis, removal of extruded disc fragments and dural
repair are the advantages offered by this technique without compromise the
contsrist stability. This approach represents an alternative to single posterior
and combined anterior-posterior approaches in the management of the thoraco
lumbar fractures with severe canal stenosis.
PMID- 9555648
TI - Infected cerebral hemorrhage by ruptured infectious anterior communicating artery
giant aneurysm in a patient with T cell acute lymphoblastic leukemia. Case
report.
AB - Although the majority of infectious (bacterial) intracranial aneurysms occur in
patients with subacute bacterial endocarditis, septic cerebral embolization and
infectious intracranial aneurysm formation can also occur in immunocompromised
patients. We report the case of ruptured bacterial aneurysm occurring in a 19
years old man immunocompromised by vigorously treated acute lymphoblastic
leukemia. This case confirms very poor prognosis for infectious aneurysms in
immunocompromised patient reported in literature, suggesting that a high index of
suspicion needs for early diagnosis and that a conservative approach (high dose
antibiotic therapy with possible delayed surgery) should be preferred unless
intracerebral hemorrhage or abscess with significant mass effect provides a clear
indication for operative intervention.
PMID- 9555649
TI - Lateral ventricle subependymomas. Case report taking into particular
consideration the aspects of magnetic resonance and review of the literature.
AB - Subependymomas are rare neuroectodermic tumours. The authors report a case of a
patient he had a subendymoma in the left lateral ventricle, with particular
attention to the MR aspects on these lesions and review of the literature.
PMID- 9555650
TI - Exophytic pontine glioblastoma mimicking acoustic neuroma.
AB - A 22-year-old male with unilateral facial, cochlear and glossopharyngeal cranial
nerve dysfunction and ataxia that was slowly progressive over one year is
described. Although clinically it was considered he probably had an acoustic
neuroma, surgery revealed a pontine glioblastoma exophytic into the
cerebellopontine angle and internal acoustic meatus. Clinicoradiological features
that distinguish this extremely rare lesion of the hindbrain from acoustic
neuroma are discussed.
PMID- 9555651
TI - Radiation-induced cerebral meningiomas. Case reports.
AB - Two cases are presented of meningiomas following external cranial irradiation in
which several features clearly indicate a causal relationship between
radiotherapy and tumour development. In one patient multiple recurred meningioma
was diagnosed 30 years after low-dose X-ray treatment of Tinea capitis; in the
other patient the meningioma was diagnosed approximately 18 years after high-dose
radiation therapy for astrocytoma. The features distinguishing radiation-induced
meningiomas from other meningiomas are reviewed. The use of radiation therapy
only in those cases in which there is clear evidence that it will have beneficial
effects and that these effects will outweigh the risks is emphasized.
PMID- 9555652
TI - Cavernous hemangioma of the skull. Case report and review of the literature.
AB - Osseous hemangiomas are rare skeletal tumors that constitute 0.7% of all osseous
neoplasms. The most common site is the vertebral column while involvement of the
calvarium is extremely rare accounting for 0.2% of all bone neoplasm. The authors
present a case of a 35-years-old man who was admitted with right parietal
swelling and review the gross appearance, pathogenesis, histopathology,
radiological features and treatment of this neoplasm.
PMID- 9555653
TI - Spontaneous movement of metallic foreign bodies. Case report.
AB - We report a case of missile injury to the brain with an unusual complication. The
bullet migrated by its mere weight to a distant location through the brain
parenchyma after initially lodged in a superficial site. Movement of the bullet
was first detected on CT scan and the significance and treatment of this finding
is emphasized.
PMID- 9555654
TI - The cytochrome P-450 inhibitor cobalt chloride prevents inhibition of renal Na,K
ATPase and redistribution of apical NHE-3 during acute hypertension.
AB - Acute systolic arterial hypertension provokes a rapid decrease in proximal tubule
sodium reabsorption and diuresis associated with inhibition of renal cortex Na,K
ATPase activity and redistribution of apical membrane Na/H exchanger (NHE-3) to
heavier density membranes containing markers of intermicrovillar cleft and
endosomes. Because cytochrome P-450-dependent arachidonate metabolites
participate in the regulation of renal sodium transport and BP, this study tested
the hypothesis that these renal responses to acute hypertension would be
prevented if cytochrome P-450 metabolism were inhibited by cobalt chloride
(CoCl2). Four groups of rats (n = 4 to 5) were studied: (1) sham-operated; (2) 50
mg of CoCl2/kg subcutaneously for 2 d; (3) acute hypertension by constricting
arteries for 5 min; and (4) acute hypertension after CoCl2 treatment as in group
3. Renal cortex was analyzed after sorbitol density gradient fractionation. CoCl2
treatment alone did not significantly affect the rate of urine output, endogenous
lithium clearance (an inverse measure of proximal tubule sodium reabsorption),
maximal activity of Na,K-ATPase, or subcellular distribution of NHE-3-containing
membranes. In non-CoCl2-treated animals, acute hypertension provoked a three- to
fourfold increase in urine output and endogenous lithium clearance, 33%
inhibition of renal cortex Na,K-ATPase activity, and redistribution of NHE-3 out
of the apical membrane peak. In CoCl2-treated animals, acute urine output and
endogenous lithium clearance increased only twofold during acute hypertension,
there was no inhibition of Na,K-ATPase activity, and there was no redistribution
of NHE-3 immunoreactivity to higher density membranes. These findings demonstrate
that CoCl2 treatment both attenuates the inhibition of proximal tubule sodium
reabsorption and diuresis and abolishes Na,K-ATPase inhibition and NHE-3
redistribution during acute hypertension, evidence that these responses may be
mediated by cytochrome P-450 arachidonate metabolites.
PMID- 9555655
TI - Regulation of Na+, K(+)-ATPase in the rat outer medullary collecting duct during
potassium depletion.
AB - Because in outer medullary collecting ducts (OMCD) of K(+)-depleted rats, K+
secretion is abolished, whereas Na+, K(+)-ATPase, which energizes this secretion,
is markedly stimulated, it has been proposed that Na+, K(+)-ATPase was mislocated
to the apical cell membrane and energized K+ reabsorption. This hypothesis has
been supported by paradoxical effects of ouabain in K(+)-depleted compared with
normal rats. However, we have recently shown that ouabain inhibits not only Na+,
K(+)-ATPase but also apical H+, K(+)-ATPase in the OMCD of K(+)-depleted rats.
Therefore, this study was designed to evaluate whether previous observations were
accounted for by Na+, K(+)-ATPase or by ouabain-sensitive H+, K(+)-ATPase. Na+,
K(+)-ATPase was distinguished from H+, K(+)-ATPase by its insensitivity to Sch
28080. Results indicate that the hydrolytic and transport activities of Na+, K(+)
ATPase, the number of its functional units, and the expression of mRNA of its
alpha 1 and beta 1 subunits were increased threefold or more in the OMCD of rats
fed a K(+)-depleted diet for 2 wk. By immunofluorescence, Na+, K(+)-ATPase
staining was strongly increased in K(+)-depleted rats but remained localized to
the basolateral pole of OMCD principal cells. In conclusion, K+ depletion is
associated with marked induction of functional Na+, K+ pumps at the basolateral
pole of rat OMCD. Therefore, reduced K+ secretion might result from inhibition of
apical K+ conductances and stimulation of basolateral K+ recycling. It is
proposed that increased Na+, K(+)-ATPase participates in the increased Na+
reabsorption prevailing in collecting ducts of K(+)-depleted rats.
PMID- 9555656
TI - Participation of mercuric conjugates of cysteine, homocysteine, and N
acetylcysteine in mechanisms involved in the renal tubular uptake of inorganic
mercury.
AB - Mechanisms involved in the renal uptake of inorganic mercury were studied in rats
administered a nontoxic 0.5 mumol/kg intravenous dose of inorganic mercury with
or without 2.0 mumol/kg cysteine, homocysteine, or N-acetylcysteine. The renal
disposition of mercury was studied 1 h after treatment in normal rats and rats
that had undergone bilateral ureteral ligation. In addition, the disposition of
mercury (including the urinary and fecal excretion of mercury) was evaluated 24 h
after treatment. In normal rats, coadministering inorganic mercury plus cysteine
or homocysteine caused a significant increase in the renal uptake of mercury 1 h
after treatment. The enhanced renal uptake of mercury was due to increased uptake
of mercury in the renal outer stripe of the outer medulla and/or renal cortex.
Ureteral ligation caused reductions in the renal uptake of mercury in all groups
except for the one treated with inorganic mercury plus N-acetylcysteine. Thus, it
appears that virtually all of the mercury taken up by the kidneys of the normal
rats treated with inorganic mercury plus N-acetylcysteine occurred at the
basolateral membrane. Urinary excretory data also support this notion, in that
the rate of excretion of inorganic mercury was greatest in the rats treated with
inorganic mercury plus N-acetylcysteine. Our data also indicate that uptake of
inorganic mercury in the kidneys of rats treated with inorganic mercury plus
cysteine occurred equally at both luminal and basolateral membranes. In addition,
the renal uptake of mercury in rats treated with inorganic mercury plus
homocysteine occurred predominantly at the basolateral membrane with some
component of luminal uptake. The findings of the present study confirm that there
are at least two distinct mechanisms involved in the renal uptake of inorganic
mercury, with one mechanism located on the luminal membrane and the other located
on the basolateral membrane. Our findings also show that cysteine and homologs of
cysteine, when coadministered with inorganic mercury, greatly influence the
magnitude and/or site of uptake of mercuric ions in the kidney.
PMID- 9555657
TI - Renal impairment in chronic cigarette smokers.
AB - To determine the effect of chronic cigarette smoking on renal function, a cross
sectional study was carried out with 30 subjects who had no known vascular
disease risk factor other than cigarette smoking, and 24 age- and sex-matched
controls without any vascular risk factor including cigarette smoking. Renal
function by radionuclide studies of renal plasma flow, GFR, and plasma endothelin
1 concentration was determined. Compared with nonsmokers, smokers had a renal
function impairment characterized by a normal GFR and a significant reduction in
renal plasma flow as reflected by MAG3 clearance (199.20 +/- 58.85 ml/min per
1.73 m2 versus 256.54 +/- 60.14 ml/min per 1.73 m2; t = 3.52, P < 0.001). MAG3
clearance was significantly correlated with age and smoking. The renal
dysfunction was associated with an increase in plasma endothelin-1 concentration
(21.56 +/- 1.15 pmol/L versus 25.01 +/- 3.21 pmol/L; t = 5.00, P < 0.001). Former
smokers as well had similar, although milder, abnormalities. In conclusion,
cigarette smokers manifest an impairment of renal function, suggesting that smoke
may have a detrimental effect on renal function.
PMID- 9555658
TI - Mesangial cells possess an asialoglycoprotein receptor with affinity for human
immunoglobulin A.
AB - Asialoglycoprotein receptor (ASGP-R), a hepatic lectin involved in the clearance
of galactose-terminal glycoproteins, is also present in extrahepatic tissues, but
its expression in renal cells is not well established. This study examines the
presence of ASGP-R in cultured mesangial cells (MC), key cells involved in the
removal of macromolecules deposited in the glomerulus. The binding of asialo
orosomucoid (ASOR) to rat MC was saturable and galactose-specific. In addition,
MC internalized and degraded ASOR in a Ca(2+)-dependent manner. Parallel studies
were performed in a homologous system (human MC), obtaining similar binding curve
and competition with unlabeled ASOR and carbohydrates. The purified receptor from
rat MC consisted of two proteins (41 and 55 kD) with similar size to the hepatic
receptor. Both subunits were detected by mRNA expression analysis (ratio 2:1).
Because the hepatic receptor presents avidity for the carbohydrates of IgA1, a
protein deposited in the glomerulus of patients with IgA nephropathy, the
interaction of IgA1 with the mesangial ASGP-R was explored. As for the
interaction with ASOR, catabolism of IgA1 by rat and human MC was Ca(2+)
dependent and was reduced with galactose. In addition, the interaction of ASOR
with rat MC was partially inhibited by incubation with IgA1 and its desialylated
form, but not by IgA2, as demonstrated in binding experiments and in receptor
purification. It is concluded that MC possess ASGP-R specific for galactose
residues of several glycoproteins, including IgA1. These data could be important
for a better understanding of the pathogenesis of IgA nephropathy.
PMID- 9555659
TI - Analyses of IgA1 hinge glycopeptides in IgA nephropathy by matrix-assisted laser
desorption/ionization time-of-flight mass spectrometry.
AB - This study was performed to analyze the structural variety of O-glycans on the
IgA1 hinge in IgA nephropathy (IgAN). The IgA1 fragments containing the hinge
glycopeptide (33-mer hinge peptide core (HP) + O-glycans) were separated from 13
IgAN patients, eight healthy control subjects, and 11 patients with other primary
glomerulonephritides by pyridylethylation, trypsin treatment, and Jacalin
affinity chromatography. Because of the use of Jacalin, only the Gal beta 1
3GalNAc residue containing IgA was analyzed. The molecular weights (MW) of the
IgA1 fragments treated by the following sequential treatment by exoglycosidases
were estimated using matrix-assisted laser desorption/ionization time-of-flight
mass spectrometry: (1) Sialidase treatment: the MW of the two observed peaks A
and B were compatible with (A) HP + 4GalNAc + 4Gal and (B) HP + 5GalNAc + 4Gal.
(2) Sialidase and galactosidase: the MW of the two identified peaks a and b were
consistent with (a) HP + 4GalNAc and (b) HP + 5GalNAc. (3) Sialidase,
galactosidase, and alpha-N-acetylgalactosaminidase. All subjects revealed one
peak, indicating the 33-mer IgA1 hinge peptide core. The intensity rate of peak
B/A was significantly decreased in the IgAN group (mean +/- SD, 1.01 +/- 0.08)
compared with the negative control subjects (healthy group, 1.15 +/- 0.06, P =
0.0048; other glomerulonephritis group, 1.13 +/- 0.10, P = 0.0049; Scheffe's F
test). These results suggested the presence of a defect in the Gal and/or GalNAc
residues in the IgA1 hinge glycopeptides in IgAN.
PMID- 9555660
TI - Thrombin regulates PDGF expression in bovine glomerular endothelial cells.
AB - The proteolytic enzyme thrombin is produced during activation of the coagulation
pathway. Intraglomerular fibrin deposition and thrombosis are common pathologic
features of several glomerular diseases, including transplant rejection. The
effect of thrombin on platelet-derived growth factor (PDGF) production and DNA
synthesis in well characterized bovine glomerular endothelial cells (G/endo) was
studied. DNA synthesis was measured as the amount of [3H]thymidine incorporated
into acid-insoluble material. PDGF released in the supernatant was measured by
Western blotting and by a radioreceptor assay. PDGF mRNA expression was analyzed
by solution hybridization, using human genomic PDGF B-chain (c-sis) and A-chain
cDNA probes. G/endo constitutively secrete PDGF activity in serum-free medium.
Thrombin stimulates PDGF production and increases the expression of mRNA that
hybridizes with labeled B-chain but not A-chain probe, whereas epidermal growth
factor and transforming growth factor-alpha stimulate the expression of PDGF A
chain mRNA. In addition, thrombin stimulates DNA synthesis with a peak effect at
24 h. Unlike endothelial cells from other microvascular beds, G/endo did not
respond to any of the three PDGF isoforms BB, AB, or AA. These data demonstrate
that bovine G/endo produce PDGF and that thrombin stimulates de novo synthesis of
PDGF from these cells. Because mesangial, but not bovine, G/endo express PDGF
receptors, PDGF released by G/endo is likely to modulate mesangial cell functions
such as proliferation and matrix production by means of a paracrine mechanism.
PMID- 9555661
TI - CD59 protects glomerular endothelial cells from immune-mediated thrombotic
microangiopathy in rats.
AB - CD59 is a cell membrane-bound complement regulatory protein on glomerular cells
that inhibits C5b-9 assembly and insertion. This report describes a recently
developed model of immune thrombotic microangiopathy (TMA) induced by the renal
artery perfusion of anti-glomerular endothelial cell (anti-GEN) antibody. To
examine the role of CD59 in protecting the GEN from immune-mediated injury, rats
underwent selective renal artery perfusion with F(ab')2 fragments of anti-CD59
monoclonal antibody to block CD59 activity or control mouse IgG followed by anti
GEN antibody or control goat IgG. Neutralization of CD59 in normal rats did not
result in any significant functional or histologic changes. Perfusion with anti
CD59 did not change deposition of the pathogenic anti-GEN IgG used to induce the
TMA model. However, neutralization of CD59 in the TMA model resulted in more C5b
9 formation in glomeruli, accompanied by increased platelet and fibrin
deposition, more severe endothelial injury, and reduced renal function compared
with the animals perfused with control F(ab')2 fragments. These results
demonstrate directly that CD59 serves a protective role for GEN in this TMA model
of rats, and confirm that C5b-9 formation has a critical pathogenic role in the
mediation of the disease. CD59 may play an important role in protecting
glomerular endothelium from other complement-mediated types of injury.
PMID- 9555662
TI - Characterization of two polymorphic sites in the human kinin B1 receptor gene:
altered frequency of an allele in patients with a history of end-stage renal
failure.
AB - On the basis of the genomic structure of the human B1 receptor (B1R) for kinins,
the presence of possible allelic polymorphisms of this gene was investigated
using restriction fragment-length polymorphism and single-strand conformation
polymorphism. The frequencies of the found alleles were determined in healthy
volunteers and in patients with a history of end-stage renal failure, because
there is evidence for a nephroprotective action of the kallikrein-kinin system.
An A1098-->G polymorphism has been identified in exon 3 in a minority of
volunteer blood donors, and is located 35 nucleotides downstream from the stop
codon and 14 nucleotides upstream from the polyadenylation signal. The frequency
of the G allele is 4.4% in the control sample and not significantly altered in
patients with a history of end-stage renal failure. A second and more frequent
polymorphism (18.1% of the alleles in the control group, prevalence of 33.3%)
consists of a single base substitution (G-699-->C) in the putative promoter
region. This polymorphism is significantly less frequent in the population of
renal failure patients (prevalence of 20.6%) and determines an increased activity
of the promoter function in constructions involving a reporter gene. The altered
prevalence of this allele was also found in some etiologic subgroups of uremic
patients. This study confirms the mapping of the B1R gene to 14q32. Other
investigators have mapped the bradykinin B2 receptor (B2R) gene to a close site
on human chromosome 14. A previously described B2R polymorphism (exon 2, C181-
>T) had an allele frequency of 9.7% in the control sample and appears to be
clinically neutral. The polymorphism of the B1R promoter may be a marker of
prognostic significance for the preservation of renal function in diseased
individuals.
PMID- 9555663
TI - A possible molecular basis of natriuresis during ischemic-reperfusion injury in
the kidney.
AB - Ischemic renal injury is associated with increased fractional excretion of
sodium, suggesting a Na+ reabsorption deficiency in renal tubules. To determine
whether alterations in expression of the major Na+ transporter genes might
contribute to the natriuresis that follows ischemic acute renal failure, the
expression of these genes was analyzed in renal cortex and medulla after ischemic
reperfusion injury. Rats were subjected to 30 min of renal pedicle clamping and
then sacrificed at 12, 24, or 48 h after reperfusion. Serum creatinine increased
significantly at 12 and 24 h, indicative of acute renal failure, but decreased
substantially by 48 h. mRNA levels for the NHE-3 Na/H exchanger of the proximal
tubule, the apical Na-K-2Cl cotransporter of the thick ascending limb of Henle,
the Na-Cl cotransporter of the distal convoluted tubule, the epithelial Na+
channel of the collecting duct, and the basolateral Na(+)-K(+)-ATPase were
measured by Northern hybridization. NHE-3 mRNA decreased by approximately 75% at
12 h and remained suppressed at 24 and 48 h after reperfusion. Na-K-2Cl
cotransporter mRNA decreased by approximately 88% at 12 h and remained suppressed
at 24 and 48 h. Na-Cl cotransporter mRNA remained unchanged at 12 h, decreased by
approximately 60% at 24 h, and returned to almost control levels at 48 h. mRNA
levels for sodium channels (beta subunit) remained unchanged. Na(+)-K(+)-ATPase
mRNA in the medulla decreased by approximately 35 to 40% at 12 and 24 h and by
70% at 48 h, whereas in cortex it decreased by only < 15% at 12 or 48 h after
reperfusion. These results suggest that sharp reductions in expression of the NHE
3 Na/H exchanger and the apical Na-K-2Cl cotransporter are major factors in the
natriuresis/diuresis that is one of the hallmarks of ischemic acute renal
failure. Lasting suppression of these transporters, despite improvement in renal
function, could contribute to the deranged NaCl and water excretion that often
leads to volume depletion during recovery from ischemic acute renal failure.
PMID- 9555664
TI - Role of IL-1 in renal ischemic reperfusion injury.
AB - Interleukin-1 (IL-1) is a central component of many acute inflammatory processes.
Blocking IL-1 receptor (IL-1R) with IL-1R antagonist (IL-1Ra) has attenuated
ischemic reperfusion injury in brain, heart, and liver models. However, the role
of IL-1 in renal ischemic reperfusion injury (IRI) is not known. Therefore, the
role of IL-1 in renal IRI was evaluated using the complementary approaches of IL
1R blockade in wild-type mice in addition to the study of renal IRI in IL-1R
knockout (KO) mice. Ischemia was induced by bilateral renal pedicle clamping for
30 min. IL-1Ra was administered at 10 mg/kg every 4 h, high doses that have been
protective in previous organ injury models in mice. IL-1R KO animals, previously
characterized as insensitive to IL-1, had the absence of IL-1R1 confirmed by DNA
blots. IL-1Ra, IL-1R KO, and control groups had similar elevations of blood urea
nitrogen (114 +/- 13, 133 +/- 11, and 120 +/- 11 mg/dl) and serum creatinine (1.7
+/- 0.3, 2.1 +/- 0.2, and 1.6 +/- 0.3 mg/dl) 24 h after ischemia. Furthermore,
acute tubular necrosis scores were also similar in IL-1Ra-treated mice (3.0 +/-
0.3), IL-1R KO mice (2.7 +/- 0.3), and control mice (3.1 +/- 0.2). However, both
IL-1Ra and IL-1R KO groups, compared with control animals, developed
significantly less infiltration of polymorphonuclear leukocytes per 10 high-power
fields in postischemic renal tissue (1111 +/- 228 and 967 +/- 198 versus 1820 +/-
190, P < 0.05). In contrast to the comparable renal functions at 24 h, recovery
of renal function was significantly accelerated in the IL-1R KO group compared
with control at both 48 (P < 0.05) and 72 (P < 0.05) h. Recovery in the IL-1Ra
group was similar to that in the control animals. These data demonstrate that IL
1 is unlikely to be beneficial in the recovery of renal function after ischemia
and may play a deleterious role.
PMID- 9555665
TI - Induction of apoptosis in ischemia-reperfusion model of mouse kidney: possible
involvement of Fas.
AB - Although ischemia-reperfusion of mouse kidney is known to cause severe renal
failure due to tubular cell death, the exact cellular mechanism responsible for
this phenomenon is not clear. To investigate the spatial and temporal development
of renal cell death and the role of Fas/APO-1/CD95 (Fas) in this process, the
left renal vessels were occluded in a group of mice for 30, 60, or 120 min
followed by reperfusion for 24 h (n = 4 for each group). Analysis of the isolated
DNA in agarose-gel electrophoresis revealed a typical ladder pattern of bands
consisting of multiples of 180 to 200 bp, considered the hallmark of apoptosis.
The intensity of the bands increased proportionately with the duration of
ischemia. Histochemical analysis using terminal deoxynucleotidyl transferase
mediated dUTP-biotin nick end labeling showed the presence of nuclei with DNA
double-strand breaks specifically in distal renal tubules of the outer medulla.
The presence of apoptosis was also confirmed by electron microscopy. Analysis of
total RNA by Northern blotting revealed one appropriate-sized band for Fas mRNA
in the normal kidney, which intensified in the ischemia-reperfused kidney.
Moreover, nonradioactive in situ hybridization revealed that distal renal tubular
epithelial cells were positive for Fas mRNA in the outer medulla. Fas antigen was
also localized to the renal tubular epithelial cells of the outer medulla by
immunohistochemistry. The number of apoptotic cells in the ischemia-reperfusion
kidney of the lpr/lpr mouse was low. These findings strongly indicate that
ischemia-reperfusion of the kidney induces apoptosis of a specific area of
tubular epithelial cells in the outer medulla through the Fas system.
PMID- 9555666
TI - Evolution of tubulointerstitial fibrosis in experimental renal infection and
scarring.
AB - Renal tubulointerstitial fibrosis may result from a loss of tubulointerstitial
volume, which produces a disproportionate increase in the density of matrix. This
study examines the relationship between fibrogenesis and collapse in scar
formation after experimental renal infection. Escherichia coli were inoculated
into the renal cortex of Sprague Dawley rats, with saline substituted in a
control group. Glomerular, tubular, and interstitial profile areas were
determined. Density of glomerular profiles was used as a measure of
tubulointerstitial collapse. Collagen type I, III, and IV expression was examined
by in situ hybridization and immunohistochemistry. Myofibroblasts were identified
by alpha smooth muscle actin immunohistochemistry, and matrix metalloproteinase-1
(MMP-1) and MMP-2 were localized with appropriate antisera. Acute interstitial
edema was followed by increasing density of glomerular profiles, paralleled by
loss of interstitial volume and progressive tubular atrophy. Glomerular profile
area remained unchanged. Density of glomerular profiles was not temporally
related to myofibroblast accumulation. Procollagen alpha 1(I), alpha 1(III), and
alpha 1(IV) transcription was focal, spatially related but temporally ordered.
Collagen I, III, and IV immunostaining was increased from days 3, 24, and 100,
respectively (P < 0.05 versus day 0 and day 100 saline). However, when corrected
for glomerular density, collagen I immunostaining decreased between days 24 and
100, whereas collagen III and IV no longer differed from day 0. MMP staining
within the lesion was confined to occasional interstitial and epithelial cells
throughout. It is concluded that in this model, contraction and collapse of the
tubulointerstitial parenchyma has a greater influence than new collagen
production on final fibrotic density.
PMID- 9555667
TI - Exogenous norepinephrine induces an enhanced microproteinuric response in
microalbuminuric insulin-dependent diabetes mellitus.
AB - Exogenous norepinephrine (NE) increases intraglomerular pressure in animal
experiments, but it is unknown whether NE induces a microproteinuric response in
humans. Moreover, it has not been studied whether possible microproteinuric and
renal hemodynamic changes induced by NE are altered in insulin-dependent diabetes
mellitus (IDDM) complicated by microalbuminuria. Therefore, the microproteinuric
and renal hemodynamic responses to exogenous NE infusions were measured in eight
matched normoalbuminuric IDDM patients (group D1), microalbuminuric IDDM patients
(group D2), and control subjects (group C). As anticipated, mean arterial
pressure (MAP)-NE dose-response curves were significantly shifted leftward in
groups D1 and D2 compared with group C (P < 0.05), indicating a higher systemic
NE responsiveness in IDDM. On separate days, NE or placebo was infused at
individually determined NE threshold doses (T; delta MAP = 0 mmHg), 20% pressor
doses (20% P; delta MAP = 4 mmHg), and pressor doses (P; delta MAP = 20 mmHg),
with measurement of urinary albumin (UalbV), IgG excretion (UIgGV), GFR (by 125I
iothalamate), and effective renal plasma flow (by 131I-hippurate). At NE pressor
dose, UalbV and UIgGV rose in all groups (P < 0.05 to 0.01), whereas urinary beta
2-microglobulin was unchanged. The increases in UalbV and UIgGV were more
pronounced in the microalbuminuric group than in the other groups (P < 0.05). An
NE dose-dependent fall in effective renal plasma flow and rise in filtration
fraction were found in all groups (P < 0.05 to 0.001 for all), whereas GFR did
not change significantly. The renal hemodynamic dose-response relationship was
similar in the groups. In conclusion, exogenous NE acutely promotes glomerular
protein leakage, and it is plausible that intraglomerular NE effects contribute
to this phenomenon. The microproteinuric response is enhanced in microalbuminuric
IDDM despite unaltered renal hemodynamic responsiveness, which may reflect a
specific NE response or a general effect of vasopressor stimuli to promote
glomerular protein leakage in patients with a preexistent defect in glomerular
permselectivity.
PMID- 9555668
TI - Neutrophil impairment associated with iron therapy in hemodialysis patients with
functional iron deficiency.
AB - Hemodialysis patients treated with recombinant human erythropoietin (rhEPO) need
adequate iron supplementation to avoid rhEPO hyporesponsiveness due to iron
deficiency. Low serum ferritin reflects absolute iron deficiency, whereas normal
or high ferritin values in combination with low transferrin saturation (< 20%)
indicate functional iron deficiency. In this study, healthy subjects (group I)
were compared with intravenous (i.v.) rhEPO-treated and i.v. iron-saccharate
treated regular hemodialysis patients that were subdivided into three groups as
follows: patients with serum ferritin > 100 and < 350 micrograms/L (group II),
patients with ferritin < 60 micrograms/L (group III), and patients with ferritin
> 650 micrograms/L but transferrin saturation < 20% (group IV). Polymorphonuclear
leukocyte (PMNL) parameters (phagocytosis, intracellular killing of bacteria,
oxidative metabolism, glucose uptake, intracellular calcium) for each group were
compared with those of multitransfused, iron-overloaded primary hematologic
patients (group V) and those of patients suffering from hereditary
hemochromatosis (group VI). Compared with PMNL obtained from healthy subjects
(group I), group II hemodialysis patients showed mild inhibition of phagocytosis
but significant inhibition of intracellular killing of bacteria. Oxidative burst
of PMNL from group II patients was also significantly reduced after stimulation
in vitro. These dysfunctions were not affected by absolute iron deficiency
(comparable data in group III patients). However, impairment of PMNL was markedly
aggravated in group IV patients. Intracellular calcium concentration under basal
conditions and after stimulation was not different. These data suggest that iron
is responsible for the PMNL dysfunctions observed in group IV patients. The PMNL
defect of group IV patients was comparable to group V and group VI patients with
normal renal function, suggesting again a direct inhibitory effect of iron. It is
concluded that hemodialysis patients with high ferritin but low serum iron and
low transferrin saturation ("functional iron deficiency") display a significant
impairment of fundamental PMNL functions during i.v. iron and rhEPO therapy. This
may result in increased risk of infectious complications. Therefore,
overtreatment of hemodialysis patients with i.v. iron should be avoided.
PMID- 9555669
TI - Intravenous infusion of total dose iron is superior to oral iron in treatment of
anemia in peritoneal dialysis patients: a single center comparative study.
AB - In the treatment of anemia of chronic renal failure, the most common cause of
recombinant human erythropoietin (rhEPO) resistance is iron deficiency. In
peritoneal dialysis (PD) patients, oral iron therapy is an accepted and
convenient method of iron supplementation. The effectiveness of oral iron,
however, is limited by many factors, including gastrointestinal side effects and
poor gastric absorption. This study prospectively compared the efficacy of single
intravenous infusion of total dose iron (ITDI group) given in an outpatient
setting with oral iron (oral group) for the treatment of anemia in PD patients.
Twenty-five adult stable PD patients with baseline hematocrit 25 to 35% were
entered into the study. Thirteen patients with serum transferrin saturation
(TSAT) < 25% received ITDI, and 12 patients with TSAT between 25 and 35% received
oral iron. One patient in the oral group received emergent blood transfusion and
was excluded from analysis. Hematocrit and iron indices were measured at monthly
intervals. Doses of rhEPO were adjusted monthly to maintain target hematocrit at
35%. At the end of the study (6 mo), despite similar baseline mean hematocrit
(31.0 +/- 0.9 versus 33.0 +/- 1.0%), comparable mean baseline weekly rhEPO dose
(7886 +/- 1449 versus 6370 +/- 1553 U/wk), and significantly lower level of mean
TSAT (11.3 +/- 3.5 versus 30.1 +/- 3.5%; P < 0.05), the ITDI group when compared
with the oral group had significantly higher mean hematocrit (36.0 +/- 1.0 versus
31.4 +/- 1.1%; P < 0.05) and TSAT (33.7 +/- 3.7 versus 22.6 +/- 4.0%; P < 0.05)
values. In addition, the final mean dose of weekly rhEPO was significantly lower
in the ITDI group (4799 +/- 981 versus 9998 +/- 1027 U/wk; P < 0.05). No patient
in the ITDI group developed an adverse reaction to intravenous iron. It is
concluded that ITDI represents a more efficacious method of iron supplementation
in PD patients receiving rhEPO. Moreover, ITDI is safe and well tolerated and can
be administered in an outpatient setting.
PMID- 9555670
TI - New strategies to prevent Staphylococcus aureus infections in peritoneal dialysis
patients.
AB - The importance of Staphylococcus aureus as etiological agent for catheter-related
infections and peritonitis in peritoneal dialysis patients is well established.
To evaluate groups at risk of developing Staphylococcus aureus infections, nasal
and exit-site cultures were performed in 76 peritoneal dialysis patients monthly
over a period of 3 yr. The risk of Staphylococcus aureus catheter infection was
significantly higher in diabetic (group 1) and immunosuppressed (group 2)
patients compared with nondiabetic and nonimmunosuppressed (group 3) patients. In
diabetic patients, Staphylococcus aureus-positive nasal cultures were more
frequent than positive cultures taken from the bland exit-site (73.3% versus
60.0%). On the other hand, both positive and negative exit-site cultures had a
better prognostic value for Staphylococcus aureus catheter infection compared
with nasal cultures. In immunosuppressed patients, both nasal and exit-site
carriages were associated with a very high risk of Staphylococcus aureus catheter
infection, but nasal swabs were far more often positive than swabs from the bland
exit-site (72.7% versus 25.0%). However, the risk of infection was also high for
non-nasal and non-exit-site carriers in this group. In nondiabetic and
nonimmunosuppressed patients, the risk of Staphylococcus aureus catheter
infection was increased only if two or more positive nasal cultures were
detected. It is concluded that in diabetic patients, antibiotic prophylaxis
should be performed in all Staphylococcus aureus exit-site carriers. All
immunosuppressed patients should be treated prophylactically. In contrast, in
nondiabetic and nonimmunosuppressed patients, prophylactic treatment should be
considered only in nasal carriers with two or more positive cultures. The overall
low peritonitis rate does not influence this prevention strategy.
PMID- 9555671
TI - Analysis of fracture prevalence in kidney-pancreas allograft recipients.
AB - Fractures occur in 11 to 26% of renal allograft recipients after transplantation
despite improvements in bone and mineral disorders. This high fracture rate is
likely a consequence of accelerated osteopenia. The cause of posttransplant bone
loss is multifactorial, and patients with insulin-dependent diabetes mellitus and
renal failure may have additional fracture risks such as low turnover bone
disease. This retrospective cohort study was undertaken to determine the long
term incidence and the potential risk factors of posttransplant fractures in
patients with insulin-dependent diabetes mellitus undergoing combined kidney
pancreas allograft transplantation. Thirty-five patients with insulin-dependent
diabetes mellitus who received a combined kidney-pancreas allograft between 1987
and 1992 were evaluated. Thirty-five kidney allograft recipients matched for age,
gender, and the date of transplant were also reviewed. The fracture incidence in
the kidney-pancreas group was 49% after transplantation. The rate of first
fracture after kidney-pancreas transplantation was 12.1% per patient year,
resulting in a 5-yr fracture-free rate of 48%. The initial fracture occurred at a
mean of 31.06 +/- 19.9 mo. Steroid exposure was found to increase the risk of
fracture, and analysis by means of a Cox regression model estimated that an
increase in cumulative steroid exposure of 10 mg/kg at any given month increased
the hazard of sustaining a fracture by 9% (95% confidence interval for hazard
ratio, 1.01 to 1.18; P = 0.031). This analysis suggests that kidney-pancreas
recipients are at significant risk of sustaining a fracture within a few years
after transplantation.
PMID- 9555672
TI - Predictors of mortality and the provision of dialysis in patients with acute
tubular necrosis. The Auriculin Anaritide Acute Renal Failure Study Group.
AB - To explore the natural history of critically ill patients with acute renal
failure due to acute tubular necrosis, we evaluated 256 patients enrolled in the
placebo arm of a randomized clinical trial. Death and the composite outcome,
death or the provision of dialysis, were determined with follow-up to 60 d. The
relative risks (RR) and 95% confidence intervals (95% CI) associated with
routinely available demographic, clinical, and laboratory variables were
estimated using proportional hazards regression. Ninety-three (36%) deaths were
documented; an additional 52 (20%) patients who survived received dialysis.
Predictors of mortality included male gender (RR, 2.01; 95% CI, 1.21 to 3.36),
oliguria (RR, 2.25; 95% CI, 1.43 to 3.55), mechanical ventilation (RR, 1.86; 95%
CI, 1.18 to 2.93), acute myocardial infarction (RR, 3.14; 95% CI, 1.85 to 5.31),
acute stroke or seizure (RR, 3.08; 95% CI, 1.56 to 6.06), chronic
immunosuppression (RR, 2.37; 95% CI, 1.16 to 4.88), hyperbilirubinemia (RR, 1.06;
95% CI, 1.03 to 1.08 per 1 mg/dl increase in total bilirubin) and metabolic
acidosis (RR, 0.95; 95% CI, 0.90 to 0.99 per 1 mEq/L increase in serum
bicarbonate concentration). Predictors of death or the provision of dialysis were
oliguria (RR, 5.95; 95% CI, 3.96 to 8.95), mechanical ventilation (RR, 1.53; 95%
CI, 1.07 to 2.21), acute myocardial infarction (RR, 1.95; 95% CI, 1.24 to 3.07),
arrhythmia (RR, 1.51; 95% CI, 1.04 to 2.19), and hypoalbuminemia (RR, 0.56; 95%
CI, 0.42 to 0.74 per 1 g/dl increase in serum albumin concentration). Neither
mortality nor the provision of dialysis was related to patient age. These
observations can be used to estimate risk early in the course of acute tubular
necrosis. Furthermore, these and related models may be used to adjust for case
mix variation in quality improvement efforts, and to objectively stratify
patients in future intervention trials aimed at favorably altering the course of
hospital-acquired acute renal failure.
PMID- 9555673
TI - The aging kidney: insights from experimental studies.
AB - The rat provides a useful experimental model to study of the mechanisms of kidney
aging. As in man, a wide diversity in the renal response to aging occurs in the
rat, and because of this variability it is important to always specify
experimental conditions, i.e., strain, gender, diet, and environment. Most aging
rats display chronic progressive nephrosis, although the rate at which injury
develops is highly variable. There are a number of known risk factors that
potentiate injury, including male gender, genetic background, obesity, high
protein/high calorie diet, and environmental exposure to pathogens. The causes of
age-dependent glomerulopathy are multifactorial and include an imbalance between
synthesis and degradation of extracellular matrix products, as well as
hemodynamic alterations. Of importance, this damage is not inevitable and can be
dissociated from normal kidney aging when optimal conditions for successful aging
are provided. There is complex and sometimes contradictory information on
vasoactive factors. It is, likely, however, that the activity of intrarenal AngII
is somehow upregulated in the aging kidney of some, but not all, strains, and
alpha 1-dependent renal nerve activity may also be enhanced. The endothelial
vasodialtory prostaglandins and NO exert an increasingly important role in the
maintenance of renal perfusion with advancing age, although their production may
be diminished. In the future, we anticipate that comparison of rats with
different genetic backgrounds will help to dissociate true aging from disease.
PMID- 9555674
TI - Hospital-acquired acute renal failure.
PMID- 9555676
TI - Women, wine, and information whiplash.
PMID- 9555675
TI - The treatment of chronic uremia by means of intermittent hemodialysis: a
preliminary report. 1960.
PMID- 9555677
TI - Sexual addiction: a new phenomenon?. Interview by J.G. Meisler.
PMID- 9555678
TI - All's fair ... but not in diabetes women's unique vulnerability: Part I.
PMID- 9555679
TI - Choices: biomedical ethics and women's health. Ethical issues and dilemmas.
PMID- 9555680
TI - Nutriceutical review of St. John's wort (Hypericum perforatum) for the treatment
of depression.
PMID- 9555681
TI - Obesity is no laughing matter.
PMID- 9555682
TI - The role of weight loss drugs in the treatment of obesity in women.
PMID- 9555684
TI - Preventing coronary disease in women: brief observations from the clinical data.
PMID- 9555683
TI - The special prenatal clinic: one approach to women and substance abuse.
AB - We aimed to determine if the trend in substance use in this central core of a
large inner-city area confirmed an increase in marijuana use among young women <
22 years of age as childbearing years were beginning or if marijuana use and
harder drug use were greatest among women beyond the teens and the early second
decade of life and to describe one prenatal care intervention. Statistical
reports for the Special Prenatal Clinic, a Harlem clinic for women with a current
or past history of substance use, were reviewed from 1985 (the clinic's
inception) through March 1996 to determine the trends, patterns, and types of
drug use. Findings chronicled the beginning and rise in crack cocaine use,
especially after 1986, confirmed an increase in marijuana use by adolescents
since 1992, and suggest that the risk for use of hard drugs increases with age,
predominantly in the childbearing years. Intervention by the Special Prenatal
Clinic aided case-finding, allowed for comprehensive care, offered women
opportunities for behavior change, and increased their chances of keeping their
babies after delivery.
PMID- 9555685
TI - Cardiovascular disease in women: gender-specific aspects of hypertension and the
consequences of treatment.
AB - The epidemiology, clinical course, response to treatment, and ultimate outcome of
essential hypertension vary as a function of gender. Three early trials on
hypertension reported an increase in all-cause mortality in treated white women
compared with black women or with men of both races. Later studies, however,
suggest that drug therapy has similar and beneficial effects in hypertensive men
and women. Women may tolerate hypertension better than do men. Diastolic
hypertension correlates with higher mortality from coronary artery disease in men
than in women. Special considerations apply to treating the hypertensive woman.
Use of oral contraceptives may precipitate or accentuate the problem. In
contrast, in the postmenopausal female, estrogen replacement may actually improve
hypertension, via several mechanisms. These include the impact of the hormone on
vasomotricity, its enhancement of baroreceptor sensitivity, and its impact on the
hyperinsulinemia characteristic of menopause. Treatment of hypertension must be
individualized with respect to gender. More data on the consequences of treatment
of women with hypertension are needed, particularly longterm studies to assess
the impact of treatment on mortality.
PMID- 9555686
TI - Bulimia: a primary care approach.
AB - More common than anorexia and less easily detected, bulimia typically begins as
an effort to control weight. Although the prognosis is better than that for
anorexia nervosa, a number of medical complications can arise related to the mode
of purging. Some of these complications can have profound deleterious sequelae if
not diagnosed and treated.
PMID- 9555687
TI - Prior oral contraceptive use is associated with higher blood pressure in older
women.
AB - Studies of young, premenopausal women suggest that changes in coronary risk
factors do not persist after discontinuation of oral contraceptive use. However,
little is known about longterm effects of past oral contraceptive use in older,
postmenopausal women, who typically have a more atherogenic profile. This study
examines the relation of past oral contraceptive use (including duration) to
heart disease risk factors in postmenopausal women. Subjects were 517 women aged
50-69 from the Rancho Bernardo Study who attended follow-up clinic visits. Past
oral contraceptive use was reported by 24.2% and two thirds had used oral
contraceptives < or = 5 years. After adjustment for covariates, the only
significant difference was that past users had higher diastolic blood pressures
than never users (p < 0.01). Among older women, the diastolic blood pressure of
past users was 3.9 mm Hg higher than that of never users (p < 0.01). Women who
used oral contraceptives for < or = 5 years had diastolic blood pressures 3.6 mm
Hg higher than those of never users (p < 0.01). No differences were found among
younger women or those who used oral contraceptives > or = 6 years. Past oral
contraceptive users may be at increased risk for heart disease because of a small
but significant elevation in diastolic blood pressure that persists many years
after discontinuing oral contraceptive use.
PMID- 9555688
TI - Predicting anonymous egg donor satisfaction: a preliminary study.
AB - Our aim was to assess the psychologic characteristics and postdonation
satisfaction of anonymous oocyte donors. Twenty-five consecutive anonymous oocyte
donors completed psychologic tests before donation and satisfaction ratings
following completion of the egg donation cycle. The average donor was 27 years
old, married, and employed outside the home. All predonation scores on the
psychologic measures were within the normal range. However, 24% of donors
reported a history of sexual assault, and 40% described having had some type of
reproductive loss. Although monetary compensation for donation was provided,
altruism was reported as the most salient motivating factor. Following oocyte
donation, 80% of women stated that they would be willing to donate again.
Postdonation satisfaction was high. A significant negative correlation was found
between predonation financial motivation and postdonation satisfaction (r = -.48,
p < 0.01) and between predonation ambivalence and postdonation satisfaction (r =
.84, p < 0.0001). Donors with high levels of predonation financial motivation or
ambivalence should be carefully screened and counseled before oocyte donation to
ensure satisfactory psychologic outcome.
PMID- 9555689
TI - Predictors of mammography use among women veterans.
AB - We examined mammography use patterns of women veterans and explored Veterans
Administration (VA) health care use and military experience as predictors of
mammography use by this population. We conducted a national telephone survey of
women veterans. A sample of 397 women veterans was selected from all military
discharges from 1971 through 1994. A 3 x 2 stratification scheme was used: three
age groups (35-49, 50-64, > or = 65 years old) and two VA user groups indicating
whether (VA user) or not (VA nonuser) they received any health care from a VA
Medical Center in the last 5 years. The response rate was 75% (297 of 397).
Analyses included bivariate techniques and weighted logistic regression. We found
that women veterans told to have a mammogram by a health care professional were
more than five times more likely to have ever had a mammogram (OR 5.41, CI 4.63
6.32) and nearly twice as likely to have had a mammogram within the past 2 years
(OR 1.81, CI 1.57-2.09) as those who were not told to do so, controlling for age,
race, VA user status, and length of military service. Regular VA users were more
likely to have had a mammogram ever and within the past 2 years, controlling for
other factors. Mammography use was not necessarily at a VA medical center.
Interventions that promote better provider-patient communication and target older
women veterans may have the most potential benefit. Whether VA health care is
filling an important gap in access to mammography for older women veterans is an
important policy question and warrants further research.
PMID- 9555690
TI - Changes in sick leave rates and the use of pregnancy-associated social benefits
among pregnant Swedish women: an outcomes study.
AB - We attempted to determine if an amended social security system has lessened the
rate of sickness absence during pregnancy in Sweden over the period 1978-1989. We
studied the records of 3998 women who gave birth in 1978, 1986, 1988, and 1989 at
the University Hospital in Linkoping and the Varnamo County Hospital.
Retrospective collection of all data concerning the rates and durations of
sickness absence during pregnancy, drawing of parental benefit, and use of
granted pregnancy benefit was performed from Sweden's standardized social
security files. Obstetric variables concerning the course and outcome of
pregnancy and delivery, as well as the health status of the newborns, were
obtained from standardized and antenatal care and delivery files. Between 1978
and 1989, the rate of sickness absenteeism during pregnancy increased by almost
100% for periods of absence not supported by a doctor's certificate and by about
50% for those with a doctor's certificate. During the same time, the average
number of days of sick leave per pregnant woman more than doubled. The changes
were most apparent among younger pregnant women. During the decade studied, no
significant differences were found with regard to antenatal care, modes of
delivery, or the health status of the newborns. In spite of the introduction
within the Swedish social security system of more generous rules for pregnant
women, the changes in the rates of registered sick leave during pregnancy
observed over time were most unfavorable. The present study indicates that the
rate of sick leave during pregnancy reflects a complex social phenomenon and
cannot be explained solely by an increase in the rate of actual illness or
sickness. Such a rate is also likely to depend on general attitudes and
expectations among pregnant women, which may vary over time. When amendments in
social benefits for pregnant women are considered to improve the health status of
the pregnant population, society ought to clearly define the precise aim pursued
and the consequences expected to escape unintended socioeconomic results.
PMID- 9555691
TI - Bilaterality and recurrence rates for lobular breast cancer: considerations for
treatment. Ann Surg Oncol 1997;4(3):198-202.
PMID- 9555692
TI - Neonatal outcome in women treated for the antiphospholipid syndrome during
pregnancy. J Perinat Med 1997;25(2):192-196.
PMID- 9555693
TI - National treatment trends for ductal carcinoma in situ of the breast. Arch Surg
1997 Jun;132:660-665.
PMID- 9555694
TI - Analysis of long-term Elmiron therapy for interstitial cystitis. Urology
1997;49(Suppl 5A):93-99.
PMID- 9555695
TI - Brachytherapy and breast cancer. Semin Surg Oncol 1997;13:190-195.
PMID- 9555696
TI - Literature Watch.
PMID- 9555697
TI - [Postoperative results of stapes revision].
AB - BACKGROUND: In this retrospective study indications, intraoperative findings,
reconstruction techniques and postoperative hearing results in revision stapes
surgery were evaluated. PATIENTS: Between March 1988 and January 1996, 150
patients underwent stapes revision. Indications for surgery were the presence of
conductive hearing loss (132), dizziness (12), sensorineural hearing loss (3),
deafness (2), and tinnitus (1). RESULTS: Intraoperative findings were lateral
migration of the implant, regrowth of bone in the oval window niche, erosion of
incus, cholesteatoma, and others. In most cases a new prosthesis (gold piston)
was inserted between incus and vestibulum. In cases with incus erosion, a
malleovestibulopexy was performed. Seventy-three percent of patients who
underwent revision stapes surgery because of conductive hearing loss showed a
hearing improvement of 20 dB or more. All patients who underwent revision stapes
surgery because of dizziness reported an improvement of their symptoms
postoperatively. CONCLUSIONS: Revision stapes surgery should be approached by
experienced surgeons, because the risk of severe sensorineural hearing loss is
higher than at the time of primary stapedectomy. Informed consent is mandatory.
PMID- 9555698
TI - [Fixation of the temporarily removed posterior wall of the auditory canal with
plate osteosynthesis: a new technique].
AB - BACKGROUND: Temporary removal of the posterior external ear canal wall allows
excellent exposure of the middle ear and epitympanum without the negative
sequelae of a cavity as can occur after canal-wall down procedures. Safe fixation
of the bony canal wall, however, has not always been possible with a risk for
prolonged healing and bone necrosis. MATERIAL AND METHODS: A new technique
permits rigid internal fixation of the posterior canal wall. A titanium miniplate
of 10 holes length commonly used for orbital rim surgery is adapted to the
cortical surface of the mastoid just posterior to the external ear canal. Six
holes for 1.3 mm screws are drilled into the cortical bone: two screws behind the
ear canal, two screws on the temporal line, and two on the mastoid tip. All
fixation material is then removed and a mastoidectomy is carried out with
preservation of the cortical bone for the screws. The external ear canal skin,
which has been incised previously near the fibrous annulus with lateral
extensions, is mobilized laterally using a newly designed retroflected
microraspatory. This creates a vital skin flap that might be essential to avoid
bone necrosis. No other skin incisions are needed in the canal. The posterior
bony canal wall is cut using an oscillating saw Osseoscalpel, secured by facial
nerve monitoring. After middle ear surgery and tympanoplasty have been completed,
the canal wall is repositioned and fastened precisely in its place with rigid
internal fixation allowing a secure stabilization. RESULTS: This new technique
has proven to be safe and reliable on the first five patients. There has been no
bone necrosis within an observation period of 18 months. CONCLUSIONS: Rigid
internal fixation is an alternative technique to safely readapt the posterior
auditory canal wall.
PMID- 9555699
TI - [Functional long-term results after open cholesteatoma surgery and ossiculoplasty
with allogenic ossicles in adulthood].
AB - BACKGROUND: Characteristic features of cholesteatoma of the middle ear are
destruction of the bone and a high tendency for recurrent disease. The choice of
surgical procedure is determined by audiological results and the rate of
recurrent cholesteatoma. PATIENTS: One hundred fifty patients who underwent
primary cholesteatoma surgery were investigated 3-5 years postoperatively.
Preoperative and postoperative audiological results and rate of revision surgery
were compared for the respective surgical procedures. All cholesteatomas were
treated with an open surgical technique. The lateral attic walls and
cholesteatomas were removed. RESULTS: Cholesteotoma recurred in 15 patients
(10%). Primary reconstruction of the ossicular chain with a tympanoplasty (type
III) was performed in 98 patients in the first operation. Approximately 80% of
patients treated with a type III tympanoplasty had a maximum postoperative air
bone gap of 20 dB in the main speech range, depending on the frequency. In about
50% of patients, this value was 10 dB or less. Comparison of preoperative and
postoperative conductive hearing loss between 250 Hz and 8000 Hz revealed an
improvement (p < 0.05) of 10 dB (500 Hz, 3000 Hz, 4000 Hz) and 15 dB (250 Hz,
1500 Hz, 2000 Hz, 8000 Hz). CONCLUSIONS: In our opinion, a second look operation
should be performed in cases where a large cholesteatoma cannot be removed with
sufficient reliability. This applies especially to a cholesteatoma in the oval
window. Here, we suggest second-look surgery after one year.
PMID- 9555700
TI - [Hearing loss caused by high dose carboplatin therapy].
AB - BACKGROUND: Carboplatin is regarded as a non-ototoxic or low-grade ototoxic
chemotherapeutic agent. METHOD: We report on three patients with a recurrence of
testicular cancer after cisplatin chemotherapy who suffered hearing loss after
subsequent high-dose carboplatin therapy. RESULTS: Audiometry demonstrated
carboplatin-induced hearing loss primarily in the mid-range and high frequencies
up to 45 dB at 3 kHz and up to 55 dB at 8 kHz. In two of three patients,
transitory-evoked otoacoustic emissions were absent after carboplatin therapy.
CONCLUSION: Following first-line cisplatin chemotherapy, salvage treatment with
high-dose carboplatin can generate hearing loss in the middle and high
frequencies.
PMID- 9555702
TI - [Voice rehabilitation after total laryngectomy. Voice prostheses or esophageal
replacement voice?].
AB - BACKGROUND: During the last years tracheoesophageal fistula has a well
established role and in several units is now the principal means of speech
rehabilitation following laryngectomy. The purpose of this study is to present
the long term results after using the Provox voice prosthesis and to compare the
phonetic results obtained with this means of speech rehabilitation with
esophageal speech. PATIENTS, METHODS, AND RESULTS: During the last 7 years, 265
laryngectomy patients were trained in our Department in an effort to develop
esophageal speech. One hundred and twelve of them developed comprehensive speech
of various quality. In another group consisting of 35 patients, a Provox low
resistance, self-retaining prosthesis was fitted. Twenty-nine of them developed a
very good voice. Ten patients of each group were tested in order to estimate the
quality of voice of the two methods. Three measurements were obtained from each
patient: the maximal intensity, the maximal phonation time, and the number of
syllables with one breath. CONCLUSION: All the results confirmed the better
quality of the tracheo-esophageal speech. The main two advantages of the
prosthesis are the effortless speech due to the low resistance of the valve and
the simple maintenance by the patient. The most important disadvantage is the
cost and the need to occlude the stoma during phonation. Conclusively each method
of speech rehabilitation should be selected individually according to the needs,
desire, and abilities of every patient.
PMID- 9555701
TI - [Hypopharyngeal carcinomas and radical operation--can one refrain from total
laryngeal excision?].
AB - BACKGROUND: Patients with hypopharyngeal carcinoma have a poor prognosis. In
reviewing patients treated at our clinic from 1977 to 1990, we wanted to find out
how this prognosis is influenced by the degree of surgical radicality (total vs.
partial laryngectomy). METHODS: From 1984 to 1990, 46 patients with carcinoma of
the hypopharynx were treated at the ENT department of ZKH St.-Jurgen-Strasse in
Bremen and followed up for 5 years. All patients had been treated by radiotherapy
and all, except 3 patients, had had additional surgery of the lymph nodes. In 14
patients the primary tumor had been only irradiated (group 1), and in 32 patients
it had been removed by surgery (groups 2 and 3). Surgical removal of the primary
tumor had been combined with partial resection of the hypopharynx and of the
larynx only (group 2) or with total laryngectomy (group 3). There were no
differences in tumor stages between groups 1 and 3, which comprised mainly stages
III and IV. Stages I and II were overrepresented in group 2. RESULTS: The 5-year
survival rate was 37% for all patients, and for groups 1, 2 + 3, 2 and 3, 31%,
40%, 58%, and 28%, respectively. DISCUSSION: These results are superior to those
obtained between 1977 and 1983 for 49 patients who had been treated either by
excision of the primary tumor combined with laryngectomy, or by irradiation
alone, without neck dissection. The respective 5-year survival rates were 19% for
all patients, 11% for the group of radiotherapy alone, and 33% for patients
undergoing additional surgery. CONCLUSION: In our opinion less radical surgical
procedures are justified for the treatment of hypopharyngeal cancer.
PMID- 9555703
TI - [Long-term functional outcome of Laccourreye hemipharyngectomy-hemilaryngectomy
with reference to oncologic outcome].
AB - BACKGROUND: Various techniques for the treatment of hypopharyngeal malignancies
are used to achieve disease control while preserving laryngeal function. PATIENTS
AND METHODS: This study details the long-term results of 22 patients (ages 39-80;
average age 57 years) following hemipharyngo-hemilaryngectomy (described by
Laccourreye) for unilateral hypopharyngeal squamous cell carcinomas (G2-G3; T1
T4; N0-N3). Follow-up was 16-83 months (average 43) and included extensive speech
and swallowing assessment. From 1989-1994 the procedure was performed in 26
patients. Two died within one year postoperatively, two were lost for follow-up,
and 22 were included in this study. RESULTS: One patient developed recurrent
disease with liver metastasis; two patients were successfully treated for
recurrent disease. Two patients developed second primary tumors, while all others
had no signs of recurrent disease. Fourteen patients had no difficulties eating
or drinking. Six patients could only eat soft foods, and two patients required a
gastrostomy feeding tube. Nineteen patients had a useful but hoarse voice, and
three patients had severe difficulties when communicating. Modulation of voice
was decreased because the supraglottic structures (mainly false cord and scar
tissue) were used for phonation. Eighteen patients were completely satisfied with
their voice. The tracheotomy was closed in 18 patients within six months, while
four patients required a tracheostoma for more than two years. CONCLUSIONS: These
data show that function-preserving surgical techniques can be successfully used
in hypopharyngeal carcinomas even for patients with advanced disease. Useful
functional results for swallowing, voice, and airway were achieved in most
patients undergoing this procedure.
PMID- 9555704
TI - [Epistaxis strategy--experiences with the last 360 hospitalizations].
AB - BACKGROUND: The purpose of this study was to analyze the therapy concept used in
the management of severe epistaxis in order to optimize the quality of our
treatment and to arrive at an optimal therapeutic concept. MATERIAL AND METHODS:
The study was performed as a retrospective analysis of the charts of all 335
patients treated as inpatients for epistaxis over a period of 6 years. RESULTS:
An increased rate of complications was found in the following three situations:
1. Age > 65 years, 2. chronic obstructive pulmonary disease, 3. several systemic
illnesses. Recurrence was increased with septal perforations and Osler's disease.
CONCLUSIONS: Localization of the site of bleeding is the first priority and
allows treatment of bleeding with bipolar electrocautery. If the bleeding vessel
is not found, insertion of a Merocel pack is recommended. Patients with
persistent or recurrent bleeding are treated in the operating theater under
general anesthesia if they are at an elevated risk for complications or have a
septal deviation which is clinically significant. The nose is systematically
visualized with the endoscope, bleeding vessels are coagulated under endoscopic
control, and, where appropriate, a septoplasty is performed. In the remaining
cases an epipharynx balloon is inserted, combined with an anterior pack.
Angiography with superselective embolization, external ligation of the ethmoidal
arteries, and endonasal obliteration of the sphenopalatine artery is reserved for
cases where the measures discussed above have failed.
PMID- 9555705
TI - [Arachnoid cyst of the sphenoid sinus].
AB - BACKGROUND: Arachnoid cysts of the paranasal sinus are rare. They have not been
described yet in the sphenoid sinus. PATIENT AND METHOD: Microscopic-endoscopic
endonasal surgery of the sphenoid sinus was performed on a 34-year-old female
with a history of chronic headaches and a suspected mucocele of the sphenoid
sinus in computed tomography (CT) and magnetic resonance imaging (MRI) studies.
An extended arachnoid cyst was found in the enlarged sphenoid sinus, which was
obliterated with collagen, fibrin glue, and abdominal fat. RESULTS: There were no
complications after the operation, and 12 months later the patient is still free
of symptoms. CONCLUSION: Arachnoidal cysts present in CT and MRI as fluid dense
lesions that can imitate a mucocele.
PMID- 9555706
TI - [Macrolide antibiotic-induced vasculitis (Churg-Strauss syndrome)].
AB - BACKGROUND: Macrolides are known to have relatively few side effects and are
prescribed in cases of allergic reaction to penicillin. The new macrolides, for
example Azithromycin and Roxithromycin, are increasingly preferred over
erythromycin at the ear, nose, and throat out-patient department due to improved
oral reabsorption (acid resistance), better penetration into tissue, prolonged
half-life, extended antibacterial activity, modest side effects, and better
pharmacokinetics. There are only few case reports concerning side effects of
macrolides. We report on the appearance of a Churg Strauss-Syndrome (CSS) in a
patient following intake of the macrolide antibiotic azithromycin and
roxithromycin. PATIENT: A 50-year-old patient with asthma for three years
presented with arthritis and mononeuritis multiplex. Laboratory and radiological
investigations revealed eosinophilia (64%), eosinophilic infiltrations of bone
marrow, raised IgE-level, and transient pulmonary infiltrates. THERAPY AND
DEVELOPMENT: Intravenous steroid therapy was started and resulted in
normalization of eosinophilia, IgE-level, and asthmatic symptoms. The neurologic
deficits showed only a weak tendency for improvement. CONCLUSION: The diagnosis
of CSS was established on the basis of clinical criterias and laboratory
investigations. The diagnosis was supported by the fact that a similar course of
the disease was observed one year ago following administration of azithromycin,
another macrolide.
PMID- 9555707
TI - [Isolated paralysis of the ramus marginalis mandibulae nervi facialis: clinical
aspects, etiology, diagnosis and therapy. An overview].
AB - BACKGROUND: Disorders of lower lip in facial expression are mostly caused by
functional impairment of the marginal mandibular branch of the facial nerve. In a
typical case, active exposure of the incisors of the mandible is not possible and
the lip appears distorted towards the healthy side. The most frequent cause of a
lesion of the marginal mandibular branch is iatrogenic injury during operations
in the mandibular or parotid region. DIFFERENTIAL DIAGNOSIS: Functional disorders
of the platysma, congenital hypoplasia or aplasia of the lower lip muscles, and
defective healing following facial palsy may lead to a similar disorder which,
however, must be differentiated from an isolated paralysis of the marginal
mandibular branch. TREATMENT: In addition to inactivation of the nerve branch on
the opposite side, several surgical procedures have been described to achieve not
only aesthetic, but also functional rehabilitation of lower lip expression. The
present review gives an overview on the causes, clinical appearance, diagnosis,
differential diagnosis, and therapy of unilateral isolated paresis of the
marginal mandibular branch of the facial nerve.
PMID- 9555708
TI - Monitoring protocols for biological weapons.
PMID- 9555709
TI - A shot in the arm for DNA vaccines.
PMID- 9555710
TI - The Biological Weapons Convention and the biopharmaceutical industry: the views
of the United Kingdom.
PMID- 9555711
TI - The emerging role of the genomics revolution in agricultural biotechnology.
PMID- 9555712
TI - In hot pursuit of extremophiles.
PMID- 9555713
TI - The engineering of drug discovery.
PMID- 9555714
TI - Remune response.
PMID- 9555715
TI - Furry flasks?
PMID- 9555716
TI - Pharming cloning ban could spread.
PMID- 9555717
TI - Detecting drug-resistant tuberculosis: beacons in the dark.
PMID- 9555718
TI - PNA, antisense, and antimicrobials.
PMID- 9555719
TI - Containing excitement over transplastomic plants.
PMID- 9555720
TI - WAPping gastroenteritis with transgenic antibodies.
PMID- 9555721
TI - Transfected human dendritic cells as cancer vaccines.
PMID- 9555722
TI - Mining the genetic riches of human populations.
PMID- 9555723
TI - Therapeutic repair of mutated nucleic acid sequences.
AB - The principle of therapeutic nucleic acid repair has been demonstrated in cell
free and cell culture experiments, in which compounds bind to and repair mutated
sequences, thereby treating the primary defects of genetic disease. The
mechanisms used to promote repair are diverse, encompassing techniques related to
antisense, triple-strand, and ribozymes. Therapeutic nucleic acid repair has the
potential to revert mutations to wild type, and therefore is more suitable than
traditional gene therapy for treating gain-of-function mutations.
PMID- 9555724
TI - Containment of herbicide resistance through genetic engineering of the
chloroplast genome.
AB - Glyphosate is a potent herbicide. It works by competitive inhibition of the
enzyme 5-enol-pyruvyl shikimate-3-phosphate synthase (EPSPS), which catalyzes an
essential step in the aromatic amino acid biosynthetic pathway. We report the
genetic engineering of herbicide resistance by stable integration of the petunia
EPSPS gene into the tobacco chloroplast genome using the tobacco or universal
vector. Southern blot analysis confirms stable integration of the EPSPS gene into
all of the chloroplast genomes (5000-10,000 copies per cell) of transgenic
plants. Seeds obtained after the first self-cross of transgenic plants germinated
and grew normally in the presence of the selectable marker, whereas the control
seedlings were bleached. While control plants were extremely sensitive to
glyphosate, transgenic plants survived sprays of high concentrations of
glyphosate. Chloroplast transformation provides containment of foreign genes
because plastid transgenes are not transmitted by pollen. The escape of foreign
genes via pollen is a serious environmental concern in nuclear transgenic plants
because of the high rates of gene flow from crops to wild weedy relatives.
PMID- 9555725
TI - Engineering passive immunity in transgenic mice secreting virus-neutralizing
antibodies in milk.
AB - Protection against enteric infections can be provided by the oral administration
of pathogen-neutralizing antibodies. To provide passive immunity, 18 lines of
transgenic mice secreting a recombinant monoclonal antibody (Mab) neutralizing
transmissible gastroenteritis coronavirus (TGEV) into the milk were generated.
The genes encoding a chimeric Mab with the variable modules of the murine TGEV
specific Mab 6A.C3 and the constant modules of a human IgG, isotype Mab were
expressed under the control of regulatory sequences derived from the whey acidic
protein, which is an abundant milk protein. The Mab 6A.C3 binds to a highly
conserved epitope present in coronaviruses of several species, which does not
allow the selection of neutralization escape mutants. Antibody expression titers
of 10(6) were obtained in the milk of transgenic mice that reduced TGEV
infectivity 10(6)-fold. The antibody was synthesized at high levels throughout
lactation. Integration of matrix attachment region sequences with the antibody
genes led to a 20- to 10,000-fold increase in the antibody titer in 50% of the
transgenic animals. Antibody expression levels were transgene copy number
independent and related to the site of integration. The generation of transgenic
animals producing virus neutralizing antibodies in milk could provide an approach
to protection against neonatal infections of the enteric tract.
PMID- 9555726
TI - Antisense inhibition of gene expression in bacteria by PNA targeted to mRNA.
AB - Peptide nucleic acid (PNA) is a DNA mimic with attractive properties for
developing improved gene-targeted antisense agents. To test this potential of PNA
in bacteria, PNAs were designed to target the start codon regions of the
Escherichia coli beta-galactosidase and beta-lactamase genes. Dose-dependent and
specific gene inhibition was observed in vitro using low nanomolar PNA
concentrations and in vivo using low micromolar concentrations. Inhibition was
more efficient for a permeable E. coli strain relative to wild-type K-12. The
potency of the anti-beta-lactamase PNAs was abolished by a six base substitution,
and inhibition could be re-established using a PNA with compensating base
changes. Antisense inhibition of the beta-lactamase gene was sufficient to
sensitize resistant cells to the antibiotic ampicillin. The results demonstrate
gene- and sequence-specific antisense inhibition in E. coli and open
possibilities for antisense antibacterial drugs and gene function analyses in
bacteria.
PMID- 9555727
TI - Molecular beacon sequence analysis for detecting drug resistance in Mycobacterium
tuberculosis.
AB - We developed a new approach to DNA sequence analysis that uses fluorogenic
reporter molecules--molecular beacons--and demonstrated their ability to
discriminate alleles in real-time PCR assays of genomic DNA. A set of overlapping
molecular beacons was used to analyze an 81-bp region of the Mycobacterium
tuberculosis rpoB gene for mutations that confer resistance to the antibiotic
rifampin. In a blinded study of 52 rifampin-resistant and 23 rifampin-susceptible
clinical isolates, this method correctly detected mutations in all of the
resistant strains and in none of the susceptible strains. The assay was carried
out entirely in sealed PCR tubes and was simple to perform and interpret. This
approach can be used to analyze any DNA sequence of moderate length with single
base pair accuracy.
PMID- 9555728
TI - Induction of primary carcinoembryonic antigen (CEA)-specific cytotoxic T
lymphocytes in vitro using human dendritic cells transfected with RNA.
AB - Dendritic cells (DC) generated from the peripheral blood mononuclear cells of
healthy individuals or from cancer patients transfected with carcinoembryonic
antigen (CEA) mRNA stimulate a potent CD8+ cytotoxic T lymphocyte (CTL) response
in vitro. DCs are effectively sensitized with RNA in the absence of reagents
commonly used to facilitate mammalian cell transfection. RNA encoding a chimeric
CEA/LAMP-1 lysosomal targeting signal enhances the induction of CEA-specific CD4+
T cells, providing a strategy to induce T-help that may be necessary to generate
and/or maintain an optimal CD8+ CTL response in vivo. CEA RNA-transfected DCs
also serve as effective targets in cytotoxicity assays, thus providing a general
method for inducing, as well as measuring, CEA-specific CTL responses across a
broad spectrum of HLA haplotypes.
PMID- 9555729
TI - Genetic engineering of proteins with cell membrane permeability.
AB - The discovery of methods for generating proteins with inherent cell membrane
translocating activity will expand our ability to study and manipulate various
intracellular processes in living systems. We report a method to engineer
proteins with cell-membrane permeability. After a 12-amino acid residue membrane
translocating sequence (MTS) was fused to the C-terminus of glutathione S
transferase (GST), the resultant GST-MTS fusion proteins were efficiently
imported into NIH 3T3 fibroblasts and other cells. To explore the applicability
of this nondestructive import method to the study of intracellular processes, a
41-kDa GST-Grb2SH2-MTS fusion protein containing the Grb2 SH2 domain was tested
for its effect on the epidermal growth factor (EGF)-stimulated signaling pathway.
This fusion protein entered cells, formed a complex with phosphorylated EGF
receptor (EGFR), and inhibited EGF-induced EGFR-Grb2 association and mitogen
activated protein kinase activation.
PMID- 9555731
TI - Sequencing exons 5 to 8 of the p53 gene by MALDI-TOF mass spectrometry.
AB - Matrix-assisted laser desorption ionization time of flight mass spectrometry was
used to sequence exons 5 to 8 of the human p53 gene. A single tube procedure was
established for target amplification and mass spectrometric (MS) sequencing. The
MS sequencing scheme is designed for high throughput and parallel sample
processing, and is amenable to full automation. Reliable sequencing data were
obtained using fmol sample amounts. The high resolution and accuracy of MS
sequencing was demonstrated by direct sequencing of a heterozygous template.
PMID- 9555730
TI - Selection for a periplasmic factor improving phage display and functional
periplasmic expression.
AB - The efficiency of both phage display in Escherichia coli and periplasmic
expression of recombinant proteins may be limited by the same periplasmic folding
steps. To search for E. coli factors that improve the efficiency of both
procedures, a library of E. coli proteins was coexpressed in a phagemid vector
that contained a poorly folding single-chain Fv antibody (scFv) fragment fused to
g3p. We enriched, by panning for antigen binding, those phagemids in which the
amount of displayed scFv is highest. We thus identified the periplasmic protein
Skp/OmpH/HlpA as improving phage display of a wide range of scFv fragments. This
occurs as a result of an increase in the amount of hybrid protein displayed on
the phage. Coexpression of skp also increases the functional yield of scFv
fragments when expressed by secretion to the periplasm.
PMID- 9555732
TI - Building a fast-track patent portfolio in the UK and Europe.
PMID- 9555733
TI - Contract research organizations on the Web.
PMID- 9555734
TI - Proteomics.
PMID- 9555735
TI - Physician leadership on National Drug Policy finds addiction treatment works.
PMID- 9555736
TI - Influenza vaccine virus strains chosen.
PMID- 9555737
TI - Parity for mental health and substance abuse treatment.
PMID- 9555738
TI - Fighting flora with flora: FDA approves an anti-Salmonella spray for chickens.
PMID- 9555739
TI - From the Centers for Disease Control and Prevention. Progress toward elimination
of measles from the Americas.
PMID- 9555740
TI - From the Centers for Disease Control and Prevention. Update: Influenza activity-
United States, 1997-98 season.
PMID- 9555742
TI - From the Centers for Disease Control and Prevention. Imported dracunculiasis-
United States, 1995 and 1997.
PMID- 9555741
TI - From the Centers for Disease Control and Prevention. Update: HIV counseling and
testing using rapid tests--United States, 1995.
PMID- 9555743
TI - A piece of my mind. Remembering Jinx.
PMID- 9555744
TI - Local anesthesia for infants undergoing circumcision.
PMID- 9555745
TI - Local anesthesia for infants undergoing circumcision.
PMID- 9555746
TI - Local anesthesia for infants undergoing circumcision.
PMID- 9555747
TI - Local anesthesia for infants undergoing circumcision.
PMID- 9555748
TI - Dietary fat and ischemic stroke.
PMID- 9555749
TI - Dietary fat and ischemic stroke.
PMID- 9555750
TI - Dietary fat and ischemic stroke.
PMID- 9555751
TI - The 16th-century observations of Pieter Pauw: balancing humors and councils.
PMID- 9555752
TI - The 16th-century observations of Pieter Pauw: balancing humors and councils.
PMID- 9555753
TI - Injuries from dog bites.
PMID- 9555754
TI - Injuries from dog bites.
PMID- 9555755
TI - Injuries from dog bites.
PMID- 9555756
TI - Epidemic of pediatric deaths from acute renal failure caused by diethylene glycol
poisoning. Acute Renal Failure Investigation Team.
AB - CONTEXT: Contaminated pharmaceutical products can result in substantial morbidity
and mortality and should be included in the differential diagnosis of deaths of
unknown origin. OBJECTIVE: To investigate an outbreak of deaths among children
from acute renal failure in Haiti to determine the etiology and institute control
measures. DESIGN: Case-control study, cohort study, and laboratory toxicologic
evaluation. SETTING: Pediatric population of Haiti. PARTICIPANTS: Cases were
defined as Haitian residents younger than 18 years with idiopathic anuria or
severe oliguria for 24 hours or longer. Febrile hospitalized children without
renal failure were enrolled as control subjects. MAIN OUTCOME MEASURE: The odds
of exposure to suspected etiologic agents among cases and controls. RESULTS: We
identified 109 cases of acute renal failure among children. The clinical syndrome
included renal failure, hepatitis, pancreatitis, central nervous system
impairment, coma, and death. Of 87 patients with follow-up information who
remained in Haiti for treatment, 85 (98%) died; 3 (27%) of 11 patients
transported to the United States for intensive care unit management died before
hospital discharge. A locally manufactured acetaminophen syrup was highly
associated with disease (odds ratio, 52.7; 95% confidence interval, 15.2-197.2).
Diethylene glycol (DEG) was found in patients' bottles in a median concentration
of 14.4%. The median estimated toxic dose of DEG was 1.34 mL/kg (range, 0.22-4.42
mL/kg). Glycerin, a raw material imported to Haiti and used in the acetaminophen
formulation, was contaminated with 24% DEG. CONCLUSIONS: An epidemic of severe
systemic toxicity and deaths from DEG-contaminated acetaminophen syrup occurred
in Haiti. Good manufacturing practice regulations should be used by all
pharmaceutical manufacturers to prevent such tragedies.
PMID- 9555757
TI - Montelukast for chronic asthma in 6- to 14-year-old children: a randomized,
double-blind trial. Pediatric Montelukast Study Group.
AB - CONTEXT: Leukotrienes are important mediators of asthma by causing
bronchoconstriction, mucous secretion, and increased vascular permeability.
Studies using compounds that block leukotrienes have demonstrated improvement in
asthma control in adults and adolescents, but children younger than 12 years, for
whom asthma is the most common chronic disease, have not been studied. OBJECTIVE:
To determine the clinical effect of montelukast, a leukotriene receptor
antagonist, in 6- to 14-year-old children with asthma. DESIGN: Eight-week,
multicenter, randomized, double-blind study. SETTING: Forty-seven outpatient
centers at private practices and academic medical centers in the United States
and Canada. PATIENTS: A total of 336 children with forced expiratory volume in 1
second (FEV1) between 50% to 85% of the predicted value, at least 15%
reversibility after inhaled beta-agonist administration, a minimal predefined
level of daytime asthma symptoms, and daily beta-agonist use. Concomitant inhaled
corticosteroids at a constant daily dose were used by 39% of patients receiving
montelukast and 33% receiving placebo. INTERVENTION: After a 2-week placebo run
in period, patients received either montelukast (5-mg chewable tablet) or
matching-image placebo once daily at bed-time for 8 weeks. MAIN OUTCOME MEASURE:
Morning FEV1 percent change from baseline. RESULTS: Mean morning FEV1 increased
from 1.85 L to 2.01 L in the montelukast group and from 1.85 L to 1.93 L in the
placebo group. This represents an 8.23% (95% confidence interval [CI], 6.33% to
10.13%) increase from baseline in the montelukast group and a 3.58% (95% CI,
1.29% to 5.87%) increase from baseline in the placebo group (P<.001 for
montelukast vs placebo). CONCLUSION: Montelukast improves morning FEV1 in 6- to
14-year-old children with chronic asthma.
PMID- 9555758
TI - Importance of functional measures in predicting mortality among older
hospitalized patients.
AB - CONTEXT: Measures of physical and cognitive function are strong prognostic
predictors of hospital outcomes for older persons, but current risk adjustment
and burden of illness assessment indices do not include these measures.
OBJECTIVE: To evaluate and validate the contribution of functional measures to
the ability of 5 standard burden of illness indices (Charlson, Acute Physiology
and Chronic Health Evaluation [APACHE] II, Disease Staging, All Patient Refined
Diagnosis Related Groups, and a clinician's subjective rating) in predicting 90
day and 2-year mortality among older hospitalized patients. DESIGN: Two
prospective cohort studies. SETTING: General medicine service, university
teaching hospital. PATIENTS: For the development cohort, 207 consecutive patients
aged 70 years or older, and for the validation cohort, 318 comparable patients.
MAIN OUTCOME MEASURE: Death within 90 days and 2 years from the index admission.
RESULTS: In the development cohort, 29 patients (14%) and 81 patients (39%) died
within 90 days and 2 years, respectively. A functional axis was developed using 3
independent risk factors: impairment in instrumental activities of daily living,
Mini-Mental State Examination score of less than 20, and shortened Geriatric
Depression Scale score of 7 or higher, creating low-, intermediate-, and high
risk groups with associated mortality rates of 20%, 32%, and 60%, respectively
(P<.001); the C statistic for the final model was 0.69. The corresponding
mortality rates in the validation cohort, in which 59 (19%) and 138 (43%) died
within 90 days and 2 years, respectively, were 24%, 45%, and 60% (P<.001); the C
statistic for the final model was 0.66. For each burden of illness index, the
functional axis contributed significantly to the predictive ability of the model
for both 90 days and 2 years. When the functional axis and each burden of illness
measure were analyzed in cross-stratified format, mortality rates increased
progressively from low-risk to high-risk functional groups within strata of
burden of illness indices (double-gradient phenomenon). The contributions of
functional and burden of illness measures were substantive and interrelated.
CONCLUSIONS: Functional measures are strong predictors of 90-day and 2-year
mortality after hospitalization. Furthermore, these measures contribute
substantially to the prognostic ability of 5 burden of illness indices. Optimal
risk adjustment for older hospitalized patients should incorporate functional
status variables.
PMID- 9555759
TI - Learning, satisfaction, and mistreatment during medical internship: a national
survey of working conditions.
AB - CONTEXT: Concerns about the working and learning environment of residency
training continue to surface. Previous surveys of residents have focused on work
hours and income, but have shed little light on how residents view their training
experience. OBJECTIVE: To provide a description of the internship year as seen by
a large cross section of second-year residents. DESIGN: Mail survey conducted in
1991. SETTING: Residency programs in the United States. PARTICIPANTS: Random 10%
sample (N=1773) of all second-year residents listed in the American Medical
Association's medical research and information database. MAIN OUTCOME MEASURES:
What and who contributes most to residents' learning during internships, degree
of satisfaction with the internship experience, on-call and sleep schedules,
incidents of perceived mistreatment or abuse, observations of unethical behavior,
and experiences of harassment or discrimination. RESULTS: A total of 1277 surveys
(72%) of 1773 mailed were returned. Overall, respondents reported a moderate
level of satisfaction with their first year of residency. On a scale of 0 to 3,
residents rated other residents as contributing most (score of 2.3) to their
learning, with special patients ranked second (2.1). During a typical work week,
residents reported that they spent an average of 56.9 hours on call in the
hospital. A total of 1185 (93%) residents reported experiencing at least 1
incident of perceived mistreatment, with 53% reporting being belittled or
humiliated by more senior residents. Among women residents, 63% reported having
experienced at least 1 episode of sexual harassment or discrimination. A total of
45% of residents reported having observed another individual falsifying medical
records, and 70% saw a colleague working in an impaired condition, most often
lack of sleep. Regression analyses suggest that satisfaction with the residency
experience was associated with the presence of factors that enhanced learning,
and fewer experiences of perceived mistreatment. CONCLUSIONS: Residents report
significant problems during their internship experience. Satisfaction with
internship is enhanced by positive learning experiences and lack of mistreatment.
PMID- 9555760
TI - Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of
prospective studies.
AB - OBJECTIVE: To estimate the incidence of serious and fatal adverse drug reactions
(ADR) in hospital patients. DATA SOURCES: Four electronic databases were searched
from 1966 to 1996. STUDY SELECTION: Of 153, we selected 39 prospective studies
from US hospitals. DATA EXTRACTION: Data extracted independently by 2
investigators were analyzed by a random-effects model. To obtain the overall
incidence of ADRs in hospitalized patients, we combined the incidence of ADRs
occurring while in the hospital plus the incidence of ADRs causing admission to
hospital. We excluded errors in drug administration, noncompliance, overdose,
drug abuse, therapeutic failures, and possible ADRs. Serious ADRs were defined as
those that required hospitalization, were permanently disabling, or resulted in
death. DATA SYNTHESIS: The overall incidence of serious ADRs was 6.7% (95%
confidence interval [CI], 5.2%-8.2%) and of fatal ADRs was 0.32% (95% CI, 0.23%
0.41%) of hospitalized patients. We estimated that in 1994 overall 2216000
(1721000-2711000) hospitalized patients had serious ADRs and 106000 (76000
137000) had fatal ADRs, making these reactions between the fourth and sixth
leading cause of death. CONCLUSIONS: The incidence of serious and fatal ADRs in
US hospitals was found to be extremely high. While our results must be viewed
with circumspection because of heterogeneity among studies and small biases in
the samples, these data nevertheless suggest that ADRs represent an important
clinical issue.
PMID- 9555761
TI - Prevention of invasive group A streptococcal disease among household contacts of
case-patients: is prophylaxis warranted? The Working Group on Prevention of
Invasive Group A Streptococcal Infections.
AB - OBJECTIVES: The Centers for Disease Control and Prevention (CDC) convened a
Working Group in October 1995 to summarize the data regarding the risk of
invasive group A streptococcal (GAS) disease among household contacts of an index
patient and the potential efficacy of chemoprophylaxis. This statement on
chemoprophylaxis for prevention of subsequent cases among household contacts is
intended for use by public health professionals and clinicians. PARTICIPANTS: The
CDC invited representatives of the American Academy of Pediatrics, the Council of
State and Territorial Epidemiologists, the Hospital Infection Control Practice
Advisory Committee, the Infectious Diseases Society of America, and experts from
academia to participate. EVIDENCE: Data on the transmission of GAS and risk
factors for severe infection were considered. Population-based surveillance data
were used to estimate the risk of invasive GAS disease among household contacts
of a case patient. The potential efficacy of chemoprophylaxis was considered
using estimates of the efficacy of various regimens in eradicating pharyngeal
carriage. CONSENSUS PROCESS: This document summarizes the data considered by the
Working Group to develop its position. The consensus achieved by group discussion
at the meeting was incorporated in a draft document, which was reviewed by all
members and revised to include suggested changes. CONCLUSIONS: The Working Group
concluded that no definite recommendations can be made at this time regarding
chemoprophylaxis for household contacts of persons with invasive GAS infection.
More data are needed to assess the risk of subsequent cases and to determine an
optimal regimen for chemoprophylaxis. Until such data are available, physicians
and health departments should base decisions regarding chemoprophylaxis on their
assessment of the risk associated with each individual case.
PMID- 9555762
TI - Hunger in an adult patient population.
AB - CONTEXT: Although clinical observations suggest that some patients experience
hunger and food insecurity, there are limited data on the prevalence of hunger in
adult patients. OBJECTIVE: To determine the prevalence of hunger and food
insecurity in adult patients at an urban county hospital. DESIGN: Cross-sectional
survey conducted in 1997. PATIENTS: The primary survey included all patients aged
18 years or older who were admitted to the medicine, surgery, and neurology
services during a 2-week period, and all patients who attended the hospital's
general medicine clinic during 1 week. A second survey included primary care
patients who received insulin from the hospital pharmacy during a 1-month period.
MAIN OUTCOME MEASURES: Rates of hunger and food insecurity. RESULTS: Of 709
eligible patients, 567 (participation rate, 80%) were interviewed in either the
clinic (n=281) or hospital (n=286). An additional 170 patients who received
insulin were interviewed by telephone (response rate, 75%). Of the primary
sample, 68 (12%) respondents reported not having enough food, 75 (13%) reported
not eating for an entire day, and 77 (14%) reported going hungry but not eating
because they could not afford food. A total of 222 (40%) had received food stamps
in the previous year and of those, 113 (50%) had their food stamps reduced or
eliminated. Recipients whose food stamps had been eliminated or reduced were more
likely to report not having enough food (18% vs 13%, P=.006), not eating for a
whole day (20% vs 16%, P=.01), going hungry but not eating (20% vs 16%, P=.08),
and cutting down on the size of meals or skipping meals (33% vs 27%, P=.01). In
multivariate analysis, independent predictors of hunger included an annual income
of less than $10000 (odds ratio [OR], 7.55; 95% CI, 3.01-18.92), drug use (OR,
3.56; 95% CI, 1.46-8.66), and a reduction in food stamp benefits (OR, 1.73; 95%
CI, 1.01-2.96). Predictors of food insecurity included an annual income of less
than $10000 (OR, 4.12; 95% confidence interval [CI], 1.98-8.58), drug use (OR,
2.11; 95% CI, 1.66-5.08), and a reduction in food stamps (OR, 2.02; 95% CI, 1.23
3.32). In addition, 103 (61%) patients in the sample of diabetics reported
hypoglycemic reactions; 32 (31%) of these were attributed to inability to afford
food. CONCLUSION: Hunger and food insecurity are common among patients seeking
care at an urban county hospital.
PMID- 9555763
TI - The Haitian diethylene glycol poisoning tragedy: a dark wood revisited.
PMID- 9555765
TI - A privacy primer for the Web: spam, bread crumbs, and cookies.
PMID- 9555764
TI - Drugs and adverse drug reactions: how worried should we be?
PMID- 9555766
TI - Management of adults recovering from alcohol or other drug problems: relapse
prevention in primary care.
AB - Patients recovering from substance use disorders are commonly seen in the primary
care setting, and relapse is a serious long-term problem for these patients.
Extrapolating from therapeutic strategies effective in specialty addiction
treatment settings, this article outlines a practical approach to relapse
prevention in the primary care setting. Working within a supportive patient
physician relationship, the primary care physician can help recovering patients
decrease their susceptibility to relapse, recognize and manage high-risk
situations, and use available self-help, pharmacological, and specialty
resources. Drawing on the therapeutic relationship and skills they already
possess, primary care physicians can have an important, productive, and
satisfying role in the long-term management of patients in recovery from alcohol
or other drug problems.
PMID- 9555767
TI - Comparison of the various electrocardiographic scoring codes for estimating
anatomically documented sizes of single and multiple infarcts of the left
ventricle.
AB - It is clinically important to estimate the size of a myocardial infarction (MI)
to predict patient prognosis, to determine the ability of a therapy to limit its
size, and to evaluate its effect on left ventricular function. Various
electrocardiographic methods have been used for these purposes but their
accuracies have not been compared with each other using an identical reference
population of anatomically measured infarcts. The capability of 4
electrocardiographic scoring methods (the Selvester score, the Minnesota code,
the Novacode, and the Cardiac Infarction Injury Score) to estimate MI size was
compared using anatomic MI size in a group of 100 deceased patients. All patients
had a standard 12-lead electrocardiogram of sufficient quality to perform manual
waveform measurements and without confounding factors such as ventricular
hypertrophy, fascicular block, or bundle branch block. The location and size of
the left ventricular infarction was measured postmortem using the anatomic method
of Ideker et al. All methods' size estimates correlated best with anatomic MI
size in the anterior location (r = 0.65 to 0.89). The Selvester score was
superior in estimating the sizes of inferior (r = 0.70) and posterolateral (r =
0.74) infarcts. For multiple infarcts all methods performed poorly (r = 0.18 to
0.44).
PMID- 9555768
TI - Relation between exercise-induced myocardial ischemia as assessed by nitrogen-13
ammonia positron emission tomography and QT interval behavior in patients with
right bundle branch block.
AB - Exercise-induced myocardial ischemia is difficult to detect with ST-T changes in
patients with right bundle branch block (RBBB). We sought to predict exercise
induced myocardial ischemia with QT interval behavior during exercise in patients
with RBBB. Twenty-two patients with angiographically proven coronary artery
disease and RBBB and 9 healthy volunteers underwent nitrogen-13 ammonia positron
emission tomography with bicycle ergometer exercise at a fixed workload of 25 W.
Regional myocardial blood flow (RMBF) and electrocardiographic changes were
measured both at rest and after 5 minutes of exercise. The QT interval was
measured from the onset of the QRS complex to the offset of the T wave in lead
V5. The deltaQT and deltaRMBF, which indicated values after 5 minutes of exercise
minus values at rest, were negatively correlated (r = -0.74, p <0.001). Exercise
induced shortening of the QT interval (422 +/- 27 to 381 +/- 38 ms, p = 0.0020)
was observed in 15 patients (group 1) and no change or prolongation (411 +/- 45
to 420 +/- 37 ms, p = NS) was observed in 7 patients (group 2). Multivessel
disease was significantly more frequent but collateral circulation was
significantly less in group 2 than in group 1 (p <0.01, p <0.05, respectively).
Cardiac output at rest was significantly lower in groups 1 and 2 than in healthy
volunteers (4.52 +/- 0.83 and 4.51 +/- 0.84 vs 6.20 +/- 0.83 L/min; p = 0.0014, p
= 0.0003). Although RMBF at rest did not differ significantly among groups 1 and
2 and healthy volunteers (0.63 +/- 0.20 vs 0.69 +/- 0.13 and vs 0.77 +/- 0.14
ml/min/g), RMBF after 5 minutes of exercise was significantly lower in group 2
than in group 1 and healthy volunteers (0.78 +/- 0.11 vs 0.96 +/- 0.20 and vs
1.20 +/- 0.18 ml/min/g; p = 0.0289, p <0.0001). The number of regions of critical
coronary artery disease was significantly greater in group 2 than in group 1 (4.0
+/- 1.2 vs 2.1 +/- 1.3, p = 0.0039). Our results suggest that the absence of QT
interval shortening during exercise may indicate severe myocardial ischemia
induced by exercise in patients with RBBB and coronary artery disease.
PMID- 9555769
TI - Predischarge two-dimensional echocardiographic evaluation of left ventricular
thrombosis after acute myocardial infarction in the GISSI-3 study.
AB - Left ventricular (LV) thrombosis can be found in patients with acute myocardial
infarction (AMI). No wide multicenter trial on AMI has provided information about
LV thrombosis until now. The protocol of the GISSI-3 study included the search
for the presence of LV thrombosis in patients from 200 coronary care units that
did not specifically focus on LV thrombosis. We examined the GISSI-3 database
results related to 8,326 patients at low to medium risk for LV thrombi in which a
predischarge echocardiogram (9 +/- 5 days) was available. LV thrombosis was found
in 427 patients (5.1%): 292 of 2,544 patients (11.5%) with anterior AMI and in
135 of 5,782 patients (2.3%) with AMI in other sites (p <0.0001). The incidence
of LV thrombosis was higher in patients with ejection fraction < or = 40% (151 of
1,432 [10.5%] vs 276 of 6,894 [4%]; p <0.0001) both in the total population and
in the subgroup with anterior AMI (106 of 597 [17.8%] vs 186 of 1,947 [9.6%]; p
<0.0001). Multivariate analysis showed that only the Killip class > I and early
intravenous beta-blocker administration were independently associated with higher
LV thrombosis risk in the subgroup of patients with anterior AMI (odds ratio
1.75, 95% confidence interval 1.28 to 2.39; odds ratio 1.32, 95% confidence
interval 1.02 to 1.72, respectively). In patients with anterior AMI, oral beta
blocker therapy given or not given after early intravenous beta-blocker
administration does not influence the occurrence of LV thrombosis. The rate of LV
thrombosis was similar in patients treated or not treated with nitrates and
lisinopril both in the total population and in patients with anterior and
nonanterior AMI. In conclusion, in the GISSI-3 population at low to medium risk
for LV thrombi, the highest rate of occurrence of LV thrombosis was found among
patients with anterior AMI and an ejection fraction < 40%. Killip class > I and
the early intravenous beta-blocker administration were the only variables
independently associated with a higher predischarge incidence of LV thrombosis
after anterior AMI.
PMID- 9555770
TI - Asynergy of the noninfarcted left ventricular inferior wall in anterior wall
acute myocardial infarction secondary to isolated occlusion of the left anterior
descending artery.
AB - There are patients in whom left ventricular (LV) wall motion decreases in the
noninfarcted region and LV systolic function declines globally despite the
presence of a localized myocardial infarct attributable to narrowing or occlusion
of a single coronary artery. This study examines angiographic characteristics of
patients with chronic hypokinesia of noninfarcted myocardium after anterior wall
acute myocardial infarction (AMI) due to narrowing of a single coronary artery,
namely, the left anterior descending (LAD) artery. The LV ejection fraction,
abnormalities in the motion of the noninfarcted LV inferior wall (SD/chord value
by Sheehan's technique), the angiographic characteristics of the infarct-related
coronary artery, the effect of acute reperfusion therapy, and presence of
coronary risk factors were examined in 85 consecutive patients. The SD/chord
value in the noninfarcted region showed a positive correlation with the LV
ejection fraction (r = 0.505, p <0.0001). By multivariate analysis, hypertension
(odds ratio = 0.53, 95% confidence interval [CI] 0.36 to 0.80), an infarct
related narrowing proximal to the origin of the first diagonal branch (odds ratio
= 0.56, 95% CI 0.38 to 0.84), and patency of the infarct-related lesion during
AMI (odds ratio = 1.56, 95% CI 1.03 to 2.30) were independent predictors of wall
motion in the noninfarct region. In some patients with single-vessel anterior
wall AMI, the motion of the noninfarcted inferior LV wall decreases during the
chronic stage and cardiac function declines severely. In most of these patients,
the infarct-related narrowing or occlusion is proximal to the origin of the first
diagonal branch of the LAD artery.
PMID- 9555771
TI - Effects of cardiac rehabilitation and beta-blocker therapy on heart rate
variability after first acute myocardial infarction.
AB - After acute myocardial infarction (AMI), rehabilitation with physical training
increases parasympathetic tone. It is unknown whether such a favorable effect of
exercise on the sympathovagal balance interacts with effects of other widespread
therapies, such as beta blockers. In 53 patients after a first, uncomplicated
AMI, we studied the combined short- and long-term influence on heart rate
variability (HRV) of rehabilitation and beta blockade. Patients were divided into
3 groups: group 1 (n = 19) underwent rehabilitation with physical training; group
2 (n = 20) was taking beta blockers and underwent rehabilitation; group 3 (n =
14) was taking beta blockers and did not enter the rehabilitation program for
logistic reasons. Patients were similar as to age, site of infarction, ejection
fraction, left ventricular diameter, and baseline stress test duration. Measures
of HRV (obtained from a 15-minute resting electrocardiogram) were the standard
deviation of the mean RR interval (RRSD), the mean squared successive differences
(MSSD), the percent of RR intervals differing >50 ms from the preceding one
(pNN50), the low-(LF) and high-(HF) frequency components of the autoregressive
power spectrum of the RR intervals and their ratio (LF/HF). Four weeks after AMI,
there was less sympathetic predominance in groups 2 and 3 (i.e., patients taking
beta blockers [p <0.05]). Rehabilitation modified HRV in groups 1 and 2 (p
<0.05), with signs of increased parasympathetic tone (group 1: MSSD +25%, pNN50
+69%, LF/HF -40%; group 2: MSSD +41%, pNN50 +48%, LF/HF -39%). These changes
persisted in the long term. In group 3, HRV was unchanged over time. Hence, after
AMI, the effects of rehabilitation and beta blockers on HRV are not redundant:
their association induces a more favorable sympathovagal balance, accelerating
the recovery of a normal autonomic profile.
PMID- 9555773
TI - Coronary angioplasty outcomes in the Healthcare Cost and Utilization Project,
1993-1994.
AB - It is estimated that >400,000 percutaneous transluminal coronary angioplasty
(PTCA) procedures are performed in the Unites States annually. This study reports
patient characteristics and outcomes for 163,527 PTCAs performed in 214 hospitals
in 17 states from 1993 to 1994. These hospitals were a 20% random sample of
hospitals in the Healthcare Cost and Utilization Project, which was designed to
reflect hospitalization in the United States, generally. Cases with International
Classification of Diseases, 9th Revision, Clinical Modification procedure codes
36.01, 36.02, and 36.05 were defined as PTCA and were categorized as to whether
acute myocardial infarction (AMI) was the principal discharge diagnosis. The
average age of 44,270 AMI discharges (27%) was 62 +/- 12 years and that of
119,257 no-AMI cases (73%) was 64 +/- 11 years; 1/3 of both groups were women,
88% were white, and almost 90% had Medicare or private insurance as the primary
payer. The states contributing the most cases were Florida (26%), California
(12%), and Wisconsin (10%). Hospital mortality was 1.7% overall and was 3.8% for
AMI and 0.8% for no-AMI cases. Bypass surgery performed during the same admission
was 3.4% overall and was 4.5% and 3.0% for AMI and no-AMI cases, respectively.
Multivariate analysis showed that advanced age, diabetes, female gender, and
Medicaid payer status were associated with increased risk of mortality. National
estimates from this 20% sample indicate that >850,000 PTCAs were performed in the
2 years, with 452,319 cases estimated for 1994. In 1994 there were an estimated
2,789 deaths and 9,903 bypass surgeries in the no-AMI subset of 327,856
procedures. For the AMI group of 124,463 procedures, there were 4,486 deaths and
5,799 bypass surgeries in 1994. This study of PTCA outcomes contains the largest
number of cases as well as the most representative sample reported to date.
PMID- 9555772
TI - Fibrinogen breakdown, long-lasting systemic fibrinolysis, and procoagulant
activation during alteplase double-bolus regimen in acute myocardial infarction.
AB - Recent clinical studies comparing accelerated versus bolus administration of
alteplase tissue plasminogen activator (t-PA) suggest similar thrombolytic
efficacy, but reveal higher bleeding complications among older patients during
the double-bolus regimen. The objective of the present study was to characterize
the hemostatic profile of t-PA administered as double-bolus doses of 50 mg, at
intervals of 30 minutes. Among 50 patients with acute myocardial infarction
treated by double-bolus t-PA thrombolysis, coagulation and fibrinolysis
parameters, as well as t-PA levels, were monitored. Monitored t-PA levels peaked
at 5 and 35 minutes and were detectable within the therapeutic range even after
90 minutes. Marked systemic fibrinolytic activation was indicated by 75%
depletion of both plasminogen and fibrinogen, as well as by 19-fold and 300-fold
increases of fibrin degradation and fibrinogen degradation products. Plasminogen
activator inhibitor activity was completely suppressed. Pronounced procoagulant
activation was reflected by a 3.4-fold increase of both factor XIIa and
prothrombin fragment 1+2, and by a threefold increase of thrombin-antithrombin
complex. Independent of t-PA weight dosage, fibrinolytic activation was more
pronounced among older patients (> or = 63 years). We conclude that t-PA after
bolus administration has a long half-life. Double-bolus regimen leads to a long
lasting systemic fibrinolytic state, which is even more remarkable among older
patients--a fact that may explain the higher bleeding complications reported for
this age group.
PMID- 9555774
TI - Continuous monitoring of global left ventricular ejection fraction during
percutaneous transluminal coronary angioplasty.
AB - Continuous monitoring of left ventricular (LV) function during percutaneous
transluminal coronary angioplasty (PTCA) was performed in 40 patients (53 +/- 2
years) with a miniature, nuclear detector system after labeling the patients' red
blood cells with technetium-99m. Balloon dilation (113 seconds, range 60 to 240)
induced on average a 0.12 ejection fraction (EF) unit (19%) decrease in the LVEF,
which was explained by a 34% increase in end-systolic counts. Balloon dilation of
the left anterior descending artery (n = 23) produced a decrease in the LVEF of
0.17 +/- 0.13 EF units compared with the decrease of 0.06 +/- 0.07 EF units in
patients undergoing dilation of the left circumflex artery (n = 9) and 0.05 +/-
0.04 EF units in patients treated for a stenosis of the right coronary artery (n
= 8), (p = 0.02). Balloon deflation was associated with an immediate return to
pre-PTCA levels. In 10 patients with 2 identical balloon occlusions, the second
occlusion led to a significantly less decrease in the LVEF (0.41 +/- 0.14 vs 0.44
+/- 0.15) and electrocardiographic ST-segment deviation (88 +/- 54 microV vs 65
+/- 42 microV) than the first. We conclude that PTCA is associated with an abrupt
transient decrease in the LVEF. The effect of balloon occlusion of the left
anterior descending artery is more pronounced than balloon occlusion of the left
circumflex and the right coronary arteries. Neither single nor multiple balloon
occlusions were associated with post-PTCA global LV dysfunction, whereas the
lesser degree of LV dysfunction and electrocardiographic signs of myocardial
ischemia during the second of 2 identical balloon occlusions suggests that
preconditioning can be induced during PTCA.
PMID- 9555775
TI - One-year follow-up of the Stent Restenosis (STRESS I) Study.
AB - We present the completed 1-year follow-up results of the original Stent
Restenosis Study (STRESS I), in which 407 patients with symptomatic ischemic
heart disease and new lesions of the native coronary circulation were randomly
assigned to treatment with either the Palmaz-Schatz coronary stent or
conventional percutaneous transluminal coronary angioplasty (PTCA). The present
study compares the safety of elective stenting to balloon angioplasty (PTCA) in
terms of freedom from clinical events up to 1 year after treatment. Patients were
enrolled and treated from January 1991 through February 1993, and follow-up data
were collected and verified until July 1995. Ninety-seven percent of all patients
had complete follow-up (deceased or alive with known clinical status) beyond 8
months, and 94% beyond 11 months. Anginal status between 9 to 15 months
postprocedure was available for 78% of patients. At 1 year, 154 patients (75%)
assigned to stent implantation and 141 (70%) to PTCA were free of all clinical
events (death, myocardial infarction, or any revascularization procedure), and
162 stent patients (79%) and 149 PTCA patients (74%) were free from death,
myocardial infarction, or target lesion revascularization. Symptom-driven target
lesion revascularization occurred in 12% of the stent group versus 17% of the
PTCA group. None of these differences in clinical events was statistically
significant. Only 2 patients in the stent group and 7 in the PTCA group had a
first event after 239 days, and freedom from angina at 1 year was reported in
equal frequency in both groups (84%). There appear to be no late adverse effects
of stent implantation. However, these results are limited by low statistical
power, narrow patient selection, and the anticoagulation regimen used in the
early experience with this device.
PMID- 9555776
TI - High anti-cytomegalovirus (CMV) IgG antibody titer is associated with coronary
artery disease and may predict post-coronary balloon angioplasty restenosis.
AB - Recent studies have demonstrated that cytomegalovirus (CMV) DNA was found in
atherosclerotic coronary arteries in restenotic lesions, and prior infection with
CMV could be a strong independent risk factor for restenosis after coronary
atherectomy. We studied the correlation between anti-CMV antibody titer and
coronary artery disease. Sixty-five patients (50 men and 15 women) with coronary
artery disease were enrolled prospectively. All had symptomatic coronary artery
disease with an angiographic documentation of a de novo single coronary lesion.
All underwent balloon coronary angioplasty and were followed for 12 months with a
thallium perfusion scan 3 months after angioplasty. Patients who had recurrent
chest pain and/or a positive thallium scan had another coronary angiography.
Blood samples were taken before angiography and 1 and 3 months later. Patients
with high anti-CMV titer > or = 1:800 had a higher prevalence of coronary artery
disease (p <0.001) than seropositive patients with a lower antibody titer (< or =
1:400); patients with high antibody titer (> or = 1:800) had a higher restenosis
rate than seropositive patients with a low antibody titer (< or = 1:400) (p
<0.05). High antibody titers against CMV (IgG) may be a strong marker for
coronary artery disease, and might predict post-coronary angioplasty restenosis.
These findings support the infectious theory of atherosclerosis (especially with
prior CMV infection), and also suggest that a chronic immunologic response has a
role in atherosclerosis and restenosis.
PMID- 9555777
TI - Mortality in the Survival With ORal D-sotalol (SWORD) trial: why did patients
die?
AB - The Survival With ORal D-sotalol (SWORD) trial tested the hypothesis that the
prophylactic administration of oral d-sotalol would reduce total mortality in
patients surviving myocardial infarction (MI) with a left ventricular ejection
fraction (LVEF) of < or = 40%. Two index MI groups were included: recent (6 to 42
days) and remote (> 42 days) with clinical heart failure (n = 915 and 2,206,
respectively). The trial was discontinued when the statistical boundary for harm
was crossed (RR = 1.65; p = 0.006). All baseline variables known to be associated
with mortality risk (e.g., LVEF, heart failure class, age) as well as variables
related to torsades de pointes (e.g., time from beginning of therapy, QTc,
gender, potassium, renal function, dose of d-sotalol) were assessed for
interaction of each variable with treatment assignment, computing RR and 95%
confidence interval (CI) from Cox regression models. The d-sotalol-associated
mortality was greatest in the group with remote MI and LVEFs of 31% to 40% (RR =
7.9; 95% CI 2.4 to 26.2). Most variables known to be associated with torsades de
pointes were not differentially predictive of d-sotalol-associated risk, except
female gender (RR = 4.7; 95% CI 1.4 to 16.5). These findings suggest that (1)
most of the d-sotalol-associated risk was in patients remote from MI with a LVEF
of 31% to 40%; comparable placebo patients had a very low mortality (0.5%); and
(2) very little objective data supports torsades de pointes or any specific
proarrhythmic mechanism as an explanation for d-sotalol-associated mortality
risk.
PMID- 9555778
TI - Design of a clinical trial for the assessment of cardioversion using
transesophageal echocardiography (The ACUTE Multicenter Study). Steering and
Publications Committees of the ACUTE Study.
AB - Patients with atrial fibrillation (AF) undergoing cardioversion are at an
increased risk of cardioembolic stroke and require anticoagulation. The
Assessment of Cardioversion Using Transesophageal Echocardiography (ACUTE)
Multicenter Study is a randomized clinical trial of patients undergoing
electrical cardioversion of AF of >2 days' duration comparing a transesophageal
guided strategy (TEE) with brief anticoagulation to the conventional
anticoagulation strategy. Patients randomly assigned to the TEE-guided strategy
receive therapeutic anticoagulation before TEE and cardioversion, followed by 4
weeks of anticoagulation. Patients with thrombus imaged by TEE have postponement
of cardioversion, continue anticoagulation for 3 weeks, and undergo a repeat TEE.
Conventional strategy patients receive 3 weeks of anticoagulation before
cardioversion, followed by 4 weeks of anticoagulation after cardioversion. The
primary end point events are ischemic stroke, transient ischemic attack, and
systemic embolization for an 8-week period from enrollment. Secondary end points
are major and minor bleeding, all-cause mortality, successful return to and
maintenance of sinus rhythm, and cost effectiveness. Analysis is based on the
intention-to-treat principle. The anticipated rates of embolism of 2.9% for
conventional strategy and 1.2% for the TEE-guided strategy are based on published
research and the completed pilot study. The ACUTE Multicenter Study will
randomize therapy and follow an estimated 3,000 patients from 65 study sites to
determine the relative efficacy of the TEE-guided and conventional approaches to
electrical cardioversion for patients in AF. The results of this investigation
will have important clinical implications for the management of patients with AF
undergoing electrical cardioversion.
PMID- 9555779
TI - Comparison of clinical and morphologic cardiac findings in patients having
cardiac transplantation for ischemic cardiomyopathy, idiopathic dilated
cardiomyopathy, and dilated hypertrophic cardiomyopathy.
AB - This article compares intergroup and intragroup clinical and morphologic findings
in patients with ischemic cardiomyopathy (IC), idiopathic dilated cardiomyopathy
(IDC), and dilated hypertrophic cardiomyopathy (HC) undergoing cardiac
transplantation (CT). Few previous publications have described findings in native
hearts explanted at the time of CT. The explanted heart in 92 patients having CT
was examined in uniform manner with particular attention to the sizes of the
ventricular cavities and the presence of and extent of ventricular scarring. Of
the 92 hearts examined, 47 had IC, 35 had IDC, and 10 had dilated HC. Although
considerable degrees of intragroup variation occurred, the mean degree of left
ventricular dilatation was similar among the patients with IC, IDC, and dilated
HC. All patients with IC had left ventricular free wall scarring more extensive
than that involving the ventricular septum, but the intragroup variation in the
amounts of scarring was considerable. Nine of the 10 patients with dilated HC
also had ventricular wall scarring, but it was more extensive in the ventricular
septum than in the left ventricular free wall and involvement of the right
ventricular wall also was present. Eight (23%) of the 35 IDC patients also had
grossly visible ventricular scars but they were small and only 1 of the 8 had
coronary narrowing and that was not in the distribution of the scarring.
Narrowing of 1 or more epicardial coronary arteries >75% in cross-sectional area
by plaque was present in all 47 IC patients, in 8 of the 35 IDC patients (7 had
no ventricular scars), and in none of the 10 dilated HC patients. Coronary
angiography was the major clinical tool allowing separation of the IC, IDC, and
HC patients. Coronary angiography did not detect narrowing in any of the 8
patients with IDC who were found to have coronary narrowing on anatomic study.
Thus, among patients with IC, IDC, and dilated HC having CT, distinctive anatomic
features allow separation of patients with IC, IDC, and dilated HC, but within
each group considerable variation in left ventricular cavity size and extent of
ventricular scarring occurs.
PMID- 9555780
TI - Low-dose dobutamine stress echocardiography in children and young adults.
AB - Dobutamine stress echocardiography has become widely accepted in the evaluation
of adult patients with coronary heart disease. We wanted to assess the
feasibility and the physiologic responses of stress echocardiography at low doses
of dobutamine in a population of normal children and adults. Once achieved, we
submitted a group of post-anthracycline patients to the test to assess the
sensitivity of low-dose dobutamine stress echocardiography in the detection of
cardiac dysfunction. Thirty-two healthy children and young adults (19 male and 13
female subjects, median age 15 years [range 6 to 26]) were studied. After the
initial study of normal subjects, we submitted a cohort of 39 patients (18 female
and 21 male, aged 6 to 25 years), who completed anthracycline chemotherapy, to
the same protocol. Dobutamine was infused at rates of 0.5 to 2.5 and 5
microg/kg/min and echocardiographic measurements were obtained at rest and at the
end of each stage. The test could be completed in 100% of the subjects without
major complications. Statistically significant differences between resting
echocardiographic values of systolic and diastolic function and values at 2.5 and
5 microg/kg/min of dobutamine were found. Moreover, dobutamine revealed or
enhanced differences between normal subjects and the post-anthracycline patients.
Thus, low-dose dobutamine stress echocardiography is feasible and safe in older
children. The test is very sensitive for the detection of subclinical cardiac
dysfunction in post-anthracycline patients and could possibly assess functional
myocardial reserve.
PMID- 9555781
TI - Jesse Efrem Edwards, MD: a conversation with the editor. Interview by William
Clifford Roberts.
PMID- 9555782
TI - Consensus for the use of fibrates in the treatment of dyslipoproteinemia and
coronary heart disease. Fibrate Consensus Group.
AB - The hypolipidemic action of fibrates has recently been shown to involve the
activation of peroxisome proliferator activated receptors establishing a
molecular mechanism for this class of drugs. Increasing clinical trial evidence
supports the efficacy of fibrates in the treatment of dyslipoproteinemias,
particularly in patients with hypertriglyceridemia and low high-density
lipoproteins.
PMID- 9555783
TI - Usefulness of ST-segment elevation in lead III exceeding that of lead II for
identifying the location of the totally occluded coronary artery in inferior wall
myocardial infarction.
AB - The presence of ST-segment elevation in lead III exceeding that of lead II,
particularly if combined with ST elevation in lead V1, proved to be a powerful
marker for occlusion of the proximal or midportion of the right coronary artery.
These findings helped to determine the extent of myocardium at risk in inferior
wall myocardial infarction and may further guide the decision to administer
thrombolytics.
PMID- 9555784
TI - Left ventricular function and coagulation activity in healed myocardial
infarction.
AB - We investigated the plasma levels of molecular markers for the thrombotic and
fibrinolytic status in patients with healed myocardial infarction to determine
the relation between left ventricular (LV) function and coagulation activity. Our
findings demonstrated that the coagulation activity was increased in patients
with healed myocardial infarction along with LV dysfunction, suggesting that
anticoagulant therapy is considered in patients with severe LV dysfunction to
prevent systemic thromboembolism.
PMID- 9555785
TI - Effect of atenolol or metoprolol on waking hour dynamics of the QT interval in
myocardial infarction.
AB - In subjects with a recent acute myocardial infarction, the hour immediately
following awakening is associated with an abrupt exaggeration of heart rate
dependent changes and variability of the QT interval. Beta blockers were observed
to blunt these waking hour changes.
PMID- 9555786
TI - Early experience with the NIR intracoronary stent.
AB - Immediate and midterm results of 61 NIR stent placement attempts in 55 native
coronary vessels in 52 patients demonstrate a high clinical success rate of 98%,
no early stent thrombosis, and a 5-month angiographic restenosis rate of 23%. The
frequency of in-stent restenosis was significantly heightened in small vessel
sizes and in diabetic patients.
PMID- 9555787
TI - Lipid lowering in a multidisciplinary clinic compared with primary physician
management.
AB - A multidisciplinary lipid reduction clinic achieved greater reduction of serum
cholesterol when compared with primary physicians among patients with coronary
heart disease. The lipid clinic was more likely than the primary physicians to
prescribe lipid-lowering medication, to prescribe multiple medications, and to
use drug doses in excess of the "starting dose."
PMID- 9555788
TI - On the necessity of the invasive predischarge test after implantation of a
cardioverter-defibrillator.
AB - The necessity of routine invasive implantable cardioverter-defibrillator (ICD)
testing before hospital discharge was analyzed in 268 patients. In 98% of the
patients, invasive ICD testing was not necessary if a preimplant
electrophysiologic test was performed; most of the observed problems can be
solved by noninvasive control.
PMID- 9555789
TI - Successful percutaneous extraction of pacemaker leads with a novel (VascoExtor)
pacing lead removal system.
AB - A new pacing lead extraction system (VascoExtor, VascoMed, Germany) with a
universally applicable locking stylet was used over a period of 12 months to
extract 25 permanent pacemaker leads (mean implantation time 3.9 +/- 3.8 years)
in 16 patients who had pacemaker infection (n = 13), lead dysfunction (n = 2), or
before an automatic defibrillator implant (n = 1). With use of this system, we
were able to successfully and safely remove 24 of 25 chronic pacing leads (96%)
in 15 of 16 patients (93%) with sole use of the locking stylet in 81%, and with
use of an array of ancillary tools in the remaining 19% of patients.
PMID- 9555790
TI - Pressure ulcers.
AB - Pressure ulcers are localized areas of tissue necrosis that result from
unrelieved pressure. They are graded or staged according to the degree of tissue
damage observed. The main etiologic factors include pressure, shearing forces,
friction, and moisture. The clinical course may be complicated by several
conditions including infection, sepsis, osteomyelitis, fistulas, and carcinoma.
Preventive measures in persons at risk can significantly reduce the incidence of
pressure ulcers. Successful management should address the four etiologic factors
as well as the general condition of the patient.
PMID- 9555791
TI - Omega-3 fatty acid-based lipid infusion in patients with chronic plaque
psoriasis: results of a double-blind, randomized, placebo-controlled, multicenter
trial.
AB - BACKGROUND: Profound changes in the metabolism of eicosanoids with increased
concentrations of free arachidonic acid (AA) and its proinflammatory metabolites
have been observed in psoriatic lesions. Free eicosapentaenoic acid (EPA) may
compete with liberated AA and result in an antiinflammatory effect. OBJECTIVE:
Our purpose was to assess the efficacy and safety of intravenously administered
fish-oil-derived lipid emulsion on chronic plaque-type psoriasis. METHODS: A
double-blind, randomized, parallel group study was performed in eight European
centers. Eighty-three patients hospitalized for chronic plaque-type psoriasis
with a severity score of at least 15 according to the Psoriasis Area and Severity
Index (PASI) participated in a 14-day trial. They were randomly allocated to
receive daily infusions with either a omega-3 fatty acid-based lipid emulsion
(Omegavenous; 200 ml/day with 4.2 gm of both EPA and docosahexaenoic acid (DHA);
43 patients) or a conventional omega-6-lipid emulsion (Lipovenous; EPA+DHA < 0.1
gm/100 ml; 40 patients). The groups were well matched with respect to demographic
data and psoriasis-specific medical history. Efficacy of therapy was evaluated by
changes in PASI, in an overall assessment of psoriasis by the investigator, and a
self-assessment by the patient. In one center neutrophil 4- versus 5-series
leukotriene (LT) generation and platelet 2- versus 3- thromboxane generation were
investigated and plasma-free fatty acids were determined. RESULTS: The total PASI
score decreased by 11.2 +/- 9.8 in the omega-3 group and by 7.5 +/- 8.8 in the
omega-6 group (p = 0.048). In addition, the omega-3 group was superior to the
omega-6 group with respect to change in severity of psoriasis per body area,
change in overall erythema, overall scaling and overall infiltration, as well as
change in overall assessment by the investigator and self-assessment by the
patient. Response (defined as decrease in total PASI of at least 50% between
admission and last value) was seen in 16 of 43 patients (37%) receiving the omega
3 emulsion and 9 of 40 patients (23%) receiving omega-6 fatty acid-based lipid
emulsion. No serious side effects were observed. Within the first few days of
omega-3 lipid administration, but not in the omega-6 supplemented patients, a
manifold increase in plasma-free EPA concentration, neutrophil leukotriene B5 and
platelet thromboxane B3 generation occurred. CONCLUSION: Intravenous omega-3
fatty acid administration is effective in the treatment of chronic plaque-type
psoriasis. This effect may be related to changes in inflammatory eicosanoid
generation.
PMID- 9555792
TI - "Rush" skin biopsy specimens in a tertiary medical center: diagnostic yield and
clinical utility.
AB - BACKGROUND: Skin biopsy specimens are submitted for "rush" or "stat" processing,
thereby indicating a sense of urgency about the clinical situation. OBJECTIVE:
Our purpose was to determine the patient population who underwent biopsy on a
"rush" basis and assess the way in which interpretation of the skin biopsy
specimen influences clinical management. METHODS: A retrospective study was
performed on the "rush" biopsy specimens sequentially requested during 1 year.
Histologic findings, the clinical situation, and the effect of the biopsy result
on clinical management were determined. RESULTS: A total of 90 adult patients,
many critically ill, were identified. The majority of patients were admitted to
hematology-oncology services (58%). The other 42% were admitted to a variety of
clinical services. The chief clinical concerns in hematology-oncology patients
were graft-versus-host disease and cutaneous infection. Only 5.5% of biopsy
specimens taken to exclude graft-versus-host disease were used in immediate
clinical decision-making compared with 45% of biopsy specimens for oncology
patients with suspected infection and 42% for all other services. CONCLUSION:
Many urgent skin biopsy specimens were not used for immediate clinical decision
making. The usefulness of skin biopsy varies with the clinical situation, and
some situations are more prone to yield equivocal histologic data. Knowledge of
these situations may reduce the number of unhelpful biopsy specimens. Therapy
based on clinical findings had often been initiated before receiving the biopsy
results, but biopsy findings are often helpful as confirmatory data. Diagnostic
findings were not necessary for a biopsy specimen to provide useful data and
nonspecific findings interpreted in light of clinical findings were also useful.
PMID- 9555793
TI - Abnormal IgG cardiolipin antibody titers in patients with Raynaud's phenomenon
and/or related disorders: prevalence and clinical significance.
AB - BACKGROUND: The prevalence of antibodies to cardiolipin (a-CL) in patients with
Raynaud's phenomenon (RP) and/or related disorders (rD) is not known. OBJECTIVE:
The purpose of this study was to determine the prevalence of these antibodies.
METHODS: We assayed IgG a-CL in 230 consecutive patients with RP/rD and compared
the results with those in a series of 230 control blood donors. RESULTS: Sixteen
percent of patients were a-CL positive versus 7.8% of the control donors (p =
0.014). The prevalence of a-CL positivity was 8.7% for primary RP, 10.5% for
secondary RP, 8% for chilblains, 25% for essential acrocyanosis, 20% for
connective tissue diseases, and 17% for undifferentiated connective tissue
diseases. Among patients with digital necrosis, 24% were a-CL positive.
CONCLUSION: The prevalence of abnormal a-CL titers is higher in patients with
RP/rD than in control donors, especially in patients with a connective tissue
disease.
PMID- 9555794
TI - A randomized trial of acidified nitrite cream in the treatment of tinea pedis.
AB - BACKGROUND: Nitric oxide is continually released from normal skin and has
antimicrobial effects. An acidified nitrite cream releases supraphysiologic
concentrations of nitric oxide and is fungicidal in vitro. OBJECTIVE: The purpose
of this study was to assess the efficacy of an acidified nitrite cream as
treatment for tinea pedis. METHODS: Sixty patients were recruited with both a
clinical diagnosis of tinea pedis and hyphae identified on direct microscopy;
they were randomly placed into an active group treated with twice-daily
application of a mixture of 3% salicylic acid in aqueous cream and 3% nitrite in
aqueous cream for 4 weeks and a control group treated with 3% salicylic acid in
aqueous cream and aqueous cream alone. Nineteen patients completed the trial in
the active group and 16 patients in the control group. Mycologic cure (negative
results on microscopy and culture) and clinical improvement were measured at 0,
2, and 4 weeks and after a 2-week interval with no treatment. RESULTS: At the end
of the treatment period, 18 of the 19 patients in the active group were
mycologically cured as were 11 of 16 in the control group (p = 0.042). Two weeks
after the cessation of treatment, 13 of 19 patients in the active group were
mycologically cured and 5 of 16 in the control group (p = 0.028). The initial
clinical scores in the active and control groups were 8.1 and 8.19 (two-tailed p
= 0.95). At 4 weeks they were 1.66 and 6.0 (two-tailed p = 0.002) and after 2
weeks with no treatment 1.45 and 7.4 (two-tailed p < 0.0002). CONCLUSION:
Acidified nitrite is effective therapy for tinea pedis.
PMID- 9555795
TI - Low-dose low-molecular-weight heparin (enoxaparin) is beneficial in lichen
planus: a preliminary report.
AB - BACKGROUND: Low-dose heparin devoid of anticoagulant activity inhibits T
lymphocyte heparanase activity, which is crucial in T-cell migration to target
tissues. OBJECTIVE: The purpose of this study was to assess the efficacy of low
dose enoxaparin (Clexane), a low-molecular-weight heparin, as monotherapy in
lichen planus. METHODS: Included in the study were 10 patients with widespread
histopathologically proven lichen planus (LP) associated with intense pruritus of
several months' duration. Patients were given 3 mg enoxaparin, subcutaneously
once weekly; three patients received four injections, and seven patients received
six injections. RESULTS: In nine patients the itch disappeared within 2 weeks.
Within 4 to 10 weeks in eight of these patients, there was complete regression of
the eruption with residual postinflammatory hyperpigmentation; in one patient,
there was marked improvement. In one patient, no effect was observed. Of the four
patients who also had oral LP, only one showed improvement. No side effects were
observed in any of the patients. CONCLUSION: These findings indicate that
enoxaparin may be a simple, effective treatment for cutaneous LP.
PMID- 9555796
TI - Coexistence of lupus erythematosus and porphyria cutanea tarda in fifteen
patients.
AB - BACKGROUND: Lupus erythematosus (LE) and porphyria cutanea tarda (PCT) may have
similar clinical presentations, and their coexistence presents special problems
in diagnosis and management. OBJECTIVE: The purposes of this study were to
describe a patient with discoid LE and PCT and to present a review of 15 patients
with coexistent LE (all variants) and PCT. METHODS: The medical records of all
patients with coexistent LE and PCT seen between 1976 and 1995 were
retrospectively reviewed. RESULTS: Of 6179 cases of LE and 676 cases of porphyria
(all variants), there were 15 patients, 6 men and 9 women, with coexistent LE and
PCT. The mean age at diagnosis of LE was 42.8 years and of PCT was 48 years. Nine
patients had discoid LE; five patients had systemic LE, and one patient had
subacute cutaneous LE. The initial diagnosis was LE in eight patients, PCT in
five patients, and simultaneous LE and PCT in two patients. Precipitating factors
for PCT included alcohol in seven patients, iron overload in one patient, and
estrogen in one patient. Treatment of LE with hydroxychloroquine 200 mg daily
precipitated PCT in two patients. Patients were treated with phlebotomy or low
dose antimalarials for PCT. Patients with systemic LE received systemic
glucocorticoid therapy. Patients with discoid LE and subacute cutaneous LE were
treated with topical glucocorticoids. CONCLUSION: The association of LE and PCT
poses therapeutic challenges. The preferred treatment for one may exacerbate the
other. Use of standard dose antimalarials for LE is inadvisable, and phlebotomy
or low-dose antimalarials should be used cautiously in patients with coexistent
disease.
PMID- 9555797
TI - Single hair grafting for the treatment of vitiligo.
AB - BACKGROUND: Vitiligo is a disease of unknown cause, and many medical and surgical
therapeutic methods are used to treat it. OBJECTIVE: Our purpose was to evaluate
the effectiveness of single hair grafting in patients with vitiligo. METHODS:
Single hairs were grafted into vitiliginous areas of 21 patients. The diameter of
the spreading pigmentation was evaluated periodically. RESULTS: Perifollicular
repigmentation around the grafted hair was observed in 15 patients (71%) within 2
to 8 weeks. The diameter of the spreading pigmentation ranged from 2 to 10 mm
during a 12-month follow-up period. In cases of generalized vitiligo,
perifollicular pigmentation was seen in one of four patients (25%), whereas it
was observed in 14 of 17 patients (82%) with localized/segmental vitiligo.
Transformation of depigmented hairs into pigmented ones occurred in five
patients. CONCLUSION: Single hair grafting appears to be an effective method for
treating localized/segmental vitiligo, especially on hairy parts of the skin,
including the eyelids and eyebrows, and for small areas of vitiligo.
PMID- 9555798
TI - Successful monotherapy of severe and intractable atopic dermatitis by
photopheresis.
AB - BACKGROUND: Patients with chronic atopic dermatitis can become unresponsive to
standard immunosuppressive therapy and thus pose a serious therapeutic problem.
OBJECTIVE: Our purpose was to evaluate the therapeutic effectiveness of
photopheresis in the management of patients with severe and intractable atopic
dermatitis. METHODS: Photopheresis was used as monotherapy in patients (n = 3)
who previously did not respond to treatment with glucocorticosteroids,
cyclosporine, phototherapy, or photochemotherapy. Patients were treated at 2-week
intervals (total number of treatments = 10). RESULTS: In all patients,
photopheresis induced clinical improvement and reduction of elevated serum levels
of eosinophil cationic protein and total IgE. Prolongation of the intervals
between treatments from 2 to 4 weeks caused worsening in one patient, whereas
shortening of treatment-free intervals improved both clinical and laboratory
findings. CONCLUSION: These studies indicate that photopheresis may be used as
monotherapy for the treatment of patients with severe atopic dermatitis that has
become intractable to standard therapeutic modalities.
PMID- 9555799
TI - High-dose UVA1 therapy for atopic dermatitis: results of a multicenter trial.
AB - BACKGROUND: The results of an open, single-center study suggested that
phototherapy with high doses of UVA1 radiation (UVA1R; 340-400 nm) is effective
for acute, severe exacerbations of atopic dermatitis (AD). OBJECTIVE: The purpose
of this study was to assess the effectiveness of high-dose UVA1 phototherapy for
acute, severe AD in a randomized multicenter trial in direct comparison with
topical glucocorticoid therapy. METHODS: Patients were treated with high-dose
UVA1R (10 days, 130 J/cm2/day; n = 20), topically with fluocortolone (10 days, 1
x daily; n = 17), or with UVA-UVB therapy (10 days, 1 x daily, minimal erythema
dose-dependent; n = 16). RESULTS: With a clinical scoring system, significant
differences in favor of high-dose UVA1R and fluocortolone therapy were observed
(p < 0.0001), as compared with UVA-UVB therapy. At day 10, high-dose UVA1R was
superior to fluocortolone (p < 0.002) therapy. Serum levels of eosinophil
cationic protein and the blood eosinophil count were significantly reduced after
high-dose UVA1 or fluocortolone, but not UVA-UVB therapy. CONCLUSION: This study
confirms the therapeutic effectiveness of high-dose UVA1 monotherapy for
treatment of severe exacerbations of AD.
PMID- 9555801
TI - Clinically significant drug interactions in dermatology.
AB - Access to information on clinically significant drug interactions is not readily
available. This can be a source of uncertainty, and locating this information can
be tedious and time-consuming. The pharmacology of drug interactions is briefly
discussed. The most common drug interactions involve altered hepatic metabolism.
At least 26 drugs are such frequent offenders that they can be considered "red
flag" drugs. In addition, an extensive list of current significant and less
significant drug interactions of particular importance to the dermatologist is
presented.
PMID- 9555800
TI - Regression of Kaposi's sarcoma during therapy with HIV-1 protease inhibitors: a
prospective pilot study.
AB - BACKGROUND: Early studies using HIV protease inhibitors (PI) showed regression of
Kaposi's sarcoma (KS) lesions in some patients. OBJECTIVE: Our purpose was to
determine prospectively the influence of PI on HIV-related KS. METHODS: KS
lesions of nine patients with progressive cutaneous disease were prospectively
evaluated clinically and by means of epiluminescence microscopy before and during
PI therapy. HIV viremia and CD4 cell count were measured in parallel. RESULTS:
All patients experienced reduction or initial stabilization of KS lesions during
the first 4 to 8 weeks of HIV-1 PI therapy. After a median follow-up of 7 months
and according to AIDS Clinical Trials Groups criteria, six patients had a partial
response, two showed stable disease, and in one noncompliant patient KS
progressed, requiring chemotherapy. With epiluminescence microscopy, a reduction
in skin surface alterations, lesional size, and color intensity was demonstrated
in six of nine patients. PI induced a median decrease in viremia of 1.66 log and
a median increase in the CD4 count of 49 cells/mm3. CONCLUSION: In this series,
HIV PI therapy reduced or stabilized KS. The efficacy of HIV-1 PI in KS may
result from the improvement in cellular immunity. These results suggest the use
of PI in AIDS-related KS regardless of the level of CD4 lymphocyte count and HIV
viremia.
PMID- 9555802
TI - Surgical pearl: lubricating jelly as a dressing in punch grafts for pitted acne
scars.
PMID- 9555803
TI - Aleukemic leukemia cutis in a patient with acute lymphoblastic leukemia.
PMID- 9555804
TI - Follicular mucinosis in association with squamous cell carcinoma of the tongue.
PMID- 9555806
TI - Microbiology of infected eczema herpeticum.
PMID- 9555805
TI - A case of cicatricial pemphigoid with simultaneous IgG autoantibodies against the
180 kd bullous pemphigoid antigen and laminin 5.
PMID- 9555807
TI - Systemic plasmacytosis with cutaneous manifestations in a white man: successful
therapy with cyclophosphamide/prednisone.
PMID- 9555809
TI - Linear lichen planopilaris of the face.
PMID- 9555808
TI - The null allele of GSTM1 does not affect susceptibility to solar keratoses in the
Australian white population.
PMID- 9555810
TI - A novel childhood pemphigus vegetans variant of intraepidermal neutrophilic IgA
dermatosis.
PMID- 9555811
TI - Acquired syphilis II in early childhood: reappearance of syphilis brephotrophica.
PMID- 9555812
TI - Fixed food eruption caused by lentils.
PMID- 9555813
TI - Eosinophilic pustular folliculitis induced by carbamazepine.
PMID- 9555814
TI - Sign of Leser-Trelat and mycosis fungoides.
PMID- 9555815
TI - Insect repellents: an overview.
PMID- 9555816
TI - Insect repellents.
PMID- 9555817
TI - Dermatoses of the glans penis: penile venereal edema.
PMID- 9555818
TI - Hepatitis C virus infection in patients with urticaria.
PMID- 9555819
TI - Topical treatment of acne vulgaris: retinoids and cutaneous irritation.
PMID- 9555820
TI - Reduced skin irritation with tretinoin containing polyolprepolymer-2, a new
topical tretinoin delivery system: a summary of preclinical and clinical
investigations.
AB - Novel tretinoin cream and gel formulations have been developed that incorporate
polyolprepolymer-2, which is a material designed to help retain drug molecules in
and on the skin when applied in topical vehicles. The results of preclinical and
clinical investigations have confirmed the beneficial impact of such a vehicle on
tretinoin tolerability. In vitro studies with selected polyolprepolymer
containing formulations have reduced initial and cumulative tretinoin
percutaneous penetration, and guinea pig studies showed that the gel formulation
containing polyolprepolymer-2 caused less erythema and edema than did the
corresponding commercially-available tretinoin gel formulation. Human studies
with tretinoin containing polyolprepolymer-2 have consistently demonstrated a
favorable tolerability profile when compared with commercially-available
tretinoin. Use of the polyolprepolymer-2-containing tretinoin formulation in
human studies has resulted in reductions in peeling--a problem commonly
associated with use of standard tretinoin formulations. These reductions in
irritation have not been at the expense of efficacy; acne clinical trial results
indicate comparable effectiveness between tretinoin containing polyolprepolymer2
and commercially-available tretinoin.
PMID- 9555821
TI - Irritation potential of a new topical tretinoin formulation and a commercially
available tretinoin formulation as measured by patch testing in human subjects.
AB - BACKGROUND: A novel tretinoin preparation uses polyolprepolymer-2, a compound
designed to reduce skin irritation by helping retain drugs on and in the surface
layers of the skin. OBJECTIVE: We used patch testing to measure the effect of
polyolprepolymer-2 on tretinoin-associated irritation. METHODS: Two patch test
studies were conducted. The first assessed the effect of polyolprepolymer-2 by
comparing commercially-available tretinoin formulations with respective
polyolprepolymer-containing formulations of 0.025% tretinoin gel and 0.025%,
0.05%, and 0.1% tretinoin creams. The second assessed the effect of the
polyolprepolymer-2 concentration on the potential decrease in irritation by
comparing: (1) a commercially-available tretinoin cream with prototype tretinoin
creams containing 20% polyolprepolymer-2 at three different concentrations of
tretinoin (0.025%, 0.05%, and 0.1%); and (2) the effect of three different
polyolprepolymer-2 concentrations (10%, 15%, and 20%) in prototype tretinoin
creams on cumulative irritation. Patch agents were assigned to subjects according
to a randomization schedule, and during a period of 5 days each subject received
three 24-hour exposures to the test materials. Twenty-four hours elapsed between
old patch removal and new patch application. RESULTS: In the first study, the
tretinoin gel and cream containing polyolprepolymer-2 caused significantly less
irritation than all equivalent formulations of the commercially-available
tretinoin gel and creams except the 0.025% cream formulation. Irritation scores
were not significantly different in terms of irritation in the 0.025% creams
although scores did indicate a trend towards lower irritation with 0.025%
tretinoin cream containing polyolprepolymer-2. In the second study, the tretinoin
gel containing polyolprepolymer-2 and the three tretinoin prototype creams also
containing polyolprepolymer-2 caused significantly less irritation than
comparable concentrations of the commercially-available tretinoin. In addition,
the 0.025% tretinoin gel formulation containing polyolprepolymer-2 was no more
irritating than the commercially-available 0.025% tretinoin cream. CONCLUSION:
Tretinoin formulations containing polyolprepolymer-2 are, in general, less
irritating than the currently marketed tretinoin formulations.
PMID- 9555822
TI - Comparative efficacy and safety of two 0.025% tretinoin gels: results from a
multicenter double-blind, parallel study.
AB - BACKGROUND: The addition of polyolprepolymer-2 in tretinoin formulations may
reduce tretinoin-induced cutaneous irritation. OBJECTIVE: This study compared the
efficacy and safety of a new 0.025% tretinoin gel containing polyolprepolymer-2,
its vehicle, and a commercially-available 0.025% tretinoin gel in patients with
mild to moderate acne vulgaris. METHODS: In this 12-week multicenter, double
blind, parallel group study, efficacy was evaluated by objective lesion counts
and the investigators' global evaluations. Subjective assessment of cutaneous
irritation by the investigators and patients evaluated safety. RESULTS: The
efficacy of the two active treatments in this 215 patient study was comparable,
and both treatments were statistically significantly more effective than vehicle.
When compared with the commercially-available tretinoin gel, the formulation
containing polyolprepolymer-2 demonstrated statistically significantly less
peeling at days 28, 56, and 84, statistically significantly less dryness by day
84, and statistically significantly less itching at day 14. Irritation scores for
the formulation containing polyolprepolymer-2 were numerically lower but not
statistically different from those of the commercially-available gel for erythema
and burning. The number of cutaneous and noncutaneous adverse events were similar
for both active medications. CONCLUSION: The two 0.025% gels studied demonstrated
comparable efficacy. However, the gel formulation containing polyolprepolymer-2
caused significantly less peeling and drying than the commercially-available
formulation by day 84 of the study.
PMID- 9555823
TI - Double-blind, vehicle-controlled, multicenter comparison of two 0.025% tretinoin
creams in patients with acne vulgaris.
AB - BACKGROUND: Preclinical study and human patch tests indicate polyolprepolymer-2
may reduce cutaneous tretinoin-induced irritation. OBJECTIVE: This study compared
the clinical efficacy and safety of a 0.025% tretinoin cream containing
polyolprepolymer-2 and its vehicle to a commercially-available 0.025% tretinoin
cream. METHODS: In this 12-week multicenter, double-blind, parallel group study
in patients with mild to moderate acne, objective lesion counts and the
investigators' global evaluations evaluated efficacy. Subjective evaluations of
skin irritation were used to study safety. RESULTS: A total of 271 patients were
enrolled. The active treatments demonstrated comparable efficacy that was
statistically significantly greater than that of the vehicle. Safety evaluations
of cutaneous and noncutaneous adverse events also indicated comparable results of
the active treatments. CONCLUSION: The commercially-available 0.025% tretinoin
cream and the 0.025% tretinoin cream containing polyolprepolymer-2 demonstrated
comparable efficacy and safety.
PMID- 9555824
TI - Mergers, acquisitions, and trauma care in the 1990s.
PMID- 9555825
TI - Measuring injury severity: time for a change?
AB - BACKGROUND: The Injury Severity Score (ISS) does not take into account multiple
injuries in the same body region, whereas a New ISS (NISS) may provide a more
accurate measure of trauma severity by considering the patient's three greatest
injuries regardless of body region. The purpose of this study was to evaluate the
ISS and NISS in patients with blunt trauma. METHODS: Consecutive individuals
treated from January of 1992 to September of 1996 at one institution were
included if they had sustained blunt trauma and satisfied triage standards (n =
2,328). For each patient, we computed the ISS and the NISS to determine how often
the two scores were identical or discrepant. Discrepant cases were then further
analyzed using receiver operating characteristic curves to determine which score
better predicted short-term mortality. RESULTS: The mean ISS was 25 +/- 13, and
the mean NISS was 33 +/- 18. The two predictive scores were identical in 32% of
patients and discrepant in 68% of patients. Patients with identical scores had a
lower mortality rate than patients with discrepant scores (10% vs. 13%; p <
0.02). In patients with discrepant scores, the area under the receiver operating
characteristic curves was greater for the NISS than the ISS (0.852 vs. 0.799; p <
0.001), and greater amounts of discrepancy were associated with increasing rates
of mortality (p < 0.001). CONCLUSIONS: The NISS often increases the apparent
severity of injury and provides a more accurate prediction of short-term
mortality. The benefit associated with using the NISS rather than the ISS must be
weighed against the disadvantages of changing a scoring system and the potential
for still greater improvements.
PMID- 9555826
TI - Changes in red cell transfusion practice among adult trauma victims.
AB - BACKGROUND: Recent attention concerning the adverse outcomes of blood transfusion
has resulted in decreased blood product usage for nonemergency care. We
hypothesized that there has also been a decrease in blood product use in the
management of seriously injured adults. METHODS: A retrospective review of
institutional database records was conducted at a regional trauma center for
adults admitted during 1991, 1993, and 1995. Data was analyzed for trends in
amount, type, and timing of blood product use. RESULTS: A total of 1,738 patients
were assessed, with 1,605 meeting inclusion. The three patient groups were
similar, including injury severity (overall mean Injury Severity Score of 23.6),
mechanism (88% blunt), and survival (87%). In 1991, 54% of the patients were
transfused a total of 2,341 units of packed red blood cells (mean 4.67 units/pt
treated) versus 42% of patients in 1995 (p < 0.0001) who received 2,018 packed
red blood cells (mean 3.57 units/patient treated, p = 0.05). A significantly
higher proportion of units was transfused in the first 24 hours of care in 1995
(64%) compared with 1991 (21%, p < 0.0001). A reduction in the use of universal
donor type-O blood use was also found (1.21 vs. 0.65 units/patient transfused, p
< 0.0001). Despite similar admission hemoglobin concentrations (124.1 vs. 125.3,
not significant), significant reductions were found in the average 24-hour (109.2
vs. 103.8, p < 0.001), lowest (96.5 vs 92.1, p < 0.01) and discharge (115.8 vs.
110.5, p < 0.001) concentrations. CONCLUSIONS: Between 1991 and 1995 there have
been significant reductions in both the number of trauma patients receiving blood
products and the total number of units transfused. These findings may reflect
lower or abandoned hemoglobin transfusion triggers and increased awareness of
complications related to transfusion.
PMID- 9555827
TI - Effect of the Advanced Trauma Life Support program on medical students'
performance in simulated trauma patient management.
AB - BACKGROUND: Part of the senior medical students' examination at the University of
Toronto involves testing with simulated patient management. We compared the
performance in these simulations of senior medical students who received Advanced
Trauma Life Support (ATLS) training with those who did not receive ATLS training.
METHODS: Thirty-two students (group I) completed a standard ATLS course, 12
students (group II) audited the ATLS course, and their performance in the trauma
simulations was compared with 44 matched control students (group III) from the
same class. Performance in the nontrauma patient simulation stations was also
analyzed. The score on each station was standardized to a maximum of 20. The
students were also graded on overall Approach (scale of 1 to 5) and pass status.
RESULTS: The mean scores (+/-SD, *p < 0.05 compared with other groups) were as
follows: Trauma Station, 17.5 +/- 1.02* for group I, 11.76 +/- 0.72* for group
II, and 14.67 +/- 0.54* for group III; Nontrauma Station, 13.05 +/- 0.95 for
group I, 12.25 +/- 0.72 for group II, and 11.88 +/- 0.80 for group III; Approach,
4.45 +/- 0.50* for group I, 2.09 +/- 0.60* for group II, 3.50 +/- 0.67* for group
III. The ATLS-trained and ATLS-audit students had higher scores in the trauma
stations than the control group, with the highest scores being in the ATLS
trained group. All ATLS-trained students passed with 62.5% honors and 37.5%
passing grades. The ATLS-audit group had 33.3% honors and 66.6% passing grades,
compared with the control group who had 84.09% pass, 9.09% borderline, and 6.82%
failure in the trauma stations. CONCLUSIONS: The ATLS course, both complete and
audit status, prepares students more appropriately for managing trauma patients
as judged by trauma simulation scenarios. Consideration should be given for
including ATLS as an integral part of the senior medical student curriculum.
PMID- 9555828
TI - Hypertonic saline activates lipid-primed human neutrophils for enhanced elastase
release.
AB - BACKGROUND: Ongoing clinical trials have revived interest in hypertonic saline
(HTS) for postinjury resuscitation; these studies have documented serum Na+
concentrations > or = 170 mmol/L. Recent animal studies have shown that HTS
enhances T-cell and monocyte function, but effects on the polymorphonuclear
neutrophil (PMN) remain unclear. The postinjury lipid mediators platelet
activating factor (PAF) and leukotriene B4 (LTB4) have been implicated in PMN
priming for cytotoxicity, which is believed to be important in the pathogenesis
of multiple organ failure. We hypothesized that HTS would stimulate PMN
superoxide (O2-) and elastase release from PAF- and LTB4-primed PMNs. METHODS:
Isolated PMNs from five donors were primed for 5 minutes with 200 nmol/L PAF or 1
micromol/L LTB4 in Kreb's-Ringer's phosphate with dextrose at a Na+ concentration
of 140 mmol/L (normal serum Na+ concentration), pelleted, and resuspended in
Kreb's-Ringer's phosphate with dextrose for 10 minutes at a Na+ concentration of
130 to 170 mmol/L. O2- generation was measured by superoxide dismutase
inhibitable reduction of cytochrome c and elastase release by cleavage of N
methoxysuccinyl-Ala-Ala-Pro-Val p-nitroanilide. RESULTS: HTS with Na+
concentration up to 170 mmol/L had no significant effect on O2- production or
elastase release from quiescent cells. Na+ concentration of 160 and 170 mmol/L,
however, activated PAF- and LTB4-primed PMNs for enhanced elastase release with
no effect on O2- production. CONCLUSION: In clinically relevant concentrations,
elevated Na+ activates lipid-primed neutrophils for enhanced elastase
degranulation. Consequently, the administration of HTS in the early postinjury
resuscitation period, when PMNs are maximally primed, may activate PMN elastase
release and thereby promote the development of multiple organ failure.
PMID- 9555829
TI - Does free fluid on abdominal computed tomographic scan after blunt trauma require
laparotomy?
AB - BACKGROUND: Abdominal computed tomographic (CT) scans are used in the evaluation
of blunt trauma. The purpose of this study was to determine if isolated
intraperitoneal fluid seen on CT scan necessitates laparotomy. METHODS: Trauma
registry records of patients who underwent abdominal computed tomography from
January 1994 through January 1997 were studied. Data were reviewed for age,
gender, CT scan interpretation, associated injuries, and operative findings.
RESULTS: Abdominal injury was identified in 126 patients. Seventy-eight patients
had evidence of solid-organ injury and 17 patients had extraperitoneal injury.
Isolated intraperitoneal fluid was identified in 31 patients. All patients with
isolated fluid underwent laparotomy; 29 of these procedures (94%) were
therapeutic. Bowel injuries occurred in 18 patients and mesenteric injuries in 8
patients. Five patients had intraperitoneal bladder rupture, and undetected solid
organ injuries were found in two patients. Other organs injured included the
stomach, pancreas, ovary, and uterus. CONCLUSION: Exploratory laparotomy was
therapeutic in 94% of patients. Isolated intraperitoneal fluid on CT scan after
blunt trauma mandates laparotomy.
PMID- 9555830
TI - A comparison of sonographic examinations for trauma performed by surgeons and
radiologists.
AB - BACKGROUND: It has been demonstrated that surgeons and surgery residents, trained
in the focused abdominal sonographic examination, are able to accurately and
reliably evaluate trauma patients. Despite this, radiologists have objected to
surgeon-performed sonography for several reasons. We set out to compare the
accuracy of sonographic examinations performed by surgery residents and
radiologists. METHODS: A retrospective review of medical records of all trauma
patients who received focused ultrasound examinations from January 1, 1995,
through June 30, 1996, at one of two American College of Surgeons-verified Level
I trauma centers in the same city was undertaken. Ultrasound examinations were
performed by surgery residents at trauma center A (TCA) and by radiologists or
radiology residents at trauma center B (TCB). Findings for each patient were
compared with the results of computed tomography, diagnostic peritoneal lavage,
operative exploration, or observation. Sensitivity, specificity, accuracy,
positive predictive value, and negative predictive value were calculated for each
group of patients. Comparison of patient charges for the trauma ultrasound
examinations at each of the trauma centers was also made. RESULTS: Patient
populations at the two centers were similar except that the mean Injury Severity
Score at TCB was higher than at TCA (11.74 vs. 9.6). Sensitivity, specificity,
accuracy, or negative predictive value were not significantly different between
the two cohorts. A significantly lower positive predictive value for examinations
performed by surgery residents was noted and attributed to a lower threshold of
the surgery residents to confirm their findings by computed tomography. Billing
data revealed that the average charge for trauma sonography by radiologists (TCB)
was $406.30. At TCA, trauma sonography did not generate a specific charge;
however, a $20.00 sum was added to the trauma activation fee to cover ultrasound
machine maintenance and supplies. CONCLUSION: Focused ultrasound examination in
the trauma suite can be as safely and accurately performed by surgery residents
as by radiologists and radiology residents and should be a routine part of the
initial trauma evaluation process.
PMID- 9555831
TI - Preferential benefit of implementation of a statewide trauma system in one of two
adjacent states.
AB - BACKGROUND: Implementation of Oregon's trauma system was associated with a
reduction in the risk of death for hospitalized injured patients. An alternative
explanation for improved outcome, however, is favorable concurrent temporal
trends, e.g., new technologies and treatments. PATIENTS AND METHODS: To control
for temporal trends, seriously injured hospitalized patients in Oregon and
Washington were compared before either state had a trauma system (1985-1988) and
when only the Oregon trauma system had been implemented (1990-1993). The study
group consisted of hospitalized injured patients aged 16 to 79 years with one or
more index injuries in six body regions, i.e., head, chest, spleen/liver, femur
or pelvis fracture, and burns. Hospital discharge claims data were analyzed,
converting International Classification of Diseases, Ninth Revision, Clinical
Modification, discharge diagnosis codes to Abbreviated Injury Scale scores and
Injury Severity Scores using a conversion algorithm. Multivariate logistic
regression models were used to estimate the differential risk-adjusted odds of
death in Oregon compared with Washington after adjustment for demographics,
injury type, and injury severity. RESULTS: Findings indicated no difference in
the risk-adjusted odds of death between Oregon and Washington while both states
functioned under an ad hoc trauma system (1985-1988). A significant reduction in
the risk of death, however, was noted in Oregon for patients with an index injury
and an Injury Severity Score > 15 compared with Washington (adjusted odds ratio
(OR) = 0.80, 95% confidence interval (CI) = 0.70-0.91) after trauma system
implementation in Oregon (1990-1993). Specifically, reductions in the risk of
death were demonstrated for patients with head injuries (adjusted OR = 0.70, 95%
CI = 0.59-0.82) or liver/spleen injuries (adjusted OR = 0.73, 95% CI = 0.54
0.99). CONCLUSION: Assuming that the two states demonstrated similar concurrent
temporal trends, the findings support the conclusion that improved outcomes among
injured patients in Oregon may be attributed to the institution of a statewide
trauma system.
PMID- 9555832
TI - Trauma patients 75 years and older: long-term follow-up results justify
aggressive management.
AB - BACKGROUND: Long-term survival rate and functional status after trauma for one of
the fastest growing segments of the population, patients 75 years and older, is
poorly documented. METHODS: Trauma patients 75 years and older who were
discharged from our Level I trauma center between June 1988 and July 1992 (n =
279) were contacted by mail or phone. Public death records were used to identify
patients who had died. A stepwise logistic regression analysis was performed to
determine predictors of poor outcome (death within 6 months). Main outcome
measures included mortality and self-assessed functional status. RESULTS: A
minimum 4-year follow-up was obtained for 81% of the 279 study patients. The mean
follow-up period was 5.4 +/- 1.1 years. Mean age at time of injury was 81 +/- 5
years (range, 75-101 years); mean Injury Severity Score was 9.4 +/- 7.7. At
follow-up, 132 patients (47%) had died, 93 patients (33%) were contacted, and 54
patients (19%) could not be located. Twelve percent of patients survived less
than 6 months after discharge. Poor survival was predicted by preexisting
diseases (dementia, p = 0.001; hypertension, p = 0.02; and chronic obstructive
pulmonary disease, p = 0.05) and not by age or severity of injury. The mean age
of patients still living was 85 +/- 3.9 years (range, 79-99 years), and 77 of 93
patients were living in an independent setting (33 alone, 44 with spouse or
family); of these, 57% reported no difficulties in performing 12 of 14 activities
of daily living. CONCLUSION: Despite higher than expected mortality after
discharge, aggressive management of trauma patients 75 years and older is
justified by the favorable long-term outcome.
PMID- 9555833
TI - Long-term psychosocial adaptation of children who survive burns involving 80% or
greater total body surface area.
AB - OBJECTIVE: To examine the psychosocial adjustment of survivors of massive
pediatric burn injuries, the change in adjustment across time, and the impact on
parents. BACKGROUND: Patients/parents were assessed at regular intervals postburn
using standardized tests of adjustment. Patients who could not be included in
standardized longitudinal assessments were administered questionnaires by
mail/telephone. METHODS: The Child Behavior Checklist, the Teacher Report Form,
the Youth Self Report Form, and the Parenting Stress Index were utilized to
assess adjustment. RESULTS: On all objective measures, the group of survivors and
their parents were within normal limits. Adjustment neither improved nor
deteriorated over time. CONCLUSION: Children who survive massive burn injuries
can achieve positive psychosocial adaptation.
PMID- 9555834
TI - A prospective study of predictors of disability at 3 months after non-central
nervous system trauma.
AB - OBJECTIVE: To delineate which injury-related, demographic, and psychosocial
variables were predictive of severe disability (limitations in the performance of
socially defined roles and tasks) at 3 months after discharge from acute
hospitalization for non-central nervous system traumatic injury. PATIENTS AND
METHODS: The study design was prospective, longitudinal, and correlational. The
sample consisted of 109 injured patients at three urban trauma centers. Data were
obtained from patient interview using the Sickness Impact Profile, the Impact of
Event Scale, and the Social Support Questionnaire; injury-related data were
obtained from the medical record and computerized trauma registries. RESULTS: The
sample had a mean age of 37.4 +/- 16.8 years, a mean number of injuries per
person of 4.4 +/- 2.8, and a mean Injury Severity Score of 15.5 +/- 9.9. Motor
vehicle crashes (34.9%) and violent injuries (33%) were the predominant causes of
injuries. Patients experienced severe levels of disability (Sickness Impact
Profile, mean = 26.1) and moderate levels of psychological distress (Impact of
Event Scale, mean = 30.6; intrusion mean = 14.6 and avoidance mean = 16.0). Three
variables were predictive of severe disability at 3 months: high levels of
intrusive thoughts (odds ratio, 2.9; 95% confidence interval, 1.1-7.7); injury
with a maximal Abbreviated Injury Scale score in an extremity (odds ratio, 2.9;
95% confidence interval, 1.2-6.9); and having not graduated from high school
(odds ratio, 3.4; 95% confidence interval, 1.2-10). CONCLUSION: Extremity
injuries, lack of high school graduation, and high level of posttraumatic
psychological distress with intrusive thoughts are risk factors for severe
disability at 3 months after discharge from the hospital.
PMID- 9555835
TI - Psychosocial factors limit outcomes after trauma.
AB - BACKGROUND: Psychological morbidity compromises return to work after trauma. We
demonstrate this relationship and present methods to identify risks for
significant psychological morbidity. METHODS: Thirty-five adults were evaluated
prospectively for return to functional employment after injury using demographic
data, validated psychological and health measures, and the Michigan Critical
Events Perception Scale. Evaluation was conducted at admission and at 1 and 5
months after injury. RESULTS: Poor return to work at 5 months was attributable to
physical disability (p < 0.05) and psychological disturbance (p < 0.05) in a
regression model that controlled for preinjury employment and psychopathologic
factors as well as injury severity. A high score on the Impact of Events Scale
administered during acute admission predicted development of acute stress
disorder at 1 month (p < 0.01, odds ratio (OR) = 9.4) and posttraumatic stress
disorder at 5 months (p < 0.05, OR = 6.7). Peritraumatic dissociation on the
Michigan Critical Events Perception Scale was predictive for development of acute
stress disorder (p < 0.05, OR = 5.8) at 1 month and posttraumatic stress disorder
(p < 0.05, OR = 7.5) at 5 months. CONCLUSION: Psychological morbidity after
injury compromises return to work independent of preinjury employment and
psychopathologic condition, Injury Severity Score, or ambulation. A high Impact
of Events Scale score or peritraumatic dissociation at admission predicts this
morbidity.
PMID- 9555836
TI - Can surgeons evaluate emergency ultrasound scans for blunt abdominal trauma?
AB - OBJECTIVE: To determine whether surgeons and residents with minimal training can
evaluate accurately emergency ultrasound (US) examinations compared with
radiologists for blunt abdominal trauma. METHODS: Over 7 months, we conducted a
prospective study comparing the evaluation of emergency US for blunt abdominal
trauma by surgeons and attending radiologists. US readings from the surgical team
and the radiologists were correlated with outcome. RESULTS: One hundred-twelve
patients were included in the study. Ninety-two patients had an US read as
negative by the surgical and radiology services with no subsequent injuries
identified. Eighteen patients had an US deemed positive by the surgical service
and radiologists. Injuries were confirmed in this group by operation or computed
tomography. One patient had an US deemed positive by the surgical team and
subsequently negative by the radiologist. A diagnostic peritoneal lavage was
performed which was negative. Another patient had an US interpreted as negative
by the surgical evaluator and positive by the radiologist. Exploratory laparotomy
was negative for intraabdominal hemorrhage or organ injury. Overall results
reveal an accuracy on US reading of 99% for the surgical team and 99% for the
attending radiologists. CONCLUSION: Surgeons and surgical residents at different
levels of training can accurately interpret emergency ultrasound examinations for
blunt trauma from the real-time images, at a level comparable to attending
radiologists.
PMID- 9555837
TI - Evaluation of alpine skiing and snowboarding injury in a northeastern state.
AB - BACKGROUND: To demonstrate the injury patterns of Alpine skiing and snowboarding
in a northeastern state and evaluate potential risk factors. METHODS: The medical
records of a single pediatric and adult Level I trauma center were evaluated from
January 1, 1990, through December 31, 1995. All admissions with injuries caused
by Alpine skiing or snowboarding were reviewed. Those patients arriving from two
local ski resorts, all of whose injuries are referred to the institution for
care, were separated out for consideration. Age, sex, type of injury, date of
injury, Injury Severity Score, operations performed, and outcome (including
mortality) were evaluated. In addition, resort utilization for the study period
was obtained from the two resorts included in the evaluation. Mortality data was
obtained from the Vermont office of the Chief Medical Examiner for the same time
period. RESULTS: For the 6-year period of the study approximately 2,978,000 skier
and snowboarder days were recorded at the study sites. Approximately 447,000 of
those days were attributed to snowboarders (15%). In all, 279 patients were
admitted for injuries (0.01%), 238 were related to Alpine skiing (incidence
0.01%) and 40 to snowboarding (incidence 0.01%). Snowboarders were statistically
younger (20 years; range, 4-44 years) than skiers (29 years; range, 6-70 years)
(p < 0.001) and had a significantly lower Injury Severity Score (15 in
snowboarders vs. 27 in skiers, p < 0.03). Two female patients were injured
snowboarding and 68 female patients were injured skiing. Eight percent of injured
snowboarders and 16% of injured skiers sustained multiple injuries (p < 0.01).
Injury patterns were significantly different. Upper extremity injuries were
almost exclusively found in snowboarders (24% vs. 7%, p < 0.003), whereas
cruciate ligament injuries occurred far more commonly in skiers (45% vs. 4%, p <
0.001 Lower extremity injuries in general were more common in skiers (78% vs.
38%, p < 0.001). Central nervous system injuries, including head and spine, were
evenly distributed over the two groups, although the snowboarders with central
nervous system injuries were younger. In addition, splenic injuries were more
common in snowboarders (13% vs. 2%, p < 0.01). Snowboarding accidents were far
more common in December, March, and April than other months. Fifty-one patients
sustained abdominal or chest injuries and only two of these required operative
intervention (two splenectomies). Other operative interventions were limited to
extremity injuries, injuries of the spine, or placement of an intracranial
pressure monitor. There were no fatalities recorded in this population, although
over the 6.5 years, there were 25 deaths related to alpine skiing and one to
snowboarding in the State (incidence 0.0000009 skier days). Victims tended to be
male: 96% of the skiers and the one snowboarder. The predominant cause of death
was blunt head trauma followed by blunt chest trauma. Helmets were not worn by
those sustaining head injuries or fatalities. Spine injuries were recorded only
in extremely young snowboarders and skiers out of control. CONCLUSION:
Snowboarders and Alpine skiers are equally prone to injury. Snowboarding
accidents are typically less severe and show significantly different injury
patterns than skiing accidents. Abdominal and chest injuries in this population
are generally amenable to nonoperative management. Prevention programs are best
targeted at safe skiing and snowboarding practices, not skiing or snowboarding in
poor conditions, use of helmets for skiers, and restraint of snowboard use in
very young children.
PMID- 9555838
TI - Secretory phospholipase A2 cleavage of intravasated bone marrow primes human
neutrophils.
AB - BACKGROUND: Recent clinical reports suggest that early femoral intramedullary rod
(IMR) fixation in patients with multiple injuries increases the risk of adult
respiratory distress syndrome (ARDS). We have shown that lipid-mediated
neutrophil (PMN) priming and elevated circulating levels of secretory
phospholipase A2 (sPLA2) within the first 24 hours after injury correlate with
the development of ARDS. We thus hypothesized that circulating lipid products,
generated by sPLA2 cleavage of intravasated bone marrow, prime PMNs for enhanced
superoxide anion (O2-) production. METHODS: Isolated PMNs from healthy volunteers
were incubated for 5 minutes with buffer or sPLA2-lysed bone marrow (100 U/mL)
collected from trauma patients. After formyl-methionyleucylphenylalanine (fMLP)
activation, O2- production was quantified by the superoxide dismutase-inhibitable
reduction of cytochrome c. Blood samples were also drawn from five injured
patients before and 24 hours after femoral IMR fixation. PMNs were isolated and
assessed for in vivo priming. RESULTS: PMNs incubated with sPLA2-lysed bone
marrow were primed for more than 3.5 times greater fMLP-induced O2- production.
Furthermore, in patients with femoral fractures, PMN O2- release in response to
fMLP after IMR fixation was more than 2.5 times higher than before fixation.
CONCLUSION: Collectively, the findings suggest that bone marrow released from
acute fracture sites may become a lipid substrate for the elevated sPLA2 levels
found in injured patients. The resultant priming of PMNs may thus render the
injured patient at risk for ARDS. Although clearly hypothetical at present, we
submit that these observations warrant further investigation because of their
clinical implications.
PMID- 9555839
TI - Early combined management of frontal sinus and orbital and facial fractures.
AB - BACKGROUND: Historically, frontal sinus fractures and associated maxillofacial
fractures were addressed at different times. We retrospectively reviewed our
experience with a series of 79 consecutive patients with bitable frontal sinus
fractures, most with associated facial fractures, who underwent early combined
cranial and maxillofacial procedures. METHODS: The operations were performed
emergently for patients with open or depressed skull fractures and hematomas with
mass effect, and electively within 2 weeks for those with closed fractures. The
cranial procedures were performed first. The nasofrontal ducts were packed with
"cigars" of bacitracin powder wrapped in Surgicel. All patients received
antibiotics for 2 weeks. RESULTS: Postoperatively, good subjective cosmetic
results were obtained except in one patient. Eight patients with lumbar drains
had expected temporary cerebrospinal fluid (CSF) leaks of less than 72 hours
duration. Six postoperative intracranial infections (four cases of meningitis,
one epidural empyema, and one intracerebral abscess) were detected; five of these
occurred in patients with open depressed fractures. Patients with preoperative
CSF leaks (p = 0.0039, Fisher's exact test) and open fractures (p = 0.065,
Fisher's exact test) were more likely to develop intracranial infections.
CONCLUSION: The combined neurosurgical and maxillofacial repairs achieved good
cosmetic outcomes, with relatively low morbidity. By combining the two-stage
procedure into one stage, standard surgical and anesthetic risks could
potentially be reduced. Preoperative CSF leaks and open fractures were associated
with a higher incidence of postoperative central nervous system infection. Early
operations did not appear to be associated with a higher complication rate.
PMID- 9555840
TI - Fractures of the greater tuberosity presenting as rotator cuff abnormality:
magnetic resonance demonstration.
AB - BACKGROUND: To show that magnetic resonance imaging (MRI) can be useful to
diagnose radiographically invisible greater tuberosity fractures in patients with
clinical presentations suspicious for rotator cuff injury. METHODS: Six patients
with subtle greater tuberosity fractures who were sent for MRI because of
possible rotator cuff tear are reviewed (age range, 27-51 years; mean, 40.5 +/-
8.4 years). Five of the patients recount direct trauma to their shoulders,
whereas one noticed shoulder pain after a fall in which she fractured her ankle.
RESULTS: MRI showed an area of edema confined to the greater tuberosity with
linear low signal extending through the tuberosity consistent with a fracture in
all cases. Although five patients had a complete set of shoulder radiographs
before MRI, these were interpreted as normal in all cases. Full-thickness rotator
cuff tears were not present in any of the cases. All of the patients were treated
conservatively with good results. CONCLUSIONS: MRI can prevent unnecessary
arthroscopy in patients clinically suspected of rotator cuff damage by showing
subtle fractures of the greater tuberosity not visible on radiographs.
PMID- 9555841
TI - Bone healing of tibial lengthening is enhanced by hyperbaric oxygen therapy: a
study of bone mineral density and torsional strength on rabbits.
AB - We investigated the effect of intermittent hyperbaric oxygen (HBO) therapy on the
bone healing of tibial lengthening in rabbits. Twelve male rabbits were divided
into two groups of six animals each. The first group went through 2.5 atmospheres
absolute of hyperbaric oxygenation for 2 hours daily, and the second group did
not go through hyperbaric oxygenation. Each animal's right tibia was lengthened 5
mm using an uniplanar lengthening device. Bone mineral density (BMD) study was
performed for all of the animals at 1 day before operation and at 3, 4, 5, and 6
weeks after operation. All of the animals were killed at 6 weeks postoperatively
for biomechanical testing. Using the preoperative BMD as an internal control, we
found that the BMD of the HBO group was increased significantly compared with the
non HBO group. The mean %BMD at 3, 4, 5, and 6 weeks were 69.5%, 80.1%, 87.8%,
and 96.9%, respectively, in HBO group, whereas the mean %BMD were 51.6%, 67.7%,
70.5%, and 79.2%, respectively, in non-HBO group (two tailed t test, p < 0.01, p
< 0.01, p < 0.01, and p < 0.01 at 3, 4, 5, and 6 weeks, respectively). Using the
contralateral nonoperated tibia as an internal control, we found that torsional
strength of lengthened tibia of the HBO group was increased significantly
compared with the non-HBO group. The mean percent of maximal torque was 88.6% in
HBO group at 6 weeks, whereas the mean percent of maximal torque was 76.0% in non
HBO group (two-tailed t test, p < 0.01). The results of this study suggest that
the bone healing of tibial lengthening is enhanced by intermittent hyperbaric
oxygen therapy.
PMID- 9555842
TI - Value of routine angiography before traumatic lower-limb reconstruction with
microvascular free tissue transplantation.
AB - From November 1993 to June 1997, long-bone defects in 40 trauma patients were
reconstructed with free osteoseptocutaneous fibula flaps. To determine the
necessity of routine angiography in traumatized lower limbs before free flap
transplantation, a prospective study was carried out. The study subjects were 34
patients, 25 males and 9 females, with an average age of 40.6 years.
Reconstruction was performed primarily for bone defects after Gustillo type III b
open fractures in 17 patients and secondarily for malunion and osteomyelitis in
17 patients. Reconstructed bone defects included 25 tibias and 9 femurs. Normal
pedal pulses were palpable in 31 patients. Angiographic findings were abnormal in
seven patients. In the three patients with abnormal pedal pulses, the particular
nonpalpable pulses correlated with the vascular lesions shown in the angiograms
(one in the tibial anterior artery and two in the tibial posterior artery). Four
patients with either injury of the peroneal artery (three cases) or
pseudoaneurysm of the tibial anterior artery (one case) had normal pedal pulses.
In all patients, microvascular transplantations were performed successfully. Our
study demonstrates the importance of thorough clinical evaluation. Preoperative
angiography of the injured lower limbs did not provide relevant additional
informations in this series. Familiarity with all available techniques makes it
possible to cope with almost any difficult posttraumatic vascular condition.
Routine recipient-site angiography before microsurgical reconstruction,
therefore, seems unjustified.
PMID- 9555843
TI - Simulation program for optimal orthopedic call: a modeling system for orthopedic
surgical trauma call.
AB - This report uses a mathematical modeling system to define optimal orthopedic
coverage for trauma centers. Data from 2,325 patients treated with emergency
orthopedic operations within 24 hours of admission at 78 randomly sampled and at
four totally sampled verified centers were used to create a profile of (1)
admission by month, day, and hour; (2) operation times; and (3) operation
duration. The reason for operation included (1) open fracture or crush (809
patients); (2) irreducible dislocations (164 patients); (3) fracture with
vascular injury (seven patients); (4) dislocation with vascular injury (17
patients); (5) compartment syndrome (11 patients); (6) femoral neck fracture in
young patients (36 patients); (7) combination of categories 1 to 6 (70 patients);
(8) fracture with multiple injuries (171 patients); and (9) urgent not emergent
(1,040 patients). The program defined the frequency that an injured patient
needing an orthopedic consult would wait beyond 30 minutes because the orthopedic
surgeon was doing a trauma related operation at a center with one or two
orthopedic surgeons on call. The probability that a patient cannot be seen
promptly by one orthopedic surgeon in a center doing 25, 50, 75, 100, 200, and
300 emergency procedures per year is 0.17, 0.74, 1.6, 3.1, 12.5, and 28 patients
per year. When two are on call, 1.3 patients, yearly, will wait more than 30
minutes in a center doing 300 emergency procedures. Thus, mandatory orthopedic
backup call for a trauma center performing fewer than 100 emergent trauma
procedures within 24 hours is unwarranted.
PMID- 9555844
TI - Selective application of laparoscopy and fibrin glue in the failure of
nonoperative management of blunt hepatic trauma.
AB - BACKGROUND: Most blunt hepatic trauma patients can be managed nonoperatively. The
current failure rate in adult blunt hepatic trauma is reportedly 0 to 19%. We
wished to evaluate the applicability of laparoscopy and fibrin glue as a
minimally invasive alternative to laparotomy in these unsuccessfully nonoperative
cases. METHODS: All adult patients with blunt hepatic trauma managed
nonoperatively at Linkou, Chang Gung Memorial Hospital Medical Center, Taipei,
Taiwan, over a 2-year period from July 1, 1994, to June 30, 1996, were eligible
for the study. A laparoscopic examination was performed on those who failed
conservative care before undertaking an exploratory laparotomy. Fibrin glue was
sprayed over the wound surface if ongoing hemorrhage was evident from any liver
laceration. The clinical data, operative and laparoscopic findings, operative
methods, and outcomes of these patients were studied. RESULTS: Of the 61
patients, 55 patients were successfully treated without operation. Of the six
failures (10%) all were liver related. After the introduction of laparoscopy, the
nontherapeutic laparotomy rate would have decreased from 100% (6 of 6) to 50% (3
of 6), and with the adjunctive use of fibrin glue, the laparotomy rate went down
to 0% (0 of 6). There were no deaths among the six patients receiving laparoscopy
and fibrin glues; and only one developed a liver abscess, for a morbidity rate of
17% (1 of 6). CONCLUSIONS: The selective use of laparoscopy and fibrin glue can
effectively reduce the nontherapeutic laparotomy rate among blunt hepatic trauma
patients who fail nonoperative management.
PMID- 9555845
TI - Relationship between systemic oxygen supply dependency and gastric intramucosal
PCO2 during progressive hemorrhage.
AB - BACKGROUND: As systemic oxygen delivery (DO2) is reduced, oxygen consumption
(VO2) is maintained until a critical level is reached (DO2crit) below which VO2
becomes supply-dependent and anaerobic metabolism ensues. We examined the
relationship between gastric intramucosal PCO2 (PiCO2) and the onset of systemic
supply dependency. We also compared PiCO2 to mixed venous and portal venous blood
PCO2 (PmvCO2 and PpvCO2) to assess their utility as premonitory indicators of
supply dependency. METHODS: Six dogs were subjected to stepwise hemorrhage to
effect a progressive decrease in DO2. Inflection points for changes in VO2,
PiCO2, PmvCO2, and PpvCO2 versus DO2 were determined. RESULTS: Mean DO2crit was
6.0 +/- 0.7 mL x kg(-1) x min(-1), whereas the DO2 at which inflection points
occurred for PiCO2 and PpvCO2 were 13.2 +/- 1.4 and 11.2 +/- 1.5 mL x kg(-1) x
min(-1), respectively (p < 0.05 for both). CONCLUSION: Continuous monitoring of
PiCO2 using capnometric recirculating gas tonometry can serve as an early
indicator of systemic hypoperfusion before the onset of systemic supply
dependency.
PMID- 9555846
TI - Resuscitation after uncontrolled venous hemorrhage: Does increased resuscitation
volume improve regional perfusion?
AB - BACKGROUND: Recent studies have questioned the use of aggressive fluid
resuscitation after uncontrolled arterial hemorrhage until the bleeding is
controlled. However, it remains unknown whether resuscitation after hemorrhage
from a venous origin (usually nonaccessible to surgical intervention) has any
beneficial or deleterious effects on regional perfusion. The aim of this study,
therefore, was to determine whether increased volume of fluid resuscitation after
uncontrolled venous hemorrhage improves hemodynamic profile and regional
perfusion in various tissues. MATERIALS AND METHODS: After methoxyflurane
anesthesia and midline laparotomy, both lumbar veins in the rat were severed,
which resulted in lowering the mean arterial blood pressure to approximately 40
mm Hg. This pressure was maintained for 45 minutes by allowing further bleeding
from the lumbar veins. The abdominal incision was then closed in layers and the
animals received either 0, 10, or 30 mL of lactated Ringer's solution
intravenously over a period of 60 minutes. Cardiac output and regional blood flow
were determined by radioactive microspheres immediately or at 1.5 hours after the
completion of resuscitation. RESULTS: Fluid resuscitation with 10 or 30 mL
lactated Ringer's solution increased mean arterial blood pressure and cardiac
output immediately after resuscitation compared with the nonresuscitated animals.
At both time points, regional perfusion in the heart, kidney and intestines
remained significantly decreased compared with the sham values, irrespective of
the volume of fluid resuscitation. Moreover, no further improvements in
hemodynamics or regional perfusion occurred when volume resuscitation was
increased from 10 mL to 30 mL. Total hepatic blood flow, however, increased with
10 mL lactated Ringer's solution compared with the other hemorrhage groups and
the increase was evident even at 1.5 hours after resuscitation. CONCLUSIONS:
Fluid resuscitation after uncontrolled venous bleeding transiently increased
cardiac output and mean arterial blood pressure compared with nonresuscitated
animals. Moderate fluid administration, i.e., 10 mL, however, did increase total
hepatic blood flow. In contrast, increasing the resuscitation volume to 30 mL did
not improve hemodynamic parameters or regional perfusion. Thus moderate instead
of no resuscitation or larger volume of resuscitation is recommended in an
uncontrolled model of venous hemorrhage.
PMID- 9555847
TI - Neuropsychological symptom presentation after electrical injury.
AB - OBJECTIVE: This study explored the relationship of neuropsychological complaints
to accident- and injury-related characteristics, affective state, and work status
in a group of electrical injury (EI) patients. METHODS: Sixty-three EI patients
and 22 electricians with no history of electrical shock completed the
Neuropsychological Symptom Checklist and the Beck Depression Inventory as part of
an extensive neuropsychological evaluation. RESULTS: The EI group endorsed
significantly more physical, cognitive, and emotional symptoms than did the
controls. Symptom complaints were not related to injury parameters or litigation
status. Only the time interval between injury and assessment accounted for
differences in symptom presentation, with patients in the postacute stages of
recovery showing the most cognitive and emotional complaints. CONCLUSION: The
neuropsychological syndrome of electrical injury survival includes physical,
cognitive, and emotional complaints. Considering that most electrically injured
patients are treated within the acute medical setting, greater attention needs to
be directed early in the course of treatment toward addressing neuropsychologic
and psychiatric issues.
PMID- 9555848
TI - Blunt injury of the ascending aorta and aortic arch: repair with hypothermic
circulatory arrest.
PMID- 9555849
TI - Successful management of combined penetrating injury of innominate artery and
trachea.
PMID- 9555850
TI - Severe brachial plexus injury as a result of snowmobiling: a case series.
AB - BACKGROUND: Documented snowmobile-related fatalities and injuries have increased;
however, reports of peripheral nerve injuries are rare. METHODS: This case series
describes a cluster of severe disabling brachial plexus injuries incurred during
snowmobiling. Medical record abstraction was used to identify relevant patient
and event characteristics. RESULTS: All study patients were younger male
snowmobile drivers. All incidents occurred at speeds in excess of 40 mph. Blood
alcohol concentrations exceeded legal intoxication limits in most cases. Complete
damage of the brachial plexus occurred in four of the six patients; severe
disability occurred in all cases. Five of the six patients sustained associated
orthopedic shoulder complex injuries. CONCLUSION: This first report of severe
peripheral nerve damage may signal the advent of more severe nonfatal snowmobile
related injuries that mimic motorcycle-related injuries, because the maximum
attainable speeds of snowmobiles have increased. Surveillance of snowmobile
related injuries is warranted to identify the full spectrum of snowmobile
injuries and recommend public safety measures.
PMID- 9555851
TI - Delayed closed reduction of rotatory atlantoaxial dislocation: case report and
literature review.
PMID- 9555852
TI - Floating knee with ipsilateral knee dislocation: case report.
PMID- 9555853
TI - Colonic injury and intraspinal penetration from high-pressure molten plastic
injection: case report.
PMID- 9555854
TI - Cytokines and cell adhesion molecules in cerebral ischemia: experimental bases
and therapeutic perspectives.
AB - The possibility of reopening an occluded cerebral artery by means of thrombolysis
has renewed interest in a number of the several mechanisms that are active during
acute cerebral ischemia. Over recent years, it has become apparent that
leukocytes play a central role not only during the healing stage of brain
infarction but also during the early phases of cerebral ischemia, when it is
postulated that these cells produce harmful effects, particularly in the presence
of reperfusion. This review is based on the critical analysis of more than 150
publications dealing with the role of leukocytes and some inflammatory mediators
(cytokines, chemokines, and adhesion molecules) in cerebral ischemia. Animal
studies indicate that leukocyte involvement is promoted by a variety of
inflammatory molecules produced immediately after the onset of cerebral ischemia.
Considerable experimental evidence suggests that these mediators play a key role
in the progression from ischemia to irreversible injury (ie, cellular death and
necrosis). However, the precise role of each molecule alone remains to be further
elucidated as well as in relation to the complex network existing among different
mediators. Progress in our understanding of the inflammatory mechanisms operating
in cerebral ischemia has enabled the testing of new compounds with promising
results in animals; in contrast, one recent controlled trial of an anti-leukocyte
molecule in acute stroke patients showed negative results. This discrepancy may
derive in part from our incomplete understanding of the complexity of the
inflammatory mechanisms involved in cerebral ischemia. Our analysis suggests that
until sufficient knowledge of the underlying disease mechanisms is acquired, more
care should be taken when testing new and potentially efficacious drugs in stroke
patients.
PMID- 9555855
TI - Sol Sherry lecture in thrombosis: how thrombin 'talks' to cells: molecular
mechanisms and roles in vivo.
PMID- 9555856
TI - Ultrastructural localization of secretory type II phospholipase A2 in
atherosclerotic and nonatherosclerotic regions of human arteries.
AB - We recently reported on the immunolocalization of type II secretory nonpancreatic
phospholipase A2 (snpPLA2) in human atherosclerotic lesions. In the present
study, we present data on the distribution and ultrastructural localization of
snpPLA2 in adjacent nonatherosclerotic and atherosclerotic regions of human
arteries. Electron microscopy (EM) of immunogold labeling techniques with a
monoclonal antibody was used to analyze arterial tissue. The human specimens
analyzed were obtained from autopsy and surgery cases. The results with EM showed
a stronger snpPLA2 immunoreactivity in regions of arteries with atherosclerotic
lesions than in regions without lesions from the same individual. snpPLA2
immunoreactivity was stronger in the arterial intima of atherosclerotic than of
nonatherosclerotic tissue. EM-immunogold examination revealed that the majority
of snpPLA2 was localized along the extracellular matrix, associated with collagen
fibers and other extracellular matrix structures. Intracellular snpPLA2 was
observed in electron-dense vesicles in intimal cells. snpPLA2 was also found in
contact with large, extracellular lipid droplets. These results support the
hypothesis that extracellular snpPLA2 is localized at sites where it may
hydrolyze phospholipids from lipoproteins and lipid aggregates retained in the
extracellular matrix of the arterial wall. This may be a mechanism for in situ
release of proinflammatory lipids, free fatty acids, and lysophosphatidylcholine
in regions of apolipoprotein B accumulation, which are abundant in
atherosclerotic lesions.
PMID- 9555857
TI - Lipoprotein lipase gene variation is associated with a paternal history of
premature coronary artery disease and fasting and postprandial plasma
triglycerides: the European Atherosclerosis Research Study (EARS).
AB - The H-allele of the intron 8 HindIII polymorphism in the lipoprotein lipase (LPL)
gene has been associated with a lower risk of myocardial infarction (MI) and
plasma levels of triglycerides (TG). To test whether the HindIII site was in
linkage disequilibrium with the functional variant LPL Serine447Stop (S447X),
subjects from the European Atherosclerosis Research Study (EARS I) were genotyped
for both polymorphic sites. This study included 515 offspring of fathers with a
premature (<55 years old) MI, who were designated cases, and 930 age- and sex
matched control subjects from five different regions of Europe. Linkage
disequilibrium between the two sites was very strong (>.99), with only three of
the four possible haplotypes identified: H+S447, H-S447, and H-X447. The
frequency of the H-X447 but not of the H-S447 haplotype was significantly lower
in cases than in control subjects (.090 versus .117, P<.01) suggesting a
protective effect for MI, with this difference being consistent in all five
regions of Europe. Compared with individuals homozygous for the H+S447 haplotype,
the odds ratio of having a paternal history of premature MI for H-X447
heterozygotes (approximately 20% of the population) was 0.71 (95% confidence
interval, 0.55 to 0.92). In addition, there was an increase of the H-X447
haplotype frequency from north to south in control subjects (0.119 in Finland to
0.143 in the Mediterranean region, P<.01). Compared with the H+S447 haplotype,
the H-X447 haplotype was associated with significantly lower concentrations of
plasma TGs (5.4% lower, P=.01), with this effect being consistent over the
regions of Europe. There was no significant evidence for a heterogeneity of
effect between males and females or between cases and control subjects, although
the effect on TG levels appeared to be the greatest in male cases (11% lower,
P=.05). In a second study (EARS II), of 332 cases and 342 control subjects,
postprandial clearance of TGs after a standard fat meal was examined. The H-X447
haplotype was associated with significantly lower postprandial triglyceride
levels than was the H+S447 haplotype (9.4% smaller area under the curve, P<.05).
Thus, the effects on MI risk and plasma lipids associated with the H allele
appeared to be mainly mediated by the X447 mutation, and although the lowering
effects associated with the H-X447 haplotype on fasting and postprandial TGs are
not large, they are consistent with the lowering effect observed on MI risk
throughout Europe.
PMID- 9555858
TI - Influence of biochemical alterations on arterial stiffness in patients with end
stage renal disease.
AB - The incremental elastic modulus of the common carotid and radial arteries is
increased in patients with end-stage renal disease (ESRD), independently of blood
pressure, wall stress, and the presence of atherosclerotic alterations. Whether
biochemical factors may be involved in the arterial changes and related to renal
dysfunction remain largely ignored. To assess this question, we measured aortic
(carotid-femoral), upper-limb (carotid-radial), and lower-limb (femoral-tibial)
pulse wave velocity (PWV) in 74 ESRD patients undergoing hemodialysis in
comparison with 57 control subjects similar in age, sex ratio, and mean blood
pressure. We evaluated arterial blood pressure by sphygmomanometry, aortic
calcifications and cardiac mass by echography, and routine biochemical
parameters, total plasma homocysteine, and plasma endothelin levels by standard
techniques. In the population of patients with ESRD, on the basis of multiple
stepwise regression analysis, aortic PWV was positively and independently
correlated with systolic blood pressure (P<.0001), age (P<.0001), prevalence of
aortic calcification (P=.0004), and the prevalence of diabetes mellitus
(P=.0043). Upper-limb PWV was influenced exclusively by mean blood pressure
(P<.0001). Lower-limb PWV was positively and independently correlated with plasma
total homocysteine (P=.0004) and plasma endothelin (P=.0187) only. At any
vascular site, PWV was not independently correlated with tobacco consumption;
plasma levels of cholesterol, triglyceride, fibrinogen, or hemoglobin; body mass
index; or the presence of bilateral nephrectomy. Finally, plasma homocysteine was
independently correlated with cardiac mass (P=.0022). This study provides
evidence that in ESRD patients, the stiffness of the arterial wall and cardiac
mass are strongly influenced by biochemical factors related to the kidney
alterations and are independent of age and blood pressure level. Increased plasma
endothelin and homocysteine may be specifically involved in the vascular damage
of lower limbs.
PMID- 9555859
TI - Role of macrophage glycosaminoglycans in the cellular catabolism of oxidized LDL
by macrophages.
AB - Macrophage binding sites for oxidized LDL (Ox-LDL) include class A scavenger
receptors (SR-As), the CD-36 molecule, and an additional but hitherto
unidentified binding site. Because cell-surface glycosaminoglycans (GAGs) were
previously shown to be involved in the cellular uptake of native LDL and
lipoprotein(a), several strategies to assess the participation of heparan sulfate
(HS) and chondroitin sulfate (CS) in macrophage catabolism of Ox-LDL were used.
First, incubation of J-774 A.1 macrophage-like cells with either heparinase or
chondroitinase, or with both enzymes together, reduced the binding, uptake, and
degradation of 125I-Ox-LDL by 20% to 45%, in comparison with control nontreated
cells, while catabolism of 125I-labeled acetylated LDL (Ac-LDL) and native LDL
were unaffected. Second, the proteoglycan (PG) cellular content was increased by
cell enrichment with exogenous GAGs or by using human monocyte-derived
macrophages from two patients with Sanfilippo mucopolysaccharidosis, which are
characterized by cellular HS accumulation. In these macrophages, cellular uptake
of 125I-Ox-LDL increased, while catabolism of 125I-Ac-LDL and native LDL were
unaffected. Experiments using conditioned media from control, heparinase
digested, or chondroitinase-digested macrophages indicated that neither secreted
GAGs nor released digestion products played any role in Ox-LDL catabolism. To
evaluate potential interactions between cell-surface GAGs and known receptors for
Ox-LDL, we used excess unlabeled Ac-LDL to block SR-As or anti-CD-36 antibodies
to block CD-36, and then examined the catabolism of 125I-Ox-LDL by GAG-enriched
or -depleted macrophages. Both excess unlabeled Ac-LDL and anti-CD-36 antibodies
reduced 125I-Ox-LDL catabolism, but only excess unlabeled Ac-LDL completely
abolished the increase in 125I-Ox-LDL catabolism on GAG enrichment of the cells,
indicating a cooperation between exogenous GAGs and cell-surface SR-As in the
catabolism of OX-LDL. Moreover, the addition of GAGases to macrophages that were
preincubated with anti-CD-36 antibodies and excess Ac-LDL further reduced
macrophage degradation of Ox-LDL in comparison with cells that were pretreated
only with anti-CD-36 antibodies and Ac-LDL, indicating a more complex role for
endogenous GAGs. Overall, these studies demonstrate a substantial contribution of
macrophage-associated GAGs in the catabolism of Ox-LDL, which is mediated in part
by a cooperation between GAGs and cell-surface SR-As.
PMID- 9555860
TI - Sterol 27-hydroxylase- and apoAI/phospholipid-mediated efflux of cholesterol from
cholesterol-laden macrophages: evidence for an inverse relation between the two
mechanisms.
AB - Cholesterol-laden, human monocyte-derived macrophages were found to contain 27
hydroxycholesterol in proportion to their content of cholesterol ester. In
accordance with previous work with human lung alveolar macrophages, there was a
significant efflux of 27-hydroxycholesterol and 3beta-hydroxy-5-cholestenoic acid
from the cultured cells. The efflux of 27-hydroxycholesterol was proportional to
the cellular content of this steroid. Incubation of cholesterol-laden macrophages
with reconstituted discoidal complexes made from apolipoprotein A-I and
phospholipids resulted in a decrease in total cellular cholesterol, an increase
in the efflux of free cholesterol, and a concomitant decrease in the total
production and efflux of 27-oxygenated steroids, in particular, 3beta-hydroxy-5
cholestenoic acid. Reconstituted discoidal complexes with the Milano variant of
apolipoprotein A-I gave virtually identical results, whereas high density
lipoprotein was less efficient. These results suggest that cultured cholesterol
laden cells can export some of their excess cholesterol in the form of 27
hydroxycholesterol, 3beta-hydroxy-5-cholestenoic acid, and free cholesterol. In
the presence of exogenous cholesterol acceptors, export of free cholesterol
becomes more effective, resulting in less cholesterol exported via the 27
hydroxylase pathway. The balance between the two mechanisms for removal of
cholesterol from macrophages may be of importance for formation of foam cells and
development of atherosclerosis.
PMID- 9555861
TI - PAI-1 plasma levels in a general population without clinical evidence of
atherosclerosis: relation to environmental and genetic determinants.
AB - Plasminogen activator inhibitor-1 (PAI-1) plasma levels have been consistently
related to a polymorphism (4G/5G) of the PAI-1 gene. The renin-angiotensin
pathway plays a role in the regulation of PAI-1 plasma levels. An insertion
(I)/deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) gene has
been related to plasma and cellular ACE levels. In 1032 employees (446 men and
586 women; 22 to 66 years old) of a hospital in southern Italy, we investigated
the association between PAI-1 4G/5G and the ACE I/D gene variants and plasma PAI
1 antigen levels. None of the individuals enrolled had clinical evidence of
atherosclerosis. In univariate analysis, PAI-1 levels were significantly higher
in men (P<.001), alcohol drinkers (P<.001), smokers (P=.009), and homozygotes for
the PAI-1 gene deletion allele (4G/4G) (P=.012). Multivariate analysis documented
the independent effect on PAI-1 plasma levels of body mass index (P<.001),
triglycerides (P<.001), sex (P<.001), PAI-1 4G/5G polymorphism (P=.019), smoking
habit (P=.041), and ACE I/D genotype (P=.042). Thus, in addition to the markers
of insulin resistance and smoking habit, gene variants of PAI-1 and ACE account
for a significant portion of the between-individual variability of circulating
PAI-1 antigen concentrations in a general population without clinical evidence of
atherosclerosis.
PMID- 9555862
TI - Biphasic regulation of transcription factor nuclear factor-kappaB activity in
human endothelial cells by lysophosphatidylcholine through protein kinase C
mediated pathway.
AB - Lysophosphatidylcholine (lysoPC), which is generated in oxidized LDL (Ox-LDL) and
abundantly exists in atherosclerotic arterial walls, has been shown to alter
various endothelial functions and induces several endothelial genes expressed in
atherosclerotic arterial walls. Nuclear factor-kappa B (NF-kappaB), a pleiotropic
transcription factor, plays an important role in regulation of expression of
various genes implicated in atherosclerosis. We have previously reported that
lysoPC transferred from Ox-LDL to endothelial surface membrane activates
endothelial protein kinase C (PKC), leading to modulated endothelial functions.
This study was aimed at determining whether lysoPC could modulate activity of
transcription factors in cultured human umbilical vein endothelial cells (HUVECs)
by using electrophoretic mobility shift assay. LysoPC was found to increase DNA
binding activity of NF-kappaB in HUVECs within 15 minutes, which peaked at 1 to 2
hours and subsequently declined to the baseline level at 6 hours. Lower
concentrations (5 to 15 micromol/L) of lysoPC markedly increased NF-kappaB
activity, but higher concentration (50 micromol/L) of lysoPC inhibited the
activity. Phorbol 12-myristate 13-acetate, a potent activator of PKC, also
augmented NF-kappaB activity in HUVECs, mimicking the effects of lysoPC;
furthermore, calphostin C and chelerythrine chloride, specific PKC inhibitors,
and alpha-tocopherol, a clinically potent PKC inhibitor, suppressed the lysoPC
induced NF-kappaB activation. These results indicate that lysoPC regulates NF
kappaB activity in a biphasic manner dependent on its concentrations and
incubation time in human endothelial cells and the endothelial PKC activation may
in part be involved in the lysoPC-induced NF-kappaB activation. Thus, the time
course and the positive and negative biphasic regulatory actions of lysoPC on NF
kappaB activity in endothelial cells might exhibit a unique effect of lysoPC in
arterial walls on the different stages of atherosclerosis.
PMID- 9555863
TI - IDL composition and angiographically determined progression of atherosclerotic
lesions during simvastatin therapy.
AB - Some patients with coronary artery disease experience continued progression of
one or more coronary lesions despite treatment with drugs that inhibit 3-hydroxy
3-methylglutaryl coenzyme A reductase activity and markedly lower plasma
cholesterol levels. We examined relationships between the progression of coronary
artery lesions and plasma lipoproteins, in particular intermediate density
lipoprotein (IDL) and its composition, in 38 patients with coronary artery
disease who had been treated with simvastatin for 2 years. Patients were given
lipid-lowering dietary advice; 3 months later they were started on simvastatin
therapy (10 mg/d) for 1 month, and after review of their plasma cholesterol
levels, the dose was increased to 20 mg/d and later to 40 mg/d if the target
level of plasma cholesterol had not been attained. Progression of lesions was
determined by serial quantitative coronary angiography (variability of 5.5%) and
was defined as an increase in percent diameter stenosis (%S)> or =10%; regression
was defined as a decrease in %S > or =10%. The proportions of cholesteryl esters
(CEs) and free cholesterol decreased significantly (P<.001), and proportions of
protein and triglycerides increased significantly (P<.001) in IDL during
simvastatin therapy. The CE content of IDL decreased significantly (-7.2 weight
[wt]%, n=20, P<.001) in nonprogressors (patients who did not show progression of
any lesions) and did not change significantly (-1.8 wt%, n=14, P=.36) in
progressors (patients who showed progression of one or more lesions without
regression of any lesion). This decrease in IDL CE content in nonprogressors was
significantly (P=.01) different compared with the corresponding change in
patients classified as progressors. Mean plasma cholesterol concentration tended
to increase in progressors (0.47 mmol/L) and tended to decrease in nonprogressors
(-0.39 mmol/L) during the initial 3-month diet period, and these changes were
significantly different (P=.02). Furthermore, this change in plasma cholesterol
level during the initial diet period was correlated significantly with the change
in IDL CE content during the entire study (r=.348, n=38, P=.03). These data
suggest that IDL CE content may be a determinant of progression of coronary
lesions and may be influenced by compliance with or metabolic response to lipid
lowering dietary advice in patients with coronary artery disease during
simvastatin treatment.
PMID- 9555864
TI - Sex and topographic differences in associations between large-artery wall
thickness and coronary risk profile in a French working cohort: the AXA Study.
AB - Previous reports have investigated associations between carotid intima-media
thickness (IMT) and cardiovascular risk factors. Our objective was to investigate
this question in greater depth by measuring both femoral and carotid IMT in
relation to sex and multifactorial coronary risk. We investigated carotid and
femoral artery IMT by using ultrasonography in 326 men and 462 women, 17 to 65
years old. We also evaluated body mass index, blood pressure, blood lipids,
glucose, smoking, and Framingham coronary risk. In both vessels, IMT was lower in
women than in men. Significant relations between carotid and femoral IMT existed
with age and most risk factors in both sexes. After adjustment for age, carotid
IMT was related to risk factors in both sexes except for diastolic blood
pressure, HDL cholesterol, and smoking in women, whereas femoral IMT was related
to triglycerides and smoking in both sexes, systolic blood pressure and blood
glucose in men, and total and HDL cholesterol in women. Significant unadjusted
and age-adjusted relations of Framingham risk existed with carotid and femoral
IMT in both sexes, but slopes of these relations were greater (1) before than
after age adjustment, (2) in men than in women at both sites, except the femoral
artery after age adjustment, and (3) at the carotid than at the femoral site in
both sexes before age adjustment. Carotid IMT in men appears to be a more
powerful predictor than it is in women and femoral IMT in both sexes in
reflecting multifactorial coronary risk burden, but these differences are partly
conditional on age.
PMID- 9555865
TI - Molecular genetic study of Finns with hypoalphalipoproteinemia and
hyperalphalipoproteinemia: a novel Gly230 Arg mutation (LCAT[Fin]) of
lecithin:cholesterol acyltransferase (LCAT) accounts for 5% of cases with very
low serum HDL cholesterol levels.
AB - In an attempt to identify genetic factors underlying extreme alterations of serum
HDL cholesterol (HDL-C) concentrations, we examined two probands with HDL-C
levels <0.2 mmol/L and subsequently screened two large cohorts of smoking men,
one with very low (0.2 to 0.7 mmol/L, n=156) and the other with elevated (1.9 to
3.6 mmol/L, n=160) HDL-C levels, for the newly detected mutations as well as some
other mutations proposed to affect HDL-C levels. One of the probands had corneal
opacities, microalbuminuria, hypertriglyceridemia, and reduced LDL apoprotein B
concentration; the other had anemia and presented with stomatocytosis in his
peripheral blood. The first proband was found to be homozygous for a novel LCAT
Gly230Arg (LCAT[Fin]) mutation, and the second was homozygous for an Arg399Cys
mutation we described previously. Transient expression of the mutant LCAT(Fin)
cDNA in COS cells disclosed markedly diminished LCAT enzyme activity. In the low
HDL-C group of men (n=156), 8 carriers of LCAT(Fin) and 1 carrier of the LCAT
Arg399Cys were identified. In addition, the frequency of the lipoprotein lipase
(LPL) Asn291Ser mutation was significantly (P<.05) higher in the low-HDL-C group
(4.8%) than in the high-HDL-C group (1.6%). In addition, we identified 1 carrier
of the intron 14G-->A mutation of cholesterol ester transfer protein (CETP) in
the high-HDL-C group and subsequently demonstrated cosegregation of the mutant
allele with elevated HDL-C levels in the proband's family. In conclusion, we have
identified a novel LCAT gene Gly230Arg mutation (LCAT[Fin]), which, together with
the LPL Asn291Ser mutation, represents a relatively common genetic cause of
diminishing HDL-C levels, at least among Finns. This article also reports
occurrence of a CETP mutation in subjects having non-Japanese roots.
PMID- 9555866
TI - Factor VIIa response to a fat-rich meal does not depend on fatty acid
composition: a randomized controlled trial.
AB - A fat-rich meal increases activated factor VII (FVIIa), but it is not clear
whether this increase depends on the fatty acid composition of the meal.
Therefore, we studied the FVIIa response to fat-rich meals with different fatty
acid composition in a randomized controlled crossover trial and investigated
whether this response is mediated by an increase in serum triglycerides. Elderly
women (> 60 years, n=91) received on separate days four different fat-rich
breakfasts (50 energy percent [en%] of fat) and a control breakfast (1.5 en% fat;
crossover). The fat-rich breakfasts differed in fatty acid composition: one rich
in palmitic acid (21.7 g), one in stearic acid (18.6 g), and the other two in
linoleic and linolenic acid-one with a ratio 3:1 (12.5/3.9 g) and the other with
a ratio of 15:1 (18.8/1.2 g). At 8 AM before the breakfast (fasting) and at 1 and
3 PM, blood samples were taken, in which FVIIa and serum triglycerides were
measured. FVIIa response to the fat-rich meals ranged from 11.6 mU/mL (95%
confidence interval: 8.3,14.9) on the stearic meal to 15.9 mU/mL (12.0,19.8) on
the linoleic/linolenic 15:1 meal at 1 PM and from 14.9 mU/mL (10.6,19.2) to 21.1
mU/mL (16.6,25.6) for the same meals at 3 PM. The responses did not differ
between the fat-rich meals. After the control breakfast, FVIIa decreased, with
6.3 mU/mL (3.9,8.7) at 1 PM and 8.7 mU/mL (6.3,11.1) at 3 PM. The triglyceride
response was lower after both linoleic/linolenic rich breakfasts compared with
the palmitic and stearic breakfast (P<.05) and was not associated with the FVIIa
response at any of the blood sampling occasions. The results of this study show
that the response of FVIIa to a fat-rich meal is independent of its fatty acid
composition and is not mediated by serum triglycerides.
PMID- 9555867
TI - Genetic analysis of the difference in diet-induced atherosclerosis between the
inbred mouse strains SM/J and NZB/BINJ.
AB - To identify the genetic factors affecting susceptibility to atherosclerosis, we
studied the inheritance of plasma total cholesterol (TC) and HDL cholesterol (HDL
C) concentrations and susceptibility to atherosclerotic lesion formation in an
(SM/J[SM] x NZB/B1NJ[NZB]) outcross, an (SM/NZB)FI[F1] x SM backcross, and the
NXSM recombinant inbred (RI) strain set. After 18 or 26 weeks on the atherogenic
diet, lesion sizes in female mice were 160+/-110 (SE) microm2 for NZB, 100+/-60
for F1, and 3800+/-920 for SM. After 0, 4, or 26 weeks on the atherogenic diet,
NZB had higher TC and HDL-C levels than either SM or F1. The F1 progeny had TC
and HDL-C levels slightly higher than or similar to the SM/J parent, while lesion
size in the F1 progeny was more similar to the NZB parent. Among the 15 RI
strains, 8 resembled NZB and F1, 3 resembled SM, and 4 were intermediate between
NZB and SM for lesion size. For the (SM x NZB)F1 x SM backcross offspring, 26
resembled NZB and F1, 7 resembled SM, and 6 were intermediate between NZB and SM
for lesion size. There was poor correlation between lesion size and plasma TC or
HDL-C in the parental strains and the backcross. These data suggest that
resistance to atherosclerosis is determined by at least one major dominant gene
contributed by the NZB strain, which we have named Ath8. Ath8 segregates
independently of genes controlling TC and HDL-C levels.
PMID- 9555868
TI - Elevated plasma fibrinogen: cause or consequence of cardiovascular disease?
AB - An association between increased plasma fibrinogen and an increased risk for
myocardial infarction (MI) is well established, but the nature of this
association is subject to debate. Our aim was to shed light on the potentially
causal nature of this association. We examined whether increased plasma
fibrinogen, due to a condition that is independent of cardiovascular events, also
increases the risk for MI. A case-control study was performed in 139 subjects
with a history of MI and 287 control subjects selected from the Rotterdam Study,
a population-based cohort of 7983 subjects aged 55 years and older. The genotype
of the -455G/A polymorphism in the fibrinogen beta-gene was determined by
polymerase chain reaction. Functional plasma fibrinogen levels were determined
according to von Clauss. The plasma level of fibrinogen was significantly higher
in subjects with one or two A alleles compared with subjects with the GG
genotype: 3.8 (95% confidence interval [CI], 3.6 to 3.9) g/L and 3.6 (3.5 to 3.7)
g/L, respectively. With increasing plasma fibrinogen level, the risk for MI
increased gradually; a rise in fibrinogen of 1 g/L was associated with a 45%
increased risk (odds ratio adjusted for age, sex, and smoking, 1.45; 95% CI, 1.12
to 1.88). There was no association between the genotype of the -455G/A
polymorphism and the risk for MI. The -455G/A polymorphism is therefore
associated with increased plasma fibrinogen levels but not with an increased risk
for MI. These findings indicate that an increased plasma fibrinogen level due to
this genetic factor does not increase the risk for MI.
PMID- 9555869
TI - Lysophosphatidylcholine is involved in the antigenicity of oxidized LDL.
AB - Lysophosphatidylcholine (LPC) is formed by hydrolysis of PC in low density
lipoprotein (LDL) and cell membranes by phospholipase A2 or by oxidation.
Oxidized (ox) LDL activates endothelial cells, an effect mimicked by LPC. oxLDL
also has the capacity to activate T and B cells, and antibody titers to oxLDL are
related to the degree of atherosclerosis. The antigen in oxLDL responsible for
its immune-stimulatory capacity is not well characterized, and we hypothesized
that LPC was involved. We demonstrate herein the presence of antibodies against
LPC, both of the IgG and IgM isotype, in 210 healthy individuals. This antibody
reactivity was not specifically related to oxidation of the fatty acid moiety in
LPC, since LPC containing only palmitic acid showed antibody titers equivalent to
those of LPC containing unsaturated fatty acids. Antibody titers to PC were low
compared with LPC, and hydrolysis of PC at the sn-2 position is thus essential
for immune reactivity. There was a close correlation between anti-oxLDL and anti
LPC antibodies. Furthermore, LPC competitively inhibited anti-oxLDL reactivity,
which indicates that LPC may explain a significant part of the immune-stimulatory
properties of oxLDL. LPC, being a lipid, is not likely to be an antigen itself.
Instead, LPC could form immunogenic complexes with peptides, which may induce and
potentiate immune reactions in the vessel wall. This study adds to the evidence
that LPC is an important component of oxLDL and emphasizes the potential role of
phospholipase A2 in atherosclerosis.
PMID- 9555870
TI - Macrophage phenotype in mice deficient in both macrophage-colony-stimulating
factor (op) and apolipoprotein E.
AB - Mice deficient in both macrophage-colony-stimulating factor (M-CSF, op) and
apolipoprotein E (apoE) have elevated cholesterol levels but are protected from
atherosclerosis. To assess the contribution of macrophage (Mphi) phenotypic
heterogeneity and scavenger receptor (SR-A) expression to this seeming paradox,
we characterized the Mphi phenotype by immunohistochemistry in these animals.
Lesion size was determined in animals fed a chow or Western-type diet, and
lipoprotein clearance studies were performed in vivo. Op0/E0 mice have fourfold
smaller aortic root lesions than op2/E0 animals despite 2.5-fold higher total
plasma cholesterol levels. Mphis in atherosclerotic lesions of op2/E0 mice
constitute a predominantly recruited and M-CSF-dependent population. In addition,
Mphis in different locations in plaques show phenotypic heterogeneity. SR-A
expression in op0/E0 mice is reduced in proportion to the decrease in Mphi
numbers, and M-CSF is thus not an essential requirement for SR-A expression in
vivo. M-CSF-deficient mice degrade injected AcLDL , showing an adequate level of
SR-A activity present in vivo. In contrast, beta-VLDL clearance in op0/E0 mice is
decreased, implicating monocytes/Mphis in its catabolism. There is prominent
lipid accumulation in op2/E0 Kupffer cells and hepatocytes but not in M-CSF
independent Kupffer Mphis from op0/E0 mice. SR-A, while abundantly expressed on
both Kupffer cells and sinusoidal endothelial cells in op2/E0 mice, remains
mainly on sinusoidal endothelial cells in op0/E0 mice. This may explain
preservation of SR-A activity in these animals. Our findings clearly illustrate
the importance of both M-CSF and M-CSF-dependent monocytes/Mphis in maintaining
cholesterol homeostasis and in atherogenesis.
PMID- 9555871
TI - Increased degradation of lipoprotein(a) in atherosclerotic compared with
nonlesioned aortic intima-inner media of rabbits: in vivo evidence that
lipoprotein(a) may contribute to foam cell formation.
AB - To investigate a potential role of lipoprotein(a) [Lp(a)] in foam cell formation,
we have measured the degradation rates of Lp(a) and LDL in the rabbit aorta in
vivo. Lp(a) (or LDL) was labeled with both 113I-TC and 125I and injected into 17
rabbits with extensive aortic atherosclerosis and into 16 rabbits without
atherosclerosis. As the protein moiety of the doubly labeled lipoproteins is
degraded, 131I-TC is trapped in the cell, whereas 125I diffuses out of the cell.
Twenty-four hours after injection, 12 samples of the aorta and biopsies from 9
other tissues were removed. The degradation rate of Lp(a) (percent of plasma pool
per gram tissue per day) was less than that of LDL in the adrenals and in the
intestine. In contrast, degradation rates of Lp(a) and LDL were similar in liver,
spleen, kidney, heart, lung, skeletal muscle, and adipose tissue. In nonlesioned
aortic intima-inner media, the degradation rate of Lp(a) was 39% of that of LDL
(t test: P <.05 in aortic arch and thoracic aorta), whereas the degradation rates
of Lp(a) and LDL were similar in atherosclerotic aortic intima-inner media. Lp(a)
degradation rates were markedly increased in atherosclerotic compared with
nonlesioned aortic intima-inner media: 28.2+/-9.2 x 10(-7)% and 5.0+/-0.6 x 10(
7)% of the plasma pool per gram tissue per day in the intima-inner media of the
proximal segment of atherosclerotic and nonlesioned aorta, respectively (t test:
P <.01). These results suggest that the metabolism of Lp(a) is different from
that of LDL in nonlesioned arterial intima, possibly reflecting that Lp(a) is
degraded by LDL receptors in arterial intima less efficiently than LDL. The
results also indicate that the degradation rate of Lp(a) is markedly increased in
atherosclerotic lesions of rabbits, supporting the idea that Lp(a) contributes to
foam cell formation during the development of atherosclerosis.
PMID- 9555872
TI - Alcohol withdrawal-induced change in lipoprotein(a): association with the growth
hormone/insulin-like growth factor-I (IGF-I)/IGF-binding protein-1 (IGFBP-1)
axis.
AB - Lipoprotein(a) [Lp(a)] is an important risk factor for cardiovascular disease.
Alcohol is one of the few nongenetic factors that lower Lp(a) levels, but the
metabolic mechanisms of this action are unknown. Alcohol inhibits the growth
hormone (GH)/insulin-like growth factor-I (IGF-I) axis. Alcohol might also affect
IGF-binding protein-1 (IGFBP-1), which is an acute inhibitor of IGF-I. We studied
how alcohol withdrawal affects Lp(a) levels and the GH/IGF-I/IGFBP-1 axis. Male
alcohol abusers (n=27; 20 to 64 years old) were monitored immediately after
alcohol withdrawal for 4 days. Twenty-six healthy men, mainly moderate drinkers,
served as control subjects. Fasting blood samples were drawn to determine Lp(a),
IGF-I, and IGFBP-1 (by ELISA, RIA, and immunoenzymometric assay, respectively).
Nocturnal (12 hours) urine collection was performed in 9 alcoholics and 11
control subjects for GH analyses (RIA). The groups were similar in age and body
mass index. Lp(a), GH, and IGF-I tended to be lower and IGFBP-1 higher in the
alcoholics immediately after alcohol withdrawal than in the control subjects.
During the 4-day observation in alcoholics, Lp(a) levels increased by 64% and IGF
I levels by 41%, whereas IGFBP-1 levels decreased by 59% (P<.001 after ANOVA for
all comparisons). Urinary GH levels tended to decline. The increase in Lp(a)
correlated inversely with the changes in IGFBP-1 (r= -.63, P<.001, n=27) and GH
(r=-.70, P<.05, n=9), but not with IGF-I. In multiple regression analysis, the
main predictors for the increase in Lp(a) were IGFBP-1 and urinary GH. In
conclusion, alcohol withdrawal induces interrelated and potentially atherogenic
changes in Lp(a) and IGFBP-1 levels.
PMID- 9555873
TI - Familial HDL deficiency characterized by hypercatabolism of mature apoA-I but not
proapoA-I.
AB - We have previously described patients with familial high density lipoprotein
(HDL) deficiency (FHD) having a marked reduction in the plasma concentration of
HDL cholesterol and apolipoprotein (apo) A-I but lacking clinical manifestations
of Tangier disease or evidence of other known causes of HDL deficiency. To
determine whether FHD in these individuals was associated with impaired HDL
production or increased HDL catabolism, we investigated the kinetics of plasma
apoA-I and apoA-II in two related FHD patients (plasma apoA-I, 17 and 37 mg/dL)
and four control subjects (apoA-I, 126+/-18 mg/dL, mean+/-SD) by using a primed
constant infusion of deuterated leucine. Kinetic analysis of plasma
apolipoprotein enrichment curves demonstrated that mature plasma apoA-I
production rates (PRs) were similar in patients and control subjects (7.9 and 9.1
versus 10.5+/-1.7 mg x kg[-1] x d[-1]). Residence times (RTs) of mature apoA-I
were, however, significantly less in FHD patients (0.79 and 1.66 days) compared
with controls (5.32+/-1.05 days). Essentially normal levels of plasma proapoA-I
(the precursor protein of apoA-I) in FHD patients were associated with normal
plasma proapoA-I PRs (7.8 and 10.4 versus 10.9+/-2.6 mg x kg[-1] x d[-1]) and
proapoA-I RTs (0.18 and 0.15 versus 0.16+/-0.03 day). The RTs of apoA-II were,
however, less in patients (3.17 and 2.92 days) than control subjects (7.24+/-0.71
days), whereas the PRs of apoA-II were similar (1.8 and 1.9 versus 1.7+/-0.2 mg x
kg[-1] x d[-1]). Increased plasma catabolism of apoA-II in FHD patients was
associated with the presence in plasma of abnormal apoA-II-HDL (without apoA-I).
These results demonstrate that FHD in our patients is characterized, like Tangier
disease, by hypercatabolism of mature apoA-I and apoA-II, but unlike Tangier
disease, by essentially normal plasma catabolism and concentration of proapoA-I.
PMID- 9555874
TI - Distribution and synthesis of apolipoprotein J in the atherosclerotic aorta.
AB - The distribution of apolipoprotein (apo) J during the development of
atherosclerosis in the human aorta was evaluated by immununohistochemical
observation, together with the other apolipoprotein A-I, A-II, B, C-III, and E.
Although apoJ was never observed in the normal aorta (ie, without any intimal
lesions or intimal thickening), it was distributed not only in the intima but
also in the media of aortas with diffuse, intimal thickening or atherosclerotic
lesions. Double immunostaining with antibodies for apoJ and alpha-smooth muscle
actin revealed apoJ deposition in smooth muscle cells (SMCs) or the aortic stroma
in the vicinity of SMCs. The extent of apoJ distribution in the aortic wall
increased with the degree of atherosclerosis development. In addition, the
distribution pattern of apoJ was very similar to that of apoA-I and E. In situ
hybridization with human apoJ cDNA demonstrated intense signals in cells
scattered within the subendothelial space and medial SMCs of the aorta with
advanced atherosclerosis but not in those of the normal aorta without intimal
thickening. Furthermore, reverse transcriptase-polymerase chain reaction of the
cultured human aortic SMCs revealed apoJ mRNA expression in these cells. The
results indicate that apoJ in the aortic wall originates from not only apoJ
circulated in the plasma but also apoJ produced by SMCs in the aortic wall.
Considering the similarities of the distribution between apoJ and apo-A-I or E,
we hypothesize that apoJ possibly has a protective role against human
atherosclerosis by its involvement with cholesterol transport from the aortic
wall to the liver.
PMID- 9555875
TI - The Working Group report on Science-Based Categories for Abstracts: Submitted to
the annual scientific sessions. American Heart Association.
PMID- 9555876
TI - Multiple beta-ketothiolases mediate poly(beta-hydroxyalkanoate) copolymer
synthesis in Ralstonia eutropha.
AB - Polyhydroxyalkanoates (PHAs) are a class of carbon and energy storage polymers
produced by numerous bacteria in response to environmental limitation. The type
of polymer produced depends on the carbon sources available, the flexibility of
the organism's intermediary metabolism, and the substrate specificity of the PHA
biosynthetic enzymes. Ralstonia eutropha produces both the homopolymer poly-beta
hydroxybutyrate (PHB) and, when provided with the appropriate substrate, the
copolymer poly(beta-hydroxybutyrate-co-beta-hydroxyvalerate) (PHBV). A required
step in production of the hydroxyvalerate moiety of PHBV is the condensation of
acetyl coenzyme A (acetyl-CoA) and propionyl-CoA to form beta-ketovaleryl-CoA.
This activity has generally been attributed to the beta-ketothiolase encoded by
R. eutropha phbA. However, we have determined that PhbA does not significantly
contribute to catalyzing this condensation reaction. Here we report the cloning
and genetic analysis of bktB, which encodes a beta-ketothiolase from R. eutropha
that is capable of forming beta-ketovaleryl-CoA. Genetic analyses determined that
BktB is the primary condensation enzyme leading to production of beta
hydroxyvalerate derived from propionyl-CoA. We also report an additional beta
ketothiolase, designated BktC, that probably serves as a secondary route toward
beta-hydroxyvalerate production.
PMID- 9555877
TI - Enterocins L50A and L50B, two novel bacteriocins from Enterococcus faecium L50,
are related to staphylococcal hemolysins.
AB - Enterocin L50 (EntL50), initially referred to as pediocin L50 (L. M. Cintas, J.
M. Rodriguez, M. F. Fernandez, K. Sletten, I. F. Nes, P. E. Hernandez, and H.
Holo, Appl. Environ. Microbiol. 61:2643-2648, 1995), is a plasmid-encoded broad
spectrum bacteriocin produced by Enterococcus faecium L50. It has previously been
purified from the culture supernatant and partly sequenced by Edman degradation.
In the present work, the nucleotide sequence of the EntL50 locus was determined,
and several putative open reading frames (ORFs) were identified. Unexpectedly,
two ORFs were found to encode EntL50-like peptides. These peptides, termed
enterocin L50A (EntL50A) and enterocin L50B (EntL50B), have 72% sequence identity
and consist of 44 and 43 amino acids, respectively. Interestingly, a comparison
of the deduced sequences of EntL50A and EntL50B with the corresponding sequences
obtained by Edman degradation shows that these bacteriocins, in contrast to other
peptide bacteriocins, are secreted without an N-terminal leader sequence or
signal peptide. Expression in vivo and in vitro transcription/translation
experiments demonstrated that entL50A and entL50B are the only genes required to
obtain antimicrobial activity, strongly indicating that their bacteriocin
products are not posttranslationally modified. Both bacteriocins possess
antimicrobial activity on their own, with EntL50A being the most active. In
addition, when the two bacteriocins were combined, a considerable synergism was
observed, especially with some indicator strains. Even though the enterocins in
some respects are similar to class II bacteriocins, several conserved features
common to class II bacteriocins are absent from the EntL50 system. The enterocins
have more in common with members of a small group of cytolytic peptides secreted
by certain staphylococci. We therefore propose that the enterocins L50A and L50B
and the staphylococcal cytolysins together constitute a new family of peptide
toxins, unrelated to class II bacteriocins, which possess bactericidal and/or
hemolytic activity.
PMID- 9555878
TI - Identification of the omega4400 regulatory region, a developmental promoter of
Myxococcus xanthus.
AB - Omega4400 is the site of a Tn5 lac insertion in the Myxococcus xanthus genome
that fuses lacZ expression to a developmentally regulated promoter. Cell-cell
interactions that occur during development, including C signaling, are required
for normal expression of Tn5 lac omega4400. The DNA upstream of the omega4400
insertion has been cloned, the promoter has been localized, and a partial open
reading frame has been identified. From the deduced amino acid sequence of the
partial open reading frame, the gene disrupted by Tn5 lac omega4400 may encode a
protein with an ATP- or GTP-binding site. Expression of the gene begins 6 to 12 h
after starvation initiates development, as measured by beta-galactosidase
production in cells containing Tn5 lac omega4400. The putative transcriptional
start site was mapped, and deletion analysis has shown that DNA downstream of
101 bp is sufficient for C-signal-dependent, developmental activation of this
promoter. A deletion to -76 bp eliminated promoter activity, suggesting the
involvement of an upstream activator protein. The promoter may be transcribed by
RNA polymerase containing a novel sigma factor, since a mutation in the M.
xanthus sigB or sigC gene did not affect Tn5 lac omega4400 expression and the DNA
sequence upstream of the transcriptional start site did not match the sequence of
any M. xanthus promoter transcribed by a known form of RNA polymerase. However,
the omega4400 promoter does contain the sequence 5'-CATCCCT-3' centered at -49
and the C-signal-dependent omega4403 promoter also contains this sequence at the
same position. Moreover, the two promoters match at five of six positions in the
10 regions, suggesting that these promoters may share one or more transcription
factors. These results begin to define the cis-acting regulatory elements
important for cell-cell interaction-dependent gene expression during the
development of a multicellular prokaryote.
PMID- 9555879
TI - Divergence of a DNA replication gene cluster in the T4-related bacteriophage
RB69.
AB - The genomes of bacteriophages T4 and RB69 are phylogenetically related but
diverge in nucleotide sequence at many loci and are incompatible with each other
in vivo. We describe here the biological implications of divergence in a genomic
segment that encodes four essential DNA replication proteins: gp45 (sliding
clamp), gp44/62 complex (clamp loader), and gp46 (a recombination protein). We
have cloned, sequenced, and expressed several overlapping segments of the RB69
gene 46-45.2-(rpbA)-45-44-62 cluster and compared its features to those of the
homologous gene cluster from T4. The deduced primary structures of all four RB69
replication proteins and gp45.2 from this cluster are very similar (80 to 95%
similarity) to those of their respective T4 homologs. In contrast, the rpbA
region (which encodes a nonessential protein in T4) is highly diverged
(approximately 49% similarity) between the two phage genomes and does not encode
protein in RB69. Expression studies and patterns of high divergence of
intercistronic nucleotide sequences of this cluster suggest that T4 and RB69
evolved similar transcriptional and translational control strategies for the
cistrons contained therein, but with different specificities. In plasmid-phage
complementation assays, we show that posttranslationally, RB69 and T4 homologs of
gp45 and the gp44/62 complex can be effectively exchanged between the two phage
replicase assemblies; however, we also show results which suggest that mixed
clamp loader complexes consisting of T4 gp62 and RB69 gp44 subunits are not
active for phage DNA replication. Thus, specificity of the gp44-gp62 interaction
in the clamp loader marks a point of departure between the T4 and RB69
replication systems.
PMID- 9555880
TI - Expression and regulation of the sodF gene encoding iron- and zinc-containing
superoxide dismutase in Streptomyces coelicolor Muller.
AB - Streptomyces coelicolor Muller contains two superoxide dismutases (SODs), nickel
containing (NiSOD) and iron- and zinc-containing SOD (FeZnSOD). The sodF gene
encoding FeZnSOD was isolated by using PCR primers corresponding to the N
terminal peptide sequence of the purified FeZnSOD and a C-terminal region
conserved among known FeSODs and MnSODs. The deduced amino acid sequence
exhibited highest similarity to Mn- and FeSODs from Propionibacterium shermanii
and Mycobacterium spp. The transcription start site of the sodF gene was
determined by primer extension. When the sodF gene was cloned in pIJ702 and
introduced into Streptomyces lividans TK24, it produced at least 30 times more
FeZnSOD than the control cells. We disrupted the sodF gene in S. lividans TK24
and found that the disruptant did not produce any FeZnSOD enzyme activity but
produced more NiSOD. The expression of the cloned sodF gene in TK24 cells was
repressed significantly by Ni, consistent with the regulation pattern in
nonoverproducing cells. This finding suggests that the cloned sodF gene contains
the cis-acting elements necessary for Ni regulation. When the sodF mRNA in S.
coelicolor Muller cells was analyzed by S1 mapping of both 5' and 3' ends, we
found that Ni caused a reduction in the level of monocistronic sodF transcripts.
Ni did not affect the stability of sodF mRNA, indicating that it regulates
transcription. S. lividans TK24 cells overproducing FeZnSOD became more resistant
to oxidants such as menadione and lawsone than the control cells, suggesting the
protective role of FeZnSOD. However, the sodF disruptant survived as well as the
wild-type strain in the presence of these oxidants, suggesting the complementing
role of NiSOD increased in the disruptant.
PMID- 9555881
TI - Iron uptake in Ustilago maydis: tracking the iron path.
AB - In this study, we monitored and compared the uptake of iron in the fungus
Ustilago maydis by using biomimetic siderophore analogs of ferrichrome, the
fungal native siderophore, and ferrioxamine B (FOB), a xenosiderophore.
Ferrichrome-iron was taken up at a higher rate than FOB-iron. Unlike ferrichrome
mediated uptake, FOB-mediated iron transport involved an extracellular reduction
mechanism. By using fluorescently labeled siderophore analogs, we monitored the
time course, as well as the localization, of iron uptake processes within the
fungal cells. A fluorescently labeled ferrichrome analog, B9-lissamine rhodamine
B, which does not exhibit fluorescence quenching upon iron binding, was used to
monitor the entry of the compounds into the fungal cells. The fluorescence was
found intracellularly 4 h after the application and later was found concentrated
in two to three vesicles within each cell. The fluorescence of the fluorescently
labeled FOB analog CAT18, which is quenched by iron, was visualized around the
cell membrane after 4 h of incubation with the ferrated (nonfluorescent)
compounds. This fluorescence intensity increased with time, demonstrating fungal
iron uptake from the siderophores, which remained extracellular. We here
introduce the use of fluorescent biomimetic siderophores as tools to directly
track and discriminate between different pathways of iron uptake in cells.
PMID- 9555882
TI - Isolation and characterization of methanophenazine and function of phenazines in
membrane-bound electron transport of Methanosarcina mazei Go1.
AB - A hydrophobic, redox-active component with a molecular mass of 538 Da was
isolated from lyophilized membranes of Methanosarcina mazei Go1 by extraction
with isooctane. After purification on a high-performance liquid chromatography
column, the chemical structure was analyzed by mass spectroscopy and nuclear
magnetic resonance studies. The component was called methanophenazine and
represents a 2-hydroxyphenazine derivative which is connected via an ether bridge
to a polyisoprenoid side chain. Since methanophenazine was almost insoluble in
aqueous buffers, water-soluble phenazine derivatives were tested for their
ability to interact with membrane-bound enzymes involved in electron transport
and energy conservation. The purified F42OH2 dehydrogenase from M. mazei Go1
showed highest activity with 2-hydroxyphenazine and 2-bromophenazine as electron
acceptors when F420H2 was added. Phenazine-1-carboxylic acid and phenazine proved
to be less effective. The Km values for 2-hydroxyphenazine and phenazine were 35
and 250 microM, respectively. 2-Hydroxyphenazine was also reduced by molecular
hydrogen catalyzed by an F420-nonreactive hydrogenase which is present in washed
membrane preparations. Furthermore, the membrane-bound heterodisulfide reductase
was able to use reduced 2-hydroxyphenazine as an electron donor for the reduction
of CoB-S-S-CoM. Considering all these results, it is reasonable to assume that
methanophenazine plays an important role in vivo in membrane-bound electron
transport of M. mazei Go1.
PMID- 9555883
TI - Suppressor mutation analysis of the sensory rhodopsin I-transducer complex:
insights into the color-sensing mechanism.
AB - The molecular complex containing the phototaxis receptor sensory rhodopsin I
(SRI) and transducer protein HtrI (halobacterial transducer for SRI) mediates
color-sensitive phototaxis responses in the archaeon Halobacterium salinarum. One
photon excitation of the complex by orange light elicits attractant responses,
while two-photon excitation (orange followed by near-UV light) elicits repellent
responses in swimming cells. Several mutations in SRI and HtrI cause an unusual
mutant phenotype, called orange-light-inverted signaling, in which the cell
produces a repellent response to normally attractant light. We applied a
selection procedure for intragenic and extragenic suppressors of orange-light
inverted mutants and identified 15 distinct second-site mutations that restore
the attractant response. Two of the 3 suppressor mutations in SRI are positioned
at the cytoplasmic ends of helices F and G, and 12 suppressor mutations in HtrI
cluster at the cytoplasmic end of the second HtrI transmembrane helix (TM2).
Nearly all suppressors invert the normally repellent response to two-photon
stimulation to an attractant response when they are expressed with their
suppressible mutant alleles or in an otherwise wild-type strain. The results lead
to a model for control of flagellar reversal by the SRI-HtrI complex. The model
invokes an equilibrium between the A (reversal-inhibiting) and R (reversal
stimulating) conformers of the signaling complex. Attractant light and repellent
light shift the equilibrium toward the A and R conformers, respectively, and
mutations are proposed to cause intrinsic shifts in the equilibrium in the dark
form of the complex. Differences in the strength of the two-photon signal
inversion and in the allele specificity of suppression are correlated, and this
correlation can be explained in terms of different values of the equilibrium
constant (Keq) for the conformational transition in different mutants and mutant
suppressor pairs.
PMID- 9555884
TI - ntn genes determining the early steps in the divergent catabolism of 4
nitrotoluene and toluene in Pseudomonas sp. strain TW3.
AB - Pseudomonas sp. strain TW3 is able to oxidatively metabolize 4-nitrotoluene and
toluene via a route analogous to the upper pathway of the TOL plasmids. We report
the sequence and organization of five genes, ntnWCMAB*, which are very similar to
and in the same order as the xyl operon of TOL plasmid pWW0 and present evidence
that they encode enzymes which are expressed during growth on both 4-nitrotoluene
and toluene and are responsible for their oxidation to 4-nitrobenzoate and
benzoate, respectively. These genes encode an alcohol dehydrogenase homolog
(ntnW), an NAD+-linked benzaldehyde dehydrogenase (ntnC), a two-gene toluene
monooxygenase (ntnMA), and part of a benzyl alcohol dehydrogenase (ntnB*), which
have 84 to 99% identity at the nucleotide and amino acid levels with the
corresponding xylWCMAB genes. The xylB homolog on the TW3 genome (ntnB*) appears
to be a pseudogene and is interrupted by a piece of DNA which destroys its
functional open reading frame, implicating an additional and as-yet-unidentified
benzyl alcohol dehydrogenase gene in this pathway. This conforms with the
observation that the benzyl alcohol dehydrogenase expressed during growth on 4
nitrotoluene and toluene differs significantly from the XylB protein, requiring
assay via dye-linked electron transfer rather than through a nicotinamide
cofactor. The further catabolism of 4-nitrobenzoate and benzoate diverges in that
the former enters the hydroxylaminobenzoate pathway as previously reported, while
the latter is further metabolized via the beta-ketoadipate pathway.
PMID- 9555885
TI - FtsZ dynamics during the division cycle of live Escherichia coli cells.
AB - The dynamics and assembly of bacterial cell division protein FtsZ were monitored
in individual, growing and dividing Escherichia coli cells in real time by
microculture of a merodiploid strain expressing green fluorescent protein (GFP)
tagged FtsZ. Cells expressing FtsZ-GFP at levels less than or equivalent to that
of wild-type FtsZ were able to grow and divide over multiple generations, with
their FtsZ rings visualized by fluorescence. During the late stages of
cytokinesis, which constituted the last one-fourth of the cell cycle, the lumen
of the FtsZ ring disappeared as the whole structure condensed. At this time,
loops of FtsZ-GFP polymers emanated outward from the condensing ring structure
and other unstable fluorescent structures elsewhere in the cell were also
observed. Assembly of FtsZ rings at new division sites occurred within 1 min,
from what appeared to be single points. Interestingly, this nucleation often took
place in the predivisional cell at the same time the central FtsZ ring was in its
final contraction phase. This demonstrates directly that, at least when FtsZ-GFP
is being expressed, new division sites have the capacity to become fully
functional for FtsZ targeting and assembly before cell division of the mother
cell is completed. The results suggest that the timing of FtsZ assembly may be
normally controlled in part by cellular FtsZ concentration. The use of wide-field
optical sectioning microscopy to obtain sharp fluorescence images of FtsZ
structures is also discussed.
PMID- 9555886
TI - The katX gene, which codes for the catalase in spores of Bacillus subtilis, is a
forespore-specific gene controlled by sigmaF, and KatX is essential for hydrogen
peroxide resistance of the germinating spore.
AB - Previous work has shown that the katX gene encodes the major catalase in dormant
spores of Bacillus subtilis but that this enzyme has no role in dormant spore
resistance to hydrogen peroxide. Expression of a katX-lacZ fusion began at
approximately h 2 of sporulation, and >75% of the katX-driven beta-galactosidase
was packaged into the mature spore. A mutation in the gene coding for the
sporulation-specific RNA polymerase sigma factor sigmaF abolished katX-lacZ
expression, while mutations in genes encoding sigmaE, sigmaG, and sigmaK did not.
Induction of sigmaF synthesis in vegetative cells also resulted in katX-lacZ
expression, while induction of sigmaG expression did not; the katX-lacZ fusion
was also not induced by hydrogen peroxide. Upstream of the in vivo katX
transcription start site there are sequences with good homology to those upstream
of known sigmaF-dependent start sites. These data indicate that katX is an
additional member of the forespore-specific sigmaF regulon. A mutant in the katA
gene, encoding the major catalase in growing cells, was sensitive to hydrogen
peroxide during sporulation, while a katX mutant was not. However, outgrowth of
katX spores, but not katA spores, was sensitive to hydrogen peroxide.
Consequently, a major function for KatX is to protect germinating spores from
hydrogen peroxide.
PMID- 9555888
TI - Identification and characterization of epoxide carboxylase activity in cell
extracts of Nocardia corallina B276.
AB - The metabolism of aliphatic epoxides (epoxyalkanes) by the alkene-utilizing
actinomycete Nocardia corallina B276 was investigated. Suspensions of N.
corallina cells grown with propylene as the carbon source readily degraded
propylene and epoxypropane, while suspensions of glucose-grown cells did not. The
addition of propylene and epoxypropane to glucose-grown cells resulted in a time
dependent increase in propylene- and epoxypropane-degrading activities that was
prevented by the addition of rifampin and chloramphenicol. The expression of
alkene- and epoxide-degrading activities was correlated with the high-level
expression of several polypeptides not present in extracts of glucose-grown
cells. Epoxypropane and epoxybutane degradation by propylene-grown cell
suspensions of N. corallina was stimulated by the addition of CO2 and inhibited
by the depletion of CO2. Cell extracts catalyzed the carboxylation of
epoxypropane to form acetoacetate in a reaction that was dependent on the
addition of CO2, NAD+, and a reductant (NADPH or dithiothreitol). In the absence
of CO2, epoxypropane was isomerized by cell extracts to form acetone at a rate
approximately 10-fold lower than the rate of epoxypropane carboxylation.
Methylepoxypropane was found to be a time-dependent, irreversible inactivator of
epoxyalkane-degrading activity. These properties demonstrate that epoxyalkane
metabolism in N. corallina occurs by a carboxylation reaction forming beta-keto
acids as products and provide evidence for the involvement in this reaction of an
epoxide carboxylase with properties and cofactor requirements similar to those of
the four-component epoxide carboxylase enzyme system of the gram-negative
bacterium Xanthobacter strain Py2 (J. R. Allen and S. A. Ensign, J. Biol. Chem.
272:32121-32128, 1997). The addition of epoxide carboxylase component I from
Xanthobacter strain Py2 to methylepoxypropane-inactivated N. corallina extracts
restored epoxide carboxylase activity, and the addition of epoxide carboxylase
component II from Xanthobacter Py2 to active N. corallina extracts stimulated
epoxide isomerase rates to the same levels observed with the purified
Xanthobacter system. Antibodies raised against Xanthobacter strain Py2 epoxide
carboxylase component I cross-reacted with a polypeptide in propylene-grown N.
corallina extracts with the same molecular weight as component I but did not
cross-react with glucose-grown extracts. Together, these results suggest a common
pathway of epoxyalkane metabolism for phylogenetically distinct bacteria that
involves CO2 fixation and the activity of a multicomponent epoxide carboxylase
enzyme system.
PMID- 9555887
TI - Use of bacteriophage lambda recombination functions to promote gene replacement
in Escherichia coli.
AB - Replacement of Escherichia coli's RecBCD function with phage lambda's Red
function generates a strain whose chromosome recombines with short linear DNA
fragments at a greatly elevated rate. The rate is at least 70-fold higher than
that exhibited by a recBC sbcBC or recD strain. The value of the system is
highlighted by gene replacement with a PCR-generated DNA fragment. The
deltarecBCD::Plac-red kan replacement allele can be P1 transduced to other E.
coli strains, making the hyper-Rec phenotype easily transferable.
PMID- 9555889
TI - Isolation and characterization of EPD1, an essential gene for pseudohyphal growth
of a dimorphic yeast, Candida maltosa.
AB - Additional copies of the centromeric DNA (CEN) region induce pseudohyphal growth
in a dimorphic yeast, Candida maltosa (T. Nakazawa, T. Motoyama, H. Horiuchi, A.
Ohta, and M. Takagi, J. Bacteriol. 179:5030-5036, 1997). To understand the
mechanism of this transition, we screened the gene library of C. maltosa for
sequences which could suppress this morphological change. As a result, we
isolated the 5' end of a new gene, EPD1 (for essential for pseudohyphal
development), and then cloned the entire gene. The predicted amino acid sequence
of Epdlp was highly homologous to those of Ggp1/Gas1/Cwh52p, a
glycosylphosphatidylinositol-anchored protein of Saccharomyces cerevisiae, and
Phr1p and Phr2p of Candida albicans. The expression of EPD1 was moderately
regulated by environmental pH. A homozygous EPD1 null mutant showed some
morphological defects and reduction in growth rate and reduced levels of both
alkali-soluble and alkali-insoluble beta-glucans. Moreover, the mutant could not
undergo the transition from yeast form to pseudohyphal form induced by additional
copies of the CEN sequence at pH 4 or by n-hexadecane at pH 4 or pH 7, suggesting
that EPD1 is not essential for yeast form growth but is essential for transition
to the pseudohyphal form. Overexpression of the amino-terminal part of Epd1p
under the control of the GAL promoter suppressed the pseudohyphal development
induced by additional copies of the CEN sequence, whereas overexpression of the
full-length EPD1 did not. This result and the initial isolation of the 5' end of
EPD1 as a suppressor of the pseudohyphal growth induced by the CEN sequence
suggest that the amino-terminal part of Epd1p may have a dominant-negative effect
on the functions of Epd1p in the pseudohyphal growth induced by the CEN sequence.
PMID- 9555891
TI - Generation and properties of a Streptococcus pneumoniae mutant which does not
require choline or analogs for growth.
AB - A mutant (JY2190) of Streptococcus pneumoniae Rx1 which had acquired the ability
to grow in the absence of choline and analogs was isolated. Lipoteichoic acid
(LTA) and wall teichoic acid (TA) isolated from the mutant were free of
phosphocholine and other phosphorylated amino alcohols. Both polymers showed an
unaltered chain structure and, in the case of LTA, an unchanged glycolipid
anchor. The cell wall composition was also not altered except that, due to the
lack of phosphocholine, the phosphate content of cell walls was half that of the
parent strain. Isolated cell walls of the mutant were resistant to hydrolysis by
pneumococcal autolysin (N-acetylmuramyl-L-alanine amidase) but were cleaved by
the muramidases CPL and cellosyl. The lack of active autolysin in the mutant
cells became apparent by impaired cell separation at the end of cell division and
by resistance against stationary-phase and penicillin-induced lysis. As a result
of the absence of choline in the LTA, pneumococcal surface protein A (PspA) was
no longer retained on the cytoplasmic membrane. During growth in the presence of
choline, which was incorporated as phosphocholine into LTA and TA, the mutant
cells separated normally, did not release PspA, and became penicillin sensitive.
However, even under these conditions, they did not lyse in the stationary phase,
and they showed poor reactivity with antibody to phosphocholine and an increased
release of C-polysaccharide from the cell. In contrast to ethanolamine-grown
parent cells (A. Tomasz, Proc. Natl. Acad. Sci. USA 59:86-93, 1968), the choline
free mutant cells retained the capability to undergo genetic transformation but,
compared to Rx1, with lower frequency and at an earlier stage of growth. The
properties of the mutant could be transferred to the parent strain by DNA of the
mutant.
PMID- 9555890
TI - The periplasmic, group III catalase of Vibrio fischeri is required for normal
symbiotic competence and is induced both by oxidative stress and by approach to
stationary phase.
AB - The catalase gene, katA, of the sepiolid squid symbiont Vibrio fischeri has been
cloned and sequenced. The predicted amino acid sequence of KatA has a high degree
of similarity to the recently defined group III catalases, including those found
in Haemophilus influenzae, Bacteroides fragilis, and Proteus mirabilis. Upstream
of the predicted start codon of katA is a sequence that closely matches the
consensus sequence for promoters regulated in Escherichia coli by the alternative
sigma factor encoded by rpoS. Further, the level of expression of the cloned katA
gene in an E. coli rpoS mutant is much lower than in wild-type E. coli. Catalase
activity is induced three- to fourfold both as growing V. fischeri cells approach
stationary phase and upon the addition of a small amount of hydrogen peroxide
during logarithmic growth. The catalase activity was localized in the periplasm
of wild-type V. fischeri cells, where its role could be to detoxify hydrogen
peroxide coming from the external environment. No significant catalase activity
could be detected in a katA null mutant strain, demonstrating that KatA is the
predominately expressed catalase in V. fischeri and indicating that V. fischeri
carries only a single catalase gene. The catalase mutant was defective in its
ability to competitively colonize the light organs of juvenile squids in
coinoculation experiments with the parent strain, suggesting that the catalase
enzyme plays an important role in the symbiosis between V. fischeri and its squid
host.
PMID- 9555892
TI - IS6110 transposition and evolutionary scenario of the direct repeat locus in a
group of closely related Mycobacterium tuberculosis strains.
AB - In recent years, various polymorphic loci and multicopy insertion elements have
been discovered in the Mycobacterium tuberculosis genome, such as the direct
repeat (DR) locus, the major polymorphic tandem repeats, the polymorphic GC-rich
repetitive sequence, IS6110, and IS1081. These, especially IS6110 and the DR
locus, have been widely used as genetic markers to differentiate M. tuberculosis
isolates and will continue to be so used, due to the conserved nature of the
genome of M. tuberculosis. However, little is known about the processes involved
in generating these or of their relative rates of change. Without an
understanding of the biological characteristics of these genetic markers, it is
difficult to use them to their full extent for understanding the population
genetics and epidemiology of M. tuberculosis. To address these points, we
identified a cluster of 7 isolates in a collection of 101 clinical isolates and
investigated them with various polymorphic genetic markers, which indicated that
they were highly related to each other. This cluster provided a model system for
the study of IS6110 transposition, evolution at the DR locus, and the effects of
these on the determination of evolutionary relationships among M. tuberculosis
strains. Our results suggest that IS6110 restriction fragment length polymorphism
patterns are useful in grouping closely related isolates together; however, they
can be misleading if used for making inferences about the evolutionary
relationships between closely related isolates. DNA sequence analysis of the DR
loci of these isolates revealed an evolutionary scenario, which, complemented
with the information from IS6110, allowed a reconstruction of the evolutionary
steps and relationships among these closely related isolates. Loss of the IS6110
copy in the DR locus was noted, and the mechanisms of this loss are discussed.
PMID- 9555893
TI - Lysis genes of the Bacillus subtilis defective prophage PBSX.
AB - Four genes identified within the late operon of PBSX show characteristics
expected of a host cell lysis system; they are xepA, encoding an exported
protein; xhlA, encoding a putative membrane-associated protein; xhlB, encoding a
putative holin; and xlyA, encoding a putative endolysin. In this work, we have
assessed the contribution of each gene to host cell lysis by expressing the four
genes in different combinations under the control of their natural promoter
located on the chromosome of Bacillus subtilis 168. The results show that xepA is
unlikely to be involved in host cell lysis. Expression of both xhlA and xhlB is
necessary to effect host cell lysis of B. subtilis. Expression of xhlB (encoding
the putative holin) together with xlyA (encoding the endolysin) cannot effect
cell lysis, indicating that the PBSX lysis system differs from those identified
in the phages of gram-negative bacteria. Since host cell lysis can be achieved
when xlyA is inactivated, it is probable that PBSX encodes a second endolysin
activity which also uses XhlA and XhlB for export from the cell. The chromosome
based expression system developed in this study to investigate the functions of
the PBSX lysis genes should be a valuable tool for the analysis of other host
cell lysis systems and for expression and functional analysis of other lethal
gene products in gram-positive bacteria.
PMID- 9555894
TI - Transformation of Rickettsia prowazekii to rifampin resistance.
AB - Rickettsia prowazekii, the causative agent of epidemic typhus, is an obligate
intracellular parasitic bacterium that grows directly within the cytoplasm of the
eucaryotic host cell. The absence of techniques for genetic manipulation hampers
the study of this organism's unique biology and pathogenic mechanisms. To
establish the feasibility of genetic manipulation in this organism, we identified
a specific mutation in the rickettsial rpoB gene that confers resistance to
rifampin and used it to demonstrate allelic exchange in R. prowazekii. Comparison
of the rpoB sequences from the rifampin-sensitive (Rifs) Madrid E strain and a
rifampin-resistant (Rifr) mutant identified a single point mutation that results
in an arginine-to-lysine change at position 546 of the R. prowazekii RNA
polymerase beta subunit. A plasmid containing this mutation and two additional
silent mutations created in codons flanking the Lys-546 codon was introduced into
the Rifs Madrid E strain of R. prowazekii by electroporation, and in the presence
of rifampin, resistant rickettsiae were selected. Transformation, via homologous
recombination, was demonstrated by DNA sequencing of PCR products containing the
three mutations in the Rifr region of rickettsial rpoB. This is the first
successful demonstration of genetic transformation of Rickettsia prowazekii and
represents the initial step in the establishment of a genetic system in this
obligate intracellular pathogen.
PMID- 9555895
TI - Visualization of penicillin-binding proteins during sporulation of Streptomyces
griseus.
AB - We used fluorescein-tagged beta-lactam antibiotics to visualize penicillin
binding proteins (PBPs) in sporulating cultures of Streptomyces griseus. Six PBPs
were identified in membranes prepared from growing and sporulating cultures. The
binding activity of an 85-kDa PBP increased fourfold by 10 to 12 h of
sporulation, at which time the sporulation septa were formed. Cefoxitin inhibited
the interaction of the fluorescein-tagged antibiotics with the 85-kDa PBP and
also prevented septum formation during sporulation but not during vegetative
growth. The 85-kDa PBP, which was the predominant PBP in membranes of cells that
were undergoing septation, preferentially bound fluorescein-6-aminopenicillanic
acid (Flu-APA). Fluorescence microscopy showed that the sporulation septa were
specifically labeled by Flu-APA; this interaction was blocked by prior exposure
of the cells to cefoxitin at a concentration that interfered with septation. We
hypothesize that the 85-kDa PBP is involved in septum formation during
sporulation of S. griseus.
PMID- 9555896
TI - Availability of O2 as a substrate in the cytoplasm of bacteria under aerobic and
microaerobic conditions.
AB - The growth rates of Pseudomonas putida KT2442 and mt-2 on benzoate, 4
hydroxybenzoate, or 4-methylbenzoate showed an exponential decrease with
decreasing oxygen tensions (partial O2 tension [pO2] values). The oxygen tensions
resulting in half-maximal growth rates were in the range of 7 to 8 mbar of O2
(corresponding to 7 to 8 microM O2) (1 bar = 10(5) Pa) for aromatic compounds,
compared to 1 to 2 mbar for nonaromatic compounds like glucose or succinate. The
decrease in the growth rates coincided with excretion of catechol or
protocatechuate, suggesting that the activity of the corresponding oxygenases
became limiting. The experiments directly establish that under aerobic and
microaerobic conditions (about 10 mbar of O2), the diffusion of O2 into the
cytoplasm occurs at high rates sufficient for catabolic processes. This is in
agreement with calculated O2 diffusion rates. Below 10 mbar of O2, oxygen became
limiting for the oxygenases, probably due to their high Km values, but the
diffusion of O2 into the cytoplasm presumably should be sufficiently rapid to
maintain ambient oxygen concentrations at oxygen tensions as low as 1 mbar of O2.
The consequences of this finding for the availability of O2 as a substrate or as
a regulatory signal in the cytoplasm of bacterial cells are discussed.
PMID- 9555897
TI - PPi-dependent phosphofructokinase from Thermoproteus tenax, an archaeal
descendant of an ancient line in phosphofructokinase evolution.
AB - Flux into the glycolytic pathway of most cells is controlled via allosteric
regulation of the irreversible, committing step catalyzed by ATP-dependent
phosphofructokinase (PFK) (ATP-PFK; EC 2.7.1.11), the key enzyme of glycolysis.
In some organisms, the step is catalyzed by PPi-dependent PFK (PPi-PFK; EC
2.7.1.90), which uses PPi instead of ATP as the phosphoryl donor, conserving ATP
and rendering the reaction reversible under physiological conditions. We have
determined the enzymic properties of PPi-PFK from the anaerobic,
hyperthermophilic archaeon Thermoproteus tenax, purified the enzyme to
homogeneity, and sequenced the gene. The approximately 100-kDa PPi-PFK from T.
tenax consists of 37-kDa subunits; is not regulated by classical effectors of ATP
PFKs such as ATP, ADP, fructose 2,6-bisphosphate, or metabolic intermediates; and
shares 20 to 50% sequence identity with known PFK enzymes. Phylogenetic analyses
of biochemically characterized PFKs grouped the enzymes into three monophyletic
clusters: PFK group I represents only classical ATP-PFKs from Bacteria and
Eucarya; PFK group II contains only PPi-PFKs from the genus Propionibacterium,
plants, and amitochondriate protists; whereas group III consists of PFKs with
either cosubstrate specificity, i.e., the PPi-dependent enzymes from T. tenax and
Amycolatopsis methanolica and the ATP-PFK from Streptomyces coelicolor.
Comparative analyses of the pattern of conserved active-site residues strongly
suggest that the group III PFKs originally bound PPi as a cosubstrate.
PMID- 9555898
TI - Variation of the ribosomal operon 16S-23S gene spacer region in representatives
of Salmonella enterica subspecies.
AB - The 16S-23S spacer regions of two ribosomal operons (rrnA and rrnE) have been
sequenced in seven representatives of the Salmonella enterica subspecies.
Isolated nucleotide substitutions were found at the same sites as in Escherichia
coli but the number of polymorphic sites was much larger, as could be expected
for a more heterogeneous species. Still, as in E. coli, most of the variation
found was due to insertions and/or deletions affecting blocks of nucleotides
generally located at equivalent regions of the putative secondary structure for
both species. Isolated polymorphic sites generated phylogenetic trees generally
consistent with the subspecies structure and the accepted relationships among the
subspecies. However, the sequences of rrnE put subspecies I closer to E. coli K
12 than to the other S. enterica subspecies. The distribution of polymorphisms
affecting blocks of nucleotides was much more random, and the presence of
equivalent sequences in distantly related subspecies, and even in E. coli, could
reflect relatively frequent horizontal transfer. The smallest 16S-23S spacers in
other genera of the family Enterobacteriaceae were also sequenced. As expected,
the level of variation was much larger. Still, the phylogenetic tree inferred is
consistent with those of 16S rRNA or housekeeping genes.
PMID- 9555899
TI - An AT-rich tract containing an integration host factor-binding domain and two UP
like elements enhances transcription from the pilEp1 promoter of Neisseria
gonorrhoeae.
AB - The pilE gene of Neisseria gonorrhoeae is transcribed from a sigma70 promoter
(pilEp1) with an AT-rich tract extending 65 nucleotides upstream of the -35 box.
Within this region is an integration host factor (IHF)-binding core consensus
sequence. We have performed a detailed analysis to determine which upstream
sequences are required for efficient transcription from pilEp1 in N. gonorrhoeae.
Deletion of sequences upstream of the AT-rich tract had no effect on the level of
transcription. However, the IHF-binding core consensus sequence and the AT-rich
sequence further upstream were both required for enhanced levels of transcription
from this promoter in both N. gonorrhoeae and an Escherichia coli strain
producing IHF. In addition, an UP-like element positioned between the -35 box and
the IHF-binding site was required for maximal transcription. The AT-rich region
upstream of the IHF-binding core consensus sequence can also act as an UP-like
element when appropriately repositioned upstream of the -35 box.
PMID- 9555900
TI - Interaction of native and mutant MecI repressors with sequences that regulate
mecA, the gene encoding penicillin binding protein 2a in methicillin-resistant
staphylococci.
AB - Methicillin resistance in staphylococci is mediated by PBP2a, a penicillin
binding protein with low affinity for beta-lactam antibiotics. The gene encoding
PBP2a, mecA, is transcriptionally regulated in some clinical isolates by mecR1
and mecI, genes divergently transcribed from mecA that encode a signal transducer
and repressor, respectively. The biochemical basis of MecI-mediated mecA
transcriptional repression was investigated by using purified MecI. In DNase I
protection studies, MecI protected a 30-bp palindrome encompassing the predicted
mecA -10 and the mecR1 -35 promoter sequences. The larger palindrome contained 15
bp of dyad symmetry within which was a smaller 6-bp palindrome. Electrophoretic
mobility shift assays established a requirement for the entire 15-bp half-site
for initial repressor binding. Fragments containing the 30-bp palindrome and the
entire mecA-mecR1 intergenic region were retarded in gels as multiple discrete
bands varying in molecular size, characteristic of cooperative DNA binding.
Glutaraldehyde cross-linking confirmed oligomerization of repressor in solution.
A naturally occurring MecI mutant (MecI*; D39G) repressed mecA transcription
sixfold less well than the wild type in vivo. Although MecI* protected the same
target sequences and exhibited similar gel shift patterns to MecI, 5- to 10-fold
more protein was required. MecI* exhibited defective oligomerization in solution,
suggesting that the MecI amino terminus is important in protein-protein
interactions and that protein oligomerization is necessary for optimum
repression.
PMID- 9555901
TI - A period-extender gene, pex, that extends the period of the circadian clock in
the cyanobacterium Synechococcus sp. strain PCC 7942.
AB - We cloned the pS1K1 plasmid in the process of apparently "complementing" a
circadian clock mutant of cyanobacterium Synechococcus sp. strain PCC 7942, SP22,
which has a 22-h period (T. Kondo, N. F. Tsinoremas, S. S. Golden, C. H. Johnson,
S. Kutsuna, and M. Ishiura, Science 266:1233-1236, 1994). Sequence analysis
revealed that SP22 did not have a mutation in the genomic DNA segment carried on
pS1K1, and the sp22 mutation was later found in a recently cloned new clock gene,
kaiC. Therefore, the period-extender gene pex that was carried on pS1K1 was a
suppressor gene for the sp22 mutation. The pex gene encoded a protein of 148
amino acid residues. No meaningful homologs were found in DNA or protein
databases including the Synechocystis genome database. The pex gene was
transcribed from 129 and 164 bp upstream of the translation initiation codon as
0.6-kb transcripts. The Pex protein was detected as a fusion protein with a
molecular mass of 15 kDa by the epitope tag fusion method using a c-Myc epitope
tag. Disruption of the pex gene in wild-type cells shortened the period of the
rhythms by 1 h, although it did not affect other properties of the rhythms,
whereas its overexpression extended the period by 3 h with a concomitant
reduction in the amplitude of the rhythms. In various clock mutants examined,
overexpression caused arrhythmicity. Thus, Pex is likely to function as a
modifier of the circadian clock in Synechococcus.
PMID- 9555903
TI - Inorganic polyphosphate in Escherichia coli: the phosphate regulon and the
stringent response.
AB - Escherichia coli transiently accumulates large amounts of inorganic polyphosphate
(polyP), up to 20 mM in phosphate residues (Pi), in media deficient in both Pi
and amino acids. This transient accumulation is preceded by the appearance of
nucleotides ppGpp and pppGpp, generated in response to nutritional stresses.
Mutants which lack PhoB, the response regulator of the phosphate regulon, do not
accumulate polyP even though they develop wild-type levels of (p)ppGpp when
subjected to amino acid starvation. When complemented with a phoB-containing
plasmid, phoB mutants regain the ability to accumulate polyP. PolyP accumulation
requires high levels of (p)ppGpp independent of whether they are generated by
RelA (active during the stringent response) or SpoT (expressed during Pi
starvation). Hence, accumulation of polyP requires a functional phoB gene and
elevated levels of (p)ppGpp. A rapid assay of polyP depends on its adsorption to
an anion-exchange disk on which it is hydrolyzed by a yeast exopolyphosphatase.
PMID- 9555902
TI - A membrane-associated protein, FliX, is required for an early step in Caulobacter
flagellar assembly.
AB - The ordered assembly of the Caulobacter crescentus flagellum is accomplished in
part through the organization of the flagellar structural genes in a regulatory
hierarchy of four classes. Class II genes are the earliest to be expressed and
are activated at a specific time in the cell cycle by the CtrA response
regulator. In order to identify gene products required for early events in
flagellar assembly, we used the known phenotypes of class II mutants to identify
new class II flagellar genes. In this report we describe the isolation and
characterization of a flagellar gene, fliX. A fliX null mutant is nonmotile,
lacks a flagellum, and exhibits a marked cell division defect. Epistasis
experiments placed fliX within class II of the flagellar regulatory hierarchy,
suggesting that FliX functions at an early stage in flagellar assembly. The fliX
gene encodes a 15-kDa protein with a putative N-terminal signal sequence.
Expression of fliX is under cell cycle control, with transcription beginning
relatively early in the cell cycle and peaking in Caulobacter predivisional
cells. Full expression of fliX was found to be dependent on ctrA, and DNase I
footprinting analysis demonstrated a direct interaction between CtrA and the fliX
promoter. The fliX gene is located upstream and is divergently transcribed from
the class III flagellar gene flgI, which encodes the basal body P-ring monomer.
Analysis of the fliX-flgI intergenic region revealed an arrangement of cis-acting
elements similar to that of another set of Caulobacter class II and class III
flagellar genes, fliL-flgF, that is also divergently transcribed. In parallel
with the FliL protein, FliX copurifies with the membrane fraction, and although
its expression is cell cycle controlled, the protein is present throughout the
cell cycle.
PMID- 9555904
TI - A Bacillus subtilis gene induced by cold shock encodes a membrane phospholipid
desaturase.
AB - Bacillus subtilis grown at 37 degrees C synthesizes saturated fatty acids with
only traces of unsaturated fatty acids (UFAs). However, when cultures growing at
37 degrees C are transferred to 20 degrees C, UFA synthesis is induced. We report
the identification and characterization of the gene encoding the fatty acid
desaturase of B. subtilis. This gene, called des, was isolated by complementation
of Escherichia coli strains with mutations in either of two different genes of
UFA synthesis. The des gene encodes a polypeptide of 352 amino acid residues
containing the three conserved histidine cluster motifs and two putative membrane
spanning domains characteristic of the membrane-bound desaturases of plants and
cyanobacteria. Expression of the des gene in E. coli resulted in desaturation of
palmitic acid moieties of the membrane phospholipids to give the novel mono-UFA
cis-5-hexadecenoic acid, indicating that the B. subtilis des gene product is a
delta5 acyl-lipid desaturase. The des gene was disrupted, and the resulting null
mutant strains were unable to synthesize UFAs upon a shift to low growth
temperatures. The des null mutant strain grew as well as its congenic parent at
20 or 37 degrees C but showed severely reduced survival during stationary phase.
Analysis of operon fusions in which the des promoter directed the synthesis of a
lacZ reporter gene showed that des expression is repressed at 37 degrees C, but a
shift of cultures from 37 to 20 degrees C resulted in a 10- to 15-fold increase
in transcription. This is the first report of a membrane phospholipid desaturase
in a nonphotosynthetic organism and the first direct evidence for cold induction
of a desaturase.
PMID- 9555905
TI - The Bacillus subtilis DinR binding site: redefinition of the consensus sequence.
AB - Recently, the DinR protein was established as the cellular repressor of the SOS
response in the bacterium Bacillus subtilis. It is believed that DinR functions
as the repressor by binding to a consensus sequence located in the promoter
region of each SOS gene. The binding site for DinR is believed to be synonymous
with the formerly identified Cheo box, a region of 12 bp displaying dyad symmetry
(GAAC-N4-GTTC). Electrophoretic mobility shift assays revealed that highly
purified DinR does bind to such sites located upstream of the dinA, dinB, dinC,
and dinR genes. Furthermore, detailed mutational analysis of the B. subtilis recA
operator indicates that some nucleotides are more important than others for
maintaining efficient DinR binding. For example, nucleotide substitutions
immediately 5' and 3' of the Cheo box as well as those in the N4 region appear to
affect DinR binding. This data, combined with computational analyses of potential
binding sites in other gram-positive organisms, yields a new consensus (DinR box)
of 5'-CGAACRNRYGTTYC-3'. DNA footprint analysis of the B. subtilis dinR and recA
DinR boxes revealed that the DinR box is centrally located within a DNA region of
31 bp that is protected from hydroxyl radical cleavage in the presence of DinR.
Furthermore, while DinR is predominantly monomeric in solution, it apparently
binds to the DinR box in a dimeric state.
PMID- 9555906
TI - Molecular analysis of the gene encoding F420-dependent glucose-6-phosphate
dehydrogenase from Mycobacterium smegmatis.
AB - The gene fgd, which codes for F420-dependent glucose-6-phosphate dehydrogenase
(FGD), was cloned from Mycobacterium smegmatis, and its sequence was determined
and analyzed. A homolog of FGD which has a very high similarity to the M.
smegmatis FGD-derived amino acid sequence was identified in Mycobacterium
tuberculosis. FGD showed significant homology with F420-dependent N5,N10
methylene-tetrahydromethanopterin reductase (MER) from methanogenic archaea and
with several hypothetical proteins from M. tuberculosis and Archaeoglobus
fulgidus, but FGD showed no significant homology with NADP-dependent glucose-6
phosphate dehydrogenases. Multiple alignment of FGD and MER proteins revealed
four conserved consensus sequences. Multiple alignment of FGD with the
hypothetical proteins also revealed portions of the same conserved sequences.
Moderately high levels of FGD were expressed in Escherichia coli BL21(DE3)
carrying fgd in pBluescript.
PMID- 9555907
TI - Mosaic structure of the smpB-nrdE intergenic region of Salmonella enterica.
AB - The Salmonella enterica smpB-nrdE intergenic region contains about 45 kb of DNA
that is not present in Escherichia coli. This DNA region was not introduced by a
single horizontal transfer event, but was generated by multiple insertions and/or
deletions that gave rise to a mosaic structure in this area of the chromosome.
PMID- 9555908
TI - Temperature sensitivity of bacteriolysis induced by beta-lactam antibiotics in
amino acid-deprived Escherichia coli.
AB - The temperature-sensitive penicillin tolerance response previously reported in
amino acid-deprived Escherichia coli (W. Kusser and E. E. Ishiguro, J. Bacteriol.
169:2310-2312, 1987) was not due to the induction of the heat shock response
resulting from a temperature upshift and was therefore unrelated to the findings
of another report (J. K. Powell and K. D. Young, J. Bacteriol. 173:4021-4026,
1991) indicating a positive correlation between the expression of heat shock
proteins and penicillin tolerance. The thermosensitive event occurred in the
lysis induction stage.
PMID- 9555909
TI - Oxygen regulation of the ccoN gene encoding a component of the cbb3 oxidase in
Rhodobacter sphaeroides 2.4.1T: involvement of the FnrL protein.
AB - The ccoNOQP gene cluster of Rhodobacter sphaeroides 2.4.1T encodes a cbb3
cytochrome oxidase which is utilized in oxygen-limited conditions for aerobic
respiration. The beta-galactosidase activity of a ccoN::lacZ transcriptional
fusion was low under high (30%)-oxygen and anaerobic growth conditions. Maximal
ccoN::lacZ expression was observed when the oxygen concentration was lowered to
2%. In an FnrL mutant, ccoN::lacZ expression was significantly lower than in the
wild-type strain, suggesting that FnrL is a positive regulator of genes encoding
the cbb3 oxidase.
PMID- 9555910
TI - A novel DNA polymerase family found in Archaea.
AB - One of the most puzzling results from the complete genome sequence of the
methanogenic archaeon Methanococcus jannaschii was that the organism may have
only one DNA polymerase gene. This is because no other DNA polymerase-like open
reading frames (ORFs) were found besides one ORF having the typical alpha-like
DNA polymerase (family B). Recently, we identified the genes of DNA polymerase II
(the second DNA polymerase) from the hyperthermophilic archaeon Pyrococcus
furiosus, which has also at least one alpha-like DNA polymerase (T. Uemori, Y.
Sato, I. Kato, H. Doi, and Y. Ishino, Genes Cells 2:499-512, 1997). The genes in
M. jannaschii encoding the proteins that are homologous to the DNA polymerase II
of P. furiosus have been located and cloned. The gene products of M. jannaschii
expressed in Escherichia coli had both DNA polymerizing and 3'-->5' exonuclease
activities. We propose here a novel DNA polymerase family which is entirely
different from other hitherto-described DNA polymerases.
PMID- 9555911
TI - The tfdK gene product facilitates uptake of 2,4-dichlorophenoxyacetate by
Ralstonia eutropha JMP134(pJP4).
AB - Uptake of 2,4-dichlorophenoxyacetate (2,4-D) by Ralstonia eutropha JMP134(pJP4)
was studied and shown to be an energy-dependent process. The uptake system was
inducible with 2,4-D and followed saturation kinetics in a concentration range of
up to 60 microM, implying the involvement of a protein in the transport process.
We identified an open reading frame on plasmid pJP4, which was designated tfdK,
whose translation product TfdK was highly hydrophobic and showed resemblance to
transport proteins of the major facilitator superfamily. An interruption of the
tfdK gene on plasmid pJP4 decimated 2,4-D uptake rates, which implies a role for
TfdK in uptake. A tfdA mutant, which was blocked in the first step of 2,4-D
metabolism, still took up 2,4-D. A mathematical model describing TfdK as an
active transporter at low micromolar concentrations fitted the observed uptake
data best.
PMID- 9555912
TI - Erwinia amylovora secretes DspE, a pathogenicity factor and functional AvrE
homolog, through the Hrp (type III secretion) pathway.
AB - Erwinia amylovora was shown to secrete DspE, a pathogenicity factor of 198 kDa
and a functional homolog of AvrE of Pseudomonas syringae pv. tomato. DspE was
identified among the supernatant proteins isolated from cultures grown in an hrp
gene-inducing minimal medium by immunodetection with a DspE-specific antiserum.
Secretion required an intact Hrp pathway.
PMID- 9555913
TI - Specific binding of Escherichia coli ribosomal protein S1 to boxA transcriptional
antiterminator RNA.
AB - We show that ribosomal protein S1 specifically binds the boxA transcriptional
antiterminator RNAs of bacteriophage lambda and the Escherichia coli ribosomal
RNA operons. Although S1 competes with the NusB-S10 antitermination complex for
binding to boxA, it does not affect antitermination by the lambda N protein in
vitro, and its role, if any, in rRNA synthesis is still unknown.
PMID- 9555914
TI - Physiological regulation of the derepressible phosphate transporter in
Saccharomyces cerevisiae.
AB - The extracellular phosphate concentration permissive for the expression of
different amounts of the active high-affinity Pho84 phosphate transporter in the
plasma membrane as well as the PHO84 messenger RNA levels in low-phosphate-grown
Saccharomyces cerevisiae cells is very narrow and essential for a tight
regulation of the transporter. The Pho84 transporter undergoes a rapid
degradation once the supply of phosphate and/or carbon source is exhausted.
PMID- 9555915
TI - The yhhP gene encoding a small ubiquitous protein is fundamental for normal cell
growth of Escherichia coli.
AB - H-NS is a major constituent of the Escherichia coli nucleoid, whereas sigmaS is a
stress-induced sigma factor. An hns null mutation affects the cellular content of
sigmaS in such a way that a remarkable accumulation of sigmaS is observed in the
logarithmic growth phase, which results in enhanced expression of a number of
sigmaS-dependent genes, including the katE gene. We isolated an extragenic
mutation that affects the expression of the katE-lacZ fusion gene in the deltahns
background. The relevant gene was identified as yhhP, which encodes a small
polypeptide of 81 amino acids. Lesion of this gene seemed to affect the stability
of sigmaS. A deletion analysis of yhhP revealed that this small protein plays a
fundamental role in the general physiology of E. coli. The yhhP-deficient cell is
not capable of growing in standard laboratory rich medium (i.e., Luria broth),
resulting in the formation of filamentous cells. Homologs of this intriguing
protein occur in a wide variety of bacterial species, including archaeal species.
PMID- 9555916
TI - Nuclease overexpression mutants of Serratia marcescens.
AB - A family of mutants overexpressing the Serratia marcescens extracellular nuclease
has been known for decades. A number of these alleles are characterized here at
the molecular level, and the mutant genes are identified, yielding a likely model
for their phenotype. The known mutations exert their effect indirectly on nucA
expression by elevating the basal SOS response of the cell. Mutations have been
found in xerC and uvrD, both of which result in partial SOS induction. A classic
nucsu allele, that of strain W1050, is also likely to be in xerC.
PMID- 9555917
TI - The Bacillus subtilis galE gene is essential in the presence of glucose and
galactose.
AB - Bacillus subtilis is unable to grow by consuming galactose because it is unable
to transport it into the cell. The transcription of galE is not influenced by
galactose but is repressed by glucose. Galactose is toxic for galE-negative
bacteria because it results in elevated levels of metabolic intermediates. These
negative effects are reduced in galK and galT mutants. Glucose is also toxic for
galE-negative strains.
PMID- 9555918
TI - Education at the crossroads: for today's practice, the DPT.
PMID- 9555919
TI - Partial body weight support with treadmill locomotion to improve gait after
incomplete spinal cord injury: a single-subject experimental design.
AB - BACKGROUND AND PURPOSE: Gait training with partial body weight support has been
used to improve gait. In this study, changes in gait relative to speed, cadence,
stride length, and percentages of stance and swing for both lower extremities
(LEs) during comfortable walking, fast walking, and running were studied in a
subject with an incomplete C-5 on C-6 spinal cord injury. SUBJECT AND METHODS: A
single-subject experimental design was used. Following a 6-week period of
baseline measurements taken at various intervals (phase AI), the subject
ambulated on a treadmill three times a week for 6 weeks with 32% of his body
weight supported (phase B). Phase B was followed by a 3-week period without
treatment during which measurements were taken at various intervals (phase AII).
Gait variables were measured once a week during comfortable walking, fast
walking, and running. Heart rate was monitored during treadmill training.
RESULTS: During comfortable walking, fast walking, and running, improvements were
seen in gait speed. During running, improvements also were seen in stride length
and percentages of stance and swing for the right LE. The largest changes were
recorded during running. Smaller changes were recorded during comfortable walking
and fast walking. CONCLUSION AND DISCUSSION: These results justify testing the
efficacy of this technique with larger groups of subjects with neurological
impairments.
PMID- 9555920
TI - The influence of experience with a set of simulated patients on diagnosis of
simulated patients not previously diagnosed.
AB - BACKGROUND AND PURPOSE: Diagnoses, to be useful, should be accurate. The purpose
of this study using fictitious patients and student judges was to test the theory
that diagnostic errors would occur when students saw simulated patients who were
similar to previously seen simulated patients. SUBJECTS: Sixty physical therapist
(PT) students and 60 non-physical therapist (NPT) students were studied. Subjects
were assigned randomly to one of three groups. METHODS: Instructions to the three
groups differed in terms of rules provided for diagnoses and instructions to
remember the patients. Students first diagnosed the same eight fictitious
patients five times. The students then diagnosed eight new patients with similar
characteristics interspersed with the original eight patients. Half of the new
patients had a diagnosis different from that of the most similar old patient.
RESULTS: Students who were given a rule for diagnosis made fewer errors than
students who were not given a rule. Students in the PT group took longer but made
fewer errors on the critical opposite-diagnosis new cases than did students in
the NPT group. CONCLUSION AND DISCUSSION: The results do not provide support for
the theory that diagnostic errors would occur when students saw patients who were
similar to previously seen patients. Students in the PT group appeared to
emphasize accuracy at the expense of speed in making their diagnoses. Given the
nature of the simulated patient information and the mode of presentation used in
the experiment, however, the conclusion that therapists in actual practice do not
make errors because of the similarity between new and previously seen patients is
not yet warranted.
PMID- 9555921
TI - Effects of electrical stimulation on edema formation in different strains of
rats.
AB - BACKGROUND AND PURPOSE: Although electrical stimulation (ES) is commonly used to
curb edema formation, efficacy has been demonstrated in only one species of frog
and one strain of rat. The purpose of this study was to determine whether
different strains of rats respond differently to ES. SUBJECTS AND METHODS: Feet
of Sprague-Dawley, Zucker-Lean, and Brown Norway rats were injured in a uniform
manner. One foot served as a control, and the other foot received four 30-minute
exposures to cathodal high-voltage pulsed current at amplitudes 10% less than
those required to induce visible muscle activity. Each treatment period was
followed by a 30-minute rest period. Limb volumes were measured before and after
trauma and after each treatment and rest period. Changes from pretrauma volumes
were analyzed by repeated-measures analysis of variance. RESULTS: Edema formation
was curbed in Zucker-Lean and Brown Norway rats but not in Sprague-Dawley rats.
CONCLUSION AND DISCUSSION: The finding that two of the three strains of rats
responded to ES suggests that some strains of rats may be suitable models for the
study of edema. That frogs and rats respond to high-voltage pulsed current
suggests that humans might respond similarly.
PMID- 9555922
TI - The relationship between head and neck posture and VDT screen height in keyboard
operators.
AB - BACKGROUND AND PURPOSE: The purpose of this study was to determine the effect of
change in video display terminal (VDT) height from desktop height (96.5 cm [38
in]) to an elevated position (109.2 cm [43 in]) on postural angles of the head
and neck and the effect on cervical spine flexion moments. SUBJECTS: Twenty-seven
persons (3 male, 24 female) who spent at least 3 hours per day using a computer
while seated were the subjects. The subjects had a mean age of 36.7 years
(SD=6.0, range=25-47). METHODS: Subjects were photographed over two 10-minute
periods while seated using a computer with the VDT at two different heights.
Later, a goniometer was used over images to record angles. RESULTS: There was no
difference in cervical flexion moment between the two screen positions. Several
postural angles of the head and neck showed changes, but the clinical relevance
of these changes is questionable. CONCLUSION AND DISCUSSION: Changing the VDT
height from 96.5 to 109.2 cm (floor to midscreen) has no effect on flexion moment
on the cervical spine during short periods of VDT operation. If flexion moment is
considered a biomechanical indicator of postural stress, it does not appear that
the elevated screen position reduces postural stress on the cervical spine during
short periods of VDT operation.
PMID- 9555923
TI - The effect of foot structure on the three-dimensional kinematic coupling behavior
of the leg and rear foot.
AB - BACKGROUND AND PURPOSE: Differences in foot structures have been reported to
account for the large variability in findings in previous studies that have
examined the relationship between foot structure and the interdependent rotations
of the lower extremity. The purpose of this study was to determine, in
individuals with radiographically distinct foot structures, the effect of foot
structure on three-dimensional kinematic behavior of the leg and rear foot during
running. SUBJECTS AND METHODS: Based on radiographic measurements, 10
recreational runners were assigned to a low rear-foot group and another 10
recreational runners were assigned to a high rear-foot group. Three-dimensional
kinematic data were collected during treadmill running. Individual axis rotations
and the "coupled" relationship between the leg and rear-foot segments were
defined using a Cardan angle system of three ordered rotations. RESULTS: The
predominant rotations suggest a combined subtalar and talocalcaneal joint axis to
favor calcaneal eversion and inversion for the low rear-foot group and tibial
medial and lateral rotation for the high rear-foot group. Group differences were
also found for the coupling ratio, which described the proportion of calcaneal
eversion and inversion transferred or coupled to tibial axial rotation.
CONCLUSION AND DISCUSSION: The rotational patterns and coupling response unique
to each foot group may enhance our understanding of lower-extremity injuries
related to certain foot structures. An assessment of the coupling relationship in
combination with traditional frontal-plane measurements may better guide
decisions regarding selection of footwear and orthoses.
PMID- 9555924
TI - Aerobic exercise for a patient with chronic multisystem impairments.
AB - Many patients with long-term disabilities have inactive lifestyles that put them
at risk for chronic diseases and secondary disabilities. The purpose of this case
report is to illustrate the process of aerobic exercise prescription for a
patient with chronic multisystem impairments. The patient was a 43-year-old man
who incurred a traumatic brain injury and multiple fractures in a motorcycle
accident 15 years previously. He subsequently developed heterotopic ossification
around the right hip. In addition, the patient had a history of smoking. We chose
a "nontraditional" mode of exercise for the patient that we believed would be
safe and effective and would accommodate his neurologic and orthopedic
impairments. The mode of exercise used was an apparatus in which the upper and
lower extremities alternately flexed and extended in a nonreciprocal fashion. The
patient attended 12 exercise sessions over a 1-month period, during which he
demonstrated acute and chronic physiological responses appropriate for the
exercise stimulus.
PMID- 9555925
TI - Clinical reasoning in the management of a 21-year-old physical therapist student
with chronic hip pain.
PMID- 9555926
TI - Referral pattern and outcome in men and women undergoing coronary artery bypass
surgery--a critical review.
AB - Women with coronary artery disease are less likely to undergo coronary artery
bypass surgery, and this may represent a potential referral bias in favor of men.
A higher in-hospital mortality rate in women compared with men has been reported
earlier. Accumulating evidence currently suggests, however, that variables other
than gender, such as advanced age, late referral, angina classification, diabetes
mellitus, concurrent medical conditions, the number of diseased vessels, the
caliber of coronary arteries, and the decreased body surface area in women may
have accounted for this difference. In fact, when these variables are taken into
account, female gender is no longer a statistically significant predictor of
operative mortality. Women appear to have comparable immediate and late survival
rates. Recurrent angina, perioperative myocardial infarction, congestive heart
failure, incomplete revascularization, and early and late graft reocclusion
following surgery are, however, more prevalent in women. Men and women show
differences in recovery experiences after discharge following bypass surgery.
When coronary bypass surgery is offered to women, the decision should be
individualized, based on the patients' perioperative baseline clinical risk
factors and coronary anatomy. Coronary artery bypass surgery should not be
withheld in women who are considered to be appropriate candidates for fear of a
reduced success rate.
PMID- 9555927
TI - Use of nuclear magnetic resonance imaging angiography to follow-up arterial
remodeling in an animal model.
AB - Appropriately sized arteries in small animals may be possible models for studying
the remodeling process as occurs after arterial balloon injury in humans.
Magnetic resonance imaging (MRI) is able to noninvasively image tissue in vivo.
To date, small animal angiography models have mostly used research-dedicated
instruments and resolution, which are not universally available. Experiments were
carried out on a rat aorta model of remodeling in vivo (n=40). Arteries were
injured by oversized balloon dilation; control arteries were uninjured.
Angiography imaging was performed immediately before sacrifice with an unmodified
clinical MRI unit, a 1.5 Tesla MR tomograph with a 20-cm-diameter coil.
Longitudinal MRI pictures of the aorta and morphometry of tissue sections to
measure luminal and arterial wall areas were analyzed with use of computer
assisted techniques. Comparison of dimensions demonstrated correlation between
MRI and histology measurements of the lumen. MRI and morphometry showed a gradual
increase in mean luminal area over 6 weeks following injury. The lumen increase
correlated with total arterial area and thickness. In this rat aorta model,
remodeling documented at histology was followed-up in vivo. The use of such
clinical MRI scanners has potential to reduce animal numbers needed to follow-up
the remodeling process after therapeutic intervention.
PMID- 9555928
TI - A comparative evaluation of femorofemoral crossover bypass and iliofemoral bypass
for unilateral iliac artery occlusive disease.
AB - The purpose of this study was to compare the results of extra-anatomic
femorofemoral crossover bypass grafting to the anatomic iliofemoral bypass
grafting procedure in the treatment of patients with unilateral iliac artery
occlusive disease with respect to patency and limb salvage. The records of all
patients with unilateral iliac artery disease who underwent revascularization
between January 1988 and December 1995 at the University of Iowa Hospitals and
Clinics (UIHC) were retrospectively reviewed; 108 patients were identified and
divided into two groups. Group I (n=68; male/female=44/24) was composed of all
patients who underwent a femorofemoral crossover extra-anatomic bypass. All
patients who underwent an iliofemoral anatomic bypass constituted group II (n=40;
male/female=24/16). The mean age for group I was 60 years (range 28-87) and for
group II, 54 years (range 14-86). The medical risk factors between both groups
were comparable. Except for the higher incidence of gangrene in group II the
indications for surgery were comparable between both groups. A
polytetrafluoroethylene graft was used in 88% of group I patients and in 90% of
group II patients (NS). In the remaining patients, an autogenous vein conduit was
used. Two patients from group I (2.9%) died in the perioperative period (NS).
Graft patency was assessed by clinical evaluation, Doppler-derived ankle/brachial
indices, and color duplex imaging. The cumulative primary and secondary patency
rates, limb salvage, and patient survival were calculated by use of life table
analysis (SE<0.1). The need for simultaneous outflow and inflow procedures at the
time of surgery was comparable between both groups. The proportion of patients
who underwent further revascularization during follow-up was also comparable. The
5-year primary and secondary graft patency rates were 81.7% and 90.3%, in group I
and 61.3% and 80.5% in group II. Although the difference between both groups was
not significant there was a tendency toward higher rates with femorofemoral
bypass. The 5-year survival rates of 80.3% for group I and 73.3% for group II
were comparable. These data suggest that there is no significant difference in
the long-term results between the femorofemoral crossover bypass grafts and
iliofemoral grafts. Both procedures result in acceptable patency and limb salvage
rates. The femorofemoral bypass is, however, more attractive, for it can be
performed under local anesthesia if needed and does not involve the creation of
the retroperitoneal incision necessary with the iliofemoral bypass.
PMID- 9555930
TI - Entering the ninth decade is not a contraindication for carotid endarterectomy.
AB - The role of carotid endarterectomy (CEA) in stroke prevention is now better
defined. However, its role in patients older than 79 years of age is
controversial. This group of patients has been excluded in most clinical trials.
In this study the authors reviewed their experience with CEA patients >79 years
old. The records of all patients older than 79 years of age who underwent a CEA
in a recent time period from January 1988 to December 1996 were retrospectively
reviewed. Forty-one patients (31 men, 10 women) were identified by computer
search. The indication for operation included transient ischemic attack in 12
(29.3%), amaurosis fugax in nine (22%), stroke in two (4.9%), and nonhemispheric
symptoms in three (7.3%). Fifteen patients (36.6%) were asymptomatic. Medical
risk factors included coronary artery disease in 26 (63.4%), hypertension in 22
(53.7%), and smoking in 12 (29.3%). The procedure was performed under EEG
monitoring in all patients. General anesthesia was administered in 37 (90%) and
regional anesthesia in four (10%). Shunts were used in four (10%) patients. The
internal carotid artery was patched in 16 patients (39%). One patient (2.4%)
developed a perioperative stroke and only one patient developed perioperative
myocardial infarction (MI). None of the patients died within 30 days of surgery.
In addition to the one MI case, five patients developed minor complications. The
average length of time for stay after CEA was 3.4 days. Patients were followed up
for an average of 20.7 months. Six patients died during follow-up. Four of those
died from an MI and two from a stroke. The authors conclude that with proper
selection of patients, CEA is safe in the octogenarian. Age alone should not be a
contraindication for CEA.
PMID- 9555929
TI - Acute mesenteric ischemia after open heart surgery.
AB - Acute mesenteric ischemia is a rare but severe complication after open heart
surgery. Its incidence (0.2-0.4%) is quite low, but mortality rates are ranging
between 70% and 100%. From October 1992 to December 1996, 4,640 patients
underwent open heart surgery with cardiopulmonary bypass: 74.6% coronary artery
bypass graft (CABG) operations, 23.2% valve replacement including aortic repairs,
and 2.2% corrections of congenital heart diseases or tumors of the heart. The
overall mortality rate (30 days) was 3.4%, and after CABG, 2.9%. Twelve patients
(0.26%), following CABG (one combined with aortic valve replacement, one with
mitral reconstruction, and one with carotid disobliteration) developed signs of
acute mesenteric ischemia in the early postoperative period (day 1 to 5). In all
patients various abdominal symptoms, leukocytosis, acidosis, hyperlactatemia,
hyperosmolality, renal failure, and, finally, hemodynamic instability were
observed. Eleven patients underwent emergency laparotomy. Mesenteric angiography
was done if possible in still stable patients (n=7); it showed severe stenosis or
occlusion prior to the operation in each case. Other diagnostic methods were not
reliable. In six patients (55%) during the first look, extensive bowel necrosis
was found and in five patients an ischemic intestine but no necrosis was
detected. Of these, three patients were affected by extensive bowel gangrene at
the second look. In the fourth patient a disseminated peripheral ischemia of the
entire small intestine was found intraoperatively. After mechanical release and
stimulation normal bowel function could be reestablished. One patient underwent
percutaneous transluminal angioplasty prior to the laparotomy. Bowel perfusion
was still deteriorated but no necrosis was found intraoperatively. These patients
were the only survivors in the investigated group; 10 of 12 patients (83.3%) died
in the early postoperative period (day 1 to day 6). Predisposing factors for
mesenteric ischemia are: arteriosclerotic patients after CABG (100%), age >70
years (91.7%), hyperosmotic dehydration (100%), and cardiac ischemia in 25%.
Mesenteric ischemia is a fatal complication with high mortality rates after open
heart surgery, especially in older, dehydrated patients with generalized
atherosclerotic vessel disease. As the acute mesenteric ischemia usually starts
during anesthesia or in the early postoperative period, setting of immediate
diagnosis is very difficult. With the occurrence of typical symptoms diagnostic
and therapeutic procedures (angiography and laparotomy) must be done very
urgently owing to the life-threatening mesenteric process. When mesenteric
gangrene already has taken place, the prognosis is very poor, despite extensive
resection. Prevention can be exercised by avoiding perioperative hyperosmotic
dehydration of patients at high risk.
PMID- 9555931
TI - Carotid-subclavian bypass for subclavian artery revascularization: long-term
follow-up and effect of antiplatelet therapy.
AB - Subclavian artery stenosis is found in up to 25% of supraaortic lesions. Bypass
grafting is the procedure of choice but controversies exist concerning the
optimal technique and the effect of postoperative antithrombotic therapy on long
term patency. The authors retrospectively analyzed 40 patients with carotid
subclavian bypasses. Stenoses were documented preoperatively by arteriography.
Patency was determined by clinical, ultrasound, or arteriographic examinations.
Cumulative patency rates were calculated by Kaplan-Meier method and analyzed by
Tarone-Ware test. Graft materials were Dacron (32), polytetrafluoroethylene
(seven) or saphenous vein (one). Indications for surgery included vertebrobasilar
insufficiency (22.5%), upper extremity ischemia (22.5%), and the combination of
both (55.0%). Perioperative mortality and morbidity were 2.5% and 10.0%,
respectively. Patients were followed up from 0 to 134 months (mean 61+/-39
months). Cumulative 5-year patency rate was 83.3%. Anticoagulation with
acetylsalicylic acid (ASA) led to significantly better 5-year patency rates
(100%) as compared with the combination of ASA and dipyridamole (64.0%, p=0.013)
or no anticoagulation (70.0%, p=0.016). Carotid-subclavian bypass led to
excellent long-term patency rates and can provide durable relief of symptoms with
minimal perioperative morbidity and mortality. Therefore, it is a worthwhile
procedure to correct proximal subclavian artery stenosis. Postoperative
medication with ASA seems to increase long-term bypass function significantly.
PMID- 9555932
TI - Effect of coacervated alpha-elastin on proliferation of vascular smooth muscle
and endothelial cells.
AB - The arterial wall injury associated with arterial graft implantation causes
smooth muscle cells (SMCs) in the media to migrate and proliferate in the intima
at the graft-artery junction resulting in anastomotic intimal hyperplasia (AIH).
An important step in developing a small-diameter prosthesis may be to stimulate
endothelialization and thereby inhibit AIH. In this study, we investigated the
effect of coacervated and crosslinked alpha-elastin on proliferation of SMCs and
endothelial cells (ECs) in vitro. Coacervation is an important step in the
conversion of proelastin to make an elastin fiber in vivo. SMCs and ECs were
prepared from porcine aortic media and endothelium, respectively. SMCs and ECs
(three to five passages, 4 x 10[4] cells/well) were seeded onto 12 well plates,
coated and crosslinked with 0 or 10 mg/mL of coacervated alpha-elastin. After the
1st, 2nd, or 3rd day of cultivation, proliferation was assayed by scintillation
counting of [3H]-thymidine incorporation. For the 4th day only, 0, 0.1, 1, 10
mg/mL concentration of coacervated alpha-elastin was coated and crosslinked. SMC
proliferation (1st, 2nd day: p<0.005; 3rd, 4th day: p<0.0001) was significantly
inhibited over time and dose dependently, eg, 0.1 mg/mL (45.7+/-2.3%: % of
control p<0.005), 1 mg/mL (5.9+/-0.7%, p<0.0005), 10 mg/mL (2.8+/-0.4%,
p<0.0005). EC proliferation was inhibited over time by 10 mg/mL of coacervated
alpha-elastin (2nd, 3rd day: p<0.005; 4th day: p<0.0001), but proliferation
(132.8+/-9.9%: % of control p=NS) was stimulated by 0.1 mg/mL of coacervated
alpha-elastin. These results suggest that coating and crosslinking a coacervated
alpha-elastin into the structure of arterial prosthesis may inhibit AIH and
stimulate endothelialization.
PMID- 9555933
TI - Experimental study of cardiac lymph dynamics and edema formation in
ischemia/reperfusion injury--with reference to the effect of hyaluronidase.
AB - This study is designed to evaluate the effect of hyaluronidase on the canine
myocardial edema derived from ischemia/reperfusion injury. The mongrel dog's
heart received 90 minutes of ischemia under cardiopulmonary bypass consisting of
30 minutes of normothermia alone and 60 minutes of hypothermia with cardioplegic
arrest. Reperfusion for 60 minutes was added thereafter. Two kinds of
cardioplegic solution, 4 degrees C St. Thomas' Hospital solution with or without
3000 units/L of hyaluronidase, were prepared. The solution was given antegradely
every 30 minutes during cardioplegic arrest. Cardiac lymph was collected
continuously from the afferent duct of the cardiac lymph node by cannulation.
Hyaluronidase in the cardioplegic solution increased cardiac lymph volume
significantly and improved postischemic recovery of cardiac function. A high
level of adenosine triphosphate was maintained at that time. The myocardial water
content at the end of reperfusion revealed a minimum increase with hyaluronidase
use. Active drainage of cardiac lymph by hyaluronidase alleviates the myocardial
edema formation, thereby preserving cardiac function.
PMID- 9555934
TI - The determination of metabolite M17 and its meaning for immunosuppressive
cyclosporin therapy.
AB - Cyclosporin A (CyA) is intensively metabolized by the hepatic cytochrome p450 III
monooxygenase A system in the human liver, the most important metabolites being
M1, M17, and M21. Because CyA and its metabolites have nephrotoxic, hepatotoxic,
and neurotoxic side effects, CyA dosage must be calculated to avoid the risk of
organ rejection through underdosage and toxic organ damage through overdosage or
accumulation of metabolites. In this study, we determined the whole-blood
concentrations of cyclosporin and metabolite M17 by high-pressure liquid
chromatography (HPLC) and by monoclonal specific and polyclonal nonspecific
fluorescence polarization immunoassay (Abbott) in patients after
immunosuppressive treatment. Patients with different resorption and
metabolization rates showed high individual variations. CyA concentrations in
patients with good liver function and low concentrations of CyA metabolites
showed a good correlation between the HPLC and the FPIA (TDx-monoclonal assay)
methods in ranges between 25 and 180 ng/mL. TDx-monoclonal was not always as
precise as HPLC. In cases of metabolic disorders, we found false high CyA
concentrations assayed with the immunologic method, caused by a crossreaction of
the elevated metabolite concentration. We found that HPLC rendered more
information about the extent of immunosuppressive activity and the metabolization
rate and showed a good correlation with the concentration of metabolite M17 and
total metabolites measured with the Abbott CyA polyclonal kit.
PMID- 9555935
TI - Arm edema, subclavian thrombosis, and pacemakers--a case report.
AB - This reports an arm edema that was initially treated as cellulitis and later
diagnosed to be subclavian thrombosis due to pacemaker wire irritation. We
present an 87-year-old Caucasian man with 5 weeks duration of left arm swelling
and pain that was treated with two courses of antibiotics. An axillary venous
Doppler study was interpreted as normal with no evidence of venous thrombosis.
However, a venogram showed evidence of thrombosis involving the left innominate,
subclavian, and axillary veins with multiple collateral veins diverting the blood
to the contralateral side and into the superior vena cava. Intravenous
anticoagulation was initiated and subsequently the patient was maintained on
warfarin (Coumadin). The thrombosis subsequently improved and the original
pacemaker was maintained. Arm edema are commonly mistaken for cellulitis, causing
a delay in a more definite diagnosis of subclavian thrombosis. In a setting of a
patient with pacemaker, subclavian thrombosis should be considered even with a
normal screening venous ultrasound test. The incidence, manifestation, venous
Doppler, and venogram findings are reviewed and discussed. Upper arm edema and
superior vena cava syndrome are the most common presentation of this subclavian
thrombosis associated with pacemakers. Venous ultrasound tests may be normal and
a venogram is usually required to establish a diagnosis.
PMID- 9555936
TI - Considerations in the surgical management of ventricular septal defect and aortic
insufficiency--a case report.
AB - A 23-year-old man presented with progressive exercise-related dyspnea and easy
fatigability. He gave a history of a murmur of aortic insufficiency since
childhood. Cardiac catheterization demonstrated severe aortic insufficiency. At
surgery the patient was found to have prolapse of the right coronary cusp into a
significant supracristal ventricular septal defect. Repair was carried out with a
Dacron patch closure of the septal defect and replacement of the valve with a 29
mm St. Jude valve. The patient recovered uneventfully and is fully active and
employed 5 years later. Review of the literature documents that this is an
uncommon lesion. The approaches to preoperative diagnosis include transesophageal
echo. The management techniques have included ventricular septal defect closure,
alone and with valvuloplasty, and septal defect closure with aortic valve
replacement. The anatomic and patient characteristics guide selection of the most
suitable management of these patients.
PMID- 9555937
TI - Genetically modified mice for the study of apolipoprotein B.
AB - Over the past five years, several laboratories have used a variety of transgenic
and gene-targeted mice to study apoB. These studies have helped in 1) generating
new mouse models suitable for investigating the genetic and environmental factors
affecting atherogenesis; 2) providing systems for investigating apoB
structure/function relationships; 3) understanding the regulation of apoB gene
expression in the intestine; 4) delineating a critical role for apoB expression
in mouse embryonic development; 5) yielding insights into the "physiologic
rationale" for the existence of the two different forms of apoB, apoB-48 and apoB
100, in mammalian metabolism; and 6) providing basic insights into mechanisms
involved in the human apoB deficiency syndrome, familial hypobetalipoproteinemia.
PMID- 9555938
TI - Adipose tissue ob mRNA expression in humans: discordance with plasma leptin and
relationship with adipose TNFalpha expression.
AB - Elevated plasma leptin levels are found in obese humans, suggesting a defect in
the function of leptin in regulating body weight and adiposity. In 53 subjects
covering a broad range of adiposity, we examined the relationships between plasma
leptin, adipose tissue ob mRNA levels, and adipose tissue TNF mRNA. There was a
highly significant correlation between plasma leptin levels and every index of
adiposity. In contrast, the relationship between ob mRNA levels and adiposity was
weak. Adipose tissue from obese subjects demonstrated higher ob mRNA levels than
adipose tissue from lean subjects (lean: 0.49+/-0.05; obese 0.87+/-0.09 arbitrary
units, P< 0.05). However, there was no significant correlation between body fat
and ob mRNA level. In addition, there was no significant relationship between ob
mRNA levels and plasma leptin levels, which were measured in the same subjects.
In addition to the measure of ob mRNA levels, adipose TNF mRNA levels were
measured in 18 subjects. TNF mRNA levels varied with ob mRNA levels (r = 0.44, P
= 0.06). These data show that plasma leptin levels are not directly related to
adipose tissue ob mRNA levels, suggesting posttranscriptional regulation of
leptin expression, either at the level of the adipocyte, or by alteration of
plasma leptin degradation or clearance. In addition, the parallel changes in ob
and TNF mRNA in adipose tissue suggest that these two important factors in the
defense against obesity may be regulated similarly.
PMID- 9555939
TI - Secretion of apoB- and apoA-I-containing lipoproteins by chick kidney.
AB - Previous studies showed that chick kidney is a site of synthesis of
apolipoprotein (apo) B(B-100) and A-I. Aims of the present study were: a) to
compare apoB and apoA-I production in chick kidney and liver; b) to investigate
whether kidney apolipoproteins were secreted as constituents of lipoproteins; and
c) to define the cellular sites of renal apolipoprotein synthesis. Kidney and
liver slices taken from the same animals were incubated with 35S-labeled amino
acids and radioactive apoB and apoA-I were immunoprecipitated from cell
homogenate and incubation medium. The percentage of total protein radioactivity
incorporated into cell plus medium apoB and apoA-I was 0.23+/-0.08 and 0.19+/
0.11 in kidney and 0.38+/-0.05 and 0.38+/-0.07 in liver, respectively (P < 0.05
kidney vs. liver). 35S-labeled medium lipoproteins were separated by density
gradient ultracentrifugation and three major classes corresponding to VLDL + IDL,
LDL, and HDL were identified. Most of the apoB secreted by the liver was found in
VLDL, IDL, and LDL whereas kidney apoB was found in VLDL, LDL and "light" HDL (d
1.070-1.130 g/ml). In both hepatic and renal lipoproteins apoA-I was found not
only in HDL but also in the other lipoproteins. Immunohistochemical analysis of
kidney sections showed that apoB and apoA-I were present almost exclusively in
the epithelial cells of proximal and distal convoluted tubules. Thus apoB and
apoA-I synthesized by the epithelial cells of the proximal and distal convoluted
tubules of chick kidneys are secreted as constituents of lipoprotein particles
floating within the density range of plasma lipoproteins. These observations
suggest that in the chick, the kidneys may contribute to the plasma lipoprotein
pool.
PMID- 9555940
TI - Gene transcription of the retinoid X receptor alpha (RXRalpha) is regulated by
fatty acids and hormones in rat hepatic cells.
AB - This work describes the molecular mechanisms of fatty acid and hormonal
modulations of the retinoid X receptor alpha (RXRalpha) in rat liver cells. We
examined the effects of different fatty acids (myristic, stearic, oleic,
linolenic, and arachidonic acids, EPA, and the peroxisomal proliferator TTA) and
several hormones (the glucocorticoid analogue dexamethasone, insulin, and
retinoic acid) on the RXRalpha mRNA and protein levels in rat hepatoma cells and
cultured hepatocytes. The fatty acids induced the RXRalpha gene expression
resulting in up to 3-fold induction. Dexamethasone alone induced the mRNA level
and, in combination with fatty acids, an additive or synergistic effect was
observed. The dexamethasone-increased mRNA level was obliterated by insulin. The
same pattern of regulation of the protein level was observed when determined in
cultured hepatocytes, but the induced protein level showed a lower magnitude of
stimulation than the mRNA level. This could indicate a post-transcriptional
modulation of the RXRalpha gene expression. Time course studies showed a maximal
induction of mRNA and protein levels after 18 h and 48 h, respectively. Our
results uniformly show that the RXRalpha gene expression is under distinct
regulation by fatty acids and hormones which suggests a coupling with the lipid
metabolizing system and the hormonal signaling pathway.
PMID- 9555941
TI - Hemin binding and oxidation of lipoproteins in serum: mechanisms and effect on
the interaction of LDL with human macrophages.
AB - Most models of lipoprotein oxidation by free radicals have excluded
macromolecular plasma components from the system. This limits their biological
significance because oxidation of lipoproteins appears to occur in the intima in
the presence of a plasma ultrafiltrate. Hemin, a product of in vivo hemoglobin
degradation, binds and oxidizes purified lipoproteins. However, it is not known
whether this occurs in the presence of plasma components that may sequester
hemin. We found that hemin in serum diluted to protein levels of the
extracellular fluid (10-30%) binds to low and high density lipoproteins (LDL,
HDL) with association constants in the nmol/L range. In the presence of H2O2,
hemin oxidizes both lipoproteins in diluted serum with formation of conjugated
dienes, thiobarbituric acid reacting substances, and F2-isoprostanes. This
appeared to be caused by the high affinity of hemin with LDL and by the Fe3+
liberated that remains associated with the particles after hemin is degraded.
Spectrophotometric and fluorescence experiments and electrophoresis of porphyrins
complex with LDL indicated that the heme ring is buried in the lipoprotein
surface-monolayer with the carboxylic groups in contact with positive regions of
the protein and the solvent. Human macrophages associated and degraded 3- to 4
times more hemin-oxidized LDL in diluted serum than native LDL. It is possible
then that at sites of LDL, accumulation in the extracellular intima, hemin and
H2O2 production could cause oxidation with potential atherogenic consequences for
cellular lipoprotein processing. This may occur even when other macromolecules of
the extracellular fluid are present.
PMID- 9555942
TI - Synergistic activation of transcription by nuclear factor Y and sterol regulatory
element binding protein.
AB - The current studies define the role of three distinct cis-elements in the
proximal promoter of the rat farnesyl diphosphate (FPP) synthase gene. The three
cis-elements, a sterol regulatory element 3 (SRE-3) flanked by an ATTGG motif
(inverted CCAAT box), and a CCAAT box, form a sterol regulatory unit that is
necessary and sufficient for sterol-regulated expression of FPP synthase promoter
reporter genes. FPP synthase promoter-reporter genes, that contain promoters with
either wild-type nucleotide sequences or mutations in one or more of the three
cis-elements, were transiently transfected into CV-1 cells. The activity of the
wild-type promoter-reporter gene increased when the cells were incubated in
sterol-depleted media or when the cells were co-transfected with a plasmid
encoding the mature form of SRE binding protein (SREBP-1a). The results with the
mutant promoter-reporter genes demonstrated that all three cis-elements were
necessary for normal expression/regulation of the reporter gene by either sterols
or by co-expressed SREBP-1a. Gel mobility shift assays demonstrated that the
synergistic binding of SREBP-1a to SRE-3 was dependent on the binding of
recombinant nuclear factor Y (NF-Y) to the DNA, consistent with the in vivo
regulation studies.
PMID- 9555943
TI - Human CD36 is a high affinity receptor for the native lipoproteins HDL, LDL, and
VLDL.
AB - Mouse and hamster SR-BI glycoproteins and their putative human counterpart CLA-I
are so far the only scavenger receptors known to bind both native and modified
lipoproteins. CD36, a multigland glycoprotein structurally related to SR-BI and
CLA-1, has been reported to bind oxidized low density lipoprotein (OxLDL) and
acetylated LDL (AcLDL). In this report, we have studied the ability of CD36 to
bind native lipoproteins. By transient expression of human CD36 in mammalian and
insect cells, we demonstrate that CD36 is a high affinity receptor for the native
lipoproteins HDL, LDL, VLDL, and, as previously reported, for OxLDL and AcLDL.
The specificity of these interactions is supported by the dose-dependent
inhibiton, effect of a monoclonal antibody against CD36. Furthermore, at least
for HDL, binding to CD36 does not require the presence of apoE. These findings,
together with preferential expression of CD36 in tissues performing very active
fatty acid metabolism (skeletal muscle, heart, mammary epithelium, and adipose
tissue) and its involvement in foam cell formation (macrophages), suggest that
binding of lipoproteins to CD36 might contribute to the regulation of lipid
metabolism, and to the pathogenesis of atherosclerosis.
PMID- 9555944
TI - Binding and intracellular trafficking of lipoprotein lipase and triacylglycerol
rich lipoproteins by liver cells.
AB - The cellular mechanisms and pathways by which lipoprotein lipase (LPL) enhances
the binding and uptake of lipoproteins remains unknown. Confocal and
immunoelectron microscopy demonstrated that primary binding of bovine LPL (bLPL)
occurs at the microvilli surface of HepG2 cells and hepatocytes. Internalized
bLPL was associated with endocytic vesicles and multivesicular bodies.
Quantitative immunofluorescence indicated that the presence of bLPL caused a
marked increase in the cell-surface binding of DiI-conjugated triacylglycerol
rich lipoproteins (DiI-TRL). Confocal microscopy showed that when DiI-TRL was
incubated with bLPL at 4 degrees C, the distributions of bound LPL and DiI-TRL
were totally coincident, and covered the apical surface of both HepG2 cells and
hepatocytes. When incubated separately, the time-courses of the internalization
of fluorescence associated with DiI-TRL and bLPL were different: DiI-TRL was
quickly internalized by both HepG2 cells and hepatocytes, and reached a plateau
at 30 min, whereas intracellular LPL increased continuously, but more slowly in
the same period. In the presence of bLPL, DiI-TRL was internalized progressively
by HepG2 and by cultured hepatocytes for up to 1 h and no saturation was reached.
At this time the intensity of labeling of bLPL was lower than of DiI-TRL and a
higher number of DiI spots did not colocalize with bLPL immunofluorescence,
suggesting that the ligands follow a different pathway after internalization. The
data suggest that when lipoprotein lipase (LPL) is associated with the
lipoproteins it directs them to specific endocytic pathways. A hypothetical model
of the intracellular pathways followed by triacylglycerol-rich lipoproteins and
LPL after internalization is proposed.
PMID- 9555945
TI - Characterization of recombinant human plasma lecithin: cholesterol
acyltransferase (LCAT): N-linked carbohydrate structures and catalytic
properties.
AB - The major N-linked carbohydrate structures were determined for recombinant human
plasma lecithin:cholesterol acyltransferase (LCAT). The analysis of the structure
of oligosaccharides by fast atom bombardment mass spectrometry (FAB-MS) and
linkage analysis was preceded by reduction and carboxymethylation of the intact
glycoproteins and digestion with trypsin and proline specific endopeptidase. The
N-glycans were subsequently released from the glycopeptides by PNGase F digestion
and the oligosaccharides were separated using a C18 Sep-pak cartridge. The data
from the combination of FAB spectrometry and linkage analysis show that the N
linked glycans present on recombinant LCAT (rLCAT) were composed primarily of
triantennary and tetraantennary structures with and without core fucosylation. A
minor population of glycans (less than 5%) contained up to three repeats of N
acetyllactosamine in one or more antennae. The LCAT activities of both
recombinant and circulating forms of plasma LCAT were determined using low
molecular weight and lipoprotein substrates. The catalytic behavior of these two
enzyme forms were found to be very similar if not identical. These findings
validate the concept that the recombinant enzyme can serve as an appropriate
model for structure/function studies of LCAT and provide the foundation for
subsequent structural studies.
PMID- 9555946
TI - The carboxy-terminal region of human lipoprotein lipase is necessary for its exit
from the endoplasmic reticulum.
AB - Certain missense substitutions on the human lipase (hLPL) gene produce mutated
proteins that are retained in different compartments along the secretory pathway.
The purpose of the present study was to elucidate whether the C-terminal domain
of the hLPL molecule could be important for secretion. We constructed by site
directed mutagenesis three carboxy-terminal mutated (F388-->Stop, K428-->Stop and
K441-->Stop) hLPL cDNAs that were expressed in COS1 cells. Immunoblotting of cell
extracts showed that all three constructs led to similar levels of protein. Both
wild type (WT) hLPL and the truncated K441-->Stop hLPL were secreted to the
extracellular medium, and presented a similar intracellular distribution pattern
as shown by immunofluorescence. Neither F388-->Stop nor K428-->Stop hLPL protein
was detected in cell medium. Immunofluorescence experiments showed that both
truncated hLPL were retained within an intracellular compartment, which became
larger. Double immunofluorescence analysis using antibodies against LPL and
antiprotein disulfide isomerase as a marker showed that the truncated K428-->Stop
hLPL was retained within the rough endoplasmic reticulum. This truncated protein
was not found in other compartments in the secretory pathway, such as Golgi
complex and lysosomes, indicating that it did not exit the endoplasmic reticulum.
Further analysis of the C-terminal region of the LPL molecular model showed both
that F388-->Stop and K428-->Stop hLPL truncated proteins are highly hydrophobic.
As retention of secretory proteins in the rough endoplasmic reticulum is a
quality control mechanism of the secretory pathway, we conclude that the C
terminal domain of hLPL is critical for correct intracellular processing of the
newly synthesized protein.
PMID- 9555947
TI - Uncoupling protein-1 mRNA expression in obese human subjects: the role of
sequence variations at the uncoupling protein-1 gene locus.
AB - Uncoupling protein-1 (UCP-1) activity in brown adipose tissue increases
thermogenesis, contributes to facultative energy expenditure in humans, and has
been implicated in the pathogenesis of rodent obesity. To determine genetic
factors controlling UCP-1 expression in humans, we measured intra- and
extraperitoneal UCP-1 mRNA abundance levels by a competitive RT-PCR method and
compared expression levels with common sequence variations in the beta3
adrenergic receptor gene and the distal UCP-1 gene promoter in obese human
subjects. While median and average UCP-1 mRNA levels in both the intra- and
extraperitoneal tissue were lower in subjects heterozygous for the Trp64Arg
mutation in the beta3-adrenergic receptor gene, this difference was not
statistically significant. However, a strong association of intraperitoneal UCP-1
mRNA abundance with the UCP-1 gene polymorphism at -3826 relative to the
transcription start site was observed that explained 19.3% of the interindividual
variability. The minor allele imparted a dose-dependent reduction on UCP gene
expression. The importance of sequence variations at the UCP-1 gene locus as a
common source of UCP-1 mRNA abundance variability was supported by allele
specific expression studies utilizing a newly identified polymorphism in exon 2
of the UCP-1 gene that predicts a substitution of alanine by threonine. In four
subjects heterozygous for the -3826 polymorphism, the mRNA species transcribed
from the wild-type allele accounted for 63+/-6% percent of total intraperitoneal
mRNA abundance. In one subject homozygous for the minor promoter allele, wild
type mRNA was also more abundant than variant mRNA. Thus, the UCP-1 polymorphism
at -3826 is probably only a marker for a frequent mutation causing reduced mRNA
expression.
PMID- 9555948
TI - Chylomicron remnant uptake is regulated by the expression and function of heparan
sulfate proteoglycan in hepatocytes.
AB - Chylomicron remnants transport cholesterol from the intestine, and are removed
from the circulation principally by the liver. While hepatic receptors, including
the low density lipoprotein (LDL) receptor account for endocytosis, heparan
sulfate proteoglycans (HSPG) participate in the initial binding of remnants to
liver cells. To explore the interactions between HSPG and endocytosis of
remnants, in the present study the expression of HSPG was inhibited in HepG2
cells transfected by a synthetic antisense oligodeoxynucleotide SYN5.
Immunofluorescent staining by a monoclonal anti-syndecan antibody showed
significant reduction in the expression of syndecan in SYN5-treated cells
compared with control cells. Remnant binding decreased by about 50-70% in SYN5
transfected cells. Monoclonal antibodies to either heparan sulphate or the LDL
receptor decreased binding by about 60-65%. The glycosylation inhibitor beta
nitrophenylxylopyranoside inhibited remnant uptake by 25%, whereas 4-nitrophenyl
beta-D-galactopyranoside had no effect on remnant binding. Heparinase completely
abolished binding at appropriate concentrations. Heparitinase was less effective
than hep arinase in inhibiting remnant binding. Suramin completely abolished the
remnant binding. Poly-arginine, poly-lysine, and protamine all reduced remnant
uptake by the cells, as did polybrene, a synthetic polycation, suggesting a role
of cation-anion interactions in remnant binding. Brefeldin A, colchicine, and
monensin caused the fluorescence associated with remnants to persist within the
cells, confirming that blockers of tubulovesicular processes and Golgi function
inhibit the intracellular transport and degradation of the remnants. Our results
show that remnant binding to liver cells depends on the LDL receptor, on the
expression of HSPG core proteins, and on the functionality of heparan sulfate in
HSPG.
PMID- 9555949
TI - In vitro factors affecting the concentration of gamma-LpE (gamma-LpE) in human
plasma.
AB - Gamma-LpE (gamma-LpE), a sphingomyelin-rich lipoprotein that contains
apolipoprotein (apo) E as its only protein component, has been proposed to play a
role in cellular cholesterol efflux by acting, like pre-beta1-LpA-I, as an
initial acceptor of cell-derived cholesterol. In order to further characterize
the presence of gamma-LpE in human plasma, we have separated gamma-LpE by two
dimensional non-denaturing polyacrylamide-gradient gel electrophoresis and
detected its presence by immunoblotting with 125I-labeled polyclonal anti-apoE
antibody. Five species of gamma-LpE were routinely detected in human plasma,
ranging in mean particle diameter from 9.5 to 16.5 nm. The largest proportion of
gamma-migrating apoE was associated with gamma-LpE having a diameter of 13.0 nm.
Neither the amount of gamma-LpE apoE (representing less than 1-2% of total plasma
apoE) nor the number of gamma-LpE subfractions was different in serum vs. plasma,
or was affected by the presence of agents able to inhibit protein dimerization.
Gamma-LpE subfractions were present in the plasma of patients having different
apoE phenotypes (i.e., apoE 2/2, 3/3, or 4/4). Incubation of plasma at 37 degrees
C (90 min) caused a significant decrease in plasma gamma-LpE (>80%) that was not
dependent on LCAT or CETP activity. Storage (at -70 degrees C) of
hypertriglyceridemic but not normolipidemic plasma resulted in an increase in
gamma-LpE. Freezing of postprandial plasma samples, containing increased amounts
of triglyceride-rich lipoproteins (TRL) enriched in apoE, also caused an increase
in gamma-LpE. Incubation of VLDL (d < 1.006 g/ml) with lipase resulted in the
production of gamma-migrating apoE. These results demonstrate that: 1) different
gamma-LpE subfractions exist in human plasma; 2) the amount of apoE associated
with gamma-LpE subfractions is dependent on in vitro conditions of plasma
storage; and 3) TRL can act as a source of gamma-LpE apoE in vitro.
PMID- 9555950
TI - Docosahexaenoic acid lowers phosphatidate level in human activated lymphocytes
despite phospholipase D activation.
AB - N-3 polyunsaturated fatty acids from marine oil have been shown to decrease T
cell-mediated immune function both in animals and humans, and to inhibit the
mitogen-induced lymphoproliferative response when added to lymphocyte culture
medium. As phosphatidic acid (PA) is a key mediator of the mitogenic process, the
present study aims to investigate whether docosahexaenoic (DHA) and
eicosapentaenoic (EPA) acids, the main n-3 fatty acids from fish oil, are able to
alter the mitogen-induced synthesis of PA, when added to the culture medium of
human peripheral blood mononuclear cells (PBMC). Incubation of PBMC in a medium
containing 5 microM DHA bound to 5 microM human delipidated serum albumin induced
a 2-fold increase in the basal PA mass whereas incubation with EPA, in the same
conditions, had no effect. In contrast, both fatty acids markedly reduced the
concanavalin A (ConA)-induced production of PA as compared with untreated cells.
Paradoxically, phospholipase D (PLD) activity, evidenced by the synthesis of
phosphatidylbutanol, was only detected in DHA-treated cells further stimulated by
ConA, indicating that both DHA and ConA are required for PLD activation.
Similarly, an increased diacylglycerol (DAG) mass was only observed in DHA
treated cells stimulated by ConA, whereas no modification occurred in control or
EPA-treated cells stimulated or not by ConA. Furthermore, 1-butanol suppressed
the ConA-induced increase of DAG mass observed in DHA-treated cells, indicating
that phosphatidate was the source of the newly synthesized diacylglycerol.
Altogether, these results show that, in concanavalin A-activated human peripheral
blood mononuclear cells, docosahexaenoate stimulates both phospholipase D and
phosphatidate phosphohydrolase activities, which ultimately results in an
increased diacylglycerol production at the expense of phosphatidate.
PMID- 9555951
TI - Coordinated release of acylation stimulating protein (ASP) and triacylglycerol
clearance by human adipose tissue in vivo in the postprandial period.
AB - The objective of this study was to determine whether Acylation Stimulating
Protein (ASP) is generated in vivo by human adipose tissue during the
postprandial period. After a fat meal, samples from 12 subjects were obtained (up
to 6 h) from an arterialized hand vein and an anterior abdominal wall vein that
drains adipose tissue. Veno-arterial (V-A) gradients across the subcutaneous
adipose tissue bed were calculated. The data demonstrate that ASP is produced in
vivo (positive V-A gradient) With maximal production at 3-5 h postprandially. The
plasma triacylglycerol (TAG) clearance was evidenced by a negative V-A gradient.
It increased substantially after 3 h and remained prominent until the final time
point. There was, therefore, a close temporal coordination between ASP generation
and TAG clearance. In contrast, plasma insulin and non-esterified fatty acid
(NEFA) had an early (1-2 h) postprandial change. Fatty acid incorporation into
adipose tissue (FIAT) was calculated from V-A glycerol and non-esterified fatty
acid (NEFA) differences postprandially. FIAT was negative during the first hour,
implying net fat mobilization. FIAT then became increasingly positive, implying
net fat deposition, and overall followed the same time course as ASP and TAG
clearance. There was a direct positive correlation between total ASP production
and total FIAT (r = 0.566, P < 0.05). These data demonstrate that ASP is
generated in vivo by human adipocytes and that this process is accentuated
postprandially, supporting the concept that ASP plays an important role in
clearance of TAG from plasma and fatty acid storage in adipose tissue.
PMID- 9555952
TI - Phytosterols partially explain differences in cholesterol metabolism caused by
corn or olive oil feeding.
AB - To examine whether phytosterols in polyunsaturated oils account for their
differential action on lipid metabolism compared with monounsaturated oils, 16
normolipidemic individuals consumed three 10-day experimental diets containing
corn oil (high in polyunsaturated fatty acids and phytosterols), olive oil (high
in monounsaturated fatty acids and low in phytosterols), or olive oil
supplemented with phytosterols given at twice the level naturally found in corn
oil (high in monounsaturated fatty acids and phytosterols). Plasma total
cholesterol concentrations after both the olive oil and the olive oil-phytosterol
treatments were higher (P < 0.001) than those after the corn oil treatment. Olive
oil treatment resulted in greater (P < 0.05) plasma LDL-cholesterol and
triglyceride concentrations compared to corn oil treatment. Addition of the
phytosterol mixture to the olive oil diet resulted in suppression of the
significant differences in LDL-cholesterol and triglyceride concentrations
between corn and olive oil. Free cholesterol fractional synthetic rates
determined by deuterium incorporation were lower (P < 0.05) with olive oil
treatment compared to corn oil treatment; the significance of this difference was
abolished with the addition of phytosterols to the olive oil diet. These results
suggest that phytosterols are partly responsible for the differences in plasma
cholesterol levels and synthesis observed between polyunsaturated and
monounsaturated oils.
PMID- 9555953
TI - Effect of a coffee lipid (cafestol) on cholesterol metabolism in human skin
fibroblasts.
AB - Consumption of boiled coffee promotes an elevation of plasma cholesterol
concentration in humans. The active compounds found in the lipid fraction of the
coffee have been identified as the diterpenes cafestol and kahweol. We have
studied the effects of pure cafestol on cholesterol metabolism in human skin
fibroblasts (HSF). The uptake of [125I]-labeled tyramine cellobiose-labeled low
density lipoprotein ([125I]TC-LDL) was decreased by about 50% (P< 0.05) after 18
h preincubation time with cafestol (20 microg/ml), as compared to the control
cells. The specific binding of radiolabeled LDL was reduced by 54% (P < 0.05)
after preincubation for 18 h with cafestol. A reduced amount of LDL receptors was
demonstrated by a protein-normalized Scatchard plot analysis (20% decrease in
Bmax) as well as by immunoblotting (25%) after cafestol incubation. No
significant effect was observed on the level of mRNA for the LDL receptor after
11 and 23 h incubation with cafestol. Furthermore, we transfected HSF cells with
a promoter region for the LDL receptor gene linked to a reporter gene,
chloramphenicol acetyl transferase (CAT). No change was seen in the CAT activity
after incubation with cafestol (20 microg/ml). Moreover, cafestol caused a 2.3
fold (P < 0.05) higher incorporation of radiolabeled [14C]oleic acid into
cholesteryl esters after 24 h incubation, as compared to control cells,
suggesting an increased acyl-CoA:cholesterol acyl transferase (ACAT) activity.
Incorporation of [14C]acetate into cholesterol was reduced by approximately 40%
(P < 0.05) with cafestol (20 microg/ml), as compared to control after 24 h
preincubation, indicating a decreased 3-hydroxy-3-methylglutaryl CoA (HMG-CoA)
reductase activity. Our results suggest that intake of cafestol may cause
increased concentration of plasma cholesterol via the down-regulation of low
density lipoprotein receptors by post-transcriptional mechanisms.
PMID- 9555954
TI - Three-fold effect of lovastatin treatment on low density lipoprotein metabolism
in subjects with hyperlipidemia: increase in receptor activity, decrease in apoB
production, and decrease in particle affinity for the receptor. Results from a
novel triple-tracer approach.
AB - To differentiate effects of lovastatin on low density lipoprotein (LDL) receptor
activity from effects on LDL metabolic properties, LDL apolipoprotein B (apoB)
turnover was studied in eight hyperlipidemic subjects during baseline and
lovastatin treatment, in the latter case with LDL tracers isolated during both
baseline (CLDL) and drug treatment (Rx-LDL) conditions. Lovastatin (40 mg/day)
significantly lowered total plasma and LDL cholesterol levels (27% and 25%,
respectively) as well as plasma triglyceride levels (30%). Using contemporaneous
tracers (C-LDL before and Rx-LDL during treatment), lovastatin caused a modest
increase in LDL fractional catabolic rate (FCR) (0.410+/-0.113 vs. 0.339+/-0.108
pools/day, P < 0.04 by paired t). The increase in LDL tracer FCR was higher when
C-LDL tracer isolated during the untreated period was injected during lovastatin
treatment (0.496+/-0.177 vs. 0.339+/-0.108 pools/day, P < 0.02). These in vivo
studies in humans were confirmed by injecting LDL tracers from two patients into
five guinea pigs. The C-LDL tracer was cleared consistently faster than the Rx
LDL tracer (0.082+/-0.018 vs. 0.057+/-0.015 pools/h, P< 0.001). The results
demonstrate three important outcomes of lovastatin treatment in these subjects:
LDL receptor activity increased by 49% (P < 0.02); LDL apoB production rate
decreased by 17% (P < 0.03), and LDL particle in vivo affinity for the LDL
receptor decreased by 15% (P < 0.01). The decrease in LDL particle affinity
partially negated the expected effect of increased LDL receptors on LDL
clearance. The present study provides an explanation for earlier observations by
several investigators using contemporaneous tracers that treatment with HMG-CoA
reductase inhibitors resulted in only modest increases in low density lipoprotein
functional catabolic rate.
PMID- 9555955
TI - Generation and initial characterization of a novel polyclonal antibody directed
against homocysteine thiolactone-modified low density lipoprotein.
AB - Elevated plasma homocysteine (homocysteinemia) are presumed to be responsible for
the development of coronary artery disease, however, the precise etiology is
unclear. We examined the possibility that the adduct formed from the reaction
between homocysteine thiolactone, a metabolic product of homocysteine, and
apolipoprotein B-100 lysyl residues of low density lipoprotein (LDL) was
immunogenic. New Zealand White rabbits were immunized with this adduct at 6-week
intervals. Antisera collected following the 3rd immunization was assayed for
antibody titers using solid phase ELISA techniques. Titers (defined as the
inverse of the greatest serum dilution in which there was a significant
difference (P < 0.05) between the percentage antibody bound from the antiserum
and the pre-immune serum) were approximately 10(5). In competition-based ELISAs,
homocysteine thiolactone-treated LDL competed for binding with the antiserum, as
the 50% inhibitory concentration was approximately 10 microg/ml. Neither
homocysteine, homocystine (homocysteine disulfide), nor Cu2-oxidized LDL competed
for binding. LDL in which lysyl residues were derivatized by acetylation or
methylation were not recognized by the antiserum. Homocysteine thiolactone
treated plasma competed for binding to the antiserum, whereas native plasma did
not. All lipoprotein fractions from the homocysteine thiolactone-treated plasma
competed for binding to the antiserum. We conclude that homocysteine thiolactone
modified LDL is highly immunogenic and specific for homocysteine thiolactone
modified lysines. The potential for using this antibody as a diagnostic tool for
measuring plasma homocysteine concentrations and the implications for
understanding diseases induced by homocysteinemia are discussed.
PMID- 9555956
TI - Enhanced detection of lipoprotein lipase by combining immunoprecipitation with
Western blot analysis.
AB - This manuscript describes the problems inherent in combining immunoprecipitation
of lipoprotein lipase (LPL) with its detection by Western blot, and how these
problems can be circumvented by the preparation of suitable immunoreagents. These
reagents used during the immunoprecipitation step, include Fab fragments of the
primary antibody (chicken anti-bovine LPL), and a covalently linked immunomatrix
of the secondary antibody (rabbit anti-chicken IgG). The use of these reagents in
conjunction with Western blot detection virtually eliminates the problem of non
relevant protein detection when analyzing LPL from complex biological samples.
Moreover, this approach can be adapted to detect any protein with the same
inherent problems as LPL, such as hepatic lipase.
PMID- 9555957
TI - Don't kill Japanese hemodialysis patients like America kills its patients.
PMID- 9555958
TI - A simple and early prognostic index for acute renal failure patients requiring
renal replacement therapy.
AB - Recent advances in technology have not substantially changed the high mortality
rate associated with acute renal failure (ARF). To obtain a simple, valid
prognostic index, we retrospectively evaluated the relative importance of
demographic data, causes (acute insults) of renal failure, and comorbid clinical
conditions for the outcome in 102 ARF patients who received renal replacement
therapy with an overall mortality rate of 65% (66 of 102). There were no
significant differences between survivors and nonsurvivors in age and gender.
Mortality according to acute insults was similar to that of the whole population
studied. Of the 10 clinical conditions at the time of the first renal replacement
therapy, mechanical ventilation (p = 0.0002), cardiac failure (p = 0.0006),
hepatic failure (p = 0.003), central nervous system dysfunction (p = 0.005), and
oliguria (p = 0.04) were found to be significantly related to mortality by
univariate analysis. Furthermore, multivariate analysis demonstrated that only
mechanical ventilation, cardiac failure, and hepatic failure were significant
risk factors. Survival was directly related to the number of significant
variables in univariate analysis: zero, 89% (8 of 9); one, 62% (21 of 34); two,
19% (5 of 27); three, 10% (2 of 20); four, 0% (0 of 8); five, 0% (0 of 4). This
simple and early prognostic index, derived from the assessment of clinical
conditions which were easily determined at the patient's bedside, could be useful
for outcome prediction in ARF patients requiring renal replacement therapy.
PMID- 9555959
TI - Centralized on-line hemodiafiltration system utilizing purified dialysate as
substitution fluid.
AB - We followed the guidelines of the Kyushu Society for Hemodiafiltration (HDF)
Therapy on the purification of dialysate used as substitution fluid and
clinically applied HDF using only 20 L or 15 L of substitution fluid in the pre-
or postdilution mode, respectively. We used a centralized on-line HDF system
consisting of a novel multi-patient dialysate delivery system applying 3
endotoxin (ET) removal filters in series, maintaining the ET level within the
criteria limit below 1.0 IU/L (measured at the first filter outlet to be 0.1 IU/L
and after the third filter to be below the sensitivity limit) irrespective of the
fluctuation in the ET level of the tap water. Low molecular weight proteins
(beta2-microglobulin, prolactin, alpha1-microglobulin, and alpha1-acid
glycoprotein) were more effectively removed in this HDF system than in
conventional hemodialysis (HD) using the same dialyzer as that in the HDF system,
and the removal of these proteins in the HDF system was enhanced as their
molecular weights increased. The clinical effect of the HDF system was
demonstrated by a decrease in joint pain accompanied by improvement in joint
motion in 6 dialysis patients followed over the long term (100 weeks).
PMID- 9555960
TI - Glucose-insulin kinetics of a bioartificial pancreas made of an AN69 hydrogel
hollow fiber containing porcine islets and implanted in diabetic mice.
AB - The goal of this study was to determine whether porcine islets encapsulated in
hollow fibers made of AN69 copolymer can correct hyperglycemia in diabetic mice
and provide normal tolerance to a glucose challenge. In vitro perifusion of
hollow fibers demonstrated the rapid kinetics of insulin release in response to
glucose. Two fibers containing islets were transplanted into the peritoneal
cavity of each of 17 streptozotocin induced diabetic mice. In 11 mice, diabetes
was reversed within 3 days with plasma glucose levels decreasing from 19.7 +/-
0.9 (mean +/- SEM) before implantation to 10.9 +/- 0.8 mmol/L. Intraperitoneal
glucose tolerance tests were performed in transplanted (n = 7), nondiabetic (n =
15), and diabetic mice (n = 6). A normal glucose pattern was observed in the
transplanted diabetic mice. This was achieved in the presence of plasma insulin
levels lower than those observed in control nondiabetic mice, suggesting the
presence of a state of hypersensitivity to insulin, which was demonstrated in
this model by exogenous insulin tolerance tests. In conclusion, encapsulation of
islets suspended in ultraculture medium in biocompatible membranes of AN69 can
provide xenograft survival, and complete normalization of glucose tolerance can
be achieved.
PMID- 9555961
TI - Effect of high concentrations of bile acids on cultured hepatocytes.
AB - High concentrations of bile acids have been reported as injurious to hepatocytes.
We report the influence of various combinations of bile acids on the liver
specific function of cultured rat hepatocytes. Using 4 bile acids (glycocholate
[GC], taurocholate [TC], glycohenodeoxycholate [GCDC], and taurochenodeoxycholate
[TCDC]), we obtained 6 bile-acid mixtures, each containing equal amounts of 2
bile acids (total bile acids [TBA], 2 mM). Changes in gluconeogenesis,
ureagenesis, DNA contents, medium alanine aminotransferase, and morphologies were
compared among the paired bile acid compositions by measuring the C/CDC ratio
([GC + TC]/[GCDC + TCDC]) of each. In terms of their relative impairments of
ureagenesis from greatest to least, the acids were GCDC, TCDC, and GC, which was
almost the same as TC. When the C/CDC ratio was 0, the values of all parameters
measured deteriorated. When the C/CDC ratio was 1 in the presence of 1 mM GCDC,
only the rate of ureagenesis was diminished. When the C/CDC ratio was infinite,
no hepatocellular injury was observed. GCDC and TCDC, together or separately,
showed significant hepatocellular injury when the TBA concentration was 2 mM.
PMID- 9555962
TI - Comparison of three solid phase supports for promoting three-dimensional growth
and function of human liver cell lines.
AB - An extracorporeal liver support system will require that liver cells maintain
their normal differentiated function. This is more likely to be achieved
utilizing a three-dimensional culture configuration rather than a simple
monolayer culture. We present data on a human liver cell line attached and
maintained on different three-dimensional supports, porous glass (Siran), silicon
(Immobasil), and calcium-alginate beads. Albumin, fibrinogen, prothrombin, alpha1
acid glycoprotein and alpha1-antitrypsin secretions were measured. Proliferation
was slower on each of the three-dimensional supports than on the monolayer
culture. The protein secretion of all 5 proteins was highest in cells
encapsulated in alginate; silicon beads supported greater protein secretion than
glass. Cells on silicon or within alginate were rounded; those on glass grew in 2
configurations as flattened monolayers and as rounded colonies. Cells in alginate
secreted as much protein as the whole liver (e.g., albumin, 14.88 g/10(12)
cells/day compared to the whole liver, approximately 12 g/day). Three-dimensional
culture of a human liver cell line leads to both proliferation and a high
synthetic capacity, an important feature of cells suitable for an extracorporeal
liver support system.
PMID- 9555964
TI - Centrifugal pumping during routine open heart surgery improves clinical outcome.
AB - Carrying out a 1,000 patient prospective, randomized study comparing a roller
pump and the BioMedicus centrifugal pump (CP), hematological parameters, blood
loss, renal function, postoperative complications, and lethality data were
evaluated. Using a validated preoperative risk stratification method (Cardiac
RiskMaster), patients were divided into different risk categories for statistical
analysis. This study verified an improved outcome with the use of a CP in routine
cardiac surgery, demonstrated by blood handling, blood loss, renal function, and
nephrological complication data. There was also a significant reduction in
neurological complications. There was no significant difference in postoperative
lethality, but high risk patients demonstrated outcomes comparable to those being
defined for medium risk patients. Routine cardiac surgical patients as well as
multimorbid patients benefit from the use of a CP. Preoperative risk
stratification is a valid tool to demonstrate how the employment of new
technologies can provide for an improved outcome without increasing overall costs
at the same time.
PMID- 9555963
TI - Coronary vascular bed perfusion with a polyethylene glycol-modified hemoglobin
encapsulated liposome, neo red cell, in rats.
AB - Whether hemoglobin (Hb) encapsulated liposomes have vasoconstrictive activity
remains controversial. We therefore examined the vascular activity of a liposome
Hb, Neo red cell (NRC), in a simple in vitro model of Langendorff perfusion of
the rat heart using Krebs-Henseleit (KH) solution as the perfusate. In the KH
solution, NRC (Hb at 1 mg/ml), however, induced an immediate and abnormal
increase in perfusion pressure. Histological examinations revealed that embolisms
were the likely cause of this disturbance. Inorganic crystals formed by the
mixing of NRC with the perfusate were a possible source of the embolisms. We
found that the addition of bovine serum albumin to the perfusate was effective in
avoiding embolic events. This protocol was used to compare the vasoconstrictive
properties of unmodified bovine Hb and NRC. Unmodified bovine Hb (1 mg/ml) caused
an increase in perfusion pressure and a decrease in the duration of bradykinin
induced relaxation. In contrast, NRC (Hb at 1 mg/ml) had no such vasoconstrictive
effects. These results provide the first information regarding perfusion of the
circulatory vascular bed by NRC and further evidence that the encapsulation of Hb
into liposomes is an effective approach to modulate Hb-related vasoconstrictive
activity.
PMID- 9555966
TI - The safety system for the rotary blood pump, combination of the valve and LVAD
pulsatile mode: in vitro test.
AB - The significant amount of regurgitation produced by a stopped rotary blood pump
is one of the major considerations for its use as an implantable left ventricular
assist device (LVAD), especially if the pump accidentally stops. The installation
of a valve is an option for the solution of this potential problem. However, this
option may lead to thrombogenic problems, particularly if the valve motion is
restricted. This in vitro study analyzes the valve performance and assesses the
credibility of a rotary blood pump valve. A pulsatile pump was used as the
natural heart and a centrifugal pump as the LVAD. The valve was positioned into
the LVAD outflow. In the low speed range (<1,000 rpm in this test condition),
normal valve motion was maintained. Also, the valve model provided a higher mean
bypass flow than the model without a valve due to reduced regurgitation. However,
the valve motion was drastically restricted when in the high speed range (>1,600
rpm in this condition). The pulsatile mode was applied to the LVAD by
periodically changing the impeller speed (40 bpm); subsequently, a constant valve
motion could be provided. A possibility exists that this pulsatile mode
application could eliminate thrombosis formation around the valve. A conclusion
was made that the combination of a valve and an LVAD in a pulsatile mode is
considered to be a unique safety system for a rotary blood pump.
PMID- 9555967
TI - New bedside test for monitoring anticoagulation during hemodialysis.
AB - Heparin therapy in patients can be monitored bedside during dialysis treatment by
activated partial thromboplastin time (APTT) measurements using portable
coagulation monitors. We verified the efficacy of the CoaguChek Plus System
(Boehringer Mannheim, GmbH, Mannheim, Germany) for this purpose. The first series
of results was obtained using CoaguChek Plus APTT controls (Level 1 and Level 2)
on 3 instruments. The coefficients of variation (CVs) were found to be in the
range of 3.6 to 5.0% based on results per instrument (n = 20) and per control
level (n = 60). The second series of results was obtained using whole blood drawn
from the arterial lines of patients during dialysis treatment. Three
determinations out of 1 ml of fresh whole blood gave an overall mean CV of 4.9%
from the 123 samples tested. Samples were taken before the onset of heparin
treatment, 2 h after treatment was started, and at the end of treatment. The
CoaguChek Plus APTT measurements were compared to measurements made using
laboratory routine method STA APTT (Boehringer Mannheim GmbH) with results from
104 whole blood samples. Regression analysis according to Passing and Bablok
showed good correlation (r = 0.885) and good agreement (y = 0.997x - 6.6) between
both methods. Ease of use, excellent performance, reliability, and rapid
availability of results within 3 min make the CoaguChek Plus APTT measurements
suitable for monitoring patients during dialysis.
PMID- 9555965
TI - A novel technique for cardiopulmonary bypass using vacuum system for venous
drainage with pressure relief valve: an experimental study.
AB - To decrease the circuit priming volume, develop safety, and simplify the
equipment, a cardiopulmonary bypass (CPB) circuit using a vacuum suction venous
drainage system with a pressure relief valve was developed. The efficacy of this
vacuum system was compared to that of a conventional siphon system. The system
contains a powerful vacuum generator and a pressure relief valve to keep the
negative pressure constant when blood suction is used. Using 8 mongrel dogs, the
feasibility and the efficacy of this CPB system was tested. The changes in the
negative pressure in the reservoir were within 5 mm Hg whether the suction lines
were switched on or off. In all animals the amount of blood in the venous
reservoir was stable throughout bypass. The decrease of priming volume was from
725 ml (siphon system) to 250 ml (vacuum system). At the end of CPB, the levels
of hemoglobin in the vacuum system were significantly higher than those in the
siphon system. These results demonstrated that this vacuum drainage system can
provide simplification and a miniaturization of the cardiopulmonary bypass
circuit resulting in low hemodilution during CPB.
PMID- 9555968
TI - Platelet protective effect of TAK-029, a novel glycoprotein IIb/IIIa antagonist:
an in vitro study.
AB - Previous studies have indicated that exposure of fibrinogen receptors associated
with the glycoprotein IIb/IIIa complex contributes to platelet loss during
cardiopulmonary bypass. TAK-029 is a newly developed reversible, nonpeptide
inhibitor of platelet glycoprotein IIb/IIIa receptors. In this study, we tested
the platelet preserving effect of TAK-029 in an in vitro model. The methods
included the comparison of the release of beta-thromboglobulin (beta-TG) between
a TAK-029 group (n = 5) and a control group (n = 5) in a mock circulation under a
shear force generated by a centrifugal pump. To evaluate the degree of beta-TG
release, deltabeta-TG/deltaT was calculated where deltabeta-TG is the increase in
beta-TG and deltaT is the time. The results showed that the value of deltabeta
TG/deltaT in the TAK-029 group was significantly lower than it was in the control
group (4.22 +/- 0.27 x 10(2) ng/ml vs. 7.33 +/- 0.66 x 10(2) ng/ml,
respectively). In conclusion, TAK-029 reduced the platelet activation under the
shear forces of an in vitro model, suggesting that TAK-029 is a potential
candidate for platelet protection during cardiopulmonary bypass.
PMID- 9555969
TI - Rivastigmine, a brain-selective acetylcholinesterase inhibitor, ameliorates
cognitive and motor deficits induced by closed-head injury in the mouse.
AB - The effects of Rivastigmine, a novel centrally-acting anticholinesterase agent,
were evaluated on cerebral edema, neurological and motor deficits, and impairment
of spatial memory induced in mice by closed-head injury (CHI). Severe injury was
induced in the left hemisphere of mice under ether anesthesia. Rivastigmine (1 or
2 mg/kg) or saline (10 ml/kg) was injected SC 5 min later. Rivastigmine (2 mg/kg)
reduced cerebral edema by at least 50% (p < 0.01), 24 h after CHI and accelerated
the recovery of motor function 7 and 14 days after CHI. Control mice (n = 24),
previously trained to find the goal platform in a Morris water maze failed to
recall or relearn its position for at least 11 days post-injury. Those given a
single injection of Rivastigmine (2 mg/kg) regained their pre-test latencies by
the third day after CHI. The neuroprotective effects of Rivastigmine on brain
edema, neurological and motor function, and performance in the Morris water maze
were completely antagonized by simultaneous SC injection of either scopolamine
(0.5 mg/kg) or mecamylamine (2.5 mg/kg). The antagonists alone had no significant
effect on any of these parameters. These data show that the reduction by
Rivastigmine of the immediate and long-term sequelae of brain injury are mediated
by increased cholinergic activity at both muscarinic and nicotinic receptors.
PMID- 9555970
TI - Neurological recovery in diabetic rats following spinal cord injury.
AB - This study was designed to assess the effect of spinal cord injury on
neurobehavioral, electrophysiological, structural, and biochemical changes in
normal and diabetic rats. Experimental diabetes was induced in Sprague-Dawley
male rats (weighing 250-280 g) with streptozotocin (50 mg/kg i.p.). Eight weeks
after the treatment with streptozotocin the animals were anaesthetized with
chloral hydrate and laminectomy was performed at T 7-8 level leaving the dura
intact. A compression plate (2.2 x 5.0 mm) loaded with a weight of 35 g was
placed on the exposed spinal cord for 5 min. Postoperative neurological function
was assessed using inclined plane test, modified Tarlov score, and vocal and
sensory score daily for 10 days. Electrophysiological changes were assessed using
somatosensory and corticomotor evoked-potentials. The animals were sacrificed at
different time intervals and injured site of the spinal cord was analyzed for
changes in vitamin E and glutathione levels (as markers of oxidative stress).
Pathological changes in spinal cord were also studied using light microscopy. The
data on neurobehavioral study clearly indicated that the compression of spinal
cord produced highly significant neurological deficit and poor recovery in
diabetic rats as compared to nondiabetic rats. Our histopathological and
electrophysiological results also confirmed that diabetic animals are more
susceptible to compressive spinal cord injury as compared to nondiabetic animals.
A higher depletion of antioxidant defense markers (vitamin E and glutathione) was
observed in diabetic rats as compared to nondiabetic rats. These results point
toward the role of free radicals in poor recovery in diabetic rats following
neurotrauma. Further studies are warranted to assess the neuroprotective
potential of antioxidants to retard the secondary pathophysiological events
following neurotrauma and to enhance the recovery.
PMID- 9555971
TI - Clinical significance of CSF glutamate concentrations following severe traumatic
brain injury in humans.
AB - Glutamate excitotoxicity is a putative mechanism of secondary damage after
traumatic brain injury (TBI). No relationship between glutamate release and
clinical status has been shown in humans, however. We hypothesize a dose-response
relationship between CSF glutamate concentrations and severity of injury,
electrophysiological deterioration as measured by somatosensory evoked potential
amplitudes, and clinical outcome. From August 1991 to March 1996, intensive
monitoring of 55 patients with severe TBI (GCS < or = 8 after resuscitation)
included twice daily CSF glutamate levels and hourly somatosensory evoked
potentials (SSEPs) for an average of 5 days. Clinical outcomes were
survival/nonsurvival and Glasgow outcome score (GOS) at 3 months or more post
injury. Glutamate levels were not associated with severity of injury,
electrophysiological deterioration, or clinical outcome. Neither peak nor mean
glutamate levels significantly improved a simple logistic regression model which
used only age and presence of bilaterally unreactive pupils to predict survival.
Using this methodology CSF glutamate concentrations did not display a dose
response relationship to severity of injury, electrophysiological deterioration,
or predict clinical outcomes following TBI in a group of 55 patients. An early
effect of glutamate, an effect dependent on time of exposure to glutamate or
other modulating effects cannot be ruled out.
PMID- 9555972
TI - Comparison between continuous brain tissue pO2, pCO2, pH, and temperature and
simultaneous cerebrovenous measurement using a multisensor probe in a porcine
intracranial pressure model.
AB - Local brain tissue oxygenation (p(ti)O2) and global cerebrovenous hemoglobin
saturation (SjO2) are increasingly used to continuously monitor patients after
severe head injury (SHI). In patients, simultaneous local and global oxygen
measurements of these types have shown different results regarding the
comparability of the findings during changes in CPP and ICP. This is in contrast
to theoretical expectations. The aim of this study was to compare p(ti)O2
measurement with cerebrovenous oxygen partial pressure measurement (p(cv)O2) in
an animal intracranial pressure model. To this end, a multisensor probe was
placed in the left frontoparietal white matter to measure p(ti)O2, pCO2
(p(ti)CO2), pH (pH[ti]), and temperature (t[ti]) while simultaneously measuring
these same parameters (p(cv)O2, p(cv)CO2 pH(cv), t[cv]) in the sagittal sinus of
9 pigs under general anesthesia. By stepwise inflating a balloon catheter, placed
in supracerebellar infratentorial compartment, ICP was increased and CPP was
decreased. The baseline levels of p(ti)O2, p(ti)CO2, and pH(ti) in the noninjured
brain tissue showed more heterogeneity compared to the findings in cerebrovenous
blood. Both, p(ti)O2 and p(cv)O2 were significantly correlated to the induced CPP
decrease. PCO2 was inversely correlated to the course of CPP in both measurement
compartments. Temperature measurement showed a positive correlation with CPP in
both compartments. These findings demonstrate that brain tissue oximetry and
cerebrovenous PO2 measurement are sensitive to CPP changes. The newly available
continuous parameters in multisensor probes could be helpful in interpreting
findings of cerebral oxygen measurement in man by analyzing the interrelationship
of these parameters.
PMID- 9555973
TI - Spreading depression induces depletion of MAP2 in area CA3 of the hippocampus in
a rat unilateral carotid artery occlusion model.
AB - Traumatic brain injury (TBI) induces neuronal cell loss in area CA3 of the
hippocampus. However, it has not yet been established why traumatic injury of the
cortex induces neuronal damage in more remote areas. Spreading depression (SD)
may be one potential mechanism for this pathophysiology. The present study
evaluated whether SD on the cortex evokes a pathological change in the
hippocampus. Forty-two Fisher rats were assigned to four groups: Group I: sham
operation (n = 7), Group II: right carotid occlusion (UO) for 7 days (n = 7),
Group III: repeated induction of SD by KCl application on dura for 7 days (n =
7), Group III' for 3 h (n = 7), Group IV: SD induction and UO for 7 days (n = 14)
Group IV' for 3 h (n = 7). In 5 out of 7 animals in Groups III' and IV', cerebral
blood flow (CBF) was monitored using laser Doppler flowmetry for 3 h during the
passage of SD. The brains were processed for immunohistochemical analysis of
microtubule-associated protein 2 (MAP2). Reactive hyperemia induced by SD was not
significantly suppressed by right carotid occlusion (194 +/- 25% and 181 +/- 42%
UO in Groups III and IV, respectively). In 6 out of 7 animals in a 7-day model of
Group IV, and 3 animals in a 7-day model of Group III, MAP2 depletion in the CA3
area of the hippocampus (partly including CA2) was observed, although no change
in the hippocampus was observed in other groups. In conclusion, SD in combination
with UO yielded reproducible lesions in CA3. Neuronal injury in the hippocampus
after brain trauma may be attributable to SD in combination with the blood flow
restriction.
PMID- 9555974
TI - Changes of amino acid levels and aspartate distribution in the cervical spinal
cord after traumatic spinal cord injury.
AB - To evaluate the role of excitatory amino acids in secondary injury occurring
after spinal cord trauma, several experimental studies focusing on the the
changes of amino acid levels in the spinal cord have been performed to date.
However, because of technical limitations, it has not been possible to correlate
the local changes of excitatory amino acids with the total tissue levels of
excitatory amino acids. To investigate the connection between the spread of
injury and the excitatory amino acids, we assessed, the local changes of
aspartate through novel experimental approaches like immunoreactivity via
fluorescence microphotometry and histopathology while also analyzing the total
tissue levels of amino acids via HPLC. These studies were performed using a model
of incomplete cervical spinal cord injury in rats. Through this approach, we
found that the levels of excitatory amino acids, such as glutamate and aspartate,
began to decrease immediately after injury. No significant decrease was observed
in the other amino acids. Similarly, local changes in aspartate in the spinal
cord were observed using fluorescence microphotometry. The decrease in the
anterior and posterior horns was rapid up to 15 min after injury, but, slowed
thereafter, suggesting that a release of excitatory amino acids occurred at the
site of primary injury almost immediately following injury. At 15-min post-injury
large neurons within the injured cord appeared intact on histopathological
analysis demonstrating that the alteration of excitatory amino acids occurs prior
to histopathological change. Histopathological change in the white matter
occurred more slowly than in the anterior and posterior horns, suggesting the
spread of the lesion by secondary damage due to an autoclastic mechanism.
PMID- 9555975
TI - The role of IL-10 in iNOS and cytokine mRNA expression during in vitro
differentiation of bovine mononuclear phagocytes.
AB - In the study reported here, we used RT-PCR with primers specific for interleukin
1 (IL-1), IL-6, IL-10, tumor necrosis factor-alpha (TNF-alpha), and nitric oxide
synthase (iNOS) to assess the cytokine mRNA expression associated with bovine
blood monocytes during their differentiation to macrophages cultured on plastic
(1 week). In addition, we used RT-PCR to assess the contribution of gammadelta T
cells as a source of interferon-gamma (IFN-gamma), the induction signal for iNOS.
Further, we evaluated cytocentrifuge preparations from the cultures for the
production of IL-10 using specific antibody. We previously demonstrated that iNOS
can be induced in cultured bovine monocytes in response to IFN-gamma and TNF
alpha but lose this capability in a short period of time. However, we demonstrate
here that iNOS induction from monocytes cultured with IFN-gamma secreting
gammadelta T cells is prolonged, suggesting that this source of IFN-gamma primes
the monocytes before exogenous stimulation. Based on mRNA expression, placement
of monocytes in culture resulted in activation, followed by quiescence. By 6 days
in culture, the iNOS message was reduced below the basal level. In addition, the
TNF-alpha message was substantially reduced, and IL-1 and IL-6 messages were
reduced below detectable levels. This correlated with an increase in IL-10
message. Downregulation of these same cytokine messages as well as IFN-gamma
message occurred within a 20-h period when IL-10 was added exogenously to
cultures of total leukocytes. At the same time, there was an increase in the
number of IL-10-positive cells and an increase in the intensity of anti-IL-10
staining within adherent cells. These results provide evidence for IL-10
regulation of some bovine mononuclear phagocyte effector functions.
PMID- 9555976
TI - Immunization with HSV-1 antigen rapidly protects against HSV-1-induced
encephalitis and is IFN-gamma independent.
AB - Herpes simplex virus type 1 (HSV-1) infection of mice frequently culminates in
fatal encephalitis. Intraperitoneal administration of heat-inactivated HSV-1 0-5
days before infection (active immunization) protected mice from encephalitis. In
addition, active immunization 2-5 days before ocular infection with HSV-1 reduced
the frequency of establishment of latent HSV-1 infection in the trigeminal
ganglion (TG). However, intraperitoneal administration of heat-inactivated HSV-1
did not induce interferon (IFN) production in the peritoneum or serum, as
determined by bioassay and ELISA. Intraperitoneal administration of heat
attenuated HSV-1 elicited IFN-gamma but not type I IFN production in the
peritoneum. The production of IFN-gamma correlated with the infiltration of CD4
and CD8 cells in the peritoneum as determined by RT-PCR. In addition, there was a
significant increase in interleukin (IL)-12 p40, IL-12p35, IL-6, IL-10, and IFN
gamma mRNA in peritoneal cells, as determined by RT-PCR following immunization
with heat-attenuated HSV-1, which was not observed using heat-inactivated HSV-1.
The results suggest that resistance to HSV-1 is induced rapidly following
immunization with viral antigen but that protection against encephalitis is
independent of the cytokines that are generated in the peritoneum.
PMID- 9555978
TI - Endothelial cell contact potentiates release of soluble tumor necrosis factor
(TNF) receptors from the monocyte-like cell line THP-1.
AB - The two tumor necrosis factor (TNF) receptors can undergo proteolytic cleavage to
form soluble receptors, TNF-R55-BP and TNF-R75-BP, that can neutralize TNF. The
aim was to study the release of soluble TNF receptor forms during monocyte
endothelial cell interaction. Monocytic THP-1 cells were used, and their release
of TNF-R75-BP was determined. Contact between THP-1 cells and confluent
endothelial cells induced fourfold higher release of TNF-R75-BP from the THP-1
cells than with these cells in suspension. The release was further increased up
to eightfold after prestimulation of the endothelial cells with interleukin-1beta
(IL-1beta). Prestimulation for 10 min gave maximal release of TNF-R75-BP from the
attached THP-1 cells. IL-1beta by itself did not induce shedding of soluble TNF
receptors in THP-1 cells. Blocking antibodies against the endothelial cell
adhesion molecules VCAM, ICAM, and E-selectin did not affect the release of TNF
R75-BP from THP-1 cells attached to the endothelium. Conditioned medium from IL
1beta-stimulated endothelial cells increased the production of TNF-R75-BP from
THP-1 cells in suspension. However, surface contact between endothelial cells and
THP-1 cells was necessary for maximal production of TNF-R75-BP. TNF-alpha
released from endothelial cells on IL-1beta stimulation did not promote shedding
of TNF-R75 from THP-1 cells. Thus, endothelial cell contact potentiates the
production of TNF-R75-BP in a monocyte-like cell line. The shedding of soluble
TNF receptors observed in this case seems to be a result of both cell attachment
and soluble factors.
PMID- 9555977
TI - The comparative anti-herpes simplex virus effects of human interferons.
AB - The mechanism(s) of anti-herpes simplex virus (HSV) activity of interferons
(IFNs) have not been clearly identified. We have tested natural and recombinant
human IFN-alpha, IFN-beta, and IFN-gamma preparations for their relative anti-HSV
activity in human corneal and Vero monkey kidney cells. The relative anti-HSV
activities in corneal cells were IFN-beta > rIFN-gamma > IFN-alpha
(lymphoblastoid) > rIFN-beta2a = rIFN-alphaA/D. IFN-beta at 100 IU/ml reduced
virus yield by 59+/-24%. The relative anti-HSV activity in Vero cells was rIFN
gamma > IFN-beta = IFN-alpha (lymphoblastoid) > rIFN-alphaA/D > rIFN-alpha2a. IFN
gamma at 100 IU/ml reduced virus yields by 90+/-4%. Reducing the multiplicity of
infection significantly increased the apparent antiviral activity of all IFNs.
The antiviral activity of IFNs could be detected by 4 h after treatment of Vero
cells but not until 8 h in corneal cells. Western blot analysis showed that none
of the IFNs detectably reduced the levels of immediate-early HSV protein, ICP4,
but some reduced ICP0 levels early during infection, the extent and duration of
the reduction varying with both IFN and cell type. The greatest effects on viral
protein levels were detected in IFN-y-treated Vero cells. These data indicated
that the targets of the anti-HSV activities of IFNs can vary with both IFN and
cell type.
PMID- 9555979
TI - Pretreatment with IFN-gamma decreases infectious complications after partial
hepatectomy in the rat.
AB - Infectious postoperative complications occur commonly after hepatectomy and may
lead to a long hospital stay or death. The potential beneficial effects of
interferon-gamma (IFN-gamma) in this setting were evaluated in a model of
hepatectomy and sepsis in rodents. Incidence of bacterial translocation was
measured in animals on days 1, 2, and 5 after partial hepatectomy. Macrophage
function was quantified by in vitro tumoricidal activity and superoxide anion (O2
) production. Survival after partial hepatectomy and cecal ligation and puncture
(CLP) was recorded. After partial hepatectomy, bacterial translocation was
decreased on days 1 and 2 in animals pretreated with IFN-gamma (p < 0.05).
Macrophages from animals treated with IFN-gamma had higher in vitro tumoricidal
activity and production of O2- (p < 0.05). Hepatectomized animals pretreated with
IFN-gamma had an increased survival after CLP (p < 0.05). IFN-gamma may be useful
in decreasing the incidence of infectious complications after partial
hepatectomy.
PMID- 9555980
TI - Production of immunoreactive 2',5'-oligoadenylate synthetase in p48-deficient
mice.
AB - 2',5'-Oligoadenylate synthetase (2'5'OAS), an enzyme induced by interferon (IFN),
is physiologically produced in IFN-untreated normal healthy mice. The enzyme is
localized mainly in the epithelium of the digestive tract, reproductive organs,
and the choroid plexus in the brain. 2'5'OAS is also detected in oocytes in the
ovary and in neurons and glial cells of both the telencephalon and cerebellum.
Here, we examined the role of p48 (ISGF3gamma), a component of IFN-stimulated
gene factor 3 (ISGF3), in the physiologic production of 2'5'OAS using p48
deficient mice generated by gene targeting. In the p48-deficient mice, the
physiologic production of 2'5'OAS localized in the following cells was severely
impaired: hepatocytes, Kupffer cells, splenocytes, epithelium of the large
intestine, oviduct, and uterus, and neurons and glial cells in both the
telencephalon and cerebellum. The results show that 2'5'OAS in these cells is
induced physiologically through a pathway including p48. However, the production
of 2'5'OAS in oocytes was not affected in the p48-deficient mice, indicating that
oocyte 2'5'OAS is produced through a p48-independent pathway. A possible function
of the GAS sequence found in the promoter region of the 2'5'OAS gene to which
Stat6 may bind also is discussed.
PMID- 9555981
TI - Interferon-induced expression of If-1h and If-1l alleles in Newcastle disease
virus-infected mouse macrophages is associated with specific differences in viral
gene transcription.
AB - We have studied the expression of cytokines and viral genes induced by Newcastle
disease virus (NDV) and Sendai virus in bone marrow-derived macrophages (BMM) and
lymphocytes from C57BL/6 mice and the congenic line B6.C-H-28c. These mice carry
the loci If-1h (high) or If-1l (low), respectively, that are responsible for up
to tenfold differences in the interferon (IFN)-alpha, IFN-beta, interleukin-6 (IL
6), and tumor necrosis factor-alpha (TNF-alpha) response to NDV but not to Sendai
virus. Only BMM but not spleen lymphocytes showed allele-specific differences in
NDV-induced cytokine levels, indicating cell-specific If-1 expression. The If-1
locus harbors IFN-inducible gene(s) whose expression is prevented in the presence
of cycloheximide. Our data provide evidence that the If-1l allele acts by
specifically suppressing the cytokine response to NDV. Cytokine production was
dependent on infectious virions, and kinetic analyses revealed a close
correlation between the amount of viral transcripts and individual cytokine mRNA.
BMM from lf-1l mice strongly restricted transcription of the NDV nucleoprotein
(NP) gene, whereas BMM from If-1h mice supported NP transcription. Following
treatment with IL-4, which inhibited constitutive IFN-beta gene expression,
however, If-1l BMM became highly permissive for transcription of the viral NP
gene and released high amounts of cytokines. We conclude that If-1l gene products
are responsible for the low producer phenotype by efficiently interfering with
NDV transcription, leading to strongly reduced intracellular levels of cytokine
inducing viral dsRNA intermediates.
PMID- 9555982
TI - IFN-gamma induces calcium transients and increases the capacitative calcium entry
in human neutrophils.
AB - We have previously reported that long-term priming of human polymorphonuclear
neutrophilic granulocytes (PMN) with interferon-gamma (IFN-gamma) increased the
fMLP-stimulated calcium influx. We now show that also after short-term incubation
with IFN-gamma, PMN calcium metabolism is modulated. Single adherent cells in
three different calcium-containing buffers (high, normal, and low [Ca2+]) were
stimulated with the bacterial peptide fMLP or the Ca-ATPase inhibitor
thapsigargin (Tg) after about 5 min preincubation with IFN-gamma. The results of
this protocol indicated that IFN-gamma increases both calcium influx and calcium
sequestration. Store dependent Ca2+ influx, directly measured on readdition of
calcium to Tg-treated cells incubated in EGTA buffer, was significantly enhanced
in IFN-gamma-treated cells. This effect of IFN-gamma was enhanced by the tyrosine
kinase inhibitor herbimycin A. Strikingly, in low extracellular calcium
concentrations, IFN-gamma induced calcium transients in 20%-60% of the cells. The
proportion of PMN responding with Ca2+ transients increased with decreasing
extracellular calcium concentration. Average lagtime from addition of IFN-gamma
to a response that could be measured was 7.3 sec, and average increase in [Ca2+]
above the basal level was 790 nM. These IFN-gamma-induced transients could not be
depressed by herbimycin A. Thus, IFN-gamma can increase capacitative calcium
influx, induce calcium transients, and possibly affect calcium sequestration in
human PMN.
PMID- 9555983
TI - Dynamic cleft maxillary orthopedics and periosteoplasty: benefit or detriment?
AB - In 1990, Drs Millard and Latham published their initial experience with dynamic
maxillary appliances (DMAs) and periosteoplasty for children with cleft lip and
palate. The technique provided for alveolar alignment and consolidation, with
elimination of oronasal fistulas. Opponents to this approach speculated about
impairments to facial growth. To date no longitudinal studies have been
published. Over the last 10 years, 35 unilateral and 10 bilateral complete clefts
have been treated with this technique. All patients have been followed and
documented clinically, orthodontically, and radiographically. Cephalometric
analyses were performed on children after the age of 6 years. The children have
excellent facial aesthetics with well-balanced lips and noses. Radiographs
demonstrate bone within the repaired alveolar clefts. Articulated impressions
show anterior and lateral crossbites in the unilateral patients that improve over
time and appear to be correctable orthodontically. The bilateral patients have
satisfactory occlusions and arch forms. Cephalometric analyses confirmed no
evidence of skeletal crossbites or midfacial growth retardation. This is a work
in progress that will continue as the children grow. Although definite and final
conclusions would be premature, it can be stated that to date all patients are
following consistent and favorable growth patterns. Our team is confident in
proceeding with this technique.
PMID- 9555984
TI - Erbium:YAG laser skin resurfacing: preliminary clinical evaluation.
AB - Each of the increasing number of resurfacing lasers uses a unique strategy to
produce tissue ablation. Erbium:YAG (Er:YAG) lasers have been used in other
applications for precise tissue removal with little thermal effect. Recovery
time, duration of erythema, and clinical improvement were evaluated using an
Er:YAG resurfacing laser (2.94-microm wavelength, 350-microsec pulse, 2 J, 3-5-mm
spot). Twenty-five patients were treated with two passes to the full face and 3
to 5 passes to the most affected aesthetic unit. At each follow-up visit, percent
epithelialization, erythema, and swelling were graded, and the presence or
absence of complications was noted. Clinical improvement was evaluated at 6
months by optical profilometry on a subset of patients. Er:YAG resurfacing
produced a transient whitening of dermis followed by a resumption of pink
appearance. The surgical end point was judged by elimination of visible rhytids
or presence of punctate bleeding. Bleeding from the dermal surface was
encountered less than customarily in dermabrasion, but more than seen with carbon
dioxide laser resurfacing. A moderate amount of tissue shrinkage was observable
during the treatment. Mean period to full epithelialization was 6.9+/-0.97 days
(range, 5-9 days). The mean duration of erythema (4.24+/-1.5 weeks) was
relatively short compared with carbon dioxide resurfacing. Clinical improvement
was 44+/-30% in the lateral canthal area and 55+/-22% in the upper lip area.
There were no infections or hypertrophic scars. Hyperpigmentation and
hypopigmentation was seen in 24% and 12% of patients respectively. Er:YAG
resurfacing is a reliable means of obtaining rhytid improvement with less
recovery time and duration of erythema compared with carbon dioxide resurfacing.
The technique is significantly different from carbon dioxide resurfacing in
selection of end point, number of passes, and energy settings.
PMID- 9555985
TI - A balloon-assisted facialplasty technique.
AB - An ongoing goal of aesthetic surgery is a reduction in complications and an
improvement in reproducibility and speed. Balloon dissector devices have been
used in other areas of surgery to achieve these goals. This report presents early
clinical experience using a balloon dissector to elevate the skin flap in
facialplasty. The first step in the technique is the creation of a tunnel from a
small preauricular incision toward the oral commissure using scissors dissection.
The balloon device is inserted into this tunnel and inflated. Unrolling the
device elevates the skin flap in the cheek and neck area. Retroauricular
dissection and final adjustment of flap size and shape is completed sharply.
Subsequent superficial musculoaponeurotic system flap development, skin
redraping, and closure is performed in a conventional fashion after customary
facialplasty incisions are made. Comparison of complications, postoperative
drainage, and time required for dissection and for hemostasis was made between a
balloon-dissected side and a conventionally dissected side in 10 patients
undergoing facialplasty. Ten additional patients were treated with balloon
dissection bilaterally. Patients ranged in age from 45 to 73 years. Mean balloon
dissection time was 1.4 minutes (range, 0.75-4 minutes). This produced an even
flap thickness in the correct plane with few if any bleeding points. Mean total
dissection time on the balloon side was significantly shorter-13.6 minutes
compared with 27.8 minutes (p < 0.003) on the conventional side. Mean difference
in time to hemostasis between conventional and balloon sides was 3.8 minutes (p <
0.001). Mean total postoperative drainage (all drains removed at 24 hours) was
13.8 cc on the balloon side and 18.8 cc on the conventional side (not
significant, p=0.08). Less ecchymosis and swelling was observed on the balloon
side compared with the scissors-dissected side. There were no skin losses,
hematomas, infections, or nerve injuries on either side. Appearance of skin
redraping was comparable on each side in all patients. Balloon dissection
represents a promising alternative means of creating rapid, reproducible skin
flap elevation in facialplasty, and is associated with a minimum of bleeding,
ecchymosis, and swelling.
PMID- 9555986
TI - Secondary use of the rectus muscle pedicle for TRAM flap volume deficiencies.
AB - The residual subxiphoid rectus muscle pedicle was rotated secondarily to a
position underneath the breast mound in 13 patients who had previously undergone
transverse rectus abdominis musculocutaneous (TRAM) flap breast reconstruction.
The indications for this maneuver were the presence of a subxiphoid muscle bulge
and a deficiency of volume or projection of the TRAM flap breast mound. This
revisional surgery was performed at least 8 weeks after the TRAM flap, typically
at the time of nipple-areolar reconstruction. Minor to moderate volume
deficiencies were corrected and aesthetic improvement was substantial. There were
no major complications. The danger of vascular compromise to the breast mound
itself or to the remobilized muscle appears to be minimal, although the need for
caution in the previously irradiated chest wall should be emphasized.
PMID- 9555987
TI - Preferential use of the ipsilateral pedicle in TRAM flap breast reconstruction.
AB - Breast reconstruction utilizing the ipsilateral transverse rectus abdominis
musculocutaneous (TRAM) flap provides superior results when compared with
contralaterally based reconstructions by preserving the medial inframammary fold
and eliminating the perixiphoid bulge. Additionally, a longer pedicle can be
obtained using the ipsilateral TRAM, thereby allowing greater mobility and
flexibility during flap transposition. These findings are based on a
retrospective review of 50 consecutive ipsilateral TRAM flap reconstructions in
38 patients. The mean patient age was 45.4 years and mean follow-up was 8.6
months. Thirty-two flaps were performed as immediate reconstructions and 18 flaps
were delayed. No patient suffered total flap loss, whereas partial flap loss was
observed in three flaps. One patient required suture removal to alleviate venous
congestion of the flap. No patient developed a postoperative hernia, but 1
patient required removal of a polytetrafluoroethylene onlay patch following graft
exposure. This technique achieves aesthetically pleasing results with acceptable
morbidity, allows greater flap mobility without disruption of the medial
inframammary fold or creation of a perixiphoid bulge, and is our method of choice
for TRAM flap breast reconstruction.
PMID- 9555988
TI - Modifications of the Lejour vertical mammaplasty: analysis of results in 100
consecutive patients.
AB - The technique of vertical mammaplasty described by Madeline LeJour nearly ten
years ago has been slow to gain wide acceptance in the United States. This is
perhaps due to the misconception by many that this technique is more technically
demanding or harder to reproduce and teach on a consistent basis. This paper
describes several modifications to Madam LeJour's procedure, including the use of
a template, a controlled excision, and a tension free nipple areola complex
closure. When applied routinely, these modifications to the LeJour mammaplasty
have produced predictable, reliable and extremely satisfying results.
PMID- 9555989
TI - Breast reconstruction in previously irradiated patients using tissue expanders
and implants: a potentially unfavorable result.
AB - There exists a paucity of definitive information on the suitability of implant
reconstructions in previously irradiated breast cancer patients. This
controversial topic prompted a review of our prosthetic reconstructions in this
select group of patients. A retrospective study of patients treated between 1976
and 1993 with lumpectomy and radiation therapy for early breast cancer revealed
67 patients with local recurrences. Nine of these patients (10 breasts) underwent
a two-stage prosthetic reconstruction following a salvage mastectomy. The average
age was 47.9 years. The mean dose of irradiation was 6,070 cGy. The average
interval from radiation therapy to placement of a tissue expander was 4.6 years.
In one patient (10%) the tissue expander extruded. The average follow-up for 8
patients (9 breasts) who underwent exchange to a permanent prosthesis was 5.1
years. In four reconstructions (40%) there was an uneventful postoperative
course. Two cases (20%) were difficult to expand and the final result lacked
projection. One patient (10%) developed an infection requiring removal of the
permanent prosthesis. Two patients (20%) developed Baker class III or IV capsular
contractures. Overall, in our group of 10 implant reconstructions, 60% of the
patients resulted in either a complication or an unfavorable result.
PMID- 9555990
TI - Split-twist FCR reconstruction for basal joint arthritis.
PMID- 9555991
TI - Venous gangrene of the upper extremity.
AB - Venous gangrene of the upper extremity is a rare entity and is the result of
massive occlusion of all venous outflow of the extremity. The syndrome is
strongly associated with hypercoagulable states including malignancy, low cardiac
output states, and hereditary or acquired hematological abnormalities. Diagnosis
can be straightforward but must be made early in the course of the process for
treatment to be effective. Treatment has historically produced only modest
results, and patients continue to suffer a high morbidity and mortality. We
present a series of 6 patients with venous gangrene or impending venous gangrene
of the upper extremities--a relatively large series. Two patients suffered from
malignancy, 3 patients suffered from low-flow cardiac states, and 1 patient
suffered from an overdose of calcium channel blockers. Hematological
abnormalities included heparin-induced thrombocytopenia and thrombosis in 3
patients, activated protein C resistance in 1 patient, and lupus anticoagulant in
1 patient. Three patients experienced other major venous thrombotic
complications, two of whom died (renal and cerebral venous infarction). Venous
gangrene of the upper extremity remains a rare occurrence but one in which early
identification and intervention may lead to improved outcomes.
PMID- 9555992
TI - Use of a multiplanar distracter for the correction of a proximal interphalangeal
joint contracture.
AB - Proximal interphalangeal (PIP) joint contractures are common complications in
hand injuries and conditions such as Dupuytren's contracture. Conventional
treatment such as splinting and serial casting may result in inadequate
improvement. Operative release of the contracture may be complicated by
neurovascular overstretch with injury to the digital nerves or vascular
compromise. Gradual distraction of the contracted joint may prevent this
neurovascular injury. The multiplanar distracter was designed for three
dimensional distraction of the mandible. Distraction may be obtained in the X, Y,
or Z planes. With this device, the angular relationship between two planes may be
altered. A 22-year-old male with a PIP joint contraction following replantation
failed conventional treatment for release. With the use of a multiplanar
distracter, the flexion contraction was reduced from 95 degrees to a more
functional 30 degrees using gradual angular distraction. The angle between the
proximal and middle phalanges were gradually changed using the ability of the
distracter to change the angular relationship in the X-Y plane. At 3 and 6 months
postdistraction, the patient has maintained his 30-degree flexion angle. The
multiplanar distracter is a simple technique that may be useful for the treatment
of PIP joint contractures that fail conventional therapy.
PMID- 9555994
TI - The total volar forearm musculocutaneous free flap for reconstruction of extended
forequarter amputations.
AB - Forequarter amputation is performed for resection of large, invasive tumors of
the shoulder girdle region. A substantial defect can usually be closed with local
or regional flaps; however, a subset of the forequarter amputation group has
emerged at this institution with more complex issues. These patients have
extensively more invasive posterior tumors, some with chest wall/rib invasion.
Local/regional flaps in these situations are inadequate, and free tissue transfer
is the only viable option. The forequarter specimen can sometimes be used as a
donor site, thereby eliminating the usual donor site morbidity. Variations of the
total forearm free flap have been sparsely described in the literature--the
majority being case reports of either pure fasciocutaneous or "filet of forearm"
flaps. We report a series of 4 patients treated over a 5 year period at this
institution using the previously undescribed total volar forearm musculocutaneous
free flap based on the brachial artery and its venae comitantes. This flap
includes the entire musculature of the volar forearm with fasciocutaneous
extensions on either side of the musculocutaneous unit. All potentially ischemic
dorsal musculature is discarded, leaving a flap that has central bulk and a
relatively large dimension. The entire flap remains extremely well vascularized,
and a substantial surface area of as much as 45 x 25 cm can be attained. A
pedicle as long as 20 cm can be dissected as far proximally in the arm as is
oncologically safe. A single artery and vein are anastomosed to either the
intrathoracic or neck vessels. All four flaps survived completely with
uncomplicated wound healing. The total volar forearm musculocutaneous flap is
extremely well vascularized and highly reliable. The flap as described provides
the ideal combination of large surface area, muscle bulk, and long vascular
pedicle. It can be dissected rapidly to minimize ischemic time and could
therefore be applicable to traumatic forequarter amputations. It has become the
flap of choice for reconstruction of extended oncological forequarter amputation
defects.
PMID- 9555993
TI - Soft-tissue complications of intra-arterial chemotherapy for extremity sarcomas.
AB - High-grade sarcomas have a high rate of local recurrence as well as distant
metastases. This has led to the development of intra-arterial chemotherapy (IAC)
as part of a multimodal approach to control local disease and/or reduce the
extent of surgical resection. Intra-arterial catheters are positioned by an
interventional radiologist into the feeding vessels of the tumor. Adriamycin and
5-fluorodeoxyuridine are infused intra-arterially. Cisplatinum, with or without
granulocyte colony stimulating factor, is given systemically. Patients usually
experience acute self-limited soft-tissue inflammation in the treated area. In
our experience of 118 patients, 3 patients experienced soft-tissue necrosis that
required excision and reconstruction. The first was treated for synovial sarcoma
of a metatarsal. After IAC with Adriamycin, she sloughed the skin, subcutaneous
tissue, and some of the posterior compartment musculature of her calf. This
tissue was debrided. A gastrocnemius flap and skin graft were used for coverage.
She is free of disease and ambulatory. The second patient was treated with IAC
Adriamycin for a radial head chondrosarcoma. She developed soft-tissue slough,
which became infected with Pseudomonas. She required extensive debridement of the
skin, subcutaneous tissue, and muscle, and was subsequently reconstructed with a
latissimus flap and a split-thickness skin graft (STSG). She later developed a
local recurrence requiring amputation. The latissimus was elevated and used to
cover the distal stump. She also is free of disease. The third patient was
treated with IAC Adriamycin for Ewing's sarcoma of the right femur. This was
complicated by fat necrosis and persistent pain. Subsequent radiotherapy only
worsened her symptoms. She underwent wide excision and muscle flap/STSG repair,
which relieved her pain. She is currently ambulatory and free of disease. In
conclusion, as the use of IAC continues, its complications may become more
common. Our experience with this previously unknown entity is illustrated and
therapeutic options are discussed.
PMID- 9555995
TI - The radial forearm osteocutaneous "sandwich" free flap for reconstruction of the
bilateral subtotal maxillectomy defect.
AB - Complex resections of the maxilla produce a three-dimensional defect that can be
difficult to reconstruct using autogenous tissue without utilizing a free tissue
transfer. The osteocutaneous flaps that have been described for reconstruction of
this area have been the scapula, iliac crest, and fibula, which are often
hampered by their bulkiness and less than ideal intraoral lining. The bilateral
subtotal maxillectomy defect is particularly difficult to reconstruct because it
requires restoration of the bony framework of the midface as well as the
restoration of the palatal and nasal lining. We present a new technique for
reconstruction of this type of defect using the osteocutaneous radial forearm
free flap. Two patients with bilateral subtotal maxillectomy defects, in whom the
entire hard palate and maxillary arch were resected, underwent primary
reconstruction. The bone from the osteocutaneous flap was osteotomized and
contoured to recreate the maxillary arch. The large skin island was folded around
the bone, as in a sandwich, and used to replace the palatal and nasal lining.
This sandwiched osteocutaneous flap allowed for secure fitting of a dental
prosthesis and the future possibility of osteointegrated implants. Long-term
stability of the bone without retrusion was achieved with an excellent functional
and aesthetic outcome. The radial forearm osteocutaneous free flap is ideal for
the reconstruction of the maxillary infrastructure in that (1) it provides bone
and thin, pliable skin in the correct proportions; (2) the described "sandwich"
technique restores an excellent functional and aesthetic state; and (3) dental
rehabilitation can be further improved by using either a prosthesis or
osteointegrated implants.
PMID- 9555996
TI - Body image concerns of reconstructive surgery patients: an underrecognized
problem.
AB - This study assessed the body image concerns of reconstructive plastic surgery
patients. Forty-three reconstructive surgery patients completed two measures of
body image. Responses were compared with a group of patients seeking cosmetic
procedures. The two groups did not differ in the degree of dissatisfaction with
their overall appearance or dissatisfaction with the specific feature for which
they were seeking surgery. Reconstructive patients did consider themselves less
healthy and less invested in their appearance than did cosmetic patients. Seven
of the reconstructive surgery patients (all scar revision patients) reported a
level of dissatisfaction and preoccupation consistent with the psychiatric
diagnostic of body dysmorphic disorder. These results underscore the importance
of screening for body image dissatisfaction in persons with an objective
deformity. Plastic surgeons are in an optimal position to identify body image
concerns in these patients and provide appropriate referrals for psychotherapy.
PMID- 9555997
TI - Free radial artery grafts: surgical technique and results.
AB - In the search for alternative conduits, the use of radial artery (RA) grafts has
found renewed interest. This study sought to evaluate prospectively the
perioperative morbidity, including the postoperative complications in the donor
forearm, and mortality in the routine use of RA grafts in coronary artery bypass
surgery. Data were obtained prospectively on 200 consecutive patients who
underwent coronary revascularization using at least one RA graft from January
1995 to April 1997. The mean age of the patents was 61.9+/-10.5 years (mean+/
standard deviation [SD]). The RA was obtained from one forearm in 197 patients
and both forearms in 3 patients. Two patients (1%) required exploration for donor
site hematomas, 4 patients (2%) had temporary perioperative dysesthesias in the
region of the lateral cutaneous nerve of the forearm, and none had donor site
wound infection. Two patients (1%) had a myocardial infarction with
electrocardiographic changes in the areas grafted by the RA in the immediate
postoperative period, indicating graft failure. The two deaths in the series were
due to comorbid factors. Our data suggest that the RA is a safe and suitable
conduit for coronary revascularization, and it provides good clinical results.
Long-term follow-up of these patients is necessary to confirm the patency of RA
conduits. Free RA grafts have the potential for use in other areas of surgery
where a conduit is necessary for revascularization procedures.
PMID- 9555998
TI - In vitro prefabrication of human cartilage shapes using fibrin glue and human
chondrocytes.
AB - We report the first generation of human cartilage from fibrin glue using a
technique of molding chondrocytes in fibrin glue developed in our laboratory.
Human costal chondrocytes were suspended in cryoprecipitate and polymerized into
a human nasal shape with bovine thrombin. After culture in vitro for 4 weeks,
this construct was implanted subcutaneously into a nude mouse. The final
construct harvested after 4 weeks in vivo demonstrated some preservation of its
original features. Histological analysis showed features of native cartilage,
including matrix synthesis and viable chondrocytes by nuclear staining.
Biochemical analysis demonstrated active matrix production. Biomechanical testing
was performed. To our knowledge this is the first reported creation of human
cartilage from fibrin glue, and the first creation of human cartilage in vitro.
This technique may become a promising means of engineering precisely designed
autogenous cartilage for human reconstruction.
PMID- 9555999
TI - Comparison of the effects of ischemic preconditioning and surgical delay on
pedicled musculocutaneous flap survival in a rat model.
AB - Both surgical delay (SD) and ischemic preconditioning (IP) have been shown to be
effective in improving the survival of pedicled musculocutaneous flaps. The goal
of our study was to determine the effects of IP and SD, separately and together,
on the survival of pedicled transverse rectus abdominis musculocutaneous (TRAM)
flaps in a rat model. Thirty-two male Sprague-Dawley rats were divided into four
groups of 8 rats each: (1) control, (2) 2-week SD, (3) IP, and (4) SD plus IP. A
TRAM flap was elevated in each rat. Flap viability was assessed on the fifth
postoperative day by computerized video planimetry. Mean area of flap survival
was compared between the control, IP, SD, and SD plus IP groups using analysis of
variance and Student's t-test. Improvement in surface area survival was seen in
musculocutaneous flaps subjected to IP, SD, and SD plus IP compared with the
control. IP and SD improved survival 1.3 and 1.4 times the control area
respectively. Differences between treatment and control flaps were statistically
significant (p < 0.04). In addition, the combination of SD plus IP improved
survival by 1.8 times, which is statistically different from controls and from
either technique individually (p < 0.002). IP and SD have similar efficacy in
improving survival in this musculocutaneous flap model. The effects of IP and SD
appear to be additive. The advantage of IP over SD is that IP can be performed
during the same operative session as the flap elevation and only adds 1 hour to
the surgical procedure.
PMID- 9556000
TI - Ischemic preconditioning of musculocutaneous flaps: effects of ischemia cycle
length and number of cycles.
AB - Previous work in our laboratory has indicated that ischemic preconditioning
improves musculocutaneous flap survival 2.5 times that of the control flap area
when the flaps are subsequently subjected to 4 hours of global ischemia. The
preconditioning protocol used in this study was arbitrarily designed to be 10
minutes of pedicle clamping followed by 10 minutes of reperfusion. This sequence
was repeated for three cycles with a total preconditioning time of 1 hour. There
are no published works comparing different preconditioning protocols in
musculocutaneous flaps. The goal of this study was to determine if the ischemic
cycle time and the number of cycles influenced the effectiveness of ischemic
preconditioning. Fifty-one male Sprague-Dawley rats were divided into one control
and six treatment groups of 6 to 10 animals in each group. A transverse rectus
abdominis musculocutaneous flap based on the inferior epigastric vessels was
elevated in each animal. Flaps were preconditioned by pedicle clamping and
reperfusion for either 5 or 10 minutes per cycle. This was repeated for one, two,
or three cycles. Controls were simply perfused for 30 minutes. Each flap was then
subjected to 4 hours of global ischemia. Flap surface survival area was
calculated on the fifth postoperative day by computerized video planimetry.
Differences in survival areas between control and preconditioned flaps were
compared using analysis of variance and t-tests. There was an overall statistical
significance in the comparison of flap survival of preconditioned flaps with that
of controls. A single 5-minute cycle improved flap survival 2.5 times the mean
control area. Two and three 5-minute cycles resulted in a reduction of the
preconditioning effect, with flap survival no different than controls. Ten-minute
preconditioning cycles increased flap survival 1.5 to 3 times the mean control
area. Flap survival was improved by increasing the number of 10-minute cycles.
Cycle time and number of cycles have definite effects on the survival areas of
preconditioned musculocutaneous flaps. Ischemic preconditioning with 10-minute
cycles is superior to 5-minute cycles. Three cycles of 10-minute preconditioning
is statistically superior to one or two cycles. Future studies are planned to
study four or more cycles and longer cycle times.
PMID- 9556001
TI - The effect of prolonged clamping and vascular stasis on the patency of arterial
and venous microanastomoses.
AB - During free tissue transfer, an artery and one or two veins must be sutured.
Either the artery or the vein can be repaired first, but the optimal order of
vascular repair has not been established. Maintaining a clamp on a vessel is
associated with vessel injury, and releasing the clamp may cause bleeding and
vascular stasis. The purpose of this study was to determine if the order of
vessel repair and the length of vascular clamping affects surgical outcome. Free
flaps were created on Sprague-Dawley rats (400-450 g) as follows: Bilateral
abdominal skin flaps (3 x 3 cm) based on the superficial inferior epigastric
vessels were elevated. The femoral artery and vein were tied and divided distal
to the branching of the inferior epigastric vessels. Proximal to the branching,
the artery and vein were divided. The animals were then randomized into four
groups as follows: In group I (N=16), the artery was repaired and then the clamps
were released to revascularize the flap. Venous stasis occurred as the vein was
being repaired because of the venous clamp. In group II (N=15), the artery was
repaired, but the clamp was maintained to prevent blood from coming in contact
with the fresh arterial anastomosis and to prevent venous stasis. The vein was
then repaired. In group III (N=15), the vein was repaired first but the venous
clamp was not released until the artery was repaired. In group IV (N=15), the
vein was repaired first and the clamps were released, allowing venous blood to
contact the fresh anastomosis while the artery was being repaired. After final
clamp removal, all anastomoses were assessed immediately for evidence of
thrombosis. Five days postoperatively the skin flap was evaluated for evidence of
necrosis and the anastomosis was inspected for evidence of late thrombosis. The
anastomoses were resected for histopathological evaluation. Flap success was
compared between groups using chi-squared analysis. Eleven of 16 flaps failed
(69%) in group I, and 3 of 15 flaps failed (20%) in each of groups II, III, and
IV. Statistical significance was reached in comparing group I with the other
three groups (p < 0.01). All failures in group I were caused by immediate venous
thrombosis. The other failures were secondary to arterial thrombosis.
Histopathological analysis failed to demonstrate any differences between the
groups. According to these results, arterial repair followed by clamp release
prior to the completion of the venous repair results in a low success rate,
probably secondary to venous stasis within the draining vein while the venous
anastomosis is being completed. If the arterial repair is performed first, then
it is recommended that the arterial clamp be maintained until the venous repair
is completed. If the vein is repaired first, then it can be clamped or unclamped
with similar results.
PMID- 9556002
TI - Reflections of a career in progress.
PMID- 9556003
TI - Exercise and cystic fibrosis: the search for a therapeutic optimum.
PMID- 9556004
TI - RSV, recurrent wheezing, and ribavirin.
PMID- 9556005
TI - The anaerobic threshold in cystic fibrosis: comparison of V-slope method, lactate
turn points, and Conconi test.
AB - Physical exercise can improve sputum clearance in patients with cystic fibrosis
(CF). To set up individual training protocols it is desirable to know the
anaerobic threshold (AT). Established methods such as blood lactate measurements
and ergometry can only be performed in specialized centers. Conconi showed that
the heart rate threshold (HRT), i.e., the deflection point from the linear
relationship between work load and heart rate, correlated significantly with the
AT in healthy adults. To assess the reliability of the HRT in CF, we performed
ergometry in 32 CF patients (mean age, 21.0 +/- 5.5 years; mean Shwachman score,
77.8 +/- 12.0) according to the Conconi protocol. The HRT was compared with the
aerobic threshold (AeT) as determined by the V-slope method and with two turn
points in the lactate performance curve (LTP1, LTP2). An HRT could be obtained in
only 17 of the 32 patients (53%). In these 17 patients there was a significant
correlation between HRT and the other thresholds, but the absolute values for the
AT differed considerably: The mean HRT was 132% higher than the AeT according to
Beaver, 107% higher than LTP1, and 19% higher than LTP2. Exercise protocols that
rely solely on the HRT in CF will lead to excessive exertion during exercise
training programs in these patients. According to these results the HRT of
Conconi is not a suitable method to determine appropriate exercise levels in CF
training programs and might even be harmful in CF patients. These results also
indicate the need to test the reliability of a diagnostic procedure that has been
developed only for healthy people.
PMID- 9556006
TI - Reduced long-term respiratory morbidity after treatment of respiratory syncytial
virus bronchiolitis with ribavirin in previously healthy infants: a preliminary
report.
AB - Previously healthy infants less than 6 months of age with severe respiratory
syncytial virus bronchiolitis who required hospitalization were identified from
hospital records. Infants had been treated either conservatively (control group,
n = 19) or with ribavirin added to conservative management (study group, n = 22).
All infants underwent a 1-year follow-up after the initial illness. There was a
significant reduction in the prevalence of reactive airway disease in the group
treated with ribavirin (P < 0.05) compared with the control group, both in terms
of the proportion of patients developing airway reactivity (59% vs. 89%) and the
number of episodes of reactive airway disease (31 vs. 70). Our data suggest that
ribavirin reduces the prevalence of airway reactivity.
PMID- 9556007
TI - Comparison of responses to an asthma symptom questionnaire (ISAAC core questions)
completed by adolescents and their parents. SCARPOL-Team. Swiss Study on
Childhood Allergy and Respiratory Symptoms with respect to Air Pollution.
AB - The primary objective of the study was to determine the impact of the identity of
the respondent (parents versus adolescents) on prevalence estimates of asthma
symptoms in Swiss adolescents. In addition, factors influencing agreement between
parents' and adolescents' responses to the same questions were analysed. One
thousand three hundred and seventy-four (78.4%) adolescents, aged 14 years, self
completed a questionnaire at school based on the International Study of Asthma
and Allergy in Childhood (ISAAC) core questions on wheezing and asthma. The same
questions were incorporated into a questionnaire to be completed by the parents
at home. The adolescents' self-reported prevalence rates of current asthma
symptoms and "asthma ever" were significantly higher than those obtained from the
parental questionnaires. 856 (62.6%) parental questionnaires were filled in by
parents without the help of the adolescents, 460 (37.4%) were completed by
parents and adolescents and 51 (3.7%) were completed by the adolescents without
the parents. Prevalence rates were higher when parents and adolescents completed
the questionnaire jointly than when questionnaires were completed by parents
alone. The level of agreement between parental and self-completed questionnaires
was moderate to low (kappa coefficients 0.22-0.68). Agreement between parental
and adolescents reports of asthma symptoms was best when questionnaires were
completed jointly by parents and adolescents, when the adolescent was a girl,
when a family history of asthma was recorded, when the adolescent was a non
smoker, and when the parental education was high. We conclude that the higher
reporting of prevalence rates of current asthma symptoms by adolescents compared
to reporting by their parents demonstrates the need to take the respondent to a
questionnaire into account when comparisons are made between prevalence studies.
The results also suggest that factors related to the family milieu influence
symptom reporting.
PMID- 9556008
TI - Serum eosinophil cationic protein (ECP) and eosinophil protein X (EPX) in
childhood asthma: the influence of atopy.
AB - The purpose of this study was to determine the value of serum measurements of
eosinophil cationic protein (ECP) and eosinophil protein X (EPX) in diagnosing
asthma in children, and to investigate the influence of concomitant allergic
diseases and atopic sensitization, assessed by skin prick tests (SPT), on these
markers. ECP and EPX were determined in 36 children with asthma, in 33 children
with other symptoms from lower airways disease (OSLA), and in 166 control
children. Sixteen children with asthma but no anti-inflammatory therapy had
significantly higher concentrations of ECP and EPX (ECP: 27.5 microg/L, P <
0.001; EPX: 59.9 microg/L, P < 0.001) than the control children (ECP: 11.2
microg/L; EPX: 26.2 microg/L). In the 20 children on anti-inflammatory therapy,
ECP values were similar to those of controls. The children with OSLA (ECP: 13.6
microg/L, P < 0.01; EPX: 47.2 microg/L, P < 0.001) differed significantly from
controls. When using the value of 24.7 microg/L (97.5 percentile in the 68 non
atopic controls) as a pathologic upper limit for ECP, 10 (63%) of the 16
asthmatic children on no maintenance medication, two (10%) of the 20 asthmatics
on maintenance therapy, and 11 (33%) of the 33 children with OSLA had high ECP;
the same figure was only 18 (11%) in the 166 control children. Both ECP and EPX
had a significant association with allergic disorders and with SPT reactivity. In
multivariate logistic regression analysis, an elevated ECP was significantly
associated with asthma (OR 2.3, 95%CI 1.1-4.9) and atopic dermatitis (2.9, 1.2
6.9), and an elevated EPX was significantly associated with asthma (2.61, 1.19
5.74) and allergic rhinoconjunctivitis (5.23, 1.46-18.73). We conclude that serum
concentrations of both ECP and EPX are higher in asthmatic than in healthy
children. However, other allergic diseases, such as allergic rhinoconjunctivitis,
atopic dermatitis, and allergic skin sensitization also raise the concentrations
of these markers. This limits their usefulness in the diagnosis of childhood
asthma.
PMID- 9556009
TI - Thoracoabdominal motion in newborns during ventilation delivered by endotracheal
tube or nasal prongs.
AB - Preterm infants have asynchronous thoracoabdominal motion (TAM) secondary to a
highly compliant chest wall and different lung mechanics compared to term
infants. We compared TAM during continuous positive airway pressure (CPAP)
administered through an endotracheal tube (ETT-CPAP) or nasal prongs (nasal
CPAP), and during synchronized intermittent mandatory ventilation administered by
nasal prongs (nasal-SIMV) in 14 preterm newborn infants. Asynchrony of TAM was
quantified by measuring relative motion of chest wall and abdomen with strain
gauges and calculating phase angles (theta). Phase angles were lower during nasal
SIMV compared to nasal-CPAP or ETT-CPAP (P < 0.05), and lower during nasal-CPAP
compared to ETT-CPAP (P < 0.05). The reduced TAM asynchrony during nasal-SIMV and
nasal-CPAP may be due to elimination of resistance of the ETT and/or effective
stabilization of the chest wall. These data suggest that nasal-SIMV may be an
effective mode of respiratory support for preterm infants requiring minimal
ventilatory support.
PMID- 9556010
TI - Effect of neonatal surfactant therapy on lung function at school age in children
born very preterm.
AB - Our aim was to evaluate long-term effects of exogenous surfactant therapy on
pulmonary functional outcome in children born very preterm. We examined 40
children aged 7-12 years who were born before 30 weeks of gestation with an
immature surfactant system, and were randomized to one of three treatment groups:
human surfactant given at birth (prophylactic), human surfactant given after
development of neonatal respiratory distress syndrome (rescue), and placebo (air)
treatment. Spirometric parameters of preterm born children were compared with
those of 20 children born at term. In addition, spirometric parameters were
monitored twice daily for 4 weeks using a home spirometer. All spirometric
parameters were significantly lower in the preterm groups than in the controls,
except for the forced vital capacity (FVC) in the prophylactically treated group.
Bronchial obstruction was found in 53% of the prophylactically treated group, in
36% of the rescue group, in 67% of the placebo group, and in 0% of the control
group. Peak expiratory flow (PEF) and FVC values were higher in those children
who received surfactant compared with the placebo group (P < 0.05). In 16
children (40%) born preterm, a beta2-agonist induced an increase in PEF > or =
15% at least three times during 2 weeks of home monitoring; eight children (20%)
had abnormal diurnal PEF variation. Multiple regression analysis indicated that
the independent variables associated with favorable outcomes in spirometric
parameters were surfactant therapy (P = 0.012-0.045) and short intubation time
after birth (P = 0.0009-0.0044). Bronchial obstruction, responsiveness to a beta2
agonist, and high diurnal PEF variation are common in children born before 30
gestational weeks. Surfactant supplementation reducing the need for mechanical
ventilation or supplementary oxygen after birth may decrease the severity of
immaturity related bronchial obstruction in childhood.
PMID- 9556011
TI - Changes in pulmonary artery pressure during the acute phase of respiratory
distress syndrome treated with three different types of surfactant.
AB - We studied the changes in acceleration time/right ventricular ejection time ratio
(AT/RVET; indicative of changes in pulmonary artery pressure) calculated from
Doppler ultrasound examinations performed before and 1, 6, and 12 h after the
first and second doses of surfactant following the administration of each of
three different surfactants during the acute phase of the respiratory distress
syndrome. Maximum fractional inspired oxygen concentration (F(I,O2)) and peak
inspiratory pressure (PIP) were recorded during each 4 h period from birth for
the first 24 h and subsequently every 24 h until 72 h. Eighty-three infants were
studied. Fifty patients weighing > 1 kg received Exosurf (n = 29) or ALEC (n =
21) and 33 weighing < or = 1 kg received Exosurf (n = 22) or Survanta (n = 11).
The AT/RVET rose rapidly after administration of all three surfactants. There was
no significant difference in the change in AT/RVET between those > 1 kg who
received Exosurf and those who received ALEC (a synthetic surfactant). Similarly,
there was no difference between those infants < or = 1 kg who received Exosurf
and those who received Survanta. The F(I,O2) requirements, but not PIP, were
lower in those infants who received Survanta at 12 and 20 h compared with those
who received Exosurf. There was no significant difference in the F(I,O2) or PIP
requirements between infants > 1 kg who received Exosurf compared with those who
received ALEC. The rise in AT/RVET found in this study after administration of
ALEC, Exosurf, or Survanta suggests that similar and rapid falls in pulmonary
artery pressure occur after all three surfactant administrations, despite the
difference in clinical response demonstrated between Exosurf and Survanta.
PMID- 9556012
TI - Rate of surfactant administration influences lung function and gas exchange in a
surfactant-deficient rabbit model.
AB - The aim of this study was to test whether the effect of surfactant treatment on
lung function in a surfactant-deficient animal model can be influenced by the
rate at which surfactant is administered. Surfactant deficiency was induced in 18
New Zealand white rabbits (weighing approx. 1 kg each) by lung lavage with normal
saline. The arterial/alveolar oxygen ratio (a/A ratio), functional residual
capacity (FRC), dynamic compliance of the respiratory system (Crs), tidal volume
(V(T)), alveolar portion of the tidal volume (V(A)) and arterial P(CO2)
(P(a,CO2)) were measured before and after lavage and 15, 30, 60, 90, and 120 min
after administration of a single dose of surfactant (Survanta, 100 mg/kg). Two
surfactant administration protocols were compared over a 2-h interval: an
infusion lasting 4 min and an infusion over 2 min. Both administrations were
given during continuous mechanical ventilation. The six lung function and gas
exchange parameters improved significantly following surfactant administration
over 2 min compared with a control group. However, only the a/A ratio and V(A)
improved following the 4-min protocol. Comparison of the two intervention
protocols yielded significantly differences in V(A) and P(a,CO2), favoring the
shorter administration. These results support the hypothesis that fast (2 min)
administration of surfactant will improve its distribution to formerly collapsed
alveoli and results in better lung function, improved ventilation, and (to a
lesser extent) better oxygenation than prolonged infusions (4 min).
PMID- 9556013
TI - A rebreathing method to determine carbon monoxide diffusing capacity in children:
reference values for 6- to 18-year-olds [corrected] and validation in adult
volunteers.
AB - The diffusing capacity of carbon monoxide (D(L,CO)) and its value normalized to
alveolar volume (D(L,CO)/V(A)) are usually estimated with the single breath
method at total lung capacity (TLC). Severely ill patients and small children are
not able to deliver a satisfactory vital capacity (VC) or hold their breath for
10 s at TLC. The aim of this study was to develop a rebreathing procedure in
which diffusing capacity can be determined during spontaneous tidal breathing.
The conventional rebreathing method during hyperventilation was modified so that
rebreathing volume and gas concentrations were kept constant by CO2 absorption
and O2 supplementation. In adult healthy volunteers and in patients who were able
to perform both tests, the diffusion indices obtained with this rebreathing
method during resting ventilation were compared with those obtained by the single
breath method. Predicted (reference) values for rebreathing D(L,CO) and
D(L,CO)/V(A) for children were determined. D(L,CO)/V(A) decreased with alveolar
volume (V(A)) and increased with alveolar ventilation (V'(A)). In adults at V'(A)
above 35 L x min(-1) rebreathing D(L,CO)/V(A) was similar to single breath
D(L,CO)/V(A) at similar alveolar volumes. The D(L,CO)/V(A) relative to their
corresponding reference values were the same for both methods in adult patients,
irrespective of ventilation distribution disturbances. In children the newly
described diffusing capacity obtained by the rebreathing method during resting
ventilation can serve as a valuable index to assess and follow a diffusion
disorder.
PMID- 9556014
TI - Detection of tidal expiratory flow limitation in infants with cystic fibrosis: a
pilot study.
PMID- 9556015
TI - Capitol Hill update.
PMID- 9556016
TI - R29 to RO1 transition at NIH.
PMID- 9556017
TI - The Henry Gray Award.
PMID- 9556018
TI - To dissect or not to dissect?
PMID- 9556019
TI - Marcello Malpighi and the foundations of functional microanatomy.
PMID- 9556020
TI - Anatomy of the shaken baby syndrome.
AB - Shaken baby syndrome refers to the constellation of nonaccidental injuries
occurring in infants and young children as a consequence of violent shaking. The
typical victim of shaken baby syndrome is a male infant younger than six months
of age who is alone with the perpetrator at the time of injury. Occurrence of the
syndrome is unrelated to race, gender, socioeconomic status, or education. The
characteristic injuries observed in shaken baby syndrome include subdural
hemorrhages, retinal hemorrhages, and fractures of the ribs or long bones.
Although each of these injuries may result from violent shaking of the victim,
the most severe brain injuries result from the addition of a forceful impact of
the infant's or child's head against a firm surface. The unique anatomic features
of the infant's head and skeletal system, which account for the type and pattern
of injuries observed in shaken baby syndrome, are emphasized in this article.
PMID- 9556021
TI - Exploring development and disease through germ-line genetic engineering in the
mouse.
AB - New developments in mouse genetics have transformed the field of genetics from a
reactive to a proactive science. Current technologies in transgenesis, chromosome
engineering, and saturation mutagenesis are introduced. These approaches permit
the creation of new mutations and consequent mutant phenotypes that facilitate
both the understanding of functions of existing genes and the search for
previously unidentified genes affecting important phenotypes in all mammals.
PMID- 9556022
TI - The bearable lightness of being: bones, muscles, and spaceflight.
AB - Bones and muscles support and move the body. Tendons link the two tissues and
serve as a mechanism for transfer of forces from muscle to bone. These three
tissues interact and respond to periods of activity or inactivity with
appropriate alterations in structure and strength. There is substantial evidence
that an environment devoid of mechanical stress on the skeleton (such as reduced
gravitational forces during spaceflight, a "microgravity environment") produces
direct effects on bone structure and function. There is little agreement
concerning the biologic mechanisms for these atrophic changes. Changes in fluid
balance and distribution coincident to spaceflight also affect muscles and bones
by an unknown mechanism. Tendon-bone junctions are presumed to be spared from the
effects of spaceflight. However, recent evidence from rodents suggests that
spaceflight profoundly effects both the skeleton and the tendon-bone junctions.
These effects include cortical bone resorption, which undermines the Sharpey's
fibers that anchor the tendon to the bone matrix. The challenge to biomedical
scientists is to devise methods for protecting spaceflight crews from these
atrophic changes; such protection would allow for longer and more extensive
spaceflights.
PMID- 9556023
TI - Anatomy education in a changing medical curriculum.
AB - How we educate students in the first two years of medical school is changing at
many institutions. Effective medical education should be viewed as a continuum,
integration of the basic sciences and clinical medicine should occur throughout
the curriculum, and self-directed, life-long learning should be emphasized.
Curricular revision may be appropriate if these fundamental concepts are absent.
The principles of three curricular models are discussed: traditional, problem
based, and systems-oriented. The ideal curriculum may draw from each of these: A
truly integrated curriculum. However, the curricular model chosen must meet the
needs of the institution and its students. As anatomists we should not shy away
from this process of change. With progressive educational approaches, we can be
leaders in this climate of curricular reform. Anatomy courses are laboratory
based and the laboratory is an outstanding small group, faculty/student
interactive opportunity. However, we must show flexibility and innovation in our
educational approaches whatever the curricular design being proposed.
PMID- 9556024
TI - Neurodegeneration and aging: role of the second genome.
AB - The latest Health Report of the World Health Organization predicts a significant
increase in the age of human populations over the next two decades. In the
developed world, at least 20% of the population will be older than 65 years. This
development together with the as yet unknown etiology of many neurodegenerative
disorders has caused an increased interest in the biology and pathophysiology of
mitochondria. Dysfunction of mitochondria has been linked to both normal aging
and neurodegenerative disorders, with the latter occurring much more frequently
at higher age. Specifically, genetic defects in mitochondria have been shown to
accumulate during life, and certain mutations of mitochondrial genes have been
implicated in the etiology of Parkinson's and Alzheimer's diseases. In addition,
a large number of new mitochondrial diseases have been identified following the
first description of mitochondrial mutations 10 years ago. While there can be
little doubt that DNA defects of mitochondria play a role in aging, specific
mutations of mitochondrial genes underlying Parkinson's or Alzheimer's diseases
remain to be identified. There is evidence, however, that mutations of the
mitochondrial genome may increase the susceptibility to neurodegeneration.
PMID- 9556025
TI - Involvement of cytokines in normal CNS development and neurological diseases:
recent progress and perspectives.
AB - Cytokines have been recognized to play an important role both in normal
development of the brain, when they act as neurotrophic factors, as well as
following injury. While both the cytokines and their receptors are synthesized
and expressed in the brain normally (albeit at low levels), it has become clear
that elevated levels are associated with many neurological disorders. In this
review, we have chosen to present the data for only a few of the cytokines,
including interleukin-1beta, interleukin-3, interleukin-6, interferon-gamma,
transforming growth factor-beta, and tumor necrosis factor-alpha. Data are
presented that suggest roles they may play in human disorders, including stroke,
multiple sclerosis, Alzheimer's disease, and several psychiatric disorders. The
results in human disease are compared with results obtained in a variety of
transgenic animal models. The mouse models have very different disorders
depending on whether a cytokine is overexpressed either peripherally or in either
astrocytes or neurons. The potential significance of this to the understanding of
human disease is discussed.
PMID- 9556026
TI - Differentiation of oligodendrocyte occurs in contact with astrocyte.
AB - We have generated stage-specific oligodendrocytes, which are identified as
immature oligodendrocytes by the expression of specific markers. These cells were
generated by using 3 types of intrinsic and extrinsic factors for influencing the
characteristics of oligodendrocyte-lineage cells. The factors included 10% serum
in the medium to induce cell proliferation, bFGF in serum-free medium to increase
survival and induce differentiation, and 0.25% trypsin to remove
nonoligodendrocyte lineage cells. We have also demonstrated that it is possible
to supply a huge amount of homogeneous populations of stage-specific immature
oligodendrocytes after 35 days' culture. The maturation of these cells is
controlled by interacting with astrocytes in vitro, resulting in the expression
of MBP isoforms (14.0 and 18.5 kDa) that may participate in mature
oligodendrocyte membrane compaction.
PMID- 9556027
TI - Anatomical distribution of the chemorepellent semaphorin III/collapsin-1 in the
adult rat and human brain: predominant expression in structures of the olfactory
hippocampal pathway and the motor system.
AB - Alterations in neuronal connectivity of the mature central nervous system (CNS)
appear to depend on a delicate balance between growth-promoting and growth
inhibiting molecules. To begin to address a potential role of the secreted
chemorepulsive protein semaphorin(D)III/collapsin-1 (semaIII/coll-1) in
structural plasticity during adulthood, we used high-resolution nonradioactive in
situ hybridization to identify neural structures that express semaIII/coll-1 mRNA
in the mature rat and human brain. SemaIII/coll-1 was expressed in distinct but
anatomically and functionally linked structures of the adult nervous system. The
olfactory-hippocampal pathway displayed semaIII/coll-1 expression in a continuum
of neuronal structures, including mitral and tufted cells of the olfactory bulb,
olfactory tubercle, and piriform cortex; and distinct nuclei of the amygdaloid
complex, the superficial layers of the entorhinal cortex, and the subiculum of
the hippocampal formation. In addition, prominent labeling was found in neuronal
components of the motor system, particularly in cerebellar Purkinje cells and in
subpopulations of cranial and spinal motoneurons. Retrograde tracing combined
with in situ hybridization also revealed that the staining of semaIII/coll-1
within the entorhinal cortex was present in the stellate neurons that project via
the perforant path to the molecular layer of the dentate gyrus. Like in the rat,
the human brain displayed discrete expression of semaIII/coll-1. Among the
structures examined, the most prominent staining was observed in the cellular
islands of the superficial layers of the human entorhinal cortex. The
constitutive expression of the chemorepellent semaIII/coll-1 in discrete
populations of neurons in the mature rat and human CNS raises the possibility
that, in addition to its function as repulsive axon guidance cue during
development, semaIII/coll-1 might be involved in restricting structural changes
that occur in the wiring of the intact CNS.
PMID- 9556028
TI - Polarized distribution and cell type-specific localization of telencephalin, an
intercellular adhesion molecule.
AB - Telencephalin is an intercellular adhesion molecule (ICAM) restricted to the
telencephalon. This study demonstrates that immunolabeled telencephalin is
targeted to the somatodendritic domain of cultured hippocampal pyramidal neurons
beginning with the first stages of dendritic differentiation. In contrast, it is
entirely excluded from all gamma-aminobutyric acid (GABA)ergic inhibitory
interneurons at all stages of development. Prior to the stage at which nearly all
pyramidal neurons express telencephalin, labeled neurons possess more extensive
dendritic arbors than unlabeled pyramidal neurons. More synaptic boutons form
with the larger, more elaborate telencephalin-expressing dendritic trees, but
bouton number per unit length is similar between neurons with and without
telencephalin. These findings suggest that telencephalin identifies pyramidal
neurons, it may identify plasma membrane as dendritic, and it may be generally
adhesive or stabilize dendritic membranes, but it is probably not specifically
synaptic. Such characteristics would be expected to be important for the
formation of cell type-specific dendritic arbors.
PMID- 9556029
TI - Y1 receptors in the nucleus accumbens: ultrastructural localization and
association with neuropeptide Y.
AB - Neuropeptide Y (NPY) is present in aspiny neurons in the nucleus accumbens (NAc),
which also contains moderate levels of ligand binding and mRNA for the Y1
receptor. To determine the potential functional sites for receptor activation, we
examined the electron microscopic immunocytochemical localization of antipeptide
antisera against the Y1 receptor in the rat NAc. We also combined immunogold and
immunoperoxidase labeling to show that, in this region, Y1 receptors are present
in certain somatodendritic and axonal profiles that contain NPY or that appose
NPY containing neurons. The Y1-like immunoreactivity (Y1-LI) was seen
occasionally along plasma membranes but was associated more commonly with smooth
endoplasmic reticulum (SER) and tubulovesicular organelles in somata and
dendrites of spiny and aspiny neurons. The mean density of immunoreactive
dendrites and spines per unit volume was greater in the "motor-associated" core
than in the shell of the NAc. Y1-LI was also seen in morphologically heterogenous
axon terminals, including those forming asymmetric excitatory-type synapses, and
in selective astrocytic processes near this type of junction. We conclude that Y1
receptors play a role in autoregulation of NPY-containing neurons but are also
likely to be internalized along with endogenous NPY in NAc. Our results also
implicate Y1 receptors in the NAc in post- and presynaptic effects of NPY and in
glial functions involving excitatory neurotransmission. In addition, they suggest
involvement of Y1 receptors in determining the output of a select population of
neurons associated with motor control in the NAc core.
PMID- 9556030
TI - Kainate-induced apoptosis correlates with c-Jun activation in cultured cerebellar
granule cells.
AB - We have investigated the involvement of c-Jun in cell death induced by exposure
of primary cultures of murine cerebellar granule cells to the glutamate receptor
agonist kainate (KA) and evaluated its possible use as a marker for apoptosis.
Using cerebellar granule cell neurones from postnatal day 7 mice, we found that 1
hr exposure to KA (1-1000 microM) induced a concentration-dependent neuronal cell
death with characteristic apoptotic morphology, including cell shrinkage, neurite
blebbing and DNA fragmentation. In addition KA-induced a concentration-dependent
expression of c-Jun mRNA and protein as determined by in situ hybridization and
immunocytochemistry respectively. DNA fragmentation was detected using terminal
transferase-mediated nick-end (TUNEL) labelling and agarose gel electrophoresis.
KA-induced cell death was significantly attenuated by the non-NMDA receptor
antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 50 microM), which shifted
the concentration-response curve significantly rightward. The number of apoptotic
cell bodies, determined by TUNEL, was also reduced by CNQX (50 microM), with only
15-20% of neurones staining positive after exposure to 1mM KA. In addition, the
number of positively stained cells for c-Jun protein and mRNA was substantially
reduced by CNQX (50 microM) as determined by random and representative cell
counts. These results show for the first time that KA induced apoptotic neuronal
death in cultured murine cerebellar granule cells involves the induction of c-Jun
mRNA and protein, suggesting the involvement of this immediate early gene in
excitotoxic receptor-mediated apoptosis and its potential use as a marker for
apoptotic cell death.
PMID- 9556031
TI - Low affinity NGF receptor expression in the central nervous system during
experimental allergic encephalomyelitis.
AB - In the central nervous system (CNS), p75, or low-affinity nerve growth factor
receptor (LNGFR), is assumed to play a critical role in mediating the effects of
neurotrophins on neuronal survival. Recent studies have shown that nerve growth
factor (NGF) can act also on immune cells through its binding to p75. Using
immunohistochemistry, we have investigated the expression of the p75 receptor in
the CNS during chronic relapsing experimental allergic encephalomyelitis (EAE) of
the Lewis rat, an animal model of multiple sclerosis (MS). We report here a
sequential expression of p75, first in Purkinje cells during the first attack,
and secondly on both endothelial and perivascular cells in the latter stages of
the disease. Moreover, starting from the second attack, p75 was also expressed on
glial ensheathing cells, likely myelinating cells, located primarily in the
dorsal roots. These data suggest that during EAE, LNGFR may play an important
role in leukocyte-endothelial cell interactions and in the maintenance of
Purkinje cells survival.
PMID- 9556032
TI - NFAT interactions with the vasoactive intestinal peptide cytokine response
element.
AB - The vasoactive intestinal peptide cytokine response element (VIP CyRE) is
responsible for mediating the transcriptional induction of the VIP gene to the
neuropoietic cytokines leukemia inhibitory factor (LIF) and ciliary neurotrophic
factor (CNTF). In investigating the sequence and function of the CyRE, we found a
region of DNA with homology to the distal NFAT site in the IL-2 promoter. In this
paper we characterize this sequence and show that the VIP NFAT site recognizes T
cell NFAT with similar affinity to the previously characterized IL-2 NFAT site.
However, despite its location in the middle of the CyRE, we find no CNTF/LIF
induced binding to it. Instead we show that in NBFL neuroblastoma cells, the
calcium ionophore A23187 induces a protein to bind to the VIP NFAT site. This
A23187-mediated induction of nuclear protein binding to an NFAT oligonucleotide
is dependent on extracellular calcium but not dependent on de novo protein
synthesis. Thus, this protein has the characteristics of an NFAT-like protein and
is recognized by an NFAT3-specific antiserum suggesting that it is indeed an NFAT
protein. The location of the NFAT site in the VIP CyRE suggests that this may be
one mechanism through which different signaling pathways engage in cross talk to
alter VIP gene transcription.
PMID- 9556033
TI - Selective outgrowth and differential tropism of amacrine and photoreceptor axons
to cell targets during early development in vitro.
AB - The axonal guidance and outgrowth in retinal neurons were investigated in
cultures of pure retinal neurons (control) or in cocultures with heterologous
BC3H-1 cells. Under control conditions, only about 10% of retinal neurons
developed axons; coculturing with BC3H-1 cells induced early axonal outgrowth and
guidance to BC3H-1 cells in most amacrine neurons. Both mechanisms were dependent
on laminin and neural cell-adhesion molecules (N-CAMs) released by BC3H-1 cells,
because they were prevented by antibodies directed against these molecules. The
protein kinase C (PKC) inhibitor, staurosporine, reduced the effect of laminin on
amacrine axonal outgrowth, suggesting that this effect was mediated by PKC. The
occurrence of structures resembling synaptic boutons and the expression of
synaptophysin at the amacrine axon ends of heterologous connections suggested
that amacrine axons establish true synaptic contacts rather than simply
overlapping with the BC3H-1 cells. In contrast to the heterologous contacts with
BC3H-1 cells, the amacrine-amacrine axonal contacts observed in the cocultures
were independent of laminin and N-CAM. Axonal outgrowth occurred in about 10% of
the photoreceptors and was not affected by BC3H-1 cells or by substratum
pretreatment with laminin or N-CAM. These results show that different mechanisms
affect axonal outgrowth and guidance in amacrine and photoreceptor neurons in
vitro, and they suggest that similar mechanisms could contribute to the
development of the scaffold of axon pathways in the retina in vivo.
PMID- 9556034
TI - RGS9: a regulator of G-protein signalling with specific expression in rat and
mouse striatum.
AB - A clone of the regulator of G-protein signalling, RGS9, was isolated from a rat
striatum-minus-cerebellum-minus-hippocampus subtracted library generated by
directional tag polymerase chain reaction subtraction. The full-length cDNA clone
encodes a 444 amino acid protein containing an 118 amino acid RGS domain, which
corresponds to an evolutionarily conserved domain that is present in all members
of the RGS family of proteins. Outside of the homology domain, RGS9 shows more
extended similarity to human RGS6 and RGS7, rat RGS12, and the C. elegans protein
EGL-10. During embryonic and early postnatal stages of development, two RGS9
transcripts of approximately 1.4 Kb and 1.8 Kb were detected in whole brain.
After postnatal day 10, accumulation of the larger transcript increased
progressively until adulthood at the expense of the smaller transcript, which was
undetectable in the adult. In adult rat brain, the 1.8-Kb RGS9 transcript was
detected in the striatum but not in other brain regions or peripheral tissues. In
situ hybridization in rat and mouse demonstrates that RGS9 mRNA is expressed
predominantly in medium-sized, spiny neurons of the neostriatum and in neurons of
the nucleus accumbens and olfactory tubercle. Relatively strong signals were also
detected in some hypothalamic nuclei. Its selective expression suggests that RGS9
may play an important role in modulation of the complex signalling pathways of
the basal ganglia.
PMID- 9556035
TI - Trisomic zygote rescue revealed by DNA polymorphism analysis in confined
placental mosaicism.
AB - Uniparental disomy can be caused by different genetic mechanisms such as gamete
complementation, chromosome duplication in monosomic zygote, or post-zygotic
aneuploidy correction. This last mechanism is well documented in human
reproduction and is related to placental mosaicism. In the case of a trisomic
zygote which has originated by paternal or maternal non-disjunction at the first
or second meiotic cell division, mosaicism will result from chromosome loss and
restoration of a 'normalized' diploid fetal karyotype. In order to enrich the
literature with new observations on this subject, we studied by DNA polymorphism
analysis ten cases of confined placental mosaicism (CPM). The finding in
placental DNA of three different alleles at polymorphic loci of chromosomes 13,
16, and 20 demonstrated the trisomic status of the zygote in three cases. On the
basis of these results, we believe that systematic DNA polymorphism analysis
could give useful additional information to improve knowledge on aneuploidy
correction in human reproduction.
PMID- 9556036
TI - Reliable co-segregation analysis for prenatal diagnosis and heterozygote
detection in Gaucher disease.
AB - Mutations in the gene encoding beta-glucocerebrosidase are the main cause of
Gaucher disease. The identification of some of these mutations in prenatal tests
is a good complement to enzymatic assay and allows diagnosis and, in some cases,
prognosis of the disease to be made. DNA analysis is particularly useful for
carrier detection since the results of biochemical analyses are often ambiguous.
The main drawback of mutation analysis for prenatal diagnosis and carrier
detection in Gaucher disease is that rare mutations account for more than 30 per
cent of the mutant alleles in most populations. The individual detection of these
mutations is too expensive and time-consuming for routine use. Here we present a
diagnostic protocol based on co-segregation analysis, using highly polymorphic
markers, to be applied when at least one disease allele does not correspond to
the most common mutations. Because of the frequency of the N370S mutation and its
relevance for prognosis, an improved PCR detection method is included.
PMID- 9556037
TI - Inhibin-B and pro-alphaC-containing inhibins in amniotic fluid from chromosomally
normal and Down syndrome pregnancies.
AB - In second-trimester Down syndrome pregnancies, levels of inhibin-A (the alpha
betaA dimer) in maternal serum and amniotic fluid (AF) are significantly higher
and lower than in normal pregnancy, respectively. Since AF also contains inhibin
B (the alpha-betaB dimer) and precursor inhibins, we have examined whether the
secretion of these inhibin isoforms may also be altered in association with Down
syndrome. AF from 45 Down syndrome and 150 chromosomally normal pregnancies
between 16 and 19 weeks' gestation were analysed, blinded to whether the sample
was from a Down syndrome or a normal pregnancy. The median (10th-90th
percentiles) inhibin-B level in the control pregnancies increased from 310.0
(80.8-1112.5) pg/ml at 16 weeks to 459.5 (193.7-1386.8) pg/ml at 19 weeks'
gestation. The corresponding figures for precursor inhibins (pro-alphaC inhibins)
were 541.8 (206.9-1322.8) pg/ml at 16 weeks and 1391.8 (433.3-2652.6) pg/ml at 19
weeks. Expressed as multiples of the median (MOM), the levels of inhibin-B and
pro-alphaC inhibins in the Down syndrome samples were 0.85 and 0.79,
respectively. Neither was significantly different from the controls. These data
suggest that, of the three inhibin subunits, abnormal production or secretion of
the inhibin betaA-subunit may underlie the decreased inhibin-A levels previously
observed in Down syndrome. Confirmation of this by quantitative assessment of the
inhibin subunit messenger ribonucleic acids would now be useful.
PMID- 9556038
TI - Prenatal testing for genetic disorders among Arabs.
AB - Since, at least in the near future, prenatal testing and abortion of affected
fetuses will remain the main way of the prevention of genetic diseases, knowledge
about the way of its acceptance in different cultures is important. The Israeli
population includes two major groups: Jewish and Arabs, but while there is wide
experience about the Jewish population and its attitude towards prenatal testing,
little is known about the Arab population. This knowledge is particularly
important, since genetic disorders are relatively frequent in the Arab world
(Teebi and Farag, 1997). From 1992 to 1996, 816 prenatal tests were performed in
our department on Arab women [143 chorionic villus sampling (CVS) procedures and
673 amniocenteses]. The indication for an early prenatal test was a high risk for
a monogenic disorder in 140 out of the 146 tests performed (143 CVS procedures
and three early amniocenteses). In 26 cases, the fetus was found to be affected
and early abortion was chosen by the couple in 25 cases (96 per cent). The 670
late prenatal tests were done for various reasons including monogenic disorders
(13 per cent), increased risk because of a previous child affected with Down
syndrome or a neural tube defect (4.8 per cent), and an increased risk for a
chromosomal aberration (78 per cent). In 31 cases of a late prenatal test, the
fetus was found to be affected and only 21 couples (70 per cent) opted for an
abortion. The major reason for this observation is probably related to religious
and cultural factors. Since Arab women do not wish to have prenatal testing for
only knowledge or reassurance, these factors should be taken into consideration
during pre-amniocentesis counselling.
PMID- 9556039
TI - The influence of smoking on maternal serum AFP and free beta hCG levels and the
impact on screening for Down syndrome.
AB - I have studied the impact of maternal smoking on the levels of maternal serum
alpha-fetoprotein (AFP) and free beta human chorionic gonadotrophin (hCG) during
the second trimester in a large series (30,727) of self-reported smokers and non
smokers whose pregnancy resulted in the birth of a normal fetus. I have confirmed
in a smaller subset of this population that self-reporting is an accurate method
of assessing smoking status as confirmed by biochemical (serum cotinine)
assessment. In addition, I have investigated marker levels among 195 pregnancies
affected by Down syndrome with smoking status confirmed by measurement of serum
cotinine. In both unaffected and Down syndrome groups, the incidence of smoking
was 19 per cent but a considerable variation was observed with maternal age when
the incidence in younger women (under 25) was 32 per cent. AFP median levels in
unaffected smokers were 3 per cent higher, whilst in the Down syndrome group
smoker medians were increased by 10 per cent compared with the non-smoker group.
Free beta hCG levels in unaffected smokers were reduced by 14 per cent, whilst in
the Down syndrome group smoker median levels were decreased by 16 per cent. In
the smoker group, the Down syndrome detection rate was 10 per cent lower than in
the non-smoker group, whilst the false-positive rate was also 2 per cent lower.
Correcting for smoking status would redress this inequality and produce an
overall 2 per cent increase in the detection rate for a 0.4 per cent increase in
the false-positive rate. This increase in screening performance may be worth
building into screening programmes, particularly in populations with a high
smoking incidence.
PMID- 9556040
TI - hCG and the free beta-subunit as screening tests for Down syndrome.
AB - Published studies have reached varying conclusions as to the benefit of replacing
human chorionic gonadotropin (hCG) measurements with the free beta-subunit of hCG
(the free beta-subunit) for Down syndrome screening. One study reports 14 per
cent higher detection for the free beta-subunit, while another finds an actual
loss in detection. To explore this issue further, we directly compared the
screening performance of hCG and the free beta-subunit, alone and in combination
with other serum markers, using banked sera obtained prior to amniocentesis and
karyotyping. Altogether, 52 Down syndrome and 5065 unaffected pregnancies were
studied. Sera were thawed and assayed for hCG and the free beta-subunit over 1
year. At a 5 per cent false-positive rate, the detection rate for hCG in
combination with maternal age and alpha-fetoprotein was higher than when the free
beta-subunit was substituted (62 versus 57 per cent). Ultrasound dating and
adding unconjugated oestriol both increased detection. The present findings,
along with those from six case control studies (our re-analysis), indicate that
the screening performances of hCG and the free beta-subunit are similar (median
change in detection 0, range -8 to +3 per cent). Under optimal sample collection
and transportation conditions, laboratories can expect to achieve similar
screening performance using either hCG or the free beta-subunit measurements.
PMID- 9556041
TI - Prenatal diagnosis of fetal corpus callosum agenesis by ultrasonography and
magnetic resonance imaging.
AB - Corpus callosum agenesis (CCA) was evaluated by ultrasound examination and
magnetic resonance imaging (MRI) in 14 cases. Ultrasonography was able to suspect
CCA by indirect signs but a definitive diagnosis of CCA was achieved in only four
cases. MRI was able to diagnose complete CCA in 13 cases and showed absence of
the posterior portion of the corpus callosum in one case. Additional neurological
abnormalities including heterotopia, gyration anomaly, asymmetry of the cerebral
hemispheres, and Dandy-Walker variant were documented in five cases, as well as
an ocular anomaly which was present in one case, by MRI examination. Prenatal
counselling for fetal agenesis of the corpus callosum is difficult as the
prognosis is uncertain. The association with other cerebral abnormalities
increases the likelihood of a poor outcome and ultrasonographic assessment of the
fetal brain is limited. We found MRI to be a safe and useful additional procedure
to complement ultrasonographic diagnosis or suspicion of CCA.
PMID- 9556042
TI - First 10,000 chorionic villus samplings performed on singleton pregnancies by a
single operator.
AB - Chorionic villus sampling (CVS) was performed in 10,000 consecutive singleton
pregnancies by a single principal operator, working in two institutions. The
procedure was performed between 8 and 32 gestational weeks: transabdominal (TA)
sampling was carried out in 8479 cases and transcervical (TC) in 1521. Patients
were referred for chromosomal risk in 89.1 per cent of cases, Mendelian disorders
in 10.5 per cent, and DNA investigations for paternity or infectious agents in
0.4 per cent of cases. The sampling success rate for both TA and TC techniques by
the second insertion was 99.8 and 99.2 per cent, respectively. TA sampling
succeeded in a higher number of cases at the first insertion (98 per cent vs.
86.8 per cent) and was associated with smaller samples (< 10 mg) in fewer cases
(3.2 per cent vs. 4.9 per cent). Cytogenetic analysis was highly successful (99.4
per cent) and accurate; however, in one case a de novo structural rearrangement
of chromosome I was not recognized. Mosaicism or rare trisomies were reported in
1.30 per cent of cases. Five diagnostic errors in DNA investigation (0.51 per
cent) ended with the birth of affected fetuses. Fetal loss through 28 weeks'
gestation in the pregnancies intended to continue was 2.58 per cent; the rate
increased with maternal age (1.22 per cent at less than 30 years to 3.8 per cent
at 40 years or more), while gestational age affected the abortion rate only at 8
weeks (odds ratio=2.22, P<0.05). Rates of premature delivery, low birth weight,
and perinatal mortality did not differ from the Italian standards. By comparison
with the Italian Birth Defects Registry data, no differences were found for the
major malformations, including transverse limb reduction defects (TLRDs) (4.34
vs. 3.28 x 10,000). Total malformations and TLRDs did not show any pattern
relation to either maternal age or gestational age.
PMID- 9556043
TI - Cardiac gene expression of GATA-4 transcription factor in human trisomy 21
fetuses with increased nuchal translucency.
AB - This study examines GATA-4 gene expression in cardiac tissue from fetuses with
trisomy 21 presenting with increased nuchal translucency thickness at 10-14 weeks
of gestation. mRNA was extracted from cardiac tissue after termination of
pregnancy at 10-18 weeks of gestation in ten trisomy 21 fetuses and 29 normal
controls. Northern and slot blots were performed and densitometric analysis of
slot blots was used to determine the steady-state levels of expression of GATA-4.
GATA-4 transcript levels were also compared with ANP and BNP, which have
previously been measured in the same panel of samples. GATA-4 expression
increased significantly with gestation but there was no significant difference
between fetuses with trisomy 21 and controls. There was no significant
association between GATA-4 expression and the steady-state level of transcripts
for the natriuretic peptides.
PMID- 9556044
TI - Attitudes towards abortion among physicians working at obstetrical and paediatric
departments in Denmark.
AB - The purpose of this study was to describe the attitudes among physicians working
in perinatal medicine towards abortion for social reasons or because of abnormal
prenatal diagnostic results. A questionnaire was sent to all physicians
registered as employed at obstetrical or paediatric departments in Danish
hospitals with a neonatal function. Of 994 questionnaires, 687 (69 per cent) were
completed and returned. There was strong consensus among all participants that
abortion is acceptable until week 21 in the case of trisomy 13 and at least until
week 19 in the case of cystic fibrosis. Furthermore, there was strong consensus
that abortion in the first trimester is acceptable in the case of an unwanted
pregnancy in a 16-year-old girl and in the case of Down syndrome. Major
controversy was found in connection with abortion in the case of Turner syndrome
until week 21, abortion in week 13 in the case of polycystic kidney disease,
abortion in week 24 in the case of Down syndrome, and abortion for social reasons
in week 21.
PMID- 9556045
TI - The distribution of nuchal translucency at 10-13 weeks of pregnancy.
AB - There is a need for a simple method of expressing nuchal translucency measurement
in early pregnancy that will allow for gestational age and be useful in screening
for Down's syndrome. To achieve this objective, we conducted a prospective study
of 561 women with singleton pregnancies that were not affected by Down's syndrome
at 10-13 weeks of gestation. Nuchal translucency measurements and crown rump
length measurements were determined. Nuchal translucency measurement increased by
about 17 per cent per week. Expressing the result as a multiple of the median
(MOM) nuchal translucency for a given crown rump length allowed for this increase
with gestational age and yielded a distribution of values that was approximately
Gaussian. About 96 per cent of values lay between 0.5 and 2.0 MOM. The variance
and therefore the false-positive rate of nuchal translucency were significantly
reduced by recording several measurements and using the average: for example, the
false-positive rate reduced from 8.3 per cent to 5.0 per cent if the average of
six measurements were used instead of one--a potential 40 per cent reduction in
the false-positive rate if the test were used in screening. Estimating the
distribution of nuchal translucency in MOM values will assist in specifying the
statistical parameters to be used in prenatal screening for Down's syndrome and
the use of repeated nuchal translucency measurements is expected to have a useful
effect on reducing the screening false-positive rate at a given MOM cut-off
level.
PMID- 9556046
TI - Prenatal diagnosis of Menkes disease.
PMID- 9556047
TI - Screening for Down syndrome at 14 weeks of pregnancy.
AB - To investigate whether statistical parameters used in Down syndrome screening
between 15 and 22 weeks of pregnancy can be used at 14 weeks, we assayed alpha
fetoprotein (AFP), unconjugated oestriol (uE3), total human chorionic
gonadotrophin (hCG), free alpha-hCG, free beta-hCG, and inhibin-A in 16
pregnancies with Down syndrome in the 14th week of pregnancy and expressed values
in multiples of the normal median. The median and standard deviation values for
these 16 pregnancies were not materially different from those published for 15-22
weeks. It is reasonable, therefore, to offer Down syndrome screening using these
markers starting at 14 completed weeks of pregnancy instead of 15 weeks. It needs
to be recognized, however, that serum AFP measurement for neural tube defect
screening is less effective at this time than between 16 and 18 weeks of
pregnancy.
PMID- 9556048
TI - Clinical management of a rare de novo translocation 46,X,t(Y;15) (p11.2
approximately 11.3;q11.2).ish t(Y;15)(DYZ3+,AMELY+,SNRPN+;D15Z+) found
prenatally.
AB - A 40-year-old woman had amniocentesis at 16 weeks' gestation. Chromosome studies
based on 15 colonies showed a de novo 46,X,t(Y;15)(p11.2 approximately
11.3;q11.2) karyotype. Using C- and Q-banding, the additional material on 15
appeared to be Yqh heterochromatin. The satellite on the small derivative
chromosome was positive by AgNOR staining. Fluorescence in situ hybridization
(FISH) studies using Y and 15 alpha satellite centromeric probes (DYZ3 and D15Z)
showed that the derivative chromosome that resembled 15p+ had a Y centromere and
that the satellited derivative had a 15 centromere. The break on Y was distal to
the amelogenin locus and on 15 it was shown to be proximal to the Prader
Willi/Angelman region by using the SNRPN probe. DNA studies ruled out uniparental
disomy of chromosome 15 and a SRY deletion. The pregnancy was continued and a
normal baby boy without any discernible abnormalities was born.
PMID- 9556049
TI - Application of the surface rendering technique of three-dimensional ultrasound in
prenatal diagnosis and counselling of Klippel-Trenaunay-Weber syndrome.
AB - Klippel Trenaunay-Weber syndrome is a complex developmental disorder
characterized by a triad of cutaneous haemangioma, varicosities of the body, and
unilateral limb hypertrophy. We describe the prenatal diagnosis of Klippel
Trenaunay-Weber syndrome at 15 weeks' gestation using the surface rendering
technique of three-dimensional ultrasound. The vivid three-dimensional images of
the affected fetus are invaluable in prenatal diagnosis and parental counselling.
PMID- 9556050
TI - Re: 'Single umbilical artery--right or left? Does it matter?' by Blazer et al.
PMID- 9556051
TI - Mental status and psychosocial functioning in XYY males.
PMID- 9556052
TI - Transient unilateral cerebral ventriculomegaly.
PMID- 9556053
TI - Bone and the hematopoietic and immune systems: a report of the proceedings of a
scientific workshop.
AB - Recent observations underscore the linkage between endochondral bone formation
and the establishment of hematopoietic marrow and suggest that interactions among
bone, marrow, and the immune system persist in the mature skeleton. A workshop
was held at the National Institutes of Health, Bethesda, Maryland, to discuss
recent work on these interactions and to identify new areas of research. Marrow
stromal cells include the precursors of the osteochondrogenic lineage, exert
important influences on osteoclastogenesis and lymphopoiesis, and mediate the
effects of some systemic factors on bone turnover. Recent evidence indicates that
hematopoietic cells can influence the differentiation of osteogenic cells and
suggests that mature lymphocytes can influence osteoclastic and osteoblastic
functions. However, interpretation of experiments may be confounded by the
potential for stage-specific responses within a cell lineage, the likelihood that
divergent pathways compete for limited pools of precursor cells, and the
possibility that important cells or factors are still unidentified. Further, in
vitro models may be limited by species and anatomical site specificities, the
absence of intermediary or accessory cells, and the absence of normal marrow
spatial organization and cellular interactions with the extracellular matrix.
Nevertheless, current approaches hold the potential for significant advances in
our understanding of the relationships between bone and the hematopoietic and
immune systems. Refinements of in vitro systems, the use of genetically
manipulated mice, and the examination of clinical syndromes promise important
insights. Collaborations among bone biologists, hematologists, and immunologists,
and between basic scientists and clinical investigators, will be crucial for
continued progress.
PMID- 9556054
TI - Seasonal deficiency of vitamin D in children: a potential target for osteoporosis
preventing strategies?
AB - Peak bone mass attained after skeletal growth is a major determinant of the risk
of developing osteoporosis later in life, hence the importance of nutritional
factors that contribute to bone mass gain during infancy and adolescence. An
adequate supply of vitamin D is essential for normal bone homeostasis. This study
was undertaken to determine what the levels are of 25-hydroxyvitamin D (25(OH)D)
that may be considered desirable in children and to assess if normal children
maintain these levels throughout the year. Vitamin D metabolites and parathyroid
hormone (PTH) serum levels were measured in 21 children in March and October,
prior to and after the administration of a daily supplement of 25(OH)D (40 microg
for 7 consecutive days). There were inverse correlations between basal 25(OH)D
levels and supplementation-induced changes in serum 1,25(OH)2D (r = 0.57, p <
0.05) and PTH (r = 0.41, p < 0.05). When basal levels of 25(OH)D were below 20
ng/ml, the supplement induced an increase in serum 1,25(OH)2D; with basal 25(OH)D
under 10-12 ng/ml, the supplement also decreased serum PTH. The lowest serum
level of 25(OH)D in 43 normal children studied in summer was 13 ng/ml. Those
results suggested that the lowest limit for desirable levels of 25(OH)D in
children was somewhere between 12 and 20 ng/ml. However, 31% of 51 normal
children studied in winter had levels below 12 ng/ml, and 80% had levels lower
than 20 ng/ml. Those children are likely to have suboptimal bioavailability of
vitamin D, which might hamper their achievement of an adequate peak bone mass.
Since cutaneous synthesis of vitamin D is rather limited in winter, oral vitamin
D supplementation should be considered.
PMID- 9556055
TI - The biological activity of nonsteroidal vitamin D hormone analogs lacking both
the C- and D-rings.
AB - 1alpha,25-dihydroxyvitamin D is a key calcium-regulating hormone but also
displays potent differentiating and antiproliferative activities on many cell
types. The structural requirements of this secosteroid hormone have been
extensively studied for the A-ring and side chain, whereas relatively little is
known about the requirements of the natural CD-ring structure for the vitamin D
like biological activity. We have embarked on a vast program in which derivatives
were synthesized and evaluated characterized by profound structural changes in
the central C/D-region. This first series of nonsteroidal analogs consists of
(1R,3S)-5-((Z,2E)-4-((1S,3S)-3-(4-hydroxy-4-methylpentyl)-1,2,2-++
+trimethylcyclopentyl)-2-butenylidene)-4-methylenecyclohexan e-1,3-diol (KS 176)
and derivatives thereof. These analogs are characterized by the absence of normal
C- and D-rings and by the presence of an unnatural five-membered ring which we
call the E-ring. KS 176 with the otherwise natural side chain structure of
1alpha,25(OH)2D3 has between 10 and 30% of the biological activity of
1alpha,25(OH)2D3 when tested in vitro (prodifferentiating effects on HL-60 and MG
63; antiproliferating activity on MCF-7 and keratinocytes) but has minimal in
vivo calcemic effects. Introduction of several side chain modifications created
analogs with increased intrinsic noncalcemic biological properties, whereas their
calcemic potency remains very low. These data demonstrate that the full CD-rings
are not mandatory for the biological activity of 1alpha,25(OH)2D3 since they can
be replaced by a new ring structure which generates an appropriate spacing of the
A-seco B-rings in relation to the side chain. The biological activity of these
nonsteroidal analogs probably involves a classical genomic activation since they
are also active in transfection assays using an osteocalcin vitamin D responsive
element coupled to a human growth hormone reporter gene.
PMID- 9556056
TI - 1,25(OH)2D3 regulates protein kinase C activity through two phospholipid
dependent pathways involving phospholipase A2 and phospholipase C in growth zone
chondrocytes.
AB - We have previously shown that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) plays a
major role in growth zone chondrocyte (GC) differentiation and that this effect
is mediated by protein kinase C (PKC). The aim of the present study was to
identify the signal transduction pathway used by 1,25(OH)2D3 to stimulate PKC
activation. Confluent, fourth passage GC cells from costochondral cartilage were
used to evaluate the mechanism of PKC activation. Treatment of GC cultures with
1,25(OH)2D3 elicited a dose-dependent increase in both inositol-1,4,5
trisphosphate and diacylglycerol (DAG) production, suggesting a role for
phospholipase C and potentially for phospholipase D. Addition of
dioctanoylglycerol to plasma membranes isolated from GCs increased PKC activity.
Neither pertussis toxin nor choleratoxin had an inhibitory effect on PKC activity
in control or 1,25(OH)2D3-treated GCs, indicating that neither Gi nor Gs proteins
were involved. Phospholipase A2 inhibitors, quinacrine, OEPC (selective for
secretory phospholipase A2), and AACOCF3 (selective for cytosolic phospholipase
A2), and the cyclooxygenase inhibitor indomethacin decreased PKC activity, while
the phospholipase A2 activators melittin and mastoparan increased PKC activity in
GC cultures. Arachidonic acid and prostaglandin E2, two downstream products of
phospholipase A2 action, also increased PKC activity. These results indicate that
1,25(OH)2D3-dependent stimulation of PKC activity is regulated by two distinct
phospholipase-dependent mechanisms: production of DAG, primarily via
phospholipase C and production of arachidonic acid via phospholipase A2.
PMID- 9556057
TI - Coupling of calcium receptors to inositol phosphate and cyclic AMP generation in
mammalian cells and Xenopus laevis oocytes and immunodetection of receptor
protein by region-specific antipeptide antisera.
AB - Ca2+ and other divalent cations modulate parathyroid hormone secretion by
interacting with cell-surface Ca2+-sensing receptors (CaRs). We assessed the
ability of these receptors to couple to Ca2+ mobilization, inositol phosphate
(InsP) accumulation, and cyclic AMP production in different expression systems.
In Xenopus laevis oocytes injected with bovine parathyroid CaR cRNA, the addition
of extracellular cations to 1.5 mM Ca2+, 5.5 mM Mg2+, or 10 microM Gd3+
significantly increased 45Ca efflux (p < 0.01). InsP accumulation also increased
dramatically when adding these cations to human embryonic kidney (HEK) 293 cells
stably transfected with wild-type bovine parathyroid CaR cDNA. Raising the
extracellular [Ca2+] ([Ca2+]o) from 0.1 to > 1.4 mM in oocytes and to > 1.0 mM in
HEK 293 cells stimulated significant increments in 45Ca efflux and InsP
accumulation, respectively (p < 0.05). In contrast, Ca2+ and Mg2+ increased InsPs
to a lesser extent in COS 7 cells transiently transfected with CaR cDNA. In HEK
293 cells stably expressing CaR cDNA, there were significant reductions in cAMP
content when adding high Ca2+, Mg2+, Gd3+, or the CaR modulator NPS R-467. Three
region-specific anti-CaR peptide antisera immunoblotted bands of approximately
140 and 155 kDa in membranes from CaR-transfected HEK 293 cells and bovine
parathyroid tissue. Immunocytochemistry demonstrated strong cell-surface staining
in CaR-transfected HEK 293 cells and parathyroid tissue, which was absent when
antisera were preabsorbed with CaR peptides. These results indicate that the
activation of the recombinant CaR by extracellular Ca2+ can couple negatively to
adenylate cyclase but positively to phospholipase C (PLC), the latter at
physiological [Ca2+]o.
PMID- 9556058
TI - Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent
post-translational prenylation of GTP-binding proteins, including Ras.
AB - Bisphosphonates are currently the most important class of antiresorptive drugs
used for the treatment of metabolic bone diseases. Although the molecular targets
of bisphosphonates have not been identified, these compounds inhibit bone
resorption by mechanisms that can lead to osteoclast apoptosis. Bisphosphonates
also induce apoptosis in mouse J774 macrophages in vitro, probably by the same
mechanisms that lead to osteoclast apoptosis. We have found that, in J774
macrophages, nitrogen-containing bisphosphonates (such as alendronate,
ibandronate, and risedronate) inhibit post-translational modification
(prenylation) of proteins, including the GTP-binding protein Ras, with farnesyl
or geranylgeranyl isoprenoid groups. Clodronate did not inhibit protein
prenylation. Mevastatin, an inhibitor of 3-hydroxy-3-methylglutatyl (HMG)-CoA
reductase and hence the biosynthetic pathway required for the production of
farnesyl pyrophosphate and geranylgeranyl pyrophosphate, also caused apoptosis in
J774 macrophages and murine osteoclasts in vitro. Furthermore, alendronate
induced apoptosis, like mevastatin-induced apoptosis, could be suppressed in J774
cells by the addition of farnesyl pyrophosphate or geranylgeranyl pyrophosphate,
while the effect of alendronate on osteoclast number and bone resorption in
murine calvariae in vitro could be overcome by the addition of mevalonic acid.
These observations suggest that nitrogen-containing bisphosphonate drugs cause
apoptosis following inhibition of post-translational prenylation of proteins such
as Ras. It is likely that these potent antiresorptive bisphosphonates also
inhibit bone resorption by preventing protein prenylation in osteoclasts and that
enzymes of the mevalonate pathway or prenyl protein transferases are the
molecular targets of the nitrogen-containing bisphosphonates. Furthermore, the
data support the view that clodronate acts by a different mechanism.
PMID- 9556059
TI - Na+ -phosphate cotransport in mouse distal convoluted tubule cells: evidence for
Glvr-1 and Ram-1 gene expression.
AB - While there is considerable evidence for phosphate (Pi) reabsorption in the
distal tubule, Pi transport and its regulation have not been well characterized
in this segment of the nephron. In the present study, we examined Na+-dependent
Pi transport in immortalized mouse distal convoluted tubule (MDCT) cells. Pi
uptake by MDCT cells is Na+-dependent and, under initial rate conditions, is
inhibited by phosphonoformic acid (41 +/- 3% of control), a competitive inhibitor
of Na+-Pi cotransport. The transport system has a high affinity for Pi (Km = 0.46
mM) and is stimulated by lowering the extracellular pH from 7.4 to 6.4 and
inhibited by raising the pH from 7.4 to 8.4. Exposure to Pi-free medium for 21 h
increased Na+-Pi cotransport from 2.1 to 5.5 nmol/mg of protein/5 minutes (p <
0.05) while parathyroid hormone, forskolin, and phorbol 12-myristate 13-acetate
failed to alter Pi uptake in MDCT cells. Reverse transcriptase polymerase chain
reaction of MDCT cell RNA provided evidence for the expression of the Npt1 but
not the Npt2 Na+-Pi cotransporter gene. However, preincubation of MDCT cells with
Npt1 antisense oligonucleotide led to only 20% inhibition of Na+-Pi cotransport,
suggesting that other Na+-Pi cotransporters are operative in MDCT cells. Indeed,
we showed, by ribonuclease protection assay, that MDCT cells express the
ubiquitous cell surface receptors for gibbon ape leukemia virus (Glvr-1) and
amphoteric murine retrovirus (Ram-1) that also function as Na+-Pi cotransporters.
In summary, we demonstrate that the pH dependence and regulation of Na+-Pi
cotransport in MDCT cells is distinct from that in the proximal tubule and
suggest that different gene products mediate Na+-Pi cotransport in the proximal
and distal segments of the nephron.
PMID- 9556060
TI - Immortalization and characterization of bone marrow stromal fibroblasts from a
patient with a loss of function mutation in the estrogen receptor-alpha gene.
AB - A male patient with abnormal postpubertal bone elongation was shown earlier to
have a mutation in both alleles of the estrogen receptor, resulting in a
nonfunctional gene. Marrow stromal fibroblasts (MSFs) derived from this patient
were called HERKOs (human estrogen receptor knock outs), and in order to obtain
continuous HERKO cell lines, they were immortalized using a recombinant
adenovirus-origin-minus SV40 virus. MSFs are unique cells because they support
hematopoesis and contain a mixed population of precursor cells for bone,
cartilage, and fat. Three established cell lines (HERKO2, HERKO4, and HERKO7)
were characterized and compared with the heterogeneous population of
nonimmortalized HERKOs for their osteogenic potential. We performed Northern
analysis of matrix genes implicated in bone development and metabolism and an in
vivo bone formation assay by transplanting the cells subcutaneously into
immunodeficient mice. All three HERKO lines expressed high amounts of collagen
1A1, osteopontin, osteonectin, fibronectin, decorin, biglycan, and alkaline
phosphatase. Except for osteopontin, expression of these genes was slightly lower
compared with nonimmortalized HERKOs. In the in vivo bone formation assay, the
heterogeneous population of nonimmortalized HERKOs formed bone with high
efficiency, while the HERKO lines induced a high-density, bone-like matrix.
Finally, all HERKO cell types secreted high levels of insulin-like growth factor
I and interleukin-6 into the culture medium relative to cells of normal human
subjects. In summary, these lines of HERKO cells retain several of the phenotypic
traits of MSFs after immortalization, including matrix and cytokine production,
and provide a valuable source of a unique human material for future studies
involving estrogen action in bone and bone marrow metabolism.
PMID- 9556061
TI - Reciprocal temporospatial patterns of Msx2 and Osteocalcin gene expression during
murine odontogenesis.
AB - Msx2 is a homeodomain transcription factor that regulates craniofacial
development in vivo and osteocalcin (Osc) promoter activity in vitro. Msx2 is
expressed in many craniofacial structures prior to embryonic day (E) E14 but is
expressed at later stages in a restricted pattern, primarily in developing teeth
and the calvarium. We examine Osc expression by in situ hybridization during
murine development, detailing temporospatial relationships with Msx2 expression
during preappositional and appositional odontogenesis and calvarial osteogenesis.
Osc expression at E14-14.5 is very low, limited to a few perichondrial
osteoblasts in the dorsal aspect of developing ribs. At E16.5 and E18.5, Osc
expression is much higher, widely expressed in skeletal osteoblasts, including
calvarial osteoblasts that do not express Msx2. No Osc is detected in early
preappositional teeth that express Msx2. In incisors studied at an early
appositional phase, Msx2 is widely expressed in the tooth, primarily in ovoid
preodontoblasts and subjacent dental papilla cells. Osc is detected only in a
small number of maturing odontoblasts that also express alpha1(I) collagen
(Colla1) and that are postproliferative (do not express histone H4). Msx2
expression greatly overlaps both histone H4 and Colla1 expression in ovoid
preodontoblasts and dental papilla cells. By the late appositional phases of
E18.5 and neonatal teeth, Osc mRNA is highly expressed in mature columnar
odontoblasts adjacent to accumulating dentin. In appositional bell-stage molars,
reciprocal patterns of Msx2 and Osc are observed in adjacent preodontoblasts and
odontoblasts within the same tooth. Osc is expressed in mature columnar
odontoblasts, while Msx2 is expressed in adjacent immature ovoid preodontoblasts.
In less mature teeth populated only by immature ovoid preodontoblasts, only Msx2
is expressed-no Osc is detected. Thus, Msx2 and Osc are expressed in reciprocal
patterns during craniofacial development in vivo, and Msx2 expression in
preodontoblasts clearly precedes Osc expression in odontoblasts. In functional
studies using MC3T3-E1 calvarial osteoblasts, Msx2 suppresses endogenous Osc, but
not osteopontin, mRNA accumulation. In toto, these data suggest that Msr2
suppresses Osc expression in the craniofacial skeleton at stages immediately
preceding odontoblast and osteoblast terminal differentiation.
PMID- 9556062
TI - Spatiotemporal assessment of fetal bovine osteoblast culture differentiation
indicates a role for BSP in promoting differentiation.
AB - Fetal bovine mandible-derived osteoblasts were cultured for the purpose of
obtaining a spatiotemporal assessment of bone matrix protein expression during in
vitro differentiation. The results obtained from electron microscopic,
immunohistological, biochemical, and molecular biological analyses indicated that
these primary cultured osteoblasts produce an abundant extracellular matrix which
mineralizes during a 14-day culture period. During this process, a restricted,
spatiotemporal pattern of bone sialoprotein expression was indicated by
immunohistological and molecular evaluations. To test the possibility that bone
sialoprotein promoted the continued morphodifferentiation of osteoblastic cells,
cultures were grown in the presence of anti-bone sialoprotein antibodies known to
interfere with cell-bone sialoprotein attachment. Compared with cultures grown in
the presence of normal rabbit serum (1:150), cultures grown in the media
containing anti-bone sialoprotein antibody (1:150) failed to mineralize as
demonstrated by von Kossa staining and failed to express osteocalcin and
osteopontin as shown by the reverse transcription polymerase chain reaction.
These results contribute to the growing evidence that bone sialoprotein is an
important determinant of osteoblast differentiation and bone formation. Matrix
protein-cell interactions may be examined using this spatiotemporally defined
model.
PMID- 9556063
TI - Human osteoblasts express a repertoire of cadherins, which are critical for BMP-2
induced osteogenic differentiation.
AB - Direct cell-cell interactions are fundamental for tissue development and
differentiation. We have studied the expression and function of cadherins in
human osteoblasts during in vitro differentiation. Using reverse transcription
polymerase chain reaction and mRNA hybridization, we found that human trabecular
bone osteoblasts (HOBs), osteoprogenitor marrow stromal cells (BMCs), and the
osteogenic sarcoma lines, SaOS-2 and MG-63, expressed mRNA for cadherin-11 (C11)
and N-cadherin (N-cad). HOBs and BMCs also expressed low levels of cadherin-4
(C4) mRNA. C11 was the most abundant cadherin protein present in human
osteoblasts, and its expression was unaffected by bone morphogenetic protein-2
(BMP-2) treatment of either BMCs or HOBs. Likewise, N-cad mRNA did not change
during BMP-2 incubation. Conversely, C4 protein, undetectable in transformed cell
lines, was down-regulated by BMP-2 treatment of normal cells. Both C11 and C4
were localized to sites of cell-cell contact in both HOBs and BMCs, colocalized
with beta-catenin, and bands corresponding to cadherins were coimmunoprecipitated
by a beta-catenin antibody, findings indicative of functional cadherins. A
decapeptide containing the HAV motif of human N-cad partially inhibited Ca2+
dependent cell-cell adhesion and completely prevented BMP-2-induced stimulation
of alkaline phosphatase activity by BMCs. Thus, human osteoblasts and their
progenitor cells express a repertoire of multiple cadherins. Cadherin-mediated
cell-to-cell adhesion is critical for normal human osteoblast differentiation.
PMID- 9556064
TI - The effects of fibroblast growth factor-2 on human neonatal calvaria osteoblastic
cells are differentiation stage specific.
AB - Fibroblast growth factors (FGFs) appear to play an important role in human
cranial osteogenesis. We therefore investigated the effects of recombinant human
FGF-2 (rhFGF-2) on human calvaria (HC) osteoblastic cells. Immunocytochemical
analysis showed that confluent HC cells express both FGF receptors -1 and -2. In
short-term culture, rhFGF-2 (0.1-100 ng/ml, 2-5 days) increased HC cell growth
and decreased alkaline phosphatase (ALP) activity and type I collagen (ColI)
synthesis, as evaluated by P1CP levels. When HC cells were induced to
differentiate in long-term culture in the presence of 50 microg/ml ascorbic acid
and 3 mM phosphate, HC cells initially proliferated, then ALP activity and ColI
synthesis decreased and calcium content in the extracellular matrix increased.
Continuous treatment with rhFGF-2 (50 ng/ml) for 1-28 days, or a transient rhFGF
2 treatment for 1-7 days, slightly increased DNA synthesis at 7 days, whereas a
late treatment for 8-28 days had no effect on cell growth. The continuous and
transient treatments with rhFGF-2 decreased ALP activity, ColI synthesis, and
matrix mineralization. This was associated with a transient fall in osteocalcin
(OC) production at 7 days. In contrast, the late rhFGF-2 treatment for 8-28 days
only slightly inhibited ALP activity and increased matrix mineralization. In
addition, both continuous and late treatments with rhFGF-2 increased OC
production in more mature cells at 3-4 weeks of culture. We also found that the
early and late treatments with rhFGF-2 had opposite effects on transforming
growth factor beta2 production in proliferating cells and more mature cells. The
results show that rhFGF-2 slightly stimulates cell growth and reduces the
expression of osteoblast markers in less mature cells, whereas it induces OC
production and matrix mineralization in more mature cells, indicating that the
effects of FGF-2 are differentiation stage specific and that FGF-2 may modulate
HC osteogenesis by acting at distinct stages of cell maturation.
PMID- 9556065
TI - Mesenchymal stem cell surface antigen SB-10 corresponds to activated leukocyte
cell adhesion molecule and is involved in osteogenic differentiation.
AB - Bone marrow contains a rare population of mesenchymal stem cells (MSCs) capable
of giving rise to multiple mesodermal tissues including bone, cartilage, tendon,
muscle, and fat. The cell surface antigen recognized by monoclonal antibody SB-10
is expressed on human MSCs but is lost during their developmental progression
into differentiated phenotypes. Here we report on the immunopurification of the
SB-10 antigen and its identification as activated leukocyte-cell adhesion
molecule (ALCAM). Mass spectrometry establishes that the molecular mass of ALCAM
is 80,303 +/- 193 Da and that it possesses 17,763 +/- 237 Da of N-linked
oligosaccharide substituents. Molecular cloning of a full-length cDNA from a MSC
expression library demonstrates nucleotide sequence identity with ALCAM. We also
identified ALCAM homologs in rat, rabbit, and canine MSCs, each of which is over
90% identical to human ALCAM in their peptide sequence. The addition of antibody
SB-10 Fab fragments to human MSCs undergoing osteogenic differentiation in vitro
accelerated the process, thereby implicating a role for ALCAM during bone
morphogenesis and adding ALCAM to the group of cell adhesion molecules involved
in osteogenesis. Together, these results provide evidence that ALCAM plays a
critical role in the differentiation of mesenchymal tissues in multiple species
across the phylogenetic tree.
PMID- 9556066
TI - Role of interleukin-6 in uncoupling of bone in vivo in a human squamous carcinoma
coproducing parathyroid hormone-related peptide and interleukin-6.
AB - OCC tumor has been established from a human squamous carcinoma associated with
humoral hypercalcemia of malignancy (HHM) and shown to overproduce parathyroid
hormone-related peptide (PTHrP) and cause aggressive hypercalcemia when implanted
into nude rats. In the present study, we have demonstrated by reverse
transcription-polymerase chain reaction and Northern blot analysis that OCC tumor
also overexpressed interleukin 6 (IL-6) mRNA and that tumor-bearing animals
exhibited a marked increase in plasma IL-6 as well as PTHrP concentrations. When
a monoclonal antibody against human IL-6 was injected to block the activities of
tumor-derived IL-6, bone loss in tumor-bearing animals was significantly
prevented. Quantitative bone histomorphometric analysis revealed that treatment
with anti-IL-6 antibody caused a substantial decrease in both osteoclast number
and eroded surface (as parameters of bone resorption) and also a significant
increase in the mineral apposition rate, but little effect on the osteoblastic
surface. These results provide in vivo evidence suggesting that in tumors
coproducing IL-6 and PTHrP, IL-6 is involved not only in the acceleration of
osteoclastic bone resorption but also, at least in part, in the suppression of
osteoblastic functions in HHM syndrome.
PMID- 9556067
TI - Cathepsin K mRNA detection is restricted to osteoclasts during fetal mouse
development.
AB - We recently identified a novel cysteine protease, cathepsin K, by random
sequencing of an osteoclast cDNA library, and in situ hybridization studies in
adult human tissues demonstrated high and specific expression in osteoclasts. To
determine whether the expression of cathepsin K mRNA during mouse embryogenesis
was more widespread, cryostat sections of early (day 11-13) and late (day 15-17)
mouse fetuses were analyzed by in situ hybridization. Serial cross-sections were
collected through each fetus, and co-reacted for tartrate-resistant acid
phosphatase (TRAP) and nonspecific esterase (NSE), selective markers for the
osteoclast, and precursor cells derived from the macrophage/monocyte lineage,
respectively. In the 11-13 day fetuses, cathepsin K mRNA was not expressed in any
extraskeletal tissue; at this stage of embryogenesis, no osteoclasts are present.
However, in the 15-17 day fetuses, a distinctive, developmental stage-dependent
pattern of cathepsin K expression was observed in osteoclasts and preosteoclasts
at sites of cartilage and bone modeling. Cathepsin K positive osteoclasts
differentiated within a peripheral zone of the osteogenic stacked cell layer of
the cartilage rudiments (prior to ossification), migrated and/or resorbed the
bone collar, and invaded the cartilage core. Furthermore, following the invasive
penetration of vasculature into the degenerating cartilage core, the calcified
cartilage was resorbed by cathepsin K positive mononuclear osteoclast precursors
(NSE+ve, negligible TRAP); cells positive for both enzymes were identified
indicative of osteoclast differentiation. The deposition of bone by osteoblasts
onto the cartilage remnants is followed by mononucleated and multinucleated
osteoclastic resorption; these osteoclasts demonstrated intense cathepsin K
expression. Similar expression patterns were observed at sites of intramembranous
ossification. No expression was observed in chondrocytes, osteoblasts, marrow, or
in any other nonskeletal tissue at these time points. These data indicated that
cathepsin K expression during embryogenesis occurred only following the onset of
osteoclast differentiation.
PMID- 9556068
TI - Characterization of serum tartrate-resistant acid phosphatase and development of
a direct two-site immunoassay.
AB - Osteoclasts secrete tartrate-resistant acid phosphatase (TRAP) to the
circulation, where the amount of TRAP is expected to correlate with the bone
resorption rate. We have developed two monoclonal antibodies, O1A and J1B, using
purified human bone TRAP as antigen. The antibodies recognized different
epitopes, allowing us to develop a two-site fluoroimmunoassay. The
immunoreactivity in fresh serum specimens was less than 10% of the concentrations
measured from the same specimens after 24 h of storage at 4 degrees C, or after
addition of 5 mM EDTA or EGTA to them. When fresh serum was gel filtrated using
Sephacryl S-200 column, all of the enzyme eluted in the void volume as a complex
with a molecular weight of more than 250 kDa. If the serum was treated with EDTA
before the gel filtration, the complex was destroyed and the enzyme eluted in
fractions corresponding to a molecular weight of 30 kDa, the size of monomeric
purified human bone TRAP. The immunoassay was used to measure TRAP concentrations
from serum samples that had been stored at 4 degrees C for 24 h. According to the
assay, premenopausal women had 13.1 +/- 3.1, postmenopausal women 17.6 +/- 4.2,
and children 32.6 +/- 12.2 microg TRAP/l of serum. We conclude that TRAP
circulates in the serum as part of a complex, which also contains Ca2+, and that
TRAP-immunoassay is a potentially useful method for determining bone resorption
rates, as long as the complex is destroyed before the assay.
PMID- 9556069
TI - Wortmannin inhibits spreading and chemotaxis of rat osteoclasts in vitro.
AB - Wortmannin (WT) and 17beta-hydroxywortmannin (HWT), which are inhibitors of
phosphatidylinositol-3(OH)-kinase (PI3K), have been shown previously to inhibit
bone resorption in vitro and in vivo, possibly by interfering with formation of
the osteoclast ruffled border. Since migration of osteoclasts also plays an
important role in the process of bone resorption, we investigated the effects of
these inhibitors on osteoclast morphology and motility. Both HWT and WT caused a
sustained decrease in the planar area of osteoclasts in vitro (half maximal
effect at 25 and 165 nM, respectively), with the effect of HWT on cell area more
readily reversible than WT. These agents also caused accumulation of
intracellular vesicles. Time-lapse video microscopy was used to record the
migration of osteoclasts in response to macrophage colony-stimulating factor (M
CSF) or vehicle, flowing passively from a micropipette positioned 200-400 microm
from the cell. M-CSF caused directed migration of osteoclasts, indicating
chemotaxis (over 3 h osteoclasts migrated 96 +/- 14 microm in response to M-CSF
vs. 11 +/- 2 microm in control experiments). Both WT (100 or 500 nM) and LY294002
(100 microM), a specific PI3K inhibitor structurally unrelated to WT,
significantly inhibited osteoclast chemotaxis in response to M-CSF. Taken
together, these effects of WT, HWT, and LY294002 are consistent with an important
role for PI3K in regulating cytoskeletal function in osteoclasts. The inhibitory
effects of WT and HWT on bone resorption may be due, in part, to impairment of
osteoclast motility.
PMID- 9556070
TI - Bone mineral density and its change in white women: estrogen and vitamin D
receptor genotypes and their interaction.
AB - Low bone mineral density (BMD) is a major risk factor for development of
osteoporosis; increasing evidence suggests that attainment and maintenance of
peak bone mass as well as bone turnover and bone loss have strong genetic
determinants. We examined the association of BMD levels and their change over a 3
year period, and polymorphisms of the estrogen receptor (ER), vitamin D receptor
(VDR), type I collagen, osteonectin, osteopontin, and osteocalcin genes in pre-
and perimenopausal women who were part of the Michigan Bone Health Study, a
population-based longitudinal study of BMD. Body composition measurements,
reproductive hormone profiles, bone-related serum protein measurements, and life
style characteristics were also available on each woman. Based on evaluation of
women, ER genotypes (identified by PvuII [n = 253] and XbaI [n = 248]) were
significantly predictive of both lumbar spine (p < 0.05) and total body BMD
level, but not their change over the 3-year period examined. The VDR BsmI
restriction fragment length polymorphism was not associated with baseline BMD,
change in BMD over time, or any of the bone-related serum and body composition
measurements in the 372 women in whom it was evaluated. Likewise, none of the
other polymorphic markers was associated with BMD measurements. However, we
identified a significant gene x gene interaction effect (p < 0.05) for the VDR
locus and PvuII (p < 0.005) and XbaI (p < 0.05) polymorphisms, which impacted BMD
levels. Women who had the (-/-) PvuII ER and bb VDR genotype combination had a
very high average BMD, while individuals with the (-/-) PvuII ER and BB VDR
genotype had significantly lower BMD levels. This contrast was not explained by
differences in serum levels of osteocalcin, parathyroid hormone, 1,25
dihydroxyvitamin D, or 25-dihydroxyvitamin D. These data suggest that genetic
variation at the ER locus, singly and in relation to the vitamin D receptor gene,
influences attainment and maintenance of peak bone mass in younger women, which
in turn may render some individuals more susceptible to osteoporosis than others.
PMID- 9556071
TI - Systemic over-secretion of growth hormone in transgenic mice results in a
specific pattern of skeletal modeling and adaptation.
AB - The effects of growth hormone (GH) over-secretion on bone modeling and remodeling
in transgenic mice were investigated using systematic and hierarchical methods.
The results showed that continual systemic stimulation of GH over-secretion in
mice resulted in an initial increase in bone mass, but its bone quality was not
comparable with that of the littermate controls. Further continual over
stimulation of GH resulted in an increase in bone resorption leading to thinner
cortices with inferior tissue mechanical properties. Three biological mechanisms
following GH over-production are formulated to explain the observed results: GH
over-secretion stimulated the production of inferior bone matrices, i.e., woven
bone and cartilage, in addition to the production of normal lamellar bone; the
increased bone formation stimulated by GH was followed by an exaggerated bone
resorption process, resulting in cortical tissue with inferior mechanical
properties; and a cortical shift occurred following GH over-stimulation that
appeared to be caused by the combined effects of GH over-secretion and a
variation in mechanical stimuli in the metallothionein-1 growth hormone
regulating hormone transgenic mice. An "Optimal Strain Environment" model is
proposed to help explain the observed results. From the results of the present
and previous studies, we believe that the primary goal of bone adaptation to a
biological perturbation, at least in mice, is to ensure proper mechanical
function by maintaining structural integrity. In the process of maintaining a
targeted whole bone structural integrity, the mechanical integrity of tissue may
be sacrificed.
PMID- 9556072
TI - Concentration of transforming growth factor beta in human bone tissue:
relationship to age, menopause, bone turnover, and bone volume.
AB - Transforming growth factor beta (TGF-beta) is thought to play an important role
in bone metabolism, but its relationship to human bone turnover and bone mass has
not been examined yet. In this study, we measured the concentration of TGF-beta
in 811 samples of male and female bone from four representative sites of the
human skeleton and in the supernatants of 72 short-term human bone marrow
cultures from the iliac crest. The concentrations of TGF-beta1 and TGF-beta2 in
the bone matrix were positively correlated with histomorphometric indices of bone
resorption and bone formation and with serum levels of osteocalcin and bone
specific alkaline phosphatase. We also observed a positive association between
the release of TGF-beta in the bone marrow cultures and serum osteocalcin.
Changes in the rate of cancellous or cortical bone remodeling with age or
menopause were accompanied by corresponding changes in skeletal TGF-beta. In
contrast, there was no significant relationship between the concentration of TGF
beta and bone volume at any skeletal site. In conclusion, our study supports the
hypothesis that TGF-beta plays an important role in human bone remodeling, but
fails to demonstrate an association between the skeletal concentration of TGF
beta and human bone mass.
PMID- 9556073
TI - Human growth hormone locally released in bone sites by calcium-phosphate
biomaterial stimulates ceramic bone substitution without systemic effects: a
rabbit study.
AB - Calcium-phosphate bone replacement biomaterial has been used as a drug carrier
for therapeutic agents. This study investigated the efficacy of local
administration of human growth hormone (hGH) by macroporous biphasic calcium
phosphate (MBCP) implants in improving the bone substitution qualities of
ceramics. hGH release from MBCP implants loaded with 1 microg of hGH was rapid
during the first 48 h and then sustained for a total of 9 days.
Immunolocalization of hGH in vitro and in vivo by transmission electron
microscopy showed its presence inside the material, indicating that it was able
to penetrate within the porosity of the ceramic during the adsorption process.
MBCP cylinders (6 x 6 mm) were loaded with 0.1, 1, and 10 microg of hGH and
implanted into rabbit femurs (n = 40). The effects of locally released hGH on
bone ingrowth and ceramic resorption were evaluated by scanning electron
microscopy and image analysis. The results indicated that hGH increased bone
ingrowth (+65%) and ceramic resorption (+140%) significantly in comparison with
control implants and that the increase was dose dependent. Biochemical parameters
monitored in rabbit plasma and urine, as well as the absence of any significant
difference between contralateral implants and the control, indicated that hGH did
not produce detectable systemic effects. Thus, the use of MBCP appears to be
effective for local delivery of hGH, resulting in improved bone substitution.
PMID- 9556074
TI - Magnesium deficiency: a cause of heterogeneous disease in humans.
PMID- 9556075
TI - Bone alkaline phosphatase during short-term treatment with insulin-like growth
factor I and growth hormone in growth hormone-deficient adults.
PMID- 9556076
TI - Angiotensin receptors and norepinephrine neuromodulation: implications of
functional coupling.
AB - The objective of this review is to examine the role of neuronal angiotensin II
(Ang II) receptors in vitro. Two types of G protein-coupled Ang II receptors have
been identified in cardiovascularly relevant areas of the brain: the AT1 and the
AT2. We have utilized neurons in culture to study the signaling mechanisms of AT1
and AT2 receptors. Neuronal AT1 receptors are involved in norepinephrine (NE)
neuromodulation. NE neuromodulation can be either evoked or enhanced. Evoked NE
neuromodulation involves AT1 receptor-mediated, losartan-dependent, rapid NE
release, inhibition of K+ channels and stimulation of Ca2+ channels. AT1 receptor
mediated enhanced NE neuromodulation involves the Ras-Raf-MAP kinase cascade and
ultimately leads to an increase in NE transporter, tyrosine hydroxylase and
dopamine beta-hydroxylase mRNA transcription. Neuronal AT2 receptors signal via a
Gi protein and are coupled to activation of PP2A and PLA2 and stimulation of K+
channels. Finally, putative cross-talk pathways between AT1 and AT2 receptors
will be discussed.
PMID- 9556077
TI - Characterization and localization of galanin receptors in human entorhinal
cortex.
AB - The neuropeptide galanin (GAL) has a widespread distribution throughout the human
cortex. The entorhinal cortex (ENT) plays a crucial role in the transfer of
cortico-cortical information related to memory and displays severe degeneration
in Alzheimer's disease (AD). However, very little is known about the pharmacology
of the GAL receptor (GALR) in normal human ENT. Therefore, we pharmacologically
visualized their distribution and characterized GALRs using in vitro receptor
autoradiography and radioligand binding assays. Autoradiograms revealed intense
GALR labeling, mainly in the substantia innominata, hypothalamus, the bed nucleus
of the stria terminalis and within layers 2 and 4 of the ENT. Kinetic experiments
showed that saturation of GALR sites by [125I]GAL (human) (hGAL) occurred within
2 h and that this binding readily reversed in the presence of a GTP analog, but
not in the presence of excess unlabeled hGAL. Analysis of [125I]hGAL binding data
from saturation experiments gave KD values of 98.6+/-21.6 pM, Bmax values of
52.9+/-32.4 fmol/mg protein and identified a high and low affinity state of the
GALR. The presence of 5'-guanylylimidodiphosphate (GppNHp) or NaCl reduced the
agonist labeling of hGALR in ENT membranes.
PMID- 9556078
TI - Bioactivity of intraduodenally and intravenously infused fragments of luminal
cholecystokinin releasing factor (LCRF).
AB - A luminal cholecystokinin releasing factor (LCRF), has been purified from
intestinal secretion and found to have a mass of 8136 daltons. The amino-terminal
41 residues have been sequenced. Previous studies showed that intraduodenal
infusion of the synthetic amino-terminal 35 amino acid peptide, LCRF1-35
significantly stimulated pancreatic protein and fluid secretion in conscious
rats, but the peptide did not stimulate amylase release from isolated, dispersed
pancreatic acini. In the present study, several fragments of LCRF were
synthesized and tested for CCK-releasing activity (pancreatic protein secretion)
to determine whether shorter fragments of LCRF exhibit the characteristic
biological activity of native LCRF and synthetic LCRF1-35. Compounds tested were
LCRF1-41, LCRF1-35, LCRF1-65 and LCRF11-25. Of the fragments shorter than LCRF1
35, only LCRF11-25 but not LCRF1-6 had significant CCK releasing activity. LCRF1
41 was equivalent to LCRF1-35 in potency and efficacy. Intravenous and
intraduodenal infusion of LCRF1-35 elicited nearly identical dose-response
curves.
PMID- 9556079
TI - Uroguanylin: gene structure, expression, processing as a peptide hormone, and co
storage with somatostatin in gastrointestinal D-cells.
AB - Guanylin/GCAP-I and uroguanylin/GCAP-II are two structurally related peptides
which play an important role in the regulation of water/electrolyte balance
within the gut. In order to enable the investigation and comparison of both
peptide hormones at the genomic level, we decided to clone the corresponding
genes. The human gene for guanylin/GCAP-I and its 5'-flanking region have been
described recently. Here, we report the three exon/two intron structure of the
human uroguanylin/GCAP-II gene and its localization on chromosome 1 p35-34, as
determined by radiation hybrid mapping. Together with data obtained for the
guanylin/GCAP-I gene we show that these genes are localized in the same
chromosomal area with other guanlyl cyclase-activating peptides like ANP etc.
Northern hybridization revealed that the expression of the uroguanylin/GCAP-II
gene is highest in the intestinal mucosa, especially in the ileum and colon. By
means of polymerase chain reaction (PCR), an expression was also observed in the
stomach where no guanylin/GCAP-I expression is detectable. Using
immunohistochemical methods, uroguanylin/GCAP-II immunoreactive material was
distinctly localized in D-type gastric and intestinal endocrine cells. Although
the comparable data on the genomic organisation of both peptide hormones verify
their high degree of relationship, this finding indicates a special task of
uroguanylin/GCAP-II within the stomach, such as regulatory functions in gastric
secretion. The redundant expression of the GCAP/GC-C system in the small and
large intestine, however, is as yet unclear.
PMID- 9556080
TI - Evidence that peroral calcium does not activate the gastrin-ECL-cell axis in the
rat.
AB - The ECL cells are histamine- and pancreastatin-secreting endocrine cells in the
oxyntic mucosa, thought to release a blood Ca2+-lowering peptide hormone upon
stimulation by gastrin. Previously, we have shown that the ECL cells do not
respond to perturbations in blood Ca2+. In the present study, we examine if Ca2+
in the gastric lumen will affect the activity of the gastrin-ECL-cell axis.
Freely fed or food deprived (48 h) rats were given an oral load of CaCl2 (or
NaCl), and the blood Ca2+ concentration was monitored. The serum gastrin
concentration at sacrifice, 3 h after ingestion of CaCl2, was measured together
with two parameters of ECL cell activity: the oxyntic mucosal histidine
decarboxylase (HDC) activity and the serum pancreastatin concentration. The
circulating concentrations of calcitonin and parathyroid hormone (PTH) were also
measured. Oral CaCl2 raised the blood Ca2+ in a dose-dependent manner. The two
highest doses (which caused damage to the oxyntic mucosa) raised the serum
gastrin concentration and the HDC activity in both fed and fasted rats; the serum
pancreastatin concentration remained unaffected. Oral CaCl2 raised the serum
calcitonin concentration and lowered the serum PTH concentration. The effects of
high doses of oral CaCl2 on the serum gastrin concentration and on the oxyntic
mucosal HDC activity could be reproduced by a high dose of NaCl. Thus the effects
are probably not due to Ca2+ per se. We conclude that the gastrin-ECL-cell axis
in the rat does not respond to peroral Ca2+. Since the ECL cells do not respond
to either circulating or peroral Ca2+ they are unlikely to secrete a calciotropic
hormone.
PMID- 9556081
TI - Autoradiographic identification of a gastrin receptor on the human parietal cell.
AB - Gastrin plays an important role in regulating gastric acid secretion and
gastrointestinal mucosal growth but its cellular sites of action in man have not
been determined. Using cryostat sections of gastric mucosal tissue we have
identified (125I-gastrin binding followed by fixation-wet emulsion
autoradiography) and characterized (125I-gastrin binding followed by counting) a
gastrin receptor binding site in the human stomach. This site displayed binding
characteristics similar to those observed in isolated cell systems: specifically,
125I-gastrin binding was rapid (t1/2 approximately 10 min at 37 degrees C),
temperature-dependent (3.5 fold more radioligand bound at 22 degrees C than at 4
degrees C) and saturable. The binding of the radioligand was also tissue specific
and was five-fold greater in the gastric body than in the gastric antrum and
duodenum. In the autoradiographs, silver grains were localized only to parietal
cells and not to other epithelial cell types. In the presence of 40 nM gastrin
grains were no longer present over parietal cells demonstrating that these sites
were both saturable and of high affinity. These data provide the first
demonstration of gastrin binding sites (putative receptors) on parietal cells in
the human stomach and suggest that gastrin acts directly on these cells to help
regulate gastric acid secretion and/or mucosal growth.
PMID- 9556082
TI - Fetal pulmonary immunoreactive adrenocorticotropin: molecular weight and cellular
localization.
AB - The hypothalamus-pituitary-adrenal axis of the sheep fetus plays a critical role
in fetal development, responsiveness to stress, and initiation of parturition. We
have recently reported that the fetal lung contains and secretes significant
amounts of immunoreactive adrenocorticotropin (iACTH). The present study was
designed to identify the molecular weight profile and the cellular location of
iACTH in this tissue. iACTH extracted from fetal lung was immunoprecipitated,
electrophoresed, and immunoblotted. Pulmonary iACTH was found in several
molecular forms. The largest peptides appeared as doublets, and had molecular
weights similar to POMC (32, 33 kD). Smaller peptides appeared in molecular
weights (17, 24, and 27 kD) which were not consistent with the post-translational
processing of POMC in fetal pituitary, but which were consistent with known
processing of POMC by chromaffin granule aspartyl protease. None of the molecular
forms of iACTH were glycosylated. Immunohistochemistry revealed that the iACTH
was contained within bronchial epithelium and within groups of cells within the
parenchyma of the lung. Both of these types of cells are consistent with
pulmonary neuroendocrine cells. The distribution of neuroendocrine cells and
apparent concordance with the iACTH-positive cells was confirmed by
immunostaining for neuron specific enolase, a marker for neuroendocrine cells
within the lung. We conclude that the lung contains unprocessed and partially
processed POMC within cells known to contain neuropeptides. We speculate that
secretion of the POMC-related peptides from these cells is physiologically
important in the late-gestation fetus.
PMID- 9556083
TI - Chromatographic and immunological identification of GnRH (gonadotropin-releasing
hormone) variants. Occurrence of mammalian and a salmon-like GnRH in the
forebrain of an eutherian mammal: Hydrochaeris hydrochaeris (Mammalia, Rodentia).
AB - The molecular variants of Gonadotropin releasing hormone (GnRH) in brain extracts
of the eutherian mammal Hydrochaeris hydrochaeris (Mammalia, Rodentia) were
characterized. An indirect method combining reverse-phase high-performance liquid
chromatography (RP-HPLC) and radioimmunoassay (RIA) with different antisera was
used. Two different forebrain regions (olfactory bulbs and preoptic-hypothalamic
region) were analyzed. Characterization of RP-HPLC fractions from preoptic
hypothalamic extracts with three different RIA systems revealed two
immunoreactive GnRH (ir-GnRH) peaks coeluting with mammalian GnRH (mGnRH) and
salmon GnRH (sGnRH) synthetic standards. These results were additionally
supported by serial dilution studies with specific antisera. Similar results were
obtained from olfactory bulb extracts with the same methodology. However, a third
ir-GnRH peak in a similar position to that of chicken GnRH II (cIIGnRH) synthetic
standard was revealed. As far as we know, this is the first report showing
chromatographic and immunological evidences for the presence of a second GnRH
variant in the forebrain of an eutherian mammal.
PMID- 9556084
TI - Scientific and ethical issues of preimplantation diagnosis.
AB - Preimplantation diagnosis (PID) offers couples at high risk of having offspring
affected with a genetic disorder the possibility of an early prenatal diagnosis.
For many couples this approach will give the opportunity to avoid a selective
termination of affected pregnancies. Substantial advances were made in PID since
the report, in 1990, of the first birth obtained after PID. Yet, many technical
hazards have to be solved for PID to become a standard clinical tool. The very
close correlation existing between the forthcoming developments in the fields of
PID and human genome mapping will improve the reliability and efficiency of
genetic diagnosis. In the near future, the procedure may also become easier and
safer. As a consequence, the indications for PID could be extended to other
genetic defects, such as multifactorial diseases. They could also be extended to
cases with no medical background, such as social gender selection or behavioural
traits. In this perspective, it is now time for both the medical and scientific
communities to identify the ethical issues related to these potential new
indications.
PMID- 9556085
TI - Hormonal regulation of appetite and food intake.
AB - Several clinical disorders are strongly influenced by hormones involved in
appetite and weight regulation. Obesity and eating disorders are of major
importance, because they are associated with severe morbidity and considered to
be among the greatest health problems in the Western world today. This review
describes recent findings in hormonal regulation of food intake by substances
acting both centrally, such as corticotropin-releasing factor, neuropeptide Y and
leptin, and peripherally, such as cholecystokinin and somatostatin. Sex hormones
and glucocorticoids play an important role in long-term regulation of metabolism.
The role of these hormones in appetite and weight changes during life as well as
during pregnancy and lactation is discussed. Furthermore, the development of
obesity and eating disorders is influenced, in particular, by steroid hormones.
Treatment with sex hormones, as in hormone replacement therapy, affects appetite
and weight and may have beneficial effects in preventing android obesity.
Currently, there is great effort in developing endogenous neurohumoral substances
into effective drugs for the treatment of obesity and eating disorders. Leptin
and neuropeptide Y analogues are of interest as potential antiobesity agents.
PMID- 9556086
TI - Fetal alcohol syndrome: a Japanese perspective.
AB - To estimate and prevent the effects of prenatal alcohol on the central nervous
system (CNS), brain dysfunction in fetal alcohol syndrome (FAS) and fetal alcohol
effects (FAE) was compared by both epidemiological and experimental studies. The
FAS infants exhibited a more severe degree of CNS involvement than the FAE
infants. The CNS involvement features were developmental delay and intellectual
impairment in both FAS and FAE. The increased risk of low birth weight and CNS
involvement were much more significant in women who were heavy drinkers or
alcoholics and smoked. The beneficial effect of supplementary zinc on the fetal
cerebrum of FAS or FAE rats was limited, never reaching the unexposed control
level. One of the most vulnerable structures in the rat fetus exposed to ethanol
in utero was the synaptic formation in the hippocampus. The consistent
dysmorphogenesis of synapses during early brain development may be associated
with the functional impairment of the CNS in FAS and FAE.
PMID- 9556087
TI - Chlamydia pneumoniae and its role in chronic obstructive pulmonary disease.
AB - The diverging of T-helper (Th) cells into predominantly Th1 and Th2 subsets on
the basis of their cytokine profiles has decisively improved our understanding of
the pathogenesis of many chronic infectious diseases. Recent data suggest that
the presence of interferon-gamma and the subsequent suppression of interleukin-4
production leads to a Th1-type response that is required for the resolution of
infections caused by intracellular pathogens. The ability of the macrophages to
respond aggressively during early antigen contact seems to be one crucial factor
in the development of an appropriate Th-cell response. Several host-related
factors can affect macrophage function and the polarization of T-cell responses,
ie the shift from a Th1 response to a Th2 one, and thus dramatically deteriorate
the resolution of infections caused by intracellular agents such as Chlamydia
pneumoniae. Chronic C. pneumoniae infection has been associated with several
common chronic diseases, quite recently with chronic obstructive pulmonary
disease. Chronic C. pneumoniae infection may amplify smoking-associated
inflammation in the bronchi and may be a contributory factor in the development
of irreversible pathological changes.
PMID- 9556088
TI - Idiopathic thrombocytopenic purpura: a guideline for diagnosis and management of
children and adults. American Society of Hematology.
AB - Idiopathic thrombocytopenic purpura (ITP, also known as immune thrombocytopenic
purpura) affects both children and adults. In childhood, the peak age is 2-4
years, girls and boys are equally affected, and in most children, the disease is
self-limited with spontaneous recovery occurring in several weeks to several
months. In adults, ITP is most common among young women, and the disease is more
insidious in its onset and chronic in its course. In both children and adults,
there are important unresolved issues in diagnosis and management that have major
cost implications. For this reason, the American Society of Hematology chose ITP
as the disease topic for its initial practice guideline in 1993. In 1996, the
practice guideline was published in Blood, the Journal of the American Society of
Hematology. This review describes the principle features of ITP in children and
adults, the process of development of the practice guideline for ITP, and the
implications of the guideline for the diagnosis and management of patients with
ITP.
PMID- 9556089
TI - Paediatric kidney transplantation.
AB - Renal transplantation is the optimal form of renal replacement therapy leading to
substantial improvement in the quality of life. It has rapidly become the
standard treatment for end-stage renal disease in children. However, despite
impressive short-term results significant long-term problems remain unsolved.
Because of the lack of effective treatment for chronic rejection and common
recipient noncompliance, allograft half-life has not improved significantly
during the last decade. A paediatric recipient is likely to need several
retransplantations in adulthood. Moreover, the immunosuppressive drugs used today
have potentially serious side-effects including nephrotoxicity and de novo
malignancy. These are especially relevant for paediatric recipients who will
continue to receive therapy for several decades. Most therapeutic protocols used
for children are derived from those used for adults. However, the metabolic
differences between an adult and a growing and developing paediatric transplant
recipient are not always adequately appreciated before these new therapies are
initiated. In the near future, we are likely to see new and more efficient drugs
become available. It is important that we try to understand their properties in
children and use them and our current arsenal on an individual basis aiming at
optimal graft survival but also at avoiding unnecessary adverse effects.
PMID- 9556090
TI - Genetics, molecular mechanisms and management of long QT syndrome.
AB - Cardiac arrhythmias cause more than 300,000 sudden deaths each year in the USA
alone. Long QT syndrome (LQT) is a cardiac disorder that causes sudden death from
ventricular tachyarrhythmias, specifically torsade de pointes. Four LQT genes
have been identified: KVLQT1 (LQT1) on chromosome 11p15.5, HERG (LQT2) on
chromosome 7q35-36, SCN5A (LQT3) on chromosome 3p21-24, and MinK (LQT5) on
chromosome 21q22. SCN5A encodes the cardiac sodium channel, and LQT-causing
mutations in SCN5A lead to the generation of a late phase of inactivation
resistant whole-cell inward currents. Mexiletine, a sodium channel blocker, is
effective in shortening the QT interval corrected for heart rate (QTc) of
patients with SCN5A mutations. HERG encodes the cardiac I(Kr) potassium channel.
Mutations in HERG act by a dominant-negative mechanism or by a loss-of-function
mechanism. Raising the serum potassium concentration can increase outward HERG
potassium current and is effective in shortening the QTc of patients with HERG
mutations. KVLQT1 is a cardiac potassium channel protein that interacts with
another small potassium channel MinK to form the cardiac I(Ks) potassium channel.
Like HERG mutations, mutations in KVLQT1 and MinK can act by a dominant-negative
mechanism or a loss-of-function mechanism. An effective treatment for LQT
patients with KVLQT1 or MinK mutations is expected to be developed based on the
functional characterization of the I(Ks) potassium channel. Genetic testing is
now available for some patients with LQT.
PMID- 9556091
TI - Hirschsprung's disease genes and the development of the enteric nervous system.
AB - Hirschsprung's disease or aganglionic megacolon causes chronic, congenital
obstipation at an incidence of 1 per 5000 live births. Two approaches have been
vital to the present understanding of the pathogenesis and genetic background of
the disease: disease linkage analyses and mouse models of aganglionic megacolon.
Because the increasing number of transgenic or natural mouse strains with
congenital megacolon has led to mutation screening in Hirschsprung's disease
patients, almost every second patient could now receive a genetic explanation for
his/her disease. The known disease genes include tyrosine kinase receptor Ret,
endothelin receptor B and its ligand endothelin 3. In addition, mutations have
been found in the gene encoding the glial cell line-derived neurotrophic factor,
the ligand for Ret, but these may only have a modifier effect. The mouse models
have also provided insight into the developmental mechanisms of the normal
intestinal innervation. We combine here the present clinical data on the gene
mutations in Hirschsprung's disease with the experimental molecular biology data,
and formulate a hypothesis on the pathogenesis of this multigenic-multifactorial
disease.
PMID- 9556092
TI - Prognosis of colorectal cancer varies in different high-risk conditions.
AB - Variation in prognosis between different colorectal cancer (CRC) patient groups
was studied by comparing the survival rates of patients belonging to three cancer
predisposition groups with those with sporadic CRC. The high-risk groups included
43 members of hereditary nonpolyposis colorectal cancer (HNPCC) families, 25
patients with familial adenomatous polyposis (FAP) and 33 patients with
underlying ulcerative colitis (UC). The control group included 122 consecutive
sporadic CRC patients. Cumulative 5-year survival was highest in HNPCC (86%),
which is significantly better than in sporadic colorectal cancer (59%, hazard
ratio 0.41, P = 0.02). Cancer associated with UC had a 5-year survival rate of
39%, which is significantly less than in sporadic cancer (hazard ratio 1.83, P =
0.03). There was no significant difference in the survival between patients with
FAP and patients with sporadic CRC (hazard ratio 1.27, P = 0.5). Exclusion of
cases detected by screening examinations slightly reduced the survival rates; 85%
for HNPCC, 53% for FAP and 28% for UC. However, the differences between the
groups remained significant. The survival of patients with HNPCC was found to be
better than that among other groups in this study, which probably relates to the
specific tumourigenesis involving DNA mismatch repair dysfunction.
PMID- 9556093
TI - Melatonin: marvel or marker?
AB - Melatonin blanches the skin of frogs, whitens the fur of hamsters, and sometimes
makes the gonads atrophy. It is remarkable that such a hormone would be put
forward as a defense against ageing. We have been examining excretion of the
urinary metabolite of melatonin, 6-sulphatoxymelatonin (6-SMT), in 150
postmenopausal women, in 72 volunteers over the age of 60 years who complained of
insomnia or depression, and in 20 healthy younger adult controls, aged 18-40
years. The acrophase or fitted peak of 6-SMT excretion was computed as a marker
of the timing of the circadian system. Total daily excretion of 6-SMT was not
significantly related to total sleep time, wake-within-sleep or sleep complaints.
Nevertheless, whereas the 20 controls displayed a normal range of 6-SMT
acrophases from 01.32 to 05.44 h, 42% of the postmenopausal women and 48% of the
symptomatic elders had acrophases outside this normal range. Those volunteers
with more deviant acrophases displayed more disturbed sleep and more sleep
complaints. These data suggest that melatonin is a useful marker of circadian
rhythm phase disorders, but suggest a need for more caution in melatonin
administration.
PMID- 9556094
TI - Melatonin receptor genes.
AB - Melatonin is produced rhythmically by the pineal gland and the retina with
increased synthesis during darkness. Pineal melatonin serves as the 'chemical
expression of darkness' conveying information on the ambient light-dark cycle
into rhythmic bodily functions. On-going debate on modes and sites of action
ranges from views of melatonin affecting each and every cell ('cure-all') to
those of melatonin having restricted actions through specific high-affinity
receptors. The present review deals with the latter view. The use of 2-[125I]
iodomelatonin has allowed the exact localization and characterization of high
affinity melatonin receptors that signal through the G(i/o) class of G proteins.
Molecular cloning of melatonin receptor genes has confirmed that most, if not
all, high-affinity melatonin-binding sites represent the G-protein-coupled
melatonin receptors. Based on sequence dissimilarities, melatonin receptors are
classified into three subtypes, Mel1a, Mel1b and Mel1c. A distribution wider than
originally thought of melatonin receptors in the human brain and peripheral sites
has brought these receptors into focus of several drug companies, promising
exciting times for research on melatonin and new therapeutic possibilities.
PMID- 9556095
TI - Integrating the actions of melatonin on human physiology.
AB - Melatonin has a diverse range of physiological effects in humans. Reported
effects include modulation of the sleep-wake, thermoregulatory, cognitive,
cardiovascular and immune systems. While integrating these broad-ranging effects
is difficult when current paradigms are used, the diverse effects of melatonin on
human physiology may be better understood by shifting our theoretical
perspective. Traditionally, research has treated melatonin as a classical hormone
for which a defined effect in physiological systems and a mechanism of action can
be elucidated. In this article, we suggest that it may be more appropriate to
view melatonin as an evolutionally stable timing signal to which each species has
adapted the timing of physiological processes. From this perspective, it appears
that the physiological role of melatonin in humans falls into two categories. The
first relates to the self-regulation of circadian timing by the suprachiasmatic
nucleus-pineal complex. The second relates to the promotion of restorative or
anabolic physiological processes. In humans, elevated melatonin levels have been
associated with reduced core temperature, increased heat loss, decreased
cardiovascular output, reduced alertness and enhanced immune responsiveness.
Taken together, these changes suggest that melatonin may increase the propensity
for physiological processes promoting nocturnal sleep or processes that occur
during the sleep period.
PMID- 9556096
TI - Melatonin and human reproduction.
AB - In photoperiodic nonhuman mammals the secretion of melatonin from the pineal
gland plays a major role in regulating reproductive physiology; in humans these
relationships are less clear. The melatonin rhythm changes throughout life with
the first substantial change in nocturnal melatonin secretion being reportedly
associated with puberty. The transition from Tanner stage 1 to Tanner stage 5 of
sexual maturation is associated with a significant reduction in nocturnal
melatonin levels, but a cause-effect relationship has not been established.
Menstrual cyclicity has been reported to be associated with fluctuations in
melatonin production but whether they are related to, eg ovulation or
menstruation is not established. At high latitudes the quantity of melatonin
produced by the pineal gland varies with season (changes in the light-dark
cycle), and there is some evidence that this changes reproductive efficiency
accordingly. Menopause is associated with a reduction in melatonin which may
relate to the changing gonadotropin levels. In males of the same age melatonin
levels also drop with no significant alteration in reproductive physiology. While
correlations between melatonin and the status of the reproductive system in
humans have been noted, whether they are functionally related remains to be
determined.
PMID- 9556097
TI - Melatonin--the key to the gate of sleep.
AB - This article reviews the evidence that melatonin, a hormone produced by the
pineal gland during the dark hours, plays a major role in the regulation of the
sleep-wake cycle. In recent years, our laboratory has been involved in a large
scale project aimed at investigating the role of endogenous melatonin in sleep
wake regulation and the effects of nonpharmacological levels of melatonin on
sleep. Based on our finding on the precise coupling between the endogenous
nocturnal increase in melatonin secretion and the opening of the nocturnal sleep
gate, we propose that the role of melatonin in the induction of sleep does not
involve the active induction of sleep, but is rather mediated by an inhibition of
a wakefulness-producing mechanism in the central nervous system. Our studies also
suggest that exogenously administered melatonin may be beneficial in certain
types of insomnia that are related to disturbances in the normal secretion of the
hormone.
PMID- 9556099
TI - Guidelines for prescribing melatonin.
AB - Although compelling logic suggests that melatonin may be effective for a variety
of disorders, there are few empirical clinical studies. The optimal dose of
melatonin is not clear; most studies have used doses that produce
supraphysiological blood levels. The timing of melatonin administration is
important. Melatonin has few immediate side-effects except drowsiness, but the
effects of chronic administration are unclear. Melatonin may be effective in
reducing jet lag. In elderly patients with poor sleep and documented low
melatonin production, melatonin may be helpful. In several studies, melatonin has
been shown to shorten sleep latency. Further studies are needed to clarify the
efficacy and safety of melatonin.
PMID- 9556098
TI - Use of melatonin for sleep and circadian rhythm disorders.
AB - Although not licensed as a drug, melatonin is widely sold as a nutritional
supplement in the USA for its purported sleep-promoting and antiageing
properties. In this article, we provide some guidelines for its use in sleep
disorders medicine. In brief, melatonin appears to promote sleep by producing
corrective circadian phase shifts, thereby improving the alignment of the
endogenous sleep propensity rhythm with the desired sleep schedule. Melatonin may
also have a direct soporific effect, especially when administered during the day.
We suggest that the direct soporific action results from the release of
accumulated sleep drive by melatonin's attenuation of the circadian alerting
signal. Melatonin has not been proven safe by the usual clinical trial criteria,
but to date no catastrophes have been related to its use. Also, there is little
information about the safety and efficacy of chronic administration.
PMID- 9556100
TI - Cutaneous findings related to cardiovascular disorders.
PMID- 9556101
TI - Dermatologic aspects of antiphospholipid syndrome.
PMID- 9556103
TI - Trichosporosis (white piedra) in Kuwait.
PMID- 9556102
TI - Proliferations of the epidermoid cyst wall.
PMID- 9556104
TI - Pathogenesis of Hashimoto's thyroiditis: apoptosis revisited.
PMID- 9556105
TI - AA line.
AB - BACKGROUND: The transverse skin line of the upper part of the forearm is a
common, easily recognized condition; however, this line has not been defined
clearly and does not correspond to other previously reported skin lines. Our
purpose was to assess the nature and associated conditions of this skin line, and
characterize the histopathologic features. METHODS: We examined 1343 healthy
Korean people. The persons showing this skin line were evaluated by history and
physical examination. Skin biopsy was performed on 10 persons showing this line:
on one side at both the lesion and contralateral, non-lesion sites. RESULTS: A
total of 480 persons (36.4%) showed this line. The incidence was significantly
higher in the female group and in the group between 10 and 19 years of age.
Histopathologic examination showed subtle edema, separation and fragmentation of
collagen bundles, and vasodilation at the transverse skin line. CONCLUSIONS: We
conclude that this skin line represents a newly defined skin line, and propose
the term AA line.
PMID- 9556106
TI - Histopathologic features of the spontaneous pustular lesions of Behcet's
syndrome.
AB - BACKGROUND: Papulopustular lesions are common in Behcet's syndrome (BS). A debate
exists as to whether they are different from ordinary acne. This has important
clinical and pathophysiologic implications. OBJECTIVE: The aim of this study was
to evaluate the histopathologic features of papulopustular lesions seen both in
BS and acne vulgaris (AV). METHODS: Representative samples were obtained from 17
patients with BS and six patients with AV. The detailed histopathologic features
were evaluated by a dermatopathologist blinded to the diagnoses. RESULTS:
Considering the epidermis, follicle epithelium, and dermis separately, no
differences could be found between the two groups. CONCLUSIONS: The
papulopustular lesions seen in these two disorders cannot be distinguished on the
basis of clinical and histopathologic findings.
PMID- 9556107
TI - Epidemiologic analysis and clinical course of 84 consecutive cases of pemphigus
in eastern Sicily.
AB - BACKGROUND: The purpose of this study was to examine the clinical and
epidemiologic features of pemphigus in eastern Sicily. METHODS: All new cases of
pemphigus seen in the Dermatology Clinic at the University of Catania during the
period January 1982 to June 1996 were studied retrospectively. RESULTS: Eighty
four patients with pemphigus represented 1.3% of 6653 patients admitted to our
clinic in a 13.5-year period, with an average annual incidence of six cases per
year. The most common form of presentation was pemphigus vulgaris (PV) (75%),
followed by pemphigus erythematosus (17%), pemphigus herpetiformis (6%), and
pemphigus vegetans (2%). In 6% of PV patients, the oral lesions were not followed
by skin involvement, and the lag time between the onset of illness and the final
diagnosis in five PV cases was prolonged, ranging from 4 to 7 years, probably due
to the mild clinical presentation of the disease. Two trauma-related PV cases
were documented; in one case, the blisters were located in a surgical scar and in
the other in a burn scar. CONCLUSIONS: Our findings showed that pemphigus has a
relatively high prevalence in eastern Sicily compared with other Italian regions;
PV is the most common variant, and may have a mild course not always requiring
aggressive therapy.
PMID- 9556108
TI - Diagnostic value of IgM deposition at the dermo-epidermal junction.
AB - BACKGROUND: Granular immunoglobulin M (IgM) deposits at the dermo-epidermal
junction (DEJ) are common in lupus erythematosus (LE); however, weak,
interrupted, linear and granular patterns of IgM at the DEJ have been reported in
sun-exposed skin in normal adults and in a heterogeneous group of diseases.
MATERIALS AND METHODS: We analyzed 200 patients with positive IgM direct tissue
immunofluorescence deposition at the DEJ, alone or in combination with other
immunoreactants, in order to determine the diagnostic significant of IgM
deposition at the DEJ. RESULTS: IgM deposition at the DEJ, commonly in
combination with other immunoreactants, was associated with LE in 57.5% of
patients. In cases with IgM deposition alone at the DEJ, only 12% had LE (strong
intensities). IgM deposition at the DEJ was associated with other dermatoses in
42.5% of patients. In non-lupus patients, IgM deposition was the sole finding in
59% of cases, and was weaker and more focal than in LE patients. CONCLUSIONS: IgM
deposition at the DEJ in patients with LE tends to exhibit a strong intensity and
is commonly detected in combination with other immunoreactants. IgM deposition
alone at the DEJ, especially of weak intensity or focal in pattern, is noted in
non-lupus patients, and has less diagnostic significance.
PMID- 9556109
TI - Trichloroacetic acid in dermatology of 1911.
PMID- 9556110
TI - Value of routine diagnostic criteria of bullous pemphigoid.
AB - BACKGROUND AND DESIGN: The clinical, histologic, and direct (DIF) and indirect
(IIF) immunofluorescence findings are used in a critical, although arbitrary,
manner in the routine diagnostic process of bullous pemphigoid (BP). Our purpose
was to estimate their relative value. In the present retrospective study, a
follow-up of at least 18 months was used as a prerequisite for the final
diagnosis of BP (63 patients) and controls (n=159). RESULTS: The clinical,
histologic, DIF, and IIF diagnostic criteria of BP were found to vary
independently of each other. Positive DIF was the most sensitive (90.5%) typical
for BP histology and positive IIF were the most specific (99%). Immunopathologic
tests were the most valuable, especially in the atypical varieties of BP. Nearly
25% of patients in this group would have been misdiagnosed if IF tests had not
been performed. Atypical cases (40%) seemed to represent a clinical continuum
over the whole spectrum of the disease. Patients with exclusively immunoglobulin
G (IgG) and C3 basal membrane zone (BMZ) deposits were significantly more often
seropositive than the rest of the DIF-positive cases; however, the class of BMZ
immunoreactants varied according to the site of biopsy. C3 was almost invariably
deposited at the BMZ of DIF-positive patients. When Igs were also present, they
were only exceptionally (5% of cases) of greater fluorescence intensity than C3.
CONCLUSIONS: The combination of clinical data plus one positive immunopathologic
test provide the best combination of sensitivity and specificity (98%), and seem
to be most appropriate in defining patient populations for study purposes. The
relationship between the classes of immunoreactants should be better evaluated
with reference to the site of skin biopsy. It may be suggested, however, that the
likelihood of BP existence is very low when in vivo C3 is absent or of lower
intensity of fluorescence than the concomitant Ig(s).
PMID- 9556112
TI - Epidemiologic observations on the natural course of pemphigus vulgaris.
AB - BACKGROUND: During the last 20 years, few prospective studies on the natural
course of pemphigus vulgaris (PV) have been performed. METHODS: Various
correlations of disease duration, clinical activity fluctuations, serology, and
coexistence with other disease states were analyzed with regard to their impact
upon the natural history of pemphigus. Thirty-seven consecutive PV patients were
involved in this 1-year retrospective follow-up study. RESULTS: The disease
activity decreases with time, but when exacerbated it is of unpredictable
intensity; skin involvement is equally distributed between the sexes; relapses
occur mostly during the first 2 years after disease onset, and can be marginally
predicted by autoantibody titers. CONCLUSIONS: Notice should be taken of the
relative frequencies of PV associated with neoplasia, ionizing radiation, and
familial occurrence.
PMID- 9556111
TI - Familial pemphigus vulgaris in mother and daughter.
AB - BACKGROUND: Pemphigus vulgaris is an autoimmune disease in which genetics appears
to be of basic importance. Although association with certain human leukocyte
antigen (HLA) alleles has been found in some ethnic groups and individuals, no
true disease susceptibility genes have been established, and familial cases are
very unusual. METHODS: We report a Polish family with pemphigus vulgaris in the
mother and daughter. The diagnosis was confirmed by cytologic, histologic, and
immunofluorescence studies. RESULTS: The course was severe and the disease long
lasting in the mother, probably due to treatment with small doses of
corticosteroids without immunosuppressive drugs. In the daughter, treated with
larger doses of corticosteroids and azathioprine, the lesions regressed within 4
months, after which maintenance therapy was instituted with 10 mg of prednisone
daily. The HLA studies performed in the daughter and her three children after the
mother had died showed identical haplotypes in both the patient and the healthy
children. The patient has given birth to a healthy child while still having a
high titer of intercellular (IC) antibodies. CONCLUSIONS: The familial occurrence
of pemphigus in first-degree relatives is suggestive of inherited susceptibility
to the disease, transmitted as a dominant trait. The identical haplotypes in the
healthy children of the patient favor the role of other, unknown factors required
for the development of the disease in predisposed individuals.
PMID- 9556113
TI - Cerebriform sebaceous nevus.
AB - A 20-year-old man presented with a well-defined, soft to firm, freely mobile
pinkish-yellow plaque of 9.5 cm over the right parieto-occipital region with a
typical cerebriform appearance. In total, nine folds were present with short
black terminal hair in the sulci area. There was no follicular plugging. Skeletal
survey and neurologic and ophthalmologic assessments were normal. Skin biopsy was
compatible with sebaceous nevus showing mature sebaceous glands in the upper
dermis and mature apocrine glands in the lower dermis with malformed hair germ.
PMID- 9556114
TI - Giant vascular eccrine spiradenoma.
AB - A 60-year-old man suffering from cardiac insufficiency consulted the Dermatology
Department, Inonu University Turgut Ozal Medical Center, because of a bleeding
tumor on his right hypochondrium. The tumor had begun as a small nodule
approximately 5 years before, and had grown slowly with time. A small,
superficial ulcer had appeared on the lesion approximately 6 months previously,
and slight bleeding had occasionally occurred. The patient had no pain and no
other complaint except bleeding. Dermatologic examination revealed a violaceous,
ulcerated, and bleeding tumoral lesion below the mid-portion of the right
costochondral line. The tumor was a non-tender, hemispheric mass, approximately 3
4 cm in size, adherent to the epidermis, but movable on the underlying tissue. An
incisional biopsy was performed with diagnoses of dermatofibrosarcoma protuberans
and desmoid tumor. Histopathologic examination revealed prominent blood-filled
vascular spaces and clearly delimited cords, showing two types of cell. The
vascular spaces contained a periodic acid-Schiff (PAS)-positive, granular,
eosinophilic material. There was no malignant transformation. The lesion was
totally excised and primarily sutured.
PMID- 9556115
TI - Pseudo-Kaposi's sarcoma (Mali type).
AB - A 75-year-old man presented with lesions on his right leg and on the dorsum of
the penis, which had appeared 5 years ago following long distance travel. His
right leg was swollen, and there was a dark-violet-colored, slightly elevated
lesion extending to the thigh and penis. Histologic examination revealed
thickening of the arteriolar walls and diffuse proliferation of the vascular
structures surrounding the arterioles and dissecting the dermal collagen fibers.
Immunohistochemical staining for Factor VIII R-A reacted positively with
arteriolar endothelium, but was negative on thin-walled vascular spaces. Femoral
angiography showed multiple fine arteriovenous (A-V) shunts especially at the one
third distal lower region of the right leg.
PMID- 9556116
TI - Malignant nodular hidradenoma.
AB - A 54-year-old male farmer was seen in May 1990 with a violaceous, exulcerated
tumor, 2x1.5 cm in diameter, localized to the sternal area of the chest. The
tumor had been present for 30 years, showing slow progressive growth; it was
excised, but recurred 2 years before our initial evaluation. The tumor was again
excised with a wide free margin. The histopathologic study showed an ill-defined,
epithelial neoformation, formed by lobules of clear polygonal cells at the deep
dermis and subcutaneous tissue; there was a second group of smaller cells with a
basaloid aspect, a few of them presenting slight atypia. The tumoral lobules were
surrounded by a myxoid material with vascular proliferation. The epidermis was
normal. The histopathologic report was of a malignant nodular hidradenoma. No
evidence of lymph node or distant metastases was found. One year after the
excision, the tumor recurred at the surgical site, and an axillary lymph node
showed metastatic cells. The lesion was excised for a third time and the patient
was lost to follow-up.
PMID- 9556117
TI - Witchcraft's syndrome: Munchausen's syndrome by proxy.
AB - A 28-year-old man presented to the Dermatology Outpatient Department with a
complaint of a burning sensation and soreness over his left cheek and left ear of
10 days duration. It had started suddenly one morning when he woke up from sleep.
He noticed a large blister with intense redness over his left cheek, associated
with a burning sensation. There was a history of similar episodes over the past
year, and all were sudden in onset, involved the cheeks, and were noticed after
waking up from sleep. The patient volunteered that the episodes were always
associated with a drinking spree the previous night. The individual was a healthy
man with a wife and two children. The patient had been dependent on alcohol for
the past year, and had been consuming alcohol for many years. On examination,
there was an eschar occupying almost the entire cheek, with a few scattered
lesions over the left tragus and left external ear. Peripheral scarring was noted
with hyperpigmentation. While the angle of the mouth was superficially involved
on the left side, the oral mucosa was normal. The right cheek also showed a few
areas of scarring with patches of alopecia. There were no similar lesions
elsewhere on the body. The peculiar history and the morphology of the lesion,
that defied any classical diagnosis description, prompted us to interrogate both
the man and his wife with regard to any serious differences. After much
persuasion and on assurance of secrecy, the wife admitted that her husband was an
alcoholic and was neglecting his family. When her efforts to prevent his drinking
failed, she resorted to this drastic measure. Each time he passed out after a
drinking bout, she poured acid on his cheek, hoping that the sequelae would
frighten him from drinking. The acid was readily available to her as she used it
for domestic cleaning. The couple were sent for psychiatric evaluation as
Munchausen's syndrome by proxy (MSBP) or witchcraft's syndrome (WS) was
suspected. Detailed psychiatric evaluation, together with psychometric
assessment, revealed that the patient had an alcohol dependence (Axis-I
diagnosis) and had a cyclothymic personality. Severe marital discord due to
alcohol dependence had been present for the past 2 years. Evaluation of the
patient's wife revealed that she was under significant psychologic distress. She
showed major depressive symptoms with a histrionic personality. She revealed that
she had resorted to using the corrosive out of frustration and anger over the
behavior of the patient while he was in an inebriated state. The couple are
currently undergoing psychiatric treatment.
PMID- 9556118
TI - Crusted scabies of the scalp in dermatomyositis patients: three cases treated
with oral ivermectin.
AB - BACKGROUND: Cutaneous features in the scalp area among adult patients are rarely
considered as a manifestation of scabies. METHODS: Three patients with clinical
and laboratory data of dermatomyositis with scalp involvement (fulfill three or
four of Bohan and Peter's criteria), of 4 years, 8 months, and 3 years duration,
were seen at our department between 1995 and 1996. For relapses of ordinary
scabies, they were treated repeatedly with local scabicide with temporary effect.
After a symptom-free period during the treatment of dermatomyositis with
corticosteroids and azathioprine, they developed diffuse redness with scales and
crusts on the scalp areas. Light microscopy examination of material taken from
these crusts showed an abundance of live mites. RESULTS: All patients were
successfully cured of scabies with a twice oral dose of 200 microg/kg ivermectin
within 8 days. CONCLUSIONS: Our patients with crusted scabies of the scalp and
dermatomyositis prompted us to change our standard diagnostic and therapeutic
regimens. Fascinating features included mimicry of scabies in patients with
dermatomyositis, location of parasites on the scalp, suppressed cell-mediated
immunity and successful cure of mange by ivermectin.
PMID- 9556119
TI - Carl Heitzmann (1836-1896): physician and illustrator.
PMID- 9556120
TI - The use of neuromuscular blocking agents in the emergency department to
facilitate tracheal intubation in the trauma patient: help or hindrance?
AB - PURPOSE: The purpose of this study is to examine the relationship between the
occurrence of a difficult intubation and (1) the use of neuromuscular blocking
agents (NMB) and (2) the presence of airway injuries. It is a retrospective
analysis of data from a trauma registry. MATERIALS AND METHODS: Registry records
of patients (n = 160) who required emergent endotracheal intubation or
establishment of a surgical airway over a 3.5-year period in the emergency
department were reviewed. Risk factors for difficult intubations were identified
and analyzed using multivariate logistic regression analysis. RESULTS: NMB were
used in 75% of patients requiring intubation. Fifteen percent of the intubations
were considered difficult. No association was found between the presence of
airway injuries and difficult intubations; however, the use of succinylcholine
was associated with a lower risk of difficult intubations compared with
intubations where a nondepolarizing NMB was used. CONCLUSIONS: The use of
succinylcholine may result in fewer difficult intubations in the trauma patient
than when a nondepolarizing NMB is used. The presence of airway injuries did not
appear to predispose to difficult intubations.
PMID- 9556121
TI - Delivery of hyperbaric oxygen therapy to critically ill, mechanically ventilated
children.
AB - PURPOSE: The purpose of this article is (1) to describe our method of mechanical
ventilation and monitoring of critically ill children during administration of
hyperbaric oxygen therapy (HBO2) in a multiplace chamber; and (2) to review the
complications they experienced during transport to the HBO2 chamber and HBO2
treatment. MATERIALS AND METHODS: A case series from a university-affiliated
children's hospital and regional hyperbaric medicine treatment facility. Patients
studied included all children who required HBO2 therapy while mechanically
ventilated at any time between April 1985 and June 1995. RESULTS: Thirty-two
children were treated with HBO2 while mechanically ventilated. Ages ranged from 3
days to 11.3 years (mean 4.8+/-3.5 years). There were 22 males. Twenty-one
children had necrotizing infections, 9 had carbon monoxide (CO) poisoning, and 2
had iatrogenic arterial air embolism. Complications or events occurring during
HBO2 therapy included hypotension (63%), bronchospasm (34%), hemotympanum (13%),
and progressive hypoxemia (6%). The only complication during transport was one
accidental extubation (3%). CONCLUSION: Hyperbaric oxygen therapy can be
administered safely to most critically ill children in a multiplace chamber if
they are monitored closely. Although complications are not uncommon, most can be
managed easily by a team skilled in treating ill children and knowledgeable of
possible complications of HBO2 therapy.
PMID- 9556122
TI - The use of phentolamine in the prevention of dopamine-induced tissue
extravasation.
AB - PURPOSE: The purpose of this study was to determine whether dopamine-induced
tissue extravasation injury could be prevented with phentolamine. MATERIALS AND
METHODS: This was a prospective, randomized, blinded, and controlled animal
study. Forty rats were evaluated to document the effects of dopamine compared
with normal saline on tissue integrity, whether any tissue damage was
concentration or volume dependent, and to determine the minimum concentration of
dopamine resulting in tissue injury. Dopamine concentrations of 0.8 mg/mL and 3.2
mg/mL were tested. In a second part of this study, an additional 40 rats were
evaluated to assess the efficacy of two different doses of phentolamine (0.5 mg
and 1 mg) or normal saline, when injected within 10 minutes of dopamine
administration to prevent or reverse tissue extravasation. Extravasation sites
were evaluated clinically and histologically at 2, 4, 6, and 8 hours and were
compared with a baseline sample. Outcome measures were as follows: (1) prebiopsy
was ectodermal erythema, induration, and blanching; (2) postbiopsy was bubbling,
darkening, pallor, and hematoma of the muscle fascia. Histology included
neutrophil migration, mast cell degranulation, edema, and hemorrhage. Fisher's
Exact Test with the Bonferroni method were used for statistical analysis.
RESULTS: Dopamine-induced extravasation resulted in tissue injury characterized
by blanching and hematoma. Damage did not appear to be volume dependent, but may
be related to the duration of infiltration. Subcutaneous injection with either
dose of phentolamine appeared to be clinically effective in preventing tissue
injury. However, microscopic evaluation of tissue samples was inconclusive.
CONCLUSION: This study clinically supported the use of phentolamine for the
prevention of dopamine-induced extravasation injury.
PMID- 9556123
TI - Decelerating flow ventilation effects in acute respiratory failure.
AB - PURPOSE: The purpose of this article is to analyze the effect of a pressure
regulated volume-controlled ventilation mode on lung mechanics and gas exchange
in patients with acute respiratory failure. MATERIALS AND METHODS: We ventilated
10 patients with two pressure-limited modes: pressure-controlled ventilation (PC)
and pressure-regulated volume-controlled ventilation (PRVC) in random order, for
1 hour each. Patients were stabilized on volume-controlled ventilation (VC) for
30 minutes before, between, and at the end of PC and PRVC to reach baseline
conditions. At the end of every VC period and at 30 and 60 minutes of PC and
PRVC, respiratory mechanics, gasometrics, and hemodynamic parameters were
collected. RESULTS: We found no significant differences between the three VC
periods. Comparing VC with the two pressure-limited ventilation modes, peak
pressure decreased from 29.4+/-9.1 cm H2O (VC) to 25.9+/-8.4 (PC 60 minutes) and
26.1+/-8.2 (PRVC 60 minutes), and PaCO2 decreased significantly from 38.6+/-3.1
mm Hg (VC) to 36.7+/-2.8 (PC 60 minutes) and 36.8+/-2.9 (PRVC 60 minutes).
CONCLUSIONS: Pressure-limited ventilation allows mechanical ventilation for the
same tidal volume as VC but results in a lower peak inspiratory pressure and a
slightly lower PaCO2. The mechanism responsible for this gas exchange effect is
unknown but is probably related to a better air distribution of the decelerated
flow. The clinical relevance of this phenomenon remains to be established.
PMID- 9556124
TI - An approach to the treatment of severe adult respiratory failure.
AB - OBJECTIVES: The purpose of this article is to evaluate outcome in adult patients
with severe respiratory failure managed with an approach using (1) limitation of
end inspiratory pressure, (2) inverse ratio ventilation, (3) titration of PEEP by
SvO2, (4) intermittent prone positioning, (5) limitation of FiO2, (6) diuresis,
(7) transfusion, and (8) extracorporeal life support (ECLS) if patients failed to
respond. PATIENTS AND METHODS: This study was designed as a retrospective review
in the intensive care unit of a tertiary referral hospital. One-hundred forty-one
consecutive patients with hypoxic (n = 135) or hypercarbic (n = 6) respiratory
failure referred for consideration of ECLS between 1990 and 1996. Overall,
initial PaO2/FiO2 (P/F) ratio was 75+/-5 (median = 66). RESULTS: Lung recovery
occurred in 67% of patients and 62% survived. Forty-one patients improved without
ECLS (83% survived); 100 did not and were supported with ECLS (54% survived).
Survival was greater in patients cannulated within 12 hours of arrival (59%)
compared with those cannulated after 12 hours (40%, P < .05). Multiple logistic
regression identified age, duration of mechanical ventilation before transfer,
four or more dysfunctional organs, and the requirement for ECLS as independent
predictors of mortality. CONCLUSIONS: An approach that emphasizes lung protection
and early implementation of extracorporeal life support is associated with high
rates of survival in patients with severe respiratory failure.
PMID- 9556125
TI - "An approach to the treatment of severe adult respiratory failure (by Rich et al,
Journal of Critical Care 13:26-36, 1998)".
PMID- 9556126
TI - Paracrine regulation of cardiac myocytes in normal and septic heart.
AB - A paracrine pathway for the regulation of cardiac contractile function by
nonmuscle cells is documented in the heart. Coronary and endocardial endothelium
release several diffusible agents, such as prostaglandins, endothelin-1, and
nitric oxide, with an action on cardiac myocyte function. Cardiac diseases
involving an immune or inflammatory mechanism, such as endotoxic shock, are now
seen as conditions in which cross-talk between different cell types in the heart
is clearly implicated. The potential biological relevance of inducible nitric
oxide synthase in the myocardium, and the subsequent production of nitric oxide
has been proposed as a mechanism of the cardiac depression observed in septic
shock. In addition to cardiac myocytes, activated microvascular endothelial cells
and cardiac endothelial cells may contribute to nitric oxide generation and,
ultimately, to the depression of myocardial contractile activity during sepsis.
This article reviews the local intercellular communication between cardiac
myocytes and endothelial cells in the normal heart and discusses some of the
mechanisms potentially claimed to depress heart function in sepsis.
PMID- 9556127
TI - Glutamate receptors are expressed by bone cells and are involved in bone
resorption.
AB - The excitatory amino acid glutamate (Glu) is a potent neurotransmitter in the
central nervous system and exerts its action via a variety of glutamate receptors
(GluRs). Because we had previously shown that a poly-glutamate (poly-Glu) peptide
stimulates bone resorption in vitro, an effect specific to Glu (Raynal, C.,
Delmas, P. D., and Chenu, C. Bone sialoprotein stimulates in vitro bone
resorption. Endocrinology 137:2347-2354; 1996), we investigated the possibility
that bone cells express GluRs, and whether they may be important for osteoclast
activity. Using immunocytochemistry on rat bone sections, we have shown that all
mature bone cells (osteoblasts and osteoclasts) express GluRs, and that the
ionotropic N-methyl-D-aspartate (NMDA) receptor 1 subunit (NMDAR1) appears most
highly expressed. Osteoclasts isolated from rabbit long bones also possessed
NMDAR1 GluRs. Bone resorption in vitro by isolated osteoclasts was inhibited by a
monoclonal antibody directed against NMDAR1, as well as by two pharmacological
antagonists of this receptor (D-AP5 and MK 801), which also antagonized poly-Glu
stimulated bone resorption. These results suggest a possible new mechanism for
regulating osteoclast activity and indicate that excitatory amino acids such as
glutamate may be important local regulators of bone cell functions.
PMID- 9556128
TI - Regulation of tenascin-C expression in bone cells by transforming growth factor
beta.
AB - Transforming growth factor-beta (TGF-beta) stimulates new bone formation when
administered locally in vivo. The extracellular matrix protein tenascin-C, which
is secreted by osteoblasts but absent from mineralized bone matrix, supports
differentiation of cultured osteoblast-like cells. The current study was
undertaken to determine whether expression patterns of tenascin-C in TGF-beta
treated bone cells are in agreement with a role for this protein as a mediator of
TGF-beta-stimulated new bone formation. Expression of tenascin-C was investigated
by immunohistochemistry in calvarial bones of mice to which TGF-beta had been
locally administered. Three days after initiation of daily TGF-beta treatment,
strong staining for tenascin-C was seen in regions where periosteal
osteoprogenitor cells were undergoing proliferation in response to TGF-beta; by
comparison, staining of periosteal surfaces of control bones was weak and
discontinuous. Seven days after initiation of a course of five daily injections
of TGF-beta, tenascin-C staining was still enhanced in treated bones. The ability
of TGF-beta to regulate expression of tenascin-C in osteoblast-like cells in
vitro was investigated using an osteosarcoma-derived cell line (ROS 17/2.8). TGF
beta caused a small but significant increase in secretion of tenascin-C into the
medium, as determined by a solid phase dot immunoassay quantitated by
densitometry. Western and northern blot analysis indicated that TGF-beta did not
influence the pattern of expression of tenascin-C splice variants. These results
indicate that TGF-beta stimulates osteoblastic tenascin-C expression and suggest
that tenascin-C may act as a mediator of TGF-beta-induced new bone formation.
PMID- 9556129
TI - Basic fibroblast growth factor induces osteoclast formation in murine bone marrow
cultures.
AB - We determined the effect of basic fibroblast growth factor (bFGF) on osteoclast
like cell (OCL) formation in bone marrow cultures using C57BL/6 mice. Cells were
cultured for 7 days with or without bFGF at various concentrations or 10(-8)
mol/L 1,25(OH)2 vitamin D3 [1,25(OH)2D3]. bFGF dose-dependently increased OCL
formation per well (10(-10) mol/ L = 40 +/- 2; 10(-9) mol/L = 146 +/- 13; 10(-8)
mol/L = 156 +/- 12) compared with control (< 7 per well). The effects of bFGF at
10(-9) and 10(-8) mol/L were similar to that of 10(-8) mol/L 1,25(OH)2D3 (154 +/-
11 per well). OCLs formed by bFGF were multinuclear, tartrate-resistant acid
phosphatase (TRAP)-positive, expressed calcitonin receptors, and formed
characteristic resorption pits. We also determined whether bFGF enhanced OCL
formation during the early proliferative or late differentiating phases of the
cultures. When bFGF (10(-8) mol/L) was added only on days 1-2 or days 3-4 of 6
day cultures, there was a significant increase in OCL formation. In contrast,
when bFGF was added only on days 5-6 few OCLs formed. Addition of bFGF at days 1
6 or days 1-2 and days 5-6 caused similar increases in OCL formation, which were
greater than OCL formation induced by treatment for days 1-2 or days 1-4. We
examined the production of prostaglandin E2 (PGE2) in the cultures because bFGF
is a potent stimulator of PGE2 synthesis in bone, and PGE2 stimulates OCL
formation. bFGF treatment significantly increased PGE2 levels in 7 day cultures
(controls = 1.4 +/- 0.1 nmol/L, 10(-8) mol/L bFGF = 132.5 +/- 0.7 nmol/L). In
addition, treatment of marrow cultures with the prostaglandin synthesis
inhibitors, indomethacin or NS-398 (both at 10(-6) mol/L), completely blocked
bFGF-induced OCL formation. We conclude that bFGF stimulates OCL formation in
C57BL/6 bone marrow cultures by mechanisms that require prostaglandin synthesis.
This pathway is likely to be one mechanism by which bFGF stimulates resorption.
PMID- 9556130
TI - Parathyroid hormone regulates the expression of the nuclear mitotic apparatus
protein in the osteoblast-like cells, ROS 17/2.8.
AB - The parathyroid hormone (PTH) signaling pathways that effect changes in
osteoblast gene expression also alter the organization of the cytoskeletal
proteins. PTH regulates the expression of nucleoskeletal proteins, such as
nuclear mitotic apparatus protein (NuMA) and topoisomerase II-alpha. NuMA is a
structural component of the interphase nucleus and organizes the microtubules of
the mitotic spindle during mitogenesis. We propose that PTH-induced alterations
in osteoblast cytoarchitecture are accompanied by changes in osteoblast nuclear
structure that contribute to changes in gene expression. We used
immunofluorescence and confocal microscopy to determine the effect of PTH on the
expression and nuclear distribution of NuMA in the rat osteosarcoma cell line,
ROS 17/2.8. Cells were treated with PTH or vehicle, then fixed and stained with
NuMA antibody. Optical sections of interphase naive cells revealed a diffuse
distribution of NuMA, interspersed with speckles, in the central nuclear planes
but not in nucleoli. During the metaphase and anaphase, NuMA localized at the
mitotic spindle apparatus. The percentage of NuMA-immunopositive ROS 17/2.8 cells
decreased with increasing confluence, but serum starvation did not attenuate NuMA
expression. Cell density-dependent changes in cytoskeletal organization were
observed in these cells. PTH treatment induced changes in cytoskeletal
organization and increased the percentage of NuMA-immunopositive ROS 17/2.8
cells. These data suggest that PTH effects changes in osteoblast nuclear
architecture by regulating NuMA, and that these alterations may be coupled to
cytoskeletal organization.
PMID- 9556131
TI - Macrophage colony-stimulating factor increases bone resorption by osteoclasts
disaggregated from human fetal long bones.
AB - Macrophage colony-stimulating factor (M-CSF) is known to play an important role
in human and murine osteoclast formation. Although M-CSF has been shown to
inhibit isolated neonatal rat osteoclasts from resorbing bone, its action on the
mature human osteoclast has not been described. We now report that M-CSF
increases osteoclastic bone resorption in a dose-responsive manner. Bone
resorption by mature human fetal osteoclasts, including pit area, depth, and
volume, was increased in the presence of M-CSF compared with vehicle. The number
of osteoclasts in the cultures was similar after 2 and 18 h in the presence of M
CSF, whereas there was a significant reduction in osteoclast number, whether
assessed as the number of tartrate-resistant acid phosphatase (TRAP)-positive or
vitronectin receptor-positive cells after 18 h in M-CSF-free cultures. The number
of nuclei per osteoclast after 2 or 18 h in M-CSF was also similar and there was
no difference in the number of vitronectin receptor-positive mononucleate cells
at 2 and 18 h. This suggests that the increased bone resorption is likely to be
accounted for by enhanced osteoclast survival in M-CSF compared with controls
rather than by formation of new osteoclasts.
PMID- 9556132
TI - Kinetic studies on epiphyseal growth cartilage in the normal mouse.
AB - The synthesis of DNA was studied in the proximal tibial growth plate of 25-day
old healthy NMRI mice by using the thymidine analog bromodeoxyuridine (BrdUrd),
which is incorporated into cells in the S-phase. Such cells were found only in
the upper three fifths of the morphologically defined proliferating zone. This
zone was therefore subdivided into a functional proliferating zone (the S-phase
zone) where most, if not all, chondrocytes proliferate, and a remaining
maturation zone. The BrdUrd containing immunoreactive cells could then be
followed at different intervals and they were found at the chondro-osseous
junction after only 36 h. By using double-labeling with BrdUrd and
iododeoxyuridine (IdUrd) the duration of cell cycle components could be
estimated; that is, the time for DNA synthesis (S-phase), second gap and mitosis
(G2 + M-phase), and remaining first gap (G1). We determined an S-phase time of
7.1 h and an average cell-cycle duration of 36 h. The G2 + M-phase was estimated
as 3.5-4 h, leaving an average G1-phase time of 25 h, which probably varies
considerably between chondrocytes. By combining these data with morphometrical
data regarding distances between cells, we calculated a total growth rate of 9.0
microm/h. Of this rate, 80% was entirely related to the process of hypertrophy-
that is, longitudinal expansion without any corresponding increase in cell number
-and 75 % was the result of processes outside the S-phase zone. Five percent of
the growth was due to the expansion of cell distances within the S-phase zone. In
this way longitudinal expansion can be studied at different levels in the growth
plate and the data permit calculation of changes in volumes of the extracellular
matrix. The largest increases in matrix volume occurred in the hypertrophic zone.
These data may serve as a basis for further studies on matrix turnover in
relation to growth.
PMID- 9556133
TI - Interaction of triiodothyronine with 1alpha,25-dihydroxyvitamin D3 on interleukin
6-dependent osteoclast-like cell formation in mouse bone marrow cell cultures.
AB - In mouse bone marrow cultures, the formation of osteoclast-like, that is,
tartrate-resistant acid phosphatase-positive (TRAP+) and calcitonin (CT) receptor
positive multinucleated cells (MNCs), induced by 10(-10) to 10(-8) mol/L
1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3], could be augmented by
triiodothyronine (T3), which alone had no effect on osteoclast-like cell
formation. The permissive effect of T3 increased the response to 1alpha,25(OH)2D3
by approximately one order of magnitude. Linear concentration dependence was
observed between 10(-11) and 10(-8) mol/L T3. Importantly, inhibition of
prostaglandin synthesis by indomethacin significantly impeded osteoclast-like
cell formation by 1alpha,25(OH)2D3 and abrogated the effect of T3 thereon. Basal
interleukin-6 (IL-6) production by cultured marrow cells was significantly
stimulated by 1alpha,25(OH)2D3. However, even at an exceedingly high
concentration of 20 ng/mL, IL-6 was ineffective in inducing osteoclast-like cell
formation. Therefore, any hormonally induced rise in IL-6 release from bone
marrow cells could not account for the observed changes in TRAP+ MNC numbers.
Nevertheless, the stimulatory effect of 1alpha,25(OH)2D3 on osteoclastogenesis
was partially dependent on IL-6 because it could be significantly blocked by a
neutralizing monoclonal anti-IL-6 antibody, and to the same extent by a
monoclonal anti-IL-6 receptor antibody. Unimpaired signaling through the IL-6/IL
6R system is also a prerequisite for the auxiliary effect of T3 on induction of
osteoclast-like cells by 1alpha,25(OH)2D3. Our data provide evidence that
1alpha,25(OH)2D3 induces osteoclast-like cell formation, at least in part, in an
IL-6-dependent mode of action, which is also subject to modulation by T3. The
mechanism of interaction of the two hormones apparently involves joint
stimulation of prostaglandin synthesis.
PMID- 9556134
TI - Low-energy laser irradiation stimulates bone nodule formation at early stages of
cell culture in rat calvarial cells.
AB - Although the acceleration of bone regeneration by laser treatment has been
reported, the mechanisms of action of laser on bone are unclear. To determine the
target cells responsible for the action of laser irradiation and roles of
irradiation on these cells during bone formation, we investigated the effects of
low-energy laser irradiation at various cell culture stages on cellular
proliferation, bone nodule formation, alkaline phosphatase activity, and
osteocalcin gene expression, employing rat calvarial cells. Osteoblast-like cells
isolated from fetal rat calvariae were irradiated once with a low-energy Ga-Al-As
laser (830 nm, 500 mW) at various cell culture stages (days 1-16). Laser
irradiation at early stages of culture significantly stimulated cellular
proliferation, ALP activity, and osteocalcin gene expression thereafter.
Furthermore, laser irradiation at earlier stages of culture significantly
stimulated a greater number (1.7-fold) and larger area (3.4-fold) of bone nodules
that had developed in the culture dish on day 21. However, these effects could
not be found by irradiation at a later date. These results suggest that laser
irradiation may play two principal roles in stimulating bone formation. One is
stimulation of cellular proliferation, especially proliferation of nodule-forming
cells of osteoblast lineage, and the other is stimulation of cellular
differentiation, especially to committed precursors, resulting in an increase in
the number of more differentiated osteoblastic cells and an increase in bone
formation. Both bone-formation-stimulating roles may be exhibited by laser
irradiation to immature cells only.
PMID- 9556135
TI - Interleukin-6 synthesis induced by prostaglandin E2: cross-talk regulation by
protein kinase C.
AB - We previously showed that prostaglandin E2 (PGE2) stimulates multiple
intracellular signaling pathways as follows: by activation of adenylate cyclase;
phosphoinositide (PI)-hydrolyzing phospholipase C and phosphatidylcholine (PC)
hydrolyzing phospholipase D; and by induction of Ca2+ influx in osteoblast-like
MC3T3-E1 cells. In this study, we investigated the effect of PGE2 on the
synthesis of interleukin-6 (IL-6) and its regulatory mechanism in MC3T3-E1 cells.
PGE2 significantly stimulated IL-6 secretion in a dose-dependent manner in the
range between 1 nmol/L and 10 micromol/L. A23187, a calcium ionophore, or
dibutyryl-cAMP significantly induced IL-6 secretion. The effect of a combination
of A23187 and dibutyryl-cAMP on IL-6 secretion was additive. The depletion of
extracellular Ca2+ by EGTA reduced the PGE2-induced IL-6 secretion. EP1 receptor
antagonist inhibited the PGE2-induced IL-6 secretion. H-89, an inhibitor of cAMP
dependent protein kinase, decreased the PGE2-induced IL-6 secretion. EP2 receptor
agonist alone stimulated IL-6 secretion. However, EP4 receptor antagonist had
little effect on IL-6 secretion. Calphostin C, a specific inhibitor of protein
kinase C (PKC), enhanced the secretion of IL-6 induced by PGE2. The stimulative
effect of PGE2 on IL-6 secretion was significantly enhanced in PKC downregulated
MC3T3-E1 cells. Pertussis toxin enhanced PGE2-induced IL-6 secretion. These
results strongly suggest that PGE2 stimulates IL-6 synthesis through both Ca2+
mobilization from extracellular space via EP1 receptor and cAMP production via
EP2 receptor in osteoblast-like cells, and that the PKC activation by PGE2 itself
regulates oversynthesis of IL-6.
PMID- 9556136
TI - Short-term treatment of recombinant murine interleukin-4 rapidly inhibits bone
formation in normal and ovariectomized mice.
AB - Estrogen deficiency contributes to an increase in bone resorption and bone
formation characterized by a high rate of bone turnover. Interleukin-4 (IL-4) is
a rapid and potent inhibitor of bone resorption. We examined the short term in
vivo effects of recombinant murine IL-4 (rmIL-4) on bone remodeling in normal and
ovariectomized mice. Eight-week-old mice were randomized into the following five
groups: (1) sham-operated mice (sham); (2) sham-operated mice infused with rmIL
4; (3) ovariectomized mice (ovx); (4) ovx infused with rmIL-4; and (5) ovx
replaced by 10 or 20 microg of 17beta-estradiol (E2) for 14 or 28 days after
ovariectomy, respectively. rmIL-4 at a dose of 5 microg/day was infused into ovx
and sham for 3 days prior to sacrifice. Analyses were performed 14 and 28 days
after operation. An increase in serum alkaline phosphatase and urinary
deoxypyridinoline levels induced by ovariectomy was inhibited by the 3-day
infusion of rmIL-4. In ovx, serum and urinary IL-6 levels were also increased
significantly 14 days after ovariectomy, which were restored by E2 but not by
rmIL-4. Histomorphometrical analysis of trabecular bone revealed that the 3-day
infusion of rmIL-4 inhibited the high rate of bone turnover induced by
ovariectomy, such as an increase in the osteoclastic surface (Oc.S/BS), number of
osteoclasts per mm bone surface (N.Oc/BS), mineralized surface per mm bone
surface (MS/BS), and bone mineral apposition rate (MAR). A significant decrease
in the bone volume (BV/TV) observed in ovx was not modulated by a 3-day infusion
of rmIL-4 prior to sacrifice. In sham, rmIL-4 also caused a significant decrease
in the Oc.S/BS, N.Oc/BS, MS/BS, and MAR, but the BV/TV was not modulated by rmIL
4. We conclude that short term infusion of rmIL-4 in vivo rapidly inhibits not
only bone resorption but also its formation in both sham-operated and
ovariectomized growing mice, resulting in a low rate of bone turnover without
modulating bone volume.
PMID- 9556137
TI - Immunolocalization and quantification of noncollagenous bone matrix proteins in
methylmethacrylate-embedded adult human bone in combination with
histomorphometry.
AB - The noncollagenous proteins (NCPs) in the bone matrix comprise growth factors
with distinct cellular effects and a series of proteins with less clear
biological actions. In order to understand the role of these proteins in bone
metabolism and in bone diseases, it is crucial to determine their localization
and quantity in normal and pathological bone. We have developed an
immunohistochemical method to detect osteopontin, osteocalcin, bone sialoprotein,
osteonectin, decorin, biglycan, and the growth factors transforming growth factor
beta, insulin-like growth factor-I, and bone morphogenetic protein-2 both in bone
matrix and in bone cells of adult human bone embedded in methylmethacrylate.
Immunohistochemistry and standard bone histomorphometry in adjacent sections
allows the localization of the proteins to metabolically active sites in bone.
The protocol works with several fixatives and with bone specimens obtained and
embedded to over 20 years ago. Most importantly, we developed a procedure to
specifically stain the mineralized matrix green in combination with a red
staining of the NCPs. Using digital image analysis it is possible to quantify the
relative amounts of NCPs (microm2 NCP area/microm2 mineralized matrix area).
Within one biopsy of normal bone cut at four different heights (at a distance of
100 microm), two adjacent sections were stained either for osteopontin or
osteonectin. Thirty trabecular and 20 cortical microscopic fields were measured,
and the NCP:mineralized matrix ratio was calculated. Stepwise analysis of the
standard error of the mean of the NCP:mineralized matrix ratios showed that
measuring about 50 microscopic fields is sufficient to obtain representative data
with a small confidence interval. In conclusion, the present procedure enables to
quantify NCPs and to relate their presence to metabolically active sites in bone.
The quantification provides the opportunity to monitor differences in
distribution (e.g., cortical vs. trabecular) and differences between normal and
pathological conditions and to assess changes in matrix composition during
treatment. This can be done by reanalyzing bone biopsies obtained in the past,
e.g., during clinical trials. Therefore, the present technique will be a valuable
tool for the study of noncollagenous bone matrix proteins in human bone.
PMID- 9556138
TI - Dynamic stochastic simulation of cancellous bone resorption.
AB - A stochastic simulation of cancellous bone resorption was developed and applied
to a simple two-dimensional lattice structure representing the vertebral body.
The simulation is based upon the concept of a basic multicellular unit (BMU)
where net resorption (-deltaB.BMU) is considered at bone/marrow surfaces. The
cancellous bone structure is defined as a binary matrix with the size of the
pixels corresponding to a square element of approximately 20 microm dimension.
The simulation considers both the probability that any surface pixel will be
activated into a BMU and, if activated, the length of the resorption cavity. The
relationship between relative stiffness and density for the simulation was
predicted by finite element analysis. The stochastic simulation was iterated
eight times with the mechanical properties assessed after each stage. Perforation
of a single trabeculae was first observed at step 2, the structure completely
lacking connectivity and mechanical integrity by step 8. The slope of the
stiffness-porosity graph was greater than unity for the first five steps, but
thereafter approached zero because the structure had lost connectivity and
effectively collapsed. The eight-step simulation was repeated five times and
demonstrated that, although the stiffness/density relationships were similar at
the extremes of density, the dependence of stiffness upon density varied. This
clearly demonstrates the stochastic nature of the simulation upon cancellous bone
structure, and is probably indicative of a significant dependence of mechanical
integrity upon perforation effects.
PMID- 9556139
TI - Assessment of cancellous bone quality in severe osteoarthrosis: bone mineral
density, mechanics, and microdamage.
AB - The role of bone microdamage (microscopic cracks or microcracks and
ultrastructural collagen matrix and bone mineral damage) in diseases such as
osteoarthrosis and osteoporosis is poorly understood. Microdamage accumulation in
vivo is influenced by age and cyclic loading, therefore, it would be useful if
the burden of microdamage in bone could be assessed by noninvasive measures such
as the radiological measurement of bone mineral density (BMD). The aim of this
study was to investigate the relationship between BMD, compressive strength and
stiffness, and microdamage in the cancellous bone of the proximal femur in
patients with severe osteoarthrosis. Trabecular bone core samples, from the
intertrochanteric region of the femur, were obtained from 34 patients, with a
mean age of 70.3 +/- 11.1 years, undergoing total hip arthroplasty for
osteoarthrosis. Cores selected from contact X-ray images were used for BMD
measurement, compressive mechanical testing or left untested (uncrushed), en bloc
staining for microdamage, and bone histomorphometry. The study shows a strong
dependence of both the elastic modulus and ultimate failure stress of the bone
samples on BMD and a significant relationship between the elastic modulus and
trabecular anisotropy (Tr. An). In multiple linear regression, BMD and Tr. An
together account for about 70% of the variance in the elastic modulus. Then
including microcrack crack density (Cr.Dn) and damage volume fraction (DxV/BV)
variables, Tr. An alone accounts for a relatively small amount of the variation
(8.5%) in ultimate failure stress and elastic modulus. The Cr.Dn accounts for
more of the variation in the ultimate failure stress than in the elastic modulus
(50% vs. 7%). In this experiment, data for Cr.Dn provide a measure of damage
associated with the ultimate failure of cancellous bone. In specimens that were
not mechanically tested, in vivo microcrack accumulation increases exponentially
with age. In conclusion, data from this study suggest that BMD and Cr.Dn are the
major determinants of cancellous bone strength, whereas BMD and Tr. An are major
determinants of cancellous bone stiffness. In bone specimens subjected to
compressive testing there was no relationship between microdamage and BMD,
suggesting that BMD cannot be used to monitor changes in the mechanical
properties of bone due to microdamage accumulation.
PMID- 9556140
TI - Vitamin D receptor gene polymorphisms and peak bone mass in southern Chinese
women.
AB - Controversial results were reported on the association of vitamin D receptor
(VDR) polymorphisms and bone mineral density (BMD). We studied allelic
frequencies of the BsmI, ApaI, and TaqI restriction fragment length polymorphisms
(RFLPs) in 144 normal healthy southern Chinese premenopausal women aged between
30 and 40 years, and correlated their peak bone mass with the VDR genotypes. In
comparison to Western populations, the B allele of the BsmI site is only found in
5% of the Chinese population. The BBAAtt genotype is virtually nonexistent in
Chinese people. Except for the slightly higher BMD values at the midlateral L-3
vertebra (13.8%, p = 0.045) and at the Ward's triangle (13.3%, p = 0.08) in the
bb subjects, no difference could be detected at other sites between the Bb and bb
subjects. The same findings were observed when comparing the Tt to tt subjects.
Analysis of the VDR genotype revealed that subjects with BbAaTt and BbAATt
haplotypes had the lowest peak bone mass. Their L2-4 lumbar spine, midlateral L-3
vertebra, and Ward's triangle BMD was 1.04, 0.90, and 0.75 standard deviation
(SD), respectively, lower than the bbAATT counterparts, but none of the
comparisons were statistically significant. However, with the low frequency of
the B allele, our study had limited power to detect a small difference in the BMD
of the various genotypes. In conclusion, although VDR polymorphism is believed to
affect calcium absorption, this study failed to confirm a strong relationship
between the VDR genotype and peak bone mass in our population with low dietary
calcium intake.
PMID- 9556141
TI - Assessment of bone mineral at appendicular sites in females with fractures of the
proximal femur.
AB - The prediction of hip fractures by measurements at remote sites or the
improvement of predictive power by measurements at multiple sites could
potentially increase the success of osteoporosis screening programs. In a cross
sectional study on 137 postmenopausal women, we tested the hypothesis that bone
assessment at the hip, the forearm, and the tibia are independently associated
with osteoporotic fractures of the hip. Bone mineral densities, geometric
features, and ultrasound properties were determined with hip dual X-ray
absorptiometry, forearm peripheral quantitative computed tomography (QCT), and
tibia speed of sound measurement. While the odds ratios for fracture
discrimination per standard deviation decrease ranged between 3 and 4 for
measurements at the hip, they were only 1.8 at the forearm and 1.4 at the tibia.
Measurements at the tibia or the forearm were neither independently associated
with osteoporotic hip fractures (p > 0.05) nor could any combination of
measurements significantly increase the power for the identification of fractures
as measured with receiver operating curves. Women who sustained trochanteric
fractures were characterized by a generalized loss of bone mineral. Cervical
fractures were associated with a decrease of bone mineral density at the hip, but
no significant alterations in bone mass or geometric properties were observed at
the tibia or at the forearm. Fracture risk prediction at the hip is therefore
preferably performed by measurements at the hip itself. Peripheral QCT at the
distal radius and tibial ultrasound seem capable of depicting women with an
increased risk for trochanteric but not for cervical fractures. The risk
assessment appears not to be improved by including information of cortical or
geometric properties of the forearm.
PMID- 9556142
TI - Effects of the bisphosphonate olpadronate in patients with carcinoma of the
prostate metastatic to the skeleton.
AB - Prostate cancer is predominantly associated with osteoblastic bone metastases,
but an increase in bone resorption has been demonstrated consistently, both
histologically and biochemically. For this reason, bisphosphonates, which
effectively suppress bone resorption, have been used in patients with prostate
cancer metastatic to the skeleton. We studied clinical and biochemical responses
5 days and 3 months after administration of the new, potent bisphosphonate,
olpadronate, in 28 patients with prostate cancer and bone metastases. All
patients received 4 mg of olpadronate intravenously daily for 5 days. No
additional treatment was given to the first 12 patients, while treatment was
continued with oral olpadronate 200 mg daily in the following 16 patients. Serum
alkaline phosphatase (ALP) activity was elevated in 93% of the patients and was
positively correlated to urinary hydroxyproline excretion (r = 0.81, p < 0.0001),
suggesting a coupling between bone formation and resorption. A rapid and
significant suppression of bone resorption was observed in all patients after
intravenous treatment. This was sustained for 4-6 weeks in all patients, but
reversed thereafter in patients not receiving oral maintenance therapy. No
significant changes in serum ALP activity were observed in either group during
the 3 months of follow-up. At the start of treatment all patients had severe bone
pain and 82% and 36% were using NSAIDs and/or opiates, respectively. Although
clinical response was not a primary objective of the study, we observed that
intravenous therapy was associated with a decrease in bone pain in 76% of
patients and a reduction in the use of analgesics. At 3 months this response was
generally sustained only in those patients who were maintained on continuous oral
therapy (p < 0.05 compared with the group treated with intravenous olpadronate
only). The clinical response thus appeared to parallel the biochemical changes in
bone resorption.
PMID- 9556143
TI - Enzyme immunoassay for a characteristic protein in the animal crude drug
lumbricus.
AB - A new method was developed to measure the content of a Lumbricus component in a
traditional Chinese medicine (TCM). An antiserum specific to Lumbricus was
elicited in a rabbit following immunization with a suspension of Lumbricus
fragments. A characteristic antigen protein, 70 kDa, was found in Lumbricus and
was purified almost to singleness using a column chromatography series of gel
filtration and DEAE-Sepharose. A selected antibody enzyme immunoassay (SAEIA) was
developed using the antiserum and the purified 70 kDa protein as a solid-phase
antigen. The SAEIA was specific to Lumbricus species, and showed no cross
reaction with any crude drugs other than Lumbricus. This SAEIA detected 70 kDa
protein in the amount of 10 ng/ml with excellent reproducibility (coefficient of
variation=3.0%) and an EC50 of 0.24 microg/ml. Using this assay, Lumbricus levels
were easily determined in a Lumbricus-based TCM Kazecoll, but not in the control
Kazecoll (Kakkonto) prepared without Lumbricus. The SAEIA for 70 kDa protein was
simple, accurate, reproducible and may provide a general analytical method for
the quality control of Lumbricus-based TCMs.
PMID- 9556144
TI - Isolation of an Escherichia coli mutant which permits the high-level expression
of a streptomycin-resistance gene derived from Pseudomonas aeruginosa.
AB - Pretreatment with streptomycin at a low concentration influenced the
susceptibility to streptomycin of a strain of Escherichia coli carrying a
streptomycin-resistance plasmid, pSA1700, derived from Pseudomonas aeruginosa.
This phenomenon was due to a mutation that occurred at about 10(-8)-10(-10) of
frequency in a regulatory gene involved in gene expression on the chromosome of
E. coli. A product encoded by the regulatory gene on the chromosome of E. coli
might normally repress gene expression by binding to part of the promoter region
of the streptomycin-resistance gene derived from P. aeruginosa.
PMID- 9556145
TI - A carbon-centered radical as a reaction species in the DNA strand-breakage by D
glucosamine.
AB - Electron spin resonance(ESR) studies using 5,5-dimethyl-1-pyrroline N-oxide
(DMPO) and sodium 3,5-dibromo-4-nitrosobenzensulfonate (DBNBS) as a spin-trapping
agent revealed the formation of both hydroxyl and carbon-centered radical-derived
spin adducts in Cu2+-containing 50 mM Tris-HCl buffered solutions (pH 7.1) of D
glucosamine, D-mannosamine, and D-galactosamine, which were previously shown to
have the ability to break the single-strand of plasmid pBR322 DNA in a nucleotide
sequence-specific manner. HCl-free D-glucosamine has higher DNA breaking
activity, and this activity is promoted more by the presence of Cu2+ than the
original D-glucosamine hydrochloride, exhibits stronger radical signals in the
ESR spectrum. It is suggested that D-glucosamine is unstable around neutral pH,
being converted into certain intermediate(s) such as a dihydropyrazine compound,
which generate(s) carbon-centered radicals, and that, besides the hydroxyl
radical, the intermediate(s) is/are responsible for DNA strand breakage.
PMID- 9556146
TI - Generation of immortalized murine forebrain cell lines expressing an alpha
isoform of Ca2+/calmodulin-dependent protein kinase II.
AB - Immortalized hybrid cells were generated by the somatic fusion of the cells from
the forebrain of embryonic mouse with N18TG2 neuroblastoma cells. Three
monoclonal hybrid cell lines, designated NF26, NF81, and NF83 (neuroblastoma
forebrain hybrid cells), expressing an alpha isoform of Ca2+/calmodulin-dependent
protein kinase II (CaM kinase II) were isolated, and their expression was
demonstrated by immunoblotting and immunocytochemistry using a monoclonal
antibody specific to the a isoform of the enzyme. The kinase activity of the
hybrid cells was 2- to 3-fold higher than that of the parent neuroblastoma line
N18TG2 cells. The neuronal origin of these lines was shown by their
immunoreactivity to neurofilament protein, a neuron specific marker. Lines NF26,
NF81, and NF83 are the first cell lines to express the gene of the alpha isoform
of CaM kinase II in the brain.
PMID- 9556147
TI - Apoptotic cell death induced by physarumin (hemagglutinin from myxomycete,
Physarum polycephalum).
AB - Physarumin, a carbohydrate-binding protein (hemagglutinin or lectin), was
isolated from the plasmodium of Physarum polycephalum. Physarumin agglutinated
not only several species of erythrocytes but also tumor cells such as AH109A
ascites hepatoma cells, sarcoma 180 ascites cells and mouse leukemia P388 cell
lines. Physarumin had tumor cell growth-inhibitory activity, and induced the
apoptosis of P388 cell lines. Physarumin-induced apoptosis required binding to a
68 kDa counter-receptor on the P388 cell surface. Since the agglutinating and
antiproliferative activities of physarumin were inhibited by asialofetuin and
thyroglobulin, respectively, it is suggested that physarumin reacts with the
galactose moiety of carbohydrate chains of physarumin receptor.
PMID- 9556148
TI - Characterization of ASK mice, a strain highly sensitive to anaphylactic shock.
AB - A mouse strain named ASK that was originally isolated from El (epilepsy) mice has
been shown to be highly sensitive to anaphylactic shock. Here, we characterized
the bases of the sensitivity of ASK mice in comparison with the parental strain,
El. More than 90% of ASK mice, but not El mice that had been sensitized either
actively or passively, died within 1 h following an antigen challenge. The
anaphylactic death was effectively blocked by diphenhydramine. Plasma histamine
levels increased by 30-50 fold in ASK after the antigen challenge, but only a 2-3
fold increase was observed in El mice. All (El x ASK) F1 mice, either male or
female, showed an ASK-like phenotype, suggesting that the impaired plasma
histamine response in El mice is due to some recessive mutation(s). Consistent
with the plasma histamine responses, cultured mast cells derived from El bone
marrow showed impaired potency to degranulate in response to surface IgE
engagement, in contrast to ASK mast cells which undergo normal degranulation.
Another characteristic feature of ASK mice is their sensitivity to histamine,
since 75% of the mice were killed by the subcutaneous administration of 100-200
mg/kg histamine, while C3H and BALB/c mice were resistant to even 600 mg/kg
histamine. Taken together, the major bases of the susceptibility to anaphylactic
shock in ASK mice are thought to be the enhanced sensitivity to histamine and the
recovered degranulation machinery in mast cells that is impaired in El mice.
PMID- 9556149
TI - Anandamide, an endogenous cannabinoid receptor ligand, also interacts with 5
hydroxytryptamine (5-HT) receptor.
AB - Interactions of anandamide (N-arachidonylethanolamide), an endogenous compound
for cannabinoid receptors, with the receptors for 5-hydroxytryptamine (5-HT),
benzodiazepine, and gamma-aminobutyric acid(A) (GABA[A]) receptors in bovine
synaptic membrane were examined. Anandamide decreased the 5-HT receptor bindings
at concentrations of 1-100 microM, although it did not cause any change in
benzodiazepine or GABA(A) receptor bindings. A high concentration of anandamide,
100 microM, significantly decrease both [3H]5-HT and [3H]ketanserin bindings. The
present study revealed that the pharmacological activity of anandamide might be
partially mediated through the 5-HT receptor.
PMID- 9556151
TI - Suppression of synaptogenesis by epileptiform discharges in hippocampal slice
culture.
AB - Using an organotypic slice culture of the hippocampus, the effects of epileptic
activities on synapse reorganization following axotomy were investigated. The
maximal amplitude of field excitatory postsynaptic potentials that reflected the
number of functional synaptic contacts were recorded 7 d after the mossy fibers
or Schaffer collaterals were transected at 8 d in vitro. Fifty microM picrotoxin
elicited epileptiform bursts, whose severity in the CA1 region was lower than
that in the CA3 region. Synapse reformation of the mossy fibers was significantly
prevented by picrotoxin, and that of Schaffer collaterals also tended to be
attenuated. Ten microM bicuculline, 1 mM pentylenetetrazol or 2 mM 4
aminopyridine also induced epileptic activities in the CA3 region and
significantly depressed synapse formation of the mossy fibers. Using cultures of
dispersed neurons, we found that the prolonged depolarization of membrane
potentials promoted neurite outgrowth. Taken together, we concluded that the
preventing effects of epileptic activities on synapse reorganization following
axotomy was due to the inhibition of the synaptogenesis process, not to a
blockade of axon outgrowth.
PMID- 9556150
TI - Effect of methylcarbonylmethyl 2(S)-[4-(4-guanidino-benzoyloxy)phenyl] propionate
methanesulfonate (TT-S24) on experimental pancreatitis in rats.
AB - The effect of methylcarbonylmethyl 2(S)-14-(4-guanidino-benzoyloxy) phenyl]
propionate methanesulfonate (TT-S24) on experimental pancreatitis in rats was
examined in comparison with that of camostat. TT-S24 showed a preventive effect
on increases in plasma amylase activity and pancreatic weight induced by cerulein
injection. TT-S24 also reduced an increase in plasma amylase activity induced by
taurocholate. TT-S24 effectively prevented the mortality induced by an injection
of a mixture of trypsin and taurocholate. TT-S24 showed no effect on an increase
in amylase activity 6 h after duodenum ligation (closed duodenal loop
pancreatitis), indicating that the drug had no effect on the initiation and
propagation step of closed duodenal loop pancreatitis. On the other hand, TT-S24
reduced an increase in amylase activity 6 h after release of the duodenum
ligation. TT-S24 showed anti-trypsin, anti-kallikrein, anti-thrombin and anti
plasmin activities. The effect of TT-S24 on some experimental pancreatitis models
was nearly equal to or somewhat more potent in most instances to that of
camostat. Therefore, TT-S24 should be useful in the clinical treatment of
pancreatitis.
PMID- 9556152
TI - Differential effects of cytotoxic drugs on mortal and immortalized B
lymphoblastoid cell lines from normal and Werner's syndrome patients.
AB - We studied the effects of nine cytotoxic drugs on three groups of B
lymphoblastoid cell lines transformed by Epstein-Barr virus (EBV): group 1,
mortal cell lines from normal individuals; group 2, immortalized cell lines from
normal individuals with strong telomerase activity; group 3, mortal cell lines
from Werner's syndrome (WS) patients. Aminoglycoside antibiotics and alkylating
drugs showed significantly stronger cytotoxic effects on immortalized cell lines
than on mortal cell lines or the cell lines before immortalization. In contrast,
topoisomerase II inhibitors showed no difference or they tended to be less
cytotoxic to immortalized cell lines. Mortal cell lines from normal individuals
and WS patients showed no difference in sensitivity against all the drugs
examined except for the topoisomerase I inhibitor, camptothecin, which had a
stronger cytotoxic effect on WS cell lines than other cell lines. We discuss the
mechanisms underlying these cytotoxic effects.
PMID- 9556153
TI - Study of the pharmacological effect of the bile salt, sodium scymnol sulfate,
from Rhizoprionodon acutus. II. Prophylactic effect of scymnol on lesion
development in a rat peripheral arterial occlusion model.
AB - The effect of scymnol on the development of lesions in a rat peripheral arterial
occlusion model, involving injection of 5% lactic acid into the femoral artery,
was investigated. In this model oral administration of scymnol significantly
prevented edematous swelling and development of lower limb lesions, including
gangrene, and also reduced changes in blood coagulation parameters, platelet
aggregation and retention rate at a dose of 10 or 30 mg/kg. However, it had no
effect on these clotting system functions in sham-operated rats at a dose of 10
mg/kg. The effects of scymnol were also compared with those of ticlopidine and
argatroban. The findings suggest that scymnol may be clinically useful for
preventing thrombotic peripheral arterial occlusive disorders. Its prophylactic
action appears to be mainly due to its potent ability to protect against
endothelial cell damage due to lactic acidosis.
PMID- 9556154
TI - Appearance of compound K, a major metabolite of ginsenoside Rb1 by intestinal
bacteria, in rat plasma after oral administration--measurement of compound K by
enzyme immunoassay.
AB - Enzyme immunoassay (EIA) for the determination of compound K (C-K), a major
metabolite of ginsenoside Rb1 (G-Rb1) from Panax ginseng root by intestinal
bacterial flora, was explored. Bovine serum albumin (BSA) was coupled to the C-26
position on the unsaturated side chain of C-K. Beta-D-galactosidase was
introduced at the C-26 position of the saturated side chain. Antiserum, obtained
by immunization of rabbits with C-K-BSA conjugate, possessed high affinity and
specificity toward C-K. The EIA for C-K by the double antibody method was
established in the range of 0.1--100 ng/tube. Plasma C-K after the oral
administration of C-K and G-Rb1 to rats was determined by the established EIA. C
K was rapidly absorbed from the gastrointestinal tract after the administration,
then slowly decreased. On the other hand, C-K appeared late and was retained for
a long period of time in the plasma after the administration of G-Rb1, which
itself is hardly absorbed.
PMID- 9556155
TI - Mechanism of free radical-induced hemolysis of human erythrocytes. II. Hemolysis
by lipid-soluble radical initiator.
AB - Hemolysis of human erythrocytes induced by free radicals initiated from lipid
soluble 2,2'-azobis(2,4-dimethylvaleronitrile) (ADVN) was examined under various
conditions. From the ESR spectra of the spin-labeled erythrocytes, it was found
that the fluidity of the membrane did not change during the radical-induced
hemolysis. The curves of the time courses of the extent of oxidation and the
conformational change of band 3 proteins were hyperbolic, though the hemolysis
curves were sigmoidal. In spite of the necessity of lipid peroxidation, the
peroxidation did not seem to relate directly to the hemolysis. It was observed
that the hemolytic holes were formed by a lateral clustering of band 3, an anion
exchange protein in erythrocytes. The competitive reaction model between lipid
peroxidation and the redistribution of oxidized band 3 proteins, which was
previously presented for the hemolysis initiated from water-soluble, 2,2'
azobis(amidinopropane)dihydrochloride (AAPH), could explain well the curves for
the hemolysis by ADVN. Further, the rates of lipid peroxidation at various
concentrations of ADVN and AAPH were calculated on the basis of the hemolysis
curves, and they were compared with the experimental values estimated from the
curves for the lipid peroxidation. The curves which showed a dependence of the
calculated rate constant on the concentration of radical initiators were similar
to those of the experimental values. These results indicate that the competitive
reaction model is appropriately represents the hemolysis induced by free radicals
which also originated from lipid-soluble initiators.
PMID- 9556156
TI - Antiproliferative constituents in Umbelliferae plants II. Screening for
polyacetylenes in some Umbelliferae plants, and isolation of panaxynol and
falcarindiol from the root of Heracleum moellendorffii.
AB - Methanol extracts of 36 samples of 21 Umbelliferae plants were screened for
polyacetylenic compounds using the ELISA for panaxytriol, and their
antiproliferative activity was checked by MTT assay using the tumor cell lines MK
1, HeLa and B16F10. The presence of antiproliferative polyacetylenes was
suggested in Angelica acutiloba (fruit), Anethum graveolens (root), Bupleurum
rotundifolium (fruit), Carum carvi (fruit and root), Coriandrum sativum (fruit),
Cryptotaenia japonica (leaf), Glehnia littoralis (fruit), Heracleum
moellendorffii (root) and Torilis japonica (fruit). Panaxynol and falcarindiol
were successfully isolated from the root of Heracleum moellendorffii as
antiproliferative polyacetylenes.
PMID- 9556157
TI - A new experimental device for the measurement of moisture emission and heat
release from respiratory organs and body surface.
AB - A new experimental device was developed to investigate respiratory diseases. The
moisture and heat released from respiratory organs and the body surface of a rat
were determined by means of this device as well as the rectal temperature. The
high recovery of results was statistically confirmed, and the measured values at
various environmental temperatures were significantly different from each other.
Some standard drugs, such as ephedrine, aminophylline and chlorpromazine, were
examined. Their stimulant or depressant actions were clearly observed. The
results of some traditional medicines for the treatment of rhinitis and bronchial
asthma from this measuring system were consistent with their clinical
applications. These results suggest that this new experimental system is not only
effective in the experimental understanding of cold-hot syndrome, but also
contributes to the evaluation of the effects of traditional medicines.
PMID- 9556158
TI - Safe and efficient transdermal delivery of desmopressin acetate by iontophoresis
in rats.
AB - Iontophoretic delivery of desmopressin acetate (DDAVP) was assessed for delivery
efficiency and drug stability, both in vitro and in vivo. The effect of current
intensity and duration of current application on the decomposition of DDAVP was
investigated in vitro. It was shown that when a current of 0.1 mA was applied for
5 min, the decomposition of DDAVP was negligible. In vivo experiments under the
same conditions showed that the antidiuretic response to DDAVP persisted for
about 6 h. Furthermore, when this iontophoresis was repeated 3 times at intervals
of 4 h, the antidiuretic response persisted for about 11 h. These results suggest
that repeated short-term iontophoresis is a safe and effective technique for
transdermal delivery of DDAVP.
PMID- 9556159
TI - Direct transport of 2',3'-didehydro-3'-deoxythymidine (D4T) and its ester
derivatives to the cerebrospinal fluid via the nasal mucous membrane in rats.
AB - We investigated the absorption and transport of 2',3'-didehydro-3'-deoxythymidine
(D4T) and its ester prodrugs from the nasal cavity in rats. The absorption of D4T
and its acetate (C2-D4T) was rapid and almost complete, although the hemi
succinate (Suc-D4T) was absorbed rather slowly; the plasma concentrations of the
prodrug, Suc-D4T, and regenerated D4T remained unchanged throughout the
experimental period (180 min). Concentrations in the cerebrospinal fluid (CSF)
following intravenous (i.v.) and intranasal (i.n.) administration were also
measured. After i.n. administration, drug concentrations were higher in the
fraction derived from the subarachnoid space located close to the nasal mucosa
than those in the fractions located far from the nasal cavity. This difference
was not found following the i.v. administration of the drugs. Following nasal
administration, the intact Suc-D4T was found in the CSF at a concentration higher
than that of D4T, although transport of the intact prodrug to the CSF was not
observed following i.v. administration. These results suggest that direct
transport of the drugs from the nasal cavity to the CSF significantly contributes
to the higher concentrations in CSF of D4T and/or its ester prodrugs, and
indicate the possible value of nasal administration for the treatment of patients
with AIDS dementia.
PMID- 9556160
TI - Activation of murine kupffer cells by administration with gel-forming (1-->3)
beta-D-glucan from Grifola frondosa.
AB - The effect of gel-forming (1-->3)-beta-D-glucan on the immunological activities
of murine kupffer cells was examined. A branched type gel-forming (1-->3)-beta-D
glucan, GRN, was administered intravenously to mice. GRN associating to kupffer
cells was detected by an immunohistochemical technique using anti-GRN antibody. A
kinetic study of the activation of kupffer cells revealed that GRN could induce
the enhanced production of cytokines and nitric oxide on 4 to 7 d after the
administration. The activities are further augmented by adding GRN in the
culture. The cytostatic activity of kupffer cells against murine lymphoma, EL-4,
was also augmented by a time course similar to nitric oxide production. The
cytostatic activity was reduced by adding an inhibitor of nitric oxide synthase,
implying that the cytostatic activity of kupffer cells to EL-4 was dependent on
nitric oxide. The administration of GRN increased the expression of CD11b, known
as a beta-glucan receptor, on kupffer cells at day 7. The above data suggest that
GRN could activate murine kupffer cells to enhance the production of cytokines
and nitric oxide, and that the activation required 4 or 7 d, at least, after the
administration with GRN.
PMID- 9556161
TI - Hepatoprotective effect of Fe-TPEN on carbon tetrachloride induced liver injury
in rats.
AB - Fe(II)-tetrakis-N,N,N',N'(2-pyridylmethyl) ethylenediamine (Fe-TPEN) catalyzes
the dismutation of superoxide, and blocks the toxic effect of paraquat on
Escherichia coli growth and survival. We examined antioxidative effects of Fe
TPEN on lipid peroxidation and t-butyl hydroperoxide induced cell damage. Fe-TPEN
inhibited the FeSO4/H2O2 induced lipid peroxidation in the rat liver homogenates
with an IC50 value of 30.2 microM, and protected Ac2F cell damage by t-butyl
hydroperoxide in a dose-dependent manner (EC50 value is 2.6 microM). Also,
hepatoprotective effect of Fe-TPEN (5 mg/kg, i.p.) was investigated using CCl4
induced liver injury in rats. This complex inhibited the elevation of serum
alanine aminotransferase (AST) and aspartate aminotransferase (ALT) levels in
CCl4 induced liver injuries, and improved submassive necrosis and fatty
degeneration of the hepatocytes. Fe-TPEN also prevented the loss of total and
nonprotein SH contents, glutathione peroxidase and glutathione-S-transferase
activity in cytosol of rat liver. Although the exact mechanism of action is not
clear, antioxidative properties as well as attenuation of hepatocellular defense
systems by Fe-TPEN seem to be important on its potent hepatoprotective effect in
CCl4-intoxicated rat.
PMID- 9556162
TI - Aromatization of 19-oxygenated androst-4-ene-3,6,17-triones with human placental
microsomes.
AB - To gain insight into the aromatization sequence of androst-4-ene-3,6,17-trione
(1), a suicide substrate of aromatase, the aromatization of its 19-hydroxy and 19
oxo analogs 2 and 3 with human placental microsomes, was studied using GC-MS.
Steroids 2 and 3 were separately incubated with the microsomes in the presence of
NADPH in air. The GC-MS analysis of the trimethylsilyl derivative of the
aromatization product indicated that both the 19-oxygenated steroids 2 and 3 were
aromatized to yield 6-oxoestrogens, 6-oxoestrone (4) and 6-oxoestradiol (5), in
each experiment. The aromatization rates of substrates 2 and 3 were 605+/-48 and
1794+/-75 pmol/mg protein/10 min, respectively. These relatively higher rates,
compared to that of the parent steroid 1 (73.2+/-6.6 pmol/mg protein/10 min),
indicates that the suicide substrate 1 is aromatized through the 19-oxygenated
intermediates 2 and 3.
PMID- 9556163
TI - Effect of arylthiolated 2,3-dimethoxy-1,4-benzoquinones on respiratory activity
and lipid peroxidation in bovine heart mitochondria.
AB - A series of arylthiolated 2,3-dimethoxy-1,4-benzoquinones was synthesized and
tested for the effect on the respiratory system and the lipid peroxidation in
bovine heart mitochondria (BHM). These quinones showed intense inhibitory
activities on the respiratory system in BHM. Their inhibitory activity in the
succinate oxidase system was greater than that in the NADH oxidase system. No
difference between the difference spectra, with and without these quinones, of
the reduced minus oxidized forms of cytochromes (cyt.) suggested that these
quinones inhibit at the site after cyt. a+a3 in the respiratory chain. Moreover,
these quinones were as efficient as exogenous ubiquinone-10 (UQ-10) for the
inhibition of lipid peroxidation. 5- And 5,6-di-arylthio groups on the quinone
ring were found to be favorable for inhibition of the respiratory system and
lipid peroxidation. Our results suggest that arylthiolated 2,3-dimethoxy-1,4
benzoquinones act as antioxidants by increasing the amount of endogenous reduced
UQ-10 in BHM.
PMID- 9556164
TI - Pharmacokinetics of intra-arterially administered pirarubicin in plasma and
cerebrospinal fluid of patients with glioma.
AB - The present paper investigates the pharmacokinetics of pirarubicin (THP) in the
plasma and cerebrospinal fluid (CSF) of two patients with glioma during
hyperosmotic disruption of the blood-brain barrier (HODBBB) and intra-arterial
combination chemotherapy. A 42-year-old Japanese man (patient A) with
glioblastoma and a 21-year-old Japanese woman (patient B) with astrocytoma
received a course of HODBBB and intra-arterial combination chemotherapy with THP,
methotrexate, peplomycin, and vindesine. Patient A was initially administered
mannitol, followed by the infusion of anticancer drugs into the right internal
carotid artery. Patient B was initially administered mannitol, followed by the
infusion of anticancer drugs into the right internal carotid artery and,
immediately thereafter, into the right vertebral artery. Samples of blood and of
CSF in the brain ventricle were obtained. THP concentration was measured by HPLC,
and the pharmacokinetic parameters of this drug were estimated in plasma and CSF.
In both patients, the plasma concentration of THP peaked at the end of infusion,
then decreased in a bi-exponential decay pattern during the remainder of the
treatment period. THP was detectable in CSF beginning 1.0 h after the initiation
of infusion, then was slowly eliminated from the ventricle. The maximum CSF
concentration of THP was 0.97% of plasma in patient A and 0.89% in patient B. The
CSF AUC of THP was 28.4% of plasma in patient A and 13.1% in patient B.
PMID- 9556165
TI - In vitro release of tranilast from oily gels and penetration of the drug into
Yucatan micropig skin.
AB - For the transdermal delivery of tranilast (TL), a drug used for the treatment of
skin diseases such as keloids and hypertrophic scars, its oily gels were
prepared; its in vitro release and penetration into Yucatan micropig skin were
evaluated. In the gels that consisted of hydrogenated soybean phospholipids (HSL)
and octyl isononanoate (IOIN), a fatty-acid ester, the release of TL from the
gels was proportional to the drug content, and the extent of TL released up to 6
h from them was approximately 70% of the amount of applied TL. On the other hand,
with the gels consisting of HSL and isocetyl isostearate (ICIS), the release of
TL from the gels was about half of that from IOIN gels, even at the same drug
concentration. When oily gels were used, the TL skin concentration was rapidly
increased compared with the level obtained with suspensions. With 0.1% IOIN gel,
a high concentration of TL (ca. 160 microg/g) in the dermis was obtained and
continued until at least 48 h. These results suggest that oily gels may be useful
for the topical application of TL.
PMID- 9556166
TI - Urinary metabolites of valproic acid in epileptic patients.
AB - The urinary excretion of valproic acid (VPA) and its metabolites (3-keto VPA, 3
OH VPA, and VPA-glucuronide) in 6 epileptic patients was studied using gas
chromatography-mass spectrometry. The amount of VPA and 3-OH VPA excreted in the
urine was low (0.1-0.5% of the dose of VPA and 0.6-1.5% of the dose of 3-OH
administered). The amount of 3-keto VPA and glucuronide (VPA-Glu) excreted was
marked (5.8-26.2% and 13.1-88.7% of the dose of VPA administered, respectively).
The urinary excretion of VPA and its metabolites by patients who have taken a
normal amount of a VPA preparation was almost the same as that of healthy
volunteers. Two epileptic patients who took a large amount of the VPA preparation
showed a high excretion of VPA-Glu without an increase in their plasma VPA-Glu.
PMID- 9556167
TI - Retention mechanism of imidazoles in connective tissue. II. Activation of
imidazoles in cupro-ascorbate system for irreversible binding formation with
aortic tissue in vitro.
AB - In order to obtain an insight into the retention mechanism of drugs with
imidazole moiety in the connective tissue, the in vitro characteristics of the
interaction between 14C-labeled imidazoles (imidazole and its 2-methyl
derivative) and slices of dog aorta were studied. We found that cupro-ascorbate
catalyzed oxidative reactions for the imidazoles led to their irreversible
binding with connective tissue, and that, from a study using protein modifiers,
the aldehydic function intrinsic to the tissue protein was involved in the
binding formation. This characteristic in vitro was observed under physiological
conditions, hence it can be extrapolated to the in vivo situation and could also
give a clue to the nature of the retention of imidazole-containing drugs in
connective tissue.
PMID- 9556168
TI - Occupational risks of zoonotic infections in Dutch forestry workers and muskrat
catchers.
AB - Lyme borreliosis (LymeB), Hemorrhagic fever with renal syndrome (HemoFRS),
Lymphocytic choriomeningitis (LymphoCM), Tick-borne encephalitis (TickBE), Q
Fever (QFever), and Weil's leptospirosis (Lepto) are known to be occupational
diseases for rural outdoor workers. We investigated the occupational infection
risks for these diseases in greater detail. Antibodies to these agents were
assessed in 312 forestry workers and muskrat catchers, and in 356 matched office
workers. Three levels of occupational exposure were distinguished: high for
active forestry workers, low for supervisory forestry staff and muskrat catchers
and zero for office workers. At high exposure the prevalence odds ratios (with
95% CI between brackets) were: LymeB 15 (5.5-42), HemoFRS 11 (1.3-501), LymphoCM
5.4 (1.0-50), TickBE 1.0 (0.3-3.0), QFever 1.0 (0.4-2.1), and Lepto 0 (0.0-33).
No significant risk of infection was found at low exposure. Part of the present
group had also been studied in 1989 and 1990. Within this cohort the conversion
rates to Borrelia burgdorferi have been estimated for the periods 1989-1990 and
1990-1993 as 0.23 and 0.066 year(-1), respectively, and the reversion rate as
0.44 year(-1). The corresponding values for HemoFRS were 0.031, 0.018 and 1.42
year(-1). Active forestry workers in the Netherlands are at high risk of
infection by LymeB, HemoFRS and LymphoCM. Prevalence of antibodies to LymeB and
HemoFRS appeared to reflect the levels of these infection hazards in recent
history.
PMID- 9556169
TI - Longterm survey (7 years) in a population at risk for Lyme borreliosis: what
happens to the seropositive individuals?
AB - In 1986, a 26% seroprevalence of IgG- anti-Borrelia burgdorferi antibodies was
observed among 950 orienteers and the incidence of new clinical infections was
0.8%. In 1993, a total of 305 seropositive orienteers were reexamined. During
that time, 15 cases (4.9%) of definite/probable Lyme disease occurred in this
seropositive group (12 skin manifestations and 3 monoarticular joint
manifestations). Among the 12 definite cases, 9 showed new clinical infections (7
EM, 1 acrodermatitis chronica atrophicans, 1 arthritis), and 3 were recurrent (2
EM, 1 arthritis). The annual incidence (0.8%) in this seropositive group was
identical to the incidence observed among the whole population in 1986. The
individual antibody titer decreased slightly but the seroreversion rate was low
(7%). Serology was not very helpful in identifying clinical cases and evolutions,
and it can be stated, that a positive serology is much more frequent in this risk
group than clinical disease.
PMID- 9556170
TI - Epidemiological aspects of tuberculosis in the Padua Health District 1985-1996.
AB - The present study was carried out in order to monitor the epidemiology of
Mycobacterium tuberculosis disease in the Padua Health District over the period
1985-1996 with a view to the situation in some population subgroups. The average
annual rate per 100,000 persons per year was 7.9 with a peak in 1994 (15.6 per
100,000 persons). The most significant variations are not per annum but between
the periods 1985-1990 and 1991-1996 (average rates per 100,000 persons: 4.8 and
10.9, respectively). The trend shows an increasing frequency in all age groups
and especially among the elderly. Immigration from endemic areas and human
immunodeficiency virus (HIV) infection appear to contribute to the increase the
number of notified cases among adults. In the last four years an increase of
tuberculosis cases was also observed among subjects with professional exposure
risk. Improvements of programs both at national and regional level are believed
to be essential to the tuberculosis control.
PMID- 9556171
TI - The effect of follow-up on limiting non-participation bias in genetic
epidemiologic investigations.
AB - The use of a comprehensive follow-up strategy to limit non-participation bias was
evaluated in a population-based case-control study of orofacial clefts. Birth
parents were requested to provide exposure data, and index children and parents
were asked to provide blood specimens. Follow-up included telephone or postal
reminders every two weeks for up to three months. Consent to participate was
received from 281 (76.6%) case mothers and 246 (72.4%) case fathers. The
corresponding totals for controls were 279 (54.7%) and 245 (49.8%). Evaluation of
participation rates by intensity of follow-up showed that 23% of case and 18% of
control families consented without reminders (first stage); 81% of cases and 83%
of controls agreed following one or two reminders (second stage); and the
remainder of participants consented following three or more reminders (final
stage). Cumulative distributions of sociodemographic characteristics differed
little between second and final stage participants. Odds ratios for maternal
multivitamin use were similar between second and final stage participants,
whereas those for maternal and paternal smoking tended to decline. Although
follow-up measures were necessary to enroll most families, use of more than two
reminders did not appear to increase the representativeness of the sample;
however, termination of recruitment after only two reminders would have led to
different conclusions. Future studies require data collection protocols that
encourage participation from all population subgroups, and one alternative is
presented.
PMID- 9556173
TI - Cytomegalovirus seroprevalence in French pregnant women: parity and place of
birth as major predictive factors.
AB - In this study we present data on cytomegalovirus (CMV) seroprevalence in pregnant
women in France. One thousand and eighteen women were enrolled in a prospective
study carried out in Grenoble. The overall rate of seropositivity, using a
specific IgG ELISA test, was 51.5 % (95 % CI: 48.5-54.5). Among a homogeneous
population of 873 women born in France with high or middle socioeconomic status,
CMV seropositivity increased with age and parity. The seroprevalence according to
age was found to depend on parity. It increased with age in women with no
children or with only one; it was higher but no more age-dependent in women with
two children or more. In addition, CMV seroprevalence was significantly higher in
women born in southern France (51.6%) than in those born in northern France
(37.4%), these findings being consistent with the existence, within France, of a
gradient in seroprevalence rate, increasing from the North to the South. A
logistic regression analysis reveals the place of birth in France as a major
predictive factor of CMV antibody status (OR: 3.5) followed by age (OR: 2) and
parity (OR: 1.7). In this study, we show an independent effect of parity on CMV
seroprevalence, arguing for the importance of child-to-mother transmission;
nevertheless, the latitude of the place of birth, even within a size-limited
country such as France, appears to be a major predictive factor of CMV
seroprevalence.
PMID- 9556172
TI - Validity and reliability in reporting sexual partners and condom use in a Swiss
population survey.
AB - OBJECTIVES: To examine the validity and reliability of indicators of sexual
behaviour and condom use in annual telephone surveys (n=2800) of the general
population aged 17 to 45 for the evaluation of AIDS prevention in Switzerland.
METHODS: A test-retest study with additional focused interviews was conducted on
a subsample (n=138) of the respondents aged 17 to 22 years. RESULTS: The
subsample included more French speaking respondents (OR: 1.7, CI: 1.1-2.5) and
more people in a stable relationship (OR: 2.2, CI: 1.5-3-3) than the initial
sample but did not differ in any other way, although no data is available on
their attitudes towards sex. The reliability of the indicators considered was
high: number of lifetime, casual sex partners in the last 6 months and condom use
with them, acquisition of a new steady partner during the year and condom use
with this partner, condom use at last intercourse. However, the focused
interviews raised questions about the validity of some of these indicators,
presumably due to imprecise wording of the questionnaire items. Among sexually
active respondents, 12.5% (95% CI: 4.7-25.5) of the men included non-penetrative
sex in the definition of 'sexual intercourse', but only 1.9% (95% CI: 0.1-10.3)
of the women. The propensity for men of counting acts or partners with whom no
penetration had taken place in the total reported sex acts or partners was not
significantly associated with any socio-demographic variables. In addition, among
the 15 respondents who had reported consistent condom use with casual sex
partners at interview, 40% (95% CI: 16.3-67.7) admitted at reinterview that
sometimes they also had unprotected sex. CONCLUSIONS: The reliability of reports
on sexual behaviour and condom use in this Swiss evaluation survey is good. The
indicators derived from the annual surveys are robust measures and the monitoring
of trends seems to be based on reliable measurement. However, more research is
required on the validity of the data.
PMID- 9556174
TI - Physical activity and bone mineral density in Italian middle-aged women.
AB - Osteoporosis is a major health issue in post-menopausal women on account of the
association between low bone mineral density and fractures. A role of physical
activity in the prevention and treatment of low bone mineral density is possible
but still unclear. The relationship between low spine bone mineral density
measured by means of dual photon absorptiometry at lumbar spines, and levels of
past and recent physical activity has been assessed by means of a population
based screening study carried out on 1373 women (age 40-64 years) in the North
East of Italy. Physical activity at work and in leisure time was investigated for
three specific periods of life: at age 12, between 15 and 19 years (during bone
formative years), and in the recent years prior to the interview (30-39 or 50-59
years). Data were analysed comparing low versus high bone mineral density tertile
(i.e., 458 and 461 women, respectively), after controlling for other known
contributory factors in the development of osteoporosis. A positive association
emerged with leisure time physical activity, with significant trends at age 15-19
(odds ratio (OR) for low versus high tertile of leisure time activity: 1.4, 95%
confidence interval (CI): 0.8-2.4) and at most recent age (OR: 1.7, 95% CI: 1.1
2.6). Risk trends with occupational physical activity were less clear and non
statistically significant. The present Southern European cross-sectional study
lends further support to the possibility that past and recent physical activity
helps increasing bone mineral density in middle-aged women. Although the most
beneficial type and intensity level of exercise has yet to be determined, the
present results provide further evidence that participation in even moderate
exercise programs should be encouraged.
PMID- 9556175
TI - Secular trends in the osteoporotic fractures of the distal humerus in elderly
women.
AB - Osteoporosis, with its sequelae of fracture, is a major, continuously increasing
threat to the health of the elderly, and therefore reliable epidemiological
information is needed for assessment of the fracture development in the future
and for effective fracture prevention. However, very little population-based
information is available concerning the nationwide numbers, incidences and
especially secular trends of osteoporotic fractures other than those occurring at
the hip. We determined the current trends in the number and incidence of
osteoporotic fractures of the distal humerus in Finnish women in 1970-1995 by
collecting from the National Hospital Discharge Register all female patients aged
60 years or more who were admitted to our hospitals in 1970-1972, 1974-1975, 1978
1980, 1983-1985 and 1988-1995 for primary treatment of first osteoporotic
fracture of the distal humerus. The fracture was defined as osteoporotic if it
occurred on individuals aged 60 years or more as a consequence of a moderate or
minimal trauma only (a fall from standing height or less). We also predicted the
fracture development till the year 2030 by a regression model, a model that took
into account the predicted changes in the fracture incidences and population at
risk. The number and incidence (per 100,000 women) of osteoporotic fractures of
the distal humerus in Finnish women aged 60 years or more increased from 42
(number) and 11 (incidence) in 1970 to 175 and 30 in 1995. The age-adjusted
incidence of osteoporotic fractures of the distal humerus also increased, from
12/100,000 women in 1970 to 28/100,000 women in 1995. If this trend continues,
the number of these fractures in Finnish women will be almost three-fold in the
year 2030 compared with that in 1995. We conclude that the number of osteoporotic
fractures of the distal humerus in elderly Finnish women is increasing more
rapidly than can be accounted for by the demographic changes alone and therefore
effective preventive measures are imperative to keep this problem in control.
PMID- 9556176
TI - Traumatic brain injury in children in Denmark: a national 15-year study.
AB - Demographic trends are reported concerning three types of traumatic brain injury
(concussions, cranial fractures, and intracranial contusions/haemorrhages) among
children in Denmark of ages up to and including 14 years, for a fifteen year
period from 1979 through 1993. The data were derived from a national computer
based hospitalization register and include 49,594 children, of whom 60% were boys
and 89% had suffered a concussion. Virtually all injuries were the result of
accidents. A major finding was that there has been a general decline in the
incidence of traumatic brain injuries, especially for boys from 5 to 14 years
old, suggesting a degree of success in preventive measures, particularly
regarding road safety. The incidence of fatal cases of intracranial
contusions/haemorrhages approximately halved over the 15 year period. However, as
a proportion of all diagnosed cases, mortality from intracranial
contusions/haemorrhages remained fairly constant at about 22%, perhaps because
there have been no markedly successful innovations in acute care. Among children
surviving a intracranial contusions/haemorrhages, rather considerable numbers
were found to have been awarded disability pension at ages under 30.
PMID- 9556177
TI - Injury mortality and morbidity among children in the United Arab Emirates.
AB - The objective of this study was to identify the major causes of accident
mortality and morbidity among children (0-14 years) in Al-Ain, United Arab
Emirates (UAE). A retrospective descriptive study was set in the Al-Ain Hospital
and Preventive Medicine Department, Ministry of Health, Al-Ain. Subjects were all
patients aged 0-14 years who were seen at Al-Ain Hospital for injury during the
12-month period January to December 1995, and all recorded deaths aged 0-14 years
in Preventive Medicine Department from 1980 to 1995. RESULTS: Mortality: 301
children (69.4% males, 30.6% females) died after accidents from 1980 to 1995. UAE
citizens and other Arabs represented the majority of deaths. Most mortality
(28.6%) occurred in the 1-4 year age group. Head and neck injury was the major
type of injury causing death (57.5%). The most common cause of accidental death
was road traffic accidents (boys 67.1%, girls 60.4%), followed by drowning and
burns (8%). Morbidity: Pediatric trauma cases seen during 1995 totaled 17,498,
representing one third of all patients attending the Hospital Emergency Room.
About 70% of encountered injuries occurred among boys; 44.6% of cases were UAE
citizens. The most common trauma type was contusion (40.2% boys; 40.6% girls),
the most common type of trauma in boys and girls (30.4% and 36%, respectively).
In the age group <5 years, the most common causes of trauma were fall (41.1%),
blunt trauma (38.7%) and burns or scalds (64%), while in 5-9 year olds, the most
common cause was road traffic accidents (40%). Finally, in 10-14 year olds, the
most frequent causes were traffic accidents (32.8%) sharp objects injuries
(38.3%), and fights and sporting (28.9%). CONCLUSION: More boys than girls
presented with injury and the majority were nationals. Road traffic accidents
mainly occurred in children over 10 years.
PMID- 9556178
TI - Hospitalizations for infectious diseases in Jewish and Bedouin children in
southern Israel.
AB - Two different population groups reside in the Negev region of southern Israel and
have equal, and free from financial barrier, access to tertiary care at a single
regional hospital. The Jewish population has a largely urban and industrialized
lifestyle, while the Moslem Bedouins are in transition from their traditional
nomadic life to settlement. To examine the differences in morbidity patterns
reflected in hospitalizations, the computerized hospitalization records of
children <15 years of age, for 1989-1991 were used (n=15,947). Rates of
hospitalizations for infectious diseases were significantly higher for Bedouins
in comparison to Jews (250 and 121/10,000 child years, respectively, odds ratio
(OR): 2.1, 95% confidence interval (CI): 2.0-2.2, p < 0.001). Rates of
hospitalization per 10,000 child years in Bedouins and Jews for diarrhea were 114
and 32 (OR: 3.7, 95% CI: 3.3-4.0, p < 0.001), respectively, and for pneumonia 55
and 19 (OR: 2.9, 95% CI: 2.6-3.3, p < 0.001), respectively. In infants the
differences were even more pronounced, especially for diarrheal diseases. In
Bedouin children infectious diseases were associated with longer hospital stay,
more pediatric Intensive Care hospitalizations (OR: 2.7, 95% CI: 1.7-4.5,p <
0.001), and higher in-hospital mortality (OR: 5.7, 95% CI: 2.8-12.2, p < 0.001).
Thus, Bedouin children are at higher risks of hospitalizations for infectious
diseases in early childhood, as compared to Jewish children. This may reflect the
differences in lifestyle, environmental and social conditions of the two
populations.
PMID- 9556179
TI - An outbreak of intrafamiliar hepatitis A associated with clam consumption:
epidemic transmission to a school community.
AB - An outbreak of hepatitis A is described involving thirteen cases in a town in
central-northern Italy. The consumption of infected clams, caught in a polluted
coastal area of the Adriatic Sea, caused hepatitis A in all five members of a
family consisting of mother, father and children, two of whom attended primary
school. The epidemic subsequently spread to the primary school with a secondary
attack rate of 7.9%, 0 for female pupils and 18.9% for males. The epidemiological
and environmental investigations showed that the critical exposure took place in
the boys' toilet in the primary school (OR: 32.79, 95% CI: 6.83-157.45). To
prevent the spreading of contagion, extra disinfection was carried out in the
whole school and health education campaigns were mounted. The good basic hygienic
conditions of the homes, together with the cooperation of school staff in
surveillance and providing information, allowed the epidemic to be controlled.
PMID- 9556180
TI - An outbreak of sheep-associated Q fever in a rural community in Germany.
AB - In spring 1996, an outbreak of Q fever occurred among residents of a rural town
(population: 300) in Germany. A retrospective cohort study was conducted to
ascertain the extent of the outbreak and to assess potential risk factors for
illness. In July 1996, all residents > or =15 years received a self-administered
questionnaire and were offered Coxiella burnetii antibody testing. Residents were
considered to have probable Q fever if they had a positive result for IgM C.
burnetii antibodies by ELISA or possible Q fever if they had fever > or =39
degrees C lasting >2 days and > or =3 symptoms (chills, sweats, severe headache,
cough, aching muscles/joints, back pain, fatigue, or feeling ill) after 1 January
1996. Two hundred (84%) of the 239 residents aged > or =15 years either completed
the questionnaire or submitted blood for antibody testing. Forty-five (23%) of
these 200 met the probable or possible case definitions. Onsets of illness
occurred in January-June 1996. Cases were geographically distributed throughout
the town. Persons reporting contact with sheep (32% vs 18%, RR: 1.8, 95% CI: 1.1
2.9) and walking near a large sheep farm located next the town (34% vs 8%, RR:
4.5, 95% CI: 1.7-12.2) were more likely to have met the case definition than
those without these exposures. Fifteen of 20 samples from the large sheep flock
were positive for C. burnetii antibodies. The sheep had lambed outdoors in
December 1995-January 1996 while the weather was extremely dry. The timing of the
outbreak after lambing, the uniform distribution of cases throughout the town and
the absence of risk factors among most case-persons suggest airborne transmission
of C. burnetii from the large sheep farm.
PMID- 9556181
TI - Skin diseases in immigrants seen as out-patients in the Institute of Dermatology
of the University of Rome 'La Sapienza' from 1989 to 1994.
AB - In the Institute of Dermatology of the University of Rome 'La Sapienza' (IDURLS)
from 1989 to 1994, 2198 immigrants from countries outside the European Community
were seen as out-patients. Their personal and pathological data were collected by
a particular software 'Questio', set up together with colleagues of the
Interdepartimental Center for Scientific Calculous (ICSC) of the University of
Rome 'La Sapienza'. The number of patients has been increasing from 326 in 1989
to 436 in 1994. Most of the people were coming from Africa, but from 1989 to 1994
the number of patients from the regions of ex-Yugoslavia has been increasing.
About one third of the immigrants were unemployed, whereas 40% of them had a job
(worker or employee), and the remaining 20% was composed by students and
housewives. Most immigrants (1474 patients) were 20-39-year-old. Their data were
compared with those of a control group composed by 2100 Italian people of the
same age and sex, seen as out-patients in IDURLS in the same period. The most
frequent skin disorders observed in immigrants were skin infectious or parasitic
diseases, above all scabies. Excluding people with scabies, both immigrants and
Italian patients shared the same skin diseases typical of young adult people:
many fungal infections, many contact dermatitis and very few skin malignant
tumors.
PMID- 9556183
TI - Autoimmunity and B-cell malignancies.
AB - There is evidence indicating that autoreactive B cells constitute a substantial
part of the B-cell repertoire. This autoreactive repertoire secrete the so called
natural autoantibodies characterized by their broad reactivity mainly directed
against very well conserved public epitopes. They fulfill the definition of an
autoantibody since they are self-reactive, but they are not self-specific. As
yet, NAA directed against determinants of polymorphism have not been reported.
Their germinal origin is suggested by their early appearance during ontogeny,
their expression of cross-reactive idiotopes and structural studies of their
sequence. As for the physiological role of the repertoire, we can assume that it
may play a major role as a first barrier of defense. It is presently unknown
whether these polyreactive B cells could constitute a pre-immune template which
through an antigen driven process may be involved in the production of immune
high affinity antibodies. This autoreactive B cell repertoire frequently
undergoes malignant transformation, although there is controversy concerning the
reasons accounting for this. It has been postulated that the continuous challenge
of this autoreactive repertoire by self-antigens could create propitious
conditions for malignant transformation to occur. However, it can be
alternatively postulated, that overexpression of certain genes reflect what
happens during ontogeny, since V genes expression is a developmentally regulated
phenomenon and not all V genes are expressed during fetal life. Some of the genes
that are recurrently expressed by these malignancies are also over-expressed in
fetal repertoires and even in the adult normal B cell repertoire. We do not know
whether it is the challenge by self-antigens or whether alternatively this over
expression simply reflects what happens with the fetal repertoire which could
have selective advantages for malignization.
PMID- 9556182
TI - Genetic typing of human and food isolates of Listeria monocytogenes from episodes
of listeriosis.
AB - Ten clinical and food Listeria monocytogenes strains isolated during the
epidemiological investigations of episodes of listeriosis (one outbreak and two
sporadic cases) that occurred in northern Italy during 1993-1995 have been
examined by DNA macrorestriction pattern analysis obtained by PFGE and RAPD
typing, in order to confirm the food vehicle of infections. The same DNA profiles
within the isolates from the three episodes were obtained by both techniques. The
Apal and Smal PFGE profiles and RAPD patterns with primer OPM-01 confirmed the
close relationship between strains from two distinct episodes. However, RAPD
analysis with primer UBC-127 distinguished between these L. monocytogenes
isolates.
PMID- 9556184
TI - B cell compartments in multiple myeloma: flow cytometric analysis of their
labelling indices and Bcl-2 protein expression.
AB - Because recent reports have suggested that non plasmacytic tumor B cells are very
rare in Multiple Myeloma (MM), we tried to characterize the B lineage in this
disease by comparing by flow cytometry in the PB and BM of MM patients and of
controls the proliferative activity (BrdU incorporation) and the Bcl-2 expression
of different B cell subsets defined by cytoplasmic light chain, CD19 or CD10
antigen expression. The labelling indices (LI) of CD19+ and CD10+ BM cells in
treated patients were higher than in controls and untreated patients. Plasma cell
LI (PCLI) were close to previously published values of PCLI flow assays and did
not correlate with the LI of BM B cells. Bcl-2 expression by BM CD19+ and CD10+
cells in patients was inferior to controls. These results agree with previously
published data about the likely polyclonal nature of most pre PC B cells in MM.
PMID- 9556185
TI - Adherent-free generation of functional dendritic cells from purified blood
monocytes in view of potential clinical use.
AB - There is increasing interest in dendritic cells (DC) that are capable of
initiating antitumor immune responses. An in vitro cell differentiation method
has recently been developed that uses GM-CSF and IL-4 to generate human DC from
adherent blood mononuclear cells cultured on tissue culture plastic. These cells
are competent for antigen uptake but express relatively low levels of co
stimulatory molecules and thus correspond to immature resident tissue DC. We have
adapted this method to consider some variables that are pertinent to clinical
use, including a large scale differentiation of functional DC in a culture system
suitable for clinical use. We report here that sizable numbers of monocytes
purified by elutriation from blood leukocytes and cultured in Teflon bags develop
with high efficiency into typical DC, as defined by morphology and membrane
phenotype. When compared with usual adherent DC, cells generated under our
adherent-free conditions exhibited lower CD1a expression and antigen capture
capacity, but maintained the ability to present soluble antigens to T cells. They
neoexpressed a high level of the co-stimulator molecule B7-2 (CD86) and was
potent accessory cells for T cell proliferation, but they lacked the CD83 marker
of DC full maturation. This study may constitute a prerequisite step for clinical
investigations in tumor immunotherapy.
PMID- 9556186
TI - Automated measurement of erythrocyte sedimentation rate and its relation to red
blood cell concentration and plasma proteins.
AB - A new automated erythrocyte sedimentation rate (ESR) system, the SEDISYSTEM was
evaluated for its stability and accuracy. It offers automated mixing of vacuum
collected blood for 5 minutes (min) and reading of the ESR for 20 min to generate
values comparable with those of the Westergren method at 1 hour (h) and 2 h. The
benefits are (1) simplified procedure, (2) reduction of biohazard and, (3)
shortening of examination time. To evaluate the basic performance of this system,
the stability of ESR values was first evaluated by keeping samples at room
temperature for up to 20 h, during which time no remarkable change was observed.
Next, a comparison between this system and the standard method of Westergren was
conducted and good agreement was obtained. To determine the factors affecting ESR
values, correlations were analyzed between the ESR obtained by SEDISYSTEM and the
standard Westergren method for red blood cell concentration, hematocrit, and
plasma proteins including fibrinogen, albumin and globulins (alpha1, alpha2, beta
and gamma). Multiple regression analysis showed significant correlation with RBC,
fibrinogen and gamma globulin. It is concluded from these results that SEDISYSTEM
is a useful new tool for the measurement of ESR.
PMID- 9556187
TI - Phorbol esters: useful tools to study megakaryocyte differentiation.
AB - This review attempts 1) to enonciate recent observations made on the effects of
phorbol esters on megakaryocyte cell lines, 2) to examine these effects taking
into account megakaryocytopoiesis in vivo and 3) to demonstrate that phorbol
esters stimulated megakaryocyte cell lines provide a good model to study the
mechanisms governing megakaryocyte maturation.
PMID- 9556188
TI - Fulminant hepatitis due to herpes simplex virus-type 2 in early phase of bone
marrow transplantation.
AB - Hepatitis due to Herpes Simplex Virus (HSV) is a rare and severe infection in
patients with impaired immunity, as bone marrow transplanted. The antemortem
diagnosis is often difficult to establish because the clinical features are
nonspecific. We report an uncommon cause of fulminant hepatic failure in a
neutropenic patient, 14 days after bone marrow transplantation. HSV-2 fulminant
hepatitis occurred during acyclovir prophylactic treatment. No observation of HSV
hepatitis in this context has been reported since prophylaxis is used. Because of
the extremely high apparent mortality associated with HSV hepatitis, and the
improved survival noted among the non-marrow-transplant recipients and prolonged
survival seen in one marrow transplant recipient, it seems reasonable to urge
early and aggressively acyclovir therapy. A liver biopsy seems to be
indispensable in the case of hepatic failure in post-marrow-transplantation in
order to make rapidly a diagnosis.
PMID- 9556189
TI - Nomenclature and state of the art on alpha1-adrenoceptors.
AB - The concept of alpha1-adrenoceptor subtypes was first suggested in the mid 1980s
on the basis of the different affinities of certain alpha1-adrenoceptor
preparations for the alpha-adrenoceptor agonist, oxymetazoline, and the
antagonists, WB4101 and phentolamine. Subsequent characterization of alpha1
adrenoceptors using radioligand binding and functional studies has led to the
identification of three native prazosin high-affinity alpha1-adrenoceptor
subtypes designated alpha1A, alpha1B and alpha1D, corresponding to the three
alpha1-adrenoceptor subtypes (alpha1a, alpha1b and alpha1d) isolated by molecular
cloning techniques. Since each of these three subtypes exhibits similar affinity
for the selective alpha1-adrenoceptor antagonist, prazosin, [3H]prazosin can be
used as a convenient probe to evaluate the interaction of compounds with these
adrenoceptor subtypes. Considerable clinical experience over the last few years
has provided convincing evidence to support the effectiveness of alpha1
adrenoceptor blockade in the treatment of bladder obstruction due to benign
prostatic hyperplasia (BPH). The distribution of alpha1-adrenoceptors in the
human prostate tissue has shown that the predominant cloned alpha1-adrenoceptor
subtype characterized by RNAase protection assays corresponds to the alpha1a
subtype, formerly classified as alpha1c. Many of the alpha1-antagonists currently
prescribed in the treatment of BPH do not exhibit in vitro selectivity between
alpha1a-, alpha1b- and alpha1d-subtypes and yet they have good clinical tolerance
in terms of low incidence of cardiovascular effects. One possibility to account
for these findings is that another alpha1-adrenoceptor subtype could be
implicated in human prostatic smooth muscle contraction. A recent report,
although confirming the presence of an alpha1a-subtype in human prostate,
suggested that an alpha1-adrenoceptor subtype with lower affinity for prazosin,
designated alpha1L, which has not been cloned yet, is in fact the predominant
alpha1-subtype involved in the contractile response of human prostatic smooth
muscle to noradrenaline.
PMID- 9556190
TI - The concept of uroselectivity.
AB - Alpha1-adrenoceptor antagonists have been shown to decrease both the voiding and
storage symptoms of benign prostatic hyperplasia (BPH). Based on the assumption
that these symptoms can be attributed to the consequences of the increase in
outflow resistance caused by noradrenaline stimulation of stromal alpha1
adrenoceptors in the enlarged prostate, prostatic alpha1-adrenoceptors have
become a target for therapeutic interventions. In some patients, alpha1
adrenoceptor antagonists in common clinical use produce intolerable side effects
which may be attributed to action on non-prostatic alpha1-adrenoceptors.
Therefore, attempts have been made to find alpha1-adrenoceptor antagonists that
have selective effects on the prostate ('uroselective' agents), to maintain
efficacy in uroflow and eliminate adverse effects. The term uroselectivity has
been used in various contexts, but drugs may be discussed as uroselective from a
receptor pharmacological, physiological, or clinical perspective. Provided that
the alpha1-adrenoceptor subtype in the prostate, bladder neck and urethra is
uniform, unique, and cannot be found in other parts of the body, drugs with
selectivity for this receptor could be called uroselective. However, available
evidence suggests that (1) more than one alpha1-adrenoceptor subtype can be found
in the lower urinary tract, and that the main alpha1-adrenoceptor mediating
contraction still remains to be definitely defined; (2) the receptor(s) is (are)
most probably not unique to the lower urinary tract, and (3) alpha1-adrenoceptor
sites outside the prostate (with still undefined subtypes) may contribute to the
lower urinary tract symptoms of BPH. Therefore, it does not seem possible to
define uroselectivity in terms of selectivity for the alpha1-adrenoceptor(s)
occurring in the prostate. Several animal models have been developed where the
potency order of effects of various alpha1-adrenoceptor antagonists on blood
pressure and urethral pressure have been measured simultaneously. Such models can
be useful when screening drugs that may be developed for therapeutic use, but
they also have limitations, since side effects that may be dose limiting
clinically are not always related to a decrease in blood pressure. Certainly, a
drug may be said to have physiological or functional uroselectivity if it lowers
outflow resistance more effectively than it affects other defined physiological
functions. A clinically meaningful definition of uroselectivity can only be made
in man and considers desired effects on obstruction and lower urinary tract
symptoms relative to adverse effects.
PMID- 9556191
TI - Functional uroselectivity.
AB - Alpha1-adrenoceptors mediating sympathetic tone to smooth muscle cells are
located within the prostatic tissue, bladder base and in the proximal urethra,
but are also widely distributed within a large number of tissues, especially the
vascular beds and the central nervous system. Compounds clinically used in the
symptomatic treatment of benign prostatic hyperplasia must therefore exhibit
functional uroselectivity. This means that they should preferentially act on the
lower urinary tract rather than the vasculature or central nervous system. Few
clinically used alpha1-adrenoceptor antagonists show selectivity for the
alpha1a/A-adrenoceptor subtype, whereas most of them have similar affinities for
the three cloned subtypes (alpha1a-, alpha1b- and alpha1d-adrenoceptors). Recent
data from in vitro studies assessing pharmacological uroselectivity and from in
vivo models evaluating functional uroselectivity challenged the relevance of the
affinity or the selectivity for a known alpha1-adrenoceptor subtype in predicting
functional uroselectivity. They suggest instead that another subtype, like the
alpha1L-adrenoceptor, might be functionally involved. In conclusion, the actual
state of knowledge on alpha1-adrenoceptor subtype distribution and function, does
not support a role of pharmacological uroselectivity in predicting functional
uroselectivity. Furthermore, functional uroselectivity can be achieved in the
absence of selectivity for the alpha1-adrenoceptor subtypes described so far.
PMID- 9556192
TI - Clinical uroselectivity of alfuzosin in the treatment of benign prostatic
hyperplasia.
AB - The efficacy of alfuzosin in improving lower urinary tract symptoms and relieving
bladder outlet obstruction has been demonstrated in numerous short- and long-term
placebo-controlled studies and large-scale open studies, involving over 16,000
patients with symptomatic benign prostatic hyperplasia (BPH). Treatment with
sustained release alfuzosin (5 mg twice daily) for 3 months resulted in a 5-point
reduction in the International Prostate Symptom Score and a 29% increase in
urinary flow rate. The benefits of alfuzosin have been confirmed in general
practice. A 1-year prospective study of 5,849 men with clinical BPH treated with
alfuzosin showed a 51% reduction in mean total symptom score, with a 56% decrease
in mean irritative symptoms. Improvement in health-related quality of life of 3
years' duration have been recorded, including a reduction in the frequency of
both diurnal and nocturnal micturition. Alfuzosin has a good safety profile.
Unlike most other alpha1-blockers, a low risk of first-dose effect is seen,
conveniently eliminating the necessity of dose titration at initiation of
therapy. Postural symptoms related to orthostatic hypotension (a common side
effect of alpha1-blockers) are infrequent, including in the elderly and
hypertensives. Central nervous system effects are also limited due to poor
penetration of the blood-brain barrier. In conclusion, the positive benefits/risk
ratio of alfuzosin allows it to be classified as a uroselective alpha1-blocker,
which provides a beneficial contribution to the management of symptomatic BPH.
PMID- 9556193
TI - Clinical uroselectivity: a 3-year follow-up in general practice. BPH Group in
General Practice.
AB - The objectives of this open-labeled study were to assess the clinical
uroselectivity of alfuzosin in a long-term follow-up study in general practice. A
total of 3,228 patients with clinical benign prostatic hyperplasia (BPH) from 812
centers were included in a prospective 3-year open-labeled study and treated with
alfuzosin (immediate-release formulation) at the recommended dosage. Symptom
score (Boyarsky, modified) and a 20-item BPH-specific health related quality of
life (HRQL) score (Urolife BPH QoL 20), which included three questions on
sexuality, were self-administered at baseline, 3, 6, 12, 18, 24, 30 and 36
months. Symptom score was significantly reduced by 54% at 3 months and this
reduction was maintained up to 36 months; the HRQL score was significantly
improved by 45.4% at 12 months and this improvement was also maintained up to 36
months. Alfuzosin was well tolerated: the quantitative and qualitative
distribution of adverse events (AEs) was similar to that previously observed in
placebo-controlled studies. 4.2% of the patients dropped out due to AEs. This
study confirms the long-term safety profile of alfuzosin in general practice and
highlights the need to measure HRQL in the context of clinical uroselectivity.
PMID- 9556194
TI - Uroselectivity: myth or reality? Concluding remarks.
PMID- 9556195
TI - Premenstrual syndrome and anxiety disorders: a psychobiological link.
PMID- 9556196
TI - Treatment-resistant depression.
AB - Our ability to treat depression has improved with the availability of receptor
specific and chemically diverse groups of antidepressants. Even now, most of the
short-term studies indicate that about 20% of depressed patients remain resistant
to treatment. Therefore, it is important to properly assess the treatment
resistant depressed (TRD) patients and to separate the truly refractory patients
from those inadequately treated. Undiagnosed medical conditions should be
eliminated. TRD is neither a clinically nor a biologically identifiable entity.
As there are no established methods for the treatment of TRD, all options should
be considered. The clinician can be enriched by the knowledge of the treatment
modalities available, and yet, in treating an individual patient, clinical
skills, intuitive judgment, family history of response to drugs and side effects,
all play a vital role. Several of the approaches described in the paper indicate
available methods and their merits in general but there is no way of ascertaining
by which particular method a patient should be treated. The three common methods
of treatment are substitution of one antidepressant drug for another, combination
therapies and augmentation techniques. These are based on clinical experiences
and not research findings. Therefore the treatment of TRD patients is more an art
than a science. The physician should assess all the psychopathological,
phenomenological and psychosocial variables to appropriately treat an individual
patient.
PMID- 9556197
TI - Do patients with panic disorder show a memory bias?
AB - BACKGROUND: Cognitive models of panic disorder are becoming more and more
influential. Therefore, research specifying cognitive processes related to panic
disorder is needed. The present study investigated memory bias for panic-related
material in patients with panic disorder. METHODS: Memory bias for panic-related
material was investigated experimentally by a memory task requiring
classification of panic-related and non-panic-related words. Sixty patients with
panic disorder and 60 controls with no diagnosis of a mental disorder
participated in the study. RESULTS: As expected, panic patients showed smaller
differences in the time needed for classification of panic-related versus non
panic-related material than controls. CONCLUSIONS: Patients with panic disorder
show a memory bias for panic-related material when conceptual implicit recall is
required. In order to clarify whether this bias is involved in the maintenance of
the disorder, it seems important to investigate whether the bias is still present
after successful therapy.
PMID- 9556198
TI - Relationships between alexithymia, emotional control, and quality of life in
patients with inflammatory bowel disease.
AB - BACKGROUND: Although the constructs of alexithymia and emotional control have
been associated with physical health, the relationship between these constructs
is unclear and their influence on health-related quality of life has not been
investigated previously. This study examined the relationships between
alexithymia, emotional control, and quality of life in 74 patients with
inflammatory bowel disease (IBD). METHODS: The subjects completed the 20-item
Toronto Alexithymia Scale (TAS-20), the Emotional Expression and Control Scale
(EEC), and the Inflammatory Bowel Disease Questionnaire (IBDQ) for assessing
quality of life. RESULTS: The TAS-20 correlated negatively and significantly with
the IBDQ global score and with subscales assessing bowel symptoms, systemic
symptoms, and emotional functioning; the emotional control subscale of the EEC
correlated positively and significantly with these measures. Although the TAS-20
correlated significantly and negatively with the emotional control subscale,
alexithymia and quality of life scores were unrelated to subscales of the EEC
assessing tendencies to either hold back or express emotions. A hierarchical
stepwise multiple regression analysis revealed that alexithymia and, to a lesser
extent, emotional control play a role in predicting quality of life in patients
with IBD. CONCLUSIONS: Alexithymia and emotional control are negatively related
constructs and each construct has an independent influence on the subjective
health status of patients with IBD.
PMID- 9556199
TI - Perceived parental attitude, alexithymia and defense style in psychiatric
outpatients.
AB - BACKGROUND: Although it is the clinical impression that alexithymia may be due to
disturbances in the early parent-child relationship and that it is associated
with primitive defense mechanisms, a possible association with neurotic defense
mechanisms, such as repression and reaction formation, has also been mentioned.
However, empirical studies on these and related issues are scarce. The aim of
this study was to determine the association between perceived parental attitude,
defense mechanisms and alexithymia. METHODS: In a cross-sectional study we
obtained data from 78 psychiatric outpatients. Alexithymia, defense mechanisms
and perceived parental attitude were measured with the Toronto Alexithymia Scale,
the Defense Style Questionnaire and the Parental Bonding Instrument. RESULTS: We
found only weak associations between perceived parental attitude and alexithymic
features. Primitive and adaptive defenses were associated with alexithymic
features in a clinically sensible way. The strongest association was found
between primitive defense mechanisms and alexithymic features. There was hardly
any association between neurotic defense mechanisms and alexithymic features.
CONCLUSIONS: The results of our study support the hypothesis that alexithymia is
associated with a primitive defense style, whereas a relation to disturbances in
early parent-child relationship could not be confirmed. It is argued that
possibly more severe traumatic experiences, such as physical and sexual abuse,
than merely a negatively perceived parental attitude, are necessary to develop
alexithymic features.
PMID- 9556200
TI - Psychosomatic and psychosocial symptoms are associated with low blood pressure in
Swedish schoolchildren.
AB - BACKGROUND: The relation between psychosomatic and psychosocial symptoms and
blood pressure was studied in Swedish schoolchildren. METHODS: Blood pressure was
measured in 122 healthy Swedish schoolchildren, aged 6-16 years. Psychosomatic
and psychosocial symptoms, delinquent behaviour, parental health and employment
status were assessed. RESULTS: Children with systolic blood pressure above + 1 SD
of mean reported significantly less symptoms (x = 1.4) than children with blood
pressure below -1 SD of the mean (x = 2.7; p < 0.05). Children with three or more
self-reported symptoms had significantly lower blood pressure than children
without symptoms both in the supine (110 +/- 12 vs. 120 +/- 18 mm Hg; p < 0.05)
and in the standing position (117 +/- 17 vs. 127 +/- 18 mm Hg; p < 0.05).
CONCLUSIONS: We conclude that psychosomatic and psychosocial symptoms in children
might be associated with low blood pressure.
PMID- 9556201
TI - Need for supportive counselling--the professionals' versus the patients'
perspective. A survey in a representative sample of 236 melanoma patients.
AB - BACKGROUND: The aim of the study was to identify melanoma patients who suffered
significant distress and were judged to be in need of supportive counselling, on
the one hand, and, on the other, to investigate patient interest in such support.
METHODS: Out of 236 melanoma patients, who constitute a representative sample of
melanoma patients in Western Austria, 215 patients participated in the study and
were assessed with regard to psychosocial distress, coping strategies, social
networks and interest in receiving psychosocial support. Multiple logistic
regression analyses were performed with regard to patient interest in receiving
psychosocial support either from the attending oncologist or from a mental health
professional. RESULTS: 65 patients (30.2%) experienced moderate and 30 patients
(14.0%) severe distress, which was predominantly caused by tumour-related fears,
tension and disturbance of emotional well-being. 83% of the severely distressed
patients wanted psychosocial support from their oncologists, whereas only half of
them were interested in additional support from a psychotherapist. In particular,
patients who showed fear of tumour progression and felt that they were
insufficiently informed about their disease preferred to consult their
dermatologist for psychosocial support. On the other hand, patients with poor
prognosis, receiving only low levels of support from their social network, and
exhibiting a depressive coping style, showed interest in getting supplementary
support from a psychotherapist. CONCLUSIONS: These findings underline the
importance of educating oncologists with a view both to improve their
communication skills and to help them identify patients making poor adjustment to
illness in order to offer them appropriate emotional support.
PMID- 9556202
TI - Psychiatric symptoms and psychological profile of patients with near fatal
asthma: absence of positive findings.
AB - BACKGROUND: We examined the presence of psychiatric symptoms and personality
characteristics in patients with asthma and near fatal asthma (NFA). An NFA
attack is defined by the presence of one or more of the following symptoms:
respiratory arrest, alteration in consciousness, need for mechanical ventilation,
Pa CO2 > 50 mm Hg. METHODS: To assess the relevance of a specific psychiatric
profile or the difference in personality characteristics existing in patients
that survived an NFA attack and asthmatic patients. The authors interviewed a
sample of 17 asthmatic patients who experienced one or more NFA attacks. A
control group of 17 control patients with asthma who never experienced NFA
attacks was enrolled. After a baseline assessment, the patients underwent an
interview concerning their personal and familiar psychiatric history and a
psychodiagnostic investigation using Hamilton scales for anxiety and depression,
Zung scales for anxiety and depression, and Minnesota Multiphasic Personality
Inventory. The study was performed in a 6-month period. RESULTS: No significant
differences in the results of psychodiagnostic tests between NFA patients and the
control group were reported. Psychiatric history was similar in the two groups.
CONCLUSIONS: Our results suggest that psychiatric symptoms and personality
characteristics are not related to the presence of asthma with or without NFA.
PMID- 9556203
TI - Isolation and characterization of CspBI, a novel NotI isoschizomer from
Corynebacterium species B recognizing 5'-GC/GGCCGC-3'.
AB - Sixty-seven bacterial strains were surveyed for the presence of type II
restriction endonucleases, especially concerning super-rare-cutting enzymes.
Fourteen strains were found to contain specific enzymes. One of them CspBI from
Corynebacterium species B was purified and characterized as an isoschizomer of
NotI, which recognizes the palindromic octanucleotide sequence 5'-GC/GGCCGC-3'
and cleaves at the position shown by the arrow. A comparison between the cleavage
patterns on different DNAs, obtained with partially purified endonucleases from
other detected producents including some strains of Corynebacterium, Cellulomonas
and Rhizobium has shown that these enzymes do not belong to super-rare-cutting
restriction endonucleases.
PMID- 9556205
TI - Midkine induces histamine release from mast cells and the immediate cutaneous
response.
AB - Midkine is a product of a retinoic acid-responsive gene and exerts a variety of
biological activities. The aim of our investigation is to determine whether human
midkine have histamine-releasing effects on mast cells, and to show the evidence
of the inflammation induced by midkine. Midkine induced histamine release from
rat peritoneal mast cells with a rapid response in a dose-dependent manner.
Extracellular calcium inhibited the histamine release induced by midkine in a
dose-dependent manner. Pertussis toxin and benzalkonium chloride inhibited the
histamine release induced by midkine. Gi-proteins exert an effect on the
histamine release of midkine. The immediate cutaneous response induced by midkine
was positive. These results suggest that midkine may take part in some
inflammation via histamine release from mast cells.
PMID- 9556204
TI - Differential expression of multidrug resistance (mdr) and canalicular
multispecific organic anion transporter (cMOAT) genes following extrahepatic
biliary obstruction in rats.
AB - The hepatic canalicular membrane has transporters that play an important role as
efflux pumps in the excretion of endogenous bile constituents or xenobiotics into
bile canaliculi. To elucidate functional significance of canalicular transporters
in the mechanism of cholestasis, mRNA expression levels of multidrug resistance
(mdr) 1b, mdr2 and canalicular multispecific organic anion transporter (cMOAT)
genes were analyzed by Southern blotting of reverse-transcribed PCR products of
liver mRNA obtained from cholestatic rats that had been subjected to bile duct
ligation. Both mdr1b and mdr2 mRNA expression increased after ligation.
Immunohistochemical study revealed that the products of both mdr1b and mdr2 were
present on the canaliculi, and that their levels increased after ligation. In
contrast, cMOAT mRNA expression was not increased, but rather attenuated by
ligation. The expression of canalicular transporters was differentially regulated
in extrahepatic biliary obstruction, indicating the different roles are played by
mdr and cMOAT in the pathogenesis of cholestasis.
PMID- 9556206
TI - Cross-linking induces homodimer formation and inhibits enzymatic activity of
chicken stomach ecto-apyrase.
AB - We have investigated the effect of cross-linking on the enzymatic activity and
oligomer formation of the chicken stomach ecto-apyrase. Cross-linking with the
hydrophobic, lysine-specific dithiobis(succinimidylpropionate) (DSP) caused equal
inhibition of ATPase and ADPase activity in both the membrane-bound and detergent
solubilized ecto-apyrase. The inhibitory effect of cross-linking was reversed
upon the addition of the reductant dithiothreitol. Western blots of aliquots of
the cross-linked samples show decreased amounts of the monomeric 80 kDa ecto
apyrase and the appearance of a 160 kDa dimer under conditions inducing enzyme
inhibition. Therefore, the chicken stomach ecto-apyrase, like the chicken gizzard
ecto-ATPase, is likely a homodimer in vivo. Unlike the related gizzard ecto
ATPase, however, the native stomach ecto-apyrase is not stimulated, but rather
inhibited by cross-linking, presumably due to different quaternary structural
stability of the two enzymes.
PMID- 9556207
TI - Detection of transmembrane helical segments at the nucleotide level in eukaryotic
membrane protein genes.
AB - The analysis of base distributions at the three codon positions, in sequences
coding for polytopic membrane proteins from Eukaryotes, reveals a global excess
of thymine and a depletion of adenine, at the second codon position. These genes
were scanned using a sliding window, in which the average ratio of T over A at
the second position of codons was computed. The scan shows that sharp peaks of
this ratio, which are responsible for the high mean value of this parameter in
the genes, correlate closely with the transmembrane segments of the membrane
proteins. These results are quite similar to our previous findings for bacterial
polytopic inner membrane proteins. This establishes the ratio of T over A at
codon position two as a universal parameter for both the characterization of the
genes of polytopic membrane proteins, and for the location of alpha-helical,
transmembrane segments of these proteins.
PMID- 9556208
TI - Induction of fructose 1,6-bisphosphatase in HL-60 leukemia cells by retinoic
acid.
AB - The expression of the fructose 1,6-bisphosphatase gene in HL-60 cells was induced
by retinoic acid. The levels of mRNA, enzyme activity and enzyme protein in the
cell line began to rapidly increase after culturing with retinoic acid for 72 h.
Retinoic acid dose-dependently increased the enzyme activity with maximal
stimulation at 1 microM. The responses of the fructose 1,6-bisphosphatase gene
expression by retinoic acid were markedly slower than those of the enzyme
expression by 1alpha,25-dihydroxyvitamin D3. When HL-60 cells were cultured in
the presence of both retinoic acid and 1alpha,25-dihydroxyvitamin D3, the effects
of the two agents on enzyme activity, protein and mRNA were additive.
PMID- 9556209
TI - Different effects of cell-permeable ceramide analogs on platelet activation.
AB - The effects of cell-permeable ceramide analogs on platelet responses induced by
agonists were investigated. When washed rabbit platelets were pretreated with
ceramide and then stimulated with thrombin or U46619, C2-ceramide (N
acetylsphingosine) dose-dependently inhibited the aggregation and arachidonic
acid liberation, whereas C6-ceramide (N-hexanoylsphingosine) and C8-ceramide (N
octanoylsphingosine) enhanced these responses. Furthermore, C6-ceramide, but not
C2-ceramide, enhanced the increase in and prevented the progressive decrease in
cytoplasmic free Ca2+ concentration induced by U46619. On the other hand,
treatment with sphingomyelinase potentiated the aggregation in response to
U46619. These results indicate that the effects of cell-permeable ceramide
analogs on platelet activation vary with N-acyl chain length.
PMID- 9556211
TI - Effects of deleting A19 tyrosine from insulin.
AB - A mutant proinsulin gene was constructed through PCR mediated mutagenesis. The
code of A19Tyr was deleted. The mutant proinsulin, (deltaY)19-lys-proinsulin
[(deltaY)19KPI], was expressed in E. coli and purified. After treatment with
trypsin and carboxypeptidase B, and Resource Q separation, (deltaY)19-human
insulin [(deltaY)19HI] was obtained. It retains 63.6% of receptor binding
activity but only 2.2% of immune activity, and shows a longer retaining time on
reverse-phase FPLC and a slower mobility by native PAGE analysis. These results
suggest that the deletion of A19Tyr causes some conformational changes on
insulin, which plays a minor role on the affinity of insulin to its receptor, and
a major role on immunogenicity of the hormone.
PMID- 9556210
TI - Lithium regulation of protein phosphorylation in rat cerebral cortex slices in
vitro.
AB - The aim of the present study was to evaluate the direct effect of Li+ and Na+-Li+
exchange on protein phosphorylation in rat cerebral cortex slices incubated in
Krebs Ringer medium. When Na+ concentration was varied in the incubation medium,
either by replacement with Li+ or sucrose, a variable effect on [32P] phosphate
incorporation into proteins was observed. Protein phosphorylation in cerebral
cortex slices was very low in the absence of Na+, and some dependence of
phosphorylating system of neural tissue on extra cellular concentration of Na+
was evident. Lithium was not able to replace sodium as far as protein
phosphorylation in cortical slices is concerned. Ouabain was more effective in a
Li+ containing medium in inhibiting protein phosphorylation, presumably due to
improper functioning of the sodium pump.
PMID- 9556212
TI - Short-term effect of dexamethasone on fatty acid and cholesterol synthesis in
isolated rat hepatocytes.
AB - The short-term effect of dexamethasone, a synthetic glucocorticoid, on both fatty
acid and cholesterol synthesis has been investigated in rat hepatocyte cultures.
Within 4h following hormone addition to the cultures, a noticeable stimulation of
labelled acetate incorporation into fatty acids was observed. Similar behaviour
was noticed when [3H]H2O was used as an independent index of the lipogenic
activity. In the same cultures, however, cholesterol synthesis from both
[14C]acetate or [3H]H2O was significantly reduced by dexamethasone addition. In
these conditions, no significative variation of cholesterol synthesis starting
from labelled mevalonate was observed.
PMID- 9556213
TI - Down-regulation of protein kinase C-alpha detected in human colorectal cancer.
AB - The down-regulation of protein kinase C (PKC) was examined by Western blot
procedure on about 30 tissue samples derived from human colorectal cancer and the
corresponding normal mucosa. PKC-alpha down-regulation was detected in 60% of the
cancer tissues compared with the respective normal mucosa and was observed in a
higher frequency with the tissues under more advanced cancer stages. However, the
frequencies of the down-regulation of PKC-delta and PKC-zeta were lower than that
of PKC-alpha. These results suggest that a decreased level of PKC-alpha may
affect the cell growth and tumor promotion in colorectal tissue.
PMID- 9556215
TI - Carbohydrates regulate the dimerization of angiotensin-converting enzyme.
AB - Regulation of the catalytic activity and supramolecular structure of angiotensin
converting enzyme was studied in reverse micelles of Aerosol OT in octane as
biomembrane model. The kinetic experiments and the sedimentation analysis
demonstrated that the enzyme can function both in monomeric and dimeric form. The
degree of dimerization was strongly dependent on the concentration and structure
of mono- and disaccharides added to the media, indicating the specific role of
carbohydrates in forming the supramolecular structure of angiotensin-converting
enzyme. The existence of carbohydrate-binding center on the enzyme molecule is
proposed.
PMID- 9556214
TI - Structural factors affect the interactions of anticardiotoxin antibodies and
cobra venom cardiotoxins.
AB - Two antibody preparations against cardiotoxins were raised by immunizing rabbits
with cardiotoxin 1 and cardiotoxin 3, respectively. The two antibody preparations
showed precipitin reactions with cardiotoxins 1, 2, 3 and 5, respectively.
However, the results of competitive enzyme-linked immunoassay revealed that the
respective cardiotoxin molecules exhibited different reactivity toward
anticardiotoxin antibodies. Moreover, the order of reactivity with antibodies was
not in line with the degree of their sequence identity. This suggest that the
anticardiotoxin antibodies may recognize conformational epitopes rather than
sequential ones in the toxin molecules. Alternatively, the four cardiotoxins
reacted well with the antibodies in the absence of competitor, suggesting that
sequence variations with cardiotoxin molecules may not exclusively influence the
potential use of the anticardiotoxin antibodies for the neutralization of the
activity of cardiotoxin variants.
PMID- 9556216
TI - Saccharide-assisted delivery of cytotoxic liposomes to human malignant cells.
AB - The overexpression of lectins by malignant cells was applied for in vitro
targeting of liposomes equipped with a saccharide vector and loaded in the lipid
phase with a lipid derivative of anticancer agent sarcolysine. The lectin
specificity of human leukemia HL-60 and human lung adenocarcinoma ACL cells was
revealed by tests with fluorescein-labeled sugar probes. With the help of
fluorescent lipid dye it was shown that active saccharide ligands increased the
level of the vectored liposome binding to malignant cells by 50-80% as compared
to liposomes without vector or with inactive one. The degree of liposome/cell
membrane fusion was monitored fluorometrically and was shown to be complete and
independent of the vectors. The targeted drug-loaded liposomes had the cytotoxic
activity 2-4 times higher as compared to the vector-free ones.
PMID- 9556217
TI - Characterization of extracellular menadion-catalyzed H2O2 production by NIH/3T3
cells.
AB - The extracellular menadione-catalyzed H2O2 production by NIH/3T3 cells was
expected to depend on plasma membrane-bound NAD(P)H:quinone oxidoreductase. This
enzyme was estimated to be a flavoprotein with the molecular mass of 70 KDa. Km
values of plasma membrane-bound NAD(P)H:quinone oxidoreductase producing H2O2
were 60 microM for NADH and 150 microM for NADPH. Ca2+ ionophore A23187
controlled menadione-catalyzed H2O2 production by the cells in time- and
concentration-dependent manner.
PMID- 9556218
TI - Investigation of the yeast mitochondrial unselective channel in intact and
permeabilized spheroplasts.
AB - The existence of an activity corresponding to the nucleotide-induced Yeast
Mitochondria Unselective Channel (YMUC2) of isolated mitochondria was
investigated in permeabilized and intact spheroplasts of the baker's yeast Yeast
Foam. In nystatin-permeabilized spheroplasts, ATP and GDP-beta-S induced a
decavanadate-sensitive stimulation of the respiration only under conditions
equivalent to those previously reported for isolated mitochondria (low phosphate
concentration, presence of a salt). On intact spheroplasts parallel measurements
of respiration rate, [ATP]/[ADP] ratio and mitochondrial transmembrane potential
allowed to show that the addition of the glucose analog 2-deoxyglucose decreased
the permeability of the inner mitochondrial membrane owing to cellular ATP
depletion. This strongly supports the hypothesis that Yeast Mitochondria
Unspecific Channel is active in situ and inhibited by cellular [ATP] depletion.
PMID- 9556219
TI - Activation of red blood cell glutathione peroxidase and morphological
transformation of erythrocytes under the action of tert-butyl hydroperoxide.
AB - Susceptibility of control and diabetic erythrocytes to oxidative stress was
measured after incubation with various concentration of tert-butyl hydroperoxide
(t-BHP). TBA-reactive substances (TBARS) formed were determined by the method of
Stocks & Dormady modified by Jain. GSH and total glutathione were estimated by
the procedure of Ellman and Akerboom and Sies. Activity of GSH peroxidase was
determined by the method of Martinez et al. Protein SH groups were determined
after membrane isolation by the method of Dodge et al. Cell morphology was viewed
under phase contrast microscope with a magnification of 500x. All results were
analyzed by the unpaired two tailed Student's t-test. Oxidative treatment of
erythrocytes with tert-butyl hydroperoxide significantly increases the reaction
rate but decreases the affinity for substrate (tert-butyl hydroperoxide). The
susceptibility of the enzyme from diabetic erythrocytes to oxidation is higher in
comparison with normal cells. The oxidation of cellular reduced glutathione (GSH)
is not correlated with oxidation of membranous protein SH-groups. Oxidative
damage of erythrocytes induces significant cell morphological transformations.
PMID- 9556220
TI - A sequence highly similar to PNG is located on chromosome 22q12 in intron 15 of
the LIMK-2 gene.
AB - In this report we describe a sequence (PNG22) highly similar to the Phospholipase
C beta3 Neighboring Gene (PNG). We also report that PNG22 is located in the q12
region on chromosome 22 between markers D22S1144 and D22S280. This finding
explains that PNG probes cross hybridize to sequences on chromosome 22. Fine
mapping using our sequence data and the complete sequence of a PAC clone
(DJ515N1), located in this region, determined that PNG22 is located in intron 15
of the LIMK-2 gene. PNG22 is 93% homologous to PNG, however it do not have the
introns described for the PNG gene, instead matching the cDNA sequence. This
leads us to suggest that PNG22 probably represents a PNG pseudogene. In this
report we also list the exon intron borders and the genomic structure of LIMK-2
and place it on the Sanger Center chromosome 22 Physical map. It also explains
the finding that PNG probes cross hybridize to sequences on chromosome 22.
PMID- 9556221
TI - Absorption and fluorescence spectra of polyene antibiotics in the presence of
human serum albumin.
AB - The alteration in the fluorescence spectra observed for the polyene antibiotics:
nystatin and amphotericin B in the presence of human serum albumin is due to a
decrease in the polar character of the antibiotic environment when these are
bound to the protein. Amphotericin B showed two types of binding sites, the first
having very high affinity (5.8 10(7) M(-1]) and a secondary binding site with an
affinity one order lower than the primary sites. This secondary binding site was
very sensitive to temperature change. Nystatin yielded only one type of binding
sites with an affinity of 1.1 10(6) M(-1). An electrostatic component was found
in the binding of both ligands, as well as an important disorder at the protein
binding sites. However the secondary binding site for AMP showed negative
entropic change value, which suggests different mechanism of binding respect to
the primary one. Conformational change induced by the temperature in the albumin
molecule was detected by nystatin binding. Fatty acids produced an interference
in the binding of both antibiotics to albumin.
PMID- 9556222
TI - Genetic variants of chicken erythrocyte histone H5.
AB - Two allelic electromorphs a and b of chicken erythrocyte histone H5 have been
detected in a sodium dodecyl sulfate polyacrylamide gel. In an acid-urea gel,
however, each of the allelic variants was found to be accompanied by a slower
migrating form. A comparison of alpha-chymotrypsin-digested products of H5.a and
H5.b revealed that they differed in N-terminal domains. The H5 variants were
distributed differently not only in various chicken races but also in distinct
lines within a breed. Allele H5b was about 2.6-4.6 as abundant as its counterpart
H5a in most chicken populations examined. These proportions were distorted in two
Leghorn lines: the ratio of H5b to H5a was only 1.6 in line H22 and increased up
to 32 in line G99.
PMID- 9556223
TI - Inosine-5'-monophosphate analogues as inhibitors of human IMP cyclohydrolase and
cellular growth.
AB - The catalytic mechanism for the enzyme, IMP cyclohydrolase, may involve a
reaction intermediate with negative charge in the 2-position of the purine ring
(Szabados, E., Hindmarsh, E., Phillips, L., Duggleby, R.G. & Christopherson, R.I.
(1994) Biochemistry 33, 14237-14245). Three analogues of IMP have been
synthesised where fluorine, chlorine or bromine has been substituted in the 2
position on the purine ring. These analogues with an electronegative substituent
may resemble a reaction intermediate for IMP cyclohydrolase; 2-fluoro IMP is a
potent inhibitor of the enzyme with a Ki value of 0.19 microM, while 2-chloro IMP
has a Ki of 1.9 microM and 2-bromo IMP is not inhibitory. However, IMP
cyclohydrolase is not inhibited in human CCRF-CEM leukaemia cells exposed to 2
fluoro inosine although it is toxic to these cells with an IC50 value of 4.9
microM.
PMID- 9556224
TI - Esterification of D-mannoheptulose confers to the heptose inhibitory action on D
glucose metabolism in parotid cells.
AB - D-mannoheptulose, but not its hexaacetate ester, inhibits, in a competitive
manner, D-glucose phosphorylation by either purified beef heart hexokinase or
crude parotid gland homogenates. Yet, D-mannoheptulose hexaacetate, but neither
the unesterified heptose nor acetate or its methyl ester, inhibits D-[5
3H]glucose utilization and D-[U-14C]glucose conversion to 14CO2 and 14C-labelled
acidic metabolites and amino acids in intact isolated parotid cells. It is
proposed, therefore, that D-mannoheptulose hexaacetate crosses efficiently the
plasma membrane of parotid cells and, after intracellular hydrolysis, allows
inhibition of D-glucose phosphorylation by the unesterified heptose. The ester of
D-mannoheptulose could thus represent a useful tool to inhibit hexose
phosphorylation and interfere with cell growth in cells otherwise resistant to
the heptose.
PMID- 9556225
TI - Protective role of superoxide dismutase in iron toxicity in yeast.
AB - It has been found that yeast mutants deficient in cytosolic superoxide dismutase
CuZnSOD are hypersensitive to ferrous iron. In contrast mutants that are
deficient in catalases and cytochrome c peroxidase do not differ from the
standard strain in this respect. These findings suggest that iron toxicity may
depend on the redox status of the cell. They also shed light on the role of
superoxide dismutases in preventing the toxic effects of oxygen.
PMID- 9556226
TI - The role of cationic amino acid residues in the lethal activity of stonustoxin
from stonefish (Synanceja horrida) venom.
AB - Stonustoxin (SNTX) is a two subunit pore-forming cytolytic protein purified from
the venom of the stonefish (Synanceja horrida). SNTX also possesses lethal
activity. Since cationic residues contribute significantly to the cytolytic
activity of several pore-forming toxins, we examined the role of lysine and
arginine residues in the lethal activity of SNTX. SNTX lost its lethal activity
when the positively-charged side chains of lysine residues were converted to
negatively-charged side chains upon succinylation. When the arginine residues
were modified using 2,3-butanedione, SNTX also lost its lethal activity. However,
the domains for cytolytic and lethal activity may not necessarily be the same.
PMID- 9556227
TI - The in vitro effect of ridogrel on platelet function in normocholesterolaemic and
familial hypercholesterolaemic type IIa subjects.
AB - Platelets from familial hypercholesterolaemia type IIa patients are hyperreactive
and produce increased amounts of thromboxane A2. These modifications of platelet
function may play an important role in the occurrence of premature
atherosclerosis. One approach to the prevention of the thromboembolic
complications of atherosclerosis is the use of antiplatelet agents which depress
platelet function. Ridogrel, a combined thromboxane synthase inhibitor and
thromboxane A2/prostaglandin endoperoxide receptor blocker inhibits platelet
aggregation. This study was designed to investigate the in vitro effect of
ridogrel on platelet function in normocholesterolaemic and familial
hypercholesterolaemia type IIa subjects. In citrated platelet rich plasma
ridogrel significantly inhibited platelet aggregation and thromboxane A2
production in response to collagen, ADP and arachidonic acid stimulation. In
washed platelets ridogrel significantly decreased aggregation and serotonin
release. Ridogrel significantly increased cAMP levels in response to thrombin
stimulation. In conclusion, ridogrel at low concentrations significantly
inhibited the in vitro function of platelets in a dose dependant manner in both
normocholesterolaemic subjects and familial hypercholesterolaemia IIa subjects.
PMID- 9556228
TI - Prevalence of activated protein C resistance in the Chinese population.
AB - In 1996, a total of 1700 subjects, including 461 healthy subjects and 1239 clinic
patients, were randomized and consecutively entered into our study. Their mean
age was 49.30+/-18.71 years, range 1-99 years. Of them, 1117 were male, and 583
were female. The mean age of the male was 42.96+/-17.64 years, and of the female,
52.60+/-18.41 years. The mean activated protein C ratio in 1700 subjects was
2.96+/-0.69, range 2.00-7.93. None of them had activated protein C ratio <2.0.
The mean activated protein C ratio in the male was 2.81+/-0.63, and in the female
was 3.04+/-0.71. None of the subjects was found to have activated protein C
resistance. DNA analysis for the Arg 506-Gln mutation was also performed on 492
out of the 1700 subjects; none of them had this mutation. We suggested that the
Chinese is not a race with the trait of activated protein C resistance.
PMID- 9556229
TI - Clinical evaluation of an immunoturbidimetric D-dimer assay in the diagnostic
procedure of deep vein thrombosis and pulmonary embolism.
AB - We investigated 128 patients with suspected deep vein thrombosis and 26 patients
with suspected pulmonary embolism. Plasma cross-linked fibrin degradation
products were measured instantly by a new rapid and fully quantitative
immunoturbidimetric assay (Boehringer Mannheim) which recognizes the D-dimer
epitope by antibody-coated latex particles. Diagnosis of deep vein thrombosis was
established by either ascending venography (n = 105) or colour duplex ultrasound
(n = 8), whereas for the exclusion of deep vein thrombosis only venography was
accepted. The sensitivity/specificity for the diagnosis of deep vein thrombosis
was 98%/44%. Patients with suspected pulmonary embolism were examined by
pulmonary angiography (n = 19) or perfusion lung scanning alone (n = 6), if
sufficient. One pulmonary embolism was diagnosed at post-mortem examination. For
pulmonary embolism, sensitivity/specificity was 100%/50%. These findings indicate
that the new immunoturbidimetric technique is as reliable as former ELISA methods
and allows to rule out thromboembolic disorders. D-dimers showed a correlation to
the extent of the deep vein thrombosis, proximal thrombosis producing higher D
dimer levels. Patients presenting immediately after the onset of symptoms were
found to have higher D-dimers than patients examined after a few days. A
quantitative D-dimer measurement thus seems to provide precious additional
information of the duration and the extent of thromboembolic disease.
PMID- 9556230
TI - Production of a recombinant antithrombotic and fibrinolytic protein, PLATSAK, in
Escherichia coli.
AB - The three main components involved in thrombosis and haemostasis are thrombin,
platelets, and plasmin. Almost all inhibitors of thrombosis are focused either on
the inhibition of thrombin or on the inhibition of platelets. We designed a
construct using the fibrinolytic activity of staphylokinase, fused via a
cleavable linker to an antithrombotic peptide of 29 amino acids. The peptide was
designed to include three inhibitory regions: (1) the Arg-Gly-Asp (RGD) amino
acid sequence to prevent fibrinogen binding to platelets; (2) a part of
fibrinopeptide A, an inhibitor of thrombin; and (3) the tail of hirudin, a potent
direct antithrombin. The amino acid sequence of the 29 amino acid peptide was
reverse translated, and the gene was chemically synthesised and cloned into an
expression vector as a 3' fusion to the staphylokinase gene. Gene expression was
induced in E. coli Top 10 cells and the fusion protein, designated PLATSAK, was
purified using metal affinity chromatography. The purified fusion protein
significantly lengthened the activated partial thromboplastin time and thrombin
time and inhibited the amidolytic activity of thrombin. The fibrinolytic activity
was almost equal to that of recombinant staphylokinase as measured with a
thrombelastograph. Platelet aggregation was not markedly inhibited by PLATSAK,
probably due to the unfavourable three dimensional structure, with the Arg-Gly
Asp sequence buried inside. Our results confirm that it is feasible to design and
produce a hybrid multifunctional protein that targets various components of the
haemostatic process.
PMID- 9556231
TI - Expanded polytetrafluoroethylene (ePTFE) vascular graft loses its thrombogenicity
six months after implantation.
AB - Although expanded polytetrafluoroethylene (ePTFE) has been believed to be an
inert material for vascular prosthesis, it shows less tendency of graft
maturation by means of endothelialization. The aim of this study is to evaluate
long-term alteration in thrombogenicity of ePTFE grafts after implantation.
Serial levels of thrombin-antithrombin III complex (TAT), D-dimer, C-reactive
protein (CRP), and prothrombin time (PT) were examined in 77 patients following
ePTFE Y-graft implantation for up to five years. TAT showed biphasic elevation
after implantation; TAT increased from 16.4+/-8.6 ng/ml to 27.4+/-10.5 ng/ml at
one day, decreased to 18.5+/-4.5 ng/ml at one week, and increased again to 25.3+/
8.5 ng/ml at two weeks. Elevated TAT gradually decreased after the second peak to
reach a lower level than that before surgery after six months. There was no
significant difference in TAT level after six months due to the difference in
diagnosis or anti-thrombotic therapy. We suggest that ePTFE grafts lose their
thrombogenicity six months after implantation, after which anti-thrombotic
therapy might be unnecessary.
PMID- 9556232
TI - Action of neurotransmitters: acetylcholine, serotonin, and adrenaline in an
experimental arterial thrombosis induced by oxygen free radicals.
AB - It is well known that high stress and particularly an enhancement of plasma
catecholamines and myocardial infarction have a close relation. In addition,
adrenaline is presented as a prothrombogenic agent in vivo. The role of the other
agents such as serotonin or acetylcholine, in the development of arterial
thrombosis is somewhat uncertain, although, the role of each of them is often
considered at the level of vascular regulation only. Therefore, the present study
was designed to investigate the effects of three neurotransmitters on
experimental arterial thrombosis model induced by generation of free radicals.
The results demonstrate that intravenously injection of adrenaline or serotonin
(1 ng/kg) stimulated arterial thrombosis formation, whereas injection of high
dose of acetylcholine (5 mg/kg) slackened the thrombosis formation.
PMID- 9556233
TI - An improved method for the detection of the G20210A transition in the prothrombin
gene.
PMID- 9556234
TI - A polymorphic cluster in the 5' region of the human coagulation factor VII gene:
detection, frequency, and linkage disequilibrium.
PMID- 9556235
TI - Effects of pneumoperitoneum on tumor implantation with decreasing tumor inoculum.
AB - INTRODUCTION: The aim of this study was to determine the effect of
pneumoperitoneum on the rate of trocar-site implantation with decreasing inoculum
of cancer cells. METHODS: A total of 0.5 ml of GW-39 human colon cancer cell
suspensions at 1 percent (approximately 3.2 x 10(5) cells) and at 0.5 percent
(approximately 1.6 x 10(5) cells; v/v) were injected into the abdomen of hamsters
through a midline incision. Animals in each group were randomized to receive
either pneumoperitoneum (1 percent = 33; 0.5 percent = 43) or not (1 percent =
32; 0.5 percent = 39). Gross and microscopic tumor implants were documented seven
weeks later at four trocar sites. RESULTS: In the 1 percent group,
pneumoperitoneum significantly increased trocar-site tumor implants from 50 to 71
percent (P < 0.001). Pneumoperitoneum also resulted in the following: 1) more
frequent involvement of all four concurrent sites (38 vs. 10 percent; P < 0.02);
2) more frequent palpable tumors (13 vs. 5 percent; P < 0.01); 3) larger tumor
mass (2.1 +/- 0.6 g vs. 0.2 +/- 0.1 g; P < 0.02). In the 0.5 percent group,
pneumoperitoneum did not significantly increase trocar-site tumor implants, and
it did not result in a larger tumor mass. The percent increase in trocar-site
implants owing to pneumoperitoneum was influenced by the amount of tumor inoculum
(21 percent in the 1 percent group; 10 percent in the 0.5 percent group). The
mass of palpable tumor implants after pneumoperitoneum decreased with decreased
inoculum: 1 percent = 2.1 +/- 0.6 g; 0.5 percent = 0.3 +/- 0.1 g (P < 0.0001).
CONCLUSIONS: Pneumoperitoneum significantly increased both tumor implantation
rate and mass when approximately 3.2 x 10(5) colon cancer cells were injected
into the peritoneal cavity. These effects of pneumoperitoneum diminished with one
half as many tumor cells injected in the peritoneal cavity.
PMID- 9556236
TI - Decision-making in rectal cancer surgery: survey of North American colorectal
residency programs.
AB - PURPOSE: Although rectal cancer is common in the United States, there is
significant variation in management and outcome of this disease. The aim of this
study is to measure the amount of variability that exists in the way colorectal
surgeons investigate and manage patients with rectal cancer. METHODS: A detailed
questionnaire covering preoperative assessment, operative technique, and follow
up of primary rectal cancer was sent to all colorectal surgeons associated with
colorectal residency programs throughout North America. RESULTS: One hundred ten
responses were obtained (response rate, 71 percent). Surgeons were in broad
agreement (>75 percent agree) on the routine preoperative use of endorectal
ultrasound and carcinoembryonic antigen and the postoperative use of endorectal
ultrasound. There was also broad agreement about the use of adjuvant therapy and
radical resection for a poorly differentiated uT2,N0 cancer, the use of total
mesorectal excision for a mid rectal cancer, and for the choice of loop ileostomy
if diversion is necessary. Two-thirds of the surgeons used adjuvant therapy and
radical resection for a uT3,N0 cancer and preferred a follow-up schedule of three
monthly visits for two years with six monthly visits for the next three years.
Opinion was divided (<63 percent agreement) on the use of a preoperative liver
scan, the approach to a moderately differentiated uT2,N0 cancer, the use of
rectal irrigation before resection, the timing of colonoscopy in a patient with
stenosing rectal cancer, and the frequency of postoperative colonoscopies.
CONCLUSIONS: There is considerable variation in the management of low rectal
cancer advocated by colorectal surgeon educators. For each histologic and
pathologic stage, opinion is divided about which operation is best. Careful
outcomes analysis is required to clarify the situation.
PMID- 9556237
TI - Mechanical, histologic, and biochemical effects of canine rectal formalin
instillation.
AB - Instillation of 4 percent formalin effectively treats radiation hemorrhagic
proctitis; however, little is known regarding its side effects. PURPOSE: The
study contained herein was undertaken to determine rectal compliance and collagen
content, mucosal and vascular histologic changes, and kinetics of formalin
absorption following instillation. METHODS: Fifteen mongrel dogs (50-60 pounds)
were randomized into five experimental groups according to time elapsed from
formalin treatment: control, acute, one week, two weeks, and four weeks. Formalin
was instilled in 30-ml aliquots to a total volume of 400 ml. Rectal compliance
(closed manometry system) was assessed pre-formalin and post-formalin at the
designated time interval. Serum formalin metabolites were determined at time 0,
0.5, 1, and 3 hours. A segment of rectal wall was analyzed for collagen content,
mucosal injury, and blood vessel density. RESULTS: Serum formalin levels peaked
within 30 minutes, returning to normal by 3 hours. With the exception of one dog,
toxic levels were not reached at any time during the study. No dogs experienced
sepsis, fever, or altered gastrointestinal function. Acute and one-week dogs
showed mild diffuse proctitis and mucosal slough, which healed within two weeks.
Rectal compliance and collagen content were unchanged. Mucosal blood vessels
decreased in number early (P = 0.03). CONCLUSIONS: Instillation of 4 percent
formalin in sequential aliquots of a small volume that is kept in contact for a
short period of time is safe. Serum formalin levels generally do not reach toxic
levels, and the slight elevation in formalin concentration that was seen returns
to normal within three hours. Formalin-induced proctitis heals within two weeks,
and no long-term changes in rectal compliance or collagen content were seen.
PMID- 9556238
TI - Surgical treatment of piles: prospective, randomized study of Parks vs. Milligan
Morgan hemorrhoidectomy.
AB - PURPOSE: The present prospective, randomized clinical trial compares the outcome
of surgical hemorrhoidectomy according to Parks and Milligan-Morgan in terms of
hospital stay, duration of incapacity to work, symptom relief, length of
morbidity, and patient convenience. METHODS: Thirty-four consecutive patients
with third or fourth degree internal hemorrhoids were randomly allocated to the
two groups. Before surgery, all patients were interviewed using a standard
questionnaire, followed by rectal examination. All patients underwent a follow-up
interview and examinations 1, 2, 4, 8, and 12 weeks after the operation. RESULTS:
No serious postoperative complications were seen. Length of hospital stay (3.2
days for Parks hemorrhoidectomy vs. 4.6 days for Milligan-Morgan
hemorrhoidectomy; 95 percent confidence interval, 0.2 and 2.6, respectively; P =
0.02) and mean duration of incapacity to work (12.3 days for Parks
hemorrhoidectomy vs. 20.2 days for Milligan-Morgan hemorrhoidectomy; 95 percent
confidence interval, 5.7 and 10.2, respectively; P < 0.001) differed
significantly between the Milligan-Morgan and Parks patients. Until two weeks
after the operation, Milligan-Morgan hemorrhoidectomy patients experienced
significantly more pain. CONCLUSIONS: Our study confirms that both operations are
safe, easy to perform, and lead to satisfactory results. However, the Parks
procedure is the preferred option, because it minimizes patients' postoperative
discomfort, is more economic, has a significantly reduced hospital stay, and has
a shorter time for return to work.
PMID- 9556239
TI - Results from pelvic exenteration for locally advanced colorectal cancer with
lymph node metastases.
AB - PURPOSE: We examined the survival benefit of pelvic exenteration for locally
advanced colorectal cancer with lymph node metastases, because this issue remains
controversial. METHODS: Medical records of 50 patients who underwent curative
pelvic exenteration for colorectal cancer were reviewed retrospectively. Nodal
metastases were examined by the clearing method in 29 patients and by the
conventional manual method in 21 patients. RESULTS: Invasion to contiguous pelvic
organs was present in 40 patients (80 percent) and absent in 10 patients (20
percent). Node metastases were present in 33 patients (66 percent). Operative
morbidity and mortality rates were 22 percent (11 patients) and 6 percent (3
patients), respectively. Respective five-year survival rates were 60 and 80
percent in the groups with and without organ invasion (no significant
difference). Five-year survival rates in patients with nodal metastases was 54.6
percent but was significantly higher, 82.4 percent, in patients without nodal
metastases. Five-year survival in 28 patients with both organ invasion and nodal
metastases was 53.6 percent. CONCLUSIONS: Long-term survival was afforded by
pelvic exenteration for locally advanced colorectal cancer with nodal metastases.
PMID- 9556240
TI - New method of radiotherapy for anal cancer with three-dimensional tumor
reconstruction based on endoanal ultrasound and ultrasound-guided afterloading
therapy.
AB - PURPOSE: Standard treatment of anal cancer is a protocol of combined chemotherapy
and percutaneous radiotherapy. We developed a new endosonography-based radiation
target simulation method, because endoanal sonography gives the best opportunity
to stage the tumor accurately. Based on this method, an afterloading needle
application procedure could be performed to optimize the radiation target
geometry and to control the application of afterloading needles. In a prospective
study, this new method was evaluated, with special regard for complications and
tumor recurrence. METHODS: Anal cancer was restaged endosonographically six weeks
after external beam radiation with 45 Gy. A computer-generated three-dimensional
reconstruction of the tumor and radiation target simulation was performed based
on endoanal sonographic imaging. By using a new type of applicator, which is
permeable to ultrasound waves, the transperineal implantation procedure of
afterloading needles could be controlled. Application needles were inserted into
the target area according to the endoanal sonography-based dosimetry planing. The
dose of the (high-dose rate) brachytherapy boost was started with two 6-Gy
fractions, each within eight days. The fraction dose was reduced to 4 Gy to
minimize side effects. Lymph node-positive tumors got additional chemotherapy (5
fluorouracil and mitomycin C). RESULTS: From January 1992 until August 1996, we
performed 42 endosonography-guided afterloading procedures in 18 patients. One
patient underwent percutaneous radiation two years before and was treated only by
afterloading radiation. In every patient, we found complete tumor remission at
the end of radiotherapy. Three patients with a high-dose rate of 2 x 6 Gy
developed radiogenic proctitis, and two patients developed ulceration, which lead
to reduction of the dose. After reduction to 4 Gy per fraction, no more side
effects could be seen. In follow-up (median, 24 (range, 1-56) months), we
detected two anal cancer recurrences (2/18 patients). CONCLUSION: The radiation
target field can be optimized by individual endosonography-based three
dimensional tumor reconstruction and radiotherapy simulation. Endosonography
guided transperineal implantation of afterloading needles can be performed
according to the computer-generated simulation by using a new type of applicator.
We could achieve total primary tumor remission in every patient. After reduction
of the afterloading dose to 2 x 4 Gy, no brachytherapy-related side effects could
be seen.
PMID- 9556241
TI - Healing after anal fistulotomy: comparative study between HIV+ and HIV- patients.
AB - PURPOSE: The aim of this work was to compare wound-healing after anal fistulotomy
in human immunodeficiency virus (HIV)+ and HIV- patients and to recognize healing
parameters in HIV+ patients. METHODS: Sixty patients were treated with
fistulotomy for intersphincteric anal fistula. For each patient, we evaluated
white blood cell count values, T CD4 counts, Centers for Disease Control and
Prevention classification, and healing duration. There were 31 HIV+ patients (7
A2; 1 A3; 7 C1; 6 C2; 10 C3). RESULTS: Seven C3 patients had incomplete healing.
Statistically, there was no difference in the healing duration in HIV+ A2, C1,
C2, and HIV-negative patients. C3 patients who did heal took longer than other
HIV+ patients. T CD4 counts were similar to healed and not healed C3 patients,
although healed C3 values of white blood cell counts were higher than not healed
C3 values (4,450 and 2,380/mm3). CONCLUSION: After anal fistulotomy, HIV+ C3
patients either had retarded healing or no healing at all. Therefore, we feel
that surgery should be done only in emergency cases of anorectal diseases or in
patients with more than 3,000 white blood cells/mm3.
PMID- 9556242
TI - Handsewn vs. stapled anastomoses in colon and rectal surgery: a meta-analysis.
AB - PURPOSE: Trials comparing handsewn with stapled anastomoses in colon and rectal
surgery have not found statistical differences. Despite this, authors have
differed in their conclusions as to which technique is superior. To help
determine whether differences in patient outcomes are present, a meta-analysis of
all trials was performed. METHOD: A meta-analysis of all randomized, controlled
trials assessing handsewn and stapled colon and rectal anastomoses was done using
a fixed-effects model. Outcome variables were mortality, technical problems, leak
rates, wound infections, strictures, and cancer recurrence. Outcomes were
assessed for all anastomoses involving the colon and for the subset of colorectal
anastomoses. RESULTS: Thirteen distinct trials met the inclusion criteria.
Intraoperative technical problems were more likely to occur with stapled than
with handsewn anastomoses for all anastomoses (P < 0.0001) and for colorectal
anastomoses (P < 0.001). Strictures were also more common following stapled
anastomoses (P = 0.015 for all anastomoses; P = 0.028 for colorectal
anastomoses). All other outcome measures, including mortality, clinical and
radiologic leak rates, and local cancer recurrence rates showed no difference
between groups. CONCLUSION: Although intraoperative technical problems and
postoperative strictures were more common with stapled anastomoses, other outcome
measures showed no difference between groups. Thus, both techniques are
effective, and the choice may be based on personal preference.
PMID- 9556243
TI - Defunctioning of the anorectum: historical controlled study of laparoscopic vs.
open procedures.
AB - BACKGROUND: Creating a defunctioning stoma for anorectal disease in patients in
whom no resection or anastomosis is required appears eminently suited for
laparoscopic techniques, with the intended advantages of early recovery, reduced
pain, and avoidance of a laparotomy. OBJECTIVES: The study contained herein was
undertaken to determine the feasibility of laparoscopic defunctioning stoma
formation using a three-port technique (including one at the stoma site) and to
compare initial results with a historical control group. METHODS: Duration of
operation (anesthetic plus surgery), the time to tolerance of a liquid and then a
solid diet, time to passage of flatus and feces, patient morphine requirements in
the first 48 hours, and day of discharge were documented. RESULTS: Nineteen
laparoscopic stomas were attempted (3 converted to open) and 23 open stomas were
formed in the control group. The laparoscopic stoma group had lower morphine
requirements (mean, 47.7 vs. 89.9 mg; P < 0.01), an earlier tolerance of both
liquid (mean, 2.1 vs. 3.7 days; P < 0.01) and solid diets (mean, 3.6 vs. 5.5
days; P < 0.001), and an earlier time to passage of both flatus (mean, 2.2 vs.
3.6 days; P < 0.001) and feces (mean, 3.7 vs. 5.6 days; P < 0.001). Operating
time was longer for the laparoscopic group (mean, 176 vs. 104 minutes; P <
0.001), whereas median time to discharge from hospital was shorter (median, 8 vs.
11 days; P = 0.014). Postoperative 30-day morbidity occurred in 1 of 19
laparoscopic group patients and 4 of 23 open group patients. CONCLUSIONS: In this
select group of patients requiring defunctioning stoma only, laparoscopic surgery
is feasible and safe and may have advantages over open procedures of less pain,
earlier tolerance of diet, earlier return of bowel function, and a shorter median
length of stay.
PMID- 9556244
TI - Role of Mycobacterium paratuberculosis in Crohn's disease: a prospective,
controlled study using polymerase chain reaction.
AB - PURPOSE: Mycobacterium paratuberculosis has been proposed as a causative agent in
patients with Crohn's disease. The purpose of this study was to determine whether
M. paratuberculosis was present in tissue from patients with Crohn's disease in a
defined geographic area. METHODS: We prospectively evaluated, using polymerase
chain reaction and culture, whether M. paratuberculosis was present in 44
specimens (37 from intestinal mucosal biopsies and 7 from surgical resections)
from patients with Crohn's disease, ulcerative colitis, or normal colonic mucosa.
RESULTS: Of the 25 specimens tested from the 21 Crohn's patients, only 1 positive
specimen was noted, whereas the 8 specimens from the 5 ulcerative colitis
patients and the 11 specimens from the 11 control patients failed to demonstrate
a positive result with polymerase chain reaction. Cultures of all specimens
revealed no growth of M. paratuberculosis. CONCLUSION: M. paratuberculosis was
only rarely detected in biopsy or surgical specimens from patients with Crohn's
disease. These results do not support a common causative role of M.
paratuberculosis in Crohn's disease.
PMID- 9556245
TI - Parameters of the rectoanal inhibitory reflex in patients with idiopathic fecal
incontinence and chronic constipation.
AB - PURPOSE: The rectoanal inhibitory reflex is a response of the internal anal
sphincter to rectal distention, reflecting the functional nature of the anal
sampling mechanism of rectal discrimination. The aim of this study was to assess
the parameters of the rectoanal inhibitory reflex in healthy volunteers and
incontinent and symptomatically constipated patients. METHODS: The rectoanal
inhibitory reflex was recorded in 42 patients using reproducible threshold
volumes. Excitatory and inhibitory latencies, maximum excitatory and inhibitory
pressures, amplitude, and slope of inhibition, slope and time of pressure
recovery, and area under the inhibitory curve were estimated. Pudendal nerve
terminal motor latency and endoanal magnetic resonance imaging were performed in
all incontinent patients. RESULTS: Significant linear trends were found for most
parameters at each sphincter level when analyzed. Recovery time and area under
the inhibitory curve differed between the sphincter levels and patient groups,
with the most rapid recovery occurring in the distal sphincter of incontinent
patients (P < 0.001). These pressure findings were not accounted for by
differences in excitation between patient groups. CONCLUSION: A coordinated
response by the internal anal sphincter to rectal distention with recovery of
anal pressure from the distal to the proximal sphincter is suggested. Continence
may rely on the character of internal anal sphincter inhibition, and recovery and
preoperative assessment of rectoanal inhibitory reflex parameters may be
important for predicting functional result following low anastomosis.
PMID- 9556246
TI - Clinical outcome of anterior overlapping external anal sphincter repair with
internal anal sphincter imbrication.
AB - Fecal incontinence caused by overt anterior sphincter defects sustained during
childbirth is usually treated by a delayed overlapping repair of the external
anal sphincter. However, an obstetric trauma is frequently associated with
disruption of the perineal body and loss of the distal rectovaginal septum. Data
regarding a combined repair, consisting of restoration of the rectovaginal septum
and perineal body, overlapping external anal sphincter repair, and imbrication of
the internal anal sphincter, are scanty. PURPOSE: This prospective study was
aimed at the following: 1) evaluating the clinical outcome of such an anterior
anal repair in patients with fecal incontinence caused by obstetric trauma; 2)
comparing the functional results with those obtained in a historical group of
patients who underwent a conventional direct sphincter repair. METHODS: During
the period between 1973 and 1989, 24 female patients (median age, 44 (range, 28
67) years) with fecal incontinence underwent direct sphincter repair (Group I).
During the period between 1989 and 1994, a consecutive series of 31 female
patients (median age, 46 (range, 23-78) years) with fecal incontinence underwent
anterior anal repair (Group II). RESULTS: At two years of follow-up, continence
had been restored in 15 patients (63 percent) in Group I, whereas restoration of
continence was successful in 21 patients (68 percent) in Group II. CONCLUSION:
The more complex anterior anal repair fails to confer clinical benefit compared
with the rather simple direct sphincter repair.
PMID- 9556247
TI - Clinical outcome and bowel function following total abdominal colectomy and
ileorectal anastomosis in the Oriental population.
AB - Total abdominal colectomy with ileorectal anastomosis is a commonly performed
surgical procedure. The postoperative outcome of these patients, however, has not
been studied in detail in the Asian population. AIM: The purpose of this study
was to analyze the functional outcome of patients following total abdominal
colectomy and ileorectal anastomosis. METHOD: All patients subjected to a total
abdominal colectomy with ileorectal anastomosis during a six-year period from
February 1989 to October 1995 were reviewed. RESULTS: Sixty-six patients
(male:female, 40:26) with a mean age of 55.2 (range, 20-88) years underwent total
abdominal colectomy with ileorectal anastomosis. Median follow-up after surgery
was 26 (range, 4-78) months. Indications for surgery were synchronous or
metachronous tumors (18), complicated pancolonic diverticular disease (15),
obstructed tumors with impending perforation (13), familial adenomatous polyposis
(7), slow-transit constipation (6), and others (7). Mean operative time was 137
+/- 48 minutes. Mean postoperative hospitalization was 13.3 +/- 11.9 days. Time
to first bowel movement and commencement of solid diet were 4.7 +/- 1.8 and 7.2
+/- 2.4 days, respectively. Four patients had prolonged postoperative ileus.
Average stool frequencies per day were 5.5 at one week, 4.3 at one month, 3.9 at
six months, 3.2 at one year, and 2.9 at two years postoperatively. Thirty-three
patients (50 percent) required antidiarrheal treatment for a transient period,
but none required long-term therapy. Ninety-seven percent of all patients rated
the functional outcome as good to excellent, and 3 percent said it was fair.
There was two perioperative mortalities. Five cases required re-laparotomy, three
for anastomotic complications and two for hemoperitoneum. Five patients had
recurrent admissions for adhesion colic, which resolved with nonsurgical therapy.
Ten patients succumbed on follow-up, six to tumor recurrence, two to unrelated
cancers (stomach and bladder), and three to medical conditions. CONCLUSION: The
functional outcome of ileorectal anastomosis is generally rated as good to
excellent by patients. Acceptable bowel function and control is regained within
six months of the operation and levels off at one year after surgery, and no
patient requires long-term antidiarrheal medication.
PMID- 9556249
TI - Epidemiologic panorama of colorectal cancer in Mexico, 1980-1993.
AB - INTRODUCTION: Colorectal cancer is the third cause of cancer-related death in the
world, with 468,000 estimated deaths in 1993. In some countries mortality rates
have started to decline, and survival rates have increased. In this study
performed in Mexico, information is presented on the increase in mortality from
this form of cancer, especially in more economically developed areas. METHODS:
The mortality trend for colorectal cancer was evaluated and standardized by five
year age groups in the period 1980 to 1993. Also, the standardized mortality
ratio was calculated for Mexico's 32 states, as was the possible association
between mortality and indicators of rurality level and fertility rates in the
different regions of Mexico. RESULTS: In the period studied, 18,962 deaths were
officially reported. The average age of death was 66 years. The mortality rate
among women (1.8) was significantly higher than among men (1.55 per 100,000
inhabitants). Mortality from colorectal cancer grew by 100 percent in both
genders (beta = 0.089; P < 0.001), especially in the age group 34 and younger, in
the 45 to 49 age group, and in the older than 75 age group (P < 0.05). The
standardized mortality ratio was greater in the states in the north of Mexico.
Finally, an inverse correlation was observed throughout Mexico between the
rurality index (r = -0.60; P < 0.001) and the fertility rates (r = -0.43; P <
0.05) and mortality from colorectal cancer. CONCLUSIONS: In this study, there is
evidence that mortality from this cancer is higher in geographic areas with
greater socioeconomic development, similar to regional patterns observed in other
countries. In Mexico, the coming years will see a serious epidemic in mortality
from this disease; therefore, immediate attention must be given to identifying
the profile of high-risk subjects and implementing early cancer detection
measures.
PMID- 9556248
TI - Increased serum levels of transforming growth factor-alpha in patients with
colorectal cancer.
AB - PURPOSE: This study was conducted to investigate the serum levels of transforming
growth factor-alpha in patients with colorectal cancer and to investigate the
clinical significance of these levels in association with tumor stage and
histologic differentiation. Also, serum levels of transforming growth factor
alpha were measured after curative surgical resection. METHODS: Serum levels of
transforming growth factor-alpha were measured in 42 consecutive patients with
colorectal cancer before surgery, in 21 patients after surgical resection (part
of the 42 preoperative patients), and in 20 healthy volunteers. We used TGF-alpha
Assay. RESULTS: Serum levels of transforming growth factor-alpha in patients with
colorectal cancer were significantly higher than in the healthy control group (P
= 0.001). Significant elevations in serum levels of transforming growth factor
alpha were found in 50 percent (21/42) of patients with colorectal cancer when
the mean + 2 standard deviations (80.4 pg/ml) of the control group were used as
the upper limit of the normal range. Serum levels of transforming growth factor
alpha tended to decrease with increasing tumor size (n = 31; r = -0.52; P =
0.002). Serum levels of transforming growth factor-alpha before surgery (89.7 +/-
44.4 pg/ml; n = 21) significantly decreased to 60.3 +/- 19.8 pg/ml after surgical
resections of tumors (P = 0.017). Serum levels of transforming growth factor
alpha completely decreased to the same serum levels of the control group after
surgical resections in all patients who had serum levels of transforming growth
factor-alpha greater than mean + 2 standard deviations (80.4 pg/ml) of the
control group preoperatively (n = 11; P = 0.002). CONCLUSIONS: Levels of
preoperative transforming growth factor-alpha in patients with colorectal cancer
appeared to be higher than levels measured in control subjects. Serum levels of
transforming growth factor-alpha before surgery significantly decreased after
surgical resections of tumors. Additional studies are warranted to determine if
serum levels of transforming growth factor-alpha may be useful as a potential
biomarker in the management of patients with colorectal cancer.
PMID- 9556250
TI - Diagnostic and therapeutic applications of monoclonal antibodies in colorectal
cancer.
AB - PURPOSE: The study contained herein was undertaken to review and summarize the
current literature on diagnostic and therapeutic applications of monoclonal
antibodies in colorectal cancer. RESULTS: Limitations of traditional imaging
techniques have encouraged development of targeted imaging strategies using
radiolabeled monoclonal antibodies. Diagnostic immunoscintigraphy can detect
lesions not identified by conventional imaging modalities, although it has not
proven useful in the management of primary colorectal cancers and in hepatic
metastases. Immunoscintigraphy shows promise in cases of local recurrence and
rising carcinoembryonic antigen values; however, the impact of immunoscintigraphy
on clinical outcomes and cost-effectiveness remains unproven. Radioimmunoguided
surgery has been advocated as a method of more accurately detecting tumor
extension and accomplishing radical resection. The technique remains
controversial, and its use is not widespread. With respect to therapeutic
applications, immunotherapy has most often been investigated in the setting of
advanced stage disease. Results in this setting have been poor. In contrast,
adjuvant immunotherapy after resection of Dukes C carcinoma has achieved
convincing results, with improvements in survival comparable with that of
adjuvant chemotherapy. Adjuvant trials are now under way to examine the
effectiveness of monoclonal antibodies in the postoperative treatment of early
stage (II) tumors and the combination of monoclonal antibodies and chemotherapy
in advanced-stage (III) tumors. Bispecific antibodies, or immunoconjugates with
cytokines or toxins, represent additional areas of interest and future
investigations. CONCLUSIONS: At present, immunoscintigraphy is not sufficient to
determine, by itself, resectability of colorectal tumor and has limited
usefulness in select cases of recurrent cancer and possibly in cases of rising
carcinoembryonic antigen values. Immunotherapy with monoclonal antibodies as a
postoperative adjuvant treatment shows promise and is currently being
investigated in national trials.
PMID- 9556251
TI - Length measuring device for transrectal ultrasonography of anorectal lesions.
AB - We, herein, describe an attachable measuring device for transrectal
ultrasonography. It is a useful piece of equipment for measuring the precise
length of a lesion and for fixing the position of the transducer under
examination for sphincteric dynamics.
PMID- 9556252
TI - Sacral insufficiency fractures--rare complication of pelvic radiation for rectal
carcinoma: report of a case.
AB - PURPOSE: The report contained herein presents a patient who developed severe back
pain because of bilateral sacral insufficiency fractures after pelvic radiation
for rectal carcinoma. METHODS: This is a case report and review of the literature
for a rare complication of pelvic radiation. RESULT: The patient was diagnosed by
computerized tomography and radionuclide bone scans. Bed rest and analgesia
followed by rehabilitation provided good relief of the symptoms. CONCLUSION: A
rare complication of pelvic radiation is insufficiency fractures of the pelvis.
Early detection is important, because significant morbidity may result from
delaying treatment. Unawareness of this complication may lead to diagnostic
difficulties and unnecessary work-up.
PMID- 9556253
TI - Involuntary contractions of the striated anal sphincters as a cause of
constipation: report of a case.
AB - PATIENT HISTORY: We present a case of anismus in a 36-year-old patient. He
complained of therapy refractory constipation that had been present for 15 years,
with delayed micturition and voiding by stages. METHODS AND RESULTS: During
digital examination of the anal canal, we found spontaneous contractions of the
sphincters at rest. The urethral pressure profile showed irregular contractions
during micturition. The electromyogram, which was performed with concentric
needle electrodes from the external anal sphincter, puborectalis, and external
vesical sphincter, revealed synchronous contractions of these muscles. Injections
of botulinum toxin into the sphincters showed good effects and no incontinence.
CONCLUSION: Focal dystonia of the striated anal and vesical sphincters is a very
rare cause of constipation but should be included in the differential diagnosis.
PMID- 9556254
TI - Self-assessment quiz. Chronic idiopathic rectal pain: risk factor for
postoperative complications in colorectal surgery: local excision of rectal
cancer should be done.
PMID- 9556255
TI - Are we there yet?
PMID- 9556256
TI - Save the trapezium: double interposition arthroplasty for the treatment of stage
IV disease of the basal joint.
AB - Twenty patients with symptomatic stage IV basal joint (pantrapezial) arthritis
were treated with double interposition arthroplasty, a new technique that
resurfaces the degenerative trapeziometacarpal and scaphotrapezial joints after
minimal distal trapezial resection. The results of the 21 procedures were
reviewed clinically and radiographically after a mean follow-up period of 34
months (minimum, 1 year). Ninety-one percent of the patients were completely
satisfied. Seventy-one percent were entirely free of pain, and an additional 24%
noted only occasional, mild, high-stress pain that did not limit their
activities. One case was a clinical failure. Objectively, all 21 basal joints
were stable, with active range of motion to within 90% of normal. Mean grip
strength increased 32%, from a force of 26.1 kg to 33.9 kg (p < .01). Key pinch
strength increased from a force of 5.3 kg to 6.0 kg (an 11% increase; p = .05). A
new method of determining changes in basal joint height indicated a mean decrease
in height of 5.3% (range, 0%-12%) at rest and 8.1% (range, 0%-20%) under axial
compression. This difference was statistically but not functionally significant.
Overall, there were 95% good or excellent results and 1 poor result. We believe
this technique is simple and preserves the osseous foundation of the basal
joints. These results compare favorably with arthroplasties that include
trapezium excision for the treatment of stage IV basal joint arthritis.
PMID- 9556257
TI - Scapholunate ligament reconstruction using a bone-retinaculum-bone autograft.
AB - This study was designed to evaluate the use of a locally available bone
retinaculum-bone graft in the reconstruction of the completely torn scapholunate
(SL) ligament. Nineteen consecutive patients (14 with dynamic instability and 5
with static instability) underwent SL ligament reconstruction using an autogenous
bone-retinaculum-bone graft taken from the third dorsal compartment region. All
patients underwent arthroscopy to document a torn SL ligament. The bone plugs on
the graft were fitted into the dorsal scaphoid and lunate, respectively, with the
retinaculum periosteal soft tissue intervening sleeve arching between these 2
bones. The SL interval was reduced and pinned for 8 weeks with cast
immobilization. The follow-up period averaged 3.6 years (minimum, 24 months). Of
the 14 patients with dynamic instability, 12 had no pain and 2 had pain with
heavy activity of the wrist. Range of motion (ROM) decreased slightly from
preoperative values, and grip strength improved 46%. Thirteen patients were
completely satisfied and returned to their former work activities, and 1 returned
to modified work activities. Of the 5 patients with static instability, 2 had no
pain after surgery, 1 had pain with heavy activity, and 2 had constant pain. ROM
in this group decreased moderately in extension/flexion from the preoperative
values. Grip strength improved 30% from preoperative values. Satisfaction was
rated as complete by 1 patient and partial by 2 patients; 2 patients were
dissatisfied. Two patients returned to their former jobs, 2 returned to modified
duties, and 1 is on disability. Reconstruction of the SL ligament using a bone
retinaculum-bone autograft is predictable in patients with dynamic instability.
Use of this technique with static SL instability is questionable; these patients
may require a stronger construct to prevent recurrence of the SL gap.
PMID- 9556258
TI - Scapholunate ligament reconstruction using a bone-retinaculum-bone autograft: a
biomechanic and histologic study.
AB - A new surgical technique has been recently described that involves reconstruction
of the dorsal aspect of the scapholunate ligament (DSLL) with a bone-retinaculum
bone (BRB) autograft preparation from Lister's tubercle. In this study, the
mechanic and histologic properties of the 2 tissues were compared. The BRB and
DSLL specimens were harvested from 6 fresh-frozen human cadaveric forearms. The
specimens were measured and then tested in tension with an MTS 810 servohydraulic
materials testing machine at a rate of 10 mm/min. The BRB autograft was
significantly weaker than the DSLL. However, because the mean cross-sectional
area of the DSLL was more than 3 times as large as that of the BRB autograft, the
failure stress (failure force/cross-sectional area) of the BRB autograft was not
significantly different from that of the DSLL. Histologically, the DSLL and BRB
autograft were also similar. These findings suggest that the BRB autograft may be
appropriate graft material for scapholunate ligament reconstruction, but that
structural parity with DSLL will ultimately depend on remodeling and hypertrophy
during healing. This also highlights the importance of using a large BRB
autograft to approximate the strength of the DSLL as much as possible, and that
the BRB autograft must be protected postoperatively as it heals and remodels.
PMID- 9556259
TI - Wide excision of the distal ulna: a multicenter case study.
AB - Excision of the distal ulna to treat degenerative disease or instability has
fallen into disfavor following reports of radioulnar impingement, carpal
instability, and distal ulnar instability. Alternative procedures for
reconstruction of the painful distal ulna have been developed to address these
problems; the results have been generally favorable. When faced with distal ulnar
reconstruction that has failed after multiple surgical procedures, or a distal
ulnar neoplasm, the surgeon is left with few treatment options. Creation of a one
bone forearm, free fibular transfer, and allograft replacement have been
attempted, with mixed outcomes. We report the results of 5 men and 7 women who
underwent wide excision of the distal ulna, defined as surgical excision of 25%
to 50% of the ulnar length. The diagnosis was failed distal radioulnar
reconstruction or excision in 8 patients, osteomyelitis in 1, congenital
pseudoarthrosis of the radius in 1, and neoplasm in 2. No soft tissue
reconstruction was performed. Patients were examined at an average of 22 months
after surgery for radiocarpal and radioulnar instability, functional outcome,
pain relief, grip strength, and range of motion. Nine of the 12 procedures
resulted in good or excellent results; 1 patient had a fair result after
resection for osteosarcoma, and the procedure in 2 patients failed, requiring
conversion to a one-bone forearm. Grip strength was restored to 75% of the normal
side and range of motion was restored to 86% of the normal side. Wide excision of
the distal ulna without soft tissue reconstruction is a simple and durable
treatment of neoplasms of the distal ulna or salvage of the failed reconstruction
of the distal radioulnar joint. We do not recommend its use in patients with
incompetency or disruption of the interosseous membrane.
PMID- 9556261
TI - Intrasound vibration in the early diagnosis of scaphoid fracture.
AB - A prospective trial was designed to assess the sensitivity and specificity of
intrasound vibration for the early detection of scaphoid fracture. We replicated
the method described by Finkenburg et al. (J Hand Surg 1993;18A:4-7) in an
attempt to corroborate their results. We found the test to be 73% sensitive and
51% specific. Because the test was not 100% sensitive, as claimed by Finkenburg
et al., we discontinued the use of this device in our hospital.
PMID- 9556260
TI - Is intrasound vibration useful in the diagnosis of occult scaphoid fractures?
AB - This study was designed to confirm the results of Finkenberg et al. (J Hand Surg
1993;18A: 4-7), who found a high sensitivity (100%) and specificity (95%) of the
intrasound vibration method in diagnosing occult scaphoid fractures. These occult
scaphoid fractures are not visible on x-ray films, but clinically the patients
are suspected of having a scaphoid fracture. A vibratory apparatus is placed over
the anatomical snuff-box and a vibration of 100 mW is emitted; a painful
sensation is produced if the scaphoid is fractured. Thirty-seven consecutive
patients with a clinically suspected scaphoid fracture were evaluated. In 6
patients, a scaphoid fracture was radiographically identified; in the remaining
31 patients, a 3-phase bone scan was obtained. Eleven wrists showed increased
uptake over the scaphoid and were considered to have an occult scaphoid fracture.
In this group, bone scintigraphy was used as the reference standard. The
vibration test was painful in 1 of 6 patients with a proven scaphoid fracture and
in 3 of the 11 patients with a positive bone scan. In contrast to the results of
Finkenberg et al, the intrasound vibration method shows a sensitivity of 24%, a
specificity of 85%, a positive predictive value of 40%, and a negative predictive
value of 65%. We conclude that the accuracy of intrasound vibration is low and
that it is not useful in the diagnosis of scaphoid fractures.
PMID- 9556262
TI - Surgical treatment of carpal tunnel syndrome and trigger digits in children with
mucopolysaccharide storage disorders.
AB - The role of surgical intervention for carpal tunnel syndrome (CTS) and trigger
digits in children with mucopolysaccharide storage disorders (MPSDs) has not been
clearly defined, particularly as the treatment of the underlying disease has
advanced to include bone marrow transplantation. This study reviews our
experience in the treatment of CTS and trigger digits in 22 children with MPSDs
who were evaluated for CTS by electromyographic (EMG)/nerve conduction velocity
(NCV) testing. Seventeen children were diagnosed with CTS by EMG/NCV testing and
were treated with bilateral open surgical release with or without flexor
tenosynovectomy. The EMG/NCV testing revealed normal results in 5 patients who
are subsequently being monitored. Forty-five digits in 8 children were diagnosed
clinically with trigger digits. Nineteen digits were treated by annular pulley
release alone. Twenty-six digits were treated by annular pulley release with
partial flexor digitorum superficialis tendon resection. The average age at the
time of hand surgery was 6.3 years, and at the time of follow-up, 9.6 years.
Postoperative EMG/NCV testing in 7 children showed 1 with improvement and 6 with
normalization. None of the patients undergoing carpal tunnel release went on to
develop thenar atrophy or absent sensibility, as has been reported in untreated
cases. Patients were evaluated for triggering digits both by preoperative tendon
palpation and by intraoperative flexor tendon excursion at the time of open
carpal tunnel release. All patients undergoing trigger release had improved
active digital flexion seen at the final follow-up visit. Because of the very
high incidence of CTS and trigger digits in this population, the authors
currently recommend routine screening of EMG/NCV for all children with MPSDs.
Early surgical intervention for nerve compression and stenosing flexor
tenosynovitis can maximize hand function in these children.
PMID- 9556263
TI - The role of ulnar nerve transposition in ulnar nerve repair: a cadaver study.
AB - Ulnar nerve transposition at the elbow is recommended to diminish nerve gaps
during neurorrhaphy. We undertook a cadaver study to determine the gap distance
that can be overcome by subcutaneous transposition at the elbow, evaluating
lacerations 2.0 cm distal to the medial epicondyle and 2.0 cm proximal to the
wrist crease. With a 100-g load on each nerve stump, gaps that could be overcome
were measured before and after transposition in different elbow and wrist
positions. For the distal forearm lacerations, wrist position significantly
affected nerve gap, while transposition and elbow position did not. Nerve gap was
significantly reduced by approximately 11 mm with wrist flexion from 0 degrees to
45 degrees. For proximal forearm lacerations, gap distance was significantly
affected by transposition and was dependent to a greater extent on the
interaction between transposition and elbow position, with wrist position having
no effect. A clinically relevant scenario for the proximal laceration compared
the pretransposition gap with the elbow and wrist at neutral with the
posttransposition gap with the elbow and wrist flexed. Posttransposition gap
reduction, with elbow and wrist flexion at 45 degrees, was approximately 9 mm and
was not significant. To span a gap near the elbow, we estimate that more than 45
degrees of elbow flexion is required.
PMID- 9556264
TI - Anatomy and internal topography of the musculocutaneous nerve: the nerves to the
biceps and brachialis muscle.
AB - One hundred twelve musculocutaneous nerves from 56 cadavers were examined to
determine branching patterns of innervation and internal neurotopography. There
were 3 distinct types of branching patterns for biceps innervation: in 62%, there
was 1 branch only; in 33%, 2 branches; and in 5%, 3 branches. The origin of the
first branch averaged 130 mm from the acromion regardless of branching type. The
maximum distance between the first and second branch was 53 mm. In 92%, there was
only 1 branch to the brachialis muscle. It always emerged from the main trunk
distal to the nerve to the biceps and averaged 170 mm from the acromion. Internal
topography was studied from 1-mm-thick serial sections of the musculocutaneous
nerve in 5 fresh cadaver arms. The group of fasciculi of the nerve to the biceps,
the nerve to the brachialis, and the lateral cutaneous nerve of the forearm were
constantly located from lateral to medial. The fasciculi of the nerve to the
biceps traveled proximally in the musculocutaneous nerve for an average distance
of 63 mm.
PMID- 9556265
TI - Microarterial anatomy of the lesser toe proximal interphalangeal joints.
AB - Successful free tissue transfer requires detailed knowledge of the pertinent
microvascular anatomy of the donor site. The lesser toe proximal interphalangeal
joints are a source of vascularized autologous tissue. In 20 adult cadaver feet,
the arterial anatomy of the second, third, and fourth toes was studied using
colored latex and India ink injection. The second, third, and fourth dorsal
metatarsal arteries produced small or absent dorsal digital arteries in 72.5% of
distal dissections. The proper digital arteries were 0.93 to 1.37 cm in length.
An additional 2.3 to 2.83 cm of length can be gained by use of the plantar
metatarsal arteries if the dorsal metatarsal or dorsal digital arteries are
inadequate. The diameter of the medial proper digital arteries (range, 1.2-1.26
mm) was larger than the lateral proper digital arteries (range, 0.66-0.99 mm).
The proper digital arteries of the lesser toes provide the predominant arterial
supply of the proximal interphalangeal joints through a system of transverse and
longitudinal arches.
PMID- 9556266
TI - Two-, four-, and six-strand zone II flexor tendon repairs: an in situ
biomechanical comparison using a cadaver model.
AB - A dynamic in vitro model of zone II flexor tendon repair was used to compare
gliding resistance, gap formation, and ultimate strength of the 2-, 4-, and 6
strand repair techniques. Each of 12 hands was mounted to a loading frame with 3
flexor tendons attached to individual pneumatic cylinders. A spring attached to a
pin through the distal end of each digit provided a 1.25-kg resistance force. The
force required to flex each proximal interphalangeal joint to 90 degrees was
determined. Following this, the tendons were sectioned and each was repaired
using a different technique so that each specimen acted as its own control. The 2
and 4-strand core sutures were placed using a suture interlock technique with
radial and ulnar grasping purchase of the tendon on each side of the transverse
part of the repair. Each repair was accomplished using a single core stitch with
the knot buried between the tendon ends. The 4-strand repair involved an
additional horizontal mattress suture with the knot buried. Repair of the dorsal
side of the tendon was performed followed by core suture placement. The palmar
portion of the peripheral locking suture was completed after core suture
placement. Following repair, each hand was remounted on the frame and cycled
1,000 times. After cyclic loading, the resulting gap between the repaired ends of
each tendon was measured, the tendons were removed from the hand, and each was
loaded to failure in tension. All tendon repairs showed a small, but not
statistically significant, increase in gliding resistance after reconstruction.
The 2-strand repair had significantly greater gap formation after cyclic loading
(mean gap, 2.75 mm) than either the 4-strand (0.30 mm) or 6-strand (0.31 mm)
repair. The tensile strength of the 6-strand repair (mean, 78.7 N) was
significantly greater than either the 4-strand (means, 43.0 N) or 2-strand (mean,
33.9 N) repair.
PMID- 9556267
TI - Differences in proliferative rate and collagen lattice contraction between
endotenon and synovial fibroblasts.
AB - Injured and surgically repaired tendons heal with the formation of scar tissue.
Scar tissue represents 1 of the most unpredictable factors contributing to
postoperative morbidity. The main cell involved in scar formation is the
fibroblast. The relative activity of fibroblasts from the fibro-osseous sheath
(the tissue surrounding the tendon in zone II) and the endotenon (the core of the
tendon) with respect to proliferation and the ability to contract a collagen
lattice were compared in vitro. The fibroblasts derived from the fibro-osseous
sheath were more active in both these respects. In addition, the amount of matrix
metalloproteinase activity was found to be greater for the fibro-osseous sheath
fibroblasts, implying a greater capacity to degrade and disorganize connective
tissue and thus migrate. These results imply that the fibro-osseous fibroblasts
represent a more active population of cells compared with endotenon fibroblasts,
and perhaps should be specifically targeted in future modes of therapy.
PMID- 9556268
TI - Excursion properties of tendon graft sources: interaction between tendon and A2
pulley.
AB - We measured excursion resistance of 4 different tendons (flexor digitorum
superficialis, the portion of the extensor indicis proprius tendon beneath the
extensor retinaculum, the portion of the extensor indicis proprius tendon distal
to the extensor retinaculum, and palmaris longus) beneath the A2 pulley.
Intrasynovial tendons (i.e., flexor digitorum superficialis and the portion of
the extensor indicis proprius beneath the extensor retinaculum) produced less
excursion resistance than extrasynovial tendons (i.e., the portion of the
extensor indicis proprius distal to the extensor retinaculum and palmaris
longus). The excursion resistance of the intrasynovial portion of the extensor
indicis proprius tendon was significantly lower than that of the extrasynovial
portion of the same tendon. Intrasynovial tendons may be preferred to
extrasynovial tendons when choosing a tendon graft source and graft gliding under
a pulley is a consideration.
PMID- 9556269
TI - Flexor tendon-pulley interaction after annular pulley reconstruction: a
biomechanical study in a dog model in vivo.
AB - The excursion resistance between the canine flexor digitorum profundus tendon and
A2 pulley was compared after pulley reconstruction using tendon grafts of either
intrasynovial or extrasynovial origin at 10 days, 3 weeks, and 6 weeks after
surgery. The changes over time in the underlying flexor digitorum profundus
tendon after pulley reconstruction were also evaluated. The excursion resistance
for both types of pulley reconstruction was significantly greater than that of
the control group at all time periods. The excursion resistance of the
extrasynovial tendon graft reconstruction was greater than that of intrasynovial
pulley reconstruction at all time periods. In conclusion, pulley reconstruction
with intrasynovial tendon grafts may facilitate tendon gliding after surgery.
PMID- 9556270
TI - The effects of proximal load on the excursion of autogenous flexor tendon grafts.
AB - To determine the relationship between the intrinsic properties of tendon and
tendon excursion in 2 types of autogenous tendon grafts, hindpaw intrasynovial
and extrasynovial tendons were transferred to the lateral and medial forepaws of
adult mongrel dogs (16 experimental and 16 control tendons). After each digit was
marked with radiopaque markers, it was placed in a specialized jig, and weights
of 25 g, 100 g, or 200 g were applied to the flexor tendons. Specialized
radiographs were obtained with the digit in flexion and extension. Tendon
excursion and joint rotation were calculated. There were no statistically
significant differences between experimental groups for tendon excursion or for
joint angular rotation (p > .05). For intrasynovial tendon grafts, the angular
rotation per millimeter tendon excursion was 10.9 degrees +/- 2.4 degrees/mm, 9.4
degrees +/- 1.2 degrees/mm, and 9.0 degrees +/- 1.4 degrees/mm with 25-g, 100-g,
and 200-g loads, respectively. Comparisons between experimental groups revealed
that a statistically significant difference could not be determined (p > .05).
With varying proximal loads, both intrasynovial and extrasynovial grafts showed
similar amounts of tendon excursion. Variations in proximal load did not
significantly influence the amount of excursion within the range of loads tested.
Based on these data, it appears that the difference in repair potential for these
2 types of tendon grafts is not related to a differential in the amount of tendon
graft excursion following transfer to the synovial space.
PMID- 9556271
TI - Staged opposition transfer.
AB - Six patients sustained extensive hand and upper limb trauma, including median
nerve and/or thenar muscle loss. Initial treatment consisted of various median
nerve and/or soft tissue reconstructions. Because of extensive palmar scarring
and lack of useful opposition (Kapandji stage 3), a 2-stage opposition transfer
was performed. In stage 1, a silicone rod was placed along the path of the
intended tendon transfer. In stage 2, the rod was removed and the donor tendon
was passed through the pseudosheath to the point of insertion at the thumb. All
patients were monitored for a minimum of 1 year and all achieved significant
functional improvement, documented by Kapandji stage 6 opposition in 1 patient
and by at least stage 7 or 8 opposition in the other 5 patients.
PMID- 9556272
TI - Ulnar nerve compression following flexor digitorum superficialis tendon transfers
around the ulnar border of the forearm to restore digital extension: case report.
AB - This case report describes a complication that occurred following long and ring
finger flexor digitorum superficialis tendon transfers routed around the ulnar
border of the forearm to restore digital extension. An ulnar mononeuropathy
developed in the early postoperative period that was characterized by decreased
ring and small finger sensation and interosseous muscle weakness. Operative
exploration demonstrated extrinsic compression of the ulnar nerve by the long and
ring finger flexor digitorum superficialis tendons. When superficialis tendon
transfers are chosen to restore digital extension, passage around the radial side
of the forearm or through the interosseous space are recommended to avoid this
potential complication.
PMID- 9556273
TI - Open reduction and internal fixation of unstable distal radius fractures with a
low-profile plate: a multicenter study of 73 fractures.
AB - A study of acute, dorsally displaced, unstable (high-energy) fractures of the
distal radius was conducted to determine the safety and efficacy of a new low
profile plate for unstable distal radius fractures. Thirteen surgeons in 11 US
cities participated in the study. A minimum follow-up period of 1 year was
required to be included in the study. Seventy-three fractures in 71 patients met
this criterion. Each fracture was treated according to a prospective protocol. An
autogenous bone graft was used in 64 fractures. All procedures were completed
using a radiolucent sterile traction table. No external fixators were used either
during or after the operation. After bone grafting and while in traction, a
fracture reduction clamp with a template preshaped to the normal contour of the
dorsal radial metaphysis molded the fracture into reduction and then allowed
precision drilling of the holes for the plate. Active wrist motion began at an
average of 14 days. Satisfactory open reduction was obtained in 93% of the
fractures and maintained in 88%. Ninety-five percent of the fractures
demonstrated good or excellent outcomes using a standardized evaluation. Eighty
one percent of the outcomes were rated as excellent. This initial report
demonstrates that the method is a safe and effective treatment for acute,
unstable, dorsally displaced fractures of the distal radius.
PMID- 9556274
TI - Self-tapping versus standard tapped titanium screw fixation in the upper
extremity.
AB - Most screws used in fracture fixation necessitate a separate step for tapping of
the screw hole. Titanium screw systems have been developed in which the screws
can be inserted directly after a drill hole is made. These self-tapping screws
thereby eliminate an operative step. A retrospective study was conducted that
evaluated all wrist and hand procedures performed between January 1992 and
December 1994 by 1 surgeon using screw fixation. The results of 39 cases treated
with standard tapped titanium screws were compared with 28 cases treated with
self-tapping titanium screws. Nearly identical union and complication rates were
obtained in each group. Comparable results can be obtained with self-tapping
screw fixation, which limits the number of instruments needed, eliminates an
operative step, and thereby may diminish operative risk and shorten operative
time.
PMID- 9556275
TI - The prefabrication of a bone graft in a rat model.
AB - The prefabrication of bone grafts in a rat model was investigated. In 26 Sprague
Dawley rats, free iliac crest bone graft was harvested, bivalved, and reinserted
heterotopically into the groin, where it was closed around the mobilized
superficial inferior epigastric vascular bundle. In half the animals, the
vascular bundle remained in continuity as a flow-through pedicle (group 1); in
the remaining animals, the pedicle was ligated and divided distal to the bone
graft. All grafts were isolated from other tissues by a silicone sheet envelope.
At 3 or 6 weeks, the grafts were re-explored and analyzed by India ink perfusion
and histologic examination for evidence of viability and neovascularization.
Three weeks after insertion, India ink perfusion of the group 1 and 2 grafts
revealed neovascularization extending to the periphery of the graft, and
histologic examination showed extensive new bone formation on endosteal,
periosteal, and trabecular surfaces of the graft. Six weeks after insertion,
creeping substitution had almost completely remodelled the cortical and
cancellous bone of both group 1 and 2 grafts to create a viable vascularized bone
graft on a pedicle. In 3 control nonvascularized grafts (free iliac cortical bone
without an implanted pedicle), all pre-existing bone of the graft was dead 3
weeks after insertion, and only very limited new bone formation was present
within the graft.
PMID- 9556276
TI - Evaluation of "neocollateral" ligament formation by magnetic resonance imaging
after total excision of the proximal interphalangeal collateral ligaments.
AB - The presence of palpable thickening and maintenance of stability within weeks of
total excision of the proximal interphalangeal (PIP) joint collateral ligaments
is an established, although somewhat mysterious, phenomenon. To further
investigate this postoperative thickening, magnetic resonance imaging (MRI) scans
were obtained on 10 joints in 9 patients who had undergone total ligament
excision for posttraumatic stiff PIP joints 3 months to 14 years earlier.
Although the ultrastructure of these newly formed structures is yet unknown,
their palpable consistency, MRI contour, distribution, and signal intensity
suggest the formation of a new soft tissue structure, albeit scar, which has all
the attributes of a collateral ligament. This MRI of a "neocollateral ligament"
would help explain the consistent observation of complete joint stability within
weeks following total excision of both PIP joint collateral ligaments. All
patients from the 14-year span sampled were found to have a similar, consistent,
linear low signal density structure crossing the joint margins and essentially
identical to that of a normal collateral ligament.
PMID- 9556278
TI - Pathologic fracture of the scaphoid due to enchondroma: treatment with
vascularized bone grafting. report of a case.
AB - Enchondroma of the scaphoid has been rarely reported. A young male manual worker
presented with a pathologic fracture on the lesion. It was successfully managed
with a vascularized bone graft from the dorsum of the distal radius.
PMID- 9556277
TI - Fitting a hand-glove prosthesis to enhance the reconstructed mutilated hand.
AB - Microsurgical reconstruction of the severely mutilated hand aimed at improving
prehensile functions often does not address the esthetic aspects of the hand. The
poor appearance of the reconstructed hand affects its active display and use. A
hand-glove prosthesis may be prescribed in this instance to enhance the overall
form and function of the mutilated hand. We reviewed 16 cases of mutilating hand
injuries in which surgical reconstructions were performed and the patients were
subsequently fitted with a hand-glove prosthesis to augment the outcome. An
improved appearance was achieved in all patients fitted with the prosthesis. The
patients' sense of confidence was also enhanced, which in turn promoted the
active and open use of the reconstructed hands. While prescribed primarily to
improve the appearance of the reconstructed hands, these prostheses were
documented to enhance the physical hand functions in 11 cases by increasing the
span of the hand and providing an opposable post and a palmar base for holding
and for anchorage. The prosthesis enhanced assistive functions of the
reconstructed hands and freed the contralateral normal hand for use in bimanual
activities, such as holding a wallet and taking out money, supporting a note pad
for writing, and holding a plate at buffet receptions. At the 18-month follow-up
visit, 13 (87%) of the patients continued to use their prosthesis. Wear and tear
were problems associated with the frequent use of the prosthesis. The expected
life span of the prosthesis with daily use ranged from 2 to 3 years. All the
patients acknowledged that the prosthesis played a role in their rehabilitation
and that it helped them to overcome the initial psychological trauma and to come
to terms with their physical loss.
PMID- 9556279
TI - Enchondroma protuberans: a case report.
AB - Enchondroma protuberans is a rare benign cartilaginous tumor. There have been
only 5 cases previously described in the world literature. It must be
differentiated from other more common and aggressive tumors to avoid radical
resection. A case report of a 7-year-old boy presenting with enchondroma
protuberans in the third metacarpal is presented. The patient underwent an
initial incisional biopsy followed by a marginal resection of the soft tissue
component and intramedullary curettage. After a 36-month follow-up period, there
is no evidence of recurrence.
PMID- 9556280
TI - Perineurioma of the finger: case report of a rare peripheral nerve sheath
neoplasm of pure perineurial cell lineage.
AB - A 1.9-cm extraneural soft tissue tumor located on the palmar aspect of the index
finger of a 50-year-old woman was excised. Depicting many histopathologic
patterns and a full range of cellularity, the tumor was exclusively composed of
epithelial membrane antigen/vimentin-positive and S-100 protein/Leu-7-negative
neoplastic cells of perineurial lineage. Soft tissue (extraneural) perineurioma,
a rare variant of benign peripheral nerve sheath tumor, should be included in the
differential diagnosis of tumor and tumor-like conditions affecting soft parts of
the hand.
PMID- 9556281
TI - Upper extremity infections in patients with the human immunodeficiency virus.
AB - Twenty-eight patients with upper extremity infections and positive for the human
immunodeficiency virus (HIV) were identified. The risk factor for HIV infection
was intravenous drug injection in 24 patients, homosexual contact in 3, and
heterosexual contact in 1. Eight of the patients had the acquired
immunodeficiency syndrome. Two of the cases were prolonged herpetic infections of
more than 6 months' duration that did not respond to oral acyclovir. The other 26
cases were bacterial in origin. Twenty-six of 28 cases responded to therapy with
resolution of the infection. One patient refused surgical treatment and one died
of systemic illness before resolution of the hand infection.
PMID- 9556282
TI - Prospective multi-center trial of a plate for dorsal fixation of distal radius
fractures.
PMID- 9556283
TI - Relation of preoperative nerve-conduction values to outcome in workers with
surgically treated carpal tunnel syndrome.
PMID- 9556284
TI - Percutaneous drainage of thoracic collections.
AB - Various infected and noninfected thoracic fluid collections may be diagnosed and
treated by interventional radiologic techniques. The core procedure of ultrasound
guided thoracentesis has been expanded to allow catheter drainage of empyema,
bronchopleural fistula, abscesses in the lung, mediastinum, pericardium, and
infected tumors. Tailored use of guidance methods permits effective evacuation of
most of these abscesses and noninfected collections. This paper details the
authors' approach to each of these entities while highlighting the results and
expected pitfalls of these techniques.
PMID- 9556285
TI - Percutaneous drainage of pleural collections.
AB - Pneumothorax is a frequent complication of interventional pulmonary procedures.
Percutaneous catheter placement enables safe and effective drainage of
pneumothoraces with rapid restoration of vital capacity, oxygenation, and lung
reexpansion.
PMID- 9556286
TI - Arterial embolization in the chest.
AB - Transcatheter therapy is an effective technique in the treatment of vascular
abnormalities in the chest. Pulmonary arteriovenous malformations, associated
with the clinical sequellae of dyspnea, stroke, brain abscess, and hemoptysis,
can be treated by transcatheter embolization with metallic coils or occlusion
balloons. The results of treatment are excellent, with improvement seen in
symptoms and physiologic parameters. The bronchial arteries and systemic
nonbronchial collateral arteries supplying the tracheobronchial tree are most
frequently involved in massive hemoptysis, a serious disorder with associated
high rates of morbidity and mortality. Transcatheter embolization of these
arteries is both safe and effective, requiring a thorough understanding of the
arterial anatomy and technique of embolization.
PMID- 9556288
TI - Pictorial essay: thoracic cardiovascular complications of acquired
immunodeficiency syndrome.
AB - Patients with acquired immunodeficiency syndrome frequently develop complications
of cardiac, pericardial, and thoracic vascular origin. The purpose of this
pictorial essay is to review the most common etiologic and diagnostic imaging
findings of these diseases. Patients with acquired immunodeficiency syndrome
often demonstrate enlargement of the cardiac silhouette on the chest radiograph.
While the cause of this finding may be clinically evident, the authors share
cases in which chest computed tomography, echocardiography, and nuclear medicine
studies better reveal the nature of underlying cardiac and pericardial
abnormalities. Thoracic vascular complications, including pulmonary hypertension,
pulmonary thromboembolism, and the sequelae of indwelling venous catheters, are
also addressed.
PMID- 9556289
TI - Segmental pulmonary arteries: two-dimensional and three-dimensional time-of
flight magnetic resonance angiography.
AB - The authors compared two-dimensional (2D) and three-dimensional (3D) time-of
flight (TOF) magnetic resonance angiography in ten healthy volunteers to
establish which of two techniques is more effective in representing the pulmonary
segmental arteries. No respiratory trigger or electrocardiogram gating was used.
Presaturation pulses were used to eliminate venous flow. Images acquired in the
sagittal planes were processed using maximum intensity projection. A total of 200
segmental arteries were evaluated with each technique by three observers (M.S.,
C.S., A.R.) in terms of vessel visibility. There was no significant difference
among the observers' interpretations (p > 0.05). On average, 2D fast, low-angle
shot breath-hold TOF sequences showed 136.1 of 200 (68%) segmental arteries, 74.1
of 100 in the right lung and 62 of 100 in the left lung. Three-dimensional fast
imaging with steady state precession showed 171.6 of 200 (85.8%) segmental
arteries, 94 of 100 in the left lung and 77.6 of 100 in the left lung. Three
dimensional imaging appeared to be better than 2D MRA for demonstration of
segmental pulmonary arteries.
PMID- 9556287
TI - Expandable metallic stents in benign tracheobronchial obstruction.
AB - Expandable metallic stents offer advantages over previously available techniques
for treating benign tracheobronchial stenosis or obstruction. Endoluminal stent
placement offers a rapid and effective means of opening up narrowed airways, and
results in excellent relief of symptoms and improvement in pulmonary function.
Because they are delivered in a nonexpanded state using flexible over-wire
systems, they can be placed using a flexible bronchoscope and can be located in
second-order bronchial branches. Metallic stents have been used to treat benign
airway obstruction caused by anastomotic narrowing after lung transplantation,
infection, congenital lesions, tracheobronchial malacia, inflammatory conditions
including relapsing polychondritis, Wegener granulomatosis, and acquired
immunodeficiency syndrome, and external compression from benign mediastinal
masses or fibrosis. The stents become epithelialized, which prevents migration
and permits ciliary activity to continue. Significant complications can occur,
including airway inflammation, stent migration, airway erosion, and stent
fracture and collapse, but more serious complications are uncommon. Computed
tomography is essential in imaging patients being considered for stent placement,
as it allows 1) accurate representation of airway anatomy in three dimensions. 2)
measurement of airway diameter, 3) evaluation of airway anatomy distal to a
narrowed segment and invisible to bronchoscopy, 4) demonstration of dynamic
changes in airway morphologic features during forced exhalation in patients with
airway malacia, and 5) demonstration of focal or diffuse air trapping in lung
peripheral to the abnormal airway. In patients who have had stent placement,
computed tomography is valuable in assessing airway morphologic features and
dynamics distal to the stent, and can be valuable in assessing stent dysfunction.
PMID- 9556290
TI - Thoracic manifestations of sickle cell disease.
AB - Sickle cell disease is the most common inherited disease in the African American
population. Multiorgan pathologic features with a predilection for thoracic
organs predominate. Acute cardiopulmonary diseases include acute chest syndrome,
pneumonia, and left ventricular failure. Cardiomegaly, pleural effusions,
pulmonary consolidation, pulmonary edema on chest radiographs, and ground-glass
opacities on computed tomographs are characteristic. Chronic changes include
sickle cell lung disease with lung fibrosis, pulmonary arterial hypertension,
hyperkinetic circulation related to severe anemia, and thoracic skeletal
abnormalities; the latter are H-shaped vertebrae, rib infarction, and
extramedullary hematopoesis.
PMID- 9556291
TI - Assessment of air trapping using postexpiratory high-resolution computed
tomography.
AB - The authors assess the utility of postexpiratory high-resolution computed
tomography (HRCT) scans in the evaluation of air trapping in patients with
obstructive lung disease. Thirteen healthy volunteers and 14 patients with
obstructive lung disease (OLD) were examined using inspiratory and postexpiratory
HRCT scans. All had pulmonary function tests. Lung attenuation was measured on
both inspiration and expiration, and the extent of air trapping on postexpiratory
scans was visually assessed. The results of the healthy volunteers were compared
with those of patients with OLD, and HRCT findings were correlated with pulmonary
function tests. Lung attenuation on expiration, its change from inspiration to
expiration, and air-trapping scores of patients with OLD were significantly
different from those of the healthy volunteers. When the healthy participants and
patients with OLD were combined and analyzed as one group, the lung attenuation
change and air-trapping score both significantly correlated with pulmonary
function tests (p < 0.001) and correlation values were similar (r = 0.61-0.89).
Air trapping was found in 61% of healthy participants and all the patients with
OLD, although the extent was significantly greater in the patients with OLD.
Inspiratory and postexpiratory HRCT can be used to evaluate air trapping in
patients with OLD. Measurements of lung attenuation and estimates of air-trapping
extent are both valuable methods of analysis.
PMID- 9556292
TI - Muscular hypertrophy of the left diaphragmatic crus: an unusual cause of a
paraspinal "mass".
AB - We present a case of marked muscular hypertrophy of the muscular portion of the
diaphragm and of the diaphragmatic crura in a professional opera singer. In this
case the right and left crus each measured 20 mm in maximum thickness. The left
crus, by nature of its vertical orientation in the sagittal plane, produced
marked deviation of the inferior left paraspinal line near the diaphragm
mimicking a retrocrural or paraspinal mass on the posteroanterior chest
radiograph. The correct diagnosis was made by computed tomography. Muscular
hypertrophy of the diaphragmatic crura should be included in the differential
diagnosis of retrocrural or paraspinal masses at the level of the diaphragm.
PMID- 9556293
TI - Fetal gender impact on multiple-marker screening results.
AB - Maternal serum alpha-fetoprotein (MSAFP), human chorionic gonadotropin (hCG), and
unconjugated estriol (uE3) are used in combination with maternal age to calculate
the risk for Down syndrome (DS) in pregnancy. Increased levels of hCG and
decreased levels of MSAFP and uE3 are consistent with an increased risk for DS.
We retrospectively evaluated second-trimester maternal serum marker levels in a
large cohort of patients with known normal outcomes and documented fetal gender.
These included 15,428 patients who had MSAFP measurements, 11,428 patients with
both MSAFP and hCG, and 6,090 patients with all three markers including uE3.
MSAFP levels in patients with female fetuses were consistently lower than those
with males. Conversely, hCG was higher in pregnancies with females as compared to
males. No gender-related difference was noted for uE3. These results would
suggest that the computed DS risk for female fetuses is higher than for males,
despite the fact that the incidence of DS is similar in both genders. This
information could be useful for calculating gender-specific DS risk; however,
this would require ultrasonographic determination of fetal sex.
PMID- 9556294
TI - Chromosome 18q paracentric inversion in a family with mental retardation and
hearing loss.
AB - We report on a mother and child with a paracentric inversion of the long arm of
chromosome 18: 46,XX,inv(18)(q21.1q23). The child had findings in common with
those seen in 18q- syndrome including: microcephaly, epicanthal folds, midface
hypoplasia, and abnormally modeled ears, dermatoglyphic whorls on fingertips,
clubfeet, hearing loss, and developmental delay. The mother and several maternal
relatives had mild mental retardation and hearing loss. Magnetic resonance
imaging of the child's brain showed abnormal myelination. Molecular studies
including PCR-based markers for the MBP locus and fluorescent in situ
hybridization with a P1 genomic clone on mother and child demonstrated only one
copy of the MBP locus (18q23) with the deletion extending beyond the MBP locus.
Therefore, the deletion in the MBP region may account for the abnormal
myelination seen in the patient. The other clinical findings, including mental
retardation and hearing loss in this family, may reflect disruption of distal or
proximal genes within the deleted MBP region or at the more proximal breakpoint
18q21.1, and may represent a contiguous gene syndrome. Further study of this
family may help define those genes functioning in the MBP region that contribute
to the phenotype of 18q- syndrome.
PMID- 9556295
TI - Identification of a mutation in the low density lipoprotein receptor gene
associated with recessive familial hypercholesterolemia in swine.
AB - Elevated blood plasma cholesterol (hypercholesterolemia) is a major risk factor
for coronary artery disease (CAD) in humans. Genetic dissection of polygenic
lipid and lipoprotein disorders in swine, a key animal model for the study of
familial hypercholesterolemia (FH) and CAD, led to the isolation of a monogenic
subphenotype (FH-r), that is inherited in the recessive (r) manner. A genome scan
mapped the FH-r locus close to the centromere of chromosome 2. Comparative
mapping showed that this region shares homology with a part of human chromosome
19 that harbors the low density lipoprotein receptor (LDLR) locus, and therefore
suggested LDLR as the prime candidate gene for FH-r. Cloning and sequencing of
hepatic LDLR cDNA from two FH-r/r and one normal (N/N) animals disclosed a single
missense mutation (R84C) in a region that corresponds to human exon 4. The C84
mutation cosegregates invariantly with hypercholesterolemia, which strongly
suggests that this mutation is responsible for the observed hyperlipidemia.
PMID- 9556296
TI - Cohen syndrome with high urinary excretion of hyaluronic acid.
AB - Cohen syndrome (MIM 216550) is an autosomal recessive disorder of unknown
pathogenesis. The clinical manifestations of Cohen syndrome can be explained as a
connective tissue disorder. We found a remarkably high level of urinary
hyaluronic acid in 3 patients with Cohen syndrome. Hyperhyaluronic aciduria is a
characteristic finding in Werner syndrome and some other conditions. We suggest
that the basic defect of Cohen syndrome is associated with a metabolic
abnormality in the extracellular matrix.
PMID- 9556297
TI - Unclassified sclerosing bone dysplasia with osteopathia striata, cranial
sclerosis, metaphyseal undermodeling, and bone fragility.
AB - Sclerosing bone dysplasias are diagnosed on the basis of a characteristic pattern
of osteosclerosis and clinical manifestations; in many of them, cause and
pathogenesis are still unknown. A 33-year-old man had five fractures of the
humerus, tibiae, and femur as a result of mild traumatic incidents that occurred
between the ages of 18 and 33 years as well as a remnant of rib fractures without
apparent trauma on radiographs. His height was 158 cm (-2.2 SD). Radiographic
evaluation showed cranial sclerosis, longitudinal striations in the metaphyses of
the femur and tibia, fan-like striation in the ilium, metaphyseal widening in the
femur and tibia, and sclerosis of the ribs. The blood chemistry findings,
including serum calcium, phosphorus, and alkaline phosphatase, were normal.
Biopsy from the ilium showed thick trabeculae composed of woven bone. The
coexistence of osteopathia striata, cranial sclerosis, metaphyseal undermodeling,
and bone fragility has not been recognized previously. Our case appears to
represent a new form of sclerosing bone dysplasia.
PMID- 9556298
TI - Autosomal-dominant branchio-otic (BO) syndrome is not allelic to the branchio-oto
renal (BOR) gene at 8q13.
AB - The manifestations of branchio-oto-renal syndrome (BOR), Treacher Collins
syndrome, tricho-rhino-phalangeal syndrome, van der Woude syndrome, and Langer
Giedion syndrome are well-defined; these conditions represent clinically and
genetically separate syndromes. Autosomal-dominant branchio-oto-renal syndrome
comprises preauricular pits, branchial fistulas, hearing loss, and renal
anomalies. However, several families have been described without one or more of
these clinical findings. In some families, the phenotypic expression is limited
to branchial anomalies, preauricular pits, and hearing loss, with no renal
dysplasia (branchio-otic or BO syndrome). In other families, branchial and renal
anomalies occur without hearing impairment. It is not known whether the variable
clinical manifestations are due to the effect of a single gene or whether these
represent different syndromes. We investigated BO syndrome in a large family to
determine whether BOR and BO syndromes are allelic to each other. The genetic
linkage analysis provides evidence that BO syndrome is not allelic to the BOR
gene at 8q13.
PMID- 9556299
TI - CHARGE syndrome: report of 47 cases and review.
AB - The acronym CHARGE refers to a syndrome of unknown cause. Here we report on 47
CHARGE patients evaluated for the frequency of major anomalies, namely coloboma
(79%), heart malformation (85%), choanal atresia (57%), growth and/or mental
retardation (100%), genital anomalies (34%), ear anomalies (91%), and/or deafness
(62%). In addition, we comment on anomalies observed very frequently in neonates
and infants with the CHARGE syndrome, including, minor facial anomalies, neonatal
brain stem dysfunction with cranial nerve palsy, and, mostly, internal ear
anomalies such as semicircular canal hypoplasia that were found in each patient
that could be tested. We propose several criteria for poor survival including
male gender, central nervous system and/or oesophageal malformations, and
bilateral choanal atresia. No predictive factor regarding developmental prognosis
could be identified in our series. A significantly higher mean paternal age at
conception together with concordance in monozygotic twins and the existence of
rare familial cases support the role of genetic factors such as de novo mutation
of a dominant gene or subtle sub-microscopic chromosome rearrangement. Finally,
the combination of malformations in CHARGE syndrome strongly supports the view
that this multiple congenital anomalies/mental retardation syndrome is a
polytopic developmental field defect involving the neural tube and the neural
crests cells.
PMID- 9556300
TI - Spondylometaphyseal dysplasia-Sedaghatian type.
AB - We present the radiological findings in two unrelated cases with
spondylometaphyseal dysplasia type Sedaghatian. We review the literature and
identify additional anomalies including disproportionately long fibulae,
dysharmonious maturation and turricephaly.
PMID- 9556301
TI - Incidence of X-linked adrenoleukodystrophy and the relative frequency of its
phenotypes.
PMID- 9556302
TI - X-linked adrenoleukodystrophy: the Australasian experience.
AB - Our objective was to review the Australasian experience of X-linked
adrenoleukodystrophy (ALD), to compare the spectrum of disease seen in
Australasia with previously published data from elsewhere, and to assess the
reliability of carrier testing. Study design was a retrospective review of
records collected over a 15-year period, the setting was an international
referral laboratory for the study of metabolic disease, and the subjects were all
known cases of ALD diagnosed in Australia and New Zealand between 1981 and 1996
and their families. We estimate that the combined incidence of ALD and its
variants in Australasia is at least 1.6 per 100,000. Of 95 affected males, 51 had
cerebral adrenoleukodystrophy, 24 had adrenomyeloneuropathy, 15 had Addison's
disease only, and 5 remained asymptomatic when last examined. However, the
distribution of phenotypes among newly diagnosed patients has changed
substantially over the last 15 years, with cerebral forms of the disease forming
a decreasing proportion of new diagnoses. The measurement of plasma very long
chain fatty acids (VLCFAs) alone detects 93% of women who can be proven to be
carriers. The addition of genetic linkage studies or assay of VLCFAs in cultured
fibroblasts improved this detection rate to the point that there were no obligate
carriers who could not be detected using a combination of two or more techniques.
PMID- 9556303
TI - X-linked adrenoleukodystrophy: phenotype distribution and expression of ALDP in
Spanish kindreds.
AB - X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder caused by
an impairment in peroxisomal beta-oxidation of very long straight-chain fatty
acids (VLCFAs). Six clinical phenotypes have been delineated: childhood cerebral
(CCALD), adolescent cerebral (AdolCALD), adult cerebral (ACALD),
adrenomyeloneuropathy (AMN), Addison-only (AO), and presymptomatic (PALD). The
distribution of phenotypes varies in different countries. We have diagnosed
biochemically 60 X-ALD Spanish patients belonging to 48 kindreds. Their
phenotypic distribution was: CCALD plus AdolCALD, 33%; ACALD, 16%; AMN, 27%; AO,
12%; and PALD, 12%. These results contrast with the distribution described in
other countries, due to a higher prevalence of the ACALD form. Regarding the
expression of the protein product (ALDP), we studied 17 kindreds using
immunochemical techniques and found absence of ALDP in 84% of cases. We also
studied 13 females from 7 negative ALDP kindreds in order to correlate ALDP
expression and the carrier status established by VLCFA measurement. In one case
with normal VLCFA levels in serum and fibroblasts, we observed mosaicism in ALDP
expression. This fact supports the use of this technique for identifying
carriers.
PMID- 9556304
TI - A multivariate logistic model (MLM) for analyzing binary family data.
AB - We consider modeling the familial correlation between 2 related individuals using
a multiple logistic regressive model. It is shown that there is a discrepancy in
the marginal probability of the second individual. We investigate the conditions
under which this discrepancy can be minimized and show how it can have a direct
effect on handling missing values and ascertainment. We derive a functional
relationship between the parameters in the model that eliminates this
discrepancy, hence solving the problems that can arise in the handling of missing
values and ascertainment. Because this methodology fails when there are more than
2 related individuals, we present a new model based on a multivariate logistic
distribution. Residual familial correlations can be directly related to the
parameters of this model. The likelihood for family data under this model is
independent of the order in which the family members enter the calculation. The
marginal probabilities can be easily computed.
PMID- 9556305
TI - Founder effect in GLC1A-linked familial open-angle glaucoma in Northern France.
AB - Open-angle glaucoma (POAG) is a highly prevalent cause of visual impairment. Six
families grouping 71 living patients affected with juvenile-onset and middle-age
POAG (age at diagnosis ranging from 10 to 65 years) were linked to the GLC1A
locus. All patients carried a mutation of an evolutionarily conserved asparagine
residue to a lysine at position 480 (N480K) in the olfactomedin-homology domain,
which is encoded by the third exon of the GLC1A gene. The N480K mutation was also
identified in 14 unaffected carriers who are at high risk of developing POAG.
Although four of the families had ancestors identified in Northern France, the
pedigrees could not be interconnected by genealogical investigation. However,
haplotype analysis indicated that all the carriers had inherited the N480K
mutation from the same founder. Screening of a selected set of 67 POAG patients
who originated from Northern France and underwent trabeculectomy before the age
of 50, detected one patient with the N480K mutation associated with the same
disease haplotype already characterized in the 6 families. This group of 72 POAG
patients is the largest one having a GLC1A mutation in common and provides a
unique tool to investigate the factors influencing the variable expressivity of
the GLC1A gene.
PMID- 9556306
TI - Pulmonary agenesis: importance of detailed cytogenetic studies.
PMID- 9556307
TI - Mosaic trisomy 22: a case presentation and literature review of trisomy 22
phenotypes.
PMID- 9556308
TI - Acceleration of partial-thickness burn wound healing with topical application of
heparin-binding EGF-like growth factor (HB-EGF).
AB - Heparin-binding EGF-like growth factor has been identified in human burn-wound
fluid and in the epithelial cells of excised human partial-thickness burns. In
the present study, the effect of heparin-binding EGF-like growth factor on burn
wound healing was evaluated by incorporating purified, recombinant heparin
binding EGF-like growth factor into slow-release cholesterol-lecithin pellets
that were applied topically to partial-thickness burns in mice. Both experimental
(heparin-binding EGF-like growth factor-treated) and control (untreated) mice
were sacrificed on days 3, 5, and 10 after burn. Total burn-wound area,
histology, keratinocyte proliferation, and in situ hybridization analysis for
transforming growth factor-alpha were determined for each wound. The mean wound
area of the experimental group on day 5 after burn was 1.07 cm2, compared with
2.20 cm2 for controls (p=0.04). Cellular proliferation (as measured by
immunohistochemical detection of 5-Bromo-2-deoxyuridine) on day 5 after burn in
marginal keratinocytes and follicular epithelial cells was greater in the
experimental group than in the control group. In situ hybridization showed up
regulation of transforming growth factor-alpha mRNA levels in experimental
animals by day 5 after burn. Topical application of heparin-binding EGF-like
growth factor significantly accelerates the reepithelialization of murine partial
thickness burns, increases keratinocyte proliferative activity, and enhances
production of endogenous transforming growth factor-alpha mRNA.
PMID- 9556310
TI - Calorigenic response of burned rats with adrenal medullectomies to
catecholamines.
AB - In previous studies, we established that circulating epinephrine (E) is not
essential for a normal hypermetabolic response to burn injury in the rat, within
the zone of thermal neutrality. In other studies, burned rats with adrenal
medullectomy (AdxB) studied at 22 degrees C were unable to maintain rectal
temperature (TR) after alpha-adrenergic blockage. These data suggest that
norepinephrine (NE) is calorigenic in such animals without formal cold
acclimation. These studies investigate the hypothesis that, contrary to the usual
belief, norepinephrine might be calorigenic in rats without formal cold
acclimation. Burned (B) and control (C) rats with adrenal medullectomies (Adx)
and Sham (S) Adx (AdxB, SAdxB, AdxC, and SAdxC) were housed at either 22 degrees
C or 28 degrees C. Calorimetry was performed during the eighth to eleventh days
after the burn. For groups housed at 22 degrees C and studied at 28 degrees C, NE
given intravenously (iv) produced an average 16.5%+/-3.3% increment in heat
production (HP) for the four groups, which was significant for AdxB, SAdxB, and
SAdxC. Intravenous administration of E produced an average increment in HP of
4.44%+/-4.1%, which was not significant. HP was significantly higher after NE
than E in three cases. Studies with animals housed at 28 degrees C and studied at
28 degrees C produced intermediate but similar results. For groups housed at 28
degrees C and studied at 22 degrees C, iv administration of E and NE produced
average decreases in He of 18%+/-6.7% for E and 10.75%+/-4.7% for NE. Except for
the AdxC group, these differences were significant. These data suggest that
chronic exposure to an ambient temperature of 22 degrees C produces an enhanced
calorigenic response to NE in burn and control rats. Based on the data presented
here, combined with earlier studies, NE must be considered as a facilitator for
hypermetabolic response to burn injury in the rat. It is interesting to speculate
whether NE is calorigenic for patients with large burn wounds, which are managed
without dressings at ambient temperatures below thermal neutrality.
PMID- 9556309
TI - Efficacy of a rise in C-reactive protein serum levels as an early indicator of
sepsis in burned children.
AB - C-Reactive protein serum levels were measured in 57 pediatric patients with 3% to
92% total body surface area burns to determine whether a defined rise in C
reactive protein serum levels could indicate sepsis earlier in burn patients. A
rise in C-reactive protein serum levels was defined as an increase of at least 3
mg/dL for 2 days or 10 mg for 1 day. Increases the first 2 days after the burn or
the day after surgery were excluded, since these injuries increase C-reactive
protein serum levels. Patients were defined as septic when they were on systemic
antibiotics and exhibited at least two of 16 specific clinical parameters. C
Reactive protein serum levels correctly predicted sepsis 82% of the time
(efficiency=82%). Nonseptic patients generally did not show increased C-reactive
protein serum levels (specificity=69%). When sepsis did occur, it always was
preceded by increased C-reactive protein (sensitivity=100%), and the increased C
reactive protein occurred 2.3+/-0.5 days before the patient was deemed septic
clinically. Hence, a defined rise in C-reactive protein serum levels can predict
sepsis sooner in burned children.
PMID- 9556311
TI - Treatment of the seriously burned infant.
AB - Infants (younger than 12 months) with large (more than 30%) burns are reported to
have poorer chances for survival than older children with similar injuries.
However, recent experience with such infants has been positive, prompting a 5
year review of management techniques. The injuries were approached in an
organized fashion that included precise fluid support, excision, and biologic
closure of full-thickness wounds within 5 days, limited exposure to high
inflating pressures (more than 40 cm H2O), weekly replacement of central venous
catheters, and intensive nutritional support via the enteral route whenever
possible. Twelve such infants were treated during the 5-year interval. Their
average age was 7.8 months (range, 1 to 12 month[s]), average weight was 8.8 kg
(range, 4.3 to 13 kg), and average burn size was 42% (range, 30% to 90%).
Inhalation injury was present in two of the children, and one child aspirated hot
liquid. Six (50%) of the infants required the support of a mechanical ventilator
for an average of 11.6 days (range, 4 to 18 days). Eight children required an
average of 5.7 operations (range, 1 to 18 operation[s]), seven required central
venous catheters, and five required arterial cannulae. Major infectious
complications were seen in four children. Complications included pneumonia (two),
catheter sepsis (two), peritonitis from a perforated ulcer (one), and wound
sepsis (two). Six children required parenteral nutritional support for an average
of 15 days (range, 5 to 36 days), and six children required enteral tube feedings
for an average of 23 days (range, 9 to 55 days). Anabolic agents were not used.
Discharge weights averaged 8.6 kg (range, 4.9 to 10.5 kg). The average ratio of
the children's discharge to admission weight was 101% (range, 73% to 120%). All
children survived and were discharged home. We conclude that these difficult
injuries can be approached successfully with a strategy that emphasizes precise
fluid repletion; early excision and biologic closure of wounds; avoidance of
ventilator-induced lung injury; and intensive nutritional support.
PMID- 9556312
TI - Purpura fulminans: a disease best managed in a burn center.
AB - Victims of purpura fulminans are overcome by a rapidly progressive and sometimes
fatal course involving large amounts of tissue loss and multiple organ system
failure. From 1986 to 1995, seven children ranging in age from 10 months to 19
years (mean, 6.2 years) were referred to the Shriners Burns Institute in
Cincinnati with purpura fulminans. Neisseria meningitidis was identified as the
precipitating pathogen in most of the patients. The mean TBSA full-thickness skin
loss was 33%. Fourteen extremities were amputated in the seven patients,
including three patients with amputations of all four extremities. Transfer to
our institution occurred after a mean delay of 20 days, usually after the
demarcation of viable tissue. In one patient, however, fasciotomies obviated
multiple impending amputations. Monitoring for elevated compartment pressures,
early fasciotomies, and expedient transfer to a burn center for a
multidiciplinary approach to care should improve the outcome in patients with
purpura fulminans.
PMID- 9556313
TI - Children with sensorimotor deficits: a special risk group.
AB - Children with spina bifida, cerebral palsy, mental retardation, developmental
delays, and seizure states are handicapped with sensorimotor deficits, including
gait or coordination instability, temperature insensitivity, and mental
simplicity. These handicaps make this distinct and unpretentious population more
susceptible to lethal burns. A 30-year review was conducted in a pediatric burn
center to examine the relationships between pediatric sensorimotor deficit and
burn injury. Of the 4874 acute burn admissions, 66 children were identified with
preexisting sensorimotor deficits. Data indicate that children with sensorimotor
deficit are more prone to burn injury from both their physical impairment and
poorly supervised environments. In addition to extended hospitalizations, these
children bear significantly higher mortality risks. Had the special supervisions
and protection required by such handicapped children been provided, 80% of the
burn injuries could have been prevented. Results emphasize that the future of
these special children with sensorimotor deficits relies on health care providers
playing a greater role in educating parents and caregivers.
PMID- 9556314
TI - Hot-press hand burn treatment.
AB - Hand injuries are common in the workplace. Modern industrial machines cause
complex occupational hand injuries. Hot-press contact hand burns generally are
encountered by workers in the dry-cleaning industry. Seventeen patients with hot
press hand burns were treated at the University of California-Irvine Medical
Center Burn Center. Eight patients (47%) required skin grafting, seven (41%) were
treated with hydrotherapy only, and two (12%) needed flaps. These results were
not what we expected.
PMID- 9556315
TI - Extracorporeal membrane oxygenation in the treatment of respiratory failure in
pediatric patients with burns.
AB - Extracorporeal membrane oxygenation (ECMO) as a treatment for pulmonary failure
from postshock respiratory distress in burned children recently has been shown to
salvage patients who were thought to have more than a 90% chance of dying. We
describe five burned children in whom severe respiratory failure--not responsive
to medical management and maximal ventilatory support--developed, and who
underwent ECMO treatment. Three (60%) cases involved flame burns, with
significant inhalation injury as diagnosed after a bronchoscopy; mean age was 3
years (2 to 4 years), with a mean total body surface area (TBSA) burn of 32% (15%
to 53%), mean third-degree burns of 25% (5% to 53%). Two (40%) cases involved
scald burns; mean age was 6 years (7 months to 11 years), with a mean TBSA burn
of 56.5% (43% to 70%), mean third-degree burns of 40% (10.5% to 70%). Outcome was
poor for those burned children who received ECMO therapy after prolonged
ventilatory support for smoke inhalation injury. Children who experience
perfusion/reperfusion shock injury to the lungs as a result of delayed
resuscitation of scald burns may have an improved chance of survival with short
courses of ECMO regardless of the burn size.
PMID- 9556316
TI - Hemolytic uremic syndrome in a child with burn injuries.
AB - We report the first case of hemolytic uremic syndrome in a patient with burns. An
unusual case of the syndrome developed in a 1-year-old black girl hospitalized
after second-degree burns to 33% of her total body surface area. Acute abdominal
distention, hemolytic anemia, hematuria, and oliguric renal failure developed 1
week after admission to the burn unit. Blood cultures grew Escherichia coli
O157:H7. She received supportive care and antibiotics, in addition to low-dose
dopamine, which promptly reversed the oliguria. Dialysis was not required, and
the child made a complete recovery.
PMID- 9556318
TI - Continuous infusion of epidural morphine in frostbite.
AB - After frostbite injury, the phases of rewarming and progressive injury may cause
intense pain for the patient. Although parenteral narcotic agents are the usual
method of pain relief, they have well-described adverse effects such as heavy
sedation, respiratory depression, and nausea and vomiting. In frostbite injury of
the lower extremities, epidural blockade has the potential to provide good pain
relief with fewer of those complications. However, the associated sympathetic
blockade is believed by many clinicians to be of no benefit and by some to be
potentially harmful. Epidural narcotics have the selective advantage of providing
analgesia without sympathetic blockade. In this case report, the use of
continuous epidural morphine during the first 24 hours after severe bilateral
frostbite injury to the feet is described. The technique provided effective pain
control, and no complications occurred. To our knowledge, use of continuous
epidural morphine after frostbite injury has not been reported previously.
Further use of this technique will be required to clarify its efficacy.
PMID- 9556317
TI - HIV seropositivity in a burn center's population.
AB - HIV infection in a patient with burn injuries complicates the care of both the
patient and the treating burn team. In the patient, HIV slows wound healing and
increases the complications seen with burns. For the treating team, HIV is a
hazard that infects the large volume of bodily fluids to which the burn team is
potentially exposed. At Saint Francis Memorial Hospital, a team of plastic
surgeons, infectious disease specialists, medical internists, psychiatrists,
social workers, and nurses was established for the care of patients with burn
injuries who have HIV. To ascertain the baseline need for this specialized care,
we interviewed 103 consecutive patients admitted to the Bothin Burn Center. Those
found to be positive by history (3 of 103) were excluded from HIV testing. Of the
remaining 100 consecutive patients, all consented to HIV testing. None of these
patients, even those with known risk factors, was found to have undiagnosed HIV
positivity. We conclude the occult incidence in the population tested is lower
than expected, and continued testing is warranted.
PMID- 9556319
TI - Proceedings of the physical and occupational therapy special interest group
meeting.
AB - At the 1997 American Burn Association meeting in New York City the Physical
Therapy/ Occupational Therapy (PT/OT) Special Interest Group met and discussed
five pertinent topics that affect therapists. A summary of the information was
received from the five discussion groups. This information is presented so that
the entire PT/OT membership can be kept informed and updated about the
information presented at this meeting. Moderators can be resources for more in
depth information regarding these topics.
PMID- 9556320
TI - Burn pain management: a guideline-based approach.
AB - The pain associated with burn injury and treatment often is managed poorly. The
purpose of this article is to describe available pain-management guidelines and
to explain how burn pain can be enhanced by using a guideline-based approach.
Data from a retrospective audit are used to highlight several of the common
causes of pain mismanagement: including inadequate pain assessment, analgesic
knowledge deficits, and incomplete documentation. Key recommendations from the
Agency for Health Care Policy and Research's Acute Pain Management Guidelines are
highlighted. Guideline-based suggestions from these and other guidelines are
presented as a basis for burn pain management-guideline development. Guidelines
for burn-pain management must be broad in scope to allow for variations in
analgesic needs across all patient populations and phases of burn recovery.
Guidelines are necessary because studies show that information and education
alone have little effect on the quality of pain management. What is effective are
guideline-based initiatives that make pain visible and care providers
accountable.
PMID- 9556321
TI - Increased protein intake during the recovery phase after severe burns increases
body weight gain and muscle function.
AB - We determined the effect of protein intake on weight gain and muscle function in
the recovery phase after severe burns. Fifteen patients with deep burns between
30% to 50% of total body surface were studied over a 3 week period-after
resolution of the hypermetabolic, catabolic state. All patients were studied in
an acute rehabilitation hospital affiliated with the burn center. Nutritional
profiles; weight gain; and muscle strength, measured by a physical therapy index
(0 to 10)--10 being the greatest progress-were measured. All patients were
provided a high-calorie, high-protein diet. Group 1 patients (n=8) also were
provided a standard nutrient supplement to maintain caloric intake at 30 to 35
kcal/kg/day and to maintain protein intake at 1.3 to 1.5 g/kg/day. Group 2
patients (n=7) were provided a high-calorie, high-protein diet plus a protein
hydrolysate (70 g/day) that provided a protein intake of 1.7 to 2 g/kg/day. Group
1 patients averaged a 1 to 1.5 pound weight gain per week or four pounds during
three weeks. Their physical therapy index at three weeks of 4+/-0.5 indicated
adequate improvement in strength and endurance. Group 2 patients averaged 2.5 to
3 pounds weight gain per week or 8.5 pounds during three weeks. Their physical
therapy index of 7+/-0.7 indicated marked gains in muscle strength. Both
measurements were significantly higher than those of Group 1. We conclude that
increased protein intake by means of adding a protein hydrolysate increases the
rate of restoration of body weight and muscle function.
PMID- 9556322
TI - Rehabilitation challenges for burn survivors with residual disfigurement:
promising directions for intervention, research, and collaboration.
PMID- 9556323
TI - Changing Faces: Taking up Macgregor's challenge.
AB - I had the good fortune to initially present the thoughts written here at the
Psychosocial Interest Group of the American Burn Association Annual Meeting in
New York City in 1997. The paper begins with a personal introduction and proceeds
to describe how Frances Cooke Macgregor's work inspired my colleagues and myself
to develop a series of programs to address the rehabilitation challenges inherent
in living with any kind of facial disfigurement. It is our sincere hope that the
programs developed by our organization, Changing Faces (based in the United
Kingdom) will contribute to the rehabilitation of people living with
disfigurement throughout the world. We especially look forward to learning how
what we have learned can be adapted to and disseminated in the United States as
we establish collaborative relationships with the dedicated group of burn
professionals there.
PMID- 9556324
TI - Silipos neck wraps.
AB - Burns of the neck are a problem. Grafted anterior necks can result in disfiguring
hypertrophic scar contractures and wrinkling of the graft. The development of
contractures can be prevented by effective splinting as soon as possible after
the burn and by following a continuous wearing schedule until scar maturation is
complete. Traditional neck conformers do not allow free neck rotation and can
lead to stiffness as a result of decreased mobility. We used Silipos neck wraps
for 10 patients who had good range of motion in the neck and who required
pressure only for flattening of grafts and wrinkle prevention. The neck wrap is
user-friendly, low in cost, and easy to fabricate and custom-fit for individual
patients.
PMID- 9556325
TI - Reliability of photographic analysis in determining change in scar appearance.
AB - Photographs frequently are used to document change in the management of
hypertrophic scars. The purpose of this study was to design a scale for the
analysis of photographs of hypertrophic scars and to test its reliability. The
subjects were four occupational and physical therapists, (two novices and two
experts), in scar management. Existing scales were modified to produce a new
scale. The subjects twice rated four slides from each of ten patients' scars, in
random order. They used a Latin Square design. Interrater and test-retest
reliabilities were calculated using a weighted kappa statistic. The newly
developed scale demonstrated interrater reliability, which ranged between 0.66
and 0.90 for all items. The test-retest reliability ranged between 0.73 and 0.89
for all items. The new scale had substantial reliability (using a single rater)
and was at least as reliable when used by novice therapists. This indicated that
training had no effect.
PMID- 9556326
TI - Incorrect comparison relating test MICs and clear zone diameter by use of NAWD.
PMID- 9556327
TI - Functions of motor proteins in echinoderm embryos: an argument in support of
antibody inhibition experiments.
AB - Antibody inhibition experiments are proving to be extremely valuable in probing
the in vivo functions of actin- and microtubule-based motor proteins in the early
development of echinoderm embryos, despite some skepticism among many cell
biologists concerning the reliability of this approach. Antibody inhibition has
revealed that motor proteins participate in diverse events during early
echinoderm development, including mitosis, cytokinesis, the transport of
exocytotic vesicles, and the assembly of motile cilia.
PMID- 9556328
TI - Dynein and dynein-related genes.
AB - Dyneins are large, multisubunit ATPases that interact with microtubules to
generate force. Dyneins move eukaryotic cilia and flagella and are in the
cytoplasm, where they are involved in the transport of particles and organelles
along microtubules and in the transport of condensed chromosomes during mitosis
[reviewed in Holzbaur et al., 1994; Gibbons, 1996]. Defects in human axonemal
dynein complexes have been shown to be associated with Kartagener's syndrome,
which is characterized by recurrent respiratory tract infections, immotile sperm
and situs inversus. Cytoplasmic and axonemal dyneins are composed of heavy,
intermediate, and light chains. The best characterised groups of dynein genes so
far are those encoding cytoplasmic heavy chains and heavy chains from the outer
arms from axonemes. These share extensive sequence similarity and are conserved
throughout species. Recently, several genes encoding intermediate and light
chains have been identified; these have encoded a remarkable diversity of
products, which also seem to be highly conserved between species, although they
fall into several complex groups. The structure of dynein heavy chain genes, the
emerging knowledge on intermediate and light chain genes and their products, and
the possible involvement of dyneins in disease are discussed.
PMID- 9556329
TI - Depletion of a Drosophila homolog of yeast Sup35p disrupts spindle assembly,
chromosome segregation, and cytokinesis during male meiosis.
AB - In the course of a genetic screen for male-sterile mutations in Drosophila
affecting chromosome segregation during the meiotic divisions in spermatocytes,
we identified the mutation dsup35(63D). Examination of mutant testes showed that
chromosome misbehavior was a consequence of major disruptions in meiotic spindle
assembly. These perturbations included problems in aster formation, separation,
and migration around the nuclear envelope; aberrations in spindle organization
and integrity; and disappearance of the ana/telophase central spindle, which in
turn disrupts cytokinesis. The dsup35(63D) mutation is caused by a P element
insertion that affects, specifically in the testis, the expression of a gene
(dsup35) encoding the Drosophila homolog of the yeast Sup35p and Xenopus eRF3
proteins. These proteins are involved in the termination of polypeptide synthesis
on ribosomes, but previous studies have suggested that Sup35p and closely related
proteins of the same family also interact directly with microtubules. An affinity
purified antibody directed against the product of the dsup35 gene was prepared;
interestingly, this antibody specifically labels primary spermatocytes in one or
two discrete foci of unknown structure within the nucleoplasm. We discuss how
depletion of the dsup35 gene product in spermatocytes might lead to the global
disruptions in meiotic spindle assembly seen in mutant spermatocytes.
PMID- 9556330
TI - Structural and molecular characterization of dynein in a gall-midge insect having
motile sperm with only the outer arm.
AB - The dipteran Monarthropalpus flavus possesses a peculiar sperm axoneme,
characterized by multiple rows of microtubular doublets linked by the outer
dynein arms only, lacking any equivalent of the central pair/radial spoke
complex. The structure of these dynein molecules was studied by electron
microscopy (EM). Using the quick-freeze, deep-etch method of EM, they were found
to be similar to outer dynein arms described previously. Two globular "heads,"
each subdivided by a cleft, are clearly discernible. "Stalks" extend from
proximal head to contact the B-tubule of the adjacent doublet. Unlike the
situation in vertebrate sperm, the stalks sometimes branch into two thinner
strands that contact the B-tubule at different sites. Treatment of demembranated
sperm cells with ATP and vanadate induces conformational changes in the dynein
outer arms. These are interpreted as the result of rotation of the dynein head
with respect to what is observed in axonemes in rigor condition (after ATP
depletion). SDS-PAGE indicates that the high-molecular-weight complement of this
molecule comprises a single heavy chain. Specific dynein heavy chain-related DNA
sequences corresponding to the catalytic-phosphate binding region were amplified
by RT-PCR. Only one axonemal dynein sequence was identified among all amplified
fragments. Southern blot analysis performed on genomic DNA using this sequence as
a probe identified two hybridizing genes, only one of which is able to encode a
functional product. Thus, genetic analysis indicates that this axonemal outer arm
dynein is a homodymer of a single heavy chain subunit. In vivo, spermatozoa of
this species are stored in a rolled configuration in female spermatheca, where
they move rapidly with a wave-like motion. This movement could not be reproduced
in vitro, except when spermatozoa were constrained in a bent configuration by
some mechanical impediment. We propose that, in the absence of both the central
pair/radial spoke complex and the inner arms, a curvature-dependent activation
acts to trigger motility in these spermatozoa.
PMID- 9556331
TI - Tubulin polyglycylation in Platyhelminthes: diversity among stable microtubule
networks and very late occurrence during spermiogenesis.
AB - The distribution of glycylated tubulin has been analyzed in different populations
of stable microtubules in a digenean flatworm, Echinostoma caproni
(Platyhelminthes). Two cellular types, spermatozoa and ciliated excretory cells,
have been analyzed by means of immunofluorescence, immunogold, and immunoblotting
techniques using two monoclonal antibodies (mAbs), AXO 49, and TAP 952,
specifically directed against differently glycylated isoforms of tubulin. The
presence of glycylated tubulin in the two cell types was shown. However, the
differential reactivities of TAP 952 and AXO 49 mAbs with the two axoneme types
suggest a difference in their glycylation level. In addition, within a single
cell, the spermatozoon, cortical microtubules underlying the flagellar membrane,
and axonemal microtubules were shown to comprise different tubulin isoforms, the
latter ones only being labelled with one of the antiglycylated tubulin mAbs, TAP
952. Similarly, the antiacetylated (6-11B-1) and polyglutamylated (GT335) tubulin
mAbs decorated the two types of axonemal microtubules, but not the cortical ones.
From these data, a subcellular sorting of posttranslationally modified tubulin
isoforms within spermatozoa, on the one hand, and a cellular sorting of
glycylated isoforms inside the whole organism, on the other hand, is demonstrated
in the flatworm E. caproni. Last, a sequential occurrence of tubulin
posttranslational modifications was observed in the course of spermiogenesis.
Acetylation appears first, followed shortly by glutamylation; glycylation takes
place at the extreme end of spermiogenesis and, specifically, in a proximo-distal
process. Thus in agreement with, and extending other studies [Bre et al., 1996],
glycylation appears to close the sequence of posttranslational events occurring
in axonemal microtubules during spermiogenesis.
PMID- 9556332
TI - Derivation of insertin.
AB - Insertin is an actin-binding protein that has been isolated from chicken gizzard
smooth muscle that has been shown to be highly homologous to amino acids 962-1292
of tensin [Weigt et al., 1992]. Because of the high homology, we investigated the
question whether the mRNAs of insertin and of tensin are derived from the same
gene by alternative splicing, whether insertin and tensin are encoded by two
different genes, or whether insertin is a proteolytic fragment of tensin. In a
Northern blot analysis, mRNA from chicken gizzard was hybridized with
oligonucleotides specific for tensin and for the insertin domain of tensin. The
tensin-specific oligonucleotide hybridized only with the previously reported 8-
and 10-kbp RNAs. However, the insertin domain-specific oligonucleotide hybridized
with a 1.2 and a 1.6 kbp RNA in addition to the 8 and 10 kbp RNA. The 1.2- and
1.6-kbp RNA occurred in small amounts, as compared with the 8- and 10-kbp RNA.
Southern blot analysis of DNA cleaved by the restriction endonucleases BamH1 and
HindIII demonstrated that only one gene for the insertin and tensin exists.
Insertin isolated from chicken gizzard smooth muscle was investigated by mass
spectrometry. The N-termini of three isolated peptides were found to begin at
adjacent amino acids and were likely to be formed from tensin by proteolysis. The
results suggest that, for insertin, an mRNA exists that is derived from one gene
common for insertin and tensin. However, the insertin-specific mRNA contributes
relatively little to expression of insertin domains in cells. Insertin
preparations from chicken gizzard contain mainly insertin domains formed from
tensin by proteolysis.
PMID- 9556333
TI - Occurrence of fibers and their association with talin in the cleavage furrow of
PtK2 cells. Video supplement.
PMID- 9556334
TI - Interactions of Listeria monocytogenes with infected host cells. Video
supplement.
PMID- 9556335
TI - Fertilization and pronuclear migration in the ctenophore, Beroe ovata. Video
supplement.
PMID- 9556336
TI - Measurement of traction forces in cells locomoting along a substratum. Video
supplement.
PMID- 9556337
TI - Computer modelling of the ciliary axoneme. Video supplement.
PMID- 9556338
TI - Actin-based vesicle dynamics and exocytosis during wound wall formation. Video
supplement.
PMID- 9556339
TI - Three flagellar motilities in Chlamydomonas unrelated to flagellar beating. Video
supplement.
PMID- 9556340
TI - "Ethnicity, Aging, and Oral Health Outcomes: Findings from the ICS-II USA
Research Locations".
PMID- 9556341
TI - [Atlas of cranial and spinal MRI--magnetic resonance imaging in carbon monoxide
poisoning and Parkinsonian syndrome].
PMID- 9556342
TI - [Atlas of cranial and spinal MRI--fever, headache and behavioral disorders].
PMID- 9556343
TI - Interdigitated solenoid model for compact chromatin fibers.
PMID- 9556344
TI - The enhancement of enzymatic rate accelerations by Bronsted acid-base catalysis.
PMID- 9556345
TI - Liposome-catalyzed unfolding of acetylcholinesterase from Bungarus fasciatus.
AB - The kinetics of thermal inactivation of acetylcholinesterase from the venom of
the snake, Bungarus fasciatus, were studied at 45-54 degrees C. An Arrhenius plot
reveals an activation energy of 113 kcal/mol. The thermally denatured enzyme
displays the spectroscopic characteristics of a partially unfolded 'molten
globule' state. The rate of thermal denaturation is greatly enhanced in the
presence of unilamellar vesicles of dimyristoylphosphatidylcholine, the energy
barrier for the transition being lowered from 113 to 52 kcal/mol. In contrast to
our findings for partially unfolded Torpedo californica acetylcholinesterase
[Shin et al. (1997) Proc. Natl. Acad. Sci. U.S.A. 94, 2848-2852], the thermally
denatured snake enzyme does not remain bound to the liposomes but is released
after unfolding and subsequently aggregates. The liposomes thus serve as
catalysts for unfolding of the snake enzyme, and its rate of unfolding in the
presence of liposomes can be described by the Michaelis-Menten equation (Km = 8 x
10(-7) M). The phospholipid vesicles display a catalytic turnover number of kcat
approximately 4 min-1, assuming 15 binding sites per vesicle for the snake
acetylcholinesterase.
PMID- 9556346
TI - Step-scan time-resolved FTIR spectroscopy of cytochrome P-450cam carbon monoxide
complex: a salt link involved in the ligand-rebinding process.
AB - Step-scan time-resolved Fourier transform infrared spectroscopy with a time
resolution of 5 micros was applied to the carbon monoxide complex of cytochrome P
450cam (CYP101) to study the bimolecular ligand-rebinding process after flash
photolysis. Spectral changes in the CO ligand stretch vibration band and in the
protein amide I' band were monitored simultaneously. In substrate complexes
having the camphor C-8, C-9, and C-10 methyl groups, rebinding of the ligand and
the relaxation of the protein proceed at the same rate within experimental
errors. For substrate complexes missing the methyl groups, the relaxation fo the
protein tends to relax slightly faster than the CO ligand rebinding to the heme
iron. compared to the (1R)-camphor and the camphane complex, the bimolecular
rebinding rate constant for P-450 bound with substrates lacking the methyl groups
are increased by a factor of 10-40. An unusual signal at about 1719 cm-1 was
found in the difference spectrum of the photolyzed minus nonphotolyzed CO complex
which has not ben reported for other heme proteins so far. This signal is
strongly pronounced in wild-type P-450cam bound with (1R)-camphor or camphane and
in the D251N mutant bound with (1R)-camphor. In contrast, substrate-free P-450
and the norbornane and norcamphor complexes reveal only a very weak signal or a
changed band shape. On the basis of the crystal structure data, we suggest that
this signal originates from the rearrangement of the hydrogen-bonding pattern or
the protonation state of the salt link between Asp297, Arg299, and the heme
propionate group.
PMID- 9556347
TI - Voltage clamp studies on S-layer-supported tetraether lipid membranes.
AB - Isolated subunits from the cell surface proteins (S-layer) of Bacillus coagulans
E38-66 have been recrystallized on a glycerol dialkyl nonitol tetraether lipid
(GDNT)-monolayer and the electrophysical features of this biomimetic membrane
have been investigated in comparison to unsupported GDNT-monolayers. The GDNT
monolayer, spread on a Langmuir-Blodgett trough, was clamped with the tip of a
glass patch pipette. In order to investigate the barrier function and potential
to incorporate functional molecules, voltage-clamp examinations on plain and S
layer-supported GDNT-monolayers were per-formed. Our results indicate the
formation of a tight GDNT-monolayer sealing the tip of the glass pipette, and a
decrease in conductance of the GDNT-monolayer upon recrystallization of the S
layer protein. Thus, the S-layer protein, apparently, did not penetrate or
rupture the lipid monolayer. The valinomycin-mediated increase in conductance was
less pronounced for the S-layer-supported than for the plain GDNT-monolayer,
indicating differences in the accessibility and/or in the fluidity of the lipid
membranes. Furthermore. in contrast to plain GDNT-monolayers. S-layer supported
GDNT-monolayers with high valinomycin-mediated conductance persisted over long,
periods of time, indicating enhanced stability. These composite S-layer/lipid
films may constitute a new tool for electrophysical and electrophysiological
studies on membrane-associated and membrane-integrated biomolecules.
PMID- 9556348
TI - Interaction of phospholipid vesicles with smooth metal-oxide surfaces.
AB - The interaction of phospholipid vesicles with planar metal oxide supports has
been previously reported as a means of preparing supported lipid bilayers, which
are useful models of biological membranes. Nevertheless, extant evidence that
bilayers are actually formed is rather circumstantial, and the necessary and
sufficient conditions for their formation have never been delineated. Here, we
tackle this problem by using smooth planar optical waveguides as the support.
Analysis of the lightmode spectra of the waveguides, measured in situ during the
deposition process, yields the mass of lipid deposited at the solid/liquid
interface. By comparing the optogeometric parameters of the structures assembled
from the vesicles with those of a lipid bilayer of known structure assembled
using the Langmuir-Blodgett technique, we show that in many cases the vesicles
remain intact and form a supported layer of vesicles rather than a bilayer, and
often mixed structures (intact vesicles embedded in a bilayer partially covering
the surface) occur. Careful analysis of the lipid deposition kinetics
corroborates this result. We have also found that divalent cations dramatically
promote attachment of mixed phosphatidylcholine/phosphatidylglycerol vesicles to
form supported vesicle layers, and bilayer formation from pure
phosphatidylcholine vesicles.
PMID- 9556349
TI - Lipids in total extracts from Acholeplasma laidlawii A pack more closely than the
individual lipids. Monolayers studied at the air-water interface.
AB - Pressure-area curves were obtained at 25, 35 and 45 degrees C for total lipid
extracts and four individual glucolipids isolated from Acholeplasma laidlawii
strain A-EF22. The glucolipids are 1,2-diacyl-3-0-(alpha-D-glucopyranosyl)-sn
glycerol (MGlcDAG), 1,2 -diacyl-3-0-[alpha-D-glucopyranosyl-(1-->2)-0-alpha-D
glucopyranosyl] -sn-glycerol (DGlcDAG), 1,2-diacyl-3-0-[alpha-D-glucopyranosyl-(1
->2)-0-(6-0-acyl-alpha-D-gluco pyranosyl)]-sn-glycerol (MADGlcDAG), and 1,2
diacyl-3-0-[glycerophosphoryl-6-0-(alpha-D-glucopyranosyl-(1-- >)-0-alpha-D
glucopyranosyl)]-sn-glycerol (GPDGlcDAG). The total lipid extracts were obtained
from A. laidlawii, grown at 37 degrees C with fatty acids of varying degrees of
unsaturation and chain length. The mean surface area per molecule was obtained
from these pressure-area curves at surface pressures equal to 10, 20, 30 and 40
mN/m. It was found that the interfacial area of the lipids increases with
increasing degree of unsaturation, but is nearly independent of the acyl chain
length at constant unsaturation. The surface charge density varied between 4.7 x
10(-3) e-/angstrom(2) and 9.4 x 10(-3) e-/angstrum(2) for the total lipid
extracts studied, but did not exhibit any consistent dependence on variations in
degree of unsaturation or acyl chain length. The mean area per molecule was found
to be smaller for the total lipid extracts than for the individual lipids. It is
concluded that the bacterium strives to regulate its lipid composition in such a
way that the packing of the lipids in the membrane is appropriately tight, and/or
to keep a slight negative spontaneous curvature of the lipid bilayer of the cell
membrane ("optimal packing"). This is in accordance with the physico-chemical
model for the regulation of the lipid composition in the membrane of A.
laidlaiwii previously presented by us (see e.g. Andersson, A.-S., Riffors, L.,
Bergqvist, M., Persson, S. and Lindblom, G. (1996) Biochemistry 35, 11119-11130).
PMID- 9556350
TI - Insulin therapy of prediabetes suppresses TH1 associated gene expression in BB
rat pancreas.
AB - Subcutaneous insulin treatment of young diabetes prone BB rats has been shown
previously to suppress the development of autoimmune diabetes. In this study the
hypothesis was tested that exogenous insulin may deviate the autoimmune process
by acting on the Th1/Th2 cytokine balance in the pancreas. BB rats were implanted
with pellets which continuously released insulin, at 50 d of age. Three weeks
later cytokine mRNA expression in the pancreas and insulitis score were
determined. While in control BB rats high levels of IFNgamma mRNA were detectable
by RT-PCR, insulin treatment almost completely suppressed IFNgamma mRNA levels
without concomitant upregulation of counterregulatory IL-10 and TGFbeta gene
expression. Insulin also suppressed gene expression of inducible nitric oxide
synthase. Mean insulitis scores were decreased after insulin treatment. We
conclude that the protective effects of insulin treatment may not be due to the
induction of protective Th2 immune reactivity but to general downregulation of
immune activation in the pancreas, and hence also of Th1 autoimmunity.
PMID- 9556351
TI - The insulin gene region and susceptibility to insulin-dependent diabetes mellitus
in four races; new insights from Afro-Caribbean race-specific haplotypes.
AB - The IDDM2 component of the genetic susceptibility to insulin-dependent diabetes
mellitus (IDDM) has been mapped to chromosome 11p15.5. The exact identity of
IDDM2 remains uncertain. It has been suggested that IDDM2 maps within the 5' VNTR
(variable number tandem repeat) polymorphism upstream of the insulin gene (INS).
This has not been confirmed and a contribution from other INS gene region
polymorphisms cannot be excluded. We present INS region genotype data from four
racial groups: the Japanese, Hong Kong Chinese, North Indian Asians and Afro
Caribbeans (two groups; one born and resident in the UK, one in Jamaica). These
races have not been previously studied with the range of INS region polymorphisms
included here. No INS polymorphism was associated with IDDM across all races.
These data from this study thus do not identify any INS polymorphism as IDDM2.
The Afro-Caribbean race showed a very different distribution of INS genotypes
from the other races and novel race-specific INS haplotypes were identified.
Analysis of these excluded a contribution to susceptibility to IDDM from the-
23HphI INS polymorphism. An Afro-Caribbean INS haplotype which differed only at
the VNTR from the very protective INS haplotype (VPH) identified in white
Caucasians was detected. Population analysis of this haplotype will allow direct
assessment of the role of the VNTR in susceptibility to IDDM. In conclusion, the
diverse Afro-Caribbean TH/INS/IGF2 haplotypes identified in this study will be
valuable in mapping IDDM2 more precisely.
PMID- 9556352
TI - Primary biliary cirrhosis an epithelitis: evidence of abnormal salivary gland
immunohistochemistry.
AB - Primary biliary cirrhosis (PBC) is an autoimmune liver disease of unknown
etiology. Nearly 93% of patients with PBC exhibit evidence of focal
sialoadenitis. In an earlier study, we reported evidence of aberrant expression
of PDC-E2, or a mimeotope, in the salivary glands of patients with PBC that had
Sjogren's syndrome. At the time of the previous study, data was not yet available
regarding patients with PBC without sicca complaints. Therefore, to investigate
the extent of salivary gland involvement in PBC, we collected lip biopsy sections
from 9 PBC patients diagnosed as PBC by liver biopsy, without clinical or
histologic features of Sjogren's syndrome and 9 PBC patients with established
Sjogren's syndrome. Using immunohistochemical staining with both a murine
monoclonal antibody. C355.1, and a human combinatorial antibody, SP4, we examined
the ducts of these salivary glands for the presence of the characteristic
aberrant staining pattern found in patients with PBC. We report that 6/9 PBC
patients fulfilling established Sjogren's syndrome criteria and 6/9 PBC patients
lacking features of Sjogren's syndrome showed intense staining of the ductal
epithelial cells of the salivary gland. These data suggest that the PBC-specific
antigen recognized by C355.1 and SP4 in bile duct epithelial cells is expressed
aberrantly in the salivary gland in 66% of patients with PBC, independent of
Sjogren's syndrome. This finding suggests a common disease process in these two
tissues. Further, expression of this molecule may be an early marker of salivary
gland involvement in patients with PBC.
PMID- 9556353
TI - Heat shock proteins and arthritis--new readers start here.
AB - The possible roles of heat shock proteins in the pathogenesis of inflammatory
arthritis have been discussed for a number of years, and investigated intensively
in both animal models and human disease. This review surveys evidence which has
pointed, on the one hand, to hsp as targets of a pathogenic immune response, and
on the other, to an immunoregulatory role for T cell recognition of self hsp. The
extent to which findings in experimental animals have led to further insights
applicable to human disease is also emphasised.
PMID- 9556354
TI - Melatonin, immune modulation and aging.
AB - Melatonin is a hormone secreted by the pineal gland in response to photoperiods
and influences many important biological processes. For one, Melatonin has been
shown to produce resistance to cancer and infectious diseases in aged animals.
Studies in animals have demonstrated melatonin-related mechanisms of action on
immunoregulation. Additionally, melatonin has been successfully used in humans,
along with interleukin-2, as a treatment of solid tumors. In vivo and in vitro
studies show melatonin enhances both natural and acquired immunity in animals.
Despite all of this intriguing evidence, melatonin's mechanism of action on the
immune system is only partially defined. It does, however, appear to act through
lymphocyte receptors, and perhaps, receptors on other immune tissues, to modulate
immune cells. In order to understand immunomodulation and anti-cancer effects,
information on melatonin and it's interactions with other endocrine hormones are
summarized.
PMID- 9556355
TI - Locomotion and chemotaxis of lymphocytes.
AB - The behaviour of locomotor T and B lymphocytes and the chemoattractants to which
they respond in vitro are reviewed. Following activation, T cells respond by
locomotion and chemotaxis to cytokine attractants including IL-15 and IL-2 and
several chemokines. In activated B cells chemotaxis may be signalled through the
antigen receptor. Conversely resting lymphocytes respond poorly to the above
signals though their locomotion is activated by contact with high endothelial
venular cells. These differences in locomotion between resting and activated
lymphocytes, together with differences in adhesion, may explain why activated
lymphocytes migrate preferentially into inflammatory sites while resting cells
recirculate.
PMID- 9556356
TI - Prevalence of islet cell antibodies (ICA) in diabetes mellitus and other diseases
in Cubans.
PMID- 9556357
TI - Glutamine as an activator of immune cells: how does it work?
PMID- 9556358
TI - Workshop: Calcium and related nutrients. Washington, DC, July 9-10, 1996.
PMID- 9556359
TI - Neuronal circuitry and synaptic connectivity of the basal ganglia.
AB - The concept of organization of the basal ganglia has changed markedly over the
last 10 years. These developments have led to the introduction of a schematic
model of the functional circuitry of the basal ganglia that accounts for normal
and abnormal basal ganglia functions. The recent introduction of powerful
techniques for the analysis of neuronal networks has led to many new developments
in our understanding of the anatomic and synaptic organization of the basal
ganglia. The objective of this article is to go from the established model of the
basal ganglia connectivity to new anatomic findings that lead to reconsideration
and refinement of some aspects of the models.
PMID- 9556360
TI - Adolescents. Abused teens.
PMID- 9556361
TI - Nursing. Mixed signals.
PMID- 9556362
TI - Satisfaction. Boomer bust.
PMID- 9556363
TI - Religion. Faith in managed care.
PMID- 9556364
TI - Kiddiecare isn't child's play.
PMID- 9556365
TI - Construction. Shock absorber.
PMID- 9556366
TI - Recent Progress of Pineal Research--40 Years After Discovery of Melatonin.
Proceedings of the AsiaPacific Pineal Meeting. Hamamatsu, Japan, March 28-31,
1997.
PMID- 9556367
TI - Length growth in fission yeast: is growth exponential?--No.
PMID- 9556368
TI - Perspectives on the Use of Interleukin-2 in Cancer Treatment. Proceedings of a
conference. San Francisco, California, USA. July 10-13, 1997.
PMID- 9556369
TI - Point-counterpoint. Mass population skin cancer screening is not worthwhile.
PMID- 9556370
TI - Point-counterpoint. Mass population skin cancer screening can be worthwhile--(if
it's done right)
PMID- 9556371
TI - Melanoma in a patient with multiple unilateral vascular tumours.
PMID- 9556373
TI - The depolarization response element in acetylcholine receptor genes is a dual
function E box.
PMID- 9556372
TI - Porous balloon catheters.
PMID- 9556374
TI - Special issue: Complement and disease.
PMID- 9556375
TI - Helpful tips for extralabel drug use: record keeping, record access, and product
labels. The FDA-Center for Veterinary Medicine and the American Veterinary
Medicine Association.
PMID- 9556376
TI - Selected resources on pediatric pain.
PMID- 9556378
TI - RP11 is the second most common locus for dominant retinitis pigmentosa.
PMID- 9556377
TI - Homozygosity for Asn86Ser mutation in the CuZn-superoxide dismutase gene produces
a severe clinical phenotype in a juvenile onset case of familial amyotrophic
lateral sclerosis.
PMID- 9556379
TI - Should dentists be obligated to report their HIV status?
PMID- 9556380
TI - [Mechanisms of host defense and granulomatous inflammation in acid-fast bacilli
infection].
PMID- 9556381
TI - [Induction and function of Th1 cells as the effector cells in anti-tuberculosis
immunity].
PMID- 9556382
TI - [Role of gamma/delta cells in tuberculous infection].
PMID- 9556383
TI - [Role of immune responses in tuberculosis].
PMID- 9556384
TI - [Merit and demerit of cytokines in the prevention and treatment of tuberculosis].
PMID- 9556385
TI - [Comment on A. Hohmann, W. Russmann, F.A. Kaszli: Quality of vision screening in
childhood].
PMID- 9556386
TI - Transmission of fungal spores in space and their conditions for survival: a
review.
AB - The transfer of fungal spores to suitable hosts or nutrient substrates frequently
depends on spore discharge and aerial transport to transmit the species. Factors
affecting spore translocation and travel have been evaluated mycologically and
mathematically and are reviewed. Global disease spread and transmission
monitoring are discussed.
PMID- 9556387
TI - Plasmid patterns of Bacillus thuringiensis strains and isolates.
AB - Bacillus thuringiensis produces crystal proteins which are toxic to several
orders of economically important insects and other invertebrates. The genes
encoding these toxins reside mainly on plasmids. This report consists of a
comparative analysis of the plasmid content of a number of B. thuringiensis
strains and isolates which may facilitate the search for novel toxin genes and
other important products of this organism.
PMID- 9556388
TI - Silhouette. Elena Lucrezia Cornaro Piscopia (1646-1684), the first university
alumna in the world.
PMID- 9556389
TI - 1997-1998 Neurobehavioral Teratology Society Membership List.
PMID- 9556390
TI - Case records of the Massachusetts General Hospital. Weekly clinicopathological
exercises. Case 13-1998. A 23-year-old man with progressive weakness and
paresthesias.
PMID- 9556391
TI - A dangerous error in the dilution of 25 percent albumin.
PMID- 9556392
TI - Prophylactic use of implanted cardiac defibrillators in patients at high risk for
ventricular arrhythmias after coronary-artery bypass graft surgery.
PMID- 9556393
TI - Prophylactic use of implanted cardiac defibrillators in patients at high risk for
ventricular arrhythmias after coronary-artery bypass graft surgery.
PMID- 9556394
TI - Increased nuchal translucency and fetal chromosomal defects.
PMID- 9556395
TI - Increased nuchal translucency and fetal chromosomal defects.
PMID- 9556396
TI - Terminal sedation.
PMID- 9556397
TI - Terminal sedation.
PMID- 9556398
TI - Treatment of pain in dying patients.
PMID- 9556399
TI - Lack of relation between culture and anorexia nervosa--results of an incidence
study on Curacao.
PMID- 9556400
TI - Social missions of academic health centers.
PMID- 9556401
TI - Social missions of academic health centers.
PMID- 9556402
TI - Unpaid expert witnesses.
PMID- 9556403
TI - Unpaid expert witnesses.
PMID- 9556404
TI - Unpaid expert witnesses.
PMID- 9556405
TI - Sparganosis in non-human primates.
PMID- 9556406
TI - The demonstration of candidal pseudohyphae in salivary smears as a method of
early diagnosis of oral candidiasis in patients with acute myeloid leukemia.
AB - To investigate the oral coloniation of candidal pseudohyphae, a salivary smear
method was tested against the use of mucosal smears in 10 patients with acute
myeloid leukemia. The salivary smears showed to be reproducible and more
sensitive than mucosal smears for the demonstration of Candida organisms. The
salivary smear method was applied to another group of 10 patients with acute
myeloid leukemia during a 28-day period. According to swab cultures, 8 patients
were colonized with Candida spp. on day 0, whereas 2 patients were unclonized on
day 0, and remained so. All colonized patients developed acute oral candidiasis.
According to the salivary smear method, 5 patients were colonized with
pseudohyphae as early as on day 0, whereas 3 patients became colonized with
pseudohyphae within the first 7 days. Pseudohyphae were detected with a median of
4 days prior to the emergence of acute oral candidiasis, and the detection of
acute oral candidiasis was associated with an increase in the quantity of
pseudohyphoae. The study suggests that the demonstration of candidal pseudohyphae
in salivary smears is an early indicator of subsequent development of acute oral
candidiasis. Further studies are neded to clairfy whether early treatment based
on this finding will reduce the occurrence of acute oral candidiasis and
disseminated candidiasis in these patients.
PMID- 9556408
TI - No evidence-based medicine.
PMID- 9556407
TI - Characterization of a 4.2-kb plasmid isolated from periodontopathic spirochetes.
AB - Oral anaerobic treponemes are assoicated with active periodontal disease and may
comprise up to 57% of the microbiota in periodontal pockets. Four treponeme
strains (designated U2a, U2b, U9b, and U9c) isolated from clincial cases were
found to harbor a new 4.2-kb plasmid when plasmid DNA was extracted and purified
employing the Qiagen Plasmid Kit. This plasmid differs from the smaller plasmids
(2.0-, 2.6-, and 2.7-Kb) reported previously by others in Treponema denticola.
The newly discovered 4.2-kb plasmid was found to be the same in all four
treponeme strains by restriction endonuclease analysis. It is a circular plasmid
since restriction with PstI, Pvu II, Sma I, Xma I, Ava 1 or Bam HI produced a
single band of the same size. Bacterial strain U2b was shown to be Treponema
socranskii and U9c to be T. denticola. The plasmid is designated "pTS1". The
presence of the same plasmid in different species of the treponemes isolated from
the same patient suggests the possibility of a naturally occurring genetic
transfer system within the oral spirochetes or their ability to take up and
maintain mobilizable plasmids.
PMID- 9556409
TI - Epidemiologic study of infants with biliary atresia.
PMID- 9556410
TI - Alternative routes of drug administration--advantages and disadvantages (subject
review)
PMID- 9556411
TI - Urinary tract infection controversy and questions.
PMID- 9556413
TI - Urinary tract infection controversy and questions.
PMID- 9556412
TI - Urinary tract infection controversy and questions.
PMID- 9556414
TI - Pediatric Residency Training in an Era of Managed Care. Proceedings of a National
Conference. May 4, 1996.
PMID- 9556415
TI - Alterations in fascin-expressing germinal center dendritic cells in neoplastic
follicles of B-cell lymphomas.
AB - Germinal center dendritic cells (GCDCs) have essential functions in retention of
immune complexes within secondary follicles, B-lymphocyte antigenic stimulation,
B-cell activation, homing of B-cells via adhesion molecules such as ICAM-1 and
VCAM-1, and B-cell survival via apoptosis. The neoplastic cells of follicular
lymphomas (FLs) are thought to derive from follicular B lymphocytes, but their
relationship to GCDCs remains unclear. This study used immunohistochemical
staining for fascin, a 55-kDa actin-bundling protein strongly expressed in GCDCs
and their processes, to evaluate their distribution in neoplastic follicles.
Forty-two cases of B-cell FL were evaluated, and immunoreactive staining for
fascin was compared with six cases of Castleman's disease (CD) and six cases of
follicular hyperplasia. FLs generally revealed decreased or absent fascin
staining GCDCs, suggesting loss of fascin expression by dendritic cells in
neoplastic follicles compared with hyperplastic follicular centers. In some
follicles, there was partial retention of dendritic architecture with islands of
residual syncytial network. Interdigitating reticulum cells in the parafollicular
regions revealed normal fascin expression with intense staining of dendritic
processes. In contrast with FLs, cases of follicular hyperplasia revealed normal
or increased fascin-positive follicular dendritic cells, and in cases of hyaline
vascular CD, follicular dendritic cells revealed tight syncytial networks. These
results suggest that GCDCs are deficient in neoplastic follicles, compared with
benign reactive or hyperplastic follicles. This alterations in the germinal
center microenvironment might explain the inability of FL cells to present
antigen to T lymphocytes and to mount an effective antitumor immune response.
PMID- 9556416
TI - Monoclonal immunoglobulin G1-kappa fibrillary glomerulonephritis.
AB - We report here a case of fibrillary glomerulonephritis arising in a 43-year-old
man with a polyclonal gammopathy, who presented with progressive renal
insufficiency, microscopic hematuria, and mild proteinuria (0.7 g/d).
Ultrastructural studies showed deposits of randomly oriented fibrils in the
glomerular mesangium and adjacent portions of some glomerular basement membranes,
with a mean fibril thickness of 14.3 nm, highly consistent with fibrillary
glomerulonephritis. The Congo red stain was negative on histologic sections.
Immunofluorescence studies revealed strong mesangial and focal glomerular
capillary staining for immunoglobulin (Ig) G, complement (C) 3, and kappa light
chains, with minimal staining for IgA, IgM, C1q, or lambda light chains. The IgG
present was entirely of the IgG1 subclass. This case is quite unusual for
fibrillary glomerulonephritis, which typically presents with polyclonal IgG
deposits and IgG4 as the dominant IgG subclass present. Monoclonal deposits are
more frequently associated with immunotactoid glomerulopathy, characterized
ultrastructurally by microtubule-like structures 30 to 50 nmn thick, often in
parallel arrays. The present case illustrates that although fibrillary
glomerulonephritis and immunotactoid glomerulopathy might be distinguishable on
ultrastructural grounds, there is overlap between these two entities with respect
to the potential composition of the glomerular deposits present.
PMID- 9556417
TI - Analysis of human papillomavirus infection and molecular alterations in
adenocarcinoma of the cervix.
AB - Although molecular alterations involved in the development of squamous cell
carcinoma of the cervix have been extensively described, these genetic changes
have not been as well characterized in the development of cervical
adenocarcinoma. Twenty-seven paraffin-embedded adenocarcinomas of the cervix,
including three cases of adenoma malignum, were analyzed for molecular
alterations associated with other gynecologic malignancies. The presence of human
papillomavirus (HPV) was assessed by polymerase chain reaction (PCR) using
internally nested consensus primers. HPV types were identified by restriction
endonuclease digestion of the PCR products, using DNA sequencing to confirm each
digestion pattern. The presence of HPV was correlated with immunohistochemical
expression of the p53 gene product, the presence of mutations in codon 12 of Ki
ras, and allelic deletion of markers associated with the development of other
gynecologic carcinomas. HPV was identified in 16 (59%) of 27 cases, including
type 18 in 7 tumors, type 16 in 7 tumors, and type 45 in 2 tumors. HPV types 16
and 45 were always identified in adjacent uninvolved cervical epithelium, but HPV
type 18 was absent from the adjacent non-neoplastic epithelium in four of the
seven positive cases. HPV was not identified in any of three cases of adenoma
malignum. Diffuse immunohistochemical staining of the p53 gene product was
present in only one (HPV-negative) tumor. A mutation in codon 12 of Ki-ras was
observed in one endocervical adenocarcinoma (with an endometrioid pattern). Loss
of heterozygosity was identified only for a marker on chromosome 6p in one
mucinous endocervical carcinoma. Most endocervical adenocarcinomas lack molecular
alterations characteristic of other histologically similar gynecologic
malignancies, as well as those described in cervical squamous cell carcinomas.
PMID- 9556418
TI - In situ hybridization with biotinylated tyramide amplification: detection of
human papillomavirus DNA in cervical neoplastic lesions.
AB - A novel peroxidase-mediated amplification system, which is based on the
deposition of biotinylated tyramide (BT) molecules, was recently described for
immunohistochemistry and in situ hybridization (ISH). We report here a highly
sensitive ISH system combined with a microwave prehybridization treatment and BT
enhancement after hybridization. Our ISH with BT amplification can detect human
papillomavirus (HPV) 16 DNA signals in the fixed SiHa cell, suggesting the
ability to detect single or few copies of HPV DNA. To confirm its diagnostic
usefulness, we used our ISH with BT amplification to detect HPV 16 DNA in 81
cases of cervical neoplastic lesions, which had been used for routine pathologic
diagnosis. Of 81 tumors, 47 (58%) showed HPV 16 DNA, of which 29 and 18 were
cervical intraepithelial neoplasia (CINs) and invasive cancers, respectively. In
almost all of the invasive cancers positive for HPV 16 DNA, ISH revealed a basic
dot signal pattern in the nuclei, suggesting that HPV DNA integrated into tumor
cell DNA. On the other hand, low-grade CINs displayed a diffuse, mainly episomal,
signal pattern, which decreased in frequency with increased grade of CIN. Our ISH
with BT amplification is highly sensitive and can be used to detect various genes
and their expressions.
PMID- 9556419
TI - Erythropoietin immunolocalization in renal cell carcinoma.
AB - Erythropoietin (EPO) is a well-recognized hormone that induces erythrocytosis in
a wide range of physiologic and pathologic situations in mammals. One of these
situations is a paraneoplastic erythrocytosis, which might be seen in association
with various neoplasms, including renal cell carcinoma (RCC), hepatoma, and
cerebellar hemangioblastoma. Although there have been multiple studies confirming
the association between this erythrocytosis and the production of EPO by tumor
cells, immunohistochemical detection of EPO in formalin-fixed, paraffin-embedded
tissue was not described. We report on the use of microwave antigen retrieval to
detect EPO in RCCs in such routinely processed tissues. We selected 19 RCCs
received as nephrectomy specimens, fixed in formalin, and routinely processed.
These cases were previously diagnosed on the basis of morphologic,
immunohistochemical, and clinical features. We examined the immunoreactivity of
these specimens with a monoclonal anti-EPO antibody. Fetal (20 wk gestational
age) liver served as a positive control. Intense positive immunoreactivity was
observed as cytoplasmic, granular staining in fetal hepatocytes. Fourteen RCCs
(10 clear cell and 4 tubulopapillary types) demonstrated unequivocal cytoplasmic
immunoreactivity. Additionally, two clear cell tumors were only focally positive,
whereas three (16%) were negative. EPO immunoreactivity might thus prove to be of
value in the diagnosis or confirmation of RCC, particularly in the context of
routinely processed material.
PMID- 9556420
TI - Cytomegalovirus infection in the colon of bone marrow transplantation patients.
AB - The histologic distinction between cytomegalovirus (CMV) infection and graft
versus-host disease (GVHD) in the colon in bone marrow transplantation (BMT)
patients relies heavily on the identification of viral inclusions, because the
morphologic features of these two diseases are otherwise similar. The aim of this
study was to assess (1) the prevalence of colonic CMV infection in BMT patients
with the use of DNA in situ hybridization (ISH); and (2) the sensitivity and
specificity of light microscopy in establishing a diagnosis of CMV infection in
the colon of these patients. Fifty-five colonic mucosal biopsy samples from 50
consecutive allogeneic BMT patients with diarrhea were evaluated histologically
for the presence of typical or atypical (suspicious, but not diagnostic) CMV
inclusions and, if negative, for the grade of GVHD. CMV DNA ISH analysis was
performed on all of the biopsy specimens and was correlated with the histologic
and clinical findings. Histologic analysis revealed only one patient with
morphologically typical CMV inclusions. Four other cases contained an isolated
atypical mesenchymal cell with features considered suspicious, but not
diagnostic, for CMV inclusions. All of these five cases exhibited histologic
features that were otherwise indistinguishable from GVHD grades 1 to 2. The
single case that was histologically positive for CMV was confirmed by DNA ISH. Of
the four histologically atypical cases, only one was confirmed to be CMV positive
by DNA ISH. Of the remaining 45 patients, 35 had GVHD, 1 had pseudomembranous
colitis, 1 had ischemic colitis, and 8 had no abnormalities found. Light
microscopic examination is a sensitive method of screening for CMV infection in
the colon of BMT patients but is less specific than DNA ISH. CMV infection is an
infrequent cause of colitis in our BMT population.
PMID- 9556421
TI - Causes of death in autopsied liver transplantation patients.
AB - Liver transplantation is an established treatment for multiple end-stage liver
diseases, yet little information is available on the autopsy-determined causes of
death in liver transplant recipients. We undertook a retrospective study of the
immediate causes of death in all liver transplant recipients who underwent
autopsy at the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania,
from January 1982 to January 1997. Infections were the most frequent cause of
death, present in 64% of a total of 321 cases. Overall, the infections were
bacterial in 48% of the cases, fungal in 22%, and viral in 12%. The ratio of
infectious to noninfectious causes of death did not change significantly during
the 15-year study period, and the relative percentages of bacterial, fungal, and
viral infections showed relatively little variation on a year-to-year basis. Two
thirds of all infections occurred during the first 100 days post transplantation.
A precipitous drop in the number of infections (and the number of deaths)
occurred by Day 90. Other major causes of death included liver failure (12%),
pulmonary failure (10%), multiple organ system (8%), and cardiovascular causes
(6%). Infections were the most frequent cause of death in this study population,
suggesting that improvement in the prevention and treatment of infections is an
important way to improve survival of liver transplant recipients.
PMID- 9556422
TI - Prostatic atrophy: an autopsy study of a histologic mimic of adenocarcinoma.
AB - Prostatic atrophy (PA) is one of the most frequent mimics of prostatic
adenocarcinoma. It occurs almost exclusively in the peripheral zone of the gland
and gained importance with the increasing use of needle biopsies for the
detection of prostatic carcinoma The etiopathogenesis is unknown, and there is
controversy related to the potential of PA as a precancerous lesion. The
frequency increases with age. Compressions caused by hyperplastic nodules,
inflammation, hormones, nutritional deficiency, or systemic or local ischemia,
are all possible factors in the pathogenesis of PA. The peripheral zone of the
prostate was step-sectioned and totally embedded from the bodies of 100
consecutively autopsied men more than 40 years of age. The fragments were
microscopically studied for presence of PA, latent (histologic) carcinoma, high
grade prostatic intraepithelial neoplasia, local arteriosclerosis, and
prostatitis. The prostates were macroscopically examined for the presence of
nodular prostatic hyperplasia. The autopsy reports provided information
concerning the presence of generalized atherosclerosis and benign or malignant
nephrosclerosis. PA was seen in 85 of the 100 prostates examined and
histologically was subtyped into simple, hyperplastic, and sclerotic atrophy. In
65 (76.47%) of 85 cases, the histologic subtypes were combined. In 33 (50.76%) of
these 65 cases, the three subtypes were seen concomitantly, favoring the
hypothesis that they represent a morphologic continuum of only one lesion.
Fibrosis of the stroma may or may not be present in simple and hyperplastic
atrophy. Hyperplastic atrophy associated with fibrosis of the stroma is the
histologic subtype that most frequently mimics adenocarcinoma Sclerotic atrophy
always presents fibrosis of the stroma. PA increases with age, and, in our study,
ischemia caused by local intense arteriosclerosis seems to be a potential factor
for its etiopathogenesis. Because there was no relation to latent (histologic)
carcinoma or high-grade prostatic intraepithelial neoplasia, PA is probably not a
premalignant lesion.
PMID- 9556424
TI - bcl-1 translocations are frequent in the paraimmunoblastic variant of small
lymphocytic lymphoma.
AB - To evaluate the usefulness of polymerase chain reaction analysis of
translocations involving the bcl-1 and bcl-2 genes in variants of CD5-positive B
cell lymphomas, we analyzed four cases classified as the paraimmunoblastic
variant of small lymphocytic lymphoma. This neoplasm, originally identified as an
aggressive, diffuse, B-lineage lymphoma related to small lymphocytic lymphoma,
can be confused with variants of mantle cell lymphoma (an immunophenotypically
and morphologically similar neoplasm). No translocations involving bcl-2 and the
immunoglobulin heavy chain gene were identified; two cases had translocations
involving the bcl-1 and the immunoglobulin heavy chain genes. The frequency of
finding this translocation suggests that these categories of neoplasms might be
extremely difficult to distinguish or that a closer relationship between these
neoplasms exists than was initially proposed.
PMID- 9556423
TI - Hormone receptor immunoreactivity in hemangioblastomas and clear cell renal cell
carcinomas.
AB - Several primary central nervous system (CNS) neoplasms, including meningiomas,
spinal cord ependymomas, and acoustic nerve schwannomas, express hormone
receptors. In the present study, we investigated hormone receptor
immunoreactivity in hemangioblastomas on the basis of recent reports of these
tumors complicating pregnancy. We also evaluated cases of renal cell carcinoma
(RCC) metastatic to the CNS, hypothesizing that estrogen receptor (ER),
progesterone receptor (PR), or androgen receptor (AR) immunoreactivity might help
to distinguish between these histologically similar neoplasms.
Immunohistochemical analysis for ERs, PRs, and ARs was performed on paraffin
embedded sections of 27 hemangioblastomas, 12 primary clear cell RCCs, and 5
clear cell RCCs metastatic to the CNS. All of the hemangioblastomas demonstrated
PR immunoreactivity, whereas 10 of 12 primary RCCs were negative. In addition,
four of the five metastatic RCC were PR positive. All but one primary RCC were ER
negative. AR immunoreactivity was seen in three hemangioblastomas, five primary
RCCs, and one metastatic RCC. Although hormone receptor immunoreactivity was
unable to distinguish between hemangioblastoma and clear cell RCC metastatic to
the CNS, the identification of PR immunoreactivity in hemangioblastomas is a new
finding that might have adjuvant therapy treatment implications.
PMID- 9556425
TI - Plasma cell granuloma of the oral cavity: a report of two cases and review of the
literature.
AB - We report two rare cases of plasma cell granuloma arising in the extragingival
oral cavity. These are tumorous proliferations composed predominantly of reactive
plasma cells. Both patients presented with solitary mass lesions that were
clinically suspicious for malignancy. One patient presented with a mass that grew
slowly for 2 years and involved the lip; in the second patient, a mass developed
in the buccal mucosa Histologically, both lesions were characterized by lobules
of plasma cells separated by thick collagenous bands. A variable number of
admixed lymphocytes and histiocytes was noted in both cases. In situ
hybridization and immunostaining for kappa and lambda light chains revealed a
polyclonal plasma cell population. In situ hybridization for Epstein-Barr virus
failed to demonstrate evidence of viral expression in either case. Both patients
are free of disease after 8-month and 12-month follow-ups. Although plasma cell
granuloma in the oral cavity is rare, it is important to recognize this entity as
a benign inflammatory lesion.
PMID- 9556426
TI - Detection of the SYT-SSX chimeric RNA of synovial sarcoma in paraffin-embedded
tissue and its application in problematic cases.
AB - We report the development of a reverse-transcriptase polymerase chain reaction
assay that detects (in paraffin-embedded, formalin-fixed tissue) the SYT
SSXchimeric RNA transcript resulting from the t(X;18) of synovial sarcoma. The
primers chosen detect both of the SSX1 and SSX2 partners, and the target sequence
is small enough (87 base pairs) to be reliably detected in archival and variably
processed consultation material. To demonstrate its usefulness, we applied it to
14 problematic cases, including spindle cell tumors of the thoracic region, of
the neck, and of subcutaneous tissue. For instance, we show that, depending on
the location, synovial sarcoma can mimic malignant solitary fibrous tumor, the
spindle epithelial tumor with thymus-like differentiation, or skin adnexal
tumors. Molecular detection of the SYT-SSX chimeric RNA should allow the
reclassification of difficult cases in which the morphologic features overlap
different entities or in which tumor nosology is still evolving.
PMID- 9556427
TI - A novel Alcian yellow-toluidine blue (Leung) stain for Helicobacter species:
comparison with standard stains, a cost-effectiveness analysis, and supplemental
utilities.
AB - Helicobacter pylori (Hp) gastritis is a worldwide problem significantly
associated with duodenal and gastric peptic ulcer disease, gastric carcinomas,
and MALT-type lymphomas. A simple, rapid, reproducible, reliable, and inexpensive
stain to detect the organism in gastric biopsy specimens is thus of great value.
To assess the reliability and cost-effectiveness of a novel Alcian yellow
toluidine blue (Leung) stain for Hp, we stained 60 endoscopic mucosal biopsy
specimens from patients with Hp gastritis and measured time to detection of
organism, Hp numbers (scale, 1-5), and technical costs. We also stained serial 5
microm step sections of 17 of these cases with the Giemsa and modified Steiner
(MS) methods, and similar measurements were made. Also, specimens from various
normal gastrointestinal sites and metaplastic lesions, as well as four cases each
of giardiasis and cryptosporidiosis, were stained with the Leung method. In the
subset of 17 cases, the Leung stain enhanced detection time and compared
favorably with the Giemsa method, though the MS method was somewhat superior. Hp
scores were similar among all groups. Mean time to detection and Hp scores were
similar in the larger (n = 60) group stained with hematoxylin and eosin and the
Leung stain. Material costs and technologist's time for Giemsa stains, however,
were greater than for the Leung stain, and technologist's time for MS was nearly
fourfold that of the Leung stain. With the Leung method, mucus from all
gastrointestinal sites and metaplastic lesions stained yellow, and this stain
provided excellent contrast and morphologic definition in giardiasis and
cryptosporidiosis. We suggest that the newly developed Alcian yellow-toluidine
blue (Leung) histochemical stain is a good choice as the standard for routine Hp
staining because it is the cheapest and easiest to prepare and because
pathologists' detection with this stain compares favorably with detection times
achieved with more traditional and established methods.
PMID- 9556428
TI - The differential diagnosis of pagetoid cells in the epidermis.
AB - In addition to Paget's disease, a heterogeneous group of processes with diverse
histogeneses can give rise to intraepidermal pagetoid cells. These diseases share
as their common denominator the presence of discrete non-Malpighian or abnormal
Malpighian cells occurring singly or in nests within the epidermis. Either
Pagetoid cells can represent the only histologic change, as in pagetoid squamous
cell carcinoma in situ or superficial spreading malignant melanoma in situ, or
they can be an expression of an associated dermal or internal malignancy, as in
sebaceous carcinoma or breast carcinoma. The histologic appearance of the
pagetoid cells in these diverse disorders can be quite similar, rendering the
differential diagnosis difficult. A review of the entities that enter into the
differential diagnosis of intraepidermal pagetoid cells is presented, emphasizing
their distinguishing histologic and immunophenotypic features and differential
diagnosis.
PMID- 9556429
TI - Extranodal multicentric Castleman's disease with cutaneous involvement.
AB - Castleman's disease (CAD) is an unusual lymphoid hyperplasia that might be
induced by an immunologic reaction to a virus or another infectious organism or
drug. CAD commonly occurs in the mediastinal lymph nodes and less frequently in
the neck lymph nodes, but other lymph nodes might be involved. Extranodal CAD is
rare. We present a 72-year-old woman with diffuse 2- to 5-cm cutaneous nodules
that had appeared a few months earlier. The patient underwent a biopsy, and the
lesions resolved within 4 months. The patient was asymptomatic except for mild
joint pains. Histopathologic findings showed a circumscribed nodule composed of
lymphoid follicles with contracted germinal centers and expanded mantle zones.
The lymphoid follicles were separated by perivascular bands of sclerotic
collagen. Aggregates of epithelioid and dendritic histiocytes were present
between follicles, with a prominent lymphoplasmacytic infiltrate and vascular
proliferation. Although extranodal CAD has been reported in the skin, we think
that this is the first reported case of multicentric cutaneous CAD without
evidence of lymph node involvement.
PMID- 9556430
TI - Post-transplantation lymphoproliferative disorder of donor origin in a sex
mismatched renal allograft as proven by chromosome in situ hybridization.
AB - We report a case of post-transplantation B-cell lymphoproliferative disorder
(PTLPD) associated with Epstein-Barr virus (EBV) that developed in a renal
allograft 5 months after transplantation. The lesion had a histologic appearance
of diffuse large B-cell lymphoma with monoclonality demonstrated by in situ
hybridization (ISH) for kappa and lambda mRNA. Both the male donor and the female
recipient were EBV seropositive. The lymphoid cells in this lesion was proven to
be of donor origin by ISH for the human Y chromosome on the paraffin-embedded
sections of the allograft. The recipient of the other kidney from the same donor
did not have evidence of lymphoma, and the patient was also free from disease 2
years after surgical removal of the lymphoma This case is an unusual PTLPD of
donor origin; the majority of such lesions in solid organ transplantations are of
recipient origin. Our findings demonstrate that the origin of PTLPD can be
documented in selected cases using ISH with probes to the Y chromosome.
PMID- 9556431
TI - ATP-dependent uptake of natural product cytotoxic drugs by membrane vesicles
establishes MRP as a broad specificity transporter.
PMID- 9556432
TI - Computer system validation: an overview of official requirements and standards.
AB - A brief overview of the relevant documents for companies in the pharmaceutical
industry, which are to be taken into consideration to fulfil computer system
validation requirements, is presented. We concentrate on official requirements
and valid standards in the USA, European Community and Switzerland. There are
basically three GMP-guidelines. their interpretations by the associations of
interests like APV and PDA as well as the GAMP Suppliers Guide. However, the
three GMP-guidelines imply the same philosophy about computer system validation.
They describe more a what-to-do approach for validation, whereas the GAMP
Suppliers Guide describes a how-to-do validation. Nevertheless, they do not
contain major discrepancies.
PMID- 9556433
TI - Software assessment under consideration of validation aspects: PPS and PMS
systems.
AB - Due to safety aspects, business risks and regulations of the FDA [FDA, 1983,
Guide to Inspection of Computerized Systems in Drug Processing. USA] and the EU
[EU-Leitfaden einer Guten Herstellpraxis for Arzneimittel, 1989, III/2244/87 Rev.
3. Jan. 1989], computer based systems used in the pharmaceutical production have
to be validated. In this paper we assessed which modules of production planning
and control (PPS) and production management systems (PMS) have to be validated
using a risk analysis procedure. It could be shown that the necessity of the
validation concerns, above all, the modules of production management systems.
Furthermore, a software supplier questionnaire was developed according to the V
model of Royce [National Computing Centre, 1989. STARTS Publications, UK.]. The
software supplier questionnaire was applied on four software products, which are
mostly used in the pharmaceutical industry. Although these were developed
according to a life cycle concept they fulfil the validation requirements,
measured with the developed questionnaire, to a different degree. Especially the
key element of the risk analysis was differently interpreted.
PMID- 9556434
TI - Validation of the process control system of an automated large scale
manufacturing plant.
AB - The validation procedure for the process control system of a plant for the large
scale production of human albumin from plasma fractions is described. A
validation master plan is developed, defining the system and elements to be
validated, the interfaces with other systems with the validation limits, a
general validation concept and supporting documentation. Based on this master
plan, the validation protocols are developed. For the validation, the system is
subdivided into a field level, which is the equipment part, and an automation
level. The automation level is further subdivided into sections according to the
different software modules. Based on a risk categorization of the modules, the
qualification activities are defined. The test scripts for the different
qualification levels (installation, operational and performance qualification)
are developed according to a previously performed risk analysis.
PMID- 9556435
TI - Validation of computer systems: practical testing of a standard LIMS.
AB - In recent years the introduction of computer systems for data handling in the
pharmaceutical industry has increased. A standard LIMS (laboratory information
management system) is software commercially available from different suppliers
not only to facilitate data handling in laboratories but also to cover GMP
requirements. Computer systems introduced in GMP-areas of pharmaceutical
companies have to be validated. For a standard LIMS, the general validation of
the program is performed by the supplier. Nevertheless, the user is always
required to cover all phases of a validation. The objective of this paper is to
discuss suitable test procedures for the most critical functions of a standard
LIMS needed during the verification step of the validation process.
PMID- 9556436
TI - Validation of a customized LIMS.
AB - The advantages of customized Laboratory Information Management's Systems (LIMS)
are their focus on the special aspects of their users' needs. Differences in the
research and development or production chain in the individual organizations lead
to an increase of interest in customized systems. Usually, also for customized
systems, the core software is commercially available. The individual application
modules as the Customized part of the LIMS are the most critical elements within
the validation process. The topic of this paper is to give an example of the
validation of a customized analytical LIMS. Validation of complex computerized
systems guarantees the intended use and is therefore an unavoidable requirement
of authorities. The audit of the supplier of the individual programmed modules,
the user requirement specifications and the acceptance testing and results,
respectively, on the software are of special interest within a customized LIMS.
The hardware suitability and the principal processing routines are also a very
important part of the whole validation process, but they will not be discussed in
detail in this paper.
PMID- 9556437
TI - Influence of Petasites hybridus on dopamine-D2 and histamine-H1 receptors.
PMID- 9556438
TI - Effects of extracts and of individual components from Petasites on prostaglandin
synthesis in cultured skin fibroblasts and on leucotriene synthesis in isolated
human peripheral leucocytes.
PMID- 9556439
TI - Study on clinical properties and mechanisms of action of Petasites in bronchial
asthma and chronic obstructive bronchitis.
PMID- 9556440
TI - Seasonal variation of the essential oil, valerenic acid and derivatives, and
velopotriates in Valeriana officinalis roots and rhizomes, and the selection of
plants suitable for phytomedicines.
AB - During the seasons 1989-1993, Valeriana officinalis plants were investigated for
their contents of essential oil, valerenic acid and derivatives, and
valepotriates. Harvesting of the subterranean parts was started in August of the
year in which the seeds were sown, and continued until the last week of April of
the subsequent year. Despite marked variations from year to year, the maximum
contents of essential oil in the subterranean parts of V. officinalis were found
in September, ranging from 1.2% to 2.1% (v/w) based on dry weight (DW). Over the
vegetation periods investigated, the composition of the oil remained more or less
constant. Valerenic acid and its derivatives, and the valepotriates reached their
maxima in February-March, with contents of 0.7-0.9% (DW) and 1.1-1.4% (DW),
respectively. During the period 1989 - 1993, five V. officinalis strains were
investigated for their contents of essential oil, valerenic acid and derivatives,
and valepotriates in order to select plants suitable for phytomedicines. The
selection procedures described in this paper finally yielded plant material (in
1993) with a satisfactory content of essential oil (0.9%) combined with a high
content of valerenic acid and derivatives (0.5%) which can be harvested in
September of the year of sowing.
PMID- 9556441
TI - The dose-response model for dioxin.
PMID- 9556442
TI - Uncertainty and variability analysis in multiplicative risk models.
AB - Currently, there is a trend away from the use of single (often conservative)
estimates of risk to summarize the results of risk analyses in favor of
stochastic methods which provide a more complete characterization of risk. The
use of such stochastic methods leads to a distribution of possible values of
risk, taking into account both uncertainty and variability in all of the factors
affecting risk. In this article, we propose a general framework for the analysis
of uncertainty and variability for use in the commonly encountered case of
multireplicative risk models, in which risk may be expressed as a product of two
or more risk factors. Our analytical methods facilitate the evaluation of overall
uncertainty and variability in risk assessment, as well as the contributions of
individual risk factors to both uncertainty and variability which is cumbersome
using Monte Carlo methods. The use of these methods is illustrated in the
analysis of potential cancer risks due to the ingestion of radon in drinking
water.
PMID- 9556443
TI - On construction of a dermal soil adherence PDF: response to Finley and Scott.
PMID- 9556444
TI - [The current situation in the offering of medico-dental care benefits in
Switzerland].
PMID- 9556445
TI - [Mouth mucosal diseases. The continuing education course Stomatology Today in
Bern of 11 November 1997].
PMID- 9556446
TI - [Unfair competition].
PMID- 9556447
TI - New hunt for the roots of resistance.
PMID- 9556448
TI - Did life begin in hot water?
PMID- 9556449
TI - France's sequencers aim to join the big league.
PMID- 9556450
TI - Death by dozens of cuts.
PMID- 9556451
TI - Transferred gene helps plants weather cold snaps.
PMID- 9556452
TI - Magnetic brain imaging traces a stairway to memory.
PMID- 9556453
TI - The vision of the pore.
PMID- 9556454
TI - Memory and awareness.
PMID- 9556455
TI - [Shoulder and elbow--a young specialty in surgery. Interview by Christiane
Weseloh].
PMID- 9556457
TI - Doctors as public speakers.
PMID- 9556456
TI - International Clearinghouse for Birth Defects Monitoring Systems. Proceedings of
the 24th annual meeting. Cape Town, South Africa, 19 November 1997. Abstracts.
PMID- 9556458
TI - Proceedings of the European Union International Symposium on Ticks and Tick-Borne
Diseases. Xi'An, People's Republic of China, September 2-6, 1996.
PMID- 9556459
TI - European Gastro Club 29th conference. Munster, 3-4 October 1997. Abstracts.
PMID- 9556460
TI - Breakfast, Cognition, and School Learning. Proceedings of a symposium. Napa,
California, USA. August 28-30, 1995.
PMID- 9556461
TI - De novo mtDNA nt 8993 (T-->G) mutation resulting in Leigh syndrome.
PMID- 9556462
TI - Clinical interpretation of "Maternal endocrine activation during pregnancy alters
neurobehavioral state in primate infants".
PMID- 9556463
TI - Postmenopausal hormone use and risk for colorectal cancer and adenoma.
AB - BACKGROUND: Accumulating evidence suggests that postmenopausal hormone use may
decrease the risk for colorectal cancer. OBJECTIVE: To examine the relation of
postmenopausal hormone therapy to colorectal adenoma and cancer. DESIGN:
Prospective cohort and nested case-control studies. SETTING: Nurses' Health
Study, a study of registered nurses recruited from 11 U.S. states. PARTICIPANTS:
59 002 postmenopausal participants in the Nurses' Health Study. MEASUREMENTS:
Self-reported data on hormone use and cases of distal colorectal adenoma and
colorectal cancer obtained from biennial questionnaires completed from 1980 to
1994. Cases of colorectal adenoma and cancer were confirmed by medical record
review. RESULTS: 470 women developed colorectal cancer, and 838 developed distal
colorectal adenomas. Current use of postmenopausal hormones was associated with a
decreased risk for colorectal cancer (relative risk [RR], 0.65 [95% CI, 0.50 to
0.83]). This association was attenuated in past users (RR, 0.84 [CI, 0.67 to
1.05]) and disappeared 5 years after hormone use was discontinued (RR, 0.92 [CI,
0.70 to 1.21]). Longer duration of current use did not afford greater protection
(RR with > or =5 years of use, 0.72 [CI, 0.53 to 0.96]). Even after exclusion of
women who reported having screening sigmoidoscopy, the relative risk for
colorectal cancer seen with current hormone use was 0.64 (CI, 0.49 to 0.82). This
suggests that the apparent protection is unlikely to be due to more intensive
screening among hormone users. Current users also had a lower risk for large (>
or =1 cm) adenomas than did women who had never used hormones (RR, 0.74 [CI, 0.55
to 0.99]), although no overall material association was seen between colorectal
adenoma and current hormone use (RR, 0.91 [CI,0.77 to 1.08]). CONCLUSIONS: The
risk for colorectal cancer was decreased among women currently receiving
postmenopausal hormone therapy, but the apparent reduction substantially
diminished upon cessation of therapy. Hormone use was inversely associated with
large colorectal adenomas but not small ones.
PMID- 9556464
TI - Aspirin use and colorectal cancer: post-trial follow-up data from the Physicians'
Health Study.
AB - BACKGROUND: In contrast to most observational studies, the randomized Physicians'
Health Study found no association between aspirin use and colorectal cancer after
5 years. OBJECTIVE: To determine the effect of randomly assigned aspirin
treatment and self-selected aspirin use on the incidence of colorectal cancer
after 12 years and to identify factors influencing the self-selection of regular
aspirin use. DESIGN: Randomized clinical trial and prospective cohort study.
SETTING: Male physicians throughout the United States. PATIENTS: 22071 healthy
male physicians who were 40 to 84 years of age in 1982. INTERVENTION: 325 mg of
aspirin every other day. In 1988, the aspirin arm of the randomized trial was
stopped early. Participants then chose to receive either aspirin or placebo for
the rest of the study. MEASUREMENTS: Annual questionnaires asking about aspirin
use and other variables, including occurrence of cancer. RESULTS: Colorectal
cancer was diagnosed in 341 patients during the study period. Over 12 years of
follow-up, random assignment to aspirin was associated with a relative risk for
colorectal cancer of 1.03 (95% CI, 0.83 to 1.28). Various gastrointestinal
symptoms and diagnoses were strong predictors of less frequent aspirin use in
1988. The relative risk for colorectal cancer in persons who used aspirin
frequently after 1988 was 1.07 (CI, 0.75 to 1.53). CONCLUSIONS: In the
Physicians' Health Study, both randomized and observational analyses indicate
that there is no association between the use of aspirin and the incidence of
colorectal cancer. The low dose of aspirin used and the short treatment period
may account for the null findings. However, other characteristics associated with
the use of aspirin in observational studies remain a plausible alternative
explanation.
PMID- 9556465
TI - Noninvasive mechanical ventilation in the weaning of patients with respiratory
failure due to chronic obstructive pulmonary disease. A randomized, controlled
trial.
AB - BACKGROUND: In patients with acute exacerbations of chronic obstructive pulmonary
disease, mechanical ventilation is often needed. The rate of weaning failure is
high in these patients, and prolonged mechanical ventilation increases intubation
associated complications. OBJECTIVE: To determine whether noninvasive ventilation
improves the outcome of weaning from invasive mechanical ventilation. DESIGN:
Multicenter, randomized trial. SETTING: Three respiratory intensive care units.
PATIENTS: Intubated patients with chronic obstructive pulmonary disease and acute
hypercapnic respiratory failure. INTERVENTION: A T-piece weaning trial was
attempted 48 hours after intubation. If this failed, two methods of weaning were
compared: 1) extubation and application of noninvasive pressure support
ventilation by face mask and 2) invasive pressure support ventilation by an
endotracheal tube. MEASUREMENTS: Arterial blood gases, duration of mechanical
ventilation, time in the intensive care unit, occurrence of nosocomial pneumonia,
and survival at 60 days. RESULTS: At admission, all patients had severe
hypercapnic respiratory failure (mean pH, 7.18+/-0.06; mean PaCO2, 94.2+/-24.2 mm
Hg), sensory impairment, and similar clinical characteristics. At 60 days, 22 of
25 patients (88%) who were ventilated noninvasively were successfully weaned
compared with 17 of 25 patients (68%) who were ventilated invasively. The mean
duration of mechanical ventilation was 16.6+/-11.8 days for the invasive
ventilation group and 10.2+/-6.8 days for the noninvasive ventilation group (P =
0.021). Among patients who received noninvasive ventilation, the probability of
survival and weaning during ventilation was higher (P = 0.002) and time in the
intensive care unit was shorter (15.1+/-5.4 days compared with 24.0+/-13.7 days
for patients who received invasive ventilation; P = 0.005). Survival rates at 60
days differed (92% for patients who received noninvasive ventilation and 72% for
patients who received invasive ventilation; P = 0.009). None of the patients
weaned noninvasively developed nosocomial pneumonia, whereas 7 patients weaned
invasively did. CONCLUSIONS: Noninvasive pressure support ventilation during
weaning reduces weaning time, shortens the time in the intensive care unit,
decreases the incidence of nosocomial pneumonia, and improves 60-day survival
rates.
PMID- 9556466
TI - Mammography use helps to explain differences in breast cancer stage at diagnosis
between older black and white women.
AB - BACKGROUND: Older black women are less likely to undergo mammography and are more
often given a diagnosis of advanced-stage breast cancer than older white women.
OBJECTIVE: To investigate the extent to which previous mammography explains
observed differences in cancer stage at diagnosis between older black and white
women with breast cancer. DESIGN: Retrospective cohort study using the Linked
Medicare-Tumor Registry Database. SETTING: Population-based data from three
geographic areas of the United States included in the National Cancer Institute's
Surveillance, Epidemiology, and End Results (SEER) program (Connecticut;
metropolitan Atlanta, Georgia; and Seattle-Puget Sound, Washington).
PARTICIPANTS: Black and white women 67 years of age and older in whom breast
cancer was diagnosed between 1987 and 1989. MEASUREMENTS: Medicare claims were
used to classify women according to mammography use in the 2 years before
diagnosis as nonusers (no previous mammography), regular users (> or =2
mammographies done at least 10 months apart), or peri-diagnosis users
(mammography done only within 3 months before diagnosis). Information on
mammography use was linked with SEER data to determine cancer stage at diagnosis.
Stage was classified as early (in situ or local) or late (regional or distant).
RESULTS: Black women were more likely to not undergo mammography (odds ratio
[OR], 3.00 [95% CI, 2.41 to 3.75]) and to be given a diagnosis of late-stage
disease (OR, 2.49 [CI, 1.59 to 3.92]) than white women. When women were
stratified by previous mammography use, the black-white difference in cancer
stage occurred only among nonusers (adjusted OR, 2.54 [CI, 1.37 to 4.71]). Among
regular users, cancer was diagnosed in black and white women at similar stages
(adjusted OR, 1.34 [CI, 0.40 to 4.51]). In logistic modeling, previous
mammography alone explained about 30% of the excess late-stage disease in black
women. In a separate model, previous mammography explained 12% of the excess late
stage disease among black women after adjustment for sociodemographic and
comorbidity information. CONCLUSION: Differences in breast cancer stage at
diagnosis between older black and white women are related to previous mammography
use. Increased regular use of mammography may result in a shift toward earlier
stage disease at diagnosis and narrow the observed differences in stage at
diagnosis between older black and white women.
PMID- 9556467
TI - Incidence of idiopathic deep venous thrombosis and secondary thromboembolism
among ethnic groups in California.
AB - BACKGROUND: Few studies have compared the incidence of deep venous thrombosis
among ethnic groups. OBJECTIVE: To determine the incidence of deep venous
thrombosis among ethnic groups. DESIGN: Analysis of the linked California Patient
Discharge Data Set from 1991 to 1994. SETTING: California. PATIENTS: 17991
patients with idiopathic deep venous thrombosis (thrombosis without cancer or
hospitalization within preceding 6 months) and 5573 patients with secondary
thromboembolism (thromboembolism occurring within 3 months of seven different
events). MEASUREMENTS: Ethnicity was determined by using race as documented in
the data set. For idiopathic deep venous thrombosis, standardized age- and sex
adjusted incidences were calculated. For secondary thromboembolism, proportional
hazards modeling was done. RESULTS: The annual incidence of idiopathic deep
venous thrombosis per 1000000 persons older than 18 years of age was 230 for
white persons, 293 for African Americans (rate ratio, 1.27 [95% CI, 1.07 to
1.51]), 139 for Hispanic persons (rate ratio, 0.60 [CI, 0.54 to 0.67]), and 60
for Asians and Pacific Islanders (rate ratio, 0.26 [CI, 0.22 to 0.30]). Compared
with white persons, Asians and Pacific Islanders who developed secondary
thromboembolism had a significantly lower relative risk (range, 0.22 to 0.61) for
all seven conditions analyzed. CONCLUSIONS: Compared with white persons, Asians
and Pacific Islanders have a very low incidence of idiopathic deep venous
thrombosis and a very low relative risk for secondary venous thromboembolism.
PMID- 9556468
TI - Can degenerative aortic valve stenosis be related to persistent Chlamydia
pneumoniae infection?
AB - BACKGROUND: The cause of age-related degenerative (tricuspid) aortic valve
calcification is largely unknown, but one typical characteristic is an active
inflammatory process. The presence of Chlamydia pneumoniae in aortic valve
stenosis was recently shown. OBJECTIVE: To test the hypothesis that if persistent
C. pneumoniae infection plays an active role in the development of aortic
stenosis, the organism can be detected in the healthy aortic valves of young
persons. DESIGN: A cadaver study. SETTING: Oulu University Hospital, Oulu,
Finland. SUBJECTS: 46 consecutive cadavers undergoing autopsy. MEASUREMENTS:
Macroscopic and histologic pathology of aortic valves was determined. The
presence of C. pneumoniae was determined by immunohistochemistry. RESULTS: 34 of
46 valves were macroscopically normal. Early lesions of aortic valve disease were
found in 12 valves (no lesions in valves from persons 20 to 40 years of age [n =
15], 4 lesions in valves from persons 41 to 60 years of age [n = 16], and 8
lesions in valves from persons older than 60 years of age [n = 15]; P = 0.004).
Fifteen of 34 normal valves (44%) and 10 of 12 valves with early lesions (83%)
had positive results on staining for C. pneumoniae (P = 0.02). In persons older
than 60 years of age, the chance of an early lesion was higher if the valve
tested positive for C. pneumoniae (7 of 8 valves with C. pneumoniae infection
compared with 1 of 7 valves without C. pneumoniae infection; P = 0.01).
CONCLUSIONS: Chlamydia pneumoniae is frequently present in aortic valves and is
associated with early lesions of aortic valve stenosis in elderly persons.
PMID- 9556469
TI - The Eisenmenger syndrome in adults.
AB - For this article, the literature on the pathophysiology, clinical features,
natural history, prognosis, and management of the Eisenmenger syndrome in adults
was reviewed. English-language articles from 1966 to the present were identified
through a search of the MEDLINE database by using the terms Eisenmenger,
congenital heart disease, and pulmonary hypertension. Selected cross-referenced
articles were also included. Articles on the pathophysiology, clinical
presentation, evaluation, natural history, complications, and treatment of the
Eisenmenger syndrome in adults were selected, and descriptive and analytical data
relevant to the practicing physician were manually extracted. The Eisenmenger
syndrome is characterized by elevated pulmonary vascular resistance and right-to
left shunting of blood through a systemic-to-pulmonary circulation connection.
Most patients with the syndrome survive for 20 to 30 years. The hemostatic
changes associated with the syndrome may lead to thromboembolic events,
cerebrovascular complications, or the hyperviscosity syndrome. Erythrocytosis is
present in most patients, but excessive phlebotomy may cause microcytosis and
exacerbate the symptoms of hyperviscosity. Other complications associated with
the Eisenmenger syndrome include hemoptysis, gout, cholelithiasis, hypertrophic
osteoarthropathy, and decreased renal function. Pregnancy or noncardiac surgery
is associated with a high mortality rate in patients with the Eisenmenger
syndrome. Because most pediatric patients with the Eisenmenger syndrome survive
to adulthood, primary care physicians should have a thorough understanding of the
syndrome; its associated complications; and medical and surgical management,
especially with regard to the appropriate timing of phlebotomy and lung or heart
lung transplantation. In addition, patients with the syndrome should undergo
routine follow-up at a tertiary care center that has physicians and nurses with
special expertise in congenital heart disease. In patients with the Eisenmenger
syndrome who are pregnant or require noncardiac surgery, a multidisciplinary
approach should be used to reduce the excessive mortality associated with these
conditions.
PMID- 9556470
TI - Have we treated AIDS too well? Rationing and the future of AIDS exceptionalism.
AB - During the past decade, medical therapy for AIDS has become more effective but
also prohibitively expensive. A medical tragedy has been transformed into a
financial crisis, and society has responded by establishing special programs and
sources of funding for AIDS. These maneuvers parallel earlier approaches to HIV
testing and reporting that have collectively come to be known as
'exceptionalism.' This paper suggests that exceptionalism in resource allocation
is a fragile, short-term solution. In the long run, AIDS exceptionalism will
create growing injustice and should be avoided. However, we should not eliminate
the advances that this exceptionalism has already achieved. Instead, we need a
working dialogue between these advances and public policy.
PMID- 9556472
TI - Heparin prophylaxis for medical patients?
PMID- 9556471
TI - A decision analysis of mandatory compared with voluntary HIV testing in pregnant
women.
AB - BACKGROUND: The benefit of antiretroviral therapy in reducing maternal-fetal
transmission of HIV during pregnancy has caused a public policy debate about the
relative benefits of mandatory HIV screening and voluntary HIV screening in
pregnant women. OBJECTIVE: To evaluate the benefits and risks of mandatory
compared with voluntary HIV testing of pregnant women to help guide research and
policy. DESIGN: A decision analysis that incorporated the following variables:
acceptance and benefit of prenatal care, acceptance and benefit of zidovudine
therapy in HIV-infected women, prevalence of HIV infection, and mandatory
compared with voluntary HIV testing. MEASUREMENTS: The threshold deterrence rate
(defined as the percentage of women who, if deterred from seeking prenatal care
because of a mandatory HIV testing policy, would offset the benefit of zidovudine
in reducing vertical HIV transmission) and the difference between a policy of
mandatory testing and a policy of voluntary testing in the absolute number of HIV
infected infants or dead infants. RESULTS: Voluntary HIV testing was preferred
over a broad range of values in the model. At baseline, the threshold deterrence
rate was 0.4%. At a deterrence rate of 0.5%, the number of infants (n = 167)
spared HIV infection annually in the United States under a mandatory HIV testing
policy would be lower than the number of perinatal deaths (n = 189) caused by
lack of prenatal care. CONCLUSIONS: The most important variables in the model
were voluntary HIV testing, the deterrence rate associated with mandatory testing
compared with voluntary testing, and the prevalence of HIV infection in women of
child-bearing age. At high levels of acceptance of voluntary HIV testing, the
benefits of a policy of mandatory testing are minimal and may create the
potential harms of avoiding prenatal care to avoid mandatory testing.
PMID- 9556473
TI - Cancer prevention: better late than never?
PMID- 9556474
TI - Ethnic differences in mammography use among older women: overcoming the barriers.
PMID- 9556475
TI - The Gram stain.
PMID- 9556476
TI - GB virus C infection in patients with type II cryoglobulinemia.
PMID- 9556477
TI - CCR5 genotype and the clinical course of HIV-1 infection.
PMID- 9556478
TI - Coming to terms with large databases.
PMID- 9556479
TI - HLA-B27-associated cardiac disease.
PMID- 9556480
TI - Granulomatous disease in common variable immunodeficiency.
PMID- 9556481
TI - Granulomatous disease in common variable immunodeficiency.
PMID- 9556482
TI - Numeracy.
PMID- 9556483
TI - Tacrolimus to treat pyoderma gangrenosum resistant to cyclosporine.
PMID- 9556484
TI - Avoidance of tick-borne diseases.
PMID- 9556485
TI - More on the most terrible of the ministers of death.
PMID- 9556486
TI - More on the most terrible of the ministers of death.
PMID- 9556487
TI - A reluctant doctor shopper.
PMID- 9556488
TI - A reluctant doctor shopper.
PMID- 9556489
TI - A reluctant doctor shopper.
PMID- 9556490
TI - A reluctant doctor shopper.
PMID- 9556491
TI - Federated Council of Internal Medicine's resource guide for residency education.
PMID- 9556492
TI - Stevie Smith: the caregiver--poet.
PMID- 9556493
TI - [Surgery videotapes].
PMID- 9556494
TI - One schedule for all GPs.
PMID- 9556495
TI - Counts or clusters?
PMID- 9556496
TI - Evidence based general practice: fact or fancy?
PMID- 9556497
TI - Special issue on the genetics of obesity.
PMID- 9556499
TI - Vascular smooth muscle, endothelial regulation and effects of aspirin in
hypertension.
AB - Dysfunction of vascular smooth muscle (VSM) is at the center of occlusive
disorders of the cardiovascular system such as hypertension, atherosclerosis,
coronary artery disease and hypoxia. In addition to circulating biogenic amines
and various neurotransmitters originating from the central nervous system and
endocrine system, various autocoids of arachidonic acid metabolism in the blood
as well as in the endothelium play an important regulatory role in the
maintenance of the tone and the contractile function of VSM. A monolayer of
endothelial cells lining the heart and large blood vessels is responsible for
producing and releasing both endocrine and paracrine substances such as
endothelins, nitric oxide, prostaglandins and prostacyclins. Aspirin,
(acetylsalicylic acid/ASA) an ancient remedy against fever and pain, is emerging
as an effective drug not only against occlusive disorders but also against
various cancers and the AIDs virus. During pregnancy induced hypertension (PIH)
and in occlusive disorders, aspirin provides relief through inhibition of
cyclooxygenase, an enzyme required for the metabolism of arachidonic acid to
produce prostaglandins and prostacyclins in platelets and in endothelial cells.
Because of its unique molecular constitution, synergistic ability and solubility
in the lipidic environment, various mechanisms of aspirin's actions are being
currently investigated. In this review, the effect of aspirin on the regulation
of VSM in the presence and absence of endothelium are discussed.
PMID- 9556498
TI - Role of E2F in cell cycle control and cancer.
AB - E2F transcription factors regulate the expression of a number of genes important
in cell proliferation, particularly those involved in progression through G1 and
into the S-phase of the cell cycle. The activity of E2F factors is regulated
through association with the retinoblastoma tumor suppressor protein (Rb) and the
other pocket proteins, p107 and p130. Binding of Rb, p107 or p130 converts E2F
factors from transcriptional activators to transcriptional repressors. The
interplay among G1 cyclins (D-type cyclins and cyclin E), cyclin-dependent
kinases (cdk4, 6, and 2), cdk inhibitors, and protein phosphatases determines the
phosphorylation state of the pocket proteins which in turn regulates the ability
of the pocket proteins to complex with E2F. E2F activity is further regulated
through direct interactions with other factors, such cyclin A, Sp1, p53 and the
ubiquitin-proteasome pathway. Deregulated expression of E2F family member genes
has been shown to induce both inappropriate S phase entry and apoptosis. An
important role for E2F in the development of cancer is suggested by the finding
that in most human neoplasias, genetic or epigenetic alterations occur that
ultimately result in the deregulation of E2F-dependent transcription. This review
will highlight recent findings on the specific roles of the individual E2F
species in regulating transcription, proliferation and apoptosis, and discuss the
growing link between E2F and cancer.
PMID- 9556500
TI - The neutral theory and natural selection in the HLA region.
AB - Based on available DNA sequence data in the HLA region of 4 Mb, we review the
degree of polymorphism at 39 loci of which most are involved in the immune
system. The extent of nucleotide differences per silent site differs greatly from
locus to locus. It is exceptionally high at classical MHC loci, intermediate at
six MHC-related pseudogenes as well as at some loci in class I and II regions,
and low in the class III region. Different exons of individual MHC loci show also
different degrees of silent polymorphism; high in the exons encoding for the
peptide binding region (PBR) and low in the exons encoding for trans-membranes
and cytoplasmic tails. The degree of polymorphism within MHC allelic lineages is
not much smaller than that between allelic lineages, contrary to the expectation
where intra-allelic sequence exchanges are restricted. The observation that many
allelic lineages at the HLA-DRB1 locus are combinations of distinct motifs in the
beta pleated sheet and alpha helix of PBR indicates that sequence exchanges occur
even within exon 2. Semi-quantitative analysis is presented about the rate of
sequence exchanges between selected and linked neutral regions, although more
sequence information is necessary to make definite conclusions. The extraordinary
MHC polymorphism is viewed from the dual function of MHC molecules that controls
the acquired immune system.
PMID- 9556501
TI - Fact and fiction
PMID- 9556502
TI - Inspiraplex symposium on asthma
PMID- 9556503
TI - Airway inflammation and structural changes in airway hyper-responsiveness and
asthma: an overview.
AB - Asthma treatment has moved from bronchodilator therapy to an emphasis on anti
inflammatory therapy. Airway inflammation is believed to induce airway hyper
responsiveness (AHR) through the release of mediators that increase the airway
response to agonists. However, the exact contribution of airway inflammation in
the physiology of airway hyper-responsiveness remains undefined. Structural
modifications in airways resulting from inflammation may contribute to the
development and persistence of AHR and the development of asthma. This paper
reviews some of the main components of airway inflammation and structural changes
in asthma, and discusses how these processes may interact to modify airway
function and induce respiratory symptoms.
PMID- 9556504
TI - Mast cells in asthma.
PMID- 9556505
TI - Lymphocytes in asthma.
PMID- 9556507
TI - Neuropeptides: do they have a role in the pathogenesis of asthma?
PMID- 9556506
TI - Cytokine expression in bronchial asthma.
PMID- 9556508
TI - Eicosanoids and asthma.
PMID- 9556509
TI - Relationship between airway smooth muscle dysfunction and airway inflammation in
asthma.
PMID- 9556511
TI - Three-dimensional production of bronchi in vitro.
PMID- 9556510
TI - Animal models of airway inflammation and remodelling.
PMID- 9556512
TI - Remodelling of the extracellular matrix in asthma: proteoglycan synthesis and
degradation.
PMID- 9556513
TI - Airway inflammation and remodelling in asthma: airway epithelial cells.
PMID- 9556514
TI - Bronchial myofibroblasts and tissue remodelling in asthma.
PMID- 9556515
TI - Increased amount of airway smooth muscle does not account for excessive
bronchoconstriction in asthma.
PMID- 9556516
TI - Mechanisms of corticosteroid resistance in asthma: role of airway remodelling.
PMID- 9556517
TI - Irritant-induced asthma and reactive airways dysfunction syndrome.
PMID- 9556518
TI - Asthma therapy: effects on airway inflammation and remodelling.
PMID- 9556519
TI - Protein folding: nucleation and compact intermediates.
AB - Experimental and theoretical studies of protein folding have led now to
understanding some basic principles of this process. In the simplest case of two
state folding it starts from the formation of the folding nucleus which
immediately grows up embracing the whole protein molecule. However, typically
folding occurs through a compact intermediate which has some native-like features
of its 3D-structure. It is possible that also in these cases the folding nucleus
is involved in the transition state between unfolded chain and compact
intermediate.
PMID- 9556520
TI - Protein folding assisted by the GroEL/GroES chaperonin system.
AB - The chaperonin system GroEL/GroES assists in the folding of proteins in the
bacterial cytosol. Recent applications of biophysical techniques for the
structural analysis of GroEL, GroES, and chaperonin-bound protein folding
intermediates have provided the basis for understanding the molecular mechanism
of GroEL/GroES action. GroEL, a double-ring complex, binds unfolded proteins at
its inner ring surface. Protein folding proceeds in the central cavity of GroEL,
after dissociation of the polypeptide has been triggered by ATP hydrolysis in
GroEL. Premature release of unfolded protein into external solution is prevented
by binding of the cofactor GroES on top of the GroEL cylinder, resulting in an
enclosed cage. Upon ATP-dependent dissociation of GroES, substrate protein is
eventually released from GroEL in a native or native-like conformation. While
current in vitro results about the structure, function, and molecular mechanism
of GroEL/GroES-assisted protein folding have led to a quite detailed picture of
this complex process, the extent to which the GroEL/GroES system actually
participates in the folding of newly-synthesized proteins in the cell is less
defined and remains a subject for further studies. Ingenious biochemical and
genetic approaches will be necessary to show whether our current view of
chaperonin action indeed accurately reflects its modus operandi inside a living
cell.
PMID- 9556521
TI - GroE chaperonin-assisted folding and assembly of dodecameric glutamine
synthetase.
AB - The folding and assembly of Escherichia coli dodecameric glutamine synthetase is
facilitated by the E. coli GroE chaperonins, GroEL and GroES. Since endogenous
glutamine synthetase monomers are bound to GroEL immediately after cell lysis and
are assembly competent, this strongly suggests that glutamine synthetase is an
authentic substrate of the GroE chaperonins. At physiological temperatures, the
in vitro reactivation of glutamine synthetase increases from 10 to 70-80% of the
original activity when the chaperonin GroEL is included. Although nucleotide
binding is sufficient to dissociate assembly competent glutamine synthetase
monomers from GroEL, the addition of GroES substantially accelerates the
dissociation, assembly, and reactivation. The interactions of glutamine
synthetase monomers with the activated chaperonin are transient (t1/2 = 10 sec)
and these monomers can be released from GroEL at high concentrations without
misfolding or inappropriate aggregation. It has been found that the nucleotide
induced conformational change of GroEL is critical for folding success of
glutamine synthetase because the simple displacement of glutamine synthetase
monomers from the GroEL chaperonin with another protein substrate inhibits
reactivation. During glutamine synthetase refolding, the "high affinity"
nucleotide-free GroEL is most efficient in preventing initial folding
intermediates from partitioning to off-pathway folding routes. Interestingly, the
more physiologically relevant "low affinity" nucleotide-bound ((ATP/ADP) GroEL-
GroES) complex is not as efficient at capturing the initial folding intermediates
of glutamine synthetase. In contrast to glutamine synthetase, non-authentic
"model" substrates such as mammalian mitochondrial rhodanese and mitochondrial
malate dehydrogenase show no differences in folding efficiencies with either the
"low affinity" or "high affinity" complexes. Besides the nature of the chaperonin
complex itself, the mechanism of GroE-assisted folding is determined by the
folding environment and, most importantly, by initial interactions of chaperonins
with folding intermediates. Glutamine synthetase interacts only transiently with
chaperonin complexes, while most of the "model" proteins exhibit relatively long
interactions times. It may be indicative of a specific evolutionary selected
mechanism of chaperonin-assisted folding (optimizing the folding kinetics),
different from that observed with non-authentic chaperonin substrates. Since the
kinetics of protein folding depends heavily on the solution environment, studies
involving in vivo chaperonin substrates under conditions that closely mimic those
found in the cell will be required to define and solve the physiologically
relevant kinetic mechanism of chaperonin-assisted folding.
PMID- 9556522
TI - Chaperones in bacteriophage T4 assembly.
AB - Protein folding in the cell is controlled at the levels of translation and post
translational modification, depends on a number of conserved proteins known as
chaperones, and is catalyzed by specific enzymes, such as protein disulfide
isomerase and peptidyl prolyl cis-trans isomerase. The chaperones stabilize
folding intermediates and participate in assembly and disaggregation of
supramolecular structures. Bacteriophage T4 is an especially convenient system
for studying of protein folding mechanisms, since its genome encodes several
virus-specific chaperones. In this review, the chaperones of phage T4 that take
part in capsid formation (gp31 and gp40) and in folding and assembly of virion
tail fibers (gp38, gp57A) have been considered. Protein encoded by gene 31
completely substitutes co-chaperonin GroES of the host cell in folding of the
major capsid protein, gp23, aided by chaperonin GroEL. The product of gene 40,
which is homologous to analogs of eukaryotic GroEL and peptidyl prolyl cis-trans
isomerase, participates in assembly of gp20 while the formation of procapsid
connector. The chaperone encoded by gene 57A is essential for folding and
oligomerization of both long and short phage tail fibers. gp38, together with
gp57A, participates in the formation of the distal part of the long fibers. This
protein seems to represent a principally new group of chaperones that change
steric structure of folded polypeptide. One phage chaperone, fibritin, encoded by
gene wac (whiskers antigen control) and taking part in assembly the subunits of
the long tail fibers is a constituent of the virion. Fibritin is a convenient
model for studying mechanisms of folding and oligomerization of fibrous proteins
due to its labile triple-stranded alpha-helical coiled-coil structure.
PMID- 9556523
TI - Isomerase and chaperone activities of protein disulfide isomerase are both
required for its function as a foldase.
AB - Protein disulfide isomerase (PDI) is not only an isomerase catalyzing the
formation of native disulfide bond(s) of nascent peptide, but also a molecular
chaperone assisting chain folding. The intrinsic chaperone activity of PDI is
independent of its isomerase activity as shown by its ability of promoting in
vitro reactivation and suppressing aggregation during refolding of denatured
proteins containing no disulfide. The -CGHC- active sites of PDI are not required
for its chaperone activity and a mutant PDI with no isomerase activity does
function in vitro and in vivo. The peptide binding site of PDI is responsible for
its chaperone activity. Both isomerase and chaperone activities are required for
PDI to function as a foldase in assisting protein folding, in other words, the
foldase activity of PDI consists of both isomerase and chaperone activities.
PMID- 9556524
TI - Artificial chaperone-assisted refolding of proteins.
AB - A new two-step procedure of protein refolding in vitro, proposed by Rozema and
Gellman and named artificial chaperone-assisted refolding, is discussed. The new
approach has been inspired by the two-step mechanism of the GroE system. In the
first step, the protein is captured by a detergent under conditions that would
normally lead to irreversible protein aggregation (heating or denaturant
removal). In the second step, removal of detergent from the protein--detergent
complex is triggered by addition of a cyclodextrin which is capable of forming
"inclusion complexes" with detergent, allowing the protein to refold. The protein
refolded with artificial chaperones (detergent and cyclodextrin) may be purified
via a two-step protocol. After refolding was complete, the solution was passed
through a 0. 22-micro(m) filter, to remove aggregated protein, and then through a
M = 10 kD cutoff filter. The second filtration was intended to allow the low
molecular-weight artificial chaperones to pass, but to retain the refolded
enzyme. The application of the above procedure for refolding of carbonic
anhydrase B from human erythrocytes, hen egg white lysozyme, pig heart citrate
synthase, and creatine kinase from rabbit skeletal muscles (MM isoenzyme) is
discussed.
PMID- 9556525
TI - Effect of natural ligands on the structural properties and conformational
stability of proteins.
AB - The effect of natural ligands on the structural properties and conformational
stability of proteins is reviewed. It is shown that the range of possible
structural transformations induced in a protein molecule by ligand release is
very wide and virtually does not depend on the nature of the protein or that of
the ligands. Ligand-free forms of protein are classified from the viewpoint of
structural property changes of a protein molecule.
PMID- 9556526
TI - Modeling of irreversible thermal protein denaturation at varying temperature. I.
The model involving two consecutive irreversible steps.
AB - The model of thermal protein denaturation involving two consecutive irreversible
steps has been analyzed. The equation describing the dependence of excess heat
capacity (Cpex) on temperature (T) under a constant scanning rate has been
obtained and used for construction of theoretical Cpex versus T profiles. The
change in the shape of theoretical profiles at varied Arrhenius equation
parameters, ratio for enthalpies of the first and second steps, and the scanning
rate have been studied. It has been shown that formal use of one-step model does
not provide adequate information about kinetic features of the process in the
case of protein denaturation following the mechanism involving two consecutive
irreversible steps.
PMID- 9556527
TI - Application of the method of thermal denaturation for investigation of alpha
chymotrypsin adducts with poly.
AB - The thermostability of conjugates, non-covalent complexes and mixtures of alpha
chymotrypsin (alpha-ChT) with poly(alkylene oxides)--poly(ethylene glycol) (PEG)
with molecular mass of 1.9 kD and diblock copolymers of ethylene and propylene
oxides (proxanols)--has been investigated. It was shown that the addition of PEG
in concentration up to 2 wt. % to the solution of alpha-ChT did not affect the
rate of the enzyme thermoinactivation. Meanwhile the addition of proxanol in the
same concentration resulted in twofold decrease in the rate constant for the slow
inactivation step, k2. Even more pronounced decrease in the thermoinactivation
rate was observed for alpha-ChT--proxanol complexes obtained by heating or under
the action of high pressure. The general tendency in the behavior of complexes of
both types was the decrease in the k2 constant as the temperature or pressure
used for complex preparation increased. The highest stabilizing effect was
observed for complex obtained by heating up to 52 degreesC and containing maximal
number of polymer chains (molar ratio proxanol/alpha-ChT was 10). For this
complex fourfold decrease in the k2 value was observed. Covalent attachment of
PEG or proxanol to enzyme gives maximal stabilizing effect with up to tenfold
decrease in the k2 value. The investigation of the thermal denaturation kinetics
of alpha-ChT and its adducts with poly(alkylene oxides) by means of fluorescence
spectroscopy has shown that the presence of polymer chains practically does not
affect the rate of protein denaturation registered by the decrease in the
intensity of protein fluorescence. The polymer chains, probably, diminish the
rate of melting of the active site-containing region of the protein molecule. At
the same time, the overall denaturation rate is independent of the presence of
polymer chains in the vicinity of the protein globule.
PMID- 9556528
TI - Decrease of dielectric constant transforms the protein molecule into the molten
globule state.
AB - The effect of organic solvents of different nature (alcohols, amides, and cyclic
ethers) on the structural properties of beta-lactoglobulin was studied by
circular dichroism and fluorescence spectroscopy. It is shown that the protein
molecule undergoes at least two consecutive conformational transitions upon
increase of the organic solvent concentration. Denaturation of the protein
molecule occurs in the first step and a transition into the highly helical non
compact state in the second. In other words, under such conditions a compact
denatured intermediate state is formed with a pronounced secondary structure,
i.e., a molten globule-like state. It is shown that decrease of the dielectric
constant of the media is responsible for structural changes of the protein
molecule.
PMID- 9556529
TI - Structural effect of association on protein molecules in partially folded
intermediates.
AB - Fluorescence and circular dichroism spectroscopy, small angle X-ray scattering
and high performance liquid gel filtration have shown that oligomerization
considerably affects the structural properties and conformational stability of
partially folded intermediates of staphylococcal nuclease. Conformational
transitions induced by different anions and association in the acid-unfolded
protein are described. It is shown that association of non-native conformations
of the protein molecule can be an additional structuring factor. The
corresponding folding schemes and phase diagrams are suggested.
PMID- 9556530
TI - Structural properties of staphylococcal nuclease in oligomeric A-forms.
AB - Association affects the structural properties of different partially folded
conformations of staphylococcal nuclease induced by anions of different nature.
It is shown that oligomerization induces new structural levels in non-native A
forms. A close structural similarity between the monomeric A2 and the dimeric
(A1)2 forms as well as between the monomeric A3 and oligomeric [(A1)2]M and [A2]M
forms is established. This suggests that association of a protein molecule in
partially folded conformations can be an additional structure forming factor.
PMID- 9556531
TI - Equilibrium unfolding of partially folded staphylococcal nuclease A2- and A3
forms is accompanied by the formation of an intermediate state.
AB - Structural properties of an equilibrium intermediate formed upon urea-induced
unfolding of more ordered staphylococcal nuclease A-forms (A2 and A3) are
studied. The effect of association on the structural properties and
conformational stability of this unfolding intermediate is also considered. A
close structural similarity (including tendency for association) is shown between
this intermediate and the least ordered A1-form, induced in the acid-unfolded
nuclease by moderate sulfate or chloride concentrations.
PMID- 9556532
TI - Thermodynamic stability of immunoglobulins and allosteric interactions with
ferritin and protein A: distinct properties of the two antibodies of IgG2a
subclass.
AB - The two anti-ferritin monoclonal antibodies of mouse IgG2a subclass, G10 and F11,
are described that have similar affinity to human spleen ferritin and identical
protein A-binding affinity. Antigen binding was shown to change significantly the
protein A-binding parameters of the IgG2a antibodies. Antigen-induced
conformational changes result in enhanced protein A-binding affinity of the G10
antibody while reduced affinity of the F11 antibody. Antigen binding does not
change inherently low affinity of the anti-ferritin IgG1 antibody C5 to protein
A. Differential scanning calorimetry revealed that the enthalpy and Gibbs free
energy of denaturation for G10 was respectively by 19 and 29% higher than the
corresponding parameters for F11. The lower structural energetics of F11 is
associated with the lack of a calorimetrically revealed folding unit that may be
responsible for distinct interaction between the antigen-binding and protein A
binding sites. This work provides experimental demonstration of the fact that
functionally significant interactions between the two spatially remote
recognition sites in antibodies of the same heavy chain isotype can be modulated
by relatively small structural variations that also result in different
thermodynamic stability.
PMID- 9556533
TI - Protein sizes and stoichiometry in the chaperone SecB--RBPTI complex estimated by
ANS fluorescence.
AB - Interaction of the SecB E. coli chaperone with model precursor protein, the
reduced form of bovine pancreatic trypsin inhibitor (RBPTI), in aqueous solution
was studied using ANS fluorescence. Binding of RBPTI by SecB-ANS led to an
increase and blue shift in the ANS fluorescence. Two ANS emission centers exist
in the proteins and their complex: the short-lived center (lifetime of
approximately 1 nsec) where ANS is strongly quenched by polar amino acid residues
and the long-lived center (6-12 nsec) where ANS emits from the hydrophobic
pocket. Estimation of the volumes and diameters of RBPTI, SecB, and the SecB-
RBPTI complex using fluorescence lifetime and polarization of ANS by a modified
Levshin--Perrin equation was done. Effective diameter of the SecB equals to 33.4
A. The diameter of the SecB--RBPTI complex is 49.8 A. The volume of the complex
equals to sum of volumes of one tetrameric SecB and four RBPTI molecules. The
binding of RBPTI molecules into the tetramer SecB is not an insertion to a "pore"
without increase of the protein sizes, but "paste" of four polypeptide molecules
to four subunits of SecB.
PMID- 9556534
TI - Reactivation of sea-urchin sperm flagella induced by rapid photolysis of caged
ATP.
AB - Sea-urchin sperm flagella in a state of rigor were reactivated by rapid
photolysis of caged ATP. After a time lag of 11-17 ms, all bends in the axonemes
present during rigor began to be propagated towards the tip as if their
propagation had not been interrupted. This result suggests that the site-specific
activity of dyneins along the length of the axoneme is preserved even during
rigor states when ATP is absent and that regulation of the activity can be
restarted immediately with a new cycle of ATP turnover. During the starting
transient, pre-existing rigor waves in the distal region were propagated without
a change in the maximal shear angle until they disappeared at the tip. This was
more evident when the rapid reactivation was triggered in high-viscosity
solution, in which only the form of new bends was greatly affected by viscous
load. After reactivation, the velocity of microtubule sliding increased and
reached a plateau within 28 ms. This time course reflects the rate of force
generation by dynein in situ.
PMID- 9556535
TI - Muscle power output limits fast-start performance in fish.
AB - Fast-starts associated with escape responses were filmed at the median habitat
temperatures of six teleost fish: Notothenia coriiceps and Notothenia rossii
(Antarctica), Myoxocephalus scorpius (North Sea), Scorpaena notata and Serranus
cabrilla (Mediterranean) and Paracirrhites forsteri (Indo-West-Pacific Ocean).
Methods are presented for estimating the spine positions for silhouettes of
swimming fish. These methods were used to validate techniques for calculating
kinematics and muscle dynamics during fast-starts. The starts from all species
show common patterns, with waves of body curvature travelling from head to tail
and increasing in amplitude. Cross-validation with sonomicrometry studies allowed
gearing ratios between the red and white muscle to be calculated. Gearing ratios
must decrease towards the tail with a corresponding change in muscle geometry,
resulting in similar white muscle fibre strains in all the myotomes during the
start. A work-loop technique was used to measure mean muscle power output at
similar strain and shortening durations to those found in vivo. The fast Sc.
notata myotomal fibres produced a mean muscle-mass-specific power of 142.7 W kg-1
at 20 degrees C. Velocity, acceleration and hydrodynamic power output increased
both with the travelling rate of the wave of body curvature and with the habitat
temperature. At all temperatures, the predicted mean muscle-mass-specific power
outputs, as calculated from swimming sequences, were similar to the muscle power
outputs measured from work-loop experiments.
PMID- 9556536
TI - Optimal shortening velocity (V/Vmax) of skeletal muscle during cyclical
contractions: length-force effects and velocity-dependent activation and
deactivation.
AB - The force-velocity relationship has frequently been used to predict the
shortening velocity that muscles should use to generate maximal net power output.
Such predictions ignore other well-characterized intrinsic properties of the
muscle, such as the length-force relationship and the kinetics of activation and
deactivation (relaxation). We examined the effects of relative shortening
velocity on the maximum net power output (over the entire cycle) of mouse soleus
muscle, using sawtooth strain trajectories over a range of cycle frequencies. The
strain trajectory was varied such that the proportion of the cycle spent
shortening was 25, 50 or 75 % of the total cycle duration. A peak isotonic power
output of 167 W kg-1 was obtained at a relative shortening velocity (V/Vmax) of
0.22. Over the range of cyclical contractions studied, the optimal V/Vmax for
power production ranged almost fourfold from 0.075 to 0.30, with a maximum net
power output of 94 W kg-1. The net power output increased as the proportion of
the cycle spent shortening increased. Under conditions where the strain amplitude
was high (i.e. low cycle frequencies and strain trajectories where the proportion
of time spent shortening was greater than that spent lengthening), the effects of
the length-force relationship reduced the optimal V/Vmax below that predicted
from the force-velocity curve. At high cycle frequencies and also for strain
trajectories with brief shortening periods, higher rates of activation and
deactivation with increased strain rate shifted the optimal V/Vmax above that
predicted from the force-velocity relationship. Thus, the force-velocity
relationship alone does not accurately predict the optimal V/Vmax for maximum
power production in muscles that operate over a wide range of conditions (e.g.
red muscle of fish). The change in the rates of activation and deactivation with
increasing velocity of stretch and shortening, respectively, made it difficult to
model force accurately on the basis of the force-velocity and length-force
relationships and isometric activation and deactivation kinetics. The
discrepancies between the modelled and measured forces were largest at high cycle
frequencies.
PMID- 9556537
TI - Morphometric and biochemical characteristics of ventricular hypertrophy in male
rainbow trout (Oncorhynchus mykiss).
AB - We examined the morphometric and biochemical effects of ventricular hypertrophy
in male rainbow trout (Oncorhynchus mykiss) during sexual maturation. Our
investigation focused on characterizing the growth of ventricular layers, on
cardiomyocyte dimensions (length, cross-sectional area and cell volume) and on
the activities of enzymes involved in intermediary metabolism. Relative ventricle
mass (100 x ventricle mass/body mass) increased by as much as 2.4-fold during
sexual maturation [as defined by an increasing gonadosomatic index (100 x gonad
mass/body mass)], and this resulted in an increased proportion of epicardium
relative to endocardium. Ventricular enlargement was associated with increased
length (+31 %) and transverse cross-sectional area (+83 %) of cardiomyocytes,
which resulted in an expansion of up to 2.2-fold in mean myocyte volume (from
1233 to 2751 micron3). These results indicate that sexual maturation induces
ventricular enlargement through myocyte hypertrophy. Cell length and cross
sectional area were similar in both myocardial layers, and myocytes were
elliptical rather than circular in transverse cross section. Ventricular
hypertrophy did not alter transverse cell shape, perhaps reflecting the
maintenance of short diffusion distances for small molecules as cells
hypertrophy. Myocyte hypertrophy could not account entirely for the sevenfold
range of ventricle masses from different-sized fish, indicating that myocyte
hyperplasia contributes substantially to ventricular growth as trout grow.
Measurements of the maximal activities of metabolic enzymes demonstrated that
ventricular hypertrophy was associated with (1) higher epicardial but not
endocardial activities of citrate synthase (by 23 %) and beta-hydroxyacyl-CoA
dehydrogenase (by 20 %); (2) lower activities of hexokinase (by 50 %) in both
layers, and (3) no change in lactate dehydrogenase or pyruvate kinase activities,
which were also similar between layers. These results suggest that the energetic
needs of the hypertrophied trout ventricle may be met through increased reliance
on fatty acid oxidation, particularly by the endocardium, but decreased reliance
on glucose as a metabolic fuel in both layers.
PMID- 9556538
TI - Analyses of cDNA and recombinant protein for a potent vasoactive protein in
saliva of a blood-feeding black fly, Simulium vittatum.
AB - A cDNA was cloned from the salivary glands of a blood-feeding black fly Simulium
vittatum. The encoded protein has been given the name Simulium vittatum erythema
protein or SVEP, because of its ability to increase blood perfusion in skin
capillaries, resulting in the well-characterized erythema of black fly bites. The
full-length cDNA contains 548 base pairs which encode 152 amino acid residues of
the nascent protein. Post-translational processing produces a mature, secreted
protein of 133 residues with a molecular mass of 15.4 kDa. Recombinant SVEP
(rSVEP) was produced in a baculovirus expression system and purified by a one
step reversed-phase HPLC procedure. Analyses of physical properties and
biological potency demonstrated fidelity of rSVEP to the native protein.
Recombinant SVEP relaxed rabbit aorta preparations when preconstricted with 2
micromol l-1 phenylephrine or 25 mmol l-1 K+ but not with 60 mmol l-1 K+.
Further, the rSVEP-induced relaxation response of phenylephrine-constricted aorta
was inhibited by glibenclamide (10 micromol l-1), suggesting that at least part
of its action to relax smooth muscle may result from the opening of ATP-dependent
K+ channels. SVEP is a novel salivary-gland-derived vasoactive protein that may
be essential for blood feeding by black flies and could potentially enhance
transmission of filarial parasites.
PMID- 9556540
TI - Factors contributing to seasonal increases in inoculative freezing resistance in
overwintering fire-colored beetle larvae dendroides canadensis
AB - The insects and microarthropods that vary seasonally in susceptibility to cross
cuticular inoculation by external ice (inoculative freezing) represent a
phylogenetically diverse group; however, few studies have explored possible
mechanisms experimentally. This study documents seasonally variable inoculative
freezing resistance in Dendroides canadensis beetle larvae and combines
immunofluorescence, in vivo removal of epicuticular lipids and in vitro chamber
studies to explore the roles of seasonal modification in the cuticle and in
epidermal and hemolymph antifreeze proteins (AFPs). Seasonal cuticular
modifications contribute to the inhibition of inoculative freezing since more
cold-hardy larvae froze inoculatively when epicuticular waxes were removed with
hexane and, in in vitro chamber experiments, cuticle patches (with the underlying
epidermis removed) from winter larvae provided greater protection from
inoculative freezing than did cuticle patches from summer larvae. The results
indicate that seasonal modifications in epidermal and hemolymph AFPs contribute
most strongly to the inhibition of inoculative freezing. Subcuticular epidermal
AFPs were present in immunocytochemically labeled transverse sections of winter
larvae but were absent in summer ones. Winter integument patches (cuticle with
epidermis) were more resistant to inoculative freezing than were summer
integument patches. Integument patches resisted inoculative freezing as well as
live winter-collected larvae only when hemolymph AFP was added. The results also
suggest that some integumentary ice nucleators are removed in cold-hardy larvae
and that AFP promotes supercooling by inhibiting the activity of these
nucleators.
PMID- 9556539
TI - Kinematic models of the buccal mass of Aplysia californica.
AB - The feeding behavior of the marine mollusc Aplysia californica is an intensively
studied model system for understanding the neural control of behavior. Feeding
movements are generated by contractions of the muscles of the buccal mass. These
muscles are internal and cannot be visualized during behavior. In order to infer
the movements of the muscles of the buccal mass, two kinematic models were
constructed. The first kinematic model assumed that the complex consisting of the
pincer-like radula and the underlying odontophore was spherical in shape. In this
model, the radula/odontophore was moved anteriorly or posteriorly and the more
superficial buccal muscles (I1/I3 and I2) were fitted around it. Although the
overall buccal mass shapes predicted by this model were similar to those observed
in vivo during protraction, the shapes predicted during retraction were very
different. We therefore constructed a second kinematic model in which the shape
of the radula/odontophore was based on the shapes assumed by those structures in
vitro when they were passively forced into protraction, rest or retraction
positions. As each of these shapes was rotated, the second kinematic model
generated overall shapes of the buccal mass that were similar to those observed
in vivo during swallowing and tearing, and made predictions about the antero
posterior length of the buccal mass and the relative location of the lateral
groove. These predictions were consistent with observations made in vivo and in
vitro. The kinematic patterns of intrinsic buccal muscles I1 and I2 in vivo were
estimated using the second model. Both models make testable predictions with
regard to the functions and neural control of intrinsic buccal muscles I2 and I3.
PMID- 9556541
TI - Defensive ink pigment processing and secretion in Aplysia californica:
concentration and storage of phycoerythrobilin in the ink gland.
AB - The marine snail Aplysia californica obtains its defensive ink exclusively from a
diet of red seaweed. It stores the pigment (phycoerythrobilin, the red algal
photosynthetic pigment, r-phycoerythrin, minus its protein) in muscular ink
release vesicles within the ink gland. Snails fed a diet of green seaweed or
romaine lettuce do not secrete ink and their ink-release vesicles are largely
devoid of ink. Successive activation of individual ink-release vesicles by ink
motor neurons causes them to secrete approximately 55 % of their remaining ink
(similar to the percentage of ink reserves released from the intact gland). The
peripheral activation of vesicles appears to be cholinergic: 70 % of isolated
vesicles were induced to squeeze ink from their valved end by solutions of
acetylcholine at concentrations of 0.5 mmol l-1 or below. Ultrastructural
analysis commonly found three cell types in the ink gland. The RER cells, the
most numerous, were characterized by an extensive rough endoplasmic reticulum
with greatly distended cisternae. This cell type is probably the site for
synthesis of the high molecular mass protein of secreted ink. The granulate
cells, less common than RER cells, had nuclear and cell areas significantly
larger than those of RER cells. In addition, granulate cells of red-algal-fed
snails had 4-14 vacuoles that contained electron-dense material with staining
characteristics similar to that of ink in mature ink-release vesicles. The
granulate cell's plasma membrane was regularly modified into grated areas, which
both localized and expanded the surface area for coated vesicle formation and
provided a sieve structure that prevented large particles in the hemolymph either
from being taken up by, or from occluding, the coated vesicles. Electron-dense
particles within coated vesicles were similar in size to those in granulate
vacuoles but larger (on average by approximately 1 nm) than those that make up
the ink. In green-seaweed-fed snails, granulate cells and their vacuoles were
present but the vacuoles were empty. The third cell type, the vesicle cell,
expands markedly, with its nucleus enlarging concurrent with cell growth until it
is on average 50 times larger in cross-sectional area than the nuclei of either
RER or granulate cells; the cytoplasm eventually becomes filled with ink, which
obscures the mitochondria, vacuoles and nucleus. Continued cell expansion ceases
with the appearance of an encircling layer of muscle and 1-3 layers of cells of
unknown origin, thereby becoming the ink-release vesicle itself. The absorption
spectra of the soluble contents of mature ink-release vesicles from snails fed
red algae had peaks characteristic of the red algal pigment r-phycoerythrin
or/and phycoerythrobilin. Immunogold localization of r-phycoerythrin showed no
statistical difference in the amount of label within the ink-release vesicles,
RER or granulate cell types. Furthermore, there was no localization of
phycoerythrin immunoreactivity within the various cellular compartments of either
the RER or granulate cells (nucleus, endoplasmic reticulum, mitochondria,
vacuoles). Immunogold labeling in the ink gland ranged from 11 to 16 % of that
for the digestive vacuoles of the rhodoplast digestive cells lining the tubules
of the digestive gland. Our observations suggest (a) that the main form of the
ink pigment in the gland is phycoerythrobilin or/and a non-antigenic form of
phycoerythrin, and (b) that separation of the bilin from phycoerythrin (or its
modification so that it is no longer antigenic) occurs before it reaches the ink
gland, probably within the vacuoles of the rhodoplast digestive cells of the
digestive gland. We propose the following model. The ink pigment,
phycoerythrobilin, is cleaved from its protein in rhodoplast digestive vacuoles
in the digestive gland. (ABSTRACT TRUNCATED)
PMID- 9556542
TI - Species-specific action and distribution of tachykinin-related peptides in the
foregut of the cockroaches Leucophaea maderae and Periplaneta americana.
AB - Nine tachykinin-related peptides (TRPs) have been isolated from the brain and
intestine of the cockroach Leucophaea maderae. In the present investigation, two
of the nine TRPs, LemTRP 1 and 5, were tested for their ability to stimulate
contractions in the foregut of the cockroaches L. maderae and Periplaneta
americana in vitro. The two LemTRPs and the related locust peptide
locustatachykinin I (LomTK I) induced contractions in the foregut of P. americana
in a dose-dependent manner, but had no myostimulatory action in L. maderae. A
half-maximal response for the LemTRPs and LomTK I was obtained at 5x10(-9)mol l
1. In both species, the neuropeptide proctolin stimulated foregut contractions.
Using an antiserum to LomTK I, we demonstrated that in both species there are
LomTK-like-immunoreactive (LomTK-LI) cell bodies and fibers within the ganglia
and nerves of the stomatogastric nervous system. However, correlated with the
species-specific action of the TRPs, we found efferent LomTK-LI nerve fibers
supplying muscle fibers in the foregut of P. americana, but not in L. maderae. In
both cockroach species, there is a rich supply of proctolin-immunoreactive fibers
to the foregut muscle. Some of the LomTK-LI fibers supplying the P. americana
foregut muscle contain co-localized proctolin immunoreactivity. These fibers
appear to be derived from a large cell body in the frontal ganglion which also
displayed co-localized immunoreactivities. Since TRP-containing neurons are
restricted to the nerves and ganglia of the stomatogastric nervous system both in
P. americana and L. maderae, TRPs may be involved in the control of foregut
movements in both species, but in P. americana the control may be more complex
with the additional peripherally projecting LomTK-LI neurons.
PMID- 9556543
TI - Cyclic-AMP-induced water uptake in a moth ovary: inhibition by bafilomycin and
anthracene-9-carboxylic acid.
AB - The ion physiology of osmotic swelling and a consequent loss of epithelial
patency was examined in the ovaries of the moth Hyalophora cecropia. After 30 min
in the presence of an activator of cyclic-AMP-dependent protein kinase (PKA), the
membrane potentials of both oocyte and follicle cells had hyperpolarized by
approximately 30 %, cytoplasmic pH had dropped from 7.26 to 7.06, a normally low
Cl- conductance had increased and the follicle cells had begun to swell. Since
ion distribution studies have indicated that conductance increases should
depolarize membranes in this system, it is proposed that hyperpolarization may be
effected by an azide-inhibitable component of the membrane potential. Nanomolar
levels of bafilomycin, an inhibitor of H+ V-ATPase, blocked the active component
and prevented osmotic swelling in response to PKA activation. Under a variety of
circumstances, correlations were seen between membrane potential and cytoplasmic
pH, suggesting that substrate availability to the proton pump may contribute to
hyperpolarization. H+ V-ATPases are known to energize ion and water transport
across many epithelia, but in this case they generate water absorption by the
epithelium. The increase in Cl- conductance was also required for the swelling
response: the Cl- channel blocker anthracene-9-carboxylic acid prevented both
swelling and hyperpolarization, as did Cl- substitution in the medium.
Differences in isotope loading rates between 36Cl- and 86Rb+ suggested that,
after PKA activation, Cl- functions other than as a counterion for K+ uptake.
PMID- 9556544
TI - Sound production in the collared dove: a test of the 'whistle' hypothesis
AB - The mechanism of sound production in the collared dove Streptopelia decaocto was
studied to test the validity of the 'whistle' model and to analyze the role of
vocal tract resonances. In this study, the vocalizations of six male adult doves
were recorded both in normal air and in a mixture of 80 % helium and 20 % oxygen
(heliox). Depending on the way in which the syrinx operates, the spectral
structure of the vocalizations is expected to show specific changes in heliox.
The effects of heliox differed substantially depending on the type of vocal
element. Except for a significant decrease in amplitude, unmodulated elements,
i.e. elements with a constant frequency, were relatively unaffected by heliox. In
contrast, modulated elements, i.e. elements with an abrupt increase in frequency,
showed a gradual increase in frequency with increasing helium concentration. This
specific increase in frequency stopped when the modulation frequency was 1.5
times the base frequency, even when the helium concentration was increased
further. In some individuals, a frequency band of half the base frequency was
also observed. In general, the proportion of modulated elements also showed a
significant decrease. The lack of change in the fundamental frequency of the
unmodulated elements and in the base frequency of the modulated elements
indicates that these vocalizations are not produced like a whistle. It is more
likely that they are the result of vibration of the syringeal membranes.
Generally, vocal tract resonances do not play an active role in the modification
of vocalizations, although they might enhance the fundamental frequency
passively. The results suggest that the almost pure tonal vocalizations are
produced as such in the syrinx and undergo limited modification when passing
through the vocal tract. The effect of heliox on the modulation frequency
suggests (1) that different sound-producing mechanisms may underlie different
types of vocalizations, and (2) that resonance properties of the vocal system may
be involved in the production or modification of the modulation frequency.
PMID- 9556545
TI - Proline powers pre-flight warm-up in the african fruit beetle pachnoda sinuata
AB - We investigated thoracic temperatures (Tth) during different activities of the
endothermic fruit beetle Pachnoda sinuata and analysed which energy substrates
are used for the pre-flight warm-up of its flight muscles. Pachnoda sinuata
elevates its Tth prior to take-off either by basking in the sun or by warming
endothermically to a narrow range around 34 degreesC. During lift-generating
tethered flight at low ambient temperatures (Ta=25 degreesC), Tth of P. sinuata
decreases steadily until it reaches 28 degreesC, which is not sufficiently high
to sustain flight. Tth remains stable during lift-generating tethered flight at
high Ta (31 degreesC). Wingbeat frequency (fw) is dependent on Tth: when Tth
declines, fw decreases in a linear manner. The proline concentrations in the
haemolymph and flight muscles decrease during warm-up. In contrast, the
carbohydrate levels in the haemolymph and flight muscles are not affected by the
warm-up process, while the glycogen level of the flight muscles declines
significantly during the first 10 s of lift-generating tethered flight. This
suggests that the energy for endothermic warm-up is produced solely by the
oxidation of proline. Measurements of the respiratory quotient (RQ) confirmed
that P. sinuata uses a combination of carbohydrates and proline to power its
flight. At rest and during lift-generating tethered flight, the RQ is
approximately 0.9. During warm-up, the RQ is significantly lower at 0.82, which
is close to the theoretical value of 0.8 for the partial oxidation of proline.
The rate of oxygen consumption during endothermic warm-up is 45 % of that during
lift-generating tethered flight
PMID- 9556546
TI - Myotomal slow muscle function of rainbow trout Oncorhynchus mykiss during steady
swimming.
AB - Strain and activity patterns were determined during slow steady swimming
(tailbeat frequency 1.5-2.5 Hz) at three locations on the body in the slow
myotomal muscle of rainbow trout Oncorhynchus mykiss using sonomicrometry and
electromyography. Strain was independent of tailbeat frequency over the range
studied and increased significantly from +/-3.3 % l0 at 0.35BL to +/-6 % at
0.65BL, where l0 is muscle resting length and BL is total body length. Muscle
activation occurred significantly later in the strain cycle at 0.35BL (phase
shift 59 degrees) than at 0.65BL (30 degrees), and the duration of activity was
significantly longer (211 degrees at 0.35BL and 181 degrees at 0.65BL). These
results differ from those of previous studies. The results have been used to
simulate in vivo activity in isolated muscle preparations using the work loop
technique. Preparations from all three locations generated net positive power
under in vivo conditions, but the negative power component increased from head to
tail. Both kinematically, and in the way its muscle functions to generate
hydrodynamic thrust, the rainbow trout appears to be intermediate between
anguilliform swimmers such as the eel, which generate thrust along their entire
body length, and carangiform fish (e.g. saithe Pollachius virens), which generate
thrust primarily at the tail blade.
PMID- 9556547
TI - Spatial vision in the prosobranch gastropod ampularia sp
AB - The eyes of gastropods of the genus Ampularia superficially resemble the well
developed camera-type eyes of Littorina littorea and Strombus raninus. The eyes
are of the closed-vesicle type, having a cornea and a lens that is separated from
the retina by a narrow vitreous body. Light and electron microscopy were used to
generate an accurate geometrical model of the Ampularia sp. eye, which was then
used to predict its optical performance. The image quality of the lens was
investigated using a modified microscope and revealed that images suffer from
severe aberrations. The focal length was estimated to be approximately 430
microm, putting the plane of best focus in or just proximal to the rhabdoms. The
aberrant optics result in a large retinal blur-circle with a diameter of
approximately 120 microm and an angular half-width of approximately 17 degrees,
allowing only comparatively poor resolution compared with the eyes of Littorina
littorea and Strombus raninus. Behavioural experiments revealed no significant
optomotor response. The results imply that Ampularia sp. has poor spatial vision,
limited by the blur-circles on the retina. The eyes appear to be suitable only
for relatively simple visual tasks, such as finding an open water surface for
breathing, but the large size of the eye allows it to perform this task even at
night.
PMID- 9556548
TI - Different effects of Gsalpha splice variants on beta2-adrenoreceptor-mediated
signaling. The Beta2-adrenoreceptor coupled to the long splice variant of Gsalpha
has properties of a constitutively active receptor.
AB - The beta2-adrenoreceptor (beta2AR) couples to the G-protein Gs to mediate
adenylyl cyclase activation. The splice variants of Gs alpha differ by a 15-amino
acid insert between the Ras-like domain and the alpha-helical domain. The long
splice variant of Gs alpha (Gs alphaL) binds GDP with lower affinity than the
short splice variant (Gs alphaS), but the impact of this difference on the
interaction of Gs alpha with the beta 2AR is not known. We studied the beta2
AR/Gs alpha interaction using receptor/G-protein fusion proteins (beta2 AR Gs
alphaS and beta2 AR Gs alphaL) expressed in Sf9 cells. Fusion of the beta2 AR to
Gs alpha promotes efficient coupling as shown by high-affinity agonist binding
and GTPase and adenylyl cyclase activation and ensures fixed stoichiometry
between receptor and G-protein. Importantly, fusion does not change the
fundamental properties of the beta2 AR or Gs alpha. The beta2 AR in beta2 AR Gs
alphaL showed hallmarks of constitutive activity (increased potency and intrinsic
activity of partial agonists, increased efficacy of inverse agonists, and
increased basal GTPase activity) compared with the beta2 AR in beta2 AR Gs
alphaS. The apparent constitutive activity of the beta2 AR in beta2 AR Gs alphaL
may be due to the lower GDP affinity of Gs alphaL compared with Gs alphaS, i.e.
Gs alphaL is more often nucleotide-free than Gs alphaS and, therefore, more
frequently available to stabilize the beta2 AR in the active (R*) state. This
study demonstrates that subtle structural differences between closely related G
protein alpha-subunits can have important consequences for the functional
properties of a G-protein-coupled receptor.
PMID- 9556549
TI - Nonclassical protein sorting to the yeast vacuole.
PMID- 9556550
TI - pICln binds to a mammalian homolog of a yeast protein involved in regulation of
cell morphology.
AB - Since its cloning and tentative identification as a chloride channel, the
function of the pICln protein has been debated. Although there is no consensus
regarding the specific function of pICln, it was suggested to play a role,
directly or indirectly, in the function of a swelling-induced chloride
conductance. Previously, the protein was shown to exist in several discrete
protein complexes. To determine the function of the protein, we have begun the
systematic identification of all proteins to which it binds. Here we show that
four proteins firmly bind to pICln and identify the 72-kDa pICln-binding protein
by affinity purification and peptide microsequencing. The interaction between
this protein and pICln was verified several ways, including the extraction of
several pICln clones from a cDNA library using the 72-kDa protein as a bait in a
yeast two-hybrid screen. The protein is homologous to the yeast Skb1 protein.
Skb1 interacts with Shk1, a homolog of the p21(Cdc42/Rac)-activated protein
kinases (PAKs). The known involvement of PAKs in cytoskeletal rearrangement
suggests that pICln may be linked to a system regulating cell morphology.
PMID- 9556551
TI - Different subcellular distribution of caspase-3 and caspase-7 following Fas
induced apoptosis in mouse liver.
AB - Caspases plays a key role in the execution phase of apoptosis. "Initiator"
caspases, such as caspase-8, activate "effector" caspases, such as caspase-3 and
7, which subsequently cleave cellular substrates thereby precipitating the
dramatic morphological changes of apoptosis. Following treatment of mice with an
agonistic anti-Fas antibody to induce massive hepatocyte apoptosis, we now
demonstrate a distinct subcellular localization of the effector caspases-3 and
7. Active caspase-3 is confined primarily to the cytosol, whereas active caspase
7 is associated almost exclusively with the mitochondrial and microsomal
fractions. These data suggest that caspases-3 and -7 exert their primary
functions in different cellular compartments and offer a possible explanation of
the presence of caspase homologs with overlapping substrate specificities.
Translocation and activation of caspase-7 to the endoplasmic reticulum correlates
with the proteolytic cleavage of the endoplasmic reticular-specific substrate,
sterol regulatory element-binding protein 1. Liver damage, induction of
apoptosis, activation and translocation of caspase-7, and proteolysis of sterol
regulatory element-binding protein 1 are all blocked by the caspase inhibitor,
benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone (Z-VAD. fmk). Our data
demonstrate for the first time the differential subcellular compartmentalization
of specific effector caspases following the induction of apoptosis in vivo.
PMID- 9556552
TI - The peptidyl-prolyl isomerase domain of the CyP-40 cyclophilin homolog Cpr7 is
not required to support growth or glucocorticoid receptor activity in
Saccharomyces cerevisiae.
AB - CyP-40 cyclophilins are found in association with molecular chaperone
Hsp90.steroid receptor complexes. The amino-terminal portion of these
cyclophilins harbors the characteristic peptidyl-prolyl isomerase (PPIase)
domain, whereas three copies of the tetratricopeptide (TPR) motif, a structure
shown to be involved in protein-protein interactions, and a putative calmodulin
binding domain are located in the carboxyl-terminal half of the protein. The TPR
domains mediate binding to Hsp90, but a requirement for the PPIase domain has not
been established. To address this, we have investigated the effects of mutations
that alter the PPIase domain of the Saccharomyces cerevisiae CyP-40 homolog,
Cpr7. Because Cpr7 is required for rapid growth and full Hsp90 activity, a
functional assessment of the PPIase domain could be performed in vivo. A mutation
in the catalytic domain altering a conserved site predicted to be essential for
isomerase activity did not compromise Cpr7 function. Furthermore, deletion of the
entire PPIase domain did not significantly affect growth or Hsp90-mediated
steroid receptor activity. These results indicate that the TPR-containing
carboxyl terminus of Cpr7 is sufficient for fundamental Cpr7-dependent activity.
PMID- 9556553
TI - Axin, a negative regulator of the wnt signaling pathway, directly interacts with
adenomatous polyposis coli and regulates the stabilization of beta-catenin.
AB - The regulators of G protein signaling (RGS) domain of Axin, a negative regulator
of the Wnt signaling pathway, made a complex with full-length adenomatous
polyposis coli (APC) in COS, 293, and L cells but not with truncated APC in SW480
or DLD-1 cells. The RGS domain directly interacted with the region containing the
20-amino acid repeats but not with that containing the 15-amino acid repeats of
APC, although both regions are known to bind to beta-catenin. In the region
containing seven 20-amino acid repeats, the region containing the latter five
repeats bound to the RGS domain of Axin. Axin and beta-catenin simultaneously
interacted with APC. Furthermore, Axin stimulated the degradation of beta-catenin
in COS cells. Taken together with our recent observations that Axin directly
interacts with glycogen synthase kinase-3beta (GSK-3beta) and beta-catenin and
that it promotes GSK-3beta-dependent phosphorylation of beta-catenin, these
results suggest that Axin, APC, GSK-3beta, and beta-catenin make a tetrameric
complex, resulting in the regulation of the stabilization of beta-catenin.
PMID- 9556554
TI - Rpb3, stoichiometry and sequence determinants of the assembly into yeast RNA
polymerase II in vivo.
AB - Stoichiometry of the third largest subunit (Rpb3) of the yeast RNA polymerase II
is a subject of continuing controversy. In this work we utilized immunoaffinity
and nickel-chelate chromatographic techniques to isolate the RNA polymerase II
species assembled in vivo in the presence of the His6-tagged and untagged Rpb3.
The distribution pattern of tagged and untagged subunits among the RNA polymerase
II molecules is consistent with a stoichiometry of 1 Rpb3 polypeptide per
molecule of RNA polymerase. Deletion of either alpha-homology region (amino acids
29-55 or 226-267) from the Rpb3 sequence abolished its ability to assemble into
RNA polymerase II in vivo.
PMID- 9556555
TI - Steroid receptor coactivator-1 interacts with the p50 subunit and coactivates
nuclear factor kappaB-mediated transactivations.
AB - Steroid receptor coactivator-1 (SRC-1) specifically bound to the transcription
factor NFkappaB subunit p50 but not to p65 as demonstrated by the yeast two
hybrid tests and glutathione S-transferase pull down assays. The p50-binding site
was localized to a subregion of SRC-1 (amino acids 759-1141) that encompasses the
previously described CBP-p300-binding domain. In mammalian cells, SRC-1
potentiated the NFkappaB-mediated transactivations in a dose-dependent manner.
Coexpression of p300 further enhanced this SRC-1-potentiated level of
transactivations, consistent with the recent findings in which CBP and p300 were
shown to be transcription coactivators of the p65 subunit (Perkins, N. D.,
Felzien, L. K., Betts, J. C., Leung, K., Beach, D. H., and Nabel, G. J. (1997)
Science 275, 523-527; Gerritsen, M. E., Williams, A. J., Neish, A. S. , Moore,
S., Shi, Y., and Collins, T. (1997) Proc. Acad. Natl. Sci. U. S. A. 94, 2927
2932). These results suggest that at least two distinct coactivator molecules may
cooperate to regulate the NFkappaB-dependent transactivations in vivo and SRC-1,
originally identified as a coactivator for the nuclear receptors, may constitute
a more widely used coactivation complex.
PMID- 9556556
TI - Mammalian thioredoxin reductase is irreversibly inhibited by dinitrohalobenzenes
by alkylation of both the redox active selenocysteine and its neighboring
cysteine residue.
AB - The immunostimulatory dinitrohalobenzene compound 1-chloro-2, 4-dinitrobenzene
(DNCB) irreversibly inhibits mammalian thioredoxin reductase (TrxR) in the
presence of NADPH, inducing an NADPH oxidase activity in the modified enzyme
(Arner, E. S. J., Bjornstedt, M., and Holmgren, A. (1995) J. Biol. Chem. 270,
3479-3482). Here we have further analyzed the reactivity with the enzyme of DNCB
and analogues with varying immunomodulatory properties. We have also identified
the reactive residues in bovine thioredoxin reductase, recently discovered to be
a selenoprotein. We found that 4-vinylpyridine competed with DNCB for
inactivation of TrxR, with DNCB being about 10 times more efficient, and only
alkylation with DNCB but not with 4-vinylpyridine induced an NADPH oxidase
activity. A number of nonsensitizing DNCB analogues neither inactivated the
enzyme nor induced any NADPH oxidase activity. The NADPH oxidase activity of TrxR
induced by dinitrohalobenzenes generated superoxide, as detected by reaction with
epinephrine (the adrenochrome method). Addition of superoxide dismutase quenched
this reaction and also stimulated the NADPH oxidase activity. By peptide analysis
using mass spectrometry and Edman degradation, both the cysteine and the
selenocysteine in the conserved carboxyl-terminal sequence Gly-Cys-Sec-Gly (where
Sec indicates selenocysteine) were determined to be dinitrophenyl-alkylated upon
incubation of native TrxR with NADPH and DNCB. A model for the interaction
between TrxR and dinitrohalobenzenes is proposed, involving a functional FAD in
the alkylated TrxR generating an anion nitroradical in a dinitrophenyl group,
which in turn reacts with oxygen to generate superoxide. Production of reactive
oxygen species and inhibited reduction of thioredoxin by the modified thioredoxin
reductase after reaction with dinitrohalobenzenes may play a major role in the
inflammatory reactions provoked by these compounds.
PMID- 9556557
TI - The Trypanosoma cruzi mucin family is transcribed from hundreds of genes having
hypervariable regions.
AB - In previous works we have identified genes in the protozoan parasite Trypanosoma
cruzi whose structure resemble those of mammalian mucin genes. Indirect evidence
suggested that these genes might encode the core protein of parasite mucins,
glycoproteins that were proposed to be involved in the interaction with, and
invasion of, mammalian host cells. We now show that the mucin gene family from T.
cruzi is much larger and diverse than expected. A minimal number of 484 mucin
genes per haploid genome is calculated for a parasite clone. Most, if not all,
genes are transcribed, as deduced from cDNA analysis. Comparison of the cDNA
sequences showed evidences of a high mutation rate in localized regions of the
genes. Sequence conservation among members of the family is much higher in the
untranslated (UTR) regions than in the sequences encoding the mature mucin core
protein. Transcription units can be classified into two main subfamilies
according to the sequence homologies in the 5'-UTR, whereas the 3'-UTR is highly
conserved in all clones analyzed. The common origin of members of this gene
family as well as their relationships can be defined by sequence comparison of
different domains in the transcription units. The regions encoding the N and C
termini, supposed to correspond to the leader peptide and membrane-anchoring
signal, respectively, (Di Noia, J. M., Sanchez, D. O., and Frasch, A. C. C.
(1995) J. Biol. Chem. 270, 24146-24149) are highly conserved. Conversely, the
central regions are highly variable. These regions encode the target sites for O
glycosylation and are made of a variable number of repetitive units rich in Thr
and Pro residues or are nonrepetitive but still rich in Thr/Ser and Pro residues.
The region putatively coding for the N-terminal domain of the mature core protein
is hypervariable, being different in most of the transcripts sequenced.
Nonrepetitive central domains are unique to each gene. Gene-specific probes show
that the relative abundance of different mRNAs varies greatly within the same
parasite clone.
PMID- 9556558
TI - Inhibitor binding within the NarI subunit (cytochrome bnr) of Escherichia coli
nitrate reductase A.
AB - We have used inhibitors and site-directed mutants to investigate quinol binding
to the cytochrome bnr (NarI) of Escherichia coli nitrate reductase (NarGHI). Both
stigmatellin and 2-n-heptyl-4-hydroxyquinoline-N-oxide (HOQNO) inhibit
menadiol:nitrate oxidoreductase activity with I50 values of 0.25 and 6 microM,
respectively, and prevent the generation of a NarGHI-dependent proton
electrochemical potential across the cytoplasmic membrane. These inhibitors have
little effect on the rate of reduction of the two hemes of NarI (bL and bH), but
have an inhibitory effect on the extent of nitrate-dependent heme reoxidation. No
quinol-dependent heme bH reduction is detected in a mutant lacking heme bL (NarI
H66Y), whereas a slow but complete heme bL reduction is detected in a mutant
lacking heme bH (NarI-H56R). This is consistent with physiological quinol binding
and oxidation occurring at a site (QP) associated with heme bL which is located
toward the periplasmic side of NarI. Optical and EPR spectroscopies performed in
the presence of stigmatellin or HOQNO provide further evidence that these
inhibitors bind at a heme bL-associated QP site. These results suggest a model
for electron transfer through NarGHI that involves quinol binding and oxidation
in the vicinity of heme bL and electron transfer through heme bH to the
cytoplasmically localized membrane-extrinsic catalytic NarGH dimer.
PMID- 9556559
TI - Peroxynitrite increases the degradation of aconitase and other cellular proteins
by proteasome.
AB - We report that exposure of aconitase to moderate concentrations of peroxynitrite,
3-morpholinosydnonimine (SIN-1; a superoxide- and nitric oxide-liberating
substance), or hydrogen peroxide, inhibits the enzyme and enhances susceptibility
to proteolytic digestion by the isolated 20 S proteasome. Exposure to more severe
levels of oxidative stress, from these same agents, causes further inhibition of
the enzymatic activity of aconitase but actually decreases its proteolytic
breakdown by proteasome. It should be noted that the superoxide and nitric oxide
liberated by SIN-1 decomposition react to form a steady flux of peroxynitrite. S
Nitroso-N-acetylpenicillamine, a compound that liberates nitric oxide alone,
causes only a small loss of aconitase activity (25% or less) and has no effect on
the proteolytic susceptibility of the enzyme. Proteasome also seems to be the
main protease in cell lysates that can degrade aconitase after it has been
oxidatively modified by exposure to peroxynitrite, SIN-1, or hydrogen peroxide.
Using cell lysates isolated from K562 cells treated for several days with an
antisense oligodeoxynucleotide to the initiation codon region of the C2 subunit
of proteasome (a treatment which diminishes proteasome activity by 50-60%), the
enhanced degradation of moderately damaged aconitase was essentially abolished.
Other model proteins as well as complex mixtures of proteins, such as cell
lysates, also exhibit enhanced proteolytic susceptibility after moderate SIN-1
treatment. Therefore we conclude that peroxynitrite reacts readily with proteins
and that mild modification by peroxynitrite results in selective recognition and
degradation by proteasome.
PMID- 9556560
TI - Reaction of O6-benzylguanine-resistant mutants of human O6-alkylguanine-DNA
alkyltransferase with O6-benzylguanine in oligodeoxyribonucleotides.
AB - Inactivation of the human DNA repair protein, O6-alkylguanine-DNA
alkyltransferase (AGT), by O6-benzylguanine renders tumor cells susceptible to
killing by alkylating agents. AGT mutants resistant to O6-benzylguanine can be
made by converting Pro140 to an alanine (P140A) or Gly156 to an alanine (G156A).
These mutations had a much smaller effect on the reaction with O6-benzylguanine
when it was incorporated into a short single-stranded oligodeoxyribonucleotide.
Such oligodeoxyribonucleotides could form the basis for the design of improved
AGT inhibitors. AGT and mutants P140A and G156A preferentially reacted with O6
benzylguanine when incubated with a mixture of two 16-mer
oligodeoxyribonucleotides, one containing O6-benzylguanine and the other, O6
methylguanine. When the 6 amino acids located in positions 159-164 in AGT were
replaced by the equivalent sequence from the Escherichia coli Ada-C protein
(mutant AGT/6ada) the preference for benzyl repair was eliminated. Further
mutation incorporating the P140A change into AGT/6ada giving mutant P140A/6ada
led to a protein that resembled Ada-C in preference for the repair of methyl
groups, but P140A/6ada did not differ from P140A in reaction with the free base
O6-benzylguanine. Changes in the AGT active site pocket can therefore affect the
preference for repair of O6-benzyl or -methyl groups when present in an
oligodeoxyribonucleotide without altering the reaction with free O6
benzylguanine.
PMID- 9556561
TI - Gar1p binds to the small nucleolar RNAs snR10 and snR30 in vitro through a
nontypical RNA binding element.
AB - The nucleolar proteins Gar1p and fibrillarin possess a typical nucleolar
glycine/arginine-rich domain and belong to ribonucleoprotein particles. Both
proteins are essential for yeast cell growth and are required for pre-rRNA
processing. In addition, Gar1p is involved in pre-rRNA pseudouridylation, whereas
fibrillarin is required for pre-rRNA methylation. Gar1p and fibrillarin are each
associated with a different subset of the small nucleolar RNAs (snoRNAs). Gar1p
is co-immunoprecipitated with the H/ACA family of snoRNAs, whereas fibrillarin is
co-immunoprecipitated with the C/D family. However, attempts to demonstrate
direct interactions between fibrillarin and snoRNAs have failed, and such
interactions between Gar1p and the H/ACA snoRNAs had not yet been reported. Among
the H/ACA snoRNAs associated with Gar1p, one can distinguish a large group of
snoRNAs that are not essential in yeast and serve as guides for pseudouridine
synthesis onto the pre-rRNA molecule. In contrast, the two snoRNAs snR10 and
snR30 are required for normal cell growth and for pre-rRNA cleavage. We show here
that Gar1p interacts in vitro directly and specifically with these two snoRNAs.
Deletion analysis of Gar1p indicates that a major RNA binding element, which is
extremely well conserved throughout evolution, lies in the middle of the protein.
However, this domain alone binds poorly to the target RNAs and an accessory
domain is required to restore efficient binding. The accessory domain can be
either one of the glycine/arginine-rich domains or a second element of the core
of the protein that is highly conserved between different species.
PMID- 9556562
TI - Preparation of MUC-1 oligomers using an improved convergent solid-phase peptide
synthesis.
AB - The sequentially repeating nature of the core mucin polypeptide chain MUC-1 on
the surface of malignant cells makes it an excellent target for cancer
immunotherapy. We describe a reliable and efficient method of synthesizing
oligomers, up to five tandem repeats and oligomer heterotope derivatives with a
15-amino acid epitope from tetanus toxin using an improved convergent solid-phase
peptide synthesis. The different oligomers were easily distinguishable by reverse
phase high pressure liquid chromatography, but they were poorly fixed and
migrated with the same migration rate, irrespective of size, in electrophoretic
studies. In contrast, the oligomer heterotopes exhibited size-dependent
electrophoretic behavior but in high pressure liquid chromatography chromatograms
the different heterotopes were eluted simultaneously in two peaks representing
the L- and D-enantiomers of the derivatives. The oligomer heterotopes were
recognized as antigens in Western blotting with a murine monoclonal antibody
against the epitope APDTR. In enzyme immunoassay studies with the same antibody
an increasing reactivity was observed against the larger oligomers and confirmed
by inhibition assays as the MUC-1 pentamer was the most efficient inhibitor.
These results support the suggestion that the pentamer attains a structure closer
to the native conformation and is more immunogenic. In conclusion, large
composite peptides can be reliably synthesized with the convergent solid-phase
peptide strategy offering an attractive option to vaccine designing and
development.
PMID- 9556563
TI - Ciao 1 is a novel WD40 protein that interacts with the tumor suppressor protein
WT1.
AB - The Wilms tumor suppressor protein, WT1, is a transcription factor capable of
activating or repressing transcription of various cellular genes. The mechanisms
involved in regulating the transcriptional activities of WT1 are beginning to be
unraveled. It appears that physical interactions of other cellular proteins (p53
and par-4) with WT1 can modulate the function of WT1. Here, we report the
identification and cloning of a novel WT1-interacting protein termed Ciao 1, a
member of the WD40 family of proteins. Ciao 1 specifically interacts with WT1
both in vitro and in vivo. This interaction alters the mobility of a WT1.DNA
complex in gel shift assays, and results in a decrease in transcriptional
activation mediated by WT1. Ciao 1 does not inhibit binding of WT1 to its
consensus nucleotide sequence and does not affect the repression activity of WT1.
Thus, Ciao 1 appears to specifically modulate the transactivation activity of WT1
and may function to regulate the physiological functions of WT1 in cell growth
and differentiation.
PMID- 9556564
TI - Sulfuryl transfer: the catalytic mechanism of human estrogen sulfotransferase.
AB - Estrogen sulfotransferase (EST) catalyzes the transfer of the sulfuryl group from
3'-phosphoadenosine 5'-phosphosulfate (PAPS) to 17beta-estradiol (E2). The
sulfation of E2 prevents it from binding to, and thereby activating, the estrogen
receptor. The regulation of EST appears to be causally linked to tumorigenesis in
the breast and endometrium. In this study, recombinant human EST is
characterized, and the catalytic mechanism of the transfer reaction is
investigated in ligand binding and initial rate experiments. The native enzyme is
a dimer of 35-kDa subunits. The apparent equilibrium constant for transfer to E2
is (4.5 +/- 0.2) x 10(3) at pH 6.3 and T = 25 +/- 2 degrees C. Initial rate
studies provide the kinetic constants for the reaction and suggest a sequential
mechanism. E2 is a partial substrate inhibitor (Ki = 80 +/- 5 nM). The binding of
two E2 per EST subunit suggests that the partial inhibition occurs through
binding at an allosteric site. In addition to providing the dissociation
constants for the ligand-enzyme complexes, binding studies demonstrate that each
substrate binds independently to the enzyme and that both the E.PAP.E2S and
E.PAP.E2 dead-end complexes form. These results strongly suggest a Random Bi Bi
mechanism with two dead-end complexes.
PMID- 9556565
TI - Metabolism of the lipid peroxidation product, 4-hydroxy-trans-2-nonenal, in
isolated perfused rat heart.
AB - The metabolism of 4-hydroxy-trans-2-nonenal (HNE), an alpha, beta-unsaturated
aldehyde generated during lipid peroxidation, was studied in isolated perfused
rat hearts. High performance liquid chromatography separation of radioactive
metabolites recovered from [3H]HNE-treated hearts revealed four major peaks.
Based on the retention times of synthesized standards, peak I, which accounted
for 20% radioactivity administered to the heart, was identified to be due to
glutathione conjugates of HNE. Peaks II and III, containing 2 and 37%
radioactivity, were assigned to 1, 4-dihydroxy-2-nonene (DHN) and 4-hydroxy-2
nonenoic acid, respectively. Peak IV was due to unmetabolized HNE. The
electrospray ionization mass spectrum of peak I revealed two prominent
metabolites with m/z values corresponding to [M + H]+ of HNE and DHN conjugates
with glutathione. The presence of 4-hydroxy-2-nonenoic acid in peak III was
substantiated using gas chromatography-chemical ionization mass spectroscopy.
When exposed to sorbinil, an inhibitor of aldose reductase, no GS-DHN was
recovered in the coronary effluent, and treatment with cyanamide, an inhibitor of
aldehyde dehydrogenase, attenuated 4-hydroxy-2-nonenoic acid formation. These
results show that the major metabolic transformations of HNE in rat heart involve
conjugation with glutathione and oxidation to 4-hydroxy-2-nonenoic acid. Further
metabolism of the GS-HNE conjugate involves aldose reductase-mediated reduction,
a reaction catalyzed in vitro by homogenous cardiac aldose reductase.
PMID- 9556566
TI - A negative vitamin D response DNA element in the human parathyroid hormone
related peptide gene binds to vitamin D receptor along with Ku antigen to mediate
negative gene regulation by vitamin D.
AB - We found that the human parathyroid hormone-related peptide (hPTHrP) gene
contained a DNA element (nVDREhPTHrP) homologous to a negative vitamin D response
element in the human parathyroid hormone gene. It bound to vitamin D receptor
(VDR) but not retinoic acid Xalpha receptor (RXRalpha) in the human T cell line
MT2 cells. VDR binding to this element was confirmed by the Southwestern assay
combined with immunodepletion using anti-VDR monoclonal antibody, and this
binding activity was repressed by 1,25-dihydroxyvitamin D3. Such a repression was
reversed by acid phosphatase treatment, suggesting that 1,25-dihydroxyvitamin D3
phosphorylates VDR to weaken its binding activity to nVDREhPTHrP. In
electrophoretic mobility shift assay, we found anti-Ku antigen antibody
specifically supershifted the MT2 nuclear proteinnVDREhPTHrP complex. The
nVDREhPTHrP-bearing reporter plasmid produced vitamin D-dependent inhibition of
the reporter activity in MT2 cells, which was markedly masked by the introduction
of the Ku antigen expression vector in the antisense orientation. On the other
hand, such a procedure did not perturb the vitamin D response element-mediated
gene stimulation by vitamin D. These results indicate that nVDREhPTHrP interacts
with Ku antigen in addition to VDR to mediate gene suppression by vitamin D.
PMID- 9556567
TI - Functional characterization of the Tn5 transposase by limited proteolysis.
AB - The 476 amino acid Tn5 transposase catalyzes DNA cutting and joining reactions
that cleave the Tn5 transposon from donor DNA and integrate it into a target
site. Protein-DNA and protein-protein interactions are important for this
tranposition process. A truncated transposase variant, the inhibitor, decreases
transposition rates via the formation of nonproductive complexes with
transposase. Here, the inhibitor and the transposase are shown to have similar
secondary and tertiary folding. Using limited proteolysis, the transposase has
been examined structurally and functionally. A DNA binding region was localized
to the N-terminal 113 amino acids. Generally, the N terminus of transposase is
sensitive to proteolysis but can be protected by DNA. Two regions are predicted
to contain determinants for protein-protein interactions, encompassing residues
114-314 and 441-476. The dimerization regions appear to be distinct and may have
separate functions, one involved in synaptic complex formation and one involved
in nonproductive multimerization. Furthermore, predicted catalytic regions are
shown to lie between major areas of proteolysis.
PMID- 9556568
TI - Regulation of syndecan-4 phosphorylation in vivo.
AB - Recent studies suggest that some of the heparan sulfate-carrying proteoglycans
may directly participate in signaling via their cytoplasmic tail. The present
investigation addresses the potential involvement of syndecan-4, a widely
expressed transmembrane proteoglycan, in this process. We found that the
cytoplasmic tail of syndecan-4 is phosphorylated on a single serine residue
(Ser183) in growth-arrested NIH 3T3 fibroblasts, with a stoichiometry of 0.3 mol
Pi/mol syndecan-4. Treatment of the cells with a protein kinase C (PKC)
activating phorbol ester lead to a 2.5-fold increase in Ser183 phosphorylation.
This increase was inhibited by a generic PKC inhibitor but not by an inhibitor
specific to the calcium-dependent conventional PKCs, suggesting that the
cytoplasmic tail of syndecan-4 is phosphorylated by a calcium-independent novel
PKC isozyme. Application of 10-30 ng/ml basic fibroblast growth factor (bFGF)
produced a 2-3-fold reduction in the phosphorylation of syndecan-4. Because
treatment with the phosphatase inhibitor calyculin prevented the bFGF-induced
decrease in syndecan-4 phosphorylation, the effect of bFGF appears to be mediated
by a protein serine/threonine phosphatase type 1 or 2A. We conclude that the
cytoplasmic tail of syndecan-4 is subject to in vivo phosphorylation on Ser183,
which is regulated by the activities of a novel PKC isozyme and a bFGF-dependent
serine/threonine phosphatase.
PMID- 9556569
TI - The heparan sulfate binding sequence of interferon-gamma increased the on rate of
the interferon-gamma-interferon-gamma receptor complex formation.
AB - Interferon-gamma (IFNgamma), in common with a number of growth factors, binds
both to heparan sulfate or heparin-related molecules and to a specific high
affinity receptor (IFNgammaR). Using surface plasmon resonance technology,
kinetic analysis of the IFNgamma. IFNgammaR complex formation was performed with
the extracellular part of IFNgammaR immobilized on a sensor chip. At the sensor
chip surface, IFNgamma was bound by two IFNgammaR molecules with an affinity in
the nanomolar range (0.68 nM). This binding was characterized by an important on
rate, kon = 7.3 x 10(6) M-1.s-1, and an off rate, koff = 5 x 10(-3).s-1. This
binding assay was used to investigate a possible role of heparin in the
IFNgamma.IFNgammaR complex formation. In contrast to growth factors for which
binding to heparin is usually required for high affinity receptor interaction, we
found in this study that IFNgamma bound to heparin displayed a strongly reduced
affinity for its receptor. This is consistent with the fact that a cluster of
basic amino acids (KTGKRKR, called the C1 domain) in the carboxyl-terminal
sequence of the cytokine was involved both in heparin and receptor recognition.
To understand how a single domain of IFNgamma could be implicated in two discrete
functions (i.e. binding to heparin and to IFNgammaR), we also analyzed in a
detailed manner the role of the IFNgamma carboxyl-terminal sequence in receptor
binding. Using forms of IFNgamma, with carboxyl terminus truncations of defined
regions of the heparin binding sequence, we found that the C1 domain functioned
by increasing the on rate of the IFNgamma.IFNgammaR binding reaction but was not
otherwise required for the stability of the complex. Interactions between the
IFNgamma carboxyl-terminal domain and IFNgammaR could increased the association
rate of the reaction either by increasing the number of encounters between the
two molecules or by favoring productive collisions. The mechanisms by which
heparan sulfate regulates IFNgamma activity may thus include both control of
selective protease cleavage events, which directly affect the cytokine activity,
and also an ability to modulate the interaction of IFNgamma with the IFNgammaR
via competitive binding to the C1 domain.
PMID- 9556570
TI - Phosphorylation of thyroid hormone receptors by protein kinase A regulates DNA
recognition by specific inhibition of receptor monomer binding.
AB - Thyroid hormone receptor (T3R) alpha-1 and its oncogenic derivative, the v-ERB A
protein, are phosphorylated by cAMP-dependent protein kinase A. Although this
phosphorylation appears to be necessary for the oncogenic properties of v-ERB A,
the mechanism by which phosphorylation influences the functions of v-ERB A and of
the normal T3R has not been established. The protein kinase A phosphorylation
site in T3Ralpha-1 is within a domain that is known to contribute to the DNA
recognition properties of these receptors. We therefore analyzed the effects of
protein kinase A phosphorylation on DNA recognition by the normal T3Ralpha and by
the v-ERB A oncoprotein. We report here that phosphorylation of these receptor
derivatives does not significantly alter the overall affinity of receptor dimers
for DNA. However, phosphorylation does notably alter DNA recognition by
preventing, or greatly inhibiting, the ability of these receptors to bind to DNA
as protein monomers. These studies suggest that the phosphorylation of T3Ralpha-1
and v-ERB A by protein kinase A may provide a means of altering promoter
recognition through a post-translational modification.
PMID- 9556571
TI - Mutagenesis of beta-Glu-195 of the Rhodospirillum rubrum F1-ATPase and its role
in divalent cation-dependent catalysis.
AB - We introduced mutations at the fully conserved residue Glu-195 in subunit beta of
Rhodospirillum rubrum F1-ATPase. The activities of the expressed wild type (WT)
and mutant beta subunits were assayed by following their capacity to assemble
into the earlier prepared beta-depleted, membrane-bound R. rubrum enzyme
(Philosoph, S., Binder, A., and Gromet-Elhanan, Z. (1977) J. Biol. Chem. 252,
8742-8747) and to restore ATP synthesis and/or hydrolysis activity. All three
mutations, beta-E195K, beta-E195Q, and beta-E195G, were found to bind as the
WTbeta into the beta-depleted enzyme. They restored between 30 and 60% of the WT
restored photophosphorylation activity and 16, 45, and 105%, respectively of the
CaATPase activity. The mutants required, however, much higher concentrations of
divalent cations and could not restore any significant MgATPase or MnATPase
activities. Only beta-E195G could restore some of these activities when assayed
in the presence of 100 mM sulfite and high MgCl2 or MnCl2 concentrations. These
results suggest that the observed difference in restoration of ATP synthesis and
CaATPase, as compared with MgATPase and MnATPase, can be due to the tight
regulation of the last two activities, resulting in their inhibition at
cation/ATP ratios above 0.5. The R. rubrum F1beta-E195 is equivalent to the
mitochondrial F1beta-E199, which points into the tunnel leading to the F1
catalytic nucleotide binding sites (Abrahams, J. P., Leslie, A. G. W., Lutter,
R., and Walker, J. E. (1994) Nature 370, 621-628). Our findings indicate that
this residue, although not an integral part of the F1 catalytic sites, affects
divalent cation binding and release of inhibitory MgADP, suggesting its
participation in the interconversion of the F1 catalytic sites between different
conformational states.
PMID- 9556572
TI - Identification and characterization of a novel 9.2-kDa membrane sector-associated
protein of vacuolar proton-ATPase from chromaffin granules.
AB - Vacuolar proton-translocating ATPase (holoATPase and free membrane sector) was
isolated from bovine chromaffin granules by blue native polyacrylamide gel
electrophoresis. A 5-fold excess of membrane sector over holoenzyme was
determined in isolated chromaffin granule membranes. M9.2, a novel extremely
hydrophobic 9.2-kDa protein comprising 80 amino acids, was detected in the
membrane sector. It shows sequence and structural similarity to Vma21p, a yeast
protein required for assembly of vacuolar ATPase. A second membrane sector
associated protein (M8-9) was identified and characterized by amino-terminal
protein sequencing.
PMID- 9556573
TI - Regulation of peroxisome proliferator-activated receptor alpha-induced
transactivation by the nuclear orphan receptor TAK1/TR4.
AB - Recently, we reported the cloning of the nuclear orphan receptor TAK1. In this
study, we characterized the sequence requirements for optimal TAK1 binding and
analyzed the repression of the peroxisome proliferator-activated receptor alpha
(PPARalpha) signaling pathway by TAK1. Site selection analysis showed that TAK1
has the greatest affinity for direct repeat-1 response elements (RE) containing
AGGTCAAAGGTCA (TAK1-RE) to which it binds as a homodimer. TAK1 is a very weak
inducer of TAK1-RE-dependent transcriptional activation. We observed that TAK1,
as PPARalpha, is expressed within rat hepatocytes and is able to bind the
peroxisome proliferator response elements (PPREs) present in the promoter of the
PPARalpha target genes rat enoyl-CoA hydratase (HD) and peroxisomal fatty acyl
CoA oxidase (ACOX). TAK1 is unable to induce PPRE-dependent transcriptional
activation and represses PPARalpha-mediated transactivation through these
elements in a dose-dependent manner. Two-hybrid analysis showed that TAK1 does
not form heterodimers with either PPARalpha or retinoid X receptor (RXRalpha),
indicating that this repression does not involve a mechanism by which TAK1
titrates out PPARalpha or RXRalpha from PPAR.RXR complexes. Further studies
demonstrated that the PPARalpha ligand 8(S)-hydroxyeicosatetraenoic acid strongly
promotes the interaction of PPARalpha with the co-activator RIP-140 but decreases
the interaction of PPARalpha with the co-repressor SMRT. In contrast, TAK1
interacts with RIP-140 but not with SMRT and competes with PPARalpha for RIP-140
binding. These observations indicated that the antagonistic effects of TAK1 on
PPARalpha.RXRalpha transactivation act at least at two levels in the PPARalpha
signaling pathway: competition of TAK1 with PPARalpha.RXR for binding to PPREs as
well as to common co-activators, such as RIP-140. Our results suggest an
important role for TAK1 in modulating PPARalpha-controlled gene expression in
hepatocytes.
PMID- 9556574
TI - Identification of pairwise interactions in the alpha-neurotoxin-nicotinic
acetylcholine receptor complex through double mutant cycles.
AB - alpha-Neurotoxins are potent inhibitors of the nicotinic acetylcholine receptor
(nAChR), binding with high affinity to the two agonist sites located on the
extracellular domain. Previous site-directed mutagenesis had identified three
residues on the alpha-neurotoxin from Naja mossambica mossambica (Lys27, Arg33,
and Lys47) and four residues on the mouse muscle nAChR alpha-subunit (Val188,
Tyr190, Pro197, and Asp200) as contributing to binding. In this study,
thermodynamic mutant cycle analysis was applied to these sets of residues to
identify specific pairwise interactions. Amino acid variants of alpha-neurotoxin
from N. mossambica mossambica at position 33 and of the nAChR at position 188
showed strong energetic couplings of 2-3 kcal/mol at both binding sites.
Consistently smaller yet significant linkages of 1.6-2.1 kcal/mol were also
observed between variants at position 27 on the toxin and position 188 on the
receptor. Additionally, toxin residue 27 coupled to the receptor residues 190,
197, and 200 at the alphadelta binding site with observed coupling energies of
1.5-1.9 kcal/mol. No linkages were found between toxin residue Lys47 and the
receptor residues studied here. These results provide direct evidence that the
two conserved cationic residues Arg33 and Lys27, located on loop II of the toxin
structure, are binding in close proximity to the alpha-subunit region between
residues 188-200. The toxin residue Arg33 is closer to Val188, where it is likely
stabilized by adjacent negative or aromatic residues on the receptor structure.
Lys27 is positioned closer to Tyr190, Pro197, and Asp200, where it is likely
stabilized through electrostatic interaction with Asp200 and/or cation/pi
interactions with Tyr190.
PMID- 9556575
TI - Immunological detection of conformational neoepitopes associated with the serpin
activity of plasminogen activator inhibitor type-2.
AB - The physiological roles of plasminogen activator inhibitor-2 (PAI-2) are not yet
well understood. Kinetic studies suggest a role in the regulation of plasminogen
activator-driven proteolysis in many cell types. This study describes a
monoclonal antibody (2H5), which uniquely recognizes neoepitope determinants on
PAI-2 appearing after thermodynamic relaxation of the molecule. Enzyme-linked
immunosorbent assays and native polyacrylamide gel electrophoresis immunoblotting
confirmed the specificity of 2H5 for urokinase type plasminogen activator.PAI-2
complexes. Examination of the affinity of 2H5 for complexes formed between PAI-2
and a synthetic 14-mer reactive site loop peptide, PAI-2 treated with tissue
plasminogen activator, or thrombin suggests that the 2H5 epitope is determined
exclusively by sequences found only on PAI-2 following proteolytic cleavage of
the Arg380-Thr381 bond and insertion of the reactive site loop into beta-sheet A.
Peptides lacking both the P13 (Glu368) and P14 (Thr367) residues did not induce a
conformational change or affect the inhibitory activity of PAI-2, indicating that
one or both of these residues are critical for PAI-2 function. To our knowledge,
this is the first description of a monoclonal antibody that can distinguish
conformational changes in PAI-2 related specifically to its potential biological
function(s).
PMID- 9556576
TI - The p53 tumor suppressor inhibits transcription of the TATA-less mouse DP1
promoter.
AB - Cell cycle progression is subject to several regulatory controls, of which the
p53 protein plays a major role in growth arrest, subsequent to the detection of
cellular aberrations. It is well documented that p53 has the ability to inhibit
transcription driven by several promoters, possibly via distinct mechanisms. In
this report, we show that expression of the cell cycle regulatory transcription
factor DP1 is strongly inhibited by p53, at the level of transcription and
probably through the basal TATA-less promoter. This inhibitory activity has a
relative specificity for the DP1 promoter compared with the functionally related
E2F1 promoter or unrelated promoters such as those of the transcription factor
ATFa or the thymidine kinase gene. Inhibition of DP1 transcription has
implications in one of the several possible mechanisms through which p53 induces
cell cycle arrest.
PMID- 9556577
TI - Bruton's tyrosine kinase-mediated interleukin-2 gene activation in mast cells.
Dependence on the c-Jun N-terminal kinase activation pathway.
AB - Cross-linking of the high affinity IgE receptor (FcepsilonRI) on mast cells
induces secretion of cytokines, including interleukin (IL)-2, through
transcriptional activation of cytokine genes. Previously, defects in the gene
coding for Bruton's tyrosine kinase (Btk) were shown to result in defective
cytokine production in mast cells, and thereby mice carrying btk mutations
exhibited diminished anaphylactic reactions in response to IgE and antigen. In
this study, we provide evidence that the transcription factors involved in the IL
2 gene expression in T cells are also required for maximal activation of the IL-2
gene in FcepsilonRI-stimulated mast cells. Among them, AP-1 (Jun/Fos) and NF-AT
were identified as candidate transcription factors that are regulated by Btk.
Consistent with our previous data indicating that Btk regulates stress-activated
protein kinases, c-Jun N-terminal kinase (JNK), c-Jun and other JNK-regulatable
transcription factors are activated by FcepsilonRI cross-linking in a Btk
dependent manner. Further, FcepsilonRI-induced IL-2 gene activation is dependent
on c-Jun and a component, SEK1, of its upstream activation pathway. Collectively,
these data demonstrate that Btk regulates the transcription of the IL-2 gene
through the JNK-regulatable transcription factors in FcepsilonRI-stimulated mast
cells.
PMID- 9556578
TI - Force required to break alpha5beta1 integrin-fibronectin bonds in intact adherent
cells is sensitive to integrin activation state.
AB - Binding of integrin receptors to extracellular ligands is a complex process
involving receptor-ligand interactions at the cell-substrate interface, signals
activating the receptors, and assembly of cytoskeletal and adhesion plaque
proteins at the cytoplasmic face. To analyze the contribution of these elements
to overall cell adhesion, we have developed a model system that characterizes the
functional binding characteristic for adhesion receptors as the force required to
separate the integrin-ligand bond. A spinning disk device was used to apply a
range of controlled hydrodynamic forces to adherent cells. The adhesion of K562
erythroleukemia cells, a cell line expressing a single fibronectin receptor,
integrin alpha5beta1, which was uniformly activated with the monoclonal antibody
TS2/16, to defined fibronectin surface densities was examined. Cell adhesion
strength increased linearly with receptor and ligand densities. Based on chemical
equilibrium principles, it is shown that adhesion strength is directly
proportional to the number of receptor-ligand bonds. This analysis provides for
the definition of a new physical parameter, the adhesion constant psi, which is
related to the bond strength and binding equilibrium constant and has units of
force-length2. This parameter can be measured by the experimental system
presented and is governed by the activation state of integrin receptors. This
simplified model isolates the integrin receptor-ligand binding parameters and
provides a basis for analysis of the functions of signaling and cytoskeletal
elements in the adhesion process.
PMID- 9556579
TI - Site-directed mutations in the vnd/NK-2 homeodomain. Basis of variations in
structure and sequence-specific DNA binding.
AB - Secondary structures, DNA binding properties, and thermal denaturation behavior
of six site-directed mutant homeodomains encoded by the vnd/NK-2 gene from
Drosophila melanogaster are described. Three single site H52R, Y54M, and T56W
mutations, two double site H52R/T56W and Y54M/T56W mutations, and one triple site
H52R/Y54M/T56W mutation were investigated. These positions were chosen based on
their variability across homeodomains displaying differences in secondary
structure and DNA binding specificity. Multidimensional NMR, electrophoretic
mobility shift assays, and circular dichroism spectropolarimetry studies were
carried out on recombinant 80-amino acid residue proteins containing the
homeodomain. Position 56, but more importantly position 56 in combination with
position 52, plays an important role in determining the length of the recognition
helix. The H52R mutation alone does not affect the length of this helix but does
increase the thermal stability. Introduction of site mutations at positions 52
and 56 in vnd/NK-2 does not modify their high affinity binding to the 18-base
pair DNA fragment containing the vnd/NK-2 consensus binding sequence, CAAGTG.
Site mutations involving position 54 (Y54M, Y54M/T56W, and H52R/Y54M/T56W) all
show a decrease of 1 order of magnitude in their binding affinity. The roles in
structure and sequence specificity of individual atom-atom interactions are
described.
PMID- 9556580
TI - Identification of residues in the neuronal alpha7 acetylcholine receptor that
confer selectivity for conotoxin ImI.
AB - To identify residues in the neuronal alpha7 acetylcholine subunit that confer
high affinity for the neuronal-specific toxin conotoxin ImI (CTx ImI), we
constructed alpha7-alpha1 chimeras containing segments of the muscle alpha1
subunit inserted into equivalent positions of the neuronal alpha7 subunit. To
achieve high expression in 293 human embryonic kidney cells and formation of homo
oligomers, we joined the extracellular domains of each chimera to the M1 junction
of the 5-hydroxytryptamine-3 (5HT-3) subunit. Measurements of CTx ImI binding to
the chimeric receptors reveal three pairs of residues in equivalent positions of
the primary sequence that confer high affinity of CTx ImI for alpha7/5HT-3 over
alpha1/5HT-3 homo-oligomers. Two of these pairs, alpha7Trp55/alpha1Arg55 and
alpha7Ser59/alpha1Gln59, are within one of the four loops that contribute to the
traditional non-alpha subunit face of the muscle receptor binding site. The third
pair, alpha7Thr77/alpha1Lys77, is not within previously described loops of either
the alpha or non-alpha faces and may represent a new loop or an allosterically
coupled loop. Exchanging these residues between alpha1 and alpha7 subunits
exchanges the affinities of the binding sites for CTx ImI, suggesting that the
alpha7 and alpha1 subunits, despite sequence identity of only 38%, share similar
protein scaffolds.
PMID- 9556581
TI - Structural elements in alpha-conotoxin ImI essential for binding to neuronal
alpha7 receptors.
AB - The neuronal-specific toxin alpha-conotoxin ImI (CTx ImI) has the sequence Gly
Cys-Cys-Ser-Asp-Pro-Arg-Cys-Ala-Trp-Arg-Cys-NH2, in which each cysteine forms a
disulfide bridge to produce a constrained two-loop structure. To investigate the
structural basis for bioactivity we mutated individual residues in CTx ImI and
determined bioactivity. Bioactivity of the toxins was determined by their
competition against 125I-labeled alpha-bungarotoxin binding to homomeric
receptors containing alpha7 sequence in the major extracellular domain and 5HT-3
sequence elsewhere. The results reveal two regions in CTx ImI essential for
binding to the alpha7/5HT-3 receptor. The first is the triad Asp-Pro-Arg in the
first loop, where conservative mutations of each residue diminish affinity by 2-3
orders of magnitude. The second region is the lone Trp in the second loop, where
an aromatic side chain is required. The overall results suggest that within the
triad of the first loop, Pro positions the flanking Asp and Arg for optimal
interaction with one portion of the binding site, while within the second loop,
Trp stabilizes the complex through its aromatic ring.
PMID- 9556582
TI - Differential regulation of formyl peptide and platelet-activating factor
receptors. Role of phospholipase Cbeta3 phosphorylation by protein kinase A.
AB - Formylated peptides (e.g. n-formyl-Met-Leu-Phe (fMLP)) and platelet-activating
factor (PAF) mediate chemotactic and cytotoxic responses in leukocytes through
receptors coupled to G proteins that activate phospholipase C (PLC). In RBL-2H3
cells, fMLP utilizes a pertussis toxin (ptx)-sensitive G protein to activate PLC,
whereas PAF utilizes a ptx-insensitive G protein. Here we demonstrate that fMLP,
but not PAF, enhanced intracellular cAMP levels via a ptx-sensitive mechanism.
Protein kinase A (PKA) inhibition by H-89 enhanced inositol phosphate formation
stimulated by fMLP but not PAF. Furthermore, a membrane-permeable cAMP analog 8
(4-chlorophenylthio)-cAMP (cpt-cAMP) inhibited phosphoinositide hydrolysis and
secretion stimulated by fMLP but not PAF. Both cpt-cAMP and fMLP stimulated
PLCbeta3 phosphorylation in intact RBL cells. The purified catalytic subunit of
PKA phosphorylated PLCbeta3 immunoprecipitated from RBL cell lysate. Pretreatment
of intact cells with cpt-cAMP and fMLP, but not PAF, resulted in an inhibition of
subsequent PLCbeta3 phosphorylation by PKA in vitro. These data demonstrate that
fMLP receptor, which couples to a ptx-sensitive G protein, activates both PLC and
cAMP production. The resulting PKA activation phosphorylates PLCbeta3 and appears
to block the ability of Gbetagamma to activate PLC. Thus, both fMLP and PAF
generate stimulatory signals for PLCbeta3, but only fMLP produces a PKA-dependent
inhibitory signal. This suggests a novel mechanism for the bidirectional
regulation of receptors which activate PLC by ptx-sensitive G proteins.
PMID- 9556583
TI - Membrane-permeant esters of phosphatidylinositol 3,4,5-trisphosphate.
AB - Phosphoinositide 3-OH kinases and their products, D-3 phosphorylated
phosphoinositides, are increasingly recognized as crucial elements in many
signaling cascades. A reliable means to introduce these lipids into intact cells
would be of great value for showing the physiological roles of this pathway and
for testing the specificity of pharmacological inhibitors of the kinases. We have
stereospecifically synthesized di-C8-PIP3/AM and di-C12-PIP3/AM, the
heptakis(acetoxymethyl) esters of dioctanoyl- and dilauroylphosphatidylinositol
3,4,5-trisphosphate, in 14 steps from myo-inositol. The ability of these
uncharged lipophilic derivatives to deliver phosphatidylinositol 3,4,5
trisphosphate across cell membranes was demonstrated on 3T3-L1 adipocytes and T84
colon carcinoma monolayers. Insulin stimulation of hexose uptake into adipocytes
was inhibited by the kinase inhibitor wortmannin and was largely restored by di
C8-PIP3/AM, which had no effect in the absence of insulin. Thus
phosphatidylinositol 3,4,5-trisphosphate or a metabolite was necessary but not
sufficient for stimulation of hexose transport. In T84 epithelial monolayers, di
C12-PIP3/AM mimicked epidermal growth factor in inhibiting chloride secretion and
potassium efflux, suggesting that phosphatidylinositol 3,4, 5-trisphosphate was
sufficient to modulate these fluxes and mediate epidermal growth factor's action.
PMID- 9556584
TI - Induction of ceramide-mediated apoptosis by the anticancer phospholipid analog,
hexadecylphosphocholine.
AB - The prototype of a new class of antiproliferative phospholipid analogs,
hexadecylphosphocholine (HePC), has been shown to inhibit tumor growth and is
currently used for the treatment of cutaneous metastases of mammary carcinomas.
Although several cellular targets of HePC, e.g. protein kinase C and
CTP:phosphocholine cytidylyltransferase, have been proposed, the mechanisms of
HePC-induced anticancer activity are still unclear. Considering that the
antiproliferative effect of HePC correlates with inhibition of
phosphatidylcholine biosynthesis, which is tightly coupled to sphingomyelin
biosynthesis, we tested the hypothesis that treatment of cells with the
anticancer drug leads to increased cellular ceramide and subsequently to
apoptotic cell death. In the present study, we showed that 25 micromol/liter HePC
induced apoptosis. In further experiments, we demonstrated that HePC inhibited
the incorporation of radiolabeled choline into phosphatidylcholine and at a later
time point into sphingomyelin. This was confirmed by metabolic labeling of the
lipid backbone using radiolabeled serine, and it was shown that HePC decreased
the incorporation of serine into sphingomyelin by 35% and simultaneously
increased the incorporation of serine into ceramide by 70%. Determination of the
amount of ceramide revealed an increase of 53% in HePC-treated cells compared
with controls. In accordance with the hypothesis that elevated ceramide levels
may be the missing link between the metabolic effects of HePC and its
proapoptotic properties, HePC-induced apoptosis was blocked by fumonisin B1, an
inhibitor of ceramide synthesis. Furthermore, we found that membrane-permeable
ceramides additively increased the apoptotic effect of HePC.
PMID- 9556585
TI - The small heat-shock protein IbpB from Escherichia coli stabilizes stress
denatured proteins for subsequent refolding by a multichaperone network.
AB - The role of small heat-shock proteins in Escherichia coli is still enigmatic. We
show here that the small heat-shock protein IbpB is a molecular chaperone that
assists the refolding of denatured proteins in the presence of other chaperones.
IbpB oligomers bind and stabilize heat-denatured malate dehydrogenase (MDH) and
urea-denatured lactate dehydrogenase and thus prevent the irreversible
aggregation of these proteins during stress. While IbpB-stabilized proteins alone
do not refold spontaneously, they are specifically delivered to the
DnaK/DnaJ/GrpE (KJE) chaperone system where they refold in a strict ATPase
dependent manner. Although GroEL/GroES (LS) chaperonins do not interact directly
with IbpB-released proteins, LS accelerate the rate of KJE-mediated refolding of
IbpB-released MDH, and to a lesser extent lactate dehydrogenase, by rapidly
processing KJE-released early intermediates. Kinetic and gel-filtration analysis
showed that denatured MDH preferentially transfers from IbpB to KJE, then from
KJE to LS, and then forms a active enzyme. IbpB thus stabilizes aggregation-prone
folding intermediates during stress and, as an integral part of a cooperative
multichaperone network, is involved in the active refolding of stress-denatured
proteins.
PMID- 9556586
TI - Production of nitric oxide by mitochondria.
AB - The production of NO. by mitochondria was investigated by electron paramagnetic
resonance using the spin-trapping technique, and by the oxidation of
oxymyoglobin. Percoll-purified rat liver mitochondria exhibited a negligible
contamination with other subcellular fractions (1-4%) and high degree of
functionality (respiratory control ratio = 5-6). Toluene-permeabilized
mitochondria, mitochondrial homogenates, and a crude preparation of nitric oxide
synthase (NOS) incubated with the spin trap N-methyl-D-glucamine-dithiocarbamate
FeII produced a signal ascribed to the NO. spin adduct (g = 2.04; aN = 12.5 G).
The intensity of the signal increased with time, protein concentration, and L
Arg, and decreased with the addition of the NOS inhibitor NG-monomethyl-L
arginine. Intact mitochondria, mitochondrial homogenates, and submitochondrial
particles produced NO. (followed by the oxidation of oxymyoglobin) at rates of
1.4, 4.9, and 7.1 nmol NO. x (min.mg protein)-1, respectively, with a Km for L
Arg of 5-7 microM. Comparison of the rates of NO. production obtained with
homogenates and submitochondrial particles indicated that most of the enzymatic
activity was localized in the mitochondrial inner membrane. This study
demonstrates that mitochondria are a source of NO., the production of which may
effect energy metabolism, O2 consumption, and O2 free radical formation.
PMID- 9556587
TI - Purification and characterization of a nitric-oxide synthase from rat liver
mitochondria.
AB - The biosynthesis of nitric oxide (NO.) in different cell types occurs
concomitantly with the conversion of L-arginine to L-citrulline by the enzyme
nitric-oxide synthase (NOS). NO. has been identified as a major participant in a
number of basic physiological functions such as neurotransmission, vasodilation,
and immune response. At the subcellular level, mitochondria have been identified
as targets for NO.; however, to date, no unambiguous evidence has been presented
to identify these organelles as sources of NO.. In this study, a NOS was isolated
to homogeneity from Percoll-purified rat liver mitochondria. Kinetic parameters,
molecular weight, requirement of cofactors, and cross-reactivity to monoclonal
antibodies against macrophage NOS suggest similarities to the inducible form.
However, the constitutive expression of the mitochondrial enzyme and its main
membrane localization indicate the presence of either a distinctive isoform or a
macrophage isoform containing posttranslational modifications that lead to
different subcellular compartments. The detection of NADPH-oxidizing activities
and a production of superoxide anion catalyzed by mtNOS and recombinant
cytochrome P450 reductase were consistent with the sequence homology reported for
these two proteins. Given the role of NO. as cellular transmitter, messenger, or
regulator, the presence of a functionally active mitochondrial NOS may have
important implications for the intermediary metabolism.
PMID- 9556588
TI - Acyl coenzyme A binding protein. Conformational sensitivity to long chain fatty
acyl-CoA.
AB - Cellular unbound long chain fatty acyl-CoAs (>14 carbon) are potent regulators of
gene transcription and intracellular signaling. Although the cytosolic acyl-CoA
binding protein (ACBP) has high affinity for medium chain fatty acyl-CoAs, direct
interaction of ACBP with >14-carbon fatty acyl-CoAs has not been established.
Steady state, photon counting fluorescence spectroscopy directly established that
rat liver ACBP bound 18-carbon cis- and trans-parinaroyl-CoA, Kd = 7.03 +/- 0.95
and 4.40 +/- 0.43 nM. Time-resolved fluorometry revealed that ACBP-bound
parinaroyl-CoAs had high rotational freedom within the single, relatively
hydrophobic (epsilon <32), binding site. Tyr and Trp fluorescence dynamics
demonstrated that apo-ACBP was an ellipsoidal protein (axes of 15 and 9 A) whose
conformation was altered by oleoyl-CoA in the holo-ACBP as shown by a 2-A
decrease of ACBP hydrodynamic diameter and increased Trp segmental motions. Thus,
native liver ACBP binds >14-carbon fatty acyl-CoAs with nanomolar affinity at a
single binding site. Acyl-CoA-induced conformational alterations in ACBP may be
significant to its putative functions in lipid metabolism and regulation of
processes sensitive to unbound long chain fatty acyl-CoAs.
PMID- 9556589
TI - Functional modulation of human recombinant gamma-aminobutyric acid type A
receptor by docosahexaenoic acid.
AB - Human gamma-aminobutyric acid type A (GABAA) receptors were expressed in the
baculovirus/Sf-9 insect cell expression system using recombinant cDNA of
alpha1beta2gamma2s subunits. The effect of unsaturated fatty acids on GABAA
receptor complexes was investigated electrophysiologically using conventional
whole cell recording under voltage clamp. Three distinct effects of
docosahexaenoic acid (DHA) on the GABA responses were observed. First, DHA, at a
concentration of 10(-7) M or greater, accelerated the desensitization after the
peak of the GABA-induced current. Second, DHA (10(-6) M) potentiated the peak
amplitude of GABA response. This potentiation by DHA was inhibited in the
presence of Zn2+ (10(-5) M); Cu2+ and Ni2+ mimicked the action of Zn2+. Zn2+ (10(
5) M) did not block the GABA response on alpha1beta2gamma2s receptor complexes.
Third, DHA, at a concentration of 3 x 10(-6) M or higher, gradually suppressed
the peak amplitude of GABA response. A protein kinase A inhibitor, a protein
kinase C inhibitor, and a Ca2+ chelator did not modify the effects of DHA on GABA
induced chloride ion current. Six unsaturated fatty acids other than DHA were
examined. Arachidonic acid mimicked the effect of DHA while e.g. oleic acid had
no effect. The inhibition of the GABA response in the presence of DHA was also
observed in cells expressing GABAA receptors of alpha1 and beta2 subunit
combinations. The data show that the gamma subunit is essential for DHA and
arachidonic acid to potentiate the GABA-induced Cl- channel activity and to
affect the desensitization kinetics of the GABAA receptor.
PMID- 9556590
TI - Syringomycin action gene SYR2 is essential for sphingolipid 4-hydroxylation in
Saccharomyces cerevisiae.
AB - The Saccharomyces cerevisiae gene SYR2, necessary for growth inhibition by the
cyclic lipodepsipeptide syringomycin E, is shown to be required for 4
hydroxylation of long chain bases in sphingolipid biosynthesis. Four lines of
support for this conclusion are presented: (a) the predicted Syr2p shows sequence
similarity to diiron-binding membrane enzymes involved in oxygen-dependent
modifications of hydrocarbon substrates, (b) yeast strains carrying a disrupted
SYR2 allele produced sphingoid long chain bases lacking the 4-hydroxyl group
present in wild type strains, (c) 4-hydroxylase activity was increased in
microsomes prepared from a SYR2 overexpression strain, and (d) the syringomycin E
resistance phenotype of a syr2 mutant strain was suppressed when grown under
conditions in which exogenous 4-hydroxysphingoid long chain bases were
incorporated into sphingolipids. The syr2 strain produced wild type levels of
sphingolipids, substantial levels of hydroxylated very long chain fatty acids,
and the full complement of normal yeast sphingolipid head groups. These results
show that the SYR2 gene is required for the 4-hydroxylation reaction of
sphingolipid long chain bases, that this hydroxylation is not essential for
growth, and that the 4-hydroxyl group of sphingolipids is necessary for
syringomycin E action on yeast.
PMID- 9556591
TI - Induction of chromosomal gene mutations in Escherichia coli by direct
incorporation of oxidatively damaged nucleotides. New evaluation method for
mutagenesis by damaged DNA precursors in vivo.
AB - We have developed a new strategy for the evaluation of the mutagenicity of a
damaged DNA precursor (deoxyribonucleoside 5'-triphosphate) in Escherichia coli.
8-Hydroxydeoxyguanosine triphosphate (8-OH-dGTP) and 2-hydroxydeoxyadenosine
triphosphate (2-OH-dATP) were chosen for this study because they appear to be
formed abundantly by reactive oxygen species in cells. We introduced the
oxidatively damaged nucleotides into competent E. coli and selected mutants of
the chromosomal lacI gene. Both damaged nucleotides induced lacI gene mutations
in a dose-dependent manner, whereas unmodified dATP and dGTP did not appear to
elicit the mutations. The addition of 50 nmol of 8-OH-dGTP and 2-OH-dATP into an
E. coli suspension induced 12- and 9-fold more substitution mutations than the
spontaneous event, respectively. The 8-OH-dGTP induced A.T --> C.G transversions,
and the 2-OH-dATP elicited G.C --> T.A transversions. These results indicate that
the two oxidatively damaged nucleotides are mutagenic in vivo and suggest that 8
OH-dGTP and 2-OH-dATP were incorporated opposite A and G residues, respectively,
in the E. coli DNA. This new method enables the evaluation and comparison of the
mutagenic potentials of damaged DNA precursors in vivo.
PMID- 9556592
TI - Regions of association between the alpha and the beta subunit of the gastric H,K
ATPase.
AB - A binding and a yeast two-hybrid analysis were carried out on the gastric H,K
ATPase to determine interactive regions of the extracytoplasmic domains of the
alpha and beta subunits of this P type ATPase. Wheat germ agglutinin
fractionation of fluorescein 5-maleimide-labeled tryptic fragments of detergent
solubilized H, K-ATPase showed that a fragment Leu855 to Arg922 of the alpha
subunit was bound to the beta subunit. The yeast two-hybrid system showed that
the region containing only a part of the seventh transmembrane segment, the loop,
and part of the eighth transmembrane segment was capable of giving positive
interaction signals with the ectodomain of the beta subunit. The sequence in the
extracytoplasmic loop close to the eighth transmembrane segment, namely Arg898 to
Thr928, was identified as being the site of interaction using this method. We
deduced that the sequence Arg898 to Arg922 in the alpha subunit has strong
interaction with the extracytoplasmic domain of the beta subunit. Again, using
yeast two-hybrid analysis, two different sequences in the beta subunit Gln64 to
Asn130 and Ala156 to Arg188 were identified as association domains in the
extracytoplasmic sequence of the beta subunit. These data enable identification
of major associative regions of the alpha-beta subunits of the H,K-ATPase.
PMID- 9556593
TI - Biophysical, biochemical, and physiological characterization of Chlamydomonas
reinhardtii mutants with amino acid substitutions at the Ala251 residue in the D1
protein that result in varying levels of photosynthetic competence.
AB - The QB binding site of the D1 reaction center protein, located within a stromal
loop between transmembrane helices IV and V formed by residues Ile219 to Leu272,
is essential for photosynthetic electron transport through photosystem II (PSII).
We have examined the function of the highly conserved Ala251 D1 residue in this
domain in chloroplast transformants of Chlamydomonas reinhardtii and found that
Arg, Asp, Gln, Glu, and His substitutions are nonphotosynthetic, whereas Cys,
Ser, Pro, Gly, Ile, Val, and Leu substitutions show various alterations in D1
turnover, photosynthesis, and photoautotrophic growth. The latter mutations
reduce the rate of QA to QB electron transfer, but this is not necessarily rate
limiting for photoautotrophic growth. The Cys mutant divides and evolves O2 at
wild type rates, although it has slightly higher rates of D1 synthesis and
turnover and reduced electron transfer between QA and QB. O2 evolution, D1
synthesis, and accumulation in the Ser, Pro, and Gly mutants in high light is
reduced, but photoautotrophic growth rate is not affected. In contrast, the Ile,
Val, and Leu mutants are impaired in photoautotrophic growth and photosynthesis
in both low and high light and have elevated rates of D1 synthesis and
degradation, but D1 accumulation is normal. While rates of synthesis/degradation
of the D1 protein are not necessarily correlated with alterations in specific
parameters of PSII function in these mutants, bulkiness of the substituted amino
acids is highly correlated with the dissociation constant for QB in the seven
mutants examined. These observations imply that the Ala251 residue plays a key
role in D1 protein.
PMID- 9556594
TI - Regulatory interactions between the human HOXB1, HOXB2, and HOXB3 proteins and
the upstream sequence of the Otx2 gene in embryonal carcinoma cells.
AB - Vertebrate Hox and Otx genes encode homeodomain-containing transcription factors
thought to transduce positional information along the body axis in the segmental
portion of the trunk and in the rostral brain, respectively. Moreover, Hox and
Otx2 genes show a complementary spatial regulation during embryogenesis. In this
report, we show that a 1821-base pair (bp) upstream DNA fragment of the Otx2 gene
is positively regulated by co-transfection with expression vectors for the human
HOXB1, HOXB2, and HOXB3 proteins in an embryonal carcinoma cell line (NT2/D1) and
that a shorter fragment of only 534 bp is able to drive this regulation. We also
identified the HOXB1, HOXB2, and HOXB3 DNA-binding region on the 534-bp Otx2
genomic fragment using nuclear extracts from Hox-transfected COS cells and 12.5
days postcoitum mouse embryos or HOXB3 homeodomain-containing bacterial extracts.
HOXB1, HOXB3, and nuclear extracts from 12.5 days postcoitum mouse embryos bind
to a sequence containing two palindromic TAATTA sites, which bear four copies of
the ATTA core sequence, a common feature of most HOM-C/HOX binding sites. HOXB2
protected an adjacent site containing a direct repeat of an ACTT sequence, quite
divergent from the ATTA consensus. The region bound by the three homeoproteins is
strikingly conserved through evolution and necessary (at least for HOXB1 and
HOXB3) to mediate the up-regulation of the Otx2 transcription. Taken together,
our data support the hypothesis that anteriorly expressed Hox genes might play a
role in the refinement of the Otx2 early expression boundaries in vivo.
PMID- 9556595
TI - Post-translational processing and turnover kinetics of presynaptically targeted
amyloid precursor superfamily proteins in the central nervous system.
AB - The amyloid precursor superfamily is composed of three highly conserved
transmembrane glycoproteins, the amyloid precursor protein (APP) and amyloid
precursor-like proteins 1 and 2 (APLP1, APLP2), whose functions are unknown.
Proteolytic cleavage of APP yields the betaA4 peptide, the major component of
cerebral amyloid in Alzheimer's disease. Here we show that five post
translationally modified, full-length species of APP and APLP2 (but not APLP1)
arrive at the mature presynaptic terminal in the fastest wave of axonal transport
and are subsequently rapidly cleared (mean half-life of 3.5 h). Rapid turnover of
presynaptic APP and APLP2 occurs independently of visual activity. Turnover of
the most rapidly arriving APP species was accompanied by a delayed accumulation
of a 120-kDa, APP fragment lacking the C terminus, consistent with presynaptic
APP turnover via constitutive proteolysis. Turnover of APLP2 was not accompanied
by detectable APLP2 fragment peptides, suggesting either that APLP2 either is
more rapidly degraded than is APP or is retrogradely transported shortly after
reaching the terminus. A single 150-kDa APLP2 species containing the Kunitz
protease inhibitor domain is the major amyloid precursor superfamily protein
transported to the presynapse. Presynaptic APP and APLP2 are sialylated and N-
and O-glycosylated, and some also carry chondroitin sulfate glycosaminoglycan
and/or dermatan sulfate glycosaminoglycan. The rapid kinetics for turnover of APP
and APLP2 predict a sensitive balance of synthesis, transport, and elimination
rates that may be critical to normal neuronal functions and metabolic fates of
these proteins.
PMID- 9556596
TI - Regulatory roles of the P domain of the subtilisin-like prohormone convertases.
AB - A unique feature of the eukaryotic subtilisin-like proprotein convertases (SPCs)
is the presence of an additional highly conserved sequence of approximately 150
residues (P domain) located immediately downstream of the catalytic domain. To
study the function of this region, which is required for the production of
enzymatically active convertases, we have expressed and characterized various P
domain-related mutants and chimeras in HEK293 cells and alpha-TC1-6 cells. In a
series of C-terminal truncations of PC3 (also known as PC1 or SPC3), PC3-Thr594
was identified as the shortest active form, thereby defining the functional C
terminal boundary of the P domain. Substitutions at Thr594 and nearby sites
indicated that residues 592-594 are crucial for activity. Chimeric SPC proteins
with interchanged P domains demonstrated dramatic changes in several properties.
Compared with truncated wild-type PC3 (PC3-Asp616), both PC3/PC2Pd and PC3/FurPd
had elevated activity on several synthetic substrates as well as reduced calcium
ion dependence, whereas Fur/PC2Pd was only slightly decreased in activity as
compared with truncated furin (Fur-Glu583). Of the three active SPC chimeras
tested, all had more alkaline pH optima. When PC3/PC2Pd was expressed in alpha
TC1-6 cells, it accelerated the processing of proglucagon into glicentin and
major proglucagon fragment and cleaved major proglucagon fragment to release GLP
1 and tGLP-1, similar to wild-type PC3. Thus, P domain exchanges generated fully
active chimeric proteases in several instances but not in all (e.g. PC2/PC3Pd was
inactive). The observed property changes indicate a role for the P domain in
regulating the stability, calcium dependence, and pH dependence of the
convertases.
PMID- 9556597
TI - The alpha-helical domain near the amino terminus is essential for dimerization of
vascular endothelial growth factor.
AB - Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen
and a key mediator of aberrant endothelial cell proliferation and vascular
permeability in a variety of human pathological situations such as tumor
angiogenesis, diabetic retinopathy, or psoriasis. By amino-terminal deletion
analysis and by site-directed mutagenesis we have identified a new domain within
the amino-terminal alpha-helix that is essential for dimerization of VEGF.
VEGF121 variants containing amino acids 8 to 121 or 14 to 121, respectively,
either expressed in Escherichia coli and refolded in vitro, or expressed in
Chinese hamster ovary cells, were in a dimeric conformation and showed full
binding activity to VEGF receptors and stimulation of endothelial cell
proliferation as compared with wild-type VEGF. In contrast, a VEGF121 variant
covering amino acids 18 to 121, as well as a variant in which the hydrophobic
amino acids Val14, Val15, Phe17, and Met18 within the amphipathic alpha-helix
near the amino terminus were replaced by serine, failed to form biological active
VEGF dimers. From these data we conclude that a domain between amino acids His12
and Asp19 within the amino-terminal alpha-helix is essential for formation of
VEGF dimers, and we propose hydrophobic interactions between VEGF monomers to
stabilize or favor dimerization.
PMID- 9556598
TI - Functional analysis of the amino-terminal 8-kDa domain of DNA polymerase beta as
revealed by site-directed mutagenesis. DNA binding and 5'-deoxyribose phosphate
lyase activities.
AB - The amino-terminal 8-kDa domain of DNA polymerase beta functions in binding
single-stranded DNA (ssDNA), recognition of a 5'-phosphate in gapped DNA
structures, and as a 5'-deoxyribose phosphate (dRP) lyase. NMR and x-ray crystal
structures of this domain have suggested several residues that may interact with
ssDNA or play a role in the dRP lyase reaction. Nine of these residues were
altered by site-directed mutagenesis. Each mutant was expressed in Escherichia
coli, and the recombinant protein was purified to near homogeneity. CD spectra of
these mutant proteins indicated that the alteration did not adversely affect the
global protein structure. Single-stranded DNA binding was probed by photochemical
cross-linking to oligo(dT)16. Several mutants (F25W, K35A, K60A, and K68A) were
impaired in ssDNA binding activity, whereas other mutants (H34G, E71Q, K72A,
E75A, and K84A) retained near wild-type binding activity. The 5'-phosphate
recognition activity of these mutants was examined by UV cross-linking to a 5
nucleotide gap DNA where the 5' terminus in the gap was either phosphorylated or
unphosphorylated. The results indicate that Lys35 is involved in 5'-phosphate
recognition of DNA polymerase beta. Finally, the dRP lyase activity of these
mutants was evaluated using a preincised apurinic/apyrimidinic DNA. Alanine
mutants of Lys35 and Lys60 are significantly reduced in dRP lyase activity,
consistent with the lower ssDNA binding activity. More importantly, alanine
substitution for Lys72 resulted in a greater than 90% loss of dRP lyase activity,
without affecting DNA binding. Alanine mutants of Lys68 and Lys84 had wild-type
dRP lyase activity. The triple alanine mutant, K35A/K68A/K72A, was devoid of dRP
lyase activity, suggesting that the effects of the alanine substitution at Lys72
and Lys35 were additive. The results suggest that Lys72 is directly involved in
formation of a covalent imino intermediate and are consistent with Lys72 as the
predominant Schiff base nucleophile in the dRP lyase beta-elimination catalytic
reaction.
PMID- 9556599
TI - Characterization of a split respiratory pathway in the wheat "take-all" fungus,
Gaeumannomyces graminis var. tritici.
AB - This article describes the first detailed analysis of mitochondrial electron
transfer and oxidative phosphorylation in the pathogenic filamentous fungus,
Gaeumannomyces graminis var. tritici. While oxygen consumption was cyanide
insensitive, inhibition occurred following treatment with complex III inhibitors
and the alternative oxidase inhibitor, salicylhydroxamic acid (SHAM). Similarly,
maintenance of a Deltapsi across the mitochondrial inner membrane was unaffected
by cyanide but sensitive to antimycin A and SHAM when succinate was added as the
respiratory substrate. As a result, ATP synthesis through complex V was
demonstrated to be sensitive to these two inhibitors but not to cyanide. Analysis
of the cytochrome content of mitochondria indicated the presence of those
cytochromes normally associated with electron transport in eukaryotic
mitochondria together with a third, b-type heme, exhibiting a dithionite-reduced
absorbance maxima at 560 nm and not associated with complex III. Antibodies
raised to plant alternative oxidase detected the presence of both the monomeric
and dimeric forms of this oxidase. Overall this study demonstrates that a novel
respiratory chain utilizing the terminal oxidases, cytochrome c oxidase and
alternative oxidase, are present and constitutively active in electron transfer
in G. graminis tritici. These results are discussed in relation to current
understanding of fungal electron transfer and to the possible contribution of
alternative redox centers in ATP synthesis.
PMID- 9556600
TI - Substrate binding and catalytic mechanism of a barley beta-D-Glucosidase/(1,4)
beta-D-glucan exohydrolase.
AB - A beta-glucosidase, designated isoenzyme betaII, from germinated barley (Hordeum
vulgare L.) hydrolyzes aryl-beta-glucosides and shares a high level of amino acid
sequence similarity with beta-glucosidases of diverse origin. It releases glucose
from the non-reducing termini of cellodextrins with catalytic efficiency factors,
kcat/Km, that increase approximately 9-fold as the degree of polymerization of
these substrates increases from 2 to 6. Thus, the enzyme has a specificity and
action pattern characteristic of both beta-glucosidases (EC 3.2.1.21) and the
polysaccharide exohydrolase, (1,4)-beta-glucan glucohydrolase (EC 3.2.1.74). At
high concentrations (100 mM) of 4-nitrophenyl beta-glucoside, beta-glucosidase
isoenzyme betaII catalyzes glycosyl transfer reactions, which generate 4
nitrophenyl-beta-laminaribioside, -cellobioside, and -gentiobioside. Subsite
mapping with cellooligosaccharides indicates that the barley beta-glucosidase
isoenzyme betaII has six substrate-binding subsites, each of which binds an
individual beta-glucosyl residue. Amino acid residues Glu181 and Glu391 are
identified as the probable catalytic acid and catalytic nucleophile,
respectively. The enzyme is a family 1 glycoside hydrolase that is likely to
adopt a (beta/alpha)8 barrel fold and in which the catalytic amino acid residues
appear to be located at the bottom of a funnel-shaped pocket in the enzyme.
PMID- 9556601
TI - Tyrosine phosphorylation of p130Cas is involved in actin organization in
osteoclasts.
AB - Integrin-mediated interaction with the extracellular matrix plays a critical role
in the function of osteoclasts, the bone-resorbing cells. This study examines the
role of p130Cas (Crk-associated substrate (Cas)) in actin organization in
osteoclasts. Multinucleated osteoclast-like cells (OCLs) were obtained in a co
culture of murine bone marrow cells and primary osteoblasts. After plating on
culture dishes, OCLs formed a ringlike structure consisting of F-actin dots at
cell periphery (actin ring). The percentage of OCLs with actin rings and its
diameter increased with time and cell spreading. Tyrosine phosphorylation of a
protein (p130) increased with actin ring formation. Treatment with cytochalasin D
disrupted actin rings and reduced tyrosine phosphorylation of p130. Using
specific antibodies, p130 was identified as Cas. By immunocytochemistry, Cas was
localized to the peripheral regions of OCLs and its distribution overlapped that
of F-actin. In OCLs derived from Src(-/-) mice, in which osteoclast activity is
severely compromised, tyrosine phosphorylation of Cas was markedly reduced.
Moreover, Cas was diffusely distributed in the cytoplasm and actin ring formation
is not observed. These findings suggest that Src-dependent tyrosine
phosphorylation of Cas is involved in the adhesion-induced actin organization
associated with osteoclast activation.
PMID- 9556602
TI - Disulfide bond structure of human epidermal growth factor receptor.
AB - The extracellular domain of the human epidermal growth factor receptor (sEGFR)
consists of 621 amino acid residues, including 50 cysteines. The connections of
the 25 disulfide bonds in the recombinant sEGFR protein, obtained from Chinese
hamster ovary cells, have been determined using N-terminal sequencing and matrix
assisted laser desorption/ionization mass spectroscopy. We identified a basic
repeat of eight cysteines with a 1-3, 2-4, 5-6, and 7-8 disulfide pairing pattern
in the two cysteine-rich regions of sEGFR. By comparison to other cysteine-rich
motifs, it was concluded that the cysteine-rich repeat of sEGFR belongs to the
laminin-type EGR-like (LE) structural motif. Three-dimensional structure models
of the two cysteine-rich regions have been built, based on the three-dimensional
structures of the LE domains from the laminin gamma1 chain and secondary
structure predictions for the EGF receptor.
PMID- 9556603
TI - Differentiation of glycine antagonist sites of N-methyl-D-aspartate receptor
subtypes. Preferential interaction of CGP 61594 with NR1/2B receptors.
AB - The binding site for the co-agonist glycine on N-methyl-D-aspartate (NMDA)
receptors has been mapped to the NR1 subunit whereas binding of the principal
agonist glutamate is mediated by the NR2 subunits. Using the novel glycine site
antagonist and photoaffinity label CGP 61594, distinct contributions of the NR2
subunit variants to the glycine antagonist binding domains of NMDA receptor
subtypes are demonstrated. High affinity sites for CGP 61594 were exclusively
displayed by NR1/2B receptors, as shown by their co-distribution with the NR2B
subunit, by subunit-selective immunoprecipitation and by functional analysis of
NR1/2B receptors expressed in Xenopus oocytes (inhibitory potency, IC50 = 45 +/-
11 nM). Other NMDA receptor subtypes are clearly distinguished by reduced
inhibitory potencies for CGP 61594, being low for NR1/2A and NR1/2D receptors
(IC50 = 430 +/- 105 nM and 340 +/- 61 nM, respectively) and intermediate for
NR1/2C receptors (IC50 = 164 +/- 27 nM). Glycine antagonist sites with low and
intermediate affinity for [3H]CGP 61594 were detected also in situ by radioligand
binding in brain areas predominantly expressing the NR2A and NR2C subunits,
respectively. Thus, [3H]CGP 61594 is the first antagonist radioligand that
reliably distinguishes the glycine site of NMDA receptor subtypes. [3H]CGP 61594
is a promising tool to identify the NR2 subunit domains that contribute to
differential glycine antagonist sites of NMDA receptor subtypes.
PMID- 9556604
TI - Inability of the acidic fibroblast growth factor mutant K132E to stimulate DNA
synthesis after translocation into cells.
AB - Acidic fibroblast growth factor (aFGF) is a potent mitogen. It acts through
activation of specific cell surface receptors leading to intracellular tyrosine
phosphorylation cascades, but several reports also indicate that aFGF enters
cells and that it has an intracellular function as well. The aFGF(K132E) mutant
binds to and activates fibroblast growth factor receptors equally strongly as the
wild-type, but it is a poor mitogen. We demonstrate that aFGF(K132E) enters NIH
3T3 cells and is transported to the nuclear fraction like wild-type aFGF. A
fusion protein of aFGF(K132E) and diphtheria toxin A-fragment (aFGF(K132E)-DT-A)
and a similar fusion protein containing wild-type aFGF (aFGF-DT-A) were
reconstituted with diphtheria toxin B-fragment. Both fusion proteins were
translocated to the cytosol by the diphtheria toxin pathway and subsequently
recovered from the nuclear fraction. Whereas translocation of aFGF-DT-A
stimulated DNA synthesis in U2OSDR1 cells lacking functional fibroblast growth
factor receptors, aFGF(K132E)-DT-A did not. The mutation disrupts a protein
kinase C phosphorylation site in the growth factor making it unable to be
phosphorylated. The data indicate that a defect in the intracellular action of
aFGF(K132E) is the reason for its strongly reduced mitogenicity, possibly due to
inability to be phosphorylated.
PMID- 9556605
TI - Homodimerization restores biological activity to an inactive erythropoietin
mutant.
AB - Erythropoietin (Epo) is believed to transduce a signal by bringing two Epo
receptors into close proximity, enabling cross-phosphorylation. We compared
monomeric Epos with homodimers in which two Epo monomers are linked by
polyglycine. Monomeric Epo mutant R103A is unable to support Epo-dependent cell
growth or trigger Janus kinase 2 and STAT5 activation, even at concentrations
greater than 7,000 times that sufficient for wild-type Epo activity. In contrast,
R103A homodimer induces proliferation and transduces signal at concentrations
similar to that of wild-type Epo monomer and homodimer. These experiments show
that two discrete domains on Epo are required for receptor binding and
activation. Our results also suggest that the EpoR can be dimerized by different
forms and sizes of molecules, as long as two recognition motifs are provided in
the same molecule. Design of other dimeric molecules may enhance our
understanding of cytokine specificity and signal transduction.
PMID- 9556606
TI - Induction of apoptosis and inhibition of cell proliferation by survivin gene
targeting.
AB - Survivin is a new IAP apoptosis inhibitor expressed during development and in
human cancer in vivo. The coding strand of the survivin gene was extensively
complementary to that of effector cell protease receptor-1 (EPR-1), prompting the
present investigation on the origin and functional relationship of these two
transcripts. Southern blots of genomic DNA were consistent with the presence of
multiple, evolutionarily conserved, EPR-1/Survivin-related genes. By pulsed field
gel electrophoresis and single- and two-color fluorescence in situ hybridization,
these were contained within a contiguous physical interval of 75-130 kilobases
(kb) on chromosome 17q25. In Northern blots, a single strand-specific probe
identified a 1.3-kb EPR-1 mRNA broadly distributed in normal adult and fetal
tissues, structurally distinct from the 1.9-kb Survivin transcript expressed in
transformed cell lines. Transient co-transfection of an EPR-1 cDNA potentially
acting as a Survivin antisense with a lacZ reporter plasmid resulted in loss of
viability of HeLa cells. In contrast, co-transfection of an antisense cDNA of
intercellular adhesion molecule-1 or a sense-oriented Survivin cDNA was without
effect. In stably transfected HeLa cells, ZnSO4 induction of an EPR-1 mRNA under
the control of a metallothionein promoter suppressed the expression of endogenous
survivin. This resulted in (i) increased apoptosis as detected by analysis of DNA
content and in situ internucleosomal DNA fragmentation and (ii) inhibition of
cell proliferation as compared with induced vector control transfectants. These
findings suggest the existence of a potential EPR-1/survivin gene cluster and
identify survivin as a new target for disrupting cell viability pathways in
cancer.
PMID- 9556607
TI - Involvement of heat shock protein 90 in the degradation of mutant insulin
receptors by the proteasome.
AB - We previously reported three families with type A insulin-resistant syndrome who
had mutations, either Asp1179 or Leu1193, in the kinase domain of the insulin
receptor. The extreme insulin resistance of these patients was found to be caused
by the decreased number of insulin receptors on the cell surface, due to the
intracellular rapid degradation (Imamura, T., Takata, Y., Sasaoka, T., Takada,
Y., Morioka, H., Haruta, T., Sawa, T., Iwanishi, M., Yang, G. H., Suzuki, Y.,
Hamada, J., and Kobayashi, M. (1994) J. Biol. Chem. 269, 31019-31027). In the
present study, we first examined whether these mutations caused rapid degradation
of unprocessed proreceptors, using the exon 13 deleted mutant insulin receptors
(DeltaEx13-IR), which were accumulated in the endoplasmic reticulum as
unprocessed proreceptors. The addition of Asp1179 or Leu1193 mutation to
DeltaEx13-IR caused accelerated degradation of the unprocessed DeltaEx13-IR in
the transfected COS-7 cells. Next, we tested whether these mutant receptors were
degraded by the proteasome. Treatment with proteasome inhibitors Z-Leu-Leu-Nva-H
(MG-115) or Z-Leu-Leu-Leu-H (MG-132) prevented the accelerated degradation of
these mutant receptors, resulting in increased amounts of the mutant receptors in
the COS-7 cells. Essentially the same results were obtained in the patient's
transformed lymphocytes. Finally, we found that these mutant receptors bound to
heat shock protein 90 (Hsp90). To determine whether Hsp90 played an important
role in the accelerated receptor degradation, we examined the effect of anti
Hsp90 antibody on the mutant receptor degradation. The microinjection of anti
Hsp90 antibody into cells prevented the accelerated degradation of both Asp1179
and Leu1193 mutant insulin receptors. Taken together, these results suggest that
Hsp90 is involved in dislocation of the mutant insulin receptors out of the
endoplasmic reticulum into the cytosol, where the mutant receptors are degraded
by the proteasome.
PMID- 9556608
TI - Characterization of recombinant and brain neuropsin, a plasticity-related serine
protease.
AB - Activity-dependent changes in neuropsin gene expression in the hippocampus
implies an involvement of neuropsin in neural plasticity. Since the deduced amino
acid sequence of the gene contained the complete triplet (His-Asp-Ser) of the
serine protease domain, the protein was postulated to have proteolytic activity.
Recombinant full-length neuropsin produced in the baculovirus/insect cell system
was enzymatically inactive but was readily converted to active enzyme by
endoprotease processing. The activational processing of prototype neuropsin
involved the specific cleavage of the Lys32-Ile33 bond near its N terminus.
Native neuropsin that was purified with a purity of 1,100-fold from mouse brain
had enzymatic characteristics identical to those of active-type recombinant
neuropsin. Both brain and recombinant neuropsin had amidolytic activities
cleaving Arg-X and Lys-X bonds in the synthetic chromogenic substrates, and the
highest specific activity was found against Boc-Val-Pro-Arg-4-methylcoumaryl-7
amide. The active-type recombinant neuropsin effectively cleaved fibronectin, an
extracellular matrix protein. Taken together, these results indicate that this
protease, which is enzymatically novel, has significant limbic effects by
changing the extracellular matrix environment.
PMID- 9556609
TI - Requirements for binding and signaling of the kinase domain receptor for vascular
endothelial growth factor.
AB - Vascular endothelial growth factor (VEGF) is a dimeric hormone that controls much
of vascular development through binding and activation of its kinase domain
receptor (KDR). We produced analogs of VEGF that show it has two receptor-binding
sites which are located near the poles of the dimer and straddle the interface
between subunits. Deletion experiments in KDR indicate that of the seven IgG-like
domains in the extracellular domain, only domains 2-3 are needed for tight
binding of VEGF. Monomeric forms of the extracellular domain of KDR bind
approximately 100 times weaker than dimeric forms showing a strong avidity
component for binding of VEGF to predimerized forms of the receptor. Based upon
these structure-function studies and a mechanism in which receptor dimerization
is critical for signaling, we constructed a receptor antagonist in the form of a
heterodimer of VEGF that contained one functional and one non-functional site.
These studies establish a functional foundation for the design of VEGF analogs,
mimics, and antagonists.
PMID- 9556610
TI - Galectin-1 is a major receptor for ganglioside GM1, a product of the growth
controlling activity of a cell surface ganglioside sialidase, on human
neuroblastoma cells in culture.
AB - Cell density-dependent inhibition of growth and neural differentiation in the
human neuroblastoma cell line SK-N-MC are associated with a ganglioside sialidase
mediated increase of GM1 and lactosylceramide at the cell surface. Because these
glycolipids expose galactose residues, we have initiated the study of the
potential role of galectins in such cellular events. Using specific antibodies,
galectin-1 but not galectin-3 was found to be present at the cell surface.
Assessment of carbohydrate-dependent binding revealed a saturable amount of
ligand sites approaching 2.6 x 10(6) galectin-1 molecules bound/cell. Presence
during cell culture of the sialidase inhibitor 2-deoxy-2,3-dehydro-N
acetylneuraminic acid or of the GM1-binding cholera toxin B subunit effected a
decrease of the presentation of galectin-1 ligands by 30-50%. The assumption that
GM1 is a major ligand for galectin-1 was reinforced by the correlation between
the number of carbohydrate-dependent 125I-iodinated GM1-neoganglioprotein binding
sites and the amount of immunoreactive surface galectin-1, the marked sensitivity
of probe binding to the presence of anti-galectin-1 antibody, and the inhibition
of cell adhesion to surface-immobilized GM1 by the antibody. The results open the
possibility that the carbohydrate-dependent interaction between ganglioside GM1
and galectin-1 may relay sialidase-dependent alterations in this cell system.
PMID- 9556611
TI - Identification and purification of the Holo-ELL complex. Evidence for the
presence of ELL-associated proteins that suppress the transcriptional inhibitory
activity of ELL.
AB - The human ELL gene on chromosome 19 undergoes frequent translocation with the
trithorax-like MLL gene on chromosome 11 in acute myeloid leukemia. Recently, it
was demonstrated that the product of the human ELL gene encodes an RNA polymerase
II elongation factor (Shilatifard, A., Lane, W. S., Jackson, K. W., Conaway, R.
C., and Conaway, J. W. (1996) Science 271, 1873-1876). In addition to its
elongation regulatory activity, ELL contains a novel type of RNA polymerase II
interaction domain that is capable of negatively regulating polymerase activity
in promoter-specific transcription in vitro (Shilatifard, A., Haque, D., Conaway,
R. C., and Conaway, J. W. (1997) J. Biol. Chem. 272, 22355-22363). Here, we
report the identification and purification of a large ELL-containing complex that
contains three proteins in addition to ELL and that we have named the Holo-ELL
complex. The Holo-ELL complex can increase the catalytic rate of transcription
elongation by RNA polymerase II. However, unlike the ELL polypeptide alone, the
Holo-ELL complex is not capable of negatively regulating polymerase activity in
promoter-specific transcription in vitro. The inability of the Holo-ELL complex
to negatively regulate polymerase activity in promoter-specific transcription
suggests that one or more of the ELL-associated proteins regulate this activity,
possibly through an interaction with the N-terminal domain of the ELL protein,
which was shown to be required for the transcriptional inhibitory activity of
ELL. Characterization of these ELL interacting proteins should help define the
regulation of the biochemical activities of ELL and how loss of this regulation
leads to the development of acute myeloid leukemia.
PMID- 9556612
TI - Immunolocalization of acyl-coenzyme A:cholesterol O-acyltransferase in
macrophages.
AB - Macrophages in atherosclerotic lesions accumulate large amounts of cholesteryl
fatty acyl esters ("foam cell" formation) through the intracellular
esterification of cholesterol by acyl-coenzyme A:cholesterol O-acyltransferase
(ACAT). In this study, we sought to determine the subcellular localization of
ACAT in macrophages. Using mouse peritoneal macrophages and immunofluorescence
microscopy, we found that a major portion of ACAT was in a dense reticular
cytoplasmic network and in the nuclear membrane that colocalized with the luminal
endoplasmic reticulum marker protein-disulfide isomerase (PDI) and that was in a
similar distribution as the membrane-bound endoplasmic reticulum marker
ribophorin. Remarkably, another portion of the macrophage ACAT pattern did not
overlap with PDI or ribophorin, but was found in as yet unidentified cytoplasmic
structures that were juxtaposed to the nucleus. Compartments containing labeled
beta-very low density lipoprotein, an atherogenic lipoprotein, did not overlap
with the ACAT label, but rather were embedded in the dense reticular network of
ACAT. Furthermore, cell-surface biotinylation experiments revealed that freshly
harvested, non-attached macrophages, but not those attached to tissue culture
dishes, contained approximately 10-15% of ACAT on the cell surface. In summary,
ACAT was found in several sites in macrophages: a cytoplasmic reticular/nuclear
membrane site that overlaps with PDI and ribophorin and has the characteristics
of the endoplasmic reticulum, a perinuclear cytoplasmic site that does not
overlap with PDI or ribophorin and may be another cytoplasmic structure or
possibly a unique subcompartment of the endoplasmic reticulum, and a cell-surface
site in non-attached macrophages. Understanding possible physiological
differences of ACAT in these locations may reveal an important component of ACAT
regulation and macrophage foam cell formation.
PMID- 9556613
TI - Identification of a major carbohydrate capping group of the L-selectin ligand on
high endothelial venules in human lymph nodes as 6-sulfo sialyl Lewis X.
AB - We investigated the molecular species of sulfated sialyl Lewis X determinants,
the putative L-selectin ligand, expressed on high endothelial venules (HEV) in
human lymph nodes. Comparison of the reactivity pattern of HEV with the
reactivity of the pure 6-sulfo, 6'-sulfo, or 6,6'-bissulfo sialyl Lewis X
determinant with hitherto known anti-sialyl Lewis X antibodies strongly suggested
6-sulfo sialyl Lewis X to be the best candidate for the major sulfated sialyl
Lewis X determinant on HEV, followed by 6,6'-bissulfo sialyl Lewis X, whereas 6'
sulfo sialyl Lewis X was unlikely. We newly generated monoclonal antibodies
(mAbs) G152 and G72 directed against 6-sulfo sialyl Lewis X, which intensely
labeled HEV in immunohistochemical examination and inhibited binding of
recombinant L-selectin-IgG to HEV, suggesting that the determinant serves as a
ligand for L-selectin. To test the concomitant expression of 6, 6'-bissulfo
sialyl Lewis X, specific mAbs (G2706, G27011, G27037, and G27039) were generated,
but all antibodies failed to react to HEV. Next, we established mAbs (AG97 and
AG273) directed against 6-sulfo Lewis X, the asialo form of 6-sulfo sialyl Lewis
X. The antibodies were not reactive to untreated HEV, but strongly reacted to
sialidase-treated HEV. This indicated the predominance of the sialylated form of
6-sulfo sialyl Lewis X and minimal expression of its asialo form, corroborating
that it was synthesized by fucosyltransferase VII, the isoenzyme that
preferentially produces the sialylated form of the determinant.
PMID- 9556614
TI - A divergent member of the transforming growth factor beta receptor family from
Schistosoma mansoni is expressed on the parasite surface membrane.
AB - To optimize reproductive success under the limitations determined by conditions
within an individual host, parasitic helminths have evolved mechanisms that allow
them to detect and respond to host factors such as species, age, sex,
reproductive condition, and immune status. Using the model helminth Schistosoma
mansoni, we have explored the possibility that parasitic helminths express signal
transducing receptor molecules on their surfaces. Here, we present the
identification of a schistosome member of the transforming growth factor beta
receptor family of cell-surface receptors, the first member of this family to be
identified in a platyhelminth. The putative protein kinase domain of the
schistosome receptor displays up to 58% amino acid identity to kinase domains of
other type I receptor serine-threonine kinases, and contains a potential "GS
domain," suggesting it is a divergent member of the type I receptor subfamily.
This receptor is expressed on the surface of the parasite's syncytial tegument
and expression of receptor messenger RNA and protein is up-regulated following
infection of the mammalian host. The receptor protein can be isolated in a
phosphorylated form from adult parasites, which together with its surface
location, suggests that it functions in transducing signals across the parasite
surface membrane.
PMID- 9556615
TI - Identification and characterization of an unusual double serine/threonine protein
phosphatase 2C in the malaria parasite Plasmodium falciparum.
AB - We have cloned a gene from Plasmodium falciparum with homology to the Mg2+
dependent serine/threonine protein phosphatase 2C (PP2C) family. The predicted
coding region is 920 amino acids long, twice the size of other members of this
family. We show that this protein can be divided into two halves (Pf2C-1 and Pf2C
2), each a complete phosphatase unit with homology to other phosphatases of this
class. To study the function of this PP2C, we have tested the ability of
different constructs to complement conditional null mutants of yeast. Our results
show that expression of the full-length protein, the first half alone, the second
half alone, or a hybrid with the N terminus of the first half and the C terminus
of the second half was able to complement the heat shock response defect of a
Schizosaccharomyces pombe strain with a PP2C (PTC1) deletion. Recombinant P.
falciparum PP2C expressed in Escherichia coli was active in dephosphorylating 32P
labeled casein in an Mg2+- or Mn2+-dependent reaction. Each half alone was also
active in recombinant form. Using the two-hybrid system, we have shown that the
two halves can interact. Gel filtration assay of P. falciparum protein extracts
suggests that full-length PfPP2C is a dimer, and phosphatase activity competition
experiments indicate that dimerization of PfPP2C is required for its optimal
activity. This unusual phosphatase molecule appears to be composed of four
catalytic units on two polypeptide chains.
PMID- 9556616
TI - Protein kinase B and rac are activated in parallel within a phosphatidylinositide
3OH-kinase-controlled signaling pathway.
AB - The GTPase Rac and the protein kinase B (PKB) are downstream targets of
phosphatidylinositide 3OH-kinase in platelet-derived growth factor-stimulated
signaling pathways. We have generated PAE cell lines inducibly expressing mutants
of Rac. Use of these cell lines suggests that Rac is involved in both platelet
derived growth factor-stimulated membrane ruffling and the activation of p70(S6K)
but not in the activation of PKB. Furthermore, expression of constitutively
active alleles of PKB in PAE cells suggests that PKB is able to regulate the
activity of p70(S6K) but not the cytoskeletal changes underlying membrane
ruffling. Thus, our results indicate that Rac and PKB are on separate pathways
downstream of phosphatidylinositide 3OH-kinase in these cells but that both of
these pathways are involved in the regulation of p70(S6K).
PMID- 9556617
TI - Activation of gene expression by a ligand-induced conformational change of a
protein-DNA complex.
AB - IlvY protein binds cooperatively to tandem operator sites in the divergent,
overlapping, promoter-regulatory region of the ilvYC operon of Escherichia coli.
IlvY positively regulates the expression of the ilvC gene in an inducer-dependent
manner and negatively regulates the transcription of its own divergently
transcribed structural gene in an inducer-independent manner. Although binding of
IlvY protein to the tandem operators is sufficient to repress ilvY promoter
specific transcription, it is not sufficient to activate transcription from the
ilvC promoter. Activation of ilvC promoter-specific transcription requires the
additional binding of a small molecule inducer to the IlvY protein-DNA complex.
The binding of inducer to IlvY protein does not affect the affinity of IlvY
protein for the tandem operator sites. It does, however, cause a conformational
change of the IlvY protein-DNA complex, which is correlated with the partial
relief of an IlvY protein-induced bend of the DNA helix in the ilvC promoter
region. This structural change in the IlvY protein-DNA complex results in a 100
fold increase in the affinity of RNA polymerase binding at the ilvC promoter
site. The ability of a protein to regulate gene expression by ligand-responsive
modulation of a protein-DNA structure is an emerging theme in gene regulation.
PMID- 9556618
TI - A multifunctional repeated motif is present in human bifunctional tRNA
synthetase.
AB - Tandem repeats located in the human bifunctional glutamyl-prolyl-tRNA synthetase
(EPRS) have been found in many different eukaryotic tRNA synthetases and were
previously shown to interact with another distinct repeated motifs in human
isoleucyl-tRNA synthetase. Nuclear magnetic resonance and differential scanning
calorimetry analyses of an isolated EPRS repeat showed that it consists of a
helix-turn-helix with a melting temperature of 59 degrees C. Specific interaction
of the EPRS repeats with those of isoleucyl-tRNA synthetase was confirmed by in
vitro binding assays and shown to have a dissociation constant of approximately
2.9 microM. The EPRS repeats also showed the binding activity to the N-terminal
motif of arginyl-tRNA synthetase as well as to various nucleic acids, including
tRNA. Results of the present work suggest that the region comprising the repeated
motifs of EPRS provides potential sites for interactions with various biological
molecules and thus plays diverse roles in the cell.
PMID- 9556619
TI - Mutations in the double-stranded RNA-activated protein kinase insert region that
uncouple catalysis from eIF2alpha binding.
AB - The interferon-induced, double-stranded RNA (dsRNA)-activated protein kinase,
PKR, inhibits protein synthesis via phosphorylation of the alpha subunit of the
translation initiation factor eIF2. A kinase insert region N-terminal of PKR
kinase subdomain V, which is conserved among eIF2alpha kinases, has been proposed
to determine substrate specificity of these kinases. To investigate the function
of this kinase insert region, selective PKR mutants were generated, and kinase
activities and eIF2alpha affinities were analyzed in vitro. The in vivo function
was investigated by growth inhibitory assays in yeast and translational assays in
COS cells. Among the 13 mutations, 5 lost kinase activity and 3 exhibited less
than 30% of wild-type eIF2alpha binding activity. The deletion of the conserved
sequence (amino acids 362-370) resulted in a protein that had no kinase activity
and only about 25% of wild-type eIF2alpha binding, suggesting that this sequence
is not only required for PKR kinase activity but also is important for substrate
interaction. It was determined that the hydrophobicity of the conserved sequence
of PKR is required for kinase activity but is not crucial for eIF2alpha binding.
The amino acid residue Glu-367 in the conserved motif was shown to be directly
involved in substrate binding but was not important for kinase activity. These
results suggest that the activation of PKR is not a prerequisite for its binding
to the substrate and that the conserved motif in subdomain V contributes to the
interaction of PKR and eIF2alpha.
PMID- 9556620
TI - Protein C inhibitor secreted from activated platelets efficiently inhibits
activated protein C on phosphatidylethanolamine of platelet membrane and
microvesicles.
AB - Protein C inhibitor (PCI) was detected in human platelets (2.9 ng/10(9) cells)
and megakaryocytic cells (1.5 ng/10(6) cells). PCI mRNA was also detected in both
platelets and megakaryocytic cells using nested polymerase chain reaction. PCI
was found to be located in the alpha-granules of resting platelets. Approximately
30% of the total amount of PCI in platelets was released after stimulation with
ADP, collagen, adrenalin, thrombin, or thrombin receptor-activating peptide.
Secreted PCI was detected on the surface of activated platelets and phospholipid
microvesicles. PCI secreted from thrombin receptor-activating peptide-stimulated
platelets inhibited activated protein C (APC) efficiently. PCI significantly
inhibited APC in the presence of phospholipid vesicles prepared using rabbit
brain cephalin (RBC) or a mixture of 40% phosphatidylethanolamine (PE), 20%
phosphatidylserine (PS), and 40% phosphatidylcholine (PC) with a second order
rate constant of 1.0 x 10(6) M-1.min-1. Of these phospholipids, PE was critical
for this inhibition. The dissociation constants of the binding of APC or PCI to
solid phase phospholipids showed that APC binds more preferably to PE than to RBC
or PS, and PCI to PE or RBC than to PS or PC. PCI binding to solid phase
phospholipids depended on the presence of PE. RBC- or PE-bound PCI inhibited APC
significantly but only weakly the gamma-carboxyglutamic acid domainless APC. The
gamma-carboxyglutamic acid fragment of protein C suppressed the PCI-mediated
inhibition of APC on solid phase RBC or PE. Most of the APC.PCI complex formed on
solid phase RBC or PE was released into the soluble phase. These findings suggest
that PCI secreted from activated platelets binds preferably to PE of platelet
membrane and microvesicles and that it inhibits phospholipid-bound APC
efficiently.
PMID- 9556622
TI - Comparison of Na-K-Cl cotransporters. NKCC1, NKCC2, and the HEK cell Na-L-Cl
cotransporter.
AB - The Na-K-Cl cotransporter (NKCC) mediates the coupled movement of ions into most
animal cells, playing important roles in maintenance of cell volume and in
epithelial Cl transport. Two forms of NKCC have been described: NKCC1, the
"housekeeping" isoform that is also responsible for Cl accumulation in secretory
epithelial cells, and NKCC2, which mediates apical Na+K+Cl entry into renal
epithelial cells. Here we examine the kinetic properties of NKCC1, NKCC2, and the
endogenous HEK-293 cell cotransporter. Stable expression of rabbit NKCC2A was
obtained in HEK-293 cells utilizing a chimera (h1r2A0.7) in which the 5'
untranslated region and cDNA encoding 104 amino acids of the N terminus are
replaced by the corresponding sequence of NKCC1. h1r2A0.7 exhibits Na and Cl
affinities near those of NKCC1, but it has a 4-fold lower Rb affinity, and a 3
fold higher affinity for the inhibitor bumetanide. The activity of h1r2A0.7 is
increased on incubation in low [Cl] media as is NKCC1, but the resting level of
activity is higher in h1r2A0.7 and activation is more rapid. h1r2A0.7 exhibits an
appropriate volume response, unlike NKCC1 for which concomitant changes in [Cl]i
appear to be the overriding factor. These results support a model in which apical
NKCC2 activity is matched to basolateral Cl exit through changes in [Cl]i.
Reverse transcriptase-polymerase chain reaction of HEK-293 cell mRNA is positive
with NKCC1 primers and negative with NKCC2 primers. Surprisingly, we found that
the behavior of the endogenous HEK cell Na-K-Cl cotransporter is unlike either of
the two forms which have been described: compared with NKCC1, HEK cell
cotransporter has a 2.5-fold lower Na affinity, an 8-fold lower Rb affinity, and
a 4-fold higher bumetanide affinity. These results suggest the presence of a
novel isoform of NKCC in HEK-293 cells.
PMID- 9556621
TI - Activation of ErbB4 by the bifunctional epidermal growth factor family hormone
epiregulin is regulated by ErbB2.
AB - Epiregulin (EPR) is a recently described member of the epidermal growth factor
(EGF) family of peptide growth factors. The ever expanding size of the EGF family
has made distinguishing the activities of these hormones paramount. We show here
that EPR activates two members of the ErbB family of receptor tyrosine kinases,
epidermal growth factor receptor (EGFR) and ErbB4. Therefore by these criteria,
EPR is qualitatively similar to another EGF family hormone, betacellulin (BTC).
Yet, here we also demonstrate quantitative differences between EPR and BTC. EPR
stimulates higher levels of EGFR phosphorylation than does BTC, whereas BTC
stimulates higher levels of ErbB4 phosphorylation than does EPR. Moreover, the
EPR and BTC dose response curves show that although EGFR is more sensitive to EPR
than is ErbB4, ErbB4 is more sensitive to BTC than is EGFR. Finally, ErbB2, which
is not activated by EPR when expressed on its own, increases the sensitivity of
ErbB4 for activation by EPR. Therefore, these results establish that EPR exhibits
novel activities and modes of regulation, which may have significant implications
for EPR function in vivo.
PMID- 9556623
TI - Membrane association of active plasmid partitioning protein A in Escherichia
coli.
AB - QsopA and SopA, proteins essential for stable maintenance of low copy number
plasmids and encoded on plasmid QpH1 of Coxiella burnetii and the F plasmid of
Escherichia coli, respectively, are shown to be membrane associated using three
independent approaches: isolation of hybrid protein A-PhoA proteins that display
PhoA (bacterial alkaline phosphatase) activity indicating a periplasmic location,
biochemical fractionation by flotation gradient centrifugation, and subcellular
localization by immunoelectron microscopy. These data provide insight into the
mechanism by which partitioning protein A spatially directs plasmids into
daughter cells at bacterial division.
PMID- 9556624
TI - Glutathione regulation of neutral sphingomyelinase in tumor necrosis factor-alpha
induced cell death.
AB - Tumor necrosis factor-alpha (TNFalpha)-induced cell death involves a diverse
array of mediators and regulators including proteases, reactive oxygen species,
the sphingolipid ceramide, and Bcl-2. It is not known, however, if and how these
components are connected. We have previously reported that GSH inhibits, in
vitro, the neutral magnesium-dependent sphingomyelinase (N-SMase) from Molt-4
leukemia cells. In this study, GSH was found to reversibly inhibit the N-SMase
from human mammary carcinoma MCF7 cells. Treatment of MCF7 cells with TNFalpha
induced a marked decrease in the level of cellular GSH, which was accompanied by
hydrolysis of sphingomyelin and generation of ceramide. Pretreatment of cells
with GSH, GSH-methylester, or N-acetylcysteine, a precursor of GSH biosynthesis,
inhibited the TNFalpha-induced sphingomyelin hydrolysis and ceramide generation
as well as cell death. Furthermore, no significant changes in GSH levels were
observed in MCF7 cells treated with either bacterial SMase or ceramide, and GSH
did not protect cells from death induced by ceramide. Taken together, these
results show that GSH depletion occurs upstream of activation of N-SMase in the
TNFalpha signaling pathway. TNFalpha has been shown to activate at least two
groups of caspases involved in the initiation and "execution" phases of
apoptosis. Therefore, additional studies were conducted to determine the
relationship of GSH and the death proteases. Evidence is provided to demonstrate
that depletion of GSH is dependent on activity of interleukin-1beta-converting
enzyme-like proteases but is upstream of the site of action of Bcl-2 and of the
execution phase caspases. Taken together, these studies demonstrate a critical
role for GSH in TNFalpha action and in connecting major components in the
pathways leading to cell death.
PMID- 9556625
TI - Evidence for in situ and in vitro association between beta-dystroglycan and the
subsynaptic 43K rapsyn protein. Consequence for acetylcholine receptor clustering
at the synapse.
AB - The accumulation of dystrophin and associated proteins at the postsynaptic
membrane of the neuromuscular junction and their co-distribution with nicotinic
acetylcholine receptor (AChR) clusters in vitro suggested a role for the
dystrophin complex in synaptogenesis. Co-transfection experiments in which alpha-
and beta-dystroglycan form a complex with AChR and rapsyn, a peripheral protein
required for AChR clustering (Apel, D. A., Roberds, S. L., Campbell, K. P., and
Merlie, J. P. (1995) Neuron 15, 115-126), suggested that rapsyn functions as a
link between AChR and the dystrophin complex. We have investigated the
interaction between rapsyn and beta-dystroglycan in Torpedo AChR-rich membranes
using in situ and in vitro approaches. Cross-linking experiments were carried out
to study the topography of postsynaptic membrane polypeptides. A cross-linked
product of 90 kDa was labeled by antibodies to rapsyn and beta-dystroglycan; this
demonstrates that these polypeptides are in close proximity to one another.
Affinity chromatography experiments and ligand blot assays using rapsyn
solubilized from Torpedo AChR-rich membranes and constructs containing beta
dystroglycan C-terminal fragments show that a rapsyn-binding site is present in
the juxtamembranous region of the cytoplasmic tail of beta-dystroglycan. These
data point out that rapsyn and dystroglycan interact in the postsynaptic membrane
and thus reinforce the notion that dystroglycan could be involved in
synaptogenesis.
PMID- 9556626
TI - Two E-boxes are the focal point of muscle-specific skeletal muscle type 1 Na+
channel gene expression.
AB - We have characterized a group of cis-regulatory elements that control muscle
specific expression of the rat skeletal muscle type 1 sodium channel (SkM1) gene.
These elements are located within a 3. 1-kilobase fragment that encompasses the
5'-flanking region, first exon, and part of the first intron of SkM1. We
sequenced the region between -1062 and +311 and determined the start sites of
transcription; multiple sites were identified between +1 and +30. The basal
promoter (-65/+11) lacks cell-type specificity, while an upstream repressor (
174/-65) confers muscle-specific expression. A positive element (+49/+254)
increases muscle-specific expression. Within these broad elements, two E boxes
play a pivotal role. One E box at -31/-26 within the promoter, acting in part
through its ability to bind the myogenic basic helix-loop-helix proteins,
recruits additional factor(s) that bind elsewhere within the SkM1 sequence to
control positive expression of the gene. A second E box at -90/-85 within the
repressor controls negative regulation of the gene and acts through a different
complex of proteins. Several of these cis-regulatory elements share both sequence
and functional similarities with cis-regulatory elements of the acetylcholine
receptor delta-subunit; the different arrangement of these elements may
contribute to unique expression patterns for the two genes.
PMID- 9556627
TI - Characterization of an 88-kDa heat shock protein of Neurospora crassa that
interacts with Hsp30.
AB - The small heat shock protein of Neurospora crassa, Hsp30, when employed in
affinity chromatography, bound two cellular proteins that were identified as
Hsp70 and Hsp88. Both Hsp70 and Hsp88 bound to Hsp30 in preference to other
proteins, but binding of Hsp88 was more selective for Hsp30, and a direct
interaction was observed. Transcripts for Hsp88, a newly characterized protein,
are present at normal temperature, but they are strongly induced by heat shock.
Its cDNA sequence predicts a protein with homology to mammalian Hsp110 family
proteins, which are distantly related to Hsp70. Hsp88 and its homologues show
greater similarity to Hsp70 in its N-terminal ATPase domain than in the C
terminal peptide-binding domain, and its ATP-binding motifs are conserved.
Nevertheless, the N-terminal domain of Hsp88 (and related proteins) is
consistently more hydrophobic and more basic than that of Hsp70 proteins. Within
the C-terminal domain, the sequence corresponding to the DnaK alpha subdomain is
conserved in the Hsp88/Hsp110 family proteins, whereas the DnaK beta subdomain
sequence is not conserved. The interaction between Hsp70 and Hsp30 may reflect
their cooperation as cochaperones for denatured proteins, whereas Hsp88 and Hsp30
may form a complex that interacts with potential substrates.
PMID- 9556628
TI - The hyaluronan receptor RHAMM regulates extracellular-regulated kinase.
AB - We have identified two RHAMM (receptor for hyaluronan-mediated motility) isoforms
that encode an alternatively spliced exon 4 (Hall, C. L., Yang, B., Yang, X.,
Zhang, S., Turley, M., Samuel, S., Lange, L. A., Wang, C., Curpen, G. D., Savani,
R. C., Greenberg, A. H., and Turley, E. A. (1995) Cell 82, 19-26 and Wang, C.,
Entwistle, J., Hou, G., Li, Q., and Turley, E. A. (1996) Gene 174, 299-306). One
of these, RHAMM variant 4 (RHAMMv4), is transforming when overexpressed and
regulates Ras signaling (Hall et al.). Here we note using flow cytometry and
confocal analysis that RHAMM isoforms encoding exon 4 occur both on the cell
surface and in the cytoplasm. Epitope-tagging experiments indicate that RHAMMv4
occurs only in the cytoplasm. Several observations suggest that both cell surface
RHAMM isoforms and RHAMMv4 are involved in regulating extracellular-regulated
kinase (ERK) activity. Affinity-purified anti-RHAMM exon 4 antibodies block the
ability of platelet-derived growth factor to activate ERK, and these reagents
modify the protein tyrosine phosphorylation profile of proteins resulting from
treatment with platelet-derived growth factor. A dominant negative form of
RHAMMv4 inhibits mutant active Ras activation of ERK and coimmunoprecipitates
with both mitogen-activated protein kinase kinase and ERK, suggesting that the
intracellular RHAMMv4 acts downstream of Ras, possibly at the level of mitogen
activated protein kinase kinase-ERK interactions. Consistent with this,
overexpression of RHAMMv4 constitutively activates ERK. These results identify a
novel mechanism for the regulation of the Ras-ERK signaling pathway and suggest
that RHAMM plays multiple roles in this regulation.
PMID- 9556629
TI - Characterization of a second member of the sentrin family of ubiquitin-like
proteins.
AB - Sentrin is a novel ubiquitin-like protein that can be conjugated to other
proteins in a manner analogous to ubiquitination. Two additional cDNA sequences
that encode proteins highly homologous to sentrin have been reported to
GenBankTM. It is not known whether these sentrin-like proteins could also
function as protein modifiers. In this report, a second member of the sentrin
family was characterized in detail. Sentrin-2 is a 95-amino acid polypeptide that
is 46% identical and 66% homologous to sentrin-1. Northern blot analysis showed
that the sentrin-2 message was expressed in all tissues, but was barely
detectable in the liver and placenta. The ability of sentrin-2 to conjugate to
other proteins was tested by expressing hemagglutinin epitope-tagged sentrin-2 in
COS cells. Western blot analysis showed that sentrin-2 could be transferred to
other proteins in a pattern similar to that of sentrin-1 conjugation and had
similar C-terminal processing. We further showed that both sentrin-1 and sentrin
2 could covalently modify RanGAP1, a Ran GTPase-activating protein critically
involved in nuclear transport. Immunocytochemical analysis showed that sentrin-2
derivatives were highly enriched in the nucleus. Taken together, our results
demonstrate that sentrin-2 is another protein modifier for the sentrinization
pathway.
PMID- 9556630
TI - Fluoroaluminate induces activation and association of Src and Pyk2 tyrosine
kinases in osteoblastic MC3T3-E1 cells.
AB - Fluoride is known to increase bone mass in vivo, probably through stimulation of
osteoblast proliferation; however, the mechanisms of fluoroaluminate action in
osteoblasts have not yet been elucidated. We have previously shown that in
osteoblastic MC3T3-E1 cells, fluoroaluminate stimulates G protein-mediated
protein tyrosine phosphorylation (Scaronuscarona, M., Standke, G. J. R., Jeschke,
M., and Rohner, D. (1997) Biochem. Biophys. Res. Commun. 235, 680-684). Although
the Ser/Thr kinases Erk1, Erk2, and p70(S6K) were activated in response to
fluoroaluminate, the identity of fluoroaluminate-activated tyrosine kinase(s)
remained elusive. In this study, we show that in MC3T3-E1 cells, fluoroaluminate
induces a 110-kDa tyrosine-phosphorylated protein that we identify as Pyk2, a
cytoplasmic tyrosine kinase related to Fak (focal adhesion kinase). The tyrosine
phosphorylation of Pyk2 increased in a dose- and time-dependent manner. The
autophosphorylation activity of Pyk2 increased 3-fold and reached its maximum
within 10 min of fluoroaluminate treatment. Fluoroaluminate also induced
activation of Src and the association of Pyk2 with Src. The phosphorylation of
Src-associated Pyk2 increased >20-fold in in vitro kinase assays, suggesting that
Pyk2 is phosphorylated by Src. Although MC3T3-E1 cells express much more Fak than
Pyk2, Src preferentially associated with Pyk2. In vitro, Pyk2 bound to the Src
SH2 domain, suggesting that this interaction mediates the Src-Pyk2 association in
cells. These data indicate that osteoblastic cells express Pyk2, which is
tyrosine-phosphorylated and activated in response to G protein activation by
fluoroaluminate, and that the mechanism of Pyk2 activation most likely involves
Src. Thus, Src and Pyk2 are tyrosine kinases involved in G protein-mediated
tyrosine phosphorylation in osteoblastic cells and may be important for the
osteogenic action of fluoroaluminate.
PMID- 9556631
TI - Acceleration of myosin light chain dephosphorylation and relaxation of smooth
muscle by telokin. Synergism with cyclic nucleotide-activated kinase.
AB - Incorporation of 32P into telokin, a smooth muscle-specific, 17-18-kDa, acidic
(pI 4.2-4.4) protein, was increased by forskolin (20 microM) in intact rabbit
ileum smooth muscle (ileum) and by 8-bromo-cyclic GMP (100 microM) in alpha-toxin
permeabilized ileum. Native telokin (5-20 microM), purified from turkey gizzard,
and recombinant rabbit telokin, expressed in Escherichia coli and purified to
>90% purity, induced dose-dependent relaxation, associated with a significant
decrease in regulatory myosin light chain phosphorylation, without affecting the
rate of thiophosphorylation of regulatory myosin light chain of ileum
permeabilized with 0.1% Triton X-100. Endogenous telokin was lost from ileum
during prolonged permeabilization (>20 min) with 0.1% Triton X-100, and the time
course of loss was correlated with the loss of 8-bromo-cyclic GMP-induced calcium
desensitization. Recombinant and native gizzard telokins were phosphorylated, in
vitro, by the catalytic subunit of cAMP-dependent protein kinase, cGMP-dependent
protein kinase, and p42/44 mitogen-activated protein kinase; the recombinant
protein was also phosphorylated by calmodulin-dependent protein kinase II.
Exogenous cGMP-dependent protein kinase (0.5 microM) activated by 8-bromo-cyclic
GMP (50 microM) phosphorylated recombinant telokin (10 microM) when added
concurrently to ileum depleted of its endogenous telokin, and their relaxant
effects were mutually potentiated. Forskolin (20 microM) also increased
phosphorylation of telokin in intact ileum. We conclude that telokin induces
calcium desensitization in smooth muscle by enhancing myosin light chain
phosphatase activity, and cGMP- and/or cAMP-dependent phosphorylation of telokin
up-regulates its relaxant effect.
PMID- 9556632
TI - Protease resistance of syntaxin.SNAP-25.VAMP complexes. Implications for assembly
and structure.
AB - A stable ternary complex formed with vesicle-associated membrane protein 2
(VAMP2) and plasma membrane proteins syntaxin 1A and synaptosome-associated
protein of 25 kDa (SNAP-25) is proposed to function in synaptic vesicle
exocytosis. To analyze the structural characteristics of this synaptic protein
complex, recombinant binary (syntaxin 1A.SNAP-25), recombinant ternary, and
native ternary complexes were subjected to limited trypsin proteolysis. The
protected fragments, defined by amino-terminal sequencing and mass spectrometry,
included a carboxyl-terminal region of syntaxin 1A, the cytoplasmic domain of
VAMP2, and amino- and carboxyl-terminal regions of SNAP-25. Furthermore, separate
amino- and carboxyl-terminal fragments of SNAP-25, when combined with VAMP2 and
syntaxin 1A, were sufficient for stable complex assembly. Analysis of ternary
complexes formed with full-length proteins revealed that the carboxyl-terminal
transmembrane anchors of both syntaxin 1A and VAMP2 were protected from trypsin
digestion. Moreover, the stability of ternary complexes was increased by
inclusion of these transmembrane domains. These results suggest that the
transmembrane domains of VAMP2 and syntaxin 1A contribute to complex assembly and
stability and that amino- and carboxyl-terminal regions of SNAP-25 may function
as independent domains.
PMID- 9556633
TI - Novel mutations of the endothelin B receptor gene in patients with Hirschsprung's
disease and their characterization.
AB - Hirschsprung's disease (HSCR) is a congenital intestinal disease, characterized
by the absence of ganglion cells in the distal portion of the intestinal tract.
Recently, three susceptibility genes have been identified in HSCR, namely the RET
protooncogene, the endothelin B (ETB) receptor gene (EDNRB), and the endothelin-3
(ET-3) gene (EDN3). To investigate whether mutations in EDNRB could be related
with HSCR in non-inbred populations in Japan, we examined alterations of the gene
in 31 isolated patients. Three novel mutations were detected as follows: two
transversions, A to T and C to A at nucleotides 311 (N104I) and 1170 (S390R),
respectively, and a transition, T to C at nucleotide 325 (C109R). To analyze
functions of these mutant receptors, they were expressed in Chinese hamster ovary
cells. S390R mutation did not change the binding affinities but caused the
decreases in the ligand-induced increment of intracellular calcium and in the
inhibition of adenylyl cyclase activity, showing the impairment of the
intracellular signaling. C109R receptors were proved to be localized near the
nuclei as an unusual 44-kDa protein with the extremely low affinity to endothelin
1 (ET-1) and not to be translocated into the plasma membrane. On the other hand,
N104I receptors showed almost the same binding affinities and functional
properties as those of the wild type. Therefore, we conclude that S390R and C109R
mutations could cause HSCR but that N104I mutation might be polymorphous.
PMID- 9556634
TI - A trace amount of the human pro-apoptotic factor Bax induces bacterial death
accompanied by damage of DNA.
AB - An amount of human pro-apoptotic Bax as low as 0.01% of total protein was
sufficient to cause cell death in Escherichia coli. The bacterial cell death was
examined using a viable bacteria-specific fluorescence indicator system and loss
of colony formation ability. Co-expression of anti-apoptotic Bcl-xL showed a
modest inhibitory effect on the cell death caused by Bax. The trace amount of Bax
elongated E. coli and accumulated monounsaturated fatty acids, suggesting an
unusual metabolism of redox in the host. In fact, an increase of KCN-dependent O2
consumption accompanied the expression of Bax. At the same time, a fluorescent pH
indicator showed the apparent accumulation of protons outside the cell,
suggesting that the membrane is intact. Bax increased the level of superoxide
anion as measured by the expression of superoxide-dependent promoter. Nicked DNA
was significantly generated, and the frequency of mutations resistant to
rifampicin was increased by 30-fold, depending upon the expression of Bax. It is
proposed that trace amounts of Bax increase oxygen consumption, triggering
generation of superoxide, which affects DNA, leading to bacterial death.
PMID- 9556635
TI - Golgi localization and functional expression of human uridine diphosphatase.
AB - A full-length E(ecto)-ATPase (Plesner, L. (1995) Int. Rev. Cytol. 158, 141-214)
cDNA was cloned from a human brain cDNA library; it encodes a 610-amino acid
protein that contains two putative transmembrane domains. Heterologous expression
of this protein in COS-7 cells caused a significant increase in intracellular
membrane-bound nucleoside phosphatase activity. The activity was highest with UDP
as substrate and was stimulated by divalent cations in the following order: Ca2+
>> Mg2+ > Mn2+. The results of immunofluorescence staining indicate that this
protein is located in the Golgi apparatus. UDP hydrolysis was increased in the
presence of Triton X-100 or alamethicin, an ionophore that facilitates movement
of UDP across the membrane, suggesting that the active site of this UDPase is on
the luminal side of the Golgi apparatus. This is the first identification of a
mammalian Golgi luminal UDPase gene. Computer-aided sequence analysis of the
EATPase superfamily indicates that the human UDPase is highly similar to two
hypothetical proteins of the nematode Caenorhabditis elegans and to an
unidentified 71.9-kDa yeast protein and is less related to the previously
identified yeast Golgi GDPase.
PMID- 9556636
TI - The calcium channel antagonist controversy.
PMID- 9556638
TI - Comparing family physicians: Canada and the United States.
PMID- 9556637
TI - Cookouts and the seasonal peak of Escherichia coli infection.
PMID- 9556639
TI - Preventing falls in the elderly.
PMID- 9556640
TI - Down syndrome and incidence of Alzheimer's disease.
PMID- 9556641
TI - Impact of patient-directed pharmaceutical advertising.
PMID- 9556642
TI - Hepatitis A vaccination.
PMID- 9556643
TI - Diagnosis and treatment of prostate cancer.
AB - In the United States, prostate cancer is the most common solid tumor malignancy
in men and second to lung cancer as the leading cause of cancer deaths in this
group. Even though prostate cancer is responsible for 40,000 deaths per year,
screening programs are a matter of controversy because scientific evidence is
lacking that early detection decreases morbidity and mortality. Furthermore,
treatment decisions are difficult to make because of the generally indolent
nature of prostate cancer and because it tends to occur in older men who often
have multiple, competing medical illnesses. Depending on the specific situation,
radical prostatectomy, radiotherapy or watchful waiting (observation) will be the
most appropriate management option. In general, localized cancer is best treated
with surgical removal of the prostate gland or radiotherapy. Hormone deprivation
therapy is the primary method of controlling metastatic prostate cancer. At
present, chemotherapy cannot cure disseminated prostate cancer. Watchful waiting
is a reasonable management alternative for prostate cancer in an older patient or
a patient with other serious illnesses.
PMID- 9556644
TI - Calcium channel antagonists: morbidity and mortality--what's the evidence?
AB - Recent studies have shown an association between the use of calcium channel
antagonists for the treatment of hypertension and an increased risk of myocardial
infarction, gastrointestinal hemorrhage and cancer. The interpretation of the
results of these studies and their application to clinical practice requires an
understanding of study design constraints, conflicting results and limitations in
extrapolating study findings to other dosage strengths, formulations or agents
within the calcium channel antagonist class. A review and critique of these
studies provides background information on the controversial subject of using
calcium channel antagonists for the treatment of hypertension. Despite the
limitations of these studies, clinicians may want to select other classes of
agents, including diuretics and beta blockers, as first-line therapy until the
morbidity and mortality effects related to the use of calcium channel antagonists
are clearly known.
PMID- 9556646
TI - Evaluation and treatment of urinary tract infections in children.
AB - Urinary tract infections (UTIs) are among the most common bacterial infections
encountered by primary care physicians. Although UTIs do not occur with as great
a frequency in children as in adults, they can be a source of significant
morbidity in children. For reasons that are not yet completely understood, a
minority of UTIs in children progress to renal scarring, hypertension and renal
insufficiency. Clinical presentation of UTI in children may be nonspecific, and
the appropriateness of certain diagnostic tests remains controversial. The
diagnostic work-up should be tailored to uncover functional and structural
abnormalities such as dysfunctional voiding, vesicoureteral reflux and
obstructive uropathy. A more aggressive work-up, including renal cortical
scintigraphy, ultrasound and voiding cystourethrography, is recommended for
patients at greater risk for pyelonephritis and renal scarring, including infants
less than one year of age and all children who have systemic signs of infection
concomitant with a UTI. Antibiotic prophylaxis is used in patients with reflux or
recurrent UTI who are at greater risk for subsequent infections and
complications.
PMID- 9556645
TI - SIDS: counseling parents to reduce the risk.
AB - Although the cause or causes of sudden infant death syndrome (SIDS) remain
unknown, the incidence of SIDS is on the decline in the United States and other
countries. This decline has been accomplished largely through public education
campaigns informing parents about several important factors associated with an
increased risk of SIDS. These factors are prone and side infant sleeping
positions, exposure of infants to cigarette smoke and potentially hazardous
sleeping environments. Risk-reduction measures such as placing healthy infants to
sleep in the supine position, avoiding passive smoke exposure both before and
after birth and optimizing crib safety are beginning to lower the SIDS rate in
this country. Through patient education, family physicians can further reduce the
incidence of the number one cause of death in infants one week to one year old.
PMID- 9556647
TI - Management of seizures and epilepsy.
AB - While the evaluation and treatment of patients with seizures or epilepsy is often
challenging, modern therapy provides many patients with complete seizure control.
After a first seizure, evaluation should focus on excluding an underlying
neurologic or medical condition, assessing the relative risk of seizure
recurrence and determining whether treatment is indicated. Successful management
of patients with recurrent seizures begins with the establishment of an accurate
diagnosis of epilepsy syndrome followed by treatment using an appropriate
medication in a manner that optimizes efficacy. The goal of therapy is to
completely control seizures without producing unacceptable medication side
effects. Patients who do not achieve complete seizure control should be referred
to an epilepsy specialist, since new medications and surgical treatments offer
patients unprecedented options in seizure control.
PMID- 9556648
TI - Office management of Bartholin gland cysts and abscesses.
AB - Bartholin gland cysts and abscesses are common problems in women of reproductive
age. Although the cysts are usually asymptomatic, they may become enlarged or
infected and cause significant pain. Often the clinician is tempted simply to
lance the cyst or abscess, since this technique can be effective for other common
abscesses. However, simple lancing of a Bartholin gland cyst or abscess may
result in recurrence. More effective treatment methods include use of a Word
catheter and marsupialization, both of which can be performed in the office.
PMID- 9556649
TI - Recognition and treatment of obsessive-compulsive disorder.
AB - Obsessive-compulsive disorder is relatively common; however, its actual incidence
has only recently become clear. The neurotransmitter serotonin appears to have a
central role in this disorder. Males and females are affected equally, with onset
usually occurring in late adolescence. Symptoms include intrusive thoughts that
lead the patient to perform repetitive rituals that interfere with daily living.
Although patients are typically distressed by these thoughts and rituals, they
seldom volunteer their symptoms. Successful diagnosis often requires specific
questioning by the physician. Treatment is directed at symptom reduction;
however, complete remission of symptoms is unusual. Pharmacologic therapy usually
includes clomipramine or antidepressant treatment with selective serotonin
reuptake inhibitors, but in dosage ranges higher than those typically used in the
treatment of depression. Behavior therapy has also been proved effective, both
alone and in conjunction with pharmacologic therapy.
PMID- 9556650
TI - Photo quiz. Projections on the glans penis.
PMID- 9556651
TI - American Heart Association issues guidelines on imaging in transient ischemic
attacks and stroke.
PMID- 9556652
TI - ACOG issues report on the management of post-term pregnancy. American College of
Obstetricians and Gynecologists.
PMID- 9556653
TI - AIDS in persons 50 years of age and older.
PMID- 9556654
TI - Extensive restriction site polymorphism at the human phenylalanine hydroxylase
locus and application in prenatal diagnosis of phenylketonuria.
AB - A total of 10 restriction site polymorphisms have been identified at the human
phenylalanine hydroxylase locus using a full-length human phenylalanine
hydroxylase cDNA clone as a hybridization probe to analyze human genomic DNA.
These polymorphic patterns segregate in a Mendelian fashion and concordantly with
the disease state in various PKU kindreds. The frequencies of the restriction
site polymorphisms at the human phenylalanine hydroxylase locus among Caucasians
are such that the observed heterozygosity in the population is 87.5%. Thus, most
families with a history of classical phenylketonuria can take advantage of the
genetic analysis for prenatal diagnosis and carrier detection of the hereditary
disorder.
PMID- 9556655
TI - A systematic approach for detecting high-frequency restriction fragment length
polymorphisms using large genomic probes.
AB - Thirteen phage clones containing low-copy sequences were isolated from a human
DNA library and tested for their ability to detect restriction fragment length
polymorphisms (RFLPs). Reported are the RFLPs revealed with each clone, all found
in frequencies useful for linkage studies. Cytological data are available for
five of the 13 clones, with regional assignments made for three of the markers by
in situ hybridization. It is concluded that phage clones containing large unique
DNA inserts detect multiple RFLPs with high efficiency. An analysis of the
relative efficiency of 20 restriction enzymes for detecting single nucleotide
changes is discussed by comparing the observed data to those expected on the
basis of recognition and potential site frequencies, as computed from the
dinucleotide distribution. Finally, in an effort to facilitate linkage studies
using polymorphic DNA sequences, experiments were made with pools of probes from
various sources.
PMID- 9556657
TI - Monoclonal antibodies to coagulation factor IX define a high-frequency
polymorphism by immunoassays.
AB - Monoclonal antibodies have been used to demonstrate a polymorphism of human
plasma coagulation factor IX antigen in double antibody solid-phase
immunoradiometric assays. This polymorphism is detected in an assay where a
monoclonal antibody (A-1) adsorbed to microtiter wells is used to bind factor IX
from diluted plasma samples. Plasma samples with the factor IX polymorphism have
less than 0.2 U/ml of apparent antigen when tested with the A-1 antibody, while
assays with other monoclonal antibodies and assays with goat antisera to factor
IX show normal amounts of factor IX antigen. Factor IX coagulant activity was
normal in samples from donors with the polymorphism. The thin-layer
polyacrylamide gel isoelectric focusing pattern of factor IX purified from a
donor with the factor IX polymorphism (IXp) was identical to that obtained with
factor IX prepared from a donor who did not have the polymorphism (IXn). Purified
radiolabeled factor IX prepared from a donor with the polymorphism showed a Ka
for the A-1 antibody that was threefold less than that measured for IXn. The gene
frequency of IXp in male blood donors is 0.25. This polymorphism may be useful as
a marker for the X chromosome in genetic studies on plasma samples. Further
studies are necessary to determine the explanation for decreased reaction of IXp
with the A-1 monoclonal antibody.
PMID- 9556656
TI - High frequency of nonclassical steroid 21-hydroxylase deficiency.
AB - Nonclassical steroid 21-hydroxylase deficiency is an autosomal recessive disorder
that is defined by clinical and hormonal criteria that distinguishes it from the
classical 21-hydroxylase deficiency. No estimates of the gene frequency of
nonclassical 21-hydroxylase deficiency, also called attenuated, late-onset,
acquired, and cryptic adrenal hyperplasia, have been published thus far. Here, we
have used HLA-B genotype data in families containing multiple members affected
with nonclassical 21-hydroxylase deficiency together with the results of
quantitative hormonal tests to arrive at estimates of gene and disease
frequencies for this disorder. We found nonclassical 21-hydroxylase deficiency to
be a far more common disorder than classical 21-hydroxylase deficiency, which
occurs in 1/8,000 births. The prevalence of the disease in Ashkenazi Jews was
3.7%; in Hispanics, 1.9%; in Yugoslavs, 1.6%; in Italians, 0.3%; and in the
diverse Caucasian population, 0.1%. The gene for nonclassical 21-hydroxylase
deficiency is in genetic linkage disequilibrium with HLA-B14 in Ashkenazi Jews,
Hispanics, and Italians, but not in Yugoslavs or in a diverse, non-Jewish,
Caucasian group. The penetrance of nonclassical 21-hydroxylase deficiency gene in
the HLA-B14 containing haplotypes was incomplete. Thus, nonclassical 21
hydroxylase deficiency is probably the most frequent autosomal recessive genetic
disorder in man and is especially frequent in Ashkenazi Jews, Hispanics,
Italians, and Yugoslavs.
PMID- 9556658
TI - Segregation analysis of hemophilia A and B.
AB - We analyzed a sample of 1,485 families with hemophilia A and B and with unknown
diagnosis. The frequency of sporadic cases was estimated to be .166 and .078 for
the two types of hemophilia, respectively. The sex ratio of mutation rates did
not differ significantly from unity. The average age of maternal grandfathers of
probands at birth of mothers with a single child, affected by hemophilia B, and
of maternal grandfathers of probands at birth of mothers with more than one child
affected by hemophilia B, was higher than the age in appropriate control groups.
PMID- 9556659
TI - Genetic analysis of idiopathic hemochromatosis using both qualitative (disease
status) and quantitative (serum iron) information.
AB - An ongoing family study of idiopathic hemochromatosis in Brittany, France,
allowed us to investigate the segregation of this trait and its linkage and
association to the HLA-A locus in 147 pedigrees, comprising 1,408 individuals
with over 900 characterized for relevant biological parameters and typed for HLA.
The joint consideration of affection status and serum iron concentration reveals
no dominance effect on the latter trait and documents the increased information
afforded by the consideration of a biological correlate of liability to affection
for disease exhibiting incomplete penetrance. Our overall results are in general
agreement with published results on a Utah family study.
PMID- 9556660
TI - Analysis of three restriction fragment length polymorphisms in the human type II
procollagen gene.
AB - Cloned genomic DNA sequences corresponding to various regions of the human type
II procollagen gene were used to analyze the DNA from 78 normal volunteers.
Southern hybridization experiments detected polymorphic HindIII, BamHI, and EcoRI
sites. The presence of the polymorphic HindIII site results in a 7.0-kilobase
(kb) band, and the absence of this site results in a 14.0-kb band. When present,
the BamH1 polymorphic site yields a 4.8-kb band, and when absent, yields a 7.2-kb
band. The presence of the EcoRI polymorphic site results in a 3.7-kb band, and
its absence results in a 7.0-kb band. Each polymorphic site was mapped. Analyses
of the data demonstrated that the sites are present in overall gene frequencies
of .39 for HindIII, .04 for BamHI, and .02 for EcoRI. Gene frequencies of the
polymorphic sites were also studied with respect to race. The polymorphic sites
are present in a Hardy-Weinberg distribution in the study population. Study of an
extended family demonstrated that the segregation of the HindIII polymorphic site
is consistent with Mendelian inheritance.
PMID- 9556661
TI - Diagnosis and carrier detection of Tay-Sachs disease: direct determination of
hexosaminidase A using 4-methylumbelliferyl derivatives of beta-N
acetylglucosamine-6-sulfate and beta-N-acetylgalactosamine-6-sulfate.
AB - 4-Methylumbelliferyl-6-sulfo-2-acetamido-2-deoxy derivatives of beta-D
glucopyranoside and beta-D-galactopyranoside were prepared by direct sulfation of
the commonly used unsulfated derivatives. Both sulfated substrates were highly
specific for hexosaminidase A, and in fractionated serum, cells, and tissue
preparations, less than 2.5% of these activities were associated with
hexosaminidase B and the intermediate isozyme fractions. Serum and leukocytes
from patients with infantile Tay-Sachs disease, including a patient with
thermolabile hexosaminidase B, had less than 2% of noncarrier activities. Carrier
values were clearly separated from those of noncarriers, and no problems were
encountered in utilizing sera from pregnant women. The % hexosaminidase A values
as derived from the ratio between the activities toward the sulfated and
unsulfated substrates in the same specimen were comparable to those obtained by
the heat-inactivation method (except for subjects with thermolabile
hexosaminidase B) and may be helpful in genotype determination in borderline
cases.
PMID- 9556662
TI - Assignment of the gene for human sphingolipid activator protein-2 (SAP-2) to
chromosome 10.
AB - Sphingolipid activator protein-2 (SAP-2) has been found to stimulate the
enzymatic hydrolysis of glucosylceramide, galactosylceramide, and sphingomyelin.
When human skin fibroblast extracts were subjected to sodium dodecylsulfate
polyacrylamide gel electrophoresis followed by electroblotting and immunochemical
staining using monospecific antibodies against SAP-2, two or three major bands
with estimated mol. wts. of 9,000-10,000 were found. These antibodies did not
crossreact with purified SAP-1, another activating protein, or with extracts of
CHO-K1 cells. A series of 22 human/Chinese hamster ovary cell hybrids containing
different human chromosomes were examined by this method. All eight hybrid clones
containing human chromosome 10 were found to have crossreacting protein in this
region. Other chromosomes could be excluded by this method. From these results,
we conclude that the gene coding for human SAP-2 is located on chromosome 10.
PMID- 9556663
TI - The presence of at least two different H-blood-group-related beta-D-gal alpha-2-L
fucosyltransferases in human serum and the genetics of blood group H substances.
AB - Sera from H normal, secretors and nonsecretors (H/-, Se/- and H/-, se/se), as
well as from H-deficient secretors (h/h, Se/- or Bombay secretors) contain
enzyme(s) for the transfer of L-fucose in the alpha-configuration to the 2
position of suitable beta-D-galactopyranosyl units. Sera from H-deficient
nonsecretors (h/h, se/se; i.e., Bombay nonsecretors) are devoid of such beta-D
Gal alpha-2-L-fucosyltransferase(s). In order to study these enzymes, a
comparison was made of the kinetic properties of the enzymes present in the sera
of H-normal nonsecretors (H/-, se/se) with those of H-deficient secretors (h/h,
Se/se) with those of H-deficient secretors (h/h, Se/-). These studies revealed a
clear difference between the two sources of enzyme: (1) the apparent Km for GDP
fucose was four times lower with the H-normal nonsecretor serum (0.008 mM) than
with the H-deficient secretor serum (0.028 mM); (2) acceptors with a type 1 or
type 3 chain proved to be better than acceptors with a type 2 chain or than
phenyl-beta-D-galactopyranoside for the enzyme present in the serum of H
deficient secretor individuals. Indeed, the synthetic type 2 compound, betaDGal
(1-->4)-3-deoxy-beta-DGlcNAc-1-OCH3, which cannot act as an acceptor of beta
DGlcNAc alpha-3/4-L-fucosyltransferases, remained unchanged in the serum of an H
deficient secretor but was a good acceptor in the serum of an H-normal
nonsecretor, and (3) the alpha-2-L fucosyltransferease activity of the H
deficient secretor serum was more sensitive to heat inactivation than that of the
H-normal nonsecretor serum (t1/2 at 46 degrees C were 10 min and 75 min,
respectively). These results show that at least two distinct alpha-2-L
fucosyltransferases are present in human serum. It is concluded that the
enzymatic activity found in the H-deficient secretor serum (h/h, Se/-) could be
the product of the Se gene and the enzymatic activity found in the H-normal
nonsecretor serum (H/-, se/se) could be the product of the H gene. This
conclusion correlates well with the finding that H and Se genes are closely
linked and might have derived by gene duplication in the course of evolution.
PMID- 9556664
TI - HLA antigens, phytohemagglutinin stimulation, and corticosteroid response.
AB - Although it is clear that the major histocompatibility complex is associated with
lymphocyte glucocorticoid sensitivity in mice, there has been less evidence for a
similar relationship in man. We have typed 158 individuals for: (1) 13 A locus
and 16 B locus antigens, (2) degree of stimulation of their purified lymphocytes
by phytohemagglutinin A (PHA), and (3) degree of inhibition of the PHA
stimulation by prednisolone and prednisolone-21-hemisuccinate. In contrasts of
individuals with a particular antigen (homozygous or heterozygous) with all
remaining individuals, HLA-B7 was found to be associated with an enhancing effect
on the log stimulation by PHA while other antigens of these series did not have
significant associations. In similar contrasts, A10 was associated with a
decrease in sensitivity to glucocorticoid inhibition of PHA stimulation as
measured by the log I50 of the suppression of PHA stimulation. Other antigens of
these series were not found to have significant associations with the
glucocorticoid sensitivity of lymphocytes in this assay.
PMID- 9556665
TI - Evidence supporting a single origin of the beta(C)-globin gene in blacks.
AB - In order to characterize the origin(s) of the beta C-globin gene in blacks, 25
chromosomes bearing this gene were characterized at eight polymorphic restriction
sites within the beta-globin gene cluster. Twenty-two of the 25 chromosomes were
identical at all sites and possessed a haplotype seen only infrequently among
beta A-bearing chromosomes in black Americans. Two different haplotypes were
observed among the three exceptional chromosomes. These haplotypes were identical
to the most common beta C allele in the 3' end of the beta-globin gene cluster,
but differed in the 5' region. Partial haplotype analysis on an additional 14
beta C alleles demonstrated complete association with the typical beta C
associated polymorphisms in the 3' region of the cluster. These data can be most
easily explained by a single origin of the mutation followed by spread of the
mutation to other haplotypes through meiotic recombination 5' to the beta-globin
gene.
PMID- 9556666
TI - Extremely high frequencies of alpha-globin gene deletion in Madang and on Kar Kar
Island, Papua New Guinea.
AB - Extremely high frequencies of the deletion form of alpha(+)-thalassemia (
alpha/), as studied by the DNA mapping technique, were found in the population of
Madang, a coastal province in the north of Papua New Guinea (PNG) and in the
population of Kar Kar, an island situated near Madang. Ninety-seven percent of
the population tested from Madang and 89% of that from Kar Kar Island were either
alpha(+)-thalassemia heterozygotes or homozygotes. By contrast, no examples of
the deletion form were detected in the Eastern Highlands of PNG. The haplotype
frequencies of alpha(+)-thalassemia (-alpha/) in Madang and Kar Kar Island were
found to be 81.33% and 66.67%, respectively. A more detailed analysis of the gene
deletion revealed that in both populations 96% were of the 4.2 kilobase (kb) type
and 4% were of the 3.7-kb type. Thus, this group is the only example in which the
4.2-kb deletion is predominant over 3.7-kb defect. The presence in high
frequencies of alpha(+)-thalassemia in the coastal area of Madang and on the
neighboring island, where malaria has long been holoendemic or hyperendemic, and
its virtual absence from the nonmalarious highlands of PNG suggest the role of
malaria as the selective factor in maintaining alpha(+)-thalassemia. If this
selective pressure is still operating, and since alpha(+)-thalassemia has no
apparent homozygous disadvantage, the abnormal haplotype (-alpha/) will be in the
process of fixation in this population.
PMID- 9556667
TI - The human salivary protein complex (SPC): a large block of related genes.
AB - We have shown that genes for at least six human parotid proteins, parotid acidic
protein (Pa), proline-rich protein (Pr), double-banded protein (Db), glycoprotein
(Gl), parotid middle-band protein (Pm), and parotid-size variant (Ps) are linked.
We have designated this complex of genes as the salivary protein complex (SPC).
Several of the genes in this complex show marked associations that are most
likely the result of linkage disequilibrium. It seems likely that the SPC arose
through the process of gene duplication. This hypothesis is supported by the
results of our present study that demonstrate the biochemical similarity of the
protein products of several SPC genes. The amino acid compositions of the major
SPC proteins are compared, including several (Ps 1 and 2, and Db) that have not
been published. All of these proteins are quite similar and consist to a large
extent of the amino acids, proline, glycine, and gix (glutamine and/or glutamic
acid).
PMID- 9556668
TI - Type IX Ehlers-Danlos syndrome and Menkes syndrome: the decrease in lysyl oxidase
activity is associated with a corresponding deficiency in the enzyme protein.
AB - Type IX of the Ehlers-Danlos syndrome (E-D IX) and the Menkes syndrome are X
linked recessively inherited disorders characterized by abnormalities in copper
metabolism. These abnormalities are associated with a severe reduction in the
activity of lysyl oxidase, the extracellular copper enzyme that initiates
crosslinking of collagens and elastin. No increase in this deficient enzyme
activity was obtained when culture media from fibroblasts of patients with E-D IX
or the Menkes syndrome were incubated with copper under various conditions in
vitro. A distinct, although small, increase in lysyl oxidase activity was
obtained, however, when copper-supplemented media were used during culturing of
the fibroblasts, although even under these conditions, the enzyme activity in the
media from the affected cells remained markedly below that of the controls.
Immunoprecipitation, dot-blotting, and immunoperoxidase staining experiments with
antisera to human lysyl oxidase indicated that fibroblasts from patients with E-D
IX or the Menkes syndrome do not secrete into their medium, or contain inside the
cell, any significant amounts of a copper-deficient, catalytically inactive lysyl
oxidase protein. These findings appear to be consistent with the hypothesis that
synthesis of the lysyl oxidase protein itself is impaired. The possibility is not
excluded, however, that a copper-deficient enzyme protein may be synthesized in
normal amounts but become degraded very rapidly inside the cell. The failure to
obtain any large increase in the deficient lysyl oxidase activity upon various
forms of copper administration suggests that it may not be possible to obtain any
significant improvement in the connective tissue manifestations of these
disorders by copper therapy.
PMID- 9556669
TI - Basic fallacies in the formulation of the paternity index.
AB - Some basic fallacies in the computation of the paternity index have been pointed
out. The general finding that the true fathers' mean paternity index is greater
than that of nonfathers is a necessary consequence of an algebraic identity,
having nothing to do with paternity or nonpaternity. It has also been shown that
the paternity index is not a likelihood ratio as claimed. The fact that a
paternity index may frequently take values less than unity leads to absurd
conclusions regarding the probability of paternity. A formula relating prior and
posterior probabilities of paternity, based solely on genetic marker testing
results (exclusion or nonexclusion), is reiterated as a substitute for the
current paternity index.
PMID- 9556670
TI - Guidelines for reporting estimates of probability of paternity.
PMID- 9556671
TI - Chromosomal imprinting and the parent transmission specific variation in
expressivity of Huntington disease.
PMID- 9556672
TI - On citizenship in a great profession.
PMID- 9556673
TI - Drug interaction triggers weakness.
PMID- 9556674
TI - Understanding "sharp, shooting" pain.
PMID- 9556675
TI - Gabapentin for lancinating neuropathic pain.
PMID- 9556676
TI - The PSA test.
PMID- 9556677
TI - The estrogen dilemma.
PMID- 9556678
TI - Update on arrhythmias.
PMID- 9556679
TI - Update on arrhythmias.
PMID- 9556680
TI - Caring for adults with chronic cancer pain.
PMID- 9556681
TI - Seven common legal pitfalls in nursing.
PMID- 9556682
TI - Caring for Cody.
PMID- 9556683
TI - Emergency! Malignant hyperthermia.
PMID- 9556684
TI - Clinical snapshot: lung cancer.
PMID- 9556685
TI - Basic assessment series. Gastrointestinal system.
PMID- 9556686
TI - Women at high risk for breast cancer.
PMID- 9556687
TI - Ensuring quality in continuing education.
PMID- 9556688
TI - Thalidomide pros and cons.
PMID- 9556689
TI - Rest in peace, Rabbi Shapiro.
PMID- 9556690
TI - Asking patients about revising advance directives.
PMID- 9556691
TI - Continuing education in an ever-changing career.
PMID- 9556692
TI - [The path to "Doctor of Medicine"--how do doctoral candidates evaluate their
dissertation?].
AB - BACKGROUND AND OBJECTIVE: The value of medical dissertations has for some time
been controversial. Critical opinions have, on the one hand, been directed
against the effort required, its duration and the concept behind these
dissertations, while asserting, on the other hand, that such dissertations hinder
studying and lead to unnecessary lengthening of the medical curriculum.
PARTICIPANTS AND METHOD: In collaboration with the Medical School in Hanover a
questionnaire was sent to all the 189 dissertationists of one year, to be
returned anonymously. It contained 16 questions about the dissertation itself,
supervision. time spent on it, total duration of medical course and effect of the
dissertation on the individual's medical studies. The answers were evaluated
statistically by explorative data analysis. RESULTS: 181 questionnaires could be
evaluated (96%). Average age of those questioned was 30.5 years, median duration
of medical studies to-data was 13 semesters. For 80% it was the first attempted
dissertation. 22% had been working on an entirely experimental topic (laboratory
or animal experiments). The median time from starting to submitting the
dissertation was 4 years, the median time of the experimental phase one year. Two
thirds of students said that work on the dissertation had not prolonged their
studies. Supervision during various phases of the dissertation was overwhelmingly
judged to have been "very good" or "good". Altogether 90% of dissertationists
thought that it had been personally meaningful, and they would recommend it to
younger costudents. CONCLUSIONS: The results of this study show that a universal
criticism of medical dissertations does not stand up to detailed enquiry.
Successful dissertationists highly rated their value both to themselves and to
scientific medicine. The medical dissertation should therefore firmly remain as
part of medical studies and of research within them.
PMID- 9556693
TI - [Strongyloides stercoralis infection in a patient with AIDS and non-Hodgkin
lymphoma].
AB - HISTORY AND CLINICAL FINDINGS: The patient, now 50 years old, an immigrant miner
from the former Yugoslavia who was known to have AIDS, was in 1992 found to have
non-Hodgkin lymphoma of the oesophagus and given five cycles of multiple
chemotherapy (CHOP) with complete remission. Subsequently he complained of
retrosternal pain, dysphagia, dry cough and upper abdominal discomfort. On
admission he had slight fever of 39.1 degrees C, but physical examination was
unremarkable. LABORATORY TESTS: Blood count revealed an eosinophilia of 41%. IgE
concentration was raised to 432IU/ml. The CD4+ T-cell count was reduced to
10/microliter, that of CD8+ to 89/microliter. ADDITIONAL TESTS: Blood culture,
fecal and sputum samples and bronchoalveolar lavage demonstrated Mycobacterium
avium intracellulare. TREATMENT AND COURSE: Treatment of the disseminated
atypical mycobacterial infection was started with clarithromycin, rifabutin,
ciprofloxacin and ethambutol. There was no improvement of the upper abdominal
discomfort, but the fever subsided. Oesophagogastroscopy excluded recurrence of
the lymphoma. Biopsy and examination of the duodenal juice revealed worms and
larvae of Strongyloides stercoralis. Stool samples contained no mycobacteria, but
strongyloides larvae were demonstrated. Albendazole was given (2 x 400 mg daily
for 6 days, followed by a maintenance dose of 1 x 400 mg daily). Repeat endoscopy
and stool sample after a month no longer showed any parasites. CONCLUSION: Even
in Western Europe, persons coming from endemic areas who, as this patient, have
various risk factors that may facilitate the occurrence of strongyloidiasis. With
early diagnosis and treatment albendazole is an efficacious drug.
PMID- 9556694
TI - [Suppurative acrodermatitis continua of Hallopeau. A differential diagnosis of
paronychia].
AB - HISTORY AND CLINICAL FINDINGS: A 39-year-old man was admitted for treatment of
bilateral inflammatory-pustular skin changes in the area of the large toes and
soles of the feet. Antibiotic treatment and an Emmert wedge resection had already
been unsuccessfully performed at another hospital for what was diagnosed as
paronychia. On admission there were inflammatory, in part erosive, red areas with
yellow and partly confluent pustules on the distal phalanges of both great toes.
The entire right nail-bed and left medial nail-bed were missing. In the area of
the capillitium, both lower arms and the sulcus coronarius there were
erythematous squamous plaques. INVESTIGATIONS: Radiography of the great toes
demonstrated dystrophic demineralisation, in part with subchondral cystic changes
of the spongiosa. Histological examination of the nail-bed showed hyperplasia and
papillomatosis, definite hyperkeratosis with a prominent granular layer, as well
as ortho- and parahyperkeratosis. Laboratory tests for inflammatory disease were
unremarkable and there was no association with HLA B27. DIAGNOSIS, TREATMENT AND
COURSE: Suppurative acrodermatitis continua of Hallopeau was diagnosed and
immunosuppressive treatment with cyclosporin A given (initially 4.4 mg/kg.
stepwise reduction to 2.5 mg/kg within 6 weeks, this dosage then continued for a
further 10 weeks). Nearly complete healing was achieved, but the condition
recurred in a mild form 2 weeks after the end of treatment. CONCLUSION:
Suppurative acrodermatitis continua of Hallopeau should be included in the
differential diagnosis of inflammatory changes of the distal phalanges.
PMID- 9556695
TI - [Diagnosis of adrenal cortex diseases].
PMID- 9556696
TI - [Hereditary hemochromatosis].
PMID- 9556697
TI - [Gastroparesis--physiopathology, diagnosis and the latest therapy].
PMID- 9556699
TI - [International comparison of clinical research in Germany].
PMID- 9556698
TI - [Vaccination against early summer meningoencephalitis].
PMID- 9556700
TI - D-lactic acidosis. A review of clinical presentation, biochemical features, and
pathophysiologic mechanisms.
AB - This report describes a case of d-lactic acidosis observed by the authors and
then reviews all case reports of d-lactic acidosis in the literature in order to
define its clinical and biochemical features and pathogenetic mechanisms. The
report also reviews the literature on metabolism of d-lactic acid in humans. The
clinical presentation of d-lactic acidosis is characterized by episodes of
encephalopathy and metabolic acidosis. The diagnosis should be considered in a
patient who presents with metabolic acidosis and high serum anion gap, normal
lactate level, negative Acetest, short bowel syndrome or other forms of
malabsorption, and characteristic neurologic findings. Development of the
syndrome requires the following conditions 1) carbohydrate malabsorption with
increased delivery of nutrients to the colon, 2) colonic bacterial flora of a
type that produces d-lactic acid, 3) ingestion of large amounts of carbohydrate,
4) diminished colonic motility, allowing time for nutrients in the colon to
undergo bacterial fermentation, and 5) impaired d-lactate metabolism. In contrast
to the initial assumption that d-lactic acid is not metabolized by humans,
analysis of published data shows a substantial rate of metabolism of d-lactate by
normal humans. Estimates based on these data suggest that impaired metabolism of
d-lactate is almost a prerequisite for the development of the syndrome.
PMID- 9556701
TI - Nosocomial colonization, septicemia, and Hickman/Broviac catheter-related
infections in bone marrow transplant recipients. A 5-year prospective study.
AB - In this 5-year prospective study of 242 bone marrow transplantation (BMT)
recipients from whom daily blood cultures via the indwelling Broviac/Hickman
catheter were obtained, there was a median of 35 catheter-days during
hospitalization, mean of 40 days, and total of 9,667 catheter-days which were
divided almost equally between neutropenic (4,771) and non-neutropenic (4,896)
days. One hundred twenty (50%) patients had a total of 161 episodes of nosocomial
bacterial or candidal infections. Overall, 81 (33%) patients experienced 100
episodes of catheter-related infections and 90 (37%) patients experienced 112
episodes of septicemia, including 51 episodes of catheter-related septicemia.
There was an incidence of 11.59 septicemia episodes, including 5.28 catheter
related septicemia episodes, 2.48 colonization only (without subsequent
septicemia), and 2.59 exit site infections only, per 1,000 catheter-days. Over a
period of a total of 6,593 afebrile days, 34 (14%) patients developed 40 episodes
of colonization, a rate of 6.07 per 1,000 afebrile days, of which 16 developed
into septicemia. Twenty-five patients had 1 episode each of exit site infection
without bacteremia. There were 10 (4%) septicemia-related deaths, 4 of which were
catheter-related; 50% of all deaths involved Pseudomonas aeruginosa. The
mortality due to catheter-related septicemic episodes was not greater than that
of the non-catheter-related episodes. Neutropenia was found to be a significant
risk factor in our study: 76% of the septicemia episodes (85/112) and 65% of the
catheter-related infectious episodes (65/100) occurred during neutropenia. There
was a higher incidence of septicemic episodes during neutropenia than during non
neutropenic periods, 17.82 versus 5.51 per 1,000 days (p < 0.0001), and a higher
rate of catheter-related infections during the neutropenic period, 13.62 versus
7.15 during non-neutropenic days per 1,000 days (0.001). Fourteen of 16
colonization episodes developed into septicemia during neutropenia versus 2/24
during non-neutropenic periods, a rate of 5.47 versus 0.47 per 1,000 afebrile
days, respectively (p < 0.0001), and 9/10 deaths occurred during neutropenia.
PMID- 9556702
TI - A review of epidemiologic studies of nonnarcotic analgesics and chronic renal
disease.
AB - The relationship of long-term and heavy exposure of nonnarcotic analgesics to the
risk of chronic renal disease (CRD) has been the object of intensive clinical,
pharmacologic, toxicologic, and epidemiologic research for 4 decades. The
clinical evidence of an increased risk has been suggestive but inconclusive. The
experimental evidence in animal models has been inconsistent, and in any case it
cannot be generalized to humans. The epidemiologic evidence has been
unsatisfactory for the most part: most of the early studies had severe
methodologic limitations; moreover, they related mainly to phenacetin-containing
drugs and did not have useful information on other analgesics. Since 1980, 9
analytical epidemiologic studies have attempted to confirm that a causal
relationship exists between phenacetin or other analgesics and CRD. In the
aggregate, despite methodologic flaws, this work suggests that excessive use of
phenacetin-containing analgesics probably causes renal papillary necrosis and
interstitial nephritis. In contrast, there is no convincing epidemiologic
evidence that nonphenacetin-containing analgesics (including acetaminophen,
aspirin, and mixtures of these two compounds) or that nonsteroidal
antiinflammatory drugs cause CRD. Moreover, the nature of dose-response
relationships, the types of renal disease possibly caused by analgesics, and the
cofactors that might be related both to analgesic use and to the development of
CRD in humans are still uncertain, and the pathologic mechanisms of analgesic
induced CRD in humans remain unclear. It may take many years before all the
outstanding issues are settled. Until they are, as a matter of good clinical
judgment it would be prudent to consider all analgesics as potentially
nephrotoxic and, as much as possible, to avoid excessive, protracted use.
PMID- 9556703
TI - Bacterial arthritis due to beta-hemolytic streptococci of serogroups A, B, C, F,
and G. Analysis of 23 cases and a review of the literature.
AB - The clinical features, essential laboratory findings, management, and outcome of
all 23 cases of septic arthritis caused by different serogroups of beta-hemolytic
streptococcus (BHS) seen at the Stanford Medical Center, Stanford, CA, from July
1, 1985, through October 31, 1996, were reviewed and compared to those found in
the literature. Group A streptococci (GAS) accounted for 9 (40%) of our cases;
group B (GBS), for 7 (30%); and Group G (GGS), for 7 (30%). No cases were caused
by Group C (GCS) or F (GFS) during this period. During the same period, GAS
accounted for 66 (33%) of 200 cases of bacteremia due to BHS, GBS, for 98 (49%);
GCS, for 12 (6%); GFS, for 4 (2%); and GGS, for 20 (10%). A review of potential
risk factors revealed that, with the exception of GGS, male and female patients
were almost equally distributed among each of the serogroups. Patients aged 50
years and older comprised 56%-77% of each group. Associated conditions and risk
factors were present among most patients (19/23, 83%); autoimmune diseases and a
chronic skin wound or trauma were notably present among patients with GAS, while
diabetes mellitus and malignancy were more common among patients with GBS.
Infected prosthetic implants were present in 7 patients, including 4/7 patients
with GGS. All patients had positive cultures of synovial fluid, and 11/23 (49%)
had positive blood cultures (GAS, 5/9; GBS, 6/7; and GGS, 0/7). The clinical
presentation and hospital course of patients infected with the different
serogroups varied. Patients infected with GAS had the most severe disease and
those with GGS the least severe. Necrotizing fascitis, shock, DIC, and admission
to the intensive care unit were found only among patients infected with GAS.
Despite aggressive management with antimicrobial therapy and surgery, 4/23
patients died (3 patients with GAS; 1 with GBS). The isolates from our patients
were not available for study; investigations by others of the biology of BHS
suggest that the production of 1 or more of the streptococcal pyrogenic exotoxins
by isolates of GAS may account for the differences in the severity of disease
among our patients with septic arthritis caused by different serogroups of BHS.
Although septic arthritis due to BHS is uncommon, such patients provide a
valuable model to study features of the host-parasite interaction that may
contribute to the observed differences in severity of disease.
PMID- 9556704
TI - Prader-Willi and Angelman syndromes. Disorders of genomic imprinting.
AB - Prader-Willi and Angelman syndromes are 2 clinically distinct disorders
associated with multiple anomalies and mental retardation. They are only
discussed together because they share a similar and uncommon genetic basis: they
involve genes that are located in the same region in the genome and are
characterized by genetic imprinting. This normal process has contributed to these
2 complex and severe conditions through inactivation of 1 copy of the genes
relevant to each disorder: the maternally derived copy of genes for Prader-Willi
syndrome in proximal 15q are normally silent, and a paternally derived copy of 1
gene for Angelman syndrome in 15q is normally silent. For both disorders, when
the normally active copy of the gene or genes is missing, abnormality results.
Since the genes for these 2 disorders are located very close together, and since
the center involved in inactivating the genes involved in imprinting may be the
same, both these disorders usually result from the same chromosomal deletion;
which disorder results depends on the parent of origin of the chromosome 15 that
becomes deleted. Both Prader-Willi and Angelman syndrome can also occur as a
result of having both members of the chromosome 15 pair derived from 1 parent, a
condition known as uniparental disomy. Both can also result from a structural
abnormality of the imprinting center, known as an imprinting mutation. In
addition, Angelman syndrome can be caused by a mutation in the gene that causes
it; a comparable cause is not present in Prader-Willi syndrome since it results
from abnormality in more than 1 gene. Finally, despite the complexity of possible
causes, all but the single gene mutation of the Angelman syndrome gene can be
detected through methylation-sensitive DNA probes, since DNA methylation is the
process by which the genes for these 2 disorders are imprinted. This unusual
property of specific areas of the DNA holds promise for future treatment of these
and other disorders related to imprinting through reversal of the imprinting
process.
PMID- 9556705
TI - [Reconstructive procedures for restoring the hypopharynx after tumor excision].
PMID- 9556706
TI - [Effect of benzalkonium chloride on ciliary epithelium of the mucosa].
PMID- 9556707
TI - [Reflections on simultaneous radio-polychemotherapy in head-neck carcinomas].
PMID- 9556708
TI - [Comments on the contribution by U. Goede. Maxillary sinus fenestration via the
middle vs. lower nasal passage].
PMID- 9556709
TI - [Aphthae and aphthous lesions of the mouth mucosa].
AB - Recurrent aphthae (or aphthoses) are the most frequent inflammatory lesions of
the oral mucosa. Aphthae can clearly be defined, but may also be barely
discernible from aphthoid erosions and ulcers of heterogeneous origin. Although a
subject of molecular research, the etiopathogenesis of oral aphthoses is still
unknown. However, the clinical differentiation of a "benign" type of aphthosis
from a "pernicious" one, such as Behcet's disease (BD), is a diagnostic matter of
great significance. BD has been found clinically in increasing numbers in central
Europe and represents an (auto-)hyperimmune multisystem life-threatening
vasculitis. In this disorder possible damage can occur to many visceral organs
and/or the cerebrospinal system. The prognosis of BD may depend on the changing
involvement of very different organs, as well as the early recognition of the
disease per se. The most prominent feature is a multilesional aphthous stomatitis
that is almost never absent during acute episodes of BD. Hence, the occurrence of
this peculiar type of aphthosis strongly indicates an active BD. The plethora of
other aphthoid lesions can be challenging to the diagnostic competence of all
physicians and may confuse the correct recognition of the severity of the disease
present. This review particularly details the wide range of diagnostic,
therapeutic and prognostic aspects of the various oral aphthoses.
PMID- 9556711
TI - [Finite element modeling and simulation of the human tympanic membrane].
AB - Besides a knowledge of material properties geometric properties are needed to
investigate the mechanical behavior of the human eardrum. Although the geometry
of the eardrum has been examined methodically, its composition has been described
in the literature. The true surface geometry of a cadaver specimen of the human
eardrum was examined under a laser-scanning microscope. Forty points (85
parameters) depicted the surface of this cadaver specimen and formed the basis
for a finite shell model. Furthermore, the coupling with the malleus and its
suspension was simulated. Additional geometric and material parameters were
chosen from the available literature. Both static behavior and the influence of a
parameter variation to modal behavior of the finite element model were tested.
ANSYS 5.1 software was used for this study.
PMID- 9556710
TI - [Principles of energy sources of totally implantable hearing aids for inner ear
hearing loss].
AB - A fully implantable hearing aid consists of a sound receptor (microphone), an
electronic amplifier including active audio-signal processing, an
electromechanical transducer (actuator) for stimulating the ear by vibration, and
an energy source. The energy source may be either a primary cell or a
rechargeable (secondary) cell. As the energy requirements of an implantable
hearing aid are dependent on the operating principle of the actuator, the
operating principles of electromagnetic and piezoelectric transducers were
examined with respect to their relative power consumption. The analysis showed
that the energy requirements of an implantable hearing aid are significantly
increased when an electromagnetic transducer is used. The power consumption of a
piezoelectric transducer was found to be less than that of the electronic
components alone. The energy needed to run a fully implantable hearing aid under
these conditions would be 38 mWH per day. Primary cells cannot provide the energy
needed for a minimum operation time of 5 years (70 WH), and therefore
rechargeable cells must be used. A theoretical appraisal was carried out on
nickel-cadmium, nickel-metal hydride, and lithium-ion cells to determine their
suitability as well as to assess the risks associated with their use in an
implant. Safety measures were drawn up from the results. Ni-MH cells were found
to be the most suitable for use as an energy source for implantable hearing-aids
because they are more robust than Li ion cells and their storage capacity is
double that of Ni-Cd cells of similar size.
PMID- 9556712
TI - [Larynx preserving surgery in carcinomas of the posterior hypopharyngeal wall by
reconstruction with a free flap].
AB - In a series of 9 patients with advanced carcinomas of the posterior wall of the
hypopharynx (2 patients with T2 tumors and 7 patients with T4 disease), we tried
to preserve the larynx with surgical therapy. The concept of laryngeal
preservation consisted of lateral pharyngotomy with free flap reconstruction of
the defect created by the tumor resection. A recommendation for surgery was given
to each patient with a neoplasm in the posterior pharyngeal wall and tumor
extension > 6 cm in diameter. The maximum tumor diameters ranged between 6.5 cm
and 12.5 cm. Reconstruction was performed in 8 cases with radial forearm flaps
while a jejunal transplant was used in one case due to the extension of tumor.
During each surgical procedure an attempt was made to preserve the superior
laryngeal nerves and transplants were adapted exactly to the resection defects.
Seven patients achieved oral swallowing within three months of surgery, while one
patient needed four months to swallow orally. One patient had persistent
aspiration and still needs a percutaneous gastrostomy. Six patients were
decannulated successfully, so that laryngectomy was avoided during postoperative
follow-up. These results show that surgical therapy of advanced carcinoma of the
posterior wall of the hypopharynx is possible with preservation of the larynx.
Additionally, functional outcome after treatment of these patients with free flap
reconstruction is comparable to other treatment modalities, such as
radiochemotherapy.
PMID- 9556713
TI - [Hyperfractionated accelerated simultaneous radiochemotherapy in advanced
hypopharyngeal carcinomas. Survival rate, retained function quality of life in a
phase II study].
AB - Forty-one patients with locally advanced hypopharyngeal carcinomas were followed
for at least 3 years (median, 60 months) after simultaneous radiochemotherapy.
Conventionally fractionated radiotherapy was administered as 5 x 2 Gy/week to a
total dose of 30 Gy within 3 weeks. From the fourth week an accelerated
hyperfractionated schedule was used as 2 x 1.4 Gy/day five days weekly given
exclusively to the first order target volume of macroscopic tumor (adding up to a
total dose of 72 Gy in six weeks). The second and third order target volumes
received conventional fractionation only to 60 Gy and 50 Gy, respectively. The
moderate acceleration of the concomitant boost scheme in the second half was
counterbalanced during the first week by the introduction of a 5-fluorouracil
bolus of 350 mg/M2 with 200 mg/M2 folinic acid and a subsequent continuous
infusion using the same dose each 24 h for 5 days. Additionally, a Mitomycin-C
bolus of 10 mg/M2 was infused at the fifth day and on the first day of the sixth
week. Six weeks after treatment the patients were restaged. In cases with
residual carcinoma salvage surgery was performed (11 patients). Late effects of
therapy were analyzed according to the Lent-Soma index and life quality according
to the European Organisation for Research and Treatment of Cancer-Module. Late
effects of treatment were tolerable and were controlled locally. The 3-year
survival rate was 39%, with a local-regional recurrence-free control rate of 71%.
Fifty-two percent of all cases of death were caused by distant metastases,
secondary carcinomas or other diseases not related to tumor recurrence. The poor
prognosis of hypopharyngeal carcinomas despite acceptable local tumor control may
be due to specific biological factors present in affected patients.
PMID- 9556714
TI - [Effect of topical corticosteroids and topical antihistaminics on ciliary
epithelium of human nasal mucosa in vitro].
AB - A normal ciliary beat frequency of ciliated cells is necessary for the
mucociliary clearance of the nose and paranasal sinuses. An in vitro
investigation was performed to evaluate the influence of topical corticosteroids
and antihistamines on the ciliary beat frequency of human nasal mucosa. The nasal
sprays examined contained the corticosteroids budesonide or fluticasone
propionate and the topical antihistamines azelastine or levocabastine. All tests
were performed on cell cultures of human nasal mucosa during constant conditions.
Three of the four nasal sprays tested contained benzalkonium chloride as
preservative. An irreversible cessation of ciliary movement was observed in all
cells exposed to nasal sprays containing benzalkonium chloride in a 50 per cent
solution. The nasal spray containing budesonide was benzalkonium chloride-free
and caused minor but fully reversible decreases in ciliary beat frequency after
20 min. As benzalkonium chloride can cause complete standstill of ciliary beat
frequency in vitro in human nasal mucosa, we recommend that this preservative
should not be used anymore in topical nasal medications.
PMID- 9556715
TI - [Early trans-sphenoid decompression in indirect traumatic optic neuropathy].
AB - BACKGROUND: Indirect traumatic optic neuropathy represents a severe, potential
vision-threatening disease process that requires close interdisciplinary
cooperation for treatment. In general, any therapy has been discussed
controversially in the literature. Based upon experiences with spinal cord
trauma, high-dose steroid therapy is recommended initially to minimize secondary
consequences following orbital trauma. The usefulness of surgical decompression
of the optic nerve has been confirmed in several studies but is still not
recommended in principle. PATIENTS AND METHOD: In nine consecutive patients with
known indirect traumatic optic neuropathy and marked losses of vision,
transsphenoidal optic decompressions were carried out with simultaneous systemic
megadose steroid therapy. RESULTS: A postoperative increase in visual acuity from
1/35 to 10/20 occurred in five patients, while no improvement in visual acuity
could be achieved in the other four patients. DISCUSSION AND CONCLUSION: Previous
reports have indicated that some authors will not recommend surgical
decompressions if a loss of sight or no light perception occurs directly after an
accident. This situation was seen in seven of our patients. The visual acuity of
four patients remained no light perception in spite of surgical treatment. In
three other patients, an increase in visual acuity from amaurosis improved to
1/35, 4/20 and 8/20, respectively, following early decompression combined with
steroids. This experience together with the positive results of other studies
supports carrying out decompressions of the optic nerve, even when an amaurosis
occurs directly after trauma.
PMID- 9556716
TI - [Strategies in ambulatory treatment of tinnitus].
PMID- 9556717
TI - [Sudden deafness. Dissection of the internal carotid artery].
PMID- 9556718
TI - [Endoscopic resection of juvenile nasopharyngeal fibromas].
AB - Current surgical approaches to juvenile nasopharyngeal angiofibromas (JNA) are
exclusively external. This implies not only incisions that are mostly visible,
but also a potential loss of function as well as secondary lesions and high
perioperative risks. Radiotherapy aims to avoid surgery, but cannot exclude
complications and possible sequelae. These consequences are commonly accepted as
the "costs" for both therapies, although neither is negligible. For both surgery
and radiotherapy, recurrences or persistence rates have been described, so that
outcome may result in questions for the treatment used as well as the
complications or sequelae. We report our experiences with two cases of JNA
operated on under endoscopic control and discuss our indications for the
endoscopic approach to these tumors, preoperative conditions, surgical technique,
and the possible difficulties of surgery and outcome. Our results encourage us to
recommend use of endoscopic surgery as a valid alternative method to approach
resections of certain JNA.
PMID- 9556719
TI - [Metastatic spread of renal cell carcinoma in the area of the ethmoid and frontal
sinuses].
AB - Metastatic lesions represent 1-8% of all malignant tumors of the mouth and jaws,
with rare sites of metastasis originating from different primary tumors,
especially the lung and breast. The vast majority of these lesions (up to 90%)
have been observed in the mandible and maxilla (5-20%). Another rare type of
cancer that usually metastasizes to the lungs, lymph nodes, bones, liver or brain
may occasionally also show spread to the paranasal sinuses. In the present paper
we report our management of a 50-year-old male with renal cell carcinoma who
developed metastases to the frontal and ethmoid sinuses.
PMID- 9556720
TI - [Sensitization to chlorhexidine].
PMID- 9556722
TI - [Guidelines in ENT. How essential are they?].
PMID- 9556721
TI - [Wound infection caused by iron].
PMID- 9556723
TI - [Subjective and objective methods for evaluating sense of smell].
PMID- 9556724
TI - [Urgent care physician and emergency physician. Responsibilities of emergency
medicine].
PMID- 9556725
TI - [Quality assurance in emergency medicine].
PMID- 9556726
TI - [The acute coronary syndrome].
PMID- 9556727
TI - [Recommendations for preclinical emergency medicine. Acute therapy of tachycardic
cardiac arrhythmias].
PMID- 9556728
TI - [Acute dyspnea].
PMID- 9556729
TI - [Preclinical emergency medicine. Acute abdomen].
PMID- 9556730
TI - [Hypersensitivity reactions].
PMID- 9556731
TI - [Cardiopulmonary resuscitation. Presentation and commentary on current
guidelines].
PMID- 9556732
TI - [Polytrauma].
PMID- 9556733
TI - [Anuria].
PMID- 9556734
TI - [50-year-old patient with left-sided inguinal pain].
PMID- 9556735
TI - [51-year-old patient with reversible infarct-like ECG changes].
PMID- 9556736
TI - [Homocysteine and atherogenesis].
PMID- 9556737
TI - [When use thrombolysis?].
PMID- 9556738
TI - [Determination of coronary flow reserve].
PMID- 9556739
TI - [Procedure for intracardiac thrombosis].
PMID- 9556740
TI - [Acetylsalicylic acid and surgical risk].
PMID- 9556741
TI - [Indications for acetazolamide in neurology].
PMID- 9556742
TI - [Metformin in diabetes therapy].
PMID- 9556743
TI - Improved nuclear magnetic resonance microscopic visualization of joint cartilage
using liposome entrapped contrast agents.
AB - RATIONALE AND OBJECTIVES: After intraarticular application of gadolinium (Gd)
DTPA the visualization cartilage surface roughness is limited because of
diffusion into the cartilage. To improve the sensitivity of magnetic resonance
(MR) arthrography to diagnose cartilage surface abnormalities, the authors have
tested liposome-entrapped contrast agents. METHODS: Using paramagnetic contrast
agents (Gd-DTPA and manganese chloride) free and entrapped in liposomes,
respectively, high resolution MR imaging investigations were performed at 7.1
tesla on intact pig temporomandibular and rabbit knee joints. RESULTS: After
intraarticular injection of the liposome-entrapped contrast agents an excellent
contrast between cartilage surface and joint space was achieved. Diffusion of the
contrast agent into the cartilage layer was prevented and the visualization of
the cartilage surface was improved markedly. Small mechanically and enzymatically
induced cartilage lesions could be assessed reliably. CONCLUSIONS: Intraarticular
injection of liposome-entrapped contrast agents can improve the potential of MR
arthrography concerning the detection of early osteoarthritic cartilage changes.
PMID- 9556744
TI - Why do anatomic backgrounds reduce lesion detectability?
AB - RATIONALE AND OBJECTIVES: Developing metrics of medical image quality requires an
understanding of how anatomic backgrounds reduce human visual detection
performance. Visual psychophysics has shown that there are two distinct ways in
which a complex background can degrade performance: (1) the presence of a
deterministic high-contrast background, (2) variability in the background from
location to location. The authors investigated how these two sources of
performance degradation reduce human visual performance locating a lesion in
anatomic backgrounds. METHODS: Human performance localizing a disk-shaped lesion
in one of four locations (four alternative forced choice) was measured for three
background conditions. In the first condition the background was a uniform gray.
In the second condition (the repeated background condition) an anatomic
background was sampled on each trial and used as a background for the four
possible lesion locations. In the third condition (the different background
condition) four different anatomic backgrounds were sampled on each trial and
used for the four possible lesion locations. Test images consisted of computer
simulated lesions mathematically projected on digital x-ray coronary angiograms.
RESULTS: For five levels of lesion contrast, visual detection performance for two
observers decreased significantly from the uniform background condition to the
repeated background condition, and decreased even further for the different
background condition. CONCLUSIONS: Study results show that both the presence of a
deterministic high-contrast background and the background variations contribute
to performance degradation of human visual detection of signals in anatomic
backgrounds.
PMID- 9556745
TI - Assessment of myocardial perfusion by intermittent harmonic power Doppler using
SonoVue, a new ultrasound contrast agent.
AB - RATIONALE AND OBJECTIVES: The authors evaluated the potential of SonoVue, a new
echo contrast agent, for the detection of myocardial perfusion abnormalities
using intermittent harmonic power Doppler (IHPD) imaging and different pulse
repetition frequencies (PRFs). METHODS: Experiments were performed in vitro (in a
tissue-mimicking phantom) and in vivo (in minipigs) in harmonic power Doppler
using an ATL HDI 3000 with second harmonic software. SonoVue was injected
intravenously in an auricular vein in bolus (dose range 0.01-0.05 mL/kg) in
closed-chest animals or as an infusion (rate = 0.1 mL/kg/minute) in open-chest
minipigs with reversible left anterior descending coronary artery (LAD)
occlusion. The animals were imaged using IHPD gated on the electrocardiogram at
end-systole (pulsing interval at each cardiac cycle). The efficacy of SonoVue was
evaluated at six PRFs from 500 to 6000 Hz either qualitatively using a subjective
scoring system or quantitatively using a digital image analyzer. RESULTS: SonoVue
at a dose of 0.01 mL/kg produced a strong and homogeneous myocardial
opacification in IHPD. Higher doses prolonged the duration of the contrast
effect. Varying the PRF allowed the discrimination of flow velocities in vitro
and the detection of perfusion differences within the myocardium during transient
LAD occlusion and during immediate reperfusion in vivo. Low PRFs were
particularly useful to differentiate the ischemic bed from the healthy one during
LAD occlusion. The high flows caused by coronary hyperemia during immediate
reperfusion were detected clearly in the reperfused area at high PRFs.
CONCLUSIONS: SonoVue is a promising agent for myocardial opacification studies
using IHPD. The latter imaging modality is particularly well suited for blood
flow detection in tissues. Varying the PRF provides additional information on
flow velocity and improves the detection of perfusion differences in the
myocardium.
PMID- 9556746
TI - Biphasic spiral computed tomography for detection of hepatocellular carcinoma
before resection or orthotopic liver transplantation.
AB - RATIONALE AND OBJECTIVES: The authors correlate computed tomography (CT) findings
in biphasic spiral technique with histopathology in patients with hepatocellular
carcinoma (HCC) who had undergone liver resection (LR) or orthotopic liver
transplantation (OLT). METHODS: Preoperative biphasic spiral CT findings in 33
consecutive patients (23 men, 10 women, aged 43-74 years; LR group: n = 17; OLT
group; n = 16) with liver cirrhosis and HCC were reviewed retrospectively by
consensus of two radiologists and correlated with pathology from liver specimens.
RESULTS: Of the 16 patients in the OLT group with 1 to 5 confirmed HCC lesions
(total lesions: 29; mean lesion diameter: 2 cm; range: 0.6-5.0 cm), CT before OLT
depicted 22 lesions in 15 patients (sensitivity for lesions with a diameter of
0.5-1.0 cm, 20%; for lesions 1.1-2.0 cm, 82%; and for lesions 2.1-3.0 cm and >
3.0 cm, 86% and 100%, respectively). Among the 17 patients in the LR group (total
lesions: 21; mean lesion diameter: 5.4 cm; range: 1.0-11.0 cm), CT detected 18
lesions. Lesion-by-lesion sensitivity, as correlated with pathology, was
calculated at 76% and 86% in the OLT and LR groups, respectively (overall
sensitivity, 80%). The diameter of CT detected lesions, compared with liver
specimens, corresponded in 90% of lesions (maximum deviation, 15%).
Characteristic CT findings of HCC included unenhanced hypoattenuating focal liver
lesions (32 lesions), with hyperattenuation (38 lesions) in the arterial phase of
contrast material administration. CONCLUSIONS: Biphasic spiral CT for
preoperative HCC detection correlated with pathology in 80%, thus proving this
technique to represent a sensitive imaging modality for pretherapeutic evaluation
of HCC.
PMID- 9556747
TI - Magnetic resonance features of the enigmatic oligodendroglioma.
AB - RATIONALE AND OBJECTIVES: The authors characterize magnetic resonance (MR)
features of oligodendroglioma that permit diagnosis. These features may be used
to guide MR stereotactic biopsies. METHODS: Fifteen patients with mixed
oligodendroglioma and four with pure oligodendroglioma were studied on a 1.5
tesla MR unit with contrast and also by computed tomography (CT). All patients
had their diagnosis confirmed by light and electron microscopy, and by
immunohistochemical staining. RESULTS: The most characteristic finding was a
honeycomb tumor matrix (4 of 19) in oligodendroglioma. The most common finding
was an amorphous pattern (12 of 19) and the least common was a large cystic
pattern (3 of 19). Contrast enhancement most commonly was minimal and dot-like or
lacy in appearance (11 of 19), or absent (5 of 19). Calcification was present in
the majority (11 of 19). CONCLUSIONS: The honeycomb and stippled amorphous
patterns reflect the cytoarchitecture of oligodendroglioma and were the most
characteristic MR features. The amorphous pattern was the most commonly
encountered pattern. There was a wider range of imaging findings on MR compared
with CT; the flocculent calcification on CT was typical, but it was not always
detected on MR. Including these characteristic areas that appear along the path
of the stereotactic biopsy may ensure a correct diagnosis of oligodendroglioma
because it most often is seen with another tumor, usually of the astrocytic
family. Identifying the oligodendrogliomatous portion of the tumor will influence
the therapy. No differences could be found in the MR appearance or biologic
behavior of pure versus mixed oligodendrogliomas.
PMID- 9556748
TI - Bedside testing (SimpliRED) in the diagnosis of deep vein thrombosis. Evaluation
of 250 patients.
AB - RATIONALE AND OBJECTIVES: The authors evaluate the sensitivity and specificity of
a bedside test (SimpliRED) in the diagnosis of deep vein thrombosis compared with
contrast phlebography. METHODS: Two hundred fifty patients, referred for
phlebography, underwent bedside testing for detection of deep vein thrombosis.
Contrast phlebography was performed immediately afterward. SimpliRED provides a
clearly visible agglutination of the patient's red blood cells in the presence of
elevated levels of cross-linked fibrin derivative (D-dimer), which is specific
for fibrin breakdown. RESULTS: In 82 (32.8%) patients, deep vein thrombosis was
confirmed venographically. An abnormal D-Dimer test was found in 79 of the 82
patients with thrombosis (sensitivity: 96.3%). The three patients who were
diagnosed falsely as normal on agglutinin testing, had venograms which showed
only an isolated calf thrombosis in small muscle veins (< 2 cm in diameter) not
requiring treatment. One hundred of 168 patients without venographic thrombosis
were diagnosed correctly by SimpliRED (specificity: 59.5%). The positive
predictive value was 53.7%; the negative predictive value was 96.8%. CONCLUSIONS:
All thrombotic disorders in the leg that required further treatment were
identified correctly. SimpliRED is a very sensitive test with moderate
specificity in the diagnosis of deep vein thrombosis. Therefore, further invasive
testing is needed only in those patients in whom the D-dimer test is abnormal. A
false-positive result of the bedside test may be nonspecific or due to elevated
levels of fibrin split products, which can occur whenever the coagulation system
has been activated by any of several conditions.
PMID- 9556749
TI - Mechanisms of accumulation of small particles of iron oxide in experimentally
induced osteosarcomas of rats: a correlation of magnetic resonance imaging and
histology. Preliminary results.
AB - RATIONALE AND OBJECTIVES: This study was conducted to investigate the
distribution and kinetics of small particles of iron oxide in osteosarcoma-like
tumors. METHODS: Magnetic resonance (MR) imaging was performed in eight athymic
nude rats with an experimentally induced osteosarcoma of the right hind leg
immediately after intravenous injection of a superparamagnetic iron oxide
preparation. Five animals received 150 mumol iron oxide/ kg and three received 50
mumol iron oxide/kg. The iron oxide preparation consisted of polythylenglycol
coated particles with a core diameter of 6 to 8 nm. The MR images were correlated
with histologic slices of the tumors. RESULTS: The tumors accumulated iron oxide
rapidly. A marked decrease in signal intensity, preferentially along the
periphery of the tumor, was followed by a partial return of the signal intensity
within the first minute. The maximum signal decrement throughout the entire tumor
exceeded 41% and 21% with one dose each of 150 mumol iron/kg and 50 mumol
iron/kg, respectively. The rate of return depended on the injected dose and tumor
area, with the signal intensity approaching the initial value before the
injection of iron oxide after 45 minutes. Histologic correlation only showed
deposition of contrast medium in the proliferative areas of the tumors, mainly
confined to the tumor margin. In addition to a predominantly extracellular
deposition, intracellular storage could be detected. CONCLUSIONS: The findings
help to advance the understanding of the distribution and kinetics of intravenous
injected small particles of iron oxide in osteosarcoma-like tumors. A first-pass
accumulation of iron oxide could be documented by MR imaging in the periphery of
osteosarcomas. Due to sieving of iron oxide particles by liver, spleen, and bone
marrow, the signal intensity at 45 minutes after the injection of iron oxide
returned to 89% (150 mumol iron oxide/kg) and 95% (50 mumol iron oxide/kg) of the
preinjection intensity.
PMID- 9556750
TI - Magnetic resonance imaging in a spinal abscess model. Preliminary report.
AB - RATIONAL AND OBJECTIVES: Magnetic resonance (MR) scan technique and lesion
detectability were evaluated using a newly developed spinal abscess model in the
New Zealand White rabbit. METHODS: To create the lesion, an epidural needle was
inserted under fluoroscopic guidance in the lumbar region and advanced to
penetrate the ligamentum flavum. Next, polyethylene tubing was fed through the
needle into the epidural space. A mixed suspension of Staphylococcus aureus
(Cowan I) and blue polystyrene microspheres then was injected. Lesions were
evaluated by MR imaging in four animals at multiple time points (3, 6, and 9
days). Imaging was performed at 1.5 tesla using a surface coil. Precontrast T2
and T1-weighted scans were first obtained. The T1-weighted scans were acquired
both with and without fat saturation, and were repeated after intravenous
contrast administration. The contrast agent used was gadoteridol (gadolinium HP
DO3A or ProHance) at a dose of 0.3 mmol/kg. RESULTS: On prospective film review,
postcontrast scans proved superior for lesion detection. A spinal abscess could
be identified postcontrast in all cases, irrespective of the use of fat
saturation. The next best imaging technique for lesion detection was the T2
weighted scan, with 5 of 8 lesions noted thereon. Visualization of lesion margins
proved to be a primary factor in prospective lesion identification. Region of
interest image analysis demonstrated the postcontrast scans to be superior to all
precontrast scan techniques for conspicuity of the interface between the abscess
and the compressed spinal cord, with these results statistically significant. The
lesions were characterized histologically by infiltrates of heterophils into the
meninges and outer spinal cord with accompanying mild hemorrhage, fibrin
exudation, and bacterial colonies. The lesions in three animals were confirmed to
be in the epidural space, with the lesion in one animal in the subdural space.
CONCLUSIONS: The current animal model was developed to study spine infection and,
specifically, imaging characteristics and lesion detectability on MR. With the
increased use of epidural catheters for pain management and the large number of
acquired immunodeficiency syndrome cases, epidural infection is becoming an
increasingly important clinical problem. Imaging technique, in particular the use
of intravenous contrast, is critical for lesion detection and evaluation.
PMID- 9556751
TI - Entomological and rodent surveillance in plague-suspected areas during September
1994 and thereafter.
AB - Studies carried out in the states of Maharashtra, Gujarat, Uttar Pradesh and
Union Territory of Delhi after the bubonic plague outbreak during 1994 revealed
the presence of seven species of rodents, viz. Rattus rattus, R. norvegicus, Mus.
musculus, Tatera indica, Suncus murinus, Bandicoota bengalensis and B. indica.
The flea species encountered were Xenopsylla cheopis and X. astia. The X. cheopis
and X. astia index recorded in different areas of Beed district of Maharashtra;
Surat, Vadodra and Baruch districts in Gujarat and Varanasi district in Uttar
Pradesh and their implications have been discussed. Insecticide suspectibility
tests carried out against DDT, dieldrin, malathion and deltamethrin with X.
cheopis collected from Maharashtra, Delhi and Varanasi revealed that this vector
species is resistant to DDT and dieldrin but susceptible to malathion and
deltamethrin. The prevalence and distribution of rodents species, high cheopis
index and prevalence of Tatera indica just at the door steps of houses in village
Mamla of Beed district provides highly congenital conditions for the
intermingling of wild and domestic rodents and transfer of flea population from
wild to domestic rodents and vice-versa. These conditions were found to be highly
supportive for bubonic plague transmission in the district. The presence of
Yersinia pestis antibodies in Rattus rattus collected from Beed, Surat and
Varanasi areas are also indicative of bubonic plague in Beed and Varanasi and
pneumonic plague in Surat during 1994.
PMID- 9556752
TI - Molecular typing of Vibrio vulnificus isolates by random amplified polymorphic
DNA (RAPD) analysis.
AB - This study was undertaken to determine molecular types and genetic similarity
among V. vulnificus isolates by RAPD analysis. We compared these results with
serotypes of V. vulnificus. Ninety-seven V. vulnificus strains including 69
strains from Chonnam University Hospital (CUH; Kwangju, Korea), 13 from Wonkwang
University Hospital (WUH; Iksan, Korea), 13 from the Japanese National Institute
of Health (JNIH) and two reference strains (ATCC 33815 and ATCC 27562) were
analyzed. Four molecular types comprising all the strains were obtained by RAPD
analysis. Type I was the most common (60/95) and included 58 strains from CUH.
Type I showed a further subdivision into seven subtypes. Type II (23/95) composed
of 11 strains from CUH, nine from WUH, three from JNIH and two reference strains.
Six type III strains comprised four WUH strains and two JNIH strains. All six
strains of type IV were from JNIH. The range of genetic similarity values among
V. vulnificus isolates was 0.24 to 1.00. The serotypes of 95 strains were 04
(84.2%), 014 (3.2%), 01 (2.1%), 013 (2.1%), and R (2.1%). The most common 04
serotype strains were distributed among types I (60 strains), II (23 strains),
III and IV (six strains). Although the V. vulnificus isolates showed a wide range
of genetic similarity values, RAPD analysis could separate V. vulnificus strains
into four molecular types, and the isolates from the same hospitals tended to
belong to the same molecular type. There was no specific correlation between
molecular types and serotypes of V. vulnificus.
PMID- 9556753
TI - The latest seroepidemiological pattern of hepatitis A in Japan.
AB - Age-specific prevalence of anti-hepatitis A virus antibody (anti-HAV) was
surveyed with 2,708 sera collected in 1994 in various areas of Japan. By age
group analyses, we found strong association of anti-HAV antibody with higher age
group. The prevalence ratios of antibody in the groups of 30-34, 35-39, 40-44, 45
49, 50-54, 55-59, 60-64 and 65 years or older were 0, 4.2, 22.0, 44.8, 57.6,
76.4, 84.5 and 91.4%, respectively. Geometric mean titers of anti-HAV antibody in
the positive age groups were approximately 6,000 mIU/ml. The seropositives among
older population were ascribed to the infections more than 40 years ago and the
high anti-HAV titers have been maintained since that time. In Japan, people
younger than 40 years of age are extremely risky to HAV infection, since 99% have
no antibody. Those in forties are also risky since two-thirds of them are
seronegative. In Japan, an inactivated vaccine was licensed in 1994. Vaccination
may be recommended for such high-risk groups as travelers going to endemic areas,
patients who have received blood product medication and child-care staffs.
PMID- 9556754
TI - Rapid and highly sensitive enzyme immunoassay for quantitative determination of
tetrodotoxin.
AB - A monoclonal antibody against tetrodotoxin (TTX) was obtained from Balb/c mice
immunized with TTX-bovine serum albumin (BSA) conjugate. The monoclonal antibody
was highly specific for TTX and had no cross-reaction to tetrodonic acid, which
is a TTX derivative, or gonyautoxins, although a minor cross-reaction to anhydro
tetrodotoxin was observed. The monoclonal antibody neutralized the lethal
activity of TTX. By using the monoclonal antibody, a rapid and highly sensitive
competitive enzyme immunoassay (EIA) for quantitative analysis of TTX was
developed. By the competitive EIA system, TTX can be determined quantitatively in
about 30 min (90 min are required if the time for preparation of the solid-phase
antigen was included), and the working range for quantitative analysis of TTX was
2-100 ng/ml. In recovery tests and examinations of TTX samples, results of the
mouse bioassay and EIA analyses correlated well (r = 0.987). Moreover, it was
demonstrated that low concentrations of TTX, which could not be detected by the
mouse bioassay, could be determined quantitatively by the competitive EIA.
PMID- 9556755
TI - Screening of human corneas for herpes simplex virus by tissue culture and
polymerase chain reaction.
AB - Superficial eye infections by herpes simplex virus (HSV) constitute a major cause
of corneal disease, necessitating the need for corneal transplantation in many
patients. Eighty-three corneas from 46 post-mortem donors received from the David
Lucas Eye Bank in Manchester were analyzed by Vero cell culture and the
polymerase chain reaction (PCR) technique to detect HSV. There was no evidence of
a characteristic cytopathic effect in any of the cultures. A 350-bp PCR product
corresponding to the HSV thymidine kinase (TK) was detected by southern blotting
in only 2.4% (2/83) of samples. In contrast, approximately 70% of samples yielded
a 758-bp PCR product. Although this low prevalence of HSV in corneas may be
encouraging, it is high for the actual transplantation program if the viral DNAs
maintain their abilities to replicate.
PMID- 9556756
TI - Detection of HeLa cell contamination--presence of human papillomavirus 18 DNA as
HeLa marker in JTC-3, OG and OE cell lines.
AB - There are warnings of the contamination of cell cultures with HeLa cells in many
laboratories in the world. The cell lines JTC-3, OG and OE that were established
in Okayama in 1959, 1969 and 1971, respectively, were examined for human
papillomavirus (HPV) 18 DNA by Southern blot hybridization. The HPV 18 DNA
detected in these three cell lines showed hybridization patterns characteristic
of the HPV 18 DNA in the HeLa cell line established in 1951. Southern
hybridization patterns of HPV 18 DNA in the cellular DNA of the C4-II cervical
cancer cell line that was established in the USA in 1962 was different from that
of HeLa cells. These results suggest that the JTC-3, OG and OE cell lines have
been contaminated by HeLa cells.
PMID- 9556757
TI - Subcellular localization of hepatitis C virus structural proteins in the liver of
transgenic mice.
AB - Hepatitis C virus (HCV) core and envelope proteins are suggested to be
responsible for the pathogenesis of hepatic and extrahepatic manifestations in
chronic hepatitis C. Moreover, the core protein is implicated in the regulation
of the transcription of cellular genes including c-myc, RB and p53. Determining
the subcellular localization of the core and envelope proteins is therefore
necessary to elucidate their behaviors, particularly in vivo ones, regarding the
interaction with transcriptional regulatory proteins or gene elements. We defined
the subcellular localization of HCV envelope and core proteins which were
expressed in substantial levels in the liver of transgenic mice. Subcellular
fractionation by ultra-centrifugation revealed that the envelope proteins were
present principally in the microsomes of the liver, while a small amount of the
protein was detected also in the nuclei. Immunohistochemistry confirmed the
localization of envelope proteins in the nuclei. In contrast, the core protein
was detected principally in the cytoplasmic fraction, where it was closely
associated with lipids. A low level of the core protein was detected also in the
nuclei and microsomal fraction. These results suggest possible interaction of the
HCV structural proteins with some factors in hepatocytes thereby perturbing
intracellular circumstances.
PMID- 9556758
TI - Synthesis and characterization of polymer-(multi)-peptide conjugates for control
of specific cell aggregation.
AB - A new synthetic approach has been applied to obtain novel di-, tetra-, and
(multi)-peptide containing polymer conjugates in quantitative yields with a high
degree of conjugation. Bis-(N-hydroxysuccinimidyl) esters of PEG (Mw = 200, 600,
1400, 2000, and 3400) were synthesized and studied in a condensation reaction
with synthetic peptides: glycine-glycine-tyrosine-arginine (GGYR), a model
peptide, and glycine-arginine-glycine-aspartic acid-tyrosine (GRGDY), a sequence
known to promote cell adhesion and aggregation. Tetra-substituted derivatives of
PEG-based conjugates were synthesized by coupling L-aspartic acid and L-aspartyl
L-phenylalanine through a condensation procedure in organic media. Poly(acrylic
acid) and co-polymers (Mw = 2000 and 5000) were studied as a model of
multifunctional linear polymers in the reaction with L-tryptophan and GGYR.
Alternative polymer-(multi)-peptide conjugates were successfully synthesized
using Starburst dendrimer PAMAM (G = 3), 'short' and 'long'-chain PEG-based
active esters and GRGDY. The structure of the intermediate precursors and peptide
conjugates was confirmed by spectral (UV-Vis, FTIR, H-NMR) and chromatographic
(RP-HPLC and SEC) methods. By varying the properties of the interconnecting
polymer--such as hydrophobicity, molecular weight, and functionality--a set of
polymer-GRGDY conjugates was synthesized.
PMID- 9556759
TI - Hepatocyte culture utilizing porous polyvinyl formal resin maintains long-term
stable albumin secretion activity.
AB - To investigate the effects of culture conditions on the maintenance of metabolic
functions of cultured hepatocytes, long-term hepatocyte culture lasting 20 days
was performed under two different culture conditions, i.e. stationary cultures
utilizing porous polymer (polyvinyl formal (PVF) resin) as a substratum and
conventional monolayer dish cultures without PVF. Metabolic activities specific
to hepatocytes were evaluated in terms of ammonia metabolism, urea synthesis, and
albumin secretion. Concerning ammonia metabolic and urea synthetic activities, no
significant differences in maintenance of these activities were found between the
two culture conditions, and these activities rapidly decreased with the elapse of
the culture period, especially during the early stage of the experiments.
However, after day 10, these activities in the stationary cultures were
maintained at a slightly more favorable level than in the monolayer cultures. On
the other hand, compared with ammonia metabolism and urea synthesis, stable and
well-maintained albumin secretion of hepatocytes (60% of the activity in day 1)
was exhibited in the stationary culture experiments, despite that this particular
activity under the monolayer culture condition gradually reduced to a very low
level (5.7% of that on day 1) at the end of the culture. From the morphological
observations, hepatocytes immobilized in the PVF resin revealed individual
spherical shapes without forming multicellular aggregation, and it was suggested
that this characteristic structure contributed to good albumin secretion of
hepatocytes. In conclusion, the advantages of the hepatocyte culture technique
utilizing PVF resin over the conventional dish culture in maintaining some
representative metabolic function specific to hepatocytes were clarified.
PMID- 9556760
TI - Poly(vinyl alcohol) synthetic polymer foams as scaffolds for cell encapsulation.
AB - Poly(vinyl alcohol) (PVA) foams were used as scaffolds in hollow fiber membrane
based cell encapsulation devices. The surrounding permselective membrane serves
as an immunoisolation barrier while allowing metabolites and other small
molecules to be freely transported. The internal matrix defines the
microenvironment for the encapsulated cells. PC12 cell-containing devices
represent one possible strategy for safe transplantation of dopamine-secreting
cells for the treatment of dopamine-deficient diseases such as Parkinson's
disease. PC12 cells--a dopamine-secreting cell line--were encapsulated with PVA
foam as a matrix material in the lumen of these hollow fibers. In this work, we
demonstrate the presence of the PVA matrix increased the catecholamine secretion
efficiency of the cells as compared to devices containing a chitosan matrix.
Devices were implanted in vivo into rodent striatum and device output of
catecholamines was measured preimplant and post-explant. Evoked stores of
dopamine remained constant (preimplant vs explant) for devices encapsulated with
the foam matrix and increased with devices encapsulated with chitosan matrix.
Cell proliferation within devices was inhibited in the presence of the foam
matrix. Cell viability and distribution was significantly improved with the
inclusion of the foam matrix in both in vitro and in vivo studies. In comparison
to chitosan--a typical matrix material for PC12 cells--addition of a foam-type
matrix altered the encapsulated cell microenvironment and resulted in more
efficient secretion of catecholamines and improved distribution within the device
resulting in smaller necrotic regions and a lower rate of cell proliferation.
PMID- 9556761
TI - Cultivation of fibroblast cells on keratin-coated substrata.
AB - By means of a cell culture method, the attachment and growth of mouse L929
fibroblast cells were studied on matrices of the (-SDS)- and (+SDS)-keratins,
which were extracted from wool in the absence and presence of sodium dodecyl
sulfate, respectively. The (+SDS)-keratin showed some toxic effect on the cell
growth, but upon washing with a pH 7/phosphate buffer, the protein behaved
similarly to a substratum of the (-SDS)-keratin. The comparative culture assay on
the keratins, collagen (type I), and glass revealed that the keratins were more
adhesive to the cells and more supportive for cell proliferation than the
collagen and glass. The results were explained by an enhanced initial adsorption
of mediator proteins from fetal bovine serum onto the keratin substrata.
PMID- 9556762
TI - Synthesis and characterization of degradable polyurethane elastomers containing
and amino acid-based chain extender.
AB - Degradable polyurethane elastomers were synthesized using a diester chain
extender. The chain extender was synthesized by a diesterification reaction
between L-phenylalanine and 1,4-cyclohexane dimethanol to yield a diester,
diamine. Soft segment chemistry (polycaprolactone diol, PCL and polyethylene
oxide, PEO) and molecular weight were varied and the impact on polyurethane
physicochemical and degradation characteristics was evaluated. It was found that
the PEO containing polyurethanes absorbed large amounts of water while the PCL
containing ones did not, indicating a large difference in bulk hydrophilicity.
The rate of water vapor permeance (WVP) through the polyurethane films generally
followed the water absorption trends. However, soft segment crystallinity, noted
by DSC, for the PCL containing polyurethanes served to reduce WVP values with
increasing PCL molecular weight. Polyurethane surface characterization was
carried out by water contact angles and XPS. The PEO containing polyurethanes
exhibited low contact angles in comparison with the PCL ones. In addition, angle
resolved XPS demonstrated soft segment surface enrichment in all cases typical
for phase segregated materials. Significant variation in the physicochemical
properties of the experimental polyurethanes was observed indicating potential
use in a variety of biomaterials applications. An in vitro degradation study was
carried out by incubating the polymers in 0.1 M TBS at 37 degrees C, pH 8.0 for
up to 56 days. Degradation was followed by measuring mass loss, change in
molecular weight by GPC and surface alteration by scanning electron microscopy.
The polyurethane containing PEO was found to exhibit substantial mass and
molecular weight loss over 56 days resulting in a porous material of little
strength. In contrast, the PCL containing polyurethane displayed modest mass and
molecular weight loss after 56 days. This polyurethane retained its strength and
displayed little surface alteration after 56 days in buffer. It was hypothesized
that differences in polyurethane hydrophilicity as well as initial molecular
weight may have been responsible for the dramatic difference in degradation rate
observed here.
PMID- 9556763
TI - Mechanical properties of a self-assembling oligopeptide matrix.
AB - We have begun studies of a novel type of biomaterial derived from a recently
discovered class of ionic self-complementary oligopeptides. These short peptides
(typically 8, 16, 24, or 32 amino acid residues with internally-repeating
sequences) self-assemble in aqueous salt solution into three-dimensional matrices
capable of favorable interactions with cells, and offer promise for useful
bioengineering design based on rational changes in sequence. In this paper we
present preliminary results on mechanical properties, combining experimental and
theoretical approaches, of one particular example of these peptide materials,
EFK8. The static elastic modulus was measured using an apparatus designed to
allow sample fabrication and mechanical testing in the same system with the
sample in aqueous solution. The material microstructure was examined by SEM and
the measurements interpreted with the aid of a model for cellular solids. Values
for the elastic modulus increased from 1.59 +/- 0.06 to 14.7 +/- 1.0 kPa for
peptide concentrations increasing from 2.7 to 10 mg ml-1. SEM photographs showed
the microstructure to consist of a relatively homogeneous lattice with fiber
thickness of 10-30 nm independent of peptide concentration, but with fiber
density increasing with peptide concentration. This behavior is consistent with
scaling predictions from the cellular solids model and yields an estimate for the
individual fiber elastic modulus in the range of 1-20 MPa. We therefore have
provided some initial physical principles for guiding improvement of the
mechanical properties of these new materials.
PMID- 9556764
TI - Left hemispheric specialization for learned, skilled, and purposeful action.
AB - Three-dimensional motion analyses were performed on trajectories of repetitive
"slicing" gestures by 4 participants with left-hemisphere lesions and limb
apraxia, 6 participants with right-hemisphere lesions, and 7 neurologically
intact participants. Left hemispheric lesioned participants with apraxia, but not
right hemispheric lesioned participants showed impaired coupling of spatial and
temporal aspects of wrist trajectories and deficits in interjoint coordination.
Both groups of brain-lesioned participants differed from control participants in
the 3-D plane of the wrist motion. The deficits of some right hemispheric
lesioned participants in controlling the plane of wrist motion may be a
consequence of left hemispatial neglect with rightward deviations. In contrast,
the deficits of apraxic participants in controlling wrist trajectories and
coordinating joint motions seem to reflect a deficit in these participants for
the movement plan.
PMID- 9556765
TI - Font-specific priming following global amnesia and occipital lobe damage.
AB - Font-specificity in visual word-stem completion priming was examined in patients
with global amnesia and Patient M.S., who had a right-occipital lobectomy. Word
stems appeared in the same or different font as study words. Amnesic patients
showed normal font-specific priming (greater priming for words studied in the
same than different font as test), despite impaired word-stem cued recall.
Patient M.S. failed to exhibit font-specific priming, despite preserved
declarative memory. Therefore, perceptual specificity in visual priming depends
on visual processes mediated by the right-occipital lobe rather than medial
temporal and diencephalic regions involved in declarative memory.
PMID- 9556766
TI - Spatial attention deficits in humans: a comparison of superior parietal and
temporal-parietal junction lesions.
AB - Although clinical evidence of spatial attention deficits, such as neglect and
extinction, is typically associated with lesions of the right temporal-parietal
junction, recent evidence has suggested an important role for the superior
parietal lobe. Two groups of patients, selected for lesions at the temporal
parietal junction including the superior temporal gyrus (TPJ group), or for
lesions involving the parietal but not the superior temporal region (PAR group),
performed cued-target detection tasks in 2 experiments. An extinction-like
response time pattern was found for the TPJ but not the PAR group. In addition,
both groups were able to use expectancy information, in the form of cue
predictiveness, suggesting that separate mechanisms mediate exogenous and
endogenous processes during attention shifts.
PMID- 9556768
TI - Lexical semantic and associative priming in Alzheimer's disease.
AB - Semantic memory impairment was investigated in patients with probable Alzheimer's
disease (AD) using a threshold oral word reading task to assess priming of
different lexical relationships. Healthy elderly controls showed significant
priming for associatively related nouns (tempest-teapot) and also for nouns
semantically related either because both designate basic-level exemplars of a
common superordinate category (cousin-nephew) or because the target names the
superordinate category of the prime (daughter-relative). AD patients, in
contrast, showed preserved priming of lexical associates but impaired priming of
certain semantic relationships. They showed no priming between words designating
coordinate exemplars within a category, despite preserved priming of the
superordinate category label. Findings are consistent with the view that at least
part of the semantic deficit in AD is due to disruption of semantic knowledge
that affects relationships among basic-level concepts, more than the
relationships between these concepts and their corresponding superordinate
category of membership.
PMID- 9556767
TI - The emergence of spatial rotation deficits in dementia and normal aging.
AB - The mental rotation required in the Road Map Test of Direction Sense (the "Road
Map Test"; J. Money, 1976; J. Money, D. Alexander, & H. T. Walker, 1965) has been
thought to be impaired as a function of age, but not dementia. However, spatial
rotation in dementia has not been investigated in reference to spatial coordinate
systems. Patients with dementia (Alzheimer's and ischemic vascular dementias) and
elderly control participants were administered the Road Map Test. The authors
analyzed whether the geocentric or egocentric coordinate system determined
rotation of Road Map Test turns and predicted impairment in dementia patients.
They found equivalent impairment in both types of dementia, greater angulation
effect in the geocentric system in patients relative to normal controls, and no
egocentric effect. Results also suggest early emergence of spatial rotation
deficit in dementia. Spatial rotation is most often associated with working
memory, which predicts the correlations found.
PMID- 9556769
TI - Inhibitory processes in covert orienting in patients with Alzheimer's disease.
AB - Previous studies of covert orienting in Alzheimer's disease (AD) have
investigated exogenous and endogenous processes separately. We aimed to
investigate how the 2 modes of orienting interact to control attention in healthy
older participants and patients with AD. The covert orienting of visual attention
task (COVAT) with abrupt onset cues was used in all experiments. In Experiments 1
and 2, predictive information was added to cues to initiate an endogenous
orienting response. Results showed that healthy older participants were able to
use endogenous processes to inhibit exogenous orienting. In contrast, patients
with AD were unable to inhibit exogenous orienting to cues even when targets
rarely appeared there. Experiment 3 investigated inhibition of return (IOR) in
patients with AD. Both healthy older controls and patients with AD showed a
normal IOR, suggesting that exogenous orienting processes are relatively
unaffected by the normal aging process or in patients with AD. A model of covert
orienting in which exogenous and endogenous orienting processes interact to
control attentional behaviors is discussed.
PMID- 9556770
TI - Independent effects of Alzheimer's disease on neuropsychological functioning.
AB - A new analytical procedure, single common factor analysis, was carried out on the
data from a relatively large sample of normals (n = 101) and patients with
Alzheimer's disease (AD; n = 180) to examine the extent to which there were
independent effects of disease status on different neuropsychological variables.
This technique uses structural equation methods to determine what all of the
variables have in common, and then controls this common factor when examining the
relationship between diagnostic group and each individual test variable. To the
extent that AD represents the sum of independent breakdowns of different
information processing domains, then there should be sets of variables that have
weak or nonexistent links to the other variables. However, the results revealed
that a large proportion of the AD-related effects on test scores was shared and
was not independent of the AD-related effects on other variables.
PMID- 9556771
TI - Intact recognition of facial emotion in Parkinson's disease.
AB - Although the basal ganglia have been shown to be critical for the expression of
emotion in prosody and facial expressions, it is unclear whether they are also
critical for recognition of emotions. Selective pathology of parts of the basal
ganglia is a hallmark of individuals with Parkinson's disease, and such patients
have been examined in several studies of emotion. We examined 18 patients with
Parkinson's disease (11 men, 7 women) and 13 age-, education-, gender ratio-, and
IQ-matched normal controls on their ability to recognize emotions signaled by
facial expressions. Parkinson's patients performed entirely normally on a
quantitative task of recognizing emotional facial expressions. The findings do
not support the notion that the sectors of basal ganglia that are dysfunctional
in Parkinson's disease are essential for recognizing emotion in facial
expressions.
PMID- 9556772
TI - Letter and category fluency in patients with frontal lobe lesions.
AB - This study examines the hypothesis that patients with frontal lobe lesions are
impaired on tests of letter but not category fluency. This hypothesis was
proposed by Moscovitch (1994), based on a series of cognitive studies with young,
normal participants. A group of patients with lateral prefrontal lesions and age
matched controls were tested on 2 tests of verbal fluency, the FAS task and a
category fluency task that used semantic categories as cues (e.g., animals).
Patients with frontal lobe lesions generated fewer items than controls on both
letter and category fluency. This effect did not interact with the type of
fluency test, suggesting that the frontal lobes are more generally involved in
verbal fluency. Moreover, this pattern of findings, along with previous results
of impaired free recall and remote retrieval in this patient group, suggests that
patients with frontal lobe lesions do not efficiently organize and develop
retrieval strategies.
PMID- 9556773
TI - Word list learning and prediction of recall after frontal lobe lesions.
AB - The effect of frontal lobe lesions on the accuracy of prediction of recall in a
word list learning task was studied. Fifty-nine patients with a focal brain
lesion and 21 non-brain-damaged control patients memorized a word list by
selective reminding and predicted before each recall trial the number of words
they would be able to recall. The patients with left frontal lesions, who were
inferior to the patients with right frontal lesions and the control patients in
word list recall, overpredicted their recall more than the other brain-damaged
patients or the control patients, especially on the 1st trial. The patients with
right frontal lesions were less accurate in the prediction of recall than the
patients with right posterior lesions or the control patients.
PMID- 9556774
TI - Working and strategic memory deficits in schizophrenia.
AB - Working memory and its contribution to performance on strategic memory tests in
schizophrenia were studied. Patients (n = 18) and control participants (n = 15),
all men, received tests of immediate memory (forward digit span), working memory
(listening, computation, and backward digit span), and long-term strategic (free
recall, temporal order, and self-ordered pointing) and nonstrategic (recognition)
memory. Schizophrenia patients performed worse on all tests. Education, verbal
intelligence, and immediate memory capacity did not account for deficits in
working memory in schizophrenia patients. Reduced working memory capacity
accounted for group differences in strategic memory but not in recognition
memory. Working memory impairment may be central to the profile of impaired
cognitive performance in schizophrenia and is consistent with hypothesized
frontal lobe dysfunction associated with this disease. Additional medial-temporal
dysfunction may account for the recognition memory deficit.
PMID- 9556775
TI - Factor structure of the Wisconsin Card Sorting Test: dimensions of deficit in
schizophrenia.
AB - The aim of this study was to explore the factorial structure of the Wisconsin
Card Sorting Test (WCST) and to identify the dimensions of deficit in
schizophrenia. WCST scores in patients with schizophrenia and schizophrenia
related psychosis (n = 292), 1st degree relatives of schizophrenic patients (n =
91), and normal controls (n = 141) were subjected to a principal factor analysis
followed by orthogonal rotation. This led to 3 factors, perseveration, failure to
maintain set, and idiosyncratic sorting. The detected factor structure was found
to be invariant across the schizophrenic and control subsamples. Moreover, it
replicated previous findings from 2 smaller samples. Only perseverations and, to
a lesser degree, idiosyncratic sorting appeared to differentiate schizophrenic
patients from comparisons. Only perseveration had good sensitivity and
specificity, as well as the most robust significant correlations with estimates
of IQ, attention, and other measures of executive functioning. Thus,
perseveration appears to be the most diagnostically useful and characteristic
WCST feature of schizophrenia.
PMID- 9556776
TI - Neuropsychological outcome following anterior temporal lobectomy in patients with
and without the syndrome of mesial temporal lobe epilepsy.
AB - The nature, pattern, and degree of neuropsychological change following anterior
temporal lobectomy (ATL) were examined as a function of the presence or absence
of the syndrome of mesial temporal lobe epilepsy (MTLE). Fifty-four patients
exhibited the syndrome of MTLE, while 34 patients were without the syndrome (non
MTLE). The test-retest performance of a group of 40 epilepsy patients who did not
undergo surgery was used to derive regression-based estimates of test-retest
change. Overall, the MTLE group did not show significant cognitive decline
following ATL. In contrast, the left non-MTLE group showed significant declines
on verbal memory, confrontation naming, and verbal conceptual ability. Further,
verbal memory was the most substantial area of decline, and was independent of
seizure outcome. Clinical and theoretical implications of these findings are
discussed.
PMID- 9556777
TI - Overview of outcomes research and management and its role in oncology practice.
AB - Outcomes assessment describes a variety of activities, including classic clinical
trials with quality of life and cost end points, observational studies examining
the outcomes of treatment in the course of routine clinical care, and the process
of managing patterns of care in clinical practice. These activities share
important common features, including an emphasis on quality of life and economic
outcomes, an explicit consideration of the importance of patient characteristics
in determining outcomes, and a broad definition of what constitutes cancer care.
The primary uses of outcomes data are to evaluate treatments and to assess the
quality of care provided by physicians, health care institutions, and health
insurance plans. Outcomes management integrates these activities through the
implementation of guidelines, ideally based on empiric data on the relationship
between medical interventions and outcomes; and the measurement of performance
against a set of quality indicators derived from those guidelines. One of the
biggest challenges facing clinicians today is how to reconcile the need to do
what is best for patients with the need to practice cost-conscious medicine. High
quality outcomes data are at the heart of the solution. This presentation is a
brief overview of outcomes research and management and its role in oncology
practice.
PMID- 9556778
TI - Overview of economic analysis of Le Chevalier Vinorelbine Study.
AB - The costs and relative cost-effectiveness of different treatments for common
illnesses are an increasing concern. New treatments for advanced non-small-cell
lung cancer are having an impact. However, these treatments vary markedly in
their direct financial costs, toxicity, and quality-of-life profiles. Direct
comparisons between most combination regimens are not yet completed. Vinorelbine
(Navelbine) is the first new agent approved in the United States for the
treatment of metastatic non-small-cell lung cancer in more than a decade. We
previously reported results of a post-hoc economic analysis that compared the
anticipated cost-effectiveness of three regimens used to treat non-small-cell
lung cancer (vinorelbine alone versus vinorelbine plus cisplatin [Platinol]
versus vindesine plus cisplatin, the assumed standard treatment in Europe).
Results showed that vinorelbine plus cisplatin was the most effective regimen.
Using vinorelbine alone as a baseline, vinorelbine plus cisplatin added 56 days
of life at an additional cost of $2,700, resulting in a cost-effectiveness ratio
of $17,700 per year of life gained. Similarly, vindesine plus cisplatin added 19
days of life at a cost of $1,150, or $22,100 per year of life gained. Compared to
vindesine plus cisplatin, vinorelbine plus cisplatin added 37 days of life at a
cost of $1,570, or $15,500 per year of life gained. We conclude that the
incremental cost-effectiveness of the vinorelbine plus cisplatin regimen was less
than most commonly accepted medical interventions. If vinorelbine is preferred
because of its favorable toxicity profile, the additional effectiveness of
cisplatin added substantial efficacy at an acceptable cost.
PMID- 9556779
TI - Cost-effectiveness of vinorelbine alone or vinorelbine plus cisplatin for stage
IV NSCLC.
AB - Le Chevalier and colleagues have reported results of a randomized controlled
clinical trial comparing vinorelbine alone, versus vinorelbine combined with
cisplatin, versus standard treatment consisting of vindesine and cisplatin in the
treatment of patients with advanced non-small-cell lung cancer (NSCLC). Data on
survival in the three study arms and estimates of the resources used to treat
these patients were extracted from the publication and inserted into Statistics
Canada's POpulation HEalth Model (POHEM). This model includes data on diagnostic
methods, treatment, and outcomes appropriate for stage at presentation, health
care utilization, and direct care costs ($ Canadian) for best supportive care and
for several "standard" chemotherapy regimens used to treat advanced NSCLC. POHEM
was then used to model the cost of care per patient and the total burden of cost
on the Canadian health care system for each of the chemotherapy treatment
strategies and for best supportive care. Based on the published survival curves
for each of the vinorelbine regimens, it was possible to estimate the survival
gain relative to the standard chemotherapy regimens and to best supportive care,
and to estimate their cost-effectiveness as cost per life year gained. Based on
this analysis, the most cost-effective standard regimen relative to best
supportive care was vinblastine/cisplatin, as it increased average survival while
reducing costs by $2,846 per case. Vinorelbine/cisplatin increased survival to a
greater degree, but inpatient administration costs associated with the delivery
of cisplatin increased treatment costs by $2,983 per case and resulted in a cost
effectiveness ratio of $6,386 per life year gained. As high-dose cisplatin is not
routinely administered in the inpatient setting in Canadian institutions,
estimates were made of the cost of outpatient administration. The cost of
outpatient care was $55 less per case demonstrating that this is the most cost
effective way to administer the regimen. Relative to etoposide/cisplatin and
vinblastine/cisplatin, outpatient vinorelbine/cisplatin proved to be cost
effective. Various chemotherapy regimens used in the management of advanced NSCLC
all fall within the boundaries of cost-effectiveness generally accepted for
health care interventions in Canada. Therefore, cost and cost-effectiveness
should not be barriers to the utilization of vinorelbine/cisplatin in Canada.
PMID- 9556780
TI - Quality of life issues in the treatment of metastatic breast cancer.
AB - The treatment of metastatic breast cancer involves the sequential selection and
delivery of hormonal therapies and cytotoxic chemotherapies. The available
therapies for metastatic breast cancer are rarely curative, although high rates
of response and modest prolongation of survival may be achieved in association
with varying degrees of treatment-related toxicity. Therefore, the selection of
appropriate therapy requires a reasoned consideration of the likelihood of
benefit from therapy balanced with the impact of therapy on the patient's quality
of life. Several instruments have been developed to measure quality of life in
cancer patients, but none has been universally accepted, and they require time
and resources to administer. Few randomized clinical trials have incorporated
quality of life assessments. Thus, the clinician must balance antitumor activity,
performance status, and the usual toxicity measures, (e.g., nausea,
myelosuppression, asthenia) as surrogates for quality of life associated with
each specific therapy. Studies have confirmed the clinical impression that
antitumor activity of treatment generally correlates with quality of life
outcome. The hormonal therapies have the quality of life advantages of limited
and non-threatening acute toxicity, rare chronic toxicity, need for infrequent
visits to health care providers, oral administration, and, in appropriately
selected patients, response and duration of response rates equivalent to those of
the cytotoxic agents. A number of cytotoxic agents have activity in the treatment
of metastatic breast cancer. Although the active single agents differ
substantially in their toxicity profiles, the dose-limiting toxicity is usually
myelosuppression. Recently, several agents with substantial activity against
breast cancer have become available, including the taxanes (paclitaxel and
docetaxel), vinorelbine, and gemcitabine. Oral formulations of vinorelbine are
being studied that may provide the additional advantages of not requiring
intravenous access, requiring fewer visits to the health care professional, and
providing patients with a greater sense of control of their treatment.
PMID- 9556781
TI - Initial control of chemotherapy-induced nausea and vomiting in patient quality of
life.
AB - The side effects commonly experienced by patients receiving chemotherapy for the
treatment of cancer can challenge many aspects of daily life. Nausea and
vomiting, the most common side effects reported by patients, affect the ability
to continue with usual life activities and, thus have a pronounced impact on
quality of life. This paper reviews studies of the impact of nausea and emesis on
quality of life, and highlights the importance of prevention of these side
effects by presenting new data on how persistent uncontrolled nausea and vomiting
can be. The Morrow Assessment of Nausea and Emesis (MANE) was used to collect
information on symptoms experienced by consecutive patients starting chemotherapy
between September 1987 and December 1995 at any of 18 geographically diverse
member sites of the University of Rochester Cancer Center Community Clinical
Oncology Program. Data from 1,413 patients were collected after each of four
successive chemotherapy treatments. Reported incidences of posttreatment nausea
and posttreatment vomiting after the first treatment were 59.4% and 28.6%,
respectively. Occurrence of nausea/vomiting at the first treatment was a strong
predictor of nausea/vomiting at later treatments. Of the 839 patients reporting
initial nausea, 763 (90.9%) reported nausea at at least one subsequent treatment,
and approximately 59% reported nausea after all three subsequent treatments.
Fewer than half (45.6%) of the patients who had no nausea at the first treatment
developed it later. The majority (72.0%) of patients reporting vomiting at the
first treatment also reported subsequent vomiting, 30.7% of whom experienced
emesis at all remaining treatments. Conversely, 76.2% of patients who were emesis
free at the first treatment remained so for all later treatments. These findings
show a continuing need for further progress in controlling nausea and vomiting,
and demonstrate the importance of aggressive nausea/vomiting control at the first
treatment. In addition, more emphasis on controlling chemotherapy-induced nausea
after its initial occurrence is necessary.
PMID- 9556782
TI - Cost-effective use of antiemetics.
AB - Direct comparison of intravenous and oral 5-HT3 antagonists has shown equivalent
efficacy if appropriate doses are given, thus allowing widespread use of the more
convenient and economical oral route. Effective antiemesis generates additional
cost savings by decreasing the resources necessary for salvage antiemetic
preparation and administration, additional physician and nursing evaluation,
clean-up and maintenance of the patient area, and possible additional
hospitalization necessitated by uncontrolled emesis. If ondansetron and
metoclopramide are compared strictly on an acquisition cost basis, ondansetron is
4 to 15 times more expensive. However, if the additional savings attributable to
better antiemetic control are taken into account, ondansetron is only 2 to 3
times more expensive and quality of life is markedly improved. In cost-utility
analysis such improvement in quality of life is taken into account through the
use of a utility score. Utility scores for antiemetic protection, however, have
not been well defined. We recently performed a pilot study asking patients
receiving chemotherapy to rate globally their quality of life (utility score)
over the preceding chemotherapy cycle, assuming that a small amount of nausea and
vomiting either had or had not occurred. An incremental utility score of 0.52
based solely on the presence or absence of nausea and vomiting was identified.
Further careful investigations to identify the incremental utility resulting from
use of various modes of oncologic supportive care are required.
PMID- 9556783
TI - Evolving role of oral chemotherapy for the treatment of patients with neoplasms.
AB - The past 20 years has seen an increasing trend toward the use of oral
chemotherapy for the treatment of patients with a variety of malignancies. The
advantages of oral chemotherapy include lower treatment cost, compared with that
of intravenous (i.v.) administration, and more convenient treatment for patients.
Several oral drugs are now used routinely for cancer treatment, and others are
under investigation. Hormonal agents, such as tamoxifen, flutamide, and megestrol
acetate, and antimetabolites, such as hydroxyurea, which are available only in
oral formulation, have proven both safe and efficacious. Several other oral
drugs, including etoposide and cyclophosphamide, have been shown to be useful and
often as effective as their i.v. formulations, and more data on the
bioavailability of these agents have become available. In addition, several new
and promising oral agents (platinum compounds, fluorinated pyrimidines,
topoisomerase I inhibitors, and others) are likely to be introduced into clinical
practice in the near future. It is possible that eventually, oral combination
chemotherapy will be an accepted and standard approach for the treatment of
patients with many types of cancer.
PMID- 9556784
TI - Improving 5-FU with a novel dihydropyrimidine dehydrogenase inactivator.
AB - GW776C85 is a new drug that has been shown to be an effective inactivator of
dihydropyrimidine dehydrogenase (DPD). Preclinical studies demonstrated that
administration of GW776C85 with 5-fluorouracil (5-FU) resulted in several
desirable pharmacologic effects. Initial clinical data on 5-FU combined with
GW776C85 suggest potentially increased antitumor activity in at least some
malignancies with tolerable toxicity, as well as several distinct economic and
quality-of-life advantages including the following: (1) The possibility of
administering 5-FU as an oral drug due to excellent bioavailability of 5-FU
following inactivation of DPD; (2) a cost-effective alternative to continuous or
protracted infusion of 5-FU without the need for hospitalization or surgical
placement of an intravenous access and availability of an ambulatory pump; and
(3) potential for less interpatient variation of 5-FU toxicity (e.g., in host
tissues, such as bone marrow and gastrointestinal mucosa cells) due to
inactivation of DPD in essentially all patients treated, permitting better 5-FU
dosing guidelines. Finally, because tumors may theoretically become resistant to
5-FU by increased levels of DPD, the use of GW776C85 to inactivate DPD may
provide a potential means by which tumor resistance can be reversed.
PMID- 9556785
TI - Phase II and III clinical trials of toremifene for metastatic breast cancer.
AB - Toremifene (Fareston) received FDA approval in 1997 for the first-line treatment
of postmenopausal women with estrogen receptor (ER)-positive or -unknown
metastatic breast cancer. Phase II and III trials have demonstrated that first
line therapy with toremifene, 60 mg/d, is as effective and as well tolerated as
tamoxifen (Nolvadex), 20 or 40 mg/d, in such patients. To date, phase III trials
have failed to show a statistically significant advantage of higher toremifene
doses over standard doses of tamoxifen in these women. Studies appeared to
indicate minimal efficacy of high toremifene doses in women with ER-negative
tumors, but the number of patients studied was small. Although results of some
trials of high-dose (240 mg/d) toremifene in tamoxifen-"refractory" patients were
negative, other trials that included prolonged (> or = 6 months) stable disease
as an indication of clinical benefit yielded positive results.
PMID- 9556786
TI - Antiestrogen therapy: uncertainties and risk assessment.
AB - Tamoxifen is by far the most clinically tested antiestrogenic drug currently used
as adjuvant therapy for breast cancer and it continues to provide considerable
benefit in this setting. The balance from clinical trials indicates a strong
association between the use of tamoxifen and an increase in uterine tumors (three
to sixfold). In rats, tamoxifen is a mutagenic, genotoxic hepatocarcinogen. These
actions are not related to its estrogen antagonist activity but have been shown
to be as a result of metabolic activation of this drug by cytochrome P450
enzymes, resulting in irreversible binding to cellular DNA. The mechanism of
endometrial cancer associated with tamoxifen treatment is unclear, although there
are two plausible hypotheses: (1), tamoxifen causes damage and mutation to DNA in
uterine cells or (2), it promotes the development of endometrial tumors through
its estrogen agonist activity. The evidence for a genotoxic effect of tamoxifen
in the uterus is highly contentious and, on balance, we have concluded that it is
more likely that the estrogenic effects of tamoxifen promote tumor development.
PMID- 9556787
TI - Adjuvant trials of toremifene vs tamoxifen: the European experience.
AB - When results from the phase II trials of toremifene (Fareston) and tamoxifen
(Nolvadex) in metastatic breast cancer were published, the Finnish Breast Cancer
Group began to plan the first trial of toremifene in an adjuvant setting. This
multicenter, randomized trial is comparing toremifene (40 mg/d) to tamoxifen (20
mg/d) in postmenopausal lymph node-positive breast cancer patients. Treatment
duration is 3 years. About 1,150 of a planned 1,460 patients have been enrolled
to date. The International Breast Cancer Study Group is also conducting two
adjuvant trials evaluating 5 years of toremifene (60 mg/d) vs tamoxifen (20
mg/d). More than 1,000 patients have been enrolled in these studies to date. The
efficacy of toremifene is being explored in all of these trials. In the Finnish
trial, additional protocols are evaluating treatment side effects, including the
formation of DNA adducts in the endometrium and leukocytes, certain ocular
problems, thromboembolic events, and subjective side effects. The effects of
toremifene on lipid levels and bone density are also being studied. An interim
safety analysis, performed in the Finnish study after 500 patients were enrolled
(mean follow-up, 18 months), showed no significant differences between toremifene
and tamoxifen in terms of efficacy or side effects. Toremifene seems to be well
tolerated and may have additional positive effects. Ongoing trials will soon
reveal how beneficial toremifene is in the adjuvant setting and whether it is
devoid of the adverse effects observed with tamoxifen.
PMID- 9556788
TI - Status of antiestrogen breast cancer prevention trials.
AB - Various ongoing double-blind clinical trials are evaluating the use of tamoxifen
(Nolvadex) as chemoprevention for breast cancer. A total of over 24,000 healthy
women have been randomized to these trials, and it should be possible, by the
year 2000, to detect any preventive effect of tamoxifen in healthy women.
Furthermore, with the large numbers of women involved, it should be possible to
evaluate prevention in subgroups of participants according to risk of the
disease, particularly those women carrying high-risk genes, such as BRCA1 and
BRCA2. Adverse effects of tamoxifen have been identified, including a transient
bone loss in premenopausal women and uterine effects, including polyps, cysts,
and endometrial cancer, in postmenopausal women. Although the potential benefit
of tamoxifen in preventing breast cancer in healthy women is likely to outweight
any potential long-term risks, the use of other tamoxifen-like drugs, such as
raloxifene (Evista) and toremifene (Fareston) is now being investigated.
PMID- 9556789
TI - Emerging role of aromatase inhibitors in the treatment of breast cancer.
AB - The new generation of potent steroidal and nonsteroidal inhibitors of the enzyme
aromatase act by decreasing estrogen production throughout the body in
postmenopausal women. The most potent of these agents may also inhibit estrogen
synthesis within metastatic breast cancer tissue. The newly developed, orally
administered, nonsteroidal competitive inhibitors, such as anastrozole
(Arimidex), letrozole (Femara), and vorozole (Rizivor), are a thousand times more
potent inhibitors of aromatase than is aminoglutethimide. Furthermore, these
agents are highly selective. In several large randomized trials, the new
inhibitors produced similar response rates as megestrol acetate (160 mg/d) in
postmenopausal women with hormone-dependent breast cancer, but showed a trend
toward improved response duration and survival. They also produced less weight
gain and fewer cardiovascular and thromboembolic side effects. In addition,
letrozole proved superior to aminoglutethimide in another randomized trial. Both
anastrozole (1.0 mg/d) and letrozole (2.5 mg/d) have now been approved as second
line treatment for hormone-dependent breast cancer in postmenopausal women in
whom disease has progressed following tamoxifen treatment. Either drug should
replace the routine use of megestrol acetate in this setting. Ongoing clinical
studies are comparing anastrozole and letrozole to antiestrogens as first-line
endocrine therapy for metastatic breast cancer. Other trials will study the
possible roles of these compounds as adjuvant therapy and chemoprevention for
breast cancer.
PMID- 9556791
TI - Pivotal trials of letrozole: a new aromatase inhibitor.
AB - Letrozole (Femara) is a nonsteroidal aromatase inhibitor that is approximately
10,000 times as potent as aminoglutethimide in vivo. Two pivotal multinational
phase III trials have compared letrozole (0.5 and 2.5 mg/d) against megestrol
acetate and aminoglutethimide, respectively, in patients with locally advanced or
metastatic breast cancer. The letrozole vs megestrol acetate trial showed the
superiority of letrozole (2.5 mg/d) over megestrol acetate with respect to
response rate, response duration, duration of overall clinical benefit (complete
response plus partial response plus stable disease > or = 6 months), time to
progression, and time to treatment failure. The letrozole-treated patients also
showed a nonsignificant trend toward better survival. In the letrozole vs
aminoglutethimide trial, letrozole (2.5 mg/d) was significantly superior in terms
of duration of overall clinical benefit and survival. There were also strong
trends favoring letrozole with regard to objective response rate and duration of
response. Unexpectedly, both trials demonstrated a dose-response effect for 2.5
mg of letrozole over 0.5 mg in terms of response and overall survival. This
finding raises the possibility that intratumoral aromatase suppression may be
more relevant in breast cancer therapy than are plasma estrogen levels.
PMID- 9556790
TI - Preclinical studies using the intratumoral aromatase model for postmenopausal
breast cancer.
AB - To determine the most effective strategies for the treatment of postmenopausal
hormone dependent breast cancer, we recently developed a model system in nude
mice. In this model, estrogen receptor-positive human breast cancer cells (MCF-7)
stably transfected with the aromatase gene are inoculated into ovariectomized,
immunosuppressed (nude) mice. These cells synthesize sufficient estrogen from
androgen substrate to stimulate their proliferation and the development of
tumors. Moreover, estrogen secreted by the tumor cells maintains uterine weight
comparable to that of the intact mouse. In the present study, we employed this
model to investigate the effects of the aromatase inhibitor, letrozole (CGS 20267
[Femara]) on mammary tumor growth and on the uterus. We also used this model to
predict the effects of combining two aromatase inhibitors, letrozole and
anastrozole (Arimidex), with the antiestrogen tamoxifen (Nolvadex). Letrozole was
found to be a highly potent inhibitor of tumor proliferation and more effective
than tamoxifen. No stimulation of uterine growth was observed with the aromatase
inhibitors. However, the combination of letrozole or anastrozole and tamoxifen
was no more effective than either aromatase inhibitor alone. The agonistic effect
of tamoxifen on the uterus was observed when it was given alone and when combined
with the aromatase inhibitors. Furthermore, letrozole had the most potent
antitumor activity when compared to other aromatase inhibitors and antiestrogens.
No additional benefit was observed by combining these agents with tamoxifen over
treatment with aromatase inhibitors alone.
PMID- 9556793
TI - [Molecular genetics of epithelial ovarian neoplasms: correlations with phenotype
and biological behavior].
AB - The phenotypic variability of epithelial ovarian neoplasms correlates with a
diversity of changes on the molecular level. Invasive serous and undifferentiated
ovarian carcinomas are characterized by p53 mutations, extensive loss of genetic
material of chromosome 17 and complex changes on many other chromosomes. These
alterations are seen only in a minority of mucinous and endometrioid carcinomas,
mainly in advanced stages. Overexpression of bcl-2 is seen most frequently in
endometrioid carcinomas (ca. 90% of cases), which in addition show microsatellite
instability in around a third of cases, as has been described in endometrioid
endometrial carcinomas. KRAS mutations are characteristic for mucinous LMP tumors
(borderline tumors) and mucinous carcinomas (40-50% of cases). Furthermore, KRAS
mutations have been described in around a third of serous LMP tumors, which in
addition show microsatellite instability in up to 40% of cases. Serous LMP tumors
never harbour complex chromosomal aberrations.
PMID- 9556792
TI - [Value of basement membrane imaging in diagnosis of invasive carcinomas].
AB - The destruction of the epithelial basement membrane is widely regarded as a clear
criterion for invasive malignant tumor growth. Since, however, defects in the
basement membrane may also occur in non-invasive conditions, such as inflammatory
and proliferative lesions, and since it has been shown that particularly in
highly differentiated squamous cell carcinomas a continuous basement membrane is
mimicked by the presence of isolated components, this criterion seems to be of
minor value for the diagnosis of malignancy. Despite these drawbacks, the
immunolocalization of basement membrane material may still be of differential
diagnostic significance in certain situations. This holds particularly true for
invasive (ductal) breast carcinomas, which usually completely lack a basement
membrane. Accordingly, sclerosing adenosis can be distinguished from invasive
carcinoma, as a distinction can be made between neoplastic (malignant) tubular
formations and reactive lesions.
PMID- 9556794
TI - [Oncocytic metaplasia/neoplasia--morphology, biochemistry, molecular genetics].
AB - The article gives a review on oncocytic metaplasia and oncocytic tumors.
Biochemical, cytochemical and molecular genetic findings are discussed. It has
been established, that defects of the respiratory chain occur predominantly in
oncocytic foci of the parathyroids and the liver. The underlying molecular
genetic mechanisms are still unclear, however. In particular, one has to assume
that oncocytic metaplasia differs pathogenetically from oncocytic neoplasia.
Furthermore, organ-dependent prognostic differences of oncocytic tumors exist.
Oncocytic carcinomas are predominantly seen in the thyroid and are scarce in
other organs. The molecular genetic basis of this phenomenon is, however, still
unknown.
PMID- 9556795
TI - [Heterogeneity of seminal vesicle amyloid. Immunohistochemical detection of
lactoferrin and amyloid of the prealbumin-transthyretin type].
AB - Localized depositions of amyloid in the seminal vesicles may occur in elderly
men. Earlier immunohistochemical studies have failed to identify immunoreactivity
of known amyloid material. In this autopsy study, all seminal vesicles of males
older than 50 years were histologically examined to determine incidence and
phenotype of seminal vesicle amyloidosis. Seven out of 50 patients (14%) showed
depositions of amyloid in the seminal vesicles. These amyloid depositions as well
as one additional case were characterized histochemically, immunohistochemically
and electronmicroscopically. All but two of these patients (75%) showed
simultaneously amyloid depositions in the heart. Lactoferrin immunoreactivity was
found in 6 patients (75%). Lactoferrin is an iron-binding, bacteriostatic
glycoprotein, which is produced in the seminal vesicles. Four patients with
lactoferrin positive amyloid in seminal vesicle showed different amyloid
depositions in the heart (immunoglobulin light chain amyloid AL-lambda). Two
cases (25%) showed the same amyloid type in heart and seminal vesicles
(prealbumin-transthyretin type amyloid). Our study shows that most amyloidoses of
the seminal vesicles are organ-limited depositions of lactoferrin. These forms of
localized amyloidosis have to be separated from senile systemic amyloidosis with
seminal vesicle involvement.
PMID- 9556796
TI - [Numerical chromosome aberrations in abortion tissue. Comparison of conventional
cytogenetics and interphase cytogenetics in paraffin sections and nuclear
suspensions].
AB - Chromosomal aberrations are an important cause of spontaneous abortions. In order
to detect numerical aberrations, paraffin-embedded tissue from 26 abortions with
known conventional cytogenetic findings (CCG; 25 numerical aberrations and one
partial trisomy 7p) was analyzed by means of interphase cytogenetics (ICG) using
centromer-specific DNA probes for chromosomes #X, #Y, #10, #18, and #13/#21.
Limit-values for the diagnosis of aneusomy in tissue sections were established by
classifying the distribution of hybridization signals by CCG data (for gain > or
= 15% of nuclei with +1 signal; for deletion > 40% of nuclei with -1 signal).
Signal distribution in tissue sections and nuclear suspensions from paraffin
blocks analyzed in parallel showed statistically a highly significant correlation
(P < 0.0001). ICG and CCG diagnoses corresponded in 18 of 20 cases suitable for
evaluation (90%; no false-positive result). No correlation between cytogenetic
and histologic findings could be found. ICG proved to be a reliable tool for the
detection of numerical chromosomal aberrations in paraffin-embedded tissue of
abortions (sections and nuclear suspensions). This, data for genetic counselling
of the parents can be provided. The limit values for diagnosis of aneusomy could
also be important for the application of ICG in tumor cytogenetics.
PMID- 9556797
TI - [Chronic transplant reaction of the kidney. A interphase cytogenetic and
immunohistologic characterization of the involved cells in relation to donor and
recipient origin].
AB - Chronic rejection is a major problem in contemporary kidney transplantation. The
purpose of this study was to determine whether renal cells are repopulated by
extra-renal cells over time or whether the graft remains permanently allogenic.
We studied nine explanted allografted kidneys of sex-mismatched donors by means
of non-isotopic in situ hybridization (NISH). We used biotinylated centromer
specific DNA probes of the human chromosomes Y and X. In a further step,
monoclonal and polyclonal antibodies against CD45, CD3, CD20, CD31, CD1a, S100,
alpha-actin, factor Vill and UEA were used to analyse the various infiltrating
cell types and the cells involved in allograft arteriopathy. In several cases
NISH and immunohistochemistry were combined to facilitate the typing of cells.
Our study showed that up to several years after transplantation the glomerular,
tubular and endothelial cells retained donor origin. The only cells of recipient
origin were the inflammatory cells, predominantly macrophages and T lymphocytes.
PMID- 9556798
TI - [Placentoid malformation of the lung].
AB - The differential diagnosis of bullous and cystiform lung alterations comprises a
relatively calculable number of various diseases, in which the most important are
rare cystic tumors and congenial malformations, such as adenomatoid cystic
malformation. We report on a rare clinical picture. In this case, the clinical
diagnosis of localized unilateral emphysema caused by local displacement and with
subsequent complications had led to "bullectomies" and pneumonectomy.
Macroscopically, spongiform solid areas in association with areas of physaliform
transformation were seen, corresponding histomorphologically to villous,
placentalike formations. The "villous stroma" revealed focally regressive
alterations, fatty islets and leiomyomatous areas. So far, the pathogenesis of
this lesion, described as "placentoid malformation" due to its pathognomonic
histological appearance, remains unclear. In contradiction to the much discussed
hypothesis that this lesion may develop from pre-existing lung emphysema, our
results suggest that this may be an independent lesion, possibly congenital
hamartous malformation with self-developing progression. The clinically
predominant emphysematic alterations are considered to be caused by a valve
mechanism due to unphysiological traction forces, the lymphatic pathways
regularly found in the border areas towards the original lung tissue, possibly
playing an important etiological part.
PMID- 9556799
TI - [Fibrillary glomerulonephritis. Case report for differential nephrotic syndrome
diagnosis].
AB - A 67-year-old male patient presented with a nephrotic syndrome. Biopsy of the
kidney revealed the characteristic of fibrillary glomerulopathy on light and
electron microscopy. Other non-nephritic causes of a nephrotic syndrome (e.g.
amyloidosis, immunotactoid glomerulopathy, light-chain glomerulopathy,
cryoglobulinaemia, collagen-III glomerulopathy, fibronectin glomerulopathy) could
be excluded. Besides the case report, differential diagnosis of fibrillary
glomerulopathies is presented.
PMID- 9556800
TI - [Leiomyosarcoma of the spermatic cord with paraneoplastic beta-hCG production].
AB - Leiomyosarcomas of the spermatic cord are very rare tumours, which, in contrast
to the rhabdomyosarcoms of childhood, occur almost exclusively in adults. We
report the case of a 51-year-old male patient with a metastasizing, pleomorphic
leiomyosarcoma of the spermatic cord. The tumour showed paraneoplastic secretion
of beta-chain human chorionic gonadotropin (beta-hCG), as was demonstrated by the
elevated levels of beta-hCG in serum samples and by immunohistochemistry.
Histologically, the tumour was a high-grade leiomyosarcoma which showed an
aggressive course with pulmonary metastases appearing 4 months after primary
surgery. A concomitant rise in the serum levels of beta-hCG was also noted at
this time. A wide spectrum of tumours with a choriocarcinomatous component or
paraneoplastic production of beta-hCG has been described, the vast majority being
carcinomas. Only two leiomyosarcomas producing beta-hCG have so far been
reported. The paraneoplastic production of beta-hCG should prevent confusion with
germ-cell tumours, especially teratomas.
PMID- 9556801
TI - [Coincidence of balloon cell melanoma with balloon cells in a dermal nevus].
AB - We report a coincidence of balloon cell melanoma and balloon cell transformation
in a dermal nevus of a 56 years old female patient. The foamy cells in both
tumors with different dignity expressed S-100 and Vimentin. HMB45 was expressed
in all balloon cells of the melanoma. Detection of HMB45 in some of the nevus
associated balloon cells was considered as an expression of cellular activation.
PMID- 9556802
TI - [Primary primitive neuroectodermal tumor of the urinary bladder.
Clinicopathologic case report and differential small cell tumor diagnosis of this
site].
AB - We report a rare case of primary primitive neuroectodermal tumour of the bladder
in an adult. A huge tumour with extensions into pelvic and retroperitoneal tissue
was found radiologically in a 62-year-old man. The patient did not complain about
remarkable clinical symptoms until 4 days before admission to hospital. Histology
of diagnostic transurethral tumour resection showed a small round-cell tumour
with focal necrosis and scattered Homer-Wright rosettes. Immunohistochemical
analysis revealed that tumour cells stained positively with 013, a monoclonal
antibody which recognizes the membrane glycoprotein p30/32MIC2. Focally, tumour
cells stained positively for vimentin, NSE, S-100 protein and synaptophysin. The
patient died 3 weeks later because of fulminant pulmonary embolism and autopsy
revealed a huge, partly exophytic but mainly endophytic tumour of the bladder
with extensions into the rectum and retroperitoneal tissue. The differential
diagnosis of small round-cell tumours in this location is discussed.
PMID- 9556804
TI - [Diagnostic imaging of the larynx. Normal anatomy of the regional spread of
pathologic changes].
AB - The primary goal of diagnostic imaging of the larynx is analysis of submucosal
structures that are not visible by clinical or endoscopic means. Therefore, image
analysis of the larynx should only be performed under knowledge of the results of
clinical diagnosis. The anatomic relationships of the laryngeal skeleton, the
intrinsic structures, and the surrounding soft tissue are presented synoptically.
PMID- 9556803
TI - [Physiology of the larynx].
AB - The larynx consists of the cartilaginous-osseous framework, elastic membranes and
ligaments, joints, muscles, nerves, vessels, and interior cavity. The laryngeal
functions are the protection of the airway during swallowing, respiration (i.e.
maintainance of the airway) and phonation. During the pharyngeal phase of
swallowing the swallow reflex induces a laryngeal closure in three levels and a
superior-anterior movement of the larynx and hyoid bone. The laryngeal airway is
maintained by the circumference of the cricoid cartilage. Phonation is the
phylogenetically recent function of the larynx and was made possible by the
laryngeal descent. The sound production is explained according to the myoelastic
aerodynamic theory. The diagnostics of laryngeal diseases is performed in close
cooperation between otorhinolaryngology and radiology. For diagnostic purposes,
the physiology of the larynx requires to take into account not only
morphological, but also functional aspects.
PMID- 9556805
TI - [Rational imaging strategies in laryngeal diseases].
AB - Clinical information is indispensable for swift and cost-effective clarification
of diseases of the larynx. While quality clarification of neurological changes in
the area of the posterior cranial fossa and in the course of the vagus nerve as a
cause of glottis malfunction is possible with MRI, localized disease of the
larynx can more effectively be assessed with low-artifact CT. In the particularly
difficult assessment of the post-operative larynx, a recurrence can be diagnosed
only after a baseline study has been carried out after the end of therapy. With
knowledge of the pretherapeutic findings, the findings immediately post-therapy,
and the operation technique used, the optimal CT examination, which can be
carried out quickly, will be able to provide more information about recurrence.
PMID- 9556806
TI - [Diagnosis and therapy of laryngeal carcinoma].
AB - Therapeutic choice in laryngeal carcinoma is influenced by the nature of the
tumor and a variety of factors involving the patient and physician. Small (T1)
and exophytic (T1, T2) tumors are suitable for radiotherapy. Limited lesions (T1,
T2) can be cured by functional endoscopic resection techniques or external
partial laryngectomies. Extensive tumors (large T2; T3) are treated by total
laryngectomy or by primary irradiation, especially in the case of a good response
to induction chemotherapy. When radiation treatment fails, surgery succeeds in
more than half of the cases. Tumors infiltrating or transgressing the laryngeal
framework (T4) can only be cured by total laryngectomy followed by radiotherapy.
Subtotal or circular ablation of the adjacent pharynx or esophagectomy needs
repair with visceral or myocutaneous grafts. Lymphatics are preferentially
treated with the same modality as used in the primary disease. Inconspicuous
lymphatics should be treated electively in most cases, with the exception of
early glottic cancer.
PMID- 9556808
TI - [Stroboscopy and imaging in interdisciplinary diagnosis of early stages of
laryngeal carcinoma].
AB - The laryngostroboscopy is regarded to be the most important functional
investigation in laryngologic and phoniatric diagnostics. She allows an analysis
of vocal fold vibrations during phonation. Stroboscopic evaluations permit to
early detect infiltrative processes of the vocal folds. Superficial alterations
of the mucous membrane that invade into the muscle cause a phonatory "standstill"
of the vocal fold in the stroboscopy, i.e. a complete lack of vibratory motion.
If such a phonatory standstill persists for more than 2 or 3 weeks, a biopsy via
microlaryngoscopy is indicated for diagnostic purposes. In comparison to
stroboscopy, imaging techniques are not of such great significance in early
laryngeal cancer. But in case of suspected infiltration of the tumor a further
diagnostic evaluation with CT or MRI is necessary to detect possible neoplastic
invasion of the laryngeal cartilage or of extralaryngeal structures. In this
paper, we present the principle of laryngostroboscopy, the examination procedure
and the stroboscopic parameters. Case reports of early laryngeal cancer
illustrate the interdisciplinary diagnostic procedure with CT, MRI and
stroboscopy.
PMID- 9556807
TI - [Diagnosis and staging of laryngeal tumors with CT and MRI].
AB - Cross-sectional imaging with CT and MRI plays an indispensable complementary role
to endoscopy in the pretherapeutic workup and staging of laryngeal neoplasms.
Adequate interpretation of the CT and MR images requires a thorough knowledge of
the patterns of submucosal spread and familiarity with the diagnostic signs of
neoplastic invasion as seen with each modality. In addition, the radiologist
should be aware of the implications of imaging for staging and treatment. Both CT
and MR imaging are highly sensitive for the detection of neoplastic invasion of
the pre-epiglottic space, paraglottic space, subglottic region and cartilage. The
high negative predictive value of both CT and MRI allows exclusion of neoplastic
cartilage invasion quite reliably. The specificity of both CT and MRI is,
however, limited and both methods may therefore overestimate the extent of tumor
spread. Nevertheless, both cross-sectional imaging methods significantly improve
the pretherapeutic staging accuracy of laryngeal tumors if used in addition to
clinical examination and endoscopic biopsy. In the presence of a submucosal mass,
CT and MRI play a key role for the diagnosis, as they may characterize the
lesion, reliably depict its submucosal extent, and guide the endoscopist of
perform deep biopsies that allow a definitive histological diagnosis.
PMID- 9556810
TI - [Postoperative complications after larynx resection: assessment with video
cinematography].
AB - In past decades, the surgical techniques for treating laryngeal carcinoma have
been vastly improved. For circumscribed tumors, voice-conserving resections are
possible and for extensive neoplasms, radical laryngectomy, sometimes combined
with chemoradiation, has been developed. Postoperative complications regarding
swallowing function are not uncommon. Radiologic examinations, especially
pharyngography and videofluoroscopy, are most often used to evaluate patients
with complications after laryngeal surgery. An optimized videofluoroscopic
technique for evaluation of complications is described. The radiologic appearance
of early and late complications, such as fistulas, hematomas, aspiration,
strictures, dysfunction of the pharyngoesophageal sphincter, tumor recurrence,
and metachronous tumors is demonstrated.
PMID- 9556809
TI - [Function preserving surgical therapy of head-neck tumors with the CO2 laser].
AB - The use of microscopically controlled laser surgery to treat tumors of the upper
aerodigestive tract has as a function maintaining form of treatment gained
significance. It is an alternative to conventional surgery, which often makes
organ removal necessary. We report on our experience with 85 patients who
underwent a laser surgical resection of malignomas of the upper aerodigestive
tract. The aim of transoral laser surgery is a histologically confirmed radical
tumor resection. Tumor resection can be individually adapted according to the
tumor extent. An unnecessary resection of cartilage and muscles can be avoided.
Provided the appropriate indication is given, laser surgery yields good oncologic
and excellent functional results.
PMID- 9556811
TI - [Pathologic swallowing pattern after tumor surgery of oro- and hypopharynx.
Analysis with differentiated deglutition imaging].
AB - Dysphagia is a common complaint following surgical intervention in the oral
cavity and hypopharynx, often leading to prolonged postoperative recovery.
Videofluoroscopy allows detailed visualization of deglutition, demonstrating the
morphology as well as the functional aspects. Therefore, videofluoroscopy
provides the basis for further therapeutic management. We discuss the pathology
of deglutition in 19 patients recovering from tumor surgery of the oro- and
hypopharynx. In most cases the results demonstrated severe impairment of both the
oral and pharyngeal phase of deglutition. Our data emphasize the importance of
the oral phase of deglutition for preparation and initiation of the following
phases.
PMID- 9556812
TI - [Functional spiral CT in after-care of irradiated laryngeal carcinomas].
AB - The importance of spiral-CT is clinically accepted for diagnosing spreading
disease and for making a decision about the therapy strategy for head and neck
tumors. Its importance for follow-up after radiotherapy was examined in 26
patients with irradiated laryngeal tumors. Using spiral-CT multiple signs of
alterations (n = 98) can be diagnosed, which are not only important for tumour
relapse, but also for assessment. Spiral-CT offers the possibility of achieving
various additional information about the larynx that cannot be obtained with
laryngoscopy. In follow-up examinations after radiation, laryngoscopy and spiral
CT are recommended as an integrated neck examination using the breath-holding
technique (separately reconstructed) and also as functional spiral-CT of the
vocal cords in "I"-phonation.
PMID- 9556814
TI - [Septic focus in the retroperitoneum--iatrogenic foreign body of cotton
(gossypiboma)].
AB - Retained surgical towels (gossypiboma) present a diagnsotic problem if they
remain asymptomatic for many years. We report on one 51 year old patient with
repeated septic temperatures in the early post-operative phase after
hemicolectomy. The contrast enhanced CT of the abdomen revealed a well-defined
round soft-tissue mass with a dense, enhanced wall containing an internal high
density wavy and striped area. At laparotomy a secondary infected surgical sponge
with abscess formation was found.
PMID- 9556813
TI - [Punch biopsy or fine needle aspiration biopsy in percutaneous lung puncture?].
AB - PURPOSE: The diagnostic accuracy and rate of complications of CT-guided core
biopsies (CB) from suspected tumors of the chest were compared to the accuracy a
complications of fine-needle aspiration biopsies (FNAB). METHODS: The accuracy in
the diagnosis of a benign or malignant lesion of 79 FNAB (19.5 G self-aspirating
cutting needle) and of 83 CB (18 G automated core biopsy) and the rates of
pneumothorax, pleural drainage and hemoptysis were retrospectively evaluated.
RESULTS: With FNAB, the sensitivity for malignant lesions was 62.1% and the
accuracy 68.4%. With CB the sensitivity amounted to 85.9% and accuracy to 86.7%.
The rate of pneumothorax was 25.3% following FNAB, with a drainage rate of 5.1%
compared to 19.3% and 6.0%, respectively, following CB. The rate of pneumothorax
and drainage increased with increasing path length through aerated lung. In
advanced emphysema, the pneumothorax rate did not increase; however, in
pneumothoraces, pleural drainage was mandatory in 20% of FNAB and in 100% of CB.
Hemoptysis without any therapeutic consequences occurred in 3.8% following FNAB
and in 6.0% following CB. CONCLUSIONS: With CB diagnostic accuracy can be clearly
increased without an obvious increase in the complication rate. However, in
patients with obvious emphysema, the pleural drainage rate of pneumothorax may be
higher following CB.
PMID- 9556815
TI - The influence of occlusive dressing and hyperbaric oxygen on flap survival and
the healing of ischaemic wounds.
AB - The effect of dressing with Duoderm (hydrocolloid) and treatment with hyperbaric
oxygen was investigated on the healing of ischaemic incisional wounds and on flap
survival in rats. After 10 days, Duoderm dressing of ischaemic wounds decreased
all strength parameters (load*S, stress*S) by 41%-44% and the improvement of
ischaemic wound healing by hyperbaric oxygen treatment shown in our previous
study was not seen. After removal of Duoderm on day 10 the biomechanical
properties had improved but not returned to normal on day 20. In the dressed
animals the shrinkage of ischaemic wounds and the extension of necrosis on the
ischaemic flaps were reduced. Dressing may be useful clinically in preventing
superficial dermal necroses. One must, however, be aware of the impairment of the
wound strength of the incisional wounds.
PMID- 9556816
TI - The effect of recombinant basic fibroblast growth factor (bFGF) in fibrin
adhesive vehicle on the healing of ischaemic and normal incisional skin wounds.
AB - Normal and ischaemic incisional wounds in rats were treated with recombinant
human basic fibroblast growth factor (rbFGF) in fibrin adhesive vehicle. After 10
days of healing the maximum load*S and stress*S (S denotes correction for
shrinkage) of ischaemic wounds were increased by 45% and 39%, respectively, after
treatment with 20 micrograms rbFGF and by 67% and 56% after treatment with 60
micrograms rbFGF. After 20 days only 20 micrograms rbFGF had any effect and
increased maximum load*S by 31% and energy at maximum (load*S, stress*S) by 40%
48%. In normal wounds 0.6-20 micrograms and 60 micrograms rbFGF decreased the
strength parameters by 19%-34% and 49%-52%, respectively, after 10 days. After 20
days there was no negative influence but 60 micrograms rbFGF increased the
biomechanical properties by 15%-24%. Treatment with the fibrin adhesive vehicle
alone decreased the biomechanical properties of ischaemic wounds after 20 days,
and of normal wounds after both 10 and 20 days. In conclusion, rbFGF can improve
the healing of ischaemic wounds and may be used in the treatment of ischaemic
wounds in patients, but it can have negative effects on normal wound healing.
PMID- 9556817
TI - The effects of L-arginine and iloprost on the viability of random skin flaps in
rats.
AB - The effects of an intravenous infusion of L-arginine as a physiological precursor
of endothelium-derived relaxing factor/nitric oxide (EDRF/NO), iloprost (a stable
prostacyclin (PGI2) analogue), and L-arginine combined with iloprost on skin
viability were studied in 9 x 3 cm random pattern skin flaps in rats. Intravenous
infusion of all drugs was started at the beginning of the operation and continued
for 60 minutes. At the end of infusion period the depth of fluorescein dye
penetration in the skin flap was assessed visually from photographic records, and
the flap survival area was measured by the grid method at the seventh
postoperative day. There was a significant reduction in distal necrosis of random
skin flaps after intravenous infusion of L-arginine, iloprost, and L-arginine
combined with iloprost (p < 0.01). Possible mechanisms that may be responsible
for impairment of endothelium-dependent vasodilation and vasospasm in the
microvasculature of random skin flap and their prevention with L-arginine and
iloprost include restoration of the depleted stores of NO which in turn causes
vasodilatation and has an antithrombotic effect.
PMID- 9556818
TI - Metabolism in myocutaneous flaps studied by in situ microdialysis.
AB - The aim of this investigation was to follow the metabolism of myocutaneous flaps
using microdialysis. After subcutaneous implantation of a microdialysis catheter
into the flap tissue, serial samples were collected and changes in composition of
the extracellular fluid assessed. Ten women underwent reconstructions with
transverse rectus abdominis myocutaneous (TRAM) or latissimus dorsi flaps.
Glucose, glycerol, and lactate concentrations were measured in the flaps and
compared with those in adipose control tissue located over the hip. A transient
rise in glucose was observed initially in the flaps. The glycerol concentration
also increased significantly, and remained increased for approximately 12 hours
after the operation. The lactate concentration changed in the same direction, but
stayed elevated in the flap tissue during the entire investigation (24 hours).
Neither of these parameters changed to the same extent in the control tissue. In
one of the patients a haematoma developed postoperatively in the flap. This
incident was accompanied by a sharp decline in glucose, and marked additional
increases in glycerol and lactate concentrations. It may well be that this
"metabolic pattern" in flap tissue signals threatening flap ischaemia. If so,
this new microdialysis technique may be useful as a postoperative surveillance
tool in myocutaneous flap surgery.
PMID- 9556819
TI - Ear reconstruction in cases of typical microtia. Personal experience based on 352
microtic ear corrections.
AB - The aim of this paper is to report my experience of 352 ear reconstructions to
correct microtia with Brent's technique (n = 184) and Nagata's technique (n =
144). The remaining 24 were atypical presentations reconstructed in a one-stage
procedure. Brent's technique is a safe, step-by-step, four-stage reconstruction
and Nagata's technique involves only two stages. Nagata's innovations include
transposing the lobule of the auricle during the first stage, carving a framework
that includes the tragus, and constructing the posterior wall of the concha
during the second stage. Cases of typical microtia have been selected to
illustrate the advantages and pitfalls of both techniques.
PMID- 9556820
TI - Use of the subgaleal fascia to construct the auditory canal in microtia
associated with aural atresia. A preliminary report.
AB - In this paper we introduce the use of a subgaleal flap to construct the auditory
canal in cases of microtia associated with aural atresia. The anatomy, the
vascularisation, and the nomenclature of the different planes that constitute the
temporal region are wellknown. The subgaleal fascia, also referred to as the
loose areolar fascia has been until now the less surgically exploited of these
planes. Nevertheless, it has a structure and a vascularisation that enables it to
be dissected and used surgically. The subgaleal flap used to line the neoauditory
canal drilled into the bone provides a vascular bed that greatly improves the
quality of the skin graft and supports the tympanoplasty. The procedure is done
while the ear is being raised, which constitutes the second stage of the two
stage ear reconstruction. This new approach has been used on 22 ears. A
preliminary analysis of the results shows that construction of the auditory canal
has been improved.
PMID- 9556821
TI - Speech outcome after cleft palate surgery with the Goteborg regimen including
delayed hard palate closure.
AB - The regimen for treatment of children with cleft lip and palate in Goteborg,
Sweden, until 1996 included early soft palate repair at 6-8 months of age and
delayed closure of the hard palate at about 8 years of age to improve maxillary
growth. The aims of this report were to describe the treatment concept and to
present speech data of 59 children treated by this method. The speech of 38
children with unilateral and 21 with bilateral cleft lip and palate was evaluated
perceptually from standardised tape recordings of repeated sentences and
spontaneous speech at five ages from 3 to 16 years of age. All patients were not
evaluated at each age level. The results showed a low prevalence of hypernasality
after hard palate closure and pharyngeal flap surgery in only five children (8%),
indicating a primary velopharyngeal insufficiency in less than 10% of the
children. Only three children with bilateral clefts had glottal articulation when
at pre-school age and no child with a unilateral cleft did. These results were
interpreted as an indication of velopharyngeal competence (VPC) in most of the
children. In addition, the speech problem found in these children consisted of
retracted oral articulation of alveo-dental pressure plosives, which is almost
always an indicator of VPC. However, we do consider that retracted oral
articulation is a problem and to improve our results further we have decided to
modify the technique for soft palate closure slightly and place the vomer flap
further anteriorly to encourage narrowing of the cleft in the hard palate, and to
close the hard palate at 3 years of age.
PMID- 9556822
TI - Skeletal analysis of craniofacial asymmetries in plagiocephaly (unilateral
coronal synostosis).
AB - Why do the craniofacial bones grow asymmetrically in patients with plagiocephaly
(unilateral coronal synostosis)? We obtained three-dimensional skeletal replicas
of two patients with the condition and analysed the deformities of the facial
bones. From this analysis we deduced that the asymmetric deformation of the
facial bones in these patients was caused by a combination of three rotations:
rotation of the calvaria toward the affected side because of premature synostosis
of the coronal and sphenofrontal sutures; rotation of the facial bones on the
horizontal plane toward the unaffected side caused by anterior displacement of
the TM (temporomandibular)-joint on the affected side; and downward rotation of
the facial bones toward the unaffected side caused by inferior displacement of
the TM-joint on the affected side.
PMID- 9556823
TI - Assessment of facial features with a range camera.
AB - We describe a new method for the quantitative analysis of facial features using a
range camera with a three-dimensional measuring program. The range camera
consists of a video camera, a light projector, and a computer. The video camera
captures a number of images of different light patterns projected on to the face.
From these, a "range image" is computed. One fully illuminated intensity image of
the face is also taken. By defining anatomical landmarks manually on the
intensity image, three-dimensional measurements are automatically obtained from
corresponding positions in the range image. The method is highly accurate and
precise, and is a simple and reliable way of assessing facial features. We
recommend that the system be adapted in clinical practice--for example, in
diagnosing syndromes and planning plastic and reconstructive surgery.
PMID- 9556824
TI - Melanoma of the face: the safety of narrow excision margins.
AB - Recent studies have shown that narrower excision margins may be safe, but the
optimal or minimum margin for melanoma is unknown. Wide margins of excision are
possible on the trunk and limbs, but functional and cosmetic constraints often
limit the extent of excision on the face. A collaborative study from two
continents (Cape Town, South Africa and Northwood, England) investigated the
outcome of different excision margins of 106 patients with stage I melanoma of
the face. The margin of excision was measured from the records of the
pathological specimen. Thirty patients had margins of less than 1 cm, 64 had
margins of between 1 and 2 cm, and 12 had margins greater than 2 cm. Primary
apposition or flap closure was possible in 85 patients. Seven patients developed
local recurrences and these were not influenced by the excision margin. This
study supports the contention that the primary treatment of cutaneous melanoma on
the face should be histologically confirmed complete excision, and that this can
be achieved with margins of excision less than 1 cm. Local recurrence is not
related to the margin of excision or to tumour thickness.
PMID- 9556825
TI - Treatment of non-healing ulcers of the lower extremity with free muscle flaps.
Case reports.
AB - The surgical management of ulcers in the lower extremity is traditionally
conservative, and includes debridement and split thickness skin grafting. In the
most intractable cases, however, this management is often not enough. In this
report of three patients with non-healing ulcers of the lower extremity
successfully treated with free muscle flaps, we advocate a more active surgical
approach to the treatment of such conditions. This is also appropriate in
patients for whom a microsurgical approach might not be considered because of
advanced age, peripheral arterio-occlusive disease, or the presence of other risk
factors.
PMID- 9556826
TI - Macrocephaly with multiple soft tissue and visceral hamartomas ("Bannayan-Zonana"
syndrome). Case report.
AB - Since its first description few cases of the rare association of macrocephaly
with multiple soft tissue and visceral hamartomas (Bannayan-Zonana syndrome) have
been reported. In this paper we report a case of a 7 year old child in whom
lipomas of the abdomen and right flank have been treated with liposuction. We
could find no previous evidence that this surgical technique has been used in the
treatment of this syndrome.
PMID- 9556827
TI - Cholesterol crystal embolism. Case report.
AB - A 60-year-old man presented with a cholesterol crystal embolism that gave a
rather confusing clinical picture. An immediate multidisciplinary approach
established the diagnosis and the rapid, dramatic skin loss that exposed vital
structures over his thigh and lower leg was reconstructed by an ipsilateral
inferior pedicled rectus abdominis musculocutaneous flap with a lateral oblique
cephalad fasciocutaneal component. The case, which a plastic surgeon would rarely
encounter, is interesting because of the diagnostic approach and the management.
PMID- 9556829
TI - [Transplantation immunology: is the manipulation of the cytokine network
therapeutically justified?].
AB - Classical allograft rejection is a cellular-mediated immune response in which the
activation of the CD4+ T helper (Th) cell plays a crucial role. After activation
the Th cell produces a variety of cytokines which are essential for initiating
allograft rejection. Th cells can be distinguished by their cytokine profile. Th
1 cells produce IL-2 and IFN gamma, which are associated with rejection. Th2
cells are characterized by the production of IL-4 and IL-10, cytokines which are
found in models when tolerance is induced. These findings are called the "Th1/Th2
paradigm" and lead to the following hypothesis: Th1 cells are responsible for
allograft rejection and manipulation of the cytokine network towards a Th2 type
cytokine pattern results in tolerance or delayed rejection. This study attempts
to answer the question whether the Th1/Th2 paradigm is a pure association or
corresponds to a mechanism which might be used therapeutically. Allograft
rejection in the absence of the proinflammatory cytokines IL-2 and IFN gamma
occurs almost unaltered. Moreover, supplying the anti-inflammatory cytokines IL-4
and IL-10 did not result in delayed rejection. Therefore, therapeutic
manipulation of the very complex cytokine network will most likely fail. Blocking
cytokine-independent T cell activation might be a better concept for induction of
allograft tolerance.
PMID- 9556828
TI - Idiopathic isolated bilaterally symmetrical brachymetacarpia of the fifth
metacarpal. Case report.
AB - We report a rare case of a 32-year-old woman with idiopathic isolated bilaterally
symmetrical brachymetacarpia of the fifth metacarpal bone, which had been present
since the age of 14. Movement, and sensory and motor function were within normal
limits, and she had no symptoms. No treatment was recommended. We know of no
similar case reports.
PMID- 9556830
TI - [Socioeconomic aspects of the changed mortality rate of coronary disease in
Switzerland 1988-1993].
AB - Mortality from ischemic heart disease (ICD 410-414) is changing. Remarkable
decreases have been observed in the age groups from 35-64 years, while overall
mortality (all age groups) has remained approximately stable. In Switzerland this
has meant a gain of some 4700 life years in the period 1988 to 1993 in the
working population (35-64 years). The object of this study was to assess the
associated change in indirect costs (productivity losses) due to premature death,
using the human capital approach. The indirect costs were CHF 519 million (CHF
7.5 million per 100,000 population) in 1993. This represents approximately half
of all indirect costs (and 25% of the total costs generated by the disease).
Compared with the year 1988, a decrease in productivity losses due to premature
death was observed amounting to CHF 46 million (-11%) in constant Swiss francs.
Society benefits from this decrease in indirect costs, a desirable development
hardly ever mentioned.
PMID- 9556831
TI - [Epidemiology and care of myocardial infarct at the Fribourg Canton Hospital
1995].
AB - PURPOSE: This study evaluates epidemiological data in a population of patients
admitted for acute myocardial infarction in a large Swiss community hospital. It
focuses on the application of recent drug treatment and newer therapeutic
techniques. METHOD: Data acquisition was based on medical records of all patients
who were admitted to the Cantonal Hospital of Fribourg in 1995. Their one-year
follow-up was obtained through questionnaires sent to general practitioners.
RESULTS: During the study period: 146 myocardial infarctions were diagnosed in
144 patients. Median age was 67.1 and 35% of patients were female. Nineteen
percent were diabetics, 51% had hypertension and 28% had a positive family
history for coronary artery disease. Active smokers made up 32%, 17% were past
smokers. Myocardial infarction was anterior in 40%, inferior in 36% and non-Q
wave myocardial infarction in 35%. Eighteen percent were subacute myocardial
infarction. Killip class on admission were as follow: class I 65%, class II 21%,
class III 1% and class IV 11%. Thrombolytic treatment was administered in 29% of
patients. Vasoactive amines were used in 27% of patients and 8% were intubated
some time during their hospital stay. At hospital discharge 81% were treated with
Aspirin, 31% with anticoagulants, 47% with an ACE inhibitor, 38% with a beta
blocker, 34% with nitrates and 25% with a calcium antagonist. Among this
population, 62% had an echocardiogram, 30% a stress test and 8% a Holter
recording. Coronary angiography was performed in 52%, which revealed 33% one
vessel disease, 28% two-vessel disease, 25% three-vessel disease and 9% normal
coronary arteries. Percutaneous coronary angioplasty was done in 53% of cases and
a coronary stent implanted in 22%. Twelve percent had surgical revascularization.
The mean hospital stay was 16.3 +/- 10.8 days, with in hospital mortality of up
to 19.2% and a one-year mortality of 25.3%. CONCLUSION: Treatment modalities of
patients admitted for acute myocardial infarction at the Hospital of Fribourg are
comparable with literature data. Hypolipemic treatment has not been prescribed as
often as recent guidelines recommend, but the use of ACE inhibitors was more
common. As in other studies, older patients have the highest mortality. The
absence of hospital coronarography facility did not seem to influence the
prognosis of that population.
PMID- 9556833
TI - [Unusual cause of cough].
PMID- 9556832
TI - Medical treatment of migraine: from mechanisms of action to contraindications.
AB - Management of migraine patients with or without aura must include appropriate
medication to treat the attack and long-term preventive therapy, especially if
the frequency of the attacks is greater than 2-4 per month. In both cases the
choice of treatment depends on its efficacy and side effects. With regard to
acute drug therapy, group studies do not suggest that ergot derivatives and
sumatriptan are superior to simple analgesics and anti-inflammatory drugs,
particularly if a prokinetic agent is added. These new substances are indicated
for severe attacks refractory to more conventional therapy. Chronic drug abuse
may induce drug-induced or rebound headaches. As regards long-term prophylaxis,
group studies suggest that calcium antagonists and 5-HT-influencing drugs are
superior concerning attacks frequency to beta-blocking agents, but involve very
frequent side effects (weight gain and somnolence). Interesting preliminary
results have also been reported with valproate and enalapril, which will
confirmation by controlled studies. Finally, the choice of drug must take into
account the patient's comorbidities (cardiovascular diseases, asthma, diabetes
etc).
PMID- 9556834
TI - [Annual General Assembly of the Swiss Association for Pneumonology and the Swiss
Association for Industrial Medicine. Zurich, 26-27 March 1998].
PMID- 9556835
TI - [Tele-immobilization of (gone) wild animals in Dutch veterinary practice. 2:
Anesthetics used in the immobilization of wild animals].
AB - In this article a review will be given of the groups of anaesthetics used for
animal capture, their developmental history, mode of action and indication for
use. A table with dosages of locally--in the Netherlands--available drugs will be
presented for a number of animal species.
PMID- 9556838
TI - [Cholera and swine welfare. Arbitrary reduction does not change anything of
industrial essence].
PMID- 9556841
TI - Duodenal mucosal permeability, bicarbonate secretion and motility. Aspects of
regulation and integration of duodenal function in the rat. Minireview based on a
doctoral thesis.
PMID- 9556842
TI - Image analysis of the duodenal endocrine cells in mice with particular regard to
optical densitometry.
AB - The endocrine cells in the murine proximal duodenum have been investigated by
means of immunohistochemistry and computerized image analysis. Five endocrine
cell types were identified, namely secretin-, gastric inhibitory polypeptide
(GIP)-, gastrin-CCK-, somatostatin- and serotonin immunoreactive cells. The
number of endocrine cells/mm3 epithelial cells was estimated and the cell
secretory index (CSI) for different endocrine cell types was determined.
Furthermore, the optical density of the cellular immunoreactivity and the
immunoreactive area in the cell were determined and an index, cell
immunoreactivity content was estimated as the optical density multiplied by the
immunoreactive area. It has been suggested that the use of this index might
better reflect the cellular peptide/amine content than does the CSI. Serotonin
immunoreactive cells were the predominant endocrine cell type, followed by
gastrin/CCK-immunoreactive cells. The numbers of secretin-, GIP- and somatostatin
immunoreactive cells were almost identical. All endocrine cell types were present
both in crypts and in villi, but were, more numerous in the crypts, except for
secretin which was more frequent in the villi.
PMID- 9556843
TI - A survey of sleep habits and sleeping difficulties in an elderly Swedish
population.
AB - A random sample of 876 subjects aged 65-79 years were investigated by means of a
questionnaire concerning sleep and related factors. Sleep problems were reported
by 23.8% of females and 13.3% of males. Moderate or major complaints of
maintaining sleep were reported by 43.5% of subjects, early morning awakening
33.4% and difficulties falling asleep 31.4%. Daytime sleepiness was more common
among males, and a relationship between daytime sleepiness and perceived poor
sleep was found. Daytime napping was common, but not related to poor sleep. The
prevalence of regular sleeping pill users was 7.6% for females and 3.0% for males
and a relationship between sleep problems, sleeping pill usage and psychiatric
symptoms was established. Among the regular sleeping pill users 39.1% had
possible depression (PD) and 63.0% had possible anxiety disorder (PA). Among
respondents with sleep complaints 29.8% had PD and 48.7% had PA. Sleep problems
were also related to impaired physical health. Various medical illnesses
contributed to sleep complaints among males, and depression affected sleep the
most among females.
PMID- 9556844
TI - Hyaluronan production in vitro by fetal lung fibroblasts and epithelial cells
exposed to surfactants of N-acetylcysteine.
AB - Fetal human lung fibroblasts and feline lung epithelial cells were exposed to
either a surfactant or N-acetylcysteine in various concentrations for 24-48
hours, after which the hyaluronan concentration in the culture medium was
determined. Most of the experiments showed no stimulatory effect of either
artificial or natural surfactant on hyaluronan synthesis. N-acetylcysteine 5-100
mg/mL induced progressive stimulation of hyaluronan synthesis by human fetal lung
fibroblasts, resulting in a maximum hyaluronan concentration six times that
released by unexposed cells. A slight increase in hyaluronan synthesis was also
observed after exposure of feline fetal lung epithelial cells to N-acetylcysteine
50-100 micrograms/mL.
PMID- 9556845
TI - Principles of antimicrobial therapy.
AB - It has been 2500 years since the Chinese began applying moldy soybean curd to
cure skin infections. Technology today has refined the benefits of antibiotic
forming molds and bacteria and has greatly increased the number of antimicrobial
drugs available to combat infection. Understanding the principles fundamental to
rational therapy with these drugs will ensure the best of possible outcomes.
PMID- 9556846
TI - Antibacterial drug therapy. Focus on new drugs.
AB - This article will focus on the drugs for which there has been a recent or renewed
interest in veterinary medicine. Some of these are new drugs that were recently
introduced. Others discussed may be human-label drugs for which there has been
recent interest in veterinary medicine because of the need for a more active drug
or convenient regimen. For drugs such as the aminoglycosides included here,
recent information has provided us with updated dosage guidelines.
PMID- 9556847
TI - Antiseptics and disinfectants.
AB - Germicidal agents used as antiseptics and disinfectants play an important role in
the control of infection in the veterinary patient. Critical to the proper use of
germicidal agents in or around the veterinary patient is knowledge of efficacy
and contraindications. The key to proper use of antiseptics and disinfectants is
using the proper germicidal agent under conditions that maximize success and
minimize complications. Although there are a number of germicidal agents
commercially available, effective antisepsis and disinfection can be achieved
through use of a few effective, yet safe germicides.
PMID- 9556848
TI - Treatment of endotoxic shock: glucocorticoids, lazaroids, nonsteroidals, others.
AB - Review of the literature would indicate that a therapy inhibiting a single step
in the inflammatory mediator cascade, although potentially beneficial, cannot
serve as the "magic bullet" in endotoxic shock. Thus, combination therapy using
drugs that target multiple steps in the mediator cascade may prove useful in the
future. Until controlled clinical studies have been performed in veterinary
medicine using the agents discussed in this manuscript (or others), many
questions will remain regarding the best possible pharmacologic therapies to use
in supplementing traditional supportive care (e.g., fluids, broad-spectrum
antimicrobials) measures. Many of the therapies discussed in this manuscript hold
tremendous potential, but must be administered before endotoxic shock occurs or
early in the course of endotoxic shock to elicit a beneficial response.
Unfortunately this is not usually possible in the clinical situation. Further,
the possibility of eliciting a detrimental response by use of drugs at
inappropriate dosages or too late in the course of the disease must be
considered. In time, therapies may be grouped into those that hold promise for
being beneficial in the patient at risk for endotoxic shock and those that are
beneficial for treatment of established endotoxic shock. Therapies that may hold
promise for the patient with established endotoxic shock possibly include the
lazaroids, certain NSAIDs, pentoxifylline, and selective inhibitors of iNOS
activity. Although still controversial, methylprednisolone and other
glucocorticoids are probably best reserved for the patient at risk for endotoxic
shock, or those identified very early in the course of endotoxemia and endotoxic
shock, and should never be used in conjunction with NSAIDs. Since no one therapy
is likely to provide the "magic bullet" for the patient in endotoxic shock,
treatment may ultimately involve combination therapy using some of these drugs
that target different pathways and mediators and may also include antibodies
against endotoxin or its mediators.
PMID- 9556849
TI - Biological response modifiers: interferons, interleukins, recombinant products,
liposomal products.
AB - The concept of enhancing the normal immune response against infections and
neoplasms has been considered for decades. The administration of various natural
and synthetic products to simulate systemic infections has largely given over to
the idea that specific cytokines can be used effectively when administered
systemically. Interferons, interleukins, and hematopoietic growth factors may
offer substantial clinical benefit in chronic viral infections, and cancers such
as osteosarcoma, melanoma, and lymphosarcoma. Erythropoietin has been shown to
have great utility in the management of chronic renal failure. At this point in
time, only recombinant products derived from humans are commercially available,
and they are expensive and not licensed for use in companion animals.
Nevertheless, these products may have significant clinical impact on several
highly fatal disorders of dogs and cats. When administered systemically,
cytokines perturb complex regulatory pathways, and serious side effects may
occur. Innovative delivery methods, such as liposomes, gene therapy, and even
oral administration may increase the therapeutic index of these molecules.
Biological response modification, cytokine biology, and associated delivery
systems are rapidly changing fields, and the small animal veterinarian will need
to watch for significant advances in these areas over the next several years.
PMID- 9556850
TI - Fluid therapy. Crystalloids and colloids.
AB - Appropriate fluid therapy requires an understanding of fluid dynamics and
pathologic alterations during various disease states. In addition, it requires an
understanding of the pharmacologic differences of available fluids. Crystalloid
fluids and colloid fluids can be used in combination to treat a variety of volume
deficient states. Synthetic colloids are also used to treat hyponcotic states.
Blood products are used to replace blood components and coagulation proteins.
Frequent monitoring and reassessment are required to prevent volume overload and
life-threatening edema.
PMID- 9556851
TI - Drugs acting on blood and/or blood forming organs.
AB - Pharmacologic therapy for anemia is oriented toward (1) providing components
needed for red blood cell production (vitamin B12 and folic acid), including
hemoglobin synthesis (iron and other minerals), and (2) stimulating bone marrow
formation of red blood cells. Drugs used to stimulate bone marrow activity will
be the focus of this article.
PMID- 9556852
TI - Treatment methods for pain in the osteoarthritic patient.
AB - Osteoarthritis is one of the most common clinical problems for which pet owners
seek veterinary consultation. Proper management of osteoarthritis is rewarding to
the patient, client, and veterinarian alike. The foundation for treatment of
osteoarthritis is weight control, exercise moderation, and administration of anti
inflammatory agents. This section of the text addresses clinically important
mechanisms of osteoarthritis and the use of anti-inflammatory agents targeted to
reduce pain and inflammation associated with the disease.
PMID- 9556853
TI - Gastrointestinal drugs.
AB - Various drugs are commonly used for the many gastrointestinal problems that are
routinely seen in dogs and cats. Many of these drugs are briefly reviewed in this
article. Anecdotal as well as documented findings are provided that will
hopefully allow the clinician to use them wisely and effectively in the many
clinical situations that arise daily. Emetics, although not used for
gastrointestinal problems, are also reviewed because of their obvious connection
with the gastrointestinal tract.
PMID- 9556854
TI - Drugs used to treat reproductive disorders.
AB - As with all aspects of medicine, it is necessary to fully understand disease
processes before treatment modalities can be designed. Many disorders in small
animal reproduction have not been completely evaluated, and further investigation
is ongoing. Many reproductive hormone products are available but have limited
clinical applicability. Other products have potential use but are not
commercially available. A thorough diagnostic evaluation is always indicated
before embarking on a treatment regimen.
PMID- 9556855
TI - Anticonvulsant therapy in small animals.
AB - Successful control of seizures with anticonvulsant drugs reflects a balance in
achieving seizure control while minimizing undesirable drug side effects.
Variability in the disposition of anticonvulsants and interaction among them are
important confounders of successful therapy. This article will provide a review
of selected anticonvulsants, focusing on drugs most likely to control seizures in
small animals. The proper use of anticonvulsants will be discussed, with emphasis
on differences in individual drug disposition, detection of these differences,
and rational approaches to responding to these differences by dose modification.
The primary target of discussion will be treatment of generalized, tonic clonic
seizures, the most common type afflicting small animals. Opinions regarding
anticonvulsive therapy vary among clinicians. Most of the comments and
recommendations offered in this discussion reflect observations made from our
therapeutic drug monitoring service and completed and ongoing clinical trials
that focus on the use of anticonvulsants used either alone or in combination with
phenobarbital.
PMID- 9556856
TI - Therapeutic information on the Internet.
AB - The internet provides a vast array of information accessible to anyone with a
personal computer, a modem, and an internet account. It can be difficult to
locate appropriate sites and determine their utility. This article provides a
point-in-time sampling of the internet for therapeutic information. The URL for
sites are provided along with a brief review of the content and its applicability
to veterinary therapeutics.
PMID- 9556857
TI - Production of toxic shock syndrome toxin by Staphylococcus aureus isolated from
mastitic cow's milk and farm bulk milk.
AB - The production of toxic shock syndrome toxin (TSST) by Staphylococcus aureus
isolated from mastitic cow's milk and farm bulk milk was examined by a reverse
passive latex agglutination method (RPLA). TSST was detected in 25 (58.1%) of 43
isolates from clinical mastitic cow's milk, in 79 (76.7%) of 103 isolates from
subclinical mastitic cow's milk, and in 95 (75.4%) of 126 isolates from farm bulk
milk, respectively. When the quantity of TSST in the isolates was determined by
RPLA, the titers ranged from 5 to 2560. TSST with RPLA titers of 640 to 2,560 was
produced by 83 (30.5%) of 272 isolates tested. Almost all of the isolates showing
RPLA titers of 640 and over produced enterotoxin C, whereas isolates showing
titers of 5 to 320 produced enterotoxin C or both enterotoxin A and C. SDS
polyacrylamide gel electrophoresis and isoelectric focusing with immunoblotting
showed that the TSST from bovine isolates had same molecular size (22 kDa) and
isoelectric point (7.2) as TSST-1 from human isolates. These findings are
consistent with previous reports.
PMID- 9556858
TI - Characterization of the systemic disease and ocular signs induced by experimental
infection with Chlamydia psittaci in cats.
AB - In addition to the commonly reported ocular signs, Chlamydia psittaci infection
of kittens resulted in fever, lethargy, lameness and reduction in weight gain
following ocular instillation of virulent organisms. The appearance of these
systemic signs was late with respect to the appearance of ocular symptoms and
occurred simultaneously with increasing levels of chlamydia-specific IgG.
Measurement of acute phase reactants and IL-6 in plasma indicated that both
became elevated concurrent with or slightly after the appearance of fever and
remained elevated after the fever began to resolve. Preliminary data also
indicated that infectious C. psittaci was present in the blood stream during this
time period. The results of ocular instillation of three different levels of C.
psittaci (10(3.8), 10(2.8) and 10(1.5) TCID50) indicated that the frequency of
infection and the severity of ocular signs were diminished in the group receiving
the lowest dose. However, the magnitude of systemic disease was similar in all
animals which exhibited clinical signs, irrespective of the dose administered.
The immune response to infection included elementary body (EB)-specific
lymphocyte proliferation as well as the development of EB-specific IgG and IgM
antibodies. The predominant antibody response was to a 45 kDa protein, the major
outer membrane protein (MOMP), lipopolysaccharide (LPS), a 58 kDa doublet and 32
and 16-19 kDa proteins.
PMID- 9556859
TI - Phenotypic expression of K88 adhesion alone or simultaneously with K99 and/or F41
adhesins in the bovine enterotoxigenic Escherichia coli strain B41.
AB - F41-positive and F41-negative derivatives of bovine enterotoxigenic Escherichia
coli strain B41 carrying K88 or K88 and K99 plasmids were investigated for
stability and expression of genes for their fimbrial antigens. Either K88 plasmid
alone or both K88 and K99 plasmids could be maintained in these strains though
stability could depend on culture medium. K99 antigen could be detected in each
strain bearing K99 plasmid. Clones that produced K88 antigen or clones that did
not produce this antigen could be isolated from each strain, except from the
strain that possessed K99 plasmid in the strain that did not possess the ability
to produce F41 antigen. Strains possessing K88 plasmid in the strain able to
produce F41 antigen produced clones expressing either both K88 and F41 antigens,
(also F41 appeared strongly expressed in some clones) or clones that produced
only F41 antigen or no antigen at all. Clones that produced only K88 antigen or
others that did not produce this antigen could be produced from a strain bearing
only K88 plasmid and that did not possess the ability to produce F41 antigen.
None of these strains bearing K88 plasmid alone or additionally K99 plasmid
produced mannose-resistant hemagglutination of horse or sheep erythrocytes at 20
degrees C as found for K99 and F41 ETEC natural strains, respectively. These
results suggested that the structures of pili when several genetic determinants
were present simultaneously may not be identical to those of original strains. In
this study, clones expressing either one, two or three adhesin bearing antigens
could be obtained from the strain B41.
PMID- 9556860
TI - Development of a PCR test based on a gene region associated with the
pathogenicity of Pasteurella multocida serotype B:2, the causal agent of
haemorrhagic septicaemia in Asia.
AB - We have developed a PCR assay to detect Pasteurella multocida serotype B:2, the
causal agent of Haemorrhagic Septicaemia (HS) in Asia. Nucleotide sequence
determination of a 16S rRNA-23S rRNA PCR product unique to B:2 strains was shown
to share amino acid sequence homology with a bacteriophage Mu protein. Primers
designed from this sequence when tested against a panel of isolates recovered
from a wide geographical area and representing a large range of bacterial genera
and species, were found to specifically amplify DNA from P. multocida, serotype
B:2. Southern hybridisation confirmed the presence of this sequence in only the
B:2 serotype of P. multocida, suggesting an association between bacterial
virulence and the presence of bacteriophage genes in the bacterial genome. The
results of this study demonstrate the potential application of PCR to the
diagnosis of HS in cattle and buffalo in Asia. Application of PCR to support
diagnosis of HS will greatly improve accuracy, laboratory response time, and will
facilitate rational deployment of resources for controlling this disease.
PMID- 9556861
TI - Ochratoxin A in food and feed: occurrence, legislation and mode of action.
AB - Ochratoxins, of which ochratoxin A (OA) is the most prevalent, are secondary
fungal metabolites of some toxigenic species of Aspergillus and Penicillium. OA
has been shown to be nephrotoxic, hepatotoxic, teratogenic, carcinogenic and
immunosuppressive. The natural occurrence of OA in food and feed stuffs is
widespread, especially in temperate areas such as Canada, Denmark, Germany,
Sweden and the United Kingdom, and detectable amounts were even found in randomly
collected human milk samples in Germany, Sweden and Italy. Of greatest concern in
humans is its implicated role in an irreversible and fatal kidney disease
referred to as Balkan Endemic Nephropathy. The mean dietary intake for humans in
the European Union was found to be in the range of 1 to 2 ng/kg bw/day. Compared
with the Provisional Tolerable Daily Intake (PTDI) proposed by the WHO of 16 ng
OA/kg bw/day for humans, the average OA intake in Europe seems to be rather low.
The main contributor to the OA intake in humans are cereals and cereal products,
other possible contributors are coffee, beer, pork, products containing pig
blood/plasma, pulses and spices. Only very few countries have regulations for OA
in food and feed products. Based on the current literature, the mechanisms
involved in the toxicity of OA indicate three major effects: (1) inhibition of
mitochondrial respiration correlated with a depletion of ATP; (2) inhibition of
tRNA-synthetase accompanied by a reduced protein synthesis; and (3) enhanced
lipid peroxidation. Generation of free radicals and lipid peroxidation as an
important mode of action of OA in vitro and in vivo is discussed in detail, as
well as counteracting effects of dietary antioxidants.
PMID- 9556862
TI - Effect of consumption of uncooked (RS2) and retrograded (RS3) resistant starch on
apparent absorption of magnesium, calcium, and phosphorus in pigs.
AB - The aim of this investigation was to study the effect of uncooked (RS2) and
retrograded (RS3) resistant starch on the size and site of the apparent
absorption of magnesium, calcium, and phosphorus in swine. In an experiment with
a parallel design, three groups of six piglets each consumed for two weeks a diet
containing either glucose, RS2 or RS3. The piglets were cannulated at the end of
the ileum which allowed estimation of the ileal and colonic mineral absorption.
Urine, feces, and ileal digesta were collected for measurement of magnesium,
calcium, and phosphorus. Dietary RS2, but not RS3, versus glucose reduced (p <
0.05) the total absorption of magnesium and calcium and the ileal absorption of
phosphorus in the pig. Differences between species or in RS and/or mineral intake
may explain why RS2 reduced the apparent absorption of magnesium and calcium in
pigs in this study and raised it in rats in earlier studies.
PMID- 9556863
TI - Iodide supplementation: 200 micrograms daily or 1,500 micrograms weekly?
AB - 25 euthyroid volunteers were divided into two groups. Each participant of group A
received 200 micrograms iodine in the form of diiodotyrosine per day for a period
of eight weeks, i.e. 7 x 200 micrograms iodine/week. Each participant of group B
received 1,500 micrograms iodide once a week for a period of eight weeks. In
addition to the basal excretion of iodine with the collected urine, the excretion
values in group A amounted to 67% of the applied dose in the eighth week. In
group B, the excretion values amounted to 65% of the applied dose in the eighth
week. Hence, no significant difference between both groups was found.
PMID- 9556864
TI - [Eating disorders in women: a representative study].
AB - The authors examined the prevalence rates of binge-eating behavior, binge-eating
disorder (BED), and bulimia nervosa in a female representative random sample in
Tyrol. The data were collected ba telephone. Of the 1,000 women, 3 (0.3%) met the
DSM-IV diagnostic criteria for anorexia nervosa, 15 (1.5%) for bulimia nervosa,
and 33 (3.3%) for binge-eating disorder. While bulimics were young and found in
all weight groups, women with BED were mostly overweight or obese and found in
all age groups. The findings show that restrained eating, dieting, and/or
excessive exercise are risk factors for developing eating disorders.
PMID- 9556866
TI - [Influence of lifestyle on the use of supplements in the Brandenburg nutrition
and cancer study].
AB - Differences in dietary habits and lifestyle factors associated with a high
dietary intake of fruit and vegetables are discussed and used to explain the
disparity between results of observational epidemiologic studies consistently
showing antioxidative vitamins to exert a protective effect on chronic diseases,
and intervention studies so far not confirming this association. Within the scope
of the "Brandenburger Ernahrungs- und Krebsstudie", the East German contribution
to the European Prospective Investigation into Cancer and Nutrition (EPIC), we
examined whether study participants using supplements on a regular basis-
minerals, vitamins, protein formulation, bran/linseed, fiber, yeast or garlic
pills--differed from those who did not report use of supplements according to
selected lifestyle factors and dietary intake of vitamins, minerals, fiber,
cholesterol, and fat from food. The study sample consisted of 10,522 participants
(4,500 men and 6,022 women) aged 35-65 years enrolled in the cohort from January
1995 to July 1996. Regular intake of one or more supplements during the past year
was reported by 32.6% of women and 25.5% of men. Vitamin supplements were used by
18.8% of the women and 15.8% of the men. Figures for minerals were 14.2% for
women and 8.6% for men, respectively. Garlic pills were taken regularly by 9.7%
of men and 9.3% of women. Prevalence of supplement use was generally higher in
women and was more pronounced in elderly participants. The most frequently used
combinations were vitamin and mineral supplements, followed by a combination of
garlic and either vitamin or mineral supplements. Increased use of supplements
was significantly associated with higher level of education attained, regular
engagement in sporting activities, health complaints, and dietary change during
the previous year. No association between use of supplements and smoking status
nor elevated alcohol consumption was observed. Body mass index above 30 was
significantly related to increased intake of garlic pills, and in women to
significantly increased use of vitamin and mineral supplements. For both men and
women, age-adjusted consumption of fruit and vegetables and intake of vitamins,
minerals, and fiber from food was higher for participants using mineral but also
vitamin supplements compared to those who did not use these supplements. For the
cohort of the "Brandenburger Ernahrungs- und Krebsstudie" we observed on the one
hand that age, gender, and health-conscious lifestyle factors were related to
supplement use. On the other hand presence of subjective health complaints was
related to supplement use, especially for use of vitamins and minerals.
Participants, who regularly consumed minerals and vitamins were also shown to
have a higher intake of foods and nutrients considered to exert an antioxidative
effect.
PMID- 9556867
TI - Energy intake of 1 to 18 year old German children and adolescents.
AB - In a sample of 695 healthy well-nourished German children and adolescents
covering the total age range from 1 to 18 years, 3d weighed diet records were
collected and measurements of body height and weight were taken. 10% non
plausible records (reported energy intake (EI):estimated basal metabolic rate
(BMR) < Cut off 1.06) were excluded from further analysis. The rate of non
plausible records was low in the childhood age groups (2-6%), higher in the male
(10%), and highest in the female adolescents (30%). Recalculation of age and sex
specific cut offs based on assumed light physical activity levels (PAL) reduced
the exclusion rate to 6.5% (total) and 20% (female adolescents). The reported
energy intake of the total sample based on plausible records (n = 627, EI:BMR >
or = 1.06) was close to the new estimations of energy requirements assuming light
physical activity which are proposed for the revision of the current FAO/WHO
energy requirements. The sample was of normal height and weight compared to the
Netherlands growth references. For a definite interpretation of the low reported
energy intake in the context of health promoting physical activity patterns of
children and adolescents more scientific evidence should be available.
PMID- 9556865
TI - [Comparison of gastric emptying, blood glucose, and oro-cecal transit times after
a conventional morning meal and a Kollath breakfast].
AB - Blood glucose kinetics and intestinal transit times were investigated in 12 adult
volunteers aged 28 to 52 years after ingestion of a conventional morning meal
made up of white flour rolls, butter, marmalade, and coffee with sugar as
compared with an isocaloric Kollath-breakfast consisting of whole wheat flakes as
a basis. For estimation of gastric emptying time the sodium-[13C]acetate breath
test technique was used. Oro-coecal transit time and gastric emptying were
determined by simultaneous administration of lactose-[13C]ureide and consecutive
drawings of breath samples in intervals of 15, 30, and 60 min through 12 h. The
13CO2-excess of the breath test samples was measured by continuous flow isotope
ratio mass spectrometry. The postprandial rise in blood glucose following the
ingestion of the Kollath-breakfast was lower as compared with the conventional
morning meal, showing significant differences between the 90 min values and the
area below the blood glucose curve. The half time of gastric emptying was not
different between the two breakfast versions (1.7 vs. 1.6 h). The oro-coecal
transit time averaged out at 4.2 h after the Kollath-breakfast and 5.3 h
following the conventional morning meal. Likewise, there were no significant
differences in the coecal retention time nor in the cumulative percentage of
13CO2-exhalation between the two breakfast versions. Concerning the blood glucose
kinetics the differences in the nutritional physiology between the breakfast
based on whole wheat flakes and the conventional breakfast as claimed by Kollath
were only detectable in outlines in our study. Gastric emptying time showed no
differences between the two breakfast versions.
PMID- 9556868
TI - [Out for appetite regulators].
PMID- 9556869
TI - [Effect of nitrates on arterial blood vessels exemplified by the radial artery].
AB - Nitrates act, in part, by causing systemic venodilation. In addition, nitrates
lead to dilation of arterial conductance vessels. The maximal dilation capacity
and threshold of arterial conductance vessels have so far not been examined
thoroughly. Therefore, we tested the radial artery diameter before and after i.v.
nitroglycerin infusions at increasing dosages (0.015, 0.05, 0.15, 0.5, and 1.5
micrograms/kg/min), 7 min each dose in 28 patients with suspected coronary artery
disease (mean age +/- SEM 58 +/- 2 years) using a high resolution ultrasound
devise. The low doses of 0.05 and 0.15 microgram/kg/min, equal to dose of 2.5
mg/12 hours and 7.5 mg/12 hours in a patient with 70 kg, led to substantial
increases in the cross sectional luminal area of the radial artery of 14.8 +/-
1.5% and 29.3 +/- 2.2%*, (*p < 0.05 vs baseline). The maximal increase (dilatory
capacity) was 53.8 +/- 3.8% (mean diameter at baseline: 2.7 +/- 0.1 mm, maximal
3.4 +/- 0.1 mm, p < 0.001). The nitrate sensitivity of the radial artery was
estimated by calculation of the ED50, the dose that caused half-maximal dilation
of the radial artery. The ED50 of the radial artery was 0.13 +/- 0.003
microgram/kg/min. In conclusion, nitroglycerin leads to a dose dependent
dilatation of peripheral conductance vessels. Low doses of 0.05 and 0.15
microgram/kg/min lead to significant arterial dilation. The maximal dilatory
capacity of the radial artery is 53.8 +/- 3.5%.
PMID- 9556870
TI - [Circulating adhesion molecules (cICAM-1, lcVCAM-1) in patients with suspected
inflammatory heart muscle disease].
AB - Some patients with non-ischemic heart failure show inflammatory changes in the
myocardium which are thought to be of causal or pathogenetic relevance for the
heart failure. The intercellular adhesion molecule-1 (ICAM-1) and the vascular
adhesion molecule-1 (VCAM-1) are membrane proteins with receptor function from
the immunoglobulin superfamily which mediate the vascular adhesion and
transmigration of leucocytes into the tissue and undergo increased expression in
chronic immunological-inflammatory processes. In addition to membrane-bound
adhesion molecules, soluble forms can be detected in serum. In the present study
we investigated the occurrence and the significance of circulating ICAM-1 and
VCAM-1 in 71 patients with non-ischemic heart failure (47 M/24 F, mean age: 55 +/
11 years). METHODS: Serum concentrations of cICAM-1 and cVCAM-1 were analyzed
using ELISA-Kits. The severity of heart failure was assessed in accordance to the
NYHA-classification and to hemodynamic parameters (mean pulmonary pressure, left
ventricular ejection fraction). Inflammatory heart disease was assessed
histologically and immunohistologically (T-lymphocytes > 7.0/mm2, increased
expression of the histocompatibility antigens of class I and II) in right
ventricular endomyocardial biopsies. 16 healthy, age-matched patients (8 M/8 F,
mean age: 55 +/- 6 years, mean ejection fraction 76 +/- 3%) without signs of
inflammation in the myocardium (mean T-lymphocytes < 3.5 cells/mm2, low
expression of HLA-class I and II) served as controls. RESULTS: The mean serum
concentrations of circulating ICAM-1 and VCAM-1 (cICAM-1, cVCAM-1) were higher in
patients with non-ischemic heart failure (372 +/- 107 ng/ml and 949 +/- 439
ng/ml) than controls (264 +/- 37 and 710 +/- 164 ng/ml) (p < 0.05). The mean
concentrations of both adhesion molecules varied as a function of the mean
pulmonary pressure and the left ventricular ejection fracture (for cICAM-1:
Pearson's r: 0.24 and -0.33, p < 0.05; for cVCAM-1: Pearson's r: 0.28 and -0.26,
p < 0.05). In 38% (n = 16) of patients with elevated concentrations of cICAM-1 (>
or = 337 ng/ml) and 41% (n = 7) of those with elevated serum levels of cVCAM-1 (>
or = 1038 ng/ml), the myocardial biopsies showed increased lymphocytic
infiltration between 7 and 22 T-lymphocytes/mm2 and an enhanced expression of the
MHC antigens of class I/II as sign of an activated inflammatory process in the
myocardium. All patients with more than 9.3 T-lymphocytes/mm2 in the myocardium
(n = 7) had higher serum levels of cICAM-1 (447 +/- 146 ng/ml, p < 0.05 compared
to controls) and of cVCAM-1 (1577 +/- 688 ng/ml, p < 0.001). Both adhesion
molecules correlated significantly with the mean number of T-lymphocytes in the
myocardium (Pearson's r: 0.31-0.37, p < 0.05). SUMMARY AND CONCLUSION: The
present study shows that the elevated levels of cICAM-1 and cVCAM-1 are often
found in the serum of patients with non-ischemic heart failure. These raised
serum levels correlate with inflammatory infiltrates in the myocardial tissue and
with the clinical and hemodynamic signs of heart failure, thus, confirming a
connection between heart failure and inflammatory changes in the myocardium.
PMID- 9556871
TI - [Lysis therapy in aortic dissection: by hypertrophic cardiomyopathy simulated
myocardial infarct].
AB - A 52-year-old patient presenting with severe thoracic pain of more than 30
minutes duration and ST-segment elevation > 1 mV in leads V1-3 was given 100 mg
rt-PA. With persisting thoracic pain and ST-segment elevation, coronary
angiography was performed 90 minutes after administration of thrombolytic
therapy. Surprisingly, angiography revealed normal coronary arteries in presence
of marked hypertrophic cardiomyopathy. New onset of thoracic pain after four
hours led to a chest radiograph demonstrating increased mediastinal widening and
new pleural effusion as compared to a baseline chest film prior to rt-PA. Spiral
computed tomography revealed overt Type B aortic dissection with an intimal flap
and communication distal to the origin of the left subclavian artery with signs
of a mediastinal hematoma. Immediate cardiac surgery with replacement of the
dissected aortic segment was successfully performed. A literature review revealed
4% of aortic dissection to present with electrocardiographic signs of acute
myocardial infarction and 13% to have concomitant coronary artery disease;
moreover 34 cases of aortic dissection were misdiagnosed as infarction and
subjected to thrombolytic agents with a mortality of 64% underlining the
importance of exclusion of dissection prior to thrombolytic therapy.
PMID- 9556872
TI - [Progressive cardiomyopathic lentiginosis].
AB - We report on a 30-year-old man with progressive cardiomyopathic lentiginosis.
This syndrome is first described by Polani and Moynahan 1972. They distinguish
between the earlier described multiple lentigines syndrome, the LEOPARD syndrome
(L-entiginosis, E-lectrocardiographic conduction defects, O-cular hypertelorism,
P-ulmonary stenosis, A-bnormalities of genitalia, R-etardation of growth, D
eafness) and the progressive cardiomyopathic syndrome. The progressive
cardiomyopathic syndrome is characterised by multiple symmetrical lentigines,
hypertrophic obstructive cardiomyopathy and retardation of growth. All
characteristics were present in our patient with only mild right ventricular
hypertrophic cardiomyopathy.
PMID- 9556873
TI - [Heart enlargement in an athlete--a diagnostic challenge].
AB - Endurance training can result in an enlargement of the heart. These athlete's
hearts are rarer than generally assumed. Pathological causes, resulting in an
eccentric hypertrophy, have to be considered. We report on a 32 year old athlete
performing approximately 10 hours of endurance training weekly. He consulted a
physician because of a drop in performance. The eccentric left ventricular
hypertrophy, diagnosed by means of echocardiography, was not interpreted as a
solely physiological cardiac adaptation because the ejection fraction did not
increase during exercise (stress-echocardiography), the left ventricular
diastolic function (maximum E/A-ratio) was impaired at rest, and the ergometric
performance was reduced in comparison to the heart size. The invasive diagnostics
including myocardial biopsy demonstrate histologically a focal fibrosis as the
result of former myocarditis. The fibrosis was possibly involved in the genesis
of the eccentric hypertrophy based on structural dilatation through a preferably
mesenchymal lesion. It remains open whether the long-term endurance training had
forced the dilatation. This case demonstrates that pathological causes must be
excluded if in athletes an enlarged heart does not concur together with a clearly
increased ergometric performance. Stress-echocardiography and endomyocardial
biopsy can considerably contribute to the differential diagnosis between
physiological and pathological cardiac hypertrophy.
PMID- 9556874
TI - [Prenatal recording of fetal heart action with magnetocardiography].
AB - Fetal magnetocardiography (fMCG) registers the magnetic field generated by the
fetal heart. In contrast to the fetal electrocardiogram, fECG permits non
invasive registration of fetal heart activity and documentation of all parts of
the PQRST-wave-forms from the second trimenon onwards. This facilitates the
determination of cardiac time intervals and establishment of reference values for
different stages of pregnancy. We examined 53 women in 104 recordings from the
10th week of gestation onwards (1 to 10 recordings per individual). The fMCG (37
magnetic channels, sampling rate 1024 Hz, bandwidth 1-200 Hz) was recorded non
invasively over the mother's abdomen in a magnetically shielded room.
Registration of fetal heart beats was generally successful from the 20/21th week
of gestation onwards. In a few cases, fetal heart beats could be registered as
early as in the 16th week. Cardiac time intervals and amplitudes of fMCG
increased concordantly with fetal growth. Mean P wave duration increased from 31
to 49 ms (p < 0.05), PQ interval from 95 to 107 ms (n.s.) and QRS duration from
36 to 52 ms (p < 0.01). The mean amplitudes of the P and R waves also increased.
FMCG, furthermore permits a prenatal diagnosis of fetal cardiac arrhythmias. We
recorded fetal arrhythmias in 20 cases (26-38th week), including episodes of
ventricular and supraventricular arrhythmias or atrioventricular blockings. Due
to its high resolution, fMCG offers new information on the development of fetal
cardiac activity which cannot be achieved by conventional methods like
cardiotocography or dopplerultrasound. Therefore, fMCG could become a new
diagnostic instrument for monitoring fetal wellbeing during pregnancy.
PMID- 9556875
TI - [Evaluation of coronary artery stenosis with respiratory gated NMR angiography].
AB - Respiratory gated MR coronary angiography is a new MR imaging technique which
permits reconstruction of the coronary arteries from a three-dimensional data set
obtained from contiguous parallel sections. In this study, respiratory gated MR
angiography was applied to assess significant coronary artery stenoses (> or =
50%). MR imaging was performed in 68 patients (50 men, 18 women) who had been
referred to cardiac catheterization because of suspected or known coronary artery
disease. The evaluation of coronary artery stenoses was performed in a blinded
manner in the proximal, middle, and distal vessel segments after multiplanar
coronary reconstruction of the MR images. Of the 680 coronary segments, 275 (40%)
were located outside the imaging volume and were, therefore, excluded from
further analysis. The highest sensitivity for stenosis detection was found in the
proximal left anterior descending (LAD) and right coronary artery (RCA) with 75%
and 71%, respectively. The overall sensitivity, however, was low with 48%. The
overall specificity was 92%. The positive and negative predictive values were 67%
and 85%, respectively. This study shows that significant coronary artery
stenoses, especially in the proximal LAD and RCA, can be correctly identified
using respiratory gated MR angiography. However, further technical improvements
are necessary before this method may become a reliable diagnostic tool in
clinical practice.
PMID- 9556876
TI - [Brief analysis of heart rate variability in for determining prognosis in the
post-myocardial infarct period: methodologically reliable alternative to long
term ECG?].
AB - Heart rate variability (HRV) has been established as an important risk parameter
in patients surviving myocardial infarction. Recently, analysis of HRV
particularly of the standard deviation of NN intervals (SDNN)--from short term
ECG recordings has been proposed as an alternative to that from 24 hour Holter
monitorings. The present study is the first to compare SDNN from short term
recordings to that from 24 hour recordings with respect to risk stratification
after myocardial infarction. In 60 patients at the time of discharge from the
hospital, SDNN from Holter monitoring averaged 93 +/- 30 ms compared to 39 +/- 18
determined from short term recordings. Patients with a prospectively defined
clinical endpoint differed significantly from those with an uneventful course
with respect to age, left ventricular ejection fraction, mean RR interval from
Holter recording (753 +/- 153 vs 921 +/- 132 ms), mean RR from short term
recording (783 +/- 153 vs 914 +/- 163 ms), and SDNN from the Hotler recording (71
+/- 27 vs 97 +/- 29 ms; p < 0.001). However, patients with and without a clinical
event could not be separated by means of SDNN measured from short term ECG
registrations (35 +/- 22 vs 41 +/- 19 ms; p = NS). Thus, SDNN measured from short
term ECG recordings does not seem to be useful regarding risk stratification of
patients after myocardial infarction. Analysis of HRV should be performed using
24 hour Holter monitoring, which provides more information and reflects circadian
fluctuation in autonomic tone.
PMID- 9556877
TI - [Renal urodilatin secretion is associated with diuresis and natriuresis after
spontaneous, supraventricular tachycardia].
AB - Patients with paroxysmal supraventricular tachycardia (SVT) may have a polyuria
after termination of tachycardia. There is increasing evidence that the renal
peptide urodilatin (ANP (95-126))--and not plasma ANP (ANP (99-126))--is the
member of the natriuretic peptide family mediating natriuresis and diuresis in
man. In patients with SVT we, therefore, analyzed the relationship between
diuresis, natriuresis, plasma ANP, urinary urodilatin excretion and renal
excretion of cyclic GMP, the second messenger in the ANP system. During and after
clinical presentation with spontaneously occurring SVT, two patients with AV
nodal and one patient with atrioventricular reentry tachycardia (heart rate 160
to 200 bpm) were studied. Urinary urodilatin excretion was correlated to diuresis
(r = 0.73) and natriuresis (r = 0.93); similarly urinary cyclic GMP excretion was
related to diuresis (r = 0.80) and natriuresis (r = 0.87; p < 0.001,
respectively). In contrast, there was no significant correlation between plasma
ANP concentrations and diuresis (r = 0.28, n.s.) or natriuresis (r = 0.11, n.s.).
As an explorative analysis, stepwise multiple linear regression identified
urinary urodilatin as the most important contributor to diuresis and natriuresis
after SVT. These data on polyuria after spontaneous SVT further support the view
that in man urodilatin is the member of the natriuretic peptide family
participating in kidney physiology.
PMID- 9556878
TI - [Percutaneous transcardiac intraluminal balloon angioplasty for reopening an
arterial thrombosis after percutaneous arterial heart catheterization in a 19
month-old patient with tetralogy of Fallot].
AB - Cardiac catheterization is a common cause of arterial thrombosis in children.
Besides heparin therapy, fibrinolysis plays a major role in the therapeutic
approaches to arterial thrombosis while surgery is rarely performed in pediatric
patients. We report on a 19 month old patient with tetralogy of fallot, who
developed thrombosis of the right femoral artery after a retrograde
interventional cardiac catheterization. We performed an antegrade balloon
angioplasty of his thrombosed femoral artery using a transvenous, transcardial
approach via a ventricular septal defect. There were no complications. Doppler
sonography showed no residual stenosis after 4 months.
PMID- 9556879
TI - [Benign liver tumors].
PMID- 9556880
TI - [Diagnosis of liver tumors--what is necessary for therapy planning?].
AB - For the surgical treatment of liver tumors, two initial steps are necessary:
functional operability must be proven and oncological and local inoperability
must be ruled out. The diagnostic process consists of a series of steps,
beginning with non-invasive procedures such as laboratory findings and
sonography, continuing with CT, CTAP, laparoscopy in the case of hepatic
cirrhosis, up to explorative laparotomy. The potential operability is re-checked
after each step. Punction, MRI and scintigraphy are implemented in special cases.
The early implementation of MRI is of particular value for the diagnosis of
certain benign processes.
PMID- 9556881
TI - [Diagnosis of liver tumors--when is scintigraphy of value?].
AB - This paper illustrates the importance of utilizing radionuclide techniques to
characterize in vivo benign liver masses. Examining the physiologic tumor
function cholescintigraphy offers a highly specific pattern for identifying focal
nodular hyperplasia (FNH): hypervascularisation, hepatocellular uptake and
impaired transport of the bilirubin like tracer documented as trapping in later
images. An hemangioma is diagnosed with high probability in case of a positive
bloodpoolscintigraphy. But false-positive results have been reported. Therefore,
a second unrelated examination, e.g. ultrasound, magnetic resonance imaging or
dynamic computerized tomography is necessary to establish this diagnose in a
sufficient certainty. If complications due to tumor growth are not expected,
both, FNH and hemangioma need no further therapy. High sensitivity is necessary
to establish resectability or tumor spread. Scintigraphic techniques are
advantageous in scanning completely the whole body. On the other hand, there are
limitations as low resolution and anatomical orientation, low specific activity
in the tumor and artificial activity near by the tumor. To measure therapy
effects and to detect recurrencies especially in borderline-cases positron
emission computed tomography (PET)-technology is recommended, because PET offers
a specific-parametric evaluation.
PMID- 9556882
TI - [Ultrasound in diagnosis of benign and malignant liver tumors].
AB - Sonography has a high sensitivity in diagnosing circumscript lesions in the liver
when modern machines are used by a skilled examiner. The exact analysis of the
sonographic imaging characteristics allows definite diagnosis in the majority of
cases. The high prevalence of benign liver tumors has to be considered. It is
substantiated by an evaluation of 731 own patients. The characteristics of the
most important circumscribed liver lesions are presented and suggestions for the
diagnostic work-up are provided.
PMID- 9556883
TI - [Diagnostic imaging of benign and malignant liver tumors: computerized tomography
or magnetic resonance tomography?].
AB - A reliable preoperative detection and characterization of all liver lesions is
necessary for the clarification of the operability of a patient. In patients, who
are considered as good candidates for a partial liver resection, a double spiral
CT with an oral bowel opacification and an intravenous contrast medium
administration is recommended. In those patients, who continue to be candidates
for partial liver resection after CT, a CT arterioportography with arterial and
portalvenous liver enhancement should be performed as the present gold standard
of preoperative liver diagnostics. The aim of CT arterioportography is the
further selection of patients for liver surgery. Because of its high specificity,
MRI is useful for the characterization of liver lesions of unknown histology. For
the differentiation between malignant (metastases) and benign (hemangioma) liver
lesions, MRI is the method of choice. Because of the expected technical
developments of MRI, a short-term comparison of CT and MRI in prospective studies
is necessary.
PMID- 9556884
TI - [Cystic liver, an indication for liver transplantation or decompressive
resection?].
AB - In patients suffering from polycystic liver disease sclerosing therapy,
decompressive hepatic resection and liver transplantation represent the main
therapeutic options. Since 1987, 10 females with highly symptomatic polycystic
liver disease underwent hepatic resection for decompression (five left lateral
bisegmentectomies, one left hemihepatectomy, one right central and three
bilateral atypical resections). Despite of a 0% lethality 3 patients developed
complications, in two cases an abscess had to be drained and in one case a
postoperatively increasing hepatic insufficiency required urgent liver
transplantation. Patient's symptoms were remarkably improved in 8 cases, but only
6 patients had a long lasting benefit over years. One patient was resected a
second time three years after the first operation and is free of symptoms for
another five years. 6/96 the "European Liver Transplant Registry" has listed 81
patients after liver transplantation because of polycystic liver disease. 5-year
survival is 78.2%. So liver transplantation offers a therapeutic alternative for
patients severely suffering from symptoms or increasing hepatic insufficiency.
PMID- 9556885
TI - [Non-parasitic liver cysts: laparoscopic and conventional fenestration].
AB - From 1992 till 1997 10 patients with solitary non-parasitic liver cysts were
treated by laparoscopically fenestration of the cysts. The size of the cysts
varied between 8 and 16 cm (median 13.5). Conversion to laparotomy was required
in one patient because of intraoperative bleeding. In nine patients the
laparoscopic procedure was finished successfully. In these cases we observed no
intraoperative complications (9/10), intraoperative blood loss amounted up to 100
ml. Median operative time amounted to 82.5 minutes (55-155). No postoperative
complications were observed. In two patients a cystadenoma was proven by
postoperative histology, in both cases a liver resection was performed. During a
median follow-up of 33 (2-43) months 2 of 7 patients treated with
laparoscopically fenestration developed a recurrence (28%).
PMID- 9556886
TI - [Diagnostic and therapeutic strategies in hepatocellular adenoma].
AB - While liver hemangioma and focal nodular hyperplasia are not considered an
indication for surgery in asymptomatic patients resection has been recommended
for hepatocellular adenoma because of the risk of rupture and malignant
transformation. Problems arise from differential diagnosis and the appropriate
surgical radicality including the indication for liver transplantation. This
retrospective analysis deals with 58 patients who underwent surgery for
hepatocellular adenoma: resection of different extension: n = 54, liver
transplantation n = 4. In 39.6% of the patients the tumor was an incidental
finding. In 62.0% of the character of the lesion was unclear prior to surgery.
Tumor rupture and bleeding occurred in 17.2%, malignant transformation in 6.9%.
Surgical morbidity was 27.6%, mortality 5.2% with the transplant patients alive
for 1.5, 7, 9 and 10 years. Two and five years after resection 2 patients
developed hepatocellular carcinoma in the liver remnant. The results confirm the
indication for surgery in hepatocellular adenoma. Diagnostic approach for solid
liver tumors without serum increase of tumor markers should rule out FNH and
hemangioma. In all other patients surgery should be considered whenever possible
with the radicality of malignant disease. Liver transplantation can be discussed
even in asymptomatic patients with multiple adenoma.
PMID- 9556887
TI - [Focal nodular hyperplasia and liver cell adenoma: operation or observation?].
AB - PATIENTS: In a 15-year period a total of 146 patients underwent surgery for
benign hepatic tumors, including 54 focal nodular hyperplasias (FNH) and 23
hepatic cell adenomas (65 hemangioma and 4 cholangioma). METHODS: The medical
records of these patients were retrospectively analyzed with respect to tumor
related symptoms, surgical procedures and postoperative complications. RESULTS:
Regardless of the type of the tumor, 70% of the patients had no or only non
specific symptoms. Most frequently, surgery was indicated due to questionable
dignity of the lesion (adenoma 70%, FNH 41%). In hepatic cell adenomas (HCA) also
perforation or bleeding of the tumor (17%) and severe symptoms (13%) required
urgent operation. In two of three cases local excision of the lesion or segmental
hepatic resection were performed, whereas extended resection procedures became
necessary only in 20 (FNH) to 34% (HCA). The mean duration of postoperative
intensive care treatment was significantly shorter in FNH and HCA than in other
benign hepatic tumors (1.0 vs. 2.0 days, p < 0.01). After resection of FNH no
fatalities or significant complications were observed. In HCA morbidity was 13%
without related mortality (hemangioma: 3% mortality; 11% morbidity). CONCLUSION:
The elective resection of benign hepatic tumors can be achieved with very low
mortality and morbidity, and usually provides longterm relief of annoying
symptoms. Whenever HCA is suspected surgery should be performed, since severe
symptoms and spontaneous hemorrhage (30%) are common in this tumor. Also
hepatocellular carcinoma can be excluded only by histologic work-up of the
operative specimen. In focal nodular hyperplasia (FNH), complications are rare
and malignant transformation does not occur even when observation is employed
only. Resection should be restricted to symptomatic or growing tumors with
subsequent cholestasis or to cases with uncertain diagnosis.
PMID- 9556888
TI - [Value of colonoscopy in tumor after-care after colorectal carcinoma].
AB - The significance of colonoscopic follow up is discussed controversially.
Colonoscopy after resection of colorectal cancer offers the possibility of direct
inspection and to take biopsies for the early detection of local recurrence or
additional neoplasms. In a retrospective study we examined the benefit of regular
colonoscopies. Between 1/1995 and 4/1996 237 colonoscopies were performed on 164
patients after resection of colorectal cancer. The evaluation was done due to the
stage of the primary tumor, the age of the patients, the time after operation and
the number of previous colonoscopies. 54 adenomas were found in 35 of 164
patients. 32% of the adenomas were diagnosed in the ascending colon or colon
transversum. Additionally three carcinomas were found. There were two local
recurrences and one metachronous neoplasm. Two patients were diagnosed without
clinical symptoms and were able to undergo potential curative resection again.
Because of the number and the localisation of diagnosed neoplasms colonoscopic
surveillance should be performed every six months in the first two years after
resection of colorectal cancer.
PMID- 9556889
TI - [Detection of hL6-mRNA: new possibilities in serologic tumor diagnosis of
colorectal carcinomas].
AB - A study was performed to detect circulating tumor cells in patients with
colorectal cancer using mRNA coding for the tumor associated antigen L6. The mRNA
was determined by Reverse Transcriptase Polymerase Chain Reaction and gel
electrophoresis. The L6 results were compared with the CEA levels. Peripheral
blood samples were taken from 109 patients with histologically verified
colorectal cancer. Statistics were carried out using CHI Square and Sokal and
Rohlf's-test. Preoperatively 81.65% showed positive L6 mRNA, whereas only 58.7%
had elevated CEA titers (p < 0.05). In all patients of the control group (n = 52)
no L6 was detectable. Concerning our results L6 seems to be a sensitive and
precise tool for diagnosing circulating tumor cells in colorectal cancer.
PMID- 9556890
TI - [10 years results after repair of recurrent problem inguinal hernia with prolene
mesh].
AB - The repair of multiple recurrences of inguinal hernias remains a surgical
challenge. In 38 patients with a problematic recurrent inguinal hernia we
implanted a polypropylene mesh (Prolene) in order to reinforce the transversalis
fascia and to repair the inguinal hernia. 20 of these were medial and 14 lateral
hernias; 4 patients had a combination of both types. All patients were
prospectively included into this study and were seen in median follow-up periods
of 3 and 6 months, as well as 4 and 9 years. As early complications hematoma of
the wound (n = 3), scrotal edema (n = 1), temporary pain at the wound site (n =
12) and paresthesia (n = 13) occurred. Two patients (n = 2) developed a femoral
hernia and one patient suffered from a persisting nerve injury of the
ilioinguinal nerve. Due to the low complication and recurrency rate the tension
free repair with polypropylene mesh is a effective method for treatment of
problematic recurrent hernias.
PMID- 9556891
TI - [The physician's responsibility for patient education--necessity, scope and
modalities].
PMID- 9556892
TI - [Diagnostic imaging in surgery].
PMID- 9556893
TI - [Technique of laparoscopic pancreatocysto-jejunostomy].
AB - Usually the development of a pancreatic pseudocyst in the course of pancreatitis
is followed by surgical intervention. In case of operation an internal drainage
is preferred to an external according to general experience. We have developed a
simplified technique of pancreatocysto-jejunostomy without Braun- or Roux-Y
anastomosis. Here we present our surgical strategy in the laparoscopic technique.
PMID- 9556894
TI - [Abdomino-thoracoscopic esophagus resection--an animal experiment study].
AB - Based on animal trials the presented study results describe a method of abdomino
thoracoscopic oesophagectomy for the treatment of oesophageal carcinoma of the
middle and lower third. Technical details and the advantages of the surgical
procedure, including the avoidance of thoracotomy and the practicability of the
thoracoscopic dissection of the oesophagus are shown. Problems exist in the
salvage of the specimen, especially in the transcervical passage of the
tumorbearing oesophageal part. A final evaluation of the importance of the
minimally invasive techniques in oesophageal surgery should not be given until
the results of clinical studies are available.
PMID- 9556895
TI - [Is there an indication for general perioperative antibiotic prophylaxis in
laparoscopic plastic hernia repair with implantation of alloplastic tissue?].
AB - The implantation of alloplastic material in laparoscopically operated groin
hernias is usually connected with perioperative prophylaxis by antibiotics. We
doubted the usefulness of the general application in these operations. Therefore
we made a prospective randomized study in 80 patients, beginning since April
1996. 40 of them received perioperatively antibiotics, other 40 ones remained
without antibiotics. These 80 patients underwent an unilateral hernioplasty and
were without major anaesthesiologic risk. Both the groups were statistically
comparable. As a result, no patient of both the groups suffered from an
infectious complication. Thus, we can recommend the laparoscopic implantation of
alloplastic meshes in "simple hernias" without perioperative antibiotic
prophylaxis. In risk patients, antibiotics should still given further.
PMID- 9556896
TI - [Inflammatory pseudotumor of the spleen as an incidental asymptomatic finding in
a 44-year-old patient].
AB - In the era of routinely used ultrasound techniques intrasplenic tumors are
diagnosed more frequently. Usually these findings are not combined with specific
symptoms. However, large cysts can lead to malfunctions of nearly located organs
by displacing. Etiopathogenetic findings in our region are mainly non parasitic,
epithelial and traumatic cysts or tumors of the spleen. We describe a large
splenic mass of a 44 years old female patient. Pathological dignity remained
unclear after using sonographic, radiological and clinical techniques. After
uncomplicated total splenectomy the histopathological diagnosis revealed a
benign, pseudoinflammatory tumor of the spleen. Inflammatory pseudotumors are a
benign response to an unknown cause. It must be a main objective of preoperative
diagnostics to distinguish them from malignant processes.
PMID- 9556897
TI - [Lipoma: a rare differential gastrointestinal tumor diagnosis].
AB - This is a case report of a female patient who during a routine follow-up after a
gastrectomy showed a tumor of the ileo-cecal valve, which--according to all
radiologic diagnostic procedures--was highly suspected to be a malignant tumor.
However, the histologic diagnosis was benign lipoma. The incidence and the
characteristics of gastrointestinal lipomas in the actual literature will be
reviewed.
PMID- 9556898
TI - Current aspects of adjuvant therapy of early stage ovarian cancer.
AB - Early ovarian cancer, stages I and II, is a rare presentation of epithelial
ovarian cancer for which adjuvant therapy may have some efficacy. More than two
decades of studies are reviewed and conclusions offered. Additionally, important
issues for the future therapy of this disease are presented.
PMID- 9556899
TI - [Luteal and extraluteal receptors for hCG and LH].
AB - The hCG/LH receptor belongs to the G-protein coupled receptor family. The gene
for the receptor has been localised to chromosome 2p21. In addition to corpus
luteum and testis as the classical target tissues for hCG and LH, hCG/LH
receptors have been described in a variety of non-gonadal human tissues (e.g.
endometrium, myometrium, fallopian tube, placenta, amnion, chorion, prostate,
CNS, adrenal gland). Besides its modulation of endocrine functions, the hCG/LH
receptor does probably transmit growth-factor like activities of hCG and LH in
many of these tissues. Moreover, activating as well as inactivating mutations of
the hCG/LH receptor gene have been described. These mutations are localised
mainly within the transmembrane region of the receptor gene (exon 11) and are
responsible for characteristic diseases such as familiar, male-limited precocious
puberty as well as hypogonadism of both sexes. This review deals with the
molecular biology of the hCG/LH receptor, its distribution within the human body,
its functions as well as with the relevance of mutations. Finally, the
therapeutic use of hCG in the treatment of AIDS-related Kaposis' sarcoma is
discussed.
PMID- 9556900
TI - [Long-term outcome of incontinence and prolapse surgery at the Heidelberg
University Gynecologic Clinic 1980-1992].
AB - OBJECTIVE: Long-term results after different types of operations for urinary
stress incontinence (minimum follow-up: 18 months) as well as multiple risk
factors for the pelvic floor were analysed in a retrospective study. STUDY
DESIGN: Between 1980 and 1992 1283 patients underwent surgery because of urinary
stress incontinence at the University Women's Hospital in Heidelberg. The data of
478 patients, 430 of these after primary and 48 after recurrent surgery, were
evaluated by questionnaires with regard to the long-term-results. RESULTS: 57% of
patients after primary surgical therapy and 37% after recurrent surgery were
cured for longer than 5 years or since the operation. A cure or improvement of
the incontinence could be observed in 80% after primary and in 73% after
recurrent surgery. Among the vaginal approaches for primary surgery the
hysterectomy combined with colporrhaphy was most successful (60% cured or more
than 5 years continent, 80.5% at least improved). The Burch colposuspension
revealed even better results among the abdominal approaches (64% cured or longer
than 5 years continent, 86% at least improved) compared to the Marshall-Marchetti
Krantz procedure with a cure rate of 33%. For therapy of the recurrent urinary
incontinence the abdominal Burch colposuspension showed the best results with
cure rates of 50% and cure or improvement in 75%. Therefore the abdominal
approach seems to be superior to vaginal techniques such as sling operations (33%
cure rate, 67% at least improved) or only re-colporrhaphy (27% cure rate, 78% at
least improved). CONCLUSION: For primary incontinence the hysterectomy with
vaginal repair or the Burch colposuspension have proved to be most successful.
For recurrent urinary incontinence the abdominal colposuspension (Burch
procedure) seems to be superior to other approaches.
PMID- 9556901
TI - [Therapy outcome in stage III (FIGO) ovarian carcinomas at the Leipzig University
Gynecologic Clinic 1976-1982 and 1985-1991].
AB - This retrospective study compares treatment results (median survival time, 5-year
survival rate) of 153 patients diagnosed with FIGO stage III ovarian cancer
treated between 1976 to 1982 (n = 73) and 1985 to 1991 (n = 80) respectively.
Between 1976 to 1982, the median survival time was 12.3 months, while it
increased up to 17.0 months during the period of 1985-1991. The 5-year survival
rate increased from 14.0% to 28.0%. This improvement may be due to a more radical
surgical approach and the use of platinum-based first-line chemotherapy. However,
the difference between the two groups was not statistically significant.
PMID- 9556902
TI - [Bioavailability of 17 beta-estradiol after transdermal administration-
dependence on the patch system].
AB - The objective of this study was to compare the pharmacokinetics of serum
estradiol concentrations after application of two different transdermal estradiol
delivery systems. Ten postmenopausal women (E2 < or = 30 pg/ml; follicle
stimulating hormone > or = 30 mIE/ml) were prospectively randomized to a
crossover treatment protocol separated by a 7-day wash out period. The absorption
of estradiol was measured after application of a patch either containing 4.0 mg
of E2 in a reservoir system or 1.8 mg of E2 in a specially designed matrix
system. Although the increase of serum estradiol concentrations after application
of the patches with the matrix system was slightly delayed, mean E2 levels over
the whole observation period of 80 hours were significantly higher than those
achieved with the reservoir system (difference of mean values: 5.1 pg/ml; p <
0.05). This observation was most striking at the end of the observation period
and after removal of the patches. Yet, fluctuations of hormone concentrations
were greater with the matrix system patches, and the areas under the E2
concentration-time curves were slightly but not significantly increased as
compared to these of the patches with the reservoir system (3211 +/- 584 vs. 2556
+/- 249 pg/ml x h). In conclusion, both transdermal estradiol delivery systems
are well suited for postmenopausal hormone substitution providing stable serum
estradiol concentrations at about 50 pg/ml, with the matrix system possibly
increasing the life span of the patch and thus the recommended application
period.
PMID- 9556903
TI - [Tocolysis with a nitroglycerin patch].
AB - We would like to present a 22 year old nullipara where preterm labor was
successfully tocolysed using a nitro-glycerine path without sequellae side
effects. Potential advantages and disadvantages of a transdermal nitro-glycerine
delivery system in comparison to the commonly used intravenous fenoterol
tocolysis is discussed.
PMID- 9556904
TI - [Tubal pregnancy after tubal sterilization by bipolar electrocoagulation].
AB - Sterilization belongs to the safest contraceptive methods. The most popular
sterilization procedure is by coagulation of the fallopian tube. The failure rate
is mainly attributed to ectopic pregnancies which can lead to the risk of life.
PMID- 9556905
TI - [Results of the marketing research study "Acceptance of physician's office
computer systems"].
AB - We report on a market research study on the acceptance of computer systems in
surgeries. 11,000 returned questionnaires of surgeons--user and nonuser--were
analysed. We found out that most of the surgeons used their computers in a
limited way, i.e. as a device for accounting. Concerning the level of utilisation
there are differentials of Men-Women, West-East and Young-Old. In this study we
also analysed the computer using behaviour of gynaecologic surgeons. As a result
two third of all nonusers are not intending to utilise a computer in the future.
PMID- 9556906
TI - [The Online Multimedica Service].
PMID- 9556907
TI - Resistance to interference in human associative learning: evidence of configural
processing.
AB - In 4 experiments the authors used 2-stage designs to study susceptibility to
interference in human discrimination learning. The experiments used a food
allergy task. In Experiment 1, participants were presented with a discrimination
in Stage 1 in which Food A predicted an allergy outcome (A-->O). In Stage 2, when
combined with Food B, Food A predicted the absence of the allergy (B-->O, AB-->no
O). In the test phase, Food A was found to have retained its Stage 1 association
with the allergy despite the potentially interfering Stage 2 trials. In
Experiment 2, a discrimination between 2 compounds (AB-->O, CD-->no O) remained
intact despite subsequent complete reevaluation of the elements, (A-->no O, B-
>no O, C-->O, D-->O); in Experiments 3 and 4, a discrimination between 2 pairs of
elements (A-->O, B-->O, C-->no O, D-->no O) remained intact despite subsequent
complete reevaluation of the AB and CD compounds, (AB-->no O, CD-->O). These
experiments yielded evidence of remarkable resistance to interference in human
discrimination learning. The results are at variance with the predictions of J.
M. Pearce's (1987, 1994a) configural theory of associative learning.
PMID- 9556908
TI - Context reinforcement degrades discriminative control: a memory approach.
AB - This study measured effects of context reinforcement on a visual discrimination.
Five pigeons responded to 1 key in the presence of 6 shorter wavelengths and to
another key for 6 longer wavelengths. Psychometric functions provided measures of
discriminative sensitivity (d') and overall stimulus control. Sensitivity and
control were slightly but significantly better when 20% of correct choices
yielded reinforcement than when 5% did. Reinforcement of pecks to the sample
stimulus reduced control substantially and sensitivity slightly; noncontingent
reinforcement during intertrial intervals also reduced control, whether such
reinforcement was signaled or not. Accuracy was excellent during an extinction
session, but it fell substantially when reinforcement for sample pecks was added
during choice extinction. Simulations based on a memory model of the
discrimination process reproduced most of the experimental findings.
PMID- 9556909
TI - The role of temporal relationships in the transfer of conditioned inhibition.
AB - Two experiments with rats investigated the temporal relationships under which
conditioned inhibition will transfer to an independently conditioned excitor (CS)
in a summation test. Experiment 1 trained 2 simultaneous inhibitors with either a
trace or delay excitatory CS. Transfer of inhibitory behavioral control depended
on the temporal relationship of the transfer CS to the unconditioned stimulus
(US). Experiment 2 extended these findings by training 2 inhibitors (1
simultaneous and 1 serial) with a single delay excitatory CS. Again, testing with
trace and delay transfer CSs found that transfer of inhibitor control depended on
the temporal relationship of the transfer CS to the US. In both studies, maximal
inhibition was observed when the inhibitor signaled US omission at the same time
as the transfer excitor signaled US presentation. The results are discussed in
terms of the temporal coding hypothesis.
PMID- 9556910
TI - Natural choice in nonhuman primates.
AB - In 5 experiments, 4 monkeys and 1 ape chose between 2 food sources, each held in
1 of the experimenter's hands while he stood in front of a cage. When choosing
between 2 sources of the same food that differed in amount, preference for the
larger amount decreased as the size of each good proportionately increased. A
second finding was that subjects were indifferent between a 2-food mixture and a
single food that was part of the mixture if the single food was the preferred
food of the mixture, a result suggesting the less preferred food had no value.
Experiment 6 replicated these effects in 4 additional monkeys. These effects may
be incompatible with previous theorizing about animal choice and may reflect a
cognitive difference between nonhuman primates and humans.
PMID- 9556911
TI - High-level expression of bovine alpha s1-casein in milk of transgenic mice.
AB - The bovine alpha s1-casein gene, isolated from a cosmid library, was introduced
into the murine germline. Transgene expression occurred in all transgenic mice,
and was confined to the lactating mammary gland. Half of the mouse lines (five
out of ten) expressed at relatively high expression levels (> 1 mg ml-1). The
highest levels of expression were obtained with a transgene containing 14.2 kb of
5' flanking sequence, in two cases expression levels comparable to (10 mg ml-1)
or well above (20 mg ml-1) alpha s1-casein levels in bovine milk were obtained.
Transcription initiation occurred at the same site in the bovine alpha s1-casein
gene in transgenic mouse as in the cow. A marked induction of expression occurred
at parturition rather than at mid-pregnancy, and thus resembled the bovine rather
than the murine developmental expression pattern. Bovine alpha s1-casein specific
immunoblotting and RIA were developed for characterization and quantification of
the recombinant protein. Using these assays, the properties of the recombinant
protein could not be distinguished from those of the natural bovine protein. In
spite of the high-level tissue-specific and correctly regulated developmental
expression of the transgene, expression levels were integration-site dependent.
This may indicate that not all cis-acting regulatory elements involved in bovine
alpha s1-casein expression were included in the transgene.
PMID- 9556912
TI - Insulin and prolactin synergize to induce translation of human serum albumin in
the mammary gland of transgenic mice.
AB - A dramatic uncoupling of the expression of chimaeric beta-lactoglobulin
(BLG)/human serum albumin (HSA) gene constructs at the RNA and protein levels was
observed in cultured mammary explants of virgin transgenic mice. Upon
explantation, both HSA RNA and protein were expressed at high levels. However,
when the explants were grown in hormone-free medium. HSA RNA continued to
accumulate, whereas the synthesis of the corresponding protein was dependent on
the presence of insulin and prolactin with a minor contribution of
hydrocortisone. The untranslated HSA RNA was indistinguishable from its
translatable counterpart in its mobility on agarose gels, was transported
normally from the nucleus to the cytoplasm and was translated efficiently in
rabbit reticulocyte lysate. In the presence of cycloheximide, HSA RNA rapidly
disappeared suggesting a dependency on ongoing protein synthesis. Its estimated
half-life of 5-6 h in hormone-free medium increased significantly in the presence
of insulin, hydrocortisone and prolactin and was comparable to that of beta
casein RNA. The uncoupling of the expression of the BLG/HSA transgenes at the RNA
and protein levels was also confirmed by in situ hybridization and
immunohystochemistry on sections from virgin mammary explants. HSA synthesis was
initiated within 13 h of the addition of insulin and prolactin in explants that
had accumulated untranslated HSA RNA and was fourfold higher than that observed
with insulin alone. Addition of hydrocortisone contributed to an additional 20%
in HSA synthesis. We believe this is the first demonstration of translational
control of exogenous milk protein gene expression in the mammary gland of
transgenic animals.
PMID- 9556913
TI - Regulation of CAT protein by ribozyme and antisense mRNA in transgenic mice.
AB - Transgenic mouse lines were engineered to express stably antisense mRNA or
antisense mRNA containing catalytic ribozyme (rbz) structures complementary to
bacterial chloramphenicol acetyltransferase (CAT) gene transcripts. One
transgenic line expressed antisense mRNA that specifically targeted full-length
CAT coding sequences (ACAT). Another transgenic line expressed full-length
antisense CAT mRNA which was modified by mutagensis to include four rbz cassettes
(rbz-ACAT) in order to compare antisense versus antisense-rbz function in vivo.
Preliminary data were also collected from a transgenic mouse line expressing
antisense mRNA targeting 72% of the 5' region of CAT coding sequences (5' ACAT).
All constructs contained similar control elements in their design. Promoter
elements were derived from the bovine alpha s1-casein gene, while the small t
intron and 3' control sequences were derived from SV40. The ability of these
various constructs to down-regulate CAT protein levels was compared by analysis
of CAT protein production in lactating double-hemizygous transgenic female mice.
Every double-hemizygous mouse analysed expressed mRNA from the alpha s1-casein
CAT construct (Clarke et al., 1994) and equivalent levels of mRNA from one of the
three antisense constructs. Transgenic mouse lines expressing both ACAT and CAT
mRNA down-regulated CAT protein levels by 90% of that found in the CAT only
transgenic population. Similarly, double-hemizygous transgenic lines expressing
both rbz-ACAT and CAT mRNA regulated CAT protein levels by 87%. Preliminary data
suggests that expression of mRNA from 5' ACAT/CAT double-hemizygote mice allowed
approximately 67% down-regulation of normal CAT protein levels. We conclude that
incorporation of multiple ribozymes within the full-length antisense CAT
construct does not enhance the effectiveness of antisense mRNA in the down
regulation of CAT protein production in our system.
PMID- 9556914
TI - Differential in vivo activities of bovine growth hormone analogues.
AB - In rodents, bovine (b) growth hormone (GH) binds only to GH receptors, while
human (h) GH binds to both GH and PRL receptors. The phenotypic consequences of
expression of bGH and hGH in transgenic mice are different and, in some cases,
opposite. In the present study, site-directed in vitro mutagenesis of the bGH
gene was used systematically to eliminate its differences from hGH at one, two,
three or four suspected of conferring lactogenic activity: D11, H18, S57 and T60,
respectively (corresponding to sites 12, 19, 57 and 60 of the bGH molecule). The
resulting bGH analogues were expressed in cell lines and in transgenic mice. All
of the seven bGH analogues produced retained their ability to bind to GH
receptors and exhibited somatogenic activity in vitro and in vivo. However, none
of them were able to bind to PRL receptors or to elicit detectable lactogenic
response in vitro. Transgenic animals expressing any of the generated analogues
were characterized by gigantism and splanchnomegaly. The effects of expression of
each of the double, triple or quadruple mutants on the seminal vesicle weight
resembled the effects of wild-type hGH and differed from the effects of
expression of wild-type bGH. There were differences between the effects of the
expression of different bGH analogues on plasma PRL levels and on the PRL
response to pharmacological blockade of catecholamine synthesis. Plasma LH levels
in ovariectomized females were suppressed by several of the analogues tested, an
effect not seen in animals expressing wild-type bGH or hGH. Dopamine turnover in
the median eminence of male mice was also altered in animals expressing different
bGH analogues but not in those expressing wild-type bGH or hGH. In ovariectomized
females, the effects of different bGH analogs on the turnover of dopamine and
norepinephrine in the median eminence included changes resembling those detected
in animals expressing hGH, as well as alterations differing from the effects of
both bGH and hGH. The results indicate that biological actions of these bGH
analogues cannot be characterized simply in terms of enhanced or reduced
somatogenic or lactogenic activity and raise a possibility that different sites,
domains or features of tri-dimensional structure of GH are involved in its
actions on different cellular targets.
PMID- 9556915
TI - Transgenic farm animals get off the ground. Transgenic Animals in Agriculture,
Conference Tahoe City, California, USA. August 24-27, 1997.
PMID- 9556916
TI - Intermediary metabolism of fast-growth tumor cells.
AB - Tumor cells show several modifications in their metabolism in comparison with
normal cells. In particular, tumor cells show an accelerated glycolysis and a low
O2 dependence, which are metabolic modifications involved in the resistance of
many tumor cell lines to radiation. Thus, a strategy to enhance the
radiosensitivity could be the transformation of the glycolytic metabolism of
tumor cells into an oxidative type of metabolism, i.e., to induce the ATP supply
to depend solely on oxidative phosphorylation. Therefore, this review emphasizes
the relevance of oxidative phosphorylation on tumor cells regarding (a) its
contribution to ATP supply for cell duplication during the proliferative phase,
and (b) the possible therapeutic implications of having oxidative rather than
glycolytic tumor cells.
PMID- 9556917
TI - Differential effects of glycosylated and non-glycosylated porcine prolactin on
estradiol and progesterone secretion by rat granulosa cells in culture.
AB - BACKGROUND: The objective was to better understand the interactions between
prolactin and ovarian function. METHODS: The effects of two variants of porcine
prolactin (pPRL) on estradiol (E2) and progesterone (P4) production by rat
granulosa cells in culture were studied using granulosa cells obtained from large
preovulatory follicles of pregnant mare serum gonadotropin (PMSG)-treated
immature Sprague-Dawley rats. Cultures were performed in the absence or presence
of hCG (0.1 IU/ml) and different concentrations of either glycosylated and non
glycosylated (g-pPRL and ng-pPRL, respectively) pPRL. RESULTS: Dose-response
studies showed that maximal stimulation occurred in all instances with g-pPRL at
the dose of 10 ng/mL during the 72-h treatment period. In the case of E2, the
maximal response was obtained in hCG-stimulated cultures, whereas the response of
P4 was higher in cultures stimulated with g-pPRL in the absence of hCG. In a
similar manner, the non-glycosylated form of pPRL increased, although to a lesser
extent, the secretion of P4 only in those cultures incubated in the absence of
hCG. In contrast to these observations, ng-pPRL was about twice as active than
the glycosylated form on the stimulation of growth of Nb2 lymphoma cells.
CONCLUSIONS: These data point out that glycosylation is involved in the
differential effects of pPRL on ovarian steroidogenesis and support the role of
carbohydrates in the structural-functional polymorphic nature of the hormone.
PMID- 9556918
TI - Effect of policosanol on arterial blood pressure in rats. Study of the
pharmacological interaction with nifedipine and propranolol.
AB - BACKGROUND: Policosanol is a natural mixture of higher aliphatic primary alcohols
isolated from sugar cane wax (Saccharum officinarum, L) with cholesterol-lowering
effects demonstrated in experimental models and in patients with type II
hyperlipoproteinemia. The purpose of this study is to determine the effect of
policosanol on arterial blood pressure and its interaction with propranolol and
nifedipine. METHODS: Single doses of policosanol (25, 50 and 200 mg/kg) orally
administered to spontaneously hypertensive rats (SHR) did not significantly
change arterial pressure. RESULTS: The study on pharmacological interactions
between policosanol (200 mg/kg) and both antihypertensive agents revealed that
pretreatment with high doses of policosanol significantly increased propranolol
induced hypotensive effects, while the effects of nifedipine remained unchanged.
CONCLUSIONS: Our results show that policosanol does not antagonize the
hypotensive effect of beta-blockers but it can increase the hypotensive effect of
beta-blockers without modifying cardiac frequency.
PMID- 9556919
TI - Leucine catabolism in mammary tissue, liver and skeletal muscle of dam rat during
lactation and weaning.
AB - BACKGROUND: This study was designed to determine the effect of lactation and
weaning on the catabolism of branched-chain amino acids (BCAA). METHODS: Rates of
transamination and oxidation of leucine and branched chain alpha-ketoacid
dehydrogenase (BCKD) activity were measured in homogenates of mammary gland,
skeletal muscle and liver on day 12 of lactation and 24 h after separation of
dams from the litter (weaning). RESULTS: Lactating dams consumed 250% more
protein than control rats, extra protein is required for protein synthesis by the
mammary gland, the extent to which the excess of amino acids consumed during
lactation is utilized or oxidized by different tissues is not known. The rate of
transamination of [1-14C] leucine by mammary tissue of lactating dams was sixfold
higher than in virgin rats. The rate of transamination remained elevated fourfold
in postweaning dams. Rates of transamination were three times higher in mammary
tissue than in muscle of lactating dams. Rate of oxidation [1-14C] leucine by
lactating mammary tissue was tenfold higher than in control tissue. CONCLUSIONS:
The capacity of mammary tissue for transamination and oxidation of leucine
increased greatly during lactation, suggesting that the mammary gland may play an
important role in the catabolism of BCAA during lactation.
PMID- 9556920
TI - Predictive value of creatine kinase (CK)-MB for diagnosis of acute myocardial
infarction after major noncardiac surgery.
AB - BACKGROUND: The aim of this study was to provide insight into the interpretation
of CK-MB data after major noncardiac surgery. METHODS: Some 3,321 patients who
underwent major non-emergent noncardiac procedures (orthopedic 31%, intrathoracic
12%, vascular 22%, other 35%) were studied. All patients had at least two CK
samples measured postoperatively. RESULTS: Acute myocardial infarction was
diagnosed in 43 (1.3%) patients using study criteria including CK-MB and
electrocardiographic data. All of the various threshold values of peak CK-MB
values and peak CK-MB as a percentage of total CK had poor positive predictive
values because of high false positive rates and the low rate of acute myocardial
infarction. CONCLUSION: These data demonstrate the need for markers of myocardial
injury with greater cardiac specificity after noncardiac surgery.
PMID- 9556921
TI - Dynamic and randomized perturbed posturography in the follow-up of patients with
polyneuropathy.
AB - BACKGROUND: The purpose of the study was to investigate and follow the
equilibrium performance of patients with chronic polyneuropathy using Dynamic
Posturography (DP) and Randomized Perturbed Posturography (RPP). METHODS:
Fourteen patients with chronic polyneuropathy, aged 53-83 years, were evaluated
by clinical investigation, vibrametry, DP and RPP in a six-year follow-up. The
patient group was compared to 14 healthy volunteers, aged 63-80 years. The DP
comprises a sensory organization (SO) part in which the platform and visual
surround are stable or referenced to the patient sway, with eyes open or closed.
In a movement coordination (MC) part, the platform makes active movements. In
RPP, the platform moves randomly in the anteroposterior direction. RESULTS:
Comparison between the first and second study of the patient group showed
decreased equilibrium scores under stable conditions and when vision was
excluded. Compared with controls, the patients showed significantly lower scores
in most of the SO test conditions except when the platform was sway referenced
with stable surround; in the MC part, the patients showed prolonged muscular
response latencies, and in the RPP, the patients showed increased sway areas.
CONCLUSIONS: The results are further evidence that proprioception is probably the
single most important sensory input for postural control in humans. Posturography
proved to be an objective method to study and follow the equilibrium performance
in patients with PN.
PMID- 9556922
TI - Plasmatic levels of theophylline in asthmatic patients. Comparative evaluations
of two different methods.
AB - BACKGROUND: There are several criteria to choose an analytical method for drug
monitoring. Such methods have to comply with standard values and quality control
as well as other subjective features such as cost and the time consumed to obtain
quantification (TCOQ). The purpose of this work was to compare two methods used
to quantify plasmatic levels of theophylline in asthmatic patients as support to
choose the best method. METHODS: We analyzed plasma samples from 30 asthmatic
pediatric patients at the pediatric service of the Hospital General de Mexico,
who were under treatment with theophylline and whose monitoring of drug levels
was indicated. Plasma samples were analyzed by liquid chromatography (HPLC) and
by enzyme immunoassay (EMIT), and were then compared with respect to reliability,
as well as cost and TCOQ. RESULTS: The difference of the plasmatic levels of
theophylline quantified by both methods was not significant (p > 0.05); both
showed a good correlation index (r = 0.995), and both were reliable based on
other validity parameters. However, TCOQ for HPLC was 20.0 +/- 5.5 min (mean +/-
SD) for each sample analyzed, and 2.3 +/- 0.5 for EMIT. With respect to the cost
of each analysis, HPLC required 2.3 +/- 0.5 USD (mean +/- SD) and EMIT 4.5 +/-
0.3 USD. CONCLUSIONS: Analytical methods used to quantify plasmatic levels of
theophylline based on HPLC and EMIT proved to be suitable, because they fulfilled
the criteria and standard values regarding quality control, although
laboratorists have to select subjectively the best method according to cost and
TCOQ, since HPLC was less expensive, and EMIT was more rapid.
PMID- 9556923
TI - Epidermal growth factor and gastrin in scleroderma/CREST syndrome.
AB - BACKGROUND: The objective of this study was to determine levels of epidermal
growth factor (EGF) and gastrin (GA) in saliva, serum, and urine in scleroderma
(Scl) and CREST syndrome. METHODS: EGF and GA levels were measured by
radioimmunoassay in saliva, serum and urine in 10 patients (51 years, median;
range, 35-66 years); 9 females and 1 male with Scl, 3 females with CREST
syndrome, and 18 age- and sex-matched controls, 17 females and 1 male free of any
systemic inflammatory disease. RESULTS: In serum, the EGF was lower in Scl/CREST
than controls (p = 0.02), while GA serum concentrations were higher in Scl/CREST
(p = 0.02). In urine, EGF in Scl/CREST was slightly lower than controls (p = NS)
and GA concentrations were higher than controls (p = 0.03). In saliva, the EGF
levels in Scl/CREST were also slightly lower than controls (p = NS), while GA
concentrations in both Scl/CREST and controls were not different (p = NS).
CONCLUSIONS: Low concentrations of EGF in serum probably play a role in the
pathogenesis of Scl/CREST. GA concentration can be increased as a consequence of
the low levels of EGF because of the structural homology of this peptide with
urogastrone, a GA inhibitor factor.
PMID- 9556924
TI - Gas exchange at rest during simulated altitude in patients with chronic lung
disease.
AB - BACKGROUND: To characterize the gasometric and oximetric response to simulated
altitudes of 3,100 m and sea level of patients with Chronic Obstructive Pulmonary
Disease (COPD) and Interstitial Lung Disease (ILD) studied at 2,240 m above sea
level. METHODS: Consecutive stable patients with COPD and ILD were studied at the
National Institute of Respiratory Diseases, a referral center for pulmonary
diseases in Mexico City, and a healthy control group. The patients breathed room
air (FIO2 = 0.21), for at least 15 min, then, a hypoxic mixture (FIO2 = 0.18,
simulating 3,100 m), and finally, a hyperoxic mixture (FIO2 = 0.28, simulating
sea level). Arterial blood gases and oxygen saturation were measured by a pulse
oximeter at the end of each stage. RESULTS: Twelve patients with COPD, 13
patients with ILD and 11 healthy controls were studied. The PaCO2 and pH were
constant in the three study stages in both groups of patients and controls. A
slope of PaO2 vs. altitude of 9 Torr per Km was found for each of the study's
patients, either by simple linear regression or multiple regression, which is
identical to that previously obtained at sea level with COPD patients (Gong et
al.). Oxygen desaturation per Km of altitude change was alinear, higher for the
hypoxic than for the hyperoxic challenge and more severe for the most hypoxic
patients. CONCLUSIONS: Exposure tests to simulated altitudes are safe, and orient
the physician concerning the patient's condition at altitudes different from the
place where the measurement is done. Alveolar ventilation remains constant
despite hypoxia or hyperoxia during the challenges. A computer model of the lung
reproduces many of the findings in the challenges of this study.
PMID- 9556925
TI - Epidemiology of lymphomas in children residing in Mexico City.
AB - BACKGROUND: The aim of this paper is to present the epidemiological
characteristics of time, subject and place of lymphomas in children residing in
Mexico City, Mexico (MC). METHODS: The type of study was a retrospective hospital
survey. All records of children with lymphomas registered between 1982 and 1991
at the main hospitals that treat children with cancer in MC were reviewed.
Neoplasms were classified into Hodgkin's disease (HD) and non-Hodgkin's lymphomas
(NonHL). Trend and incidence by sex, age and area of residence in MC were
evaluated. Time of diagnosis, as well as parental occupation and educational
level, were registered. RESULTS: A trend was only observed for HD in the total
group (r:0.62; P = 0.05). In 1991, incidence for HD was 6.12 (rates x 10(6)) and
3.87 for NonHL. The highest average incidence was found in children 5-9 years of
age (5.40) for HD, and in the age groups of 1-4 and 5-9 (3.10 and 3.33,
respectively), for NonHL. Incidence was higher among boys for both lymphoma
categories, but the male-to-female ratio was much higher in HD. Time of
diagnosis, incidence in terms of place of residence, and parental educational
level and occupation also differed from one lymphoma category to the other.
CONCLUSION: The epidemiology of HD is different from that of NonHL, both showing
a pattern similar to that of Latin American children.
PMID- 9556926
TI - Detection of antibodies against Trypanosoma cruzi in donors from a blood bank in
Cuernavaca, Morelos, Mexico.
AB - BACKGROUND: Surveys carried out in the Mexican state of Morelos indicate the
presence of Chagas' disease. The aim of this work was to perform a pilot study to
detect the presence of antibodies against Trypanosoma cruzi in donors from the
Blood Bank at the Regional Hospital of Cuernavaca, Morelos. METHODS: From March
September 1993, blood samples from 318 donors (284 men and 34 women) were
collected. The of age range donors was from 18-45 years. Antibodies against T.
cruzi were determined using a commercial ELISA kit. RESULTS: Fifty-four (17%)
serum samples had antibodies against T. cruzi: 34 out of 284 men, and 20 out of
34 women were positive (11.9 and 58.8%, respectively). Of the 128 individuals who
donated blood more than once, 9 (7%) were positive and had previously donated
blood from 1-4 times. Antibodies against Leishmania sp. and T. rangeli were not
determined. CONCLUSIONS: Based on the results of this study, procedures to detect
antibodies against T. cruzi in blood donors and the application of a
questionnaire inquiring into risk factors for T. cruzi infection should be
implemented.
PMID- 9556927
TI - Anterior choroidal artery territory infarction: a case report and review.
AB - A patient was admitted with frequent episodes of transient neurologic symptoms
formerly described as "capsular warning syndrome". The neurologic examination
revealed right-sided hemiplegia, diminished pinprick, decreased light touch and
extensor right plantar response. The only documented risk factor was
hypertriglyceridemia, and diagnosis was anterior choroidal artery territory
infarction. This report critically reviews the clinical features of this vascular
lesion and the MRI findings.
PMID- 9556928
TI - Evaluation of the cryohemolysis test for hereditary spherocytosis.
PMID- 9556929
TI - [Continuous blood pressure monitoring during stress ECG].
AB - Using conventional methods (Riva-Rocci, oscillometric), non-invasive blood
pressure measurements allow readings to be obtained only at discrete times, at
intervals of at least one or two minutes. During exercise ECG recording,
continuous blood pressure monitoring capable of detecting brief blood pressure
changes is desirable. Our new approach is based on the known dependency of pulse
wave velocity and blood pressure. The pulse transit time is derived from an ECG
and a simultaneously recorded photoplethysmogram, and the blood pressure is
computed using a linear model. In addition to the conventional ECG device, only a
finger or ear sensor is required, so that the application of the method is quite
easy. Results indicating dynamic blood pressure variations during an exercise ECG
are presented.
PMID- 9556930
TI - [Measuring breath alcohol concentration during artificial ventilation. Model
studies of the effect of temperature and humidity on measurements by various
sampling systems].
AB - The present paper examined the question as to the extent to which the taking of
gas samples for the purpose of measuring the breath alcohol concentration (BAC)
in the expired air of patients on artificial respiration is influenced by
temperature and humidity. For this purpose a lung model standardized at different
alcohol concentrations was used, in which the temperature (T: 25, 30 and 35
degrees C) and the relative humidity (RH: 50, 75 and 95%) were varied.
PMID- 9556931
TI - Electron-microscopic examination of silicon-carbide-coated endovascular stents.
AB - The problem of restenosis in blood vessels after balloon angioplasty could not be
overcome by the use of metallic stents as had been anticipated. With respect to
restenosis, clinical and experimental results now focus the attention on the risk
that stents could initiate or potentiate vascular lesions, especially by
inhomogenous stent expansion. Here the stent design seems to dominante depending
on the use of well rounded structural stent-elements with appropriate surfaces
and a material deposition which is compatible with a homogeneous stent expansion.
With respect to hemocompatibility the surface quality of the stents is of great
importance, too. Coating of surfaces of metallic stents for the enhancement of
hemocompatibility might create new risks of blood vessel damages and requires a
careful consideration of the co-expansional behaviour of the metallic substrate
and the coating material. With these problems in mind the surface coated stent
Tensum 3 of the Biotronik company was investigated.
PMID- 9556932
TI - [Intrafemoral pressure measurement in different cement removal procedures during
hip prosthesis replacement operations--experimental study with cadaver femora].
AB - During primary hip arthroplasty an increase in intramedullary pressure (IMP) of
up to 1000 mm Hg can be observed. As a result of this increased intrafemoral
pressure, intramedullary constituents can pass into the venous circulation
creating a risk of fat embolism syndrome (FES). In the present experimental study
on 9 femora obtained from human corpses, we investigated the question as to
whether various methods of cement removal during total hip revision arthroplasty
are also associated with increased intramedullary pressure and a risk of FES. The
IMP was recorded with a standardized experimental set-up during removal of cement
from the proximal and distal regions, including removal of the cement "tip" and
the intramedullary plug. The methods employed for this purpose included the
osteotome and mallet, a compressed air powered chisel, and a modified
intracorporal lithotripter. All the methods induced fluctuations in the IMP the
highest values being recorded for the conventional method using the osteotome and
mallet (45 mm Hg) and the lowest values for the intracorporeal lithotripter (7.5
mm Hg). Working on the distal cement caused higher fluctuations in comparison
with the proximal region. The study failed to reveal any increase in mean IMP,
and all measured values were in the low pressure range (considerably below 150 mm
Hg). While there seems to be no apparent risk of an FES developing during removal
of cement, careless manipulation of the distal cement plug may result in higher
intrafemoral pressures--above 150 mm Hg--thus increasing the risk of a fat
embolism syndrome.
PMID- 9556933
TI - [Effect of surface hardness of the femur head prosthesis on abrasive wear forces
in pairing with polyethylene for artificial hip joints].
AB - The problem of wear has become a major issue in total joint replacement. A
correlation between biomaterial hardness and abrasive wear mechanisms may be
assumed. To investigate the effect of hardness, cobalt-chromium (CoCr) femoral
heads coated with hard amorphous-hydrogenated carbon (a-CH) were tested against
uncoated heads under conditions of abrasive wear. The heads were paired with
polyethylene (UHMWPE) discs in a ball-on-disc machine. The abrasive wear
resistance of the heads increased with surface hardness, and qualitatively
differing patterns of wear were observed on the UHMWPE surfaces, depending on the
abrasive wear of the matching areas of the heads. Accordingly, when evaluating
biomaterials for their suitability for use in total joint replacement, hardness
should be considered one of the relevant factors among the material properties
with an influence on wear.
PMID- 9556935
TI - Enhancing management of cancer pain: contribution of the internal working model.
AB - The purpose of this article is to organize the current knowledge regarding
patient-related factors that can have an impact on cancer pain management by
using the construct of the internal working model: a theoretical framework for
integrating current knowledge and interpreting and predicting factors related to
the management of cancer pain. These factors include patients' beliefs and
misconceptions about cancer pain and pain treatment, meanings that patients
ascribe to their pain, their expectations about pain relief, and communication
between patients and clinicians about pain control. The construct of the internal
working model predicts and explains factors related to pain control and provides
implications for practice. It has potential utility in enhancing the quality of
cancer pain management.
PMID- 9556934
TI - Nurses' and pharmacists' exposure to antineoplastic drugs: findings from
industrial hygiene scans and urine mutagenicity tests.
AB - Data from 83 nurses and pharmacists handling antineoplastic drugs and 35
nurse/pharmacist controls who participated in a national study of antineoplastic
drug-handling risks were examined to investigate antineoplastic drug exposure.
Measures of external exposure included self-completion drug logs and industrial
hygiene scans conducted in clinical settings. Internal exposure was measured by
urine mutagenicity tests on end-of-week 24-hour urine specimens. To control for
potential confounders, the staff was asked to complete food and hobby diaries and
to avoid identified mutagenic substances for 1 week before collection of 24-hour
urine samples. On the scans of the drug handlers, 13% showed one or more spots of
drug contamination on gloved and ungloved hands, gowns, or shoes. Of the 24-hour
urine samples, 15% were mutagenic for Salmonella typhimurium: Rates did not
differ significantly for drug handlers and controls. Among nurses who both
prepared and administered antineoplastics, those with positive mutagenicity tests
handled more doses of the drugs, used less skin protection, and had more skin
contact with the drugs than those with negative tests. Nurses who only
administered the drugs and had positive mutagenicity tests handled fewer doses of
drugs than those with negative tests, but they also reported less use of
protection and more skin contact. For both groups of nurses, skin contact with
antineoplastics was associated with positive mutagenicity test results (p <
0.01).
PMID- 9556936
TI - Spouses' view during their partners' illness and treatment.
AB - Nine spouses of people who had suffered from acute leukemia or highly malignant
lymphoma were interviewed about their everyday life experiences throughout their
partner's illness and treatment, and concerning their view of the professional
care provided. The transcribed texts were subjected to phenomenological
hermeneutic analysis. The spouses felt they were in a situation of overall severe
crisis (i.e., experiencing feelings of distress, restrictions, and limited or
lack of support). The analysis revealed three family types: the couple acting as
a unit, the couple acting independently on equal terms, and the couple acting
separately with the spouse in a subordinate position. The spouses' evaluation of
the entire experience varied according to the family type and the spouses'
personal resources, which influenced the availability and utilization of their
social network as well as the support of health-care staff. Contentment was
related to the couple acting as a unit or the couple acting independently on
equal terms and taking control over the situation, actively asking for support
and requiring the staff to meet their needs. Discontentment was related to
subordination of the spouse to the partner or to health-care staff, and failure
of the couple to obtain support between them or from others. Empowering the
spouses may mean helping them develop their skills, providing them with
opportunities and authority, and assisting them in gaining access to resources
based on knowledge of the family type, the consent of the partner, and the
spouse's freedom to make choices. This may well lead to increased efficiency and
have positive effects for the patient, for the spouse, and for them both as a
couple.
PMID- 9556937
TI - Involvement of relatives in the care of the dying in different care cultures:
involvement in the dark or in the light?
AB - The aim of this prospective study was to increase existing knowledge about the
involvement of relatives in care of the dying and to shed light on the relatives'
sense of coherence. Six relatives were followed via qualitative interviews during
the patients' final period of life and after their deaths. The patients died in
different forms of care: surgical department, nursing home, inpatient hospice
ward, and at home. What the relatives had in common was that they had, in
different ways, followed the patient from the first symptoms, through different
forms of care, up until death. Some participated very actively in the care.
Relatives' involvement in care can be described as involvement in the light or
involvement in the dark. Involvement in the light is based on a trusting
relationship between the family and the staff. Involvement in the dark is based
on insufficient interplay and collaboration, in which the relatives are not seen
or acknowledged by the staff, but instead must grope around in the dark when they
try to support the patient. Rapid course of illness can be a risk factor for
involvement in the dark. It seems that the relatives' sense of coherence was an
important factor enabling them to be involved in the light. Humanistic care can
constitute a buffer, thereby increasing the possibilities for relatives to be
involved in the light.
PMID- 9556938
TI - Information needs, uncertainty, and anxiety in women who had a breast biopsy with
benign outcome.
AB - A retrospective, descriptive study to determine the information needs of women
who underwent a breast biopsy with a benign outcome and to ascertain the levels
of uncertainty and anxiety they experienced was conducted in two community health
care sites in Winnipeg, Manitoba. A sample of 70 women completed a four-part
survey after learning the benign breast biopsy diagnosis. The survey consisted of
an Information Needs Questionnaire, Mishel Uncertainty in Illness Scale-
Community Form, State-Trait Anxiety Inventory, and a Demographic Questionnaire.
Before the study, nine information needs were identified in a focus group
composed of women (n = 9) who had a benign breast biopsy. The nine information
needs were arranged in 36 pairs in the Information Needs Questionnaire. Profiles
of information needs were developed through Statistical Analysis Systems analysis
using Thurstone's Law of Comparative Judgement--Case V. The most important
information need of women who underwent a benign breast biopsy was knowing when
they would learn the diagnosis. The next four information needs were categorized
as information about the risks of developing breast cancer. Information about
follow-up and diagnostic tests were less important than information about the
threat of breast cancer. Women experienced heightened uncertainty and anxiety
levels related to the benign breast biopsy experience. Profiles of information
needs were developed for women experiencing various levels of uncertainty and
anxiety, women of different age groups, and women who experienced with a loved
one with breast cancer.
PMID- 9556939
TI - Fatigue in women with breast cancer receiving radiation therapy.
AB - Fatigue is a common complaint of individuals receiving treatment for cancer.
There is a dearth of rigorous research investigating the clinical course and
prognosis of fatigue over the course of radiation therapy. Seventy six patients
with breast cancer receiving external radiation therapy were followed
longitudinally from the onset of treatment to 6 months post-treatment. Fatigue
significantly increased over the course of treatment, was highest at the last
week of treatment, and returned to pretreatment levels by 3 months after
treatment. Fatigue was not influenced by the patient's age, stage of disease,
time since surgery, weight, and length of time since diagnosis. Fatigue was
significantly related to symptom distress, psychologic distress, and self
reported fatigue relief strategies. The most frequently reported self-relief
strategies were "sit" and "sleep." Fatigue had a negative impact on the patient's
quality of life. Impairment in quality of life was evident by the end of
treatment, with improvement by 3 and 6 months after treatment. The second week
through to the last week of radiation therapy are critical times to target
interventions for the management of fatigue. The amelioration of concomitant
symptoms is a supportive approach that might be helpful. Self-help strategies
focusing on the cessation of activity and increasing rest were reported as
successful by patients.
PMID- 9556940
TI - Correlates of fatigue in survivors of breast cancer.
AB - The purpose of this report is to describe variables associated with fatigue for
disease-free survivors of breast cancer. On the basis of Mishel's theory of
illness uncertainty and the antecedents of uncertainty, a cross-sectional,
descriptive, correlational design was used to examine (a) the relationship of
fatigue with cancer-related variables and the presence of concurrent illness and
(b) whether fatigue and educational level explained a significant proportion of
the variation in illness uncertainty. The Mishel Uncertainty in Illness Scale
(MUIS) and a single fatigue item on the McCorkle & Young Symptom Distress Scale
were used as variable measures. Data were collected from 109 women 1 to 6 years
after treatment for Stage I to III breast cancer with no known metastasis.
Findings showed that low to moderate fatigue persisted for women, which was
related significantly to the presence of concurrent illness. When concurrent
illness was taken into account, fatigue was significantly related to treatment
with chemotherapy, irrespective of length of time since treatment, age, disease
stage, or tamoxifen use. Finally, fatigue and education level explained a
significant level of the variation in illness uncertainty. Nurses can identify
and assist women who are at risk for fatigue and illness uncertainty after
treatment for breast cancer ends.
PMID- 9556941
TI - Development of a preparatory sensory information videotape for women receiving
chemotherapy for breast cancer.
AB - This study describes the development and testing of a preparatory sensory
information (PSI) videotape for women receiving chemotherapy for breast cancer.
In telephone interviews, 40 women described the sensations they experienced
before, during, and after receiving chemotherapy. Sensations described by the
women were linked with procedural and temporal elements identified by certified
advanced practice oncology nurses to develop a script for the PSI videotape.
Women currently receiving chemotherapy or who had completed chemotherapy within
the last 6 months were asked to share their experiences on videotape. After
editing, a 20-minute PSI videotape was produced. Pilot testing with a group of 20
women demonstrated that the intervention helped to prepare them for the sensory
experiences associated with chemotherapy and was helpful in developing
anticipatory coping and self-care behaviors.
PMID- 9556942
TI - Regional decrease in brain glucose metabolism in asymptomatic gene carriers of
Machado-Joseph disease: a preliminary report.
AB - BACKGROUND: The molecular abnormality responsible for Machado-Joseph disease
(MJD), a neurodegenerative disorder, has recently been described. It has also
been previously documented using positron emission tomography (PET) with [18F]-2
fluoro-2-deoxy-D-glucose (FDG) to record the metabolic changes in the brains of
symptomatic subjects affected with MJD. The present study evaluated these changes
in asymptomatic MJD gene carriers, previously identified by molecular analysis.
METHODS: PET with FDG was used to study glucose metabolism in the brains of three
asymptomatic MJD gene carriers who were identified by molecular analysis, and in
10 normal control subjects. RESULTS: By comparison with data obtained from normal
control subjects, significantly decreased glucose utilization was found in the
cerebellar hemisphere and occipital cortex of these three asymptomatic MJD gene
carriers, suggesting preclinical disease activity. The sensitivity of diagnosis
based on PET examination alone was 100% in this study, using significant decrease
in glucose metabolism in the cerebellar hemisphere as a criterion. CONCLUSIONS:
Measurement of regional brain metabolism by PET is noninvasive, and subclinical
reduction of FDG consumption in the cerebellar hemisphere and occipital cortex is
found to act as an objective marker of disease activity. Based on the results
from a limited number of patients, the sensitivity of PET is sufficient to
justify its routine use in the investigation of asymptomatic at-risk MJD
subjects.
PMID- 9556943
TI - High resolution computed tomography of temporal bone fracture.
AB - BACKGROUND: High resolution computed tomography (HRCT) is highly efficient in
demonstrating the anatomy of the temporal bone. This study evaluates its
application to temporal bone fractures (TBF). METHODS: We collected data from 26
cases of TBF in the past two years. All cases underwent HRCT examination. The
clinical information was reviewed and correlated with the imaging findings.
RESULTS: Eighty-six percent of the cases had longitudinal fractures. Axial scans
were the most useful in identifying the fracture line. Mastoid opacification on
routine head computed tomography (CT) was also useful in indicating possible
TBFs. Complications of TBF, such as ossicular chain disruption, facial nerve
damage or otorhino-liquorrhea, were identified clearly using HRCT. CONCLUSIONS:
To minimize or prevent the sequelae of TBF, accurate radiologic evaluation is
necessary as soon as possible after injury. HRCT of the temporal bone delineates
the bony and soft tissue anatomy with high accuracy and we recommend it as the
diagnostic modality of choice.
PMID- 9556944
TI - Impact of nutritional status on the survival of lung cancer patients.
AB - BACKGROUND: Weight loss, disease extent, performance status and sex have emerged
as prognostic factors for lung cancer. The assessment of performance status is
rather subjective and crude. Parameters of nutritional status were used in this
study to represent the performance status of patients. The prevalence of protein
calorie malnutrition in lung cancer patients and the impact of this on patient
survival were also investigated. METHODS: Nutritional status was assessed in 150
newly diagnosed lung cancer patients. Anthropometric and biochemical parameters
measured were: weight/height ratio, percent of standard triceps skin-fold
thickness, percent of standard arm muscle circumference, serum albumin,
transferrin, creatinine height index and total lymphocyte count. Performance
status and survival time were estimated for all patients. RESULTS: The prevalence
of abnormality in each nutritional parameter ranged from 15 to 31%. Most of the
patients (59%) had at least one abnormal nutritional parameter. A low profile of
performance status was associated with lower nutritional parameters such as
triceps skin-fold thickness, percent of standard arm muscle circumference, serum
albumin and creatinine height index. Patients who died within six months after
diagnosis had significantly lower values of all nutritional parameters than those
who survived more than six months. Patients with more abnormal parameters tended
to have poorer survival rates. CONCLUSIONS: Both anthropometric and biochemical
nutritional parameters might be reliable indicators for the assessment of
performance status and survival for patients with lung cancer.
PMID- 9556945
TI - The management of patients with advanced motor neuron disease.
AB - BACKGROUND: There is no specific treatment for motor neuron disease (MND) except
hospice or palliative care to improve patients' quality of life and decrease
complications. This topic is seldom discussed in Taiwan. METHODS: A retrospective
study was conducted of patients with terminal MND who were treated and died at
the Veterans General Hospital-Taipei from March 1986 through April 1996.
Patients' characteristics, management, length of survival and cause of death were
analyzed. RESULTS: Twenty-three patients (M/F, 17/6) were included. The median
age of onset was 59 years (range, 24-69). The median interval from onset of
symptoms to diagnosis was nine months (range, 2-36). Seventeen patients received
mechanical ventilation for an average median of six months. Nineteen patients had
dysphagia, 17 received long-term nasogastric tube feeding, one had gastrostomy
and one was treated with cricopharyngeal myotomy. Pain over the neck, trunk or
limbs was reported by 18 patients; none received narcotics. Only two patients
received respiratory exercise training and two had a cervical collar for
stabilization. Electronic communication aids were not available. The median
survival from onset of symptoms was 36 months (range, 7-99). The causes of death
included sepsis (n = 13), respiratory failure (n = 7), heart disease (n = 2) and
MND-related cachexia (n = 1). Cardiopulmonary resuscitation was performed for 12
patients. CONCLUSIONS: In Taiwan, management of patients with advanced MND is
mainly hospital-based and most of the effort is focused on life-sustaining. More
attention needs to be paid to improvement of the quality of life and dignity of
the patient.
PMID- 9556946
TI - The mechanism of successful colposuspension in genuine stress incontinence.
AB - BACKGROUND: Colposuspension (Burch procedure) is one of the most effective
surgical procedures for the cure of genuine stress incontinence in women. The aim
of the current study was to understand the mechanism of successful
colposuspension for treatment of this condition. METHODS: Thirty-five patients
with primary genuine stress incontinence underwent colposuspension. Preoperative
investigation included detailed history taking, urinalysis, pelvic floor
relaxation assessments, one-hour pad test, Q-tip test, urodynamic study and
perineal ultrasound urethrocystography. Follow-up results were estimated after
one year. RESULTS: Twenty-five (71.4%) patients were completely cured; four
(11.4%) patients showed significant improvement and six (17.1%) had recurrence of
incontinence. The overall success rate was 82.9%. The complication rate was 20%.
Urodynamic data revealed a significant increase in the maximal stress urethral
closure pressure and proximal urethral transmission ratios. Perineal ultrasound
urethrocystography and Q-tip test revealed a significant anatomic correction in
bladder neck descent. CONCLUSIONS: This study confirmed that surgical cure of
urinary incontinence can be achieved by restoration of the vesical neck from a
dependent position in the pelvis to a position high behind the symphysis pubis,
with subsequent improved pressure transmission ratios.
PMID- 9556947
TI - Acupuncture utilization in Taiwan.
AB - BACKGROUND: The objective of this study was to examine the prevalence of
acupuncture utilization in Taiwan by people over 20 years of age. METHODS:
Stratified cluster sampling was used to randomly select 20 villages and
neighborhoods (townships), a total of 8,280 people, from northern, central,
southern and eastern Taiwan. A structured questionnaire was used to collect
information during home visits. A total of 5,805 questionnaires were valid for
use in the study. RESULTS: The complete rate of home visits was 70.1%; 73.2% of
those interviewed recognized acupuncture as one of the common therapeutic methods
used in traditional Chinese medicine, whereas only 12.4% had received acupuncture
treatment. Typical interviewees who had received acupuncture treatment were
generally ethnic from southern Fukien and aged from 30-39 years; 58.3% of the 716
interviewees had received acupuncture treatment from licensed practitioners,
while the remainder were treated by non-licensed practitioners. CONCLUSIONS: The
response rate to the questionnaire was high (70.1%). However, the percentage of
people who had received acupuncture treatment was only 12.4%, while many people
(73.2%) were familiar with it. Approximately 40% of those who received
acupuncture treatment did so from non-licensed practitioners. This may reveal
either a lack of awareness by the public or a lack of public protection of health
and safety.
PMID- 9556948
TI - Second trimester selective termination in a dizygotic twin pregnancy with
discordancy for Down's syndrome: a case report.
AB - A 34-year-old woman with a twin pregnancy underwent genetic amniocentesis in a
local hospital at 18 weeks' gestation. Fetal chromosome analysis showed a boy
without abnormal findings (46, XY) and another boy with trisomy 21 (47, XY, +21).
Sonography showed a fetal nuchal translucency thickness for the normal twin of
4.4 mm, and of 8.0 mm for the affected twin. The affected twin was terminated by
ultrasonographically guided intracardiac injection of 2.5 ml (5 mEq) potassium
chloride solution at 21 weeks' gestation. Serial ultrasound scans and
coagulopathy tests were unremarkable. Labor was induced at 39 weeks' gestation. A
healthy 3,080 g male infant was born vaginally with Apgar scores of 8 and 9 at
one and five minutes, respectively. At the time of writing (one month after
delivery), the mother and baby continue to do well. To our knowledge, this is the
second successful case in Taiwanese literature of selective birth in twins with
discordancy for Down's syndrome.
PMID- 9556949
TI - Spindle cell carcinoma of the lung: a clinicopathologic presentation of three
cases.
AB - Three patients with spindle cell carcinoma located in the lower respiratory tract
are presented, including cases of two monophasic and one biphasic tumor. On light
microscopic examination, the spindle cell components of the tumors were
histologically characterized by sheets of fusiform spindle cells that closely
resembled a sarcoma. Keratin expression in the spindle cell components of these
tumors, as shown by anti-cytokeratin antibody staining, demonstrated their
epithelial nature. It is supposed that the spindle cell component displays a
spectrum of phenotypes originating from epithelial cells with varying degrees of
mesenchymal transformation. It is difficult to establish a diagnosis of this rare
primary pulmonary malignancy prior to surgical intervention. A review of the
literature allowed for a summary of the clinicopathologic characteristics of this
tumor.
PMID- 9556950
TI - Genitourinary tuberculosis complicated with adrenal involvement and primary
adrenocortical insufficiency: a case report.
AB - Genitourinary tuberculosis (TB) rarely involves the adrenal gland. A 67-year-old
man presented with progressively hyperpigmented skin and an enlarged mass over
both testes. Early morning plasma cortisol concentration was low and
adrenocorticotropic hormone (ACTH) concentration was high. A rapid ACTH
stimulation test revealed the absence of plasma cortisol response and confirmed a
diagnosis of primary adrenocortical insufficiency. An abdomen computed tomography
(CT) scan disclosed enlargement of the right adrenal gland and punctuate
calcification over the left one. This is compatible with tuberculous adrenalitis.
Currettage biopsy of the prostate demonstrated chronic granulomatous inflammation
with Langerhan's giant cells, but without TB bacilli. Anti-TB treatment, in
addition to glucocorticoid and mineralocorticoid replacement, was administered.
The testicular mass decreased progressively though the results of a subsequent
ACTH stimulation test, six months later, disclosed no significant change. A
follow-up CT scan, one and a half years later, showed a decrease in the size of
the right adrenal mass.
PMID- 9556951
TI - High resistance index of Doppler ultrasound in tuberculous peritonitis presenting
as abdominal carcinomatosis: report of two cases.
AB - The radiologic features of tuberculous peritonitis (TB peritonitis) are seldom
reported, and the use of color Doppler ultrasound in the diagnosis of TB
peritonitis is even less common. Herein, we present two patients (a 29-year-old
woman and a 56-year-old woman) who were evaluated for months of progressive
enlargement of the abdomen, poor appetite and weight loss. In both patients,
clinical and laboratory examinations suggested carcinoma, except a very high
vascular resistance (resistance index 1.0 and 0.89, respectively) of the tumor
feeding vessels detected by color Doppler ultrasound. TB peritonitis was finally
diagnosed by exploratory laparotomy. Both patients were treated using a four-drug
regimen of isoniazid, rifampicin, ethambutol hydrochloride and pyrazinamide for
nine months and were clinically cured. In conclusion, if color Doppler ultrasound
reveals normal ovaries, ascites containing thin, delicate incomplete or complete
septa, and only a few high-resistance tumor feeding vessels in the abdominal
cavity (resistance index > or = 0.80), TB peritonitis should be considered.
PMID- 9556952
TI - [Skin manifestations in diabetes can be diagnosed early. Perforated dermatoses:
only scratching artefacts?].
PMID- 9556953
TI - [Sleep deprivation in depression].
PMID- 9556954
TI - [Antidepressive therapy--safety in steering in spite of it].
PMID- 9556955
TI - [Candida and the gastrointestinal tract. A medical-research evaluation].
AB - In immunocompetent persons, Candida species are members of the normal flora of
the gastrointestinal tract. Budding yeasts, in particular Candida albicans, can,
however, in patients with a corresponding disposition, spread topically and
systemically, that is, they may become pathogenic. In hematological/oncological
patients with severe immunodeficiency, for example, the mycelium may infiltrate
the muscularis mucosae, with involvement also of the vascular system. The
relationships between recurrent diarrhea and Candida are still discussed
controversial; various data do, however, suggest that massive colonization with
Candida might well represent a(n additional) diarrhea-provoking factor. Similar
considerations may also be assumed to apply to diarrhea induced by antibiotic
therapy. For immunocompetent persons, guidelines exist for the yeast cell count
in the stools. The interpretation of quantitative findings must, however, always
be made on an individual basis and against the background of clinical symptoms
and/or any particular predisposition of the patient. Reliable treatment of
superficial candidasis can be achieved with oral polyene antifungal antibiotics
(nystatin, amphotericin B).
PMID- 9556956
TI - [Dysphagia after antibiotics? Radiologic examination shows no useful finding].
PMID- 9556957
TI - [Acne in childhood].
PMID- 9556958
TI - Anesthesia control using midlatency auditory evoked potentials.
AB - This paper shows the development of a system to control inhalation anesthetic
concentration delivered to a patient based upon that patient's midlatency
auditory evoked potentials (MLAEP's). It was developed and tested in dogs by
determining response to the supramaximal stimulus of tail clamping. Prior to tail
clamp, the MLAEP was recorded along with inhalational anesthetic concentration
and classified as responders or nonresponders as determined by tail clamping.
This was performed at a number of different anesthetic levels to obtain a data
training set. The MLAEP's were compacted by means of discrete time wavelet
transform (DTWT), and together with anesthetic concentration value, a stepwise
discriminant analysis (SDA) was performed to determine those features which could
separate responders from nonresponders. It was determined that only three
features were necessary for this recognition. These features were then used to
train a four-layer artificial neural network (ANN) to separate the responders
from nonresponders. The network was tested using a separate set of data,
resulting in a 93% recognition rate in the anesthetic transition zone between
responders and nonresponders, and 100% recognition rate outside this zone. The
anesthetic controller used this ANN combined with fuzzy logic and rule-based
control. A set of ten animal experiments were performed to test the robustness of
this controller. Acceptable clinical performance was obtained, showing the
feasibility of this approach.
PMID- 9556959
TI - Filter matrix estimation in automated DNA sequencing.
AB - In four-color fluourescence-based automated DNA sequencing, a 4 x 4 filter matrix
parameterizes the relationship between the dye-intensity signals of interest and
the data collected by an optical imaging system. The filter matrix is important
because the estimated DNA sequence is based on the dye intensities that can only
be recovered via inversion of the matrix. In this paper, we present a calibration
method for the estimation of the columns of this matrix, using data generated
through a special experiment in which DNA samples are labeled with only one
fluorescent dye at a time. Simulations and applications of the method to real
data are provided, with promising results.
PMID- 9556960
TI - Systematic method for determining intravenous drug treatment strategies aiding
the humoral immune response.
AB - This paper delineates a systematic method for determining "optimal" intravenous
drug delivery strategies for patients having illnesses that primarily evoke a
humoral immune response and are treatable by antibiotics. The method derives from
a nonlinear, distributed predator-prey model that captures the dominant antigen
and antibody interaction. This model is developed from relevant physiology, past
predator-prey-type modeling work, available data, and pertinent parameter
identification. Embedding this predator-prey model into a larger class of
uncertain systems, by a finite dimensional approximation and a transformation to
a linear fractional representation, enables the application of robust control
based on linear matrix inequality optimization techniques. The optimization
problem is solved by minimizing an upper bound on a measure of the total drug
delivered subject to patient recovery (stability to healthy equilibrium state).
Specifically, the paper addresses the treatment of Haemophilus influenzae through
modeling, controller development, and simulations of infected adult patients
subjected to typical and proposed intravenous antibiotic treatments. Through
simulations the proposed intravenous drug strategy shortens patient recovery
time, lowers peak drug concentrations and decreases the total drug administered
when compared to standard antibiotic strategies.
PMID- 9556961
TI - A critical analysis of linear inverse solutions to the neuroelectromagnetic
inverse problem.
AB - This paper explores the possibilities of using linear inverse solutions to
reconstruct arbitrary current distributions within the human brain. We formally
prove that due to the underdetermined character of the problem, the only class of
measurable current distributions that can be totally retrieved are those of
minimal norm. The reconstruction of smooth or averaged versions of the currents
is also explored. A solution that explicitly attempts to reconstruct averages of
the current is proposed and compared with the minimum norm and the minimum
Laplacian solution. In contrast to the majority of previous analysis carried out
in the field, in the comparisons, we avoid the use of measures designed for the
case of dipolar sources. To allow for the evaluation of distributed solutions in
the case of arbitrary current distributions we use the concept of resolution
kernels. Two summarizing measures, source identifiability and source visibility,
are proposed and applied to the comparison. From this study can be concluded: 1)
linear inverse solutions are unable to produce adequate estimates of arbitrary
current distributions at many brain sites and 2) averages or smooth solutions are
better than the minimum norm solution estimating the position of single point
sources. However, they systematically underestimate their amplitude or strength
especially for the deeper brain areas. Based on these result, it appears unlikely
that a three-dimensional (3-D) tomography of the brain electromagnetic activity
can be based on linear reconstruction methods without the use of a significant
amount of a priori information.
PMID- 9556962
TI - Bipolar stimulation of a three-dimensional bidomain incorporating rotational
anisotropy.
AB - A bidomain model of cardiac tissue was used to examine the effect of transmural
fiber rotation during bipolar stimulation in three-dimensional (3-D) myocardium.
A 3-D tissue block with unequal anisotropy and two types of fiber rotation (none
and moderate) was stimulated along and across fibers via bipolar electrodes on
the epicardial surface, and the resulting steady-state interstitial (phi e) and
transmembrane (Vm) potentials were computed. Results demonstrate that the
presence of rotated fibers does not change the amount of tissue polarized by the
point surface stimuli, but does cause changes in the orientation of phi e and Vm
in the depth of the tissue, away from the epicardium. Further analysis revealed a
relationship between the Laplacian of phi e, regions of virtual electrodes, and
fiber orientation that was dependent upon adequacy of spatial sampling and the
interstitial anisotropy. These findings help to understand the role of fiber
architecture during extracellular stimulation of cardiac muscle.
PMID- 9556963
TI - An externally powered, multichannel, implantable stimulator-telemeter for control
of paralyzed muscle.
AB - An implantable integrated stimulator and telemetry system has been developed. The
system is capable of fulfilling the stimulus and telemetry needs of advanced
functional neuromuscular stimulation (FNS) applications requiring multiple
channels of stimulation and multiple channels of sensor or biopotential sensing.
This system provides a command control structure, an inductive radio frequency
link providing power to the implant device as well as two-way transcutaneous
communication, an ASIC for decoding the command and for providing functional
control within the implant, and modular circuitry providing the application
specific implant functions. Biocompatible hermetic packaging, lead systems, and
in-line connectors suitable for long-term implantation, provide encapsulation for
the circuitry and access to the electrodes and sensors used in the application.
The first implant configuration realized from this modular system is targeted for
clinical implementation in persons with tetraplegia at the C6 level for
restoration of hand function, using wrist position as the command control source.
The implant device realized has ten channels of stimulation and telemetry used to
control and sense a joint angle transducer implanted in the radio-carpal joint of
the wrist. A prototype device has been fabricated and is undergoing testing in an
animal.
PMID- 9556964
TI - Measurement of friction on straight catheters in in vitro brain and phantom
material.
AB - As part of our studies on the magnetic stereotaxis system (MSS), a means of
delivering therapies to the bulk brain, we have measured the frictional forces on
a thin, straight tube used to simulate a catheter. Experiments were done with a
spring-loaded, stainless steel tube of 1.9-mm diameter which was passed through
5.5 cm of gelatin phantom or, alternatively, through in vitro calf brain. The
dynamic response of the tube to sudden displacement of the outer end of the
spring yields estimates of the tube's friction per unit length. Twenty-three runs
in the two media were analyzed for the static and dynamic frictional forces
exhibited. In these series the static frictional forces were found to be (0.0132
+/- 0.0012) N cm-1 [(1.32 +/- 0.12) g cm-1] of length in the gelatin phantom and
(0.0079 +/- 0.0008) N cm-1 [(0.79 +/- 0.08) g cm-1] of length in brain. The
kinetic friction coefficient, b, was found to be (8.4 +/- 2.1) N s m-1/cm length
of catheter in brain and (16.3 +/- 7.6) N s m-1/cm length of catheter in the
phantom material. Based on these figures, the MSS will be capable of moving
straight catheters of similar friction that are 20-cm long at rates of
displacement of 0.02 to 0.05 cm s-1 in the white and grey matter of the brain.
Future studies will evaluate the forces arising from curved paths. Unanswered
questions remain as to the mechanical difference between in vivo and in vitro
brain, between animal and human brain, and the involvement of sulci in practical
paths of motion.
PMID- 9556965
TI - A Kalman filter approach to track fast impedance changes in electrical impedance
tomography.
AB - In electrical impedance tomography (EIT), an estimate for the cross-sectional
impedance distribution is obtained from the body by using current and voltage
measurements made from the boundary. All well-known reconstruction algorithms use
a full set of independent current patterns for each reconstruction. In some
applications, the impedance changes may be so fast that information on the time
evolution of the impedance distribution is either lost or severely blurred. In
this paper, we propose an algorithm for EIT reconstruction that is able to track
fast changes in the impedance distribution. The method is based on the
formulation of EIT as a state-estimation problem and the recursive estimation of
the state with the aid of the Kalman filter. The performance of the proposed
method is evaluated with a simulation of human thorax in a situation in which the
impedances of the ventricles change rapidly. We show that with optimal current
patterns and proper parameterization, the proposed approach yields significant
enhancement of the temporal resolution over the conventional reconstruction
strategy.
PMID- 9556966
TI - System for quantitative three-dimensional echocardiography of the left ventricle
based on a magnetic-field position and orientation sensing system.
AB - Accurate measurement of left-ventricular (LV) volume and function are important
to monitor disease progression and assess prognosis in patients with heart
disease. Existing methods of three-dimensional (3-D) imaging of the heart using
ultrasound have shown the potential of this modality, but each suffers from
inherent restrictions which limit its applicability to the full range of clinical
situations. We have developed a technique for image acquisition using a magnetic
field system to track the 3-D echocardiographic imaging planes and 3-D image
analysis software including the piecewise smooth subdivision method for surface
reconstruction. The technique offers several advantages over existing methods of
3-D echocardiography. The results of validation using in vitro LV's show that the
technique allows accurate measurement of LV volume and anatomically accurate 3-D
reconstruction of LV shape and is, therefore, suitable for analysis of regional
as well as global function.
PMID- 9556967
TI - Successive order scattering transport approximation for laser light propagation
in whole blood medium.
AB - An analytical solution method of the radiative transport equation, describing
light scattering distribution in whole blood, is derived by applying successive
order scattering approximation and transport approximation. By separating
coherent components of scattered fluxes, the transport equation can be
represented in terms of each order scattering flux, and the equations for each
order scattering flux have a simplified integration term of scattering
contribution that usually makes the solution complicated or even impossible.
Also, actual phase function can be used for calculation of angular dependent
scattering distribution that is approximated by the sum of the zeroth- and first
order Legendre polynomial in diffusion theory, or the sum of isotropic and
coherent components in transport approximation. The method is then used to
calculate reflectance from a half-space blood medium. It is found that first
order scattering flux alone produces a good agreement with experimental data and
higher-order scattering fluxes are negligible in whole blood.
PMID- 9556968
TI - Open-loop tracking performance of a limb joint controlled by random, periodic,
and abrupt electrical stimulation inputs to the antagonist muscle pair.
AB - The ability of the cat's ankle joint to track various input signals when
controlled by electrically elicited motor unit recruitment, firing rate and
antagonist muscle coactivation was examined. Pseudo-random, sinusoidal and
staircase signals were used to control the soleus and tibialis anterior muscles
isometrically and with a 250-g pendulum. Tracking was evaluated through cross
correlation for pseudo-random and sinusoidal signals, and by rise time and steady
state error in step signals. Better tracking was obtained in isometric conditions
than in load-moving conditions. Pseudo-random signals resulted in 250-ms delay
between input and isometric torque output. For load-moving conditions, 340-ms and
400-ms delay in torque and angle were obtained. For sinusoids, delays decreased
from 240 ms at 0.5 Hz, to 140 ms at 2 Hz in isometric conditions. Time delays for
angle were between 300 and 400 ms, decreasing as frequency increased. Poor cross
correlation was found for torque in load-moving conditions, because of pendulum
nonlinear dynamics. Step size was not uniform in staircase trials, with steady
state errors between 9% and 39%, and rise times between 200 and 1000 ms. It is
concluded that open-loop joint control results in poor tracking, presumably
because it is devoid of feedback mechanisms.
PMID- 9556969
TI - Fields and currents in the organs of the human body when exposed to power lines
and VLF transmitters.
AB - A study is made of the electric fields and currents induced in the organs of the
human body when exposed to high-voltage 50-60-Hz transmission lines and 10-30-kHz
high-power transmitters. Relevant analyses previously carried out are summarized
and supplemented with detailed investigations that complete the picture.
Incomplete, misleading, and incorrect statements and methods in the related
literature are pointed out, completed, and corrected. The major contribution is
to provide quantitatively accurate, relatively simple analytic formulas that
relate the incident electric field to the induced field in the organs of the
body. The formulation and solution of the underlying integral equation are
carried out in the Appendix.
PMID- 9556970
TI - Effect of electrode size on impedance images of two- and three-dimensional
objects.
AB - The sensitivity of an impedance imaging system to small cylindrical
inhomogeneities in two-dimensional (2-D) and three-dimensional (3-D) saline tanks
was studied for different height electrodes and different height targets.
Experimental results were compared with analytical models. Inhomogeneities in the
3-D tank having limited vertical extent were detected by electrodes of vertical
size comparable to that of the inhomogeneity. Taller electrodes had increased
sensitivity to short targets to only a limited extent. When the electrode height
was more than twice that of the target, sensitivity decreased or remained the
same with further increases in electrode height. The system was less sensitive to
inhomogeneities in the 3-D tank than to those in the 2-D tank. The
distinguishability of conductors was greater than that of insulators in the 3-D
tank, and the opposite was true in the 2-D tank, consistent with an analytical
result.
PMID- 9556971
TI - A note on the compartmental analysis and related issues in laser Doppler
flowmetry.
AB - Compartmental analysis (CA) in laser Doppler flowmetry (LDF) means deciphering
the nutritional and thermoregulating flows from the measured perfusion flux.
Based on the new theories proposed in [1] and [2], the CA is formulated here as
an optimal approximation without directly involving the geometric information of
the vessel network. It is seen that this approximation approach could also solve
the biological zero (BZ) problem simultaneously, therefore, it actually provides
a systematic solution to the BZ problem without estimating the BZ flux
experimentally. In addition, the BZ problem with compartmental differences is
reformulated, and the condition under which multiple compartments can be treated
as a single one is investigated. The result, together with some computer
simulations, showed that the theory in [2] is still an easy and useful
approximation in practice. This note serves as an useful supplement to [1] and
[2] and may help to solve and clarify some critical problems in LDF.
PMID- 9556972
TI - Localized prior knowledge and optimal interpolation in high-resolution
tomography.
AB - The problem of electromagnetic tomographic reconstruction is approached in terms
of the derivation of a minimum norm interpolator, incorporating a priori
knowledge gained from a previous reconstruction. An algorithm is suggested for
the initial estimate and both images are compared to that of bilinear
interpolation.
PMID- 9556973
TI - [Increased antibiotic resistance in severely ill patients].
PMID- 9556974
TI - [Thiazolidindiones in type II diabetes mellitus].
PMID- 9556975
TI - [Cell cycle and cancer].
PMID- 9556976
TI - [Echinococcosis. Detection, prevention and control].
PMID- 9556977
TI - [Melatonin. Physiology, pathophysiology and possible therapeutic approaches].
PMID- 9556978
TI - [Finasteride or sabal extract in acne?].
PMID- 9556979
TI - [Medical education: 'plus ca change, plus c'est la meme chose'].
AB - Medical curricula are being overhauled at increasingly short intervals. Fashion
is one of the driving forces behind the changes, sometimes at the expense of
reason. There is no scientific proof that one type of curriculum produces better
doctors than an other. A caring and humanistic attitude in physicians is probably
less dependent on specific training than on innate personality traits and the
example of role models. The Dutch Journal of Medicine is launching two
initiatives intended to contribute to the education of medical students: an
almost free subscription is offered after the first year, and a (quarterly)
student edition will appear from 1998.
PMID- 9556980
TI - [How to continue after an error in family practice?].
AB - Not just malfunctioning doctors make mistakes and errors, all doctors do.
Patients suffer through errors, while the doctor is burdened by feelings of guilt
and self-reproach. Furthermore the taboo on errors in medicine impedes doctors
from learning from mistakes. Adequate management of these situations is of great
importance. In order to minimise emotional damage to the patient and his
relatives and to improve the quality of medical practice, acknowledgement of
having made a mistake comes first; the general practitioner should be aware of
personal defence mechanisms such as projection, denial or rationalisation. He
should share his experience with some colleagues; in an atmosphere of trust the
emotions of regret, shame and anger can be aired. Next the peer group assists in
analysing the incident step by step. This analysis makes it possible to learn
from the error and perhaps to take measures to prevent recurrence. Thereafter
management with respect to the patient or his relatives should be established
with aid of the group. Guidelines are: make an appointment with the patient
without delay; take ample time and avoid disturbance; listen to the patient and
respect his feelings; express regret with regard to the consequences for the
patient; contact the patient again after an interval to check if new questions
have arisen. This approach is helpful in restoring the patient-doctor relation
after a mistake.
PMID- 9556981
TI - [Clinical drug research in children: current international guidelines. Committee
for Proprietary Medicinal Products].
AB - Drugs research in children entails a number of problems: medical-ethical,
pharmacological (owing to the immaturity of the organs and the growth and
development of the child) and financial (because children do not use many drugs).
Consequently, children are exposed to insufficiently tested drugs and new
therapeutic possibilities are withheld from them. Currently, little clinical
drugs research in children is being carried out, but this is about to change. By
now, European guidelines have been drawn up for the performance of clinical drugs
trials according the 'good clinical practice' standards in children. In the
Netherlands, a cooperative body has been set up (the Pediatric Pharmacology
Network), which is to promote and coordinate paediatric pharmacological research
in according with these guidelines.
PMID- 9556982
TI - [Neurosurgical stereotactic treatment in Parkinson's disease].
AB - For patients with Parkinson's disease who have become unresponsive to
pharmacotherapy or have developed severe motor complications due to medical
therapy, a number of symptomatic neurosurgical interventions are available:
thalamotomy, thalamic stimulation and pallidotomy. These stereotactic operations
are performed under local anaesthesia. The target is located using anatomical and
physiological techniques, after which the neuro-ablative or neuromodulatory
procedure is performed. The choice of the target depends on the symptoms of the
patient that most impair daily functioning. In case of dominating tremor,
thalamic surgery is performed. Patients who are mainly incapacitated by rigidity,
hypokinesia or pharmacotherapy-induced dyskinesias are suitable candidates for
pallidotomy. Contraindications are cognitive dysfunction, severe disturbance of
gait and balance, advanced cerebral atrophy on CT or MRI, limited life expectancy
and a poor general condition enhancing surgical risk, e.g. coagulation disorders
or uncontrolled hypertension. Surgical treatment of Parkinson's disease is being
carried out in clinical trials in the Netherlands in the Academic Medical Centre
in Amsterdam, the Academic Hospital in Groningen and the St. Elisabeth Hospital
in Tilburg.
PMID- 9556983
TI - [Immunology in clinical practice. VIII. Role of cytokines in the pathogenesis of
bacterial infections].
AB - Cytokines are small proteins that can be produced by many different cell types
involved in inflammation. The cytokine network consists of pro-inflammatory
cytokines, facilitating inflammation, and anti-inflammatory cytokines, reducing
inflammation at least in part by inhibiting the production of pro-inflammatory
cytokines. The production of cytokines is enhanced during bacterial infections.
The balance between pro- and anti-inflammatory cytokines critically determines
the outcome of infection. Excessive systemic release of pro-inflammatory
cytokines such as tumour necrosis factor alpha and interleukin 1 may contribute
to organ failure in patients with fulminant sepsis. On the other hand, the local
action of pro-inflammatory cytokines, at the site of a compartmentalized
infection, is required for an adequate host antibacterial defence. Therefore,
neutralization of pro-inflammatory cytokines may benefit some patients with
bacterial sepsis but harm others.
PMID- 9556984
TI - [Communication disorders in children; experiences with a multidisciplinary
outpatient diagnosis].
AB - Communication disorders in children can be caused by impaired hearing. However,
also other factors can adversely influence speech and language development, such
as mental retardation, lack of language stimulation and anatomical defects of
speech organs. Speech and language development can be regarded as a symptom;
therefore a multidisciplinary diagnostic procedure is essential to the planning
of an adequate therapy programme. In the Netherlands a great variety in diagnosis
and treatment exists. A child with a communication disorder is usually seen by
five specialists, and the interval between recognition of the communication
problem by the parents and the final diagnosis, after which therapy starts,
sometimes lasts almost three years. Besides that, in a majority of cases speech
and language therapy is offered. In order to change this process for the better a
prospective research programme was started in the Academic Hospital Groningen,
the Netherlands, with a protocolled multidisciplinary diagnostic approach. The
first findings are encouraging: 89% of 209 children with supposed communication
disorders were diagnosed after one visit to the outpatient clinic.
PMID- 9556985
TI - [Incidence of postoperative wound infections in The Netherlands].
AB - OBJECTIVE: To inventory postoperative infections in Dutch hospitals. DESIGN:
Descriptive study. SETTING: National organization for quality assurance in
hospitals, Utrecht, the Netherlands. METHOD: In 36 Dutch hospitals data on
surgical patients, surgical site infections and risk factors were collected,
using standardised methods, as part of a quality system by which hospitals could
compare their infection rates with the rates in the database. RESULTS:
Surveillance of surgical site infections was introduced in 36/118 (31%)
hospitals. Data on 32,869 surgical procedures were collected, 1115 (3.4%)
surgical site infections were found. The infection rates by wound contamination
class varied from 2.2% (95% confidence interval (CI): 2.0-2.4) in clean wounds to
11% (95% CI: 9.3-12.8) in dirty wounds; the infection rates by duration of
operation varied from 3% (95% CI: 2.8-3.2) in operations lasting less than two
hours to 10.8% (95% CI: 6.0-18.5) in operations lasting more than 8 hours; the
infection rate by ASA classification varied from 2.7% (95% CI: 2.3-3.2) in class
I to 15.5% (95% CI: 8.4-26.5) in patients in class IV. Advanced age, emergency,
preoperative stay were recognised as risk factors. The infection rates in the
most frequently recorded types of operation varied from 0.2% (95% CI: 0.0-1.1) in
varicose veins to 9.8% (95% CI: 7.2-13.2) in femoral bypass grafts. The use of
antimicrobial prophylaxis varied per type of operation. The micro-organisms most
frequently isolated were Staphylococcus aureus. Staphylococcus epidermidis,
Pseudomonas aeruginosa, and Escherichia coli. Of the infections 32% were
identified in the first week following surgery. Of the infected patients 88%
stayed in hospital during one or more days following the onset of infection.
PMID- 9556986
TI - [Prevalence of mental disorders in persons with Parkinson's disease].
AB - OBJECTIVE: To determine the prevalence of cognitive disorder, depression, anxiety
and psychotic symptoms in persons with Parkinson's disease in the general
population. DESIGN: Cross-sectional study. SETTING: The Netherlands. METHOD:
Between May and September 1995, a random sample of 384 persons with Parkinson's
disease (members of the Parkinson's disease patient organisation plus 24 Dutch
nursing home patients) were investigated with the Composite International
Diagnostic Interview (CIDI) and the General Health Questionnaire (GHQ-12).
RESULTS: The 1-month prevalence of DSM-III-R psychiatric disorder was 39.1%, of
which 13.3% cognitive impairment, 5.5% depression (2.3% major depression and 4.7%
dysthymia), and 24.5% anxiety disorder (4.9% agoraphobia and 11.5% social
phobia). Psychiatric comorbidity mainly concerned anxiety disorder, in
combination with depression (21%) or cognitive disorder (28%). Four out of ten
persons who ever had a depression or anxiety disorder, developed the first
episode after the onset of Parkinson's disease. CONCLUSION: The prevalence of
psychiatric disorder in persons with Parkinson's disease was high, compared with
figures of the general population, notably for anxiety and cognitive disorder,
but not for depression.
PMID- 9556988
TI - [3 patients with accidental hypothermia; customized rewarming].
PMID- 9556987
TI - [Sudden death in young persons caused by arrhythmogenic right ventricular
dysplasia].
AB - A previously healthy boy aged 14 developed persistent ventricular tachycardia
while engaged in sports; ultrasonography revealed arrhythmogenic right
ventricular dysplasia (ARVD). He was treated with a class III antiarrhythmic drug
but nevertheless died 4 years later during recreational activities. An uncle of
the boy was found to have died suddenly on a playing field, 25 years previously
at the age of 20. In ARVD, fibrolipomatous areas in the right ventricle lead to
dilations of the wall where (sometimes fatal) re-entrant tachycardias may
develop. An autosomal dominant heredity with variable expression and penetrance
is considered probable, while the genetic defect was located recently.
Examination and, if necessary, pharmacotherapy of relatives of an ARVD patient
may reduce the risk of a fatal arrhythmia.
PMID- 9556989
TI - [Treatment of genital prolapse in very old women].
PMID- 9556990
TI - [Treatment of genital prolapse in very old women].
PMID- 9556991
TI - [Treatment of genital prolapse in very old women].
PMID- 9556992
TI - [Pain control in the final stage of life].
PMID- 9556993
TI - [Combination of anxiety disorder and alcohol dependence].
AB - Three patients, two men aged 47 and 37 and a woman aged 32, are described. All
three suffered from a combination of alcohol addiction and anxiety disorder. None
of them had previously received adequate treatment because on the one hand they
had been refused by psychiatric institutes because of their alcohol addiction,
and on the other the institutes for the care of addicted had not diagnosed the
anxiety disorder. About 150,000 people are estimated to have both an alcohol
addiction and an anxiety disorder in the Netherlands. The importance of making a
correct diagnosis and providing proper treatment for both disorders is
emphasized.
PMID- 9556994
TI - [Lactation-induced amenorrhea as birth control method].
AB - Improving access to quality care in family planning, a recent document of the
World Health Organization, reviews the epidemiological and clinical evidence
relevant to medical eligibility of well established contraceptive methods.
Breastfeeding is widely regarded as unreliable for individual contraception. The
document, however, argues that the lactational amenorrhoea method (LAM) is a safe
and effective family planning method. Worldwide, LAM is the most important way of
fertility regulation and its efficacy is confirmed in many studies, with a 2%
risk of pregnancy in the first six months after birth. Taking into account
certain well defined conditions (frequent feedings, no supplementary feeding
before 4-6 months, method only to be used in the absence of menstruation), LAM
can be relied on for contraceptive protection for up to 1 year post partum.
PMID- 9556995
TI - [Rehabilitation possibilities for hearing-impaired subjects].
AB - Hearing impairment is a symptom, not a diagnosis. A number of types of hearing
impairment can be distinguished. The self-reported hearing problems cluster
around six hearing factors, the most important of which are speech understanding
in noise and localisation of a sound source. For these capabilities equivalent
functioning of both ears is important. The general practitioner can determine
diagnosis and severity of the impairment using rather simple tools. When the
cause of the impairment cannot be reduced in a proper way an adaptation of the
sound to the impaired ear will be indicated. This can be arranged by either an
ENT specialist or a centre for audiology. The selection of a proper hearing aid
requires expertise and particular attention for the complaints. It is of the
utmost importance that the hearing-impaired person can try out the effects of the
hearing aid in daily circumstances for some weeks. If the patient, members of the
family or the prescriber are not satisfied with the results, supplementary help
is required, for example training in communication skills or special devices.
PMID- 9556996
TI - [Myocardial tissue vitality: clinical relevance, pathophysiology and
identification].
AB - Heart failure is an increasing clinical problem because of the rising frequency
of admissions and the high mortality. Excellent long-term results are obtained
with heart transplantation, whereas the long-term prognosis is poor when patients
are treated medically. It has recently been demonstrated that, in patients with
depressed left ventricular (LV) function, revascularization may be an alternative
form of therapy, since improvement of LV function, which is an important
prognostic factor, may occur after coronary revascularization. Recovery of LV
function after revascularization may occur in patients with dysfunctional but
viable myocardium, whereas no recovery can be expected in patients with scar
tissue. Improvement of LV function after revascularization can be explained on
the basis of the concept of myocardial tissue vitality': chronically ischaemic
myocardium temporarily loses the facility to contract, but the contraction is
regained after revascularization (once the ischaemia is eliminated). For the
selection of patients who may profit by a revascularization procedure, techniques
have been developed for the identification of dysfunctional but viable tissue.
The myocardial glucose metabolism can be visualized by administration of 18F
desoxyglucose (FDG) and imaging by positron emission tomography or 'single photon
emission computer tomography'. Vital tissue shows diminished perfusion with
intact glucose metabolism (FDG perfusion mismatch); a vital tissue shows
diminished perfusion without glucose metabolism (FDG perfusion match).
Scintigraphy of the membrane of the myocardial cell can also be investigated
using 201Tl scintigraphy. Reserve contractility of the myocardium can be
visualized by echocardiography during administration of dobutamine.
PMID- 9556998
TI - [Inventory and follow-up of patients with surgery for (uterine) vaginal prolapse,
combined with or without, (masked) stress incontinence].
AB - OBJECTIVE: Evaluation of the development or persistence of urinary stress
incontinence in patients operated on because of prolapsed uterus, with
cooperation between gynaecologists and urologists. DESIGN: Retrospective.
SETTING: Department of Gynaecology and Obstetrics, Leyenburg Hospital, The Hague,
the Netherlands. METHODS: In 178 patients subjected to prolapse correction in the
period 1992-1996, presence of urinary incontinence was analysed by means of a
written enquiry after an average of 22 months. The 91 patients who had visited
the gynaecological outpatient clinic and were seen together with a urologist,
were subjected to urodynamic examination in the absence of symptoms of stress
incontinence and were operated in cooperation with the urologist. Four groups
were distinguished on the basis of preoperative features: group I (n = 37) with
manifest stress incontinence, group II (n = 22) with masked stress incontinence,
group III (n = 32) in whom no (masked) stress incontinence could be demonstrated
and group IV (n = 87) not subjected to urodynamic examination. The patients of
groups I and II, in addition to prolapse correction, were also subjected to
urethral suspension. RESULTS: Twenty-five (68%) of the group with manifest stress
incontinence were free of stress incontinence after the operation, while eight
patients (22%) reported improvement (a total of 89%). In 22 of the 54 patients
(41%) who preoperatively had no incontinence symptoms, urodynamic examination
revealed a masked stress incontinence. Sixteen of them (73%) did not develop
symptoms of stress incontinence after the operation, while eight (15%) did
develop such symptoms. Thirty of the 32 patients (94%) who preoperatively had no
(masked) stress incontinence remained symptom-free. Out of 64 patients without
preoperative incontinence, who were operated without urological cooperation, 12
(19%) developed stress incontinence.
PMID- 9556999
TI - [Consensus antithrombotic prophylaxis of vascular incidents in patients with
manifest atherosclerotic vascular diseases. Central Guidance Organization for
Peer Review].
AB - The consensus on antithrombotic prophylaxis of vascular incidents in patients
with manifest atherosclerotic vasculopathy was preceded by a systematic
classification of results from relevant articles according to 'evidential value':
from randomized prospective trials of sufficient quality and size, via less
adequate or non-randomized trials to the current opinion in the Netherlands. The
principal advice was to prescribe antithrombotic prophylaxis, mostly
acetylsalicylic acid, for patients with manifest atherosclerotic vasculopathy (in
head, heart and (or) legs). With regard to the question what drug should be
preferred for patients with intermittent claudication, no consensus could be
reached for lack of adequate research. Acetylsalicylic acid is not more effective
in higher than in lower doses, but in higher doses it has more side effects;
therefore lower doses are preferred: 80-100 mg per day, and for neurological
indications, 30 mg or more per day. Use of coumarin derivates is only to be
preferred in patients with atrial fibrillation who have suffered a TIA or a non
crippling cerebral infarction, in patients with atrial fibrillation and a cardiac
disorder such as large myocardial infarction or a left ventricular aneurysm, and
in patients who have undergone a cardiac valve operation. Since the proportion of
pros and cons of antithrombotic prophylaxis may change during a patient's life,
the indication should be reconsidered periodically.
PMID- 9557000
TI - [Seroprevalence of human T-cell lymphotropic virus type I in Curacao and
predictive variables for that infection].
AB - OBJECTIVE: To determine the seroprevalence of human T-cell leukaemia virus (HTLV)
type I and predictive variables in Curacao. DESIGN: Descriptive. SETTING: St.
Elisabeth Hospital, Curacao. METHODS: A total of 2531 sera were randomly
collected from a total population of approximately 145,000 over a period of three
months (of seven the sex was not known). An initial ELISA test was performed to
detect anti-HTLV-I antibodies. If this test was positive an ELISA re-test (in
duplicate) was performed. If one of these re-tests was found positive a western
blot confirmation test was performed. The association with age, sex, social class
and history of syphilis were analysed with multiple logistic regression models
and adjusted for confounding. RESULTS: The estimated prevalence of HTLV-I was
1.9% (49/2524). No significant sex differences were observed (odds ratio (OR):
1.13; 95% confidence interval (95% CI): 0.62-2.05). Increasing age (p for trend =
0.0003) and lower social class (OR: 1.86; 95% CI: 1.03-3.38) were important
predictive factors for HTLV-I infection. Members of the lower social classes and
persons 50 years or older were at relatively high risk (OR: 3.91; 95% CI: 2.21
6.94). CONCLUSION: HTLV-I infection is endemic in the island of Curacao, as in
other Caribbean islands. The estimated prevalence is 1.9%. Age and lower social
class were important predictive factors for HTLV-I infection.
PMID- 9557001
TI - [Progressive myelopathy caused by human T-cell lymphotropic virus type I (HTLV-I)
in 3 patients in The Netherlands].
AB - One man and two women (aged 30, 44 and 46, respectively) were seen between 1987
and 1992 with a myelopathy caused by the human T-cell lymphotropic virus type I
(HTLV-I). The first symptoms were impaired gait in the man and micturition
disorders in the women. Diagnosing took 2 to 4 years, possibly due to the fact
that many Dutch physicians are unfamiliar with the disease. The diagnosis was
based on originating from an endemic area (i.e. Surinam and the Caribbean basin),
the clinical picture and the presence of antibodies against HTLV-I in blood and
CSF. The disease in a number of years leads to spastic paraparesis, incontinence
for urine and dependence on a wheelchair.
PMID- 9557002
TI - [Effect of protein restriction on deterioration of kidney function].
PMID- 9557003
TI - [Dutch drug registration: more openness highly desired].
PMID- 9557004
TI - [Thyroglossal cyst].
AB - The thyroglossal cyst is a wellknown cause of a swelling in the neck. The
generally accepted technique of treatment was described in 1928, but many
recurrences are still seen in daily clinical practice. The radical technique of
removal of cysts and sinuses of the thyroglossal duct according to Sistrunk is
the method of choice. Over an 8-year period 40 cases were treated in this fashion
in the University Hospital Groningen, the Netherlands, with an average follow-up
of 5 years and 3 months; in 29 it was the first operation. Only 1 patient of the
23 treated according to Sistrunk had a recurrence for which he had to be treated
again. Six patients were treated otherwise; 3 of them had a recurrence. It is
concluded that the first surgery (according to Sistrunk), if correctly performed,
offers the best chance for cure.
PMID- 9557005
TI - [Ovum fertilization using surgically obtained sperm: additional risk to offspring
unlikely with meticulous procedure].
AB - In the Netherlands a presumed higher risk of transmission of genetic
abnormalities to the offspring in programmes of intracytoplasmatic sperm
injection (ICSI) using surgically retrieved sperm (microscopic epididymal sperm
aspiration (MESA) or testicular sperm extraction (TESE)) has triggered a
moratorium. However, the ICSI-MESA/TESE-programme should be resumed under
conditions for the following reasons: the source of the sperm is not a accurate
standard of its genetic contents: the cause of the male infertility and the
morphology and function of the injected spermatozoon appear to be better
criteria; animal experiments and clinical results are reassuring as to the
proposed risk; it is uncertain whether the complex genetical mechanisms involved
in spermiogenesis and sperm maturation can be unraveled in the laboratory in due
course; the exodus of patients to neighbouring countries will be stopped and
biological material necessary for human research will become available. The
conditions are that (a) only morphologically normal and motile sperm should be
used, (b) ICSI should be preceded by genetical screening and succeeded by long
term follow up of the offspring.
PMID- 9557006
TI - [Last word on hormone replacement and breast cancer?].
AB - A very large meta-analysis of the Collaborative Group on Hormonal Factors in
Breast Cancer has revealed an increasing risk of breast cancer with longer
durations of use of hormonal replacement therapy (HRT). This risk increase is
restricted to current users of HRT or women who ceased use recently. A 35%
increase of the relative risk of breast cancer was found after 5 years of HRT use
or longer. After cessation of HRT use the excess breast cancer risk disappeared
in 5 years, even after long durations of use. The risk increase was greater for
women of normal or lean body weight than for more obese women. Tumours found in
women who ever used HRT were diagnosed at a lower clinical stage, which suggests
that enhanced screening might be involved. However, the increased breast cancer
mortality in HRT users, as found in other studies, rather suggests a biologic
mechanism Long-term use of HRT is not yet common in the Netherlands, but an
increasing trend is present. Thus, the benefits of long-term use of HRT must be
carefully weighted against the risks.
PMID- 9557007
TI - [Hormone replacement therapy following breast carcinoma].
AB - Additional advantages of hormone suppletion therapy (HST) in women with
climacteric complaints are the reduced risks of development of cardiovascular
disease and osteoporosis. A disadvantage is the enhanced risk of breast cancer.
More and more women with a treated primary breast cancer nowadays have a
relatively favourable prognosis; they might also profit by HST, especially if
chemotherapy for breast cancer has led to an early menopause. Recent pilot
studies of the connection between HST and recurrence of breast cancer are
inadequate as to methodology and size to permit definite conclusions. There are
numerous arguments for a connection between exposure to oestrogens and
development of breast cancer. As long as it has not been demonstrated that HST
does not lead to enhanced risk of breast cancer recurrence, the general
recommendation should be not to administer HST to patients with treated breast
carcinoma.
PMID- 9557008
TI - [Immunology in clinical practice IX. Systemic vasculitis].
AB - A diagnosis of vasculitis generally requires histopathological proof of
vasculitis, particularly because many other disease entities may mimic vasculitis
('vasculitis-look-alikes'). Vasculitis can be primary (idiopathic) or secondary
to other diseases, especially infectious diseases. The primary vasculitides are
classified according to the size of the vessels involved and the nature of the
inflammation, in combination with clinical symptoms. The detection of
autoantibodies, particularly the antineutrophil cytoplasmic antibodies (ANCA), in
some of the primary vasculitides, has facilitated the diagnosis of those diseases
and has given more insight into their pathophysiology. Treatment of primary
vasculitis still consists of corticosteroids whether or not in combination with
immunosuppression. New insights in pathophysiology may provide more specific and
less toxic treatment modalities.
PMID- 9557009
TI - [Nitric oxide inhalation in newborn infants with pulmonary hypertension].
AB - Nitric oxide (NO) is an important endogenous vasodilator. NO, produced in the
endothelial cell, causes vasodilation by relaxation of the vascular smooth muscle
cell. Inhalation of NO plays a role in the treatment of persistent pulmonary
hypertension of the newborn, a syndrome with considerable morbidity and
mortality. NO inhalation specifically leads to pulmonary vasodilation without
systemic hypotension, since NO binds avidly to haemoglobin. Neonates with
pulmonary hypertension associated with lung hypoplasia, meconium aspiration
syndrome, infantile inspiratory distress syndrome due to surfactant deficiency,
and sepsis have been treated with inhaled NO. Literature data on NO inhalation
and experience in our units with NO inhalation show an improvement in arterial
oxygen tension and a decreased need for extracorporeal membrane oxygenation, but
no reduction in mortality. NO toxicity as a result of NO inhalation in the
newborn has not been reported yet.
PMID- 9557010
TI - [Increase in number of premature births in The Netherlands: comparison of 1983
and 1993. Scientific Guidance Commission of the National Neonatology
Registration].
AB - OBJECTIVE: Survey of changes in the number of preterm and very low birth weight
infants in the Netherlands in ten years. DESIGN: Descriptive. SETTING: TNO
Preventive en Gezondheid, sector Jeugd, Leiden, the Netherlands. METHODS: All
infants with a gestational age less than 32 weeks and (or) a birth weight less
than 1500 g from the National Neonatal Register born in 1993 were selected,
supplemented with data from a questionnaire for hospitals not taking part in the
register. The data were compared with those on similar infants from the 'Project
on preterm and small for gestational age' infants born in 1983. RESULTS: The
total number of preterm and very low birth weight infants increased from 1423 in
1983 to approximately 1882 in 1993. There was also an increase in terms of
proportion, from 8.4 per thousand to 9.6 per thousand. The proportion of preterm
infants never treated in a neonatal intensive care unit decreased from 40% in
1983 to 14% in 1993, probably due to increased centralization of neonatal
intensive care facilities. In the same time mortality decreased for all
gestational age categories. CONCLUSION: Both the total number and the survival of
preterm and very low birth weight infants increased considerably over a decade.
This caused a considerable increase in intensive care days and is therefore an
important reason for the increased requirement of neonatal intensive care cots.
PMID- 9557011
TI - [Increase in perinatal referral to regional centers of premature birth in The
Netherlands: comparison 1983 and 1993].
AB - OBJECTIVE: To determine changes in referral of preterm newborns. DESIGN:
Descriptive. SETTING: Foundation for Perinatal Epidemiology the Netherlands,
Leiden. METHODS: Data regarding hospital of birth, referral, need of intensive
care and mortality of the infants < 32 weeks and (or) < 1500 g birth weight born
in 1993 from the National Neonatology Register were supplemented with data from a
questionnaire for hospitals not included in the register. The data were compared
with those of similar infants from the 'Project on preterm and small for
gestational age', born in 1983. RESULTS: In 1983, 61% of the preterm infants were
treated in a perinatal centre: 39% were not referred. In 1993 these numbers were
89% and 11%, respectively. The contribution of antenatal referral increased from
29% to 47% while that of postnatal referral decreased from 41% to 25%. Mortality
decreased from 25.4% in 1983 to 14.3% in 1993. CONCLUSION: Regionalization of
high risk perinatal care resulted in concentration of care for preterm infants.
At the same time, in-hospital mortality decreased by almost 50%.
PMID- 9557012
TI - [Impediments to incubator home care in The Netherlands].
AB - OBJECTIVE: To determine whether incubator home care is desirable and feasible.
DESIGN: Inventory. SETTING: Four neonatal units representative of the type of
care in general hospitals in the Netherlands. METHOD: The relevant data on all
infants with a birth weight < or = 2000 g admitted in the last 3 months of 1996
to one of four hospitals were analysed. Conditions for incubator home care were
determined (e.g. absence of need for special care, vital function monitoring or
nasogastric tube feeding). RESULTS: Forty-nine infants were enrolled. Mean
hospital stay was 28.7 days in an incubator plus 19.7 days in a cot. When infants
were placed in a cot they usually still needed tube feeding and monitoring of
vital functions and sometimes parenteral nutrition, medication or extra oxygen
which made home discharge impossible. Therefore a pilot study of actual home care
could not be carried out. CONCLUSION: Although early home discharge is very
desirable for newborn infants, the number of infants eligible for incubator home
care is so small that further attempts to organise it are not useful.
PMID- 9557013
TI - [Sequelae of premature birth: substantial medical consumption and physical
limitations; survey among parents of 10-year-olds].
AB - OBJECTIVE: To determine health and disabilities of preterm infants at age 10.
DESIGN: Prospective follow-up study. SETTING: TNO Preventive en Gezondheid,
sector Jeugd. Leiden, the Netherlands. METHOD: A questionnaire on medical
consumption and physical disabilities was sent to the parents of a Dutch cohort
of infants born alive in 1983 with a gestational age < 32 weeks and (or) a birth
weight < 1500 g. The data were compared with outcomes at 5 years of age and with
a peer group in mainstream education (data collected in a representative sample
from the school health care system). RESULTS: Questionnaires on 75% of the
eligible children were returned. Almost 40% of the preterm children had been
admitted to hospital after the age of 5. Children in special education were
significantly more often treated by a physiotherapist and (or) speech therapist.
Overall 45% of the children suffered from a physical disability. This was six
times as frequent as in a peer group from the school health survey. Although the
assessment of physical disabilities was based on a paediatric examination at age
5 and on a parental questionnaire at age 10, differences were small. CONCLUSION:
Mild developmental problems and learning disabilities are frequent in preterm
infants. Research of preventive methods and timely interventions are needed and
should be incorporated in the facilities for neonatal intensive care.
PMID- 9557014
TI - [Iatrogenic tension pneumothorax following faulty positioning of gastric tube].
AB - A 74-year-old man was admitted with respiratory insufficiency and required
mechanical ventilation. Enteral nutrition was given via a nasogastric feeding
tube, but persistent food retention occurred. The chest X-ray showed the
nasogastric tube to be in the right pleural space. After the tube was withdrawn
the patient developed a tension pneumothorax and a closed-tube thoracostomy was
performed. The patient's recovery was uneventful, with resolution of the
pneumothorax. It is necessary to be alert with respect to the tube position,
which, if doubtful, should be checked by chest X-ray. Recognition of an aberrant
position is necessary to minimize related morbidity.
PMID- 9557015
TI - [Pill cycle disturbance in simultaneous use of itraconazole and oral
contraceptives].
AB - Since the introduction of itraconazole in the Netherlands, the Netherlands
Pharmacovigilance Foundation LAREB and the Inspectorate for Health Care received
15 reports of pill cycle disturbances and one of pregnancy occurring during
simultaneous use of itraconazole and oral contraceptives. Twelve women used oral
contraceptives containing ethinylestradiol and desogestrel. In these women, the
withdrawal bleeding was either delayed or did not occur at all; one of these
women reported a transiently positive pregnancy test after previous breakthrough
bleedings. Three women who used a contraceptive containing ethinylestradiol and
levonorgestrel had a breakthrough bleeding. One woman who used an oral
contraceptive containing ethinylestradiol and cyproterone acetate became pregnant
during the concomitant use of itraconazole. The possible mechanism involved
remains to be explained. Although an influence of itraconazole on the reliability
of oral contraceptives is uncertain, additional contraceptive measurements might
be considered.
PMID- 9557016
TI - [Health Council's report 'preoperative evaluation: reconsideration of basic
assumptions'].
PMID- 9557017
TI - [Prader-Willi syndrome in young infants].
PMID- 9557018
TI - [Prader-Willi syndrome in young infants].
PMID- 9557019
TI - ['Labor storm' following cervical ripening with prostaglandin gel].
AB - In three pregnant women aged 26, 31 and 26 years with post-term pregnancy and
(or) worsening preeclampsia and an immature cervix, parturition was induced by
intracervical application of dinoprostone. This was followed within a few hours
by bradycardia of the infants, with a labour frequency of about 5 per 10 minutes
and contractions lasting at least 1 minute. After suppression of labour (in two
patients, one of whom meanwhile had developed placental detachment), caesarean
section was performed without delay. One child by then had sustained major
cerebral damage: the other two recovered well. A potentially dangerous adverse
effect of intracervical application of prostaglandin gel is excess uterine
activity. The higher sensitivity to prostaglandins in several conditions
complicating pregnancies (such as serotinicity and preeclampsia), may play a role
in this complication. Careful application of the gel, adequate foetal monitoring
and using half the normal dose in risk patients could be helpful in preventing
foetal distress after intracervical application of prostaglandin gel.
PMID- 9557020
TI - [Vision rehabilitation of patients with old-age macular degeneration].
AB - Age-related degeneration of the macula retinae occurs in two forms: the serious
form with invasion of blood vessels and leakage, and the atrophic form. Both
forms ultimately lead to a central scotoma. The prevalence of the terminal stage
of age-related macular degeneration varies from 1% in the age group 65-74 years
to 11% in those 85 years or over. A total of 58,500 persons in the Netherlands
have age-related macular degeneration and an estimated 22,000 persons depend on
visual or optic aids. Aids for close vision are good illumination, magnification
(reading glasses, magnifying glasses, telescopic lenses, television reading
lenses (with possibility of changing contrast), large-letter books, playing cards
with large symbols) and auditory aids. Aids for distant vision reduce troublesome
light (sunglasses, filter) or enlarge the image (telescopic aids). Future new
aids derive from modern computer technology (personal computer, integrated
braille reader and speech synthesizer) or are based on opto-electronic image
processing and presentation (mini-cameras with mini-VDUs in a sort of helmet).
Effective use of aids depends on attention for the patient's desires and
possibilities and on counselling in handling aids. Ophthalmological checkups
remain useful for the prevention and (or) treatment of accessory disorders.
PMID- 9557021
TI - [Allogeneic bone marrow transplantation in the treatment of (lysosomal) storage
diseases].
AB - The first report of a positive effect of allogeneic bone marrow transplantation
(BMT) on the clinical course in a patient with a lysosomal storage disease was
described in 1981. Since then, over 200 patients have been treated in this way
but data are scarce and fragmentary. Allogeneic BMT involves replacement of the
patient's haemopoietic system by that of a donor. The new cells that repopulate
the body can correct the metabolic disturbance. Most experience with allogeneic
BMT was gained in patients with mucopolysaccharidosis type I, metachromatic
leukodystrophy and adrenoleukodystrophy. Allogeneic BMT reduces the amount of
storage material in internal organs: skeletal abnormalities and neurological
symptoms are at best stabilized. Transplantation-related mortality and morbidity
are high. The applicability of allogeneic BMT is limited.
PMID- 9557022
TI - [Clinical judgment and decision making in medical practice. A retiree with
fatigue and foot drop].
AB - A 64-year-old former civil servant consulted his general practitioner because of
severe fatigue. Later he began to lose weight and gradually developed chronic
sensorimotor polyneuropathy characterized by sensory nerve loss which started in
his legs. After a year he needed a wheel chair and developed cachexia. IgG
paraprotein was detected. Morbid-anatomical examination of enlarged
supraclavicular lymph nodes revealed plasma cell angiofollicular hyperplasia,
characteristic of Castleman's disease. Treatment with corticosteroids led to
marked improvement of the patient's condition. He was able to walk again, using
an ankle orthosis on both legs.
PMID- 9557023
TI - [Characterization of 100 patients with tuberculosis treated in the Academic
Medical Center in Amsterdam].
AB - OBJECTIVE: To inventory both clinical and demographical data of patients with
tuberculosis in the AMC, as well as diagnostic procedures, response to therapy
and rate of resistance. DESIGN: Retrospective, descriptive. SETTING: The Academic
Medical Center. Amsterdam, the Netherlands. METHOD: The medical records of all
patients with a bacteriologically confirmed infection with Mycobacterium
tuberculosis complex between January 1993 and December 1995 were studied.
RESULTS: 70 out of 100 patients with tuberculosis were not born in the
Netherlands. Out of 50 patients tested 18 were HIV positive. The most common
abnormality seen on X-rays of non-HIV positive patients were caverns. The X-ray
of HIV positive patients showed no abnormalities in 39%; there was no correlation
with CD4 cell count. In 74% of the patients with pulmonary tuberculosis the
diagnosis was made by culture of the sputum. Treatment consisted of INH,
rifampicin, pyrazinamide and ethambutol. Twelve patients were infected with
resistant strains, of which two were multidrug resistant. Four patients died of
tuberculosis. CONCLUSION: Tuberculosis was seen mostly among immigrants. Only
half the patients with tuberculosis were tested for presence of HIV antibodies.
Culture and staining of sputum played a key role in the diagnosis of
tuberculosis. Multiresistant tuberculosis was present in 2% of the patients.
Death due to tuberculosis in this population was 4%.
PMID- 9557024
TI - [Tuberculosis in HIV-positive and HIV-negative drug users in Amsterdam].
AB - OBJECTIVE: To determine and to compare the incidences of active tuberculosis in
HIV positive and HIV negative drug users and to describe the main characteristics
of the tuberculosis cases. DESIGN: Prospective. SETTING: Municipal Health
Service, Amsterdam, the Netherlands. METHOD: Data of the ongoing cohort study of
HIV infection in Amsterdam drug users, including HIV serostatus and CD4 cell
counts, from 1986 until 1996 were completed with data from the tuberculosis
registration of the tuberculosis department of the Amsterdam Municipal Health
Service and analysed statistically. RESULTS: Of 872 participants 24 persons
developed culture confirmed tuberculosis during a total follow-up period of 4000
person years (py) (0.6 per 100 py). Nineteen persons were HIV positive (1.54 per
100 py) and 5 HIV negative (0.18 per 100 py). Multivariately, HIV infection and
higher age increased the risk of tuberculosis substantially (relative risks 12.9;
95% confidence interval (CI): 3.4-48.8 and 6.8: 95% CI: 1.3-35.0 respectively).
Thirteen of 22 pulmonary tuberculosis cases (59%) were detected by half-yearly X
ray screening of the chest. Tuberculosis occurred relatively early in the course
of HIV infection at a mean CD4 cell number of 390/microliter. All but one patient
completed the tuberculosis treatment. CONCLUSION: HIV infection increases the
risk of active tuberculosis in Amsterdam drug users 13-fold. The incidence of
tuberculosis in HIV negative drug users in 6 times higher than that in the
overall Amsterdam population. Periodic chest X-ray screening contributes
substantially to case-finding of active tuberculosis in Amsterdam drug users.
PMID- 9557025
TI - [Connection between 2 tuberculosis outbreaks demonstrated after 8 years by DNA
fingerprinting of the causative mycobacteria].
AB - OBJECTIVE: To determine the possible connection between two outbreaks of
tuberculosis at an 8-year interval by DNA fingerprinting of the causative
mycobacteria. DESIGN: Descriptive. SETTING: Regional Public Health Services
Zeeland and Noord-Holland, the Netherlands. METHOD: The source patients of the
tuberculosis explosions in an island in the province of Zeeland (28 persons
infected) and an island of the Noord-Holland area (36 persons infected) were
identified in 1986 and 1994 respectively. In 1994. spoligotyping was performed on
dead bacteria from the suspected source from 1986. to analyse the chain of
transmission. RESULTS: Identical spoligotyping patterns of the source patients
proved the transmission of a Mycobacterium tuberculosis strain from a father to
his son around 1986. Lack of a positive Mantoux test in the son prohibited
prevention of the 1994 explosion. CONCLUSION: Thanks to the applicability of
spoligotyping on non-vital mycobacteria this DNA method contributed
retrospectively to demonstration of a connection between two out-breaks of
tuberculosis at an 8-year interval.
PMID- 9557026
TI - [Acute myocardial infarct following sulprostone administration].
AB - Because of intrauterine foetal death at 35 weeks, parturition in a woman aged 35
years was induced by intravenous sulprostone. A few hours after its start she
sustained a myocardial infarction for which she was treated. Coronary angiography
4 weeks later showed normal coronary arteries and good left ventricular function.
Mild cardiovascular reactions such as bradycardia and mild hypotension are
frequently observed adverse effects. In some instances, sulprostone can induce
myocardial ischaemia. However, the possibility of a myocardial infarction is not
mentioned in the product information of sulprostone. As there was an obvious
temporal relationship and other causative factors were sufficiently excluded, the
causal relation between the administration of sulprostone and the occurrence of
myocardial infarction can be regarded as almost certain. Several experimental
studies provide support for the hypothesis that coronary spasms play a major role
in the pathophysiology of a myocardial infarction during the administration of
sulprostone.
PMID- 9557027
TI - [Circulatory arrest following sulprostone administration in postpartum
hemorrhage].
AB - In a woman aged 39 cardiac arrest occurred 3.5 hours after administration of 250
micrograms sulprostone directly into the uterine wall for a post-partum
haemorrhage after manual removal of the placenta. A long period of resuscitation
was necessary. After further evaluation the woman demonstrated specific
contraindications to the administration of sulprostone. as formulated by the
French authorities: age > 35 years, heavy cigarette smoking, and cardiovascular
risk factors. In the Netherlands sulprostone is registered for intravenous
administration only. We would strongly advise against administration directly
into the uterine wall.
PMID- 9557028
TI - [Cost-effectiveness of pneumococcal vaccination of the elderly].
PMID- 9557029
TI - [Cost-effectiveness of pneumococcal vaccination in the elderly].
PMID- 9557030
TI - [Residents not-in-training and hospital physicians: pariahs in the hospital].
PMID- 9557031
TI - [Hospital mortality and survival following partial pancreaticoduodenectomy].
PMID- 9557033
TI - [What are the consequences of the new American guidelines for the diagnosis of
diabetes mellitus in The Netherlands?].
AB - The American Diabetes Association (ADA) recently issued new guidelines for
classification and diagnosis of diabetes mellitus. The main change is the
decrease of the liminal value of the fasting plasma glucose level from 7.8 to 7.0
mmol/l. A fasting level of 6.1-6.9 mmol/l indicates impaired glucose tolerance
(which eliminates the category 'impaired glucose tolerance', which was
established on the basis of a slightly increased 2-hour glucose level after
ingestion of 75 g glucose). Consequently, the ADA criteria render the oral
glucose tolerance test (GTT) redundant for clinical practice. Given these
criteria, the prevalence of diabetes mellitus among the general Dutch population
will change only slightly, but the number of persons to be classified in a
different category after their introduction is considerable: 39.2% of the ADA
diabetics are not diabetics according to the current WHO classification, while
38.1% of the WHO diabetics are not diabetics according to the ADA criteria. The
criteria established by the ADA accommodate clinical practice, in which the GTT
is hardly used anymore. The WHO still has to decide about whether or not
accepting the ADA guidelines.
PMID- 9557032
TI - [Old, short-of-breath and confused; delirium as a manifestation of pulmonary
embolism in geriatric patients].
AB - Two women aged 88 and 70 and a man aged 90 years had become increasingly confused
and short of breath over a period of a few weeks. Blood gas analysis revealed
serious hypoxia. For lack of an explanation of the respiratory insufficiency,
pulmonary emboli were assumed; this assumption could be confirmed by ventilation
perfusion scintigraphy. Parallel with the treatment of the emboli the delirium
cleared. Because of restlessness, initial treatment with low molecular weight
heparin subcutaneously twice daily was preferred.
PMID- 9557034
TI - [Diabetes mellitus: current classification based on cause and sharpened blood
glucose limits for diagnosis].
AB - Recently new definitions were agreed for the glucose tolerance test (GTT), for
impaired glucose tolerance and for the classification of diabetes mellitus. The
World Health Organization and the American Diabetes Association have been active
on this point. The fasting glucose value has been lowered and been brought into
line with the two hour value of the GTT. Fasting glucose values can now be used
for the diagnosis of diabetes mellitus and of impaired glucose tolerance. The new
classification is based on differences in cause of the diabetes. The
classification includes diabetes mellitus types 1 and 2, pregnancy diabetes and
'other forms of diabetes'.
PMID- 9557035
TI - [A new subtype of diabetes mellitus: maternally inherited diabetes and deafness
(MIDD)].
AB - Diabetes mellitus comprises many subtypes, the pathogenesis of each of which
involves a combination of inherited and environmental factors. Recently a new
subtype of diabetes mellitus was recognized in a Dutch pedigree, designated as
'maternally inherited diabetes and deafness' (MIDD). Impaired hearing is an
associated phenomenon of the disease. Approximately 1.3% of all diabetic cases in
the Netherlands exhibit the MIDD subtype. MIDD shows a strictly maternal
heredity. In MIDD there is a guanine-for-adenine substitution at position 3243 in
mitochondrial DNA. Mitochondria carrying this mutation exhibit a decreased
functionality. In carriers of the MIDD mutation the insulin secretion by the
pancreas in response to stimulation by glucose is impaired.
PMID- 9557036
TI - [From absenteeism to work incapacity; changed role of physicians involved].
AB - Hardly any part of the legal regulations on absenteeism and incapacity for work
has remained unchanged since 1993 in the Netherlands. The system is becoming
increasingly complicated. The essence of the changes is that employers'
responsibility has greatly increased. The new regulations mean a transition from
industrial health care to Factories Act services and from the industrial
insurance board to implementing organs. The legislator emphasizes the evaluation
of what people with health disorders are still able to do. Prevention of
absenteeism/ incapacity for work and reintegration are given great attention.
Treating physicians should not let the complicated regulations keep them from
fulfilling their tasks concerning sick employees, since it is increasingly in the
patient's interest that chronicity be prevented whenever possible.
PMID- 9557037
TI - [The Montignac method: scientific foundation debatable].
AB - Obesity is a major health issue in Western society. In the Netherlands every
fifth person suffers from obesity and every third person is on a weight-reducing
diet. The Montignac method is a very popular diet. The diet is claimed to be a
nutritional science. The method is based on several hypotheses about the
metabolism of carbohydrates and fatty acids: carbohydrates with a low glycaemic
index are preferred, carbohydrates are not to be eaten in combination with fatty
acids, fruit is propagated but must not be combined with other components. The
scientific literature refutes the hypotheses of Montignac regarding the metabolic
effects of carbohydrates and fatty acids. As a method to lose weight, the
conventional recommendations of caloric restriction, less intake of saturated
fatty acids and more physical activity should be preferred to the Montignac diet.
PMID- 9557038
TI - [Diagnosis and treatment of hypertension prior to and following introduction of a
protocol].
AB - OBJECTIVE: To determine the compliance with and the outcome of a practice
guideline introduced for the management of hypertension. DESIGN: Retrospective
medical record survey. SETTING: The outpatient clinic of general internal
medicine of the Academic Medical Hospital Nijmegen, the Netherlands. METHOD:
Daily practice in a period before (1988) and one after (1993) implementation of
the guideline were compared. By means of an inventory form we evaluated the
compliance with the guideline, the decrease in blood pressure after 1 year's
follow-up and the number and dosages of the prescribed drugs. Total costs were
approximated from the number of visits and the number of laboratory and imaging
evaluations. RESULTS: Compliance with the guideline in 1993 was 72% (24) compared
with 65% (27) in 1988. This improvement was predominantly achieved by the junior
residents. In 1993 in 15 patients (19%) blood pressure was measured without
medication having been stopped. The guideline regarding the frequency of blood
pressure measurement was observed in 7 patients (9%). The decrease in systolic
and diastolic blood pressure was larger in 1993 than in 1988 (p < 0.05). This
result was achieved by a larger number of blood pressure lowering drugs (1.40
(1.06) in 1993 vs. 1.17 (0.98) in 1988): the mean dose of the prescribed drugs
was lower. The number of visits rose by 10% to 7.8 (3.7) and the number of
diagnostic laboratory procedures by 25% to 956.
PMID- 9557039
TI - [Percutaneous jugular Tesio catheter useful for long-term hemodialysis:
experiences in 26 patients].
AB - OBJECTIVE: Inventory of the Tesio catheter (TC), its functioning and
complications. DESIGN: Retrospective descriptive file investigation. SETTING:
Rijnstate Hospital, Arnhem, the Netherlands. METHOD: From the hospital files of
the patients with chronic renal insufficiency who from July 1992 until October
1995 received a TC, we collected data on indications for placing and removing,
duration, complications of the TC and mortality. RESULTS: Data were suitable for
26 patients, 8 men and 18 women, mean age 63 year (range: 33-79). The indications
proved to be short life expectancy, failure of other vascular access and expected
long catheter dialysis. The total number of days the TC was in situ was 2780
(median: 80.5: range: 15-559). Fourteen patients showed no complications, one
patient had dysfunction of the TC due to thrombosis, local infection occurred
around the insertion opening in five and bacteremia in seven patients. In one
patient, with a prosthetic cardiac valve, the catheter had to be removed
prematurely because of an infection. No deaths due to the TC occurred.
CONCLUSION: The TC appears to be a safe form for long-term haemodialysis.
PMID- 9557040
TI - [Isolated traumatic dorsal dislocation of the metacarpophalangeal joint of the
index finger].
AB - A woman aged 36 sustained a dislocation of the metacarpophalangeal joint of the
index finger occurred during a volleyball match. It appeared to be a complex
dislocation with entrapment of soft tissue, which is rare. Open reduction with a
volar approach gave a good result. The postoperative course was uneventful.
Adequate treatment necessitates rapid diagnosis. The herniation of the head of
the metacarpal bone through the volar surface precluded closed repositioning. The
palmar surgical approach is difficult but gives good anatomical results. The
dorsal approach is safer but more laborious. Rapid mobilization is necessary for
a good long-term result.
PMID- 9557041
TI - [Clostridium difficile outbreak in surgical wards].
AB - OBJECTIVE: To evaluate the clinical consequences of a hospital outbreak of
Clostridium difficile infections in the Netherlands. DESIGN: Descriptive.
SETTING: Diakonessen Hospital Utrecht, the Netherlands. METHODS: In the period
from 1 August 1995 to 1 September 1996 C. difficile infections were recorded
(gastrointestinal symptoms after use of antibiotics and findings at C. difficile
toxin assay in faeces, or sigmoidoscopy). The monthly incidence of infections
increased to 5 patients in December 1995; at that time strict hygienic measures
were implemented and perioperative antimicrobial prophylaxis was adjusted. Data
on the clinical course were collected retrospectively from the records of the
patients involved. RESULTS: In 20 patients, admitted for various reasons to the
surgical wards, hospital stay was complicated by a C. difficile infection. The
mean age was 70 years. Eleven patients presented with diarrhoea, eight patients
had nausea and vomiting as well. Diagnosis was confirmed by C. difficile toxin
determination in most patients (n = 15). Despite antibiotic treatment in 19
patients, recurrences were seen in five patients (25%) and five patients died
(25%). The monthly incidence declined to 0-1 per month. CONCLUSION: C. difficile
infections in surgical patients carry a significant morbidity and mortality.
Preventive hygienic measures are important to control spread of the infection.
PMID- 9557042
TI - [The relationship between health gain and effort in mass screening for breast
cancer].
PMID- 9557043
TI - [Heart tamponade: a life-threatening complication of a central venous catheter].
PMID- 9557044
TI - [Future developments in heredity research. I. Technological possibilities].
PMID- 9557045
TI - [Rhinologic changes in cystic fibrosis and hypogammaglobulinemia].
AB - Nasal and paranasal findings in cystic fibrosis and hypogammaglobulinaemia are
presented. Two cases are discussed. Case one that is 20 year old man with
oedemato-polypoid changes of nasal mucosa and diagnosis of cystic fibrosis was
made during his staying in hospital. Case 2 that is 12 year old boy with
previously diagnosed hypogammaglobulinaemia also presented oedemato-polypoid
changes of nasal mucosa. Both pharmacological and surgical treatments were
brought. Authors' observations are compared with the literature and necessity of
detailed diagnosis of oedemato-polypoid changes of nasal and paranasal sinus'
mucosa is stressed.
PMID- 9557046
TI - [Treatment of bilateral vocal cord paralysis: surgical technique and functional
results].
AB - The authors present possibilities of the surgical treatment in bilateral vocal
cord paralysis. We described the technique of the operation which is being used
in our department in such a cases. 13 patients were analyzed after operations (11
women, 2 men). Bilateral vocal cord paralysis was caused by thyroidectomy (11
cases), virus infection (1 case) and in the course of multiple sclerosis (1
case). Functional results were evaluated by subjective examination, indirect
laryngoscopy, spirometry and video-laryngoscopy. The effects of the treatment
were satisfied.
PMID- 9557047
TI - [Mucocele of the paranasal sinuses].
AB - Twelve cases selected from the group of 123 chronic rhinosinusitis patients are
presented in the paper. Severe headaches were noted as the most typical
complaints of the clinical picture of the disease. The most cases were
accompanied by rhinitis and paranasal sinusitis symptoms. The best diagnostic
method of mucocele is MRI. The endoscopic sinus surgery is a safe and effective
method of the treatment in a case of mucocele.
PMID- 9557048
TI - [The effect of nitrous oxide on middle ear pressure in secretory otitis media in
children].
AB - The preliminary results of the nitrous oxide application during children
anesthesia with secretory otitis media was presented. The different otological
operations in which nitrous oxide is contraindicated were mentioned. The nitrous
oxide influence on the middle ear pressure increase was emphasized. It was
confirmed by tympanograms. Necessity of the further investigations in this
subject were emphasized due to encouraging results.
PMID- 9557049
TI - [Ultrasonographic characteristics of neck lesions and the value of ultrasound
examination in postoperative monitoring of patients with laryngeal cancer].
AB - The purpose of this study was to evaluate the superiority of ultrasound
examination of the neck in comparison with palpation in patients operated on and
irradiated because of the larynx cancer. Close follow up by means of
ultrasonography all patients after initial operation is essential to detect
recurrence early, while surgical salvage is still feasible. Scars, oedema and
anatomical changes due to prior surgery and radiotherapy make the clinical
examination very difficult. Apart from demonstrating non palpable nodes,
ultrasound may also depict nodal size, multiplicity, relation to the surrounding
vessels, invasion of the carotid artery and malignant extension in the salivary
glands or thyroid. 12 pictures of ultrasound were presented.
PMID- 9557050
TI - [Use of mucolytic preparations (Mucosolvan) in selected diseases of the upper
respiratory tract. Part II].
AB - The majority of publications in the recent years emphasizes the importance of
mucolytic preparations in the upper respiratory tract diseases. There have been
very few report about the important role which mucolytic drugs may play in the
diseases of the upper respiratory tract. This paper undertakes the task of
attempting to evaluate the usefulness of Mucosolvan preparation in laryngological
diseases. The main condition of the successful treatment of otolaryngological
diseases is maintaining the efficient mechanism of the clearing of upper
respiratory tract. This is achieved by means of the mucocilia apparatus, namely
cilia and mucosa protecting the epithelium from harmful factors. Tests were
carried out on 60 patients with paranasal sinuses and ear diseases. The first
group comprised 45 patients who were qualified on the basis of inflammatory
changes in paranasal sinuses. The second group comprised 12 children and 3 adults
with otitis media with effusion. Mucosolvan which was used in the supplementary
treatment fulfilled our expectations. The use of the mucolytic drug accelerated
the healing process, proper regeneration of the epithelium and the reduction of
the period of drug administration.
PMID- 9557051
TI - [The possibility of tinnitus suppression by electrical stimulation].
AB - The authors described the treatment of 36 patients with persistent tinnitus. In
the past the patients were treated with other methods without positive results.
After audiological examinations Promontory Stimulator (Cochlear Co.) for
electrical stimulation was used. During the electrical stimulation one electrode
was inserted in external auditory meatus and the other on planum mastoideum.
Bursts of biphasic pulses of 0.1 ms duration were used during electrical
stimulation. Electrical stimulation was applied 10 min. during 10 days. The
patients estimated effects of treatment and results are presented in table. The
authors obtained satisfactory results in 48% of the patients.
PMID- 9557052
TI - [The sixtieth anniversary of Miodonski's paraboloid head lamp reflector].
AB - On the 60th anniversary of the elaboration by Miodonski of the optical solutions
and his construction of the Paraboloid Headlamp and its application to clinical
practice, the author compares its characteristics with other types of lamp used
in otolaryngology on the example of Clar's Headlamp and Headmirror. This
comparison shows that even now Miodonski's Paraboloid Headlamp due to its
qualities, has no equal. The merits of Miodonski's Headlamp are as follows: 1.
Permits a change of the axis of illumination under sterile condition; 2. Gives
the most powerful light; 3. Permits binocular inspection of very narrow and long
canals and ducts allowing for enlargement from the time that Miodonski added a
magnifying and mobilizing lens to his headlamp in 1961.
PMID- 9557053
TI - [Basic principles of LIFE--autofluorescence bronchoscopy. Results of 194
examinations in comparison with standard procedures for early detection of
bronchial carcinoma--overview].
AB - BACKGROUND: Conventional bronchoscopy in the identification of preneoplasias and
carcinoma in situ (CIS) has been inadequate to date. Tissue autofluorescence was
found to differentiate normal mucosa from dysplastic or carcinomatous bronchial
mucosa. This principle resulted in the development of the LIFE System (Light
Imaging Fluorescence Endoscope, Xillix Techn., Vancouver, BC), now in routine use
worldwide at 35 centres. In a prospective multicentric study in North America the
relative sensitivity for diagnosing intraepithelial neoplasias of combined white
light (WLB) and LIFE bronchoscopy in 173 at-risk patients was 6.3 as compared to
WLB alone. A similar European multicentric study will be completed by spring of
1998. PATIENTS AND RESULTS: We report on our experience with the routine use of
the LIFE System over 23 months. 194 examinations (165 patients) were performed.
Moderate to severe dysplasias and in situ carcinomas were diagnosed with a
relative sensitivity of 2.7 by the combined WLB-LIFE examination as compared to
WLB alone. CONCLUSION: Autofluorescence bronchoscopy as a routine investigation
without need of photosensitizers in patients with a high risk for lung cancer can
lead to a substantial increase in the detection rate of CIS and moderate to
severe dysplasias compared to white light bronchoscopy alone.
PMID- 9557054
TI - [Current indications for resection of tuberculoid lung changes--relics of the pre
chemotherapy era?].
AB - The spectrum of indications for elective resection of pulmonary tuberculosis was
considerably reduced by clinical evaluation of the effective antituberculous
chemotherapy and is limited only to a few pathomorphological processes and
clinical situations today. The same estimation is valid in case of nontuberculous
mycobacteriosis with clinical importance. The combined therapy with new macrolid
antibiotics, quinoloses and Rifampicin-derivatives current enlarged the options
of conservative therapy. Thus the surgery of pulmonary tuberculosis are rare
operations and are essentially limited to the therapy of late complications of a
former collapse therapy, of destroyed lungs and bronchiectasis with recurrent
infect exacerbations and life threatening or massive recurrent haemoptysis.
PMID- 9557055
TI - [Nosocomial ventilator-associated pneumonias caused by Aspergillus fumigatus in
non-immunosuppressed, non-neutropenic patients].
AB - We observed three cases of severe ventilator-associated pneumonia due to
Aspergillus fumigatus in non-immunosuppressed, non-neutropenic patients. Autopsy
confirmed an angioinvasive pattern of spreading with septic foci. In all cases
conditions associated with temporary immunodysfunction like underlying diseases,
antecedent sepsis or pneumonia, coinfections or steroid therapy were present.
Although Aspergillus fumigatus was isolated in all cases in cultures of
tracheobronchial secretions, the correct diagnosis was not obtained during
lifetime. Our cases demonstrate that pneumonia due to Aspergillus fumigatus must
be taken into account also in this patient population.
PMID- 9557056
TI - [Rapid prediction of rifampin susceptibility of Mycobacterium tuberculosis].
PMID- 9557057
TI - [DNA fingerprints of Mycobacterium tuberculosis isolates of patients confined for
therapy noncompliance show frequent clustering].
PMID- 9557058
TI - [Comparison of anterior rhinomanometry and impulse oscillometry in nasal
provocation with histamine].
AB - Anterior rhinomanometry (aR) is the standard method for measurement of nasal
resistance, but it has some drawbacks because it requires full co-operation of
the patient and the results are disturbed by forced ventilation due to stenosis.
The patient must generate flow by active ventilation. Resistance results from the
flow/pressure ratio. Forced oscillation technique (IOS) does not affect
spontaneous breathing. Flow/pressure ratio is generated externally by a
loudspeaker. IOS measures not only resistance but also reactance. Whereas former
methods used only a single frequency IOS is capable of applying and analysing
frequencies between 0 and 100 Hz. The range from 5 to 35 Hz is useful for
diagnostic issues. We compared IOS with aR in nasal provocation tests with
histamine and checked the sensitivity of resistance (R) and reactance (X) at
different frequencies. METHOD: 20 patients (13 m, 7 f) underwent nasal challenge
test using increasing doses of histamine (max. 3.2 mg). Resistance (aR, IOS) and
reactance (IOS) were measured parallel. To compare the two methods, we calculated
the dose of histamine which is required to double nasal resistance. RESULTS: 1.
IOS demonstrates the increase of R at all frequencies. 2. The highest increase of
R is measured at a frequency of 5 Hz (5 Hz: NaCl 0.41 +/- 0.25; Hist. 1.26 +/-
0.57; 35 Hz: NaCl 0.36 +/- 0.172; Hist. 0.60 +/- 0.1 kPa/l/s, p < 0.001). 3. The
critical dose is significantly lower in IOS than in aR (2.29 +/- 2.59 vs. 1.06 +/
1.16 mg/ml, p < 0.02). 4. Basal values of R do not differ significantly between
aR and IOS (0.37 +/- 0.12 vs. 0.41 +/- 0.25 kPa/l/s, p < 0.001). CONCLUSIONS: We
conclude from our results that IOS is at least equivalent to aR in measuring
nasal resistance. R at 5 Hz is the most important parameter in IOS. IOS is less
dependent on the cooperation of the patient. In case of stenosis it does not
require forced ventilation to achieve the required flow-pressure ratio.
PMID- 9557059
TI - [Diagnostic value of somatostatin receptor scintigraphy with indium-111
pentetreotide in small-cell bronchial carcinoma].
AB - Small-cell lung cancer (SCLC) cells may express somatostatin receptors [14].
Receptor-positive tissue can be visualised in vivo by scintigraphy with
radiolabelled somatostatin analogues. In a prospective study we examined 18
patients with histologically proven SCLC for the diagnostic value of somatostatin
receptor scintigraphy using indium-111 pentetreotide. Planar whole body scanning
was performed 4 and 24 hours after administration. Additional SPECT imaging of
the thorax and the abdomen was done at 24 hours. The results were compared with
conventional staging procedures: ultrasound, x-ray, computed tomography and bone
scintigraphy. In all 18 patients the primary tumour was correctly identified. Out
of 13 patients with mediastinal lymphoma formation 10 patients showed positive
SRS. In 2 more patients SRS showed mediastinal uptake while CT scanning was
negative. The detection of distant metastases in patients with extensive disease
was true positive in 8 cases (OSS, HEP, BRA), false negative in 4 cases (PLE,
ADR, HEP), corresponding to a sensitivity of 67%. In 2 patients cerebral
metastases were no longer detectable by SRS after previous local irradiation.
Even though the method is limited in respect of revealing distant metastases in
the upper abdominal area due to physiological uptake in liver, spleen and
kidneys, differentiation between limited disease (LD) and extensive disease (ED)
was possible in all cases. We conclude that [111In]pentetreotide scintigraphy is
a suitable method for the detection of SCLC primary tumours and a substantial
tool for differentiation between LD and ED if combined with ultrasonography of
the upper abdomen.
PMID- 9557060
TI - [Surgery of late complications of previous active treatment of lung tuberculosis
with extrapleural plombage].
AB - Between January 1984 and February 1997 10 patients with late complications of a
former active collapse therapy were operated. In case of our patients between
1943 and 1960 the collaps therapy was carried out with the extrapleural
instillation of plombs for therapy of pulmonary tuberculosis. At present main
complications were infections of plombs with pleurobronchial and pleurocutaneus
fistulas and perforation of plombs. By all patients both extirpation and
pleurectomy were necessary. In case of 5 patients additionally lung resection was
required, in case of 3 patients a thoracoplasty and by 1 patient a myoplasty.
Although there are considerable destructions of lung parenchym in a part the
results of long-term follow up are satisfactory: 6 patients are so far without
complaints; only 1 patient died 10 years postoperative. Prerequisite for a
successful therapy are the knowledge of the surgical methods of the collaps area,
the used materials, the pathomorphological pulmonary changes and the good
cooperation between pneumologists and thoracic surgeons.
PMID- 9557061
TI - Hypermobility syndrome.
PMID- 9557063
TI - Postpartum psychiatric illness: the role of the pediatrician.
AB - PPD occurs in 10% to 20% of postpartum women. Maternal depression can affect a
child's development significantly. Pediatricians can screen for maternal
psychiatric illness with little effort; of all the health care professionals,
they may be in the best position to do so. Pediatricians can help affected
mothers obtain appropriate treatment and help mobilize social resources. This
simple process can minimize morbidity to pediatric patients.
PMID- 9557062
TI - Cephalosporins: an update.
AB - The cephalosporins are the largest and most diverse family of antimicrobial
agents available. Although they rarely are considered drugs of first choice for
the therapy of bacterial infections, they are the most commonly prescribed agents
for both ambulatory and hospitalized patients. The first-generation agents have
the most limited spectrum of bactericidal activity, but they are the most potent
against Gram-positive microbes. The third- and fourth-generation agents have a
broad spectrum of activity that includes the majority of Gram-negative pathogens.
However, they are less active than their first-generation counterparts against
Gram-positive bacteria, especially S aureus. The cephalosporins generally are
well tolerated, and the oral agents are palatable. However, their use is limited
by increasing resistance among certain groups of bacteria and high cost,
especially of the parenteral and recently licensed oral agents. The prudent
physician need not be familiar with all cephalosporins, but should be
knowledgeable about a select few.
PMID- 9557064
TI - Diagnosis and management of headache in children.
PMID- 9557065
TI - Index of suspicion. Case 1. Diagnosis: infectious mononucleosis.
PMID- 9557066
TI - Index of suspicion. Case 2. Diagnosis: recurrent bacterial meningitis.
PMID- 9557067
TI - Index of suspicion. Case 3. Diagnosis: glucose-6-phosphate dehydrogenase
deficiency.
PMID- 9557068
TI - Erythromycin.
PMID- 9557069
TI - Nasal septal hematoma.
AB - Nasal septal hematoma is a rare but potentially serious complication of nasal
trauma. Proper management consists of early recognition, prompt surgical
evacuation of the hematoma, and antimicrobial therapy if a secondary nasal septal
abscess is suspected. Clindamycin is recommended as initial therapy until the
results of cultures and susceptibility studies are available.
PMID- 9557070
TI - [Influenza and its prophylaxis].
PMID- 9557071
TI - [Evaluation of electrophysiologic properties of the heart atrium in patients with
electrically induced atrial fibrillation].
AB - Paroxysmal palpitation is a frequent non-specific symptom observed in clinical
practice. It is not always possible to identify the arrhythmogenic cause of this
complaint. The induction of paroxysmal atrial fibrillation (PAF) during
transoesophageal pacing (TEP) was found to be particularly useful when arrhythmia
paroxysms were not evidenced by standard electrocardiography or by 24-hour Holter
monitoring. The objective of the present study was a comparative assessment of
the electrophysiological parameters obtained from a patient group with PAF
induced during TEP and from a patient group with no arrhythmia, in order to
determine the hazard of spontaneous PAF occurrence. The study included 116
patients complaining of palpitations who underwent TEP. Of these, 53 were
selected (34 males and 19 females; mean age, 47.6 +/- 13.1) in whom a sustained
PAF episode (> 30 sec) had been induced during TEP. These patients are referred
to Group I. Group II (control) comprised the remaining 63 patients (38 males and
25 females; mean age 45.5 +/- 8.5) in whom no PAF episode had been induced during
TEP. All patients (Group I and Group II) underwent echocardiography, 24-hour
Holter monitoring, exercise test and TEP. During TEP the following parameters
were evaluated: left atrial effective refractory period (AERP), sinoatrial
conduction time (SACT), maximal and corrected sinus node recovery time (SNRT and
CNRT), Wenckebach periodicity (WP) and mean cycle duration (CD). Thus, the AERP
value amounted to 299.8 +/- 42.4 msec and 259.5 +/- 54.9 msec (p < 0.001) for
Group I and Group II, respectively. The SACT and SNRT values totalled 132.3 +/-
45.1 msec and 1011.1 +/- 165.6 msec in Group I, and 103.2 +/- 29.9 msec and 838.3
+/- 172.7 msec in Group II, respectively (p < 0.001). Compared to the control
(235 +/- 95.7 msec; 200.3 +/- 64.9 msec, respectively), the group of patients
with electrically-induced PAF (Group I) showed significantly longer CNRT (383.4
+/- 172.5 msec, p < 0.001) and WP (350.8 +/- 59.3 msec, p < 0.001). The study had
led to the following finding: patients with electrically-induced PAF had
significantly longer left effective refractory periods, sinoatrial conduction
times, maximal and corrected sinus node recovery times and Wenckebach
periodicities.
PMID- 9557072
TI - [Activity of cathepsin B and collagenase in urine and excretion of fibronectin
and TGF-beta 1 in urine of patients with membranous glomerulonephritis].
AB - In 30% cases nephrotic syndrome is due to membranous glomerulonephritis (MG).
Fifty percent of patients reveal end stage renal disease in 15 years follow-up.
The another 50% gain persistent remission. The pathogenesis of disease is not
known. Protein accumulation in glomeruli leads to progressive loss of kidney
structure and function in MG. Also the role of tissue proteolytic systems and
growth factors in this process is not known. We aimed to estimate urine cathepsin
B, collagenase activity and urine excretion of TGF-beta 1 and fibronectin in MG.
MG patients revealed increased urine cathepsin B activity (10.58 +/- 8.73 pmol
AMC/mg creatinine/min. vs. control 7.11 +/- 2.05 pmol AMC/mg creatinine/min. [p <
0.05]), urine collagenase activity (8.59 +/- 4.26 pmol AMC/mg creatinine/min. vs.
control 3.84 +/- 2.09 pmol AMC/mg creatinine/min. [p > 0.02]) and increased urine
excretion of fibronectin (214 +/- 335 ng/mg creatinine vs. control 12.7 +/- 6.7
ng/mg creatinine [p < 0.05]) and increased urine excretion of TGF-beta 1 (283.55
+/- 248.13 pg/ml vs. control 36.11 +/- 48.01 pg/ml [p < 0.05]). The results
indicates on glomerular overproduction of TGF-beta 1 and urinary leak of
proteolytic enzymes which may exacerbate glomerular proteolytic activity in MG.
This may lead to glomerular protein accumulation and progressive loss of kidney
function and structure in MG. Increased urine fibronectin excretion in MG
patients seems to confirm the hypothesis.
PMID- 9557073
TI - [Cognitive function in patients with systemic sclerosis].
AB - Central nervous system involvement is seldom reported in patients with systemic
sclerosis (SSc). Cognitive functions were determined in 21 patients with definite
SSc and 42 healthy controls. Thyroid function was also measured in order to
eliminate the effect of hypothyroidism on cognitive functioning. It was found
that the SSc patients with normal thyroid function showed defective long-term and
recent memory, learning ability, criticism, perception and visuo-perceptual
skills, their simple reaction time was prolonged. Similar but less advanced
cognitive defects were shown in the SSc patients with overt or latent
hypothyroidism. The obtained results indicate that the central nervous system
involvement is more common in patients with SSc than it has been reported
earlier.
PMID- 9557074
TI - [Risk factors for atherosclerosis in offspring of parents with primary
hypertriglyceridemia].
AB - High triglycerides and low fibrinolysis activity are considered as a significant
predictors for atherosclerosis. The aim of our study was: 1-to compare these risk
factors levels in children with positive family history of hypertriglyceridemia
(HTG) with children from healthy families and 2-to assess the association between
triglyceride and fibrinolysis activity in offspring (y) and parental risk factors
(xl ... xn) for atherosclerosis. The study population consisted of: I Group 15
children 7-12 years old and their parents from HTG families and II Group 26
control children 5-12 years old from healthy families. Triglyceride (TG), total
cholesterol, cholesterol esters, LDL-Ch, HDL-Ch, HDL2Ch, apolipoprotein AI and
BII, fibrinogen plasma level were determined. Plasminogen activator inhibitor
(PAI-1) and fibrinolysis activity and (ELT) were determined. We found significant
differences in clinical examinations (higher blood pressure and ECG disturbances
more frequently), HDL-Ch and HDL2-Ch plasma level was lower in children with
positive family history than in control children. Multiple regression analysis of
parental variables demonstrated, that children's TG and ELT are strongly
determined by parental lipids and haemostasis parameters in children with
positive family history of HTG.
PMID- 9557075
TI - [Case report presentation for treatment of pure red cell aplasia].
AB - We presented a case of a 34 year old male patient with pure red cell aplasia. He
was treated with antithymocyte globulin (Pasteur Merieux, France) at a dose of
175 mg in 350 ml 0.9% NaCl in intravenous drip infusion--10 drip/min for 5
consecutive days. The therapy resulted in normalization of morphological
parameters. Patient was under clinical observation. After 9 years when hemoglobin
level decreased monoclonal antibody OKT3 og IgG 2a type (Cilag Ag International,
Switzerland) at a dose of 5 mg intravenous for 10 consecutive days was applied.
During the first and second therapy course symptoms of serum sickness and "flu
like" syndrome was observed. The results of the two treatment appeared positive.
We received normalization of morphological parameters.
PMID- 9557076
TI - [Distal tubular acidosis in a patient with insulin dependent diabetes mellitus-
selected pathophysiologic, diagnostic and therapeutic aspects].
AB - This case report describes a 42 years old male patients with distal tubular renal
acidosis in whom the symptomatology of this disorder was markedly changed by the
presence of concomitant endocrine and exocrine insufficiency of the pancreas.
Pathophysiological, diagnostic and therapeutic aspects of coexistence of these
two type of pathology are stressed.
PMID- 9557077
TI - [Adrenomedullin].
PMID- 9557079
TI - [Video-thoracoscopy in thoracic diseases].
PMID- 9557078
TI - [The role of eosinophils in inflammation].
PMID- 9557080
TI - [Clinical use of thrombopoietin--hypotheses and clinical promises].
PMID- 9557081
TI - [Hemodialysis yesterday and today].
PMID- 9557083
TI - [Progress in diagnosis and treatment of glomerulopathies].
PMID- 9557082
TI - [Kidney transplantation in Warsaw and Poland in the years 1966-1996].
PMID- 9557084
TI - [The role of mesangial matrix in kidney diseases].
PMID- 9557085
TI - [Recurrence of primary glomerulopathy in children after kidney transplantation].
PMID- 9557086
TI - Cancer in endstage renal failure: potential pathogenic factors.
PMID- 9557087
TI - [Metabolism of magnesium and lipid disturbances in chronic renal failure].
PMID- 9557088
TI - [Function of the left heart atrium during hemodialysis].
AB - In 23 chronic uremic patients effect of four-hour hemodialysis on function the
left atrium of the heart was investigated. The reference group consisted of 17
healthy subjects. The function was evaluated by cross-sectional Doppler
echocardiography. Before hemodialysis maximal (LAmax) and minimal (LAmin) left
atrial dimensions and left atrial dimension obtained in M-mode of long axis in
parasternal projection (LAa), pre-ejection period (PEPlp), ejection time (ETlp),
PEPlo/ETlp ratio and left atrial fiber shortening fraction (FS%lp) were
significantly higher in chronic uremic patients than those found in healthy
subjects. Four-hour hemodialysis induced decreases in these indices, but only a
lowering of LAa, PEPlp/ETlp ratio was statistically significant in comparison
with pre-dialysis period. No correlation was found between changes of the
investigated indices of the left atrial function and body weight loss during
hemodialysis.
PMID- 9557089
TI - [Progress in clinical diagnosis of urinary tract infection in adults].
PMID- 9557090
TI - [Evaluation of the treatment efficacy of secondary hyperparathyroidism with oral
pulse doses of alphacalcidol].
AB - The purpose of the study was to evaluate the effectiveness of the oral pulse
therapy with high doses of alphacalcidol (1 alpha(OH)D3) in secondary
hyperparathyroidism. 16 hemodialysis patients with 4 to 9-fold iPTH serum
elevation were given ones in week oral 1 alpha(OH)D3 in doses from 5.0 to 7.0
micrograms (0.1 microgram/b.m.) according to serum levels of calcium, phosphate,
activity of alkaline phosphatase with its bone fraction. Serum iPTH levels were
measured every 3rd month of the treatment. The dialysate calcium was reduced to
1.25 mmol/l. CaCO3 was used as a main phosphate binder in doses from 3.0 to 9.0
g/day. After first three months of treatment the serum iPTH levels decreased from
486.0 +/- 200 pg/ml to 218.0 +/- 117 pg/ml (p = 0.0001). Calcium levels increased
from 2.39 +/- 0.2 mmol/l to 2.52 +/- 0.29 mmol/l (p > 0.05). Phosphate levels
increased from 2.15 +/- 0.67 mmol/l to 2.17 +/- 0.62 mmol/l (p > 0.05). Alkaline
phosphatase levels decreased from 35.2 +/- 17.3 IU/l to 31.1 +/- 7.78 IU/l (p >
0.05). Bone isoenzyme of alkaline phosphatase decreased from 19.2 +/- 13.4 IU/l
to 15.5 +/- 7.51 IU/l (p > 0.05). Because of early serum hypercalcemia, doses of
1 alpha(OH)D3 had to be reduced in 2 patients. In 8 patients (50%) demonstrating
decrease of serum iPTH levels (below 200 pg/ml) after first 3 months of treatment
doses of 1 alpha(OH)D3 were reduced in the following months. We conclude that
oral 1 alpha (OH)D3 pulse therapy is effective for parathyroid activity
suppression in patients with severe hyperparathyroidism. To avoid dangerous
hypercalcemia and adynamic bone disease serum iPTH and calcium levels should be
strictly monitored.
PMID- 9557091
TI - [Diagnosis and treatment of urinary tract infection in children].
PMID- 9557093
TI - Our favourite drink.
PMID- 9557092
TI - [Comparison of the clinical course of pneumonia and concentration of
immunoglobulin in patients treated with a standard method and with the addition
of gmma-venin P].
AB - The therapy with immunoglobulin have been used since many years, although its
clinical efficacy still is uncertain. The aim of this study was to compare the
clinical course of severe pneumonia and concentration of immunoglobulin in
patients admitted to the intensive care units (ICU). The patients were treated
either with antibiotics only or with antibiotics and Gamma-Venin P. Investigates
group consisted of 30 patients with severe pneumonia. 15 of them (group A) were
treated with antibiotics only, and another 15 (group B) with antibiotics and
Gamma-Venin P. Immunoglobulins were administrated intravenously in the maximum
single dose 3.0 g/kg. The serum concentration of immunoglobulin were measured
before and every second day after beginning of the treatment. 27 patients
completed the study due to protocol (14 patients in group A and 13 patients in
group B). Only two patients revealed sings of intolerance of Gamma-Venin P during
the first infusion of immunoglobulin. The clinical course of pneumonia and
duration of treatment in ICU were similar in both groups. Statistically
significant differences in concentration of immunoglobulins in patients treated
without immunoglobulin infusion in comparison with patients with Gamma-Venin P
were not found. We conclude, that infusion of immunoglobulins did not improve the
clinical course of the severe pneumonia.
PMID- 9557094
TI - Stroke management in the decade of the brain.
PMID- 9557095
TI - Accidental ingestions in childhood.
AB - One-hundred and twelve cases of accidental poisoning were admitted over a 2-year
study period (December 1990 to December 1992). Data was collected upon admission
and patients were subsequently followed-up. Fifty-four percent of admission were
boys. Majority of them were toddlers between the ages of 1 and 3 years. Thirty
percent of accidental ingestions occurred during the school/public holidays.
These occurred when the caretakers were preoccupied. Forty-nine percent of
patients ingested oral medication; 16% ingested household liquids and the rest
ingested other household products like cockroach tablets and thermometer mercury.
The most commonly ingested medications were paracetamol, salicylate and
bronchodilators, whilst chlorox, kerosene and detergents were the common
household liquids ingested. The ability of the caregivers to quantitate the
ingested product was poor. The mean hospital stay of the patients was 2.5 days.
The majority of them were admitted for observation which did not require
antidotes. Four cases were observed in the intensive care unit. There were no
fatalities during the study period. Forty-four percent of the patients had
samples taken for toxicology analysis, of which, less than half had positive
results. All the patients were advised on the safety measures to look out for
after admission. Less than 10% of cases had prior knowledge of such measures
before the accidents occurred.
PMID- 9557096
TI - Caesarean and postpartum hysterectomy.
AB - AIM OF STUDY: To review the cases of caesarean and post-partum hysterectomy
performed over a 10-year period (1986-1996) in a teaching hospital, looking
specifically at the associated morbidity. METHOD: Retrospective review of case
files. RESULTS: During the study period, there were 14 cases of caesarean and
post-partum hysterectomy. Caesarean hysterectomy was performed in 0.17% of
caesarean sections and a hysterectomy was done in 0.02% of cases following a
vaginal delivery. Uterine atony was associated with 43% of cases. Histological
evidence of placenta accreta or increta was noted in 7 (50%) cases, while 8 (57%)
cases had placenta praevia. A subtotal hysterectomy was performed in 7 cases,
where the mean operating time was significantly shorter than that in cases of
total hysterectomy. There were no maternal deaths. Fever (28%), urinary tract
infection (21%) and chest infection/atelectasis (21%) were the common post
operative morbidity. Relaparotomy for continuing vaginal bleeding was required in
2 cases. CONCLUSIONS: Emergency peri-partum hysterectomy for obstetric
haemorrhage is a rare operation (1 in 2,550 deliveries). In spite of the intra
operative risks and post-operative morbidity, it remains a potentially life
saving procedure.
PMID- 9557097
TI - Does heart rate really predict survival in septic shock?
AB - BACKGROUND: Normalisation of heart rate after 24 hours of treatment is proposed
to predict the survival outcome in septic shock patients. METHODS: The medical
and surgical patients charts from 1991-1993 were selected for the diagnosis of
septic shock (according to the definition of ACCP/SCCM Consensus Conference), and
reviewed. Also included were patients with available variables to complete APACHE
II and septic severity score. RESULTS: Tachycardia was observed more in the non
survivors (9 patients) both in shock (107.8 vs 93.4) and non-shock states (112.3
vs 93.2). Heart rate in the survival group decreased below the cut-off value,
which is 95 beats/min, as specified by ACCP/SCCM. Comparison between APACHE II
and SSS was not well correlated because of the small sample size. Elements in
creating a predictor and its categorisation are mentioned. CONCLUSION: Heart rate
was concluded to be a simple predictor reflecting physiologic derangements in
septic shock. It is recommended that further study needs to be carried out to
unravel a predictor of clinical value in terms of practicality, especially that
involving the inflammatory aspect of the disease process.
PMID- 9557098
TI - Comparing treatment response and complications between podophyllin 0.5%/0.25% in
ethanol vs podophyllin 25% in tincture benzoin for penile warts.
AB - AIM: The aims of this study were to: 1) ascertain if podophyllin resin in 0.5%
[PE(0.5%)] and 0.25% [PE(0.25%)] in ethanol (PE) self-applied sequentially for 3
days with 4 days break cycle is as effective as supervised podophyllin 25% in
tincture benzoin (PB) applied in the clinic biweekly in treating penile warts and
2) ascertain if PE causes less skin irritation than PB. METHODS AND RESULTS: The
clearance rate of penile warts was 36.4% (4/11) in PE (0.5%) treated group, 66.7%
(4/6) in the PE (0.25%) treated group and 33.3% (6/18) for PB treated group after
1 week (ns). The wart clearance rate at 6 weeks for PE (0.5%) treated group, PE
(0.25%) treated group and PB treated group were 81.8% (9/11), 100% (6/6) and
83.3% (15/17) respectively (ns). There were 47 individual warts on the penis of
the 17 patients in the PE treated group and 58 individual warts on the penis of
the 18 patients in the PB treated group. Based on the response of individual
warts to the 2 treatment regimens, the clearance rate was 42.6% (20/47) for the
PE treated group and 25% (15/56) for the PB treated group after 1 week treatment
(ns). At 6 weeks follow-up, the clearance rate for the PE treated group and the
PB treated group were 85.1% (40/47) and 73.2% (41/56) respectively (ns). Skin
irritation including superficial erosions, pain and itch were observed in 47%
(8/17) in patients treated with PE compared to 38.9% (7/18) in patients treated
with PB (ns) during the 6 weeks follow-up period. The clearance rate of patients
treated with PE (0.25%) was compared to those treated with PE (0.5%). Four out of
six of PE (0.25%) treated patients had clearance of warts after 1 week and 100%
clearance at the end of 6 weeks. None experienced any skin irritation.
CONCLUSION: This study demonstrates that 0.5% podophyllin (and possibly 0.25%
podophyllin) in ethanol is effective in eradicating penile warts. It can be used
by patients for self-treatment at home with greater convenience and is more cost
effective than the conventional podophyllin 25% in tincture benzoin paint.
PMID- 9557100
TI - Anomalous pancreatico-biliary junction--a non-dilated biliary system and
gallbladder carcinoma.
AB - Anomalous pancreatico-biliary junction (APBJ) is commonly associated with cystic
dilatation of the bile ducts but recently, several cases without the cystic
dilatation have been reported. We treated a young female patient with intractable
back and epigastric pain of three months duration. The spine was normal on
magnetic resonance imaging (MRI), but several lymph nodes were seen around the
coeliac axis. An APBJ, a non-cystic biliary system, non-filling of the
gallbladder and an irregular right margin of the bile duct were evident on
endoscopic retrograde pancreatography (ERCP), which was highly suggestive of
gallbladder (GB) malignancy. At surgery, the GB was hard with local infiltration
of the bile duct. Numerous large para-aortic and supraduodenal lymph nodes were
present and only a biopsy was possible. Details of the case are presented and the
growing etiological importance of an APBJ, especially without cystic biliary
dilatation in gallbladder carcinogenesis is discussed.
PMID- 9557099
TI - Audit of changes in serum urea and electrolytes following peri-operative
intravenous fluid therapy.
AB - One thousand and eleven patients discharged from the postoperative recovery ward
with intravenous infusions were reviewed in order to audit the extent of
assessment of serum urea and electrolytes (U&Es) and the change in serum U&Es
over the perioperative period. 69.7% had preoperative U&Es estimation, 42.5% had
both a pre- and postoperative estimation and in 5%, only a postoperative estimate
was undertaken. 12.2% of patients whose U&Es were measured had an abnormal
preoperative serum potassium compared to 17.2% postoperatively (NS). Compared to
a preoperative incidence of 13%, more patients (27.3%) had an abnormal
postoperative serum sodium (p < 0.0001). There was a tendency towards
postoperative hyponatraemia: 10.0% in the preoperative period compared to a
postoperative 25.3% (p < 0.0001). More tests were performed in the elderly (83.9%
in age > 65 years versus 69% in age 17-64-p < 0.0001) who were more likely to
have electrolyte disturbances preoperative hypokalaemia (p < 0.05), postoperative
hyperkalaemia (p < 0.05), postoperative hyponatraemia (p < 0.03) and raised serum
urea, both pre- and postoperatively (p < 0.0001 and p < 0.0005 respectively).
Patients undergoing intraabdominal procedures did not have significantly
different peri-operative electrolyte abnormalities. Fewer tests were performed in
emergency patients, who were hypokalaemic in the postoperative period compared to
elective patients (p < 0.01). There was a higher incidence of preoperative
hyponatraemia and raised serum urea in the emergency group (p < 0.001 and p <
0.0002 respectively). Neurosurgical emergencies often had a degree of
preoperative hypokalaemia which persisted after surgery (p < 0.0001). Results
indicate an increased risk of serum electrolyte abnormalities following peri
operative intravenous fluid therapy. However in the majority of patients, the
magnitude of the change is not significant clinically.
PMID- 9557101
TI - Case report of Usher's syndrome in two sisters--first reported case in Singapore.
AB - A 28-year-old Chinese woman presented with poor night vision since childhood.
Ocular examination showed pigmentary retinopathy and systemic examination
revealed sensorineural hearing loss. Family history showed a similar condition in
her youngest sister. Ocular and systemic examination of her sister showed similar
findings. This is presented as the first case report of Usher's syndrome in
Singapore. A general discussion of Usher's syndrome is also presented.
PMID- 9557102
TI - Left mesocolic hernia or peritoneal encapsulation?--a case report.
AB - This is a case report of an 11-year-old boy with left mesocolic hernia. This
condition is very similar to peritoneal encapsulation and a literature review of
both conditions is done. Confusion among authors in naming them accordingly is
addressed.
PMID- 9557103
TI - Spiral computed tomography demonstration of active haemorrhage in blunt abdominal
trauma.
AB - In blunt abdominal trauma, patients may still be actively bleeding despite being
physiologically stable. Fast computed tomography scanning permits the detection
of active haemorrhage by localising the site of extravasation of contrast
enhanced blood. Though a specific sign of active bleeding, particularly arterial
haemorrhage, it is insensitive to the slow, continuous venous oozing associated
with retroperitoneal and pelvic skeletal injuries. However, its presence will
have a critical influence on further surgical intervention. The imaging features
of this uncommon entity are demonstrated in our case report.
PMID- 9557104
TI - What you need to know: acute primary angle closure glaucoma.
PMID- 9557105
TI - What you need to know: detecting alcohol problems in general medical practice.
AB - In the US, about 11% to 20% of patients presenting to general medical clinics are
diagnosed as suffering from alcohol abuse or dependence. Alcohol screening in
primary care settings, whether in the US or Singapore, can utilise various
strategies for the early detection of alcohol problems. This paper briefly
reviews several self-reports and screening procedures to assist general
practitioners in identifying problem drinkers. The use of CAGE questionnaire,
MAST, and its variation, SAAST and the AUDIT, are discussed and evaluated.
Likewise, useful biochemical markers of excessive alcohol consumption like the
liver enzymes (AST, ALT, GGT), MCV, CDT are described. They can be combined with
each other to improve validity or used in conjunction with self-report screening
tests for more accurate detection of problem drinkers. In particular, use of the
AUDIT for routine screening of alcohol problems in primary care settings is
recommended. Selective administration to those with at least two drinks per
setting can overcome time constraints. Alternatively, sequential screening
utilising the TRAUMA questionnaire with frequency and quantity questions
administered to higher frequency drinkers can circumvent concerns about direct
questioning. Use of self-reports and when possible, biochemical screening for
alcohol problems should be a standard part of primary care practice.
PMID- 9557106
TI - The Malai Ika Daigaku (Syonan Medical College) in Malacca (1944 to 1945) during
the Japanese occupation of Singapore and Malaya.
AB - During the Japanese Occupation of Singapore and Malaya (1941-1945), Singapore was
renamed Syonan (or Syonanto) and Malaya was called Malai (or Marai; Marei). On 27
April 2603 (1943) the Japanese Military Administration established. The Marai Ika
Daigaku (Syonan Medical College) at the Tan Tock Seng Hospital (Hakuai Byoin),
Syonan. The Medical College shifted to the General Hospital, Malacca in February
2604 (1944) where it functioned till the end of the Japanese Occupation in
September 2605 (1945).
PMID- 9557107
TI - Geriatric medicine perspectives from the United States.
PMID- 9557108
TI - Nonspecific inhalative challenge tests--methods and importance.
AB - Nonspecific bronchial hyperresponsiveness is a common symptom, the prevalence
depends especially on the inhalative exposure and on the status of atopy. Testing
of nonspecific bronchial hyperresponsiveness is easy to perform and can be done
with different methods. They all are reliable and safe for the patient. To assess
the result of provocation challenge, it is necessary to look at all lung function
parameters as well as on the clinical signs. A lot of persons with nonspecific
bronchial hyperresponsiveness develop a constant airway disease within the next
years. So, early detection of nonspecific bronchial hyperresponsiveness is very
important to control these patients or for starting therapy.
PMID- 9557109
TI - Chronic bronchitis--alterations of the bronchial mucosa.
AB - The mucociliary transport system is usually an important defense system which
protects the body against a variety of noxious agents. Reactions of the bronchial
mucosa to chronic infections are seen in the ciliated cells, the amount of
globlet cells, in modifications of the basement membrane underlying the bronchial
epithelium and an altered percentage of inflammatory cells. In ciliated cells the
following atypia can be seen: thickening of the ciliar membrane, swollen cilia,
formation of compound cilia, disarrangement of microtubules. Common alterations
of the basement membrane are: increased diameter of the basement membrane zone,
inhomogeneous staining pattern of the basement membrane zone, formation of
cytoplasmatic protrusions, formation of double layers of the basement membrane
and increased number of cytoplasmatic bound vesicles. Structural abnormalities of
the basement membrane will lead to disturbances of the zone of transition and
have to be interpreted as a sign of disregulation in the process of diffusion and
resorption. The inflammatory response of the epithelium during chronic bronchitis
and asthma shows many similarities. The bronchial epithelium has a specific
reaction pattern which supports the response against different noxious agents. So
all findings have to be interpreted as unspecific pathological changes. All
alterations may show different degrees of severity and are dependent on
individual pattern and the severity of chronic process. Electronmicroscopical
examinations in combination with lightmicroscopical findings and immuno
histochemistry and seen in context with clinical data help to understand the
mechanism of the inflammatory process.
PMID- 9557110
TI - [Apgar score and umbilical cord blood pH, Fisher's index and amniotic fluid index
AFI].
AB - The relation between umbilical cord blood pH intra partum cardiotocography,
amniotic fluid index and Apgar score was studied in 32 newborns. We found that
cord blood pH, intra partum cardiotocography, amniotic fluid index, and Apgar
score were rather poorly related.
PMID- 9557111
TI - [Esophagogastric bypass anastomosis for benign stricture of cardia].
AB - The aim of the study is to discuss our observations concerning oesophagogastric
bypass anastomosis in cases with scar stricture of cardia in long-term achalasia
(megaoesophagus). The Heller operation is ineffective in such patients and the
resection of cardia with oesophagogastric anastomosis is a large and
controversial operation. 16 patients were operated (6 of them after ineffective
cardiomyotomy). In all cases long-term dysphagia, big loss of weight and large, S
shaped oesophagus lying on the diaphragm were found. The left side thoracotomy
was performed and fundus of the stomach was dislocated to the chest through
dilatatored oesophageal hiatus and with the oesophagus above the cardia. There
were no postoperative complications. However, dysphagia regressed. The remote
results (from 1 year to 7 years) in 11 patients were analysed. The general
condition was satisfactory. No dysphagia and gastrooesophageal reflux was
revealed. Anastomosis was efficient in X-ray examination. Our observations
indicate that oesophagogastric anastomosis is a procedure of choice in the
treatment of long-term achalasia with stricture of cardia and megaoesophagus.
PMID- 9557112
TI - [Investigations on the pathogenesis of primary varicose veins].
AB - The data from the clinical course and epidemiology of primary varicose veins of
lower limb suggest that sex hormones can directly influence the development of
the disease through their intracellular receptor localised in cells of venous
wall. The purpose of this study was to determine the stereometric differences in
the structure of healthy and varicose veins of lower limb and to determine the
presence and localisation of oestrogen and progesterone receptors in the cells of
vein. The segments of greater saphenous vein obtained from the 8 women operated
for varicose vein were used for the study. The segments of the greater saphenous
vein obtained from 8 women that underwent femoro-popliteal venous bypass
procedure were used as control group. The vein samples for stereometric analysis
were preserved in Buin's solution, embedded in paraffin and then evaluated with
automatic analyser MagiCal. To determine the presence of oestrogen and
progesterone receptors the immunohistochemic analysis LAB with monoclonal
antibodies produced by DAKO was used. The decreased smooth muscle fraction in
venous wall, thickening of adventitia, the change of the smooth muscle cells to
stroma cells ratio in the muscular layer of venous wall and change of muscular
layer to adventitia ratio were observed in varicose veins in comparison with
control group. The oestrogen receptors were found in the nuclei of the smooth
muscle cells and endothelium. The progesterone receptors were localised in nuclei
of smooth muscle cells and cells of subendothelial layer. It seems that
quantitative analysis of sex hormones receptor in the venous wall could be useful
in the determination of patients with increased risk of the development of
primary varicose veins.
PMID- 9557113
TI - [Evaluation of bone mass density after extensive resections within the alimentary
tract].
AB - The authors have examined a group of 30 patients at 24-36 months after extensive
resections within the alimentary tract. The bone density assessment has been
done. The results were compared to those obtained from another group of 30
patients awaiting sinister operations. Bone loss was found in all postoperative
patients. However, it was statistically significant only in patients after
pancreatoduodenectomy.
PMID- 9557114
TI - Pregnancy and delivery prognostic risk score for women with congenital heart
disease and acquired valvular heart disease.
AB - Hemodynamic changes related to pregnancy in women with Congenital Heart Disease
(ConHD) or Acquired Valvular Heart Disease (AVHD) require special medical care
during pregnancy and especially immediately prior to, and after delivery.
Following a five year retrospective study (1978-1982), the authors monitored
prospectively over a period of 12 years (1983-1994), 378 pregnancies in 252 women
with ConHD and AVHD. Based on the results of the initial clinical examination and
monthly follow-up visits, a numerical risk score was assigned for each patient.
The study showed good conformity between the predictive risk score values and the
patient's condition in the course of pregnancy and delivery. Thus, this method
represents a novel and potentially very useful clinical tool for management of
pregnancy in patients with ConHD and AVHD.
PMID- 9557115
TI - [The effect of long-term therapy of obstructive sleep apnea syndrome with CPAP
for symptoms of daytime sleepiness].
AB - The study was undertaken to investigate whether a long-term CPAP therapy improves
the symptoms of daytime sleepiness in patients with the obstructive sleep apnoea
syndrome. Seventy six patients (72 men and 4 women) with AHI = 53(+/- SE = 3),
BMI 35 (+/- SE = 0.8), mean age 46.3 (+/- SE = 11.4) have undergone CPAP therapy
for at least one year (mean: 2.48 +/- SE = 0.33). The aggravation of alterations
of the daytime sleepiness was estimated using the questionnaire from Sleep
Laboratory at the Marburg University and the Epworth Sleepiness Scale (ESS).
After the CPAP therapy, we have observed the decrease of the symptoms of the
excessive daytime sleepiness (p < 0.001). Negative correlation between CPAP
compliance and ESS outcome was observed (r = 0.4; p < 0.001). There was not
correlation between the term of using CPAP and the degree of the complaints
decrease.
PMID- 9557116
TI - [The effect of ischemic preconditioning on early death in acute Q-wave myocardial
infarction].
AB - Ischaemic preconditioning is still a laboratory-based phenomenon, not
conclusively documented in patients. In this study it was of interest whether
there is any beneficial influence of ischemic preconditioning on 30-day in
hospital mortality in patients undergoing acute Q-wave myocardial infarction. All
men and women admitted to our ward between December 1994 and July 1996 with their
first acute Q-wave myocardial infarction were divided into two groups. I group-
29 patients with prodromal angina, defined as chest pain episodes in the 24-hour
period before myocardial infarction. II group--25 patients who showed no chest
pain before infarction onset. Both groups did not differ statistically in view of
age, sex, smoking habits and adjunctive therapy. The use of streptokinase in the
I and II group was also similar--in 58.6% and 56% of patients respectively in the
first and second group. In the I group there was no fatal outcome, all 5 death
cases occurred in the II group. The results are statistically significant and
suggest lower in-hospital mortality in Q-wave myocardial infarction patients with
previous ischaemic preconditioning.
PMID- 9557117
TI - [Neurologic manifestations of HIV infections and AIDS].
AB - The paper presents the review of neurological manifestations of HIV infection.
The pathogenesis of changes caused by HIV within central nervous system is
discussed. The most common neurological syndromes occurring in AIDS patients as
well as the division of these changes concerning peripheral and central nervous
system are described.
PMID- 9557118
TI - [Sepsis in surgery: pathogenesis, new therapeutic approaches].
AB - Sepsis and septic shock are phenomena with a characteristic clinical picture and
etiologically related to injury. Chains of events from injury (e.g., infection)
through activation of immunological system to multiple organ failure are
responsible for sepsis. Neutralization of endotoxins, TNF, interleukins and so
on, can improve the treatment of sepsis in the future.
PMID- 9557119
TI - [Glucocorticosteroids in bronchial asthma. II. Use of cortisol markers in various
biological materials for evaluation of adrenocortical function].
AB - Glucocorticosteroids (GS) being widely used in asthma treatment are sometimes
applied in high doses and for long period. This treatment is often connected with
adrenocortical suppression. Adrenocortical function assessment in GS treated
patients with different doses and forms of drug is of great diagnostic and
prognostic importance. In the presented work the methods of adrenocortical
function assessment are discussed, especially serum cortisol level and non
invasive: saliva and urine cortisol assays.
PMID- 9557120
TI - [Headaches as the main symptom of advanced craniopharyngioma in a 14-year old
girl].
AB - Craniopharyngioma of advanced stage in a 14-year old girl is described. The only
symptom of the disease through the one year before recognition was cephalea. The
disclosure of calcifications in the x-ray image of sella turcica region helped to
establish diagnosis.
PMID- 9557121
TI - [Urinary diversion to the large intestine in adults].
AB - The paper presents the history of technique and concepts of urinary diversion to
colon and rectum from the mid-XIXth century until today, including the
contribution of Polish surgeons--Krynski, Laskownicki and Kielkiewicz.
Contraindications and complications of this type of definitive urinary diversion
is briefly discussed. Authors also present the outcome of ureterosigmoidostomy
performed according to method proposed by Goodwin in 25 patients cystectomized
for infiltrating transitional cell carcinoma of the bladder, who were operated on
at the Department of Urology, Medical School in Warsaw. These patients were in
poor general condition and short life expectancy, which depended upon tumour
stage and grade as well as preoperative urographic evaluation of urinary tract.
PMID- 9557123
TI - Cutaneous, multilocular T-cell lymphosarcoma in a horse--clinical,
ultrasonographic and pathological findings.
AB - Clinical, ultrasonographic and pathological findings of a cutaneous, multilocular
T-cell lymphosarcoma (malignant lymphoma) in a 13-year-old, brown Austrian
warmblood mare are reported. The horse was under clinical observation, and the
tumours were sonographically monitored over an 8 month period, revealing
worsening of body condition, weight loss, lameness of the left hindlimb and a
slight increase in the tumours size. Most of the tumours were covered by normal
skin, one showed ulceration. Ultrasonography of the tumours allowed accurate
anatomical localization in relation to the adjoining tissue, assessment of their
internal structure, of involvement of adjacent muscles and of a regional lymph
node, and it facilitated the percutaneous fine-needle aspiration. Necropsy
confirmed muscular infiltration in three locations. Light microscopy and
immunohistology led to the diagnosis of a T-cell lymphosarcoma.
PMID- 9557122
TI - Immunohistological examination on the distribution of collagen types I, III, IV
and V in bovine post partum placentomes.
AB - This paper describes the in situ presence and distribution of collagen types I,
III, IV and V in the bovine placenta. The objective was to determine whether
there are qualitative and/or quantitative differences in the collagen content of
placentomes originating from cows with retained placenta and cows with normal
discharge of placenta. Twelve h post partum discharge of the placenta or the
incidence of retained placenta was monitored. From 57 cows one placentome per cow
was collected within 1 h post partum. The cows were divided into three groups:
retained placenta after caesarean section (Group 1), retained placenta after
spontaneous calving (Group 2) and normal discharge of placenta within 12 h post
partum after spontaneous calving (Group 3). A pilot study was conducted to
establish the technique of collecting the placentomes and to verify the applied
immunohistological methods used in this work. In the following study, 32
placentomes were used to determine the amount of collagen (types I, III, IV and
V) with qualitative and semi-quantitative methods using immunohistochemical
techniques. Collagen types I, III, IV and V were found in large quantities in the
maternal tissue. In the fetal connective tissue the amount of these collagen
types was smaller. In the placentomes of the three groups, no qualitative or
quantitative differences could be detected.
PMID- 9557124
TI - Evidence of the existence of alpha 1B-adrenoceptors on hepatocytes of domestic
fowl (Gallus domesticus).
AB - In liver cell membranes of laying hens alpha 1-adrenergic receptors were
characterized using 3H-prazosin. Specific binding was saturable and indicative of
a single class of high-affinity binding sites with a KD of 0.40 +/- 16 nM and a
Bmax of 390 +/- 38 fmol/mg membrane protein. Preincubation of membranes with
chlorethylclonidine significantly diminished the binding of 3H-prazosin (Bmax =
99 +/- 14 fmol/mg membrane protein). Furthermore, competition experiments
revealed a rank order of prazosin >> phentolamine = oxymetazoline >> WB 4101,
with Ki values of 0.71 +/- 0.62, 20 +/- 6, 32 +/- 13, and 119 +/- 48 nM,
respectively. These results suggest the existence of alpha 1B-adrenergic
receptors in hen liver cell membranes.
PMID- 9557126
TI - Assessment of subacute mammary inflammation by soluble biomarkers in comparison
to somatic cell counts in quarter milk samples from dairy cows.
AB - The usefulness of soluble markers in indirectly differentiating inflamed quarters
from healthy quarters of 30 Holstein Friesian cows was tested over a follow-up
period of 20 weeks. In comparison to N-acetyl-beta-D-glucosaminidase (NAGase),
lactate dehydrogenase (LDH), Na+, K+ and Cl- the somatic cell counts (SCC) were
determined in foremilk samples. The soluble parameters were measured by means of
an autoanalyzer system (Beckman CX5CE) equipped with solid state ion electrodes.
Due to different types of inflammatory reactions it is considered to be
advantageous to perform two tests in parallel for assessing the mammary gland
status. Cell-damaging processes should best be detected by measuring elevated LDH
activity, whereas the impairment of the blood-udder barrier is recorded by the
respective elevation of the indicators Na+ and Cl-. Among all variables, SCC
included, the soluble parameters showed the least dispersions, whereas those of
SCC were the most unfavourable in this respect. Moreover, NAGase/LDH and Na+/Cl-
among all variables had the highest correlation coefficients of 0.85 and 0.86,
respectively. Threshold values as decision limits are proposed. Additionally, an
inter-quarter comparison and evaluation improved the diagnostic value of each
indirect mastitis parameter analyzed. By means of discriminant analysis, it is
shown that the distribution of inflammation within the udders of this herd was
unequal.
PMID- 9557125
TI - Field isolates of Mycoplasma ovipneumoniae exhibit distinct cytopathic effects in
ovine tracheal organ cultures.
AB - Ovine tracheal ring explants were infected with four different Mycoplasma
ovipneumoniae and one M. arginini field isolate and their ability to induce
cytopathic effects was tested by measuring ciliary activity and intracellular
calmodulin release. Infected tracheal rings showed significantly decreased
ciliary activity as compared to the non-infected control rings. There were,
however, marked differences between isolates in the onset and severity of the
effects which correlated with their ability to produce hydrogen peroxide.
Infected tracheal rings released more calmodulin than the non-infected controls.
The amount of calmodulin released also varied between isolates, and somewhat
reflected the degree of loss of ciliary activity in the corresponding rings
induced by the different isolates. Light and electron microscopic examinations of
infected tracheal rings revealed disorganisation and sloughing of the epithelium,
and association of mycoplasmas only with the cilia. Following repeated in vitro
passages, the organisms had reduced ability to inhibit ciliary activity which
correlated with decreased hydrogen peroxide production. Addition of catalase to
the organ cultures delayed loss of ciliary activity. These results suggest that
M. ovipneumoniae induced ciliostasis in ovine tracheal ring explants which
correlated with hydrogen peroxide production. Furthermore, these M. ovipneumoniae
induced injuries to respiratory epithelial cells could contribute to the role
that this organism may play in sheep respiratory disease.
PMID- 9557127
TI - Evaluation of the efficacy of perorally administered glutamic acid-chelated iron
and iron-dextran injected subcutaneously in Duroc and Norwegian Landrace piglets.
AB - The goals of this study were to evaluate the effect of orally administered amino
acid-chelated iron (Fe) compared to injected Fe-dextran on haematology and weight
gain in two different breeds raised under commercial conditions. Altogether 92
Duroc (D) pigs and 84 Norwegian Landrace (L) pigs from two different herds were
included in the study. The day after birth the litters were divided in two groups
(split litters). Group (Gr.) 1 was given 4 ml of a 50% solution of Super Fe-MAX
(52 mg glutamic acid-chelated Fe in a water solution) orally, while Gr. 2 was
subcutaneously (s.c.) injected with Idofer (180 mg Fe as ferridextran). Until
weaning at 5 weeks, all the piglets had free access to a 3% solution of Super Fe
MAX (0.78 mg Fe/ml), access to pelleted food being given from 1 week of age. The
piglets were weighed and bled before treatment the day after birth (day 1) and on
days 4, 7, 14, 21 and 35. All piglets were weighed on days 28 and 49, while 72 of
the L pigs were also weighed on days 77, 98 and 119. At weaning D pigs in Gr. 1
and Gr. 2 had a mean body weight of 8.64 kg and 8.30 kg, respectively, the
corresponding figures for the L pigs being 10.82 kg and 10.34 kg. As regards the
72 L pigs followed to day 119, the mean weight in Gr. 1 and Gr. 2 was 80.6 kg and
80.2 kg, respectively. A significantly lower weight gain in the piglets with a
birth weight below 1.2 kg in Gr. 2 compared with Gr. 1 indicated that excess
administration of Fe to small piglets may have a detrimental effect on weight
gain. From day 7 (D pigs) and on days 14 and 21 (L pigs), Gr. 2 had a
significantly higher haemoglobin concentration (Hb) than Gr. 1. Nevertheless, Hb
levels were also adequate in Gr. 1 in both breeds. There was a negative
correlation between changes in Hb during the first weeks and the initial value.
Though haematological values seemed to show inter-breed differences, with higher
average erythrocyte counts (RBC) and Hb and lower mean cell volume (MCV) in the D
pigs, the ability to avoid Fe deficiency nevertheless appeared to be the same in
both breeds.
PMID- 9557128
TI - Infectious bovine mastitis caused by environmental organisms.
AB - The purpose of this study was to determine the prevalence of environmental
mastitis in dairy herds and identify the main environmental pathogens, and to
evaluate the influence of season, housing and management. A total of 20,310
quarters of 5216 animals from 52 dairy herds in 32 counties was examined. Milk
samples were aseptically collected for laboratory examination from mammary glands
testing positive to any of the field tests. From these, 736 environmental
infections were identified. The most frequently isolated environmental pathogens
were algae of the genus Prototheca sp. (41.2%), Streptococcus uberis (21.1%),
fungi (19.5%), enterobacteriacea (8.3%) and Nocardia sp. (6.6%). The occurrence
of mastitis was not influenced by the herd size, use of dry cow therapy, or post
milking teat dipping. A tendency for increased occurrence of environmental
mastitis during the months of September to February (hot and wet weather) was
observed, suggesting a seasonal influence.
PMID- 9557129
TI - Cytological, immunocytochemical and biochemical cerebrospinal fluid
investigations in selected central nervous system disorders of dogs.
AB - Cerebrospinal fluid (CSF) obtained from 20 clinically healthy dogs and from 15
dogs affected by neurological disorders were examined for total and differential
cell counts, immunocytochemistry for canine distemper virus antigen, total
protein concentration and electrophoretic separation, and glucose and enzyme
determination. Dogs affected by canine distemper showed an increase in
macrophages, presence of specific inclusion bodies, and an increase in total
protein concentration and gamma-globulin fraction. In bacterial
meningoencephalomyelitis pleocytosis, increase of total proteins with special
regard to high molecular weight proteins, elevated levels of lactate
dehydrogenase (LDH), alterations of LDH isoenzyme profile, and decrease in
glucose levels were detected; inflammatory disorders were more often
characterized by an increase in LDH level, while in non-inflammatory disorders
(hydrocephalus and spinal cord neoplasia) no variation in LDH levels was
detected. Analysis of CSF in dogs appears relatively easy to perform and may help
in establishing the condition of the blood-brain barrier as well as in the
diagnosis of neurological disorders.
PMID- 9557130
TI - Identification and characterization of Arcobacter isolates from broilers by
biochemical tests, antimicrobial resistance patterns and plasmid analysis.
AB - A total of 89 Arcobacter butzleri isolates obtained from freshly slaughtered
broilers was investigated for their biochemical capacities by using the API CAMPY
system as well as additional growth and tolerance tests, for their antimicrobial
resistance patterns and their plasmid content. Among these techniques,
biochemical profiling and antimicrobial resistance testing proved to be the most
discriminatory methods as confirmed by the calculation of discriminatory indices.
These two methods might represent valuable tools for epidemiological analysis of
A. butzleri isolates. Small plasmids of up to 5 kbp were detectable in only 21 of
the 89 isolates while the remaining 68 A. butzleri isolates were plasmid-free.
PMID- 9557132
TI - Late lesions of experimental contagious caprine pleuropneumonia caused by
Mycoplasma capricolum ssp. capripneumoniae.
AB - A clinical, bacteriological, serological and patho-anatomical study was carried
out on 12 goats surviving the acute stage of contagious caprine pleuropneumonia
(CCPP), experimentally produced with Mycoplasma capricolum ssp. capripneumoniae
(M. capripneumoniae), with the major aims of investigating the chronic stage of
the disease and elucidating the possibility of a carrier state beyond the acute
fulminant phase. The goats were killed 9, 16, 82 or 126 days after the onset of
acute clinical signs. On day 9, clinical signs included low grade fever and
persistent coughing. Thereafter, only intermittent coughing was recorded. Serum
titres of complement-fixing antibodies to M. capripneumoniae were high at the
period of fever but dropped thereafter. Post-mortem examination showed acute
fibrinous pleuropneumonia on days 9 and 16, and chronic pleuropneumonia on days
82 and 126, including sequester formations in goats killed on day 126. Mycoplasma
capripneumoniae was isolated on days 9 and 16 but not on later occasions. The
study showed that goats recovered from acute CCPP may have lesions for a long
time thereafter but provide no evidence of a carrier state among long-term
survivors.
PMID- 9557131
TI - A Salmonella monitoring programme in egg production farms in Germany.
AB - A programme monitoring the prevalence of Salmonella infections in egg production
farms with different types of flock management was conducted over a period of 18
months. Three laying hen farms with floor pens and five farms with batteries were
examined from September 1992 to March 1994. A total of 569 samples (293 feed and
276 faeces) were processed in parallel by fivefold fractional enrichment in
Rappaport/Vasiliadis medium and in potassium tetrathionate crystal violet broth.
By using such elaborate methods, high detection rates of Salmonella were
obtained. Two thirds of all isolates were found in the third to fifth selective
enrichment procedure. Salmonella (S.) Tennessee was the most common serovar
isolated (from 24.5% of the samples) whereas S. Enteritidis was the second most
common isolate (23.7%). Salmonella were isolated from 33.1% of the feed samples
(97/293), a result which may stimulate further discussion on the prevention of
potential contamination of feed stuff with Salmonella and other pathogens. The
number of Salmonella isolations from floor pens was significantly higher than
from batteries. As time progressed an increase in the number of Salmonella
isolations occurred in samples taken from the floor pens. The development of a
less costly routine monitoring programme to detect Salmonella in samples taken
from barns with layer flocks is recommended.
PMID- 9557134
TI - KNI-577, a potent small-sized HIV protease inhibitor based on the dipeptide
containing the hydroxymethylcarbonyl isostere as an ideal transition-state mimic.
PMID- 9557133
TI - Control of proliferative enteropathy in growing/fattening pigs using growth
promoters.
AB - The aim of this study was to evaluate the effect of different antibiotics used as
growth promoters on the control of porcine intestinal adenomatosis when
administered in weaning, growing and fattening pig diets, according to Annex I of
the European Union directive (70/524/EEC and its subsequent amendments to date)
for the use of feed additives. On a farm with a previous history of proliferative
enteropathy outbreaks, 648 weaned piglets (23 days old) were divided into nine
experimental groups according to bodyweight and sex ratio, each group comprising
four pens with 18 pigs in each pen. One group served the trial as a negative
(unmedicated) control: another (the positive control) received monensin via feed
at 100 p.p.m. up to the end of the growing phase (107 days old) and 50 p.p.m. up
to slaughter age (156 days old). The remaining seven groups were offered feed
with the addition of the following antibiotics: virginia-mycin (50-20 p.p.m.),
avilamycin (40-20 p.p.m.), spiramycin (50-20 p.p.m.), zinc bacitracin (50-10
p.p.m.), avoparcin (40-20 p.p.m.), tylosin (40-20 p.p.m.) and salinomycin (60-30
p.p.m.), respectively. The performance of the pigs in the positive control group
was very satisfying and among the highest in the trial, verifying earlier field
studies. As a general conclusion it seems that all tested growth promoters had a
beneficial effect compared with the untreated control, indicated by the decrease
of mortality rate, the elimination of diarrhoeal incidence and the enhancement of
growth performance, although the proliferative enteropathy control achieved by
each substance was not always satisfactory. More specifically, the antibiotic
growth promoters tested can be scaled according to their total efficacy as
follows: 1. Salinomycin, tylosin, spiramycin; 2. Virginiamycin, zinc bacitracin,
avilamycin; and 3. Avoparcin. Finally, it is considered that part of the growth
promotion efficacy of the tested substances is due to their potential capacity to
control porcine intestinal adenomatosis; thus, in future growth performance
trials, the disease background of the trial farms must be examined, especially
for porcine enteropathy challenges.
PMID- 9557135
TI - Suramin analogues with a 2-phenylbenzimidazole moiety as partial structure;
potential anti HIV- and angiostatic drugs, 2: Sulfanilic acid-, benzenedisulfonic
acid-, and naphthalenetrisulfonic acid analogues.
AB - The synthesis of suramin analogues bearing a 2-phenyl-benzimidazole moiety is
described. Aminoarene sulfonic acids 2a-e are acylated with 3,4-dinitrobenzoyl
chloride 3 yielding the amides 4a-e which are hydrogenated to the corresponding
diamines 5a-e. These are treated with 3-nitrobenzaldehyde, yielding the
azomethines 7a-e and their isomers 8a-e and 9a-e. Key step in the synthesis of
the target compounds 12a-e is the oxidation of the azomethines with oxygen to the
benzimidazoles 10a-e. These are hydrogenated to the amines 11a-e reacting with
phosgene to yield the symmetric ureas 12a-e. Results of the anti-HIV, cytostatic,
and antiangiogenic screening are presented.
PMID- 9557136
TI - New NO-donors with antithrombotic and vasodilating activities, Part 20.
Azodioxides activated by electron acceptors in geminal or vicinal position.
AB - Twenty-two nitroso compounds with cyano, acyloxy, or carbonyl groups in geminal
position were prepared, eight of them for the first time. In the solid state
these compounds dimerize to colorless azodioxides. Exceptions are the 4
nitrobenzoyloxynitroso compounds 7b, f, and g which form bright blue crystals. In
vitro (Born test, collagen) considerable antiplatelet activity was observed in
each class of compounds. Azodioxides with cyano groups in geminal position (3a,
b) were most active (IC50 approximately 10 microM) suggesting the importance of
strong electron withdrawing groups in geminal position to the azodioxide partial
structure. When administered orally to rats (60 mg/kg) all compounds inhibited
the thrombus formation in mesenteric arterioles and venules. The acetyloxy
derivatives 5d and 5e were most active (18-21% inhibition in arterioles and 11
15% inhibition in venules). In aqueous media at 37 degrees C the cyanonitroso
compound 3b and the benzoyloxynitroso compound 7a decomposed to nitric oxide and
its reduced form nitrosohydrogen. This suggests that the above pharmacological
effects are mediated by a NO dependent mechanism.
PMID- 9557137
TI - New NO-donors with antithrombotic and vasodilating activities, Part 21.
Pseudonitrosites and other azodioxides with vicinal electron acceptors.
AB - Twelve vicinally substituted nitro-nitroso compounds (pseudonitrosites) were
synthesized, nine of them for the first time. In the solid state the dimeric
azodioxides are present. In the class of the pseudonitrosites 2a-h, all compounds
exhibited comparatively strong antiplatelet activity in vitro (Born test,
collagen). Four of them showed an IC50 below 10 microM, 2a being the most active
substance with an IC50 = 2.1 microM. When administered orally to rats (60 mg/kg)
small antithrombotic effects were observed. The pseudonitrosite 6d was the most
active compound (18% inhibition in arterioles). The in vitro decomposition of 2a
at 37 degrees C gave NO and N2O, indicating that the above pharmacological
effects were mediated by an NO-dependent mechanism. The replacement of the nitro
group in the pseudonitrosite partial structure by other electron acceptors i.e.
acetyl, carboxyl, or acetyloxy groups leads to inactive (10a) or less active
compounds (10b, e).
PMID- 9557139
TI - Nitric oxide production by cells infiltrating amphibian skin grafts.
AB - In vivo injection of the edible frog Rana esculenta with NOS inhibitor, L-NMMA
caused prolongation of skin allograft and xenograft viability, statistically
significant only in the latter case. In the present studies skin allo- and
xenografts at the latent or rejection phase were excised from the hosts (Bufo
bufo, R. temporaria, and R. esculenta) and incubated in vitro for 24 hrs in a
medium only or in the presence of competitive (L-NMMA, L-NAME, L-aminoguanidyne)
and noncompetitive (dexamethasone and cycloheximide) inhibitors of NO synthesis.
In some experiments graft infiltrating cells were washed out and cultured
separately from the respective skin fragments. The nitrite level was measured in
the culture supernatant using Griess reagent. The nitrite level was negligible in
the control skins, autografts, and xenografts depleted of graft infiltrating
cells, as well as in allo- and xenografts excised at the rejection phase. In the
case of grafts excised at the latent phase, the nitrite amount was substantial in
supernatant from allografts and significantly higher in xenografts. A high level
of nitrite was also present in supernatants from graft infiltrating cells. It is
concluded that the NO contributes to some stages of the rejection process of the
anuran skin grafts, this contribution being especially significant in the case of
xenografts. The main source of this agent are graft infiltrating phagocytic
cells.
PMID- 9557140
TI - An attempt at comparing external changes taking place during maturation of male
mice with the development of the process of spermatogenesis.
AB - Evaluation of the degree of sexual maturation was performed in male mice of two
selected lines differing in respect of body weight. Four developmental stages
were distinguished: (1) loosening of the skin between the urinary papilla and the
anus, (2) projection of the scrotum, (3) descent of the testes to the scrotum,
(4) demonstration of sexual drive. Histological examination of the testes
revealed that at the first developmental stage the animals had clearly immature
gonads. In a few, not numerous, seminiferous tubules spermatogenesis had reached
the phase of primary spermatocytes. At the second stage of development the male
gonads reached the phase of secondary spermatocytes and sporadically of early
spermatids. At the third stage of the animals development, the spermatogenesis
observed in numerous cross-sections of the seminiferous tubules reached the
spermatid phase and in males at the fourth stage some sperm cells appeared in the
lumen of the tubules. A greater diameter of the sperminiferous tubules was
demonstrated in the heavy line males than in the light line animals. In males of
the heavy line the diameter of the Leydig cells increased between the third and
fourth stage. The investigation results suggest that the accepted criteria of
determination of sexual maturation stages correspond to various phases of changes
taking place in the process of spermatogenesis.
PMID- 9557141
TI - Magnetic resonance angiography in patients with brain infarction.
AB - This study evaluated the role of magnetic resonance angiography (MRA) in
detecting extra- or intracranial vascular disease in 118 patients with brain
infarction and the accuracy of MRA diagnosis when compared with conventional
angiography in patients who had both investigations. Magnetic resonance
angiography ruled out extra- and intracranial large vessel disease in 36% of the
patients. MRA also demonstrated extra- or intracranial disease in 56% (probably
symptomatic in 31, possibly symptomatic in 18, and asymptomatic in 17 patients),
and provided no information in 8% of the 118 patients. Among the 176 major
vessels visualized by both MRA and conventional angiography, conventional
angiography confirmed the presence of 9/10 extracranial and 32/40 intracranial
large vessel abnormalities detected on MRA. There were two false-negative
findings on MRA: occlusion of a distal branch of middle cerebral artery, and an
asymptomatic posterior cerebral artery stenosis. Magnetic resonance angiography
is a clinically useful method for screening extra- and intracranial disease in
patients with brain infarction and selecting high-yield patients for conventional
angiography.
PMID- 9557138
TI - Earthworm immune responses.
AB - The knowledge of the immunity in annelids started with the use of earthworms as
biomarkers indicating changes caused by environmental pollution. Defence
strategies effectively protect earthworms against bacterial infections and
parasitic invasion. A natural immunity formed by anatomical and chemical
protective barriers prevents damage of the underlying tissues, body fluid losses,
and microbial infections of the body cavity. The internal defence mechanisms of
annelids involve phagocytosis, nodule formation and encapsulation, blood
coagulation and wound repair, and antibacterial immune proteins. The
antibacterial activity of coelomic fluid associated with lysozyme-like substances
and inducible humoral molecules support haemocytic reactions in the annelid
defence system.
PMID- 9557142
TI - Power Doppler imaging and color Doppler flow imaging for the evaluation of normal
and pathological vertebral arteries.
AB - Recently, an ultrasound method for vascular applications using the amplitude of
the reflected echosignal for the generation of intravascular color signals has
been introduced. We compared the utility of this power Doppler imaging (PDI) with
conventional color Doppler flow imaging (CDFI) for examination of vertebral
arteries (VA). Forty-nine patients with signs and symptoms suggesting ischemia
within the posterior circulation were evaluated. Quality of blood flow
visualization by PDI and CDFI at the different VA segments was classified
according to a four point scale. Furthermore, combined sonographic findings were
correlated with the results of digital substraction and/or magnetic resonance
angiography (DSA, MRA). Power Doppler imaging provided a significantly superior
visualization of the intertransversal VA, whereas display of the intracranial V4
segment was superior significantly on CDFI. Both methods were complementary for
the evaluation of the VA at the origin. With respect to the angiographic
findings, combined CDFI and PDI achieved a sensitivity of 90.63% and a
specificity of 97.22% for the differentiation of healthy and pathologic VAs.
Power Doppler imaging is complementary to CDFI for the sonographic assessment of
VA disease. Combined use of PDI and CDFI achieves a high sensitivity and
specificity, thus increasing diagnostic confidence.
PMID- 9557143
TI - Observer variability in the measurement of the size of intracranial aneurysms
using power TCD.
AB - This study assessed the observer variability for measurement of intracranial
aneurysmal size visualized on color "power" Transcranial Doppler Ultrasound
(TCD). Patients with recent subarachnoid hemorrhage underwent color "power" TCD
blind to angiography. Identified aneurysms were measured from the frozen image
(in real time or from video tape) using the trackball function. Two observers
measured the maximum (systolic) and minimum (end diastolic) area of each
aneurysm, and an adjacent reference artery. Each observer was blind to the
other's results. Interobserver variability was assessed using the Bland and
Altman technique. Thirty-nine aneurysms were identified in 32 patients in 10
months. The maximum cross-sectional area of the aneurysm was 38:41 mm2 (observer
1:observer 2), and the mean difference was -3 mm2 (95% confidence interval [CI]
of the difference -5.4-1.46 mm2). The maximum cross-sectional area of the
reference artery was 26:28 mm2 (observer 1:observer 2), and the mean difference
was -2 mm2 (95% CI -5.7-1.2 mm2). Neither difference was significant.
Intraobserver reliability also was good. The measurement of intracranial aneurysm
and artery size with power TCD is reliable sufficiently for use in longitudinal
studies of changes in aneurysm size.
PMID- 9557144
TI - SPECT and lumbar MRI in back pain with emphasis on changes in end plates in
association with disc degeneration.
AB - Over a two-year period, 48 sequential patients were selected because they showed
type I or II end plate changes on magnetic resonance imaging (MRI) and/or had
positive single-photon emission computerized tomography (SPECT) scan in the area
of disc degeneration. They were selected out of a large group of patients who
were being evaluated by MRI and SPECT scan for low back pain. In this group of 48
patients, 47 had positive SPECT scans at the disc space, which on MRI indicates
degenerative disc disease. Of these, 38 had end plate changes on the MRI, but 10
did not have end plate changes on the MRI even though their SPECT was positive.
None of the 48 patients had evidence of other pathology such as fracture,
metastatic disease or spondylolysis. The MRI changes were both of type I and type
II and thought to represent increased vascularization of the fibrous tissue or
fatty replacement of marrow in the area of the end plate. Based on this study, we
are proposing that a positive end plate SPECT in degenerative disc disease is
related to marrow changes in the region of the end plate of the disc. Also, we
are proposing that SPECT may be of value in delineating early end plate changes
prior to the MRI showing type I or type II change in the same area.
PMID- 9557145
TI - The influence of different gases on acoustic properties of a spherosome-based
ultrasound contrast agent (BY963). A transcranial Dopplersonography study.
AB - Ultrasound contrast agents improve the signal-to-noise ratio of reflected
ultrasound, enhancing the diagnostic value of transcranial Doppler (TCD). In dog
studies, we investigated the time course of TCD signal amplitude after
application of a phospholipid-containing ultrasound contrast agent (BY963) filled
with different gases. The median time of Doppler amplitude enhancement exceeding
5 dB was determined using isoflurane-, isopentane-, trichlortrifluoroethane-, air
, argon-, and perfluoropentane-filled BY963 (69, 72, 75, 78, 88, and 245 seconds
respectively). The decrease of time-intensity curve and the duration of signal
enhancement showed significant differences comparing the different gases (p =
0.04 and 0.03, respectively). The time course of in vitro stability of BY963
agitated with the different gases measured by absorbance of light (500 nm) showed
a retarded decay for perfluoropentane, a rapid decrease for air, isopentane,
trichlortrifluoroethane, and argon, and a very rapid decrease using isoflurane.
The time course of the different gases depended on the physiochemical properties
(lipophilicity and the solubility in water) of the gas encoated in the
phospholipid shell. Perfluoropentane-filled BY963 showed the highest in vitro
stability and the longest duration of TCD enhancement compared with the other
gases used.
PMID- 9557146
TI - A preliminary study comparing the sensitivity of serial monthly enhanced MRI
after standard and triple dose gadolinium-DTPA for monitoring disease activity in
primary progressive multiple sclerosis.
AB - We performed this study to evaluate and compare the numbers of total and new
enhancing lesions detected on serial monthly brain magnetic resonance imaging
(MRI) after the injection of a standard dose (SD) and a triple dose (TD) of
gadolinium-DTPA (Gd) in patients with primary progressive multiple sclerosis
(PPMS). Every 4 weeks for 3 months and in two separate sessions, MRI scans were
obtained from 5 patients with PPMS, 5 (early) and 20 minutes (delayed) after SD
(0.1 mmol/kg) or TD (0.3 mmol/kg) Gd injection. In 2 patients, T1-weighted scans
with a magnetization transfer pulse (MT) after SD and TD injection were also
obtained. There were 13 enhancing lesions (5 of which were new) on the early SD
scans, 15 (5 new) on the delayed SD scans, 17 (6 new) on the early TD scans and
18 (7 new) on the delayed TD scans. TD MRI scans detected more enhancing lesions
than SD scans in 3 patients (two of them were those with the lowest disability).
The application of the MT pulse did not change the numbers of enhancing lesions
seen after the injection of SD and TD of Gd in the remaining two patients. No
side effects were reported and no significant changes in blood test parameters
were found throughout the study. Our results suggest that serial monthly TD MRI,
delayed scanning, MT T1-weighted scans or their combination, although safe, have
a limited role for monitoring disease evolution in patients with PPMS.
PMID- 9557148
TI - Calcified cystic lesions in a patient with epilepsy and progressive dementia.
AB - A 67-year-old woman had intractable epilepsy and developed a progressive dementia
with upper motor neuron signs over the last 6 years. Magnetic resonance imaging
(MRI) revealed multiple areas of large calcified cysts, which increased in number
and size over the last 3 years. Discussion includes the appearance of these
lesions radiologically and pathologically, as well as their differential
diagnosis and clinical significance, focusing on the increasing detection of
these lesions with current imaging techniques.
PMID- 9557147
TI - Three-dimensional reconstruction of the power flow Doppler imaging of
intracranial vascular structures in the neonate.
AB - Three-dimensional (3D) ultrasonography reconstructing from power flow Doppler
imaging (PF) is able to image the 3D structures of the vascular systems. We tried
to display the 3D images of intracranial vascular structures in 5 neonates with a
portable data processor. Data acquisition was performed using PF through the
anterior fontanel. We succeeded in reconstructing vivid 3D images of the anterior
cerebral arteries (ACA), basilar artery (BA), internal carotid arteries (ICA),
middle cerebral arteries (MCA), lenticulostriate arteries (LSA), internal
cerebral vein (ICV), the vein of Galen (GV) and straight sinus (SS) in all
subjects. The MCA could be displayed in only a proximal portion. The images of
the LSAs were fainter than the other vessels. These problems are based on the
character of PF; the flow signal, sampling from the small sized vessels and the
perpendicular vessels to ultrasonic beam, is weak. The images of these vessels
are fainter than other vessels. These limitations of PF performance directly
influence the quality of the 3D images. The benefits and limitations of 3D
ultrasonography system are discussed.
PMID- 9557149
TI - Extrarolandic origin of spike and myoclonus activity in epilepsia partialis
continua: a magnetoencephalographic and positron emission tomography study.
AB - The dipole sources of interictal spike activity were localized and the myoclonus
activity back-averaged by combined magnetoencephalography and surface
electromyographic measurements in a child who had epilepsia partialis continua
without a structural brain lesion. Dipole sources were matched with metabolic
information obtained from interictal 5-fluoro-D-glucose positron emission
tomography (PET) and superimposed onto high-resolution magnetic resonance images.
Dipole sources of interictal epileptic discharges clustered within the inferior
parietal cortex, which also showed a regional hypermetabolism on PET scans. The
dipole sources of reafferent activity following myocloni in the postcentral gyrus
were associated with a local hypometabolism Although there was no obvious phase
relationship between interictal spikes and myoclonic jerks, the myocloni were
initiated from within the interictal spike area in the extrarolandic cortex. The
data demonstrate that motor symptoms may be a remote effect of epileptic activity
within functional brain circuits.
PMID- 9557150
TI - Isolated straight sinus thrombosis: clinical and neuroradiologic correlates.
AB - A rare case of straight sinus thrombosis in a 36-year-old female with sudden
onset of status migrainosus is presented. This condition was demonstrated by a
linear density in the midline on a noncontrast computed tomography scan, as a
filling defect at the location of straight sinus on magnetic resonance imaging,
and by the inability to visualize blood flow in the straight sinus on magnetic
resonance venography, with a similar demonstration on a 4-vessel digital
subtraction angiography.
PMID- 9557151
TI - Intra-axial posterior fossa cryptococcosis: MRI findings.
AB - Two case reports of intra-axial posterior fossa cryptococcosis in immunocompetent
patients are presented. Magnetic resonance findings of solitary abscesses with
mildly irregular peripheral enhancement within the medulla, and irregular
peripheral enhancement with a nodular component within the right cerebellum are
described.
PMID- 9557152
TI - Presymptomatic brain lesions on MRI in a patient with intravascular malignant
lymphomatosis.
AB - A 58-year-old man with a intravascular malignant lymphomatosis initially
developed myeloradiculopathy without cerebral symptoms. His MRI, however,
demonstrated solid, wedge-shaped, and well-demarcated lesions in the deep white
matter and a string-shaped lesion along with nerve fibers in the splenium of
corpus callosum. A variety of cerebral symptoms manifested a month afterward. The
possibility of this disease should be considered in cases of undiagnosed
myeloradiculopathy with such silent brain lesions.
PMID- 9557153
TI - Spontaneous resolution of subdural hematoma. MRI findings.
AB - A 33-year-old man suffered a traumatic subdural hematoma with complete
spontaneous resolution, as demonstrated by computed tomography scanning and
magnetic resonance imaging. After resolution, there was obliteration of the
subarachnoid space on the affected side, giving rise to relative dilation of the
subarachnoid space over the uninvolved convexity. A resolved subdural hematoma
should be considered in the differential diagnosis of such an asymmetry.
PMID- 9557154
TI - Cerebello-thalamo-cerebral diaschisis: a case report.
AB - This reports positron emission tomography and [18F]fluorodeoxyglucose (PET-FDG)
in a 69-year-old woman who underwent resection of the left cerebellar hemisphere
for an acoustic neurinoma 17 years earlier. Functional impairment in cerebral
cortical and subcortical structures was evaluated by studying the level of
glucose metabolic activity at rest. Relative glucose metabolism was reduced in
the prefrontal cortex contralateral to the cerebellar lesion. Contralateral
thalamic metabolism was reduced significantly. The results suggest that this
phenomenon of "crossed cerebello-thalamo-cerebral diaschisis" is related to a
functional depression of the cerebello-thalamo-cortical pathway.
PMID- 9557155
TI - The alter ego of heat shock proteins.
PMID- 9557156
TI - Screening for primary immunodeficiencies in the clinical immunology laboratory.
PMID- 9557157
TI - Immunoglobulin- and hepatitis B surface antigen-specific circulating immune
complexes in chronic hepatitis B virus infection.
AB - For assessing the role of circulating immune complexes (CIC) in chronic hepatitis
B virus (HBV) infection, CICs containing IgM, IgG, and HBsAg were determined by
C1q and conglutinin (K) assays in 216 patients with chronic HBV infection and 54
healthy controls. The concentration of each type of CIC in patients is higher
than in controls (P = 0.0001). CIC is a common feature of chronic HBV infection
with 95.8% of cases having at least one abnormal test result. At least one type
of HBsAg-CIC is positive in 54.2% of patients. HBsAg-CIC positivity is associated
with HBeAg positivity (P = 0.0001), higher aminotransferase levels (P < 0.002),
and younger age (P = 0.001). IgG-CIC or IgM-HBsAg-CIC correlates with higher
aminotransferase activity (P = 0.001). In conclusion, HBsAg-CIC correlates with
HBV replication. IgG-CIC and/or IgM-HBsAg-CIC correlate with disease activity.
Immune-mediated injury may play a role in the pathogenesis of chronic HBV
infection.
PMID- 9557158
TI - Expression of 70-kDa heat-shock protein during acute graft-versus-host disease.
AB - Acute lethal graft-versus-host disease (GVHD) was induced in unirradiated (LEW x
DA)F1 rats by injection of DA parental lymphoid cells. Control rats received the
same dose of (LEW x DA)F1 cells. The level of hsp70 at different stages of GVHD
was examined in the spleen, lymph nodes, thymus, liver, lung, kidney, heart, and
skeletal muscles of GVHD and control animals. Hsp70 was present in all organs
analyzed in both groups and, with the exception of the spleen and lymph nodes,
detectable levels remained constant during the disease. However, the spleen and
lymph nodes of GVHD rats showed distinct changes in the hsp70 levels throughout
the course of the disease. Expression of hsp70 in spleen and lymph nodes was
augmented 7 and 14 days after induction of the disease. During the last stages of
GVHD, 18-21 days after the induction, expression of hsp70 diminished to a level
similar to that in untreated and control animals. Elevated levels of hsp70 in
lymphoid organs during GVHD suggest an involvement of hsp70 in the pathology of
the disease.
PMID- 9557159
TI - Characterization of the altered cutaneous reactivity of transgenic mice whose
keratinocytes overexpress B7-1.
AB - B7-1 (CD80) is a second signal molecule usually associated with "professional"
APCs that prevents the induction of T-cell clonal anergy and induces IL-2
production during antigen presentation. Tg mice whose epidermal KC overexpress B7
1 exhibit exaggerated and persistent CHS to a variety of haptens that lasts up to
8 weeks after hapten challenge. These Tg mice also exhibit significantly enhanced
ear-swelling responses to irritants that are not persistent. Exaggerated CHS was
not reflected in the draining lymph node. T-lymphocyte proliferative responses
after sensitization and local challenge with haptens, as there were no
significant differences between the B7-1 Tg and the NTg mice. However, RT-PCR
analysis of mouse ear skin at the hapten challenge site indicated that B7-1 Tg
mice had an alteration in the kinetics of in situ lymphokine transcripts compared
to NTg mice: IFN-gamma transcripts were first detectable in Tg mouse skin at 2
weeks versus 24 h for NTg mice. RNase protection assays to detect inflammatory
cytokine transcripts at hapten application sites indicated that B7-1 Tg mice
responded to hapten application with increased TNF-alpha, IL-6, and TNF-beta
transcripts compared to NTg mice. Thus, hapten-induced ear swelling in these Tg
mice may be mediated by enhanced inflammatory cytokines during the early phase (1
14 days). IFN-gamma-producing lymphocytes may be responsible for the late phase
of the ear-swelling response (14-42 days). These data indicate that B7-1
overexpression by KC in mouse skin directly or indirectly affects the nature of
cutaneous inflammation induced by haptens and irritants.
PMID- 9557160
TI - Influence of microbial stimulation on hypergammaglobulinemia and autoantibody
production in pristane-induced lupus.
AB - Pristane induces a lupus-like syndrome characterized by autoantibody production
and glomerulonephritis in nonautoimmune strains of mice. Although it has been
suggested that this syndrome results from nonspecific immune activation, there is
little evidence so far that B cells are activated nonspecifically by pristane or
that this promotes autoimmunity. In this study, we examined whether polyclonal
hypergammaglobulinemia occurs in pristane-induced lupus, and its relationship to
the production of anti-DNA, nRNP/Sm, and Su autoantibodies. In conventionally
housed mice, there was a marked increase in total IgM and IgG3 2 weeks after i.p.
pristane injection, followed by increased IgG1, IgG2a, and IgG2b levels. IgM
levels were higher in pristane-treated specific pathogen-free (SPF) mice than in
conventionally housed mice, whereas IgG and IgA levels were reduced. Pristane
induced anti-nRNP/Sm and Su autoantibodies in SPF mice, but their onset was
delayed and levels were lower than those in conventionally housed mice. There was
no consistent relationship between total IgG1, 2a, and 2b hypergammaglobulinemia
and production of anti-nRNP/Sm and Su autoantibodies. Moreover, the total Ig
levels were similar in the anti-nRNP/Sm-positive and -negative groups. In
contrast, production of IgM anti-ssDNA antibodies paralleled IgM
hypergammaglobulinemia in some, but not all, mice. These studies indicate that
pristane-induced lupus is associated with marked hypergammaglobulinemia, the
magnitude of which is influenced by the microbial environment. However, anti
nRNP/Sm and Su autoantibody production is at least partly independent of
polyclonal B cell activation. The data strongly suggest that pristane-induced
lupus is not exclusively the consequence of nonspecific immune stimulation. They
also point to the importance of microbial stimulation in the development of
hypergammaglobulinemia in this inducible lupus model.
PMID- 9557161
TI - Taxol involution of collagen-induced arthritis: ultrastructural correlation with
the inhibition of synovitis and neovascularization.
AB - Collagen-induced arthritis (CIA) is an animal model of rheumatoid arthritis (RA)
that can be regressed with Taxol (paclitaxel), a chemotherapeutic agent. To
identify structural changes that occur with involution, the synovium from naive,
untreated CIA, and Taxol-treated CIA rats were evaluated by light microscopy plus
transmission and scanning electron microscopy. Analysis included detailed images
of vascular networks using polymeric corrosion casts. The CIA synovium was
morphologically similar to human RA synovium. In CIA, the integrity of the
intimal lining is lost by Type-B synoviocytes becoming highly elongated and
polarized toward the joint space, resulting in non-overlapping cellular processes
and the elimination of the basal lamina. In addition, the lining expanded from a
width of 6-10 microns in naives to 200-250 microns in CIA due primarily to
increased numbers of both Type-A and -B synoviocytes and more interstitial
matrix. Vascular corrosion casts of CIA synovium illustrated a marked increase in
blood vessel volume and an extensive interconnecting vascular architecture;
neovascular arrays were observed to project toward the synovial surface. In Taxol
treated CIA, the synoviocyte and neovascular components reverted to the naive
synovium morphology, suggesting that this agent might be useful in the therapy of
RA.
PMID- 9557162
TI - Is there IgA from gut mucosal origin in the serum of children with Henoch
Schonlein purpura?
AB - Thirty-two children with Henoch-Schonlein purpura with or without renal symptoms
were studied to characterize the IgA hyperglobulinemia observed in the serum of
most patients. It was shown that only the IgA1 subclass concentration was
increased. Secretory IgA and IgA to gliadin levels were frequently increased in
serum, with a good correlation between them. Circulating IgA immune complexes
were detected often and contained high activity to gliadin. In contrast, IgA
activity to tetanus toxoid did not change. We failed to show any differences in
renal involvement. These data suggest that elevation of serum IgA in Henoch
Schonlein purpura is due in part to a disturbance of the gut mucosal immune
system, and the presence of circulating IgA immune complexes with dietary
antigens can be postulated but cannot explain the occurrence of urinary symptoms.
PMID- 9557163
TI - IL-10 production in common variable immunodeficiency.
AB - Common variable immunodeficiency, (CVI) is a heterogeneous primary
immunodeficiency disease in which there are T and B cell defects. Since IL-10 in
conjunction with anti-CD40 promotes secretion of IgG, IgA, and IgM by CVI B
cells, these studies were performed to investigate IL-10 production in CVI.
Mitogen or anti-CD3 stimulated CVI peripheral blood mononuclear cells, or
isolated T cells produced an insignificant amount of IL-10 over background
levels. CVI monocyte IL-10 production was substantial and greater than that of
normal controls. Anti-IL-10-neutralizing antibody strongly enhanced CVI T cell
proliferative responses to PHA, but only to an insignificant extent, soluble
antigens. IL-2 plus anti-IL-10 enhanced CVI proliferative responses to antigens
significantly more over baseline than for cells of similarly tested normal
controls. These data suggest that CVI T cell secretion of IL-10 is deficient, but
that monocyte-derived IL-10, plus a relative lack of IL-2 production, could
contribute to the defects of cell proliferation in this disorder.
PMID- 9557164
TI - Identification of autoimmune thrombocytopenic purpura-related epitopes using
phage-display peptide library.
AB - A random heptapeptide phage-displayed library was screened with two serum samples
from autoimmune thrombocytopenic purpura (AITP) patients to address the
repertoire of autoantigenic epitopes involved in platelet destruction. We
obtained a panel of affinity-selected phage clones that have been shown to react
in enzyme-linked immunosorbent assay with autoantibodies from other AITP
patients. None of the peptides obtained has been described previously as possibly
being an epitope for antiplatelet antibodies, and the majority of them did not
show any homology with known platelet glycoproteins. We conclude that peptides
identified in this study could represent discontinuous epitopes or mimotopes of
natural autoantigens. Also, they could be present in still-unknown proteins
involved in AITP pathogenesis.
PMID- 9557165
TI - Occupational asthma: prevention by definition.
PMID- 9557167
TI - Chemicals in the workplace: incorporating human neurobehavioral testing into the
regulatory process.
AB - In February 1996, the United Kingdom Health and Safety Executive sponsored a
workshop on the role of human neurobehavioral tests in the regulation of chemical
exposures in the workplace. This paper presents the review of neurobehavioral
testing that was initially prepared for the workshop but has been expanded and
updated for publication. Information sources for the review were drawn from
"preamble to the regulation," in the 1989 air contaminants project, an attempt by
the Occupational Safety and Health Administration to update the 1968 regulatory
limits of workplace exposures. The scientific citations listed in the preamble
provide a chemical database to review for evidence of neurobehavioral testing to
support limit setting. Several conclusions emerged: 1) A wide range of nervous
system effects were reported in the scientific citations for the 172 chemicals
identified with effects on the nervous system; 2) Citations of studies with human
neurobehavioral test results are used to support limit setting, but many are old
studies primarily of acute effects; 3) There is frequently a delay of several
years after publication before studies with neurobehavioral testing are cited in
regulatory forums; 4) With the 1989 proposed regulatory limits never legally
adopted, there has not been an update for most of the substances affecting the
nervous system since 1971; 5) Investigators should be more aware of the
regulatory process and submit studies reporting neurobehavioral test results to
organizations that regulate and recommend workplace exposure limits; 6) Issuances
in the Federal Register by the U.S. Environmental Protection Agency provide a
framework for assessing neurotoxic risks that can be used by investigators to
help identify and report nervous system effects using neurobehavioral testing in
a more uniform fashion.
PMID- 9557168
TI - Occupational obstructive airway diseases in Germany.
AB - In industrialized countries, occupational asthma caused by allergens and
irritants due to workplace exposure is increasing. More than 8,000 such claims
were made in Germany (10.5% of all decided occupational disease claims) in 1995;
1,900 were confirmed (6.5% of all confirmed claims). The legal basis and the
occupational disease-related regulations of trade-assigned statutory accident
insurance institutions ('Berufsgenossenschaften') in Germany are described.
Hitherto, three occupational disease categories for obstructive airway disorders
existed: due to sensitizing agents, due to chemical-irritative or toxic agents,
and due to isocyanates. Approximately 40% of accepted claims for occupational
asthma and rhinitis result from exposure to flour. Ongoing changes in the
recognition of work-related airway disease symptoms account for differences in
the incidence and prevalence as reported over the years. Recently, chronic
obstructive bronchitis and/or emphysema of hard coal miners have been included in
the German list of occupational diseases.
PMID- 9557169
TI - Airways inflammation and glucan exposure among household waste collectors.
AB - A field study was made on 17 workers collecting unsorted household waste, eight
workers collecting organic/nonorganic separated waste, and 24 controls.
Measurements of airborne endotoxin and (1-->3)-beta-D-glucan were made in their
working environments. Examinations consisted of a questionnaire for symptoms,
spirometry, airway responsiveness, and blood and sputum sampling for
determination of cell counts, eosinophilic cationic protein (ECP), and
myeoloperoxidase (MPO). A higher proportion of waste collectors reported
diarrhea, congested nose, and unusual tiredness as compared to controls. The
number of blood lymphocytes was higher among waste collectors and were dose
related to the amount of airborne (1-->3)-beta-D-glucan at the workplaces. The
amount of ECP and the number of macrophages were lower in sputum among waste
collectors as compared with controls. The results suggest that certain dusts from
household waste may cause airway inflammation as well as general symptoms, and
the effects were associated with higher (1-->3)-beta-D-glucan levels.
PMID- 9557166
TI - Methodological considerations for the accurate determination of lead in human
plasma and serum.
AB - Studies which accurately measure plasma or serum lead (Pb) are needed to evaluate
the 'biologically active' fraction of Pb in the circulation, and to clarify the
role of plasma in the transportation of Pb between different compartments of the
body. We evaluated several methodological aspects which influence the
determination of Pb in plasma and serum. Generally, venous blood was obtained by
different sampling methods (routine and ultraclean) from 3 subjects without
history of Pb exposure. After centrifugation (800 g) for 10 min, the plasma or
serum was analyzed by inductively coupled plasma-high-resolution mass
spectrometry (ICP-MS). Several evaluations were conducted, including 1)
comparison of an ultraclean serum collection method with a plasma collection
method that used a commercial Vacutainer-type tube for trace metals (EDTA
anticoagulant); 2) the effect of whole blood standing time prior to
centrifugation on plasma or serum Pb concentration; and 3) comparison of a method
using commercial heparinized Vacutainer tubes to an ultraclean plasma sampling
method that utilized a low-Pb heparin anticoagulant. Plasma or serum iron (Fe)
levels were also measured to evaluate hemolysis. The 3 subjects had whole blood
Pb (blood-Pb) levels of 1.8, 2.0, and 2.7 micrograms/dl. Their corresponding
ultraclean serum-Pb levels were 0.40%, 0.30%, and 0.48% of their whole blood-Pb
levels, respectively. By comparison, the EDTA Vacutainer method plasma-Pb values
were 1.7%, 1.5%, and 2.4% of whole blood-Pb, respectively. Whole blood standing
(clotting) times of 15, 40, and 70 min before centrifugation resulted in
increasing ultraclean serum-Pb levels of 0.21%, 0.81%, and 1.2% of whole blood-Pb
(1.8 micrograms/dl), respectively. Whole blood standing time had no effect on
plasma-Pb levels when heparin Vacutainers were used, or when a low-Pb heparin was
used to obtain ultraclean plasma. However, plasma collected using the commercial
heparin Vacutainer method contained consistently higher and more variable Pb
levels than samples collected using the ultraclean plasma-Pb method. Hemolysis,
when present, contributed significantly to both plasma-Pb and serum-Pb levels. In
conclusion, plasma-Pb and serum-Pb levels are dependent upon methodologic
processing techniques, including Pb contamination control, redistribution due to
EDTA anticoagulant, hemolysis, and time dependency in sample processing. While
true plasma-Pb and serum-Pb levels by any method have yet to be defined, these
data provide a methodological basis from which to investigate variation in Pb
partitioning between whole blood and plasma within individuals.
PMID- 9557170
TI - Indirect assessment of 4,4'-diphenylmethane diisocyanate (MDI) exposure by
evaluation of specific humoral immune responses to MDI conjugated to human serum
albumin.
AB - BACKGROUND: A study of occupational asthma among workers exposed to 4,4'
Diphenylmethane Diisocyanate (MDI). OBJECTIVE: To demonstrate if serum
concentrations of MDI-specific IgG or IgE are sensitive biological markers of
disease or of MDI exposure. METHODS: The study group consisted of nine MDI
exposed workers and nine nonexposed workers. Air sampling for MDI and
polymethylene polyphenyl isocyanate, occupational and medical histories,
respiratory physical exams, pre- and postshift spirometry, and self-administered
peak expiratory flow rates were performed. Serum specific IgE and IgG antibodies
to an MDI-human serum albumin (HSA) conjugate were assayed by the
radioallergosorbent test and the enzyme-linked immunosorbent assay, respectively,
and compared to nine nonexposed laboratory controls. RESULTS: No definitive cases
of occupational asthma were documented. The mean level of MDI-specific IgG was
significantly greater among exposed workers compared to nonexposed workers and
laboratory controls (p = 0.04). Mean levels of TDI and HDI-specific IgG were also
increased. CONCLUSION: This study demonstrates that serum concentrations of MDI
specific IgG appear to be a moderately sensitive biological marker of MDI
exposure, but not an indicator of occupational asthma. Workers with IgG
antibodies specific for one diisocyanate-HSA conjugate exhibit cross-reactivity
to antigens prepared with other diisocyanates.
PMID- 9557171
TI - Biological monitoring of workers exposed to carbon disulfide (CS2) in a viscose
rayon fibers factory.
AB - The exposure-excretion relationship to carbon disulfide (CS2) vapor in 407
exposed workers was studied during the second half of the working week. Carbon
disulfide concentrations were also determined in 50 nonexposed subjects. The
geometric mean value for CS2 in urine samples from the latter was: 0.23
microgram/l (95% upper limit = 0.52 microgram/l) when log-normal distribution was
assumed. Among the exposed workers, the CS2 level in urine samples collected
after the first half shift exceeded the 95% upper limit of nonexposed subjects in
every case. The time-weighted average intensity of exposure to CS2 vapor was
measured using personal diffusive samplers (in which carbon cloth served as an
adsorbent). CS2 concentrations in urine were determined in samples collected at
the end of the first half shift from the 407 exposed cases as well as from 50
nonexposed controls. There was a significant correlation (p < 0.0001) between the
exposure to CS2 vapor at concentrations of up to 64 mg/m3 and the levels of CS2
measured in the urine samples after four hours of exposure. The correlation
indicated that a mean level of 15.5 micrograms CS2/l urine (95% confidence range,
13.8-17.1 micrograms/l) was excreted following an exposure to CS2 at 31 mg/m3
(the current occupational exposure limit).
PMID- 9557172
TI - Workplace violence at government sites.
AB - A government agency and its contractors employing nearly 96,000 workers
throughout the country was surveyed for documented incidents of violence in the
workplace. Thirty-five occupational medicine and related professionals (36% of
those surveyed) from 27 locations returned the questionnaire. Of the responders,
20 individuals reported 74 incidents of workplace violence, with nearly 30% of
these occurrences involving weapons, including 11 with guns. In a companion
survey of human resource departments from 28 locations, there were 16 responders
(57% of those surveyed) with 13 of them documenting 96 additional incidents. No
duplicate reporting of the same event occurred between the two surveys.
Approximately 70% of the agency workers were employed in locations covered by the
51 responders. Although the data are limited, the number of incidents and level
of violence appear to be increasing over time. Of the 108 incidents for which
time of occurrence was known, 32 were defined as "very serious," which included
physical assault, threat or assault with a weapon, murder, suicide, or stalking.
Verbal threats, verbal assaults, and vandalism were defined as "serious"
incidents. A Cochran-Armitage trend test for an increasing proportion over time
of "very serious" vs. "serious" events was statistically significant, with a P
value of 0.026.
PMID- 9557173
TI - Impact of managers' personal determinants in notifying workplace hazards.
AB - Notification about work hazards is a legal requirement in advanced industrial
countries, but workers have claimed, that in many cases, they do not receive
enough information regarding risks, exposure, and medical problems. The recent
professional literature on the subject has explored the ways in which
notification is delivered without sufficiently considering the psychological
incentives and barriers that may affect managers in transmitting risk
information. The present study aimed at examining managers' personal determinants
and notification of work hazards in a sample of 106 managers and 460 workers in
40 departments of three industrial plants in Israel. Results of our study showed
that both managers and workers perceived the importance of the delivery of safety
information as quite high (means of 3.43 and 3.7, respectively, out of 5), with
managers reporting that they rely primarily on personal modes of communication.
Immediate supervisors were regarded by both groups as the most important persons
in notification. Managers having past experience in treating injured workers
notified more, primarily using personal notification. The most important personal
determinants that positively predicted managers' notification were their sense of
self-efficacy and positive expectation of notification. Outcome denial and coping
by distancing were negatively correlated with notifying about these risks.
PMID- 9557174
TI - Women who quit maquiladora work on the U.S.-Mexico border: assessing health,
occupation, and social dimensions in two transnational electronics plants.
AB - This cohort study of 725 women examined the health, occupational, and social
factors that contribute to quitting work in two transnational electronics
maquiladoras (assembly plants) in Tijuana, Mexico. The estimated cumulative
probabilities of quitting were 68% and 81% by 1 and 2 years of employment. After
adjusting for other factors, women who had a history of smoking or surgery and
those who returned to work after a paid leave due to illness were more likely to
quit. In contrast, women with a history of chronic illness had lower quitting
rates. The nationality of the company and the work shift also significantly
influenced quitting rates, but demographic characteristics and health care visits
did not have a significant effect. Women selectively leave maquiladora
employment, often due to health-related events. The healthy worker effect is
difficult to measure in a mobile population with high turnover.
PMID- 9557175
TI - Work-related injuries among Iowa farm operators: an analysis of the Iowa Farm
Family Health and Hazard Surveillance Project.
AB - In 1994, the Iowa Farm Family Health and Hazard Surveillance Project carried out
a two-stage, stratified, cluster survey of Iowa farms using a mail survey. With
data from this representative sample of Iowa farmers, we examined the
associations between farm-work-related injuries and possible risk factors for 390
principal farm operators. Forty (10.3%) of these operators reported being injured
while doing farm work. We developed a logistic regression to assess associations
between potential risk factors and injury. We found three factors significantly
associated with injury: younger age (odds ratio [OR] = 3.1, confidence interval
[CI] = 1.1-9.3), having an impairment or health problem that limits work (OR =
2.4, CI = 1.5-3.8), and hand or arm exposure to acids or alkalis (OR = 2.6, CI =
1.1-5.9). In the univariate analysis, safety training did not seem to protect
farmers from injuries.
PMID- 9557176
TI - [Treatment of primary hyperhidrosis: a new indication for video thoracoscopy].
PMID- 9557177
TI - [Training of inspiratory muscles in chronic obstructive lung disease. Its impact
on functional changes and exercise tolerance].
AB - The aim of this study was to evaluate the impact of inspiratory muscle training
on lung function and exercise tolerance in patients with chronic obstructive
pulmonary disease (COPD). Thirty-five patients with stable COPD were enrolled. We
measured lung function variables and peak inspiratory and expiratory pressures
(PImax and PEmax). Tests of progressive maximal exercise tolerance and stable
submaximal exercise tolerance were administered. Two study groups were formed.
Group A patients (n = 20) were enrolled in a respiratory muscle training program
lasting four months. Group B (n = 15) was the control group. At the end of the
study period the patients underwent testing similar to the first battery of
tests. All showed moderate to severe obstruction with no significant differences
between groups (FEV1: group A 37.6 +/- 13%, group B 36.6 +/- 12%; FVC: group A
80.4 +/- 15%, group B 80 +/- 12%). Nor were there any significant differences
between the two groups in initial results of either maximal respiratory pressures
or exercise tolerance. No lung function changes were observed in either group.
PImax in group A increased significantly at the end of the study (from 54 +/- 9
to 78 +/- 16 cmH2O; p < 0.001); there were no changes in group B. No changes were
seen in VO2max or ventilatory response and/or gasometry during exercise in any of
the groups. The trained group, on the other hand, experienced a significant
decrease in dyspnea evaluated on the Borg scale exercise in maximal (5.7 +/- 1.1
versus 4.7 +/- 1.2, p < 0.005) and submaximal (5.9 +/- 0.9 versus 4.9 +/- 1.3, p
< 0.005) and an increase in time of submaximal exercise tolerance (5.5 +/- 2
versus 7 +/- 3 min, p < 0.05), changes that were not observed in the control
group. Based on these results, and although specific training of inspiratory
muscles does not appear to improve lung function in patients with COPD, it is
accompanied by a decreased sense of dyspnea during exercise and greater
tolerance.
PMID- 9557178
TI - [Bronchial carcinoid tumors: a prospective study].
AB - We report the results of a study performed in the thoracic surgery department of
Hospital General Universitario of Valencia from October 1989 to December 1996. Of
the 621 patients diagnosed of lung cancer during this period, 320 underwent the
usual surgical excision, 18 were confirmed histologically as bronchial carcinoid
tumors, indicating an incidence of 5.6% of all pulmonary neoplasms resected in
our department. The symptoms most often reported were recurring infection (44.5%)
and chest pain (33.3%). Only one patient presented carcinoid syndrome. The most
common radiologic presentation was solitary pulmonary nodule (50%). The tumor was
visible by fiberoptic bronchoscopy in 9 cases. Diagnosis was by bronchial biopsy
in four cases. Confirmation was by immunohistochemical analysis of the specimen
in all cases. Electron microscopy and immunohistochemical techniques using
neuroendocrine panmarkers is considered fundamental for differentiating between
neuroendocrine neoplasms and typical and atypical carcinoid tumors. Thirteen
(72.2%) of the 18 patients studied were diagnosed of typical carcinoids and 5
(27.8%) of atypical carcinoids. Neuroendocrine marking showed neurospecific
enolase in 15 patients and chromogranin positivity in 10.
PMID- 9557179
TI - [Guidelines for indications and use of domiciliary continuous oxygen (DCO)
therapy. SEPAR guidelines].
PMID- 9557180
TI - [Drug treatment of pulmonary tuberculosis in the 19th century].
PMID- 9557181
TI - [Solitary adrenal metastasis of pulmonary cancer].
AB - We describe the case of a 46-year-old man with lung cancer and simultaneous
solitary adrenal metastases. Adrenalectomy was performed 12 weeks after lung
resection through a right subcostal laparotomy. Treatment was complemented with
chemotherapy. Twelve months after adrenalectomy the patient was found free of
signs of disease and was in satisfactory condition. The advantages of and
indications for surgical resection of suprarenal metastasis are discussed in the
light of published literature. In some cases, survival may improve with exeresis
and chemotherapy.
PMID- 9557182
TI - [Endobronchial metastasis of uterine leiomyosarcoma].
PMID- 9557183
TI - [Article by Rubia et al., "The evaluation of lung vascular compliance by the
dobutamine stress test in patients who are candidates for extensive lung
resections"].
PMID- 9557184
TI - [Management of pleural effusion].
PMID- 9557185
TI - Red lipstick: a source of barium to humans and the environment.
PMID- 9557186
TI - Aqueous phase ethylation atomic emission spectroscopy for the determination of
methylmercury in fish using permeated dimethylmercury calibration.
PMID- 9557187
TI - Shaker bath adaptation to the Environmental Protection Agency's cadmium column
reduction method (method 353.3) for the determination of nitrate in water
samples.
PMID- 9557188
TI - Effects of monitor well purging technique on selected chemical properties of
surficial groundwater.
PMID- 9557189
TI - Trace metals in moose (Alces alces) liver.
PMID- 9557190
TI - Metals and organochlorine compounds in fish from Latvian lakes.
PMID- 9557191
TI - Distribution of heavy metal residues in some tissues of Caretta caretta
(Linnaeus) specimen beached along the Adriatic Sea (Italy).
PMID- 9557192
TI - Heavy metals in sediments from Coatzacoalcos River, Mexico.
PMID- 9557193
TI - Avian exposure to pesticides in Costa Rican banana plantations.
PMID- 9557194
TI - Influence of spray adjuvants on the behavior of trifluralin in the soil.
PMID- 9557196
TI - Long-term DDT pollution in tropical soils: effect of DDT and degradation products
on soil microbial activities leading to soil fertility.
PMID- 9557195
TI - Isoxaflutol herbicide soil persistence and mobility in summer corn and winter
wheat crops.
PMID- 9557197
TI - Removal of malathion residues on lettuce by washing.
PMID- 9557198
TI - Chlorpyriphos, quinalphos, and lindane residues in sesame seed and oil (Sesamum
indicum L.).
PMID- 9557199
TI - Occurrence of three pesticides in community water supplies, Kenya.
PMID- 9557200
TI - Environmental estrogens in agricultural drain water from the central valley of
California.
PMID- 9557201
TI - Mutagenicity of river water in Korea.
PMID- 9557202
TI - Transplacental transfer of asbestos in pregnant mice.
PMID- 9557203
TI - Hyperglycemia induced in rabbits exposed to ochratoxin.
PMID- 9557204
TI - Acute administration of methylmercury changes in vivo dopamine release from rat
striatum.
PMID- 9557205
TI - Cadmium-induced scale deformation in carp (Cyprinus carpio).
PMID- 9557206
TI - Azinphosmethyl exposure to grass shrimp (Palaemonetes pugio) life stages with
emphasis on larval acetylcholinesterase activity.
PMID- 9557207
TI - Selective growth inhibition of the musty-odor producing cyanobacterium
Oscillatoria cf. chalybea by natural compounds.
PMID- 9557208
TI - Exposure of juvenile rainbow trout (Oncorhynchus mykiss) to methoxychlor results
in a dose-dependent decrease in growth and survival but does not alter male
sexual differentiation.
PMID- 9557209
TI - Environmental endocrine modulators and human health: an assessment of the
biological evidence.
AB - Recently, a great deal of attention and interest has been directed toward the
hypothesis that exposure, particularly in utero exposure, to certain
environmental chemicals might be capable of causing a spectrum of adverse effects
as a result of endocrine modulation. In particular, the hypothesis has focused on
the idea that certain organochlorine and other compounds acting as weak estrogens
have the capability, either alone or in combination, to produce a variety of
adverse effects, including breast, testicular and prostate cancer, adverse
effects on male reproductive tract, endometriosis, fertility problems,
alterations of sexual behavior, learning disability or delay, and adverse effects
on immune and thyroid function. While hormones are potent modulators of
biochemical and physiological function, the implication that exposure to
environmental hormones (e.g., xenoestrogens) has this capability is uncertain.
While it is reasonable to hypothesize that exposure to estrogen-like compounds,
whatever their source, could adversely affect human health, biological
plausibility alone is an insufficient basis for concluding that environmental
endocrine modulators have adversely affected humans. Diethylstilbestrol (DES) is
a potent, synthetic estrogen administered under a variety of dosing protocols to
millions of women in the belief (now known to be mistaken) that it would prevent
miscarriage. As a result of this use, substantial in utero exposure to large
numbers of male and female offspring occurred. Numerous studies have been
conducted on the health consequences of in utero DES exposure among the adult
offspring of these women. There are also extensive animal data on the effects of
DES and there is a high degree of concordance between effects observed in animals
and humans. The extensive human data in DES-exposed cohorts provide a useful
basis for assessing the biological plausibility that potential adverse effects
might occur following in utero exposure to compounds identified as environmental
estrogens. The effects observed in both animals and humans following in utero
exposure to sufficient doses of DES are consistent with basic principles of dose
response as well as the possibility of maternal dose levels below which potential
non-cancer effects may not occur. Significant differences in estrogenic potency
between DES and chemicals identified to date as environmental estrogens, as well
as an even larger number of naturally occurring dietary phytoestrogens, must be
taken into account when inferring potential effects from in utero exposure to any
of these substances. The antiestrogenic properties of many of these same
exogenous compounds might also diminish net estrogenic effects. Based on the
extensive data on DES-exposed cohorts, it appears unlikely that in utero exposure
to usual levels of environmental estrogenic substances, from whatever source,
would be sufficient to produce many of the effects (i.e., endometriosis, adverse
effects on the male reproductive tract, male and female fertility problems,
alterations of sexual behavior, learning problems, immune system effects or
thyroid effects) hypothesized as potentially resulting from exposure to chemicals
identified to date as environmental estrogens.
PMID- 9557211
TI - IL-1 receptor antagonist gene polymorphism in patients with secondary acute
myeloid leukaemia.
AB - Acute myeloid leukaemia (AML) may not only occur as a de novo disease but may
evolve from a preceding myelodysplastic syndrome (MDS) or may result from therapy
for a previous malignancy. These secondary acute myeloid leukaemias (sAML)
possess some common biological and clinical features of the corresponding de novo
disorders. The cytokine interleukin-1 (IL-1) is known to have a role in
haematopoiesis, and modulation of its action might contribute to the deregulation
of proliferation seen in leukaemia. It has recently been reported that a variable
number tandem repeat (VNTR) polymorphism in the IL-1 receptor antagonist (IL-1ra)
gene is closely associated with the severity of many inflammatory and autoimmune
diseases, and may also play a role in the pathogenesis of sAML. We sought to
confirm this finding in a large group of patients classified as having sAML. We
found no differences in either the genotypic or allele frequencies of the
polymorphism studied when compared with those of normal controls or other
haematological disorders. No differences were observed in allele frequencies
between younger and older patients, or between those patients who had an
antecedent myelodysplasia and those who had received prior chemotherapy or
radiotherapy. We conclude that the described polymorphism in the IL-1ra gene is
not associated with the development of sAML.
PMID- 9557210
TI - Allogeneic cell-mediated immunotherapy for breast cancer after autologous stem
cell transplantation: a clinical pilot study.
AB - Allogeneic cell therapy (allo-CT) is emerging as an effective treatment for
patients relapsing after allogeneic bone marrow transplantation (BMT), indicating
that tumor cells resisting chemoradiotherapy may still respond to immunocompetent
allogeneic lymphocytes. We investigated possible graft-versus-tumor (GVT) effects
in six patients with metastatic breast cancer that would be comparable to the
graft-versus-leukemia (GVL) phenomenon occurring after allogeneic BMT in
hematologic malignancies. The patients were cytoreduced with high-dose
chemotherapy and autologous stem cell transplantation (ASCT), and were treated
ambulatory with allo-CT consisting of adoptive transfer of HLA-matched donor
peripheral blood lymphocytes (PBL) activated in vivo with human recombinant
interleukin-2 (rIL-2). If no graft-versus-host disease (GVHD) developed, allo-CT
was augmented with infusion of donor PBL, preactivated in vitro with rIL-2.
Treatment was well tolerated, with low therapy-related toxicity in all patients.
Two patients developed signs and symptoms compatible with GVHD grade I-II, one of
whom shows no evidence of disease at more than 34 months out. In the remaining
patients, progression-free survival following allo-CT ranged between 7 and 13
months. Allogeneic cell-mediated, cytokine-activated immunotherapy might be
utilized for induction of GVT in metastatic breast cancer. A search for
techniques to boost chimerism without severe GVHD is indicated.
PMID- 9557212
TI - Inhibitory effect of interleukin-10 on human leukocyte interferon-alpha
production by Sendai virus.
AB - Treatment of human peripheral blood leukocytes (hPBL) with Sendai virus induces
significant production of human interferon-alpha (IFN-alpha). Addition of human
recombinant interleukin-10 (IL-10) to hPBL in vitro prior to treatment with
Sendai virus resulted in considerable inhibition of IFN-alpha production.
Downregulation of IFN-alpha production was IL-10 concentration-dependent and
observed at IL-10 concentrations of as low as 0.05 ng/ml, with a median effective
dose (ED50) of about 5 ng/ml. Inhibition of IFN-alpha production by IL-10
occurred at an early stage of Sendai virus induction. The inhibitory effect of IL
10 on leukocyte interferon production was specific and blocked by pretreatment
with neutralizing polyclonal anti-IL-10 antibody. This downregulatory effect is
at the transcriptional level, since IL-10 inhibits IFN-alpha mRNA accumulation
upon Sendai virus treatment. These data suggest that leukocyte IFN-alpha
production is a highly regulated process that is modulated by cytokines such as
IL-10 during early immunological response to infection.
PMID- 9557213
TI - Open-label phase I study of combination therapy with zidovudine and interferon
beta in patients with AIDS-related Kaposi's sarcoma: AIDS Clinical Trials Group
Protocol 057.
AB - The aim of this study was to identify a safe and tolerable dose of recombinant
interferon-beta (IFN-beta) used in conjunction with a fixed dose of zidovudine in
patients with early-stage, good-prognosis AIDS-related Kaposi's sarcoma. We
conducted a phase I, dose-escalation controlled trial of 22.5, 45 of 90 million
units of IFN-beta given by daily subcutaneous injection with 500 mg per day of
oral zidovudine. At the time of this study, this was standard of care for HIV
infection. Patients were sequentially enrolled at three medical centers. Tumor
response, drug tolerance, antiviral studies and CD4 changes were assessed. Four
patients were enrolled at each dose level, and escalation proceeded when at least
four patients had tolerated two weeks of therapy without dose-limiting toxicity.
ACTG Kaposi's sarcoma tumor response criteria were used to assess response.
Fifteen patients were enrolled. The combination of IFN-beta and zidovudine was
well tolerated, and the dose-limiting toxicities were local skin necrosis and
systemic symptoms. Despite generally good prognostic characteristics, only two
patients achieved a clinical complete response and three addition patients had
stable disease for a prolonged period of time (range 24-44 weeks). There was no
correlation between baseline CD4 cell counts and tumor response, nor between the
antiviral effect of IFN-beta as measured by decreases in immune-complex
dissociated p24 antigen and tumor response. Higher doses of IFN-beta did not
result in more tumor responses or in greater antiviral activity. The maximum
tolerated dose of IFN-beta in combination with 500 mg per day of zidovudine was
45 million units by subcutaneous injection per day. IFN-beta is well tolerated in
patients with AIDS-related Kaposi's sarcoma when used in conjunction with
zidovudine. However, the antitumor response rate in good-prognosis patients is
low. Further studies of this agent should be in the context of four-drug
antiretroviral regimens where viral suppression is greatest and any antitumor
activity of IFN-beta may be observed.
PMID- 9557214
TI - Thrombopoietin in vitro and in vivo.
AB - The characterization of the c-Mpl receptor resulted from studies on a murine
retrovirus, and proved an important step in the identification of a key
hemopoietic regulator. First proposed and named in 1958, the ultimate
characterization of the long-awaited 'thrombopoietin' (TPO) came with the
molecular cloning and characterization of the in vitro and in vivo properties of
the c-Mpl ligand. Gene targeting experiments have demonstrated that the TPO/Mpl
receptor signalling pathway is the principal physiological regulator of
megakaryocytes and platelets. Analysis of signalling through c-Mpl has provided
important insights into the function of this pathway, which, as with other
members of the hemopoietin receptor family, involves activation of the JAK/STAT
and Ras signalling cascades. Preclinical studies have documented a role for this
molecule in overcoming thrombocytopenia following chemo/radiotherapy in several
animal models. Clinical studies have demonstrated the safety and efficacy of Mpl
ligand in elevating platelet counts. The identification of thrombopoietin has
provided an important impetus in understanding megakaryocyte and platelet
physiology, and provided a new therapeutic that will find application in a
variety of clinical contexts.
PMID- 9557215
TI - Immunotherapy of cancer using dendritic cells.
AB - While the promise of harnessing the immune system for a therapeutic effect has
remained largely unfulfilled for many years, the discovery of the central role of
dendritic cells in stimulating antigen-specific immune responses has prompted new
enthusiasm for immunotherapy of malignancies. Elucidation of the pathways of
dendritic cell development and trafficking, acquisition and processing of
antigen, and stimulation of T cells has suggested methods for generating and
antigen-loading dendritic cells for use in immunotherapy protocols. Animal models
have demonstrated that dendritic cells can stimulate protective antitumor
responses in vivo. Phase I clinical trials have been initiated to address the
safety and feasibility of immunizations with dendritic cells in humans with
various malignancies.
PMID- 9557216
TI - Molecular mechanisms of pancreatic beta-cell destruction in autoimmune diabetes:
potential targets for preventive therapy.
AB - Mononuclear cell infiltration into the islets of the pancreas (insulitis) is
characteristic of autoimmune diabetes. T lymphocytes are the predominant
subpopulation seen in insulitis, and are involved in the autoimmune process.
Insulin-producing beta cells are thought to be destroyed by cytotoxic T cells,
cytokines or nitric oxide, and beta-cell death occurs, at least partly, via
apoptosis. Beta-cell death induced by cytokines is inhibited by Bcl-2, suggesting
its potential as a tool for gene therapy. The Fas/Fas-ligand system plays a
critical role in inducing insulitis and overt diabetes in nonobese diabetic (NOD)
mice, a model of autoimmune diabetes. T-cell receptor gene usage in infiltrating
T cells is not restricted in NOD mice, but there are some observations indicating
relative restriction in human IDDM patients. Preventive strategies might be
developed by focusing on these molecules involved in beta-cell destruction. The
establishment of screening techniques for detecting prediabetic patients is also
necessary to allow successful intervention.
PMID- 9557217
TI - Active specific T-cell-based immunotherapy for cancer: nucleic acids, peptides,
whole native proteins, recombinant viruses, with dendritic cell adjuvants or
whole tumor cell-based vaccines. Principles and future prospects.
AB - Whereas tumor cells are poor immunogens, recombinant tumor cells or dendritic
cells as well as engineered viruses have been demonstrated to elicit specific
antitumor immune responses leading to tumor growth suppression and long-lasting
immunity in mouse tumor models. Single cytotoxic T lymphocyte-defined epitope
based strategies have proved useful for immunization in tumor-bearing mice. This
strategy is under investigation in human melanoma, along with adjuvants such as
cytokines or dendritic cells. Flt3L is an in vivo dendritic-cell growth factor
that offers new prospects in the field of active specific immunotherapy. These
immunotherapeutic approaches are being tested in clinical trials, and may open up
novel avenues for disease-free patients with poor prognostic factors.
PMID- 9557218
TI - The sebaceous gland and acne--40 years on.
PMID- 9557219
TI - The organ-maintained human sebaceous gland.
AB - In the absence of epidermal growth factor (EGF) and phenol red in the maintenance
medium, human sebaceous glands apparently retain in vivo rates of cell division
and lipogenesis over 7 days and also retain in situ morphology. This is
reversible on the re-addition of 10 ng/ml EGF and 10 mg/ml phenol red. The
addition of 600 pM 17 beta-oestradiol results in a significant fall in the rate
of lipogenesis over 7 days' maintenance, without affecting the rate of cell
division. This effect is apparently due to abnormal differentiation of newly
formed sebocytes. Neither 1 nM testosterone nor 1 nM dihydrotestosterone has any
effect on rates of cell division or lipogenesis over 7 days. 1 microM 13-cis
retinoic acid causes a significant reduction in the rate of lipogenesis over 7
days.
PMID- 9557220
TI - The human sebocyte culture model provides new insights into development and
management of seborrhoea and acne.
AB - Seborrhoea and acne are exclusively human diseases and sebaceous gland
differentiation is species specific. Therefore, fundamental research on human
sebaceous cell function and control requires human in vitro models. The human
sebocyte culture model, introduced in 1989, has been used in several studies to
elucidate sebaceous gland activity and its regulation at the cellular level.
Cultured human sebocytes have been shown to preserve important sebocytic
characteristics, although they undergo an incomplete terminal differentiation in
vitro. In vitro synthesis of free fatty acids without bacterial involvement and
marked interleukin 1 alpha expression at the mRNA and protein levels with no
further induction by lipopolysaccharides lead to the assumption that human
sebocytes may initiate acne lesions by an intrinsic mechanism. Androgens affected
sebocyte activity in vitro in a manner dependent on the localization of the
sebaceous glands. In vitro stimulation of sebocyte proliferation by androgens
could be completely abolished by spironolactone. Cultured sebocytes strongly
expressed type 1 5 alpha-reductase and metabolized testosterone to
androstenedione, 5 alpha-androstanedione, 5 alpha-dihydrotestosterone,
androsterone and 5 alpha-androstanediol, whereas the levels of 5 alpha-reductase
activity were probably not feedback regulated. 4,7 beta-Dimethyl-4-aza-5 alpha
cholestan-3-one, a type 1 5 alpha-reductase inhibitor, induced an early, marked
down-regulation of 5 alpha-reductase activity in human sebocytes in vitro, while
hydrofinasteride, a type 2 inhibitor, required 10(3)-fold higher concentrations
to induce similar effects. Stimulation of sebocyte proliferation by insulin,
thyroid-stimulating hormone and hydrocortisone indicates that the hormonal
control of the sebaceous gland could be a complex mechanism. Retinoids inhibited
sebocyte proliferation in a dose-dependent manner and down-regulated lipid
synthesis and sebocyte differentiation in vitro. Isotretinoin was the most potent
compound. On the other hand, vitamin A was found essential for sebocyte activity
and differentiation in vitro and could be partially substituted by synthetic
retinoids. The inhibitory effect of isotretinoin on sebocyte proliferation was
barely affected by the presence of vitamin A. The low persistent isotretinoin
levels or, more likely, the considerably elevated tretinoin concentrations
detected in human sebocytes after treatment with isotretinoin in vitro may be
responsible for the inhibitory effect of this compound on sebocyte activity.
PMID- 9557221
TI - Modelling the infundibulum in acne.
AB - The human sebaceous-pilosebaceous infundibulum was isolated and maintained for 7
days. Infundibular viability was maintained over 7 days in this medium. The
addition of 1 ng/ml interleukin 1 alpha (IL-1 alpha) caused hypercornification of
the infundibulum similar to that seen in comedones which could be blocked by
1,000 ng/ml IL-1 receptor antagonist. However, in contrast to interferon gamma 1,
IL-1 alpha had no effect on the expression of intercellular adhesion molecule or
human leucocyte antigen type DR in infundibular keratinocytes. The addition of 5
ng/ml epidermal growth factor or 5 ng/ml transforming growth factor alpha to the
medium caused a disorganization of the keratinocytes of the infundibulum. We are
now, therefore, able to model histologically the major infundibular changes in
acne. Furthermore, we suggest that IL-1 alpha causes the scaling seen in many
inflammatory skin diseases.
PMID- 9557222
TI - Activity of 5-alpha-reductase and 17-beta-hydroxysteroid dehydrogenase in the
infrainfundibulum of subjects with and without acne vulgaris.
AB - Linoleic acid deficiency, interleukin 1, retinoids and androgens have been
implicated as causative factors in the follicular hyperkeratinization seen in
acne. The goal of this study was to test the hypothesis that more androgens are
produced in follicles of acne subjects compared to subjects without acne. Thirty
four subjects (males and females with and without acne) were studied. The
activity of 5 alpha-reductase (5 alpha-R) and 17 beta-hydroxysteroid
dehydrogenase (17 beta-HSD) was determined in keratinocytes cultured from the
infrainfundibulum and epidermis. Mean enzyme activities were slightly higher in
the acne groups compared to the groups without acne, but differences were not
statistically significant, perhaps due to limitations of this in vitro model. The
activity of both 5 alpha-R and 17 beta-HSD was significantly greater in
infrainfundibular keratinocytes compared to epidermal keratinocytes in all
subject groups. 17 beta-HSD activity was 2.5- to 7-fold greater than the activity
of 5 alpha-R in infrainfundibular keratinocytes. The regulation of 17 beta-HSD by
endogenous factors may be important in determining the directional activity of 17
beta-HSD and hence the local concentration of testosterone within the
infrainfundibulum. Additional studies of the effects of androgens on follicular
keratinization are needed.
PMID- 9557223
TI - Mechanisms of androgen induction of sebocyte differentiation.
AB - It has been difficult to induce the expected sebocyte differentiation in vitro
with dihydrotestosterone (DHT). We reasoned that our culture system lacks
differentiating factors, and peroxisome proliferator-activated receptors (PPARs)
were the prime candidates. We tested PPAR activators informative about diverse
PPAR subtypes, with and without DHT (10(-6) M): BRL-49653 (10(-6) M, PPAR-gamma),
WY-14643 (10(-6) M, PPAR-alpha), and linoleic acid (LIN, 10(-4) M, PPAR-delta).
Treatments were added in serum-free medium to cultures of rat preputial
sebocytes. Control, DHT, BRL and BRL + DHT treatments caused 11, 25, 66 and 80%,
respectively, of preputial cell colonies to differentiate into lipid-forming
colonies (LFCs) (p < 0.001). WY induced 20% and LIN over 95% LFC formation. PPAR
gamma mRNA was identified in preputial sebocytes by the RNase protection assay.
These data suggest that differentiation of sebocytes is transduced by PPARs and
have implications for the development of new treatments for acne.
PMID- 9557224
TI - The isolation and characterization of androgen-dependent genes in the flank
organs of golden Syrian hamsters.
AB - To elucidate the molecular action of androgens, we have isolated two androgen
dependent genes, FAR-17a and -17c, from the cDNA library of flank organs of male
golden Syrian hamsters by a differential hybridization method. FAR-17a has been
reported previously. Androgens regulated the expression in the flank organs, ear
lobe and skin. FAR-17a protein was located in sebaceous glands. FAR-17c has a
similar expression pattern to that of FAR-17a, but its response to androgen is
faster than that of FAR-17a. It is expressed strongly in the liver, sebaceous
glands and brain. The homology search and mRNA expression pattern suggested that
it might encode a stearyl CoA desaturase (SCD) of golden Syrian hamsters. The SCD
is a key enzyme in fatty acid biosynthesis and its expression is controlled by
temperature, nutritional conditions and hormones. This is the first report that
the mRNA expression of stearyl CoA is regulated by androgens.
PMID- 9557225
TI - Heterogeneity and quantitative differences of type 1 5 alpha-reductase expression
in cultured skin epithelial cells.
PMID- 9557226
TI - Incidence of increased androgen levels in patients suffering from acne.
PMID- 9557227
TI - Propionibacterium acnes colonization in acne and nonacne.
AB - Propionibacterium acnes is a number of the resident bacterial flora and resides
in sebaceous follicles. Age-related and body-dependent quantitative differences
exist, indicating the role of sebum as an important ecological factor for P.
acnes. Acne patients demonstrate marked increases in this organism which
generates inflammation through a variety of mechanisms.
PMID- 9557228
TI - Bacterial resistance in acne.
AB - Antibiotics play a major role in acne therapy. Physicians base treatment choices
on personal perceptions of efficacy, cost-effectiveness or risk-benefit ratios
and rarely take bacterial resistance into account. It is well documented that
resistant strains of coagulase-negative staphylococci within the resident skin
flora increase in both prevalence and population density as duration of therapy
increases. Acne patients represent a considerable reservoir of resistant strains
of these important nosocomial pathogens which can be transferred to close
contacts. Resistance in cutaneous propionibacteria has received scant attention
in view of the central role of Propionibacterium acnes in inflammatory acne.
Isolates resistant to one or more anti-acne antibiotics (most commonly
erythromycin) have been reported in Europe, the USA, Japan and New Zealand.
Carriage of resistant strains results in therapeutic failure of some but not all
antibiotic regimens. In our region, skin carriage of resistant strains by 60% of
acne patients and 1 in 2 of their close contacts suggests that resistant strains
are widely disseminated. We are beginning to gain an understanding of those
factors which encourage resistance development and can identify those patients
most likely to possess resistant propionibacterial floras. Recommendations for
the use of antibiotics in acne therapy to help prevent the emergence of
resistance in P. acnes include the implementation of antibiotic usage policies
and the encouragement of improved prescribing habits.
PMID- 9557229
TI - Propionibacterium acnes and acne.
PMID- 9557230
TI - Resistance to erythromycin and clindamycin in cutaneous propionibacteria is
associated with mutations in 23S rRNA.
PMID- 9557231
TI - The adhesion of cutaneous micro-organisms to human skin lipids.
PMID- 9557232
TI - Construction of a lux reporter system for the analysis of the regulation of
Staphylococcus epidermidis lipases.
PMID- 9557233
TI - The pilosebaceous unit is part of the skin immune system.
AB - It is well established that the functional state of sebaceous glands in vivo is a
tightly regulated process orchestrated through the interaction of male sex
hormones and functional androgen receptors expressed on sebocytes. In the last
few years, however, it has become increasingly apparent that sebocytes like
epidermal keratinocytes express a variety of cytokines which are implicated in
inflammatory and immune responses. For example, sebocytes in vivo have been found
to highly express tumor necrosis factor alpha (TNF-alpha) as determined by
immunohistochemical and electron-microscopic methods. Moreover, certain
neuropeptides including vascular intestinal peptide and proopiomelanocortin
(POMC) peptides as well as their receptors have been localized within the
pilosebaceous unit of murine and human skin. Since POMC peptides such as alpha
melanocyte-stimulating hormone have recently been shown to exert important
immunoregulatory effects by antagonizing the function of proinflammatory
cytokines (e.g interleukin 1, interleukin 6 and TNF-alpha), induction of
immunosuppressive cytokines (like interleukin 10), modulation of costimulatory
molecule expression (e.g. B7-2) or suppression of macrophage-derived nitric
oxide, complex interactions between these mediators and their target cells within
the pilosebaceous gland seem to exist. The successful cultivation of sebocytes
will provide a model by which the effect of these mediators can be studied in
detail in order to shed light onto the various pathophysiological conditions of
sebaceous glands.
PMID- 9557234
TI - Inflammatory acne represents hypersensitivity to Propionibacterium acnes.
AB - Hypersensitivity to P. acnes may account for the great variation in acne
severity. Alternative explanations such as hyperandrogenism fail to account for
disease severity in large numbers of patients.
PMID- 9557235
TI - The possible role of reactive oxygen species generated by neutrophils in
mediating acne inflammation.
AB - The purpose of this study was to investigate the possible role of reactive oxygen
species (ROS) generated by neutrophils in mediating acne inflammation.
Antibiotics used for the treatment of acne significantly inhibited ROS generated
by neutrophils, when compared to other antibiotics. Metronidazole, which is
effective in the treatment of acne, markedly inhibited ROS generated by
neutrophils. The drug is known to have no significant effect on the growth of
Propionibacterium acnes. The proportion of linoleic acid is markedly decreased in
acne comedones. Linoleic acid significantly suppressed ROS generated by
neutrophils. The ability of neutrophils to produce ROS was significantly
increased in patients with acne inflammation. These results seem to reveal the
involvement of ROS generated by neutrophils in the disruption of the integrity of
the follicular epithelium, which is responsible for inflammatory processes of
acne.
PMID- 9557236
TI - Inflammation in acne vulgaris: failure of skin micro-organisms to modulate
keratinocyte interleukin 1 alpha production in vitro.
PMID- 9557237
TI - Vascular endothelial growth factor expression induced by proinflammatory
cytokines (interleukin 1 alpha, beta) in cells of the human pilosebaceous unit.
PMID- 9557238
TI - Clinical aspects of acne.
AB - Acne vulgaris may present in a wide variety of clinical forms depending on the
type, number and severity of the predominant lesion. Thus there may be mild,
moderate or severe comedonal or inflammatory acne, the latter with many subtypes.
Furthermore, the number and extent of the lesions do not necessarily predict the
response to therapy, and patients may also be categorized as therapeutically
responsive or therapeutically refractory. Finally, there may be alterations in
the clinical manifestations and therapeutic response depending on the
distribution of the lesions, age of the patient and provoking or complicating
factors.
PMID- 9557239
TI - A review of infantile and pediatric acne.
AB - Acne occurs primarily in the first year of life and at puberty. Neonatal and
infantile acne may reflect the relatively high androgens from the adrenal in
girls and the adrenal and testes in boys characteristic of this age. Early in
puberty, acne in boys and girls is primarily comedonal and midfacial. The best
predictors of severe acne are early onset of comedones and serum levels of
dehydroepiandrosterone sulfate. Early recognition and therapy of acne may prevent
scarring and psychological stress.
PMID- 9557240
TI - Variation in pilosebaceous duct keratinocyte proliferation in acne patients.
PMID- 9557242
TI - Acneiform dermatoses.
AB - Acneiform dermatoses are follicular eruptions. The initial lesion is
inflammatory, usually a papule or pustule. Comedones are later secondary lesions,
a sequel to encapsulation and healing of the primary abscess. The earliest
histological event is spongiosis, followed by a break in the follicular
epithelium. The spilled follicular contents provokes a nonspecific lymphocytic
and neutrophilic infiltrate. Acneiform eruptions are almost always drug induced.
Important clues are sudden onset within days, widespread involvement, unusual
locations (forearm, buttocks), occurrence beyond acne age, monomorphous lesions,
sometimes signs of systemic drug toxicity with fever and malaise, clearing of
inflammatory lesions after the drug is stopped, sometimes leaving secondary
comedones. Other cutaneous eruptions that may superficially resemble acne
vulgaris but that are not thought to be related to it etiologically are due to
infection (e.g. gram-negative folliculitis) or unknown causes (e.g. acne
necrotica or acne aestivalis).
PMID- 9557241
TI - Continuous education for acne--basics, pathogenesis, differential diagnosis,
clinic and therapy. Development of an interactive hypermedia application on CD
ROM for computer-based learning and instruction.
PMID- 9557243
TI - Coping with acne vulgaris. Evaluation of the chronic skin disorder questionnaire
in patients with acne.
AB - The present study investigated how patients with acne vulgaris cope with their
disease. By means of questionnaires, relations and interactions between acne and
psyche were evaluated. In addition to the evaluation of a specific questionnaire
for patients with chronic skin disorders (CSD), assessing psychosocial impairment
by the disease, depression and social anxiety were investigated in patients with
acne. The study included 50 patients with acne. The CSD showed significant
correlations with Beck's depression inventory, the interaction-anxiety
questionnaire and the health locus of control scale. The CSD revealed significant
differences compared to a control group of 33 patients with healthy skin.
Furthermore the patients' attitudes towards triggering factors and disease
related limitations in everyday life are presented. The results of the study
demonstrate that patients with acne suffer from emotional distress and
psychosocial problems caused by their disease; however, impairment is not
correlated with the objective severity of acne.
PMID- 9557244
TI - Psychotherapeutic approach in acne treatment.
AB - From a medical psychological point of view, acne vulgaris can be schematically
divided into two clinical pictures: (1) the common adolescent eruption, more mind
influencing and thus somatopsychic; (2) the less frequent acne of adults (young
adults for the most part), both as a continuation of adolescent acne and, more
rarely, as a never before experienced cutaneous affection, and thus psychosomatic
in a strict sense. We believe that the dermatologist can treat both of these
clinical manifestations, even from a psychological aspect, from the very first
visit with the patient using the first step in psychotherapy: counseling. The
principal points of this approach are presented, with special attention to the
differences to be considered in the two clinical pictures specified as well as to
the opportuneness and timing of an eventual liaison consultation with
psychologists/psychiatrists in realizing other therapeutic strategies.
PMID- 9557245
TI - Topical drug treatment in acne.
AB - The main part of acne treatment uses the topical route. More than 50% of acne
patients belong to the group presenting with acne comedonica and papulopustulosa.
Whenever small nodes or scarring occur, systemic comedication is indicated,
however. Topical treatment affects at least three of the four main pathogenetic
factors responsible for the development of acne, i.e. hyperseborrhea,
hyperkeratosis, microbial colonization and inflammation. The agents currently
available influence at least one of these factors but often have additional
properties. Those which act in a comedolytic and anticomedogenic manner are the
retinoids tretinoin, isotretinoin, adapalene and tazarotene and azelaic acid as
well, some of the retinoids having additional anti-inflammatory potency. Azelaic
acid has strong antibacterial potency without inducing bacterial resistance
similar to benzoyl peroxide. Unfortunately, bacterial resistances are beginning
to emerge as a significant problem. Propionibacterium acnes resistance to the
commonly used erythromycin can also be transferred to clindamycin, whereas no
resistance has been reported to nadifloxacin so far. Today, more and more
evidence comes up that topical antiandrogenic agents will soon be available to
treat the important factor seborrhea, because patients with marked hyperseborrhea
frequently relapse. Finally, liposome encapsulation of agents including
phospholipids can enhance penetration and efficacy but, particularly with regard
to retinoids, can lead to higher absorption and adverse drug reactions.
PMID- 9557246
TI - New insight into the topical management of excessive sebum flow at the skin
surface.
AB - The sebum flow dynamics at the skin surface results from a multistep process
starting with sebocyte proliferation, intracellular lipid synthesis, cell lysis
in the sebaceous duct, storage of sebum in the follicular reservoir, discharge
through the follicular opening and spreading over the stratum corneum. A handful
of topical products may decrease the sebum output, most of them acting at the
level of the follicular reservoir function. Among them, elubiol exhibits a
clinically relevant effect on oily skin.
PMID- 9557247
TI - An overview of topical antibiotics for acne treatment.
AB - Topical use of antibiotics is currently a widely accepted effective and safe
treatment for acne. A review of the articles published in the past 30 years
revealed that topical application of antibiotics such as erythromycin,
clindamycin or tetracycline showed clinical effectiveness for mild to moderate
inflammatory acne, especially when they are combined with zinc, tretinoin or
benzoyl peroxide, while they showed little influence on noninflammatory acne. The
main mechanism of action of topical antibiotics for acne treatment is inhibition
of inflammation caused by bacteria rather than a direct bactericidal effect. The
adverse reactions of topical antibiotics are mostly minor and negligible, while
special attention should be given to the risk of development of resistant strains
of Propionibacterium acnes. The development of new antibiotics is promising and
will provide a wider range of therapeutic options for refractory cases.
PMID- 9557248
TI - Systemic antibiotics for acne.
AB - Antibiotic therapy for acne is very common. Antibiotics are frequently used in
acne, either systemically or topically. Systemic antibiotics are indicated as
treatment of moderate and quite severe acne or if acne is considered as very
serious by the patient for psychological or social reasons. Results are very
often excellent, but failure is possible; in this case using another treatment,
especially isotretinoin, is necessary. A few antibiotics are useful:
tetracyclines (tetracycline, doxycycline, minocycline, lymecycline),
erythromycin, co-trimoxazole and trimethoprim. Their side effects are reviewed.
During pregnancy the best antibiotic is erythromycin. For the nursing mother it
is generally said that tetracyclines are contraindicated but the risks if they
exist are certainly slight. The mechanism of action of systemic antibiotics for
acne is not perfectly clear as it is not only antimicrobial: they diminish
chemotaxis of polymorphonuclear leukocytes, modify the complement pathways and
inhibit the polymorphonuclear leukocyte chemotactic factor and the lipase
production in Propionibacterium acnes.
PMID- 9557249
TI - Oral retinoids in the treatment of seborrhoea and acne.
AB - Isotretinoin is an extremely effective drug if given systemically in severe forms
of seborrhoea and acne, being the only retinoid with potent sebostatic
properties. Its unique activity on the sebaceous gland still remains unclear
since isotretinoin barely binds to cellular retinoic-acid-binding proteins and to
retinoic acid receptors. Its bioavailability is approximately 25% and can be
increased by food 1.5-2 times; after 30 min, the drug is detectable in the blood
and maximal concentrations are reached 2-4 h after oral intake. The major
metabolites of isotretinoin in blood are 4-hydroxy- and 4-oxo-isotretinoin, while
several glucuronides are detectable in the bile. 4-Oxo-isotretinoin is present in
plasma in a 2- to 4-fold higher concentration 6 h after a single dose. Steady
state concentrations appear after 1 week. The half-life elimination rate of the
parent compound ranges from 7 to 37 h while that of some metabolites does so from
11 to 50 h. Isotretinoin crosses the placenta and is recognized as a strong
teratogenic compound. About 10-30% of the drug is metabolized via its isomer
tretinoin. Excretion of isotretinoin occurs after conjugation with the faeces or
after metabolization with the urine. The epidermal levels of isotretinoin are
rather low and no progressive accumulation, either in serum or in the skin, is
found. After discontinuation of therapy, isotretinoin disappears from serum and
skin within 2-4 weeks. Isotretinoin is the most effective drug in reducing
sebaceous gland size (up to 90%) by decreasing proliferation of basal sebocytes,
suppressing sebum production and inhibiting sebocyte differentiation in vivo. The
molecular basis for its antisebotrophic activity has not been fully elucidated.
Isotretinoin also exhibits anti-inflammatory activities. Systemic isotretinoin is
today the regimen of choice in severe seborrhoea, since it reduces sebocyte lipid
synthesis by 75% with daily doses as low as 0.1 mg/kg after 4 weeks. Patients who
have received oral isotretinoin therapy for seborrhoea do not usually experience
a relapse for months or years. In severe acne, a 6- to 12-month treatment with
isotretinoin 1 mg/kg/day reduced to 0.5 or 0.2 mg/kg/day according to the
response is recommended (cumulative dose of > 120 mg/kg). Contraception is
essential during isotretinoin treatment in women of childbearing age 1 month
before, during and for 3 months after discontinuation of treatment.
PMID- 9557250
TI - Oral contraceptives and cyproterone acetate in female acne treatment.
AB - The sebaceous gland is a target of androgens, and hormonal influences play an
important role in the multifactorial pathogenesis of acne. In both men and women,
acne may be related to an excessive hypersensitivity of the sebaceous end organ
to androgens. However, in women, the ovarian and adrenal production and the
plasma transport of androgens may be implicated, particularly in late-onset or
persistent acne or with associated hirsutism. Many reports have shown that
females with acne frequently have abnormal levels of circulating androgens.
Hormonal treatment is not usually the first line in female acne. But in relation
to the possibilities, particularly the tetracyclines, this may be a choice when
one prescribes a pill like Dianette to a young woman presenting a mild acne and
who requests contraception. However, antiandrogen treatment is sometimes
mandatory, especially in resistant acne in adult women and/or in female acne
which is resistant or relapsing rapidly after treatment with Roaccutane and which
is often related to hyperandrogenism. Finally, in severe prepubertal acne, the
possible cause is an adrenal enzymatic block of which the only treatment is
hormonal.
PMID- 9557251
TI - Other antiandrogens.
AB - Various substances of steroidal or nonsteroidal structure may serve as an
alternative for the antiandrogenic treatment of acne. Compounds with
antiandrogenic properties like cimetidine or ketoconazole are rarely administered
for acne due to their weak effects. In contrast, spironolactone is an effective
antiandrogen that shows good treatment effects in hirsutism and acne. Side
effects occur frequently and are dose dependent. Isotretinoin--the most effective
agent in acne therapy--has been under discussion for additional antiandrogenic
properties for years. At present there is additional evidence for the
antiandrogenic effects of isotretinoin. Regarding substances acting on both
levels, androgen receptor binding and 5 alpha-reductase inhibition, the question
is raised whether the term 'antiandrogen' should be amplified by including the 5
alpha-reductase inhibitors. This would pay tribute to the biological aspect of
antiandrogenicity that takes into account not only the mode of action but also
the effects of the substance. Under this aspect type 1 5 alpha-reductase
inhibitors may gain attention in the future.
PMID- 9557252
TI - Why and when the treatment of acne fails. What to do.
AB - The majority of acne patients show a good response to the proper acne treatment.
However, a small percentage not exceeding 10-15% do not respond as satisfactorily
as expected. The main reason for the treatment failure is the poor patient
compliance. In order to improve the patient compliance the strategy for the
treatment of acne has to be carefully planned and includes the following:
discussion before treatment; give clear instructions; explain the rhythm of
improvement; explain the role of cosmetics; explain the role of sunbathing;
explain the expected side effects. It has to be emphasized that all acne cases
can be adequately controlled if the relationship between doctor and patient has
been built on trust and confidence, maximizing the patient compliance.
PMID- 9557253
TI - Comedonal diffusion of minocycline in acne.
PMID- 9557254
TI - Oral isotretinoin in HIV-positive women with acne: report of three cases.
PMID- 9557255
TI - A new concept of drug delivery for acne.
AB - Adapalene is a stable naphthoic acid derivative that displays a strong retinoid
agonist pharmacology. This drug controls cell proliferation and differentiation,
and possesses significant anti-inflammatory action. The retinoid action of
adapalene are mediated by the ligand-activated gene transcription factors
retinoic acid receptors RAR beta and RAR gamma. We describe here how an aqueous
gel containing adapalene was selected for the topical treatment of acne.
PMID- 9557256
TI - Polymorphisms in the human cytochrome P-450 1A1 gene (CYP1A1) as a factor for
developing acne.
AB - Cytochromes P-450 are a supergene family of enzymes involved in the metabolism of
a wide range of endogenous and foreign compounds. The existing genetic variations
of the distinct isozymes lead to interindividually different metabolic capacity.
Since vitamin A, endogenous retinoids and their natural metabolites are
morphogenic for the sebaceous gland, we investigated the polymorphisms of
cytochrome P-450 1A1, as being one of the most active isozymes involved in their
interconversion. From the known mutations, two were investigated; an additional
cleavage site for MspI in the 3'-flanking region identified as a thymine-to
cytosine transition 1,194 bp downstream of exon 7 (m1) and an adenine-to-guanine
transition at position 4889 in exon 7 (m2). We studied 96 acne patients for m1
and m2 mutations by restriction fragment length polymorphism and allele-specific
polymerase chain reaction, respectively, and compared the results with 408
reference individuals. No statistically significant difference was found in the
distribution of m2 alleles; the frequency was 3.13 and 3.06% of the alleles,
respectively (odds ratio = 1.02, confidence limits 0.41-2.52, p = 0.96). In
contrast, a trend to an overrepresentation of m1 alleles in acne patients was
observed; allele frequency was 8.33 in the patients and 6.99% in the control
subjects, respectively (odds ratio 1.21, 95% confidence limits 0.68-2.16, p =
0.52). As the m1 mutation might define a marker for alterations on regulatory
sites, the biological efficacy of natural retinoids could be greatly impaired by
their rapid metabolism to inactive compounds. The resulting deficit of active
natural retinoids may lead to abnormal sebocyte differentiation and
hyperkeratinization of the follicular canal implicating the development of acne
in some patients.
PMID- 9557257
TI - Monitoring of isotretinoin therapy by measuring the plasma levels of isotretinoin
and 4-oxo-isotretinoin. A useful tool for management of severe acne.
AB - BACKGROUND: Isotretinoin for oral therapy in severe acne conglobata and acne
nodulocystica represents a significant achievement; however, the drug exerts
several mucocutaneous and systemic adverse effects, besides its teratogenic
potency. OBJECTIVE: The aim of this study was to investigate the plasma levels of
isotretinoin and of 4-oxo-isotretinoin over long-term treatment of severe acne
and to assess any correlation with the given dose, the clinical improvement and
the occurrence of side effects. METHODS: Forty-one patients with severe acne and
acne-related disorders were studied under long-term oral intake of isotretinoin.
Therapeutic effects and side effects were evaluated prior, during and at the end
of therapy. The plasma levels of isotretinoin and of its major metabolite 4-oxo
isotretinoin were measured by reversed-phase HPLC and were correlated with the
administered oral dose and the number and frequency of side effects. RESULTS:
Dose-dependent plasma levels of isotretinoin and its metabolite were observed. At
a mean dosage of 0.75-1.0 mg/kg/day, 404 +/- 142 ng/ml were measured, whereas the
plasma levels of 4-oxo-isotretinoin were 1-2x higher. The plasma levels
correlated well with the orally administered dose of isotretinoin and the
observed mucocutaneous side effects. CONCLUSION: The study demonstrates that
measuring of the plasma levels may be a helpful tool to monitor the individual
therapeutic dose regimen in patients with severe acne in order to minimize
undesired side effects and to control oral intake.
PMID- 9557258
TI - Fine-needle aspiration of Merkel cell carcinoma of the skin with cytomorphology
and immunocytochemical correlation.
AB - Merkel cell carcinoma (MCC) of the skin is a rare, primary malignant skin
neoplasm which can present as a cutaneous nodule. These neoplasms are seen
primarily in the elderly and located in the head and neck area or extremities.
Twenty-nine aspirates from primary and metastatic lesions obtained by
percutaneous fine-needle aspiration in 19 patients have been studied. The
cytomorphologic features, clinical information, and immunocytochemical (ICC)
findings are detailed. Aspirate smears demonstrated small-to-intermediate-sized
cells with a loosely cohesive pattern. Nuclei were round with finely granular
chromatin and multiple, small nucleoli. Cells possessed a thin rim of cytoplasm,
and infrequent pseudorosette formations were noted in cell groups. ICC results
were universally positive for cytokeratin, which showed a paranuclear "dot-like"
pattern. Neuron-specific enolase, epithelial membrane antigen, and S-100 protein
were positive in varying degrees. Leukocyte common antigen was universally
negative. The diagnosis of MCC of the skin by FNA can be made by applying
cytologic features in addition to ancillary studies and clinical information.
PMID- 9557259
TI - Ultrasound-guided fine-needle aspiration cytology diagnosis of gallbladder
lesions: a study of 82 cases.
AB - Carcinoma of the gallbladder (GB) is among the five most common forms of cancers
and tops the list of gastrointestinal malignancies in females of the Delhi
region. Lack of specific signs and symptoms prevents early detection of GB
carcinoma. However, in recent years ultrasonographically (US)-guided fine-needle
aspiration (FNA) cytology has been found to be a reliable procedure for its
diagnosis. The present study was carried out during a period of 5 yr (1986-1990)
in 64 female and 18 male patients to find out the diagnostic utility of US-guided
FNA cytology in gallbladder lesions. Ultrasonography in these 82 cases revealed a
mass in the gallbladder/GB area in 74 (90.2%), a mass in the GB/pancreas in 1
(1.2%), gallstones in 32 (39.0%), and miscellaneous gallbladder lesions in 4
(4.9%). The other findings included space-occupying lesions in liver in 18
(22.0%), portal lymphadenopathy in 12 (14.6%), and infiltration in other organs
in 7 (8.5%). The initial cytodiagnosis was malignancy in 48 cases, inflammatory
in 12, and inadequate in 22. Following review of the smears by one of the
investigators (D.K.D.), the number of malignant cases remained 48 (58.5%). There
were 10 (12.2%) inflammatory and 24 (29.3%) inadequate cases. Adenocarcinoma was
the most common malignancy (83.3%), followed by squamous-cell and adenosquamous
carcinoma (12.5%) and small round cell tumors (4.2%). The 10 inflammatory lesions
showed slight (+) to excessive (+3) neutrophilic infiltration and included one
case each of xanthogranulomatous cholecystitis and a necrotizing granulomatous
lesion likely to be of tuberculous etiology.
PMID- 9557260
TI - Optimization of the peritoneal lavage.
AB - Review of 275 consecutive peritoneal lavages and concurrent histologic material
from gynecologic operations suggested that cytologic evaluation was clinically
indicated for only 60.7% of the lavages, representing 46% of the patients in the
study. More than one concurrent lavage was received from 21.6% of all patients in
the study, comprising 50% of patients with malignant lavages, 18.7% of patients
with benign lavages, and 5.3% of patients for whom cytologic evaluation of
peritoneal lavage was not clinically indicated. Malignant cells were diagnosed in
15% of the 167 lavages for which cytologic examination was clinically indicated.
In this series of patients, identification of malignant cells in peritoneal
lavages did not increase the tumor stage beyond that obtained solely from
examination of the concurrent histologic material. There were no false-positive
cytologic diagnoses and no lavages in which neoplastic cells were misinterpreted
as benign. A significant number of lavages, including several from patients with
histologically confirmed peritoneal tumor, were sparsely cellular and/or
excessively bloody. It is suggested that although peritoneal lavages might be
collected during all gynecologic operations, only specimens from selected cases
should be submitted for cytologic evaluation, and greater attention should be
given to specimen collection to ensure that only well-preserved and
representative material from the peritoneum is submitted for cytologic
evaluation.
PMID- 9557261
TI - Fine-needle aspiration cytology of amyloid associated with nonneoplastic and
malignant lesions.
AB - To assess the value of fine-needle aspiration (FNA) cytology for the diagnosis of
amyloid, we retrospectively studied all FNA cases diagnosed as having amyloid
during a 6-yr period (1990-1996). FNA was performed on both superficial and deep
locations. A total of 6 cases containing amyloid was studied, including primary
medullary thyroid carcinoma, metastatic medullary thyroid carcinoma to a
vertebrae, multiple myeloma, squamous-cell carcinoma of the lung metastatic to a
hilar lymph node, primary pulmonary amyloid, and amyloid tumor in a vertebral
body in a patient with primary systemic amyloidosis. Despite the location or
disease association, the cytologic appearance of amyloid in all cases was
similar. On Diff-Quik stain, amyloid appeared as amorphous, irregular, waxy
basophilic to metachromatic clumps of material. Papanicolaou stain revealed
cyanophilic to organophilic clumps of material with occasional prominent
fissures. In all 6 cases, amyloid was confirmed by Congo red stain and in 3 cases
by a thioflavin T stain. In 4 of the 6 cases (67%), amyloid was associated with
an underlying malignancy. In 3 cases malignant cells were admixed with the
amyloid, and in another case malignancy was present at a distant site. We
conclude that FNA biopsy is a helpful initial procedure for the evaluation of
patients with amyloid deposits. The clinical implications of amyloid found in any
particular body site include both benign and malignant conditions. The presence
of an associated neoplasm must be especially considered in the differential
diagnosis of amyloid deposits.
PMID- 9557262
TI - Renal medullary carcinoma: report of a case with positive urinary cytology.
AB - Renal medullary carcinoma is an aggressive neoplasm of the renal pelvis arising
in patients with a history of sickle-cell trait. The authors report a case of
renal medullary carcinoma with positive urinary cytology. Due to the location of
the tumor in the renal pelvis and the loosely cohesive nature of poorly
differentiated neoplasms, the presence of renal medullary carcinoma in a urinary
cytology specimen is not surprising. The cytologic characteristics as well as the
ultrastructural features are described.
PMID- 9557263
TI - Metastatic pulmonary leiomyosarcoma: cytopathologic diagnosis on sputum
examination.
AB - Pulmonary metastasis of sarcomas is not uncommon. Rarely, endobronchial
involvement may result in exfoliation of diagnostic cells in sputum. This case
report is of a 71-yr-old man with a history of lower leg leiomyosarcoma who
developed multiple lung metastases. Sputum examination revealed malignant cells
with pleomorphic, elongated, and cigar-shaped nuclei and occasional bipolar
cytoplasmic processes. Immunoperoxidase studies on the smears using desmin and
smooth muscle actin were strongly positive, consistent with leiomyosarcoma.
Confirmation of metastatic lung disease by sputum cytology not only has
prognostic importance but also obviates the need for further investigations.
PMID- 9557264
TI - Malignant melanotic schwannoma fine-needle aspiration biopsy findings.
AB - We describe the cytologic, histologic, and clinical features of two cases of
melanotic schwannoma, arising in the neck and superior mediastinum, respectively.
Cytologic findings in both cases included the presence of cells with heavily
pigmented cytoplasm, showing long branching projections. The cells were arranged
in clusters, with ill-defined boundaries. Histologic findings included
interlacing fascicles of cells, with abundant melanin pigment, calcification, and
necrosis. Immunohistochemical stains were positive for S. 100 protein and anti
human melanoma (HMB45). Both patients died with metastases.
PMID- 9557265
TI - Fine-needle aspiration cytology of malignant retroperitoneal paraganglioma.
AB - The cytologic findings in a fine-needle aspiration sample are described from a
large retroperitoneal mass in a 56-yr-old male. The aspiration was performed
under CT guidance using a 22-gauge needle, maintaining negative pressure. For
cytologic study, on-site smears were prepared and stained by the Papanicolaou
method. Additionally, cytospin, filter preparations, cell blocks from the
aspirate, histology, and electron microscopy of the tumor tissue were performed.
Also, immunodiagnostic staining for neuron-specific enolase (NSE), chromogranin,
S-100 protein, vimentin, HMB45, cytokeratin, and Grimelius preparation was
performed on cytologic and histologic material. The cytologic material was
characterized by cords, suggestive acinar structures, and small follicle-like
clusters of cells, while cell blocks from the aspirate showed oval or spindle
shaped nuclei with a somewhat fasciculated appearance. However, sections from the
tumor tissue showed an organoid "zellballen" pattern. The nuclei were round,
oval, spindly, and epithelioid, with moderate to scanty cytoplasm, smooth nuclear
membranes, fine, evenly dispersed chromatin, slight hyperchromasia, and mild
pleomorphism. No intranuclear vacuoles were seen. Positive immunohistochemical
staining for NSE, chromogranin, and Grimelius preparation was noted in the tumor
cells, while staining for vimentin, HMB45, and cytokeratin was negative. Electron
microscopy of the tumor tissue revealed the presence of variable numbers of
round, membrane-bound, electron-dense neurosecretory granules. The cytohistologic
and ultrastructural findings are presented, as well as the results of
immunodiagnostic staining which helped in the diagnosis of retroperitoneal
paraganglioma, an infrequently reported tumor.
PMID- 9557267
TI - Fine-needle aspiration cytology of renal angiomyolipoma: report of a case with
immunocytochemical and electron microscopic findings.
AB - A case is presented in which the diagnosis of renal angiomyolipoma was made by
computed tomography (CT)-guided, fine-needle aspiration cytology and the
examination of a cell block. The tumor was characterized by epithelioid smooth
muscle cells, blood vessels and fat in the cytologic material. The cytodiagnosis
was further substantiated by positive staining of the epithelioid muscle cells
for markers of muscle-specific actin, HMB45, and trace positivity for vimentin
but not with S100 protein, desmin, or cytokeratin. Further studies for the
recently described crystalloids were also performed by using the periodic-acid
Schiff stain with and without diastase treatment and electron microscopy on the
cytologic material. However, no such crystalloids were found. A preoperative
cytologic diagnosis of renal angiomyolipoma was considered to be of value due to
the difference in management between angiomyolipoma and a renal carcinoma, both
of which can present as a renal mass on imaging.
PMID- 9557266
TI - Metastatic papillary oncocytic carcinoma of the pancreas to the liver diagnosed
by fine-needle aspiration.
AB - A 37-year-old white male with a large pancreatic mass was referred to our
institution with a hypodense liver lesion detected on CT scan. A fine-needle
aspiration (FNA) was performed on the liver lesion. Diff-Quik smears demonstrated
scattered papillary structures and single neoplastic cells with abundant well
defined dense granular cytoplasm. Eccentrically located nuclei were noted with
single prominent nucleoli. Cell block preparations showed papillary structures
lined by cells with abundant pink granular cytoplasm, hyperchromatic nuclei, and
prominent single nucleoli. Electron microscopic examination displayed numerous
but poorly preserved mitochondria. The diagnosis of papillary carcinoma with
oncocytic features was made. Only two previous cases of pancreatic oncocytic
tumors diagnosed by FNA have been reported in the literature. We present an
additional case, notable in that the diagnosis was made in a metastatic liver
nodule.
PMID- 9557268
TI - Bronchioloalveolar carcinoma: diagnostic pitfalls and immunocytochemical
contribution.
AB - Because bronchioloalveolar carcinoma (BAC) commonly displays bland cytologic
appearance, there is a good potential for misinterpretation. The aim of this
study was twofold: one was to identify the most reproducible cytomorphologic
features to distinguish BAC from conventional lung adenocarcinoma (CLA) on fine
needle aspiration (FNA), and the other was to investigate the staining
characteristics of these two variants of lung carcinoma with P53 tumor suppressor
gene immunostain and their potential value in the distinction between the two
entities. Cytology records of 13 histologically documented BACs was retrieved: 7
FNA, 3 bronchial washing/bronchial brushing (BW/ BB), and 3 scraping smears of
surgical specimens. Two cases had both FNA and BW/BB material. Immunostains for
P53 protein, carcinoembryonic antigen (CEA), and Ki67(MIB-1) monoclonal
antibodies were performed on 13 BACs (FNA cell blocks and tissue) and on 11 FNA
cell blocks of CLA. Cytologically, BAC showed uniform cells with abundant, lacy
cytoplasm, and bland, folded nuclei arranged singly, in papillary clusters, and
sheets. Immunocytochemically, one BAC and one CLA were technically unacceptable.
Of the 12 remaining BAC cases, 10 were reactive with CEA, 9 reactive with Ki67 (>
5%), and 4 reactive with P53. Of the 10 remaining CLAs, 9 were positive with CEA,
9 were reactive with Ki67 (> 5%), and 8 were reactive with P53. We conclude that
BAC demonstrates distinctive cytologic features, but difficulty may be
encountered with well-differentiated CLA, metastatic adenocarcinoma, and other
lesions. Immunocytochemically, CEA and Ki67 do not appear to be discriminate, but
P53 may be of value in distinguishing BAC from CLA. Attention to subtle nuclear
changes, characteristic grouping, cellular arrangement, and P53 reactivity could
enable cytopathologists to accurately diagnose BAC.
PMID- 9557270
TI - Is the cytologic diagnosis of esophageal glandular dysplasia feasible?
AB - Barrett's esophagus is a premalignant condition in which the normal stratified
squamous epithelium of the esophagus is replaced by metaplastic glandular
epithelium. Patients with Barrett's esophagus are at increased risk for the
development of esophageal adenocarcinoma. Because dysplasia precedes the
development of frank adenocarcinoma, the cytologic detection of esophageal
glandular dysplasia represents a potentially inexpensive and efficient means of
monitoring disease progression to adenocarcinoma and identifying high-risk
patients. This article discusses the current status of exfoliative cytology as a
screening test for glandular dysplasia of the esophagus.
PMID- 9557269
TI - PAPNET computer-aided rescreening for detection of benign and malignant glandular
elements in cervicovaginal smears: a review of 61 cases.
AB - An increasing proportion of the recent cytodiagnostic literature has focused on
automation of the Pap smear screening process in hopes of finding a feasible
system to aid in the reduction of the number of reported false-negative cases. In
a sense, these systems can be thought of as computer-driven sensitivity enhancers
for better detection of abnormalities in smeared cervicovaginal specimens. The
PAPNET system (Neuromedical Systems, Inc., Suffern, NY) relies on a neural
network of artificial-intelligence technology to recognize the complex cellular
arrays present in Pap smears, and was originally intended to aid in the
identification of morphologically abnormal cells of squamous origin. Herein, we
present the results of 61 smears containing a mixture of known diagnostically
important benign, dysplastic, and malignant glandular cellular abnormalities
which were reviewed by the PAPNET technology. The PAPNET system detected the
diagnostic glandular material in 44 of the 45 benign cases reviewed (98%
detection rate). In addition, the PAPNET technology identified abnormal cellular
material in 15 of the 16 studied smears from patients with malignant/dysplastic
morphology (94% detection rate). These data indicate that the PAPNET neural
networks are capable of detecting cells with aberrant glandular cytomorphology.
In both cases missed by the PAPNET system, the number of abnormal cells per slide
was very low, indicating that as with human screeners, the capabilities of this
semiautomated method may be exceeded when an extreme paucity of diagnostic
cellular material is present in a given slide. Further and larger reviews of
glandular abnormalities by automated technologies are needed to assess these
systems for their true efficacy at diminishing false-negative cases.
PMID- 9557271
TI - Cytohistologic discrepancies in cervical intraepithelial neoplasia and value of
repeat cervical smears taken during colposcopy.
PMID- 9557272
TI - [Antimicrobial activities of cefcapene against clinical isolates from respiratory
tract infections of outpatients].
AB - In order to evaluate antimicrobial activity of cefcapene (CFPN), minimum
inhibitory concentrations (MICs) of CFPN and reference drugs were determined
against clinical isolates from respiratory tract infection of out patients that
were obtained in our laboratory from January to June of 1997. The results are
summarized as follows; 1. The MIC90 of CFPN against penicillin (PC)-susceptible
Streptococcus pneumoniae (PSSP) was equal to those of benzylpenicillin (PCG),
ampicillin (ABPC) and cefditoren (CDTR), and was lower than those of cefaclor
(CCL), cefdinir (CFDN) and erythromycin (EM). 2. The MIC90 of CFPN against PC
intermediate S. pneumoniae (PISP)/PC-resistant S. pneumoniae (PRSP) was equal to
that of CDTR, and was lower than those of PCG, ABPC, CCL, CFDN and EM. CFPN
showing strong antimicrobial activities against PISP. 3. CFPN showed strong
antimicrobial activities against beta-lactamase producing and non-producing
Haemophilus influenzae. The MIC90 of CFPN was stronger than those of ABPC, CCL,
CFDN and EM, and was approximately equal to that of CDTR. CFPN also showed strong
antimicrobial activities against strains which did not produce any beta-lactamase
and were resistant to CCL with MIC of > or = 25 micrograms/ml. 4. Antimicrobial
activities of CFPN against Moraxella subgenus Branhamella catarrhalis was
stronger than that of ABPC and CCL, though the MIC90 of CFPN was rather high,
3.13 micrograms/ml. 5. CFPN showed strong antimicrobial activities against PISP
and beta-lactamase producing H. influenzae, and also against the CCL-resistant H.
influenzae indicative mutations of penicillin-binding proteins (PBPs). From those
results, cefcapen-pivoxil was found to be clinically effective against community
acquired respiratory tract infection.
PMID- 9557273
TI - [In vitro antibacterial activities of cefteram and other beta-lactam agents
against recent clinical isolates].
AB - In vitro antibacterial activity of the third-generation oral cephem cefteram
(CFTM)--ten years after its first use in the clinical setting--against recent
clinical isolates was evaluated and compared with those of other oral cephems. A
total of 851 clinical isolates belonging to 13 species used in this study were
collected from five medical institutions across Japan during 1996. CFTM showed
excellent antibacterial activity against methicillin-susceptible S. aureus and S.
pyogenes, equivalent to those of other third-generation oral cephems, except
cefixime. Of the S. pneumoniae strains, a high proportion, 34.1%, were penicillin
resistant strains (PRSP), with MIC values of 2.0 micrograms/ml or above, but the
MIC50 of CFTM against PRSP was 1.0 microgram/ml. CFTM and the other third
generation oral cephems showed potent antibacterial activity against E. coli, K.
pneumoniae, and P. mirabilis. A few strains of E. coli, however, were highly
resistant to third-generation oral cephems; that might include extended-spectrum
beta-lactamase producing strains. MIC values against P. vulgaris varied
significantly, depending on whether they were determined by the broth micro
dilution method or the agar dilution method; growth was observed at high
concentrations in the broth micro-dilution method, in which the skip phenomenon
was demonstrated, but not in the agar dilution method. The reason for this
discrepancy is unknown. Most strains of S. marcescens, C. freundii, and E.
cloacae demonstrated resistance to CFTM and the other third-generation oral
cephems. CFTM and the other third-generation oral cephems showed excellent
antibacterial activities against M. (B.) catarrhalis, N. gonorrhoeae, and H.
influenzae, including ampicillin-resistant strains.
PMID- 9557275
TI - [Change of cytokines and clinical efficacy of panipenem/betamipron in obstetric
and gynecological infections. Yamagata Study Group of Panipenem/Betamipron in
Obstetric and Gynecological Infections].
AB - Efficacy and safety of panipenem/betamipron (PAPM/BP) in treatment of obstetric
and gynecological infections, and change of interleukin-6 (IL-6) and interleukin
8 (IL-8) levels in blood, as markers of infection, were investigated. The results
were as follows; 1) Clinical efficacy of PAPM/BP by drip infusion of 1-2 g/day
for 3-14 days against 52 patients with intrauterine infection (n = 29),
pelveoperitonitis (n = 19), and other infections were 14 "Excellent" in 14 cases,
"Good" in 35 cases, and efficacy rate was 94.2% (49/52). Both efficacy rate analy
by causative organisms and eradication rate were 35/37 (94.6%). No subjective or
objective side effects and no abnormal labolatory findings were observed. 2)
Changes of IL-6 (> 4 pg/ml) levels in serum, as an infection marker, were
observed in 8 cases out of 14 cases (57.1%), and correlation between CRP and IL-6
in the treatment process was noticed. However, changes of serum IL-8 (> 12.5
pg/ml) were observed in only 2 cases of those 14 cases (14.3%), indicative that
IL-8 has no significance as a marker of infection.
PMID- 9557274
TI - [The antimicrobial susceptibilities and serotypes of Pseudomonas aeruginosa
isolated from sputum].
AB - During the period of January 1992 and August 1995, 75 strains of Pseudomonas
aeruginosa were isolated from sputum at the Hiroshima Prefectural Hiroshima
Hospital. The antimicrobial susceptibilities and serotypes of those strains were
investigated. The results are summarized as follows: 1. The analyses of
antimicrobial susceptibilities revealed that meropenem (MEPM) was the most active
among the carbapenems tested against those P. aeruginosa strains with MIC of < or
= 6.25 micrograms/ml. All of the strains were thus found to be susceptible to
MEPM, while 9 strains out of 75 (12%) were resistant to imipenem showing cross
resistance to biapenem. 2. The activities of the beta-lactams other than
carbapenems were found to be the order of cefozopran > or = ceftazidime >
aztreonam > piperacillin with MIC50 and MIC90 ranging of 3.13-6.25 micrograms/ml
and 25- > or = 100 micrograms/ml, respectively. 3. Among aminoglycosides tested,
3 strains (4.0%) of the strains showed resistance to amikacin, however none of
them were resistant to tobramycin. 4. Distribution of serotypes among the strains
was; type G 22.7%, type M 21.3%, type A 16.0%, type B 13.3% and type E 8.0%.
Strains of types M and E showed multiple resistance to beta-lactams except
carbapenems. As documented in this study, the frequency of isolation of beta
lactam-resistant P. aeruginosa (including carbapenem-resistant) is steadily
increasing. Continuous surveillance of antimicrobial susceptibility among
clinically isolated P. aeruginosa seems to be necessary.
PMID- 9557276
TI - [Significance of coronary risk factors and coronary arteriosclerosis for coronary
vasospasm].
AB - The clinical significance of coronary arteriosclerosis and coronary risk factors
was investigated in patients with coronary spasm. Coronary spasm induction test
with acetylcholine was performed in 140 consecutive patients (85 males and 55
females) with chest pain in our hospital. The patients were divided into
positive, borderline, and negative groups according to the results of the test.
The positive and borderline groups were categorized as the coronary contractive
group. The coronary sclerosis index was used to evaluate the degree of coronary
arteriosclerosis. Coronary risk factors were evaluated in terms of hypertension,
diabetes mellitus, hyperlipidemia, obesity, history of smoking and drinking, and
family history of cardiovascular events. Patients could be divided into 34.3% in
the positive group and 23.6% in the borderline group, i.e. 57.9% in the coronary
contractive group, and 42.1% in the negative group. There were more males than
females in both positive and coronary contractive groups. The proportion of males
in the coronary contractive group was higher in patients over 60 years of age
than in patients under 60. In contrast, the proportion of females was higher in
patients under 60 than in patients over 60. In male patients, the coronary
sclerosis indices in the positive, borderline, and coronary contractive groups
were higher than those in the negative group. The indices in female patients in
the positive and coronary contractive groups were higher than the index in the
negative group. There were no differences in terms of the presence or absence, or
the degree of organic stenosis between spastic sites and nonspastic branches in
the positive group. The history of smoking in male patients was significantly
more common in the positive group than in the negative group. The family history
was more relevant in female patients in the positive or coronary contractive
group compared to the negative group. Moreover, the history of smoking in the
coronary contractive group was significantly more common than that in the
negative group. The development of coronary spasm may be determined, at least in
part, by the degree of coronary sclerosis as well as by gender and age. Smoking
habits in both sexes and family history in females are proposed as the most
important risk factors for coronary spasm.
PMID- 9557277
TI - [Usefulness of intracoronary injection of acetylcholine and ergonovine in
patients with variant angina].
AB - The correlation was examined between the angina-producing arteries predicted to
be responsible for the sites of ST segment elevation during spontaneous ischemic
attacks and the arteries in which spasm was induced by intracoronary injection of
either acetylcholine or ergonovine in patients with variant angina. From 1991
January to 1996 June, 42 patients with variant angina, 40 men and 2 women with a
mean age of 61.6 years old, underwent the acetylcholine provocation test within 2
weeks of observation of the last ST segment elevation. After discontinuation of
antianginal agents for at least 24 hours, a bolus of acetylcholine was injected
in incremental doses of 20, 50 micrograms (occasionally 80 micrograms) into the
right coronary artery and of 20, 50 and 100 micrograms incrementally into the
left coronary artery to provoke coronary spasm. Intracoronary injection of
ergonovine was added in nine patients, in whom intracoronary injection of
acetylcholine failed to document coronary spasm on the arteries predicted to be
responsible for the sites of ST segment elevation during anginal attacks.
Ergonovine was injected in total doses of 40 micrograms into the right coronary
artery and of 64 micrograms into the left coronary artery. Positive spasm was
defined as induction of more than 99% reversible stenosis. The correlation
between the arteries predicted to be responsible for the sites of ST segment
elevation during attacks and the vessels in which spasm was induced by
acetylcholine test was 78.6% for all patients and 80.0% for all sites of ST
segment elevation. By adding the ergonovine test after the acetylcholine test,
the correlation increased to 95.2% for all patients and 95.6% for all sites of ST
segment elevation. The correlation observed agrees with previous studies in which
the ergonovine test was performed in patients without induced spasm by
intracoronary injection of acetylcholine and that the super-imposed ergonovine
test is useful for diagnosing patients with variant angina.
PMID- 9557278
TI - [Effects of antihypertensive treatment on the thickening of the basal portion of
the interventricular septum in essential hypertension].
AB - Previous echocardiographic studies have indicated that the basal portion of
interventricular septum is locally thickened in many patients with essential
hypertension. This retrospective study investigated whether this localized
thickening is decreased by antihypertensive treatment. Twenty-four patients with
mild essential hypertension (15 males, 9 females, mean [+/- SD] 55 +/- 9 years)
were selected who had local thickening at the basal portion of interventricular
septum (> or = 11 mm) on echocardiograms recorded within 3 months after the first
visit and were followed up by echocardiography 6 months or more after the start
of antihypertensive treatment. Interventricular septal wall thickness at the mid
portion (IVST), posterior wall thickness (PWT), left ventricular mass index
(LVMI), aorto-septal angle, blood flow velocity in left ventricular outflow
tract, and the thickness of the basal portion of interventricular septum (septal
wall maximum thickness within 1.5 cm apex side from the joint of interventricular
septum and aorta in the long-axis view of B-mode echocardiograms) were measured.
Blood pressure was significantly decreased from 152.7 +/- 8.7/93.1 +/- 8.0 mmHg
to 140.0 +/- 8.2/86.6 +/- 8.2 mmHg by treatment (p < 0.0001). The thickness of
the basal interventricular septum was significantly reduced by treatment from
12.3 +/- 1.7 mm to 10.3 +/- 1.4 mm (p < 0.0001). Mean IVST, PWT and LVMI were
slightly reduced by treatment, but the differences were not statistically
significant. These results suggest that the thickening of basal interventricular
septum is induced by high blood pressure, and the measurement of the thickness of
basal interventricular septum might be a useful tool to estimate and monitor the
effect of antihypertensive treatment in patients with mild essential
hypertension.
PMID- 9557279
TI - [Serial changes in mitral regurgitation after mitral valve repair with artificial
chordae tendineae: assessment by transesophageal echocardiography].
AB - Serial changes in mitral regurgitation after anterior mitral valve repair were
examined by transesophageal echocardiography (TEE) in 34 of 86 consecutive
patients with pure mitral regurgitation who underwent anterior mitral valve
repair from 1987 to 1996. The patients were divided into two groups: 15 patients
undergoing mitral repair with polytetrafluoroethylene (PTFE; PTFE group) and 19
undergoing conventional mitral repair without PTFE (non-PTFE group). The PTFE
group included 11 men and 4 women with a mean age of 52.1 years. They were
followed for mean 22.8 +/- 12.0 months. The non-PTFE group included 12 men and 7
women with a mean age of 53.9 years. They were followed for mean 33.9 +/- 20.4
months. Mitral regurgitation jet areas were observed at the time of operation, 1
month after mitral valve repair, and in the late follow-up period. Regurgitation
jet areas were 0.7 +/- 0.7, 1.1 +/- 0.9 and 2.5 +/- 2.1 cm2 in the PTFE group,
and 1.1 +/- 1.3, 2.4 +/- 1.7, 4.7 +/- 2.9 cm2 in the non-PTFE group. The jet area
was significantly smaller in the PTFE group than in the non-PTFE group at 1 month
after operation and in the late follow-up period. Moderate to severe
regurgitation was observed in two patients (13.3%) in the PTFE group, and eight
patients (42.1%) in the non-PTFE group. Mitral valve repair with PTFE showed
better results than conventional mitral valve repair without PTFE during the mean
follow-up period of 23 months.
PMID- 9557280
TI - [Dor operation for end-stage ischemic cardiomyopathy].
AB - Endoventricular circular patch plasty (Dor operation) was used to treat end-stage
dilated ischemic cardiomyopathy in 13 patients from January to December, 1997.
There were 10 men and three women aged from 57 to 78 years (mean 63 years).
Single, double, triple and left main trunk coronary disease was present in one,
two, eight and two patients, respectively. Mean ejection fraction was 22% (6-30%)
and signs of congestive heart failure were clear in all patients [New York Heart
Association (NYHA) class III in eight patients and class IV in five patients].
Angina pectoris was present in five patients. Six patients had associated
significant mitral regurgitation. Coronary artery bypass grafting (mean 3.2
grafts) was used in 11 patients and mitral valve reconstruction was performed in
6 patients (4: replacement and 2: repair) combined with akinetic area exclusion
by the Dor technique. All patients were successfully weaned from cardiopulmonary
bypass without mechanical support and no perioperative death occurred. Three
patients died in hospital at 1-2 postoperative months due to pneumonia, stroke
and heart failure, respectively. Two patients died during the late period due to
stroke and sudden death. Among the eight survivors, six patients were in NYHA
class I-II and two patients in class III. Ejection fraction increased from 22% to
36%, end-diastolic and systolic volume indices decreased from 168 +/- 58 to 123
+/- 39 ml/m2 and from 131 +/- 60 to 81 +/- 33 ml/m2, respectively. Pulmonary
capillary wedge pressure decreased from 19 +/- 10 to 14 +/- 5 mmHg. The Dor
procedure is an effective surgical alternative for patients with end-stage
ischemic cardiomyopathy who are considered to be candidates for cardiac
transplantation.
PMID- 9557281
TI - [Randomized, double-blind, placebo-controlled study of supplemental vitamin E on
attenuation of the development of nitrate tolerance].
AB - The attenuation of intracellular production of cyclic guanosine monophosphate
(cGMP) has been known as a mechanism of nitrate tolerance. A recent in vitro
study have shown an increase in superoxide levels and a reduced activation of
guanylate cyclase in tolerant vessels. We investigated the preventive effect of
an antioxidant, vitamin E, on the development of nitrate tolerance. In this
double-blind, placebo-controlled study, 24 normal volunteers and 24 patients with
ischemic heart disease (IHD patients) were randomized to receive either vitamin E
(200 mg t. i. d.; vitamin E group) or placebo (placebo group). Vasodilator
response to nitroglycerin was assessed with forearm plethysmography by measuring
the change in the forearm blood flow before and 5 min after sublingual
administration of 0.3 mg nitroglycerin, and at the same time, blood samples were
taken from veins to measure the platelet cGMP level. Measurements of the forearm
blood flow and blood sampling were obtained serially at baseline (day 0), 3 days
after taking vitamin E or placebo alone (day 3), and 3 days after application of
a 10 mg/24 hr nitroglycerin tape concomitantly with oral vitamin E or placebo
(day 6). The response of forearm blood flow (%FBF) and cGMP (%cGMP) after
sublingual nitroglycerin on day 0(%FBF: normal volunteers 32 +/- 12% vs 31 +/-
11%, IHD patients 35 +/- 15% vs 34 +/- 15%; %cGMP: normal volunteers 38 +/- 10%
vs 35 +/- 11%, IHD patients 37 +/- 11% vs 38 +/- 12%; vitamin E group as placebo
group) and day 3(%FBF: normal volunteers 33 +/- 9% vs 32 +/- 12%, IHD patients 35
+/- 12% vs 33 +/- 13%, %cGMP: normal volunteers 38 +/- 10% vs 37 +/- 11%, IHD
patients 36 +/- 14% vs 37 +/- 10%, vitamin E group vs placebo group) were not
different between the two groups. On day 6 %FBF and %cGMP in the placebo group
were significantly lower compared with day 0, and there were significant
differences in them between the two groups (%FBF: normal volunteers 30 +/- 12% vs
17 +/- 9%, p < 0.01; IHD patients 28 +/- 14% vs 17 +/- 8%, p < 0.01; %cGMP:
normal volunteers 35 +/- 11% vs 8 +/- 5%, p < 0.01; IHD patients 38 +/- 10% vs 12
+/- 4%, p < 0.01, vitamin E group vs placebo group). In conclusion, the
combination therapy with vitamin E is potentially a useful method to prevent the
development of nitrate tolerance.
PMID- 9557282
TI - [Radioimmunoimaging of aortic dissection and acute bowel infarction with
radiolabeled [correction of radioiodinated] murine antismooth muscle myosin
antibody.
PMID- 9557283
TI - [Enhanced expression of hepatocyte growth factor/c-Met by myocardial ischemia and
reperfusion in a rat model].
PMID- 9557284
TI - [Upregulation of angiotensin-converting enzyme during the healing process after
injury at the site of percutaneous transluminal coronary angioplasty in humans].
PMID- 9557285
TI - [In vivo gene transfection with heat shock protein 70 enhances myocardial
tolerance to ischemia-reperfusion injury in rat].
PMID- 9557286
TI - [Cardiovascular imaging in-a-month. A 51-year-old man with acute abdomen].
PMID- 9557287
TI - [References cited in literature].
PMID- 9557288
TI - Epidemiological study and genetic analysis of GB virus C infection in general
population from an area endemic for hepatitis C.
AB - The aim of this work was to study the prevalence, potential risk factors,
clinical and laboratory features of GB virus C (GBV-C) infection in general
population from an area endemic for hepatitis C. A reverse transcriptase
polymerase chain reaction (RT-PCR) for detection of GBV-C RNA was used to examine
the prevalence of GBV-C RNA in both hepatitis C virus (HCV) endemic (R town) and
nonendemic areas (M town) in Yamagata prefecture, Japan. In R town, GBV-C RNA was
detected in 23 (2.9%) out of the 800 residents, whereas anti-HCV and HCV-RNA were
found in 226 (28.3%) and 163 (20.4%), respectively. The prevalence of GBV-C RNA
in R town (2.9%) was higher than that in M town (1.0%), although the difference
was not statistically significant. The individuals with anti-HCV had
significantly higher frequency of active GBV-C-infection than those without anti
HCV in both towns. No evidence indicating that GBV-C infection affected the
severity of hepatitis C was obtained. The multivariate analysis revealed that the
young anti-HCV positive individuals with a history of blood transfusion had
higher incidence of active GBV-C infection. The phylogenetic analysis showed that
the GBV-C isolates from both R and M towns were divided into two separate branch
groups designated HG and Asia GB groups.
PMID- 9557289
TI - Prevalence of hepatitis B, hepatitis C, and GB virus C/hepatitis G virus
infections in liver disease patients and inhabitants in Ho Chi Minh, Vietnam.
AB - The prevalence of hepatitis B virus (HBV), hepatitis C virus (HCV), and GB virus
C or hepatitis G virus (GBV-C/HGV) infections was determined in 289 patients with
liver disease in Ho Chi Minh City and 890 healthy inhabitants of its rural area,
Dalat City, Vietnam, respectively. Serum HCV RNA and GBV-C/HGV RNA were detected
by reverse transcription-polymerase chain reaction (RT-PCR). HBsAg, HCV
antibodies, and GBV-C/HGV RNA were detected in 139 (47%), 69 (23%), and ten (3%)
subjects, respectively, often accompanied by elevated serum levels of alanine
aminotransferase. HBsAg and HCV antibodies or HCV antibodies and GBV-C/HGV RNA
were detectable simultaneously in 8% and 2% of the patients, respectively. In the
inhabitants, HBsAg, HCV antibodies, and GBV-C/HGV RNA were found in 51 (5.7%),
nine (1.0%), and 11 (1.2%) subjects, respectively. Thus, the prevalence of HBsAg,
HCV antibodies, and GBV-C/HGV RNA was significantly higher in liver disease
patients than those in the general population. In the samples from 69 patients
and nine inhabitants who were seropositive for HCV antibodies, HCV RNA was
detectable in 42 (61%) and 4 (44%), respectively. In patients with liver disease,
ten belonged to HCV genotype 1a, ten to HCV 1b, three to HCV 2a, four to HCV 2b,
and two to HCV 3a by PCR with genotype-specific primers. Nine patients had mixed
genotypes, and the remaining four were not classified. Of the GBV-C/HGV RNA
positive individuals, two patients and two inhabitants were positive for HBsAg,
while none of the residents had HCV antibodies, although six HCV antibodies (60%)
and four HCV RNA (40%) were found in patients. When a phylogenetic tree of GBV
C/HGV was constructed based on the nucleotide sequences, the 21 isolates were
classified into at least two genotypes; four isolates belonged to G2, and 17 to
G3. The results indicate that in Ho Chi Minh HCV infection prevails with broad
distribution of genotypes together with HBV infection among patients with liver
disease. This study suggests that GBV-C/HGV infection occurs independently in the
two different districts in association with HCV infection.
PMID- 9557290
TI - Hepatitis B virus DNA is frequently found in liver biopsy samples from hepatitis
C virus-infected chronic hepatitis patients.
AB - Human hepatitis B virus (HBV) and hepatitis C virus (HCV) are two major etiologic
agents of chronic hepatitis, which is closely related to the development of
hepatocellular carcinoma (HCC). A possible involvement of HBV co-infection was
investigated in ongoing HCV-related liver diseases in HCV-infected patients. A
prevalence of anti-HBc in anti-HCV-positive/HBsAg-negative chronic hepatitis
patients and a low copy number of HBV DNA were found in most of the liver biopsy
samples of anti-HCV-positive/HBsAg-negative patients. The present data suggest
that HBV co-infects frequently with HCV and may play an important role in the
development of HCC in the anti-HCV-positive/HBsAg-negative patients with chronic
hepatitis.
PMID- 9557291
TI - Genetic complexity of the hypervariable region 1 (HVR1) of hepatitis C virus
(HCV): influence on the characteristics of the infection and responses to
interferon alfa therapy in patients with chronic hepatitis C.
AB - HCV exists within its host as pools of related genetic variants referred to as
quasispecies. The hypervariable region 1 (HVR1) of the E2 envelope gene is
subjected to strong selective pressure from neutralizing antibodies. The genetic
complexity of this region is defined as the total number of genetic variants
within the quasispecies population. The genetic complexity of the HVR1 region was
examined in patients with chronic hepatitis C and its relationship with the
epidemiology of HCV infection, and its influence on liver disease and the
response to interferon treatment were determined in 114 patients with chronic
hepatitis C. The genetic complexity of the HVR1 major variants was measured
before treatment by using a polymerase chain reaction (PCR)-single-strand
conformation polymorphism (SSCP) technique, and was compared with
epidemiological, clinical, virological and histological features. The patients
were treated with 3 megaunits of interferon (IFN) alfa for 3 to 6 months and the
response to treatment was assessed at 3, 6 and 12 months. The HVR1 could be
studied in 101 of the 114 patients (89%). Genetic complexity was significantly
higher in patients infected through blood transfusion than intravenous drug use
(mean complexity index: 5.7 +/- 2.3 vs. 4.7 +/- 1.5, respectively; P = 0.04).
This relationship was independent of age and the estimated time since infection.
No significant relationship was found with other parameters of infection or liver
disease. In univariate analysis, the genetic complexity of HVR1 major variants
did not affect the rates of ALT normalization at months 3 and 6 of IFN treatment.
HVR1 genetic complexity was lower in patients with a sustained virological
response than in non-responders (4.0 +/- 1.7 vs. 5.4 +/- 2.0, respectively; P =
0.07). In multivariate analysis of pretreatment parameters associated with a
sustained virological response to treatment, three parameters appeared to be
independent predictors of such a response: a low viral load (P < 0.04), a low
anti-HCV core IgM titer (P = 0.03) and a low genetic complexity of HVR1 major
variants (P < 0.04). In conclusion, the HVR1 of HCV has a quasispecies
distribution in infected individuals. Its genetic complexity is significantly
higher in transfusion recipients than in intravenous drug users, suggesting that
the size of the initial inoculum affects the later emergence and development of
viral quasispecies. The genetic complexity of HVR1, together with viral load and
the anti-HCV IgM titer, are independent predictors of a sustained virological
response to IFN alfa in patients with chronic hepatitis.
PMID- 9557292
TI - Predominance of HCV type 2a in saliva from intravenous drug users.
AB - Paired serum and saliva samples were collected simultaneously from 50 intravenous
drug users with serologically proven hepatitis C virus infection. The oral health
of the volunteers was also assessed. Hepatitis C virus RNA was detected by nested
PCR, employing primers from the 5' noncoding region. Positive PCR products were
sequenced using the Sequenase PCR Product Sequencing Kit (Amersham Life
Sciences). HCV RNA was detected in 33 (66%) of the 50 serum samples. HCV RNA was
detected in 19 (57.6%) of the corresponding 33 saliva samples. There was no
correlation between oral health status or HIV seropositivity and the detection of
HCV in saliva. However, subjects with HCV in their saliva were significantly more
likely to complain of xerostomia (P < 0.05). Isolate genotypes were identified in
paired serum and saliva of 15 intravenous drug users. HCV genotypes 1, 2, 3 and 6
were detected in both specimens. In seven cases, a differing HCV genotype was
found in serum compared to the paired saliva specimen. The distributions of
genotypes in serum and saliva were very different, with genotype 2a more common
in saliva than serum (P < 0.005). These data suggest that in some cases the
source of salivary HCV may not be serum transudation along the periodontal
membrane or across damaged mucosa, and that an alternative local source, possibly
the salivary glands themselves, should be considered.
PMID- 9557293
TI - Serological evidence of SV40 infections in HIV-infected and HIV-negative adults.
AB - SV40 is a simian polyomavirus that was a contaminant of some viral vaccines
administered to people between 1955 and 1962. SV40 DNA has recently been found
associated with several types of human tumors, suggesting that the virus is
present in humans. We examined sera from patients infected with human
immunodeficiency virus type 1 (HIV-1) as well as from HIV-1-negative controls to
determine the prevalence of SV40 neutralizing antibodies using a specific plaque
reduction assay. We found that 16.1% of HIV-infected patients (n = 236) were
seropositive for SV40, as compared to 12.0% of HIV-negative control volunteers (n
= 108) and 11.1% of HIV-negative patients (n = 72). These differences were not
statistically significant. As individuals born between 1941 and 1962 had the
highest chance of having received SV40-contaminated poliovaccines, we analyzed
SV40 seropositivity rates based on year of birth. SV40 antibody rates for HIV
infected patients born before 1941, between 1941 and 1962, and after 1962 were
17.1%, 16.3%, and 11.8%, respectively. For the HIV-negative subjects, the rates
were 12.5%, 12.0%, and 9.7%, respectively. There was no correlation between SV40
seropositivity and either the stage of disease in HIV-infected patients or the
race/ethnicity. Also, there was no correlation between the presence of SV40
neutralizing antibody and the titer of neutralizing antibody to human
polyomavirus BKV. The SV40 seropositivity rates in the patients born between 1941
and 1962 may be explained by the likelihood of those individuals having received
SV40-contaminated vaccines, but the detection of SV40 neutralizing antibody in
individuals born after 1962 (with no risk of having received contaminated
vaccines) is significant. Although cross-reactive antibodies might theoretically
contribute to the observed reactivities, these results suggest that SV40
neutralizing antibodies are present in certain individuals and raise the
possibility that SV40 continues to infect humans long after vaccines were freed
from contamination.
PMID- 9557294
TI - Evaluation of an expanded two-ELISA approach for confirmation of reactive serum
samples in an HIV-screening programme for pregnant women.
AB - Serum specimens were collected from 31,232 pregnant women in Amsterdam between
1988 and 1995 in a screening programme for human deficiency virus (HIV)
infection. The sera of 56 (0.179%) women tested were confirmed as positive for
HIV. A total of 67 sera reacted positive or borderline by the screening enzyme
linked immunosorbent assay (ELISA) and indeterminate or negative by HIV-1 Western
blot; 42 of these specimens were available for evaluation of the strategy for
diagnosis of HIV infection. A two-ELISA approach with the second ELISA based on a
principle different from that of the screening ELISA, expanded with the use of a
membrane immunoassay based on two synthetic peptides specific for HIV-1 gp41 and
HIV-2 gp36 envelope proteins, was compared with the Western blot analysis.
Indeterminate results were resolved with a nucleic acid sequence-based
amplification assay (NASBA) for HIV-1 RNA and a strip immunoassay (SIA) for the
simultaneous detection of antibodies to HIV-1 or HIV-2 and HIV-1 p24 antigen.
Eleven samples were weakly or borderline positive by the screening test and gave
indeterminate results by Western blot. The expanded two-ELISA approach designated
these sera as HIV-negative, and confirmed negative by NASBA and the SIA. Twenty
one samples showed borderline or positive results on the screening test and
negative results by Western blot. Again, these sera were characterised as HIV
negative by the expanded two-ELISA procedure, and this characterisation was
confirmed by both NASBA and the SIA. Five HIV-2-positive serum samples were
recognised by the expanded two-ELISA approach and the SIA; these sera were
negative by NASBA. Finally, another five serum samples were weakly or borderline
positive by both ELISAs and positive by the membrane immunoassay; of these five,
two sera generated positive patterns and the other three indeterminate patterns
on Western blots, and four were positive by the NASBA assay. Follow-up serum
specimens from these five women were negative and the reactivity of the initial
specimens was thus likely to have been the result of cross-contamination. Our
results demonstrate the effectiveness of a simple confirmation approach of two
HIV ELISAs expanded with a membrane spot assay to discriminate between infection
with HIV-1 or HIV-2. The data also indicate the importance of retesting
individuals with indeterminate or positive confirmational results to exclude the
possibility of contamination as the cause of reactivity of the original specimen.
PMID- 9557295
TI - Molecular epidemiology of adenovirus type 7 in Israel: identification of two new
genome types, Ad7k and Ad7d2.
AB - The molecular epidemiology of Adenovirus type 7 in Israel was investigated. Fifty
seven adenovirus isolates identified as serotypes 7 or 7a which were recovered
from patients in Israel between 1968 and 1995 were analyzed by restriction
enzymes digestion using BamHI for primary discrimination and identification of
genome types and by six additional enzymes: BstEII, HpaI, BglI, BglII, BclI, and
XbaI for confirmation and determination of genomic subtypes. Four digestion
patterns were identified with BamHI; one of them was new. Using BstEII, two
patterns were obtained, one of them new. Digestion with the other five enzymes
yielded known patterns. The analysis revealed four different genomic types and
subtypes, which circulated in Israel in different years: subtype 7a1; type 7b, a
type with a new BamHI pattern which was designated type 7K, and a subtype with a
new BstEII pattern which differed from type 7d by one restriction site and was
designated type 7d2. Twenty-two isolates from 1968 through 1975 and from 1984
were Ad7a1. Three isolates from 1973-1974 were Ad7b. Five isolates from 1968
through 1973 were Ad7K and 27 isolates from 1992 through 1995 were Ad7d2. This
demonstrates the temporal change in the circulating genome types with up to three
genome types cocirculating in 1 year (1973). The two new types, Ad7k and Ad7d2
could have evolved in Israel or could have been imported by travellers and
immigrants from neighboring or distant countries.
PMID- 9557296
TI - Consistent polymerase chain reaction-single-strand conformation polymorphism
pattern of human herpesvirus-8 in the course of classical Kaposi's sarcoma
assumes its clonal origin.
AB - There is emerging evidence that Kaposi's sarcoma-associated herpesvirus (KSHV or
HHV-8) has a central role in the pathogenesis of Kaposi's sarcoma (KS). The
occurrence of HHV-8 in classical KS biopsies is reported irrespective of its
clinical stage (patch, plaque, nodular). HHV-8 was detected in 25 of 28 formalin
fixed paraffin-embedded classical KS samples by nested polymerase chain reaction.
In addition, in six patients multiple tumors were available (n = 21). Single
strand conformation polymorphism (SSCP) analysis of the amplicons showed uniform
SSCP pattern of samples belonging to the same patient regardless of whether the
KS was multiplex or developed again years after the first excision. Most of the
SSCP patterns were confirmed by further sequence analysis. The presence of the
same sequence variant of HHV-8 in various samples of the same patient supports
the clonal origin of classical Kaposi's sarcoma.
PMID- 9557297
TI - Homotypic and heterotypic IgG and IgM antibody responses in adults infected with
small round structured viruses.
AB - Antibody responses to recombinant Norwalk (rNV) and Mexico (rMXV) viral capsid
proteins were studied in 39 adults involved in outbreaks of gastroenteritis
associated with genogroup 2 small round structured viruses (SRSVs). Nineteen
individuals were involved in outbreaks associated with MXV-like strains and 20 in
outbreaks associated with four other genogroup 2 SRSVs. IgG antibodies were
measured in acute and convalescent sera using indirect enzyme-linked
immunosorbent assay (ELISA), and IgM was measured by indirect and capture ELISAs.
Nineteen (49%) patients demonstrated a significant rise in IgG to rMXV with four
(10%) patients also showing anamnestic responses to rNV. Fourteen patients were
positive in the rMXV IgM-capture ELISA, representing 74% of patients
demonstrating IgG rises. IgG and IgM responses to rMXV were observed in both
groups, although higher levels of responses were seen in adults infected with MXV
like strains than those infected with non-MXV genogroup 2 viruses. No significant
IgM responses were observed to rNV. These results indicate that, following SRSV
infection, adults show a rise in antibody which is broadly reactive to viruses
within but not between genogroups, although greater homotypic than heterotypic
responses are produced. These findings have implications for interpretation of
seroepidemiological studies and serodiagnosis of SRSV infections using
recombinant capsids.
PMID- 9557298
TI - Transport of viruses through fetal membranes: an in vitro model of perinatal
transmission.
AB - A model system for perinatal transmission of viral infections was developed and
transport of infectious virus particles through fetal membranes was investigated.
Viruses of different families known to cause serious intrauterine infections were
selected, including relevant and model viruses: the DNA-viruses HSV-1 and -2 as
well as the animal herpes viruses BHV-1 and SHV-1, the RNA-virus BVDV as a model
for hepatitis C virus, HIV-1 and -2, and PPV as a model for parvovirus B19.
Migration of infectious virus from the maternal to the fetal side of the membrane
could be detected as early as 20 min after the start of incubation. A peak of
virus migration was observed after 1-2 hr. 0.02-1% of HSV-1 and 0.03-0.2% of HSV
2 were transported from the maternal side of the membrane to the fetal side. Only
0.01% of PPV migrated to the fetal side, whereas no transport of BVDV was
observed. HIV-1 (1.4%) and HIV-2 (0.8%) seemed to be transported at higher rates.
The concept of an active transport of infectious virus is compatible with the
kinetics of penetration of the fetal membrane. The question of whether different
receptors for the individual viruses on the cellular surface account for
differences in virus transport will require further investigation. The fetal
membrane acts as a protective barrier for the fetus, reducing greatly infectious
titers or even preventing completely penetration of virus.
PMID- 9557299
TI - Detection of respiratory syncytial virus RNA in blood of neonates by polymerase
chain reaction.
AB - During the winter season of 1994/1995, nasopharyngeal aspirates and blood samples
of neonates who were admitted to the Neonatal Intensive Care Unit (NICU) (group
1) and infants with respiratory tract disease (group 2) were examined
prospectively for the presence of respiratory syncytial virus (RSV). Examination
of nasal washes were done by antigen detection and blood samples were tested by
nested reverse transcription and polymerase chain reaction (RT-PCR). The results
of the 41 neonates studied were as follows: 14/41 were positive for RSV antigen
in nasal washes and for RSV-RNA in blood, 5/41 were only RSV antigen positive,
13/41 neonates had negative nasal washes; 6 had positive RT-PCR results in blood.
In 9/41 cases only blood samples were available. Five of these were positive by
RT-PCR testing. Group 2 included 20 infants hospitalized with respiratory tract
disease, e.g., pneumonia, bronchiolitis, or Upper Respiratory Tract Infection
(URTI). Eleven out of twenty were positive for RSV antigen in nasal washes and
6/20 were also positive for RSV-RNA in blood. The conclusion is that viremia may
be a frequent occurrence in neonates and young children.
PMID- 9557300
TI - [The study of ototoxicity in Gallus domesticus by recording distortion products].
AB - Distortion products (DP) were recorded and a morphological cochlear study was
made of a sample of 60 ears from chickens (Gallus domesticus. Leghorn breed) and
the ages of 15, 23, 29 and 60 days, after intoxication by intramuscular
gentamicin injection (40 mg per kg weight and day for 8 days). Spontaneous or
transitory otoacoustic emissions were not obtained in any case. DP recordings
showed a 2F1-F2 response in every frequency band ranging from 0.7 to 6 KHz. The
DP incidence shifted with the age of the chickens and differed significantly (p <
0.001) in the groups of 29 and 60 day-old chickens (m = 100%) and in the 29-day
old (m = 64%) and 60-day-old (m = 62%) intoxicated chickens. We found no
significant differences in DP amplitude in subpopulations. In the intoxicated
groups, the proximal segment of the ototic membrane disappeared in the macula
lagenae and a loss of contact with the hair cells appeared. Degenerative vacuolar
phenomena were observed in the support cells and cellular loss in the spiral
ganglion.
PMID- 9557301
TI - [Changes in the middle ear mucosa of the Wistar rat after experimental resection
and obstruction of the eustachian tube].
AB - Eustachian tube (ET) disfunction, alone or combined with other factors, is the
main source of middle ear pathogenesis and can lead to other physiopathological
events that originate disease (serous otitis media, adhesive otitis,
cholesteatoma). In seven Wistar rats (study group), experimental mechanical
obstruction of the left Eustachian tube was performed. Using an anterior cervical
incision, the osteocartilaginous junction of the ET was severed and obliterated
with a bit of muscle in order to prevent rechanneling. After a period of six
months, the middle ear mucosa was removed for histological study. Comparisons
were made of the experimental ear and the opposite ear, as well as the ears of
three rats in the control group. We compared our findings with those of other
authors and reviewed experimental animal models of serous otitis media and
cholesteatoma that have been used to study the influence of ET in middle ear
disease.
PMID- 9557302
TI - [Cochlear implants in post-lingual persons: results during the first five years
of the clinical course].
AB - Abundant literature is available on the results of cochlear implants in
postlingual persons. Nevertheless, there are few long-term studies with a follow
up of more than 1 year. We present the outcomes of 37 postlingual patients with a
5-year follow-up period. We examined the modifications that occurred with changes
in coding strategy (MPEAK-SPEAK). After activation, the coding strategy was SPEAK
in 10 patients. MPEAK in 20: 7 other SPEAK had changed from MPEAK. Significant
improvement (p < 0.01) was observed in all the tests in the first 6 months.
Subsequent assessments revealed a constant improvement in all tests. The results
were statistically significant (p < 0.05) for vowels, consonants and bisyllables.
Performance with the SPEAK strategy was better than with MPEAK. These results
were statistically significant for consonants (p < 0.05), monosyllables (p <
0.05) and bisyllables (p < 0.01). We concluded that the results of postlingual
patients after cochlear implantation showed clear benefits of these devices in
profound bilateral deafness, better results with the SPEAK coding strategy than
with MPEAK and constant improvement in results, even after the first year of
surgery.
PMID- 9557303
TI - [The study of otoacoustic emissions in diabetes mellitus].
AB - Cochlear activity was evaluated by means of otoacoustic emission in patients with
normal hearing and insulin-dependent diabetes mellitus. Twenty diabetic subjects
were studied by recording click evoked otoacoustic emissions (TEOAE) and
distortion products otoacoustic emissions (DPOAE) 2fl-f2 and comparing the
results with those obtained in a control group of non-diabetic with normal
hearing. The results obtained in the diabetic group showed a statistically
significant decrease in mean amplitude, in the amplitude of every click evoked
otoacoustic emissions and in the mean amplitudes of various distortion products
compared with the control group. These findings suggest the presence of cochlear
disorders in diabetic patients, probably produced by impaired functional
properties of the outer hair cells.
PMID- 9557304
TI - [Endonasal dacryocystorhinostomy. A comparative study of microscopic and
endoscopic techniques].
AB - A comparative study was made of endonasal dacryorhinostomy using either a 0
degree or 30 degrees rigid endoscope or a Zeiss operating microscope in 25
patients with chronic epiphora and complete stenosis of the nasolacrimal duct
confirmed by dacryocystography. The success rate in both groups was similar
(80%). Computed tomography is useful in post-traumatic cases.
PMID- 9557305
TI - [Morphological comparative imaging study of the pharynx in patients with
obstructive sleep apnea syndrome (OSAP), healthy snorers and controls].
AB - A morphological study was made of the pharynx of 106 subjects, including obese
and non-obese patients with obstructive sleep apnea syndrome (OSAS), obese and
non-obese healthy snorers and controls. A CT scan was made of each subject and
the luminal area was measured on all sections. The influence of obesity on airway
size was determined. Airway lumina generally were narrower in patients with OSAS,
of intermediate size in healthy snorers, and widest in controls. Luminal
narrowing was the result of increased pharyngeal wall thickness and directly
related to the degree of obesity. This pattern was evident throughout the
pharynx, except for the hypopharynx, where the airway size was similar in all the
patients studied.
PMID- 9557306
TI - [Bacteriology in infectious and obstructive adenoid-tonsillar pathology].
AB - Infectious and obstructive adenotonsillar processes are common in the pediatric
population. Bacteriological and serological studies were made of acute
tonsillitis, recurrent acute tonsillitis with tonsillar hypertrophy, and
tonsillar hypertrophy. Positive cultures were more frequent in tonsils than in
adenoids. Pathogenic microorganisms were isolated more often in infectious than
in obstructive processes. Anti-streptococcal antibody titers were raised in
infectious processes, but remained within normal limits in obstructive processes.
Serum total IgE levels were similar in both processes. These findings show that
tonsillar hypertrophy is not related directly with microorganisms or atopic
pathology.
PMID- 9557307
TI - [Surgery of the laryngeal framework: type I thyroplasty].
AB - Eight type I thyroplasties were performed. All the patients had a breathy voice
related with unilateral vocal cord paralysis. Several causes were involved. All 8
patients achieved good glottic closure and the free edges of the vocal cords mi
closed uniformly. Acoustic parameters were studied using Dr. Speech version 2.0
for Windows. The SPSS program was used for statistical analysis. The study showed
significant improvement in maximum phonation time, shimmer, and normalized noise
energy. Modifications in the surgical technique are discussed.
PMID- 9557308
TI - [Lateral cervical branchial cysts: a retrospective study].
AB - The cause of lateral cervical branchial cysts is debated. Some authors claim that
they are congenital, whereas others believe that they are acquired, being their
likely origin cystic degeneration of the cervical lymph nodes. Their protocol of
study and differential diagnosis with respect to malignant neck masses are of
special interest. A retrospective clinical study was made of 13 cervical
branchial cysts seen by one of the authors over a decade-long period. Based on
the results, their probable origin is discussed and a study protocol is proposed.
Although it has been discussed by some authors, we conclude that the origin of
branchial cysts cannot be determined through this type of clinical study.
Computed tomography and fine-needle aspiration currently are essential diagnostic
methods in the study protocol of these lesions.
PMID- 9557309
TI - [Incomplete ciliary axonema: anther cause of ciliary dysmotility syndrome?].
AB - Immotile cilia syndrome is associated with different ciliary defects, although
the clinical presentation is similar in every case. A study was made of a 36-year
old woman with recurrent respiratory infections since birth, chronic sinusitis
and chronic bronchitis with bronchiectasias. Her medical history included a
tubaric pregnancy and two miscarriages. Nasal mucociliary transport was
investigated on two occasions at a 1-year interval using an isotopic technique.
Ciliary ultrastructure was studied by electron microscopy after obtaining two
biopsies from the inferior and middle turbinates separated by a 1-year interval.
The sweat test and blood immunoglobulins were normal. The absence of mucociliary
transport was verified on both occasions. An abnormality was observed in 30% of
the cilia in the form of semicircular ciliary cross-sections, with only 7 pairs
of peripheral microtubules. The central pair was normal. We termed this anomaly
"incomplete ciliary axonema" and believe that it could be another cause of
immotile cilia syndrome.
PMID- 9557311
TI - [Mastoid osteosarcoma].
AB - A case of osteogenic sarcoma of the mastoid region of the temporal bone in a 28
year-old male is reported. The rarity of the site is emphasized and the
fundamental clinical and therapeutic features are discussed. The literature is
reviewed.
PMID- 9557310
TI - [Cholesteatoma of the external ear canal. A case report].
AB - Cholesteatoma of the external ear canal is rare in otological practice. The case
of a 62-year-old woman with local extension but scant symptoms or signs is
reported. The literature is reviewed and the cause and treatment are discussed.
PMID- 9557312
TI - [Dysphagia in Forestier's disease (vertebral ankylosing hyperostosis)].
AB - Forestier's disease is characterized by the formation of vertebral bridges which
joint the ventral aspect of the vertebral bodies by ossification of the anterior
vertebral longitudinal ligament. A 58-year-old man with idiopathic ankylotic
hyperostosis had pronounced osteophytosis of the neck that produced the unusual
symptom of dysphagia. The literature is reviewed and the pathogenic criteria,
diagnosis, and therapy are discussed.
PMID- 9557313
TI - [Laryngeal paraganglioma].
AB - A case of laryngeal paraganglioma in a 65-year-old male was treated by
supraglotic laryngectomy. This controversial tumor is analyzed and guidelines are
given for its clinical and histological (immunohistochemical) diagnosis and
treatment.
PMID- 9557314
TI - [Small cell carcinoma of the parotid gland. A case report].
AB - A case of small-cell carcinoma (SCC) of the parotid gland in an 82-year-old woman
is reported. SCC arising in major salivary glands are extremely rare. By
immunohistochemical study, this case was classified as a small-cell carcinoma
with neuroendocrine differentiation. These neoplasms seem to have a far better
prognosis than those arising from the bronchial tree. Treatment is mainly local
and regional surgery with complementary radiotherapy.
PMID- 9557316
TI - Ultrasonographic study of feline lower urinary tract diseases: 32 cases.
AB - The objective of the study was to describe the ultrasonographic findings of
urinary bladder urolithiasis and to determine the diagnostic value of the
technique in feline lower urinary tract diseases (LUTD). Physical examination of
the urinary system and routine clinicopathological analysis of the blood and
urine were performed on 32 cats presented with clinical symptoms of LUTD.
Cystosonography was done on all of the cats, while plain radiography was
performed on 8 and double contrast cystography on 2 cats. Sonography of the
bladder provided the following diagnoses: urolithiasis and chronic cystitis: 24
cases, chronic cystitis without urolithiasis: 4 cases, bladder neoplasm: 1 case,
negative sonographic finding: 3 cases. Bladder calculi and/or plugs were
diagnosed easily, up to a size of 2 mm, according to acoustic shadowing and/or
reverberation and gravitation. When the bladder was empty, it was filled up with
physiologic saline solution to visualise its contents more easily. Sonography
proved to be a useful technique for diagnosing urinary bladder calculi and/or
plugs even when they were radiolucent and for distinguishing among the different
causes of LUTD. Although ultrasonography is a valuable diagnostic tool,
radiography is still necessary to explore lower urinary tract diseases,
especially when cystosonography provides negative results or urethral obstruction
is suspected.
PMID- 9557315
TI - [Post-laryngectomy tracheomalacia. The use of self-expandable metal prostheses].
AB - Tracheomalacia is an uncommon disorder in laryngectomized patients, but it is an
important therapeutic problem. Self-expandable metal prostheses can be used in
its treatment. We report the successful implantation of two tracheal prostheses
in a laryngectomized patient.
PMID- 9557317
TI - Ultrasonographic findings of renal dysplasia in cocker spaniels: eight cases.
AB - A retrospective study of eight young Cocker Spaniels aged 9-24 months was
performed to describe the ultrasonographic findings of histologically confirmed
renal dysplasia. Ultrasonography revealed kidneys of significantly (p < 0.001)
reduced volume in all dogs. During qualitative evaluation, two different types of
sonographic alterations could be seen. In one type of the ultrasound alterations,
corticomedullary demarcation was distinct and the renal cortex was remarkably
thin, which was best seen in the dorsal (frontal) imaging plane. In the other
type of the ultrasound appearance, overall increased echogenicity with poor
corticomedullary demarcation was noticed, and the kidneys could hardly be
separated from their surroundings. These features were best recognised in the
sagittal (coronal) imaging plane. In one dog with secondary hypercalcaemia, a
hyperechoic corticomedullary area was also seen. Post-mortem histological
diagnosis revealed renal dysplasia and secondary fibrosis. Based on ultrasound
findings alone, renal dysplasia (renal familial disease) can be suspected when
small kidneys with thin echogenic cortex are present in young dogs. An ultrasound
image, similar to that of fibrotic kidneys (increased overall echogenicity and
reduced corticomedullary definition) cannot be differentiated from chronic
inflammatory disease and from end-stage kidneys. Therefore, ultrasound-guided
biopsy or post-mortem histology is necessary for the definitive diagnosis of
renal dysplasia. This is the first study reporting on the ultrasound appearance
of renal dysplasia in Cocker Spaniel dogs.
PMID- 9557318
TI - Diagnostic value of certain mastitis markers in following up the clinical and
bacteriological changes in pharmacotherapeutic studies.
AB - Trends of certain mastitis markers were studied in udder quarters (n = 201)
showing clinical symptoms of acute mastitis. Besides the clinical examination,
before the first treatment (baseline sample), and about 3 weeks later, 17 to 24
days following the last treatment (control sample) milk samples were collected
for bacteriological identification of the mastitis pathogens and for the
determination of certain inflammatory markers: somatic cell count (SCC), N-acetyl
beta-D-glucosaminidase (NAGase) and alpha 1-antitrypsin (ATR) activities, as well
as bovine serum albumin (BSA) and chloride (Cl-) concentrations. Based upon the
clinical and bacteriological status as well as the SCC recorded at the control
investigations, 6 groups were established (recovered, latently infected,
subclinical mastitis: bacteriologically positive and negative, as well as
clinical mastitis: bacteriologically positive and negative). As compared to the
baseline samples, all parameters decreased in the case of recovered udder
quarters, as well as in those with abated latent infection or subclinical
mastitis at the time of control examination. Comparing the control samples of the
different categories, characteristic differences were found in NAGase activity,
indicating the grade of cytodamaging effect of mastitis. Of the other markers,
ATR and Cl- proved to be more adequate for the differentiation than BSA. It can
be concluded that, in addition to SCC, first of all NAGase can be recommended for
use as an inflammatory parameter in pharmacodynamic studies. Besides these two
parameters, ATR and Cl- can also be chosen as a possible third marker.
PMID- 9557319
TI - Comparison of the protein patterns of Erysipelothrix rhusiopathiae strains by SDS
PAGE and autoradiography.
AB - The proteins of 12 Erysipelothrix rhusiopathiae strains were radiolabelled with L
[35S] methionine, and the protein fractions were detected by sodium dodecyl
sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and autoradiography. The
strains were found to differ from each other in their protein patterns; thus, it
was concluded that the method applied could provide useful data for the
identification of strains. The described procedure was used for determining the
percentage contents of protein fractions of identical molecular mass within the
strains compared. The results show that there is no significant correlation
between the type of the strains and the percentage of identical molecular weight
fractions.
PMID- 9557320
TI - Extrapiscine development of Myxobolus drjagini Akhmerov, 1954 (Myxosporea:
Myxobolidae) in oligochaete alternative hosts.
AB - The extrapiscine development of Myxobolus drjagini, a myxosporean parasite of the
head, operculum and buccal cavity of the silver carp (Hypophthalmichthys
molitrix), was studied in experimentally infected oligochaetes, Tubifex tubifex.
After infection of uninfected tubificids with mature spores of M. drajagini,
development of actinosporean stages was first observed by light microscopy 27
days after infection. Triactinomyxon stages of M. drjagini emerged from the worms
after 91 days of intraoligochaete development. In histological sections, early
pansporocysts were found in the gut epithelium of the experimental oligochaetes
42 days after infection. Mature pansporocysts, each containing 8 triactinomyxons,
appeared 79 days after infection. After rupture of the epithelial cell and the
pansporocyst, free actinosporean stages were found in the gut lumen of the
oligochaete. Actinosporean stages released from oligochaetes appeared in the
water 91 days after infection. They were floating in the water and showed a
typical triactinomyxon form. Each triactinomyxon had three pyriform polar
capsules, a sporoplasm with 14 secondary cells inside the spore body, a
moderately long style and slightly bent, trifurcated, conically ending tails. The
total length of the triactinomyxon measured approximately 198 microns. The
prevalence of infection in 51 oligochaetes proved to be 9.8%. No infection was
found in the control oligochaetes.
PMID- 9557321
TI - Attempts to analyse Anguillicola crassus infection and the humoral host response
in eels (Anguilla anguilla) of Lake Balaton, Hungary.
AB - Since the introduction of Anguillicola crassus into Europe, anguillicolosis has
been a considerable problem in several countries. From 1991, periodical eel
mortality occurred in Lake Balaton, Hungary. However, eels with a worm burden of
20 to 50 parasites did not show severe swimbladder lesions, which observation
cast doubts on the primary aetiological role of the parasite in the eel kill. In
order to study the pathology of the infection, from the spring of 1996 until
October of the same year, 51 eels were collected from two regions of Lake Balaton
and examined for swimbladder changes. To detect humoral antibodies, an enzyme
linked immunosorbent assay (ELISA) was performed, using cuticular-oesophageal
worm antigen. The results of the test show the applicability of the method.
However, no direct correlation was found between antibody levels or the intensity
of infection and the swimbladder lesions. The low level of specific antibodies
and the increasing severity of swimbladder changes in the autumn suggest that
parasite-induced immunity is insufficient to prevent reinfection.
PMID- 9557322
TI - Effects of vitamin E and selenium on some rumen parameters in lambs.
AB - The effects of supplemented selenium and vitamin E on a number of rumen
parameters such as the population of rumen protozoa, pH, concentration of
volatile fatty acids and ammonia nitrogen in the rumen content were studied.
Eight lambs were randomly allocated into two groups: a control group and an
experimental group receiving vitamin E (DL-alpha-tocopheryl acetate, 250 mg/kg of
feed) and selenium (sodium selenite, 0.3 mg/kg of feed) supplementation. Samples
of rumen content were taken from all lambs three times daily once a week (before
feeding as well as 3 and 6 h after feeding) over a period of 10 consecutive
weeks. In addition, the lambs were weighed at the end of experiment. The total
counts and percentage proportions of rumen protozoa, the pH value, and the levels
of ammonia nitrogen and volatile fatty acids were determined in the samples of
rumen content. The levels of acetic acid, propionic acid, butyric acid and total
volatile fatty acids, the total counts of protozoa, and the percentage proportion
of Diplodinium were found to be significantly higher in the supplemented than in
the control group (P < 0.05, P < 0.01), whereas the pH values and the percentage
proportion of Dasytricha ruminantium were significantly lower in the supplemented
group than in the control (P < 0.05). However, there was no statistically
significant difference between the two groups in ammonia nitrogen levels. The
body mass gain of lambs in the supplemented group was significantly higher than
that of the control animals (P < 0.01). Combined selenium and vitamin E
supplementation of the lambs' ration caused an increase in the levels of volatile
fatty acids, total counts of protozoa, and body mass gain while decreasing the pH
value of the rumen content.
PMID- 9557323
TI - Zoonoses in the meat industry: a review.
AB - Zoonoses are diseases, the infections of which can be transmitted between man and
animals. Only a few are of importance with respect to poultry meat and meat from
cattle, sheep, horses and goats. Advances in the control of diseases such as
tuberculosis, brucellosis and trichinosis in animals have reduced the hazards
posed to workers in the meat industry and to consumers of meat. However,
inspection of animals ante- and post-mortem cannot detect all infectious agents
present. This applies particularly to bacteria such as Campylobacter, Salmonella,
verotoxigenic and other pathogenic Escherichia coli and Yersinia. Protection of
meat workers from infection depends upon taking normal hygienic precautions,
which also protect the meat from contamination from the workers. Consumers are
exposed to a smaller range of zoonoses than meat workers because they encounter
only meat that has passed inspection. In addition, heavily contaminated parts of
the animal, such as the hide, feathers and viscera have been removed. Further
advances in making meat safer are likely to result from the introduction of
Integrated Quality Assurance systems. These involve identifying, monitoring and
keeping records of the disease status and treatment of each animal (or poultry
flock) so that its history is known when it reaches the abattoir. They should
also include programmes aimed at minimising colonisation by zoonotic bacteria
such as camplyobacters, salmonellas and verotoxigenic Escherichia coli.
PMID- 9557324
TI - The subchondral bone plate.
AB - Pauwels (1965) and subsequent workers in the same field have shown that the
distribution of the subchondral density within a joint surface can serve as a
parametric measurement which reflects the main stress acting on a joint. Our own
investigations on anatomical specimens have demonstrated that this subchondral
mineralization does indeed show regular distribution patterns from which
conclusions about the mechanical situation within an individual joint may be
drawn. Since radiographical densitometry and histological methods are only
available for determining the adaptive reaction of the bone to the particular
mechanical situation in a joint after death, the information obtained applies
only to an end situation and tells us nothing about the development of the
changes with time. Furthermore, investigations carried out on human specimens by
radiographical densitometry mostly apply to samples of a particular age, since
such specimens can be acquired only from departments of pathology, forensic
medicine or anatomy. The functional reactions of the bone tissue to repeated long
term changes in the loading--lengthy immobilization and subsequent
remobilization, for instance, or heavy loading over a considerable period of time
-cannot be followed by any ordinary method in experimental animals, since the
death of the animal is a prerequisite for the precise quantitative examination of
the bone tissue. This applies also to attempts to follow the process by means of
animal experiments. CT OAM has been developed as a method which, based on CT, can
provide a surface representation of the 3-D density distribution in the joints of
living subjects. Comparative studies were carried out to establish and confirm
the validity of the procedure. These have shown (1) that the results obtained
from anatomical specimens are identical with those obtained in the living; (2)
that secondary CT sections are suitable for evaluation and that the spectrum of
joint surfaces examined can be extended to include the whole joint (if this were
not so, effects caused by the apparatus--particularly the partial-volume effect-
would render the procedure impossible); and finally (3) that the distribution of
the Hounsfield density within the subchondral bone represents the distribution of
the mineralization. The mineralization patterns found by us in different joints
of normal subjects have shown that these patterns can be brought into line with
current models of joint mechanics. The radiocarpal joint, for instance, has
revealed the various types of loading occurring within physiological limits.
Information has also been obtained about the age-related changes taking place in
the hip, wrist and ankle joints. The increase of the total mineralization in
gymnasts can be related to the qualitative and quantitative adaptation to an
increased peak loading, and reduced mineralization to a lengthy reduction in use
during, for instance, postoperative immobilization. In groups of patients with
various diseases of mechanical origin (shoulder instability, malalignment of the
main axis, defective repositioning of healed fractures, rupture of the rotator
cuff, meniscectomy or rupture of the anterior cruciate ligament), a pattern of
mineralization is found which is different from the normal picture. These
findings reflect the abnormal mechanical situation. The mineralization pattern of
the femoropatellar joint has revealed the differing etiologies of medial and
lateral cartilage damage and the examination of patients with lunatomalacia has
made it possible to recognize a genetic disposition. The postoperative comparison
of the mineralization patterns of patients with genu varum who have undergone a
correction osteotomy and the results of animal experiments on various procedures
for reconstructing the anterior cruciate ligament or a primary replacement of the
meniscus, have produced results which make it possible to judge the success or
failure of the operation. (ABSTRACT TRUNCATED)
PMID- 9557325
TI - HIV/AIDS and deafness.
PMID- 9557326
TI - Emerging from our isolation.
PMID- 9557327
TI - How do deaf and hearing mothers regain eye contact when their infants look away?
AB - The authors examine the effects that results when 9-month-old deaf and hearing
infants break eye contact during face-to-face interactions with their deaf or
hearing mothers. Of particular interest are mothers' responses when their infant
looks away, and mothers' degree of success at regaining visual attention by using
active bids in either the tactile, visual, or auditory modes. The authors also
examine instances of maternal observing and waiting for the infant to reinitiate
visual contact. For deaf infants, visual and tactile modalities are particularly
important for communicating, interacting, and gaining information about their
environment. While hearing parents have been shown to compensate intuitively for
a deaf child's inability to perceive auditory cues (Koester, 1992, 1995), deaf
parents may offer important insights into the use of other modalities to elicit
and maintain a deaf infant's attention. Results of the study indicate a greater
reliance among deaf mothers on visual strategies to regain infant attention, and
a greater emphasis on vocalizations by hearing mothers, regardless of infant
hearing status.
PMID- 9557328
TI - Assessing substance abuse problems in deaf and hard of hearing individuals.
AB - Professionals who provide services to deaf and hard of hearing individuals may
encounter situations related to abuse of alcohol and other drugs. Getting access
to an agency that can provide an appropriate chemical dependency assessment for a
deaf or hard of hearing person is difficult because there are no formalized
assessment tools normed or specifically designed to use with such individuals.
Additionally, most assessors are unfamiliar with how to work with deaf and hard
of hearing people, less likely to be fluent in American Sign Language, and
unaware of appropriate treatment options. The present article provides an
overview of chemical dependency, assessment issues, and considerations unique to
the deaf and hard of hearing population. A chemical dependency assessment tool
developed by the Minnesota Chemical Dependency Program for Deaf and Hard of
Hearing Individuals is described, as well as a case study that illustrates
application of the assessment process.
PMID- 9557329
TI - Mathematics reform in the education of deaf and hard of hearing students.
AB - In response to increased demand for competent workers who possess skills in
problem solving, cooperative work, and technology, education professionals have
set out to reform mathematics education. The purpose of the present study was to
determine the state of mathematics reform in the education of deaf and hard of
hearing students. A national survey was sent to administrators and faculty at
schools for the Deaf seeking information on mathematics programs and instruction.
Data were analyzed by profession (i.e., administrator, teacher) and grade level
(K-4, 5-8, 9-12). Results show that some aspects of reform (e.g., problem
solving, use of concrete materials) have been incorporated into the deaf
education mathematics curriculum but that many 'traditional' techniques (e.g.,
drill and practice, rote memorization) remain in use. Data support the need for
increased attention to mathematics education reform within deaf education.
Recommendations are provided to professionals in the field to better prepare
students for the 21st century.
PMID- 9557330
TI - The Deaf Mentor Experimental Project for young children who are deaf and their
families.
AB - The Deaf Mentor Experimental Project investigated the efficacy of deaf mentor
services to young deaf children and their families. These services focused on
deaf adults (mentors), who made regular home visits to the children and their
families; shared their language (American Sign Language), culture, and personal
knowledge of deafness with the families; and served as role models for the
children. The children also received regular home visits from a hearing parent
adviser who helped the family promote the child's early listening, English, and
literacy skills. The result was a bilingual-bicultural home environment for these
children. The children who received deaf mentor services were compared to matched
children who did not receive these services but who received parent adviser
services. Children receiving this early bilingual-bicultural programming made
greater language gains during treatment time, had considerably larger
vocabularies, and scored higher on measures of communication, language, and
English syntax than the matched children.
PMID- 9557331
TI - A comparison study of educational involvement of hearing parents of deaf and
hearing children of elementary school age.
AB - This study was conducted to determine if a difference exists in level of
educational involvement between hearing parents of deaf children and hearing
parents of hearing children. Participating parents were asked to complete a 23
question survey about their involvement in their children's education over the
past year. Neither group of parents demonstrated a significantly higher level of
involvement in their children's education. However, parents of deaf children
observed their children in the classroom more than parents of hearing children;
parents of hearing children volunteered in their child's classroom more than
parents of deaf children.
PMID- 9557332
TI - National survey of school counselors working with deaf and hard of hearing
children. Two decades later.
AB - The first national survey of school counselors for deaf children was conducted by
Marie Curtis in 1975. She found that deaf students needed counseling services and
that existing services were poor to fair in meeting these students' needs. The
purpose of the present study was to follow up on Curtis's study by seeking
current information on the demography of school counselors as well as the present
roles and skills of counselors working with deaf children. Survey respondents
indicated that they spent most of their time providing individual and group
counseling. A large majority of respondents said their communication skills with
students were adequate or better. The three most frequently identified student
problems seen were "problems with peer relations," "difficulty with decision
making." and "poor self-esteem." Comparisons between the present study and the
Curtis study indicate that counselor competence has improved in the intervening
years. Specifically, survey respondents in the present study gave themselves much
higher ratings in the areas of communication skills, training, and counseling
skills.
PMID- 9557333
TI - Profiling Hispanic deaf students. A first step toward solving the greater
problems.
AB - As the number of Hispanic individuals in the United States increases, so does the
number of Hispanic hearing impaired children. This trend gives cause for concern
within current educational systems because research suggests that Hispanic
hearing impaired students demonstrate a lower rate of scholastic success than
hearing and deaf peers (Bennett, 1988). One step toward solving this problem is
to reexamine educational and assessment techniques employed with this diverse
population. A logical first stage would include construction of demographic
"profiles" or descriptions of student populations. The present study provides
such information and identifies the unique characteristics of Hispanic students
at the Texas School for the Deaf. The author discusses trilingual
(ASL/English/Spanish) situations and problems related to multilingual home and
school environments. A model is proposed for language instruction and support
services programs.
PMID- 9557334
TI - The association between racelessness and achievement among African American deaf
adolescents.
AB - Generally, deaf students do not achieve as well academically as their hearing
peers. Within the deaf population, African American deaf students achieve less
well academically than their White peers. There are, of course, both deaf and
hearing African American students who excel in school. What then, are the factors
that contribute to the accomplishments of successful African American deaf
students in school? The present study explored the relationship of the construct
of racelessness to school success among African American deaf adolescents. Data
were collected on 32 deaf adolescents from six public schools. There was little
support for racelessness as a robust construct in the present study. Although
exceptions existed, there was no significant relationship between racelessness
and achievement.
PMID- 9557335
TI - [Some personal comments on the care given to patients with benign prostatic
hypertrophy in the primary care environment].
PMID- 9557336
TI - [The Urinary Tract Diseases Dispensary and Clinic of the Instituto Rubio (1885).
1st hospital service specializing in urologic pathology in the history of Spanish
medicine. 1st period. The Instituto Rubio in Hospital de la Princesa (1880
1896).(I)].
AB - In May 1880, a royal decree signed by the Minister of the Interior, F. Romero
Robledo, created the Institute of Operative Therapy under the gratuitous
direction of Dr. Federico Rubio y Gali. Although it was located at the Hospital
de la Princesa of Madrid, it was not dependent on the Institutions of Charity.
According to the royal decree, major surgical procedures and specialized
operative techniques would be performed at this Institute. Thus, the first
teaching hospital was created in Spain, with operating rooms, dispensaries and
polyclinics dedicated primarily to surgical specialties which were established at
the Institute after 1880. The Institute's section for Diseases of the Urinary
Tract, created in October 1885, was entrusted to the Madrid citizen Enrique
Suender Rodriguez (1829-1897), the leading specialist in urology in our country
at that time (his 100th death anniversary was commemorated last year) and whose
assistant was Luis Gonzalez Bravo y Serrano.
PMID- 9557337
TI - [The Urinary Tract Diseases Dispensary and Clinic of the Instituto Rubio (1885).
!st hospital service specializing in urologic pathology in the history of Spanish
medicine. 2nd period. The Instituto Rubio in Moncloa (1896-1936).(II)].
AB - In 1896, for different reasons and requirements, the Institute of Operative
Therapy of the Hospital de la Princesa was transferred to a new and ample site in
the Moncloa district in Madrid, with building complexes and pavillions for the
dispensaries and policlinics for practically all surgical specialties, with all
the necessary equipment. This came to be known as the "Rubio Institute". Luis
Gonzalez Bravo y Serrano, Suender's assistant, was in charge of the new
Dispensary and Clinic for Diseases of the Urinary Tract of the Institute until
1929; Carlos Negrete de los Reyes was his assistant. Both specialists' initiative
and drive led to the creation of the Spanish Urological Society in 1911. They
were elected President and Secretary, respectively, to the first Board of the
Society. This article reviews the activities of the specialists in Diseases of
the Urinary Tract of the new Institute in the provision of care, in the field of
teaching and research, from their brilliant beginnings to their decline in 1936,
when the Spanish Civil War broke out. In my view, for all the contributions of
those who worked in this Section and its significant influence on the Spanish
specialists during its existence of more than 50 years, the Dispensary and Clinic
of Diseases of the Urinary Tract of the Rubio Institute should be considered the
catalyst and essence of Spanish urology and the Spanish Urological Society.
PMID- 9557338
TI - [Transurethral resection in the treatment of benign prostatic hypertrophy:
analysis of its results].
AB - OBJECTIVE: To analyze the results achieved with transurethral resection in the
treatment of benign prostatic hyperplasia. METHODS: We analyzed the results
achieved with transurethral resection in 400 patients with benign prostatic
hyperplasia who had been treated at the Joaquin Albarran teaching hospital. The
procedure was utilized for prostates weighing up to 50 gm and middle lobe
involvement independent of its size. Sterile water was used as irrigant since it
permits excellent vision, it is low-cost and carries a low risk of complications
associated with intraoperative osmotic diuresis. RESULTS: 4.75% of the cases
required blood transfusion (not more than two units). The intraoperative
complication rate was 2.75%; hemorrhage (2%), capsular perforation (0.5%), and
one death from myocardial infarction (0.25%). Hematuria resolved within 48 h
postoperatively in 83.75% and the urethral catheter was removed in 82.75% within
the first 72 h. Urinary tract infection was the most common postoperative
complication; 8.5% were acute and 3.25% presented late. Urethral stenosis was
observed in 2.25% and sclerosis of the neck was observed in 1.75%. Good results
were achieved in 360 patients (90%). The mean length of hospital stay was 3.8
days. There were two deaths (0.5%); both were due to myocardial infarction.
CONCLUSIONS: Transurethral resection in the treatment of benign prostatic
hyperplasia achieved good results in 90% of our patients. The length of hospital
stay was short and the mortality rate was low.
PMID- 9557339
TI - [Renal carcinoma with tumor thrombus in the vena cava and auricle. Experience and
review].
AB - OBJECTIVES: To report on our experience in the treatment of renal cell carcinoma
with vena caval or right atrial extension, with special reference to the level of
involvement and the surgical technique indicated for each case. METHODS: From
early 1975 to April, 1997, 212 patients underwent surgery for renal cell
carcinoma. Of these, 15 patients (11 male, 4 female), aged 27 to 73 years, had a
tumor thrombus extending to the inferior vena cava. The tumor was located in the
right kidney in 11 patients and in the left kidney in 4 patients. The tumor
thrombus was infrahepatic in 10 cases, it extended beyond the suprahepatic veins
in 3 cases, and 2 cases showed right atrial extension. The 10 patients with
infrahepatic caval thrombus underwent radical nephrectomy with cavotomy and
thrombus removal. In the remaining 5 patients with suprahepatic or atrial
extension, thrombus removal was performed via cardiopulmonary by-pass with
hypothermic circulatory arrest, with the assistance of a team of cardiac
surgeons. RESULTS: Pathological staging showed 2 T3cNoMo, 1 T3bNoMo and 2 T3bN1Mo
in the patients who underwent cardiopulmonary bypass. There were 5 T3bNoMo, 2
T3bN2Mo, 1 T3bN2M1, 1 T4NoMo and 1 T4N1M1 in the group of patients with
infrahepatic thrombus. There were two postoperative deaths. The overall survival
rate was poor. Six patients are alive at 3-26 months' follow-up and 9 have died
from disease progression. Patients with lymph node involvement or metastasis at
the time of diagnosis had a worse survival rate. CONCLUSIONS: Surgical treatment
of renal cancer with vena caval extension is specially difficult depending on the
level of involvement, which must therefore be determined with precision. MRI is
an effective and noninvasive technique. Tumors with thrombus below the
suprahepatic veins can be managed by the direct approach with cavotomy. The use
of cardiopulmonary bypass is advocated for tumors with suprahepatic caval or
atrial extension. Tumors with caval-atrial extension have a negative influence on
survival.
PMID- 9557340
TI - [Characterization of the DURR (dynamic urethral resistance relation] in the study
of function lower urinary tract symptoms in the male].
AB - OBJECTIVES: To determine the type and to quantify the DURR phenomena in the male.
METHODS: We conducted a clinical and urodynamic study in 31 male patients with
functional lower urinary tract symptoms. RESULTS: DURR is produced by two types
of mechanisms: urethral rigidity and contraction of the urethral wall. The
patients with DURR produced by rigidity showed a higher score for irritative
urinary symptoms. The patient with DURR produced by the contraction of the
urethral wall had greater urodynamic consequences (increased opening pressure and
PURR curve). The obstructive urinary symptoms were more intense when the DURR
presented in the second phase of voiding (after reaching the maximum flow).
CONCLUSIONS: The DURR phenomena have clinical and urodynamic consequences in
males with functional lower urinary tract symptoms; therefore their type and
quantity should be adequately determined.
PMID- 9557341
TI - [Occlusive urethral systems: can they constitute an alternative in the management
of female stress incontinence?].
AB - OBJECTIVE: To determine the utility of the urethral plug in the management of
female stress urinary incontinence. METHODS: A prospective clinical study was
conducted in 20 female patients with stress urinary incontinence in order to
evaluate the efficacy of a new urethral plug. The mean age was 59.6 +/- 6.2 years
(range 40-66). The study design included 3 visits (4 weeks). The results were
considered "positive" when urinary incontinence decreased and the patient
referred a subjective sensation of improvement, and "negative" if otherwise.
RESULTS: Positive results were demonstrated in 8 patients (40%). Ten patients
(50%) refused to continue, mainly due to urinary tract infection in 7 cases
(35%), difficulties in plug use (loss of plugs, anomalous urethral anatomy,
cystocele,...) in 6 cases (30%) and urethral mucosa irritation in one case (5%).
No plug migrated into the bladder. The initial urinary incontinence grade in the
positive cases were: minor in 4 (50%), mild in 2 (25%) and severe in 2 (25%). We
found no statistical relationship between the urinary incontinence grade and
clinical results. The patients used a median of 5 plugs per day. Of the 10
patients who completed the study, 5 (50%) refused to continue using the plug and
5 (50%) decided to continue using the plug in combination with electrostimulation
and/or pelvic floor exercises. CONCLUSIONS: The use of the urethral plug in the
management of female stress urinary incontinence is not an alternative to
surgical treatment or pelvic floor rehabilitation. However, it could be useful
for patients who are unwilling or unfit for surgery. Finally, the urethral plug
is an alternative to the use of collecting systems or devices in female stress
urinary incontinence.
PMID- 9557342
TI - [Metanephric renal adenoma].
AB - OBJECTIVE: To describe a case of metanephric adenoma, a rare and little known
tumor with no potential to malignancy. This tumor type can occasionally coexist
with Wilms' tumor, with which it is histogenically related. METHODS/RESULTS: A 54
year-old female patient was referred to the Urology Service for a small mass in
the left kidney that had been incidentally detected during an ultrasound
evaluation. Patient evaluation disclosed a solid, circumscribed, unencapsulated
mass of 2.3 cm in its largest segment. It was mainly localized in the medulla of
the kidney, although it was extensively in contact with the renal cortex.
Histologically, it was comprised of small epithelial cells in a tubular or
papillary arrangement, without atypia, mitosis, necrosis or invasion of adjacent
renal parenchyma or vascular structures, and with abundant psammoma-like
calcifications. The histological findings were characteristic of metanephric
adenoma. CONCLUSION: Metanephric adenoma is an uncommon, morphologically distinct
tumor type, with characteristic histopathological features. Despite its size, it
is benign and should be distinguished from renal cell carcinoma or Wilms' tumor.
PMID- 9557343
TI - [Abscessed primary retroperitoneal leiomyoma].
AB - OBJECTIVE: To describe a case of primary retroperitoneal leiomyoma presenting as
pelvic abscess. METHODS/RESULTS: A patient who had consulted for fever and
hypogastric and perineal pain is described. The diagnostic imaging techniques
disclosed a heterogeneous pelvic mass compatible with an abscess, which was
drained. After the purulent material had been drained, the mass was removed
surgically. The pathological analysis of the surgical specimen disclosed a
retroperitoneal leiomyoma. CONCLUSION: An abscessed primary retroperitoneal
leiomyoma is a very uncommon tumor.
PMID- 9557344
TI - [Paratesticular adenomatoid tumor, presentation as epididymal pain].
AB - OBJECTIVE: To describe an additional case of adenomatoid tumor of the epididymis.
METHODS/RESULTS: A 55-year-old man consulted for epididymal pain. Palpation and
ultrasound evaluation disclosed an epididymal tumor. The patient underwent
orchidectomy; histological examination of the surgical specimen confirmed an
adenomatoid tumor. CONCLUSIONS: Adenomatoid tumor of the epididymis is an
uncommon tumor of the paratesticular tissue. Although its etiopathogenesis
remains unclear, there appears to be a mesothelial involvement. Ultrasound
evaluation and clinical examination are essential in making the preoperative
diagnosis. It is a benign tumor and surgical excision can achieve cure. If the
intraoperative frozen section is found to be benign, the tumor can be excised or
enucleated without semicastration.
PMID- 9557345
TI - [A rare type of neoplasia. Report of 2 cases].
AB - OBJECTIVE: To report two additional cases of carcinosarcoma of the bladder and
review the literature. METHODS/RESULTS: Two cases of bladder tumor are described.
Both patients were male whose median age at diagnosis was 69.5 years. They had
consulted for post-void hypogastric pain and hematuria. A diagnosis of bladder
tumor was made on the basis of the radiological and ultrasound findings and a
partial cystectomy was performed. Histological examination with
immunohistochemical techniques revealed carcinosarcoma of the bladder.
CONCLUSIONS: Carcinosarcoma is a mixed tumor with a high grade of malignancy and
is rarely located in the bladder. Its clinical presentation is not unlike that of
other bladder tumors. Diagnosis is always by histology using immunological
techniques. It has a very poor prognosis. Because it is a rare tumor type, its
natural history is unknown and treatment remains unclear, although radical
surgery continues to be the most widely utilized.
PMID- 9557346
TI - [Systemic lupus erythematosus and pyeloureteral obstruction. Description of a
case].
AB - OBJECTIVE: To discuss the clinical implications of systemic lupus erythematosus
(SLE) as a complication of a urological condition. METHODS: Herein we describe a
patient who presented with acute pyelonephritis due to ureteropelvic juntion
stenosis, and a superimposed activation of SLE that had not been previously
detected. RESULTS: This form of presentation led to a delay in making the
diagnosis since it was focused urologically. The diagnosis of SLE was based on
the clinical features, determination of antinuclear antibodies (ANA) and a
decrease in serum complement. CONCLUSION: When a patient consults with fever
arising from a urological condition that is refractory to conventional therapy,
it is mandatory to make the differential diagnosis from other disease entities,
as shown in this case.
PMID- 9557347
TI - [Basaloid prostatic proliferations].
PMID- 9557348
TI - A giant left renal cyst presenting as obesity: a unique presentation.
AB - OBJECTIVE: Benign renal cysts are commonly found in adult patients. However,
giant renal cysts measuring more than 15 cm in greatest diameter or containing
more than 1500 cc of fluid are rarely seen. A giant renal cyst presenting as
obesity, a unique form of presentation, is described herein. METHODS/RESULTS: We
report the unique case of 78-year-old male who was diagnosed with a 25 cm left
renal cyst after presenting solely with diffuse progressive abdominal distention.
He had no other signs or symptoms and had been followed at our institution for
seven years with a diagnosis of obesity. The patient was effectively treated by
open renal cyst decortication. CONCLUSIONS: Giant renal cyst measuring > or = 15
cm or containing more than 1500 cc of fluid rarely occur. This case is unique in
that unlike other adult patients, this patient presented with no sign or symptom
other than diffuse, nonlateralizing, abdominal distension.
PMID- 9557349
TI - [Financing health].
PMID- 9557350
TI - [Quality of prescription at an on-demand clinic: a preliminary examination].
AB - OBJECTIVES: To analyse the qualitative composition of medication prescribed to
paediatric patients, in function of the intrinsic value of the medication and
active principles used, and to evaluate risks run by children through being
exposed to medication. DESIGN: An observational, descriptive, crossover study.
SETTING: Paediatrics service of Puerto de la Torre Health Centre (Malaga);
serving a fundamentally urban population, with rural areas round about.
PARTICIPANTS: All the patients seen during two consecutive weeks of November
1994. 15 cases of the 457 seen were excluded. The unit of analysis was a visit.
MAIN MEASUREMENTS: Age, reason for consultation and medication prescribed at each
attendance were recorded. Four age groups were defined: A (0-12 months), B (12-36
months), C (36-60 months) and D (> 60 months). On the basis of the initial
records, the following quantitative variables per visit were broken down: number
of drugs; number of drugs with high intrinsic value (HIV); number of drugs with
low intrinsic value (LIV); number of active principles; number of HIV active
principles; and number of LIV active principles. RESULTS AND CONCLUSIONS: The
incidence of medical prescription in the attendance sample was 85.1%. It was
highest in group C and lowest in group A. Average medication per attendance was
1.36 +/- 0.08. Group C was identified as the group with the highest average of
drugs prescription, HIV drugs, active.
PMID- 9557351
TI - [Diagnosing community health by factorial analysis].
AB - OBJECTIVE: To identify the needs of medical care and to determine priorities in
the delivery of health services by the factorial analysis of the health
indicators obtained from study of the demographic, economic and family features
of those registered at a Primary Care Centre. DESIGN: Descriptive and crossover.
SETTING: Tlalpan area, Federal District, Mexico, divided into geo-statistical
zones. Patients and other participants. A randomised sample of 590 dwellings,
with proportional coverage, based on 173,000 inhabitants and 17,895 ordinary
dwellings. INTERVENTION: Survey conducted in the home (April-July, 1993).
MEASUREMENTS AND MAIN RESULTS: 16 health markers were classified into four
categories, demographic, social, health-damaging and family. Nine markers with a
reading on the Pearson's correlation index over 0.40 were chosen. Factorial
analysis determined two main factors. CONCLUSIONS: The identification of the main
risk factors by means of factorial analysis helped in diagnosing community
health. A project needs to be worked out to define a methodology for studying
medically dysfunctional families and to introduce a prevention and early
diagnosis programme for Diabetes Mellitus.
PMID- 9557352
TI - [Validation of an instrument for identifying styles of the professional practice
of the primary care doctor].
AB - OBJECTIVE: To elaborate and validate a questionnaire for identifying common
styles of Primary Care doctors' practice. SETTING: Primary Health Care. Public
sector in Spain. DESIGN: This was a study to validate a questionnaire
administered in two phases with different samples. In the first phase, the items
(item-total correlation, using Alpha on eliminating item), validity of
construction, empirical validity and internal consistency, were analysed. In the
second, discriminatory validity and reliability of the questionnaire (test
retest) were calculated. MEASUREMENTS AND MAIN RESULTS: 81.5% of the doctors
replied in the first phase; and 100% in the second. Two factors were isolated
with the Principal Components procedure, which confirmed the validity of the
questionnaire's construction (52% variance explained). Internal consistency
(Alphas ranged between 0.55 and 0.75) and reliability (ranging between 0.50 and
0.95 in function of the time elapsed) were also demonstrated. CONCLUSIONS: This
instrument could be used to differentiate two styles in practice, characterised
by focusing on the physical illness vs the psycho-social aspects of the disease
process. The instrument is also useful because it gives the feeling of control
over the task.
PMID- 9557353
TI - [The special training month for tutors and residents in family medicine in
Valencia: evaluation of 3 cases].
AB - OBJECTIVE: To evaluate the activity in the special training month (STM) for
tutors and residents in Family Medicine in Valencia between 1994 and 1996.
DESIGN: Descriptive and longitudinal. SETTING: Thirteen teaching health centres.
PARTICIPANTS: 48 tutors and 102 residents. MEASUREMENTS AND MAIN RESULTS:
Requests from tutors for clinical recycling, research and other activities.
Evaluations of hospital staff, tutors and residents. 41.6% of tutors did their
STM in three years, 29.2% in 2 years and 29.2% in one. Of the 105 evaluations
sent in, 92 (87.6%) were for clinical recycling, 9 (8.6%) research and 4 (3.8%)
other activities. The most visited specialities were Dermatology, Cardiology,
Radiology and Rheumatology. Staff evaluated as very good the interest shown and
punctuality; between good and very good, their knowledge and skills, with
commentaries in 36% of evaluations on improvement of coordination between levels.
64.4% of tutors considered the STM very favourably, reflected in nine
commentaries that the activity was motivating and in six that it promoted
relationships between the Primary and Specialist care levels; and that it had an
objective repercussion on teaching through 44 clinical sessions reported during
1996. Improvements were proposed in the organisation of teaching activities. 49%
of residents were assigned a set tutor. CONCLUSIONS: The STM is valued positively
by tutors, residents and staff.
PMID- 9557354
TI - [Relationship between anxiety and family dynamics].
AB - OBJECTIVE: In the present study we tried to find the likely association between
anxiety and a disturbed family dynamic in patients who attended Primary Care for
consultation. DESIGN: An observational, crossover study with 150 patients (64.7%
women) chosen by systematised random sampling was performed. Patients were
grouped in various bivariable categories: sex, marital status, where from,
cultural level, occupation, size of family, stage of their life-cycle, family sub
system and income, which were compared with the results from the Stai Anxiety and
the Apgar Family tests. 95% significance level; two months data-gathering.
RESULTS: Among the most relevant findings were negative correlation in the value
of the Stai Anxiety test vs the Apgar Family test, with r = -0.27 and level of
significance between [-0.42 < r < -0.12]. A multivariant study using Dummy type
variables found association between Anxiety and being Female, with a Beta
coefficient of -6.2172 [CI -10.2044/-2.0342]. There was also association of size
of family and disturbed family dynamic, with Beta coeff. = -0.2437 and CI [
0.4706/-0.0168]. CONCLUSIONS: a) There is a correlation between anxiety and
disturbed family dynamic. b) Being female is a risk factor, when before anxious
patients, of a disturbed family dynamic. c) Family size is also a risk factor,
before an anxious patient, of a disturbed family dynamic.
PMID- 9557355
TI - [A retrospective evaluation of the behaviour of groups under out-patient care at
a health center].
AB - OBJECTIVES: To study and analyse the Out-Patient Care Groups (OCGs), and evaluate
how they affect use of health resources. DESIGN: An observational, retrospective
study. SETTING: Ciudad Jardin Health Centre, Malaga. PARTICIPANTS: 2999 patients
with a clinical history opened before 31.12.95, chosen from 5 of the 17 medical
lists at the Health Centre, were included. RESULTS: The statistical analysis was
performed with the SPSS software package of the Calculation Centre at Malaga
University. A descriptive test produced the following results: 33% of the
patients were classified in OCG 41 (combination of 2 or 3 out-patient diagnosis
groups in people over 34); 19% belonged to groups of stable or unstable chronic
illnesses (OCGs 8, 9 and 10); and 9% had acute children's diseases. Then multiple
regression constructed a model with the OCGs as independent variable and annual
visits, further tests performed and referral to specialists as dependent
variables. In this model the OCGs were able to explain 20.3% of resource
consumption. CONCLUSIONS: In the retrospective study and with a limited sample of
2999 patients, the OCGs are able to explain 20.3% of resource consumption.
However, it does seem a valid model for discriminating between normal and over
using patients.
PMID- 9557356
TI - [Do the complaints of primary care users vary with the care model?].
AB - OBJECTIVES: 1. To compare the traditional model (TM) and Primary Care teams
(PCTs) on the index of complaints. 2. To determine whether the reasons for
complaints vary with the care model. DESIGN: An observational, cross-sectional
study. SETTING: Primary Care Area 4, INSALUD, Madrid, covering 526,987
inhabitants. PARTICIPANTS: The complaints presented at PC Centres during 1993
were included. Those presented for reasons not concerning the centre were
excluded. In all, 448 complaints were studied. MEASUREMENTS AND MAIN RESULTS:
Significant differences were found in the general index of complaints according
to the care model. Statistically significant differences were detected between
PCT and the TM for complaints due to disagreement with the treatment and
disagreement with the follow-up procedures. CONCLUSIONS: Since the indicators of
prescription profiles and the following of procedures are better in PCTs than in
the TM, perhaps patients should be encouraged to participate more in the taking
of clinical decisions. This would help the introduction of improvements both in
the technical quality of treatment and in the follow-up of chronic diseases to be
perceived as such by patients. At present, as this study suggests, they are
causes of greater dissatisfaction.
PMID- 9557357
TI - [Correction of social inequalities in health: reform of primary health care as a
strategy].
AB - OBJECTIVES: To evaluate the impact of a policy to define priorities for the
reform of primary health care services among small areas according to health and
social indicators. DESIGN: Qualitative study of the changes in the provision of
primary health care services after a priority setting exercise based in social
and a health indicators. SETTING: The city of Barcelona (Catalonia, Spain).
PARTICIPANTS: The 66 basic health areas in which the city is divided for health
care planning. INTERVENTION: Areas are ranked according to their health and
social indicators, giving greater priority to those areas with unfavorable
indicators for the development of the reform of primary health care services and
a associated allocation of resources. RESULTS: Although at first new investments
were determined by preexisting processes based in opportunity criteria, clear
changes are observed. Three years after, there are improvements in the provision
for services in all priority areas, or they are in the midst of change.
CONCLUSIONS: In a context of tightening resources and of resistance to change, it
is possible to introduce objective criteria to set priorities to improve primary
health care services selectively in areas with most unfavorable indicators. This
process has the capacity to overrun obstacles and resistances.
PMID- 9557358
TI - [Health related life styles of the young].
PMID- 9557359
TI - [Urinary tract infections in primary care].
PMID- 9557360
TI - [Study of tuberculosis in Bages county between 1991 and 1995: incidence and
monitoring].
PMID- 9557361
TI - [Urinary tract infections in pregnant women in a rural environment].
PMID- 9557362
TI - [Who are the authors who publish in primary care journals and where do they
work].
PMID- 9557363
TI - [A reasoned approach to the pharmacologic treatment of Alzheimer's disease].
PMID- 9557364
TI - Arthritis and hepatitis.
AB - Arthritis has a fascinating relationship with hepatitis of diverse origins.
Either condition can predominate and the correct diagnosis may be elusive,
especially in the early stages. Humoral autoimmune mechanisms appear to serve as
a bridge connecting the two target organs, whether the syndromes are caused by
viral infections or unspecified etiologies. Maintaining a keen awareness of and
being able to recognize the clinical arthritis-hepatitis syndromes are critical,
enabling the physician to establish accurate diagnoses, to prescribe the correct
therapies, and to predict outcomes.
PMID- 9557365
TI - Nonmedicinal therapies for osteoarthritis.
AB - Given the modest efficacy of medicinal therapy for OA, nonpharmacologic therapy
is popular. Convincing evidence exists to support the efficacy of exercise and
muscle strengthening for patients with knee OA. Weight loss is likely to be
effective, as are some types of biomechanical alterations, possibly including
elastic knee supports and the use of canes and crutches. The clinical management
of patients with OA should sample broadly from these treatments, especially
because they may offer other health benefits as well (i.e., aerobic exercise and
weight loss). The optimal use of these modalities requires a team approach to
patient care, in which the physician works closely with a physical therapist and
nutritionist. This integrated approach may lead to decreases in pain and
disability for the patient with OA.
PMID- 9557366
TI - [Heart-lung interaction: the "spatial" competition].
PMID- 9557367
TI - [The echocardiographic assessment of mitral stenosis].
PMID- 9557368
TI - Current coronary interventional practice.
PMID- 9557369
TI - [Ventricular systolic function. The intramyocardial mechanics and the indices of
systolic ejection: the different physiological and clinical significance].
PMID- 9557370
TI - [Tumor necrosis factor and heart failure].
PMID- 9557371
TI - Non-surgical myocardial ablation: for hypertrophic obstructive cardiomyopathy.
PMID- 9557372
TI - [Collateral circulation and the coronary reserve].
AB - The mechanisms regulating coronary collateral circulation are largely unknown
owing to both the complex and variable nature of clinical models and the
difficulty to obtain quantitative and differentiated flow measurements within the
various coronary tree portions. With the aim of assessing collateral flow
reserve, we studied 19 patients with effort angina, without myocardial infarction
and with isolated occlusion of either the left anterior descending coronary
artery (n = 14) or the circumflex coronary artery (n = 5). Flow values were
measured basally, during atrial pacing induced tachycardia and following ev
dipyridamole infusion (0.56 mg/kg of body weight in 4 min), by means of positron
emission tomography and nitrogen-13 ammonia as flow tracer, within both regions
depending on collateral circulation and the remote ones. Results have been
compared with those obtained in 13 normal subjects. Basal flow values in regions
depending on collateral circulation and in the remote regions (0.61 +/- 0.11 vs
0.63 +/- 0.17 ml/min/g) were found to be similar, but lower than in normal
subjects (1.00 +/- 0.20 ml/min/g, p < 0.01). During atrial pacing, flow increased
to 0.83 +/- 0.25 and to 1.11 +/- 0.39 ml/min/g, in the regions depending on
collateral circulation and in the remote regions, respectively (p < 0.05 as
compared to baseline); again, values were lower than in normal subjects (1.86 +/-
0.61 ml/min/g, p < 0.01). Dipyridamole infusion further increased flow in the
remote regions (1.36 +/- 0.57 ml/min/g, p < 0.01 as compared to atrial pacing)
but it did not in the regions depending on collateral circulation (0.94 +/- 0.37
ml/min/g, NS as compared to atrial pacing); both values were lower than in normal
subjects (3.46 +/- 0.78 ml/min/g, p < 0.01). Flow reserve in the regions
depending on collateral circulation was found to have a direct linear correlation
with the one in the remote regions (r = 0.83; p < 0.01). In conclusion, in spite
of basal hypoperfusion, collateral circulation maintains a flow reserve which,
even if reduced, is able to cope with moderate increments in oxygen consumption.
An analogous flow reduction can be observed in the remote regions, suggesting
that the entire coronary tree is involved, beyond the obstructive lesions of the
main arterial branches.
PMID- 9557373
TI - [The influence of left systolic ventricular function on right ventricular
function after an acute myocardial infarct].
AB - The aim of this study was to assess the interaction between left ventricular and
right ventricular systolic function after acute myocardial infarction (AMI). The
study population comprises 27 normal subjects and 71 patients assessed at
predischarge (12 +/- 7 days) after AMI and divided into two subgroups, 24 with
inferior AMI and 47 with non inferior AMI. The three groups were comparable for
sex, age, heart rate and blood pressure. Right ventricular function was evaluated
by two-dimensional assessment of tricuspid annular plane systolic excursion
(TAPSE) and by Doppler analysis of right ventricular outflow tract. Left
ventricular systolic function was evaluated by two-dimensional determination of
ejection fraction and wall motion score index, and by Doppler analysis of left
ventricular outflow tract. The overall AMI population showed reduced TAPSE,
velocity-time integral (both p < 0.05) and peak velocity (p < 0.005) of right
ventricular outflow tract, prolongation of Q-S2 interval and increase of pre
ejection period/acceleration time ratio (both p < 0.05) in comparison with
normals. These alterations were accompanied by a decrease of left ventricular
ejection fraction and increase of wall motion score index. (p < 0.0001) The
changes of right ventricular indexes were confirmed in patients with inferior AMI
who had also lower left ventricular ejection fraction (46 +/- 9%). Functional
parameters of the right ventricle were not significantly modified in patients
with non inferior AMI who had greater left ventricular ejection fraction (53 +/-
8.6%). In the overall AMI population, and in particular in inferior AMI, we found
univariate relations between time-velocity integrals of left ventricular and
right ventricular outflow tract and between left ventricular ejection fraction
and TAPSE. Only in inferior AMI creatinkinase peak was related to time-velocity
integral of right ventricular outflow tract (r = -0.59, p < 0.01). In conclusion,
the magnitude of right ventricular systolic impairment developing after left
ventricular AMI depends on the degree of left ventricular dysfunction, likewise
by changes of hemodynamic load imposed to the right ventricle. AMI location and,
only in inferior AMI, infarct extension participate in determining this
dysfunction.
PMID- 9557374
TI - [A failed improvement in pulmonary function and exercise capacity with carvedilol
in congestive heart failure despite an excellent effect on left ventricular
function].
AB - This study was aimed at investigating in chronic heart failure (CHF) the effects
that beta-blockade with carvedilol may have on lung function, and their
relationship with left ventricular (LV) performance and peak exercise oxygen
uptake (VO2p). CHF causes disturbances in ventilation and pulmonary gas transfer
(stress failure of alveolar-capillary membrane) that participate in limiting
VO2p. Carvedilol improves LV function and not VO2p. Twenty-one NYHA functional
class II-III patients were randomized (2 to 1) to carvedilol (25 mg bid., 14
patients) or placebo (7 patients) for 6 months. Rest forced expiratory volume
(FEV1), vital capacity (VC), total lung capacity (TLC), carbon monoxide diffusing
capacity (DLCO), its alveolar-capillary membrane component (DM), pulmonary venous
and transmitral flows (for monitoring changes in LV end-diastolic pressure, EDP),
LV diastolic (EDD) and systolic (ESD) dimensions, stroke volume (SV), ejection
fraction (EF), fiber shortening velocity (VCF) were measured at baseline and at 3
and 6 months. VO2p, peak ratio of dead space to tidal volume (VD/VTp),
ventilatory equivalent for CO2 production (VE/VCO2), VO2 at anaerobic threshold
(VO2at) were also determined. FEV1, VC, TLC, DLCO, DM were impaired in CHF
compared to 14 volunteers, and did not vary with treatment. Carvedilol reduced
EDP, EDD, ESD, and increased EF, SV, VCF, without affecting VO2p, VO2at, VD/VTp,
VE/VCO2, at 3 and 6 months. Placebo was ineffective. In CHF, carvedilol exerts
neutral effects on ventilation and pulmonary gas transfer and ameliorates LV
function at rest. This proves that antifailure treatment may not be similarly
effective on cardiac and pulmonary function; and does not contradict the
possibility that persistence of lung impairment may contribute to lack of
improvement in exercise performance with carvedilol.
PMID- 9557375
TI - [Tryptase levels are elevated during spontaneous ischemic episodes in unstable
angina but not after the ergonovine test in variant angina].
AB - Activated mast cells are present in human coronary atheromas, as well as in the
adventitia of patients with variant angina, and may play an important role in
plaque rupture and coronary vasomotion. To assess whether or not activation of
mast cells is a primary event, we measured serum levels of tryptase, a specific
marker of mast cell activation, in 8 patients with unstable angina during a
spontaneous ischemic episode (Group 1) and in 5 patients with variant angina
(Group 2) during ergonovine-induced coronary spasm. Blood samples were collected
as soon as possible after the onset of pain and ECG changes (0 min), and after 5,
15 and 60 min. Tryptase levels in Group 1 were 0.13 U/l (range 0.017-0.44) at the
onset of pain and significantly raised to 0.75 U/l (range 0.05-2.49) at 5 min,
decreasing to 0.076 U/l (range 0.018-0.16) at 15 min and to 0.085 U/l (range 0.01
0.25) at 60 min (p = 0.035). Conversely, tryptase levels in Group 2 were 0.09 U/l
(range 0.07-0.13) at 0 min, 0.11 U/l (range 0.07-0.22) at 5 min, 0.10 U/l (range
0.07-0.18) at 15 min, 0.11 U/l (range 0.07-0.17) at 60 min (NS). In conclusion,
tryptase levels raise during spontaneous ischemic episodes in unstable angina,
but not after ergonovine-provoked ischemia in variant angina, suggesting that a
primary, yet unknown stimulus, may activate mast cells during some ischemic
episodes in unstable angina.
PMID- 9557376
TI - [A multimedia echocardiographic archive].
AB - The widespread diffusion of echocardiography requires to rationalize clinical
examination archives; the recent improvement in computer processing speed and the
addition of image processing capabilities on standard personal computer by using
multimedia technology provide a low-cost solution to improve video digital
acquisition and base management. Furthermore, the diffusion of computer networks
supports the possibility of sending images in digital format from a work station
to another. In this study we describe the setting-up of a system for
echocardiographic image acquisition, storage, base management and analysis based
on a standard multimedia Macintosh personal computer using readily available not
dedicated software. We tested the overall efficiency of this system in terms of
time required to perform hardware and software procedures, storage capacity of
the archive and possibility to exchange information with other wire-linked
computer work-stations or via modem. This system has proven to require an
acceptable time to perform all the procedures showing a high level of
connectivity with other standard personal computer work-stations; however, some
limitations with regard to time required in sending via modem long movie files
need to be pointed out. In conclusion, in our experience new multimedia personal
computer could offer to every physician with a minimum informatic knowledge the
well known advantages of digital-video, at a reasonable cost.
PMID- 9557377
TI - [The superior vena cava obstruction syndrome after the implantation of a
permanent pacemaker: a clinical case report].
AB - Occlusion of the superior vena cava is a rare but serious complication of
transvenous endocardial pacing. We describe 1 case of superior vena cava
obstruction associated with permanent transvenous DDD pacemaker, following local
infection. Thrombolytic therapy was initially effective, resulting in relief of
signs of obstruction. However systemic infection occurred 3 months later. The
patient was subsequently submitted to surgical removal of the infected pacemaker
apparatus. Several therapeutical options described in previous papers are
reviewed: anticoagulants, thrombolytics, percutaneous dilatation, surgical
removal of the catheter. In conclusion, when a chronic process induced by local
infection is present, surgical treatment is the best therapeutical approach.
PMID- 9557378
TI - [The hypertension specialist].
PMID- 9557379
TI - Similarity as an explanatory construct.
AB - Theories can be found throughout cognitive science that give an explanatory role
to similarity. Such theories can be contrasted with those that model thought
using abstract rules. We lay out four possible explanatory roles for similarity.
We then review the computational pros and cons of similarity- and rule-based
models and outline the empirical work that speaks to the psychological
plausibility of the two frameworks. We conclude that an adequate model of human
thought must take advantage of both the flexibility of similarity-based inference
and the compositionality and certainty associated with rule-based inference.
PMID- 9557380
TI - Two dogmas of conceptual empiricism: implications for hybrid models of the
structure of knowledge.
AB - Concepts seem to consist of both an associative component based on tabulations of
feature typicality and similarity judgments and an explanatory component based on
rules and causal principles. However, there is much controversy about how each
component functions in concept acquisition and use. Here we consider two
assumptions, or dogmas, that embody this controversy and underlie much of the
current cognitive science research on concepts. Dogma 1: Novel information is
first processed via similarity judgments and only later is influenced by
explanatory components. Dogma 2: Children initially have only a similarity-based
component for learning concepts; the explanatory component develops on the
foundation of this earlier component. We present both empirical and theoretical
arguments that these dogmas are unfounded, particularly with respect to real
world concepts; we contend that the dogmas arise from a particular species of
empiricism that inhibits progress in the study of conceptual structure; and
finally, we advocate the retention of a hybrid model of the structure of
knowledge despite our rejection of these dogmas.
PMID- 9557381
TI - Similarity-based categorization and fuzziness of natural categories.
AB - The adequacy of similarity to prototype as an account of categorization in
natural concepts was assessed by analyzing the monotonicity of the relation
between typicality of an item in a category and the probability of a positive
categorization response using data from McCloskey and Glucksberg (1978). The
analysis revealed a strong underlying similarity-based threshold curve, with
systematic deviations. Further data collection showed that deviations from the
curve could be attributed to the effects of unfamiliarity and non-categorical
associations on typicality judgments, as well as differences between the
perceptual appearance of an item (which tended to boost typicality) and its
underlying nature (which tended to boost categorization). The results are
discussed in terms of the different presuppositions and task constraints involved
in rating typicality as opposed to performing a categorization.
PMID- 9557382
TI - Alternative strategies of categorization.
AB - Psychological studies of categorization often assume that all concepts are of the
same general kind, and are operated on by the same kind of categorization
process. In this paper, we argue against this unitary view, and for the existence
of qualitatively different categorization processes. In particular, we focus on
the distinction between categorizing an item by: (a) applying a category-defining
rule to the item vs. (b) determining the similarity of that item to remembered
exemplars of a category. We begin by characterizing rule application and
similarity computations as strategies of categorization. Next, we review
experimental studies that have used artificial categories and shown that
differences in instructions or time pressure can lead to either rule-based
categorization or similarity-based categorization. Then we consider studies that
have used natural concepts and again demonstrated that categorization can be done
by either rule application or similarity calculations. Lastly, we take up
evidence from cognitive neuroscience relevant to the rule vs. similarity issue.
There is some indirect evidence from brain-damaged patients for neurological
differences between categorization based on rules vs. that based on similarity
(with the former involving frontal regions, and the latter relying more on
posterior areas). For more direct evidence, we present the results of a recent
neuroimaging experiment, which indicates that different neural circuits are
involved when people categorize items on the basis of a rule as compared with
when they categorize the same items on the basis of similarity.
PMID- 9557383
TI - Similarity and rules: distinct? Exhaustive? Empirically distinguishable?
AB - The distinction between rule-based and similarity-based processes in cognition is
of fundamental importance for cognitive science, and has been the focus of a
large body of empirical research. However, intuitive uses of the distinction are
subject to theoretical difficulties and their relation to empirical evidence is
not clear. We propose a 'core' distinction between rule- and similarity-based
processes, in terms of the way representations of stored information are
'matched' with the representation of a novel item. This explication captures the
intuitively clear-cut cases of processes of each type, and resolves apparent
problems with the rule/similarity distinction. Moreover, it provides a clear
target for assessing the psychological and AI literatures. We show that many
lines of psychological evidence are less conclusive than sometimes assumed, but
suggest that converging lines of evidence may be persuasive. We then argue that
the AI literature suggests that approaches which combine rules and similarity are
an important new focus for empirical work.
PMID- 9557384
TI - Reuniting perception and conception.
AB - Work in philosophy and psychology has argued for a dissociation between
perceptually-based similarity and higher-level rules in conceptual thought.
Although such a dissociation may be justified at times, our goal is to illustrate
ways in which conceptual processing is grounded in perception, both for
perceptual similarity and abstract rules. We discuss the advantages, power and
influences of perceptually-based representations. First, many of the properties
associated with amodal symbol systems can be achieved with perceptually-based
systems as well (e.g. productivity). Second, relatively raw perceptual
representations are powerful because they can implicitly represent properties in
an analog fashion. Third, perception naturally provides impressions of overall
similarity, exactly the type of similarity useful for establishing many common
categories. Fourth, perceptual similarity is not static but becomes tuned over
time to conceptual demands. Fifth, the original motivation or basis for
sophisticated cognition is often less sophisticated perceptual similarity. Sixth,
perceptual simulation occurs even in conceptual tasks that have no explicit
perceptual demands. Parallels between perceptual and conceptual processes suggest
that many mechanisms typically associated with abstract thought are also present
in perception, and that perceptual processes provide useful mechanisms that may
be co-opted by abstract thought.
PMID- 9557385
TI - Similarity and the development of rules.
AB - Similarity-based and rule-based accounts of cognition are often portrayed as
opposing accounts. In this paper we suggest that in learning and development, the
process of comparison can act as a bridge between similarity-based and rule-based
processing. We suggest that comparison involves a process of structural alignment
and mapping between two representations. This kind of structure-sensitive
comparison process--which may be triggered either by experiential or symbolic
juxtapositions--has a twofold significance for cognitive development. First, as a
learning mechanism, comparison facilitates the grasp of structural commonalities
and the abstraction of rules; and, second, as a mechanism for the application and
extension of previously acquired knowledge, comparison processes facilitate the
application of abstract knowledge to new instances.
PMID- 9557386
TI - Measles control in Australia. Report of the Measles Control in Australia
Workshop, 5 November 1997.
AB - The proceedings of the Measles Control in Australia Workshop held on 5 November
1998 are presented in this report. Prompted by the possibility of a global
elimination campaign in the near future the Workshop considered the factors
involved in elimination of measles from Australia. Epidemiology, surveillance,
laboratory diagnosis methods, mathematical modelling, and the cost and logistics
were all addressed. Mass vaccination for all 2-18 year olds, and a routine 2-dose
regimen with scheduled doses at 12 months and school entry were recommended.
Intensified surveillance, based on a sensitive case definition and laboratory
confirmation (measles specific IgM) of suspected cases was identified as a
crucial component of the campaign. The continuation of high vaccination coverage
for each of the two doses would be essential to maintain elimination once
established.
PMID- 9557387
TI - Methodology for measuring Australia's childhood immunisation coverage.
PMID- 9557389
TI - Gonococcal conjunctivitis outbreak.
PMID- 9557390
TI - Communicable Diseases Surveillance.
PMID- 9557388
TI - Immunisation and asthma.
PMID- 9557391
TI - An overview of antigen presentation and its central role in the immune response.
PMID- 9557393
TI - Molecular requirements for assembly and intracellular transport of class I major
histocompatibility complex molecules.
PMID- 9557392
TI - How do endogenous proteins become peptides and reach the endoplasmic reticulum.
PMID- 9557394
TI - Peptide-major histocompatibility complex class I complex: from the structural and
molecular basis to pharmacological principles and therapeutic applications.
PMID- 9557395
TI - Immune response of beta 2-microglobulin-deficient mice to pathogens.
PMID- 9557396
TI - CNS neurons: the basis and benefits of low class I major histocompatibility
complex expression.
PMID- 9557397
TI - Suppression of MHC class I antigen presentation by human adenoviruses.
PMID- 9557398
TI - Herpesvirus evasion of the immune system.
PMID- 9557399
TI - Intracellular transport of molecules engaged in the presentation of exogenous
antigens.
PMID- 9557400
TI - Biologic consequences of defective major histocompatibility complex class II
presentation.
PMID- 9557401
TI - Managed cost.
PMID- 9557402
TI - Attic cholesteatoma in the anterior epitympanum.
PMID- 9557403
TI - Varicosities and vascular masses.
PMID- 9557404
TI - Unilateral antrochoanal polyp with bilateral nasal obstruction.
PMID- 9557405
TI - Branchio-oto-renal syndrome (BOR syndrome, Melnick-Fraser syndrome).
PMID- 9557406
TI - Internal auditory canal.
PMID- 9557407
TI - Local recurrence of carcinoma of the tongue after glossectomy: patient prognosis.
AB - We conducted a retrospective review of the prognosis for patients with local
recurrence after surgical treatment of carcinoma of the tongue. Glossectomy for
squamous cell carcinoma of the tongue was performed in 167 patients. Local
recurrence developed in 32 patients including 21 with local recurrence alone, 10
with locoregional recurrence and one with locodistant recurrence. The incidence
of local recurrence increased with tumor stage (from 16% of T1 tumors to 46% of
T4 carcinomas). Eleven (34%) patients underwent surgical salvage for local
recurrence, with only one (9%) patient surviving free of carcinoma at 43 months
post-surgical salvage. All of the remaining 21 patients with local recurrence
were treated palliatively and all died within one year. Patients who underwent
surgical salvage had significantly higher survival rates compared to those
treated palliatively. Close follow-up after glossectomy is important for early
detection of local recurrence amenable to surgical salvage. However, the overall
prognosis for patients with local recurrence was poor, with a three-year
actuarial survival rate of only 3%. Therefore, prevention of local recurrence
with adequate initial surgical treatment is essential.
PMID- 9557408
TI - Conservative management of traumatic pseudodiverticulum in the neonate.
AB - Traumatic pseudodiverticulum of the pharynx is an uncommon entity which generally
occurs in infants after traumatic intubation or suctioning. A case of an infant
presenting with stridor, drooling and cervical crepitus is presented.
PMID- 9557409
TI - Revision endoscopic sinus surgery: the Thomas Jefferson University experience.
AB - Since its introduction, functional endoscopic sinus surgery (FESS) has
demonstrated success rates of 76% to 98%. A small group of the patients in whom
initial FESS and optimal medical therapy fail require revision endoscopic sinus
surgery (RESS). This group has recently been studied by several authors, and we
have evaluated a group of 90 RESS patients selected from 753 consecutive primary
FESS patients. Patients were followed for a mean of 22.8 months. Extent of
disease, history of polyps, allergy, previous traditional endonasal sinus
surgery, male gender, chronic steroid use, and the presence of a deviated septum
all appeared to adversely affect RESS outcome. The surgeon's knowledge of the
sinus anatomy is critical, especially in revision sinus cases in which landmarks
are distorted or absent. In our review, RESS was associated with a 1% major
complication rate and was successful in 67% of patients. Computer-assisted
endoscopic sinus surgery integrates preoperative imaging with realtime endoscopic
visualization, augments the surgeon's knowledge of anatomy, and helps to minimize
patient risk.
PMID- 9557410
TI - Internal jugular vein thrombophlebitis.
PMID- 9557411
TI - Fungal sinusitis: progression of disease in immunosuppression--a case report.
AB - Fungal sinusitis is a disease which can be grouped into invasive and noninvasive
forms. The invasive entities include the acute/fulminant and chronic/indolent
forms. The noninvasive entities include the fungus ball and allergic forms. The
noninvasive forms, however, can develop into invasive disease under certain
immunosuppressive states. The patient in this case report had the fungus ball
form of fungal sinusitis which evolved into chronic, and then the acute/fulminant
form approximately two weeks after undergoing cadaver-donor kidney
transplantation. Due to the patient's immunosuppressed state, the fungus spread
beyond the sinus region and eventually lead to fulminant disseminated disease.
The severity of the fungal disease corresponded directly to the severity of the
patient's immunosuppression.
PMID- 9557412
TI - Animal bites to the head and neck.
AB - There is controversy regarding the timing of repair and the use of prophylactic
antibiotics in patients with animal bites to the head and neck. In this paper we
review our experience with such wounds, and address surgical management and the
use of prophylactic antibiotic therapy. A retrospective review of the medical
records of 29 patients with animal bites to the head and neck was conducted. All
patients were seen and treated at a large teaching hospital in Houston, Texas
over an 18-month period. Seventy-six percent of our patients were 12 years old or
younger. Most came to the emergency room soon after sustaining their injuries,
and their wounds were repaired primarily with favorable results. There were no
cases of wound infection. Ninety percent were treated with prophylactic
antibiotics. The wounds of the 10% of patients who did receive antibiotics were
similar to those of the other patients and healed well without infection. Wounds
resulting from animal bites to the head and neck can be repaired primarily when
treated shortly after injury. Further prospective, randomized studies are
recommended to evaluate the effectiveness and necessity of prophylactic
antibiotic therapy in this patient population.
PMID- 9557413
TI - Oat cell carcinoma of the tongue from an unknown primary.
AB - Oat cell carcinoma is rarely diagnosed in the head and neck and can be primary or
secondary. Primary tumors arise from amine precursor uptake and decarboxylation
cells which are found throughout the head and neck. Secondary deposits
metastasize most commonly from the lungs. We report a 64-year-old woman with a
known pancreatic oat cell carcinoma who came to the ENT Department with
dysphagia. On examination, a lesion was seen at the base of the tongue and was
histologically an oat cell carcinoma. No treatment was administered and the
patient died one month after discharge. This report highlights the difficulty in
determining the primary site when a rare tumor metastasizes to the head and neck
and no autopsy findings are obtained. To our knowledge, oat cell carcinoma of the
tongue has not been previously reported.
PMID- 9557414
TI - Blood lipids.
PMID- 9557415
TI - Impact of user fees in health.
PMID- 9557416
TI - Impact of user charges on government health facilities in Tanzania.
AB - Utilisation of outpatient services in government owned district hospitals in Dar
es Salaam, declined by more than 50% following the introduction of user charges
in these health facilities in mid July 1993. Outpatient attendances in the
private health facilities studied remained constant throughout the year although
these charged higher fees. Education and employment status were found to be major
factors influencing utilisation of public versus private health facilities.
Public facility users (62.8%) had five to eight years of formal education.
Private facility users with five to eight years of education were 45.5% and those
with more than years of education were 47.1%. While 68.6% of public facility
users paid for their own healthcare, more than a quarter (27.3%) had their costs
met by relatives or friends. The employer paid for 72% of private facility users,
49.2% of whom stated that this was the reason why they used private facilities.
Despite introduction of charges in public hospitals, availability of prescribed
medication was poor. Drugs were reported to be always available by only 27.3% of
public health facility users compared to 80% of private health facility users.
PMID- 9557417
TI - Re: Malaria treatment in peri-urban area of Kisumu town.
PMID- 9557418
TI - Assessment of rational drug use and prescribing in primary health care facilities
in north west Ethiopia.
AB - A study on rational drug use was undertaken in nine health centres (HCs) and nine
health stations (HSs) in Ethiopia. Prescribing, patient care and facility
specific factors were measured using drug use indicators. Prescribing patterns of
drugs were also assessed. With only few exceptions, the drug use indicators in
HCs and HSs and between retrospective and prospective studies were similar
despite differences in manpower and facilities. The average consultation time (in
minutes) in HSs and HCs was 5.1 +/- 0.8 and 5.8 +/- 1.06, respectively. The
dispensing time (in minutes) was 1.5 +/- 0.7 in HSs and 1.9 +/- 0.6 in HCs. Both
patient care indicators seem to be adequate to influence patient satisfaction to
the overall health service and patient knowledge of important dosage
instructions. Most drugs (more than 89% in HCs and 71% in HSs) were actually
dispensed from the health facilities and labelling was satisfactory. Prescribing
by generic names (average: 75% in HCs and 83% in HSs) was encouraging. While the
availability of key drugs was ensured, essential documents were missing in most
facilities or they were unpopular for use, and those available required revision
and updating. Polypharmacy in which the number of drugs/encounter was < 2.5 was
minimal, but that a large proportion of the prescriptions contained two or more
drugs could result in adverse drug-drug interactions. The most frequently
prescribed drugs were anti-infectives and analgesics accounting for over 76% in
HCs and 82% in HSs and in most cases they are probably prescribed with little
justification. The exposure of patients to antibiotics (average: 60% in HCs and
65% in HSs) was unacceptably high to justify epidemiological trends. The high
exposure of patients to injections, especially in the HSs (over 37%), should be
seen from the health and economic points of view. The results revealed priority
areas for intervention. They also provide standard references to compare drug use
situations and their change over time in different settings, area and time in
Ethiopia.
PMID- 9557419
TI - Sexually transmitted disease risk assessment used among low-risk populations in
east central Africa: a review.
AB - In sub-Saharan Africa where sexually transmitted diseases (STDs) are prevalent
but health resources are scarce, algorithms that act as STD/HIV risk assessment
(RA) tools for family planning (FP) and maternal/child health (MCH) clinic
attenders may be useful. These RA algorithms generally comprise questions about a
person's social, economic, demographic, behavioural and clinical background. The
answers can be scored or scaled to indicate a higher probability of current
STD/HIV infection and thus the need for testing or treatment. RA can be done
alone, or can be combined with clinical examination where laboratory diagnosis is
not feasible. But how accurate are RA tools? We reviewed six studies at African
sites that examined the use of RA combined with a clinical algorithm for STD
screening of clinic attendees. Researchers reported the standard measures of test
accuracy: sensitivity (per cent of infected women found positive by the tool);
specificity (per cent of uninfected women found negative by the tool), and
positive predictive value (per cent of women found positive by the tool who are
truly infected). Most algorithms had low sensitivity (< 50%) and low positive
predictive value (< 20%). The addition of clinical examination, and of leucocyte
esterase (LE) testing, improved accuracy. But algorithms that performed well in
one site were less accurate at other sites. For illustrative purposes, we
considered a hypothetical population of 1,000 women attending a FP clinic. With a
prevalence of cervical gonorrhoea of five per cent, algorithm sensitivity of 40%,
and algorithm specificity of 75%, the positive predictive value of the RA tool
would be 7.7%. In other words, 20 (7.7%) women diagnosed as infected would
actually have gonorrhoea, and 237 false positive women would be treated
needlessly, with the attendant costs and risks. However, with a disease
prevalence above 50%, as might prevail for vaginal infections, and the same
sensitivity and specificity figures, the positive predictive value may reach 70
80%. Risk assessment appears to be a relatively easy way to integrate STD
management into family planning and MCH practice. However, there is no evidence
to show its effectiveness for screening low-risk populations. We urge improvement
of these tools, including information on the behaviour of male partners, and
addition of simple screening tests such as leucocyte esterase dipsticks.
PMID- 9557420
TI - Socio-cultural and economic aspects of AIDS in Uganda: a review.
AB - AIDS is long-established in Uganda; prevalence rates are high. Most transmission
is by heterosexual intercourse, and has been associated with population
movements, especially of traders. Treatment resources are very limited and
expensive. Some sexual practices inhibit contraceptive use. Attitudes towards
AIDS and its testing reveal contradictions, although contraceptive knowledge is
widespread. Folk beliefs have not been studied. Government guidelines have been
produced, although these do not inform clinical attitudes. Indications suggest
that prevalence in the long-term may be decreasing.
PMID- 9557421
TI - Comparison of protection afforded by single measles vaccination and late
revaccination schedules.
AB - An intervention study compared the protection afforded vaccinees by single
measles vaccination and late revaccination schedules in 1990-94. During the
intervention a single revaccination (after initial vaccination at nine months of
age) was applied to children at any point in time between 12 and 23 months of
age. Cases of measles aged 10-23 months were identified through an active
surveillance system and in this period 5, 11 and 11 cases of revaccinated, single
vaccination and unvaccinated children were identified. Measles incidence rates
were 392.2-415.6 (mean = 405.6, SD = 6.7), 75.4-112.1 (median = 91.7, SD = 13.3)
and 12.8-15.2 (mean = 13.9, DS = 0.99) per 100,000 population in children who
were unvaccinated, with single vaccination and revaccinated respectively.
Relative risk of contracting measles in children who were unvaccinated or with
single vaccination was 26.5-32.5 (mean = 29.4, SD = 2.3) and 5.8-8.8 (mean = 6.8,
SD = 1.2) respectively compared with revaccinated children. Vaccine efficacies
that were determined were 73-81% (mean = 77.2, SD = 2.9) and 96.2-96.9% (mean =
96.6, SD = 0.27) for single vaccination and late revaccination schedules
respectively. It was concluded that late revaccination affords vaccinees better
protection than single vaccination through improvement in vaccine.
PMID- 9557422
TI - Epidemiological features of severe paediatric malaria in north western Ethiopia.
AB - Malaria remains a major public health challenge in sub-Saharan Africa, yet our
knowledge of the epidemiology of malaria in terms of patterns of mortality and
morbidity is limited. To examine the clinical and epidemiological presentation of
severe life-threatening malaria in Humera, north western Ethiopia studies were
conducted among the childhood population in the community, those presenting to
out-patient facilities and those admitted to the district hospital. The overall
P. falciparum parasite rate among children aged 0-9 years resident within the
area was only 12% confirming the low level of endemicity in this area. P. vivax
infections were present in 5% of children. Between July 1993 and June 1994 peak
out-patient presentation with Plasmodium falciparum coincided with the rains with
over 50% of cases occurring between August and October whilst P. vivax infections
were predominant during the hot, dry months. Malaria was an important cause of
paediatric admission to the local district hospital with an estimated 4.7% of the
at-risk childhood community warranting intensive clinical management each year.
Case fatality rates were high and the clinical spectrum of severe disease
indicated a preponderance of cerebral malaria cases. In addition, respiratory
distress was a feature in 12% of the malaria admissions. The suggestion that the
coexistence of Plasmodium falciparum and Plasmodium vivax may serve to reduce the
severe clinical consequences of P. falciparum malaria is not supported by these
observations.
PMID- 9557423
TI - T-lymphocytopaenia, opportunistic infections and pathological findings in
Ghanaian AIDS patients and their sexual partners.
AB - Ninety-nine patients at Center for Disease Control (CDC) clinical stage IV were
studied. Twelve (12.12%) of these patients turned out to be HIV seronegative. Ten
out of the 12 HIV negative patients were immunocompetent whereas the other two
had proportional decreases in both CD4+ and CD8+ T-lymphocytes. HIV-1, HIV-2, and
dual infection, were detected in 51.5%, 2%, and 22.2% respectively of clinical
AIDS patients. The other 12.12% of clinical AIDS patients were indeterminate for
HIV antibodies. All HIV positive patients with the exception of two, were
immunocompromised with respect to CD4+ and CD8+ T-lymphocyte counts. Two healthy
spouses and three children of patients who died from the disease were
seronegative for HIV antibodies. Herpes simplex virus type 2 (HSV-2) and
cytomegalovirus (CMV) antibody titres were higher in HIV infected than uninfected
blood. Patients with chronic diarrhoea, lymphadenopathy, pneumonia, and
tuberculosis, either alone or in combination of two or more of such symptoms,
were found to be more likely to be confirmed by serology and immunology as
definitive AIDS patients in Ghana. In postmortem studies on 20 patients,
pneumonia due to tuberculosis constituted the major cause of death.
Toxoplasmosis, cytomegaloviral eosophagitis and enteritis, and cryptococcosis
were the major opportunistic infections detected. Programmed cell death
(apoptosis) was found by the DNA gel electrophoresis method to be an unlikely
major mechanism of accelerated culture induced death of PBMCs from CDC stage IV
AIDS patients.
PMID- 9557424
TI - Duration of symptoms and case fatality of sleeping sickness caused by Trypanosoma
brucei rhodesiense in Tororo, Uganda.
AB - Although there have been recent molecular biological studies for evidence of
possible changes in trypanosome biochemistry, such studies are not yet
complemented by parallel clinical studies to determine the possible implications
to the sleeping sickness patient. The study of the duration of symptoms and the
case fatality of T. b. rhodesiense showed that the disease progressed to the
stage of central nervous system involvement between three weeks to two months of
infection. Most (> 80%) deaths occurred within six months of illness. The case
fatality rate of treated sleeping sickness patients was 6% of which the rate in
the late-stage of sleeping sickness was more than two and a half times that in
the early stage. The incidence of melarsoprol encephalopathy was 2.5% and case
fatality due to this condition was 1.0% and similar to previous findings. Thus it
appears the virulence of T. b. rhodesiense circulating in south east Uganda has
not changed during the past decades.
PMID- 9557425
TI - Perforation of terminal ileum and appendix in typhoid enteritis: report of two
cases.
AB - Two cases of simultaneous typhoid perforation of terminal ileum and appendix are
reported from Harare Central Hospital. These findings have not been reported
before. Perforations were associated with schistosomiasis and HIV/AIDS.
Definitive diagnosis was made only after laparotomy, serology and histopathology.
With early diagnosis, effective resuscitation and timely intervention, this life
threatening condition is not necessarily fatal. Septic shock is however, an
ominous sign of poor prognosis. In the tropics, bradycardia, leukopaenia and
perforation in a febrile patient with right iliac fossa tenderness should arouse
suspicion. Perforations may occur in patients with underlying diseases.
PMID- 9557426
TI - Complications of typhoid perforation of the ileum in children after surgery.
AB - Sixty six consecutive cases of typhoid perforation of the ileum in children
between the ages of four and 14 years were analysed. 62.1% of the children were
boys and 37.9% girls, a boy/girl ratio of 1.6:1.0. Postoperative complications
included: wound infection, gaped wounds, intestinal obstruction secondary to
adhesions, wound dehiscence and pneumonia. The most serious complication was
enterocutaneous fistula and the most frequent was wound infection. These
postoperative complications adversely affected the morbidity and mortality rates
of these severely ill and debilitated patients with typhoid perforation of the
ileum--a serious complication of enteric fever.
PMID- 9557427
TI - Evaluation of the efficacy of thiamine and pyridoxine in the treatment of
symptomatic diabetic peripheral neuropathy.
AB - The clinical response to therapeutic doses of two vitamins were determined in
diabetic patients with symptomatic peripheral neuropathy. Of 200 consecutive
patients, 100 were randomly allocated to treatment with both thiamine (25 mg/day)
and pyridoxine (50 mg/day) group A and the rest group B to treatment with an
identical tablet containing 1 mg/day each of thiamine and pyridoxine. Pain,
numbness, paraesthesia and impairment of sensation and ankle in the legs were
graded into none, mild, moderate or severe. Blood thiamine levels were measured
using HPLC fluorimetry. Four weeks after starting treatment the grade was less
than on the first visit in 88.9%, 82.5% and 89.7% of those whose worst symptoms
were pain, numbness and paraesthesia respectively for group A compared with
11.1%, 40.5% and 39.4% respectively for group B. The severity of signs of
peripheral neuropathy decreased in 48.9% of patients in group A compared with
11.4% in group B. The mean (s.e.) pre-treatment whole blood thiamine levels
decreased with increasing severity of symptoms: 64.2 (2.81), 57.7 (3.25) and 52.2
(2.14) micrograms/l for those with mild, moderate and severe symptoms
respectively (analysis of variance, p = 0.03). Diabetic peripheral neuropathy in
Dar es Salaam is associated with thiamine deficiency. Dietary guidelines for
diabetic patients should emphasize a balanced diet.
PMID- 9557428
TI - Frequency of foetal haemoglobin and haemoglobin values in various haemoglobin
genotypes in Calabar, Nigeria.
AB - The frequency of foetal haemoglobin (HbF) and haemoglobin (Hb) levels were
determined among 108 subjects with different haemoglobin genotypes in Calabar,
between March and October, 1996. Hb-genotype was determined using the cellulose
acetate method, while HbF and Hb were estimated using the modified Betke alkaline
denaturation method and cyanmethaemoglobin techniques respectively. Haemoglobin
genotype SS individuals had the highest mean HbF concentration of (3.05 +/- 1.61)
as compared to AA and AS subjects with means of 0.195 +/- 0.25 and 1.072 +/- 0.98
respectively. This relationship was statistically significant (P < 0.02). On the
other hand, AA subjects had the highest mean haemoglobin concentration (12.79 +/-
1.19) while SS subjects had the lowest (10.65 +/- 2.06). This study has indicated
the persistence of HbF into adult life in this locality. Since HbF is associated
with natural anti-sickling properties, its role as a monitoring factor in the
management of sickle cell anaemia is examined in detail.
PMID- 9557429
TI - Pattern of surgical admissions in Gondar Teaching Hospital, Ethiopia.
AB - A retrospective study based on the principal discharge diagnosis of 4121 surgical
in-patients, who were admitted to Gondar College of Medical Sciences Hospital
over a three year period, is made to document the commonest surgical conditions
prevalent in the north west region of Ethiopia. Intestinal obstruction was the
commonest cause of surgical admission followed by head injury and soft tissue
injury.
PMID- 9557431
TI - Nephrotic syndrome in Nigerian children with homozygous sickle cell disease.
AB - Two hundred and seventy two children with the nephrotic syndrome were seen and
followed up at the Paediatric Renal Unit of the University of Nigeria Teaching
Hospital, Enugu over 12 1/2 year period, between June 1983 and December 1995. Of
these, there were nine (3.3%) children with homozygous sickle cell disease (SS).
This latter group had a mean age of 9.6 +/- 3.2 years, male to female ratio of
1:2 and serum cholesterol of 3.13 +/- 1.48 mmol/l at the time of diagnosis. The
mortality rate was 55.6% in these sicklers, death occurring within one and a half
to five years of diagnosis. Causes of death were attributable to sickle cell
disease in 60%, renal diseases in 20%, and other causes in 20%. Renal biopsy in
two of the sicklers showed membrano-proliferative glomerulonephritis (MPGN) and
focal glomerulosclerosis (FGS) respectively. Homozygous sickle cell disease does
seem to predispose to the development of the nephrotic syndrome and those that do
develop nephrotic syndrome exhibit some special characteristics, when compared to
non-sicklers with nephrotic syndrome. These include older age of onset of the
nephrotic syndrome, reverse sex ratios, lower serum cholesterol, higher mortality
rate and sickle cell complications rather than chronic renal failure as the major
cause of death.
PMID- 9557430
TI - Evaluation and planning in national tuberculosis control programmes: the
usefulness of the standardised patient treatment card.
AB - Through systematic evaluation of information contained in tuberculosis patients
treatment cards, we present an example of a rapid operations evaluation method
for identifying issues important to a national tuberculosis programme (NTP).
Analysis of all 279 treatment cards of patients scheduled to attend one specific
clinic day was made ((Kinondoni district in Dar es Salaam, Tanzania). Two hundred
and twenty five patients (81%) were diagnosed as having pulmonary tuberculosis.
Males accounted for 61% of cases. Ninety two per cent were cases without prior
history of treatment. Of all patients, those under 15 years and those aged 25 to
54 years were more likely to be sputum smear-negative compared with other age
groups. A chest radiograph was obtained as recommended to support the diagnosis
in only 61 (38%) of 160 cases diagnosed as sputum smear-negative pulmonary
tuberculosis. Initial drug dosing based on weight (mg/kg) revealed frequent
dosing errors of isoniazid (97%) and pyrazinamide (65%), almost exclusively
overdosing, in sputum smear-positive patients. Systematic examination of patient
treatment cards provided usefull information and raises issues important to NTP
planning and operations. Weaknesses in the execution of the national programme in
Dar es Salaam were identified: the under-utilisation of chest radiography to
diagnose sputum smear-negative tuberculosis and overdosing of certain drugs.
PMID- 9557432
TI - Aetiological and epidemiological aspects of acute head injury in Malawi.
AB - One hundred and four patients (88 males and 16 females) with acute head injuries
admitted to the Queen Elizabeth Central Hospital, Blantyre from July 1st to
December 31st 1995 were prospectively studied using a questionnaire. Forty seven
(45.2%) of the injuries were caused by road traffic accidents, 42(40.4%) by
assaults, nine (8.7%) resulted from falls from heights, two (1.9%) from
occupational injuries and the remaining four (3.8%) were of miscellaneous
origins. RTA associated head injuries involved 17 (36.2%) pedestrians; 14 (29.8%)
vehicular passengers, 10 (21.3%) pedal cyclists; five (10.6%) drivers and one
motor cyclist. Malawi males aged between 20 and 29 were mostly involved. Assault
related head injuries occurred also in young adult males commonly at the weekend
with more than 50% occurring on Saturday and Sunday. Fifty per cent were
sustained at home, a quarter on the streets and surprisingly few at drinking
houses making them the safest place to be in Malawi to avoid assaults! Alcohol
usage was not statistically significant among those assaulted; it was not
possible to define its aetiological role among assailants. The head injuries
associated with falls from heights (FFH) involved eight males and one female;
five were children. Strategies for the prevention of assaults, the various types
of road traffic accidents and falls from heights are discussed.
PMID- 9557433
TI - Drug induced rhabdomyolysis: case report.
AB - Rhabdomyolysis results from skeletal muscle injury leading to the release of
intracellular contents into blood and urine. Its diverse aetiology includes
severe exercise, muscle trauma or ischaemia, metabolic disorders, infections and
exposure to drugs and toxins. Known risk factors include heredity disorders of
glycogen and lipid metabolism as well as a history of substance abuse. A case of
rhabdomyolysis associated with exposure to opiates and benzodiazepines is
described and the pathogenesis and treatment are reviewed. The rhabdomyolysis was
complicated by acute renal failure; the patient fully recovered. It is suggested
that rhabdomyolysis should be borne in mind in patients presenting with altered
mental status, or fluid and electrolyte abnormalities, in particular, if they
also give a history of substance abuse.
PMID- 9557434
TI - Alcohol-related road traffic accidents.
PMID- 9557435
TI - Drinking and driving in an urban setting in Kenya.
AB - A roadside alcohol prevalence survey of drivers randomly selected from the
general traffic was conducted in Eldoret, Kenya. Blood alcohol concentration
(BAC) data obtained by a breath test in 90% of the sample (n = 479) was analysed
by demographic and travel characteristics. 19.9% had a positive breath test (BAC
> or = 5 mg%), 8.4% had BACs greater than 50 mg%, and 4% exceeded 80 mg%. A
greater proportion of males (20%) had been drinking compared to females (12.5%):
all drivers with high BACs (> or = 50 mg%) were males. The likelihood of having
consumed alcohol was greater in motorists aged 25 years and above (20.4%) than in
younger drivers aged 16-24 years (15.4%), their mean BACs were also more elevated
(57 mg% versus 31 mg%). In comparison to operators of public service vehicles
(PSV), people driving personal cars were more than twice as likely to have been
drinking: with 21.9% being BAC positive against 10.8% (OR = 2.3; 95% CI, 1.0 to
6.3, p = 0.05). Educated individuals with skilled careers tended to indulge in
drink-driving to a greater extent than professional drivers (operators of public
transport, taxi and heavy goods vehicles), with BAC prevalence rates of 23.7% and
15.5%, respectively. Other circumstances influencing the probability of drink
driving were number of vehicle occupants, distance to destination, road location,
time of the night and whether it was a weekend or weekday. These findings are
discussed in relation to the potential for promotion of relevant deterrent
measures, including the establishment of an appropriate BAC legal limit for
drivers in Kenya.
PMID- 9557436
TI - Nutritional status of rural children in the Lesotho Highlands.
AB - A baseline cross-sectional study was done to evaluate the nutritional status of
the population of the Mohale Dam catchment area before construction of the dam
commenced. In this article we report on the anthropometric, clinical and dietary
assessment of the children less than 15 years of age in the study population. A
two stage stratified sampling technique was used to randomly select 29 of the 83
villages in the study area. Children under 15 years of age from 395 households,
representing approximately 50% of households in the selected villages, were
included in the study. Anthropometric measurements of body height and weight in
relation to age and sex indicated undernutrition varying, with few exceptions,
from high to very high levels in children under 15 years. Stunting, indicating
chronic undernutrition, was of particular concern in children, even from the
first year of life. Very few clinical signs of nutritional deficiencies were
found except for a goitre prevalence of 17.5% in 10 to 14 year old children. This
was supported by the very low urinary iodine excretion (median 1.3 micrograms/dL)
which indicated a severe iodine deficiency. Dietary evaluation showed high
initiation rates of breastfeeding as well as a long duration of breastfeeding.
Complementary foods were introduced at an early age, resulting in low exclusive
breastfeeding rates. Regular meals were reported but qualitative analysis of the
diet showed that a too small variety of foods were eaten, with an irregular
intake of protein-rich foods and milk. Quantitative data on 3- < 5-year-old
children showed that micro-nutrient intakes were low and that the energy intake
of these children was inadequate. The results showed that these nutritionally
vulnerable children should be monitored for the impact of the dam construction on
their nutritional status.
PMID- 9557437
TI - Factors influencing completion of treatment among tuberculosis patients in
Mbarara District, Uganda.
AB - An organised TB treatment programme was started in Uganda in 1989. A cohort
analysis of treatment outcome among 1400 patients seen in Mbarara district in
1995 showed a very low compliance rate of 56% and this study attempted to look at
operational factors that may be associated with this low compliance rate. The
factors that are associated with enhanced completion of treatment include; being
smear positive: use of short course chemotherapy; previous TB treatment; if
patient returned for repeat smear; if patient did not change unit; and if patient
did not change district. Gender and age were not associated with compliance. On
unconditional logistic regression, previous TB treatment and being smear positive
were found not to be statistically significant. Change of health unit after
intensive phase showed the highest risk, with an adjusted odds ratio of 22.31. Of
the significant factors only use of standard chemotherapy and change of health
unit after intensive phase can be altered to improve compliance.
PMID- 9557439
TI - Major congenital malformations among neonatal referrals to a Nigerian university
hospital.
AB - Major congenital malformations are unrecognised as a major cause of neonatal
morbidity in many African countries. We have studied the contribution of major
congenital malformations to morbidity among neonates referred to the University
College Hospital, Ibadan, Nigeria over a four year period (1992-1995). Major
congenital malformations were found in 11.1% of 1276 neonatal referrals and
ranked fourth among the most common problems in such neonates (after sepsis,
jaundice and tetanus but ahead of prematurity and perinatal asphyxia). The
commonest malformations seen included spina bifida (22.5%), anorectal
malformation (13.4%), omphalocoele (9.9%) and tracheo-oesophageal fistula (8.5%).
Neonates with major congenital malformations presented significantly earlier than
other neonates but mortality during the first admission was similar in the two
groups. It is concluded that major congenital malformations pose a significant
burden of morbidity in referred neonates to the hospital. Health services
planners should take this into account in order to allocate the necessary
resources for the diagnosis and management of such children.
PMID- 9557438
TI - Exercise-induced bronchospasm: a pilot survey in Nairobi school children.
AB - Exercise-induced bronchospasm (EIB), a common feature of asthma in children, has
been used as the outcome measure in community-based surveys of childhood asthma
to circumvent difficulties arising from relative lack of objectivity in the use
of questionnaires in communities with different cultural and language
orientations. We report here the results of the first community-based study of
childhood asthma in Kenya using EIB as the outcome measurement. The data was
collected in a pilot study to develop methodology for a larger subsequent study.
The survey targeted grade four children in five Nairobi City Council school each
representing a neighbourhood social economic status (SES). Out of 597 eligible,
408 children took part in the study (68% participation rate). EIB defined as
decline in FEV1 of 15% or more, post-exercise was found in 10.5% (95% CI; 10.3,
10.7) of the children studied, the highest rate reported so far in Africa. While
boys were more likely to exhibit EIB compared to girls, the prevalence of EIB
tended to decrease with age, especially among children residing in low SES
neighbourhoods where the EIB prevalence rates tended to be lower compared to
those among children from higher SES neighbourhoods. However, none of these
differences was statistically significant. This study confirms the feasibility of
undertaking exercise challenge tests in the African context and we recommend that
additional studies of similar nature be carried out in other populations of
Africa to explore the potential of using an exercise test as a marker of asthma
in epidemiologic studies.
PMID- 9557441
TI - HLA-antigens in black patients with hepatocellular carcinoma.
AB - To determine whether genetically determined immune response factors could be
involved in the pathogenesis of hepatocellular carcinoma, we performed HLA-A and
HLA-B typing in 55 black patients with histologically-proven hepatocellular
carcinoma, and HLA-DR and HLA-DQ typing in 47 of these patients. The HLA typing
was also carried out in a control group of normal black patients. The HLA typing
was done by a standard microlymphocytotoxicity method. No difference in HLA-A,
HLA-DR and HLA-DQ frequencies between patients and controls were noted. HLA-B21
was present in 10.9% of patients compared to 1.8% of control subjects (corrected
p < 0.005; relative risk = 6.6) and HLA-B49 was present in 7.3% of patients
compared with 1.1% of normal control subjects (corrected p < 0.007; relative risk
= 7.1). These findings suggest that genetic factors may play a role in the
pathogenesis of hepatocellular carcinoma.
PMID- 9557442
TI - Antibiotic resistance of prevalent Salmonella and Shigella strains in northwest
Ethiopia.
AB - Salmonella and Shigella strains were isolated prospectively from in- and
outpatient specimens of the Gondar College teaching hospital over a two year
period, from June 1994 to May 1996. Of 7993 miscellaneous specimens cultured, 80
yielded Salmonella and 147 Shigella. Serogroup B dominated among the salmonella,
accounting for 61% of isolates, followed by S. typhi (21%). S. flexneri (58.5%)
and S. dysenteriae (36.7%) were the most frequently isolated species among the
Shigella. Results of sensitivity testing to five commonly used antibiotics in the
area: ampicillin, chloramphenicol, gentamicin, tetracycline and cotrimoxazole,
showed multiple drug resistance among the isolates of both salmonella and
shigella. Only 4% of shigella were sensitive to all five antibiotics screened for
in the study. Overall sensitive of shigella isolates to individual antibiotics
was 8.8% to tetracycline, 10% to ampicillin, 28% to co-trimoxazole and 98% to
gentamicin. No resistance was observed to nalidixic acid among 108 shigella
strains tested for this antibiotic. The continued sensitivity of S. typhi to
chloramphenicol, cotrimoxazole, ampicillin and the other commonly used
antibiotics is noted. It is recommended that nalidixic acid be introduced into
the area under strict regulation for treatment of severe cases of shigella
dysentery, an illness which is highly endemic in the region and the cause of
occasional epidemics with high mortality.
PMID- 9557440
TI - Cardiac abnormalities in children with malignancies at Kenyatta National
Hospital.
AB - This was a cross-sectional survey in which 80 children with malignancies were
studied at the Kenyatta National Hospital to determine cardiac status before and
during cancer therapy. An equal number of age and sex matched subjects admitted
to the surgical wards for minor procedures was recruited as a comparison group.
All the subjects underwent clinical cardiac assessment. Chest radiographs,
electrocardiograms (ECG), echocardiograms, haemograms and renal function tests
were also performed. Overall, 13 cases (16.3%) had abnormal cardiac findings
compared to 7 (8%) in the comparison group (p = 0.429). Sixteen, two and five
subjects had abnormal velocity of circumferential fibre shortening, ejection
fraction and pericardial effusion respectively. Three out of the five subjects
with pericardial effusion were cancer patients who had not undergone treatment.
Mitral valve prolapse with regurgitation was diagnosed in one cancer patient.
Though not statistically significant, children with malignancies appear to have a
higher frequency of acquired cardiac abnormalities than those without cancers.
Since a larger proportion of the abnormalities occurred in cancer children before
commencement of treatment, the pathology is more likely to have resulted from the
malignancies than therapy. There was no evidence to suggest that cancer treatment
contributed to cardiac morbidity. We recommend that all oncology patients undergo
cardiac evaluation on admission.
PMID- 9557443
TI - Intraleucocyte malaria pigment in asymptomatic and uncomplicated malaria.
AB - While malaria pigment or haemozoin is known to be an end product of haemoglobin
digestion by the malaria parasite, its clinical significance is just beginning to
be elucidated. We have studied the distribution of intraleucocyte malaria pigment
in 92 children, consisting of 32 children with asymptomatic malaria, 32 children
with mild or uncomplicated malaria and 28 children with no malaria. Over 90% of
children in each of the three groups had pigment-containing monocytes and the
numbers of pigment-containing monocytes were not significantly different between
the three groups. While over 90% of children in both the asymptomatic malaria and
uncomplicated malaria groups had pigment-containing neutrophils, 71.4% of the no
malaria group had such neutrophils. The numbers of pigment containing neutrophils
was highest in the uncomplicated malaria group, followed by the asymptomatic
malaria group with the no malaria group having the least numbers. The pigmented
neutrophil: monocyte ratio followed the same pattern. It was concluded that the
number of pigment-containing neutrophils and the pigmented neutrophil:monocyte
ratio may be a marker of the severity of malaria infection when one considers the
conditions: no malaria, asymptomatic malaria and mild malaria. Further work to
verify this hypothesis across the full spectrum of the manifestations of malaria
infection is needed.
PMID- 9557444
TI - Evaluation of two rapid hepatitis B surface antigen detection tests for screening
in a blood bank.
AB - The sensitivity and specificity of two rapid, low cost latex agglutination HBsAg
detection tests were compared to a EIA HBsAg detection test using serum samples
from 371 pregnant women in Kajiado, a rural Kenyan district. The sensitivity of
the latex agglutination tests when compared to the EIA was 70.6% and 61.8%, while
specificity was 92.0% and 85.2% respectively for the same tests. In view of their
low sensitivity these rapid tests are not suitable for screening blood in
district hospitals.
PMID- 9557445
TI - Using epidemiologic tools to control an outbreak of diarrhoea in a textile
factory, Bulawayo, Zimbabwe.
AB - Dysentery is endemic in Zimbabwe. More than 260,000 cases and a case fatality of
four per thousand were reported in 1993. In late July 1994, the Health Services
Department in Bulawayo was informed of two cases of Shigella dysenteriae type I
at a textile factory that employs 138 workers. Workers were interviewed at the
factory regarding the date of the onset of illness, symptoms, food consumed, and
treatment received. Factory water supply, cooking, and sanitary facilities were
inspected. Stool and water samples were obtained for analysis. A case was defined
as an employee presenting with diarrhoea with onset from July 24 to August 25,
1994. Of the 99 workers on day and evening shifts, 75 (75%) were interviewed.
Thirty eight workers met the case definition (Attack Rate 51%). Common symptoms
were abdominal cramps (71%), and blood in stools (37%); median duration of
diarrhoea was 11 days (range 5 to 32 days). Thirty seven (64%) of 58 workers who
drank borehole water were ill compared to one (6%) of the 17 who did not (RR =
10.8, 95% CI = 1.6-73). No food items consumed were significantly associated with
the illness. Two different shigella species (2 sonnei and 2 boydii) were isolated
from five (13%) of 38 stool specimens. Water samples from the two boreholes
yielded numerous faecal coliforms. Neither borehole was registered as required by
the municipal bylaws, which also forbid use of borehole water for drinking. The
epidemiologic and laboratory evidence implicate contaminated borehole water as
the most likely cause of this outbreak. Enforcement of municipal bylaws on
drilling, registration and use of boreholes is essential to avoid further
outbreaks of waterborne diseases.
PMID- 9557446
TI - Serum calcium, phosphate and alkaline phosphate levels in epileptic children
treated with phenobarbitone.
AB - A longitudinal study to estimate the serum calcium, phosphate and alkaline
phosphatase levels of 89 ambulatory epileptic children, aged between 3 years and
12 years, and having generalised tonic-clonic seizures, was carried out. None was
on any form of medication for the treatment of seizures prior to presentation.
Each patient received only phenobarbitone during the period of study. Serum
levels of the biochemical parameters were determined at presentation, 6 months
and 12 months, while serum phenobarbitone levels were estimated at 6 months and
12 months. Mean serum calcium, phosphate and alkaline phosphatase of the patients
remained within the normal range. Using the paired 't' test, the differences in
the levels of the parameters at the three measurements were not statistically
significant (P > 0.05). Serum phenobarbitone levels remained within the
therapeutic range during the period of study. Our results show that over a 12
month period, serum levels of calcium, phosphate, and alkaline phosphatase,
remain normal in ambulant epileptic children treated with phenobarbitone.
PMID- 9557447
TI - Ethnic differences in the severity of varicella in adults in northern Saudi
Arabia.
AB - The severity of varicella infection in 124 expatriates from the Asian continent
was compared to that in 120 Saudi nationals, seen in Arar Central Hospital, Arar,
Saudi Arabia, between January 1992 and December 1994. Persistent fever (defined
as a raised body temperature more than 37.4 degrees C lasting more than 5 days),
extensive skin eruptions (defined as extensive, when more than 50% of the body
surface was affected) and transient elevation of hepatic enzymes (aspartate
transaminases > 37 U/L and alanine transaminases > 40 U/L) after excluding other
possible causes, occurred significantly more in expatriates than in Saudis. The
mean duration of the illness in expatriates was 15.9 +/- 3.41 days as compared to
a mean duration of 13.1 +/- 3.52 days in Saudis. This difference was
statistically significant (p < 0.01 Student's t-test). The findings in this study
suggest that varicella infection runs a more severe course in expatriates from
the Asian continent as compared to the Saudis. Treatment with the antiviral agent
acyclovir may be indicated in this group of expatriates with varicella infection.
PMID- 9557448
TI - Secondary bacterial infection in Ghanaian patients with scabies.
AB - From 110 patients with secondarily infected scabies lesions, 105 bacteria
consisting of 66 aerobes and 39 anaerobes were isolated. A mixture of aerobic and
anaerobic bacteria was present in 15 (13.6%). The predominant aerobic and
anaerobic bacteria were staphylococcous aureus 39.1% and pepostreptococcus spp.
14.2% respectively. Organisms that resided in the mucus membranes close to or in
contact with the lesions predominated in those infections. Most organisms were
recovered from the finger and buttock lesions. These organisms were mainly staph.
aureus, beta-haemolytic streptococci group. A and peptostreptococcus. More than
80% of staph. aureus isolated were resistant to penicillin. Less than 20% of the
anaerobes were resistant to penicillin. The enteric Gram-negative, E. coli and
Klebsiella spp. showed 100% sensitivity to Amoxycilin/clavulanic acid and
gentamicin. Pseudomonas spp. were only susceptible to gentamicin,
Amoxycillin/clavulanic acid proved to be the most active therapeutic agent in in
vitro against the isolated microorganisms.
PMID- 9557449
TI - Haematological changes in human immunodeficiency virus infection. Part I: Review
article.
AB - This review attempts to put together the changes in the blood and bone marrow
observed in those who are infected with human immunodeficiency virus (HIV). These
are contribution of many published and unpublished data and experience on; blood
counts, blood film and bone marrow films prepared and stained by MayGrunwald
Giemsa or Leishman stain. Some changes in haemostasis are also included. The
salient changes are cytopaenias; leucopaenia, anaemia, thrombocytopaenia, and
bone marrow hypoplasia, although the latter occurs, it is found in a minority of
cases. Other changes include myelodysplasia, functionally defective cells, and
enhanced bleeding tendency particularly in those with bleeding defects. There are
also malignancies associated with HIV infection such as Kaposi's Sarcoma and
malignant lymphomas. The pathogenesis of these events are multi-factorial, varied
and involve; killing of cells by the virus, syncytial formation by the cells,
destruction of the stem cells, immune and drugs effects. These mechanisms are
modified by factors of viral, host environment and their interactions. Changes
are commonly found in patients with acquired immunodeficiency syndrome (AIDS) but
can be seen in some cases anytime during the course of the disease. Once
developed the changes are progressive. The management of these complications
remain individualised and symptomatic. Treatment trials with the haematopoesis
growth factors, particularly colony stimulating factors are producing some
encouraging results. However other cytokines, for example, interleukin-6 may be
having untoward effect such as association with the causation of Kaposi's sarcoma
and the malignant non-Hodgkin's lymphomas. While standard approaches to the
management of the malignancies tend to be the practice, adjustments are usually
necessary in most patients.
PMID- 9557450
TI - Haematological changes in human immunodeficiency virus infection. Part II.
AB - This second part of the review looks at change seen in the bone marrow
haemostasis and malignancies found in HIV infection. Examination of bone marrow
is requested in the presence of cytopaenias, splenomegaly, lymphomas and
myelodysplasia. The findings include marrow hypocellularity, myelodysplasia and
poor marrow recovery. Dysmegakaryocytpoiesis is found in 88% while
dyserythropoeisis in 83% of cases. Mechanisms leading to these pertubations
include direct HIV effect on marrow progenitor cells, effect of drugs and other
infective diseases. Altered levels and functions of growth modifies IL6 and G-CSF
are also to contribute. Haemostatic disorder frequently noted is bleeding due to
thrombocytopaenia. Non-Hodgkin's lymphomas with aggressive characteristics and
Kaposi's sarcoma are the commonly associated malignancies. Currently IL6 is being
linked with the causation of KS and NHL. While standard approaches to the
management of these malignancies tend to be the practices, adjustments are
usually necessary in most patients.
PMID- 9557451
TI - Renal glycosuria treated as diabetes mellitus: case report.
AB - A case of renal glycosuria is reported. A 55 year old female was diagnosed and
treated in an upcountry hospital for diabetes mellitus. She developed symptoms of
hypoglycaemia while on an oral hypoglycaemic agent, leading to her admission in
Mulago Hospital. Persistent glycosuria was noted despite treatment and normal
serum glucose. Oral glucose tolerance test and timed urine glucose showed a
normal curve but high urine sugar. A diagnosis of renal glycosuria was made, oral
hypoglycaemic therapy was stopped, patient improved and was discharged. Though
renal glycosuria is a benign condition, mistaken diagnosis for diabetes mellitus
puts patients at risk of hypoglycaemia due to treatment. Diagnosis of the
condition requires physicians' awareness of its existence in our community and
the use of Marbles' criteria obviates confusion with diabetes mellitus though it
does not absolutely exclude Fanconi syndrome.
PMID- 9557452
TI - Sexual abuse of minors: emerging medical and social problem in Malawi.
AB - Sexual abuse is one of the most dehumanising human offenses. There has been an
increasing public concern and outcry regarding the escalating wave of sexual
abuse of young girls in Malawi, in the recent past. Four young girls, aged
between two and seven years who were sexually abused by adult males aged between
20 and 70 years seen and managed in the department within the past two years, are
presented to illustrate the problem. Their physical injuries, varied reactions
and those of their immediate families to the abuse; possible predisposing factors
to the abuses; the related medical, psychosocial as well as legal management of
such incidents, in the light of limited public awareness, and lack of adequately
and appropriately trained personnel and facilities in Malawi are discussed. With
the scare of AIDS and an increasing disintegration of the traditional family
fabric, there is a high potential for an increase, not only of the prevalence of
sexual abuse of minors in Malawi, but also the variety and severity of sequelae.
It is therefore recommended that there is need to create public awareness about
sexual abuse, train and equip the relevant personnel to appropriately manage such
cases, as well as enact and enforce the relevant legal provisions, so as to curb
the menace, for the well-being of the society.
PMID- 9557453
TI - Recurrent cutaneous necrotizing vasculitis in a patient with Kikuchi's disease:
case report.
AB - Kikuchi's disease or histiocytic necrotizing lymphadenitis without granulocytic
infilteration, is a clinico-pathologic entity well described in developed
countries. We report a case of this disorder presenting with recurrent cutaneous
necrotizing vasculitis, with the dual objective of highlighting this condition in
developing countries and presenting an uncommon manifestation of this disorder.
PMID- 9557454
TI - [Video laparoscopic surgery and rectal prolapse. Our experience in rectopexy].
AB - BACKGROUND: Laparoscopy is gaining an important role in the treatment of benign
colorectal disorders. The aim of this study is the evaluation of clinical and
functional results in 4 patients submitted to a laparoscopy rectopexy according
to Wells. METHODS: Four females (22-76, mean 53.7 years) affected from a total
rectal prolapse with fecal incontinence underwent this procedure from 1993
through 1995. Six months after surgery, at the end of a rehabilitation program
consisting of kinesitherapy, bio-feedback and electrostimulations, all patients
have been re-evaluated by means of a clinical exam, anorectal manometry,
defecography. RESULTS AND CONCLUSIONS: Preliminary results seem satisfactory and
may allow to prefer this approach instead of the traditional open one.
PMID- 9557455
TI - [The laparoscopic approach to the polycystic liver and adnexal cysts].
AB - Having re-examined the nosographic data acquired on the subject of hepatic
polycystosis and uterine adnexal cysts, the authors report the results of their
experience. On the basis of the evaluation of these results (no laparotomic
conversion, no postoperative complications, reduced hospital stay), which are
comparable to those reported in the literature, the authors conclude that the
modern technology may be used to advantage in all cases where laparoscopic
surgery is not difficult, does not require numerous tests and does not entail a
high risk of complications.
PMID- 9557456
TI - Does cholecystectomy always resolve biliary disease?
AB - OBJECTIVE: To evaluate long-term effects of cholecystectomy on typical gallstone
symptoms and associated digestive syndrome. DESIGN: Clinical prospective study on
selected patients. SETTING: First Surgical Clinic--Catania University. SUBJECTS:
143 gallstone patients, divided in highly symptomatic Group 1 (79) and mild
symptomatic Group 2 (64), who underwent cholecystectomy during period 1991/92.
MAIN OUTCOME MEASURES: 125/143 patients compiled a set questionnaire to detect
any subjective postoperative disorders and to evaluate whether they were similar
to preoperative symptoms or were new ones. RESULTS: 125/143 patients completed
the 12-month follow-up programme, which revealed a 30% (38/125) with
postcholecystectomy symptoms and 13.4% (17) with a postcholecystectomy syndrome.
Moreover, 10% (13) of the patients reported the same digestive symptoms as before
treatment. Statistical analysis confirmed that cholecystectomy was efficacious in
curing gallstone related symptoms and digestive disorders in both Groups with a
general improvement in clinical picture (p > 0.01). No significant statistical
difference in the incidence of postcholecystectomy dyspeptic symptoms was found
between the 2 Groups. CONCLUSION: Cholecystectomy is often efficacious in curing
both typical gallstone related symptoms and digestive syndrome. Cholecystectomy
patterns of failure in curing digestive disorders is unpredictable preoperatively
on the basis of clinical features of the disease.
PMID- 9557457
TI - [Ventrolateral hernias of the abdominal wall. The anatomicopathologic, clinical
and therapeutic considerations].
AB - Ventral lateral hernias of the abdominal wall are rare. On the basis of their
location we can classify them as follows: hernias of the aponeurosis of the
transversus muscle, hernias of the rectal sheath and transmuscular hernias of the
iliac region. In a group of 3134 hernias of the abdominal wall observed in a
period of 16 years, 11 ventral lateral hernias have been encountered (0.3%). The
diagnosis often presents great difficulties as the symptoms and the clinical
findings are not typical. They must be differentiated from hematomas of the
rectus sheath, abscess or intra-abdominal processes. Echography and Computed
Tomography have an important role in their detection. Nevertheless in some
patients the true diagnosis is reached only intraoperatively. The treatment
generally consists in surgical correction by layer closure of the fascial or
muscular defect. In selected cases the use of prosthetic material and video
laparoscopic repair are indicated.
PMID- 9557458
TI - [Benign ulcers of the cecum].
AB - Benign ulceration of the cecum is an uncommon lesion that was originally
described by Cruveilhier in 1832. Etiology is unknown and symptomatology not
pathognomonic. Pre-operative and intraoperative diagnosis is rare and difficult.
Definitive diagnosis is usually obtained by histologic evaluation of the surgical
specimen after a right hemicolectomy performed for a suspect of a neoplasm of the
cecum. The authors present 7 cases of cecal ulcers and suggest that preoperative
diagnosis may be due after a colonoscopy with biopsy. This examination may be
performed only in that cases that appear without symptoms of acute abdomen. The
authors suggest also to perform right hemicolectomy.
PMID- 9557459
TI - [Current trends in in the treatment of spontaneous pneumothorax].
AB - In agreement with a number of published reports we state that video thoracoscopy
is the best means for pnx classification (Vanderschueren RJA) and for the choice
of its treatment. Video thoracoscopy and recent innovations in video-assisted
thoracic surgery (VATS), together produce a significant improvement in the
results. Between February 1992 and September 1994, we treated 143 pnx in 133
patients, 118 males, mean age 34 years (range 14-82); 5 of which undergoing a
bilateral treatment and another 5 having to undergo a retreatment. On the basis
of the endoscopic classification (Vanderschueren RJA), 26.1% of the cases fell
into category I and 67.4% into the higher category, 6.5% presented enlarged
bullous emphysema (GBE). Twenty-seven patients (20.3%), classified as category I
at the first appearance of pnx, were treated by means of a chest tube
thoracostomy. The remaining patients underwent surgical treatment: 106 treatments
by VATS (74.1%) and 10 (7%) by an axillary thoracotomy. By VATS we performed: 77
ligature/resections of bullous lesions, 9 resections of pulmonary apex, 9
adhesiolysis, 7 GBE treatment by the "spaghetti technique", 2 coagulations of
blebs, 1 suture and 1 parenchymal laceration repair by clips. No patients treated
by a chest tube thoracostomy or who underwent thoracotomy presented recurrence at
the follow-up (mean 33 months, range 15-46). We had a single complication (0.9%),
2 treatment conversions (1.9%) and in 3 patients (2.8%) a thoracotomy was
necessary four days later. In thoracotomy we performed 5 resections of bullous
lesions and 2 "capitonages" were effected in those patients treated in the first
instance; 2 parenchyma tear repairs and 1 lobectomy in those patients treated
after the failure of VATS.
PMID- 9557460
TI - [Meckel's diverticulum in childhood. The authors' own experience].
AB - Meckel's diverticulum occurs in approximately 2 percent of the population and may
present at any age. Although Meckel's diverticulum may produce an intestinal
obstruction or perforation, simulating an appendicitis, hemorrhage is its most
important clinical presentation. From 1989 to 1994, Meckel's diverticulum was
discovered in ten children at laparotomy. Three cases were asymptomatic,
representing an incidental finding at laparotomy. Of the seven symptomatic
patients, four presented with bowel obstruction (intussusception), three had
rectal bleeding one of whom had diverticulitis. Contrast studies--in
gastrointestinal hemorrhage--were not helpful in establishing the diagnosis;
colonoscopy and gastroscopy ruled out other causes of bleeding. Five of seven
symptomatic patients had an intestinal resection while two a diverticulectomy
after assessment that the ulcer did not require resection. No postoperative
morbidity and mortality is reported in either groups. A Meckel's diverticulum
found incidentally at laparotomy should be always resected as the risk of
complication is high and that of resection low.
PMID- 9557461
TI - Severe head trauma. Review of the factors influencing the prognosis.
AB - A series of 72 severely head injured patients are reported, 24 (33%) with
surgical intracranial hematomas. All patients were intensively cared for under
the same therapeutic regime; intracranial pressure (ICP) was monitored and
treated if increased. The series mortality was 39%. Uncontrollable increase of
ICP (UI-ICP), always fatal, was observed in 18% of patients and in 13 of 28
deaths (46%); the incidence of UI-ICP among deaths was higher in patients less
than in those more than 40 years old (55% vs 25%). Patients with UI-ICP were
frequently deeply comatose and with arterial hypotension on admission; almost all
died in the first days. Patients directly admitted from the scene with well
staffed Life Flight Helicopter Emergency Care compared with those directly
admitted from the scene with different type of ambulance service (paramedics,
police, firemen and private) had a mortality rate significantly less (20% vs 54%)
and an incidence of UI-ICP strongly lower both among patients (5% vs 29%) and
among deaths (25% vs 54%). Thus in this small series intensive care after
admission was not effective to obtain good results if patients had received poor
preadmission emergency care. Review of the literature on main clinical predictors
of outcome in severe head injury, have made possible some observations. Ischemic
and intracranial hypertension brain lesions were generally present in patients
killed by head trauma; while diffuse axonal injury, frequently responsible for
vegetative, severe disability survival and late deaths, was observed only in 20
30% of postmortem examinations. Old age, poor neurological status and
cardiocirculatory and respiratory disturbances prior to and upon admission
positively worsened the outcome, while intracranial hematomas had a more variable
predictive value. Intracranial hypertension was a definitively ominous predictor
only if very high when the risk to be or become uncontrollable seems to be much
elevated. UI-ICP, often fatal despite any aggressive therapy, was the single most
frequent killer after severe head injury, responsible for about half of all
deaths after admission. The different outcome among severe head injury series
could be conceivably related to a different frequency of UI-ICP. Besides the
severity of head injury and delay and mode of admission, we suggest that
preadmission respiratory and cardiocirculatory and the quality of emergency
medical system could strongly affect the incidence of uncontrollable increase of
ICP in admitted patients and thus the mortality rate and favorable recovery of
the series. The advanced preadmission emergency care service with intensive care
after admission could significantly explain the better results often observed in
severe head injury series.
PMID- 9557462
TI - [Further comment on central venous catheter infections].
AB - Many reports from the surgical literature document the incidence of catheter
related sepsis varies between 1 and 10 per cent. In many instances sepsis is
secondary to contamination from normal saprophyte cutaneous bacteria. In our
Institute we set down a standardized methodology to reduce the contamination of
venous central access from cutaneous bacteria. Of 31 patients studied, none had
bacteria in the last 5 cm of central venous catheter, 2 had streptococcus alpha
haemolytic colonies and coagulase negative staphylococcus colonies at the same
time on skin over the region of venepuncture. With our paper we had attained
one's awareness that it is very difficult to obtain zero per cent in
contamination of central venous catheter, mainly in immunodepressed or critical
patients, but with careful dressing and with new technology it is possible to
reduce the contamination and following sepsis.
PMID- 9557463
TI - [Intraoperative radiotherapy in abdominal-pelvic cancer surgery].
AB - Intraoperative radiotherapy consists in the irradiation of the affected area,
exposed using anesthesiological and laparotomic procedures, following the removal
of a neoplasia using palliative or macroscopically radical surgical. This
increases local tumour control and augments the selectivity of treatment between
healthy and neoplastic tissues, thus obtaining a marked improvement in survival
or palliation. The authors analyse the data reported in international literature
regarding the possible use of intraoperative radiotherapy in patients undergoing
abdomino-pelvic oncological surgery. The aim of the study was to evaluate this
method for use in selected and combined treatment in which surgery represents an
obligatory step. Studies were carried out in a few highly specialised centres
given that special technical, logistic and professional skills were required. The
populations studied were often very small with a marked prevalence of feasibility
studies compared to random studies. In spite of this intraoperative radiotherapy
is undoubtedly indicated in locally advanced gastric, rectal and vesical
neoplasia, it represents a valid palliative solution in pancreatic neoplasia and
in pelvic recidivation, and an effective alternative solution to mutilating
surgery in the initial stages of vesical cancer. Positive results are obtained in
prostate and uterine cancer, but they are reported by non-conclusive studies.
Toxicity is acceptable and non-limiting within a given range of doses and
irradiated volume. The "repercussion" in terms of knowledge, experience,
scientific integration between oncological surgeons and radiotherapists is basic,
with a marked improved in the management of cancer treatment.
PMID- 9557464
TI - [Heredity and colorectal cancer].
AB - The authors underline the role of inheritance in colorectal cancer and reporting
the genealogical study of two families with high incidence of colorectal cancers
personally observed. They thought that the genetic endowment (oncogenes,
suppressor genes, microsatellite instability, protein-kinase C) was implicated
directly in the genesis of disease.
PMID- 9557465
TI - [Diverticula of the right colon. The diagnosis and treatment of complications].
AB - BACKGROUND: Diverticula are localized in the right colon with a rate of 6.7-14%
in Western countries. Two types of diverticula have been described in the right
colon, on the basis of etiologic and pathological features: multiple diverticula
and solitary diverticulum of the caecum. The most common clinical presentation of
the right-sided colonic diverticula is an acute inflammatory complication, which
is difficult to distinguish from other causes of right iliac fossa pain. METHODS:
A survey of the literature is presented and personal experience relative to 4
cases of acute diverticulitis of the right colon observed over a 10-year period
is described. RESULTS: In all the patients the preoperative diagnosis was acute
appendicitis. In two cases the poor clinical conditions of the patients were
associated with the free perforation of a solitary caecal diverticulum and
diffuse faecal peritonitis. A temporary caecostomy was therefore required. In two
cases a localized inflammatory mass was found around a perforated solitary
diverticulum of the caecum. An ileocaecal resection was performed. CONCLUSIONS:
The purpose of this study is to emphasize the epidemiological, etiologic and
clinical features of right-sided colonic diverticula, and the diagnostic and
therapeutic management of their complications.
PMID- 9557466
TI - [Gastric leiomyoblastoma. Its preoperative diagnosis by echo-guided needle
aspiration. A report of 2 clinical cases].
AB - The authors report two cases of gastric leiomyoblastoma, one benign and one
malignant, come to clinical observation for digestive hemorrhage; in both cases a
preoperating diagnosis of benignity or malignity was made and in one case even of
histotype, thanks to fine needle biopsy. After a short introduction regarding
some historical notes, the predictive parameters of malignity, the classification
of this rare myoid tumor, the authors discuss the distribution of the pathology
in the population, the symptomatology, the diagnostic "iter" with particular
regard to the needle biopsy, the surgical treatment, and the indispensable
parameters for formulating a correct prognosis.
PMID- 9557467
TI - [The ingestion of foreign bodies for the purpose of self-injury. The conservative
treatment of 2 clinical cases].
AB - Although not rare, the ingestion of foreign bodies becomes uncommon when it is
done with intent to cause self-damage. When used for this purpose, foreign bodies
usually take the form of liquid substances, such as caustic agents, detergents,
poisons, etc. It is less rare in certain situations like psychiatric and prison
settings. The author reports two cases of foreign bodies voluntarily swallowed by
patients in prison.
PMID- 9557468
TI - [Bilateral adrenal lymphoma. A case report].
AB - A rare case of malignant non-Hodgkin lymphoma of the adrenal gland in a 59-year
old male is reported. This patient, completely healthy, observed for a routine
check after a laparoscopic cholecystectomy performed one year before, underwent
an explorative laparatomy for getting information about a retroperitoneal mass,
ultrasound scan observed. A CT guided needle biopsy was inconclusive to clarify
this rare haematological diagnosis.
PMID- 9557469
TI - [The utility of isolating the recurrent nerve and parathyroids in the prevention
of complications in thyroid surgery. The role of the superior laryngeal nerve and
C cells].
AB - The authors emphasize systematic isolation of the recurrent nerve and of the
parathyroids, to prevent complications in surgery of the thyroid. Moreover they
try to underline the significance of the superior laryngeal nerve and the role of
parafollicular cells (today unknown) for a rational and modern therapy of the non
neoplastic diseases of the thyroid.
PMID- 9557470
TI - [The use of the BAR-Valtrac-type pressure stapler in surgery of the large
intestine].
AB - A total of 148 patients underwent colon resection between June 1993 and November
1994 at the General Surgery Division of Busto Arsizio Hospital; anastomosis was
performed using BAR Valtrac in 58 patients (39%), namely 28 males and 30 women
with a mean age of 66.3 years. Surgery was elective in 90% of cases and in 84% of
patients was secondary to neoplastic pathologies. Recanalisation occurred within
a mean of 5.5 days after surgery, whereas the average hospital stay was 14.4
days. The authors report the absence of mortality and the low morbidity levels
connected to the use of this anastomotic technique. Emphasis is also laid on the
absence of anastomotic stenosis in all endoscopic controls performed to date.
PMID- 9557471
TI - [Pefloxacin versus ceftriaxone in single-dose antibiotic prophylaxis in general
clean-contaminated surgery. The Pefloxacin Study Group].
AB - Single-shot surgical prophylaxis is today used in all clean-contaminated surgery,
because it is able to reduce the incidence of post-surgical infections. The aim
of this clinical trial is to evaluate the efficacy of Pefloxacin 800 mg i.v. slow
infusion in single administration 1-2 hours before surgery versus ceftriaxone 2 g
i.v. 1-2 hours before surgery in 297 patients suffering from clean-contaminated
surgery, especially biliary surgery and gastrectomy. Efficacy of prophylaxis in
259 patients, evaluable according to the protocol, was evaluated in terms of
appearance of post-surgical infections (urinary, respiratory and wound
infections). In the Pefloxacin group (128 patients), no cases of wound infections
were observed, except one case of wound sterile secretion, without dehiscence,
(0.81%), one case of urinary infection (0.81%) and three cases of respiratory
infections (2.34%). In the ceftriaxone group (131 patients), three cases of wound
sterile secretion without dehiscence (2.36%), one case of urinary infections
(0.76%) and four cases of respiratory infections (3.05%) were observed. From this
study we can conclude that single-shot surgical prophylaxis with pefloxacin, drug
with microbiological and pharmacokinetics characteristics suitable for
prophylaxis, is able to prevent postsurgical nosocomial infections as well as
ceftriaxone, considered a reference drug largely used in this indication.
PMID- 9557472
TI - [Echography at "high resolution" in the diagnosis of cervical lymphadenopathies
in follow-up of thyroid carcinoma].
AB - BACKGROUND: In the diagnosis and follow-up of differentiated thyroid cancer (DTC)
patients, a major clinical objective is to differentiate whether the cause of
enlarged neck lymph nodes is either tumorous or inflammatory. High-frequency (7.5
10 MHz) ultrasound examination proved to be highly informative in this regard. An
oval shape of the examined lymph node (longitudinal/anteroposterior diameter
ratio, L/A > 1.5) and a central echogenic hilus indicate a benign
lymphadenopathy. Roundness (L/A < or = 1.5), absence of the central echogenic
hilus and a parenchymatous echogenicity are considered as signs of malignancy.
METHODS: A series of 131 lymph nodes in DTC patients were examined at ultrasound
and, on the basis of round shape (L/A < or = 1.5) in association with either one
or both the other features (absence of central echogenic hilus, homogenous
internal echo), 94 lymph nodes were classified a "malignant" and 37 "benign". The
ultrasonographic diagnosis was evaluated with either cytologic or histologic
diagnosis in all "malignant" nodes and in 7/30 "benign" nodes. In the other 30
"benign" nodes volume shrinkage or lymph node disappearance was observed during
follow-up period. RESULTS: According to the results obtained, the ultrasound
features utilized provided a good diagnostic accuracy (87%) with only 5 false
positive case. CONCLUSIONS: High-frequency sonography, therefore, must be
considered a useful and accurate method for evaluating suspected lymphadenopathy
in DTC patients.
PMID- 9557473
TI - [HIV infection and the endocrine system in children].
AB - HIV infected children characteristically develop a failure to thrive in 25% to
100% of symptomatic cases, with a significantly reduced survival time. The
pathogenic mechanism for HIV-driven failure to thrive is not yet understood.
Likely it is multifactorial, endocrine dysregulation surely plays a major, even
if not yet fully clarified, role in this complication. Global evaluation of
endocrine data could allow to better understand the mechanisms underlying the
failure to thrive in HIV-infected children, also in relationship with the current
manifestations of the HIV infection. The results of the endocrine studies could
also be related with additional features of the children, as their immunological
status. It is well known that endocrine and immune functions are closely related
in animals and in humans. Thus, the evaluation of the results of studies could
provide some interesting information about the relationships between them in the
HIV-infected child. Such relationships, if present, also could help to better
define therapeutic interventions in these children.
PMID- 9557474
TI - [Agenesis of the thyroid lobe associated with Hashimoto's thyroiditis].
AB - A thyroid hemiagenesis in association with Hashimoto's thyroiditis and mild
hypofunction in a 40 years woman, is described. It is an unusual association. The
clinical, hormonal, immunological, instrumental and cytological diagnosis has
been established. The importance of the scintigraphic pattern and the
differential diagnosis with other pathological situations, such as Plummer's
disease and several destroying processes, is emphasized. It is suggested that
thyroid hemiagenesis has not to be regarded as clinically insignificant, in
consideration of a possible association with pathologies of the normally
developed lobe (Graves' disease, myxoedema, goiter, Hashimoto's thyroiditis, and
especially neoplastic degeneration) or with nonthyroid diseases
(hyperparathyroidism).
PMID- 9557475
TI - [Hyperfunctioning thyroid carcinoma. Description of a case].
AB - Differentiated thyroid cancers account for 1% of all neoplasias but only for 2.3%
of thyroid nodules. A particular condition is represented by the association with
hyperthyroidism, which is found in about 7% of cases. Even more rarely may be
themselves cause of thyrotoxicosis. In the present paper, the case of a 66-year
old male patient, bearing a recently appeared goiter, referred to us for
suspicion of lung cancer and hyperthyroid symptoms, is reported. Among
appropriate investigations, the finding of high titer of thyroglobulin in the
aspiration needle and cytology examination suggested that thyroid lesion was
primary and not metastatic, while scintiscan with J-131 isotope showed that
excess of thyroid hormones was just due to it; histological diagnosis was of
papillary carcinoma. As to the pathogenesis of the neoplasma during
hyperthyroidism, a causal role of thyroid stimulating auto-antibodies has been
suggested in the cases associated with Graves' disease, absent in our patient,
which could elicitate cancer progression in the mean time. Interestingly,
activating mutation of thyroid hormone receptor (TSH-r) gene has been
demonstrated in a hyperfunctioning differentiated cancer. Notwithstanding the
unexpected clinical behaviour may appear very rare, molecular biology studies on
aspiration biopsies (FNAB) will allow, in the future, to better define the
neoplastic nature of some hot nodules. In personal opinion, this particular
pathology must be attently searched both for its implications in the prognosis
and therapeutic strategy and because it could be less rare than generally
considered up to now.
PMID- 9557476
TI - Toxic nodular goiter and thymic hyperplasia in an adult. Case report.
PMID- 9557477
TI - [The diagnosis of thyroid nodules].
PMID- 9557478
TI - [Echographic markers of fetal chromosomopathies. Diagnostic possibilities with
transvaginal ultrasonography and our experience].
AB - OBJECTIVE: Aim of this study was to evaluate, during early pregnancy, the
correlation of some anomalies and malformations with fetal chromosomopathies.
EXPERIMENTAL DESIGN: Morphostructural and biometric anomalies in chromosomopathic
fetuses were evaluated. PATIENTS: 1331 pregnancies at high risk for genetic
disease and malformations referred to our center for prenatal diagnosis. METHOD:
Scans were performed using endovaginal convex probes (5.0 to 7.0 MHz). SURVEYS:
Urinary, cardiac and cerebral malformations as well as alterations of bone growth
were evaluated. RESULTS: With respect to the other malformations, cystic hygroma
is more frequently associated with an abnormal fetal karyotype. CONCLUSIONS: The
majority of morphostructural abnormalities diagnosed during first trimester by
transvaginal sonography cannot, in according to personal experience, be used as
markers of chromosomopathies.
PMID- 9557479
TI - [Changes in fetal karyotype in non-immune hydrops fetalis].
AB - BACKGROUND AND METHODS: Among the pregnant patients who underwent an
amniocentesis at our department of prenatal diagnosis (Division of Gynecology and
Obstetrics of the University "Federico II" in Naples) from 1989 to 1996, 16
patients were affected by non-immune hydrops faetalis associated with chromosomal
diseases. RESULTS: The karyotype test revealed at an ultrasound exam of the fetus
that 11 cases were affected by trisomy 21, 4 cases by Turner syndrome and one
case by trisomy 18. This study took into consideration all the pathogenetic
factors and the diagnostic problems of non-immune hydrops faetalis in fetus
affected by associated chromosomal associated anomalies. CONCLUSIONS: Since the
incidence of the chromosomal anomalies on fetus affected by non-immune hydrops
foetal is was very high, there was the necessity to carry out a routine karyotype
test if the ultrasonography revealed anomalies of the hydrops, during the first
three months of pregnancy.
PMID- 9557480
TI - [Early prognostic ultrasonographic indices in pregnancy with fetal cystic
hygroma].
AB - OBJECTIVE: Aim of this study was the correlation of same early ultrasonographic
signs with fetal karyotype, prognosis of pregnancy and neonatal outcome.
EXPERIMENTAL DESIGN: Volume of cystic hygroma and presence of septations are
correlated with fetal karyotype and an ultrasonographic follow-up was carried out
during pregnancy. Details concerning neonatal outcome were recorded at delivery.
PATIENTS: Diagnosis was performed in 13 patients between 8.3 to 16.5 weeks'
gestation referred to our center for prenatal diagnosis or for obstetric reasons.
METHOD: Ultrasonographic examinations were performed using 5.0 and 6.0 MHz
endovaginal convex probes. SURVEYS: Hygroma was diagnosed as a cystic dilatation
in the nuchal region larger than 3 mm in diameter in the anterolateral aspects.
The volume was calculated considering the lesion as spherical and using the
standard formula for an ellipsoid volume; the presence of septations was
considered. RESULTS: A volume greater than 70 cc3 and the presence of septations
demonstrated a strictly correlation with fetal karyotype, evolution of the
features, pregnancy and neonatal outcome. CONCLUSIONS: Prognosis varies depending
on fetal karyotype, volume, presence of septations and other associated
malformations. The volume of the hygroma and the presence of septa are associated
with higher incidence of chromosomal diseases and a poorer fetal prognosis.
PMID- 9557481
TI - [Preliminary diagnostic evaluation of submucosal myoma using operative
hysteroscopy].
AB - BACKGROUND AND AIM: The authors aim to underline the importance of preliminary
diagnostic evaluation in the treatment of submucous leiomyoma using hysteroscopy.
MATERIALS AND METHODS: The study examined 18 patients monitored at the Institute
of Obstetrics and Gynecology of "La Sapienza" University of Rome between January
and December 1995 in whom it was possible to make a correct definition of the
lesion to be treated (number, site, size, etc.) using 3 different diagnostic
methods: hysteroscopy (HS), transvaginal scan (TSV) and transvaginal
echohysterography (TVHS) The authors focused attention on three different
parameters: leiomyoma size, extension (intracavity/intramural portion) and
evaluation of the residual leiomyoma, which are essential for optimal endoscopic
resection. RESULTS: HS enabled the number, size, site, origin, base, submucous
portion and relations with tube operings to be evaluated, but did not allow the
myometrial part of the lesion to be examined. CONCLUSIONS: Integration with TSV,
even if this does not allow a precise definition of the extension, highlights the
size, site, involvement of myometrial structure and relations with the
perimetrium, thus allowing the possibility of evaluating the residual myometrium.
Compared to the above methods, TVHS highlights the effective extension (namely
the submucous/intramural portion) and localization of the neoformation.
PMID- 9557482
TI - [Sexual activity, cardiotocographic findings and time of delivery in physiologic
pregnancy. Survey of a population controlled by ambulatory cardiotocography].
AB - STUDY DESIGN: Out of 720 patients with physiological pregnancy coming weekly to
the cardiotocography service, it was decided to verify if, in comparison with
controls, sexual activity after the 37th week, might make some differences as
regard to duration of pregnancy, incidence of PROM and cesarean section. RESULTS:
Only a small minority was sexually active. From statistical tests it was observed
that sexual intercourse coincided with a greater parity, a lower maternal age, a
greater number of nonstress test with uterine contractions and an average
duration of pregnancy, slightly lower than in controls (38.80 vs 39.76 weeks).
Most of the pregnancies over the 40th week and the greatest incidence of cesarean
sections due to fetal distress were observed in sexually inactive patients. A
sexual activity after the 37th week did not indicate a greater incidence of PROM
CONCLUSIONS: According to personal opinion and provided there is not an obstetric
pathology, there are advantages and not disadvantages from a less prohibitionist
habit concerning sex by the end of the period of pregnancy.
PMID- 9557483
TI - [Delivery at the Institute for Gynecology and Obstetrics of the Messina
University Polyclinic. Comparison of two periods].
AB - BACKGROUND: Delivery methods and current pregnancy monitoring, comparing the last
twenty-years in the light of new medical and diagnostic findings are presented.
METHODS AND RESULTS: Moreover, examining carefully vaginal and laparotomic
delivery it is to be noticed that a more careful wait can increase spontaneous
deliveries, with the due exceptions, so that the rate of cesarean section is
established on current values. CONCLUSIONS: At last it is to be hoped that
maternal mortality and morbility decrease and particularly fetal mortality so as
to guarantee a future devoid of psychophysic handicaps to newborn infants.
PMID- 9557484
TI - Contraception in diabetic women.
AB - There is a very strong need for an effective and reliable method of contraception
in the diabetic woman. An unplanned pregnancy that occurs when her diabetes is
not under good control can have disastrous consequences, ranging from abortion to
a congenitally malformed fetus. The most important factor in the contraceptive
decision for the diabetic patient, especially the IDDM patient, is that the
choice be made not by the clinician alone or the patient alone, but through a
carefully through-out process that involves both patient and physician.
PMID- 9557485
TI - [Simultaneous intrauterine and tubal pregnancy. A clinical case].
AB - The presence at the same time of intrauterine and ectopic (heterotopic) pregnancy
is unusual. A case of acute abdomen by tubaric haemorrage in a patient with
ectopic pregnancy and evolutive intrauterine pregnancy during first trimester is
reported. After surgical therapy, the intrauterine pregnancy had a good
evolution.
PMID- 9557486
TI - [Treatment of endometriosis with GnRH analogues].
AB - BACKGROUND: Since a continuous administration of adequate doses of luteinizing
hormone-releasing hormones (LHRH) or of an agonist leads to a hypogonadism-like
condition, it is possible to use this effect for the treatment of endometriosis.
The present study reports the results obtained in the Gynaecology and Obstetrics
Institute of the Second University of Naples, with a long-acting formulation of a
GnRH analogues (D-Trp6-LHRH) in biodegradable microcapsules, at monthly
intervals. MATERIALS AND METHODS: The study was carried out on 40 women with
endometriosis diagnosed by laparoscopy or laparotomy. The duration of treatment
in patients in stage I-II was of 6 months, in patients in stage III or IV was of
9 months. RESULTS: After 12 months from the end of therapy, 27 patients did not
show any sign of endometriosis with ultrasound and clinical examination; 13
patients still showing endometriosis were from III or IV stage. CONCLUSIONS: This
long-acting formulation should offer a better approach for chronic treatment.
PMID- 9557487
TI - [Evaluation of hemoglobin and hematocrit in pregnant women receiving folate and
iron supplements].
AB - BACKGROUND AND AIMS: From week 8 there is a reduction in hemoglobin and
hematocrit (owing to the increased plasma volume which exceeds the increased
erythrocytic content) that continues to fall steadily until week 16-22,
flattening out at a level of 10-11 g/100 ml for hemoglobin and 32-34% for
hematocrit. Bone marrow produces red blood cells and hemoglobin in proportion to
the increase in plasma volume, provided that there is an adequate iron supply
(higher in pregnancy compared to the usual dietary intake). For this reason, the
authors examined the systematic supplementation of pregnant women with ferrous
gluconate and folic acid, another important element for numerous metabolic
reactions which is also lacking in pregnancy owing to increased requirements.
METHODS: The study showed that pregnant patients receiving folic acid and iron
supplements from week 5 to 40 presented hematocrit readings and hemoglobin levels
from week 12 that were constantly higher compared to the population not receiving
supplements, with statistically significant and highly significant differences
respectively. The few collateral effects observed in a limited group of patients
allow the authors to define the tolerability of the proposed treatment as
"excellent". They emphasise, however, the importance of constant supplementation
with folic acid and iron throughout pregnancy to avoid sideropenic anemia, with
considerable benefits in terms of the physical conditions of the pregnant woman,
the supply of O2 to the villi, fetal wellbeing and the need to resort to possible
blood transfusions in the event of major blood losses at birth.
PMID- 9557488
TI - [Use of arginine in intruterine growth retardation (IUGR). Authors' experience].
AB - BACKGROUND: Asymmetrical intrauterine growth retardation (IUGR) represents a
foetal mechanism, consequent to placental insufficiency, due to many factors:
genetic, vascular, malformative. At present, no therapy is really efficient. The
aim of this study was to evaluate the efficacy, in these pathological conditions,
of the use of L-arginine. This amino-acid improves GH-RH incretion, with
consequent increase of plasmatic GH influencing somatic growth. L-arginine
moreover, is the obligatory precursor for nitric oxide (NO) enzymatic synthesis
(Endothelial-derived relaxing factor). NO helps the prolapse of smooth
musculature and, consequently, the improvement of placental blood circulation.
METHODS: On the basis of the double activity of NO, vasodilatation and GH-RH
induction, 43 pregnant women have been treated suffering from IUGR, diagnosed by
ultrasonic examination an by evaluation of Doppler velocimetry values, from 30th
week of gestation, administering L-arginine (Bioarginina, 6 g per os/day).
Periodically, USG and Doppler velocimetry examinations were performed to evalue
foetal growth and possible increase of peripheral vessels resistance. RESULTS: 32
patients improved the clinical course of pregnancy: 19 recovered the whole
retardation; 9 only one week; 4 had premature delivery after 36 weeks with foetal
weight coincident with gestational age. CONCLUSIONS: The positive results suggest
the prosecution of clinical studies in order to attempt the achievement of an
effective pharmacological treatment of IUGR.
PMID- 9557489
TI - [Mitochondrial DNA and pediatric illness].
PMID- 9557490
TI - [Congenital dysplasia of the hip in children of immigrants from developing
countries].
AB - BACKGROUND: Aim of study was to ascertain the possible presence of congenital
dysplasia of the hip in infants (CDH) in the population immigrated from countries
where the problem is surely neglected from the local health service and estimate
its incidence. Moreover to observe the impact of the CDH problem on the parents
of these children, sometimes of scarce culture or rather of scarce comprehension
of the language. Finally, to verify the answer of parents to the medical
prescriptions and to the not simple therapeutic formality. METHODS: From 1989 to
1996, the hip has been examined by Graf ultrasounds (US) method on a population
of 181 infants born from developing countries' immigrants in Italy; 77 of them
were Egyptians. RESULTS: Even if the density of the population studied was not
very high, the results presented in this paper are innovative and differ from the
literature on this matter. Among the 362 hips examined with US, only 5 hips were
found to be pathologic (4 Egyptians and 1 Philippine; 2 type uD and 3 type IIC of
Graf), and they were treated and recovered with a harm in about 3 months.
CONCLUSIONS: This work underlines the necessity that all immigrated infants
should be studied with US hip exams and that CDH in these people should not be
under-evaluated: the very low occurrence of this pathology in developing
countries is probably mainly due to scarsity of studies on this matter. This
allows not only to avoid hip dislocation in these subjects, but also to the
society to avoid the necessary cost of the subsequent treatment of well more
serious diseases such as osteoarthritis of the hip on dysplastic basis, in
subjects that likely will stay in our country definitely, becoming Italian
citizens to all effects.
PMID- 9557491
TI - [Results of periumbilical approach to hypertrophic pyloric stenosis treatment.
Personal experience].
AB - BACKGROUND: Ramstedt's pyloromyotomy is the universally accepted treatment for
hypertrophic pyloric stenosis. It could be performed through different surgical
approaches: Robertson muscle splitting incision, transverse right transrectal
incision, median longitudinal incision laparoscopic approach and circumumbilical
incision. METHODS: This latter technique was successfully personally utilized for
the treatment of 33 consecutive patients; 29 patient were male and 4 female, age
ranged from 15 to 52 days (median value 32.6 days), previously full term, normal
weighing newborns. In all patients but one, the large pyloric mass bulged through
the incision and the Ramstedt's pyloromyotomy was performed as usual. In one
case, the pyloromyotomy has been done through the incision by holding the large
pylorus firmly beneath the abdominal wall. The operative time has been quite
similar to that obtained with the transverse right incision. The mean
hospitalization period has been of four days. RESULTS: No operative or
postoperative complications were observed. Particularly, despite no antibiotics
were used, no wounds infections occurred. CONCLUSIONS: The esthetic result was
satisfying in all cases after one month follow-up.
PMID- 9557492
TI - Lactose, oligosaccharide and monosaccharide content of milk from mothers
delivering preterm newborns over the first month of lactation.
AB - BACKGROUND: Monosaccharide, lactose and oligosaccharide content of milk from
mothers delivering prematurely (PT milk) was studied to evaluate whether changes
occur during lactation, as observed in milk from mothers delivering at term (T
milk). METHODS: To study a homogeneous population, women having the most common
phenotype (secretory both Lewis and A, B, or H phenotype) were selected. Milk
samples from 26 mothers who delivered between the 27th and 35th week of gestation
were collected at the 4th, 10th, and 30th post-partum days. Monosaccharides,
lactose and oligosaccharides were measured by high-pressure liquid
chromatography. RESULTS: Lactose concentration increased significantly (p < 0.05)
from 52.81 +/- 8.2 g/L on day 4 to 69.24 +/- 9.36 g/L on day 30. During the same
period of time oligosaccharide content decreased significantly (p < 0.05) from
25.61 +/- 5.19 g/L to 15.83 +/- 6.05 g/L. Monosaccharides did not show
statistically significant variations. CONCLUSIONS: Our results indicate that PT
milk contains in addition to lactose, a substantial amount of oligosaccharides
and a lower percentage of monosaccharides. Compared to T milk, in the colostral
phase PT milk presents significantly lower lactose concentration (p < 0.0001); on
the contrary its oligosaccharide content is significantly higher (p < 0.0001).
The physiological role of human milk carbohydrates in view of the peculiar needs
of the preterm newborn is also discussed.
PMID- 9557493
TI - [From atopic dermatitis to asthma].
AB - Atopic dermatitis (AD) is the most common chronic skin disorder in infancy and
childhood and is the main hallmark of atopic constitution. The disease is
multifactorial, and although genetic predisposition is certainly a prerequisite,
a number of environmental factors modulate the phenotypic expression of AD. The
majority of affected children shows IgE sensitisation towards a large variety of
foods and aeroallergens. Since at least 1600, it has been recognized that
patients with AD have a high predisposition to develop asthma. Recent
epidemiological studies show that AD is commonly seen in individuals from
families with a history of asthma. In addition, in population where asthma is
uncommon, AD is also uncommon. The sex distribution of AD and asthma is the same,
with boys affected significantly more often by these two atopic diseases and in
similar proportions. The ETAC project (Early Treatment of the Atopic Child) is a
large multicenter, multi-national, double blind, placebo controlled, randomised
trial. The main objective of the study is to stop the progression from AD to
asthma in young children with AD using early therapeutic intervention with
Cetirizine and the second objective is to investigate the main risk factors for
the onset of asthma. The results of this study indicate that exposure to potent
allergens such as cat or mite significantly increased the risk of sensitisation
to these allergens. Prolonged breast feeding was associated with a lowest
sensitisation rate to cow milk proteins and to egg. Therefore environmental
factors seem to play a crucial role in IgE sensitisation in children with AD.
PMID- 9557494
TI - [Diabetes, hypothyroidism and celiac disease in Down's syndrome. A case report].
AB - It is well known that Down's syndrome patients frequently suffer from immune
system diseases leading to the production of autoantibodies and the onset of
correlated pathologies. These disorders become increasingly frequent as the
patients grow older and the onset of one autoimmune disease often predisposes the
development of others. Autoimmune thyroiditis is the most frequent disorder and
appears to affect 39% of adult patients. Over the past years a number of reports
have been published regarding the coexistence of various autoimmune diseases in
DS patients, but little is still known about the relationship between these
pathologies and celiac disease. In order to contribute to knowledge regarding the
prevalence of this association, the authors report a case of a DS patient who
developed diabetes mellitus, hypothyroidism and celiac disease at different
times. This case provides further confirmation of the association between Down's
syndrome and autoimmune pathologies. The authors feel that follow-up programmes
for DS patients should include an evaluation of thyroid function and antithyroid
antibodies given that the onset of glandular hypofunction may be very subtle.
Furthermore, they should also include tests to assay glycemia, anti-pancreatic
insula and anti-insulin antibodies for diabetes and AGA and EMA for celiac
disease.
PMID- 9557495
TI - [Medical and surgical therapy of familial hypophosphatemic vitamin D resistant
rickets with ambulation disorders].
AB - Three children with familial hypophosphatemic rickets showed, in the untreated
state, active rickets of the metaphyseal areas of long bones. All were treated
with combined phosphate /1-2 g daily by mouth in 4-5 divided doses) and vitamin
D2 therapy for 2-5 years. The radiological appearance of the metaphyses became
practically normal in two, whereas little change took place in the endosteal bone
surface. Bone biopsies demonstrated osteomalacia. Therefore, two subjects were
given phospate (1-2 g daily) and 1-alpha-hydroxyvitamin D (0.25-0.50 microgram
daily) for 2 years; then phosphate (1 g daily) and 1.25 dihydroxyvitamin D (0.25
0.50 microgram daily) combined therapy for 5 years; the third patient had
phosphate (1 g daily) and 1.25 dihydroxyvitamin D (0.25 microgram daily) combined
therapy for 2 years. After therapy with low doses of 1.25 dihydroxyvitamin D, X
rays showed a nearly normal bone aspect, without nephrocalcinosis in all
patients. All subjects were submitted to osteothomies with positive results.
PMID- 9557496
TI - Anaesthetic management of children with type II and III Gaucher disease.
AB - The anaesthetic management of two children with Gaucher disease is described. The
cases were a girl aged 12 and a boy aged 4 who had undergone 13 and 3 anaesthetic
interventions respectively for endoscopic, orthopaedic, general, otolaryngologic
and dental surgical procedures over a total period of 11 years. Anaesthetic
management of these patients can be achieved with various agents and techniques,
but care is needed to identify preoperative end-organ dysfunction and prevent
postoperative respiratory insufficiency. In particular, regional anaesthesia,
when suitable, has certain advantages that have made it a worthwhile alternative
to general anaesthesia.
PMID- 9557497
TI - [A case report of reversible biliary pseudolithiasis caused by ceftriaxone in
childhood: does the problem deserve greater attention?].
AB - The authors report the case of a nine-year-old girl admitted to hospital with
signs of meningeal irritation during the course of hyperpyretic phlogosis of the
upper airways who presented, after 6 days' treatment with CFTX, at a dose of 50
mg/kg/day (1.5 g/day), therefore at the maximum recommended dose for the
antibiotic in question, symptomatic cholecystic "pseudolithiasis" which resolved
two weeks after the suspension of the drug. This case appears to concord with
recent reports of "pseudolithiasis" in childhood that appeared with doses not
regarded as being at risk, and it draws attention to the etiopathogenetic
importance of other factors, including familial recurrence. The authors recommend
a reasonable use of CFTX and the need to be "vigilant" both in relation to the
onset and evolution of the clinical condition described above.
PMID- 9557498
TI - [Volocimetric evaluation of spermatic vessels with echo color doppler in patients
with idiopathic varicocele].
AB - BACKGROUND AND AIMS: There is a high incidence of varicocele or dilatation of the
spermatic vessels associated with reflux in the male population varying,
according to statistics, from 4.5 to 30.7%. Among the numerous hypotheses put
forward to explain infertility in approximately 50% of patients with varicocele,
it has recently been shown that there is an increased concentration of
noradrenalin in the spermatic vessel which might be responsible for chronic
arterial vasoconstriction affecting the gonads, leading to endothelial
hyperplasia and consequent infertility. MATERIALS AND METHODS: In this study the
authors have evaluated the bilateral flow of spermatic arteries at the level of
the scrotum in patients with varicocele and in the healthy (varicocele-free)
population with normal and hypospermatogenesis. RESULTS: In all groups and in the
absence of other major pathologies (including arterial hypertension), no
significant differences were found in systolic peak velocity (SPV) in relation to
the presence or otherwise of varicocele and the degree of reflux. Mean SPV ranged
between 3.5 and 4 cm/sec in patients with hypo- and/or normal zoospermia both in
the varicocele and healthy population. CONCLUSIONS: In line with other authors,
we feel that despite the lack of substantial differences in arterial flow in the
patients examined, it is not possible at present to explore the testicular
microcirculation and possible hypoperfusion using eco color-Doppler, in spite of
the fact that the method shows a high level of diagnostic accuracy in the
diagnosis of phlogistic pathologies and/or twisting of the spermatic cord. New
approaches might be provided through the improved study of the microcirculation
using power Doppler which appears to be more sensitive than eco color-Doppler in
visualizing small intraparenchymal vessels.
PMID- 9557499
TI - [Major renal trauma. Therapeutic approaches and our experience].
AB - METHODS: During a 12-year period, 110 patients with renal blunt trauma have been
observed. Renal exploration was performed in 17 patients (15.45%). Absolute
indications for exploration were bleeding and pulsatile perirenal hematoma and
associated abdominal injuries. Salvage was successful in 76.48% of the kidneys
explored and hemostatic nephrectomy was required in 23.52%. The success rate was
based on early vascular control and reconstructive techniques of renorrhaphy,
partial nephrectomy and coverage with omental pedicle flaps. RESULTS: At follow
up, hypertension occurred in only 3 patients and resolved spontaneously after 3-6
months. CONCLUSIONS: On the basis of personal experience, the conclusion is drawn
in that when renal exploration is required, reconstruction can be successful in a
high percentage of patients.
PMID- 9557500
TI - [Protein and amino acid metabolism in chronic renal failure].
AB - Some degrees of protein deficiency, suggestive of abnormal protein metabolism,
are a well-known feature of chronic renal failure (CRF). Serum albumin
concentration, an index of malnutrition and deranged protein metabolism, is
frequently decreased relatively early in CRF, even in absence of heavy
proteinuria: a more subtle but characteristic abnormality is found in the plasma
profile of amino acids. In addition, there is an accumulation in the plasma and
tissues of many products of protein metabolism; some of these have been
considered as uremic toxins, while others are largely undefined. The origin of
abnormalities in protein metabolism are multifactorial. The defect are caused at
least partly by dietary deficiency, as well as by the inability of the failing
kidney to excrete normal end products of nitrogen and protein metabolism and by
the effect of altered uremic milieu on overall metabolism.
PMID- 9557501
TI - [Unusual development of urothelioma of the upper urinary tract].
AB - A case of extrarenal spreading of transitional cell carcinoma caused by rupture
of ureterohydronephrosis by ureteral transitional cell carcinoma is reported.
Ultrasonography and CT revealed the presence of a severe right
ureterohydronephrosis with large septa and a 2 cm diameter exophytic neoplasia of
the middle ureter. Nephroureterectomy was performed with excision of a perirenal
mass. Histologic examination revealed the presence of transitional cell carcinoma
in the perirenal mass, caused by dissemination after renal rupture. CT and
ultrasonography were not able to differentiate hydronephrosis from pericapsular
spreading because of the extreme disruption of the renal parenchyma.
PMID- 9557502
TI - [Major complications of percutaneous nephrolithotripsy (PCNL). Analysis of our
cases].
AB - The major complications occurred in 140 cases of percutaneous nephrolithotomy,
from March 1988 to December 1996 are studied. They were: 1 important hemorrhage
with secondary nephrectomy, 1 intestinal fistula resolved with parenteral
therapy, 1 hyponatriemic syndrome which required an intraperitoneal drainage and
1 global kidney functional exclusion after 3 months. Etiopathogenesis and
suggestions for prevention are discussed as well as the necessity of adequate
training.
PMID- 9557503
TI - [Mullerian duct cysts. Description of two cases with a minimally invasive
therapeutic approach].
AB - Among cystic lesions of the male pelvis, the mullerian duct cyst represents the
most commonly recognized abnormality. These lesions are midline in location and
should not be confused with the big or cystic utricle because of its different
embryologic development. The cysts are usually small and asymptomatic. Two cases
of big and symptomatic mullerian cysts treated by minimal invasive approach
consisting of aspiration and endoscopic marsupalization are presented.
PMID- 9557504
TI - [Liposarcoma of the spermatic cord].
AB - A case of well differentiated liposarcoma of the spermatic cord in a 80 year old
man is presented. The preoperative diagnosis of spermatic cord liposarcoma is not
easy; however, a careful comparison between clinical and ultrasonographic
findings can lead to diagnostic suspicion. The treatment of choice is the
excision of the liposarcoma associated with orchiectomy and high ligation of the
spermatic cord to reduce the risk of recurrence. Postoperative radiotherapy may
be indicated for poor differentiated liposarcomas.
PMID- 9557505
TI - [Renal multifocal carcinoma with adrenal gland metastasis in a patient previously
treated with radical nephrectomy: what kind of therapy. Review of the
literature].
AB - A case of multiple adrenal metastases due to renal cells carcinoma, associated
with a multifocal simultaneous renal cells carcinoma has been observed in a
female patient previously submitted to radical contralateral nephrectomy for the
same disease. In particular, stress is laid on computerized tomography scan
diagnosis and surgical procedure.
PMID- 9557506
TI - Augmentation ileocystoplasty in a case of eosinophilic cystitis.
AB - Eosinophilic cystitis (EC) is a rare form of bladder inflammation characterized
by massive eosinophilic infiltration of the bladder wall. The most frequent signs
and symptoms are pollakiuria, urgency, macroscopic haematuria and hypogastric
pain: the involvement of the ureters may cause hydronephrosis and renal failure.
Eosinophilia and eosinophiluria are present in 35% and in 50% of the cases
respectively. EC may evolve towards sclerosis up to the anatomoclinical picture
of small retracted bladder, which requires to be differentiated from tubercular
cystitis, interstitial cystitis and cancer. Imaging techniques are not definitely
diagnostic. Diagnosis can be reached only by biopsy with the microscopic
demonstration of eosinofilic infiltration of the whole bladder wall in the early
and acute stages, while fibrosis with poor cellularity predominates in the
chronic stages. Etiology is unknown and the hypothesis of an allergic origin is
unproved even though remissions or recoveries induced by steroidal therapy have
been reported. Surgical therapy of EC, as in our observation, is absolutely
required to correct urgency and incontinence and to prevent renal failure when
the urinary upper tract has been primarily or secondarily involved.
PMID- 9557508
TI - What can be done about Indian medical research?
PMID- 9557507
TI - [Recurrent urinary tract infections. Biological suppositions and clinical
treatment with thymopentin].
AB - BACKGROUND: Urinary tract infections (UTI) are a common usual pathological event.
They relapse often due to the periurethral colonization of microorganisms from
the intestinal bacterial flora. They also constitute an important and
considerable social and clinical problem. The absence of inducing organic
conditions or an infective focus at the base of the pathogenetic mechanism
suggests the existence of alterations of the immune response of the subject.
MATERIALS AND METHODS: In this work we wanted to verify if, in those subjects
with relapsing UTI (more than four events every year) cure with "biological"
response modifiers, particularly "thymopentin", meaningfully reduced the number
of events. RESULTS: The results obtained confirm that for those cases in which
the chemo-antibiotic therapy did not have the expected results, it is rational to
support it with an immune-modulating drug (thymopentin). In fact the post-therapy
reduction of UTI observed during two years of follow-up is statistically
significant when compared to the average of UTI before therapy. CONCLUSIONS: The
"cost-benefits" analysis should prove to be a saving in favour of the use of
thymopentin, taking into consideration the reduction of chemo-antibiotics
consumption and the lower number of working hours lost every year.
PMID- 9557509
TI - Continuous ambulatory peritoneal dialysis in India.
PMID- 9557510
TI - Prevalence of Helicobacter pylori infection in disorders of the upper
gastrointestinal tract in south India.
AB - BACKGROUND: Helicobacter pylori (H. pylori) is the most common human infection.
Though most individuals are asymptomatic, H. pylori plays a key role in the
aetiology of many upper gastrointestinal disorders. The prevalence of duodenal
ulcer in south India is high but there are very few reports regarding the
prevalence of H. pylori infection in various upper gastrointestinal disorders in
south Indians. Therefore, we studied the prevalence of H. pylori infection in
upper gastrointestinal disorders in south Indians. METHODS: Three hundred and
thirty-five patients with various upper gastrointestinal disorders were included
in the study. Seventy-five patients with no gastrointestinal disease based on
symptoms and endoscopy were taken as controls. The H. pylori status was
determined by the urease test, serology and histology and the prevalence compared
between various upper gastrointestinal disorders, with controls and with one
another. RESULTS: The prevalence of H. pylori was high in the patients and
controls. Duodenal ulcer patients had a significantly higher prevalence compared
to controls (p < 0.001) and those with other upper alimentary disorders. There
was no significant difference between patients with other disorders and controls
nor between each other (p > 0.05). CONCLUSION: The prevalence of H. pylori
infection is high in south India. It is closely associated with duodenal ulcer.
More population-based studies are required to evaluate the relationship of H.
pylori with other disorders of the upper gastrointestinal tract.
PMID- 9557511
TI - Iodine deficiency disorders in Car Nicobar (Andaman and Nicobar Islands).
AB - BACKGROUND: The term 'Iodine deficiency disorders' (IDDs) reflects the spectrum
of health effects due to iodine deficiency at all ages. So far, no survey for IDD
has been carried out in the Andaman and Nicobar Islands (A&N). Therefore, we
aimed to determine the status of IDDs at Car Nicobar Island and to assess the
iodine content of salt available for consumption on the island. METHODS: The
study population comprised tribal school children between 7 and 18 years of age
in government schools of Car Nicobar, A&N. Children were selected from each
school by the simple random sampling method using the random number table. The
same sampling method was used for each school till completion of the desired
sample size for that school. Casual urine samples (in screw-capped plastic
bottles for iodine estimation) and blood samples (on No. 3 Whatman filter paper
for TSH estimation) were collected from a randomly selected sub-sample of
students. Salt samples for iodine estimation were collected from 'captains'
(village headman) of each village and the headmasters of the schools and
'canteens' in government retail outlets in the villages. RESULTS: Of the 969
children surveyed, 160 (16.5%) had goitre. The prevalence was significantly more
among females (23.6%) than males (9.7%). Analysis of 105 urine samples showed
that the median urinary iodine excretion level was 7.0 micrograms/dl. The median
TSH values in subjects was 5.7 mU/L. Fifty (82.5%) of the 54 salt samples had
adequate iodine (> or = 15 parts per million). CONCLUSIONS: IDDs pose a mild-to
moderate public health problem in Car Nicobar Island. The supply of iodized salt
and its iodine content was found to be satisfactory at the time of the study.
PMID- 9557512
TI - Attitudes of medical and nursing students towards blood donation.
AB - BACKGROUND: Data on the attitudes of medical and nursing students towards blood
donation are scanty. Since this group is a potential but under-utilized source of
blood donors, studying their attitudes could provide insights into donor-related
behaviour and, hence have implications for donor recruitment programmes. METHODS:
The attitudes towards blood donation and frequency of donation of 307 medical and
nursing students were studied using a scale to measure affect, behaviour and
cognition. RESULTS: The attitudes were found to be positive in all three scales.
While the behaviour scale significantly discriminated donors from non-donors, no
significant differences were observed in the affect and cognition scales.
CONCLUSION: In a medically-oriented population, donors and non-donors do not
differ significantly in their sentiments towards blood donation. Other social
variables may account for donor behaviour which need to be studied further.
PMID- 9557514
TI - Is a 'lot' necessarily better than a 'little'? Impact of aggressive cardiac
revascularization strategies.
PMID- 9557513
TI - Aspirin: a neuroprotective agent at high doses?
AB - Aspirin, acetylsalicylic acid, is routinely used in clinics as an analgesic,
antipyretic and in the secondary prevention of stroke. These effects are caused
by low doses of the drug (0.3-3.6 g/day) through the inhibition of cyclo
oxygenase, the enzyme responsible for prostaglandin synthesis. Higher doses of
aspirin (4-6 g/day) are used in the treatment of inflammatory conditions such as
rheumatoid arthritis and recent laboratory findings suggest that it could play a
role in neuroprotection against glutamate excitotoxicity. This article reviews
the possible mechanisms of action of high-dose aspirin in neuroprotection.
PMID- 9557515
TI - Autologous bone marrow transplantation in chronic myeloid leukaemia.
PMID- 9557516
TI - Cost-effectiveness of cardiovascular screening and intervention programmes.
PMID- 9557517
TI - Teaching research methodology to postgraduates: is dissertation the only method?
PMID- 9557518
TI - MD/MS dissertations--the case in favour.
PMID- 9557519
TI - Does India perform medical research in areas where it is most needed?
AB - This paper attempts to map medical research in India and answer an important
policy question by literature analysis. I match the disease pattern on the basis
of mortality and morbidity statistics with journals used by Indian medical
researchers to publish their work as shown by the Science Citation Index (SCI).
The former reflects the needs while the latter reflects the areas in which
research is being done. The limited statistics available from both the Government
of India and the World Health Organization point to diarrhoeal diseases, diseases
of children, respiratory diseases, circulatory system diseases, infectious
diseases, malaria and tuberculosis as the major medical problems faced by India.
The journals used often by Indian medical researchers to publish their work, as
seen from the SCI (1981-85), show that in terms of number of publications, they
are mainly active in general medicine, pharmacology, tropical medicine,
neurosciences, radiology, oncology and pathology. In terms of the share of the
world's literature in different subfields, India is second only to USA in
andrology, third in tropical medicine after the USA and the UK, tenth in hygiene
and public health, and eleventh in general and internal medicine, and radiology
and nuclear medicine. Overall, India's share in the medical journal literature is
not only much less than that of many other countries, both advanced and middle
level, but also much less than that of India's share of the literature in
physics, chemistry, mathematics and engineering. Data on the observed citation
impact of Indian research in different subfields of medicine show that the work
done in India in general is not integrated well into international research.
India could be much more purposive in her research priorities and probably should
invest much more in medical research.
PMID- 9557520
TI - New government--new start for health?
PMID- 9557521
TI - Monsoon delights.
PMID- 9557522
TI - An intradermal vaccine protocol against hepatitis B in a haemodialysis
population.
PMID- 9557523
TI - Distribution of vascular lesions in ischaemic stroke.
PMID- 9557524
TI - Quality of life in cancer: the emerging arbiter.
PMID- 9557525
TI - Supplementary feeding component of the ICDS for expectant women.
PMID- 9557526
TI - New criteria for liver transplantation in adults: the combined Groningen and
Rotterdam protocol.
AB - A combined protocol for liver transplantation has been written by the teams of
Groningen and Rotterdam. This is to ensure that the criteria for selection and
timing of liver transplantation, and the procedures for patient evaluation, are
identical or at least very similar. Also, the waiting list procedures in the two
centres, including the criteria used to decide which patient will be transplanted
first, are very similar. Currently, most patients with liver cirrhosis or
filminant liver failure should be considered as liver transplant candidates
unless a contraindication is found. Most contraindications are relative and are
the subject of a careful balance of pros and cons. The detection and care of
liver patients starts with the general practitioner. Referral to liver
transplantation centres is the final step. In the Netherlands, liver disease is
relatively rare and therefore patients are best served when the expertise is
concentrated in a few liver centres.
PMID- 9557527
TI - The effect of renal transplantation on hyperhomocysteinaemia in dialysis
patients, and the estimation of renal homocysteine extraction in patients with
normal renal function.
AB - BACKGROUND: The pathophysiology of hyperhomocysteinaemia in chronic renal failure
(CRF) is unknown. Possible mechanisms are decreased renal homocysteine (Hcy)
catabolism or inhibition of extrarenal Hcy metabolism by uraemic toxins. METHODS:
We studied the short-term effect on plasma Hcy concentration of improvement of
renal function after successful kidney transplantation (n = 8), and determined
renal Hcy extraction by measurement of total Hcy in arterial and renal venous
blood in 7 cardiac patients with normal renal function. RESULTS: Post
transplantation, plasma Hcy decreased with improving renal function. In the
cardiac patients, no significant renal Hcy extraction could be demonstrated, but
tubular disposal of the filtered load could not be excluded. CONCLUSIONS: Because
loss of such renal metabolism could lead to hyperhomocysteinaemia in CRF, it is
necessary to determine the renal extraction of free Hcy in subjects with normal
renal function to further investigate renal homocysteine metabolism.
PMID- 9557528
TI - Pretreatment serum LDH as additional staging parameter in small-cell lung
carcinoma.
AB - BACKGROUND: In patients with limited disease staged small-cell lung cancer
(SCLC), overall survival is still poor. Therefore, a retrospective study was
carried out of 48 patients with limited disease staged SCLC to select a parameter
which can identify prognostic subgroups at the time of diagnosis. MATERIALS AND
METHODS: Follow-up varied from 3 to 96 months during which 38 patients died.
Based on clinical outcome, patients were clustered into three groups: complete
remission (CR) (n = 16); local recurrence (LOC) (n = 7); and distant recurrence
(DIS) (n = 25). Age, gender and pretreatment biochemical parameters were
correlated with clinical outcome and survival. RESULTS: No differences in
survival were found in patients with LOC (14% 2-year survival) and DIS (16% 2
year survival) (P = 0.67). Patients with complete remission demonstrated a
significantly better survival (75% 2-year survival). LDH was found to be the only
significant correlate of both tumour progression and survival. All patients with
pretreatment LDH levels > 240 IU/l (n = 13) demonstrated tumour recurrence. The
survival rate of patients with LDH levels < 240 IU/l (41% 2-year survival) was
much better than that of patients with LDH levels > 240 IU/l (8% 2-year survival)
(P = 0.0001). CONCLUSION: LDH may be used for the identification of prognostic
subgroups in limited disease SCLC. Patients showing pretreatment LDH levels > 240
IU/l have an extremely high risk of tumour recurrence, whereas survival is poor.
In patients with LDH levels, < 240 IU/l survival is significantly better.
PMID- 9557529
TI - Aortic graft infection by Lactobacillus casei: a case report.
AB - A 65-year-old man with an abdominal aortic endoprosthesis presented with fever
without other symptoms. Investigations revealed Lactobacillus casei bacteraemia.
The Lactobacillus graft infection was at first successfully treated by antibiotic
therapy. However, during follow-up a relapse occurred, and after surgical
replacement of the graft the patient was cured. At surgery an aortoenteric
fistula was found as source of the infection.
PMID- 9557530
TI - Primary thyroid lymphoma.
AB - A 71-year-old woman presented with a rapidly growing goitre which was diagnosed
as chronic autoimmune thyroiditis. Despite treatment with levothyroxine, she
developed progressive airway obstruction. Biopsy revealed a primary thyroid
lymphoma which was successfully treated with radiotherapy.
PMID- 9557532
TI - Depression and myocardial infarction: implications for medical prognosis and
options for treatment.
AB - Mental depression and myocardial infarction (MI) are closely related. The current
paper reviews pathophysiological mechanisms that could link depression to MI and
discusses the pros and cons of different pharmacological and non-pharmacological
treatment modalities that could be considered. The selective serotonin reuptake
inhibitors lack arrhythmogenic effects, and have a beneficial effect in addition
to depression on psychological factors, such as anxiety and mood disturbances,
which are not uncommon in post-MI patients. Studies to further determine the
impact of depression on the outcome of MI, and the place of different treatment
modalities are in progress.
PMID- 9557531
TI - Hypereosinophilic syndrome presenting with diarrhoea and anaemia in a patient
with systemic lupus erythematosus.
AB - We describe a patient with quiet systemic lupus erythematosus who developed a
hypereosinophilic syndrome. The patient presented with gastrointestinal
eosinophilia which caused diarrhoea, malabsorption and anaemia due to
deficiencies of vitamins. The hypereosiniphilic syndrome completely resolved
after treatment with prednisone.
PMID- 9557533
TI - Modulatory role of protein tyrosine kinase activation in the receptor-induced
contractions of the bovine cerebral artery.
AB - Changes in contractile force were measured during isometric contraction of the
bovine middle cerebral artery caused by stimulation of various receptors and by
application of high K+, caffeine, and protein kinase C (PKC)-activators. The
protein tyrosine kinase (PTK)-inhibitors, such as genistein and tyrphostin, were
applied before testing the effect on the contractions or during the maximal
plateau of the contraction. The contractions induced by serotonin, prostaglandin
F2 alpha, endothelin-1, and thromboxane A2 were significantly and dose
dependently depressed by the PTK-inhibitors (IC50 2-15 microM). In contrast,
contractions were significantly augmented by 1 microM pervanadate, an inhibitor
of phosphoprotein tyrosine phosphatase. Lineweaver-Burk plotting of the dose
response curves with an increase in inhibitor concentration indicated that the
receptor affinity for each agonist remained unchanged in spite of marked
depression of the responses. Although the effect was not significant,
contractions induced by both high K+ and caffeine were also depressed slightly by
PTK-inhibitors in the same range of concentrations used for receptor-induced
contractions. Contractions induced by PKC-activators, such as 1-oleoyl-2-acetyl
sn-glycerol and phorbol-12,13-diacetate, were significantly depressed by PTK
inhibitors at concentrations similar to those used for receptor-induced
contractions. The results suggest that receptor stimulations which produce
sequential activation of phospholipase C and PKC can activate PTK and trigger the
so-called "PTK-cascade" causing a sustained or long-lasting contraction similar
to the cerebral vasospasm observed clinically.
PMID- 9557534
TI - Roentgenological study of the sagittal diameter of the cervical spinal canal in
normal adult Japanese.
AB - The sagittal diameter of the cervical spinal canal on roentgenograms in normal
adult Japanese aged 15 years or over, 505 males and 492 females, was investigated
to define the normal distribution and lower limit. Lateral roentgenograms of
cervical spinal canals were taken at a constant focus-film distance of 1.5 m. The
mean +/- SD magnification coefficient was 1.17 +/- 0.02. The mean +/- SD sagittal
diameters of the cervical spinal canals at each vertebral level were: C-1, 21.0
+/- 2.2 mm; C-2, 18.0 +/- 1.7 mm; C-3, 15.8 +/- 1.5 mm; C-4, 15.2 +/- 1.5 mm; C
5, 15.3 +/- 1.5 mm; C-6, 15.7 +/- 1.5 mm; and C-7, 15.9 +/- 1.4 mm. The lowest
mean -2 SD values were: C-1, 16.6 mm; C-2, 14.6 mm; C-3: 12.8 mm; C-4, 12.2 mm; C
5, 12.3 mm; C-6, 12.7 mm; and C-7, 13.1 mm. The smallest diameter was at the C-4
level, but there was no significant difference between values at the C-4 and C-5
levels. Males had significantly larger diameters than females (mean difference
0.8 mm) (p < 0.01). Younger subjects had greater diameters than older subjects.
The incidence of spondylotic changes was 40.1% in subjects aged 50-59 years,
57.7% in those aged 60-69 years, and 76.6% in those aged 70-79 years. Males had a
higher incidence than females. Ossification of the posterior longitudinal
ligament was observed in 2.1% of all subjects. This study suggests that patients
with a sagittal diameter in the cervical spinal canal of less than 12 mm have a
high risk of cervical myelopathy.
PMID- 9557535
TI - Third ventricular neuroepithelial cyst originating from the massa intermedia-
case report.
AB - A 47-year-old female presented with a 3-year history of progressive emotional
disturbance. Computed tomography and magnetic resonance imaging revealed a cyst
in the third ventricle causing hydrocephalus. Endoscopic surgery found the cyst
originated at the massa intermedia. Histological examination confirmed the
diagnosis of neuroepithelial cyst. Neuroepithelial cyst originating from the
massa intermedia may be due to persistence of neuroepithelial crest at this
location.
PMID- 9557536
TI - Autopsy findings in a long-term survivor with glioblastoma multiforme--case
report.
AB - Autopsy detected no tumor tissues in a patient who died 6.5 years after the
diagnosis of glioblastoma multiforme. A 54-year-old male developed left
hemiparesis one month prior to admission. Computed tomography demonstrated a
cystic lesion in the right frontal region with irregular ring-like enhancement.
The tumor was extensively removed together with the surrounding tissue followed
by irradiation (whole brain 32.4 Gy, local 28.8 Gy), and intravenous
administration of interferon-beta. Histological examination confirmed the
diagnosis of glioblastoma multiforme. He died of accidental head trauma 6.5 years
after surgery. Autopsy of the brain detected no evidence of glioblastoma
multiforme. The only findings were cerebral edema and hematoma caused by head
trauma, as well as histological changes due to radiation damage. This case
apparently confirms the histological disappearance of tumor tissue in a long-term
survivor with glioblastoma multiforme.
PMID- 9557537
TI - Facial spasm and paroxysmal tinnitus associated with an arachnoid cyst of the
cerebellopontine angle--case report.
AB - A 59-year-old female presented with a 3-year history of hemifacial spasm and
paroxysmal tinnitus associated with an arachnoid cyst of the cerebellopontine
angle, which was identified preoperatively by magnetic resonance imaging.
Surgical decompression of the cyst and arterial decompression of the facial and
acoustic nerves at their root exit zones resulted in complete resolution of the
symptoms.
PMID- 9557538
TI - Magnetic resonance imaging of non-specific inflammatory granulation involving the
skull base--two case reports.
AB - A 55-year-old male presented with a 20-day history of nuchal pain and hypoglossal
nerve paresis on the right. T2-weighted magnetic resonance (MR) imaging showed an
isointense lesion with a small hypointense part in the hypoglossal canal and
caudal clivus. A 66-year-old female presented with a long-standing history of
left orbital pain. T2-weighted MR imaging showed a hypointense lesion occupying
the orbital apex which on recurrence became isointense. The histological
diagnosis of both lesions was non-specific inflammatory granulation. The T2
weighted MR imaging appearance of this entity is variable, and can change within
the clinical course of the same lesion.
PMID- 9557539
TI - Usefulness of neuroendoscopy in treating supracollicular arachnoid cysts--case
report.
AB - A 12-year-old girl presented with a supracollicular arachnoid cyst manifesting as
a compressive headache. Neurological examination on admission revealed no deficit
except bilateral papilledema. Stereotactic cyst puncture failed to perforate the
cyst wall. The wall was then punctured using microforceps under neuroendoscopic
guidance, followed by cystoperitoneal shunting. Her headache disappeared
immediately after surgery. Neuroendoscopy is useful in treating a deep-seated
arachnoid cyst.
PMID- 9557540
TI - Surgical correction of trigonocephaly: theoretical basis and operative
procedures.
AB - Trigonocephaly involves premature fusion of both the metopic suture and the
sutures in the skull base. Surgical treatment by opening of the prematurely fused
metopic suture and expansion of the anterior cranial base by creating
"neosutures" was used to treat three children with trigonocephaly. The
combination of lateral canthal advancement and radical forehead remodeling
achieved excellent results. These procedures can also prevent the development of
midface hypoplasia such as hypotelorism. The two younger patients, aged 0 and 6
months, achieved rapid bone growth in the defects and normalization of
intercanthal and interpupillary distances. The older patient, aged 8 years,
retained some skull defects at follow-up. The optimal age for surgery is 3-6
months, which allows good cosmetic results and minimizes visual repercussions
with relatively low perioperative risks.
PMID- 9557541
TI - [Psychopathological alteration of the auditory structure in schizophrenia; "the
experience of no-sounds"].
AB - According to recent cognitive theories, the greater part of the perceptional
meaning and representative meaning are both pre-determined, or pre-organized as a
set of meaning, which has a biophysiological and socio-cultural origin. Humans
however, drive some kind of sensational Gestalt from each sense organ, and this
is incapable of being transformed into language (representative pre-meaning),
this enabling us to experience the possibility of truly private meaning in our
own right. The author has emphasized this two moments of the meaning, that is,
private moments of meaning vs. institutional moments. The author has offered the
phenomenological hypothesis of auditory experience and elaborated the relation
between these two moments in it. Then, the author has testified its validity in
the process of describing and analysing the pathological alteration of auditory
sensation in schizophrenia. Auditory space is thought to be differentiated into a
three-dimensional structure. That is, a dimension of background, a dimension of
signs, and a dimension of symbols, and we accept environmental-sounds, event
sounds, symbolic sounds in each level. Close investigations about 5
schizophrenics revealed that these patients undergo a strange silent experience
before the onset of delusional ideas, descriptively and phenomenologically, this
phenomenon appeared to be initiated by the deprivation of the dimension of
background sounds (referred to as "the experience of no-sounds"). This
experiences often occurred especially when they are eager to listen to the
surrounding sounds (for example, noises in the neighborhood, classroom chatter),
in order to solve their own interpersonal difficulties. Furthermore, the author
described the ambivalent nature of patients' thinking in this pathological
auditory situation, in which one idea of the polarity of dichotomy was forced to
switch to the another one, influenced by an attribute of surrounding sounds. With
regard to this aspect, the patients experienced both the physiological changes in
the auditory structure as well as the psychological turmoil. The author has
emphasized the need to appreciate this ambiguous nature of the psychological
context mixed with the physiological context, which is supposed to be very
important from psychotherapeutical viewpoint.
PMID- 9557543
TI - [A survey of drug utilization in psychiatric hospitals in Japan: the basic
analysis of the current status of prescription patterns].
AB - Although concern about the prescription pattern of psychotropics is growing,
there have been very few surveys in Japan. In this survey conducted in 1993,
prescription data, patient characteristics, etc. were collected for 2,395
inpatients from 18 psychiatric hospitals. Their mean age was 48.4 (S.D. = 13.6).
Of these patients, 1,818 (75.9%) were diagnosed with schizophrenia, 115 (4.8%)
with mood disorder, and 102 (4.3%) with mental retardation. The results were as
follows. 1) They were prescribed an average of 10.1 different drugs: of these,
5.6 were various psychotropics (2.6 neuroleptics, 1.2 antiparkinsonian drugs, 1.0
hypnotics). 2) The mean daily dose of antipsychotics was 1,082 mg of
chlorpromazine equivalent. 3) The most commonly prescribed neuroleptic was
haloperidol (53.2% of the total patients) followed by levomepromazine (48.7%),
chlorpromazine (24.8%), bromperidol (18.7%), and zotepine (18.3%).
PMID- 9557542
TI - [A study on late catatonia--the psychopathological study of its symptoms,
courses, subtypes, and treatments].
AB - It was discussed at the beginning of this century whether to categorize "late
catatonia" in "manic-depressive disorder", in "schizophrenia", or to consider
itself as another clinical entity. Sommer was the first to make a clinical report
on "late catatonia"; however Kraepelin had reported on cases with very similar
symptoms prior to Sommer, and called them "involutional melancholia" or
"presenile psychosis". Followed by a couple of decades, Jacobi's clinical report
gave "late catatonia" the impressions as having a very poor prognosis. It was
then stated by M. Bleuler that approximately 30% of "late schizophrenia" was well
fitted into "late catatonia". According to Huber who carried out a survey
utilizing the same criterion for "late schizophrenia" some 30 years later, no
such concordance was found. Hence, it may be said that some kind of change in
symptoms has occurred. Symptom-transitions of 16 "late catatonia" subjects were
analysed in detail. "Late catatonia" is a symptomatic concept with characteristic
progressive symptoms: Stage 1 (prodrome and primary depression), Stage 2
(anxiety, irritation), Stage 3 (hallucination, delusion), Stage 4 (catatonia),
and the residual stage. "The complete type" which progresses to Stage 4 stepwise,
may end up developing "malignant catatonia". In this case, it may be life
threatening unless suitable treatment is carried out. This disease may be divided
into 2 types of clinical courses; a multi-phasic course with intermittent
remission, and a mono-phasic course which is chronic. Transition to the residual
stage may occur at any point. In practice, there are 3 other subtypes; these
three are called "the abortive types" (anxious/irritated type,
depressive/delusional type, residual type). These cases are most typically
considered as depression with severe anxiety and irritation, and in case
flattening of affect becomes the major symptoms, it is often misdiagnosed as
"organic dementia". Considering treatment, the majority was nonrespondent to
neuroleptics, especially those at stage 4; however, ECT (electroconvulsive
therapy) was observed to be effective in some cases.
PMID- 9557544
TI - [Sexuality in bacteria].
PMID- 9557545
TI - [Molecular mechanisms for the regulation of meiosis in fission yeast].
PMID- 9557546
TI - [Sexual reproduction and gametogenesis in algae].
PMID- 9557548
TI - [Conjugation in protozoa].
PMID- 9557547
TI - [Sexual reproduction in cellular slime molds: a prototypic mating system].
PMID- 9557550
TI - [Mechanism underlying germline formation in Drosophila melanogaster].
PMID- 9557549
TI - [Germ-line stem cells and sex determination in hydra].
PMID- 9557551
TI - [Sex and reproduction in the nematode C. elegans].
PMID- 9557552
TI - [Origin and differentiation of primordial germ cells in teleost].
PMID- 9557553
TI - [Formation of primordial germ cells (PGCs) in amphibia].
PMID- 9557554
TI - [Formation and migration of avian primordial germ cells].
PMID- 9557555
TI - [Developmental potential of embryonic and somatic cells in mammals].
PMID- 9557556
TI - [The origin and development of mammalian germ cell line].
PMID- 9557557
TI - [Gene expression in mouse primordial germ cell].
PMID- 9557558
TI - [Proliferation and differentiation of mouse fetal germ cells].
PMID- 9557559
TI - [Functional analyses of mammalian spermatogenic genes].
PMID- 9557560
TI - [Mechanism of gonadal differentiation and spermatogenesis in teleost].
PMID- 9557561
TI - [Mechanism of spermatogenesis in amphibians].
PMID- 9557562
TI - [Mechanisms of sex-determination in Drosophila].
PMID- 9557563
TI - [Sex determination and differentiation in amphibians].
PMID- 9557564
TI - [Sexual differentiation of gonads and gametogenesis in the avian species].
PMID- 9557565
TI - [Sex-determining genes and gonadal sex differentiation in mammals].
PMID- 9557566
TI - [Differentiation of mammalian gonads].
PMID- 9557568
TI - [Mutations affecting germ cell development and teratocarcinogenesis in mice].
PMID- 9557567
TI - [Functions of TGF-beta superfamily members in reproduction].
PMID- 9557569
TI - [Spermatogenesis in mammalian testis].
PMID- 9557570
TI - [Zygote-constructing ability of spermatogenic cells in mammals].
PMID- 9557571
TI - [Cell cycle control through meiotic and early cleavage cycles].
PMID- 9557572
TI - [Genomic imprinting and mammalian development].
PMID- 9557573
TI - [Genomic imprinting in germ cells].
PMID- 9557574
TI - [Imprinted X chromosome inactivation].
PMID- 9557575
TI - [Genomic imprinting during oogenesis and embryonic development].
PMID- 9557576
TI - [Studies of genomic imprinting using mouse cells containing a human chromosome].
PMID- 9557577
TI - [Genetic control of flowering: transition from vegetative to reproductive
growth].
PMID- 9557578
TI - [Molecular genetic analysis of flower formation].
PMID- 9557579
TI - [Germ cell formation and gametophyte differentiation in higher plants].
PMID- 9557580
TI - [Sex determination and sex expression in higher plants].
PMID- 9557581
TI - [Plasticity in sex expression of angiosperm].
PMID- 9557582
TI - Expanded Programme on Immunization (EPI). Progress towards elimination of measles
in the Americas.
PMID- 9557583
TI - Environmental health services in Europe. 1. An overview of practice in the 1990s.
PMID- 9557584
TI - An empirical study of preferred settings for lumbar support on adjustable office
chairs.
AB - The preferred settings for lumbar support height and depth of 43 male and 80
female office workers were investigated. All subjects were equipped with
identical modern office chairs with foam-padded backrests adjustable in both
height and depth. Measurements of lumbar support settings were recorded in the
workplace, outside of working hours, on four different occasions, over a 5 week
period. Preferred lumbar support height and depth settings extended to both
extremes of the adjustment range. The mean preferred height setting was 190 mm
above the compressed seat surface. The mean depth setting (horizontal distance
from front of seat to lumbar support point) was 387 mm. A regression model
examining the effects of standing height, Body Mass Index (BMI) and gender on
mean preferred lumbar support height showed a significant relationship between
preferred height and BMI. Higher lumbar supports were chosen by subjects with
greater BMIs. Gender and standing height were not associated with preferred
lumbar support height settings. Preferred lumbar support depth was not
significantly associated with standing height, gender or BMI. Older subjects were
more likely to readjust their lumbar support from a disrupted position than
younger subjects, indicating that older users are more sensitive to the position
of their lumbar support. Subjects who reported recent back pain or discomfort
that they believed to be associated with their chair or office work were found to
set their lumbar support significantly closer to the front of the seat, probably
to ensure greater support for their back. Based on the evidence that a high
proportion of users do make adjustments to the height and depth of their lumbar
support, and the finding that different groups of users, with different physical
characteristics, adjust the position of their lumbar support in distinct and
predictable ways, the researchers conclude that office chairs with traditional
padded fixed-height lumbar supports are unlikely to provide a comfortable or
appropriate seat for the wide range of potential users.
PMID- 9557585
TI - What is 'heavy'?
AB - One of the work practices frequently taught to employees is to estimate the
heaviness of load before it is actually handled. If it is 'heavy', then one
should ask for help. However, limited information can be found in the ergonomics
literature about what a person perceives as a 'heavy load'. This study was
conducted on 20 male and 20 female workers in the package delivery industry to
estimate the amounts of load that correspond to various levels of load heaviness
(e.g. 'somewhat heavy'). Experienced employees were used for this purpose. The
distribution of loads within each heaviness level was developed using fuzzy sets
theory. The maximum load (i.e. 23 kg) defined by the US National Institute for
Occupational Safety and Health represents a 'somewhat heavy' load based on the
analysis of load distribution (corresponding to a 1.0 certainty factor). Also,
the 40 kg considered in the 1981 NIOSH guidelines may be classified as a 'very
heavy' load. A comparative analysis of the results of this study with norms
established in prior research indicates that one should be more careful in the
interpretation of statistical norms for human perception of load handling. A
'moderate' level of load heaviness (i.e. 14 kg) can be handled by 85% of the
worker population.
PMID- 9557586
TI - The impact of flicker from fluorescent lighting on well-being, performance and
physiological arousal.
AB - In working environments all over the world, fluorescent tubes are by far the
dominating light source. Still, there have been very few studies on the impact of
the non-visible flicker from fluorescent tubes. The purpose of the study was to
compare the impact on subjective well-being, performance and physiological
arousal of fluorescent light powered by conventional and high-frequency ballasts.
Thirty-seven healthy males and females were subjected to either condition in a
laboratory office on two separate occasions with 1 week in between. Although the
methodology was quite extensive, only a few general effects were observed.
However, when the light was powered by the conventional ballasts, individuals
with high critical flicker fusion frequency (CFF) responded with a pronounced
attenuation of EEG alpha waves, and an increase in speed and decrease in accuracy
of performance. These results may be understood in terms of heightened arousal in
the central nervous system in response to the pronounced light modulation caused
by the conventional ballasts. In order to alleviate this potential stress source,
it is recommended that fluorescent lighting be powered by electronic high
frequency ballasts of good quality.
PMID- 9557588
TI - Validation of a frequency-weighted filter for continuous biomechanical stress in
repetitive wrist flexion tasks against a load.
AB - This experiment validates a frequency-weighted filter for continuous measurements
of force, posture and repetition using a stimulated industrial task. A peg
transfer task was used requiring subjects to repetitively insert pegs into holes
with controlled resistance. Ten subjects performed the task for six conditions.
All wrist flexion angular data were recorded continually using an
electrogoniometer and processed through the filter. Subjective discomfort was
reported after performing the task for 1 h using a 10 cm visual analogue scale.
Results from linear regression analysis showed that the instrument reliably
estimated subjective discomfort (r2 = 0.873). Applications and limitations of
this instrument are explored.
PMID- 9557587
TI - Agreement between a frequency-weighted filter for continuous biomechanical
measurements of repetitive wrist flexion against a load and published
psychophysical data.
AB - A previous pilot study demonstrated that a force and frequency-weighted filter
network could be developed for processing continuous biomechanical measures of
repetitive wrist motions and exertions. The current study achieves the objective
by modelling subjective discomfort for repetitive wrist flexion using controlled
posture, pace and force. A three-level fractional factorial experiment was
conducted involving repetitive wrist flexion (2 s/motion, 6 s/motion, 10
s/motion) from a neutral posture to a given angle (10 degrees, 28 degrees, 45
degrees) against a controlled resistance (5 N, 25 N, 50 N) using a Box Behnken
design. Ten subjects participated. Discomfort was reported on a 10 cm visual
analogue scale. Results of response surface regression analysis revealed that
main effects of force, wrist flexion angle, and repetition were all significant
(p < 0.05) and that no second-order effects were observed. Linear regression
analysis on these factors established a discomfort model on which the filter
characteristics were based. The pure error test model revealed no significant
lack of fit (p > 0.05). The continuous model was compared and agreed with
discrete psychophysical data from other published studies. The model was used for
generating parameters for a force and frequency-weighted digital filter that
weighs continuous wrist postural signals with corresponding force in proportion
to the equal discomfort function as a function of frequency of repetition. These
filters will enable integration of large quantities of biomechanical data in
field studies.
PMID- 9557589
TI - Measures of operator performance in complex, dynamic microworlds: advancing the
state of the art.
AB - Microworld research provides a useful complement to field studies and highly
controlled laboratory studies, aiming to strike a balance between
representativeness and experimental control. Yet microworld research has
associated methodological difficulties, particularly the problem of performance
measurement. Researchers generally adopt a variety of measures to provide
converging evidence concerning questions of interest. To confront problems with
existing measures, this paper examines a series of objective measures used to
characterize the performance of human operators in process control. These
measures include novel, quantitative extensions to existing graphical analyses
and new graphical representations. The measures are applied in the context of a 6
month longitudinal study using an interactive, thermal-hydraulic process control
microworld (DURESS II). The following measures are discussed: steady-state time,
action transition graph complexity, the path length in state space diagrams, the
area under distance-to-goals graphs, divergence from the temperature goal line in
mass inventory versus energy inventory graphs, and the proportion of control
actions near the beginning of the trials represented by timelines. Two case
studies emphasize the performance and strategy differences of individual
operators across the battery of measures.
PMID- 9557590
TI - Exercise performance during inspiratory resistance breathing under exhaustive
constant load work.
AB - The purpose of this study was to determine the effects of different inspiratory
resistances on exercise performance and to describe physiological and subjective
responses during constant load work of an intensity that elicits the maximum
sensitivity to respiratory factors of respirator wear. Nine subjects (mean age
25.8 +/- 4.8 years) performed exhaustive treadmill exercise during constant load
work of 80% of maximal aerobic capacity while inspiring against one of five
randomly assigned inspiratory resistance conditions. For inspiratory resistances
of 0.20 kPa (R1), 0.29 kPa (R2), 0.39 kPa (R3), and 0.49 kPa (R4), measured at a
steady air flow rate of 85 L min-1, average performance times were 84, 75, 54,
and 30% of the control condition. Performance time reductions were significant
for R3 and R4 trials. Results also indicated a significantly reduced mean
respiration rate, minute ventilation, and oxygen ventilatory equivalent (VE/VO2)
for the R4 condition at exercise breakpoint compared to control. For resistances
R1-R4, mean VE/VO2 were significantly reduced from control by approximately 12,
17, 19, and 31%. At breakpoint, mean ratings of perceived exertion were similar
for control, R1, R2, and R3 conditions but were significantly lower for R4 versus
control. Breathing comfort did not differ significantly between resistances below
the R3 level, but discomfort was significantly greater for conditions R3 and R4.
These findings suggest that the impact of the respiratory limitations of
respirators can be diminished by employing respirators with inspiratory
resistances below the R3 level.
PMID- 9557591
TI - Mental performance in extreme environments: results from a performance monitoring
study during a 438-day spaceflight.
AB - During their stay in a space habitat, astronauts are exposed to many different
stressors that may entail detrimental effects on mood and performance. In order
to monitor the effects of the space environment on different human information
processing functions during an extraordinary long-term space mission, the
cognitive. visuo-motor and time-sharing performance of one Russian cosmonaut was
repeatedly assessed (29 times) during his 438-day stay in space. The performance
tasks used were chosen from the AGARD-STRES battery and included grammatical
reasoning, Sternberg memory-search, unstable tracking, and a dual-tasks
consisting of unstable tracking with concurrent memory-search. In addition to
performance assessment, several subjective ratings concerning mood and workload
were collected. Comparisons of pre-flight, in-flight, post-flight and two follow
up assessments 6 months after the mission revealed, (1) no impairments of basic
cognitive functions during the flight, (2) clear impairments of mood, feelings of
raised workload, and disturbances of tracking performance and time-sharing during
the first 3 weeks in space and the first 2 weeks after return to Earth, (3) an
impressive stability of mood and performance during the second to fourteenth
month in space, where mood and performance had returned to pre-flight baseline
level, and (4) no long-lasting performance deficits at follow-up assessments.
From these results it is concluded that the first 3 weeks of long-term
spaceflights and the first 2 weeks back on Earth represent critical periods where
adverse effects on attentional processes are to be expected, induced by the
demands to adjust to the extreme environmental changes. The stability of mood and
performance observed after successful adaptation to the space environment
indicates that mental efficiency and emotional state can be maintained on a level
as high as on Earth even during extraordinary long-term space missions.
PMID- 9557593
TI - The cells observed inside capsules of larvae in the course of experimental
trichinellosis in mice.
AB - In the course of trichinellosis in mice the numerous cells inside larval capsules
were observed. Beginning on 14 day post infection (dpi) they were seen in about
7% of infected muscles fibers but at 21 dpi the percentage of capsules with the
cells amounted to 77. In the next stage of infection the number of capsules
containing cells continued to increase and reach almost 100% at 60 dpi. The
identification of the cells was carried out by the indirect immunoenzymatic
method using anti-CD4+, anti-CD8+ and anti-macrophage (Mac-1 antigen) monoclonal
antibodies. In course of observation the level of CD4+ cells decreased from 11.3
to 0.7, of CD8+ from 17.7 to 3.0 and of macrophages from 71.0 to 23.1%. The most
numerous CD4+ cells were seen at 14 dpi while the CD8+ and macrophages at 21 dpi.
Beginning on 28 dpi negatively reacting cells inside larval capsules were also
observed. The number of these cells increased from 23.8 to 73.2% at 60 dpi and
their identification requires further investigations. The role and the function
of all these cells are discussed.
PMID- 9557592
TI - Macrophages during infection with Trichinella spiralis in mice.
AB - Behaviour of macrophages in experimental mice trichinellosis was investigated
using the immunoenzymatic technique with monoclonal antibodies CD11b/CD18 within
the framework of avidin-biotin-DAB. The maximum and earliest mobilization of
macrophages 7 day post infection (dpi) was observed in the lamina propria of the
intestinal mucosa. The highest level of macrophages in the muscles tissue was
noted on day 21 of infection, however as early as in 28 dpi, their maximum level
was observed inside the larval capsules. They line, especially between 35-42 dpi
internal capsule surface.
PMID- 9557595
TI - Plasmapheresis in the treatment of trichinellosis.
AB - Four patients with severe form of trichinellosis were treated with
plasmapheresis. We noticed clinical improvement and favourable alterations in
laboratory profiles (morphology and immune response parameters in the blood). The
effect of plasmapheresis therapy in patients with trichinellosis was considered
beneficial. No major complications of plasmapheresis were observed.
PMID- 9557594
TI - Detection of Trichinella SP. invasion and clinical appraisal of patients in the
late stage of trichinellosis in a new epidemic focus in Wielkopolska.
AB - A clinical and an epidemiological analysis was presented of a trichinellosis
focus from Wielkopolska region. The studies included 20 persons and
trichinellosis was diagnosed in 15 cases. The focus was characterized by
asynchronous invasion with Trichinella sp. in individual affected persons in the
course of a prolonged period (around 2.5 months) and by reporting of the patients
to the Clinic during approximately 30 to 90 days after the disease signs/symptoms
developed. Retrospective analysis and a set of specialized tests permitted to
clarify causes of persisting complaints, presented by the patients, as well as to
establish the diagnosis at late stages of trichinellosis.
PMID- 9557596
TI - Trichinellosis in Poland during recent 5 years (1992-1996).
PMID- 9557597
TI - Epidemiological and epizootiological problems of trichinellosis in Poland.
PMID- 9557598
TI - The red fox (Vulpes Vulpes) as reservoir of Trichinella sp. in Poland.
PMID- 9557599
TI - Clinical aspects of late sequelae of trichinellosis.
AB - Clinical analysis and the set of laboratory studies, performed in 25 patients
one, two, three or six years after surviving acute period of trichinellosis,
documented complaints in 22 patients (88.0%) in the form of muscle complaints
(68.2%), cardiovascular complaints (45.4%), generalized weakness (40.9%) and
fatigability (31.8%). No significant alterations were demonstrated in
electrocardiographic records. In 71.4% examined patients lactic dehydrogenase
activity was augmented. Presence of IgG antibodies against the E/S antigen of
Trichinella sp. was disclosed in 24 (96%) patients, including 22 patients
(88.0%), in whom high titres of the antibodies were found. Morphological studies
on muscle tissue (performed in 5 patients) disclosed alterations typical of
trichinellosis in 4 patients and presence of Trichinella larvae, calcified to a
significant extent, in 2 patients. The long term persistence of IgG class
antibodies against Trichinella antigen in patients who survived acute period of
trichinellosis a few years earlier points to a chronic antigenic stimulation,
probably reflecting progressive destruction of Trichinella larvae in muscle
tissue. This may also be expressed in complaints reported by the patients. The
problem requires further observations and clinical studies.
PMID- 9557600
TI - All-trans retinoic acid (ATRA) in patients with chronic myeloid leukemia in the
chronic phase.
AB - Since in vitro observations indicated that all-trans retinoic acid (ATRA),
especially in combination with IFNalpha, can exert significant suppressive
effects on Ph+ cells, we investigated the effects and the pharmacokinetic profile
of ATRA in a selected cohort of patients with Ph+ chronic myeloid leukemia (CML)
in chronic phase. Eighteen patients were treated with ATRA at a dose of 80
mg/m2/day (p.o.), divided into two equal doses after meals, for 7 consecutive
days every other week for a maximum of 12 courses (1 course = 1 week on and 1
week off). Pharmacokinetic profiles of ATRA were evaluated during intermittent
therapy on days 1 and 7 of course 1; on day 1 of course 2; on day 1 of course 6.
Out of the 18 patients treated with ATRA, 11 (61%) went off study before the
sixth course of treatment because of progressive hyperleukocytosis (seven cases),
or thrombocytosis (one case), or refusal (three cases). Seven (39%) patients
completed the first six courses (12 weeks) of treatment with ATRA and two of them
(11%) maintained a white blood cell (WBC) <10 x 10[9]/l which was induced by the
pretreatment with hydroxyurea. One patient completed the 12th course of ATRA
maintaining WBC <10 x 10(9)/l, platelets <500 x 10(9)/l and spleen not palpable.
The treatment with ATRA was well tolerated and only one patient discontinued the
therapy because of non-hematological side-effects. The area under the
concentration-time curve (AUC) decreased significantly (P< 0.001) during the
first week of therapy. By adopting an intermittent dosing regimen, 1 week on/ 1
week off (1 course), at the start of courses 2 and 6, we obtained the ATRA AUCs
equivalent to the ones achieved on day 1 of course 1. In conclusion, our results
showed that ATRA alone appeared to be unable to control the WBC expansion in the
CML patients in chronic phase. Moreover, it did not induce any remarkable
cytoreductive effects on the platelet count and on the hemoglobin level. The
major interest of ATRA would be in combination with other therapies. If ATRA was
given in combination with IFNalpha or other agents, dose reduction of these would
not be planned. On the basis of the pharmacokinetic profile, ATRA should be
administered intermittently rather than continuously.
PMID- 9557601
TI - Association of HLA phenotype and response to interferon-alpha in patients with
chronic myelogenous leukemia.
AB - Twenty to 25% of patients with chronic myelogenous leukemia (CML) treated with
interferon-alpha (IFN-A) achieve a complete cytogenetic response (CCR). However,
cells bearing rearrangement of BCR/ABL can still be detected many years after
achieving a CCR despite the absence of clinical evidence of active disease. It
has been suggested that the disease is kept in a dormant state by immune
mechanisms. How this is achieved is not known, but it has been speculated that
p210BCR/ABL might be presented by malignant cells through HLA molecules, thus
making them the target for specific immune cell killing. Because specific
peptides will be expressed in association with certain HLA molecules, different
HLA phenotypes could be associated with different response rates to IFN-A. The
response to IFN-A-based therapies in 239 patients with chronic phase CML was
analyzed according to their HLA phenotype. One hundred and ninety-four (81%)
achieved complete hematologic response, 142 (59%) had a cytogenetic response
which was major (MCR) in 93 patients (39%): complete (CCR) in 71 (30%) and
partial (PCR) in 22 (9%). Patients with an HLA-B27 phenotype had the best
response rate to IFN-A: 10 of 14 (71%) had an MCR, including eight (57%) with a
CCR (P=0.02). Patients with HLA-B35, -A3, and -A31 also showed a trend towards a
higher response rate, whereas patients with HLA-B18 had the lowest response rate
(MCR 17%). Patients with HLA-B27 and those with HLA-A31 showed a trend for better
survival, whereas patients with HLA-A2, -B7, or -B18 had a trend for shorter
survival. We conclude that response to IFN-A in patients with CML may be
associated with the HLA phenotype. However, a much larger population would be
required to determine if the impact of HLA phenotype on survival is independent
of other clinical prognostic features. These findings could be relevant for the
understanding of immune mechanisms of control of CML and possibly the design of
immune therapy for this disease.
PMID- 9557602
TI - The impact of age on outcome in lymphoblastic leukaemia; MRC UKALL X and XA
compared: a report from the MRC Paediatric and Adult Working Parties.
AB - The purpose of the study was to examine the influence of age on outcome in a
large cohort of children and adults with lymphoblastic leukaemia who were treated
on two similar trials. Factors influencing outcome were examined in 2204 patients
aged over 1 year treated between 1985 and 1992 on the parallel Medical Research
Council Trials UKALL X and XA, for children and adults, respectively. There was a
progressive worsening in survival with increasing age from 85% (95% CI 83-87) at
5 years for children aged 1-9 to 24% (CI 17-31) for patients over 40. Induction
failures, deaths in remission and bone marrow relapses increased significantly
with age. Analysis of clinical and biological features showed dominance of early
B-ALL in childhood and increasing incidence of the Ph' chromosome with age. Over
80% of eligible children, but a much lower proportion of adults especially those
over 40, was entered. Compliance was stricter in the paediatric trial but most
deviations in adults involved giving more treatment. Analysis of results in a
proportional hazards model confirmed the overwhelming independent influence of
age; with all other factors equal a 10 year old had half the risk of treatment
failure of a 20 year old and a 44 year old double the risk. Selective entry to
therapeutic trials and increased treatment-related toxicity are features of adult
ALL but age itself remains a dominant prognostic factor. While improved
supportive care and refinements of conventional therapy may have some effect on
prognosis, new understandings and treatment approaches to adult ALL are needed.
PMID- 9557603
TI - Comparative genomic hybridization as part of a new diagnostic strategy in
childhood hyperdiploid acute lymphoblastic leukemia.
AB - The detailed definition of karyotype changes associated with hyperdiploid acute
lymphoblastic leukemia (ALL) is a precondition for their exploitation in minimal
residual disease studies with fluorescence in situ hybridization analysis (FISH).
In addition, certain karyotype patterns may have different prognostic
implications. We have therefore used comparative genomic hybridization (CGH) to
analyze the quantitative karyotype abnormalities in 14 cases of hyperdiploid ALL
and correlated the results with those obtained by flow cytometry and conventional
cytogenetic analyses. Despite an overall good agreement between the karyotypes
obtained by classical banding techniques and CGH, we came across at least one
karyotype discrepancy per case. Clarification of the discordant findings with
fluorescence in situ hybridization (FISH) showed that all stem lines had been
correctly defined by CGH. In eight cases, however, cytogenetic analyses revealed
structural abnormalities that were undetectable by CGH. The other discrepancies
were mainly due to a cytogenetic misinterpretation of similar sized and shaped
chromosomes. Based on these findings we present a new diagnostic strategy for
childhood ALL that includes flow cytometry and classical cytogenetics as well as
CGH for the analysis of aneuploid cases and FISH to resolve the unavoidable
discrepancies.
PMID- 9557604
TI - Refractory anemia with severe dysplasia: clinical significance of morphological
features in refractory anemia.
AB - Refractory anemia (RA) in myelodysplastic syndromes (MDS) are very heterogeneous
diseases regarding their morphology, clinical features and survival. We proposed
the new designations 'RA with severe dysplasia (RASD)' and 'RA with minimal
dysplasia (RAminiD)'. In our criteria, RASD is considered present if a bone
marrow (BM) examination shows Pseudo-Pelger-Huet anomalies of mature neutrophils
> or =3% and/or micromegakaryocytes (mMgk) of megakaryocytes > or =10% in RA
patients. RAminiD is defined as RA cases other than RASD. After the
reclassification of 58 primary RA patients, the group was composed of 45 RAminiD
and 13 RASD patients. The blast percentage in the BM and the frequency of
cytogenetic abnormalities observed in the RASD patients were intermediate between
those in the RAminiD and RAEB patients. The analysis of survival curves revealed
differences among the three groups; the RASD patients had lower survival
probabilities than those of the RAminiD group, and significantly higher
probabilities than those of the RAEB group. (RAminiD vs RASD, P=0.06; RASD vs
RAEB, P=0.004.) Our data indicate that in RA patients, RASD is a distinct subset
of RA with an unfavorable clinical outcome.
PMID- 9557605
TI - Localization of Fas and Fas ligand in bone marrow cells demonstrating
myelodysplasia.
AB - Frequent apoptosis in the bone marrow of patients with myelodysplastic syndromes
(MDS) was demonstrated on frozen sections using the terminal deoxytransferase
(TdT)-mediated dUTP nick end labeling (TUNEL) method. The overall mean percentage
of TUNEL-positive cells was about 17% in the bone marrow of MDS, while bone
marrow from control cases exhibited a mean of 3.4% (P < 0.001). To elucidate the
mechanism of apoptosis in bone marrow cells of MDS, the expression of Fas antigen
and Fas ligand (FasL) was examined by RT-PCR and immunohistochemistry. All MDS
cases showed expression of Fas mRNA (12/12) and most exhibited an expression of
FasL mRNA (10/12) by RT-PCR. Basically, control cases did not show positive
signals for Fas and FasL mRNA, however, a very weak band was detected in three
cases (3/10) for Fas and in one case (1/10) for FasL mRNA by RT-PCR.
Immunohistochemical examination revealed positive staining for Fas (11/12) and
FasL (12/12) in the bone marrow of MDS, while all the bone marrow samples from
control cases were negative for anti-Fas (0/15) and for anti-FasL (0/15)
antibody. Double staining clarified that TUNEL-positive apoptotic cells expressed
Fas antigen on the cell surface, although not all Fas-positive cells were TUNEL
positive. The Fas-positive cells of MDS bone marrow included hematopoietic cells
expressing CD34 antigen, neutrophil elastase, a marker for myeloid series of
cells, or glycophorin A, a marker for erythroid cells. However, CD68-positive
cells which were macrophage lineage cells, did not express Fas antigen strongly.
In contrast, positive staining for FasL was detected in hematopoietic cells and
CD68-positive cells in the bone marrow of MDS. These results suggest that the Fas
FasL system plays an important role in inducing apoptosis in the bone marrow of
MDS and works in an autocrine (hematopoietic cell-hematopoietic cell interaction)
and/or paracrine (hematopoietic cell-stromal cell interaction) manner.
PMID- 9557606
TI - Lymphotoxin-alpha is an autocrine growth factor for chronic lymphocytic leukemia
B cells.
AB - Lymphotoxin-alpha (LT), also called TNF-beta, which belongs to the 'TNF family'
was originally isolated from a lymphoblastoid cell line. LT enhances the
proliferation of activated B cells and augments B cell proliferation induced by
IL-2. It functions as an autocrine growth factor for EBV-infected B cell lines
and has been implicated in the pathogenesis of B cell malignancies. We tested the
expression of LT mRNA in B-CLL and found that LT was expressed in highly purified
leukemic cells in 11 out of 11 patients examined. Regulation of expression of LT
mRNA is aberrant in B-CLL cells, since LT mRNA expression was not detected in
fresh peripheral blood mononuclear cells or B cells identified in seven out of
seven normal individuals. In addition, LT mRNA expression was detected for up to
6 days in purified unstimulated in vitro cultures of B-CLL cells.
Glucocorticosteroids, that have been effectively used in the treatment of
lymphoid malignancies, were added to the cultures and abrogated the LT mRNA
expression after an incubation time of 12 h. Addition of recombinant LT to
cultures increased proliferation of B-CLL cells while proliferation of these
cells was inhibited by antisense oligonucleotides against LT mRNA. B-CLL cells
cultured with LT antisense oligonucleotides (asLT) as well as glucocorticoid
treated cells showed reduced viability and a DNA fragmentation ladder
characteristic of apoptosis suggesting a relationship between down-regulation of
LT mRNA expression and the induction of apoptosis. These studies support the role
of LT in the growth regulation and development of B-CLL cells.
PMID- 9557607
TI - Phenotypical heterogeneity of CD4+CD8+ double-positive chronic T lymphoid
leukemia.
AB - Chronic T lymphoid leukemias are defined as leukemias of post-thymic T cells. The
CD4+CD8+ double-positive (DP) phenotype is seen in a few cases. Since DP
generally occurs in thymic T cells, whether the DP T leukemia cells represent
thymic or peripheral T cells has been a matter of controversy. To address this
issue, we studied phenotypical features in eight cases of DP T cell leukemia.
Thymic DP T cells and peripheral CD8+ T cells have CD8 of alphabeta subunit,
while CD8alphaalpha is induced in CD4+ T cells on activation with IL-4. We found
that two patients with DP T large granular lymphocyte leukemia (LGLL) showed dim
expression of CD8alphaalpha, identical to the phenotype on IL-4-activated DP-T
cells. The leukemic cells of these patients expressed IL-4 mRNA and produced high
levels of IL-4. These findings suggest that they may be derived from peripheral
CD4+ T cells. Three patients with adult T cell leukemia/lymphoma (ATLL) showed
CD8alphaalpha, suggestive of an activated peripheral T cell origin. One case
expressed CD8alphaalpha dim and IL-4 mRNA, while the other two cases expressed no
IL-4 mRNA and showed CD8alphaalpha bright phenotype, features not found in normal
T cell populations. Three patients with T-prolymphocytic leukemia (T-PLL)
expressed CD8alphabeta. The DP phenotype is relatively common in T-PLL, and
CD4+CD8alphabeta+ is characteristic of thymic T cells. The DP T-PLL cells did not
express TdT,CD1 or recombination activating gene-1 (RAG-1), which is down
regulated at the late stage of thymic T cell development. On the basis of these
findings, we propose a late thymic origin for DP T-PLL. The phenotype of DP T
cells differed for each entity and appeared to correlate with minor normal DP T
cell population.
PMID- 9557608
TI - Drug resistance in multiple myeloma: cyclosporin A analogues and their
metabolites as potential chemosensitizers.
AB - The malignant clone in myeloma is not eradicated by chemotherapy. Cyclosporins
inhibit drug transport mechanisms, particularly the multidrug transporter p
glycoprotein 170, leading to their use as chemosensitizers. In myeloma,
clonotypic blood B cells represent the major drug-resistant subset. This study
compares the ability of cyclosporin A analogues and metabolites to inhibit
cellular transporter(s) in myeloma and normal B cells in vitro, and evaluates
their potential role in vivo. Cyclosporin A (CsA), CsG, PSC 833 or SDZ 280-446,
and primary CsA and CsG metabolites, were tested for their ability to inhibit
drug transport mechanisms of ex vivo malignant B cells from 81 patients with
multiple myeloma as compared to B cells from normal donors, as measured by the
export of the dye rhodamine 123 (Rh123) using multiparameter flow cytometry. The
majority of myeloma B and normal B cells had efficient transporter function as
measured by their CsA-sensitive export of Rh123. CsA and CsA analogues mediated
efficient inhibition of this transport. Inhibition of dye transport by normal B
cells required an approximately six-fold greater concentration of the synthetic
peptolide SDZ 280-446 than was needed to optimally inhibit transport by myeloma B
cells. PSC 833 and CsG were inhibitory at concentrations approximately five-fold
lower than were required for CsA. Assessment of inhibitory potency in vivo
indicated that the in vivo chemosensitizer levels of CsA and PSC 833 exceeded the
transporter inhibitory concentration by four- and 20-fold respectively. In vivo,
cyclosporins are rapidly and almost completely converted to metabolites. AM1 and
AM4N, primary metabolites of CsA, mediated inhibition of transport, as did CsG
metabolites GM1, GM4N and GM9. AM1 and GM9 are known to reach steady-state in
vivo levels that exceed the inhibitory concentration identified here by 1.1- to
1.9-fold. Thus, cyclosporin metabolites, which accumulate in the blood during
infusion of CsA and other cyclosporins, are shown here to be effective
chemosensitizers for normally drug-resistant myeloma cells in vitro. Cyclosporin
metabolites are considered to be less toxic than the parent drugs, suggesting
that novel chemosensitization strategies designed to minimize concentrations of
parent drug and maximize accumulation of primary metabolites in vivo may optimize
cytotoxicity to the malignant clone in myeloma.
PMID- 9557609
TI - Identification of a commonly deleted region at 17p13.3 in leukemia and lymphoma
associated with 17p abnormality.
AB - Fluorescence in situ hybridization (FISH) was performed in 17 myeloid leukemia
patients and seven lymphoid leukemia/ lymphoma patients who exhibited chromosomal
abnormalities on the short arm of chromosome 17, in order to detect a commonly
deleted region on chromosome band 17p13. Twenty-four leukemia/lymphoma patients
studied cytogenetically at our institution over a period of 10 years had
detectable 17p abnormalities such as translocation (six patients), addition (11
patients) and deletion of 17p13 (seven patients). A 17p abnormality was the only
abnormality present in three patients. Most of the patients had additional
complex cytogenetic abnormalities. The diagnosis was acute myeloid leukemia (AML)
in 10 patients, two each with chronic myeloid leukemia (CML), acute lymphoblastic
leukemia (ALL), chronic lymphocytic leukemia (CLL) and myelodysplastic syndrome
(MDS) and the remaining three with malignant lymphoma (ML). Seven cosmid probes
(D17S34, cCI17-624, cCI17-453, D17S379, cCI17-636, cCI17-732 and TP53) which
mapped on 17p13 were used to analyze the allelic deletion. Eighty percent (19 out
of 24) of the informative leukemia patients exhibited allelic loss in 17p13.3 at
cC17-624. The smallest region of an overlapping deletion was observed on
chromosome band 17p13.3 between cCI17-624 and cCI17-453. Patients with
translocation involving 17p also showed deletion at cCI17-624 and cCI17-453. We
hypothesize that this region contains a novel tumor suppressor gene(s) that is
involved in leukemogenesis.
PMID- 9557610
TI - Acquisition of the Ph chromosome and BCR-ABL fusion product in AML-M2 and t(8;21)
leukemia: cytogenetic and FISH evidence for a late event.
AB - A patient with the M2 subtype of AML who had a 45,X,-X,t(8;21) karyotype at
diagnosis was found to have the Ph chromosome in one out of 37 evaluated cells 18
months after the initial diagnosis. Interphase FISH studies utilizing a BCR-ABL
dual-color probe did not detect a fusion product 4 months prior to the appearance
of one Ph-positive cell. Nineteen months post diagnosis and 5 months after
clinical relapse all evaluated cells had the Ph chromosome in a clone
characterized by t(8;21). These observations suggest that late appearing Ph is a
secondary event which may be either therapy-related or consistent with one of the
later events in a multistep pathogenesis of AML.
PMID- 9557611
TI - Characterization of proteins binding the 3' regulatory region of the IL-3 gene in
IL-3-dependent and autocrine-transformed hematopoietic cells.
AB - Previously we documented the prolongation of the IL-3 mRNA half-life in an
autocrine-transformed cell line. This cell line has an intracisternal type A
particle transposition in the IL-3 mRNA 3' untranslated region which displaced
four out of six AUUUA motifs involved in IL-3 mRNA destabilization. In this
study, the proteins binding to the IL-3 mRNA AU-rich elements (ARE) were
examined. Specific protein binding was detected to the wild-type IL-3 ARE region
which contained 6 AUUUA motifs (AU6). In contrast, no binding was detected to the
mutated IL-3 ARE region which contained only two AUUUA motifs (AU2). Proteins
with apparent molecular weights of 36, 40, 43, 46, 55, 57, 68 and 95 kDa were
bound to AU6 motif. The hnRNP C and AUF-1 (hnRNP D) proteins were determined to
be two of the IL-3 ARE binding proteins. Incubation of protein extracts with
antibodies to hnRNP C and AUF-1 significantly decreased the protein binding to
the IL-3 ARE. Treatment of IL-3 dependent cells with calcium ionophores
eliminated the proteins binding to the ARE in wild-type IL-3-dependent FL5.12
cells and also resulted in the accumulation of IL-3 mRNA transcripts with a long
half-life. These results indicated that there was a specific complex which bound
the IL-3 mRNA 3' ARE. Mutations which truncate the IL-3 ARE eliminate the ability
of proteins to bind this regulatory region and can result in autocrine
transformation due to the presence of IL-3 mRNA transcripts with a long half
life.
PMID- 9557612
TI - Antisense sequences of the nbl gene induce apoptosis in the human promyelocytic
leukemia cell line HL-60.
AB - Apoptosis is induced by the transcriptional inhibitor actinomycin D (Act D) in
various cell types, particularly many leukemic cell lines such as HL-60. A common
feature of these cell lines is their high constitutive expression level of the
nbl gene, which was originally isolated by virtue of its abundance in a Namalwa
Burkitt lymphoma cDNA library. In contrast, cell lines which constitutively
express nbl at low levels appear not to undergo typical apoptotic death in
response to Act D. Apoptotic induction by Act D in cells which normally express
nbl at high levels was found in this study to be closely associated with a
decline in nbl mRNA levels, raising the possibility that apoptosis could be
induced by lowering nbl expression levels in such cells. Transient expression of
nbl antisense sequences in HL-60 cells decreased cell viability, and induced
typical apoptotic morphology such as cell shrinkage, chromatin condensation and
nuclear fragmentation. Incubation with nbl antisense oligomers also induced
similar features in HL-60 cells and in another high nb-expressing cell line,
Jurkat, but had little effect in HepG2 cells which constitutively express nbl at
low levels. These findings suggest that lowering constitutively high levels of
nbl expression can induce apoptosis.
PMID- 9557613
TI - V-myc in a simple, single gene retroviral vector causes rapid induction of
leukemia and concomitant apoptosis following bone marrow transplantation.
AB - We have previously developed an in vivo model of leukemogenesis utilizing mice
reconstituted with genetically modified bone marrow cells. Based on those
studies, a new single gene retroviral vector has been engineered which
efficiently transfers v-myc into immature murine bone marrow cells. All
reconstituted mice developed leukemia with a short latency period (5-11 weeks).
In addition to hyperproliferation associated with elevated levels of PCNA,
extensive apoptosis was also observed in all leukemic animals with p53
accumulating in the apoptotic cells. Whereas bax encoded protein, an effector of
p53 apoptotic activity was detected in apoptotic cells, p21Waf1 protein, a
potential mediator of p53 growth suppression was not detected in these cells
suggesting that v-myc-induced apoptosis was independent of the ability of p53 to
induce p21Waf1. These results indicate that apoptosis, a part of the cellular
response to v-myc expression, does not prevent leukemia development and that
hyperproliferation rather than abrogation of oncogene-induced apoptosis appears
to be a critical event in v-myc-induced leukemia.
PMID- 9557614
TI - Characterization of the chimeric retinoic acid receptor RARalpha/VDR.
AB - The chimeric receptor, RARalpha/VDR, contains the DNA-binding domain of the
retinoic acid receptor (RARalpha) and the ligand-binding domain of the vitamin D
receptor (VDR). The ligand-binding properties of RARalpha/VDR are equivalent to
that of VDR, with an observed Kd for 1alpha,25 dihydroxy-vitamin D3 (D3) of 0.5
nM. In CV-1 cells, both RARalpha and RARalpha/VDR induce comparable levels of
ligand-mediated transcriptional activity from the retinoic acid responsive
reporter gene, beta(RARE)3-TK-luciferase, in the presence of the ligand predicted
from the receptor ligand-binding domain. Two chimeric RAR receptors were
constructed which contained the ligand-binding domain of the estrogen receptor
(ER): RARalpha/ER and ER/RARalpha/ER. Both RARalpha/ER and ER/RARalpha/ER bind
beta-estradiol with high affinity, and are transcriptionally active only from
palindromic RAREs (TREpal and/or (TRE3)3). Only RARalpha/VDR matched in kind and
degree the functional characteristics of RARalpha: (1) maximally active from the
beta(RARE); (2) moderately active from the TREs; (3) inactive from the retinoic X
receptor response elements (RXREs) ApoA1 and CRBP II; (4) forms heterodimers with
RXRalpha; and (5) binds to the betaRARE. F9 embryonal carcinoma cell lines were
generated which express RARalpha/VDR mRNA (F9RARalpha/VDR cells) and compared
with F9 wild-type (F9-Wt) cells, which do not express VDR mRNA. Treatment with
all-trans retinoic acid (tRA) inhibits cell growth and induces the
differentiation morphology in both F9-Wt and F9-RARalpha/VDR cells; whereas,
treatment with D3 is similarly effective only for F9-RARalpha/VDR cells. It is
concluded RARalpha/VDR is an useful 'tool' to pinpoint, or to augment
transcription from RAREs in gene pathways controlled by RAR without inhibiting
the retinoid responsiveness of endogenous RARs.
PMID- 9557615
TI - Terminal megakaryocytic differentiation of TF-1 cells is induced by phorbol
esters and thrombopoietin and is blocked by expression of PML/RARalpha fusion
protein.
AB - We have analyzed the differentiation program of growth factor-dependent TF-1
erythroleukemia cells as well as clones with inducible expression of the APL
specific PML/RARalpha protein. We have shown that TF-1 cells may be induced to
megakaryocytic differentiation by phorbol ester (phorbol dibutyrate, PDB)
addition, particularly when combined with thrombopoietin (Tpo). RT-PCR studies
showed that Tpo induces Tpo receptor (TpoR or c-mpl), whose expression was
further potentiated by PDB addition. When the cells are induced with both PDB and
Tpo erythropoietin receptor (EpoR) expression was inhibited. In the absence of
Zn2+-induced PML/RARalpha expression, PDB and Tpo induced megakaryocytic
differentiation of TF-1 MTPR clones as observed in 'wild-type' TF-1 cells.
Conversely, when PML/RARalpha expression was induced by Zn2+, PDB and Tpo
treatment of these clones caused only a reduced level of megakaryocytic
differentiation. These observations indicate that: (1) TF-1 cells as well as
other erythroleukemic cells, possess the capacity to differentiate to
megakaryocytic cells when grown in the presence of protein kinase (PKC)
activators and more efficiently when combined with Tpo; (2) the PML/RARalpha gene
has a wide capacity to interfere with the program of hematopoietic
differentiation, including megakaryocytic differentiation. Finally, we also
observed that PML/RARalpha expression in TF-1 cells induces an up-modulation of
interleukin-3 receptor, c-kit and c-mpl, a phenomenon which may offer these cells
a growth advantage.
PMID- 9557616
TI - The low cycling status of mobilized peripheral blood CD34+ cells is not
restricted to the more primitive subfraction.
AB - Mobilized peripheral blood progenitor cells (PBPC) have been shown to differ
qualitatively from bone marrow (BM) progenitors. The released progenitor cells
are predominantly in G0/G1 and show a relatively high percentage of rhodamine
dull cells. Within the BM these last two features are characteristic of the more
primitive progenitors. Although the mobilized PB cells can give rise to long-term
repopulation and thus contain stem cells, the frequency of stem cells is not much
higher if long-term initiating cell (LTC-IC) assays are used. To determine
whether quiescent stem cells are selectively released or the low-cycle status of
PB progenitors is related to the release from the BM microenvironment, the cell
cycle status and rhodamine content in the PB and BM during mobilization were
studied and compared with steady-state BM. More differentiated and more primitive
progenitors were separated based on differentiation markers and cloned in single
cell assay. In mobilized PB 54% of the CD34+ cells (n=5) were rhodamine dull
compared to 22% in steady-state BM (P=0.014) [n=6]. The percentage of CD34+ cells
in the S/G2M phases of the cell cycle was 2.1% in the mobilized PB (n=11), and
18% in steady-state BM (n=11) [P=0.002]. During mobilization the fraction of
cells in the S/G2M phase of the cell cycle was 16% in BM (n=7), similar to steady
state BM (P=0.34). The released progenitors represented a selection of BM
progenitors, with significantly more primitive progenitors (CD34+/13+/33dim) and
less lymphoid precursors (CD34+/19+). Within the more differentiated
CD34+113+/33bright, myelomonocytic precursors, both in PB as well as in BM, the
percentage S/G2M was relatively higher than in the CD34+/13+/33dim subfraction:
in normal BM: median 18% vs 8% (P=0.006) [n=8]; in mobilized PB 3% vs 2% (P=0.03)
[n=10]; and in BM during mobilization 24% vs 7% (P=0.01) [n=6]. The cycle status
of mobilized PB progenitors was low both in the primitive and more differentiated
subfractions. During the mobilization period the BM progenitors are cycling as in
steady-state BM. The low-cycle status of the mobilized PB progenitors may be
related to the loss of contact with the micro-environment.
PMID- 9557617
TI - Cutaneous T cell lymphomas: mycosis fungoides, Sezary syndrome and HTLV-I
associated adult T cell leukemia (ATL) in Mali, West Africa: a clinical,
pathological and immunovirological study of 14 cases and a review of the African
ATL cases.
AB - Cutaneous T cell lymphomas (CTCL) are rare lymphoproliferative diseases, which
are frequently suspected to be of viral origin. As very few data were available
concerning cutaneous T cell lymphomas in tropical Africa, we undertook a
clinical, histopathological, immunological and viro-molecular study of patients
with a clinical diagnosis of cutaneous lymphoma, in Bamako, Mali. While prior to
this study, no case of CTCL had been reported in this country, 14 patients (five
women, nine men; mean age 58 years) with a diagnosis of cutaneous lymphoma were
seen over a period of 30 months (1992-1994) in the only dermatological department
in Mali. Clinically, the most frequent pattern was an infiltrated erythrodermia
similar to Sezary syndrome. Nodular lesions and/or plaques were rarely observed.
All these cutaneous tumors were T cell lymphoproliferations, only one expressing
the CD8+ antigen. A comprehensive analysis of all the available data permitted
characterization of three cases of adult T cell leukemia/lymphoma (ATL)
associated with HTLV-I (one definitive case, of leukemic type, with demonstration
of clonal integration of HTLV-I proviral genome and two probable ATL cases),
three cases of Sezary syndrome (SS), two cases of mycosis fungoides (MF) and five
cases of pleomorphic cutaneous lymphoma. In one case, the differentiation between
MF and pleomorphic cutaneous lymphoma could not be established. HTLV-I
serological and/or molecular markers were restricted to the three ATL cases. From
the unique definitive ATL case, a T cell line was established from culture of
peripheral blood mononuclear cells and sequence analysis of the env gene and the
U3-LTR region demonstrated that the virus present in this patient belonged to the
cosmopolitan subtype A. Thus, we report here the first evidence of HTLV-I
infection and associated ATL in Mali. This is the second ATL case described for
the whole Sahelian region (one ATL of the lymphoma type was reported previously
in a Mauritanian patient). Furthermore, we demonstrate that the main types of
CTCL described in Europe and North America are also present in this African area
and that the prevalence of these diseases is greatly underestimated in such
regions. Furthermore, no association was observed between HTLV-I/II infection and
SS, MF or pleomorphic cutaneous lymphoma in Mali in contrast to other studies.
PMID- 9557618
TI - Quality of life in adult patients with acute myeloid leukemia receiving intensive
and prolonged chemotherapy -- a longitudinal study.
AB - Intensification of treatment for acute myeloid leukemia (AML) in adult patients
resulted in a substantial improvement in long-term prognosis. Therefore, the
assessment of quality of life (QL) of patients undergoing treatment is of growing
interest. This study was designed to evaluate QL in patients with AML treated
according to the protocol of the German AML-Cooperative Group (Munster, Germany).
The EORTC QLQ-C 30 questionnaire was used to analyze QL throughout therapy,
evaluating defined specific parameters at 12 different time-points. Sixty-one
patients were recruited within the first 30 months of the study. Those 28
patients who have completed the course of inpatient treatment (n=28) are
evaluated for changes in the conceptually distinct QL domains: Physical
Functioning (P<0.001), Role Functioning (P=0.001), Emotional Functioning (P <
0.001) and Social Functioning (P=0.007) improve significantly from beginning of
chemotherapy to the end of inpatient treatment. Individual assessment of Global
Health Status and Subjective QL improves significantly over the same time (P<
0.001). At the end of inpatient treatment patients suffer significantly less from
fatigue, nausea/emesis, loss of appetite and sleep disturbance (P < 0.001).
Although most patients with AML eventually relapse, the evaluation of QL in
patients undergoing treatment shows that subjective benefit outweighs the adverse
effects of antileukemic therapy.
PMID- 9557619
TI - Contrast in cytokine expression between patients with monoclonal gammopathy of
undetermined significance or multiple myeloma.
AB - We investigated whether differences in IL-6 and IL-1beta expression could be
detected in monoclonal plasma cells from patients with MGUS or MM. Expression of
IL-6 and IL-1beta in bone marrow cells was determined using cell sorting to
enrich for plasma cells followed by reverse transcriptase/polymerase chain
reaction (RT/PCR). Nineteen patients (six MGUS, two primary amyloid (AL), 11 MM)
were studied. IL-6 mRNA expression was detectable in the sorted CD38+/CD45-
plasma cell populations from 0/6 MGUS, 0/2 AL and 5/11 MM patients. All five MM
patients with autocrine IL-6 expression demonstrated an elevated plasma cell
labeling index. IL-1beta mRNA was detectable in the sorted CD38+/CD45- plasma
cell populations from 1/6 MGUS, 0/2 AL and 10/11 MM patients. In situ
hybridization (ISH) confirmed that the IL-1beta producing cells were plasma
cells. In conclusion, autocrine production of IL-6 parallels a high labeling
index and aberrant expression of IL-1beta correlates with the diagnosis of MM.
Follow-up of IL-1beta-positive MGUS patients will determine whether aberrant
expression of IL-1beta will predict those MGUS patients that will eventually
progress to MM.
PMID- 9557620
TI - Characterization of the immunoglobulin light chain variable region gene expressed
in multiple myeloma.
AB - We studied the organization, diversification and clinical significance of the
immunoglobulin light chain (IgL) variable region genes expressed in 17 kappa
chain and 16 lambda-chain producing multiple myeloma (MM) samples. The V genes
from 31 MM samples had over 84.9% homology to the known germline Vkappa/lambda
genes, whereas one Vkappa and one Vlambda gene had only 75.5% and 65.9% homology,
respectively. While all five Jkappa segments were equally used, only Jlambda-1 or
Jlambda-2/3 was used among seven Jlambda segments. N nucleotide addition was
found at two Vkappa-Jkappa and five Vlambda-Jlambda junctions. The lambda-chain
complementarity determining region (CDR)-3 was longer and more variable than the
kappa-chain CDR-3 mainly due to junctional flexibility of Vlambda and Jlambda
segments. Somatic mutations were more frequent in the Jlambda than the Jkappa
segments, and were distributed in the CDR-3 as well as the frame work region
(FWR)-4. Those of the Jkappa segments, however, were limited to FWR-4. In FWR-4,
replacement mutations were clustered at codon 106 of kappa-chain and 103 of
lambda-chain. Thus nucleotide mutation or conservation was dependent on position,
indicating a structural necessity of IgL for the development of myeloma cells in
addition to a non-random distribution of mutations. There was no characteristic
IgL sequence according to the isotype of M-protein, clinical stage or renal
complication.
PMID- 9557621
TI - Malignant plasma cell lines express a functional CD28 molecule.
AB - The function of CD28 molecules that are present on malignant plasma cells of
human myeloma cell lines (HMCL) was studied. First, myeloma cells expressed a
similar density of CD28 antigen to that of normal T cells. The myeloma CD28
molecules were able to bind B7-Ig molecules as well as L cells transfected with a
B7-1 cDNA, and anti-CD28 mAb inhibited the binding. Myeloma cells did not express
B7-1 antigens but a low density of B7-2 antigens. The myeloma B7-2 molecules of
two HMCL were able to bind CTLA-4 protein. No autocrine CD28:B7-2 activation
could be evidenced as we found no spontaneous binding of the p85 subunit of PI-3
kinase to CD28 molecules. In addition, a blocking anti-CD28 mAb did not affect
the IL-6-dependent or autonomous proliferation of the HMCL. The activation of
myeloma CD28 molecules with or without TPA stimulation did not affect the
proliferation, survival, differentiation, expression of activation antigens and
cytokine receptors or cytokine production of myeloma cells. However, the
triggering of myeloma CD28 molecules by B7-1 transfectant cells resulted in
binding of the p85 subunit of PI-3 kinase to CD28 molecules as previously shown
for T cell CD28 molecules. This expression of a large density of CD28 molecules
able to bind B7 molecules might contribute to a downregulation of the immune
control of myeloma cells.
PMID- 9557622
TI - Profound abnormality of the B/T lymphocyte ratio during chemotherapy for
pediatric acute lymphoblastic leukemia.
AB - The fluorescence-activated cell sorter (FACS) was utilized to phenotype
lymphocyte compartments in children receiving intensive chemotherapy for acute
lymphoblastic leukemia (ALL). Sixteen patients (eight males and eight females) of
diverse ages, risks of relapse, and within weeks 7-53 of maintenance/continuation
chemotherapy treatment were arbitrarily selected for study. All 16 patients had
profound B cell lymphopenia. In contrast, T cell numbers were often normal or
marginally low, and accounted for up to 98% of the lymphocyte populations. No
abnormality in T cell phenotypes could be demonstrated. Due to the highly skewed
B/T lymphocyte ratios in these ALL patients, the absolute white blood cell counts
and lymphocyte percentages were not predictive of the underlying B cell
lymphopenia. Patients were also tested for serum immunoglobulin levels and most
had abnormally low IgG and IgM. None of four patients immunized with the 1996
1997 influenza virus vaccine seroconverted to at least two vaccine antigens as
compared to 10 of 10 healthy, age-matched controls. In total, these data
highlight for the first time the profound abnormality of the B/T lymphocyte ratio
in patients during treatment for ALL, and argue for consideration of B cell
targeted immunotherapy.
PMID- 9557624
TI - Use of the comet test in the evaluation of multidrug resistance of human cell
lines.
AB - The comet test is a reported method for measuring DNA damage in individual
mammalian cells. In the present report, the ability of this test to detect
multidrug resistance (MDR) was evaluated. For this purpose, two human leukemia,
well-characterized parental cell lines, HL60 and CEM, and their derived multidrug
resistant cells, HL60/DNR and CEM/VBL, were cultured with or without different
anti-cancer agents. To evaluate the comet test, two DNA-damaging agents were
used: daunorubicin (DNR), which is involved in MDR, and ambamustine (AMBA), which
is independent from MDR. Moreover, in order to evaluate the specificity of the
comet test, the activity of vinblastine (VBL), an MDR-related, DNA-independent
anti-cancer drug, was also tested. Finally, the specificity of the comet test in
detecting MDR was confirmed by culturing parental or resistant cells with DNR
with or without the revertant agent verapamil (VER). Results confirm that the
comet test is able to predict cellular chemoresistance when DNA damaging agents
are tested. Finally, experiments on the role of the comet test in evaluating
certain aspects of DNA repair are discussed.
PMID- 9557623
TI - Demonstration of clonality in neutrophils using FISH in a case of chronic
neutrophilic leukemia.
AB - A patient previously diagnosed with chronic neutrophilic leukemia (CNL) was
studied using fluorescent in situ hybridization (FISH) to determine clonality of
neutrophils. By cytogenetic studies the patient's blood and bone marrow had an
11q14 deletion and were negative for the Philadelphia (Ph) chromosome. FISH was
performed on peripheral blood smears using probes for the bcr/abl translocation
and a probe for 11q23 (MLL). The patient's white blood cells were negative for
the bcr/abl translocation; neutrophils and eosinophils, but not lymphocytes, were
monosomic for the 11q23 probe indicating a clonal population within the
neutrophil population.
PMID- 9557625
TI - More on purine analog-induced apoptosis in B cell chronic lymphocytic leukemia.
PMID- 9557626
TI - Complement values in B chronic lymphocytic leukemia: prognostic significance and
correlation with cell maturation stage.
PMID- 9557628
TI - Identification and characterization of a porcine torovirus.
AB - A porcine torovirus (PoTV) was identified and characterized; it is a novel member
of the genus Torovirus (family Coronaviridae, order Nidovirales), closely related
to but clearly distinct from the already recognized equine torovirus (ETV) and
bovine torovirus (BoTV) representatives. Immunoelectron microscopy of feces from
piglets revealed elongated, 120- by 55-nm particles which were recognized by a
torovirus-specific antiserum. Amplification by reverse transcriptase (RT) PCR
with primers designed to detect conserved regions (on the basis of the genomes of
BoTV strain Breda and ETV strain Berne) resulted in the identification of the 489
bp nucleocapsid gene, encoding a 18.7-kDa protein. The sequence identity in this
region between PoTV and both ETV and BoTV was only about 68%, whereas the latter
two show 81% identity. Neutralizing antibodies directed against ETV were found in
sera of adult and young pigs. In all 10 herds sampled, seropositive animals were
present, and 81% of randomly selected adult sows possessed antibodies. A
longitudinal study with RT PCR showed that piglets shed virus in the feces for 1
or more days, starting 4 to 14 days after weaning.
PMID- 9557630
TI - Switch to unusual amino acids at codon 215 of the human immunodeficiency virus
type 1 reverse transcriptase gene in seroconvertors infected with zidovudine
resistant variants.
AB - Sequences of the human immunodeficiency virus type 1 (HIV-1) reverse
transcriptase (RT) domain were determined by direct sequencing of HIV-1 RNA in
successive plasma samples from eight seroconverting patients infected with virus
bearing the T215Y/F amino acid substitution associated with zidovudine (ZDV)
resistance. At baseline, additional mutations associated with ZDV resistance were
detected. Three patients had the M41L amino acid change, which persisted. Two
patients had both the D67N and the K70R amino acid substitutions; reversion to
the wild type was seen at both positions in one of these patients and at codon 70
in the other one. Reversion to the wild type at codon 215 was observed in only
one of eight patients. Unusual amino acids, such as aspartic acid (D) and
cysteine (C), appeared at position 215 in four patients during follow-up. These
variants isolated by coculturing were sensitive to ZDV. Overgrowth of these
variants suggests that they have better fitness than the original T215Y variant.
Intraindividual nucleoside substitutions over time were 10 times more frequent in
codons associated with ZDV resistance (41, 67, 70, 215, and 219) than in other
codons of the RT domain. The predominance of nonsynonymous substitutions observed
over time suggests that most changes reflect adaptation of the RT function. The
variance in sequence evolution observed among patients, in particular at codon
215, supports a role for chance in the evolution of the RT domain.
PMID- 9557629
TI - Neutralization of human immunodeficiency virus type 1 by antibody to gp120 is
determined primarily by occupancy of sites on the virion irrespective of epitope
specificity.
AB - We investigated the relative importance of binding site occupancy and epitope
specificity in antibody neutralization of human immunodeficiency virus (HIV) type
1 (HIV-1). The neutralization of a T-cell-line-adapted HIV-1 isolate (MN) was
analyzed with a number of monovalent recombinant Fab fragments (Fabs) and
monoclonal antibodies with a range of specificities covering all confirmed gp120
specific neutralization epitopes. Binding of Fabs to recombinant monomeric gp120
was determined by surface plasmon resonance, and binding of Fabs and whole
antibodies to functional oligomeric gp120 was determined by indirect
immunofluorescence and flow cytometry on HIV-infected cells. An excellent
correlation between neutralization and oligomeric gp120 binding was observed, and
a lack of correlation with monomeric gp120 binding was confirmed. A similar
degree of correlation was observed between oligomeric gp120 binding and
neutralization with a T-cell-line-adapted HIV-1 molecular clone (Hx10). The
ratios of oligomer binding/neutralization titer fell, in general, within a
relatively narrow range for antibodies to different neutralization epitopes.
These results suggest that the occupancy of binding sites on HIV-1 virions is the
major factor in determining neutralization, irrespective of epitope specificity.
Models to account for these observations are proposed.
PMID- 9557631
TI - Activation of caspases in pig kidney cells infected with wild-type and CrmA/SPI-2
mutants of cowpox and rabbitpox viruses.
AB - The cowpox virus (CPV) CrmA and the equivalent rabbitpox virus (RPV) SPI-2
proteins have anti-inflammatory and antiapoptosis activity by virtue of their
ability to inhibit caspases, including the interleukin-1beta-converting enzyme
(ICE; caspase-1). Infection of LLC-PK1 pig kidney cells with a CPV CrmA mutant,
but not with wild-type (wt) CPV, results in the induction of many of the
morphological features of apoptosis (C. A. Ray and D. J. Pickup, Virology 217:384
391, 1996). In our study, LLC-PK1 cells infected with CPV delta crmA, but not
those infected with wt CPV, showed induction of poly(ADP-ribose) polymerase
(PARP)- and lamin A-cleaving activities and processing of the CPP32 (caspase-3)
precursor to a mature 18-kDa form. Surprisingly, infection of LLC-PK1 cells with
either wt RPV (despite the presence of the SPI-2 protein) or RPV delta SPI-2
resulted in cleavage activity against PARP and lamin A and the appearance of the
mature subunit of CPP32/caspase-3. The biotinylated specific peptide inhibitor Ac
Tyr-Val-Lys(biotinyl)-Asp-2,6-dimethylbenzoyloxymethylketone [AcYV(bio)KD-aomk]
labeled active caspase subunits of 18, 19, and 21 kDa in extracts from LLC-PK1
cells infected with CPV delta crmA, wt RPV, or RPV delta SPI-2 but not wt CPV.
Mixed infection of LLC-PK1 cells with wt RPV and wt CPV gave no PARP-cleaving
activity, and all PARP cleavage mediated by SPI-2 and CrmA mutants of RPV and
CPV, respectively, could be eliminated by coinfection with wt CPV. These results
suggest that the RPV SPI-2 and CPV CrmA proteins are not functionally equivalent
and that CrmA, but not SPI-2 protein, can completely prevent apoptosis in LLC-PK1
cells under these conditions.
PMID- 9557632
TI - Human immunodeficiency virus type 1 subtype F reverse transcriptase sequence and
drug susceptibility.
AB - We sequenced and phylogenetically analyzed the reverse transcriptase (RT) regions
of the pol genes of 14 human immunodeficiency virus type 1 (HIV-1) isolates from
Romanian patients, which were classified as subtype F on the basis of env gene
structure. The RT sequences showed that the strains clustered phylogenetically
and were equidistant from other HIV-1 subtypes as shown by the neighbor-joining
and maximum-likelihood methods, allowing us to define HIV-1 subtype F according
to the pol classification. The subtype F RT sequences differed from reported
group M RT sequences by 10.94% (for nucleotides) and 7.6% (for amino acids).
Phenotypic analysis of subtype F susceptibility to three classes of
antiretroviral compounds showed an increase in the 50% inhibitory concentration
of the tetrahydroimidazo[4,5,1-jk] [1,4]-benzodiazepin-2-(1H)-one and -thione
(TIBO) derivate R82913 for one strain which was naturally resistant to this
compound. This first report of subtype F pol sequences confirms the perfect
correlation between the phylogenetic positions determined by env and pol analyses
and suggests that virus variability might influence the efficacy of
antiretroviral treatments. This finding warrants a global evaluation of the
phenotypic and genotypic susceptibility of HIV-1 subtypes to antiretroviral
drugs.
PMID- 9557633
TI - Functional role of hepatitis C virus chimeric glycoproteins in the infectivity of
pseudotyped virus.
AB - The putative envelope glycoproteins of hepatitis C virus (HCV) likely play an
important role in the initiation of viral infection. Available information
suggests that the genomic regions encoding the putative envelope glycoproteins,
when expressed as recombinant proteins in mammalian cells, largely accumulate in
the endoplasmic reticulum. In this study, genomic regions which include the
putative ectodomain of the E1 (amino acids 174 to 359) and E2 (amino acids 371 to
742) glycoproteins were appended to the transmembrane domain and cytoplasmic tail
of vesicular stomatitis virus (VSV) G protein. This provided a membrane anchor
signal and the VSV incorporation signal at the carboxy termini of the E1 and E2
glycoproteins. The chimeric gene constructs exhibited expression of the
recombinant proteins on the cell surface in a transient expression assay. When
infected with a temperature-sensitive VSV mutant (ts045) and grown at the
nonpermissive temperature (40.5 degrees C), cells transiently expressing the E1
or E2 chimeric glycoprotein generated VSV/HCV pseudotyped virus. The resulting
pseudotyped virus generated from E1 or E2 surprisingly exhibited the ability to
infect mammalian cells and sera derived from chimpanzees immunized with the
homologous HCV envelope glycoproteins neutralized pseudotyped virus infectivity.
Results from this study suggested a potential functional role for both the E1 and
E2 glycoproteins in the infectivity of VSV/HCV pseudotyped virus in mammalian
cells. These observations further suggest the importance of using both viral
glycoproteins in a candidate subunit vaccine and the potential for using a
VSV/HCV pseudotyped virus to determine HCV neutralizing antibodies.
PMID- 9557634
TI - Cross-reactions between the cytotoxic T-lymphocyte responses of human
immunodeficiency virus-infected African and European patients.
AB - The great variability of protein sequences from human immunodeficiency virus
(HIV) type 1 (HIV-1) isolates represents a major obstacle to the development of
an effective vaccine against this virus. The surface protein (Env), which is the
predominant target of neutralizing antibodies, is particularly variable. Here we
examine the impact of variability among different HIV-1 subtypes (clades) on
cytotoxic T-lymphocyte (CTL) activities, the other major component of the
antiviral immune response. CTLs are produced not only against Env but also
against other structural proteins, as well as some regulatory proteins. The
genetic subtypes of HIV-1 were determined for Env and Gag from several patients
infected either in France or in Africa. The cross-reactivities of the CTLs were
tested with target cells expressing selected proteins from HIV-1 isolates of
clade A or B or from HIV type 2 isolates. All African patients were infected with
viruses belonging to clade A for Env and for Gag, except for one patient who was
infected with a clade A Env-clade G Gag recombinant virus. All patients infected
in France were infected with clade B viruses. The CTL responses obtained from all
the African and all the French individuals tested showed frequent cross-reactions
with proteins of the heterologous clade. Epitopes conserved between the viruses
of clades A and B appeared especially frequent in Gag p24, Gag p18, integrase,
and the central region of Nef. Cross-reactivity also existed among Gag epitopes
of clades A, B, and G, as shown by the results for the patient infected with the
clade A Env-clade G Gag recombinant virus. These results show that CTLs raised
against viral antigens from different clades are able to cross-react, emphasizing
the possibility of obtaining cross-immunizations for this part of the immune
response in vaccinated individuals.
PMID- 9557635
TI - Elongation of the cytoplasmic tail interferes with the fusion activity of
influenza virus hemagglutinin.
AB - The hemagglutinin (HA) of fowl plague virus was lengthened and shortened by site
specific mutagenesis at the cytoplasmic tail, and the effects of these
modifications on HA functions were analyzed after expression from a simian virus
40 vector. Elongation of the tail by the addition of one to six histidine (His)
residues did not interfere with intracellular transport, glycosylation,
proteolytic cleavage, acylation, cell surface expression, and hemadsorption.
However, the ability to induce syncytia at a low pH decreased dramatically
depending on the number of His residues added. Partial fusion (hemifusion),
assayed by fluorescence transfer from octadecylrhodamine-labeled erythrocyte
membranes, was also reduced, but even with the mutant carrying six His residues,
significant transfer was observed. However, when the formation of fusion pores
was examined with hydrophilic fluorescent calcein, transfer from erythrocytes to
HA-expressing cells was not observed with the mutant carrying six histidine
residues. The addition of different amino acids to the cytoplasmic tail of HA
caused an inhibitory effect similar to that caused by the addition of His. On the
other hand, a mutant lacking the cytoplasmic tail was still able to fuse at a
reduced level. These results demonstrate that elongation of the cytoplasmic tail
interferes with the formation and enlargement of fusion pores. Thus, the length
of the cytoplasmic tail plays a critical role in the fusion process.
PMID- 9557636
TI - Identification of regions of poliovirus 2BC protein that are involved in
cytotoxicity.
AB - The expression of poliovirus 2BC protein in yeast and mammalian cells leads to a
number of metabolic and morphological alterations, such as growth inhibition,
intracellular membrane proliferation, blockade of the exocytic pathway, and
enhanced membrane permeability. Yeast cells that express poliovirus 2BC in an
inducible manner were used to identify the regions of 2BC implicated in the
modifications of these cellular functions. Several 2BC deletion mutants were
generated to define the minimal portion of 2BC required to alter these
activities. Additional deletion mutants that were obtained by random mutagenesis
followed by selection in yeast cells provided new insights into the structure and
mechanism of action of 2BC. The activity responsible for membrane proliferation
is located in 2C, while the activities responsible for membrane permeabilization
and inhibition of the exocytic pathway are located in 2B. Several regions of 2B
and 2C required for the different functions of 2BC were identified. Thus, the
integrity of the N termini of both 2B and 2C is necessary for 2BC-induced
cytotoxicity. It is also possible to separate the different cellular alterations
provoked by 2BC by the use of several 2BC variants. Deletion of amino acids 52 to
65 in 2B generates a 2BC deletion variant, 2bC deltaAvrII, that still blocks
yeast growth but is unable to enhance membrane permeability or to inhibit the
exocytic pathway. On the other hand, 2Bcl28*.32b and 2Bcl28*.3c, which contain
only 73 and 77 amino acids of 2B, interfere with yeast division and enhance
membrane permeability but affect the exocytic pathway only weakly and do not
induce membrane proliferation. Our findings indicate that Saccharomyces
cerevisiae represents a useful model system to analyze the functions of
poliovirus 2BC and show the feasibility of separating the activities assigned to
this protein.
PMID- 9557637
TI - Coding sequences enhance internal initiation of translation by hepatitis A virus
RNA in vitro.
AB - Hepatitis A virus (HAV), unlike other picornaviruses, has a slow-growth phenotype
in permissive cell lines and in general does not induce host cell cytopathology.
Although there are no published reports of productive infection of HeLa cells by
HAV, HAV RNA appears to be readily translated in HeLa cells when transcribed by
T7 RNA polymerase provided by a recombinant vaccinia virus. The 5' noncoding
region of HAV was fused to poliovirus (PV) coding sequences to determine the
effect on translation efficiency in HeLa cell extracts in vitro. Conditions were
optimized for utilization of the HAV internal ribosome entry segment (IRES).
Transcripts from chimeric constructs fused precisely at the initiation codon were
translated very poorly. However, chimeric RNAs which included 114 or more
nucleotides from the HAV capsid coding sequences downstream of the initiation
codon were translated much more efficiently than those lacking these sequences,
making HAV-directed translation efficiency similar to that directed by the PV
IRES. Sixty-six nucleotides were insufficient to confer increased translation
efficiency. The most 5'-terminal HAV 138 nucleotides, previously determined to be
upstream of the IRES, had an inhibitory effect on translation efficiency.
Constructs lacking these terminal sequences, or those in which the PV 5'-terminal
sequences replaced those from HAV, translated three- to fourfold better than
those with the intact HAV 5'-terminal end.
PMID- 9557638
TI - Interaction of poliovirus with its purified receptor and conformational
alteration in the virion.
AB - Polypeptides of amino acids 1 to 241 (PVR241) and 1 to 330 (PVR330) of the human
poliovirus receptor (hPVR) were produced in a baculovirus expression system.
PVR241 contained extracellular domains 1 and 2 of hPVR, and PVR330 contained
extracellular domains 1, 2, and 3. These peptides were purified by immunoaffinity
column chromatography with an anti-hPVR monoclonal antibody (MAb). After the
purification, PVR241 and PVR330 appeared to retain their native conformation as
judged by reactivity with an anti-PVR MAb that recognized domain 1 of hPVR in a
conformation-dependent manner. The virulent Mahoney strain of poliovirus type 1
was mixed with the purified PVRs in various concentrations. An average of at
least 43 PVR330 molecules were able to bind to one virion particle under the
conditions used. The equilibrium dissociation constant between the PVR330
molecule and the PVR binding site (canyon) on the virion was determined to be
4.50 +/- (0.86) x 10(-8) M at 4 degrees C. Higher rates of conformational change
of the virus (160S) to 135S and 80S particles were observed as the concentration
of PVR330 was increased. In this in vitro system, the ratio of the amount of the
135S particle to that of the 80S particle seemed to be always constant. After the
disappearance of the 160S particle, the amount of the 80S particle was not
increased by further incubation at 37 degrees C. These results suggested that the
80S particle was not derived from the 135S particle under the conditions used in
this study.
PMID- 9557639
TI - Foot-and-mouth disease virus virulent for cattle utilizes the integrin
alpha(v)beta3 as its receptor.
AB - Adsorption and plaque formation of foot-and-mouth disease virus (FMDV) serotype
A12 are inhibited by antibodies to the integrin alpha(v)beta3 (A. Berinstein et
al., J. Virol. 69:2664-2666, 1995). A human cell line, K562, which does not
normally express alpha(v)beta3 cannot replicate this serotype unless cells are
transfected with cDNAs encoding this integrin (K562-alpha(v)beta3 cells). In
contrast, we found that a tissue culture-propagated FMDV, type O1BFS, was able to
replicate in nontransfected K562 cells, and replication was not inhibited by
antibodies to the endogenously expressed integrin alpha5beta1. A recent report
indicating that cell surface heparan sulfate (HS) was required for efficient
infection of type O1 (T. Jackson et al., J. Virol. 70:5282-5287, 1996) led us to
examine the role of HS and alpha(v)beta3 in FMDV infection. We transfected normal
CHO cells, which express HS but not alpha(v)beta3, and two HS-deficient CHO cell
lines with cDNAs encoding human alpha(v)beta3, producing a panel of cells that
expressed one or both receptors. In these cells, type A12 replication was
dependent on expression of alpha(v)beta3, whereas type O1BFS replicated to high
titer in normal CHO cells but could not replicate in HS-deficient cells even when
they expressed alpha(v)beta3. We have also analyzed two genetically engineered
variants of type O1Campos, vCRM4, which has greatly reduced virulence in cattle
and can bind to heparin-Sepharose columns, and vCRM8, which is highly virulent in
cattle and cannot bind to heparin-Sepharose. vCRM4 replicated in wild-type K562
cells and normal, nontransfected CHO (HS+ alpha(v)beta3-) cells, whereas vCRM8
replicated only in K562 and CHO cells transfected with alpha(v)beta3 cDNAs. A
similar result was also obtained in assays using a vCRM4 virus with an engineered
RGD-->KGE mutation. These results indicate that virulent FMDV utilizes the
alpha(v)beta3 integrin as a primary receptor for infection and that adaptation of
type O1 virus to cell culture results in the ability of the virus to utilize HS
as a receptor and a concomitant loss of virulence.
PMID- 9557641
TI - Origin and rapid evolution of a novel murine erythroleukemia virus of the spleen
focus-forming virus family.
AB - The Friend spleen focus-forming virus (SFFV) env gene encodes a glycoprotein with
apparent Mr of 55,000 that binds to erythropoietin receptors (EpoR) to stimulate
erythroblastosis. A retroviral vector that does not encode any Env glycoprotein
was packaged into retroviral particles and was coinjected into mice in the
presence of a nonpathogenic helper virus. Although most mice remained healthy,
one mouse developed splenomegaly and polycythemia at 67 days; the virus from this
mouse reproducibly caused the same symptoms in secondary recipients by 2 to 3
weeks postinfection. This disease, which was characterized by extramedullary
erythropoietin-independent erythropoiesis in the spleens and livers, was also
reproduced in long-term bone marrow cultures. Viruses from the diseased primary
mouse and from secondary recipients converted an erythropoietin-dependent cell
line (BaF3/EpoR) into factor-independent derivatives but had no effect on the
interleukin-3-dependent parental BaF3 cells. Most of these factor-independent
cell clones contained a major Env-related glycoprotein with an Mr of 60,000.
During further in vivo passaging, a virus that encodes an Mr-55,000 glycoprotein
became predominant. Sequence analysis indicated that the ultimate virus is a new
SFFV that encodes a glycoprotein of 410 amino acids with the hallmark features of
classical gp55s. Our results suggest that SFFV-related viruses can form in mice
by recombination of retroviruses with genomic and helper virus sequences and that
these novel viruses then evolve to become increasingly pathogenic.
PMID- 9557640
TI - Monoclonal antibodies to distinct sites on herpes simplex virus (HSV)
glycoprotein D block HSV binding to HVEM.
AB - HVEM (for herpesvirus entry mediator) is a member of the tumor necrosis factor
receptor superfamily and mediates entry of many strains of herpes simplex virus
(HSV) into normally nonpermissive Chinese hamster ovary (CHO) cells. We used
sucrose density centrifugation to demonstrate that purified HSV-1 KOS virions
bind directly to a soluble, truncated form of HVEM (HVEMt) in the absence of any
other cell-associated components. Therefore, HVEM mediates HSV entry by serving
as a receptor for the virus. We previously showed that soluble, truncated forms
of HSV glycoprotein D (gDt) bind to HVEMt in vitro. Here we show that antibodies
specific for gD, but not the other entry glycoproteins gB, gC, or the gH/gL
complex, completely block HSV binding to HVEM. Thus, virion gD is the principal
mediator of HSV binding to HVEM. To map sites on virion gD which are necessary
for its interaction with HVEM, we preincubated virions with gD-specific
monoclonal antibodies (MAbs). MAbs that recognize antigenic sites Ib and VII of
gD were the only MAbs which blocked the HSV-HVEM interaction. MAbs from these two
groups failed to coprecipitate HVEMt in the presence of soluble gDt, whereas the
other anti-gD MAbs coprecipitated HVEMt and gDt. Previous mapping data indicated
that site VII includes amino acids 11 to 19 and site Ib includes 222 to 252. The
current experiments indicate that these sites contain residues important for HSV
binding to HVEM. Group Ib and VII MAbs also blocked HSV entry into HVEM
expressing CHO cells. These results suggest that the mechanism of neutralization
by these MAbs is via interference with the interaction between gD in the virus
and HVEM on the cell. Group Ia and II MAbs failed to block HSV binding to HVEM
yet still neutralized HVEM-mediated entry, suggesting that these MAbs block entry
at a step other than HVEM binding.
PMID- 9557642
TI - Nuclear matrix attachment regions of human papillomavirus type 16 point toward
conservation of these genomic elements in all genital papillomaviruses.
AB - The gene functions, transcriptional regulation, and genome replication of human
papillomaviruses (HPVs) have been extensively studied. Thus far, however, there
has been little research on the organization of HPV genomes in the nuclei of
infected cells. As a first step to understand how chromatin and suprachromatin
structures may modulate the life cycles of these viruses, we have identified and
mapped interactions of HPV DNAs with the nuclear matrix. The endogenous genomes
of HPV type 16 (HPV-16) which are present in SiHa, HPKI, and HPKII cells, adhere
in vivo to the nuclear matrixes of these cell lines. A tight association with the
nuclear matrix in vivo may be common to all genital HPV types, as the genomes of
HPV-11, HPV-16, HPV-18, and HPV-33 showed high affinity in vitro to preparations
of the nuclear matrix of C33A cells, as did the well-known nuclear matrix
attachment region (MAR) of the cellular beta interferon gene. Affinity to the
nuclear matrix is not evenly spread over the HPV-16 genome. Five genomic segments
have strong MAR properties, while the other parts of the genome have low or no
affinity. Some of the five MARs correlate with known cis-responsive elements: a
strong MAR lies in the 5' segment of the long control region (LCR), and another
one lies in the E6 gene, flanking the HPV enhancer, the replication origin, and
the E6 promoter. The strongest MAR coincides with the E5 gene and the early-late
intergenic region. Weak MAR activity is present in the E1 and E2 genes and in the
3' part of L2. The in vitro map of MAR activity appears to reflect MAR properties
in vivo, as we found for two selected fragments with and without MAR activity. As
is typical for many MARs, the two segments with highest affinity, namely, the 5'
LCR and the early-late intergenic region, have an extraordinarily high A-T
content (up to 85%). It is likely that these MARs have specific functions in the
viral life cycle, as MARs predicted by nucleotide sequence analysis, patterns of
A-T content, transcription factor YY1 binding sites, and likely topoisomerase II
cleavage sites are conserved in similar positions throughout all genital HPVs.
PMID- 9557643
TI - Human immunodeficiency virus type 1 attachment to HeLa CD4 cells is CD4
independent and gp120 dependent and requires cell surface heparans.
AB - The binding of human immunodeficiency virus type 1 (HIV-1) (Hx10) virions to two
different cell lines was analyzed by using a novel assay based on the detection,
by anti-HLA-DR-specific antibodies, of HLA-DR+ virus binding to HLA-DR- cells.
Virion attachment to the CD4+-T-cell line A3.01 was highly CD4 dependent in that
it was potently inhibited by CD4 monoclonal antibodies (MAbs), and little virus
binding to the CD4- sister A2.01 line was observed. By contrast, virion binding
to HeLa cells expressing moderate or high levels of CD4 was equivalent to, or
lower than, binding to wild-type CD4- HeLa cells. Moreover, several CD4 MAbs did
not reduce, but enhanced, HIV-1 attachment to HeLa-CD4 cells. CD4 was required
for infection of HeLa cells, however, demonstrating a postattachment role for
this receptor. MAbs specific for the V2 and V3 loops and the CD4i epitope of
gp120 strongly inhibited virion binding to HeLa-CD4 cells, whereas MAbs specific
for the CD4bs and the 2G12 epitopes enhanced attachment. Despite this, all gp120-
and gp41-specific MAbs tested neutralized infectivity on HeLa-CD4 cells. HIV-1
attachment to HeLa cells was only partially inhibited by MAbs specific for
adhesion molecules present on the virus or target cells but was completely
blocked by polyanions such as heparin, dextran sulfate, and pentosan sulfate.
Treatment of HeLa-CD4 cells with heparinases completely eliminated HIV attachment
and infection, strongly implicating cell surface heparans in the attachment
process. CD4 dependence for HIV-1 attachment to target cells is thus highly cell
line specific and may be replaced by other ligand-receptor interactions.
PMID- 9557644
TI - Cellular transcription factors enhance herpes simplex virus type 1 oriS-dependent
DNA replication.
AB - The herpes simplex virus type 1 (HSV-1) origin of DNA replication, oriS, contains
three binding sites for the viral origin binding protein (OBP) flanked by
transcriptional regulatory elements of the immediate-early genes encoding ICP4
and ICP22/47. To assess the role of flanking sequences in oriS function, plasmids
containing oriS and either wild-type or mutant flanking sequences were tested in
transient DNA replication assays. Although the ICP4 and ICP22/47 regulatory
regions were shown to enhance oriS function, most individual elements in these
regions, including the VP16-responsive TAATGARAT elements, were found to be
dispensable for oriS function. In contrast, two oriS core-adjacent regulatory
(Oscar) elements, OscarL and OscarR, at the base of the oriS palindrome were
shown to enhance oriS function significantly and additively. Specifically,
mutational disruption of either element reduced oriS-dependent DNA replication by
60 to 70%, and disruption of both elements reduced replication by 90%. The
properties of protein-DNA complexes formed in gel mobility shift assays using
uninfected and HSV-1-infected Vero cell nuclear extracts demonstrated that both
OscarL and OscarR are binding sites for cellular proteins. Whereas OscarR does
not correspond to the consensus binding site of any known transcription factor,
OscarL contains a consensus binding site for the transcription factor Sp1. Gel
mobility shift and supershift experiments using antibodies directed against
members of the Sp1 family of transcription factors demonstrated the presence of
Sp1 and Sp3, but not Sp2 or Sp4, in the protein-DNA complexes formed at OscarL.
The abilities of OscarL and OscarR to bind their respective cellular proteins
correlated directly with the efficiency of oriS-dependent DNA replication.
Cooperative interactions between the Oscar-binding factors and proteins binding
to adjacent OBP binding sites were not observed. Notably, Oscar element mutations
that impaired oriS-dependent DNA replication had no detectable effect on either
basal or induced levels of transcription from the ICP4 and ICP22/47 promoters, as
determined by RNase protection assays. The Oscar elements thus appear to provide
binding sites for cellular proteins that facilitate oriS-dependent DNA
replication but have no effect on transcription of oriS-flanking genes.
PMID- 9557645
TI - Grossly defective nef gene sequences in a human immunodeficiency virus type 1
seropositive long-term nonprogressor.
AB - We have been investigating a long-term nonprogressor who was found to be human
immunodeficiency virus type 1 (HIV-1) seropositive in 1985 and has survived with
stable CD4+ T-cell counts (>1,000 CD4 cells/microl) without any AIDS-related
illness. We have previously reported that repeated attempts to measure HIV-1 RNA
in the peripheral mononuclear cells obtained from this subject have invariably
failed. In the present study, we have analyzed the molecular nature of the HIV-1
quasispecies infecting this patient by PCR amplification of two proviral regions,
the 5' long terminal repeat (5'LTR)/gag leader and the nef gene, directly from
fresh uncultured peripheral mononuclear cells, followed by length polymorphism
analysis (with 1994, 1995, and 1996 samples) and sequencing (with a 1996 sample).
Only proviral forms with nef deletions were revealed by length polymorphism
analysis in samples from all three time points. Sequence analysis of the nef gene
from the 1996 sample confirmed the presence of similar proviral quasispecies
characterized by the presence of several deletions located in the nef-alone and
the nef/U3 overlapping regions. Length polymorphism analysis of the 5'LTR/gag
leader region suggested the existence of two major quasispecies populations, one
characterized by the presence of forms carrying deletions in the U3 region and
the other showing a completely intact, full-length 5'LTR. Evidence of the role of
nef gene defects in long-term survival of HIV-1-infected patients has been
provided so far in two independent investigations involving patients infected
with HIV through blood transfusion. Here we show the existence of a similar
condition in a subject who acquired HIV-1 seropositivity through the sexual
route.
PMID- 9557646
TI - The roles of Pol and Env in the assembly pathway of human foamy virus.
AB - Human foamy virus (HFV) is the prototype of the Spumavirus genus of retroviruses.
These viruses have a genomic organization close to that of other complex
retroviruses but have similarities to hepadnaviruses such as human hepatitis B
virus (HBV). Both HFV and HBV express their Pol protein independently of their
structural proteins. Retroviruses and hepadnaviruses differ in their requirements
for particle assembly and genome packaging. Assembly of retroviral particles
containing RNA genomes requires only the Gag structural protein. The Pol protein
is not required for capsid assembly, and the Env surface glycoprotein is not
required for release of virions from the cell. In contrast, assembly of
extracellular HBV particles containing DNA requires core structural protein and
polymerase (P protein) for assembly of nucleocapsids and requires surface
glycoproteins for release from the cell. We investigated the requirements for
synthesis of extracellular HFV particles by constructing mutants with either the
pol or env gene deleted. We found that the Pol protein is dispensable for
production of extracellular particles containing viral nucleic acid. In the
absence of Env, intracellular particles are synthesized but few or no
extracellular particles could be detected. Thus, foamy virus assembly is distinct
from that of other reverse transcriptase-encoding mammalian viruses.
PMID- 9557647
TI - Mutations in rotavirus nonstructural glycoprotein NSP4 are associated with
altered virus virulence.
AB - Rotaviruses are major pathogens causing life-threatening dehydrating
gastroenteritis in children and animals. One of the nonstructural proteins, NSP4
(encoded by gene 10), is a transmembrane, endoplasmic reticulum-specific
glycoprotein. Recently, our laboratory has shown that NSP4 causes diarrhea in 6-
to 10-day-old mice by functioning as an enterotoxin. To confirm the role of NSP4
in rotavirus pathogenesis, we sequenced gene 10 from two pairs of virulent and
attenuated porcine rotaviruses, the OSU and Gottfried strains. Comparisons of the
NSP4 sequences from these two pairs of rotaviruses suggested that structural
changes between amino acids (aa) 131 and 140 are important in pathogenesis. We
next expressed the cloned gene 10 from the OSU virulent (OSU-v) and OSU
attenuated (OSU-a) viruses by using the baculovirus expression system and
compared the biological activities of the purified proteins. NSP4 from OSU-v
virus increased intracellular calcium levels over 10-fold in intestinal cells
when added exogenously and 6-fold in insect cells when expressed endogenously,
whereas NSP4 from OSU-a virus had little effect. NSP4 from OSU-v caused diarrhea
in 13 of 23 neonatal mice, while NSP4 from OSU-a caused disease in only 4 of 25
mice (P < 0.01). These results suggest that avirulence is associated with
mutations in NSP4. Results from site-directed mutational analyses showed that
mutated OSU-v NSP4 with deletion or substitutions in the region of aa 131 to 140
lost its ability to increase intracellular calcium levels and to induce diarrhea
in neonatal mice, confirming the importance of amino acid changes from OSU-v NSP4
to OSU-a NSP4 in the alteration of virus virulence.
PMID- 9557648
TI - Structured-tree topology and adaptive evolution of the simian immunodeficiency
virus SIVsm envelope during serial passage in rhesus macaques according to
likelihood mapping and quartet puzzling.
AB - Species-specific strains of simian immunodeficiency virus (SIV) are nonpathogenic
in African primates. The SIV strain most closely related to human
immunodeficiency virus type 2 (HIV-2) is SIVsm, the strain specific to the sooty
mangabey (Cercocebus atys). Infection of Asian primates with SIV causes AIDS and
allows the study of the adaptive evolution of a lentivirus to replicate
efficiently in a new host, providing a useful animal model of HIV infection and
AIDS in humans. Serial passage of SIVsm from sooty mangabeys in rhesus macaques
drastically shortened the time of disease progression from 1.5 years to 1 month
as the retrovirus adapted to these Asian hosts. In the present study we analyzed
the quasispecies nature of the SIVsm envelope gene (env) during serial population
passage in rhesus macaques. We asked ourselves if phylogenetic evidence could be
provided for the structured topology of the SIVsm env tree and subsequently for
the adaptive evolution of SIVsm env. Likelihood mapping showed that phylogenetic
reconstruction of the passage was possible because a high percentage of the
sequence data had a "tree-like" form. Subsequently, quartet puzzling was used and
produced a phylogeny with a structure parallel to the known infection history.
The adaptation of SIVsm to Asian rhesus macaques appears to be an ordered process
in which the env evolves in a tree-like manner, particularly in its constant
regions.
PMID- 9557649
TI - Hepatitis delta antigen mediates the nuclear import of hepatitis delta virus RNA.
AB - Hepatitis delta virus (HDV) RNA replicates in the nuclei of virus-infected cells.
The mechanism of nuclear import of HDV RNA is so far unknown. Using a fluorescein
labeled HDV RNA introduced into partially permeabilized HeLa cells, we found that
HDV RNA accumulated only in the cytoplasm. However, in the presence of hepatitis
delta antigen (HDAg), which is the only protein encoded by HDV RNA, the HDV RNA
was translocated into the nucleus, suggesting that nuclear import of HDV RNA is
mediated by HDAg. Deletion of the nuclear localization signal (NLS) or RNA
binding motifs of HDAg resulted in the failure of nuclear import of HDV RNA,
indicating that both the NLS and an RNA-binding motif of HDAg are required for
the RNA-transporting activity of HDAg. Surprisingly, any one of the three
previously identified RNA-binding motifs was sufficient to confer the RNA
transporting activity. We have further shown that HDAg, via its NLS, interacts
with karyopherin alpha2 in vitro, suggesting that nuclear import of the HDAg-HDV
RNA complex is mediated by the karyopherin alpha2beta heterodimer. The nuclear
import of HDV RNA may be the first biological function of HDAg in the HDV life
cycle.
PMID- 9557650
TI - Hepatitis C virus core protein binds to the cytoplasmic domain of tumor necrosis
factor (TNF) receptor 1 and enhances TNF-induced apoptosis.
AB - The hepatitis C virus (HCV) core protein is known to be a multifunctional
protein, besides being a component of viral nucleocapsids. Previously, we have
shown that the core protein binds to the cytoplasmic domain of lymphotoxin beta
receptor, which is a member of tumor necrosis factor receptor (TNFR) family. In
this study, we demonstrated that the core protein also binds to the cytoplasmic
domain of TNFR 1. The interaction was demonstrated both by glutathione S
transferase fusion protein pull-down assay in vitro and membrane flotation method
in vivo. Both the in vivo and in vitro binding required amino acid residues 345
to 407 of TNFR 1, which corresponds to the "death domain" of this receptor. We
have further shown that stable expression of the core protein in a mouse cell
line (BC10ME) or human cell lines (HepG2 and HeLa cells) sensitized them to TNF
induced apoptosis, as determined by the TNF cytotoxicity or annexin V apoptosis
assay. The presence of the core protein did not alter the level of TNFR 1 mRNA in
the cells or expression of TNFR 1 on the cell surface, suggesting that the
sensitization of cells to TNF by the viral core protein was not due to up
regulation of TNFR 1. Furthermore, we observed that the core protein blocked the
TNF-induced activation of RelA/NF-kappaB in murine BC10ME cells, thus at least
partially accounting for the increased sensitivity of BC10ME cells to TNF.
However, NF-kappaB activation was not blocked in core protein-expressing HeLa or
HepG2 cells, implying another mechanism of TNF sensitization by core protein.
These results together suggest that the core protein can promote cell death
during HCV infection via TNF signaling pathways possibly as a result of its
interaction with the cytoplasmic tail of TNFR 1. Therefore, TNF may play a role
in HCV pathogenesis.
PMID- 9557651
TI - Substitution of ras for the herpesvirus saimiri STP oncogene in lymphocyte
transformation.
AB - STP-C488 (STP of herpesvirus saimiri [HVS] group C strain 488 [C488]) is the only
virus-encoded protein found to associate with cellular ras and activate ras
signal transduction pathways. To investigate an important role for ras signal
transduction in STP-dependent growth transformation, we constructed recombinant
strains of HVS C488 in which the STP-C488 oncogene was replaced with cellular
normal ras (c-ras) or viral oncogenic ras (v-ras). Recombinant HVS deltaSTP/v-ras
immortalized primary common marmoset T lymphocytes to interleukin-2-independent
growth as efficiently as wild-type HVS C488 (wt HVS), while recombinant HVS
deltaSTP/c-ras did so with low efficiency. Whereas wt HVS immortalized CD4- CD8+
single-positive T lymphocytes, HVS deltaSTP/c-ras- and HVS deltaSTP/v-ras
immortalized cells were principally CD4+ CD8+ double-positive T lymphocytes. In
addition, HVS deltaSTP/v-ras-immortalized T cells showed a high level of ras
expression and exhibited an adherent macrophage-like morphology. These phenotypes
were likely caused by the drastic activation of AP-1 transcriptional factor
activity. Finally, HVS deltaSTP/v-ras and HVS deltaSTP/c-ras each induced
lymphoma in one of two common marmosets, although onset of disease was more rapid
with the v-ras virus. These results demonstrate that ras can substitute for the
STP oncogene of HVS C488 to allow immortalized growth of primary lymphoid cells
and that an activated form of ras does so more efficiently than the normal
cellular form of ras.
PMID- 9557653
TI - Collaboration of antibody and inflammation in clearance of rabies virus from the
central nervous system.
AB - To investigate the involvement of various cellular and humoral aspects of
immunity in the clearance of rabies virus from the central nervous system, (CNS),
we studied the development of clinical signs and virus clearance from the CNS in
knockout mice lacking either B and T cells, CD8+ cytotoxic T cells, B cells,
alpha/beta interferon (IFN-alpha/beta) receptors, IFN-gamma receptors, or
complement components C3 and C4. Following intranasal infection with the
attenuated rabies virus CVS-F3, normal adult mice of different genetic
backgrounds developed a transient disease characterized by loss of body weight
and appetite depression which peaked at 13 days postinfection (p.i.). While these
animals had completely recovered by day 21 p.i., mice lacking either B and T
cells or B cells alone developed a progressive disease and succumbed to
infection. Mice lacking either CD8+ T cells, IFN receptors, or complement
components C3 and C4 showed no significant differences in the development of
clinical signs by comparison with intact counterparts having the same genetic
background. However, while infectious virus and viral RNA could be detected in
normal control mice only until day 8 p.i., in all of the gene knockout mice
studied except those lacking C3 and C4, virus infection persisted through day 21
p.i. Analysis of rabies virus-specific antibody production together with
histological assessment of brain inflammation in infected animals revealed that
clearance of CVS-F3 by 21 days p.i. correlated with both a strong inflammatory
response in the CNS early in the infection (day 8 p.i.), and the rapid (day 10
p.i.) production of significant levels of virus-neutralizing antibody (VNA).
These studies confirm that rabies VNA is an absolute requirement for clearance of
an established rabies virus infection. However, for the latter to occur in a
timely fashion, collaboration between VNA and inflammatory mechanisms is
necessary.
PMID- 9557652
TI - Absence of macrophage inflammatory protein-1alpha prevents the development of
blinding herpes stromal keratitis.
AB - Prior studies in our laboratory have suggested that the CC chemokine macrophage
inflammatory protein-1alpha (MIP-1alpha) may be an important mediator in the
blinding ocular inflammation which develops following herpes simplex virus type 1
(HSV-1) infection of the murine cornea. To directly test this hypothesis, MIP
1alpha-deficient (-/-) mice and their wild-type (+/+) counterparts were infected
topically on the scarified cornea with 2.5 x 10(5) PFU of HSV-1 strain RE and
subsequently graded for corneal opacity. Four weeks postinfection (p.i.), the
mean corneal opacity score of -/- mice was 1.1 +/- 0.3 while that of the +/+ mice
was 3.7 +/- 0.5. No detectable infiltrating CD4+ T cells were seen histologically
at 14 or 21 days p.i. in -/- animals, whereas the mean CD4+ T-cell count per
field (36 fields counted) in +/+ hosts was 26 +/- 2 (P < 0.001). In addition,
neutrophil counts in the -/- mouse corneas were reduced by >80% in comparison to
the wild-type controls. At 2 weeks p.i., no interleukin-2 or gamma interferon
could be detected in six of seven -/- mice, whereas both T-cell cytokines were
readily demonstrable in +/+ mouse corneas. Also, MIP-2 and monocyte
chemoattractant protein-1 protein levels were significantly lower in MIP-1alpha
/- mouse corneas than in +/+ host corneas, suggesting that MIP-1alpha directly,
or more likely indirectly, influences the expression of other chemokines.
Interestingly, despite the paucity of infiltrating cells, HSV-1 clearance from
the eyes of -/- mice was not significantly different from that observed in +/+
hosts. We conclude that MIP-1alpha is not needed to control virus growth in the
cornea but is essential for the development of severe stromal keratitis.
PMID- 9557654
TI - Scaffold attachment region-mediated enhancement of retroviral vector expression
in primary T cells.
AB - We have studied retroviral transgene expression in primary human lymphocytes. Our
data demonstrate that transgene expression is high in activated primary CD4+ T
cells but significantly decreased in mitotically quiescent cells. Incorporation
of a DNA fragment from the scaffold attachment region (SAR) of the human beta
interferon gene into the vector improved transgene expression, particularly in
quiescent cells. The SAR element functioned in an orientation-dependent manner
and enhanced expression of Moloney murine leukemia virus- and murine embryonic
stem cell-based vectors. Clonal analysis of transduced T cells showed that the
SAR sequence did not confer position-independent expression on a transgene but
rather prevented the decrease of expression when cells became quiescent. The SAR
sequence also enhanced transgene expression in T cells generated from
retrovirally transduced CD34-enriched hematopoietic progenitor-stem cells in a
SCID-hu thymus-liver mouse model. We have used the SAR-containing retroviral
vector to express the RevM10 gene, a trans-dominant mutant of the human
immunodeficiency virus type 1 (HIV-1) Rev gene. Compared to a standard retroviral
vector, the SAR-containing vector was up to 2 orders of magnitude more efficient
in inhibiting replication of the HIV-1 virus in infected CD4+ peripheral blood
lymphocyte populations in vitro. This is the first demonstration that SAR
elements can be used to improve retroviral vector expression in human primary T
cells.
PMID- 9557655
TI - Cell cycle dysregulation by human cytomegalovirus: influence of the cell cycle
phase at the time of infection and effects on cyclin transcription.
AB - Human cytomegalovirus (HCMV) infection inhibits cell cycle progression and alters
the expression of cyclins E, A, and B (F. M. Jault, J.-M. Jault, F. Ruchti, E. A.
Fortunato, C. Clark, J. Corbeil, D. D. Richman, and D. H. Spector, J. Virol.
69:6697-6704, 1995). In this study, we examined cell cycle progression, cyclin
gene expression, and early viral events when the infection was initiated at
different points in the cell cycle (G0, G1, and S). In all cases, infection led
to cell cycle arrest. Cells infected in G0 or G1 phase also showed a complete or
partial absence, respectively, of cellular DNA synthesis at a time when DNA
synthesis occurred in the corresponding mock-infected cells. In contrast, when
cells were infected near or during S phase, many cells were able to pass through
S phase and undergo mitosis prior to cell cycle arrest. S-phase infection also
produced a delay in the appearance of the viral cytopathic effect and in the
synthesis of immediate-early and early proteins. Labeling of cells with
bromodeoxyuridine immediately prior to HCMV infection in S phase revealed that
viral protein expression occurred primarily in cells which were not engaged in
DNA synthesis at the time of infection. The viral-mediated induction of cyclin E,
maintenance of cyclin-B protein levels, and inhibitory effects on the
accumulation of cyclin A were not significantly affected when infection occurred
during different phases of the cell cycle (G0, G1, and S). However, there was a
delay in the observed inhibition of cyclin A in cells infected during S phase.
This finding was in accord with the pattern of cell cycle progression and delay
in viral gene expression associated with S-phase infection. Analysis of the mRNA
revealed that the effects of the virus on cyclin E and cyclin A, but not on
cyclin B, were primarily at the transcriptional level.
PMID- 9557656
TI - An array of novel murine spleen focus-forming viruses that activate the
erythropoietin receptor.
AB - The Friend spleen focus-forming virus (SFFV) env gene encodes a 409-amino-acid
glycoprotein with an apparent Mr of 55,000 (gp55) that binds to erythropoietin
receptors (EpoR) to stimulate erythroblastosis. We reported previously the in
vivo selection during serial passages in mice of several evolutionary
intermediates that culminated in the formation of a novel SFFV (M. E. Hoatlin, E.
Gomez-Lucia, F. Lilly, J. H. Beckstead, and D. Kabat, J. Virol. 72:3602-3609,
1998). A mouse injected with a retroviral vector in the presence of a
nonpathogenic helper virus developed long-latency erythroblastosis, and
subsequent viral passages resulted in more pathogenic isolates. The viruses taken
from these mice converted an erythropoietin-dependent cell line (BaF3/EpoR) into
factor-independent derivatives. Western blot analysis of cell extracts with an
antiserum that broadly reacts with murine retroviral envelope glycoproteins
suggested that the spleen from the initial mouse with mild erythoblastosis
contained an array of viral components that were capable of activating EpoR. DNA
sequence analysis of the viral genomes cloned from different factor-independent
cell clones revealed env genes with open reading frames encoding 644, 449, and
187 amino acids. All three env genes contained 3' regions identical to that of
SFFV, including a 6-bp duplication and a single-base insertion that have been
shown previously to be critical for pathogenesis. However, the three env gene
sequences did not contain any polytropic sequences and were divergent in their 5'
regions, suggesting that they had originated by recombination and partial
deletions of endogenously inherited MuLV env sequences. These results suggest
that the requirements for EpoR activation by SFFV-related viruses are dependent
on sequences at the 3' end of the env gene and not on the polytropic regions or
on the 585-base deletions that are common among the classical strains of SFFV.
Moreover, sequence analysis of the different recombinants and deletion mutants
revealed that short direct and indirect repeat sequences frequently flanked the
deletions that had occurred, suggesting a reverse transcriptase template jumping
mechanism for this rapid retroviral diversification.
PMID- 9557657
TI - The Cys-rich region of hepatitis A virus cellular receptor 1 is required for
binding of hepatitis A virus and protective monoclonal antibody 190/4.
AB - The hepatitis A virus cellular receptor 1 (HAVcr-1) cDNA codes for a class I
integral membrane glycoprotein, termed havcr-1, of unknown natural function which
serves as an African green monkey kidney (AGMK) cell receptor for HAV. The
extracellular domain of havcr-1 has an N-terminal Cys-rich region that displays
homology with sequences of members of the immunoglobulin superfamily, followed by
a Thr/Ser/Pro (TSP)-rich region characteristic of mucin-like O-glycosylated
proteins. The havcr-1 glycoprotein contains four putative N-glycosylation sites,
two in the Cys-rich region and two in the TSP-rich region. To characterize havcr
1 and define region(s) involved in HAV receptor function, we expressed the TSP
rich region in Escherichia coli fused to glutathione S-transferase and generated
antibodies (Ab) in rabbits (anti-GST2 Ab). Western blot analysis with anti-GST2
Ab detected 62- and 65-kDa bands in AGMK cells and 59-, 62-, and 65-kDa bands in
dog cells transfected with the HAVcr-1 cDNA (cr5 cells) but not in dog cells
transfected with the vector alone (DR2 cells). Treatment of AGMK and cr5 cell
extracts with peptide-N-glycosidase F resulted in the collapse of the havcr-1
specific bands into a single band of 56 kDa, which indicated that different N
glycosylated forms of havcr-1 were expressed in these cells. Treatment of AGMK
and cr5 cells with tunicamycin reduced binding of protective monoclonal Ab (MAb)
190/4, which suggested that N-glycans are required for binding of MAb 190/4 to
havcr-1. To test this hypothesis, havcr-1 mutants lacking the N-glycosylation
motif at the first site (mut1), second site (mut2), and both (mut3) sites were
constructed and transfected into dog cells. Binding of MAb 190/4 and HAV to mut1
and mut3 cells was highly reduced, while binding to mut2 cells was not affected
and binding to dog cells expressing an havcr-1 construct containing a deletion of
the Cys-rich region (d1- cells) was undetectable. HAV-infected cr5 and mut2 cells
but not mut1, mut3, d1-, and DR2 cells developed the characteristic cytoplasmic
granular fluorescence of HAV-infected cells. These results indicate that the Cys
rich region of havcr-1 and its first N-glycosylation site are required for
binding of protective MAb 190/4 and HAV receptor function.
PMID- 9557658
TI - Transgenic mice secreting coronavirus neutralizing antibodies into the milk.
AB - Ten lines of transgenic mice secreting transmissible gastroenteritis coronavirus
(TGEV) neutralizing recombinant monoclonal antibodies (rMAbs) into the milk were
generated. The rMAb light- and heavy-chain genes were assembled by fusing the
genes encoding the variable modules of the murine MAb 6A.C3, which binds an
interspecies conserved coronavirus epitope essential for virus infectivity, and a
constant module from a porcine myeloma with the immunoglobulin A (IgA) isotype.
The chimeric antibody led to dimer formation in the presence of J chain. The
neutralization specific activity of the recombinant antibody produced in
transiently or stably transformed cells was 50-fold higher than that of a
monomeric rMAb with the IgG1 isotype and an identical binding site. This rMAb had
titers of up to 10(4) by radioimmunoassay (RIA) and neutralized virus infectivity
up to 10(4)-fold. Of 23 transgenic mice, 17 integrated both light and heavy
chains, and at least 10 of them transmitted both genes to the progeny, leading to
100% of animals secreting functional TGEV neutralizing antibody during lactation.
Selected mice produced milk with TGEV-specific antibody titers higher than 10(6)
as determined by RIA, neutralized virus infectivity by 10(6)-fold, and produced
up to 6 mg of antibody per ml. Antibody expression levels were transgene copy
number independent and integration site dependent. Comicroinjection of the
genomic beta-lactoglobulin gene with rMAb light- and heavy-chain genes led to the
generation of transgenic mice carrying the three transgenes. The highest antibody
titers were produced by transgenic mice that had integrated the antibody and beta
lactoglobulin genes, although the number of transgenic animals generated does not
allow a definitive conclusion on the enhancing effect of beta-lactoglobulin
cointegration. This approach may lead to the generation of transgenic animals
providing lactogenic immunity to their progeny against enteric pathogens.
PMID- 9557659
TI - Relative replicative fitness of zidovudine-resistant human immunodeficiency virus
type 1 isolates in vitro.
AB - Replication of mixtures of two or more human immunodeficiency virus type 1 (HIV
1) variants would be expected to result in the eventual selection of the fittest
virus due to Darwinian competition among the variants. The relative proportions
of known HIV-1 variants (which may differ only by a single nucleotide from a
standard "wild-type" virus, HIV-1HXB2) in mixed viral cultures were quantified by
analysis of automated sequence signals of reverse transcriptase PCR products.
With this method, the relative levels of replicative fitness of several
zidovudine (3'-azidothymidine)-resistant HIV-1HXB2 variants were estimated under
controlled in vitro conditions by measuring the rate of change in the proportions
of viral variants as they replicated in cell cultures both in the presence and in
the absence of drug selection pressure. These variants were engineered to contain
commonly observed zidovudine resistance mutations in the HIV-1 reverse
transcriptase (M41L, K70R, T215Y, and M41L+T215Y). In the absence of zidovudine,
all variants tested displayed reduced replicative fitness compared to wild-type
HIV-1HXB2. The order of relative fitness was wild type > K70R >> T215Y =
M41L+T215Y > M41L. Mixed cultures in the presence of zidovudine showed a dose
dependent selection pressure against the wild-type virus which varied according
to the resistance profile of each virus. The information gathered from this
approach provides insight into competition among multiple HIV-1 variants, which
likely occurs in vivo with drug selection pressure, and may be applicable in more
complex mathematical models for predicting the emergence of HIV-1 variants after
the initiation of antiretroviral therapy.
PMID- 9557661
TI - Effect of cleavage mutants on syncytium formation directed by the wild-type
fusion protein of Newcastle disease virus.
AB - The effects of Newcastle disease virus (NDV) fusion (F) glycoprotein cleavage
mutants on the cleavage and syncytium-forming activity of the wild-type F protein
were examined. F protein cleavage mutants were made by altering amino acids in
the furin recognition region (amino acids 112 to 116) in the F protein of a
virulent strain of NDV. Four mutants were made: Q114P replaced the glutamine
residue with proline; K115G replaced lysine with glycine; double mutant K115G,
R113G replaced both a lysine and an arginine with glycine residues; and a triple
mutant, R112G, K115G, F117L, replaced three amino acids to mimic the sequence
found in avirulent strains of NDV. All mutants except Q114P were cleavage
negative and fusion negative. However, addition of exogenous trypsin cleaved all
mutant F proteins and activated fusion. As expected for an oligomeric protein,
the fusion-negative mutants had a dominant negative phenotype: cotransfection of
wild-type and mutant F protein cDNAs resulted in an inhibition of syncytium
formation. The presence of the mutant F protein did not inhibit cleavage of the
wild-type protein. Furthermore, evidence is presented that suggests that the
mutant protein and the wild-type protein formed heterooligomers. By measuring the
syncytium-forming activity of the wild-type protein at various ratios of
expression of mutant and wild-type protein, results were obtained that are most
consistent with the notion that the size of the functionally active NDV F protein
in these assays is a single oligomer, likely a trimer. That a larger oligomer,
containing a mix of both wild-type and mutant F proteins, has partial activity
cannot, however, be ruled out.
PMID- 9557662
TI - Phosphorylation of the core protein of hepatitis B virus by a 46-kilodalton
serine kinase.
AB - Core protein is the major component of the core particle (nucleocapsid) of human
hepatitis B virus. Core particles and core proteins are involved in a number of
important functions in the replication cycle of the virus, including RNA
packaging, DNA synthesis, and recognition of viral envelope proteins. Core
protein is a phosphoprotein with most, if not all, of the phosphorylation on C
terminal serine residues. In this study, we identified a serine kinase activity
from the ribosome-associated protein fraction of cytoplasm that could
specifically bind and phosphorylate the C-terminal portion of recombinant core
protein. This kinase is referred to as core-associated kinase (CAK). CAK could be
inhibited by the kinase inhibitors heparin and manganese ions but not by
spermidine, DRB, H89, or H7, indicating that CAK is distinct from protein kinase
A and protein kinase C. CAK could be partially purified by heparin-Sepharose CL
6B and phosphocellulose P11 columns. By using a far-Western assay, three specific
proteins, of 46, 35, and 13 kDa, were shown to interact with the C-terminal part
of the core protein. These three proteins were present only in the eluted
fractions that contains the CAK activity. An in-gel kinase assay showed that a 46
kDa kinase in the same fraction could bind and phosphorylate the C-terminal part
of the recombinant core protein. These results indicate that this 46-kDa kinase
is most probably CAK. A similar 46-kDa kinase, which exhibits the same profile of
sensitivity to kinase inhibitors as that of CAK, is present in both purified
intracellular core particles and extracellular 42-nm virions, suggesting that CAK
is a candidate for the core particle-associated kinase.
PMID- 9557660
TI - The herpes simplex virus type 1 U(L)17 gene encodes virion tegument proteins that
are required for cleavage and packaging of viral DNA.
AB - Previous studies have suggested that the U(L)17 gene of herpes simplex virus type
1 (HSV-1) is essential for virus replication. In this study, viral mutants
incorporating either a lacZ expression cassette in place of 1,490 bp of the 2,109
bp U(L)17 open reading frame [HSV-1(deltaU(L)17)] or a DNA oligomer containing an
in-frame stop codon inserted 778 bp from the 5' end of the U(L)17 open reading
frame [HSV-1(U(L)17-stop)] were plaque purified on engineered cell lines
containing the U(L)17 gene. A virus derived from HSV-1(U(L)17-stop) but
containing a restored U(L)17 gene was also constructed and was designated HSV
1(U(L)17-restored). The latter virus formed plaques and cleaved genomic viral DNA
in a manner indistinguishable from wild-type virus. Neither HSV-1(deltaU(L)17)
nor HSV-1(U(L)17-stop) formed plaques or produced infectious progeny when
propagated on noncomplementing Vero cells. Furthermore, genomic end-specific
restriction fragments were not detected in DNA purified from noncomplementing
cells infected with HSV-1(deltaU(L)17) or HSV-1(U(L)17-stop), whereas end
specific fragments were readily detected when the viruses were propagated on
complementing cells. Electron micrographs of thin sections of cells infected with
HSV-1(deltaU(L)17) or HSV-1(U(L)17-stop) illustrated that empty capsids
accumulated in the nuclei of Vero cells, whereas DNA-containing capsids
accumulated in the nuclei of complementing cells and enveloped virions were found
in the cytoplasm and extracellular space. Additionally, protein profiles of
capsids purified from cells infected with HSV-1(deltaU(L)17) compared to wild
type virus show no detectable differences. These data indicate that the U(L)17
gene is essential for virus replication and is required for cleavage and
packaging of viral DNA. To characterize the U(L)17 gene product, an anti-U(L)17
rabbit polyclonal antiserum was produced. The antiserum reacted strongly with a
major protein of apparent Mr 77,000 and weakly with a protein of apparent Mr
72,000 in wild-type infected cell lysates and in virions. Bands of similar sizes
were also detected in electrophoretically separated tegument fractions of virions
and light particles and yielded tryptic peptides of masses characteristic of the
predicted U(L)17 protein. We therefore conclude that the U(L)17 gene products are
associated with the virion tegument and note that they are the first tegument
associated proteins shown to be required for cleavage and packaging of viral DNA.
PMID- 9557663
TI - The class II membrane glycoprotein G of bovine respiratory syncytial virus,
expressed from a synthetic open reading frame, is incorporated into virions of
recombinant bovine herpesvirus 1.
AB - The bovine herpesvirus 1 (BHV-1) recombinants BHV-1/eG(ori) and BHV-1/eG(syn)
were isolated after insertion of expression cassettes which contained either a
genomic RNA-derived cDNA fragment (BHV-1/eG(ori)) or a modified, chemically
synthesized open reading frame (ORF) (BHV-1/eG(syn)), which both encode the
attachment glycoprotein G of bovine respiratory syncytial virus (BRSV), a class
II membrane glycoprotein. Northern blot analyses and nuclear runoff transcription
experiments indicated that transcripts encompassing the authentic BRSV G ORF were
unstable in the nucleus of BHV-1/eG(ori)-infected cells. In contrast, high levels
of BRSV G RNA were detected in BHV-1/eG(syn)-infected cells. Immunoblots showed
that the BHV-1/eG(syn)-expressed BRSV G glycoprotein contains N- and O-linked
carbohydrates and that it is incorporated into the membrane of infected cells and
into the envelope of BHV-1/eG(syn) virions. The latter was also demonstrated by
neutralization of BHV-1/eG(syn) infectivity by monoclonal antibodies or
polyclonal anti-BRSV G antisera and complement. Our results show that expression
of the BRSV G glycoprotein by BHV-1 was dependent on the modification of the BRSV
G ORF and indicate that incorporation of class II membrane glycoproteins into BHV
1 virions does not necessarily require BHV-1-specific signals. This raises the
possibility of targeting heterologous polypeptides to the viral envelope, which
might enable the construction of BHV-1 recombinants with new biological
properties and the development of improved BHV-1-based live and inactivated
vector vaccines.
PMID- 9557664
TI - Dendritic cells efficiently induce protective antiviral immunity.
AB - Cytotoxic T lymphocytes (CTL) are essential for effective immunity to various
viral infections. Because of the high speed of viral replication, control of
viral infections imposes demanding functional and qualitative requirements on
protective T-cell responses. Dendritic cells (DC) have been shown to efficiently
acquire, transport, and present antigens to naive CTL in vitro and in vivo. In
this study, we assessed the potential of DC, either pulsed with the lymphocytic
choriomeningitis virus (LCMV)-specific peptide GP33-41 or constitutively
expressing the respective epitope, to induce LCMV-specific antiviral immunity in
vivo. Comparing different application routes, we found that only 100 to 1,000 DC
had to reach the spleen to achieve protective levels of CTL activation. The DC
induced antiviral immune response developed rapidly and was long lasting. Already
at day 2 after a single intravenous immunization with high doses of DC (1 x 10(5)
to 5 x 10(5)), mice were fully protected against LCMV challenge infection, and
direct ex vivo cytotoxicity was detectable at day 4 after DC immunization. At day
60, mice were still protected against LCMV challenge infection. Importantly,
priming with DC also conferred protection against infections in which the homing
of CTL into peripheral organs is essential: DC-immunized mice rapidly cleared an
infection with recombinant vaccinia virus-LCMV from the ovaries and eliminated
LCMV from the brain, thereby avoiding lethal choriomeningitis. A comparison of DC
constitutively expressing the GP33-41 epitope with exogenously peptide-pulsed DC
showed that in vivo CTL priming with peptide-loaded DC is not limited by turnover
of peptide-major histocompatibility complex class I complexes. We conclude that
the priming of antiviral CTL responses with DC is highly efficient, rapid, and
long lasting. Therefore, the use of DC should be considered as an efficient means
of immunization for antiviral vaccination strategies.
PMID- 9557665
TI - Two RING finger proteins, the oncoprotein PML and the arenavirus Z protein,
colocalize with the nuclear fraction of the ribosomal P proteins.
AB - The promyelocytic leukemia (PML) protein forms nuclear bodies which are relocated
to the cytoplasm by the RNA virus lymphocytic choriomeningitis virus (LCMV). The
viral Z protein directly binds to PML and can relocate the nuclear bodies. Others
have observed that LCMV virions may contain ribosomes; hence, we investigated the
effects of infection on the distribution of ribosomal P proteins (P0, P1, and P2)
with PML as a reference point. We demonstrate an association of PML bodies with P
proteins by indirect immunofluorescence and coimmunoprecipitation experiments,
providing the first evidence of nucleic acid-binding proteins associated with PML
bodies. We show that unlike PML, the P proteins are not redistributed upon
infection. Immunofluorescence and coimmunoprecipitation studies indicate that the
viral Z protein binds the nuclear, but not the cytoplasmic, fraction of P0. The
nuclear fraction of P0 has been associated with translationally coupled DNA
excision repair and with nonspecific endonuclease activity; thus, P0 may be
involved in nucleic acid processing activities necessary for LCMV replication.
During the infection process, PML, P1, and P2 are downregulated but P0 remains
unchanged. Further, P0 is present in virions while PML is not, indicating some
selectivity in the assembly of LCMV.
PMID- 9557666
TI - Hepatitis C virus structural proteins assemble into viruslike particles in insect
cells.
AB - Hepatitis C virus (HCV) is a leading cause of chronic hepatitis in the world. The
study of HCV has been hampered by the low level of viral particles in infected
individuals, the inability to propagate efficiently the virus in cultured cells,
and the lack of a convenient animal model. Due to these obstacles, neither the
structure of the virus nor the prerequisites for its assembly have been clearly
defined. In this report, we describe a model for the production and purification
of HCV-like particles in insect cells using a recombinant baculovirus containing
the cDNA of the HCV structural proteins. In insect cells, expressed HCV
structural proteins assembled into enveloped viruslike particles (40 to 60 nm in
diameter) in large cytoplasmic cisternae, presumably derived from the endoplasmic
reticulum. Biophysical characterization of viruslike particles by CsCl and
sucrose gradient centrifugation revealed biophysical properties similar to those
of putative virions isolated from infected humans. The results suggested that HCV
core and envelope proteins without p7 were sufficient for viral particle
formation. Analysis of particle-associated nucleic acids demonstrated that HCV
RNAs were selectively incorporated into the particles over non-HCV transcripts.
The synthesis of HCV-like particles in insect cells may provide an important tool
to determine the structural requirements for HCV particle assembly as well as to
study viral genome encapsidation and virus-host interactions. The described
system may also represent a potential approach toward vaccine development.
PMID- 9557667
TI - Temporal mapping of transcripts in herpesvirus 6 variants.
AB - To define the molecular features characteristic of the early stages of infection
of lymphocytes with human herpesvirus 6 (HHV-6) variant A or B, we studied the
temporal regulation of expression of selected sets of viral genes. Thus, U42,
U94, U89-U90, U73, and U39 are alpha genes since their transcripts (i) were made
in the presence of inhibitors of protein synthesis and (ii) were detected 3 h
after infection of untreated cells. U41, U53, U31, and U19 are beta genes since
their expression is inhibited by cycloheximide but not by phosphonoacetate, an
inhibitor of DNA synthesis. U100 is a gamma gene since its spliced transcript
encoding the structural glycoprotein gp82/105 was first detected 16 h after
infection of untreated cells but could not be detected in cells treated with
phosphonoacetate. HHV-6 variants differ in the transcription patterns of their
genes. U16-U17 originates a splice transcript and is regulated as alpha in HHV-6B
and as beta in HHV-6A. U91 generates two transcripts, amplified as 476- and 374
bp PCR fragments. The 476-bp fragment is alpha in HHV-6A-infected cells but beta
in HHV-6B-infected cells. Conversely, the 374-bp fragment is beta in HHV-6A
infected cells and alpha in HHV-6B-infected cells. Furthermore, the spliced
product of U18-U19-U20 (526 bp) is beta in HHV-6A-infected cells, but only a
partially spliced form (1.9 kb) was detected at late stages of infection in HHV
6B. HHV-6 transcription was also studied in nonproductive lymphoid cells, and the
same transcription pattern detected during lytic infection was observed. Also,
HHV-6 variants maintain the differences in U91, U16-17, and U18-U19-U20. We
conclude that, as expected from the sequencing data, gene expression is generally
similar in HHV-6 variants. However, transcription of selected genes in HHV-6A and
HHV-6B differs with respect to temporal regulation and splicing pattern.
Furthermore, the identification of viral functions expressed during the different
stages of lytic replication suggests that reverse transcription-PCR for HHV-6
genes is a useful diagnostic approach to differentiate between latent and
productive HHV-6 infection.
PMID- 9557668
TI - Antiviral activity of the proteasome on incoming human immunodeficiency virus
type 1.
AB - Following cell surface receptor binding and membrane fusion, human
immunodeficiency virus (HIV) virion cores are released in the cytoplasm. Incoming
viral proteins represent potential targets for cytosolic proteases. We show that
treatment of target cells with the proteasome inhibitors MG132 and lactacystin
increased the efficiency of HIV infection. Proteasome inhibitors were active at
the early steps of the viral cycle. Incoming p24Gag proteins accumulated in the
cytosol, and larger amounts of proviral DNA were synthesized. In vitro, purified
20S proteasome degraded HIV virion components. Thus, degradation of incoming
viral proteins by the proteasome represents an early intracellular defense
against infection.
PMID- 9557670
TI - Effect of water-based microencapsulation on protection against EDIM rotavirus
challenge in mice.
AB - We determined the capacity of microcapsules formed by the combination of sodium
alginate, an aqueous anionic polymer, and spermine hydrochloride, an aqueous
cationic amine, to enhance protection against rotavirus challenge in mice. Adult
BALB/c mice were orally inoculated with either free or microencapsulated
rotavirus (simian rotavirus strain RRV) and challenged 6 or 16 weeks later with
murine rotavirus strain EDIM. Virus-specific humoral immune responses were
determined at the time of challenge and 4 days after challenge by intestinal
fragment culture. We found that spermine-alginate microcapsules enhanced
protection against challenge 16 weeks after immunization but not 6 weeks after
immunization. Quantities of virus-specific immunoglobulin A produced by small
intestinal lamina propria lymphocytes were correlated with the degree of
protection against challenge afforded by spermine-alginate microcapsules.
Possible mechanisms by which microcapsules enhance protection against rotavirus
challenge are discussed.
PMID- 9557669
TI - Involvement of endoplasmic reticulum chaperones in the folding of hepatitis C
virus glycoproteins.
AB - The hepatitis C virus (HCV) genome encodes two envelope glycoproteins (E1 and E2)
which interact noncovalently to form a heterodimer (E1-E2). During the folding
and assembly of HCV glycoproteins, a large portion of these proteins are trapped
in aggregates, reducing the efficiency of native E1-E2 complex assembly. To
better understand this phenomenon and to try to increase the efficiency of HCV
glycoprotein folding, endoplasmic reticulum chaperones potentially interacting
with these proteins were studied. Calnexin, calreticulin, and BiP were shown to
interact with E1 and E2, whereas no interaction was detected between GRP94 and
HCV glycoproteins. The association of HCV glycoproteins with calnexin and
calreticulin was faster than with BiP, and the kinetics of interaction with
calnexin and calreticulin were very similar. However, calreticulin and BiP
interacted preferentially with aggregates whereas calnexin preferentially
associated with monomeric forms of HCV glycoproteins or noncovalent complexes.
Tunicamycin treatment inhibited the binding of HCV glycoproteins to calnexin and
calreticulin, indicating the importance of N-linked oligosaccharides for these
interactions. The effect of the co-overexpression of each chaperone on the
folding of HCV glycoproteins was also analyzed. However, the levels of native E1
E2 complexes were not increased. Together, our data suggest that calnexin plays a
role in the productive folding of HCV glycoproteins whereas calreticulin and BiP
are probably involved in a nonproductive pathway of folding.
PMID- 9557671
TI - Epizootic hemorrhagic disease: analysis of tissues by amplification and in situ
hybridization reveals widespread orbivirus infection at low copy numbers.
AB - A recent outbreak of hemorrhagic fever in wild ruminants in the northwest United
States was characterized by rapid onset of fever, followed shortly thereafter by
hemorrhage and death. As a result, a confirmed 1,000 white-tailed deer and
pronghorn antelope died over the course of 3 months. Lesions were multisystemic
and included severe edema, congestion, acute vascular necrosis, and hemorrhage.
Animals that died with clinical signs and/or lesions consistent with hemorrhagic
fever had antibody to epizootic hemorrhagic disease virus serotype 2 (EHDV-2) by
radioimmune precipitation but the antibody was limited exclusively to class
immunoglobulin M. These findings, indicative of acute infection, were
corroborated by the observation that numerous deer were found dead; however,
clinically affected deer were rarely seen during the outbreak. Furthermore, only
in animals with hemorrhagic lesions was EHDV-2 isolated and/or erythrocyte
associated EHDV-2 RNA detected by serotype-specific reverse transcription (RT)
PCR. By using a novel RT in situ PCR assay, viral nucleic acid was localized to
the cytoplasm of large numbers of tissue leukocytes and vascular endothelium in
tissues with hemorrhage and to vessels, demonstrating acute intimal and medial
necrosis. Because PCR amplification prior to in situ hybridization was essential
for detecting EHDV, the virus copy number within individual cells was low, <20
virus copies. These findings suggest that massive covert infection characterized
by rapid dissemination of virus facilitates the severe and lethal nature of this
disease.
PMID- 9557673
TI - Carbohydrates facilitate correct disulfide bond formation and folding of
rotavirus VP7.
AB - It is well established that glycosylation is essential for assembly of enveloped
viruses, but no information is yet available as to the function of carbohydrates
on the nonenveloped but glycosylated rotavirus. We show that tunicamycin and,
more pronouncedly, a combination of tunicamycin and brefeldin A treatment caused
misfolding of the luminal VP7 protein, leading to interdisulfide bond
aggregation. While formation of VP7 aggregates could be prevented under reducing
conditions, they reoccurred in less than 30 min after a shift to an oxidizing
milieu. Furthermore, while glycosylated VP7 interacted during maturation with
protein disulfide isomerase, nonglycosylated VP7 did not, suggesting that
glycosylation is a prerequisite for protein disulfide isomerase interaction.
While native NSP4, which does not possess S-S bonds, was not dependent on N
linked glycosylation or on protein disulfide isomerase assistance for maturation,
nonglycosylated NSP4 was surprisingly found to interact with protein disulfide
isomerase, further suggesting that protein disulfide isomerase can act both as an
enzyme and as a chaperone. In conclusion, our data suggest that the major
function of carbohydrates on VP7 is to facilitate correct disulfide bond
formation and protein folding.
PMID- 9557674
TI - A cellular protein binds vaccinia virus late promoters and activates
transcription in vitro.
AB - Available evidence indicates that the transcription of the late class of vaccinia
virus genes requires the participation of several virus-encoded proteins in
addition to the viral RNA polymerase. In this report we describe the
identification of a protein present in extracts of uninfected HeLa cells that
binds avidly to viral late promoter DNA. The protein bound specifically to
several different vaccinia virus late promoters but not an early nor an
intermediate promoter. DNase I footprinting localized the protein's binding site
to nucleotides surrounding the transcriptional start site of the I1L promoter.
Optimal promoter binding required sequences in the highly conserved TAAAT motif
at the transcriptional start site as well as sequences immediately upstream;
however, one variation on the motif's sequence did not affect promoter binding by
the protein. Partially purified late promoter binding protein (LPBP) was capable
of stimulating the transcription activity of extracts depleted of LPBP on a late
promoter-driven template, establishing LPBP as a transcription activator in
vitro. These results suggest that a cellular protein is responsible for targeting
vaccinia virus late promoters for initiation of transcription.
PMID- 9557672
TI - Simian immunodeficiency virus replicates to high levels in sooty mangabeys
without inducing disease.
AB - A serologic survey of primates living in a French zoo allowed identification of
three cases of infection with simian immunodeficiency virus in sooty mangabeys
(Cercocebus atys) (SIVsm). Viral isolates, which were designated SIVsmFr66,
SIVsmFr74, and SIVsmFr85, were obtained after short-term culture of mangabey
lymphoid cells. Phylogenetic analysis of gag and env sequences amplified directly
from mangabey tissues showed that the three SIVsmFr were genetically close and
that they constituted a new subtype within the diverse SIVsm-SIVmac-human
immunodeficiency virus type 2 (HIV-2) group. We could reconstruct the
transmission events that likely occurred in 1986 between the three animals and
evaluate the divergence of SIVsmFr sequences since transmission. The estimated
rate of mutation fixation was 6 x 10(-3) substitutions per site per year, which
was as high as the rate found for SIVmac infection in macaques. These data
indicated that SIVsmFr replicated at a high rate in mangabeys, despite the
nonpathogenic character of infection in this host. The viral load evaluated by
competitive PCR reached 20,000 viral DNA copies per 10(6) lymph node cells. In
addition, productively infected cells were readily detected in mangabey lymphoid
tissues by in situ hybridization. The amounts of viral RNA in plasma ranged from
10(5) to 10(7) copies per ml. The cell-associated and plasma viral loads were as
high as those seen in susceptible hosts (humans or macaques) during the
asymptomatic stage of HIV or SIVmac infections. Thus, the lack of pathogenicity
of SIVsm for its natural host cannot be explained by limited viral replication or
by tight containment of viral production.
PMID- 9557675
TI - Expression kinetics and mapping of the thymidine kinase transcript and an
immediate-early transcript from channel catfish virus.
AB - Three transcripts from the terminal repeat of the channel catfish virus (CCV;
also known as ictalurid herpesvirus 1) genome were mapped by S1 nuclease and
primer extension analyses as well as by cDNA sequencing. These transcripts, TR3,
TR5/6, and TR6, are encoded by open reading frame (ORF) 3, ORFs 5 and 6, and ORF
6, respectively, and correspond to those previously identified by sequence
analysis (A. J. Davison, Virology 186:9-14, 1992). ORF 5 has previously been
determined to encode thymidine kinase, but ORF 3 and ORF 6 encode proteins of
unknown function. Although all three transcripts accumulate to high levels in
cells infected in the presence of cycloheximide, kinetic analysis demonstrates
that TR5/6 and TR6 are either early or late transcripts that leak through the
cycloheximide block. In addition, two transcripts from the terminal repeat of the
CCV genome that were mapped previously and were thought to be immediate-early in
character, TR8a/9 and TR9, exhibit kinetics characteristic of early or late
transcripts. TR3 is an immediate-early transcript that appears to have a very
short half-life. In the 3' untranslated region of TR3, there are three copies of
an AU-rich element which has previously been shown to be involved in
destabilization of the oncogene c-fos and granulocyte/macrophage colony
stimulating factor mRNAs. mRNA destabilization may represent another mechanism by
which herpesviruses regulate the rapid switch in expression from immediate-early
genes to early genes during the transition to the early phase of infection.
PMID- 9557676
TI - The role of nucleocapsid and U5 stem/A-rich loop sequences in tRNA(3Lys) genomic
placement and initiation of reverse transcription in human immunodeficiency virus
type 1.
AB - We have studied the effect of mutations in the human immunodeficiency virus type
1 (HIV-1) nucleocapsid (NC) sequence on tRNA(3Lys) genomic placement, i.e., the
in vivo placement of primer tRNA(3Lys) on the HIV-1 primer binding site (PBS).
HIV-1 produced from COS cells transfected with wild-type or mutant proviral DNA
was used in this study. We have found that mutations in the amino acid sequences
flanking the first Cys-His box in the NC sequence produce the maximum inhibition
of genomic placement. A similar finding was obtained when the NC-facilitated
annealing of primer tRNA(3Lys) to the HIV PBS in vitro was studied. However,
since the genomic placement of tRNA(3Lys) occurs independently of precursor
protein processing, the NC mutations studied here have probably exerted their
effect through one or both of the precursor proteins, Pr55gag and/or Pr160(gag
pol). One mutation in the linker region between the two Cys-His boxes, P31L,
prevented packaging of both Pr160(gag-pol) and tRNA(3Lys) and prevented the
genomic placement of tRNA(3Lys). Both packaging and genomic placement were
rescued by cotransfection with a plasmid coding for wild-type Pr160(gag-pol). For
other linker mutations [R7R10K11 S, R32G, and S3(32-34)], packaging of Pr160(gag
pol) and tRNA(3Lys) was not affected, but genomic placement was, and placement
could not be rescued by cotransfection with plasmids coding for either Pr55gag or
Pr160(gag-pol). After placement, the initiation of reverse transcription within
extracellular virions is characterized by a 2-base DNA extension of the placed
tRNA(3Lys). This process requires precursor processing, and those NC mutations
which showed the most inhibition of initiation were in either of the two NC Cys
His boxes. Destabilization of a U5 stem-A-rich loop immediately upstream of the
PBS (through deletion of four consecutive A's in the loop) did not affect the in
vivo genomic placement of tRNA(3Lys) but resulted in the presence in the
extracellular virus of longer cDNA extensions of tRNA(3Lys), with a corresponding
decrease in the presence of unextended and 2-base-extended tRNA(3Lys).
PMID- 9557677
TI - Mutational scan of the human immunodeficiency virus type 2 integrase protein.
AB - Retroviral integrase (IN) cleaves linear viral DNA specifically near the ends of
the DNA (cleavage reaction) and subsequently couples the processed ends to
phosphates in the target DNA (integration reaction). In vitro, IN catalyzes the
disintegration reaction, which is the reverse of the integration reaction.
Ideally, we would like to test the role of each amino acid in the IN protein. We
mutagenized human immunodeficiency virus type 2 IN in a random way using PCR
mutagenesis and generated a set of mutants in which 35% of all residues were
substituted. Mutant proteins were tested for in vitro activity, e.g., site
specific cleavage of viral DNA, integration, and disintegration. Changes in 61 of
the 90 proteins investigated showed no phenotypic effect. Substitutions that
changed the choice of nucleophile in the cleavage reaction were found. These
clustered around the active-site residues Asp-116 and Glu-152. We also found
alterations of amino acids that affected cleavage and integration differentially.
In addition, we analyzed the disintegration activity of the proteins and found
substitutions of amino acids close to the dimer interface that enhanced
intermolecular disintegration activity, whereas other catalytic activities were
present at wild-type levels. This study shows the feasibility of investigating
the role of virtually any amino acid in a protein the size of IN.
PMID- 9557678
TI - Transactivation-competent bovine papillomavirus E2 protein is specifically
required for efficient repression of human papillomavirus oncogene expression and
for acute growth inhibition of cervical carcinoma cell lines.
AB - The papillomavirus E2 proteins can function as sequence-specific transactivators
or transrepressors of transcription and as cofactors in viral DNA replication. We
previously demonstrated that acute expression of the bovine papillomavirus type 1
(BPV1) E2 protein in HeLa and HT-3 cervical carcinoma cell lines greatly reduced
cellular proliferation by imposing a specific G1/S phase growth arrest. In this
report, we analyzed the effects of a panel of point mutations in the BPV1 E2
protein to identify the functional requirements for acute growth inhibition.
Disruption of E2-specific transactivation by mutations within either the
transactivation domain or the DNA binding domain severely impaired E2-mediated
growth inhibition in HeLa and HT-3 cells, even though these mutants retain
various other E2 activities. This result indicates that functional
transactivation activity is required for acute E2-mediated growth inhibition.
HeLa cells, which contain a wild-type p53 gene, and HT-3 cells, which contain a
transactivation-defective p53 gene, exhibited similar responses to the E2
mutants, suggesting that identical functions of the E2 protein were required for
growth arrest regardless of p53 status. Replacement of the E2 transactivation
domain with that of the herpes simplex virus VP16 generated a chimeric
transactivator that efficiently stimulated expression of an E2-responsive
reporter plasmid yet was completely defective for growth inhibition, suggesting
that an E2-specific transactivation function is required for growth arrest.
Surprisingly, the transactivation-defective E2 mutants were also markedly
defective in their ability to repress transcription of the native human
papillomavirus type 18 (HPV18) E6/E7 oncogenes in HeLa cells and of the HPV18
promoter present in a transfected reporter plasmid. These mutants were also
defective in their ability to increase p53 levels. Therefore, efficient
repression of the HPV18 promoter in HeLa cells is not merely a consequence of the
binding of an E2 protein to appropriately situated binding sites in the promoter.
PMID- 9557679
TI - The transmembrane domains of Sindbis virus envelope glycoproteins induce cell
death.
AB - Sindbis virus, the prototype alphavirus, kills cells by inducing apoptosis. To
investigate potential mechanisms by which Sindbis virus induces apoptosis, we
examined whether specific viral gene products were able to induce cell death.
Genes encoding the three structural proteins--capsid, the precursor E1 (6K plus
E1), and the precursor E2 (P62 or E3 plus E2)--were cotransfected with a beta
galactosidase reporter plasmid in transient-transfection assays in rat prostate
adenocarcinoma AT3 cells. Cell death, as determined by measuring the loss of blue
cells, was observed in AT3 cells transfected with 6K plus E1 and with P62 but not
in cells transfected with capsid. Deletion mutagenesis of P62 indicated that
large regions of the cytoplasmic domain and extracellular domain were not
essential for the induction of cell death. However, constructs containing the
minimal E3 signal sequence fused to the E2 transmembrane domain and the minimal
E3 signal sequence fused to the E1 transmembrane domain induced death as
efficiently as full-length P62 and 6K plus E1, whereas no cell death was observed
after transfection with a control construct containing the E3 signal sequence
linked to the transmembrane domain of murine CD4. These data demonstrate that
intracellular expression of the transmembrane domains of the Sindbis virus
envelope glycoproteins can kill AT3 cells.
PMID- 9557680
TI - Assembly of the herpes simplex virus capsid: preformed triplexes bind to the
nascent capsid.
AB - The herpes simplex virus type 1 (HSV-1) capsid is a T=16 icosahedral shell that
forms in the nuclei of infected cells. Capsid assembly also occurs in vitro in
reaction mixtures created from insect cell extracts containing recombinant
baculovirus-expressed HSV-1 capsid proteins. During capsid formation, the major
capsid protein, VP5, and the scaffolding protein, pre-VP22a, condense to form
structures that are extended into procapsids by addition of the triplex proteins,
VP19C and VP23. We investigated whether triplex proteins bind to the major capsid
scaffold protein complexes as separate polypeptides or as preformed triplexes.
Assembly products from reactions lacking one triplex protein were
immunoprecipitated and examined for the presence of the other. The results showed
that neither triplex protein bound unless both were present, suggesting that
interaction between VP19C and VP23 is required before either protein can
participate in the assembly process. Sucrose density gradient analysis was
employed to determine the sedimentation coefficients of VP19C, VP23, and VP19C
VP23 complexes. The results showed that the two proteins formed a complex with a
sedimentation coefficient of 7.2S, a value that is consistent with formation of a
VP19C-VP23(2) heterotrimer. Furthermore, VP23 was observed to have a
sedimentation coefficient of 4.9S, suggesting that this protein exists as a dimer
in solution. Deletion analysis of VP19C revealed two domains that may be required
for attachment of the triplex to major capsid-scaffold protein complexes; none of
the deletions disrupted interaction of VP19C with VP23. We propose that preformed
triplexes (VP19C-VP23(2) heterotrimers) interact with major capsid-scaffold
protein complexes during assembly of the HSV-1 capsid.
PMID- 9557681
TI - Transmission of human T-cell leukemia virus type 1 to mice.
AB - Human T-cell leukemia virus type 1 (HTLV-1) is associated with adult T-cell
leukemia/lymphoma, HTLV-1-associated myelopathy/tropical spastic paraparesis, and
other diseases. For prevention of the transmission of HTLV-1 and manifestation of
these diseases, a small-animal model, especially a mouse model, would be useful.
We injected HTLV-1-producing T cells (MT-2) intraperitoneally into neonatal
C3H/HeJ mice. While the antibody against HTLV-1 antigens was not detectable in
C3H/HeJ mice, HTLV-1 provirus was frequently detected in the spleen, lymph nodes,
and thymus by PCR. HTLV-1 provirus was present at the level of 0 to 30 molecules
in 10(5) spleen cells at the age of 15 weeks. In addition, a 59-bp flanking
sequence of the HTLV-1 integration site was amplified from the spleen DNA by
linker-mediated PCR and was confirmed to be derived from the mouse genome. HTLV-1
provirus was found in the T-cell fraction of the mouse spleen. These results
indicate that mice can be infected by HTLV-1 and could serve as an animal model
for the study of HTLV-1 infection and its pathogenesis in vivo.
PMID- 9557683
TI - Minimal template requirements for initiation of minus-strand synthesis in vitro
by the RNA-dependent RNA polymerase of turnip yellow mosaic virus.
AB - From mutational analysis of the 3'-terminal hairpin of turnip yellow mosaic virus
(TYMV) RNA and use of nonstructured C-rich RNA templates, we conclude that the
main determinant in the tRNA-like structure of TYMV RNA for initiation of minus
strand synthesis by the viral RNA-dependent RNA polymerase (RdRp) is the non-base
paired 3' ACC(A) end. Base pairing of this 3' end reduces the transcription
efficiency drastically, and deletion of only the 3'-terminal A residue results in
a fivefold drop in efficiency. The two C residues of the 3' ACCA end are required
for efficient transcription, as shown by substitution mutations. However, the 5'
A residue is not specifically involved in initiation of transcription, as shown
by substitution mutations. Furthermore, the hairpin stem and loop upstream of the
3' ACCA end also do not interact with the RdRp in a base-specific way. However,
for efficient transcription, the hairpin stem should be at least five bp in
length, while the calculated deltaG value should be less than -10.5 kcal/mol.
Unexpectedly, the use of nonstructured C-rich RNA templates showed that the RdRp
can start internally on an NCCN or NUCN sequence. Therefore, a possible function
of the tRNA-like structure of TYMV RNA may be to prevent internal initiation of
minus-strand synthesis.
PMID- 9557682
TI - Cloning of novel isoforms of the human Gli2 oncogene and their activities to
enhance tax-dependent transcription of the human T-cell leukemia virus type 1
genome.
AB - The expression of human T-cell leukemia virus type 1 (HTLV-1) is activated by
interaction of a viral transactivator protein, Tax, and cellular transcription
factor, CREB (cyclic AMP response element binding protein), which bind to a 21-bp
enhancer in the long terminal repeats (LTR). THP (Tax-helping protein) was
previously determined to enhance the transactivation by Tax protein. Here we
report novel forms of the human homolog of a member of the Gli oncogene family,
Gli2 (also termed Gli2/THP), an extended form of a zinc finger protein, THP,
which was described previously. Four possible isoforms (hGli2 alpha, beta, gamma,
and delta) are formed by combinations of two independent alternative splicings,
and all the isoforms could bind to a DNA motif, TRE2S, in the LTR. The longer
isoforms, alpha and beta, were abundantly expressed in various cell lines
including HTLV-1-infected T-cell lines. Fusion proteins of the hGli2 isoforms
with the DNA-binding domain of Gal4 activated transcription when the reporter
contained a Gal4-binding site and one copy of the 21-bp sequence, to which CREB
binds. This activation was observed only in the presence of Tax. The 21-bp
sequence in the reporter was also essential for the activation. These results
suggest that simultaneous binding of hGli2 and CREB to the respective sites in
the reporter seems to be critical for Tax protein to activate transcription.
Consequently, it is probable that the LTR can be regulated by two independent
signals through hGli2 and CREB, since the LTR contains the 21-bp and TRE2S
sequences in the vicinity.
PMID- 9557684
TI - The mouse H-2A region influences the envelope gene structure of tumor-associated
murine leukemia viruses.
AB - C57BL/10 (B10) strains congenic at the mouse major histocompatibility locus (H-2)
were injected with a modified ecotropic SL3-3 murine leukemia virus (MuLV) to
determine the effect of the H-2 genes on the envelope gene structure of
recombinant MuLVs. All tested strains rapidly developed T-cell lymphomas, and
recombinant proviruses were detected in the tumor DNAs by Southern blot. The
B10.D2 (H-2d), B10.Br (H-2k), B10.Q (H-2q), and B10.RIII (H-2r) strains exhibited
a TI phenotype in which almost all tumors contained type I recombinants. These
recombinants characteristically acquire envelope gene sequences from the
endogenous polytropic viruses but retain the 5' p15E (TM) gene sequences from the
ecotropic virus. The parental B10 (H-2b) strain, however, had a novel phenotype
that was designated NS for nonselective. Only 30% of the B10 tumors had
detectable type I recombinants, whereas a proportion of the others appeared to
contain type II recombinants that lacked the type I-specific ecotropic p15E gene
sequences. Studies of other B10 congenic strains with hybrid H-2 loci and
selected F1 animals revealed that the NS phenotype was regulated by a dominant
gene(s) that mapped to the A region of H-2b. These results demonstrate that a
host gene within the major histocompatibility complex can influence the genetic
evolution of pathogenic retroviruses in vivo.
PMID- 9557685
TI - Natural isolates of simian virus 40 from immunocompromised monkeys display
extensive genetic heterogeneity: new implications for polyomavirus disease.
AB - Simian virus 40 (SV40) DNAs in brain tissue and peripheral blood mononuclear
cells (PBMCs) of eight simian immunodeficiency virus-infected rhesus monkeys with
SV40 brain disease were analyzed. We report the detection, cloning, and
identification of five new SV40 strains following a quadruple testing
verification strategy. SV40 genomes with archetypal regulatory regions
(containing a duplication within the G/C-rich regulatory region segment and a
single 72-bp enhancer element) were recovered from seven animal brains, two
tissues of which also contained viral genomes with nonarchetypal regulatory
regions (containing a duplication within the G/C-rich regulatory region segment
as well as a variable duplication within the enhancer region). In contrast, PBMC
DNAs from five of six animals had viral genomes with both regulatory region
types. It appeared, based on T-antigen variable-region sequences, that
nonarchetypal virus variants arose de novo within each animal. The eighth animal
exclusively yielded a new type of SV40 strain (SV40-K661), containing a
protoarchetypal regulatory region (lacking a duplication within the G/C-rich
segment of the regulatory region and containing one 72-bp element in the enhancer
region), from both brain tissue and PBMCs. The presence of SV40 in PBMCs suggests
that hematogenous spread of viral infection may occur. An archetypal version of a
virus similar to SV40 reference strain 776 (a kidney isolate) was recovered from
one brain, substantiating the idea that SV40 is neurotropic as well as kidney
tropic. Indirect evidence suggests that maternal-infant transmission of SV40 may
have occurred in one animal. These findings provide new insights for human
polyomavirus disease.
PMID- 9557686
TI - Infectious molecular clones with the nonhomologous dimer initiation sequences
found in different subtypes of human immunodeficiency virus type 1 can recombine
and initiate a spreading infection in vitro.
AB - Recombinant forms of human immunodeficiency virus type 1 (HIV-1) have been shown
to be of major importance in the global AIDS pandemic. Viral RNA dimer formation
mediated by the dimerization initiation sequence (DIS) is believed to be
essential for viral genomic RNA packaging and therefore for RNA recombination.
Here, we demonstrate that HIV-1 recombination and replication are not restricted
by variant DIS loop sequences. Three DIS loop forms found among HIV-1 isolates,
DIS (CG), DIS (TA), and DIS (TG), when introduced into deletion mutants of HIV-1
recombined efficiently, and the progeny virions replicated with comparable
kinetics. A fourth DIS loop form, containing an artificial AAAAAA sequence
disrupting the putative DIS loop-loop interactions [DIS (A6)], supported
efficient recombination with DIS loop variants; however, DIS (A6) progeny virions
exhibited a modest replication disadvantage in mixed cultures. Our studies
indicate that the nonhomologous DIS sequences found in different HIV-1 subtypes
are not a primary obstacle to intersubtype recombination.
PMID- 9557687
TI - Predominance of HLA-restricted cytotoxic T-lymphocyte responses to serotype-cross
reactive epitopes on nonstructural proteins following natural secondary dengue
virus infection.
AB - We examined the memory cytotoxic T-lymphocytic (CTL) responses of peripheral
blood mononuclear cells (PBMC) obtained from patients in Thailand 12 months after
natural symptomatic secondary dengue virus infection. In all four patients
analyzed, CTLs were detected in bulk culture PBMC against nonstructural dengue
virus proteins. Numerous CD4+ and CD8+ CTL lines were generated from the bulk
cultures of two patients, KPP94-037 and KPP94-024, which were specific for NS1.2a
(NS1 and NS2a collectively) and NS3 proteins, respectively. All CTL lines derived
from both patients were cross-reactive with other serotypes of dengue virus. The
CD8+ NS1.2a-specific lines from patient KPP94-037 were HLA B57 restricted, and
the CD8+ NS3-specific lines from patient KPP94-024 were HLA B7 restricted. The
CD4+ CTL lines from patient KPP94-037 were HLA DR7 restricted. A majority of the
CD8+ CTLs isolated from patient KPP94-024 were found to recognize amino acids 221
to 232 on NS3. These results demonstrate that in Thai patients after symptomatic
secondary natural dengue infections, CTLs are mainly directed against
nonstructural proteins and are broadly cross-reactive.
PMID- 9557688
TI - Chromosome structure and human immunodeficiency virus type 1 cDNA integration:
centromeric alphoid repeats are a disfavored target.
AB - Integration of retroviral cDNA into host chromosomal DNA is an essential and
distinctive step in viral replication. Despite considerable study, the host
determinants of sites for integration have not been fully clarified. To
investigate integration site selection in vivo, we used two approaches. (i) We
have analyzed the host sequences flanking 61 human immunodeficiency virus type 1
(HIV-1) integration sites made by experimental infection and compared them to a
library of 104 control sequences. (ii) We have also analyzed HIV-1 integration
frequencies near several human repeated-sequence DNA families, using a repeat
specific PCR-based assay. At odds with previous reports from smaller-scale
studies, we found no strong biases either for or against integration near
repetitive sequences such as Alu or LINE-1 elements. We also did not find a clear
bias for integration in transcription units as proposed previously, although
transcription units were found somewhat more frequently near integration sites
than near controls. However, we did find that centromeric alphoid repeats were
selectively absent at integration sites. The repeat-specific PCR-based assay also
indicated that alphoid repeats were disfavored for integration in vivo but not as
naked DNA in vitro. Evidently the distinctive DNA organization at centromeres
disfavors cDNA integration. We also found a weak consensus sequence for host DNA
at integration sites, and assays of integration in vitro indicated that this
sequence is favored as naked DNA, revealing in addition an influence of target
primary sequence.
PMID- 9557689
TI - The Epstein-Barr virus BARF1 gene encodes a novel, soluble colony-stimulating
factor-1 receptor.
AB - Epstein-Barr virus (EBV) is a ubiquitous herpesvirus associated with infectious
mononucleosis and several tumors. The BARF1 gene is transcribed early after EBV
infection from the BamHI A fragment of the EBV genome. Evidence shown here
indicates that the BARF1 protein is secreted into the medium of transfected cells
and from EBV-carrying B cells induced to allow lytic replication of the virus.
Expression cloning identified colony-stimulating factor-1 (CSF-1) as a ligand for
BARF1. Computer-assisted analyses indicated that subtle amino acid sequence
homology exists between BARF1 and c-fins, the cellular proto-oncogene that is the
receptor for CSF-1. Recombinant BARF1 protein was found to be biologically
active, and it neutralized the proliferative effects of human CSF-1 in a dose
dependent fashion when assayed in vitro. Since CSF-1 is a pleiotropic cytokine
best known for its differentiating effects on macrophages, these data suggest
that BARF1 may function to modulate the host immune response to EBV infection.
PMID- 9557690
TI - Two types of virus-related particles are found during transmissible
gastroenteritis virus morphogenesis.
AB - The intracellular assembly of the transmissible gastroenteritis coronavirus
(TGEV) was studied in infected swine testis (ST) cells at different postinfection
times by using ultrathin sections of conventionally embedded infected cells,
freeze-substitution, and methods for detecting viral proteins and RNA at the
electron microscopy level. This ultrastructural analysis was focused on the
identification of the different viral components that assemble in infected cells,
in particular the spherical, potentially icosahedral internal core, a new
structural element of the extracellular infectious coronavirus recently
characterized by our group. Typical budding profiles and two types of virion
related particles were detected in TGEV-infected cells. While large virions with
an electron-dense internal periphery and a clear central area are abundant at
perinuclear regions, smaller viral particles, with the characteristic morphology
of extracellular virions (exhibiting compact internal cores with polygonal
contours) accumulate inside secretory vesicles that reach the plasma membrane.
The two types of virions coexist in the Golgi complex of infected ST cells. In
nocodazole-treated infected cells, the two types of virions coexist in altered
Golgi stacks, while the large secretory vesicles filled with virions found in
normal infections are not detected in this case. Treatment of infected cells with
the Golgi complex-disrupting agent brefeldin A induced the accumulation of large
virions in the cisternae that form by fusion of different membranous
compartments. These data, together with the distribution of both types of virions
in different cellular compartments, strongly suggest that the large virions are
the precursors of the small viral particles and that their transport through a
functional Golgi complex is necessary for viral maturation.
PMID- 9557691
TI - T-cell-line-tropic human immunodeficiency virus type 1 that is made resistant to
stromal cell-derived factor 1alpha contains mutations in the envelope gp120 but
does not show a switch in coreceptor use.
AB - The NL4.3 T-cell-line-tropic human immunodeficiency virus type 1 strain is
sensitive to the CXC chemokine stromal cell-derived factor 1alpha (SDF-1alpha),
the natural ligand for CXC chemokine receptor 4 (CXCR4); the 50% inhibitory
concentration (IC50) in MT-4 cells is 130 ng/ml. We generated resistant virus
through passaging of the virus in the presence of increasing concentrations of
SDF-1alpha. After 24 passages, the virus was no longer sensitive to SDF-1alpha
(SDF-1alpha(res) virus) (IC50, >2 microg/ml) and became resistant to SDF-1beta
(IC50, >2 microg/ml) and to a specific CXCR4 monoclonal antibody (IC50, >20
microg/ml). The SDF-1alpha(res) virus was about 10-fold less sensitive than the
wild-type virus to the bicyclam AMD3100, a specific CXCR4 antagonist. The SDF
1alpha(res) virus contained the following mutations in the gp120 molecule: N106K
in the V1 loop; S134N and F145L in the V2 loop; F245I in the C2 loop; K269E,
Q278H, I288V, and N293D in the V3 loop; a deletion of 5 amino acids (FNSTW) at
positions 364 to 368 in the V4 loop; and R378T in the CD4 binding domain.
Replication of the NL4.3 wild-type virus and the SDF-1alpha(res) virus was
demonstrated in U87 cells that coexpressed CD4 and CXCR4 (U87.CD4.CXCR4) but not
in U87.CD4.CCR5 cells. Thus, the resistant virus was not able to switch to the CC
chemokine receptor 5 (CCR5) coreceptor (the main coreceptor for macrophage-tropic
viruses). The SDF-1alpha(res) virus replicated in HOS.CD4 cells expressing CCR1,
CCR2b, CCR3, CCR4, CCR5, and CXCR4 but also in HOS.CD4.pBABE cells. However, all
HOS transfectant cells expressed a low level of CXCR4. Neither of the two virus
strains was able to infect HOS.CXCR4 or HOS.CCR5 transfectants, demonstrating the
necessity of the CD4 receptor. The T-cell-line-tropic SDF-1alpha(res) virus was
thus able to overcome the inhibitory effect of SDF-1alpha through mutations in
gp120 but still needed CXCR4 to enter the cells.
PMID- 9557692
TI - The 30-base-pair deletion in Chinese variants of the Epstein-Barr virus LMP1 gene
is not the major effector of functional differences between variant LMP1 genes in
human lymphocytes.
AB - One group of sequence variants of Epstein-Barr virus is characterized by a 10
amino-acid deletion within the CTAR-2 functional domain of the latent membrane
protein, LMP1. A role for this deletion in enhancing the tumorigenicity of the
viral oncogene in rodent fibroblasts was recently demonstrated. We examined the
effect of this deletion upon LMP1 function in four human lymphoid cell lines by
using three natural variants of LMP1: the prototype B95.8 gene and the CAO and
AG876 genes, both of which have codons 343 to 352 of the B95.8-LMP1 deleted.
These experiments revealed that LMP1-mediated upregulation of CD40 and CD54 was
markedly impaired (by 60 to 90%) with CAO-LMP1 compared with B95.8-LMP1. In
contrast, the function of AG876-LMP1 was indistinguishable from that of B95.8
LMP1 in two lines and was only slightly impaired in the other two lines.
Activation of NF-kappaB by CAO-LMP1 was not impaired in any of the lines; rather,
activation of an NF-kappaB reporter by CAO-LMP1 was consistently about twofold
greater than the activation with B95.8- or AG876-LMP1. Therefore, while the CAO
LMP1 is functionally distinct from the prototype B95.8-LMP1 in human lymphocytes,
the 10-amino-acid deletion appears not to be directly responsible. This
conclusion was confirmed by using a B95.8-LMP1 mutant with codons 343 to 352
deleted and chimerae of CAO- and B95.8-LMP1 in which the CTAR-2 domains of these
genes were exchanged. Sequences outside the CTAR-2 domain were implicated in the
distinct functional characteristics of CAO-LMP1 in human lymphoid cells.
PMID- 9557693
TI - Control of adenovirus early gene expression during the late phase of infection.
AB - The adenovirus gene regulatory program occurs in two distinct phases, as defined
by the onset of DNA replication. During the early phase, the E1A, E1B, E2, E3,
and E4 genes are maximally expressed, while the major late promoter (MLP) is
minimally expressed and transcription is attenuated. After the onset of DNA
replication, the IVa2 and pIX genes are expressed at high levels, transcription
from the MLP is unattenuated and fully activated, and early gene expression is
repressed. Although the cis elements and trans-acting factors responsible for the
late-phase activation of the MLP have been identified and characterized and the
role of DNA replication in activation has been established, the mechanism(s)
underlying the commensurate decrease in early gene expression has yet to be
elucidated. The results of this study demonstrate that this decrease depends on a
fully functional MLP. Specifically, virus mutants with severely deficient
transcription from the MLP exhibit a marked increase in expression of the E1A,
E1B, and E2 early genes. These increases were observed at the level of
transcription initiation, mRNA accumulation, and protein production. In addition,
expression from the late gene pIX, which is not contained within the major late
transcription unit (MLTU), is also markedly increased. To begin the analysis of
the mechanisms underlying these late-phase effects, mixed-infection experiments
with mutant and wild-type viruses were performed. The results show that the
effects on early gene expression, as measured both at the protein and RNA levels,
are mediated in trans and not in cis. These observations are consistent either
with a model in which one or more late protein products encoded by the MLTU acts
as a repressor of early gene expression or with one in which the wild-type MLP
competes with early promoters for limiting transcription factors.
PMID- 9557694
TI - Retrotransposition of nonviral RNAs in an avian packaging cell line.
AB - Retroviruses produced from the quail packaging cell line SE21Q1b predominantly
contain cellular RNAs instead of viral RNAs. These RNAs can be reverse
transcribed and integrated into the genomes of newly infected cells and are
thereafter referred to as newly formed retrogenes. We investigated whether
retrogene formation can occur within SE21Q1b cells themselves and whether this
occurs intracellularly or via extracellular reinfection. By using packaging cell
line mutants derived from the SE21Q1b provirus and selectable reporter
constructs, we found that the process requires envelope glycoproteins and a
retroviral packaging signal. Our results suggest that extracellular reinfection
is the primary route of retrotransposition of nonviral RNAs.
PMID- 9557695
TI - A broad range of chemokine receptors are used by primary isolates of human
immunodeficiency virus type 2 as coreceptors with CD4.
AB - Like human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency
virus (SIV), HIV-2 requires a coreceptor in addition to CD4 for entry into cells.
HIV and SIV coreceptor molecules belong to a family of seven-transmembrane-domain
G-protein-coupled receptors. Here we show that primary HIV-2 isolates can use a
broad range of coreceptor molecules, including CCR1, CCR2b, CCR3, CCR4, CCR5, and
CXCR4. Despite broad coreceptor use, the chemokine ligand SDF-1 substantially
blocked HIV-2 infectivity of peripheral blood mononuclear cells, indicating that
its receptor, CXCR4, was the predominant coreceptor for infection of these cells.
However, expression of CXCR4 together with CD4 on some cell types did not confer
susceptibility to infection by all CXCR4-using virus isolates. These data
therefore indicate that another factor(s) influences the ability of HIV-2 to
replicate in human cell types that express the appropriate receptors for virus
entry.
PMID- 9557696
TI - Secondary structures in the capsid protein coding sequence and 3' nontranslated
region involved in amplification of the tobacco etch virus genome.
AB - The 3'-terminal 350 nucleotides of the tobacco etch potyvirus (TEV) genome span
the end of the capsid protein (CP)-coding sequence and the 3' nontranslated
region (NTR). The CP-coding sequence within this region contains a 105-nucleotide
cis-active element required for genome replication (S. Mahajan, V. V. Dolja, and
J. C. Carrington, J. Virol. 70:4370-4379, 1996). To investigate the sequence and
secondary structure requirements within the CP cis-active region and the 3' NTR,
a systematic linker-scanning mutagenesis analysis was done. Forty-six mutations,
each with two to six nucleotide substitutions, were introduced at consecutive
hexanucleotide positions in the genome of a recombinant TEV strain expressing a
reporter protein (beta-glucuronidase). Genome amplification activity of each
mutant in the protoplast cell culture system was measured. Mutations that
severely debilitated genome amplification were identified throughout the CP
coding cis-active sequence and at several distinct locations within the 3' NTR.
However, based on a computer model of RNA folding, mutations that had the most
severe effects mapped to regions that were predicted to form base-paired
secondary structures. Linker-scanning mutations predicted to affect either strand
of a base-paired structure within the CP-coding cis-active sequence, a base
paired structure between two segments of the CP-coding cis-active sequence and a
contiguous 14-nucleotide segment of the 3' NTR, and a base-paired structure near
the 3' terminus of the 3' NTR inactivated genome amplification. Compensatory
mutations that restored base pair interactions in each of these regions restored
amplification activity, although to differing levels depending on the structure
restored. These data reveal that the 3' terminus of the TEV genome consists of a
series of functionally discrete sequences and secondary structures and that the
CP-coding sequence and 3' NTR are coadapted for genome amplification function
through a requirement for base pair interactions.
PMID- 9557697
TI - Recombinant vaccinia virus coexpressing the F protein of respiratory syncytial
virus (RSV) and interleukin-4 (IL-4) does not inhibit the development of RSV
specific memory cytotoxic T lymphocytes, whereas priming is diminished in the
presence of high levels of IL-2 or gamma interferon.
AB - In order to investigate if immune responses to the fusion (F) protein of
respiratory syncytial virus (RSV) could be influenced by cytokines, recombinant
vaccinia viruses (rVV) carrying both the F gene of RSV and the gene for murine
interleukin-2 (IL-2), IL-4, or gamma interferon (IFN-gamma) were constructed. In
vitro characterization of rVV revealed that insertion of the cytokine gene into
the VP37 locus of the vaccinia virus genome resulted in 100- to 1,000-fold higher
expression than insertion of the same gene into the thymidine kinase (TK) locus.
In comparison, only a two- to fivefold difference in the level of expression of
the F protein was observed when the gene was inserted into either of these two
loci. Mice vaccinated with rVV expressing the F protein and high levels of IL-2
or IFN-gamma cleared rVV more rapidly than mice inoculated with a control rVV and
developed only low levels of RSV-specific serum antibody. In addition, these
recombinants were much less effective at priming RSV-specific memory cytotoxic T
lymphocytes (CTL) and IFN-gamma production by spleen cells than rVV expressing
the F protein alone. In contrast, mice vaccinated with rVV expressing high levels
of IL-4 showed signs of delayed rVV clearance. RSV-specific serum antibody
responses were biased in favor of immunoglobulin G1 (IgG1) in these mice, as
there was a significant reduction in IgG2a antibody responses compared with serum
antibody responses in mice vaccinated with rVV expressing the F protein alone.
However, vaccination with rVV expressing the F protein together with high levels
of IL-4 did not alter the development of RSV-specific memory CTL or IFN-gamma
production by RSV-restimulated splenocytes.
PMID- 9557698
TI - Characterization of a human foamy virus 170-kilodalton Env-Bet fusion protein
generated by alternative splicing.
AB - Primate foamy viruses (FVs) express, in addition to the 130-kDa envelope protein,
a 170-kDa glycoprotein, which reacts with antisera specific for the envelope and
Bel proteins. We determined the exact nature of this 170-kDa glycoprotein by
using the molecularly cloned human FV (HFV). Radioimmunoprecipitation analysis of
293T cells transfected with appropriate expression constructs by using antisera
specific for the HFV Env, Bel1, and Bel2 proteins, as well as reverse
transcription-PCR analysis of HFV-infected cells, demonstrated that this protein
is an Env-Bet fusion protein that is secreted into the supernatant. However, it
is only loosely associated, or not associated, with viral particles. gp170 is
generated by an alternatively spliced Env mRNA using a splice donor and splice
acceptor pair localized within the env open reading frame (ORF), which is
normally used to generate Bell and Bet transcripts derived from the internal
promoter within the env ORF. gp170 is expressed at a level 30 to 50% of the Env
precursor gp130. However, it alone does not confer infectivity to HFV particles,
because capsids derived from proviruses expressing only the gp170 were not
released into the supernatant. In contrast, viruses derived from proviral clones
deficient in gp170 expression showed similar in vitro infectivity and replication
kinetics to wild-type virus. Furthermore, both types of viruses were inactivated
to a similar extent by neutralizing sera, indicating that shedding of gp170
probably does not affect the humoral immune response in the infected host.
PMID- 9557699
TI - A proline-rich motif (PPPY) in the Gag polyprotein of Mason-Pfizer monkey virus
plays a maturation-independent role in virion release.
AB - Virus assembly represents one of the last steps in the retrovirus life cycle.
During this process, Gag polyproteins assemble at specific sites within the cell
to form viral capsids and induce membrane extrusion (viral budding) either as
assembly progresses (type C virus) or following formation of a complete capsid
(type B and type D viruses). Finally, the membrane must undergo a fusion event to
pinch off the particle in order to release a complete enveloped virion.
Structural elements within the MA region of the Gag polyprotein define the route
taken to the plasma membrane and direct the process of virus budding. Results
presented here suggest that a distinct region of Gag is necessary for virus
release. The pp24 and pp16 proteins of the type D retrovirus Mason-Pfizer monkey
virus (M-PMV) are phosphoproteins that are encoded in the gag gene of the virus.
The pp16 protein is a C-terminally located cleavage product of pp24 and contains
a proline-rich motif (PPPY) that is conserved among the Gag proteins of a wide
variety of retroviruses. By performing a functional analysis of this coding
region with deletion mutants, we have shown that the pp16 protein is dispensable
for capsid assembly but essential for virion release. Moreover, additional
experiments indicated that the virus release function of pp16 was abolished by
the deletion of only the PPPY motif and could be restored when this motif alone
was reinserted into a Gag polyprotein lacking the entire pp16 domain. Single
amino-acid substitutions for any of the residues within this motif confer a
similar virion release-defective phenotype. It is unlikely that the function of
the proline-rich motif is simply to inhibit premature activation of protease,
since the PPPY deletion blocked virion release in the context of a protease
defective provirus. These results demonstrate that in type D retroviruses a PPPY
motif plays a key role in a late stage of virus budding that is independent of
and occurs prior to virion maturation.
PMID- 9557700
TI - The putative alpha helix 2 of human immunodeficiency virus type 1 Vpr contains a
determinant which is responsible for the nuclear translocation of proviral DNA in
growth-arrested cells.
AB - Several viral determinants were shown to play a role in the ability of human
immunodeficiency virus type 1 (HIV-1) to infect nondividing cells. In particular,
Vpr and Gag matrix (MA) were recognized to be involved in the nuclear transport
of the viral preintegration complex. The goal of the present study was to
evaluate the ability of isogenic HIV-1 viruses harboring different vpr and gag
genes to infect nondividing cells. Surprisingly, our results reveal that the
introduction of mutations in the MA nuclear localization signal marginally
affected the ability of proviruses to establish infection in growth-arrested HeLa
or MT4 cells. In contrast, we show that in our experimental system, the absence
of Vpr expression leads to a reduction in viral infectivity and production which
correlates with a decrease in the synthesis and nuclear transport of proviral DNA
as determined by PCR analysis. Moreover, our data demonstrate that this reduction
of viral replication is also observed with proviruses containing different
mutated Vpr alleles. In particular, the Vpr Q65E mutant, which contains a
substitution in the second predicted amphipathic alpha-helical structure located
in the central region of the protein, is associated with an impairment of the
protein nuclear localization and a concomitant reduction of the nuclear transport
of proviral DNA. The results of this study provide evidence that a putative
amphipathic alpha-helical structure in the central region of Vpr contains a
determinant involved in the nuclear translocation of the preintegration complex
in nondividing cells.
PMID- 9557701
TI - Role of matrix in an early postentry step in the human immunodeficiency virus
type 1 life cycle.
AB - The matrix protein of human immunodeficiency virus type 1 (HIV-1) has been
reported to play a crucial role in the targeting of the Gag polyprotein precursor
to the plasma membrane and in the incorporation of viral envelope glycoproteins
into budding virions. In this report, we present evidence that mutation of a
highly conserved Leu at matrix amino acid 20 blocks or markedly delays virus
replication in a range of cell types, including T-cell lines, primary human
peripheral blood mononuclear cells, and monocyte-derived macrophages. These
mutations do not impair virus assembly and release, RNA encapsidation, or
envelope glycoprotein incorporation into virions but rather cause significant
defects in an early step in the virus life cycle, as measured by single-cycle
infectivity assays and the analysis of viral DNA synthesis early postinfection.
This infectivity defect is independent of the type of envelope glycoprotein
carried on mutant virions; similar results are obtained in pseudotyping
experiments using wild-type or truncated HIV-1 envelope glycoproteins, the
amphotropic murine leukemia virus envelope, or the vesicular stomatitis G
protein. Intriguingly, matrix residue 20 mutations also increase the apparent
binding of Gag to membrane, accelerate the kinetics of Gag processing, and induce
defects in endogenous reverse transcriptase activity without affecting virion
density or morphology. These results help elucidate the function of matrix in HIV
1 replication.
PMID- 9557702
TI - Bovine viral diarrhea virus strain Oregon: a novel mechanism for processing of
NS2-3 based on point mutations.
AB - Bovine viral diarrhea virus (BVDV) isolates can either be cytopathogenic (cp) or
noncytopathogenic (noncp). While both biotypes express the nonstructural protein
NS2-3, generation of NS3 strictly correlates with the cp phenotype. The
production of NS3 is usually caused by cp specific genome alterations, which were
found to be due to RNA recombination. Molecular analyses of the cp BVDV strain
Oregon revealed that it does not possess such genome alterations but nevertheless
is able to generate NS3 via processing of NS2-3. The NS3 serine protease is not
involved in this cleavage, which, according to protein sequencing, occurs between
amino acids 1589 and 1590 of the BVDV Oregon polyprotein. Transient-expression
studies indicated that important information for the cleavage of NS2-3 is located
within NS2. This was verified by expression of chimeric constructs containing
cDNA fragments derived from BVDV Oregon and a noncp BVDV. It could be shown that
the C-terminal part of NS2 plays a crucial role in NS2-3 cleavage. These data,
together with results obtained by site-specific exchanges in this region,
revealed a new mechanism for NS2-3 processing which is based on point mutations
within NS2.
PMID- 9557703
TI - Insertion of a sequence encoding light chain 3 of microtubule-associated proteins
1A and 1B in a pestivirus genome: connection with virus cytopathogenicity and
induction of lethal disease in cattle.
AB - Pestiviruses represent the first RNA viruses for which recombination with
cellular protein-coding sequences has been reported. As a result of such
recombinations cytopathogenic (cp) pestiviruses can develop from
noncytopathogenic (noncp) viruses. In the case of bovine viral diarrhea virus
(BVDV), the generation of cp mutants is linked to the induction of the lethal
syndrome mucosal disease (MD) in cattle. The cp BVDV JaCP was isolated from an
animal which had come down with MD. The genome of JaCP contains a novel kind of
cellular insertion (LC3*) which is flanked by duplicated pestivirus sequences.
Neither insertion nor duplication is present in the genome of the accompanying
noncp virus JaNCP. As part of the viral polyprotein, the insertion in the JaCP
genome is translated into a polypeptide almost identical to a fragment of light
chain 3, a subunit of the microtubule-associated proteins 1A and 1B from the rat.
Transient-expression studies revealed that the LC3* sequence is able to induce an
additional cleavage of the viral polyprotein. The respective cleavage occurs
directly downstream of the LC3*-encoded sequence and is not dependent on the NS3
serine protease. Insertion of LC3* into an infectious noncp pestivirus cDNA clone
without duplicated viral sequences resulted in recovery of a defective cp virus
able to replicate only in the presence of a noncp helper virus. In contrast,
introduction of both insertion and duplication led to an autonomously replicating
cp virus.
PMID- 9557704
TI - Identification of a novel cellular TPR-containing protein, SGT, that interacts
with the nonstructural protein NS1 of parvovirus H-1.
AB - The nonstructural protein NS1 of autonomous parvoviruses is essential for viral
DNA amplification and gene expression and is also the major cytopathic effector
of these viruses. NS1 acts as nickase, helicase, and ATPase and upregulates P38
driven transcription of the capsid genes. We report here the identification of a
novel cellular protein that interacts with NS1 from parvovirus H-1 and which we
termed SGT, for small glutamine-rich tetratricopeptide repeat (TPR)-containing
protein. The cDNA encoding full-length SGT was isolated through a two-hybrid
screen with, as bait, the truncated NS1dlC69 polypeptide, which lacks the C
terminal transactivation domain of NS1. Full-length NS1 and SGT interacted in the
two-hybrid system and in an in vitro interaction assay. Northern blot analysis
revealed one major transcript of about 2 kb that was present in all rat tissues
investigated. Rat sgt cDNA coded for 314 amino acids, and the protein migrated in
sodium dodecyl sulfate-polyacrylamide gel electrophoresis with an apparent
molecular mass of 34 kDa. SGT could be detected in both the nucleus and the
cytoplasm of rat cells, as determined by indirect immunofluorescence analysis and
Western blotting of fractionated cellular extracts with an affinity-purified
antiserum raised against recombinant SGT (AC1.1). In H-1 virus-infected rat and
human cells, compared to mock-infected controls, differences in the migration of
SGT polypeptides were revealed after Western blot analysis of total cellular
extracts. Moreover, the transient expression of NS proteins was sufficient to
induce SGT modification. These results show that cellular SGT, which we have
identified as an NS1-interacting protein, is modified by parvovirus infection as
well as NS expression.
PMID- 9557705
TI - Forced evolution reveals the importance of short open reading frame A and
secondary structure in the cauliflower mosaic virus 35S RNA leader.
AB - Cauliflower mosaic virus pregenomic 35S RNA begins with a long leader sequence
containing an extensive secondary structure and up to nine short open reading
frames (sORFs), 2 to 35 codons in length. To test whether any of these sORFs are
required for virus viability, their start codons were mutated either individually
or in various combinations. The resulting viral mutants were tested for
infectivity on mechanically inoculated turnip plants. Viable mutants were
passaged several times, and the stability of the introduced mutations was
analyzed by PCR amplification and sequencing. Mutations at the 5'-proximal sORF A
and in the center of the leader resulted in delayed symptom development and in
the appearance of revertants. In the central leader region, the predicted
secondary structure, rather than the sORF organization, was restored, while true
reversions or second-site substitutions in response to mutations of sORF A
restored this sORF. Involvement of sORF A and secondary structure of the leader
in the virus replication cycle, and especially in translation of the 35S RNA via
ribosome shunting, is discussed.
PMID- 9557706
TI - Recombinant vaccine-induced protection against the highly pathogenic simian
immunodeficiency virus SIV(mac251): dependence on route of challenge exposure.
AB - Vaccine protection from infection and/or disease induced by highly pathogenic
simian immunodeficiency virus (SIV) strain SIV(mac251) in the rhesus macaque
model is a challenging task. Thus far, the only approach that has been reported
to protect a fraction of macaques from infection following intravenous challenge
with SIV(mac251) was the use of a live attenuated SIV vaccine. In the present
study, the gag, pol, and env genes of SIV(K6W) were expressed in the NYVAC
vector, a genetically engineered derivative of the vaccinia virus Copenhagen
strain that displays a highly attenuated phenotype in humans. In addition, the
genes for the alpha and beta chains of interleukin-12 (IL-12), as well as the IL
2 gene, were expressed in separate NYVAC vectors and inoculated intramuscularly,
in conjunction with or separate from the NYVAC-SIV vaccine, in 40 macaques. The
overall cytotoxic T-lymphocyte (CTL) response was greater, at the expense of
proliferative and humoral responses, in animals immunized with NYVAC-SIV and
NYVAC-IL-12 than in animals immunized with the NYVAC-SIV vaccine alone. At the
end of the immunization regimen, half of the animals were challenged with
SIV(mac251) by the intravenous route and the other half were exposed to
SIV(mac251) intrarectally. Significantly, five of the eleven vaccinees exposed
mucosally to SIV(mac251) showed a transient peak of viremia 1 week after viral
challenge and subsequently appeared to clear viral infection. In contrast, all 12
animals inoculated intravenously became infected, but 5 to 6 months after viral
challenge, 4 animals were able to control viral expression and appeared to
progress to disease more slowly than control animals. Protection did not appear
to be associated with any of the measured immunological parameters. Further
modulation of immune responses by coadministration of NYVAC-cytokine recombinants
did not appear to influence the outcome of viral challenge. The fact that the
NYVAC-SIV recombinant vaccine appears to be effective per se in the animal model
that best mirrors human AIDS supports the idea that the development of a highly
attenuated poxvirus-based vaccine candidate can be a valuable approach to
significantly decrease the spread of human immunodeficiency virus (HIV) infection
by the mucosal route.
PMID- 9557707
TI - Adenovirus type 12-induced fragility of the human RNU2 locus requires p53
function.
AB - Adenovirus type 12 (Ad12) infection of human cells induces four chromosomal
fragile sites corresponding to the U1 small nuclear RNA (snRNA) genes (the RNU1
locus), the U2 snRNA genes (RNU2), the U1 snRNA pseudogenes (PSU1), and the 5S
rRNA genes (RN5S). Ad12-induced fragility of the RNU2 locus requires U2 snRNA
transcriptional regulatory elements and viral early functions but not viral
replication or integration, or chromosomal sequences flanking the RNU2 locus. We
now show that Ad12 cannot induce the RNU1, RNU2, or PSU1 fragile sites in Saos-2
cells lacking the p53 and retinoblastoma (Rb) proteins but that viral induction
of fragility is rescued in these cells when the expression of wild-type p53 or
selected hot-spot mutants (i.e., V143A, R175H, R248W, and R273H) is restored by
transient expression or stable retroviral transduction. We also observed weak
constitutive fragility of the RNU1 and RNU2 loci in cells belonging to xeroderma
pigmentosum complementation groups B and D (XPB and XPD) which are partially
defective in the ERCC2 (XPD) and ERCC3 (XPB) helicase activities shared between
the repairosome and the RNA polymerase H basal transcription factor TFIIH. We
propose a model for Ad12-induced chromosome fragility in which interaction of p53
with the Ad12 E1B 55-kDa transforming protein (and possibly E4orf6) induces a p53
gain of function which ultimately perturbs the RNA polymerase II basal
transcription apparatus. The p53 gain of function could interfere with chromatin
condensation either by blocking mitotic shutdown of U1 and U2 snRNA transcription
or by phenocopying global or local DNA damage. Specific fragilization of the
RNU1, RNU2, and PSU1 loci could reflect the unusually high local concentration of
strong transcription units or the specialized nature of the U1 and U2 snRNA
transcription apparatus.
PMID- 9557708
TI - The envelope protein encoded by the A33R gene is required for formation of actin
containing microvilli and efficient cell-to-cell spread of vaccinia virus.
AB - The vaccinia virus (VV) A33R gene encodes a highly conserved 23- to 28-kDa
glycoprotein that is specifically incorporated into the viral outer envelope. The
protein is expressed early and late after infection, consistent with putative
early and late promoter sequences. To determine the role of the protein, two
inducible A33R mutants were constructed, one with the late promoter and one with
the early and late A33R promoter elements. Decreased A33R expression was
associated with small plaques that formed comets in liquid medium. Using both an
antibiotic resistance gene and a color marker, an A33R deletion mutant,
vA33delta, was isolated, indicating that the A33R gene is not essential for VV
replication. The plaques formed by vA33delta, however, were tiny, indicating that
the A33R protein is necessary for efficient cell-to-cell spread. Rescue of the
large-plaque phenotype was achieved by inserting a new copy of the A33R gene into
the thymidine kinase locus, confirming the specific genetic basis of the
phenotype. Although there was a reduction in intracellular virus formed in cells
infected with vA33delta, the amount of infectious virus in the medium was
increased. The virus particles in the medium had the buoyant density of
extracellular enveloped viruses (EEV). Additionally, amounts of vA33delta cell
associated extracellular enveloped viruses (CEV) were found to be normal.
Immunogold electron microscopy of cells infected with vA33delta demonstrated the
presence of the expected F13L and B5R proteins in wrapping membranes and EEV;
however, fully wrapped vA33delta intracellular enveloped viruses (IEV) were rare
compared to partially wrapped particles. Specialized actin tails that propel IEV
particles to the periphery and virus-tipped microvilli (both common in wild-type
infected cells) were absent in cells infected with vA33delta. This is the first
deletion mutant in a VV envelope gene that produces at least normal amounts of
fully infectious EEV and CEV and yet has a small-plaque phenotype. These data
support a new model for VV spread, emphasizing the importance of virus-tipped
actin tails.
PMID- 9557710
TI - Transduction of dendritic cells by DNA viral vectors directs the immune response
to transgene products in muscle fibers.
AB - Immune responses to vector-corrected cells have limited the application of gene
therapy for treatment of chronic disorders such as inherited deficiency states.
We have found that recombinant adeno-associated virus (AAV) efficiently
transduces muscle fibers in vivo without activation of cellular and humoral
immunity to neoantigenic transgene products such as beta-galactosidase, which
differs from the experience with recombinant adenovirus, where vibrant T-cell
responses to the transgene product destroy the targeted muscle fibers. T cells
activated following intramuscular administration of adenovirus expressing lacZ
(AdlacZ) can destroy AAVlacZ-transduced muscle fibers, indicating a prior state
of immunologic nonresponsiveness in the context of AAV gene therapy. Adoptive
transfer of dendritic cells infected with AdlacZ leads to immune mediated
elimination of AAVlacZ-transduced muscle fibers. AAVlacZ-transduced antigen
presenting cells fail to demonstrate beta-galactosidase activity and are unable
to elicit transgene immunity in adoptive transfer experiments. These studies
indicate that vector-mediated transduction of dendritic cells is necessary for
cellular immune responses to muscle gene therapy, a step which AAV avoids,
providing a useful biological niche for its use in gene therapy.
PMID- 9557709
TI - A tandem array of minimal U1 small nuclear RNA genes is sufficient to generate a
new adenovirus type 12-inducible chromosome fragile site.
AB - Infection of human cells with adenovirus serotype 12 (Ad12) induces metaphase
fragility of four, and apparently only four, chromosomal loci. Surprisingly, each
of these four loci corresponds to a cluster of genes encoding a small abundant
structural RNA: the RNU1 and RNU2 loci contain tandemly repeated genes encoding
U1 and U2 small nuclear RNAs (snRNAs), respectively; the PSU1 locus is a cluster
of degenerate U1 genes; and the RN5S locus contains the tandemly repeated genes
encoding 5S rRNA. These observations suggested that high local levels of
transcription, in combination with Ad12 early functions, can interfere with
metaphase chromatin packing. In support of this hypothesis, we and others found
that an artificial tandem array of transcriptionally active, but not inactive, U2
snRNA genes would generate a novel Ad12-inducible fragile site. Although U1 and
U2 snRNA are both transcribed by RNA polymerase II and share similar enhancer,
promoter, and terminator signals, the human U1 promoter is clearly more complex
than that of U2. In addition, the natural U1 tandem repeat unit exceeds 45 kb,
whereas the U2 tandem repeat unit is only 6.1 kb. We therefore asked whether an
artificial array of minimal U1 genes would also generate a novel Ad12-inducible
fragile site. The exogenous U1 genes were marked by an innocuous U72C point
mutation within the U1 coding region so that steady-state levels of U1 snRNA
derived from the artificial array could be quantified by a simple primer
extension assay. We found that the minimal U1 genes were efficiently expressed
and were as effective as minimal U2 genes in generating a novel Ad12-inducible
fragile site. Thus, despite significant differences in promoter architecture and
overall gene organization, the active U1 transcription units suffice to generate
a new virally inducible fragile site.
PMID- 9557711
TI - Increased misincorporation fidelity observed for nucleoside analog resistance
mutations M184V and E89G in human immunodeficiency virus type 1 reverse
transcriptase does not correlate with the overall error rate measured in vitro.
AB - Nucleoside analog-resistant variants of human immunodeficiency virus type 1 (HIV
1) reverse transcriptase (RT) that displayed higher in vitro polymerase fidelity
were previously identified via nucleotide insertion and mispair extension assays.
To evaluate the contribution of increased nucleotide insertion and primer
extension fidelities on the overall error rate of HIV-1 RT, we have measured the
impact of two such mutations, E89G and M184V, on DNA copying fidelity in an M13
phage-based forward mutation assay. Using this assay, we observed mutation
frequencies of 8.60 x 10(-3), 6.26 x 10(-3), 5.53 x 10(-3), and 12.30 x 10(-3)
for wild-type, E89G, M184V, and double-mutant E89G/M184V HIV-1 RTs, respectively.
Therefore, the overall polymerase fidelities of wild-type, E89G, M184V, and
E89G/M184V HIV-1 RTs are similar (less than twofold differences) for DNA
dependent DNA synthesis. Thus, rather large increases in fidelity of
deoxynucleoside triphosphate insertion and mispair extension observed previously
appear not to influence the overall error rate of these mutants. However, a
qualitative analysis of the mutations induced revealed significant differences in
the mutational spectra between the wild-type and mutant enzymes.
PMID- 9557712
TI - Epithelial uptake and transport of cell-free human immunodeficiency virus type 1
and gp120-coated microparticles.
AB - Cell-free human immunodeficiency virus type 1 (HIV-1) can be taken up and
released by a monolayer of primary human gingival cells and remain infectious for
CD4+ cells. Virus-sized latex particles covalently coated with purified native
HIV-1 envelope glycoprotein gp120 are also transported through the primary
epithelial cells. This process is significantly stimulated by increasing the
intracellular cyclic AMP (cAMP) concentration. Inhibition experiments with mannan
and alpha-methyl-mannopyranoside indicated that mannosyl groups are involved in
the interaction between gp120 and gingival cells. An increase of cellular
oligomannosyl receptors by incubation with the mannosidase inhibitor
deoxymannojirimycin augmented transcellular transport of the gp120-coated
particles. The results suggest that infectious HIV can penetrate gingival
epithelia by a cAMP-dependent transport mechanism involving interaction of the
lectin-like domain of gp120 and mannosyl residues on glycoproteins on the mucosal
surface. Penetration of HIV could be inhibited by soluble glycoconjugates present
in oral mucins.
PMID- 9557713
TI - Detection of a novel bovine lymphotropic herpesvirus.
AB - Degenerate PCR primers which amplify a conserved region of the DNA polymerase
genes of the herpesvirus family were used to provide sequence evidence for a new
bovine herpesvirus in bovine B-lymphoma cells and peripheral blood mononuclear
cells (PBMC). The sequence of the resultant amplicon was found to be distinct
from those of known herpesvirus isolates. Alignment of amino acid sequences
demonstrated 70% identity with ovine herpesvirus 2, 69% with alcelaphine
herpesvirus 1, 65% with bovine herpesvirus 4, and 42% with bovine herpesvirus 1.
Phylogenetic analysis placed this putative virus within the tumorigenic
Gammaherpesvirinae subfamily, and it is tentatively identified as bovine
lymphotropic herpesvirus. This novel agent was expressed in vitro from infected
PBMC, and cell-free supernatants were used to transfer infection to a bovine B
cell line, BL3. Analysis, with specific PCR primers, of DNA from bovine PBMC and
lymphoma cells identified infection in blood of 91% of adult animals (n = 101),
63% of lymphomas (n = 32), and 38% of juveniles (n = 13). Of the adults,
herpesvirus infection was present in 94% of animals that were seropositive for
bovine leukemia virus (BLV) (n = 63) and in 87% of BLV-seronegative animals (n =
38). Of the seropositive group, 17 animals exhibited persistent lymphocytosis,
and 100% of these were herpesvirus positive by PCR. A role for bovine
lymphotropic herpesvirus as a cofactor in BLV pathogenesis is considered.
PMID- 9557714
TI - Chemokine receptor utilization by human immunodeficiency virus type 1 isolates
that replicate in microglia.
AB - The role of human immunodeficiency virus (HIV) strain variability remains a key
unanswered question in HIV dementia, a condition affecting around 20% of infected
individuals. Several groups have shown that viruses within the central nervous
system (CNS) of infected patients constitute an independently evolving subset of
HIV strains. A potential explanation for the replication and sequestration of
viruses within the CNS is the preferential use of certain chemokine receptors
present in microglia. To determine the role of specific chemokine coreceptors in
infection of adult microglial cells, we obtained a small panel of HIV type 1
brain isolates, as well as other HIV strains that replicate well in cultured
microglial cells. These viruses and molecular clones of their envelopes were used
in infections, in cell-to-cell fusion assays, and in the construction of
pseudotypes. The results demonstrate the predominant use of CCR5, at least among
the major coreceptors, with minor use of CCR3 and CXCR4 by some of the isolates
or their envelope clones.
PMID- 9557715
TI - A virus with a mutation in the ICP4-binding site in the L/ST promoter of herpes
simplex virus type 1, but not a virus with a mutation in open reading frame P,
exhibits cell-type-specific expression of gamma(1)34.5 transcripts and latency
associated transcripts.
AB - The herpes simplex virus type 1 L/S junction-spanning transcripts (L/STs) are a
family of multisized transcripts expressed at high levels in cells infected with
mutant viruses that (i) do not express ICP4, (ii) specify forms of ICP4 unable to
bind to the consensus ICP4 binding site, or (iii) contain mutations in the ICP4
binding site located at the transcriptional start site of the L/STs. By
extension, the failure to detect the L/STs in wild-type virus-infected cells is
due to the repressive effect of ICP4 bound to its cognate binding site upstream
of the L/ST transcription initiation site. ORF-P, the first and largest open
reading frame (ORF) encoded by the L/STs, overlaps >90% of the ORF encoding ORF
34.5, a putative neurovirulence factor, which is transcribed from the opposite
DNA strand. Viruses with mutations in the overlapping region of ORF-P and ICP34.5
exhibit premature shutoff of infected-cell protein synthesis and are highly
attenuated following intracranial inoculation of juvenile mice. To determine
whether the premature protein shutoff and neuroattenuated phenotypes of ORF-P ORF
34.5 double mutants are a consequence of alterations in ORF-P, ORF-34.5, or both,
viruses containing mutations only in ORF-P or only in the ICP4 binding site in
the L/ST promoter were isolated and characterized. Mutant virus L/ST-n38 contains
a single-base-pair transition mutation in ORF-P codon 38, resulting in
translational termination of the ORF-P protein (OPP). This mutation does not
alter the amino acid sequence of ICP34.5. Expression of a truncated form of OPP
by mutant virus L/ST-n38 did not result in premature shutoff of infected-cell
protein synthesis and produced no other observable phenotype relative to wild
type virus in in vitro tests. Moreover, the 50% lethal dose (LD50) of L/ST-n38
was comparable to that of wild-type virus following intracranial inoculation of 3
week-old mice, as were the latency and reactivation phenotypes of the virus.
These properties of L/ST-n38 indicate that the attenuated phenotype of ORF-P ORF
34.5 double mutants is a consequence of mutations that affect the function of
ICP34.5 and not the function of OPP. Mutant virus LST-4BS contains four single
base-pair substitutions in the ICP4 binding site in the L/ST promoter that
abrogate the binding of ICP4 to this site, leading to high-level expression of
the L/STs and OPP. LST-4BS induced premature shutoff of viral and cellular
protein synthesis and was slightly growth restricted in cells of neural lineage
(SK-N-SH human neuroblastoma cells) but was wild type for these two parameters in
cells of nonneural lineage (immortalized primate Vero cells). Of particular
interest was the observation that L/ST-4BS exhibited cell-type-specific
expression of both the gamma(1)34.5 transcripts and the latency-associated
transcripts (LATs). Thus, expression of these transcripts was barely detectable
in cells of neural lineage (NB41A3 mouse neuroblastoma cells) but was wild type
in Vero cells. In vivo, L/ST-4BS was reactivated from mouse trigeminal ganglia
with reduced efficiency and delayed kinetics relative to wild-type virus. L/ST
4BS was completely attenuated for neurovirulence (LD50 > 10(6) PFU) relative to
wild-type virus (LD50 < 900 PFU), although the four single-base-pair
substitutions lie outside the coding region for the neurovirulence factor,
ICP34.5. Collectively, the complex in vitro and in vivo phenotypes of L/ST-4BS
can be attributed to (i) disruptions of the ICP4 binding site in the L/ST
promoter and subsequent overexpression of the L/STs and OPP; (ii) alterations in
ORF-O, which is also mutated in L/ST-4BS; or (iii) alterations in other cryptic
genes or cis-acting elements.
PMID- 9557716
TI - Effectiveness of postinoculation (R)-9-(2-phosphonylmethoxypropyl) adenine
treatment for prevention of persistent simian immunodeficiency virus SIVmne
infection depends critically on timing of initiation and duration of treatment.
AB - (R)-9-(2-Phosphonylmethoxypropyl)adenine (PMPA), an acyclic nucleoside
phosphonate analog, is one of a new class of potent antiretroviral agents.
Previously, we showed that PMPA treatment for 28 days prevented establishment of
persistent simian immunodeficiency virus (SIV) infection in macaques even when
therapy was initiated 24 h after intravenous virus inoculation. In the present
study, we tested regimens involving different intervals between intravenous
inoculation with SIV and initiation of PMPA treatment, as well as different
durations of treatment, for the ability to prevent establishment of persistent
infection. Twenty-four cynomolgus macaques (Macaca fascicularis) were studied for
46 weeks after inoculation with SIV. All mock-treated control macaques showed
evidence of productive infection within 2 weeks postinoculation (p.i.). All
macaques that were treated with PMPA for 28 days beginning 24 h p.i. showed no
evidence of viral replication following discontinuation of PMPA treatment.
However, extending the time to initiation of treatment from 24 to 48 or 72 h p.i.
or decreasing the duration of treatment reduced effectiveness in preventing
establishment of persistent infection. Only half of the macaques treated for 10
days, and none of those treated for 3 days, were completely protected when
treatment was initiated at 24 h. Despite the reduced efficacy of delayed and
shortened treatment, all PMPA-treated macaques that were not protected showed
delays in the onset of cell-associated and plasma viremia and antibody responses
compared with mock controls. These results clearly show that both the time
between virus exposure and initiation of PMPA treatment as well as the duration
of treatment are crucial factors for prevention of acute SIV infection in the
macaque model.
PMID- 9557717
TI - A role for the Sendai virus P protein trimer in RNA synthesis.
AB - The SeV P protein is found as a homotrimer (P3) when it is expressed in mammalian
cells, and trimerization is mediated by a predicted coiled-coil motif which maps
within amino acids (aa) 344 to 411 (the BoxA region). The bacterially expressed
protein also appears to be trimeric, apparently precluding a role for
phosphorylation in the association of the P monomers. I have examined the role of
P trimerization both in the protein's interaction with the nucleocapsid (N:RNA)
template and in the protein's function on the template during RNA synthesis. As
with the results of earlier experiments (32), I found that both the BoxA and BoxC
(aa 479 to 568) regions were required for stable binding of P to the N:RNA.
Binding was also observed with P proteins containing less than three BoxC
regions, suggesting that trimerization may be required to permit contacts between
multiple BoxC regions and the N:RNA. However, these heterologous trimers failed
to function in viral RNA synthesis, indicating that the third C-terminal leg of
the trimer plays an essential role in P function on the template. We speculate
that this function may involve the movement of P (and possibly the polymerase
complex) on the template and the maintenance of processivity.
PMID- 9557718
TI - fus-1, a pH shift mutant of Semliki Forest virus, acts by altering spike subunit
interactions via a mutation in the E2 subunit.
AB - Semliki Forest virus (SFV), an enveloped alphavirus, is a well-characterized
paradigm for viruses that infect cells via endocytic uptake and low-pH-triggered
fusion. The SFV spike protein is composed of a dimer of E1 and E2 transmembrane
subunits, which dissociate upon exposure to low pH, liberating E2 and the
fusogenic E1 subunit to undergo independent conformational changes. SFV fusion
and infection are blocked by agents such as ammonium chloride, which act by
raising the pH in the endosome and inhibiting the low-pH-induced conformational
changes in the SFV spike protein. We have previously isolated an SFV mutant, fus
1, that requires more acidic pH to trigger its fusion activity and is therefore
more sensitive to inhibition by ammonium chloride. The acid shift in the fusion
activity of fus-1 was here shown to be due to a more acidic pH threshold for the
initial dissociation of the fus-1 spike dimer, thereby resulting in a more acidic
pH requirement for the subsequent conformational changes in both fus-1 E1 and fus
1 E2. Sequence analysis demonstrated that the fus-1 phenotype was due to a
mutation in the E2 spike subunit, threonine 12 to isoleucine. fus-1 revertants
that have regained the parental fusion phenotype and ammonium chloride
sensitivity were shown to have also regained E2 threonine 12. Our results
identify a region of the SFV E2 spike protein subunit that regulates the pH
dependence of E1-catalyzed fusion by controlling the dissociation of the E1/E2
dimer.
PMID- 9557719
TI - Evolution of hepatitis C virus quasispecies in hypervariable region 1 and the
putative interferon sensitivity-determining region during interferon therapy and
natural infection.
AB - To study hepatitis C virus (HCV) genetic mutation during interferon (IFN)
therapy, the temporal changes in HCV quasispecies heterogeneity were compared
before and after treatment for nine patients infected with HCV genotype 1,
including four nonresponders, four responders who relapsed after therapy, and one
responder who experienced a breakthrough of viremia during therapy. Nine
untreated patients with an average time between specimens of 8.4 years served as
controls. Sequences from the second envelope glycoprotein gene hypervariable
region 1 (HVR1) and the putative IFN sensitivity-determining region (ISDR) of the
nonstructural NS5A gene were analyzed by heteroduplex mobility assays and
nucleotide sequencing. A strong positive correlation was found between the
percent change in a heteroduplex mobility ratio (HMR) and percent change in
nucleotide sequence (r = 0.941, P < 0.001). The rate of fixation of mutations in
the HVR1 was significantly higher for IFN-treated patients than for controls
(6.97 versus 1.31% change in HMR/year; P = 0.02). Similarly, a higher rate of
fixation of mutations was observed in the ISDR for IFN-treated patients than for
untreated controls, although the result was not significant (1.45 versus 0.15
amino acid changes/year; P = 0.12). On an individual patient basis, IFN therapy
was associated with measurable HVR1 and ISDR mutation in nine of nine (100%) and
two of nine (22.2%) patients, respectively. Evolution to IFN-resistant ISDR
sequences was observed in only one of nine IFN-treated patients. These data
suggest that IFN therapy frequently exerts pressure on the HCV envelope region,
while pressure on the ISDR was evident in only a subset of patients. Thus, the
selection pressures evoked on HCV genotype 1 quasispecies during IFN therapy
appear to differ among different patients.
PMID- 9557720
TI - A chimeric Ty3/Moloney murine leukemia virus integrase protein is active in vivo.
AB - This report describes the results of experiments to determine whether chimeras
between a retrovirus and portions of Ty3 are active in vivo. A chimera between
Ty3 and a Neo(r)-marked Moloney murine leukemia virus (M-MuLV) was constructed.
The C-terminal domain of M-MuLV integrase (IN) was replaced with the C-terminal
domain of Ty3 IN. The chimeric retroviruses were expressed from an amphotrophic
envelope packaging cell line. The virus generated was used to infect the human
fibrosarcoma cell line HT1080, and cells in which integration had occurred were
selected by G418 resistance. Three independently integrated viruses were rescued.
In each case, the C-terminal Ty3 IN sequences were maintained and short direct
repeats of the genomic DNA flanked the integration site. Sequence analysis of the
genomic DNA flanking the insertion did not identify a tRNA gene; therefore, these
integration events did not have Ty3 position specificity. This study showed that
IN sequences from the yeast retrovirus-like element Ty3 can substitute for M-MuLV
IN sequences in the C-terminal domain and contribute to IN function in vivo. It
is also one of the first in vivo demonstrations of activity of a retrovirus
encoding an integrase chimera. Studies of chimeras between IN species with
distinctive integration patterns should complement previous work by expanding our
understanding of the roles of nonconserved domains.
PMID- 9557721
TI - gag, vif, and nef genes contribute to the homologous viral interference induced
by a nonproducer human immunodeficiency virus type 1 (HIV-1) variant:
identification of novel HIV-1-inhibiting viral protein mutants.
AB - We previously demonstrated that expression of the nonproducer F12-human
immunodeficiency virus type 1 (HIV-1) variant induces a block in the replication
of superinfecting HIV that does not depend on the down-regulation of CD4 HIV
receptors. In order to individuate the gene(s) involved in F12-HIV-induced
interference, vectors expressing each of the nine F12-HIV proteins were
transfected in HIV-susceptible HeLa CD4 cells. Pools of cell clones stably
producing each viral protein were infected with HIV-1, and virus release was
measured in terms of reverse transcriptase activity in supernatants. We hereby
demonstrate that HeLa CD4 cells expressing the F12-HIV gag, vif, or nef gene were
resistant, to different degrees, to infection with T-cell-line-adapted HIV-1
strains. Conversely, expression of either the tat, rev, or vpu F12-HIV gene
increased the rate of HIV release, and no apparent effects on HIV replication
were observed in cells expressing either the F12-HIV vpr, pol, or env gene. No
variation of CD4 exposure was detected in any of the uninfected HeLa CD4 pools.
These data indicate that F12-HIV homologous viral interference is the consequence
of the synergistic anti-HIV effects of Gag, Vif, and Nef proteins. Retrovirus
vectors expressing F12-HIV vif or nef allowed us to further establish that the
expression of each mutated protein (i) inhibits the replication of clinical HIV-1
isolates as well, (ii) impairs the infectivity of the virus released by cells
chronically infected with HIV-1, and (iii) limitedly to F12-HIV Vif protein,
induces HIV resistance in both vif-permissive and vif-nonpermissive cells. The
levels of action of F12-HIV vif and nef anti-HIV effects were also determined. We
observed that HIV virions emerging from the first viral cycle on F12-HIV vif
expressing cells, although released in unaltered amounts, had a strongly reduced
ability to initiate the retrotranscription process when they reinfected parental
HeLa CD4 cells. Differently, we observed that expression of F12-HIV Nef protein
affects the HIV life cycle at the level of viral assembling and/or release. For
the first time, an inhibitory effect on the HIV life cycle in both acutely and
chronically infected cells induced by mutated Vif and Nef HIV-1 proteins is
described. These genes could thus be proposed as new useful reagents for anti-HIV
gene therapy.
PMID- 9557722
TI - Deletion analysis of a defective interfering Semliki Forest virus RNA genome
defines a region in the nsP2 sequence that is required for efficient packaging of
the genome into virus particles.
AB - The 1,244-nucleotide genome of Semliki Forest virus (SFV) defective interfering
(DI) RNA 19 (DI-19) is coterminal with the infectious genome and contains two
major deletions. One deletion removes the end of the nsP1 gene and the beginning
of the nsP2 gene, and the other removes the end of the nsP2 gene, the nsP3 and
nsP4 genes, and all of the structural protein genes (M. Thomson and N. J.
Dimmock, Virology 199:354-365, 1994). Like all DI SFV RNAs, DI-19 contains three
regions that are conserved. Region a comprises the 5' terminus continuous with
part of the nsP1 gene, region b comprises a central part of the nsP2 gene, and
region c comprises the 3' terminus and the associated untranslated region. A
deletion analysis of the 265-nucleotide b region (nucleotides 679 to 943,
inclusive) was undertaken to determine its role in genome replication and
packaging into DI virus particles. Deleted plasmids were constructed and
transcribed, and the resulting DI RNAs were transfected into SFV-infected BHK
cells. Putative progeny DI virus particles that had been released into the tissue
culture fluid were then serially passaged in new monolayers together with added
high-multiplicity SFV, and cells and tissue culture fluids were tested for the
presence of DI RNA by reverse transcription-PCR. DI RNA that had all of the b
region deleted was replicated well in BHK-21 cells, as shown by the presence of
large amounts of negative-sense DI RNA and an increase in the amount of positive
sense RNA in the cytoplasm, but was packaged very inefficiently, as indicated by
very low amounts of DI RNA in the tissue culture fluid. The genome of a deletion
mutant that retained the 3' 224 nucleotides of region b was packaged
successfully, but one that retained only the 5' 41 nucleotides was not detected
in the tissue culture fluid. These and other data suggest that nucleotides 720 to
777 of region b are of particular importance in the packaging process. This
finding agrees with data obtained with Ross River virus and contrasts with the
well-studied Sindbis alphavirus major packaging signal that is located within the
nsP1 gene.
PMID- 9557723
TI - African origin of human T-lymphotropic virus type 2 (HTLV-2) supported by a
potential new HTLV-2d subtype in Congolese Bambuti Efe Pygmies.
AB - We identified a potential new subtype within human T-cell lymphotropic virus type
2 (HTLV-2), HTLV-2d, present in members of an isolated Efe Bambuti Pygmy tribe.
Two of 23 Efe Pygmies were HTLV-2 seropositive, with HTLV-2 Western blot and
enzyme-linked immunosorbent assay reactivities. From one of them the entire
genome of the HTLV-2 strain Efe2 could be amplified and sequenced. In all gene
regions analyzed, this strain was the most divergent HTLV-2 strain, differing by
2.4% (tax/rex) to 10.7% (long terminal repeat) from both subtypes HTLV-2a and
HTLV-2b, yet major functional elements are conserved. The similarity between the
HTLV-2 Efe2 Gag and Env proteins and the corresponding HTLV-2a and -2b proteins
is consistent with the observed serological reactivity. In the proximal pX
region, one of the two alternative splice acceptor sites is abolished in HTLV-2
Efe2. Another interesting feature of this potential new subtype is that it has a
Tax protein of 344 amino acids (aa), which is intermediate in length between the
HTLV-2a Tax protein (331 aa) and the HTLV-2b and -2c Tax proteins (356 aa) and
similar to the simian T-cell lymphotropic virus type 2 (STLV-2) PP1664 Tax
protein. Together these two findings suggest a different phenotype for the HTLV-2
Efe2 strain. Phylogenetic analyses confirmed that the Pygmy Efe2 strain
potentially belonged to a new and quite divergent subtype, HTLV-2d. When the STLV
2 bonobo viruses PP1664 and PanP were used as an outgroup, it was clear that the
Pygmy HTLV-2 Efe2 strain had the longest independent evolution and that HTLV-2
evolution is consistent with an African origin.
PMID- 9557724
TI - A 68-nucleotide sequence within the 3' noncoding region of simian hemorrhagic
fever virus negative-strand RNA binds to four MA104 cell proteins.
AB - The 3' noncoding region (NCR) of the negative-strand RNA [3'(-)NCR RNA] of the
arterivirus simian hemorrhagic fever virus (SHFV) is 209 nucleotides (nt) in
length. Since this 3' region, designated 3'(-)209, is the site of initiation of
full-length positive-strand RNA and is the template for the synthesis of the 5'
leader sequence, which is found on both full-length and subgenomic mRNAs, it is
likely to contain cis-acting signals for RNA synthesis and to interact with
cellular and viral proteins to form replication complexes. Gel mobility shift
assays showed that cellular proteins in MA104 S100 cytoplasmic extracts formed
two complexes with the SHFV 3'(-)209 RNA, and results from competition gel
mobility shift assays demonstrated that these interactions were specific. Four
proteins with molecular masses of 103, 86, 55, and 36 kDa were detected in UV
induced cross-linking assays, and three of these proteins (103, 55, and 36 kDa)
were also detected by Northwestern blotting assays. Identical gel mobility shift
and UV-induced cross-linking patterns were obtained with uninfected and SHFV
infected extracts, indicating that the four proteins detected are cellular, not
viral, proteins. The binding sites for the four cellular proteins were mapped to
the region between nt 117 and 184 (68-nt sequence) from the 3' end of the SHFV
negative-strand RNA. This 68-nt sequence was predicted to form two stem-loops,
SL4 and SL5. The 3'(-)NCR RNA of another arterivirus, lactate dehydrogenase
elevating virus C (LDV-C), competed with the SHFV 3'(-)209 RNA in competition gel
mobility shift assays. UV-induced cross-linking assays showed that four MA104
cellular proteins with the same molecular masses as those that bind to the SHFV
3'(-)209 RNA also bind to the LDV-C 3'(-)NCR RNA and equine arteritis virus 3'(
)NCR RNA. However, each of these viral RNAs also bound to an additional MA104
protein. The binding sites for the MA104 cellular proteins were shown to be
located in similar positions in the LDV-C 3'(-)NCR and SHFV 3'(-)209 RNAs. These
data suggest that the binding sites for a set of the cellular proteins are
conserved in all arterivirus RNAs and that these cell proteins may be utilized as
components of viral replication complexes.
PMID- 9557726
TI - Gene expression and regulation from the p7 promoter of Aedes densonucleosis
virus.
AB - The nonstructural proteins NS1 and NS2 are thought to be expressed from the p7
promoter of Aedes densonucleosis virus (AeDNV). To study gene expression from the
p7 promoter, eight different plasmids were constructed by fusing beta
galactosidase or beta-glucuronidase into the genome so that the reporter gene was
in different open reading frames and under the transcriptional control of the p7
promoter. After transfection into C6/36 Aedes albopictus cells, constructs
generated comparable amounts of RNA, but only the NS1 and NS2 fusion constructs
produced appreciable levels of active enzyme. NS1 and NS2 fusion constructs
contained wild-type AeDNV sequences from the p7 promoter downstream to nucleotide
458. The remaining constructs, with the exception of p7GUS.rf3, lacked some or
all of these necessary sequences and inefficiently produced protein. These data
suggest that sequences downstream of the p7 promoter play a role in translational
regulation of gene expression from the p7 promoter of AeDNV.
PMID- 9557725
TI - Epidemiology of infection with Epstein-Barr virus types 1 and 2: lessons from the
study of a T-cell-immunocompromised hemophilic cohort.
AB - In apparent contrast to earlier work on Epstein-Barr virus (EBV) carriage in the
general Caucasian population, in vitro virus isolations from human
immunodeficiency virus (HIV)-positive male homosexual cohorts have shown frequent
examples of multiple EBV infection and an overall prevalence of type 2 EBV
strains exceeding 30%. Here we ask to what extent these findings might hold true
in another T-cell-immunocompromised cohort, HIV-positive hemophilic patients.
Resident EBV strains were rescued within lymphoblastoid cell lines derived from
the blood and throat washings of 39 such individuals, using the same in vitro
protocols of virus isolation as for the homosexual cohort. A mean of 19
independent cell lines was made per patient, and in each case the resident virus
was characterized by PCR-based viral genomic analysis and by immunoblotting to
reveal the viral "EBNAprint." By these criteria a significant proportion (14 of
39) of the hemophilic cohort carried more than one EBV strain, suggesting that T
cell impairment does indeed sensitize virus carriers to reinfection with new
strains of exogenously transmitted virus. However, the overall incidence of type
2 EBV infection was 10%, which is close to that observed in the earlier work with
healthy carriers and substantially lower than that seen in HIV-positive
homosexuals. We infer that type 2 EBV is relatively rare in the general Caucasian
population but has become endemic in the homosexual community.
PMID- 9557727
TI - Cell-to-cell contact as an efficient mode of Epstein-Barr virus infection of
diverse human epithelial cells.
AB - We show clear evidence for direct infection of various human epithelial cells by
Epstein-Barr virus (EBV) in vitro. The successful infection was achieved by using
recombinant EBV (Akata strain) carrying a selective marker gene but without any
other artificial operations, such as introduction of the known EBV receptor
(CD21) gene or addition of polymeric immunoglobulin A against viral gp350 in
culture. Of 21 human epithelial cell lines examined, 18 became infected by EBV,
as ascertained by the detection of EBV-determined nuclear antigen (EBNA) 1
expression in the early period after virus exposure, and the following selection
culture easily yielded a number of EBV-infected clones from 15 cell lines. None
of the human fibroblasts and five nonhuman-derived cell lines examined was
susceptible to the infection. By comparison, cocultivation with virus producers
showed approximately 800-fold-higher efficiency of infection than cell-free
infection did, suggesting the significance of direct cell-to-cell contact as a
mode of virus spread in vivo. Most of the epithelial cell lines infectable with
EBV were negative for CD21 expression at the protein and mRNA levels. The
majority of EBV-infected clones established from each cell line invariably
expressed EBNA1, EBV-encoded small RNAs, rightward transcripts from the BamHI-A
region of the virus genome, and latent membrane protein (LMP) 2A, but not the
other EBNAs or LMP1. This restricted form of latent viral gene expression, which
is a central issue for understanding epithelial oncogenesis by EBV, resembled
that seen in EBV-associated gastric carcinoma and LMP1-negative nasopharyngeal
carcinoma. The results indicate that direct infection of epithelial cells by EBV
may occur naturally in vivo, and this could be mediated by an unidentified,
epithelium-specific binding receptor for EBV. The EBV convertants are viewed, at
least in terms of viral gene expression, as in vitro analogs of EBV-associated
epithelial tumor cells, thus facilitating analysis of an oncogenic role(s) for
EBV in epithelial cells.
PMID- 9557728
TI - Borna disease virus-induced neurological disorder in mice: infection of neonates
results in immunopathology.
AB - Borna disease virus (BDV) is a neurotropic nonsegmented negative-stranded RNA
virus that persistently infects warm-blooded animals. In horses and other natural
animal hosts, infections with BDV cause meningoencephalitis and behavioral
disturbances. Experimental infection of adult mice takes a nonsymptomatic course,
an observation previously believed to indicate that this animal species is not
suitable for pathogenesis studies. We now demonstrate that BDV frequently induces
severe neurological disease in infected newborn mice. Signs of neurological
disease were first observed 4 to 6 weeks after intracerebral infection. They
included a characteristic nonphysiological position of the hind limbs at an early
stage of the disease and paraparesis at a later stage. Histological examination
revealed large numbers of perivascular and meningeal inflammatory cells in brains
of diseased mice and, unexpectedly, no increase in immunoreactivity to glial
fibrillar acidic protein. The incidence and severity of BDV-induced disease
varied dramatically among mouse strains. While only 13% of the infected C57BL/6
mice showed disease symptoms, which were mostly transient, more than 80% of the
infected MRL mice developed severe neurological disorder. In spite of these
differences in susceptibility to disease, BDV replicated to comparable levels in
the brains of mice of the various strains used. Intracerebral infections of
newborn beta2-microglobulin-deficient C57BL/6 and MRL mice, which both lack CD8+
T cells, did not result in meningoencephalitis or neurological disease,
indicating that the BDV-induced neurological disorder in mice is a cytotoxic T
cell-mediated immunopathological process. With this new animal model it should
now be possible to characterize the disease-inducing immune response to BDV in
more detail.
PMID- 9557729
TI - Virus-specific CD4+ T cells eliminate borna disease virus from the brain via
induction of cytotoxic CD8+ T cells.
AB - Persistent Borna disease virus infection of the brain can be prevented by
treatment of naive rats with a virus-specific CD4+ T-cell line prior to
infection. In rats receiving this treatment, only a transient low-level
encephalitis was seen compared to an increasingly inflammatory reaction in
untreated infected control rats. Virus replication was found in the brain for
several days after infection before the virus was cleared from the central
nervous system. The loss of infectivity from the brain was confirmed by negative
results by reverse transcription-PCR with primers for mRNA, by in situ
hybridization for both genomic and mRNA, and by immunohistology. Most
importantly, in vitro assays revealed that the T-cell line used for transfusion
had no cytotoxic capacity. The kinetics of virus clearance were paralleled by the
appearance of CD8+ T cells and the expression of perforin in the brain. Testing
of lymphocytes isolated from the brains of CD4+ T-cell-treated rats after
challenge revealed high cytotoxic activity due to the presence of CD8+ cytotoxic
T cells at time points when brain lymphocytes from infected control rats induced
low-level cytolysis of target cells. Neutralizing antiviral antibodies and gamma
interferon were shown not to be involved in the elimination of virus from the
brain.
PMID- 9557730
TI - Structure of a neutralizing antibody bound monovalently to human rhinovirus 2.
AB - The structure of a complex between human rhinovirus 2 (HRV2) and the Fab fragment
of neutralizing monoclonal antibody (MAb) 3B10 has been determined to 25-A
resolution by cryoelectron microscopy and three-dimensional reconstruction
techniques. The footprint of 3B10 on HRV2 is very similar to that of neutralizing
MAb 8F5, which binds bivalently across the icosahedral twofold axis. However, the
3B10 Fab fragment (Fab-3B10) is bound in an orientation, inclined at
approximately 45 degrees to the surface of the virus capsid, which is compatible
only with monovalent binding of the antibody. The canyon around the fivefold axis
is not directly obstructed by the bound Fab. The X-ray structures of a closely
related HRV (HRV1A) and a Fab fragment were fitted to the density maps of the
HRV2-Fab-3B10 complex obtained by cryoelectron microscope techniques. The
footprint of 3B10 on the viral surface is largely on VP2 but also covers the VP3
loop centered on residue 3064 and the VP1 loop centered on residue 1267. MAb 3B10
can interact directly with VP2 residue 2164, the site of an escape mutation on
VP2, and with VP1 residues 1264 to 1267, the site of a deletion escape mutation.
Deletion of these residues shortens the VP1 loop, moving it away from the MAb
binding site. All structural and biochemical evidence indicates that MAb 3B10
binds to a conformation epitope on HRV2.
PMID- 9557731
TI - Cryoelectron microscopic examination of human immunodeficiency virus type 1
virions with mutations in the cyclophilin A binding loop.
AB - The human immunodeficiency virus type 1 capsid protein contains a conserved
P217X4PX2PX5P231 motif. Mutation at Pro-222 decreases virion incorporation of
cyclophilin A, while mutation at Pro-231 abolishes infectivity. Although viral
RNA incorporation and protease cleavage of the Gag precursor were not affected by
these mutations, cryoelectron microscopy revealed a loss of virion maturation in
P231A particles.
PMID- 9557732
TI - Human and simian T-cell leukemia viruses type 2 (HTLV-2 and STLV-2(pan-p))
transform T cells independently of Jak/STAT activation.
AB - Human T-lymphotropic virus type 1 (HTLV-1) and HTLV-2 differ in pathogenicity in
vivo. HTLV-1 causes leukemia and neurologic and inflammatory diseases, whereas
HTLV-2 is less clearly associated with human disease. Both retroviruses transform
human T cells in vitro, and transformation by HTLV-1 was found to be associated
with the constitutive activation of the Jak/STAT pathway. To assess whether HTLV
2 transformation may also result in constitutive activation of the Jak/STAT
pathway, six interleukin-2-independent, HTLV-2-transformed T-cell lines were
analyzed for the presence of activated Jak and STAT proteins by electrophoretic
mobility shift assay. In addition, the phosphorylation status of Jak and STAT
proteins was assessed directly by immunoprecipitation and immunoblotting with an
antiphosphotyrosine antibody. Jak/STAT proteins were not found to be
constitutively activated in any of the T-cell lines infected by the type 2 human
and nonhuman primate viruses, suggesting that HTLV-2 and the cognate virus simian
T-lymphotropic virus type 2 from Pan paniscus transform T cells in vitro by
mechanisms at least partially different from those used by HTLV-1.
PMID- 9557733
TI - Bovine leukemia virus-induced lymphocytosis and increased cell survival mainly
involve the CD11b+ B-lymphocyte subset in sheep.
AB - In this study, we show that bovine leukemia virus (BLV)-induced persistent
lymphocytosis (PL) results from the in vivo expansion of the CD11b+ B-lymphocyte
population. This subset shares phenotypic characteristics with murine and human B
1 cells. BLV interactions with the sheep B-1-like subset were explored. We found
that B-1- and B-2-like cells are initially infected to similar extents. However,
in long-term-infected sheep, the viral load is higher in B-1-like cells and only
B-1- and not B-2-like cells show increased ex vivo survival compared to that in
uninfected sheep. Ex vivo viral expression was found in both B-1- and B-2-like
cells, indicating that both cell types support viral replication. Finally,
cycloheximide and a protein kinase C inhibitor (H7) that blocks the ex vivo
activation of viral expression did not affect the increased survival in B-1-like
cells, suggesting that resistance to apoptosis is acquired in vivo. Collectively,
these results indicate a peculiar susceptibility of sheep B-1-like cells to BLV
transforming effects and further support the involvement of increased survival in
BLV pathogenesis.
PMID- 9557734
TI - Biological characterization of Rev variation in equine infectious anemia virus.
AB - Sequence analysis identified significant variation in the second exon of equine
infectious anemia virus (EIAV) rev. Functional analysis indicated that limited
amino acid variation in Rev significantly altered the export activity of the
protein but did not affect Rev-dependent alternative splicing. EIAV Rev can
mediate export through two independent cis-acting Rev-responsive elements (RREs),
and differences among Rev variants were more pronounced when both RREs were
present. Variation in Rev may be an important mechanism for regulation of virus
replication in vivo and may contribute to changes in clinical disease.
PMID- 9557735
TI - Functions of conserved motifs in the RNA-dependent RNA polymerase of a yeast
double-stranded RNA virus.
AB - At least eight conserved motifs are visible in the totivirus RNA-dependent RNA
polymerase (RDRP). We have systematically altered each of these in the
Saccharomyces cerevisiae double-stranded RNA virus ScVL1 by substituting the
conserved motifs from a giardiavirus. The results help define the conserved
regions of the RDRP involved in polymerase function and those essential for other
reasons.
PMID- 9557736
TI - Herpes simplex virus 2 UL45 is a type II membrane protein.
AB - In addition to eleven glycoproteins, the herpes simplex virus type 2 (HSV-2)
genome encodes several proteins with potential membrane-spanning segments but no
asparagine-linked carbohydrates. One of these is UL45. Fractionation of infected
cells showed that HSV-2 UL45 is an integral membrane protein, and analysis of
UL45 mutants with potential glycosylation sites showed that it has a type II
membrane orientation, the first HSV protein known to have this orientation.
Furthermore, it is detectable in infected cells at a time similar to that when
glycoproteins gB and gD are detected, consistent with a role in cell-cell fusion,
which has previously been found for HSV-1 UL45.
PMID- 9557737
TI - Different patterns of neuronal infection after intracerebral injection of two
strains of pseudorabies virus.
AB - Pseudorabies virus (PRV), a swine neurotropic alphaherpesvirus, is known to
invade the central nervous system (CNS) of a variety of animal species through
peripherally projecting axons, replicate in the parent neurons, and then pass
transsynaptically to infect other neurons of a circuit. Studies of the human
pathogen herpes simplex virus type 1 have reported differences in the direction
of transport of two strains of this virus after direct injection into the primate
motor cortex. In the present study we examined the direction of transport of
virulent and attenuated strains of PRV, utilizing injections into the rat
prefrontal cortex to evaluate specific movement of virus through CNS circuitry.
The data demonstrate strain-dependent patterns of infection consistent with
bidirectional (anterograde and retrograde) transport of virulent virus and
unidirectional (retrograde) transport of attenuated PRV from the site of
injection. The distribution of infected neurons and the extent of transsynaptic
passage also suggest that a release defect in the attenuated strain reduces the
apparent rate of viral transport through neuronal circuitry. Finally, injection
of different concentrations of virus influenced the onset of replication within a
neural circuit. Taken together, these data suggest that viral envelope
glycoproteins and virus concentration at the site of injection are important
determinants of the rate and direction of viral transport through a multisynaptic
circuit in the CNS.
PMID- 9557738
TI - Role of the N-terminal zinc finger of human immunodeficiency virus type 1
nucleocapsid protein in virus structure and replication.
AB - Nucleocapsid protein (NCp7) of human immunodeficiency virus type 1 is found
covering the genomic RNA in the interior of the viral particle. It is a highly
basic protein with two zinc fingers of the form CX2CX4HX4C which exhibit strong
affinity for a zinc cation. To study the structure-function relationship of the N
terminal zinc finger of NCp7, this domain was either deleted or changed to
CX2CX4CX4C. We examined virus formation and structure as well as proviral DNA
synthesis. Our data show that these two NC mutations result in the formation of
particles with an abnormal core morphology and impair the end of proviral DNA
synthesis, leading to noninfectious viruses.
PMID- 9557739
TI - PITALRE, the catalytic subunit of TAK, is required for human immunodeficiency
virus Tat transactivation in vivo.
AB - The human cdc2-related kinase PITALRE is the catalytic component of TAK, the Tat
associated kinase. Previously, we have proposed that TAK is a cellular factor
that mediates Tat transactivation function. Here we demonstrate that transient
overexpression of PITALRE specifically squelches Tat-1 activation of both a
transfected and an integrated human immunodeficiency virus type 1 (HIV-1) long
terminal repeat (LTR), suggesting that PITALRE mediates Tat function as a
multiprotein complex. A catalytic mutant of PITALRE, D167N, was found to be more
efficient than wild-type PITALRE in squelching Tat transactivation. Neither wild
type PITALRE nor D167N was able to squelch transactivation of the human T-cell
leukemia type 1 LTR by the Tax protein. Additionally, we show that artificial
targeting of PITALRE to a nascent RNA element, in the absence of Tat, activated
HIV-1 LTR expression. These results indicate that a PITALRE-containing complex
mediates transactivation by Tat and suggest that Tat proteins function by
localizing such a PITALRE-containing complex to the site of the transcribing
provirus.
PMID- 9557740
TI - Antibody response in mice inoculated with DNA expressing foot-and-mouth disease
virus capsid proteins.
AB - Candidate foot-and-mouth disease (FMD) DNA vaccines designed to produce viral
capsids lacking infectious viral nucleic acid were evaluated. Plasmid DNAs
containing a portion of the FMDV genome coding for the capsid precursor protein
(P1-2A) and wild-type or mutant viral proteinase 3C (plasmids P12X3C or P12X3C
mut, respectively) were constructed. Cell-free translation reactions programmed
with pP12X3C (wild-type 3C) and pP12X3C-mut produced a capsid precursor, but only
the reactions programmed with the plasmid encoding the functional proteinase
resulted in P1-2A processing and capsid formation. Baby hamster kidney (BHK)
cells also produced viral capsid proteins when transfected with these plasmids.
Plasmid P12X3C was administered to mice by intramuscular, intradermal, and
epithelial (gene gun) inoculations. Anti-FMD virus (FMDV) antibodies were
detected by radioimmunoprecipitation (RIP) and plaque reduction neutralization
assays only in sera of mice inoculated by using a gene gun. When pP12X3C and
pP12X3C-mut were inoculated into mice by using a gene gun, both plasmids elicited
an antibody response detectable by RIP but only pP12X3C elicited a neutralizing
antibody response. These results suggest that capsid formation in situ is
required for effective immunization. Expression and stimulation of an immune
response was enhanced by addition of an intron sequence upstream of the coding
region, while addition of the FMDV internal ribosome entry site or leader
proteinase (L) coding region either had no effect or reduced the immune response.
PMID- 9557741
TI - Human T-cell leukemia virus type 1 pX-I and pX-II open reading frames are
dispensable for the immortalization of primary lymphocytes.
AB - Human T-cell leukemia virus type 1 (HTLV-1) infects and transforms CD4+ T
lymphocytes both in vivo and in vitro. Although the Tax protein of HTLV-1 has
been strongly implicated as a transforming agent, other virally encoded proteins
may also play a role in the transformation process. In addition to the rex and
tax genes, the pX region of the HTLV-1 genome contains two open reading frames
(pX-I and pX-II) which encode the putative viral accessory proteins known as
p12I, p30II, and p13II. Mutations in the ACH molecular clone of HTLV-1 that are
predicted to abrogate the expression of p12I, p13II and p30II were constructed.
These mutations had no effect on viral replication or the immortalization of
primary lymphocytes. Although these proteins are dispensable for viral
replication and immortalization in vitro, it remains possible that they alter
infection in vivo.
PMID- 9557742
TI - The rubella virus nonstructural protease requires divalent cations for activity
and functions in trans.
AB - The rubella virus (RUB) nonstructural (NS) protease is a papain-like cysteine
protease (PCP) located in the NS-protein open reading frame (NSP-ORF) that
cleaves the NSP-ORF translation product at a single site to produce two products,
P150 (the N-terminal product) and P90 (the C-terminal product). The RUB NS
protease was found not to function following translation in vitro in a standard
rabbit reticulocyte lysate system, although all of the other viral PCPs do so.
However, in the presence of divalent cations such as Zn2+, Cd2+, and Co2+, the
RUB NS protease functioned efficiently, indicating that these cations are
required either as direct cofactors in catalytic activity or for correct
acquisition of three-dimensional conformation of the protease. Since other viral
and cell PCPs do not require cations for activity and the RUB NS protease
contains a putative zinc binding motif, the latter possibility is more likely.
Previous in vivo expression studies of the RUB NS protease failed to demonstrate
trans cleavage activity (J.-P. Chen et al., J. Virol. 70:4707-4713, 1996). To
study whether trans cleavage could be detected in vitro, a protease catalytic
site mutant and a mutant in which the C-terminal 31 amino acids of P90 were
deleted were independently introduced into plasmid constructs that express the
complete NSP-ORF. Cotranslation of these mutants in vitro yielded both the native
and the mutated forms of P90, indicating that the protease present in the mutated
construct cleaved the catalytic-site mutant precursor. Thus, RUB NS protease can
function in trans.
PMID- 9557743
TI - Recombinant respiratory syncytial virus (RSV) bearing a set of mutations from
cold-passaged RSV is attenuated in chimpanzees.
AB - A set of five missense mutations previously identified by nucleotide sequence
analysis of subgroup A cold-passaged (cp) respiratory syncytial virus (RSV) has
been introduced into a recombinant wild-type strain of RSV. This recombinant
virus, designated rA2cp, appears to replicate less efficiently in the upper and
lower respiratory tracts of seronegative chimpanzees than either biologically
derived or recombinant wild-type RSV. Infection with rA2cp also resulted in
significantly less rhinorrhea and cough than infection with wild-type RSV. These
findings confirm the role of the cp mutations in attenuation of RSV and identify
their usefulness for inclusion in future live attenuated recombinant RSV vaccine
candidates.
PMID- 9557744
TI - Immunogenicity and protective efficacy in mice of influenza B virus vaccines
grown in mammalian cells or embryonated chicken eggs.
AB - The immunogenicity and protective efficacy of formalin-inactivated influenza
B/Memphis/1/93 virus vaccines propagated exclusively in Vero cells, MDCK cells,
or embryonated chicken eggs (hereafter referred to as eggs) were investigated.
Mammalian cell-grown viruses differ from the egg-grown variant at amino acid
position 198 (Pro/Thr) in the hemagglutinin gene. The level of neuraminidase
activity was highest in egg-grown virus, while MDCK and Vero cell-derived viruses
possessed 70 and 90% less activity, respectively. After boosting, each of the
vaccines induced high levels of hemagglutinin-inhibiting, neuraminidase
inhibiting, and neutralizing antibodies that provided complete protection from
MDCK-grown virus challenge. Mammalian cell-derived virus vaccines induced serum
antibodies that were more cross-reactive, while those induced by egg-grown virus
vaccines were more specific to the homologous antigen. Enzyme-linked immunospot
analysis indicated that cell-grown virus vaccines induced high frequencies of
immunoglobulin G (IgG)-producing cells directed against both cell- and egg-grown
virus antigens, whereas egg-grown virus vaccine induced higher frequencies of IgG
and IgM-producing cells reacting with homologous antigen and low levels of IgG
producing cells reactive with cell-grown viruses. These studies indicate that
influenza B virus variants selected in different host systems can elicit
different immune responses, but these alterations had no detectable influence on
the protective efficacy of the vaccines with the immunization protocol used in
this study.
PMID- 9557745
TI - Determinants of entry cofactor utilization and tropism in a dualtropic human
immunodeficiency virus type 1 primary isolate.
AB - Human immunodeficiency virus type 1 strain 89.6 is a dualtropic isolate that
replicates in macrophages and transformed T cells, and its envelope mediates CD4
dependent fusion and entry with CCR5, CXCR-4, and CCR3. To map determinants of
cofactor utilization by 89.6 and determine the relationship between cofactor use
and tropism, we analyzed recombinants generated between 89.6 and T-cell-tropic
(HXB) or macrophage-tropic (JRFL) strains. These chimeras showed that regions of
89.6 env outside V3 through V5 determine CXCR-4 utilization and T-cell line
tropism as well as CCR5 utilization and macrophage tropism. However, the 89.6 env
V3 domain also conferred on HXB the ability to use CCR5 for fusion and entry but
not the ability to establish productive macrophage infection. CCR3 use was
conferred on HXB by 89.6 env V3 or V3 through V5 sequences. While replacement of
the 89.6 V3 through V5 region with HXB sequences abrogated CCR3 utilization,
replacement of V3 or V4 through V5 separately did not. Thus, CCR3 use is
determined by sequences within V3 through V5 and most likely can be conferred by
either the V3 or the V4 through V5 domains. These results indicate that cofactor
utilization and tropism in this dualtropic isolate are determined by complex
interactions among multiple env segments, that distinct regions of the Env
glycoprotein may be important for utilization of different chemokine receptors,
and that determinants in addition to cofactor usage participate in postentry
stages in the virus replication cycle that contribute to target cell tropism.
PMID- 9557746
TI - Patterns of CCR5, CXCR4, and CCR3 usage by envelope glycoproteins from human
immunodeficiency virus type 1 primary isolates.
AB - Coreceptor usage by Envs from diverse primary human immunodeficiency virus type 1
isolates was analyzed by a vaccinia virus-based expression and assay system.
Usage of recombinant CCR5 and CXCR4 correlated closely with fusogenicity toward
macrophages and T-cell lines expressing endogenous coreceptors. Surprisingly,
recombinant CCR3 was utilized by most primary and T-cell-line-adapted Envs.
Endogenous CXCR4 in macrophages was functional as a coreceptor.
PMID- 9557747
TI - Detection of viral proteins after infection of cultured hepatocytes with rabbit
hemorrhagic disease virus.
AB - The calicivirus rabbit hemorrhagic disease virus (RHDV), which replicates
predominantly in the livers of infected rabbits, cannot be propagated in tissue
culture. To enable the performance of in vitro studies, rabbit hepatocytes were
isolated by liver perfusion and gradient centrifugation. After inoculation with
purified RHDV, more than 50% of the cells proved to be infected. Protein analyses
led to the detection of 13 RHDV-specific polypeptides within the infected cells.
These proteins were assigned to defined regions of the viral genome, resulting in
a refined model of RHDV genome organization.
PMID- 9557748
TI - Respiratory syncytial virus infection of human alveolar epithelial cells enhances
interferon regulatory factor 1 and interleukin-1beta-converting enzyme gene
expression but does not cause apoptosis.
AB - The induction kinetics of the transcriptional activities of interferon regulatory
factor 1 (IRF-1), interleukin-1beta-converting enzyme (ICE), and CPP32 by
respiratory syncytial virus (RSV) infection of human type II alveolar epithelial
cells (A549 cells) were analyzed semiquantitatively by reverse transcriptase PCR.
The appearance of ICE and CPP32 protein in cell lysate was examined by Western
blotting analysis. The induction of apoptosis by RSV infection was examined by
the appearance of DNA fragmentation detected by terminal
deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling. RSV
moderately enhanced IRF-1 mRNA as early as 4 h after infection, and this
enhancement lasted several hours. Following induction of the IRF-1 gene, ICE gene
expression increased significantly, and an increase of ICE protein was observed
in the RSV-infected cell lysate. These increments were observed in cells treated
with live RSV but not in cells treated with inactivated RSV or control antigen.
However, no infection-specific increase of CPP32 gene expression or the protein
was observed. No nucleosomal fragmentation was observed in RSV-infected cells
during the whole course of infection, despite the appearance of extensive
cytopathic change and cell death. These observations suggest that RSV infection
of human alveolar epithelial cells induces the ICE gene and its protein as a
result of increased IRF-1 induction but that the increased ICE was insufficient
to cause apoptosis in the RSV-infected cells. ICE might not be able to activate
CPP32, which is thought to be the more important protease for apoptosis.
PMID- 9557749
TI - Identification of a full-length cDNA for an endogenous retrovirus of miniature
swine.
AB - Endogenous retroviruses of swine are a concern in the use of pig-derived tissues
for xenotransplantation into humans. The nucleotide sequence of porcine
endogenous retrovirus taken from lymphocytes of miniature swine (PERV-MSL) has
been characterized. PERV-MSL is a type C retrovirus of 8,132 bp with the greatest
nucleic acid sequence identity to gibbon ape leukemia virus and murine leukemia
virus. Constitutive production of PERV-MSL RNA has been detected in normal
leukocytes and in multiple organs of swine. The copy numbers of full-length PERV
sequences per genome (approximately 8 to 15) vary among swine strains. The open
reading frames for gag, pol, and env in PERV-MSL have over 99% amino acid
sequence identity to those of Tsukuba-1 retrovirus and are highly homologous to
those of endogenous retrovirus of cell line PK15 (PK15-ERV). Most of the
differences in the predicted amino acid sequences of PK15-ERV and PERV-MSL are in
the SU (cell attachment) region of env. The existence of these PERV clones will
enable studies of infection by endogenous retroviruses in xenotransplantation.
PMID- 9557750
TI - Feline coronavirus type II strains 79-1683 and 79-1146 originate from a double
recombination between feline coronavirus type I and canine coronavirus.
AB - Recent evidence suggests that the type II feline coronavirus (FCoV) strains 79
1146 and 79-1683 have arisen from a homologous RNA recombination event between
FCoV type I and canine coronavirus (CCV). In both cases, the template switch
apparently took place between the S and M genes, giving rise to recombinant
viruses which encode a CCV-like S protein and the M, N, 7a, and 7b proteins of
FCoV type I (K. Motowaka, T. Hohdatsu, H. Hashimoto, and H. Koyama, Microbiol.
Immunol. 40:425-433, 1996; H. Vennema, A. Poland, K. Floyd Hawkins, and N. C.
Pedersen, Feline Pract. 23:40-44, 1995). In the present study, we have looked for
additional FCoV-CCV recombination sites. Four regions in the pol gene were
selected for comparative sequence analysis of the type II FCoV strains 79-1683
and 79-1146, the type I FCoV strains TN406 and UCD1, the CCV strain K378, and the
TGEV strain Purdue. Our data show that the type II FCoVs have arisen from double
recombination events: additional crossover sites were mapped in the ORF1ab
frameshifting region of strain 79-1683 and in the 5' half of ORF1b of strain 79
1146.
PMID- 9557751
TI - Theiler's virus infection of perforin-deficient mice.
AB - Theiler's virus, a murine picornavirus, infects the central nervous systems of
C57BL/6 mice and is cleared after approximately 10 days by a process which
requires CD8+ cytotoxic T cells. We used perforin-deficient C57BL/6 mice to test
the role of this protein in viral clearance. Perforin-deficient mice died from
viral encephalomyelitis between days 12 and 18 postinoculation. They had high
levels of viral RNA in their central nervous systems until the time of death. In
contrast, viral RNA had disappeared by day 11 postinoculation in wild-type
C57BL/6 mice. Cytotoxic T cells can kill infected cells by two main mechanisms:
the secretion of the pore-forming protein perforin or the interaction of the Fas
ligand with the apoptosis-inducing Fas molecule on the target cell. Our results
demonstrate that clearance of Theiler's virus from the central nervous system in
C57BL/6 mice is perforin dependent.
PMID- 9557752
TI - Identification of a putative receptor for porcine reproductive and respiratory
syndrome virus on porcine alveolar macrophages.
AB - To identify the receptor which may determine the macrophage tropism of porcine
reproductive and respiratory syndrome virus (PRRSV), monoclonal antibodies (MAbs)
against porcine alveolar macrophages (PAM) were produced. Two MAbs (41D3 and
41D5) which completely blocked PRRSV infection of PAM were further characterized.
It was found that they reduce the attachment of PRRSV to PAM and
immunoprecipitate a 210-kDa membrane protein from PAM. This protein was detected
on the cell membranes of PAM but not of PRRSV-nonpermissive cells. A
colocalization was found between the reactive sites of MAb 41D3 and PRRSV on PAM
membranes. All PRRSV-infected cells in tissues of experimentally infected pigs
reacted with MAb 41D3. Taken together, all these data suggest that the identified
210-kDa membrane protein is a putative receptor for PRRSV on porcine macrophages.
PMID- 9557753
TI - Single amino acid insertion in loop 4 confers amphotropic murine leukemia virus
receptor function upon murine Pit1.
AB - Pit1 is the human receptor for gibbon ape leukemia virus (GALV) and feline
leukemia virus subgroup B (FeLV-B), while the related human protein Pit2 is a
receptor for amphotropic murine leukemia virus (A-MuLV). The A-MuLV-related
isolate 10A1 can utilize both Pit1 and Pit2 as receptors. A stretch of amino
acids named region A was identified in Pit1 (residues 550 to 558 in loop 4) as
critical for GALV and FeLV-B receptor function. We have here investigated the
role of region A in A-MuLV and 10A1 entry. Insertion of a single amino acid in
region A of mouse Pit1 resulted in a functional A-MuLV receptor, showing that
region A plays a role in A-MuLV infection. Moreover, the downregulation of 10A1
receptor function by changes in region A of human Pit1 indicates that this region
is also involved in 10A1 entry. Therefore, region A seems to play a role in
infection by all viruses utilizing Pit1 and/or Pit2 as receptors.
PMID- 9557754
TI - Processing of the Borna disease virus glycoprotein gp94 by the subtilisin-like
endoprotease furin.
AB - Open reading frame IV (ORF-IV) of Borna disease virus (BDV) encodes a protein
with a calculated molecular mass of ca. 57 kDa (p57), which increases after N
glycosylation to 94 kDa (gp94). The unglycosylated and glycosylated proteins are
proteolytically cleaved by the subtilisin-like protease furin. Furin most likely
recognizes one of three potential cleavage sites, namely, an arginine at position
249 of the ORF-IV gene product. The furin inhibitor decRVKRcmk decreases the
production of infectious BDV significantly, indicating that proteolytic cleavage
of the gp94 precursor molecule is necessary for the full biological activity of
the BDV glycoprotein.
PMID- 9557755
TI - Influenza virus-infected epithelial cells present viral antigens to antigen
specific CD8+ cytotoxic T lymphocytes.
AB - We have investigated the mechanisms involved in the clearance of viral infection
at the epithelium level by analyzing the activity of influenza virus-specific
cytotoxic T lymphocytes (CTL) against virus-infected CMT-93 intestinal epithelial
cells. Epithelial cells infected with live influenza virus effectively present
viral antigens and were lysed by both homotypic and heterotypic influenza virus
specific CD8+ T cells. These results shed new light on the control of viral
infection through the elimination of virus-infected epithelial cells by virus
specific CTL and demonstrate that CMT-93 cells furnish an appropriate model for
in vitro evaluation of CTL activity against virus-infected epithelial cells.
PMID- 9557756
TI - Molecular evidence for nosocomial transmission of human immunodeficiency virus
from a surgeon to one of his patients.
AB - We have investigated the molecular evidence in favor of the transmission of human
immunodeficiency virus (HIV) from an HIV-infected surgeon to one of his patients.
After PCR amplification, the env and gag sequences from the viral genome were
cloned and sequenced. Phylogenetic analysis revealed that the viral sequences
derived from the surgeon and his patient are closely related, which strongly
suggests that nosocomial transmission occurred. In addition, these viral
sequences belong to group M of HIV type 1 but are divergent from the reference
sequences of the known subtypes.
PMID- 9557757
TI - Identification of hepatitis G virus particles in human serum by E2-specific
monoclonal antibodies generated by DNA immunization.
AB - In order to elucidate the structure and morphology of hepatitis G virus (HGV), a
recently isolated flavivirus, we generated a panel of eight monoclonal antibodies
(MAbs) against the putative second envelope protein (E2) following DNA
immunization. The MAbs were shown to be specific for four different epitopes on
recombinant E2. MAb Mc6 was the only antibody able to detect the linear epitope
LTGGFYEPL. In addition, Mc6 was able to immunoprecipitate viral particles in
human blood samples as detected by reverse transcription-PCR amplification of HGV
RNA. This precipitation could be competed by addition of saturating amounts of
the linear peptide or abolished by addition of Nonidet P-40. We conclude that,
albeit lacking the N-terminal sequence of a functional core protein, HGV builds
classical viral particles displaying E2 envelope protein on their outer surfaces.
PMID- 9557758
TI - Ablation of teflon granuloma with the free-electron laser emitting in the eight-
to nine-micron range.
AB - In this study, we developed a rat model for Teflon granuloma and used this model
to evaluate the removal of the granuloma at laser wavelengths at which Teflon has
a maximal absorption. Twenty-four Teflon granulomas were created in 12 rats, and
the gross and histologic effects from laser incision at four different
wavelengths (8.25, 8.5, 8.75, and 10.6 microm) were evaluated acutely and at 7
and 14 days postoperatively. Polytetrafluoroethylene, or Teflon, is a relatively
inert substance that has been used over the past 4 decades for endoscopic
injection into the thyroarytenoid muscle of the larynx for the purposes of
laryngeal rehabilitation in cases of unilateral vocal fold paralysis or
incomplete glottic closure. In certain cases in which formation of granulomatous
reaction to the Teflon occurs, patients may have significant dysphonia or airway
compromise. Once Teflon has infiltrated the surrounding tissue planes, it is
exceedingly difficult to remove endoscopically. Endoscopic removal of this
granuloma is usually attempted with the carbon dioxide (CO2) laser and has had
limited success. Examination of the infrared absorption spectrum of
polytetrafluoroethylene reveals strong absorption in the mid-infrared region in
the 8- to 9-microm range, with minimal absorption at 10.6 microm. Therefore, this
absorption spectrum predicts a more efficient vaporization of Teflon at
wavelengths near 8.5 microm. Using the free-electron laser to generate 8.25-, 8.5
, and 8.75-microm laser light, we found Teflon granuloma ablation was far
superior to CO2 laser ablation at 10.6 microm. The 8.25-, 8.5-, and 8.75-microm
wavelengths selectively ablated Teflon granuloma with minimal to no collateral
thermal injury to tissue. The differences in thermal effects observed while
actually using the lasers were confirmed histologically.
PMID- 9557759
TI - Pharmacologic inhibition of collagen in an experimental model of subglottic
stenosis.
AB - Subglottic stenosis occurs as a complication of prolonged endotracheal intubation
secondary to inflammation with development of scar tissue and subsequent
fibrosis. Collagen I and III levels increase during the healing process. Steroids
alter the inflammatory response, decreasing recruitment of macrophages and
fibroblasts. Beta-aminopropionitrile (betaAPN) inhibits the development of
collagen cross-linking. A mechanism that would minimize hypertrophic scarring was
sought. Eighteen dogs were anesthetized, had tracheostomies performed, and later
had cautery of the mucosa and inner layer of the cricoid cartilage. Of 18
survivors, 6 animals were used as controls, 6 animals received oral Decadron, 2
mg/d, and 6 animals received oral betaAPN, 40 mg/d. There were 9 early deaths--5
in the steroid group. Animals were painlessly sacrificed, and the specimens were
sectioned at the cricoid cartilage level and were stained immunohistochemically
for antibodies to collagen types I to VI. Analysis of the area of scar and the
intensity of stain was performed with Mocha image analysis software. Collagen III
increased in control animals to 14.38 +/- 1.85 (intensity stain index), but this
reaction was reduced by betaAPN (5.77 +/- 1.78, p < .01). Steroids had no
significant effect on formation of any type of collagen. Lathyrogens (betaAPN)
may offer a pharmacologic tool to reduce scar tissue.
PMID- 9557760
TI - Unilateral versus bilateral botulinum toxin injections in adductor spasmodic
dysphonia.
AB - Thyroarytenoid injection of botulinum toxin is the therapy of choice in spasmodic
dysphonia. However, there is no convincing evidence as to whether unilateral or
bilateral injections are to be preferred. For this reason, a prospective study
was designed in which voice quality, duration of effect, and side effects were
assessed. Twenty-seven patients with adductor spasmodic dysphonia were treated
with percutaneous injections of botulinum toxin. The first treatment consisted of
injection of 5 units in the left thyroarytenoid muscle. The second treatment, 2.5
units in both sides, took place when the effect of the first procedure had
completely ceased. All patients underwent both procedures. By means of self
rating scales, effects and side effects were assessed over at least 3 months.
There was no difference between the procedures in duration of voice improvement,
nor in the occurrence of breathy dysphonia. After a bilateral injection,
statistically more patients reported swallowing problems. However, most patients
preferred the bilateral injection, in spite of more and longer-lasting side
effects.
PMID- 9557761
TI - Endoscopic management of pediatric posterior glottic stenosis.
AB - Open laryngofissure with posterior cartilage grafting is advocated by some as the
main treatment for posterior glottic stenosis in children. Endoscopic
arytenoidectomy has been tried and recommended for bilateral vocal cord paralysis
in children, but little published experience exists in its use for the treatment
of pediatric posterior glottic stenosis. We describe our experience with this
technique in 11 children ages 2 to 12 years, 6 of whom were under the age of 5
years. Nine of 11 patients at the initial surgery were tracheotomy-dependent; 2
others had previous laryngofissure with cartilage grafting, but continued to
suffer from severe airway limitations. Modified carbon dioxide laser
arytenoidectomies resulted in decannulation in 5 of 9 children and marked
improvements in the 2 children without tracheotomies, as documented by flow
volume loops and symptoms. Endoscopic arytenoidectomy, in our experience, is not
as successful as open techniques described in previously published series of
children, and requires multiple procedures due to the regrowth of granulation
tissue. However, endoscopic repair is a viable option for low-grade stenosis and
does not preclude an open repair in the future. It is also useful as an
adjunctive procedure to augment the repair from an open approach.
PMID- 9557762
TI - Method for removing endobronchial beads.
AB - The development of rigid bronchoscopes, Hopkins rod telescopes, and optical
forceps has increased the efficacy and safety of removing endobronchial foreign
bodies. These instruments have become the method of choice for managing the
majority of foreign bodies. Spherical foreign bodies, such as beads, remain
difficult to manage. Securing the foreign body by passing a Fogarty catheter
through the lumen, inflating the balloon, and trapping the foreign body between
the balloon and the bronchoscope allows controlled removal.
PMID- 9557763
TI - Laryngeal radionecrosis versus recurrent cancer: a clinical approach.
AB - A group of 38 patients was studied by positron emission tomography utilizing
fluorine18-labeled deoxyglucose (FDG-PET) scanning to examine the ability to
differentiate postirradiation laryngeal recurrent cancer from radionecrosis. The
resulting 79% correct diagnosis showed the technique to be far superior to
conventional computed tomography scanning (61%) and clinical examination (43%).
An algorithmic approach to evaluating and treating patients with radionecrosis
and/or recurrent cancer by utilizing FDG-PET scanning is presented.
PMID- 9557764
TI - Corniculate-cuneiform flap for reconstruction in the extended vertical partial
laryngectomy.
AB - The extended vertical partial laryngectomy involves removal of the vocal cord and
adjacent arytenoid cartilage. Arytenoid sacrifice predisposes the patient to
postoperative aspiration, since adequate laryngeal closure during swallowing
cannot be accomplished. Various techniques have been previously described for
reconstruction of this defect. We present five patients who had reconstruction of
this area with a local, mucosally based corniculate-cuneiform flap. All patients
were decannulated, had no long-term aspiration, maintained socially acceptable
voice quality, and had no tumor recurrence with a minimum of 3 years of follow
up. Our preliminary data suggest that this flap can be used in previously
irradiated patients. The corniculate-cuneiform flap is an effective method of
reconstruction in patients undergoing an extended vertical partial laryngectomy.
PMID- 9557765
TI - Long-term excitability and fine tuning of nerve pedicles reinnervating strap
muscles in the dog.
AB - Contraction of paralyzed striated muscles has been restored by stimulating
reinnervating pedicles with currents of low intensity. In order to allow clinical
application, stable, long-term excitability must emulate the parameters necessary
for the stimulation of normal motor nerves. In 6 dogs, the ansa hypoglossi nerve
was implanted into the contralateral denervated sternohyoid muscle and surrounded
with a bipolar cuff electrode. Three of the reinnervating pedicles were
chronically paced with a Medtronic Itrel II Multiprogrammable Pulse Generator
(0.5 V, 0.2 second on [30 pulses per second, 0.21-millisecond pulse width], 2.9
seconds off). At reexploration after 8 months (6 months for 1 dog), frank
contraction confirmed by electromyography tracings occurred in all animals with
currents in the range of 0.1 to 0.5 mA. Muscle force was further manipulated by
selective release of blocking currents (600 Hz, 1.7 to 0.4 mA) superimposed over
regular stimulation (50 Hz, 0.3 to 1.7 mA). Nerve and muscle vitality were
histologically confirmed. Long-term, low-intensity conduction capabilities, fine
tuning, good tolerance of implanted electrodes, and lack of fatigue suggest that
reinnervating pedicles may be successfully used for pacing when clinically
indicated.
PMID- 9557766
TI - Airflow and pressure characteristics of three different tracheostoma valves.
AB - Tracheoesophageal speakers can achieve speech without digital occlusion by using
a tracheostoma valve. Laryngectomized patients who are successful with this
device can regain considerable freedom. However, little is known about which
valve suits the patient best. Valve aerodynamics may give a guideline for its
use. Three major tracheostoma valves, each divided into four subtypes, were
repeatedly measured in this study. Dynamic pressure and airflow rate signals were
sampled through an analog-digital interface into a computer. Considerable
aerodynamic differences were observed between the tested valves. The maximum
airflow rates, closing pressures, and resistances at low velocities were
compared. The presented data may help increase the successful use of tracheostoma
valves in tracheoesophageal speakers. Patient factors and additional valve
factors should always be taken into account. Further clinical study to validate
the clinical relevance of the data is needed.
PMID- 9557767
TI - Correlations between pathologic changes in the stapes and conductive hearing loss
in otosclerosis.
AB - The goal of this temporal bone study was to quantify the relationship between
specific histologic changes at the stapes footplate and the magnitude of the air
bone gap in otosclerosis. The study material comprised 26 specimens with
otosclerosis and 37 age-matched controls. Detailed anatomic measurements were
made on each histologic section through the stapes footplate in each bone,
resulting in 30 different measurement parameters for each bone. For frequencies
250 to 2,000 Hz, the conductive hearing loss correlated highly with (p < .01) and
appeared to be caused primarily by narrowing and loss of the annular ligament,
especially at the posterior stapediovestibular joint space. The size of the air
bone gap appeared to be determined by the extent and degree of this pathologic
change. Schuknecht's hypothesis that bony ankylosis of the footplate would be
associated with an air-bone gap of >30 dB was supported by our data. However, the
degree and extent of bony footplate ankylosis could not be reliably predicted by
the size of the air-bone gap.
PMID- 9557768
TI - Role of superoxide dismutase in otitis media with effusion.
AB - The concentration of superoxide dismutase (SOD) in middle ear effusion (MEE) was
measured by the electron spin resonance trapping method in order to clarify the
role of SOD in otitis media with effusion (OME) in children. The SOD levels in
mucoid MEEs were significantly higher than those in serous and purulent MEEs.
There was no significant difference in the levels of SOD between neutrophil
dominant MEEs and mononuclear cell-dominant MEEs, and the levels were negatively
correlated with the number of neutrophils in the MEEs. Moreover, the levels were
significantly increased in patients having recurrence of MEE within 3 months
compared with patients without recurrence of MEE. Although it is known that SOD
plays an important role in protecting the host from oxygen radicals, the findings
in this study suggest that SOD might be related to the chronicity of OME.
PMID- 9557769
TI - Management of unilateral vocal cord paralysis by injection medialization with
teflon paste. Quantitative results.
AB - This paper prospectively analyzes eight patients who were selected for injection
medialization of a unilateral vocal cord paralysis by a transcutaneous technique.
Preoperative and postoperative videolaryngoscopic recordings of the position of
the paralyzed cord were made with a scoring system correlated to the laryngeal
airflow measurements. Quantitative acoustic recordings of the patient's voice
were also taken and compared with the patient's own subjective analysis of his or
her voice. Results indicate that Teflon injection by the transcutaneous method
gives a statistically and clinically improved voice in the short term.
PMID- 9557770
TI - Loss of cochlear nucleus neurons following aminoglycoside antibiotics or cochlear
removal.
AB - This study compared the effects of aminoglycoside ototoxicity and surgical
ablation of the cochlea in infancy on the survival of neurons in the rat cochlear
nucleus (CN). Ototoxicity was induced by a single, systemic dose of gentamicin
sulfate and furosemide on postnatal day 6 (P6), P7, or P10, and assessed by the
elevation of auditory brain stem response thresholds, as described in a companion
paper. Unilateral cochlear removals were performed under Saffan anesthesia on P6,
P9, and P12. Rats were painlessly sacrificed in adulthood, and the formalin
perfused brains and cochleas were embedded in wax, sectioned, and stained.
Ototoxic treatment at P6 through P10 did not reduce neuron counts in the CN.
Cochlear removal at P6 resulted in a 40% loss of CN neurons, but removal at P12
did not result in CN neuron loss. These data suggest that the critical period for
the dependence of CN neurons on afferent input from the cochlea ends at the same
time that susceptibility to aminoglycoside ototoxicity begins.
PMID- 9557771
TI - Effects of head rotation on pharyngeal function during normal swallow.
AB - This study quantified the effects of head rotation on pharyngeal swallowing in
healthy subjects. Videofluoroscopic and oropharyngeal manometric examinations of
pharyngeal swallowing were performed on seven volunteers with the head in neutral
and rotated positions. Videofluoroscopic study revealed that head rotation
swallow causes the bolus to lateralize away from the direction of head rotation.
Pharyngeal manometric study indicated that the pharyngeal peak pressures toward
the side of head rotation were significantly increased, whereas the pharyngeal
pressures opposite the side of head rotation were not affected. Head rotation
swallow produced a significant fall in upper esophageal sphincter (UES) resting
pressure and a delay in UES closing. We concluded that the head rotation swallow
in normal subjects not only alters the bolus pathway, but also has a useful
effect on both pharyngeal clearance and UES dynamics.
PMID- 9557773
TI - Pneumoparotitis: a new diagnostic technique and a case report.
AB - Pneumoparotitis is a rare cause of parotid gland swelling. We report a case of
self-induced pneumoparotitis that resulted in subcutaneous emphysema and
pneumomediastinum after an open biopsy of the parotid gland. We suggest a new
method for diagnosing this condition. This is done by insufflation of the cheeks
with contrast in the oral cavity. A reflux of air and contrast is subsequently
demonstrated by a computed tomography scan of the area.
PMID- 9557774
TI - Pneumo-membranous labyrinth: an unusual complication of a stapedectomy.
PMID- 9557772
TI - Human olfactory mucosa in schizophrenia.
AB - Recent evidence indicates that developmental anomalies may underlie some symptoms
of schizophrenia, while psychophysical studies have demonstrated olfactory
deficits in this disease. The postmortem olfactory mucosa of elderly
schizophrenic patients was examined to characterize the molecular phenotype of
this tissue. The distribution of developmentally regulated cytoskeletal proteins,
a synaptic vesicle protein, a neural marker protein, a receptor for trophic
molecules, axonal guidance and cell migration proteins, and neuronal and glial
cytoskeletal proteins of various degrees of phosphorylation was examined by
immunohistochemistry. Both schizophrenic and control subjects exhibited
dystrophic neurites that were immunoreactive for synaptophysin, microtubule
associated proteins (MAP1B), and neurofilament proteins. No major histochemical
or morphologic differences in either the expression or distribution of these
proteins were observed in the olfactory epithelium of schizophrenic compared to
control subjects. These studies indicated that dystrophic neurites frequently
occurred in the olfactory mucosa of both schizophrenics and neurologically normal
adults. The absence of major immunocytochemical abnormalities suggested that
olfactory deficits in schizophrenia may be due to more subtle cellular or
molecular differences or to abnormalities in olfactory regions of the central
nervous system rather than in the olfactory epithelium.
PMID- 9557775
TI - Tracheal diverticulum presenting with recurrent laryngeal nerve paralysis.
PMID- 9557776
TI - Traumatic pseudoaneurysm: a possible early lesion in the spectrum of epithelioid
hemangioma/angiolymphoid hyperplasia with eosinophilia.
AB - We describe a vascular lesion that develops secondary to trauma (pseudotraumatic
aneurysm) and study its relation to epithelioid hemangioma (EH)/angiolymphoid
hyperplasia with eosinophilia (ALHE). Four lesions are described, all with a
distinct history of trauma to the site from which they arose. They presented with
masses in the subcutaneous tissue of the head. They were studied by
immunohistochemical methods to identify their component cells. The lesions all
demonstrated marked thickening of the wall of small and medium-sized arteries,
with capillary vascular proliferations. One lesion demonstrated increased
eosinophils. Myxoid changes were noted in all lesions. We hypothesize that these
lesions may represent an early form of EH/ALHE.
PMID- 9557777
TI - Nodular melanosis due to epithelial neoplasms: a finding not restricted to
regressed melanomas.
AB - Nodular or tumoral melanosis consists of nodular or sheetlike deposits of
melanophages in the dermis. When nodular melanosis is present, a completely
regressed malignant melanoma is a major diagnostic consideration. We present a
case of nodular melanosis due to regression of a pigmented basal cell carcinoma
with pilar differentiation. In addition to this case, we present five additional
cases of epithelial neoplasms with melanin deposition in the stroma. In each
case, the source of the melanin was non-neoplastic dendritic melanocytes
intermingled among the tumor cells. Therefore, if nodular melanosis is found,
pigmented epithelial neoplasms should also be considered in the differential
diagnosis.
PMID- 9557778
TI - Primary malignant melanoma with rhabdoid features: a histologic and
immunocytochemical study of three cases.
AB - Malignant rhabdoid tumors are morphologically characterized by the presence of
sheets of large polygonal cells with abundant cytoplasm containing eosinophilic
inclusions. They have vesicular nuclei, often with prominent central nucleoli.
The term rhabdoid tumor was originally coined to describe a group of rare,
aggressive renal neoplasms of childhood. Since then, similar lesions, so-called
extrarenal malignant rhabdoid tumors have been increasingly reported. The
evidence to date suggests that, at least in extrarenal locations, rhabdoid tumors
do not constitute a homogeneous entity, but rather represent the shared
morphological pattern of a diverse range of malignant neoplasms. Although such
rhabdoid features are not uncommon in metastatic malignant melanoma, they have
only once been briefly described in a primary lesion. We report three further
cases of cutaneous primary malignant melanoma with rhabdoid morphology.
PMID- 9557779
TI - Histologic differentiation of desmoplastic melanoma from cicatrices.
AB - Desmoplastic malignant melanoma (DMM) is a rare variant of melanoma that can be
very difficult to diagnose correctly both clinically and histologically. The
problem is compounded by the fact that many lesions persist at previous biopsy or
excision sites so that scar tissue is often present admixed with or adjacent to
the spindle cell neoplasm which may exhibit fibroblastic differentiation itself.
In order to assess this problem, we compared and contrasted the histologic
features of six DMM with 15 examples of cicatrices from various sources. Mature
scars were readily differentiated from DMM by light microscopy. In contrast,
immature scar and DMM had many features in common including hypercellularity,
nodular lymphoid infiltrates, myxoid stroma, and atypical nuclei. The presence of
a melanocytic proliferation within the epidermis above the dermal component,
neurotropism, and S-100 and/or HMB-45 positivity of neoplastic cells were the
only features that permitted reliable differentiation between the two. Clinical
correlation and review of previous biopsy specimens are crucial in preventing a
delayed diagnosis of DMM. Re-excision is advised in all questionable cases.
PMID- 9557780
TI - Which direction do nevus cells move? Abtropfung reexamined.
AB - In 1893, Unna published his theory of Abtropfung in which he suggested that
melanocytic nevus cells originate in the epidermis and drop off into the dermis.
We studied 3,534 nevi from patients of all ages to reassess this almost sacred
concept. If Unna was correct, one would expect that in childhood most nevi would
be junctional, while in late adult life almost all nevi would be intradermal. In
our series, no child under age 10 had a purely junctional nevus, 52% had compound
nevi, and 48% had dermal nevi. In patients older than age 60, 12% had junctional
nevi, 23% had compound nevi, and 65% had dermal nevi. Our data fail to support
the concept of Abtropfung; they fit better with the contradictory theory of
upward migration of nevus cells.
PMID- 9557781
TI - Stromelysin-3: a potent marker for histopathologic differentiation between
desmoplastic trichoepithelioma and morphealike basal cell carcinoma.
AB - Histopathological differentiation between desmoplastic trichoepithelioma (DTE)
and morphealike basal cell carcinoma (BCC) is a difficult problem because of
their similar morphological features. The matrix metalloproteinase stromelysin-3
(ST-3), which is expressed as a specific fibroblastic factor especially
surrounding carcinoma cells, was studied in these both conditions of wholly
different clinical outcome. Using formalin-fixed paraffin-embedded tissues, we
found positive immunoreactivity for ST-3 in fibroblastic cells surrounding
morphealike BCC cells in 34 (68%) of 50 cases, whereas the epithelial tumor cells
themselves were negative. In none of the 12 cases of DTE did we observe
expression of ST-3 in fibroblasts. We conclude that the antibody against ST-3
protein is an immunohistochemical marker to distinguish morphealike BCC from DTE.
PMID- 9557783
TI - Fibronectin and the extracellular matrix in the perforating disorders of the
skin.
AB - Despite detailed microscopic descriptions and clinical observation, little is
known regarding the pathogenesis of the perforating disorders of skin, which have
traditionally been subdivided into numerous microscopic entities associated with
various clinical settings. An increasing body of evidence now suggests that the
perforating disorders of skin are akin, and may constitute an expanded single
pathologic entity. Each of the classic perforating disorders of skin, including
elastosis perforans serpiginosa, perforating folliculitis, reactive perforating
collagenosis, Kyrle's disease, and perforating disorder of uremia, have been
shown to extrude collagen, elastin, and related extracellular matrix components
through the epidermis. Considering a shared pathogenic mechanism among these
entities, we explored the possible role of the extracellular matrix, in
particular fibronectin, in perforating disorders of skin. Using
immunohistochemical and serum determinations of extracellular matrix
constituents, including fibronectin, collagen type IV, laminin, and tenascin, we
showed consistent serum elevation and/or deposition of fibronectin, in each case,
without a commensurate increase in laminin, collagen type IV, and tenascin. We
propose that elevated serum and tissue concentrations of fibronectin may be
responsible for inciting, in a physiologically aberrant manner, increased
epithelial migration and proliferation culminating in perforation.
PMID- 9557782
TI - Cytotoxic T cells in basal cell carcinomas of skin.
AB - Previous studies have suggested the importance of CD8+ cytotoxic T-cells of hosts
against neoplasms. Earlier studies and our previous investigation showed that a
majority of tumor infiltrating T-cells in human basal cell carcinomas (BCCs)
belonged to CD4+ T-cells. CD8+ cells were also present in the peritumor areas of
human BCCs, but in smaller numbers. Published evidence indicates the importance
of cytotoxic T-cells in antitumor immunity. Cytotoxic T-cells have been
identified by using monoclonal antibodies against various cytotoxic T-cell
components. In this study, we used monoclonal antibodies to perforin to evaluate
the role of cytotoxic T-cells in the host response against basal cell carcinomas.
Perforin-expressing T-cells could be identified in the infiltrate of BCCs in
frozen tissue sections, and also in antigen-retrieved paraffin-embedded sections
of BCCs, and the presence of perforin-expressing T-cells correlated with the
infiltration of CD8+ T-cells. These results suggest that cytotoxic T-cells play a
role in host defense against human BCCs.
PMID- 9557784
TI - Automated measurement of melanoma cross-sectional area.
AB - The object of this study was to evaluate the prognostic impact of a cross
sectional area measured in routinely stained slides of cutaneous melanoma using
fully automated image analysis. Hematoxylin-eosin stained slides of 238 specimens
of primary cutaneous melanoma with Clark levels III to V were evaluated by
digital image analysis using color video images, a scanning stage, and autofocus
equipment. The cross-sectional area was significantly related to metastasis-free
survival. Lesions with a cross-sectional area < or = 12 mm2 showed a 2-year
metastasis-free survival rate of 92+/-2% compared with 41+/-8% in lesions with a
cross-sectional area > 12 mm2 (log rank test: z = 71, p < 0.0001). The same was
true for overall survival (98+/-1% compared with 82+/-6%; z = 42.12, p < 0.0001).
In multivariate analysis, the cross-sectional area seems to provide prognostic
information in addition to that provided by Breslow's index. In cases with
regression and in small melanomas with vertical growth, however, metastatic
spread may occur in lesions with a small cross-sectional area. It was concluded
that automated measurement of the cross-sectional area may be helpful in
assessing prognosis in cutaneous melanoma.
PMID- 9557785
TI - Estrogen and progesterone receptors in androgenic alopecia versus alopecia
areata.
AB - In some situations, hair growth is under hormonal control. Androgenic alopecia is
characterized as hormonally driven hair loss in the genetically susceptible
individual. During pregnancy, hair growth is increased, as estrogen appears to
prolong the anagen phase. However, postpartum hair loss is common, and thus may
be related to a decrease in estrogen and or progesterone levels. In contrast,
alopecia areata is not considered to be under hormonal control. We compared the
immunohistochemical staining characteristics of nine cases of androgenic alopecia
with those of 13 cases of alopecia areata using estrogen receptor (ER) and
progesterone receptor (PR) markers. Estrogen receptor positivity in the dermal
papilla was found in only two of 13 cases of alopecia areata, and in one case of
androgenic alopecia. Six of 13 cases of alopecia areata demonstrated focal
reactivity with the progesterone marker in a similar location, while only three
cases of androgenic alopecia showed positivity with this antibody. Examination of
the perifollicular fibroblasts for the ER marker showed positivity in one of 13
cases of alopecia areata and in one case of androgenic alopecia. Two cases of
alopecia areata revealed focal staining in this location for the PR marker, while
the androgenic alopecia cases failed to stain. These results indicate that
estrogen and progesterone receptor expression is not significantly increased or
decreased in the pilosebaceous units or surrounding mesenchymal cells in
androgenic alopecia vs. alopecia areata. Therefore, an indirectly mediated
process of estrogen/progesterone control on hair growth and development must be
presumed for cases of androgenic alopecia.
PMID- 9557786
TI - Expression of proliferating cell nuclear antigen (PCNA) and apoptosis related
antigen (LeY) in epithelial skin tumors.
AB - We semiquantitatively analyzed expression of PCNA and LeY in seborrheic keratosis
(SK), actinic keratosis (AK), Bowen's disease (BD), and squamous cell carcinoma
(SCC), using immunocytochemically stained tissue sections. PCNA expression
increased in a stepwise fashion from low levels in normal skin to higher
expressions within SK, AK, BD, and SCC. The levels of LeY protein also increased
in this order. The PCNA expression pattern shifted from expression limited to the
basal and suprabasal cell layers (in normal skin and SK) to expression extending
to the upper squamous and granular layers (in AK, BD, and SCC). On the other
hand, the pattern of LeY expression shifted from the granular (in normal skin) to
the upper squamous (in SK and AK) and suprabasal layers (in BD and SCC). These
findings suggest that PCNA expression is related to the degree of cell
proliferation and that LeY expression is related to the degree of differentiation
or keratinization of tumor cells. In addition, PCNA and LeY show a reciprocal
relationship in their expression.
PMID- 9557787
TI - Vesiculo-bullous dermatomyositis.
AB - Cutaneous manifestations of dermatomyositis (DM) commonly include Gottron's
papules, cuticular erythema and telangiectasia, periorbital edema with a
"heliotrope" rash, a papulosquamous eruption of the hairline, face, and trunk, as
well as poikiloderma. Very few references can be found concerning vesicular and
bullous lesions, however. We present two patients with dermatomyositis who
manifested vesicular and bullous lesions who were initially misdiagnosed.
Although rare, it is important to recognize this form of DM to avoid
misdiagnosis. Furthermore, in some cases, vesiculo-bullous DM may portend a poor
prognosis.
PMID- 9557788
TI - Sarcoidal foreign-body granulomatous dermatitis associated with ophthalmic drops.
AB - Sarcoidal granulomas are found in sarcoidosis and in reactions to foreign
materials. We report the case of an 81-year-old woman with glaucoma who presented
with multiple brown-black asymptomatic papules over the chin and involving nasal
mucosa and columella of 1-year duration. Biopsy of the nasal mucosa and cutaneous
papules showed sarcoidal granulomas associated with brown-black intracellular
pigment within multinucleated giant cells. Electron-probe x-ray microanalysis
demonstrated high sulfur content. Clinical studies showed no evidence of systemic
sarcoidosis. Two of three ophthalmologic drops contained sodium bisulfite;
bisulfite is known to cause allergic reactions. Although the exact substance
causing the granulomatous reaction is unknown, the distribution of the lesions-
nasal mucosa and columella (via the nasal lacrimal duct) and the underlying chin-
implicate the eyedrops in the production of the pigmented granulomatous nodules.
PMID- 9557789
TI - Grover's-like disease in the setting of bone marrow transplantation and
autologous peripheral blood stem cell infusion.
AB - Four cases of a Grover's-like disease in patients with leukemia/lymphoma, who
underwent high-dose chemotherapy and either allogeneic/autologous bone marrow
transplantation or autologous stem cell infusion, are described. Three of four
patients had fever prior to the onset of their rash. In addition to suprabasilar
clefts, acantholysis, and dyskeratosis, typical of Grover's disease, there was a
chemotherapeutic effect in the form of keratinocytes with atypical nuclei. So
called "starburst cells," which have been purported to be specific for high-dose
etoposide (VP-16) therapy, were seen in two cases, but only one of these patients
received etoposide. In one patient with clinical vesicles, direct
immunofluorescence ruled out paraneoplastic pemphigus. In conjunction with 18
similar cases in the literature, the following conclusions were reached: (a) the
pathogenesis probably involves the combined effects of fever (with sweating),
occlusion, and chemo/radiation therapy; (b) no single chemotherapeutic agent can
be consistently implicated; and (c) in addition to graft-versus-host disease, the
eruption of lymphocyte recovery, and other cutaneous eruptions in the setting of
bone marrow transplantation, the differential diagnosis includes paraneoplastic
pemphigus, which direct immunofluorescence excludes.
PMID- 9557790
TI - Cutaneous malakoplakia in a patient with acquired immunodeficiency syndrome
(AIDS).
AB - Malakoplakia is an uncommon granulomatous lesion that afflicts predominantly
immunocompromised individuals but is extremely rare in acquired immunodeficiency
syndrome (AIDS). We report a case of cutaneous malakoplakia in an AIDS patient
that presented as a banal right axillary abscess which resolved after excision
and drainage. The rarity of malakoplakia in AIDS may be due to a relative or
selective preservation of antimicrobial function of monocytes. Malakoplakia is
distinguished from other inflammatory or neoplastic lesions by the presence of
Michaelis-Gutmann bodies. A correct diagnosis is usually made only after biopsy
and is an indication to use antimicrobial agents with adequate cellular
penetration and concentration.
PMID- 9557791
TI - Benign sebaceous neoplasm with prominent epidermal component.
AB - A 65-year-old woman presented with a solitary nodule within an erythematous
plaque in her right groin. Histopathologic examination showed central lobular
proliferation of basaloid cells admixed with mature sebaceous cells and a lateral
extensive intraepidermal component composed mostly of lobules of mature sebocytes
consistent with intraepidermal epithelioma with sebaceous differentiation and
focal invasion. Although various cutaneous neoplasms may show an intraepidermal
growth pattern, extensive sebaceous differentiation in such a neoplasm, as seen
in this case, has not been described. Electron-microscopic study revealed that
the basaloid cells have features of pluripotential cells. This observation
supports the previously reported concept that intraepidermal epithelioma may be
composed of a group of heterogeneous tumors with various degrees and lines of
differentiation. Additionally, sebaceous epithelioma/adenoma should be considered
in the differential diagnosis of the cutaneous neoplasms with an intraepidermal
growth pattern.
PMID- 9557792
TI - Multiple pigmented basal cell carcinomas.
AB - Basal cell carcinoma is the most common of all skin cancers and the most
prevalent one among Caucasians. Rarely, these tumors are seen in other races. We
report a 77-year-old Korean woman who presented with multiple darkly pigmented
enlarging nodules on her scalp, face, trunk, and extremities. The patient had
first noted a 6-mm pigmented lesion on her left eyebrow 10 years previously.
Since then, other lesions had appeared in many locations on her body. She had
been otherwise healthy and without a history of exposure to arsenic or radiation.
There was no family history of skin cancer, xeroderma pigmentosum, or basal cell
nevus syndrome. On physical examination, multiple darkly pigmented dome-shaped
papules and nodules were present on her scalp, face, right forearm, lower
abdomen, and inguinal areas. They ranged in size from 0.5 mm to 2 cm. The larger
ones showed central ulceration. Multiple biopsy specimens from different sites
showed pigmented basal cell carcinomas. Clinically, there was no evidence of
nevus sebaceus, xeroderma pigmentosum, basal cell nevus syndrome, or
immunodeficiency. Clinical workup including chest radiography, abdominal
ultrasound, bone scan, and brain computerized axial tomography scan did not
demonstrate primary or secondary tumors. The results of serologic and hematologic
tests were also within normal limits. This is an unusual case report of multiple
pigmented basal cell carcinomas in an Asian woman without any predisposing risk
factors.
PMID- 9557793
TI - Painful hyperplasia and hypertrophy of pacinian corpuscles in the hand: report of
two cases with immunohistochemical and ultrastructural studies, and a review of
the literature.
AB - Hypertrophy and hyperplasia of pacinian corpuscles in the hand are very rare,
with only 29 cases previously published. We describe two new cases in middle-aged
patients whose chief complaint was progressive digital pain. Immunohistochemical
and electronmicroscopic investigations indicated that the lump replicates the
structure of enlarged pacinian corpuscles and should not be considered as a real
tumor, nor connected to neurofibromatosis. No recurrence was observed after
surgical excision. Although local trauma was encountered in 55% of the reported
cases, the pathogenesis of such a lesion is still speculative.
PMID- 9557794
TI - Benign myoepithelioma of the skin.
AB - A case of cutaneous myoepithelioma is reported. The tumor was composed of spindle
shaped, epithelioid, and plasmacytoid (hyaline) cells. It exhibited a widespread
immunoreactivity for low molecular weight keratins and protein S-100, being
irregularly positive for smooth muscle actin. Ultrastructural studies of tumor
cells showed a variable content of intermediate filaments, with focal densities
resembling smooth muscle dense bodies. A well-developed basal lamina, pinocytotic
vesicles, and some desmosomes were also observed. In spite of being accepted as
an individual entity, myoepitheliomas probably belong to a family of lesions that
include mixed tumors. Therefore, this case can be considered as a salivary-gland
type tumor, probably originating from myoepithelial cells of sweat glands. The
existence of this unique neoplasm provides further support to the debated role of
myoepithelial cells in the development of mixed tumors.
PMID- 9557795
TI - Cutaneous epithelioid angioleiomyoma.
AB - We describe an unusual dermal neoplasm with epithelioid morphology. A 44-year-old
man presented with a solitary, tender, 4-mm nodule on the leg. Excisional biopsy
showed several well-circumscribed dermal epithelioid tumor nodules, prominent
vascularity, and smooth muscle differentiation. We suggest the term cutaneous
epithelioid angioleiomyoma for this neoplasm. In a review of the literature, we
found reports of two similar cases and a recent report describing five cutaneous
epithelioid leiomyosarcomas. Cutaneous epithelioid angioleiomyoma represents a
rare variant of dermal smooth muscle tumor and could represent the benign
counterpart to the recently described epithelioid leiomyosarcoma of the skin.
PMID- 9557796
TI - Skin as the primary site of Hodgkin's disease: a case report of primary cutaneous
Hodgkin's disease and review of its relationship with non-Hodgkin's lymphoma.
AB - We report an elderly patient who presented with a single cutaneous nodule of
primary cutaneous Hodgkin's disease (PCHD). Reed-Sternberg cells, expressing CD30
and CD15, but not leukocyte common antigen (CD45RB), were identified in the
neoplastic cells. Southern blot analysis failed to detect T-cell receptor or
immunoglobulin gene rearrangement. A work-up for systemic disease at the time of
presentation was negative, supporting the diagnosis of PCHD. Nevertheless, 1 year
later, the disease course was complicated by the development of nodal HD and
nonHodgkin's lymphoma (NHL). This case report supports the existence of this
rare, but distinct, cutaneous tumor.
PMID- 9557797
TI - Quantitative ultrasonography of the liver in cats during obesity induction and
dietary restriction.
AB - A study was designed to evaluate quantitative ultrasonographic characteristics of
a diffuse parenchymal disease in an experimental model of subclinical fatty
infiltration of the liver using diet-induced obesity and dietary restriction in
the cat. Ultrasound images of livers were quantitatively analysed by a video
signal analysis technique before, during and at the end of obesity induction, and
then during and following dietary restriction. Attenuation and brightness
(backscatter coefficient) were correlated with hepatic lipid content obtained
from the livers by surgical and ultrasound-guided percutaneous biopsy.
Attenuation and backscatter increased as hepatic lipid content increased. Both
attenuation and backscatter significantly correlated with the hepatic lipid
content (P=0.002 and P=0.02 respectively). This model of subclinical fatty
infiltration of the liver in the cat demonstrates that hepatic lipid content
increases as a consequence of obesity and of severe dietary restriction.
Infiltration of the liver with fat may be evaluated non-invasively using
quantitative ultrasonography by the video signal analysis technique. This method
of image analysis may prove useful for the evaluation of diffuse parenchymal
organ disease.
PMID- 9557798
TI - Clinical biochemical parameters of the endangered Catalonian donkey breed: normal
values and the influence of sex, age, and management practices effect.
AB - Twelve clinical biochemical parameters were determined in 97 animals of all age
groups and both sexes of the endangered Catalonian donkey breed. Significant sex
differences were observed for phospholipid concentration (P<0.01). Evaluating the
effect of management practices on the various parameters showed significant
differences for total bilirubin (P<0.001) and creatinine (P<0.05) concentrations
and gamma-glutamyltransferase (P<0.05) activity. Moreover, it was observed that
inorganic phosphorus concentration decreased with age (P<0.001), whereas albumin
and triglyceride concentrations increased with age (P<0.01 and P<0.001,
respectively). Comparison of biochemical ranges obtained for the Catalonian
donkey breed with reference ranges for other breeds and populations (Mammoth, USA
donkeys, UK donkeys, Indian donkeys and Poitou donkeys), indicated that most
values were similar, with the exceptions of enzymatic activities mainly. The
results reported in the present study could serve as reference ranges for donkey
populations.
PMID- 9557799
TI - Effects of weight gain and loss on metabolic rate, glucose tolerance, and serum
lipids in domestic cats.
AB - Weight gain is a common problem in domestic cats, but little is known about its
metabolic effects. The purpose of this study was to determine the effects of diet
induced weight gain and subsequent weight loss on metabolic rate, body
composition, and glucose tolerance. Gain of approximately 20 per cent body weight
(divided approximately equally between fat and fat-free mass) over three months
resulted in insulin resistance in females, indicated by increases in basal
insulin concentration (68.2+/-7.9 to 119+/-16.5 pmol litre(-1), P<0.05), insulin
peak response to glucose (241.1+/-31.6 to 315.0+/-23.0 pmol litre(-1), P<0.05),
and deltaI/deltaG (14.2+/-2.6 to 18.1+/-1.3 pmol mmol(-1), P<0.05) compared with
pre-gain values. The same numerical trend was noted in male cats, however,
changes were not significant (P>0.05). Alterations in serum lipids included
significant (P<0.05) elevations in triglyceride concentrations in male cats and
decreased beta-lipoprotein concentrations in both genders. Weight loss over three
months normalised basal insulin, insulin response to glucose, and serum
triglyceride concentrations, and resulted in significant (P<0.05) decreases in
serum concentrations of beta- and prebeta-lipoproteins, cholesterol, and
triiodothyronine. Diet-induced weight gain of three months' duration, followed by
three months' maintenance of increased body weight did not affect fasting or
resting metabolic rate. Development and severity of impaired glucose tolerance,
insulin resistance, and other changes may be affected by duration and possibly
severity of weight gain.
PMID- 9557800
TI - The isolation and purification of a dual specific mast cell-derived protease from
parasitised caprine jejunal tissue.
AB - A mast cell granule protease has been isolated and purified from nematode
infected caprine jejunal homogenate by FPLC techniques and termed Goat Mast Cell
Protease (GMCP). The purification steps were monitored for proteolytic activity
against the synthetic substrate carboxybenzoyl-L-lysine thiobenzyl ester (BLT)
and the presence of a homogenous protease preparation in the final sample was
shown by SDS-PAGE electrophoresis. This protease was compared with enzymatic
activity from isolated mucosal mast cells, which demonstrated the putative mast
cell-derived source of the purified enzyme. Rabbit antiserum was raised against
the protease and through the use of immunohistochemistry and Western blotting
techniques the mast cell origin of the protease was confirmed. NH2-Terminal amino
acid sequence analysis demonstrated a high degree of homology between GMCP and
other previously isolated mast cell proteases including sheep mast cell protease
(SMCP). Substrate analysis showed that GMCP also had an unusual dual chymotrypsin
like and trypsin-like activity similar to SMCP and bovine duodenase.
PMID- 9557801
TI - Recombinant porcine follicle stimulating hormone produced in baculovirus-insect
cells induces rat ovulation in vivo and gene expression of tissue plasminogen
activator in vitro.
AB - Superovulatory responses in cattle are known to be highly variable. In the
present study, a recombinant porcine follicle stimulating hormone (rpFSH)
produced in baculovirus-insect cells was utilised to evaluate the role of this
recombinant FSH in control of the ovulatory process. Immature hypophysectomised
rats were implanted with oestrogen pellet (10 mg diethylstilbestrol) and then
primed with pregnant mare serum gonadotropin (PMSG, 17.5 IU, sc). Fifty-two hours
later, 100 microg rpFSH or saline was injected (sc) to induce ovulation. All rats
that received rpFSH ovulated with about eight ova rat(-1), whereas none of the
control animals did. Ovulation induced by rpFSH was associated with an increase
in the ovarian activity and message levels of tissue-type plasminogen activator
(tPA), a protease important in the preovulatory degradation of the follicle wall.
Furthermore, addition of rpFSH to the cultured rat granulosa cells resulted in a
significant increase in tPA enzyme activity. These results demonstrate that rpFSH
produced in baculovirus-insect cells has biological potency in ovulation as well
as gene expression of tPA, providing a large advantage of this massive expression
system in the reproduction of domestic animals.
PMID- 9557802
TI - Activity of N-acetylglucosamine-1-phosphate transferase in sheep liver
microsomes: in vivo and in vitro inhibition by tunicamycin.
AB - The neurological disease of livestock known as annual ryegrass toxicity, caused
by ingestion of bacterial toxins called corynetoxins, has been shown to be
produced experimentally by injection of tunicamycin, a related antibiotic. In
this study the effects of tunicamycin inhibition on the activity of the enzyme, N
acetylglucosamine-1-phosphate transferase, in sheep liver rough microsomes were
measured in vitro and in vivo. Enzyme activity was dependent on Triton X-100 and
exogenous dolichyl phosphate for maximal activity, although there was measurable
activity in their absence. The transferase enzyme was very sensitive to in vitro
(inhibition can be detected below 10 ng ml(-1)). In vivo, sheep treated
parenterally with a single dose of tunicamycin showed a time and dose-dependent
decrease in enzyme activity, which was almost completely inhibited for up to 14
days after a sublethal dose of toxin. In addition, the yield of rough microsomes
was lower from toxin-treated sheep than from control animals.
PMID- 9557803
TI - Bisphosphonates: a potential role in the prevention of osteoporosis in laying
hens.
AB - Osteoporosis in layers is associated with the modelling and remodelling of
medullary bone. Cancellous bone volume (CBV) decreases initially during medullary
bone modelling and continues to decrease during subsequent remodelling. In an
attempt to maintain peak structural bone mass, the bisphosphonate, alendronate,
was administered to pullets before medullary bone modelling. At point of lay CBV
was significantly greater (P<0.01) in the alendronate group (17.59 per cent) than
in controls (13.79 per cent), while medullary bone volume (MBV) was not
significantly affected. After 20 weeks, CBV remained significantly higher
(P<0.02) in the alendronate group (12.72 per cent) than in controls (9.80 per
cent) and MBV was lower in the alendronate group than the control group. CBV was
however reduced and MBV increased in both groups compared with values at point of
lay. Alendronate therefore appeared to prevent the bone loss associated with
medullary bone modelling but not that which occurs during remodelling.
PMID- 9557804
TI - Scrapie associated fibril detection from formaldehyde fixed brain tissue in
natural cases of ovine scrapie.
AB - The medulla oblongata of the brains of 71 scrapie-suspect cases were routinely
fixed in 10 per cent formal saline and assessed for vacuolation on HE-stained
sections. A pool of fresh brain material was also dissected from each animal and
extracts prepared for the routine detection of scrapie-associated fibrils by
negative stain transmission electron microscopy. The remaining formaldehyde fixed
medulla samples, which were not used for the histological examination, were coded
and subjected to a pretreatment with sodium borohydride and then processed using
the routine fibril detection procedure. Of the 71 samples tested 46 were
considered positive by all three test procedures. Sixteen samples were negative
for all three tests. Four samples were positive by histopathological examination
and positive for fibrils using fresh tissue, but fibrils could not be detected in
the fixed tissue preparations. Conversely, there were five fixed samples in which
fibrils could be detected which were negative for the other two tests. The
fibrils observed in fixed preparations were indistinguishable from those observed
in fresh tissue extracts. The sensitivity of the test for fibril detection using
fixed tissue was 92 per cent and the specificity 76 per cent. It is concluded
that scrapie-associated fibrils can be recovered from formaldehyde fixed tissue,
as presented for routine histopathological examination, and therefore the method
has potential in the retrospective analysis of archived brain tissue where only
fixed material was stored.
PMID- 9557805
TI - Effects of dobutamine on isovolumic and ejection phase indices of cardiac
contractility in conscious healthy dogs.
AB - The aim of this study was to determine cardiac contractility using indices
derived from cardiac catheterisation in conscious healthy dogs during dobutamine
infusion. Eight dogs were studied. An ECG was recorded together with left
ventricular pressure and volume which were measured using a conductance catheter
with an integrated microtip pressure sensor. Eight indices of left ventricular
systolic performance were derived from these records. Measurements were realised
under basal conditions and during an incremental dobutamine challenge. The
maximal rate of rise in ventricular pressure (max dP/dt), max dP/dt divided by
the developed pressure and the mean systolic ejection rate were the most
sensitive indices to detect dobutamine induced changes in contractility with
maximal percentage changes of 122+/-11 per cent, 130+/-7 per cent and 102+/-24
per cent respectively. Ejection fraction increased significantly during
dobutamine infusion (maximal percentage change of 43+/-9 per cent) whereas the
pre-ejection period (PEP) and the left ventricular ejection time (LVET) decreased
significantly (maximal percentage change of -41+/-2 per cent and -28+/-3 per cent
respectively). All these six indices were significantly correlated with each
other. Conversely, the ratio PEP/LVET and the LVET corrected for heart rate
dependency showed a maximal percentage change of only -10+/-1 per cent and -16+/
7 per cent, respectively, during the dobutamine infusion and were not
significantly correlated with the other contractility indices. This study
demonstrated the feasibility of the conductance method to determine cardiac
contractility in conscious healthy dogs submitted to a pharmacological stress
testing and provides control values for eight indices of left ventricular
contractility during dobutamine infusion at increasing dosages.
PMID- 9557806
TI - Effects of transport and indomethacin on telemetered body temperature and release
of cortisol and prolactin in pre-pubertal pigs.
AB - Previous research indicates that acute physical stress (restraint) raises core
temperature in growing pigs via a prostaglandin-dependent mechanism. This study
investigated whether transport stress affects body temperature in pigs and
whether any such changes might involve endogenous prostaglandins. Pre-pubertal
boars (n = 7) were implanted with venous catheters and biotelemetry devices for
the measurement of core temperature. They were transported for two hours, with
and without indomethacin (IND) pre-treatment, and blood samples were taken at 15
minute intervals for the determination of plasma cortisol and prolactin
concentrations. The results indicated that, contrary to predictions, body
temperature tended to fall during transport and that the effect was exaggerated
by IND. By contrast, cortisol concentrations increased during transport and were
unaffected by IND whereas the tendency for transport to stimulate prolactin
release was reversed by IND.
PMID- 9557807
TI - Variations in effectiveness of antigen retrieval pretreatments for diagnostic
immunohistochemistry.
AB - Enzymatic and non-enzymatic pretreatments for antigen retrieval (AR) on formalin
fixed, paraffin-embedded, deparaffinised sections were compared and optimised by
immunostaining of tissues infected with 13 different pathogens. Enzymatic
pretreatment was achieved by incubating slides in 0.25 per cent trypsin (TR) and
non-enzymatic pretreatments by heating them in a microwave oven (MWO) or an
autoclave (AC). Three different buffers of different pH and molarity including
phosphate buffer (PB), citrate buffer (CB) and acetate buffer (AB) were used as
AR solutions. All of them were effective regardless of molarity, for the MWO with
a processing time of 20 minutes, and the AC with a processing time of 15 minutes.
The detectability of many viral antigens was significantly improved by MWO or TR
pretreatment, but that of most bacterial antigens was not improved and that of
some viral antigens was decreased by TR pretreatment. These results suggest that
AR pretreatment is a prerequisite procedure for immunohistochemical detection of
many infectious agents but the optimal pretreatment has to be individualised for
each agent.
PMID- 9557808
TI - Medullary bone and humeral breaking strength in laying hens.
AB - To test the hypothesis that large amounts of medullary bone in the humeral
diaphysis may increase breaking strength, various parameters of bone quality and
quantity were examined in two large flocks of hens near end of lay. We conclude
that the amount of medullary bone in the humerus of hens during the laying period
influences bone strength. This medullary bone may not have any intrinsic
strength, but may act by contributing to the fracture resistance of the
surrounding cortical bone. Using a quantitative, low dose, radiographic
technique, we can predict, from early in the laying period, those birds which
will develop large amounts of medullary bone in their humeri by the end of the
laying period. The formation of medullary bone in the humeral diaphysis is not at
the expense of the surrounding radiographed cortical bone.
PMID- 9557809
TI - Plasma pharmacokinetics of intravenous and intramuscular furosemide in the camel
(Camelus dromedarius).
AB - Single bolus intravenous (i.v.) and intramuscular (i.m.) doses of furosemide (1.5
mg kg(-1)) were administered in a crossover design to three female and three male
adult, dromedary camels. Plasma furosemide concentrations were assayed by HPLC
and sodium, potassium and chloride concentrations were measured using ion
selective electrodes. Plasma furosemide concentration-time plots indicated multi
compartment disposition, and there was considerable intersubject variability in
the pharmacokinetic parameters. The mean (SD) i.v. terminal elimination half-life
was 118 (67) minutes. The systemic clearance was 5.4 (1.2) ml min(-1) kg(-1). and
the steady-state volume of distribution was 0.43 (0.14) litre kg(-1). The mean
absorption time after i.m. dosing was 33 (62) minutes, while the absolute
bioavailability was 71 (20) per cent. The glucuronide metabolite of furosemide
was not detected in plasma. Clearance was lower, volume of distribution was
larger, and half-life was longer compared with published data for dogs, horses,
rats and humans. Plasma potassium and sodium concentrations were significantly
diminished (P<0.05) by an average of 35.6 per cent (two to six hours post-dose)
and 11.3 per cent (eight hours post-dose), respectively. Plasma chloride
concentrations were not significantly affected by furosemide administration.
PMID- 9557810
TI - Effect of administration of a novel recombinant bovine interferon on length of
oestrous cycle in cattle.
AB - In ruminants, extensive reproductive loss occurs during the process of maternal
recognition of pregnancy and it has been suggested that trophoblast interferons
may be potential therapeutic agents. This paper reports results from a trial
using eight first lactation Holstein-Friesian heifers to test the efficacy of a
novel recombinant bovine interferon produced in bacteria in extending the life of
the corpus luteum. Oestrus was synchronised in these animals and 0.1 mg of this
non-glycosylated interferon was infused into the uterus twice daily for 13 days
starting approximately 12 days after oestrus. This treatment resulted in an
extension of the lifespan of the corpus luteum by 5.5 days (P=0.028) compared
with untreated controls. In these animals the interovulatory period was extended
by 6.4 days (P=0.009). Administration of this protein did not have any adverse
effects either on body temperature or on daily milk yields. The results indicate
that this novel interferon may have potential therapeutic application for
reducing embryo mortality.
PMID- 9557811
TI - Effect of a novel recombinant bovine interferon and trophoblast secretory
products on protein metabolism by endometrial explants from cattle and sheep.
AB - The effect of a novel recombinant bovine interferon on the rate of protein
synthesis, as measured by the rate of leucine incorporation, in endometrial
explants from cows and ewes was investigated and compared with the effect of
trophoblast secretory proteins and of a recombinant bovine interferon-alpha1.
Exposure of cultured bovine endometrial tissue to the novel recombinant bovine
interferon mimicked the effect of pregnancy in reducing the rate of protein
synthesis in both caruncular and intercaruncular endometrium. This effect was
similar to that seen with naturally produced trophoblast secretory proteins and
it was more pronounced than that seen when endometrial tissue was treated with a
related recombinant bovine interferon-alpha1. Ovine endometrial cultures were
unaffected by exposure to this novel recombinant bovine interferon. This novel
recombinant interferon exhibited potent antiviral properties (an activity of 1.6
x 10(10) international reference units/mg protein) and may prove to be a valuable
reagent in studying the maternal recognition of pregnancy in the cow and reducing
embryo mortality.
PMID- 9557812
TI - Nitric oxide as the final metabolic mediator of cervical ripening.
PMID- 9557813
TI - Clinical application of nitric oxide donors and blockers.
PMID- 9557814
TI - Nitric oxide--another factor in cervical ripening.
PMID- 9557815
TI - Cervical ripening after nitric oxide.
PMID- 9557816
TI - Clinical andrology.
PMID- 9557817
TI - Urgently wanted for ICSI: clinical andrologists.
PMID- 9557818
TI - Andrology and clinical sciences.
PMID- 9557819
TI - Current problems with spermatid conception.
PMID- 9557820
TI - Chronic treatment of female rhesus monkeys with low doses of the antiprogestin ZK
137 316: establishment of a regimen that permits normal menstrual cyclicity.
AB - Large doses of antiprogestin typically disrupt menstrual cyclicity. A chronic low
dose regimen of the potent new antiprogestin ZK 137 316, which permits continued
menstrual cyclicity but alters gonadal-reproductive tract activity, was
established. Rhesus monkeys received vehicle (n = 6) or 0.01 (n = 8), 0.03 (n =
8) or 0.1 (n = 5) mg ZK 137 316/kg body weight daily for five menstrual cycles (C
1 to C-5). Oestradiol, progesterone and gonadotrophin profiles were normal during
cycles involving vehicle and 0.01 and 0.03 mg ZK 137 316/kg body weight. In the
0.1 mg/kg group, mid-cycle oestradiol and gonadotrophin surges, and subsequent
progesterone production, were absent in C-3 and C-5. Ovarian cyclicity was
accompanied by timely menstruation in the vehicle and 0.01 mg/kg groups. By C-3,
half the animals in the 0.03 mg/kg group and all animals in the 0.1 mg/kg group
were amenorrhoeic. A corpus luteum was noted during the mid-luteal phase of C-5
in the vehicle, 0.01 mg/kg and 0.03 mg/kg groups. Large antral and cystic
follicles were evident in the 0.1 mg/kg group. Thus, a daily treatment with 0.01
mg/kg ZK 136317 permitted normal menstrual cyclicity in macaques. While the daily
administration of 0.03 mg/kg ZK 136 317 allowed ovarian cyclicity, menstruation
was disrupted in some animals. Increasing the dose to 0.1 mg/kg antagonized
pituitary function and resulted in anovulation and amenorrhoea. A chronic low
dose regimen of the antiprogestin ZK 137 316, which permits normal
ovarian/menstrual cyclicity, has potential as a contraceptive in women.
PMID- 9557821
TI - Chronic treatment of cycling rhesus monkeys with low doses of the antiprogestin
ZK 137 316: morphometric assessment of the uterus and oviduct.
AB - The long-term effects of the antiprogestin ZK 137 316 on reproductive tract
morphology in rhesus macaques were investigated. The monkeys were injected daily
(i.m.) for five menstrual cycles with vehicle or 0.01, 0.03 or 0.1 mg ZK 137
316/kg body weight. Reproductive tracts (n = 3/ group) were collected during the
mid-luteal phase (day 8) of the fifth cycle in the control, 0.01 and 0.03 mg/kg
groups, or 6-7 days after the oestradiol peak in the 0.1 mg/kg group. ZK 137 316
treatment resulted in a dose-dependent atrophy of the endometrium, marked by
reduced mitotic activity in the glands, compaction of the stroma, degradation of
spiral arteries and dilation of veins. There was no effect of ZK 137 316 on
myometrial or oviductal weight. Treatment with 0.1 and 0.03 mg/kg, but not 0.01
mg/kg resulted in fully ciliated and secretory oviducts, indicating a dose
dependent blockade of progesterone antagonism of oestrogen-dependent oviductal
differentiation. In the endometrium, the suppressive action of progesterone on
oestrogen and progestin receptors was also blocked by ZK 137 316 in a dose
dependent manner. However, endometrial atrophy appeared due to inhibition of
progesterone action together with a blockade of oestrogen-dependent
proliferation. The profoundly suppressed endometrium produced by chronic low-dose
ZK 137 316 treatment is unlikely to support implantation. Such treatment may
therefore provide a novel contraceptive modality.
PMID- 9557822
TI - Somatotropic axis and body weight in pre-menopausal and post-menopausal women:
evidence for a neuroendocrine derangement, in absence of changes of insulin-like
growth factor binding protein concentrations.
AB - The altered function of the somatotropic axis observed in perimenopause may
underlie the changes in body weight and fat distribution. The aim of the present
study was to evaluate, in pre-menopausal and post-menopausal women with body mass
index (BMI) > or = or <25, the basal plasma levels of growth hormone (GH),
insulin-like growth factor (IGF)-I and -II, IGF binding protein (IGFBP)-1 and -3,
and the response of GH and IGFBP-1 and -3 to GH releasing hormone (GHRH) and GHRH
plus arginine tests. GH and IGF-I basal concentrations were significantly higher
in pre-menopausal than in post-menopausal women, while IGF-II, IGFBP-1 and IGFBP
3 concentrations did not vary significantly. IGFBP-1, but not IGFBP-3,
concentrations were higher in lean than in obese patients. Insulin concentrations
were significantly higher in obese patients, while no differences were observed
between pre-menopausal and post-menopausal women. In all subjects, GH
concentrations increased significantly during GHRH test; pre-menopausal and lean
women showed a higher response compared to post-menopausal and obese women. The
GHRH plus arginine test stimulated GH response in all women, irrespective of age
and BMI. IGFBP-1 and -3 concentrations did not vary in response to GHRH or GHRH
plus arginine tests. The somatotropic axis undergoes modifications in post
menopausal women, apparently not involving IGFBP-1 and -3. Arginine infusion
restores the response of GH to GHRH, in both post-menopausal and obese subjects.
A somatostatinergic hyperactivity at the climateric period may underlie the
changes both in body weight and somatotropic axis.
PMID- 9557823
TI - Insulin-like growth factor (IGF)-I and IGF binding protein-3 concentrations in
fluid from human stimulated follicles.
AB - Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) play an
important role in regulating follicle growth and maturation. We have evaluated
whether responsiveness to gonadotrophins during an in-vitro fertilization (IVF)
treatment is related to follicular fluid IGF-I and IGFBP-3 concentrations. We
also investigated if a difference is present in IGF-I and IGFBP-3 concentrations
between patients treated with human menopausal gonadotrophin (HMG) and patients
treated with highly purified follicle stimulating hormone (FSH). We have measured
IGF-I and IGFBP-3 in follicular fluid from pre-ovulatory follicles in an IVF
programme. All 70 patients were stimulated after being down-regulated with a
gonadotrophin-releasing hormone (GnRH) analogue. IGF-I concentrations in
follicular fluid were significantly inversely correlated with the number of
ampoules FSH administered and number of days of FSH administration, and
significantly correlated with the number of follicles aspirated. IGFBP-3
concentrations were not correlated with any other parameter measured nor were IGF
I and IGFBP-3 concentrations correlated. IGFBP-3 concentrations were
significantly higher in patients receiving highly purified FSH compared with
patients receiving HMG (P < 0.005). These results are new evidence that IGF-I
concentration in follicular fluid is higher in women who respond better to
follicular stimulation, i.e. women who grow many follicles, women who need a
shorter duration of stimulation and women who need fewer ampoules FSH before
oocyte retrieval.
PMID- 9557825
TI - First established pregnancy after controlled ovarian hyperstimulation with
recombinant follicle stimulating hormone and the gonadotrophin-releasing hormone
antagonist ganirelix (Org 37462).
AB - This case report describes the first established pregnancy after the use of
gonadotrophin-releasing hormone (GnRH) antagonist, ganirelix (Org 37462;
Organon), to prevent a premature luteinizing hormone surge during ovarian
hyperstimulation with recombinant human follicle stimulating hormone (rhFSH). The
pregnancy progressed normally and ended with the birth of a healthy boy and a
girl after an elective Caesarean section at gestational age of 37 weeks. This
case illustrates, for the first time, the use of a GnRH antagonist in combination
with a pure FSH preparation for ovarian stimulation.
PMID- 9557824
TI - Polycystic ovary syndrome: anomalies in progesterone production.
AB - The underlying cause of anovulation and miscarriage in polycystic ovary syndrome
(PCOS) is unknown. Progesterone may play an important role in oocyte
fertilization and embryo implantation. Therefore, in this study we analyse the
endocrine function of luteinizing granulosa cells to synthesize progesterone in
vivo and in vitro in PCOS and normal patients participating in an in-vitro
fertilization programme. Human luteinizing granulosa cells were obtained from 10
patients with normal ovaries (controls) and 10 patients with PCOS by follicular
aspiration of individual follicles of each patient and pooled in an attempt to
obtain three groups: cells from follicle sizes < or =10,>10< or =15 and > or =16.
Serum concentrations of oestradiol and progesterone on the day of human chorionic
gonadotrophin (HCG) injection were significantly higher (P < 0.01 and P < 0.05)
in PCOS patients than in controls. After HCG stimulation, in-vitro progesterone
production was enhanced in granulosa cells of the control group and
concentrations increased with follicular size as expected. However, the
concentration of progesterone of PCOS patients did not increase with follicular
size and there was a significant difference between normal and PCOS groups in
follicles >10< or =15 mm (P < 0.05) and > or =16 mm (P < 0.01). Oestradiol
production was increased in follicles > or =16 mm in both groups, although this
did not reach significance. In summary, it seems that PCOS granulosa cells
demonstrate an abnormal capacity to synthesize progesterone in vivo and in vitro.
The understanding of granulosa cell function in PCOS may explain the anovulation
and miscarriage that occurs in these patients.
PMID- 9557826
TI - Increase of large granular lymphocytes in human ejaculate containing antisperm
antibodies.
AB - Using flow cytometry, we studied the expression of the CD16 antigen by
lymphocytes present in human semen samples from three groups of patients: 60
fertile men attending for vasectomy, 60 sterile patients without antisperm
antibodies (ASA) and 18 immunological sterile patients with ASA in their
ejaculate. No significant difference was found in the concentration of leukocytes
or subpopulations of these cells (monocytes, lymphocytes and granulocytes)
between fertile, sterile without ASA and immunological sterile groups. However,
we detected a predominance of macrophages/monocytes within the population of
seminal leukocytes. No statistically significant difference was found in the
absolute number of T and B lymphocytes between the three groups studied. However,
a significant increase in the number of CD16+ lymphocytes was observed in the
ejaculate of sterile patients with ASA as compared to the other groups. This
finding might establish an important parameter in the follow-up and prognosis of
patients with immunological sterility.
PMID- 9557827
TI - High frequency of well-defined Y-chromosome deletions in idiopathic Sertoli cell
only syndrome.
AB - Idiopathic Sertoli cell-only syndrome (SCOS) is characterized by azoospermia,
small testes, absence of germ cells in the testes, elevated follicle stimulating
hormone and normal testosterone concentrations. The Y-chromosome is involved in
the regulation of spermatogenesis and in the pathogenesis of a fraction of
idiopathic male infertility. An azoospermia factor (AZF) is present on the Y
chromosome long arm euchromatic region (Yq11) and two gene families (DAZ and RBM)
have been identified within this region. The aim of this study was to investigate
whether a specific pattern of Yq11 microdeletions may be associated with
idiopathic SCOS. Eighteen idiopathic subjects showing a testicular cytological
picture of bilateral SCOS were selected and tested by polymerase chain reaction
for a set of 29 Y-specific sequence-tagged sites (STS). We found Yq
microdeletions in 10 out of 18 patients (55.5%) while the fathers or brothers of
six out of 10 patients deleted for Yq were shown to carry an intact Y-chromosome.
These deletions may therefore be considered as de-novo deletions and the cause of
SCOS. The analysis of the microdeletions allowed us to identify two homogeneous
regions that have a high incidence of deletion. The smallest deletion, common to
all patients, is located in Yq interval 5. We therefore speculate that there is a
relationship between specific, well-characterized Yq11 microdeletions and a
testicular picture of SCOS, identifying an Y-related region frequently deleted in
this syndrome. In conclusion, the findings of this study demonstrate that a large
percentage of idiopathic SCOS may be genetically determined and identify an Y
related region that seems to possess one or more still unknown genes essential
for spermatogenesis.
PMID- 9557828
TI - Efficiency of MicroSort flow cytometry for producing sperm populations enriched
in X- or Y-chromosome haplotypes: a blind trial assessed by double and triple
colour fluorescent in-situ hybridization.
AB - Using fluorescent in-situ hybridization (FISH) we have evaluated, on a blind
basis, the efficiency of flow cytometry to separate human X- and Y-chromosome
bearing spermatozoa. Our data demonstrate that human spermatozoa can be sorted to
a purity of 80-90% for X spermatozoa and of 60-70% for Y spermatozoa. Our results
using triple FISH fully agree with the sorting treatment used in each case and
corroborate the efficiency of the flow sorting technique for sperm sex selection.
In these limited samples (200-500 sperm/donor), the frequencies of disomic or
diploid spermatozoa were not increased when comparing the sorted samples with
unselected samples or with our control series.
PMID- 9557829
TI - Origin and mechanisms of non-disjunction in human autosomal trisomies.
AB - Chromosomal aneuploidy is one of the major causes of pregnancy wastage. In this
review we summarize the knowledge about the origin and mechanisms of non
disjunction in human autosomal trisomies 8, 13, 15, 16, 18, and 21, accumulated
during the last decade by using DNA polymorphism analysis. Maternal meiosis I non
disjunction is the most important single class, but chromosome-specific patterns
exist. For the acrocentric chromosomes 15 and 21, meiosis I errors predominate
among the maternal errors, in contrast to trisomy 18 where meiosis II errors
predominate. For trisomy 16, virtually all cases are due to maternal meiosis I
non-disjunction. Postzygotic (mitotic) non-disjunction constitutes 5-15% of cases
of trisomies 15, 18, and 21, whereas for trisomy 8 and trisomy 8 mosaicism the
majority of cases are due to mitotic non-disjunction. For paternal non
disjunction of chromosomes 18 and 21, meiosis II or mitotic errors predominate.
There is aberrant meiotic recombination associated with maternal meiotic non
disjunction in all trisomies studied in detail so far. Advanced maternal age
remains the only well documented risk factor for maternal meiotic non
disjunction, but there is, however, still a surprising lack of understanding of
the basic mechanism(s) behind the maternal age effect.
PMID- 9557830
TI - Prenatal diagnosis of Fukuyama-type congenital muscular dystrophy by
microsatellite analysis.
AB - We applied microsatellite analysis to prenatal diagnosis of Fukuyama-type
congenital muscular dystrophy (FCMD), an autosomal recessive severe muscular
dystrophy associated with brain malformations. Recent identification of the FCMD
gene locus at 9q31-q33 provided the basis for prenatal diagnosis and carrier
detection. We recently developed new microsatellite markers which are closer to
the FCMD gene and improved the phenotype probability. Nine fetuses in eight
unrelated FCMD families, including a twin pregnancy, were analysed using the
newly developed markers. Four fetuses showed over 99% probability of being
healthy either as normal homozygote (n = 1) or heterozygote carrier (n = 3) and
were born without signs of FCMD. The other five fetuses were diagnosed with a
probability of FCMD of 99% or greater; all of the latter parents decided to
terminate the pregnancies. Brain malformations characteristic of FCMD in one of
the aborted fetuses confirmed the diagnosis of FCMD at 19 weeks of gestation.
PMID- 9557831
TI - Laparoscopic management of organic ovarian cysts: is there a place for frozen
section diagnosis?
AB - Only benign ovarian cysts can be treated by laparoscopic surgery. Although
clinical examination and the results of pre-operative work-up do make a real
contribution in indicating the benign or malignant nature of cysts, only
histology can provide the absolute diagnosis. In this context, the goal of this
study was to establish whether there is any advantage in performing frozen
section during laparoscopic surgical management of organic ovarian cysts. Between
January 1989 and March 1996, 228 patients underwent an adnexectomy for an ovarian
mass. After the pre-operative work-up and the diagnostic phase of laparoscopy, 26
patients (11.4%) presented with suspected signs of malignancy restricted purely
to the ovary. These 26 patients underwent a laparoscopic adnexectomy with
extraction of the excised tissues using an endoscopic bag, followed by frozen
section. For all these patients the results of the frozen section concluded that
the lesion was benign. In every case the definitive histological results
confirmed the frozen section findings. This strategy enabled us to avoid
laparotomy, especially for the nine post-menopausal patients whose adnexal masses
appeared to be complex by ultrasound. These encouraging preliminary results need
to be confirmed by a larger series of patients, so as to specify the place of
frozen section in the laparoscopic surgical management of organic ovarian cysts.
PMID- 9557833
TI - Effect of parental age on fertilization and pregnancy characteristics in couples
treated by intracytoplasmic sperm injection.
AB - The purpose of this study was to investigate any influence of maternal and/or
paternal age on gamete characteristics and pregnancy outcomes in intracytoplasmic
sperm injection (ICSI) cycles. In all, 821 consecutive ICSI cases were analysed
retrospectively. While a significant linear decline in semen volume was detected,
no significant differences in the concentration, motility or morphology of the
spermatozoa were found with paternal ageing. A significant decline in the number
of oocytes retrieved and the number of mature oocytes obtained was found with
advancing maternal age. An increase in the occurrence of digyny was noted with
parental ageing, while no difference in single or bipronuclear fertilization was
found. Older women had a decreased incidence of single pronucleus formation and
an increase in digyny, but no significant difference in the percentage of oocytes
that underwent two-pronuclear fertilization was detected with regard to maternal
ageing. Pregnancy outcomes were not influenced by the age of the male partner,
while a strong negative correlation was found with maternal ageing. To better
analyse male partner ageing as a factor affecting pregnancy outcome, we analysed
a subgroup of patients with a female partner aged <35 years who underwent ICSI.
No paternal influence on ICSI pregnancy outcome was found in this subgroup of
patients. We conclude that the influence on pregnancy outcome after ICSI is
related mostly to maternal and not paternal age.
PMID- 9557832
TI - The role of transvaginal ultrasonography in the detection of pelvic pathologies
in the infertility workup.
AB - To assess the efficiency of transvaginal ultrasonography (TVUS) in the screening
of pelvic pathologies in the initial workup of infertile women, we carried out a
prospective comparison of sonographic diagnosis with laparoscopic and
pathological findings. Between February 1994 and April 1995, 133 premenopausal
non-pregnant women underwent TVUS on the day before laparoscopy. The efficiency
of TVUS in detecting pelvic pathologies was 90.2% with a sensitivity of 86.2%, a
specificity of 97.8% and positive and negative predictive values of 98.6 and
78.8% respectively. If the six false-negative cases with a histological diagnosis
of minimal endometriosis were defined as 'normal pelvis', sensitivity and
specificity could be corrected to 92.5 and 98.6% respectively. Endometriomas were
diagnosed by TVUS with an efficiency of 96.4%, with a sensitivity and a
specificity of 90 and 96.7 % and with positive and negative predictive values of
75 and 99.1% respectively. The sensitivity of vaginal sonographic
characterization of pelvic adhesions was 61.1% with a specificity and positive
predictive value of 98.2 and 84.6%. The negative predictive value of TVUS was
94.1%. These data suggest that it is not possible to characterize pelvic
adhesions, especially filmy adhesions, with acceptable accuracy. However, in the
initial workup of infertile women, if the patient is young, if both
hysterosalpingography and TVUS are negative, laparoscopy could be postponed. In
couples with severe male factor infertility and for whom in-vitro fertilization
or intracytoplasmic sperm injection is the treatment of choice, laparoscopy might
be avoided where the TVUS is negative.
PMID- 9557834
TI - Cumulative pregnancy rates and selective drop-out of patients in in-vitro
fertilization treatment.
AB - The validity of the cumulative pregnancy rate (CPR) calculated by life-table
approach, obtained in a transport in-vitro fertilization (IVF) programme, was
tested by the determination of possible influence of selective drop-out of
patients with a poor treatment prognosis. A cohort of 1211 patients who had a
first IVF cycle was followed, and the CPR after three IVF cycles was assessed.
First cycles of patients who discontinued treatment after failed IVF, and of
those who did not achieve a pregnancy but proceeded to a subsequent cycle, were
compared for fertilization rate and for occurrence of prognosticators of poor
treatment outcome: oocyte yield < or =2, and replacement of <2 embryos. The CPR
after three cycles was 54.9%. No differences were found in the first and second
cycles of patients who continued treatment and those who dropped out. Selective
drop-out of patients with a poor treatment prognosis was not found. Therefore,
although calculations of CPR using life-table analysis generally overestimate the
real probability of pregnancy after successive IVF cycles, the calculated CPR
after three IVF cycles gives a reliable indication of the chance of occurrence of
a pregnancy for the population studied.
PMID- 9557835
TI - Transient retardation in embryo growth in normal female mice made pregnant by
males whose testes had been heated.
AB - In three separate experiments, using three different strains of mice, when normal
females were mated by males whose testes had been heated once to 42 degrees C for
20 min, the embryos at 10.5 days post-coitum were approximately 20% smaller than
control embryos. In one experiment, the difference was still present, although
proportionately less, at 15.5 and 18.5 days and, in another experiment, a
difference could be seen in 11.5 and 13.5 day old embryos but not in 12.5, 14.5,
15.5 or 18.5 day old embryos. The frequency of mating and pregnancy rates were
unaffected. In one experiment, the time available for mating was restricted to 4
h instead of overnight, without effect on the result. In another experiment,
other males were heated for 30 min, and these showed a period of infertility from
10 to 32 days later, preceded and followed by the production of smaller than
normal embryos; litter size was also reduced in the period after the return of
fertility in these animals. The yolk sacs and the trophoblasts of the embryos
sired by the heated males were also slightly smaller than those sired by the
controls in the two experiments in which these were measured. The pattern of
weight reduction is thus different from that seen in gynogenetic embryos or when
the gene for insulin-like growth factor (IGF)-II is disrupted, and suggests a
reduction in embryo growth at the earlier stages, with compensatory growth
occurring later in pregnancy.
PMID- 9557836
TI - Comparison of the fertilizing capability of spermatozoa from ejaculates,
epididymal aspirates and testicular biopsies using intracytoplasmic sperm
injection.
AB - A prospective study was carried out to compare the fertilizing capability and
pregnancy outcome following intracytoplasmic sperm injection (ICSI) using
spermatozoa obtained from ejaculates, or surgically from epididymis or
seminiferous tubules. A total of 77 ICSI cycles (one per patient) was included.
In all, 28 patients had severe oligoasthenoteratozoospermia, 19 patients had
obstructive azoospermia and 30 patients had non-obstructive azoospermia. The main
outcome measures were fertilization rate per injected metaphase II oocyte and the
clinical pregnancy rate per embryo transferred back to the female recipients. In
patients with severe oligoasthenoteratozoospermia, the fertilization and
pregnancy rates were 79 and 25 %. In patients with obstructive azoospermia, for
whom epididymal spermatozoa were used, these were 75 and 28%, and in the non
obstructive group for which testicular spermatozoa were used for injection, they
were 69 and 21% respectively. These rates were not significantly different in the
three groups (P = 0.85 and P = 0.14 respectively), suggesting that spermatozoa
from the ejaculates and epididymal or testicular biopsies are able to fertilize
equally by using ICSI. Live birth per embryo transfer was significantly reduced
in patients with non-obstructive azoospermia compared to the other two groups.
The high abortion rate (50%) in the group in which testicular spermatozoa were
used raises doubts about the developmental competence of such embryos.
PMID- 9557837
TI - Glutathione in spermatozoa and seminal plasma of infertile men.
AB - Glutathione has a central role in the defence against oxidative damage; however,
the data on glutathione concentrations in the semen of infertile men are limited.
To expand this knowledge the glutathione content of the ejaculates and blood
plasmas of 77 infertile men and 11 controls were analysed. The concentrations of
total glutathione were assessed in spermatozoa, seminal plasma and blood plasma
using a coupled spectrophotometric assay. In the spermatozoa of patients with
oligozoospermia the glutathione concentrations (2.57+/-0.96 nmol/10[8]
spermatozoa; mean +/- SD) were significantly lower than in the controls (3.49+/
0.87 nmol/10[8] spermatozoa; P +/- 0.03). The glutathione content of spermatozoa
from patients with normozoospermia showed large variations (3.04+/-1.37
nmol/10[8] spermatozoa). An association between the intracellular glutathione
content and the ability to penetrate bovine cervical mucus was observed (r = 0.2,
P = 0.04). The intracellular glutathione concentrations correlated with the
glutathione levels in seminal plasma (r = 0.46, P < 0.0001). There was no
correlation between glutathione concentrations in blood plasma and those in
seminal plasma or in spermatozoa. The glutathione concentrations in seminal
plasmas did not differ between the different groups, however, correlated with the
serum follicle stimulating hormone concentrations (r = 0.53, P = 0.005). This
study demonstrated that intracellular glutathione levels of spermatozoa are
decreased in certain populations of infertile men.
PMID- 9557838
TI - The effect of colchicine treatment on sperm production and function: a review.
AB - Colchicine is used for the treatment of various diseases including gouty
arthritis, familial Mediterranean fever (FMF) and Behcet's disease. As a
modulator of the microtubules at the cytoskeleton level, it arrests cell division
at metaphase and inhibits microtubular-dependent cell motility. Controversy
exists as to the adverse effect of colchicine on sperm production and function in
healthy subjects as well as in gout, FMF and Behcet's patients. Sperm analysis
shows a spectrum of pathology, from oligo- and azoospermia to normospermia with
disturbances in sperm motility. These inconsistent sperm pathologies can be
explained in part by the variability of the pathophysiology of the underlying
disease. Thus, it seems that colchicine by itself may not have a significant
direct adverse effect on sperm production and function.
PMID- 9557840
TI - Successful treatment of idiopathic anejaculation with electroejaculation after
microsurgical vas aspiration.
AB - This case report describes a couple suffering from infertility secondary to
psychogenic anejaculation, which was refractory to all conservative treatment
modalities. A first trial of microsurgical vas aspiration in combination with in
vitro fertilization (IVF) resulted in a pregnancy. After 2 years, three more
trials of microsurgical vas aspiration in combination with either IVF or subzonal
insemination (SUZI) resulted in embryo transfer without pregnancy. Finally, after
3 years, spermatozoa obtained by rectal probe stimulation under general
anaesthesia were cryopreserved. A second intracytoplasmic sperm injection (ICSI)
procedure using these cryopreserved spermatozoa also resulted in a second
pregnancy. Although sperm concentration was in the normal range, in all samples
obtained by either rectal probe electrostimulation or microsurgical vas
aspiration, motility was <30% in all but two samples.
PMID- 9557839
TI - DAZ (Deleted in AZoospermia) genes encode proteins located in human late
spermatids and in sperm tails.
AB - We analysed the location of proteins encoded by the DAZ (Deleted in AZoospermia)
genes in human testis tissue and in mature spermatozoa. The DAZ genes are known
to be expressed exclusively in the human male germ line, and are candidate genes
for the expression of the azoospermia factor AZFc mapped recently to distal Yq11.
They encode testis-specific RNA binding proteins, the function of which is not
yet known. Immunostaining experiments with antibodies prepared for the specific
peptide domain encoded by the DAZ2 transcript (formerly SPGY1) revealed the
presence of DAZ proteins in the innermost layer of the male germ cell epithelium
and in the tails of spermatozoa. This suggests a function for DAZ proteins in the
RNA metabolism of late spermatids, presumably in the storage or transport of
testis-specific mRNA, the translation of which is repressed until the formation
of mature spermatozoa. Deletion of DAZ genes is supposed not to interfere with
human sperm maturation but to result in a gradual reduction of mature
spermatozoa.
PMID- 9557841
TI - Male subfertility induced by acute scrotal heating affects embryo quality in
normal female mice.
AB - The aim of this experiment was to design a suitable mouse model for male
subfertility in which to study the effect of decreased sperm quality on embryo
quality in vivo and in vitro. To achieve male subfertility, testes of adult male
mice were immersed in water at either 42 degrees C (heated) or 33 degrees C
(controls) during 20 min. Twenty-eight days after treatment, all heat stressed
males showed a significant decrease in relative testis weight [384.7 mg in
controls (286.7-460.6) versus 323 mg in stress heated groups (117.9-405.6); P <
0.001], sperm concentration [3.75 x 10(6)/ml (2.75-7.25) versus 1.00 x 10(6)/ml
(0-4.00); P < 0.001] and progressive sperm motility [57.5% (48.0-79.0) versus
42.5% (14.0-66.0); P < 0.001]. Moreover, after mating to heat exposed males, not
only the number of pregnant females (20/22 versus 18/30) but also the weight of
their embryos [275.4 mg (78.7-339.4) versus 261.8 mg (68.1-339.0); P < 0.001] was
significantly lower at 14.5 days post coitum when compared to controls. Neither
the number of resorption sites nor the number of viable embryos per pregnant
female was significantly different between groups. Also, the in-vitro
fertilization rate of oocytes, fertilized by spermatozoa collected from heat
stressed males, was significantly lower (44.9%; P < 0.0001) when compared to
controls (65.1%; P < 0.0001). In conclusion, the results of this study suggest
that male subfertility induced by acute scrotal heating may result in impaired
sperm quality, reduced embryo weight in vivo and decreased fertilization rate in
vitro.
PMID- 9557842
TI - Permeation of human ovarian tissue with cryoprotective agents in preparation for
cryopreservation.
AB - The recent improvements in the treatment of cancer by chemo- and radiotherapy
have led to a significant increase in the survival rates of patients with
malignant disease, but at the expense of distressing side effects. One major
problem, especially for younger patients, is that aggressive therapy destroys a
significant proportion of the follicular population, which can result in either
temporary or permanent infertility. Freeze-banking pieces of ovarian cortex prior
to treatment is one strategy for preserving fecundity. When the patient is in
remission, fertility could, theoretically, be restored by autografting the thawed
tissue at the orthotopic site or by growing isolated follicles to maturity in
vitro. Recent studies have found good follicular survival in frozen-thawed human
ovarian tissue but to optimize the process an effective cryopreservation method
needs to be developed. An essential part of such a technique is to permeate the
tissue with a cryoprotectant to minimize ice formation and the extent of this
equilibration is an important determinant of post-thaw cellular survival. In the
current study, we have investigated the diffusion of four cryoprotective agents
into human tissue at both 4 degrees C and 37 degrees C. We have also studied the
effect of adding different concentrations of the non penetrating cryoprotective
agent, sucrose, to the freezing media using the release of lactate dehydrogenase
as a measure of its protective effect. At 4 degrees C propylene glycol and
glycerol penetrated the tissue significantly slower than either ethylene glycol
or dimethyl sulphoxide. At the higher temperature of 37 degrees C all four
cryoprotectants penetrated at a faster rate, however concern about enhanced
toxicity prevents the use of these conditions in practice. Thus, the results
suggest that the best method of preparing tissue for freezing is exposure for 30
min to 1.5 M solutions of ethylene glycol or dimethyl sulphoxide at 4 degrees C;
this achieved a mean tissue concentration that was almost 80% that of the bathing
solution. We also report that the addition of low concentrations of sucrose to
the freezing medium does not have a significant protective effect against
freezing injury.
PMID- 9557843
TI - Dithiothreitol prevents age-associated decrease in oocyte/conceptus viability in
vitro.
AB - The present study was designed to ascertain whether the negative effects on
reproductive potential of post-ovulatory ageing in vitro of oocytes can be
prevented by antioxidant therapy. Mouse metaphase II (MII) oocytes were aged in
vitro for 12 h prior to insemination in the presence of varying concentrations of
L-ascorbic acid, 6-methoxy-2,5,7,8-tetramethylchromane-2-carboxylic acid
(Trolox), L-cystine dihydrochloride, ethylenediaminetetraacetic acid (EDTA), beta
mercaptoethanol and DL-dithiothreitol (DTT). In-vitro ageing of oocytes was
associated with lower fertilization rate, higher proportion of concepti
exhibiting cellular fragmentation at 24 h post-insemination and lower percentage
of concepti reaching the blastocyst stage. Ascorbic acid, Trolox and EDTA had no
effect on cellular fragmentation or potential of oocytes for development.
However, the probability of an oocyte reaching the blastocyst stage was decreased
(P < or = or = 0.05) in oocytes incubated in the presence of L-cystine (50 and
500 microM) and beta-mercaptoethanol (5, 50 and 500 microM) when compared to
control aged oocytes. Age-associated cellular fragmentation at 24 h post
insemination was partially prevented (P < or = 0.05) by incubating oocytes in the
presence of beta-mercaptoethanol (500 microM). DTT (50 and 500 microM) increased
(P < or = 0.05) fertilization rate and number of cells at 81 h post-insemination
to levels similar to those exhibited by control oocytes. Furthermore, both age
associated fragmentation at 24 h post-insemination (P < or = 0.05) and decreased
potential of oocytes for development to the blastocyst stage (P < or = 0.05) were
prevented, at least in part, by culturing oocytes in the presence of DTT (50
microM). Although the mechanism by which DTT exerts its beneficial effects on
aged oocytes remains to be elucidated, it may protect oocytes by preventing
oxidation of free thiol groups and/or altering a redox-independent signalling
pathway that mediates cellular fragmentation and death.
PMID- 9557844
TI - Comparison of microscopic epididymal sperm aspiration and intracytoplasmic sperm
injection/in-vitro fertilization with repeat microscopic reconstruction following
vasectomy: is second attempt vas reversal worth the effort?
AB - Since 1986, we have performed microscopic reconstruction in 18 men following
failed microscopic vasectomy reversal. Between 1994 and 1996, nine couples have
undergone microscopic epididymal sperm aspiration (MESA)/ intracytoplasmic sperm
injection (ICSI) treatment for male infertility due either to congenital absence
of the vas deferens (CAVD) or inoperable excurrent duct obstruction. We compared
the cost efficiency of repeat vasectomy reversal to that for MESA combined with
ICSI/in-vitro fertilization (ICSI/IVF). The cost of male partner procedures
(vasectomy reversal, MESA) was based on physician and hospital charges, while the
cost of ICSI/IVF included preparation of the female partner (medications and
physician charges) and procedures (physician and hospital charges including
oocyte retrieval, micromanipulation, and embryo transfer). Our cost examination
does not include charges related to follow-up visits, prenatal monitoring,
complications of pregnancy (i.e. miscarriage) or delivery in either group.
Overall patency and pregnancy rates in the repeat vasectomy reversal group were
78 and 44% respectively. The cost per delivered baby (including multiple
metachronos deliveries per couple) was $14892. Fertilization of oocytes has been
achieved in 37/72 (51%) and pregnancies have occurred in 6/9 (67%) attempts and
5/9 (56%) report delivery. The average cost per pregnancy was $25637 and the
average cost per delivered baby (or ongoing pregnancy) was $35570. The cost per
delivery by MESA/ ICSI/IVF is 2.4 times the charges per delivery obtained through
repeat vasectomy repair. Couples attempting to overcome infertility caused by
vasal obstruction should be informed that vas reconstruction remains a cost
effective means of re-establishing fertility even in men who have previously
failed vasectomy reversal.
PMID- 9557845
TI - Post-ovulatory ageing of the human oocyte and embryo failure.
AB - We carried out a prospective study of 221 healthy women who were attempting
pregnancy. During the study, women collected daily urine samples and kept daily
records of intercourse. Ovulation and early pregnancy losses were later
identified by immunoassays of urinary human chorionic gonadotrophin and steroid
metabolites. We have used these data to examine whether the risk of early
pregnancy loss was higher with post-ovulatory ageing of the oocyte. 192
pregnancies were ranked by the probability that the oocyte might have aged before
fertilization. There was a statistically significant increase in the risk of
early loss as the likelihood of oocyte ageing increased (P < 0.05). No similar
risk was observed for clinical miscarriages. Post-ovulatory ageing of the oocyte
prior to fertilization may cause early pregnancy failure in humans as it does in
several other mammalian species.
PMID- 9557846
TI - Effect of phosphate on the second cleavage division of the rat embryo.
AB - Development of the rat embryo is arrested at the 2-cell stage in vitro in the
presence of inorganic phosphate (Pi). Rat embryos were affected by exposure to
1.19 mM KH2PO4 in modified hamster embryo culture medium-1 at the late 2-cell
stage only. When exposure durations were 6 h, embryos whose exposure timings were
prior to cleavage had a reduced rate of development to the blastocyst stage (2
8%) when compared with embryos with no exposure to Pi (97%, P < 0.05). When
exposure durations were 18 h, all embryos were arrested at the 2- to 4-cell
stage. These timings would correspond to the G2 to M phase of the second cell
cycle. Maturation-promoting factor (MPF), which is regulated by a phosphorylation
cascade, controls cell division, and its kinase activity is necessary in order
for the cell to enter the M phase. However, the histone H1 kinase activity levels
and the patterns of the state of phosphorylation of cdc2 were the same in blocked
and non-blocked embryos. Because MPF was active in blocked embryos, the
developmental block in rat 2-cell embryos caused by phosphate was not due to MPF
activity or its phosphorylation cascade.
PMID- 9557847
TI - Predictive value of the results of a first in-vitro fertilization cycle on the
outcome of subsequent cycles.
AB - This study examines the relationship between the first cycle of in-vitro
fertilization (IVF) and subsequent cycles. The results of all IVF cycles
conducted at The Hammersmith Hospital or The Royal Masonic Hospital between 1988
and 1995 were studied including those cycles where egg recovery was abandoned due
to poor ovarian response. All patients underwent a standardized treatment
protocol. Of those women who achieved a clinical pregnancy during their first IVF
attempt, 33% achieved a pregnancy during their second cycle, statistically
significantly different from the 24% of patients conceiving during a second cycle
who had failed to conceive during their first. 36% of those who achieved a
biochemical pregnancy in their first cycle became pregnant in their second. Age
was an important factor in the success of IVF treatment, with pregnancy rates of
48% in the 20-25 year age group falling to 8% in those aged > or =41 years.
Cumulative pregnancy rates were 26% after one cycle, increasing to 43% after two
cycles and reached 80% after seven cycles. A previous pregnancy significantly
improved a couple's probability of conception in a later IVF cycle. Overall
pregnancy rates per cycle were constant for the first three attempts. Cumulative
pregnancy rates continued to rise to 72% after six cycles. Thus the more cycles a
couple undergo (up to six) the greater their chance of a pregnancy.
PMID- 9557848
TI - A prospective, randomized, double-blind study for the evaluation of assisted
hatching in patients with advanced maternal age.
AB - The objective of this study was to determine if assisted hatching improved the
rates of implantation, clinical pregnancy and ongoing pregnancy for in-vitro
fertilization (IVF) patients aged > or =36 years. On the day of oocyte
aspiration, consenting patients were randomized according to whether all embryos
underwent the hatching procedure (hatched; n = 41) or all embryos remained
unhatched (controls; n = 48). Patients in both groups were treated with
methylprednisolone and doxycycline starting on the day of oocyte retrieval and
continuing for 4 days. The hatching procedure was performed approximately 55 h
after insemination on all potential embryos for transfer and employed the release
of acidified acid Tyrode's medium against the zona pellucida to create an opening
approximately 20 microm in diameter. No significant differences were noted in the
mean age, number of oocytes aspirated and number of embryos transferred between
the hatched and control groups. In addition, no significant differences were
observed in the rates of implantation (11.1 versus 11.3%), clinical pregnancy
(39.0 versus 41.7%) and ongoing pregnancy (29.3 versus 35.4%) between the hatched
and control groups respectively. These results suggest that assisted hatching may
have no significant impact on IVF success rates in the patient population
studied.
PMID- 9557849
TI - In-vitro fertilization and intracytoplasmic sperm injection in the treatment of
infertility after testicular cancer.
AB - Treatment of testicular cancer (TC) may cause infertility due to reduced sperm
quality with or without an ejaculation problem. In cases of anejaculation or
retrograde ejaculation, spermatozoa can be obtained by transrectal
electroejaculation (TE) or testicular sperm extraction (TESE) and used for in
vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). In this
study, 15 out of 17 couples evaluated for infertility after TC, underwent a total
of 21 treatment cycles, resulting in 18 embryo transfers. Spermatozoa were
obtained by TE in 16 cycles, by masturbation in three cycles and by TESE in one.
In one cycle no spermatozoa were found using TESE. Fertilization and cleavage was
achieved by IVF in seven cycles and ICSI in 11 cycles; average fertilization
rates of 57 and 55% respectively were observed. Twelve clinical pregnancies
occurred, of which 11 have been delivered or are ongoing. The ongoing pregnancy
rate was 57% per cycle. These results show that infertility after testicular
cancer can be treated effectively with IVF and that ICSI even permits treatment
of patients who have severe oligozoospermia.
PMID- 9557850
TI - Chromosome analysis in human oocytes remaining unfertilized after in-vitro
insemination: effect of maternal age and fertilization rate.
AB - The incidence of chromosomal abnormalities was studied in 719 unfertilized human
oocytes obtained from our in-vitro fertilization (IVF) programme. To make
chromosome preparations, a gradual fixation/air-drying method was utilized. Of
388 oocytes successfully karyotyped, 70 (18.0%) were abnormal. The abnormalities
included 33 aneuploidies (8.5%) (14 hyperhaploidies and 19 hypohaploidies), 25
diploidies (6.4%) and 15 structural abnormalities (3.9%), three of them being
accompanied by aneuploidy. Of the 33 aneuploidies, 16 (48.5%) showed the loss or
gain of dyads (so-called non-disjunction), while 17 (51.5%) showed the loss or
gain of monads (so-called predivision). There was no maternal age-dependent
increase in the incidence of aneuploidy. Unfertilized oocytes from patients with
a high fertilization rate (>25%) had a significantly higher (11.4%, P < 0.05)
incidence of diploidy compared with the oocytes from the remaining patients (4.3
and 4.0%), suggesting that diploid oocytes might have a lower fertilizing
ability.
PMID- 9557851
TI - Fluorescent in-situ hybridization on human embryos showing cleavage arrest after
freezing and thawing.
AB - Our current freezing-thawing policy is to transfer only embryos that cleave
further in the 24 h following thawing. The purpose of our study was to
investigate the incidence of numerical abnormalities for chromosomes X, Y and 1
in blastomeres of human preimplantation embryos that survived cryopreservation
but did not cleave further after thawing. A total of 63 embryos surviving a
freezing-thawing cycle but not cleaving further within 24 h after thawing were
screened. Of the 63 screened embryos that showed cleavage arrest 24 h after
thawing, 56 embryos (88.9%) remained arrested 48 h after thawing and slightly
more than half of these (29/56; 51.8%) showed further deterioration in
morphological quality. Seven embryos (11.1%) showed signs of further cleavage;
five embryos showed additional cleavage of one blastomere and two developed a
blastocoelic cavity. Fluorescent in-situ hybridization (FISH) with three specific
probes for simultaneous detection of chromosomes X, Y and 1 was performed and was
successful in 60 out of 63 embryos. Of these successfully labelled embryos, 26
(43.3%) were in the diploid range: 12 (20%) were uniformly diploid for the
chromosomes X, Y and 1; three embryos showed aneuploidy in all their blastomeres
(two were XXY-karyotype and one was monosomy 1) and in 11 embryos nondisjunction
was detected. Thirteen embryos were categorized as being either haploid,
triploid, tetraploid or hexaploid. Nine embryos were classified as mosaic and 12
as being highly abnormal or chaotic. These preliminary results suggest that a
large proportion of embryos that do not cleave further after freezing and thawing
carry chromosomal aberrations. This finding supports our policy of not
transferring cryopreserved embryos which do not cleave further 24 h following
thawing.
PMID- 9557852
TI - An evaluation of propofol toxicity on mouse oocytes and preimplantation embryos.
AB - Mouse biological assays were used to investigate potential adverse effects of
propofol on the oocyte's competence to fuse with spermatozoa and on the embryo's
ability to develop to the blastocyst stage. Cumulus-enclosed metaphase II oocytes
were exposed for 1 h to 0.01, 0.1, 0.4, 1 and 10 microg/ml propofol (Diprivan)
and subjected to a sperm-oocyte fusion test based on the dye (Hoechst 33342)
transfer technique. Oocytes exposed to 0.4, 1 and 10 microg/ml propofol showed a
significant reduction in the rate of sperm fusion and underwent pronuclei
formation at a rate similar to that of sperm fusion. In a second trial, mouse 1
cell and 2-cell embryos were exposed to varying propofol concentrations for 14h
and then checked for subsequent development. Although adverse effects were not
observed in 2-cell embryos, treatment of 1-cell embryos with propofol
concentrations ranging from 0.01 to 10 microg/ml resulted in the inhibition of
cleavage to blastocyst stage. We conclude that propofol can negatively influence
fertilization in the mouse by impairing the oocyte's ability to fuse with
spermatozoa, without interfering with the sperm-induced activation of the cell
cycle. Moreover, we document the peculiar sensitivity to propofol of mouse 1-cell
embryos as compared with 2-cell embryos.
PMID- 9557853
TI - Induction of inducible nitric oxide synthase expression in human secretory
endometrium.
AB - The endometrial secretory phase is characterized by stromal oedema, a
premenstrual increase in stromal macrophages and an increased cytokine production
as menstruation approaches. Nitric oxide (NO) is a mediator of vasodilatation and
cytotoxicity which is synthesized from L-arginine by NO synthases (NOS). These
enzymes are either constitutively expressed or induced by lipopolysaccharides
and/or cytokines. The presence and function of the inducible isoform of NOS
(iNOS) in normal human endometrium has not been fully elucidated until recently.
Frozen tissue sections taken from 22 women who underwent hysterectomy and
adnexectomy for benign disease were immunostained with antibodies raised against
the different NOS isoforms to investigate the presence of NOS in human
endometrium. iNOS stained positive in the glandular epithelial cells of the
secretory endometrium. Staining was either weak or absent in the proliferative
and inactive endometrium, as well as in the oviduct and the glandular epithelium
of the endocervix. The stroma remained uniformly negative. Immunoreactivity for
endothelial constitutive NOS (eNOS) was confined exclusively to endothelial
cells. Furthermore, epithelial cells from endometrium, oviduct and endocervix and
all endothelial cells showed positive staining for reduced nicotinamide adenine
dinucleotide phosphate (NADPH)-diaphorase, which is a histochemical marker for
NOS activity. Reverse transcriptase polymerase chain reaction (RT-PCR) was
performed in order to assess the presence of NOS mRNA. Abundant expression of
iNOS mRNA was detected in the secretory phase endometrium only. The strong
expression of inducible NO synthase in human secretory phase endometrium suggests
that the increased production of NO, probably induced by cytokines, may be
relevant to the process of menstruation.
PMID- 9557854
TI - Human endometrial perfusion after tubal occlusion.
AB - We examined variations in human endometrial microvascular perfusion across one
menstrual cycle in women who had undergone tubal ligation and did not report
unusual menstruation. Endometrial red blood cell flux was monitored by laser
Doppler fluxmetry via a fibreoptic probe atraumatically inserted transvaginally
into the uterus of each of 13 conscious volunteers. The observations obtained
have been compared with those previously reported from a matched control group of
women [B.J. Gannon et al., Hum. Reprod., 12, 132-139 (1997)]. Women who had
undergone tubal occlusion for sterilization exhibited greater endometrial
perfusion during menstruation (cycle days 0-5), at the time of ovulation (cycle
days 13-16) and in the late secretory phase (cycle days 23-28) than occurred in
controls. In addition, vasomotion in the study group was lower than that in
controls in the early and late secretory phase (cycle days 17-22 and 23-28).
Tubal occlusion appeared to alter endometrial perfusion. It is possible that the
reported menstrual changes in women following tubal ligation are a consequence of
altered endometrial perfusion; a possible causative relationship is discussed.
PMID- 9557855
TI - The shape of the endometrium evaluated with three-dimensional ultrasound: an
additional predictor of extrauterine pregnancy.
AB - The objective of this prospective follow-up study was to evaluate the potential
utility of three-dimensional (3D) ultrasound to differentiate intrauterine from
extrauterine gestations. Fifty-four pregnancies with a gestational age <10 weeks
and with an intrauterine gestational sac <5 mm in diameter formed the study
group. The configuration of the endometrium in the frontal plane of the uterus
was correlated to eventual pregnancy outcome. After exclusion of three patients
with a poor 3D-image quality the endometrial shape was asymmetrical with regard
to the median longitudinal axis of the uterus in 84% of intrauterine pregnancies,
whereas the endometrium showed a symmetry in the frontal plane in 90% of
extrauterine pregnancies (P = 0.0000001). Intrauterine fluid accumulation may
distort the uterine cavity, thus being responsible for false-positive as well as
false-negative results. The evaluation of the endometrial shape in the frontal
plane appears to be a useful additional means to distinguish intrauterine from
extrauterine pregnancies, especially when a gestational sac is not clearly
demonstrated with conventional ultrasound.
PMID- 9557856
TI - Immunology of human implantation: from the invertebrates' point of view.
AB - Pregnancies in outbred mammals may be regarded as successfully developed
homografts. One of the hypotheses that attempts to answer the enigma of why the
fetus is not rejected (fetal-maternal relationships are based on reciprocal
expressions of foreign transplantation antigens) claims for the existence of
possible evolutionary links between invertebrate allorecognition and mammalian
implantation, based on some cellular similarities. This essay further discusses
the possible evolutionary perspectives between vertebrates and invertebrates
alloimmunities from a different viewpoint. We discuss similarities between
natural transplantation in colonial marine invertebrates, which are followed by
chimerism and a state of tolerance, and two natural transplantation events in the
mammalian systems which both have records for prolonged chimerism and tolerance:
the phenomenon of dizygotic twin fusions and the situation of fetal cells
implantation. Earlier comparative evolutionary perspectives are revisited.
PMID- 9557857
TI - Maternal serum androgens in human pregnancy: early increases within the cycle of
conception.
AB - Previous studies have demonstrated elevations in testosterone and androstenedione
initiated within the cycle of conception in pregnant non-human primates, and
minimal data in the human support the same picture. In the present study we have
investigated a group of patients scheduled for artificial insemination with
regular menstrual cycles. For this study all patients provided blood samples at 5
days after the luteinizing hormone (LH) surges and daily through the luteal phase
and into early pregnancy (n = 12). Patients who did not become pregnant served as
normal controls (n = 9). We have measured 17-hydroxyprogesterone (17-OHP) as a
marker of luteal activity not obscured by progesterone within the cycle of
conception and testosterone and androstenedione as the major androgens. There
were no significant changes in testosterone and androstenedione in the non
pregnant controls, but both testosterone and androstenedione were significantly
elevated in the pregnant luteal phase, with the first increases occurring at 15
and 14 days respectively after the LH surge. Three of 12 pregnant patients did
not demonstrate a dramatic increase in either testosterone or androstenedione and
when examined more carefully a corresponding lack of increase in 17-OHP in those
same subjects indicated less than optimal luteal activity, suggesting that these
androgens were products of the corpus luteum. In three subjects in which
consecutive non-pregnant and pregnant cycles were followed there was a dramatic
increase from the non-pregnant luteal phase to the pregnant luteal phase
indicating that the more important observation may be the concentrations of
androgens in the conceptive luteal phase compared to some baseline, either
previous luteal phase or even follicular phase. We have also studied changes in
dehydroepiandrosterone sulphate and found that there was no significant
contribution to this increase in androgens in early conception. These studies
demonstrate a significant increase in both testosterone and androstenedione
presumably of ovarian, specifically luteal, origin and that adrenal androgen
production is not a factor in these changes.
PMID- 9557858
TI - Simultaneous bilateral tubal pregnancy following in-vitro fertilization and
embryo transfer.
AB - A case of simultaneous bilateral tubal pregnancy resulting from in-vitro
fertilization and embryo transfer is presented. Repeated transvaginal ultrasound
examinations confirmed an intrauterine sac but no fetus. A diagnosis of early
missed abortion was incorrectly made and a curettage was performed. The
pathological examination showed the presence of decidua and Arias-Stella
phenomenon but no chorionic villi. Diagnostic laparoscopy and laparotomy
performed 40 days after embryo transfer (eighth week of gestation), revealed
bilateral tubal pregnancy. Bilateral salpingectomy was performed.
PMID- 9557859
TI - A woman with three ectopic pregnancies after in-vitro fertilization and embryo
transfer.
AB - Although a higher incidence of ectopic pregnancy has been reported after in-vitro
fertilization (IVF) and embryo transfer, three ectopic pregnancies in the same
woman is very rare. A patient of 32 years underwent IVF-embryo transfer six times
within 3 years. Three of four conceptions resulted in ectopic pregnancies. The
first involved simultaneous intrauterine and left tubal pregnancy, the second was
a right tubal pregnancy, and the third was a right interstitial pregnancy. In IVF
embryo transfer, bilateral salpingectomy does not remove the risk of interstitial
or cornual pregnancy.
PMID- 9557860
TI - Fecundity in Thai and European regions: results based on waiting time to
pregnancy.
AB - Very little is known about the frequency of subfecundity in different cultures,
ethnic groups and regions. To fill this gap, the European Study Group on
Infertility and Subfecundity established data on the prevalence of infertility
and subfecundity in five European regions. In this study, a comparison of
fecundity was made between 4035 Caucasian women from five European countries and
1496 Asian women from southern Thailand. Fecundity was measured using 'time to
pregnancy', i.e. the time women took to conceive after stopping contraceptive
methods. The Thai primigravid women had a shorter time to pregnancy than European
women, whereas time to pregnancy was found to be longer among Thai multigravidae,
although this was not statistically significant. This study has illustrated that
cross-culture comparison of subfecundity is difficult despite using a common
protocol and questionnaire because of differences in the use of contraceptive
methods and a different concept of pregnancy planning. The distribution of time
to pregnancy for the Thai women was not outside the variation found within the
European samples.
PMID- 9557861
TI - Recurrent miscarriage: principles of management.
AB - Recurrent miscarriage is a heterogeneous condition which has many possible
underlying causes. Ideally, couples with the problem should be managed in a
dedicated miscarriage clinic, with thorough investigations according to a
protocol, with structured history and investigation sheets. Counselling is an
important feature and may be provided by a specially trained counsellor, or
specialized nurse appropriately trained in counselling. Counselling should
include an explanation of the possible underlying causes of the condition, and of
the prognosis of each of the conditions. There is no definite cause of
miscarriage in approximately half of the patients. No treatment is needed in this
group, apart from reassurance and tender loving care. Treatment of unproven
value, for example progesterone support in early pregnancy, should not be
offered. Treatment offered empirically or as part of a research project should
have a sound scientific and statistical basis, and should include careful
counselling with informed consent of the patient. There are many controversial
issues in the management of recurrent miscarriage; consequently, there is a need
for locally agreed guidelines for management. Women who conceive again should be
offered regular monitoring, including serial ultrasonography in the first
trimester of pregnancy. An active audit programme to review regularly the various
outcome measures set against defined targets should be established in the clinic.
PMID- 9557862
TI - Obstetric and perinatal outcome after oocyte donation: comparison with in-vitro
fertilization pregnancies.
AB - The obstetric and perinatal outcome in 51 oocyte donation pregnancies (61
infants) was compared with that of a control group of standard in-vitro
fertilization (IVF) patients (97 pregnancies, 126 infants). The oocyte recipients
(mean +/- SD age 33.5+/-4.7 years) included 39 women with ovarian failure and 12
women with functioning ovaries. In oocyte recipients, first trimester bleeding
(53%) occurred significantly more often than in IVF mothers (31%, P < 0.01).
Pregnancy-induced hypertension was observed in 31% of oocyte recipients compared
with 14% in IVF mothers (P < 0.05). There was no difference in the duration of
pregnancies or in the preterm delivery rate between the two groups. When
restricting analysis to singleton pregnancies, 63% of oocyte recipients were
hospitalized in the antenatal period compared with 29% in the IVF group (P <
0.001). The Caesarean section rate was 57% in the oocyte donation group and 37%
in the IVF group (P < 0.05). Birthweight in singleton pregnancies was similar in
both groups. The perinatal mortality rate was 3.3% in the oocyte donation group
and 0% in the IVF group. In conclusion, oocyte donation pregnancies are
associated with an increased risk compared with IVF pregnancies, but the
complications are usually manageable and most oocyte recipients experience a good
pregnancy outcome.
PMID- 9557863
TI - Activated autologous blood therapy in recurrent spontaneous abortion--results of
a pilot study.
AB - This study was undertaken to investigate the influence of activated autologous
blood therapy on immunological parameters and on the clinical outcome in patients
with recurrent spontaneous abortion. In a prospective trial, 36 women with
recurrent spontaneous abortion were treated with intramuscular reinjections of
extracorporally haemolysed and ultraviolet irradiated autologous blood. A
comprehensive immunological investigation revealed significant changes in
lymphocyte subpopulations, plasma complement levels, mitogen stimulation and
immunoglobulin levels during the treatment period. No side-effects were reported
by the patients. From June 1994 to November 1995, 22 intrauterine and one
extrauterine pregnancies occurred, resulting in 19 (86%) live births, two (9%)
spontaneous abortions and one (4%) artificial abortion compared with a 64% live
birth rate in the historical control group. We conclude that activated autologous
blood therapy has detectable effects on the immune system, and seems to be
promising for further investigation concerning the treatment of idiopathic
recurrent spontaneous abortion.
PMID- 9557864
TI - Term delivery in a woman with severe congenital neutropenia, treated with growth
colony stimulating factor.
AB - The patient was diagnosed in childhood as having severe congenital neutropenia
and had recurrent admissions with severe infections. In 1987, prior to getting
married, she was sterilized. She continued to require i.v. antibiotics when she
contracted a severe infection. On one occasion, she was treated with growth
colony stimulating factor (G-CSF). Her increased neutrophil count was sustained
following this treatment. In June 1993, she wished to start a family and
underwent in-vitro fertilization (IVF) treatment. G-CSF was given prior to oocyte
retrieval. She conceived on her first cycle and an ultrasound scan revealed a
singleton pregnancy. Throughout the course of the pregnancy, her white cell count
was monitored closely and remained at <1.0x10(9)/l. The pregnancy progressed
uneventfully and at 37 weeks gestation she was admitted for G-CSF injections. At
38 weeks she was delivered of a boy weighing 3350 g, by elective Caesarean
section. His white cell count was normal. This is the first case of G-CSF being
used before conception and during pregnancy in a patient with congenital
neutropenia. It shows that advances in cytokine therapy and close
interdisciplinary liaison can lead to a successful outcome and help patients, who
would otherwise remain childless, to achieve a family.
PMID- 9557866
TI - Reply to Rinkevitch: Immunology of human implantation: from the invertebrate's
point of view.
PMID- 9557865
TI - Gamete donation guidelines. The Corsendonk consensus document for the European
Union.
PMID- 9557867
TI - Is colour Doppler useful in the diagnosis of functional ovarian cysts?
PMID- 9557868
TI - Time to rethink the indiscriminate use of testicular biopsy for sperm retrieval?
PMID- 9557869
TI - Glycans of higher plant peroxidases: recent observations and future speculations.
AB - Plant peroxidases are composed of a peptide and associated heme, calcium and
glycans. The 3D structure of the major cationic peanut peroxidase has revealed
the sites of the heme and calcium. But the diffraction of the glycans was not
sufficient to show their structure. This review presents research that has been
executed to obtain putative glycans and their binding sites, and to gain an
indirect insight into these glycans. It also offers approaches that will be used
to determine the function of the glycans on the peanut peroxidase. Some
comparisons are made with other plant glycoproteins including peroxidases from
plants other than peanut.
PMID- 9557870
TI - Three-dimensional structure of a glycosphingolipid having a novel carbohydrate
linkage, Galbeta1-4(Fucalpha1-3)Glcbeta1-3Galbeta, determined by theoretical
calculations.
AB - The novel glycosphingolipid, SEGLx (Galbeta1-4(Fucalpha1-3)Glcbeta1-3GalbetaCer),
which was identified by us (Kawakami Y, et al. (1993) J Biochem 114: 677-83),
shows a characteristic spectrum on 1H-NMR analysis, in which the anomeric proton
resonances of a reducing end galactose and a glucose are split. To elucidate the
structural characteristics of SEGLx, we determined its three-dimensional (3D)
structure by means of computer simulation, involving such techniques as molecular
mechanics (MM2), the semiempirical molecular orbital method (AM1), molecular
dynamics (Amber), and computer 3D modelling. With the hypothesis that all OH
group(s) of a ceramide participate in intramolecular hydrogen bonds, two kinds of
stable conformers, horizontal and right-angled ones, were formed, depending on
the ceramide species. The present findings suggest that the chemical species of
both the long chain base and fatty acid moieties, mainly the occurrence of OH
group(s), affect the chemical shifts of the anomeric proton resonances not only
of the reducing terminal galactose but also the penultimate glucose through the
formation of intramolecular hydrogen bonds. Computer simulation through
theoretical calculation and 3D modelling was shown to be the best means of
confirming the results obtained by experimental analysis.
PMID- 9557872
TI - High temperature conjugation of proteins with carbohydrates.
AB - A new procedure was used to conjugate lactose and dextran with BSA without using
coupling or activating reagents. The method is simple, rapid and cheap. Reducing
sugars covalently bind to proteins when lyophilized together and briefly heated
to a high temperature.
PMID- 9557874
TI - Expression, purification, and biochemical characterization of a recombinant
lectin of Sarcocystis muris (Apicomplexa) cyst merozoites.
AB - The mature major microneme protein of Sarcocystis muris cyst merozoites, which is
known as a dimeric lectin with high affinity to galactose and some of its
derivatives, was expressed in Escherichia colias a histidine-tagged fusion
protein. The recombinant polypeptide, which was recognized by a monoclonal
antibody directed against the native lectin, was purified from inclusion bodies
after solubilization and refolding, using a combination of metal chelate and
lactose affinity chromatography. The apparent molecular mass of the refolded
polypeptide as determined by sodium dodecyl sulfate-polyacrylamide gel
electrophoreses was 16 kDa, whereas gel filtration chromatography clearly
demonstrated that the recombinant protein, like its native counterpart, exists as
a homodimer of two non-covalently associated subunits. Inhibition of
haemagglutination suggests that the combining site of the recombinant lectin
recognizes N-acetyl-galactosamine as the dominant sugar, thus confirming the
correct folding of the monosaccharide combining site in the renatured lectin. To
the best of our knowledge, this work represents the first reported detailed
characterization of a recombinant lectin from apicomplexan parasites, and may
contribute to a better understanding of the process of host cell recognition and
invasion by these obligate intracellular protozoa.
PMID- 9557873
TI - Combined preparative enzymatic synthesis of dTDP-6-deoxy-4-keto-D-glucose from
dTDP and sucrose.
AB - dTDP-6-deoxy-4-keto-D-glucose (1), the common intermediate in the biosyntheses of
the manifold deoxysugars, was synthesized on a gram-scale by the combination of
sucrose synthase and dTDP-D-glucose 4,6-dehydratase in a fed batch, starting the
reaction with dTDP. This process allowed a dTDP conversion with a 100% rate. An
easy and efficient three-step purification with anion-exchange chromatography and
gel filtration gave 1.1 g of 1 in an overall yield of 73%. This work realizes a
first step for an economic access to activated deoxysugars.
PMID- 9557875
TI - Purification and properties of recombinant beta-galactosidase from Bacillus
circulans.
AB - A gene encoding beta-galactosidase from Bacillus circulans which had hydrolysis
specificity for the beta1-3 linkage was expressed in Escherichia coli. The beta
galactosidase was purified from crude cell lysates of E. coli by column
chromatographies on Resource Q and Sephacryl S-200 HR. The enzyme released
galactose with high selectivity from oligosaccharides which had terminal beta1-3
linked galactose residues. However it did not hydrolyse beta1-4 linked
galactooligosaccharides. Moreover, Galbeta1-3GlcNAc, Galbeta1-3GalNAc, and their
p-nitrophenyl glycosides were regioselectively synthesized in 10-46% yield by the
transglycosylation reaction using this enzyme.
PMID- 9557876
TI - T lymphocyte activation results in an increased expression of beta-1,4
galactosyltransferase: phorbol ester induces a similar enhancement in the absence
of mitosis.
AB - We previously showed that in vitro activated human T lymphocytes expressed
increased amounts of beta-1,6-branched N-linked oligosaccharides (Lemaire S etal.
(1994) J Biol Chem269: 8069-74), which have been proposed to participate in the
regulation of the immune process. In the present paper, we compared the activity
and expression of beta-1,4-galactosyltransferase (GalT), one of the
glycosyltransferases involved in the biosynthesis of these beta-1,6-branched N
linked oligosaccharides, before and after in vitro activation of T lymphocytes
after a 40h treatment with a mixture of phorbol 12-myristate 13-acetate and
Phaseolus vulgaris lectin. After treatment, the enzymatic activity of the GalT
was significantly increased and immunoblot experiments performed with a
monoclonal antibody to human GalT showed an increased intensity of the GalT band
at 49 kDa, attributable to an enhancement of GalT mRNA level, as shown by
Northern blots. However, treatment of the same T-lymphocytes by phorbol ester
alone, which is unable to induce mitosis, resulted in a comparable increase of
the expression of GalT. Moreover, these phorbol ester-treated T lymphocytes,
analysed by flow cytometry exhibited a two-fold increase in the expression of
GalT. Finally, confocal fluorescence microscopy performed on all T lymphocytes
(treated or not) showed that the flow cytometric signal of GalT originates from
intracellular, Golgi-associated antigen only since no surface GalT was detected.
PMID- 9557871
TI - NetOglyc: prediction of mucin type O-glycosylation sites based on sequence
context and surface accessibility.
AB - The specificities of the UDP-GalNAc:polypeptide Nacetylgalactosaminyltransferases
which link the carbohydrate GalNAc to the side-chain of certain serine and
threonine residues in mucin type glycoproteins, are presently unknown. The
specificity seems to be modulated by sequence context, secondary structure and
surface accessibility. The sequence context of glycosylated threonines was found
to differ from that of serine, and the sites were found to cluster. Non-clustered
sites had a sequence context different from that of clustered sites. Charged
residues were disfavoured at position -1 and +3. A jury of artificial neural
networks was trained to recognize the sequence context and surface accessibility
of 299 known and verified mucin type O-glycosylation sites extracted from O
GLYCBASE. The cross-validated NetOglyc network system correctly found 83% of the
glycosylated and 90% of the non-glycosylated serine and threonine residues in
independent test sets, thus proving more accurate than matrix statistics and
vector projection methods. Predictions of O-glycosylation sites in the envelope
glycoprotein gp120 from the primate lentiviruses HIV-1, HIV-2 and SIV are
presented. The most conserved O-glycosylation signals in these evolutionary
related glycoproteins were found in their first hypervariable loop, V1. However,
the strain variation for HIV-1 gp120 was significant. A computer server,
available through WWW or E-mail, has been developed for prediction of mucin type
O-glycosylation sites in proteins based on the amino acid sequence. The server
addresses are http://www.cbs.dtu.dk/services/NetOGlyc/ and netOglyc@cbs.dtu.dk.
PMID- 9557877
TI - Studies on the interaction between hyaluronan and a rat colon cancer cell line.
AB - Binding studies with 125I-Tyr labelled hyaluronan (HA) on a cultured rat colon
cancer cell line were performed to characterize the association of HA to tumour
cells in vitro. Results show a specific and saturable binding (Kd=1.36 nM) which
indicates the presence of an HA binding receptor on the tumour cells. There is a
specific constant increase of cell-associated HA over time, which indicates that
HA is specifically taken up by the cells through endocytosis. The binding of 125I
Tyr labelled HA was more effectively inhibited by unlabelled HA of high MW in
relation to low MW species of the polysaccharide indicating that the receptor
binds HA of high MW with greater affinity than low MW species. In competition
experiments, the HA-binding could not be inhibited by other polysaccharides such
as chondroitin sulphate and heparin. Nor could ligands for scavenger receptors
and antibodies directed towards ICAM-1, CD 44 and RHAMM (Receptor for HA Mediated
Motility) significantly inhibit the association of HA to tumour cells.
PMID- 9557878
TI - Inflammation-induced expression of sialyl LewisX is not restricted to alpha1-acid
glycoprotein but also occurs to a lesser extent on alpha1-antichymotrypsin and
haptoglobin.
AB - Acute and chronic inflammation-induced expression of sialyl LewisX has already
been shown to occur on alpha1-acid glycoprotein. We now demonstrate that this
phenomenon is not restricted to alpha1-acid glycoprotein but also occurs on two
other acute-phase proteins. ie on alpha1-antichymotrypsin and on haptoglobin. The
level of expression of sialyl LewisX on these proteins was lower than on alpha1
acid glycoprotein, in all likelihood because alpha1-acid glycoprotein is the only
acute-phase protein containing tetraantennary glycans. No expression of sialyl
LewisX was detectable on alpha1-protease inhibitor, a protein with a high
diantennary glycan content. Non-sialylated LewisX was not detectable on these
major acute-phase proteins in any of the conditions studied. This indicates that
the majority of the a3-linked fucose residues are present as sialyl LewisX on
alpha1-acid glycoprotein, alpha1-antichymotrypsin and haptoglobin. The absolute
contribution to the total phenotype in plasma of protein containing this
determinant in a multivalent form was highest for alpha1-acid glycoprotein. This
leads us to propose that alpha1-acid glycoprotein is, among the acute-phase
proteins studied, the one with the highest potential for interference with the
extravasation of leukocytes by binding to the selectins.
PMID- 9557879
TI - MMC and LD simulations of alpha-D-Manp-(1-->2)-beta-D-Glcp-OMe: comparison to
long-range heteronuclear NMR coupling constants and to the crystal structure.
AB - The conformational flexibility and the dynamics of alpha-D-Manp(1-->2)-beta-D
Glcp-OMe have been investigated by Metropolis Monte Carlo (MMC) and Langevin
dynamics (LD) simulations. The two simulation techniques employ different force
fields, namely the HSEA force field and a CHARMm-based force field. The former
shows less conformational flexibility than the latter, in which a multiple energy
minima conformational space is sampled. Long-range heteronuclear nuclear magnetic
resonance (NMR) coupling constants have been measured by selective excitations of
the carbons at the glycosidic linkage. Calculated 3J(C,H) values from MMC and LD
simulations show excellent agreement to those from NMR experiments. The X-ray
crystal structure has a conformation within a region of the conformational space
populated in both force fields.
PMID- 9557880
TI - Studies on the conformational behaviour of GlcNAc-Man3-GlcNAc2 oligosaccharides
using molecular dynamics simulations.
AB - Three-dimensional structures of the natural substrate unit for the enzyme N
acetylglucosamine-transferase II, GIcNAc-Man3-GlcNAc2, were investigated by
molecular modelling methods. Molecular dynamics (MD) and molecular mechanics
calculations on two hexasaccharides, namely GlcNAc-Man3-GlcNAc2-Asn and GlcNAc
Man3-GlcNAc2-OMe were performed by the Biosym/MSI software using the CVFF and
CFF95 force fields in vacuum. The MD simulations were calculated for 3 ns at
different simulation temperatures and for two values of dielectric constant,
epsilon=1 and epsilon=4. From each 3 ns trajectory, 3050 structures have been
optimized. The local minima obtained have been clustered into families exhibiting
similar values of glycosidic torsional angles phi, psi, and omega. The influence
of the simulation conditions and force fields used on the conformational
behaviour and structure of the title oligosaccharides is discussed.
PMID- 9557881
TI - Removal of 106 amino acids from the N-terminus of UDP-GlcNAc: alpha-3-D-mannoside
beta-1,2-N-acetylglucosaminyltransferase I does not inactivate the enzyme.
AB - UDP-GlcNAc: alpha-3-D-mannoside beta-1,2-N-acetylglucosaminyltransferase I (GnTI,
EC 2.4.1.101) plays an essential role in the conversion of oligomannose to
complex and hybrid N-glycans. Rabbit GnTI is 447 residues long and has a short
four-residue N-terminal cytoplasmic tail, a 25-residue putative signal-anchor
hydrophobic domain, a stem region of undetermined length and a large C-terminal
catalytic domain, a structure typical of all glycosyltransferases cloned to date.
Comparison of the amino acid sequences for human, rabbit, mouse, rat, chicken,
frog and Caenorhabditis elegans GnTI was used to obtain a secondary structure
prediction for the enzyme which suggested that the location of the junction
between the stem and the catalytic domain was at about residue 106. To test this
hypothesis, several hybrid constructs containing GnT I with N- and C-terminal
truncations fused to a mellitin signal sequence were inserted into the genome of
Autographa californica nuclear polyhedrosis virus (AcMNPV), Sf9 insect cells were
infected with the recombinant baculovirus and supernatants were assayed for GnTI
activity. Removal of 29, 84 and 106 N-terminal amino acids had no effect on GnTI
activity; however, removal of a further 14 amino acids resulted in complete loss
of activity. Western blot analysis showed strong protein bands for all truncated
enzymes except for the construct lacking 120 N-terminal residues indicating
proteolysis or defective expression or secretion of this protein. The data
indicate that the stem is at least 77 residues long.
PMID- 9557882
TI - The generation and characterization of a rat neural cell line overexpressing the
alpha2,6(N) sialyltransferase.
AB - In order to examine the effects of altered protein sialylation on neural cell
function, B104 rat neuroblastoma cells were stably transfected with the cDNA
coding for alpha2,6(N) sialyltransferase (ST(6)N). Lectin blot analysis of the
clones demonstrated an increase in staining of the Sambucus nigra lectin, which
detects alpha2,6 linked sialic acid, in parallel with enzyme activity. There was
a concomitant decrease in staining by the Maackia amurensis lectin which labels
alpha2,3-linked sialic acid, indicating that the individual sialyltransferase
enzymes may compete for penultimate galactose acceptor sites. While there was an
initial increase in protein-bound sialic acid in parallel with enzyme activity,
the sialylation of the cells was demonstrated to be saturable. There was an
inverse relationship between cell adhesion to a fibronectin substrate and ST(6)N
activity suggesting that the negatively charged sugar acts to modulate cell
substrate interaction. These cells will provide an ideal model system with which
to further investigate the effect of altered sialic acid on neural cell function.
PMID- 9557884
TI - Previously undescribed spondyloepiphyseal dysplasia associated with
craniosynostosis, cataracts, cleft palate, and mental retardation: report of four
sibs.
AB - We report on four Japanese sibs (three brothers and one sister) with a previously
unreported syndrome of spondyloepiphyseal dysplasia, craniosynostosis, cataracts,
cleft palate, and mental retardation. Most clinical manifestations were evident
neonatally, but skeletal changes and cataracts became substantial in early
childhood. Radiological anomalies comprised coronal synostosis, mild epiphyseal
dysplasia, particularly in the distal tibiae, strikingly delayed patellar
ossification, mild metaphyseal splaying, hypoplastic ilia with iliac flare, and
platyspondyly with ovoid-shaped or posteriorly humped vertebral bodies. The
nonconsanguineous parents were mildly mentally retarded, and sibs of both gender
were equally affected; thus, inheritance was likely autosomal recessive.
PMID- 9557883
TI - Concanavalin A binding and endoglycosidase D resistance of beta1,2-xylosylated
and alpha1,3-fucosylated plant and insect oligosaccharides.
AB - The binding to concanavalin A (Con A) by pyridylaminated oligosaccharides derived
from bromelain (Manalpha1,6(Xylbeta1,2) Manbeta1,
4GlcNAcbeta1,4(Fucalpha1,3)GlcNAc), horseradish peroxidase
(Manalpha1,6(Manalpha1,3) (Xylbeta1,2)Manbeta1, 4GlcNAcbeta1,4(Fucalpha1,3)
GlcNAc), bee venom phospholipase A2 (Manalpha1,6Manbeta1,4GlcNAcbeta1,4GlcNAc and
Manalpha1,6(Manalpha1,3)Manbeta1,4GlcNAcbeta1,4 (Fucalpha1,3)GlcNAc) and zucchini
ascorbate oxidase (Manalpha1,6(Manalpha1,3) (Xylbeta1,2)Manbeta1,4
GlcNAcbeta1,4GlcNAc) was compared to the binding by Man3GlcNAc2, Man5GlcNAc2 and
the asialo-triantennary complex oligosaccharide from bovine fetuin. While the
fetuin oligosaccharide did not bind, bromelain, zucchini, Man2GlcNAc2 and
horseradish peroxidase were retarded (in that order). The alpha1,3-fucosylated
phospholipase, Man3GlcNAc2 and Man5GlcNAc2 structures were eluted with 15 mM
alpha-methylmannoside. It is concluded that core alpha1,3-fucosylation has little
or no effect on ConA binding while xylosylation decreases affinity for ConA. In a
parallel study comparing the endoglycosidase D (Endo D) sensitivities of
Man3GlcNAc2, IgG-derived GlcNAcbeta1,
2Manalpha1,6(GlcNAcbeta1,2Manalpha1,3)Manbeta1,+
++4GlcNAcbeta1,4(Fucalpha1,6)GlcNAc, the phospholipase Manalpha1,6(Manalpha1,3)
Manbeta1, 4GlcNAcbeta1,4(Fucalpha1,3)GlcNAc, and horseradish and zucchini
pyridylaminated N-linked oligosaccharides, it was found that only the Man3GlcNAc2
structure was cleaved. The IgG structure was sensitive only when beta
hexosaminidase was also present. Thus, in contrast to core alpha1,6-fucosylated
structures, such as those present in mammals, the presence of core alpha1,3
fucose, as found in structures from plants and insects, and/or beta1,2-xylose, as
found in plants, causes resistance to Endo D.
PMID- 9557885
TI - Prevalence of 22q11 region deletions in patients with velopharyngeal
insufficiency.
AB - Velo-cardio-facial syndrome, DiGeorge syndrome, conotruncal anomaly face
syndrome, tetralogy of Fallot, and pulmonary atresia with ventricular septal
defect are all associated with hemizygosity of 22q11. While the prevalence of the
deletions in these phenotypes has been studied, the frequency of deletions in
patients presenting with velopharyngeal insufficiency (VPI) is unknown. We
performed fluorescence in situ hybridization for locus D22S75 within the 22q11
region on 23 patients with VPI (age range 5-42 years) followed in the
Craniofacial Clinic at the University of Florida. The VPI occurred either as a
condition of unknown cause (n=16) or as a condition remaining following primary
cleft palate surgery (n=7). Six of sixteen patients with VPI of unknown cause and
one of seven with VPI following surgery had a deletion in the region. This study
documents a high frequency of 22q11 deletions in those presenting with VPI
unrelated to overt cleft palate surgery and suggests that deletion testing should
be considered in patients with VPI.
PMID- 9557886
TI - Three new cases of spondylocarpotarsal synostosis syndrome: clinical and
radiographic studies.
AB - Spondylocarpotarsal synostosis syndrome (SSS) or congenital synspondylism is a
recently delineated clinical entity. At least 15 patients have been reported. We
present 3 new patients, 2 of whom were sibs born to first-cousin parents. All of
our patients had multiple synostoses involving cervical, thoracic and/or lumbar
vertebral bodies and carpal/tarsal bones, scoliosis/lordosis, and short stature.
Sensorineural deafness was found in 2 of the 3 patients. Analysis of clinical
manifestations suggests clinical variability and genetic heterogeneity in SSS. Of
a total of 18 SSS patients, 10 were five pairs of sibs from five families, with
first-cousin consanguinity of parents in 3, indicating that at least one type of
SS is an autosomal-recessive disorder.
PMID- 9557888
TI - Characterization of a supernumerary marker derived from chromosome 17 by
microdissection in an adult with MR/MCA.
AB - We describe a 38-year-old adult who has a supernumerary marker chromosome in 40%
of metaphase cells which was identified by reverse in situ hybridization with a
DNA probe made by microdissection to be derived from chromosome 17. The
breakpoints are estimated by G-banding and fluorescence in situ hybridization
(FISH) to consist of the region from 17p11.1 to proximal 17q21. The propositus
displayed severe growth retardation, kyphoscoliosis, bilateral cataracts, severe
calcaneovalgus deformity of the feet, dysmorphic facies, profound mental
retardation, and multiple medical problems requiring ongoing medical management.
These problems included a mitral valve prolapse with regurgitation, recurrent
upper and lower respiratory tract infections, and severe respiratory
insufficiency. The relatively long survival of this patient enabled us to
describe the natural history of this rare chromosomal mutation.
PMID- 9557887
TI - Further delineation of a new (Van Den Ende-Gupta) syndrome of blepharophimosis
contractural arachnodactyly, and characteristic face.
AB - We report on 2 unrelated Indian girls with blepharophimosis, arachnodactyly,
digital contractures which improved spontaneously, elbow deformity, beaked nose,
everted lips, and large ears, findings similar to those in 2 cases reported
previously by Van Den Ende et al. [1992, Am J Med Genet 42:467-469] and Gupta et
al. [1995, J Med Genet 32:809-812], thus delineating a new syndrome of
contractural arachnodactyly with characteristic facial anomalies.
PMID- 9557889
TI - Smith-Magenis syndrome resulting from a de novo direct insertion of proximal 17q
into 17p11.2.
AB - We report on a de novo intrachromosomal rearrangement of chromosome 17 in a
patient with Smith-Magenis syndrome (SMS). This 11-year-old boy had short
stature, midfacial hypoplasia, and behavioral problems characteristic of this
syndrome. Cytogenetic analysis showed that the proximal long arm of a chromosome
17 (q11.2-q21.3) was inserted into its short arm at p11.2, resulting in an
apparent deletion of the SMS critical region [ins(17)(p11.2q11.2q21.3)].
Fluorescence in situ hybridization studies (FISH) demonstrated that the inserted
segment included both the ERBB2 and RARA loci, and dual color hybridizations
defined the insertion as direct, with ERBB2 located more proximally on the short
arm of the der(17). The resulting deletion of the short arm included loci c130G3,
D17S258, FLI, and D17S29, while the more proximal loci, D17S446 and D17S58,
remained apparently unaffected and in their native locations. The CMT1A locus
also remained in its native location on the short arm of the metacentric der(17)
chromosome. A de novo intrachromosomal insertional rearrangement of chromosome 17
in a case of SMS has not been reported previously and further illustrates the
instability of this chromosomal region.
PMID- 9557890
TI - Camptodactyly, myopia, and fibrosis of the medial rectus of the eye in two sibs
born to consanguineous parents: autosomal recessive entity?
AB - Unaffected but consanguineous parents suggest autosomal recessive inheritance of
a previously apparently undescribed syndrome of camptodactyly, fibrosis of the
medial rectus muscle of the eye, severe myopia, facial anomalies, joint
contractures, and mild scoliosis in a 13-year-old Turkish girl and her 11-year
old brother. The girl also had ptosis.
PMID- 9557891
TI - Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers-Danlos
National Foundation (USA) and Ehlers-Danlos Support Group (UK).
AB - Categorization of the Ehlers-Danlos syndromes began in the late 1960s and was
formalized in the Berlin nosology. Over time, it became apparent that the
diagnostic criteria established and published in 1988 did not discriminate
adequately between the different types of Ehlers-Danlos syndromes or between
Ehlers-Danlos syndromes and other phenotypically related conditions. In addition,
elucidation of the molecular basis of several Ehlers-Danlos syndromes has added a
new dimension to the characterization of this group of disorders. We propose a
revision of the classification of the Ehlers-Danlos syndromes based primarily on
the cause of each type. Major and minor diagnostic criteria have been defined for
each type and complemented whenever possible with laboratory findings. This
simplified classification will facilitate an accurate diagnosis of the Ehlers
Danlos syndromes and contribute to the delineation of phenotypically related
disorders.
PMID- 9557892
TI - Neuropathologic findings in a case of OFDS type VI (Varadi syndrome).
AB - Oral-facial-digital syndrome type VI (OFDS VI) or Varadi syndrome is a rare
autosomal-recessive disorder distinguished from other oral-facial-digital
syndromes by metacarpal abnormalities with central polydactyly and by cerebellar
abnormalities. Histopathologic characterization of the cerebellar abnormalities
has not been described previously. We describe the neuropathologic findings in a
stillborn, 21-week estimated gestational age (EGA) male fetus diagnosed
antenatally with signs of OFDS VI. Autopsy findings included: facial
abnormalities, postaxial central polydactyly of the right hand, bilateral bifid
toes, and absence of cerebellar vermis with hypoplasia of the hemispheric cortex.
Microscopic analysis of the cerebellum demonstrated absence of the subpial
granular cell layer and disruption or dysgenesis of the glial architecture. These
histopathologic findings suggest that a primary neuronal or glial cell defect,
rather than an associated Dandy-Walker malformation, may account for the
cerebellar abnormalities in this form of oral-facial-digital syndrome.
PMID- 9557893
TI - Retinal changes and tumorigenesis in Ramon syndrome: follow-up of a Brazilian
family.
AB - We report on the clinical evolution of the Brazilian family with Ramon syndrome
described by de Pina-Neto et al. [1986, Am J Med Genet 25:441-443]. Three members
(patients IV-2, IV-18, and IV-19) have developed pigmentary changes in the retina
and paleness of the optic disk. Patient IV-18 also has developed giant
hypertrophy of the labia minora that, when examined histopathologically, was
found to be due to neoplastic fibroblast and epithelial proliferation caused by a
fibromatous process similar to that reported in the gingivae of the patients with
this syndrome. Audiologic function of patient IV-2 was normal, and no skin
lesions were detected. The articular signs and symptoms show that the affected
relatives developed rheumatoid arthritis, which is currently inactive in patient
IV-18, whereas patient IV-2 did not develop these alterations.
PMID- 9557894
TI - Heterogeneity in hereditary pancreatitis.
AB - Hereditary pancreatitis (HP) is the most common form of chronic relapsing
pancreatitis in childhood, and may account for approximately 25% of adult cases
with chronic idiopathic pancreatitis. Recently, an arginine-histidine (R117H)
mutation within the cationic trypsinogen gene was found in 5/5 families studied
with HP. In this study we report on the results of linkage and direct mutational
analysis for the common R117H mutation examined in 8 nonrelated families with
hereditary pancreatitis. Two-point linkage analysis with the 7q35 marker D7S676,
done initially in 4 families, yielded lod scores that were positive in 2,
negative in one, and weakly positive in one. Direct mutational analysis of exon 3
of the cationic trypsinogen gene in 6 families showed that all symptomatic
individuals tested were heterozygous for the R117H mutation. Also, several
asymptomatic but at-risk relatives were found to be heterozygous for this
mutation. Affected individuals in the remaining 2 families did not have the
mutation. Radiation hybrid mapping using the Genebridge 4 panel assigned the
trypsinogen gene to chromosome region 7q35, 2.9 cR distal to ETS WI-9353 and 3.8
cR proximal the dinucleotide repeat marker D7S676. The negative linkage and
absence of the trypsinogen mutation in 2/8 families suggest locus heterogeneity
in HP. Analysis of the R117H mutation is useful in identifying presymptomatic "at
risk" relatives and in genetic counseling. Also, it can be useful in identifying
children and adults with isolated chronic idiopathic pancreatitis.
PMID- 9557895
TI - Genetic counseling in Angelman syndrome: the challenges of multiple causes.
AB - The causal heterogeneity of Angelman syndrome (AS) makes providing information
regarding recurrence risk both important and challenging, and may have a dramatic
impact on reproductive decision-making for the nuclear and extended family. Most
cases of AS result from typical large de novo deletions of 15q11-q13, and are
expected to have a low (<1%) risk of recurrence. AS due to paternal uniparental
disomy (UPD), which occurs in the absence of a parental translocation, is
likewise expected to have a <1% risk of recurrence. Parental transmission of a
structurally or functionally unbalanced chromosome complement can lead to 15q11
q13 deletions or to UPD and will result in case-specific recurrence risks. In
instances where there is no identifiable large deletion or UPD, the risk for
recurrence may be as high as 50% as the result of either a maternally inherited
imprinting center (IC) mutation or a ubiquitin-protein ligase (UBE3A) gene
mutation. Individuals with AS who have none of the above abnormalities comprise a
significant proportion of cases, and some may be at a 50% recurrence risk.
Misdiagnoses, as well, can be represented in this group. In light of the many
conditions which are clinically similar to AS, it is essential to address the
possibility of diagnostic uncertainty and potential misdiagnosis prior to the
provision of genetic counseling. Summaries of the different causal classes of AS
as an algorithm for determination of recurrence risks are presented.
PMID- 9557896
TI - Terminal deletion of the long arm of chromosome 10: a new case with breakpoint in
q25.3.
AB - Since the first patient with partial deletion of the long arm of chromosome 10
was described in 1978, another 23 cases have been reported, with the breakpoint
ranging from 10q23.3-26.2. To contribute further to the delineation of the
monosomy 10qter syndrome, we describe a female child who, at age 3 6/12 years,
was diagnosed with a de novo deletion of the long arm of chromosome 10, with a
breakpoint in 10q25.3. The phenotypic manifestations in this child are compatible
with those of previously reported cases. However, in contrast to most other
patients, we found a moderate expression of the syndrome, with no genitourinary
or cardiac malformations and with only mild retardation. Based on our
observations and those of others, we conclude that a typical craniofacial
appearance and varying degrees of psychomotor retardation are always found in
patients with 10q- syndrome.
PMID- 9557897
TI - Lethal syndrome of skeletal dysplasia and progressive central nervous system
degeneration.
AB - We describe 3 sibs (2 males and 1 female) with multiple congenital anomalies,
poor growth, seizures, and progressive central nervous system (CNS) degeneration
leading to death in infancy. Radiographic changes in all 3 were similar, and
included moderate shortness of long bones, platyspondyly, and hypoplastic pelvis.
Autopsies showed diffuse encephalomyelopathy and enlargement of the lateral and
third ventricles. Lysosomal enzyme activities were normal. Collagen type II
analysis on 2 of the sibs indicated normal collagen. Chromosomes appeared normal.
Even though the radiographic and chondroosseous morphologic findings in these
sibs have a certain similarity to Dyggve-Melchior-Clausen syndrome, their
clinical course does not fit this condition. These infants appear to represent a
new syndrome of bone dysplasia and CNS degeneration inherited as an autosomal
recessive trait.
PMID- 9557898
TI - Dilemma of trisomy 20 mosaicism detected prenatally: is it an innocent finding?
AB - The clinical significance of mosaicism trisomy 20 detected prenatally following
amniocentesis remains uncertain, due to the rarity of liveborn cases with
inconsistent clinical findings, the short postnatal follow-up, and failure in
evaluating other fetal tissues for the presence of the trisomy. We report on a 15
month-old 46,XX chromosome constitution in white blood cells, while skin
fibroblasts demonstrated trisomy 20 mosaicism (54%) by fluorescence in situ
hybridization (FISH) analysis. Clinical examination of the baby showed only minor
phenotypic signs (bilateral epicanthal folds, delayed closure of fontanel with no
other gross anomalies), but demonstrated a considerable developmental delay in
gross and fine motor skills along with hypotonicity. This is the second oldest
described liveborn with trisomy 20 mosaicism confirmed in skin fibroblasts. This
cytogenetic aberration along with her developmental delay suggests that the two
findings are related and that aberration affects various fetal tissues and is not
confined to extra-embryonic tissue as suggested previously. Yet, an undiagnosed
condition may be the cause of the child's developmental delay. Based on this case
and following a review of the literature we suggest that when mosaic trisomy 20
is identified in amniocytes, further evaluation is required. Cord blood should be
analyzed preferably by FISH. During counseling the parents should be advised of
an additional risk, such as developmental delay, even when fetal cord karyotype
and detailed ultrasonic scan are normal.
PMID- 9557899
TI - Supernumerary nipple in association with Becker nevus vs. Becker nevus syndrome:
a semantic problem only.
PMID- 9557900
TI - Becker nevus syndrome and supernumerary nipples.
PMID- 9557901
TI - Can we rely on the family history?
PMID- 9557902
TI - Pilomatrixomas in Rubinstein-Taybi syndrome.
PMID- 9557904
TI - Predictions of protein secondary structures using factor analysis on Fourier
transform infrared spectra: effect of Fourier self-deconvolution of the amide I
and amide II bands.
AB - Fourier self-deconvolution (FSD) was performed on protein amide I and II Fourier
transform infrared (FTIR) spectra to test if the resultant increased band shape
variation would lead to improvements in protein secondary structure prediction
with our factor analysis based restricted multiple regression (RMR) methods. FTIR
spectra of 23 proteins dissolved in H2O were measured and normalized to a
constant amide I peak absorbance. The deconvolved spectra were renormalized by
area so that the deconvolved spectra sets had the same area as before. Principal
component analysis of the deconvolved spectra sets was carried out, which was
followed by a selective multiple linear regression (RMR) analysis of the
principal component loadings with regard to the fractional components (FC) of
secondary structure. As compared to analyses based on the original spectra set,
helix and sheet predictions were not noticeably improved by FSD; but, if a very
large number of component spectra (16) were retained in the pool to select which
loadings to be used in the RMR optimization, better predictions of turn and
"other" resulted. The prediction quality varied depending on the deconvolution
parameters used.
PMID- 9557903
TI - FTIR microspectroscopic study of cell types and potential confounding variables
in screening for cervical malignancies.
AB - FTIR microscopy was applied to the analysis of cell types and other variables
present in Pap smears to ascertain the limitations of infrared spectroscopy in
the diagnosis of cervical cancer and dysplasia. It was found that leukocytes, and
in particular lymphocytes, have spectral features in the phosphodiester region
(1300-900 cm[-1]) suggestive of what has previously been described as changes
indicative of malignancy. Endocervical cells and fibroblasts have similar
spectral features to HeLa cells and consequently could also confound diagnosis.
The use of ethanol as a fixative and dehydrating agent results in retention of
glycogen in cervical cell types and thus minimizes spectral changes in the
glycogen region due to sampling technique. Spectra of seminal fluids exhibit
strong bands in the phosphodiester/carbohydrate region; however, sperm
contamination should be easily detectable by the presence of a distinctive
doublet at 981/968 cm(-1). Erythrocyte spectra exhibit a reduction in glycogen
band intensity, but can be discerned by a relatively low-intensity nu(s) PO2-
band. Endocervical mucin spectra exhibit a reduction in glycogen bands and a very
pronounced nu(s) PO2- band, which is similar in intensity to the corresponding
band in HeLa cells. Thrombocytes have strong bands in the phosphodiester region,
but thrombocytes can be discerned from other cell types by the presence of two
small broad bands at 980 and 935 cm(-1). Candida albicans is characterized by
strong bands in the polysaccharide region which could potentially obscure
diagnostic bands if C. albicans is present in large numbers. Spectra of bacteria
common to the female genital tract, in general, also have strong absorptions in
the polysaccharide region; however, bacterial contamination is usually minimal
and would not be expected to obscure cervical cell spectra. Nylon threads and
bristles from cervical sampling implements produce characteristic IR profiles
which allow for easy identification. Given the number of potential confounding
variables associated with cervical cytology, a multivariate statistical or neural
network analysis would appear to be necessary before the implementation of FTIR
technology in clinical laboratories.
PMID- 9557905
TI - Evidence for global mobility in the premelting of a polynucleotide from
temperature-dependent Raman optical activity.
AB - The backscattered Raman and Raman optical activity (ROA) spectra of poly(rA)
poly(rU) at 20 degrees C and 45 degrees C in buffered aqueous solution between
650 and 1750 cm(-1) are reported. Although the intensity of the majority of the
Raman bands increase by varying amounts as the temperature is raised in
accordance with the well-known hypochromic effect, the reverse effect is found
for the ROA signals which we attribute to thermal accessibility of a greater
number of distinct conformations leading to cancellation of ROA signals. The
difference ROA spectrum obtained by subtracting the spectrum recorded at 45
degrees C from that recorded at 20 degrees C displays a very similar sign pattern
to those at both 20 degrees C and 45 degrees C throughout the spectral region
examined. This indicates that the same average structure is maintained in this
temperature range and that the thermal fluctuations are correlated through the
bases, the glycosidic link, the sugar ring, and the phosphate backbone of both
strands. These results indicate that ROA may be a useful new probe of the
dynamics of nucleic acid in solution.
PMID- 9557906
TI - FT-Raman investigation of alkaloids in the liana Ancistrocladus heyneanus.
AB - The applicability of the micro-FT-Raman technique for studying alkaloids in vitro
and for observing alkaloids in plant cells is demonstrated. This technique is
examined using fresh plant material of Ancistrocladus heyneanus, a tropical liana
known to produce pharmacologically interesting naphthylisoquinoline alkaloids as
secondary metabolites. It will be shown that it is possible to localize and
identify some of these alkaloids in different parts of the plant by means of
Raman microspectroscopic studies. Data on the in situ structure and the spatial
distribution can be obtained, which could provide information about the
biosynthesis of the alkaloids in the plant.
PMID- 9557907
TI - Luminescence and structure of the protonated forms of meso-tetraarylporphyrins in
solution.
AB - A comparative study of the spectral-luminescent properties (at 293 K and 77 K) of
meso-tetrakis(o-tolyl)porphyrin (o-TTP) and meso-tetraphenylporphyrin (TPP), and
also meso-tetrakis(n-propyl)porphyrin (TPrP) in nonaqueous acid media has been
carried out with the aim to reveal effects associated with the influence of
methyl groups which hinder sterically the twist of the phenyl rings enhancing
their conjugation with the macrocycle in acid medium. On the basis of the
spectral data it is concluded that although the introduction of the methyl groups
diminishes this twist of phenyls it does not eliminate it completely (the
absorption spectra of protonated o-TTP are intermediate between those of TTP and
TPrP). The fluorescence spectra of the protonated forms of o-TTP and TPP at 77 K
are approximately mirror-symmetrical to the Q(0-0) and Q(0-1) absorption bands;
on the elevation of the temperature up to 293 K the fluorescence and absorption
bands broaden, the Stokes shift largely increases, and the mirror symmetry of the
spectra disappears, which is indicative of changes in solute-solvent interactions
in the S1 state. The analysis of the obtained data on the energetics of
photophysical processes leads to the conclusion that the significant role of
radiationless deexcitation in the S1-->S0 channel, characteristic of the
protonated form of TPP, is retained at 77 K. The introduction of the methyl
groups at the ortho positions sharply decreases the corresponding rate constant,
so that the S1-->T1 intersystem crossing becomes the main channel of
deexcitation. The influence of heavy atoms (the Cl- and Br- anions) on the
luminescence of the protonated forms has been investigated. It is shown that,
analogous to the case of octaethylporphyrin investigated earlier, in nonaqueous
media the protonated species of o-TTP form bis adducts of the dihydrochloride
type. Contrary to this, the experiments with meso-tetrakis(p
sulfophenyl)porphyrin (TPPS) in aqueous solutions have shown that the TPPS
dications do not add counterions, whereas the influence of Cl- and Br- on
fluorescence is realized according to the external heavy-atom effect mechanism.
For nonaqueous o-TTP solutions with admixtures of HCl and CF3COOH the short
wavelength fluorescence from the S3 (B1) level has been detected whose unusual
peculiarity is its enhancement in passing from 293 K to 77 K.
PMID- 9557909
TI - Death under anesthesia in the Middle East--a historical anecdote.
PMID- 9557908
TI - Amphotericin B toxicity as related to the formation of oxidatively modified low
density lipoproteins.
AB - The effect of amphotericin B on the oxidation and degradation of low- and high
density lipoproteins was investigated by UV-vis spectroscopy, electron
microscopy, electrophoresis, and size-exclusion chromatography. Two formulations
of the drug were used: the commercial Fungizone and a new, less toxic, liposomal
formulation, AmBisome. It was shown that Fungizone strongly enhanced the
oxidative deformation of low-density lipoprotein structure while AmBisome did not
bind to this lipoprotein fraction and did not affect its oxidation. It was shown
that amphotericin B contained in Fungizone extracted cholesterol from low-density
lipoproteins which sensitized them to oxidation. Both formulations of
amphotericin B studied here did not bind to high-density lipoprotein and did not
affect the process of its oxidation.
PMID- 9557910
TI - Prevention of post-operative nausea and vomiting following laparoscopic surgery-
ephedrine vs propofol.
AB - Postoperative nausea and vomiting (PONV) are relatively common troublesome
distressing symptoms. The incidence is reported to be as high as 20-51%. Ninety
adult ASA I and II patients scheduled for laparoscopic gynecological or surgical
interventions, were randomly and equally assigned to one of the three groups in
the immediate postoperative period: Group 1 received 0.1 ml.kg(-1) normal saline
intravenously, while Group 2 received 0.5 mg.kg(-1) ephedrine intramuscularly and
Group 3 received 0.25 mg.kg(-1) propofol intravenously as preventive antiemetic
therapy. Sixty-six, 33 and 50 percent of patients experienced nausea and vomiting
syndrome in Group 1, 2 and 3 respectively. Both ephedrine and propofol proved to
have antiemetic properties. Ephedrine treated group of patient had significant
less emetic score than propofol. No significant hemodynamic changes were recorded
in both groups.
PMID- 9557911
TI - Use of esmolol to attenuate hemodynamic responses during cataract extraction.
AB - Esmolol attenuates hemodynamic responses to tracheal intubation and extubation in
young patients, but has less well documented pharmacokinetics and efficacy in
older patients. Following cataract surgery, application of pressure on the eye
during eye bandaging may have vasomotor effects. The present study of older
patients having cataract surgery investigated 1) the effects of normal saline 1.0
ml. 10kg(-1) or esmolol 4.0 mg.kg(-1) IV given 90 secs prior to tracheal
intubation and of normal saline 0.5 ml.10 kg(-1) or esmolol 2.0 mg.kg(-1) IV
given 60 sec prior to each of eye bandaging and tracheal extubation; 2) the time
to onset and duration of action of esmolol; 3) the cardiovascular effects of eye
bandaging. Esmolol attenuated the cardiovascular effects of tracheal intubation,
eye bandaging and tracheal extubation, but caused relative bradycardia and
hypotension after induction and hypotension after extubation. Its effect occurred
within 60-90 secs and lasted about 6 mins. Pressure on the eye during bandaging
in those not given esmolol caused hypertension without tachycardia.
PMID- 9557912
TI - Electroconvulsive therapy and intraocular pressure.
AB - Psychiatric patients receiving phenothiazine, tricyclic antidepressant and
antiparkinsonian drugs for prolonged periods, occasionally develop mydriasis and
angle closure glaucoma. Suxamethonium, usually given to modify the convulsion of
electroconvulsive therapy (ECT) increases intraocular pressure (IOP) by about 7-8
mmHg, the increase being maximal and having returned to baseline 2 min and 6 mins
after injection, respectively. We studied the effects on IOP of an electrically
induced convulsion following induction of anesthesia using methohexitone 1 mg.kg(
1) and suxamethonium 0.5 mg.kg(-1) in 21 consecutive cooperative psychiatric
patients, all receiving antipsychotropic drugs. IOP was recorded sequentially
from before induction of anesthesia to after resumption of spontaneous
respiration. Their mean IOP was 15.3 (SD 3.7) mmHg prior to induction of
anesthesia, 13.5 (SD 3.5) mmHg after loss of eyelash reflex following injection
of methohexitone, 16.1 (SD 2.4) mmHg after cessation of muscle fasciculations
induced by suxamethonium, 19.2 (SD 5.6) mmHg after cessation of convulsion and
15.5 (SD 4.4) mmHg following resumption of regular spontaneous respiration. The
successive stepwise changes in the mean IOP were all statistically significant (p
< 0.001 each change compared with the preceding pressure; paired 't' tests).
These data reveal that the reduction in IOP produced by methohexitone is reversed
by the increase in IOP produced by suxamethonium. Collated with the time course
of the effects of barbiturates and suxamethomium on IOP, the increase in IOP
observed following the induced convulsion was not greater than that expected
after suxamethonium alone, suggesting that the induced convulsion during ECT does
not pose an ocular hazard to psychiatric patients receiving medications which
have iatrogenic glaucomatous potential.
PMID- 9557913
TI - Gastric emptying of indigestible solids--a rat model.
AB - The effects of ingestion of digestion of digestible solids and liquids on gastric
emptying of indigestible solids were studied. Thirty rats were allocated to one
of five groups; in four groups, rats had been fasted for 24 h before the
experiment, whereas in the fifth group, they had not been fasted. In all groups,
ten steel balls (1.0 mm in diameter) were inserted through an orogastric cannula
into the stomach under brief halothane anesthesia. In the four groups of fasted
rats, one of the following substance was then given into the stomach: (1) 0.5 g
digestible solids; (2) 1.0 ml saline; (3) 1.0 ml contrast medium (45% wv sodium
diatrizoate); (4) no substance (control group). Three hours later, the number of
balls which had passed into the intestine was counted. Ingestion of 0.5 g meal in
fasted rats significantly delayed gastric emptying of steel balls (P < < 0.001),
whereas there was no difference in gastric emptying of steel balls between fasted
rats and fully fed rats. Ingestion of the contrast medium (P < < 0.001), but not
that of saline, significantly delayed the emptying of the balls. Therefore,
ingestion of digestible solids or liquids may delay gastric emptying of
indigestible solids. Clinical implications of gastric emptying of indigestible
solids are discussed.
PMID- 9557914
TI - Post dural puncture headache--a review article.
PMID- 9557915
TI - Use of the laryngeal mask for management of the compromised airway--a case
report.
AB - A 54-year old woman was scheduled for thoracotomy for excision of a tumor of the
left upper lobe. Reduced thyromental distance and thyroid enlargement were
identified by the preoperative physical examination and inability to visualize
the larynx was encountered during direct laryngoscopy. A 37-Fr left sided double
lumen tube was inserted in trachea with great difficulty after three failed
attempts. One lung anesthesia underwent uneventfully and postoperatively it was
decided to exchange the double lumen tube to a single lumen tracheal tube. After
the extubation, five failed attempts of reintubation were performed. A laryngeal
mask airway (LMA) size 3 was passed easily achieving an airtight airway. The
patient underwent an uneventful prolonged (105 min) weaning via the LMA which was
left in place until the patient regained full consciousness. Peripheral oxygen
saturation remained greater than 95% throughout the airway manipulation. LMA
insertion is an easy non-invasive technique and should be considered whenever
airway management proves difficult.
PMID- 9557916
TI - Dystonic movements following thalamonal and alfentanil induction--a case report.
AB - A 62 year old woman developed dystonic movements following induction of
anesthesia with thalamonal and alfentanil. The patient remained awake during the
episode. A small dose of thiopental sodium followed by succinylcholine aborted
the unpleasant state. The case is being presented to emphasize the point that
even small doses of opioid narcotic can cause tonic movements and frank seizures
in some patients.
PMID- 9557917
TI - Will the millimetre of mercury be replaced by the kilopascal?
PMID- 9557918
TI - Does it matter whether blood pressure measurements are taken with subjects
sitting or supine?
AB - BACKGROUND: Several guidelines for the management of hypertension do not give
special preference to a specific position of the patient during blood pressure
measurement, suggesting that blood pressure readings taken with patients sitting
and with patients supine are interchangeable. OBJECTIVE: To test whether there is
any difference between the blood pressure readings with patients sitting and
supine. DESIGN AND METHODS: Blood pressure and heart rate were measured three
times each for 245 subjects (171 hypertensives), with subjects both sitting and
supine, simultaneously on both arms, with a Hawksley random-zero sphygmomanometer
on the right arm and a semi-automatic oscillometric device (Bosomat) on the left
arm. The sequence of the two positions was randomized. The procedure was repeated
on a second occasion for 49 subjects (41 hypertensives) with the sequence of the
positions reversed. Because there was no systematic difference among the three
readings per position, the averages of the three blood pressure and heart rate
readings with subjects sitting and supine were compared and the influences of
age, body mass index, hypertension and medication on the difference were
examined. RESULTS: We found no influence of the subject's body posture on the
systolic blood pressure. We found a higher diastolic blood pressure [by 5.2+/-0.4
mmHg (mean+/-SEM), P< 0.001 with Hawksley random-zero sphygmomanometer] and a
greater heart rate [by 1.5+/-0.3 beats/min (mean+/-SEM), P< 0.001] with subjects
sitting. The sitting minus supine differences for diastolic blood pressure and
heart rate decreased significantly with increasing age (P< 0.001). We found no
effect of body mass index, hypertension and medication on the sitting - supine
differences. CONCLUSIONS: The subject's body posture influenced especially the
diastolic blood pressure and heart rate, both of them being significantly higher
with patients sitting rather than supine. This effect decreased with age. Thus,
for indirect blood pressure measurement, diastolic blood pressure values obtained
with subjects sitting and supine cannot automatically be regarded as equivalent.
PMID- 9557919
TI - Family history as a predictor of blood pressure in a longitudinal study of
Australian children.
AB - BACKGROUND: Sex both of parent and of child might influence associations between
parental hypertension and blood pressure in offspring. OBJECTIVE: To examine
these associations. DESIGN: A cohort of Australians was surveyed 3-yearly from
age 9 to 18 years. SETTING: A community-based sample. PARTICIPANTS: When they
were aged 18 years, 630 of 1565 participants who had been selected randomly at
the age of 9 years were re-surveyed. MAIN OUTCOME MEASURES: Systolic and
diastolic blood pressures. RESULTS: Paternal hypertension was reported by 18% of
men and 15% of women and maternal hypertension by 15% of men and 14% of women. By
the time they were aged 9 years, systolic blood pressure was significantly higher
in sons [117.8 mmHg, 95% confidence interval (CI) 116A-119.2 versus 114.7 mmHg,
CI 113.4-116.0] and daughters (118.2 mmHg, CI 116.9-119.5 versus 114.9 mmHg, CI
112.8-117.0) of hypertensive fathers than it was in sons and daughters of
normotensive fathers. When they were aged 18 years, paternal hypertension
predicted blood pressures in men and women independently of their weight at
birth, fitness, alcohol consumption and weight for height for age. Systolic blood
pressures increased more rapidly (by 0.6 mmHg/year) in men with hypertensive
fathers. CONCLUSIONS: Systolic blood pressure in young adults differs in relation
to parental hypertension according to the sex of the affected parent and the sex
of the offspring. This could reflect unmeasured environmental variables or the
action of sex-related genetic or intrauterine factors.
PMID- 9557920
TI - Trends in the prevalence, detection, treatment and control of arterial
hypertension in the Belgian adult population.
AB - OBJECTIVES: To discuss changes during the past decades in the prevalence and in
the patterns of detection, treatment and control of arterial hypertension in the
general Belgian population aged 25-64 years. DESIGN: Data from two cross
sectional cardiovascular disease risk factor surveys of the general population
aged 25-64 years during the first and second halves of the 1980s (the Belgian
Inter-university Research on Nutrition and Health study of 1980-1984 and the
World Health Organization Multinational Monitoring of Trends and Determinants in
Cardiovascular Diseases study of 1985-1992) are compared. PARTICIPANTS: Age
stratified and sex-stratified random samples from the general population yielded
9372 participants in the former study and 4904 participants in the latter.
METHODS: In both studies, blood pressure measurements and other variables were
collected in the same standardized way and by the same observers. RESULTS: For
both sexes, overall age-standardized prevalences of hypertension (subjects with
systolic blood pressure > or = 160 mmHg or diastolic blood pressure > or = 95
mmHg or currently being administered antihypertensive drug treatment) were found
to be significantly (P< 0.001) higher in the former than they were in the latter
study. A significant decline in population mean systolic blood pressure values
was observed for both sexes on going from the former data to the latter (falls of
6.0 and 7.3 mmHg for men and women, respectively, P< 0.01). In log-linear models,
adjusted for age, a highly significant (P< 0.0001) favourable shift in the
population distribution over the various categories of detection, treatment and
control of hypertension was observed. This trend exhibited a significant sex
difference, however, there being a much more favourable trend for women.
CONCLUSIONS: In Belgium, favourable trends in the prevalence and in the patterns
of detection, treatment and control of arterial hypertension and in the levels of
systolic blood pressure were observed. The so-called 'rule of halves' is no
longer valid.
PMID- 9557921
TI - Endocrinological abnormalities in angiotensinogen-gene knockout mice: studies of
hormonal responses to dietary salt loading.
AB - OBJECTIVE: Physiological roles of the renin-angiotensin system in maintaining
blood pressure and sodium-water balance in angiotensinogen gene-knockout mice
were evaluated with special reference to endogenous pressor substances. METHODS:
Angiotensinogen-gene knockout mice and control mice were fed a 0.3 or 4% NaCl
diet for 2 weeks. Systolic blood pressure and urinary excretions of electrolytes,
creatinine, aldosterone, adrenaline, noradrenaline, dopamine and vasopressin were
measured. RESULTS: About 60% of our angiotensinogen-gene knockout mice did not
survive until weaning. These mice presented with hypotension and polyuria.
Urinary excretion of aldosterone from such mice was significantly lower (not
detected) than that from control mice (2.0+/-0.3 pg/mg creatinine). In contrast,
urinary excretion of vasopressin from angiotensinogen-gene knockout mice (0.7+/
0.1 ng/mg creatinine) was greater than that from control mice (0.3+/-0.1 ng/mg
creatinine), and those of adrenaline and of noradrenaline were similar for
knockout and control mice. After salt loading (a 4% NaCl diet), angiotensinogen
gene knockout mice exhibited a significant increase in systolic blood pressure
(from 68.3+/-2.9 to 95.9+/-5.9 mmHg), significant decreases in urinary excretions
of adrenaline (from 65+/-8 to 40+/-7 pg/mg creatinine) and noradrenaline (from
467+/-48 to 281+/-41 pg/mg creatinine) and no change in excretion of vasopressin
compared with such mice fed a 0.3% NaCl diet CONCLUSION: The present results with
angiotensinogen-gene knockout mice confirm that the renin-angiotensin system
plays fundamental roles in maintaining the blood pressure and sodium-water
balance. Because the vasopressin and catecholaminergic systems may be altered by
lack of angiotensin in angiotensinogen-gene knockout mice, these systems perhaps
are not able to restore blood pressure and sodium-water depletion to normal
levels in these mice.
PMID- 9557922
TI - Plasma hydrogen peroxide production in hypertensives and normotensive subjects at
genetic risk of hypertension.
AB - BACKGROUND: Oxygen free radicals may play roles in hypertension both in
arteriolar constriction and in formation of lesions. OBJECTIVE: To quantify free
radical production in blood plasma of genetic hypertensives. DESIGN: Hydrogen
peroxide levels were measured, because it is one of the most stable reactive
oxygen species. METHODS: An electrode technique was used to determine plasma
hydrogen peroxide levels after blockade of endogenous catalase with sodium azide.
This method was validated by an independent spectrophotometric technique.
RESULTS: Members of the essential hypertensive group (n=21) had higher plasma
hydrogen peroxide levels (3.16+/-0.14 versus 2.50+/-0.16 micromol/l, P=0.005)
than did members of the normotensive group (n=29). Furthermore, within the
normotensive group, those with a family history of hypertension (n=15) exhibited
higher hydrogen peroxide levels (2.83+/-0.27 versus 2.14< or =0.13 micromol/l,
P=0.03) than did those without such a family history (n=14). Plasma hydrogen
peroxide levels in these 50 subjects were correlated to their mean arterial
pressures (r=0.54, P < 0.001). When hypertensives were grouped with normotensives
without a family history of hypertension, the correlation improved (r=0.70, P<
0.001). Statistical analysis (two-way analysis of variance) revealed that a
family history of hypertension was a better predictor of plasma hydrogen peroxide
production than was blood pressure status (P=0.003 versus P=0.093). Further
investigations showed that superoxide is produced in plasma and that one of its
sources is xanthine oxidase. CONCLUSIONS: Hydrogen peroxide is produced in blood
plasma and elevation of its level could constitute a pathogenic factor in
vascular organ damage attendant upon systemic hypertension.
PMID- 9557923
TI - Activation by calcium of erythrocyte Na+/H+ exchange in men.
AB - OBJECTIVE: To determine whether protein kinase C is necessary for the calcium
activation of the Na+/H+ exchange in human erythrocytes by studying activation by
calcium of erythrocyte Na+/H+ exchange in control cells, in protein kinase C
depleted cells after downregulation of protein kinase C with phorbol-12-myristate
13-acetate and in cells that had been treated beforehand with phorbol-12
myristate-13-acetate with and without the calpain inhibitor E-64d. METHODS:
Erythrocyte Na+/H+ exchange was measured by determining the initial rates of the
influx of Na+ into Na+-depleted, acid loaded cells. The effects of various
concentrations (0-1 mmol/l) of CaCl2 and the effects of 1 mmol/l CaCl2 on
activation of the intracellular pH and on the external Na+ activation of Na+/H+
exchange were studied. The effects of 1 mmol/l CaCl2 on Na+/H+ exchange in
control cells and cells that had been incubated beforehand with and without 1
micromol/l phorbol-12-myristate-13-acetate and with E-64d and 1 micromol/l
phorbol-12-myristate-13-acetate for 1, 2, 3 and 24 h were also investigated.
RESULTS: Addition of Ca2+ to a concentration in the range 0-1 mmol/l in the
presence of calcimycin resulted in stimulation of Na+/H+ exchange: 1 mmol/l CaCl2
increased (P< 0.001) the erythrocyte Na+/H+ exchange by 74%. Calcium increased
the maximum rate for activations by intracellular pH and by external Na+ of
Na+/H+ exchange, whereas it did not affect the Michaelis-Menten constants for
activation by intracellular H+ and external Na+. However, calcium did not
activate the Na+/H+ exchange in protein kinase C downregulated erythrocytes and
administration of the calpain inhibitor E-64d could not prevent this
inactivation. CONCLUSION: Our data indicate that protein kinase C is necessary
for the activation by calcium of the erythrocyte Na+/H+ exchange.
PMID- 9557924
TI - Potent 'new pressor protein' related to coagulation factor XII is potentiated by
inhibition of angiotensin converting enzyme.
AB - BACKGROUND: 'New pressor protein' was observed after tryptic activation of human
and rat plasma in vitro, which is done conventionally for prorenin measurements.
RESULTS: It is potently pressor, heat labile, possesses enzyme activity, and has
a relative molecular mass > 30 kDa with isoelectric point(s) 4.7-4.9. New pressor
protein equivalent to only 0.01 ml human, or rat, plasma injected intravenously
quickly raises systolic blood pressure in 300 g anesthetized, ganglion-blocked,
bioassay rats by about 15 mmHg. For unknown reasons, this is potentiated to about
45 mmHg after treatment with angiotensin I converting enzyme inhibitors (such as
captopril and enalapril). New pressor protein activity in rats remains normal 24
h after bilateral nephrectomy, suggesting that it has an extrarenal origin and,
furthermore, excluding the possibility of an association with renin-angiotensin
system. Systolic blood pressure elevation is greater than the diastolic one,
implicating cardiotonic effects. Human plasma new pressor protein was purified
using standard biochemical techniques and its N-terminal sequence (19 residues)
found to be homologous with the beta factor XIIa fragment of coagulation factor
XII. This was supported by demonstrating inhibition of new pressor protein
activity in vitro using the factor XII-specific corn trypsin inhibitor. Also,
human new pressor protein activity in humans congenitally deficient in
coagulation factor XII is very low. The high potency and multiphasic, cardiotonic
effects of injected new pressor protein suggest that it interacts synergistically
with other systems in the body. This was confirmed by showing that, within 10 min
of total bilateral adrenalectomy, responses to new pressor protein decreased
markedly. CONCLUSIONS: New pressor protein's action requires adrenal (medullary?)
involvement, but its mechanism of action and that of its potentiation by
angiotensin converting enzyme inhibitors remain unknown. The physiologic and
clinical relevance of these observations depends on whether activation of new
pressor protein can occur in vivo.
PMID- 9557925
TI - Low-dose transdermal scopolamine decreases blood pressure in mild essential
hypertension.
AB - BACKGROUND: Increasing cardiovascular parasympathetic nervous activity could have
antihypertensive effects. Low-dose transdermal scopolamine increases vagal
cardiac modulation of sinus node and baroreflex sensitivity in healthy subjects
and in cardiac patients. OBJECTIVE: To study the short-term effects of
transdermal scopolamine on blood pressure and cardiovascular autonomic control in
patients with mild essential hypertension. DESIGN: A randomized, double-blind,
placebo-controlled crossover trial with 12 untreated middle-aged [aged 39+/-5
years (mean+/-SD)] patients with mild essential hypertension. METHODS: We
recorded the electrocardiogram, auscultatory sphygmomanometric and continuous
photoplethysmographic finger arterial pressure, and spirometry signals with
patients supine and 70 degrees tilted during controlled (0.25 Hz) breathing.
Cardiovascular autonomic regulation was analyzed with power spectrum analysis of
R-R interval and arterial pressure variability and a spontaneous sequence method
for baroreflex sensitivity. In addition, a deep-breathing test was performed to
assess maximal breathing-related sinus arrhythmia. RESULTS: Transdermal
scopolamine treatment significantly decreased blood pressure both when patients
lay supine and when they were in the 70 degrees tilted position. Scopolamine also
slowed heart rate and increased baroreflex sensitivity and R-R interval high
frequency variability for both body positionings. In addition, scopolamine
accentuated respiratory sinus arrhythmia during deep breathing and blunted the
tilt-induced increase in heart rate. Scopolamine did not affect blood pressure
variability. CONCLUSIONS: Transdermal scopolamine decreases arterial pressure,
increases baroreflex sensitivity and accentuates vagal-cardiac modulation of
sinus node in patients with mild hypertension. Our study supports the hypothesis
that increasing cardiovascular parasympathetic activity could have
antihypertensive effects in essential hypertension.
PMID- 9557927
TI - Enhanced inhibition by melatonin of alpha-adrenoceptor-induced aortic contraction
and inositol phosphate production in vascular smooth muscle cells from
spontaneously hypertensive rats.
AB - OBJECTIVE: To test the hypothesis that the enhanced inhibition by melatonin of
the norepinephrine-induced vasoconstriction and formation of inositol phosphate
in spontaneously hypertensive rats are mediated by its antioxidant effect
METHODS: Aortic rings from spontaneously hypertensive rats and age-matched Wistar
Kyoto rats were used for measuring vascular contraction forces. Cultured aortic
smooth muscle cells were prelabelled with myo-[2-3H]-inositol for evaluation of
formation of inositol phosphate after exposure to agonist or antagonist Basal or
forskolin-induced formation of cyclic AMP was evaluated using a [3H]-cyclic AMP
assay system. Oxygen-derived free radicals were generated with a hypoxanthine and
xanthine oxidase system. RESULTS: The inhibition of the norepinephrine-induced
aortic contraction by melatonin was more potent in spontaneously hypertensive
than it was in Wistar-Kyoto rats. The inhibition of the norepinephrine-induced
formation of inositol phosphate by 0.3-300 micromol/l melatonin was also greater
in smooth muscle cells from spontaneously hypertensive rats than it was in those
cells from Wistar-Kyoto rats. In contrast, the inhibition of the norepinephrine
induced formation of inositol phosphate in smooth muscle cells from spontaneously
hypertensive and Wistar-Kyoto rats by 2-iodomelatonin, an agonist of melatonin
receptors, was not different. Prazosin, but not yohimbine, eliminated or
partially inhibited the norepinephrine-induced formation of inositol phosphate in
smooth muscle cells from Wistar-Kyoto rats or from spontaneously hypertensive
rats, respectively. In the presence both of prazosin and of melatonin, the
norepinephrine-induced production of inositol phosphate was abolished in smooth
muscle cells from spontaneously hypertensive rats. Furthermore, superoxide
dismutase significantly inhibited the norepinephrine-induced aortic contraction
and formation of inositol phosphate in smooth muscle cells from spontaneously
hypertensive rats, but not in those cells from Wistar-Kyoto rats. In contrast,
catalase had no effect on the norepinephrine-induced formation of inositol
phosphate and vascular contraction either in cells from spontaneously
hypertensive rats or in cells from Wistar-Kyoto rats. Hypoxanthine-xanthine
oxidase induced formation of more inositol phosphate in smooth muscle cells from
spontaneously hypertensive rats than it did in those from Wistar-Kyoto rats.
Melatonin and superoxide dismutase similarly inhibited the hypoxanthine-xanthine
oxidase-induced formation of inositol phosphate more in cells from spontaneously
hypertensive rats than it did in those from Wistar-Kyoto rats. However, melatonin
had no effect either on basal or on the forskolin-induced formation of cyclic AMP
in smooth muscle cells from rats of both strains. CONCLUSION: The enhanced
inhibitory effect of melatonin on the norepinephrine-induced cellular production
of inositol phosphate in spontaneously hypertensive rats was not mediated by
melatonin receptors or alpha-adrenoceptors. Rather, the antioxidant effect of
melatonin could become important in spontaneously hypertensive rats, which are
suspected to have a lower cellular content of antioxidants or a greater
sensitivity to superoxide anions, or both, of the vascular tissue.
PMID- 9557926
TI - Forearm vasorelaxation in hypertensive renal transplant patients: the impact of
withdrawal of cyclosporine.
AB - OBJECTIVE: To determine whether cyclosporine A-induced hypertension in renal
transplant recipients is accompanied by impairment of endothelium-dependent
vasodilatation, which has been suggested by in-vitro and in-vivo animal
experiments. DESIGN AND METHODS: In-vivo endothelium-dependent and endothelium
independent vasodilatation, and plasma concentrations of vasoactive hormones in
16 renal transplant patients were determined while they were being treated with
cyclosporine A, and 16 weeks later, after their treatment had been changed to
azathioprine therapy. The vasodilator response of the forearm vascular bed was
measured by strain gauge venous occlusion plethysmography during intra-arterial
infusion of acetylcholine (endothelium-dependent vasodilatation) and
nitroprusside (endothelium-independent vasodilatation). Postischemic reactive
flow was measured after 10 min of arterial occlusion. In addition, plasma
concentrations of norepinephrine, and the prostanoids prostaglandin E2 and
thromboxane B2, and also concentration of cyclosporine A in blood, were measured.
Glomerular filtration rate and renal blood flow were estimated 1 day before the
plethysmography study during each treatment period. RESULTS: Upon changing from
cyclosporine A to azathioprine treatment, mean arterial pressure fell
significantly by 12+/-3% (P< 0.05). Glomerular filtration rate and renal blood
flow increased by 13+/-5 and 19+/-8%, respectively (both P< 0.05), while renal
vascular resistance fell by 48+/-11% (P< 0.01). Both baseline forearm blood flow
and baseline forearm resistance did not change after conversion (5.7+/-0.7 versus
4.9+/-0.6 ml/100 ml/min, and 27.3+/-4.2 versus 26.2+/-3.2 arbitrary units). The
absolute and relative forearm blood flow responses, and forearm vascular
resistance responses to infusions of acetylcholine and nitroprusside were similar
during treatments with cyclosporine A and azathioprine. Peak postischaemic
forearm blood flow was 42+/-12% higher during cyclosporine A treatment than it
was during azathioprine treatment (P< 0.05), but the minimal postischaemic
forearm vascular resistance did not differ for these treatments. Plasma
prostaglandin E2 and thromboxane B2 levels decreased by 34+/-7 and 45+/-8%,
respectively, after changing treatment, but norepinephrine levels did not change.
CONCLUSIONS: Our data indicate that cyclosporine A-induced hypertension in renal
transplant recipients is not accompanied by an increase in forearm vascular
resistance. In addition, changing from cyclosporine A to azathioprine treatment
did not cause changes in endothelial vasodilator functioning, although mean
arterial pressure decreased significantly. Our results do not support the
hypothesis that attenuation of endothelial vasodilator functioning contributes to
the development of cyclosporine A-induced hypertension.
PMID- 9557928
TI - Different effects of calcium antagonists on fluid filtration of large arteries
and albumin permeability in spontaneously hypertensive rats.
AB - OBJECTIVE: To compare the effects of chronic administration of two
dihydropyridines, nifedipine and amlodipine, and the non-dihydropyridine Ca2+
antagonist mibefradil on fluid filtration of large arteries and extravasation of
albumin in spontaneously hypertensive rats. METHODS: Spontaneously hypertensive
rats aged 2 months were randomly allocated to oral treatment once a day with 30
mg/kg mibefradil (n=12), 100 mg/kg nifedipine (n=12), 20 mg/kg amlodipine (n=12)
or placebo (n=12) for 1 month. Instantaneous blood pressure of rats under
pentobarbital anaesthesia was recorded at the end of the treatment Fluid
filtration across the carotid arterial wall was determined in situ in the
isolated carotid artery. Extravasation of 25 mg/kg Evans Blue dye that had been
injected intravenously was used to assess whole vascular permeability to albumin
after chronic treatment with mibefradil. RESULTS: Similar reductions in mean
arterial pressure were obtained in all Ca2+ antagonist-treated rats. Heart rate
was similar in rats in control, nifedipine and amlodipine groups but was
significantly lower in mibefradil-treated rats (by 19%, P< 0.001). Fluid
filtration across the carotid wall was greater in all Ca2+ antagonist-treated
animals. However, fluid filtration was significantly less in mibefradil-treated
rats than it was in nifedipine-treated, and amlodipine-treated rats. Furthermore,
administration of mibefradil did not significantly modify extravasation of
albumin in all tested tissues (pancreas, testis, spleen, lung, kidney, intestine,
liver, skeletal muscle) except for cardiac and brain tissues, in which the
permeability of albumin was increased by 24 and 33%, respectively, compared with
values for the control group (P < 0.05). CONCLUSION: These results indicate that
Ca2+ antagonists increase fluid filtration through large arteries from
spontaneously hypertensive rats. That the lower fluid filtration in mibefradil
treated rats was associated with no change in extravasation of albumin in most
tissues and especially in skeletal muscle suggests that vascular permeability in
hypertensive rats was impaired less by mibefradil treatment than it was by
dihydropyridine Ca2+ antagonist treatments.
PMID- 9557929
TI - A study of the interactive effects of oral contraceptive use and dietary fat
intake on blood pressure, cardiovascular reactivity and glucose tolerance in
normotensive women.
AB - OBJECTIVE: To investigate the interactive effects of oral contraceptive pill use
and dietary fat intake on cardiovascular haemodynamics and metabolic parameters
in young normotensive women. DESIGN: Thirty-two women participated, of whom 16
were taking oral contraceptive pills (ethinyl-oestradiol plus levonorgestrel) and
16 were age-matched and weight-matched controls not taking such pills. Subjects
consumed either a high-fat or a low-fat diet for 2 weeks in an open, randomized,
crossover study lasting 6 weeks. Investigations were performed at the end of each
diet during the luteal phase of the menstrual cycle. METHODS: Blood pressure was
measured by 24 h ambulatory recording; cardiovascular reactivity was determined
by examining blood pressure responses to systemic infusions of noradrenaline and
angiotensin II and to the cold pressor test; and carbohydrate metabolism was
investigated by an intravenous glucose-tolerance test. RESULTS: Plasma
triglyceride levels were significantly higher in women taking oral contraceptive
pills compared with non-users on both diets; however, responses of lipoprotein
levels to the two diets did not differ between study groups (total and low
density lipoprotein cholesterol levels decreased by 15 and 17% in oral
contraceptive pill users and by 14% each in non-users, on the low-fat compared
with the high-fat diet). Fasting plasma insulin levels, the insulin-production
response to administration of glucose (insulin area under the curve) and resting
clinic and night-time systolic blood pressures were all significantly reduced on
the low-fat diet, but only in non-users. Blood pressure responses to
noradrenaline and maximal heart rate response to cold were significantly
attenuated during the low-fat diet in oral contraceptive pill users. During the
low-fat diet, resting systolic, 24 h systolic and diastolic blood pressures and
insulin area under the curve were all significantly higher for women taking the
oral contraceptive pills. Users of these pills also exhibited a greater systolic
sensitivity to administration both of noradrenaline and of angiotensin II and had
a higher plasma renin activity irrespective of dietary phase. CONCLUSIONS: These
results confirm that oral contraceptive pills have the potential to cause adverse
effects on blood pressure, cardiovascular reactivity and the insulin-production
response to administration of glucose and suggest that some of the beneficial
effects of a low-fat diet on these parameters may be negated in women taking oral
contraceptive pills.
PMID- 9557930
TI - The impact of genetic hypertension on insulin secretion and glucoregulatory
control in vivo: studies with the TGR(mRen2)27 transgenic rat.
AB - OBJECTIVE: To examine the associations among hypertension, insulin secretion,
glucose tolerance and insulin resistance in vivo. DESIGN: Glucose tolerance and
insulin secretion during an intravenous glucose tolerance test and action of
insulin on whole-body glucose kinetics in the post-absorptive state and during
hyperinsulinaemia were examined in conscious, unrestrained TGR(mRen2)27 rats and
age-matched transgene-negative controls. METHODS: Glucose tolerance and insulin
secretion were examined after intravenous administration of 500 mg glucose/kg
body weight. Endogenous glucose production and whole-body glucose disposal were
estimated using [3-3H]-glucose during euglycaemic-hyperinsulinaemic clamping.
Muscle glucose utilization was estimated using 2-deoxy-[1-3H]-glucose. RESULTS:
Despite there being higher insulin levels, whole-body glucose turnover was
significantly lower in post-absorptive TGR(mRen2)27 rats than it was in transgene
negative controls. This was associated with significant suppression of glucose
uptake/phosphorylation by oxidative skeletal muscles. TGR(mRen2)27 rats also
exhibited significantly lower blood glucose levels, higher plasma insulin levels
and higher rates of disappearance of glucose after intravenous administration of
glucose. During hyperinsulinaemia, steady-state glucose infusion rates required
to maintain euglycaemia in TGR(mRen2)27 rats were significantly greater,
indicating that an increase in whole-body action of insulin had occurred. This
was due to significantly greater suppression of endogenous production of glucose:
insulin-stimulated glucose disposal rates did not differ significantly between
the two groups. CONCLUSIONS: The results indicate that TGR(mRen2)27 rats have an
enhanced and sensitized insulin-secretory response to glucose, together with a
greater than normal hepatic action of insulin. Insulin-mediated glucose disposal
was not impaired. The results therefore do not support the hypothesis that
hypertension plays a primary role in the development of insulin resistance.
PMID- 9557931
TI - Angiotensin converting enzyme inhibition modulates cardiac fibroblast growth.
AB - BACKGROUND: The progression of left ventricular hypertrophy and cardiac fibrosis
in hypertensive heart disease is influenced by sex and age. Although angiotensin
converting enzyme inhibition has been shown to prevent progression of the disease
in postmenopausal women, the interaction of angiotensin II and estrogen in this
process before and after the menopause is poorly understood. OBJECTIVE: To
investigate the influence of the angiotensin converting enzyme inhibitor
moexiprilat on serum, estrogen and angiotensin II-induced cardiac fibroblast
growth. METHODS: Neonatal rat cardiac fibroblasts were incubated with 1 and 10%
fetal calf serum, 10(-7) mol/l angiotensin II, 10(-9) mol/l estrone, 10(-9) mol/l
17beta-estradiol and 10(-8) mol/l moexiprilat. Proliferation was measured in
terms of incorporation of bromodeoxyuridine. Western blot analysis was performed
using antibodies directed against the growth-related immediate early genes c-fos
and Sp-1. All experiments were performed at least three times. RESULTS: Fetal
calf serum stimulated cardiac fibroblast proliferation (1% fetal calf serum 2.0+/
0.028-fold; 10% fetal calf serum 2.7+/-0.028-fold). Angiotensin II and estrone
stimulated proliferation of cardiac fibroblasts grown in the absence of fetal
calf serum (angiotensin II 4.2+/-0.075-fold; estrone 2.9+/-0.034-fold) and
further increased proliferation in the presence of 1% fetal calf serum
(angiotensin 11 4.3+/-0.072-fold); estrone 3.8+/-0.045-fold) and 10% fetal calf
serum (angiotensin II 4.8+/-0.112-fold; estrone 4.1+/-0.047-fold). Coincubation
with moexiprilat specifically inhibited proliferation induced by angiotensin II
and estrone but not by serum, and angiotensin II type 1 receptor blockade
inhibited angiotensin II-induced but not estrone-induced cell growth. Western
blot analysis showed that the expression of c-fos and Sp-1 was induced in a time
dependent fashion by angiotensin II (to maxima of 5.0-fold for c-fos and 3.0-fold
for Sp-1) and estrone (15.2-fold for c-fos and 6.2-fold for Sp-1). This effect
was completely inhibited by moexiprilat. CONCLUSIONS: Angiotensin converting
enzyme inhibition modulates cardiac fibroblast growth induced by angiotensin II
and estrone. This mechanism might contribute to the beneficial effects of
angiotensin converting enzyme inhibition in postmenopausal patients with
hypertensive heart disease.
PMID- 9557932
TI - Renal response to the angiotensin II receptor subtype 1 antagonist irbesartan
versus enalapril in hypertensive patients.
AB - OBJECTIVE: To compare the acute and sustained renal hemodynamic effects on
hypertensive patients of 100 mg irbesartan and 20 mg enalapril each once daily.
PATIENTS: Twenty patients (aged 35-70 years) with uncomplicated, mild-to-moderate
essential hypertension and normal serum creatinine levels completed this study.
STUDY DESIGN: After random allocation to treatment (n=10 per group),
administration schedule (morning or evening) was determined by further random
allocation, with crossover of schedules after 6 weeks' therapy. Treatment and
administration assignments were double-blind. Twenty-four-hour ambulatory blood
pressure was monitored before and after 6 and 12 weeks of therapy. Renal
hemodynamics were determined on the first day of drug administration and 12 and
24 h after the last dose during chronic treatment. RESULTS: Administration of
each antihypertensive agent induced a renal vasodilatation with no significant
change in glomerular filtration rate. However, the time course appeared to
differ: irbesartan had no significant acute effect 4 h after the first dose, but
during chronic administration a renal vasodilatory response was found 12 and 24 h
after the dose; enalapril was effective acutely and 12 h after administration,
but no residual effect was found 24 h after the dose. Both antihypertensive
agents lowered mean ambulatory blood pressure effectively, with no significant
difference between treatments or between administration schedules (morning versus
evening). CONCLUSIONS: Irbesartan and enalapril have comparable effects on blood
pressure and renal hemodynamics in hypertensive patients with normal renal
functioning. However, the time profiles of the renal effects appear to differ,
which might be important for long-term renoprotective effects.
PMID- 9557934
TI - Is hyperinsulinaemia during withdrawal of ethanol due to an increase in secretion
of insulin or a decrease in clearance of insulin?
PMID- 9557933
TI - Assessment of control of hypertension in the population.
PMID- 9557935
TI - Stage-related chondrogenic potential of human limb bud mesenchyme cells, in
vitro: role of protein kinase C.
PMID- 9557936
TI - Extracellular matrix interferes with colorimetric estimation of cell number.
PMID- 9557937
TI - Fibronectin production by cultured human lung fibroblasts in three-dimensional
collagen gel culture.
AB - In vivo, fibroblasts are distributed in a three-dimensional (3-D) connective
tissue matrix. Fibronectin is a major product of fibroblasts in routine cell
culture and is thought to regulate many aspects of fibroblast biology. In this
context, we sought to determine if the interaction of fibroblasts with a 3-D
matrix might affect fibronectin production. To examine this hypothesis,
fibronectin production by fibroblasts cultured in a 3-D collagen gel or on
plastic dishes was measured by ELISA. Fibroblasts in 3-D gel culture produced
more fibronectin than those in monolayer culture. Fibroblasts in 3-D culture
produced increasing amounts of fibronectin when the collagen concentration of the
gel was increased. The 3-D nature of the matrix appeared to be crucial because
plating the fibroblasts on the surface of a plastic dish underneath a collagen
gel was not different from plating them on a plastic dish in the absence of
collagen. In addition to increased fibronectin production, the distribution of
the fibronectin produced in 3-D culture was different from that of monolayer
culture. In monolayer culture, more than half of the fibronectin was released
into the culture medium. In 3-D culture, however, approximately two-thirds
remained in the collagen gel. In summary, the presence of a 3-D collagen matrix
increases fibroblast fibronectin production and results in greater retention of
fibronectin in the vicinity of the producing cells.
PMID- 9557938
TI - Culture of human main pancreatic duct epithelial cells.
AB - Attempts to grow human pancreatic duct epithelial cells in long-term culture have
proven difficult. We have developed a system of growing these cells for several
passages by adapting methods used to culture dog pancreatic duct cells.
Epithelial cells were enzymatically dissociated from the main pancreatic duct and
plated onto collagen-coated culture inserts suspended above a human fibroblast
feeder layer. After primary culture, the cells were either passaged onto new
inserts or plastic tissue culture plates in the absence of collagen. Cells grown
on the latter plates were maintained in a serum-free medium. Primary pancreatic
duct epithelial cells grow steadily to confluence as a monolayer in the feeder
layer system. After primary culture, cells passaged onto new inserts with fresh
feeder layer or plastic plates and fed with serum-free medium continued to
develop into confluent monolayers for up to four passages. The cells were
columnar with prominent apical microvilli, sub-apical secretory vesicles, and
lateral intercellular junctions resembling the morphology of normal in vivo
epithelial cells. These cells were also positive for cytokeratin 19, 7, and 8 and
carbonic anhydrase II, as measured by immunohistochemistry. Metabolically, these
cells synthesized and secreted mucin, as measured by incorporation of tritiated N
acetyl-D-glucosamine. In conclusion, we demonstrated that human pancreatic
epithelial cells from the main duct can be successfully grown in culture and
repeatedly passaged using a feeder layer system, with serum-free medium, and in
organotypic cultures.
PMID- 9557940
TI - Properties of a polarized primary culture from rat renal inner medullary
collecting duct (IMCD) cells.
AB - A primary culture from rat renal IMCD cells was established to investigate the
permeability characteristics of the luminal and contraluminal plasma membranes of
the papillary collecting duct in vitro. Freshly isolated IMCD cells were grown on
filters in a special "epithelial cell" medium. Confluency was proved with an
epithelial volt/ohm meter. After 7 d of culture the transepithelial resistance
reached more than 1000 omega x cm2. A polarization of the cells with regard to a
basolateral localization of a lactate efflux system, and an L-alanine transport
system was achieved. The hypotonicity-activated release systems for the organic
osmolytes sorbitol and betaine were also located basolaterally, whereas taurine,
glycerophosphorylcholine, and myo-inositol left the cells at both cell poles but
with different capacity. Morphological observations revealed also that the
monolayer was well differentiated. Thus, a model of a renal collecting duct
epithelium was established which can be used to analyze polarized and
differentiated transport processes across the epithelial cells and their plasma
membranes.
PMID- 9557939
TI - A comparative molecular analysis of four rat smooth muscle cell lines.
AB - Transcriptional regulation of smooth muscle cell (SMC) differentiation is a
rapidly growing area of interest that has relevance for understanding intimal
disease. Despite the wealth of data accumulating in vitro, however, no study has
compared the cell-specific marker profile, transfectability, promoter activity,
and growth characteristics among several SMC culture systems. Accordingly, we
performed a comprehensive analysis of the marker profile, growth properties,
transfectability, and SMC promoter activity in four rat SMC lines (A7r5, adult
and pup aortic, and PAC1). Despite alterations in chromosomal number and
structure, A7r5, adult aortic, and PAC1 cells express all SMC markers studied
including SM alpha-actin, SM calponin, SM22, tropoelastin, and to a lesser
extent, SM myosin heavy chain (SMMHC). In contrast, pup aortic cells express very
low or undetectable levels of all the above markers except tropoelastin. Adult
aortic, pup, and PAC1 cells display similar growth curves and levels of proto
oncogene transcripts, whereas those in the A7r5 line are comparatively less. All
cell lines studied except pup cells show expression of SMC differentiation genes
during active growth, indicating that growth and differentiation are not mutually
exclusive in cultured smooth muscle. Transfection studies reveal dramatic
differences in DNA uptake and SMC-restricted promoter activity between cell
lines. Collectively, these results provide detailed information relating to SMC
molecular biology in culture that should facilitate the selection of a cell line
for studying the transcriptional regulatory mechanisms underlying SMC
differentiation.
PMID- 9557941
TI - Ligand-dependent and -independent interactions with the transforming growth
factor type II and I receptor subunits reside in the aminoterminal portion of the
ectodomain of the type III subunit.
AB - The type III receptor for transforming growth factor beta (TGFbeta), which
exhibits no kinase activity, binds TGFbeta1 and TGFbeta2 and is involved in
assembly and activity of the multi-subunit TGFbeta signal transduction complex.
Recently we showed that TGFbeta receptor type III (TbetaRIII) can participate in
a complex composed of the dimeric TGFbeta ligand and a type III, II, and I
receptor subunit. The interaction of the TbetaRIII subunit with TbetaRII is
TGFbeta-dependent, whereas interaction with TbetaRI is TGFbeta-independent. Here
we use coexpression of the three types of TGFbeta receptors in baculoviral
infected insect cells to determine which parts of the unglycosylated TbetaRIII
receptor participate in the binding of TGFbeta, the TGFbeta-dependent interaction
with TbetaRII and the TGFbeta-independent interaction with TbetaRI. The results
suggest that the first 500 amino acid residues in the aminoterminal portion of
TbetaRIII exhibit all three properties.
PMID- 9557942
TI - Application and evaluation of the alamarBlue assay for cell growth and survival
of fibroblasts.
AB - Cell proliferation assays are essential to developing an understanding of the
molecular mechanisms that modulate cell growth and differentiation. In this
paper, we describe the application of alamarBlue, a new and versatile metabolic
dye, for the detection of Swiss 3T3 fibroblast proliferation and/or survival. As
a redox indicator, alamarBlue is reduced by reactions innate to cellular
metabolism and, therefore, provides an indirect measure of viable cell number.
Various assay parameters were optimized for a 96-well format to achieve a
detectable range of fibroblast cell number from 100 to 20,000 cells/well, which
is similar to that obtained with traditional (3-(4,5-dimethylthiazol-2-yl)-2,5
diphenyl tetrazolium bromide (MTT) and [3H]thymidine assay techniques. Standard
(reference) curves generated with a known fibroblast stimulator were used to
facilitate quantitation and comparison of unknown test substances. The alamarBlue
assay offers the advantages of technical simplicity, freedom from radioisotopes,
versatility in detection, no extraction, and excellent reproducibility and
sensitivity. We anticipate that this simple and versatile alamarBlue assay, when
used alone or in conjunction with other bioassays, will be a useful tool for
investigating the complex mechanisms of cellular proliferation.
PMID- 9557944
TI - Effects of H2O2 on the growth, secretion, and metabolism of hybridoma cells in
culture.
AB - The effect of low concentrations of hydrogen peroxide (H2O2) (5 x 10(-7)-9.5 x
10(-7) M) on cell growth and antibody production was investigated with murine
hybridoma cells (Mark 3 and anti-hPL) in culture. Cell growth, measured by flow
cytometry with morphological parameters, was significantly stimulated by H2O2 (8
x 10(-7) M) but H2O2 concentration of 7 x 10(-6) M and above increased cell
death. H2O2 stimulation of antibody production was nonsignificant. The metabolism
of cells treated with 8 x 10(-7) or 1 x 10(-5) M H2O2 was similar to that of the
control in terms of glucose and glutamine consumption, lactate and ammonia
production, and amino acid concentrations in the medium. The concentrations of
lactate dehydrogenase, a marker of cell death, in test and control cells were
similar. However, concentrations of intracellular free radicals measured by flow
cytometry with dihydrorhodamine 123 (DHR 123) and dichlorofluorescein diacetate
(DCFH-DA) as fluorochromes were different. The reactive oxygen species content of
cells in 8 x 10(-7) M H2O2 was similar to that of the controls, but there was a
sudden, marked production of superoxide anions (detected with DHR 123) and H2O2
or peroxides (detected with DCFH-DA) by cells incubated with 1 x 10(-5) M H2O2
which increased with increasing H2O2 until cell death.
PMID- 9557943
TI - Maturation-dependent gene expression in a conditionally transformed liver
progenitor cell line.
AB - We have isolated a conditionally transformed liver progenitor cell line with
phenotypic similarities to both hepatoblasts (bipotent embryonic liver cells that
give rise to hepatocytes and intrahepatic biliary epithelial cells) and liver
epithelial cells (primitive hepatic cells isolated from adult livers capable of
generating both hepatocytic and biliary lineages). Cell line L2039 was derived
from E14 fetal mouse liver after transformation with temperature-sensitive SV-40
large T antigen. At 33 degrees C, these cells have an epithelial morphology with
a high nucleocytoplasmic ratio and express both hepatocytic and biliary genes,
including albumin, alpha-fetoprotein, glutamine synthetase, insulinlike growth
factor II receptor, fibronectin and laminin, and cytokeratins 8 and 19, a set of
markers characteristic for hepatoblasts. The presence of cytokeratin 14,
vimentin, and several oval-cell antigens link cell line L2039 to nonparenchymal
liver epithelial cell populations thought to contain progenitor cells. Serum
free, hormonally defined media conditions and extracellular matrix requirements
were determined for growth and differentiation of this cell line. During culture
on type IV collagen at 39 degrees C, L2039 cells cease dividing and demonstrate
hepatocytic differentiation with the assumption of a hepatocytelike morphology
and glucocorticoid-dependent regulation of liver-specific genes, including
albumin, alpha-fetoprotein, phosphoenolpyruvate carboxykinase, and liver-enriched
transcription factors. The number of albumin-positive cells increases during
culture at 39 degrees C, indicating that L2039 cells convert from a
prehepatocytic to a hepatocytic phenotype. Under conditions specific for
hepatocytic differentiation, C/EBPs were expressed and differentially regulated,
with C/EBPbeta and C/EBPdelta upregulated early and C/EBPalpha only slightly
expressed after 7 d, indicating that C/EBPalpha may not be a crucial factor in
commitment to the hepatocytic phenotype.
PMID- 9557945
TI - Prostaglandins act as neurotoxin for differentiated neuroblastoma cells in
culture and increase levels of ubiquitin and beta-amyloid.
AB - Although chronic inflammatory reactions have been proposed to cause neuronal
degeneration associated with Alzheimer's disease (AD), the role of prostaglandins
(PGs), one of the secretory products of inflammatory reactions, in degeneration
of nerve cells has not been studied. Our initial observation that PGE1-induced
differentiated neuroblastoma (NB) cells degenerate in vitro more rapidly than
those induced by RO20-1724, an inhibitor of cyclic nucleotide phosphodiesterase,
has led us to postulate that PGs act as a neurotoxin. This study has further
investigated the effects of PGs on differentiated NB cells in culture. Results
showed that PGA1 was more effective than PGE1 in causing degeneration of
differentiated NB cells as shown by the cytoplasmic vacuolation and fragmentation
of soma, nuclei, and neurites. Because increased levels of ubiquitin and beta
amyloid have been implicated in causing neuronal degeneration, we studied the
effects of PGs on the levels of these proteins during degeneration of NB cells in
vitro by an immunostaining technique, using primary antibodies to ubiquitin and
beta-amyloid. Results showed that PGs increased the intracellular levels of
ubiquitin and beta-amyloid prior to degeneration, whereas the degenerated NB
cells had negligible levels of these proteins. These data suggest that PGs act as
external neurotoxic signals which increase levels of ubiquitin and beta-amyloid
that represent one of the intracellular signals for initiating degeneration of
nerve cells.
PMID- 9557946
TI - Molecular models of two competitive inhibitors, IL-2delta2 and IL-2delta3,
generated by alternative splicing of human interleukin-2.
AB - Molecular models of IL-2delta2 and IL-2delta3, two alternative splice variants of
human IL-2 without exon 2 and 3, respectively, are described. These alternative
splice variants attract particular interest as potential competitive inhibitors
of the cytokine. Tertiary structure of IL-2 consists of four-helix bundle
including helices A, B, C and D and a beta-pleated sheet. Exon 2 encodes the A-B
loop (Asn30-Lys49 residues) linking helices A and B running in one direction.
Rotation of the helix A around putative centre during the construction of IL
2delta2 model have not produced any significant changes in the hydrophobic core
of IL-2 molecule. However, a large hole was formed on the surface of IL-2delta2
molecule instead of A-B loop in IL-2 fold. A high affinity IL-2 receptor is
formed by combination of alpha, beta, and gamma(c) chains. Comparison of the
model of the receptor bound IL-2 with the model of IL-2delta2 has shown that
their beta-chain binding sites have minimum differences as distinct from alpha
and gamma(c) chain-binding sites. Exon 3 encodes Ala50-Lys97 fragment which forms
helices B and C with their short connecting loop. Model IL-2delta3 consists of
helices A and D and long linking loop. This loop was composed of A-B and C-D
loops which run in opposite directions in IL-2 structure and contain beta-strands
making a beta-pleated sheet. Conformation of the linking loop relatively to
helices A and D was stabilized by creation of a disulphide bond between cysteines
105 and 125. In addition, the hydrophobic residues of beta-sheet interact with
the hydrophobic surface of A-D helical complex and close the latter from contacts
with solution. Comparison of the model of IL-2 bound to receptor with IL-2delta3
model has shown that absence of helices B and C in IL-2delta3 model results in
insignificant conformational changes only in residues interacting with gamma(c)
chain of the receptor. The beta/gamma(c) heterodimer is an intermediate affinity
receptor of IL-2. Most likely, both IL-2delta2 and IL-2delta3 are naturally
occurring IL-2 antagonists since they keep the ability of binding with an
intermediate affinity receptor of this cytokine and fail to engage the alpha
chain of its high affinity receptor.
PMID- 9557947
TI - Human extracellular proteins display a different pattern of local sequence
similarity with the four classes of human T-cell receptor V-regions than foreign
proteins and human intracellular proteins: a preliminary report.
AB - A pool of 110 randomly selected/generated amino acids sequences was used to
perform specific local sequence similarity alignment analysis with the pool of
279 reported sequences of human T-cell receptor (TCR) V-regions. The 110 analyzed
sequences were divided, according to their origin and nature, into six protein
groups, as: human intracellular (hi), extracellular/transmembrane (he) and
extracellular adhesive matrix (ha) proteins, 'average' human proteins (hum),
proteins of non-human origin (nhum) and randomly generated quasi-protein
sequences (r). These sequences were decomposed into all their overlapping 11-mer
segments, generating a total of 56,836 derived peptides (at least 8000 per
group). Each derived peptide was aligned with the 279 human TCR V-regions and
assigned to the category (alpha-like, beta-like, gamma-like or delta-like)
corresponding to the class (V alpha, Vbeta, Vgamma or Vdelta) of the V-region
encompassing the most similar segment, as determined by the performed similarity
search. The six protein groups were found to differ significantly in their
distribution of derived peptides among the four categories. According to the
binomial tests results, human proteins from the extracellular compartment (he,
ha) comprise a higher proportion of delta-like segments (P = 2.3 x 10(-2) and P <
10(-8), respectively) than the 'average' human proteins (hum). In addition, and
in accordance with this finding, proteins that are normally not found in that
topological compartment comprise a lower proportion of delta-like peptides (P =
1.4 x 10(-5) and P < 10(-8) for groups nhum and hi, respectively) than the
'average' human proteins (hum). In contrast, these proteins comprise a higher
proportion of gamma-like segments (P = 8.3 x 10(-3), P = 1.4 x 10(-3) and P = 1.7
x 10(-4), for groups r, nhum and hi, respectively) than the 'average' human
proteins (hum). These findings indicate significant differences between proteins
encountered in the extracellular compartment--that are normally immunologically
tolerated--and those the presence of which is usually non-tolerated. The results
suggest that the discrimination and the reaction of the human immune network to
proteins found in the extracellular compartment correlate with the proteins'
pattern of preferential local sequence similarity with the Vgamma and Vdelta
classes of human TCR V-regions, implying a specific and an important role of
gammadelta-cells in the maintenance of the immune homeostasis. Whether this
implication represents a rule associated with self-tolerance, will be
investigated by future analyses.
PMID- 9557948
TI - Effect of PGE2 on the cell surface molecule expression in PMA treated thymocytes.
AB - PGE2 is produced by cells of the thymic microenvironment. The effects of PGE2 are
mediated by cAMP through binding to its intracellular receptor protein kinase A
(PKA). Phorbol 12-myristate 13-acetate (PMA) is known to modulate CD molecule
expression on thymocytes, probably through activation of protein kinase C (PKC).
We have hypothesized that cross-talk between these two signalling pathways may
affect modulation of the CD molecules on the cell surface of thymocytes. For this
purpose, we compare the effects of PMA alone or combined with PGE2 on CD3, CD4
and CD8 expression on mouse thymocytes by flow-cytometric analysis. PMA treatment
almost completely abolished CD4 expression and slightly decreased CD3 and CD8
expression. PGE2 alone did not change the CD3, CD4 and CD8 molecule expression.
Combined with PMA, PGE2 can overcome the decrease induced by PMA of the CD3
expression and partially reduced the disappearance of the CD4 molecule. On the
other hand PGE2 accelerated the loss of CD8 molecule expression. These events
occurred only in CD4+ CD8+ immature thymocytes. An analogue of cAMP (dibutyryl
cAMP) mimics the effect of PGE2, but not Br-cGMP. This differential regulation by
PGE2 of the CD molecule expression on immature thymocytes may provide additional
evidence on the role of PGE2 during the process of thymic differentiation.
PMID- 9557949
TI - Activation of influenza-specific memory cytotoxic T lymphocytes by Concanavalin A
stimulation.
AB - Traditionally, the in vitro activation of virus-specific memory cytotoxic T
lymphocytes (CTLs) has been achieved by stimulating the CTLs with antigen
presenting cells (APCs) infected with an appropriate virus or pulsed with virus
specific antigenic peptides. Here, we describe the utilization of the polyclonal
activator Concanavalin A (ConA) for in vitro restimulation of memory CTLs from
virus-primed mice. Using this simple method, the activation of splenocytes with
ConA for 3 days (i) eliminates the need to stimulate with virus-pulsed APCs and
(ii) generates CD8+ CTLs that exhibit virus specificity and MHC-restricted lytic
activity similar to CTLs obtained by conventional viral restimulation. In vitro
ConA stimulation of splenocytes from BALB/c mice primed with the A/Texas/77 or
A/Japanese/57 strain of influenza virus and from C57L/J mice infected with the
A/Texas strain, generated CTLs with specific lytic activity. Hence reactivation
of memory CTLs by this method is a general phenomenon rather than a mouse or
viral strain-specific one. The ConA stimulation method used here had a recall of
long-term (1 year) memory CTLs that effectively lysed virally infected targets.
Further ConA-stimulated effector lymphocytes from virally primed animals have
been shown to recognize and subsequently lyse target cells pulsed with virus or
virus-derived peptides. The ConA reactivation of specific anti-viral CTLs may
facilitate (i) studying anti-viral CTL responses and (ii) identifying of viral
epitopes when unknown or when appropriate viral stimulation is impossible.
PMID- 9557950
TI - Purification and characterization of lipopolysaccharide induced TNF-like factor
from rabbit serum.
AB - A TNF-like factor was purified from lipopolysaccharide (LPS) induced New Zealand
white rabbit serum. The TNF-like factor was purified by DEAE-Sephacel, Sephacryl
S-200, Mono-Q, CM-affi gel Blue, Superose 12 H/R preparative columns to the
specific activity of 4 x 10(6) U/mg protein. The purified protein was 45 kDa in
its oligomeric form and 22 kDa in its monomeric form. Rabbit TNF-like factor had
a pI value of 5.0 and was resistant to trypsin digestion. The TNF-like factor
reacted with polyclonal-Ab against human TNFalpha on immunoblot and
immunoprecipitation analysis and interacted with human TNF receptors. Taken
together, rabbit TNF-like factor might be a high molecular weight form of rabbit
TNFalpha.
PMID- 9557951
TI - Signalling initiated with CD4-TCR or TCR-TCR interactions: comparison of tyrosine
phosphorylation patterns and CD45 effects.
AB - Antigen-triggered response in T cells is mediated by the T cell receptor
(TCR)/CD3-complex. This signalling, however, is modulated by a number of other
surface molecules. Among the most important of these is the CD4/CD8 molecule
which associates with the TCR/CD3-complex and binds to the MHC complex. The
molecular mechanisms involved in interactions between TCR-TCR and TCR-CD4 are not
fully understood. We have earlier described an experimental model that allows us
to dissect signals involving CD4-TCR interactions and those involving TCR-TCR
interactions using a mouse CD4-CD8- T cell hybridoma cell-line transfected either
with the TCR from a mouse T-helper 2 cell-line (D10) alone or with both the TCR
and the CD4 molecule. To further characterize these two different modes of
signalling in T lymphocytes we have studied the tyrosine phosphorylation patterns
resulting from these interactions. In addition, we have studied the modulatory
effect of the CD45 molecule on these interactions. In contrast to some earlier
reports, we found that both the patterns of induced tyrosine phosphorylation and
the effects of CD45 modulation were essentially similar in the CD4-TCR and the
TCR-TCR signal transduction cascades. The results are consistent with a purely
synergistically amplifying function for CD4 on the TCR-mediated signalling.
PMID- 9557952
TI - Nucleotide sequence analysis of a human monoclonal antibody 22-13 reactive with
lung tumor-associated antigen.
AB - A human monoclonal antibody (HuMAb) 22-13 (IgG1, kappa) recognizes a cytoplasmic
antigen associated primarily with human lung tumors. This study reports the
primary nucleotide and deduced amino acid sequences of the rearranged heavy and
light chains of the HuMAb 22-13. This HuMAb uses a VH gene member of the V(H)Ia
gene family, 51P1 and is productively rearranged with a D-D fusion product of the
D(LR)2 and D(XP)2 germ line DH genes and the germ line JH3 gene. HuMAb 22-13
Vkappa belongs to the kappa light chain variable subgroup IIIb family and appears
to be derived from the Humkv325 germ line gene and is rearranged with a germ line
Jkappa5 gene. The results reveal that production of a HuMAb 22-13 is achieved by
rearrangement of the 51P1/Humkv325 germ line variable region gene combination,
associated with the autoimmune repertoire and that HuMAb 22-13 has a striking
sequence homology to rheumatoid factors (RFs) of the Wa idiotypic family. HuMAb
22-13 and Wa RFs have in common V(H)Ia and VkappaIIIb gene segments, but use
different DH, JH and Jkappa gene segments. However, in spite of this structural
similarity, HuMAb 22-13 does not display rheumatoid factor activity. Taken
together with the reported findings, these data indicate the representation of
the shared usage of highly homologous variable region genes in entirely different
humoral immune responses in the human system.
PMID- 9557953
TI - Antibody reactivity to conserved linear epitopes of Plasmodium falciparum
erythrocyte membrane protein 1 (PfEMP1).
AB - The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family of
protein antigens are involved in adhesion of P. falciparum infected erythrocytes
to the capillary endothelium of the host. Antibodies to variable regions of these
proteins, measured by agglutination, correlates with clinical protection against
falciparum malaria. In this study we investigated the occurrence of antibodies to
conserved sequences of these very variable proteins in a population living in an
area endemic for falciparum malaria. Using the ELISA method, we were able to
measure an antibody response to three synthetic peptides derived from conserved
regions of PfEMP1. The antibody responses to these peptides increased with age
and were higher in individuals with asymptomatic P. falciparum infection compared
to individuals presenting with fever attributable to falciparum malaria. This
indicates that antibodies recognising the conserved regions of PfEMP1 arise upon
exposure to the parasite, and that these may be involved in the development of
protection against malaria. Antibodies to the Pfalhesin peptide of the human
aniontransporter, band3, were measured by the same method. The magnitude of this
antibody response did not correlate with neither age nor clinical protection.
PMID- 9557954
TI - A hemagglutinin-based multipeptide construct elicits enhanced protective immune
response in mice against influenza A virus infection.
AB - Multipeptide constructs, comprising adjacent sequences of the 317-341
intersubunit region of immature influenza A hemagglutinin (H1N1), were designed
and the functional properties of these branched peptides were compared to that of
the corresponding linear peptides. In vivo studies revealed that the
immunogenicity of the peptides was dependent on the presence of the hydrophobic
fusion peptide (comprised in FP3), encompassing the N-terminal 1-13 sequence of
the HA2 subunit. Antibody and T cell recognition, however, was directed against
the 317-329 HA1 sequence, comprised in the P4 peptide. Multiple copies of P4,
covalently linked by branched lysine residues, significantly enhanced the
efficiency of antibody binding and the capacity of peptides to elicit B- and T
cell responses. A fraction of peptide induced antibodies reacted with immature or
with proteolitically cleaved hemagglutinin (HA) molecules pretreated at low pH.
Immunization with a multipeptide construct, (P4)4-FP3, not only resulted in
elevated antibody and T cell responses but conferred enhanced protection against
lethal A/PR/8/34 (H1N1) infection as compared to its subunit peptides. The
beneficial functional properties of this artificial peptide antigen may be
acquired by multiple properties including: (i) stabilized peptide conformation
which promotes strong, polyvalent binding to both antibodies and MHC class II
molecules; (ii) appropriate P4 conformation for antibody recognition stabilized
by the covalently coupled fusion peptide, resulting in the production of virus
cross reactive antibodies which inhibit the fusion activity of the virus; (iii)
activation of peptide specific B cells which potentiate antigen presentation and
peptide specific T cell responses; and (iv) generation of helper T cells which
secrete lymphokines active in the resolution of infection.
PMID- 9557955
TI - Lack of IL-1 receptor antagonistic activity of the capsular F1 antigen of
Yersinia pestis.
AB - Because capsular F1 antigen of Yersinia pestis is reported to share sequence
homology with interleukin-1 receptor antagonist (IL-1ra), we investigated the
potential IL-1 receptor antagonistic activity of F1 on human endothelial cells
(EC). The biological activities of IL-1 receptor antagonist (IL-1ra) or IL-1ra
like molecule were measured by its ability to suppress the IL-1beta-mediated
induction of adhesion molecules (ICAM and ELAM) on EC and of IL-6 secretion by
these cells. Two different, purified, immunogenic and biologically active
preparations of F1, at concentrations up to 10-fold higher than that of IL-1ra,
did not exhibit any inhibitory activities of IL-1ra. These F1 preparations also
did not activate peripheral blood mononuclear cells to produce IL-4 or IL-10,
cytokines which might downregulate pro-inflammatory cytokine production in
response to infection. Thus, even though there is a high degree of similarity
between F1 antigen and IL-1ra in three-dimensional structure by computer modeling
and sequence homology, our work indicates that F1 antigen of Y. pestis does not
have IL-1ra-like activity.
PMID- 9557956
TI - Cytokines serum levels as the markers of thyroid activation in Graves' disease.
AB - In order to examine which cytokine could be used as a marker of the biological
effect of thyroid hormones or anti-thyroid antibodies in Graves' disease (GD)
patients, we simultaneously evaluated the concentrations of TSH, free thyroid
hormones (fT3 and fT4), anti-thyroid antibodies (anti-TPO and anti-TG) and a
group of cytokines: interleukin-2 (IL-2), tumour necrosis factor alpha
(TNFalpha), interleukin-6 (IL-6) and their soluble receptors (sIL-2R, sTNFalphaR,
sIL-6R) as well as interleukin-10 (IL-10) in eight GD females and nine normal
controls. We found that serum sIL-2R concentrations of GD patients had only the
tendency to be higher versus controls, but strong positive correlations between
fT3 and fT4 and sIL-2R in peripheral blood of GD subjects were revealed. We
showed that sIL-2R was the best cytokine marker, showing very good correlation
with the endocrine status of GD patients.
PMID- 9557957
TI - Oral administration of one dose of cholera toxin induces a systemic immune
response prior to a mucosal immune response by a direct presentation in the
spleen.
AB - In the present report the results indicate that the oral administration of one
dose of CT in rats results in an antibody immune response in the spleen 48 h
later, whereas no antitoxin antibody forming cells were found in the Peyer
patches (PP), mesenteric lymph node (MLN) and lamina propria (LP) of the small
intestine. At this time the main isotype of the antitoxin antibodies in the
spleen were IgG and IgM, 5 days after the priming, few antitoxin AFC were
observed in the MLN, IgG being the main isotype, whereas no IgM antitoxin AFC
were found. At 1 week after priming the number of antitoxin AFC in the MLN
reached similar values to those observed in the spleen. When cells from the
spleen of rats primed orally with one dose of CT were cultured during 4 days in
the presence of inhibitory doses of anti-Ia MAb (OX6), the number of antitoxin
AFC was diminished when compared with that observed when cells were cultured in
the absence of anti-Ia. The main isotype of antitoxin AFC observed when cells
were analyzed after culture was IgM and it was the isotype most affected by the
treatment with MAb anti-Ia. These results strongly suggest that an in situ
presentation of the antigen did occur in the spleen. On the other hand, when the
secondary immune response was studied 48 h after boosting, antitoxin AFC were
found in the PP, MLN, SP and LP and 5 days after the booster a 20-30-fold
increase was observed in all lymphoid tissues studied, indicating that the
secondary immune response found in the spleen was mainly due to the recruitment
of memory cells from Peyer's patches. However, when spleen cells were cultured 48
h after the immunization in the presence of inhibitory doses of anti-Ia a little
decrease in the number of AFC was observed when compared with the controls (in
absence of anti-Ia). The analysis of the antitoxin antibodies in sera and
intestinal fluids were in line with the results presented above. The results
shown in this report indicate that the systemic immune response observed after
the oral administration of CT could be due in part to an in situ presentation of
the antigen in the systemic compartments, especially in the spleen.
PMID- 9557959
TI - Molecular cloning of the cDNA encoding the constant region of the immunoglobulin
A heavy chain (C alpha) from a marsupial: Trichosurus vulpecula (common brushtail
possum)
AB - A cDNA encoding the brushtail possum immunoglobulin A heavy chain constant region
(C alpha) was isolated by screening a mesenteric lymph node cDNA library with a
porcine C alpha exon 3 probe. The larger of the two positive clones isolated
(Tv4a) consisted of 1325 bp of possum cDNA that included an open reading frame of
1191 bp. Its deduced amino acid sequence had a high degree of sequence identity
with known eutherian C alpha sequences. This clone appears to encode the entire
possum IgA heavy chain constant region. The possum C alpha sequence had a
nucleotide sequence identity of 57.7% with porcine C alpha, 51% with mouse C
alpha, 46.7% with dog C alpha and 45.9% with human C alpha2. The corresponding
amino acid identities were 46.7, 45.6, 49.4 and 49%, respectively.
PMID- 9557958
TI - A fetal sheep liver extract reverses age-related increments in spontaneous and
induced cytokine production by indirect environmental effects.
AB - BALB/c, DBA/2 and C57BL/6 mice of different ages (ranging from 8 to 110 weeks of
age) were used as spleen cell donors to assay cytokine production from ConA
activated spleen and Peyer's Patch (PP) lymphocytes. As reported in an earlier
publication, there was an age-related decline in IL-2 production in all strains,
with a general increase in IL-4 and IL-10 production with age, this being
particularly marked for PP cell preparations. Similar conclusions were reached
from independent analysis of CD44hi and CD44lo cell populations in these groups
(memory vs. naive cells, respectively). Interestingly, IL-6 production was
dramatically increased (some 4-5-fold in the different strains) and significantly
increased levels of IL-6 were detected in the serum of aged mice. A previously
described sheep fetal liver extract was able to reverse, to varying degrees,
these cytokine changes associated with aging. Interestingly, when cells from aged
mice were adoptively transferred to lethally irradiated young (8 week)
recipients, the cytokine production phenotype of cells harvested from recipient
mice 3 weeks later was that of the aged donor, unless recipients were treated
continually with extract. Treatment of the donor alone produced minimal changes
in cytokine production 3 weeks following adoptive transfer. The effect of extract
was reversed in treated aged mice by concomitant daily intravenous infusion of
the competitive inhibitor of nitric oxide synthesis (NG-monomethyl-L-arginine
(NMMA)), which also decreased the increased serum nitrate levels in mice treated
with extract. Our data suggest an important role for reactive nitrogen products,
themselves induced by fetal liver extract, in age-associated changes in cytokine
production.
PMID- 9557960
TI - Enhanced prevalence of T cells expressing TCRBV8S2 and TCRBV8S3 in hearts of
chronically Trypanosoma cruzi-infected mice.
AB - We have analysed the relative T cell receptor (TCR) BV gene usage in T cells from
hearts and spleens of CBA/HJ mice chronically infected with the Tulahuen strain
of Trypanosoma cruzi. During chronic infection, CBA/HJ mice recruit T cells at
the major site of inflammation (i.e. the heart), with over-representation of
certain TCRBV gene subfamilies (TCRBV8S2 and TCRBV8S3). In contrast, no signal or
a very weak message from a limited number of T cells was recorded from one heart
of the control group. No alteration of TCRBV distribution was recorded in spleens
of chronically infected CBA/HJ. Our findings indicate that there is a
preferential TCRBV gene usage in the T cell response in the hearts of chronically
infected mice. Furthermore, the pattern of CDR3 lengths in inflammatory T cells
was altered.
PMID- 9557961
TI - Association of viral load in plasma samples of HIV-infected hemophilia patients
with autoantibodies and gp120-containing immune complexes on CD4+ lymphocytes.
AB - OBJECTIVE: We investigated whether the induction of antilymphocyte autoantibodies
and immune complexes is associated with the activity of HIV replication. METHODS:
Viral HIV-1 RNA was measured in the plasma samples of 84 HIV+ hemophilia patients
and correlated with the IgM, IgG, IgM/IgG and IgM/IgG/gp120 load of circulating
CD4+ lymphocytes, CD4+ and CD8+ cell counts, plasma neopterin levels and in vitro
T-cell responses to mitogens and pooled allogeneic stimulator cells. RESULTS:
Compared to patients with no immune complexes, on circulating CD4+ lymphocytes,
viral load was increased in patients with IgM, IgM/IgG or IgM/IgG/gp120
complexes. Sequential analysis of HIV+ patients showed that peaks of retroviral
activity were associated with the subsequent formation of CD4+ lymphocyte
reactive IgM and IgG autoantibodies and gp120-containing immune complexes.
CONCLUSION: The induction of autoantibodies and immune complexes attached to CD4+
lymphocytes is associated with periods of increased viral activity in HIV
infected patients.
PMID- 9557962
TI - Effects of some antigenic fractions of Leishmania major on nitric oxide
production and IL-12 secretion by murine peritoneal macrophages.
AB - Nitric oxide (NO) and IL-12 are important mediators of the immune response to
Leishmania major. In this study, the effects of L. major promastigotes, crude
antigenic fraction (CAF) and its subfractions on NO production and IL-12
secretion by BALB/c mice peritoneal macrophages is investigated. The subfractions
of CAF, namely, fractions 1, 2 and 3, that were in the molecular weight range of
97.4-66, 66-45 and below 45 kDa, respectively, were separated by SDS-PAGE. NO
production was determined by using Griess reagent and IL-12 was measured by
ELISA. It was found that NO production was stimulated by promastigotes but not by
CAF or its subfractions. IL-12 secretion was stimulated by promastigotes, CAF and
fraction 1 while fractions 2 and 3 did not have any effect.
PMID- 9557963
TI - Class II MHC antigen-expressing cells in the pulp tissue of human deciduous teeth
prior to shedding.
AB - The distribution and ultrastructure of the class II major histocompatibility
complex (MHC) antigen-expressing cells in the pulp tissue of human deciduous
teeth during the process of physiological root resorption was surveyed by
histochemical and immunocytochemical methods using an anti-human leukocyte
antigen (HLA)-DR-monoclonal antibody. Dental pulp was found to contain numerous
HLA-DR-positive cells of various shapes; those showing a dendritic appearance
were located mainly in the periphery of the pulp tissue, associated closely with
the odontoblasts. The immunopositive cells sometimes extended their cytoplasmic
processes into the dentinal tubules and increased in number in the areas affected
by dental caries, attrition or restorative procedures, implicating their role in
immunosurveillance. The immunopositive cells were located consistently at the
pulp-dentin border during the stage of active resorption, adjacent to the
preodontoclasts or odontoclasts, and covered the exposed dentin surface after the
detachment of the odontoclasts until the onset of cementum formation. These data
suggest that the HLA-DR-immunopositive cells in the coronal pulp of human
deciduous teeth play an inductive role in the differentiation, migration and/or
activation of the odontoclasts and cementoblast-like cells during the stages of
tooth resorption.
PMID- 9557964
TI - Immunohistochemical localization of vascular endothelial growth factor in the
endocrine glands of the rat.
AB - Vascular endothelial growth factor (VEGF) is a secreted polypeptide with specific
effects on endothelial cell growth and vascular permeability. While previous
studies have focused on the expression of VEGF associated with angiogenesis in
tumor and embryonal tissues, little is known about the role of VEGF in normal
adult tissues. In the present study, a specific antibody was used to study the
immunohistochemical localization of VEGF in the entire body of normal adult rats.
Intense to moderate immunoreactivities for VEGF were detected in some endocrine
cell types, namely, the parafollicular cell of thyroid gland, B cell of endocrine
pancreas, N cell of adrenal medulla and a minority of the thyrotrophs of the
pituitary gland. A certain exocrine cell type, i.e., the surface mucous cell of
stomach, was also immunoreactive for VEGF. At the ultrastructural level, VEGF
immunoreactivity was localized exclusively in the secretory granules of all
immunopositive endocrine and exocrine cells examined. The present study provided
immunohistochemical evidence for the occurrence of VEGF in subsets of endocrine
and exocrine cells of normal adult rats, suggesting that these secretory cells
regulate local vascular permeability through a paracrine action of VEGF.
PMID- 9557965
TI - Ultrastructural changes of the myoepithelium of the dilator pupillae during
miosis and mydriasis in the rat iris.
AB - Changes in the three-dimensional structures of the myoepithelium of the dilator
pupillae (MDP) during mydriasis and miosis were investigated in the rat by
scanning electron microscopy (SEM) and transmission electron microscopy (TEM).
Following fixation, SEM specimens were treated with sodium hydroxide to expose
the muscle surface. Significant morphological differences were noted in the
anterior surface of the MDP between mydriasis and miosis. In the mydriatic eye, a
highly rugged structure with numerous linear folds was oriented circularly or
obliquely together with spherical bulges. These structures, presumably
corresponding to the highly contractile portion of the myoepithelial cells, were
more prominent near the pupillary margin than near the ciliary margin, indicating
that the MDP may contract much more strongly in the pupillary margin. In the
miotic eye, the anterior surface of the MDP showed less conspicuous linear folds
in the pupillary area, and was almost flat in the ciliary area. Radially oriented
ridges were observed only in the pupillary area. These findings suggest that the
contraction of the sphincter pupillae in miosis induces a stretching of the MDP
toward the pupil and a circular shrinkage of the MDP. Ultrastructural changes of
the MDP particularly near the pupillary margin may play an important role in
regulation of the pupil diameter as a diaphragm of the eye because morphological
changes such as the linear folds, spherical bulges, and ridges were more
prominent near the pupillary margin than those near the ciliary margin.
PMID- 9557966
TI - Fine structure of the tongue and lingual papillae of the penguin.
AB - The tongue in four species of penguin was investigated by light microscopy and by
scanning electron microscopy, with special reference to the lingual papillae. 1)
The middle of the penguin tongue contains a pair of long cartilages and long
tendons accompanied by striated muscle bundles. 2) Large, spine-like, and
caudally directed lingual papillae (filiform-like papillae) densely cover the
dorsal surface of the tongue, apparently serving to catch fishes. 3) By light
microscopy, the dorsal lingual epithelium with the lingual papillae are seen as a
thick cornified layer, but the lateral and lower surfaces have a thinner
cornified layer. 4) The connective tissue core (CTC) under the epithelium of the
lingual papilla shows a stereo structure similar to but smaller than the external
form of the papilla. The CTC contains some blood vessels and nerve fibers; the
lingual glands are found in the submucous layer only in the posterior tongue. 5)
Bundles of nerve fibers in the lamina propria of the tongue were
immunohistochemically positive for PGP 9.5, and it appeared that Merkel
corpuscles were distributed in the connective tissue closely beneath the
epithelium of the finger-like papillae, though they were only weakly
immunoreactive for PGP 9.5. 6) Numerous fine filaments of elastic fibers are
found closely beneath the epithelial cell layer of the dorsal surface of the
tongue including the lingual papillae, while there are very few of them on the
lateral and lower sides of the tongue.
PMID- 9557968
TI - Elastic properties of living fibroblasts as imaged using force modulation mode in
atomic force microscopy.
AB - Using the force modulation mode in atomic force microscopy, we measured elastic
properties of living mouse fibroblasts (NIH3T3) in a culture medium. The
topographic images of the cellular surface and the corresponding elastic images
of the cellular surface were able to be captured simultaneously with high spatial
resolution. The consecutive images were useful for examining time-dependent
changes in the cellular surface. We observed that some cells continued to shrink
and change their softness for 2 hours. Then the force modulation mode in atomic
force microscopy shows potential use in analyzing time-dependent regional elastic
properties of living cells with high spatial resolution.
PMID- 9557967
TI - Localization of cytoskeletal filaments during membrane rearrangement in rat
parietal cells stimulated with gastrin.
AB - When stomachs are stimulated to secrete acid, the intracellular canaliculi of the
parietal cell increase and there is a concomitant depletion of the cytoplasmic
tubulovesicular system. This change is believed to occur through the
transformation of tubulovesicular membranes into intracellular canaliculi. This
study was undertaken to examine the distribution of the cytoskeletons in rat
gastric parietal cells during this process. In the resting parietal cells, actin
filaments decorated with heavy meromyosin (HMM) were found in the cores of
microvilli, extending from the apex of microvilli into the pericanalicular
cytoplasm and forming radial networks. In some cases, these actin filaments were
also associated with the tubulovesicles. Moreover, tubulovesicular membranes were
rare in the 300 nm zone around intracellular canaliculi but numerous actin
filaments were seen in this region. Soon after stimulation of the parietal cells
by gastrin, tubulovesicles were closely associated with the intracellular
canaliculi, while actin filaments networks adjacent to the canaliculi diminished
and their labeling with HMM seemed less orderly. By immunocytochemistry,
immunogold particles indicating ezrin were associated with microvillous membranes
in the resting as well as stimulated parietal cells but were absent on the
tubulovesicular membranes. When intermediate filaments were immunocytochemically
investigated using anti-cytokeratin immunogold particles clearly labeled
filamentous bundles present around the intracellular canaliculi, perinuclear
spaces and under the basolateral cell membrane. Their localization was not
changed after stimulation. These results suggest that actin filaments in the
cytoplasm around the intracellular canaliculi may play a key role in the
translocation of the tubulovesicles toward the intracellular canaliculi during
the acid secreting process.
PMID- 9557969
TI - Lymphatic network and nerve plexus in the myenteric layer of the monkey jejunum:
a topographic study using an enzyme-histochemical method.
AB - The topographic relationship between the lymphatic network and the nerve plexus
in the myenteric layer of the monkey jejunum was studied by an enzyme
histochemical method. Identification of the lymphatics was achieved by a 5'
nucleotidase staining method, and the enteric neural components were visualized
by acetylcholinesterase staining. A well-developed lymphatic network and a dense
nerve plexus were demonstrated throughout the myenteric layer. Numerous segments
of the initial lymphatics, with their blind endings at the apical parts, tended
to gather toward the ganglion and run along the primary nerve strands. Elements
of the tissue interstitium separated the lymphatics from the enteric nerves.
Nerve terminals were often located closely beneath the endothelium of the initial
lymphatics and were exposed to the subendothelial tissue on the side facing the
abluminal surface of the lymphatic endothelium. These findings suggest that the
lymph flow in the initial lymphatics might be regulated by the enteric nervous
system, and that the transport of tissue fluid by the lymphatics might serve as a
suitable microenvironment for the enteric nerves.
PMID- 9557970
TI - Corticosteroids stimulate the differentiation of growth hormone cells but
suppress that of prolactin cells in the fetal rat pituitary.
AB - An organ culture study was carried out to examine the effects of adrenal
corticosteroids on the development of growth hormone (GH) cells and prolactin
(PRL) cells. The adenohypophysial primordia were separated from 13.5-day-old
fetal rats and maintained in vitro for 8 days with or without cortisol.
Immunohistochemical examination of these explants showed that cortisol stimulated
the differentiation of GH cells but suppressed that of PRL cells in a dose
dependent manner. In the absence of cortisol there were more PRL cells.
Corticosterone had a similar effect on the developing adenohypophysis. When the
pituitary primordia of Day 16.5 were cultured for 5 days and studied by the in
situ hybridization technique, the expression of GH and PRL mRNA was found to be
parallel with the immunoreactivity of the respective hormones. These data are
discussed in relation to the normal development of GH and PRL cells in the fetal
rat adenohypophysis.
PMID- 9557971
TI - C-Fos-like immunoreactivity in the upper cervical spinal dorsal horn neurons
following noxious chemical stimulation of the nasal mucosa in pentobarbital
anesthetized rats.
AB - Noxious chemical stimulation of the rat nasal mucosa with mustard oil induces the
expression of Fos-like immunoreactivity in trigeminal and other brain stem
neurons which contribute to upper airway protective reflexes such as sneezing,
coughing and apnea. To examine the role of nociceptive processing in the upper
cervical spinal cord, we investigated the Fos-like immunoreactivity of the
brainstem and upper cervical spinal cord following the injection of mustard oil
(10 microl of 10%) into the nasal mucosa of pentobarbital anesthetized rats. Two
hours after the application of mustard oil, numerous Fos-immunoreactive neurons
were found in the mediolateral end of the C1 and dorsolateral division of the C2.
The mean numbers of the Fos-immunoreactive neurons in the laminae I and II of the
ipsilateral first and second spinal segments were significantly greater than in
the control (vehicle treated) rats. There were no significant differences in the
mean number of Fos-immunoreactive neurons in the contralateral C1 between the
mustard oil and vehicle-treated rats. These results suggest that the C1-C2 dorsal
horn neurons process the nociceptive information from nasal mucosa as well as
other areas innervated by the trigeminal nerves, and that ethmoidal nerves may
contribute to the exclusive conveyance of nociceptive information.
PMID- 9557972
TI - Morphodifferentiation of skeletal muscle fiber ends at the myotendinous junction
in the postnatal Chinese hamster: a scanning electron microscopic study.
AB - The postnatal morphodifferentiation of muscle fiber ends at the myotendinous
junction was examined by scanning electron microscopy in gastrocnemius muscles of
the Chinese hamster. Muscle fiber ends during the first week were simply conical
or slightly complex, having a few pit-like invaginations and longitudinal and
narrow clefts. By the second week, fiber ends gradually became complicated with
an increased number of clefts and finger-like processes. Pits and short clefts
linearly arranged towards the fiber tip were visible until the second week. This
possibly indicates the linear elongation of the clefts by the fusion of adjacent
pits to one another and to preexisting clefts. By the fourth week, the fiber ends
had almost fully matured and displayed numerous cytoplasmic processes and lateral
grooves.
PMID- 9557973
TI - GABAergic projections from the lateral lemniscus to the inferior colliculus of
the rat.
AB - The objective of the present study was to provide direct evidence regarding
GABAergic projections from the nuclei of the lateral lemniscus to the central
nucleus of the inferior colliculus (ICC), and from the ICC to the opposite ICC.
Projections of GABAergic neurons in the rat were investigated by a combination of
fluorogold (FG) retrograde tracing and GABA immunocytochemistry. FG was first
injected into a frequency-defined region (11-13 kHz) in the center of the ICC,
and 1-2 weeks was allowed for retrograde transport. Vibratome sections were then
cut through the brainstem and stained with GABA antibody. Double-labeling was
taken as evidence of GABAergic neurons projecting to the ICC. The results from FG
retrograde labeling alone showed that neurons in the dorsal nucleus of the
lateral lemniscus (DNLL) bilaterally, in the intermediate and ventral nucleus of
the lateral lemniscus (INLL and VNLL) ipsilaterally, and in the ICC
contralaterally project to the ICC. GABA immunostaining alone showed substantial
numbers of GABA positive neurons in the nuclei of the lateral lemniscus and the
inferior colliculus. FG and GABA double-labeled neurons were present in all
nuclei of the lateral lemniscus that project to the ICC. The greatest
concentration of double-labeled neurons was found bilaterally in the DNLL,
suggesting a prominent GABAergic projection from the DNLL to the ICC. The
presence of many double-labeled neurons in the ipsilateral INLL and VNLL suggests
that there are also GABAergic inputs from the INLL and VNLL to the ICC. No double
labeled neurons were found in the contralateral ICC, which suggests the
possibility of a prominent non-GABAergic projection.
PMID- 9557974
TI - Establishment of conditionally immortalized rat utricular epithelial cell lines
using a retrovirus-mediated gene transfer technique.
AB - Supporting cells in the inner ear sensory epithelium are most likely hair cell
progenitors. In an effort to establish an in vitro model system of hair cell
differentiation, we developed immortalized epithelial cell lines by transferring
the tsA58 allele of the SV40 large T antigen oncogene into neonatal rat utricular
supporting cells using a retrovirus. The established cell lines have been stably
maintained continuously for more than 25 passages and display many features
similar to primary supporting cells. They grow in patches and assume a polygonal
morphology. Immunocytochemical characterization of the established cell lines
reveals that these cells can be labeled by epithelial cell markers, but not by
fibroblast, glial or neuronal markers. The immortalized cells grow rapidly in
serum medium at permissive temperature, but the majority cease proliferation when
cultured in serum free medium at non-permissive temperature. These cells respond
to mitogenic growth factors including bFGF, EGF and TGF-alpha and express growth
factor receptors in a manner similar to the primary supporting cells.
Furthermore, we find that the cells undergo a morphological differentiation when
cultured in serum free medium at non-permissive temperature in the presence of
bFGF. Under these conditions, the cells shrink in size, become elongated, and
express early hair cell markers such as calretinin and calmodulin. The utricular
epithelial cell line we have established may potentially provide an invaluable
system for studying hair cell differentiation and regeneration.
PMID- 9557975
TI - Low intensities and 1.3 ratio produce distortion product otoacoustic emissions
which are larger in heterozygous (+/dn) than homozygous (+/+) mice.
AB - The f2/f1 frequency ratio of 1.3 in combination with stimulus levels of L1/L2 =
50/60 and 50/50 dB SPL produced a higher level of distortion product otoacoustic
emissions (DPOAE) in the heterozygous (+/dn) mice than in the homozygous (+/+)
mice. These results suggest that the dn gene carriers have a unique cochlear
trait which may be related to the dn gene locus and expressed via a frequency-
and intensity-dependent DPOAE function.
PMID- 9557976
TI - Changes in cochlear antioxidant enzyme activity after sound conditioning and
noise exposure in the chinchilla.
AB - Exposure to low level noise prior to a high level exposure reduces noise-induced
hearing loss in mammals. This phenomenon is known as sound conditioning or
'toughening'. Reactive oxygen intermediates have been implicated in noise-induced
cochlear damage. To evaluate if in situ antioxidant processes may play a role in
the toughening phenomenon initiated by low level noise exposure we analyzed
glutathione reductase, gamma-glutamyl cysteine synthetase, and catalase in stria
vascularis and organ of Corti fractions from cochleae of chinchillas exposed to a
sound conditioning paradigm. Chinchillas were either (A) kept in quiet cages
(control), (B) exposed to conditioning noise of a 0.5 kHz octave band (90 dB for
6 h/day for 10 days), (C) exposed to high level noise (105 dB for 4 h) or (D)
exposed to conditioning noise (B) followed by exposure to the higher level noise
(C). Each of the noise exposure conditions (B, C, D) induced changes in the
levels of these three antioxidant enzymes. The enzyme-specific activity data for
the four subject groups support the following two hypotheses. (1) Changes in
glutathione reductase, gamma-glutamyl cysteine synthetase, and catalase play a
role in attenuating hearing loss associated with sound conditioning followed by
high level noise. (2) Hair cells in the organ of Corti are protected from noise
induced damage by increasing stria vascularis levels of catalase, a hydrogen
peroxide scavenging enzyme, and of enzymes involved in maintaining glutathione in
the reduced state. The model formulated by these hypotheses suggests that agents
that protect or augment the glutathione system in the cochlea may be protective
against noise-induced hearing loss.
PMID- 9557977
TI - Neural encoding of single-formant stimuli in the ventral cochlear nucleus of the
chinchilla.
AB - Responses of the principal unit types in the ventral cochlear nucleus of the
chinchilla were studied with a single-formant stimulus set that covered
fundamental frequency (f0) from 100 Hz to 200 Hz and formant center frequency
(F1) from 256 to 782 Hz. Temporal coding for f0 and F1 was explored for 95
stimulus combinations of f0 (n = 5) and F1 (n = 19) in primarylike, onset and
chopper unit categories. Several analyses that explored temporal coding were
employed including: autocorrelation, interspike interval analysis, and
synchronization to each harmonic of f0. In general, the representation of f0 is
better in onset and chopper units than in primarylike units. Nearly all units in
the cochlear nucleus showed a gain in phase locking to the envelope (f0) of the
single-formant stimulus relative to the auditory nerve. The fundamental is
represented directly in neural discharges of units in the cochlear nucleus with
an interval code (also Cariani and Delgutte, 1996; Rhode, 1995). The formant is
represented in the temporal domain in primarylike units, though some chopper and
onset units also possess the ability to code F1 through discharge synchrony.
Onset-I units, which are associated with the octopus cells, exhibited the
strongest phase locking to f0 of any unit types studied. The representation of f0
and F1 in the temporal domain is weak or absent in some units. All-order
interspike interval distributions computed for populations of units show
preservation of temporal coding for both f0 and F1. Results are in agreement with
earlier amplitude modulation studies that showed nearly all cochlear nucleus unit
types phase lock to the signal envelope better than auditory nerve fibers over a
considerable range of signal amplitudes.
PMID- 9557978
TI - Frequency-shaped amplification changes the neural representation of speech with
noise-induced hearing loss.
AB - Temporal response patterns of single auditory nerve fibers were used to
characterize the effects of a common hearing-aid processing scheme, frequency
shaped amplification, on the encoding of the vowel /epsilon/ in cats with a
permanent noise-induced hearing loss. These responses were contrasted with
responses to unmodified stimuli in control and impaired cats. Noise-induced
hearing loss leads to a degraded representation of the formant frequencies, in
which strong phase locking to the formants is not observed in fibers with best
frequencies (BFs) near the formants and there is a wide spread of formant phase
locking to fibers with higher BFs (Miller et al., 1997a,b). Frequency shaping
effectively limits the upward spread of locking to F1, which improves the
representation of higher frequency components of the vowel. However, it also
increases phase locking to harmonics in the trough between the formants, which
decreases the contrast between F1 and the trough in the neural representation.
Moreover, it does not prevent the spread to higher BFs of responses to the second
and third formants. The results show a beneficial effect of frequency shaping,
but also show that interactions between particular gain functions and particular
spectral shapes can result in unwanted distortions of the neural representation
of the signal.
PMID- 9557979
TI - Effects of noise on inferior colliculus evoked potentials and cochlear anatomy in
young and aged chinchillas.
AB - Like many aging humans, the aging chinchilla tends to lose high-frequency
sensitivity at a faster rate than low-frequency sensitivity. This feature,
combined with its excellent low-frequency hearing, makes the chinchilla
attractive as an animal model for studying the relationship between noise-induced
hearing loss (NIHL) and age-related hearing loss (AHL). In the present study, we
examined susceptibility to noise in 15 aged (10-15 years old) and 15 young
chinchillas. Two levels of noise were used, with the aim of determining whether
age-related differences exist in the magnitude and rate of recovery from
temporary threshold shifts produced by a moderate-level (95 dB) noise exposure,
or in susceptibility to permanent threshold shifts and cochlear damage caused by
a high-level (106 dB) noise exposure. Thresholds and response amplitudes at 0.5,
1, 2, 4, 8 and 16 kHz were determined from evoked potentials recorded from the
inferior colliculus. Cochlear histology was performed on animals exposed to high
level noise. The results suggest that older animals are equally vulnerable to
moderate-level noise, but may be slightly more vulnerable to high-level noise.
For moderate-level exposures, there appears to be a simple additive relationship
(in dB) between AHL and NIHL. For high-level exposures, the relationship may be
more complex.
PMID- 9557980
TI - Development of auditory function in the tammar wallaby Macropus eugenii.
AB - Auditory brainstem responses (ABRs) were evoked in developing wallabies by click
and tone burst stimuli delivered by bone conduction and air conduction, at
progressive stages of post-natal (pouch) life. ABRs were recorded through the
onset of auditory responses (95-110 days), the opening of the external ear canal
(125-130 days) and the maturation of ABR thresholds and latencies to values
corresponding to those in adults ( > 180 days). ABRs were evoked in response to
bone-conducted clicks some days prior to the age at which an acoustically evoked
response was first observed (around 95 days of pouch life). ABRs could be evoked
by bone-conducted and intense air-conducted stimuli prior to opening of the ear
canal. A trend of decreasing threshold and latency with age was observed for both
modes of stimulation. The morphology of the ABR became more complex, according to
both increased age and increased stimulus intensity. The ABR waveforms indicated
relatively greater mechanosensitivity to bone-conducted stimuli than to air
conducted stimuli, prior to opening of the ear canal. Following opening of the
ear canal, thresholds to air-conducted clicks and tones were substantially
reduced and decreased further over the next 10-20 days, while thresholds to bone
conducted clicks continued slowly to decrease. Thresholds to tone bursts in the
centre frequency range (4-12 kHz) remained less than those for low (0.5-1.5 kHz)
and higher (16 kHz) frequencies. Latencies of an identified peak in ABR waveforms
characteristically decreased with age (at constant stimulus intensity) and with
stimulus intensity (for a given age). ABR waveforms obtained at progressive ages,
but judged to be at corresponding sensation levels, underwent maturational
changes, independent of conductive aspects of the wallabies' hearing, for 2-3
weeks after opening of the ear canal.
PMID- 9557981
TI - A new method for the automated detection of spontaneous otoacoustic emissions
embedded in noisy data.
AB - There is, as yet, no universally agreed upon method for the detection of
spontaneous otoacoustic emissions (SOAEs). In this paper, we augment extant
techniques by presenting a new automated approach. The new procedure reliably
labels the spectral peaks as SOAEs, rejects noisy data such as that due to body
movements or breathing, provides a subject-specific measure of the probability
that a particular peak is erroneously identified as a SOAE, and can be
accomplished on-line. Comparison of results with this new approach and with
methods undertaken previously in this laboratory and elsewhere are made. The
estimated prevalence of SOAEs for the new method is as large as that for any
method previously proposed.
PMID- 9557982
TI - Contralateral frequency-modulated tones suppress transient-evoked otoacoustic
emissions in humans.
AB - In order to test the sensitivity of the human medial olivocochlear bundle (MOCB)
to stimulus frequency fluctuations, changes in transient-evoked otoacoustic
emission (TEOAE) amplitude induced by frequency modulated (FM) tones were
measured in 18 normal-hearing subjects. The results revealed that TEOAE amplitude
was reduced by contralateral FM tones at 40 dB above pure-tone threshold, with
significant influences of both modulation rate (MR) and modulation depth (MD).
This finding is discussed in the light of other recent results indicating
amplitude fluctuation and frequency bandwidth effects in MOCB activation in
humans.
PMID- 9557983
TI - Induction of endolymphatic hydrops in the guinea pig by perisaccular deposition
of sepharose beads carrying and not carrying immune complexes.
AB - We tried to induce endolymphatic hydrops in guinea pig cochleas by unilateral,
perisaccular deposition of sepharose beads carrying immune complexes. Controls
consisted of the deposition of sepharose beads without immune complexes and the
contralateral, untreated ear. The effects of the treatment were studied by light
microscopy and electrophysiological recordings of the gross cochlear potentials
1, 2, and 6 weeks after treatment. Each condition included six animals. Analysis
of variance of the morphometric data concerning the ears treated with deposition
of the beads showed a statistically significant difference (P = 0.04) between the
degree of hydrops found for the beads with immune complexes and for those
without. The difference between the treated ears and the contralateral untreated
ears was significant (P = 0.01) for the beads with immune complexes and not
significant (P = 0.8) for those without immune complexes while there was no
significant effect of post-treatment time interval. Analysis of variance of the
electrophysiological data, collected in response to tone bursts at the apex of
the cochlea, showed no significant differences between the results for the beads
with and without immune complexes. Therefore these results were pooled. One week
after treatment the pooled results for the compound action potential showed a
small decrease in amplitude, just significant at 2 kHz, but not at 4 and 8 kHz.
This decrease disappeared completely after 6 weeks. The pooled results for the
negative summating potential (SP) showed a significant increase in magnitude at
all frequencies decreasing with post-treatment interval. The cochlear
microphonics did not demonstrate any change in amplitude after treatment. The
results indicate that deposition of sepharose beads with immune complexes induces
endolymphatic hydrops. Also, deposition of the sepharose beads itself may have
induced hydrops together with enhancement of the SP. SP enhancement may be
related to the development of endolymphatic hydrops rather than to the presence
of hydrops as such. This may be based on pressure build-up while hydrops
develops.
PMID- 9557985
TI - Salicylate and quinine selectively increase spontaneous firing rates in secondary
auditory cortex.
AB - This study presents firing rates for simultaneously recorded spontaneous and
stimulus driven multi-unit activity in primary auditory cortex (AI), anterior
auditory field (AAF) and secondary auditory cortex (AII) in cats before and after
application of salicylate or quinine. From 21 cats, in three cortical areas
simultaneously, a total of 1533 multi-unit files were obtained. The data suggest
(1) that both salicylate and quinine significantly increase spontaneous firing
rates in AII, whereas in AI and AAF both quinine and salicylate reduced the
spontaneous rate; (2) the effect of both drugs was to increase spontaneous rates
for recording sites with high characteristic frequency (CF) and a tendency to
decrease them for low CF sites; (3) the mean stimulus driven firing rates were
not affected by either drug except for a decrease produced by quinine in AI; (4)
changes in driven firing rate were positively correlated with changes in
spontaneous firing rates. This suggests that tinnitus inducing agents selectively
increase spontaneous firing rates in the extralemniscal pathway.
PMID- 9557984
TI - Expression of mRNA encoding vasopressin V1a, vasopressin V2, and ANP-B receptors
in the rat cochlea.
AB - The expression of mRNAs encoding vasopressin V1a, V2, and ANP-B receptors in the
rat cochlea was examined by PCR and in situ hybridization. After reverse
transcription of rat cochlear RNA, cDNA was amplified by PCR using pairs of
primers specific to these receptors. After subcloning of the PCR products, clones
with sequences identical to those cloned previously from the rat liver (V1a
receptor), kidney (V2 receptor) and brain (ANP-B receptor) were obtained. The
localization of expression of those receptors in the developing and adult rat
cochlea was examined by in situ hybridization using 35S-labeled cRNA probes. The
V1a and V2 receptors were expressed throughout the whole of the neonatal rat
cochlea, while no expression was detected in the adult cochlea. The ANP-B
receptor was expressed throughout the whole of the neonatal cochlea. In the adult
cochlea, expression was observed in the spiral ganglion and the spiral ligament.
These results suggest that vasopressin may play a role in the development of the
cochlea, and that natriuretic peptide may play a role in the function of the
spiral ganglion and the spiral ligament.
PMID- 9557986
TI - Distribution of Eph-related molecules in the developing and mature cochlea.
AB - Receptors and ligands of the Eph family have recently been shown to influence the
development of a variety of tissues. In the present study, the temporal and
spatial distribution of Eph receptors and ligands were investigated in the
embryonic and postnatal cochlea using Northern blot and immunohistochemical
analysis. The results of Northern blot experiments revealed that a large number
of Eph family members were present in embryonic cochlear and vestibular ganglia.
Immunohistochemical studies revealed that ligands and receptors of the GPI
subclass were distributed in complementary patterns within the differentiating
spiral limbus, inner sulcus and outer sulcus. The distribution of these molecules
became more restricted beginning in the first postnatal week. In contrast,
members of the transmembrane subclass of Eph ligands were largely associated with
cochlear neurons and their target hair cells. Expression of these ligands
appeared to increase during the second postnatal week, corresponding to the
period of peripheral nerve fiber reorganization in the cochlea. Together, these
studies suggest that multiple Eph family members play unique roles in formation
of the cochlea.
PMID- 9557988
TI - The pain of interstitial cystitis.
PMID- 9557987
TI - Induction of immune-mediated hearing loss in SCID mice by injection of MRL/lpr
mouse spleen cells.
AB - Induction of immune-mediated hearing loss in SCID mice by injection of MRL/lpr
mouse spleen cells The MRL/lpr mouse, which has a mutation in the Fas gene
encoding a cell-surface receptor for apoptosis, shows an accumulation of abnormal
immunocompetent cells and SLE-like disease. It has recently been reported that
this mouse also manifests sensorineural hearing loss (SHL) with cochlear
pathology at 20 weeks of age. We examined the effects of injecting MRL/lpr spleen
cells on the development of SHL in severe combined immunodeficient (SCID) mice,
which originally develop neither SHL nor cochlear pathology. Immune-mediated SHL
and cochlear pathology were, indeed, transferred to the SCID mice by the
injection of spleen cells from the MRL/lpr mice. These findings suggest that cell
mediated immunity is involved in the development of SHL and cochlear pathology.
PMID- 9557989
TI - Intraoperative transvesical cystoscopy for urogynecologic procedures.
AB - Intraoperative cystoscopy is a useful adjunct to surgical procedures that may
compromise the integrity of the lower urinary tract. Ureteral injury and the
placement of intravesical sutures are risks, especially at teaching facilities,
during operations such as retropubic urethropexy, paravaginal repair, or even
simple hysterectomy. The conventional use of transurethral cystoscopy during open
surgical cases may require repositioning of the patient if not previously placed
in Allen stirrups. Alternative practices of bladder examination include placement
of a standard cystoscope via an intentional cystotomy through the dome of the
bladder. The authors have implemented the direct insertion of a 2 mm
microlaparoscope through the bladder dome to verify an intact lower urinary
system and found this method to be both efficacious and safe. Visualization is
not compromised by the slightly smaller visual field compared to the standard 0
degrees or 30 degrees cystoscope. The perspective of the bladder neck region may
be more easily oriented from the superior viewing angle. The authors prefer
transvesical cystoscopy with the microlaparoscope for its ease of use, compared
to their experience of performing a small cystotomy or routine transurethral
cystoscopy.
PMID- 9557990
TI - New ambulatory surgical methods using an anatomical classification of urinary
dysfunction improve stress, urge and abnormal emptying.
AB - The aim of the study was to introduce an anatomical classification for the
management of urinary dysfunction based on the Integral Theory, a new connective
tissue theory for female incontinence. Eighty-five unselected patients, aged 27
83 years, 12 with pure stress symptoms and 73 with mixed incontinence symptoms,
were classified as having laxity in the anterior, middle or posterior zones of
the vagina, using specific symptoms, signs and urodynamic parameters summarized
in a pictorial algorithm. Special ambulatory surgical techniques, which included
the creation of neoligaments, repaired specific connective tissue defects in the
anterior (intravaginal slingplasty (IVS), n = 85), middle (cystocele repair, n =
6), or posterior zones (uterine prolapse repair, n = 31, or infracoccygeal
sacropexy, n = 33). Almost all patients were discharged within 24 hours of
surgery, without postoperative catheterization, returning to fairly normal
activities within 7-14 days. At (mean) 21-month follow-up cure rates were: stress
incontinence 88% (n = 85), frequency 85% (n = 42), nocturia 80% (n = 30), urge
incontinence 86% (n = 74), emptying symptoms 50% (n = 65). Mean objective urine
loss (cough stress test) was reduced from 8.9 g preoperatively to 0.3 g
postoperatively, and mean residual urine >50 ml from 110 ml to 63 ml, P = <0.02.
Pre- and postoperative urodynamics indicated that detrusor instability was not
associated with surgical failure. Two new directions, based on the Integral
Theory, are presented for the management of female urinary dysfunction, an
anatomical classification which delineates three zones of vaginal damage, and a
series of ambulatory surgical operations which repair these defects. The
operations are fairly simple, safe, effective and easily learnt by any practising
gynecologist.
PMID- 9557991
TI - Transabdominal repair of cystocele by wedge colpectomy during combined abdominal
vaginal surgery.
AB - The aim of the study was to evaluate the effectiveness of transabdominal wedge
colpectomy as surgical treatment for cystocele. One hundred and sixty-three women
with either first or second-degree cystocele (Beecham classification), rectocele
and concomitant stress urinary incontinence or benign pelvic masses were
submitted for a combined operation. Transabdominal repair of the cystocele was
performed by wedge colpectomy employing two different absorbable sutures, Vicryl
and PDS. The choice of suture was not random but depended on the period at which
surgery was performed. Data obtained were analyzed with Student's t-test and
Fisher's exact test. The cystocele cure rate was 90.2% (110 out of 122) at 3-year
follow-up and was significantly associated with the preoperative degree, being
95.5% and 76.5% in first and in second degree, respectively (P = 0.003). At 1
year follow-up the cure rate was significantly associated with the type of the
suture employed (P = 0.01). At 2-year follow-up rectocele cure rate was 97.2% and
vaginal vault prolapse appeared in 3.5% of cases. Stress urinary incontinence
relapsed in 10% of patients after Burch colposuspension. After the operation
94.1% of the women declared normal coitus. In the present series wedge colpectomy
was found to be effective in repairing first-degree cystocele, whereas a high
incidence of relapse was observed when second-degree cystocele was present
preoperatively. The suture material employed influenced the cure rate.
PMID- 9557992
TI - Augmentation of urethral pressure profile by voluntary pelvic floor contraction.
AB - The aim of the investigation was to study the repeatability of urethral pressure
profile (UPP) and to quantify the influence of voluntary pelvic floor contraction
on the UPP. Seventy-two patients underwent one UPP at rest and one UPP during a
pelvic floor contraction. The functional urethral length (FUL) and the maximum
urethral closure pressure (MUCP) were recorded. To establish repeatability the
UPP was repeated twice in 18 patients in rest, and in 15 patients during a
contraction. We used the repeatability coefficient instead of the correlation
coefficient. Forty-eight patients, had no major anatomical abnormalities (group
A); 24 had grade 2 or more prolapse (group B). In both groups we found a
shortening of the FUL and an increase in MUCP during a contraction. The UPP was
reproducible, both at rest and during a contraction. In conclusion, we found a
significant and constant increase in MUCP and a shortening of the FUL during a
contraction. Unlike other studies we found the UPP to have good reproducibility.
However, we used the repeatability coefficient instead of the correlation
coefficient.
PMID- 9557993
TI - Cystocele--a radical cure by suturing lateral sulci of the vagina to the white
line of pelvic fascia. 1909.
PMID- 9557994
TI - Pentosanpolysulphate for interstitial cystitis.
AB - Interstitial Cystitis (IC) is a chronic disease of unknown etiology which
primarily affects women aged 40-60 years. Many plausible theories for the
development of IC have been postulated, and one current theory is that these
patients have a quantitative and qualitative defect in the glycosaminoglycan
(GAG) layer of the urothelium. Such a defect may allow toxic substances in the
urine to gain access to the lamina propria and initiate a chronic inflammatory
process. Pentosanpolysulphate (PPS) is a sulphated proteoglycan similar in
structure to heparin sulphate, which is quantitatively the major GAG on cell
surfaces. Exogenously administered PPS has been shown in several studies to
decrease bladder pain and urinary frequency and to increase the voided volume.
Further studies are required to evaluate the role of PPS in the management of IC
patients, with particular emphasis on dosage, route of administration and
combination with other compounds.
PMID- 9557995
TI - Pelvic floor muscle exercises in genuine urinary stress incontinence.
AB - Pelvic floor muscle exercises, in the treatment of genuine stress incontinence,
have been used successfully since 1948. One may expect a significant improvement
(warranting no further therapy), or cure rate of about 50%. These exercises have
a long-lasting effect. Poorly motivated women should be discouraged to follow
exercise sessions. An active co-operation between urogynecologist,
physiotherapist and the patient is important in order to avoid undertreated and
dissatisfied women. The option to be operated upon must be easily available.
PMID- 9557996
TI - Introl bladder neck support prosthesis: international clinical experience.
AB - The Introl bladder neck support prosthesis is a ring-shaped silastic device with
two prongs located at one side such that when placed within the vaginal canal the
bladder neck is suspended in a fashion similar to a surgical urethropexy. Since
its initial description in 1988 the device has undergone clinical trials in the
US and Japan, documenting its effectiveness in the treatment of stress and mixed
incontinence in women. Introl is available for clinical use in the United States
and has been well accepted by practicing clinicians. In Japan, exposure has
occurred through clinical trials, which resulted in a high efficacy rate, i.e.
81% of the patients had either maximum benefit or benefit in the global
usefulness rating, and 26% experienced minor adverse effects. This paper will
summarize Introl clinical study findings and describe various clinical
observations made during increased clinical usage.
PMID- 9557997
TI - Clinical usefulness of urinary control urethral insert devices.
AB - Urinary control urethral insert devices have been introduced as a non-surgical
remedy to treat female urinary incontinence. Several early clinical trials have
demonstrated the degrees of safety and efficacy, and have defined the morbidity
and complications of these urethral inserts. This is a descriptive review of
urethral insert devices in clinical use or currently undergoing clinical
investigation.
PMID- 9557999
TI - Re: change in urethral pressure during voluntary pelvic floor muscle contraction
and vaginal stimulation. Bo K, Talseth T. Int Urogynecol J 1997;8:3-7.
PMID- 9557998
TI - Clinical value of vaginal cones for the management of female stress incontinence.
AB - In women with mild stress incontinence (mean urine loss of 3.7 g/h), pelvic floor
training using vaginal cones resulted in a subjective success rate of 70%
(19/27), that is complete cure or reduction by >50% of the original severity.
However, in women with severe stress incontinence (mean urine loss of 20.7 g/h)
cone therapy was successful in only 14% (7/50). The predictive value of six
parameters (age, parity, urine loss by pad test, frequency of incontinence,
contractile strength of the vagina, and perceived problems) was analyzed and two
showed significant prognostic values: a smaller amount of urine loss and less
frequent incontinence. It is concluded that vaginal cone therapy is one physical
treatment option for stress incontinence but is of no clinical effect for those
with severe incontinence.
PMID- 9558000
TI - Tumor and dendritic cells as cellular vaccines: confrontation and perspectives--a
symposium in writing.
PMID- 9558001
TI - Tumor antigen presentation: changing the rules.
AB - Cell-based tumor vaccines have been developed on the basis of the hypothesis that
tumor cells can be genetically modified to present antigen to T lymphocytes
directly. Contrary to expectations, cross-priming is the predominant pathway for
activation of tumor-specific CD8+ T cells, while direct presentation of antigen
dominates activation of tumor-specific CD4+ T cells. These results pose
interesting paradoxes for the generation of immune responses, and have definite
implications for the development of anti-cancer vaccines.
PMID- 9558002
TI - Tumor immunotherapy: cytokines and antigen presentation.
AB - Increasing the ability of tumor-reactive T cells to mediate tumor regression in
vivo has been a major goal of tumor immunologists. Progress toward this goal has
been aided by the identification of tumor-associated antigens on both
experimental mouse tumors and human tumors. However, the self-like nature and low
immunogenicity of these antigens has made it clear that other measures to enhance
the effectiveness of the T cells reactive to these antigens are essential if
immunotherapy is to be clinically effective. An increased understanding of
antigen processing and presentation is an important step in this process, as is
the use of cytokines to increase immune responsiveness. Despite recent advances,
there is still much to be learned before the specificity of the immune system is
safely harnessed to halt malignant cell growth effectively.
PMID- 9558003
TI - Immunotherapy of cancer with dendritic-cell-based vaccines.
AB - Animal studies have shown that vaccination with genetically modified tumor cells
or with dendritic cells (DC) pulsed with tumor antigens are potent strategies to
elicit protective immunity in tumor-bearing animals, more potent than
"conventional" strategies that have been tested in clinical settings with limited
success. While both vaccination strategies are forms of cell therapy requiring
complex and costly ex vivo manipulations of the patient's cells, current
protocols using dendritic cells are considerably simpler and would be more widely
available. Vaccination with defined tumor antigens presented by DC has obvious
appeal. However, in view of the expected emergence of antigen-loss variants as
well as natural immunovariation, effective vaccine formulations must contain
mixtures of commonly, if not universally, expressed tumor antigens. When, or even
if, such common tumor antigens will be identified cannot be, predicted, however.
Thus, for the foreseeable future, vaccination with total-tumor-derived material
as source of tumor antigens may be preferable to using defined tumor antigens.
Vaccination with undefined tumor-derived antigens will be limited, however, by
the availability of sufficient tumor tissue for antigen preparation. Because the
mRNA content of single cells can be amplified, tumor mRNA, or corresponding cDNA
libraries, offer an unlimited source of tumor antigens. DC transfected with tumor
RNA were shown to engender potent antitumor immunity in animal studies. Thus,
immunotherapy using autologous DC loaded with unfractionated tumor-derived
antigens in the form of RNA emerges as a potentially powerful and broadly useful
vaccination strategy for cancer patients.
PMID- 9558004
TI - Keeping the immune system alerted against cancer.
PMID- 9558007
TI - A case report of immunotherapy on a patient with advanced gastric cancer by
adoptive transfer of OK-432-reactive HLA-matched allogeneic lymphocytes.
AB - Adoptive immunotherapy (AIT) for non-hematological malignancies, using HLA
matched donor lymphocytes, has been rarely reported. For a 35-year-old male
patient with peritoneal disseminated advanced gastric cancer, we performed AIT
using lymphocytes from his HLA-matched 37-year-old brother and a streptococcal
preparation, OK-432, as an antigen. After the donor had been immunized by
intradermal administration of OK-432, OK-432-reactive lymphocytes were induced in
vitro and transferred to the patient intravenously with OK-432. Low-dose systemic
immunochemotherapy, using interleukin-2, 5-fluorouracil and cyclophosphamide, was
concurrently administered with AIT. As a result, the Schnitzler metastasis in the
patient reduced in size without any significant graft-versus-host-related
complications. One of the effector mechanisms of therapeutic benefit was
suggested to be cytokine release from the transferred OK-432-reactive
lymphocytes. Our findings suggest the safety and efficacy of AIT using
lymphocytes from an HLA-matched sibling and OK-432 as an antigen. Further studies
to investigate the use of tumor-associated antigen and an HLA-matched sibling's
lymphocytes for AIT of advanced cancer are warranted.
PMID- 9558006
TI - Effects of paclitaxel on cytokine synthesis by unprimed human monocytes, T
lymphocytes, and breast cancer cells.
AB - Paclitaxel or Taxol has attracted a great deal of attention in recent years
because of its immense success as a chemotherapeutic agent for numerous types of
cancer. It is known that paclitaxel stabilizes microtubules, and this
characteristic is the presumed primary mechanism for its antitumor activity.
Recently, however, paclitaxel's ability to regulate gene expression, particularly
in the murine system, has been reported by several groups. Here, we present
research examining paclitaxel's ability to alter expression of the interleukin
1beta (IL-1beta) and IL-8 cytokines in primary human monocytes, T lymphocytes,
and four human breast cancer cell lines: MCF-7, ZR-75-1, MDA-MB-468, and MDA-MB
231. This report shows for the first time that treatment with 5-50 microM
paclitaxel increases steady-state levels of IL-1beta mRNA in unprimed human
monocytes, MCF-7, and ZR-75-1 cells. Monocytes from eight donors in 16
experiments showed increased IL-1beta secretion upon treatment; however, the
increase in IL-1beta production by monocytes was predicated on culturing in the
absence of fetal bovine serum or in the presence of autologous human serum. In
contrast to the IL-1beta results, paclitaxel did not have significant effects on
IL-8 expression by monocytes, T lymphocytes, or the breast cancer cells. These
data show a specific effect of paclitaxel on cytokine synthesis by both immune
cells and cancer cells.
PMID- 9558005
TI - Contribution of the T cell receptor BJ gene to recognition of the P91A tumor
antigen in DBA/2 mice.
AB - To understand specific immune responses against a tumor, it is important to
characterize T cells that recognize the tumor antigen. The mouse P91A antigen is
one of the well-defined tumor antigens that is expressed on the P911 cell line,
and T cells responding to the antigen in DBA/2 mice were reported to be
restricted to BV8S2/S3 families in their T cell receptor (TCR) BV gene usage. We
have further characterized the P91A-responding T cells in DBA/2 mice, focusing on
TCR BJ gene usage and using the polymerase chain reaction/enzyme-linked
immunosorbent assay and DNA sequencing studies of their third complementarity
determining (CDR3) regions. As a result, T cells with cytotoxic activity to the
P91A antigen, induced from murine spleen cells both in vivo and in vitro, showed
predominant use of the BJ2S1 gene segment in both BV8S2 and BV8S3 T cells
compared to unmanipulated murine spleen cells. Sequencing studies of the CDR3
regions in the BV8S3 T cells revealed clonal expansion of T cells with the BV8S3
BJ2S1 combination in two of three DBA/2 mice tested. In the remaining mouse,
clonal expansion was not detected despite predominant use of the BJ2S1 segment by
these T cells. These data suggest that P91A-recognizing T cells would
predominantly use the BV8S2/S3-BJ2S1 combination. Analysis of T cells with these
TCR BV-BJ gene combinations may contribute to the evaluation, monitoring and
development of a T-cell-mediated immunotherapeutic strategy.
PMID- 9558009
TI - Relationship between muscle abnormalities and symptom duration in lumbosacral
radiculopathies.
AB - A long held notion in the electrodiagnostic literature is that paraspinal muscles
tend to show electromyographic abnormalities early on in a lumbosacral
radiculopathy and that more distal muscles become abnormal later in the disease
process. The purpose of this study was to determine whether paraspinal muscles
and other major proximal and distal muscle abnormalities are related to
lumbosacral radiculopathy symptom duration. A multivariate logit analysis of 139
patients (retrospectively identified) with electrodiagnostically confirmed
lumbosacral radiculopathies was used to test these hypotheses. Maximum likelihood
estimates showed no evidence of correlation between abnormal paraspinal muscles
and symptom duration. Symptom duration was also insignificant for the remaining
five lower limb muscles analyzed. We conclude that the probability of having
electromyographic abnormalities is not related to symptom duration. A prospective
study is needed to confirm these findings. Nonetheless, clinicians should use
caution when interpreting electrodiagnostic findings based on symptom duration.
PMID- 9558008
TI - Comparison of visual inspection and statistical analysis of single-subject data
in rehabilitation research.
AB - Single-subject designs are being advocated to conduct outcome research in
rehabilitation environments. The methods provide an alternative to traditional
designs based on statistical comparisons across groups. Data analysis in single
subject research does not rely on statistical hypothesis testing of responses
collected from a sample of subjects. Instead, visual inspection of patient
responses graphed over time is the usual method of data analysis in single
subject research. This study examined the agreement between visual analysis and
statistical tests of single-subject data for 42 hypothetical single-subject
graphs. Specially constructed graphs allowed the systematic manipulation of
different treatment effect sizes across a commonly used single-subject design.
Thirty-two rehabilitation and health care providers rated each of the 42 graphs
to determine whether a clinically significant treatment effect existed across the
phases of the designs. Data analysis focused on two questions: (1) How much
agreement was there between visual judgments and the results of statistical
tests? and (2) What level of treatment effect was required to produce a finding
of visual versus statistical significance? The agreement between visual analysis
and statistical significance was high (86%). The sensitivity of visual inferences
compared with statistical test results was 0.84, specificity was 0.88, and
positive predictive value was 0.91. Both visual and statistical procedures were
sensitive to medium and large treatment effects in the 42 single-subject graphs
examined in this study.
PMID- 9558010
TI - Impaired hypothalamus-pituitary-adrenal axis in men with spinal cord injuries.
AB - Twenty-five men with spinal cord injuries were studied for evaluation of the
hypothalamus-pituitary-adrenal axis, using corticotropin-releasing hormone and
insulin-induced hypoglycemia. Twenty-five age-matched healthy male volunteers
served as controls. Three spinal cord-injured subjects had hyperprolactinemia,
three had elevated basal follicle-stimulating hormone levels, one had an elevated
basal luteinizing hormone level, and four had hypotestosteronemia. The mean
plasma adrenocorticotropin response to corticotropin-releasing hormone of spinal
cord-injured subjects was smaller than that of the healthy controls but did not
reach a statistical significance. The cortisol response to corticotropin
releasing hormone of the spinal cord-injured subjects was significantly lower
than that of healthy controls. However, the difference disappeared if a
correction was made for baseline values. Six spinal cord-injured subjects did not
have a cortisol response to insulin-induced hypoglycemia, and they had either a
minimal or no adrenocorticotropin response. Another 11 spinal cord-injured
subjects had a maximal cortisol response to insulin-induced hypoglycemia below
the lowest limit of normal, i.e., 0.5 micromol/l. Among these spinal cord-injured
subjects, three had a less than 50% increase of plasma adrenocorticotropin after
insulin-induced hypoglycemia. These findings are consistent with the notion that
spinal cord-injured subjects have an altered central neurotransmitter tone and
substantiate the hypothesis that an afferent neural pathway exists between the
adrenal and hypothalamus and may modulate stress-induced secretion of
adrenocorticotropin. Long-term abnormal adrenocorticotropin secretion may cause
mild adrenocortical atrophy and, thereby, a reduced cortisol response.
PMID- 9558011
TI - Common causes of knee effusions in spinal cord injury: a random study.
AB - Patients with spinal cord injury are predisposed to knee effusions owing to
osteoporosis, heterotopic ossification, trauma, and benign hydrarthrosis. This
retrospective review discusses 11 patients with spinal cord injury and knee
effusions seen during two years. One objective is to correlate the initial
diagnosis based on clinical findings with the final diagnosis based on synovial
fluid analysis and radiographic studies. Another is to describe the variety and
complexity of clinical situations that involve knee effusions in spinal cord
injury. The initial diagnosis was different from the final diagnosis in all of
our cases. The final diagnoses were trauma (6 cases), pseudogout (2 cases),
spasticity, fracture of the tibial plateau, septic joint, and tears of the
anterior cruciate and lateral collateral ligaments. Knee effusions in this unique
population must be carefully investigated to avoid erroneous diagnoses based on
the initial clinical presentation, which can be complicated by multiple medical
problems.
PMID- 9558012
TI - Evident transsynaptic degeneration of motor neurons after spinal cord injury: a
study of neuromuscular jitter by axonal microstimulation.
AB - Neuronal degradation accompanied with axonal degeneration has been known to occur
in spinal motor neurons after an upper level of spinal cord lesion. In the
present study, the functional integrity of neuromuscular transmission was
assessed by utilizing a sensitive electrodiagnostic method comprising of
stimulated single-fiber electromyography (SFEMG), along with axonal
microstimulation, in paralytic muscles of patients with spinal cord injury (SCI).
Neuromuscular jitter was measured in anterior tibial muscles for 30 patients with
SCI and also for 12 normal controls. Mean jitter of 37.4 +/- 14.7 (mean +/- SD)
micros, as obtained in SCI patients, was found to be significantly greater than
the results of 20.1 +/- 8.4 micros in normal controls (P < 0.01). Jitter
measurement was not significantly different in varied functional scales of SCI. A
positive correlation was noted between the increased jitter and the disease
duration from the onset of cord lesion till the time of stimulated SFEMG test (r
= 0.68; P < 0.01). The present abnormal finding of neuromuscular jitter provides
an electrophysiologic evidence for axonal degeneration and suggests that
transsynaptic degeneration of motor neuron may occur below the level of cord
lesion in SCI patients. Furthermore, the neuronal degradation in SCI was
positively correlated with the course duration of the disease.
PMID- 9558013
TI - Effect of activities of daily living on fiber type atrophy of the vastus
lateralis muscle in patients with joint disorders.
AB - The histopathologic study was performed to elucidate whether the fiber type
atrophy of the vastus lateralis muscle in patients with hip or knee joint
disorders is related to the activities of daily living (ADL) or habitual physical
activity. Subjects were 16 female patients, 52.4 +/- 16.0 yr of age (mean +/-
standard deviation), who underwent a vastus lateralis muscle biopsy at the time
of total hip or knee replacement. At the time of referral to the rehabilitation
center, the Functional Independence Measure (FIM) motor score and habitual
physical activity at home were evaluated, and the diameter and atrophy factor for
each muscle fiber type were measured on the histopathologic preparations of the
biopsied muscles. The data were analyzed using ttest, one-way analysis of
variance (ANOVA), Kruskal-Wallis one-way ANOVA, Spearman's correlation
coefficient, and partial correlation coefficient. The patients showed muscle
fiber atrophy and small angular fibers, and the atrophy factor was significantly
increased in type 1, 2A, and 2B fibers, in that order (one-way ANOVA, P < 0.05).
The patterns of the fiber type atrophy, consisting of normal, type 2B atrophy,
type 2AB atrophy, and type 1 and 2AB atrophy, had a significant relationship with
the fiber type atrophy (Spearman's correlation coefficient; rho = 0.834, P <
0.001). The FIM motor score showed a significant correlation with the atrophy
factor (r = -0.584, P < 0.05), and significant differences were recognized among
the four patterns of the fiber type atrophy (Kruskal-Wallis one-way ANOVA, P <
0.05). In conclusion, the muscle atrophy and patterns of the fiber type atrophy
of the vastus lateralis muscle in patients with joint disorders may be related to
changes in the FIM motor score.
PMID- 9558014
TI - Varied morphology of spontaneous single muscle fiber discharges.
AB - Fibrillation potentials and positive sharp waves have rather stereotypical
morphologies generally conforming to a triphasic initially positive and biphasic
initially positive waveform, respectively. Careful attention during the needle
electromyographic examination of muscle tissue with unstable resting membrane
potentials, however, frequently reveals spontaneous potentials with appearances
conforming to not only those described above but also waveforms with morphologies
that can best be characterized as a blend of both a fibrillation potential and
positive sharp wave. These "hybrid" or composite waveforms are hypothesized to
arise from an electrical summation of two single muscle fibers repetitively
discharging in a time-locked manner. Five individuals with lower motor neuron
disorders displaying spontaneous discharges at rest during the needle
electromyographic were examined. The spontaneous discharges were categorized
according to their morphology. Stereotypical positive and negative onset
fibrillation potentials and positive sharp waves from these patients were
digitized. Computer simulations summating the digitized waveforms were successful
in reproducing all of the observed "hybrid" waveforms documented in the patients.
The supposition of two single muscle fibers discharging within a temporal domain
conducive to electrical summation is an extension of the concept that electrical
summation of muscle fibers comprising a motor unit summate to generate an
electrical representation of that motor unit.
PMID- 9558015
TI - Subjective recovery time after exhausting muscular activity in postpolio and
control subjects.
AB - The purpose of this study was to determine whether the time to subjectively fully
recover after the performance of exhausting muscular exercise was greater in
unstable postpolio as compared with stable postpolio or control subjects. Twenty
five unstable (those complaining of declining muscle strength) postpolio, 16
stable (those denying declining muscle strength) postpolio, and 25 control
subjects performed an isometric contraction of the knee extensor (quadriceps
femoris) musculature at 40% of maximal torque until they were no longer able to
do so. Five-second maximal effort contractions were made every 30 s through 2 min
after the time of failure was reached and then at 1-min intervals through 10 min
after failure was reached. Subjects reported the duration of time required to
subjectively fully recover from this activity. Choices of "less than 1 day," "1
day," "2 days," etc., up to "greater than 2 wk" were given to the subjects for
their response. Analysis was by nonparametric ANOVA and appropriate post hoc
comparison procedures. Unstable postpolio subjects reported a greater recovery
time than either the stable postpolio or control subjects (mean +/- SD of 2.6 +/-
3.0 days, 0.6 +/- 1.0 days, and 0.7 +/- 1.1 days, respectively, P < 0.05). Thus,
the reported recovery time from exhausting isometric muscular exercise was found
to be greater in unstable postpolio subjects than stable postpolio or control
subjects. The cause for this finding is unknown and requires further
investigation.
PMID- 9558017
TI - Transient osteoporosis of the hip during pregnancy: a case report.
AB - Transient osteoporosis associated with pregnancy is a rare, self-limiting
skeletal disorder, the origin of which remains unclear. We report the case of a
36-year-old Japanese woman who developed pain in the left hip, groin, and knee in
the seventh month of pregnancy. The pain gradually worsened and prevented weight
bearing. The hip and knee pain progressed to bilateral involvement and persisted
after an emergent cesarean section at 35 weeks. Radiographs after delivery
revealed gross osteopenia of both the femoral heads, left distal femur, and
proximal tibia, consistent with transient osteoporosis associated with pregnancy.
The patient remained mostly wheelchair-dependent because of severe hip and knee
pain. Several weeks later, the patient was started on alendronate, a
biphosphonate, which provided dramatic relief of hip and knee pain. The patient's
ambulatory function subsequently improved dramatically as a result of pain relief
and assistance with gait training. This case is unique for several reasons.
First, it is rare for transient osteoporosis associated with pregnancy to involve
both hip joints, and it rarely involves the knee. Second, this is the first
reported case of pain management of transient osteoporosis associated with
pregnancy being successfully treated with an antiresorptive agent. Finally, the
use of alendronate in transient osteoporosis associated with pregnancy may help
shorten disability by providing pain relief and decreasing the fracture risk
associated with this disease.
PMID- 9558016
TI - Comparison of three protocols for breathing exercises during immersion in 38
degrees C water for chronic obstructive pulmonary disease.
AB - Respiratory function test, arterial blood gas analysis, and ejection fraction
were used to compare three protocols of breathing exercises during immersion in
38 degrees C water. Therapy was given for 2 mo to patients with stable chronic
obstructive pulmonary disease. Protocol A consisted of a total exercise period of
20 min/wk (10 min/day, 2 days/wk) and was performed by 7 patients (5 cases of
asthma and 2 cases of emphysema). Protocol B consisted of a total exercise period
of 120 min/wk (20 min x 2 per day at 10:00 am and 3:00 pm, 3 days/wk) and was
performed by 9 patients (6 asthmas and 3 emphysemas). Protocol C consisted of a
total exercise period of 120 min/wk (20 min/day, 6 days/wk) and was performed by
8 patients (4 asthmas and 4 emphysemas). The ratio of forced expired volume in
one second to forced vital capacity (FEV1.0%) was significantly increased in
protocols B and C (P < 0.01). The ratio of forced vital capacity to the predicted
normal value (%FVC) was not changed in any of the three protocols. A significant
increase in peak flow was observed in protocols B and C (P < 0.05). The maximal
expiratory flow at 25% (V25) was not changed in any of the three protocols. PaO2
was significantly increased and PacO2 was significantly decreased in protocol B
(P < 0.01 and P < 0.05, respectively), whereas only PaCO2 was significantly
decreased in protocol C (P < 0.05). Ejection fraction was increased in protocols
B and C. These results suggest that exercise for a total period of 120 min/wk is
preferable to that of 20 min/wk in COPD.
PMID- 9558018
TI - Paranoia--an unusual presentation of hydrocephalus.
AB - Hydrocephalus commonly occurs after traumatic brain injury. Normal pressure
hydrocephalus after traumatic brain injury is usually associated with a failure
to progress in therapy and a plateauing or regression of functional abilities.
Behavior disturbances are commonly seen as unfortunate sequelae of traumatic
brain injury. However, normal pressure hydrocephalus has not been reported to
cause aberrant, antisocial behavior. This case report details the course of a
patient who sustained a traumatic brain injury and, subsequently, developed
normal pressure hydrocephalus associated with paranoia, delusions, and violent
behavior.
PMID- 9558019
TI - Chronic fatigue syndrome: a literature review from a physiatric perspective.
AB - To examine the literature on chronic fatigue syndrome (CFS), especially as it
relates to cognitive deficits and exercise, more than 200 articles related to CFS
were selected from computer-based research as well as pertinent articles noted in
the references of individual articles. All were relevant articles on CFS,
although articles in a foreign language were excluded. CFS is a controversial
diagnosis of exclusion, but certain subgroups do appear to exist. It may
represent multiple diseases or multiple stages of the same disease. Although
cognitive deficits are commonly reported, the measured impairments are relatively
subtle and are in the area of complex information processing speed, or
efficiency. Magnetic resonance imaging, single-photon emission computer
tomography, and neuroendocrine studies present preliminary evidence suggestive of
the cerebral involvement primarily in the white matter. The weakness and fatigue
may be the result of alterations in the central nervous system, not in the
peripheral muscles. However, it is hard to separate the documented weakness and
endurance deficits from deconditioning. Autonomic symptoms such as orthostatic
intolerance and a predisposition to neurally mediated syncope may be explained by
cardiovascular deconditioning, a postviral idiopathic autonomic neuropathy, or
both. The review points out the need for more carefully designed studies of CFS
that focus on the relationship between neuropathology, psychopathology and
neuropsychologic functioning. The role of exercise as a stimulus for exacerbation
or in treatment needs to be further studied using clear diagnostic criteria as
well as control groups that carefully match the activity level.
PMID- 9558020
TI - Biomagnetic 3-dimensional spatial and temporal characterization of electrical
activity of human stomach.
AB - Biomagnetic measurements are based on the noninvasive recording of magnetic
signals produced by biological sources such as nervous system and muscle. The aim
of this study was to obtain multichannel magnetic field recordings from the human
gastrointestinal tract and to localize the sources of these signals three
dimensionally. The magnetic field was recorded in eight human healthy subjects
using a sensor array with 37 superconducting quantum interference devices
(SQUIDs); an electrogastrogram was recorded simultaneously. Biomagnetic source
localization was carried out with an iterative nonlinear optimization algorithm
using the model of an equivalent current dipole (ECD) and correlated to magnetic
resonance imaging (MRI) in four volunteers. Magnetogastrograms and
electrogastrograms demonstrated a similar frequency distribution with a peak at
3/min. In all subjects the centers of the calculated dipoles plotted vs time
showed a characteristic migration across the stomach area. One volunteer
demonstrated tachygastric episodes, during which his magnetic field amplitudes
increased fivefold and his dipole migration disappeared. In absence of an attack
his recordings changed to normal. This demonstrates multichannel magnetic
recordings can be used to localize the sources of the biomagnetic field, which
could be useful for the understanding of motility disturbances.
PMID- 9558021
TI - Effect of local injection of botulinum toxin on sphincter of Oddi cyclic motility
in dogs.
AB - To study effects of intrasphincteric injections of botulinum toxin on the
sphincter of Oddi cyclic motility and responses to motilin and cholecystokinin,
four conscious dogs with duodenal cannula underwent manometry of the common bile
duct, sphincter of Oddi, and duodenum. After baseline recording, each dog had
intrasphincteric injections of saline or botulinum toxin. The injections of
saline had no effect, whereas botulinum toxin significantly reduced mean basal
pressure, amplitude, and motility index of the sphincter of Oddi. These effects
took place in four to seven days and reached a maximum in seven to 10 days. The
basal pressure returned to the baseline level in 28 weeks, but the amplitude and
motility index remained low. The pressure parameters of motilin-induced premature
phase III-like activity also decreased, but action of cholecystokinin was not
affected. These results indicate that the botulinum toxin injections reduce
sphincter of Oddi phasic contractile activity for a prolonged period of time.
PMID- 9558022
TI - Small intestinal transit time and intraluminal pH in ileocecal resected patients
with Crohn's disease.
AB - The pH and transit times of the gut are important for the delivery of active drug
from several tablets used in the treatment of Crohn's disease (CD). Many patients
with CD undergo an ileocecal resection, which might influence small intestinal pH
and transit time. The effect of ileocecal resection on these variables has not
previously been studied. Intraluminal pH and transit time were measured in nine
ileocecal-resected CD patients and 13 healthy volunteers using pH-sensitive
radiocapsules. Small intestinal transit time (SITT) was significantly shorter in
ileocecal-resected patients (5.2 hr, controls 8.0 hr). The pH levels of the small
intestine were identical in patients and controls, whereas cecal pH was 0.9 pH
units higher in resected CD patients. The time spent with pH higher than 5.5,
6.0, 6.5, and 7.0 was significantly shorter in patients than in controls. There
was no correlation between the SITT and the length of resected ileum or between
the SITT and the time elapsed since the resection. We conclude that ileocecal
resection decreases the SITT and the time with pH higher than 5.5-7.0. The study
indicates that this reduction of the SITT is mainly due to the resection of the
ileocecal valve and is, to a certain extent, independent of the length of
resected ileum. An ileocecal resection might therefore affect the delivery of
active drug from tablets with pH-dependent delivery.
PMID- 9558024
TI - Polymorphism of motilin gene in patients with Crohn's disease.
AB - An increasing body of evidence supports the concept of genetic heterogeneity
within inflammatory bowel disease (IBD). In this study, a polymorphism of the
motilin gene, which determines an amino acid substitution in the motilin protein,
has been investigated in IBD patients. Fifty patients with ulcerative colitis
(UC), and 52 with Crohn's disease (CD) were investigated for anti-neutrophil
cytoplasmatic antibodies (ANCA) and the polymorphism in the second exon of the
motilin gene. Sixty unrelated blood donors served as controls. ANCA were found in
30% of UC and 13% of CD. In controls the DNA polymorphism identified two alleles
(1 and 2) at a frequency of 42% and 58%, respectively. Patients with either UC or
CD showed a slight increase in the frequency of allele 2 (69% and 60%,
respectively; P > 0.05 vs controls). This allele was predominant in ANCA-positive
CD patients (86%; P < 0.04) while in UC it did not differ. All ANCA-positive CD
patients had the disease confined to the colon. A polymorphism of second exon of
the motilin gene, leading to a protein variant, is significantly more frequent in
the subset of ANCA-positive CD patients. This subgroup of patients appears to
share peculiar genetic and clinical features.
PMID- 9558025
TI - Refractory, disfiguring vulvar pyoderma gangrenosum and Crohn's disease.
PMID- 9558023
TI - IL-10 synergizes with IL-4 and IL-13 in inhibiting lysosomal enzyme secretion by
human monocytes and lamina propria mononuclear cells from patients with
inflammatory bowel disease.
AB - Tissue injury and inflammation in inflammatory bowel disease (IBD) are associated
with enhanced monocytic lysosomal enzyme release. In this study, peripheral
monocytes and lamina propria mononuclear cells (LPMNC) were isolated from IBD
patients and normal controls. Cells were stimulated with lipopolysaccharide after
treatment with IL-13, IL-4, and IL-10, and enzyme secretion was assessed by using
the corresponding p-nitrophenyl glycosides as substrates. Molecular forms of
cathepsin D were examined to describe the mode of enzyme release. IL-10 and IL-4
strongly down-regulate enzyme secretion in IBD monocytes. IBD monocytes showed a
diminished responsiveness to the inhibitory effect of IL-13. Impaired monocyte
response was not found with combinations of IL-13 and IL-10 or IL-4 and IL-10.
LPMNC from involved IBD mucosa showed significantly higher enzyme secretion
compared with LPMNC from noninvolved IBD mucosa but responded inefficiently to
either IL-4, IL-13, or IL-10 alone. However, combined treatment with IL-10 and IL
4 or IL-10 and IL-13 strongly suppressed enzyme release by these cells. Both the
precursor and mature forms of cathepsin D were elevated in IBD patients. While IL
13 reduced mainly the precursor form, the effect of IL-4 and IL-10 concerns both
the precursor and mature form of cathepsin D. Our results favor the potent
clinical utility of combined treatment, thus improving chances of developing
effective treatments for human IBD.
PMID- 9558026
TI - Increased prevalence of autoantibodies in celiac disease.
AB - Several features suggest an immune mechanism operates in celiac disease.
Information on the autoantibody repertoire in this condition is lacking. The
purpose of the study was to investigate the reactivity of celiac patients sera to
various autoantigens widely distributed in the human intestine. Seventy children,
celiacs and controls, were evaluated for serum autoantibodies using ELISA and
immunofluorescence. Celiac patients had increased prevalence of serum anti-single
stranded DNA (14%), anti-double-stranded DNA (23%), anti-cardiolipin (14%), and
anti-endomysial autoantibodies (63%). The relevance of this finding on the
extraintestinal manifestations of celiac disease or the coexistence of autoimmune
conditions and celiac disease remains to be determined.
PMID- 9558028
TI - Effects of fiber laxatives and calcium docusate on regional water content and
viscosity of digesta in the large intestine of the pig.
AB - The aim of this study was to determine how bulk fibers and calcium docusate
affect regional dehydration and digesta viscosity throughout the large intestine.
Fifty-two pigs were fed a chow diet supplemented with a bulk laxative, placebo,
or calcium docusate for three days, after which the pigs were sacrificed and the
contents of the large bowel were analyzed. Digesta occurred as a continuum from
liquid (cecum, 91.2% water content) to solid (rectum, 70.5% water content). The
observed 20.7% difference in water content resulted in a 240-fold increase in
viscosity. Half of this water is reabsorbed in the first 18% of the large bowel
length where viscosity remains relatively low. Compared to placebo, calcium
docusate and calcium polycarbophil had no significant effect on digesta water
content or viscosity, polycarbophil exhibited significantly (P < 0.05) lower
digesta viscosity in three bowel segments, and psyllium exhibited significantly
(P < 0.01) lower viscosity in six bowel segments and higher water content in nine
bowel segments. In conclusion, the majority of digesta dehydration occurs early
in the proximal large bowel, while the greatest increases in viscosity occur in
the distal bowel. Relatively small decreases in digesta water content result in
large increases in digesta viscosity. Psyllium, and to a lesser extent
polycarbophil, are able to resist dehydration, resulting in a softer digesta.
PMID- 9558027
TI - Mast cell degranulation induces delayed rectal allodynia in rats: role of
histamine and 5-HT.
AB - Visceral hypersensitivity is a common feature of functional bowel disorders,
where an increased number of mast cells have often been described. Thus, we
investigated the effect of an experimental mast cell degranulation induced by BrX
537A on somatic (tail heating) and visceral (rectal distension) sensitivity in
rats and the involvement of histamine and/or serotonin on this last response.
After BrX-537A administration, the latency of tail withdrawal reflex was
shortened within the 2- to 8-hr period. Moreover, BrX-537A reduced the distension
volume threshold from 0.8 ml to 0.4 ml inducing allodynia, from 6 to 12 hr after
its administration. This effect was suppressed by doxantrazole (mast cell
stabilizing agent) and WAY 100635 (5-HT1A receptor antagonist), and reproduced by
5-HTP (5-HT precursor) and 8-OH-DPAT (5-HT1A receptor agonist). However, neither
granisetron (5-HT3 receptor antagonist) nor H1, H2, or H3 histamine receptor
antagonists modified the BrX-537A-induced allodynia. Consequently, mast cell
degranulation initiates a delayed somatic and visceral allodynia, with the
participation of serotonin, through 5-HT1A receptor activation, on the visceral
response.
PMID- 9558029
TI - Cytomegalovirus-induced gastrointestinal disease in previously healthy adults.
PMID- 9558030
TI - Asymptomatic Helicobacter pylori gastritis is associated with increased sucrose
permeability.
AB - Our aim was to investigate whether there are changes in permeability to sucrose
in asymptomatic Helicobacter pylori gastritis. Nineteen asymptomatic subjects
with Helicobacter pylori-associated gastritis with no or mild mucosal atrophy and
19 age- and sex-matched normal controls were studied by peroral load of sucrose
(100 g). The fraction of the given oral dose of sucrose excreted in urine was
increased in subjects with Helicobacter pylori gastritis (median 0.08% versus
0.04% in controls). Sucrose excretion was not related to atrophy, intestinal
metaplasia, or inflammation in the gastric mucosa. However, sucrose permeability
was related to the degree of inflammatory (neutrophil) activity, since moderate
activity was associated with higher sucrose excretion than mild activity (median
0.13% vs 0.07%). Asymptomatic Helicobacter pylori gastritis was associated with
an increased sucrose permeability, which could be a sign of gastric mucosal
leakage. This could have implications for the diseases and complications
associated with Helicobacter pylori infection.
PMID- 9558031
TI - Pathological changes in the formation of Helicobacter pylori-induced gastric
lesions in Mongolian gerbils.
AB - We examined pathological changes in the formation of Helicobacter pylori-induced
gastric lesions in Mongorian gerbils. H. pylori (NCTC11637) was orally
administered once to the animals and was detected in the gastric mucosa of all
gerbils given the bacteria. The number of viable H. pylori increased during the
initial two weeks and thereafter reached a plateau level. The initial
pathological changes were found at one week, ie, edema/congestion and a white
viscous substance only in the antrum. At two weeks, superficial damage appeared
in the antrum, although inflammatory cell infiltration had not occurred.
Gastritis with lymphoid follicles was observed in the antrum and fundus from
three weeks. At four weeks, mucosal lesions were detected as a few hemorrhagic
spots in the fundus adjacent to the antrum. In the control animals, however, no
pathological changes were observed even at four weeks. In the gastric mucosa
infected with H. pylori, myeloperoxidase activity was negligible at two weeks,
but was extremely elevated at four weeks. Similarly, neutrophil chemotactic
activity was only slightly increased at two weeks, but was markedly elevated at
four weeks. These results indicate that H. pylori infection induces initial
pathological changes only in the antrum, but mucosal lesions occur in the fundus
adjacent to the antrum. Furthermore, it is demonstrated that the initial
superficial damage is generated by factors other than chemokines and neutrophil
associated factors, although mucosal inflammation may contribute to the
subsequent formation of lesions and ulcers.
PMID- 9558033
TI - Prevalence of Helicobacter pylori infection in children from urban and rural West
Virginia.
AB - Our objective was to evaluate the prevalence rate of Helicobacter pylori (HP) in
children from urban and rural areas of West Virginia. In all, 1164 blood samples
were collected from children who attended a local health fair, pediatric clinics,
and emergency departments of four different hospitals located in urban and rural
counties. Socioeconomic status was determined in 303 children. Serum HP antibody
(IgG) was measured by enzyme immunoassay (EIA). A total of 468 (40%) samples were
HP positive. HP acquisition correlated with increasing age, family crowding, and
community location (urban/rural) but not with gender, water source used
(city/well), or socioeconomic status. The prevalence rate of HP in the children
of West Virginia is higher than any data previously reported from the United
States. The results correlated with only few socioeconomic criteria, suggesting
that other factors may contribute to the increased prevalence of HP infection in
the children of West Virginia.
PMID- 9558032
TI - Low prevalence of Helicobacter pylori infection in patients with hamartomatous
fundic polyps.
AB - Helicobacter pylori infection of the gastric mucosal surface was investigated in
patients with hamartomatous fundic polyps or hyperplastic polyps and in patients
without endoscopic evidence of disease (healthy subjects). Presence of H. pylori
infection was determined by culture, histologic examination, and the endoscopic
phenol red test. Adherence of H. pylori was evaluated with scanning electron
microscopic examination of antral biopsy specimens. Both prevalence of H. pylori
infection (P < 0.001) and H. pylori adherence (P < 0.05) were less in patients
with hamartomatous fundic polyps than in healthy subjects and patients with
hyperplastic polyps. However, the percentages of plasma cells in gastric mucosa
that contained IgA and of gastric epithelial cells that expressed Lewis b did not
differ significantly among the three groups. These findings suggest that defense
mechanisms against the attachment of H. pylori other than IgA or Lewis b antigen
are present in patients with hamartomarous fundic polyps.
PMID- 9558035
TI - Phosphatidylcholine-associated aspirin accelerates healing of gastric ulcers in
rats.
AB - Based on our previous studies that aspirin (ASA) -induced gastric ulceration in
rats can be significantly reduced if the drug is chemically associated with
phosphatidylcholine (PC), we undertook the present study to compare gastric ulcer
healing rates in rats administered either unmodified or PC-complexed ASA. Gastric
ulcers were induced in anesthetized rats by briefly exposing the mucosal surface
to 0.2 ml 60% acetic acid followed by randomization of the rats to study groups;
daily intragastrically administered saline (control), ASA (36, 54 mg/kg), or ASA
PC complex. In contrast to the 65-70% reduction in ulcer size recorded in
controls, ulcer healing was significantly retarded in rats administered
unmodified ASA. Conversely, the size of the experimentally induced ulcers was
less than control values in rats daily administered the PC-associated ASA,
suggesting an acceleration in the rate of ulcer healing. Daily intragastric
administration of ASA to rats over the study period also resulted in a
significant decrease in surface hydrophobicity from control values as measured by
contact angle analysis. However, surface hydrophobicity was partially restored in
rats administered the PC-complexed ASA. Consistent with these findings, it was
determined that ASA-treated rats had a lower hematocrit than control values, as
an index of gastrointestinal bleeding, whereas this parameter remained at control
levels in rats administered the PC-complexed ASA. We conclude that PC-associated
ASA promotes ulcer healing above the values measured in rats treated with ASA or
saline. This property may be attributable to the fact that in contrast to
unmodified ASA, which aggravates ulcer healing by transforming the stomach to an
acid-permeable state, the protective hydrophobic lining of the stomach is
maintained in rats administered PC-associated ASA, thereby allowing ulcer healing
of the tissue to proceed.
PMID- 9558034
TI - Double-blind comparison of lansoprazole 15 mg, lansoprazole 30 mg, and placebo in
the maintenance of healed gastric ulcer.
AB - Our purpose was to compare the safety and efficacy of lansoprazole 15 mg and 30
mg with placebo in preventing recurrence in 49 patients with a history of gastric
ulcer. Within one month, 40% of patients receiving placebo experienced ulcer
recurrence compared to 0% and 7% of patients receiving lansoprazole 15 mg and 30
mg, respectively. All placebo patients became symptomatic, experienced ulcer
recurrence or withdrew from the study by month 9. As compared to placebo, a
significantly (P < 0.001) higher percentage of patients treated with lansoprazole
15 mg (83%) and lansoprazole 30 mg (93%) with healed gastric ulcer disease
remained healed at month 12. Of patients asymptomatic at baseline, 100% and 59%
of those treated with lansoprazole 15 mg and 30 mg, respectively, remained
asymptomatic at month 12. The incidence of adverse events was comparable among
the treatment groups. Lansoprazole safely and effectively reduces ulcer
recurrence in patients with a history of gastric ulcer disease.
PMID- 9558036
TI - Gastroduodenal mucosal protection induced by dehydroleucodine: mucus secretion
and role of monoamines.
AB - In previous work we have demonstrated that dehydroleucodine (DhL) prevents
gastric damage induced by necrosis-inducing agents such as absolute ethanol
(EtOH). In this study we examine the effects of DhL on gastroduodenal morphology
and monoamine levels by histological and biochemical methods, respectively, as an
approach to elucidating the cytoprotective mechanism of the drug. Histological
evidence shows that DhL prevents formation of gastroduodenal mucosal lesions
induced by EtOH and that this protective effect is related to the ability of the
drug to stimulate mucus production. DhL itself does not affect the tissue
concentration of NE, DA and 5-HT. However, it prevents the depletion of DA and 5
HT provoked by EtOH. We propose that the abundant mucoid blanket secreted after
treatment with DhL acts as a diffusion barrier against EtOH. It is also possible
that DhL could act as a "cell stabilizer," by inhibiting the degranulation of
cells containing monoamines.
PMID- 9558037
TI - Inhibition of human gastric lipase secretion by glucagon-like peptide-1.
AB - Glucagon-like peptide-1 (GLP-1) may be one of the enterogastrone hormones of the
ileal brake mechanism. We therefore studied its effects on gastric lipase
secretion in healthy volunteers and vagotomized patients during infusion of
pentagastrin. The intestinal incretin hormone GLP-1 (glucagon-like peptide-1, 7
36 amide) was investigated because of its inhibitory effects on gastric acid
secretion and motility. GLP-1 infused intravenously in amounts corresponding to
the postprandial release significantly inhibited pentagastrin-stimulated gastric
lipase secretion and lipolytic activity. The inhibitory effect of GLP-1 persisted
in vagotomized patients, suggesting that fundic chief cells, from which gastric
lipase is released, or neighboring inhibitory cells could be equipped with GLP-1
receptors. Vagotomized patients had significantly higher plasma concentrations of
gastrin and secretin. No significant changes of gastrin, secretin, and CCK
secretion were seen during GLP-1 infusion in the vagotomized patients, whereas
secretin decreased significantly in the healthy volunteers. GLP-1 seems to be a
naturally occurring inhibitor of gastric lipase secretion acting via a nonvagal
mechanism. Our results indicate that gastric lipase secretion is subject to
hormonal stimulatory as well as inhibitory mechanisms.
PMID- 9558038
TI - Adaptive cytoprotection against deoxycholate-induced injury in human gastric
cells in vitro: is there a role for endogenous prostaglandins?
AB - The majority of previous work investigating adaptive cytoprotection has involved
in vivo studies, which have suggested that this protective response is in large
part mediated by endogenous prostaglandins (PGs). The aim of this study was to
investigate adaptive cytoprotection under in vitro conditions in human gastric
cells and to better delineate the role of endogenous PGs in this protective
response. AGS cells (a human gastric carcinoma cell line) were characterized
morphologically and subsequently used for all experiments. Sodium deoxycholate
was used as both the mild irritant and the damaging agent, and cell injury was
quantified using both a commercial viability/cytotoxicity kit as well as
transepithelial permeability studies. Finally, endogenous PG synthesis in
response to varying concentrations of deoxycholate was determined. AGS cells were
determined to be morphologically similar to gastric mucous cells. Pretreatment of
cells with low-dose deoxycholate significantly attenuated injury upon subsequent
exposure to damaging concentrations of deoxycholate, and this protection was
determined to be dependent upon both concentration and duration of mild irritant
exposure. Preincubation of AGS cells with indomethacin reversed protection
induced by mild irritant pretreatment and also significantly increased cellular
susceptibility to injury. Results of the permeability studies closely paralleled
those assessing cell mortality. While deoxycholate exposure increased PG
synthesis, the concentrations required were much higher than those needed to
initiate protection. Adaptive cytoprotection exists in AGS cells under in vitro
conditions independent of intact blood flow, neural innervation, or circulating
humoral mediators. While this protection is reversed by indomethacin, it appears
that this reversal results from increased cellular injury secondary to diminished
basal PGs, rather than inhibition of endogenous PG synthesis.
PMID- 9558039
TI - Gastroprotection by 4-methylpyrazole against ethanol in humans.
AB - 4-Methylpyrazole (4-MP), a specific inhibitor of alcohol dehydrogenase, exerts
gastroprotection of unusually long duration in rats. We tested the hypothesis
that pretreatment with 4-MP might protect the human gastric mucosa against
alcohol-induced acute injury. Fourteen healthy volunteers received pretreatment
with either 4-MP, 15 mg/kg body weight dissolved in 50 ml of orange juice, or
placebo and 2 hr later 100 ml of 40% ethanol. The endoscopic appearance of the
gastric mucosa was evaluated and scored (scale 0-5) and mucosal biopsies were
obtained just before pretreatment and 30 min after ethanol for histologic
examination and prostaglandin E2 measurement. In the 4-MP group the mean
endoscopic injury score was significantly lower than that in placebo group, in
both the body and the antrum. Histologically, 4-MP significantly reduced
disruption of surface epithelium and completely prevented the deep hemorrhagic
mucosal lesions. In the 4-MP group no changes in gastric mucosal PGE2 levels were
detected. In rats, 4-MP did not inhibit gastric acid output, whereas it markedly
increased the adherent gastric mucus evaluated by the alcian blue recovery
method. When lipid peroxidation was induced by carbon tetrachloride in hepatic
microsomes, 4-MP caused significant inhibition of malondialdehyde generation. We
conclude that 4-MP provides significant protection of the human stomach against
alcohol-induced acute mucosal injury. 4-MP, besides inhibiting the conversion of
alcohol to acetaldehyde, might protect the gastric mucosa by increasing adherent
gastric mucus and by scavenging free radicals.
PMID- 9558040
TI - Bombesin prevents gastric injury in the rat: role of gastrin.
AB - Bombesin or gastrin-releasing peptide prevents gastric injury by an unknown
mechanism. Since exogenous gastrin is a gastroprotective agent, this study was
undertaken to test the hypothesis that gastroprotection by bombesin involves
release of endogenous gastrin. Subcutaneous bombesin (10-100 microg/kg) dose
dependently reduced macroscopic injury to the acid-secreting portion of the
stomach caused by 1 ml of orogastric acidified ethanol (150 mM hydrochloric acid
50% ethanol). Blockade of type A cholecystokinin receptors with intraperitoneal
MK-329 (1 mg/kg) reversed intravenous cholecystokinin (5 nmol/kg)-induced
gastroprotection, but not that of bombesin. In contrast, intraperitoneal type B
cholecystokinin (gastrin) receptor blockade with L-365,260 (25 mg/kg) diminished
the protective actions of both subcutaneous bombesin (100 microg/kg) and
intravenous gastrin (25 pmol/kg). In additional studies, subcutaneous bombesin
(10-100 microg/kg) dose dependently increased serum gastrin levels
(radioimmunoassay). Both the gastroprotective actions of bombesin and bombesin
induced gastrin release were enhanced following immunoneutralization of
endogenous somatostatin with intraperitoneal somatostatin antibody (2 mg). These
data indicate that bombesin prevents gastric injury primarily by release of
endogenous gastrin and both effects are modified by endogenous somatostatin.
PMID- 9558041
TI - Impact of ingested liquids on 24-hour ambulatory pH tests.
AB - A prospective investigation of the impact of ingested liquids on 24-hr pH test
scores was conducted. Eighty-two patients contributed 142 samples. The liquids
used were coffee/tea (N = 35), water (N = 32), fruit juice (N = 29), cola (N =
34), and beer (N = 12). The pH of cola, juice, and beer are approximately 3.0.
The parameters studied included: total test time, total drink time, total minutes
of pH < 4.0 during drink, minutes of < pH 4.0 10 min before drink, and minutes of
pH < 4.0 10 min following drink. Analysis was performed using one-way ANOVA and
repeated measures. Age of patients, total test time, and total time pH < 4.0 were
not significantly different (P > 0.05). The total time to consume the drink was
significantly greater (P < 0.05) for beer than all other liquids. The total time
(7.7 +/- 6.0 min) pH < 4.0 for cola was significantly different (P < 0.023) than
beer (3.3 +/- 3.7 min), tea/coffee (1.4 +/- 6.5 min), and water (1.1 +/- 2.5
min). The percentage of total time pH < 4.0 was not significantly different (P >
0.05) among any of the liquids. The percentage of time pH < 4.0 during the drink
was the highest for cola (63 +/- 47%) and juice (51 +/- 57%); water, coffee/tea,
and beer were not significantly different (P > 0.05). Although the impact of cola
and juice were the greatest, none of these had an impact that exceeded 0.5%. The
lack of impact of beer appears to be due to the increased period of time it takes
to consume. We conclude that the impact of ingested fluids is minimal and can
probably be disregarded in most patient groups.
PMID- 9558043
TI - Concurrent fluoroscopy and manometry reveal differences in laparoscopic Nissen
and anterior fundoplication.
AB - A prospective double-blind randomized trial was initiated to examine two types of
laparoscopic fundoplication (Nissen and anterior). Thirty-two patients with
proven gastroesophageal reflux disease presenting for primary laparoscopic
antireflux surgery were randomized to undergo either Nissen fundoplication (N =
13) or anterior hemifundoplication (N = 19). Postoperative fluoroscopic and
manometric examination was carried out concomitantly. Nissen fundoplication
resulted in significantly greater elevation of resting (33.5 vs 23 mm Hg) and
residual lower esophageal sphincter pressures (17 vs 6.5 mm Hg) and lower
esophageal ramp pressure (26 vs 20.5 mm Hg) than the anterior partial
fundoplication. A smaller radiologically measured sphincter opening diameter was
seen following Nissen fundoplication (9 mm) compared with anterior fundoplication
(12 mm). Lower esophageal ramp pressure correlated weakly (r = 0.37, P = 0.04)
with postoperative dysphagia. It is concluded that the type of fundoplication
performed significantly influences postoperative manometric and video barium
radiology outcomes. The clinical relevance of this requires further
investigation.
PMID- 9558042
TI - Effect of amino acids on lower esophageal sphincter characteristics and
gastroesophageal reflux in humans.
AB - The effect of a commercially available mixed amino acids solution, when given
either intravenously or intragastrically, on lower esophageal sphincter (LES)
pressure, frequency of transient LES relaxations (TLESRs) and gastroesophageal
reflux (GER) was investigated in six healthy volunteers. LES pressure and
esophageal pH were simultaneously recorded on three separate occasions 1 hr
before (basal) and 3 hr during intravenous or intragastric infusion of amino
acids (250 mg protein/kg/hr) or saline (control). No significant changes in LES
pressure were seen in the control experiment. Intravenous amino acids caused a
rapid and sustained (P < 0.01) decrease in LES pressure whereas intragastric
amino acids decreased LES pressure only gradually and temporarily (P < 0.01). In
the three experiments no significant differences were observed in TLESR
frequency, the number of GER episodes, the mechanism of reflux, or duration of
acid exposure. In healthy subjects both intragastric and, especially, intravenous
infusion of amino acids significantly decrease LES pressure but do not affect the
frequency of TLESRs or GER episodes during a continuous liquid gastric load.
PMID- 9558044
TI - Most Helicobacter pylori-infected patients have specific antibodies, and some
also have H. pylori antigens and genomic material in bile: is it a risk factor
for gallstone formation?
AB - Bile may contain a 130-kDa protein endowed with aminopeptidase activity and the
ability to promote cholesterol crystallisation. As >90% of H. pylori strains have
a similar peptidase activity, and half the isolates express a 110- to 140-kDa
antigen, the CagA protein, we investigated a possible association between H.
pylori infection and gallstones, and the presence in bile samples of factors
related to H. pylori that could increase cholesterol crystallization. The
prevalence of H. pylori infection was 82.1% in 112 patients with gallstones and
80.3% in 112 controls (NS). Fifteen bile samples out of 23 specimens from
infected patients (65.2%) contained anti-CagA antibodies. A approximately 60-kDa
antigen only reacting with an anti-CagA antibody was found in five bile samples
(21.7%) from 23 infected patients. One bile sample (4.1%) contained ureA and cagA
genes of H. pylori. The homology of CagA with the N-terminal sequence of
aminopeptidase N was very low. We concluded that the presence of specific
antibody to H. pylori in most bile samples tested and of an H. pylori putative
antigen in a discrete number of cases may represent factors that increase the
risk of gallstone formation.
PMID- 9558045
TI - Intracellular calcium affects neutrophil chemoattractant expression by
macrophages in rats with cerulein-induced pancreatitis.
AB - Pancreatitis complicated with infection often results in the development of
multiple organ failure. We investigated the role of altered intracellular calcium
as a priming signal for cytokine-induced neutrophil chemoattractant expression in
this process. Agents modulating cytosolic Ca2+ were utilized to study the in vivo
and in vitro cytokine-induced neutrophil chemoattractant expression for
macrophages in rats with cerulein-induced pancreatitis after intraperitoneal
administration of lipopolysaccharide as a septic challenge. Pretreatment with the
calcium channel blocker verapamil significantly reduced serum cytokine-induced
neutrophil chemoattractant concentrations in rats with cerulein-induced
pancreatitis after septic challenge. Lipopolysaccharide-stimulated in vitro
cytokine-induced neutrophil chemoattractant (CINC) production by peritoneal
macrophages was significantly enhanced by pretreatment with thapsigargin (an
inhibitor of the endoplasmic reticulum-resident Ca2+-ATPase), but not by A23187
(a calcium-specific ionophore, extracellular Ca2+ influx). Pretreatment with
U73122 (a phospholipase C inhibitor) inhibited lipopolysaccharide-stimulated but
not basal cytokine-induced neutrophil chemoattractant production, while verapamil
(a calcium channel blocker), TMB-8 (an inhibitor of calcium release from
endoplasmic reticulum), and W7 (calmodulin antagonist) completely abrogated the
chemoattractant production. Altered intracellular calcium, due to Ca2+ efflux
from intracellular stores, may be involved in the "priming" of macrophages to
release cytokine-induced neutrophil chemoattractant following triggering with
lipopolysaccharide during acute cerulein pancreatitis.
PMID- 9558046
TI - Lymphoepithelial cyst of the pancreas: a case report and review of the
literature.
PMID- 9558047
TI - Analysis of human T-cell antigen receptor variable beta gene usage following
vaccination with recombinant HBsAg.
AB - We analyzed the TcR Vbeta gene usage before and after vaccination with the
hepatitis B vaccine since changes in the TcR Vbeta gene families would be
considered to provide preliminary evidence of a mechanism to prevent HBV
infection. Six healthy adult volunteers received immunizations. TcR Vbeta usage,
T-cell proliferation, and HLA class II alleles were examined in peripheral blood
mononuclear cells (PBMC) both before and after vaccination. Furthermore, TcR
Vbeta usage in postimmunization PBMC was also compared with PBMC cultured with
recombinant HBsAg (rHBsAg). The level of in vitro T-cell proliferation in the
presence of rHBsAg increased significantly (P < 0.01) in PBMC isolated after
vaccinations. Increases in the different TcR Vbeta genes were also observed in
each individual following vaccinations, regardless of the similarity in their HLA
alleles. Specific HBV-related antigen-responsive T cells were induced after HB
vaccination, without any common restriction for the TcR Vbeta gene families. The
mechanism that helps prevent HBV infection was thus found to involve multiclonal
alterations in the TcR Vbeta repertoire.
PMID- 9558048
TI - Ultrastructural study of development of hepatic necrosis induced by TNF-alpha and
D-galactosamine.
AB - Recent studies have suggested an association between tumor necrosis factor-alpha
(TNF-alpha) and the development and progression of acute liver failure. To
investigate the role of TNF-alpha in the mechanism of massive hepatic necrosis,
we studied a mouse model of TNF-alpha and D-galactosamine (GalN) -induced hepatic
necrosis by ultrastructural analysis. Administration of GalN caused edema of
hepatocellular microvilli and widening of sinusoidal endothelial fenestrae (SEF);
administration of TNF-alpha caused only a widening of the SEF. Massive hepatic
necrosis with hemorrhage was seen 6 hr after concomitant administration of TNF
alpha and GalN. In the ultrastructural analysis, edema of the hepatocellular
microvilli, widening of the SEF, and transmigration of red blood cells (RBC) and
platelets to the space of Disse without exfoliation and necrosis of the
sinusoidal endothelial cells were observed. Fibrin deposits were seen in areas
adjacent to injured hepatocytes. The diameter of the SEF was significantly
greater than in the nontreated group and the groups treated with TNF-alpha or
GalN alone. These results suggest that as a consequence of the increase in
diameter of the SEF, transmigration of RBCs and platelets to the space of Disse
may have resulted in massive hepatic necrosis due to occlusion of the
microcirculation.
PMID- 9558049
TI - Chronic splanchnic hemodynamic effects of spironolactone with unrestricted sodium
diet in patients with compensated cirrhosis.
AB - The purpose of this study is to determine the hemodynamic effects of
spironolactone administration associated with an unrestricted sodium diet (salt
10 g) in patients with compensated cirrhosis and portal hypertension. We studied
the hemodynamic changes following eight weeks of administration of either placebo
(N = 6) or spironolactone (100 mg/day) (N = 6 Pugh-Child's A and 6 B). No
significant changes were observed after the administration of the placebo.
Spironolactone induced a significant reduction in the hepatic venous pressure
gradient (HVPG) (-10.1 +/- 13.3%, P < 0.05), which was associated with a
significant reduction of cardiac output (-11.5 +/- 9.3%, P < 0.01), plasma volume
(-8.1 +/- 4.7%, P < 0.01), and wedged hepatic venous pressure (-10.5 +/- 11.6%, P
< 0.05). There was no significant change in hepatic blood flow and there was no
significant correlation between the change in the HVPG and the change in
circulating plasma volume. A decrease in the HVPG greater than 10% was observed
in eight of 12 patients (67%), defined as responders, at eight weeks. Six of six
(100%) grade A patients and two of six (33%) grade B patients responded. This
study demonstrated that spironolactone with an unrestricted sodium diet decreased
the HVPG in grade A patients but did not significantly decrease the HVPG in grade
B patients.
PMID- 9558050
TI - Gastric cancer occurring at anastomosis after gastrojejunostomy without
gastrectomy.
PMID- 9558051
TI - Adenocarcinoma of the upper esophagus arising in cervical ectopic gastric mucosa:
rare evidence of malignant potential of so-called "inlet patch".
PMID- 9558052
TI - Polypoid ganglioneuroma of colon.
PMID- 9558053
TI - The history of the Southwestern Surgical Congress: 1949-1998. Introduction.
PMID- 9558054
TI - 50 years of abdominal surgery at the Southwestern Surgical Congress: common
problems and uncommon surgeons.
PMID- 9558055
TI - 50 years of thoracic and cardiac surgery at the Southwestern Surgical Congress:
from tuberculosis to the artificial heart.
PMID- 9558056
TI - 50 years of vascular surgery at the Southwestern Surgical Congress: evolution of
a new specialty.
PMID- 9558057
TI - 50 years of breast, endocrine, and oncologic surgery at the Southwestern Surgical
Congress: earlier diagnosis and improved outcomes.
PMID- 9558058
TI - 50 years of trauma, burns, and surgical critical care at the Southwestern
Surgical Congress.
PMID- 9558059
TI - 50 years of general surgery at the Southwestern Surgical Congress.
PMID- 9558060
TI - CpG oligodeoxynucleotides trigger protective and curative Th1 responses in lethal
murine leishmaniasis.
AB - Synthetic oligodeoxynucleotides containing CpG dinucleotides (CpG-ODN) mimic the
immunostimulatory qualities of bacterial DNA. We asked whether immunostimulation
by CpG-ODN predisposes for a commitment toward a Th1 vs a Th2 response in
Leishmania major infection, a model for a lethal Th2-driven disease, in BALB/c
mice. CpG-ODN induced Th1 effector T cells in vitro and conveyed protective
immunity to disease-prone BALB/c mice in vivo. Conversion to a Th1-driven
resistant phenotype was associated with IL-12 production and maintained the
expression of IL-12R beta2-chains. Most strikingly, CpG-ODN were even curative
when given as late as 20 days after lethal L. major infection, indicating that
CpG-ODN revert an established Th2 response. These findings imply an important
role of bacterial DNA and CpG-ODN in the instruction of adaptive immune
responses. They also point to the therapeutic potential of CpG-ODN in redirecting
curative Th1 responses in Th2-driven disorders.
PMID- 9558061
TI - Predictable TCR antigen recognition based on peptide scans leads to the
identification of agonist ligands with no sequence homology.
AB - The potential of CD4+ T cells for cross-recognition of self and foreign Ags has
important implications for the understanding of thymic selection, lymphocyte
survival, and the occurrence of autoimmune diseases. Here, we define the
extensive flexibility of Ag recognition for three human CD4+ autoreactive T cell
clones (TCC) by using ligands with single and multiple amino acid (aa)
substitutions. Our results demonstrate that the spectrum of tolerated ligands and
the resulting stimulatory potency of peptides for a TCC can be predicted by the
relative influence of each aa. Using this approach, we have identified
stimulatory ligands not sharing a single aa in corresponding positions with the
Ag used to establish the TCC. These results argue for an independent contribution
of each aa in the peptide sequence to the affinity of the MHC/peptide complex to
the TCR.
PMID- 9558062
TI - Liposomal formulation of a self lymphoma antigen induces potent protective
antitumor immunity.
AB - We developed a liposome carrier for a model nonimmunogenic, self Ag. This carrier
reproducibly converted lymphoma Ig into a potent tumor rejection Ag in mice. A
single immunization induced protection against challenges representing 20 to 100
times the minimum lethal dose of parental tumor. This protective effect required
minimal amounts of incorporated Ag and IL-2 and elicited specific Abs (compared
with free Ag or liposomal control Ig which did not elicit any specific Abs);
depletion experiments demonstrated a requirement for effector CD4+ and CD8+ T
cells. Head-to-head comparisons, indicating superior potency and induction of
specific T cell activation, distinguished liposomal from prototype, carrier
conjugated Ag. These results provide a strategy for formulating weak tumor or
other clinically important Ags into vaccines.
PMID- 9558063
TI - IL-12 and IL-18 differentially regulate the transcriptional activity of the human
IFN-gamma promoter in primary CD4+ T lymphocytes.
AB - We analyzed the molecular mechanisms by which IL-12 and IL-18 induce
transcriptional activity of the IFN-gamma promoter in primary human CD4+ T cells.
In transfection experiments, we found that IL-18 directly induces IFN-gamma
promoter activity, whereas significant activation with IL-12 required
costimulation with alphaCD3/CD28. Furthermore, IL-12 caused in vivo protection of
a STAT4 (-236) binding site, whereas stimulation with IL-18 or IL-12 plus
alphaCD3/CD28 induced occupancy of a downstream AP-1 site. Mutation of this AP-1
site abrogated both IL-12- and IL-18-mediated promoter activation, whereas
mutation of the STAT site inhibited IL-12-dependent activation. These data
suggest that both AP-1 and STAT4 are required for IL-12-dependent IFN-gamma
promoter activity, whereas IL-18 causes direct activation via AP-1. This
differential activation of the IFN-gamma promoter gives further insights into
molecular pathways governing Th1 T cell development and differentiation.
PMID- 9558064
TI - Thymic lineage commitment rather than selection causes genetic variations in size
of CD4 and CD8 compartments.
AB - During their development, immature CD4+ CD8+ thymocytes become committed to
either the CD4 or CD8 lineage. Subsequent complete maturation of CD4+ and CD8+
cells requires a molecular match of the expressed coreceptor and the MHC
specificity of the TCR. The final size of the mature CD4+ and CD8+ thymic
compartments is therefore determined by a combination of lineage commitment and
TCR-mediated selection. In humans and mice, the relative size of CD4+ and CD8+
peripheral T cell compartments shows marked genetic variability. We show here
that genetic variations in thymic lineage commitment, rather than TCR-mediated
selection processes, are responsible for the distinct CD4/CD8 ratios observed in
common inbred mouse strains. Genetic variations in the regulation of lineage
commitment open new ways to analyze this process and to identify the molecules
involved.
PMID- 9558065
TI - T:T antigen presentation by activated murine CD8+ T cells induces anergy and
apoptosis.
AB - Using an IL-2-secreting, noncytolytic, H-Y-specific, CD8+ T cell clone, the
functional consequences of Ag presentation by T cells to T cells were
investigated. Incubation of the T cells with H-Y-soluble peptide led to
nonresponsiveness to Ag rechallenge. This was due to the simultaneous induction
of apoptosis, involving approximately 40% of the T cells, and of anergy in the
surviving cells. These effects were strictly dependent upon bidirectional T:T
presentation, in that exposure of C6 cells to peptide-pulsed T cells from the
same clone induced proliferation but not apoptosis or anergy. The inhibitory
effects of T:T presentation were not due to a lack of costimulation, since the T
cells expressed levels of CD80 and CD86 higher than those detected on cultured
dendritic cells and equipped them to function as efficient APCs for primary CD8+
T cell responses. Following incubation with soluble peptide, CD80 expression
increased, and high levels of CTLA-4 (CD152) expression were induced. Although
addition of anti-CTLA-4 Ab augmented proliferation in response to soluble
peptide, no protection from apoptosis or anergy was observed. Neither Fas nor TNF
alpha was expressed/produced by the C6 cells, and coligation of MHC class I
molecules and TCR failed to reproduce the effects of T:T presentation. Taken
together, these data suggest that T:T Ag presentation induces anergy and
apoptosis in murine CD8+ T cells and may reflect the regulatory consequences of
T:T interactions in the course of clonal expansion in vivo.
PMID- 9558066
TI - Identification of a developmentally regulated phase of postselection expansion
driven by thymic epithelium.
AB - To investigate events following the initiation of positive selection, we have
used reaggregate organ cultures to follow the maturation of purified CD4+8+69+
thymocytes; these thymocytes represent a subpopulation of thymocytes which have
already received positive selection signals. Using a dilution analysis of an FITC
based membrane-binding dye, 5-(and -6)-carboxyfluorescein diacetate succinimidyl
ester, to allow a quantitative measure of proliferation, we show that while newly
selected CD4+ and CD8+ cells are nondividing, both subsets subsequently undergo a
wave of postpositive selection proliferation involving multiple cell divisions.
Moreover, in the presence of fetal stromal cells, postselection expansion is more
extensive in newborn thymocytes compared with adult thymocytes, suggesting that
this phase of expansion is developmentally regulated. We also show that
proliferation of CD4+ and CD8+ cells is seen in reaggregates of purified MHC
class II+ thymic epithelial cells, while CD4+ and CD8+ cells generated from bcl-2
transgenic CD4+8+69+ thymocytes in the absence of stromal cell support survive
but do not proliferate; this observation indicates that MHC class II+ thymic
epithelial cells are both necessary and sufficient to mediate this wave of cell
division. Finally, the maturation of CD4+8+69+ thymocytes and the subsequent
proliferation of CD4+ and CD8+ cells occur in the presence of MHC-mismatched
thymic stromal cells, suggesting that the later stages of positive selection and
the associated postselection events do not depend on interactions with the same
peptide/MHC complexes responsible for initiation.
PMID- 9558067
TI - CD8+ cells are not necessary for allograft rejection or the induction of
apoptosis in an experimental model of small intestinal transplantation.
AB - Allospecific CTL can function as cellular effectors of solid organ graft
rejection; however, the specific mechanisms of cell damage remain undetermined.
In this study we examined the role of CD8+ T cells in apoptosis and rejection of
small intestinal allografts. ACI rat intestinal grafts transplanted into Lewis
rat recipients showed apoptosis of epithelial crypt cells on day 3 posttransplant
as determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine
triphosphate nick end labeling staining. By day 7 numerous apoptotic crypt cells
were detected in allografts, but were rarely observed in FK506-treated allograft
recipients, isografts, or native intestine of allograft recipients. To further
investigate the mechanism of rejection, recipient rats were depleted of CD8+
cells by treatment with OX-8 mAbs the day before and the day after
transplantation of rat small intestinal allografts. Depletion of CD8+ cells from
allograft recipients did not alter the tempo or the histologic features of
rejection compared with those in the control (IgG-treated) group. Moreover, there
was no difference in the number of apoptotic crypt epithelial cells in the grafts
of control and CD8-depleted rats. Reverse transcriptase-PCR analyses determined
there were similar levels of transcripts for Fas, Fas ligand, perforin, and
granzyme B in control and CD8-depleted allograft recipients. By Western blot it
was determined that the levels of Fas ligand protein were increased in the CD8
depleted group compared with those in control and FK506-treated allograft
recipients. These data suggest that CD8 cells are not required for tissue injury
or apoptotic cell death in small intestine allograft rejection.
PMID- 9558068
TI - Mouse CD1-autoreactive T cells have diverse patterns of reactivity to CD1+
targets.
AB - Humans and mice contain significant populations of T cells that are reactive for
autologous CD1 molecules. Using a panel of five mouse CD1 (mCD1)-autoreactive T
cell hybridomas, we show here that this autoreactivity does not correlate with
the level of CD1 expression. In some cases, these autoreactive T cells can
distinguish between different cell types that express the same CD1 molecule,
suggesting that some factor in addition to CD1 expression is critical for
autoreactive T cell stimulation. To determine whether a CD1-bound ligand may be
required, we expressed mutant mCD1 molecules that are defective for the putative
endosomal localization sequence in the cytoplasmic domain. We demonstrate that
mCD1, like its human CD1 homologues, is found in endosomes, and that it
colocalizes extensively with the DM molecule. We further demonstrate, by site
directed mutagenesis, that the tyrosine in the cytoplasmic sequence is required
for this endosomal localization. A T cell hybrid expressing Vbeta8 and Valpha14,
the major TCR expressed by NK1+ T cells, exhibited greatly diminished reactivity
to mutant CD1 molecules that do not traffic through endosomes, although the
reactivity of other T cell hybrids to this mutant was not greatly affected.
Therefore, we propose that at least some of the autoreactive T cells require
endosomally derived CD1-bound ligands, and that they are capable of
distinguishing between a diverse set of such self-ligands, which might be either
autologous lipoglycans or peptides.
PMID- 9558069
TI - Phorbol esters induce differentiation of human CD34+ hemopoietic progenitors to
dendritic cells: evidence for protein kinase C-mediated signaling.
AB - The intracellular signals that mediate the differentiation of pluripotent
hemopoietic progenitors to dendritic cells (DC) are largely undefined. We have
found that the phorbol ester PMA by itself induced 47% +/- 8.7% of input human
CD34+ hemopoietic progenitors to differentiate into cells with morphology and
surface Ag phenotype characteristic of DC by day 7 of culture. Functionally, PMA
generated DC processed and presented whole soluble Ag and also induced resting T
cell proliferation and Ag-specific CTL effector function. Unlike cytokine-driven
DC differentiation, PMA suppressed proliferation and induced cell death (in part
via apoptosis) in cells that did not differentiate to DC. The effects of PMA were
blocked by inhibitors of protein kinase C activation, suggesting a central role
for this signaling molecule. PMA-mediated signaling also induced expression of
the RelB transcription factor, an NF-kappaB family member implicated in DC
differentiation. These findings suggest that phorbol esters activate protein
kinase C, which then initiates the terminal component of an intracellular
signaling pathway(s) involved in the DC differentiation of CD34+ hemopoietic
progenitors.
PMID- 9558070
TI - Modulation of naive CD4 T cell activation with altered peptide ligands: the
nature of the peptide and presentation in the context of costimulation are
critical for a sustained response.
AB - Altered peptide ligands containing single amino acid substitutions have the
potential to be used for modulating immune function. Using a panel of moth
cytochrome c peptides, we demonstrate that different phases of naive CD4 T cell
response are alternately modulated depending on altered peptide ligand dose and
accessory molecule expression by APC. Weak agonists presented at high
concentration, and with costimulation, efficiently induced early phase naive T
cell activation as assessed by IL-2R/CD69 expression, but could only promote
sufficient IL-2 for a short-lived proliferative response. In contrast, strong
agonists and heteroclitic peptides induced early phase T cell activation even at
low concentrations with costimulation, and allowed sustained IL-2 secretion and
proliferation. In the absence of accessory molecule help, early and late phase
activation was impaired with weak agonists, whereas strong agonists partially
compensated for a lack of costimulation for early phase activation, and also
promoted enhanced IL-2 with sustained proliferation. These studies support the
hypothesis that the naive T cell response will be determined by the balance
between provision of accessory molecule help and the affinity of peptide/MHC
complexes for individual TCRs, and suggest that extended IL-2 production is the
main facet of naive CD4 activation that is affected by altering the nature of the
peptide.
PMID- 9558071
TI - MHC class I is required for peripheral accumulation of CD8+ thymic emigrants.
AB - MHC molecules influence the fate of T lymphocytes at two important stages of
their differentiation. Recognition of self peptide/MHC complexes in the thymus
determines whether immature T cells should live and mature into immunocompetent T
cells or whether they should die. In the periphery, recognition of Ags presented
by MHC molecules induces T cell activation, proliferation, and differentiation
into effector/memory T cells. We describe in this work a third role that MHC
molecules play in T cell physiology. CD8+ thymic emigrants require presence of
MHC class I molecules in the periphery to seed the peripheral lymphoid organs.
Numbers of CD8+ T cells are reduced severely in both the thymus and the periphery
of beta2-microglobulin-deficient (beta2m[-/-]) mice. When grafted with wild-type
(beta2m[+/+]) thymic epithelium, immature beta2m(-/-) T cells that populate the
graft develop into functional mature CD8+ cells. However, significant numbers of
peripheral CD8+ cells in grafted beta2m(-/-) mice can be observed only after
injection of MHC class I-expressing cells in the periphery. Thus, naive T cells
in the periphery do not passively await antigenic stimulation, but actively
engage in interactions with self MHC molecules that may promote their survival.
PMID- 9558072
TI - IFN-gamma receptor deletion prevents autoantibody production and
glomerulonephritis in lupus-prone (NZB x NZW)F1 mice.
AB - (NZB x NZW)F1 female (BW) mice spontaneously develop an autoimmune disease,
characterized by the production of autoantibodies (autoAbs) and
glomerulonephritis, which can be delayed by neutralizing IFN-gamma Abs and
accelerated by IFN-gamma injections. To define the role of IFN-gamma in the
pathogenesis of glomerulonephritis, we established a population of BW mice
deficient in IFN-gammaR (BWgammaR[-/-]) by repeated crossing; these mice were
compared with BWgammaR(+/+) and +/- littermates. Of the BWgammaR(+/+) and +/-
mice, 50% showed immune complex glomerulonephritis with heavy proteinuria at 8 mo
of age, while only 10% of the BWgammaR(-/-) mice were affected at 14 mo. The
serum concentration of anti-dsDNA and anti-histone Abs was dramatically reduced
in BWgammaR(-/-) mice. The role of IFN-gamma in promoting class switch to IgG2a
and IgG3 could not fully account for the impaired production of anti-dsDNA in
BWgammaR(-/-) animals since, IgM and IgG1 levels were also reduced. There was a
high incidence of B cell lymphoma in the BWgammaR(-/-) mice, which might be
related to the suppression of autoAb production. Thus, the absence of
glomerulonephritis in BWgammaR(-/-) mice is likely due to a dramatic yet
unexplained effect of the inactivation of IFN-gamma signaling on autoAb
production.
PMID- 9558073
TI - Cross-reactivity in murine fluoroquinolone photoallergy: exclusive usage of TCR
Vbeta13 by immune T cells that recognize fluoroquinolone-photomodified cells.
AB - Fluoroquinolone antibacterial agents are well known to elicit photosensitivity as
an adverse effect, and their cross-reactivity has been clinically documented. The
photoallergenicity of fluoroquinolones is mainly derived from their photohaptenic
moiety, and photomodification of skin epidermal cells with fluoroquinolones is
thought to be an initial step for this photoallergy. Here we have explored, both
in vivo and in vitro, T cell responses to fluoroquinolone-photomodified cells,
focusing on their photoantigenic cross-reactivity. Cells were derivatized with
fluoroquinolones under exposure to UV-A, and fluoroquinolone photoadducts were
detected in photomodified cells by immunostaining, flow cytometry, and cell ELISA
using fluoroquinolone-specific mAb. T cell-mediated hypersensitivity induced and
elicited by s.c. injection of fluoroquinolone-photomodified epidermal cells was
cross-reactive among six fluoroquinolones. In addition, lymph node cells from
mice sensitized with fluoroquinolone-photomodified cells proliferated well in
vitro not only to Langerhans cell-enriched epidermal cells photoderivatized with
corresponding fluoroquinolone, but also to those photomodified with any of five
other fluoroquinolones, supporting their cross-reactivity. In three
fluoroquinolones tested, Th1 populations that expanded after in vitro
photoantigenic stimulation of immune lymph node cells expressed the same Vbeta13
of TCR. The sensitivity could be transferred by the i.v. administration of this
Vbeta13+ T cell line into naive recipients, in which a high percentage of
Vbeta13+ cells infiltrated at the challenge site. These findings suggest that
these fluoroquinolones carry the same photoantigenic epitope, which is recognized
by Vbeta13+ T cells, leading to fluoroquinolone photosensitivity and cross
reactivity.
PMID- 9558074
TI - Reprogramming of lipopolysaccharide-primed macrophages is controlled by a
counterbalanced production of IL-10 and IL-12.
AB - We studied the potential role of a cytokine regulatory mechanism(s) in LPS
dependent reprogramming and modulation of TNF-alpha and nitric oxide (NO)
responses in mouse peritoneal macrophages. Reciprocal regulation of TNF-alpha and
NO production by LPS-primed and LPS-stimulated macrophages was found to be
dependent on the presence of soluble secretory products released by the cells
during the initial LPS priming interaction. Pretreatment of naive macrophages
with different mouse recombinant cytokines such as rIL-10, rIL-12, and rIFN-gamma
dose dependently and differentially regulated subsequent LPS-induced production
of TNF-alpha, IL-6, and NO by cytokine-primed cells. Analysis of IL-12 and IL-10
levels present in culture supernatants of LPS-primed and LPS-stimulated
macrophages revealed a high degree of correlation between the profiles of TNF
alpha and IL-12 as well as NO and IL-10. Furthermore, LPS priming of macrophages
in the presence of anti-IL-12-neutralizing mAb attenuated TNF-alpha responses
while at the same time up-regulated NO production. In contrast, neutralization of
endogenous IL-10 with anti-IL-10 mAb resulted in considerable TNF-alpha response
at LPS priming doses under conditions that would otherwise strongly inhibit TNF
alpha production. We also found that the initial LPS priming of naive macrophages
differentially and dose dependently regulates expression of mRNAs for IL-10, IL
12, and IFN-gamma in LPS-primed macrophages. Collectively, our data provide
experimental support for the hypothesis that a cytokine regulatory network, most
probably autocrine, tightly controls the reciprocal modulation of TNF-alpha and
NO responses in LPS-primed macrophages.
PMID- 9558075
TI - TCR usage by homocysteine-specific human CTL.
AB - We have recently demonstrated that homocysteine can modify HLA class I Ags and
induce homocysteine-specific CTL (Hom-CTL) responses in humans. Here, we have
investigated TCR usage by Hom-CTL from five patients with ankylosing spondylitis
or reactive arthritis. TCR of HLA-A68-restricted Hom-CTL from two unrelated
donors share the same TCR Valpha, Vbeta, and Jbeta gene segments (AV4, BV23, and
BJ2S1, respectively) with similar third complementarity determining regions
(CDR3) of the beta-chains. Interestingly, the Va and Vbeta gene segments employed
by an HLA-B27-restricted Hom-CTL clone are also closely related to AV4 and BV23,
indicating strong selection pressure for AV4, BV23, and related gene products in
the homocysteine-specific TCR. An arginine or lysine residue frequently appeared
at position alpha93 in the CDR3 of the TCR alpha-chains from Hom-CTL restricted
by HLA-A68 or -B8. This may suggest a potential salt bridge between the carboxyl
group of homocysteine and specific TCR. TCR usage by HLA-B27-restricted Hom-CTL
from unrelated individuals appears to be less conserved, although two T cell
clones from one individual rearranged the same V gene segments with identical
lengths of CDR3. Implications of these data for the molecular mechanisms for
homocysteine modification of HLA Ags are also discussed.
PMID- 9558076
TI - Bcmd decreases the life span of B-2 but not B-1 cells in A/WySnJ mice.
AB - Peripheral B cells are divided into two subpopulations, B-1 and B-2, the
relationship of which remains obscure. We recently showed that the Bcmd mutation
in A/WySnJ mice reduces average B cell life span, yielding 90% fewer peripheral B
cells. Despite this defect, A/WySnJ mice have an elevated proportion of
peritoneal CD5+ B cells, suggesting that Bcmd may be the first B-cell-intrinsic
gene to differentially affect the B-1 and B-2 subpopulations. To test this
hypothesis in detail, we have used in vivo BrdU labeling and four-color
cytofluorometry to examine the numbers and turnover rates of sIgM+CD23-CD43+ (B
1) and sIgM+CD23+CD43- (B-2) splenocytes in A/WySnJ and A/J mice. The results
show the expected 90% reduction of splenic B-2 cells among A/WySnJ mice, but a
normal splenic B-1 cell pool. Increased B-1 cell renewal cannot explain this
undiminished pool, because BrdU labeling kinetics reveals an identical splenic B
1 subset turnover rate of approximately 4%/day in both A/WySnJ and A/J strains.
Thus, B-1 cells are Bcmd-independent but B-2 cells are Bcmd-dependent, suggesting
Bcmd functions in a positive signaling pathway that imparts longevity to
quiescent B cells, but that is not required for cycling B cells. Moreover these
results show that the requisites for maturation and longevity differ between the
B-1 and B-2 subsets.
PMID- 9558077
TI - Generation of the germline peripheral B cell repertoire: VH81X-lambda B cells are
unable to complete all developmental programs.
AB - The generation of VH81X heavy chain lambda-light chain-expressing B cells (VH81X
lambda+ B cells) was studied in VH81X heavy chain transgenic mice as well as in
VH81X JH (-/-) and VH81X JH (-/-) Ck (-/-) mice, in which competition resulting
from expression of heavy and light chains from the endogenous heavy and kappa
light chain loci was prevented. We show that although lambda light chain gene
rearrangements occur normally and give rise to light chains that associate with
the transgenic heavy chain to form surface and soluble IgM molecules, further B
cell development is almost totally blocked. The few VH81X-lambda+ B cells that
are generated progress into a mature compartment (expressing surface CD21, CD22,
CD23, and low CD24 and having a relatively long life span) but they also have
reduced levels of surface Ig receptor and express higher amounts of Fas Ag than
VH81X-kappa+ B cells. These VH81X-lambda+ B cells reach the peripheral lymphoid
organs and accumulate in the periarteriolar lymphoid sheath but are unable to
generate primary B cell follicles. In other heavy chain transgenic mice (MD2,
M167, and M54), lambda+ B cells are generated. However, they seem to be
preferentially selected in the peripheral repertoire of some transgenic heavy
chain mice (M54) but not in others (MD2, M167). These studies show that a crucial
selection step is necessary for B cell survival and maintenance in which B cells,
similar to T cells, receive signals depending on their clonal receptors.
PMID- 9558078
TI - Differential capacities of CD4+, CD8+, and CD4-CD8- T cell subsets to express IL
18 receptor and produce IFN-gamma in response to IL-18.
AB - IL-12 and IL-18 have the capacity to stimulate IFN-gamma production by T cells.
Using a T cell clone, we reported that IL-18 responsiveness is generated only
after exposure to IL-12. Here, we investigated the induction of IL-18
responsiveness in resting CD8+, CD4+, and CD4-CD8- T cells. Resting T cells
respond to neither IL-12 nor IL-18. After stimulation with anti-CD3 plus anti
CD28 mAbs, CD8+, CD4+, and CD4-CD8- T cells expressed IL-12R, but not IL-18R, and
produced IFN-gamma in response to IL-12. Cultures of T cells with anti-CD3/anti
CD28 in the presence of rIL-12 induced IL-18R expression and IL-18-stimulated IFN
gamma production, which reached higher levels than that induced by IL-12
stimulation. However, there was a substantial difference in the expression of IL
18R and IL-18-stimulated IFN-gamma production among T cell subsets. CD4+ cells
expressed marginal levels of IL-18R and produced small amounts of IFN-gamma,
whereas CD8+ cells expressed higher levels of IL-18R and produced more IFN-gamma
than CD4+ cells. Moreover, CD4-CD8- cells expressed levels of IL-18R comparable
to those for CD8+ cells but produced IFN-gamma one order higher than did CD8+
cells. These results indicate that the induction of IL-18R and IL-18
responsiveness by IL-12 represents a mechanism underlying enhanced IFN-gamma
production by resting T cells, but the operation of this mechanism differs
depending on the T cell subset stimulated.
PMID- 9558079
TI - Fas/Fas ligand signaling during gestational T cell development.
AB - Most thymocytes express high levels of Fas Ag (Apo-1/CD95); however, the role of
Fas/Fas ligand-mediated apoptosis in thymocyte development remains unclear.
During gestational development of thymocytes in C57BL/6(B6) +/+ mice, the highest
levels of Fas ligand mRNA and Fas ligand protein expression were detected at
gestational day (GD) 15, and there was a ninefold decrease in Fas ligand mRNA
expression between GD 15 and 17 accompanied by a sixfold increase in Fas mRNA.
Apoptotic thymocytes were first detected in the medulla at GD 15, and increasing
numbers of cortical clusters and scattered, single apoptotic cells were present
on GD 16 and 17. Thus, early apoptosis correlated with high expression of Fas
ligand. High levels of Fas ligand mRNA were maintained throughout gestational
development in thymocytes of Fas-deficient B6-lpr/lpr mice, but cortical clusters
and scattered apoptotic cells were decreased relative to B6 +/+ mice before GD
17. Kinetic analysis of fetal thymic organ cultures treated with anti-Fas Ab
demonstrated that thymocytes become sensitive to Fas-mediated apoptosis during
the transition from the CD4-CD8- to the CD4+CD8+ phenotype. More mature CD4+CD8+
thymocytes and CD4+ and CD8+ thymocytes became resistant to Fas-mediated
apoptosis after GD 17, despite high expression of Fas. However, low avidity
engagement of the TCR on Fas-sensitive CD4+CD8+ thymocytes before GD 17 induced
resistance to Fas-mediated apoptosis. The present results indicate that Fas plays
a critical role in mediating apoptosis during early gestational thymocyte
development and that thymocytes that receive a survival signal through TCR/CD3
become resistant to Fas-mediated apoptosis.
PMID- 9558080
TI - The actin-bundling protein fascin is involved in the formation of dendritic
processes in maturing epidermal Langerhans cells.
AB - Dendritic cells (DC) are characterized by their unique potential to prime naive T
cells. Epidermal Langerhans cells (LC), the DC resident in the epidermis, gain
this immunostimulatory capacity following Ag contact in vivo or during in vitro
culture of epidermal cell suspensions. To analyze differential gene expression in
maturing LC, we constructed a highly representative cDNA library of cultivated LC
(cLC) in lambda ZAP II containing 18 x 10(6) independent clones. This library was
screened with freshly isolated Langerhans cell (fLC)- and cLC-derived probes for
cLC-specific cDNAs. The cDNAs identified were sequenced and analyzed by database
searches. Two cDNA fragments were identified as fragments of fascin, indicating
that fascin is differentially expressed in LC. By competitive RT-PCR, we
confirmed that fascin is highly expressed in cLC cultivated for 1, 2, and 3 days,
while no signals were obtained with fLC. Western blot and immunofluorescence
analysis revealed cLC-specific expression of fascin on the protein level as well.
Fascin is known to be involved in the organization of the actin cytoskeleton in
cytoplasmatic extensions of nerve growth cones. Its differential expression in
maturing LC coincides with the formation of numerous dendritic projections in LC.
Their formation was inhibited by incubation of LC with fascin antisense
oligonucleotides during cultivation. Therefore, we conclude that fascin is
necessary for the formation of the dendritic processes of maturing Langerhans
cells and may thus influence T cell-LC interaction.
PMID- 9558081
TI - A cytokine cascade including prostaglandin E2, IL-4, and IL-10 is responsible for
UV-induced systemic immune suppression.
AB - Even though all of the energy contained with the UV wavelengths of solar
radiation is absorbed within the epidermis and upper layers of the dermis, UV
irradiation can suppress immune responses to Ag introduced at distant
nonirradiated sites. In addition, data from a number of laboratories have
suggested that one consequence of UV exposure is suppressed Th1 cell activation
with normal or enhanced Th2 cell activation, resulting in a shift to a Th2-like
phenotype. Cytokines secreted by UV-irradiated keratinoctyes, particularly IL-10,
have been shown to play a major role in the induction of systemic immune
suppression and differential activation of T helper cell subsets. Although IL-10
can influence Th1 cell activation by altering Ag presentation and suppressing IFN
gamma secretion, the major signal for the development of a Th2 response is IL-4.
Here we tested the hypothesis that UV irradiation induces IL-4 secretion. UV
irradiation induced serum IL-4 in a dose-dependent fashion. Injecting UV
irradiated mice with anti-IL-4 blocked immune suppression. We could find no
evidence, however, supporting secretion of IL-4 by UV-irradiated keratinocytes.
Rather, we suggest that prostaglandins released by irradiated keratinocytes
induce serum IL-4 since treating UV-irradiated mice with a cyclooxygenase-2
inhibitor blocked its production. Moreover, we found that treating UV-irradiated
mice with anti-IL-4 suppressed serum IL-10 levels. In addition, injecting normal
mice with PGE2 induced serum IL-4 and IL-10. We suggest that UV exposure
activates a cytokine cascade (PGE2 --> IL-4 --> IL-10) that ultimately results in
systemic immune suppression.
PMID- 9558082
TI - Antiviral cytotoxic activity across a species barrier in mixed xenogeneic
chimeras: functional restriction to host MHC.
AB - Reconstitution of lethally irradiated mice with a mixture of mouse and rat bone
marrow cells (mouse + rat-->mouse) results in mixed xenogeneic chimerism and
donor-specific tolerance. The current study demonstrates that mouse and rat T
lymphocytes that have developed in xenogeneic chimeras are restricted to Ag
presentation by mouse, but not rat, APC. Restriction to host Ags results in
functional immunocompetence with generation of antiviral cytotoxic activity in
vivo, within and across species barriers. These data demonstrate for the first
time that the host thymus is sufficient to support development and positive
selection of functional cross-species T lymphocytes. The superior
immunocompetence, as compared with fully xenogeneic (rat-->mouse) chimeras, may
prove to be of significant benefit in the clinical application of
xenotransplantation to solid organ transplantation and immune reconstitution for
AIDS.
PMID- 9558083
TI - Potent apoptotic signaling and subsequent unresponsiveness induced by a single
CD2 mAb (BTI-322) in activated human peripheral T cells.
AB - Manipulation of CD2 molecules with CD2 mAb pairs has been shown to deliver
apoptotic signals to activated mature T cells. We show that BTI-322, a CD2 mAb
directed at a peculiar epitope of CD2, can trigger on its own the apoptotic death
of IL-2-activated peripheral T cells and of OKT3-stimulated T cells, contrasting
in this respect with a series of other mouse or rat CD2 mAb. F(ab')2 fragments
were as potent as the whole Ab. BTI-322-induced apoptosis proceeded in a few
hours and was independent of the Fas/Fas ligand system. Less than 5 ng/ml of BTI
322, added at the beginning of culture, were able to eliminate within 4 days most
CD3+ cells from OKT3- and IL-2-stimulated lymphocytes, the only cells remaining
being CD16+CD2- NK cells. T cell proliferative responses induced by a mitogenic
CD2 mAb pair or by PHA-P (which mainly binds to CD2) were not inhibited by BTI
322. In this case, the apoptotic effect was successfully counteracted by
simultaneous enhancement of T cell divisions. Thus, the killing effect of BTI-322
was most effective when T cells were exclusively stimulated through the CD3/TCR
complex. Apoptosis of the responding T cells may explain why T cells recovered
from a primary MLC performed in the presence of BTI-322 responded to third party
cells but not to the primary stimulatory cells. These data constitute the
rational basis for the use of BTI-322 for inducing tolerance in human
allotransplantation.
PMID- 9558084
TI - Transgenic expression of Fas in T cells blocks lymphoproliferation but not
autoimmune disease in MRL-lpr mice.
AB - Fas is a member of the TNF receptor family. Binding of Fas ligand to Fas induces
apoptosis in Fas-bearing cells. Fas is expressed in various cells, including
thymocytes, peripheral T cells, and activated B cells. The mouse lpr mutation is
a loss of function mutation of Fas. MRL-lpr/lpr mice develop lymphadenopathy and
splenomegaly, and produce multiple autoantibodies, which results in autoimmune
disease. In this report, we describe the establishment of a line of Fas
transgenic MRL-lpr mice in which mouse Fas cDNA was expressed using the T cell
specific murine lck promoter. The transgenic mice expressed functional Fas in
thymocytes and peripheral T cells, but not in B cells. The transgenic mice did
not accumulate abnormal T cells (Thy-1+ B220+), but still accumulated B cells
(Thy-1- B220+); they produced a large quantity of Igs (IgG1 and IgG2a), including
anti-DNA Abs, and developed glomerulonephritis. These results suggest that
autoreactive or activated B cells must be killed through Fas expressed in the B
cells by the Fas ligand expressed in activated T cells.
PMID- 9558085
TI - Critical roles of glycosaminoglycan side chains of cartilage proteoglycan
(aggrecan) in antigen recognition and presentation.
AB - Systemic immunization of BALB/c mice with proteoglycan (aggrecan) from fetal
human cartilage induces progressive polyarthritis, an experimental disease
similar to human rheumatoid arthritis. The development of the disease in this
genetically susceptible murine strain is based on cross-reactive immune responses
between the immunizing fetal human and mouse self-proteoglycans. One of the cross
reactive and arthritogenic T cell epitopes (92GR/QVRVNSA/IY) is localized in the
G1 domain of human/murine proteoglycan. Susceptible BALB/c mice, however, develop
arthritis only if both the chondroitin sulfate (CS) and keratan sulfate (KS) side
chains of the arthritogenic human proteoglycans are removed. The function of
these two glycosaminoglycan side chains is opposite. The presence of a KS side
chain in adult proteoglycan inhibits the recognition of arthritogenic T cell
epitopes, prevents the development of T cell response, and protects animals from
autoimmune arthritis. In contrast, the depletion of the CS side chain generates
clusters of CS stubs and provokes a strong B cell response. These carbohydrate
specific B cells are the most important proteoglycan APC. Taken together,
proteoglycan-induced progressive polyarthritis is dictated by three major
components: genetic background of the BALB/c strain, highly specific T cell
response to epitope(s) masked by a KS chain in aging tissue, and the presence of
proteoglycan (CS stub)-specific B cells required for sufficient Ag presentation.
PMID- 9558086
TI - Increasing immunogenicity of antigens fused to Ig-binding proteins by cell
surface targeting.
AB - Fusion of antigenic proteins to Ig-binding proteins such as protein A from
Staphylococcus aureus and its derived ZZ fragment is known to increase
immunogenicity of the fused Ag in vivo. To shed light on the origin of this
effect, we used snake toxins as Ags and observed that 1) fusion of toxins to ZZ
enhanced their presentation to a toxin-specific T cell hybridoma (T1B2), using
A20 B lymphoma cells, splenocytes, or peritoneal exudate cells as APCs; 2) this
enhancement further increased when the number of fused Ig-binding domains varied
from two with ZZ to five with protein A; and 3) the phenomenon vanished when the
fusion protein was preincubated with an excess of free ZZ or when P388D1
monocytes cells were used as APCs. Therefore, ZZ-fused toxins are likely to be
targeted to surface Igs of APCs by their ZZ moiety. Furthermore, ZZ-alpha and
toxin alpha stimulated similar profiles of toxin-specific T cells in BALB/c mice,
suggesting a comparable processing and presentation in vivo for both toxin forms.
To improve the targeting efficiency, ZZ-alpha was noncovalently complexed to
various Igs directed to different cell surface components of APCs. The resulting
complexes were up to 10(3)-fold more potent than the free toxin at stimulating
T1B2. Also, they elicited both a T cell and an Ab response in BALB/c mice,
without the need of any adjuvant. This simple approach may find practical
applications by increasing the immunogenicity of recombinant proteins without the
use of adjuvant.
PMID- 9558087
TI - Differential requirement for p56lck in fetal and adult thymopoiesis.
AB - The protein tyrosine kinase p56lck is critical for the generation of mature
thymocytes in adult mice. However its requirement during the maturation of
thymocytes from the fetal to the adult stage has not been clearly defined. We
analyzed prenatal and postnatal thymocyte maturation in mice deficient for p56lck
(lck[-/-]). Before birth, lck appears to play a crucial role in the expansion and
proliferation of CD4+CD8+ double positive thymocytes, whereas proliferation and
absolute numbers of CD4-CD8- double negative thymocyte precursors remained within
the normal range until the end of the second week postnatal. Three weeks after
birth, the total numbers of double negative and immature single positive
thymocytes underwent a dramatic reduction that correlated with a decrease in the
double positive population. This ontogenic defect was associated with a
significant decrease in the proliferation rates of thymocyte precursors. Our data
suggest that signaling via p56lck kinase is differentially required within a
given phenotypically defined thymocyte subpopulation, depending on its stage of
thymocyte maturation.
PMID- 9558088
TI - Nuclear factor kappaB is required for peptide antigen-induced differentiation of
a CD4+CD8+ thymocyte line.
AB - NF-kappaB transcription factors are known to regulate the expression of a number
of genes involved in T cell activation and function. Some evidence has suggested
that they also play a role in T cell development. However, the role of NF-kappaB
in Ag-induced thymocyte differentiation has not been directly addressed to date.
Here we critically examine this role by employing DPK, a CD4+CD8+ thymocyte line
that undergoes differentiation upon TCR engagement in a process that closely
mimics positive selection. Expression of a degradation-resistant form of
IkappaBalpha in DPK cells results in constitutive inhibition of NF-kappaB
activity. We find that in the absence of NF-kappaB activity, MHC-peptide-induced
differentiation of DPK is blocked. Furthermore, differentiation induced by a
nonphysiologic stimulus, anti-TCR Ab, is greatly reduced. Altogether, our data
indicate a requirement for NF-kappaB in the developmental changes associated with
positive selection.
PMID- 9558089
TI - Thymic alterations induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin are strictly
dependent on aryl hydrocarbon receptor activation in hemopoietic cells.
AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related congeners affect the
immune system, causing immunosuppression and thymic atrophy in a variety of
animal species. TCDD is believed to exert its effects primarily through the
ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR).
Although the AhR is found at high levels in both thymocytes and thymic stroma, it
is uncertain in which cells TCDD is activating the AhR to cause alterations in
the thymus. Some investigators have suggested that stromal elements, primarily
epithelial cells, within the thymus are the primary targets for TCDD. Others have
suggested that atrophy is due to a direct effect on thymocytes, either by
apoptosis or by altering the development of progenitor cells. By producing
chimeric mice with TCDD-responsive (AhR[+/+]) stromal components and TCDD
unresponsive (AhR[-/-]) hemopoietic components, or the reverse, we have clarified
the role of stromal vs hemopoietic elements in TCDD-induced thymic alterations.
Our results show that the targets for TCDD-induced thymic atrophy and phenotypic
alterations are strictly in the hemopoietic compartment and that TCDD activation
of epithelial cells in the stroma is not required for thymic alterations.
Furthermore, changes observed in the putative stem cell populations of these
chimeric mice are also dependent on TCDD activation of the AhR in hemopoietic
elements.
PMID- 9558090
TI - CTLA-4 regulates tolerance induction and T cell differentiation in vivo.
AB - Cytotoxic T lymphocyte Ag-4 (CTLA-4; CD152) is an important T cell regulatory
molecule. In vitro experiments have shown that the blockade of signals through
CTLA-4 augments T cell expansion, while CTLA-4 cross-linking results in decreased
T cell proliferation due to decreased IL-2 production. However, less is known
about the role of CTLA-4 in regulating an ongoing immune response. In this study,
we examined the role of CTLA-4 in the expansion, decline, tolerization, and
differentiation of T cells following treatment with staphylococcal enterotoxin B
(SEB). Anti-CTLA-4 treatment resulted in increased numbers of SEB-reactive T
cells and blockade of subsequent tolerance induction. Further examination of the
SEB-reactive cells from anti-CTLA-4-treated mice demonstrated that both the CD4+
and CD8+ Vbeta8+ T cells produced IL-4, providing evidence that not only do
signals through CTLA-4 regulate T cell-tolerizing events, but they also play an
important role in the differentiation of T cells in vivo.
PMID- 9558091
TI - Mouse cell surface antigens: nomenclature and immunophenotyping.
AB - This paper reviews cell surface Ags expressed on mouse hemopoietic and
nonhemopoietic cells. The review will cover molecules included in the cluster of
differentiation (CD) from CD1 to CD166 and lymphocyte Ag (Ly) series from Ly-1 to
Ly-81 as well as some new Ags without current CD or Ly assignments. In addition
to an update on mouse nomenclature, there will be a discussion of some known
functions of the molecules and brief comments on the use of particular Ags for
immunophenotyping of cell subsets. Several novel markers mentioned may prove
useful in mouse immunology research.
PMID- 9558092
TI - Selective inhibition of expression of the chemokine receptor CCR2 in human
monocytes by IFN-gamma.
AB - IFN-gamma is a potent activator of mononuclear phagocyte function and promotes
the development of Th1 responses. Moreover, it induces and modulates chemokine
production in a variety of cell types, including mononuclear phagocytes. In the
present study, we examined the effect of IFN-gamma on the expression of CC
chemokine receptors in human monocytes. IFN-gamma selectively and rapidly
inhibited expression of the monocyte chemotactic protein (MCP) receptor CCR2 with
an ED50 of approximately 50 U/ml. The effect was rapid (detectable after 1 h) and
reversible. Other chemokine receptors (CCR1, CCR3, CCR4, and CCR5) were not
substantially affected, and CXCR4 was reduced. IFN-gamma acted in concert with
LPS, TNF-alpha, and IL-1beta in inhibiting CCR2 expression. IFN-gamma-treated
monocytes showed a shorter half-life of CCR2 mRNA compared with untreated cells,
whereas the rate of nuclear transcription was unaffected. The inhibition of CCR2
mRNA expression by IFN-gamma was associated with a lower number of surface
receptors and lower chemotactic responsiveness. Thus, IFN-gamma, an inducer of
MCP-1 and MCP-3 in mononuclear phagocytes, selectively inhibits expression of the
MCP receptor CCR2 in monocytes. These results are consistent with an emerging
paradigm of divergent regulation by several agents of chemokine production and
receptor expression in monocytes. The inhibition of MCP-1R expression may serve
as a means of retaining mononuclear phagocytes at sites of inflammation and as a
feedback mechanism in the regulation of recruitment from the blood.
PMID- 9558093
TI - Characterization of Oct2 from the channel catfish: functional preference for a
variant octamer motif.
AB - The Ig heavy chain enhancer of the channel catfish (Ictalurus punctatus) has an
unusual position and structure, being found in the 3' region of the mu gene and
containing eight functional octamer motifs of consensus (ATGCAAAT) and variant
sequences. The presence of multiple octamer motifs suggests that an Oct2
homologue may play an important role in driving expression of the Ig heavy chain
locus in a teleost fish. To test this hypothesis, two catfish Oct2 cDNAs (alpha
and beta) were cloned by screening a catfish B cell cDNA library. Catfish Oct2
alpha and beta isoforms are derived by alternative RNA splicing; as determined by
Southern analysis, Oct2 is a single copy gene. In comparisons with mammalian
Oct2, the catfish Oct2 isoforms show high sequence conservation in their N
terminal regions and POU domains, but extensive divergence in their C-terminal
regions. Catfish Oct2 a and beta are tissue restricted, bind both consensus and
variant octamer motifs, and activate transcription in both catfish and murine
cells. In contrast, mouse Oct2 activated transcription in mouse but not catfish
cells. Catfish Oct2 beta is a more potent transcriptional activator than Oct2
alpha. In transient expression assays, catfish Oct2 beta showed a marked
preference for the octamer variant, ATGtAAAT, which occurs twice in the catfish
enhancer. Mouse Oct2 also showed increased activity with the variant octamer when
tested in mouse B cells. Gel-shift analysis competition assays indicated that
catfish Oct2 binds the consensus octamer motif with an apparently higher affinity
than it does the variant motif.
PMID- 9558094
TI - Posttranslational regulation of TCR Valpha allelic exclusion during T cell
differentiation.
AB - We have previously shown that phenotypic allelic exclusion of TCR alpha-chain is
functional only in mature thymocytes. A significant proportion of immature
thymocytes (TCRlow) express more than one cell surface alpha-chain, but mature
thymocytes (TCRhigh) show phenotypic allelic exclusion and express only a single
alpha-chain. We have analyzed thymocytes for both surface and intracellular alpha
chain expression and find that the majority of mature thymocytes express a second
alpha-chain intracellularly. This result is predicted by a model in which the
developmentally regulated allelic exclusion of the TCR alpha-chain is caused by
competition between alpha-chains for the beta-chain rather than by models in
which one alpha-chain is down-regulated or in which selection favors cells with
only a single alpha-chain species. Changes in the relative amounts of alpha- and
beta-chains available for pairing may therefore allow competition between the two
alpha-chains for the beta-chain. Peripheral T cells also frequently express
second alpha-chains in the cytoplasm (18-27%), despite a rather low frequency of
dual alpha-chain expression on the cell surface (2-4%). The frequency of
nonsurface expressed alpha-chains is reduced somewhat compared with thymocytes,
indicating that an additional level of control of allelic exclusion operates
during the maturation of peripheral T cells.
PMID- 9558095
TI - Extracellular HIV-1 Tat protein induces the rapid Ser133 phosphorylation and
activation of CREB transcription factor in both Jurkat lymphoblastoid T cells and
primary peripheral blood mononuclear cells.
AB - Extracellular HIV-1 Tat protein (0.1-100 ng/ml) induced a rapid (peak at 30 min)
increase in the Ser133 phosphorylation levels of the transcription factor CREB in
serum-starved Jurkat cells, as revealed by Western blot and indirect
immunofluorescence analyses. Nuclear cAMP-responsive element (CRE) binding
activity in electrophoretic mobility shift assays was constitutive in
unstimulated Jurkat cells, showing only a small increase upon Tat treatment.
However, transient transfection experiments performed with various
chloramphenicol acetyl-transferase (CAT) constructs showed that Tat produced a
fourfold induction of CAT activity only in the presence of a CRE-dependent CAT
construct. Moreover, the use of plasmids encoding for GAL4-CREB fusion proteins
demonstrated that Tat induction of pG4-CAT reporter gene required the CREB moiety
of the GAL4-CREB fusion protein and that Ser133 CREB was essential for Tat
activity. Extracellular Tat also stimulated Ser133 CREB phosphorylation in
freshly isolated PBMC; this effect was completely blocked by either staurosporin,
a broad-spectrum inhibitor of various protein kinases, or PD 98059, a specific
inhibitor of mitogen-activated protein kinases (MAPK). Furthermore, extracellular
Tat induced a rapid (peak at 5-15 min) stimulation of the MAPK catalytic activity
in primary PBMC. Altogether, these findings suggest that HIV-1 Tat protein
activates CREB in lymphoid cells through a signal cascade involving the MAPK
pathway.
PMID- 9558096
TI - Differentiation-specific, octamer-dependent costimulation of kappa transcription.
AB - By mutational analysis of the octamer-TATA box intervening region in the mouse
SP6 kappa promoter, we have mapped two octamer-dependent, costimulatory regions,
A and B. The A region was active in late B cells only, while the B region was
active throughout B cell differentiation. The B region was TATA proximal and
contained a heptamer and an E box of the E2A type that is common in Vkappa
promoters. Mutation of the heptamer element did not decrease transcriptional
stimulation from this region, but mutations in, or immediately 5' of, the E box
core sequence did. A protein binding to this region could be detected in nuclear
extracts. The complex could only partially be competed with a muE5 binding site
and could not be supershifted with Abs raised to E2A gene products, indicating
that it may represent a novel E-box binding complex. The A region was located
proximal to the octamer and contained a CCCT element that is conserved both with
regard to position and sequence in human VkappaII promoters. By mutational
analysis, the transcriptional stimulatory activity was mapped to the CCCT element
that also is part of an early B cell factor (EBF) binding site. In late B cells,
a novel protein (FA), which did not bind to the EBF binding site in the mb1
promoter, interacted with the A region. This protein was found to be expressed at
lower levels in early B cells as well as in HeLa cells. Thus, the octamer
flanking sequence contains positive control elements that may act independently
but that differ in the stage of B cell differentiation at which they are active.
One of these factors is an example of an ubiquitously expressed transcription
factor that participate in differentiation-specific transcriptional activation.
PMID- 9558097
TI - IFN-gamma induction of the human monocyte chemoattractant protein (hMCP)-1 gene
in astrocytoma cells: functional interaction between an IFN-gamma-activated site
and a GC-rich element.
AB - We characterized regulation of the human monocyte chemoattractant protein-1 (hMCP
1) gene by IFN-gamma in astrocytoma cells, because astroglial cells express
chemokines in several central nervous system inflammatory states. It was found
that IFN-gamma-induced hMCP-1 transcription was rapid, transient, and mediated by
a 213-bp promoter-proximal regulatory region of the gene. Our studies on both in
vitro and in vivo states of the hMCP-1 regulatory region established requirement
of an IFN-gamma-activated site (GAS) and the presence of IFN-gamma-inducible GAS
binding activity involving at least STAT-1alpha for IFN-gamma-induced hMCP-1
expression. Unexpectedly, in vivo genomic footprinting of the proximal regulatory
region of the IFN-gamma-induced gene revealed protection of a GC-rich sequence
(GC box) with the same temporal pattern as that seen at the GAS; in vitro, this
GC-rich element is associated with nuclear factor Sp1. These observations
suggested a cooperative interaction between the GAS and the GC box element.
Interestingly, site-specific mutations that abolished GC-box or GAS-element
function produced clearly disparate results. Disruption of the GC box did not
affect fold induction by IFN-gamma but reduced promoter-reporter expression by
half. Conversely, GAS mutation abrogated induction but did not affect the
magnitude of expression. These results establish the importance of the GAS
element for induction of hMCP-1 and further our understanding of IFN-gamma
mediated transcriptional induction by providing the first evidence in vivo for
inducible signaling to the GC box by this cytokine.
PMID- 9558098
TI - Target recognition of beta2-glycoprotein I (beta2GPI)-dependent anticardiolipin
antibodies: evidence for involvement of the fourth domain of beta2GPI in antibody
binding.
AB - Beta2-glycoprotein I (beta2GPI) is an absolute requirement for the binding of
autoimmune anticardiolipin Abs (aCL) to cardiolipin (CL). We evaluated the target
recognition of human beta2GPI by IgG derived from two patients with primary and
two with secondary antiphospholipid syndrome. The total IgG serum fractions and
beta2GPI affinity-purified IgGs were assessed by using various domain-deleted
mutants (DM) of human beta2GPI (DMs: I-III, I-IV, II-V, III-V, IV-V, and V) and
mouse mAbs against individual beta2GPI domains. The four IgGs bound slightly to
CL in the absence of beta2GPI and showed increased binding in the beta2GPI
presence. Following affinity purification of the IgGs on a beta2GPI column,
reactivity toward CL was absent. DMs containing domain V inhibited the binding of
biotinylated beta2GPI to CL. The addition to CL-coated plates of DM V, but not
the other DMs, reduced the binding of all four IgGs. The anti-beta2GPI IgGs bound
only to complete beta2GPI and DM I-IV coated on the plates. The binding to plate
adsorbed beta2GPI could be inhibited by complete beta2GPI and DM I-IV, the latter
being a more efficient inhibitor. Further, the human anti-beta2GPI IgGs could
compete with the binding to beta2GPI of Cof-21 mouse mAb (directed at domain IV),
but not with the two other mouse mAbs. The results suggest that some
"autoimmune:" beta2GPI-dependent anticardiolipin Abs recognize a beta2GPI target
that is distinct from the CL-binding site in domain V. The target site for some
antiphospholipid syndrome IgGs appear to reside in domain IV of beta2GPI.
PMID- 9558099
TI - Molecular cloning and functional characterization of the pig analogue of CD59:
relevance to xenotransplantation.
AB - In this work, we report the cloning of the cDNA for the porcine analogue of human
CD59. Degenerate primers, derived from the N-terminal sequence of pig erythrocyte
CD59, were used to obtain the corresponding cDNA sequence. From this sequence,
gene-specific primers were designed and used to amplify the 3' and 5' ends of the
cDNA using the rapid amplification of cDNA ends (RACE) method. The complete 768
bp cDNA so obtained consisted of a 84-bp 5' untranslated region, a 26-amino-acid
NH2-signal peptide, a 98-amino-acid coding region, including putative N
glycosylation sites and a glycosylphosphatidylinositol-anchoring signal, and a
312-bp 3' untranslated region. The mature protein sequence was 48% identical to
human CD59 at the amino acid level. Northern blot analysis revealed several
distinct CD59 transcripts, and a variability in expression levels of the
different transcripts in the panel of tissues screened. Stable expression of pig
CD59 in a CD59-negative human cell line conferred protection against lysis by
complement from pig and several other species. Separate expression of pig and
human CD59 at similar levels in the same cell line allowed a direct functional
comparison between these two analogues. Pig CD59 and human CD59 showed similar
activity in inhibiting lysis by complement from all species tested; in
particular, expressed pig CD59 efficiently inhibited lysis by human complement.
The relevance of these data to current work in the engineering of pig organs for
xenotransplantation is discussed.
PMID- 9558100
TI - Dendritic cells express multiple chemokine receptors used as coreceptors for HIV
entry.
AB - Cells of the dendritic lineage are thought to be among the first cells infected
after mucosal exposure to HIV. In this study, we have identified the presence of
multiple chemokine receptors on dendritic cells (DC) that may function as
coreceptors for HIV entry. DC effectively used CCR5 for entry of macrophage (M)
tropic isolates. CCR3, the eotaxin receptor, initially identified on eosinophils,
is expressed on DC and may be used as an entry coreceptor by certain dual-tropic
strains. CXCR4 was not expressed on DC, although SDF-1 induced a calcium flux and
DC could be infected by T cell line (T)-tropic HIV. Our findings provide evidence
for the presence of a non-CXCR4 SDF-1 receptor on DC that is used mainly by T
tropic strains of HIV. DC from individuals homozygous for a 32-bp deletion of the
CCR5 gene are also infectable with M-tropic strains of HIV-1, and this infection
is inhibited by stromal cell-derived factor (SDF)1, suggesting that this receptor
can also be used by M-tropic HIV for entry. Delineation of the spectrum of
coreceptor usage on DC may offer new approaches to interfere with the initiation
and propagation of HIV infection.
PMID- 9558101
TI - Lymphocytes produce IL-1beta in response to Fcgamma receptor cross-linking:
effects on parenchymal cell IL-8 release.
AB - Neutrophils mediate tissue injury in response to immune complexes, although the
factors that induce their recruitment are incompletely understood. We have
reported that lymphocytes may be important regulators of monocyte and macrophage
IL-8 release in the presence of immobilized IgG. Since tissue parenchymal cells
are important local producers of IL-8 but are not directly stimulated by FcgammaR
cross-linking, we hypothesized that lymphocytes may also regulate parenchymal IL
8 release. Supernatants from lymphocytes incubated on immobilized IgG induced
primary human fibroblasts and human mesangial cells to produce IL-8 (17 +/- 3.5
and 44 +/- 8 ng/ml, respectively). Fibroblast and mesangial cell IL-8 mRNA levels
were similarly increased by the conditioned lymphocyte supernatant. Immobilized
anti-human FcgammaRIII, but not FcgammaRI or FcgammaRII Abs, could stimulate this
IL-8-inducing activity in lymphocytes, suggesting that FcgammaRIII-bearing
lymphocytes were responsible. Supernatants from lymphocytes incubated on
immobilized IgG contained 2.2 +/- 0.8 ng/ml of IL-1beta, while enriched monocyte
preparations from the same donors incubated on immobilized IgG released only 0.1
+/- 0.04 ng/ml of IL-1beta (p = 0.05). Consistent with the identification of IL
1beta as the lymphocyte factor, fibroblast or mesangial cell IL-8 release induced
by the IgG-stimulated lymphocyte supernatants was inhibited by 1) the combination
of IL-1R antagonist and soluble type II IL-1R, 2) an IL-1-converting enzyme
inhibitor, or 3) anti-IL-1beta but not preimmune Abs. These data suggest that
targeted deposits of IgG can stimulate FcgammaRIII-bearing lymphocytes to produce
IL-1beta, which induces parenchymal cell IL-8 release.
PMID- 9558102
TI - Induction of a Th1 immune response and simultaneous lack of activation of a Th2
response are required for generation of immunity to leishmaniasis.
AB - Experimental systems based on immunization with plasmid DNA or immune-stimulating
complexes were used to delineate the requirements for generation of protective
immunity against murine leishmaniasis. Vaccination with plasmid DNA encoding the
host-protective Leishmania major parasite surface Ag-2 primed for an essentially
exclusive Th1 response that protected mice against L. major infection. In
contrast, parasite surface Ag-2 in immune-stimulating complexes generated an
immune response with mixed Th1-like and Th2-like properties that was not
protective despite the activation of large numbers of CD4+ T cells secreting IFN
gamma. These results indicate that a Th1 response is sufficient to protect
against cutaneous leishmaniasis, but the induction of a simultaneous Th2 response
abrogates the Th1 effector function. DNA vaccines may therefore have an advantage
for diseases in which protection depends on the induction of Th1 responses.
PMID- 9558103
TI - Mice lacking IL-12 develop polarized Th1 cells during viral infection.
AB - Studies in IL-12-deficient mice established the necessity for IL-12 to generate a
Th1 cytokine response that is often required for elimination of intracellular
pathogens. In this study, we demonstrate that mice with a targeted disruption of
the IL-12p40 and/or p35 gene effectively control liver damage induced by mouse
hepatitis virus (MHV) infection, similar to wild-type animals. In contrast, MHV
infected IFN-gamma receptor-deficient (IFN-gammaR[-/-]) mice showed an increased
susceptibility to coronaviral hepatitis. Surprisingly, MHV-infected mice lacking
IL-12 produced a polarized Th1-type cytokine response, as evidenced by high IFN
gamma and nondetectable IL-4 production by CD4+ splenocytes and normal virus
specific serum IgG2a/IgG1 ratios. The virus-induced type 1 cytokine secretion
pattern was not reversed in IL-12-deficient mice by in vivo neutralization of IFN
gamma nor in IFN-gammaR(-/-) mice receiving IL-12-neutralizing Abs. In IL-12
deficient mice, Th1-type responses were also generated upon immunization with
inactivated MHV. In contrast, following immunization with keyhole limpet
hemocyanin, mice lacking IL-12 mounted strongly reduced specific IgG2a and
increased IgE responses, indicative of a type 2-dominated cytokine pattern. These
findings demonstrate that following a virus infection, IL-12 is not essential for
the generation of polarized T cell type 1 cytokine expression and associated
immune responses, which is in marked contrast to nonviral systems. Our data
suggest that viruses may selectively induce IFN-gamma production and Th1-type
immune reactions even in the absence of IL-12.
PMID- 9558104
TI - Immunopathology of herpetic stromal keratitis: discordance in CD4+ T cell
function between euthymic host and reconstituted SCID recipients.
AB - Infection of the mouse cornea with herpes simplex virus (HSV) results in an
immunopathologic disease of the eye termed herpetic stromal keratitis (HSK), in
which the principal orchestrator is the CD4+ T cell. The mouse genotype largely
determines susceptibility or resistance to HSK. BALB/c mice (H2dIgh-1a) are
susceptible, while its congenic C.B-17 strain (H2dIgh-1b), which differs only in
the Ig heavy chain locus, is resistant to HSK. As the magnitude and duration of
viral replication as well as anti-HSV immune responses were similar in both
strains, it was determined whether resistance was due to failure of CD4+ T cells
to organize the immunopathologic reaction. Adoptive transfer of HSV-primed or
naive CD4+ T cells from resistant C.B-17 strain into HSV-infected SCID mice
resulted in HSK lesions indistinguishable from those caused by similar transfers
of BALB/c CD4+ T cells. Similar results were obtained with transfers of whole T
cell populations as well as with unfractionated splenocytes from the resistant
mice. These results show that while intact C.B-17 mice exhibit resistance to HSK,
they possess potentially pathogenic CD4+ T cells in their repertoire. The data
suggest that the HSV-infected SCID mouse provides a proinflammatory
microenvironment that overrides regulatory controls and/or cause activation of
quiescent cells into aggressive effector T cells that orchestrate HSK.
PMID- 9558105
TI - Effect of antigen-processing efficiency on in vivo T cell response magnitudes.
AB - T lymphocytes eradicate and provide long-term immunity to infections caused by
intracellular pathogens. The mechanisms that determine in vivo T cell response
sizes are poorly understood. Although it is speculated that the relative
processing efficiency of different epitopes determines the hierarchy of T cell
responses following immunization, this hypothesis has not been rigorously tested.
We therefore mutagenized the secreted p60 Ag of Listeria monocytogenes to alter
the efficiency of T cell epitope generation. Ag-processing efficiencies in cells
infected with the different L. monocytogenes mutants ranged from one H2-Kd
associated p60 217-225 epitope generated per 15 intracellularly degraded p60
molecules (1/15) to one epitope per 350 degraded p60 molecules (1/350), i.e., a
spectrum encompassing a 20-fold range of efficiencies. Mice infected with L.
monocytogenes secreting inefficiently processed p60 (1/350) did not mount p60 217
225-specific T cell responses. However, increasing the efficiency of Ag
processing by a factor of 5 to 1/70 restored the T cell response size to normal,
while further increases in the efficiency of p60 217-225 generation to 1/50,
1/35, and 1/17 did not further augment specific T cell responses. Our studies
demonstrate an Ag-processing threshold for in vivo T cell activation.
Surprisingly, once this threshold is achieved, further enhancement of Ag
processing efficiency does not enhance the size of T cell responses.
PMID- 9558107
TI - Intraepithelial infiltration by mast cells with both connective tissue-type and
mucosal-type characteristics in gut, trachea, and kidneys of IL-9 transgenic
mice.
AB - IL-9 transgenic mice were analyzed for the presence of mast cells in different
tissues. In these mice, increased mast cell infiltration was found in the gastric
and intestinal epithelium as well as in the upper airways and kidney epithelium,
but not in other organs, such as skin. IL-9 transgenic mast cells do not show
signs of massive degranulation such as that found in IL-4 transgenic mice and are
not involved in spontaneous pathologic changes. Gastric mast cells showed a
phenotype related to connective-type mast cells, since they were stained by
safranin, and strong expression of mouse mast cell protease-4 and -5 was found in
this organ. However, they also expressed proteases related to the mucosal cell
type, such as mouse mast cell protease-1 and -2. In vitro, although IL-9 by
itself did not induce mast cell development from bone marrow progenitors, it
strongly synergized with stem cell factor for the growth and differentiation of
mast cells expressing the same protease pattern as that observed in IL-9
transgenic mice. Since constitutive stem cell factor expression was observed in
vivo, and anti-c-Kit Abs inhibited IL-9 transgenic mastocytosis in the gut, this
synergistic combination of factors is likely to be responsible for the
mastocytosis observed in IL-9 transgenic mice. Taken together, these data
demonstrate that IL-9 induces the in vivo amplification of a nonclassical mast
cell subset with a mucosal localization but expressing proteases characteristic
of both connective tissue-type and mucosal mast cells.
PMID- 9558106
TI - Vascular adhesion protein-1 and ICAM-1 support the adhesion of tumor-infiltrating
lymphocytes to tumor endothelium in human hepatocellular carcinoma.
AB - T cell-mediated mechanisms are important in the defense against solid organ
tumors. Why some tumors are more heavily infiltrated by T cells than others is
poorly understood but is likely to depend upon adhesive interactions between
circulating lymphocytes and tumor endothelium. In support of this hypothesis, the
present study shows that primary human hepatocellular carcinomas (HCC) are more
heavily infiltrated with T cells than colorectal hepatic metastases (CHM), and
that their tumor vessels express high levels of several adhesion molecules. In
HCC, an intense T cell infiltrate is observed within the tumor associated with
strong expression of ICAM-1 and vascular adhesion protein-1 (VAP-1) on tumor
endothelium. In contrast, fewer T cells infiltrated CHM and these tumors have
little ICAM-1 and no detectable VAP-1 or VCAM-1 on tumor endothelium. T cells
infiltrating both tumors are LFA-1 and very late Ag (VLA)-4 high. In vitro tissue
binding studies demonstrated that T cells bound readily to tumor endothelium in
HCC, and Abs to ICAM-1, VAP-1, and to a lesser extent VCAM-1 could inhibit this
binding. VAP-1 supported sialic acid-dependent adhesion under shear stress,
suggesting that VAP-1 and ICAM-1 mediate, respectively, tethering and firm
adhesion. In contrast, very few T cells bound to tumor vessels in CHM. Thus our
data suggest that the VAP-1/VAP-1 receptor and ICAM-1/LFA-1 pathways are
important in the recruitment of T cells to HCC. The strong expression of VAP-1 on
tumor endothelium distinguishes HCC from CHM and supports our previous hypothesis
that VAP-1 is an important hepatic endothelial adhesion molecule.
PMID- 9558108
TI - Preprosomatostatin messenger RNA is expressed by inflammatory cells and induced
by inflammatory mediators and cytokines.
AB - Somatostatin (SOM) is a 14-amino acid cyclic peptide that regulates granulomatous
inflammation. SOM inhibits the release of IFN-gamma from murine granuloma T cells
that express SOM receptors. SOM is synthesized as preprosomatostatin (ppSOM), a
precursor peptide that is cleaved to release active SOM. In this paper, we
demonstrate that granuloma cells express mRNA for this important immunoregulator,
and that inflammatory mediators rapidly induce ppSOM mRNA in the splenocytes of
uninfected, normal (NL) mice. We developed a sensitive, quantitative PCR assay
that measures ppSOM mRNA down to 100 transcripts per microg of total RNA.
Dispersed granuloma cells expressed authentic ppSOM mRNA as determined by RT-PCR
and cDNA sequencing. The PCR assay readily detected ppSOM mRNA in splenocytes
isolated from schistosome-infected mice, but not in splenocytes from NL mice.
Splenic ppSOM mRNA expression correlated with the onset of parasite egg
deposition and granuloma formation. A 4-h in vitro stimulation with LPS, rIL-10,
rIFN-gamma, rTNF-alpha, prostaglandin E2, or dibutyryl cAMP induced ppSOM mRNA in
NL splenocytes that otherwise lacked this transcript. Splenocytes from severe
combined immunodeficient or recombination activating gene 1-deficient mice
expressed ppSOM after exposure to rIL-10, suggesting that neither T nor B cells
are necessary for ppSOM mRNA induction. A survey of cell lines demonstrated
expression of ppSOM mRNA by P388D1 and J774A.1 macrophage-like cells. These data
suggest that SOM, which is probably derived from macrophages, is an inducible
component of the innate immune system that regulates T cell IFN-gamma production.
PMID- 9558109
TI - An antagonistic IL-4 mutant prevents type I allergy in the mouse: inhibition of
the IL-4/IL-13 receptor system completely abrogates humoral immune response to
allergen and development of allergic symptoms in vivo.
AB - We have analyzed in vivo effects of the murine IL-4 mutant Q116D/Y119D (QY),
which forms unproductive complexes with IL-4Ralpha and is an antagonist for IL-4
and IL-13 in vitro. Treatment of BALB/c mice with QY during immunization with OVA
completely inhibited synthesis of OVA-specific IgE and IgG1. BALB/c-derived
knockout mice lacking either IL-4 or IL-4Ralpha also did not develop specific IgE
or IgG1, but mounted a much stronger IgG2a and IgG2b response than wild-type
mice. In contrast, QY treatment of normal BALB/c mice suppressed specific IgG2a,
IgG2b, and IgG3 synthesis, which may indicate the development of tolerance toward
the allergen. Associated with the lack of IgE synthesis in QY-treated wild-type
mice and in IL-4(-/-) mice used as a control was the failure to develop immediate
cutaneous hypersensitivity or anaphylactic shock upon rechallenge. Interestingly,
QY treatment also inhibited humoral immune responses and allergic reactivity in
SJL/J mice, a strain that did not produce IgE, but displayed IgE-independent mast
cell degranulation mediated by specific IgG1. We conclude that QY inhibits Ag
specific humoral immune responses and allergic symptoms mediated either by IgE or
IgG1. It needs to be clarified how QY abrogates synthesis of IgG2a, IgG2b, and
IgG3, but the induction of tolerance toward nonhazardous protein Ags should be
advantageous for therapy of atopic disorders and other Th2-dominated diseases.
PMID- 9558110
TI - Lidocaine and its analogues inhibit IL-5-mediated survival and activation of
human eosinophils.
AB - Eosinophils and cytokines active on eosinophils, especially IL-5, are believed to
be critically involved in chronic allergic diseases. IL-5 activates eosinophils
and enhances their survival in vitro by delaying apoptosis. In this study, we
found that lidocaine and six analogues blunt responses of eosinophils to IL-5.
Lidocaine and its derivatives inhibit IL-5-mediated eosinophil survival in a
concentration-dependent manner (IC50 = 110 microM for 30 pg/ml IL-5). At
suboptimal lidocaine concentrations, the eosinophil survival response to IL-5
shifts and more IL-5 is required to maintain survival. The inhibitory effect
requires at least 24-h exposure of eosinophils to lidocaine, and the protein
kinase C activator, PMA, completely reverses the inhibition. A multiparameter
flow-cytometric analysis shows that lidocaine hastens the apoptosis of
eosinophils normally delayed by IL-5. Lidocaine does not affect IL-5R expression
or IL-5-induced protein tyrosine phosphorylation. Lidocaine also inhibits
eosinophil survival mediated by IL-3 or granulocyte-macrophage CSF, although less
potently than that mediated by IL-5. Furthermore, lidocaine inhibits eosinophil
superoxide production stimulated by IL-5, granulocyte-macrophage CSF, or IL-3,
but not that stimulated by platelet-activating factor, immobilized IgG, or PMA.
Lidocaine and its derivatives show novel immunomodulatory properties and are able
to blunt eosinophil responses to cytokines in addition to their local anesthetic
or antiarrhythmic properties. Thus, lidocaine and its derivatives may represent a
new class of therapeutic agents to treat patients with allergic diseases.
PMID- 9558111
TI - Impaired macrophage function and enhanced T cell-dependent immune response in
mice lacking CCR5, the mouse homologue of the major HIV-1 coreceptor.
AB - The CC-chemokine receptor CCR5 has been shown to be the major coreceptor for HIV
1 entry into cells, and humans with homozygous mutation in the ccr5 gene are
highly resistant to HIV-1 infection, despite the existence of many other HIV-1
coreceptors. To investigate the physiologic function of CCR5 and to understand
the cellular mechanisms of these clinical observations, we generated a CCR5
deficient mouse model (ccr5[-/-]) by targeted deletion of the ccr5 gene. We found
that although developed normally in a pathogen-free environment, CCR5-deficient
mice showed reduced efficiency in clearance of Listeria infection and exert a
protective effect against LPS-induced endotoxemia, reflecting a partial defect in
macrophage function. In addition, CCR5-deficient mice had an enhanced delayed
type hypersensitivity reaction and increased humoral responses to T cell
dependent antigenic challenge, indicating a novel role of CCR5 in down-modulating
T cell-dependent immune response.
PMID- 9558112
TI - Induction and enhancement of Fc(epsilon)RI-dependent mast cell degranulation
following coculture with activated T cells: dependency on ICAM-1- and leukocyte
function-associated antigen (LFA)-1-mediated heterotypic aggregation.
AB - Activated mast cells are known to reside in close apposition to T cells in
various inflammatory processes. In this regard, we have reported that activated
mast cells form heterotypic aggregates with activated lymphocytes. To determine
whether this interaction would result in mast cell degranulation, we examined the
effect of EL-4, 2B4, or freshly isolated T cells, activated by PMA or immobilized
anti-CD3 mAb, on histamine release from murine bone marrow-derived cultured mast
cells (BMCMC). Coculturing BMCMC with activated but not with resting T cells
resulted in significant histamine release. Also, Fc(epsilon)RI cross-linking
induced degranulation was augmented when BMCMC were cocultured with activated T
cells. Supernatants of activated T cells failed to exert the stimulatory effect.
Separation of the two cell populations with a porous membrane prevented
degranulation, indicating that BMCMC activation was adhesion dependent. Indeed,
the kinetics of histamine release paralleled the kinetics of the formation of
heterotypic aggregates, which peaked after 12 h of coculture. Introduction of
anti-LFA-1 and anti-intercellular adhesion molecule-1 mAb inhibited the adhesion
induced mast cell degranulation. These data suggest a heretofore unrecognized
mast cell activation pathway induced by LFA-1/intercellular adhesion molecule-1
mediated heterotypic aggregation with activated T cells.
PMID- 9558113
TI - Posttranslational modifications affect the activity of the human monocyte
chemotactic proteins MCP-1 and MCP-2: identification of MCP-2(6-76) as a natural
chemokine inhibitor.
AB - Chemokines are important mediators in infection and inflammation. The monocyte
chemotactic proteins (MCPs) form a subclass of structurally related C-C
chemokines. MCPs select specific target cells due to binding to a distinct set of
chemokine receptors. Recombinant and synthetic MCP-1 variants have been shown to
function as chemokine antagonists. In this study, posttranslationally modified
immunoreactive MCP-1 and MCP-2 were isolated from mononuclear cells. Natural
forms of MCP-1 and MCP-2 were biochemically identified by Edman degradation and
mass spectrometry and functionally characterized in chemotaxis and Ca2+
mobilization assays. Glycosylated MCP-1 (12 and 13.5 kDa) was found to be two- to
threefold less chemotactic for monocytes and THP-1 cells than nonglycosylated MCP
1 (10 kDa). Natural, NH2-terminally truncated MCP-1(5-76) and MCP-1(6-76) were
practically devoid of bioactivity, whereas COOH-terminally processed MCP-1(1-69)
fully retained its chemotactic and Ca2+-inducing capacity. The capability of
naturally modified MCP-1 forms to desensitize the Ca2+ response induced by intact
MCP-1 in THP-1 cells correlated with their agonistic potency. In contrast,
naturally modified MCP-2(6-76) was devoid of activity, but could completely block
the chemotactic effect of intact MCP-2 as well as that of MCP-1, MCP-3, and
RANTES. Carboxyl-terminally processed MCP-2(1-74) did retain its chemotactic
potency. Although comparable as a chemoattractant, natural intact MCP-2 was found
to be 10-fold less potent than MCP-1 in inducing an intracellular Ca2+ increase.
It can be concluded that under physiologic or pathologic conditions,
posttranslational modification affects chemokine potency and that natural MCP-2(6
76) is a functional C-C chemokine inhibitor that might be useful as an inhibitor
of inflammation.
PMID- 9558114
TI - Hydrogen peroxide induces up-regulation of Fas in human endothelial cells.
AB - Hydrogen peroxide (H2O2), an oxidant generated by inflammatory cells, is an
important mediator of injury of endothelial cells (ECs). Here we show that H2O2
induces up-regulation of the expression of Fas, a death signal, in human ECs in
culture. Flow cytometric analysis with a mAb against human Fas showed that
incubation for 24 h with H2O2 induced a dose-dependent increase in the level of
Fas in ECs. Coincubation with catalase, which rapidly degrades H2O2, inhibited
H2O2-induced up-regulation of Fas. H2O2 also induced a dose-dependent increase in
Fas mRNA level. A significant increase in Fas mRNA levels was observed from 6 h
after stimulation with H2O2. Vanadate, a protein phosphatase inhibitor,
significantly enhanced Fas mRNA and protein levels in H2O2-treated ECs. On the
other hand, genistein, a tyrosine kinase inhibitor, inhibited H2O2-induced Fas
mRNA expression. Furthermore, a flow cytometric method with propidium iodide
staining and electron microscopic analysis showed that incubation with an
agonistic Ab against Fas (anti-Fas IgM) induced apoptosis in H2O2-treated cells.
These findings suggest that H2O2 induces up-regulation of Fas in ECs and that
activation of protein tyrosine kinase may be involved in the mechanism of H2O2
induced Fas expression. Therefore, Fas-mediated apoptosis may have a pathologic
role in H2O2-induced EC injury and thereby provide a new therapeutic target.
PMID- 9558115
TI - Involvement of the IL-2 receptor gamma-chain (gammac) in the control by IL-4 of
human monocyte and macrophage proinflammatory mediator production.
AB - IL-4 has potent anti-inflammatory properties on monocytes and suppresses both IL
1beta and TNF-alpha production. Well-characterized components of the IL-4
receptor on monocytes include the 140-kDa alpha-chain and the IL-2R gamma-chain,
gammac, which normally dimerize 1:1 for signaling from the receptor. However,
mRNA levels for gammac were very low in 7-day-cultured monocytes. As mRNA levels
for gammac declined with culture, so too did the ability of IL-4 to down-regulate
LPS-induced TNF-alpha production. In contrast, IL-4 consistently down-regulated
IL-1beta production by cultured monocytes. Immunoprecipitation and Western blot
analyses demonstrated that 7-day-cultured monocytes do not express the
functionally active 64-kDa gammac protein. This was associated with decreased
STAT6 activation by IL-4. Studies with Abs to gammac and an IL-4 mutant that is
unable to bind to gammac showed that IL-4 can suppress IL-1beta but not TNF-alpha
production by LPS-stimulated monocytes in the presence of little or no
functioning gammac. IL-4 also suppressed IL-1beta but not TNF-alpha production by
Mono Mac 6 cells, which express minimal levels of gammac. For gammac-expressing
LPS/PMA-activated U937 cells, IL-4 decreased both TNF-alpha and IL-1beta
production. These results suggest that functional gammac is not present on in
vitro-derived macrophages, and that while some anti-inflammatory responses to IL
4 are lost with this down-regulation of functional gammac, others are retained.
We conclude that different functional responses to IL-4 by human monocytes and
macrophages are regulated by different IL-4 receptor configurations.
PMID- 9558116
TI - Human polymorphonuclear leukocytes adhere to complement factor H through an
interaction that involves alphaMbeta2 (CD11b/CD18).
AB - The work presented here demonstrates that human complement factor H is an
adhesion ligand for human neutrophils but not for eosinophils. The adherence of
polymorphonuclear leukocytes (PMNs) to plastic wells coated with factor H
depended on divalent metal ions and was augmented by C5a and TNF-alpha. PMN
adhesion to factor H in the presence or absence of C5a was blocked specifically
by mAbs against CD11b or CD18. Affinity purification using factor H Sepharose
followed by immunoprecipitation using mAbs to various integrin chains identified
Mac-1 (CD11b/CD18) as a factor H binding receptor. The presence of surface bound
factor H enhanced neutrophil activation resulting in a two- to fivefold increase
in the generation of hydrogen peroxide by PMNs stimulated by C5a or TNF-alpha.
When factor H was mixed with PMNs, 1.4 to 3.8-fold more cells adhered to
immobilized heparin or chondroitin A. In addition, augmented adhesion of PMNs was
measured when factor H, but not HSA or C9, was absorbed to wells that were first
coated with heparin or chondroitin A. The adhesion of PMNs to glycosaminoglycan
factor H was blocked by mAbs to CD11b and CD18. These studies demonstrate that
factor H is an adhesion molecule for human neutrophils and suggest that the
interaction of factor H with glycosaminoglycans may facilitate the tethering of
this protein in tissues allowing factor H to serve as a neutrophil adhesion
ligand in vivo.
PMID- 9558117
TI - Regulation of E-cadherin-mediated adhesion in Langerhans cell-like dendritic
cells by inflammatory mediators that mobilize Langerhans cells in vivo.
AB - Adhesion of Langerhans cells (LC) to keratinocytes is mediated by E-cadherin. IL
1, TNF-alpha, and LPS mobilize LC from epidermis and presumably attenuate LC
keratinocyte adhesion. To determine whether these mediators modulated LC E
cadherin-dependent adhesion directly, we characterized their effects on LC-like
dendritic cells expanded from murine fetal skin (FSDDC). FSDDC were propagated
from day 16 C57BL/6 fetal skin and isolated as aggregates (FSDDC-A) in which
homophilic adhesion was mediated by E-cadherin. IL-1, TNF-alpha, and LPS induced
dissociation of FSDDC-A that began within 4 to 8 h and was complete within 20 h.
Anti-IL-1RI mAb inhibited disaggregation caused by IL-1alpha and IL-1beta, but
not that induced by TNF-alpha or LPS. Anti-TNF-alpha mAb inhibited the effect of
TNF-alpha and LPS, but not that caused by IL-1alpha or IL-1beta. Flow cytometry
of FSDDC-A revealed that IL-1, TNF-alpha, and LPS induced increased expression of
MHC class II, CD40, and CD86 and decreased E-cadherin expression that was
temporally related to dissociation of aggregates. IL-1 and TNF-alpha caused a
rapid reduction in FSDDC E-cadherin mRNA levels that preceded the decrease in E
cadherin surface expression. These results demonstrate that cytokines that induce
LC emigration in vivo act directly on LC-like cells in vitro, reduce E-cadherin
mRNA levels, down-regulate E-cadherin surface expression, and induce a loss of E
cadherin-mediated adhesion.
PMID- 9558118
TI - IFN-gamma limits macrophage expansion in MRL-Fas(lpr) autoimmune interstitial
nephritis: a negative regulatory pathway.
AB - IFN-gamma is capable of enhancing and limiting inflammation. Therefore, an
increase in IFN-gamma in autoimmune MRL-Fas(lpr) mice could exacerbate or thwart
renal injury. We have established a retroviral gene transfer approach to incite
interstitial nephritis in MRL-Fas(lpr) mice that is rapid, enduring, and
circumscribed. Renal tubular epithelial cells (TEC) were genetically modified to
secrete macrophage (Mphi) growth factors (CSF-1-TEC, GM-CSF-1-TEC) and infused
under the renal capsule. To determine the impact of IFN-gamma in Mphi growth
factor-incited renal injury, we constructed a MRL-Fas(lpr) IFN-gamma-receptor
(IFN-gammaR)-deficient strain. Gene transfer of CSF-1 or GM-CSF incited more
severe interstitial nephritis in IFN-gammaR-deficient than in IFN-gammaR-intact
MRL-Fas(lpr) mice, consisting of an increase of Mphi. To determine the mechanism
responsible for the increase in Mphi in IFN-gammaR-deficient MRL-Fas(lpr) mice,
we evaluated Mphi proliferation, apoptosis, and recruitment. Proliferation of
bone marrow Mphi from IFN-gammaR-intact MRL-Fas(lpr) costimulated with CSF-1 or
GM-CSF and IFN-gamma was reduced twofold, while the IFN-gammaR-deficient MRL
Fas(lpr) bone marrow Mphi remained stable. Furthermore, we detected more
proliferating and fewer apoptotic Mphi within the interstitium in IFN-gammaR
deficient MRL-Fas(lpr) mice. Using unilateral ureteral ligation we established
that IFN-gammaR signaling does not alter Mphi recruitment into the kidney. Thus,
the increase in Mphi elicited by Mphi growth factors in IFN-gammaR-deficient MRL
Fas(lpr) mice is a result of enhanced proliferation and decreased apoptosis, and
is independent of recruitment. Taken together, we suggest that IFN-gamma provides
a negative regulatory pathway capable of limiting Mphi-mediated renal
inflammation.
PMID- 9558119
TI - Disparate roles for TNF-alpha and Fas ligand in concanavalin A-induced hepatitis.
AB - Apoptosis is a physiologic process that serves to eliminate cells during
development or in response to immunologic regulation. In acute inflammation,
however, apoptosis triggered by the overproduction of "death factors" such as TNF
alpha or Fas ligand (FasL) may contribute to tissue injury. Both TNF-alpha and
FasL are presumed to convey an apoptotic signal by activating a cascade of
cysteine-aspartate proteases, which includes IL-1beta-converting enzyme or
caspase-1. In the present study, we evaluated the contribution of TNF-alpha and
FasL, as well as the role of caspase-1, in Con A-induced hepatitis. We report
here that TNF-alpha and FasL mRNA and protein levels are both increased in the
livers of Con A-challenged mice. Using a novel inhibitor of TNF-alpha, we can
confirm that Con A-induced hepatitis is primarily TNF-alpha dependent. Blockade
of FasL with a soluble Fas immunoadhesin does not prevent liver injury in animals
treated with Con A alone. However, administration of a matrix metalloproteinase
inhibitor exacerbates liver injury, in part through a FasL-dependent process,
since pretreatment with the soluble Fas immunoadhesin reduces liver injury in
this model. In addition, mice lacking functional caspase-1 are resistant to Con A
induced hepatitis, even after pretreatment with a matrix metalloproteinase
inhibitor. We conclude that TNF-alpha plays a predominant role in Con A-induced
liver injury, although concomitant activation of FasL can also lead to apoptotic
injury. Furthermore, Con A-induced hepatitis is caspase-1 dependent.
PMID- 9558120
TI - Dendritic cells are required for the development of chronic eosinophilic airway
inflammation in response to inhaled antigen in sensitized mice.
AB - Asthma is characterized by chronic eosinophilic inflammation of the airways, and
allergen-specific Th2 lymphocytes are thought to play a major role in the
development and maintenance of this type of inflammation in allergic asthma. It
is generally accepted that airway dendritic cells (DC) are essential for
stimulating naive T cells in a primary immune response to inhaled Ag and for the
development of allergic sensitization. We have examined the role of airway DC in
stimulating memory T cells in a secondary response to inhaled Ag and the
subsequent development of chronic airway inflammation. In our mouse model of
asthma, OVA aerosol challenge in OVA-sensitized mice leads to CD4-dependent
peribronchial and perivascular eosinophilic inflammation, lung Th2 cytokine
production, and systemic IgE production. We have used conditional depletion of
airway DC by treatment of thymidine kinase-transgenic mice with the antiviral
drug ganciclovir to deplete DC during the secondary exposure to OVA. In
sensitized thymidine kinase-transgenic mice, a significant decrease in the number
of bronchoalveolar CD4 and CD8 T lymphocytes and B lymphocytes was seen after
ganciclovir treatment. In addition, Th2 cytokine-associated eosinophilic airway
inflammation was almost completely suppressed. These studies demonstrate for the
first time that the DC is essential for presenting inhaled Ag to previously
primed Th2 cells in the lung, leading to chronic eosinophilic airway
inflammation. Altering the function of airway DC may therefore be an important
target for new anti-asthma therapy.
PMID- 9558121
TI - A p55 TNF receptor immunoadhesin prevents T cell-mediated intestinal injury by
inhibiting matrix metalloproteinase production.
AB - Anti-TNF-alpha Ab therapy has been shown to be of benefit in the treatment of
active Crohn's disease, but the tissue-injuring processes in the gut mediated by
TNF-alpha that might be inhibited by neutralizing Ab are unknown. In this work,
we have used a p55 TNF receptor-human IgG fusion protein (TNFR-IgG) to prevent
the severe mucosal injury that ensues when lamina propria T cells in explant
cultures of human fetal small intestine are directly activated with the lectin
PWM. Following T cell activation and associated with mucosal injury, there is a
marked elevation of soluble TNF-alpha in organ culture supernatants and a large
increase in TNF-alpha mRNA transcripts. The addition of TNFR-IgG at the onset of
cultures greatly reduced PWM-induced tissue injury, without inhibiting the
increase in TNF-alpha and IFN-gamma transcripts seen following T cell activation.
Mucosal injury in this model is mediated by endogenously-produced matrix
metalloproteinases (MMPs). When TNFR-IgG was added to PWM-stimulated explants,
there was a reduction in MMPs in the explant culture supernatants, especially
stromelysin-1. Recombinant TNF-alpha and IL-1beta added directly to mucosal
mesenchymal cell lines also caused an increase in MMP production, but only the
former was inhibited by the TNFR-IgG. These results suggest that one of the ways
in which TNF-alpha causes tissue injury in the gut is by stimulating mucosal
mesenchymal cell to secrete matrix-degrading metalloproteinases. Neutralization
of this activity should help maintain tissue integrity.
PMID- 9558122
TI - Flt-3 ligand increases microchimerism but can prevent the therapeutic effect of
donor bone marrow in transiently immunosuppressed cardiac allograft recipients.
AB - C3H (H2k) mice received 50 x 10(6) B10 (H2b) bone marrow (BM) cells either alone
or with flt-3 ligand (FL) (10 microg/day), tacrolimus (2 mg/kg/day), or both
agents for 7 days. Donor MHC class II+ (IAb+) cells were quantitated in spleens
by immunohistochemical analysis, and donor class II DNA detected in BM by PCR.
Donor cells were rare in the BM alone and BM + FL groups, whereas there was a
substantial increase in chimerism in the BM + tacrolimus group. Addition of FL to
BM + tacrolimus led to a further eightfold increase in donor cells and enhanced
donor DNA compared with the BM + tacrolimus group. This increase in donor cells
was almost 500-fold compared with BM alone. C3H recipients of B10 heart
allografts given perioperative B10 BM and tacrolimus (days 0-13) exhibited a
markedly extended median graft survival time (MST, 42 days) compared with those
given tacrolimus alone (MST, 22 days). Addition of FL (10 microg/day; 7 days) to
BM + tacrolimus prevented the beneficial effect of donor BM (MST, 18 days). BM
alone or BM + FL resulted in uniform early heart graft failure (MST < 8 days).
Functional studies revealed maximal antidonor MLR and CTL activities in the BM-
and BM + FL-treated groups, with minimal activity in the tacrolimus-treated
groups. Thus, dramatic growth factor-induced increases in chimerism achieved
under cover of immunosuppression may result in augmented antidonor T cell
reactivity and reduced graft survival after immunosuppressive drug withdrawal.
With FL, this may reflect striking augmentation of immunostimulatory dendritic
cells.
PMID- 9558123
TI - Complement-fixing elicited antibodies are a major component in the pathogenesis
of xenograft rejection.
AB - Hamster to rat cardiac xenografts undergo delayed rejection as compared with the
hyperacute rejection of discordant xenografts. Elicited xenoreactive Abs (EXA)
are thought to initiate hamster to rat cardiac xenograft rejection. In this
study, we demonstrate that following transplantation of a hamster heart, rats
generated high levels of EXA. Adoptive transfer into naive recipients of purified
IgM, IgG2b, or IgG2c, but not IgG1 or IgG2a EXA, induced xenograft rejection in a
complement-dependent manner. Ability of EXA to cause rejection correlated with
complement activation, platelet aggregation, and P-selectin expression in the
xenograft endothelium. Cyclosporin A (CyA) administration, after transplantation,
totally suppressed IgG1, IgG2a, IgG2b, and IgG2c EXA, and inhibited IgM EXA
production, but failed to overcome rejection. Administration of cobra venom
factor (CVF), 1 day before and at the time of transplantation, resulted in
complement inhibition during 3 days after transplantation, which failed to
overcome rejection. Combination of CyA and CVF, which we have previously shown to
overcome rejection, resulted in suppression of IgG EXA production and in the
return of IgM XNA to preimmunization serum levels, 3 to 7 days after
xenotransplantation, while complement remained inhibited. Thus, under CyA/CVF
treatment, complement activation by hamster cells was suppressed following
xenotransplantation, and presumably for this reason xenograft rejection did not
occur. In conclusion, our data demonstrate that EXA play a pivotal role in the
pathogenesis of xenograft rejection and that CyA and CVF suppress xenograft
rejection by preventing exposure of xenograft endothelial cells to complement
activation by EXA.
PMID- 9558124
TI - Requirement for in vivo production of IL-4, but not IL-10, in the induction of
proliferative suppression by filarial parasites.
AB - Loss of T lymphocyte proliferation and the emergence of a host response that is
dominated by a Th2-type profile are well-established features of human
filariasis. We have previously reported that adherent peritoneal exudate cells
(PEC) from mice transplanted with adult Brugia malayi parasites suppress the
proliferation of lymphocytes without blocking Ag-cytokine production in vitro. We
now show that infection of mice with the infective larval (L3) stage of B. malayi
generates a similar population of PEC. Suppressive cells are generated within 7
days of infection and mediate their effects through a nitric oxide-independent
pathway. Both L3 and adult infection elicit high levels of host IL-4 whereas the
microfilarial stage of the parasite induces IFN-gamma production and does not
generate a similar form of suppression. Production of host IL-4 was necessary to
allow the generation of suppressive PEC, given that IL-4-deficient mice implanted
with adult parasites failed to induce proliferative block. However, IL-10
deficient mice implanted with adult parasites resulted in T cell suppression,
indicating that IL-10 is not essential for the induction of hyporesponsiveness.
Neither IL-4 nor IL-10 were directly responsible for ablating cellular
proliferation in vitro, as the addition of neutralizing Ab to either cytokine did
not reverse the proliferative block. Thus, IL-4 produced in vivo in response to
filarial L3 and adult parasites is essential for the induction of proliferative
suppression but is not itself the suppressive factor.
PMID- 9558125
TI - Relative tissue distributions of cyclosporine and sirolimus after concomitant
peroral administration to the rat: evidence for pharmacokinetic interactions.
AB - The authors sought to determine the effect of concomitant peroral (PO)
administration of cyclosporine (CsA) and sirolimus (SRL, rapamycin) on the tissue
distributions of CsA and SRL in the rat. Groups of four adult male Wistar-Furth
rats were treated for 14 days with 2.5, 5.0, or 10.0 mg CsA/kg x day. Other
groups of four adult male Wistar-Furth rats were treated for 14 days with a 1-to
6.25 weight-to-weight ratio of SRL to CsA at SRL doses of 0.4, 0.8, or 1.6 mg/kg
x day. Concentrations of CsA and SRL in homogenates of heart, intestinal, kidney,
liver, lung, muscle, spleen, and testes were compared to those in whole blood
(WB). There was a large, dose-dependent, distinctive distribution of CsA among
rat tissues, as has previously been well documented. At a constant molar dose
ratio, concomitant oral administration of SRL produced an approximately two-fold
increase in the concentrations of CsA in rat tissues, although SRL did not change
the CsA tissue-to-WB partition coefficients. Concomitant oral CsA administration
produced dose-dependent increases in SRL tissue concentrations and decreases in
the SRL tissue-to-WB partition coefficients. The increases in tissue and WB
concentrations on coadministration of both agents may be explained either by an
increase in absorption caused by competition between the two agents for binding
sites on P-glycoprotein in the gut, a reduced rate of metabolism, or to an as yet
unidentified elimination mechanism. The dose-independent and unchanged CsA tissue
to-WB partition coefficients suggest that SRL does not affect the equilibrium of
CsA between the central and tissue compartments, namely the tissue uptake or
intracellular binding. Altered values of the SRL tissue-to-WB partition
coefficients suggest that, under the conditions studied, CsA disturbs the
equilibrium of SRL between the central and tissue compartments.
PMID- 9558126
TI - A model for the prediction of digoxin-drug interactions at the renal tubular cell
level.
AB - Digoxin-drug interactions are relatively common causes of digitalis toxicity.
Recently, the clinical importance of the renal tubular secretion of digoxin has
been proven by documenting drug interactions at this level. The authors describe
a model using cultured renal tubular cell monolayers that can be used to predict
drug interactions with the cardiac glycoside. This model accurately documents
known clinical digoxin interactions such as those with verapamil and propafenone.
The common feature of these interactions is that they involve P-glycoprotein
substrates (e.g., digoxin, vincristine, vinblastine) or inhibitors (e.g.,
quinidine, cyclosporine). In the case of the newly described interaction of
digoxin with itraconazole, the model preceded the emergence of clinical cases.
PMID- 9558127
TI - Population pharmacokinetics of vancomycin in Japanese adult patients.
AB - Population pharmacokinetic parameters of vancomycin (VCM) in Japanese adult
patients infected with methicillin-resistant Staphylococcus aureus (MRSA) were
estimated using 1253 items of serum concentration data from 190 patients obtained
in routine drug monitoring. The two-compartment linear model was adopted, and VCM
clearance (CL) was correlated with the creatinine clearance (CLcr), which was
observed or estimated by the Cockcroft-Gault equation. The population
pharmacokinetic analysis program NONMEM with first-order conditional estimation
method was used. The results showed VCM clearance to be linearly correlated with
CLcr (CL [ml/min] = 0.797 x CLcr) when the estimated CLcr was <85 ml/min, but no
linear relationship at higher than this level because of the lack of accuracy in
the CLcr estimates. The interindividual variability of CL was 38.5%; K12 and K21
were 0.525 hr(-1) and 0.213 hr(-1), respectively. The distribution volume at
steady state (V[SS]) was 60.71, with no significant dependence on the actual body
weight. The interindividual variability of Vss was 25.4%. The calculated half
life (t1/2,beta) in a typical patient with CLcr of 85 ml/minute was 12.8 hours.
Residual variability was 23.7%. These results were compared to those of healthy
volunteers, and guidelines for dosage adjustment in VCM therapy are discussed.
PMID- 9558128
TI - Valproate as monotherapy for juvenile myoclonic epilepsy: dose-effect study.
AB - Sodium valproate enteric-coated tablets were used in this double-blind,
randomized, cross-over study of 16 patients with juvenile myoclonic epilepsy
comparing 1000 mg and 2000 mg VPA daily in b.i.d. administration with 6 months of
observation on each dose. Myoclonic, absence, and generalized tonic-clonic
seizures were registered separately. Subjective side-effects were monitored, and
a computerized neuropsychologic test battery was performed on each dose. There
was no significant difference in seizure frequency between the two doses. Only
25% of the patients were seizure free throughout the study despite concentrations
well within the normally proposed therapeutic range for VPA. During the higher
dose, 37.5% of the patients had an improved seizure control, but 25% of the
patients had an increase in seizure frequency compared to the lower dose.
However, there was no correlation between VPA concentrations and subjective side
effects or neuropsychologic test results. Our observations point out the
possibility that the common strategy of increasing plasma levels in difficult-to
treat patients until side effects occur should perhaps be reconsidered, but this
suggestion needs further confirmation.
PMID- 9558129
TI - A population pharmacokinetic model of cyclosporine in the early postoperative
phase in patients with liver transplants, and its predictive performance with
Bayesian fitting.
AB - The availability of personal computer programs to individualize drug regimens has
stimulated interest in modeling population pharmacokinetics. This study used the
NPEM2 software to determine cyclosporine population pharmacokinetic parameter
values and distributions in a first group of 25 recipients of liver transplants
during their first postoperative week. On a second group of 25 patients, the
authors used these values to evaluate Bayesian predictive performance of
cyclosporine blood concentrations with the USC*PACK PC program. During the study
period, all the patients have been treated by continuous intravenous infusion.
The one-compartment model pharmacokinetic parameter-the slope of volume to body
weight (Vs) and the elimination rate constant (Kel) values found (mean values: Vs
= 2.177 l/kg, Kel = 0.235 h(-1); median values: Vs = 1.559 l/kg, Kel = 0.163 h(
1); the percent coefficient of variation (Vs = 92%, Kel = 79%) appear reasonable
and show the ability of NPEM2 to deal with sparse data. When the predictions were
studied with day 1, day 2, or day 3 concentrations, predictive bias was
respectively -0.030, -0.013, and 0.013 microg/ml, suggesting a greater clearance
of cyclosporine immediately after surgery, the clearance decreasing in the days
after. With the first three blood levels and the Bayesian fitting procedure, it
was possible to predict at least half the subsequent measured blood levels of
each patient accurately (within 20%) in more than three-quarters (76%) of the
second group of recipients of transplants, and for 40% of patients the authors
obtained accurate predictions in 100% of the subsequent blood levels. For a few
patients (12%) they found quite poor predictions. The reason for this is unclear.
The results suggest that this population model and the Bayesian fitting procedure
using two or three blood levels can be reasonably and carefully used to control,
in real time, cyclosporine blood levels in a majority of new patients with liver
transplants.
PMID- 9558130
TI - Ability of a first-pass pharmacokinetic model to characterize cyclosporine blood
concentrations after administrations of Sandimmune or Neoral formulations.
AB - Most recent cyclosporine (CsA) pharmacokinetic (PK) studies have focused on
noncompartmental analysis. Because CsA undergoes significant first-pass
elimination after oral dosing, the most appropriate compartment model may need to
take this process into account for the construction of a valid population PK
model for Sandimmune (SAN) and Neoral (NEO) formulations. Twenty patients with
cardiac transplants were stabilized for at least 4 weeks on a certain dose of
SAN, then changed to the same daily dose of NEO. Blood samples were obtained at
times 0, 1, 2, 3, 4, 6 and 12 hours after dosing at steady state. Pharmacokinetic
modeling was performed using ADAPT II. Quality of fit was assessed by visual
graph inspections, R2 values, and Akaike criterion test. Eight pharmacokinetic
models were constructed and evaluated. These included one- and two-compartment
with and without a first-pass effect and a time-lag. Neoral and SAN data were
consistently best fitted using a two-compartment or the two-compartment first
pass model. However, a time-lag process was found to be necessary for SAN. The
use of a two-compartment first-pass with (SAN) or without (NEO) a time-lag
process appears to fit CsA concentrations at least as well as a two-compartment
model. This first-pass model may be very useful for population pharmacokinetics
and Bayesian control analysis.
PMID- 9558131
TI - Safety and efficacy of a two-compartment Bayesian feedback program for
therapeutic tobramycin monitoring in the daily clinical use and comparison with a
non-Bayesian one-compartment model.
AB - The predictive value of a two-compartment Bayesian feedback program for
tobramycin dose optimization was retrospectively evaluated in 199 hospitalized
patients and compared with that of a simple non-Bayesian one-compartment model.
Before dose adjustment, 64% of the patients were underdosed indicating that
tobramycin monitoring is still necessary to avoid ineffective antibiotic therapy.
When physicians adhered to the dose instructions calculated with the Bayesian
method, 90% of the patients had optimal concentration-time profiles as opposed to
only 53% of the 43 patients in whom dose recommendations were not followed. In
young patients with normal renal function, precision and accuracy of the Bayesian
feedback and the one-compartment method were well correlated, whereas in elderly
patients (> 60 years) and patients with impaired renal function (estimated
creatinine clearance < 60 ml/minute), the Bayesian method was significantly more
precise. Multiple regression analysis revealed that renal function was the only
independent variable predicting the performance of the Bayesian program. The
results of this study indicate that the Bayesian feedback method is a reliable
method for the therapeutic tobramycin monitoring under clinical conditions and in
particular, elderly patients in whom renal impairment is frequent.
PMID- 9558132
TI - Correlation between concentrations of melatonin in saliva and serum in patients
with delayed sleep phase syndrome.
AB - Exogenous melatonin, which can be used to treat certain circadian rhythm
disorders, maximally advances delayed rhythms when administered 5 hours before
the endogenous melatonin starts to increase. The time of the start of the
endogenously melatonin is defined as Dim Light Melatonin Onset (DLMO). The DLMO
concentration has been defined in serum to be 10 pg/ml. Because of the greater
practicability of frequent saliva sampling over blood sampling, we have validated
radioimmunoassay (RIA) measurements of melatonin in saliva in patients diagnosed
as suffering from a typical circadian rhythm disorder: Delayed Sleep Phase
Syndrome (DSPS). Based on these results we have defined the equivalent salivary
DLMO concentration to be 4 pg/ml.
PMID- 9558133
TI - Population pharmacokinetic parameters of gentamicin in patients with solid
tumors: estimation by one- and two-stage methods.
AB - Gentamicin monitoring has been improved with the introduction of Bayesian methods
but the usefulness depends on the quality of the population parameters (PP) used.
The objective of this study was to determine PP of gentamicin in patients with
solid tumors. A total of 198 adult patients with cancer were included in the
analysis. Population parameters were estimated by both a two-stage and a one
stage method (NPEM, Non Parametric Expectation Maximization). Individual
parameters (IP) were estimated by the Sawchuk-Zaske method and by nonlinear
regression. The estimated distribution volume and clearance of gentamicin (mean
+/- SD) were 18.37 +/- 5.021 (0.30-0.32 l/kg of dosing weight) and 3.34 +/- 1.6
l/h, respectively. No significant differences between IP or PP obtained by the
different methods were found. The results indicated a wide variability of
gentamicin pharmacokinetics making monitoring necessary and that patients with
solid tumors may have larger gentamicin volume and slower clearance than normal
patients. These observations imply that different population pharmacokinetic
parameters should be used for this group of patients.
PMID- 9558134
TI - Development of a quantitative vancomycin immunoassay for the Abbott AxSYM
analyzer.
AB - A novel fluorescence polarization immunoassay for vancomycin on Abbott AxSYM
analyzer is described. The immunoassay allows for the accurate quantification of
vancomycin in the presence of the crystalline degradation product (CDP). It
displays dilution linearity from 1.0 microg/ml to 100.0 microg/ml, coefficients
of variation ranging from 2.94% to 4.26%, recovery from 98% to 105%, and a
sensitivity of <2.0 microg/ml. The assay demonstrates no cross-reactivity to
crystalline degradation product, and to commonly-prescribed and over-the-counter
drugs, as well as a minimum interference from endogenous substances.
PMID- 9558135
TI - Abbott AxSYM Vancomycin II assay: multicenter evaluation and interference
studies.
AB - The authors evaluated the performance characteristics of the Abbott AxSYM
Vancomycin II immunoassay in sera of patients with (n = 93 samples) and without
(n = 327 patients) renal dysfunction. Correlation of vancomycin measurements with
the Abbott AxSYM Vancomycin, Abbott TDx/TDxFLx, Syva enzyme-multiplied
immunoassay technique (EMIT), DuPont automated chemistry analyzer (ACA), and high
performance liquid chromatography methods showed acceptable correlation as
indicated by: slope values >0.95, r-values >0.97, y-intercepts <1.7 microg/ml,
and S(y/x) ranging from 9% to 15% of the average vancomycin value. The AxSYM
Vancomycin II assay showed acceptable correlation with AxSYM vancomycin,
TDx/TDxFLx, and high-performance liquid chromatography methods in 93 samples from
patients with renal dysfunction. This monoclonal antibody-based assay showed no
apparent interference from the presence of human antimouse antibody (HAMA) or the
microbiologically inactive vancomycin crystalline degradation product (CDP). The
authors conclude that the AxSYM Vancomycin II assay showed satisfactory agreement
with other methods tested in this study.
PMID- 9558136
TI - Determination of lamotrigine in biologic materials by a simple and rapid liquid
chromatographic method.
AB - Lamotrigine (LTG), a newly introduced antiepileptic drug, appears to have
potential therapeutic advantages for the treatment of patients with partial-onset
seizures. Increasing clinical application and research of LTG demand a simpler
and more rapid analytical procedure to determine LTG concentration in body fluids
and tissues. The authors have developed an effective one-step procedure for
sample preparation followed by high-performance liquid chromatography (HPLC) to
quantitate LTG in plasma, urine, and brain tissues. Body fluids and brain
homogenates were treated with cold acetonitrile to precipitate protein. The
samples were fractionated on a 250 x 4.6 mm C18 reversed-phase column with an
isocratic mobile system consisting of potassium phosphate buffer, acetonitrile,
and methanol (70:16:14). The method had a LTG detection limit of 0.02 microg/ml
in plasma and 0.03 microg/ml in urine. The coefficients of variation were <2.7%
for intraday and 4.2% for interday analyses. The recovery of LTG added to plasma,
urine, and brain homogenate ranged from 98% to 100%. The method was applied to a
clinical study to determine plasma and urine concentrations of LTG in subjects
receiving a single oral dose of LTG. The calculated pharmacokinetic parameters
were comparable to those previously reported. The method proved to be simple,
fast, reproducible, and useful in clinical investigation and monitoring of LTG
concentrations.
PMID- 9558137
TI - Improved one-step solid-phase extraction method for morphine, morphine-3
glucuronide, and morphine-6-glucuronide from plasma and quantitation using high
performance liquid chromatography with electrochemical detection.
AB - This communication describes an improved one-step solid-phase extraction method
for the recovery of morphine (M), morphine-3-glucuronide (M3G), and morphine-6
glucuronide (M6G) from human plasma with reduced coextraction of endogenous
plasma constituents, compared to that of the authors' previously reported method.
The magnitude of the peak caused by endogenous plasma components in the
chromatogram that eluted immediately before the retention time of M3G has been
reduced (approximately 80%) significantly (p < 0.01) while achieving high
extraction efficiencies for the compounds of interest, viz morphine, M6G, and M3G
(93.8 +/- 2.5, 91.7 +/- 1.7, and 93.1 +/- 2.2%, respectively). Furthermore, when
the improved solid-phase extraction method was used, the extraction cartridge
derived late-eluting peak (retention time 90 to 100 minutes) reported in our
previous method, was no longer present in the plasma extracts. Therefore the
combined effect of reducing the recovery of the endogenous components of plasma
that chromatographed just before the retention time of M3G and the removal of the
late-eluting, extraction cartridge-derived peak has resulted in a decrease in the
chromatographic run-time to 20 minutes, thereby increasing the sample throughput
by up to 100%.
PMID- 9558138
TI - An abbreviated area-under-the-curve monitoring for tacrolimus in patients with
liver transplants.
AB - This study aims to assess the predictability of individual tacrolimus (FK)
concentrations at different time points for the area under the curve (AUC) and to
find the best sampling time for the abbreviated AUC to predict the total body
exposure of FK. A total of 23 FK blood concentration versus time profiles (11
blood samples per 12 hours) was studied in 12 stable patients with liver
transplants at steady state. Each AUC was calculated by the trapezoidal rule, and
the relationship between individual concentrations or abbreviated AUC and total
AUC was determined by linear regression. The trough concentrations from the
morning dose predict AUC better than the trough concentration from the evening
dose (r2 = 0.71 for morning dose and r2 = 0.35 for evening dose). In the case of
single drug concentration, the 4-hour concentration could predict the total AUC
reasonably well (r2 = 0.73). From stepwise multiple regression, the abbreviated
AUC at 1, 2.5, 6, and 9 hours could predict the total AUC most accurately (r2 =
0.99). This study shows that the four levels at 1, 2.5, 6, and 9 hours or 1, 4,
and 12 hours as an abbreviated AUC is as good as a full pharmacokinetic study.
Alternatively, 4-hour concentration is a good predictor of the total body
exposure of FK in the stable patients with liver transplants.
PMID- 9558140
TI - New modified fluorescence polarization immunoassay does not falsely elevate
vancomycin concentrations in patients with end-stage renal disease.
AB - Recent literature has urged caution in the interpretation of vancomycin serum
concentrations in patients with end-stage renal disease (ESRD), because falsely
elevated levels in excess of 70% have been reported with the most commonly used
fluorescence polarization immunoassay (FPIA). The purpose of this study was to
evaluate the performance of a recently modified FPIA assay for use in patients
with ESRD, in comparison to high-performance liquid chromatography (HPLC) and an
enzyme-mediated immunoassay technique (EMIT). Serum vancomycin samples were
prospectively collected from adults with ESRD undergoing chronic hemodialysis.
Each sample was stored at -70 degrees C until analyzed in duplicate by FPIA,
EMIT, and HPLC. In an in vitro experiment, blank serum samples with 15 microg/ml
vancomycin were spiked with increasing amounts of CDP and analyzed in duplicate
with the modified FPIA assay. When compared to HPLC, no statistically significant
difference was found in patients with ESRD with the use of the modified FPIA
assay (mean concentrations, HPLC 14.92 microg/ml, FPIA 15.96 microg/ml), with
FPIA exhibiting a positive bias of 0.64 microg/ml and a precision of +/-3.49
microg/ml (n = 18, p = 0.44). The mean EMIT concentration was 18.34 microg/ml,
with a positive bias of 3.43 microg/ml and a precision of +/-5.17 microg/ml (p <
0.01). The addition of increasing amounts of CDP to vancomycin in vitro resulted
in concentrations similar to those expected in the absence of significant cross
reactivity with the modified FPIA assay. The modified FPIA assay is a
satisfactory tool for monitoring vancomycin serum concentrations in patients with
ESRD undergoing hemodialysis. Results obtained with EMIT were not as precise as
with FPIA.
PMID- 9558139
TI - Comparison of two high-performance liquid chromatographic methods for monitoring
plasma concentrations of haloperidol and reduced haloperidol.
AB - Two high-performance liquid chromatographic methods for monitoring haloperidol
(HAL) and reduced haloperidol (RHAL) plasma concentrations were compared. In one
method ultraviolet detection and a C18 column were used (UV method); in the other
method electrochemical detection and a CN-column were used (EC method). Both
methods are accurate and precise. For plasma samples spiked with HAL or RHAL, an
excellent correlation was observed between the concentrations of HAL and RHAL
found with both methods (r < or = 0.99, p < 0.01). However, for plasma obtained
from patients treated with HAL the correlation between the two methods was poor
(r > or = 0.71, p < 0.01). The main reason for the discrepancy between the two
methods is probably interference of comedications or their metabolites, mostly in
the EC method. Although the quantitation limit of the UV method (2 ng/ml for HAL
and RHAL) is higher than that of the EC method (0.5 ng/ml for HAL and RHAL), the
UV method is to be preferred for monitoring plasma levels in psychiatric patients
because there is less interference from comedication.
PMID- 9558141
TI - Successful therapy of refractory graft versus host disease with tacrolimus and
Psoralen plus ultraviolet light.
AB - The authors report a patient who developed severe graft versus host disease
(GVHD) after undergoing a matched, unrelated bone marrow transplant. Her symptoms
worsened despite treatment with cyclosporine, high doses of methylprednisolone,
and antithymocyte globulin. After treatment with tacrolimus (FK506) and Psoralen
plus ultraviolet light (PUVA), there was complete resolution of all clinical and
laboratory evidence of GVHD. This combination may be beneficial to other patients
who develop severe GVHD that is resistant to conventional therapy.
PMID- 9558142
TI - Therapeutic drug monitoring of tacrolimus (FK506) using tandem mass spectrometry.
PMID- 9558143
TI - Consensus report of the Working Group on: "Molecular and Biochemical Markers of
Alzheimer's Disease". The Ronald and Nancy Reagan Research Institute of the
Alzheimer's Association and the National Institute on Aging Working Group.
AB - The ideal biomarker for Alzheimer's disease (AD) should detect a fundamental
feature of neuropathology and be validated in neuropathologically-confirmed
cases; it should have a sensitivity >80% for detecting AD and a specificity of
>80% for distinguishing other dementias; it should be reliable, reproducible, non
invasive, simple to perform, and inexpensive. Recommended steps to establish a
biomarker include confirmation by at least two independent studies conducted by
qualified investigators with the results published in peer-reviewed journals. Our
review of current candidate markers indicates that for suspected early-onset
familial AD, it is appropriate to search for mutations in the presenilin 1,
presenilin 2, and amyloid precursor protein genes. Individuals with these
mutations typically have increased levels of the amyloid Abeta42 peptide in
plasma and decreased levels of APPs in cerebrospinal fluid. In late-onset and
sporadic AD, these measures are not useful, but detecting an apolipoprotein E e4
allele can add confidence to the clinical diagnosis. Among the other proposed
molecular and biochemical markers for sporadic AD, cerebrospinal fluid assays
showing low levels of Abeta42 and high levels of tau come closest to fulfilling
criteria for a useful biomarker.
PMID- 9558144
TI - CSF tau and Abeta42: logical biomarkers for Alzheimer's disease?
PMID- 9558145
TI - Methodological and research issues in the evaluation of biological diagnostic
markers for Alzheimer's disease.
PMID- 9558147
TI - The development of biological markers for the diagnosis of Alzheimer's disease.
PMID- 9558146
TI - Cerebrospinal fluid tau protein as a potential diagnostic marker in Alzheimer's
disease.
PMID- 9558148
TI - Diagnostic markers for Alzheimer's disease.
PMID- 9558149
TI - Role of genetics in tests of genotype, status, and disease progression in early
onset Alzheimer's disease.
PMID- 9558150
TI - Evaluation and use of diagnostic tests in Alzheimer's disease.
PMID- 9558151
TI - Biological markers of Alzheimer's disease.
PMID- 9558152
TI - Biological markers of Alzheimer's disease.
PMID- 9558153
TI - Some remarks on biological markers of Alzheimer's disease.
PMID- 9558154
TI - Biomarkers in Alzheimer's disease.
PMID- 9558155
TI - Amyloid beta protein in plasma as a diagnostic marker for Alzheimer's disease.
PMID- 9558156
TI - Biochemical diagnostic markers to detect early Alzheimer's disease.
PMID- 9558157
TI - Managed care and the practice of rheumatology.
PMID- 9558158
TI - Persistent Chlamydia trachomatis infection: in vitro phenomenon or in vivo
trigger of reactive arthritis?
PMID- 9558159
TI - Transforming growth factor-beta and platelet derived growth factor regulation of
fibrillar fibronectin matrix formation by synovial fibroblasts.
AB - OBJECTIVE: To investigate factors regulating fibronectin fibrillar matrix
formation by synovial fibroblasts. METHODS: Basal and cytokine stimulated
extracellular matrix (ECM) fibronectin produced by synovial fibroblasts was
identified by immunofluorescence and Western blot. Alternative mRNA splicing of
fibronectin was studied by reverse transcription polymerase chain reaction. The
integrin receptor responsible for supporting fibronectin fibrillar matrix was
identified by blocking antibodies and receptor levels studied by Western blot.
RESULTS: Transforming growth factor-beta (TGF-beta) or platelet derived growth
factor (PDGF), but not interleukin 1 or exogenous fibronectin, induced ECM
fibronectin. ECM fibronectin was blocked by the addition of antibody to the
alpha5beta1 integrin. Cytokines did not significantly change alternative mRNA
splicing of fibronectin or levels of alpha5beta1 integrin expression. CONCLUSION:
Synovial cell production of a fibrillar fibronectin matrix is induced by growth
factors, including TGF-beta and PDGF. This induction is mediated by the
alpha5beta1 integrin. Since fibrillar fibronectin formation was not strongly
dependent on increased fibronectin or alpha5beta1 integrin levels, this effect
may be mediated by growth factor induced changes in receptor affinity.
PMID- 9558160
TI - Infrequent detection of cytomegalovirus and Epstein-Barr virus DNA in synovial
membrane of patients with rheumatoid arthritis.
AB - OBJECTIVE: To study the role of the cytomegalovirus (CMV), Epstein-Barr virus
(EBV), herpes simplex virus types 1 and 2 (HSV-1 and 2), varicella zoster virus
(VZV), and human herpes virus 6 (HHV-6) in the etiology of rheumatoid arthritis
(RA). METHODS: Polymerase chain reaction (PCR) was used to detect DNA of the
different herpes viruses in synovial membranes from 31 patients with chronic RA
and 14 control patients. Specific antibodies were determined by indirect
immunofluorescence and ELISA. RESULTS: Out of 31 patients with RA, CMV DNA was
detected in synovial membranes from 2 patients and EBV DNA was detected in
synovial membranes from 2 other patients. All samples from the patients with RA
were negative for DNA from HSV-1 and 2, VZV, and HHV-6. All samples from the 14
control patients were negative in all PCR assays. No statistically significant
differences in IgG antibodies were found for CMV, HSV-1, VZV, and HHV-6 in
patients with RA compared to controls. Higher titers of IgG antibodies against
EBV viral capsid antigen were found in patients with RA, with a significance of p
< 0.05. CONCLUSION: Both CMV and EBV DNA were detected in synovial membranes from
6% of the patients with RA. We cannot exclude the possibility that these viruses
were associated with disease development in a minority of patients with RA.
PMID- 9558161
TI - Mannan binding lectin in rheumatoid arthritis. A longitudinal study.
AB - OBJECTIVE: Low serum levels of mannan binding lectin (MBL) are associated with
increased risk of recurrent infections. We determined whether there was an
association between serum MBL levels and the course and prognosis of rheumatoid
arthritis (RA). METHODS: MBL was analyzed in sera from 99 patients with RA who
were included in a longterm prospective study. RESULTS: Compared with controls, a
high fraction of patients lacked detectable MBL in serum (11 vs 3%; p = 0.025).
Comparing patients with MBL serum levels above and below the median revealed that
those with levels below the median were younger at onset of RA (p = 0.043) and
had higher erythrocyte sedimentation rate (p = 0.006), joint swelling score (p =
0.019), limitation of joint motion score (p = 0.027), and annual increase in
radiographic destruction score (p = 0.053). CONCLUSION: MBL insufficiency may be
a contributing pathogenetic factor in RA.
PMID- 9558162
TI - Early radiographic joint space narrowing and erosion and later malalignment in
rheumatoid arthritis: a longitudinal analysis.
AB - OBJECTIVE: To analyze the time course of development of radiographic erosion,
joint space narrowing, and malalignment in a longitudinal study of radiographs of
the hands and wrists of 58 patients with rheumatoid arthritis (RA) taken over 18
years. METHODS: Among 210 consecutive patients in a reported cohort, 58 had at
least one prior available radiograph 2-18 years earlier. A total of 141 hand and
wrist radiographs in the 58 patients were scored for joint space narrowing,
erosion, and malalignment in individual joints. RESULTS: Of the 58 patients
studied, all developed joint space narrowing, 56 (96.5%) developed erosions,
while only 24 (41.4%) developed malalignment. In radiographs of 22 patient
studied within the first 5 years of disease, joint space narrowing was seen in 17
(77.3%), erosion in 16 (72.7%), and malalignment in only 3 (13.6%). Radiographic
progression was seen in all 36 patients in whom the interval between radiographs
was longer than 2 years. CONCLUSION: Joint space narrowing and erosion are seen
in hand radiographs of most patients with RA seen in treatment centers within the
first 5 years of disease. By contrast, malalignment develops in fewer patients,
and generally only after 5 years of disease.
PMID- 9558163
TI - Longterm health outcomes of patients with rheumatoid arthritis treated in managed
care and fee-for-service practice settings.
AB - OBJECTIVE: To compare health care utilization and longterm health outcomes among
patients with rheumatoid arthritis (RA) treated in managed care and fee-for
service practice settings. METHODS: We compared levels of health care
utilization, treatments, and health outcomes between 57 patients with RA treated
predominantly in managed care settings and 125 patients with RA treated
predominantly in fee-for-service practice settings. These patients were
participants in a community based cohort study of health outcomes in RA, and had
been followed prospectively for up to 13 years (mean followup 10.3 yrs).
Information on physician visits, hospitalizations, diagnostic testing,
treatments, and 3 measures of health status (global arthritis status, pain,
functional disability measures of the Health Assessment Questionnaire) was
collected using biannual mailed questionnaires. RESULTS: All measures of health
care utilization were similar between the managed care and fee-for-service
groups, as was the use of the major types of arthritis treatments. Average global
arthritis status scores, pain scores, and functional disability scores were
closely comparable in the 2 groups. Over time, global arthritis status scores and
disability scores worsened in both groups, but the rates of worsening did not
differ between groups. CONCLUSION: In this cohort, longterm health outcomes, as
well as treatments and health care utilization, were similar among persons with
RA who were treated in managed care and fee-for-service practice settings.
PMID- 9558165
TI - SLICC/ACR Damage Index in Afro-Caribbean patients with systemic lupus
erythematosus: changes in and relationship to disease activity, corticosteroid
therapy, and prognosis.
AB - OBJECTIVE: To apply the recently described Systemic Lupus International
Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR
DI) in a well defined cohort of patients with systemic lupus erythematosus (SLE)
and to study its association with disease activity, corticosteroid therapy, and
prognosis. METHODS: We conducted a record review of 90 patients with SLE followed
at a single center for a mean period of 6 years with periodic evaluations of SLE
Disease Activity Index (SLEDAI), cumulative damage according to SLICC/ACR-DI, and
therapy. Overall disease activity during the disease course was calculated as
weighted averages of SLEDAI (WAS). RESULTS: Mean SLICC/ACR-DI was 0.6 six months
after diagnosis and increased to 2.4 at last assessment. Thirteen patients (14%)
remained free of accumulated damage at last visit. Index scores showed
significant correlations with WAS scores and the number of disease exacerbations
(SLEDAI > 10), but not with age, mean daily, or cumulative corticosteroid dosage.
High WAS scores were independently associated with poorer survival, but SLICC/ACR
DI scores were not. CONCLUSION: SLICC/ACR-DI scores correlate with overall
disease activity, but not with length or intensity of corticosteroid therapy.
While easily applicable, its prognostic value is subordinate to that of
persistent disease activity.
PMID- 9558164
TI - High seroprevalence of Helicobacter pylori infection in patients with systemic
sclerosis: association with esophageal involvement.
AB - OBJECTIVE: To determine the prevalence and clinical relevance of Helicobacter
pylori infection in patients with systemic sclerosis (SSc). METHODS: Serum
samples were obtained from 124 patients with SSc (67 with limited cutaneous SSc,
57 with diffuse cutaneous SSc). Fifty samples from age and sex matched
individuals were used as controls. IgG antibodies to H. pylori infection were
measured by ELISA. RESULTS: IgG antibodies to H. pylori were found in 55.6% (69
of 124) of the patients with SSc, significantly more than in the controls. There
was a significant correlation of the presence of antibodies to H. pylori with the
prevalence of esophageal hypomotility in the patients with SSc (p < 0.02).
CONCLUSION: Patients with SSc have H. pylori infection at a higher prevalence
than the general population. H. pylori might play a role in the development of
esophageal dysfunction in SSc.
PMID- 9558166
TI - The pathogenic 16/6 idiotype in patients with silica associated systemic lupus
erythematosus (SLE) and uranium miners with increased risk for development of
SLE.
AB - OBJECTIVE: To investigate the prevalence of the 16/6 idiotype (16/6 Id), a major
cross reactive idiotype of anti-DNA antibodies involved in the pathogenesis of
experimental lupus, in subjects with an exogenous risk for the development of
systemic lupus erythematosus (SLE). METHODS: The titer of 16/6 Id was determined
by ELISA in sera of uranium miners exposed to heavy quartz dust: 15 developed
definite and 12 probable SLE, 34 had clinical symptoms, and 27 had only
serological signs (medium to high titer anti-dsDNA antibodies) of possible
connective tissue disease (CTD) development. RESULTS: The prevalence of 16/6 Id
was higher in all groups compared to healthy blood donors. It was 18.5% in miners
with SLE (definite and probable) and 22.2-26.5% in miners with clinical and/or
serological signs for developing CTD. All 16/6 Id positive miners were positive
for anti-dsDNA antibodies and other autoantibodies associated with CTD. The
prevalence of 16/6 Id in anti-dsDNA positive miners correlated slightly with
CTD/SLE symptoms: 55.6% in patients with SLE, 47.4% in miners with possible
CTD/SLE, and 22.2% in miners without CTD symptoms. Further, at short term
followup, disease progressed in 2 miners of the 16/6 Id positive, but not in 16/6
Id negative miners. CONCLUSION: The detection of 16/6 Id in miners exposed to
quartz dust may indicate a higher risk for development of SLE, warranting further
studies of the role of 16/6 Id in the development of SLE in a cohort with the
same sex, ethnicity, geographic region, and occupation.
PMID- 9558168
TI - High frequency of abnormal levels of IgA anti-beta2-glycoprotein I antibodies in
patients with systemic lupus erythematosus: relationship with antiphospholipid
syndrome.
AB - OBJECTIVE: To determine the frequency of IgA, in addition to IgM and IgG, anti
beta2-GPI and anticardiolipin (aCL) antibodies in patients with systemic lupus
erythematosus (SLE), and to relate the presence of these antibodies to symptoms
of antiphospholipid antibody syndrome (APS). METHODS: Sera from 100 blood bank
donors (controls) and 48 patients with SLE were tested by ELISA. The same enzyme
conjugates were used in the measurement of aCL and anti-beta2-GPI. Medical
records were reviewed for the presence of manifestations of APS: arterial
occlusion, pulmonary embolism, cerebrovascular accident, transient ischemic
attack, venous thrombosis (deep or superficial), hemolytic anemia,
thrombocytopenia, repeated fetal loss, leg ulcers, seizures, avascular bone
necrosis, cerebritis, or migraine. RESULTS: Above normal levels of antibodies of
all 3 isotypes against beta2-GPI were found in 5% of controls and 73% of patients
with SLE. Antibodies against cardiolipin in the 2 groups were found in 5 and 37%,
respectively. IgA anti-beta2-GPI was found in 2% of controls and 58% of patients
with SLE; in contrast, only 2% of patients with SLE had IgA aCL. In the 48
patients studied, thrombosis and fetal loss were present in 10 (Group 1), other
manifestations of APS were present in 18 (Group 2), and none in 20 (Group 3).
Antibodies to beta2-GPI of all 3 isotypes were found in a higher proportion of
APS (Group 1 plus Group 2) (82%) than in Group 3 (50%) (p < 0.01, chi-squared).
There was also a significantly higher proportion of patients with elevated anti
beta2-GPI in Group 1 (90%) than in Group 3 (p < 0.02). There was a significantly
higher frequency (p < 0.01) and level (p < 0.05) of IgA anti-beta2-GPI in
patients with APS than in those with no APS manifestations. Moreover, compared to
aCL and with other isotypes of anti-beta2-GPI, the highest antibody levels were
observed in IgA antibeta2-GPI. CONCLUSION: The sensitivity of the anti-beta2-GPI
antibody test for APS in patients with SLE is significantly increased by
measuring IgA, in addition to IgM and IgG isotype.
PMID- 9558167
TI - Autoantibodies to beta2-glycoprotein I in systemic lupus erythematosus and
primary antiphospholipid antibody syndrome: clinical correlations in comparison
with other antiphospholipid antibody tests.
AB - OBJECTIVE: To examine relationships between anti-beta2-glycoprotein (beta2-GPI)
antibodies and other antiphospholipid antibody (aPL) tests (aPL ELISA and the
lupus anticoagulant or LAC) and the associations of each of these aPL tests with
individual clinical manifestations of the antiphospholipid antibody syndrome
(APS). METHODS: IgG and IgM anti-beta2-GPI antibodies were determined by ELISA in
281 patients with SLE, primary APS, or other connective tissue diseases.
Frequencies, sensitivities, specificities, and predictive values and correlations
of anti-beta2-GPI were compared to the aPL ELISA (IgG and IgM) and LAC for
individual (and combined) features of APS. RESULTS: Among 139 patients with
positive aPL ELISA and/or LAC tests, 57 (41%) had anti-beta2-GPI antibodies (IgG
and/or IgM) compared to 11% of patients with SLE negative for these tests (p =
0.00001). In 130 patients with APS, anti-beta2-GPI occurred in 42% and tended to
be more specific but less sensitive than the aPL ELISA or LAC. When all 3 aPL
tests were combined, the best sensitivities and negative predictive values were
achieved; however, specificity and positive predictive values remained low. Anti
beta2-GPI antibodies occurred more frequently in primary APS (58%) vs secondary
antiphospholipid syndromes (33%) (p = 0.008, OR = 2.9). Among 79 patients with
SLE negative by both aPL ELISA and LAC, 9 (11 %) were positive for anti-beta2
GPI, 7 of whom had clinical features consistent with APS (representing 5% of all
with APS). Stepwise multiple logistic regression analysis revealed beta2-GPI to
be most strongly associated with neurological syndromes other than stroke, deep
venous thrombosis, and recurrent fetal loss, while LAC was most strongly
correlated with stroke and thrombocytopenia. IgM aPL antibodies also were
independently associated with neurological syndromes and recurrent fetal loss.
CONCLUSION: Testing for beta2-GPI antibodies may be clinically useful in the
diagnosis of APS but cannot supplant other aPL ELISA or LAC. Multivariate
analyses suggest that anti-beta2-GPI antibodies may play a more central role in
certain clinical manifestations of APS than antibodies detected by the aPL ELISA
or LAC.
PMID- 9558169
TI - A close temporal relationship of liver disease to antiribosomal P0 protein
antibodies and central nervous system disease in patients with systemic lupus
erythematosus.
AB - OBJECTIVE: To determine whether there is a close temporal relationship of liver
disease to serum IgG and/or IgM antiribosomal P0 protein antibodies (anti-P0) and
central nervous system (CNS) lupus in patients with systemic lupus erythematosus
(SLE). METHODS: The study included 70 patients with active SLE. Of these, 30 had
IgG and/or IgM anti-P0 and 14 had CNS lupus other than psychiatric disease
(nonpsychiatric CNS lupus). Of these 14 patients, 11 had anti-P0. Laboratory
manifestations of liver disease were retrospectively analyzed. RESULTS: Liver
disease not attributed to any cause other than SLE (SLE liver disease) was
present in 8 of the 11 patients with anti-P0 with nonpsychiatric CNS lupus
(72.7%), in none of the 19 patients with anti-P0 without nonpsychiatric CNS lupus
(0%), and in one of the 40 patients without anti-P0 (2.5%). The prevalence of SLE
liver disease was significantly greater in patients with anti-P0 with
nonpsychiatric CNS lupus than in the other 2 groups (p < 0.0001). Mean levels of
liver enzymes (lactate dehydrogenase, glutamic oxaloacetic transaminase,
glutamate pyruvate transaminase, gammaglutamyl transpeptidase) were significantly
higher in patients with anti-P0 with nonpsychiatric CNS lupus than in the other 2
groups. Serial studies in 3 patients showed that the appearance of anti-P0 and
liver dysfunction slightly preceded the onset of nonpsychiatric CNS lupus.
CONCLUSION: Anti-P0 may be related to the pathogenesis of CNS lupus and SLE liver
disease found simultaneously in SLE. The appearance of anti-P0 and liver
dysfunction may predict onset of CNS lupus.
PMID- 9558170
TI - Decreased Fcgamma receptor III (CD16) expression on peripheral blood mononuclear
cells in patients with Sjogren's syndrome.
AB - OBJECTIVE: To examine the expression of surface structures important in natural
killer (NK) cell function and the roles of serum factors affecting the expression
of surface antigens on these cells in patients with Sjogren's syndrome (SS).
METHODS: Peripheral blood mononuclear cells (PBMC) of 18 patients with SS were
analyzed by immunofluorescence on a flow cytometer. The antigen recognized by
autoantibodies in their sera was analyzed by immunofluorescence and by
immunoprecipitation. RESULTS: Expression of Fcgamma receptor III (CD16), an
important indicator of NK cytolytic activity, on PBMC was significantly decreased
in patients with SS who have extraglandular disease, while the expression of
Fcgamma RI and II was normal. Moreover, F(ab')2 of IgG in these patients' sera
was shown to bind to CD16+ cells. Immunoprecipitation study showed that it bound
to CD16 itself. CONCLUSION: The depressed expression of CD16 on PBMC and the
presence of antibody binding to CD16 in the patients' sera may be, at least in
part, responsible for the altered function of NK cells observed in SS.
PMID- 9558171
TI - Prevalence of Raynaud's phenomenon in 2 ethnic groups in the general population
of Estonia.
AB - OBJECTIVE: To compare the prevalence of Raynaud's phenomenon (RP) in 2
genetically different ethnic groups in Estonia: Estonians, who are Finno-Ugric
people, and Slavs, who are Indo-European people, and to investigate the risk
factors of RP. METHODS: A random sample of 5248 Estonians and 4341 Slavs were
surveyed by mail questionnaire (Phase I) for suspected RP. A subsample of 1739
subjects was interviewed and examined (Phase II) to make a formal diagnosis of
RP, using the color charts, and to collect additional pertinent information.
RESULTS: Of these 1739 subjects examined in Phase II, 226 women and 162 men were
diagnosed to have RP. The age adjusted prevalence of RP was significantly higher
among Slavs (women 11.4 +/- 1.3%, men 13.0 +/- 1.6%) compared to Estonians (women
7.8 +/- 1.0%, p = 0.023; men 8.2 +/- 1.5%, p = 0.031). Based on logistic
regression analysis, the diagnosis of RP among women was associated with a Slavic
ethnic origin, the presence of connective tissue disorders or cardiovascular
diseases, a family history of RP, a history of dysphagia and frostbite, smoking,
and a lower body mass index (BMI). Among men RP was associated with manual work,
vibrating tool use, a history of frostbite and injuries to the fingers. older
age, and a lower BMI. CONCLUSION: Our results revealed a significant difference
in the prevalence of RP between 2 ethnic groups living in the same geographic
region. The risk factors associated with RP show considerable sex differences, RP
being mostly constitutional in women and occupational in men.
PMID- 9558173
TI - Human neutrophil elastase in temporal (giant cell) arteritis: plasma and
immunohistochemical studies.
AB - OBJECTIVE: Few enzymes are able to attack the internal elastic lamina, which is
destroyed in temporal arteritis (TA). Because human neutrophil elastase (HNE) is
one of these, its role in the pathogenesis of TA was examined in patients
undergoing temporal artery biopsy for suspected TA. METHODS: Over a 6 month
period, 33 patients undergoing temporal artery biopsy were prospectively included
in the study. TA was diagnosed in 15 patients; 9 of them had positive temporal
artery biopsy. The other 18 patients made up the non-TA group. Nineteen healthy
age matched subjects (mean age 74 +/- 9 yrs) served as controls. Levels of plasma
HNE bound to alpha1-antitrypsin (pHNE-alpha1AT) were measured by ELISA. The
presence of HNE in the temporal artery wall of 7 TA and 7 non-TA patients was
evaluated immunohistochemically. RESULTS: Age, neutrophil counts, and erythrocyte
sedimentation rates were similar in TA and non-TA patients. The mean pHNE
alpha1AT concentration in the TA group (84 +/- 20 microg/l) was significantly
higher (p < 0.001) than in the non-TA group (51 +/- 26 microg/l) or in healthy
controls (52 +/- 23 microg/l). The diagnostic sensitivity of pHNE-alpha1AT > 50
microg/l was 100%. Immunohistochemistry detected no HNE within the temporal
artery wall of any patient. CONCLUSION: High levels of pHNE-alpha1AT were
associated with TA. Our preliminary results indicate this could be a diagnostic
marker for TA. Further studies are needed to confirm its reliability. Because HNE
was not detected locally, no conclusions can be drawn as to its pathogenic role
in TA.
PMID- 9558174
TI - An open study of pamidronate in the treatment of refractory ankylosing
spondylitis.
AB - OBJECTIVE: Bisphosphonates inhibit the development of delayed type
hypersensitivity chronic inflammation and suppress inflammation and
cartilage/bone erosion in diverse murine arthritis models. We evaluated
antiinflammatory properties of the bisphosphonate pamidronate in patients with
ankylosing spondylitis (AS) refractory to nonsteroidal antiinflammatory drugs.
METHODS: Patients included 14 men and 2 women. The first group of 8 patients
(Group 1) received pamidronate as a 30 mg intravenous infusion once a month for 3
months, followed by a 60 mg dose once a month for an additional 3 months. Eight
additional patients (Group 2) received only the 60 mg dose once a month for 3
months. Clinical assessments included the BASDAI (Bath AS Disease Activity
Index), BASFI (Functional Index), and BASMI (Metrology Index), and laboratory
assessments hemoglobin and erythrocyte sedimentation rate (ESR) at baseline and
one month after final 60 mg dose of pamidronate. Mean BASDAI score at study entry
was 6.7 for both groups. RESULTS: A significant improvement was observed in
disease activity score in Group 1 after 6 monthly infusions of pamidronate (mean
BASDAI 4.21; p = 0.03), in the BASMI score (p = 0.01), and the ESR (p = 0.009). A
significant improvement in the BASMI was noted in Group 2 patients (p = 0.007)
after 3 monthly infusions of pamidronate, but not in the BASDAI score (mean 5.01;
p = 0.07) or the ESR (p = 0.12). CONCLUSION: Preliminary data suggest pamidronate
may possess antiinflammatory activity in patients with AS, particularly with
prolonged administration; this agent deserves further evaluation in a controlled
trial.
PMID- 9558172
TI - Prevalence and characterization of novel pANCA, antibodies to the high mobility
group non-histone chromosomal proteins HMG1 and HMG2, in systemic rheumatic
diseases.
AB - OBJECTIVE: To determine the immunodiagnostic value of antibodies to the high
mobility group non-histone chromosomal proteins HMG1 and HMG2, which have been
identified as novel target antigens of perinuclear antineutrophil cytoplasmic
antibodies (pANCA), in sera from patients with systemic rheumatic diseases.
METHODS: Anti-HMG1 or HMG2 antibody was assayed by ELISA and Western blotting in
sera from patients with systemic rheumatic diseases. These antibodies were
analyzed for the relationship with pANCA detected by indirect immunofluorescence
in these diseases, and with clinical features in rheumatoid arthritis (RA) and
systemic lupus erythematosus (SLE). RESULTS: Anti-HMG1 or HMG2 antibody was
frequently detected in sera from patients with RA (48%), SLE (45%), Sjogren's
syndrome (SS) (44%), and systemic sclerosis (SSc) (41%). In these diseases, anti
HMG1 antibody was detected more frequently than anti-HMG2 antibody. In sera from
patients with RA, the positivity for anti-HMG1 and HMG2 antibodies was
significantly correlated with the positivity for pANCA (p < 0.0001). Anti
HMG1/HMG2 antibodies were associated with some disease activity variables, e.g.,
erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, joint
score and hand grip strength in RA, and CH50, C3, C4, and IgG in SLE. CONCLUSION:
Anti-HMG1/HMG2 antibodies are detected commonly in systemic rheumatic diseases,
particularly in RA, SLE, SS, and SSc. HMGI and HMG2 seem to be the significant
target antigens of pANCA in RA. These antibodies are significantly associated
with disease activity indices in RA and SLE.
PMID- 9558175
TI - Increased frequency of Sjogren's syndrome in patients with spondyloarthropathy.
AB - OBJECTIVE: To determine the prevalence of sicca symptoms and Sjogren's syndrome
(SS) in spondyloarthropathy (SpA) patients with ankylosing spondylitis (AS) and
undifferentiated SpA (uSpA). METHODS: Patients with SpA with inflammatory back
pain and/or peripheral arthritis presenting to the university outpatient clinic
were diagnosed as AS (n = 40) and uSpA (n = 65) according to established
criteria. Patients with SpA with sicca symptoms and/or positive antinuclear
antibody (ANA) were investigated for SS by minor salivary gland biopsy and/or
sialography. To assess sicca symptoms in this cohort systematically we mailed a
validated questionnaire with 6 questions on dryness of eyes and mouth to all 105
SpA patients and 150 healthy controls, a positive answer to > or = 3 questions
was taken as suggestive of SS. There was no significant difference in baseline
characteristics between patients and controls. RESULTS: In 8/105 SpA patients (5
uSpA, 3 AS; 6 female, 2 male) SS diagnosis by the European criteria indicated a
frequency of 7.6%. Of 105 SpA patients, 12 were ANA+ (11.4%), of whom 7 had SS;
thus, ANA were detected in 7/8 SpA patients with SS (88%). Of the 84 SpA patients
responding to the questionnaire (80%), 10 gave a positive answer to > or = 3
questions (11.9%) compared to 2 of 131 (1.5%) controls (87.3%) (odds ratio = 8.7,
95% CI 2.3-32.5, p < 0.01). CONCLUSION: The data suggest increased prevalence of
sicca symptoms and SS in SpA patients with AS and uSpA. The occurrence of a
secondary SS in a variety of inflammatory diseases suggests that salivary gland
involvement in these conditions results from as yet unidentified shared
pathogenic mechanisms resulting in nonspecific inflammation in this location.
PMID- 9558176
TI - Musculoskeletal surgery in psoriatic arthritis.
AB - OBJECTIVE: To determine the probability that patients with psoriatic arthritis
(PsA) will require musculoskeletal surgery. To identify factors predictive of
surgery in patients with PsA. To determine the clinical outcome of patients with
PsA who underwent surgery compared to patients who did not. METHODS: The database
of the Psoriatic Arthritis Clinic was searched to identify individuals who had
undergone musculoskeletal surgery. Biological and clinical data such as
erythrocyte sedimentation rate (ESR), rheumatoid factor, clinical pattern, nail
changes, functional class, number of inflamed joints, and radiological damage, as
well as health scores such as Arthritis Impact Measurement Scale 2 (AIMS-2), SF
36, and Health Assessment Questionnaire (HAQ) were available for these patients.
Patients who had surgery were compared to those who did not. RESULTS: Out of 444
patients with confirmed PsA, 31 had musculoskeletal surgery (6.98%). This
probability increased with the duration of PsA. Surgery patients had their first
operation at an average of 13.9 years (range 1-46) after onset of joint disease.
Age at onset of PsA, clinical pattern, constancy of clinical pattern over time,
rheumatoid factor, functional class, symmetry, nail changes, and the time
separating the onset of skin disease and the onset of joint disease were not
significantly different at the 0.05 confidence level. Patients who had surgery
had significantly more radiological damage (p < 0.001) and more actively inflamed
joints (p < 0.02) at first assessment than patients who did not. AIMS2, SF-36,
and HAQ scores at final review were not statistically different across both
groups. CONCLUSION: In our patients the probability of having musculoskeletal
surgery for PsA was 7%. It increased with disease duration. Patients had their
first surgery after an average of 13 years. The number of actively inflamed
joints and the extent of radiological damage at first assessment were highly
predictive of subsequent surgery: patients with the highest numbers of severely
affected joints, both clinically and radiologically, were more likely to have
surgery. "Baseline characteristics" such as ESR, rheumatoid factor, functional
class, clinical pattern, nail changes, and symmetry were not predictive of
subsequent orthopedic surgery.
PMID- 9558177
TI - HLA markers and progression in psoriatic arthritis.
AB - OBJECTIVE: To investigate whether the addition of all serologically defined HLA
antigens to a baseline model further influences the predisposition to disease
progression in psoriatic arthritis (PsA). METHODS: Patients with PsA followed
prospectively over 19 years were studied. Clinical and laboratory assessments of
both active inflammation and clinical damage were performed at 6 month intervals
according to a standard protocol. Progression of damage was defined as transition
to higher damage states defined by the number of damaged joints. A model that
provides estimates of the ratio of transition rates for an individual with the
antigen versus one without, and examines the antigen effect on each of the 3
transition rates, was used. HLA antigens were examined in groups by loci under
the assumption of common effects across transitions when added to the basic
model. The significance levels were examined in comparison with Bonferroni type
corrections. Likelihood ratio chi-squared statistics were used as a basis for the
significance levels. In total, 292 patients with PsA were included in the study.
RESULTS: Only HLA-B22 was added to the original model, which includes HLA-B39,
providing risk for progression in early stages, HLA-B27 in the presence of HLA
DR7 providing risk for progression through all states, and DQw3 providing
increased risk in the absence of DR7, while in the presence of DR7 it provides
"protection." HLA-B22 provides protection from disease progression through all
states. CONCLUSION: This study extends our report that HLA antigens serve as
markers for disease progression in PsA.
PMID- 9558178
TI - Synovial Chlamydia trachomatis in patients with reactive arthritis/Reiter's
syndrome are viable but show aberrant gene expression.
AB - OBJECTIVE: We used reverse transcription-polymerase chain reaction (RT-PCR)
assays to assess expression of genes from Chlamydia trachomatis in synovial
tissues of patients with reactive arthritis (ReA)/Reiter's syndrome (RS) to
determine viability/metabolic activity of the bacterium in joints of infected
patients. METHODS: Synovial biopsies were obtained from 18 patients with ReA, RS,
or other arthritides; nucleic acids from 16 samples were PCR positive for
chlamydial chromosomal DNA. RT-PCR assays targeting primary transcripts from C.
trachomatis rRNA operons, and mRNA from the bacterial omp1, hsp60, glyQS, and r
protein S5 and L5 genes, were used to characterize viability/metabolic activity.
Host actin mRNA was assessed as control in each sample preparation. RESULTS: RT
PCR of host cell actin mRNA in the 18 patient samples confirmed the quality of
all RNA preparations. RNA from 14/16 PCR positive samples was positive by RT-PCR
for chlamydial rRNA primary transcripts. Each of these same 14 samples was also
RT-PCR positive in assays targeting glyQS, r-protein S5 and L5, and hsp60 mRNA.
However, none of the 14 samples showing chlamydial rRNA and mRNA was positive for
omp1 transcripts. CONCLUSION: Synovial chlamydia are viable/metabolically active,
since primary rRNA transcripts and mRNA from chlamydial genes specifying
components of the bacterial protein synthetic system were present in most patient
samples assayed. Expression of omp1, encoding the major outer membrane protein,
is strongly attenuated in persistently infecting synovial chlamydia, while that
of hsp60, specifying a highly immunogenic heat shock protein of the organism, is
not downregulated.
PMID- 9558179
TI - Antibodies to Klebsiella pneumoniae in Dutch patients with ankylosing spondylitis
and acute anterior uveitis and to Proteus mirabilis in rheumatoid arthritis.
AB - OBJECTIVE: To determine whether the association between increased humoral
reactivity against Klebsiella and HLA-B27 associated diseases could be confirmed
in Dutch patients with ankylosing spondylitis (AS) and acute anterior uveitis
(AAU). METHODS: Under coded conditions sera from Dutch patients with AS, AAU, and
rheumatoid arthritis (RA) and from HLA-B27 positive and negative healthy controls
were studied for IgA anti-Klebsiella (K54) and IgG anti-Proteus antibodies with
the indirect immunofluorescence assay on whole bacteria fixed in suspension with
paraformaldehyde. Each group consisted of at least 17 sera. RESULTS: IgA anti
Klebsiella antibody titers were elevated in AS and HLA-B27 negative AAU compared
to the HLA-B27 positive and negative controls or patients with active RA (p <
0.001). Furthermore, patients with active RA had elevated levels of IgG
antibodies against P. mirabilis compared to every other test or control group (p
< 0.001). There was no significant difference between the AS and RA patients in
terms of serum C-reactive protein levels, although these were significantly
elevated in both compared to healthy controls (p < 0.001), suggesting that the
antibody elevations were not due to a nonspecific inflammatory effect. The same
sera were blindly tested with negative results by 2 other centers. The
discrepancies are probably the result of differences in the methods used.
CONCLUSION: Our data support the hypothesis that Klebsiella are involved in the
pathogenesis of AS and AAU and that the same might be true for Proteus in RA.
PMID- 9558180
TI - Polyarthritis and periostitis induced by Escherichia coli. Lipopolysaccharide
injection in young male hamsters.
AB - OBJECTIVE: To describe the clinicopathological manifestations of
lipopolysaccharide (LPS) induced arthritis in the hamster and to compare its time
of onset, duration, and severity with other forms of experimentally induced
arthritis. METHODS: A preparation containing 30 microg LPS from Escherichia coli
was injected subcutaneously for 5 to 21 days into young male hamsters
(Mesocricetus auratus). Arthritis was quantified by measuring soft tissue
swelling of affected joints with calipers. After decalcification, paraffin
sections were cut and stained with hematoxylin and eosin, Giemsa, and azan. Acute
phase reactant apolipoprotein serum amyloid A (apoSAA) levels were determined by
ELISA. RESULTS: Symmetrical polyarthritis developed within 3 days and persisted
for 14-21 days, provided the hamsters received daily LPS injections. Most
prominent were lesions in the carpal-metacarpal joints of the front legs and in
the tarsal-metatarsal joints of the hind legs. Animals in whom LPS injections
were discontinued after 4 or 7 days recovered completely. Histological findings
of exudative synovitis, periarticular soft tissue swelling, and juxtaarticular
periostitis were associated with a sharp rise in serum titers of apoSAA.
CONCLUSION: The unusually rapid onset of arthritis and periostitis in this
experimental animal model suggests that its systemic manifestations were not
mediated by a classical immune response, and may represent an "innate" response
of targeted cells within the synovial membrane and periosteum to bacterial cell
wall endotoxins.
PMID- 9558181
TI - In vitro effects of diacerhein and rhein on interleukin 1 and tumor necrosis
factor-alpha systems in human osteoarthritic synovium and chondrocytes.
AB - OBJECTIVE: To evaluate the in vitro effects of diacerhein, a new drug for the
treatment of osteoarthritis (OA), and its active metabolite, rhein, on
interleukin 1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha)
synthesis and expression in human OA synovial membrane, and on the IL-1beta and
TNF-alpha receptors on human OA chondrocytes. METHODS: Levels of IL-1beta and TNF
alpha were determined using specific ELISA in culture medium of human synovial
membrane explants incubated in the presence of 1 microg/ml of lipopolysaccharide
with or without therapeutic concentrations of diacerhein (1.4, 2.7, 5.4 x 10(-5)
M) and rhein (1.7, 3.5, 7.0 x 10(-5) M). IL-1beta mRNA level was quantitated by
Northern blotting. Using radioligand binding experiments, we determined the
effects of these agents on the density and affinity of chondrocyte IL-1 and TNF
receptors. RESULTS: IL-1beta synthesis was significantly inhibited by diacerhein
and rhein, with maximum inhibition at 5.4 x 10(-5) M for diacerhein (p < 0.02)
and 3.5 x 10(-5) M for rhein (p < 0.05). The effect of both agents on IL-1beta
was found to be translational and/or post-translational, judging by the absence
of effect on gene expression level. Both agents produced dose and time dependent
decreases in the number of IL-1 receptors (IL-1R) on OA chondrocytes. This effect
was mediated through a reduction in the level of the type I IL-1R as shown by
experiments using a blocking monoclonal antibody against this receptor type. Both
agents also markedly reduced the IL-1 induced synthesis and expression of
stromelysin 1. Neither diacerhein nor rhein significantly affected the level of
synthesis of TNF-alpha or the level of TNF-R. CONCLUSION: Diacerhein and rhein
can effectively inhibit the synthesis of IL-1beta on human OA synovium, as well
as the action of this cytokine at the cartilage level, by reducing the number of
chondrocyte IL-1R. The effects of these agents seemed "selective" to the IL-1
system.
PMID- 9558182
TI - Gastric administration of recombinant 65 kDa heat shock protein delays the
severity of type II collagen induced arthritis in mice.
AB - OBJECTIVE: The 65 kDa heat shock protein (HSP) chaperonin is a highly conserved
intracellular protein. HSP are involved in the pathogenesis of arthritis, but are
not able to induce experimental arthritis. T cell clones recognizing the 180-188
amino acid sequence of 65 kDa HSP are present in inflamed synovium of both
adjuvant arthritis and rheumatoid arthritis (RA). Oral administration of bovine
collagen II or co-chaperonin 10 kDa HSP has been shown to induce an immune
tolerance state to collagen induced arthritis (CIA). We investigate the effect of
oral gavage with 65 kDa HSP on CIA. METHODS: We immunized 6-8-week-old DBA1 male
mice with bovine type II collagen. A group of 25 mice were given oral recombinant
mycobacterial 65 kDa HSP before immunization (30 microg in 200 microl phosphate
buffered saline (PBS) at Days -7, -5, -2) while PBS alone was administered in 27
controls. A 3rd group was fed 65 kDa HSP according to the same protocol but was
not immunized with collagen II (n = 8). The clinical arthritis score was recorded
3 times/week until Day 60. Antibodies to collagen II were determined by ELISA.
RESULTS: The incidence of arthritis was comparable in the 2 groups (72 vs 70%).
The onset of arthritis was not delayed in mice fed HSP. However, the severity of
arthritis was lower 10 days after arthritis onset in animals fed 65 kDa HSP
(clinical score 1.83 +/- 0.79 vs 2.74 +/- 1.1; p < 0.0001). No animals in Group 3
had arthritis. Serum IgG anti-type II collagen levels were decreased in HSP
treated mice (optical density 0.33 +/- 0.21 vs 0.46 +/- 0.21; p < 0.0001).
However, the ratio of IgG1/IgG2a antitype II collagen antibody response remained
unchanged in the mice fed 65 kDa HSP. CONCLUSION: These results suggest that oral
administration of 65 kDa HSP may diminish collagen induced arthritis.
PMID- 9558183
TI - Ambulatory activity as an objective and quantifiable measure of nonsteroidal
therapy.
AB - OBJECTIVE: To quantify any increase in short term spontaneous ambulatory activity
resulting from the use of nonsteroidal antiinflammatory drugs (NSAID) in patients
with rheumatoid arthritis (RA). METHODS: Double blind placebo controlled
crossover study of 8 women with RA using conventional assessments and the Numact
activity monitor. RESULTS: Patients' ambulatory activity was 50% greater during
NSAID treatment compared to placebo treatment. Effect size calculated at 0.62,
suggesting good sensitivity to change. The increased activity occurred late
morning. CONCLUSION: Spontaneous ambulatory activity is an objective and relevant
measure of disability.
PMID- 9558184
TI - A randomized double blind trial of verbal NSAID education compared to verbal and
written education.
AB - OBJECTIVE: We performed a double blind randomized controlled trial to investigate
whether patients taking nonsteroidal antiinflammatory drugs (NSAID) knew more
about these drugs at followup depending on whether they were randomized to
receiving or not receiving an NSAID information sheet. The patients were unaware
they were in a study. METHODS: All patients received verbal education on the side
effects of NSAID that was standardized and always given by the same
rheumatologist. Thirty patients randomly received an NSAID information sheet and
26 patients did not. At next clinic followup, after reading a letter of
explanation about the study and signing a consent form, patients completed a
questionnaire asking about their knowledge of NSAID. RESULTS: Outcome variables
assessed within the questionnaire included whether NSAID : (1) can decrease
inflammation; (2) help with pain; (3) cause stomach upset and bleeding in the
bowels. None of these variables were statistically significant. The only variable
that was statistically significantly different between the groups was their
report of whether they had received an information sheet about NSAID (p<0.00004).
A greater proportion of patients who received the NSAID information sheet
correctly reported they had received one compared to those who had not received
one and who said they had not received one (85% in the former group, 70% in the
latter group). The group who received the NSAID information sheet were more apt
to say that NSAID can help with their pain (odds ratio 6.1, p<0.05). Education
level was positively correlated with knowledge (p<0.04). However, level of
education explained only 11% of the variance in overall knowledge scores (r=0.34)
among all patients. CONCLUSION: An information sheet may not add educational
value over verbal information by a physician in a clinic setting.
PMID- 9558185
TI - Paleopathology in osseous remains from the 16th century. A survey of rheumatic
diseases.
AB - OBJECTIVE: To describe the rheumatic conditions found in skeletal remains of
Amerindian ancestry disinterred from a 16th century Mexican cemetery. METHODS: A
physical anthropologist and 2 rheumatologists surveyed the recovered skeletal
remains. RESULTS: We examined the skeletal remains of 443 subjects. We found 19
cases of Pott's disease, 17 of osteoarthrosis in various anatomical locations, 2
spondyloarthropathies, probably ankylosing spondylitis or diffuse idiopathic
skeletal hyperostosis, one probable septic arthritis in the stemoclavicular
joint, and 2 compression fractures of the spine. We found no cases of gout or
rheumatoid arthritis. CONCLUSION: This is the first report on the presence of
rheumatic conditions in colonial Mexico. Studying the remains of these
populations can provide useful information about the origin and evolution of
different rheumatic conditions.
PMID- 9558186
TI - Juvenile rheumatoid arthritis in a Canadian First Nations (aboriginal)
population: onset subtypes and HLA associations.
AB - OBJECTIVE: To determine onset subtypes and HLA associations of juvenile
rheumatoid arthritis (JRA) in a First Nations (aboriginal) population; to
determine whether population frequencies of HLA antigens may explain the
distribution of subtypes of JRA in this population. METHODS: All patients were
children from Manitoba and Northwestern Ontario seen in a single pediatric
rheumatology clinic between 1975 and 1996. Patients were identified from a clinic
registry. Controls were adults of Algonkian Cree and Ojibway heritage. Class I
and II major histocompatibility (HLA) typing was performed for First Nations
patients and controls. RESULTS: There were a total of 74 First Nations patients
with JRA. The relative frequency of rheumatoid factor (RF) positive polyarticular
JRA was higher and that of pauciarticular JRA was lower in First Nations compared
with Caucasian patients (42 versus 3% and 22 versus 58%, respectively; p =
0.00000). HLA-DRB1*04 (63%), 08 (43%), and 1402 (25%) were the most common DRB1
antigens among controls. The main subtypes of DRB1*04 were 0404 (33% of controls)
and 0407 (23%). HLA typing was performed for 39 First Nations patients; 27 were
Cree or Ojibway, 4 were from other tribes, and 8 were part First Nations. Among
Cree and Ojibway, 59% of controls and 63% of patients with RF positive
polyarticular JRA (n = 16) had HLA-DRB1 antigens bearing the rheumatoid arthritis
(RA) shared epitope (OR 1.16, 95% CI: 0.38, 3.48). The OR for polyarticular RF
positive JRA in those with DRB1*0802 and 0901 were 0.15, 95% CI: 0.02; and 1.24
and 5.83, 95% CI: 1.58, 28.38, respectively. CONCLUSION: There was a high
frequency of the RA shared epitope represented by both HLA-DRB1*0404 and 1402 in
this Algonkian population. This high frequency may explain the high frequency of
RF positive polyarticular JRA. DRB1*0802 may be protective, whereas DRB1*0901 may
increase the risk for this subtype of JRA.
PMID- 9558187
TI - Cyclosporine in the treatment of an unusual case of juvenile systemic sclerosis.
AB - We describe a child who initially presented with juvenile dermatomyositis (JDM).
Four years after the complete remission of JDM she developed systemic sclerosis
without internal organ involvement. She was unresponsive to a combination of
systemic corticosteroid therapy and pencillamine. The institution of cyclosporine
induced a complete remission.
PMID- 9558188
TI - A case of multicentric reticulohistiocytosis in a 6-year-old child.
AB - Multicentric reticulohistiocytosis (MR) is a rare disease in which an
infiltration of histiocytic cells causes destructive polyarthritis and
characteristic cutaneous lesions. It predominantly affects women between the ages
of 40 and 50 years. Effective treatment has not been well established. We
describe a case diagnosed in a 6-year-old girl. This is the youngest patient with
MR reported to date.
PMID- 9558189
TI - Antinuclear antibody negative systemic lupus erythematosus presenting as
bilateral facial paralysis.
AB - Cranial neuropathy, and particularly facial palsy, is a rare occurrence in
patients with systemic lupus erythematosus (SLE). We describe a 16-year-old
female who developed bilateral facial palsy concomitant with cutaneous bullous
eruption, alopecia, mucosal ulcers, arthritis, lymphadenopathy, parotid
enlargement, and proteinuria. The lack of positive antinuclear antibody (ANA) at
presentation obscured the diagnosis. Her followup course clarified the diagnosis
of SLE. We believe this is the first report of ANA negative SLE presenting as
bilateral facial palsy.
PMID- 9558190
TI - Corticosteroids and systemic lupus erythematosus pancreatitis: a case series.
AB - OBJECTIVE: To determine whether (1) corticosteroids cause pancreatitis in
patients with systemic lupus erythematosus (SLE); (2) SLE pancreatitis occurs in
the setting of a generalized SLE flare; and (3) corticosteroids can be used to
treat SLE pancreatitis. METHODS: A total of 8 patients over a 10 year period with
pancreatitis and SLE were identified retrospectively from a hospital database at
the University of California San Diego Medical Center. RESULTS: All 8 patients
received therapeutic doses of corticosteroids as part of their treatment for SLE
and pancreatitis. All patients manifested both clinical and biochemical
resolution of their pancreatitis with the administration of corticosteroids. No
patient in our study experienced immediate complications related to
corticosteroids. Only 2 of the 8 patients manifested active concurrent systemic
disease related to the SLE. CONCLUSION: Corticosteroids do not cause pancreatitis
in patients with SLE, and they should be administered during episodes of acute
pancreatitis if clinically necessary. Pancreatitis does not tend to occur in the
setting of a generalized SLE flare.
PMID- 9558191
TI - Unusual coronary artery ectasia and stenosis in a patient with systemic lupus
erythematosus and acute myocardial infarction.
AB - Acute myocardial infarction is an important and sometimes fatal complication of
systemic lupus erythematosus (SLE). We describe a case of acute myocardial
infarction in a 23-year-old woman with SLE. Angiography revealed coronary ectasia
in the left main and proximal circumflex coronary arteries, as well as a stenotic
lesion in the left anterior descending artery. The possible pathophysiology is
discussed.
PMID- 9558192
TI - Catastrophic antiphospholipid antibody syndrome in primary systemic sclerosis.
AB - We describe the first case of catastrophic antiphospholipid antibody syndrome
(APS) in a patient with progressive systemic sclerosis (SSc). After initial
presentation with digital gangrene the patient developed rapidly progressive
multiorgan failure and died within 19 hours. Postmortem examination revealed
extensive multiorgan arterial microthrombi of days' to months' duration. This
suggests that a subclinical state of thrombosis existed before onset of
catastrophic APS. Given the poor prognosis of established catastrophic APS there
is a need for a means to detect subclinical thrombosis and treat "at risk"
patients before clinically apparent thrombosis occurs.
PMID- 9558193
TI - Arterial obliteration in POEMS syndrome: possible role of vascular endothelial
growth factor.
AB - Acute arterial obliteration is a newly acknowledged manifestation of the POEMS
syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly,
endocrinopathy, M protein, skin changes), in which overproduction of
proinflammatory cytokines has been implicated. We describe a case in which serum
levels of proinflammatory cytokines were normal or slightly raised. In contrast,
vascular endothelial growth factor (VEGF) was greatly increased. This angiogenic
and vascular permeability factor is involved in the development of atheromatous
and thrombotic lesions and may be responsible for the arterial complications of
the disorder.
PMID- 9558194
TI - Refractory hyperglycemia complicating an evolving connective tissue disease:
response to cyclosporine.
AB - A 33-year-old woman with longstanding rheumatoid arthritis and Sjogren's syndrome
developed type B insulin resistance (diabetes mellitus due to anti-insulin
receptor antibodies) simultaneous with the evolution of her rheumatic disease to
mixed connective tissue disease. Cyclosporine therapy induced a remission of
receptor antibody mediated insulin resistance and controlled clinical
manifestations of her systemic lupus erythematosus and dermatomyositis, but had
no effect on the sclerodermatous features of her illness.
PMID- 9558195
TI - The pyramids of rheumatoid arthritis.
PMID- 9558196
TI - Genotyping HLA-B27 in spondyloarthropathies.
PMID- 9558197
TI - Assessment of sexual function in patients with rheumatic disorders.
PMID- 9558198
TI - Giant cell (temporal) arteritis and secondary amyloid: a matter of disease
duration?
PMID- 9558199
TI - A case of empty sella after steroid pulse therapy for nephrotic syndrome.
PMID- 9558200
TI - Orthostatic sympathetic derangement of baroreflex in patients with fibromyalgia.
PMID- 9558201
TI - Antinuclear antibody negative lupus associated with dystrophic calcification.
PMID- 9558202
TI - Septic arthritis caused by Neisseria sicca.
PMID- 9558204
TI - Risk Assessment for Neurobehavioral Toxicity
PMID- 9558203
TI - First report of giant cell arteritis--in the Talmud.
PMID- 9558229
TI - preface
PMID- 9558274
TI - A new source of cells contributing to the developing gastrointestinal tract
demonstrated in chick embryos.
AB - BACKGROUND & AIMS: Smooth muscle cells in the walls of the gastrointestinal tract
are thought to derive solely from mesoderm surrounding the primitive gut. A
population of neuroepithelial cells has recently been shown to migrate from the
ventral part of the neural tube in the region joined by the vagus nerve. We
sought to determine if these cells contributed to the development of the stomach
and intestine. METHODS: Cells of the ventral hindbrain of chick embryos were
tagged by replication-deficient retroviral vectors containing the lacZ gene,
providing a permanent label that is transmitted without dilution as the cells
divide. Embryos were processed for detection of labeled cells. Specific markers
were used to determine differentiation of progeny in the gastrointestinal tract.
RESULTS: Cells labeled in the ventral neural tube migrate in association with the
vagus nerve. Labeled cells are found in the intestine and stomach after time for
further migration and differentiation. Using a specific marker, they were clearly
identified as smooth muscle cells. CONCLUSIONS: Some of the smooth muscle cells
of the gastrointestinal tract are derived from precursor cells that originate in
the ventral part of the hindbrain neural tube. Their developmental importance and
functional significance remain to be determined.
PMID- 9558273
TI - Chemoprevention of spontaneous intestinal adenomas in the adenomatous polyposis
coli Min mouse model with aspirin.
AB - BACKGROUND & AIMS: Colorectal cancer is a significant source of morbidity and
mortality in the United States and other Western countries. Epidemiological and
experimental data indicate that regular use of aspirin reduces colon cancer risk.
This study was designed to determine if aspirin would significantly inhibit
gastrointestinal tumor formation in a mouse model of familial adenomatous
polyposis. METHODS: Six-week-old male and female C57BL/6J +/+ (control) and
C57BL/6J ApcMin/+ (Min) mice were fed either a control AIN-76A diet or one
supplemented with 250 or 500 parts per million (ppm) aspirin (n = 6 per group)
for 7 weeks. RESULTS: All of the Min mice, but no control mice, developed
gastrointestinal tumors. Aspirin significantly reduced tumor multiplicity (number
of tumors per mouse) in the small intestine, but not the colon, from an average
of 35.8 tumors per mouse (control diet) to 16 and 18.5 tumors per mouse with 250
and 500 ppm aspirin, respectively. Total tumor load (sum of tumor diameters per
mouse) was also significantly reduced, from 93.2 mm in total diameter to 40. 4
and 45.0 mm with 250 and 500 ppm aspirin, respectively. Results were not
significantly different because of sex or aspirin dose. CONCLUSIONS: High doses
of aspirin are effective chemopreventive agents in a mouse model of spontaneous
intestinal tumor formation.
PMID- 9558275
TI - Intractable upper gastrointestinal ulceration due to aspirin in patients who have
undergone surgery for peptic ulcer.
AB - BACKGROUND & AIMS: Postsurgical ulcer recurrence is a challenging problem. The
aim of this study was to define the role of aspirin in postsurgical ulcers.
METHODS: We studied 30 patients with postsurgical ulcer and aspirin abuse.
Preoperatively 13 had stenosis, 7 bleeding, and 7 perforation or penetration; 18
had undergone vagotomy and 11 gastrectomy. RESULTS: Of 30 patients, 15 admitted
long-term aspirin use (1-4 g/day), whereas 15 denied use but had positive
salicylate blood levels (15.1 +/- 2.25 mg/100 mL; >1 mmol/L). Gastrin or gastric
secretion was normal in the 24 patients tested. On follow-up, 3 (10%) healed
after surgery (all stopped taking aspirin), whereas 27 continued and had new
ulcers; 12 (44%) developed stenosis, and 6 (23%) developed bleeding. A second
operation was required in 16 patients who had continued aspirin abuse, which was
surreptitious in 10 (63%). Thirteen of these 16 had recurrent ulceration (7 [43%]
with stenosis and 1 with bleeding); 1 died and 2 stopped taking aspirin and
healed. A third operation was required in 8 patients. All had continued aspirin
abuse (75% surreptitiously), and all again had relapses (3 with stenosis); 1
underwent an unsuccessful fourth operation, and 3 died. CONCLUSIONS: With
continued aspirin abuse, recurrent ulceration is the rule, and complications,
especially stenosis, are common. Surreptitious aspirin abuse, if discovered, is a
clear contraindication to elective ulcer surgery, because aspirin-abuse
ulceration is incurable by gastric surgery.
PMID- 9558276
TI - Cost analysis of alternative approaches to colorectal screening in familial
adenomatous polyposis.
AB - BACKGROUND & AIMS: The commercial availability of gene testing for familial
adenomatous polyposis (FAP) represents an important advance in screening for
inherited colon cancer. We investigated the financial impact of this diagnostic
tool on colorectal screening for FAP. METHODS: Decision analysis was used to
compare per-person costs with third-party payers of three colorectal screening
strategies used to diagnose FAP in at-risk persons. The strategies included
conventional serial flexible sigmoidoscopy and two different APC gene testing
approaches. RESULTS: For 1 at-risk relative who begins screening at age 12 years,
average screening costs are $2625 when genotyping the proband first, $2674 when
genotyping the at-risk relative first, and $3208 for conventional sigmoidoscopy.
The cost advantage of genotyping increases as the pedigree size increases. For a
pedigree of 5 at-risk relatives, sigmoidoscopy would have to cost less than
$85.60 (professional plus facility fee) for conventional screening to compete
with genotyping. The cost advantage of genotyping is diminished for at-risk
relatives who begin FAP screening at older ages. CONCLUSIONS: The choice of least
expensive FAP screening strategy depends on the cost of flexible sigmoidoscopy,
patient age when screening starts, and pedigree size. Genotyping can
substantially reduce the cost of FAP screening and, when possible, should start
with the proband.
PMID- 9558277
TI - Curling of Curling's ulcer
PMID- 9558278
TI - Bone mineral density assessment in children with inflammatory bowel disease.
AB - BACKGROUND & AIMS: Children with inflammatory bowel disease (IBD) are at risk for
osteoporosis because of undernutrition, delayed puberty, and prolonged
corticosteroid use. The aim of this study was to compare bone mineral density
(BMD) in children with IBD with that in normal children and to assess the effects
of nutritional and hormonal factors and corticosteroid dosages on BMD. METHODS:
One hundred sixty-two subjects (99 with IBD and 63 healthy sibling controls) were
enrolled. Patients underwent anthropometric assessment, pubertal staging, bone
age radiography, and BMD assessment by dual energy x-ray absorptiometry of the
lumbar spine, femoral neck, and radius. Laboratory evaluations included serum
calcium, phosphate, alkaline phosphatase, 25-hydroxyvitamin D, 1,25
dihydroxyvitamin D, parathyroid hormone, osteocalcin, urinary N-telopeptides,
albumin, insulin-like growth factor I, and testosterone or estradiol. Cumulative
corticosteroid doses were calculated. RESULTS: BMD Z scores at the lumbar spine
and femoral neck were lower in patients with IBD, and lower in those with Crohn's
disease compared with those with ulcerative colitis. Low BMD persisted after
correction for bone age in girls with Crohn's disease (lumbar spine, P = 0.004;
femoral neck, P = 0.002). Cumulative corticosteroid dose was a significant
predictor of reduced BMD. BMD did not correlate with measures of calcium
homeostasis, except elevated serum phosphate and urine calcium levels in girls.
CONCLUSIONS: Low BMD occurs in children with IBD (more in Crohn's disease than in
ulcerative colitis), especially pubertal and postpubertal girls. Cumulative
corticosteroid dose is a predictor of low BMD, but other factors in Crohn's
disease remain undetermined.
PMID- 9558279
TI - Tropomyosin isoforms in intestinal mucosa: production of autoantibodies to
tropomyosin isoforms in ulcerative colitis.
AB - BACKGROUND & AIMS: Autoantibodies against tropomyosins (TMs) have been reported
in ulcerative colitis (UC). In this study the hTM isoforms (hTM1-5) present in
intestinal epithelial cells and in smooth muscle were investigated, and the
immunoreactivity against hTMs by immunoglobulin G (IgG) produced in vitro by
colonic mucosal lymphocytes (LPMCs) from patients with UC, Crohn's disease (CD),
and controls was examined. METHODS: TMs were extracted from colonic and jejunal
epithelial cells and smooth muscle, and hTM isoforms were identified using
isoform-specific monoclonal antibodies by enzyme-linked immunosorbent assay and
transblot analysis. The immunoreactivity of IgG produced by colonic LPMCs was
analyzed against the recombinant hTM isoforms. RESULTS: The major hTM isoforms
present in colonic and jejunal epithelial cells are hTM5 and hTM4, whereas
intestinal smooth muscle contains the hTM1-3 isoforms. The IgG synthesized in
vitro by LPMCs from UC (n = 19) recognized hTM5 and hTM1, more significantly (P <
0.04 to <0.001) when compared with CD (n = 12) and controls (n = 17). However,
IgG produced by LPMCs from CD did not show such anti-hTM reactivity. Mucosal anti
hTM IgG mainly belonged to the IgG1 subclass. CONCLUSIONS: Intestinal epithelial
cells and smooth muscle have distinct hTM isoforms. Patients with UC, and not CD,
show mucosal autoantibody response against hTM isoforms, particularly hTM5 and
hTM1.
PMID- 9558280
TI - Bismuth subsalicylate markedly decreases hydrogen sulfide release in the human
colon.
AB - BACKGROUND & AIMS: Hydrogen sulfide is one of the main malodorous compounds in
human flatus. This toxic gas also has been implicated in the pathogenesis of
ulcerative colitis. Therefore, a treatment that reduces colonic H2S levels could
be clinically useful in the treatment of flatus odor and of ulcerative colitis.
In this study the ability of bismuth subsalicylate, a compound that binds H2S, to
reduce H2S release in the colon, was tested. METHODS: Homogenates made from human
and rat feces were incubated with and without bismuth subsalicylate, and gas
production was measured. Fecal samples from 10 healthy subjects were analyzed
before and after ingestion of bismuth subsalicylate (524 mg four times a day) for
3-7 days. RESULTS: Fecal homogenates showed a dose-dependent relationship between
the concentration of bismuth subsalicylate and H2S release. Treatment of subjects
with bismuth subsalicylate produced a >95% reduction in fecal H2S release.
CONCLUSIONS: The ability of bismuth subsalicylate to dramatically reduce H2S
could provide a clinically useful means of controlling fecal and/or flatus odor
and of decreasing the putative injurious effects of H2S on the colonic mucosa.
PMID- 9558281
TI - Inhibition of epidermal growth factor receptor kinase induces protease-dependent
apoptosis in human colon cancer cells.
AB - BACKGROUND & AIMS: The epidermal growth factor receptor (EGFR) is under
investigation as a therapeutic target for cancers. Colon cancer cell lines are
variably dependent on autocrine stimulation of EGFR. We therefore examined the
effects of a selective EGFR tyrosine kinase inhibitor, PD 153035, on
proliferation and survival of five colon cancer cell lines whose autonomous
proliferation is either EGFR ligand dependent or EGFR ligand independent.
METHODS: Effects of inhibitors were screened by MTS growth assays, [3H]thymidine
incorporation, terminal deoxynucleotidyl transferase-mediated deoxyuridine
triphosphate nick-end labeling assay, fluorescence microscopy, immunoblotting,
and in vitro protease assays. RESULTS: PD 153035 caused dose-dependent cytostasis
(200 nmol/L to 1 micromol/L) and apoptosis (>10 micromol/L) in ligand-dependent
cell lines and caused variable apoptosis (>10 micromol/L) but no cytostasis in
ligand-independent cell lines. Apoptosis induced by 10 micromol/L PD 153035 was
not associated with induction of p53 protein expression but was accompanied by
activation of caspases that cleave poly(ADP-ribose) polymerase, lamin B1, and Bcl
2. Inhibition of caspase 3-like protease activity by DEVD-fluoromethylketone
significantly delayed the onset of PD 153035-induced apoptosis. CONCLUSIONS: The
EGFR tyrosine kinase inhibitor PD 153035 induces cytostasis and caspase-dependent
apoptosis in EGFR ligand-dependent colon cancer cell lines. These observations
encourage further investigation of EGFR tyrosine kinase inhibitors for treatment
of colorectal neoplasms.
PMID- 9558282
TI - Short-chain fatty acids induce cell cycle inhibitors in colonocytes.
AB - BACKGROUND & AIMS: We tested the hypothesis that short-chain organic acids in the
colon derived from dietary pectin, wheat bran, and oat bran are protective
against the development of colon cancer because they induce transforming growth
factor (TGF)-beta1, which in turn inhibits cell growth by inducing cyclin
directed kinase (cdk) inhibitors. METHODS: U4 human colon carcinoma cells
differentiate into water- and salt-transporting columnar enterocytes and
therefore model normal colonocytes. The composition and kinase activity of
cdk/cyclin complexes were determined by immunoprecipitation and Western blotting
studies in U4 cells treated in vitro with short-chain fatty acid (SCFA) mixtures
that mimic the digestion products of wheat bran, oat bran, pectin, and cellulose
(as control), which is largely unfermentable. RESULTS: Induction of the cdk
inhibitors p21cip1 and p27kip1 by fiber-mimicking SCFA mixtures occurs much more
rapidly and is many-fold greater than their induction by TGF-beta1. The SCFA
mixtures most effective in causing growth inhibition and cdk inhibitor production
mimicked those from wheat bran > oat bran > pectin. CONCLUSIONS: cdk inhibitor
induction by SCFA mixtures is not mediated by TGF-beta1. The SCFA mixture
mimicking digested wheat bran fiber was the most effective of all mixtures tested
in inhibiting cell growth through induction of cdk inhibitors.
PMID- 9558284
TI - Direct evidence of mast cell involvement in Clostridium difficile toxin A-induced
enteritis in mice.
AB - BACKGROUND & AIMS: The pathogenesis of Clostridium difficile toxin A-induced
intestinal inflammation is not completely understood. The aim of this study was
to define the contribution of mast cells to the fluid secretion and neutrophil
infiltration associated with toxin A-induced enteritis. METHODS: Fluid secretion
and neutrophil infiltration in toxin A- or buffer-challenged ileal loops were
assessed in normal, mast cell-deficient, and mast cell-deficient KitW/KitW-v mice
that had undergone selective repair of their mast cell deficiency. The effect of
a specific substance P-receptor antagonist was also studied. RESULTS: Intestinal
fluid secretion and neutrophil recruitment were significantly diminished in mast
cell-deficient KitW/KitW-v and mast cell-deficient MgfSl/MgfSl-d mice compared
with the respective normal mice. Mast cell-reconstituted KitW/KitW-v mice showed
responses similar to the normal congenic mice. Administration of a specific
substance P-receptor antagonist (CP-96,345) reduced toxin A-induced intestinal
fluid secretion and inhibited neutrophil infiltration in normal, mast cell
deficient KitW/KitW-v, and mast cell-reconstituted KitW/KitW-v mice. CONCLUSIONS:
C. difficile toxin A elicits intestinal fluid secretion and neutrophil
infiltration by both mast cell-dependent and -independent pathways, and substance
P participates in both pathways.
PMID- 9558283
TI - Rotavirus infection of cultured intestinal epithelial cells induces secretion of
CXC and CC chemokines.
AB - BACKGROUND & AIMS: Rotaviruses are the major cause of pediatric gastroenteritis
worldwide. The target cell of rotavirus infection is the mature enterocyte of the
small intestine. Recently, intestinal epithelial cells have been shown to produce
chemoattractant mediators in response to cytokine stimulation and bacterial
infection, suggesting a potentially important role of epithelial cells in
initiating immune responses. In this study, the production of chemokines by
cultured intestinal epithelial cells after rotavirus infection was investigated.
METHODS: Two human intestinal epithelial cell lines (HT29 and Caco-2) were
infected with sucrose-purified rotavirus (strain SA114F) and assayed by reverse
transcription polymerase chain reaction and enzyme-linked immunosorbent assay for
chemokine expression. Virus-like particles and inactivated rotavirus were used to
test the importance of viral attachment and replication. RESULTS: Increased
messenger RNA expression and secretion of immunoreactive interleukin 8, growth
related peptide alpha, and RANTES (regulated upon activation, normal T cell
expressed and secreted) were detected in rotavirus-infected cells. Chemokine
production was time and dose dependent and required viral replication.
CONCLUSIONS: Rotavirus infection induces the expression of a subset of chemokines
in intestinal epithelial cells. These data support the hypothesis that chemokine
secretion by enterocytes may play a role in the initiation and modulation of the
immune response to rotavirus infection.
PMID- 9558285
TI - Regional differences in L-selectin expression in murine intestinal lymphocytes.
AB - BACKGROUND & AIMS: The expression of the lymphocyte homing receptor and
activation marker L-selectin is different in colon and small intestinal
intraepithelial lymphocytes (IELs). In this study, the mechanism of this
difference in L-selectin expression was investigated. METHODS: L-selectin
expression on lymphocytes was measured by flow cytometry. L-selectin messenger
RNA (mRNA) was detected by reverse-transcription polymerase chain reaction. L
Selectin expression on peripheral lymphocytes was analyzed after incubation with
cytokines, food and bacterial antigens, and homogenates of small and large bowel.
RESULTS: L-selectin was expressed by none of the small intestinal IELs but by 30%
of those in the colon and by 60% of splenocytes. mRNA for L-selectin was
detectable in isolated lymphocytes of all three sites. L-Selectin was down
regulated in colon IELs during colitis and up-regulated in small intestinal IELs
after in vitro culture for 48 hours. Incubation of splenocytes with small
intestinal homogenates led to a rapid down-regulation of L-selectin (1% vs. 60%
untreated). Preincubation with a metalloproteinase inhibitor prevented L-selectin
loss. CONCLUSIONS: The mechanism of the differential expression of L-selectin in
mouse small intestine and colon appears to be an increased functional activity of
a metalloproteinase (sheddase) in the small intestine compared with the colon.
PMID- 9558286
TI - The inaccuracy of duplex ultrasonography in predicting patency of transjugular
intrahepatic portosystemic shunts.
AB - BACKGROUND & AIMS: A prospective double-blinded study with preset sonographic
criteria has not been performed to assess the accuracy of duplex ultrasonography
in determining the patency of transjugular intrahepatic portosystemic shunts
(TIPS). The purpose of this study was to determine the sensitivity and
specificity of duplex ultrasonography in predicting shunt malfunction using
accepted preset sonographic criteria. METHODS: Sixty ultrasonographic and
venographic follow-up comparisons were made on 38 cirrhotic patients who had
undergone TIPS placement for variceal bleeding (n = 28) or intractable ascites (n
= 10). Ultrasonographic results were analyzed by one of two board-certified
ultrasonographers without knowledge of venographic findings. RESULTS: Of the 31
occluded (n = 8) and stenotic (n = 23) shunts, ultrasonography accurately
predicted a shunt malfunction (occlusion or stenosis) in only 11 studies and
incorrectly predicted patency in 20. Compared with venography, ultrasonography
had a sensitivity of 35% and a specificity of 83% in predicting TIPS stenosis or
occlusion. CONCLUSIONS: These results suggest that duplex sonography is not a
sensitive test in predicting the presence of a hemodynamically significant
stenosis and that shunt status should be assessed by venography and direct portal
pressure measurements until a more reliable and proven noninvasive
ultrasonographic criterion is devised.
PMID- 9558287
TI - "Salvage" transjugular intrahepatic portosystemic shunts: gastric fundal compared
with esophageal variceal bleeding.
AB - BACKGROUND & AIMS: The optimal emergency treatment for gastric fundal variceal
bleeding is still unclear. In this study, the efficacy of transjugular
intrahepatic portosystemic stent/shunt (TIPS) in patients with uncontrolled
gastric fundal vs. esophageal variceal bleeding was compared. METHODS: One
hundred twelve consecutive patients with uncontrolled variceal bleeding required
emergency TIPS, 84 with esophageal varices (EV group) unresponsive to endoscopic
and vasoconstrictor therapy and 28 with gastric fundal varices (GV group)
unresponsive to vasoconstrictor therapy. Clinical and biochemical data were
retrieved, and the two groups were compared. RESULTS: Variceal bleeding was
controlled in all patients after TIPS except for 1 in each group. There were no
significant differences between the two groups in terms of markers of disease
severity, severity of bleeding, or portal hemodynamics. During a median follow-up
period of 7 months, 20 in the EV group (24%) and 8 in the GV group (29%)
developed clinical rebleeding. Most early rebleeding (within 7 days after TIPS)
was related to esophageal ulceration secondary to previous sclerotherapy. Rates
of mortality were similar in both groups. CONCLUSIONS: These results suggest that
emergency TIPS is equally effective in the immediate short-term control of
gastric fundal variceal bleeding compared with esophageal variceal bleeding.
PMID- 9558288
TI - Interferon alfa therapy for chronic hepatitis B in children: a multinational
randomized controlled trial.
AB - BACKGROUND & AIMS: Treatment of chronic hepatitis B with interferon alfa is not
approved in children. The aim of this study was to evaluate the safety and
efficacy of interferon alfa (IFN-alpha) in children with chronic hepatitis B and
increased transaminase levels. METHODS: Children were given either IFN-alpha2b (6
megaunits/m2 thrice weekly for 24 weeks) or no treatment. Clearance of markers of
viral replication was evaluated 24 weeks after therapy and after 48 weeks of
observation in controls. RESULTS: Of 149 children enrolled, 144 were evaluable
(70 treated and 74 controls). Serum hepatitis B e antigen and viral DNA became
negative in 26% of treated children and 11% of controls (P < 0.05). Serum
aminotransferase levels normalized and liver histology improved among responders.
Hepatitis B surface antigen became undetectable in 10% of treated patients and 1%
of controls. Female gender and interferon treatment were the only significant
predictors of response. Ethnic origin, baseline aminotransferase level, initial
DNA levels, and histology did not correlate with response. Most adverse reactions
were mild or moderate, and dose was reduced in 24% of children. CONCLUSIONS: In
children with chronic hepatitis B, INF-alpha promotes loss of viral replication
markers and surface antigen and improves aminotransferases and histology.
PMID- 9558289
TI - Heterogeneity of hemochromatosis in Italy.
AB - BACKGROUND & AIMS: Patients with hemochromatosis show variable phenotype
expression. We evaluated the frequency of hemochromatosis gene (HFE) mutations
and the contribution of HFE genotype, ancestral haplotype, ethnic background, and
additional factors (alcohol intake, hepatitis viruses, and beta-thalassemia
trait) to the severity of iron overload in a large series of Italian patients
with a hemochromatosis phenotype. METHODS: HFE genotype was studied in 188
patients. Phenotype evaluation was available in 153 men and 20 women and was
based mainly on iron removed. HFE genotype was determined by a polymerase chain
reaction restriction assay and ancestral haplotype through D6S265 and D6S105
microsatellite analysis. RESULTS: The frequency of C282Y homozygotes was 64%,
with a decreasing gradient from north to south. C282Y homozygotes showed more
severe iron overload than the other HFE genotypes. In the same group, ancestral
haplotype was associated with a more severe phenotype. Additional factors may
favor the development of a relatively mild hemochromatosis phenotype in patients
nonhomozygous for the C282Y mutation. CONCLUSIONS: Hemochromatosis in Italy is a
nonhomogenous disorder in which genetic and acquired factors are involved. In
patients with a single or no HFE mutation, further studies will enable a
differentiation between true genetic disorders and interactions between genetic
and acquired factors.
PMID- 9558290
TI - Expression of HLA-linked hemochromatosis in subjects homozygous or heterozygous
for the C282Y mutation.
AB - BACKGROUND & AIMS: In the absence of a genetic test, diagnostic criteria for
hereditary hemochromatosis have been imprecise. The identification of the HFE
gene and the C282Y mutation allow definition of expression of this disease and
reassessment of diagnostic criteria. The aim of this study was to analyze the
concordance between the genetic diagnosis and the previous clinical diagnosis in
families with hemochromatosis. METHODS: Three hundred subjects were tested for
the C282Y mutation and were grouped as homozygous, heterozygous, or homozygous
normal. RESULTS: All adults previously diagnosed as homozygous or heterozygous
for HLA-linked hereditary hemochromatosis carried at least one C282Y mutation.
Two adolescents, previously thought to be homozygous, had no C282Y mutation. Of
127 subjects homozygous for the mutation, 105 met criteria for diagnosis. Iron
overload was not expressed in 6.7% of homozygous men and 32.7% of homozygous
women. The iron indices in 8 of 171 subjects heterozygous for the C282Y mutation
were within the range previously regarded as indicative of homozygosity. Seven of
these 8 carried the H63D mutation. CONCLUSIONS: In Australia, 17.3% of subjects
homozygous for the C282Y mutation do not express iron overload to meet current
diagnostic criteria of hemochromatosis. In subjects heterozygous for the
mutation, 4.8% have iron overload in the range previously diagnosed as
homozygous. Nonexpression is common, particularly in women.
PMID- 9558291
TI - Circulating xanthine oxidase and neutrophil activation during human liver
transplantation.
AB - BACKGROUND & AIMS: Oxygen free radicals, generated by xanthine oxidase (XO) and
activated leukocytes, are involved in reperfusion injury in experimental liver
transplantation. The roles of XO and neutrophil activation during reperfusion in
clinical liver transplantation were studied. METHODS: In 10 patients undergoing
liver transplantation, we assessed plasma concentrations of circulating XO by
enzyme-linked immunosorbent assay (ELISA), the purine metabolites hypoxanthine,
xanthine, and urate by high-performance liquid chromatography, lactoferrin by
ELISA, and malondialdehyde fluorometrically up to 48 hours postoperatively.
RESULTS: During reperfusion after portal vein declamping, elevated plasma
concentrations of XO (52.1 ng/mL [range, 8.0-440.1]), hypoxanthine (81.62
micromol/L [48.2-108.7]), xanthine (21.01 micromol/L [8.7-22.3]), and lactoferrin
(532.6 ng/mL [370.4-1326.6]) were observed compared with the preoperative levels
(0 ng/mL [0-12], 1.88 micromol/L [0.62-3.15], 0.95 micromol/L [0-0.41], and 164.3
ng/mL [73.7-334.1], respectively; all P < 0.05). No changes occurred in urate or
malondialdehyde. After portal vein declamping, XO, hypoxanthine, and xanthine
levels were substantially greater in the hepatic than portal vein (all P < 0.05).
Marginal transhepatic differences occurred in lactoferrin. CONCLUSIONS:
Reperfusion during liver transplantation is associated with liberation of
xanthine oxidase, hypoxanthine, and xanthine from the liver into the circulation.
During reperfusion, intravascular neutrophil activation takes place in the
hepatic circulation.
PMID- 9558292
TI - Cholesterol saturation, not proteins or cholecystitis, is critical for crystal
formation in human gallbladder bile.
AB - BACKGROUND & AIMS: Biliary proteins are promoters of cholesterol crystallization
in artificial model bile. However, their pathogenic importance for cholesterol
precipitation in native gallbladder bile (GB) is uncertain. The aim of this study
was to evaluate the significance of biliary lipids and proteins on cholesterol
crystal detection time (ChCDT) of GB in patients with gallstones. METHODS: ChCDT
and concentrations of lipids, albumin, mucins, aminopeptidase N, alpha1-acid
glycoprotein, haptoglobin, and immunoglobulins (Igs) were measured in GB of 92
patients, 52 of whom had cholesterol gallstones. RESULTS: ChCDT was markedly
reduced in gallstone patients. Compared with patients without gallstones, they
had a significant increase in cholesterol saturation and total protein, albumin,
mucin, and IgG biliary concentrations. In univariate analysis, ChCDT of GB was
significantly correlated with cholesterol saturation and total lipid, protein,
Ig, aminopeptidase N, and alpha1-acid glycoprotein concentrations. However,
stepwise logistic regression analysis showed that only cholesterol saturation
independently correlated to ChCDT. Gallbladder inflammation correlated with the
concentration of Igs, but subtraction of IgG from GB did not modify the ChCDT.
CONCLUSIONS: Biliary cholesterol transport and saturation, but not proteins,
appear critical for the cholesterol crystallization abnormality observed in
native bile from patients with gallstones.
PMID- 9558293
TI - Reduced plasma cholesterol and increased fecal sterol loss in multidrug
resistance gene 2 P-glycoprotein-deficient mice.
AB - BACKGROUND & AIMS: mdr2 P-glycoprotein (Pgp) deficiency in mice leads to the
absence of biliary phospholipids and cholesterol in the presence of normal bile
salt secretion. The aim of this study was to evaluate the importance of the
biliary pathway in cholesterol homeostasis by determining the effects of mdr2 Pgp
deficiency on hepatic and plasma lipid levels and cholesterol kinetics in chow
fed mice. METHODS: Hepatic lipid content, enzyme activities, plasma lipoprotein
levels, and fecal sterol excretion were measured in wild-type (+/+) and mdr2 Pgp
deficient (-/-) mice. Cholesterol kinetics were determined using radiotracer
techniques. RESULTS: No differences in hepatic lipid content were observed
between (-/-) and (+/+) mice. Plasma high-density lipoprotein cholesterol and
apolipoprotein A-I levels were strongly reduced in (-/-) mice compared with
controls, whereas the apolipoprotein B contents of very-low-density lipoprotein
and low-density lipoprotein were increased. Hepatic activity of 3-hydroxy-3
methylglutaryl-coenzyme A reductase was threefold greater in (-/-) mice than in
controls; however, compartmental analysis of plasma cholesterol decay showed no
differences in cholesterol synthesis between (-/-) and (+/+) mice. A dual isotope
approach for estimating cholesterol absorption yielded approximately 50% lower
values in (-/-) mice than in controls. Surprisingly, (-/-) mice showed a fourfold
increase in fecal neutral sterol secretion. CONCLUSIONS: This study unequivocally
establishes the important direct role of biliary lipids in the regulation of
plasma lipid levels in mice.
PMID- 9558295
TI - Bumetanide-sensitive cell swelling mediates the inhibitory effect of ethanol on
proteolysis in rat liver.
AB - BACKGROUND & AIMS: Ethanol is known to inhibit proteolysis and to cause
intracellular protein accumulation in the liver. The aim of this study was to
investigate the mechanism underlying the antiproteolytic effect of ethanol.
METHODS: The effects of ethanol on proteolysis and cell volume were assessed in
the isolated perfused rat liver by established tracer techniques. RESULTS:
Infusion of ethanol (20 mmol/L) led to an increase of the intracellular water
space by 9.3% +/- 0.4% (n = 3), which was abolished by methylpyrazole and
mimicked by acetaldehyde (5 mmol/L). Ethanol-induced cell swelling was completely
abolished by bumetanide (5 micromol/L), an inhibitor of Na-K-2Cl cotransport.
Ethanol (20 mmol/L) inhibited proteolysis by 18.6% +/- 2.0% (n = 4) in a
colchicine-sensitive way. This antiproteolytic effect was quantitatively mimicked
by equipotent hyposmotic hepatocyte swelling and by acetaldehyde. Ethanol-induced
inhibition of proteolysis was abolished in the presence of methylpyrazole (100
micromol/L), bumetanide (5 micromol/L), furosemide (100 micromol/L), and insulin
(35 nmol/L), i.e., conditions that also prevented ethanol-induced cell swelling.
CONCLUSIONS: Ethanol causes, via acetaldehyde, bumetanide-sensitive cell
swelling, which in turn mediates the antiproteolytic effect of this alcohol. The
data indicate the involvement of cell hydration changes in mediating metabolic
ethanol effects and could suggest the activation of a putative Na-K-2Cl
cotransport in liver by ethanol/acetaldehyde.
PMID- 9558294
TI - Concanavalin A-induced liver cell damage: activation of intracellular pathways
triggered by tumor necrosis factor in mice.
AB - BACKGROUND & AIMS: Concanavalin A (con A) induces tumor necrosis factor (TNF)
dependent hepatocyte apoptosis resembling immune-mediated fulminant hepatic
failure in humans. Intracellular pathways originating at the TNF receptor are
either linked to apoptosis, nuclear factor (NF)-kappaB translocation, or Jun
kinase (JNK) activation. The aim of this study was to study TNF-dependent
pathways after con A injection in vivo. METHODS: Con A, con A plus anti-TNF, and
control buffer were injected into BALB/c mice. Immunofluorescence, Western blot,
Northern blot, gel shift, Erk, and JNK activity and DNA fragmentation experiments
were performed at different time points after injection. RESULTS: DNA
fragmentation in hepatocytes was increased 4-24 hours after con A injection. JNK
was activated maximally (>20-fold) directly after con A injection, whereas
binding and nuclear translocation of NF-kappaB was maximal after 4 hours. All
pathways were blocked by anti-TNF. JNK activation was specific because related
ERK 1 + 2 were not activated after con A. High nuclear expression of c-Jun was
already evident 1 hour after con A injection; however, in contrast to JNK, anti
TNF treatment did not block c-Jun nuclear expression and DNA binding.
CONCLUSIONS: In the con A model, activation of TNF-dependent pathways is
associated with apoptosis of hepatocytes. Their modulation in vivo may have
implications to develop new therapeutic strategies to prevent apoptosis.
PMID- 9558296
TI - Pituitary adenylate cyclase-activating peptide stimulates rat pancreatic
secretion via secretin and cholecystokinin releases.
AB - BACKGROUND & AIMS: Pituitary adenylate cyclase-activating polypeptide (PACAP)
stimulates protein and/or amylase secretion from isolated rat pancreatic acini.
The effect of PACAP on pancreatic secretion in vivo and its mechanism of action
were studied. METHODS: Rats were prepared with pancreatic duct cannulation,
pyloric ligation, and bile diversion into duodenum, and 2.5, 5, and 10 nmol/kg
PACAP-27 was administered intravenously while pancreatic juice was collected for
30 minutes. In other groups of rats, the effect of 10 nmol/kg PACAP-27 was
studied under the influence of either atropine; loxiglumide, an antisecretin
serum; a combination of both loxiglumide and the antiserum; or a PACAP antagonist
(PACAP 6-38). Plasma secretin and cholecystokinin concentrations were measured by
radioimmunoassay. RESULTS: (1) PACAP dose-dependently increased pancreatic
secretion of fluid, bicarbonate, and protein; (2) the increase in pancreatic
secretion paralleled that of plasma secretin and cholecystokinin; (3) a
combination of loxiglumide and antisecretin serum eliminated the PACAP-stimulated
pancreatic secretion, whereas loxiglumide or antisecretin serum alone partially
but significantly blocked pancreatic secretion; (4) atropine failed to influence
PACAP-induced pancreatic secretion; and (5) PACAP antagonist profoundly
suppressed the PACAP action. CONCLUSIONS: PACAP-27 dose-dependently stimulates
pancreatic secretion of fluid, bicarbonate, and protein in rats. This effect is
mediated by release of both secretin and cholecystokinin and is independent of
cholinergic tone.
PMID- 9558298
TI - Leukocyte-endothelial cell interactions: molecular mechanisms and implications in
gastrointestinal disease.
AB - Leukocyte-endothelial cell adhesion is now recognized to represent an early and
rate-limiting step in the leukocyte infiltration and accompanying tissue injury
that is associated with acute and chronic inflammatory diseases of the
gastrointestinal tract. Adhesive interactions such as leukocyte rolling,
adherence, and transendothelial migration are influenced by a variety of
physical, chemical, and molecular factors that ultimately result in a net up
regulation or down-regulation of the inflammatory response. Coordination of this
process is made possible by the mediator-specific, time-sensitive expression of
adhesion glycoproteins on the surface of leukocytes and/or vascular endothelial
cells. In this review, the different families of relevant adhesion molecules that
participate in the coordinated recruitment of leukocytes into inflamed tissue are
described and then discussed in terms of the pathophysiological alterations
observed in selected experimental models of gastrointestinal disease. These
include ischemia/reperfusion injury, radiation enteritis, inflammatory bowel
disease, and the inflammatory responses to substances liberated by Helicobacter
pylori and Clostridium difficile.
PMID- 9558297
TI - Hypercalcemia due to endogenous overproduction of 1,25-dihydroxyvitamin D in
Crohn's disease.
AB - Hypercalcemia may occur in various granulomatous diseases. Two patients with
Crohn's disease who had hypercalcemia, hypercalciuria, and excessively high serum
levels of 1,25-dihydroxyvitamin D [1,25(OH)2D] are described. Both had numerous
noncaseating, epithelioid granulomas in bowel biopsy samples. A direct
correlation was observed between serum 1,25(OH)2D levels and both serum and
urinary calcium concentrations. Also, calcium and 1,25(OH)2D levels strongly
paralleled the clinical activity of disease. Prompt therapy with prednisone in
the patient who had symptomatic hypercalcemia and with prednisone and mesalamine
in the other patient without hypercalcemic symptoms led to normalization of
calcium and serum 1,25(OH)2D levels, but 25-hydroxyvitamin D [25(OH)D] levels
remained unchanged. Four months after discharge, recurrence of Crohn's disease
symptomatology together with an increase in calcium and serum 1,25(OH)2D levels
was observed in 1 patient; after increasing the prednisone dose, levels decreased
and rapid clinical resolution was noted. These cases appear to be the first
reported instances of hypercalcemia in patients with Crohn's disease. Excessive
synthesis of 1,25(OH)2D may have been inhibited by an action of corticosteroids
on the 1alpha-hydroxylation of 25(OH)D in the activated macrophage of Crohn's
granulomas. Crohn's disease should be added to the list of granulomatous diseases
responsible for 1,25(OH)2D-mediated hypercalcemia.
PMID- 9558299
TI - Our new president--Donald O. Castell, M.D.
PMID- 9558300
TI - Editorial
AB - As clinical dermatologists, we are all striving to achieve the highest possible
accuracy in our clinical acumen and diagnostic skills. Over the past decade, one
relatively simple advance, epiluminescence microscopy with the use of the
dermatoscope, has significantly contributed to our diagnostic skills in the
detection of benign versus pigmented lesions. In the paper by Kawabata and
Tamaki, these authors delineate distinctive dermatoscopic features of acral
lentiginous melanoma in situ, and contrast this with melanocytic nevi. The
restructuring of healthcare delivery systems by third party payers and
governmental programs is impacting on the pattern of our medical practices. In
Canada, this has limited access to widespread use of techniques such as Mohs'
micrographic surgery. The article by Arlette and colleagues has further supported
the well-established studies indicating that Mohs' micrographic surgery for high
risk skin cancers has a dramatic benefit. Healthcare restructuring has also led
to a decreased number of trainees in a number of subspecialties, including
dermatology. This decrease in manpower has been an impetus to look at alternative
forms of care for underserviced areas. Telemedicine, the use of
telecommunications technology to provide healthcare services over a distance, has
been examined as one attempt at solving this problem. In the Point-Counterpoint
articles, we have two distinct views on the future of telemedicine as it applies
to dermatology. Over the past decade, there have been dramatic advances in our
understanding at a molecular nature of various disease processes. This rapid
development has translated into a large number of therapies. Regulatory agencies
such as the Food and Drug Administration in the United States, or the Health
Protection Branch in Canada, are caught between demands to bring effective
therapies to the market in an expedited fashion, and yet establish efficacy and
maintain safety of new therapeutic entities. This occurs by a multistaged
approval process. During the early phases, exposure is limited in order to
accumulate preliminary data on pharmacology and toxicity. In the Critical
Appraisal CME series, Muglia and DiGiovanna describe early testing processes in
Phase 1 clinical trials. Calciphylaxis is a severe disease associated with
calcification of the skin, subcutaneous tissue and potentially, internal organs.
While the disease itself is relatively uncommon, the manifestations are quite
distinctive. In this issue of the Journal, we have a review of calciphylaxis from
Richard Worth, as well as a preamble by Dr. Goodall and a case report by Kalaaji
et al. illustrating the consequences of this rare but distinctive entity.
PMID- 9558301
TI - Effect of occlusion on cell proliferation during epidermal healing.
AB - BACKGROUND: Occlusive dressings influence epithelization of superficial wounds by
some unknown mechanism(s). OBJECTIVE: The effects of occlusion on epidermal cell
proliferation in two types of wounds were examined. METHODS: Partial-thickness
wounds and tape-stripped skin wounds were compared. An immunohistochemical
technique, employing PC10 - a monoclonal antibody against proliferating cell
nuclear antigen (PCNA) - was applied to formalin-fixed, paraffin-embedded porcine
tissue sections. RESULTS: The number of PC10-positive cells was low during the
migratory phase, then increased to a peak of proliferation 2 to 3 days after
resurfacing. An overall increased proliferative response (mean = 21%) was seen in
occluded compared to control partial-thickness wounds (day 10 postoperatively);
an opposite effect of occlusion on epidermal proliferation was seen in tape
stripped skin. Occlusion decreased the proliferative response (mean = 42%)
compared to air-exposure. CONCLUSION: Occlusion increased epidermal cell
proliferation in wounds (where the entire surface epithelium and papillary dermis
was removed), whereas an opposite effect was seen in tape-stripped skin from
which only the stratum corneum had been removed.
PMID- 9558302
TI - Distinctive dermatoscopic features of acral lentiginous melanoma in situ from
plantar melanocytic nevi and their histopathologic correlation.
AB - BACKGROUND: An acral lentiginous melanoma in situ on the sole is often difficult
to differentiate with the naked eye from an acquired plantar melanocytic nevus.
Recent technical advances in epiluminescence microscopy have contributed to the
differentiation of these two pigmented skin lesions. OBJECTIVE: In this study,
the correlation between dermatoscopic and histopathologic findings of acral
lentiginous melanoma in situ on the sole are compared to those of acquired
plantar melanocytic nevi. METHODS: Three acral lentiginous melanomas in situ on
the sole, and two cases of acral lentiginous melanoma were compared with 50
acquired plantar melanocytic nevi by means of dermatoscopy and histopathology.
RESULTS: The dermatoscopic surface profiles of acquired melanocytic nevi were
composed of linear pigmentation accentuated mainly on the sulcus superficialis.
Histologically, some areas of the sulcus superficialis corresponded to rete
ridges of the epidermis, and nests of nevus cells were also often located there.
In contrast, the acral lentiginous melanomas in situ showed diffuse, irregularly
shaped pigmentation distributed in a disorderly fashion over the entire surface.
Histologically, isolated areas of proliferation and small nest formations of
atypical melanocytes were irregularly distributed in the epidermis. CONCLUSION: A
distinctive dermatoscopic feature of acral lentiginous melanoma in situ is
diffuse and irregular pigmentation over the entire surface of the lesion. This
feature is helpful for differentiating acral lentiginous melanoma in situ from
acquired plantar melanocytic nevi.
PMID- 9558303
TI - Basal cell carcinoma of the periocular region.
AB - BACKGROUND: Basal cell carcinomas of the periocular area present a particular
challenge because of the likelihood of damage to vital structures. OBJECTIVE:
More than 10-years experience of treating basal cell carcinomas by Mohs
micrographic surgery was reviewed. METHODS: Chart analysis of 233 periocular
basal cell carcinomas was performed. All patients were contacted either in
clinical follow-up or by telephone review. RESULTS: Two hundred and thirty-three
periocular basal cell carcinomas were analyzed out of a total of 3, 192 basal
cell carcinomas treated during this period (7.3%). Patients ranged in age from 17
to 102 years with a mean age of 58.8 years and a median of 59.0 years. Of the
patients, 54.5% were female. Mohs micrographic surgery was the prime therapy in
177 patients (75. 9%). Of the lesions, 48.5% occurred in the medial canthal area,
35. 2% on the lower eyelid, 10.7% on the upper eyelid, and 5.6% on the lateral
canthus. There was no significant difference between the left/right distribution
in males and females. The average follow-up time was 34 months (standard
deviation 26.38 months). A cumulative rate of no recurrence tabulated by modified
life table analysis was 0.9864. CONCLUSION: This study further documents the
problems associated with basal cell carcinoma of the periocular area as well as
the value of Mohs micrographic surgery as treatment.
PMID- 9558304
TI - Direct immunofluorescence diagnosis of pemphigus without biopsy.
AB - BACKGROUND: Direct immunofluorescence (DIF) is a necessary examination tool for
the diagnosis of pemphigus. The suction-blister-method splits the skin at the
lamina lucida and it is possible with a scalpel to separate the entire epidermis
from the dermis. OBJECTIVE: The study was to determine whether DIF is reliable on
epidermal sheets separated using a suction apparatus. METHODS: Thirteen patients
were selected for this study: (nine with pemphigus vulgaris (PV), one with
paraneoplastic pemphigus (PP), and three with pemphigus erythematosus (PE).
Frozen epidermal sheets, separated from the dermis with a scalpel, were used as a
substrate. Diagnosis with routine fluorescein isothiocyanate (FITC) antibodies
was made. RESULTS: In all patients a pericellular deposition of IgG was evident
and in eight of these patients a pericellular deposition of C3 was present. In
two cases of PE and one of PP, the C3 deposits were also present in the lower
part of basal keratinocytes. CONCLUSION: This diagnostic method without skin
biopsy is easy to perform and, together with the histology and clinical aspects,
could be a useful tool in the diagnosis of pemphigus. We recommend this method
when the patient is allergic to local anaesthetics, the patient easily produces
hypertrophic scars, or in follow-up of already biopsied patients.
PMID- 9558305
TI - Lymphoid markers, activation markers, and adhesion molecules in cutaneous biopsy
specimens from HIV+ patients with disease progression. The Military Medical
Consortium for the Advancement of Retroviral Research.
AB - BACKGROUND: One important factor in understanding the pathogenesis of human
immune deficiency virus (HIV) disease is documenting the patterns of immune
dysregulation present in HIV-positive patients. The cells which home to skin are
mainly certain subsets of T cells and, as opposed to the peripheral blood, where
circulating factors may inhibit terminal phenotypic differentiation, the
cutaneous environment potentiates differentiation during cutaneous eruptions.
OBJECTIVE: The authors' aim was to characterize the inflammatory dermatoses in
biopsy specimens from HIV-positive patients with immunohistochemical stains for
lymphoid markers, activation markers, and adhesion molecules and to determine if
there was any correlation with the type of dermatosis and the HIV-disease stage.
METHODS: Lymphoid and activation markers as well as adhesion molecules were
studied on cutaneous biopsy specimens from 96 inflammatory dermatoses in HIV
positive patients. The dermatoses included psoriasiform dermatoses with and
without a lichenoid component, perivascular lymphoid dermatoses, perivascular and
periadnexal inflammatory dermatoses, spongiotic dermatoses, granulomatous
dermatoses, and neutrophilic dermatoses with and without vasculitis. RESULTS:
Although there was a decrease in CD4/CD8 ratios in the cutaneous inflammatory
dermatoses with progression of the disease, the ratios of CD4/CD8 cells were far
higher than those in the peripheral blood. There were also increasing numbers of
CD23+ cells and increased E-Selectin expression on endothelial cells from the
early stages of disease, with no consistent pattern of ICAM-1 expression on
epithelial cells with disease progression. CONCLUSIONS: The expression of
lymphoid markers, activation markers, and adhesion molecules in the skin with
progression of HIV disease, is consistent with a T helper (Th)1 to Th0/Th2
cytokine pattern of immune dysregulation. This cytokine pattern may be modified
by the cytopathic effects of HIV on lymphoid and dendritic populations and by
effects of other concurrent infections. Significant numbers of CD4+ T cells in
skin infiltrates, with low peripheral CD4 T-cell counts, suggest that the
cutaneous T-cell populations may be distinctive.
PMID- 9558306
TI - Undergraduate dermatology education in Canada: a survey.
AB - BACKGROUND: Two reviews done in the 1980's showed that many Canadian medical
schools scheduled relatively little time for dermatological teaching. Many
students did not have a real clinical exposure to dermatology. OBJECTIVE: The
purpose of this study was to obtain new data to reevaluate the undergraduate
training in dermatology in Canada. METHODS: A survey was sent to the coordinators
of undergraduate dermatology of all 16 Canadian medical schools. RESULTS: The
survey of medical schools demonstrates the current status of dermatology
undergraduate teaching across Canada. Although many improvements have been made
in the way dermatology is taught to medical students, many of the problems
noticed in the 1980s remain unresolved. CONCLUSION: Because dermatological care
in Canada is often rendered by nondermatologists, the dermatologists should
emphasize the importance of undergraduate training in their specialty.
PMID- 9558307
TI - Phase 1 clinical trials.
AB - BACKGROUND: In the United States, drug development and approval is a complex
process regulated by the Food and Drug Administration under the authority
outlined in the Code of Federal Regulation. The goal of this multi-step process
is to determine safety and efficacy of new therapeutic entities. Initially,
exposure of humans to new therapeutic agents is accomplished in a graded and
limited fashion. This approach seeks to minimize risks to study participants from
exposure to damaging agents. During early phases, limiting exposure to a few
individuals results in the accumulation of preliminary data on pharmacology,
short-term toxicity, and efficacy. The inherent limitations of this process
necessitate careful critique and caution in extrapolation of phase 1 data.
OBJECTIVES: The purpose of this article is to provide a review of the drug
approval process focusing on phase 1 trials, which are the earliest human
exposure to a new drug. The purpose, variations, and significance of phase 1
trials are described, and a framework is provided to critically evaluate data
published from these trials. CONCLUSIONS: Phase 1 trials are primarily designed
to accumulate short-term safety (toxicity) and pharmacological data. Although
preliminary efficacy may be addressed ("proof of concept" efficacy), it is a
secondary endpoint. The numbers of patients are small, the numbers of patients
receiving efficacious doses are very small, and controls are absent. Evaluation
of efficacy and of long-term toxicity requires longer, larger, and controlled
studies.
PMID- 9558308
TI - Calciphylaxis: a cause of necrotic ulcers in renal failure.
AB - BACKGROUND: Calciphylaxis is a rare and life-threatening condition occurring in
patients with end-stage renal disease on dialysis. The diagnosis is frequently
delayed or missed and therapy is often unsuccessful. OBJECTIVE: The clinical and
pathological components of calciphylaxis are emphasized in a patient that may
facilitate early diagnosis and initiation of therapy. RESULTS: Early recognition
of the clinical signs and symptoms of calciphylaxis is crucial. The tissue
diagnosis requires large elliptical biopsies because histological findings are
segmental and often missed. CONCLUSION: Early diagnosis and intervention in
calciphylaxis is critical. Parathyroidectomy should be considered in all cases.
PMID- 9558309
TI - Calciphylaxis: pathogenesis and therapy.
AB - BACKGROUND: Calciphylaxis is a rare, painful and debilitating disease in which
calcification of the skin and subcutaneous tissues or of internal organs can lead
to skin necrosis, discolouration, and other skin lesions. The typical patient has
end-stage renal disease (ESRD) and hyperparathyroidism. Selye originally
characterized this syndrome in rats and distinguished it from other syndromes of
abnormal calcification by the following sequence: sensitizers, latent period, and
challengers. There has been recent debate regarding misdiagnosis and failure to
differentiate this category of patients even in clinical studies. OBJECTIVE: In
this article the clinical manifestations of calciphylaxis are described; the
importance of distinguishing this condition from other calcification syndromes is
explained; risk factors, sensitizers, and challenges are reviewed; treatments of
choice are discussed; and the merits of parathyroidectomy are evaluated.
CONCLUSION: It is important to consider calciphylaxis in a differential diagnosis
of calcification syndromes and in treating patients with ESRD and
hyperparathyroidism, because early diagnosis and treatment can interrupt the
progression of the disease process; the disease is painful and debilitating; and
inappropriate treatment such as corticosteroid administration may aggravate the
condition. Skin biopsy is an important diagnostic tool when the condition is
suspected. Parathyroidectomy may be justified because the untreated disease
itself has significant rates of morbidity and mortality and because this
treatment occasionally leads to dramatic clinical improvement.
PMID- 9558310
TI - Photoaffinity labeling of oxidosqualene cyclase and squalene cyclase by a
benzophenone-containing inhibitor.
AB - A new orally active oxidosqualene:lanosterol cyclase (OSLC) inhibitor (Ro48-8071;
Morand, O. H. et al. (1997) J. Lipid Res. 38, 373-390) showed potent
noncompetitive inhibition of bacterial squalene:hopene cyclase (SHC) from
Alicyclobacillus acidocaldarius (IC50 = 9.0 nM, KI = 6.6 nM) and OSLC (IC50 = 40
nM, KI = 22 nM for homogeneous rat liver OSLC). A tritium-labeled isotopomer
(18.8 Ci/mmol) of this nonterpenoid inhibitor, which possesses a benzophenone
(BP) photophore, was chemically synthesized as a photoaffinity label. Specific,
efficient covalent modification of both OSLC and SHC enzymes was observed after
UV irradiation at 360 nm. Labeling of both OSLC and SHC by [3H]Ro48-8071 was
competitively displaced by coincubation with a 1000-fold molar excess of 18-thia
2, 3-oxidosqualene or the nonterpenoid inhibitor BIBX79. Displacement of labeling
of OSLC was also achieved with the suicide substrate (3S)-29-methylidene-2,3
oxidosqualene. Thus, the nonsubstrate Ro48-8071 and both terpenoid and
nonterpenoid inhibitors of these enzymes appear to share a common binding site.
PMID- 9558311
TI - Pressure denaturation of proteins: evaluation of compressibility effects.
AB - One of the key pieces of information from pressure denaturation experiments is
the standard volume change for unfolding (Delta V(o)). The pressure dependence of
the volume change, the standard compressibility change (Delta K(o)T), is
typically assumed to be zero in the analysis of these experiments. We show here
that this assumption can be incorrect and that the neglect of compressibility
differences can skew the interpretation of experimental results. Analysis of
experimental, variable-pressure NMR data for bovine pancreatic ribonuclease A in
2H2O at pH 2.0 and 295 K yielded the following statistically significant, non
zero values: Delta K(o) T = 0.015 +/- 0.002 mL mol-1 bar-1, Delta V(o) = -21 +/-
2 mL mol-1, and Delta G(o) = 2.8 +/- 0.3 kcal mol-1. The experimental protein
stability is in good agreement with one (Delta G(o) = 2.5 kcal mol-1) determined
independently for the same protein by calorimetry at atmospheric pressure under
equivalent conditions [Makhatadze, G. I., Clore, G. M., and Gronenborn, A. M.
(1995) Nat. Struct. Biol. 2, 852-855]. The positive value for Delta K(o)T
indicates that the denatured form of ribonuclease A is more compressible than the
native form; this is explained in terms of an interplay between the intrinsic
compressibility of the protein and solvation effects. When the same data were
fitted to a model that assumes a zero compressibility change, the Delta G(o)
value of 4. 0 +/- 0.1 kcal mol-1 returned by the model no longer agreed with the
independent measurement, and the Delta V(o) returned by the model was a very
different -59 +/- 1 mL mol-1. By contrast, it was not possible to carry out a
similar thermodynamic analysis of fluorescence spectroscopic data for the
denaturation of staphylococcal nuclease to yield well-defined values of Delta
G(o), Delta V(o), and Delta K(o)T. This limitation was shown by evaluation of
synthetic data to be intrinsic to spectroscopic data whose analysis requires
fitting of the plateaus at either side of the transition. Because NMR data do not
have this requirement, they can be analyzed more rigorously.
PMID- 9558312
TI - Molecular basis of resistance to HIV-1 protease inhibition: a plausible
hypothesis.
AB - The binding thermodynamics of the HIV-1 protease inhibitor acetyl pepstatin and
the substrate Val-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln, corresponding to one of the
cleavage sites in the gag, gag-pol polyproteins, have been measured by direct
microcalorimetric analysis. The results indicate that the binding of the peptide
substrate or peptide inhibitor is entropically driven; i.e., it is characterized
by an unfavorable enthalpy and a favorable entropy change, in agreement with a
structure-based thermodynamic analysis based upon an empirical parameterization
of the energetics. Dissection of the binding enthalpy indicates that the
intrinsic interactions are favorable and that the unfavorable enthalpy originates
from the energy cost of rearranging the flap region in the protease molecule. In
addition, the binding is coupled to a negative heat capacity change. The dominant
binding force is the increase in solvent entropy that accompanies the burial of a
significant hydrophobic surface. Comparison of the binding energetics obtained
for the substrate with that obtained for synthetic nonpeptide inhibitors
indicates that the major difference is in the magnitude of the conformational
entropy change. In solution, the peptide substrate has a higher flexibility than
the synthetic inhibitors and therefore suffers a higher conformational entropy
loss upon binding. This higher entropy loss accounts for the lower binding
affinity of the substrate. On the other hand, due to its higher flexibility, the
peptide substrate is more amenable to adapt to backbone rearrangements or subtle
conformational changes induced by mutations in the protease. The synthetic
inhibitors are less flexible, and their capacity to adapt is more restricted. The
expected result is a more pronounced effect of mutations on the binding affinity
of the synthetic inhibitors. On the basis of the thermodynamic differences in the
mode of binding of substrate and synthetic inhibitors, it appears that a key
factor to understanding resistance is given by the relative balance of the
different forces that contribute to the binding free energy and, in particular,
the balance between conformational and solvation entropy.
PMID- 9558313
TI - Penetration and intracellular routing of nucleus-directed peptide-based shuttles
(loligomers) in eukaryotic cells.
AB - Loligomers are multitasking, peptide-based shuttles that are able to penetrate
cells and self-localize into distinct cellular compartments. In particular,
loligomer 4 incorporates internalization and nuclear import sequences as well as
reporter groups. The intracellular routing of loligomer 4 was analyzed by
microscopy and flow cytometry, to define and demonstrate localization events.
Electron micrographs of CHO cells exposed to a biotinylated derivative of
loligomer 4 as well as confocal images of CHO cells treated with rhodamine
labeled loligomer 4 indicate their presence in the cytosol, endocytic vesicles,
and the nucleus of CHO cells. Loligomer 4 accumulates irreversibly inside cells.
Uptake of loligomer 4 by six mammalian cell lines (Daudi, EL4, CHO, COS-7, VERO,
and HeLa) was proven by flow cytometry, establishing the generality of the
principle. Cells presented as monolayers typically were less able to endocytose
the construct than cells grown in suspension. Cellular accumulation of loligomer
4 varied between cell lines with COS-7 and VERO cells showing the highest level
of uptake. Plasmids harboring reporter genes could be transported efficiently
inside CHO cells, suggesting that loligomer 4 either alone or noncovalently
associated with large macromolecules can effectively reach the nucleus of cells.
In summary, loligomer 4 constructs provide a simple synthetic platform for the
design of guided intracellular agents.
PMID- 9558314
TI - Solution structure of an intramolecular DNA triplex linked by hexakis(ethylene
glycol) units: d(AGAGAGAA-(EG)6-TTCTCTCT-(EG)6-TCTCTCTT).
AB - A DNA molecule was designed and synthesized with three octanucleotide stretches
linked by two hexakis(ethylene glycol) chains to form an intramolecular triplex
in solution. The structural data obtained from a series of NMR NOESY spectra
yielded interproton distances, and COSY experiments provided dihedral angle
information for analysis of deoxyribose ring pucker. Using distance geometry
followed by simulated annealing with restrained molecular dynamics and relaxation
matrix refinement, a well-refined ensemble of conformations was calculated.
Although some NOE cross-peaks involving protons of the hexakis(ethylene glycol)
linker could be identified, most could not be assigned and the conformations of
the linkers were not determined. The deoxyribose conformations are predominantly
of the S type, except for the protonated cytosine residues in the third strand
which show hybrid N and S character. Overall, the duplex part of the molecule
resembles a B-DNA double helix with the third strand bound in its major groove by
Hoogsteen hydrogen bonds. This structure provides a basis for comparison with
triplexes containing noncanonical or nonnatural nucleotides.
PMID- 9558315
TI - Solution structure of an intramolecular DNA triplex containing 5-(1-propynyl)-2'
deoxyuridine residues in the third strand.
AB - Incorporation of the modified base 5-(1-propynl)-2'-deoxyuridine (propynylU) in
the third strand of a triplex leads to enhanced triplex stabilization. To
investigate effects of the propyne nucleotide on triplex structure and the
factors underlying the increased stability, we have determined the solution
structure of the intramolecular DNA pyrmidine-purine-pyrimdine d(AGAGAGAA-(EG)6
TTCTCTCT-(EG)6-PCPCPCPP) (PDD-EG), which contains 5-(1-propynl)-2'-deoxyuridine
(P) in the third strand and hexakis(ethylene glycol) linkers [(EG)6]. The
structure was calculated using X-PLOR with distance and dihedral angle restraints
obtained from two-dimensional NMR experiments and refined with the direct
relaxation matrix method. The structures show that the extended aromatic electron
cloud of the propynylU nucleotide stacks well over the 5'-neighboring
nucleotides, resulting in increased stabilization. The propynylU nucleotides also
affect the overall structure of the triple helix. A comparison of the structure
to that of the nonmodified intramolecular DNA triplex of the same sequence,
d(AGAGAGAA-(EG)6-TTCTCTCT-(EG)6-TCTCTCTT) (DDD-EG), shows that PDD-EG has a more
A-DNA like X displacement and inclination than DDD-EG yet still maintains
predominantly S-type sugar puckers as found in DDD-EG and other DNA triplexes.
PMID- 9558316
TI - Fidelity of mutant HIV-1 reverse transcriptases: interaction with the single
stranded template influences the accuracy of DNA synthesis.
AB - We have used random sequence mutagenesis and complementation in a bacterial
selection system to establish a large library of immunodeficiency virus type 1
(HIV-1) reverse transcriptase (RT) mutants with amino acid substitutions in the
beta3-beta4 region of the fingers subdomain [Kim, B., Hathaway, T. R., and Loeb,
L. A. (1996) J. Biol. Chem. 271, 4872-4878]. We show here that one of these
mutants, D76V, exhibits increased accuracy of copying both DNA and RNA templates
in a primer extension assay with biased dNTP pools. More detailed analysis of DNA
dependent polymerization showed that the D76V mutation conferred an up to 14-fold
increase in fidelity of nucleotide insertion and a 9-fold reduced mutation rate
in an M13mp2 lacZalpha forward mutation assay. Substitution at D76 with
positively charged (D76R) and nonpolar (D76V and D76I) residues increased
replicational accuracy, while substitutions with negatively charged (D76E) and
polar residues (D76S and D76C) had little effect on fidelity. We propose that D76
affects replicational accuracy by mediating interaction between the fingers
subdomain and the single-stranded template. Our work shows that the Escherichia
coli complementation system can yield HIV RT mutants with increased fidelity that
have not been isolated from the natural host and that are valuable in
understanding the molecular bases of replicational accuracy.
PMID- 9558317
TI - Characterization of Y122F R2 of Escherichia coli ribonucleotide reductase by time
resolved physical biochemical methods and X-ray crystallography.
AB - Ribonucleotide reductase (RNR) from Escherichia coli catalyzes the conversion of
ribonucleotides to deoxyribonucleotides. It is composed of two homodimeric
subunits, R1 and R2. R2 contains the diferric-tyrosyl radical cofactor essential
for the nucleotide reduction process. The in vitro mechanism of assembly of this
cluster starting with apo R2 or with a diferrous form of R2 has been examined by
time-resolved physical biochemical methods. An intermediate, Fe3+/Fe4+ cluster
(intermediate X), has been identified that is thought to be directly involved in
the oxidation of Y122 to the tyrosyl radical (*Y122). An R2 mutant in which
phenylalanine has replaced Y122 has been used to accumulate intermediate X at
sufficient levels that it can be studied using a variety of spectroscopic
methods. The details of the reconstitution of the apo and diferrous forms of
Y122F R2 have been examined by stopped-flow UV/vis spectroscopy and by rapid
freeze quench electron paramagnetic resonance, and Mossbauer spectroscopies. In
addition the structure of this mutant, crystallized at pH 7.6 in the absence of
mercury, at 2.46 A resolution has been determined. These studies suggest that
Y122F R2 is an appropriate model for the examination of intermediate X in the
assembly process. Studies with two mutants, Y356F and double mutant Y356F and
Y122F R2, are interpreted in terms of the possible role of Y356 in the putative
electron transfer reaction between the R1 and R2 subunits of this RNR.
PMID- 9558318
TI - Preparation, characterization, and complete heteronuclear NMR resonance
assignments of the glutaredoxin (C14S)-ribonucleotide reductase B1 737-761
(C754S) mixed disulfide.
AB - The first committed step in de novo DNA biosynthesis involves the conversion of
ribonucleotides to the corresponding deoxyribonucleotides catalyzed by the enzyme
ribonucleotide reductase. Reduction of disulfides in ribonucleotide reductase is
essential and is catalyzed by the protein disulfide reductants glutaredoxin or
thioredoxin. The interaction region between Escherichia coli glutaredoxin-1 and
E. coli ribonucleotide reductase has been localized to the C-terminal end of the
B1 subunit of ribonucleotide reductase. We have demonstrated that a 25-residue
peptide corresponding to this C-terminal sequence is a very good substrate for
glutaredoxin via a fluorescence assay and that this peptide binds in a specific
manner via isothermal titration calorimetric measurements. By selectively
mutating the two cysteines in the peptide, we have identified the electrophilic
cysteine as C759 (B1 numbering) and prepared a mixed disulfide between E. coli
glutaredoxin-1 (C14 --> S) and the C759 monothiol form of the peptide. The
peptide and the protein have been labeled with 13C and 15N, and complete
heteronuclear NMR resonance assignments have been completed for both the peptide
and the protein in the complex. By using half-filtered NOESY spectra,
intermolecular NOEs between the protein and the peptide have been identified and
the binding site on glutaredoxin has been mapped. The electrostatic charge
distribution of the protein in this region is very positive, thus providing an
excellent match for the highly negatively charged peptide. In addition, the
electrostatic potential of the peptide provides a rationale for the observed
cysteine selectivity in the reaction between glutaredoxin and the B1 peptide.
PMID- 9558319
TI - Transcriptional activator-coactivator recognition: nascent folding of a kinase
inducible transactivation domain predicts its structure on coactivator binding.
AB - A model of transcriptional activator-coactivator recognition is provided by the
mammalian CREB activation domain and the KIX domain of coactivator CBP. The CREB
kinase-inducible activation domain (pKID, 60 residues) is disordered in solution
and undergoes an alpha-helical folding transition on binding to CBP
[Radhakrishan, I., Perez-Alvarado, G. C., Parker, D., Dyson, H. J., Montminy, M.
R., and Wright, P. E. (1997) Cell 91, 741-752]. Binding requires phosphorylation
of a conserved serine (RPpSYR) in pKID associated in vivo with the biological
activation of CREB signaling pathways. The CBP-bound structure of CREB contains
two alpha-helices (designated alphaA and alphaB) flanking the phosphoserine; the
bound structure is stabilized by specific interactions with CBP. Here, the
nascent structure of an unbound pKID domain is characterized by multidimensional
NMR spectroscopy. The solubility of the phosphopeptide (46 residues) was enhanced
by truncation of N- and C-terminal residues not involved in pKID-CBP
interactions. Although disordered under physiologic conditions, the pKID fragment
and its unphosphorylated parent peptide exhibit partial folding at low
temperatures. One recognition helix (alphaA) is well-defined at 4 degreesC,
whereas the other (alphaB) is disordered but inducible in 40% trifluoroethanol
(TFE). Such nascent structure is independent of serine phosphorylation and
correlates with the relative extent of engagement of the two alpha-helices in the
pKID-KIX complex; whereas alphaA occupies a peripheral binding site with few
intermolecular contacts, the TFE-inducible alphaB motif is deeply engaged in a
hydrophobic groove. Our results support the use of TFE as an empirical probe of
hidden structural propensities and define a correspondence between induced fit
and the nascent structure of peptide fragments.
PMID- 9558320
TI - Thermodynamics of bovine spleen galectin-1 binding to disaccharides: correlation
with structure and its effect on oligomerization at the denaturation temperature.
AB - Isothermal titration calorimetry (ITC) measurements of the binding 1-beta
carbohydrate-substituted galactopyranoside derivatives to galectin-1 from bovine
spleen, a dimer with one binding site per subunit, were performed at 283-285 and
298 K. The disaccharides were lactose, methyl beta-lactoside, lactulose, 4-O-beta
D-galactopyranosyl-D-mannopyranoside, 3-O-beta-D-galactopyranosyl-D-arabinose, 2'
O-methyllactose, lacto-N-biose, N-acetyllactosamine, and thiodigalactopyranoside.
The site binding enthalpies, DeltaHb, are the same at both temperatures and range
from -42.2 +/- 3.3 kJ mol-1 for thiodigalactopyranoside to -24.5 +/- 0.5 kJ mol-1
for lacto-N-biose, and the site binding constants range from 4.86 +/- 0.78 x
10(3) M-1 for methyl beta-lactoside at 297.8 K to 6.54 +/- 0.97 x 10(4) M-1 for N
acetyllactosamine at 281.3 K. The binding reactions are enthalpically driven,
exhibit enthalpy-entropy compensation, and, with the exception of N
acetyllactosamine, follow a van't Hoff dependence of the binding constant on
temperature. The number of contacts at distances <4.0 A between the disaccharide
and galectin was determined from the energy-minimized conformation of the complex
derived from the X-ray crystallographic structure of the galectin-N
acetyllactosamine complex determined by Liao et al. [Liao, D. I., Kapadia, G.,
Ahmed, H., Vasta, G. R., and Herzberg, O. (1994) Proc. Natl. Acad. Sci. U.S.A.
91, 1428-1432]. The binding enthalpies calculated from changes in the solvent
accessible surface areas of the galectin binding site upon binding of the
disaccharide were in close agreement with the experimental values for lactose,
lactulose, lacto-N-biose, and N-acetyllactosamine, all of which exhibit binding
enthalpies >-36 kJ mol-1. Differential scanning calorimetry measurements on
solutions of galectin and its disaccharide complexes show that the galectin dimer
does not dissociate upon denaturation in contrast to the legume lectins. At the
denaturation temperature, the galectin in the absence of sugar exists as a
tetramer, and the extent of this association is substantially reduced in the
presence of a disaccharide.
PMID- 9558321
TI - Pressure dependence of amide hydrogen-deuterium exchange rates for individual
sites in T4 lysozyme.
AB - We report measurements of the pressure dependence of rate constants for the
exchange of amide residue protons with solvent deuterium for T4 lysozyme. Data
obtained at nine pressures from 0.1 to 200 MPa are analyzed using an elementary
kinetic model and the formalism of transition state theory which yield activation
volumes for the exchange process. Resolution of individual amide sites was
accomplished using the HSQC two-dimensional (2D) NMR experiment on uniformly
(15)N-labeled protein. The observed activation volumes span the range from 2.75
to -25.1 mL/mol at 22 degreesC and pH* 7.5. When corrected for the pressure
dependence of the ionic product for water and for the reported activation volume
for the amide exchange reaction in model compounds, the portion of the activation
volume associated with the accessibility of the solvent or catalyst to the amide
sites ranges from -15.1 to 12.8 mL/mol. There is no simple correlation between
the activation volumes and the protection factors for amide hydrogen exchange.
The activation volumes for residues in close proximity in either the primary
sequence or the folded structure may differ considerably. There is no trivial
correlation between the activation volume and the secondary structural unit in
which a residue is located, and activation volumes for residues that are
apparently structurally coupled may be very different. The modest sizes of the
activation volumes obtained under these conditions are in contrast to large
values reported for bovine pancreatic trypsin inhibitor at more extreme
conditions of 60 degreesC and pH* 8 where major unfolding events or structural
rearrangements may dominate the mechanism [Wagner, G. (1983) Q. Rev. Biophys. 16,
1-57].
PMID- 9558322
TI - Structural examination of the influence of phosphorylation on the binding of
fibrinopeptide A to bovine thrombin.
AB - Upon addition of thrombin, fibrinopeptides A and B are cleaved off from the N
termini of four chains of fibrinogen (Aalpha Bbeta gamma)2, and sites of
polymerization are exposed, resulting in formation of a fibrin clot. For the
fibrinogen Aalpha chain, cleavage occurs most prevalently at the Arg16-Gly17
peptide bond. About 25-30% of the human fibrinogen Aalpha chains are
phosphorylated in nature at the position of Ser3, but the function for this
modification is not understood. Previous NMR studies indicated that the N
terminal portion (1ADSGE5) of unphosphorylated fibrinopeptide A does not interact
with the surface of bovine thrombin. Kinetic and NMR studies have now been
carried out to assess whether phosphorylation at Ser3 allows the N-terminal
segment (1ADSGEGDFLAEGGGVR16) to become anchored on the thrombin surface, leading
to formation of a catalytically more efficient enzyme-substrate complex. Kinetic
results indicate that phosphorylation leads to an approximately 65% increase in
substrate specificity (kcat/Km) toward hydrolysis of fibrinogen Aalpha(1-20). 31P
NMR studies reveal that the phosphorylated group does interact with thrombin, and
1H line broadening studies suggest that phosphorylation does promote binding of
amino acids 1-5. Two-dimensional transferred nuclear Overhauser effect
spectroscopy studies of bound fibrinopeptide A(1-16 Ser3P) indicate that
phosphorylation allows new through-space interactions involving amino acid
residues 1ADSGE5 to be observed. Computational docking of the peptide onto the X
ray structure of thrombin suggests that the phosphate may interact with basic
residues at the rim of the heparin binding site of thrombin. As a result, the
phosphate may serve as an anionic linker between the fibrinopeptide and the
enzyme thrombin.
PMID- 9558323
TI - The p51 subunit of human immunodeficiency virus type 1 reverse transcriptase is
essential in loading the p66 subunit on the template primer.
AB - Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is a
dimeric enzyme consisting of p66 and p51 subunits. The functional role of the p51
subunit remains elusive since all the catalytic functions appear to be executed
through the p66 subunit. We report here that the p51 subunit, in addition to
providing structural support to the p66 subunit, may be involved in facilitating
the loading of the p66 subunit on to the template-primer (TP). This possibility
is supported by following observations: (i) Upon binding to the TP, the p51
subunit can be dissociated by acetonitrile treatment and the template-primer
bound p66 monomer alone is capable of catalyzing DNA synthesis. (ii) Photo-cross
linking of template-primer to HIV-1 RT is abolished by dissociation of the p51
subunit prior to the TP binding but remains unaffected after the TP binding step.
(iii) The p66-TP covalent complex selectively generated by UV irradiation and
separated by gel electrophoresis can incorporate a single nucleotide in situ upon
its renaturation in the gel. (iv) Treatment of HIV-1 RT with (tert
butyldimethylsilyl)spiroaminooxathioledioside (TSAO), an inhibitor that
specifically binds to the beta7 beta8 loop of p51, destabilizes the heterodimeric
enzyme, resulting in the subsequent loss of DNA binding.
PMID- 9558324
TI - Structure of cyclodextrin glycosyltransferase complexed with a derivative of its
main product beta-cyclodextrin.
AB - Crystals of the inactive mutant Glu257-->Ala of cyclodextrin glycosyltransferase
were soaked with the cyclodextrin (CD) derivative S-(alpha-D-glucopyranosyl)-6
thio-beta-CD. The structural analysis showed its beta-CD moiety with no density
indication for the exocyclic glucosyl unit. For steric reasons, however, the
position of this unit is restricted to be at only two of the seven glucosyl
groups of beta-CD. The analysis indicated that the enzyme can cyclize branched
alpha-glucans. The ligated beta-CD moiety revealed how the enzyme binds its
predominant cyclic product. The conformation of the ligated beta-CD was
intermediate between the more symmetrical conformation in beta-CD dodecahydrate
crystals and the conformation of a bound linear alpha-glucan chain. Its scissile
bond was displaced by 2.8 A from the position in linear alpha-glucans.
Accordingly, the complex represents the situation after the cyclization reaction
but before diffusion into the solvent, where a more symmetrical conformation is
assumed, or the equivalent state in the reverse reaction. Furthermore, a unifying
nomenclature for oligosaccharide-binding subsites in proteins is proposed.
PMID- 9558325
TI - Diradylglycerols alter fatty acid inhibition of monoacylglycerol acyltransferase
activity in Triton X-100 mixed micelles.
AB - The activity of hepatic monoacylglycerol acyltransferase (MGAT) (EC 2.3.1.22), a
developmentally expressed microsomal enzyme, is inhibited by long-chain fatty
acids, and stimulated by its product 1, 2-diacyl-sn-glycerol. Because the
quantities of fatty acids and diacylglycerols are likely to vary in membranes
during different physiological conditions and could thereby alter MGAT activity,
we examined their combined effects on MGAT in Triton X-100/phospholipid mixed
micelles. MGAT's product, 1,2-diC18:1-sn-glycerol, which is also normally a
cooperative activator of the activity, reversed the 50% inhibition caused by 10
mol % oleic acid. The presence of oleic acid also allowed low concentrations (<10
mol %) of 1, 2-diC18:1-sn-glycerol to stimulate MGAT activity without the lag
that is observed in the absence of fatty acid. At 12.6 mol %, 1, 2-monoC18:1-sn
glycerol ether, which alone has no effect on MGAT activity, became an activator
in the presence of 10 mol % oleic acid. Kinetic studies revealed that in the
presence of 15 mol % oleic acid, 1,2-diC18:1-sn-glycerol ether increased the
apparent Vmax by 3. 8-fold while minimally altering the apparent Km for palmitoyl
CoA. Other neutral lipids including tri-C18:1-glycerol, ceramide, and cholesterol
oleate did not stimulate MGAT in either the presence or the absence of fatty
acid. Assay conditions altered MGAT's apparent relative preferences for potential
monoradylglycerol substrates. The presence of phospholipids and of MGAT's 1,2
diacyl-sn-glycerol product increased the enzyme's apparent preference for its 2
monoacyl-sn-glycerol substrate by selectively increasing the apparent Vmax 2.7
fold only when 2-monoC18:1-sn-glycerol was the substrate. Thus, in addition to
previously reported regulation of MGAT by phospholipids and intracellular lipid
second messengers, these studies lend additional support to the hypothesis that
changes in other membrane-associated lipids, such as long-chain fatty acids and
diradylglycerols, may also profoundly alter the activity of MGAT.
PMID- 9558326
TI - Site-directed mutagenesis probing the catalytic role of arginines 165 and 166 of
human cytomegalovirus protease.
AB - Human cytomegalovirus (CMV) is a member of the Herpesviridae family of viruses
that also includes herpes simplex viruses (HSV-1 and HSV-2), varicella-zoster
virus (VZV), human herpes virus-6, 7, and 8 (HHV-6, HHV-7, and HHV-8), and
Epstein-Barr virus (EBV). Each member of this family encodes a serine protease
that is a potential target for antiviral therapeutic intervention. We recently
reported the crystal structure of CMV proteases [Qiu, X., Culp, J. S., DiLella,
A. G., Hellmig, B., Hoog, S. S., Janson, C. A., Smith, W. W., and Abdel-Meguid,
S. S. (1996) Nature 383, 275-279] and proposed that the highly conserved Arg165
and Arg166 residues are involved in stabilizing the oxyanion intermediate in
human herpes protease catalyzed reactions through the backbone NH and side chain,
respectively. In the current study, site-directed mutagenesis was carried out to
probe the catalytic function of these two amino acid residues. Substitution of
Arg166 with an alanine has led to ablation of enzymatic activity without
detectable change in CMV protease conformation, supporting suggestions from the
crystal structure that Arg166 side chain plays a major role in catalysis. The
wild-type has a Km = 138 +/- 17 microM and kcat = 19.9 +/- 1.1 min-1, while R166A
has only residual activity, with a kcat = 0.012 +/- 0.001 min-1 and an unaltered
Km = 145 +/- 18 microM. In the crystal structure, the side chain of Arg166 was
shown previously to hold a water molecule that can act as a hydrogen-bond donor
to the oxyanion and was thus proposed to stabilize the oxyanion intermediate.
However, kinetic characterization of the mutant R165A only reveals a 2.7-fold
lower activity than wild-type, with a Km = 166 +/- 19 microM and a kcat = 7.4 +/-
0.4 min-1. These results confirm that Arg165 side chain is not involved in the
stabilization of the oxyanion. It is likely that Arg165 only utilizes the
backbone NH for catalysis as suggested by the crystal structure.
PMID- 9558328
TI - Electrostatic stabilization in methionine aminopeptidase from hyperthermophile
Pyrococcus furiosus.
AB - The thermostability of methionine aminopeptidase from a hyperthermophile P.
furiosus (PfMAP) was extremely high: the denaturation temperature was 106.2
degreesC at pH 10.2. To explore the contribution of electrostatic interaction to
the superior thermostability of PfMAP, the thermostability of PfMAP was examined
by differential scanning calorimetry (DSC) in various salt concentrations in the
acidic region far from the isoelectric point of PfMAP. (1) In 20 mM glycine
buffer, the DSC curve of PfMAP exhibited a single peak. Transition temperatures
(Tm) were lowered with decreasing pH from 4 to 3. The heat denaturation of PfMAP
was not reversible. (2) Denaturation enthalpy (DeltaH) measured at different pHs
linearly correlated with Tm up to 102 degreesC, suggesting that the denaturation
heat capacity (DeltaCp) for PfMAP is constant up to 100 degreesC. DeltaCp was
estimated to be 0.82 J K-1 g-1. (3) In the presence of 10-100 mM KCl at pH 3.2,
two peaks appeared on the DSC curves. The first peak shifted to lower
temperatures with increasing concentration of KCl and, oppositely, the second one
to higher temperatures. It was found that the first and second peaks originated
from the heat denaturation of the native form of PfMAP and the melting of the non
native associated form having molten globule-like structure, respectively, judged
from the CD spectra and ultracentrifugation analyses. This indicates the
following: first, the attractive electrostatic interaction is an important factor
in stabilizing the native form of PfMAP; second, the presence of KCl stimulates
the formation of the molten globule-like state of PfMAP and stabilizes it. (4) In
a comparison of the sequence and crystal structure of PfMAP, which has been
recently determined (1xgs.pdb), with those of MAP from Escherichia coli (EcMAP),
it was predicted that the extra four short-range ion pairs less than 3 A involved
in PfMAP are crucial candidates as determinants for the superior thermostability
of PfMAP.
PMID- 9558327
TI - Identification of amino acid residues associated with modulation of flavin
containing monooxygenase (FMO) activity by imipramine: structure/function studies
with FMO1 from pig and rabbit.
AB - The activity of the flavin-containing monooxygenase (FMO) can be modulated by a
number of nitrogen-containing compounds in a manner that is both isoform and
modulator-dependent. We now show that the direction (activation or inhibition)
and extent of modulation can also be dependent on substrate concentration.
Imipramine activates methimazole metabolism catalyzed by rabbit FMO1 or FMO2 at
methimazole concentrations greater than 50 or 100 microM, respectively, and
inhibits at lower methimazole concentrations. The extent of the activation
increases as the substrate concentration increases, and the extent of inhibition
increases as the substrate concentration decreases. With either inhibition or
activation, the magnitude of the effect shows a similar, direct dependency on
imipramine concentration. In contrast, imipramine inhibits the metabolism of
methimazole catalyzed by pig FMO1 at all substrate concentrations. The structural
basis for this unique ortholog difference between the responses of rabbit and pig
FMO1 to imipramine was studied by random chimeragenesis and site-directed
mutagenesis. Results with chimeras indicated that modulation of FMO1 activity by
imipramine is controlled to a great extent by two areas of the FMO primary
structure (residues 381-432 and 433-465). Four amino acids in these regions
(positions 381, 400, 420 and 433) and one additional residue (position 186) were
identified by site-directed mutagenesis as primary determinants of the imipramine
response. When the residues at these positions in rabbit FMO1 are exchanged for
the corresponding residues of pig FMO1, a mutant with the functional properties
of pig FMO1 is produced. Our results suggest that the response of FMO1 to
imipramine involves a distribution between two sites that is regulated by
structural features that do not alter the overall binding. The inhibition
observed, although it appears to be competitive, likely does not involve
competition for a binding site since alteration of imipramine metabolism has no
effect on the parameters of methimazole metabolism.
PMID- 9558329
TI - Penicillin biosynthesis: energy requirement for tripeptide precursor formation by
delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine synthetase from Acremonium
chrysogenum.
AB - In nonribosomal peptide formation by multifunctional enzymes, peptide synthetases
catalyze the activation and directed condensation of amino acids. The peptide
synthetase involved in penicillin biosynthesis (ACV synthetase) forms the
tripeptide delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine from the respective L
amino acids and ATP. So far, the energy requirements for the nonribosomal process
have not been clearly established. For ACV synthetase we show that ATP
consumption depends on the reaction conditions employed. By simultaneously
estimating peptide and AMP production by employing fluorescence detection and UV
spectroscopy, respectively, we have determined the energy consumption with high
accuracy. Under unfavorable reaction conditions more than 20 mol of ATP are
consumed/mol of tripeptide formed, while optimal conditions permit the expected
energy requirement of one ATP for each carboxyl group activation, corresponding
to three ATP for tripeptide formation. The third ATP is required for the
activation of L-valine to maintain the valyl-thioester stage for epimerization
and peptide bond formation, and this high-energy bond is sacrificed by hydrolytic
removal of the product. No extra energy is required for the directed transport in
peptide elongation. Additional energy consumed has been traced to hydrolytic loss
of activated intermediates, as has been shown by the analysis of incomplete
reaction mixtures.
PMID- 9558331
TI - Proteolytic fragments of the Alzheimer's disease associated presenilins-1 and -2
are phosphorylated in vivo by distinct cellular mechanisms.
AB - The majority of familial Alzheimer's disease mutations are linked to the recently
cloned presenilin (PS) genes, which encode two highly homologous proteins (PS-1
and PS-2). Full-length PS proteins undergo endoproteolytic cleavage within their
hydrophilic loop domain resulting in the formation of C-terminal (CTF) and N
terminal fragments (NTF). PS-2 was found to be phosphorylated as a full-length
protein within its N-terminal domain. In contrast, PS-1 is phosphorylated
selectively after proteolytic processing within its approximately 20 kDa CTF
involving protein kinase C (PKC) and/or protein kinase A (PKA). We now have found
that the CTF of the highly homologous PS-2 is also phosphorylated. Surprisingly,
the PS-2 CTF is not phosphorylated by PKC or PKA. Instead, the PS-2 CTF is
constitutively phosphorylated in vivo by serine/threonine protein kinases, which
are independent of phorbol ester and intracellular cAMP. In vitro the large
hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be
phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC.
Quantitative analysis of in vitro phosphorylation demonstrates the presence of
two phosphorylation sites for CK-1 and a single site for CK-2. A deletion
analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic
sequence containing three potential phosphorylation sites for CKs (serines 327,
330, and 335). These data suggest that CK type protein kinases phosphorylate the
CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the
potential phosphorylation sites are located directly adjacent to the recently
identified caspase cleavage sites.
PMID- 9558330
TI - Selective inactivation of parvulin-like peptidyl-prolyl cis/trans isomerases by
juglone.
AB - In contrast to FK506 binding proteins and cyclophilins, the parvulin family of
peptidyl-prolyl cis/trans isomerases (PPIases; E.C. 5.2.1.8) cannot be inhibited
by either FK506 or cyclosporin A. We have found that juglone, 5-hydroxy-1,4
naphthoquinone, irreversibly inhibits the enzymatic activity of several
parvulins, like the E. coli parvulin, the yeast Ess1/Ptf1, and human Pin1, in a
specific manner, thus allowing selective inactivation of these enzymes in the
presence of other PPIases. The mode of action was studied by analyzing the
inactivation kinetics and the nature of products of the reaction of E. coli
parvulin and its Cys69Ala variant with juglone. For all parvulins investigated,
complete inactivation was obtained by a slow process that is characterized by
pseudo-first-order rate constants in the range of 5.3 x 10(-)4 to 4. 5 x 10(-)3 s
1. The inactivated parvulin contains two juglone molecules that are covalently
bound to the side chains of Cys41 and Cys69 because of a Michael addition of the
thiol groups to juglone. Redox reactions did not contribute to the inactivation
process. Because thiol group modification was shown to proceed 5-fold faster than
the rate of enzyme inactivation, it was considered as a necessary but not
sufficient condition for inactivation. When measured by far-UV circular dichroism
(CD), the rate of structural alterations following thiol group modification
parallels exactly the rate of inactivation. Thus, partial unfolding of the active
site of the parvulins was thought to be the cause of the deterioration of PPIase
activity.
PMID- 9558332
TI - Site-directed mutagenesis combined with chemical modification as a strategy for
altering the specificity of the S1 and S1' pockets of subtilisin Bacillus lentus.
AB - By combining site-directed mutagenesis with chemical modification, we have
altered the S1 and S1' pocket specificity of subtilisin Bacillus lentus (SBL)
through the incorporation of unnatural amino acid moieties, in the following
manner: WT --> Cysmutant + H3CSO2SR --> Cys-SR, where R may be infinitely
variable. A paradigm between extent of activity changes and surface exposure of
the modified residue has emerged. Modification of M222C, a buried residue in the
S1' pocket of SBL, caused dramatic changes in kcat/KM, of an up to 122-fold
decrease, while modification of S166C, which is located at the bottom of the S1
pocket and is partially surface exposed, effected more modest activity changes.
Introduction of a positive charge at S166C does not alter kcat/KM, whereas the
introduction of a negative charge results in lowered activity, possibly due to
electrostatic interference with oxyanion stabilization. Activity is virtually
unaltered upon modification of S156C, which is located toward the bottom of the
S1 pocket and surface exposed and whose side chain is solvated. An unexpected
structure-activity relationship was revealed for S166C-SR enzymes in that the
pattern of activity changes observed with increasing steric size of R was not
monotonic. Molecular modeling analysis was used to analyze this unprecedented
structure-activity relationship and revealed that the position of the beta-carbon
of Cys166 modulates binding of the P1 residue of the AAPF product inhibitor.
PMID- 9558333
TI - Identification of a new all-trans-retinol metabolite produced through a new
retinol metabolic pathway.
AB - In vitro incubation of all-trans-retinol (atROL) with kidney homogenate from
vitamin A-deficient and retinoic acid-supplemented (VAD-RAS) female rats produces
a new retinol metabolite. Reverse-phase (RP) and normal-phase (NP) high
performance liquid chromatography (HPLC) analysis showed that this metabolite
coelutes with the unknown all-trans-retinol (atROL) metabolite previously found
in the day 10 conceptus and kidneys of vitamin A-deficient rats maintained on all
trans-retinoic acid (VAD-RA) and given 2 microg of [3H]atROL. Normal-phase (NP)
HPLC purification of the metabolite collected from a RP HPLC column further
separated the radiolabeled material into two components. The two isolated
compounds have identical or very similar spectroscopic properties. Their nuclear
magnetic resonance (1H NMR) and mass spectra (MS) indicated that they are
isomers. Spectroscopic studies of the metabolites and their derivatives showed
that they are nine-carbon fragments resulting from an oxidative cleavage of the
side chain of atROL. The cleavage occurs at C-9, and the product is then oxidized
to a keto group. The primary hydroxy group from atROL is preserved in the
metabolite. A sulfide bridge is formed between C-11 and C-14, which interrupts
the conjugation. The formation of the new metabolites, possessing a 2,5
dihydrothiophene ring, is catalyzed by an enzyme(s) located in the cytosolic
fraction of kidneys. The process represents a new retinol metabolic pathway;
however, its biological significance is unknown.
PMID- 9558334
TI - Inhibition kinetics and affinity labeling of bacterial squalene:hopene cyclase by
thia-substituted analogues of 2, 3-oxidosqualene.
AB - Five sulfur-containing analogues of 2,3-oxidosqualene (OS) were evaluated as
inhibitors of squalene:hopene cyclase (SHC) from Alicyclobacillus acidocaldarius.
In these analogues, sulfur replaces carbons at C-6, C-10, C-14, C-18, or C-19 of
OS. Each analogue was a submicromolar inhibitor of SHC with IC50 values ranging
from 60 to 570 nM. Enzyme inhibition kinetic analysis was performed using
homogeneous recombinant A. acidocaldarius SHC. While analogues 9 (S-14, Ki = 109
nM, kinact = 0.058 min-1) and 11 (S-19, Ki = 83 nM, kinact = 0.054 min-1) were
time-dependent inhibitors of SHC, analogues 7 (S-6, Ki = 127 nM) and 8 (S-10, Ki
= 971 nM) showed no time dependency with SHC. Analogue 10 (S-18) was the most
potent inhibitor and showed time-dependent irreversible inhibition (Ki = 31 nM,
kinact = 0.071 min-1). Kinetic analysis for the five analogues with purified rat
liver OSLC was conducted to compare the vertebrate and prokaryotic enzymes.
Affinity labeling experiments, using either [17-3H]10 or [22-3H]10 with crude and
with pure recombinant SHC, clearly showed specific labeling. A single major
radioactive band at 72 kDa on SDS-PAGE indicated that irreversible covalent
modification of SHC had occurred. These results suggest that the presence of
sulfur at C-18 of OS can interrupt the cyclization and that an intermediate
partially cyclized cation may be captured by a nucleophilic residue of the SHC
active site.
PMID- 9558335
TI - An AP-1 site in the nerve growth factor promoter is essential for 1, 25
dihydroxyvitamin D3-mediated nerve growth factor expression in osteoblasts.
AB - 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the active metabolite of vitamin D,
induces nerve growth factor (NGF) synthesis in a variety of different cell lines.
The mechanism by which 1,25(OH)2D3 induces NGF, however, is poorly understood. We
used a series of full-length and truncated NGF promoter-human growth hormone
(hGH) reporter gene plasmids to investigate the mechanism of 1,25(OH)2D3-induced
NGF expression in osteoblasts. Untransfected rat osteosarcoma cells (ROS 17/2.8)
treated with 1,25(OH)2D3 showed a 2-fold increase in NGF expression compared to
control cells. ROS 17/2.8 osteosarcoma cells were transfected with the NGF-hGH
reporter plasmids and treated with 10(-)8 M 1,25(OH)2D3. The full-length NGF
promoter (-1800 to +120)-hGH reporter construct showed an approximately 2-fold
increase in hGH release. Plasmids with successive 5'-deletions showed enhanced
hGH expression in treated cells and control cells. A similar series of NGF
promoter-hGH reporter gene constructs, lacking the AP-1 site located within the
first intron of the NGF gene, were also transiently transfected into ROS 17/2.8
cells. When these cells were treated with the same dose of 1,25(OH)2D3, no
increase in hGH expression was seen compared to control cells, demonstrating that
this AP-1 site is essential for 1,25(OH)2D3-mediated NGF up-regulation. Since
1,25(OH)2D3 is known to activate the transcription of several genes through its
interaction with the vitamin D receptor (VDR), we performed a series of gel
electrophoretic mobility shift assays to determine if the VDR binds directly to
the AP-1 sequence. No evidence of VDR binding, either as a homodimer or as a
heterodimer, to the AP-1 sequence was observed. Treatment of ROS 17/2.8 cells
with 1,25(OH)2D3, however, resulted in an increase in AP-1 binding activity;
however, no significant changes in c-jun and c-fos levels were observed. Our data
show that in osteoblasts, 1,25(OH)2D3 induces NGF expression indirectly by
increasing AP-1 binding activity.
PMID- 9558336
TI - Ligand binding and covalent structure of an oxygen-binding heme protein from
Rhodobacter sphaeroides, a representative of a new structural family of c-type
cytochromes.
AB - The amino acid sequence of an oxygen-binding heme protein (SHP) from Rhodobacter
sphaeroides has been determined. The cysteines, which bind the single heme group
in the 112-residue protein, are located at positions 43 and 46. SHP is similar in
size to the large membrane-bound form of the class I cytochrome c5 of Azotobacter
vinelandii (116 residues) and in the location of the heme binding site at
positions 48 and 51. Two extra cysteines in SHP (residues 89 and 97) are located
in positions similar to those of cytochrome c5 (residues 98 and 101) and form a
disulfide bridge in both proteins. In total, four regions of alpha-helix are
predicted, covering 46% of the protein, which is comparable to that in other
small cytochromes. SHP is thus distantly related to small class I c-type
cytochromes but is representative of a distinct family by virtue of its high-spin
nature, the lack of a strong sixth ligand, and its capacity to bind oxygen.
Potentially, the most important characteristic of SHP is its ability to
transiently bind oxygen during autoxidation, which occurs with a half-life of 3
min with a 4-fold excess of O2. SHP also binds carbon monoxide, azide, and
cyanide. The kinetics of reduction by free flavins indicate that SHP is less
reactive than other class I cytochromes c and that the heme is less accessible to
solvent. There is localized positive charge (+3) at the site of reduction of SHP,
although the overall protein charge is -2. This may account in part for the
ability of SHP to bind anions.
PMID- 9558337
TI - Hepatocyte growth factor/scatter factor has distinct classes of binding site in
heparan sulfate from mammary cells.
AB - Hepatocyte growth factor/scatter factor (HGF/SF) is a heparan sulfate (HS)
binding growth factor and morphogen for mammary epithelial cells that is produced
by mammary stromal fibroblasts. HS chains, purified as peptidoglycans from a
panel of cell lines representative of the ductal epithelial cell (Huma 123), the
myoepithelial cell (Huma 109), the stromal fibroblast (Rama 27), and malignant
mammary epithelial cells (MCF-7 and ZR-75), were used in a biosensor-based assay
to identify the classes of HGF/SF-binding sites in the polysaccharide chains. At
least three distinct binding sites were identified. One site exhibits fast
association and fast dissociation kinetics [kass (1.4-7.7) x 10(6) M-1 s-1; kdiss
0. 0032-0.0096 s-1] and is present on the HS from benign Huma 123 epithelial
cells, Huma 109 myoepithelial-like cells, and ZR-75 malignant cells. The second
binding site, found on HS from the malignant MCF-7 cells, has slower HGF/SF
binding kinetics (kass 0.20 x 10(6) M-1 s-1; kdiss 0.00055 s-1). The third
binding site possesses fast association and slow dissociation kinetics (kass 1.1
x 10(6) M-1 s-1; kdiss 0.00020 s-1) and was found on the HS isolated from the
culture medium of the Huma 123 benign epithelial cells. The first and second
binding sites have a similar Kd, 1-3 nM, while the third binding site has a
considerably higher affinity for HGF/SF (Kd 200 pM). The three binding sites seem
to be mutually exclusive, since each sample of HS possessed just one of the
sites.
PMID- 9558338
TI - Nonproteolytic incorporation of protein ligands into human alpha 2-macroglobulin:
implications for the binding mechanism of alpha 2-macroglobulin.
AB - alpha 2-Macroglobulin (alpha 2M) is a complex tetrameric protein of 718 kDa. In
native alpha 2M, each of the four subunits contains a thiol ester between the
side chains of Cys949 and Gln952. Cleavage of the thiol ester with small
nucleophiles destabilizes the native conformation and causes a major
conformational change in alpha 2M, which leads to exposure of receptor binding
sites and a change in electrophoretic mobility. Recently it has been shown that
nucleophilic cleavage of the four thiol esters in alpha 2M is a reversible
process with energy requirements dependent on the nucleophile [Gron, H.,
Thogersen, I. B., Enghild, J. J., and Pizzo, S. V. (1996) Biochem. J. 318, 539
545]. The present study is a further investigation of the properties of alpha 2M
with cleaved thiol esters and the potential for incorporation of protein ligands
at the site of the thiol ester. The thiol ester in alpha 2M was cleaved by NH3.
After removal of excess NH3, the alpha 2M derivative was incubated with excess
protein ligand (hen egg lysozyme or bovine insulin) at 23, 37, or 50 degreesC,
leading to covalent incorporation of the ligands in alpha 2M as analyzed by SDS
PAGE, gel filtration, and centrifugal microfiltration. Receptor binding studies
and native pore-limit PAGE confirmed that the alpha 2M derivatives with ligand
incorporated remained in the receptor-recognized, "fast" migrating conformation.
This is the first demonstration of nonproteolytic, covalent incorporation of
protein ligands into receptor-recognized alpha 2M.
PMID- 9558339
TI - Recognition properties of a sequence-specific DNA binding antibody.
AB - A sequence-specific DNA-binding antibody was previously generated by
incorporating a 17 amino acid alpha-helix from the DNA-binding domain of the
transcription factor TFEB into the HCDR3 site of a recombinant human Fab
fragment. The recombinant DNA-binding antibody, called Fab-E box, binds the TFEB
recognition sequence CACGTG (an E box site) with a 5-10-fold lower affinity than
TFEB. Here, we have determined the precise kinetics of interaction of Fab-E box
with DNA and show that the lower affinity of Fab-E box relative to TFEB for E box
DNA is due to a higher dissociation rate. DNase I protection assays show Fab-E
box physically interacts with one half-site of the E box. Additional DNA target
sites of Fab-E box were identified by DNase I protection assays. A compilation of
these binding sites indicates that the recognition elements for Fab-E box binding
include a half-site of the E box, CAW, with an 8 bp consensus sequence identified
as YNYYCAWW. Thus, the DNA determinants for Fab-E box recognition extend beyond
one-half site of the E box sequence, with preferences for pyrimidines and A+T
rich sequences in the 5' and 3' outer regions of the binding site, respectively.
Apparent dissociation constants of Fab-E box for a subset of these target DNA
sequences are 5-10-fold greater than the DNA-binding affinity of the antibody
with the E box site. Therefore, these results identify important DNA specificity
determinants for high-affinity binding by Fab-E box.
PMID- 9558340
TI - Properties of overlapping EREs: synergistic activation of transcription and
cooperative binding of ER.
AB - We have designed a novel estrogen-responsive unit, overERE, which consists of two
overlapping ERE separated by 5 bp (center-to-center). In gel retardation assays,
this sequence forms a low-mobility complex that migrates like an estrogen
receptor tetramer. The receptor-overERE complex was specific and was supershifted
by anti-ER H222 antibodies. Dose response studies showed that the formation of
the receptor tetramer-overERE complex was cooperative. Truncated receptors were
used to assess the contribution of the receptor domains. Deletion of the E domain
of the ER prevented the formation of an ER-tetramer complex, which reflects a
novel function of this receptor domain. In transfection experiments, 17-beta
estradiol activated transcription from an overERE-containing promoter 4-6 times
better than from an ERE-containing promoter. This synergistic effect was observed
using either the natural hormone (17-beta-estradiol) or xenoestrogens (phenol
red, chlordane). We conclude that two overlapping estrogen-responsive elements
can elicit synergistic induction of transcription.
PMID- 9558341
TI - Saccharomyces cerevisiae possesses two functional homologues of Escherichia coli
endonuclease III.
AB - We previously identified two distinct genes of Saccharomyces cerevisiae
redoxyendonuclease (SCR1 and SCR2) which possess a high degree of sequence
similarity to Escherichia coli endonuclease III [Augeri, L., Lee, Y. M., Barton,
A. B., and Doetsch, P. W. (1997) Biochemistry 36, 721-729]. The proteins encoded
by SCR1 and SCR2 were overexpressed in E. coli and purified to apparent
homogeneity. Both proteins recognized and cleaved DNA substrates containing
dihydrouracil, 2,6-diamino-4-hydroxy-5N-methylformamidopyrimidine (FaPy-7-MeGua),
and abasic sites but not DNA substrates containing uracil or 8-oxoguanine.
Purified Scr2, but not Scr1, possesses spectral properties which indicate the
presence of an iron-sulfur center. Kinetic parameters for Scr1 and Scr2 were
determined by using an oligonucleotide containing a single dihydrouracil.
Analysis of the deduced amino acid sequences of Scr1 and Scr2 suggests that Scr2
bears an iron-sulfur motif, while Scr1 does not have this motif. However, Scr1
has a long, positively charged N-terminus that could be a mitochondrial transit
sequence. Targeted gene disruption of SCR1 and SCR2 produced a double mutant that
had no detectable enzymatic activity against the dihydrouracil-containing
substrate. Northern blot analysis showed that SCR1 was induced by menadione, but
SCR2 was not. These results indicate that although Scr1 and Scr2 are both
functional homologues of E. coli endonuclease III, they differ from each other
with respect to their amino acid sequences and inducibility by DNA damaging
agents, suggesting that their precise biological roles may be different.
PMID- 9558342
TI - Role of base G-2 of pre-tRNAfMet in cleavage site selection by Escherichia coli
RNase P in vitro.
AB - In this study, a protocol for the purification of fully active Escherichia coli
RNase P holoenzyme from a strain overproducing both the C5 protein and the M1 RNA
components is described. A total of 0. 8 mg of homogeneous enzyme, with a 1:1
protein/RNA subunit stoichiometry, was recovered from a 1 L bacterial culture. In
addition, a convenient and reliable method based on capillary gel electrophoresis
was developed to measure initial rates of pre-tRNA maturation by RNase P. Using
these tools, the kinetic parameters of cleavage by RNase P of various mutants of
pre-tRNAfMet showing maturation defects in vivo [Meinnel and Blanquet (1995) J.
Biol. Chem. 270, 15906-15914] were investigated in vitro and the locations of
cleavage sites were determined from the length of the various products of the
reaction. The nucleotide at position -2 of pre-tRNAfMet is shown to be important
only in the selection of the cleavage site, whereas it has no role in the
efficiency of the reaction. It is concluded that base G-2 acts as an
antideterminant by preventing an alternative cleavage by RNase P. In addition,
the presence of G-2 alone is enough to fully compensate for the lack of a G at
position +1 of pre-tRNAfMet.
PMID- 9558344
TI - Unexpected electrophoretic migration of RNA with different 3' termini causes a
RNA sizing ambiguity that can be resolved using nuclease P1-generated sequencing
ladders.
AB - It has been widely believed that the electrophoretic migration difference of
otherwise identical RNAs with a P versus OH terminus would be the same as occurs
for DNA, a fairly reproducible approximately 1/2 nucleotide (nt) offset. RNA with
a 5'-OH indeed migrates =1 nt slower than if it had a 5'-P. Surprisingly,
however, RNA with a 3'-OH terminus (generated by many cellular RNases of
interest) migrates anywhere from approximately 1/4 to approximately 2 nts slower
than the otherwise identical molecule with a 3'-P or 2', 3'-cyclic-P terminus (as
present on standard RNase-generated sequencing ladders). This previously
unrecognized variability in electrophoretic migration offset causes a 1-2 nt
ambiguity in a commonly used method of RNA size determination. We also show two
ways to overcome this problem and enable rigorous sizing of 3'-OH terminating
RNAs. Most convenient is to use sequencing standards generated by nuclease P1,
which is generally sequence-nonspecific but we show becomes G-specific or A
preferential under certain reaction conditions.
PMID- 9558343
TI - Expression, purification, and initial kinetic characterization of the large
subunit of the human mitochondrial DNA polymerase.
AB - Faulty replication of the human mitochondrial genome is thought to be the cause
of many diseases; moreover, the low selectivity of the mitochondrial DNA
polymerase has been implicated as the cause of many side effects observed in the
treatment of viral infections such as HIV. To better understand how the
mitochondrial genome is replicated, we cloned a cDNA encoding the large subunit
of human DNA polymerase gamma, the enzyme that replicates the mitochondrial
genome. The large subunit was recombinantly expressed and purified to near
homogeneity. The purified enzyme demonstrated both polymerase and 3'-5'
exonuclease activity. The purified protein was examined in single nucleotide
incorporation assays, demonstrating that the enzyme had a maximum polymerization
rate of 3.5 s-1 and a dissociation rate from the DNA substrate of 0.03 s-1,
affording a calculated processivity of 116. The dissociation constants for the
enzyme binding to DNA and nucleoside triphosphate were 39 nM and 14 microM,
respectively. The 3'-5' exonuclease rate was measured at 0. 18 s-1. Though the
slow rate of polymerization suggests that the large subunit of human DNA
polymerase gamma may require accessory factors to increase its processivity of
polymerization, the kinetic parameters indicate that the large subunit of DNA
polymerase gamma could replicate the mitochondrial genome in a physiologically
relevant time frame. This study provides the initial characterization of the
large subunit of DNA polymerase gamma and establishes the baseline for
examination of the effects of accessory proteins such as the putative small
subunit.
PMID- 9558345
TI - The DNA binding domain of the human c-Abl tyrosine kinase preferentially binds to
DNA sequences containing an AAC motif and to distorted DNA structures.
AB - The c-Abl tyrosine kinase protein is implicated in the signaling pathway as well
as in transcription, DNA repair, apoptosis, and several other vital biological
processes essential for cell proliferation or differentiation. The interaction of
c-Abl with DNA is important for some of these functions, but the exact nature of
this interaction is still a matter of controversy. The present study addresses
the DNA-binding properties of the human c-Abl protein. Using CASTing experiments,
the consensus binding site 5'-AA/CAACAAA/C was determined. The central highly
conserved AAC triplet appears to constitute the crucial core element in the
binding sequences of the c-Abl protein. The c-Abl DNA-binding domain recognizes
specific sequences and interacts with deformed DNA structures such as four-way
junctions and bubble DNA containing a large single-stranded loop, as determined
by electromobility shift assay, melting temperature studies, and binding to
specific oligonucleotides covalently linked to beads. Additional competition
experiments suggest that the interaction mainly involves contacts within the
minor groove of the double helix. The DNA-binding properties of c-Abl are
reminiscent of those of high-mobility group (HMG)-like proteins such as LEF-1 and
SRY. However, the circular permutation and ring closure assays and DNA unwinding
experiments reveal that, unlike HMGs, c-Abl does not bend its target sequence. In
addition, it is shown that the protein potentiates the DNA relaxation activity of
topoisomerase I. These findings indicate that the interaction of c-Abl with DNA
is both sequence-selective and structure-dependent.
PMID- 9558346
TI - Dimerization of MoMuLV genomic RNA: redefinition of the role of the palindromic
stem-loop H1 (278-303) and new roles for stem-loops H2 (310-352) and H3 (355
374).
AB - Genomic RNAs from retroviruses are packaged as dimers of two identical RNA
molecules. In Moloney murine leukemia virus, a stem-loop structure (H1) located
in the encapsidation domain Psi (nucleotides 215-564) was postulated to trigger
RNA dimerization through base pairing between auto complementary sequences. The
Psi domain also contains two other stem-loop structures (H2 and H3) that are
essential for RNA packaging. Since it was suspected than H1 is not the only
element involved in RNA dimerization, we systematically investigated the
dimerization capacity of several subdomains of the first 725 nucleotides of
genomic RNA. The efficiency of dimerization of the various RNAs was estimated by
measuring their apparent dissociation constants, and the specificity was tested
by competition experiments. Our results indicate that the specificity of
dimerization of RNA nucleotides 1-725 is driven by motifs H1-H3 in domain Psi. To
define the relative contributions of these elements, RNA deletion mutants
containing different combinations of H1-H3 were constructed and further analyzed
in competition and kinetic experiments. Our results confirm the importance of H1
in triggering dimerization and shed new light on the mechanism of dimerization.
H1 is required to provide a stable dimer, probably through the formation of
extended intermolecular interactions. However, H1-mediated association is a slow
process that is kinetically enhanced by H3, and to a lesser extent by H2. We
suggest that they facilitate the recognition between the two RNAs, most likely
through their conserved GACG loops. Our results reinforce the idea that
dimerization and packaging are two closely related processes.
PMID- 9558347
TI - Spectroscopic, kinetic, and electrochemical characterization of heterologously
expressed wild-type and mutant forms of copper-containing nitrite reductase from
Rhodobacter sphaeroides 2.4.3.
AB - We report the development of a high-yield heterologous expression system for the
copper-containing nitrite reductase from a denitrifying variant of Rhodobacter
sphaeroides. Typical yields of wild-type protein are 20 mg L-1, which can be
fully loaded with copper. Nitrite reductase contains an unusual blue-green Type 1
copper center with a redox/electron transfer function and a nearby Type 2 center
where nitrite binds and is reduced to nitric oxide. The wild-type enzyme was
characterized by: (1) its blue-green Type 1 optical spectrum; (2) its EPR
spectrum showing rhombic character to its Type 1 center and nitrite perturbation
to its Type 2 center; (3) its 247-mV Type 1 midpoint potential which is low
relative to other Type 1 centers; and (4) its kinetics as measured by both steady
state and stopped-flow methods. The Type 2 copper reduction potential as
monitored by EPR in the absence of nitrite was below 200 mV so that reduction of
the Type 2 center by the Type 1 center in the absence of nitrite is not
energetically favored. The mutation M182T in which the methionine ligand of Type
1 copper was changed to a threonine resulted in a blue rather than blue-green
Type 1 center, a midpoint potential that increased by more than 100 mV above that
of the wild-type Type 1 center, and a somewhat reduced nitrite reductase
activity. The blue color and midpoint potential of M182T are reminiscent of
plastocyanin, but the Type 1 cupric HOMO ground-state electronic g value and
copper hyperfine properties of M182T (as well as cysteine and histidine ENDOR
hyperfine properties; see next paper) were unchanged from those of the blue-green
native Type 1 center. His287 is a residue in the Type 2 region whose imidazole
ring was thought to hydrogen bond to the Type 2 axial ligand but not directly to
Type 2 copper. The mutation H287E resulted in a 100-fold loss of enzyme activity
and a Type 2 EPR spectrum (as well as ENDOR spectra; see next paper) which were
no longer sensitive to the presence of nitrite.
PMID- 9558348
TI - Electronic structural information from Q-band ENDOR on the type 1 and type 2
copper liganding environment in wild-type and mutant forms of copper-containing
nitrite reductase.
AB - Q-band ENDOR elucidated proton and nitrogen hyperfine features to provide spin
density information at ligands of blue-green Type 1 and catalytic Type 2 copper
centers in nitrite reductase. The blue-green Type 1 center of nitrite reductase
has a redox, electron-transfer role, and compared to the blue center of
plastocyanin, it has the following structural differences: a shortened Cu-Smet
bond length, a longer Cu-Scys bond length, and altered ligand-copper-ligand bond
angles (Adman, E. T., Godden, J. W., and Turley, S. (1995) J. Biol. Chem. 270,
27458-27474). The hyperfine couplings of the two Type 1 histidine (N delta)
ligands showed a larger percentage difference from each other in electron spin
density than previously reported for other blue Type 1 proteins, while the
cysteine beta-proton hyperfine couplings, a measure of unpaired p pi spin density
on the liganding cysteine sulfur, showed a smaller electron spin density. A
mutation of the Type 1 center, M182T, having the copper-liganding Met182
transformed to Thr182, caused the center to revert to an optically "blue" center,
raised its redox potential by approximately 100 mV, and led to the loss of
activity (prior paper). Surprisingly, in M182T there was no change from native
Type 1 copper either in the histidine or cysteine hyperfine couplings or in g
values and Cu nuclear hyperfine couplings. The conclusion is that the optical and
redox alterations due to changed Type 1 methionine ligation need not be
concurrent with electron spin delocalization changes in the HOMO as reported from
its essential cysteine and histidines. A detailed picture of the nitrogen
couplings from the three histidine (N epsilon) ligands of the Type 2 center
indicated a substantial ( approximately 200%) electronic hyperfine inequivalence
of one of the histidine nitrogens from the other two within the Type 2 HOMO and
thus provided evidence for electronic distortion of the Type 2 site. In the
presence of the nitrite substrate, hyperfine couplings of all histidines
diminished. We suggest that this nitrite-induced decreased covalency would
correlate with an increased Type 2 redox potential to assist electron transfer to
the Type 2 center. Dipole-coupled, angle-selected exchangeable proton features,
observed over a range of g values, predicted a ligand-water proton distance of
2.80 A from copper, and these water protons were eliminated by nitrite. His287 is
not a Type 2 ligand but is positioned to perturb an axial water or a nitrite of
Type 2 copper. In the presence of nitrite the mutant H287E showed no evidence for
the loss of water protons and no diminished ligand histidine covalency. H287E has
vastly diminished activity (prior paper), and the ENDOR information is that NO2-
does not bind to Type 2 copper of H287E. In summary, the electronic information
from this study of native and suitably chosen mutants provided a test of the
highest occupied molecular orbital (HOMO) wave function at Type 1 and Type 2
coppers and an intimate electronic insight into functional enzymatic properties.
PMID- 9558349
TI - NADPH-flavodoxin reductase and flavodoxin from Escherichia coli: characteristics
as a soluble microsomal P450 reductase.
AB - In addition to their endogenous roles as an activation system for various
Escherichia coli metabolic pathways, the soluble flavoproteins flavodoxin (Fld)
and NADPH-flavodoxin (ferredoxin) reductase (Fpr) can serve as an electron
transfer system for microsomal cytochrome P450s. Furthermore, since Fld and Fpr
are structurally similar to the functional domains (FMN binding and NADPH/FAD
binding domains, respectively) of NADPH-cytochrome P450 reductases (P450
reductases), these bacterial proteins represent a potentially useful model system
for eukaryotic P450 reductases. Here we delineate similarities and differences
between the E. coli Fpr-Fld system and rat P450 reductase as electron donors to
bovine 17alpha-hydroxylase/17,20-lyase P450 (P450c17). Importantly, recombinant
Fpr, in combination with recombinant Fld, supports both the hydroxylase and lyase
activities of P450c17 to the same proportional extent (hydroxylase-to-lyase
ratio) as does P450 reductase. Maximum P450c17 turnover [5-6 mol of 17alpha-OH
progesterone (mol of P450c17)-1 min-1] was achieved using a large molar excess
(50-100-fold over P450c17) of a 1:1 ratio of Fpr-Fld, although this rate was an
order of magnitude less than the maximal P450 reductase-supported activity. Using
these conditions, we have examined the effects of increasing ionic strength and
the presence of cytochrome b5 (b5) on these two systems. Critical Fld-P450c17
electrostatic interactions are disrupted at moderate ionic strength (>100 mM
NaCl) as evidenced by significant inhibition (>50%) of Fpr-Fld-supported P450c17
activity while much higher ionic strength (300 mM NaCl) is required to disrupt
P450 reductase-P450c17 interactions to the same extent. Interestingly, cytochrome
b5 was found to dramatically inhibit both P450 reductase- and Fpr-Fld-supported
P450c17 progesterone 17alpha-hydroxylase activity while in contrast 17alpha-OH
pregnenolone lyase activity was stimulated by b5. Investigation of the fate of
reducing equivalents from NADPH added to Fpr under aerobic conditions revealed
that the majority of the protein-bound FAD of Fpr is converted to the
hydroquinone form. In constrast, the FMN of Fld is reduced by Fpr to a stable
blue, neutral semiquinone which serves as the predominant electron donor to
P450c17 in reconstitution assays. Thus, while the Fpr-Fld system and P450
reductase are fundamentally different with respect to their electrostatic
interactions with P450c17, their ability to support maximal P450c17 turnover, and
the FMN redox states (one-electron-reduced for Fld and two-electron-reduced for
P450 reductase) capable of transferring electrons to microsomal cytochrome P450s,
these differences do not appear to influence the relative catalytic efficiency of
the P450c17 hydroxylase and lyase reactions.
PMID- 9558350
TI - The flavoprotein component of the Escherichia coli sulfite reductase: expression,
purification, and spectral and catalytic properties of a monomeric form
containing both the flavin adenine dinucleotide and the flavin mononucleotide
cofactors.
AB - The flavoprotein component (SiR-FP) of the sulfite reductase from Escherichia
coli is an octamer containing one FAD and one FMN per polypeptide chain. SiR
FP60, a SiR-FP fragment starting with alanine-52, was overexpressed in E. coli
and purified as a monomer. The N-terminal part of the native protein contains
thus all the determinants required for the polymerization. SiR-FP60 retains both
FAD and FMN with comparable contributions of the two flavins and the catalytic
properties of SiR-FP. Thus, SiR-FP60 can be considered as a reliable simplified
model of the sulfite reductase flavoprotein component. The formation and the
stabilization of the neutral FMN semiquinone is thermodynamically favorable in
SiR-FP60 upon reduction with photoreduced deazaflavin, dithionite, or NADPH.
Generation of FMNH* is explained from a disproportionation of electrons between
the reduced and oxidized FMN moieties during an intermolecular reaction, as shown
with SiR-FP23, the FMN-binding domain of SiR-FP. The neutral FAD semiquinone can
be observed only within SiR-FP43, the isolated FAD-binding domain. NADPH was used
as a titrant or in excess to demonstrate that electron transfer is possible only
because the FMN cofactor is coupled to FAD as an electron acceptor in the
protein. The electron distribution within the various reduced forms of SiR-FP60
has been compared with that of the reduced forms of cytochrome P450 reductase,
bacterial cytochrome P450, and nitric-oxide synthase. Despite the conservation of
the bi-flavin-domain structure between these proteins over evolutionary time,
each of them provides significantly different flavin reactivities.
PMID- 9558352
TI - High hydrostatic pressure can reverse aggregation of protein folding
intermediates and facilitate acquisition of native structure.
AB - The present work demonstrates that high hydrostatic pressure can increase protein
folding by reducing nonspecific aggregation. Protein aggregation is one of the
main side reactions that competes with protein folding, and it typically results
from interactions among partially folded intermediates. It is known that
oligomeric proteins can be dissociated by the application of high hydrostatic
pressure. Since protein aggregates can be described as nonspecific protein
oligomers, it can be predicted that they can be completely or partially
dissociated by pressure. The enzyme rhodanese is prone to slow aggregation in 3.9
M urea, and it is widely used as a model for the folding of a protein which
readily aggregates. In the present study, it was demonstrated that this
aggregation process could be completely reversed under high hydrostatic pressure.
Release of the pressure led to renewed protein aggregation. In addition, it was
demonstrated that refolding of urea-denatured rhodanese at 2 kbar pressure led to
an increased yield of the native enzyme. The final recovery was increased up to
approximately 25% in contrast to approximately 5% recovery observed under ambient
pressure. The recovery can be further increased in the presence of 4 M glycerol,
where 56% of the protein was recovered by treatment with high pressure. These
observations suggest that some protein aggregation can be limited without the use
of chemical additives, and they show that the pressures needed to maintain
solubility are considerably less than those typically required for dissociation
of specific oligomers and unfolding of polypeptide chains.
PMID- 9558351
TI - Bacterial expression of a mitochondrial cytochrome c. Trimethylation of lys72 in
yeast iso-1-cytochrome c and the alkaline conformational transition.
AB - Saccharomyces cerevisiae iso-1-cytochrome c has been expressed in Escherichia
coli by coexpression of the genes encoding the cytochrome (CYC1) and yeast
cytochrome c heme lyase (CYC3). Construction of this expression system involved
cloning the two genes in parallel into the vector pUC18 to give the plasmid
pBPCYC1(wt)/3. Transcription was directed by two promoters, Lac and Trc, that
were located upstream from CYC1. Both proteins were expressed in the cytoplasm of
E. coli cells harboring the plasmid. Semianaerobic cultures grown in a fermentor
produced 15 mg of recombinant iso-1-cytochrome c per liter of culture. Attempts
to increase production by addition of IPTG suppressed the number of copies of the
CYC1 gene within the population. Wild-type iso-1-cytochrome c expressed with
pBPCYC1(wt)/3 in E. coli was compared to the same protein expressed in yeast. At
neutral pH, the two proteins exhibit indistinguishable spectroscopic and physical
(Tm, Em') characteristics. However, electrospray mass spectrometry revealed that
the lysyl residue at position 72 is not trimethylated by E. coli as it is by S.
cerevisiae. Interestingly, the pKa of the alkaline transition of the protein
expressed in E. coli is approximately 0.6 pKa unit lower than that observed for
the cytochrome expressed in yeast (8.5-8.7). 1H NMR spectroscopy of the
bacterially expressed cytochrome collected at high pH revealed the presence of a
third alkaline conformer that is not observed in the corresponding spectrum of
the cytochrome expressed in yeast. These observations suggest that Lys72 can
serve as an axial ligand to the heme iron of alkaline iso-1-ferricytochrome c if
it is not modified posttranscriptionally to trimethyllysine.
PMID- 9558353
TI - Effects of various imidazole ligands on heme conformation in endothelial nitric
oxide synthase.
AB - We have evaluated the influence of a series of substituted imidazoles on the heme
structure of endothelial nitric oxide synthase (eNOS). Optical, MCD, and EPR
spectra reveal widely differing effects on heme spin state and geometry. 1
Substituted imidazoles always yield low-spin heme complexes, but the size of the
2- and 4-substituent influences their structural effects on the heme. Methyl
substituents lead to low-spin complexes while the bulky phenyl group yields high
spin complexes. The only exception to this behavior is provided by 2
aminoimidazole. Although this compound has three functional groups which can
serve as an axial ligand to the heme, its binding to eNOS leads to a pure high
spin complex. This result can only be interpreted as due to a direct binding of 2
aminoimidazole to the guanidine binding subdomain of L-arginine. MCD spectra also
imply that an O-ligand is present in the low-spin resting eNOS, while EPR data
reveal the presence of two low-spin heme complexes in resting eNOS and its
imidazole complexes. EPR also distinguishes four different high-spin forms of
eNOS generated by different imidazole analogues. This series of ligands promises
to be useful in probing the subtle structural difference among the active sites
of three NOS isozymes and in developing selective inhibitors to these important
enzymes.
PMID- 9558354
TI - Context-dependent nature of destabilizing mutations on the stability of FKBP12.
AB - The context-dependent nature in which mutations affect protein stability was
investigated using the FK506-binding protein, FKBP12. Thirty-four mutations were
made at sites throughout the protein, including residues located in the
hydrophobic core, the beta-sheet, and the solvent-exposed face of the alpha
helix. Urea-induced denaturation experiments were used to measure the change in
stability of the mutants relative to that of the wild type (Delta DeltaGU-F). The
results clearly show that the extent of destabilization, or stabilization, is
highly context-dependent. Correlations were sought in order to link Delta DeltaGU
F to various structural parameters. The strongest correlation found was between
Delta DeltaGU-F and N, the number of methyl(ene) groups within a 6 A radius of
the group(s) deleted. For mutations of buried hydrophobic residues, a correlation
coefficient of 0.73 (n = 16,where n is the number of points) was obtained. This
increased to 0.81 (n = 24) on inclusion of mutations of partially buried
hydrophobic residues. These data could be superimposed on data obtained for other
proteins for which similarly detailed studies have been performed. Thus, the
contribution to stability from hydrophobic side chains, independent of the extent
to which a side chain is buried, can be estimated quantitatively using N. This
correlation appears to be a general feature of all globular proteins. The effect
on stability of mutating polar and charged residues in the alpha-helix and beta
sheet was also found to be highly context-dependent. Previous experimental and
statistical studies have shown that specific side chains can stabilize the N-caps
of alpha-helices in proteins. Substitutions of Ile56 to Thr and Asp at the N-cap
of the alpha-helix of FKBP12, however, were found to be highly destabilizing.
Thus, the intrinsic propensities of an amino acid for a particular element of
secondary structure can easily be outweighed by tertiary packing factors. This
study highlights the importance of packing density in determining the
contribution of a residue to protein stability. This is the most important factor
that should be taken into consideration in protein design.
PMID- 9558355
TI - Biochemical and physical characterization of the active FAD-containing form of
nitroalkane oxidase from Fusarium oxysporum.
AB - Nitroalkane oxidase from Fusarium oxysporum catalyzes the oxidation of
nitroalkanes to aldehydes with production of nitrite and hydrogen peroxide. The
enzyme has a molecular weight of 47 955 +/- 39, as determined by MALDI-TOF mass
spectrometry; under nondenaturing conditions, the aggregation state of the enzyme
is best described by a tetramer-dimer self-associating model, with an association
constant of (8.5 +/- 4.4) x 10(6) M-1 (pH 7.0 and 4 degreesC). The amino acid
composition and the N-terminal amino acid sequence do not match any known protein
or open reading frame. The inactive 5-nitrobutyl-1,5-dihydroflavin found in the
enzyme as purified was converted to FAD, allowing characterization of the active
FAD-containing enzyme. With nitroethane as substrate, the Vmax and Km values are
655 +/- 45 min-1 and 2.9 +/- 0.5 mM at pH 8.0 and 30 degreesC, respectively. One
mole of FAD per mole of monomer enzyme is required for catalysis. No activity can
be detected with amino acids or alpha-hydroxy acids as substrates. Reversible
removal of the FAD cofactor yields inactive enzyme. The properties of the FAD
cofactor in nitroalkane oxidase are within the range described for other
oxidases. The UV-visible absorbance spectrum of the active enzyme shows maxima at
446, 384, and 274 nm; the extinction coefficient at 446 nm is 11.7 mM-1 cm-1. The
neutral form of the flavin semiquinone, with maxima at 536 and 342 nm, is
kinetically stabilized. The UV-visible absorbance spectrum of the reduced enzyme
is typical of the anionic form of a flavin, with a peak centered at 335 nm. The
affinity of the enzyme for sulfite is low (Kd value of 13.8 +/- 0.9 mM at pH 7.0
and 25 degreesC); this result, along with the stabilization of the neutral flavin
semiquinone, suggests the presence of a weak positive charge near the N(1)-C(2)=O
of FAD. The reduction potential of the enzyme is -367 mV. Benzoate and
phenylacetic acid are competitive inhibitors, with Kis values of 5.1 +/- 0.6 and
13.1 +/- 2.3 mM, respectively. Binding of benzoate to nitroalkane oxidase results
in spectral changes similar to those observed with d-amino acid oxidase. The
absorbance spectrum of the flavin bound to nitroalkane oxidase is pH-dependent,
with a pKa value of 8.4.
PMID- 9558356
TI - Joint molecular modeling and spectroscopic studies of DNA complexes of a
bis(arginyl) conjugate of a tricationic porphyrin designed to target the major
groove.
AB - To target selectively the major groove of double-stranded B DNA, we have designed
and synthesized a bis(arginyl) conjugate of a tricationic porphyrin (BAP). Its
binding energies with a series of double-stranded dodecanucleotides, having in
common a central d(CpG)2 intercalation site were compared. The theoretical
results indicated a significant energy preference favoring major groove over
minor groove binding and a preferential binding to a sequence encompassing the
palindrome GGCGCC encountered in the Primary Binding Site of the HIV-1
retrovirus. Spectroscopic studies were carried out on the complexes of BAP with
poly(dG-dC) and poly(dA-dT) and a series of oligonucleotide duplexes having
either a GGCGCC, CCCGGG, or TACGTA sequence. The results of UV-visible and
circular dichroism spectroscopies indicated that intercalation of the porphyrin
takes place in poly(dG-dC) and all the oligonucleotides. Thermal denaturation
studies showed that BAP increased significantly the melting temperature of the
oligonucleotides having the GGCGCC sequence, whereas it produced only a
negligible stabilization of sequences having CCCGGG or TACGTA in place of GGCGCC.
This indicates a preferential binding of BAP to GGCGCC, fully consistent with the
theoretical predictions. IR spectroscopy on d(GGCGCC)2 indicated that the guanine
absorption bands, C6=O6 and N7-C8-H, were shifted by the binding of BAP,
indicative of the interactions of the arginine arms in the major groove. Thus,
the de novo designed compound BAP constitutes one of the very rare intercalators
which, similar to the antitumor drugs mitoxantrone and ditercalinium, binds DNA
in the major groove rather than in the minor groove.
PMID- 9558357
TI - Sequence specific collective motions in a winged helix DNA binding domain
detected by 15N relaxation NMR.
AB - The recognition between transcription factors and their DNA binding sites is a
highly dynamic process. During transcriptional regulation, transcription factors
must bind to or dissociate from their cognate DNA binding sites. The winged helix
DNA binding motif is one of many highly conserved DNA binding motifs identified
in transcription factors. Backbone dynamics has been studied on the 15N- and 2H
enriched winged helix family member Genesis. Our data show that the overall
motions of the single domain Genesis are better described by more than two
autocorrelation times (taum). Our data also demonstrate that Genesis shows
structure specific conformation exchange characterized by Rex. Therefore, our
results indicate that the structure of Genesis is highly dynamic and that
secondary structure elements in Genesis have collective motions in the nanosecond
to millisecond time scale. Since the winged helix DNA binding motif is highly
conserved, this unique dynamic property observed in Genesis is also likely to be
conserved in other winged helix family members and important in DNA binding.
PMID- 9558358
TI - Inhibition of calmodulin-activated smooth-muscle myosin light-chain kinase by
calmodulin-binding peptides and fluorescent (phosphodiesterase-activating)
calmodulin derivatives.
AB - Aspects of the biochemistry of calmodulin have been addressed that bear on its
cell biological role as a mediator of Ca2+ regulation. Calmodulin-binding
peptides derived from the amino acid sequence of smooth-muscle myosin light-chain
kinase (MLCK) were characterized as inhibitors of calmodulin activation of MLCK
catalyzed phosphorylation of the smooth-muscle regulatory light chain (MLC). MLCK
activity was determined by measuring the rate of formation of one of the reaction
products, ADP, in a coupled enzymatic assay by continuous fluorimetric monitoring
of NADH removal in 100 microM CaCl2 at ionic strength 0.15 M, pH 7.0 and 21
degreesC. The Km value of calmodulin was 3.5 nM, a value 16-35-fold greater than
the Kd value of calmodulin for MLCK [Torok, K., and Trentham D. R. (1994)
Biochemistry 33, 12807-12820]. The different Km and Kd values are most likely
associated with the rate-limiting step in MLC phosphorylation being associated
with product release from MLCK. The values of the inhibition constants, Ki, were
the following: Ac-R-R-K-W-Q-K-T-G-H-A-V-R-A-I-G-R-L-CONH2 (Trp peptide), 8.6 (+/
1. 4 sd) pM; Y4-analogue of Trp peptide (Tyr peptide), 7.3 (+/-0.1) nM; and A-R-R
K-W-Q-K-T-G-H-A-V-R-A-I-G-R-L-S-S (RS20-like peptide), 0. 11-0.39 nM. The Ki
values were consistent with kinetically determined Kd values of the peptides to
calmodulin. Kinetic determination of Kd values required the use of a
fluorescently labeled calmodulin, 2-chloro-(epsilon-amino-Lys75)-[6-(4-N, N
diethylamino-phenyl)-1,3,5-triazin-4-yl]-calmodulin (TA-calmodulin).1 Since, as
here, Lys75 is a convenient labeling site on calmodulin for the introduction of
fluorescent probes, the biological activity of the Lys-modified calmodulins was
evaluated. TA-calmodulin and calmodulin selectively modified by 1-N, N
dimethylaminonaphthalene-5-sulfonyl chloride (dansyl-C1) at Lys75 (dansyl
calmodulin) were characterized as activators of cyclic AMP phosphodiesterase
(PDE) and inhibitors of MLCK. The Km value for dansyl-calmodulin was equal to
that of calmodulin, and that of TA-calmodulin was 3.5-fold greater. TA-calmodulin
and Lys75-labeled dansyl-calmodulin thus distinguish between PDE and MLCK being
agonists to the former and antagonists to the latter.
PMID- 9558359
TI - Inhibition of type I and type II phospholipase A2 by phosphatidyl-ethanolamine
linked to polymeric carriers.
AB - We have previously shown that cell surface proteoglycans protect the cell
membrane from the action of extracellular phospholipase A2 (PLA2) enzymes [Dan,
P., Nitzan, D. W., Dagan, A., Ginsburg, I., and Yedgar, S. (1996) FEBS Lett. 383,
75-78]. Cell-impermeable PLA2 inhibitors (ExPLIs) were prepared by linking
phosphatidylethanolamine (PE) to polymeric carriers, specifically,
carboxymethylcellulose, heparin, or hyaluronic acid. The structure of these
inhibitors enables the incorporation of their PE moiety into the membrane while
the polymer remains at the membrane surface. In the present study, we show that
the ExPLIs are effective inhibitors of the hydrolysis of different phospholipids
in biological (Escherichia coli) and model (phospholipid vesicle) membranes, by
diverse types of PLA2 enzymes, specifically human recombinant synovial fluid and
C. atrox (type II), as well as Naja mocambique and porcine pancreatic (type I)
PLA2. It is proposed that the external polymers of the ExPLIs, which are anchored
to the membrane by the PE, mimic the naturally occurring cell surface
proteoglycans and similarly protect membranes from the action of exogenous PLA2.
PMID- 9558360
TI - Phosphorylation of the gamma subunit of the retinal photoreceptor cGMP
phosphodiesterase by the cAMP-dependent protein kinase and its effect on the
gamma subunit interaction with other proteins.
AB - Cyclic GMP phosphodiesterase, a key enzyme in phototransduction, is composed of P
alpha beta and two P gamma subunits. Interaction of P gamma with P alpha beta or
with the alpha subunit (T alpha) of transducin is crucial for the regulation of
cGMP phosphodiesterase in retinal photoreceptors. Here we have investigated
phosphorylation of P gamma by cAMP-dependent protein kinase and its functional
effect on the P gamma interaction with P alpha beta or T alpha in vitro. P gamma,
but not P gamma complexed with T alpha (both GTP and GDP forms), is
phosphorylated. Measurement of 32P radioactivity in phosphorylated P gamma,
analysis of phosphorylated P gamma by laser mass spectrometry, identification of
phosphoamino acid, and phosphorylation of mutant forms of P gamma indicate that
only threonine 35 in P gamma is phosphorylated. Phosphorylation of P gamma
mutants also reveals that the C and N terminals of P gamma which are required for
the regulation of P alpha beta functions are not involved in the P gamma
phosphorylation but that arginine 33, which is ADP-ribosylated by an endogenous
ADP-ribosyltransferase, is required for the phosphorylation. Phosphorylated P
gamma has a higher inhibitory activity for trypsin-activated cGMP
phosphodiesterase than nonphosphorylated P gamma, indicating that the P gamma-P
alpha beta interaction is affected by P gamma phosphorylation. Nonphosphorylated
P gamma inhibits both the GTPase activity of T alpha and the binding of a
hydrolysis-resistant GTP analogue to T alpha, while P gamma phosphorylation
reduces these inhibitory activities. These observations suggest that a P gamma
domain containing threonine 35 is involved in the P gamma-T alpha interaction,
and P gamma phosphorylation regulates the P gamma-T alpha interaction. Our
observation suggests that P gamma phosphorylation by cAMP-dependent protein
kinase may function for the regulation of phototransduction in vertebrate rod
photoreceptors.
PMID- 9558361
TI - Chemical rescue of Klebsiella aerogenes urease variants lacking the carbamylated
lysine nickel ligand.
AB - Klebsiella aerogenes urease possesses a dinuclear metallocenter in which two
nickel atoms are bridged by carbamylated Lys217. To assess whether carbamate
specific chemistry is required for urease activity, site-directed mutagenesis and
chemical rescue strategies were combined in efforts to place a carboxylate group
at the location of this metal ligand. Urease variants with Lys217 replaced by
Glu, Cys, and Ala (K217E, K217C/C319A, and K217A proteins) were purified, shown
to be activated by incubation with small organic acids plus Ni(II), and
structurally characterized. K217C/C319A urease possessed a second change in which
Cys319 was replaced by Ala in order to facilitate efforts to chemically modify
Cys217; however, this covalent modification approach did not produce active
urease. Chemical rescue of the K217E, K217C/C319A, and K217A variants required 2,
2, and 10 h, respectively, to reach maximal activity levels. The highest activity
generated [224 micromol of urea degraded.min-1.(mg of protein)-1, for K217C/C319A
urease incubated with 500 mM formic acid and 10 mM Ni at pH 6.5] corresponded to
56% of that measured for in vitro activation of the wild-type apoprotein. While
the K217E apoprotein showed minimal structural perturbations, the K217C/C319A
apoprotein showed a disordering of some active site residues, and the K217A
apoprotein revealed a repositioning of His219 to allow the formation of a
hydrogen bond with Thr169, thus replacing the hydrogen bond between the amino
group of Lys217 and Thr169 in the native enzyme. Importantly, these structures
allow rationalization of the relative rates and yields of chemical rescue
experiments. The crystal structures of chemically rescued K217A and K217C/C319A
ureases revealed a return of the active site residues to their wild-type
positions. In both cases, noncovalently bound formate was structurally equivalent
to the Lys-carbamate as the bridging metallocenter ligand. We conclude that
carbamate-specific chemistry is not required for urease catalysis.
PMID- 9558362
TI - The impact of all-trans-retinoic acid on the coagulopathy of acute promyelocytic
leukemia.
PMID- 9558363
TI - Detection of infectious simian immunodeficiency virus in B- and T-cell lymphomas
of experimentally infected macaques.
AB - An increasing frequency of malignant lymphomas occurs among patients infected by
human immunodeficiency virus. Because of the close similarities to human
malignancies, we used a nonhuman primate model to study the pathogenesis of
simian immunodeficiency virus (SIV)-associated malignancies. Specifically, we
investigated (1) the presence of the SIV genome in tumor cells, (2) the presence
of coinfecting viruses, and (3) the presence of a rearrangement of the
immunoglobulin and c-myc genes. We observed 5 cases of non-Hodgkin's lymphomas (4
of B- and 1 of T-cell origin) among 14 SIV-infected cynomolgus monkeys. No c-myc
translocation was observed in the tumors, whereas B-cell lymphomas were
characterized either by a monoclonal (in 2 of 4) or by an oligoclonal (in 2 of 4)
VDJ rearrangements of the immunoglobulin heavy chain gene. Molecular, biological,
and immunological analyses did show the presence of infectious SIV in the tumor
cells of 1 T-cell and 2 oligoclonal B-cell lymphomas. Neither Simian T
lymphotropic nor Epstein-Barr viruses were detectable, whereas Simian herpes
virus Macaca fascicularis-1 was detectable at a very low copy number in 3 of 4 B
cell lymphomas; however, only 1 of these also harbored the SIV genome. These
results support the possibility that SIV may be directly involved in the process
of B or T lymphomagenesis occurring in simian acquired immunodeficiency syndrome.
PMID- 9558364
TI - Differential deactivation of human dendritic cells by endotoxin desensitization:
role of tumor necrosis factor-alpha and prostaglandin E2.
AB - The endotoxin (lipopolysaccharide)-induced cytokine response is followed by a
state of unresponsiveness to lipopolysaccharide (LPS) referred to as LPS
tolerance or endotoxin desensitization. LPS tolerance, which can be
experimentally induced in vitro and in vivo, is also known to occur in septic
disease. Here, we evaluated whether dendritic cells (DC), the most potent antigen
presenting cells, are also subject to this phenomenon. Single doses of LPS added
at the initiation of DC culture inhibited in a dose-dependent fashion the
production of tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10),
and IL-12, but not the production of IL-8, in response to a second LPS challenge
in day-5 DC. In addition, the LPS-induced expression of the CD83 maturation
antigen was inhibited in these cells. Moreover, the endocytic activity of DC
generated in the presence of LPS was dramatically reduced. DC desensitized with
LPS were potent stimulators of T-cell proliferation but poor inducers of
interferon-gamma (IFN-gamma) production in the allogeneic mixed leukocyte
reaction. TNF-alpha and prostaglandin E2, two major products of LPS stimulation,
could replace LPS for the induction of tolerance to LPS. Moreover, treatment of
desensitized DC with TNF-alpha plus prostaglandin E2 fully restored CD83
expression and partially restored IL-12 production as well as the IFN-gamma
inducing activity of DC in the mixed leukocyte reaction. Our data show that human
DC are highly susceptible to the induction of LPS tolerance, which seems to be a
state of differential deactivation in which some functions are impaired whereas
others are retained. Tolerization at the level of the professional antigen
presenting cell by inflammatory mediators may play an important role in septic
disease and in the origin of cancers associated with chronic inflammation.
PMID- 9558365
TI - Characterization of CKbeta8 and CKbeta8-1: two alternatively spliced forms of
human beta-chemokine, chemoattractants for neutrophils, monocytes, and
lymphocytes, and potent agonists at CC chemokine receptor 1.
AB - Two new members of human beta-chemokine cDNA were isolated based on structural
and functional similarities to human leukotactin-1. One of these clones was
identical to the previously isolated human beta-chemokine, CKbeta8, whereas the
other is a splicing variant of CKbeta8, therefore named CKbeta8-1. CKbeta8 was
short in 51 nucleotides (17 amino acids) compared with CKbeta8-1. The mature
proteins of CKbeta8-1 and CKbeta8 consisted of 116 and 99 amino acids with
calculated molecular weights of 12,500 and 10,950, respectively. Both CKbeta8-1
and CKbeta8 were potent agonists at CCR1. These chemokines chemoattracted
neutrophils, monocytes, and lymphocytes. They also significantly suppressed
colony formation by human bone marrow, granulocyte-macrophage, erythroid, and
multipotential progenitor cells stimulated by combinations of growth factors. To
our knowledge, this is the first example that an alternative splicing produces
two active beta-chemokines from a single gene.
PMID- 9558366
TI - A novel fusion between MOZ and the nuclear receptor coactivator TIF2 in acute
myeloid leukemia.
AB - Chromosomal abnormalities of band 8p11 are associated with a distinct subtype of
acute myeloid leukemia with French-American-British M4/5 morphology and prominent
erythrophagocytosis by the blast cells. This subtype is usually associated with
the t(8;16)(p11;p13), a translocation that has recently been shown to result in a
fusion between the MOZ and CBP genes. We have cloned the inv(8)(p11q13), an
abnormality associated with the same leukemia phenotype, and found a novel fusion
between MOZ and the nuclear receptor transcriptional coactivator TIF2/GRIP-1/NCoA
2. This gene has not previously been implicated in the pathogenesis of leukemia
or other malignancies. MOZ-TIF2 retains the histone acetyltransferase homology
domains of both proteins and also the CBP binding domain of TIF2. We speculate
that the apparently identical leukemia cell phenotype observed in cases with the
t(8;16) and the inv(8) arises by recruitment of CBP by MOZ-TIF2, resulting in
modulation of the transcriptional activity of target genes by a mechanism
involving abnormal histone acetylation.
PMID- 9558368
TI - Loss of imprinting in disease progression in chronic myelogenous leukemia.
AB - The pathophysiologic role of the Philadelphia chromosome translocation in chronic
myelogenous leukemia (CML) has been known for nearly 20 years. However, the most
significant morbidity and mortality in CML are caused by progression to blast
crisis, about which comparatively little is known at the molecular level. Genomic
imprinting is a chromosomal modification leading to parental-origin-specific gene
expression in somatic cells. Recently, we and others have described loss of
imprinting (LOI) of the insulin-like growth factor-II gene (IGF2), leading to
biallelic rather than monoallelic expression in a wide variety of solid tumors.
We have now examined the imprinting status of IGF2 in samples from CML patients
in stable phase, accelerated phase, and blast crisis. Five of six stable-phase
patients showed normal imprinting, but LOI was found in all six cases of advanced
disease (three accelerated phase, three blast crisis), which was statistically
highly significant (P < .01). Thus, LOI represents a novel type of genetic
alteration in CML that appears to be specifically associated with disease
progression.
PMID- 9558367
TI - Expression of a knocked-in AML1-ETO leukemia gene inhibits the establishment of
normal definitive hematopoiesis and directly generates dysplastic hematopoietic
progenitors.
AB - The t(8;21)-encoded AML1-ETO chimeric product is believed to be causally involved
in up to 15% of acute myelogenous leukemias through an as yet unknown mechanism.
To directly investigate the role of AML1-ETO in leukemogenesis, we used gene
targeting to create an AML1-ETO "knock-in" allele that mimics the t(8;21).
Unexpectedly, embryos heterozygous for AML1-ETO (AML1-ETO/+) died around E13.5
from a complete absence of normal fetal liver-derived definitive hematopoiesis
and lethal hemorrhages. This phenotype was similar to that seen following
homozygous disruption of either AML1 or CBFbeta. However, in contrast to AML1- or
CBFbeta-deficient embryos, fetal livers from AML1-ETO/+ embryos contained
dysplastic multilineage hematopoietic progenitors that had an abnormally high
self-renewal capacity in vitro. To further document the role of AML1-ETO in these
growth abnormalities, we used retroviral transduction to express AML1-ETO in
murine adult bone marrow-derived hematopoietic progenitors. AML1-ETO-expressing
cells were again found to have an increased self-renewal capacity and could be
readily established into immortalized cell lines in vitro. Taken together, these
studies suggest that AML1-ETO not only neutralizes the normal biologic activity
of AML1 but also directly induces aberrant hematopoietic cell proliferation.
PMID- 9558369
TI - High CD34(+) cell counts decrease hematologic toxicity of autologous peripheral
blood progenitor cell transplantation.
AB - Optimal numbers of CD34(+) cells to be reinfused in patients undergoing
peripheral blood progenitor cell (PBPC) transplantation after high-dose
chemotherapy are still unknown. Hematologic reconstitution of 168
transplantations performed in patients with lymphoproliferative diseases was
analyzed according to the number of CD34(+) cells reinfused. The number of days
from PBPC reinfusion until neutrophil recovery (>1.0 x 10(9)/L) and unsustained
platelet recovery (>50 x 10(9)/L) were analyzed in three groups defined by the
number of CD34(+) cells reinfused: a low group with less than or equal to 2.5 x
10(6) CD34(+) cells/kg, a high group with greater than 15 x 10(6) CD34(+)
cells/kg, and an intermediate group to which the former two groups were compared.
The 22 low-group patients had a significantly delayed neutrophil (P < .0001) and
platelet recovery (P < .0001). The 41 high-group patients experienced
significantly shorter engraftment compared with the intermediate group with a
median of 11 (range, 8 to 16) versus 12 (range, 7 to 17) days for neutrophil
recovery (P = .003), and a median of 11 (range, 7 to 24) versus 14 (range, 8 to
180+) days for platelet recovery (P < .0001). These patients required
significantly less platelet transfusions (P = .002). In a multivariate analysis,
the amount of CD34(+) cells reinfused was the only variable showing significance
for neutrophil and platelet recovery. High-group patients had a shorter hospital
stay (P = .01) and tended to need fewer days of antibotic administration (P =
.12). In conclusion, these results suggest that reinfusion of greater than 15 x
10(6) CD34(+) cells/kg after high-dose chemotherapy for lymphoproliferative
diseases further shortens hematopoietic reconstitution, reduces platelet
requirements, and may improve patients' quality of life.
PMID- 9558370
TI - BCR-ABL antisense oligodeoxynucleotide in vitro purging and autologous bone
marrow transplantation for patients with chronic myelogenous leukemia in advanced
phase.
AB - BCR-ABL antisense oligodeoxynucleotides (ODN) have provided evidence of
antileukemia effect when tested in vitro against Philadelphia-positive (Ph-pos)
cells and in vivo when injected into leukemic mice. On the basis of the results
obtained in vitro at diagnosis, eight patients with chronic myelogenous leukemia
(CML) were selected and submitted to autologous bone marrow transplantation
(ABMT) with bone marrow (BM) cells purged in vitro with junction-specific (J-sp)
BCR-ABL antisense ODN at the time of transformation in accelerated phase or
during second chronic phase. Mononuclear BM cells were treated in vitro for 24 or
72 hours with 150 micro/mL of antisense ODN yielding a median recovery of 47.6%
mononuclear cells, 48.8% CD34(+) cells, and 20.3% clonogenic cells. After a
conditioning regimen including busulphan and etoposide, the reinfused treated
cells allowed engraftment and hematologic reconstitution in all patients.
Evaluation of the antileukemic effect by standard cytogenetic analysis and
fluorescence in situ hybridization showed a complete karyotypic response in two
cases and a minimal or no response in the other six. The patient autografted in
second chronic phase died in blast crisis 7 months after ABMT; of the seven
patients autografted in transformation, three developed blast crisis 21 to 39
months after reinfusion, one died from unrelated BMT complications 30 months
after ABMT, and three are in persistent second chronic phase 14 to 26 months
after autograft. The low toxicity of the protocol and the hemopoietic
reconstitution observed in all patients make this approach feasible; the marked
karyotypic response observed in some patients and the duration of the second
chronic phase show that ODN-mediated BM purging and autograft is a promising
treatment for this high-risk group of CML.
PMID- 9558371
TI - Inhibition of P-glycoprotein and recovery of drug sensitivity of human acute
leukemic blast cells by multidrug resistance gene (mdr1) antisense
oligonucleotides.
AB - To overcome the problem of multidrug resistance, we investigated the
effectiveness of phosphrothioate antisense oligonucleotides (MDR1-AS) in
suppressing multidrug resistance gene (mdr1) expression in drug-resistant acute
myelogenous leukemia (AML) blast cells and the K562 adriamycin-resistant cell
line K562/ADM. The percentage of cells with the mdr1 gene product P-glycoprotein
(P-gp) was decreased from 100% to 26% by 20 micromol/L MDR1-AS in the K562/ADM
cells, and from 48.1% to 10.2% by 2.5 micromol/L MDR1-AS in the AML blast cells.
Western blot analysis also showed a decrease in the amount of P-gp in the MDR1-AS
treated K562/ADM cells. This effect was specific to MDR1-AS, and not observed
with sense or random control oligonucleotides. The expression of mdr1 mRNA in
K562/ADM and AML blast cells treated with MDR1-AS was decreased compared with the
random control. Intracellular rhodamine retention and [3H]daunorubicin also
increased after antisense treatment. Chemosensitivity to daunorubicin increased
in MDR1-AS-treated blast cells up to 5.9-fold in the K562/ADM cells and 3.0- to
6.4-fold in the AML blast cells. The expression of mdr1 mRNA derived from colony
cells decreased in the MDR1-AS-treated groups. No inhibitory effect of the
oligonucleotides on normal bone marrow progenitors was observed. These findings
suggest that MDR1-AS is useful to overcome multidrug resistance in the treatment
of leukemia.
PMID- 9558372
TI - The P2X1 receptor, an adenosine triphosphate-gated cation channel, is expressed
in human platelets but not in human blood leukocytes.
AB - Extracellular adenosine triphosphate (ATP) and adenosine diphosphate (ADP)
activate multiple types of P2-nucleotide receptors expressed in platelets or
leukocytes. Electrophysiological and biochemical studies have indicated
expression of the P2X1 receptor, an ATP-gated cation channel, in human and rat
platelets, rat basophilic leukemia (RBL) cells, and phorbol myristate acetate
(PMA)-differentiated HL-60 myeloid cells. Although these findings suggest that
P2X1 receptors are present in both blood leukocytes and blood platelets, the
relative levels of P2X1 receptor expression and function in human blood
leukocytes and platelets have not been directly characterized. On the basis of
both immunoblot analysis and functional assays of P2X1 receptor-mediated ionic
fluxes, we report that there is significant expression of P2X1 receptors in human
platelets, but not in neutrophils, monocytes, or blood lymphocytes. Thus, unlike
platelets and myeloid progenitor cell lines, fully differentiated human blood
leukocytes do not express functionally significant numbers of P2X1 receptors,
suggesting the downregulation of P2X1 receptor gene expression during the
differentiation of phagocytic leukocytes. By contrast, P2X1 receptor expression
is strongly maintained during megakaryocytic differentiation and platelet
release. Immunoblot analysis indicated that the platelet P2X1 receptor migrates
as an approximately 60-kD protein during SDS-electrophoresis under reducing or
nonreducing conditions. Treatment of platelet membranes with endoglycosidase-F
causes the P2X1 receptor band to migrate as a 46-kD protein, verifying the highly
glycosylated nature of the mature receptor protein. Additional studies of
nucleotide-induced changes in Ca2+ influx/mobilization demonstrated that the
platelet P2X1 receptors are pharmacologically distinct from the well
characterized ADP receptors of these cells. This finding suggests a unique role
for these ATP-gated ion channels during hemostasis or thrombosis.
PMID- 9558373
TI - Interleukin-3-induced activation of the JAK/STAT pathway is prolonged by
proteasome inhibitors.
AB - One facet of cytokine receptor signaling involves the activation of signal
transducers and activators of transcription (STATs). STATs are rapidly activated
via tyrosine phosphorylation by Janus kinase (JAK) family members and
subsequently inactivated within a short period. We investigated the effect of
proteasome inhibition on interleukin-3 (IL-3) activation of the JAK/STAT pathway
following stimulation of Ba/F3 cells. Treatment of Ba/F3 cells with the
proteasome inhibitor, N-acetyl-L-leucinyl-L-leucinyl-norleucinal (LLnL), led to
stable tyrosine phosphorylation of the IL-3 receptor, beta common (betac), and
STAT5 following stimulation. The effects of LLnL were not restricted to the
JAK/STAT pathway, as Shc and mitogen-activated protein kinase (MAPK)
phosphorylation were also prolonged in LLnL-treated cells. Further investigation
showed these stable phosphorylation events were the result of prolonged
activation of JAK2 and JAK1. These observations were confirmed using
pharmacologic inhibitors. In the presence of LLnL, stable phosphorylation of
STAT5 and betac was abrogated if the tyrosine kinase inhibitor, staurosporine,
was added. The effect of staurosporine on STAT5 phosphorylation could be overcome
if the phosphatase inhibitor, vanadate, was also added, suggesting phosphorylated
STAT5 could be stabilized by phosphatase, but not by proteasome inhibition per
se. These observations are consistent with the hypothesis that proteasome
mediated protein degradation can modulate the activity of the JAK/STAT pathway by
regulating the deactivation of JAK.
PMID- 9558374
TI - Regulation of the erythroid transcription factor NF-E2 by cyclic adenosine
monophosphate-dependent protein kinase.
AB - Activation of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (A
kinase) promotes hemoglobin synthesis in several erythropoietin-dependent cell
lines, whereas A-kinase-deficient murine erythroleukemia (MEL) cells show
impaired hemoglobin production; A-kinase may regulate the erythroid transcription
factor NF-E2 by directly phosphorylating its p45 subunit or by changing p45
interactions with other proteins. We have mapped the major A-kinase
phosphorylation site of p45 to Ser(169); Ala substitution for Ser(169) resulted
in a protein that was no longer phosphorylated by A-kinase in vitro or in vivo.
The mutant protein formed NF-E2 complexes that bound to DNA with the same
affinity as wild-type p45 and functioned normally to restore beta-globin gene
expression in a p45-deficient MEL cell line. Transactivation properties of the
(Ser (169)--> Ala) mutant p45 were also indistinguishable from wild-type p45 when
Gal4-p45 fusion constructs were tested with a Gal4-dependent reporter gene.
Transactivation of the reporter by both mutant and wild-type p45 was
significantly enhanced when A-kinase was activated by membrane-permeable cAMP
analogs or when cells were cotransfected with the catalytic subunit of A-kinase.
Stimulation of p45 transactivation by A-kinase required only the N-terminal
transactivation domain of p45, suggesting that A-kinase regulates the interaction
of p45 with downstream effectors.
PMID- 9558375
TI - Generation of a primitive erythroid cell line and promotion of its growth by
basic fibroblast growth factor.
AB - An immortalized cell line representing the primitive erythroid (EryP) lineage was
established from in vitro-differentiated progeny (embryoid bodies [EBs]) of
embryonic stem (ES) cells using a retroviral insertional mutation, and has been
termed EB-PE for embryoid body-derived primitive erythroid. Even though EB-PE
cells are immortalized, they show characteristics of normal EryP cells, such as
gene expression and growth factor dependency. In addition, EB-PE cells can
differentiate further in culture. Investigation of growth factor requirements of
EB-PE cells showed that basic fibroblast growth factor (bFGF) and erythropoietin
(Epo) play unique roles in EB-PE proliferation and differentiation. While bFGF
was a strong mitogen, Epo was required for both proliferation and
differentiation. The unique proliferative response to bFGF coincided with
upregulation of its receptor, fibroblast growth factor receptor (fgfr-1), and
downregulation of erythropoietin receptor (EpoR) gene expression. Studies of
primary EryP cells derived from early EBs, when tested in a colony-formation
assay, also provided evidence for the mitogenic role of bFGF in concert with Epo.
PMID- 9558376
TI - Systematic method to obtain novel genes that are regulated by mi transcription
factor: impaired expression of granzyme B and tryptophan hydroxylase in mi/mi
cultured mast cells.
AB - The mi locus encodes a member of the basic-helix-loop-helix-leucine zipper
protein family of transcription factors (hereafter called MITF). We have reported
that the expression of several genes was impaired in cultured mast cells (CMCs)
of mi/mi genotype, and demonstrated the involvement of MITF in the transcription
of these genes. To obtain new genes whose transcription may be regulated by MITF,
we prepared a subtracted cDNA library using +/+ and mi/mi CMCs. We found two
clones carrying the granzyme (Gr) B and tryptophan hydroxylase (TPH) cDNAs in the
subtracted library. The expression of the Gr B and TPH genes decreased in mi/mi
CMCs, and recovered to nearly normal level by the overexpression of normal (+)
MITF but not of mutant (mi) MITF. The +-MITF bound three and one CANNTG motifs in
the Gr B and TPH promoters, respectively, and transactivated these two genes,
indicating the involvement of +-MITF in their expression. Because TPH is the rate
limiting enzyme for serotonin synthesis, we examined the serotonin content of +/+
and mi/mi CMCs. The serotonin content was significantly smaller in mi/mi CMCs
than in +/+ CMCs. The introduction of +-MITF but not of mi-MITF normalized the
serotonin content in mi/mi CMCs.
PMID- 9558377
TI - Interactions of erythropoietin, granulocyte colony-stimulating factor, stem cell
factor, and interleukin-11 on murine hematopoiesis during simultaneous
administration.
AB - We investigated how in vivo effects of single hematopoietic cytokines change if
given in combination for a prolonged time. Mice were treated with every
combination of recombinant human (rh) erythropoietin (EPO), rh granulocyte colony
stimulating factor (G-CSF), recombinant rat (rr) stem cell factor (SCF), and rh
interleukin (IL)-11 by continuous infusion over 7 days (full factorial design
with three dose levels for each cytokine). Burst-forming unit-erythroid (BFU-E),
colony-forming unit-erythroid (CFU-E), and colony-forming unit-granulocyte
macrophage (CFU-GM) were determined in bone marrow and spleen, reticulocytes,
hematocrit, granulocytes, and thrombocytes in the peripheral blood. An analysis
of variance (ANOVA) and multiple comparison of means was used to evaluate the
data. For several cell types, cytokine effects superimposed in an additive way if
combined. However, in a large number of circumstances, nonadditive pairwise
interactions were found. They differed in type and magnitude involving high-dose
saturation, high-dose antagonistic effects, and even effect reversals
(qualitative interactions). Hence, in general, it was not possible to foresee the
combination effects on the basis of existing knowledge of single effects. On the
other hand, the cytokine network was robust and no system hazards were observed
under multiple cytokine combinations. The results illustrate that the cytokine
network has nonlinear dynamic properties in vivo with dose-response
characteristics of one cytokine being continuously modified by other cytokines.
PMID- 9558378
TI - The effect of alpha4 beta1-integrin binding sequences of fibronectin on growth of
cells from human hematopoietic progenitors.
AB - Highly regulated interactions between adhesion receptors on progenitor cells and
their extracellular matrix ligands are essential for the control of hematopoiesis
in bone marrow stroma. We have examined the relationship between alpha4beta1
integrin-mediated adhesion and growth of CD34(+) cells by assessing their
adhesive and migratory patterns of proliferation in a mixture of hematopoietic
growth factors in the presence of different recombinant fragments of the
HepII/IIICS region of fibronectin. CD34(+) cells were isolated from cord blood
and placed in culture wells containing serum-free medium and growth factors.
Wells were precoated with either the H120 fragment of fibronectin, which contains
three alpha4beta1-integrin binding sites, or the H0 fragment, which lacks the two
highest affinity alpha4beta1 binding sequences. Proliferation of single cells of
CD34(+)38(+)DR+ and CD34(+)38(-)DR+ phenotypes occurred in contact with the H120
substrate and was associated with migration. Larger numbers of cells were used to
quantitate proliferative responses. Cells growing in wells coated with H120
formed attachments to the base of the wells throughout the culture period. Higher
total cell counts were consistently found in wells coated with H120 compared with
H0 and bovine serum albumin controls. The difference was first apparent at day 8
of culture and reached a maximum at days 11 through 13, when expansion with H120
was a mean of 1.8-fold higher than that seen with H0 (P= .0001). The greatest
expansion (2.25-fold) with H120 compared with H0 was seen when the growth factor
concentrations were reduced to 1/16 of the standard levels (P = .001). The
increase in total cell numbers was not at the expense of CD34(+) cells as numbers
of these were similar in H120 and control cultures. These results provide
evidence for synergy between growth factors and integrins that may be relevant to
understanding hematopoiesis in marrow stroma.
PMID- 9558379
TI - Ineffective platelet production in thrombocytopenic human immunodeficiency virus
infected patients.
AB - Thrombocytopenia has been characterized in six patients infected with human
immunodeficiency virus (HIV) with respect to the delivery of viable platelets
into the peripheral circulation (peripheral platelet mass turnover), marrow
megakaryocyte mass (product of megakaryocyte number and volume), megakaryocyte
progenitor cells, circulating levels of endogenous thrombopoietin (TPO) and
platelet TPO receptor number, and serum antiplatelet glycoprotein (GP) IIIa49-66
antibody (GPIIIa49-66Ab), an antibody associated with thrombocytopenia in HIV
infected patients. Peripheral platelet counts in these patients averaged 46 +/-
43 x 10(3)/microL (P = . 0001 compared to normal controls of 250 +/- 40x
10(3)/microL), and the mean platelet volume (MPV) was 10.5 +/- 2.0 fL (P > 0.3
compared with normal control of 9.5 +/- 1.7 fL). The mean life span of autologous
111In-platelets was 87 +/- 39 hours (P = .0001 compared with 232 +/- 38 hours in
20 normal controls), and immediate mean recovery of 111In-platelets injected into
the systemic circulation was 33% +/- 16% (P = .0001 compared with 65% +/- 5% in
20 normal controls). The resultant mean peripheral platelet mass turnover was 3.8
+/- 1.5 x 10(5) fL/microL/d versus 3.8 +/- 0.4 x 10(5) fL/microL/d in 20 normal
controls (P > .5). The mean endogenous TPO level was 596 +/- 471 pg/mL (P = .0001
compared with 95 +/- 6 pg/mL in 98 normal control subjects), and mean platelet
TPO receptor number was 461 +/- 259 receptors/platelet (P = .05 compared with 207
+/- 99 receptors/platelet in nine normal controls). Antiplatelet GPIIIa49-66Ab
levels in sera were uniformly increased in HIV thrombocytopenic patients (P <
.001). In this cohort of thrombocytopenic HIV patients, marrow megakaryocyte
number was increased to 30 +/- 15 x 10(6)/kg (P = .02 compared with 11 +/- 2.1 x
10(6)/kg in 20 normal controls), and marrow megakaryocyte volume was 32 +/- 0.9 x
10(3) fL (P = .05 compared with 28 +/- 4.5 x 10(3) fL in normal controls). Marrow
megakaryocyte mass was expanded to 93 +/- 47 x 10(10) fL/kg (P = .007 compared
with normal control of 31 +/- 5.3 x 10(10) fL/kg). Marrow megakaryocyte
progenitor cells averaged 3.3 (range, 0.4 to 7.3) CFU-Meg/1,000 CD34(+) cells
compared with 27 (range, 0.1 to 84) CFU-Meg/1,000 CD34(+) cells in seven normal
subjects (P = .02). Thus, thrombocytopenia in these HIV patients was caused by a
combination of shortening of platelet life span by two thirds and doubling of
splenic platelet sequestration, coupled with ineffective delivery of viable
platelets to the peripheral blood, despite a threefold TPO-driven expansion in
marrow megakaryocyte mass. We postulate that this disparity between circulating
platelet product and marrow platelet substrate results from direct impairment in
platelet formation by HIV-infected marrow megakaryocytes.
PMID- 9558380
TI - Identification of human and mouse hematopoietic stem cell populations expressing
high levels of mRNA encoding retrovirus receptors.
AB - One obstacle to retrovirus-mediated gene therapy for human hematopoietic
disorders is the low efficiency of gene transfer into pluripotent hematopoietic
stem cells (HSC). We have previously shown a direct correlation between
retrovirus receptor mRNA levels in mouse HSC and the efficiency with which they
are transduced. In the present study, we assayed retrovirus receptor mRNA levels
in a variety of mouse and human HSC populations to identify HSC which may be more
competent for retrovirus transduction. The highest levels of amphotropic
retrovirus receptor (amphoR) mRNA were found in cryopreserved human cord blood
HSC. The level of amphoR mRNA in Lin- CD34(+) CD38(-) cells isolated from frozen
cord blood was 12-fold higher than the level in fresh cord blood Lin- CD34(+)
CD38(-) cells. In mice, the level of amphoR mRNA in HSC from the bone marrow (BM)
of mice treated with stem cell factor and granulocyte-colony stimulating factor
was 2.8- to 7.8-fold higher than in HSC from the BM of untreated mice. These
findings suggest that HSC from frozen cord blood and cytokine-mobilized BM may be
superior targets for amphotropic retrovirus transduction compared with HSC from
untreated adult BM.
PMID- 9558381
TI - Telomerase activity in candidate stem cells from fetal liver and adult bone
marrow.
AB - Telomerase is a ribonucleoprotein polymerase that synthesizes telomeric repeats
onto the 3' ends of eukaryotic chromosomes. Activation of telomerase may prevent
telomeric shortening and correlates with cell immortality in the germline and
certain tumor cells. Candidate hematopoietic stem cells (HSC) from adult bone
marrow express low levels of telomerase, which is upregulated with proliferation
and/or differentiation. To address this issue, we stimulated purified candidate
HSC from human adult bone marrow with stem cell factor (SCF), interleukin-3 (IL
3), and Flt3-ligand (FL). After 5 days in culture, activity was detected in total
cell extracts from IL-3-, SCF + FL-, SCF + IL-3-, FL + IL-3-, and SCF + IL-3 + FL
stimulated cultures, but not from cells cultured in SCF or FL alone. Within the
CD34(+) fraction of the cultured cells, significant activity was found in the
CD34(+)CD71(+) fraction. In addition, PKH26 staining confirmed that detectable
telomerase activity was present in dividing PKH26(lo) cells, whereas nondividing
PKH26(hi) cells were telomerase negative. Because in these experiments no
distinction could be made between cycling "candidate" stem cells that had
retained or had lost self-renewal properties, fetal liver cells with a
CD34(+)CD38(-) phenotype, highly enriched for cycling stem cells, were also
examined and found to express readily detectable levels of telomerase activity.
Given the replication-dependent loss of telomeric DNA in hematopoietic cells,
these observations suggest that the observed telomerase activity in candidate
stem cells is either expressed in a minor subset of stem cells or, more likely,
is not sufficient to prevent telomere shortening.
PMID- 9558382
TI - Growth-supporting activities of fibronectin on hematopoietic stem/progenitor
cells in vitro and in vivo: structural requirement for fibronectin activities of
CS1 and cell-binding domains.
AB - Fibronectin (FN) is supposed to play important roles in various aspects of
hematopoiesis through binding to very late antigen 4 (VLA4) and VLA5. However,
effects of FN on hematopoietic stem cells are largely unknown. In an effort to
determine if FN had a growth-supporting activity on hematopoietic stem cells,
human CD34(+)/VLA4(bright)/VLA5(dull) hematopoietic stem cells and a murine stem
cell factor (SCF)-dependent multipotent cell line, EML-C1, were treated with or
without FN in a serum and growth-factor-deprived medium, and then subjected to
clonogenic assay in the presence of hematopoietic growth factors. The
pretreatment of the CD34(+) cells with FN gave rise to significantly increased
numbers of granulocyte-macrophage colony-forming units (CFU-GM), erythroid burst
colony-forming units, and mixed erythroid-myeloid colony-forming units. In
addition, the numbers of blast colony-forming units and CFU-GM that developed
after culture of EML-C1 cells with SCF and the combination of SCF and interleukin
3, respectively, were augmented by the pretreatment with FN. The augmented colony
formation by FN was completely abrogated by the addition of CS1 fragment, but not
of GRGDSP peptide, suggesting an essential role of FN-VLA4 interaction in the FN
effects. Furthermore, the effects of various FN fragments consisting of RGDS
containing cell-binding domain (CBD), heparin-binding domain (HBD), and/or CS1
portion were tested on clonogenic growth of CD34(+) cells. Increased colony
formation was induced by CBD-CS1 and CBD-HBD-CS1 fragments, but not with other
fragments lacking CBD or CS1 domains, suggesting that both CS1 and CBD of FN were
required for the augmentation of clonogenic growth of hematopoietic
stem/progenitor cells in vitro. In addition to the in vitro effects, the in vivo
administration of CBD-CS1 fragment into mice was found to increase the numbers of
hematopoietic progenitor cells in bone marrow and spleen in a dose-dependent
manner. Thus, FN may function on hematopoietic stem/progenitor cells as a growth
supporting factor in vitro and in vivo.
PMID- 9558383
TI - Sustained phenotypic correction of murine hemophilia A by in vivo gene therapy.
AB - Hemophilia A is caused by a deficiency of blood coagulation factor VIII (FVIII)
and has been widely discussed as a candidate for gene therapy. While the natural
canine model of hemophilia A has been valuable for the development of FVIII
pharmaceutical products, the use of hemophiliac dogs for gene therapy studies has
several limitations such as expense and the long canine generation time. The
recent creation of two strains of FVIII-deficient mice provides the first small
animal model of hemophilia A. Treatment of hemophiliac mice of both genotypes
with potent, human FVIII-encoding adenoviral vectors resulted in expression of
biologically active human FVIII at levels, which declined, but remained above the
human therapeutic range for over 9 months. The duration of expression and FVIII
plasma levels achieved were similar in both hemophiliac mouse strains. Treated
mice readily survived tail clipping with minimal blood loss, thus showing
phenotypic correction of murine hemophilia A by in vivo gene therapy.
PMID- 9558385
TI - Platelet factor 4 modulates fibroblast growth factor 2 (FGF-2) activity and
inhibits FGF-2 dimerization.
AB - Platelet factor 4 (PF-4) inhibits angiogenesis in vitro and in vivo. The
mechanism of inhibition is poorly understood. We have investigated the mechanism
of inhibition by examining the interaction of PF-4 and the fibroblast growth
factor-2 (FGF-2)/fibroblast growth factor receptor (FGFR) system. PF-4 inhibited
the binding of FGF-2 to high-affinity and low-affinity binding sites in murine
microvascular endothelial cells (LEII cells) and proliferation. Maximum
inhibition of binding to endothelial FGF receptors was observed at PF-4
concentrations between 5 and 10 microg/mL (half maximum inhibition at 0.6
micro/mL), and proliferation was completely inhibited at 2 microg/mL. At this
concentration, PF-4 reduced internalization of 125I-FGF-2 by threefold and
delayed degradation. To gain insight into the mechanism of inhibition, we have
analyzed the interaction of PF-4 with FGF-2/FGFR by using mutant heparan sulfate
deficient Chinese hamster ovary (CHO) cells transfected with the FGFR-1 cDNA
(CHOm-FGFR-1) and by examining the direct interaction with FGF-2. In the absence
of heparin, PF-4 inhibited binding of 125I-FGF-2 to CHOm-FGFR-1 cells in a
concentration-dependent manner, although not completely. In the presence of
heparin, PF-4 abolished totally the stimulatory effect of heparin. Furthermore,
PF-4 complexed to FGF-2 and inhibited endogenous or heparin-induced FGF-2
dimerization. These results indicate that PF-4 interacts with FGF-2 by complex
formation, inhibiting FGF-2 dimerization, binding to FGF receptors, and
internalization. This mechanism most likely contributes to the antiangiogenic
properties of PF-4.
PMID- 9558384
TI - Factor XIIIa cross-linking of the Marburg fibrin: formation of alpham.gamman
heteromultimers and the alpha-chain-linked albumin. gamma complex, and disturbed
protofibril assembly resulting in acquisition of plasmin resistance relevant to
thrombophila.
AB - The truncated Aalpha-chain of fibrinogen Marburg is partly linked with albumin by
a disulfide bond. Based on the recovery of the first six amino acid residues
assigned to the subunit polypeptides of fibrinogen (the Aalpha-and gamma-chains)
and albumin, 0.33 mol of albumin was estimated to be linked to 1 mol of the
Marburg fibrinogen. When the Marburg fibrinogen was clotted with thrombin-factor
XIIIa-Ca2+, various alpham gamman heteromultimers were produced, and part of the
albumin was cross-linked to the gamma-chain. Acid-solubilized Marburg fibrin
monomer failed to form large aggregates that could be detected by monitoring
turbidity at A350, but it was able to enhance tissue-type plasminogen-activator
catalyzed plasmin generation, though not as avidly as the normal control,
indicating that the double-stranded protofibrils had, to some extent, been
constructed. This idea seems to be supported by normal factor XIIIa-catalyzed
cross-linking of the fibrin gamma-chains. However, the cross-linked Marburg
fibrin, being apparently fragile and translucent, was highly resistant against
plasmin, and its subunit components were considerably retained for 48 hours as
noted by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Although the
exact mechanisms are still unclear, the albumin-incorporated factor XIIIa-cross
linked Marburg fibrin seems to have undergone a critical structural alteration(s)
to acquire resistance against plasmin. This aquisition of plasmin resistance may
be contributed to the postoperative pelvic vein thrombosis and recurrent
pulmonary embolisms in the patient after caesarian section for her first delivery
at the age of 20 years.
PMID- 9558386
TI - Hypoxia stimulates urokinase receptor expression through a heme protein-dependent
pathway.
AB - Hypoxia underlies a number of biologic processes in which cellular migration and
invasion occur. Because earlier studies have shown that the receptor for
urokinase-type plasminogen activator (uPAR) may facilitate such events, we
studied the effect of hypoxia on the expression of uPAR by first trimester human
trophoblasts (HTR-8/SVneo) and human umbilical vein endothelial cells (HUVEC).
Compared with control cells cultured under standard conditions (20% O2), HTR
8/SVneo cells and HUVEC cultured in 1% O2 expressed more uPAR, as determined by
flow cytometric and [125I]-prourokinase ligand binding analyses. Increased uPAR
expression paralleled increases in uPAR mRNA. The involvement of a heme protein
in the hypoxia-induced expression of uPAR was suggested by the observations that
culture of cells with cobalt chloride, or sodium 4, 5-dihydroxybenzene-1,3
disulfonate (Tiron), an iron-chelating agent, also stimulated uPAR expression,
and that the hypoxia-induced uPAR expression was inhibited by adding carbon
monoxide to the hypoxic atmosphere. Culture of HTR-8/SVneo cells with vascular
endothelial growth factor (VEGF) did not increase uPAR mRNA levels, suggesting
that the hypoxia-mediated effect on uPAR expression by these cells did not occur
through a VEGF-dependent mechanism. The functional importance of these findings
is suggested by the fact that HTR-8/SVneo cells cultured under hypoxia displayed
higher levels of cell surface plasminogen activator activity and greater invasion
through a reconstituted basement membrane. These results suggest that hypoxia may
promote cellular invasion by stimulating the expression of uPAR through a heme
protein-dependent pathway.
PMID- 9558387
TI - gp130, the cytokine common signal-transducer of interleukin-6 cytokine family, is
downregulated in T cells in vivo by interleukin-6.
AB - gp130 is a common signal-transducing receptor component for the interleukin-6 (IL
6) family of cytokines. To investigate the expression of gp130 in T-cell subsets
and its regulation, anti-murine gp130 monoclonal antibody (MoAb) was used for
flow cytometric analysis. In normal mice, gp130 was differentially expressed in
thymocyte and splenic T-cell subpopulations defined by CD4/CD8 expression. In
aged MRL/lpr mice, although gp130 expression was detectable in splenic CD4(+) or
CD8(+) T cells, gp130 expression was significantly downregulated. Because serum
levels of IL-6 and soluble IL-6 receptor (sIL-6R) are elevated in these mice, we
examined the possibility that the downregulation of gp130 expression on splenic T
cells might be produced in response to continuous activation of gp130 by high
levels of serum IL-6. In transgenic mice overexpressing IL-6, gp130 expression in
the splenic T cells was significantly decreased. After stimulation with IL-6 in
vitro, the level of gp130 on CD4(+) or CD8(+) splenic T cells from normal mice
was significantly decreased. These results suggest that the expression of gp130
in splenic T cells could be downregulated by the IL-6 stimulation under
physiological or pathological circumstances.
PMID- 9558388
TI - Interleukin-12 inhibits graft-versus-host disease through an Fas-mediated
mechanism associated with alterations in donor T-cell activation and expansion.
AB - We have recently made the paradoxical observation that a single injection of
recombinant murine interleukin-12 (IL-12) on the day of bone marrow
transplantation (BMT) inhibits graft-versus-host disease (GVHD) in lethally
irradiated mice receiving fully major histocompatability complex (MHC)-mismatched
bone marrow and spleen cells. We have now examined the mechanism of this effect
of IL-12 on acute GVHD. By day 4 post-BMT, IL-12-treated mice showed marked
reductions in splenic donor CD4(+) and CD8(+) T cells compared with GVHD
controls. Expression of the early activation markers IL-2R alpha chain (CD25) and
CD69 on splenic donor CD4(+) cells was considerably higher at early time points
(36 and 72 hours post-BMT) in IL-12-treated mice compared with GVHD controls.
However, the later, GVHD-associated increase in CD25 and very late antigen-4 (VLA
4) expression on donor T cells was greatly depressed in IL-12-protected mice
compared with GVHD controls. The marked GVHD-associated expansion of host
reactive T helper cells by day 4 was also completely inhibited in the IL-12
treated group. Expression of Fas was increased on donor CD4 cells of IL-12
treated mice compared with those of controls on days 3 through 7 post-BMT.
Furthermore, the ability of IL-12 to protect against GVHD was at least partially
dependent on the ability of donor cells to express functional Fas molecules. We
conclude that IL-12 treatment at the time of BMT markedly perturbs the activation
of alloreactive donor CD4(+) T cells that play a critical role in the
pathogenesis of acute GVHD. We hypothesize that these perturbations culminate in
Fas-dependent apoptosis of donor T cells, thus impeding their expansion and their
GVHD-promoting activity.
PMID- 9558389
TI - High CD30 ligand expression by epithelial cells and Hassal's corpuscles in the
medulla of human thymus.
AB - CD30 is a member of tumor necrosis factor (TNF) receptor superfamily that is
expressed by activated T cells in the presence of interleukin-4 (IL-4). Although
CD30 can mediate a variety of signals, CD30-deficient mice have impaired negative
selection of T cells, suggesting that at least in the context of murine thymus,
CD30 is a cell death-mediating molecule. The ligand for CD30 (CD30L) is a
membrane-associated glycoprotein related to TNF, which is known to be expressed
mainly by activated T cells and other leukocytes. However, the nature of CD30L
expressing cells involved in the interaction with CD30+ thymocytes is unclear. We
report here that in postnatal human thymus the great majority of CD30+ cells are
double positive (CD4+CD8+), activated, IL-4 receptor-expressing T cells which
selectively localize in the medullary areas. Moreover, many medullary epithelial
cells and Hassal's corpuscles in the same thymus specimens showed unusually high
expression of CD30L in comparison with other lymphoid or nonlymphoid tissues.
These findings provide additional information on the nature and localization of
CD30+ thymocytes and show that epithelial cells are the major holder of CD30L in
the thymic medulla.
PMID- 9558390
TI - Myc is essential for transformation by TEL/platelet-derived growth factor
receptor beta (PDGFRbeta).
AB - The t(5;12) translocation identified in patients with chronic myelomonocytic
leukemia (CMML) encodes a TEL/platelet-derived growth factor receptor beta
(PDGFRbeta) fusion protein. A key hypothesis for how the TEL/PDGFRbeta fusion
protein would function as an oncogene is that it represents a constitutively
active version of the normal PDGFRbeta. A link between the function of the
t(5;12)-encoded TEL/PDGFRbeta fusion protein and Myc expression is suggested by
the fact that Myc is induced by PDGF and is essential for entry of cells into the
S phase of the cell cycle. We here show that the kinase activity of TEL/PDGFRbeta
is necessary for Ba/F3 cells to acquire interleukin-3 (IL-3) independence and
that, in contrast to their untransfected counterpart, Ba/F3 cells stably
transfected with TEL/PDGFRbeta maintain a high level of Myc expression after
removal of IL-3. Using dominant negative mutants of Myc, we show that a threshold
of active Myc is essential for TEL/PDGFRbeta to transform Ba/F3 and Rat-1 cells.
The findings that the kinase activity of TEL/PDGFRbeta and a threshold of active
Myc are involved in TEL/PDGFRbeta transformation may allow for the development of
therapeutic strategies in patients with t(5;12)+ CMML using specific inhibitors
of the PDGFRbeta kinase as well as compounds designed to interfere specifically
with Myc.
PMID- 9558391
TI - Detection of lymphoma in bone marrow by whole-body positron emission tomography.
AB - Positron emission tomography (PET) is a whole-body imaging technique using 18
fluorine-fluorodeoxyglucose (FDG), whose uptake is increased in tumor cells.
Published studies have shown PET to be an effective method of staging lymphoma
and to be more sensitive than CT at detecting extranodal disease. The purpose of
this study was to determine whether the increased marrow uptake of FDG observed
in some lymphoma patients during routine staging PET scans represented marrow
involvement by disease. PET scans of 50 patients with Hodgkin's (12) and non
Hodgkin's (38) lymphoma were analyzed by three independent observers and the
marrow graded as normal or abnormal using a visual grading system. Unilateral
iliac crest marrow aspirates and biopsies were performed on all patients. The PET
scan and marrow histology agreed in 39 patients (78%), being concordant positive
in 13 and concordant negative in 26 patients. In 8 patients the PET scan showed
increased FDG uptake but staging biopsy was negative; in 4 of these 8 patients
the PET scan showed a normal marrow background with focal FDG "hot spots" distant
from the site biopsied. In 3 patients the marrow biopsy specimen was positive but
the PET scan normal; 2 of these 3 patients had non-Hodgkin's lymphoma whose
malignant cells did not take up FDG at lymph node or marrow disease sites.
Therefore, there were only 5 patients (10%) in whom there was a difference
between the PET scan and biopsy result which could not be fully explained. Visual
interpretation of marrow FDG uptake during whole-body staging PET scans can
correctly assess marrow disease status in a high proportion of lymphoma patients.
PET has the potential to reduce the need for staging marrow biopsy.
PMID- 9558392
TI - Constitutive expression of the promyelocytic leukemia-associated oncogene PML
RARalpha in TF1 cells: isoform-specific and retinoic acid-dependent effects on
growth, bcl-2 expression, and apoptosis.
AB - Two major isoforms of PML-RARalpha are associated with (15;17)-positive acute
promyelocytic leukemia (APL); however, functional differences between these
isoforms have been difficult to define, and the molecular mechanism by which each
isoform contributes to the pathogenesis of APL is not fully understood. To
address these issues, the 'short' (S) and 'long' (L) isoforms of PML-RARalpha
were constitutively expressed in the factor-dependent human erythroleukemia cell
line, TF1. Expression of the L, but not the S, isoform inhibited growth of these
cells in the presence of granulocyte-macrophage colony-stimulating factor (GM
CSF). In the absence of GM-CSF, the S isoform partially protected against
apoptosis, while the L isoform accelerated cell death. Treatment with all-trans
retinoic acid (ATRA) inhibited cell growth and caused apoptosis only in PML
RARalpha-expressing cells, and these effects of ATRA were more marked in cells
expressing the L isoform. ATRA treatment also led to downregulation of bcl-2 and
endogenous RARalpha in PML-RARalpha-expressing cells, but had little effect on
the level of exogenously expressed PML-RARalpha. We conclude that (1) subtle
differences exist in the biologic activities of the L and S isoforms of PML
RARalpha, and (2) both isoforms are capable of transducing an ATRA-mediated
signal that leads to downregulation of bcl-2 and induction of programmed cell
death.
PMID- 9558393
TI - Highly sensitive fluorescence in situ hybridization method to detect double
BCR/ABL fusion and monitor response to therapy in chronic myeloid leukemia.
AB - We investigated a new method using fluorescence in situ hybridization and DNA
probes that span the common breakpoints of t(9;22)(q34;q11.2) and that detect
double BCR/ABL fusion (D-FISH) in bone marrow cells with this translocation, one
on the abnormal chromosome 9 and one on the Philadelphia chromosome (Ph
chromosome). D-FISH patterns were abnormal in 30 of 30 specimens with classic,
simple, complex, and masked Ph chromosomes. Based on 200 nuclei from each of 30
normal specimens, the mean percentage of false-positive cells was 0.25 +/- 0.39.
Thirty-seven specimens from 10 patients were studied before treatment and two or
more times at 4-month intervals after treatment with interferon-alpha2b (IFN
alpha2b) with or without ara-C. Based on 200 nuclei, the results of D-FISH in
these specimens correlated closely with quantitative cytogenetics and accurately
quantified disease within a few percent. We studied 6, 000 nuclei for each of six
specimens, three normal and three from patients with chronic myeloid leukemia
(CML) in cytogenetic remission. The normal cutoff for 6,000 nuclei was 0.079% and
patients in cytogenetic remission had residual disease ranging from 7 (0.117%) to
53 (0.883%) Ph-positive nuclei. We conclude that D-FISH can detect the Ph
chromosome and its variant translocations and accurately quantify disease in CML
at diagnosis and at all times after treatment, including cytogenetic remission.
PMID- 9558394
TI - Prognostic value of numerical chromosome aberrations in multiple myeloma: A FISH
analysis of 15 different chromosomes.
AB - Recent observations indicate that chromosome aberrations are important prognostic
factors in patients with multiple myeloma (MM) treated with high-dose
chemotherapy. Nevertheless, the inherent problems of conventional cytogenetics
have hampered the systematic evaluation of this parameter in series of patients
treated with conventional chemotherapy. Fluorescence in situ hybridization (FISH)
analysis is an attractive alternative for evaluation of numerical chromosomal
changes. In the present study, we analyze the relationship between aneuploidies
of 15 different chromosomes assessed by FISH and prognosis in a series of 63
patients with MM treated with conventional chemotherapy. After a median follow-up
of 61 months (range, 6 to 109), 49% of patients are still alive with a median
survival of 33 months. The overall incidence of numerical chromosome
abnormalities was 70%. This incidence significantly increased when seven or more
chromosomes were analyzed (53 patients), reaching 81%. Trisomies of chromosomes
6, 9, and 17 were associated with prolonged survival (P = .033, P = .035, and P =
.026, respectively); by contrast, overall survival (OS) was lower in cases with
monosomy 13 (as assessed by deletion of Rb gene, P = .0012). From the clinical
point of view, loss of Rb gene was associated with a poor performance status; low
hemoglobin levels; high creatinine, C-reactive protein, and lactic dehydrogenase
serum levels; high percentage of bone marrow plasma cells (BMPC); extensive bone
lytic lesions; and advanced clinical stage. Other chromosome abnormalities such
as trisomy of chromosome 9 and 17 were associated with good prognostic features
including high hemoglobin levels, early clinical stage, beta2microglobulin less
than 6 micro/mL, and low percentage of BMPC. A multivariate analysis for OS
showed that S-phase PC greater than 3% (P = .010) and beta2microglobulin serum
levels greater than 6 micro/mL (P = .024), together with monosomy of chromosome
13 (P = .031) and nontrisomy of chromosome 6 (P = .048) was the best combination
of independent parameters for predicting survival in patients with MM. According
to these results, chromosomal analysis is of great use in patients with MM at
diagnosis to have a correct prognostic evaluation for clinical decision making.
PMID- 9558395
TI - Neutropenia associated with T-cell large granular lymphocyte leukemia: long-term
response to cyclosporine therapy despite persistence of abnormal cells.
AB - T-cell large granular lymphocyte (T-LGL) leukemia is clinically indolent, but is
associated with severe neutropenia in approximately 50% of cases. The
pathogenesis of the neutropenia is unclear. We report reversal of severe
neutropenia associated with T-LGL leukemia in five patients treated with
cyclosporine (CSA). All five had persistent neutrophil counts below 0.5 x
10(9)/L, two had agranulocytosis, and four had recurrent infections. Increased
populations of LGL were present in blood and marrow, with a T-LGL immunophenotype
(CD3(+)CD8(+)CD16(+/-)CD56(+/-)CD57(+)) shown by multiparameter flow cytometry,
and clonal T-cell receptor (TCR) gene rearrangements in two of two pretreatment
blood samples studied. CSA was initiated at doses of 1 to 1.5 mg/kg orally every
12 hours, with subsequent dose adjustments based on trough serum levels. Four
patients attained normal neutrophil counts with CSA alone; one required addition
of low-dose granulocyte-macrophage colony-stimulating factor. Time to attainment
of 1.5 x 10(9)/L neutrophils ranged from 21 to 75 days. Attempts to taper and
withdraw CSA resulted in recurrent neutropenia. Three patients have maintained
normal neutrophil counts on continued CSA therapy for 2, 8, and 8.5 years. Two
patients died 1.7 and 4.6 years after initiation of CSA despite normal neutrophil
counts-one of metastatic melanoma and one of complications after aortofemoral
bypass surgery. Despite resolution of neutropenia, increased populations of T-LGL
cells have persisted in all patients during CSA therapy, as shown by morphology
and flow cytometry and by the presence of clonal TCR gene rearrangements in four
patients' posttreatment blood samples. We conclude that CSA is an effective
therapy for neutropenia associated with T-LGL leukemia, and that resolution of
neutropenia despite persistence of abnormal cells implies that CSA may inhibit T
LGL secretion of yet unidentified mediators of neutropenia.
PMID- 9558397
TI - Expression of the T-cell-specific tyrosine kinase Lck in normal B-1 cells and in
chronic lymphocytic leukemia B cells.
AB - Src family kinases play a key role in mitogenesis. The exquisitely tissue
specific distribution of different Src family members suggests that a fine tuning
of their expression might be a key prerequisite for cell homeostasis. We tested B
cells from patients affected by B-cell chronic lymphocytic leukemia (B-CLL) for
expression of Src family kinases. The T-cell-specific tyrosine kinase Lck was
found to be expressed at significant levels in CLL B-cells. This finding could be
accounted for either by ectopic expression of Lck in B-CLL or by specific
expression of this kinase in normal B-1 cells, which are believed to be the
normal counterpart of CLL B cells. To answer this question B cells from different
sources, characterized by a different size of the B-1 subpopulation, were tested
for Lck expression. The results show that Lck expression is a feature of CD5(+),
B-1 cells, suggesting a potential role for Lck in the self-renewal capacity of
this B-cell subpopulation and supporting the notion that B-1 cells are the subset
undergoing oncogenic transformation in B-CLL. Furthermore, we show that the CD5(
), B-2 subpopulation, while normally lacking Lck expression, acquires the
capacity to express Lck ectopically upon transformation by EBV.
PMID- 9558396
TI - Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia:
correlations with In vitro and In vivo chemoresponses.
AB - B-cell chronic lymphocytic leukemia (B-CLL) represents a neoplastic disorder
caused primarily by defective programmed cell death (PCD), as opposed to
increased cell proliferation. Defects in the PCD pathway also contribute to
chemoresistance. The expression of several apoptosis-regulating proteins,
including the Bcl-2 family proteins Bcl-2, Bcl-XL, Mcl-1, Bax, Bak, and BAD; the
Bcl-2-binding protein BAG-1; and the cell death protease Caspase-3 (CPP32), was
evaluated by immunoblotting using 58 peripheral blood B-CLL specimens from
previously untreated patients. Expression of Bcl-2, Mcl-1, BAG-1, Bax, Bak, and
Caspase-3 was commonly found in circulating B-CLL cells, whereas the Bcl-XL and
BAD proteins were not present. Higher levels of the anti-apoptotic protein Mcl-1
were strongly correlated with failure to achieve complete remission (CR) after
single-agent therapy (fludarabine or chlorambucil) (P = .001), but the presence
of only seven CRs among the 42 patients for whom follow-up data were available
necessitates cautious interpretation of these observations. Higher levels of the
anti-apoptotic protein BAG-1 were also marginally associated with failure to
achieve CR (P = .04). Apoptosis-regulating proteins were not associated with
patient age, sex, Rai stage, platelet count, hemoglobin (Hb) concentration, or
lymph node involvement, although higher levels of Bcl-2 and a high Bcl-2:Bax
ratio were correlated with high numbers (>10(5)/microL) of white blood cells
(WBC) (P = .01; .007) and higher levels of Bak were weakly associated with loss
of allelic heterozygosity at 13q14 (P = .04). On the basis of measurements of
apoptosis induction by fludarabine using cultured B-CLL specimens, in vitro
chemosensitivity data failed to correlate with in vivo clinical response rates (n
= 42) and expression of the various apoptosis-regulating proteins. Although
larger prospective studies are required before firm conclusions can be reached,
these studies show the expression in B-CLLs of multiple apoptosis-regulating
proteins and suggest that the relative levels of some of these, such as Mcl-1,
may provide information about in vivo responses to chemotherapy. In vitro
chemosensitivity data, however, do not appear to be particularly useful in
predicting responses in B-CLL.
PMID- 9558398
TI - 6q deletions in acute lymphoblastic leukemia and non-Hodgkin's lymphomas.
AB - Deletions on the long arm of chromosome 6 are frequently found in acute
lymphoblastic leukemia (ALL) and non-Hodgkin's lymphomas (NHL). We have used
polymerase chain reaction analysis to study loss of heterozygosity of 16
microsatellite markers on chromosome 6 in 74 ALL and 54 NHL patients. Our results
show that deletions of 6q in ALL are more frequent than what has been reported in
previous studies, occurring in at least 32% of the patients. The corresponding
figure for NHL patients is 7%. Our results define a region of minimal deletion in
ALL of less than 500 kb between markers D6S1709 and D6S434. The common region of
deletion in NHL is located telomeric of this region. Thus, two different tumor
suppressor genes on chromosome 6q seem to be relevant for the development of
lymphoid malignancies.
PMID- 9558399
TI - A strong expression of CD44-6v correlates with shorter survival of patients with
acute myeloid leukemia.
AB - CD44 is a ubiquitous cell-surface glycoprotein that displays many variant
isoforms (CD44v) generated by alternative splicing of exons 2v to 10v. The
expression of variant isoforms is highly restricted and correlated with specific
processes, such as leukocyte activation and malignant transformation. We have
herein studied CD44v expression in acute myeloid leukemia (AML) and, for
comparison, in normal myelopoiesis. Protein expression of total CD44 and of CD44
3v, -6v, and -9v isoforms has been measured using specific monoclonal antibodies
and flow cytometry. The composition of variant exon transcripts has been analyzed
by semi-quantitative reverse transcriptase-polymerase chain reaction followed by
Southern hybridization with exon-specific probes. Our data show that (1) CD44-6v
isoforms are expressed on 12.0% +/- 2.5% of normal CD34(+) cells; this expression
is sharply upregulated through monopoiesis and, inversely, downregulated during
granulopoiesis. Also, CD44-3v and CD44-9v isoforms are detected on 10% and 14% of
normal monocytes, respectively. (2) Sixty-nine from a total of 95 AML patients
display a variable proportion (range, 5% to 80%) of CD44-6v+ leukemic cells. (3)
A shorter overall survival characterizes the group of AML patients displaying
more than 20% of CD44-6v+ leukemic cells (8 months v 18 months, P < .02). These
data suggest, for the first time, that the protein expression of CD44-6v
containing isoforms may serve as a new prognostic factor in AML.
PMID- 9558400
TI - Inhibition of BCR-ABL expression with antisense oligodeoxynucleotides restores
beta1 integrin-mediated adhesion and proliferation inhibition in chronic
myelogenous leukemia hematopoietic progenitors.
AB - Chronic myelogenous leukemia (CML) is characterized by the continuous
proliferation and abnormal circulation of malignant hematopoietic progenitors.
This may be related to the unresponsiveness of CML progenitors to beta1 integrin
adhesion receptor-mediated inhibition of progenitor proliferation by the marrow
microenvironment. In hematopoietic cell lines, the BCR-ABL oncogene product,
p210(BCR-ABL), interacts with a variety of cytoskeletal elements important for
normal integrin signaling. We studied the role of p210(BCR-ABL) in abnormal
integrin function in CML by evaluating the effect of inhibition of BCR-ABL
expression with antisense oligodeoxynucleotides (AS-ODNs) on integrin-mediated
adhesion and proliferation inhibition of malignant primary progenitors from CML
marrow. Preincubation of CML CD34(+)HLA-DR+ (DR+) cells with breakpoint-specific
AS-ODNs significantly increased adhesion of CML progenitors to stroma and
fibronectin (FN). Pretreatment with breakpoint-specific ODNs also resulted in
significant inhibition of CML progenitor proliferation after ligand or antibody
mediated beta1 integrin engagement. Breakpoint-specific ODNs were significantly
more effective in restoring CML progenitor adhesion and proliferation inhibition
than control ODNs. BCR-ABL mRNA and p210(BCR-ABL) levels in CML CD34(+) cells
were significantly reduced after incubation with breakpoint-specific AS-ODN.
These studies indicate a role for BCR-ABL in abnormal circulation and defective
integrin-dependent microenvironmental regulation of proliferation of CML
hematopoietic progenitors.
PMID- 9558401
TI - Raised neutrophil phospholipase A2 activity and defective priming of NADPH
oxidase and phospholipase A2 in sickle cell disease.
AB - Intermittent painful crises due to vasoocclusion are the major clinical
manifestation of sickle cell disease (SCD), but subclinical episodes may also
occur. There is sparse evidence for the involvement of neutrophils in the
pathophysiology of SCD, but production of cytokines by the damaged endothelium
might influence neutrophil function and modulate responses to subsequent cytokine
exposure. In addition, the activation of neutrophils in the microcirculation
could itself exacerbate vasoocclusion. To test whether neutrophil inflammatory
responses were altered in SCD, neutrophil phospholipase A2 and NADPH oxidase
activity in response to in vitro priming by granulocyte-macrophage colony
stimulating factor (GM-CSF) and tumor necrosis factor-alpha (TNF-alpha) were
measured both during and between painful crises. Resting levels of neutrophil
phospholipase A2 activity in steady-state SCD (4.0% +/- 0. 5% of total cell
radioactivity) were raised relative to control values (2.0% +/- 0.2%, n = 10, P =
.008). There was no defect of agonist-stimulated phospholipase A2 or NADPH
oxidase activity in steady-state SCD; however, the ability of phospholipase A2 to
respond to priming with GM-CSF was attenuated to 63% +/- 17% of control values (n
= 10, P = .04). Similarly, neutrophil NADPH oxidase activity after priming with
GM-CSF and TNF-alpha was, respectively, 65% +/- 11% (n = 7, P = .03) and 57% +/-
7% of control (n = 10, P = .007) in steady-state disease, and was further reduced
during painful vasoocclusive crises to 34% +/- 9% and 25% +/- 3% of control for
GM-CSF and TNF-alpha, respectively. These data were not explained by poor splenic
function or any racial factor, as normal cytokine responses were seen in
splenectomized patients in remission from Hodgkin's disease and in healthy Afro
Caribbean subjects. Abnormal neutrophil cytokine priming responses were not
observed in either patients with rheumatoid arthritis or iron-deficiency anemia.
Our findings are indicative of an ongoing inflammatory state in SCD between
painful crises involving neutrophil activation and an abnormality of cytokine
regulated neutrophil function, which may compromise the host defenses against
certain microorganisms.
PMID- 9558402
TI - Galectin-3 activates the NADPH-oxidase in exudated but not peripheral blood
neutrophils.
AB - Galectin-3, a lactose-binding mammalian lectin that is secreted from activated
macrophages, basophils, and mast cells, was investigated with respect to its
ability to activate the human neutrophil NADPH-oxidase. The galectin-3-induced
activity was determined with in vivo exudated cells (obtained from a skin
chamber) and compared with that of peripheral blood neutrophils. Galectin-3 was
found to be a potent activator of the NADPH-oxidase only in exudated neutrophils
and the binding of galectin-3 to the surface of these cells was increased
compared with peripheral blood cells. Different in vitro priming protocols
resulting in degranulation were used to mimic the exudation process in terms of
increasing the receptor exposure on the cell surface. Galectin-3 could induce an
oxidative response similar to that in exudated cells only after a significant
amount of the intracellular organelles had been mobilized. This increase in
oxidative response was paralleled by an increased binding of galectin-3 to the
surface of the cells. The major conclusion of the study is that galectin-3 is a
potent stimulus of the neutrophil respiratory burst, provided that the cells have
first experienced an extravasation process. The results also imply that the
neutrophil response to galectin-3 could be mediated through receptors mobilized
from intracellular granules, and we report the presence of galectin-3-binding
proteins in such organelles.
PMID- 9558403
TI - Reduced ex vivo interleukin-8 production by neutrophils in septic and nonseptic
systemic inflammatory response syndrome.
AB - Ex vivo cytokine production by circulating lymphocytes and monocytes is reduced
in patients with infectious or noninfectious systemic inflammatory response
syndrome. Very few studies have addressed the reactivity of polymorphonuclear
cells (PMN). To analyze further the relative contribution of systemic
inflammatory response syndrome alone or in combination with infection we studied
the interleukin-8 (IL-8) production by PMN isolated from patients who had
undergone cardiac surgery with cardiopulmonary bypass (CPB) and patients with
sepsis. Cells were activated with either lipopolysaccharide (LPS) or heat-killed
streptococci. Compared with healthy controls, the release of IL-8 by PMN in both
groups of patients was significantly reduced whether activated by LPS,
independently of its concentration and origin, or by heat-killed streptococci.
These observations suggest that stressful conditions related to inflammation,
independently of infection, rapidly dampened the reactivity of circulating PMN.
We investigated whether the observed diminished reactivity of PMN might reflect
an endotoxin tolerance phenomenon. Our in vitro experiments with PMN from healthy
controls indicated that PMN could not be rendered tolerant stricto sensu.
However, our data suggested that LPS-induced mediators such as IL-10 may be
responsible for the observed anergy in patients.
PMID- 9558404
TI - Mechanisms of transcription in eosinophils: GATA-1, but not GATA-2,
transactivates the promoter of the eosinophil granule major basic protein gene.
AB - Granule major basic protein (MBP) is expressed exclusively in eosinophils,
basophils, and placental trophoblasts. To identify the cis-elements and
transcription factors involved in regulating MBP expression, we subcloned 3.2 kb
of sequence upstream of the exon 9 transcriptional start site (P2 promoter) and
serial 5' deletions into the pXP2 luciferase reporter vector. An 80% decrement in
promoter activity was obtained when MBP sequences between bp -117 to -67 were
deleted. To identify transcription factors that bind to and transactivate through
the bp -117 to -67 region, we first compared the upstream genomic sequences of
human and murine MBP; a potential GATA binding consensus site was conserved in
the 50-bp region between the two genes. To determine which GATA proteins bind
this consensus site, we performed electrophoretic mobility shift assays (EMSAs),
which showed that both GATA-1 and GATA-2 can bind to this consensus site. To
determine the functionality of this site, we tested whether GATA-1 and GATA-2,
either individually or in combination, can transactivate the MBP promoter in the
Jurkat T cell line. Cotransfection with a GATA-1 expression vector produced 20
fold augmentation of MBP promoter activity, whereas GATA-2 had no activity. In
contrast, combined cotransfection of GATA-1 and GATA-2 decreased the ability of
GATA-1 to transactivate the MBP promoter by approximately 50%. Our results
provide the first evidence for a GATA-1 target gene in eosinophils, a negative
regulatory role for GATA-2 in MBP expression, and possibly eosinophil gene
transcription in general during myelopoiesis.
PMID- 9558405
TI - Erythroid maturation and globin gene expression in mice with combined deficiency
of NF-E2 and nrf-2.
AB - NF-E2 binding sites, located in distant regulatory sequences, may be important
for high level alpha- and beta-globin gene expression. Surprisingly, targeted
disruption of each subunit of NF-E2 has either little or no effect on erythroid
maturation in mice. For p18 NF-E2, this lack of effect is due, at least in part,
to the presence of redundant proteins. For p45 NF-E2, one possibility is that NF
E2-related factors, Nrf-1 or Nrf-2, activate globin gene expression in the
absence of NF-E2. To test this hypothesis for Nrf-2, we disrupted the Nrf-2 gene
by homologous recombination. Nrf-2-deficient mice had no detectable hematopoietic
defect. In addition, no evidence was found for reciprocal upregulation of NF-E2
or Nrf-2 protein in fetal liver cells deficient for either factor. Fetal liver
cells deficient for both NF-E2 and Nrf-2 expressed normal levels of alpha- and
beta-globin. Mature mice with combined deficiency of NF-E2 and Nrf-2 did not
exhibit a defect in erythroid maturation beyond that seen with loss of NF-E2
alone. Thus, the presence of a mild erythroid defect in NF-E2-deficient mice is
not the result of compensation by Nrf-2.
PMID- 9558406
TI - Comparative oxidation of hemoglobins A and S.
AB - The mutant hemoglobin S (HbS) previously was reported to undergo accelerated
autooxidation during incubation in vitro. However, subsequent observations have
raised the possibility that this might be explained by adventitious association
of molecular iron with HbS, rather than reflecting an inherent property of HbS.
Using purified HbA and HbS obtained from genotypic HbAS donors, we found that the
observed oxidation rate of HbS, but not of HbA, is indeed exaggerated by
adventitious iron. This result suggests a preferential partitioning of molecular
iron to HbS over HbA, which was further supported by experimentation. However,
after elimination of this effect, there still remains a significant increase in
inherent autooxidation rate for HbS. Physiologic oxidants (superoxide, peroxide,
hydroxyl radical) and various Fe(III) chelates all stimulate oxidation of oxyHb,
but they do so equivalently for HbA and HbS. Nevertheless, these mechanisms also
would contribute to excessive biologic oxidation of HbS because the cytoplasm of
sickle red blood cells, unlike that of normal cells, would be exposed to abnormal
amounts of oxidants and low-molecular-weight iron compounds.
PMID- 9558407
TI - Mouse hypoxia-inducible factor-1alpha is encoded by two different mRNA isoforms:
expression from a tissue-specific and a housekeeping-type promoter.
AB - Hypoxic induction of erythropoietin (Epo) and other oxygen-dependent genes is
mediated by the hypoxia-inducible factor-1 (HIF-1), a heterodimeric
transactivator consisting of an alpha and a beta subunit. We previously found
that the mouse gene encoding HIF-1alpha harbors two alternative first exons (I.1
and I.2), giving rise to two different HIF-1alpha mRNA isoforms. Here, we show by
RNase protection analysis that the exon I.1-derived mRNA isoform is
differentially expressed in mouse tissues, being highest in kidney, tongue,
stomach, and testis, but undetectable in liver, whereas the exon I.2 mRNA isoform
is ubiquitously expressed. Sequence and methylation analysis showed that, in
contrast to exon I.1, exon I.2 resides within a region showing typical features
of a CpG island, known to be associated with the 5' end of housekeeping genes. We
identified a 232-bp minimal exon I.2 promoter that strongly induced reporter gene
expression in mouse L929 fibroblasts and Hepa1 hepatoma cells. In contrast to
L929 cells, the exon I.1 promoter was inactive in Hepa1 cells and hypoxic
exposure (1% O2) markedly reduced exon I.2 promoter activity in Hepa1 cells.
Prolonged exposure of mice to hypoxia (7.5% O2 for up to 72 hours) also caused a
decrease in liver HIF-1alpha mRNA, whereas aldolase mRNA levels increased. These
findings might be related to the relatively low Epo levels in the adult liver.
PMID- 9558408
TI - Identification of patients who may benefit from prophylactic immunotherapy after
bone marrow transplantation for acute myeloid leukemia on the basis of lymphocyte
recovery early after transplantation.
AB - Two hundred and one patients (median age, 29 years) with acute myeloid leukemia
(AML) underwent bone marrow transplantation (BMT) from HLA-identical sibling
donors after conditioning with melphalan-total-body irradiation (TBI) (57%),
cyclophosphamide-TBI (35%), or chemotherapy alone (8%). Graft-versus-host disease
(GVHD) prophylaxis included cyclosporine alone (68%), cyclosporine-methotrexate
(26%), or T-cell depletion (6%). The probability of relapse was calculated as a
function of the absolute lymphocyte count (10(9)/L) on days 27 to 30
posttransplant (<0.1 v >/=0.1, <0.2 v >/=0.2, and <0.3 v >/=0.3). In each of
these 12 comparisons, the probability of relapse was higher for the group with
the lower lymphocyte count. Because the difference was most significant (P =
.004) for an absolute lymphocyte count of <0.2 on day 29 (3-year relapse
probability, 42%) versus >/= 0.2 (16%), this variable was included in a Cox model
to determine factors independently affecting relapse. Multivariate analysis
showed that conditioning regimens other than melphalan-TBI, a low lymphocyte
count on day 29, French-American-British (FAB) subtypes M4-7, and a nucleated
cell dose of > 2.42 x 10(8)/kg was associated with a higher risk of relapse. We
conclude that slow lymphocyte recovery after allogeneic BMT, to < 0.2 x 10(9)/L
29 days in this analysis, appears to be associated with a higher risk of relapse
in patients with AML. This group of patients may benefit from posttransplant
immune manipulations such as abbreviated GVHD prophylaxis, or donor cell or
cytokine administration to enhance graft-versus-leukemia reactions to reduce
relapse.
PMID- 9558409
TI - Efficient retroviral-mediated gene transfer to human cord blood stem cells with
in vivo repopulating potential.
AB - Recent studies have shown efficient gene transfer to primitive progenitors in
human cord blood (CB) when the cells are incubated in retrovirus-containing
supernatants on fibronectin-coated dishes. We have now used this approach to
achieve efficient gene transfer to human CB cells with the capacity to regenerate
lymphoid and myeloid progeny in nonobese diabetic (NOD)/severe combined
immunodeficiency (SCID) mice. CD34(+) cell-enriched populations were first
cultured for 3 days in serum-free medium containing interleukin-3 (IL-3), IL-6,
granulocyte colony-stimulating factor, Flt3-ligand, and Steel factor followed by
two 24-hour incubations with a MSCV-NEO virus-containing medium obtained under
either serum-free or serum-replete conditions. The presence of serum during the
latter 2 days made no consistent difference to the total number of cells, colony
forming cells (CFC), or long-term culture-initiating cells (LTC-IC) recovered at
the end of the 5-day culture period, and the cells infected under either
condition regenerated similar numbers of human CD34(+) (myeloid) CFC and human
CD19(+) (B lymphoid) cells for up to 20 weeks in NOD/SCID recipients. However,
the presence of serum increased the viral titer in the producer cell-conditioned
medium and this was correlated with a twofold to threefold higher efficiency of
gene transfer to all progenitor types. With the higher titer viral supernatant,
17% +/- 3% and 17% +/- 8%, G418-resistant in vivo repopulating cells and LTC-IC
were obtained. As expected, the proportion of NEO + repopulating cells determined
by polymerase chain reaction analysis of in vivo generated CFC was even higher
(32% +/- 10%). There was no correlation between the frequency of gene transfer to
LTC-IC and colony-forming unit-granulocyte-macrophage (CFU-GM), or to NOD/SCID
repopulating cells and CFU-GM (r2 = 0.16 and 0.17, respectively), whereas values
for LTC-IC and NOD/SCID repopulating cells were highly and significantly
correlated (r2 = 0.85). These findings provide further evidence of a close
relationship between human LTC-IC and NOD/SCID repopulating cells (assessed using
a >/= 6-week CFC output endpoint) and indicate the predictive value of gene
transfer measurements to such LTC-IC for the design of clinical gene therapy
protocols.
PMID- 9558410
TI - Epitope specificity of CD44 for monoclonal antibody-dependent facilitation of
marrow engraftment in a canine model.
AB - Primary graft rejection after marrow transplantation occurs more frequently in
patients receiving HLA-haploidentical compared with HLA-identical sibling
transplants. Both human and experimental animal data suggest that the cells
responsible for this phenomenon are either host natural killer (NK) cells, T
cells, or both. To investigate the mechanisms of graft rejection, we have
developed a canine model of marrow transplantation, which uses DLA-nonidentical
unrelated donors in the absence of postgrafting immunosuppression. In this model
most animals rejected their marrow grafts after a preparative regimen of 9.2 Gy
total body irradiation (TBI). However, engraftment of DLA-nonidentical marrow can
be facilitated when the recipients are pretreated with monoclonal antibody (MoAb)
S5, which recognizes CD44. In this report, we extended these observations by
first cloning the canine CD44 and, next, mapping the epitope recognized by S5,
which was located in a region conserved among human and canine CD44 and was
distinct from the hyaluronan binding domain. However, in vitro binding of S5
caused a conformational change in CD44, which allowed increased hyaluronan
binding. Then, we reexamined the in vivo model of marrow transplantation and
compared results with MoAb S5 to those with two other anti-CD44 MoAbs, IM7 and
S3. Only MoAb S5 significantly increased the engraftment rate of DLA-nonidentical
unrelated marrow, whereas the two other anti-CD44 MoAbs were ineffective. The
enhanced in vivo effect was not related to differences in the MoAbs' avidities,
since both S5 and IM7 had equivalent binding to CD44, but most likely related to
the specific epitope that S5 recognizes. Thus, this study shows that the effect
of the anti-CD44 MoAb S5 in facilitating engraftment is epitope specific and if
one is to use an anti-CD44 to facilitate engraftment of marrow in humans, one
cannot assume that any anti-CD44 would work.
PMID- 9558411
TI - Low transplant mortality in allogeneic bone marrow transplantation for acute
myeloid leukemia: a randomized study of low-dose cyclosporin versus low-dose
cyclosporin and low-dose methotrexate.
AB - Sixty patients undergoing allogeneic bone marrow transplant for acute myeloid
leukemia (AML) in first remission (CR1; n = 49) or more advanced phase (n = 11)
were entered in a prospective trial of graft-versus-host disease (GvHD)
prophylaxis: low-dose cyclosporin A (IdCSA; 1 mg/kg/d from day -1 to +20 day; n =
28) or IdCSA plus low-dose methotrexate (IdMTX; 10 mg/m2 for day +1, 8 mg/m2 for
days +3, +6, and +11; n = 32). Primary end points were acute GvHD (aGvHD) and
transplant-related mortality (TRM); secondary end points were relapse and
survival. The conditioning regimen consisted of cyclophosphamide (120 mg/kg) and
fractionated total body irradiation (3.3 Gy/d for 3 consecutive days). The
actuarial risk of developing aGvHD grade II-III was 61% for IdCSA alone and 34%
for IdCSA + IdMTX (P = .02). The actuarial risk of TRM at 1 year was 11% versus
13%, respectively, and older patients (>/= 29 years) had higher TRM than younger
patients (22% v 5%, P = .01). The age effect was significant in the IdCSA group
(P = .04) but not in the IdCSA + IdMTX group (P = .1). The median follow-up is
4.4 years, with an overall actuarial survival of 78% for CR1 patients and 36% for
patients with advanced disease. For patients in CR1 the outcome of the two
regimens was as follows: survival 77% versus 80% (P = .6), relapse 20% versus 9%
(P = .1), and TRM 13% versus 17% (P = .6). This study suggests that TRM can be
reduced in AML patients undergoing allogeneic marrow transplants with a mild
conditioning regimen and low-dose immunosuppression, and this translates in a 78%
5-year survival for CR1 patients. Beyond CR1 the major obstacle remains leukemia
relapse, which is not prevented by low-dose in vivo immunosuppression.
PMID- 9558412
TI - A multicenter study of platelet recovery and utilization in patients after
myeloablative therapy and hematopoietic stem cell transplantation.
AB - An observational study was conducted at 18 transplant centers in the United
States and Canada to characterize the platelet recovery of patients receiving
myeloablative therapy and stem cell transplantation and to determine the clinical
variables influencing recovery, determine platelet utilization and cost, and
incidence of hemorrhagic events. The study included 789 evaluable patients
transplanted in 1995. Clinical, laboratory, and outcome data were obtained from
the medical records. Variables associated with accelerated recovery in
multivariate models included (1) higher CD34 count; (2) higher platelet count at
the start of myeloablative therapy; (3) graft from an HLA-identical sibling
donor; and (4) prior stem cell transplant. Variables associated with delayed
recovery were (1) prior radiation therapy; (2) posttransplant fever; (3) hepatic
veno-occlusive disease; and (4) use of posttransplant growth factors. Disease
type also influenced recovery. Recipients of peripheral blood stem cells (PBSC)
had faster recovery and fewer platelet transfusion days than recipients of bone
marrow (BM). The estimated average 60-day platelet transfusion cost per patient
was $4,000 for autologous PBSC and $11,000 for allogeneic BM transplants. It was
found that 11% of all patients had a significant hemorrhagic event during the
first 60 days posttransplant, contributing to death in 2% of patients. In
conclusion, clinical variables influencing platelet recovery should be considered
in the design and interpretation of clinical strategies to accelerate recovery.
Enhancing platelet recovery is not likely to have a significant impact on 60-day
mortality but could significantly decrease health care costs and potentially
improve patient quality of life.
PMID- 9558413
TI - Oligoclonal protein bands and Ig isotype switching in multiple myeloma treated
with high-dose therapy and hematopoietic cell transplantation.
AB - Multiple myeloma (MM) is usually characterized by production of a single serum
monoclonal protein of constant isotype and light-chain restriction. Multiple Ig
isotypes and isotype switches, which are rare in untreated patients, are reported
to be more common in patients undergoing myeloablative therapy. These additional
protein bands, detected by immunofixation electrophoresis (IFE), could be due to
altered paraprotein production by the malignant plasma cell clone or oligoclonal
Ig production during recovery of B-cell function after myeloablative therapy. We
analyzed abnormal protein bands (APB), distinct from the presenting paraprotein,
in 550 patients receiving high-dose therapy with autologous hematopoietic cell
transplantation at a single institution. Fifty-five patients (10%) had APB, 48
had oligoclonal bands (OB), and 23 had an apparent isotype switch (IS) on IFE (16
had both OB and IS). Morphologic and flow cytometric examination of bone marrow
in 17 patients with IS showed no evidence of a clonal plasma cell isotype switch.
Patients with APB had significantly higher complete response to therapy (67% v
37%, P = .001). To assess the independent prognostic relevance of APB, a
multivariate analysis was performed among 471 patients surviving at least 12
months from first transplant (all patients developing APB had done so by 12
months from first transplant). APB (in 50 patients) was a favorable feature for
both event-free (rank 3, P = .004) and overall survival (rank 3, P = .0005). We
propose that OB and IS are likely to be due to recovery of Ig production rather
than alterations in the biology of the malignant plasma cell clone.
PMID- 9558414
TI - Congenital anhaptoglobinemia versus acquired hypohaptoglobinemia.
PMID- 9558415
TI - Community pharmacy strives for continuity of care.
PMID- 9558416
TI - Oral naratriptan approved for migraine attacks.
PMID- 9558417
TI - Spike in managed care enrollment curbed employer health costs in 1997, survey
shows.
PMID- 9558418
TI - Report identifies research priorities for improving end-of-life care.
PMID- 9558419
TI - Accessing investigational anticancer agents outside of clinical trials.
PMID- 9558420
TI - Helping HIV-infected patients at the clinic.
PMID- 9558421
TI - Change of perspective.
PMID- 9558422
TI - The vertically integrated pharmacy department.
AB - Pharmacy's challenges and opportunities during a transition from a traditional
hospital to an integrated health system are discussed with reference to the
experience of a medical center in Vancouver, Washington. When a traditional
hospital makes the transition to an integrated health system, pharmacy directors
must consider how the core business will be affected, how pharmacy can add value,
and how to best apply the skills of the pharmacy department. A well-trained staff
that shares a view of the new organization and that can think outside the
traditional hospital paradigm is required. New health systems will focus on
quality-related outcomes at low cost and on disease management. Partnerships
between providers and health care staff will be beneficial. To compete for
capitated contracts, health systems will need to deliver services other than
acute care to a broad geographic area, and primary care will be more prominent.
There will be a shift toward outpatient services, and pharmacy departments will
be under increasing pressure to develop outpatient pharmaceutical services.
Pharmacy departments will also need to develop treatment guidelines for
outpatients and to better manage drug costs by working with new business clients,
improving continuity of care, increasing patients' access to care, having
pharmacists provide hospice care, and implementing remote prescription-order
entry. New health systems will need to have a clear understanding of how their
core business is changing; the organizational strategy of a health system must
include effective communication of change to staff members with the goal of
overcoming traditional thinking.
PMID- 9558423
TI - Catecholamines and their blockade in congestive heart failure.
AB - The hemodynamic effects of sympathetic nervous system stimulation and the
benefits of catecholamine blockade in patients with congestive heart failure
(CHF) are discussed. Prolonged stimulation of the sympathetic nervous system
promotes disease progression in patients with CHF. The level of circulating
norepinephrine is the factor most closely correlated with prognosis. Long-term
catecholamine stimulation of beta-receptors in the myocardium reduces the ability
of catecholamines to improve cardiac contractility. CHF patients have higher
vascular resistance (afterload) than healthy persons, increasing the strain on
the heart. Also, beta 1-adrenergic activity stimulates renin release, which is
deleterious in CHF. Clinical trials suggest that long-term (greater than one
month), carefully dose-adjusted therapy with beta-blockers improves symptoms,
ventricular ejection fraction, exercise time, and quality of life in patients
with CHF, but it is unclear whether beta-blockers reduce mortality. Some patients
cannot tolerate even the lowest starting dosages of beta-blockers, and withdrawal
of these agents may result in clinical and hemodynamic deterioration. Carvedilol,
which has beta-blocking, alpha-blocking, and antioxidant properties, is
associated with a reduction in hospitalizations and symptoms and improvements in
ejection fraction it also appears to reduce mortality, although confirmatory
studies are needed. Initiation of carvedilol therapy can cause symptomatic and
hemodynamic worsening in the short term, and some patients cannot tolerate it.
Adrenergic blocking agents are important components of therapy for CHF.
Carvedilol may prove useful in reducing symptoms and improving survival in these
patients.
PMID- 9558424
TI - Drug stability and pyridine generation in ceftazidime injection stored in an
elastomeric infusion device.
PMID- 9558425
TI - FDA comments on activities in states concerning narrow-therapeutic-index drugs.
PMID- 9558426
TI - In favor of Coumadin over generic warfarin.
PMID- 9558427
TI - Reflections on generic warfarin.
PMID- 9558428
TI - Somatropin administration by three drug-delivery systems.
PMID- 9558429
TI - Oral syringe for extemporaneously preparing doses.
PMID- 9558430
TI - [The central vein catheter--a (simple) routine measure?].
PMID- 9558431
TI - [Pharmacologic aspects of polyunsaturated fatty acids in parenteral nutrition].
AB - Despite immense progress in intensive-care medicine, mortality rates of 30-70% in
sepsis and SIRS are still an unresolved problem. Particularly the failure of
respiratory and other vital functions is a major cause of death. Besides
infectious stimuli (viruses, bacteria, fungi) a variety of non-infectious
triggers (tissue damage, immune complexes, complement activation, etc.) can
initiate the development of organ failure. These inflammatory reactions aim
physiologically towards inactivation and removal of the stimulating agents as
well as the induction of reparative processes. In states of prolonged activation
of humoral and cellular mediator systems the natural host defence mechanisms
react in an uncontrolled manner causing tissue damage and organ failure. So far
there are no efficient therapeutic strategies to influence these complex
inflammatory reactions. In the development of SIRS and sepsis, pro-inflammatory
lipid mediators play a crucial role. Omega-3-fatty acids (omega-3-PUFAs) have
shown anti-inflammatory and antithrombotic properties in a great number of
experimental and clinical studies. These effects seem to be related to the uptake
of eicosapentaenoic acid (EPA) into cellular membrane lipid pools and its
subsequent metabolisation. After inflammatory activation EPA is released besides
arachidonic acid (AA) and competes with AA for metabolisation via the cyclo- and
lipoxygenase pathway. Compared to AA the derivatives of EPA have less pro
inflammatory and chemotactic characteristics. With regard to prophylactic and
therapeutic consequences it appears reasonable to supplement omega-3-PUFAs to
attenuate the inflammatory response by modulating the generation of lipid
mediators during inflammation.
PMID- 9558433
TI - [Aloys Martin and the Society of German Physicians in Paris].
AB - The news about the discovery of the anaesthetic properties of ether swept rapidly
from America to Europe. The first informations concerning this topic reached
England in late fall of 1846 and after that came to France and especially Paris.
The German physician Aloys Martin from Munich who was living in Paris at that
time was largely responsible for conveying the news about these new findings in
medical science to the German-speaking nations. Controversial discussions
concerning the anaesthetic properties of ether developed among the members of
various scientific circles right after the news from America had reached the city
-and many members of the "Verein Deutscher Aerzte in Paris" (Association of
German Physicians in Paris) took part in them, Martin then was one of the club's
most active members and repeatedly reported on the new method as a correspondent
for the widely read "Augsburger Allgemeine Zeitung": Documents discovered
recently at the archives of the "Leopoldinisch-Carolinischen Akademie" of Halle
provide an interesting insight into this association, whose members tried to find
out more about the anaesthetic properties and side effects of ether carrying out
a series of well appreciated self-experiments in the spring of 1847. The
following text reports on the history of the "Verein Deutscher Aerzte in Paris"
which has largely fallen into oblivion and emphasizes the importance of Aloys
Martin whose name is strongly attached to the spread of the use of ether
throughout the German-speaking countries.
PMID- 9558432
TI - [Electrophysiologic arousal reactions during sufentanil-/isoflurane anesthesia].
AB - PURPOSE: There is controversy about relevant EEG signal changes indicating
adequate or inadequate anaesthesia. Differences of drug-induced and nociceptive
mediated signal changes have not been studied in detail. The present study
investigates whether signal changes during decreases of depth of anaesthesia due
to surgical stimulation depend on different isoflurane concentrations during
sufentanil anaesthesia. METHODS: Following IRB approval and written informed
consent 28 patients (ASA: I; age 43 +/- 11 y) scheduled for elective abdominal
surgery were included in the study. Anaesthesia: propofol (2.0 mg/kg) and
sufentanil (1.0 micrograms/kg). Following endotracheal intubation (vecuronium 0.1
mg/kg) patients were normoventilated (P(ET)CO2: 36-38 mmHg). Randomly assigned to
steady-state anaesthesia (group 1: P(ET)Isoflurane 0.2%, (14n); group 2:
P(ET)Isoflurane 0.6%, (14n) during the start of surgery. Monitoring: heart rate
(HF), mean arterial blood pressure (MAP), P(ET)CO2, arterial oxygen saturation
and rectal temperature. EEG (16 channels referenced to Cz; CATEEM, Medisyst,
Linden) recorded 5 min before until 10 min after the start of surgery. EEG
analysis (FFT: 4s, 256/s, 0.45-35.0 Hz): topographical distribution of power
spectral densities (delta, theta, alpha 1, and alpha 2). Artifact control: ECG
and EOG. RESULTS: Surgical stimulation resulted in increases of MAP in both
groups (p < 0.05 vs BL), whereas HR was only slightly affected in group 2 when
compared with BL. Other variables except of EEG data did not change over time. In
group 1 (0.2% isoflurane) surgical stimulation resulted in decreases of delta
over the whole cortex (F2, C3, P3, O1) and in marked increases of alpha
predominantly at central leads (C3)(p < 0.05 vs BL). In group 2 (0.6% isoflurane)
nociceptive stimulation was associated with decreases of faster waves (alpha:
F3)(p < 0.05 vs BL) and increases in delta at fronto-central areas (F3, C3)(p <
0.05 vs BL). CONCLUSIONS: EEG recordings are useful in assessing pharmacodynamic
drug effects. In contrast, intraoperative EEG recordings have a low correlation
to clinical signs of changes in the anaesthetic state. Previous studies
demonstrate paradoxical EEG-arousal reactions during isoflurane anaesthesia. The
present data suggest that classical or even paradoxical EEG arousal due to
nociceptive stimulation may depend on the isoflurane concentration. It seems
reasonable that the ascending reticular formation is functionally blocked by
isoflurane in a dose-dependent manner.
PMID- 9558434
TI - [Control of the position of the central venous catheter--problems in choice of
methods].
PMID- 9558435
TI - [Development and current status of electrocardiographic position control of the
central venous catheter].
PMID- 9558436
TI - [Control of central venous catheter position by ECG recording with the guide
wire].
PMID- 9558437
TI - [ECG control of the position of the central venous catheter using the Seldinger
guide wire: clinical and economic aspects].
PMID- 9558438
TI - [The cava-catheter from the medico-legal viewpoint].
PMID- 9558439
TI - [Is the laryngeal mask a device for preclinical resuscitation?--Pro].
PMID- 9558440
TI - [Is the laryngeal mask a device for preclinical resuscitation?--Contra].
PMID- 9558441
TI - [Successful resuscitation after bolus injection of tissue-type plasminogen
activator in emergency admission].
AB - We report on a 30-year old female patient with suspected fulminant pulmonary
embolism and cardiac arrest following ambulatory arthroscopy nine days before the
event. After 15 minutes of unsuccessful cardiopulmonary resuscitation (CPR) on
the ambulance the patient was transferred to the emergency unit of a hospital and
was treated with bolus injection of 50 mg t-PA initially and 50 mg over the next
two hours. Five minutes after the initial bolus the circulation could be
stabilised and the patient could be extubated the next morning. The patient did
not present any neurological deficit on the day of discharge nor did she show any
bleeding complications. The time elapsing from notice to emergency service to
arrival at hospital was about 35 minutes. DISCUSSION: In patients with massive
and life-threatening pulmonary embolism thrombolysis offers an opportunity to
manage this critical situation. Due to the serious prognosis of these patients
the potential benefit of thrombolysis outweighs the lack of preceding diagnostic
procedures and the risk of potential side-effects. CONCLUSION: In the light of an
excellent outcome of this patient thrombolytic therapy with t-PA appears to be
justified under continued CPR if fulminant pulmonary embolism is suspected.
PMID- 9558442
TI - Neither castration nor steroid-replacement change the apparent molecular size of
FSH in the sheep pituitary.
AB - Gonadal steroids alter the apparent molecular size of intrapituitary Follicle
Stimulating Hormone (FSH) in rats and monkeys as well as increase the percentage
of acidic FSH isohormones in sheep. Hence, we hypothesized that the molecular
size of ovine (o) FSH would be increased by gonadal steroids. Extracts of
pituitaries from rams and wethers, as well as, from wethers which had been
implanted with dihydrotestosterone (DHT), 17 beta-estradiol (E2) or both steroids
(n = 4-6 per treatment group) were subjected to analytical gel permeation
chromatography using Sephadex g-100 Superfine. FSH concentrations in
chromatographic fractions were determined by radioimmunoassays. Although FSH in
pituitaries of non-implanted wethers eluted slightly earlier (i.e. larger) than
FSH in pituitaries from E2-implanted wethers as evaluated by distribution
coefficients (Kds) during chromatography (P < 0.05), gonadal steroids did not
consistently increase Kds but tended to decrease them. When Kds were extrapolated
to apparent molecular weights using a series of standard proteins (bovine serum
albumin (bSA), ovalbumin (OA), carbonic anhydrase (CA) and cytochrome c (CC))
that were included in each chromatogram, the differences between treatment groups
were not statistically significant (P > 0.05). Thus, in contrast to rats and
monkeys, neither castration nor steroid-replacement appears to alter the
molecular size of FSH in the sheep pituitary as evaluated by analytical gel
permeation chromatography.
PMID- 9558443
TI - Unilateral spontaneous abdominal cryptorchidism: structural and ultrastructural
study of sperm morphology.
AB - Sperm morphology of three healthy boars and three boars with spontaneous
abdominal cryptorchidism in the right testis has been evaluated by light
microscopy. For each boar, two ejaculates have been analysed, corresponding to
semen collections at the ages of 6.5 months (first collection) and 8 months
(seventh collection). A comparative study of the sperm malformations present in
the seventh semen collection between the healthy boars and the unilateral
abdominal cryptorchid boars has also been performed by light microscopy. Sperm
malformations of the seventh semen collection from the unilateral abdominal
cryptorchid boars have been examined by scanning and transmission electron
microscopy. The frequency of mature spermatozoa, immature spermatozoa, aberrant
spermatozoa and detached heads maintained normals values in the first and the
seventh semen collection from the unilateral abdominal cryptorchid boars. The
comparative study of sperm abnormalities in the seventh semen collection between
the cryptorchid boars and the healthy boars indicated that the unilateral
abdominal cryptorchid boars had a significantly higher frequency of primary
abnormalities, and a significantly lower frequency of secondary abnormalities.
Some primary abnormalities, such as crater defect, knobbed acrosome defect,
nuclear crests and abaxial tails were only observed in the unilateral abdominal
cryptorchid boars. It was concluded that unilateral abdominal cryptorchidism
provokes disturbances in the late stages of spermiogenesis, at testicular level.
Alterations in the sperm maturation process at epididymal level were not found.
PMID- 9558445
TI - Adverse effects of nonsteroidal anti-inflammatory drugs on the gastrointestinal
system.
AB - Two enzymes, cyclo-oxygenase (COX) and 5-lipoxygenase, act upon arachidonic acids
to produce prostaglandins and leukotrienes. Inhibition of COX-2 by non-steroidal
anti-inflammatory drugs (NSAIDs) lowers synthesis of proinflammatory
prostaglandins and produces analgesia. COX-2 is highly inducible by endotoxin, IL
1, hypoxia, epidermal growth factor (EGF), benzo[a]pyrene, and transforming
growth factor beta 1(TGF-beta 1). COX-1 in constitutively expressed. Conventional
NSAIDs also inhibit the synthesis of cytoprotective prostaglandins by COX-1 in
the gastrointestinal tract. Surplus arachidonic acids accumulate and enhance the
generation of leukotrienes via the lipoxygenase pathway inducing neutrophil
adhesion to endothelium and vasoconstriction. The NSAIDs harboring a carboxyl
group also inhibit oxidative phosphorylation (OXPHOS) lowering adenosine
triphosphate (ATP) generation leading to loss of mucosal cell tight junctions and
increased mucosal permeability. Administration of NSAIDs that do not interfere
with OXPHOS, and concomitant use of prostaglandin analogues to restore
cytoprotection reduces complications of NSAID use. However, no NSAID that lacks
potential for serious gastrointestinal toxicity is currently available. Selective
inhibitors of COX-2 and 5-lipoxygenase are newer, promising drugs. Surprisingly,
COX-2 null mice are able to mount an inflammatory response, suffering however,
from kidney dysfunction and a shortened life span. Results of clinical studies on
the long-term use of NSAID drugs such as selective inhibitors are still pending.
PMID- 9558444
TI - A role for lipoxygenase metabolites of arachidonic acid in porcine ovulation.
AB - Prostaglandins, products of arachidonic acid via the cyclooxygenase pathway, are
essential to the porcine ovulatory process in that inhibition of their synthesis
results in ovulation failure. Studies in the rat have shown that ovulation is
also preceded by a rise in three ovarian hydroxyeicosatetraenoic acids, products
of the lipoxygenase pathway, and inhibition of this pathway also inhibits
ovulation. Experiments were designed, using a pregnant mare serum
gonadotropin/human chorionic gonadotropin (hCG)-treated prepuberal gilt model, to
measure pre-ovulatory changes in follicular fluid concentrations of 15
hydroxyeicosatetraenoic acid (15-HETE), and to compare the effects of
indomethacin and nordihydroguaiaretic acid (NDGA) on ovulation in the pig and on
15-HETE and prostaglandin F2 alpha synthesis both in vivo and in vitro.
Follicular fluid concentrations of 15-HETE were elevated significantly just prior
to the expected time of ovulation (40 h after hCG). When indomethacin (10 mg) was
injected into the ovarian stalk at 24 h after hCG, follicular fluid
concentrations of both 15-HETE and prostaglandin F2 alpha were lower (P < 0.01)
than controls at 40 h and ovulation rate was suppressed (P < 0.01). When NDGA (5
mg) was administered in the same manner, ovulation rate was suppressed (P <
0.01), but the levels of 15-HETE and prostaglandin F2 alpha were not altered.
Synthesis of 15-HETE by cultured granulosa and theca interna cells was reduced by
the presence of NDGA (1 mg/ml), whereas indomethacin (100 ng/ml) lowered 15-HETE
production in theca interna cells only. These results clearly demonstrate that
indomethacin can block the lipoxygenase as well as the cyclooxygenase pathways,
depending on the dose used, and suggest that lipoxygenase metabolites of
arachidonic acid are involved in the ovulatory process in the pig.
PMID- 9558446
TI - Abnormal proinsulin levels in thyroid dysfunction measured by a sensitive
proinsulin immunochemiluminoassay.
AB - Abnormalities of carbohydrate metabolism in hyperthyroid patients have been long
noted. Elevated proinsulin level is considered as an early marker of B-cell
impairment. Proinsulin levels in hyperthyroid patients decreased after
antithyroid drug therapy. However, proinsulin in hypothyroid patients was only
rarely reported, and the difference was only demonstrated after glucose
stimulation-there was a greater response of proinsulin secretion after thyroxine
therapy-and the basal fasting proinsulin level was not different after therapy.
One of the reasons might be that the assay was not sensitive enough to detect the
change of basal proinsulin levels in patients with hypothyroidism after therapy.
A newly developed immunochemiluminometric assay of proinsulin was used to
demonstrate that the suppressed proinsulin level increased after thyroxine
therapy in hypothyroid patients (4.2 +/- 2.4 vs. 10.0 +/- 5.6 pmol/L, p < 0.05; n
= 7). On the other hand, our study also confirmed that the proinsulin levels
decreased in hyperthyroid patients after antithyroid therapy by methimazole (27.8
+/- 26.0 vs. 15.8 +/- 15.7 pmol/L, p < 0.05; n = 12). In conclusion, proinsulin
increased in hypothyroid patients after thyroxine therapy and decreased in
hyperthyroid patients after methimazole therapy. The results demonstrated there
is a high correlation between thyroid function and B-cell function in hypothyroid
as well as hyperthyroid patients.
PMID- 9558447
TI - Two sensitive immunometric assays for serum thyroid stimulating hormone
evaluated.
AB - This study was conducted to evaluate the analytical performance (functional
sensitivity, reproducibility, parallelism, and accuracy) of two recent commercial
kits marketed as third generation immunometric assays for measuring serum thyroid
stimulating hormone (TSH). One assay is automated; the other is manual. Accuracy
by method comparisons was evaluated using 86 patient samples assayed by an
established third generation immunometric assay as the comparative method. The
new assays met the third generation criterion for functional sensitivity (CV < or
= 20 percent at TSH < or = 0.02 mIU/L), were reproducible (CVs < 11 percent), and
measured serum TSH in parallel with the calibrator curves. Linear regression
analysis of the intermethod comparison data showed highly correlated (R > .095)
results; however, the regression slopes were non-unity, indicating patient sample
results were not transferable between methods. Clinical laboratories choosing a
third generation TSH assay should validate the performance characteristics of the
selected method to ensure reliable results for patient care.
PMID- 9558448
TI - Pneumocystis carinii pneumonia diagnosed by non-induced sputum stained with a
direct fluorescent antibody.
AB - Non-induced expectorated sputum (NIS) stained with tinctorial stains is not
considered useful in the diagnosis of Pneumocystis carinii pneumonia (PCP). The
diagnostic yield of NIS was evaluated in human immunodeficiency virus (HIV)
infected patients, when stained with a more sensitive direct fluorescent antibody
for PCP-direct fluorescent antibody (PC-DFA). A retrospective analysis was
carried out on fifty-five HIV-infected patients with PCP, who had NIS submitted
for staining with PC-DFA. Thirty had positive NIS with PC-DFA and all had
clinical courses consistent with PCP. Twenty-five had negative NIS with PC-DFA
and were diagnosed as having PCP, by autopsy (n = 2), by a positive
bronchoalveolar lavage (n = 10), or by having a clinical course consistent with
PCP (n = 13). Thus, the sensitivity of NIS stained with PC-DFA was 55 percent
(30/55). This is within the range reported in the literature for induced sputum
for the diagnosis of PCP. Non-induced sputum stained with PC-DFA can be useful
for the diagnosis of PCP in HIV-infected patients.
PMID- 9558449
TI - Mechanism of Hoechst 33342-induced apoptosis in BC3H-1 myocytes.
AB - Hoechst 33342, a bisbenzimidazole dye, binds to adenine/thymine rich regions in
the minor groove of deoxyribonucleic acid (DNA). This dye induces apoptosis in
BC3H-1 myocytes. The mechanism of Hoechst 33342-induced apoptosis was
investigated. Inhibitors of ribonucleic acid (RNA) synthesis, protein synthesis,
and serine or cysteine proteases failed to prevent BC3H-1 myocyte death induced
by Hoechst 33342. Apoptosis may be dependent on increased p53 expression. Hoechst
33342 had no effect on p53 expression in BC3H-1 myocytes. Lactate oxidation, a
monitor of mitochondrial function, was altered by Hoechst 33342 in dose dependent
manner. Also, nuclear extracts were used to assay endogenous topoisomerase I
activity which was inhibited by Hoechst 33342 treatment of BC3H-1 myocytes.
Therefore, Hoechst 33342 appears to initiate apoptosis in BC3H-1 myocytes by a
pathway which is independent of de novo RNA and protein synthesis. However, the
dye does initiate mitochondrial dysfunction and inhibition of nuclear
topoisomerase I as two important steps in the apoptotic pathway.
PMID- 9558450
TI - A laboratorian's view on the College of American Pathologists' Laboratory
Accreditation Program for Clinical Laboratories.
PMID- 9558451
TI - By choice or by chance: factors that influenced my life and career.
PMID- 9558452
TI - The physiological basis of diving to depth: birds and mammals.
AB - There is wide diversity in the animals that dive to depth and in the distribution
of their body oxygen stores. A hallmark of animals diving to depth is a
substantial elevation of muscle myoglobin concentration. In deep divers, more
than 80% of the oxygen store is in the blood and muscles. How these oxygen stores
are managed, particularly within muscle, is unclear. The aerobic endurance of
four species has now been measured. These measurements provide a standard for
other species in which the limits cannot be measured. Diving to depth requires
several adaptations to the effects of pressure. In mammals, one adaptation is
lung collapse at shallow depths, which limits absorption of nitrogen. Blood N2
levels remain below the threshold for decompression sickness. No such adaptive
model is known for birds. There appear to be two diving strategies used by
animals that dive to depth. Seals, for example, seldom rely on anaerobic
metabolism. Birds, on the other hand, frequently rely on anaerobic metabolism to
exploit prey-rich depths otherwise unavailable to them.
PMID- 9558453
TI - Animal adaptations for tolerance and exploitation of poisonous sulfide.
AB - Many aquatic animal species can survive sulfide exposure to some extent through
oxidation of the sulfide, which results mainly in thiosulfate. In several
species, sulfide oxidation is localized in the mitochondria and is accompanied by
ATP synthesis. In addition, blood-based and intracellular compounds can augment
sulfide oxidation. The formation of thiosulfate requires oxygen, which results in
an increase in oxygen consumption of some species. If not all sulfide is
detoxified, cytochrome C oxidase is inhibited. Under these conditions, a sulfide
dependent anaerobic energy metabolism commences.
PMID- 9558454
TI - Biological ice nucleation and ice distribution in cold-hardy ectothermic animals.
AB - For many ectotherms, overwintering survival depends on the avoidance or
regulation of ice nucleation and growth within their body fluids. Freeze
avoidance via supercooling plays an important role in the cold hardiness of many
small species, particularly terrestrial arthropods, that do not survive the
freezing of their body fluids. In contrast, mechanisms that limit supercooling
and initiate freezing at relatively high temperatures promote survival of the few
invertebrates and vertebrates that tolerate freezing. These mechanisms include
inoculative freezing, which results from contact with ice in the environment, and
various ice nucleating proteins, microbes, and crystalloid compounds. In freeze
tolerant ectotherms, cold hardiness is influenced by complex, seasonally changing
interactions among physiological factors, ice nucleators, and the physical
microenvironment. Extraorgan sequestration of ice is a major adaptation of freeze
tolerance. For most freeze-tolerant species, ice growth is primarily restricted
to extracellular compartments; however, intracellular freezing also occurs in
some species.
PMID- 9558455
TI - The role of vitrification in anhydrobiosis.
AB - Numerous organisms are capable of surviving more or less complete dehydration. A
common feature in their biochemistry is that they accumulate large amounts of
disaccharides, the most common of which are sucrose and trehalose. Over the past
20 years, we have provided evidence that these sugars stabilize membranes and
proteins in the dry state, most likely by hydrogen bonding to polar residues in
the dry macromolecular assemblages. This direct interaction results in
maintenance of dry proteins and membranes in a physical state similar to that
seen in the presence of excess water. An alternative viewpoint has been proposed,
based on the fact that both sucrose and trehalose form glasses in the dry state.
It has been suggested that glass formation (vitrification) is in itself
sufficient to stabilize dry biomaterials. In this review we present evidence
that, although vitrification is indeed required, it is not in itself sufficient.
Instead, both direct interaction and vitrification are required. Special
properties have often been claimed for trehalose in this regard. In fact,
trehalose has been shown by many workers to be remarkably (and sometimes
uniquely) effective in stabilizing dry or frozen biomolecules, cells, and
tissues. Others have not observed any such special properties. We review evidence
here showing that trehalose has a remarkably high glass-transition temperature
(Tg). It is not anomalous in this regard because it lies at the end of a
continuum of sugars with increasing Tg. However, it is unusual in that addition
of small amounts of water does not depress Tg, as in other sugars. Instead, a
dihydrate crystal of trehalose forms, thereby shielding the remaining glassy
trehalose from effects of the added water. Thus under less than ideal conditions
such as high humidity and temperature, trehalose does indeed have special
properties, which may explain the stability and longevity of anhydrobiotes that
contain it. Further, it makes this sugar useful in stabilization of biomolecules
of use in human welfare.
PMID- 9558456
TI - Routes and mechanism of fluid transport by epithelia.
AB - The mechanism of fluid transport by leaky epithelia and the route taken by the
transported fluid are in dispute. A consideration of current mathematical models
for coupling of solutes and water, as well as the methodologies for the study of
fluid transport, shows that local osmosis best accounts for water movement.
Although it seems virtually certain that the tight junctions are water permeable,
the fraction of absorbed fluid that crosses the tight junction cannot yet be
determined with confidence.
PMID- 9558457
TI - Molecular architecture of tight junctions.
AB - The tight junction creates a regulated barrier in the paracellular pathway and,
together with the actin-rich adherens junction, forms a functional unit called
the apical junction complex. A growing number of tight junction-associated
proteins have been identified, but functions are defined for only a few. The
intercellular barrier is formed by rows of the transmembrane protein occludin,
which is bound on the cytoplasmic surface to ZO-1 and ZO-2. These proteins are
members of the membrane-associated guanylate kinase (MAGUK) protein family and
are likely to have both structural and signaling roles. Junctional plaque
proteins without known functions include cingulin, p130, and 7H6; single reports
describe ZA-1TJ and symplekin. Many cellular signaling pathways affect assembly
and sealing of junctions. Transducing proteins, which localize within the
junction, include both heterotrimeric and rho-related GTP-binding proteins, PKC
zeta and nonreceptor tyrosine kinases. Control of perijunctional actin may be the
unifying mechanism for regulating paracellular permeability.
PMID- 9558458
TI - Regulation of the movement of solutes across tight junctions.
AB - The intercellular tight junction is the rate-limiting barrier in the paracellular
pathway for permeation by ions and larger solutes. A variety of widely used
electrical and flux approaches are used in the analyses of solute permeation
through this pathway; however, each has limitations in practice. It is now clear
that solute permeation across tight junctions is dynamically regulated by
intracellular events with a common effector mechanism apparently tied to the
cytoskeleton. These pathways, which regulate tight junction solute permeability,
are targets that produce epithelial barrier dysfunction in a variety of disease
states. However, regulation of solute permeation across the junctional barrier
may also represent a potential means to improve bioavailability of orally
administered bioactive solutes.
PMID- 9558459
TI - Role of tight junctions in establishing and maintaining cell polarity.
AB - The tight junction (TJ) is not randomly located on the cell membrane, but
occupies a precise position at the outermost edge of the intercellular space and,
therefore, is itself considered a polarized structure. This article reviews the
most common experimental approaches for studying this relationship. We then
discuss three main topics. (a) The mechanisms of polarization that operate
regardless of the presence of TJs: We explore a variety of polarization
mechanisms that operate at stages of the cell cycle in which TJs may be already
established. (b) TJs and polarity as partners in highly dynamic processes:
Polarity and TJs are steady state situations that may be drastically changed by a
variety of signaling events. (c) Polarized distribution of membrane molecules
that depend on TJs: This refers to molecules (mainly lipids) whose polarized
distribution, although not the direct result of TJs, depends on these structures
to maintain such distribution.
PMID- 9558460
TI - Codependence of renal calcium and sodium transport.
AB - Calcium and sodium absorption by the kidney normally proceed in parallel.
However, a number of physiological, pharmacological, pathological, and genetic
conditions dissociate this relation. In each instance, the dissociation can be
traced to the distal convoluted tubule, where calcium and sodium transport are
inversely related. Based on the identification of the relevant sodium
transporters in these cells and on analysis of the mechanism of calcium
transport, an explanation for this inverse relation can be developed. Apical
membrane calcium entry is mediated by voltage-sensitive calcium channels that are
activated upon membrane hyperpolarization. Basolateral calcium efflux is effected
primarily by Na+/Ca2+ exchange. According to the model, inhibition of sodium
entry through either the Na-Cl cotransporter or the Na+ channel hyperpolarizes
the cell, as does parathyroid hormone, thereby activating the calcium entry
channel and increasing the driving force for diffusional entry. Membrane
hyperpolarization also increases the driving force of calcium efflux through the
Na+/Ca2+ exchanger. Thus sodium-dependent changes of calcium transport are
indirect and occur secondarily through effects on membrane voltage.
PMID- 9558461
TI - Aquaporin-2 and -3: representatives of two subgroups of the aquaporin family
colocalized in the kidney collecting duct.
AB - Since the molecular identification of the first aquaporin in 1992, the number of
proteins known to belong to this family has been rapidly increasing. These
members may be separated into two subgroups based on gene structure, sequence
homology, and function. Regulation of the water permeability of the collecting
ducts of the kidney is essential for urinary concentration. Aquaporin-2 and -3,
which are representative of these subgroups, are colocalized in the collecting
ducts. Understanding these subgroups will elucidate the differences between
aquaporin-2 and -3. Aquaporin-2 is a vasopressin-regulated water channel located
in the apical membrane, and aquaporin-3 is a constitutive water channel located
in the basolateral membrane. In contrast to aquaporin-3, which appears to be less
well regulated, many studies have now identified multiple regulational mechanisms
at the gene, protein, and cell levels for aquaporin-2, thus reflecting its
physiological importance. Evidence of the participation of aquaporin-2 in the
pathophysiology of water-balance disorders is accumulating.
PMID- 9558462
TI - Molecular mechanisms of prostaglandin transport.
AB - Despite the fact that prostaglandins (PGs) have low intrinsic permeabilities
across the plasma membrane, they must cross it twice: first upon release from the
cytosol into the blood, and again upon cellular uptake prior to oxidation. Until
recently, there were no cloned carriers that transported PGs. PGT is a broadly
expressed, 12-membrane-spanning domain integral membrane protein. When
heterologously expressed in HeLa cells or Xenopus oocytes, it catalyzes the
rapid, specific, and high-affinity uptake of PGE2, PGF2 alpha, PGD2, 8-iso-PGF2
alpha, and thromboxane B2. Functional studies indicate that PGT transports its
substrate as the charged anion. The PGT substrate specificity and inhibitor
profile match remarkably well with earlier in situ studies on the metabolic
clearance of PGs by rat lung. Because PGT expression is especially high in this
tissue, it is likely that PGT mediates the membrane step in PG clearance by the
pulmonary circulation. Evidence is presented that PGT may play additional roles
in other tissues and that there may be additional PG transporters yet to be
identified molecularly.
PMID- 9558463
TI - Organic cation transporters in intestine, kidney, liver, and brain.
AB - This review focuses on sodium-independent transport systems for organic cations
in small intestine, liver, kidney, and brain. The roles of P-glycoproteins (MDR)
and anion transporters (OATP) in organic cation transport are reported, and two
members of the new transporter family OCT are described. The OCT transporters
belong to a superfamily that includes multidrug-resistance proteins, facilitative
diffusion systems, and proton antiporters. They mediate electrogenic transport of
small organic cations with different molecular structures, independently of
sodium and proton gradients. The current knowledge of the distribution and
functional properties of cloned cation transport systems and of cation transport
measured in intact plasma membranes is used to postulate identical or homologous
transporters in intestine, liver, kidney, and brain.
PMID- 9558464
TI - Role of cardiac neural crest cells in cardiovascular development.
AB - The discovery in the chick embryo that a specific region of the neural crest,
termed the cardiac neural crest, is essential for septation of the cardiac
outflow tract and for aortic arch artery development has led to the
classification of a whole series of human cardiac defects as neural crest
associated. Recently, several mouse genetic models have been effectively employed
to yield new insights into the relationship between cardiac neural crest and
structural heart development. In all the animal models of neural crest-related
heart defects, prenatal mortality is too high to be attributed to structural
defects of the heart alone, and there are obvious signs of severe cardiac
dysfunction. The evidence indicates that poor viability is from impaired cardiac
excitation-contraction coupling and contractile function at the myocyte level.
The continued study of experimental and genetically defined models with neural
crest-associated heart defects will prove useful in identifying the common
pathways by which the neural crest contributes to normal heart development.
PMID- 9558465
TI - Molecular insights into cardiac development.
AB - Recent discoveries have led to a greater appreciation of the diverse mechanisms
that underlie cardiac morphogenesis. Genetic strategies (primarily gene targeting
approaches in mice) have significantly broadened research in cardiovascular
developmental biology by illuminating new pathways involved in heart development
and by allowing the genetic evaluation of pathways that have previously been
implicated in these events. Advances have also been made using biochemical and
cell- and tissue-based approaches. This review summarizes the author's
interpretation of current trends in the effort to understand the molecular basis
of cardiac-development, with an emphasis on insights obtained from genetic
models.
PMID- 9558466
TI - Normal and abnormal consequences of apoptosis in the human heart.
AB - Knowledge about apoptosis has become essential for understanding many aspects of
cardiac structure and function. In the human heart there are major periods of
morphogenesis that begin only after birth, and some of these processes recur
intermittently for many years. Although the exact mechanisms by which these
events are initiated or terminated remain poorly understood, it is clear that
their benefits may be mirrored in destructive effects. In this review, selected
examples include normal morphogenesis of the cardiac conduction system and the
normal postnatal involution of the right ventricle, both of which are mediated by
apoptosis. Destructive counterparts include familial heart block ending in fatal
arrhythmias, similar results in the long QT syndrome, and the pathogenesis of
both Uhl's anomaly and arrhythmogenic right ventricular dysplasia; in each
apoptosis is an important factor.
PMID- 9558467
TI - Electrical and calcium signaling in dendrites of hippocampal pyramidal neurons.
AB - This review discusses recent data regarding the different types of voltage-gated
Na+, Ca2+, and K+ channels in dendrites of CA1 pyramidal neurons and their
function for synaptic integration and plasticity. Na+ and Ca2+ channels are
uniformly distributed throughout the dendrites, although Na+ channels in the soma
and proximal dendrites differ in their inactivation properties from Na+ channels
in more distal regions. Also, different regions of the neuron express different
subtypes of Ca2+ channels. K+ channels are unevenly distributed, with the distal
dendrites expressing a more than fivefold greater density of a transient A-type
K+ channel than proximal regions. These K+ channels exert profound control over
the excitability of the pyramidal neurons and the spread of synaptic potentials
throughout the dendrites. The ways in which the active properties of dendrites
may contribute toward the induction and maintenance of long-term synaptic
plasticity are discussed.
PMID- 9558468
TI - The synaptic vesicle cycle.
AB - The ins and outs of the synaptic vesicle cycle are being examined in increasing
detail with diverse investigative tools in a variety of cell types, particularly
those with large granules. The cycle begins with the opening of a fusion pore
that connects the vesicle lumen to the extracellular fluid. Sensitive
electrophysiological techniques reveal the often-stuttering behavior of single
pores in non-neuronal cells, through which small molecules trickle until the
fusion pore expands and the remaining contents erupt from the vesicle. The
granule membranes are then retrieved by multiple processes that appear to act in
parallel and that are distinguished from each other kinetically and
ultrastructurally. Following endocytosis, synaptic vesicles are then shuttled
back into the vesicle pool, where they briefly mix with other vesicles, become
immobilized, and remain gelled with their neighbors, even while moving en masse
again to the presynaptic membrane as a prelude for another round of exocytosis.
PMID- 9558469
TI - Surfactant proteins: molecular genetics of neonatal pulmonary diseases.
AB - Genetic and phenotypic complexity has been described for diseases of varied
etiology. Groups of patients with varied phenotype can be used in association
studies as an initial approach to identify contributing loci. Although
association studies have limitations, their value is enhanced by using candidate
genes with functions related to disease. Surfactant proteins have been studied in
the etiopathogenesis of neonatal pulmonary diseases. SP-A and SP-B polymorphisms
are found at a higher frequency in certain groups of patients with respiratory
distress syndrome (RDS), and SP-B mutations are linked to the pathogenesis of
congenital alveolar proteinosis (CAP). Phenotypic heterogeneity is observed for
both CAP and RDS. The available data suggest that a number of factors contribute
to the etiology of CAP and RDS and, therefore, a multidisciplinary approach of
clinical, genetic, epidemiologic, and statistical considerations is necessary for
an in-depth understanding of the pathophysiology of these and other pulmonary
diseases.
PMID- 9558470
TI - PreBotzinger complex and pacemaker neurons: hypothesized site and kernel for
respiratory rhythm generation.
AB - Identification of the sites and mechanisms underlying the generation of
respiratory rhythm is of longstanding interest to physiologists and
neurobiologists. Recently, with the development of novel experimental
preparations, especially in vitro en bloc and slice preparations of rodent
brainstem, progress has been made In particular, a site in the ventrolateral
medulla, the preBotzinger Complex, is hypothesized to contain neuronal circuits
generating respiratory rhythm. Lesions or disruption of synaptic transmission
within the preBotzinger Complex, either in vivo or in vitro, can abolish
respiratory activity. Furthermore, the persistence of respiratory rhythm
following interference with postsynaptic inhibition and the subsequent discovery
of neurons with endogenous bursting properties within the preBotzinger Complex
have led to the hypothesis that rhythmogenesis results from synchronized activity
of pacemaker or group-pacemaker neurons.
PMID- 9558471
TI - Sexual differentiation of avian brain and behavior: current views on gonadal
hormone-dependent and independent mechanisms.
AB - Gonadal hormones are known to act during development to establish permanent sex
differences in the anatomy and function of the vertebrate brain. They also act on
the adult brain to activate reproductive behaviors. However, there are wide gaps
in our understanding of how sexually dimorphic neural circuits translate into sex
differences in behavior and other CNS functions. Moreover, not all sexually
dimorphic properties of the adult brain can be attributed to known effects of
gonadal hormones during development or adulthood, and factors other than gonadal
steroids may contribute to these sex differences. This paper reviews sexual
differentiation and the role of gonadal steroids and non-gonadal factors on
sexually dimorphic development of the avian brain.
PMID- 9558473
TI - The luteinizing hormone receptor.
AB - The luteinizing hormone receptor (LHR) is a member of the subfamily of
glycoprotein hormone receptors within the superfamily of G protein-coupled
receptor (GPCR)/seven-transmembrane domain receptors. Over the past eight years,
major advances have been made in determining the structure and function of the
LHR and its gene. The hormone-binding domain has been localized to exons 1-7 in
the extracellular (EC) domain/region of the receptor, which contains several
leucine-rich repeats. High-affinity binding of LH and human chorionic
gonadotrophin (hCG) causes secondary hormone or receptor contacts to be
established with regions of the EC loop/transmembrane module that initiate signal
transduction. Models of hormone-receptor interaction have been derived from the
crystal structures of hCG and of the ribonuclease inhibitor, which also contains
leucine-rich repeats. Such models provide a framework for the interpretation of
mutational studies and for further experiments. The extracellular domain of the
receptor has been overexpressed in vitro, which will facilitate crystallographic
resolution of the structure of the receptor-binding site. The transmembrane
domain/loop/cytoplasmic module transduces the signal for coupling to G proteins.
Several constitutive, activating mutations that cause human disease have been
found in helix VI and adjacent structures. These mutations have provided valuable
information about mechanisms of signal transfer and G protein coupling. The
structure of the LHR gene has been elucidated, and the regulation of its
transcription is beginning to be understood. Valuable insights into receptor
evolution have been derived from analysis of sequence homologies, the gene
structure of glycoprotein hormone receptors and other members of the GPCR family,
and the glycoprotein hormone receptor-like precursors identified in several
invertebrate species.
PMID- 9558472
TI - The physiology of parathyroid hormone-related protein: an emerging role as a
developmental factor.
AB - Parathyroid hormone-related protein (PTHrP) is the agent responsible for humoral
hypercalcemia of malignancy. Its pathogenic role in this syndrome is well
established and attention has focused in recent years on the elucidation of the
roles played by PTHrP in normal developmental and adult physiology. This review
focuses on studies of the past two years: (a) elucidation of the
posttranslational processing pattern of PTHrP, the mechanisms of action of the
various secretory forms of PTHrP, the role of PTHrP as an intracrine regulator of
cell growth and cell death; (b) the emergence of PTHrP as a critical
developmental factor in the mammary gland, epidermis, and the skeleton; and (c)
the advances in understanding of the roles of PTHrP in the regulation of
pancreatic islet mass, vascular smooth muscle tone and proliferation, and materno
fetal calcium transfer across the placenta.
PMID- 9558474
TI - Sex in the 90s: SRY and the switch to the male pathway.
AB - In mammals the male sex determination switch is controlled by a single gene on
the Y chromosome, SRY. SRY encodes a protein with an HMG-like DNA-binding domain,
which probably acts as a local organizer of chromatin structure. It is believed
to regulate downstream genes in the sex determination cascade, although no direct
targets of SRY are clearly known. More genes in the pathway have been isolated
through mutation approaches in mouse and human. At least three genes, SRY itself,
SOX9, and DAX1, are dosage sensitive, providing molecular evidence that the sex
determination step operates at a critical threshold. SRY initiates development of
a testis from the bipotential cells of the early gonad. The dimorphic male and
female pathways present a rare opportunity to link a pivotal gene in development
with morphogenetic mechanisms that operate to pattern an organ and the
differentiation of its cells. Mechanisms of testis organogenesis triggered
downstream of SRY include pathways of cell signaling controlling cell
reorganization, cell proliferation, cell migration, and vascularization.
PMID- 9558475
TI - Special topic: apoptosis.
PMID- 9558476
TI - Proteolytic activities that mediate apoptosis.
AB - Since the discovery that cells can activate their own suicide program,
investigators have attempted to determine whether the events that are associated
with this form of cell death are genetically determined. The discovery that the
ced-3 gene of Caenorhabditis elegans encodes a cysteine protease essential for
developmentally regulated apoptosis ignited interest in this area of research. As
a result, we now know that cell death is specified by a number of genes and that
this biologic process contributes significantly to development, tumorigenesis,
and autoimmune disease. In this review I summarize what is currently known about
signaling pathways involved in apoptosis, with particular emphasis on the
function of the cysteine proteases known as caspases. However, there is also
evidence that protease-independent cell death pathways exist. Is there a
relationship between these two distinct mechanisms? If so, how do they
communicate? Finally, even though the involvement of tumor necrosis factor/nerve
growth factor family of receptors and cysteine proteases has been elegantly
established as a component of many apoptotic signaling pathways, what happens
downstream of these initial events? Why are only a selected group of cellular
proteins--many nuclear--the targets of these proteases? Are nuclear events
essential for apoptosis in vivo? Are the cellular genes that encode products
involved in apoptotic signaling frequent targets of mutation/alteration during
tumorigenesis? These are only a few questions that may be answered in the next
ten years.
PMID- 9558477
TI - The many roles of c-Myc in apoptosis.
AB - The proto-oncogene c-myc encodes a transcription factor c-Myc, which is of great
importance in controlling cell growth and vitality. The quantity of c-Myc is
carefully controlled by many mechanisms, and its actions to induce and repress
genes are modulated by interactions with other regulatory proteins. Understanding
the kinetic and quantitative relationships that determine how and what genes c
Myc regulates is essential to understanding how Myc is involved in apoptosis.
Reduction of c-myc expression and its inappropriate expression can be associated
with cellular apoptosis. This review outlines the nature and regulation of the c
myc gene and of c-Myc and presents the systems and conditions in which Myc
related apoptotic events occur. Hypotheses of the mechanisms by which expression
and repression of c-myc lead to apoptosis are discussed.
PMID- 9558478
TI - Cell cycle regulation and apoptosis.
AB - Tissue homeostasis requires a balance between cell proliferation and death.
Apoptosis and proliferation are linked by cell cycle regulators, and apoptotic
stimuli affect both cell proliferation and death. Glucocorticoids induce G1
arrest and apoptosis in transformed lymphoid cells. Decreased expression of the
cell cycle components c-myc and cyclin D3 is essential for glucocorticoid-induced
growth arrest and death in dividing cells. Other G1 regulators, such as p53, pRb,
and E2F, have also been implicated in apoptosis. Mice lacking either p53 or E2F
display aberrant cell proliferation and tumor formation, suggesting that these
proteins are involved in the elimination of abnormal cells through apoptosis. In
contrast, pRb induces G1 arrest and suppresses apoptosis in cultured cells. Mice
that lack pRb are nonviable and show ectopic mitosis and massive cell death,
suggesting that pRb is an apoptotic suppressor. Further analysis of common
components of apoptotic and cell cycle machinery may provide insight into the
coordinated regulation of these antagonistic processes.
PMID- 9558479
TI - The mitochondrial death/life regulator in apoptosis and necrosis.
AB - Both physiological cell death (apoptosis) and, in some cases, accidental cell
death (necrosis) involve a two-step process. At a first level, numerous
physiological and some pathological stimuli trigger an increase in mitochondrial
membrane permeability. The mitochondria release apoptogenic factors through the
outer membrane and dissipate the electrochemical gradient of the inner membrane.
Mitochondrial permeability transition (PT) involves a dynamic multiprotein
complex formed in the contact site between the inner and outer mitochondrial
membranes. The PT complex can function as a sensor for stress and damage, as well
as for certain signals connected to receptors. Inhibition of PT by
pharmacological intervention on mitochondrial structures or mitochondrial
expression of the apoptosis-inhibitory oncoprotein Bcl-2 prevents cell death,
suggesting that PT is a rate-limiting event of the death process. At a second
level, the consequences of mitochondrial dysfunction (collapse of the
mitochondrial inner transmembrane potential, uncoupling of the respiratory chain,
hyperproduction of superoxide anions, disruption of mitochondrial biogenesis,
outflow of matrix calcium and glutathione, and release of soluble intermembrane
proteins) entails a bioenergetic catastrophe culminating in the disruption of
plasma membrane integrity (necrosis) and/or the activation of specific
apoptogenic proteases (caspases) by mitochondrial proteins that leak into the
cytosol (cytochrome c, apoptosis-inducing factor) with secondary endonuclease
activation (apoptosis). The relative rate of these two processes (bioenergetic
catastrophe versus protease and endonuclease activation) determines whether a
cell will undergo primary necrosis or apoptosis. The acquisition of the
biochemical and ultrastructural features of apoptosis critically relies on the
liberation of apoptogenic proteases or protease activators from mitochondria. The
fact that mitochondrial events control cell death has major implications for the
development of cytoprotective and cytotoxic drugs.
PMID- 9558480
TI - Regulation of ceramide production and apoptosis.
AB - Ceramide is a sphingosine-based lipid signaling molecule that regulates cellular
differentiation, proliferation, and apoptosis. The emerging picture suggests that
coupling of ceramide to specific signaling cascades is both stimulus and cell
type specific. Ceramide action is determined within the context of other stimuli
and by the subcellular topology of its production. Here, we discuss the pathways
of ceramide generation and the interaction of ceramide with caspases and other
apoptotic signaling cascades.
PMID- 9558481
TI - A view of sur/KIR6.X, KATP channels.
AB - ATP-sensitive potassium channels, termed KATP channels, link the electrical
activity of cell membranes to cellular metabolism. These channels are
heteromultimers of sulfonylurea receptor (SUR) and KIR6.X subunits associated
with a 1:1 stoichiometry as a tetramer (SUR/KIR6.X forms the pores, whereas SUR
regulates their activity. Changes in [ATP]i and [ADP]i gate the channel. The
diversity of KATP channels results from the assembly of SUR and KIR6.X subtypes
KIR6.1-based channels differ from KIR6.2 channels mainly by their smaller unitary
conductance. SUR1- and SUR2-based channels are distinguished by their
differential sensitivity to sulfonylureas, whereas SUR2A-based channels are
distinguished from SUR2B channels by their differential sensitivity to diazoxide.
Mutations that result in the loss of KATP channels in pancreatic beta-cells have
been identified in SUR1 and KIR6.2. These mutations lead to familial
hyperinsulinism. Understanding the mutations in SUR and KIR6.X is allowing
insight into how these channels respond to nucleotides, sulfonylureas, and
potassium channel openers, KCOs.
PMID- 9558482
TI - ClC and CFTR chloride channel gating.
AB - Chloride channels are widely expressed and play important roles in cell volume
regulation, transepithelial transport, intracellular pH regulation, and membrane
excitability. Most chloride channels have yet to be identified at a molecular
level. The ClC gene family and the cystic fibrosis transmembrane conductance
regulator (CFTR) are distinct chloride channels expressed in many cell types, and
mutations in their genes are the cause of several diseases including myotonias,
cystic fibrosis, and kidney stones. Because of their molecular definition and
roles in disease, these channels have been studied intensively over the past
several years. The focus of this review is on recent studies that have provided
new insights into the mechanisms governing the opening and closing, i.e. gating,
of the ClC and CFTR chloride channels.
PMID- 9558483
TI - Functional properties and physiological roles of organic solute channels.
AB - Membrane channels provide routes for the rapid, passive movement of solutes
across plasma and intracellular membranes. It is generally assumed that the major
physiological role of membrane channels is to transport inorganic ions for
processes such as transepithelial salt absorption and secretion, cell volume
regulation, signal transduction, and control of membrane electrical properties.
Increasing evidence indicates, however, that channels play an important role in
organic solute transport in a wide variety of cell types and organisms. Some of
the major physiological roles of organic solute channels include uptake of
nutrients, excretion of metabolic waste products, volume-regulatory organic
osmolyte transport, and control of mitochondrial metabolism. This article reviews
the functions and characteristics of channels that participate in the transport
and regulation of both charged and electroneutral organic solutes.
PMID- 9558484
TI - Assessment of microsatellite instability in a cell line from a patient with
xeroderma pigmentosum variant.
AB - Cells from patients with xeroderma pigmentosum (XP) variant are thought to be
defective in postreplication repair. This DNA repair pathway is not well defined
in human cells and the exact genetic defect of XP variant is unknown. In another
cancer-prone hereditary disorder, hereditary nonpolyposis colon cancer, tumors
are characterized by a DNA mismatch repair defect with microsatellite
instability. Since there are some similarities between postreplication repair and
mismatch repair, we investigated microsatellite instability, the hallmark of a
DNA mismatch repair defect, in a lymphoblastoid cell line from a patient with XP
variant. Two normal lines and one nucleotide excision repair-defective XP group A
line were used as controls. In a host cell microsatellite instability assay, the
recently developed shuttle vector pZCA29 was transfected into these cells and
replicated plasmid recovered after 3 days. The plasmid contains two CA repeat
tracts that interrupt the reading frame of the lacZ gene. Reversion to active
beta-galactosidase, detectable by a color reaction of bacterial transformants,
represents the frequency of frameshift mutations in the CA repeat tracts during
replication of the plasmid, and thereby the host cells' microsatellite
instability. We did not find any significant differences in the mutation
frequencies of the plasmids after passage through either cell line. This
indicates that there is no microsatellite instability in the examined XP variant
cell line.
PMID- 9558485
TI - Differential role of catalase and glutathione peroxidase in cultured human
fibroblasts under exposure of H2O2 or ultraviolet B light.
AB - The purpose of this study was to elucidate the differential contribution of
catalase and glutathione peroxidase (GSH-Px) to H2O2 scavenging in cultured human
dermal fibroblasts. Responses of the cells in terms of both enzyme activities
were examined by using two sorts of inhibitors, 3-amino-1H-1,2,4-triazole (AT)
for catalase and DL-buthionine-[S,R]-sulfoximine (BSO) for GSH-Px, under exposure
to H2O2 or ultraviolet (UV) B radiation. AT treatment resulted in a decrease in
H2O2 scavenging activity, while BSO treatment did not affect H2O2 scavenging.
When fibroblasts were exposed to a low concentration of H2O2 (100 microM). AT
treatment resulted in a significant decrease in cell survival, but BSO treatment
did not affect survival. At higher concentrations of H2O2 ranging from 500 microM
to 1 mM, BSO-treated fibroblasts showed reduced survival. In addition, AT
treatment was much more cytotoxic in the presence of UVB than BSO treatment. The
intracellular levels of H2O2 in fibroblasts treated with AT or BSO were also
determined. BSO-treated cells showed similar H2O2 levels to control cells, but
the intracellular H2O2 levels of AT-treated fibroblasts were 1.4-fold higher than
found in control cells. These results with human dermal fibroblasts indicate that
catalase acts as a primary defence against oxidative stress from exogenous or
endogenous H2O2 at low concentrations. In contrast, GSH-Px helps protect the cell
from damage during exposure to high concentrations of H2O2.
PMID- 9558486
TI - Flow cytometric and microscopic characterization of the uptake and distribution
of phosphorothioate oligonucleotides in human keratinocytes.
AB - Gene-specific inhibition by antisense oligonucleotides has been successful in a
large number of systems. In an attempt to use this strategy for the modulation of
skin disease-specific gene expression, we studied oligonucleotide uptake in
cultured human keratinocytes. This study revealed a heterogeneous uptake of
fluorescently labeled phosphorothioate oligonucleotides. Flow cytometric and
microscopic analysis showed two fluorescent cell populations with differences in
intensity: a 'bright' population of highly fluorescent small cells and a 'dim'
population of less fluorescent but larger cells. The heterogeneity in uptake
between these two populations was not a result of differences in cell cycle
phases of the keratinocytes, as shown by flow cytometric sorting and measurements
of relative DNA content. In both populations the oligonucleotides were
transported intracellularly and were mainly located in the cytoplasm. A typically
speckled localization pattern was demonstrated by confocal laser scanning
microscopy. We used propidium iodide (PI) to assess viability, and showed that in
nonviable (PI-permeable) keratinocytes the oligonucleotides accumulated in the
nucleus. The use of a lipidfection reagent also changed the intracellular
distribution of oligonucleotides from a punctate cytoplasmic pattern to an
intense nuclear localization. The process of uptake by the viable keratinocytes
was dependent on oligonucleotide concentration, incubation time and temperature.
This study underlines the importance of kinetic studies on oligonucleotide uptake
in human keratinocytes which must be considered when specific oligonucleotides
are used against skin disease-specific genes.
PMID- 9558487
TI - 5 alpha-reductase activity in the human hair follicle concentrates in the dermal
papilla.
AB - Hair growth depends on a close interaction of different cell populations of the
hair follicle. In certain regions of the body, androgens interfere with this
highly regulated cooperation in a yet poorly understood manner. The response of
hair follicles to androgens can be categorized as androgen-dependent, e.g. in the
beard, androgen-sensitive, e.g. in the frontal scalp of affected individuals, or
androgen-independent, e.g. in the occipital scalp. At the target cell level, the
balance between 5 alpha-reductase, 17 beta-hydroxysteroid-dehydrogenase (17 beta
HSD) and 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) yields metabolites
with different androgenic potential. We examined this target cell-specific
androgen metabolism in microdissected intact sub-units of dermal papillae,
connective tissue sheaths (CTS) and root sheaths. In dermal papillae, 5 alpha
reductase predominated with an accumulation of the strong androgen 5 alpha
dihydrotestosterone. The specific activity of 5 alpha-reductase in the papillae
exceeded those in the other hair follicle compartments by a factor of at least 14
in the scalp (5.4, 0.4 and 0.1 pmol/h per mm3 in the papilla, CTS and root
respectively and at least 80 in the beard (16.0, 0.2 and 0.4 pmol/h per mm3 in
the papilla, CTS and root respectively). The root sheath keratinocytes expressed
low 5 alpha-reductase levels, but high 17 beta-HSD levels, with androstenedione
as the major metabolite. The CTS expressed both 5 alpha-reductase and 17 beta
HSD, resulting in androstenedione, 5 alpha-androsterone and 5 alpha
androstanedione. In the CTS and the root sheath, only minor amounts of 5 alpha
DHT were found. In beard papillae, the 5 alpha-reductase activity was three times
that in the occipital scalp papillae. These results indicate that the androgen
response of hair follicles depends on a differentiated intrafollicular androgen
metabolism and that the dermal papilla might be a primary target in this process.
PMID- 9558488
TI - Apoptosis in murine hair follicles during catagen regression.
AB - Catagen hair follicle involution has been reported to involve apoptosis, although
the precise mechanism has not been satisfactorily resolved. Previous studies have
involved solely morphological or electron microscopical methods. We report here
studies on murine hair follicles during the first postnatal hair cycle conducted
using the terminal deoxy-nucleotidyl transferase-mediated dUTP nick end-labeling
(TUNEL) method. Electrophoresis of DNA isolated from the hair follicles of the
same animals was carried out in order to confirm the systematic fragmentation of
DNA that typifies apoptosis. On day 10, when all the follicles were growing,
there was no evidence of staining with TUNEL in the hair bulbs. Electrophoresis
similarly did not show characteristic DNA ladders. By day 15, a few positive
cells were observed in the hair bulbs and the numbers had increased by day 17
when many positive cells were seen, especially in the lower portions of the
follicles. Electrophoresis demonstrated DNA ladders on days 15, 16 and 17,
although the DNA ladder on day 15 was less prominent than that on day 17. These
studies confirmed that apoptosis, as identified by techniques that measure DNA
fragmentation, occurs in the lower regions of hair follicles towards the end of
catagen.
PMID- 9558489
TI - Ultraviolet B radiation increases steady-state mRNA levels for cytokines and
integrins in hairless mouse skin: modulation by topical tretinoin.
AB - Chronically sun-damaged human skin has a wrinkled, aged appearance as a result of
alterations in the dermal extracellular matrix. Secondary effectors such as
cytokines and integrins may mediate the effects of UV radiation on the skin by
regulating the synthesis of metalloproteinases and structural proteins including
collagen. The aim of this study was to semi-quantify the steady-state mRNA levels
of interleukin-1 alpha, tumor necrosis factor alpha, transforming growth factor
beta, collagenase, stromelysin, collagen, and integrins (alpha, and alpha2) in
the skin of hairless mice that were either treated with UV or concurrently
treated with UV and topical tretinoin for 5 weeks. Total RNA was extracted from
the skin of the mice, reverse transcribed to cDNA, and amplified by the
polymerase chain reaction in the presence of 32P-dCTP using gene-specific
primers. Results were normalized relative to glyceraldehyde-3-phosphate
dehydrogenase levels. Steady-state mRNA levels of the cytokines and integrins
were increased by UV radiation. Concurrent UV and topical tretinoin treatment
superinduced the expression of interleukin-1, increased alpha 1, and decreased
alpha 2 integrin expression. Immunofluorescence analysis showed increased dermal
localization of beta 1 integrin in UV and tretinoin treated skin. These results
suggest that cytokines and integrins may be involved in the mechanism of photo
damage.
PMID- 9558490
TI - The morphologic changes in lamellar bodies and intercorneocyte lipids after tape
stripping and occlusion with a water vapor-impermeable membrane.
AB - It has been reported that artificial restoration of barrier function by a water
vapor-impermeable membrane after tape stripping induces barrier abrogation in
hairless mice, impeding rather than enhancing barrier recovery. To address this
issue, we examined the morphologic changes in the epidermis after tape stripping
and occlusion with a water vapor-impermeable membrane in murine skin. Male
hairless mice were used for all studies of barrier perturbation and occlusion.
Barrier disruption was achieved by repeated application of cellophane tape.
Immediately after tape stripping the animals were wrapped in a tightly fitting
water vapor-impermeable membrane. Transepidermal water loss (TEWL) was measured
20 min after tape stripping and 14, 24, 36, 48 and 60 h after occlusion. For
electron microscopy the samples were treated with osmium tetroxide (OsO4) or
ruthenium tetroxide (RuO4). When tape-stripped animals were wrapped in a water
vapor-impermeable membrane, thereby preventing water flux, barrier function did
not recover normally. These results demonstrate that an artificial block to TEWL
with an impermeable membrane did not enhance barrier recovery. By electron
microscopy many transitional cells and lacunae of various sizes were seen within
the intercellular spaces of the stratum corneum after occlusion following tape
stripping. Occlusion also caused alterations in both lipid lamellar membrane
structures in the stratum corneum interstices and the lamellar bodies in the
cytosol of granulocytes and transitional cells. Secreted lamellar body contents
also appeared to be abnormal in the stratum corneum-stratum granulosum junction.
PMID- 9558491
TI - Quantitative and objective evaluation of wound debriding properties of
collagenase and fibrinolysin/desoxyribonuclease in a necrotic ulcer animal model.
AB - Proteolytic enzymes have been used for wound debridement for many years. The two
enzymes most widely used in Europe are fibrinolysin/desoxyribonuclease and
collagenase. Despite their frequent use, very few placebo-controlled studies
comparing the enzymes with vehiculum only, or with each other, are available. In
a specially developed necrotic ulcer animal model, combined with a computer image
analysis technique to measure necrotic and total wound surface areas
quantitatively, we assessed the wound-cleansing properties of fibrinolysin/DNase
oleogel, collagenase ointment, saline-soaked gauze control treatment, and new
galenic formulations of collagenase, including placebos. The average relative
area of necrotic tissue present in the wound after 1 week was 31% for collagenase
ointment and 56% for fibrinolysin/DNAse oleogel (P = 0.0037). Collagenase gel was
significantly (P = 0.0007) better in removing necrosis than placebo (gel only).
Fibrinolysin/DNAse was not significantly more effective than the three placebo or
control treatments (placebo film, placebo gel, saline-soaked gauzes). We conclude
that collagenase is a suitable enzyme for wound debridement, but we were not able
to detect clinical efficacy of fibrinolysin/DNAse in this model.
PMID- 9558492
TI - Reduced expression of mRNA for transforming growth factor beta (TGF beta) and TGF
beta receptors I and II and decreased TGF beta binding to the receptors in in
vitro-aged fibroblasts.
AB - Previous studies have demonstrated that the expression of type I collagen, the
most abundant protein in the dermis, is reduced in in vitro-aging fibroblast
cultures, but the mechanism controlling the reduction of type I collagen
expression is not understood. Recent studies, however, have demonstrated that
transforming growth factor beta (TGF beta) plays an important role in the
regulation of type I collagen expression. The purpose of this study was to
investigate the role of TGF beta in downregulation of type I collagen expression
in in vitro-aged fibroblasts. We compared the expression of mRNA for alpha 1 (I)
collagen, TGF beta, TGF beta type I receptor and TGF beta type II receptor in
early and late-passage fibroblasts by Northern blot hybridizations. The mRNA
levels of alpha 1(I) collagen, TGF beta, and TGF beta receptors I and II in late
passage fibroblasts were reduced to 62%, 62%, 59% and 59%, respectively, of those
in early-passage fibroblasts. We also compared TGF beta receptor binding in early
and late-passage fibroblasts using receptor binding assays. The affinity of 125I
TGF beta in late-passage fibroblasts was lower than that in early-passage
fibroblasts. These results suggest that the reduction of type I collagen
expression in in vitro-aged fibroblasts is regulated by reduced expression of TGF
beta and TGF beta receptors I and II and by decreased TGF beta receptor binding
ability of the fibroblasts.
PMID- 9558493
TI - Morphological alterations and cell blebbing in UV-irradiated human epidermis.
PMID- 9558494
TI - Relationship between keratinocyte proliferative activity, HMB-45 reactivity, and
the presence of suprabasal melanocytes in acral nevi.
PMID- 9558495
TI - Inhibitory effects of basic fibroblast growth antisense oligodeoxynucleotide on
in vitro proliferation of mouse 3T3 fibroblasts.
PMID- 9558496
TI - Dental unit waterlines: taking the high road ... now.
PMID- 9558497
TI - Effectively using current sterilization systems.
PMID- 9558498
TI - Restoration of the aesthetically demanding patient.
PMID- 9558499
TI - Bleaching tetracycline-stained teeth. A combined approach.
PMID- 9558500
TI - Specialty endodontics: diagnostic challenges, Part 1.
PMID- 9558501
TI - Forecasting growth: high-tech breakthroughs open a new era in orthodontics.
PMID- 9558502
TI - Allergenic materials: a dental office concern. Interview by Phillip Bonner.
PMID- 9558503
TI - Exploring dental practice growth.
PMID- 9558504
TI - Computer literacy can save big bucks.
PMID- 9558505
TI - Hemisection and vital treatment of a fused tooth--literature review and case
report.
AB - Fusion and gemination of permanent teeth are developmental anomalies of the
dental hard tissues which may require endodontic and surgical treatment for
functional, orthodontic or aesthetic reasons. Following a review of the dental
literature on tooth fusion and gemination, a case of fusion of a maxillary
central incisor and a supernumerary tooth and its endodontic and surgical
treatment is presented.
PMID- 9558506
TI - Evaluation of technical quality of endodontic treatment--reliability of intraoral
radiographs.
AB - The purpose of this study was to evaluate: 1) the use of the conventional
buccolingual radiographic projection for estimating the technical quality of
endodontic treatment and 2) the effect of the surrounding tissues on these
evaluations. The material consisted of three radiographs of each of 108 extracted
roots: a clinical radiograph, an in vitro radiograph taken in the buccolingual
projection, and an in vitro radiograph taken in the mesiodistal projection. The
radiographs were analysed by two observers and consensus was reached and used in
the analyses. The agreement between the two observers was good, but statistically
significant differences were found between recordings of the seal in the clinical
radiographs and the in vitro radiographs taken in the buccolingual projection.
The length of the root filling in each of the three projections was interpreted
to be the same, while both inadequate seal and visible lumen apical to the root
filling were recorded less frequently in the clinical radiographs than in either
of the two in vitro projections. This difference was most pronounced in molar
teeth. It was concluded that the lengths of root fillings could be measured
correctly in clinical radiographs. Due to the anatomy of root canals in incisors
and canines, there was a risk of misinterpreting an inadequate seal as adequate
in these teeth. The large amount of tissue surrounding molar teeth tended to
cause an underregistration of both inadequate seal and lumen apical to the root
fillings in these regions.
PMID- 9558507
TI - Comparison of three instruments in the preparation of curved root canals.
AB - The transportation produced in the apical and middle areas of 30 mesiobuccal root
canals of human mandibular molars was evaluated after circumferential
instrumentation using stainless steel K-files (group A), nickel-titanium K-files
(group B), and clockwise/counterclockwise file rotation using Flexogates (group
C). The canals were instrumented with files #15 to #35 in size. Apical
transportation was assessed radiographically while that occurring in the middle
area was studied microscopically in cross-sections. Although apical
transportation was greatest in the canals of group A, this difference was not
statistically significant (P > 0.05). With respect to the middle area of the root
canal, considerable transportation was observed in 7 of the 30 instrumented
roots. Of these, five belonged to group A and two to group B, a difference which
was not statistically significant (P > 0.05). The best results for transportation
in the middle area of the canal were obtained in group C, in which no
transportation occurred. This difference was significant when compared with the
transportation observed in group A (P = 0.02) but not with that in group B (P >
0.05).
PMID- 9558508
TI - Survival of avulsed permanent maxillary incisors in children following delayed
replantation.
AB - The purpose of this study was to identify the variables that significantly
influenced the survival of incisors replanted after extended extra-alveolar
duration at The Hospital for Sick Children, Toronto, Canada, between June 1988
and December 1993. Survival analysis was used to identify variables that
significantly influence the retention of replanted incisor teeth. Survival was
defined as the time that elapsed between the replantation of an avulsed incisor
and the time it was finally lost. Information on 9 variables was collected for 38
patients (25 males; 13 females) and 52 replanted permanent maxillary incisors.
The mean extra-alveolar duration for the sample was 123 min. The mean follow-up
interval was 942 days (range: 364-2126 days). Incisors replanted with open apices
had a significantly decreased survival compared with teeth with mature apices (P
= 0.04; relative risk 4.2). There was also a significant association between
increased survival and obturation of the root canal with gutta-percha and sealer
(P = 0.006; relative risk 10.0). A trend towards improved survival of replanted
incisors was found for children older than 11 years old at the time of
replantation (P = 0.09; relative risk 2.8). These results are consistent with
previous studies and may assist clinicians and parents in the decision-making
process associated with the management of avulsed teeth in children.
PMID- 9558509
TI - Traumatic dental injuries in a cohort of 16-year-olds in northern Sweden.
AB - The prevalence and yearly incidence of traumatic tooth injury between 1 and 16
years of age were studied in a cohort of 16-year-olds, born in 1975, and residing
in the County of Vasterbotten, northern Sweden. The study comprised 3007 dental
records from the public dental health service. The general distribution was 50.3%
girls and 49.7% boys. The records showed that 35% of the children on one or more
occasions had sustained injury to their primary or permanent dentition. The
frequency was nearly twice as high for boys (64%) as for girls (36%). Twenty-five
percent of the 16-year-olds had met with tooth injury more than once and this
group consisted predominantly of boys. The incidence of injury episodes to
primary and permanent teeth was 28 per 1000 per year. The boys had sustained
trauma to their teeth most frequently when they were 4 years of age and between
the ages of 8 and 11. This was also true for girls at 4 and at 9 years of age,
although less evidently so. In the primary dentition, the majority of dental
injuries had affected the supporting tissue of the maxillary incisors. In the
permanent dentition, 75% of the traumatised teeth were upper incisors. Fractures
of varying severity constituted 60% of all registered diagnoses in this
dentition, followed by subluxation (19%) and concussion (11%).
PMID- 9558511
TI - Childhood obesity: a risk factor for traumatic injuries to anterior teeth.
AB - The relationship between obesity and traumatic dental injuries was evaluated in a
study population of 938 6- to 11-year-old schoolchildren from Rome, Italy, and it
was suggested by the lifestyle and the physical activity of obese children,
which, according to many authors, is different from the lifestyle of other
children. The subjects were examined at school: presence and type of dental
injury, overjet, incisor protrusion, upper lip incompetence and presence of
obesity were recorded. Trauma predisposition was evaluated with a questionnaire
investigating the behaviour which may predispose to impacts. Six out of eight
questions in this questionnaire concerned the children's lifestyle and the trauma
predisposition score was therefore also considered an estimate of lifestyle and
physical activity. The dental injury prevalence of the study population was 21.3%
and obesity prevalence was 11.4%. Of the obese children 30.8% had dental injuries
vs. only 20.0% of non-obese subjects (P = 0.007). Obese children had only enamel
and enamel-dentine fractures and the main reported trauma cause was indoor play;
conversely, lean children also had other types of injuries and the most
frequently reported cause was outdoor play. The main predisposing factors
significantly affecting the probability of dental injury, evaluated with multiple
logistic regression, were upper lip uncoverage (OR: 1.23; P = 0.02), overjet
larger than 3 mm (OR: 1.68; P = 0.001) and obesity (OR: 1.45; P = 0.01).
Surprisingly, trauma predisposition was a protective factor (OR: 0.50; P =
0.00001). The results of this study were explained by the significant inverse
correlation between obesity and trauma-predisposing behaviour, thus suggesting
that subjects frequently playing sports and lively games were not only less obese
but also more skillful and, for this reason, less prone to trauma when they fell
or sustained impacts.
PMID- 9558510
TI - Effect of calcium hydroxide dressing on seal of permanent root filling.
AB - Low apical leakage along root fillings following an application of calcium
hydroxide was reported in a few methylene blue dye penetration studies. It has
been found recently that methylene blue is decolored by calcium hydroxide,
indicating that the short penetration of methylene blue may not be due to a tight
seal only. Of the 80 roots of human maxillary central incisors used in this
study, 40 roots (group 1) received calcium hydroxide root canal dressing whereas
another 40 roots (group 2) did not. All the roots were then obturated with gutta
percha and Tubli-Seal sealer. Leakage along 20 filled roots in each group was
measured using a modified fluid transport model at 48 h, 2, 4, 8 and 16 weeks
after obturation; whereas leakage of another 20 filled roots in each group was
measured using dye penetration with 1% methylene blue. Using the fluid transport
model, no significant difference was found between the two groups at any time
interval (P = 0.4847, 0.3875, 0.9490, 0.4786, 0.9148 respectively after 48 h, 2,
4, 8 and 16 weeks); using the methylene blue penetration method, leakage in group
1 (with root canal dressing) was significantly less than that in group 2 (without
root canal dressing) (P = 0.0374). The contradiction in results from the
different models indicated that problems existed with the models.
PMID- 9558512
TI - Apical leakage in canals filled with glass ionomer sealer and gutta-percha after
dentin conditioning.
AB - This study assessed in vitro apical leakage in root canals filled with gutta
percha and Ketac-Endo using different dentin conditioning and filling techniques.
The root canals of 63 single-rooted teeth were instrumented and randomly divided
into the following four groups: group A--canals were irrigated with 25% tannic
acid and filled with Ketac-Endo and a standardized gutta-percha cone; group B-
canals were irrigated with 1% NaOCl and filled as in group A; group C--canals
were irrigated with 25% tannic acid and filled with Ketac-Endo and a chloroform
softened gutta-percha cone adapted to the canal walls; group D--canals were
irrigated with 1% NaOCl and filled with Grossman's sealer and laterally condensed
gutta-percha. After storage for 72 hours at 37 degrees C and 100% humidity, the
gutta-percha was removed to a level 4 mm short of the working length, using a
Peeso reamer. Teeth were immersed in India ink for 48 hours and cleared, and the
coronal extent of dye penetration examined under a binocular dissecting
microscope at x 15 magnification. The mean value of leakage for group A was 0.86
mm, for group B 2.23 mm, for group C 2.34 mm, and for group D 0.56 mm. Tukey's
multiple comparison test disclosed significant differences (P < 0.05) between
group A and groups B and C, and between group D and groups B and C. Differences
between groups A and D, as well as between groups B and C, were not significant.
PMID- 9558513
TI - Delayed endodontic and orthodontic treatment of cross-bite occurring after
luxation injury in permanent incisor teeth.
AB - A case is presented in which combined endodontic and orthodontic therapy was
performed in traumatically injured teeth 12 months after an accident. Calcium
hydroxide treatment was used to halt any possible resorption during orthodontic
treatment. The teeth were repositioned in a desirable manner without any
complication by orthodontic treatment. Root canal obturation was accomplished
after the completion of active orthodontic treatment. Recall examination 12
months after completion of root canal treatment showed clinical and radiographic
evidence of healing.
PMID- 9558515
TI - Are posts mandatory for the restoration of endodontically treated teeth?
AB - In this era of fiscal and professional accountability, variations in the
utilization of posts to improve the retention of crowns or other restorations on
endodontically treated teeth are no longer acceptable. This practice ignores not
only the potential for root perforations during post space preparations, but also
the adhesive properties of modern resin-based materials. Since the retention of
restorations hinges on many other factors, the placement of posts does not
necessarily assure service quality and may even lead to deleterious changes. The
need to reappraise the utilization of posts in the restoration of endodontically
treated teeth cannot be overstated.
PMID- 9558514
TI - Cyst-like lesion of a developing tooth induced by mandibular fracture.
AB - A dentigerous cyst-like formation in the lower canine region caused by mandibular
fracture in a 10-year-old boy is reported. His medical history revealed that he
had been unconscious for about 2 weeks after traumatic head injuries sustained in
a traffic accident, and a complicated mandibular fracture had been left untreated
until his dentist diagnosed the lesion. Eleven months after trauma, a dentigerous
cyst measuring 20 mm in diameter was found in the fracture area. The lesion was
enucleated and the boy's postoperative recovery was uneventful. The mass
completely enveloped the developing canine, and epithelial cells proliferated
into the connective tissue. However, there was no distinct epithelial lining.
Small round cell infiltrations and several vessels with thrombosis were noted in
the cyst wall. The cause of cyst formation was considered to be infection of the
canine tooth bud and the surrounding soft tissue.
PMID- 9558516
TI - A quantitative comparison of traditional and non-peroxide bleaching agents.
AB - Single-rooted premolar teeth, stained with blood utilizing the technique devised
by Freccia & Peters (1981), were subjected to traditional and non-peroxide
bleaching agents. Colour changes were recorded over a period of 7 days using a
Speedmaster R75-CP Reflection Densitometer. The most efficient removal of
staining occurred after the application of 30% hydrogen peroxide, with sodium
perborate being 75% as effective. All bleaching agents realized their optimum
efficacy within the first 3 days. A combination of three enzymes (amylase, lipase
and trypsin) with disodium edetate was not as effective as the routine bleaching
agents; however, the combination did have a modifying effect on the blood stains.
It is suggested that other non-peroxide agents should be investigated to
determine their efficacy in removing staining from experimentally induced blood
stained teeth.
PMID- 9558518
TI - Effect of eugenol on macrophage adhesion in vitro to plastic surfaces.
AB - This study was performed to investigate the in vitro effect of eugenol on
substrate adherence capacity of macrophages. Macrophages were obtained from
Wistar rats. The adherence capacity of macrophages to the plastic surface of
Eppendorf tubes was determined. Assays were carried out in these tubes for 15 min
of incubation at 37 degrees C in a humidified atmosphere of 5% CO2 in air.
Control peritoneal macrophages showed an adherence index = 52.5%. Eugenol
decreased the adherence index of macrophages in a dose-dependent manner. A 1:1000
dilution of eugenol decreased the adherence index of macrophages by 16.6% (P <
0.05). Lower dilutions (1:100 and 1:10) greatly decreased the adherence index by
51% and 96.2% respectively (P < 0.01). Taking into account that substrate
adherence is the first step in the phagocytic process of macrophages and in
antigen presentation, eugenol could inhibit macrophage function and modulate
immune and inflammatory reactions in dental pulp and periapical tissues.
PMID- 9558517
TI - Sealing capacity in vitro of thermoplasticized gutta-percha with a solid core
endodontic filling technique.
AB - This study assessed the sealing capacity of two endodontic gutta-percha filling
techniques. Thirty-four single-rooted fully developed teeth were endodontically
accessed, instrumented and randomly divided into two experimental groups (n = 12)
and two control groups (n = 5). In Group A, root canals were obturated using a
solid core thermoplastic technique (Densfil), in Group B and Group C (negative
control) canals were obturated with laterally condensed gutta-percha, and in
Group D (positive control) canals were left unobturated. AH-26 was used as the
sealer. Two days later, the teeth were conventionally prepared for testing apical
and coronal leakage, immersed in india ink for 5 days and subsequently cleared.
The linear coronal and apical extent of dye penetration was measured under a
light dissecting microscope. The mean apical leakage for Group A was 1.39 mm, and
for Group B 2.76 mm, whereas the mean coronal leakage for Group A was 2.87 mm,
and for Group B 4.03 mm. The differences between the groups were not
statistically significant (P > 0.05).
PMID- 9558519
TI - Prospective study of two retrograde endodontic apical preparations with and
without the use of CO2 laser.
AB - This article covers a 4-year study that reports 320 cases in which endodontic
surgery was performed for residual apical lesions or lesions that could not be
treated in a conventional way. Four groups of 80 teeth each were formed and they
were followed up after a 12-month interval. The first group comprised cases
treated with a micro bur, retrograde filling and IRM; the second, cases treated
at the apical and radicular portions with a CO2 laser; the third, cases in which
the retrograde cavity was prepared with an ultrasonic device instead of a micro
bur; and the fourth group comprised cases treated in a similar way to the second
group, i.e., cases treated at the apical and radicular portions, but with a CO2
laser instead of a micro bur. After 12 months, the results showed a better
prognosis with ultrasonic treatment. Regardless of technique, the CO2 laser did
not improve the healing process.
PMID- 9558520
TI - Periodontal ligament vitality and histologic healing of teeth stored for extended
periods before transplantation.
AB - A previous study evaluated the viability of dog periodontal ligament cells as
indicated by tritiated thymidine uptake after extended storage in Hank's balanced
salt solution and Conditioned Medium. The purpose of this study was to evaluate
histologic healing following the identical storage parameters established in the
earlier study. Additionally, for Conditioned Medium, matched pairs (teeth
evaluated for tritiated thymidine uptake and transplanted teeth) were examined in
an attempt to correlate periodontal ligament vitality and healing. Forty-six
extracted endodontically treated dogs' teeth were randomly grouped and stored in
Hank's balanced salt solution or Conditioned Medium for 6, 48, and 96 h and then
transplanted into 6-, 48-, and 96-h sockets. The control group teeth were
transplanted without storage into 6-, 48-, or 96-h sockets. After 6 months the
dogs were killed and the teeth were prepared for histologic evaluation according
to Andreasen. Complete healing, inflammatory root resorption, and replacement
resorption were evaluated and compared. Overall, significantly better healing was
observed for teeth stored in Conditioned Medium than for teeth stored in Hank's
balanced salt solution. Conditioned Medium was not significantly different from
controls. Additionally, there was a positive correlation between periodontal
ligament viability and healing for Conditioned Medium. These results confirmed
the importance of periodontal ligament viability in successful replantation and
the potential of Conditioned Medium as a storage medium for avulsed teeth.
PMID- 9558521
TI - Oral injury and mouthguard usage by athletes in Japan.
AB - The use of mouthguards in contact sports effectively prevents oral injury and
preserves oral structures. We investigated oral injuries and awareness concerning
mouthguards among Japanese high school soccer and rugby players. Athletes were
asked a series of questions concerning their history of oral injury while
participating in sports, and their pattern of mouthguard use was determined. The
data were evaluated statistically using chi-square analysis. The incidence of
oral injuries was 32.3% for soccer athletes and 56.5% for rugby athletes, with
0.8% and 24.1% of the respective groups having mouthguards. There were
significant differences between the soccer and rugby groups (P < 0.001). Although
81.8% of soccer athletes thought mouthguards were unnecessary, only 26.2% of
rugby athletes shared this opinion and there was a significant difference between
the soccer and rugby groups. Many soccer athletes had insufficient knowledge
about mouthguards and were not concerned about preventing oral injury, although
it was in fact a common problem in their sport. Athletes as well as coaches must
be made aware of the high risk of oral injury when playing soccer, rugby, and
other contact sports.
PMID- 9558522
TI - The external and internal anatomy of human mandibular canine teeth with two
roots.
AB - This study investigated the internal anatomy of 65 human mandibular canines with
two well-defined roots. The teeth were decalcified and injected with gelatin
coloured with india ink. Diaphanization was carried out using clear resin to
allow permanent preservation. It was found that all mandibular canines with two
roots had two root canals. Lateral canals were found in 68.9% of teeth and 19.7%
had lateral canals at the bifurcation. The results of the external measurements
(cusp tip to root apex) showed that the average buccal root length was 23.0 mm
and the average lingual root length was 22.7 mm. The maximum and minimum buccal
lengths were 26.7 mm and 17.9 mm respectively and the maximum and minimum lingual
lengths were 27.2 mm and 17.1 mm respectively. The buccal root was the larger of
the two in 47.7% of teeth and 43.1% had roots of equal size. The lingual root was
larger than the buccal root in 9.2% of cases. Clinicians should be aware of the
anatomical variation that exists for mandibular canines.
PMID- 9558523
TI - Transplantation of displaced and dilacerated anterior teeth.
AB - The therapy of dilacerated permanent anterior teeth usually involves surgically
removing the tooth. Subsequently, orthodontic methods for closing the space or
keeping it open are preferred until the patient reaches an age when definitive
implantological or prosthetic treatments may be used. Anterior tooth
transplantation should be considered as an alternative to surgically extracting
the tooth. This study describes a period of investigation covering 3 years during
which neither replacement resorption nor inflammatory resorption was diagnosed in
the five transplanted teeth. The clinical tooth mobility was similar to that of
the adjacent teeth. In spite of the vertical loss of bone shown radiographically
no pathologically enlarged pockets or recessions have been found. It is not yet
possible to make any comments on the prognosis for the long term.
PMID- 9558525
TI - A procedure to raise the tip during correction of the unilateral cleft lip nasal
deformity.
AB - A method is reported for the correction of the depressed nasal tip in the cleft
lip deformities. Open exposure of the nasal frame, septal chondral anterior
reinsertion, and lipocutaneous composite graft taken from the submastoid or
retroauricular region and positioned at the basis of the columella are the main
points of the method. The first results, in 22 patients, are discussed and seem
promising.
PMID- 9558524
TI - A case of combined dental development abnormalities: importance of a thorough
examination.
AB - This report describes a case of combined dental development abnormalities. A
patient with a previous ectopically erupted supernumerary maxillary canine
presented a new ectopically erupted supernumerary premaxillary tooth with dens
invaginatus (Oehlers' type 2) and an aberrant coronal morphology, including a pit
in the distal portion of the palatal surface. This tooth would have been
diagnosed earlier if a panoramic radiograph had been taken at the first visit 5
months before. This case represents a good example of combined dental development
abnormalities, i.e., a numerical anomaly (the supernumerary tooth), an alteration
of dental position (the ectopic eruption), an alteration of dental morphology
(the aberrant coronal shape), and the invagination. This case highlights the
importance of a thorough examination, including complementary radiography, of
patients with a dental anomaly.
PMID- 9558526
TI - Secondary rhinoplasty: analysis of the deformity and guidelines for management.
AB - Secondary rhinoplasty aims at modifying the functional and cosmetic defects
caused by an improperly performed a primary procedure. Correction follows a
logical sequence from which there is no reason to deviate if one wishes to
achieve sure results. The sequence includes analysis of the deformity, accurate
photographic documentation, functional and diagnostic examination, consultation
with the patient, and precise planning of the different steps of surgery.
Deformities are grouped in four different sectors depending on the
characteristics of the repair: upper, intermediate, lower, and inner. However,
defects may involve more than one sector, making it difficult or impossible to
establish a precise boundary between them. The surgical technique requires a wide
exposure of the operating field so that the surgeon can clearly evaluate the
anatomical deformities and carry out the necessary corrections. For this reason,
the open approach is the solution of choice. Two types of grafts are commonly
used in revision rhinoplasty, cartilage and bone. They become necessary to
reestablish function and to restore volume and/or contour. We strongly believe
that only autologous grafts can be used. Grafting materials, their sources, and
applications in different clinical cases are described here.
PMID- 9558527
TI - Double interdomal suture in nasal tip sculpturing.
AB - The authors stress that conservative correction should be the main goal in
rhinoplasty in general and in the surgical treatment of the nasal tip in
particular. After outlining contemporary concepts and criteria relating to the
modeling of an aesthetically pleasing nasal tip and the consequent surgical
planning for its achievement as well as the specific indications for tip plasty,
they go on discuss the technical aspects of tip projection and rotation. A
personal technique is proposed for reshaping and sculpturing the tip, completed
by a double interdomal suture with different application points during closed
rhinoplasty. The technique also involves ancillary procedures consisting in the
execution of a series of incisions with a radial pattern at the domal level and,
when necessary, in the undersurface of the lateral crus. The procedure is
explained in detail and the results are illustrated and discussed.
PMID- 9558528
TI - Technical devices in otoplasty to obtain a natural appearance.
AB - This article outlines the importance given by plastic surgeons to correcting the
external ear malformations. The objective is to create ears with a normal
appearance. Despite more than 200 methods proposed by different authors, a
procedure for otoplasty that gives constant and lasting surgical results has not
yet been found. Following some critical remarks, both anatomical and surgical,
the author proposes a method that, in his experience, gives good results, more
natural and reliable, and is free from failures.
PMID- 9558529
TI - Refinements in microvascular repair of extended oromaxillofacial defects with
radial forearm free flap.
AB - The radial forearm free flap (RFFF) is one of the most widely used and versatile
fasciocutaneous free flaps in head and neck reconstruction because of its
qualities--the consistent vascular anatomy; the thin and pliable nature; the
minimal hair presence; and the possibility of harvesting and transferring it as a
composite tissue flap, with bone, tendon, and nerve. The RFFF provides a method
of single-stage reconstruction of wide residual defects after excision of
advanced cancer (T3-T4) in the head and neck region. We present our ten-year
experience with RFFF and the good results obtained with some refinements, which
allowed us to verify the efficacy of the oral competence using the palmaris
gracilis tendon as a sling. We also present the possibility of harvesting long
segments of radius (up to 18 cm), and the discovery that use of antithrombotic or
anticoagulant therapy is not necessary for the flap survival. This treatment does
not guarantee a complete recovery, but it can improve the quality of the
patient's life.
PMID- 9558530
TI - The auriculoparotid region (APR): resection and reconstruction.
PMID- 9558531
TI - Managed care: effect on future practice.
PMID- 9558532
TI - Stability of transverse maxillary dental arch dimensions following orthodontic
surgical correction of anterior open bites.
AB - A sample of 130 patients with vertical maxillary hyperplasia; mandibular
hypoplasia with a high mandibular plane angle; narrow, tapered maxillary dental
arch form; and anterior vertical open bite were collected from three different
institutions to evaluate the stability of transverse maxillary arch dimensions
after correction of the open bite. Surgical treatment consisted of Le Fort I or
bimaxillary osteotomies. Intermolar, interpremolar, and anterior arch widths were
measured three-dimensionally on dental casts using a Reflex microscope, and
transverse stability after orthodontic or surgical maxillary expansion was
analyzed. Orthodontic expansion followed by a one-piece Le Fort I intrusion
osteotomy was performed in 77 patients, and surgical maxillary expansion by a
multisegment Le Fort I intrusion osteotomy was performed in 53 patients. The
increase of transverse arch width and the relapse after orthodontic or surgical
expansion were not significantly different. The transverse arch width in these
two groups did not relapse in 20% of the patients after a mean follow-up of 69
months. An additional bilateral sagittal split osteotomy had no detectable effect
on stability. Patients who underwent a multisegment Le Fort I osteotomy
stabilized with rigid internal fixation showed better transverse stability than
those with intraosseous wire fixation and maxillomandibular fixation. Maxillary
intermolar and interpremolar arch width relapses were not correlated with tongue
interposition or loss of interdigitation. The relapse of these arch widths showed
significant correlations with clockwise rotation of the mandible but not with
changes of overbite or overjet.
PMID- 9558533
TI - Effect of presurgical incisor extrusion on stability of anterior open bite
malocclusion treated with orthognathic surgery.
AB - The records of 40 nongrowing open bite patients treated with orthodontics and
maxillary surgery were divided into two groups and evaluated. The extrusion group
(n = 19) included those patients who had presurgical maxillary incisor extrusion
of at least 1.5 mm. In the nonextrusion group (n = 21), the maxillary incisors
were maintained or intruded prior to surgery. Statistical analysis showed no
relationship between presurgical extrusion of the maxillary incisors and the
stability of open bite correction; the maxillary incisors were generally stable
long term in both groups. Overbite decreased a mean of -0.97 mm in the extrusion
group and -0.67 mm in the nonextrusion group during the mean 5-year 10-month
follow-up period after appliance removal. Twenty-five percent (10 of 40, 5 from
each group) of the sample had no incisal overlap long term. These findings
suggest that a moderate amount of presurgical incisor extrusion or lack of
extrusion are stable long term and have little influence on posttreatment
stability of open bites. The decrease in overbite observed after treatment may
result from the influence of various dental, skeletal, and soft tissue factors
rather than from any single factor.
PMID- 9558534
TI - Surgical Class III treatment: long-term stability and patient perceptions of
treatment outcome.
AB - To evaluate long-term changes after surgical correction of skeletal Class III
deformity, postoperative cephalometric radiographs at 1 year and 2 or more years
postsurgery were digitized for 92 patients who had received either a bilateral
sagittal split osteotomy for mandibular setback, Le Fort I maxillary advancement,
or a combination of the two procedures. Patients' perceptions of treatment were
determined by four self-administered questionnaires: satisfaction, postsurgical
perception of occlusion and function, problems with facial sensation, and
postsurgical perceptions. From 1 year to longest follow-up, there were almost no
mean changes in landmark positions for the maxillary advancement group and
minimal mean changes in the mandibular setback and two-jaw groups. In all three
groups, more than 90% of the patients showed no clinically significant long-term
changes, which suggests that long-term changes are less likely after Class III
than Class II treatment. At long-term recall, 89% of the patients expressed
satisfaction with their treatment and would recommend it to others, 74% reported
improved social interaction, and 63% said their appearance changed as they
expected. The predominant problems reported were altered facial sensation for 67%
of the patients and surprise at the length of recovery for 52%.
PMID- 9558535
TI - Binder syndrome: literature review and long-term follow-up on two cases.
AB - Binder syndrome has a characteristic clinical appearance including midface
hypoplasia, flattened nose, convex upper lip, broad philtrum, crescent-shaped
nostrils, and a deep fold or fossa between nose and upper lip. The incisors may
be in crossbite with overangulation of the maxillary incisors, and a Class III
occlusion is common. Radiographic features include small or absent anterior nasal
spine, thin labial plate over incisor roots, nasomaxillary hypoplasia, and
skeletal Class III relation. This article reviews the literature in reference to
Binder syndrome and presents two patients treated by two different techniques
with long-term follow-up. The first patient was treated with traditional
orthognathic procedures, whereas the second was treated with a growth-center
implant to the nose and orthodontics to treat the occlusion.
PMID- 9558536
TI - Horizontal anchorage in the ascending ramus--a technical note.
AB - The ascending ramus provides a volume of bone that can receive horizontal screws
of large sizes in the retromolar area, between the internal and external oblique
lines. This area is not prone to disuse resorption and the only vital structure
to consider is the neurovascular bundle. In this article two systems that make
use of this anatomic opportunity are presented. One is an intraoral distractor,
used for mandibular lengthening by gradual distraction. The other is a screw
anchor that provides absolute anchorage for orthodontic tooth movement.
PMID- 9558537
TI - Health-related quality of life following orthognathic surgery.
AB - A randomized controlled trial was conducted to compare the effects of rigid and
wire fixation on health-related quality of life following surgical mandibular
advancement in patients with Class II malocclusions. Sixty-four patients randomly
selected to receive rigid fixation with bicortical position screws were compared
with 63 patients randomly selected to receive nonrigid fixation with inferior
border wires. Quality of life was measured using the Sickness Impact Profile, a
generic measure of health-related quality of life, and the Oral Health Status
Questionnaire, a specific measure of oral health and function designed for use
with orthognathic surgery patients. Patients were evaluated prior to application
of orthodontic appliances, approximately 2 weeks before surgery, and 1 week, 8
weeks, 6 months, 1 year, and 2 years following surgery. Neither instrument
revealed a statistically significant difference in quality of life between wire
and rigid fixation at any time period. The health-related disability associated
with Class II malocclusion is modest compared to many other medical conditions.
Nonetheless, orthognathic surgery patients exhibit progressive and statistically
significant improvement in health-related quality of life across a wide variety
of functional domains, regardless of the fixation method used.
PMID- 9558539
TI - Paediatric dentistry in Hong Kong.
PMID- 9558538
TI - A simple classification of orthognathic surgery complications.
AB - Although orthognathic surgery has now become a routine part of oral and
maxillofacial surgery practice, the complexity of such surgery together with the
detailed planning involved makes it a difficult area of surgery to follow in the
literature. The plethora of literature on the subject of complications in
orthognathic surgery makes it essential to devise a simple classification of
complications so that comparative studies can be identified and grouped together
for more meaningful interpretation. The aim of this article is to present a brief
and coherent overview of the main complications associated with orthognathic
surgery for the purpose of establishing a simple classification of complications
for future reference.
PMID- 9558540
TI - The management of drooling in children and patients with mental and physical
disabilities: a literature review.
AB - Amongst the duties of the paediatric dentist is the provision of oral care to
patients with the problem of drooling. Many, but certainly not all, of these
patients have physical and/or learning disabilities. Various methods have been
advocated for the management of drooling in the paediatric patient and older
patients with disabilities, including behavioural programmes, biofeedback
techniques, physiotherapy, biofunctional oral appliances, medication and surgery.
It is of paramount importance that the patients and/or carers understand the
advantages and disadvantages of any treatment method being considered. The
paediatric dentist has an important role to play in explaining the different
options to the patients and carers, and in implementing some treatment
modalities, particularly non-surgical approaches. Referral to surgical
specialists should be seen as 'a last resort' and suggested only if other
treatment methods have been exhausted. If pharmacological or surgical treatment
is carried out, careful monitoring for the development of dental caries and other
problems is essential. The aim of this paper is to provide the paediatric dentist
with concise overall knowledge of the causes of drooling and treatment options
available.
PMID- 9558541
TI - Oral health advice: reported experience of mothers of children aged 5 years and
under referred for extraction of teeth under general anaesthesia.
AB - AIMS: To examine the reported receipt of oral health education among mothers of
children who required the extraction of teeth under general anaesthesia. DESIGN:
Cross-sectional study using questionnaires completed at interview. SAMPLE: 150
mothers of children aged 5 or younger who had been referred for extraction of
teeth under general anaesthesia. SETTING: Dental School, University of Wales
College of Medicine. RESULTS: 27% of mothers recalled receiving advice from their
dentist about dental care during their pregnancy. With regard to their child's
oral health, 48% had received dietary advice and 31% oral hygiene advice from the
same source. All children lived in areas with suboptimal water fluoride levels;
27% of mothers had been advised by their dentist to give their child fluoride
supplements. Few of the mothers recalled receiving advice about oral health from
their health visitor.
PMID- 9558542
TI - Dental problems associated with hypophosphataemic vitamin D resistant rickets.
AB - OBJECTIVE: To review a series of cases of hypophosphataemic vitamin D resistant
rickets. SUBJECTS INCLUDED: Seventeen cases, aged between 2 years 1 month and 15
years 9 months at first referral, and with an established diagnosis of vitamin D
resistant rickets from twelve families were included in the review. Information
was drawn from patient records for follow-up periods between 9 months and 20
years 4 months. SETTING: All subjects had been referred to the Eastman Dental
Hospital between 1973 and 1997. FINDINGS: Abscessed non-carious primary and/or
permanent teeth were a presenting feature in eleven of the seventeen cases.
Although attrition and exposure of the abnormally formed dentine accounted for
the route of infection in primary teeth, the route for microbial invasion of
pulpal tissues in permanent teeth remained unexplained in a number of patients.
The possible part played by infractures of the enamel as a portal of entry for
infection is discussed. Enamel defects were observed in only six patients, in
three of whom these changes were limited to the primary dentition. Taurodontism
of permanent molar teeth was confirmed as a feature of the condition in the more
severely affected male subjects.
PMID- 9558543
TI - Salivary alterations in insulin-dependent diabetes mellitus.
AB - OBJECTIVES: To examine the flow rate and composition of unstimulated whole saliva
and of serum in children with newly diagnosed insulin-dependent diabetes mellitus
(IDDM) and to compare these with values for a group of healthy controls. DESIGN:
Cross-sectional. SETTING: Diabetic Department of a University Hospital in
Thessaloniki, Greece. SUBJECTS AND METHODS: The test group was made up of 10
recently diagnosed child patients with IDDM, aged 4-15 years and free of other
systemic disease. Ten healthy children aged 5-17 years served as controls.
Children were clinically examined before unstimulated saliva was collected over a
5 minute period and blood samples taken. Saliva and serum measurements included
glucose, total proteins, albumin and immunoglobulins (IgA, IgG). RESULTS: No
significant difference was seen in salivary flow rate between the two groups.
Significantly greater concentrations of glucose were seen in saliva and serum in
children with IDDM. Neither total protein nor albumin differed significantly
between the two groups. Salivary IgA concentration was higher in the test group
as was serum IgG. CONCLUSIONS: Findings in this sample suggest that changes in
salivary composition may, together with estimated glucose levels, play a helpful
diagnostic role in the early stages of IDDM in some children.
PMID- 9558544
TI - Restoration of permanent teeth in young rural children in Cambodia using the
atraumatic restorative treatment (ART) technique and Fuji II glass ionomer
cement.
AB - Several recent studies have demonstrated the success of the ART (atraumatic
restorative treatment) technique under field conditions in developing countries.
The ART technique involves removal of caries using only hand instruments, and
placing a glass ionomer cement (GIC) restoration. OBJECTIVES: To estimate the
longevity of Fuji II GIC ART restorations placed in permanent teeth by dental
nurse students under field conditions in rural Cambodia. DESIGN: Clinical field
trial. SETTING: One high school in rural Cambodia. SAMPLE AND METHODS: 53
subjects between the ages of 12 and 17 who had dental caries were selected to
participate. Subjects were randomly assigned to a dental nurse student for cavity
preparation and placement of ART restorations (without cavity conditioning).
RESULTS: 92.1% of the carious lesions required class I or class V restorations,
and 85.4% were in the lower molars. 89 teeth were filled. At 1 and 3 years 86.4%
and 79.5% of restorations were still present. Restorations were assessed by one
dentist according to standard criteria. 76.3% of the restorations were judged to
be successful at 1 year, and 57.9% at 3 years. CONCLUSIONS: Factors which may
have affected the success rates included: the material used, technical factors,
failure to condition the cavity prior to restoration, and inexperience of the
operators. The results suggest that ART restorations in permanent teeth using
Fuji II GIC are only moderately successful after 3 years. Better results could be
expected by using a dentine conditioner in conjunction with one of the newer
stronger glass ionomer cements.
PMID- 9558545
TI - Root abnormalities, talon cusps, dentes invaginati with reduced alveolar bone
levels: case report.
AB - This is a case report of a Caucasian female who presented with an unusual
combination of dental anomalies: short roots on the maxillary central incisors
and premolars, talon cusps, dentes invaginati, low alveolar bone heights,
tubercles of Carabelli on the maxillary first and second permanent molars, with
pyramidal root morphology in three of the second permanent molars. None of the
anomalies alone are particularly uncommon but they have not previously been
reported together. The occurrence of the anomalies is probably incidental as the
conditions are aetiologically unrelated.
PMID- 9558546
TI - The dental problems and management of a patient suffering from congenital
insensitivity to pain.
AB - Congenital insensitivity to pain is a rare condition usually manifested in
childhood by a history of unrecognized trauma, indifference to painful stimuli or
self-mutilation. This paper describes the management of a 13-month-old male who
had severely lacerated his tongue by habitually chewing it, using soft polyvinyl
mouthguards retained with a minimal amount of denture fixative.
PMID- 9558547
TI - A case report of an unusual mandibular swelling in a 4-year-old child possibly
caused by a jellyfish sting.
AB - Animal bites and stings may not figure highly in the differential diagnosis of
facial swelling in the United Kingdom but should be considered in those who have
been in a tropical area. This case report documents details of the presentation
and investigation of a case of jellyfish sting that appeared as a facial swelling
in a 4-year-old girl who had recently been on holiday in Greece. The report
emphasizes the requirement to consider unusual aetiological factors in cases of
facial swelling.
PMID- 9558548
TI - Multiple endocrine neoplasia syndrome type IIb: a case report.
AB - Multiple endocrine neoplasia type IIb (MEN IIb) is a syndrome, part of which can
involve neoplastic change in the thyroid and adrenal glands. It has unusual oro
facial manifestations including mucosal neuromata on the lips, cheeks and tongue.
A child aged 3 years and 10 months presented with mucosal tags at the corners of
the mouth, early eruption of permanent teeth, malocclusion and facial asymmetry.
Biopsy of the excess mucosal tissue suggested a diagnosis of either MEN type IIb
or neurofibromatosis. Genetic testing eventually confirmed MEN type IIb. The
patient has been followed up regularly for 9 years. He has developed modular
lesions on his tongue and irregular enlargement of his lower lip, but to date
there have been no signs of tumour development. This report emphasizes the
importance of thorough examination of the oral mucosa and follow-up of any
abnormalities.
PMID- 9558549
TI - Dens invaginatus in a primary canine: a case report.
AB - This article describes an unusual case of dens invaginatus in a primary canine. A
5-year-old boy presented with an infected mandibular primary canine. A periapical
radiograph showed a developmental disturbance in the crown diagnosed as dens
invaginatus. A necrotic pulp has been removed from the tooth and the root canal
obturated with a resorbable paste. Six weeks later the tooth was found to be
asymptomatic. A composite restoration replaced the temporary filling material.
Dens invaginatus may appear in the primary dentition, and early diagnosis is
important for preventative treatment.
PMID- 9558550
TI - Implant-supported prosthesis in a child with hereditary mandibular anodontia: the
use of ball attachments.
AB - This report describes the provision of an implant-supported hybrid overdenture in
an 8-year-old child with mandibular anodontia. An interdisciplinary approach to
treatment planning was employed. Two implant fixtures were placed in the canine
regions and ball attachments connected to provide support and retention for the
prosthesis. There was only one implant-related complication during the first
follow-up year. Close follow-up during the child's growing years is essential for
the maintenance of the peri-implant tissues and to replace the prosthesis as
mandibular growth occurs.
PMID- 9558551
TI - Treatment of avulsed permanent teeth in children. UK National Guidelines in
Paediatric Dentistry. Royal College of Surgeons, Faculty of Dental Surgery.
PMID- 9558552
TI - Standards, parameters, and taking care of people.
PMID- 9558553
TI - Vertical ridge augmentation around dental implants using a membrane technique and
autogenous bone or allografts in humans.
AB - This study investigated the effect on vertical bone regeneration of the addition
of demineralized freeze-dried bone allograft or autogenous bone chips to a
membrane technique. Twenty partially edentulous patients with vertical jawbone
deficiencies were selected for this study. The patients were divided into two
groups of 10 individuals. The 10 patients of Group A received 26 Branemark
implants in 10 surgical sites. The 10 patients of Group B received 32 implants in
12 surgical sites. Fifty-two out of 58 implants (22 in Group A and 30 in Group B)
extended 1.5 to 7.5 mm superior to the bone crest. Titanium-reinforced expanded
polytetrafluoroethylene membranes were used to cover the implants and, before
complete membrane fixation, demineralized freeze-dried bone allograft particles
were condensed under the membrane in Group A, and autogenous bone chips were used
in Group B. At the reentry after 7 to 11 months the membranes were removed and a
small biopsy was collected from 11 sites comprehending the miniscrews. The
clinical measurements from Group A demonstrated a mean vertical bone gain of 3.1
mm (SD = 0.9 mm, range 1 to 5 mm) with a mean percentage of bone gain of 124% (SD
= 46.6%). The measurements from Group B showed a mean vertical bone gain of 5.02
mm (SD = 2.3 mm, range 1 to 8.5 mm) with a mean percentage of bone gain of 95%
(SD = 26.8%). Histomorphometric analysis of the present study clearly
demonstrated a direct correlation between the density of the pre-existing bone
and the density of the regenerated bone. The mean percentage of new bone-titanium
contact was from 39.1% to 63.2%, depending on the quality of the pre-existing
bone. Both the clinical and histologic results indicate a beneficial effect of
the addition of demineralized freeze-dried bone allograft or autogenous bone
particles to vertical ridge augmentation procedures in humans.
PMID- 9558554
TI - Guided tissue regeneration using a resorbable membrane in gingival recession-type
defects: a histologic case report in humans.
AB - This case report clinically and histologically evaluated the regeneration of
gingival tissues with the use of resorbable membranes. The study was performed on
a premolar for which extraction was planned. The exposed root surface was
thoroughly cleaned and planed with curettes and rotary instruments, and two
notches were created on the facial aspect of the exposed root surface. A
resorbable Resolute membrane (WL Gore) was applied above the defect to allow for
gingival regeneration. After a 6-month healing period, a block section containing
the root and the regenerated tissues was removed. The biopsy specimen was
processed to obtain thin ground sections. The histologic analysis demonstrated
the formation of a newly generated periodontal tissue from the deepest notch
toward the coronal gingiva. The newly formed tissue was composed of a coronal
area of connective tissue attachment and an apical area of bone fibers and
cementum. The present report histologically demonstrates the ability of a
resorbable membrane to allow complete regeneration of the periodontal ligament in
the coverage of gingival recessions.
PMID- 9558555
TI - Implants in regenerated bone: long-term survival.
AB - This retrospective multicenter study analyzed 526 implants placed and loaded in
regenerated bone. Both autogenous and allogeneic bone grafts were used in
combination with a barrier membrane to reconstruct bone using either a
simultaneous or staged approach. Implants were followed from 6 to more than 74
months postloading. Eight of the implants were lost, for a success rate of 97.5%.
The type of graft material did not affect the clinical success of the implants,
nor did the use of submerged versus nonsubmerged implants or a staged versus a
simultaneous approach. In conclusion, regenerated bone reacted to implant
placement in a manner that was clinically similar to native bone.
PMID- 9558556
TI - Restoration of the severely worn dentition using a systematized approach for a
predictable prognosis.
AB - Dental literature supports the concept that vertical dimension of occlusion is
normally not lost in severely worn dentition, and the bite should generally not
be opened to facilitate dental reconstruction. However, restoration of a
periodontally sound but severely worn dentition, at existing vertical dimension,
frequently presents unique challenges in patient management, diagnosis, treatment
planning, and restorative methodology. This report reviews and demonstrates an
integrated and planned approach to this complex treatment situation that can lead
to a favorable and predictable prognosis. The approach also allows a practitioner
free use of various techniques if certain goals of occlusion are followed.
PMID- 9558557
TI - Volumetric changes following barrier regeneration procedures for the surgical
management of grade II molar furcation defects in baboons: II. Bone, cementum,
epithelium, and connective tissue.
AB - In Part I, a computer imaging technique was used to measure the volumetric fill
that occurred in surgically created grade II molar furcation defects after they
had been treated using the principles of guided tissue regeneration. In Part II,
the volumetric fill for each of the specific tissues comprising the defect fill
(epithelium, connective tissue, bone, and cementum) was compared. The histologic
material consisted of defects treated using one of three types of surgical
treatment as well as untreated control sites. All volumetric measurements were
expressed as a percentage of the original surgically created defect size, with
100% indicating complete healing of the defect. The results indicate that none of
the defects achieved complete healing. Teeth receiving flap debridement had the
most overall defect fill (79.50% comprised of 17.13% bone, 35.81% connective
tissue, 37.35% epithelium, and 9.71% cementum). Teeth that received a
biodegradable barrier showed a mean overall defect fill of 74.98% (7.41% bone,
47.13% connective tissue, 36.20% epithelium, and 9.26% cementum. Sites treated
with an exclusion barrier showed 70.75% overall fill (9.63% bone, 40.89%
connective tissue, 39.00% epithelium, and 10.48% cementum). The untreated control
teeth showed a mean overall fill of 78.70% (5.56% bone, 59.11% connective tissue,
31.06% epithelium, and 4.27% cementum). No significant differences were found
among teeth within the same animal and between treatment and controls. The
following conclusions were drawn: (1) connective tissue comprised nearly one half
of the total fill of the surgically created defects; (2) the percentage of new
bone growth was significantly lower than anticipated; and (3) no significant
differences were found among the treatment modalities and the untreated control
sites for each of the specific tissue types.
PMID- 9558558
TI - An integrated approach to optimizing orofacial health, function, and esthetics: a
5-year retrospective study.
AB - The restorative dentist treats patients with needs that often transcend dental
disciplines. This dentist will be responsible for long-term dental maintenance
and should logically oversee interdisciplinary reconstruction. This case report
demonstrates an integrated treatment approach and 5-year retrospective study
involving a patient with maxillary anterior excess, pronounced overjet, and
advanced periodontitis. Extraction and radical alveolectomy with removable
prosthesis is often considered in such cases; however, results are often less
than optimum function, esthetics, and general oral health. In this case, a
previously undescribed anterior maxillary rotating segmental ostectomy was
integrated with restorative, periodontal, and removable full and partial denture
procedures.
PMID- 9558559
TI - Effect of treatment on cyclosporine- and nifedipine-induced gingival enlargement:
clinical and histologic results.
AB - The clinical and histologic responses to periodontal treatment of gingival
enlargements, induced when cyclosporine and nifedipine were administered singly
or in combination, were evaluated. A significant correlation was noted between
plaque, gingivitis, and gingival overgrowth. Severity of enlargement appeared to
be greater in patients on combined therapy. All treatment approaches such as
scaling, root planning, gingivectomy, and periodontal flaps, and a combination of
therapies, were effective in the management of gingival overgrowth up to 1 year
after completion of treatment. Adjunctive use of chlorhexidine was found to be
beneficial.
PMID- 9558560
TI - Biocompatibility of Optibond and XR-Bond adhesive systems in nonhuman primate
teeth.
AB - This study evaluated the histologic responses of two different adhesive systems
on the teeth of seven healthy adult monkeys. Class V cavities in 128 teeth were
observed at 7,21 to 27, and 90 to 97 days. Statistical data showed no significant
differences in pulp inflammation between the Optibond (Kerr), XR-Bond (Kerr), and
IRM (Caulk) groups in pulps at the three time intervals. Some odontoblastic
disruption and inflammation was seen in pulps restored with XR-Primer at the
three time intervals. Pulp healing was similar in teeth treated with both direct
capped Optibond and calcium hydroxide, and there was no significant increase in
pulpal inflammation with time. No abscesses or necrotic pulps were seen in any
teeth. Optibond and XR-Bond adhesive systems are biologically acceptable in
nonhuman primate pulp tissues.
PMID- 9558561
TI - Sinus pericranii.
AB - Sinus pericranii is an anomalous extracranial vascular malformation that is in
continuity with the intracranial dural venous sinuses. Five case reports, three
congenital and two traumatic, are described. Clinical management, including
evaluation, diagnosis, and treatment, is discussed. Awareness of this entity by
plastic surgeons will allow for earlier diagnosis and appropriate surgical
management, resulting in decreased risk of complications.
PMID- 9558562
TI - Treatment of craniofacial asymmetry with dynamic orthotic cranioplasty.
AB - Dynamic Orthotic Cranioplasty (DOC) was developed to treat craniofacial
deformities associated with positional plagiocephaly. This investigation
describes the treatment of more than 750 patients with the DOC Band since 1988.
All patients undergoing DOC treatment were fit with a custom fabricated orthosis
made from a plaster impression taken from the infant's head. When the orthosis
was applied, the corrective pressure was directed to hold growth at the calvarial
prominences and redirect symmetrical growth. A detailed medical history was
obtained and anthropometric measurements were taken at start, exit, 12, 18, and
24 months follow-up. This information was recorded in a database created in
Microsoft Excel. Mean length of treatment was 4.3 months with an average entrance
age of 6.9 months. Analysis of anthropometric data showed significant reduction
in mean cranial vault, skull base, and facial asymmetries. Correction of the more
difficult skull base was documented with computed tomography. Our anthropometric
and clinical observations document complete or near complete correction of
asymmetry for a wide variety of head shapes. Based on the results of this
investigation, we are able to support the earlier claims of our pilot study,
which concluded that DOC is effective in the treatment of positional
plagiocephaly.
PMID- 9558563
TI - Surgical correction of unilateral cleft lip nasal deformity.
AB - Fifty-five patients with unilateral cleft lip nasal deformities were operated on
from March 1992 to June 1996. Thirty-one patients were male and 24 were female.
Three patients were 2 to 5 years of age, 7 patients were 6 to 10 years old, 12
patients were 11 to 15 years old, 13 were 16 to 20 years old, and 20 were greater
than 21 years of age. The average follow-up period was 16 months. Combined
operative procedures, depending on the severity of the cleft lip nasal deformity,
were the following: (1) a reverse-U incision and Z-plasty for a mild vestibular
web, (2) a reverse-U incision and V-Y plasty for a moderate vestibular web, (3)
open rhinoplasty incision combined with a reverse-U incision and V-Y plasty for
severe flattening or buckling of the cleft lower lateral cartilage, (4) lower
lateral cartilage suspension or repositioning with or without an onlay cartilage
graft, (5) alar base advancement, (6) bone graft on the piriform aperture, (7)
septoplasty and corrective rhinoplasty, and (8) columella lengthening with an
auricular composite graft. A nasal splint was applied for 3 to 6 months in every
patient to maintain the corrected nostril contour. Most patients were satisfied
with their surgical results. We suggest that to achieve a good contour of the
nose, bony and cartilaginous deformities should be corrected simultaneously with
correction of the soft tissue.
PMID- 9558564
TI - Use of scanning electron microscopy in the evaluation of craniosynostosis.
AB - The cause of craniosynostosis continues to elude researchers. Although several
studies have looked at the ultrastructure of normal suture closure, no previous
studies have examined the microarchitecture of the synostotic suture. Our goal
was to assess the scanning electron microscope (SEM) as a viable and useful tool
in examining craniosynostosis. Our hypothesis is that the SEM is a powerful
analytical tool that can evaluate nonsynostotic, partial synostotic, and complete
synostotic cranial sutures. We analyzed the cranial suture of 3 human infants
with nonsyndromic sagittal craniosynostosis. The specimens were separated into
three groups, which included regions of partial and complete synostosis and a
region of open suture. Histological examination provided cellular and tissue data
about craniosynostosis, whereas the SEM provided detailed information regarding
the trabecular microarchitecture of the synostosed suture. The SEM produced
quality images of complete and partially synostotic sutures and open sutures. At
low magnification, the SEM characterized the general bony microarchitecture of
cranial sutures in a manner different from, but complementary to, standard
histological sections. At higher magnification, the SEM allowed us a look at the
cellular population of craniosynostotic sutures in a way that surpasses standard
light microscopy. The SEM is an excellent tool for the study of craniosynostosis
and has proved invaluable in our ability to evaluate the microarchitecture and
cellular population of the fusing suture. We believe we have proven our
hypothesis by demonstrating the SEM to be a powerful analytical tool that can
evaluate nonsynostotic, partial synostotic, and complete synostotic cranial
sutures.
PMID- 9558566
TI - Surgical and implantation reconstruction in a patient with giant-cell central
reparative granuloma.
AB - The giant-cell central reparative granuloma, unlike other giant-cell neoplasias,
is mainly found in maxillary bones, particularly in the mandible. We report a
patient study of giant-cell central reparative granuloma in the mandible
extending from dental elements 34 to 44. The patient underwent excision of a
neoplasm and reconstruction of the mandible via an autologous bone graft of the
iliac crest. To restore fully, functionally, and aesthetically the masticatory
apparatus after verification of graft stability, four osseointegrated implants
were fixed, and an "overdenture" prosthesis was then applied, thus finally
solving the problem.
PMID- 9558565
TI - Reasons for removal of rigid internal fixation devices in craniofacial surgery.
AB - Despite the widespread use of rigid fixation techniques in craniofacial surgery,
there is a paucity of studies in the literature that serve to better define the
reasons for the subsequent removal of plates and screws. The current study
appears to be the first to attempt to assess these issues among a broad range of
craniofacial surgery patients. Fifty-five patients who underwent hardware removal
following craniofacial surgery at the University of Michigan Medical Center
between 1989 and 1995 were retrospectively studied via an in-depth chart review.
Common reasons for hardware removal included palpable/prominent hardware in 19
patients (34.5%), loosening of plates and screws in 14 patients (25.5%), pain in
14 patients (25.5%), infection in 13 patients (23.6%), wound dehiscence/exposure
of hardware in 11 patients (20%), and removal at the time of secondary procedures
in 5 patients (9.1%). It is hoped that this study will serve as a tool to define
more completely the risk of needing subsequent hardware removal among
craniofacial surgery patients treated with rigid internal fixation.
PMID- 9558567
TI - Use of microcomputed tomography scanning as a new technique for the evaluation of
membranous bone.
AB - Previous basic bone studies in cranial bone biology and bone grafting have used
calipers, volume displacement, and cephalometric tracings to measure membranous
bone and to infer fundamental properties of cranial bone. These tools have
limited accuracy and reproducibility. Histomorphometry has also been used in the
quantitative analysis of cranial bone; however, two-dimensional histology is
unable to capture a precise representation of the three-dimensional structure of
bone. For the first time, we have used the advanced technology of three
dimensional microcomputed tomographic (micro-CT) scanning as a highly accurate
and automated tool to precisely measure changes in bone stereology, volume and
projection, and microarchitecture in the evaluation of membranous bone. The
advantages of this technology are numerous and include the rapid and
nondestructive three-dimensional analysis of bone microstructure at resolutions
between 10 and 75 microns. Measures of "connectivity" in three dimensions and the
architectural parameter of "anisotropy" are available through micro-CT imaging
but can only be inferred through two-dimensional histological series. We
successfully imaged two full-thickness cranial bone specimens and one cancellous
iliac bone graft. The images demonstrate a similarity between the two membranous
specimens and a marked difference in comparison with the endochondral graft.
These differences are borne out by mathematical analysis, and their significance
is discussed. The utility of micro-CT in the evaluation of membranous bone was
displayed by its ability to rapidly calculate differences in bone stereology and
to quantitatively measure morphological changes at an ultrastructural level. We
believe the benefits of this system will prove to be extremely useful for
investigations into the basic biology of membranous bone, bone grafts, and
craniofacial interfaces, and we encourage its use by other scientific
investigators in the field of craniofacial surgery as they strive for more
scientifically rigorous tools to understand the basic biology of membranous bone.
PMID- 9558568
TI - Orbital hemangiopericytoma: case report of a long-term recurrency.
AB - Among tumors concerning the orbit, hemangiopericytoma is one of the most unusual
forms. This tumor has a vascular origin and usually appears as a fleshy, well
circumscribed mass, characterized by slow growth and lack of soreness. Its
biological traits include a mostly benign nature, a potential malignancy, and,
most of all, a highly frequent recidivation. This study of double recidivation
shows this can occur even after a long lapse of time and the new tissue can
acquire malignant traits. Finally, we describe the modes of the surgical
approach, which aims at intervening the most radical cases to reduce recidivation
to a minimum.
PMID- 9558569
TI - Intracranial migration of microplates versus wires in neonatal pigs after frontal
advancement.
AB - Several case reports have demonstrated that microplates migrate intracranially
when used in the reconstruction of the neonatal craniofacial skeleton. We
conducted a study to analyze the validity of this finding, to calculate the rate
of intracranial plate migration, and to compare the migration of microplates to
standard surgical wire. We hypothesized that, because of constant bone generation
and resorption in the developing cranial skeleton, both microplates and wires
would migrate and resorption in the developing cranial skeleton, both microplates
and wires would migrate intracranially. Bilateral supraorbital osteotomies were
performed in five 6-week-old Yucatan minipigs. The right side was repaired by
fixating the bone segment with 32-gauge stainless steel wire. The left side was
fixed with two microplates (Leibinger Corp, Dallas, TX). The pigs were monitored
for 6 months. During this time each pig was injected with a fluorescent bone dye
on the first day of each month. One pig was killed at 3 months and used for
midpoint comparison. We found that both microplates and wires migrated
intracranially in these neonatal pigs. None of the plates or wires penetrated the
dura, but several pieces of hardware from each group migrated far enough to rest
directly on the dural surface. The rate of plate and wire migration also varied
slightly among animals, but the mean rate remained relatively constant at 0.91
mm/month. Computed tomographic scans and morphometric analysis revealed no
significant difference between the fracture healing and facial growth of the
microplate and wire sides. We conclude that the biology of bone deposition in the
calvarium causes any stationary foreign body on the surface of the skull to
migrate intracranially in the neonate.
PMID- 9558570
TI - Growing skull fractures: strategies for repair and reconstruction.
AB - Most skull fractures in growing children heal rapidly and without significant
contour irregularity. Skull fractures in infants associated with dural injuries,
however, may progressively enlarge as a result of bone erosion by leptomeningeal
herniation at the dural tear sites and are known as "growing skull fractures."
Over a 6-year period, seven growing skull fractures occurred in a population of
592 consecutive pediatric head injuries at Cardinal Glennon Children's Hospital
(prevalence, 1.2%). Prompt recognition of growing skull fractures, repair by
regional craniectomy and pericranial dural inlay graft, and immediate contour
reconstruction with rigidly fixed cranial bone graft ensure reliable aesthetic
and functional restoration of the growing neurocranium.
PMID- 9558571
TI - Growing skull fracture after cranial vault reshaping in infancy.
AB - Growing skull fractures are reported in three infants undergoing cranial vault
surgery for craniosynostosis. Although primary dural injury was overt in only one
patient, an extensive dural defect with spatially coincident bony absence was
identified in all patients at late exploration. The coincidence of dural injury,
deficient overlying bone, and a pulsatile growing brain are necessary conditions
for the development of growing skull fractures. With the advent of increasingly
radical cranial vault procedures during infancy, the potential for this
complication to arise may increase. Definitive correction requires autogenous
tissue reconstruction of the dural and bony defect.
PMID- 9558572
TI - Use of free composite graft for a large defect in the anterior skull base.
AB - Until recently, most skull base tumors, particularly those extending into the
orbit or anterior or middle cranial fossa base, were excised incompletely because
of the technical difficulty in performing en bloc resections. However, improved
craniofacial surgical techniques, recent developments in technology and
equipment, improved imaging techniques, interdisciplinary collaboration, and
improved anesthetic techniques have enabled a wide range of attempts resulting in
successful clinical outcome. We present a case of recurrent meningioma with
intracranial and extracranial extension in which three previous operations left a
large craniectomy defect in the frontal area as well as a frontal lobe defect.
After removal of the tumor, we reconstructed the large defect using composite
graft (free bone and fascia lata).
PMID- 9558573
TI - McCune-Albright syndrome progressing with severe fibrous dysplasia.
AB - We present the case of an 11-year-old girl with McCune-Albright syndrome
associated with severe fibrous dysplasia. In addition to bone lesions, she has
apparent manifestations of precocious puberty. In examination, a mass at the
mentum spreading to mandibular corpus bilaterally was seen. This mass has
affected the mandibular teeth. It was nearly 20 x 20 x 15 cm in size and had
local necrotic regions on it. The lower lip was expanded too much by the mass.
Another mass filled the left maxillary sinus, expanding the left zygomatic region
outwardly and closing the left nasal fossa completely. A rectangular skull shape
was related to the involvement of cranial bones. After stainless steel, custom
made mandibular prosthesis was prepared, the patient underwent surgery. A partial
mandibulectomy was performed, and resulting mandibular bone defect was
reconstructed by steel prosthesis. Craniofacial involvement occurs in 100% of
disseminated cases. In the dental literature, mandibular involvement was found in
20% of cases. However, in studied literature, we did not find a dramatic
mandibular lesion as severe as that presented here.
PMID- 9558574
TI - The feet in Pfeiffer's syndrome.
AB - Broad toes are the classic clinical finding occurring in the feet in Pfeiffer's
syndrome patients, but few cases undergo formal radiological assessment. However,
the feet in other craniosynostosis syndromes resulting from mutations of the
fibroblast growth factor receptor 2 gene have anomalies at many other sites
within the feet, which raised the possibility that there may also be a wider
range of anomalies other than broad big toes in the feet of those with Pfeiffer's
syndrome. The object of this study was to assess prospectively the incidence and
pattern of clinical and radiographic anomalies of the feet of patients with a
confirmed diagnosis of Pfeiffer's syndrome. Twenty-two Pfeiffer's syndrome
patients were examined both clinically and radiologically for anomalies of the
feet. Clinical examination revealed broad big toes in 12 patients and syndactyly
in 2. Radiographs of the feet were evaluated by a radiologist with an interest in
skeletal dysplasia as well as by members of the Craniofacial team. A wider range
of radiological than clinical anomalies involving the phalanges, metatarsals, and
tarsals was seen. The severity of the anomalies observed ranged from normal to
those resembling the feet of Apert's syndrome patients. Only 4 patients had
radiologically normal feet. These radiographic findings suggest that there is a
range of foot anomalies more extensive than the broad big toes, which are
classically associated with Pfeiffer's syndrome.
PMID- 9558575
TI - Correction of posterior sagittal craniosynostosis.
AB - Craniosynostosis involving the posterior sagittal suture results in a
characteristic skull deformity known as bathrocephaly. Surgical correction of
this deformity using the reverse pi procedure has yielded inconsistent results.
We present a new method for expanding the transverse posterior skull while
simultaneously reducing the longitudinal dimension. An absorbable microplate
reinforced bone strut is used as a framework on which the remainder of the skull
is reconfigured; its stability prevents relapse. The posterior skull squeeze is
produced using absorbable mesh plates. Use of rigid fixation is limited to
absorbable hardware in the growing craniofacial skeleton.
PMID- 9558576
TI - Apert's syndrome correlates with low fibroblast growth factor receptor activity
in stenosed cranial sutures.
AB - Recent genetic studies have shown that Apert's syndrome results from mutations of
the fibroblast growth factor (FGF) receptor 2 gene. We were interested in
investigating the expression of FGF receptor 2 at the tissue level in children
with Apert's syndrome. We studied FGF receptor activity in cranial sutures of
children with Apert's syndrome and nonsyndromic, isolated craniosynostosis.
Fourteen children between the ages of 6 months and 12 months were studied. Five
of these children had Apert's syndrome with coronal suture stenosis. Nine
children had an isolated, nonsyndromic coronal stenosis. Stenosed and nonstenosed
cranial sutures were removed at the time of cranioplasty, fixed, decalcified, and
paraffinized. Immunohistochemistry was performed with labeled, specific anti-FGR
receptor 2 antibodies. We found lower levels of FGF receptor 2 staining in both
stenosed and unstenosed sutures of children with Apert's syndrome compared with
those from children with a nonsyndromic suture stenosis. Furthermore, fused
sutures from children with Apert's syndrome demonstrated lower levels of FGF
receptor 2 staining than unfused sutures from the same sample. The findings
suggest that Apert's syndrome correlates with low FGF receptor 2 activity in
cranial sutures. These results are consistent with and similar to our findings in
Crouzon's syndrome, and support genetic studies showing localized mutational
changes occurring at the FGF receptor 2 gene for both Apert's and Crouzon's
syndromes. Furthermore, the findings suggest the possibility that variable
expression of FGF receptor 2 occurs at the tissue level in patients with Apert's
syndrome.
PMID- 9558577
TI - Production of human-inducible nitric oxide synthase in radicular cysts.
AB - To examine if nitric oxide (NO) is produced in radicular cysts, NO synthase (NOS)
production was analyzed. Periapical tissues were removed from patients at the
time of endodontic surgery. Frozen tissue sections were histologically evaluated
with hematoxylin-eosin staining. Production of human-inducible NOS (iNOS) in
apical cysts was then immunohistochemically examined. Immunoreactive human iNOS
was widely distributed in epithelial cells, endothelial cells, fibroblasts,
macrophages, or polymorphonuclear leukocytes. Remarkably, iNOS-positive cells
were significantly present around blood vessels, and cells residing apart from
the blood vessels showed weak or no iNOS production, suggesting that only cells
around blood vessels could be stimulated for iNOS synthesis. These data
demonstrated the possibility that several, but not all, cells could be stimulated
to synthesize iNOS in inflamed tissues. In the presence of iNOS, NO can be
produced spontaneously in periapical lesions and may play a crucial role in the
regulation of chronic infection.
PMID- 9558578
TI - Apical leakage of a new glass ionomer root canal sealer.
AB - A new glass ionomer root canal sealer (Ketac-Endo) has been developed. The
purpose of this study was to compare the apical leakage of Ketac-Endo and AH26
using two different filling techniques and a controlled vacuum procedure. Sixty
four extracted human maxillary anterior teeth were instrumented and divided into
four groups of 15 roots each. The groups were obturated as follows: group 1, a
single cone technique and Ketac-Endo; group 2, a lateral condensation technique
and Ketac-Endo; group 3, a single cone technique and AH26; and group 4, a lateral
condensation technique and AH26. After storage in 100% humidity at 37 degrees C
for 1 wk, the root surfaces were coated with two layers of nail polish and sticky
wax. All specimens were immersed in a vacuum flask containing 2% methylene blue
dye solution. The air was evacuated with a vacuum pump. The roots were sectioned
longitudinally, and the linear extent of dye penetration was measured.
Statistical analysis revealed that there were no significant differences between
any of the groups.
PMID- 9558579
TI - Relative distribution of plasma cells expressing immunoglobulin G subclass mRNA
in human dental periapical lesions using in situ hybridization.
AB - Immunoglobulin G (IgG)-producing plasma cells are the predominant immunoglobulin
secreting plasma cells in human dental periapical lesions, compared with
immunoglobulin A- and immunoglobulin M-producing plasma cells. In this study, the
cells expressing mRNA, that encoded the distinct IgG subclasses, were detected
using an in situ hybridization technique in 25 periapical lesions. These lesions
consisted of 14 periapical granulomas and 11 radicular cysts. Four
oligonucleotide probes were chemically synthesized from IgG subclass-specific
hinge region genes to ensure specificity of the probes. Plasma cells expressing
mRNA, which coded for the IgG subclasses, were detected in formalin
fixed/paraffin wax-embedded sections. Background staining was negligible in all
of the sections tested. The in situ hybridization method used in this study was
both specific and sensitive for the detection of mRNA encoding each of the four
distinct IgG subclasses, whereas the cells retained good morphology. The relative
proportions of plasma cells expressing each of the IgG subclass-specific mRNAs in
both granulomas and cysts were as follows: IgG1 (57.4 and 55.5%); IgG2 (34.1 and
34.6%); IgG3 (4.0 and 4.3%); and IgG4 (4.0 and 5.5%). There were no significant
differences between the percentages of plasma cells expressing each of the IgG
subclass mRNAs between the two types of lesions. IgG1 producing plasma cells
comprised the highest proportion of IgG-producing plasma cells in both types of
periapical lesion. IgG2-producing plasma cells were next in abundance, followed
by plasma cells for either IgG3 or IgG4, which were in roughly equivalent
numbers.
PMID- 9558580
TI - Dense-cored vesicles in human dental macrophage-like pulpal cells.
AB - In the human dental pulp of five healthy premolars, we detected the presence of
vesicles in the cytoplasm of macrophage-like cells. There were, in general, two
types of vesicles, with regard to their size and content. The first was of
smaller size (35 to 55 nm), and they were electron optically empty. The second
type included larger vesicles (100 to 150 nm) presenting a heavily and
homogeneously osmiophilic dense core. Their overall morphology was strikingly
similar to the well-known, dense-cored vesicles of the sympathetic and
neuroendocrine systems. This morphological evidence may be considered as an
adjunctive support for the neural crest derivation of the dental pulp.
PMID- 9558581
TI - Transformation and preliminary characterization of primary human pulp cells.
AB - The odontoblast is the cell responsible for dentin formation and mineralization
during tooth development. A number of primary pulp cell culture systems have been
used to study the mechanism of dentinogenesis in vitro. One of the difficulties
in using primary cells is the limited number of cell divisions they will undergo.
In this study, this problem was addressed by transfecting primary cultures of
human pulp cells with an SV40-adenovirus construct. This resulted in the
establishment of transformed human pulp cells, which were named HPC-T. A series
of preliminary experiments were performed to characterize these cells, including
their morphology, cell proliferation, alkaline phosphatase production, and
cytogenetic make-up. The results demonstrate that SV40-transformed human pulp
cells retain many of the characteristics of the parent primary cells and may be
useful in the study of pulp cell function in vitro.
PMID- 9558582
TI - Bacterial leakage of mineral trioxide aggregate as compared with zinc-free
amalgam, intermediate restorative material, and Super-EBA as a root-end filling
material.
AB - Several dye leakage studies have demonstrated the fact that mineral trioxide
aggregate (MTA) leaks significantly less than other root-end filling materials.
The purpose of this study was to determine the time needed for Serratia
marcescens to penetrate a 3 mm thickness of zinc-free amalgam, Intermediate
Restorative Material (IRM), Super-EBA, and MTA when these materials were used as
root-end filling materials. Fifty-six, single-rooted extracted human teeth were
cleaned and shaped with a series of .04 Taper rotary instruments (Pro-series 29
files). Once the canals were prepared in a crown down approach, the ends were
resected and 48 root-end cavities were ultrasonically prepared to a 3 mm depth.
The teeth were then steam sterilized. Using an aseptic technique, under a laminar
air flow hood, the root-end cavities were filled with amalgam, IRM, Super-EBA,
and MTA. Four root-end cavities were filled with thermoplasticized gutta-percha
without a root canal sealer and served as positive controls. Another four root
end cavities were filled with sticky wax covered with two layers of nail polish
and served as negative controls. The teeth were attached to presterilized
(ethylene oxide gas) plastic caps, and the root ends were placed into 12-ml vials
of phenol red broth. Using a micropipette, a tenth of a milliliter of S.
marcescens was placed into the root canal of each tooth. To test the sterility of
the apparatus set-up, the root canals of two teeth with test root-end filling
materials and one tooth from the positive and negative control groups were filled
with sterile saline. The number of days required for S. marcescens to penetrate
the four root-end filling materials and grow in the phenol red broth was recorded
and analyzed. Most of the samples filled with zinc-free amalgam leaked bacteria
in 10 to 63 days. IRM began leaking 28 to 91 days. Super-EBA began leaking 42 to
101 days. MTA did not begin leaking until day 49. At the end of the study, four
of the MTA samples had not exhibited any leakage. Statistical analysis of the
data indicated Mineral Trioxide Aggregate to be a most effective root-end filling
material against penetration of S. marcescens.
PMID- 9558583
TI - Apical extrusion of debris using two hand and two rotary instrumentation
techniques.
AB - The purpose of this study was to investigate the quantity of apical debris
produced in vitro using two hand and two rotary instrumentation techniques. Sixty
minimally curved, mature human mandibular premolars with single canals were
divided into 4 groups of 15 teeth each and prepared using step-back
instrumentation with K-files, balanced force with Flex-R files, Lightspeed nickel
titanium instruments, or .04 taper ProFile Series 29 rotary nickel-titanium
files. Debris extruded through the apical foramen during instrumentation was
collected on preweighed filters. The mean weight of extruded debris for each
group was statistically analyzed using a Kruskal Wallis one-way analysis of
variance and a Mann-Whitney U rank sum tested. Although all instrumentation
techniques produced apically extruded debris, step-back instrumentation produced
significantly more debris than the other methods (p < 0.0001). There was no
difference between balanced force hand instrumentation and the two rotary nickel
titanium instrumentation methods (p > 0.05). Hand or engine-driven
instrumentation that uses rotation seems to reduce significantly the amount of
debris extruded apically when compared with a push-pull (filing) technique.
Decreased apical extrusion of debris has strong implications for a decreased
incidence of postoperative inflammation and pain.
PMID- 9558584
TI - Perforation repair comparing mineral trioxide aggregate and amalgam using an
anaerobic bacterial leakage model.
AB - The purpose of this study was to evaluate the ability of mineral trioxide
aggregate (MTA) and amalgam to seal furcal perforations in extracted human molars
using an anaerobic bacterial leakage model. Furcal perforations were made in 39
maxillary and mandibular human molars with a high-speed bur. These were randomly
divided into two experimental groups of 18, with the remaining three teeth used
as positive controls. Experimental group 1 was repaired with MTA and group 2 with
amalgam. Three additional teeth without perforations served as negative controls.
A dual chamber anaerobic bacterial leakage model was assembled. Brain heart
infusion broth with yeast extract, hemin, menadione, and the chromogenic
indicator bromcresol purple was used as the culture broth for Fusobacterium
nucleatum. Eight of 18 amalgam samples leaked, whereas none of the 18 MTA samples
leaked. MTA was significantly better than amalgam in preventing leakage of F.
nucleatum past furcal perforation repairs.
PMID- 9558585
TI - A histopathological study of the effects of low-power laser irradiation on wound
healing of exposed dental pulp tissues in dogs, with special reference to lectins
and collagens.
AB - This study investigated the effects of low-power laser irradiation on exposed
pulp tissue in dogs. Gallium-aluminium-arsenide diode laser (300 mW) irradiation
was applied to the exposed surface of the pulp, and histopathological changes
were observed at 1, 3, and 7 wk after the operation. In addition, the lectin
(concanavalin A, Dolichos biflorus agglutinin, peanut agglutinin, Ricinus
communis agglutinin I, soybean agglutinin, Ulex europeus agglutinin I, and wheat
germ agglutinin) binding pattern and distribution of collagens (type I, III, and
V) were examined to determine the histochemical and immunohistochemical nature of
wound healing. The fibrous matrix formation and the continuing changes in the
dentin bridge formation of the irradiation group were observed earlier (1 wk
after the operation) than in the nonirradiation control group. Lectin
histochemistry and collagen immunohistochemistry showed that concanavalin A,
peanut agglutinin, wheat germ agglutinin, and collagens (types I, III, and V)
were distributed in the fibrous matrix and dentin bridge. The expression of these
lectins and collagens occurred earlier in the laser irradiation group than in the
control group. These results suggest that laser irradiation accelerates wound
healing of the pulp and the expression of the lectins and collagens. Furthermore,
D-glucose-, D-mannose-, N-acetyl-D-galactosamine-, and N-acetyl-neuraminic acid
binding sugars and type I, III, and V collagens play an important role in the
healing of pulp wounds.
PMID- 9558586
TI - Histopathological evaluation of the tissue reactions to Endo-Fill root canal
sealant and filling material in rats.
AB - In this in vivo study, the tissue reactions to silicone-based Endo-Fill root
canal filling material were histopathologically evaluated. The reaction of rat
connective tissue to polyethylene tube implants that were filled with Endo-Fill
were evaluated at 2 days, at 1, 2, 4, and 8 weeks. Four tube were implanted in
each rat subcutaneously, and a total of 15 rats were used. Rats were killed, and
the specimens were examined under the light microscope (x115 and x230). At the
end of 8 wk, a thin fibrous wall with an almost completed advanced healing
process was observed around the implant material, but no capsule formation or any
inflammatory infiltration was seen.
PMID- 9558587
TI - Dowel space preparation in root canals filled with glass ionomer cement.
AB - The aim of this study was to evaluate post space preparation difficulties in
canals filled with Ketac Endo and with Grossman's sealer. Sixty-three single
rooted teeth were prepared using a step-back technique and were divided into four
groups: group 1--canals were irrigated with 25% tannic acid and filled with Ketac
Endo and a single-cone technique; group 2--canals were irrigated with 1% sodium
hypochlorite and fillings done as in the previous group; group 3--canals were
irrigated with 25% tannic acid and filled with Ketac Endo and one gutta-percha
cone previously adapted with chloroform; and group 4--canals were irrigated with
1% sodium hypochlorite and filled with Grossman's sealer and a lateral
condensation technique. After 72 h, canals post space were prepared using Peeso
drills. The time required was measured in seconds and analyzed by Tukey multiple
comparison test (level 5%). Post space preparation time for groups 1 to 3 was
longer than for group 4 and longer for group 1 than for groups 2 to 4.
PMID- 9558588
TI - Demonstration of a possible source of error with an electric pulp tester.
AB - The purpose of this study was to determine whether electrical current can travel
between adjacent teeth through contacting interproximal amalgam restorations.
Twenty-two extracted human premolars were restored with class II amalgam
restorations. They were then mounted in pairs in self-curing resin, simulating
adjacent teeth. Only their restorations were allowed to contact. An electrical
multimeter was used to supply electrical current and to measure any current
passing through the mounted teeth. One current measurement was made from the
buccal enamel of a tooth to the occlusal surface of the filling in that tooth. A
second measurement was made from the buccal enamel of the same tooth to the
occlusal surface of the adjacent filling. These two measurements were made for
all 11 trials. Statistically, all current that entered the first tooth passed to
the adjacent tooth. This finding suggests a potential source of error when using
an electric pulp tester.
PMID- 9558589
TI - Topical anesthetic as an adjunct to local anesthesia during pulpectomies.
AB - A technique is described using topical anesthetic to supplement local anesthesia.
It is the author's opinion that it enhances patient comfort during pulpectomies
on teeth with irreversible pulpitis.
PMID- 9558591
TI - Bleaching teeth: report of a survey, 1997.
AB - Vital tooth bleaching is here--it is a viable, predictable concept providing
great patient acceptance and satisfaction. Practitioners are advised to educate
patients routinely about bleaching and to upgrade themselves and their auxiliary
staff to be able to accomplish all aspects of bleaching.
PMID- 9558590
TI - Two-stage pontic retainer fabrication: a case report of a new technique for an
immediate provisional bridge.
PMID- 9558592
TI - Esthetic correction for teeth with fluorosis and fluorosis-like enamel
dysmineralization.
PMID- 9558593
TI - Surgical tooth lengthening: biologic variables and esthetic concerns.
PMID- 9558594
TI - Case report: in-office tooth whitening procedure with 35% carbamide peroxide
evaluated by the Minolta CR-321 Chroma Meter.
PMID- 9558595
TI - Chewing tobacco and cancer: a growing threat.
PMID- 9558596
TI - Chewing tobacco and oral cancer: Part Two.
PMID- 9558597
TI - Spit tobacco: not a safe alternative.
AB - Contrary to popular belief spread by misleading advertisements, spit tobacco is
not a safe alternative to cigarettes. An abundance of evidence indicates that
these products are not only dangerous to health, but often lethal. In Michigan, a
statewide educational campaign is now underway to alert the public to the facts
about spit tobacco. The National Institute of Health recommends that dentists ask
all patients, beginning at age 5, about their tobacco use. The use of nationally
known celebrities seems a critically important ingredient in this anti-tobacco
campaign, in order to offset the glamorous advertisements from the tobacco
industry. Ultimately, however, it is steady, sure, ever-serious reminders by
health professionals of the dangers of spit tobacco that will carry the most
weight. Above all, it is the dentist who has this opportunity and this
responsibility.
PMID- 9558598
TI - The crash of Comair flight 3272.
PMID- 9558599
TI - Lack of communication limits your dental practice.
PMID- 9558600
TI - Washtenaw Community College's Alternative Dental Assistant Education Project.
PMID- 9558601
TI - [Bacteremia: a Spanish multicenter study with 5000 cases. The Hospital Infection
Study Group (GEIH)].
AB - INTRODUCTION: Bacteremia is one of the most common nosocomial infections and is
still a severe condition that frequently represents a life-threatening problem
for the patient. MATERIAL AND METHODS: SEPSIS DATA is a software programme
developed by the SEIMC (Spanish Society of Infectious Diseases and Clinical
Microbiology) nosocomial infection study group, and it has been designed to
collect under common criteria bacteremia cases from Spanish hospitals. In this
study, we analyse the results from the first 5,000 cases prospectively collected
from 34 hospitals with the following distribution by number of beds: 8 hospitals
with less than 200, 15 between 200 and 499.6 between 500 and 999 and 5 with more
than 1,000 beds. RESULTS: Male patients (60%), older than 61 years (52%) are the
predominant group. Bacteremia acquisition was extra-hospital in 58% of the cases.
Most frequent underlying disease was neoplasm (22%) and 9% of the patients had
HIV infection. Most frequent bacteremia sources were urinary tract (19.6%),
primary (16%) and respiratory tract (15%). Most commonly isolated micro-organisms
were E. coli (23%). S. aureus (13%), coagulase-negative Staphylococci (12%) and
S. pneumoniae (8%). Microorganisms average time to grow in laboratory was 1.95
days. Origin focus of bacteremia was reported in 30% of the cases. Antibiotic
therapy used was active against pathogen isolate in 96% of the cases. Adequate
treatment was started empirically from the first day in 76% of the cases. Third
generation cephalosporines were the antibiotic group most used (28%). Among the
observed complications, 7.68% of the episodes occurred with shock and 2.68% with
septic metastasis. Crude mortality until the end of episode was 16.64%.
PMID- 9558602
TI - [Community-acquired bacteremias].
PMID- 9558603
TI - [Hospital-acquired bacteremias].
PMID- 9558604
TI - [Bacteremias of urinary origin in patients with a bladder catheter].
PMID- 9558605
TI - [Community-acquired bacteremias of respiratory origin].
PMID- 9558606
TI - [Hospital-acquired bacteremias of respiratory origin].
PMID- 9558607
TI - [Bacteremias of gastrointestinal origin].
PMID- 9558608
TI - [Catheter-associated bacteremia].
PMID- 9558610
TI - [Bacteremia in bronchopathy patients].
PMID- 9558609
TI - [Primary bacteremia].
PMID- 9558611
TI - [Bacteremia in patients with tumor diseases. The Hospital Infection Study Group
(GEIH)].
PMID- 9558612
TI - [Bacteremia in HIV-infected and IVDA patients].
PMID- 9558613
TI - [Nosocomial bacterial infection. Spanish reality in the '90-s].
PMID- 9558614
TI - [Treatment and course of meningitis caused by penicillin-resistant pneumococcus].
PMID- 9558615
TI - [Nosocomial pneumonia. Etiologic spectrum, diagnostic methods and treatment].
PMID- 9558616
TI - [New concepts of sepsis and septic syndrome. Etiologic correlations].
PMID- 9558617
TI - [Infectious arthritis: current etiologic profile].
PMID- 9558618
TI - [Severe infections of the skin and soft tissues].
PMID- 9558619
TI - [Spontaneous bacterial peritonitis in liver cirrhosis. Physiopathology, treatment
and prevention].
PMID- 9558620
TI - [New bacteria causing infectious diseases].
PMID- 9558621
TI - [Cefotaxime: current status and future prospectives after 15 years of
experience].
PMID- 9558622
TI - Methods in dental public health research and practice: a new feature for the
JPHD.
PMID- 9558623
TI - Establishing maternal and child health data collection priorities for state and
local oral health programs.
AB - OBJECTIVE: This paper identifies specific data items for use by state and local
agencies in a maternal and child oral health needs assessment model. METHODS: A
modified Delphi approach was used to develop consensus on items for inclusion in
the data set and their relative importance. Initially, 31 data items were chosen
from several national sources. All state dental directors, along with other
selected administrators and advisory committee members for this process, were
asked to categorize each of the data items as core (essential), important but
optional, or of lesser importance. Short comments about each data item were
accepted, as were additions to the list of data items. Two rounds of comments
were held. RESULTS: Eleven data items/types of information were selected as core
items to be included in all needs assessments. All but one of these items were
determined by the scores of the respondents. The advisory committee strongly
recommended that at least one core item relate to the public's perception of oral
health. Some differences in perceived importance of several items existed among
the state dental directors, local dental directors, and the advisory committee.
Twenty-one items were identified as being important, but optional, and seven were
considered less than important and not included in the model data set.
CONCLUSIONS: A modified Delphi approach facilitated the development of core and
optional data items for a model oral health needs assessment. This model has
potential for a common reporting mechanism so that states and local dental
programs can share data.
PMID- 9558624
TI - Validity of two methods for assessing oral health status of populations.
AB - OBJECTIVE: This investigation assessed two methods for estimating epidemiologic
indicators of oral health status among children: (1) a visual-only screening,
performed independently by a dental hygienist and a registered nurse; and (2) a
parent- or guardian-completed questionnaire. The indicators included dichotomous
variables measuring dental caries and treatment needs, presence of sealants,
injuries to the anterior teeth, and dental fluorosis. METHODS: Following training
and calibration, data were collected over an eight-day period in April 1994 among
632 elementary schoolchildren (aged 5 to 12 years) in Monticello, Georgia. Both
screening and questionnaire findings were compared pairwise with results from
visual-tactile examinations done by a dentist. Validity, represented by
sensitivity, specificity, and predictive values, was assessed for screening
results from the dental hygienist, the nurse, and the parent-completed
questionnaire. RESULTS: Validity was high for screening for caries and treatment
needs (> 90% for sensitivity, specificity, and predictive values in a sample
having 30% to 40% prevalence). Less valid data--mainly an effect of false
negatives--were obtained for fluorosis, injuries, and presence of sealants. No
significant difference in validity was observed between the nurse and the dental
hygienist. One-third of respondents to the questionnaire did not know if their
children needed fillings (a proxy for untreated decay) or had received sealants;
only knowledge of restorations was comparable to results from screening.
Intraexaminer reliability for the two screeners ranged from 85 to 100 for percent
agreement and 0.70 to 0.93 for kappa scores. CONCLUSIONS: Screening by dental
hygienists or nurses can provide valid data for surveillance of dental caries and
treatment needs. Training for visual assessment of fluorosis and injuries must be
improved to diminish the proportion of false negatives. A parent-completed
questionnaire is less effective than visual screening for evaluating oral health
status in children.
PMID- 9558625
TI - Measuring beliefs about orthodontic treatment: a questionnaire approach.
AB - OBJECTIVES: Few studies have examined what parents and orthodontists expect from
and value about orthodontic treatment. In this study, we designed and tested a
questionnaire to outline what drives consumer demand for children's orthodontic
care. Further, we present data from the questionnaire to illustrate how
expectations and values pertaining to orthodontic treatment relate to
sociodemographic variables. METHODS: Subjects were 220 Pennsylvania orthodontists
and 220 parents at a university orthodontic clinic who were administered a
questionnaire designed to assess what parents and orthodontists value about and
expect from orthodontic treatment. Items for the questionnaire were developed via
a qualitative, telephone interview process. Data were analyzed using factor
analysis and reliability analysis for scale development, and analysis of variance
for preliminary validity assessment. RESULTS: Through factor analysis, the
questionnaire was reduced from 84 to 52 items, and eight scales were examined:
expected treatment benefits, expected treatment risks (short- and long-term),
expected treatment inconveniences, value of treatment benefits, value of risks
(short- and long-term), and value of treatment inconveniences. For parents, the
reliability for all scales was in the acceptable range. For orthodontists, only
the "short-term risks" scale failed to attain an acceptable reliability.
Preliminary validity was assessed through examining relationships between
demographic variables and subscale scores. For parents, income, father's
education level, and sex of respondent were related to treatment expectations and
values. For orthodontists, age, sex, and patient volume were related to treatment
values. CONCLUSIONS: The questionnaire developed in the present study was found
to be practical and reliable for use with providers and consumers of orthodontic
care and can be used to explore factors affecting the demand for orthodontic
care. Implications of possible unrealistic treatment expectations on the part of
orthodontists and parents also are discussed.
PMID- 9558626
TI - Comparing the impact of oral disease in two populations of older adults:
application of the geriatric oral health assessment index.
AB - OBJECTIVES: This study compares the distributional and psychometric properties of
the Geriatric Oral Health Assessment Index (GOHAI) in two samples of older
adults, and examines how the self-perceived impact of oral disease, as measured
by the GOHAI, varies in accordance with sample sociodemographic and health
characteristics. METHODS: Results are based on survey data from two samples of
older men: a Medicare sample of patients using community physicians (n = 799;
mean age = 74) and users of VA ambulatory health care (n = 542; mean age = 72).
RESULTS: The findings indicate significant differences between samples in mean
GOHAI scores, with the VA sample exhibiting worse scores. A number of
similarities in psychometric properties of the instrument across the two samples
were found: high internal consistency reliability and similar inter-item and item
scale correlations. Factors analyses revealed somewhat different structures
between the two samples, but explained similar amounts of variance; regression
analyses indicated that income and self-rated oral health were significant
predictors of GOHAI scores in both samples. CONCLUSIONS: The GOHAI exhibits
satisfactory psychometric properties in both samples of older men. Results
suggest continued use of the GOHAI as an indicator of the impact of oral
conditions on functioning and well-being in a variety of samples.
PMID- 9558628
TI - Restorative certainty and varying perceptions of dental caries depth among
dentists.
AB - OBJECTIVE: The question of whether dentists who most frequently identify tooth
surfaces for definite restoration perceive dental caries as significantly deeper
than other dentists is assessed. METHODS: One group of 20 dentists independently
examined 145 unrestored approximal tooth surfaces on 16 bitewing radiographs and
recorded their restorative and depth decisions. Another group of 15 dentists
similarly scored 304 unrestored surfaces on 30 bitewing radiographs. Each group
of dentists was later divided into four subgroups according to the number of
surfaces designated for definite restoration by each dentist. RESULTS: As the
number of tooth surfaces designated for definite restoration increased, mean
caries depth (P < .05 for the high vs low subgroups) and the percent of
dentinally carious surfaces increased, while the percent of surfaces assessed as
sound decreased. Dentists with the lower numbers of surfaces designated for
definite restoration came closest to the true histologic mean caries depth of the
examined tooth surfaces. CONCLUSIONS: Dentists who designated high numbers of
approximal tooth surfaces for definite restoration assessed caries as deeper than
other dentists, and deeper than was proven histologically.
PMID- 9558627
TI - Evaluation and use of an index of oral health status.
AB - OBJECTIVES: The goals of this investigation were (1) to evaluate the Oral Health
Status Index in relation to demographic characteristics, socioeconomic status,
and preventive behaviors of an adult population; and (2) to understand how
individual index components performed as indicators of oral health status
compared to the composite index. METHODS: The Oral Health Status Index (OHSI) was
used on a probability sample of adults, aged 18-93 years, living in the Detroit
tricounty area. Data were collected on 509 subjects via in-home dental
examinations. Bivariate and multivariate analyses were used to compare the OHSI
and its components, including decayed, missing, and replaced teeth, free ends,
and moderate and severe periodontal disease measures. RESULTS: The mean OHSI
score for subjects was 77.3 (SE = 1.83) with a range of -8.0 to 100.0. In
regression analyses, OHSI scores were positively correlated with subjects'
education level, self-rated oral health scores, and frequency of dental checkups
and negatively correlated with age, nonwhite race, and smoking. Of the index
components, missing teeth performed well as an indicator of oral health status.
Missing teeth were positively correlated with age, nonwhite race, and smoking and
negatively correlated with education level, self-rated oral health, and use of
Medicaid. About 53 percent of variance in OHSI scores was explained by the
multivariate models, compared to 46 percent for missing teeth. CONCLUSIONS:
Choosing an indicator of oral health status likely will depend upon the
characteristics of the population to be studied. As a composite measure of oral
health status, the OHSI performed acceptably; however, missing teeth, an index
component, also worked well. Continued evaluation of the OHSI is warranted.
PMID- 9558629
TI - [Is otoacoustic emission useful in the differential diagnosis of occupational
noise-induced hearing loss?].
AB - It is very difficult to distinguish between occupational noise-induced hearing
loss and other diseases with cochlear hearing loss by the means of conventional
audiometric tests. Otoacoustic emission measurement is a relatively new tool for
assessing the inner ear function. It gives an opportunity of monitoring the
status of the outer hair cells, the elements which are the most sensitive to
noise-induced damage. In this study the results of distortion product otoacoustic
emission (DPOAE) measurement in subjects with industrial noise-induced hearing
loss, presbycusis and hearing impairment caused by gentamycin, are presented. In
all these cases pure-tone audiometry revealed similar shape of the audiograms
with cochlear hearing loss mainly at high frequencies. In the cases of industrial
noise-induced hearing loss, DPOAE measurements demonstrated a very typical shape
of DP-gram with the decrease (notch) in otoacoustic primarily at the frequencies
of 3-4 kHz. Such a notch in DP-grams was not observed in the cochlear hearing
loss caused by factors other than noise. The data indicate that otoacoustic
emissions may be useful in the differential diagnosis of occupational noise
induced hearing loss.
PMID- 9558630
TI - [Evaluation of dynamic changes in hearing impairment in subjects exposed to noise
while testing for transient evoked otoacoustic emission].
AB - A group of 74 miners, aged 19-35 years, exposed to industrial noise at average
level of 82-88 dBA for 1.5 to 15 years were examined by means of otoacoustic
emission (TEOAE). The group was divided into three subgroups, depending on the
duration of noise exposure. The results obtained in miners were compared to the
results of the control group nonexposed to noise at the workplace. Otoacoustic
emission was weaker in subjects exposed to noise. Significant differences in
responses were found in subgroups II and III as compared to controls. The results
were compared to the data reported by other authors. The role of otoacoustic
emission in providing information about dynamics changes in hearing impairment,
depending on the duration of noise exposure, in subjects exposed to industrial
noise, was emphasised.
PMID- 9558631
TI - [Analysis of accidents in selected occupations in the Szczecin shipyard S.A. in
the years 1989-93].
AB - In a five-year follow-up study (1989-93), 1317 work-related accidents and their
relation to occupational exposure among male workers employed at the Szczecin
Shipyard were analysed. The highest rates of accidents were found among welders,
fitters, electrical mechanics and platers. The role of the age, duration of
employment, type of the job performed and its contribution to the rate and
pattern of accidents, were also investigated.
PMID- 9558632
TI - [Evaluation of patient exposure to radiation during x-ray diagnostic examinations
(in selected health service centers in the city of Wroclaw and in the province of
Wroclaw)].
AB - In 35 x-ray laboratories, randomly selected, in the city of Wroclaw an in the
voivodship, the following measurements were performed: -exposure doses (mGy) for
different kinds of x-ray examinations, -exposure doses (mGy) for examinations
employing conventional intensifying cassettes and cassettes equipped with
intensifying screens of rare earths, -basic exposure parameters, ie high voltage
(kV), anodic current intensity (mA), and exposure duration. An average number of
exposure per one examination was also defined. The values of standard deviation
(SD) for doses measured and for exposure parameters were identified. The doses
were compared with the values recommended in "Basic Safety Standards for
Protection Against Ionizing Radiation" (IAEA, Safety Series No 115). Two
differences were discussed between the values measured and those recommended,
particularly in exposures when conventional cassettes were used. The assessment
of exposure parameters for the same x-ray examinations performed in different
laboratories pointed to a lack of any analogy between the results. It bears
witness to the fact that x-ray equipment is very much diversified, and that
subjective factors play a significant role.
PMID- 9558634
TI - [Evaluation of the carcinogenic effect of ceramic fibers in experiments on rats
and mice].
AB - The carcinogenic effect of Kaowoll raw and thermally used ceramic fibres was
assessed in experiments on rats and mice. The fibers were applied
intraperitoneally in doses by 25 and 5 mg, and the animals were observed over
their life-span. It was found that Kaowoll fibers were carcinogenic and that high
temperature did not change these properties.
PMID- 9558633
TI - [A quantitative assessment of health risk induced by occupational exposure to
inorganic arsenic].
AB - The risk of neoplastic disease, primarily lung cancer, induced by occupational,
inhalation exposure to nonorganic arsenic was assessed. In order to identify
individual risk in the linear dose-response relationship which would serve as a
basis for the risk assessment among persons exposed occupationally, the author
also analysed the latest epidemiological studies performed in Sweden, as well as
repeated analyses of American studies. This allowed to diminish individual risk
by several times. It is thought that a diminished value of individual risk is, in
the light of the most up-to-date epidemiological studies, closer to the reality
than the value proposed by the Environmental Protection Agency (EPA). Having the
value of individual risk related to occupational exposure, equal 1.79 x 10(-4),
lung cancer risk after forty years of employment under the exposure level within
the range of currently binding MAC values for arsenic (0.05 mg/m3) accounts for
8.95 x 10(-3), thus slightly exceeding the adopted value of 1 x 10(3). Whereas a
new value, proposed by the Expert Group for Chemical Factors of the International
Commission for Updating the list of MAC and MAI values in 1996, equals 0.01, so
the risk for a forty-year employment accounts for 1.79 x 10(-3), in fact the
value corresponding to that already approved. In addition, the assessment
indicated that smoking increases by 4-6 times the risk of lung cancer induced by
exposure to arsenic.
PMID- 9558635
TI - [The effect of stress in the workplace on the risk of ischemic heart diseases-
the role of epidemiologic studies].
AB - Among numerous areas of occupational medicine, the studies of the impact of
psychosocial factors on the development of cardiovascular diseases have been
progressing most rapidly. The role of epidemiological studies in analysing the
effect of this group of stressors on the incidence of ischaemic heart disease is
discussed. The most significant outcome of the studies regarding selected
psychological reactions referred to Karasek and Theorell's model of psychic
burden/control, the role of life events, A type behavior and other selected
personality changes. The authors stress that issues such as so called 'selection
phenomenon', adequate size of the populations investigated, accurate selection of
measurement methods, control of confounding factors and the cause-effect
inference based on cross-sectional studies, are the major limitations in
epidemiological studies of the effect of occupational stress on the state of
health. Further progress in this area depends on how far these limitations could
be overcome.
PMID- 9558636
TI - [Allergic conditions for diseases of the respiratory tract from occupational
exposure to acid anhydrides].
AB - Acid anhydrides are highly reactive, low molecular weight compounds that are used
widely in industry. Work-related exposure to this group of substances may cause
occupational asthma. Because of low molecular weight, these compounds are not
able to induce antibody responses without conjugating with human proteins. Acid
anhydrides may act as haptens when conjugated with human serum albumin (HSA). The
induction mechanism of immediate and late bronchial hyperresponsiveness to acid
anhydrides appears to be at least partly mediated by IgE antibodies. Other
clinical syndromes, which may be caused by acid anhydrides such as pulmonary
disease-anemia (PDA), and late respiratory systemic syndrome (LRSS) associated
with TMA exposure, appear to be associated with IgG antibodies to TMA as well as
with IgE. Significant cross-reaction occurs between different compounds of this
group, particularly regarding IgE antibodies. As inhalational exposure to acid
anhydrides may result in serious pulmonary disease, adequate protection of
potentially exposed workers or their removal, if affected, from exposure is
essential.
PMID- 9558637
TI - [Some issues regarding the use of electroencephalography and brain evoked
potentials in occupational medicine].
AB - On the basis of the literature data, the practical value of
electroencephalography (EEG) and tests of brain evoked potentials, particularly
visual evoked potentials (VEP) and somatosensory evoked potentials (SSEP) in the
diagnosis of occupational diseases of the nervous system is discussed.
Electroencephalographic changes and the results of the evoked potential tests
performed in persons exposed to organic solvents and heavy metals are analysed.
The author postulates how the research in this field should be oriented and
stresses the need to incorporate the method of evoked potentials into diagnostic
procedures, especially in the case early symptoms of the nervous system
dysfunction induced by occupational factors.
PMID- 9558638
TI - [Actual and perspective activities of the European Union concerning protection
against noise].
AB - In most industrialised countries exposure to noise is one of major health
problems which, because of its social and economic dimension has been given
priority in the area of preventive activities. It is estimated that only in
Europe about 25-30 million people are employed in conditions under exposure to
noise at excessive levels, harmful to the hearing organ, generating the risk of
hearing loss (disability), and in consequence limiting the possibility of active
life. Acknowledging the significance of the problem and its consequences the
World Health Organization (WHO) in cooperation with the International (ISA) and
European Federation of Audiological Society (EFAS) has developed the programme
for the protection against noise. The prime aims of the programme are to
establish the cooperation between scientists, health services and technicians in
order to promote knowledge and exchange of experience, to improve workers'
health, and to identify the biological, neuropsychological and psycho-social
effect of noise exposure on the hearing ability. The authors discuss basic
objectives and adopted strategies of experimental and clinical studies carried
out in countries of the European Union, participating in the implementation of
the programme. The WHO guidelines for the reduction in noise exposure in the
working, municipal and recreation environments are also presented.
PMID- 9558639
TI - [Individual autonomy and the principles of occupational health care].
AB - The effect of work-related diseases on the health condition of the population at
large has increased the interest in etiology and epidemiology of these diseases
and intensified activities aimed at providing effective treatment of occupational
diseases, but first of all at preventing their occurrence. That is why workers
are now recognised as the largest population group subjected to active
counselling. In order to meet the recommendations of the International Labour
Organization, Polish labour law has been modified so that every worker is
guaranteed an opportunity to benefit from medical prevention within the range
required by his/her working conditions. This concern for workers' health
contributed to the fact that health has now become a supreme value to which all
other values and human needs are submitted. The author discusses the issues of
compulsory prophylactic examinations and protection against employment at a
workplace that is inadmissible because of health reasons, in the perspective of
the human right to keep his/her own ailments in secret and the right to freedom
of choice concerning his/her own health and living and conditions.
PMID- 9558640
TI - [Costs and benefits of medical prevention in small enterprises].
AB - The current transformation of Polish economy towards free market compels a
rational management of resources and more effective instruments for the cost
benefit control in small enterprises. One of the most important areas of
activities in small enterprises is the promotion of medical prevention at the
workplace. Employers are committed to ensure that all workers have access and
benefit from medical prevention, as well as to bear all costs involved in
prevention programmes, periodical prophylactic examinations, and actions aimed at
promoting workers' health and improving working conditions. Planning these
improvements, health certificates and recommendations resulting from the
evaluation of working conditions should be taken into consideration. New legal
regulations create the ground for employers to choose the most effective and
appropriate measures for providing preventive care. The aim of the study was to
elaborate and implement the cost-benefit analysis of medical prevention
activities in enterprises, thought as one of decision-making tools to be used by
employers. The principles of the cost-benefit analysis in enterprises algorithm
of proceedings and the instructions how the analysis should be implemented, were
elaborated. In addition, a supportive computer system was developed. The cost
benefit analysis was already implemented as a pilot project in several
enterprises what helped to modify the method and collect numerical data necessary
to perform the analysis and to define the scope of its application.
PMID- 9558641
TI - Speed-dependent motion-sensitive responses in V5: an fMRI study.
AB - This fMRI study examined motion-sensitive responses in human area V5 as a
function of stimulus speed. Consistent with electrophysiological findings, we
observed optimal responses at intermediate speeds of around 7 degrees/s to 30
degrees/s. The results are consistent with a nonlinear (inverted "U") dependency
on speed that was also observed in V3a. V1 activation was observed to decrease
linearly as speed increased. This is consistent with the fact that speed
sensitive cells in V1 have been shown to be tuned to much slower speeds than in
V5.
PMID- 9558642
TI - Mapping voxel-based statistical power on parametric images.
AB - Using a classic technique based on the noncentral F-distribution method for
computing statistical power, we developed a general approach to the estimation of
voxel-based power in functional brain image data analysis. We applied this method
to PET data from a large sample (N = 40) of subjects performing the Wisconsin
Card Sorting (WCST) paradigm analyzed with SPM95, produced statistical power maps
for a range of samples sizes and smoothing filter widths, and examined the
effects of sample size and image smoothing on the expected reliability of
activation findings. At an uncorrected alpha of 0.01, a fixed filter size of 10
mm3, and a range of power thresholds, maps revealed that the power to reject the
null hypothesis in brain regions implicated in the task at Ns of 5 and 10 may not
be sufficient to ensure reliable replication of significant findings and so
should be interpreted with caution. At sample sizes approaching 20 subjects,
sufficient power was found in the right dorsolateral prefrontal cortex (BA 46/9),
right and left inferior parietal lobule (BA 40), and left inferior temporal lobe
(BA 37), comprising the cortical network typically observed during the WCST.
Filter size needed to maximize power varied widely, but systematically, across
the brain, tending to follow known neuroanatomical landmarks. Statistical power
considerations in brain imaging studies are critical for controlling the rate of
false negatives and assuring reliable detection of cognitive activation. The
variation of filter size for maximizing power across the brain suggests that the
underlying neuroanatomy of functional units is an important consideration in the
a priori selection of filter size.
PMID- 9558643
TI - Nonlinear aspects of the BOLD response in functional MRI.
AB - Functional magnetic resonance imaging (fMRI) using blood oxygenation level
dependent (BOLD) contrast has progressed rapidly and is commonly used to study
function in many regions of the human brain. This paper introduces a method for
characterizing the linear and nonlinear properties of the hemodynamic response.
Such characterization is essential for accurate prediction of time-course
behavior. Linearity of the BOLD response was examined in the primary visual
cortex for manipulations of the stimulus amplitude and duration. Stimuli of 1, 2,
4, and 8 s duration (80% contrast) and 10, 20, 40, and 80% contrast (4 s
duration) were used to test the hemodynamic response. Superposition of the
obtained responses was performed to determine if the BOLD response is nonlinear.
The nonlinear characteristics of the BOLD response were assessed using a
Laplacian linear system model cascaded with a broadening function. Discrepancies
between the model and the observed response provide an indirect measure of the
nonlinearity of the response. The Laplacian linear system remained constant
within subjects so the broadening function can be used to absorb nonlinearities
in the response. The results show that visual stimulation under 4 s in duration
and less than 40% contrast yield strong nonlinear responses.
PMID- 9558644
TI - Functional connectivity in single and multislice echoplanar imaging using resting
state fluctuations.
AB - A previous report of correlations in low-frequency resting-state fluctuations
between right and left hemisphere motor cortices in rapidly sampled single-slice
echoplanar data is confirmed using a whole-body echoplanar MRI scanner at 1.5 T.
These correlations are extended to lower sampling rate multislice echoplanar
acquisitions and other right/left hemisphere-symmetric functional cortices. The
specificity of the correlations in the lower sampling-rate acquisitions is lower
due to cardiac and respiratory-cycle effects which are aliased into the pass-band
of the low-pass filter. Data are combined for three normal right-handed male
subjects. Correlations to left hemisphere motor cortex, visual cortex, and
amygdala are measured in long resting-state scans.
PMID- 9558645
TI - Functional clustering: identifying strongly interactive brain regions in
neuroimaging data.
AB - Brain imaging data are generally used to determine which brain regions are most
active in an experimental paradigm or in a group of subjects. Theoretical
considerations suggest that it would also be of interest to know which set of
brain regions are most interactive in a given task or group of subjects. A subset
of regions that are much more strongly interactive among themselves than with the
rest of the brain is called here a functional cluster. Functional clustering can
be assessed by calculating for each subset of brain regions a measure, the
cluster index, obtained by dividing the statistical dependence within the subset
by that between the subset and rest of the brain. A cluster index value near 1
indicates a homogeneous system, while a high cluster index indicates that a
subset of brain regions forms a distinct functional cluster. Within a functional
cluster, individual brain regions are ranked at the center or at the periphery
according to their statistical dependence with the rest of that cluster. The
applicability of this approach has been tested on PET data obtained from normal
and schizophrenic subjects performing a set of cognitive tasks. Analysis of the
data reveals evidence of functional clustering. A comparative evaluation of which
regions are more peripheral or more central suggests distinct differences between
the two groups of subjects. We consider the applicability of this analysis to
data obtained with imaging modalities offering higher temporal resolution than
PET.
PMID- 9558646
TI - [Mechanism of cellular cholesterol removal: a communication system between
extracellular cholesterol transport and intracellular cholesterol homeostasis].
AB - Cholesterol efflux is one of the essential events in cellular cholesterol
homeostasis since peripheral cells do not catabolize the cholesterol molecule.
There are two distinct mechanisms for the efflux. One is the non-specific
classical pathway mediated by physicochemical diffusion of cholesterol through
the aqueous phase and its esterification on high density lipoprotein (HDL) by
lecithin: cholesterol acyltransferase (LCAT). The other is the specific and
biological pathway in which new HDL particles are generated from cellular lipid
by the direct interaction of cell membrane and amphiphilic apolipoproteins that
have dissociated from HDL. The latter reaction consists of binding of
apolipoprotein to the specific binding site of the cellular surface and
subsequent mobilization of intracellular cholesterol for the HDL generation
mediated by intracellular signal transduction. This reaction seems to be a major
source of plasma HDL.
PMID- 9558647
TI - [Role of nitric oxide in learning and memory processes].
AB - Nitric oxide (NO) is a free radical gas that is synthesized from L-arginine by NO
synthase (NOS). Activation of NMDA, non-NMDA or metabotropic glutamate receptors
causes NO formation through NOS activation. From data obtained in experiments
performed by microdialysis together with nitrate assay, we have proposed that NO
production in the cerebellum following non-NMDA and metabotropic glutamate
receptor activation may be independent of NOS activity, while NMDA receptor
mediated NO production depends on its activity. Glial cells appear to play a role
in modulating NO production by regulating L-arginine availability. Activation of
NMDA receptors and the increase in intracellular calcium concentration is a
trigger for the long-term potentiation (LTP). NO acts as a retrograde messenger
in the hippocampal LTP to enhance glutamate release from presynaptic nerve
terminal, in which cyclic GMP may be involved. Behavioral studies demonstrate
that NO is involved in some forms of learning and memory. Our studies suggest
that NMDA/NO/cyclic GMP signaling plays a role in spatial working memory.
Further, it is suggested that NO production in the brain is altered by aging.
These results support the hypothesis that NO plays a role in mechanism of
synaptic plasticity.
PMID- 9558648
TI - [Techniques for evaluating neuronal death of the retina in vitro and in vivo].
AB - This review describes the techniques to evaluate retinal neurodegeneration
induced by excitatory amino acids and transient ischemia. Glutamate-induced
neurotoxicity was examined in cultured rat cortical cells. Cultures obtained from
the retinas of fetal rats were incubated in Eagle's minimal essential medium
supplemented with 10% fetal calf serum or 10% horse serum at 37 degrees C in a
humidified 5% CO2 atmosphere for 10-14 days. The neurotoxicity induced by
glutamate was quantified by trypan blue exclusion. The viability of cultures was
markedly reduced by a 10-min exposure to glutamate followed by incubation with
glutamate-free medium for 1 hr. N-methyl-D-aspartate (NMDA)-induced retinal
damage was examined in adult rats. Transverse sections of the retinas through the
optic disk were stained with hematoxylin and eosin. A single intravitreal
injection of NMDA damaged the ganglion cell layer and the inner plexiform layer
without affecting the other retinal layers 7 days after injection. Retinal
ischemia was induced by elevating the intraocular pressure for 45 min through the
needle which was placed in the anterior chamber. Ischemia-induced retinal damage
was inhibited by MK-801. These results indicate that the techniques described in
this review can be employed to develop new drugs possessing neuroprotective
action against neurodegeneration that occurs during retinal ischemia.
PMID- 9558649
TI - [Effects of KB-R7943, a novel Na+/Ca2+ exchange inhibitor, on myocardial
ischemia/reperfusion injury].
AB - The effects of KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea
methanesulfonate) on major ion transporters were studied in canine cardiac
sarcolemmal and sarcoplasmic reticular vesicles. KB-R7943 inhibited the Na+/Ca2+
exchange more potently than the Na+/H+ exchange, the Na+/K(+)-ATPase and the
Ca2(+)-ATPase. The effects of KB-R7943 on ischemia/reperfusion-induced injury
were studied in isolated rat perfused hearts in comparison with those of
diltiazem and lidocaine. In normal hearts, diltiazem (10 microM) and lidocaine
(100 microM) markedly reduced contractile function, but KB-R7943 (1, 10 microM)
had no such effect. In the hearts subjected to 25-min ischemia and 30-min
reperfusion, KB-R7943 concentration-dependently and significantly improved post
ischemic recovery of left ventricular developed pressure, left ventricular
dP/dtmax and left ventricular end-diastolic pressure by pre-ischemic treatment (5
min) or post-ischemic treatment (10 min). Diltiazem and lidocaine showed similar
improvement of recovery by pre-ischemic treatment, but they had no effect by post
ischemic treatment. Furthermore, the effect of KB-R7943 on arrhythmia was studied
in anesthetized rats subjected to 5-min cardiac ischmeia and 10-min reperfusion.
KB-R7943 (1, 10 mg/kg, i.v.) dose-dependently reduced the incidence and the
duration of ventricular fibrillation. These results indicate that KB-R7943, a
selective Na+/Ca2+ exchange inhibitor, has beneficial effects against myocardial
ischemia/reperfusion injury and suggest that activation of the Na+/Ca2+ exchange
mainly occurs immediately after reperfusion in the pathophysiological process of
myocardial ischemia/reperfusion injury.
PMID- 9558650
TI - [Effect of liver hydrolysate on ethanol- and acetaldehyde-induced deficiencies].
AB - Since it has been reported that amino acids have alleviating effects on ethanol-
and acetaldehyde-induced toxicity, we investigated the effect of liver
hydrolysate derived from bovine liver on ethanol- or acetaldehyde-induced
toxicity and deficiency models of mice and rats in the present study. Liver
hydrolysate improved the deficiencies of beam walking and food intake of mice in
a dose-dependent fashion when challenged with ethanol at the dose of 5 ml/kg,
p.o. According to the analysis using selective inhibitors for alcohol
dehydrogenase and acetaldehyde dehydrogenase, it has been suggested that this
improvement effect of liver hydrolysate is mainly due to the reduction of
acetaldehyde toxicity. No effect of liver hydrolysate was found in coma and death
produced by orally treated ethanol at 10 ml/kg. In contrast, liver hydrolysate
dose-dependently decreased the coma and death of mice administered acetaldehyde
at 1.8 ml/kg, p.o. Furthermore, an increase in serum GPT activity, which was
caused by twice oral administration of acetaldehyde at 1.2 ml/kg at interval of 1
hr, was inhibited by liver hydrolysate. These results suggest that liver
hydrolysate has a protective effect against ethanol- and acetaldehyde-induced
toxicity.
PMID- 9558651
TI - [Neurosurgery and molecular biology: (series 1) basic knowledge for understanding
molecular biology of the cell].
PMID- 9558652
TI - [Carotid endarterectomy: recent controversies].
PMID- 9558653
TI - [Usefulness of multiple burr-hole operation for child Moyamoya disease].
AB - Excellent results of multiple burr-hole operation (MBHO) for child moyamoya
disease are reported in this study. Three patients of moyamoya disease had MBHO.
After MBHO, transient, ischemic attacks disappeared in a patient despite
progressing stenosis of the major cerebral arteries, and remarkable neurological
improvement was recognized in a patient who had encephaloduroarteriosynangiosis.
Another patient slowly improved and became able to go to junior high school. N
isopropyl-p-[123I] iodoamphetamine (IMPSPECT) findings also improved in all
patients. There was no mortality or morbidity, and no new neurological deficits
or bleedings developed during the follow up period. The authors recommend the
MBHO as the surgical treatment of choice for not only adult but also child
moyamoya disease because of its safety and effectiveness, and also report the
usefulness of MBHO for the patients who have already received other bypass
operations.
PMID- 9558654
TI - [Subarachnoid hemorrhage in 'Vital Statistics of Japan', 1993-1995: variability
with age and sex].
AB - The incidence and death rate of subarachnoid hemorrhage (SAH) varies with age and
sex. Female preponderance in the incidence of SAH is a well-known fact. However,
the degree varies with age. Autopsy data, records of natural history of
unruptured aneurysms, epidemiological and clinical cooperative studies have
provided a great amount of information regarding the statistics of subarachnoid
hemorrhage. But, each individual study has its own limitation, such as a bias in
case selection in autopsy or clinical studies, predominance of aged population in
the epidemiological cohort studies, limited frequency in the detection of
unruptured aneurysms in the entire population. These shortcomings are reflected
in the variability in the statistical data of these studies. Death records in
'Vital Statistics of Japan', published annually by Ministry of Health and Welfare
of Japan, exhibit the numbers of deaths by cause (according to ICD-9 or 10 code),
sex and age. In this study, we calculated the death rates of SAH (per 100,000) in
1993-1995 for each age group of both sexes based on the published data. Deaths
from breast cancers and automobile accidents (AMA) were assessed in the same
manner and compared with the results of SAH. The annual death rate of SAH for all
people in Japan is 10.7 per 100,000 population and the average age of death is
65.6 y.o. The death rate is 8.2 for men, and 13.1 for women. Average age at the
death is 60.2 y.o. in men, and 68.8 y.o. in women (p < 0.001). The age-adjusted
death rate to 1985 Japanese population was 7.3 for men and 9.2 for women. Below
age 60, rate of death caused by SAH is higher for men than women, but the ratio
reverses in the population over 60. For men, the death rates after the age of 40,
50, 60 and 70 were 16.4, 20.4, 24.1 and 29.2 respectively. For women, the rates
were 25.0, 32.8, 44.1 and 62.4. The female-to-male ratio of the death rates
increases with age. Female sex should be considered as a risk factor for death
from SAH. Number of deaths from breast cancers was about 90% of those from SAH in
women. There was a difference in the age distribution; deaths caused by breast
cancer tend to occur in younger age than those caused by SAHs. Mean age of death
was 59.3 for breast cancer and 68.8 for SAH. Deaths caused by SAH is 1.4 times
more likely to occur than those by breast cancer for a 50 year-old woman for the
rest of her life, 1.9 times for a 60 y.o. woman, and 2.7 times for a 70 y.o.
woman. Regular examination to detect breast cancer is widely performed in Japan
among elderly women. We believe that a similar screening effort should be
targeted for unruptured aneurysms from the standpoint of the medico-social cost.
Automobile accidents (AMA) victimize as many people as SAH in Japan, about 13,000
per year. For males over the age of forty, AMA victims are more than those from
SAH. However, conversely females' deaths from SAH occur three times frequently as
those from AMAs. The fact should be taken into consideration when screening for
unruptured aneurysms.
PMID- 9558655
TI - [Treatment of tuberculous meningitis: marker of cure].
AB - A 49-year-old male with tuberculous meningitis was reported. When admitted to our
hospital with mild right hemiparesis, he was alert but he developed
disorientation 7 days later. A diagnosis of tuberculous meningitis was reached
because of elevated levels of adenosine-deaminase at 19.6U/liter in the
cerebrospinal fluid. MRI showed a marked enhancement in the basal cisterns and an
enhanced intraparenchymal lesion in the brainstem. Chronological changes of MRI
findings did not closely correlate with the clinical course. Slight meningeal
enhancement on MRI seems to remain for a long time without active tuberculous
meningitis, and absence of the meningeal enhancement on MRI is not necessarily
appropriate as a marker of cure of tuberculous meningitis.
PMID- 9558656
TI - [A case of hemangiopericytoma with multiple extracranial metastasis: a case
report].
AB - A case of a patient with hemangiopericytoma with multiple extracranial
metastasis, who has survived for more than twenty years is reported. A fifty-five
year-old male presented brain tumor twenty years ago. He underwent total removal
of the tumors, but recurrences occurred each time. Liver metastasis was found
seven years ago. After that multiple metastases extended to the lung, vertebra
and pancreas and operations and irradiations were performed. At present, there is
no progression of the tumors and he enjoyed a high quality of life. We concluded
that, to ensure long time survival, a patient with hemangiopericytoma must be
monitored carefully for local recurrence and systemic metastases.
PMID- 9558657
TI - [Intratumoral hemorrhage associated with cystic meningioma under observation: a
case report].
AB - Cystic meningiomas are not commonly encountered and are said to account for only
1 to 2% of all types of meningioma. There have been several reports on them and
most of them were discussed under the aspect of the mechanism of cystic
formation. Though few reports present the process of cystic formation, here we
were able to present the process of cystic formation with intratumoral
hemorrhage. The case was a 56-year-old man who presented with urinary
incontinence. MRI revealed a large cystic tumor in the right frontal lobe and he
was admitted to another hospital. After 20 days, MRI incidentally revealed
hematoma near the intratumoral cyst. Two weeks later, MRI revealed that the
hematoma flowed out the cyst and the cavity of the hematoma communicated with the
cyst. Angiography showed that the tumor was fed by the left anterior ethmoid
artery. After surgical removal of the tumor, histopathological diagnosis was that
the tumor was a transitional meningioma and there were no findings of malignancy.
Commonly, intratumoral hemorrhage is unusual for a meningioma but we suspect that
there are not a few cases in which small hemorrhage occurred without symptoms and
the hematoma cavity joined the intratumoral cyst while the cyst grew gradually.
PMID- 9558658
TI - [Superior sagittal sinus occlusion due to calvarial metastasis of renal cell
carcinoma: 2 cases report].
AB - We report two cases of superior sagittal sinus (SSS) occlusion due to calvarial
metastasis of renal cell carcinoma. Both cases were presented with bulging of the
skull. No stigmata of increased intracranial pressure was detected. Cerebral
angiogram showed the occlusion of the SSS. Tumor cells did not penetrate into the
dura mater nor the galea and the tumors were able to be removed easily in both
cases. One case without collateral circulation showed recanalization of the SSS
on the postoperative angiography. Another case with development of collateral
circulation did not show recanalization of SSS on the postoperative magnetic
resonance angiography. In the latter case, cortical veins flowed into the
occluded portion. We consider that SSS should be preserved to prevent venous
congestion in the cases where collateral circulation has not developed.
PMID- 9558659
TI - [Neurinoma arising from the first branch of the trigeminal nerve: a case report].
AB - A case of a neurinoma arising from the first branch of the trigeminal nerve in a
40-year-old female is reported. The patient was admitted with the chief complaint
of loss of Lt. visual acuity and mild hypoesthesia in the area of the first
branch of the trigeminal nerve. A CT scan and MRI revealed a tumor extending
through the superior orbital fissure into the orbita. Subtotal resection of the
tumor was performed by a fronto-orbito-zigomatic approach and a histological
diagnosis of neurinoma was made. Although the hypoesthesia remained, the visual
acuity was markedly improved postoperatively. A neurinoma arising from the first
branch of the trigeminal nerve is very rare. To our knowledge, including our
case, only five cases which were described for clinical and diagnostic features
and surgical management have been reported. There were three males and two
females, and the age ranged from 1 to 57 years. Neurologically, all cases
presented hypoesthesia in the area of the first branch of the trigeminal nerve
and exophthalmus on admission. Visual disturbance was found in three cases.
Radiologically, the enlargement of the superior orbital fissure was revealed in
two cases. Angiography performed in three cases demonstrated the avascular mass.
Three patients received CT scan and only the present case used MR imaging.
Surgical resection was performed in all cases through various approaches. The
fronto-orbito-zygomatic approach which was chosen in our case was useful for
obtaining a sufficient operative view. As in our case, excellent outcome was
achieved in three other cases due to successful tumor resection.
PMID- 9558660
TI - [A case of clear cell meningioma originating from the cerebellar tentorium].
AB - We report herein on a case of clear cell meningioma originating from the
cerebellar tentorium, surgically treated by occipital transtentorial approach
(OTT). A 67-year-old woman was admitted to our hospital in September, 1996,
complaining of gait disturbance. MRI revealed an isointense mass on T1 and T2 WI,
clearly enhanced with gadolinium in the right upper cerebellum originating from
the tentorium. A left vertebral angiogram showed tumor stain from the right
superior cerebellar artery. The tumor was subtotally removed by OTT on September
24, 1996. Gamma knife radiosurgery was performed for regrowing tumor 6 months
after surgery. Histological examination revealed that the tumors were composed of
sheets of clear, glycogen-rich cells and lobulated by thin connective tissues.
There were no malignant findings, but some tumor cells had infiltrated into the
cerebellar cortex. Immunohistochemistry showed that tumor cells were positive for
EMA and vimentin, but negative for keratin. MIB-1 staining index was 7.02%. From
these findings, this case was diagnosed as a typical clear cell meningioma
originating from the cerebellar tentorium. From a review of the literature
including our case, clear cell meningioma may be clinicopathologically malignant,
so careful follow-up will be necessary.
PMID- 9558661
TI - [Transsphenoidal surgery and gamma-knife radiosurgery for a treatment of
recurrent craniopharyngioma with moyamoya vessels].
AB - A recurrent craniopharyngioma associated with moyamoya vessels was successfully
treated by partial removal of the tumor via the transsphenoidal approach followed
by gamma-knife radiosurgery. This 19-year-old man was first treated by partial
tumor removal and radiotherapy (54Gy) at the age of 6 years. Growth hormone and
human chorionic gonadotropin were given from the ages of 13 to 18 years. At ag 17
years, follow-up magnetic resonance imaging (MRI) revealed regrowth of the tumor.
At the age of 19 years, he was readmitted for treatment of the enlarging remnant
tumor. Neurological examination revealed bilateral blindness. MRI showed marked
suprasellar, sphenoidal and bilateral cavernous sinus extension of the tumor.
Angiography revealed stenosis of the right internal carotid artery and the M1 and
A1 segments of the right cerebral arteries, as well as occlusion of the C3
segment of the left internal carotid artery. There were vault and ethmoidal
moyamoya vessels. The patient underwent tumor removal via the transsphenoidal
approach, instead of craniotomy, to avoid injury to the transdural anastomosis.
The intrasellar solid tumor was partially removed. The tumor was then irradiated
by the gamma knife. MRI 15 months after the treatment showed marked reduction of
the tumor. The pathogenesis of the moyamoya phenomenon and the choice of the
treatment in this patient are discussed.
PMID- 9558663
TI - Unilateral dermis-fat graft implantation in the pediatric orbit.
AB - The purpose of this study was to evaluate the role of the dermis-fat graft (DFG)
as an orbital implant in the pediatric age group. A retrospective study was made
of a series of 16 patients who had undergone unilateral orbital implantation of a
DFG. The ages of the patients at the time of surgery ranged from 2 months to 17
years, with followup ranging from 2 to 15 years. Growth of the graft was
clinically apparent in the younger children. Increasing proptosis required
surgical debulking of the graft in six of eight children who were 4 years old or
younger at the time of DFG implantation. None of the eight children who were 9
years or older at the time of DFG implantation required surgical debulking.
Indeed, five of the older patients demonstrated some degree of graft atrophy.
Dermis-fat grafts placed in the orbits of young children appear to grow after
implantation. This growth of the implant may help stimulate orbital growth,
potentially leading to more symmetry between the involved and uninvolved sides.
PMID- 9558662
TI - Rate of vascularization of coralline hydroxyapatite spherical implants pretreated
with saline/gentamicin, rTGF-beta 2, and autogenous plasma.
AB - Several authors have reported significant exposure rates using the hydroxyapatite
orbital implant in the treatment of the anophthalmic socket. Histologic studies
by ourselves and others have suggested that lack of fibrovascular ingrowth into
the implants may contribute to conjunctival breakdown and exposure. Recently,
much attention has been given to angiogenic factors, such as rTGF-beta 2 and
those found in plasma, in accelerating wound healing and fibrovascular ingrowth.
This pilot study compares the rate of vascularization of hydroxyapatite orbital
implants pretreated with plasma, rTGF-beta 2, and a saline/gentamicin solution
with that in untreated controls ina population of New Zealand albino rabbits.
Hydroxyapatite orbital spheres were implanted subcutaneously and in enucleated
orbits. Untreated implants were used as a control. Implants pretreated with
plasma, rTGF-beta 2, and a saline/gentamicin solution were removed and examined
histologically at weekly intervals for the first 3 weeks after implantation.
Histologic studies demonstrated that the rate of vascularization significantly
increased between 2 and 3 weeks postoperatively in all study groups. Pretreating
the implants with rTGF-beta 2 in phosphate buffered solution (PBS) or autogenous
plasma did not significantly increase the rate of vascularization in comparison
with controls at weeks 1 and 2. However, pretreating the implants with a
saline/gentamicin solution or PBS alone was associated with an increased rate of
vascularization at weeks 2 and 3. No statistically significant difference in
vascularization was noted between the subcutaneous and orbital implants at any
week. Hydroxyapatite implants pretreated with saline/gentamicin or phosphate
buffered solutions underwent more rapid vascularization at weeks 2 and 3 in
comparison with controls. Additionally, all groups were noted to have a more
rapid rate of ingrowth between weeks 2 and 3 than between weeks 1 and 2. Plasma
and rTGF-beta 2 (at the dose used) did not significantly alter the rate of
vascularization of hydroxyapatite implants during the first 2 to 3 weeks. The
significance of these findings is discussed.
PMID- 9558664
TI - Paralytic ectropion: a complication of malar implant surgery.
AB - The use of the malar implant to augment the malar-zygomatic eminence is rapidly
becoming a popular aesthetic procedure; however, this surgery can lead to
paralysis or paresis of the facial nerve. Paralytic ectropion may result from
orbicularis oculi dysfunction. We report two cases of paralytic ectropion as a
result of malar implant placement. Conservative management for mild orbicularis
oculi dysfunction consisted of topical lubricants and observation, whereas
persistent ectropion required surgical repair. Paralytic ectropion and secondary
exposure keratopathy are possible complications of malar implant surgery.
PMID- 9558665
TI - A modified surgical technique in the treatment of facial nerve palsies.
AB - The ophthalmic complications associated with facial nerve palsy present a
challenging problem to the treating ophthalmologist. Over the last hundred years,
a wide variety of techniques have been used to rehabilitate patients with facial
nerve palsy. Each of these techniques is associated with unique complications. We
describe a significantly modified surgical technique for the rehabilitation of
patients with facial nerve palsy that has not, to our knowledge, previously
appeared in the literature.
PMID- 9558666
TI - Effectiveness of homologous cadaveric fascia lata and role of suture fixation to
tarsus in frontalis suspension.
AB - The results of frontalis suspension (double rhomboid technique with preserved
homologous cadaver fascia) were compared in two surgical groups: 1) patients in
whom the fascia was sutured to the tarsus and 2) patients in whom the fascia was
not sutured to the tarsus. The study was performed to determine the optimum
surgical technique and to determine whether preserved cadaver fascia is a
suitable suspensory material. All data retrospectively reviewed included 1)
predisposing cause of severe blepharoptosis, 2) results in the two groups of
patients, suture fixation and nonsuture fixation, and 3) surgical complications.
Of the 27 patients (36 eyelids), the fascia was sutured to the tarsus in 15
patients (20 eyelids) and not sutured to the tarsus in 12 patients (16 eyelids).
In the suture fixation group, no undercorrections occurred, but four of 20
eyelids had lower than expected eyelid creases and six had residual
dermatochalasis. Six patients had lagophthalmos with corneal exposure that
required intense corneal lubrication, and three such patients required temporary
tarsorrhaphy for 3 weeks. In the group without suture fixation, two patients had
undercorrection (one with ocular cicatricial pemphigoid and the other with
myotonic dystrophy). The mean followup period was 44 months. We conclude that
preserved fascia provides excellent results with or without fixation of the
fascia to the tarsus. In patients with suture fixation, the eyelid crease may
form just above the point at which the fascia is sutured to tarsus and result in
a low eyelid crease. Excision of excess skin should be considered at the time of
frontalis suspension in selected patients in whom the fascia is fixated to the
tarsus or who have preexisting dermatochalasis. Patients with suture fixation may
have significant temporary postoperative lagophthalmos.
PMID- 9558667
TI - Hering's law and eyebrow position.
AB - A patient with bilateral but asymmetrical brow ptosis is presented in whom the
frontalis action on the relative position of the eyebrows could be demonstrated
to obey Hering's law of equal innervation. The neurological basis for this
finding is discussed, along with the implications for the surgical management of
brow ptosis.
PMID- 9558668
TI - The endoscopic forehead lift.
AB - Endoscopic techniques are being successfully applied to address eyebrow and
forehead ptosis. The methods rely on extensive subperiosteal and subgaleal
release of the forehead and scalp flap, allowing the elevation of soft tissues.
Ablation of the depressor supercilli and procerus can be performed to address
skin folding in the glabellar region. The mobilized frontotemporal flap is then
elevated to the desired level and fixated with microscrews to the outer table of
the skull. Laterally, the flap is fixed to the deep temporalis fascia. The
technique relies upon a solid knowledge of the regional anatomy and the use of
specialized instruments now available for dissecting under the flap. The
endoscopic forehead lift can achieve results comparable to those obtained by the
open coronal forehead lift while minimizing the incidence and extent of
postoperative cutaneous anesthesia and telogenic hair loss, which frequently
follows open coronal forehead surgery. In addition, the endoscopic technique is
able to address eyebrow ptosis in the balding male without causing disfiguring
scarring.
PMID- 9558669
TI - Interleukin-8 and monocyte chemotactic protein-1 gene expression and protein
production by human orbital fibroblasts.
AB - Orbital inflammation is common, but the mechanisms underlying leukocytic
infiltration of orbital tissue are poorly understood. We studied resident human
orbital fibroblasts (OF) interleukin-8 (IL-8), and monocyte chemotactic protein-1
(MCP-1) mRNA expression and protein secretion in response to lipopolysaccharide
(LPS) or recombinant human cytokines that are present during inflammation. Third
passaged cultured human OF were left unstimulated or incubated with varying
concentrations of LPS, recombinant interleukin-1-beta (rIL-1 beta), recombinant
tumor necrosis factor-alpha (rTNF-alpha), or recombinant interferon-gamma (rIFN
gamma) for 2, 4, 8, or 24 h. Northern blot analysis and ELISA were performed to
determine OFIL-8 and MCP-1 mRNA expression and protein secretion, respectively.
Experiments were performed in triplicate and repeated four times on different
cell lines. OF lacked constitutive IL-8 or MCP-1 gene expression, but produced
substantial dose-dependent increases in steady-state IL-8 and MCP-1 mRNA
expression by 2 h of LPS or cytokine stimulation (rIL-1 beta > fTNF-alpha > LPS >
rIFN-gamma), maintained at 24 h ELISA for IL-8 and MCP-1 proteins showed
significant time- and dose-dependent OF secretion after exposure to recombinant
cytokine or LPS (rIL-1 beta > rTNF-alpha > LPS), measured after 4 h of exposure
(p < 0.01). This increased in the media over the next 20 h. rIFN-gamma was a
potent stimulant of OF MCP-1, significant by 2 h (p < 0.05), but only a weak
stimulant of IL-8 at 24 h. OF secreted IL-8 and MCP-1 in response to LPS and
proinflammatory cytokines, indicating that these resident cells within the orbit
have the capacity to actively participate in the initiation and propagation of
orbital inflammation. Strategies aimed at modulating local mediators may be
helpful in the management of orbital inflammatory disease.
PMID- 9558670
TI - The "dural tail sign": not always a meningioma.
AB - Periorbital masses are often referred to oculoplastic surgeons. We report a 20
year-old patient presenting with a tender supertemporal mass that on gadolinium
enhanced magnetic resonance imaging (MRI) demonstrated a prominent dural
enhancement adjacent to the mass, the so-called "dural tail sign." This sign has
been reported to be highly specific for a meningioma; however recent literature
challenges this view. In this case as well, the "dural tail sign" was not
produced by a meningioma.
PMID- 9558672
TI - Cystic basal cell carcinoma of the orbit and eyelids.
AB - When basal cell carcinoma develops cystic change, its clinical and radiological
features vary, leading to confusion in differential diagnosis We report four
cases with cystic formation of 62 patients with orbital and adnexal basal cell
carcinoma encountered during the last 12 years. The salient clinical,
radiological, and histopathological features of these cases are presented and
differential diagnosis of large cystic lesions in the orbit is discussed. When
the basal cell carcinoma develops cystic changes it mimics other orbital cysts,
including inclusion cysts due to penetrating injury, mucoceles, and necrotic
metastatic tumors.
PMID- 9558671
TI - Carcinoma of the male breast metastatic to both orbits.
AB - We report the case of a 43-year-old man who presented with painless proptosis of
the right eye of 6 weeks' duration. Examination demonstrated a tense right orbit
and decreased vision and extraocular motility bilaterally. Diagnostic evaluation
included computed tomographic imaging of the head and orbits, a therapeutic trial
of high-dose systemic corticosteroids, and orbital biopsy, which revealed the
presence of metastatic adenocarcinoma. The primary tumor was found to be an
estrogen-receptor-positive, infiltrating ductal adenocarcinoma of the right
breast. Therapy included lumpectomy of the breast mass, orbital irradiation, and
hormonal therapy. Metastatic carcinoma of the breast should be considered in the
differential diagnosis of orbital neoplastic disease in the male patient.
PMID- 9558673
TI - Rounding of the inferior rectus muscle: a helpful radiologic findings in the
management of orbital floor fractures.
AB - The authors describe a patient with an orbital floor fracture that did not
demonstrate a distinct fracture on computed tomography (CT) imaging. The key
radiologic finding was rounding of the inferior rectus muscle.
PMID- 9558674
TI - Standardized range of conformers and symblepharon rings.
AB - Conformers and symblepharon rings are routinely used to keep fornices formed
after socket surgery or in the presence of conjunctival cicatricial disease.
However, there is no accepted standard size or shape of conformers or
symblepharon rings. We measured the ideal conformer and symblepharon sizes in
patients undergoing socket surgery and designed six conformer and symblepharon
sizes. The full set of six conformers and symblepharon rings is available to the
surgeon at the end of surgery. We have successfully used these conformers and
symblepharon rings in over 600 cases during the last 7 years. These standardized
sizes allow more accurate fitting of conformers and symblepharon rings.
PMID- 9558675
TI - Incision site tissue necrosis after dacryocystorhinostomy.
AB - Incision site tissue necrosis (ISTN) after surgical procedures of the facial area
is rare. In this article, two patients who have suffered from ISTN after
dacryocystorhinostomy (DCR) are reported. No known causes have been found for
this complication; however, over-cauterization could be considered a contributing
factor in at least one of our cases.
PMID- 9558676
TI - Primary herniation of the lacrimal gland.
PMID- 9558677
TI - Pacemaker event counters: possible sources of error in calculation of AV
synchrony in VDD single lead systems as an example for present limitations.
PMID- 9558678
TI - Tilt table testing of young adult patients: improved speed and sensitivity using
an isoproterenol bolus and a continuous 60 degrees tilt.
AB - The tilt table is a diagnostic device used to induce vagal syncope and determine
etiology. Sensitivity enhancing techniques, such as the administration of
isoproterenol, can be applied to children and young adults to compensate for the
otherwise low sensitivity (20%-30%) observed in that population. This study
describes an improved test that offers a simplified approach while decreasing the
amount of time involved by up to 50%, without compromising sensitivity. This 45
minute procedure relies on sensitization with isoproterenol administered as a 2-
to 80 micrograms bolus instead of a continuous infusion. The isoproterenol is
injected at the 30th minute of a 45-minute 60 degrees tilt test without returning
the patient to the supine position. In this study, the isoproterenol bolus tilt
test was found to be "positive" in 24 of 30 patients reporting unexplained
syncope: 10 cases before the 30th minute (11.2 +/- 8.4 min) and 14 cases after
administration of 5.1 +/- 1.9 micrograms of isoproterenol.
PMID- 9558679
TI - Subclavian venogram as a guide to lead implantation.
AB - Recent reports have raised doubts regarding the safety and efficacy of the blind
subclavian venipuncture technique for intracardiac lead implantation. To permit a
more lateral entry, we used a simple subclavian venogram performed through the
brachial vein of the ipsilateral arm of 22 consecutive unselected patients
undergoing lead implantation (19 permanent pacemakers and 3 intracardiac
defibrillators). A total of 35 leads were implanted (31 left pectoral and 4 right
pectoral). Lead insertion by venogram technique was used successfully in all
patients. Two inconsequential arterial punctures occurred. There were no
pneumothoraces infections, or other complications. Lateral placement should
facilitate lead manipulation and minimize "subclavian crush." The method of
ipsilateral venogram guided lead insertion appears to be safe and reliable and
deserves consideration in patients who require permanent lead placement via the
subclavian vein approach.
PMID- 9558680
TI - "In-line" bipolar, steroid-eluting, high impedance, epimyocardial pacing lead.
AB - Recent advances in electrode surface designs have eliminated traditional
threshold differences between endo- and epicardial pacing leads. Since the
epicardial approach offers the potential of direct left ventricular pacing and
the transvenous approach may not be feasible or warranted in all instances, more
advanced leads are being designed to optimize epicardial pacing capabilities.
This study was conducted to evaluate a bipolar epimyocardial lead. Six immature
canines (age 3 months) were instrumented. The lead (Medtronic model 10389) is a
single-pass, "in-line" bipolar electrode with low current drain and high
impedance, with an intramyocardial steroid-eluting cathode and nonsteroid
epicardial anode. Twelve ventricular leads were implanted (two per animal) and
the animals followed for 6 months with weekly analysis of pacing and sensing
capabilities. Results at explant were compared with implant values and showed no
significant differences between sensed R waves or in R wave slew rates in
unipolar or bipolar modes. Explant lead impedances remained high in both modes:
bipolar, 1658 +/- 331; and unipolar, 1327 +/- 308 omega (P < 0.05). Chronic
voltage (V) threshold at 0.5 ms showed no significant change from implant values
during the study: unipolar, 0.3 +/- 0.06 versus 1.0 +/- 0.8; and bipolar, 0.4 +/-
0.06 versus 1.6 +/- 1.2. Histologic review showed negligible fibrous reaction at
the electrode-tissue interface. This study introduces a high impedance, low
threshold, "in-line" bipolar pacing lead design capable of stable chronic pacing
with implant facilitated by a single suture technique.
PMID- 9558681
TI - Scoring method for assessing rate adaptive pacemakers: application to two
different activity sensors.
AB - To optimize programming of rate adaptive pacemakers (RAPs), we explored a new
mathematical method to assess the performance of RAPs during daily-life tests,
using customized Windows-based software. By stepwise discriminant analysis and
linear regression, this method allows calculation of the acceleration and
deceleration capacity of pacemakers and their general behavior during effort and
recovery phases. Twenty-three patients (10 females and 13 males; 68 +/- 8 years)
with chronic atrial fibrillation and a slow ventricular response were evaluated.
They randomly received an accelerometer-controlled VVIR Dash Intermedics
pacemaker (10 patients) or a vibration piezoelectric-controlled VVIR Sensolog III
Siemens pacemaker (13 patients). All patients underwent the same test protocol: 6
minutes walking, 1.5 minutes climbing stairs, 1.5 minutes descending stairs, and
0.5 minutes sit-ups. By definition, the pacemaker responsiveness slope was
programmed so that the heart rate response of paced patients during the walking
test corresponded best to that of healthy controls. The slope was left unchanged
for the other tests. We considered four scores: an acceleration score (EA score),
an effort rate score (ER score), a deceleration score (RD score), and a recovery
rate score (RR score). Scores ranged from -10 (hypochronotropic behavior of the
pacemaker) to +10 (hyperchronotropic behavior), based on daily-life tests of 15
healthy controls (7 females and 8 males, 65 +/- 9 years). A score of 0
represented exact concordance with healthy controls. During stair descent, the
Sensolog III produced excessive acceleration (EA score = +2.9 +/- 1.1) compared
to: (1) stair climbing (EA score = -4.0 +/- 1.9; P = 0.01, with the same
pacemakers); and (2) the Dash (+1.8 +/- 1.9; P = 0.04) and healthy controls (P =
0.02). The sit-up tests revealed a hypochronotropic response of both pacemakers
compared to healthy controls, with a larger difference for the Sensolog III (EA
score = -2.0 +/- 5.8; P = 0.04; RD score = -6.8 +/- 3.8' P = 0.02). We conclude
that activity-driven pacemakers can accommodate brief activities, except for
isovolumetric exercise such as sit-ups. During daily activities, accelerometer
driven pacemakers seem to provide a heart rate resoibse closer to that of healthy
controls. Our new mathematical analysis is a simple and reproducible method for
evaluating and quantifying the efficacy of any sensor-driven pacemaker.
PMID- 9558682
TI - Venous dysfunction and the change of blood viscosity during head-up tilt.
AB - The precise stimulus that induces vasovagal syncope is still unclear. We have
previously demonstrated that the peripheral distribution of blood volume (venous
pooling) is a strong predictor of tilt induced vasovagal reaction. We
hypothesized that an increase in venous pooling during tilt accentuates the
measured increase in blood viscosity. This hypothesis is based on the previously
demonstrated increase in venous pressure and subsequent increase in
transcapillary fluid transudation during tilt. The increased blood viscosity, in
turn, increases vascular shear rate, which may alter the vasoconstrictive and
other cardiovascular responses to decreased preload. We measured blood viscosity
(supine and tilt) in 56 patients with a history of orthostatic intolerance (37
with venous pooling [VP] and 19 without venous pooling [non-VP]). VP and non-VP
were separated into subgroups based on blood pressure and heart rate response to
tilt. There was a positive correlation between blood viscosity and plasma
aldosterone in the supine. In the group as a whole, neither supine blood
viscosity nor its increase during tilt differed between VP and non-VP. However,
the tilt induced increase of blood viscosity was significant only in patients
with tilt provoked tachycardia plus normal blood pressure response in VP group.
We suggest that the increase of blood viscosity in this group led to the normal
blood pressure response. The positive correlation between supine blood viscosity
and supine plasma aldosterone indicates that the normal blood pressure response
in this group possibly was via stimulation of the renin-angiotensin-aldosterone
system.
PMID- 9558683
TI - Effects of procainamide on the excitable gap composition in common human atrial
flutter.
AB - The composition of the excitable gap (EG) in common atrial flutter (AF1) was
determined before and during infusion of procainamide (PA) in 9 patients (6 men
and 3 women; age 70 +/- 7 years). The EG was determined by introducing a
premature stimulus after every 20th AF1 complex detected using a quadripolar
electrode catheter placed just above the tricuspid valve. Diastole was scanned in
2- to 4-ms decrements to the atrial effective refractory period (ERP). The
relationship between the coupling interval and the return cycle length (CL)
determined a reset-response curve (RRC), which described the EG. PA (15 mg/kg)
was administered during AF1 over 30 minutes and RRC was repeated at maximum AF1
CL. PA prolonged AF1 CL from 227 +/- 29 to 296 +/- 62 ms (P < 0.01) but did not
terminate AF1. ERP during AF1 prolonged from 169 +/- 24 to 219 +/- 41 ms (P <
0.01). Control EG was 57 +/- 16 ms or 25% +/- 6% of AF1 CL and on PA EG was 77 +/
30 ms (P = 0.01), which was still 26% +/- 7% of the CL. Without drug, RRC was
mixed in eight cases demonstrating an EG composed of fully excitable tissue (10
+/- 4 ms or 19% +/- 10% of the EG) and partially refractory tissue (48 +/- 18
ms). PA did not change the duration of the fully excitable region (13 +/- 10 ms
or 19% +/- 15% of EG). Peak PA plasma concentration was 47 +/- 20 mumol/L. PA
prolonged AF1 CL, ERP, and EG duration but did not change the proportion of AF1
CL occupied by the EG. The persistance of fully excitable tissue at the head of
the wavefront in the presence of PA may largely explain its inefficacy in the
acute termination of common AF1.
PMID- 9558684
TI - Hemodynamic benefits of right ventricular outflow tract pacing: comparison with
right ventricular apex pacing.
AB - To assess optimal hemodynamics in relation to stimulation site during right
ventricular pacing, 17 consecutive patients who underwent cardiac catheterization
were studied. In all patients, right ventricular apex and right ventricular
outflow tract stimulation was performed at 85, 100, and 120 beats/min. Cardiac
index at both pacing sites was compared using the left ventricular outflow tract
continuous wave Doppler technique. Comparison of the two stimulation sites
demonstrated that right ventricular outflow tract pacing resulted in a higher
cardiac index at 85 beats/min (2.42 +/- 1.2 vs 2.04 +/- 1.0 L/min per m2, P <
0.002) at 100 beats/min (2.78 +/- 1.4 vs 2.35 +/- 1.1 L/min per m2, P < 0.001)
and 120 beats/min (3.00 +/- 1.5 vs 2.61 +/- 0.9 L/min per m2, P < 0.001). From a
total of 51 paired observations, 45 showed an increase in cardiac index during
outflow tract pacing as compared to apex pacing. Right ventricular outflow tract
pacing at 120 beats/min resulted in a lower cardiac index than right ventricular
apex pacing in patients with significant coronary artery disease and/or impaired
left ventricular function (ejection fraction < or = 50%), whereas right
ventricular outflow tract pacing produced higher cardiac indices in the absence
of these abnormalities. Right ventricular outflow tract pacing resulted in higher
cardiac indices as compared to apex pacing in all other subgroups at all other
pacing sites tested. It is concluded that stimulation of the right ventricular
outflow tract offers a significant hemodynamic benefit during single chamber
pacing as compared to conventional apex pacing, particularly in the absence of
significant coronary artery disease and/or left ventricular dysfunction.
PMID- 9558685
TI - Efficacy of ventricular rate stabilization by right ventricular pacing during
atrial fibrillation.
AB - To assess the effect of right ventricular pacing on rate regularity during
exercise and daily life activities, 16 patients with sinoatrial disease and
chronic atrial fibrillation (AF) were studied. Incremental ventricular pacing was
commenced at 40 beats/min until > 95% of ventricular pacing were achieved during
supine, sitting, and standing. Thirteen patients also underwent randomized paired
submaximal exercise tests in either a fixed rate mode. (VVI) or a ventricular
rate stabilization (VRS) mode in which the pacing rate was set manually at 10
beats/min above the average AF rate during the last minute of each exercise
stage. The pacing interval for rate regularization was shortest during standing
(692 +/- 26 ms) compared with either supine or sitting (757 +/- 30 and 705 +/- 26
ms, respectively, P < 0.05). During exercise VRS pacing significantly increased
the maximum rate (119 +/- 5.2 vs 106 +/- 4.2 ms, P < 0.05), percent of
ventricular pacing (85% +/- 5% vs 23% +/- 7%, P < 0.05), rate regularity index
(5.8% +/- 1.6% vs 13.4% +/- 1.9%, P < 0.05), and maximum level of oxygen
consumption (12.4 +/- 0.5 vs 11.3 +/- 0.5 mL/kg, P < 0.05) compared with VVI
pacing. There was no change in oxygen pulse or difference in symptom scores in
this acute study between the two pacing modes. It is concluded that right
ventricular pacing may significantly improve rate regularity and cardiopulmonary
performance in patients with chronic AF. This may be incorporated in a pacing
device for rate regularization of AF using an algorithm that is rate adaptive to
postural and exercise stresses.
PMID- 9558686
TI - Experience with a lead fixation/suture sleeve.
AB - Current anchoring systems on pacemaker leads are crude in comparison to the lead
technology. Poor anchoring technique may cause damage to the lead or early
displacement from incorrect suture tension. We describe experience with a locking
anchoring sleeve that applies a constant gripping force to the lead body. This
can be locked and unlocked to allow optimal positioning after fixation of the
sleeve to underlying tissues. The sleeve was fitted to a 55D polyurethane lead
(Medtronic 4024, 7 Fr, bipolar, steroid eluting) implanted in the ventricular
position in 22 patients at four European centers. All implants were
uncomplicated; data were collected on handling and ease of use. Assessments were
made using a scale of 1-10 (10 = excellent, 5 = equivalent to conventional
sleeve). Overall ease of use compared to conventional sleeve was 7.79 +/- 0.62
(mean +/- SD). Mean scoring of flexibility of the lead at the transition points
was 7.92 +/- 0.72; ability to lock/unlock the sleeve scored 6.28 +/- 1.78. Ease
of suturing around the sleeve scored 8.07 +/- 0.77, and ability to slide the
sleeve along the lead body scored 6.48 +/- 1.99. Chest X rays at 6 weeks showed
no change in lead position with respect to postimplant films, and all leads
showed a straight path on either side of the sleeve with no evidence of conductor
distortion. Follow-up to 3 years has been without problem. All leads remain
intact and in place, with stable thresholds and no evidence of erosion. There
have been no complaints of patient discomfort. We conclude that this device is
safe and effective and offers a significant advance in lead fixation.
PMID- 9558687
TI - Thoracoscopic radiofrequency ablation of the myocardium.
AB - Radiofrequency (RF) catheter ablation has been used for the treatment of
ventricular tachycardia (VT), however, in some patients VT might result from
subepicardial macroreentry that could be successfully terminated by epicardial
approach. This study examined the feasibility of thoracoscopic RF ablation of
myocardium from epicardium using a custom made electrode. In five mongrel dogs,
the thoracoscope was introduced through the 7th intercostal space. A 500-KHz
continuous wave RF energy was connected to a custom made multiple electrode
probe. Under thoracoscopic guidance, the heart was exposed and the RF probe was
introduced. RF ablation was performed on the nonvascular ventricular wall of the
beating heart. The left ventricular free wall and right ventricular outflow tract
were satisfactorily visualized and ablated. The total dose of RF energy ranged
from 50 to 500 J, and the estimated volume of ablated lesions ranged from 41.0
799 mm3. There were significant correlations between the RF discharge output and
the irradiated lesion volume (P < 0.01), and the depth of the lesions (P < 0.01).
Grossly, after RF ablation the ventricular myocardium demonstrated a circular,
well-demarcated area of thermal injury. Volume and depth of the lesion depended
upon the total dose of delivered RF energy. Thoracoscopic RF ablation appears to
be a minimally invasive and useful method for creating irradiated myocardial
lesions from epicardial surface. This method could be technically feasible for
the treatment of Vts for which endocardial RF ablation is ineffective.
PMID- 9558689
TI - Cardiac rehabilitation in patients with rate responsive pacemakers.
AB - This study investigated the suitability of our oxygen pulse reserve (OPR) method
for tailoring parameters of rate responsive pacemakers and planning aerobic
rehabilitation programs. We selected 11 patients, NYHA Classes I-III (7 males and
4 females; mean age 60 years, range 18-83), with rate responsive pacemakers
implanted for high degree AV block and chronotropic incompetence. Five pacemakers
had activity sensors, 4 had temperature sensors, and 2 had dual sensors. All
patients underwent a cardiopulmonary stress test (CPX). We determined anaerobic
threshold time (ATT), VO2/AT, total exercise time (TET), VO2 Max, and VO2 AT/VO2
Max. OPR (mL-O2/beat) was calculated for each patient using the formula OPR =
(VO2 Max - VO2 resting)/(HR Max - HR resting). During CPX, this slope was used as
the rate response tailoring guideline by comparing the mL-O2/beat equation and
the pacing rate. Rate response settings were modified until the optimal
relationship between theoretical and paced rate was obtained. The work protocol
yielded rate response settings capable of providing pacing rates within +/- 10
beats of the theoretical values. Data relating to theoretical and measured rates
have been analyzed statistically. Patients underwent an aerobic rehabilitation
program that followed the American College of Sports Medicine guidelines. Pacing
rate at the anaerobic threshold was considered the border for an aerobic
workload. After 2-7 months, all patients showed an evident improvement in ATT
(92%), VO2/AT (48%), TET (49%), VO2 Max (23%), and VO2 AT/VO2 (21%).
Particularly, two patients improved from Weber Class C to A, and three improved
from C to B. At each CPX step, the mean values of pacing rate and theoretical
rate almost overlap, and the relevant coefficients suggest an excellent
correlation (P < 0.001). Our OPR method for tailoring rate response provides the
basis for an effective rehabilitation program with functional advantages for
patients.
PMID- 9558688
TI - Effects of hydrophilic and lipophilic beta-blockers on heart rate variability and
baroreflex sensitivity in normal subjects.
AB - To evaluate the effect of a hydrophilic and a lipophilic beta-blocker on the
autonomic nervous system, 20 normal subjects were studied under baseline
conditions and 7 days after being randomly assigned to metoprolol (200 mg/day),
nadolol (80 mg/day), and placebo. Under each condition, the time-domain
parameters were analyzed by means of 24-hour ECG monitoring and the frequency
domain parameters by means of the autoregressive method using 10-minute ECGs
during rest, controlled respiration, and after a head-up tilt test. The alpha
index (the gain in the relationship between the RR period and systolic arterial
pressure variability) was also calculated. Both nadolol and metoprolol
significantly increased all of the time-domain parameters except the standard
deviation of the RH intervals; they also modified the frequency-domain
parameters. Both blunted the significant reduction in the high frequency (HF)
component and alpha index during tilt. In normal subjects, hydrophilic and
lipophilic beta-blockers similarly modify the time- and frequency-domain
parameters that are particularly evident when high sympathetic tone is present
(during daytime and tilt). The value of the alpha index was increased by both
beta-blockers in the HF, but not in the low frequency band; this difference might
be due to the fact that the former is a measure of the vagal component of the
baroreflex control and the latter a measure of the sympathetic component. The
effects of hydrophilic and lipophilic beta-blockers on the time- and frequency
domain parameters of heart rate variability are similar.
PMID- 9558690
TI - JT dispersion in Wolff-Parkinson-White syndrome: effect of eccentric ventricular
depolarization on the dispersion of repolarization.
AB - There is much interest in QT dispersion for noninvasive risk stratification of
patients at risk of arrhythmias. However, little is known about the genesis of
abnormal QT dispersion. In particular, whether eccentric ventricular
depolarization, as seen in preexcitation, can lead to abnormal dispersion of
repolarization is unknown. We studied 24 children aged 1-19 years (mean +/- SD,
11 +/- 5 years) with manifest preexcitation due to Wolff-Parkinson-White syndrome
who had successful catheter ablation. Standard ECGs done preablation, early
postablation (< 1 week), mid postablation (> 1 week, < 2 months), and late
postablation (> 2 months) were reviewed. The QRS duration prior to ablation
ranged from 90-160 ms (mean +/- SD, 123 +/- 21 ms). On the preablation ECG, the
JT and JTc dispersions showed no relationship to the QRS duration (r = 0.04 and
0.07, respectively). There was no change in JT dispersion when the preablation
(42 +/- 15 ms) ECG was compared to early (43 +/- 15 ms), mid (44 +/- 13 ms), and
late postablation (48 +/- 19 ms) ECGs. There was no significant change in JTc
dispersion as well. Thus, JT dispersion is unrelated to QRS duration and
unaffected by catheter ablation in patients with Wolff-Parkinson-White syndrome.
Eccentric ventricular depolarization does not lead to abnormal dispersion of
repolarization.
PMID- 9558691
TI - Transvenous single lead atrial defibrillation: efficacy and risk of ventricular
fibrillation in an ischemic canine model.
AB - Transvenous atrial defibrillation with multiple atrial lead systems has been
shown to be effective in models without the potential for ventricular
arrhythmias. The specific aim of this study was to evaluate the efficacy and
safety of transvenous single lead atrial defibrillation in a canine model of
ischemic cardiomyopathy. Ten dogs had ischemic cardiomyopathy induced by repeated
intracoronary microsphere injections. The mean LV ejection fraction decreased
from 71% +/- 9% to 38% +/- 14% (P = 0.003). Spontaneous atrial fibrillation (AF)
developed in four dogs, and in six AF was induced electrically. Atrial
defibrillation thresholds (ADFTs) were determined with synchronous low energy
shocks using a transvenous tripolar lead with two defibrillation coils (right
ventricle, superior vena cava) and an integrated sensing lead (RV coil vs
electrode tip). The ADFTs derived by logistic regression were compared at 50% and
90% probability of success (ED50, ED90): ED50 was 2.4 +/- 1.7 J and 2.9 +/- 2.1
J, respectively, for 5- and 10-ms monophasic shocks, and 1.8 +/- 0.9 J,
respectively, for 5- and 10-ms biphasic shocks. Immediately after 3 of 2,179
(0.1%) synchronized shocks, ventricular fibrillation (VF) developed. VF was
induced in 3 of 1,062 (0.3%) shocks with integrated sensing (RV coil vs electrode
tip) compared to 0 of 1,117 shocks when a separate bipolar RV sensing electrode
was used for synchronization. In our canine model of ischemic cardiomyopathy, low
energy atrial defibrillation via a transvenous single lead system was highly
effective. However, there was a small but definite risk of VF induction, which
seemed to be greater when an integrated as opposed to a true bipolar RV sensing
was used.
PMID- 9558692
TI - Rhythm management in atrial fibrillation--with a primary emphasis on
pharmacological therapy: Part 1.
AB - Atrial fibrillation (AF) is the most common, sustained, symptomatic
tachyarrhythmia that clinicians are called upon to manage. Management strategies
include ventricular rate control coupled with anticoagulation, versus restoration
and maintenance of sinus rhythm. Rate control may be achieved pharmacologically,
with agents that impair AV nodal conduction directly and/or by increasing
parasympathetic/sympathetic balance, or by modifying or ablating the AV nodal
region anatomically. Rhythm control may be achieved by electrical or
pharmacological conversion followed by maintenance of sinus rhythm by
pharmacological (or occasionally ablative) therapies. This article will present
current approaches to rate and rhythm control issues in AF. Part 1, the current
manuscript, details approaches to rate control and includes a drug selection
algorithmic conclusion. It also introduces the subject of the pursuit of sinus
rhythm. Parts 2 and 3, to be published in subsequent editions of PACE, will deal
with therapeutic measures to restore and maintain sinus rhythm.
PMID- 9558693
TI - Stepwise strategy on the cost of risk stratification after acute myocardial
infarction: a retrospective simulation study.
AB - Stratification of postinfarction patients at high risk of mortality and/or other
adverse events can be improved by combining several prognostic markers. As the
clinical impact of risk stratification has only recently emerged in prospective
trials, there are a lack of data regarding the cost-effectiveness of multimarker
strategies. This study performed a comprehensive search of a postinfarction
database and simulated different risk stratification strategies involving left
ventricular ejection fraction, signal-averaged electrocardiography, Holter
monitoring, and heart rate variability, The parameters were assessed before
discharge in 417 survivors of acute myocardial infarction followed-up for 1 year.
Cardiac mortality was used as the clinical endpoint. A statistical computer model
of a stepwise strategy using every feasible sequence of the four tests was used
and, based on prices derived from European and American centers, the cost
estimates of all possible combinations were compared. During the 1 year after
myocardial infarction there were 24 cardiac deaths (5.8%). In all the population,
6% had all four tests positive (cardiac mortality 20%); 25% had at least three
tests positive (cardiac mortality 12.5%); 58% had at least two tests positive
(cardiac mortality 8.3%); and 92% presented with at least one test positive
(cardiac mortality 6.3%). The cost of performing all the tests ranged between
$398 and $1,887 for each patient. However, by selecting patients according to a
step wise strategy, the costs ranged from $96 (> or = 1 test positive) to $510
(for the least expensive sequences of four tests positive). For each of the
centers considered, the costs resulting from the risk stratification protocol
were determined by the number of variables combined and sequences of tests
adopted. Thus, a step wise strategy using the combination of all four parameters,
starting with analysis of Holter variables and finishing with signal-averaged
electrocardiography, appears to be the most appropriate and the least expensive
approach for selecting patients at high risk of cardiac death.
PMID- 9558694
TI - FDA reform: new law to impact EP and pacing services at home and abroad.
PMID- 9558695
TI - Possible involvement of cerebral hypoperfusion as trigger of neurally-mediated
vasovagal syncope.
AB - It is well known that some patients with neurally mediated syncope have a feeling
of aura before the onset of syncope. A case is reported in which cerebral
dysfunction recorded by EEG was present before the onset of a vasovagal reaction.
The vasovagal reaction, bradycardia and/or asystole, was preceded by abnormal EEG
findings when the patient complained of feeling a headache, photophobia, and
nausea. These findings suggest that cerebral hypoperfusion, such as with cerebral
vasospasms, before the onset of bradycardia might be involved in the mechanism of
neurally mediated syncope in patients with an aura.
PMID- 9558696
TI - Accidental entry of an implantable cardioverter defibrillator lead into the left
hepatic vein detected by transesophageal echocardiography.
AB - We report a case of accidental entry of an implantable cardioverter defibrillator
lead into the hepatic vein, which was not noted on fluoroscopy but was apparent
when transesophageal echocardiography (TEE) was used incidentally. The lead was
depicted in the hepatic vein as strongly echogenic, accompanied by an acoustic
shadow. Additional bending of the stylet was helpful for successful advancement
of the lead. TEE provides additional information in such cases, although
indications for its use should be explored because of its possible complications.
PMID- 9558697
TI - Transcoronary ethanol ablation of the atrioventricular node in a young patient
with tricuspid atresia.
AB - Catheter ablation of AV conduction with radiofrequency energy can be challenging
in the presence of structural abnormalities of the AV junction, either
congenitally or after reconstructive surgery. We used transcoronary ethanol to
ablate the AV node in a patient with classic tricuspid atresia and refractory
intraatrial reentry tachycardia. This approach provides an alternative means of
creating complete heart block with catheter-based techniques, when radiofrequency
catheter ablation is technically impossible or ineffective.
PMID- 9558698
TI - Lipoinjection as a treatment of pacemaker pocket neuralgia.
AB - Chronic severe pacemaker pocket neuralgia secondary to inadequate subcutaneous
tissue between the pacemaker and overlying skin typically is treated by surgical
pocket revision or relocation of the system. A case of this complication
successfully treated by lipoinjection is reported. Additional experience is
needed to confirm the usefulness of the technique as a means of providing
symptomatic relief without the risks associated with more invasive procedures.
PMID- 9558699
TI - Reposition of an implantable cardioverter defibrillator generator from an
abdominal pocket to a subpectoral location using the existing electrode.
AB - The size of today's implantable cardioverter defibrillator generators makes a
subpectoral position feasible even when an existing generator is located
abdominally. Elective replacement with reposition of the generator from an
abdominal to a subpectoral pocket without implantation of another electrode is
described.
PMID- 9558701
TI - 11 patients in whom atrial fibrillation was converted by a right atrial electrode
and a left pectoral patch.
PMID- 9558700
TI - Cerebral embolism due to a retained pacemaker lead: a case report.
AB - There are only a few reported cases of a pacemaker lead migrating inadvertently
into the left atrium or ventricle. An unusual complication of unremoved, unwanted
pacemaker lead is presented. The free tip of the lead caused cerebral embolism
after perforating the interatrial septum.
PMID- 9558702
TI - [How myosin works].
PMID- 9558703
TI - [The influence of myosin light chains and their function].
PMID- 9558705
TI - [Proteoglycans--structure and functions].
PMID- 9558704
TI - [Myotonic dystrophy--dynamic mutation and disease pathogenesis].
PMID- 9558706
TI - [Obesity genes].
PMID- 9558707
TI - [Bacterial transcription termination].
PMID- 9558708
TI - [CpG islands--the only unmethylated fragments of DNA in the vertebrate genome].
PMID- 9558709
TI - [Metabolism of phosphorylated derivatives of 8-oxo-2'-deoxyguanosine].
PMID- 9558710
TI - [Capillary electrophoresis: a new tool for biomolecule separation].
PMID- 9558711
TI - Stable isotope methodology for kinetic studies of interconversion of cortisol and
cortisone in a human subject.
AB - Oral administration of 5 mg each of deuterium-labeled cortisol ([1,1,19,19,19
2H5]cortisol, cortisol-d5) and cortisone-d5 ([1,1,19,19,19-2H5]cortisone) to a
human subject on two different occasions four weeks apart provided a useful means
of characterizing the kinetics of the interconversion of cortisol and cortisone.
From the data on plasma concentration measurements of cortisol-d5, cortisone-d5,
cortisone-5, endogenous cortisol and endogenous cortisone by gas chromatography
mass spectrometry, it was demonstrated that (1) the plasma concentration ratio of
cortisone-d5 to cortisol-d5 approached a plateau 4-5 h following either the
cortisol-d5 or cortisone-d5 administration and the plateau values for the
cortisone-d5 and cortisol-d5 administration were almost identical (about 0.43)
and (2) dosing with only 5 mg of the deuterium-labeled steroids suppressed the
plasma concentrations of endogenous cortisol and cortisone.
PMID- 9558712
TI - Synthesis of 6 beta-aminoestradiol and its biotin, acridinium, and fluorescein
conjugates.
AB - Amination of 3,17 beta-Bis[(2-trimethylsilylethoxy) methoxy]-1,3,5(10)
estratriene-6-one (2) using NaCNBH4 and NH4OAc afforded 3,17-bis(SEM)-6
aminoestradiol (3) as a mixture of alpha and beta-isomers in 60:40 ratio.
Hydrolysis of the mixture of 3 using HF and separation by preparative high
performance liquid chromatography afforded pure 6 beta-aminoestradiol (4) in good
yield. The relative stereochemistry of the amino group in 4 was established by
NMR. The biotinylated estradiol probe (7), chemiluminescent probe (9), and
fluorescent probe (11), were prepared from 6 beta-aminoestradiol (4) and the
corresponding biotin, 10-(3-sulfopropyl)-N-tosyl-N-(3-carboxypropyl)acridinium-9
carboxamide, and 5-carboxyfluorescein N-succinimidyl esters in 43-63% yields and
> 99% purity.
PMID- 9558713
TI - An unusual dienone-phenol rearrangement product formed during the synthesis of
mometasone furoate (Sch 32088).
AB - The structure of an unusual dienone-phenol rearrangement product 4 obtained
during the synthesis of mometasone furoate (Sch 32088) was assigned on the basis
of NMR and x-ray crystallographic data. The mechanism of formation is discussed.
PMID- 9558714
TI - Synthesis of new immunogens for estrone and estradiol-17 beta and antisera
evaluation.
AB - Syntheses of the 6 alpha-O-carboxymethyl ether derivatives of estrone and
estradiol-17 beta and the preparation of their bovine serum albumin conjugates
are described. The generation and evaluation of antisera produced from these
conjugates is discussed.
PMID- 9558715
TI - DNA polymorphism in B-domain of the estrogen receptor-alpha among Japanese women.
AB - A silent mutation in B-domain of the estrogen receptor-alpha (ER B) change codon
87 (from GCG to GCC) is clinically correlated with frequent spontaneous abortion
and familial history of breast cancer among Caucasian patients. However, none of
the 167 Japanese female patients and 46 Japanese female healthy volunteers showed
ER B variant. Therefore, this DNA polymorphism might involve a genetic racial
difference, and appears not to be correlated with frequent spontaneous abortion
or familial history of breast cancer at least among Japanese women.
PMID- 9558717
TI - Ergosteroids. II: Biologically active metabolites and synthetic derivatives of
dehydroepiandrosterone.
AB - An improved procedure for the synthesis of 3 beta-hydroxyandrost-5-ene-7,17
dione, a natural metabolite of dehydroepiandrosterone (DHEA) is described. The
synthesis and magnetic resonance spectra of several other related steroids are
presented. Feeding dehydroepiandrosterone to rats induces enhanced formation of
several liver enzymes among which are mitochondrial sn-glycerol 3-phosphate
dehydrogenase (GPDH) and cytosolic malic enzyme. The induction of these two
enzymes, that complete a thermogenic system in rat liver, was used as an assay to
search for derivatives of DHEA that might be more active than the parent steroid.
Activity is retained in steroids that are reduced to the corresponding 17 beta
hydroxy derivative, or hydroxylated at 7 alpha or 7 beta, and is considerably
enhanced when the 17-hydroxy or 17-carbonyl steroid is converted to the 7-oxo
derivative. Several derivatives of DHEA did not induce the thermogenic enzymes
whereas the corresponding 7-oxo compounds did. Both short and long chain acyl
esters of DHEA and of 7-oxo-DHEA are active inducers of the liver enzymes when
fed to rats. 7-Oxo-DHEA-3-sulfate is as active as 7-oxo-DHEA or its 3-acetyl
ester, whereas DHEA-3-sulfate is much less active than DHEA. Among many steroids
tested, those possessing a carbonyl group at position 3, a methyl group at 7, a
hydroxyl group at positions 1, 2, 4, 11, or 19, or a saturated B ring, with or
without a 4-5 double bond, were inactive.
PMID- 9558716
TI - Estrogen-dependent gene regulation by an oxidative metabolite of
diethylstilbestrol, diethylstilbestrol-4',4"-quinone.
AB - Diethylstilbestrol (DES) is a well-characterized carcinogen in humans and animals
although its mechanisms of carcinogenicity are not yet known. While the
estrogenic activity of DES is important, there is evidence that oxidative
metabolism also plays an important role for its toxicity. DES is oxidatively
metabolized in vivo and in vitro to a number of compounds including
diethylstilbestrol-4',4"-quinone (DQ), an unstable and reactive intermediate, and
Z,Z-dienestrol (ZZ-DIEN). Estrogen receptor (ER) binding assays with mouse
uterine cytosol indicate that DES, DQ and ZZ-DIEN have relative binding
affinities of 286, 3.6 and 0.3, respectively, relative to estradiol as 100. In
addition, DQ binds irreversibly and specifically to ER suggesting that DQ may be
biologically active despite its rapid metabolism and lower binding affinity
compared to DES. To test this, COS-1 cells were transfected with an estrogen
responsive reporter construct containing of VitA2 estrogen response element (ERE)
with or without an ER expression vector. In the presence of ER, treatments with
DES, DQ and ZZ-DIEN resulted in 11, 10, and 2-fold induction of chloramphenicol
acetyltransferase (CAT) activity, respectively. This induction was mediated by
estrogen receptor since it was suppressed by pretreatment with a 10-fold excess
of the pure antiestrogen ICI 182,780. These data indicate that DQ is a
biologically active intermediate that is capable of transactivation of estrogen
responsive genes through the ER. Furthermore, the data suggest that the ability
of DQ to irreversibly bind ER may result in persistent stimulation of ER. This
persistent stimulation may be related to the carcinogenicity of DES.
PMID- 9558718
TI - Synthesis and biological activity of 11,19-bridged progestins.
AB - A synthetic approach to 11,19-bridged progestins is described. The key step in
the synthesis is a 6-endo-trig radical cyclisation. The new progestins were
tested for their biological activities in vitro and in vivo and compared to those
of known progestins.
PMID- 9558719
TI - Integrating advanced laparoscopy into surgical residency training. Society of
American Gastrointestinal Endoscopic Surgeons (SAGES).
AB - SAGES was founded to further the advancement of surgeons performing
gastrointestinal endoscopy. In part due to the society's previous efforts,
training in flexible endoscopy is now recognized as a mandatory component of
training in general surgery. SAGES has more recently promoted the safe practice
of laparoscopic surgery, which since 1991 has evolved to be a standard component
of the practice of most general surgeons. Consistent with the goal of continuing
to provide the public with surgeons competent in performing all varieties of
appropriate laparoscopic procedures, SAGES joins other major surgical
organizations in addressing the concern that, while basic laparoscopic procedures
are mastered during residency training in general surgery, advanced procedures
and the skills required to initiate safely an experience in them often are not.
Incorporation of advanced laparoscopic surgical skills into surgical residency
and the safe incorporation and performance of advanced laparoscopic operations
into surgical practice are dynamic processes. With the above proposals, SAGES
hopes to facilitate both processes. We have, herein, set forth suggested
curriculum guidelines for resident training in laparoscopic surgery. We have
outlined measures by which resident and faculty training in advanced laparoscopic
surgical skills may be realized. Focusing on adequately training the trainers is
essential in order to facilitate residency training in the future. As practice
patterns evolve and the frequency of laparoscopic operations increases, the
opportunities for residents to learn required skills will increase. As a result,
they will be able to accomplish safely such procedures. In that setting, the
proposed special efforts outlined above may no longer be necessary.
PMID- 9558720
TI - Guidelines for granting of privileges for laparoscopic and/or thoracoscopic
general surgery. Society of American Gastrointestinal Endoscopic Surgeons
(SAGES).
PMID- 9558721
TI - Granting of privileges for gastrointestinal endoscopy by surgeons. Society of
American Gastrointestinal Endoscopic Surgeons (SAGES).
PMID- 9558722
TI - Obesity after genetic ablation of brown adipose tissue.
AB - Brown adipose tissue (BAT) has been proposed to play an important role in the
regulation of energy balance. The unique presence of uncoupling protein (UCP)
permits BAT to expend calories unrelated to the performance of work with the net
result being the generation of heat. The role of BAT in mediating diet-induced
thermogenesis had led to the suggestion that BAT activity contributes to
metabolic inefficiency and, as such, might provide a cellular and molecular
explanation for protection from obesity. In order to directly test this
hypothesis, we recently created mice with isolated BAT deficiency by using a
suicide DNA transgenic vector in which regulatory elements of the UCP gene were
used to drive brown fat specific expression of diptheria toxin A-chain (DTA).
Transgenic mice are characterized by reduced energy expenditure and marked
obesity, associated with insulin resistance and NIDDM with both receptor and post
receptor components. Feeding of a "Western diet" which derives 41% of its
calories from fat leads to a synergistic effect on the development of obesity and
its accompanying disorders in transgenics. The results of our studies support a
critical role for BAT in the nutritional homeostasis of mice and suggest that the
intact thermogenic function of BAT is required for protection from diet induced
obesity. Obese UCP-DTA mice have many features in common with obesity as it
appears in most humans, and should therefore be a useful model that may aid
studies of the pathogenesis and treatment of human obesity, NIDDM and their
complications.
PMID- 9558723
TI - Nutritional and hormonal regulation of the gene for malic enzyme.
AB - In vivo, refeeding starved chickens stimulates transcription of the avian gene
for malic enzyme in liver; in hepatocytes in culture, triiodothyronine (T3) and
insulin stimulate transcription of this gene. In vivo, starvation, and in
hepatocytes in culture, glucagon, medium-chain fatty acids (MCFA) and long-chain
fatty acids (LCFA) inhibit transcription of the malic enzyme gene. We have
defined a T3-response unit in the 5'-flanking DNA of the malic enzyme gene; it
contains one major T3 response element and several minor ones; maximum
responsiveness is dependent on the presence of all of these elements. LCFA
probably act by inhibiting binding of T3 to its nuclear receptor. MCFA appear to
act by a different mechanism. Inhibitory MCFA have chain lengths of six, seven or
eight carbons; a common feature of other inhibitory compounds is that they can be
metabolized to MCFA. Eight-carbon fatty acids with a hydroxyl on the 2- or 3
carbon are more potent inhibitors than octanoate, whereas 2-bromo-fatty acids and
2-hydroxy hexanoate are not inhibitory. In transfection experiments with a large
variety of constructs derived from the malic enzyme 5'-flanking DNA, the ability
of fatty acids to inhibit promoter function localizes to regions of DNA that
contain T3REs. Promoter function of artificial T3REs also is inhibited by MCFA.
Inhibition of promoter function using malic enzyme DNA is relatively constant in
magnitude irrespective of the size of the T3 response. We postulate that MCFA
directly regulates one of the functions of the T3 receptor.
PMID- 9558724
TI - Polyunsaturated fatty acid inhibition of fatty acid synthase transcription is
independent of PPAR activation.
AB - Polyunsaturated fatty acids (PUFA) of the (n-6) and (n-3) families inhibit the
rate of gene transcription for a number of hepatic lipogenic and glycolytic
genes, e.g., fatty acid synthase (FAS). In contrast, saturated and
monounsaturated fatty acids have no inhibitory capability. The suppression of
gene transcription resulting from the addition of PUFA to a high carbohydrate
diet: occurs quickly (< 3 h) after its addition to a high glucose diet; can be
recreated with hepatocytes cultured in a serum-free medium containing insulin and
glucocorticoids; can be demonstrated in diabetic rats fed fructose; and is
independent of glucagon. While the nature of the intracellular PUFA inhibitor is
unclear, it appears that delta-6 desaturation is a required step in the process.
Recently, the fatty acid activated nuclear factor, peroxisome-proliferator
activated receptor (PPAR) was suggested to be the PUFA-response factor. However,
the potent PPAR activators ETYA and Wy-14643 did not suppress hepatic expression
of FAS, but did induce the PPAR-responsive gene, acyl-CoA oxidase (AOX).
Similarly, treating rat hepatocytes with 20:4 (n-6) suppressed FAS expression but
had no effect on AOX. Thus, it appears that the PUFA regulation of gene
transcription involves a PUFA-response factor that is independent from PPAR.
PMID- 9558725
TI - RRR-alpha-tocopherol regulation of gene transcription in response to the cell
oxidant status.
AB - RRR-alpha-Tocopherol, but not RRR-beta-tocopherol, negative regulates
proliferation of vascular smooth muscle cells at physiological concentrations. At
the same concentrations RRR-alpha-tocopherol inhibits protein kinase C activity,
whereas RRR-beta-tocopherol is ineffective. Furthermore, RRR-beta-tocopherol
prevents the inhibition of cell growth and of protein kinase C activity caused by
RRR-alpha-tocopherol. The negative regulation by RRR-alpha-tocopherol of protein
kinase C activity appears to be the cause of smooth muscle cell growth
inhibition. RRR-alpha-Tocopherol does not act by binding to protein kinase C
directly but presumably by preventing protein kinase C activation. A second RRR
alpha-tocopherol effect has been found at the level of AP 1, the latter becoming
activated by RRR-alpha-tocopherol under condition of protein kinase C inhibition
or down regulation. AP-1 inhibition by RRR-alpha-tocopherol is seen, however,
under condition of protein kinase C stimulation. Compositional changes of AP-1
have been found to be at the basis of the RRR-alpha-tocopherol effects. RRR-beta
tocopherol, provided with similar antioxidant properties, not only it does not
affect AP 1 but it prevents the effects of RRR-alpha-tocopherol. Moreover, it has
been observed that RRR-alpha-tocopherol is able to affect TRE regulated gene
transcription. It is concluded that RRR-alpha-tocopherol acts specifically in
vascular smooth muscle cells, by controlling a signal transduction pathway
leading to cell proliferation by a non-antioxidant mechanism.
PMID- 9558726
TI - Effects of retinoids on gene expression in different epithelial models in vivo
and in vitro.
AB - We have previously reported that the induction of Vitamin A deficiency results in
a threefold decrease in the hepatic expression of cellular retinol binding
protein I (CRBP I) mRNA in vivo and that the treatment of intestinal cell lines
in vitro with retinoids leads to the induction of CRBP I transcription. In the
present paper we extend the analysis to retinoid-dependent gene expression in the
testicular epithelium in vivo and in the intestinal cell line FRIC B. In rat
testis excess Vitamin A results in the reduced production of mature spermatozoa
and in the premature release of immature germ cells in the lumen, while Vitamin A
deficiency leads to almost complete degeneration of the germinal epithelium. We
show reduced level of expression of CRBP I mRNA in vitamin A deficient testis.
Retinoid treatment of cultured intestinal cells, which induces a reorganization
of the actin cytoskeleton, has no effect on the expression of the differentiation
induced gene Dri 42. The results show that even though unable to trigger by
themselves the differentiation process, retinoids exert a direct effect on the
expression of specific genes.
PMID- 9558727
TI - Antioxidant modulation of cytokines and their biologic function in the aged.
AB - The oxidant/antioxidant balance is an important determinant of immune cell
function, including maintaining integrity and functionality of membrane lipids,
cellular proteins, nucleic acids, and for control of signal transduction and gene
expression in immune cells. Optimal levels of antioxidants are needed for
maintenance of the immune response across all age groups. This need might be more
critical, however, in the aged. Age-associated dysregulation of immune response,
particularly of cytokine production and T-cell-mediated function, is well
documented. The well-known age-related increase in free radical formation and
lipid peroxidation contributes, at least in part, to this phenomenon. This review
will summarize animal and human studies undertaken by the authors as well as
those by other investigators on the effect of antioxidants, vitamin E, beta
carotene, and glutathione on cytokine production and T-cell-mediated function in
the aged.
PMID- 9558728
TI - Interleukin-6 and related cytokines: effect on the acute phase reaction.
AB - The acute phase response is the answer of the organism to disturbances of its
physiological homeostasis. It consists of a local and a systemic reaction. The
latter is characterized by dramatic changes in the concentration of some plasma
proteins called acute phase proteins. Interleukin-6 (IL-6) has been identified in
vitro and in vivo as the major hepatocyte stimulating factor. Subsequently,
additional hepatocyte stimulating factors, such as leukemia inhibitory factor,
oncostatin-M, interleukin-11 and ciliary neurotrophic factor have been
discovered. IL-t and related cytokines belong to the so-called alpha-helical
cytokine family characterized by four antiparallel helices. IL-6 and IL-6-type
cytokines exert their action via plasma membrane receptor complexes consisting of
specific cytokine binding subunits and a common signal transducing protein gp130.
In this presentation we focus on structure/function studies of IL-6, its receptor
subunits gp80 and gp130, the internalization of the ligand/receptor complex and a
recently elucidated signal transduction pathway. We have shown that protein
tyrosine kinases of the JAK family are associated with the cytoplasmic domain of
gp130 and are activated in response to IL-6. Subsequently, the transcription
factors--named STATs (signal transducers and activators of transcription)--STAT1
alpha and STAT3 are transiently recruited to the cytoplasmic domain of gp130,
where they become tyrosine phosphorylated by JAK kinases. In addition to the
tyrosine phosphorylation we have observed that IL-6 also induces a serine
phosphorylation of STAT3. This modification occurs with a delayed time-course as
compared to the tyrosine phosphorylation and is inhibited by the protein kinase
inhibitor H7. We propose that the STAT3 serine phosphorylation is required for
transactivation of IL-6 target genes which is also inhibited by H7.
PMID- 9558729
TI - Selenium and immune function.
AB - Selenium (Se), an essential nutrient required for optimal growth of mammalian
cells, affects the immune functions of a host in vivo. Utilizing a mouse model
system and healthy human volunteers, we have shown that Se enhances the capacity
of lymphocytes to respond to stimulation with mitogen or alloantigen, to
proliferate, and to differentiate into cytotoxic effector cells. Supplementation
with Se resulted in a significant increase in the tumor cytotoxicity of mouse
cytotoxic lymphocytes, lymphokine activated killer cells and macrophages, and
human cytotoxic lymphocytes and natural killer (NK) cells. Se also appears to
abrogate the age-related deficiency of lymphocytes from an aged host to respond
to stimulation by proliferation and differentiation into cytotoxic effector
cells. These effects occurred in the absence of changes in the endogenous levels
of interleukin-1, interleukin-2, or interferon-gamma, and were related to the
ability of Se to enhance the expression of the alpha (p55) and/or beta (p70/75)
subunits of the interleukin-2 receptor (IL-2R) on the surface of activated
lymphocytes and NK cells. This resulted in a greater number of functional IL
2R/cell and in enhanced proliferation and clonal expansion of cytotoxic precursor
cells. The molecular mechanism that mediates the effects of Se on immune cell
function does not appear to be related to the function of Se as an antioxidant or
to gene activation.
PMID- 9558730
TI - Modulation of pro-inflammatory cytokine biology by unsaturated fatty acids.
AB - The production of pro-inflammatory cytokines, such as interleukins 1 and 6 and
tumour necrosis factors, occurs rapidly following trauma or invasion of the body
by pathogenic organisms. The cytokines mediate the wide range of symptoms
associated with trauma and infection, such as fever, anorexia, tissue wasting,
acute phase protein production and immunomodulation. In part, the symptoms result
from a co-ordinated response, in which the immune system is activated and
nutrients released, from endogenous sources, to provide substrate for the immune
system. Although the cytokine mediated response is an essential part of the
response to trauma and infection, excessive production of pro-inflammatory
cytokines, or production of cytokines in the wrong biological context, are
associated with mortality and pathology in a wide range of diseases, such as
malaria, sepsis, rheumatoid arthritis, inflammatory bowel disease, cancer and
AIDS. Cytokine biology can be modulated by antiinflammatory drugs, recombinant
cytokine receptor antagonists and nutrients. Among the nutrients, fats have a
large potential for modulating cytokine biology. A number of trials have
demonstrated the anti-inflammatory effects of fish oils, which are rich in n-3
polyunsaturated fatty acids, in rheumatoid arthritis, inflammatory bowel disease,
psoriasis and asthma. Animal studies, conducted by ourselves and others, indicate
that a range of fats can modulate pro-inflammatory cytokine production and
actions. In summary fats rich in n-6 polyunsaturated fatty acids enhance IL1
production and tissue responsiveness to cytokines, fats rich in n-3
polyunsaturated fatty acids have the opposite effect, monounsaturated fatty acids
decrease tissue responsiveness to cytokines and IL6 production is enhanced by
total unsaturated fatty acid intake. There are a large number of potential
cellular mechanisms which may mediate the effects observed. The majority relate
to the ability of fats to alter the composition of membrane phospholipids. As a
consequence of alterations in phospholipid composition, membrane fluidity may
change, altering binding of cytokines to receptors and G protein activity. The
nature of substrate for various signalling pathways associated with cytokine
production and actions may also be changed. Consequently, alterations in
eicosanoid production and activation of protein kinase C may occur. We have
examined a number of these potential mechanisms in peritoneal macrophages of rats
fed fats with a wide range of fatty acid composition. We have found that the
total C18:2 and 20:4 diacyl species of phosphatidylethanolamine in peritoneal
macrophages relates in a positive curvilinear fashion with dietary linoleic acid
intake; that TNF induced IL1 and IL6 production relate in a positive curvilinear
fashion to linoleic acid intake; that leukotriene B4 production relates
positively with dietary linoleic acid intake over a range of moderate intakes and
is suppressed at high intakes, while PGE2 production is enhanced. There was no
clear relationship between linoleic acid intake and membrane fluidity, however
fluidity was influenced in a complex manner by the type of fat in the diet, the
period over which the fat was fed and the presence of absence of TNF stimulation.
None of the proposed mechanisms, acting alone, can explain the positive effect of
dietary linoleic acid intake on pro-inflammatory cytokine production. However
each may be involved, in part, in the modulatory effects observed.
PMID- 9558731
TI - Beneficial effects of cytokine induced hyperlipidemia.
AB - Infection, inflammation and trauma induce marked changes in the plasma levels of
a wide variety of proteins (acute phase response), and these changes are mediated
by cytokines. The acute phase response is thought to be beneficial to the host.
The host's response to injury also results in dramatic alterations in lipid
metabolism and circulating lipoprotein levels which are mediated by cytokines. A
large number of cytokines including TNF, the interleukins, and the interferons
increase serum triglyceride levels. This rapid increase (1-2 h) is predominantly
due to an increase in hepatic VLDL secretion while the late increase may be due
to a variety of factors including increased hepatic production of VLDL or delayed
clearance secondary to a decrease in lipoprotein lipase activity and/or
apolipoprotein E levels on VLDL. In animals other than primates, cytokines also
increase serum cholesterol levels, most likely by increasing hepatic cholesterol.
Cytokines increase hepatic cholesterol synthesis by stimulating HMG CoA reductase
gene expression and decrease hepatic cholesterol catabolism by inhibiting
cholesterol 7 alpha-hydroxylase, the key enzyme in bile acid synthesis. Injury
and/or cytokines also decrease HDL cholesterol levels and induce alterations in
the composition of HDL. The content of SAA and apolipoprotein J increase,
apolipoprotein A1 may decrease, and the cholesterol ester content decreases while
free cholesterol increases. Additionally, key proteins involved in HDL metabolism
are altered by cytokines; LCAT activity, hepatic lipase activity, and CETP levels
decrease. These changes in lipid and lipoprotein metabolism may be beneficial in
a number of ways including: lipoproteins competing with viruses for cellular
receptors, apolipoproteins neutralizing viruses, lipoproteins binding and
targeting parasites for destruction, apolipoproteins lysing parasites,
redistribution of nutrients to cells involved in the immune response and/or
tissue repair, and lipoproteins binding toxic agents and neutralizing their
harmful effects. Thus, cytokines induce marked changes in lipid metabolism that
lead to hyperlipidemia which represents part of the innate immune response and
may be beneficial to the host.
PMID- 9558732
TI - Localization of somatostatin receptor subtype mRNA in the rat gastrointestinal
tract and regulation of SSTR1 gene expression.
AB - Somatostatin and its receptors are widely distributed in the central nervous
system and peripheral tissues including those of the gastrointestinal tract (GI
tract). The expression patterns of the five known SSTR genes have been analysed
in detail by reverse transcription polymerase chain reaction amplifications and
in situ hybridizations using tissues dissected from different parts of rat
stomach and gut. While SSTR1 mRNA is present at relatively high amounts
throughout the gastrointestinal tract, the levels of SSTR2, 3 and 4 mRNAs vary in
different regions and SSTR5 mRNA has not been detected. In situ hybridizations
revealed the presence of SSTR3 mRNA in enterocytes and in neurons of the
myenteric and submucous plexus. These findings are consistent with a role of
SSTR3 in the observed somatostatin-mediated inhibition of acetylcholine release
from myenteric neurons and of secretomotor neuron activity in the submucous
plexus. Sequence analyses of the SSTR1 gene promoter revealed the absence of the
canonical TATA and CAAT motifs and the presence of a variety of potential binding
sites for transcriptional regulators. Among these are binding sites for GCF, AP
2, AP-4, response elements for somatostatin (SOM-RE), epidermal growth factor
(EGF-RE) and cytocines (GAS and NFIL) as well as for tissue-specific factors such
as Pit-1 (pituitary) and IDX-1 (pancreatic cells). Mobility shift assays have
confirmed that nuclear proteins of pancreatic RIN1046-38 and pituitary GH3 tumour
cells bind to oligonucleotides containing the overlapping Pit-1 and IDX-1 binding
sites. Thus, the Pit-1/IDX-1 sites may be critical for the activation of the
SSTR1 gene in these cell-types.
PMID- 9558733
TI - Potential influence of increased sub-lethal UV-A irradiation on aquatic food
production (Aquaculture).
AB - In the tropics organisms have permanently adapted to deal with extremely high
intensities of light, temperature and other environmental factors. Especially in
coastal environments and fish farmings conditions can easily reach and exceed the
tolerance limits of an organism. The UV-A band has been shown to be a potent
modulator of light induced effects and general physiological functions in
organisms. The biological endpoints and underlying mechanisms still have to be
investigated. Our experiments were carried out with the easy to handle sub
tropical Convict-Cichlid fish (Cichlasoma nigrofasciatum) as a model organism. In
our studies we observed that constant sub-lethal UV-A irradiation had a
significant effect on the general metabolism and on the sensitivity towards other
environmental stress factors in this fish. We found that, in addition to the
depression of the general metabolism, sub-lethal UV-A irradiation in combination
with elevated environmental temperature had a deleterious effect on the
population. The threshold temperature for a sudden increase in mortality of the
fish receiving the additional sub-lethal UV-A irradiation was 32 degree C. The
fish were grown and adapted at 27-29 degrees C. A total of 78% of the fish
receiving an additional UV-A irradiation died by high temperature stress while
the reference population remained at a normal level (3%). The metabolic rate (MR)
of the UV-A survivors during temperature stress was less than half the average
value obtained in the reference population. After the environmental temperature
returned below the apparent upper tolerance limit for this fish, the MR of UV-A
population gradually increased to normal. Apparently a constant elevated sub
lethal dose of UV-A leads to the destabilization of an organism, making it more
sensitive for other environmental stress factors. These observations seem to be
important considerations in fish farming in the tropical and subtropical regions.
PMID- 9558734
TI - Regulation of the LDL receptor gene expression by hormones.
AB - Promoter activity of the LDL receptor gene is stimulated by insulin and estradiol
and mediated by SRE-1, which acts as a hormone sensitive cis-elemente. Using the
antisense technique we reveal that SREBP-1 is selectively involved in the signal
transduction pathway of insulin and IGF-I.
PMID- 9558735
TI - Influence of dietary fiber on DNA adduct formation in rat tissues.
AB - The occurrence of DNA-adduct-like indigenous compounds (I-compounds) was examined
in tissue samples of rats differing in their microbial state and diet with or
without pectins of different degrees of esterification (DE). For 21 days groups
of six germfree and ten conventional rats were each fed either pectin-free or
with diets containing 7.5% of three differently esterified pectin preparations
(pectin A: DE 92.6%; pectin B: DE 70.8%; pectin C: DE 34.5%). DNA was isolated
from colonic mucosa, liver, lung, kidney and measured by the highly sensitive 32P
postlabelling assay for DNA adduct analysis. In germfree animals I-compounds were
detected in all tissue samples after feeding the low-esterified pectin C. Under
the higher-esterified pectins, A and B, a weak adduct formation could be
demonstrated only in the liver, but not in the colonic mucosa, lung, and kidney.
In conventional animals DNA adducts were found in all samples of colonic mucosa
with the highest intensity in the control group, followed by the low-esterified
pectin C group, and a weak intensity under the higher-esterified pectins A and B.
The experiments show a tendency to a higher number and intensity of spots in the
germfree compared with the conventional rats, in rats with a pectin-free compared
with the pectin diet, and under the low-esterified compared with the higher
esterified pectins.
PMID- 9558736
TI - Pathobiochemical effects of graded magnesium deficiency in rats.
AB - Severe Mg deficiency changed mineral homeostasis, induced membrane damage,
increased lipid peroxidation and cytokine concentrations, and reduced
immunocompetence. In order to investigate whether the pathobiochemical effects
correlate directly with the degree of Mg deficiency or whether there might be a
threshold with no detectable effects above, diets with 70, 110, 208, 330 and 850
ppm Mg were fed to growing Wistar rats. After feeding the diets for 0, 10, 20 and
30 days parameters of free radical action (malondialdehyde and vitamin E
content), mineral content (Mg, Ca, Fe) in various tissues (liver, spleen, heart,
kidney, muscle) and plasma parameters (Mg, Ca, Fe, alanine- and aspartate
aminotransferase) were measured. After 30 days 6-keto-prostaglandin F1 alpha,
thromboxane B2, tumor necrosis factor-alpha, and immunoglobulins (IgG, IgM, IgA)
were additionally analyzed. Tissue Mg content was either unchanged or only
slightly reduced in severe Mg deficiency. Tissue Fe content rose when the
extracellular Mg concentration was below 0.25 mM. There was a close positive
correlation between tissue Fe and malondialdehyde content, and malondialdehyde
was negatively correlated with vitamin E content. Below a threshold of about 0.25
mM plasma Mg concentration, transaminases increased in plasma. The same threshold
could be observed for the increase of tissue Ca content, except in the kidney
where calcifications were found already in mild Mg deficiency. Tumor necrosis
factor-alpha and 6-keto-prostaglandin F1 alpha were increased when the plasma Mg
concentration was below 0.15 mM, and thromboxane B2 was increased when plasma was
lower than 0.25 mM. IgG and IgA were significantly reduced below 0.25 mM plasma
Mg and IgM below 0.4 mM plasma Mg. Mild Mg deficiency, therefore, can be
compensated and might not lead to pathological symptoms if not combined with
other pathobiological conditions.
PMID- 9558737
TI - Cosinor analysis of circadian oscillations of amino acid catabolizing enzymes in
temporal pattern of nutrient input.
AB - Circadian oscillations of liver tyrosine aminotransferase (TAT) tryptophan
oxygenase (TO), alanine aminotransferase (ALAT), aspartate aminotransferase
(ASAT), and glutamate dehydrogenase (GLDH) in temporal pattern of protein input
have been investigated. Cosinor analysis of oscillations parameters revealed the
glucocorticoid induction of TO activity and protein induction of TAT activity
rhythm. ALAT, ASAT, and GLDH activities showed 24 h fluctuations, but the
regulation mechanisms remain unclear.
PMID- 9558738
TI - Anti-gliadin and anti-endomysium antibodies in children with celiac disease
consuming a gluten free diet.
AB - A group of 26 children (13 boys and 13 girls; average age 12.2 years) with CD who
had been on a gluten free diet for 5-15 years was examined in order to find out
how effectively they could manage their diet. The diagnosis of CD was established
on the basis of ESPGAN criteria (1969). 5-15 years ago. Antigliadin antibodies,
IgG-, and IgA-AGA (by fluorescence enzyme immunoassay), Gliastick by ELISA
technique, and Anti-endomysium antibodies (by indirect immunofluorescence on
sections of monkey esophagus) were examined in the serum. Only 5 patients had no
antigliadin or anti-endomysium antibodies. In 21 cases the IgG-AGA showed
positive results; the IgA-AGA was positive in 6, the Gliastick in 19, and the
anti-endomysium antibodies in 8 cases. The main cause of the mismanagement of the
diet was inadequate food labeling; so it seems to be important to also establish
a Food Intolerance Data Bank in Hungary. The 5 sero-negative children volunteered
for a gluten challenge; 3 of them became positive in a few weeks or months. Two
patients remained negative even after 1 year. Their gluten sensitivity may not
prove to be permanent.
PMID- 9558740
TI - Attempt to differentiate between individual glutathione peroxidases in biological
samples.
AB - Routine determinations of glutathione peroxidases (GPx) still suffer from poor
standardization and usually from lack of specification. The different types of
glutathione peroxidases present in cellular homogenates may be differentially
estimated by their distinct substrate specificities. Complex lipid hydroperoxides
required for this approach, however, are not generally available nor easily
standardized due to their molecular heterogeneity and tendency to form micelles.
We therefore developed a simple procedure for the differential estimation of the
major cellular types of GPx, the cytosolic GPx (cGPx) and the phospholipid
hydroperoxide glutathione peroxidase (PHGPx) taking advantage of the peculiar
susceptibility of PHGPx to deoxycholate. It proved to reliably determine the
activities of both purified cGPx and PHGPx, in mixtures thereof, and in
homogenates of tissue samples (e.g., testes), and some (e.g. ECV 304) but not all
(e.g. THP-1) cultured cell lines. The method allows the differential estimation
of cGPx and PHGPx, if the samples do not contain further types of GPx.
PMID- 9558739
TI - Parenteral selenium supplementation in critically ill patients--effects on
antioxidant metabolism.
AB - Decreased plasma selenium (Se) levels are common in critically ill patients.
Oxidative stress is regarded as one possible cause of the Se deficiency. We
investigated in 20 critically ill patients with decreased plasma selenium
concentrations the antioxidant metabolism during parenteral selenium
supplementation (week 1: 2 x 500 micrograms; week 2:1 x 500 micrograms, week 3:3
x 100 micrograms sodium selenite). As marker of oxidative stress we measured the
plasma malondialdehyde levels on days 0, 1, 3, 7, 14, and 21. The content of
reduced and oxidized glutathione as well as the leucocyte activity marker
elastase were estimated on the same days. Initial plasma Se levels were
considerably decreased (0.44 +/- 0.1 mumol/l, mean +/- SEM). After one day of
supplementation Se concentrations were in the reference range. Plasma
malondialdehyde levels and the ratio of oxidized and reduced glutathione were
initially elevated and decreased beginning on day 3 of supplementation. The mean
elastase level was 113 +/- 10 micrograms/l on day 0. On day 3 elastase values
decreased significantly (85 +/- 13 micrograms/l, p < 0.05; day 21, 19 +/- 7
micrograms/l, p < 0.001). Antioxidant metabolism showed significant changes
beginning after 72 hours of therapy. This latency may be explained with the
induction of the enzyme glutathione peroxidase. The lowered plasma Se
concentrations measured in the critically ill patients and the significant
effects on antioxidant metabolism during supplementation emphasized the
importance of selenium administration in these patients.
PMID- 9558741
TI - Test system for quantification of stop codon suppression by selenocysteine
insertion in mammalian cell lines.
AB - A convenient test system was designed to investigate the efficiencies of
selenocysteine inserting sequences (SECIS) responsible for the cotranslational
incorporation of selenocysteine into selenoproteins of mammals. It comprises an
expression vector in which the lacZ and luc genes are separated by an in-frame
TGA stop codon. The coding regions are followed by a multicloning region allowing
exchange of putative SECIS elements. Stop codon suppression associated with
selenocysteine incorporation is readily estimated on the basis of relative
luciferase activity measurements, thus providing a measure of SECIS efficiency.
PMID- 9558742
TI - Probing the presumed catalytic triad of a selenium-containing peroxidase by
mutational analysis.
AB - Glutathione peroxidases (GPx) are characterized by a catalytically active
selenium which forms the center of a strictly conserved triad composed of
selenocysteine, glutamine, and tryptophan. In order to check the functional
relevance of this structural peculiarity, six molecular mutants of phospholipid
hydroperoxide glutathione peroxidase (PHGPx) were designed, isolated, and
investigated kinetically. Replacement of the selenocysteine in position 46 by
cysteine decreased k + 1, i.e., the reaction rate of reduced enzyme with
hydroperoxide, by three orders of magnitude. The rate of regeneration of the
reduced enzyme by glutathione (k' + 2) was similarly affected. Additional
substitution of Gln81 or Trp136 by acid residues resulted in a further decrease
of k + 1 by three orders of magnitude, whereas histidine or neutral residues in
these positions proved to be less deleterious. The data support the hypothesis
that the typical triad of selenocysteine, glutamine, and tryptophan is indeed a
novel catalytic center in which the reactivity of selenium is optimized by
hydrogen bonding provided by the adjacent glutamine and tryptophan residues.
PMID- 9558743
TI - Plasma arachidonic acid and serum thromboxane B2 concentrations in
phenylketonuric children are correlated with dietary compliance.
AB - Phenylketonurics display lower arachidonic acid levels in plasma lipids,
reflecting the lower intake due to the dietary treatment poor in phenylalanine
rich animal foods. Plasma arachidonic acid levels and serum thromboxane B2
concentrations have been measured in 13 treated phenylketonuric children and
compared with those of 12 healthy controls. A direct relationship between plasma
arachidonic acid and thromboxane B2 concentrations has been observed only in
phenylketonurics, whose plasma arachidonic acid status correlated negatively with
their dietary compliance. These results suggest that the low consumption of
animal fats may contribute to modulate the production of arachidonic acid-derived
platelet eicosanoids.
PMID- 9558745
TI - Fruit: comparisons of attitudes knowledge and preferences of primary school
children in England and Germany.
AB - Primary school children's fruit consumption and attitudes, knowledge and
preferences towards fruit were investigated using interview techniques in schools
in England (Nottinghamshire) and Germany (North East) and analysed on the basis
of culture, sex and social class. Children from both countries had strong
positive attitudes to increase fruit consumption and differed little in their
ability to correctly identify five fruits (including tropical fruits). Fruit
preferences also showed many similarities with more than 95% of children from
both Germany and England choosing apples as fruits they liked, followed closely
by strawberries, oranges, pears, grapes, and bananas. Fruit consumption by German
children was, however, higher than English children both at breakfast and during
the school break. Strategies for increasing fruit consumption in English children
are discussed in relation to the findings obtained.
PMID- 9558744
TI - Clinical application of the polyunsaturated n-3 fatty acids usage in pediatric
practice.
AB - The investigation of the effectiveness of a diet supplemented with n-3 PUFA in
children with glomerulonephritis was done. Patients receiving "Polyen" achieved
better clinical remission, more rapid decrease of hypercholesterolemia, and
hypercoagulation than the patients from the control group. We can recommend
"Polyen" usage in the treatment of glomerulonephritis in children.
PMID- 9558746
TI - Lipid status in adolescents born with low birth weight.
AB - The study compared anthropometric parameters and lipid status of adolescent boys
and girls (14-16 y) born with LBW or ABW. Values for body weight and height of
LBW adolescents were lower than those for ABW's. BMI differed significantly
between LBW and ABW boys. In LBW boys, serum LDL-C level was somewhat lower, and
the ApoA1 concentration was higher than in ABW's. Other lipid parameters did not
differ among the corresponding groups. These data suggest that
hypercholesterolemia, which is seen in LBW adults, must develop in older ages,
and the irregular lifestyle including improper nutritional habits may promote its
occurrence in this vulnerable group.
PMID- 9558747
TI - Some data on the prevalence of obesity in Hungarian adult population between 1985
88 and 1992-94.
PMID- 9558748
TI - Study of nutritional behavior in a group of Lithuanian men.
AB - Nutritional status of men, aged 50, which is considered as a high risk group for
noncommunicable heart diseases was investigated. The study showed that the
chemical composition of diet could be considered as a risk factor for
cardiovascular diseases. This diet is too rich in simple sugars and fats,
especially of animal origin, and poor in complex sugars and antioxidants.
PMID- 9558749
TI - Effect of dietary fish oil on fecal bile acid and neutral sterol excretion in
healthy volunteers.
AB - Diet-induced increases in fecal excretion of secondary bile acids (deoxy- and
lithocholic acid) and certain neutral sterols (4-cholesten-3-one and 5a-cholestan
3-one) play a role in colon cancer development, whereas dietary fish oil (FO) has
been implicated as a protective agent. In the present study the effects of FO and
corn oil (CO) on these fecal parameters were investigated in 12 healthy
volunteers consuming a low fat (30% of energy) controlled basal diet. After 4
weeks of FO supplementation (4.4 g omega-3 fatty acids/day), daily excretion of
lithocholic acid showed a trend to lower values compared to CO consumption (p =
0.2), whereas other bile acids were not different during both study periods.
Daily excretion of the putative colon carcinogen 4-cholesten-3-one was
significantly lower in the FO compared to the CO period. This may be another
biochemical mechanism by which FO exerts its protective effect on colon cancer
development.
PMID- 9558750
TI - The changes of lymphocyte membrane receptors in bronchial asthma and atopic
dermatitis in pediatric patients receiving treatment with polyenic fatty acids.
AB - The influence of a diet supplemented with n-3 PUFA on the immune status of
children with atopic dermatitis and asthma was investigated. The results of the
investigation have shown the improvement of cell immunity along with a decrease
in the clinical manifestation of the disease. n-3 PUFA could be used as
immunocorrectors in combination with pathogenic treatment of children with
allergic diseases.
PMID- 9558751
TI - Coexistence of multiple periodic and chaotic regimes in biochemical oscillations
with phase shifts.
AB - The numerical study of a glycolytic model formed by a system of three delay
differential equations reveals a multiplicity of stable coexisting states:
birhythmicity, trirhythmicity, hard excitation and quasiperiodic with chaotic
regimes. For different initial functions in the phase space one may observe the
coexistence of two different quasiperiodic motions, the existence of a stable
steady state with a stable torus, and the existence of a strange attractor with
different stable regimes (chaos with torus, chaos with bursting motion, and chaos
with different periodic regimes). For a single range of the control parameter
values our system may exhibit different bifurcation diagrams: in one case a
Feigenbaum route to chaos coexists with a finite number of successive periodic
bifurcations, in other conditions it is possible to observe the coexistence of
two quasiperiodicity routes to chaos. These studies were obtained both at
constant input flux and under forcing conditions.
PMID- 9558752
TI - Do MTS have the function of message transmission?
AB - Structurally, microtubules (MTs) are composed of protofilaments of the subunit
protein. They are prominent components of the cytoplasmic matrix and perform
important functions as cytoskeletal elements for the determination of cell shape
and as key elements in intracellular motility such as mitosis and the
translocation of cell organelles. These functions are thought to depend on the
controlled assembly and disassembly of MTs in the cytoplasm and on the
interaction of MTs with each other and with other cytoplasmic components. I think
that apart from these cellular functions. MTs have the function of message
transmission. Although no direct evidence is available to explain this point at
present, a number of indirect evidences have been obtained by many scientists
e.g.: brain tissue has circumstantial the highest tubulin concentration, MTs have
the property of self-assembly and disassembly, microtubule(MT) network is a key
factor in differentiation of plant cells.
PMID- 9558753
TI - Community perception on OPD performance of a teaching hospital in Gondar town.
AB - Among 2605 heads of households interviewed in Gondar Town, 1,099 (42%) had
visited the Out Patient Department of the Gondar College of Medical Sciences
Hospital during the past one year. Of these, 856 (78%) were dissatisfied with the
services. The pharmacy was perceived as the worst unit of the Department. Among
the 1,042 visitors who had gone to the pharmacy, 76% were unable to buy all the
drugs prescribed by the physicians. The outcome of treatment as perceived by the
visitors were 671 (61%) improved and 71 (7%) died at home after seeking
consultation at the OPD. Mechanisms of improving hospital performances such as
greater community participation and improved management system are suggested.
PMID- 9558754
TI - Persistent diarrhoea: socio-demographic and clinical profile of 264 children seen
at a referral hospital in Addis Ababa.
AB - Acute diarrhoea is a major public health problem in Ethiopian children under five
years of age. Reports for other developing countries indicate that persistent
diarrhoea is emerging as an important cause of mortality and morbidity in this
age group. Little is, however, known about the extent of the condition in our
setting. The socio-demographic and clinical characteristics of children with
persistent diarrhoea seen at a teaching hospital in Addis Ababa over an 18-month
period is presented. Of 5,762 children with all forms of diarrhoea seen during
the study period 264 (5%) had persistent diarrhoea. Most of the children (83%)
were below 18 months of age and the peak occurrence was between the ages of seven
and 12 months. The majority (86%) of the patients had associated malnutrition and
83% of the infants under four months of age were either fully or partially
weaned. Watery diarrhoea with no dehydration was the main clinical feature.
Nearly 7% of the patients had dysentery. Average family income was low and
parental literacy level seem to have had no effect. It is suggested that
breastfeeding and appropriate weaning practices be strongly promoted. Further
work is proposed in order to determine the magnitude of the problem and identify
the risk factors associated with the disease, including the unfavourable child
and family unit characteristics and care seeking behaviours.
PMID- 9558755
TI - Neonatal sepsis in Addis Ababa, Ethiopia: a review of 151 bacteremic neonates.
AB - A retrospective study of 542 neonatal sepsis cases was undertaken. Bacteremia was
confirmed in 151 cases. There were a total of 195 (36%) deaths. Fifty nine (39%)
of the deaths were from the bacteremia cases. The incidence of sepsis was 11 per
1000 live births. Klebsiella was the leading etiologic agent (38%), with a
mortality rate of 54%. Low birth weight was found to be a predisposing factor for
the development of sepsis and mortality. The high incidence of sepsis, the
increase in mortality rate and the spread of nosocomial infection is discussed.
PMID- 9558756
TI - Klebsiella oxytoca outbreak at the Ethio-Swedish Children's Hospital (ESCH).
AB - Klebsiella oxytoca outbreak at the Ethio-Swedish Children's Hospital, is
described. The organism was isolated for the first time on Oct. 1992 at the
emergency room and subsequently spread to all wards including the neonatal unit
of the hospital. The isolates were resistant to Ampicillin, Amoxicillin,
Chloramphenicol, Co-trimoxazole and Gentamicin, but sensitive to Amikacin and
ceftriaxone. Eighty six percent (182) of the isolates were from blood specimen.
Nine out of ten suspected intravenous infusion bags were positive for Klebsiella
oxytoca. The source of this nosocomial infection and possible control measures
are discussed.
PMID- 9558757
TI - AIDS related knowledge and behaviours among college students, Gondar, Ethiopia: a
comparative study.
AB - AIDS-related knowledge and behaviours among students at the Gondar College of
Medical Sciences, Gondar, Ethiopia were evaluated based on identical surveys
conducted in 1990 and 1992. One hundred three second year students provided
information in 1992. Analysis indicated that 49% were engaged in sexual
intercourse and only a third of these group used condom despite their improved
knowledge and belief on condom compared to their previous position in 1990 (p <
0.004). On the other hand, their sexual behaviours regarding sexual contact with
high risk individuals decreased compared to 1990 (p < 0.0005). Their general
level of AIDS-related preventive knowledge increased over time (p < 0.002),
although there was no significant difference in knowledge observed among
different sexes and departments. Among the sexually active, a large proportion of
students (22%) still had sexual contact with high risk individuals and only 33%
of them were using safer methods. Continuing efforts, including peer education,
specific health education interventions are still crucially needed to bring a
positive change in sexual behaviour.
PMID- 9558758
TI - Behcets' disease: a case report.
AB - A 20 year old male patient presented with recurrent panuveitis associated with
painful buccal and genital ulcers, subcutaneous nodules and pustules
(dermatographia) on the trunk, and positive pathergy (skin hypersensitivity to
needle pricks) test. Laboratory examinations were nonrevealing except for a
minimal rise in ESR. This patient meets the criteria set by James and Spiteri for
Bechets' Disease. This disease and its prognosis is discussed. Early recognition
and treatment of this blinding and potentially fatal disorder is emphasised.
PMID- 9558759
TI - The importance of the maxillary sinuses in facial development: a case report.
AB - A case of mandibular asymmetry is presented. It appears that in this patient the
mandible was adapted to changes in the maxillary sinus area. Abnormal bone growth
of unknown aetiology inside the sinus most likely caused complete remodelling in
the maxillary sinuses and asymmetry of the mandible. Special tests used for
detailed assessment of the patient supported the definitive diagnosis.
PMID- 9558760
TI - Treatment changes in Class I and mild Class II malocclusions using the en masse
removable appliance.
AB - The aim of this retrospective study was to examine the dental changes which
occurred during buccal segment retraction in 39 subjects considered suitable for
treatment with headgear to the maxillary dentition. Initially, a removable en
masse appliance was fitted to distalize the buccal segments. Once the molar
relationship was corrected, fixed appliances were placed for upper arch
consolidation and/or alignment. Only five subjects required lower appliance
therapy. Twenty-nine individuals had upper second molars extracted as an adjunct
to treatment: in the remaining 10 patients these teeth were left in situ.
Corresponding lower second molars were extracted in 19 children, whilst 20 pairs
of teeth were not removed. Measurements were made at the start of treatment, the
completion of buccal segment retraction, and when active treatment was complete.
After the first stage, molars and premolars had been retracted nearly 4 mm,
whilst the canines showed 2 mm spontaneous distal drift. The inter-molar width
had increased by 4 mm and arch perimeter by 5 mm. There was a 5 per cent
reduction in crowding. Spontaneous changes were also seen in the lower arch,
despite the absence of any therapy. Crowding was slightly improved and inter
molar width increased, apparently as a response to the expansion in the opposing
jaw. At the end of treatment, upper arch retraction and expansion were reduced as
the teeth were integrated with the lower dentition: the canines required less
than 1 mm further retraction. In the lower arch, the expansion of the molars was
essentially stable. The extraction of upper second molars did not appear to
influence the outcome of treatment. Although slightly more movement appeared to
occur in the extraction group, few measurements showed statistical significance.
PMID- 9558761
TI - Dental changes in the mandible during initial Bass appliance therapy.
AB - The aim of this study was to analyse movements of lower molars and incisors
during 6 months of Bass appliance therapy and to evaluate the dental arch space
attained. The sample consisted of 53 patients with severe Class II, division 1
malocclusions. The analyses were performed on lateral cephalograms and dental
casts. Sixteen of the patients were followed for 6 months before treatment.
Dental space in the lower jaw decreased 0.7 mm (n = 16) during the observation
period and increased 1.8 mm (n = 53) during the 6 months of treatment. The molars
moved posteriorly a total of 0.7 and tipped distally 2.4 degrees during
treatment. The incisors moved anteriorly 0.3 mm and tipped mesially 0.5 degree.
PMID- 9558762
TI - Soft and hard tissue changes in Class III patients treated by bimaxillary
surgery.
AB - A cephalometric study of 17 non-growing dentate Class III subjects treated by
bimaxillary surgery was undertaken to assess the results of treatment and to
evaluate the correlation between soft and hard tissue change. It was concluded
that: (i) the orthognathic profiles achieved were brought about by a combination
of maxillary advancement and mandibular setback; (ii) a strong correlation in the
horizontal direction occurred between all the selected landmarks of the lower lip
and chin, but only between superior labial sulcus and point A in the upper lip;
highest intra-group correlations were seen between corresponding soft and hard
tissue points; the ratios of soft tissue to corresponding hard tissue movements
in lower lip and chin approached 1:1; (iii) in the vertical direction, a strong
correlation occurred in the lower lip and chin; highest intra-group correlations
were not necessarily with corresponding landmarks; and (iv) vertical movement of
landmarks on the nasal base and upper lip generally showed poor or weak
correlation with corresponding soft tissue points. The most reliable hard tissue
predictors of horizontal and vertical soft tissue change are tabulated for
application in bimaxillary surgery for the Class III patient.
PMID- 9558763
TI - A proportional analysis of some facial height and depth variables in 10 to 16
year old children.
AB - A method for analysing the horizontal and vertical proportions of the face is
described, based on natural head orientation (NHO). It demonstrates how
individual deviations from the mean proportions can be quantified both
horizontally and vertically. Correlation between facial depth to height (index 1)
and the mandibular plane angle was determined and found to be fairly strong and
highly significant (r = 0.5, P < 0.001). Facial depth to height and lower facial
height to total facial height (index 2) relationships were found to be strongly
correlated at each age between 10 and 16 years, with only small mean differences.
For this reason the norm values presented for 12-year-old children for indices 1
and 2 should be applicable to orthodontic patients within this age range. The
relationship between mandible and maxilla (index 3) increases continually between
10 and 16 years in boys, and between 10 and 14 years in girls, about 0.3 units a
year. It can provide supplementary information for individual case analysis. For
boys the increase was 2.2 units per year between 14 and 16 years of age.
PMID- 9558764
TI - Eruption of premolars subsequent to autotransplantation. A longitudinal
radiographic study.
AB - One-hundred-and-eighteen premolars transplanted at a stage with 3/4 to 4/4 root
development with an open apical foramen were followed using a standardized
clinical and radiographic technique for signs of periodontal ligament healing,
root development, and tooth eruption. Root growth was unimpeded in 26 per cent,
impaired in 55 per cent, and arrested in 19 per cent. Eruption of transplants
occurred at the time of periodontal and alveolar healing, and before any
significant root growth. Furthermore, autotransplanted premolars created growth
of the alveolar process along with the eruption process.
PMID- 9558765
TI - Early radiographic diagnosis of apical root resorption during orthodontic
treatment: a study of maxillary incisors.
AB - The purpose of this study was to evaluate the sensitivity of digital radiographs
for detection of (i) simulated root resorption cavities in an experimental model
and (ii) orthodontically-induced apical root resorption in vivo. The severity of
root resorption after 3 and 6 months treatment was studied in relation to root
form. The experimental study cavities, drilled in mandibular roots in a dry
skull, were recorded in conventional and digital radiographs. In vivo root
resorption was evaluated on digital radiographs of 92 maxillary incisors after 3
and 6 months treatment with fixed appliances. The results showed a similar
sensitivity for the two methods. Sensitivity increased significantly with cavity
size. After 3 months apical root resorption was detected in only a few teeth. The
number had increased significantly after 6 months. There was a higher degree of
root resorption in teeth with blunt and pipette-shaped apices. In such teeth a 3
month radiographic control is recommended.
PMID- 9558766
TI - The relationship between irregularity of the incisor teeth, plaque, and
gingivitis: a study in a group of schoolchildren aged 11-14 years.
AB - The relationship between irregularity of teeth and periodontal disease was
investigated in 201 children aged 11-14 years. The upper and lower incisor teeth
were assessed for spacing, labio-lingual displacement, and mesiodistal overlap at
each of the six contact areas. Plaque and gingivitis were assessed at six sites
on each of the four upper and four lower incisor teeth. There was evidence for a
direct relationship between the number of contact areas with tooth displacement
combined with overlap and the number of sites with gingival redness (R = 0.25, P
< 0.001), bleeding (R = 0.18, P < 0.01), and profuse bleeding (R = 0.25, P <
0.001). There was no evidence for a relationship between labio-lingual
displacement alone and gingivitis. One-hundred-and-twenty-eight subjects without
tooth displacement combined with incisor overlap had, respectively, 34, 15, and
35 per cent fewer sites with redness (P < 0.01), bleeding (P < 0.05), or profuse
bleeding (P < 0.01) than the 73 subjects with overlap. The statistical
significance of these differences was unaffected by covariate adjustment to take
account of the effect on gingivitis of variation in the number of sites with
plaque. There was no evidence of a relationship between incisor overlap and
amount of plaque in these subjects. The results indicate that overlapping of
incisor teeth is directly related to gingivitis and this relationship cannot be
explained simply by an effect on oral hygiene.
PMID- 9558767
TI - Dental maturation in subjects with extreme vertical facial types.
AB - The purpose of this research was to investigate whether there is a difference in
dental maturation between skeletal open bite and skeletal deep bite subjects of
the same chronological age. The material consisted of 40 lateral headfilms and 40
panoramic radiographs of 20 male and 20 female white subjects, with a mean
chronological age of 9 years and 2 months (range: 7 years 6 months to 10 years 11
months). These subjects were selected on the basis of lower anterior face height
as a percentage of total face height and on the amount of open or deep-bite from
a total sample of 400 subjects. The persons exhibiting the most extreme values at
both ends of the distribution were selected to create two groups with 20 subjects
in each (10 males and 10 females). Thus, the groups represented subjects with
either a large lower anterior face height associated with an open bite or a small
lower anterior face height associated with a deep bite. A double blind
determination of dental maturation, expressed by dental age, for each subject was
performed on the panoramic radiographs using the system of Demirjian et al.
(1973). A covariance analysis was used to eliminate variability introduced by the
large age range of the sample. The skeletal open bite and deep bite groups
presented mean dental ages of 120.48 and 114.00 months, respectively. Statistical
analysis demonstrated that this difference was statistically significant at P <
0.05. Therefore, it seems that skeletal open bite subjects presented a slight
tendency to have an advanced dental maturation, expressed by dental age, as
compared with skeletal deep bite subjects.
PMID- 9558768
TI - Surface roughness of orthodontic wires via atomic force microscopy, laser
specular reflectance, and profilometry.
AB - The surface roughness of orthodontic archwires is an essential factor that
determines the effectiveness of arch-guided tooth movement. Using the non
destructive techniques of atomic force microscopy (AFM) and of laser specular
reflectance, the surface roughness of 11 nickel-titanium orthodontic wires, a
stainless steel and a beta-titanium wire was measured. The results were compared
with those obtained using surface profilometry. The smoothest wire, stainless
steel, had an optical roughness of 0.10 micron, compared with 0.09 micron from
AFM and 0.06 from profilometry. The surface roughness for the beta-titanium wire
measured by all three methods was approximately 0.21 micron, while that of the
NiTi wires ranged from 0.10 to 1.30 microns. As the surface roughness not only
affects the effectiveness of sliding mechanics, but also the corrosion behaviour
and the aesthetics of orthodontic components, the manufacturers of orthodontic
wires should make an effort to improve the surface quality of their products.
PMID- 9558769
TI - Morphological aspects of the mid-palatal suture in the human foetus: a light and
scanning electron microscopy study.
AB - Morphological features of the mid-palatal suture were studied in human foetuses
from 4 to 9 months of intra-uterine life. The foetuses were divided into three
age groups, GI (16-23 weeks), GII (24-31 weeks) and GIII (32-39 weeks). The mid
palatal suture in GI foetuses is rectilineal in form with a wide space between
the palatal processes of the maxilla. The suture has a sinuous nature in GII and
GIII foetuses due to growth of the bone processes crossing the mid-line. A wide
zone of cellular proliferation observed in GI narrows in GII and GIII foetuses.
The imbricating nature of the suture in GII and GIII is caused by bone growth
adjacent to the mid-palatal suture. Sharpey's fibres, emerging from the bone
processes, run to the median region of the mid-palatal suture and are observed
from GI foetuses onwards. The collagen fibres of the mid-palatal suture are
orientated transversely under the oral epithelium and exhibit a regular meshwork
with a predominance of sagittal fibres in the median region of the suture. These
fibres are orientated transversely and obliquely at the junction with the nasal
septum.
PMID- 9558770
TI - Helicobacter-related diseases today.
PMID- 9558771
TI - Seat-belt injuries to the supra-aortic trunks.
AB - Five seat-belt related injuries to the supra-aortic and cervical vessels
occurring in four patients are reported. All patients but one were symptomatic,
none presented with stroke, and in one case arterial lesion was revealed by
delayed onset of symptoms. Outcome of surgical treatment was overall good.
Systematic search of such injuries and surgical repair of those without major
neurological signs might be advisable.
PMID- 9558772
TI - Immediate TRAM flap breast reconstruction in an obese patient with relapsing
benign phyllodes tumor: report of a case.
AB - The authors present a case of relapsing benign phyllodes cystosarcoma of the
breast in an obese female treated with a simple mastectomy and an immediate
reconstruction using a bipedicled transverse rectus abdominis musculocutaneous
(TRAM) flap. After a brief review of treatment options for phyllodes tumors, they
discuss the advantages of TRAM flap breast reconstruction, suggesting that it may
also be applied in obese patients.
PMID- 9558773
TI - A case of pediatric systemic lupus erythematosus with early onset and unusual
serologic and clinical findings.
AB - The authors report on a case of Pediatric Systemic Lupus Erythematosus (SLE) in a
female child aged 3 1/2 with a set of peculiar clinical and serologic
characteristics; early onset of the disease, non-specific clinical signs, high
serum levels of IgG and a clinical course characterized by the absence of renal
neurological and articular involvement.
PMID- 9558774
TI - Rifaximin and Helicobacter pylori eradication.
AB - In this study, we tested the effectiveness of Rifaximin, a surface antibiotic
which is not absorbed when given orally, in the eradication of Helicobacter
pylori (HP). The drug was combined in triple therapy either with Amoxicillin and
Omeprazole or with Erythromycin-ethylsuccinate and Omeprazole. Twenty-three
patients complaining of dyspeptic symptoms and gastric infection due to HP were
evaluated. The patients were randomly given one of the following therapeutic
protocols: Rifaximin susp. 600 mg/day x 3/day (at least two hours after meals:
10:00 am, 2:00 pm, 9:00 pm), Amoxicillin tab. 1 g x 2/day (at least two hours
after meals: 10:00 am, 9:00 pm), Omeprazole tab. 40 mg/day (in the morning before
breakfast) (protocol A) and Rifaximin susp. 600 mg/day x 3/day and Erythromycin
ethylsuccinate tab. 600 mg x 3/day (at least two hours after meals: 10:00 am,
2:00 pm, 9:00 pm), Omeprazole tab. 40 mg/day (in the morning before breakfast)
(protocol B). Both therapeutic protocols were prescribed for two weeks. At least
one month after the end of the treatment the patients were controlled to
ascertain eradication of the infection. The follow-up carried out after treatment
showed that HP infection was eradicated in 6 of 10 patients in the first group
(protocol A) and in 1 of 10 in the second group (protocol B). These patients were
HP-negative in all the tests performed: histological, CP-TEST, culture test. The
data collected showed a reasonable level of effectiveness of the protocol using
the combination Rifaximin-Amoxicillin and Omeprazole. However, they do not differ
from the reported data in the literature which show a similar effectiveness of
the combination Omeprazole-Amoxicillin at the same doses. Different formulations
that makes it possible for the drug to reach these "protected areas" would
probably be more effective.
PMID- 9558775
TI - Anti-TNF-alpha antibodies are not associated with Helicobacter pylori induced
gastritis.
AB - Over the past few years, it has been suggested that increased gastric production
of some cytokines, including tumor factor-alpha (TNF-alpha), play a crucial role
in the pathogenesis of H. pylori associated gastroduodenal diseases. On the other
hand, it has been postulated that the presence of autoantibodies directed against
several cytokines could represent or a down-regulatory response of the host to
limit the damage associated with chronic bacterial infection or a specific
cytokine inhibitor. The aim of this study was to evaluate whether serum anti-TNF
alpha antibodies are produced in response to H. pylori infection. The anti-TNF
alpha antibody titer among H. pylori positive and H. pylori negative patients
showed no statistically significant difference. Interestingly, after eradication
of H. pylori, no significant modification in anti-TNF-alpha antibody levels was
found. In H. pylori positive patients, no correlations (either positive or
negative) was demonstrated between anti-TNF-alpha antibody and activity of
gastritis, nor between these antibodies levels and presence of duodenal ulcer.
The lack of correlation between anti-TNF-alpha antibody levels and activity of
gastritis indicates that these autoantibodies do not affect the clinical course
of the H. pylori associated gastroduodenal diseases. Therefore, the biological
and clinical relevance (if any) of anti-TNF-alpha antibodies in H. pylori
associated gastritis remains to be better elucidated.
PMID- 9558776
TI - Evaluation of cardiovascular parameters by continuous 24 hour monitoring in
diabetic hypertensive patients with autonomic neuropathies.
AB - Correlations between scores of autonomic neuropathy severity in diabetic
hypertensive subjects and behaviour of cardiovascular parameters detected by
continuous 24 hour monitoring were investigated in order to reveal any
alterations hat indicated onset and progression of disautonomy. R-R and Q-T
patterns, circadian pressure rhythm and ECG Holter over 24 hours were analysed in
30 patients divided into various groups (age, duration of disease, treatment) and
10 controls. Three autonomic tests (deep breathing, postural hypotension, lying
to standing) were performed and the relative Ewing scores recorded. Data obtained
were analysed using Pearson's correlation test and simple linear regression. The
results not only confirm circadian rhythm demodulation of arterial pressure, but
also show progressive correlation between the scores obtained and modified
cardiovascular parameters. According to the authors, detection of these
intermediate alterations may be useful in forecasting possible onset or evolution
of dysautonomic pathologies.
PMID- 9558777
TI - A diary model for monitoring blood pressure in the elderly.
AB - Activity can significantly change blood pressure. Twenty four hour ambulatory
blood pressure monitoring (Holter method) was introduced to optimize diagnosis
and the changes in blood pressure. It was flanked by the purpose to use diaries
to correlate symptoms and pressure changes, pressure changes and psychophysical
activity, life style and drugs. The diary model adopted by us for 380 elderly
subjects between 65 and 85 years old is divided into four main sections: 1.
general activities (8 items); 2. situational variations (7 items); 3. correlation
between symptoms and pressure changes; 4. drug treatment and pressure changes.
The aim of our study was to assess the compliance of the elderly to keeping a
diary. Our results showed that compliance was satisfactory in 352/380 subjects
(93%).
PMID- 9558778
TI - Calcified retroperitoneal fibroma.
AB - A case of 31-year-old male with a retroperitoneal tumor is described. Abdominal
ultrasound revealed a left para-aortic calcific mass, adjacent to the left lobe
of the liver and to the upper pole of the left kidney. A CT-scan of the abdomen
showed the mass to originate from the left adrenal gland. At operation, a large,
retroperitoneal mass, adherent to the left kidney and the spleen, but not
infiltrating, was excised. Histologically the tumor was diagnosed as a calcified
osteo-producing fibroma. Benign retroperitoneal tumors represent about 25% of all
retroperitoneal neoplasm. This reported case represents a retroperitoneal tumor
of slow growth and benign clinical course whose characteristic consists of the
heavy calcifications which are normally absent in a fibroma type mass.
PMID- 9558779
TI - Pursuing health care fraud and abuse.
PMID- 9558780
TI - Deconstructing the Columbia/HCA investigation.
AB - Every issue raised by the current investigation into the business practices of
Columbia/HCA serves as a signpost for the progress and problems inherent in
market-driven health care reform. Actions against Columbia/HCA by regulators
reveal deeply rooted resistance to the profit-motivated reforms embodied in the
company's philosophy: the public's reluctance to accept necessary reductions in
excess hospital capacity; the legal and cultural obstacles to the overdue
alignment of physician and hospital economic interests; and the myriad
reimbursement and accounting problems involved in the vertical integration of
health care delivery. The investigation also underscores the antiquation of the
reimbursement mechanisms and control systems in place for financing the delivery
of care to Medicare beneficiaries.
PMID- 9558781
TI - Columbia/HCA: a failure of leadership.
PMID- 9558782
TI - Columbia/HCA: villain or victim?
PMID- 9558783
TI - Market realities meet balanced government: another look at Columbia/HCA.
PMID- 9558784
TI - Costs and use of mental health services before and after managed care.
AB - This paper tracks access, utilization, and costs of mental health care for a
private employer over nine years during which mental health benefits were carved
out of the medical plan and managed care was introduced. Prior to the carve-out,
mental health costs increased by around 30 percent annually; in the first year
after the change, costs dropped by more than 40 percent; in the six follow-up
years, costs continued to decline slowly. This cost reduction was not
attributable to decreased initial access, as the number of persons using any
mental health care increased following the change. Instead, the cost reduction
was the result of (1) fewer outpatient sessions per user, (2) reduced probability
of an inpatient admission, (3) reduced length-of-stay for an inpatient episode,
and (4) substantially lower costs per unit of service.
PMID- 9558785
TI - Costs and incentives in a behavioral health carve-out.
AB - A carve-out of mental health and substance abuse services initiated in 1993 by
the Group Insurance Commission (GIC) of the Commonwealth of Massachusetts
resulted in changes in the costs of those services. Those changes were related to
incentives in the contract between the GIC and its managed behavioral health
vendor. Total and plan costs were reduced by 30-40 percent after adjusting for
trends. Incentives to produce savings of this magnitude not only were a
consequence of the payer/vendor contract but, we speculate, derive from the
growth potential facing companies in the managed behavioral health care market.
PMID- 9558786
TI - Beyond health promotion: reducing need and demand for medical care.
AB - A population's medical need represents its illness burden. Medical demand
represents the service level requested for a particular need. Medical care costs
are, in large part, a function of need and demand. Our review of health education
programs designed to reduce health risks and reduce costs identified thirty-two
programs with documented effectiveness, generally achieving claims reductions of
20 percent. Specific program features including chronic disease self-management,
risk reduction, and increased self-efficacy appear important. A broadened
definition of health promotion focused on increased personal responsibility for
health-related actions and directed at improvement of long-term health outcomes
also could reduce health care costs.
PMID- 9558787
TI - Analyzing the evidence on European health care reforms.
AB - Health system reform, in Europe as elsewhere, has often been influenced as much
by theory and conjecture as by fact and experience. In a study published in
September 1997, the Regional Office for Europe of the World Health Organization
(WHO) drew together the available evidence about the health care systems in the
fifty-one countries of the European region. This paper focuses on western
European countries. It reviews a variety of policy strategies and then explores
implications from this European experience for the formulation of U.S. health
care policy.
PMID- 9558788
TI - Courts as gatekeepers in managed care settings.
PMID- 9558789
TI - The 'Mona Lisa' of health policy: primary care at home and abroad.
PMID- 9558790
TI - Children's health insurance, access to care, and health status: new findings.
AB - Despite various policy initiatives, a substantial number of children in the
United States remain uninsured, have problems with access to health care, or are
in fair or poor health. These difficulties are not evenly distributed across the
population. Hispanic children, those whose parents have little education, and
those who live in families without an employed parent are at disproportionately
high risk of encountering these problems. Although multivariate analyses would be
required to disentangle the complex relationships among these factors, these
descriptive data reveal the segments of the population to which new health
related programs, such as CHIP-funded state plans, might most productively be
directed. Issues concerning children's health are likely to remain on the
national policy agenda for some time to come. Because MEPS is a continuing data
collection effort, it will enable researchers and policymakers to follow trends
in these issues over time. For example, MEPS data will support evaluations at the
national level to determine whether children who lack health insurance or a usual
source of care will actually face fewer barriers after CHIP-funded programs are
implemented. This paper provides a baseline against which to evaluate the impact
of CHIP and other policy changes on the health and well-being of America's
children.
PMID- 9558791
TI - Insurance agents: ignored players in health insurance reform.
AB - In this paper we use the reforms to the individual health insurance market in New
Jersey to illustrate the intricate interaction between insurance agents and
insurance reform initiatives. Until recently, policymakers who designed reforms
to the health insurance market largely ignored the role of agents in selling
individual health insurance policies. These reforms have the potential to
overturn the agent's traditional role, and agents can influence how the reforms
are implemented.
PMID- 9558792
TI - Addressing the needs of chronically ill persons under Medicare.
PMID- 9558793
TI - Health plan accountability and reporting: issues and challenges.
PMID- 9558794
TI - Potential effects of raising Medicare's eligibility age.
AB - Recent fiscal pressures on Medicare and an already enacted increase in Social
Security's normal retirement age have generated discussion of raising Medicare's
age of entitlement. This DataWatch examines potential impacts of raising
Medicare's eligibility age to sixty-seven on public-sector health spending and
individual insurance coverage. The proposed increase would affect a substantial
fraction of beneficiaries without having a commensurate effect on expenditures,
even in the long run. It is estimated that if the eligibility age were sixty
seven, upwards of 500,000 persons ages sixty-five and sixty-six would be left
without any insurance, and even more would not be able to afford coverage with
benefits similar to those of Medicare.
PMID- 9558795
TI - Satisfaction with care: do Medicare HMOs make a difference?
AB - Differences in satisfaction with care and perceptions of doctor/patient
interactions were compared for Medicare beneficiaries enrolled in health
maintenance organizations (HMOs) and beneficiaries in the fee-for-service (FFS)
sector (nonenrollees). After controlling for covariates, beneficiaries expressed
satisfaction with their care, regardless of where they received it. However, HMO
enrollees were more likely than nonenrollees were to be very satisfied with the
costs of care and with getting care at one location. In contrast, for every
components-of-care measure, nonenrollees were more likely than HMO enrollees were
to indicate high satisfaction with the quality of interaction with their
physicians.
PMID- 9558796
TI - Preventable hospitalizations and socioeconomic status.
AB - "Preventable" hospitalizations have been proposed as indicators of poor health
plan performance. In this study of elderly Medicare beneficiaries, however, we
found that preventable hospitalizations are also more common among elders of
lower socioeconomic status (SES). The relationship persisted even when an up-to
date severity-of-illness adjustment system was used. To the extent that
indicators of health plan "performance" reflect enrollees' characteristics, plans
will be rewarded for marketing their services to wealthier, healthier, and better
educated patients. Further work is needed to clarify issues of accountability for
preventable hospitalizations and other putative indices of health plan
performance.
PMID- 9558797
TI - State regulation, payment policies, and nurse-midwife services.
AB - State regulatory and reimbursement policies continue to exert a strong influence
on health workforce policy. Surveys conducted in 1991 and 1995 for the purpose of
examining the impact of state regulation on the supply and practice of certified
nurse-midwives (CNMs) showed that the single best predictor of the distribution
and practice activities of CNMs was the degree to which state policies
facilitated or restricted CNM practice.
PMID- 9558798
TI - Foundations today: finding a new role in the changing health care system.
PMID- 9558799
TI - A U.S. Senator on government regulation.
PMID- 9558800
TI - Medicare: still looking for solutions.
PMID- 9558801
TI - Evils of cost shifting.
PMID- 9558802
TI - A new commission to guide the managed care revolution.
PMID- 9558803
TI - A combination approach to children's health insurance.
PMID- 9558804
TI - Scope of hypnosis education in academia: results of a national survey.
AB - The present article examines the current status of hypnosis training and the
attitudes of program chairs toward inclusion of such training in doctoral
education. A brief survey on hypnosis training was sent to all psychology
doctoral programs accredited by the American Psychological Association (n = 218)
as well as 24 nonaccredited doctoral programs. Twenty-six percent of responding
programs (n = 44/170) report offering either required or elective coursework in
hypnosis. Of those programs offering a course in hypnosis, the mean semester
credit hours earned was 3. Although many program directors support opportunities
for hypnosis education in doctoral education, other constraints (e.g., available
faculty, required coursework) limit its availability.
PMID- 9558805
TI - When hypnosis causes trouble.
AB - Like any other effective intervention, hypnotic treatment can occasionally cause
harmful effects as well as beneficial ones. The first step in avoiding clinical
complications is recognizing that they can occur. A review of the literature,
however, suggests a long-standing inattention to the potential harmfulness of
hypnotic interventions, including patients' unexpected reactions, leading to
clinical complications, including amnesia, catharsis, paralysis, disorientation,
literalness of response, accelerated transference, and memory contamination. In
addition to these unexpected reactions by patients, complications can also arise
from a practitioner's need for power and by the inappropriately narrow focus on
the hypnotic process itself, leading to distraction from the more fundamental
clinical process.
PMID- 9558806
TI - The inpatient treatment of patients suffering from (motor) conversion symptoms: a
description of eight cases.
AB - This article presents a preliminary study that used two controlled randomized
trials to study the effect of hypnosis in the treatment of eight patients with
(motor) conversion symptoms. Controlled research into the treatment of conversion
symptoms is scarce and can often be criticized on methodological grounds. It
would appear, however, that both the use of suggestive and behavioral therapeutic
techniques and eclectic treatment programs yield good results in the treatment of
conversion symptoms. The results of the study suggest that comprehensive clinical
treatment including hypnosis has enough promise to be studied in clinical trials.
In the interpretation of the results, special attention is given to primary
diagnosis, duration of complaints, traumatic experiences in childhood,
dissociative capacity, and hypnotizability.
PMID- 9558807
TI - Surreptitious observation of responses to hypnotically suggested hallucinations:
a test of the compliance hypothesis.
AB - Suggestions for arm levitation and for visual, auditory, tactile, and taste
hallucinations were administered twice via audiotape to a group of high
suggestible students and low suggestible simulators. During one of the
administrations, participants were led to believe they were alone, but their
behavior was surreptitiously recorded on videotape and observed on a video
monitor. During the other administration, they were observed openly by an
experimenter who had not been informed about group assignment. When unaware that
they were being observed, simulators were significantly less responsive to
suggestion and engaged in substantially more role-inappropriate behavior. In
contrast, the responsiveness of nonsimulating students was not affected by the
presence of an experimenter, and they exhibited little role-inappropriate
behavior even when alone. These data indicate that the responses of suggestible
individuals reflect internally generated changes in experience and are not due to
simple intentional compliance (i.e., faking).
PMID- 9558808
TI - Posthypnotic responding: knowing when to stop helps to keep it going.
AB - The authors examined the effect of specifying (cue) or not specifying (no cue)
the cancellation cue for posthypnotic suggestion. Responding was indexed on
formal, embedded, informal, and postexperimental tests. Thirty-six real,
hypnotized participants and 20 simulating participants took part in an
application of the real-simulating paradigm. Responding declined across the four
tests. Real participants in the cue condition maintained responding longer than
simulators in the cue condition, and they also maintained responding longer than
reals and simulators in the no cue condition. The findings highlight the
interactional influence of individual, interpersonal, and situational factors in
posthypnotic responding and underscore the active involvement of individuals in
hypnotically initiated events.
PMID- 9558809
TI - If we build it, they will come.
PMID- 9558810
TI - Personal problems? The Members' Assistance Program can help.
PMID- 9558811
TI - Giving time to your profession can make a difference.
PMID- 9558812
TI - Dementia's impact on pain sensation: a serious clinical dilemma for dental
geriatric care givers.
AB - Dementia's impact on pain sensation is not well understood. Very little research
has been done in this area, our clinical knowledge is poor, and there is no
published information available to practitioners. This article reviews the
current literature and discusses the need for further research. The number of
patients with dementia is growing. This patient group will require dental
diagnosis and treatment, and cannot be ignored by dentists. A humane approach to
treatment must be adopted.
PMID- 9558814
TI - Dental practice review in Ontario.
PMID- 9558815
TI - Patient satisfaction with dentures made by dentists and denturologists.
AB - BACKGROUND: Within Quebec and elsewhere in Canada, patients requiring removable
prostheses consult either dentists or denturologists. In this article, we
describe the socioeconomic characteristics of 410 edentulous individuals seeking
replacement of their dentures, and compare the levels of satisfaction experienced
by the patient groups provided with conventional dentures by dentists and by
denturologists. METHODS: All subjects responded to announcements seeking
participants in a clinical trial. The announcements indicated that all
participants would receive new prostheses. Data were collected via telephone
interviews. Sociodemographic variables included sex, age, education level and
family income. Subjects were asked to evaluate their present maxillary and
mandibular prostheses for general satisfaction, stability, comfort, ability to
chew, ability to clean and appearance. Age, cost and the provider (dentist or
denturologist) of the original prostheses were also recorded, and responses were
then compared between the groups of subjects treated by dentists (N = 91) and
denturologists (N = 319). RESULTS: There were no significant differences in the
sociodemographic characteristics of the two groups, except for a small difference
in mean age (two years). Both groups had paid approximately the same amount for
their complete prostheses. As expected, most individuals were satisfied with
their maxillary prostheses, but dissatisfied with their mandibular prostheses.
Significantly more subjects in the denturologist treatment group than the dentist
treatment group gave their mandibular prostheses a poor rating for general
satisfaction (p = 0.003), comfort (p = 0.04) and stability (p = 0.016).
CONCLUSIONS: These results suggest that the edentulous patients treated by
dentists and denturologists share similar sociodemographic characteristics, and
pay a similar cost for treatment. However, those treated by denturologists seem
to be more dissatisfied with their mandibular prostheses than those treated by
dentists.
PMID- 9558813
TI - The forgotten discipline of dentistry.
PMID- 9558816
TI - Determinants of positive and negative attitudes toward dentistry.
AB - Previous studies have primarily investigated the determinants of negative
attitudes toward dentistry. Little is known about the reasons for positive
attitudes. Using a group of university students who were surveyed during 1996,
this study therefore examined both positive and negative attitudes to dentistry.
It was initially predicted that dentally anxious individuals would be more likely
to have negative feelings about dentistry than non-dentally anxious individuals,
and would attribute this attitude to specific experiences. The study found that
the majority of participating students had a positive attitude toward dentistry,
and that participants with low levels of dental anxiety were more likely to have
a positive attitude than those with a high level of anxiety. However, highly
dentally anxious individuals were just as likely to feel positive toward
dentistry as they were to feel negative. A substantial proportion of students
claimed to have had painful or distressing experiences at the dentist during
their adolescence. However, experiencing a painful or distressing incident was
not related to having a negative attitude. The majority of the students who felt
negative toward dentistry attributed this attitude to an unspecific experience,
although dentally anxious individuals were likely to be more specific than non
dentally anxious individuals. Women participants appeared to have experienced
painful or distressing incidents at a younger age than the men. The authors
concluded that the factors involved in the development and maintenance of an
individual's attitude toward dentistry are complex, and that dentists should be
concerned with the promotion of positive attitudes rather than attempting to
resolve negative ones.
PMID- 9558817
TI - Posterior composite resin simplification--what of scientific validation?
PMID- 9558818
TI - Eating disorders among college women: prevention, education, and treatment
responses.
AB - Eating-related problems, particularly among college women, represent a
significant health concern on university campuses. Body image dissatisfaction,
weight preoccupation, and unhealthy weight management are prevalent among even
normal-weight students, but discussions of broad college health interventions in
this area have been limited. Two conceptual tools that are useful in developing a
comprehensive health center response to eating disorders in the college setting
are described. The diagnosis of Eating Disorders Not Otherwise Specified is
suggested as a framework for defining target populations and eating problems
requiring intervention, and a picture of the prototypical eating problem
candidate is developed. A multiple-level model of intervention that includes
preventive, intermediate, and remedial responses to varied forms of eating
related concerns is described. The intervention model is illustrated with
examples, and limitations of the method are discussed.
PMID- 9558819
TI - Vitamin C status of a campus population: college students get a C minus.
AB - Diet and the vitamin C status of two samples of college students were examined.
Nonsmoking participants were recruited from a campus population during the fall
and winter months. The prevalence of vitamin C deficiency (plasma vitamin C
concentrations less than 11 mumol/L) ranged from 1% to 2% in the sampled campus
populations. Marginal vitamin C status (plasma vitamin C concentrations from 11
to less than 28 mumol/L) was observed in 12% of the fall sample and 16% in the
winter sample. Participants with marginal vitamin C status consumed significantly
fewer servings of fruits and vegetables daily than participants with adequate
vitamin C status. Marginal vitamin C status, which is even more pronounced in
smokers, has been associated with fatigue and increased severity of respiratory
tract infections. Because the vitamin C status of many college students, both
smokers and nonsmokers, may be inadequate, health promotion or wellness programs
for all students should emphasize the importance of adequate fruit and vegetable
consumption.
PMID- 9558821
TI - Pregnancy testing and counseling: a university health center's 5-year experience.
AB - Profiles and related sexual histories of 2,029 women who sought pregnancy tests
at a university health center over a 5-year period were examined. Rates of
pregnancy (30%) were consistent over the 5 years. The highest rates of testing
were among seniors and juniors, with graduate students reporting the highest
levels of unintended pregnancy. More than 37% of the women indicated they had not
used any method of contraception at the time of risk; 29% of the women who had
used condoms reported that the device had either torn or slipped off. The women
with previous pregnancies were more likely to test positive and to terminate the
pregnancy than were the women who had never been pregnant. The findings are
discussed with reference to sexually education programs and pregnancy counseling.
PMID- 9558820
TI - Obstacles to condom use: the combination of other forms of birth control and
short-term monogamy.
AB - Two hundred thirty-seven college students involved in heterosexual relationships
were surveyed to determine the effects of relationship type and use of forms of
contraception other than condoms on condom use. Findings indicated that in the
context of a short-term, monogamous relationship, the use of another form of
birth control was associated with decreased condom use. In addition, 20% of the
participants reported that they had wanted to use a condom for disease prevention
on at least one occasion but had decided not to do so because they were using
another form of contraception. Implications for preventive health are discussed.
PMID- 9558823
TI - The medical excuse game as it is played at Duke University.
PMID- 9558822
TI - Alcohol consumption, strength of religious beliefs, and risky sexual behavior in
college students.
AB - Relationships among alcohol use, strength of religious convictions, and unsafe
sexual practices of 210 students at a large public university in the "bible belt"
were examined. The women with strong religious beliefs consumed less alcohol and
were less likely to engage in risky sexual behavior than were female participants
with weaker religious convictions. Among the men, religious conviction was not
significantly correlated with alcohol consumption or risky sexual behavior, but
alcohol consumption and inconsistent use of condoms and multiple sexual partners
were significantly correlated. Men had higher rates of alcohol consumption and
unprotected sexual activity than women did, yet the two groups did not differ in
overall frequency of sexual activity. Future research is needed to (a) provide
greater understanding of gender differences in alcohol use, risky sexual
behavior, and religious beliefs of college students in the region and (b)
determine whether similar correlations exist in other areas of the country.
PMID- 9558824
TI - Multitracer studies on the accumulation of radionuclides in mushrooms.
AB - We used the multitracer technique to study the transfer of several radionuclides
to two mushroom species. Radionuclides accumulated in the fruiting bodies of the
mushrooms in the order of 83Rb > 65Zn > 54Mn > 22Na > 75Se and 85Sr > 60Co > 88Y,
102Rh, 139Ce, 143.144Pm, 146.153Gd and 173Lu > 175Hf. The concentration ratio
values for 83Rb, 65Zn and 54Mn in the fruiting bodies were more than 10, whereas
those for 60Co, 88Y, 102Rh, 121mTe, 175Hf and the rare earth elements were less
than 1. There were major differences in the accumulations of the alkali elements.
PMID- 9558825
TI - Chromosome aberrations in bone marrow cells of C3H/He mice at an early stage
after whole-body irradiation.
AB - Murine acute myeloid leukemia is characterized by chromosome 2 aberrations, and
genesis of the marker chromosome 2 by radiation is suspected to be an initiating
event of radiation leukemogenesis. A detailed analysis of the type and frequency
of chromosome 2 aberrations in murine bone marrow cells at an early stage after
irradiation is provided here. A total of 40 male C3H/He mice was exposed to 137Cs
gamma-ray at a dose of 1, 2 or 3 Gy, and sacrificed 24 hours after irradiation.
Metaphase samples prepared from bone marrow cells were Q-banded for karyotyping
or painted with DNA probes specific to chromosome 2. In 5 mice analyzed by
karyotyping, one mouse showed high frequency of the marker aberrations as well as
other chromosome 2 aberrations. Chromosome painting analysis for the rest of the
mice also detected 3 animals showing significantly high frequencies of chromosome
2 aberrations. Dose-dependence of the frequencies was observed even among those
mice that tended to be sensitive. The results indicated that there was a subgroup
of mice carrying hypersensitive chromosome 2. The subgroup could be leukemia
sensitive if radiation-induced chromosome aberrations are responsible for an
early change in myeloid leukemogenesis.
PMID- 9558826
TI - Single dose radiocurability of four murine solid tumors and a predictive assay
for the curability in situ.
AB - Correlations between radiocurability and kinetic parameters were investigated in
four transplantable tumor types in WHT/Ht mice. The radiation dose to achieve 50%
tumor control at 120 days after irradiation, i.e., TCD50/120, was 30 Gy for
squamous cell carcinoma H, 32 Gy for squamous cell carcinoma NOS, 46 Gy for
rhabdomyosarcoma KAS, and 63 Gy for fibrosarcoma YAS. The tumor cell kinetic
parameters investigated were specific growth delay, volume doubling time, 125I
iododeoxyuridine (IUdR) uptake rate, and specific cell loss rate. The specific
cell loss rate was defined as the ratio of cell loss rate in non-irradiated
tumors to the rate in irradiated tumors, and was obtained by measuring the
retention rate of radioactivity in the tumors. No correlations were found between
specific growth delay, volume doubling time, 125I-IUdR uptake rate, and TCD50.
However, the specific cell loss rate correlated with the TCD50. Therefore, the
125I-IUdR labeling method may be useful as an in situ predictive assay for tumor
radiocurability.
PMID- 9558827
TI - Single-strand breaks in oligodeoxyribonucleotides induced by fission neutrons and
gamma radiation and measured by gel electrophoresis: protective effects of
aminothiols.
AB - The technique of high-resolution gel electrophoresis using
oligodeoxyribonucleotides of known composition as model systems, offers a simple
quantitative estimate of DNA damage in aqueous solution induced by ionizing
radiation. The fraction of damaged DNA can be quantitatively defined in terms of
the increased electrophoretic mobilities of the damaged oligonucleotides,
relative to the mobility of the unirradiated and intact oligonucleotides. The
usual direct strand breaks can be observed at gamma-ray dosages of 200 Gy.
However, at a gamma-ray dosage of 400 Gy, only a broad background, attributed to
heterogeneously and multiply damaged oligonucleotide fragments with overlapping
and varying electrophoretic mobilities, can be distinguished. On the other hand,
individual bands due to resolvable DNA fragments are evident even at dosages as
high as 400 Gy for fission neutrons. When double-stranded oligonucleotides are
exposed to gamma-ray dosages of 200 Gy, the fraction of damaged DNA approaches 30
40%. This damage can be almost completely suppressed (> 99%) if the irradiations
are conducted in aqueous solutions in the presence of 0.5-1.0 mM concentrations
of the thiols cysteamine or 3-(3-methylaminopropylamino)propanethiol (WR-151326).
The rate constant of reaction of OH radicals with small double stranded
oligonucleotides 16 base pairs long, KDNA, is found to be closer to the diffusion
controlled value (> 3 x 10(9) M-1 s-1) than the magnitudes of KDNA for the higher
molecular weight, native DNA reported in the literature. These observations
suggest that oligonucleotides represent more simple model systems than native DNA
in solutions for studying the mechanisms of radioprotection exerted by thiols of
different structures.
PMID- 9558828
TI - Conversion of cycles per minute to hertz incorrect.
PMID- 9558829
TI - Infection with the human immunodeficiency virus (HIV) may have occurred as early
as the late 1940s.
PMID- 9558830
TI - Partners for two decades: AOA and the National High Blood Pressure Education
Program.
PMID- 9558831
TI - Effect of lymphatic and splenic pump techniques on the antibody response to
hepatitis B vaccine: a pilot study.
AB - Osteopathic manipulative treatment (OMT) facilitates the movement of lymphatic
fluid and may enhance the immunologic response to infection or injected antigen.
In this investigation, two groups of volunteers were vaccinated with recombinant
hepatitis B vaccine, given at 0, 5, and 25 weeks. The experimental group (n = 20)
received OMT (lymphatic and splenic pump) three times per week for 2 weeks after
each vaccination. Control subjects (n = 19) received vaccine but no OMT.
Resultant serum antibody levels were measured by enzyme immunoassay. Fifty
percent of subjects in the treatment group achieved protective antibody titers (>
or = 10 mIU/mL) on the 13th week with an average titer of 374 mIU/mL. Only 16% of
the control subjects had positive antibody responses, with average titers of 96
mIU/mL. At all time points from week 6 on, the average anti-hepatitis B titer was
higher in the treatment group than in the control group. These data suggest an
enhanced immunologic response in subjects who received OMT.
PMID- 9558832
TI - Utilization of nicotine nasal spray in smoking cessation.
AB - It is widely accepted that nicotine replacement therapy can help patients to quit
smoking. Recent approval by the US Food and Drug Administration of a nicotine
nasal spray gives clinicians greater flexibility in choosing the best replacement
therapy for a particular patient. Four types of smoking cessation therapy are
currently available (gum, patch, nasal spray, and bupropion). These differ with
respect to their onset and duration of action, adverse effects, and cost. This
article focuses on which patients may benefit most from the use of nicotine nasal
spray. Instructions for proper administration and dosing of the nicotine nasal
spray are discussed as well as how to taper it appropriately, and how to avoid-
and manage--adverse effects. Additionally, the cost of the nicotine nasal spray
is reviewed and compared with over-the-counter products and bupropion. Resources
for behavioral support are provided as well.
PMID- 9558833
TI - Communication for osteopathic manipulative treatment (OMT): the language of lived
experience in OMT pedagogy.
AB - Questions about the scientific merits of osteopathic manipulative treatment (OMT)
and the search for consistent, effective teaching methods for OMT persist in the
discourse of the osteopathic medical curriculum. Although grounded on scientific
principles, the philosophy of osteopathic medicine in the words of Andrew Taylor
Still, William G. Sutherland, and other prominent osteopathic medical scholars
advances concepts in metaphoric language that may seem obscure and dated to many
of today's students. Evidence in the literature of osteopathic medicine supports
the congruence of phenomenology with the philosophy and methods used to teach
OMT. Phenomenology offers an alternative paradigm to address questions of
scientific merit and could provide a consistent language to a rigorous,
scientific approach to communication for OMT pedagogy. The authors propose a
solution for the tactical adaptation of a communication strategy based on an
interpretation of osteopathic medical methodology and phenomenology.
PMID- 9558834
TI - Neuroleptic malignant syndrome related to use of clozapine.
AB - A 19-year-old man presented to a community hospital with a sudden change in level
of consciousness, fever, and muscle rigidity. The patient had a history of
schizophrenia and was being treated with clozapine. Despite a high index of
suspicion for neuroleptic malignant syndrome, definitive care was delayed for
more than 24 hours after the patient was transferred to a tertiary care center.
This case illustrates the importance of primary care physicians being able to
recognize and diagnose this syndrome, particularly as the use of atypical
antipsychotic agents increases.
PMID- 9558835
TI - Nebulized lidocaine in the treatment of refractory tussive syncope.
AB - Tussive syncope is a rare condition that often responds to treatment of the
underlying cause of coughing. Therefore, the workup and diagnosis of the cause is
essential. However, at times, the cough is refractory to conventional treatment.
The use of nebulized lidocaine in such instances may be an important adjunctive
therapy.
PMID- 9558836
TI - [Retinal light damage].
PMID- 9558837
TI - [Method and evaluation of experimental retinal reattachment].
AB - An animal model of retinal reattachment is needed to study experimental macular
relocation and recovery of reattached retina. The purpose of this study was to
develop and evaluate a simple technique of retinal reattachment. We used the
right eye of 13 pigmented rabbits for this experiment. 3 weeks before the
operation, the eyes underwent a gas induced vitreous compression with sulfur
hexafluoride gas. Transcleral subretinal hydrodissecction was used to create a
partial (60-70% of the whole retina) retinal detachment. Retinal reattachment was
observed in ten eyes 18 hours after the operation. The dark-adapted
electroretinograms (ERGs) were recorded in 3 rabbits from 3 days to 3 months
after the surgery. Selected eyes were enucleated for histology. The amplitude of
ERGs (a-wave and b-wave) were reduced to 30% and 40% of the control eyes on day
3. These waves were restored up to 70% and 80% of normal at 2 weeks and showed no
significant changes thereafter. Degeneration and loss of photoreceptors in the
early days after surgery as seen by light microscopy were almost completely
restored to normal at 3 months after surgery. This model provides large retinal
detachment and reattachment with minimized inflammatory response.
PMID- 9558838
TI - [Effect of ultraviolet-filtering contact lens on rabbit eyes after exposure to
ultraviolet light].
AB - We evaluated the protective effect of a newly designed soft contact lens (SCL) on
rabbit eyes. This SCL absorbs the ultraviolet B light of wavelengths between 280
nm and 320 nm. Three weeks after resecting the nictitating membrane, the rabbit
corneas were covered either by the new SCL or a conventional SCL. The eyes were
exposed to ultraviolet light from two 15 W lamps placed 20 cm anteriorly for 3
hours. Another three hours after the exposure, the cornea was examined first with
a slitlamp biomicroscope after staining with fluorescein and then by
histopathological means after enucleation. Six eyes wearing the new SCL showed
moderate superficial punctate keratopathy. Six eyes wearing conventional SCL
showed severe superficial keratopathy or corneal erosion. These findings were in
good agreement with the histopathological findings. The new ultraviolet-filtering
SCL was thus effective in protecting the rabbit cornea under our experimental
conditions.
PMID- 9558839
TI - [Clinical features of 10 cases with phlyctenular keratitis].
AB - We investigated 15 eyes of 10 patients with phlyctenular keratitis. The patients
were 6 men and 4 women, and their ages ranged between 3 and 56 years (mean, 17.8
years). The follow-up periods ranged from 0.5 to 48 months (mean, 14 months).
Clinically, complications in many cases were papillary hyperplasia in palpebral
conjunctiva, meibomian gland infarct, chalazion, and blepharitis. Microbial
examination from the lid margin before treatment revealed bacteria in 4 eyes of 4
patients out of 9 eyes of 8 patients. The level of serum specific IgE antibody
was high in only 1 patient out of 6. We classified the clinical course into 3
stages, namely, infiltrative, nodule, and cicatricial stages. We also
investigated the transition of the disease among the stages. All the cases of the
infiltrative stage progressed to the nodule stage, and 92% of the nodule stage
went on to the cicatricial stage. However 14% of the cicatricial stage cases
reverted to the infiltrative stage and 7% to the nodule stage.
PMID- 9558840
TI - [Correlation of pathological features of surgically excised choroidal neovascular
membranes with age-related macular degeneration and indocyanine green
videoangiographic findings].
AB - We surgically excised subfoveal neovascular membranes from eight patients with
age-related macular degeneration. The correlation of the histopathological
features of choroidal neovascularization and preoperative indocyanine green (ICG)
videoangiographic findings were studied. Neovascular membranes which demonstrated
hyperfluorescence at an early phase of ICG videoangiography had many vascular
channels and a large lumen without enclosure of retinal pigment epithelium (RPE).
Fibrovascular tissues contained small vessels with fibrotic stroma that showed
hyperfluorescence only at a late phase of ICG videoangiography. In contrast, the
membrane which showed hypofluorescence of ICG videoangiography was composed of
paucivascular fibrotic tissue covered extensively with RPE. Moreover, newly
formed vessels with proliferative endothelium could be observed in the
neovascular membranes that showed weak fluorescence or hypofluorescence. These
results could provide a morphological basis for the interpretation of ICG
videoangiographic features of choroidal neovascularization. It also may be useful
in planning the treatment for subfoveal neovascular membranes.
PMID- 9558842
TI - [Mobility of orbital implant covered by own sclera].
AB - We evaluated in 7 eyes the mobility of a newly designed orbital implant made of
hydroxyapatite. This orbital implant has a screw peg and is covered with a piece
of sclera from the enucleated eye of the patient. The implant was well tolerated
and there were no cases of proptosis during the follow-up of 1.8 +/- 0.6 years.
Assuming the mobility of a healthy eye as 100%, photographic analysis showed the
mobility of the anterior orbit to be 92.6% in adduction, 85.9% in abduction,
84.9% in supraduction, and 90.9% in infraduction. The mean tugging weight of the
implant was, when measured by a strain gauge, 344.2 +/- 29.2 g in adduction and
327.6 +/- 33.4 g in abduction. These values corresponded to 90.4 +/- 4.4% and
89.5 +/- 5.3% respectively of those in a healthy eye. The presence of the orbital
implant did not affect the electrooculogram as compared to a healthy eye.
Cinematic studies using magnetic resonance imaging (MRI) showed that the
constriction and extension of the extraocular muscles, which were sewn onto the
orbital implant, matched that of a healthy eye.
PMID- 9558841
TI - [Aqueous levels of eosinophil cationic protein and major basic protein in
patients with retinal detachment associated with atopic dermatitis].
AB - We measured the aqueous levels of eosinophil cationic protein (ECP) and major
basic protein (MBP) to investigate a possible relationship between cytotoxic
eosinophil granule proteins and retinal detachment (RD) in patients with atopic
dermatitis. While aqueous ECP was detected in only 1 of 15 cases of RD associated
with atopic dermatitis, aqueous MBP was detected in 6 of 14 cases (42.9%). 11
cases of RD without atopic dermatitis were also studied, but neither ECP nor MBP
was detected. Although the role of aqueous ECP and MBP was not elucidated, the
results indicate that cytotoxic eosinophil granule proteins, especially MBP, are
present in aqueous humor in certain cases of RD associated with atopic
dermatitis.
PMID- 9558843
TI - [Neovascularization from the scleral wound as the cause of vitreous rebleeding
after vitrectomy for proliferative diabetic retinopathy].
AB - Vitreous hemorrhage recurred in 11 eyes out of a series of 120 eyes treated by
vitrectomy for proliferative diabetic retinopathy during a 10-month period.
Neovascularization from the scleral wound, or fibrovascular proliferation, was
identified as the cause of rebleeding in 4 eyes from findings during
revitrectomy. None of the 4 eyes showed retinal disorders attributable as the
cause of rebleeding. Rebleeding in these 4 eyes developed after an average of 9.0
weeks after initial surgery. The proliferative membrane was oval in shape and
expanded from the residual vitreous which had been incarcerated in the scleral
wound. The proliferative membrane obtained during revitrectomy was poor in
cellular components and contained extracellular matrix. Blood vessels of various
sizes were also present. Electron microscopically, the membrane was rich in
extracellular components. It contained two types of cells, i.e., high and low
electron density cells. These cells often had microvilli and seemed to be of
epithelial origin. The findings show that vitreous rebleeding may develop from
fibrovascular proliferation from the scleral wound after diabetic vitrectomy. The
proliferated membrane showed histological similarities with the fibrovascular
proliferation usually seen in the diabetic retina and may represent a type of
anterior proliferation secondary to retinal ischemia.
PMID- 9558844
TI - [Characteristics of retinal detachment in eyes with choroidal colobomas].
AB - We reviewed 6 eyes of 6 patients (1 male and 5 females) with retinal detachment
associated with choroidal coloboma. Three of these 6 eyes had visible retinal
breaks within or at the margin of the coloboma. In one eye, no retinal breaks
were noted before or during vitreous surgery, and shallow retinal detachment was
localized in the posterior fundus. One eye with bullous retinal detachment with
retinal breaks within the coloboma had been having serous retinal detachment
localized in the nasal area close to the optic nerve head. In all of these five
eyes; vitrectomy, relaxing retinotomy inside the coloboma close to its edges, and
cyanoacrylate retinopexy resulted in successful reattachment of the retina.
Schisis-like separation similar to that in pit-macular syndrome was noted in the
posterior retinal in one eye which had no visible retinal break. Non
rhegmatogenous retinal detachment may exist in association with choroidal
colobomas.
PMID- 9558845
TI - [Chorioretinal malformation in vascular loop formation on the optic disc].
AB - We have studied the eyes of a 57 year-old man, with good visual acuity, who was
found to have an unusual prepapillary vascular loop formation in both eyes.
Ophthalmoscopic examination revealed that the central retinal vein ran a course
beneath the retinal pigment epithelium in right eye. Fluorescein angiography
showed the prepapillary vascular loops to originate from the central retinal
artery in both eyes. We also noted arterial, but not arteriovenous, shunt
formation in the retina of both eyes. By indocyanine green angiography we
demonstrated the presence of a drainage system, the so called posterior ciliary
vein, which was connected directly to the central retinal vein temporal to the
optic disc in the right eye. We believe this to be a new type of chorioretinal
vascular formation which is different from the chorio-vaginal vein and the optico
ciliary vein.
PMID- 9558846
TI - [Studies on utility of MR T2-weighted images using multishot echo-planar imaging
for hepatic mass lesions].
AB - MR T2-weighted images using multishot echo-planar imaging (EPI) and fast spin
echo (FSE) sequences were obtained in 22 patients with hepatic masses. Multishot
EPI sequences included eight-shot breath-hold EPI and 16-shot EPI without breath
hold, while FSE sequences included nonfat-suppressed respiratory-triggered FSE,
fat-suppressed respiratory-triggered FSE, and nonfat-suppressed breath-hold FSE.
Signal-to-noise ratio, contrast-to-noise ratio and artifacts were compared
between EPI and FSE images of 47 hepatic masses. In evaluating solid tumors, EPI
provided image quality equal or superior to that of FSE, whereas in the
evaluation of nonsolid tumors FSE showed better image quality than EPI. In
conclusion, it was demonstrated that in the evaluation of hepatic solid tumors T2
weighted eight-shot breath-hold EPI can replace both nonfat-suppressed
respiratory-triggered FSE and breath-hold FSE, and it was suggested that eight
shot breath-hold EPI can replace fat-suppressed respiratory-triggered FSE to
reduce patient discomfort and increase examination throughput.
PMID- 9558847
TI - [Results of radiation therapy for limited small-cell lung cancer].
AB - Results of radiotherapy were reviewed in 68 patients with limited small-cell lung
cancer from the aspect of local control. Thirty-one patients achieved CR (46%),
while the other 31 remained at PR. The 1-, 2-, 3-, and 5-year cumulative survival
rates were 57%, 28%, 21%, and 16%, respectively, for 15 months in MST. Thirty-six
patients developed local recurrence (53%) and 46 had distant metastasis (68%).
The thirty-one patients with CR had a 43% 2-year-survival rate and 23 months in
MST. The remaining 37 patients (PR + NC) had respective figures of 13% and 13
months (p < 0.025). There was no statistically significant difference between
radiation dose and local thoracic failure among the patients. Of the 31 patients
with CR, 28 had achieved CR at 45Gy (17 received 55Gy or more, and 11 less than
55Gy). In the former, the local control rate, 2-year-survival and MST were 94%,
53% and 44 months, while in the latter these were 45%, 27% and 17 months,
respectively. Thirty-five patients were irradiated by the shrinking field
technique according to tumor reduction; however, this technique did not influence
the treatment results. To obtain better results, it is first necessary to achieve
CR at initial chemo-radiotherapy. As to irradiation, randomized trials between
50Gy and 60Gy would require patients with CR at 45Gy.
PMID- 9558848
TI - [C-MOS flat-panel sensor for real time X-ray imaging].
AB - Flat-panel, self-scanning, solid state diagnostic x-ray imaging devices using
complementary metal-oxide-semiconductor (C-MOS) arrays are under investigation. A
unit device with a 5 cm by 5 cm sensor area was developed and tested. The device
consists of a CsI scintillator and C-MOS detector arrays. The detector arrays are
composed of a regular arrangement of pixels (256 x 256), each of which is made of
a C-MOS photodiode sensor coupled to a C-MOS FET (field effect transistor). A
common FET gate line is connected to all the FET gates along each column. A
common date line is connected to all the FET drains of each row. The source
contact of each FET is connected to that of its corresponding photodiode. A
positive gate pulse applied to a gate turns on all FETs connected to the date
lines. The readout continues column by column. Correlated double sampling
circuits and an offset variance compensation circuit were installed to reduce
noise. A sampling speed of 15 frames per second and spatial resolution of 2.5
line per mm were achieved. Noise level and maximum signal were 1.5 mV rms and 1.8
V, respectively. Image quality was considered acceptable for clinical use. It is
also discussed how to fabricate a large area sensor with the unit device.
PMID- 9558849
TI - [Is medical linac suitable for high-precision stereotactic irradiation?:
investigations in geometrical accuracies of gantry and couch].
AB - Linac-based radiosurgery has many advantages over the gamma knife, including low
initial cost and no need of source replacement. On the other hand, most of the
medical linacs currently in use were not originally designed to be applied for
radiosurgery, and, therefore, careful quality assurance programs are required. In
the gantry-head of a linac, a small CCD video camera is mounted in a position
optically identical to that of the x-ray source. The video signal from the camera
was digitalized to be evaluated for geometrical errors. A metal ball fixed to the
stereotactic base frame via XYZ-sliding rods was used as a simulated target.
Displacements of the target from the isocenter were measured during rotation of
the gantry. Displacements in the gantry-rotation plane were satisfactorily small,
while those perpendicular to it were maximal at gantry position angles of 0
degree and 180 degrees. This error night be caused by gravitational vending of
the heavy gantry head. Although other major errors of the linac were within one
millimeter, the center of coach rotation around the isocenter did not coincide
with the center of gantry rotation, probably owing to gravitational vending.
Special care should be taken when very small collimators are employed.
PMID- 9558850
TI - [Placing two parallel catheters by Seldinger's approach through the femoral
artery for CT angiography and CT during arterioportography: evaluation of
efficacy and safety].
AB - The purpose of this study was to evaluate the efficacy and safety of placing two
parallel catheters by Seldinger's approach through the femoral artery for CT
angiography (CTA) and CT during arterioportography (CTAP). We performed an
analysis of 30 patients. Two introducers were successfully placed in all cases.
Only one minor complication was observed, a localized inguinal hematoma. The
CTA/CTAP procedures were successful in all patients except six who had anatomical
variations of the hepatic arterial supply. Our methods proved to be useful and
safe for patients with standard hepatic arterial supply.
PMID- 9558851
TI - [New methods for measuring atlanto-axial vertical subluxation in rheumatoid
arthritis by MR imaging].
AB - We proposed two new methods of measuring atlanto-axial vertical dislocation in
rheumatoid arthritis by MR imaging. One is the distance from the subdental
synchondrosis of the axis to the diameter of the ring of the atlas. The other is
the distance from the midpoint of the anteroposterior ends of the inferior margin
of the axis to the diameter of the ring of the atlas. Values were also determined
by the Ranawat method and the Redlund-Johnell method. There was good correlation
between values determined by the new methods and those determined by the Ranawat
method and Redlund-Johnell method.
PMID- 9558852
TI - [Three-dimensional MR angiography of HCC and portal and hepatic veins using
superparamagnetic iron oxide].
AB - We examined a new MR technique for obtaining 3D-MRA images of the liver that
simultaneously depicts HCC and the portal and hepatic veins. Five patients with
clinically suspected HCC were studied with superparamagnetic iron oxide (SHU
555A) used as a negative contrast medium for the liver. In our study, a 3D
rotational display was provided on the CTR monitor from 2D-TOF images by computed
reconstruction, clearly showing HCC and portal and hepatic veins on the same
image. Our method was found to be of great value in planning surgery of the
liver.
PMID- 9558853
TI - [Three-dimensional gadolinium-enhanced dynamic MRI of whole liver using
spectrally selected enhanced fast gradient recall sequence].
AB - Three-dimensional gadolinium-enhanced dynamic MRI of whole liver using the
spectrally selected enhanced fast gradient recall sequence (spec IR-efgre3d) was
performed in five patients with HCC. Ten HCC nodules were confirmed by CTA, CTAP
and Lipiodol CT, and all of them were detected with dynamic MRI. MIP images
reconstructed from 3D gadolinium-enhanced dynamic MR studies clearly showed the
main portal vein and its branches in all cases. Portal vein thrombosis was also
demonstrated with the MIP images.
PMID- 9558854
TI - Obstruction of the right ventricle outflow tract during right cardiac prolapse.
AB - We observed cardiac prolapse following right pneumonectomy in which the patient
experienced a 90 degree rotation of the heart and compression of right
ventricular outflow tract from behind by the aorta, which led to an increase in
right atrial pressure and a decrease of pulmonary artery pressure and cardiac
output. Compression of the right ventricular outflow tract by the base of the
aorta was observed as an additional shock inducing factor in right cardiac
prolapse.
PMID- 9558855
TI - The double fold free radial forearm flap for skin large fistule closure after
pharyngoesophageal operation.
AB - Reported herein is a case who underwent a one-stage closure of pharyngostome
utilizing a double fold free radial forearm flap (FRF) was performed. By use of a
thin and large FRF, this operative method permits the closure of a large fistula
and thus satisfies cosmetic requirements.
PMID- 9558856
TI - [Open heart surgery without blood transfusion for cyanotic congenital cardiac
defects].
AB - Between November 1994 and January 1997, 42 cases of cyanotic congenital cardiac
defects underwent definitive surgery at Matsudo Municipal Hospital. We evaluated
30 cases, each weighing from 7 to 20 kg. The procedures were performed at the age
of 9 months to 6 years (mean age-2.4 years). The body weights were 7.7 to 20 kg
(mean weight-11.4 kg). The preoperative diagnoses were Tetralogy of Fallot (TOF)
in 19 cases, Fontan candidates in 6 and the others in 5. We classified them into
3 groups; Group A--15 cases were completed with non-blood transfusion, Group B--8
cases used only plasma protein fraction and Group C--7 cases used blood
transfusion. Cardiopulmonary bypass (CPB) system is a semi-closed circuit and
priming volume is 400 to 600 ml. There is no difference among the 3 groups in
operative age, body weight, operation time, CPB time, aortic cross clamp time,
bleeding and postoperative state. The same results were obtained in minimum base
excess and urine output during CPB and the changes of hematocrit and total
protein. In Groups A and B, CPB blood was returned to the patient as soon as
possible after CPB was weaned, but in Group C, blood transfusion was performed
without the return of CPB blood. In all groups, hemodynamics were stable.
Retrospectively, it is thought that blood transfusion was not necessary in Group
C and the use of the plasma protein fraction was not needed in Group B. In
conclusion, the open heart surgery can be performed safely without blood
transfusion for cyanotic congenital cardiac defects.
PMID- 9558857
TI - [Postoperative complications after coronary bypass operations in patients with
pulmonary impairment].
AB - The postoperative courses of 112 patients with pulmonary disease (59 with
obstructive disease = Group 0, 38 with restrictive disease = Group R and 15 with
mixed disease = Group M) who underwent elective coronary artery bypass grafting
were retrospectively reviewed. Preoperative pulmonary function test (percentage
of vital capacity = %VC and percentage of forced expiratory volume at 1 second =
FEV1.0%) of these group showed typical abnormal values, and velocity ratio of 50%
and 25% of maximum expiratory flow volume (V50/V25) of each groups were measured
abnormal values (3.99 +/- 1.44 of Group O, 4.26 +/- 1.42 of Group R and 3.74 +/-
1.82 of Group M). The our strategy for these groups were a). Using
skeletonization method for harvesting internal mammary artery (IMA) b) Take care
not to injure the phrenic nerve and open the pleural cavity as surgical
techniques (Harvesting IMA) and c) Administration of theophylline derivatives and
corticosteroids to prevent bronchospasm d) Administration of concentrated serum
albumin and diuretics to prevent pulmonary edema as therapeutic measures. The
length of stay in the intensive care unit and ventilation time of each groups
were not significantly longer. Patients of group M had more respiratory
complications (atelectasis, pleural effusion, pneumothrax, bronchospasm, and
pneumonia) than did patients of group R (p < 0.05), but did not more nonpulmonary
complications and hospital deaths. The four in hospital deaths (2 with group O, 1
with group R and 1 with group M) were not directly related to pulmonary
complications. Thus, result of CABG in patients with pulmonary impairment
definitely proved to be satisfactory by our strategy, but mixed pulmonary
diseased significantly had more pulmonary complications.
PMID- 9558858
TI - [Mid-term evaluation of cryopreserved aortic allograft].
AB - Recently aortic root replacement and free-hand aortic valve replacement with
cryopreserved allograft are accepted and established as useful procedures in USA
and Europe. Otherwise allograft aortic valve failure due to structural valve
degeneration, progressive loss of leaflet extensibility or progressive aortic
root dilatation are reported. Aortic root replacement and free-hand aortic valve
replacement with cryopreserved allograft were performed on three patients in the
Department of Cardiovascular Surgery, NCVC between March of 1992 and March of
1994. We evaluated the mid-term function of implanted allograft. Case 1, 2, 58
year-old male and 42-year-old male with aortic regurgitation due to Aortitis had
modified Bentall procedures with composite graft and had redo surgery for aortic
regurgitation due to graft detachment with cryopreserved allograft using "aortic
root replacement". Case 3: 54-year-old male received a cryopreserved allograft
for aortic stenosis/regurgitation using "free-hand technique". Postoperative
echocardiogram showed excellent valve function without regurgitation any
calcification in all cases. However chest computed tomography suggested the new
calcification of allograft wall at 15 months after operation in Case 1 who was
administered steroid agents, despite no calcification in Case 2 during 17 months
follow-up.
PMID- 9558859
TI - [An analysis of the mechanism of postoperative hyperbilirubinemia following
resection of thoracic esophageal cancer in terms of hepatic venous oxygen
saturation and excessive systemic reactions].
AB - Hepatic venous oxygen saturation (ShvO2), parameters of systemic circulation and
cytokine (Interleukin 6) (IL-6)) level were measured in 21 patients with thoracic
esophageal cancer in order to analyze the mechanism of occurrence of
postoperative hyperbilirubinemia (PHB). ShvO2 fell during operation, especially
during intrathoracic procedures, and a significant correlation was noted between
the total time during which ShvO2 was below 60% and the postoperative peak serum
bilirubin level (peak-Bil) (r = 0.595, p = 0.0037). Patients with PHB (group H)
had worse systemic circulation and a lower oxygen supply postoperatively than
patients without PHB (group N). Body weight and water balance recovered earlier
in group N. Postoperatively, numbers of peripheral lymphocytes and platelets
changed lower in group H, while CRP and IL-6 changed higher in group H.
Furthermore, a significant correlation was noted between the IL-6 level just
after operation and peak-Bil (r = 0.669, p = 0.0006). These results suggests PHB
results from intraoperative liver hypoxia and poor postoperative systemic
circulation. Individual severeness of reactions to the operative stress,
excessive or adequate, plays a role in the occurrence of PHB as well.
PMID- 9558860
TI - [Clinical benefits of normothermic cardiopulmonary bypass on postoperative
systemic metabolism].
AB - To evaluate the influence of body temperature during cardiopulmonary bypass (CPB)
on postoperative systemic metabolism, 32 patients undergoing elective cardiac
surgery were randomly assigned to either hypothermia (n = 16) or normothermia (n
= 16). Serial hemodynamic parameters and blood samples were obtained after
surgery. CPB and operation times were significantly shorter and the platelet
reduction ratio during CPB [ = (platelets before CPB-platelets after
CPB)/platelets before CPB] was significantly lower in normothermic patients than
in hypothermic patients. The platelet reduction ratio was dependent on the
minimum rectal temperature during CPB, the operation time, and the CPB time. In
the early postoperative period, hypothermic patients had abnormally high systemic
vascular resistance and a reduced cardiac index compared with the normothermic
patients. There were no differences between 2 groups in postoperative hepatic and
renal functions, changes in oxygen consumption, arterial-venous PCO2 or arterial
venous pH gradient. This study suggested a beneficial influence of normothermic
CPB on postoperative hemodynamics. Normothermic CPB was not associated with
adverse effects on postoperative metabolic recovery.
PMID- 9558861
TI - [Postoperative infections related to pacing wires, pulmonary arterial catheters,
and drainage tubes temporarily inserted during open-heart surgery].
AB - Bacterial examinations of temporary pacing wires (P-wires), pulmonary arterial (P
A) catheters, and drainage tubes temporarily inserted during open-heart surgery
were performed in 213 patients. Bacteria were detected in 19 (2.8%) of 672
specimens gathered from the subject patients, with coagulase-negative
Staphylococcus (CNS) being most frequently observed. P-wires accounted for 17 out
of 19 of the culture-positive specimens, and 7 of the P-wires remained in place
for more than two weeks. The frequency of infection with the P-wires was
significantly higher than with the P-A catheters or drainage tubes. The period of
time that the P-wire was left in place significantly longer than for P-A catheter
or drainage tube. There was, however, no statistically significant difference
between the culture-positive and negative groups in respect to age, detention
periods, operation times, CPB times, or length of ICU stay. As a result of these
findings, we have concluded that P-wires should be removed as soon as possible
following surgery, and in any case, a meticulous care should be taken to prevent
transcutaneous infection.
PMID- 9558862
TI - [Mediastinoscopic drainage for descending necrotizing mediastinitis].
AB - A case of descending necrotizing mediastinitis that was treated by
mediastinoscopic drainage is reported. The patient was a 56-year-old diabetic
woman. A hypopharyngeal abscess extended to the mediastinum through the neck. No
septic condition was noted. Chest CT showed that the abscess reached 4 cm below
the tracheal bifurcation. Pus was drained under direct observation by
mediastinoscopy, and a drain was placed in an appropriate position. After
operation, lavage was performed through the drain, and cure was achieved on the
42nd postoperative day. This technique should be considered as surgical treatment
for descending necrotizing mediastinitis in the absence of serious complication
such as sepsis, because it has a more reliable drainage effect than the
conventional transcervical method, and because it is less invasive than
thoracotomy.
PMID- 9558863
TI - [Transcatheter stent-graft implantation for the treatment of acute aortic
dissection--rupture of aneurysm because of perigraft leakage].
AB - An 82-year-old woman was diagnosed as having acute type B aortic dissection. At
bed rest, her systolic blood pressure was kept less than 120 mmHg. Four days
later the aneurysm threatened to rupture. Because she presented a high operative
risk for open-chest surgery, a stent-graft was implanted across the dissection
site via transcatheter. The entry site to the aneurysm was closed by the stent
graft, and postoperative aortograph demonstrated that contrast medium did not
enter the false lumen except for a trivial projection. A CT scan 6 days after the
stent-graft implantation unexpectedly demonstrated the false lumen not only had
not thrombosed, but had expanded. As a result, 8 days after the operation the
aneurysm ruptured into the left pleural cavity, and the patient died. An autopsy
revealed the stent-graft was exactly implanted across the entry site, but that
the diameter of the graft was slightly larger than that of the aorta.
Consequently, a portion of the rim of the graft had been wraped after
implantation, causing perigraft leakage. Leakage is one of the gravest
complications of the stent-graft implantation, to prevent it, a new design for
stent-graft device is essential.
PMID- 9558864
TI - [The usefulness of thoracoscopic surgery for pleuritis carcinomatosa].
AB - We performed thoracoscopic surgery for pleuritis carcinomatosa, in which re
expansion of the collapsed lung was impossible, by employing tube thoracostomy.
One of the treatments used for pleuritis carcinomatosa was drainage of the
pleural effusion followed by re-expansion of the collapsed lung. The
decortication and biopsy of the pleura and the pleural effusion drainage with the
thoracoscopic procedure were performed, allowing control of the pleural effusion
and re-expansion of the collapsed lung to be accomplished. We conclude that
thoracoscopic surgery is useful for the thoracic treatment of pleuritis
carcinomatosa.
PMID- 9558866
TI - [A case of Pryce type I intrapulmonary sequestration].
AB - A twenty-year-old asymptomatic man hospitalized because of a vascular murmur and
abnormal shadow in the left lower lung on X-ray film. An aortogram revealed an
abnormal artery arising from the descending thoracic aorta and supplying the left
basal segment, which had no other pulmonary arteries. Although lung ventilation
scintigraphy demonstrated reduced ventilation to the left lower lobe, bronchogram
showed an almost normal bronchial tree except that peripheral branches were
slightly thin. A clinical diagnosis of Pryce type I intrapulmonary sequestration
was made, and left lower lobectomy was performed successfully. We have analyzed
31 cases of Pryce type I intrapulmonary sequestration in Japan. A vascular murmur
is often heard, and a chest X-ray usually shows either a mass shadow or increased
vascular markings. In most of those cases, an abnormal artery arises from the
descending thoracic aorta and it supplies the left basal segment. Because this
type of sequestration causes hemoptysis and infections, surgical intervention is
indicated.
PMID- 9558865
TI - [A case of graft replacement of the ascending aorta to the aortic arch and the
partial descending aorta in a single stage for thrombosed aortic dissection
(DeBakey type II + IIIb)].
AB - We report here a case of graft replacement of the ascending aorta to the aortic
arch and the middle portion of the descending aorta in a single stage for
thrombosed aortic dissection. The patient was a 53-year-old male who was
transferred to our hospital with a diagnosis of thrombosed aortic dissection.
Conservative therapy was continued but three weeks after the onset, chest
enhanced CT scan and digital subtraction angiography revealed an opacified false
lumen in the ascending aorta and a ulcer like projection in the middle portion of
the descending aorta. He was therefore diagnosed as having redissecction in
DeBakey type II + IIIb thrombosed aortic dissection. Graft replacement of the
ascending aorta, the aortic arch, and a part of the descending aorta was
performed in a single stage via median stenotomy with the aid of extracorporeal
circulation and selective cerebral perfusion. Postoperative digital subtraction
angiography showed satisfactory reconstruction of the thoracic aorta. The patient
is still leading a normal life two years after the operation.
PMID- 9558867
TI - [An emergent operation for metastatic cardiac tumor of malignant cystosarcoma
phyllodes].
AB - A 47-year-old woman was transferred to our hospital under endotracheal intubation
with severe hemodynamic deterioration. A left mastectomy had been performed 8
months earlier and histology of the specimen showed malignant cystosarcoma
phyllodes. An angiography and echocardiography suggested massive mass of the
right ventricle extending to the pulmonary artery. An emergent life-saving
operation was required using cardiopulmonary bypass. A huge multilobular tumor
was resected from the right ventricle through the pulmonary artery as much as
possible and a tricuspid valvuloplasty was also performed. The patient was weaned
from cardiopulmonary bypass, then satisfactorily recovered from hemodynamic
disturbances. Nevertheless, she died 15 days later due to multiple organ failure.
Microscopic examination of resected specimen showed the neoplastic stromal cells
that increase mitotic activity and have sarcomatous characteristics, consistent
with a metastatic cystosarcoma phyllodes. This is a second case of operation for
cardiac metastasis of cystosarcoma phyllodes using cardiopulmonary bypass, so far
presented in the literature of the world reviewed by the authors.
PMID- 9558868
TI - [Cystic thymoma without solid mass lesions on diagnostic imaging--a case report].
AB - A 68-year-old man was referred to our hospital because of an abnormal shadow on a
chest X-ray film. A chest CT scan and MRI demonstrated a cystic mass without
solid lesions on the anterior mediastinum. The CT scan also showed that it was a
well-defined and homogenous mass without contrast enhancement effect. 67Ga and
201T1 scintigrams showed no uptake in the mass. Needle aspiration cytology was
performed, and there was no evidence of neoplasms. A thymic cyst was diagnosed,
and then an operation was performed. At the operation, the cystic tumor was
removed along with thymic tissues by a median sternotomy. On the cut section of
the resected specimen, the tumor was found to be a cyst with small solid nodules
on the wall. Pathologic examination revealed that the tumor was a cystic thymoma.
We consider that patients with cystic tumors on the anterior mediastinum should
obtain histopathologic diagnosis because of the difficulty in excluding neoplasms
such as thymoma.
PMID- 9558869
TI - [Malignant fibrous histiocytoma of the diaphragm--a case report].
AB - A 56-year-old woman was admitted to our hospital with the chief complaint of left
back pain. We detected left pleural effusion on chest X-ray and performed chest
drainage. No malignant cells were detected in the effusion. Chest CT demonstrated
a tumor shadow over the left diaphragm and left pleural effusion 6 months later.
She underwent en bloc resection of the tumor and left diaphragm. Histological
evaluation revealed malignant fibrous histiocytoma (MFH). Recurrent tumors were
found in the abdomen 8 months after the operation, and she underwent resection of
the abdominal recurrent tumors. Histological evaluation of the recurrent tumors
also showed MFH. The patient died 28 months after the first operation.
PMID- 9558870
TI - [Combined rupture of trachea and esophagus following blunt trauma--a case
report].
AB - A 49-year-old man was involved in a motor vehicle crash and was admitted to a
local hospital. The following day, he was transferred to our hospital because of
worsening dyspnea. Initial examination revealed no subcutaneous emphysema, and
chest computed tomography (CT) demonstrated no mediastinal air. A left
thoracentesis tube was placed for pneumothorax, which reduced the patient's
respiratory distress. He had a persistent, productive cough, which worsened when
he drank water. A repeat chest CT on the fifth hospital day revealed a tracheo
esophageal fistula. Bronchoscopy and esophagoscopy confirmed the diagnosis. He
underwent repair of the trachea and esophagus. The ruptured membraneous portion
of the trachea was closed with interrupted sutures and covered with pedicled
pericardial flap. The perforated anterior esophageal wall was sutured in layers
and reinforced with a fifth intercostal muscle flap. A gastrostomy tuve was
placed for feeding access. Within 6 weeks, the patient recovered completely.
PMID- 9558871
TI - [Left atrial isolation for chronic atrial fibrillation associated with aortic
arch dissection and aortic valve disease in a 70-year-old man].
AB - A 70-year-old male with aortic regurgitation, chronic atrial fibrillation (Af)
and chronic aortic dissection of the aortic arch was treated simultaneously. We
found a limited dissection in front of aortic arch during operation. We performed
total arch replacement using a branched prosthesis and aortic valve replacement
in addition to a modified left atrial isolation for chronic Af under the aid of
extracorporeal circulation, and selective cerebral perfusion. Left atrial
isolation is a simpler procedure than maze procedure and left side maze procedure
for eliminating Af. This simple procedure makes possible a simultaneous extended
operation for complicated aortic and cardiac disease even in an elderly patient.
PMID- 9558872
TI - [Huge localized mesothelioma of the diaphragm in a 17-year-old female--a case
report with calculated tumor volume doubling time].
AB - An operative case of localized mesothelioma of the pleura developed in a 17-year
old female was reported. She was admitted to our hospital complaining of right
chest pain. A chest X-ray film showed a huge mass in the right lower field of the
lung. After the embolization of the right inferior phrenic artery, which was the
main feeder to the tumor, it was then successfully resected combined with the
right diaphragm and the right lower lobe of the lung. Histologically, the tumor
was diagnosed as benign localized mesothelioma (solitary fibrous tumor of the
pleura). Further histological and immunohistochemical study revealed that it had
developed from the connective tissue under the parietal mesothelium of the
diaphragm. As chest roentgenograms had been undertaken during past two years, the
tumor volume doubling time was calculated at 153 days. Despite the short tumor
volume doubling time as like primary lung cancer, she is alive without recurrence
5 years after the operation.
PMID- 9558873
TI - [A case of ruptured descending thoracic aortic aneurysm due to Salmonella
infection].
AB - A 66-year-old male was admitted to our hospital because of pyrexia, chest pain
and hemosptum. Inflammatory findings were made and salmonella enteritidis was
detected by bacterial examination of sputum and stool. Enhanced chest CT
examination disclosed a descending thoracic aortic aneurysm which had ruptured
into the left lower lobe of the lung. Under a diagnosis of ruptured mycotic
descending thoracic aortic aneurysm, an emergency operation was performed. A left
posterolateral thoracotomy carried out after axillo-bilateral femoral bypass
grafting. A pseudoaneurysm of the descending thoracic aorta had ruptured into the
left lower lobe of the lung. After resection of the aneurysm, closure of both
ends of the intact descending thoracic aorta and a left lower lobectomy were
carried out. An ascending aorta-infrarenal abdominal aorta bypass was performed
because of insufficient visceral arterial blood flow through the axillo-bilateral
femoral bypass. The patient's immediate postoperative recovery was complicated by
paraplegia. Chloramphenicol and levofloxacin were administered for three months,
after which his recovery followed a good course.
PMID- 9558874
TI - [Initial clinical experiences of the ABIOMED BVS SYSTEM 5000 in Japan].
AB - The initial clinical experience of the ABIOMED BVS SYSTEM 5000 in Japan is
reported. The system is a paracorporeal pulsatile assist device intended for
temporary ventricular support. It consists of a pneumatic drive console, a blood
pump, and the atrial and arterial cannulas. The pump is of a dual chamber design,
with the upper chamber as a passive, gravity filled resevoir and the lower
chamber as a pumping chamber. Since the system is designed to be simple, safe and
automatically controlled, no additional personnel is required to control
perfusion. This report describes our initial clinical experiences with the
ABIOMED BVS SYSTEM 5000 in Japan. This device was used in three patients with
post cardiotomy cardiogenic shock and fulminant myocarditis. The first patient
developed acute occlusion of left main coronary artery who required emergent
surgical revascularization following PTCA and stent implantation. He couldn't
wean from CPB and required the insertion of an LVAD. The second case suffered
from a cardiac arrest after CABG and could not be resuscitated. The ABIOMED BVS
5000 was inserted and the patient successfully weaned from support. The third
patient developed fulminant myocarditis and was supported with the system for 269
hours and was successfully weaned after near complete myocardial recovery. Our
initial experience with the ABIOMED BVS SYSTEM 5000 indicates that the system can
provide complete cardiac support allowing full recovery from a cardiac variety of
causes of dysfunction. The device has the potential to improve the survival rate
of patients with severe acute recoverable myocardial damage. It is expected that
this device can be a viable tool for treatment of intractable heart diseases.
PMID- 9558875
TI - [Two surgical cases of right parasternal minimal incision for aortic valve
replacement].
AB - Although median sternotomy has been used as a good approach to all cardiac valves
and coronary arteries, advantages of the minimal invasive cardiac operation have
been reported recently. We employed the right parasternal minial incision,
reported by Cosgrove et al. for two cases of aortic valve replacement. In the
first case, we were able to get a good operation field and easily implanted a
mechanical prosthesis. In contrast, we had some difficulties with the second case
where in addition to the third and fourth cartilages, a second cartilage
resection was necessary because the aortic root lay at a cephalic level.
Moreover, the operation field was restricted because we left several rib
cartilages to preserve the right internal thoracic artery. The cannula had to be
inserted via the right atrium as we failed to insert it in the right femoral
vein, and the aortic root deviated more medially than usual. From these
experiences, it is important to check the position of aortic root, and if the
cannula cannot be inserted in the femoral vein, cannulation via the right atrium
can ve utilized in the minimal invasive cardiac operation.
PMID- 9558876
TI - [Clinical significance of hepatitis G virus (GBV-C/HGV)].
PMID- 9558877
TI - [The clinical significance of plasma tissue plasminogen activator (t-PA) levels
in severe acute or fulminant hepatitis].
AB - We studied the tissue plasminogen activator (t-PA) levels in the plasma of
patients with acute hepatitis (AH), severe acute hepatitis (AHs) and fulminant
hepatitis (FH). Plasma t-PA levels were measured consecutively on the first,
third and seventh days of hospitalization. Plasma t-PA levels were markedly
higher in AHs and FH than in AH (p < 0.05, p < 0.01, respectively) on the first
day, but did not differ significantly between AHs and FH on this day. The t-PA
levels decreased markedly on the third and seventh days in AHs (both p < 0.05),
but did not change from the first day to the third and seventh days in FH. The t
PA levels on the third and seventh days were higher in FH than in AHs (both p <
0.05). There was a significant increase in the plasma t-PA level before an
episode of encephalopathy in FH compared with levels in AHs. These observations
suggest that t-PA level may be useful as a prognostic parameter in patients with
acute hepatic injury.
PMID- 9558878
TI - [Transjugular intrahepatic portosystemic shunt for the treatment of refractory
ascites].
AB - Five cirrhotic patients with refractory ascites were treated with transjugular
intrahepatic portosystemic shunt (TIPS). Before TIPS, although patients were
received salt restriction (5 g/day), diuretic therapy (furosemide 112 mg/day,
spironolactone 140 mg/day), albumin infusion and paracentesis, ascites did not
show improvement. After TIPS, urine volume and urinary sodium excretion increased
significantly. Mean body weight decreased significantly from 73 kg before TIPS to
63 kg a month after TIPS. Improvement of ascites after TIPS were associated with
a significant reduction in the dose of diuretics. On discharge, complete
resolution of ascites was found in 2 patients and mild ascites remained in 3
other patients. Four patients presented 6 episodes of shunt stenosis in the
follow-up period, and were treated with balloon dilatation. Ascites increased on
shunt dysfunction and showed improvement after balloon dilatation. Post-TIPS
encephalopathy was seen in 2 patients and one of 2 was disabled. In conclusion,
although post-TIPS shunt dysfunction and encephalopathy are common. TIPS is an
effective therapy for refractory ascites in patients with cirrhosis.
PMID- 9558879
TI - [A case of pyogenic granuloma in the cervical esophagus].
PMID- 9558880
TI - [A case report of gastric leiomyosarcoma developed at the fornix prolapsed into
the duodenum].
PMID- 9558881
TI - [Effect of drainage and injection factor XIII with fibrinogen for hepatic biloma
resulting from transcatheter arterial embolization in patients with
hepatocellular carcinoma--report of two cases].
PMID- 9558883
TI - [Two cases of Castleman's disease originated in the retroperitoneum].
PMID- 9558882
TI - [A case of anticonvulsive drug-induced liver injury accompanied by a transient
appearance of antimitochondrial antibody, M2].
PMID- 9558884
TI - Alternative medicine: readers have their say.
PMID- 9558885
TI - Alternative medicine: readers have their say.
PMID- 9558886
TI - Alternative medicine: readers have their say.
PMID- 9558887
TI - Alternative medicine: readers have their say.
PMID- 9558888
TI - Psoas abscess: an uncommon disease.
PMID- 9558889
TI - Hogs and health.
PMID- 9558890
TI - An open letter to North Carolina doctors: Wall Street mentality and health care-
a poison pill?
PMID- 9558891
TI - Coccidioidomycosis in a patient with atopic dermatitis.
PMID- 9558892
TI - Colocutaneous fistula. A rare complication of percutaneous gastrostomy.
PMID- 9558893
TI - Bloody diarrhea caused by Escherichia coli O157:H7.
PMID- 9558894
TI - Niacin. Help for your cholesterol--harm for your liver.
PMID- 9558895
TI - How does North Carolina law enforcement limit youth access to tobacco products? A
study of officers' attitudes and behaviors.
PMID- 9558896
TI - The role of the medical profession in a managed care environment. Statement of
the Bioethics Committee of the North Carolina Medical Society.
PMID- 9558897
TI - "Cage" technology revolutionizes approach to spinal fusion surgery.
PMID- 9558899
TI - A program to control breast and cervical cancer in North Carolina.
PMID- 9558898
TI - How do North Carolina prenatal care providers counsel and test pregnant women for
HIV? Survey measures knowledge of HIV testing benefits.
PMID- 9558900
TI - Response to a high infant mortality rate. The Guilford County Adopt-A-Mom
Program.
PMID- 9558901
TI - Isolated extremity soft tissue injury. An occupational hazard in rural eastern
North Carolina.
PMID- 9558902
TI - Emergency events involving hazardous substances in North Carolina, 1993-1994.
PMID- 9558903
TI - Shortening hospitalization after appendectomy in children.
PMID- 9558904
TI - Management of lower extremity venous stasis ulcers in a comprehensive wound care
clinic.
PMID- 9558905
TI - [Quality of life in medicine].
PMID- 9558906
TI - [DRG's and cost/efficacy indicators in nephrology and dialysis. Results at a
hospital division].
AB - The Diagnosis Related Groups (DRGs) classification system correlates hospital
performance with their relative costs and encourages more efficient productive
processes. We report the following parameters: a) the distribution of hospital
discharges according to the Major Diagnostic Categories (MDCs) and DRGs; b) the
relationship between mean length of stay and threshold values; c) economic
analysis of the cost-reimbursement pay-off. The results showed that 71.3% of DRGs
belonged to nephro-urological MDC 11 and 28.7% in other internal MDCs (mainly
involving cardiac and respiratory system). Of the latter, 67.7% were utilized for
dialysis and transplant patients and kidney donors. In MDC 11 the most common
DRGs were: the surgical DRG 315, produced by the vascular accesses for
hemodialysis and by insertion of Tenckoff catheter for peritoneal dialysis, DRG
316 by cases of acute and chronic renal failure, DRG 332 by biopsy-proven
glomerulonephritides. The length of stay was most commonly within range of one
third of threshold value for specific DRG; there was a low percentage of one-day
stays and outlier cases. The economic analysis demonstrated that mean daily
reimbursement sum was 590,714 ITL. Analysis of the overall costs yielded a mean
daily cost of 455,838 ITL. In conclusion, quality indicators show that,
appropriately, our specialist activity is largely devoted to the diagnosis and
treatment of acute and chronic nephropathies and complications following dialysis
and renal transplant.
PMID- 9558907
TI - [High prevalence of hepatitis C virus infection in patients with non-Hodgkin's
lymphoma at the onset. Preliminary results of an Italian multicenter study].
AB - 143 patients with non-Hodgkin lymphoma (NHL) at the onset entered this
perspective study on NHL-associated risk factors. They were 87 males and 56
females with a mean age of 52.3 years (range 14.6-82.3). An associated hepatitis
C virus (HCV) infection was found in 16 of the 143 NHL cases (11.2%; 95% CI 6.5
17.5). They were 11 males and 5 females [mean age 59.9] year with disseminated
(13/16) or localized NHL disease (3/16)]. The NHL histological subgroup was low
grade (6/16), intermediate grade (2/16) or high grade (8/16). The cell origin was
B in 15/16 cases and B cell-T cell rich in 1/16. The discovery of HCV infection
was contemporary to lymphoma diagnosis in 6/16 cases but preceded the NHL onset
in the other 10 patients. In these 10 patients the median time between HCV
infection diagnosis and NHL onset was 3.6 years (range 1-14.5). These data
confirm that in Italy the prevalence of HCV infection in patients with NHL
(11.2%) is significantly higher than expected in the general population (1.3
3.2%). The finding that, in most cases, HCV infection was definitely antecedent
to NHL onset, usually by years, adds evidence to the possible causative role of
the HCV in lymphomagenesis.
PMID- 9558909
TI - [Chronic lymphatic leukemia and large granular lymphocytes].
AB - Chronic large granular lymphocyte leukemia is a rather rare disorder (less than
5% of LLC). Its subtype CD3+/CD8+ is often a clonal disease and without malignant
characteristics. This kind of disease shows a clinical and laboratory
heterogeneity, probably due to the immunological and functional variety of
granular lymphocytes. In some cases of LGL leukemia an associated pathology,
especially rheumatoid arthritis and chronic infections, has been reported. On the
contrary, the relationship with neoplasms has been rarely proved in literature:
only occasional studies have been reported and anyway they are not supported by a
sufficient number of cases. Two cases of LGL leukemia are here delineated: a
woman with advanced breast adenocarcinoma and another one with Sjogren disease.
The first one had a rapidly fatal course, while the other one had a prolonged
clinical course with chronic neutropenia (13 years follow-up). The association
between carcinoma and LGL leukemia may be just a casual finding but the
hypothesis of a possible relationship is however very interesting on account of
the important role of granular lymphocytes in controlling tumoral growth.
Moreover, both patients had concomitant chronic HCV-correlated infection: maybe
it will worth making a prevalence study with a greater number of cases, in order
to evaluate a probable relationship between these pathologies. The growth factor
G-CSF may be useful in the treatment of infections that often occur in patients
with severe neutropenia.
PMID- 9558908
TI - Five day intermittent vs seven day continuous 2-chlorodeoxyadenosine infusion for
the treatment of hairy cell leukemia. A study by Italian Group for the Hairy Cell
Leukemia.
AB - The new purine-analogue 2-chlorodeoxyadenosine (2-CdA) has proved to induce an
high CR rate and a long lasting disease free survival. In this study we compare
the efficacy and toxicity of 2-CdA employed in two different schedules (A and B).
Forty-one patients have been enrolled from 1994: 22 p. (group A) were treated
with a single cycle of 2-CdA given as two hour i.v. infusion on 5 consecutive
days (0.15 mg/kg/die); while 19 p. (group B) with continuous i.v. infusion for 7
consecutive days (0.10 mg/kg/die). Response criteria were those proposed by NCI.
The Hairy Cell Index (HCI) was calculated using DBA44 MoAb. At three months, the
responses in group A (19/22) were: 5 CR (26.3%), 6 GPR (31.5%), 5 PR and 3 NR.;
in group B (17/19): 6 CR (35.3%), 3 GPR (17.6%), 4 PR and 4 NR. Overall response
at six months was respectively 84.2% and 76.5%. At six months the responses were:
in group A (18/22): 9 CR (50%), 4 GPR (22.2%), 3 PR, 2 NR; in group B (16/19): 4
CR (25%), 6 GPR (37.5%), 3 PR, 3 NR. Overall response at 6 months was
respectively 88.8% (group A) and 81.2% (group B). The 5 day intermittent schedule
appears efficient, well tolerated and suitable for out-patient treatment. DBA44
MoAb appears useful to better define the HCI and to distinguish CR from GPR.
PMID- 9558910
TI - [MALT lymphoma of the left lacrimal and mammary glands, liver cirrhosis caused by
HCV and type II cryoglobulinemia].
AB - We describe a case of MALT (mucosa-associated lymphoid tissue) lymphoma
associated to post-hepatitis C liver cirrhosis, type II cryoglobulinaemia,
gastrointestinal bleedings and thromboses. HCV infection justified the
association between the first three pathologies, while gastrointestinal bleedings
and thromboses were respectively attributed to portal hypertension secondary to
liver cirrhosis and to some thrombophilic conditions. Among the latter there was
also an antithrombin III deficiency. The singularity of the case and some
difficulties met in its treatment, justify the report.
PMID- 9558911
TI - [Clinical spectrum of extrapulmonary sarcoidosis. From the onset to organ
transplantation].
PMID- 9558912
TI - [Role of autologous stem cell transplantation in the treatment of Hodgkin's
lymphoma].
AB - Among lymphomas, treatment of Hodgkin's disease (HD) allows the highest cure
rate. Radiotherapy (RT) represents first choice therapy in early stages,
providing complete remission (CR) rate even superior to 90%. Chemotherapy (CHT)
or, when indicated, the combined modality treatment (CHT + RT) is successful, in
terms of long overall survival (> 10 yrs) in more than 60% of patients with
advanced stage disease at onset. Considering all stages of disease at onset,
about 75% of patients can be cured. However, the remaining 25% results resistant
to the conventional approach (CHT +/- RT) or, mainly, relapses after first CR.
For these poor prognosis patients, it has been assessed the possibility of
inducing (or reinducing) a CR by using high dose CHT with stem cells rescue.
Autologous stem cell transplantation (ASCT) consists in the administration of
antiblastic drugs at so high dosages to require the consequent reinfusion of stem
cells, preventively harvested and cryopreserved, thus dramatically decreasing the
risk of a prolonged bone marrow aplasia. This procedure is currently performed as
intensification treatment in selected cases of patients with advanced stage at
onset, once in CR after first-line therapy. Therefore, the development of
prognostic models aimed to define with higher sensibility and specificity
patients at high risk of relapse and to be submitted to ASCT as consolidation
therapy, is becoming of increasing interest.
PMID- 9558913
TI - Mechanosensitive ion channels in nonspecialized cells.
PMID- 9558915
TI - [Treatment of hypothyroidism].
PMID- 9558914
TI - Calcium and neuronal death.
PMID- 9558916
TI - [The importance of HIV in the Spanish woman].
PMID- 9558917
TI - [Results of treatment of Graves-Basedow disease with 131I at low calculated
doses].
AB - OBJECTIVE: To evaluate the results of treatment of Graves' disease with 131I at
low calculated doses. METHODS: A total of 333 patients with Graves' disease were
treated with low calculated doses of 131I on the basis of thyroid size and 131I
uptake (mean doses = 6.6 +/- 1.9 mCi). The mean follow-up was 24.4 months (range
12-145). RESULTS: The accumulated likelihood of hypothyroidism at 145 months of
follow-up was 89.8% (Kaplan-Meier method) and relapse 26%. Pretreatment levels of
T3 above 9 nmol/l were associated with a lower incidence of hypothyroidism (p =
0.049, Mantel-Cox method). Pretreatment levels of T4 above 300 nmol/l were
associated with a higher risk of therapy failure (odds ratio 3.27; 95% confidence
interval = 1.3-8.2, Cox method). Age, sex, previous therapy with anti-thyroid
agents or surgery, 131I uptake, initial and total dose of 131I, number of
administered doses and development of transient hypothyroidism were not
predictive of the evolution of thyroid function. CONCLUSION: Therapy of
hyperthyroidism (Graves' disease) with low calculated doses of 131I shows a high
incidence of hypothyroidism, also increasing the cost involved in estimating the
dose and long-term follow-up.
PMID- 9558918
TI - [Prevalence of psychiatric disturbances and psychopathologic status in patients
with systemic lupus erythematosus].
AB - BACKGROUND: Psychiatric disorders are commonly associated with systemic lupus
erythematosus (SLE). Some authors consider that these disorders can be associated
with cognitive impairment. OBJECTIVES: The objectives of this study were to
establish the particular prevalence of psychiatric disorders in these patients
and to investigate the relationship between psychiatric disorders, cognitive
impairment, life quality, psychological status and adjustment to illness.
MATERIAL AND METHODS: A cross-sectional study is reported of 46 spanish patients
with systemic lupus erythematosus (SLE) attending the outpatients clinics of the
Internal Medicine and Rheumatology Departments at a University Hospital. The
following instruments were used: a Structured Clinical Interview for DSM-III-R,
the Nottingham Health Profile, the Symptom Check-List 90-Revised, the
Psychological Adjustment to Illness Scale and the Integrated Program of
Neuropsychological Assessment Test-Barcelona. RESULTS: The prevalence of
psychiatric disorders at interview was 33%. The most common diagnoses were
affective disorders and psycho-organic syndrome. Affective disorders were
associated with a poorer life quality, number of hospitalizations and psychiatric
background. Adjustment to illness accounted for the psychologic status of the
patients.
PMID- 9558919
TI - [Epidemiology of Paget's disease. Peculiarities in the province of Zamora].
AB - BACKGROUND: Some paramyxovirus (measles, respiratory syncytial virus, and dog's
distemper virus) are currently considered to be responsible for Paget's disease
of the bone. A relevant role is also given to inheritance as predisposing factor.
Some authors have found an association between HLA antigens with this disease,
but without unanimous agreement. Although this hypothesis of an interaction
between a genetic factor and a viral infectious agent is the most accepted
universally, there is not yet a definitive cause for the disease. The
participation of some other environmental factors has not been ruled out.
METHODS: One hundred and forty patients in the Zamora province were studied. The
geographic distribution in the different areas of the province was analyzed and
also whether there was family aggregation all cases. HLA-I was determined in 59
patients and HLA-II in cases with aggregation. The mineral composition (calcium,
fluorine, magnesium, nitrates, and chlorine) analysis of public running water was
carried out in all population centers in the province. RESULTS: Aggregation was
found in four families (four, two, four, and three siblings, respectively).
Although HLA-I antigens were determined in 59 patients, no association was found.
HLA-II antigens were also determined in the involved patients with family links
and no association was found between these antigens and the disease. A much
higher aggregation was found in some particular areas in our province and these
foci coincided with some characteristics of mineral composition of public running
waters. CONCLUSIONS: There is a genetic factor predisposing to the disease, as
family aggregation occurs with a higher frequency than would otherwise be
expected. Nevertheless, no association with HLA antigens was found. This disease
is more common in some particular geographic areas, thus supporting the
hypothesis of an environmental factor as trigger. An association was found
between mineral composition of public running waters and patient geographic
distribution.
PMID- 9558920
TI - [Primary adrenal failure and AIDS: report of 11 cases and review of the
literature].
AB - OBJECTIVE: To know the prevalence of adrenal insufficiency (AI) in our patients
with acquired immunodeficiency syndrome (AIDS) and to compare the clinical
manifestations with those reported in previous series in the literature. PATIENTS
AND METHODS: Retrospective study with review of clinical records of patients with
AIDS diagnosed of AI (plasma cortisol after synthetic ACTH < 18 micrograms/dl) in
our hospital for a period of 6 and a half years. RESULTS: Eleven out of 65
patients (17%) with the hormonal study performed were diagnosed of AI. The
prevalence of AI in our patients with AIDS was 1.66%. The response of plasma
cortisol to synthetic ACTH was abnormal in the 11 patients (mean increase: 1.89
micrograms/dl). Nine out of the 11 patients had a decreased basal plasma cortisol
level (mean: 4.75 micrograms/dl). Basal plasma ACTH levels were increased (mean:
638.9 pg/ml) in seven out of nine patients. Patients were severely
immunosuppressed (mean CD4: 21/microliter). While the clinical course was
subacute (mean: 5.1 weeks), nine out of the eleven patients developed an adrenal
crisis which required emergency therapy. Ten patients had an opportunist
infection--M. tuberculosis (3), M. avium-intracellulare (3), Cytomegalovirus (3),
histoplasmosis (1)--which could involve the adrenal glands in ten patients. All
patients responded to treatment but their mean survival was 5.6 weeks.
CONCLUSIONS: Although the prevalence of AI in our patients with AIDS was low
(1.66%), it is important to be aware of the disease and to order a basal plasma
cortisol value after synthetic ACTH, as treatment improves the life quality of
patients if AI is confirmed, despite a short survival time.
PMID- 9558921
TI - [Casual fall, pain, and abdominal distension].
PMID- 9558922
TI - [Skin rash and pulmonary nodule].
PMID- 9558923
TI - [William's syndrome. Report of a case with family involvement].
AB - Williams' syndrome (WS) is a rare genetic condition of autosomal dominant
inheritance with varying penetrance, which consists of supravalvular aortic
stenosis, a characteristic dysmorphic facies named "elf face", mental retardation
and other clinical manifestations including transient infantile idiopathic
hypercalcemia, growth retardation, and frequent dental problems. It usually
presents sporadically, and there are only a few cases of family involvement
reported in the literature. Recent studies show that mutations in the elastin
gene at chromosome 7q11.23, which occur approximately in 90% of cases, could be
the cause of the different clinical manifestations in this syndrome. In this
paper we report a case of family involvement with five family members involved
with WS (three siblings, the mother, and the siblings' maternal uncle) and all
had cardiac structural disorders (supravalvular aortic stenosis being the most
frequent), a characteristic face and a low intellectual coefficient. The
complementary tests included blood chemistry, chest X-ray, and echocardiogram,
which led to the diagnosis of the associated valve pathology. Three patients
required therapeutic catheterism with Stent valve implant and valve prosthetic
replacement to control cardiac manifestations.
PMID- 9558924
TI - [Classical Kaposi sarcoma of aggressive course].
AB - The aggressive variant of the classical Kaposi sarcoma (KS), though uncommon, has
an utmost relevance because its evolutive characteristics entail a great
morbidity and mortality. Three classical KS cases are reported which manifested
an unusually aggressive course, with extensive cutaneous and visceral
involvement. One of the patients was diagnosed of a non-Hodgkin lymphoma 12
months later. None of the three patients responded to the different therapeutic
regimens used: polychemotherapy, monochemotherapy and interferon-alfa,
respectively. The three patients died within two years after diagnosis. In KS
patients with pulmonary involvement, working in coal mines was recorded as
occupational antecedent. These three cases illustrate the different clinical and
therapeutic characteristics of an uncommon subtype in the KS spectrum in general
and of its classical variant in particular. Likewise, the possible role of
occupational exposure in the etiopathogenesis of KS is discussed.
PMID- 9558925
TI - [Factors modifying alcoholemia].
PMID- 9558926
TI - [New antiviral agents in chronic viral hepatitis].
PMID- 9558927
TI - [Perforation of vena cava inferior as a late complication of an Antheor type
filter].
PMID- 9558928
TI - [Subacute lupus erythematosus and psoriasis].
PMID- 9558929
TI - [Inaccuracy of bibliographic references: are non-read articles cited?].
PMID- 9558930
TI - [Prevalence of hepatitis C virus infection in patients with lichen planus in
Badajoz province].
PMID- 9558931
TI - [Os odontoideum: an entity to be considered in every acute bulbospinal
involvement].
PMID- 9558932
TI - [Personality and anesthesiology. An area to explore].
PMID- 9558933
TI - [Anatomical description of a natural perforation present in the human lumbar pia
mater].
AB - OBJECTIVE: The pia mater has always been considered more permeable than other
meningeal membranes. Natural pia mater perforations found in some animals at-test
to this membrane's permeability. Such perforations, however, have never been
demonstrated in human tissue. Our objective was to study human pia mater from the
dorsal lumbar region, looking for perforations that facilitate the diffusion of
substances to the spinal cord following subarachnoid administration. MATERIAL AND
METHOD: The specimens were removed from four human cadavers aged 70, 72, 77 and
78 years between 8 and 12 hours after death. The specimens were fixed in a
phosphate glutaraldehyde buffer solution, followed by desiccation in acetone and
critical point elimination of acetone, treatment with carbon and metallization
with gold. RESULTS: The pia mater was composed of a smooth surfaced, thin layer
of cells and underlying connective tissue formed mainly of collagen fibers and
fundamental amorphous matter. The collagen fibers were oriented in various
directions. Throughout the surface of the pia mater, natural circular, elliptical
and ovoid perforations were distributed irregularly. Size varied. Most measured
over 10 to 15 micrometers in diameter or less than 5 to 8 micrometers. Inside the
openings, fibers similar to collagen fibers could be seen at the point where they
would normally be found beneath the cell layer. CONCLUSION: The total thickness
of the pia mater varies in different zones of the spine, as a result of
variations in the thickness of the cell layer and in the underlying extracellular
layer. The existence of natural fenestrations in all the analyzed specimens of
human dorsal lumbar pia mater accounts for the high permeability of this
membrane, which permits substances administered in spinal fluid to reach the
spinal cord. These natural fenestrations are areas where the cell surface in
absent, with underlying collagen fibers usually visible. The pia mater is
generally believed to be composed of a complete cell layer that forms a barrier
between the central nervous system and the subarachnoid space; however, the
presence of fenestrations would indicate that such a barrier does not exist, the
base membrane being placed under the connective fibers, the only intact structure
prior to medullary glial cells.
PMID- 9558934
TI - [Is crystalloid cardioplegia still a valid technique for myocardial myocardial
protection?].
AB - OBJECTIVES: The routine use of a cardioplegic solution for myocardial protection
during the ischemic phase of cardiac surgery represents a great therapeutic
advance. Two cardioplegic solutions are currently in use: crystalloid and blood
solutions. As blood cardioplegia has been shown to offer superior myocardial
protection, its use at present is widespread. We did a retrospective study to
assess whether crystalloid cardioplegia might nevertheless continue to be useful.
PATIENTS AND METHODS: Forty patients with heart disease underwent surgery between
March 1994 and March 1995, with the use of crystalloid cardioplegia (group A).
Blood cardioplegia was used in 72 patients during the same period (group B).
RESULTS: There were no significant differences in clinical (age, arterial
hypertension, diabetes, chronic bronchial disease, severity of angina, severity
of heart disease) or surgical (emergency, percent use of the internal thoracic
artery, duration of extracorporeal circulation) variables. The percentage of
patients with low ejection fraction was higher in group B as a result of
preoperative selection. The mean number of grafts was higher in group B than in
group A (3.5% and 2.5, respectively) (p < 0.01). Postoperative results (use of
inotropics, counterpulsation balloon, creatine phosphokinase, perioperative
myocardial infarction or hospital mortality) were not significantly different.
The percent of supraventricular arrhythmias after surgery was higher in group A
than in group B (20% and 5%, respectively) (p < 0.05) and lactic dehydrogenase
level was lower in group A than in group B (472 and 572 mu/l, respectively) (p <
0.05). CONCLUSIONS: We believe that crystalloid cardioplegia continues to be a
valid and effective myocardial protection technique in heart patients with
preserved left ventricular systolic function.
PMID- 9558935
TI - [Changes in therapeutic attitude based on transesophageal echocardiography in
cardiac surgery].
AB - Transesophageal echocardiography is a monitoring system that is changing the
practice of cardiovascular anesthesia and surgery by providing real time images
of cardiovascular anatomy and pathophysiology. Our hospital's anesthesiology and
postoperative intensive care departments, in particular the cardiac anesthesia
team, initiated a joint project in June 1993 with the echocardiography laboratory
team to incorporate this surgical monitoring system. Here we report the wealth of
information we obtained and describe the possibility of modifying a therapeutic
approach based on the images visualized, even when conventional monitoring gives
contradictory information. Two illustrative case reports are included.
PMID- 9558936
TI - [Asystole after intravenous administration of ranitidine].
PMID- 9558937
TI - [Voluntary intoxication with isoniazid].
PMID- 9558938
TI - [Accidental intra-arterial diazepam injection].
PMID- 9558939
TI - [Spanish anesthesiologist in European scientific forums: The European Society of
Anesthesiologists and The European Society of Regional Anesthesia].
PMID- 9558940
TI - [Tracheal rupture after endotracheal intubation: clinical developments in two
cases].
PMID- 9558941
TI - [Acute myocardial infarction during catheterization of the left subclavian vein].
PMID- 9558942
TI - [Age limit for liver transplantation].
PMID- 9558943
TI - Thyroid function in acute pancreatitis.
AB - OBJECTIVES: To analyze changes in the thyroid function in patients with acute
pancreatitis. METHODS: Admission serum levels of triiodothyronine (T3), reverse
triiodothyronine (rT3), thyroxine (T4) and thyrotropin (TSH) were determined in
20 patients with pancreatitis and 20 healthy control patients. Another group of
20 patients with upper digestive haemorrhage was included to study possible
changes in the pattern of thyroid function in hemodynamic alterations. In
addition, laboratory indicators of liver, renal and pancreatic functions were
measured in all groups. RESULTS: Our results demonstrated low levels of T3 in 20%
of patients with pancreatitis and increased rT3 levels in 75% of them.
Thyrotropin was always among reference ranges and only one case presented a low
level of T4. No significant alterations were detected in patients with upper
digestive haemorrhage. CONCLUSIONS: These results suggest that pancreatitis may
play a role in the genesis of these changes, since other factors such as diet and
cellular hepatic alteration appear to have had no effect on the levels of thyroid
hormones in these patients. In other studies those changes in the thyroid
function can be relationed with the prognosis in acute pancreatitis.
PMID- 9558944
TI - Endoscopic pancreatic stent drainage improves pain in chronic pancreatitis.
AB - Pain in chronic pancreatitis is due to intraglandular neural affection and to
pancreatic duct drainage obstruction with an increased intraductal pressure. To
achieve pain relief, medical, surgical and endoscopic procedures have been
developed. AIM: To evaluate the efficacy of pancreatic duct stenting in patients
with narcotic-dependent pain due to chronic pancreatitis. PATIENTS AND METHOD:
From May-1994 to May-1996, ten patients (medium age: 47.5 yr) with alcoholic
chronic pancreatitis were selected for this procedure. Pancreatography showed
single or multiple Wirsung strictures in all cases. Papillotomy and pancreatic
duct sphincterotomy were performed before stenting. Strictures were negotiated
with a 7F dilating catheter over a guide wire, and intraductal calculi were
removed as well. We used 7F plastic stents with variable lengths (5-10 cm), that
were exchanged when the patient presented pain recurrence. Stent survival time
was defined as the patient's pain-free time. RESULTS: In 6 of the 10 patients
stent placement was carried out successfully. A single distal Wirsung stricture
was diagnosed in 3 patients while in the remaining 3 there were several
strictures associated to ductal lithiasis in two of them. Mean time to achieve
pain relief was 3 days and mean stent survival time was 166.5 days. There were no
complications due to the procedure. CONCLUSIONS: When placed through the
stricture, endoscopic pancreatic stent drainage is effective in achieving pain
relief. It is a safe procedure with no complications in our short series.
PMID- 9558945
TI - Acute biliary pancreatitis: sphincter of Oddi and choledochal pressure.
AB - Twenty four patients with biliary pancreatitis were divided into three groups: A
(18 subjects underwent surgery on the biliary tract seven days after admission to
hospital when acute signs disappeared); B (3 cases were operated two months
later), and C (3 patients underwent emergency surgery for acute cholescistitis
with simultaneous acute pancreatitis). A cholecistectomy-choledochostomy through
a Kehr tube was performed in all patients. Pressure in the main biliary duct
(MBD) was measured. Only group A was significant (18 cases). As a control,
another group, group D was considered (52 biliary cholecysto-choledochal
lithiasis patients without pancreatitis and without transduodenal
sphincterotomy). Group A: 1) The mean pressure in MBD on the fourth postoperative
day (11 days after onset of pancreatitis) was low (p < 0.0001) in relation to
that of group D with Oddi's sphincter (SO) normal; 2) in group A, no significant
differences (p-NS) were found in relation to positions: during fasting, 4.4 +/- 4
cm H2O in the upright position, and 5.3 +/- 2 when lying (in group D, 9.9 +/- 4.1
cm H2O upright, and 7.76 +/- 3.6 lying with p = 0.0001), and 3) a slow
improvement of pressure was observed and, on the 25th day after operation, it was
nearly normal (9 cm H2O upright and 7 cm lying with p < 0.001). Group B: biliary
surgery at 2 months; mean pressure in MBD meartly normal. Group C: 1) 4 days
after emergency surgery, the pressure in MBF (15 cm H2O upright and 11.7 lying)
was higher than in subjects with normal SO, probably due to compression of the
distal part of MBD by the inflamed pancreas, and 2) from the 11th day the
pressure followed the same evolution as that of group A. In conclusion, in
patients with acute biliary pancreatitis, operated on the biliary tract when
acute signs disappeared, MBD pressure is low (p < 0.0001) in reference to normal
on the fourth post-operatory day (11 days after onset of pancreatitis) and no
significant differences were found in relation to positions (upright and lying).
The pressure changes are transient (4-5 weeks) and most probably due to the
lesions and malfunction of the SO related to pancreatitis.
PMID- 9558946
TI - [Hepatocellular carcinoma associated to porphyria cutanea tarda and hepatitis C
virus infection without cirrhosis].
AB - The molecular basis of porphyria cutanea tarda is defective activity of hepatic
uroporphyrinogen decarboxylase. A common characteristic is liver dysfunction than
goes from cirrhosis to hepatocellular carcinoma. A high prevalence of hepatitis C
virus markers has been demonstrated. We study a patient with PCT and hepatitis C
virus markers that finally develops to hepatocellular carcinoma without previous
cirrhosis. Previous studies with association of PCT and hepatitis C virus
markers, have found liver diseases ranging from cirrhosis to hepatocellular
carcinoma. The importance of this study is the absence of cirrhosis.
PMID- 9558947
TI - [Surgical treatment of hepatolithiasis. Presentation of a case].
PMID- 9558948
TI - [Massive lower intestinal hemorrhage in Wegener's disease].
PMID- 9558949
TI - [Blocking of T-type calcium channels: new horizons in the therapeutic potential
of calcium antagonists].
PMID- 9558950
TI - [Nocturnal arterial hypertension and cardiovascular risk].
PMID- 9558951
TI - [Left ventricular filling in young patients with systemic lupus erythematosus in
stable phase].
AB - OBJECTIVE: The aim of this study was to evaluate the left ventricle filling
pattern in patients with stable systemic lupus erythematosus (SLE). METHODS: This
prospective study was performed in 22 healthy controls and in 24 patients with
stable SLE. These two groups were submitted to a clinical, electrocardiographic
and echocardiographic evaluation. RESULTS: Gender distribution and mean age were
similar in both groups (p = NS). Patients with SLE were more symptomatic (21%)
than control patients (0%) (p < 0.01). Left ventricular dimensions, wall
thickness, and systolic function were not significantly different between the two
groups. However, pericardial effusion was more frequently found in patients with
SLE (21%) when compared to the control group (0%) (p < 0.05). When compared to
the control group, patients with SLE showed an abnormal left ventricular filling
pattern. Peak late mitral flow velocity was 0.45 +/- 0.2 m/sec in SLE patients
and 0.36 +/- 0.1 m/sec in the control group (p = 0.001). CONCLUSION: These
results demonstrate that patients with stable SLE, when compared to healthy
controls, are frequently associated with cardiovascular symptoms, asymptomatic
pericardial effusion, and an abnormal left ventricular filling pattern.
PMID- 9558952
TI - [Partial pericardectomy using videothoracoscopy].
AB - OBJECTIVE: The aim of this study is to assess the validity of videothoracoscopy
in the treatment of chronic pericardial effusions. STUDY PATIENTS: We studied 13
consecutive patients with chronic pericardial effusions and an indication for
surgical treatment. The patients, 10 female and 3 male, had a mean age of 48
years (21-72 years). Eleven patients had recurrent pericardial effusion and two
patients had anterior mediastinal masses of unknown etiology and a large
pericardial effusion. METHODS: A videothoracoscopy was performed in every
patient, under general anesthesia with a double-lumen endotracheal tube. The
thoracic cavity was inspected, the pericardial effusion was drained and a partial
pericardectomy was performed. RESULTS: There was no postoperative mortality or
morbidity. Average duration of postoperative thoracic drain and postoperative
stay were, 1.2 and 2.4 days respectively. Follow-up ranged from 1 to 48 months
(mean 23.3 months). One patient died due to progression of his malignant disease.
There were no cases of recurrent pericardial effusions. CONCLUSIONS: Video
assisted pericardectomy is a safe technique that should be considered in the
treatment of chronic pericardial effusions.
PMID- 9558953
TI - [New parameter for explaining the "natural protection" of the female sex in
cardiovascular risk (the value of arterial baroreceptors)].
PMID- 9558954
TI - [Association of nutritional status, body composition, serum lipids and
apolipoproteins, and haptoglobin phenotype in a population of 9- to 12-year
olds].
PMID- 9558955
TI - [Coronary disease in patients undergoing heart transplantation: are there
predisposing factors?].
PMID- 9558956
TI - [Evaluation of myocardial viability using overload echocardiography in coronary
disease with severe left ventricular dysfunction: influence on the therapeutic
decision and results of revascularization].
PMID- 9558957
TI - [Diagnosis of coronary disease in patients having undergone a heart transplant:
does myocardial perfusion tomoscintigraphy allow to exclude heart
catheterization?].
PMID- 9558959
TI - [Variation in the calculation of the left ventricular mass using three
dimensional echocardiography].
PMID- 9558958
TI - [Elevation of the ST segment in derivations with Q wave in early exertion test
after acute myocardial infarct: a marker for ischemia/viability].
PMID- 9558960
TI - [Value of echocardiography and heart Doppler in the diagnosis and therapeutic
orientation of congestive heart failure--the importance of diastolic
dysfunction].
AB - Echocardiography and cardiac-Doppler are very useful techniques to achieve
etiologic diagnosis and evaluate therapeutic strategies for heart failure, and
left ventricular hypertrophy is known as a serious risk factor for cardiovascular
disease morbidity and mortality. Echocardiography establishes, in an easy and
noninvasive way, the etiologic diagnosis of heart failure and is a very sensitive
technique for the diagnosis and follow-up of patients with left ventricular
hypertrophy. On the other hand, diastolic dysfunction is an early manifestation
of several conditions associated with heart failure emerging from the diastolic
mechanism. The author emphasizes the role of cardiac Doppler in the early
diagnosis of diastolic dysfunction and how findings provided by this procedure
can lead to more adequate therapeutic measures and assess accurate prognostic
information.
PMID- 9558961
TI - Optimizing timing of surgical correction in patients with severe aortic
regurgitation: the role of symptoms.
PMID- 9558962
TI - Laser and serum opsonic activity.
AB - The purpose of this study was to investigate the effects of low level laser (LLL:
GaA1As diode laser; 830 nm) on serum opsonic activity, which was assessed by
neutrophil-associated chemiluminescence (CL) response to zymosan opsonized with
sera irradiated in vitro with various doses of LLL. We used both lucigenin
dependent CL (LgCL) for superoxide (O2-) detection and luminol-dependent CL
(LmCL) which detects myeloperoxidase (MPO)-dependent formation of hypochlorous
acid in combination with MPO inhibitor, sodium azide (NaN3). When serum opsonic
activity was assessed by LgCl, NaN3, markedly enhanced the responses, suggesting
that O2- is accumulated due to the MPO blockade, leading to the excitation of
LgCl. However, LLL-irradiation had no effects on serum opsonic activity. On the
other hand, when serum opsonic activity was assessed by LmCl, NaN3, strongly
inhibited the response. The effects of LLL at different output powers were
characterized by similar values, but significantly higher values were observed at
the highest dose tested (60 mW for 1 min) in the absence of NaN3. Since this
enhancement effect disappeared with NaN3, it was suggested that high dose LLL
irradiation probably activated the opsonic activity by facilitating neutrophils
to degranulate MPO. However, lower doses used for therapeutic purposes had no
effects at any output powers tested.
PMID- 9558963
TI - Inhibitory capacity of some fractions isolated from a green barley extract upon
TNF alpha production by the cells of the THP-1 human monocytes line.
AB - A green barley extract commercialized as an antiinflammatory product under the
name of "Natural SOD" was fractionated based on the molecular weights principle.
Knowing that the TNF alpha cytokine plays an important role in inducing
inflammatory phenomena, by the use of two determination methods (ELISA and
cytotoxicity), the fractions obtained were analysed for their capacity to
modulate TNF alpha production/release by an LPS-activated human monocytes line
(THP-1). The results pointed to the existence of 3 groups of substances
(fractions 3, 4 and 9) apt to modulate TNF alpha production, fraction 4 being the
most active. Of the TNF alpha determination methods, ELISA proved to be more
sensitive as it detected not only free TNF alpha identified also by the
cytotoxicity test, but also TNF alpha complexed with its soluble receptors. The
presence of these substances in Natural SOD, fractions with modulatory action
upon TNF alpha production, might partly account for the clinical efficiency of
this product in the treatment of inflammatory affections reported in humans.
PMID- 9558964
TI - Antidiphtheria and antitetanus immunity of recruits in Romania.
AB - The concern for maintaining a high antidiphtheria and antitetanus immunity level
is permanent. The paper approaches the study of antidiphtheria and antitetanus
immunity levels in a group of young recruits (who had been administered a DT
booster 5-7 yrs before). The titres of antibodies were determined concomitantly
by the neutralization test (NT) in vivo and by the passive hemagglutination assay
(PHA) in vitro. The results obtained by the neutralization tests revealed (by the
estimations shown by the geometrical means) a high antidiphtheria and antitetanus
immunity level proved by an exceeding of the protection limits (0.03 IU/ml and
0.01 IU/ml) of 89 x and 953 x, respectively. The analysis of individual titres
obtained by NT showed that of 540 subjects in whom diphtheria antitoxin was
determined, 93.52% had protective titres, while of 619 subjects in whom the
tetanus antitoxin was evaluated, 97.26% were immune. The results obtained by PHA
were comparable with those obtained using the reference methods.
PMID- 9558965
TI - Plasmid profile analysis and restriction enzyme analysis in characterizing
Shigella flexneri isolates from an outbreak.
AB - Shigella flexneri strains which are multiply resistant to antimicrobial agents
were isolated from 11 children from an orphanage in Cluj-Napoca during an
epidemiological investigation initiated by the Department of Epidemiology.
Plasmid profile analysis and restriction endonuclease analysis were used in
conjunction with biotyping, serotyping and antimicrobial susceptibility testing
for identifying epidemiological related isolates. All strains were serotype 2a
and with one exception all of them showed the same resistotype. Plasmid profile
analysis differentiated S. flexneri isolate into four patterns, with two common
plasmids of 3.5 and 1.9 kb. This study indicates that this outbreak was caused by
at least two different strains of S. flexneri which were not differentiated by
the classical technique-biotyping, serotyping and antimicrobial susceptibility
pattern.
PMID- 9558966
TI - Incidence of Chlamydia trachomatis genital infections in Bucharest (1988-1996).
AB - 2230 patients from Bucharest with genital infections were investigated (1988
1996) to identify the chlamydial etiology. The rate of isolation of Chlamydia
trachomatis was of 33.8%. The highest percentages were reported in patients
clinically diagnosed with cervicitis (56.2%) and non-gonococcal urethritis (36%);
as well as in patients aged 31-35 years, single, who had genital urinary
infections in history.
PMID- 9558967
TI - Rapid test for the detection of methicillin-resistance of staphylococci by ATP
dependent bioluminescence.
AB - Methicillin resistance of staphylococci is a marker of multiple resistance to
antimicrobial drugs. The authors present their own variant of applying ATP
dependent bioluminescence for the rapid testing of methicillin resistance. It
consists in the measurements of the total bacterial ATP obtained by extraction.
The authors test the method on 23 Staphylococcus strains and compare the results
with those obtained by the diffusion method, the screening method with the
antibiotic included in the agar and the broth dilutions method. The results
obtained by ATP-dependent bioluminescence were in agreement with those obtained
by broth dilutions method.
PMID- 9558968
TI - Viral etiology of acute respiratory infections in infants and young children.
AB - 114 children with acute respiratory infections were investigated to detect the
viral etiological agents. The following methods were used: the direct
immunofluorescence technique for the rapid diagnosis from tracheobronchial
aspirates and the serological reactions--hemaglutinoinhibition and complement
fixation reaction--to determine the increase of antibodies titres. Of 55.2%
respiratory infections with a viral etiology, 60.3% represent acute infections of
the lower respiratory tract. Due to the influenza epidemic reported between
October 1996 and February 1997 (with a higher number of cases than in the last 5
years), most viral respiratory infections were caused by influenza viruses
(57.14%). The direct immunofluorescence technique proved to be sensitive and
specific in detecting the viral etiological agents which caused respiratory
infections. Thus, using this technique, a positive diagnosis was made in 68.2% of
cases, of which 49.2% were positive by the hemagglutination and complement
fixation reactions, too. The test specificity could have been higher if the
pathological products had been prelevated within the first three days after the
onset of the disease.
PMID- 9558969
TI - Prevalence of tsetse fly and ruminant trypanosomosis in Katsina-Ala Local
Government Area, Nigeria.
AB - The prevalence of ruminant trypanosomosis and tsetse flies was investigated in
Katsina-Ala Local Government Area--a sleeping sickness endemic area--between the
valleys of River Benue, Katsina-Ala and Donga in Central Nigeria. Analysis of
three hundred and twenty blood samples showed that among semi-nomadic animals,
about one cattle (21.3%; 0.213, confidence interval C1 +/- 0.06) and two sheep
(38.0%; 0.380, C1 +/- 0.10) out of five carried mature trypanosome infections.
Significantly lower (P < 0.05) values (12.5%; 0.125, C1 +/- 0.08) were recorded
among peri-domestic West African Cross Red Sokoto (WAD x RS) goats. Trypanosoma
vivax was the most prevalent species encountered; it was diagnosed in 10.3% of
the ruminant population and responsible for 42.8% of the infections in all
animals. Corresponding figures for T. congolense were 5.9% and 24.6%,
respectively. T. brucei infections were low in cattle (1.8%) and absent in goats.
Males and young stock had lower infection but the difference was not significant
(P > 0.05) except between the ages in cattle. Glossina tachinoides was the only
tsetse species encountered and responded to acetone odour attractant in biconical
traps.
PMID- 9558970
TI - [Cytological observations on the protozoan Pneumocystis carinii].
PMID- 9558971
TI - Modulation of cell adhesion by tyrosine kinases and phosphatases inhibitors.
AB - Integrin-mediated activation of monocytes is an important aspect involved in the
increase of proinflammatory cytokine messages. Tyrosine phosphorylation of
proteins is one of the earliest events involved in these processes: Therefore, we
selected two inhibitors, one for tyrosine kinases (quercitin) and another for
tyrosine phosphatases (sodium orthovanadate) and we studied their capacity to
modulate monocyte adhesion to fibronectin. Our results showed that quercitin
strongly inhibits both tyrosine phosphorylation and cell adhesion. Sodium
orthovanadate induces a modest increase of tyrosine phosphorylation and a weak
enhancement of cell adhesion. When a combination of the two inhibitors was used,
the tyrosine phosphorylation level displayed a strong enhancement. In contrast,
cell adhesion was inhibited, but to the same degree. These observations indicate
that tyrosine kinases may be more important than tyrosine phosphatases in the
modulation of cell adhesion by flavonoid compounds.
PMID- 9558972
TI - Experimental studies on bacterial product CANTASTIM derived from Pseudomonas
aeruginosa. II. Protective effect in Salmonella typhimurium infection.
AB - Stimulation of the host defense system in a nonspecific way may provide effective
treatment of recurrent infections. CANTASTIM is a bacterial product that has been
successfully used in cancer immunotherapy as well as in chronic infections
treatment. The nonspecific protective effect of CANTASTIM was investigated in two
models of experimental infection with Salmonella typhimurium in mice.
Prophylactic administration of CANTASTIM (three days before challenge) enhanced
peritoneal macrophages bactericidal activity and significantly increased survival
of treated mice. When CANTASTIM was administered 72 h after bacterial challenge,
in a sublethal infection model with Salmonella typhimurium, by activating
macrophages, NK and T cells, it increased the survival rate. The cell populations
and molecular mechanisms involved in the prophylactic and therapeutic protective
effect CANTASTIM seem to be partially different.
PMID- 9558973
TI - Experimental studies on the bacterial product CANTASTIM derived from Pseudomonas
aeruginosa. III. Suppression of lipopolysaccharide-induced tumor necrosis factor
alpha: are the lipid components involved?
AB - We previously reported that the bacterial immunomodulator CANTASTIM inhibited the
LPS-induced TNF-alpha production in murine macrophages both in vivo and in vitro.
In this report, we compared the activity of CANTASTIM with that of two
phospholipids (cardiolipin and phosphatidylethanolamine) which are among the
components of its lipid fraction. We noticed a significant reduction in the
production of TNF-alpha upon stimulation with LPS in murine peritoneal
macrophages pretreated for at least 3 h with CANTASTIM or cardiolipin. CANTASTIM
was active at much lower concentrations than cardiolipin. Preliminary experiments
with partially deacylated CANTASTIM indicated some decrease of TNF-alpha
secretion. However, further studies are necessary to clarify this matter. Also,
while CANTASTIM and its partially deacylated derivative could trigger the TNF
alpha secretion in murine macrophages, individual phospholipids did not. Based on
these results, we concluded that CANTASTIM could induce the TNF-alpha suppression
by multiple mechanisms, including the induction of regulatory cytokines such as
IL-10 and CD14 receptor blockade/downregulation.
PMID- 9558974
TI - Experimental studies on bacterial product CANTASTIM derived from Pseudomonas
aeruginosa with immunomodulatory properties. IV. Tyrosine phosphorylation as an
effect of stimulation on different cell populations.
AB - The bacterial product derived from Pseudomonas aeruginosa (trade mark-CANTASTIM)
proved immunomodulatory effects in different systems, both in vitro and in vivo
experimental animal models, as well as in clinical trials. Among the results
obtained regarding CANTASTIM, the following immunomodulatory properties could be
mentioned: an increase of the activated T cell subpopulations and humoral
mediated immune processes, facilitation of phagocytic processes, stimulation of
cytotoxic activity reflected in the improvement of the capacity of defense in
several tumoral and infectious diseases. To better elucidate the intimate
mechanisms by which CANTASTIM modulates the cellular functions on different
cellular populations, we used tyrosine phosphorylation as an estimate of cell
activation on peripheral blood lymphocytes (PBL) and a monocyte cell line (THP
1). In PBL, the treatment with CANTASTIM renders them more susceptible to CD3
stimulation than non-treated cells. In monocytes, CANTASTIM and two phospholipid
components of CANTASTIM modulated in a different manner the cellular adhesion on
fibronectin and tyrosine phosphorylation leading to the conclusion that these
phospholipid components do not fully explain CANTASTIM modulatory properties on
cell adhesion processes.
PMID- 9558975
TI - Modulation of CD14 expression on human granulocytes by a bacterial product
"Cantastim" derived from Pseudomonas aeruginosa.
AB - Pathophysiological effects of infection with Gram-negative bacteria depend on
recognition by host cells of LPS, a major component of the outer membrane of
these microorganisms. CD14 is an immunological marker and also the receptor for
LPS on phagocytic cells. The aim of the present study was to investigate the
capacity of a bacterial immunomodulator, named Cantastim, which is used as a
therapeutical agent in neoplasic diseases and chronic infections, to modulate the
CD14 expression on human granulocytes. Our preliminary results showed that
Cantastim can not influence the expression of CD14 on granulocytes obtained from
healthy donors, but on the other hand Cantastim was able in vitro and in vivo to
down-regulate the expression of this marker on granulocytes from a patient with
neoplasic disease.
PMID- 9558976
TI - Application of ELISA with antigenic glycolipids in early diagnosis of pulmonary
tuberculosis.
AB - Antibodies against M. tuberculosis antigenic glycolipids were determined by
enzyme-linked immunosorbent assay (ELISA) in 80 sera from patients suspected of
pulmonary tuberculosis, with suggestive clinical signs and radiological
abnormalities, but smears negative. The test was also performed on 68 control
sera from patients with bacteriologically confirmed pulmonary tuberculosis, in
different stages of disease. We obtained the test sensitivity of 89.5% for the
confirmed tuberculosis patient sera. Low levels of specific antibodies and the
sensitivity of 75% were found when using ELISA in smears negative patients at the
onset of clinical tuberculosis. The experimental results showed that ELISA could
be used as a supporting test in early diagnosis of pulmonary tuberculosis.
PMID- 9558977
TI - Interactions between Borrelia burgdorferi and eukaryote cells: comparative
ultrastructural aspects.
AB - In the present study, mammalian VERO cells, human polymorphonuclear leukocytes
(PMN) and mouse peritoneal macrophages (MPM) were coincubated with B31 Borrelia
burgdorferi strain (Bb) and examined by transmission electron microscopy. The
results indicate that the spirochete adheres to the mammalian cells mainly by the
apical pole and less frequently by the lateral wall. In VERO cells and MPM cell
penetration is accomplished especially by cytoplasmic membrane destruction, the
spirochete appearing free in the cytoplasm, but also by phagocytosis. In this
latter case the pathogen is seen in phagosome. In PMN the internalization takes
place exclusively by phagocytosis, the spirochete undergoing destruction in
phagosomes. Sometimes an alteration of the phagosomal membrane is observable,
probably produced by the pathogen as a mechanism to avoid fusion with the
lysosome. Other aspects indicate the contribution of the parasitized cell
cytoskeleton to the spreading of Borrelia to adjacent cells. MPM does not
represent a very efficient barrier against Bb, as can be seen from the cellular
behaviour of the spirochetes in this study, PMN seems to a more efficient
barrier, by its unique capacity to destroy the microorganism after phagocytosis.
PMID- 9558978
TI - Macromolecular synthesis and ultrastructural changes induced in human larynx
carcinoma cells following photodynamic therapy in vitro.
AB - Human larynx carcinoma cells (HEp2) were sensitized with different concentrations
of Hematoporphyrin and irradiated with a He-Ne laser at different fluences. The
degree of PDT-effects were estimated by two parameters: a) macromolecular
synthesis and b) observations using electron microscopy. All experiments were
evaluated after 68 hr at 37 degrees C. The results showed that PDT exposure of
HEp2 cells is characterized by: 1) inhibition of macromolecular synthesis and 2)
different cellular and subcellular lesions. Summing up, these studies indicate
the existence of a strong correlation between different PDT exposures and the
degree of biochemical and ultrastructural changes in human larynx carcinoma cells
in vitro.
PMID- 9558979
TI - Freeze-drying of some strains of biotechnological interest (Aureobasidium
pullulans).
AB - Optimal freeze-drying conditions for Aureobasidium pullulans were investigated.
Protective substances were used to compensate for the stress reported during
freezing (gelatin, calf serum) and desiccation (saccharose, raffinose,
trehalose), used in different combinations.
PMID- 9558980
TI - Prevalence of hepatitis B and C virus markers among the members of the medical
sanitary staff from the Faculty of Dentistry "Carol Davila" University of
Medicine and Pharmacy, Bucharest.
AB - This study was developed in an attempt to estimate the prevalence of hepatitis B
and C virus markers in the sanitary personnel from dentistry clinics which
represents a high risk group concerning both contamination and transmission of
the infection. The results of the study showed a higher contamination by virus B
than virus C. The distribution of contamination depending upon the position held
by the staff members revealed a higher contamination incidence among medium level
personnel than among high level personnel. The need to initiate this study is due
to the high incidence of contamination with hepatitis B virus which calls for the
implementation of prophylaxis measures to protect both the medical personnel and
the patients.
PMID- 9558981
TI - A hypertension treatment update
PMID- 9558982
TI - New ways to protect your vision
PMID- 9558983
TI - Does dietary fat still matter?
PMID- 9558984
TI - Coping with cancer fatigue
PMID- 9558985
TI - Aspirin and NSAIDs. Is aspirin safe to take with another nonsteroidal anti
inflammatory?
PMID- 9558986
TI - Treating a seizure. What follow-up do I need after a first seizure?
PMID- 9558987
TI - Stiff neck. Recently, I've had several bouts with a stiff neck. Should I be
worried?
PMID- 9558988
TI - US sees first legal case of physician assisted suicide.
PMID- 9558989
TI - BMA calls for smoking to be banned in public places.
PMID- 9558991
TI - Rapid HIV testing urged in the US.
PMID- 9558990
TI - German doctors vote to prescribe heroin to misusers.
PMID- 9558992
TI - Florida doctor is investigated over experimental treatment.
PMID- 9558994
TI - Commentary: grounded theory and the constant comparative method.
PMID- 9558995
TI - Intravascular volume optimisation during repair of proximal femoral fracture.
Intravascular volume was depleted perioperatively in control group.
PMID- 9558996
TI - Intravascular volume optimisation during repair of proximal femoral fracture.
Differences in outcome were probably due to chance.
PMID- 9558997
TI - Working in management. Doctors do better financially than managers do.
PMID- 9558998
TI - Working in management. Having public health doctors as managers is not the
solution.
PMID- 9558999
TI - Drug and Therapeutics Bulletin defends its stance over donepezil.
PMID- 9559001
TI - Breast feeding does not always work. All mothers should be offered help and
support to breast feed.
PMID- 9559000
TI - Rationing health care. Patients need to be prioritised.
PMID- 9559002
TI - Breast feeding does not always work. Various supplements to breast feeding are
possible.
PMID- 9559003
TI - The disorganized state of primary care.
PMID- 9559004
TI - Cross-disciplinary training: time to remove the blinders.
PMID- 9559005
TI - Princess Diana's tragic legacy.
PMID- 9559006
TI - Familial abuse: a multifaceted problem.
PMID- 9559007
TI - Familial abuse: a multifaceted problem.
PMID- 9559008
TI - Overpopulation and Rwanda.
PMID- 9559009
TI - Helicobacter pylori.
PMID- 9559010
TI - Breast self-examination techniques.
PMID- 9559011
TI - Fluoridation and fracture.
PMID- 9559012
TI - Trends and variations in length of hospital stay for childbirth in Canada.
AB - BACKGROUND: Early discharge after childbirth is widely reported. In this study
the authors examined trends in maternal length of hospital stay in Canada from
fiscal year 1984-85 through fiscal year 1994-95. They also examined variations in
length of stay in 1994-95 in most of the Canadian provinces and the territories.
METHODS: Epidemiologic analyses of the temporal and geographic variations in
maternal length of hospital stay in Canada from 1984-85 to 1994-95 (even years
only), based on hospital discharge data collected by the Canadian Institute for
Health Information, with a total of 1,456,800 women for the 6 study years.
RESULTS: Mean length of hospital stay decreased during the decade, from 5.3 days
in 1984-85 to 3.0 days in 1994-95, with similar trends for both cesarean and
vaginal delivery. The decrease resulted from both increasing rates of short stay
(less than 2 days) and decreasing rates of long stay (more than 4 days).
Substantial temporal and interprovincial variations in several medical and
obstetric complications were also observed but did not explain the corresponding
variations in length of stay. The reduction in length of hospital stay was not
restricted to uncomplicated cases: there was an equivalent decrease in cases with
complications. In 1994-95 the average length of hospital stay in Alberta was 2.6
days, 0.3 to 1.7 days shorter than in the other provinces and the territories.
INTERPRETATION: Length of hospital stay for childbirth has decreased
substantially in Canada in recent years, but there remain important
interprovincial variations. These trends and variations are not likely due to
changes or differences in patient-specific factors.
PMID- 9559014
TI - Safe motherhood: can we make a difference?
PMID- 9559013
TI - Surviving social assistance: 12-month prevalence of depression in sole-support
parents receiving social assistance.
AB - BACKGROUND: Although it is generally recognized that poverty and depression can
coexist among single parents receiving social assistance, there is insufficient
research on this topic. The goals of this study therefore were to investigate the
prevalence, correlates and health care expenditures associated with depression
among sole-support parents receiving social assistance. METHODS: Sole-support
parents who had applied for social assistance in 2 regions of southwestern
Ontario were included in the study. Depression was diagnosed with the 1994
University of Michigan Composite International Diagnostic Interview short forms.
RESULTS: The 12-month prevalence rate of depressive disorder among the parents
interviewed was 45.4% (345/760). A total of 247 (32.5%) had major depressive
disorder alone, 19 (2.5%) had dysthymia, and 79 (10.4%) had both major depressive
disorder and dysthymia ("double depression"). Those with major depressive
disorder, particularly double depression, had significantly higher rates of
coexisting psychiatric disorder than those without depressive disorders. Parents
with depression reported higher rates of developmental delay and behaviour
problems in their children than parents without depression. Expenditures for
health care services were higher for parents with depression and for their
children than for parents without depressive disorder and their children.
INTERPRETATION: Single parents receiving social assistance have high rates of
depression. Such parents with depression also have higher rates of other
psychiatric disorders and higher expenditures for health care services, and their
children have higher rates of developmental delay and behaviour problems.
PMID- 9559015
TI - Society's interest in protection for the fetus.
PMID- 9559016
TI - Unconventional therapies for cancer: 1. Essiac. The Task Force on Alternative
Therapies of the Canadian Breast Cancer Research Initiative.
AB - Physicians and patients have been frustrated by the lack of reliable information
on unconventional therapies. To help fill this gap in the area of breast cancer
therapy, the Canadian Breast Cancer Research Initiative formed a task force to
advise it on how best to promote research into unconventional therapies. As part
of the work of the task force, a review of the available literature was carried
out for each of the following products: Essiac, green tea, Iscador, hydrazine
sulfate, vitamins A, C and E, and 714-X. The first article in this series on
unconventional therapies for cancer describes the methodology used to obtain and
evaluate the information and provides a summary of the findings on Essiac.
Subsequent articles will cover the other products. For most of the products
reviewed, there has been some indication of possible benefit but no definitive
evidence. Innovative and collaborative research needed to meet the information
needs of growing numbers of patients and their physicians is now being sponsored
by the Canadian Breast Cancer Research Initiative. Open communication between
patients and physicians is also necessary for the maintenance of an appropriate
therapeutic partnership and for the identification and control of side effects.
The Ontario Division of the Canadian Cancer Society, a partner in the Canadian
Breast Cancer Research Initiative, supported the preparation of a patient
information piece on unconventional therapies to accompany the series. This item
will assist patients who are considering such therapies and will promote open
communication between patients and their physicians.
PMID- 9559017
TI - [The physician's professional competence and ethics education].
PMID- 9559019
TI - MDs aiming for hospital boardroom may face humbling experience, CEO warns.
Interview by Patrick Sullivan.
PMID- 9559018
TI - Of mice and mostly men--hantavirus pulmonary syndrome.
PMID- 9559020
TI - The brutal politics of health care.
AB - The 1998 federal budget received less than glowing reviews for its provisions
regarding health care, but Charlotte Gray says this lack of health care
initiatives should surprise no one. After all, there won't be a federal election
for another 3 years.
PMID- 9559021
TI - Malpractice concerns lead to unprecedented cooperation as CMPA, CMA seek answers.
PMID- 9559022
TI - Alendronate-induced esophagitis.
PMID- 9559023
TI - Alzheimer's disease.
PMID- 9559024
TI - Geriatrics photo quiz. Horner's syndrome.
PMID- 9559025
TI - Red lesion on chest wall.
PMID- 9559026
TI - Thyroid dysfunction: how to manage overt and subclinical disease in older
patients.
AB - Thyroid dysfunction is relatively common in older patients, but its clinical
presentation varies. It may be obvious from the classic presenting symptoms, or
it may be asymptomatic and discovered incidentally during routine testing. The
clinical diagnosis of hypothyroidism and hyperthyroidism can be difficult in
older patients, because many of the usual symptoms may be mistaken for the
effects of aging or other medical conditions. Even so, these diseases in their
overt forms are always significant and require treatment. On the other hand,
subclinical hypo- and hyperthyroidism are often incidental biochemical
abnormalities that may or may not require intervention.
PMID- 9559027
TI - Type 2 diabetes: treatment goals and pharmaceutical therapies. 2.
AB - The most important treatments for type 2 diabetes remain weight reduction and
physical activity, but an increasing armamentarium of drug therapies has much
improved our ability to control blood glucose levels. Each of the known metabolic
defects in type 2 diabetes can now be treated by different classes of drugs.
Although the side effects of these drug therapies are relatively mild and
infrequent, physicians need to be on guard for possible problems. Primary care
physicians can manage most patients with type 2 diabetes. Specialists in
endocrinology, ophthalmology, and podiatry are valuable resources.
PMID- 9559028
TI - Management strategies for problem behaviors in the patient with dementia.
AB - Psychiatric and behavioral problems are present in most patients with dementia
and are usually the clinician's main focus of management. Differential diagnosis
of these problems can be challenging, but the effort is essential for planning
appropriate therapy. Pharmacologic interventions are available for treatment of
depression, agitation, aggression, psychotic symptoms, wandering, and sleep
disorders. Given the less than favorable risk-benefit ratio of most psychotropic
drugs in the population of older patients with dementia, the importance of
nonpharmacologic strategies and limiting treatment goals should not be
overlooked.
PMID- 9559029
TI - How the principles of geriatric assessment are shaping managed care.
AB - In traditional geriatric medicine, comprehensive assessment is considered crucial
to the care of frail older patients. The principles of geriatric assessment-
identifying high-risk patients and targeting them for preventive interventions-
are also practiced by managed care organizations (MCOs). Self-reported health
surveys and administrative data are two methods used by MCOs to identify members
at high risk for adverse health outcomes and functional decline who may benefit
from geriatric case management. For a successful partnership with primary care
physicians, it is very important that geriatric care managers should be
knowledgeable in the principles of geriatric medicine.
PMID- 9559030
TI - Ramsay Hunt syndrome: a challenging herpes zoster virus infection.
PMID- 9559031
TI - Mayo Committee Governance System.
PMID- 9559032
TI - Barriers to cancer screening in Mexican-American women.
AB - OBJECTIVE: To test the simultaneous effect of various established predictors of
breast and cervical cancer screening (breast self-examination, clinical breast
examination by a physician, Papanicolaou [Pap] smear, and pelvic examination) in
a low-income, Mexican-American sample. MATERIAL AND METHODS: A total of 188
Mexican-American women participated in a face-to-face structured interview in
their preferred language. We tested a model with four established predictors of
breast and cervical cancer screening--communication skills, knowledge of cancer,
access to health care (finances and availability of care), and anxiety about
cancer. Simultaneous structural equations analysis was used to form latent
variables and to control for the effect of all predictors concurrently. RESULTS:
Screening behavior was inversely associated with anxiety about cancer when all
other predictors were statistically controlled. In addition, anxiety
substantially affected the relationship between communication skills and
screening behavior. Unexpectedly, knowledge of cancer was positively, rather than
negatively, associated with anxiety about cancer. Predictors in the model
demonstrated an excellent fit of the proposed model to the data. CONCLUSION:
Successful cancer screening programs for Mexican-American women must address not
only access barriers but also communication skills, knowledge, and, perhaps most
importantly, anxiety.
PMID- 9559033
TI - Long-term outcome of patients who undergo tonometry as part of a general physical
examination.
AB - OBJECTIVE: To determine the value of including tonometry as part of a general
physical examination. MATERIAL AND METHODS: Between Feb. 14, 1977, and Dec. 31,
1980, 849 residents of Rochester, Minnesota, underwent measurement of intraocular
pressure by trained ophthalmic technicians at the request of a nonophthalmologist
physician as part of a general physical examination. In 1995 and 1996, these
cases were reviewed to determine how many patients in this study cohort had
subsequently been diagnosed as having glaucoma. The outcome was derived from the
examination of medical records and from the responses to mailed questionnaires
and telephone interviews with study patients and their physicians. RESULTS: In
patients whose intraocular pressures were less than 16 mmHg at baseline, the risk
of being diagnosed as having glaucoma within 10 years was 1% (95% confidence
interval [CI], 0 to 2%) and within 15 years was 2% (95% CI, 0 to 4%). In patients
whose pressure in the higher-pressure eye was 16 to 21 mmHg at baseline, the risk
of having glaucoma in 10 years was 3% (95% CI, 2 to 5%) and in 15 years was 5%
(95% CI, 3 to 7%). Twenty-four patients were found at baseline to have an
intraocular pressure of 22 mmHg or higher in at least one eye or a difference of
5 mmHg or more between the two eyes. In this group, the risk of having glaucoma
in 10 years was 17% (95% CI, 0 to 31%) and in 15 years was 26% (95% CI, 6 to
43%). CONCLUSION: When included as part of a general physical examination of
older persons, tonometry and a few simple questions provide information that can
be used to help the clinician determine the advisability of more detailed
ophthalmic examinations.
PMID- 9559034
TI - Clinical determinants of hemodynamic and symptomatic responses in 2,000 patients
during adenosine scintigraphy.
AB - OBJECTIVE: To determine whether subsets of patients referred for a clinically
indicated radionuclide adenosine stress study respond differently to a standard
infusion of adenosine. MATERIAL AND METHODS: We assessed multiple clinical and
hemodynamic variables in the first 2,000 patients who underwent adenosine
perfusion studies in our laboratory. A relevant clinical variable was defined as
one that was significantly associated with changes in heart rate and blood
pressure during adenosine infusion. Relevant clinical variables that were most
significantly related to hemodynamic variables included age, gender, rhythm
(atrial fibrillation), diabetes, and left ventricular function. These variables
were then related to symptomatic responses (adverse effects) to adenosine
infusion. To determine whether the different peripheral responses to adenosine
reflected clinically important differences in coronary vasodilatation, we
compared perfusion imaging with coronary angiographic findings in the 408
patients who underwent both studies within 6 months of each other. RESULTS: The
decrease in systolic blood pressure was greater and the reflex tachycardia was
less in patients 70 years of age or older and in those with insulin-dependent
diabetes in comparison with younger patients and those without type 1 diabetes.
Men had smaller decreases in blood pressure and smaller increases in heart rate
than did women. Patients with atrial fibrillation and those with left ventricular
ejection fraction less than 40% had smaller decreases in blood pressure and
smaller increases in heart rate than did those in sinus rhythm or those with an
ejection fraction of 40% or more. Age 70 years or older, male gender, atrial
fibrillation, and left ventricular ejection fraction less than 40% were
associated with fewer symptoms and less severe chest pain in comparison with
patients without these variables. For patients with coronary angiograms, the
relationship between coronary artery disease evident on angiography and perfusion
abnormalities noted on scintigraphy was not different for any of the relevant
clinical variables. CONCLUSION: Common clinical patient subsets are associated
with different peripheral hemodynamic and symptomatic responses to infusion of
adenosine. Despite these observations, however, the ability to detect coronary
artery disease with perfusion imaging is not obviously altered.
PMID- 9559035
TI - Hemoglobin Old Dominion/Burton-upon-Trent, beta 143 (H21) His-->Tyr, codon 143
CAC-->TAC--a variant with altered oxygen affinity that compromises measurement of
glycated hemoglobin in diabetes mellitus: structure, function, and DNA sequence.
AB - OBJECTIVE: To determine the nature and characteristics of a unique hemoglobin
variant that causes a spurious increase in glycated hemoglobin (HbA1c). MATERIAL
AND METHODS: Blood specimens from four unrelated persons with this hemoglobin
variant were examined by conventional laboratory methods, including
electrophoresis, high-performance ion-exchange chromatography, and isoelectric
focusing; by amino acid sequence analysis, polymerase chain reaction-based DNA
sequence analysis, and electrospray ionization mass spectrometry, to establish
the molecular structure; and by studies of oxygen affinity under varied
conditions, to define the functional characteristics of the hemoglobin variant.
RESULTS: The unique hemoglobin variant observed in these four cases is due to the
mutation CAC-->TAC, at beta-globin gene codon 143, corresponding to beta 143
(H21) His-->Tyr. This amino acid substitution affects an important 2,3
diphosphoglycerate binding site and slightly increases the oxygen affinity of the
hemoglobin variant. CONCLUSION: A hitherto unrecognized hemoglobin variant,
encountered in four unrelated persons of Irish or Scots-Irish ancestry,
hemoglobin Old Dominion/Burton-upon-Trent, beta 143 (H21) His-->Tyr, has now been
characterized at the molecular, structural, and functional levels. Although it is
associated with a slight increase in oxygen affinity, it is without hematologic
effect, and its only clinical significance is that it coelutes with HbA1c on ion
exchange chromatography and thereby causes a spurious increase in HbA1c and
compromises the use of this analyte to monitor the treatment of diabetes
mellitus.
PMID- 9559036
TI - Major depression in medically ill patients.
AB - Major depression is one of the most common psychiatric problems complicating the
treatment and prognosis of patients with active medical illness. Recognizing and
treating major depressive conditions in this population can often be challenging,
even for the most seasoned clinicians. This article reviews the medical and
neurologic conditions that have been associated with the high prevalence rates of
major depression. Highlights of the evaluation process that help confirm this
suspected diagnosis are addressed, and management issues are discussed. Brief
reviews of supportive psychotherapeutic tools that the clinician may find helpful
are included, as well as current advances in pharmacologic interventions.
PMID- 9559037
TI - Coinfection with Babesia microti and Borrelia burgdorferi in a western Wisconsin
resident.
AB - A 68-year-old woman, who had not traveled outside of western Wisconsin, was
hospitalized after 4 weeks of chills, fevers, myalgias, neuralgias in her right
arm, and pain in the right upper quadrant of her abdomen. Physical examination
revealed hepatosplenomegaly, and laboratory studies showed anemia,
thrombocytopenia, increased aspartate transaminase level, and microscopic
hematuria. Wright's stain of a blood smear revealed intraerythrocytic organisms
consistent with Babesia species. A polymerase chain reaction of whole blood
specimens along with an increased serologic titer confirmed the diagnosis of
Babesia microti. Indirect immunofluorescent antibody serology and Western blot
analysis revealed a simultaneous infection with Borrelia burgdorferi. Coinfection
with B. microti and B. burgdorferi may occur in endemic areas where both
organisms are carried by the same tick vector, Ixodes scapularis. The intensity
and duration of illness seem to be greatest in patients with concurrent
infection.
PMID- 9559038
TI - Esophagogastric hematoma mimicking a malignant neoplasm: clinical manifestations,
diagnosis, and treatment.
AB - Esophagogastric hematoma is a rare condition occurring spontaneously or after
esophageal instrumentation. In this report, we describe a patient with acute
dysphagia in whom a lower esophageal mass was detected radiographically. Upper
endoscopy revealed an esophageal mass that extended from the mid-esophagus to the
gastroesophageal junction and was associated with a malignant-appearing ulcerated
mass (5 to 6 cm) in the cardia. Gastric cancer with esophageal extension was the
presumptive diagnosis. Computed tomography showed that the esophageal mass had a
density similar to blood, a finding suggesting the presence of an esophageal
hematoma. Biopsy specimens of the ulcer revealed acute inflammation but no
malignant involvement. The patient was treated conservatively, and the initial
symptoms resolved. Esophagogastric hematomas can mimic a neoplasm; thus,
establishing the correct diagnosis is important because this condition has a
favorable prognosis, and only conservative treatment is needed.
PMID- 9559040
TI - Clinician's guide to hepatitis C.
AB - Hepatitis C virus infection is common, often silent, and almost always chronic
and can lead to cirrhosis and hepatocellular cancer. Deaths related to chronic
hepatitis C are expected to increase dramatically in the future. Many cases of
infection are asymptomatic and are undiagnosed because of a lack of recognition
by patients and physicians. All patients currently or previously at risk of
infection should undergo screening, including those who received blood
transfusions before 1992. Interferon is the only effective therapy, but
disappearance of virus is sustained in only 10 to 15% of patients. The
combination of interferon and oral ribavirin therapy may increase the sustained
response rate to about 40%. New agents such as hepatitis C virus-specific
protease inhibitors may be available in the next 5 to 10 years, and treatment is
evolving toward multiple-drug regimens analogous to those used for human
immunodeficiency virus (HIV) infection. In contrast to public funding for drug
development in HIV, such funding for hepatitis C has been limited.
PMID- 9559041
TI - Wilkins, Crick, and Watson: Nobel Prize for work on the structure of DNA.
PMID- 9559039
TI - Theophylline: recent advances in the understanding of its mode of action and uses
in clinical practice.
AB - Theophylline, a drug that has been used for several decades, has several
different actions at a cellular level, including inhibition of phosphodiesterase
isoenzymes, antagonism of adenosine, enhancement of catecholamine secretion, and
modulation of calcium fluxes. Recently, theophylline was found to have several
immunomodulatory and anti-inflammatory properties, and thus interest in its use
in patients with asthma has been renewed. The use of theophylline in the
treatment of asthma and chronic obstructive pulmonary disease has diminished with
the advent of new medications, but theophylline remains beneficial, especially in
the patient with difficult refractory symptoms. In the future, theophylline may
be used as treatment for bradyarrhythmias after cardiac transplantation,
prophylactic medication to reduce the severity of nephropathy associated with
intravenous administration of contrast material, therapy for breathing problems
during sleep, and treatment for leukemias.
PMID- 9559042
TI - A 31-year-old man with fever, dyspnea, and pulmonary infiltrates.
PMID- 9559043
TI - Immune cholangitis: liver allograft rejection and graft-versus-host disease.
AB - A pronounced similarity exists between liver allograft rejection and graft-versus
host disease (GVHD) in the damage and eventual destruction of small intrahepatic
bile ducts. Although an immunologic reaction has an important role, precisely
identifying the target antigens or reason for persistence of the immune response
has been difficult. An important difference between GVHD and liver rejection is
the development of obliterative arteriopathy only in rejection. The three main
histopathologic features of acute rejection are a predominantly mononuclear but
mixed portal inflammation, subendothelial inflammation of portal or terminal
hepatic veins (or both), and bile duct inflammation and damage. In acute
rejection, a controversial issue is determining when therapeutic intervention is
needed. The recommended approach is to base treatment on a combination of
histopathologic changes and liver injury or dysfunction. Chronic rejection, which
usually does not occur before 2 months after transplantation, is characterized by
two main histopathologic features: (1) damage and loss of small bile ducts and
(2) obliterative arteriopathy. Acute GVHD begins within the first month after
transplantation and most commonly involves the skin, gastrointestinal tract, and
liver, whereas chronic GVHD usually develops more than 80 to 100 days after liver
transplantation and affects 30 to 50% of long-term survivors. Recognition of the
early, cellular stages of chronic GVHD is important in preventing irreversible
damage.
PMID- 9559044
TI - Ischemic cholangitis.
AB - Ischemia-induced bile duct lesions have been collectively labeled as ischemic
cholangitis. The biliary epithelium is dependent on arterial blood flow, unlike
the hepatic parenchyma with its dual arterial and portal venous blood supply. As
such, the biliary epithelium is susceptible to injury when arterial blood flow is
compromised. This compromise can occur at the level of the major, named hepatic
artery branches or at the microscopic, peribiliary capillary plexus level.
Typically, ischemic cholangitis manifests as segmental strictures and
cholangiectases with resultant mechanical impairment of bile flow and,
occasionally, secondary infection of the biliary system. Ischemic cholangitis
after liver transplantation is becoming an important problem and likely is
attributable to numerous factors. Hepatic arterial infusion of chemotherapy and
systemic vasculitis are other causes of ischemic cholangitis. The role of
ischemia in other chronic biliary and ductopenic diseases remains speculative.
PMID- 9559045
TI - Overcoming the barriers to cancer screening.
PMID- 9559046
TI - Malignant pyoderma and Wegener's granulomatosis.
PMID- 9559047
TI - Granulomatous vasculitis associated with herpes virus.
PMID- 9559048
TI - Diabetic retinopathy. Screening and prevention of blindness. A doctoral thesis.
AB - Diabetic eye disease is a major cause of blindness in the Western World and
remains one of the most serious complications of diabetes mellitus. Retinopathy
is the ocular complication of diabetes that most often leads to impaired vision.
In recent years laser treatment has been introduced that can significantly
decrease the likelihood of blindness in diabetic patients, if the eyes are
treated at the appropriate stage of the disease. It remains a public health
problem to make sure that each patient is treated at the optimal time in the
development of the eye disease. Several types of screening programs have been
designed throughout the world to meet this problem. We now report on our active
screening program for diabetic eye disease and describe the sight and eye
condition of the diabetic patients who have been involved in this program. In
1980, regular eye screening for diabetic retinopathy was initiated at Department
of Ophthalmology, Landakot Hospital. The number of diabetic patients seen
regularly has increased considerably since then, with 70-80% of type 1 diabetic
patients in the country participating in the program in 1990, increasing to over
90% in 1994. About a fifth of type 2 diabetics in the country participated in the
program in 1990. The patients have undergone annual eye examinations and fundus
photography. Laser treatment is administered for proliferative retinopathy and
diabetic macular edema according to the Diabetic Retinopathy Study and Early
Treatment Diabetic Retinopathy Study criteria. In 1990, we embarked on a cross
sectional study to evaluate the prevalence of retinopathy and visual impairment
of the type 1 and type 2 patients participating in our program. At the time of
study, 205 insulin-taking patients, with age at diagnosis of less than 30 years,
participated in our screening program. Out of those, retinopathy was present in
106 (52%), patients proliferative retinopathy in 26 (13%) and macular edema in 19
(9%). Visual acuity of 196 patients (96%) was equal or better than 6/12 in their
better eye, 6 patients (3%) had 6/18-6/36 in their better eye, and 2 patients
(1%) had equal or worse than 6/60 in their better eye, or legally blind. We
concluded that the prevalence of retinopathy and visual impairment in type 1
diabetic patients in the country was low compared with other countries. In 1990,
out of 245 diabetic patients with Type 2 diabetes, retinopathy was present in 100
patients (41%), proliferative retinopathy had been present in 17 (7%) and 24
(10%) had diabetic macular edema. A total of 224 patients (91%) had visual acuity
equal or better than 6/12 in their better eye, 17 patients (7%) with 6/18-6/36 in
their better eye, and 4 patients (1.6%) equal or worse than 6/60 in their better
eye, or legally blind. We concluded that the prevalence of visual impairment of
those type 2 diabetic patients participating in our screening program at the time
of study was low compared with population-based studies from other countries. In
1992 we examined ways to make the screening program more efficient by identifying
subgroups at low risk for developing eye disease that required treatment and
therefore needed less frequent screening. We studied whether diabetic eye disease
screening programs could be trimmed by excluding children and examining diabetic
patients without retinopathy every other year. We examined all children under the
age of 15 at the time of study and went through the files of all patients under
age 15 examined from 1980 to 1992 at our diabetic eye screening program. We also
followed for two years the type 1 and type 2 diabetic patients found to have no
retinopathy in 1990, establishing their retinopathy stage two years later. Our
results indicated that diabetic children under the age of 12 do not need regular
screening for eye disease. Biannual examinations seemed to suffice in type 1 and
2 diabetic patients without retinopathy. (ABSTRACT TRUNCATED)
PMID- 9559049
TI - Activated glutamate intermediate in the enzymatic synthesis of glutamine. 1960.
PMID- 9559050
TI - Advances in the enzymology of glutamine synthesis.
AB - Meister's proposal of a gamma-glutamyl-P intermediate in the glutamine synthetase
reaction set the scene for understanding how the stepwise activation of the
carboxyl group greatly increased its susceptibility toward nucleophilic attack
and amide bond synthesis. Topics covered in this review include: the discovery of
the enzymatic synthesis of glutamine; the role of glutamine synthetase in
defining the thermodynamics of ATPases; early isotopic tracer studies of the
synthetase reaction; the proposed intermediacy of gamma-glutamyl-phosphate; the
mechanism of methionine sulfoximine inhibition; stereochemical mapping of the
enzyme's active site; detection of enzyme reaction cycle intermediates;
borohydride trapping of gamma-glutamyl-P; positional isotope exchanges catalyzed
by glutamine synthetase; regulation of bacterial enzyme; and a brief account of
how knowledge of the atomic structure of bacterial glutamine synthetase has
clarified ligand binding interactions. Concluding remarks also address how the so
called "Protein Ligase Problem" may be solved by extending the catalytic
versatility of carboxyl-group activating enzymes.
PMID- 9559051
TI - Hepatic glutamine transport and metabolism.
AB - Although the liver was long known to play a major role in the uptake, synthesis,
and disposition of glutamine, metabolite balance studies across the whole liver
yielded apparently contradictory findings suggesting that little or no net
turnover of glutamine occurred in this organ. Efforts to understand the unique
regulatory properties of hepatic glutaminase culminated in the conceptual
reformulation of the pathway for glutamine synthesis and turnover, especially as
regards the role of sub-acinar distribution of glutamine synthetase and
glutaminase. This chapter describes these processes as well as the role of
glutamine in hepatocellular hydration, a process that is the consequence of
cumulative, osmotically active uptake of glutamine into cells. This topic is also
examined in terms of the effects of cell swelling on the selective stimulation or
inhibition of other far-ranging cellular processes. The pathophysiology of the
intercellular glutamine cycle in cirrhosis is also considered.
PMID- 9559052
TI - Enzymes utilizing glutamine as an amide donor.
AB - Amide nitrogen from glutamine is a major source of nitrogen atoms incorporated
biosynthetically into other amino acids, purine and pyrimidine bases, amino
sugars, and coenzymes. A family comprised of at least sixteen amidotransferases
are known to catalyze amide nitrogen transfer from glutamine to their acceptor
substrates. Recent fine structural advances, largely as a result of X-ray
crystallography, now provide structure-based mechanisms that help to explain
fundamental aspects of the catalytic and regulatory interactions of several of
these aminotransferases. This chapter provides an overview of this recent
progress made on the characterization of amidotransferase structure and
mechanism.
PMID- 9559053
TI - Mechanistic issues in asparagine synthetase catalysis.
AB - The enzymatic synthesis of asparagine is an ATP-dependent process that utilizes
the nitrogen atom derived from either glutamine or ammonia. Despite a long
history of kinetic and mechanistic investigation, there is no universally
accepted catalytic mechanism for this seemingly straightforward carboxyl group
activating enzyme, especially as regards those steps immediately preceding amide
bond formation. This chapter considers four issues dealing with the mechanism:
(a) the structural organization of the active site(s) partaking in glutamine
utilization and aspartate activation; (b) the relationship of asparagine
synthetase to other amidotransferases; (c) the way in which ATP is used to
activate the beta-carboxyl group; and (d) the detailed mechanism by which
nitrogen is transferred.
PMID- 9559054
TI - Mechanisms of cysteine S-conjugate beta-lyases.
AB - Mercapturic acids are conjugates of S-(N-acetyl)-L-cysteine formed during the
detoxification of xenobiotics and during the metabolism of such endogenous agents
as estrogens and leukotrienes. Many mercaturates are formed from the
corresponding glutathione S-conjugates. This chapter focuses on (a) the discovery
of the cysteine S-conjugate beta-lyases; (b) the involvement of pyridoxal-5
phosphate; (c) the influence of the electron-withdrawing properties of the group
attached to the sulfur atom; and (d) the potential of cysteine S-conjugates as
pro-drugs.
PMID- 9559055
TI - gamma-Glutamyl transpeptidase: catalytic mechanism and gene expression.
AB - The gamma-glutamyl transpeptidases are key enzymes in the so-called gamma
glutamyl cycle involving glutathione synthesis, the recovery of its constituents,
and in the transport of amino acids. This membrane-bound ectoenzyme thus serves
to regulate glutathione synthesis. This chapter deals with the active site
chemistry of gamma-glutamyl transpeptidase, including the role of side-chain
groups on the light subunit as well as several serine residues in the catalytic
process. Also considered are genomic studies indicating (a) the presence of a
single gene in mouse and rat; (b) the occurrence of multiple genes in humans; (c)
the involvement of multiple promoters for gene expression; and (d) how these
multiple promoters may play a role in the tissue-specific expression of gamma
glutamyl transpeptidases.
PMID- 9559056
TI - Enzymology of bacterial lysine biosynthesis.
AB - Bacteria have evolved three strategies for the synthesis of lysine from aspartate
via formation of the intermediate diaminopimelate (DAP), a metabolite that is
also involved in peptidoglycan formation. The objectives of this chapter are
descriptions of mechanistic studies on the reactions catalyzed by
dihydrodipicolinate synthase, dihydrodopicolinate reductase,
tetrahydrodipicolinate N-succinyl-transferase, N-succinyl-L,L-DAP
aminotransferase, N-succinyl-L,L-DAP desuccinylase, L,L-DAP epimerase, L,L-DAP
decarboxylase, and DAP dehydrogenase. These enzymes are discussed in terms of
kinetic, isotopic, and X-ray crystallographic data that allow one to infer the
nature of interactions of each of these enzymes with its substrate(s), coenzymes,
and inhibitors.
PMID- 9559057
TI - Collagen hydroxylases and the protein disulfide isomerase subunit of prolyl 4
hydroxylases.
AB - Prolyl 4-hydroxylases catalyze the formation of 4-hydroxyproline in collagens and
other proteins with an appropriate collagen-like stretch of amino acid residues.
The enzyme requires Fe(II), 2-oxoglutarate, molecular oxygen, and ascorbate. This
review concentrates on recent progress toward understanding the detailed
mechanism of 4-hydroxylase action, including: (a) occurrence and function of the
enzyme in animals; (b) general molecular properties; (c) intracellular sites of
hydroxylation; (d) peptide substrates and mechanistic roles of the cosubstrates;
(e) insights into the development of antifibrotic drugs; (f) studies of the
enzyme's subunits and their catalytic function; and (g) mutations that lead to
Ehlers-Danlos Syndrome. An account of the regulation of collagen hydroxylase
activities is also provided.
PMID- 9559058
TI - [The medical responsibility of an allergist].
AB - The professional civil responsibility of an allergy physician should be restored
to the more general framework of medical responsibility. This is at present the
objective of considerable public debate. From now on it is known that the
developments at present and to come for the most part go beyond the strict
requirement of the juridical process. They take up fully a real choice of
society. What place do we wish to give to physicians in the future? What new
outlines relating to care should be adopted? What must be done for the victims of
medical accidents? These are the fundamental questions that we ask ourselves
today. The choices that apply, influence, must persuade our society, its made of
action and the relationships between the various' components. It must be said
that the stakes are enormous. It must also be said that all of this will not be
achieved without clashes.
PMID- 9559059
TI - [Masked and labelled food allergens].
AB - Several food proteins are used as food additives or may be contained in foods as
contaminants. These masked allergens are at high risk of inducing severe clinical
reactions: acute asthma, laryngeal angioedema, anaphylactic shock or even death.
The present regulation requires labelling only if the level of food ingredients
is superior to 25% of the final product. Several immunologic methods can detect
low levels of proteins, equal or inferior to 2%. However a level of 1% or less
may be noxious, suggesting a need for a specific line of food products which
could be guaranteed free of ... and which might be recommended to patients with
food allergy.
PMID- 9559060
TI - [Application of flow cytometry to the analysis of activation of human basophils.
Immunologic validation of the method].
AB - Among the different methods used for the analysis of human basophil activation as
histamine and leukotriene release, flow cytometry presents several methodological
advantages. Moreover, preliminary results obtained for a wide allergen panel have
demonstrated its high sensitivity and specificity. We present here the results of
the methods used to validate the flow cytometric analysis of human basophil
activation by double anti-IgE FITC/anti-CD63 PE labelling of human leucocytes.
The use of multiple labelling by monoclonals having different specificities have
shown that the selected cells express the phenotype CD14-, CD19-, CD41- or +/-,
CD45+, CD63- or +. This phenotype is related to human basophils. We have also
demonstrated that the expression of CD63 is related to basophil activation and
not to aggregated platelets which are also able to express this marker.
PMID- 9559061
TI - [Testing basophil activation by flow cytometry in the diagnosis of allergy to
hymenopteran venom].
AB - Diagnosis of allergy to hymenoptera venom must be precise and depends on
indisputable bio-clinical criteria, because of specific immunotherapy for
indications such as systemic and/or anaphylactic reactions. Until nowadays,
diagnosis was by specific IgE, histamine release and skin tests, most often done
for the venoms of wasp, honey bee and hornet at the same time since, in 7-8 cases
in 10 the patients had not identified the responsible insect. Basophil activation
test (TAB) by Flux cytometry and measurement of leukotriene C4 (LTC4) are new
techniques of great reliability. The work shows the correlations between the
different immunobiological parameters by reference to TAB by CAF and measurement
of LTC4. When the overall results for mixed venoms or those for single venoms are
considered, the correlations between TAB, LTC4 and the other parameters are
highly significant. It can now be considered objectively that TAB by CTF and
measurement of LCT4 are the two highest-performing techniques for diagnosis of
hymenoptera venom allergy and so validates them.
PMID- 9559063
TI - [Contact eczema by proxy to benzoyl peroxide].
PMID- 9559062
TI - [Antibiotic tolerance. Clinical and biological evaluation methods. Preliminary
study of 42 patients].
PMID- 9559064
TI - [Contact eczema to 17 beta estradiol].
PMID- 9559065
TI - Female dispersal, social organization, and infanticide in langurs: are they
linked to human disturbance?
AB - Female dispersal in gregarious animals can involve the desertion of a site,
desertion of a social group, or both. Group desertion may be related to
inbreeding avoidance. Group fidelity may result from cooperation among females in
a group. Site fidelity will be more likely when food can be monopolized and when
the population density is close to habitat saturation. The degree of habitat
saturation was approximated with a measure of human disturbance. The influence of
these various factors on the incidence of female dispersal was investigated for
langur populations using data from the literature. The results suggest that
female dispersal in langurs involved site desertion, not group desertion. The
incidence of female dispersal may affect the social organization of langurs. I
propose that when females do not disperse, male takeovers prevail, whereas in
populations where female dispersal regularly occurs bisexual groups are disbanded
or new groups are formed, a process I call female split-merger. Male takeover is
thought to occur when site fidelity is high, female split-merger when site
fidelity is low. These processes were indeed found to occur in these
circumstances. The dispersal of females might prevent infanticide, whereas male
takeover might promote it. Indeed, in studies with male takeover, more infants
fell victim to infanticide than in studies with female split-merger. Therefore,
female dispersal in langurs is an effective female counterstrategy to
infanticide. The factor that had the most profound effect on female dispersal,
social organization, and infanticide was habitat saturation. Habitat saturation
was measured as the degree of human disturbance, and its influence on the
behavior of langurs is probably of relatively recent date. This may lead to an
evolutionary transient situation and may explain the discrepancy between current
socioecological theories and the behavior of langurs in populations lacking
female dispersal.
PMID- 9559066
TI - Chromosome diversity of the genus Aotus from Colombia.
AB - Description of six Colombian karyomorphs is completed through an extensive
cytogenetic characterization of 35 Aotus (owl monkeys) specimens. The description
of a new karyomorph for Colombian Aotus by chromosome on Q, G, R, and C,
sequential banding is included. Pairs of karyomorphs 2 and 3 and 6 and 9 with 2n
of 54, and 50, respectively, as well as karyomorphs 7 and 8 with 46 and 58
chromosomes were strongly suspected to represent different species on the grounds
of large karyotypic differences. A proposal for a chromosome nomenclature of
Aotus karyomorphs that aims to clarify Aotus taxonomy is presented which achieves
a precise correspondence of different banding patterns, based on Q, G, R, and C
sequential banding and chromosome measurements. Although our contribution is not
a universal nomenclature system, unique criteria for chromosome denomination
within Aotus karyomorphs are established. Previous systems of chromosome
nomenclature have not successfully addressed the nomenclature of chromosomes of
the same karyotype.
PMID- 9559067
TI - [Spontaneous hematoma of the kidney. Apropos of 3 cases].
AB - The objective of this study was to illustrate the diagnostic and therapeutic
aspects of renal haematomas based on 3 cases observed in the Casablanca urology
department and a review of the literature. In 50% of cases, the haematoma is
secondary to adenocarcinoma or angiomyolipoma, requiring specific treatment.
PMID- 9559068
TI - [Acute obstructive renal insufficiency and pregnancy. Apropos of a case].
AB - Acute renal failure caused by obstruction by the gravid uterus is a rare
complication of pregnancy. We report a case of obstructive acute renal failure in
a patient at 28 weeks of gestation. Serum creatinine was 65 mg/l. Ultrasound
examination showed a solitary right kidney. The course was marked by premature
delivery. Renal function spontaneously returned to normal. This case suggests
that acute obstructive uropathy should be considered to be a physiological
phenomenon, especially on the right side.
PMID- 9559069
TI - [Peritonitis due to spontaneous rupture of pyonephrosis. Apropos of a case].
AB - Description of a case of peritonitis in a 60-year-old diabetic woman. Emergency
laparotomy revealed a purulent effusion derived from a pyonephrotic and calculous
left kidney. The patient was cured by left nephrectomy.
PMID- 9559070
TI - [Enterococci as uropathogens. Frequency of isolation and sensitivity to
antibacterial agents].
AB - 221 clinically significant enterococcal strains (191: E. faecalis, 27: E.
faecium, 3 others) were isolated from the urine of patients hospitalised with UTI
over an 18-month period (1995-1996). The susceptibility of the isolates to 8
antimicrobial agents was determined by agar dilution method (NCCLS). All
enterococci were sensitive to vancomycin and most of them (over 92%) to
penicillin and ampicillin. Only 3.14% of E. faecalis and 3.70% of E. faecium were
resistant to ciprofloxacin. A relatively high incidence of resistance of
enterococci to aminoglycosides was observed: 46.07% and 51.85% to streptomycin,
42.41% and 44.44% to gentamicin, 70.68% and 77.78% to amikacin for E. faecalis
and E. faecium, respectively. Among the resistant to penicillin and amino
glycosides enterococci of the two species was found a great percent "high level"
resistance. There were no beta-lactamase producers among our strains. The
established multiresistance accompanied by "high level" resistance requires
careful consideration of antimicrobial therapy of enterococcal UTI.
PMID- 9559071
TI - [Retroperitoneal ganglioneuroma. Apropos of a case].
AB - Ganglioneuroma is a rare tumour in adults. We report the case of a 26-year-old
woman admitted in our department with right renal colic. Ultrasonography and
computed tomography showed a heterogeneous retroperitoneal mass measuring 8 x 7
cm in diameter and displacing the ureteropelvic junction and right kidney
anteriorly and laterally. The preoperative diagnosis was retroperitoneal tumour.
Surgical exploration revealed a totally resectable retroperitoneal tumour with a
histological diagnosis of ganglioneuroma.
PMID- 9559072
TI - [The treatment of prune-belly syndrome at the University Hospital Center at
Abidjan (Treichville)].
AB - Over the past 10 years, we have seen sixteen children (15 males and 1 female)
with the prune-belly syndrome. We have managed 12 of these children, but 4 of
them were never reviewed. Abdominal wall reconstruction was performed in 11
children by dissection of spermatic vessels and fixing the testis in the scrotum.
Because of our conservative approach to the management of urinary tract
dilatation, we performed only one nephrostomy and 3 unilateral nephro
ureterectomies. Seven children were reviewed. The result of abdominal wall
reconstruction was good in terms of cosmetic appearance and psychologic effect
for the parents; we have observed no atrophic testes after orchidopexy. One of
these children suffers from chronic renal failure, while the other children have
good renal function. Prune-belly syndrome is a disease with a broad spectrum. The
prognosis depends on the degree of renal dysplasia. These children require long
term follow-up.
PMID- 9559073
TI - [Appendiceal mucocele disclosed by a psoas tumor. Apropos of a case].
AB - Mucocele of the appendix is a rare lesion. Rupture of appendicular mucocele into
the psoas is uncommon. We report a case of a 77-year-old man, with psoas tumor on
abdominopelvic ultrasonography and computed tomography. The preoperative
diagnosis was type III hydatid cyst of the psoas, psoas tumor or retroperitoneal
mass. Surgical exploration revealed an appendicular mucocele ruptured into the
psoas. Appendicectomy was performed with an uneventful postoperative course after
3 years. The authors discuss the diagnostic and therapeutic problems raised by
this rare lesion.
PMID- 9559074
TI - [Rigid ureteroscopy. Apropos of 88 cases].
AB - Rigid ureteroscopy has become a common tool for the diagnosis and management of
several diseases of the upper urinary tract. Between April 1990 and April 1996,
92 ureteroscopy procedures were performed in 88 patients in the B Urology
Department of Avicennes hospital for diagnostic or therapeutic purposes. The
commonest therapeutic procedure was stone manipulation (72 cases). The overall
success rate was 90.8% (Distal ureter: 89.6%, mid ureter: 80%, lumbar ureter:
100%) and the complication rate was 4%. Therapeutic ureteroscopy was also used to
dry ureterovaginal fistula (4 cases) and ureteral fistula with retroperitoneal
urinoma (2 cases), and to remove a double J stent which had migrated into the
pelvic ureter (3 cases). Diagnostic ureteroscopy was performed for 7 ureteral
strictures including 3 extrinsic compressions and 4 ureteral strictures all
treated with dilatations after biopsy. One false passage was observed among
diagnostic ureteroscopy procedures. Rigid ureteroscopy is a minimally invasive
and reliable technique for the management of ureteric calculi and for the
diagnosis and treatment of other ureteric lesions.
PMID- 9559076
TI - [Primary urothelial carcinoma of the urethra. Apropos of a case].
AB - We report an unusual case of primary transitional cell carcinoma in the bulbar
urethra. The patient was a 52-year-old man with a history of sexually transmitted
disease. The clinical presentation was bladder retention with urethral bleeding.
Radiological examination and cystoscopy showed a bulbar urethral tumor. The
pathological diagnosis was Grade III transitional cell carcinoma with invasion of
the corpus spongiosum (T2). Partial resection of the urethra was performed and
the patient has been without evidence of disease for two years.
PMID- 9559075
TI - [ST52 treatment of cancer of the prostate during the hormonal resistance phase].
AB - OBJECTIVE: Stilboestrol phosphate (ST 52) was evaluated on pain, general status,
life expectancy and PSA, in a retrospective study of patients with prostatic
carcinoma and relapse to hormonal treatment. MATERIAL AND METHODS: 32 patients
were treated by infusion of Stilboestrol phosphate at a daily escalating dose
from 1.2 to 3 g over a period of 10 days, then subsequently oral administration.
RESULTS: Minor complications, especially nausea were observed in 12 cases but no
major complication or interruption of treatment. Improvement for pain alone or
with general status was obtained in 50% (16 cases) at 3 months, but at one year
only 10% were still improved. Median survival was 8 months, with 19.4 months for
responders at the end of infusions and 4.2 months for non-responders
respectively. CONCLUSION: Stilboestrol phosphate can obtain a clinical response
with low morbidity when relapse to hormonal treatment occurs. Infusion responders
have a better life expectancy.
PMID- 9559077
TI - [Torsion of an undescended testis. Apropos of a case].
AB - The authors report an uncommon case of torsion of an inguinal undescended testis
occurring in a 15-year-old child. He consulted seven days later for isolated left
inguinal pain. Physical examination showed a left inguinal mass, and only the
right testis was palpable within the scrotum. Sonography revealed left inguinal
mass with echogenic and heterogeneous contents in keeping with undescended
testis. The diagnoses of testis tumor or testis torsion were suggested. Surgical
exploration revealed a mass suggesting a testis tumor. Orchidectomy was
performed. Histological examination showed that the mass corresponded to a
necrotic ischemic testis without tumor cells. In the light of this case, the
authors analyse the diagnostic aspects and management of torsion of an
undescended testis.
PMID- 9559078
TI - Learning to talk about it.
PMID- 9559079
TI - Risk factors as determinants of dental neglect in children.
AB - Although neglect represents over a half of both reported and substantiated cases
of child maltreatment each year, it is misunderstood and under-reported. Dental
neglect, a form of physical neglect, is ignored to an even greater degree.
Certain families appear to be more at risk for neglect, in some form, than
others. Predisposing risk factors that may increase the incidence of neglect
include characteristics of parents and children, family situations, socioeconomic
and demographic circumstances, and parental beliefs and practices. Dentists,
particularly pediatric dentists, are in unique positions to evaluate not only the
dental needs of children, but also family situations and circumstances that might
affect their dental well-being. Knowledge and understanding of the various risk
factors discussed will enable dentists to address the problem of dental neglect
from a preventive approach, rather than strictly treating is results. Further
research is needed to develop effective methods for both the evaluation and, if
necessary, the education of at-risk individuals on the importance of good oral
hygiene and professional care.
PMID- 9559080
TI - Child abuse and neglect: assessment of dental students' attitudes and knowledge.
AB - Although many North American dental schools have increased their curriculum hours
dedicated to the issue of child maltreatment, the majority of schools still
allocate only one to two clock hours for this subject. The purpose of this study
was to evaluate the self-perceived knowledge of and attitude toward child abuse
and neglect, of undergraduate dental students at the University of Texas Dental
Branch at Houston, as well as the effectiveness of the various educational
methods used in the instruction of this material. Students in general, recognized
a need for improvement of both the quality and quantity of this aspect of their
undergraduate curriculum. The results indicate, however, that the child
maltreatment curriculum at this institution had minimal effect on the acquisition
and retention of information related to this subject. Dental educators have the
responsibility to see that their students are competent, not only in the
technical aspects of dentistry, but in their social responsibilities, as well.
The ability to recognize suspected cases of child maltreatment is such a
responsibility.
PMID- 9559081
TI - Severe bone loss caused by orthodontic rubber bands; management and nine-year
follow-up: report of case.
AB - This case reports the early diagnosis and treatment of an iatrogenic acute
localized periodontitis arising from the incorrect use of orthodontic elastic
rubber bands to close a maxillary midline diastema in an eight-year-old girl. The
case illustrates the misdiagnosis and mismanagement of a transitional diastema in
the "ugly duckling" stage of the mixed dentition. The nine-year follow-up shows
that thorough periodontal and orthodontic management has allowed successful
retention of both maxillary permanent central incisors, which had initially
pathological grade 3 vertical mobility, little remaining alveolar bone, and a
hopeless prognosis.
PMID- 9559082
TI - A comparison of the bond strength to enamel and dentin of two compomers: an in
vitro study.
AB - The aim of this study was to evaluate the bond strength of two resin-reinforced
glass ionomer cements to etched and unetched enamel and to dentin. Thirty-six
noncarious human premolar teeth were used. Flat buccal and lingual surfaces were
prepared. Dyract and Compoglass were used. The teeth were distributed at random
into six groups of six teeth each. The materials were handled according to
manufacturers' instructions. In groups 1 and 3 the enamel was etched with 37
percent phosphoric acid. All samples were sheared with an Autograph AG5 machine
at a crosshead speed of 0.5 mm/min. Two way ANOVA and comparison with the Tukey
test were used to evaluate the results. These showed that on etched enamel Dyract
had a significantly higher bond strength (p = 0.02); on unetched enamel
Compoglass had a statistically higher bond strength (p = 0.003), and on dentin
the materials provided the same bond strength. Overall, disregarding surfaces,
there was no difference between the two materials.
PMID- 9559084
TI - Preeruptive intracoronal radiolucencies: review and report of case.
AB - Intracoronal radiolucencies in unerupted teeth are an uncommon radiographic
finding; but their early detection and classification allow the most appropriate
management protocol to be developed. Early separation of lesions into those that
are developmental and remain static and those that are reactive and aggressive is
necessary for a controlled outcome. The current paper reviews possible formative
mechanisms and describes a case of severe intracoronal resorption resulting in
loss of the tooth.
PMID- 9559083
TI - A retrospective radiographic survey of embedded primary molar roots in Saudi
adult patients.
AB - This retrospective study reports the radiographic prevalence of embedded primary
molar roots within Saudi adult dentulous patients. Embedded roots of primary
molars were viewed radiographically by evaluation of the records of 300 patients.
Embedded primary molar roots were detected in 7 percent of the viewed patient
radiographs. Fifty-five percent of the embedded roots demonstrated the
concomitant existence of partial bony ankylosis. The remaining 45 percent of the
embedded roots were surrounded by an intact lamina dura and periodontal ligament
space. The frequency of occurrence demonstrated an age-based relationship,
showing 9 percent prevalence in the older age-group (41-50 yr.) as compared to a
45 percent occurrence seen in the younger (15-20 yr.) group. Seventy-seven
percent of the embedded roots were found within the mandible as compared with a
23 percent occurrence in the maxilla.
PMID- 9559085
TI - Early treatment of posterior and anterior crossbite in a child with bilaterally
constricted maxilla: report of case.
AB - A case report of a young patient with anterior and bilateral posterior crossbite
was presented. She was severely brachyfacial with a mild Class III malocclusion
due to slight maxillary retrusion. Early orthodontic therapy using a simple,
removable, maxillary expansion appliance provided the patient with a stable,
functional occlusion and good esthetics.
PMID- 9559086
TI - Infraclusion of primary molars: reports of cases.
AB - A review of twenty-five patients (nine boys and sixteen girls with a mean age of
13.6 years) with infraclusion of primary molars is reported. There were thirty
two infracluded teeth, twenty-one (65.6 percent) maxillary primary molars and
eleven (34.4 percent) mandibular primary molars. The primary first molar was
found to be in infraclusion in four (12.5 percent) cases and the primary second
molar in twenty-eight (87.5 percent) cases. Submergence was mild in fifteen
cases, moderate in five, and severe in twelve. The permanent successor was
lacking in four (12.5 percent) infracluded teeth. Aplasia of a nonsuccedaneous
tooth was observed in four patients (more than one aplasia in three of them).
Sixty-five percent of the teeth distal to the infracluded tooth had some degree
of mesioversion, and 34.4 percent showed a distoversion of the mesial tooth.
Twenty-one patients underwent orthodontic therapy because of malocclusion induced
by the submerged tooth or for other reasons. A total of twenty-five (78.1
percent) teeth had to be extracted (surgical extraction in seventeen cases). An
alveolotomy made to help the succedaneous tooth to erupt was necessary in ten
cases.
PMID- 9559087
TI - Is your next young patient pre-anorexic or pre-bulimic?
AB - Eating disorders often have their roots in the preteen years. Pediatric dentists
may provide the initial warning for the care of these youngsters. An introduction
is provided to the demographics, diagnosis, and treatment of anorexic and bulimic
young females (primarily) and males.
PMID- 9559088
TI - Profile of primary teeth with pulpal involvement secondary to caries.
AB - The objective of this retrospective study was to determine the profile of primary
teeth with pulpal involvement secondary to caries that required pulp therapy or
extractions. Three hundred and ninety teeth were selected in 215 children (twelve
years old and under) at an inner-city clinic in the United States over an
eighteen-month period. An analysis of frequency distribution was done. Molar
teeth were most affected by this stage of caries with morbidity increasing with
age. In the under-six-year-olds, however, maxillary incisors were most affected.
Extraction was the predominant treatment selected for the incisors with this
degree of caries. Pulp therapy was the treatment of choice for molar teeth in the
under-six-year-olds, but this trend was reversed with the number of extractions
increasing in the six-to-twelve-year-old children.
PMID- 9559089
TI - Sexually transmitted diseases and children: there is good news, but....
AB - A review is provided of a series of federal agency reports on sexually
transmitted diseases among children and young adults. While there have been
marked decreases in the number of reports of disease, continued infection of
youngsters less than fifteen years of age is a continuing reality.
PMID- 9559091
TI - Temporal variation of allozyme frequencies in Aedes albifasciatus (Diptera:
Culicidae) from Argentina.
AB - Aedes albifasciatus is a floodwater mosquito widely distributed in Argentina. It
is important from economic and medical points of view. A 4-year survey of
seasonal variation in allele frequencies in a population of this species was
undertaken to determine possible changes in the genetic structure and their
correlation with environmental conditions. Significant temporal variation was
detected at most of the loci, but it did not follow a cyclic or seasonal pattern.
Multivariate analysis of principal components showed a remarkable homogeneity of
samples collected from December 1993 to April 1995 and a clear differentiation of
the November 1991, March 1992, and November 1993 samples. This variation could be
correlated with the magnitude of rainfall occurring in the area. Passive
transport of larvae by water streams and river freshets produced by floods would
have mixed larvae from breeding sites with different allele frequencies, causing
the genetic differentiation observed.
PMID- 9559090
TI - Dental caries prevalence and dental health care of Mexican-American workers'
children.
AB - The purpose of this study was to determine the prevalence of dental caries and
the use of dental services in a pediatric population of Mexican-American migrant
workers. The results were compared with the Mexican-American child population
from the Hispanic Health and Nutrition Examination Survey (HHANES). One hundred
thirty three-to-sixteen-year-old children participated in the study. The children
who were born in Mexico and those who spoke Spanish had seen the dentist less
often and had a higher incidence of decayed teeth than those who were born in the
US and than those who spoke English (p < 0.05). The children from low-income
families had visited the dentist less frequently and did so at an older age than
those from high income families (p < 0.05). When compared with HHANES, the
children in this study visited the dentist at an older age, had been to the
dentist less often, were less likely to have dental insurance, and had a higher
incidence of dental caries than the children from HHANES (p > 0.05). This study
demonstrated a general lack of dental health knowledge, a disproportionate
prevalence of decayed teeth and unmet dental need in the Mexican-American migrant
workers' children.
PMID- 9559092
TI - Genetic specificity of stress-induced anemia in rats.
AB - There is a genetic difference in rat hemoglobin (Hb) beta-chain structure, with
alternate alleles, A and B, at a single locus. This study was designed to find
out whether marrow sensitivity due to gamma exposure and experimentally induced
anemia in age-matched adult rats is entirely strain specific or is a combination
of both strain and Hb genotype. Eight strains of inbred and outbred rats
comprising AA and BB types were examined. The data indicate that there is a
relationship between marrow sensitivity and Hb genotypes in response to
erythropoietic stress caused by three techniques.
PMID- 9559093
TI - Comparison of mtDNA variants among Mediterranean and New World introductions of
the Mediterranean fruit fly Ceratitis capitata (Wied.).
AB - Restriction enzyme cleavage sites of mitochondrial DNA (mtDNA) from the
Mediterranean fruit fly (Ceratitis capitata) were found to vary among
Mediterranean and New World populations. A restriction map for six populations
(one from Greece and five from the New World) is constructed for the
Mediterranean fruit fly. Six diagnostic restriction enzymes (EcoRI, EcoRV,
HaeIII, HindIII, SstI, XbaI) are assigned three geographically distinct main
types, CI, CII, and CIII.
PMID- 9559095
TI - Allozyme polymorphism and geographic variation in the small brown planthopper,
Laodelphax striatellus (Homoptera: Delphacidae).
AB - The small brown planthopper, Laodelphax striatellus, immigrates annually into
Japan over the East China Sea from the Asian mainland. It is not known whether
this long-distance dispersal has any effect on the genetic structure of Japanese
L. striatellus populations. The dispersal of L. striatellus is suspected to be
relevant to the population dynamics of infection with the parasitic bacterium
Wolbachia, which causes cytoplasmic incompatibility in L. striatellus. Wolbachia
infection has spread within and among Japanese L. striatellus populations due to
this cytoplasmic incompatibility. In the present study, the geographic
differences among II L. striatellus populations from Japan and Taiwan was
investigated using allozyme polymorphism. FST values on three enzyme loci (GPI,
PGM, and AK) indicated a geographically differentiated population structure.
Significant differentiation was found even among populations located along the
course of the long-distance dispersal. The results indicated that long-range
dispersal of L. striatellus does not occur regularly over the main islands of
Japan and that it does not have a large effect on the population structure of L.
striatellus. This conclusion is in agreement with the geographically variable
life history of L. striatellus adapted to local climates. The short-term rice
stripe epidemic, which is vectored by L. striatellus, in northwestern Kyushu,
Japan, during 1985 and 1986 corresponds to these results. Based on the present
findings, short-distance dispersal was considered to drive the spatial spread of
Wolbachia infection among L. striatellus populations.
PMID- 9559094
TI - Genetic variation in some populations of the golden-striped salamander,
Chioglossa lusitanica (Amphibia: Urodela), in Portugal.
AB - Genetic variation in the golden-striped salamander (Chioglossa lusitanica) was
assessed in 231 individuals from four Portuguese populations by means of
horizontal starch gel electrophoresis and isoelectric focusing. Three of 19
enzyme systems, representing 21 presumptive loci, were found to be polymorphic:
phosphoglucomutase 1 (PGM1), peptidase B (PEPB), and peptidase D (PEPD). The
observed average heterozygosity in Chioglossa lusitanica (0.027) is significantly
lower than that observed for other amphibians, either urodeles or salamandrids.
Differences in allele frequencies and the presence of private alleles are
indicative of a high degree of population differentiation. PEPD, in particular,
seems to be a diagnostic locus separating the southernmost population studied
from the others.
PMID- 9559096
TI - Sequences of exon 6 and the adjacent intron boundaries of the rat platelet
derived growth factor A-chain gene: implications for alternative splicing.
AB - Platelet-derived growth factor (PDGF) is a potent stimulator of vascular smooth
muscle cell growth. Two isoforms of PDGF A-chain mRNA that either include (long
form) or exclude (short form) exon 6 are produced as a result of alternative
splicing in mouse, rabbit, and human. The short form of PDGF A-chain is expressed
in both resting and activated cells, while the long form is present predominantly
in activated cells. Reverse transcription-polymerase chain reaction analysis with
primers encompassing exon 6 revealed the presence of both long- and short-form
PDGF A-chain transcripts in rat vascular smooth muscle cells. The nucleotide
sequences of exon 6 and its intron boundaries were determined from rat vascular
smooth muscle cell cDNA and rat leukocyte genomic DNA. Translation of the long
form of PDGF A-chain mRNA was shown to terminate in the 70-base pair exon 6.
Conserved sequences that may contribute to the regulation of alternative RNA
splicing were identified in intron 5.
PMID- 9559097
TI - Actions of sodium fluoride on acetylcholinesterase activities in rats.
AB - This study was carried out to observe the effects of sodium fluoride on
acetylcholinesterase (AChE) activities in the cerebral synaptic membranes (SPM)
and the peripheral red blood cells (RBC) of rats by in vivo and in vitro
experiments. In the in vivo study, pregnant rats ingested ad libitum fluorinated
drinking water (5, 15, 50 ppm F-) during their gestation and lactation. It was
shown that the AChE activities of the SPM and peripheral RBCs in maternal rats
exposed 5-50 ppm F- for 60 days were elevated significantly by 30.0-67.6% and
12.5-31.9% in a dose-dependent manner, respectively. The AChE activities of their
offspring 80 days after birth were also increased (8.7-28.7% for SPM and 20.6
32.4% for RBC). In contrast, the AChE activities of SPM in vitro were inhibited
by 5.0-50.0 mmol F-/L treatment in a time- and dose-dependent manner. Analysis
with the Hanes plots suggested that the enzymesubstrate kinetics are consistent
with a mixed type of inhibition.
PMID- 9559098
TI - Lead induced disorders in hematopoietic and drug metabolizing enzyme system and
their protection by ascorbic acid supplementation.
AB - Effect of vitamin C supplementation in restoring lead induced alterations in
hematopoietic system and drug metabolizing enzymes were investigated in male
rats. Intraperitoneal administration of 20 mg/kg lead produced a significant
inhibition of heme synthesis in blood and liver and drug metabolism in liver.
Toxic insult by lead also resulted into a marked decline in tissue thiols and
vitamin C levels. Oral supplementation of vitamin C (100 mg/kg for 3 days)
completely restored blood delta aminolevulinic acid dehydratase, uroporphyrinogen
I synthetase and a few drug metabolizing enzymes. Level of vitamin C and
sulfhydryl contents too recovered to a great extent. A marked reduction in blood
and liver lead concentration occurred on vitamin C supplementation although renal
lead contents were marginally reduced in lead exposed animals. The results, thus,
indicate a significant protective action of vitamin C against toxic effects of
lead on heme synthesis and drug metabolism.
PMID- 9559099
TI - Hematomas and limb skeletal malformations in chicken embryos following exposure
to 5-fluoro-2-deoxyuridine.
AB - Vascular injury or interruption may play a role in vertebrate limb teratogenesis.
Since 5-fluoro-2'-deoxyuridine (FdU) can cause vascular injury in the murine limb
and skull prior to the appearance of skeletal malformations in these structures,
we studied the effects of this chemical on skeletal development in the chick
embryo and noted any vascular injury. The yolk sacs of day three chick embryos
(Hamburger and Hamilton states 17-19) were injected with solutions of vary
concentrations of FdU in saline. The embryos developed until the 10th day of
incubation when they were fixed for study. Uninjected, saline injected, and sham
injected control embryos were similarly fixed. Upon gross inspection, frequent
diffuse and saccular hematomas, as well as fluid-filled blisters, were noted in
the limbs of embryos treated with FdU. After the embryos were fixed and cleared,
and the skeletons stained, significant skeletal malformations were observed in
these limbs. Bony elements of both the upper and lower limbs were affected in at
least some of the embryos. The combination of FdU-induced hematomas and blisters
with associated skeletal malformations in the same regions of some embryos
suggests a relationship between these phenomena.
PMID- 9559100
TI - Infectious disease surveillance in China.
AB - A national system of infectious disease surveillance was established in 1959 in
China. Now it consists of three subunits, namely, national disease reporting
system (NDRS), nationwide disease surveillance points (DSPs), and surveillance
network for specific infectious diseases. There are 35 notifiable infectious
diseases, which are divided into Classes A, B, and C. The functions of the
surveillance include explaining the natural history of infectious diseases,
describing the distribution of case occurrence, triggering disease-control
effort, monitoring epidemic of infectious diseases during natural disasters,
predicting and controlling epidemics and providing the base of policy adjustment.
PMID- 9559101
TI - Effects of some thiol chelators on enzymatic activities in blood, liver and
kidneys of acute arsenic (III) exposed mice.
AB - The effects of meso 2, 3-dimercaptosuccinic acid (DMSA), sodium 2, 3
dimercaptopropane 1-sulfonate (DMPS) and S-adenosyl L-methionine (SAM) on the
enzymatic activities of mice were studied. The mice were given intraperitoneal
(i.p.) injections of these chelating agents (1 mmol/kg) and 3 h later the
activity of delta-aminolevulinic acid dehydratase (ALAD) in the blood, and
aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma
glutamyltranspeptidase (gamma-GT), alkaline phosphatase (ALP) in the liver and
kidney were determined. The activity of blood ALAD was significantly increased by
the administration of DMSA and SAM while DMPS had only a moderate effect. The
activities of other hepatic enzymes changed little when the mice were treated
with these chelating agents, except for a significant reduction in hepatic ALP
activity following DMPS administration. Arsenic (III) administration markedly
increased the activities of ALT and ALP in the liver and kidneys. The changes in
the enzymatic activities by treatment with arsenic were prevented by injection of
DMSA, DMPS and SAM, DMSA being the most effective. These results indicate that
DMSA, DMPS and SAM were not toxic to the liver or kidneys of mice and that
treatment with DMSA is more effective than DMPS or SAM in protecting mice from
acute hepatic or renal toxicity caused by arsenic.
PMID- 9559102
TI - A new concept in the control of iron deficiency: community-based preventive
supplementation of at-risk groups by the weekly intake of iron supplements.
AB - Iron deficiency (ID), defined as an insufficient supply of iron to the cells of
the body after iron reserves have been exhausted, is the most prevalent single
nutritional deficiency, affecting over 2,000 million people, mostly in the
developing world. Infants, small children, adolescents and pregnant and fertile
age women are most vulnerable. Only about 50% of people with ID develop iron
deficiency anemia (IDA), since this is a late manifestation of chronic ID. Based
on the average daily iron requirement and on the rate of iron reutilization from
red cell hemoglobin destruction, it can be estimated that after iron stores have
been depleted, it takes about 4 months of ID erythropoiesis for adult women to
have a drop in hemoglobin concentration [Hb] of 10 g/l, if the iron intake is
only 70% of requirement. IDA can be defined by a [Hb] below an appropriate cut
off point for age, sex, physiological condition and altitude above sea level, or
by a [Hb] increment of more than 10 g/l to the administration of adequate doses
of iron. More than 85% of the nutritional anemias are IDA alone, or of iron
combined with folate or other nutrient deficiencies.
PMID- 9559103
TI - Developmental lead exposure alters the distribution of protein kinase C activity
in the rat hippocampus.
AB - Chronic low-level lead (Pb) exposure in children is known to cause a deficit in
learning and memory. In vitro studies have demonstrated that Pb altered protein
kinase C (PKC) activity. Especially, hippocampal PKC has been correlated with
performance in several learning tasks. The effects of Pb exposure on hippocampal
PKC were investigated during development at various postnatal ages: postnatal day
(PN) 7, 14, 28, and 56. Two-tenth % Pb acetate was administered to pregnant and
lactating dams and then administered to weanling rats in drinking water. PKC
activity was measured in both membrane and cytosolic fractions from the
hippocampi of the controls and Pb-exposed animals. Pb-induced increase in PKC
activity in the cytosolic fraction was observed in the PN56 rats. In contrast,
PKC activity was decreased by Pb at PN7 in the membrane fraction. Furthermore, a
significant decrease in the ratio of membrane to cytosolic PKC activity which is
representative of PKC distribution was observed in the PN28 and PN56 Pb-exposed
rats relative to the same-age controls. This study indicates that chronic Pb
exposure during development influences hippocampal PKC activity and distribution.
These changes may be involved in the subclinical neurotoxicity of chronic Pb
exposure in young children.
PMID- 9559104
TI - Hematological parameters in Bufo arenarum injected with sublethal dose of lead
acetate.
AB - Lead has been recognized as a high risk toxic for most organisms including human.
The effects of Pb in non-mammalian vertebrates are poorly known, particularly in
anuran amphibians. The purpose of this study was to determine the effect of this
metal on some hematological parameters of adult Bufo arenarum. It was found that
all parameters remained unaltered within normal ranges, with the exception of
reticulocyte counts which was significantly increased compared to the in controls
(3.7% vs. 0.2%). It is suggested that the selective change found in reticulocyte
count might be considered as an early response of a biomarker to sublethal
exposition of Bufo arenarum to lead.
PMID- 9559105
TI - Comparative study on 4 EIA kits for screening antibody to hepatitis C virus in
pooled sera.
AB - Four enzyme immunoassay (EIA) test kits, 1 Canadian product and 3 Chinese
products, were used in the comparative study. Each pool consisted of 5 sera, and
the 5 single sera were tested as controls. The tests were carried out according
to the instructions, keeping the same dilution of each serum in single and pool
samples. It was found that with the Canadian kit, the positive and negative
results of pooled sera had no difference from that of the controls (P > 0.10). In
the case of Chinese Yali and Kehua kits, the positive results of pooled sera
showed no difference from the controls (P > 0.10), but the optical density (OD)
of negative pools were increased (P < 0.01), though quite distant from the cut
off values. In the case of Changzheng kit, the OD of positive pools were
significantly lower than those of the controls (P < 0.05), and weak positive
samples missed the detection. However this problem could be overcome by blocking
the microwells beforehand. Our experiment demonstrate that not all EIA test kits
are suitable for screening pools for antibody to hepatitis C virus, and that it
is important to assess the sensitivity of the EIA kit to be used for this
purpose.
PMID- 9559106
TI - Inhibition of the specific 3H-DL-Glu binding in the hippocampus of rat brain by
lead.
AB - The effect of Pb2+ on 3H-DL-Glutamate (3H-DL-Glu) binding in the membrane
preparations from the hippocampus of rat brain was investigated with a view to
explaining the cognitive and learning deficits produced by the heavy metal. The
results indicated that Pb2+ (3.1-25.0 mumol.L-1) inhibited 3H-DL-Glu binding in a
concentration-dependent manner. Scatchard analysis further revealed that at a
concentration of 6.3 mumol.L-1 Pb2+ interfered with binding mainly through
significantly decreasing the density of binding sites. This finding provided an
important insight into Pb2(+)-induced impairments in learning and memory
previously documented in children and in experimental animals chronically exposed
to Pb2+.
PMID- 9559107
TI - Detection of cytogenetic effects in peripheral lymphocytes of students exposed to
formaldehyde with cytokinesis-blocked micronucleus assay.
AB - Cytokinesis-blocked micronucleus assay was applied as a biological dosimeter to
detect abnormalities in human peripheral lymphocytes of thirteen students exposed
to formaldehyde (FA) during a 12-week (10 h per week) anatomy class. Breathing
zone air samples collected during dissection procedures showed a mean
concentration of 2.37 ppm (3.17 mg/m3). Ten students from the same school but
without FA exposure served as controls. Chromosome aberrations (CA) and sister
chromatid exchanges (SCE) were detected in both groups. The micronuclei (MN) rate
(6.38 +/- 2.50 /1000) and CA rate (5.92 +/- 2.40%) in the FA-exposed group showed
a significant increase (P < 0.01) when compared with those of the controls (3.15
+/- 1.46 /1000 and 3.40 +/- 1.57% respectively). A correlation between MN and CA
in individuals was observed. SCE in the exposed group were also increased (P <
0.05), but not so greatly as MN or CA. The results indicated that FA might damage
the chromosomes of human lymphocytes.
PMID- 9559108
TI - Informatics: transforming raw data into real medical information.
PMID- 9559109
TI - A PC-based workstation for real-time acquisition, processing, and display of
electromyogram signals.
AB - A system for real-time acquisition, processing, display, and logging of multiple
channels of the EMG waveform has been described. By designing this system around
the configuration of a standard PC, custom hardware was avoided. Similarly,
software was designed in a higher-level language (C), simplifying the programming
burden and minimizing custom software development. Components of the software are
available off the shelf. The computational capacity of generic PCs facilitates
very high rates of numeric calculation, as required by some advanced EMG
amplitude estimation algorithms. Computational capacity is expected to increase,
facilitating ever more numerically intensive EMG algorithms that are likely to be
developed in the future. The system described here has been used in the
development of an adaptive window EMG amplitude-estimation algorithm. The system
is extensible and can be altered for many uses related to EMG and biosignal
processing.
PMID- 9559110
TI - Validating medical equipment repair and maintenance metrics, Part II: Results of
the 1997 survey.
PMID- 9559111
TI - A new approach to acoustical evaluation of human respiratory sounds.
AB - The authors developed a method for more precise detection and analysis of the
physical features of respiratory and voice sound transmission to the chest wall.
Based on their findings using this method, they designed several devices for
acoustic examination and evaluation of components of human respiratory sounds.
These devices analyze forced expiratory sounds, distinguish between air-borne and
structure-borne sounds, and distinguish abnormalities in voice transmission to
the chest wall. Tests of the devices on human subjects confirmed the validity of
the authors' theoretical models, which offer promise for the development of a new
class of medical diagnostic instruments.
PMID- 9559113
TI - Skin-temperature distribution under a new type of defibrillating electrode.
AB - The temperature rises under a new type of x-ray-transparent, improved current
density-distribution defibrillation electrode applied to pig skin were measured
at four sites with fiberoptic thermal probes. Three anesthetized pigs, ranging in
weight from 79 to 92 lb, were used. Temperature-time curves were obtained and the
maximum temperature was identified. For 17 measurements at each site, the maximum
temperature rise for a 360-joule shock was 317.3 +/- 53.0 millidegrees Celsius.
PMID- 9559112
TI - An electronic circuit simulating T-type calcium-channel current from the
sinoatrial node.
AB - A circuit that simulates T-type calcium-channel current characteristics of the
sinoatrial (SA) node was developed from discrete electronic components and tested
at physiologic membrane voltage ranges. The circuit design was based on the T
type calcium-channel current dynamics obtained from a mathematical model of the
SA node membrane, which, in turn, is based on physiologic data. The design was
held at a resting membrane potential and then stepped to new voltages over the
entire operating range of the T-type calcium channel. The circuit was validated
by comparing its transient response current with the predicted current from the
mathematical model. In addition, the peak currents of the circuit were compared
with plots of peak current obtained from the mathematical model and physiologic
data. By showing that the electronic circuit mimics the T-type calcium-channel
current dynamics found within the SA node, the results may provide a foundation
for developing a novel cardiac pacemaker that is based on the ion-channel
characteristics of excitable tissue.
PMID- 9559114
TI - Bioimpedance measurements.
PMID- 9559116
TI - Human factors usability test and evaluation.
PMID- 9559115
TI - The clinical engineer: a ghost hunter or manager of EMI.
AB - The management of EMI and risk control in the clinical environment presents the
clinical engineer with new challenges and responsibilities. The keys to
successfully meeting these challenges and responsibilities are education,
cooperation, and the ability to be creative in the quest for solutions to
problems of ever-increasing complexity. Experience in detecting and analyzing
test results, which is gained over time, enhances the skills that clinical
engineering professionals bring to this challenge. Attention to EMI risks has
been influenced by a number of factors, including a spirit of cooperation between
manufacturers and users, concerns over patient care and perceived product
efficacy, and an increasing number of regulations by European and U.S. regulatory
agencies. As a result, device emissions are being reduced and device immunity to
EMI is improving. Further improvements in device immunity are still needed. The
radio spectrum with regard to intentional radiators is in a continual state of
flux. As industry attempts to improve labor efficiency through the use of radio
communications, new and higher-powered sources of RF--both internal and external
to the physical plant--appear each day in the clinical environment. Since the
distance between intentional radiators and potentially susceptible devices is
usually beyond the control of an institution, industry must continue to reduce
device susceptibility. There should be a stronger dialogue between institutions
(even if they do not have proactive EMI reduction programs) and manufacturers to
identify ways to improve device immunity to EMI and to increase product
designers' and users' awareness of potential problems.
PMID- 9559117
TI - [Immunologic aspects of cellular therapy].
PMID- 9559118
TI - [Effect of hemorrhagic shock on learning processes in late posthemorrhagic
period].
PMID- 9559119
TI - [Modification with corticosteroids of behavioral effects of corticoliberin
administered into the neostriatum].
PMID- 9559120
TI - [Urokinase receptors in human monocytes during angina].
PMID- 9559121
TI - [Effect of serotonin antibodies on the functional activity of T-, B-lymphocytes,
and peritoneal macrophages].
PMID- 9559122
TI - [The role of saliva in supplying of esophageal and gastric mucosa with
catecholamines in rats].
PMID- 9559123
TI - [Modifying effect of hypokinesia on reparation regeneration of the liver].
PMID- 9559124
TI - [Generation of 5alpha-androstan-3beta,17beta-diol in the rat hypophysis].
PMID- 9559126
TI - [Characteristics of effect of fibrinolysis system on ADP- and serotonin-dependent
human thrombocyte aggregation].
PMID- 9559125
TI - [Comparative analysis of neurotropic activity exorphins--derivatives of dietary
proteins].
PMID- 9559127
TI - [Receptor mechanism of the neuroprotective effect of GABAergic agents].
PMID- 9559128
TI - [Steroid hormones--modulators of the lipid composition of lysosomal membranes of
skin fibroblasts].
PMID- 9559130
TI - [Study of the restorative effect of various pharmacologic preparations during
acute sublethal thermal stress induced by microwaves].
PMID- 9559129
TI - [Effect of subchronic administration of tolcapone on release of striatum dopamine
and its metabolites induced by L-DOPA and carbidopa].
PMID- 9559131
TI - [Comparative analysis of effects of adapromine, midantan, and bromantane on the
bioelectric activity of the rat brain].
PMID- 9559132
TI - [Effect of nicotinamide on development of experimental allergic
encephalomyelitis].
PMID- 9559133
TI - [Effect of various lipopolysaccharides of gram-negative bacteria on the
macrophage activity, oxidative metabolism, and liver microsomal activity].
PMID- 9559134
TI - [Changes in alpha-B-crystalline in heart transplants].
PMID- 9559135
TI - [Effect of duration and number of cell cycles after mutagenic exposure on the
frequency of sister chromatid exchange].
PMID- 9559136
TI - [Regulation of expression of human fibroblast interferon gene by human leukocyte
interferon and cytopathogenic alpha-virus].
PMID- 9559138
TI - [Effect of biliary stasis on lipid peroxidation and bile composition in in vitro
experiment].
PMID- 9559137
TI - [Effect of the novel antineoplastic agent cycloplatam on the structure and
synthesis of DNA].
PMID- 9559139
TI - [Effect of administration to mice of cytokines (G-CSF and stem cell factor) on
hematopoietic progenitor cells mice].
PMID- 9559140
TI - [Activity of growth hormone-releasing peptide-2 in cultured cells of human
pituitary adenoma and its interaction with growth hormone-releasing hormone and
somatostatin].
PMID- 9559141
TI - [Characteristics of development of oxidative stress in blood plasma of patients
with familial hypercholesterolemia].
PMID- 9559142
TI - [Suppressor activity of bone marrow cells in patients with stomach neoplasms.
Effect of prostaglandins, growth transforming factor-beta, and nitric oxide].
PMID- 9559143
TI - [Effect of morphine and antipain on synthesis of RNA in neurons and hepatocytes
of WAG and F344 rats].
PMID- 9559144
TI - [Effect of chalone and antichalone on free radical processes in the rat liver].
PMID- 9559145
TI - [Study of blood ultrastructure in pathological pregnancy].
PMID- 9559146
TI - [Morphologic evaluation of growth ability of central axons in the peripheral
nerve].
PMID- 9559147
TI - [Morphologic evaluation of occlusion of arteries by hydrogel with enhanced
hemostatic effect].
PMID- 9559148
TI - [Incidence of cancer in Mauritius in 1989-1993].
AB - Systematic registration of cases of cancer was introduced in Mauritius as of
1989. This article analyzes the data concerning the incidence and mortality of
the disease from 1989 to 1993. At the end of each year, the archives of the
Central Laboratory of Hospitals, the admissions register at the only center for
radiotherapy, the discharge resumes of patients classified as suffering from
cancer of all the regional hospitals and the archives of the Medical Assistance
Service regarding treatment abroad were examined and information drawn from them
in order to fill out the information form of the cancer register (10 items per
case). For the period studied, 4293 new cases of cancer were detected of which
1784 (41.6%) among men. The main organs affected were, for men: the lungs (12%),
the mouth/pharynx (10%), and the stomach (8%); for women: the breast (24%), the
cervix (21%), and the ovaries (6%). The incidence of cancer has increased at an
annual average of 8% for both sexes, reaching in 1993 the standard (world)
incidence of respectively 106 and 122 cases per 100,000. Over the same period,
cancer rose to 2nd to 3rd place in causes of death, accounting for approximately
8 to 9% of deaths. The ratio of mortality/incidence is 0.85 among men and 0.58
among women. The distribution of cancer according to age, location and ethnic
group points to interesting and significant results which can be subsequently
compared to that of other countries in the region. The second phase of
registering cancer in Mauritius is presently being undertaken.
PMID- 9559149
TI - [Registry of cancer in Reunion: data of the first five years of registration
(1988-1992)].
AB - After explaining the purposes of a general cancer register in Reunion Island and
describing objectives and running, main results from 1988 to 1992 are introduced.
Comparison with EUROCIM network shows that cancer standardized incidence (all
sites) in Reunion Island is at the same level as in Martinique and lower than in
other registers. Nevertheless some cancers are particularly frequent. For men, as
for most European registers, lung cancer (15%) is the most frequent diagnosed
cancer, followed by esophagus and stomach cancers. Reunion Island belongs to
areas with highest incidence rates for esophagus cancer. Breast cancer (21%),
despite a lower incidence than in Europe, is still the first female cancer,
followed by cervix cancer (18%) which incidence, as in Martinique, is very high.
We don't notice high discrepancies between mortality rates and incidence rates in
Reunion Island during that period.
PMID- 9559150
TI - [Cancer in Madagascar. Experience of the Institut Pasteur de Madagascar from
September 1992 to June 1996].
AB - The Unit of the anatomo-pathology in the "Institut Pasteur de Madagascar" (IPM)
examined in the period from September 1992 to June 1996 tissue specimens from
10,275 patients. Tumorous pathology presented 40% of the tissues and half of
which were of malign etiology. 64% of the cancer diagnosed were in females.
Cervical cancer was most frequently observed (17%), followed by breast cancer
(16%). Cancer in the gastro-intestinal tract (15%) was most often located in the
colon without sex difference. Stomach cancer occurring predominantly in males
presented 25% of the total cases of cancer in the gastro-intestinal tract. Cancer
of liver is rarely diagnosed despite the high prevalence of infection with
hepatitis B virus. Skin cancer constituted 9% of the malign diagnosis and was
mainly found in males. Children under 15 years old presented 7.4% of the total
cases of malignancy with the haematopoietic tissues (30%) and the eyes (17%) as
the most frequent topic locations. Due to a very low seroprevalence of the HIV in
Madagascar, malign tumours associated to AIDS were only seen in a few rare cases.
The review of cancer cases in the IPM may not be representative for the cancer
epidemiology of Madagascar because of a general very low level of health care
coverage, especially in the rural areas. Furthermore, a major part of the
specimens originates from easily accessible organsystems, whereas other organs
seem less investigated due to lack of appropriate available technique. Therefore,
it is not feasible for the moment to establish a cancer register in Madagascar,
although the Unit of Pathology in the IPM can offer a valid cancer diagnostical
service.
PMID- 9559151
TI - [Prevalence of thyroid cancer in Reunion from scintigraphic data].
AB - This work is a retrospective two years study of thyroid cancer, diagnosed in
Reunion Island, using scintigraphic cold regions. Between April 1993 and April
1995, 1,364 thyroid scintigraphic studies were performed in the CHD F. Guyon at
Saint Denis, Reunion). These studies resulted from all types of indication and of
them 691 had cold regions, with 22 thyroid cancers among them, (i.e. a prevalence
of 3.20% of cold areas). Analysis of these cancers allowed recognition of various
characteristics. A large majority (82%) were in females, whose median age at the
time of diagnosis was 49 years (as opposed to 48 years for the male patients).
The associated cold zones were usually isolated cold nodules. Anatomical
pathology investigation indicated six were papillary, five mixed, three vesicular
nodule, four microcarcinoma, one each of anaplastic, one follicullar thyroid
carcinoma, and two were metastases. Their geographical distribution was
superposed on their medical demography. Treatment was surgical, but a variety of
procedures was used. Generally the diagnostical, therapeutical and follow up
procedures were not standardised. Needle cell biopsy was virtually excluded from
the decision-making trees and a variety of protocols was used. In addition there
are no local epidemiological data available concerning thyroid cancers. An
improved method for dealing with these cancers appears to be essential for
Reunion. It must be associated with a greater awareness from medical
practitioners, agreement on procedures for diagnosis, treatment and follow up and
the setting up of a register for thyroid cancer in the "Department". Some thought
before detailed involvement should be given to the setting up of a team, trained
in needle cell biopsy, and an associated metabolic radiotherapy facility, so
allowing appropriate procedures and follow up for thyroid cancers in this
"Department".
PMID- 9559154
TI - [Genomic subtypes of hepatitis C virus: epidemiology, diagnosis and clinical
consequences].
AB - Hepatitis C virus demonstrates a high degree of variability HCV isolates have
been classified into at least six genotypes, according to the percentage of
nucleotide sequence homology. Geographical differences in the distribution of
virus genotypes are well documented. Types 1, 2 and 3 are the major types
observed in Japan, Western Europe and North America; type 4 has been found in
Central and Northern Africa and in the Middle East; type 5 has been described in
South Africa, type 6 in South-East Asia. The relative prevalence of these
genotypes varies between different regions. In the Indian subcontinent, subtype
1b seems to be the most prevalent type, but many isolates have been described,
related to genotype 3, in Northern and Southern India, Pakistan and Nepal. HCV
genotypes may have potential clinical implications: a) the association with the
severity of liver disease is still controversial; b) the association between some
genotypes, particularly 1b, and a poor response to interferon alpha therapy has
been well established; c) genotyping may be useful for identifying some unusual
modes of transmission of the virus. Finally, the variability of HCV virus has
major implications for the design of new vaccines strategies since there is no
cross-protection between different HCV types.
PMID- 9559155
TI - [Hepatitis G virus: a new agent responsible for viral hepatitis].
AB - Modern biology has allowed to detect a new hepatitis virus called G (HGV),
joining an already important member of hepatitis viruses. Thus the share of viral
hepatitis non A-non D decreases. The HGV belongs to the Flaviviridae and is
similar to the HCV. Transmission occurs essentially by contaminated blood. There
are still some open questions, particularly concerning the real pathogenic
responsibility of the virus, which is far from clear considering latest
publications. Further studies are necessary to precise epidemiologic data, ways
of transmission, and pathogenic properties.
PMID- 9559156
TI - [Vaccination against hepatitis B in France in 1996].
AB - A national campain aimed at promoting immunization against hepatitis B was
launched in 1994. Two years later, a survey was designed to estimate the
situation of the hepatitis B vaccination in France. Around ninety per cent of
physicians were hepatitis B vaccinated. The rate of vaccinated population among
public hospitals personnel were more than 90% and lower in private hospitals
(79%). A quarter of the general population was vaccinated and the higher rate
(69%) was observed in the 13-20 years young people. Progressively the
contribution of the physicians to the vaccination was increasing (89% in 1996).
After a selective vaccination of risk groups and the instauration of the
prevention of mother/infant transmission, the French programme was extended to
cover adolescents and children. The success of the hepatitis B vaccination
campain was obtained by the promotion message toward population and physicians.
PMID- 9559162
TI - [The island of Mauritius: insularity, tropicality, modernity, a dialogue in the
form of a lesson].
AB - Mauritius, a lost volcanic island in the indian ocean situated at the 20th degree
of latitude, is a tiny state which got its independence in 1968. The isolation,
the tropicality, the demographic boom, the ethnic diversity and the absence of
raw materials could funnel this peaceful beauty to become a hot-bed of
desperation and violence. This place which is one of the most densely populated
areas, is an example of modern democracy and cultural coexistence. Owing to a
skillful and pragmatic politic, its leaders have transformed handicaps into trump
cards. The allocation of a part of the GNP for social and hygienic investments
had been the locomotive pulling the train of improvements and raising the
standard of living for the inhabitants. The ageing population, the rapidity of
evolution the demographic and health transitions are expression of this skillful
politic. In less than twenty years, this island conquered underdevelopment and
proved that there is no tropical fatality when a programme of health accompanies
development.
PMID- 9559163
TI - [Insularity and epidemic risks in Reunion].
AB - The risks of epidemics in Reunion island depend on determining or favourable
factors. The determining factors, links in the epidemic chain, may or may not
exist but they can be introduced from the outside. The risk of importing these
factors is especially important when the exchanges with the epidemic zones are
easy and frequent. Reunion island, at the moment exempt from certain pathologies
such as malaria, dengue-fever and urinary Schistosomiasis, is a good example.
However, if the presence of these determining factors is necessary, that is not
enough in itself. Other factors come into play; in particular physical
(leptospirosis) or socio-economic conditions (cysticercosis, intestinal parasitic
diseases). The latter play a major role in the hygienic conditions and also in
the research and prevention which are easier on an island.
PMID- 9559164
TI - [Dengue, arbovirus and migrations in the Indian Ocean].
AB - An arbovirus requires a competent haematophagous arthropod for transmission from
one vertebrate to another susceptible host. Air transportations allow quick
transfers from place to place and the diffusion of potential vectors or
infectious hosts. The merchandise transportation by containers allowed the
diffusion of Ae. albopictus from Asia through Africa and America. Emerging
arbovirusis may occur in zones where they do not exist. Dengue which originally
was located in southeastern Asia, is the most important arbovirusis in the world.
The occurrence of dengue haemorrhagic fever (DHF) in Asia and America, mostly in
urban areas, increased the global concern about dengue. Likewise, cases of DHF
are not reported in Africa and in the Indian Ocean southwestern islands. The
principal vector of dengue, Aedes aegypti, was present during the dengue 1
outbreak in Comoros, in 1993. In the other islands, only few specimens of Ae.
aegypti are observed, and described mostly as none anthropophilic forms. The role
of Ae. albopictus as vector of dengue was suspected and reported during outbreaks
in Seychelles and Reunion island in 1977-1978. Yellow fever, present in Africa
mostly in restricted areas, is absent in Asia. Japanese encephalitis considered
as an emerging disease in India could expand through the islands. Rift valley
fever, with periodic epizootics in domestic ungulates in Africa, was described as
a new disease in Madagascar in 1990-1991. Crimean-Congo haemorrhagic fever is
also present in Madagascar. Humans can be infected by vector bite or by handling
infectious animal products. The distribution of other viruses (West Nile,
Sindbis, Wesselsbron or Chikungunya) is discussed.
PMID- 9559165
TI - [Epidemiological surveillance of grippe and dengue. Reunion, 1996].
AB - The local Welfare and Health Authorities together with the country council of
Reunion Island set up a medical supervision network for influenza and dengue
fever in March 1996. Influenza of which the spreading over the island has never
been well-researched is anticipated by a vaccination campaign organised in an
empirical way after a model from the mother country (France). Dengue fever of
which one of the vectors is omnipresent on the island ranged in an epidemic way
in 1978. The aim of this network based on watching doctors, the laboratories of
the island as well as the Pasteur Institute of Madagascar, is to adapt the
prevention (Flu) and alert the Health Authorities in case of epidemic (Dengue).
The article shows the results of 1996 observation and touches on the future of
this type of supervision in a tropical environment.
PMID- 9559166
TI - [Origin of malaria epidemics on the plateaus of Madagascar and the mountains of
east and south Africa].
AB - The Highlands of Madagascar were malaria free until 1878, when a severe epidemic
occurred, following the development of irrigated rice farming. Then, the disease
became endemic. Between 1949 and 1962, malaria was "eradicated" on the Highlands
by joint house spraying and chemoprophylaxis measures. The main vector An.
funestus disappeared. In 1986-1988, a very severe epidemic with high lethality
rate devastated the Highlands. It is now under control. Thanks to the data of a
religious dispensary, we could follow the evolution of malaria on the Highlands
from 1971 to 1995. The number of cases begin to grow in 1975 when the
surveillance was neglected. A second step was observed in 1979, when
chemoprophylaxis/chemotherapy centres were closed. Then, the increase of malaria
became exponential up to 1988. At the time, the prevalence had became similar to
that of 1948, before the eradication. The epidemic is not due to global warming
because the temperature has been stable for the last 30 years. The malaria rise
was due the cancellation of control measures. When control was reactivated, the
epidemic ceased. In Swaziland, Zimbabwe and South Africa, malaria epidemics were
also due to control failure. In Uganda Highlands, above 1500 m, malaria rise
seems linked to the environmental changes, e.g. the cultures which replace
papyrus swamp in the valley. But malaria did not overcame the altitude of 1900
which it had already reached in 1960. Rainfall should also be considered as a key
factor in the epidemics. In the Sahel West Africa, temperature increased from 0.5
degree C to 01 degree C degree in the last 25 years, but rainfall decreased from
30%. As a result, one of the vector, Anopheles funestus disappeared and malaria
prevalence dropped by 60 to 80%. It is not acceptable to predict the future
evolution of malaria in taking in account only one parameter: the temperature.
The whole factors involved in the epidemiology should be taken into account. The
predictions based only on the temperature increase (global warming) can be
totally wrong if the rainfall, for example, decreases.
PMID- 9559168
TI - [AIDS in Madagascar. I. Epidemiology, projections, socioeconomic impact,
interventions].
AB - Madagascar is still among the rare states of low prevalence of HIV. The
seroprevalence rate is nevertheless rising. The aim of this study is to show the
current view of the epidemic, its future tendency, its economical and social
impact on people and what measures to be taken at the national scale. In
Madagascar, we can state by 1995 20 cases of notified AIDS and probably 130 cases
of non-notified AIDS. Seroprevalence data are collected every year by the
National Reference Laboratory STD/AIDS. But, they are insufficient to estimate
the number of infected people. So, they had been completed by a serosurveillance
study of AIDS and syphilis in middle of 1995 and at the beginning of 1996.
Pregnant women, persons with STDs and prostitutes are been screened in the six
biggest cities of the Island. Results show, not only a high prevalence of
syphilis, but also indicate that now, we have about 5,000 seropositive people in
the country. Besides, by the number of people with STDs, it is estimated that one
million Malgasy adults risk to be infected. Based on estimates of the epidemic,
be it the cases of a high scenario, (Kenya) or of a low one (Thailand) by the
year 2015, the seroprevalence rate could represent 3% or 15% of adults.
Demographic consequences of the epidemic will be serious, particularly if HIV
spreads quickly. Nevertheless, it does not stop the increase of population.
Therefore, there will be more infected people with the disease, especially young
people between 15 and 49 years old. The increase of dead people will be serious.
Social consequences of the epidemic (case of high scenario) will be gravely felt,
in particular by the rise of the number of AIDS orphans. Tuberculosis outbreak
can be observed too. This disease is already a serious problem in Madagascar. At
last, the epidemic will bring with it a high increase of money spent on health
and will have grave consequences on agriculture, industry and commerce.
Nevertheless, Madagascar still benefit a big luck which is the prevention of the
epidemic not to be exploded in a near future. For this, struggle against it is
particularly effective on its start. In addition to counselling given to infected
people and care-given to patients, means of prevention of AIDS contamination in
all target groups must be set up quickly. It is about broadcasting information on
AIDS, community education, controlling other STDs e.g. (importance of
medicaments' program), promoting the use of condoms and screening HIV new cases.
Only an urgent coordination of everyone's efforts can control the epidemic of
AIDS.
PMID- 9559169
TI - [Aids in Madagascar. II. Intervention policy for maintaining low HIV infection
prevalence].
AB - The HIV seroprevalence per 100,000 adults Malagasy rose from 20 in 1989, to 30 in
1992, and to 70 in 1995. In that year, the total number of HIV infected people in
the Big Island was estimated at 5,000, the number of people sick with AIDS at
130, and the people at risk at more than 1,000,000. The latter are the persons
infected with other STDs and individuals (or their partners) with risky sexual
behaviour (e.g. numerous sexual partners, occasional sexual partners, and/or
sexual contacts with commercial sex workers). The HIV prevalence rate is low as
compared with those of other countries. Nevertheless, the spread of the HIV
infection is alarming in some parts of the country and the risk factors are also
present, namely: the high prevalence of STDs, numerous sexual partners, the low
use of condoms in all groups, the development of tourism, the development of
prostitution associated with social and economical problems, and internal and
international migrations (with risky sexual contacts). Therefore, the still low
but rising HIV prevalence in 1995 does not warrant complacency. To estimate the
trend of HIV prevalence within the population, it is useful to know two different
assumptions, as follows: firstly, a controlled evolution of the epidemic (low
epidemic) and secondly, a very fast spread of the epidemic (high epidemic). If we
consider the 5,000 individuals seropositive in July 1995, the Aids Impact Model
(AIM) projection model shows that HIV seroprevalence rates among adults in 2015
might be between 3% (when the progression course of HIV epidemic is low) and 15%
(when the progression course of HIV epidemic is high). By 2015 AIDS could have
severe demographic, social, and economic impacts. Then, it is necessary to take
measures to prevent contamination. Five major interventions are required: public
information about AIDS, HIV transmission mechanism, and its prevention,
communities education via the respected people and the notabilities to promote
moral values, reduce the number of sexual partners, delay visit of sexual
activity, and advice for infected couples; screening of blood donors and the
supposed high risk group; control of STDs; reduction of the number of sexual
partners; promotion of condom use, abstinence, and fidelity. To sum up, the fight
against AIDS is not only the health professional workers' problem. It concerns
all Malagasy people. Therefore, successfullness in prevention efforts to slow the
epidemic needs concerted, collective, and long lasting actions from all sectors
of the society for the nation's future and the well-being of the rising
generations.
PMID- 9559170
TI - [Epidemiologic study of the main human intestinal nematodes in the middle west of
Madagascar].
AB - An epidemiological study of human intestinal helminthiasis was conducted during
July and August 1995, in the middle west of Madagascar, with 4571 adults and
children ranging from six months to 90 years, in 61 communities between Betafo
and Miandrivazo. Faecal examination utilising the MIF concentration method
revealed that ascariasis was the dominant nematodosis in the middle west with
high prevalences in the high-altitude communities. Ascaris lumbricoides
prevalences increase among children and women. Interesting more than 50% of the
pattern, ascariasis is a public health problem and its association with infant
malnutrition is statistically significant. Hookworm infection prevalence is
higher in low-altitude communities, it increases among adults. The Trichuris
trichiura prevalences were lower than the prevalences of ascariasis and hookworm
infection in all of the communities. Important variations of the prevalences of
intestinal helminthiasis are observed essentially in relation with climatic
conditions.
PMID- 9559175
TI - [Impact of antivectorial control on malarial morbidity and mortality in a health
district of the Madagascar highlands].
AB - After the dramatic increase of malaria infections from 1985 to 1988 in the
Highlands of Madagascar, the vector control programme was reactivated. In order
to evaluate the impact of this strategy in the district of Arivonimamo, we have
analysed the morbidity and the mortality data collected in all the health care
centers of this district. Since 1988, extensive residual house spraying has been
carried out on a yearly basis in the eastern part of this district whereas the
western part was not included in this spraying programme. Data from each area
were compared. In the eastern part, a dramatic decrease of morbitity and
mortality related to malaria was observed, the benefit was 69% of expected simple
cases, 87% of expected serious cases and 40% of expected deaths due to malaria.
It has to be noted that only presumptive cases have been reported since no
laboratory facilities are available in these health centers. Nevertheless such
findings provide strong support to the continuation of the spraying programme,
maybe in a less intensive way, together with an accurate epidemiological
surveillance.
PMID- 9559179
TI - [Importation of Plasmodium falciparum malaria, in Reunion Island, from 1993 to
1996: epidemiology and clinical aspects of severe forms].
AB - Located in the Indian ocean, Reunion island, a French overseas territory, is free
of malaria since the 1960's. As malaria is still highly endemic in the
neighbouring countries, imported cases are averaging 130 to 150 cases per year.
From 1993 to 1996, about 483 cases of imported malaria were admitted in Reunion.
Five severe complicated Plasmodium falciparum malaria cases occurring in non
immune persons, required further treatment in the intensive care unit (age 40 +/-
8 years, duration: 14.8 +/- 7.4, SAPS: 21 +/- 10). Three patients died. As short
stay travellers, patients were contaminated in Madagascar (4) and in Malawi (1)
and presented with an associated pathology: alcohol and tobacco abuses (2 cases),
AIDS (1 case). In all cases, chemoprophylaxis was either inadequate (chloroquine
alone, 3 cases) or absent (2 cases) and the diagnosis and the appropriate
treatment were delayed. Moreover, patients were either self-treating themselves,
or initially refused to be admitted. Parasitemia was very high. Two patients died
within an hour following their admission before diagnosis could be made and
quinine treatment be initiated (rupture of the spleen, multiple organ failure).
One patient died at day 7 (acute respiratory distress syndrome, renal failure).
Two survived under respiratory assistance and hemodialysis and presented the
usual intensive care complications (respiratory nosocomial infection, acute
cholecystitis). In Reunion island, imported P. falciparum still accounts for a
high rate of morbidity and few fatalities, despite a sophisticated curative
health system. Delay in diagnosis and institution of an appropriate treatment is
frequent in non-immune persons who develop fever and non-specific symptoms. It
markedly increases the risk of complications and death from falciparum malaria as
well as morbidity cofactors. Emphasis must be placed on appropriate information
of health personnel and travellers.
PMID- 9559180
TI - [Human diseases transmitted by Culicidae in southwest Indian Ocean islands].
AB - South-West Indian Ocean islands were inhabited at the beginning and free from all
kind of vector. In Madagascar, Mayotte, Moheli and Anjouan, malaria vectors were
carried by the first settlements. According to epidemics, the anopheles arrived
in 1867 in Mauritius, 1869 in La Reunion and 1920 in Grande Comore. Rodrigues,
Saint-Brandon and the Seychelles are still free from malaria vectors in the
coastal part of Madagascarcar and in Comores archipelago, malaria is stable with
a permanent transmission. Unstable malaria is seasonaly transmitted in the high
territories of Madagascar; it was the same in Mauritius and Reunion island before
the eradication campaign. Lymphatic filariasis is quoted in Madagascar, but
Comores archipelago is an area with high transmission. The incidence of the
disease is moderate in La Reunion and Mauritius and very low in Chagos and
Seychelles archipelagos. There is no transmission in Rodrigues and St Brandon.
Epidemics of dengue were described during the second part of the XIXth century in
Mauritius and La Reunion, then in 1943 in Mayotte. But the disease was controlled
in the fifties by the antimalaria campaign. A new epidemy appeared in Seychelles
by the end of 1976 and then in Reunion and Mauritius next year. An isolated
outbreak was described in Grande Comore only in 1994.
PMID- 9559181
TI - [A great Franco-Mauritian epidemiologist: Joseph Desire Tholozan (1820-18970].
AB - Born in 1820 from French parents in Diego Garcia, an islet then linked to
Mauritius where he started in Port-Louis his school years, Joseph Desire Tholozan
was an original personality. He undertook medical studies in France (M. D.
thesis, Paris, 1843) after having joined the military Health Service (1841) as a
surgeon serving in various garrisons in the country and later at the Hospital of
the Valde-Grace in Paris (1849). Successful at the "agregation" of Medicine in
1853, he later participated to the Crimean War (1854-1855) where he performed
interesting medical observations. In 1858, he was appointed personal physician to
Nasreddin Shah and remained in Persia until his death in Teheran (1897) where he
is buried. Tholozan published between 1847 and 1892 over fifty articles and books
dealing chiefly with infectious pathology and epidemiology, written at a time
when microbial etiology and specificity of such diseases were wholly unknown. He
considered chiefly bubonic plague, studying as soon as 1871 the focus of the
Iranian Kurdistan, a research which will be resumed by M. Baltazard and his
collaborators between 1947 and 1971, i.e. a century later. He was also deeply
interested by the "oriental" cholera of which he recalled masterly the history
and geography in the Near and Middle East. He also performed, while in Crimea and
Persia, personal observations on tuberculosis, diptheria, remittent fever,
acrodynia and had studied in France in his early years various other diseases
such as cutaneous staphylococcic infections, glanders, pulmonary haemorrhagies,
etc. In Persia, he reorganized Public Health and medical teaching and educated
many local physicians and surgeons. Being assured of the unlimited confidence of
the Shah, he played an important cultural role, promoting French influence in
Persia. Holder of many French and foreign decorations, Tholozan was Fellow of the
French Academies of Sciences and Medicine. His name was given by Laboulbene to
Ornithodoros tholozani, a tick vector of a recurrent fever (spirochetosis due to
Borrelia persica), of which he had described both the symptoms and the vector in
1882.
PMID- 9559182
TI - Surgical skills for family physicians. Do family physicians make the cut?
PMID- 9559183
TI - Well-baby care in the new millennium. Evidence-based care and the new Rourke Baby
Record.
PMID- 9559184
TI - Flaws in critical appraisal.
PMID- 9559185
TI - Protecting patients against "quackery".
PMID- 9559186
TI - Opportunity for change.
PMID- 9559187
TI - Is topical tretinoin safe during the first trimester?
AB - QUESTIONOne of my patients conceived while using a topical tretinoin preparation
for acne. I know this drug is related to Accutane, which is teratogenic. How
should I advise her?ANSWERAvailable evidence suggests that topical tretinoin does
not increase teratogenic risk in humans.
PMID- 9559188
TI - Ophthaproblem. Macular hole.
PMID- 9559189
TI - Dermacase. Phytophotodermatitis.
PMID- 9559190
TI - Strategy to prevent recurrent homelessness among the mentally ill.
PMID- 9559191
TI - Cost-effective management of patients with dyspepsia.
PMID- 9559193
TI - Practice choices of graduating family medicine residents.
AB - OBJECTIVE: To examine the types of practices family medicine residents chose
during the first 2 years after residency, and how these choices have changed over
a 15-year period. DESIGN: Mailed survey. SETTING: Areas served by graduates of
the Queen's University family medicine residency program. PARTICIPANTS: Two
hundred thirty (76%) of the 303 graduates from 1977 to 1991 of the Queen's
University family medicine residency program responded to the questionnaire. MAIN
OUTCOME MEASURES: Type of practices residents entered immediately out of
residency: whether they began full-time, part-time, locum tenens, or other type
of practice; length of time spent in the first practice situation; and proportion
of residents who had settled into a full-time practice within 2 years of
completing residency. RESULTS: Residents who graduated before 1985 were
significantly more likely to go into full-time practice immediately out of
residency (P = .0001). The earlier residents had graduated from the program, the
more likely they were to go immediately into full-time practice. This finding was
not affected by residents' age, sex, size of community of origin, exposure to
rural teaching sites, marital status, or how well prepared for practice they
felt. Residents graduating before 1985 were also more likely to be in full-time
practice within 2 years of completing their residency program (P = .003).
CONCLUSIONS: Recent family medicine residents did not enter full-time practice
immediately out of residency as often as those who had graduated earlier, nor did
they commit to full-time practice within 2 years of graduating as often as
residents graduating before 1985 did.
PMID- 9559192
TI - Procedures in ambulatory care. Which family physicians do what in southwestern
Ontario?
AB - OBJECTIVE: To determine how often family physicians perform 12 ambulatory care
procedures and factors associated with procedure performance. DESIGN: Mailed,
self-administered survey. The survey was conducted according to the Dillman Total
Design method. SETTING: Family physicians' offices in London, Ont, and in
surrounding communities. PARTICIPANTS: A total of 395 family physicians
practising within the London area were mailed surveys, 237 in London and 158
outside London. Response rates were 80.6% and 75.9%, respectively. Nonresponders
did not differ significantly from responders in sex but included more solo
practitioners. MAIN OUTCOME MEASURES: Performance of ambulatory care procedures,
sex, and practice characteristics of participant family physicians. RESULTS: For
all responders, activities significantly associated with procedure performance
were delivering babies, managing psychological problems, working emergency, and
teaching. Mean total procedure scores ranged from 6.55 for managing psychological
problems to 7.68 for working emergency. Sex-specific analysis showed that
practice location and years in practice were significant factors for female but
not for male family physicians. Mean total procedure scores for female physicians
were 7.06 (outside London) and 4.74 (in London). CONCLUSIONS: Factors associated
with procedure performance for family physicians in and around London included
delivering babies, working in emergency, managing psychological problems, and
teaching. Practice location was a significant factor for only female family
physicians; those practising outside London performed procedures more than their
urban counterparts and at similar rates to male physicians.
PMID- 9559194
TI - Participation in CME activities.
AB - OBJECTIVE: To compare the continuing medical education (CME) activities of family
physicians in the province of Quebec with more than 25 years in practice with
those with less than 25 years in practice. DESIGN: Mailed questionnaire survey.
SETTING: Family practices in the province of Quebec. PARTICIPANTS: All physicians
(n = 722) with more than 25 years in practice (expressed as older) and a matched
sample of 721 physicians with less than 25 years in practice (expressed as
younger). MAIN OUTCOME MEASURES: Types of CME activities and time spent on them,
participant characteristics. RESULTS: Older physicians spent more time in
individual CME activities than younger ones (21 hours vs 18 hours monthly).
Younger physicians, however, spent more time in group CME activities than older
ones did (100 hours vs 80 hours yearly). Excluding physicians who devoted no time
to CME activities, only two activities differentiated between the two groups:
older physicians spent more time than their younger colleagues reading and
listening to audiocassettes. CONCLUSIONS: Older physicians maintained their
clinical competence by participating in different CME activities from younger
physicians. They participated in as many CME activities as their younger
colleagues.
PMID- 9559195
TI - Trends in vasectomy. Analysis of one teaching practice.
AB - PROBLEM BEING ADDRESSED: How can a teaching practice develop a referral service
and incorporate educational opportunities for family medicine residents, clinical
clerks, and community family physicians? OBJECTIVE OF PROGRAM: To develop a high
quality vasectomy service within a teaching practice to change the surgical
procedure to the no-scalpel vasectomy (NSV) technique; to educate family medicine
residents, clinical clerks, and community family physicians about vasectomy and
the NSV technique; and to monitor outcomes and compare them with published
results. MAIN COMPONENTS OF PROGRAM: The program took place in an urban family
medicine residency program. Data on number of procedures, types of patients
choosing vasectomy, and outcomes are presented, along with information on number
of learners who viewed, assisted with, or became competent to perform NSV.
CONCLUSIONS: A few family medicine residents and some interested community
physicians could be trained to perform NSV competently. Involving learners in the
procedure does not seem to change the rate of complications.
PMID- 9559196
TI - Evidence-based well-baby care. Part 1: Overview of the next generation of the
Rourke Baby Record.
AB - PROBLEM BEING ADDRESSED: Well baby and child care in the primary care setting has
not always been based on evidence that has been shown to be effective in
preventing and detecting disease and injury. OBJECTIVE OF THE PROGRAM: To help
physicians and nurses provide care that is more effective than a routine complete
examination, the Rourke Baby Record has been revised to include evidence-based
recommendations for preventive care for infants and young children. The revision
incorporates the approach and recommendations of the Canadian Task Force on the
Periodic Health Examination. The updated record is now called the Rourke Baby
Record: Evidence-Based Infant/Child Health Maintenance Guide (Rourke Baby Record:
EB). MAIN COMPONENTS OF PROGRAM: Part 1 of this two-part article briefly
describes the background for development and presents an overview of the revised
record. Part 2 discusses in detail the evidence that exists for maneuvers
included in the education and advice section of the revised record. CONCLUSION:
Using the Rourke Baby Record: EB and incorporating it into their office record
systems as a working guide will help increase the effectiveness of the primary
preventive care physicians provide to infants and young children.
PMID- 9559197
TI - Evidence-based well-baby care. Part 2: Education and advice section of the next
generation of the Rourke Baby Record.
AB - PROBLEM BEING ADDRESSED: Well baby and child care in the primary care setting has
not always been based on evidence that has been shown to be effective in
preventing and detecting disease and injury. OBJECTIVE OF THE PROGRAM: To help
physicians and nurses provide care that is more effective than a routine complete
examination, the Rourke Baby Record has been revised to include evidence-based
recommendations for preventive care for infants and young children. The revision
incorporates the approach and recommendations of the Canadian Task Force on the
Periodic Health Examination. The updated record is now called the Rourke Baby
Record: Evidence-Based Infant/Child Health Maintenance Guide (Rourke Baby Record:
EB). MAIN COMPONENT OF PROGRAM: Part 2 of this two-part article discusses the
maneuvers included in the education and advice section of the record. These
maneuvers are discussed under the subheadings safety, behaviour, family coping,
high-risk children, and other. CONCLUSION: Using the Rourke Baby Record: EB and
incorporating it into their office record systems as a working guide will help
increase the effectiveness of the primary preventive care physicians provide to
infants and young children.
PMID- 9559198
TI - Case report: retinal detachment associated with atopic dermatitis.
PMID- 9559199
TI - Canadian breast cancer initiative. One way to help women living with breast
cancer.
PMID- 9559200
TI - Canadian Perinatal Surveillance System.
PMID- 9559201
TI - Eat well, live well. Time to promote healthy eating.
PMID- 9559202
TI - Articulating a message. Presentation skills for family physicians.
PMID- 9559203
TI - Our strength for tomorrow: valuing our children. Part 8: Addressing the
determinants of health. CFPC's task force on child health.
PMID- 9559204
TI - Preventing another blood scandal. How can family physicians help?
PMID- 9559205
TI - Gastroesophageal reflux disease.
AB - Chronic GERD is an unremitting, incurable disorder that recurs rapidly upon
discontinuation of therapy. Primary complications of GERD include esophagitis,
esophageal stricture and Barrett esophagus. Current therapy focuses on modifying
risk factors, inhibiting the production of acid and enhancing esophageal gastric
motility. In patients with uncomplicated heartburn, nondrug therapy should be the
initial therapeutic approach, with patient education a major step in promoting
lifestyle changes and improving the outcome. Maintenance therapy is central to
the management of GERD. If symptoms persist to suggest complicated disease,
further diagnostic tests (endoscopy) are indicated. H2 receptor antagonists
usually resolve symptoms in 50% to 70% of patients, and PPIs in 74% to 96% of
patients. Agents that improve esophageal motility, such as cisapride, may provide
symptomatic relief of heartburn, but healing effects are inconsistent. In
refractory disease, therapy is individualized to the patient, and may include
combination therapy, more aggressive single line therapy or an appropriate
surgical approach.
PMID- 9559206
TI - Utility of serology in determining Helicobacter pylori eradication after therapy.
AB - OBJECTIVE: To determine the usefulness of four serological tests in confirming
cure of H pylori infection before the previously reported six-month post
treatment delay. PATIENTS AND METHODS: As part of a prospective, blinded,
controlled trial, in which patients with duodenal ulcers were randomized to
receive different combinations of antibiotics, serum samples were obtained in 89
patients before treatment, as well as on several occasions after treatment.
Antibody titres were determined by ELISA with Bio-Rad immunoglobulin (Ig) A, Bio
Rad IgG, Pyloriset EIA-A for IgA and Pyloriset EIA-G for IgG. Eradication was
confirmed with antral biopsy three months after therapy. RESULTS: The percentage
drop in titre following treatment was significantly larger for the group of
patients who were treated successfully with all four kits. Optimal cut-offs for
identifying successful therapy were determined, and accuracy improved as the
interval between testing and therapy was prolonged. Six months after therapy, the
IgG test from Bio-Rad achieved 100% sensitivity and 80% specificity, and that
from Pyloriset achieved 88% sensitivity and 100% specificity. At three months,
however, test performance was quite good, with 90% sensitivity and 80%
specificity when using a Pyloriset IgA titre drop of 20% or greater to predict
successful eradication. CONCLUSION: Serology is a simple, easily available,
noninvasive method that exhibits good positive predictive value in the
confirmation of successful cure of H pylori infection three or six months after
treatment.
PMID- 9559207
TI - Postliver transplant allograft reinfection with a lamivudine-resistant strain of
hepatitis B virus: long-term follow-up.
AB - Lamivudine is a nucleoside analogue with efficacy in the suppression of hepatitis
B viral (HBV) replication. In a previously reported study, lamivudine was
administered to patients with chronic, actively replicating HBV infection who
subsequently underwent liver transplantation. Patients became serum HBV DNA
negative in response to lamivudine before transplantation, which was continued in
the post-transplant period. Two of four patients surviving the immediate
postoperative period developed allograft reinfection 240 and 409 days post
transplant. The strain of the reinfecting virus was analyzed, and a mutation in
the YMDD region of the viral polymerase conferring resistance to lamivudine was
discovered. The long term follow-up of these two patients is reported. The first
patient developed ascites 16.5 months after allograft reinfection. A transjugular
liver biopsy performed 18 months after the emergence of the lamivudine-resistant
strain revealed cirrhosis and lobular hepatitis without rejection. The gradient
between hepatic vein wedged and free pressures was 13 mmHg, consistent with
portal hypertension. The second patient, 16 months after allograft reinfection
with the lamivudine-resistant strain, is without clinical evidence of portal
hypertension, although liver enzymes remain elevated. Both patients were given a
trial of famciclovir, which did not significantly suppress HBV viremia. In
conclusion, lamivudine-resistant HBV strains with the YMDD mutation may have an
aggressive clinical course with rapid progression to cirrhosis. Famciclovir did
not appear to be an effective rescue agent in these two patients.
PMID- 9559209
TI - Survey of gastroenterologists on the diagnosis and treatment of adult patients
with celiac disease in British Columbia.
AB - A recent survey of physician specialists from New York City suggested that few
patients with celiac disease are seen and that management experience is limited.
The present study, using a survey similar to that of the New York City
investigation, evaluated the diagnostic and management experience of specialists
for adult celiac disease patients in British Columbia. Four hundred and four
patients were reported in the combined clinical practice experience of the
responding physicians. Of these, 59, or 15%, were diagnosed in the prior year.
Although each physician diagnosed an average of 2.4 new celiac disease patients
per year in their entire practice experience, an average of over 4.0 new celiac
disease patients were detected in the past year. Most patients presented with
diarrhea, weight loss, anemia or nutrient deficiency, but about 14% were
asymptomatic or diagnosed by an incidental small intestinal biopsy done at upper
gastrointestinal endoscopy. Specialist physicians in British Columbia usually
refer patients to their family physicians, dietitians and patient support groups
for continued care and appear to rarely rely on serological assays, including
antibody tests, for detection of celiac disease in adults. An associated or
complicating lymphoma was detected in 16 of 404 patients (4%). Recognition of
biopsy-defined celiac disease appears to be increasing in British Columbia.
PMID- 9559210
TI - Setting the stage for the new graduate.
PMID- 9559211
TI - An ethicist's commentary on the dog being used to carry drugs.
PMID- 9559208
TI - Altered colonic environment, a possible predisposition to colorectal cancer and
colonic inflammatory bowel disease: rationale of dietary manipulation with
emphasis on disaccharides.
AB - A recurrent theme in the schema of pathogenetic mechanisms attributed to
colorectal cancer (CRC) and inflammatory bowel disease (IBD) is the interaction
between genes and environment. Dietary and other environmental factors, and lower
intestinal flora and their chemical interactions occur in the pathogenesis of
both. Events at the mucosal surface may be influenced by factors in the luminal
environment and by contributions of the host. In addition, both forms of IBD-
Crohn's disease (CD) and ulcerative colitis (UC)--have distinctive associated
host events. Even within CD and UC, different clinical patterns and prognoses may
have different specific host mechanisms. Some of the current putative
pathogenetic processes in CRC and IBD are reviewed. Particular attention is given
to hypotheses relating to the role of dietetic substances, mainly fibre and dairy
products, and how they may affect disease formation. It is argued that within the
context of hypotheses proposed for possible beneficial effects of these two
dietetic factors, CRC and IBD may be considered together. Further support is lent
to arguments that similar and additional hypothetical features ascribed to
beneficial effects of fibre may be attributed to disaccharides, lactose and its
derivatives, lactulose and lactitol.
PMID- 9559212
TI - The Canadian Animal Health Network: Canada's response to the World Trade
Organization.
PMID- 9559213
TI - Comparison of 3 methods of selenium assessment in cattle.
AB - Three tests are routinely done to assess blood status of selenium in cattle:
serum selenium, whole blood selenium, and glutathione peroxidase. The objective
of this study was to compare the various analytical methods for determining blood
selenium status in groups of mature cows and beef calves. Twenty to 30 blood
samples per herd were collected from 8 beef herds in central Alberta and 1 dairy
in Alberta herd twice a year from the spring of 1992 through the fall of 1995,
and once from 185 spring calves in 2 beef herds in Saskatchewan. Serum and whole
blood samples were submitted to 1 laboratory and whole blood samples were
submitted to a 2nd laboratory. Samples for glutathione peroxidase determinations
were submitted to a 3rd laboratory. Pearson's correlation coefficients and
Cohen's kappa were calculated for each possible comparison among the different
measures. The best agreement was observed between serum and whole blood analysis
within Laboratory A. The remaining comparisons reflected poor agreement.
Comparison of herd-level assessment resulted in better agreement than comparison
of individual sample results among laboratories and procedures for all
combinations tested. Serum selenium analysis was the only laboratory procedure
for which external reference material was utilized. Serum selenium, whole blood
selenium, and glutathione peroxidase measure different compartments of the blood
selenium pool. The time frame of interest, supplementation practices, and the
stability of recent dietary intake determine the optimum assessment method for
individual animals or herds. Determination of the serum status or of blood
selenium is more consistently measured at the herd-level than for individual
samples.
PMID- 9559214
TI - Reproductive consequences of an X-autosome translocation in a swine herd.
AB - A survey was conducted on the chromosome makeup and breeding data of pigs housed
at the Arkell Research Station, University of Guelph, to determine the
reproductive impact of a reciprocal translocation previously identified as
t(Xp+;14q-). Blood samples were cultured and chromosome spreads were examined to
identify carriers in the herd. Gonadal features of carrier boars and piglets and
their age-matched normal counterparts were studied, and the reproductive history
of carrier sows, including the number of breedings required for conception, mean
litter size, prevalence of still births and malformations, and sex distribution
among the piglets, was compared with that of normal (noncarrier) sows. Our
observations on testicular histology confirmed that X-autosome translocation
carrier boars are sterile, and the analysis of reproductive data showed that the
most striking effects of t(Xp+;14q-) on sows are the 50% increase in the number
of breedings required for conception and the over 25% reduction in litter size
compared with that of normal sows. The reproductive impact of this and similar
translocations on the herd and on the swine industry in general is discussed.
PMID- 9559215
TI - Oslerus osleri tracheobronchitis: treatment with ivermectin in 4 dogs.
AB - Oslerus osleri tracheobronchitis was diagnosed in 4 young dogs following
endoscopic visualization of tracheal nodules and identification of larvae in
airway cytologic samples. All dogs improved when ivermectin was administered (200
400 micrograms/kg body weight); however, most (3/4) required serial treatments in
order to achieve long-term resolution of clinical signs.
PMID- 9559216
TI - A different approach to controlling the cat population.
PMID- 9559217
TI - History and clinical signs.
PMID- 9559218
TI - Bioluminescence-based assays for detection and characterization of bacteria and
chemicals in clinical laboratories.
AB - OBJECTIVES: To survey recent advances in the application of bioluminescence to
public health problems. The usefulness of bacterial (lux) and eucaryotic (luc)
luciferase genes is presented, along with several examples that demonstrate their
value as "reporters" of many endpoints of clinical concern. CONCLUSIONS: The
development of new technologies for monitoring biological and chemical
contaminants is in continuous progress. Recent excitement in this area has come
from the use of genes encoding enzymes for bioluminescence as reporter systems.
Applications of the recombinant luciferase reporter phage concept now provide a
sensitive approach for bacterial detection, their viability, and sensitivity to
antimicrobial agents. Moreover, a number of fusions of the lux and luc genes to
stress inducible genes in different bacteria can allow a real-time measurement of
gene expression and determination of cellular viability, and also constitute a
new tool to detect toxic chemicals and their bioavailability.
PMID- 9559219
TI - Establishing reference intervals for DPC's free testosterone radioimmunoassay.
AB - OBJECTIVE: To establish reference intervals for serum free testosterone for DPC's
Free Testosterone assay. METHODS: We used data from healthy subjects and patients
to determine reference intervals by parametric and non-parametric methods after
partitioning by sex and age. RESULTS: In males, there was a significant decrease
in free testosterone concentrations with age. Reference intervals derived from a
combination of 2075 "healthy" and patients' results gave similar values by
parametric and nonparametric methods. However, the subgroups failed the test for
Gaussian distribution. For each decade from 20 years on and > or = 60 years, the
intervals based on 2.5th and 97.5th percentiles were: 24.1-94.8, 25.0-89.3, 23.4
81.7, 22.5-80.4, and 21.5-74.3 pmol/L respectively, in females, there was little
change with age. The frequency distribution of 1915 patients was positively
skewed, and showed a wider range than "healthy." Using square roots of values
gave a Gaussian distribution. The central 95% intervals based on 187 "healthy"
subjects were: 0.5-8.1 and 0.0-6.4 pmol/L for 20-59 and > or = 60 years,
respectively. CONCLUSION: Developing reference intervals for free testosterone
was complicated by the need to partition data by gender and age, difficulty in
establishing disease in subjects and presence of physiological and other factors
which can affect concentration in health and disease.
PMID- 9559220
TI - Analytical evaluation of the testosterone assay on the Bayer Immuno 1 system.
AB - OBJECTIVES: To evaluate the analytical performance of the testosterone assay
performed on the Bayer immuno 1 system from Bayer Corporation. DESIGN AND
METHODS: The precision was measured using three Bayer TESTpoint Ligand controls,
three Medical Decision Pools and the Bayer SETpoint Testosterone calibrators. The
linearity was verified by diluting two serum samples containing high testosterone
concentrations with the zero calibrator and the minimum detectable concentration
determined by repetitive analysis of the zero calibrator. The assay was
correlated with the Diagnostic Products Corporation (DPC) Total Testosterone
assay using 342 serum samples. The reference values were determined using serum
samples from 75 women and 60 men. RESULTS: The assay showed within-run
coefficients of variation (CVs) varying from 1.1-8.4% and between-day CVs from
1.5-4.9% for testosterone concentrations varying from 1.77 to 66.96 nmol/L. The
minimum detectable concentration was estimated at 0.11 nmol/L. The assay
linearity proved excellent. A good correlation between the Bayer Immuno 1 and the
DPC assays was observed with different categories of serum samples (Immuno 1 =
1.11 x DPC-0.32, r = 0.989, Sy[symbol: see text]x = 2.07 nmol/L). The reference
values were estimated at 0.3-3.2 nmol/L for females and 9.3-35.6 nmol/L for
males. CONCLUSIONS: The Bayer Immuno 1 Testosterone assay demonstrates the
analytical characteristics required for its utilization in the clinical
laboratory.
PMID- 9559221
TI - A simple spectrophotometric enzyme assay with absolute specificity for
arylsulfatase A.
PMID- 9559222
TI - Correlation of sweat chloride concentration with genotypes in cystic fibrosis
patients in Saguenay Lac-Saint-Jean, Quebec, Canada.
AB - OBJECTIVES: Saguenay Lac-Saint-Jean, a geographically isolated region of
northeastern Quebec has a high incidence of cystic fibrosis (CF) and three
mutations only account for 94% of the CF chromosomes. The objective of the
present study was to determine whether different mutations in the cystic fibrosis
transmembrane conductance regulator (CFTR) gene had different effects upon the
sweat chloride concentration. DESIGN AND METHODS: The sweat chloride
concentration of 114 patients was measured by quantitative pilocarpine
iontophoresis. RESULTS: CF patients carrying the A455E mutation, usually
associated with pancreatic sufficiency, had lower sweat chloride concentrations
than those carrying mutations associated with pancreatic insufficiency (delta
F508 and 621 + 1G-->T). CONCLUSIONS: Our results confirm that mutations resulting
in a reduction of the chloride current at the apical membrane of epithelial cells
induce lower sweat chloride values. However, there are differences in the
chloride current between genotypes, even if they are composed of mutations
apparently having the same functional effect.
PMID- 9559223
TI - Effects of antihypertensive drugs on cholesterol metabolism of human mononuclear
leukocytes and hepatoma cells.
AB - OBJECTIVES: Primary prevention trials of antihypertensive therapy have shown
conflicting results on coronary events. Potential interference of
antihypertensive agents with cellular lipid metabolism may alter the
atherosclerotic risk of individuals. DESIGN AND METHODS: The effects of the
calcium antagonist's verapamil, diltiazem, and nifedipine and of the beta
blockers propranolol and metoprolol on low density lipoprotein (LDL) receptor
activity, cholesterol esterification rate, oleate incorporation in triglycerides
and sterol synthesis were studied in freshly isolated human leukocytes and HEP G2
cells. RESULTS: Up to a concentration of 3-10 mumol/L, verapamil, propranolol,
and metoprolol led to an increased cellular content of 125I-LDL by an inhibition
of degradation. In mononuclear cells verapamil stimulated accumulation and
degradation. No effect on binding was observed. Diltiazem was only stimulatory on
125I-LDL processing in leukocytes. Beta blockers and verapamil significantly
reduced the LDL mediated 14C-oleate incorporation in cholesterol esters. In the
presence of 25-hydroxycholesterol the esterification was not diminished, which
suggests that cholesterolacyltransferase (ACAT) was not affected per se. Whereas
all the agents induced the synthesis of lanosterol, metoprolol inhibited
cholesterol synthesis. None of the agents had a significant influence on 14C
oleate incorporation in triglycerides, suggesting a specific influence on
cholesterol metabolism. CONCLUSIONS: Antihypertensive drugs affect the
cholesterol metabolism on a cellular level. Mechanisms are an interference with
degradation of LDL and consequent alterations of cholesterol esterification.
Using leukocytes as peripheral cells and HEP G2 as a model of human liver, these
results may have importance when antihypertensive long-term therapy is conducted
for primary or secondary prevention of atherosclerotic complications.
PMID- 9559224
TI - Laboratory survey of prostate specific antigen testing in Ontario.
PMID- 9559225
TI - Patients with suspicious digoxin levels: evaluation of the potential contribution
of crossreactive digoxin metabolites.
PMID- 9559226
TI - Multicenter evaluation of the Abbott AxSYM procainamide and N-acetylprocainamide
assays: comparison with Abbott TDx/TDxFLx, Syva EMIT 2000, DuPont ACA, and HPLC
methods.
PMID- 9559227
TI - US and CT findings of secondary neoplasms of the thyroid--a pictorial essay.
AB - Although clinical series report a low (3%) incidence of metastases to the thyroid
gland, autoptic studies have showed occurrences as high as 17%, probably because
of the high vascularization of the thyroid. We selected 9 patients who had
pathologically proven thyroid metastases at CT and US, during follow-up for a
known primary neoplasm. The most common originating neoplastic primaries include
mostly those that generally give rise to blood-borne metastases such as breast
and lung cancers, mucoid adenocarcinoma of the stomach, colon cancer and renal
cancer, as well as melanoma and leiomyosarcoma. Because of its diffusion,
sensitivity, and noninvasiveness, ultrasonography can justifiably be introduced
in the staging protocols of those neoplasm that more frequently give blood-borne
metastases to the thyroid, but a US-guided biopsy is warranted for hypoechoic or
otherwise suspicious nodules. This holds particularly true in disease-free
patients or previously diagnosed with generally slow-growing malignancies (breast
or kidney), since the secondary localization, often metachronous in our
experience, may be effectively managed surgically. CT features, on the other
hand, are extremely variable and are directly dependent on the histology of the
primary lesion, as well as the size of the secondary lesions.
PMID- 9559228
TI - Contrast-enhanced breast MRI for cancer detection using a commercially available
system--a perspective.
AB - The diagnosis and treatment of breast cancer are dependent upon early detection
of the disease by physical examination and mammography. Although mammography is a
relatively good and cost-effective method of early breast cancer detection, there
are some inherent weaknesses associated with this imaging modality that limit its
sensitivity and specificity. Contrast-enhanced MRI of the breasts provides the
additional capability to answer questions raised or unanswered with conventional
imaging methods. This paper reviews contrast-enhanced breast MRI interpretation
guidelines and patient preselection criteria for diagnostic problem cases.
Technical aspects using a commercially available three-dimensional (3D) spoiled
gradient-echo technique are discussed.
PMID- 9559229
TI - Differential diagnosis of hepatic tumors with delayed enhancement at gadolinium
enhanced MRI: a pictorial essay.
AB - Hepatic lesions with delayed enhancement are sometimes encountered on gadolinium
enhanced MRI of the liver. This study illustrates the varied appearances of
several pathologic entities with delayed enhancement, including hepatic
hemangioma, hepatic metastases, intrahepatic cholangiocarcinoma, focal nodular
hyperplasia, hepatic abscess, hepatocellular carcinoma, and hepatocellular
carcinoma after transcatheter arterial chemoembolization, and presents the
utility of arterial-phase dynamic MRI in the differential diagnosis of these
lesions. Possible causes of these delayed enhancements are also discussed.
PMID- 9559230
TI - Neuroimaging on delayed postanoxic encephalopathy with lesions localized in basal
ganglia.
AB - A 59-year-old woman suffered from prolonged hypotension with myocardial
infarction. Sixteen days after the episode, she showed bradykinesia, gait
disturbance, and postural tremor. MRI revealed low signa intensities in the
bilateral caudate nuclei and putamen on the T1-weighted image and high signal
intensities on the T2-weighted image. PET with 18F-FDG revealed a severe decrease
in glucose metabolism in bilateral basal ganglia. It is concluded that prolonged
hypotension may induce localized delayed anoxic lesions in basal ganglia.
PMID- 9559231
TI - Primary malignant pulmonary hemangiopericytoma.
AB - A primary malignant pulmonary hemangiopericytoma was diagnosed in a 45-year-old
woman who complained of 10 months of cough and exertional dyspnea. One year after
resection of the mass, a metastatic lesion was removed from the contralateral
lung. The literature on this unusual pulmonary lesion is reviewed.
PMID- 9559232
TI - Direct duodenal invasion of hepatocellular carcinoma. Intestinal hemorrhage
treated by transcatheter arterial embolization.
AB - This report describes a case of direct duodenal invasion of hepatocellular
carcinoma with massive intermittent gastrointestinal (GI) bleeding. Progressive
anemia was intractable by supportive therapy alone, and repeated blood
transfusion was necessary. Transcatheter arterial embolization was finally
carried out, which dramatically reduced the amount of transfusion. Owing to
severe blood loss, patients with GI tract involvement generally have a poor
prognosis.
PMID- 9559233
TI - Differentiation between hepatic cavernous hemangioma and malignant tumor with T2
weighted MRI: comparison of fast spin-echo and breathhold fast spin-echo pulse
sequences.
AB - PURPOSE: The goal of our study was to compare a T2-weighted breathhold fast spin
echo (BHFSE) technique with T2-weighted nonbreathhold fast spin-echo (FSE)
technique for characterizing cavernous hemangioma of the liver and
differentiating this entity from malignant tumor. MATERIALS AND METHODS: Eighteen
patients with cavernous hemangiomas and 18 patients with malignant hepatic tumors
were studied with T2-weighted MRI with a nonbreathhold FSE technique with and
without fat suppression and with a BHFSE technique without fat suppression.
Hepatic lesions were analyzed quantitatively using signal intensity (SI) and
contrast-to-noise (C/N) ratio. In addition, images were qualitatively compared
for accuracy in characterizing hepatic lesion. RESULTS: Quantitatively,
hemangioma had significantly higher SI and C/N ratios than did the malignant
tumor on every pulse sequence (P < 0.01). Qualitatively, all malignant tumors
were correctly categorized; differentiation between cavernous hemangioma and
malignant tumor was impossible in three cases of cavernous hemangioma with the
three pulse sequences (92% accuracy, 100% sensitivity, and 83% specificity).
CONCLUSION: T2-weighted FSE and BHFSE MRI shows comparable levels of accuracy for
differentiating between hepatic cavernous hemangioma and malignant tumor. Because
overlap may exist using quantitative measurement, morphologic patterns must be
carefully analyzed, supporting that quantitative analysis and morphologic
evaluation are complementary.
PMID- 9559234
TI - Hepatic adenoma and focal nodular hyperplasia: MR findings with superparamagnetic
iron oxide-enhanced MRI.
AB - Two cases are presented in which the MRI findings following superparamagnetic
iron oxide (SPIO) enhancement of hepatic adenoma and focal nodular hyperplasia
(FNH) are described. Benign liver lesions show uptake of iron oxide particles,
which allows differentiation from malignant liver lesions and tumors of other
cell origin. There have been several publications in the literature, but the SPIO
enhanced MR findings of hemorrhage in a hepatic adenoma have not been previously
described. To illustrate the role of SPIO-enhanced MRI in the differential
diagnosis of adenoma from FNH, the SPIO-enhanced MR features of FNH are
presented.
PMID- 9559235
TI - Rheumatoid nodules: MRI characteristics.
AB - Rheumatoid nodules are not uncommon in patients with rheumatoid arthritis. Two
patients with rheumatoid arthritis and rheumatoid nodules are described. The MRI
characteristics and enhancement patterns of five nodules are examined.
PMID- 9559236
TI - Criminal behavior and mental disorder: impediments to assigning moral
responsibility.
PMID- 9559237
TI - A capitated model for a cross-section of severely mentally ill clients:
hospitalization.
AB - Hospitalization outcomes are examined in a three year random assignment
controlled study of two capitated Integrated Service Agencies (ISAs) in
California. Study participants were a cross-section of severely mentally ill
clients. Using the flexibility of capitated funding, the urban ISA reduced
inpatient length of stay and days, but not admissions. Elements of the capitated
ISA model worked together to produce clinically appropriate and less costly use
of inpatient services. At the rural ISA, admissions were reduced substantially
during the first two years of the demonstration but not costs.
PMID- 9559238
TI - Computerized depression screening and awareness.
AB - The DEPRESSION Awareness, Recognition and Treatment (D/ART) program under the
sponsorship of the National Institutes of Health has made consistent efforts to
help educate many communities around the nation about depression. One important
aspect of this effort includes offering free screening for depression to the
general public. Since new technology often promotes curiosity and interest, a
computerized depression screening and awareness program was created to use at
fairs and other local events. Individuals who participated completed a
computerized version of the Center for Epidemiological Studies Depressed Mood
Scale (CES-D) and then received a one page printout that described the common
symptoms of depression, a score indicative of their level of depressed mood, a
brief explanation of the score, and a telephone number where additional
information could be obtained. This paper details the construction of the
computerized version of the CES-D including an evaluation of psychometric
properties and consumer satisfaction with the program.
PMID- 9559239
TI - An empirical assessment of rural community support networks for individuals with
severe mental disorders.
AB - The community support network has been well-established as a requirement for
community treatment of individuals with severe mental disorders. This network
generally consists of a multidisciplinary set of organizations that interrelate
in some manner with individuals in the community. The question of coordination
within this network has been much discussed; however little published research
has empirically examined the types and extent of coordination among network
organizations. In particular, little attention has been given to community
support networks in rural communities. In each of seven rural counties,
information was obtained on inter-actions among organizations in the community
support network. These networks were analyzed to yield information on network
density and centralization. Using measures of centrality, the most central
organizations in each network were identified. Exchanges of information were the
most common type of interaction among organizations in each network. Client
referrals occurred less frequently, and sharing of resources was an even rarer
phenomenon. Network analysis of community support networks provides an objective
perspective on the structure of community support networks. An understanding of
exchange among organizations within these networks is of value to administrators,
clinicians, and planners interested in achieving greater effectiveness, as well
as to patients, their families, and advocacy groups concerned with access and
quality of care.
PMID- 9559240
TI - The relationship between housing characteristics, emotional well-being and the
personal empowerment of psychiatric consumer/survivors.
AB - In this research, we examine the relationships between the housing
characteristics and dimensions of community adaptation for 107 psychiatric
consumer/survivors. Hypotheses about which housing characteristics best predict
which dimensions of adaptation were made based on previous research and theory.
Using a longitudinal research design, we found, after controlling for demographic
variables and prior adaptation, that the number of living companions, housing
concerns, and having a private room all significantly predicted different
dimensions of community adaptation. The findings partially support our
theoretical expectations and illuminate the relationship between physical, social
and organizational aspects of community-based housing and the adaptation of
psychiatric consumer/survivors. We discuss the implications of the results for
policy and practice in providing housing for this population.
PMID- 9559241
TI - Job terminations among persons with severe mental illness participating in
supported employment.
AB - For persons with psychiatric disabilities, maintaining a job is often more
difficult than acquiring a job. A large proportion of jobs end unsatisfactorily.
This study explored job terminations among 63 persons with severe mental illness
who participated in competitive jobs through supported employment programs. More
than half of the job terminations were unsatisfactory, defined as the client
quitting without having other job plans or being fired. Baseline ratings of
demographic and clinical characteristics, preemployment skills training, and
early ratings of job satisfaction and work environment did not predict
unsatisfactory terminations. Clients with better work histories were less likely
to experience unsatisfactory terminations. In addition, unsatisfactory
terminations were associated retrospectively with multiple problems on the job
that were related to interpersonal functioning, mental illness, dissatisfaction
with jobs, quality of work, medical illnesses, dependability, and substance
abuse. These results suggest that supported employment programs need to address
job maintenance with interventions that identify and address different types of
difficulties as they arise on the job.
PMID- 9559242
TI - A mental health program report card: a multidimensional approach to performance
monitoring in public sector programs.
AB - This report presents a comprehensive, multi-dimensional mental health program
performance monitoring system that has recently been implemented in the
Department of Veterans Affairs. Principles underlying the development of the
system are reviewed and 68 specific monitors are described addressing four major
performance domains: access, inpatient care, outpatient care, and economic
performance. Simple methods are presented for identifying outliers, for
generating summary performance scores across series' of related monitors, and for
adjusting results for differences in patient characteristics across locales.
Although still technically imperfect, and therefore requiring continuous
improvement, monitoring systems such as the one presented can be useful tools
guiding and improving service delivery and mental health system performance, and
providing a medium of accountability to consumers and other stakeholders.
PMID- 9559243
TI - Management approaches for mental health program report cards.
PMID- 9559244
TI - Response to Rosenheck and Cicchetti's "a mental health program report card: a
multidimensional approach to performance monitoring in public sector programs".
PMID- 9559245
TI - T-cell technology in the diagnosis & management of cutaneous T-cell lymphoma.
AB - Cutaneous T-cell lymphoma (CTCL) is a malignancy of mature, clonal, helper (CD4+)
T-cells that have a propensity for localizing in the skin. This article discusses
the new immunologic and molecular advances and their practical application in the
management of CTCL.
PMID- 9559246
TI - Systemic lupus erythematosus in pregnancy.
AB - Systemic lupus erythematosus is an inflammatory autoimmune disease that can
affect multiple organ systems. The most popular theory regarding the origin of
its clinical manifestations is that autoantibodies and circulating immune
complexes become trapped in the capillaries of visceral structures.
PMID- 9559247
TI - Benign prostatic hyperplasia.
AB - Insight into the dysfunctional physiology of benign prostatic hyperplasia has
expanded appropriate therapies. As the proportion of the population to whom BPH
will be a problem increases our attention is directed to evolution in clinical
management.
PMID- 9559248
TI - Management of impotence in primary care.
AB - A diversity of successful new therapies for men with impotence dysfunction offers
renewed optimism about restoration for erectile dysfunction. A minimum of basic
laboratory investigation, history, and physical is necessary before embarking on
therapy.
PMID- 9559249
TI - Lyme disease: diagnosis & management.
AB - Lyme disease is the most common vector borne illness occurring in the United
States. Most cases occur in the East. Prompt recognition of typical features and
understanding the limitations of laboratory testing are essential in order to
provide appropriate management. Outcome in cases treated early is uniformly good.
PMID- 9559250
TI - Market consolidation--the key to the future.
AB - Widespread market consolidation, ongoing changes in Medicare and reimbursement
schedules, the evolution of managed care. These megatrends have created a
revolution in the eyecare industry with much instability in the marketplace.
Practice consolidation on a local level allows practitioners to take charge of
their destiny.
PMID- 9559251
TI - A review of the implantable cardioverter defibrillator trials.
AB - Clinical ventricular tachycardia and ventricular fibrillation are associated with
a high recurrence rate, and through the 1980s and the early 1990s a variety of
therapies have been proposed including the implantable cardioverter defibrillator
(ICD). Over the past decade it has been recognized that prospective randomized
trials are imperative if the proper role for any therapy is to be defined. The
Antiarrhythmic Versus Implantable Defibrillator (AVID) trial recently was
concluded and helped define the role of the ICD in high-risk patients. Other
trials are studying patients at high risk for sudden death who have not yet had a
clinical event. The recently concluded Multicenter Automatic Defibrillator
Implantation Trial and CABG Patch Trial helped determine the proper role of the
ICD in various pre-event high-risk subsets. These trials are summarized in
detail.
PMID- 9559252
TI - Ventricular tachycardia and fibrillation in normal hearts.
AB - Although ventricular tachyarrhythmias usually occur in the setting of definable
heart disease, up to 15% of ventricular tachycardias and 10% of ventricular
fibrillation occur in patients without heart disease. Of the various clinical
entities comprising these idiopathic ventricular tachyarrhythmias, a few well
defined clinical syndromes have been described, such as idiopathic right
ventricular outflow tract tachycardia, idiopathic left posterior fascicular
ventricular tachycardia, and the right bundle branch block and ST segment
elevation syndrome of idiopathic ventricular fibrillation. Many advances have
been made in the past few years in our understanding and treatment of idiopathic
ventricular tachyarrhythmias, and these advances are the subject of this review.
PMID- 9559253
TI - Implications and treatment of atrial fibrillation after cardiothoracic surgery.
AB - Atrial fibrillation (AF) is the most commonly encountered arrhythmia that occurs
after cardiothoracic surgery. It develops in up to 40% of patients, most
frequently in the first few postoperative days. The strongest risk factors for AF
are age and male gender. The pathogenesis of this arrhythmia probably involves
increased sympathetic activity in the setting of slowed atrial conduction. The
development of postoperative AF is associated with an increased morbidity, higher
costs, and prolonged hospitalization. The use of prophylactic beta-blockers and
procainamide reduces the incidence of AF whereas digoxin, verapamil, and
amiodarone appear less effective. Once AF occurs, the mainstay of treatment
remains rate control, anticoagulation, and restoration of sinus rhythm.
PMID- 9559254
TI - Diagnosis and management of neurocardiogenic syncope.
AB - The medical term syncope is derived from the Greek word "synkoptein," the
original meaning of which was "to cut short". Because it is both a symptom and a
sign, the physician may often find the evaluation of syncope a difficult and
frustrating endeavor. Over the course of the past decade it has become apparent
that transient alterations in autonomic nervous system activity, resulting in
hypotension and bradycardia, are common causes of syncope. At the same time it
has become apparent that these are a heterogenous group of disorders which, while
sharing some characteristics, are nonetheless distinct maladies. This article
attempts to briefly review our current understanding of these disorders and
suggests guidelines on their diagnosis and management.
PMID- 9559255
TI - Heart rate variability.
AB - Heart rate variability is a recognized tool for the estimation of cardiac
autonomic modulations. Recently, several studies have advanced the field of heart
rate variability in three areas: 1) in technical modes of electrocardiogram
processing and heart rate variability assessment, 2) in physiologic understanding
and interpretation, and 3) in clinical and practical use. The most recent
technical studies concentrate on the analysis of nonlinear aspects of heart
period variations and on coherence between electrocardiogram variability and
other physiologic factors such as respiration. Principal physiologic
investigations studied the components of heart rate variability attributable to
the individual limbs of the autonomic nervous system. It is becoming recognized
that behavior and responses to the environment, including the psychosocial
environment, play an important role in long-term heart rate variability.
Established clinical applications of heart rate variability are presently
restricted to the assessment of risk after myocardial infarction and to the early
diagnosis of diabetic neuropathy. Nevertheless, recent studies indicate that
heart rate variability might soon become a similarly powerful tool for risk
prediction and monitoring of disease progression in congestive heart failure and
for monitoring or reinnervation after heart transplantation.
PMID- 9559256
TI - Cardiac pacing in children.
AB - Indications for cardiac pacing in pediatric patients continue to expand. In
addition to its traditional use in sinus and atrioventricular nodal disease,
applications for cardiac pacing now include treatment of tachyarrhythmias after
repair of congenital heart disease, reduction of left ventricular outflow tract
obstruction in hypertrophic cardiomyopathy, and prevention of sudden death in the
congenital long QT syndrome. Whereas many benefits have been well documented in
adults, they remain anecdotal in children. Programmable features such as rate
response and antitachycardia pacing contribute to pacemaker versatility and
facilitate the achievement of normal hemodynamics in children requiring long-term
pacing therapy.
PMID- 9559257
TI - New Doppler techniques for the evaluation of regurgitant and shunt volumes.
AB - The aim of this review is to highlight some relatively new applications of
Doppler echocardiography in children. Recent observations of flow dynamics
through a restricted orifice have revealed that flow through an opening converges
toward the orifice in a series of proximal isovelocity hemispheric surfaces. The
flow convergence region can be demonstrated by Doppler echocardiography as a
color mosaic on the ventricular side of the mitral valve in the presence of
mitral regurgitation and on the left-ventricular side of a ventricular septal
defect with left-to-right shunting. The continuity principle dictates that
regurgitant flow rate can be calculated as the product of the hemispheric surface
area of the flow convergence region and the velocity at that hemispheric surface.
Using this principle, investigators have made quantitative flow measurements of
mitral regurgitation, ventricular septal defect flow and aortic regurgitation.
These studies demonstrate that this new technique of noninvasive quantification
has the potential of providing direct measures of regurgitant and shunt flow.
However, further validation in the pediatric population is needed before it can
be incorporated into routine clinical practice.
PMID- 9559258
TI - Current therapy of the patent ductus arteriosus.
AB - The patent ductus arteriosus (PDA) was the first congenital heart lesion to be
treated surgically and also the first to be treated with nonsurgical catheter
intervention. Surgical ligation and division of the ductus remains the gold
standard for consistently achieving complete occlusion. Transaxillary muscle
sparing thoracotomy and video-assisted thoracoscopic ligation, however, have
evolved as surgical alternatives with reduced trauma, shorter hospitalization,
and excellent cosmetic result but are associated with a significant rate of
residual or recurrent duct patency. With aggressive application of critical
pathway methods, significant reduction in cost has been achieved for surgical PDA
closure. Nonsurgical transcatheter closure nevertheless has gained widespread
acceptance, mostly employing detachable or nondetachable stainless steel coils.
Coils have superseded the previously popular Rashkind PDA occluder (USCI/Bard,
Tewksbury, MA) because of significantly lower cost, less cumbersome handling,
smaller delivery catheters, and superior occlusion rates. Various coil
implantation techniques and detachment mechanisms have been devised. Large PDAs
with smallest diameter greater than 5 mm, however, still are better treated
surgically until appropriate devices become available.
PMID- 9559259
TI - Interventional therapy for coarctation of the aorta.
AB - The optimal interventional management of coarctation of the aorta (CoA) remains
controversial. Although some are strong advocates for surgery, the timing of
operation in elective cases has been a matter of debate. Among those who advocate
balloon angioplasty, some recommend dilation only of recurrent CoA. Others
recommend dilation of native CoA, but only beyond a certain age. Finally, some
are strong proponents of balloon angioplasty, even in the neonatal period,
recognizing the need for reintervention (balloon dilation or surgery) in a
significant proportion of patients. Recent reports suggest similar or slightly
superior acute results of balloon dilation for native compared with recurrent
CoA. Balloon-expandable stents are being used increasingly in complex CoAs and in
failed dilations. A large multicenter study is required to determine the
respective clinical roles of surgery and balloon dilation in the management of
CoA.
PMID- 9559261
TI - Arrhythmias.
PMID- 9559260
TI - Lung transplantation in children.
AB - Fewer than 50 pediatric lung transplants are performed each year. Surgical
advances in the field have resulted in improved operative outcomes and in
technical innovations that have broadened both the target population and the
donor pool. At the same time, late referral of critically ill patients and
shortage of donor organs result in death prior to transplantation for many
children, and substantial biological barriers exist that prevent achievement of
satisfactory long-term outcomes for the many who do undergo a successful surgical
procedure. Until we can better understand and overcome these barriers, lung
transplantation must be considered a palliative rather than curative procedure.
In this article, a brief overview of pediatric lung transplantation is offered,
and contributions to the recent literature are summarized.
PMID- 9559262
TI - Pediatrics.
PMID- 9559263
TI - A molecular approach to understanding human sterol metabolism using yeast
genetics.
AB - The availability of the sequenced genome of Saccharomyces cerevisiae (yeast) has
culminated in the use of this model eukaryote to study human diseases at a basic
level. This article describes the advantages of studying lipid metabolism in this
genetically facile organism, including examples of conserved functions and
genetic approaches to identifying new components of cholesterol homeostasis.
PMID- 9559264
TI - Genetic analysis of hydroxymethylglutaryl-coenzyme A reductase regulated
degradation.
AB - Hydroxymethylglutaryl-coenzyme A reductase degradation occurs in the endoplasmic
reticulum, and is regulated by the mevalonate pathway. In order to discover the
molecules that mediate the degradation process and its control, we conducted a
genetic analysis of the degradation of the yeast Hmg2p isozyme of
hydroxymethylglutaryl-coenzyme A reductase. Hmg2p degradation occurs by the
action of HRD genes that direct Hmg2p to the ubiquitin-proteasome pathway.
Regulation of HRD-dependent Hmg2p degradation appears to occur by the action of a
separate set of CRD genes.
PMID- 9559265
TI - CaaX converting enzymes.
AB - Proteins that contain a carboxyl-terminal CaaX motif undergo post-translational
processing involving prenylation, endoproteolysis and methylesterification. Two
yeast genes, AFC1 and RCE1, which are candidates for genes encoding CaaX
converting enzymes, were recently identified. Rce1p is required for the full
penetrance of the activated Ras2pval19 phenotype in yeast, indicating its
possible utility as a new target in Ras-based malignancies. Advances in our
current understanding of CaaX convertases and the functional importance of CaaX
proteolysis are discussed.
PMID- 9559266
TI - Expression of large genomic clones in transgenic mice: new insights into
apolipoprotein B structure, function and regulation.
AB - Extensive manipulation of the apolipoprotein B gene in yeast and bacterial
artificial chromosome clones and subsequent expression of these clones in
transgenic mice have provided fresh insights into several aspects of
apolipoprotein B biology, including the identification of sequences important for
lipoprotein (a) assembly, the demonstration that intestinal expression of
apolipoprotein B is controlled by DNA sequences > 50 kb from the gene, and the
extraordinary finding that apolipoprotein B is expressed in the heart.
PMID- 9559267
TI - Two 7 alpha-hydroxylase enzymes in bile acid biosynthesis.
AB - The addition of a 7-hydroxyl group is an early and often rate-limiting step in
the synthesis of bile acids. This reaction is catalysed by two cytochrome P450
enzymes known as cholesterol 7 alpha-hydroxylase and oxysterol 7 alpha
hydroxylase. cDNAs encoding these proteins have been isolated and used to define
two evolutionarily conserved pathways that produce 7 alpha-hydroxylated bile
acids.
PMID- 9559268
TI - Acyl CoA:cholesterol acyltransferase genes and knockout mice.
AB - Acyl coenzyme A:cholesterol acyltransferase (ACAT) (EC 2.3.1.26) is an enzyme,
located in the endoplasmic reticulum of many types of cells, that catalyzes
cholesterol ester formation from cholesterol and fatty acyl CoA substrates.
Sterol esterification by ACAT or homologous enzymes is conserved in evolution
dating back to yeast. The recent cloning of a human cDNA for ACAT, together with
genome sequencing projects, has led to the identification of an ACAT gene family
and provided molecular tools for determining ACAT's functions in vivo. Summarized
here is the current knowledge concerning the molecular genetics of ACAT.
PMID- 9559269
TI - Roles for the methylation of phosphatidylethanolamine.
AB - The methylation of phosphatidylethanolamine is an auxiliary pathway for
phosphatidylcholine biosynthesis in liver. Two forms of the enzyme,
phosphatidylethanolamine N-methyltransferase, which catalyses this reaction, are
located on the endoplasmic reticulum and mitochondria-associated membranes. Both
forms are encoded by a single murine gene, Pempt, located on chromosome 11. The
expression of the gene begins at birth. An inverse relationship exists between
the rate of liver growth and the expression of phosphatidylethanolamine N
methyltransferase. However, disruption of the Pempt gene does not alter liver
growth in mice or cause any other obvious phenotype.
PMID- 9559270
TI - Niemann-Pick disease type C.
AB - Niemann-Pick type C (NPC) is an autosomal recessive lysosomal storage disease.
Fibroblasts from individuals with Niemann-Pick type C exhibit defective
intracellular cholesterol transport. Linkage analysis has led to the recent
cloning of the NPC1 gene on human chromosome 18, which is the major disease
locus. Analysis of NPC1 reveals homologies with key regulators of cholesterol
homeostasis and a Drosophila morphogen receptor.
PMID- 9559272
TI - Update on low density lipoprotein receptor mutations.
AB - Recent research has focused on the rapid detection of new LDL receptor gene
variants and large scale screening for known mutations. Whether the nature of the
mutation in the LDL receptor gene in familial hypercholesterolaemia determines
clinical variability has been examined, as well as the potential value of
detecting mutation carriers for clinical practice. There is also evidence that
some patients with clinical familial hypercholesterolaemia do not have detectable
defects in the LDL receptor or apolipoprotein B.
PMID- 9559271
TI - Related membrane domains in proteins of sterol sensing and cell signaling provide
a glimpse of treasures still buried within the dynamic realm of intracellular
metabolic regulation.
AB - Recent discoveries in the regulation of cholesterol metabolism have documented a
two step proteolytic pathway that regulates nuclear targeting of the sterol
regulatory element binding proteins. Sterol regulatory element binding protein
cleavage activating protein is a newly identified protein that modulates the
proteolytic maturation of the sterol regulatory element binding proteins. It
contains a domain that is quite similar in sequence to the membrane spanning
region of the rate controlling enzyme of cholesterol biosynthesis, 3-hydroxy-3
methylglutaryl coenzyme A reductase. The membrane domain of the reductase is
involved in its post-translational regulation by cholesterol. The molecular
defect in the intracellular cholesterol storage disease, Niemann-Pick type C, has
also recently been identified. Surprisingly, the affected gene encodes a protein
with similarity to the membrane domains that are conserved in 3-hydroxy-3
methylglutaryl reductase and sterol regulatory element binding protein cleavage
activating protein. Furthermore, the cell surface receptor for the sterol
modified hedgehog morphogen, Patched, also contains a membrane domain with
significant similarity to this putative sterol monitoring domain. These recent
developments suggest a common mechanism for sensing intracellular sterol levels
and cell signaling, which is based on the function of related membrane domains
that are contained in key regulatory proteins.
PMID- 9559273
TI - Receptor-associated protein: a specialized chaperone and antagonist for members
of the LDL receptor gene family.
AB - Members of the LDL receptor gene family mediate cellular uptake of various
extracellular ligands, including lipoprotein particles. Ligand interactions with
these receptors can be antagonized by a 39 kDa receptor-associated protein.
Recent biochemical, cellular, and genetic studies have shown that receptor
associated protein is a molecular chaperone/escort protein for LDL receptor
related protein, a member of the LDL receptor gene family that binds multiple
ligands. These studies indicate that receptor-associated protein interacts with
LDL receptor-related protein at multiple sites and assists the proper folding and
disulfide bond formation of LDL receptor-related protein within the endoplasmic
reticulum. Following the completion of folding, receptor-associated protein
remains associated with the receptor during its subsequent trafficking along the
early secretory pathway, thereby preventing premature ligand interaction with the
receptor. The ability of receptor-associated protein to universally inhibit
ligand interactions with members of the LDL receptor gene family underscores the
use of this protein as a tool in the study of ligand-receptor interactions.
PMID- 9559275
TI - Nutrition and therapeutics.
PMID- 9559274
TI - Genetics and molecular biology.
PMID- 9559276
TI - Genetics and molecular biology.
PMID- 9559277
TI - Lipid metabolism.
PMID- 9559278
TI - Hyperlipidaemia and cardiovascular disease.
PMID- 9559279
TI - Atherosclerosis: cell biology and lipoproteins.
PMID- 9559280
TI - Therapy and clinical trials.
PMID- 9559281
TI - Current indications and techniques in evaluating inflammatory disease and
neoplasia of the sinonasal cavities.
AB - Imaging strategies of the sinonasal cavities have undergone extensive revision
over the last 5-year period. The traditional imaging examination of the paranasal
sinuses, plain film radiography, does reasonably well in diagnosing maxillary,
frontal, and sphenoid sinusitis. However, it less reliable in depicting
abnormalities in the ethmoid sinuses, the most common area first affected with
inflammatory disease. Compared with sinus computed tomography (CT), plain films
prove to be less specific and sensitive in depicting the extent of sinus
abnormalities. One series plainly concluded that sinus radiographs were not
reliable enough to be an integral part of the clinical decision process. The use
of plain radiographs of the sinuses has clearly been reduced by medical cost
containment concerns, replacement by superior techniques, and by clear weaknesses
of the modality. Although it is inexpensive and easily accessible, the low
sensitivities and inaccuracies of plain film radiography have resulted in the
current use of CT and high-field-strength (1.5 Tesla) magnetic resonance imaging
(MRI). By using this cross-sectional imaging, we now visualize directly the
pathologic conditions within the sinuses, as well as the normal anatomy. We
discuss current use of diagnostic imaging in the evaluation of patients with
nasosinusoidal complaints (most commonly resulting from acute and chronic
inflammatory disease), with complications of sinonasal inflammatory disease, and
with suspected/documented neoplasia. In addition to developing an imaging
algorithm to provide the information affecting clinical decision making, we
detail the specific imaging techniques necessary accurately to obtain that
information. We also review the specific concerns about imaging patients in the
intensive care unit and touch on several emerging imaging techniques. The imaging
workup in pediatric patients and patients with congenital anomalies is beyond the
scope of this review.
PMID- 9559282
TI - Measurement of panic disorder by a modified panic diary.
AB - The psychometric characteristics of panic diary measures were investigated in a
sample of 37 patients suffering from panic disorder with agoraphobia. Following
recommendations made in the recent consensus development conference on the
assessment of panic disorder, daily ratings included not only the occurrence of
panic attacks but also fear of panic, expectancy of panic, and expected
aversiveness of panic. These new measures were reliable and, on the whole,
demonstrated good divergent and convergent validity. Further, adding such
measures increased the incremental validity of panic disorder assessment.
PMID- 9559283
TI - Convergent and divergent validity of the Beck Anxiety Inventory for patients with
panic disorder and agoraphobia.
AB - Psychometric properties of the Beck Anxiety Inventory (BAI) (Beck and Steer,
1990) were investigated in a sample of 82 patients suffering from panic disorder
with agoraphobia. Before and after brief treatment, patients completed a battery
of questionnaires and, for 2-week periods, kept a daily panic diary in which they
recorded panic attacks, fear of panic, and average anxiety. The BAI demonstrated
excellent internal consistency and good test-retest reliability over a 5-week
interval. A partial multitrait, multimethod correlation matrix provided evidence
of convergent validity with other measures of anxiety and of divergent validity
vis a vis measures of depression. Factor analyses of pretest scores and residual
gain scores used to address criticism that the BAI is excessively panic-centric
yielded mixed results. In one analysis, the BAI was loaded with multimethod
measures of panic and anxiety and, in the other, with questionnaire methods of
assessing anxiety and depression. However, the BAI was clearly distinguished from
measures of fear of fear, a central construct in panic disorder, and agoraphobic
avoidance. Finally, the BAI proved sensitive to change with treatment, yielding
effect sizes for improvement comparable to those of other anxiety measures.
PMID- 9559284
TI - Panic disorder with smothering symptoms: evidence for increased risk in first
degree relatives.
AB - Klein's (1993: Arch Gen Psychiatry 50:306-317) "false suffocation alarm" theory
of spontaneous panic attacks posits that central receptors compare CO2, O2, and
lactate levels and trigger panic when an impending "false" state of suffocation
is detected. Several investigators have found abnormalities of respiratory
physiology in subjects with panic disorder. Twin and family studies have
suggested that both panic disorder and tidal volume response to CO2 are
inherited. We hypothesized that, if smothering symptoms are a marker for a
hypersensitive suffocation detector and if this hypersensitivity is familial,
then relatives of panic subjects with smothering symptoms would have higher rates
of panic with smothering than relatives of panic subjects without smothering. We
conducted a family study involving 104 panic disorder probands and 247 of their
interviewed first-degree relatives. Probands and their relatives were interviewed
using the Schedule for Affective Disorders and Schizophrenia--Lifetime Version
for Anxiety Disorders to determine their panic disorder and smothering symptom
status. Relatives of panic probands with smothering symptoms had an almost
threefold higher risk for panic and an almost sixfold higher risk for panic with
smothering symptoms when compared with relatives of panic probands without
smothering. We conclude that panic disorder with smothering symptoms may be a
subtype of panic disorder associated with increased familial risk and may be a
group of interest to genetic investigators. These findings provide the first
empiric evidence from a family study in support of Klein's false suffocation
alarm theory of spontaneous panics.
PMID- 9559285
TI - Episodic and chronic obsessive-compulsive disorder.
AB - Several lines of evidence support the concept of obsessive-compulsive disorder
(OCD) as a heterogeneous illness. Using a range of factors such as demographic,
psychosocial, and clinical variables, we compared OCD patients with chronic (n =
55) versus episodic (n = 46) courses of illness. Patients were evaluated monthly
for 1 year while receiving no treatment. Significant differences in sex ratio,
age at onset of the disorder, illness duration, type of symptoms, and familial
history were found between the two groups. These findings are consistent with the
concept of OCD as a heterogeneous disorder. Patients with an episodic course of
the disorder may be a distinct subgroup within the whole group of obsessive
compulsive patients.
PMID- 9559286
TI - Cardiovascular and catecholamine response to orthostasis in panic and obsessive
compulsive disorder and normal controls: effects of anxiety and novelty.
AB - OBJECTIVE: Studies of the cardiovascular and catecholamine response to
orthostatic challenge in panic disorder patients have yielded conflicting
results. Failure to control for the effects of both anxiety and novelty, which
contribute to subjects' response to orthostatic challenge in control patients,
could possibly account for this. METHODS: The blood pressure, pulse, plasma
norepinephrine and epinephrine responses to orthostasis were examined in patients
with panic disorder, obsessive-compulsive disorder (to control for nonspecific
anxiety effects), and controls, on two separate days a week apart (to control for
novelty). RESULTS: All measures showed robust and significant increases with
orthostatic challenge that were generally similar across groups. Pressure
responses were greater on average on the first compared with the second day and
panic disorder patients had higher plasma norepinephrine levels throughout the
study and a diminished diastolic blood pressure response on the first day.
CONCLUSIONS: These findings in general support the absence of consistent
peripheral autonomic nervous system differences in response to orthostatic
challenge in panic disorder patients.
PMID- 9559287
TI - Course of obsessive-compulsive symptoms in Tourette's syndrome.
PMID- 9559288
TI - Open-label pilot study of tramadol hydrochloride in treatment-refractory
obsessive-compulsive disorder.
PMID- 9559289
TI - Intratumoral genetic heterogeneity in primary head and neck squamous carcinoma
using microsatellite markers.
AB - We investigated intratumoral genetic variability using 13 of the most frequently
altered microsatellite loci in primary head and neck squamous carcinoma to
determine the extent and the implication of this feature on the interpretation of
the genetic analysis of these tumors. DNA extracted from four spatially different
samples of 17 prospectively resected specimens, in addition to matching normal
mucosa, was tested. Overall, the highest incidence of loss of heterozygosity was
noted at chromosomes 3p and 9p loci (70% in each). Chromosomes 8p and 17p loci
showed 35% and 40% loss of heterozygosity, respectively. Loss of heterozygosity
was homogeneously manifested in all different samples of tumors with these
alterations. Microsatellite instability was noted in two (17%) tumors, one of
which showed intratumoral heterogeneity. Our study indicates that single sample
analysis may reflect the genetic alterations in a given primary head and neck
squamous carcinoma using these markers.
PMID- 9559290
TI - Renal primitive neuroectodermal tumor: a morphologic, cytogenetic, and molecular
analysis with the establishment of two cultured cell lines.
AB - We report two patients with renal primitive neuroectodermal tumor (PNET) in whom
the diagnosis was established by both a cytogenetic and a molecular analysis.
Histologically, both renal tumors were composed of uniform immature round cells
with a positive immunoreactivity for O13 (p30/32 MIC2). The cytogenetic analysis
with in situ hybridization (chromosome painting) demonstrated reciprocal
translocation t(11;22)(q24;q12) specific to PNET in the cultured cells derived
from each tumor. The reverse transcriptase-polymerase chain reaction (RT-PCR) in
both tumors demonstrated EWS/ FLI-1 fusion transcripts, representing the
molecular equivalent of t(11;22). A Southern blot analysis also confirmed EWS
gene rearrangement in both renal tumors. In addition, the authors also
established two new cell lines (designated as FU-RPNT-1 and FU-RPNT-2) from renal
PNETs. When transplanted into athymic mice, FU-RPNT-1 and FU-RPNT-2 reproduced
and maintained the morphologic and molecular characteristics of the original
tumors. In conclusion, the detection of t(11;22) and EWS/FLI-1 fusion transcripts
is considered to provide a novel adjunctive method for diagnosing renal PNET.
These newly established cell lines thus may be used to investigate the biologic
behavior related to renal PNETs.
PMID- 9559291
TI - Comparison of genetic changes in frozen biopsies and microdissected archival
material from the same colorectal liver metastases.
AB - Microdissection of tissue sections from formalin-fixed, paraffin-embedded tumor
material allows separation of microscopic sites within a sample. DNA can easily
be extracted, and polymerase chain reaction (PCR) technology makes it possible to
perform different molecular biologic analyses on small cell populations. The
presence of normal cells or tumor heterogeneity may cause false negatives in
allelic imbalance (AI) studies. Microdissected well-defined cell populations from
a tumor section are assumed to increase the sensitivity of AI analyses. The
present study has evaluated this in colorectal liver metastases by comparing
genotypes in frozen biopsies with genotypes in microdissected archival samples
from the same patients. Constitutional genotypes were obtained from corresponding
peripheral blood leukocytes as well as normal liver tissue. Archival samples (n =
43) from 16 patients were analyzed after microdissection with 2-5 of 10 selected
microsatellite markers. Frozen biopsies from one metastasis of each patient had
previously been investigated at numerous microsatellite loci. From those results
we selected, for the comparable analysis of archival samples, 41 tumor genotypes
at 10 loci representing 11 heterozygotes, 13 AI, 7 losses of heterozygosity
(LOHs), 8 homozygotes, and 2 microsatellite unstable cases. The microdissected
samples revealed AI or a complete loss of one allele (LOH) in 5 of 11 (45%)
genotypes that were previously evaluated as unchanged (retained heterozygosity)
in the frozen biopsies, and LOH in 8 of 13 (62%) genotypes at loci known to
exhibit AI in the frozen biopsies. Microsatellite instability, LOH, and
homozygosity found in the frozen samples were all confirmed by analyses of the
archival material. Intertumoral genetic heterogeneity was found in samples from
two patients. The same allelic intensities were seen in DNA from tumor-close
liver tissue as in blood DNA from the same patient except in one sample. The
present study shows a 54% increase in sensitivity of genetic alterations if pure
tumor cell components are used (five "new" AIs and LOHs and eight "new" LOHs
among previously scored heterozygotes [n = 11] and AI [n = 13], respectively). In
total, a 93% success rate (108/115 analyses) was obtained using standard PCR
conditions for the 10 selected markers. The fact that standard PCR conditions and
5-micron tumor sections are used shows how easy these analyses are to perform,
and that only minor amounts of valuable archival material is used.
PMID- 9559292
TI - Gene expression of malignant rhabdoid tumor cell lines by reverse transcriptase
polymerase chain reaction.
AB - Malignant rhabdoid tumors (MRT) are characterized by unique neoplastic cells
demonstrating phenotypic diversity. By using the reverse transcriptase-polymerase
chain reaction, we have detected expression of various genes before and after
differentiation induction with four different agents in four established MRT cell
lines (TM87-16, STM91-01, TTC642, and TTC549). The agents used in this study were
all-trans retinoic acid (RA), 12-O-tetradecanoylphorbol-13-acetate (TPA),
interleukin-3, or interferon-gamma. Before and after induction, c-myc, IGF-II,
IGF-I receptor, and IGF-II receptor were constitutively expressed by all four
cell lines. The neurofilament medium-size (NF-M) was constitutively expressed by
the TM87-16 and TTC642, and the S100 protein alpha subunit was expressed by TM87
16, TTC642, and TTC549. Chromogranin A was expressed by TM87-16 only after
treatment with either TPA or RA. MyoD, N-myc, tyrosine hydroxylase, N-CAM, trkA,
and the S100 protein beta subunit were not expressed by any cell line before or
after induction with these agents. All the MRT cell lines in this study except
TM87-16 were highly resistant to differentiation induction. The proliferating
cells in TM87-16 and TTC642 expressed mRNA profiles characteristic of
neuroectoderm.
PMID- 9559294
TI - DNA extraction from formalin-fixed, paraffin-embedded tissues: protein digestion
as a limiting step for retrieval of high-quality DNA.
AB - Several DNA extraction methods have been used for formalin-fixed, paraffin
embedded tissues, with variable results being reported regarding the suitability
of DNA obtained from such sources to serve as template in polymerase chain
reaction (PCR)-based genetic analyses. We present a method routinely used for
archival material in our laboratory that reliably yields DNA of sufficient
quality for PCR studies. This method is based on extended proteinase K digestion
(250 micrograms/ml in an EDTA-free calcium-containing buffer supplemented with
mussel glycogen) followed by phenol-chloroform extraction. Agarose gel
electrophoresis of both digestion buffer aliquots and PCR amplification of the
beta-globin gene tested the suitability of the retrieved DNA for PCR
amplification.
PMID- 9559293
TI - Molecular alterations of the RB1, TP53, and MDM2 genes in primary and xenografted
human osteosarcomas.
AB - We report the status of the RB1, TP53, and MDM2 genes in human osteosarcomas and
cell lines established from surgical specimens and transplanted into athymic
naked mice. By using reverse transcriptase-polymerase chain reaction (RT-PCR) as
a prescreening technique and posterior sequencing, we observe new mutations in
the RB1 gene, notably a duplication in tandem of exons 3 through 6. TP53
mutations appear in codons most frequently mutated in osteosarcomas. We have not
seen MDM2 gene amplification in any reported case. These molecular alterations
appear in different osteosarcomas not simultaneously present in the same tumor
sample. A link has been described between these three genes in the pathways that
control the cell cycle and the tumoral progression, but their functions are
probably independent in the development of osteosarcomas. TP53 mutations appear
in adult patients, whereas RB1 alterations occur mostly in younger patients.
PMID- 9559295
TI - A microplate allele-specific oligonucleotide hybridization assay for detection of
factor V Leiden.
AB - Factor V Leiden is the most common genetic risk factor for thrombosis. Currently,
the determination of factor V Leiden genotype is limited to laboratories with
expertise in molecular methods to develop "home brew" assays using polymerase
chain reaction (PCR) to amplify genomic DNA, followed by analysis of Mnl I
restriction fragments. These methods are not standardized, are labor intensive,
and have low throughput. We describe a method for determination of factor V
Leiden genotype using allele-specific oligonucleotide capture probes coated onto
96 well plates, requiring only a thermal cycler and a microplate
spectrophotometer to perform. With an automated strip washer and plate reader,
genotypes could be determined in 80 min from completion of PCR. Within-run and
between-run coefficients of variation for the assay were < 10%. In all 160 cases
studied, the microplate assay correctly identified the factor V genotype. The
microplate oligonucleotide hybridization assay is a simple and reliable system
for determination of factor V Leiden genotype. The assay offers an automatable,
high-throughput alternative to current testing methodologies.
PMID- 9559296
TI - A method to monitor mRNA levels in human breast tumor cells obtained by fine
needle aspiration.
AB - A method based on the reverse transcriptase-polymerase chain reaction (RT-PCR)
was developed that allows the determination of relative mRNA expression levels in
fine-needle aspirates from human tumors. The method was developed for the c-erbB
2 gene, using the porphobilinogen deaminase (PBGD) gene as an internal standard.
It was validated for mRNA isolated from cell lines and for material obtained by
fine-needle aspiration from human breast cancer. Gene expression levels were
determined by measuring the activity of radiolabeled RT-PCR-amplified gene
specific bands with a phosphor imager. At least four points are measured on the
log-linear part of the amplification cycle versus signal intensity curves, and
subsequently the distance between the curves of the gene of interest and that of
an internal standard gene is used to calculate the relative expression levels.
The method worked equally well with the BRCA1 gene, illustrating that it can be
generalized to other genes. The method is suitable to measure or monitor
semiquantitively gene expression levels in accessible human tumors in situ.
PMID- 9559297
TI - [Adverse seizure reactions after electroconvulsive therapy. Study of personal
cases and review of the literature].
AB - OBJECTIVE: To determine what are the risk factors for the occurrence of unwanted
seizures after an ECT session, and what is the best attitude regarding future
ECT. METHOD: We have reviewed all the case reports published in the literature
between 1946 and 1995 and have carried out a prospective case-control study of
all incidental seizure type side effects among a group of 43 patients treated
consecutively using the same procedure within the same institution in 1993.
RESULTS: Results from the literature are presented in tables I to IV and results
from our case-control study in tables V to VIII. Twenty seven seizure type side
effects are reported in 22 published papers reporting the case of 24 patients.
Most accidents occur during the first ECT and the occurrence of non convulsive
seizures is greatly increased in case of coexisting EEG-monitoring. In our own
study the overall incidence is 0.95%. Risk factors are neurologic disease,
psychotropic medication, history of prolonged seizure during previous ECT.
CONCLUSION: It appears that no unique risk factor but a summation of several
risks (personal or family history of seizure, psychotropic medications, high
energy level of electric stimuli) for specific subjects increases the risk for
seizures after ECT. ECT can be resumed if necessary after occurrence of a post
ECT seizure with addition of anti-epileptic medication.
PMID- 9559298
TI - [Evaluation of the quality of life of chronic psychotic patients living in
supportive housing].
AB - This study concerns 46 chronically mentally ill patients living in community
support systems. Their quality of life was measured with a validated
questionnaire: the "Subjective Quality of Life Questionnaire" ("SQLP"). Both
patients and their care givers separately completed the same version of the
questionnaire. This study first shows the feasibility of such inquiries with
chronically mentally ill patients. It gives a description of the patient's
feeling which is different from the usual medical point of view. The life domains
the patient is very satisfied with are mostly restricted to food, material
conditions, and relationship with the care-givers, but exclude the other
relationships. Our data also allow to estimate the degree of agreement and
disagreement between the care-givers and their patients.
PMID- 9559299
TI - [Psychiatric emergency department of the Pinel hospital center].
AB - According to objective expressed by 1992's decree about psychiatric's emergency,
Philippe Pinel's hospital in Amiens have emergency ward since march 1994.
Computing activity within hospital allow to surround characteristics of patients
who come to psychiatric's hospital emergency, 2,122 patients have been examined
in 1995, either 6 a day. 220 were consultations, 1,920 were admittance to
hospital. Among these 2,122 patients, 20.5% don't know mental hospital, 19% don't
know psychiatry, 40% have a relapse and 20% where hospitalized but without met
again a doctor. On the average, one hour was dedicated to patient in 1995. On a
level with sociocultural, men are 59%, which 26% between 30 and 39 years, and 25%
between 40 and 49 years. Among the patients, 69% live alone, and 12% have social
difficulty. Patients are sent by General Hospital (27%), general practitioners
(24%, but this number grow in 1996), and various psychiatric institutions (10%).
The main symptoms are: sadness and depression (40%), anxiety (37%), sleep
disruption (31%), alcoholism (23%), bodily symptoms (16%), attempt to suicide
(15%), social problems (14%). After observation, diagnosis are: psychosis (30%),
neurosis (23%), alcoholism (19%), "anti-social" personality (10%), and drug
addiction (7%). Among these 2,122 patients in 1995, 90.5% (1920) are sent to
hospital, which 72% with their assent, and 28% under constraint. Consultations
(9.5%) are sent to psychiatric's institution (43%), general hospital (35%), and
psychiatrist (6%). In conclusion, computing activity within psychiatric's
emergency could enable best reception, guidance, and collaboration with social or
medical colleague.
PMID- 9559300
TI - [Is the functioning of our brain of an addictive nature?].
AB - The concept of addiction is increasingly bound to a general model of
heterogeneous and polymorphous dependences. In this paper we examine upstream
what could found this universal addictive principle, asking the question of the
neurobiological root of addictivity. In other words, is the root of our brain
working in an addictive way? To answer affirmatively to this question we gather
two sets of datas: firstly, the conditions of the brain addictivity and secondly,
the brain mechanisms that suggest this kind of addictive working. These datas are
common if we consider them one by one, but their synthesis in a bundle of
heuristic clues could be interesting to examine and to submit to thought. The
model we suggest proposes that the architecture of our brain and the type of
functioning of our neurones, imply the presence of a natural addictive set of
problems in all human beings, between a fight against cerebral background noise-
a dysphoric source--and a stimulation need. Finally, considering some
neurobiological data in the last five years, we propose a triangular model of the
addict brain, that involves three associated systems: "arousal" system, "liking"
system and "wanting" system. This model, supported by the sensation seeking one,
will allow us to suggest an explanation of the processes that lead to
pathological addictions, according to the principles of a natural and universal
addictivity.
PMID- 9559301
TI - [Validation of the French version of the revised Personal Style Inventory
(revised Personal Style Inventory, PSI-II, Robins et al., 1994)].
AB - The aim of the present study is to determine the validity and reliability of the
French version of the PSI-II. The PSI-II is a self-rating scale divided into two
subscales containing each 24 items and rating sociotropy and autonomy. 202
university students (170 females, 32 males) with a mean age of 21.54 years (sd =
4.16) were included. They filled out the PSI-II and the Interpersonal Dependency
Inventory (IDI). The construct validity was explored using an exploratory
principal components analysis followed by an orthogonal varimax rotation. The
results had shown a three-factor solution with a "sociotropy" factor and two
"autonomy" factors. The Cronbach alpha coefficients were respectively 0.83 and
0.72 for the sociotropy and autonomy subscales. The Pearson correlations between
the PSI-II and IDI subscales showed significant correlation first between the
sociotropy subscale and the two subscales of the IDI rating dependency, the
values were respectively 0.67 (p < 0.001) and 0.44 (p < 0.001), and secondly
between the autonomy subscales of the PSI-II and IDI, the value was 0.39 (p <
0.001). The sociotropy subscale items correlated significantly with the total
score of the subscale with a mean of 0.46. 23 items of the autonomy subscale
correlated with the total score with a mean of 0.36. The sociotropy and autonomy
scores were respectively 93.98 (sd = 14.22) and 84.55 (sd = 11.69). The French
version of the PSI-II had satisfactory metrological parameters and allows to
study sociotropy and autonomy in French population.
PMID- 9559302
TI - [Tridimensional Personality Questionnaire (TPQ): validation in a French-speaking
control population].
AB - Among the dimensional scales that measure personality, Cloninger's TPQ
(Tridimensional Personality Questionnaire) holds a place apart in the literature,
because the hypotheses it relies on are partially biological. The questionnaire
(100 forced binary items) includes three axes: "Novelty Seeking", "Harm
Avoidance" and "Reward Dependence", each theoretically bound to a preferential
neuromediator, respectively dopamine, serotonin and norepinephrine. Each axis
includes four minor subscales. The study presented here is the analysis of 104
control volunteers from both genders (59 males). This database is the first to be
published with a French-speaking population. The comparison with Cloninger's
normative database shows many similarities: the mean values for the 3 axes are
relatively close. The population studied here is younger and this factor could
play a role in the somewhat higher mean novelty seeking scores found here. The
three axes show a normal distribution. Skewness and kurtosis are between -1 and
+1 for all the subscales, except here for NS2. Factorial structure is quite
similar to Cloninger's results. The three first axes correspond to the variables
isolated in the first studies and the fourth one includes the same subscales as
in the large American database. Inverse correlation between age and novelty
seeking, positive correlation between female gender and harm avoidance and reward
dependence were also found. However, no correlation was found between novelty
seeking and male gender. A correlation was found between level of instruction and
NS1 only, not with the whole NS axis. Eighty-seven % of volunteers presented with
at least one standard deviation on at least one axis and 68% on at least two.
This does not seem to have been described previously. It can be a sign of the
difficulty of human beings to show a balanced personality. In conclusion, the
database presented here shows many similarities with Cloninger's normative
database. This underscores its value for comparisons in clinical trials in the
future.
PMID- 9559303
TI - [Bulimia and autoimmunity].
AB - In the first part of this study, we investigated the rate of natural
autoantibodies, in a sample of 31 female inpatients with bulimia nervosa
according to DSM III-R criteria. The control (age and sex matched) group
consisted in high school students including 10 females without eating disorders,
depressive disorder or immunological disease. We investigated especially natural
autoantibodies reacting with compounds of the central nervous system (Dopamine,
Dopamine beta Hydroxylase, Serotonin). Our first conclusion is that there is a
lower level of these natural auto-antibodies among female patients with bulimia
nervosa. In the second part of the study, we have especially investigated the
correlation between impulsivity in bulimia nervosa and the rate of natural
autoantibodies against serotonin.
PMID- 9559305
TI - [Fluoxetine: relations between plasma concentration and therapeutic effects in 32
patients with major depression and treated with 20 mg/day].
AB - The aim of this clinical study was to investigate 32 melancholic patients treated
by fluoxetine (20 mg/day). The clinical examination to evaluate the
antidepressant effect of fluoxetine was realized by using the HDS/MES criteria.
The patients were divided into three groups (responders, partial responders with
or without a relapse, non responders) according to their clinical evolution
during treatment. Fluoxetine and norfluoxetine were evaluated by HPLC after 3
weeks of treatment. In the present study, 53% of the patients have a positively
reaction to the 21 day's treatment. Our results showed no correlation between the
psychiatric scores and the plasma concentrations of fluoxetine and norfluoxetine.
PMID- 9559304
TI - [Absence of frontal lobe dysfunction and working memory deficits in young
schizophrenic patients].
AB - The impairment in tasks requiring intact frontal lobe functions has been
repeatedly shown in schizophrenics. However, the relative roles of confounding
factors, like duration of the disease, social withdrawal, or antidopaminergic
medication, are not clearly demonstrated. We studied the performance of 12 young
active patients, with chronic residual schizophrenia that had recent onset, and
12 control subjects, with frontal lobe tests and with a battery designed to
explore working memory. The results show normal performance in schizophrenia. The
small number of patients does not allow definitive conclusions, but this study
suggests that a frontal dysfunction may not be present early in the evolution of
schizophrenia in active patients.
PMID- 9559306
TI - [Secondary dermatologic effects of serotonin reuptake inhibitor antidepressants:
hypothesis of cross-reacting allergy. Apropos of 2 cases].
AB - Toxidermia is a well-known complication of antidepressant therapy. The authors
report two cases of adverse cutaneous reactions after treatment by several
serotonin uptake blockers. The first case concerns a 38-year-old woman, who
suffered from depressive disorder. She has been treated with fluoxetine. After
eight days, a cutaneous reaction appeared. This reaction subsided when fluoxetine
was stopped. Two months later, she had a prescription of paroxetine, and the same
skin adverse effect appeared. The cutaneous lesion decreased with the suppression
of paroxetine. The chronology of the eruption suggests that it was caused by an
adverse reaction to the both serotonin uptake blockers. The second case concerns
a 40-year-old man who had several prescriptions of antidepressant treatment in a
period of one year: fluoxetine, fluvoxamine, paroxetine and sertraline. Each time
a cutaneous reaction appeared. It is advisable to substitute after an adverse
effect a medication from one of the other classes of antidepressants. But what we
saw in these cases is that the serotonin uptake blockers could be involved in the
same allergic reaction while these drugs have different chemistry structures.
Only three of them have the same excipient. These cases ask the question of cross
reactivity between the serotonin uptake blockers.
PMID- 9559307
TI - [Psychiatric manifestations as the only clinical sign of hypothyroidism. Apropos
of a case].
AB - This article intends to demonstrate, by presenting a clinical case, the
importance of the thyroid examination in psychiatric practice. After a brief
presentation of the evolution of the conceptions regarding the relation between
thyroid insufficiency and psychiatric pathology, a clinical case is reported.
This 63 years old man was admitted in a psychiatric ward because of his
persecutive delusions and behavioral disorders (agitation, agressivity).
Cognitive (namely memory) impairment was also present at the time of admission.
The endocrine investigation has documented, in spite of the absence of any
suggestive physical signs, a thyroid insufficiency. After the replacement
treatment, all symptoms but the cognitive dysfunction disappeared. The patient's
evolution is presented clinically, also rated on MMSE and MADRS scales, and
biologically (TSH and T4 determination) for a 4 months period. The absence of any
pathognomonical psychiatric finding, the possibility of the absence of other
signs and symptoms (namely physical) in the hypothyroid state, the presence of
potentially irreversible cognitive deterioration, as well as the inocuity and
sensibility of thyroid hormones examination justify the systematic thyroid
evaluation for all new psychiatric patients.
PMID- 9559308
TI - [Apropos of specific psychiatric disorders in men].
PMID- 9559309
TI - Regulation of keratinocyte proliferation.
AB - 1. In physiological situations the proliferation of epidermal cells
(keratinocytes) in the skin is a tightly controlled process. 2. However, in many
common skin diseases, such as in psoriasis, the control mechanisms go awry
resulting in pathological epidermal hyperplasia (thickening). 3. In those
situations the keratinocytes enter the alternative pathway of proliferation
characterized by excessive growth rate, aberrant responses to growth factors,
faulty differentiation, and increased migratory capacity. 4. The participation of
different growth factors in enhancing or inhibiting keratinocyte growth, both in
physiological and pathological conditions, has been reviewed. 5. The regulatory
processes governing epidermal growth have relevance for the understanding of the
mechanism of action of the drugs used in the treatment of skin diseases
associated with epidermal hyperplasia.
PMID- 9559310
TI - Tumor resistance to antimetabolites.
AB - 1. The inherent or acquired resistance of certain tumors to cytotoxic drug
therapy is a major clinical problem. 2. Resistance to the chemotherapeutic
antimetabolites (e.g., methotrexate, 5-fluorouracil, tomudex and gemcitabine) is
no exception. 3. Mechanisms of resistance include mutations, amplification of
target genes, altered drug transport, differences in nucleoside and nucleobase
salvage pathways, DNA damage-response pathways and cell cycle control pathways.
PMID- 9559311
TI - Antioxidant and pharmacodynamic effects of pyridoindole stobadine.
AB - 1. The review summarizes the most important data known so far on chemistry,
pharmacodynamics, toxicology and clinics of the investigational agent,
pyridoindole stobadine. 2. Stobadine was shown to be able to scavenge hydroxyl,
peroxyl and alkoxyl radicals, to quench singlet oxygen, to repair oxidized amino
acids and to preserve oxidation of SH groups by one-electron donation. These
effects originated from its ability to form a stable nitrogen-centered radical on
indole nitrogen. Consequently, it was able to diminish lipid peroxidation and
protein impairment under oxidative stress. 3. In various in vitro and in vivo
animal models, stobadine was shown to diminish the impairment of the myocardium
induced by mechanisms involving reactive oxygen species (e.g., myocardial
infarction, hypoxia/ reoxygenation, catecholamine overexposure). 4. The
neuroprotective effect of stobadine was demonstrated in a series of in vivo and
in vitro models (brain in situ, brain slices, spinal cord, autonomic ganglia,
etc.) during ischemia/reperfusion and hypoxia/ reoxygenation or in the presence
of chemical systems generating free oxygen radicals, and so forth. Stobadine
improved animal survival rate and synaptic transmission recovery, maintained SH
tissue level and diminished lipid peroxidation as well as impairment of Ca
sequestering intracellular systems. 5. Oxidation of low-density lipoproteins
(LDLs), which plays a major role in the development of atherosclerosis, was
decreased by stobadine in vitro. Both lipid and protein (apo B) components of LDL
were protected against Cu(2+)-induced oxidation by this agent. 6. Stobadine
proved to be an effective protectant in models of free radical pathology in vivo,
such as cyclophosphamide-, MNNG- or 60Co-induced mutagenesis and alloxan-induced
hyperglycemia. 7. Besides other remarkable pharmacodynamic effects, stobadine
exerts antidysrhythmic, local anesthetic, alpha-adrenolytic, antihistaminic,
myorelaxant and antiulcerogenic actions. 8. Pharmacokinetic analyses demonstrated
that stobadine was readily absorbed from the gastrointestinal tract. Thanks to
its balanced lipo-hydrophilic properties, it was distributed over both water and
lipid phases in biological tissues. It was shown to easily penetrate the blood
brain barrier. 9. Acute, subchronic and chronic toxicity studies in several
animal species, as well as numerous analyses of embryotoxicity, teratogenicity,
mutagenicity and genotoxicity, revealed only a negligible toxic potential of this
agent. 10. Phase-one clinical study demonstrated safety of the compound. Only
slight side effects--namely, a slight hypotension and a slight sedative effect-
were observed subsequent to the highest dose used. In phase-two clinical study,
the patients with angina pectoris treated for 4 weeks with stobadine showed a
significant decrease in the frequency of anginal attacks, in the number of self
administrations of sublingual nitroglycerine and in plasma lipoprotein,
cholesterol and triglyceride levels. A slight decrease in systolic and diastolic
blood pressure also was observed. 11. It is suggested that stobadine may be
considered a contribution to the search for new effective cardio- and
neuroprotectants based on antioxidant or free radical scavenging mechanisms of
action.
PMID- 9559312
TI - Ranolazine: a novel metabolic modulator for the treatment of angina.
AB - 1. Ranolazine shifts ATP production away from fatty acid oxidation toward glucose
oxidation. 2. Because more oxygen is required to phosphorylate a given amount of
ATP during fatty acid oxidation than during carbohydrate oxidation, the
ranolazine-induced shift in substrate selection reduces the cell's demand for
oxygen without decreasing its ability to do work. The shift also maintains
coupling of glycolysis to glucose oxidation during ischemia, thus reducing tissue
acidosis. 3. This unique, non-hemodynamic mechanism offers the potential to treat
angina without reducing blood pressure, heart rate or myocardial contractility.
4. At least three double-blind, randomized, placebo-controlled clinical trials
have yielded data consistent with this hypothesis.
PMID- 9559313
TI - Fetal digoxin treatment enhances the binding capacity of thymic glucocorticoid
receptors in adult female rats.
AB - 1. Hormonal imprinting is provoked in the perinatal critical period in the
presence of the appropriate hormone or molecules similar to it. As a consequence
of hormonal imprinting, the developing receptor finishes its maturation normally
(in the presence of the adequate hormone) or abnormally (under the effect of
foreign molecules that are able to bind to the receptor). 2. Digoxin--which has a
steroid character--caused faulty imprinting by treatments at the 15th, 17th and
20th days of pregnancy. In the adult (3-month-old) animals, the density of thymic
glucocorticoid receptors was significantly elevated, whereas the density of
uterine estrogen receptors was not, without any change in receptor affinity. 3.
The experiments call attention to the steroid receptor imprinting effect of fetal
digoxin treatment that must be considered in regard to this treatment at this
period and later in regard steroid treatments.
PMID- 9559314
TI - Vasodilatation induced by nicotine in the isolated perfused rat kidney.
AB - 1. In isolated perfused rat kidney, under a constant flow of 8-10 ml/min, mean
basal perfusion pressure was found to be 82.57 +/- 8.96 mm Hg (n = 70). 2. After
a bolus injection of 10 micrograms/0.1 ml phenylephrine (PE) which causes maximum
vasopressor response, a 93.27 +/- 0.56 mm Hg increase in basal perfusion pressure
was recorded (n = 70). In control experiments, a submaximum dose of PE (3 x 10(
6) M) caused a 68.37 +/- 0.47 mm Hg (n = 5) increase in perfusion pressure. 3.
Nicotine, at a dose of 100 micrograms/0.1 ml, decreased the perfusion pressure
raised by submaximum dose of PE. This nicotine-induced dilatation was 24.97 +/-
3.27% of maximum PE constriction (n = 5). 4. Nicotine-induced dilatation was not
affected by atropine, guanethidine, hexamethonium, tetrodotoxin, capsaicin,
indomethacin, quinacrine, NG-nitro-L-arginine, methylene blue, glibenclamide,
tetraethylammonium, 4-aminopyridine and ouabain (n = 5).
PMID- 9559315
TI - The influence of Ca2+ on the effects of glucagon on hepatic glycolysis.
AB - 1. The influence of Ca2+ on the effects of glucagon on glycolysis was
investigated in the isolated perfused rat liver. Livers from fed rats were
perfused in an open system with Krebs/Henseleit-bicarbonate buffer (pH 7.4).
Glucose release, lactate plus pyruvate production (glycolysis) and oxygen uptake
were measured. The following results were obtained: 2. In livers perfused with
Ca(2+)-free Krebs/Henseleit-bicarbonate buffer and after depletion of the
intracellular pools, the initial and transient stimulation of glycolysis, which
is normally observed shortly after the onset of glucagon infusion, was more
pronounced when compared to livers perfused with normal perfusion fluid (2.5 mM
Ca2+) and without previous depletion of the intracellular pools (controls); the
subsequent inhibition of glycolysis was delayed in Ca(2+)-free perfused livers
and was less pronounced in comparison with the controls at the end of the
glucagon infusion period (20 min). 3. Perfusion with a Ca(2+)-free medium
supplemented with EDTA, without previous depletion of the intracellular pools,
also produced a substantial reduction in the effects of glucagon on glycolysis.
4. Ca(2+)-free perfusion did not affect the stimulative action of glucagon on
glucose release (glycogenolysis) and oxygen uptake. 5. Glycolysis inhibition by
cAMP also was abolished in Ca(2+)-free perfused livers, and the initial
stimulation was enhanced. 6. Mn2+, a metal ion known as a competitor of Ca2+,
considerably reduced the action of glucagon on glycolysis; Mn2+ did not affect
the basal rates of glycolysis. 7. Sr2+, a metal ion that is often recognized as
Ca2+ by several biological structures and processes, increased the inhibitory
action of glucagon on glycolysis. 8. Several organic compounds, which directly or
indirectly take part in Ca2+ fluxes, were also able to diminish (e.g., verapamil)
or even to abolish (carbenoxolone) the inhibitory action of glucagon on
glycolysis. 9. It was concluded that, under the conditions of the living cell,
Ca2+ is important for glycolysis inhibition by glucagon. In principle at least,
the results can be explained in terms of the known Ca2+ dependencies of several
protein kinases and protein phosphatases.
PMID- 9559316
TI - Acute and chronic effect of ethanol on (Na + K)-ATPase activity and cyclic AMP
response to vasopressin in rat papillary collecting duct cells.
AB - 1. We evaluated the effects of ethanol on (Na + K)-ATPase activity and cAMP
response to vasopressin in native and cultured rat papillary collecting duct
(PCD) cells. 2. A significant increase in (Na + K)-ATPase and Mg(2+)-ATPase
activities was found in PCD cells either isolated from chronic ethanol-fed rats
or cultured in the presence of ethanol. 3. Acute treatment with ethanol resulted
in a biphasic effect on the activity of (Na + K)-ATPase, which was enhanced below
1% ethanol and inhibited at higher concentrations. 4. Chronic ethanol treatment
did not change the cAMP response of PCD cells to vasopressin. Acutely, in turn,
this response was enhanced by ethanol per se. 5. It is suggested that the
antinatriuretic effect of ethanol could be at least in part mediated by a (Na +
K)-ATPase enhancement in PCD cells. Acutely, ethanol could normalize water
balance by its peripheral effects on distal nephron.
PMID- 9559317
TI - Effects of d-amphetamine on the frequency of the spontaneous contraction of the
portal vein in rat.
AB - 1. Effects of d-amphetamine on the frequency of spontaneous contraction of the
longitudinal muscle of the portal vein were studied in Wistar rats. Its effects
on the circular muscles of the pulmonary artery and stomach also were tested. 2.
d-Amphetamine increased the frequency of the spontaneous contraction of the
portal vein. The ratio of the frequency of the spontaneous contraction of the
portal vein before and after d-amphetamine treatment also was increased. The
effect was not affected in the presence of prazocin, (+)-lysergic acid
diethylamide, atropine and haloperidol. These results that the d-amphetamine
elicited response was not due mainly to the activation of adrenergic,
serotoninergic (5-HT), cholinergic or dopaminergic receptors. 3. Increasing
extracellular calcium or sodium ion concentrations decreased the frequency of the
spontaneous contraction of the portal vein. However, the ratios of the frequency
of the spontaneous contraction of the rat portal vein before and after d
amphetamine treatment in media containing different extracellular calcium or
sodium concentrations were not significantly altered. Tetrodotoxin did not alter
the effect of d-amphetamine on the frequency of spontaneous contractions. It
appeared that calcium and sodium ions may not take part in the effects of d
amphetamine on the frequency of the portal vein. 4. An increase in extracellular
potassium ion concentrations increased the frequency of the spontaneous
contractions of the portal vein. In addition, the ratios of the frequency of the
spontaneous contractions of the rat portal vein before and after d-amphetamine
treatment in media containing different extracellular potassium ion
concentrations were significantly altered. Tetraethylammonium chloride (TEA) and
4-aminopyridine (4-AP) increased the spontaneous contractions of the portal vein.
However, TEA and 4-AP did not increase the d-amphetamine-elicited increasing
effect on the frequency of spontaneous muscle contractions. 5. Levochromakalim, a
potassium channel opener, decreased the frequency of the spontaneous contractions
of the portal vein. Levochromakalim also decreased the effect of d-amphetamine on
the frequency of spontaneous contractions of the muscle. It appeared that
potassium ion may be associated with the effects of d-amphetamine on the activity
of the portal vein. 6. d-Amphetamine potentiated, whereas prazosin decreased, the
noradrenaline-elicited contracture of the rat pulmonary artery in a dose
dependent manner. 7. d-Amphetamine elicited contracture of the circular muscle of
rat stomach, whereas it did not alter the frequency of the spontaneous
contraction of the muscle. 8. Both 5-HT and d-amphetamine elicited the
contracture of the circular muscle of rat stomach. Ketanserin decreased the 5-HT
elicited response, whereas it did not alter the d-amphetamine-elicited response
in the muscle. d-Amphetamine did not alter the frequency of the spontaneous
contraction of the stomach. 9. It is concluded that d-amphetamine has different
effects on the frequency of spontaneous smooth muscle contractions. It increased
the frequency in the portal vein, but it did not alter the frequency in stomach
circular muscle.
PMID- 9559318
TI - Imprinting of thymic glucocorticoid receptor and uterine estrogen receptor by a
synthetic steroid hormone at different times after birth.
AB - 1. Single allylestrenol treatment (hormonal imprinting) of 3-day old rats reduced
the density of thymus glucocorticoid receptors and increased the density of
uterus estrogen receptors at adult age. 2. Similar treatment of 7-, 14-, or 28
day old animals did not alter the binding capacity of the receptors of the adult
animals at all. 3. In 3-day-old animals, the direction of imprinting was similar
to the prenatal imprinting of the thymus glucocorticoid receptor (reduction),
whereas neonatal treatment of uterine estrogen receptors decreased receptor
density, and imprinting on the 4th day increased it. This means that the
imprintability persists only to the 4th day; its consequence can be changed. 4.
The experiments demonstrate that hormonal imprinting can be provoked by
allylestrenol not only pre- or neonatally, as was done in previous experiments,
but also a few days later. The imprintability was lost between the 4th and 8th
day of life.
PMID- 9559319
TI - Contractile responses of proximal and distal trachea segments isolated from rats
subjected to immunological stimulation: role of connective tissue mast cells.
AB - 1. Anaphylaxis-induced contractions of proximal and distal tracheal segments
isolated from 14-day ovalbumin (OA)-sensitized rats were studied. 2. OA-induced
contractions in distal segments were significantly greater than those observed in
proximal segments. 3. Pretreatment of the rats with compound 48/80 or with sodium
cromoglycate (SCG) aerosolization significantly reduced OA-induced contractions
of trachea distal segments, whereas the contractions of proximal segments were
reduced only by compound 48/80. 4. Mepacrine reduced and indomethacin increased
the OA-induced contractions in all tracheal segments. Nor-dihydroguaiaretic acid
increased the OA-induced contractions in distal tracheal segments, whereas
dazoxiben inhibited the contractions in these same segments; neither of these
drugs had any effect on the contractions in proximal tracheal segments. 5. The
depletion of connective tissue mast cells and subsequent in vitro treatment with
indomethacin increased the OA-induced contractions in both segments. 6. We
conclude that the contractions of tracheal muscle from OA-sensitized rats depends
on the topographic and anatomical origin of the airway tissue. 7. Mediators
released by connective tissue mast cells in proximal and distal segments play a
pivotal role in this response and may account for variations in the intensity of
contraction seen after the addition of OA.
PMID- 9559320
TI - Attempts to classify dependence-liable drugs by using a simple drug
discrimination test in mice.
AB - 1. In a simple discrimination test using a two-compartment shuttle box with mice,
we examined the action properties of dependence-liable drugs. In mice trained to
discriminate morphine from saline, neither methamphetamine (MAP) nor cocaine
(COCA) was generalized to the discriminative stimulus effects of morphine. 2.
Similarly, in mice trained to discriminate MAP from saline, COCA, which is known
to have neuronal mechanisms in common with MAP, was generalized to the stimulus
effects of MAP, but morphine was not. 3. Dihydroetorphine (DHE), which has
receptor mechanisms in common with morphine, was generalized to the
discriminative stimulus effects of morphine, whereas it was not generalized to
the effects of MAP. Thus, the present discrimination test might be useful for the
first screening of compounds with unknown neuronal mechanisms, particularly for
classification into groups having separate neuropharmacological mechanisms in
common.
PMID- 9559321
TI - The effects of captopril and naloxone on restraint-cold-stress- and ethanol
induced gastric lesions in rats.
AB - 1. This study was undertaken to investigate the effect of captopril (1
microgram/kg or 1 mg/kg, i.p.) on the actions of naloxone (5 mg/kg, i.p. in
gastric ulceration induced by ethanol and restraint-cold-stress. 2. Neither
naloxone (5 mg/kg, i.p.) nor captopril (1 mg/kg, i.p.) alone induced any change
in the indices of the ulcer in either group. 3. Captopril at a lower dose (1
microgram/kg, i.p.), when combined with naloxone (5 mg/kg, i.p.), significantly
reduced cumulative ulcer length only in the ethanol-treated group (from 54.9 +/-
7.2 mm to 22.5 +/- 6.2 mm). 4. However, a high dose of captopril (1 mg/kg) plus
naloxone pretreatment caused a significant reduction in both ethanol (from 54.9
+/- 7.2 mm to 24.9 +/- 6.5 mm) and restraint-cold-stress (from 19.0 +/- 3.0 mm to
5.3 +/- 1.0 mm)-induced ulcer formation. 5. Acetylsalycilic acid, when used
together with captopril, increased the ulcer formation induced by stress. 6.
Naloxone, by increasing the release of prostaglandins, has been shown to prevent
ulcer formation induced by several noxious stimuli. 7. Therefore, the effect of
the combination might be due to the synergistic interaction of both drugs on
prostaglandin synthesis.
PMID- 9559322
TI - In vitro studies of the ultrastructural changes induced by guanidine in the
nerves, muscle fibers and neuromuscular junction of the mouse diaphragm.
AB - 1. The incubation of mouse isolated diaphragm with guanidine for 60 min produced
ultrastructural changes in the neuromuscular junction, the intramuscular
fascicles of the phrenic nerve and the skeletal muscle fibers. 2. The main
morphological characteristics of both the end terminals and the nerve fibers were
a swollen appearance and an electron-lucent axoplasm. In addition, the
mitochondria in these regions were markedly swollen and showed a rarefaction of
their cristae as well as a "washed aspect" of their matrix. Occasional periaxonal
vacuoles were present in the myelinated axons. There was a reduction in the
number of synaptic vesicles, which was accentuated by the enlarged areas of the
majority of the terminals. 3. Muscle cells underwent a range of morphological
alterations in the myofibrils and mitochondria. The most drastic type of necrosis
affecting these cells was complete dissolution of the myofibrils, which resulted
in an apparently "empty" cell with only the sarcolemma and a few mitochondria
remaining intact. 4. Tetrodotoxin was unable to provide total protection against
these guanidine-induced changes. 5. We conclude that the ultrastructural effects
evoked by guanidine may be associated with modifications in the permeability of
the axolemmal and sarcolemmal membranes as a result of changes in ionic
conductance. Such ionic disturbances also interfere with the metabolism of
mitochondria and the sarcoplasmic reticulum and may account for the well-known
inhibitory effect of guanidine on K+ channels and consequently on Ca2+ and Na+
conductances. 6. It is also suggested that the guanidine-induced alterations in
the presynaptic and postsynaptic sites could have independent mechanisms of
action.
PMID- 9559323
TI - Calcium dobesilate increased endothelium-dependent relaxation in isolated rabbit
aorta.
AB - 1. The aim of this study was to investigate the effects of calcium dobesilate on
relaxant and contractile responses in the isolated rabbit aorta. 2. Calcium
dobesilate (10(-6) and 10(-4) M) shifted the concentration-response curve induced
by noradrenaline (10(-8)-10(-4) M) downward and to the right, the IC50 being 5.1
+/- 1.1 x 10(-7) M in the control and 7.5 +/- 1.2 x 10(-6) M and 3.1 +/- 1.9 x
10(-6) M in the presence of calcium dobesilate, 10(-6) M and 10(-4) M
respectively. 3. Calcium dobesilate, 10(-5) M, increased the endothelium
dependent relaxation induced by acetylcholine (10(-8)-10(-5) M) but had no
actions in the absence of endothelium.
PMID- 9559324
TI - Effects of chronic ethanol consumption on extramitochondrial fatty acid oxidation
and ethanol metabolism by rat kidney.
AB - 1. We evaluated the effects of chronic ethanol consumption on microsomal and
peroxisomal fatty acid oxidation and on ethanol oxidation by the kidney. 2. When
mature rats were fed 20% ethanol for 10 weeks, an increase in alcohol
dehydrogenase and catalase activities were observed in the kidney. 3. Renal
microsomal and peroxisomal oxidation of fatty acids also increased by the
treatment, but total cytochrome P450 content did not. 4. We concluded that
chronic ethanol consumption results in an increased extramitochondrial
disposition of fatty acids and ethanol oxidation by the kidney.
PMID- 9559326
TI - Effect of YM435, a novel dopamine DA1 receptor agonist, in a canine model of
acute congestive heart failure.
AB - 1. The effects of YM435, a dopamine DA1 receptor agonist, were evaluated in a
canine model of acute congestive heart failure. 2. The model was induced in open
chest anesthetized dogs by left anterior descending coronary artery ligation,
volume loading, and intravenous infusion of angiotensin II. This resulted in a
moderate and stable congestive heart failure characterized by reduction in
cardiac output and increases in left ventricular end-diastolic pressure and total
peripheral vascular resistance. 3. Intravenous infusion of YM435 (1
microgram/kg/min) significantly decreased left ventricular end-diastolic
pressure, total peripheral vascular resistance and mean blood pressure and
significantly increased cardiac output and renal blood flow in this model. 4.
These results indicate that intravenous infusion of YM435 can improve
hemodynamics and cardiac function in a canine model of acute congestive heart
failure. YM435 may be a useful therapeutic agent for the treatment of congestive
heart failure.
PMID- 9559325
TI - Effect of hydroxypropyl-beta-cyclodextrin on the central stimulant activity of (
)-ephedrine and an oxazolidine prodrug in rats.
AB - 1. Hydroxypropyl-beta-cyclodextrin (HP-beta-CD) increases the stability of the
oxazolidine prodrug toward hydrolysis. 2. The binding constant (Kb) and rate
constant (Kc) for the hydrolysis of the prodrug-HP-beta-CD complex were
calculated from the kinetic data. 3. Ion-spray mass spectra confirmed prodrug-HP
beta-CD complexation. 4. Mass spectral and kinetic data indicated 1:1
stoichiometry for the complex. 5. A significant elevation of locomotor activity
in rats was observed when either (-)-ephedrine or the prodrug was administered by
either the intraperitoneal or the oral route. 6. Addition of HP-beta-CD
potentiated the central nervous system effect of both (-)-ephedrine and the
prodrug when administered intraperitoneally. However, when the drugs were
administered orally, HP-beta-CD caused a decrease in activity.
PMID- 9559327
TI - Stimulation of duodenal bicarbonate secretion by carbenoxolone in rats: a
comparative study with prostaglandin E2.
AB - 1. The effects of carbenoxolone on duodenal HCO3- secretion were examined in
anesthetized rats and compared with those of prostaglandin E2 (PGE2). 2. After 18
hr fasting, the duodenal loop (1.7 cm) that was made between the pyloric ring and
the area just proximal to the outlet of the common bile duct was perfused with
saline (pH 4.5), the pH of perfusate and the transmucosal potential difference
(PD) were continuously monitored and HCO3- output was determined by titration
with 10 mM HCl. 3. Under these conditions, duodenal pH, PD, and HCO3- secretion
were increased in response to PGE2 (0.3 and 1.0 mg/kg) given intravenously as a
single injection. Carbenoxolone (0.1-1.0 mg/kg, intravenously) also caused an
increase in duodenal pH and HCO3- output in a dose-dependent manner, with a
concomitant rise in PD; at 1 mg/kg, the magnitude of HCO3- output was almost
equivalent to that induced by PGE2 at 0.3 mg/kg. 4. Prior administration of
indomethacin, a cyclooxygenase inhibitor (5 mg/kg, subcutaneously), did not
affect the HCO3- stimulatory action of carbenoxolone or PGE2. 5. Duodenal HCO3-
secretion was also increased by intravenous injection of dibutylyl adenosine
3',5'-cyclic monophosphate (dbcAMP) but not by isobutylmethyl xanthine (IBMX; 10
mg/kg), an inhibitor of phosphodiesterase, but the former action was
significantly potentiated in the presence of IBMX. Likewise, the pretreatment of
IBMX significantly enhanced the HCO3- stimulatory action of PGE2 but had no
effect on the HCO3- response induced by carbenoxolone. 6. These results suggest
that carbenoxolone stimulates duodenal HCO3- secretion in rats, similar to PGE2
and this mechanism does not involve endogenous prostaglandins and is not
associated with the intracellular accumulation of cAMP.
PMID- 9559328
TI - Effects of ryanodine and cyclopiazonic acid on skinned fibers of ventricular
myocardium from neonatal and adult rats.
AB - 1. We examined the effects of ryanodine and cyclopiazonic acid (CPA) on Ca2+
release from myocardial sarcoplasmic reticulum (SR) with skinned fibers of
neonatal rat ventricular myocardium. 2. Both ryanodine and CPA concentration
dependently reduced the caffeine-induced tension in skinned fibers with
functional SR preserved; 1 microM ryanodine and 20 microM CPA reduced the
caffeine-induced tension to less than 20% of control values. 3. Both agents had
no effect on the Ca(2+)-tension relation of skinned fibers without functional SR.
4. These results suggest that ryanodine and CPA inhibit Ca2+ release from the SR
and Ca2+ uptake into it in neonatal myocardia. 5. Thus, less-negative inotropic
effects of ryanodine and CPA on neonatal myocardia compared with those on adult
myocardia (Agata et al., 1993; Tanaka and Shigenobu, 1989) could not be ascribed
to lack of drug effects on the SR per se.
PMID- 9559329
TI - Effects of the antihypertensive drug efonidipine hydrochloride on albuminuria and
renal histopathology in young spontaneously hypertensive rats with diabetes.
AB - 1. We investigated the renal protective effect of efonidipine hydrochloride
(efonidipine, NZ-105) in STZ-induced spontaneously hypertensive rats (SHRs, 8
weeks of age). Diabetic SHRs were treated with 15 mg/kg/day of efonidipine for 12
weeks. 2. The dosage of efonidipine was chosen after preliminary studies
demonstrated that it showed mild antihypertensive action (within 20% decrease of
systemic blood pressure). 3. In the diabetic SHRs, the excretion of urinary
albumin was increased (1.78 +/- 0.09 mg/day) at 4 weeks and reached 4.41 +/- 0.12
mg/day at 12 weeks. The levels of urinary albumin in the diabetic SHRs after
treatment with efonidipine were significantly less than those in the diabetic
SHRs at 8 and 12 weeks (P < 0.01). 4. Levels of creatinine clearance were
decreased in the diabetic SHRs after treatment with efonidipine. 5. In light
microscopy, the ratio of glomerular tuft to Bowman's areas was significantly
decreased compared with those in the diabetic SHRs (P < 0.05). 6. These findings
suggest that efonidipine inhibits the development of albuminuria and glomerular
enlargement in the streptozotocin-induced diabetic SHRs and may become a useful
antihypertensive drug with a renal protective effect.
PMID- 9559330
TI - Effect of chronic administration of L-arginine, NG-nitro-L-arginine or their
combination on morphine concentration in peripheral tissues and urine of the
mouse.
AB - 1. Chronic administration of L-arginine (200 mg/kg, i.p) twice a day for 4 days
decreased the antinociceptive response to subcutaneously, but not to
intracerebroventricularly, administered morphine in male Swiss-Webster mice, as
measured by the tail-flick test. 2. The decreased antinociceptive response to
morphine was reversed by concurrent administration of NG-nitro-L-arginine (L-NNA)
(5 mg/kg, IP), an inhibitor of nitric oxide synthase. 3. The concentrations of
morphine in mice treated chronically with L-arginine and then given morphine (10
mg/kg, SC) were determined in the peripheral tissues. L-Arginine treatment
significantly increased the concentration of morphine in spleen and lungs, did
not modify it in liver, kidneys and urine. L-NNA by itself had no effect on the
distribution of morphine in peripheral tissues but reversed the changes induced
by chronic treatment with L-arginine. 4. Acute administration of L-arginine (200
mg/kg, IP) did not modify either the morphine antinociception or the morphine
distribution in peripheral tissues. 5. Previous studies from this laboratory
indicated that chronic treatment with L-arginine decreases the concentration of
morphine in several brain regions and spinal cord of mice. 6. The facts that
chronic treatment with L-arginine does not alter antinociception induced by ICV
administered morphine and it increases the concentration of morphine in
peripheral tissues while decreasing it in brain regions after peripheral
administration of morphine suggest that the decreased antinociception induced by
subcutaneously administered morphine may be related to its decreased entry into
the brain.
PMID- 9559331
TI - Effect of the administration of fish oil by gavage on activities of antioxidant
enzymes of rat lymphoid organs.
AB - 1. The effect of administration of fish oil by gavage on catalase (CAT),
glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities of the
lymphoid organs and liver was compared with those of soybean oil and cocoa
butter. 2. Fish oil did not affect the activities of SOD and CAT but reduced that
of GSH-Px in the spleen. In contrast, cocoa butter reduced the CAT activity in
the thymus and liver, and soybean oil decreased CAT activity in the thymus. 3.
The content of thiobarbituric acid reactive substances of the lymphoid organs was
not modified but was increased in plasma.
PMID- 9559332
TI - The cardiovascular effects of the administration of L-NAME during the early
posthemorrhagic period.
AB - 1. The effects of the various doses of NG-nitro-L-arginine methyl ester (L-NAME,
10 and 30 mg/kg) on some cardiovascular and biochemical parameters during the
early posthemorrhagic period were studied in anesthetized rabbits subjected to
hemorrhagic hypovolemia. 2. Hemorrhagic shock was produced by intermittent
bleeding of 40% of the estimated blood volume for 15 min. Blood samples were
taken before and after bleeding (0, 15 and 60 min). Simultaneously, the mean
arterial pressure (MAP) and the heart rate (HR) were measured. Hemorrhaged
rabbits were treated by L-NAME10 or L-NAME30 (10 or 30 mg/kg, i.v. bolus
injection, respectively) or the corresponding volumes of saline (0.6 ml, i.v.
bolus) immediately after the end of bleeding. 3. The observed cardiovascular
parameters (MAP, HR) were significantly reduced after the end of bleeding in all
rabbits. 4. The rise of the MAP was significantly more pronounced 30 min after
the injection of L-NAME30 in comparison with the corresponding values in the
saline (S) group. In contrast, L-NAME10 produced only a small, insignificant
increase in the MAP in hemorrhaged rabbits. 5. The L-NAME30-induced rise of the
MAP was accompanied by a severe bradycardia, hyperkalemia and an aggravated
metabolic acidosis, more severe than the corresponding disturbance of the acid
base status in the S group. The changes in the acid-base parameters were observed
both in arterial (pH, excess base) and in venous blood (pH) of hemorrhaged
rabbits. 6. In conclusion, the i.v. bolus injection of L-NAME30 (immediately
after the end of bleeding) produced a significant increase in the MAP during the
first hour after the injury, but the presumable inhibition of the endothelial
constitutive nitric oxide synthase during the early posthemorrhagic period
resulted in severe cardiovascular and metabolic disturbances.
PMID- 9559333
TI - Protective effects of grape seed proanthocyanidins and selected antioxidants
against TPA-induced hepatic and brain lipid peroxidation and DNA fragmentation,
and peritoneal macrophage activation in mice.
AB - 1. The comparative protective abilities of a grape seed proanthocyanidin extract
(GSPE) (25-100 mg/kg), vitamin C (100 mg/kg), vitamin E succinate (VES) (100
mg/kg) and beta-carotene (50 mg/kg) on 12-O-tetradecanoylphorbol-13-acetate (TPA)
induced lipid peroxidation and DNA fragmentation in the hepatic and brain
tissues, as well as production of reactive oxygen species by peritoneal
macrophages, were assessed. 2. Treatment of mice with GSPE (100 mg/kg), vitamin
C, VES and beta-carotene decreased TPA-induced production of reactive oxygen
species, as evidenced by decreases in the chemiluminescence response in
peritoneal macrophages by approximately 70%, 18%, 47% and 16%, respectively, and
cytochrome c reduction by approximately 65%, 15%, 37% and 19%, respectively,
compared with controls. 3. GSPE, vitamin C, VES and beta-carotene decreased TPA
induced DNA fragmentation by approximately 47%, 10%, 30% and 11%, respectively,
in the hepatic tissues, and 50%, 14%, 31% and 11%, respectively, in the brain
tissues, at the doses that were used. Similar results were observed with respect
to lipid peroxidation in hepatic mitochondria and microsomes and in brain
homogenates. 4. GSPE exhibited a dose-dependent inhibition of TPA-induced lipid
peroxidation and DNA fragmentation in liver and brain, as well as a dose
dependent inhibition of TPA-induced reactive oxygen species production in
peritoneal macrophages. 5. GSPE and other antioxidants provided significant
protection against TPA-induced oxidative damage, with GSPE providing better
protection than did other antioxidants at the doses that were employed.
PMID- 9559334
TI - Cyclosporin A and FK-506 inhibit development of superantigen-potentiated collagen
induced arthritis in mice.
AB - 1. Staphylococcal enterotoxine B (SEB; superantigen) accelerated the onset of
arthritis in mice preimmunized with type II collagen (SEB-potentiated collagen
induced arthritis). Cyclosporin A and FK-506 inhibited the induction and
development of clinical signs and histopathological changes of SEB-potentiated
collagen-induced arthritis in mice. 2. Simultaneously, both cyclosporin A and FK
506 inhibited the development of humoral and cellular immunity to type II
collagen. 3. The expression of IL-2 receptor (CD25) by SEB on splenocyte T cells
from collagen-preimmunized mice was inhibited by both agents in ex vivo
experimentation.
PMID- 9559335
TI - Inhibition by ginsenosides Rb1 and Rg1 of methamphetamine-induced hyperactivity,
conditioned place preference and postsynaptic dopamine receptor supersensitivity
in mice.
AB - The ginsenosides Rb1 and Rg1, the major components of ginseng saponin, inhibited
not only methamphetamine-induced hyperactivity but also conditioned place
preference (CPP) in mice following a single or repeated administration. Dopamine
(DA) receptor supersensitivity, which developed in methamphetamine-induced CPP
mice, was also inhibited by both Rb1 and Rg1. Therefore, the present results
suggest that Rb1 and Rg1 may be the active components of ginseng saponin in the
modulation of methamphetamine-induced dopaminergic behaviors such as
hyperactivity and CPP, supporting our previous conclusion that ginseng saponin
might modulate methamphetamine-induced dysfunction at both the pre- and
postsynaptic DA receptors.
PMID- 9559336
TI - Miconazole as inflammatory agent. II: Time course of pleurisy and drug
interference.
AB - 1. Miconazole-induced pleurisy was characterized by edema development and
leukocyte infiltration. 2. This response was inhibited by chlorpheniramine,
methysergide and steroidal and nonsteroidal anti-inflammatory drugs. 3. After
miconazole injection, no mast cells were found in the pleural cavity. 4. Our
results support the concept that biogenic amines released from mast cells and
cyclooxygenase-derived mediators may contribute to the pathogenesis and evolution
of miconazole inflammation.
PMID- 9559337
TI - Adhesins of immunoglobulin-like superfamily from earthworm Eisenia foetida.
AB - 1. From the biologically active extract (G-90) isolated from the tissue
homogenate of Eisenia foetida immunoglobulin-like structures were isolated and
named G-90/4. 2. G-90/4 in nanogram concentrations stimulated cell proliferation
more than did the original G-90. It lyses cells in microgram concentrations. 3. G
90/4 acts as an adhesion molecule between the receptors of adjacent cells. 4. The
increase in proliferative activity was accompanied by the elevation of
cytoplasmic protein containing tyrosine. 5. Immunohistochemical analyses confirm
immunoglobulin-like transmembrane structures in the connective and muscular
tissues of E. foetida.
PMID- 9559338
TI - 6-OHDA lesions to amygdala and hippocampus attenuate memory-enhancing effect of
the 3-7 fragment of angiotensin II.
AB - We have previously shown that facilitatory effect of angiotensin II (AII) on the
retrieval of memory is mediated by the dopaminergic system. In the present study,
we searched for the influence of the 3-7 fragment of angiotensin II [AII(3-7)] on
the retrieval processes in a passive avoidance situation after bilateral 6-OHDA
lesions to the central amygdala (CA) and the CA4 field of the hippocampus (HI).
AII(3-7) given 15 min before the retention testing, at the
intracerebroventricular dose of 1 nmol, significantly prolonged avoidance
latencies in sham-operated rats (i.e. improved retrieval of memory for the
electric footshock experienced during the learning trial). Bilateral lesions to
CA totally abolished, and to HI significantly diminished, this facilitatory
effect. An increase of spontaneous locomotor activity in rats lesioned to CA and
a decrease in rats lesioned to HI were unlikely to interfere with the cognitive
effect of AII (3-7). These results suggest that the anatomical substrate of
facilitating retrieval of information activity of AII(3-7) is closely related to
the dopaminergic projection from the ventral tegmental area and substantia nigra
to CA and HI.
PMID- 9559339
TI - An FHIT tumor suppressor gene?
AB - The FRA3B at 3p14.2 is the most common of the constitutive aphidicolin-inducible
fragile sites. Using independent approaches, four groups of investigators have
cloned and characterized this fragile site. The results of these studies have
revealed that the FRA3B differs from other heretofore cloned rare fragile sites.
First, instability as manifested by chromosome breakage occurs over a large
region of DNA, encompassing at least 500 kb. Second, sequence analysis has not
revealed trinucleotide repeat motifs, characteristic of the rare fragile sites.
In addition to containing the FRA3B, band 3p14 is also likely to contain a tumor
suppressor gene, as evidenced by the presence of deletions, rearrangements, and
allele loss in a variety of human tumors, including lung, renal, nasopharyngeal,
cervical, and breast carcinomas. The recently cloned FHIT gene in 3p14.2 is a
promising candidate tumor suppressor gene, since aberrant FHIT transcripts have
been found in a significant proportion of cancer-derived cell lines and primary
tumors of the digestive and respiratory tracts. Nonetheless, several lines of
evidence garnered over the past year have called into question the role of FHIT
as a classical tumor suppressor gene, and raised the question of whether its
apparent involvement simply reflects its location within an unstable region of
the genome. In the following study, we have summarized the evidence in support of
FHIT as a tumor suppressor gene as well as evidence against such a role, and the
experimental evidence needed to demonstrate that FHIT functions as a tumor
suppressor gene in the pathogenesis of human tumors. The paradigm of FHIT
emphasizes that confirming the role of a candidate tumor suppressor gene may
prove difficult, particularly for those genes that are located in genetically
unstable regions.
PMID- 9559340
TI - Detection of APC mutations by a yeast-based protein truncation test (YPTT).
AB - APC gene mutations play a role in the initiation step of colorectal
carcinogenesis in both familial adenomatous polyposis (FAP) and non-FAP patients.
Almost all of the APC mutations are nonsense or frameshift mutations, which
truncate the APC protein and are thought to inactivate normal APC function. We
show a novel method for detecting nonsense and frameshift APC gene mutations by
using Saccharomyces cerevisiae. Polymerase chain reaction (PCR)-amplified APC
fragments are cloned directly into yeast expression vectors in vivo, and the
yeast expresses a hemagglutinin epitope (HA)-tagged APC peptide. When an APC
fragment contains a nonsense or frameshift mutation, HA-tagged truncating APC
peptide can be detected by Western blotting using an anti-HA antibody. We
identified both germ-line and somatic APC mutations in patients with FAP and non
FAP colorectal tumors, respectively. This method, called the yeast-based protein
truncation test (YPTT), is simple and fairly cheap, and it can be applied to any
genes that are inactivated by protein truncating mutations.
PMID- 9559341
TI - Gain of 3q and deletion of 11q22 are frequent aberrations in mantle cell
lymphoma.
AB - We used comparative genomic hybridization (CGH) to screen for DNA copy number
changes in 34 specimens from 27 cases of mantle cell lymphoma (MCL). The most
common gains were detected at 3q (52%), 8q (30%), and 15q (26%), whereas the most
frequent losses involved 13q (41%), 1p (33%), 6q (30%), 9p (30%), and 11q (30%).
The gain of 3q, with a minimal common region at 3q26.1-27, appeared in more than
half of the lymphomas, suggesting the location of an important oncogene here. A
common deleted region at 11q22 was found in one-third of the patients, which
suggests that this region may harbor a tumor suppressor gene important in the
tumorigenesis of MCL. The mean number of changes was higher in more aggressive
blastoid variants of MCL than in lymphomas with typical morphology. Our results
show that the chromosomal regions affected in MCL are highly consistent and are
different from those seen in other types of non-Hodgkin's lymphoma.
PMID- 9559342
TI - Allelotyping demonstrates common and distinct patterns of chromosomal loss in
human lung cancer types.
AB - Allelic loss is a hallmark of tumor suppressor gene (TSG) inactivation. We have
allelotyped 29 paired lymphoblastoid and lung cancer cell lines derived from 11
patients with small cell (SCLC) and 18 patients with non-small cell lung
carcinomas (NSCLC). Statistical analysis indicated that a threshold of 30%
separated non-random allelic loss from the random genetic deletions of
malignancy. We have identified non-random allelic loss at 42 of 54 (78%) specific
chromosomal regions examined, with 22 regions (52%) common between the two major
lung cancer histologic types. There were 3 regions (7%) with allelic loss
specific for SCLC and 17 regions (41%) specific for NSCLC. Furthermore, there
were significant differences in loss of heterozygosity (LOH) frequencies between
NSCLC and SCLC at 13 regions on eight chromosome arms (3p, 5q, 6q, 9p, 10q, 11p,
13q, and 19p). Eight homozygous deletions were present in seven cell lines at
four regions, 3p12, 3p14.2, 9p21, and 10q23-25. We have also identified novel
sites of chromosomal deletions. In particular, there was frequent loss at 11p13
in SCLC and loss at 6p21.3 and 13q12.3 in NSCLC. In this study, we demonstrate
that a) non-random allelic losses in lung cancer involve multiple regions; b)
some losses are common to both NSCLC and SCLC subtypes, whereas others are
subtype specific; c) there are genetic deletions at novel chromosomal regions;
and d) several homozygous deletions have been noted. Our studies demonstrate the
usefulness of continuous cell lines for detailed allelotyping, for comparing
genetic abnormalities between SCLC and NSCLC, and for identifying homozygous
deletions.
PMID- 9559343
TI - Mutational inactivation of aminoacylase-I in a small cell lung cancer cell line.
AB - Small cell lung cancer (SCLC) cell lines and tumors invariably exhibit loss of
heterozygosity (LOH) or, in rare cases, homozygous deletions involving part or
all of chromosome arm 3p, suggesting the presence of 1 or more tumor-suppressor
genes in this region. The gene encoding aminoacylase-I (ACYl) is localized on
chromosome segment 3p21.1. ACYl enzymatic activity, protein, and mRNA have been
demonstrated to be expressed at either undetectable or very low levels in a group
of SCLC cell lines and tumors. The demonstration of mutational inactivation of
ACYl would support the hypothesis that ACYl inactivation in SCLC confers a
selective growth advantage. One of four SCLC cell lines with undetectable Acyl
enzymatic activity and protein exhibited a compound mutation: nonconservative
missense point mutations at codons 195 and 254. No wildtype sequence transcripts
were identified in the cell line. Although nonmutational mechanisms for low or
undetectable ACYl enzymatic activity, protein, and mRNA expression are most
frequently operant in SCLC, the demonstration of a mutation supports selection
for ACYl inactivation. Analysis of normal liver and a liver metastasis from the
same patient from whom the NCI-H711 cell line was derived demonstrated that the
mutation was neither germline nor an early event in the development of SCLC. It
is of interest that several genes involved in the regulation of intracellular
protein degradation are encoded by chromosome band 3p21 and display unusual
expression in SCLC. The presence of other loci involved in protein degradation on
chromosome band 3p21 and their aberrant expression in SCLC suggest that a variety
of mechanisms involved in the normal degradation of intracellular proteins may be
perturbed in this neoplasm.
PMID- 9559344
TI - Investigation of the genes for RET and its ligand complex, GDNF/GFR alpha-I, in
small cell lung carcinoma.
AB - RET is a receptor tyrosine kinase expressed in neuroendocrine cells and in tumors
of these cell types. RET activation may be mediated by a ligand complex
comprising glial cell line-derived neurotrophic factor (GDNF) and GDNF family
receptor alpha-1 (GFR alpha-1). Activating RET mutations are found in the
inherited cancer syndrome multiple endocrine neoplasia type 2 and in a subset of
the related sporadic tumors, medullary thyroid carcinoma and pheochromocytoma,
both being derived from neuroendocrine tissues. In one small study, mutations
were identified in another tumor with neuroendocrine features, small cell lung
carcinoma (SCLC). To determine whether RET mutations contribute to the
pathogenesis of SCLC, we examined a panel of 54 SCLC cell lines. No mutations
were identified in RET exons 10, 11, and 13-16, regions previously implicated in
SCLC or other neuroendocrine tumors. We further examined the expression pattern
of RET and the genes encoding the components of its ligand complex GDNF and GFR
alpha-1, in 21 SCLC lines by using RT-PCR. Although we found no consistent
pattern of expression for these three genes, RET was expressed in 57% of SCLC
lines. Thus, although RET mutations appear unlikely to be an important step in
the tumorigenesis of SCLC, the frequent expression of this gene suggests that RET
may have a mitogenic role in a subset of SCLC cell lines.
PMID- 9559345
TI - Loss of 18q predicts poor survival of patients with squamous cell carcinoma of
the head and neck.
AB - Tumor suppressor genes play an important role in normal growth regulation. Loss
or inactivation of these genes has been implicated in the development of squamous
cell cancer and progression of neoplasia. Previous studies in our laboratories
have implicated chromosome 18 long-arm deletions as a possible marker of
progression in head and neck squamous cell cancer (HNSCC). To test this
hypothesis, we evaluated DNA from 67 HNSCC patients for loss of heterozygosity
(LOH) at 18q loci, and for association of LOH with survival. Tumor and normal DNA
were extracted from fresh tissue and paraffin blocks and were amplified by PCR
using primers for three microsatellite repeat polymorphisms in 18q (D18S336,
D18S34, and MBP). A total of 27 (40%) patients had LOH of 18q, and these patients
had a statistically significantly poorer two-year survival compared to those
without 18q LOH (30% vs. 63%; P = 0.008). In a Cox proportional hazards model in
which time from diagnosis to death was the outcome variable, patients with 18q
LOH had an unadjusted relative risk (RR) of death of 2.46 (P = 0.005). When 18q
LOH was placed in a multivariate model controlling for possible confounders in
the study, the RR for death was still elevated (RR = 2.10; P = 0.025). The
observation of a prognostic association between 18q LOH and poor patient survival
suggests that loss of an 18q tumor suppressor gene or genes is important in the
progression of HNSCC.
PMID- 9559346
TI - Investigation of genetic alterations associated with the grade of astrocytic
tumor by comparative genomic hybridization.
AB - Comparative genomic hybridization (CGH) is a technique that allows the detection
of losses and gains in DNA copy number across the entire genome. We used CGH to
study the genetic alterations that occur in primary astrocytomas, including 14
glioblastomas (GBM), 12 anaplastic astrocytomas (AA), and 7 low-grade
astrocytomas (LGA). The average numbers of total aberrations in GBM, AA, and LGA
were 9.7, 5.4, and 4.0, respectively. The average number of DNA sequence losses
in GBM was significantly higher than that in AA or LGA (P < 0.01). Frequently
altered regions (> eight cases) observed in all grades of astrocytoma were 7p13
p12 (gain), 7q31 (gain), 8q24.1-q24.2 (gain), 9p21 (loss), 10p12-p11 (loss),
10q22-qter (loss), 13q21-q22 (loss), and 20q13.1-q13.2 (gain). Loss of 9p, 10p,
or 10q, and the gain or amplification of 7p, were observed frequently in GBM
(64%, 57%, 64%, and 50% of cases, respectively). Frequent alterations found in AA
were losses of 9p, 10q, and 13q, and gains of 1q, chromosome 7, 11q, and Xq.
Whereas 7p13-p11 amplification occurred exclusively in cases with the loss of all
or part of chromosome 10, this change never occurred in cases having an increase
in copy number of 8q, which was the most frequent change observed in LGA (four of
seven cases). These results may indicate that an increase in copy number of 8q is
an important event in GBM, with a genetic pathway, which is distinct from that in
GBM with 7p amplification.
PMID- 9559347
TI - Novel WT1 mutation, 11p LOH, and t(7;12) (p22;q22) chromosomal translocation
identified in a Wilms' tumor case.
AB - About 5-10% of sporadic Wilms' tumors (WT) are associated with mutations in the
Wilms' tumor 1 gene (WT1). More than 90% of patients with Denys-Drash syndrome
(DDS; characterized by renal nephropathy, gonadal anomaly, and predisposition to
WT) show constitutional intragenic WT1 mutations. We describe a novel WT1 stop
mutation in exon 2. This heterozygous germline mutation was detected in a one
year-old girl who was bilaterally affected with Wilms' tumor but without any
other clinical manifestations of DDS. The C-to-A transversion is predicted to
result in a polypeptide comprising only the first 165 amino acids of the WT1
protein. Loss of heterozygosity (LOH) studies comparing tumor DNA with lymphocyte
DNA revealed LOH for the entire short arm of chromosome 11 in tumor tissue. In
addition to the chromosome 11 lesions, the tumor showed a seemingly balanced
chromosomal translocation t(7;12) (p22;q22) as the only visible cytogenetic
aberration.
PMID- 9559348
TI - Discontinuing antidepressant treatment in major depression.
AB - Maintenance treatments in bipolar disorders and schizophrenia are securely
established, and their discontinuation is associated with high but modifiable
risk of early relapse. The benefits of long-term antidepressant treatment in
major depression and the risks of discontinuing medication at various times after
clinical recovery from acute depression are not as well defined. Computerized
searching found 27 studies with data on depression risk over time including a
total of 3037 depressive patients treated for 5.78 (0-48) months and then
followed for 16.6 (5-66) months with antidepressants continued or discontinued.
Compared with patients whose antidepressants were discontinued, those with
continued treatment showed much lower relapse rates (1.85 vs. 6.24%/month),
longer time to 50% relapse (48.0 vs. 14.2 months), and lower 12-month relapse
risk (19.5 vs. 44.8%) (all p < 0.001). However, longer prior treatment did not
yield lower postdiscontinuation relapse risk, and differences in relapses off
versus on antidepressants fell markedly with longer follow-up. Contrary to
prediction, gradual discontinuation (dose-tapering or use of long-acting agents)
did not yield lower relapse rates. Relapse risk was not associated with
diagnostic criteria. More previous illness (particularly three or more prior
episodes or a chronic course) was strongly associated with higher relapse risk
after discontinuation of antidepressants but had no effect on response to
continued treatment; patients with infrequent prior illness showed only minor
relapse differences between drug and placebo treatment.
PMID- 9559349
TI - A glutamatergic model of ECT-induced memory dysfunction.
AB - Electroconvulsive therapy (ECT) is an efficacious treatment for a variety of
neuropsychiatric conditions including major depression, mania, catatonia,
Parkinson's disease, and neuroleptic malignant syndrome. However, ECT-induced
memory dysfunction complicates the treatment and is a major concern for both
patients and providers. We briefly review ECT-induced memory dysfunction and
propose a glutamatergic model for it. (Articles examined were retrieved by a
Medline search on the terms electroconvulsion and glutamate, with language
limited to English.) Specifically, we hypothesize that ECT-induced memory
dysfunction results from neuronal insults due to excessive release of excitatory
amino acids and activation of their receptors, which produce cation and water
flux and reversible oxidative stress. This model offers multiple testable
hypotheses; exploring them may help to identify the risk factors for this
significant side effect of ECT treatment and may thus yield effective agents for
its prevention and treatment.
PMID- 9559350
TI - Enactment and the treatment of abuse survivors.
AB - Regardless of the approach employed, treatment of patients with histories of
sexual or other abuse is a formidable challenge. One reason for this is the
vulnerability to "enactment" inherent in therapeutic work with such patients.
Enactment is a recently elaborated psychoanalytic notion, defined as a pattern of
nonverbal interactional behavior between the two parties in a therapeutic
situation, with unconscious meaning for both. It involves mutual projective
identification between therapist and patient. This paper clarifies the nature of
enactment (conceptualized here as involving either refusal or actualization of
the transference by the therapist) and its treatment implications. Transference
countertransference enactment paradigms encountered in work with survivors of
abuse are presented. The therapeutic consequences of failing to recognize and
respond to such enactments in work with these patients are explored. Unrecognized
enactments may lead therapists unwittingly to abdicate the therapeutic role by
becoming abusive, abused or vicariously traumatized, excessively guilty,
seductive, overinvolved, and/or exhortatory or to implant false memories. Ways of
utilizing enactment to advance treatment are also described and illustrated.
PMID- 9559352
TI - St. John's wort.
PMID- 9559351
TI - When the patient asks the doctor's help in ending life: a request for assisted
suicide by a man with AIDS.
PMID- 9559353
TI - Impulsive aggression: a behavior in search of clinical definition.
PMID- 9559354
TI - Gender and health policy.
PMID- 9559355
TI - Trends in the evaluation of managed mental health care.
PMID- 9559356
TI - Effect of gamma irradiation on unsporulated and sporulated Toxoplasma gondii
oocysts.
AB - The effect of 137Cs irradiation on unsporulated and sporulated Toxoplasma gondii
oocysts was investigated as a model system for sterilisation of fruit
contaminated with other coccidia such as Cyclospora or Cryptosporidium.
Unsporulated oocysts irradiated at > or = 0.4 to 0.8 kGy sporulated but were not
infective to mice. Sporulated oocysts irradiated at > or = 0.4 kGy were able to
excyst, and sporozoites were infective but not capable of inducing a viable
infection in mice. Toxoplasma gondii was detected in histologic sections of mice
up to 5 days but not at 7 days after feeding oocysts irradiated at 0.5 kGy.
Transmission electron microscopy revealed that sporozoites from irradiated
oocysts penetrated enterocytes and all cells in the lamina propria except for red
blood cells. Sporozoites appeared normal ultrastructurally and formed a typical
parasitophorous vacuole containing a well-developed tubulovesicular membrane
network. Raspberries inoculated with sporulated T. gondii oocysts were rendered
innocuous after irradiation at 0.4 kGy. Results indicate that irradiation at 0.5
kGy is effective in "killing" coccidian oocysts on fruits and vegetables.
PMID- 9559357
TI - Multiparasite communities in animals and humans: frequency, structure and
pathogenic significance.
AB - Individual humans and animals are subject to infection by a variety of parasites
(broadly defined to include viruses, bacteria and other non-protozoan
microparasites) at any one time. Multiple parasite infections occur frequently in
populations of wild animals as well as in humans from developing countries. In
some species and regions, hosts with multiple infections are more common than
hosts with either no infection or a single infection. Studies, predominantly on
animals, show that a wide variety of environmental and host-dependent factors can
influence the structure and dynamics of the communities of parasites that make up
these multiple infections. In addition, synergistic and competitive interactions
can occur between parasite species, which can influence the likelihood of their
successful transmission to other hosts and increase or decrease their overall
pathogenic impact. This review summarises aspects of our current knowledge on the
frequency of multiparasite infections, the factors which influence them, and
their pathogenic significance.
PMID- 9559358
TI - Caenorhabditis elegans as a model for parasitic nematodes.
AB - Caenorhabditis elegans has become a popular model system for genetic and
molecular research, since it is easy to maintain and has a very fast life-cycle.
Its genome is small and a virtually complete physical map in the form of cosmids
and YAC clones exists. Thus it was chosen as a model system by the Genome Project
for sequencing, and it is expected that by 1998 the complete sequence (100
million bp) will be available. The accumulated wealth of information about C.
elegans should be a boon for nematode parasitologists, as many aspects of gene
regulation and function can be studied in this simple model system. A large array
of techniques is available to study many aspects of C. elegans biology. In
combination with genome projects for parasitic nematodes, conserved genes can be
identified rapidly. We expect many new areas of fertile research that will lead
to new insights in helminth parasitology, which are based not only on the
information gained from C. elegans per se, but also from its use as a
heterologous system to study parasitic genes.
PMID- 9559359
TI - Levamisole binding sites in Haemonchus contortus.
AB - Larval and adult extracts from isolates of Haemonchus contortus were assayed for
specific [3H]levamisole binding activity. All of the tissue preparations
displayed [3H]levamisole binding sites. The sensitive isolate SE and resistant
isolate RJ showed no differences in larval and adult binding data. Larval SE
extracts had higher receptor density (Bmax = 648 fmol mg-1) and dissociation
constant (Kd = 1.28 microM) for [3H]levamisole than larval extracts of the
American isolate RUSA (Bmax = 87 fmol mg-1 and Kd = 0.15 microM). Extracts of
adult SE and RUSA isolates contain as much as 327 fmol mg-1 of protein and 205
fmol mg-1 of protein, respectively, and similar dissociation constants (Kd = 0.77
microM and Kd = 0.81 microM, respectively). There was a good correlation between
specific binding activity of larval and adult extracts in both SE and RUSA
isolates. The nicotinic cholinergic antagonist alpha-bungarotoxin had no effects
in either isolate on [3H]levamisole binding activity. The results confirm that
levamisole acts at a cholinergic receptor in H. contortus, and suggest that
target site modification could be involved in the development of levamisole
resistance.
PMID- 9559360
TI - Pruritus and dermal response to insect antigens in sheep infested with Bovicola
ovis.
AB - This study examined the relationships among louse density, pruritus and dermal
response to insect antigens in sheep infested with Bovicola ovis. Polypay and
Columbia ewes were allocated to two groups, infested and naive, and louse
densities and pruritus were monitored for 15 months. Ten months after the initial
infestation, all sheep were tested for hypersensitivity on the midside and ears
by intradermal injection of soluble extracts of B. ovis, Stomoxys calcitrans and
Musca autumnalis. The areas of skin reactions were measured at 20 min, 1, 3 and
24 h after injection and skin thickness was measured at 24 h. Louse densities on
Polypays were approximately 10 times greater than on Columbias, and pruritus was
correlated with louse numbers at most inspections. Most pruritic behaviour was
directed to the sides of infested sheep. Wheal and flare reactions developed
rapidly to all extracts in both infested and naive ewes. Reactions to louse
extract were larger in infested than naive sheep at all four times after
injection. In the infested Polypays, reactions to louse extract were greater than
to the fly extracts, but in naive sheep there was little difference among
extracts. Reactions in naive Columbias were larger than in naive Polypays at 20
min, 1 and 3 h, but had almost completely abated in both groups at 24 h.
Reactions in infested Columbias were greater than in infested Polypays at 20 min,
but at 24 h reactions in the Polypays were larger. Louse numbers and pruritus
were correlated with wheal areas and skin thickness at 24 h, but there was little
relationship with the size of reactions at earlier times. These findings are
consistent with the development of a hypersensitive response to B. ovis and
suggest that dermal reactions to lice may influence sheep susceptibility.
PMID- 9559361
TI - Identification and characterisation of a dense granule-associated protein in
Neospora caninum tachyzoites.
AB - Neospora caninum is an apicomplexan parasite which is morphologically and
ultrastructurally very similar to Toxoplasma gondii. In order to identify
molecules involved in host cell entry and subsequent modification of the
parasitophorous vacuole, a polyclonal antiserum directed against N. caninum
tachyzoites was raised in a rabbit. Subcellular fractionation of tachyzoites was
performed using the non-ionic detergent Triton-X-114. Membrane fractions were
analysed by immunoblotting using the polyclonal antiserum. One of the
immunoreactive protein bands had a mol. wt of 33,000 and was subsequently named
Nc-p33. Affinity-purified anti-Nc-p33 antibodies were used to characterise this
polypeptide using SDS-PAGE, isoelectric focusing, Western blot analysis and
immuno-EM. Nc-p33 was found in two isolates of N. caninum (NC-1 and Liverpool),
but could not be detected in T. gondii tachyzoites. Immunogold EM revealed that
Nc-p33 constituted a dense granule-associated protein, and Western blotting
demonstrated that Nc-p33 was most likely identical to the recently described
antigen NCDG1. Shortly after invasion, this dense granule protein was targeted to
the parasitophorous vacuole membrane, and, at later timepoints after infection,
was also found on the parasitophorous vacuolar network. This suggested that Nc
p33 could play a functional role in the modification of the parasitophorous
vacuole and its membrane.
PMID- 9559362
TI - Inhibition of growth of Lucilia cuprina larvae using serum from sheep vaccinated
with first-instar larval antigens.
AB - Whole first-instar Lucilia cuprina larvae were homogenised and sequentially
extracted with a series of buffers of progressively more severe solubilising
power. The final extract, using a buffer containing 6 M-urea, was fractionated by
preparative isoelectric focussing. At each step in this process, protein
fractions were tested in sheep vaccination trials for their ability to induce
immune responses affecting the growth of L. cuprina larvae which fed on the sera
from vaccinated sheep. One isoelectric focussing fraction (pH 5.9-6.7) containing
a number of larval proteins induced an immune response which inhibited the growth
of larvae by a mean of 84 +/- 7% in an in vitro feeding bioassay. The recovery of
larvae after feeding on sera from sheep vaccinated with this fraction was
significantly reduced by 35 +/- 13%. This antilarval effect was shown to be
mediated by ingested ovine antibodies. Immunofluorescence and immunogold
localisations showed that the immune response was directed at proteins from the
larval peritrophic membrane, larval cuticle and, to lesser extent, basement
membranes and microvilli of digestive epithelial cells. Electron microscopic
examination of larvae feeding on sera from sheep vaccinated with this fraction
showed that the normally semi-permeable peritrophic membrane was blocked on the
luminal side by an electron-lucent layer of undefined composition. It is
postulated that this layer prevents nutrients from moving from the gut to the
underlying digestive epithelial cells, thereby starving the larvae. The sera from
sheep vaccinated with another isoelectric focussing fraction (pH 3.4-5.5) reduced
the mean larval weight by 56 +/- 13% without significant effects on larval
survival.
PMID- 9559363
TI - The effects of excretions/secretions of Ostertagia circumcincta on ovine abomasal
tissues in vitro.
AB - Products excreted/secreted by Ostertagia circumcincta stimulated the in vitro
release of pepsinogen from intact abomasal mucosal sheets and caused the
contraction of strips of abomasal smooth muscle, also in vitro. However,
responses occurred only when tissues had been derived from animals that were
assumed to have experienced prior exposure to the parasite. The overall median
responses for pepsinogen secretion in response to ES, expressed as the ratio of
stimulated secretion to basal secretion, were 1.8 for previously exposed animals
and 0.9 for parasite-naive animals. For the smooth muscle from the previously
exposed animals, the overall median response to ES, expressed as a percentage of
the maximal response to carbachol in the same tissues, was 27.0. No responses
were seen in muscle from any parasite-naive animal. These results suggest that
the responses obtained were hypersensitivity reactions to antigens released by
the worms during in vitro culture, and occurring in tissues from animals
sensitised by exposure to O. circumcincta in the natural environment.
PMID- 9559364
TI - Latitudinal differences in species and community richness and in community
structure of metazoan endo- and ectoparasites of marine teleost fish.
AB - Relative species diversity of gastrointestinal helminths of 55 teleost fish
species did not differ significantly at different latitudes, whereas relative
species diversity of metazoan ectoparasites on the heads and gills of 108 teleost
fish species showed a significant increase with decreasing latitude and from deep
to surface waters. Abundance of endoparasites also was the same at all latitudes,
whereas abundance of ectoparasites increased with decreasing latitude and from
deep to shallow waters. A comparative analysis using phylogenetically independent
contrasts supported these conclusions. Possible reasons for the differences
between endo- and ectoparasites are discussed. A detailed analysis of the
community structure of gastrointestinal helminths of five Antarctic and three
tropical teleosts and of metazoan ectoparasites on the heads and gills of five
Antarctic and seven tropical fish species showed the following: abundance and
prevalence of infection of endoparasites are similar in Antarctic and tropical
fish, but are much greater for tropical than for Antarctic ectoparasites.
Relative species diversity of endoparasites is similar for Antarctic and tropical
endoparasites, but much greater for tropical than Antarctic ectoparasites. In
both Antarctic and tropical fish, different fish of the same species may have
different dominant species of endo- and ectoparasites, although there is a
greater range of dominant species of tropical ectoparasites, a consequence of the
greater species pool available. The most dominant parasite (irrespective of
species) represented 80-99% of all endoparasites of Antarctic, and about 50-80%
of all endoparasites of tropical fish. The most dominant parasites (irrespective
of species) represented about 90-100% of all ectoparasites of Antarctic, and
about 20-70% of all ectoparasites of tropical fish, the difference a consequence
of the greater species pool of tropical ectoparasites available. The data suggest
that both endo- and ectoparasites live in assemblages not structured by
interspecific competition.
PMID- 9559365
TI - The development and persistence of phanerozoites in experimental infections of
Plasmodium sasai.
AB - Phanerozoites of Plasmodium sasai parasitised virtually all tissues of Takydromus
tachydromoides infected by inoculation of blood, and persisted until each lizard
died, 2-296 days postinoculation. At 4 days postinoculation, phanerozoites were
larger than at 2 and 6 days; many were observed rupturing, suggesing a maturation
time of approximately 4 days. The proliferation of phanerozoites decreased after
2 months postinoculation, but small phanerozoites were still present at 296 days.
A few encysted phanerozoites (chronozoites) appeared at 2 days postinoculation,
but from 75 days comprised over half of parasites present in most tissues. Some
differences in mean size and shape were evident among various organs.
Phanerozoites occurred in connective tissue and endothelium in all organs, but
were most plentiful in the heart in every infection, often occurring in clusters
of > 30 schizonts, with up to 105 found in single sections at 4 days.
Phanerozoites did not parasitise reticular cells of the spleen and bone marrow,
in contrast to Plasmodium mexicanum as described in unnatural host species.
Little difference was seen between two strains of P. sasai in its natural host T.
tachydromoides and a strain isolated from Takydromus smaragdinus.
PMID- 9559366
TI - Analysis of infraspecific variation among five strains of Eimeria maxima from
North America.
AB - Two laboratory strains from the eastern shore of Maryland 15 years ago and from
an Ontario broiler house 23 years ago and three recent field strains of Eimeria
maxima (isolated in Maryland, North Carolina and Florida) were examined for
phenotypic and genotypic variation using protein profiles, random amplified
polymorphic DNA-PCR analysis and DNA sequences obtained from the internal
transcribed spacer regions of the rRNA genes. Staining profiles obtained by one
dimensional SDS-PAGE of sporozoite proteins were identical in all five strains.
Using random amplified polymorphic DNA-PCR analysis with high %G-C content
decamers as primers, we were able to confirm that the five strains are all E.
maxima, but were unable to discern any relationships among them because of the
limited number of shared polymorphisms identified. In contrast, cloning and
sequencing of the internal transcribed spacer-1, 5.8S rDNA and internal
transcribed spacer-2 regions of the rRNA genes provided sufficient sequence
information to infer phylogenetic relationships among the strains. Almost all of
the infraspecific variation was located in the internal transcribed spacer
regions. Only two base changes were identified within the 5.8S rRNA gene.
Evolutionary relationships among the strains inferred using parsimony analysis of
the aligned internal transcribed spacer sequences were well supported, but the
hypothesised relationships did not correlate well with the demonstrated
immunological cross-reactivities of these strains.
PMID- 9559367
TI - Mitochondrial ND1 gene sequences used to identify echinostome isolates from
Australia and New Zealand.
AB - Echinostomes were collected in Australia and New Zealand as cercariae,
metacercariae or adults. Using DNA sequences from the mitochondrial ND1 gene
Echinostoma revolutum and Echinostoma paraensei were discovered in Australia. The
presence of a further five, as yet unidentified, echinostome species was inferred
in Northern Australia and a further isolate, closely allied to E. revolutum,
occurs in New Zealand. ND1 sequences of species within the genus diverge from
each other by 9.6-30.8%. Sequence divergence levels among strains within a single
species are 0-3.6%. The phylogenetic tree produced from the Australasian
isolates, in addition to species described previously, identifies the 37-collar
spine species as a well supported monophyletic group. The five unidentified
Australian species cluster away from the 37-collar-spine group. These
unidentified species appear to divide further into > 37-collar-spine and < 37
collar-spine clusters. Three strains of E. revolutum, collected as metacercariae
from snails, were identified from two ponds located 6 km apart. Two of these
strains may be cycling through a planorbid snail, Glyptophysa sp., as first
intermediate host; however, this hypothesis could not be confirmed as specimens
could not be obtained to match sequences between larvae and adults.
PMID- 9559368
TI - Inheritance of levamisole and benzimidazole resistance in an isolate of
Haemonchus contortus.
AB - Reciprocal crosses between an isolate of Haemonchus contortus resistant to both
benzimidazole and levamisole anthelmintics and a susceptible isolate were
performed in order to determine the mode of inheritance of these resistances. F1
and F2 generations and parent isolates were assayed for susceptibility to
thiabendazole and levamisole in vitro. For each drug all of the filial
generations were intermediate in susceptibility between the parent isolates, and
analysis indicated that resistance was inherited as an incompletely recessive
character determined by more than one gene in each case. There was no evidence of
maternal inheritance. Results of both the in vitro assays and in vitro selection,
followed by determination of sex ratio in the survivors, as well as studies on
adult worms, provided no evidence for sex-linkage. This work illustrates that in
vitro assays coupled with minimal studies in sheep are useful for determining
inheritance of resistance, yet use fewer experimental animals than traditional
studies.
PMID- 9559369
TI - Chemo-orientation of echinostome cercariae towards their snail hosts: amino acids
signal a low host-specificity.
AB - The cercariae of Pseudechinoparyphium echinatum and Echinostoma revolutum
approach their intermediate host snails by turning back when swimming in
decreasing concentration gradients of snail conditioned water. Host stimuli are
small molecular amino compounds, probably amino acids. This response was
inhibited reversibly when the cercariae were treated with 0.45 microM-silver
nitrate. As silver nitrate binds to the ciliated papillae of the cercarial
surface, papillar chemoreceptors may be involved. Snail conditioned water from
different snail species stimulated different intensities of chemo-orientation in
both species of digeneans. However, when the samples of water conditioned with
different snail species or even fish, tadpoles and leeches were diluted to the
same total amino acid concentrations, the intensities of cercarial responses were
similar. Therefore, some specificity of the chemo-orientation seemed to be
achieved only by the total concentration of amino acids and not by particular
mixtures of amino acids. In fact, amino acid spectra released by freshwater
snails varied not only among different snail species, but also within the same
species.
PMID- 9559370
TI - Chemo-orientation of echinostome cercariae towards their snail hosts: the
stimulating structure of amino acids and other attractants.
AB - The cercariae of Pseudechinoparyphium echinatum and Echinostoma revolutum locate
their host snails by turning back when swimming in decreasing gradients of the
small molecular weight fraction (< 500) of snail conditioned water. Fractionation
and chemical modifications of snail conditioned water from Lymnaea stagnalis
showed that amino acids are necessary for the stimulating activity of snail
conditioned water. A complete mixture of amino acids in concentrations determined
from snail conditioned water had a high attraction. However, differently composed
mixtures of amino acids and even single amino acids also had the same attraction
as this complete mixture when used in concentrations corresponding to the total
concentration of amino acids in snail conditioned water. Experiments with
analogues and derivatives of amino acids showed that the primary alpha-amino
group and the alpha-carboxyl group are necessary for the full effectiveness of
amino acids. The highest effect was elicited by L-amino acids with a primary
alpha-amino group, whereas the amino acid type and the chain length seemed to be
unimportant. However, the full attraction of snail conditioned water was not
achieved by amino acids alone. Chemical modifications of snail conditioned water
suggested that the additional stimuli were neither inorganic ions nor organic
acids or lipids. As the full attraction of snail conditioned water was obtained
when the amino acid mixture of snail conditioned water was combined with its
content of urea and ammonia, we conclude that the cercariae use only these
excretory products as additional signals for their chemo-orientation. Chemo
orientation to amino acids, urea and ammonia seems to reflect a strategy to
locate a broad spectrum of aquatic hosts.
PMID- 9559371
TI - Seroprevalence of antibodies to Neospora caninum and Toxoplasma gondii in water
buffaloes (Bubalus bubalis) from Egypt.
AB - Sera from 75 water buffaloes from Egypt were examined using a direct
agglutination test incorporating mercaptoethanol for antibodies to Neospora
caninum and Toxoplasma gondii. Antibodies to N. caninum were found in 51 (68%) of
75 buffaloes in titres of 1:20 (six buffaloes), 1:40 (15 buffaloes), 1:160 (one
buffalo), 1:320 (one buffalo) and > or = 1:640 (28 buffaloes), using N. caninum
formalin-preserved whole tachyzoites as antigen. Antibodies to T. gondii were not
found in a 1:100 dilution of serum of any of the 75 buffaloes, using T. gondii as
antigen, indicating specificity in the detection of antibodies to N. caninum.
This is the first report of N. caninum prevalence in water buffaloes, which are
economically very important domestic animals in developing countries.
PMID- 9559372
TI - An evolutionary definition of parasitism.
PMID- 9559373
TI - Comparison of vessel diameters in electron beam tomography and quantitative
coronary angiography.
AB - Electron beam tomography (EBT) has been shown to permit non-invasive imaging of
the coronary arteries after intravenous injection of contrast agent and 3
dimensional reconstruction. We compared the vessel diameters in EBT
reconstructions to quantitative coronary angiography (QCA). 10 patients were
investigated by EBT and QCA. 3-dimensional EBT reconstructions (shaded surface
display) were performed after acquisition of 40 axial cross-sections of the heart
with 3 mm slice thickness (1 mm overlap) which were obtained triggered to the ECG
in breathhold following intravenous injection of 120-160 ml of contrast agent. A
fixed lower reconstruction threshold of 80 HU was used to selectively visualize
the contrast-enhanced coronary artery lumen. At 60 sites in the coronary artery
system, the vessel diameters measured in the EBT reconstructions were compared to
the diameters found in quantitative analysis of the patients' coronary
angiograms. The correlation coefficient of the vessel diameters in EBT and QCA
was 0.83. Mean vessel diameters were not significantly different in EBT and QCA
(3.06 +/- 0.93 vs. 2.97 +/- 0.94 mm). However, very small vessel diameters tended
to be underestimated in the EBT reconstructions, which was due to the partial
volume effect. It only vessel diameters measured in the left main or left
anterior descending coronary artery were compared to QCA, the correlation
increased to 0.87, since these vessel segments are less prone to artifacts in the
EBT investigation. Vessel diameters in EBT and QCA correlated reasonably well.
Due to partial volume effects, the diameter of very small vessels and stenotic
segments tends to be underestimated by EBT.
PMID- 9559374
TI - Smoking correlates with flow-mediated brachial artery vasoactivity but not cold
pressor vasoactivity in men with coronary artery disease.
AB - Impaired endothelial function is observed as altered vasomotion in both the
peripheral and coronary circulation in the presence of cardiovascular risk
factors and early atherogenesis. An improvement in endothelium-dependent
vasoactivity has been reported with both cholesterol reduction and smoking
cessation. This study was performed to determine whether smoking status in
coronary artery disease (CAD) effects both flow-mediated and cold pressor
vasoactivity. We studied 25 men (ages 30-59), 12 smokers and 13 nonsmokers with
angiographically documented coronary artery disease and cardiac risk factors who
were grouped as smokers and nonsmokers. Using 7.5 MHz ultrasound, we measured
brachial artery diameter and Doppler flow velocity at baseline, following 5 mins
of ipsilateral blood pressure cuff occlusion and release (flow-mediated), during
contralateral ice water hand immersion (cold pressor test) and after sublinqual
nitroglycerin administration (an endothelium-independent vasodilator). Flow
mediated percent diameter change was significantly less in the smokers than
nonsmokers (1.9 +/- 5.7% vs 11.4 +/- 7.2%, p < 0.001). Both smokers and
nonsmokers responded similarly to the cold pressor test (-3.9 +/- 2.3 vs -1.2 +/-
0.2%) and nitroglycerin (15.1 +/- 7.6 vs 17.5 +/- 8.3%). Cholesterol level did
not appear to be an independent determinant of flow-mediated vasoactivity when
smoking status was taken into account. Flow-mediated vasoactivity is associated
with smoking status in the presence of coronary artery disease but cold pressor
induced vasoactivity is not.
PMID- 9559375
TI - An analogue laser optical disc in comparison with cinefilm for visual analysis of
coronary narrowings before and after coronary angioplasty.
AB - This study evaluated an analogue laser optical disc (MVP) as an alternative for
cinefilm angiography in the visual analysis of coronary angiograms. Visual
analysis was performed independently by 5 observers using cinefilm and MVP before
and after PTCA (194 coronary lesions in 88 patients) and the outcomes were
compared with QCA. The mean percentage diameter stenosis on cinefilm and MVP
yielded similar results compared to QCA. Regression analysis showed a good
correlation between the mean cinefilm and MVP values per diameter stenosis (p <
0.001). Bland-Altman plots confirmed these findings. Qualitative analysis for
detection of coronary dissections after PTCA showed an incidence of 31.3%
(cinefilm) and 21.8% (MVP) (p < 0.05). The results of this study indicate that
the visual analysis of the coronary angiograms using the analogue laser optical
disc (MVP) yields similar results compared to the cinefilm concerning coronary
lesion severity, although there is an underestimation of coronary dissections.
PMID- 9559376
TI - Normal left ventricular volumes and ejection fraction: assessment with
quantitative digital cardioangiography.
AB - The aim of this study was to assess the accuracy and precision of a digital
angiography system, the General Electric DX system, as compared to conventional
left ventricular cineangiography. After a phantom study, sixty patients with
normal coronary arteries and normal left ventricles (LV) were studied. The LV
contours were manually traced from raw or subtracted digital runs and from the
cine films in an independent manner. A regression formula was used to adjust the
DX derived data to the cine film results (Vcorrected = 0.693 Vmeasured +8.65 ml).
There was an excellent correlation between the two methods in the end-diastolic
volume index (r = 0.97, sd = 4.2 ml/m2), the end-systolic volume index (r = 0.95,
sd = 2.7 ml/m2), the stroke volume index (r = 0.93, sd = 4.1 ml/m2), and the
ejection fraction (r = 0.85, sd = 3.45%). We conclude that manual tracing of LV
contours from either raw or subtracted digital images provides reliable and
accurate measurement of LV volume and ejection fraction.
PMID- 9559377
TI - Contribution of long axis motion of left ventricular outflow to calculation of
left ventricular stroke volume.
AB - Stroke volume can be calculated by using noninvasive Doppler techniques. The
products of pulsed Doppler stroke distance of left ventricular outflow and left
ventricular outflow area can often be used to calculate stroke volume. However,
left ventricular outflow also moves longitudinally toward the apex of the
ventricle during systole, so that zero velocity flow cannot be detected by the
usual pulsed Doppler studies. We evaluated the contribution of these zero
velocity flow to the noninvasive estimation of left ventricular stroke volume in
20 patients with left ventricular disease and in 20 age matched healthy controls.
Left ventricular stroke distance was calculated by summing the Doppler stroke
distance and the outflow long axis motion. The percentage of zero velocity flow
for total stroke volume was calculated in each group. Cardiac output was also
measured by thermo-dilution technique. The percentage of zero velocity flow for
total noninvasive stroke volume in patients with left ventricular disease was 2.5
+/- 1.1 ml (4.0 +/- 1.5%), significantly lower than in normal subjects, 3.6 +/-
1.0 ml (5.5 +/- 1.5%) (p < 0.05). These long axis motions are significantly
reduced, especially in left ventricular disease. Amplitudes of the left
ventricular outflow long axis motion were correlated with Doppler stroke distance
in all (r = 0.54, p < 0.01). In patients with myocardial infarction, stroke
volume by thermo-dilution methods and calculated stroke volume showed good
correlation both only by Doppler stroke distance (y = 1.044x + 0.547, r = 0.968)
and by Doppler and long axis motion (y = 0.989x + 0.521, r = 0.974). Compared
with stroke volume measured by thermodilution method, stroke volume calculated
only by Doppler stroke distance was underestimated. We thus demonstrated the
influence of zero velocity flow on left ventricular outflow both in patients with
left ventricular disease and in normal subjects.
PMID- 9559378
TI - Left atrial function in congestive heart failure: assessment by transmitral and
pulmonary vein Doppler.
AB - The relation of transmitral flow patterns and pulmonary venous velocities was
analyzed from 50 heart failure patients (28 men, 22 women; mean [+/- SD] age 61
+/- 9 years) with a left ventricular ejection fraction < 40%. Doppler
echocardiography was performed in all patients. Transmitral flow measurements
included early (E) and atrial (A) velocities and deceleration time of E wave
(DT). Patients were assigned to two groups according to E/A ratio, DT, or both:
20 patients in the restrictive group, and 30 patients in the nonrestrictive
group. Pulmonary venous flow was obtained by the transthoracic approach. Systolic
(S), diastolic (D) and atrial reversal (Ar) velocities were measured. Of the
study population, 13 patients had simultaneously determined pulmonary capillary
wedge pressure (PCWP). The results showed a lower S (28 +/- 11 vs. 51 +/- 10
cm/sec, p < 0.01), a higher D (66 +/- 13 vs. 44 +/- 10 cm/sec, p < 0.01) and a
smaller Ar (12 +/- 10 vs. 24 +/- 9 cm/sec, p < 0.01) in the restrictive group
compared with those in nonrestrictive group. In the subgroup of patients
undergoing invasive hemodynamic studies, there was no relationship between PCWP
and atrial reversal velocity. However, a significant correlation was observed for
pulmonary systolic (r = -0.70, p < 0.01) and diastolic (r = 0.76, p < 0.01)
velocities to PCWP. These findings suggest a reduction in left atrial compliance
and atrial systolic function and both play important roles in heart failure
patients with the restrictive transmitral flow pattern.
PMID- 9559379
TI - Left ventricular volumes assessed by different new three-dimensional
echocardiographic methods and ordinary biplane technique.
AB - Three-dimensional (3D) echocardiography may overcome the problems with inadequate
accuracy and reproducibility of 2D volume measurements of the left ventricle.
AIMS: To establish the in vitro accuracy and reproducibility of two new methods
for 3D echocardiographic volume determination as compared to biplane
measurements. METHODS: Validation of volume measurements by a multiplane 3D
method was performed on asymmetric latex phantoms (n = 8, true volumes 45-304 ml)
using rotational acquisition of 90 image planes. Porcine agarose-filled
asymmetrical left ventricles (n = 7, true volumes 34-280 ml) were measured by the
same multiplane 3D method based on images acquired by probe rotation axis
perpendicular (A) and parallel (B) to the ventricular long axis. Ventricular
volumes were also obtained by a simplified 3D system using only the three
standard apical views (C) and by the ordinary biplane Simpson's method (D).
RESULTS: On latex phantoms systematic deviation from true volumes by multiplane
3D was less than 2%, and 95% variability of individual measurements from this
mean was +/- 4.9%. For accuracy on left ventricles, systematic bias was small
with all the methods (< 5%), but 95% variability of individual measurements was
+/- 9.0%, 15.4%, 18.8% and 41.3% of true volumes for methods A-D respectively.
Corresponding results in the same range were obtained for inter- and
intraobserver variability. CONCLUSION: Individual in vitro volume estimates of
left ventricles are of similar quality using apical multiplane or apical triplane
3D echocardiography. Both methods were superior to the ordinary apical biplane
method, but inferior to multiplane 3D method with the probe directed
perpendicular to the ventricular long axis.
PMID- 9559380
TI - In vitro examination of the coronary artery wall after balloon angioplasty using
intracoronary ultrasound.
AB - After autopsy 12 human coronary arteries were investigated by intracoronary
ultrasound in order to measure the vessel wall dimensions and to detect damage on
the vessel wall architecture after balloon angioplasty. Histology revealed
artherosclerosis in 11/12 arteries. A total of 41 representative coronary
segments were selected for further off-line ultrasound and histological analysis.
Intracoronary ultrasound and histological measurements of the vessel wall
thickness after balloon dilatation demonstrated a good correlation between the
maximum thickness of the intima (histology 0.62 mm vs. intracoronary ultrasound
0.65 mm, r = 0.87) and the intima-media complex (0.80 mm vs. 0.83 mm, r = 0.87),
in contrast to a weak one between the minimum thickness (r = 0.46 and r = 0.37).
A total of 21 cases of damage occurred during angioplasty; intracoronary
ultrasound detected 17. Further analysis showed that it imaged 10 of 11 cases of
damage involving more than 30 degrees of the vessel circumference and 7 of 10
cases of damage involving less than 30 degrees of the vessel circumference. After
balloon angioplasty of diseased coronary arteries, intracoronary ultrasound is
therefore reliable in measuring the maximum wall thickness and in imaging damage
involving more than 30 degrees of the vessel wall circumference.
PMID- 9559381
TI - Differences in pain assessment and decisions regarding the administration of
analgesics between novices, intermediates and experts in pediatric nursing.
AB - This article describes a study examining the influence of expertise on nurses'
pain assessments and decisions regarding pharmacological interventions in
children. In an experimental design, novices (n = 271), intermediates (n = 222),
and experts (n = 202) in pediatric nursing, various cases were presented. Each
case consisted of a combination of a vignette and a video. Subjects were asked
(1) to assess the child's pain intensity, (2) to specify their confidence in the
assessment, and (3) to state whether or not they would administer a non-narcotic
analgesic. The results indicated that expertise did not influence assessments of
pain intensity. However, expertise did have a distinct impact on both the
subjects' confidence in their decisions, and the decision to administer
analgesics. Experienced nurses were most confident and were most inclined to
administer analgesics. The findings of this study are placed in the context of a
general theory on the development of expertise, which assumes that experts'
decision-making is based on cognitive structures that describe features of
prototypical or even actual patients, so called "illness scripts". From this
theory it can be deduced that mainly practical experience is responsible for the
(lack of) differences in decision-making between novices, intermediates and
experts.
PMID- 9559382
TI - Student nurses perceptions of their interpersonal skills: a re-examination of
Burnard and Morrison's findings.
AB - Heron's six category intervention analysis is a component of many counselling
courses and is used extensively by teachers of interpersonal skills within
nursing curricula. The popularity of this framework has generated a number of
studies which have attempted to offer empirical support for the theory. The aim
of this study was to re-evaluate some of these findings. Utilising an earlier
research instrument, a set of findings are offered and comparisons made with
previous work. Our findings suggest that student nurses perceive themselves to be
most skilled in the use of supportive, prescriptive and cathartic interventions
and least skilled in the use of informative, catalytic and confronting
interventions. A discussion of the new findings and their implications is
offered.
PMID- 9559383
TI - Humor in nursing practice: a phenomenological study.
AB - Humor is an important but underutilized resource in nurse-patient interaction.
The multidimensional value of humor in providing nursing care has recently begun
to receive attention. The purpose of this phenomenological study was to describe
the meaning of nurses' use of humor in their nursing practice. Twenty-one
registered nurses enrolled in a graduate nursing program described in detail an
experience they had using humor in providing nursing care. The 21 written
descriptions were analyzed using Colaizzi's phenomenological method. Five themes
emerged in which humor was found to (a) help nurses deal effectively with
difficult situations and difficult patients, (b) create a sense of cohesiveness
between nurses and their patients and also among the nurses themselves, (c) be an
effective therapeutic communication technique that helped to decrease patients'
anxiety, depression, and embarrassment, (d) be planned and routine or be
unexpected and spontaneous, and (e) create lasting effects beyond the immediate
moment for both nurses and patients.
PMID- 9559384
TI - Quality of STD care in an urban Zambian setting: the providers' perspective.
AB - The aim of this paper is to analyse obstacles to optimal STD care in an urban
setting in Zambia. Eight-two health professionals answered a questionnaire with
closed and open-ended questions. More than 50% were not satisfied with their
working conditions, due to heavy workload, lack of equipment/drugs, poor salary,
and lack of continuing education. Negative opinions about STD patients were
common. Treatment and preventive activities were considered important but most
respondents found patient compliance poor--especially for partner notification.
To improve the quality of STD care, training in STD management should be combined
with improved working conditions.
PMID- 9559385
TI - Coping strategies of enrolled nurses in nursing homes: shifting between
organizational imperatives and residents' needs.
AB - In today's nursing homes, which can be considered modern versions of "total
institutions", enrolled nurses expend much energy coping with problems which
arise from the day-to-day care of seriously impaired patients. The problems they
encounter include the burden of never ending work, having to cope with deviant
and problematic behaviour, handling emotional disturbance and, on a more abstract
level, balancing self-interest and power with love and affection. The grounded
theory approach was used to discover the coping strategies employed by enrolled
nurses. On the criterium of favouring either organizational imperatives or
residents' needs, six strategies were differentiated, and placed into one of two
categories. The discovery during research of two distinct nursing teams, each
inclining towards the strategies available within one of these two categories,
not only has important theoretical implications, but also practical consequences
for the training of student nurses, the labour market and the quality of care.
PMID- 9559386
TI - Pharmacist and nurse: a team approach towards primary health care or a convenient
"therapeutic alliance"?
AB - This paper explores the nature of the therapeutic alliance between nurses and
community pharmacists in the South African context. To gain a better insight into
the relatively new phenomenon, a combination of qualitative and quantitative
methods was employed. The partnership developed in S.A. between the nurse and the
pharmacist allows the pharmacists to "expand" their professional activities
without "invading" the nurses' professional domain, and reaping substantial
benefits in the process. These include potential increases in profits, enlarging
the clientele base and improving the image of the pharmacy, by shifting the focus
from a place of disease to a place of health, as well as creating the vision of
the pharmacist as a team member in providing primary health care. As far as the
nurses are concerned, it grants them the possibility to practice their profession
in a very convenient set-up and affords them greater professional autonomy.
PMID- 9559387
TI - Testing a model of absence and intent to stay in employment: a study of
registered nurses in Malta.
AB - This study used a cross-sectional, correlational design to test a model of
absence and turnover of registered nurses developed from a review of the research
literature (Gauci Borda and Norman, 1997). Testing the model involved comparing
the relationship between job satisfaction, kinship responsibility, pay,
employment opportunity, intent to stay in employment and absence for male and
female registered nurses. All registered nurses (n = 254) working in clinical
areas on a full-time shift basis, in one large general hospital in Malta were
surveyed by questionnaire and their absence data were obtained from the hospital
personnel records. A response rate of 67% (n = 171) was achieved. The results
showed that nurses were satisfied with their job and intended to stay in their
present employment for the next 12 months. Relationships between variables
differed between male and female nurses, with job satisfaction being associated
with intent to stay for male nurses but not for females and kinship
responsibility and intent to stay being associated with absence in female but not
male nurses. In contrast to many previous studies of nurses, an association was
found between job satisfaction and absence. Several variables, including fear of
change, which may influence intent to stay of Maltese nurses, were identified.
The proposed model of absence and turnover stood up reasonably well to testing,
but the results for the whole sample, and the sub-samples of male and female
nurses supported different parts of the model. The main implication for future
research is that male and female nurses should be studied separately due to
differences found between the two groups.
PMID- 9559388
TI - Factors influencing turnover and absence of nurses: a research review.
AB - This review of the nursing literature aims to identify the factors with the
greatest influence on turnover and absence of qualified nurses, possible common
factors influencing both, and the relationship between absence and turnover. A
hypothetical model grounded in the literature which depicts the expected
relationships between these variables is presented for testing in an empirical
study. The review identifies intent to stay in current employment as the variable
with the greatest influence on turnover. Intent to stay is in turn most strongly
associated with job satisfaction. Other variables are identified by single
studies as having an influence on intent to stay, but are not supported by the
results of other studies; exceptions are pay, opportunity for alternative
employment and kinship responsibility, which are supported by the results of two
studies. The relationship between job satisfaction and absence is unclear and
requires further investigation. However, job satisfaction is identified as
possibly influencing both absence and intent to stay and kinship responsibility
is identified as a common antecedent of absence and intent to stay. Similarly,
absence is identified as an antecedent to turnover. Thus, it is expected that
absence would be positively related to turnover and negatively related to intent
to stay. Understanding such relationships should allow identification of
management strategies to reduce both turnover and absence.
PMID- 9559389
TI - Fishing for understanding: nurses knowledge and attitudes in relation to
nutritional care.
AB - Many studies have demonstrated that malnutrition is a significant problem amongst
hospital patients, but little is known about what nurses actually do, and what
factors influence this. This study aimed to explore the nutritional attitudes,
knowledge base and nursing care of qualified nurses in an acute hospital. A
survey of nurses' records for documented nutrition related activities was carried
out for all (141) patients from five wards for two weeks, followed by a
questionnaire, focused on nutrition-related attitudes, activities and knowledge,
to all qualified nurses of these and a further four wards (110 nurses). Results
revealed evidence of some knowledgeable and pro-active attitudes and nursing
care; however, there was little association between knowledge, stated attitudes
and behaviour and discrepancies were observed between questionnaire responses and
documented activities. Ajzen and Fishbein's (1980) theory relating beliefs,
attitudes, intentions and behaviour was not supported although this might be
attributed, in part at least, to nurses not regarding weighing patients as
nutritional assessment. Behaviour appeared to have been influenced by a variety
of factors and relationships between attitudes, knowledge and activities seemed
far from straightforward.
PMID- 9559390
TI - Feeding difficulty in elderly patients with dementia: confirmatory factor
analysis.
AB - The latent structure of feeding difficulty in elderly patients with dementia was
investigated using multivariate statistical techniques including exploratory and
confirmatory factor analysis. A survey design of 345 elderly patients with the
diagnosis of dementia using a questionnaire completed by key workers and primary
nurses, was used in local psychogeriatric and continuing care of the elderly
facilities. Feeding difficulty and nursing intervention were estimated followed
by fitting of latent variable models of feeding difficulty to the data using
structural equation modelling. Three models of feeding difficulty in elderly
patients with dementia, with 2, 3 and 4 factor structures respectively were
compared. All three models showed a good fit to the data as assessed by several
standard criteria. The 3 and 4 factor models, however, showed significantly
better fit than the 2 factor model. The 4 factor model introduced a latent
variable of "oral difficulty" with feeding which merits further investigation.
This study demonstrates the possibility of developing reliable and validated
scales for the assessment of feeding difficulty in elderly patients with
dementia.
PMID- 9559391
TI - The helping relationship in the community setting: the relevance of Rogerian
theory to the supervision of Project 2000 students.
AB - A series of twenty-six interviews, fourteen with district nursing sisters and
twelve with students they supervised, was conducted in 1992 in one Project 2000
demonstration district in England. The data were collected as part of an English
National Board funded research study; data were reinterpreted in 1994 and formed
one element in the author's PhD thesis. Participants described the ways in which
a supervisor might enable a student to learn during a community placement. One of
the most important means by which supervisors could provide assistance was by
creating an environment in which the students felt supported. Students described
how supervisors demonstrated concern, acceptance and understanding, attributes
which bore striking resemblance to the qualities of congruence, unconditional
positive regard and empathic understanding identified by Carl Rogers as enabling
learning.
PMID- 9559392
TI - Support and coping of male hemodialysis-dependent patients.
AB - The purpose of this descriptive-correlational study was to describe coping
strategies used by males with chronic renal failure who are dependent on
hemodialysis; to describe their social networks; to describe the perceived
support, conflict, and reciprocity within their interpersonal relationships; and
to examine the relationships among the variables support, conflict, reciprocity,
social networks, and coping strategies. Social support was conceptualized as a
coping resource or source of assistance in coping with the renal illness- or
hemodialysis-related stressor. The Ways of Coping questionnaire and the
Interpersonal Relationship Inventory were administered to 30 participants while
in hospital. Although, both problem-focused and emotion-focused forms of coping
were used, participants primarily used problem-focused coping, in particular,
"seeking social support". Overall, the participants perceived relatively high
levels of support and moderate to high levels of reciprocity with members of
their social networks. Participants experienced a moderate level of conflict in
their interpersonal relationships. Both escape-avoidance and conflict were
positively associated with the number of people in the household. Positive
reappraisal was negatively associated with the number of close relatives. The
small sample size prohibits generalizability of the results. Longitudinal studies
with a larger randomly selected sample would yield insights into the long-term
psychological outcomes of different coping strategies and into the bi-directional
relationship of support from social network and coping in this population.
Implications for nurses are discussed.
PMID- 9559393
TI - Theory and research: a linkage to benefit practice.
AB - This paper begins with a critical overview of what the extant literature sees as
the relationship between research, theory and practice. Most scholars maintain
that there are two main viewpoints: research exists to build theory from practice
and/or research exists to test existing theory in practice. It will be argued
that is too simplistic a view and four specific linkages will be proffered:
Theory Testing Research, Theory Generating Research, Theory Evaluating Research
and Theory Framed Research. All four will be discussed and their contribution to
the knowledge base of nursing practice explored. In concluding, an argument will
be put forward proposing the view that undertaking research without considering
theory is an empty and non-productive exercise.
PMID- 9559394
TI - Attitudes of Asian and American graduate nursing students towards death and
dying.
AB - This study compared the difference in attitudes towards death and dying between
17 Asian and 11 American graduate nursing students. Asian and American students
did not significantly differ in attitudes related to fear of death, of self, or
others, but Asian students were significantly more afraid than American students
of their own process of dying. Asian students were more averse than American
students to interacting and discussing death with dying patients. Talking about
death with dying patients was the most difficult aspect of care for both groups.
However, Asian students gained more personal satisfaction than American students
in caring for dying patients. The findings provoke discussion regarding
differences in nursing practice by Asian and American graduate nursing students.
PMID- 9559395
TI - Tuberculin surveys--why?
PMID- 9559396
TI - Fluoroquinolones: a new treatment for tuberculosis?
AB - The fluoroquinolones have secured an important place in the management of
bacterial infection, they are well absorbed orally, are found in respiratory
secretions in higher concentrations than in serum and are concentrated inside
macrophages. The agents are well tolerated and have an excellent safety record in
long-term therapy. No new antituberculosis agents have been developed since the
introduction of rifampicin into clinical use, so fluoroquinolones have been
investigated for potential efficacy in tuberculosis. In vitro studies have shown
that they are active against Mycobacterium tuberculosis at achievable
concentrations. Treatment studies in mice have demonstrated efficacy. Few
clinical studies have been performed in humans, but ciprofloxacin has
demonstrated significant early bactericidal activity. Regimens including a
fluoroquinolone have been comparable to other standard regimens, although the
outcome in human immunodeficiency virus (HIV) seropositive patients was
significantly poorer. There is still insufficient clinical data to use
fluoroquinolones in first-line treatment of tuberculosis, but they may find a
role in the management of multidrug-resistant infections or in patients with
adverse reactions to other agents.
PMID- 9559397
TI - National tuberculin survey of Kenya, 1986-1990.
AB - SETTING: The first tuberculin survey conducted in Kenya by the World Health
Organisation in 1958-1959 found an annual risk of tuberculosis infection (ARTI)
of 2.5%. OBJECTIVE: To estimate the ARTI and its trend in recent years and to
compare the estimated incidence rates with the notification rates. DESIGN: A
tuberculin survey was held in 12 randomly selected districts in the period 1986
1990. Tuberculin testing with 2TU PPD RT 23 + Tween 80 was performed in 40,365
primary schoolchildren aged 6-13. RESULTS: Of 14,984 non BCG-vaccinated children,
1,380 (9.2%) had indurations of > or = 10 mm. Double testing with PPD RT 23 and
PPD-scrofulaceum in 980 non BCG-vaccinated children revealed a high level of
infections due to mycobacteria other than tuberculosis (MOTT). Therefore, the
prevalence of tuberculous infection was based on the sum of 50% of the
indurations of 17 mm and all indurations of 18 mm or more multiplied by two. The
prevalence of tuberculous infection in schoolchildren aged on average 8.4 years,
'weighted' for the population size according to the provisional results of the
1989 census, was calculated at 5.5%. The corresponding ARTI is 0.6%. CONCLUSION:
The ARTI has declined by an average 4.6% per year. The tuberculosis problem
differs from one area to the next, with the highest prevalences of infection on
the coast and in Eastern Kenya, and the lowest in Western Kenya. Although the
average ratio of observed and estimated incidences indicate that 70% of incident
cases are notified, considerable inter-district variations are observed.
PMID- 9559398
TI - The molecular epidemiology of tuberculosis in Zaragoza, Spain: a retrospective
epidemiological study in 1993.
AB - SETTING: The incidence of tuberculosis (TB) in Spain is one of the highest in
Europe. In Zaragoza region the incidence rate of tuberculosis and the acquired
immune deficiency syndrome (AIDS) are close to the national average. OBJECTIVE:
To better define the molecular epidemiology of tuberculosis in an area of Europe
where this has not been previously studied. DESIGN: A retrospective
epidemiological study on tuberculosis was conducted in Zaragoza, a region of
Spain, in 1993. The study population consisted of 226 patients from whom positive
culture and complete clinical and demographic data were available. Mycobacterium
tuberculosis strains were typed by standard restriction fragment length
polymorphism (RFLP). A cluster was defined as two or more isolates with identical
RFLP patterns when five or more copies of IS6110 are present. The 137 non
clustered patients were compared with the 89 clustered patients and studied by
using univariate analysis. RESULTS: Thirty-nine percent of the patients were
clustered, suggesting possible recent transmission. Infection with drug-resistant
M. tuberculosis was associated with a decreased risk of being in a cluster. The
strains isolated from human immunodeficiency virus (HIV)-positive patients were
not associated with clustering. We found that immigration was not a major
determinant in the total number of TB cases. CONCLUSION: Immigration, HIV and
drug resistance were not associated with recent transmission. More than 50% of
the clusters contained two or three patients, indicating that small outbreaks
were responsible for most of the tuberculosis cases. Our RFLP typing results
indicate that a TB control programme should be implemented in Spain in order to
lower transmission of TB.
PMID- 9559399
TI - Nationwide surveillance of drug-resistant tuberculosis in The Netherlands: rates,
risk factors and treatment outcome.
AB - SETTING: The Netherlands, 1993 and 1994. OBJECTIVE: To determine 1) rates of drug
resistance in relation to nationality and country of birth, 2) risk factors for
drug resistance, 3) treatment outcome of drug-resistant cases, and 4) rates of
primary and acquired drug resistance. DESIGN: Retrospective study of all cases
notified with bacillary tuberculosis in The Netherlands in 1993 and 1994.
RESULTS: Drug resistance to one or more drugs was reported in 268 (14.6%) of all
1836 cases, of whom 203 (76%) were foreign born. In Dutch patients rates of
isoniazid (H) (2.9%) and streptomycin resistance (3.6%) were lower than in
foreign patients (8.6% and 10.6% respectively, P < 0.001). Multidrug (H and
rifampicin [R]) resistance was reported in 0.5% of Dutch-born and 1.4% of foreign
cases (P = 0.055). Rates of acquired resistance to H (11.4%) and HR (5.7%) were
higher than rates of primary resistance to these drugs (5.2% and 0.7%
respectively, P < 0.05), but the number of retreatment cases was low (6.8% of all
cases). Drug resistance was associated with immigration but not with drug use,
homelessness or human immunodeficiency virus (HIV) co-infection. One fifth (20%)
of drug-resistant cases was diagnosed by active case finding. Treatment outcome
in sensitive and resistant cases was compared. CONCLUSION: These findings suggest
that drug resistance is imported, but it is unclear to what extent drug
resistance among foreigners has been transmitted or created in The Netherlands.
Drug resistance data should be monitored in Dutch and foreign patients
separately.
PMID- 9559400
TI - Origin and management of primary and acquired drug-resistant tuberculosis in The
Netherlands: the truth behind the rates.
AB - SETTING: The Netherlands, May 1994 to May 1996. OBJECTIVE: 1) To estimate to what
extent drug-resistant tuberculosis was acquired or recently transmitted in The
Netherlands, 2) to assess the relevance of drug resistance data as routinely
collected, and 3) to describe case management. DESIGN: Prospective descriptive
study. Patients diagnosed with drug-resistant tuberculosis were interviewed.
Information on patient management and contact tracing was collected. IS6110
restriction fragment length polymorphism (RFLP) patterns of all strains were
compared with those of the National RFLP library and clusters were analyzed.
RESULTS: In total 193 cases were included in the study. Acquired drug resistance
(ADR) was rare. Dutch ADR patients reported receiving treatment a long time
previously (mean age 58, mean treatment interval 23 years). Most foreign ADR
patients had been treated recently in their country of origin. Of 151 primary
drug-resistant (PDR) cases, 129 (85%) were foreign-born, of whom few (8%-19%) had
been infected in The Netherlands. Few Dutch PDR cases had been infected recently
(mean age 49 years). Rifampicin resistance was more frequently observed in
foreign ADR cases than in foreign PDR cases (28% vs 5%; P < 0.001). One third of
cases had not been treated according to treatment guidelines. CONCLUSION: Only a
small proportion of drug-resistant cases resulted from recent infection or
treatment in The Netherlands. General rates of ADR and PDR do not reflect current
Dutch programme performance. For programme monitoring, ADR/PDR rates and their
trends must be reported and evaluated in Dutch and foreign patients separately.
PMID- 9559401
TI - Drug-resistant tuberculosis in human immunodeficiency virus infected persons in
Italy. The Italian Drug-Resistant Tuberculosis Study Group.
AB - OBJECTIVE: To describe the prevalence and epidemiological-clinical
characteristics of tuberculosis (TB) resistance to first-line drugs in Italian
human immunodeficiency virus (HIV)-infected subjects. DESIGN: Prospective,
observational multicenter (25 Centers of Infectious Diseases) study.
Mycobacterium tuberculosis strains from 167 HIV co-infected subjects with TB (149
new cases, 18 relapses) were tested at a central laboratory for susceptibility to
rifampin (R), isoniazid (H), pyrazinamide (Z), ethambutol (E) and streptomycin
(S) and for DNA fingerprint type. Drug susceptibility results were related to
patients' epidemiological, clinical and laboratory features. RESULTS: Drug
resistance patterns among new TB cases were as follows: R = 1%, Z = 6%, S = 8%, H
+ S = 3%, S + Z = 4%. TB resistant to at least R + H (MDR-TB) was detected in 36%
of new cases due to an MDR-TB outbreak which was the largest thus far in Europe,
involving 7/25 participating institutions, and was demonstrated by conventional
and molecular epidemiology evidence. With multivariate analysis, MDR-TB was
associated with hospital exposure to MDR-TB (OR = 39.3, P < 0.001) and previous
use of anti-TB drugs (OR = 9.8, P = 0.008). CONCLUSION: As drug-resistant
tuberculosis in Italy is thus far relatively scarce, detection of a large MDR-TB
epidemic among HIV-infected subjects was alarming. Aggressive control measures
are urgently needed to prevent the spread of MDR-TB throughout the country and
among the general population.
PMID- 9559402
TI - The bacteriology of pulmonary tuberculosis in a population with high human
immunodeficiency virus seroprevalence.
AB - SETTING: A public sector urban university hospital in Soweto, South Africa.
OBJECTIVE: To describe the utility of sputum smear microscopy and the prevalence
of Mycobacterium tuberculosis resistance to antituberculosis drugs according to
human immunodeficiency virus (HIV) serostatus in adults. DESIGN: A retrospective
descriptive study of consecutive cases using a record review. RESULTS: We studied
412 adults with culture-proven pulmonary tuberculosis, of whom 185 (44.9%) were
HIV-seropositive and had a significantly lower sputum smear positivity than HIV
seronegatives (68% versus 79%, P < 0.05). Smear positivity was significantly
higher in HIV-infected patients with CD4 counts < or = 50/mm3 compared to those
with CD4 counts of 201-300/mm3 (P < 0.05). In patients with and those without a
history of previous treatment for tuberculosis, resistance to one or more
antituberculosis drugs was found in 32.2% and 13.6% of cases, respectively, while
resistance to both isoniazid and rifampicin (multidrug-resistant tuberculosis
[MDR]) was found in 15.3% and 4.5% of patients, respectively. There was no
significant difference in resistance between HIV-positive and seronegative
patients. CONCLUSION: A strong tuberculosis control programme and good
surveillance will be required to prevent the further spread of MDR tuberculosis.
Surveys such as these are useful for monitoring control programmes.
PMID- 9559403
TI - Lack of direct correlation between CD4 T-lymphocyte counts and induration sizes
of the tuberculin skin test in human immunodeficiency virus type 1 seropositive
patients.
AB - SETTING: The study was conducted in Bobo-Dioulasso, Burkina Faso, where
Mycobacterium tuberculosis infection and human immunodeficiency virus type 1 (HIV
1) infection are prevalent. OBJECTIVE: To identify proportions of representative
(test) populations who are reactive to the tuberculin skin test, and to study the
relationship between CD4 T-lymphocyte counts and the induration size of the
tuberculin skin test in these groups. DESIGN: A group of 435 healthy students was
tuberculin skin tested in order to evaluate the intensity of skin testing in a
'normal' population. The study group consisted of 195 subjects with or without
tuberculosis, and with or without HIV-1 infection, who received a tuberculin skin
test and a CD4 T lymphocyte count on the same day. RESULTS: In total, 90% of the
control (nontuberculous, HIV negative) subjects, 32% of the HIV-1 seropositive
subjects, 76.5% of the tuberculous patients and 57% of the tuberculous HIV-1
seropositive patients were tuberculin positive. There was no direct correlation
between the induration size of reactions to the tuberculin skin test and CD4 T
lymphocyte count in these study groups using linear regression analysis.
CONCLUSION: In vivo skin testing using tuberculin yields clinically significant
information on the degree of immunodeficiency which is different from that of CD4
T-lymphocyte counts. The tuberculin skin test should therefore be used as an
independent marker of the weakened immunological status of HIV-1 seropositive
subjects.
PMID- 9559404
TI - Tuberculosis patients and practitioners in private clinics in India.
AB - SETTING: Rural and urban areas of Maharashtra, a large state in Western India.
OBJECTIVE: To understand tuberculosis (TB) management practices among private
medical practitioners (PPs) and the treatment behaviour of the patients they
manage. DESIGN: Prospective study of help-seeking patterns and treatment
behaviour among 173 pulmonary TB patients diagnosed in private clinics, and the
TB management practices of 122 PPs treating these patients. RESULTS: The first
source of help for 86% of patients was a PP. The diagnostic and treatment
practices of PPs were inadequate; 15% did not consider sputum examination to be
necessary, and 79 different treatment regimens were prescribed by 105 reporting
PPs. Sixty-seven percent of the patients diagnosed in private clinics remained
with the private sector, and the rest shifted to public health services within
six months of treatment. The treatment adherence rate among the patients in
private clinics was 59%. There were discrepancies between the reported management
practices of the PPs and what their patients actually followed. CONCLUSION: The
study identifies and highlights the need to educate PPs and their TB patients,
and indicates ways in which PPs could be meaningfully involved in efforts to
revitalize the national TB control programme.
PMID- 9559405
TI - Bronchial asthma in two chemical fertilizer producing factories in eastern Saudi
Arabia.
AB - SETTING: Two urea fertilizer producing factories in Saudi Arabia. OBJECTIVE: To
determine the prevalence of respiratory symptoms and diseases in employees
exposed to ammonia gas. DESIGN: A cross-sectional study involving 161 exposed
subjects and 355 controls. All completed a respiratory symptoms questionnaire,
with additional questions on present and past occupations. Ammonia concentrations
were measured in the different sections of the factories. RESULTS: The ammonia
levels in factory B were well below the threshold limit value (TLV) (range 0.02
7.0 mg/m3 of air). In factory A the range was 2.0-130.4 mg/m3. The control and
exposed groups were comparable with respect to their smoking habits. The exposed
subjects in factory A had significantly higher relative risks (RR) for all
respiratory symptoms; the same was true for haemoptysis (RR: 4.1, 95% confidence
interval: 1.63-10.28). Bronchial asthma, chronic bronchitis, and a combined
diagnosis were significantly higher among those exposed to high cumulative
ammonia levels. However, in the logistic regression analysis ammonia
concentration was significantly related to cough, phlegm, shortness of breath
with wheezing and bronchial asthma. CONCLUSION: Exposure to ammonia gas in the
workplace is significantly associated with increase in respiratory symptoms and
bronchial asthma. Re-engineering measures to lower the levels of ammonia in
factory A are strongly recommended. The affected employees should be removed from
further exposure and followed up.
PMID- 9559406
TI - Implementing tuberculosis control programmes in Kaduna State, Nigeria.
AB - This paper discusses the impact of pre-payment versus free drug therapy on case
finding and treatment of tuberculosis patients. While the Kaduna State
tuberculosis pilot project introduced fees mainly as a cost-recovery measure,
evaluation of several cohorts revealed that while it led to a reduction in the
proportion of diagnosed smear-positive patients that could afford treatment, it
markedly enhanced compliance in those willing to pay. Ways to balance this trade
off are suggested.
PMID- 9559408
TI - Tuberculosis due to drug-resistant Mycobacterium bovis in pregnancy.
AB - We describe the management practices adopted in a case of pulmonary and extra
pulmonary tuberculosis caused by an isoniazid/pyrazinamide resistant strain of
Mycobacterium bovis in a 26-week pregnant woman. She was initially treated with
rifampin, isoniazid and ethambutol, pre-term delivery was induced and
streptomycin was then added to the regimen. Screening of the new-born revealed no
signs of either disease or infection. Isoniazid prophylaxis was not administered
and the new-born was vaccinated and isolated from the mother for two months;
however she continued to be fed with her mother's milk for the whole period.
PMID- 9559407
TI - Polymerase chain reaction of pleural biopsy specimens for rapid diagnosis of
tuberculous pleuritis.
AB - SETTING: Government-administered regional teaching hospital. OBJECTIVE: To
improve timeliness and sensitivity of laboratory diagnosis of tuberculous
pleuritis. DESIGN: We applied polymerase chain reaction (PCR) to detect DNA
(IS6110) specific for Mycobacterium tuberculosis complex in pleural biopsy
specimens. RESULTS: Of 28 patients with pleural disease, 11 were diagnosed by
microbiology (smear/culture of sputum or pleural fluid) with tuberculous
pleuritis, eight were diagnosed with tuberculous pleuritis by histology (of
pleural biopsies) and/or clinical presentation, and nine were diagnosed with
carcinomatous pleuritis. Seventeen of the patients' pleural biopsies were PCR
positive. Based on microbiological results, the sensitivity of the PCR assay was
100% (11/11). On the other hand, based on the results of the histological and
clinical data, sensitivity and specificity of the PCR results were 89% (17/19)
and 100% (9/9), respectively. CONCLUSION: PCR of pleural biopsy specimens can be
a useful method when employed in combination with microbiological and
histological examinations of pleural biopsy for rapid diagnosis of tuberculous
pleuritis.
PMID- 9559409
TI - The effect of ranitidine on the tuberculin skin test.
PMID- 9559410
TI - Missed opportunities for prevention of tuberculosis.
PMID- 9559411
TI - Comparison of coronary hemodynamics during infusions of dobutamine and adenosine
in patients with angina pectoris.
AB - Pharmacologic stress tests are used to evaluate the significance of coronary
arterial stenosis, and adenosine and dobutamine are often used for this purpose.
The aim of this study was to examine coronary hemodynamics in 16 patients with
stable exertional angina who had organic stenosis (> 90%) in the left anterior
descending coronary arteries and in 13 control subjects at baseline and during
separate intravenous infusions of dobutamine (20 micrograms/kg per min
[corrected]) and adenosine (140 micrograms/kg per min [corrected]). Measurements
of great cardiac vein blood flow and lactate and oxygen contents in the blood
from the aortic root and great cardiac vein were analyzed in patients with
ischemic signs of myocardial ischemia (ST-segment depression in the precordial
ECG leads and/or myocardial lactate production) during the infusions (in 11
patients during adenosine infusion and in 12 patients during dobutamine infusion)
and in control subjects. Myocardial oxygen consumption during adenosine infusion
did not change compared with the baseline in both groups, whereas it increased
during dobutamine infusion in both groups (p < 0.01 compared with the baseline in
each case). However, great cardiac vein blood flow was significantly increased
compared with the baseline during both infusions in both groups (p < 0.01
compared with baseline in each case), and the oxygen contents of great cardiac
vein blood, which contains effluent from the ischemic region, showed no decrease
but increased significantly during both infusions in the patients in comparison
with control subjects. Although the global oxygen supply was excessive,
myocardial ischemia occurred during dobutamine and adenosine infusions in the
patients. As myocardial oxygen consumption remained unchanged during adenosine
infusion, regional myocardial flow reduction, possibly as a result of flow
maldistribution, may contribute, at least partly, to adenosine-induced myocardial
ischemia. An increase in myocardial oxygen consumption may be the principal cause
of myocardial ischemia during dobutamine infusion, but an inappropriate flow
increase in normal myocardium may occur during dobutamine-induced ischemia.
PMID- 9559412
TI - Relationship between serum cholesterol and the risk of acute myocardial
infarction in a screened cohort in Okinawa, Japan.
AB - Coronary heart disease (CHD) is rare in Japanese subjects and serum cholesterol
levels are low. However, no data have been published relating the effect of serum
cholesterol levels to the incidence of acute myocardial infarction (AMI) in
Japan. Data from a large community-based mass screening registry are available
for the geographically isolated island of Okinawa, Japan (1980 census, 1.11
million). A total of 38,053 participants (17,859 men and 20,194 women) whose
serum cholesterol levels were determined in the 1983 mass screening were examined
to determine whether they had experienced AMI. Every case of AMI that occurred
during a 3-year period (1 April 1988 to March 1991) throughout Okinawa was
recorded in a separate registry. The total number of cases of AMI was 1,021 (674
men and 347 women). Of these, 65 patients (41 men and 24 women) were identified
by name, sex, birth date, and zip code in the mass screening registry. The
cumulative incidence of AMI increased with the serum level of cholesterol: 42.1
(serum cholesterol < or = 167 mg/dl), 133.5 (serum cholesterol 168-191 mg/dl),
188.9 (serum cholesterol 192-217 mg/dl), and 323.0 (serum cholesterol > or = 218
mg/dl) per 100,000 screened subjects. Multiple logistic analysis was conducted to
examine the effect of serum cholesterol on the risk of AMI with adjustment for
other variables such as sex, age, systolic and diastolic blood pressure, and
proteinuria. The adjusted odds ratio (95% confidence interval) of the observed
serum levels of cholesterol was 1.66 (1.29-2.15) with a reference serum
cholesterol level of < or = 167 mg/dl. The risk of AMI increased in proportion to
the serum level of cholesterol. Serum cholesterol is an independent predictor of
AMI in Okinawa, Japan.
PMID- 9559413
TI - Impaired atrial contraction in patients with atrial flutter and gradual recovery
after cardioversion.
AB - The risk of thromboembolism after cardioversion of atrial flutter is
controversial. The present study provides evidence for blood stasis in the atria
of patients with atrial flutter and for gradual recovery of atrial contraction
after cardioversion, which justifies prophylactic treatment at cardioversion, as
for atrial fibrillation. We examined atrial thrombi and peak flow velocity in the
left atrial appendage as an index of blood stasis in 5 consecutive patients with
atrial flutter. Transesophageal echocardiography revealed a thrombus in 1
patient, and peak flow velocity in the left atrial appendage was inversely
correlated with left atrial dimension (r = -0.90, p < 0.05). After restoration of
sinus rhythm, transmitral flow velocity in late diastole was also examined to
evaluate the recovery of atrial contraction. The recovery of transmitral flow
velocity the next day and 1 week after cardioversion was correlated with flow
velocity in the left atrial appendage before cardioversion (r = 0.89, p < 0.05; r
= 0.97, p < 0.01, respectively). These findings suggest that some patients with
atrial flutter have impaired atrial contraction and that prolonged impairment
after cardioversion is also possible. Atrial enlargement and low flow velocity in
the atrial appendage were predictive factors for such patients.
PMID- 9559414
TI - Relationship between calcium channel antagonists and nocturnal hypotension and
autonomic imbalance in patients with a previous myocardial infarction.
AB - The present study was conducted to evaluate the effect of calcium channel
antagonists on diurnal changes in blood pressure and on autonomic function in 71
patients who were receiving a calcium channel antagonist because they had
previously suffered a myocardial infarction. Ambulatory blood pressures and
Holter ECGs were recorded simultaneously for 24 h. Autonomic function was
assessed by heart rate variability. Nocturnal systolic pressure was > or = 90
mmHg in 63 patients (group I) and < 90 mmHg in 8 patients (group II). Significant
day to night changes in high-frequency power (from 4.3 +/- 1.2 to 4.5 +/- 1.0/m2)
as well as in the ratio of low-frequency power to high-frequency power (from 1.3
+/- 0.1 to 1.1 +/- 0.2) were observed in group I. whereas such changes were
blunted in group II. When the calcium antagonist was discontinued or the dose was
reduced in group II, the autonomic imbalance improved along with elevation of
nocturnal systolic blood pressure. Thus, nocturnal blood pressure should be
monitored when such drugs are administered for the treatment of ischemic heart
disease to a patient with a previous myocardial infarction. If nocturnal
hypotension occurs, the dose should be reduced or the drug should be
discontinued.
PMID- 9559415
TI - Hormonal and cardiorenal responses to acute saline loading in mild congestive
heart failure--the effect of angiotensin converting enzyme inhibition.
AB - We investigated cardiorenal responses to acute saline loading in patients with
mild congestive heart failure (CHF) with and without angiotensin-converting
enzyme (ACE) inhibition. Saline loading (infusion of 250 ml of normal saline) was
performed on 10 patients with mild CHF and 10 control subjects. Although saline
loading reduced plasma renin activity and plasma angiotensin II to a similar
extent in both groups, it increased cardiac output, renal blood flow, and the
ratio of renal blood flow to cardiac output in the mild CHF group but not in the
control group. After saline loading, urinary sodium excretion was higher in the
control than in the mild CHF group. In the mild CHF group, saline loading was
performed again after an ACE inhibitor (delapril) had been administered for 5
days. Although delapril increased cardiac output and renal blood flow under basal
conditions, saline loading did not affect these variables. Delapril improved
urinary sodium excretion after saline loading. Thus, the renin-angiotensin
aldosterone axis may contribute to cardiorenal hemodynamics and renal sodium
handling in patients with mild CHF. This effect may attenuate the natriuretic
response to acute saline loading, and administration of an ACE inhibitor improves
this attenuation.
PMID- 9559416
TI - Altered calcium handling in compensated hypertrophied rat cardiomyocytes induced
by pressure overload.
AB - To investigate Ca2+ handling in compensated hypertrophied cardiomyocytes, we
measured Ca2+ transients and contraction of hypertrophied rat left ventricular
myocytes induced by aortic constriction (AC). The fluorescence ratio (I405/I480)
after indo-1/AM loading and circumferential length were simultaneously measured
in isolated myocytes. The amplitude of Ca2+ transients (Ca-Amp) was higher in
rats with AC than in sham-operated rats (Sham) (0.25 +/- 0.08 vs 0.17 +/- 0.05).
There was a positive correlation between Ca-Amp and fractional shortening (FS) in
both AC and Sham rats, whereas the ratio of FS/Ca-Amp was smaller in AC rats.
These observations suggest that compensated hypertrophied cardiomyocytes exhibit
an adaptive increase in Ca-Amp, associated with reduced myofilament
responsiveness to an increase in Ca2+. Isoproterenol and forskolin increased Ca
Amp and FS, and decreased time to 50% decline of Ca2+ transients. Although
myocytes from AC rats exhibited reduced responsiveness to isoproterenol,
responses to forskolin did not differ between the 2 groups. The reduced beta
adrenergic response in Ca2+ handling was probably due to altered beta
adrenoceptor numbers, G-protein function and/or their coupling process.
PMID- 9559417
TI - Effect of manidipine hydrochloride, a calcium antagonist, on isoproterenol
induced left ventricular hypertrophy.
AB - We examined the effect of a calcium antagonist, manidipine hydrochloride, on
cardiac hypertrophy and the expression of the atrial natriuretic peptide (ANP),
transforming growth factor beta 1 (TGF-beta 1), and extracellular matrix protein
genes in rats with isoproterenol-induced cardiac hypertrophy. Rats were
continuously infused with saline or isoproterenol (0.5 mg/kg per day) for 7 days
using an osmotic minipump. Treatment with manidipine hydrochloride (once a day at
3 mg/kg) began 1 day before minipump implantation and continued until the end of
the experiments (each group; n = 6). After treatment, left ventricular weight was
measured and mRNA was extracted and analyzed by Northern blot hybridization.
Isoproterenol increased left ventricular weight (2.40 +/- 0.04 g/kg; p < 0.01)
without increasing blood pressure. ANP, collagen type I and type III, and
fibronectin mRNAs were increased 1.5-(p < 0.01), 1.9- (p < 0.01), 2.7- (p <
0.01), and 3.2-fold (p < 0.01), respectively, by isoproterenol infusion. However,
TGF-beta 1, collagen type IV, and laminin B1 and B2 mRNA levels were unchanged by
isoproterenol. Manidipine hydrochloride prevented isoproterenol-induced left
ventricular hypertrophy (2.26 +/- 0.02 g/kg; p < 0.01) and expression of mRNA of
ANP (0.9-fold of the control value; p < 0.01), collagen types I (1.1-fold; p <
0.01) and type III (1.6-fold; p < 0.01), and fibronectin (1.1-fold; p < 0.01).
Thus, manidipine hydrochloride prevented cardiac hypertrophy and changes in the
expression of genes for ANP and interstitial components of extracellular matrix
induced by isoproterenol.
PMID- 9559418
TI - Limitations of angiotensin-converting enzyme inhibitor in restenosis of a deep
arterial injury model.
AB - Cilazapril (CLZ) has been reported to reduce intimal hyperplasia in a rat carotid
model of restenosis. The purpose of this study was to determine whether CLZ
inhibits restenosis after deep arterial injury in lathyritic rats. The lathyritic
rat was used as a model of deep arterial injury; in this model the internal
elastic lamina is easily broken by balloon injury because of the fragility of the
connective tissue. Deep arterial injury is defined as rupture of the internal
elastic lamina with damage to both the intima and the media. The rats were
divided into 4 groups (n = 40): mild injury (intimal damage with intact internal
elastic lamina), mild injury +CLZ, deep injury, and deep injury +CLZ. In the CLZ
treated groups, the drug was administered orally (10 mg/day) from 7 days before
balloon injury until the time of sacrifice 21 days after balloon injury. The
intimal hyperplasia was determined histologically using a computerized
morphometry program. At sacrifice, blood pressure was lower in the CLZ-treated
groups than in the untreated (control) rats (p < 0.05). In the mild injury model,
CLZ decreased intimal hyperplasia markedly. In contrast, CLZ failed to reduce
intimal hyperplasia in the rats with deep injury. CLZ markedly decreased
neointimal hyperplasia in mild injury. In contrast, CLZ failed to reduce intimal
area in deep injury. The type of arterial injury seems to determine the
effectiveness of CLZ.
PMID- 9559419
TI - A case of pulmonary embolism caused by paroxysmal nocturnal hemoglobinuria.
AB - A patient with pulmonary embolism caused by paroxysmal nocturnal hemoglobinuria
(PNH) is described. PNH sometimes causes venous thrombosis in the extremities,
hepatic vein, or cerebral vein, but pulmonary embolism rarely occurs.
PMID- 9559420
TI - Aortic root replacement for Takayasu arteritis associated with ulcerative colitis
and ankylosing spondylitis--report of a case.
AB - A 26-year-old man was admitted for treatment of congestive heart failure
resulting from aortic regurgitation. The patient had been on medical treatment
for ulcerative colitis (UC) since he was 14 years old and for ankylosing
spondylitis (AS) since he was 20 years old. On admission, gradients of blood
pressure among the extremities were observed. Echocardiography revealed marked
dilation of the left ventricle (LV), hypokinetic wall motion of the LV, slightly
prolapsed aortic cusps with annular dilatation, and severe aortic regurgitation.
Computed tomographic scans demonstrated an aneurysmal dilation of the ascending
aorta and thickening of the descending and abdominal aortic wall. Digital
subtraction angiography demonstrated an aneurysmal dilation of the ascending
aorta; however, there was no clear evidence of steno-occlusive lesions in the
brachiocephalic vessels. Blood studies showed positive inflammatory signs and
negative rheumatoid factor. HLA typing showed A2, 24(9), B27, 67, Cw1, 7, and
DR1, 2. Based on these data, the diagnosis of Takayasu arteritis associated with
UC and AS was made. Aortic root replacement was performed. Steroid therapy was
restarted immediately after surgery. Histologic studies of the aortic wall showed
findings compatible with Takayasu arteritis. The combination of these rare
diseases suggests that they have a common pathophysiologic background.
PMID- 9559421
TI - Surgical treatment of discrete subaortic stenosis in an adult.
AB - We report on an adult patient with discrete-type subaortic stenosis. A 48-year
old man who had progressed asymptomatically since childhood despite heart murmur
was transferred to our hospital. The patient was diagnosed as having severe
aortic stenosis with a pressure gradient of 100 mmHg across the aortic valve,
associated with a grade II aortic regurgitation. A conventional aortic valve
replacement was scheduled. During surgery, the aortic valve was found to be
tricuspid but incompetent as a result of shrinking and thickening of the left
coronary cusp. A circumferential fibromuscular ridge was observed under the
cusps, which corresponded to Kelly's type II discrete subaortic stenosis. Because
of the small subaortic area and deformity of the cusp, we performed aortic valve
replacement after excision of all cusps and the fibromuscular ridge. Early
corrective surgery is recommended for discrete subaortic stenosis to prevention
regurgitation progression.
PMID- 9559422
TI - A case of severe verapamil overdose.
AB - We report here on a 73-year-old woman who ingested 3.6 g (40 mg x 90 tablets) of
verapamil in a suicide attempt. On arrival, the patient was awake and well
oriented. Two and a half hours after ingestion, she lost consciousness, as her
heart rate and blood pressure began to decrease. Cardiac monitoring showed
atrioventricular dissociation. Although she suffered from extreme hypotension, an
echocardiogram revealed that the wall motion of the heart was almost normal, and
cardiac output measured with a Swan-Ganz catheter was well preserved. The plasma
verapamil concentration in this patient was 1499 ng/ml 4 h after ingestion.
Hyperglycemia and hypokalemia, laboratory data revealed, continued for 18 h after
admission. The patient was successfully resuscitated with intravenous saline,
dopamine, and norepinephrine. Besides reporting on this case, we also report on a
treatment for severe verapamil overdose.
PMID- 9559423
TI - Ischemic and non-ischemic myocyte damage and antimyosin monoclonal imaging.
AB - Antimyosin monoclonal antibody is a specific marker of impaired sarcolemmal
integrity resulting not only from ischemia but also from non-ischemic myocardial
injury, such as infection, inflammatory, or immunologic reactions, and alcohol or
drug intoxication. In addition, antimyosin accumulation has been demonstrated in
some forms of cardiomyopathy with unknown as well as known etiologies. Antimyosin
positivity appears to indicate precisely the extent of myocardial necrosis and to
reflect cardiac dysfunction in an acute stage of active myocardial damage caused
by ischemia and inflammation. However, the correlation is not necessarily good in
the chronic stages of the disease or in idiopathic cardiomyopathic hearts; in
other words, cardiac antimyosin uptake can be detected even in myocardial tissue
with a normal histologic appearance independent of the presence of inflammatory
responses, myocyte necrosis, or functional or morphologic deterioration. Thus,
antimyosin is useful not only for detecting and quantifying acute myocardial
necrosis but also for specifically identifying ongoing or latently progressing
myocardial degeneration and sarcolemmal disruption, which will certainly lead to
myocardial necrosis. These characteristics may contribute to the early detection
of myocardial damage and lead to the investigation of pathophysiologic
mechanisms. Further progress in immunologic and radiolabeling techniques is
necessary for better specificity and less antigenicity against humans in
antimyosin monoclonal antibody imaging.
PMID- 9559424
TI - Comparative study of dobutamine stress electron-beam computed tomography and
exercise thallium scintigraphy in the diagnosis of patients with suspected
coronary artery disease.
AB - To evaluate the diagnostic value of dobutamine stress electron-beam computed
tomography (EBCT) as compared with exercise stress thallium-201 single-photon
emission computed tomography (201T1-SPECT) for the detection of myocardial
ischemia, 10 patients with proven or suspected coronary artery disease underwent
both tests. Nine of the 10 patients also underwent coronary angiography. EBCT
images were analyzed objectively to evaluate systolic wall thickening and
analyzed segmentally to determine the distribution of the coronary arteries.
Dobutamine stress EBCT revealed the presence of ischemia in 59 segments, whereas
exercise stress 201T1-SPECT revealed ischemia in 51 segments (agreement = 73%).
The advantage of dobutamine stress EBCT was demonstrated in the
inferior/posterior segments as compared with the results of exercise stress 201T1
SPECT. The overall sensitivity for detecting ischemic regions supplied by
coronary arteries with significant stenosis (diameter stenosis > 50%) was 83% for
dobutamine stress EBCT and 79% for exercise stress 201T1-SPECT (p = NS), with
specificities of 75% and 82% (p = NS). Thus, dobutamine stress EBCT presents a
reasonable alternative to exercise stress 201T1-SPECT for the objective
assessment of patients with suspected coronary artery disease.
PMID- 9559425
TI - Characterization of left ventricular opacification using sonicated serum albumin
in patients with dilated cardiomyopathy and myocardial infarction.
AB - To elucidate whether the mode of left ventricular opacification using sonicated
serum albumin (SSA) is dependent upon the severity of left ventricular
dysfunction, SSA was administered intravenously to 26 patients with dilated
cardiomyopathy, 24 patients with anteroseptal myocardial infarction, and 9 normal
control subjects. The left ventricular inflow pattern in echocardiograms on the
apical 4-chamber view was classified into 2 types: straight or whirling. The
ratio of left ventricular opacified area to left ventricular end-diastolic area,
called the percent left ventricular effective fraction (%LVEF), was also
calculated. The inflow pattern was straight in all normal control subjects and 9
myocardial infarction patients, whereas 15 myocardial infarction and all dilated
cardiomyopathy patients showed the whirling pattern. Percent LVEF was
significantly smaller in patients with dilated cardiomyopathy (45 +/- 22%, p <
0.0001) and myocardial infarction (65 +/- 14%, p < 0.001) than in normal control
subjects (84 +/- 7%). The area that was not opacified was observed only in the
infarcted area in cases of myocardial infarction, and over wide regions in cases
of dilated cardiomyopathy. In addition, there were significant correlations
between %LVEF and ejection fraction or peak filling rate. These findings indicate
that contrast echocardiography using SSA can reflect sensitively the severity of
left ventricular dysfunctions and detect the regions involved in patients with
dilated cardiomyopathy and myocardial infarction.
PMID- 9559426
TI - Assessment of the Bjork-Shiley prosthetic valve orifice area in the aortic
position.
AB - The actual orifice area of a valve is still considered to be a valuable index for
assessing prosthetic valve function. Valve orifice area as calculated by Gorlin's
formula is, however, not constant but changes in proportion to the transvalvular
flow rate. The purpose of the present study was to examine the relationship
between orifice area and flow rate across the Bjork-Shiley prosthetic valve as
calculated by Gorlin's formula, and to modify the formula in a series of patients
with the Bjork-Shiley prosthetic valve in the aortic position. Fifty-six patients
who had received aortic valve replacement with a Bjork-Shiley prosthetic valve
underwent cardiac catheterization. Prosthetic valve orifice area was calculated
by Gorlin's formula and then plotted against flow rate across the valve with
respect to valve size. The relationship between orifice area and flow was linear.
The discharge coefficient of Gorlin's formula was plotted against flow rate, and
a linear correlation was obtained. By substituting Gorlin's formula for an
empiric coefficient into the function for transvalvular flow rate, a modified
formula that can predict the actual orifice area of the prosthetic valve is
obtained.
PMID- 9559427
TI - Outcome of medically treated Stanford type B aortic dissection.
AB - Optimal treatment for patients with uncomplicated type B dissection remains a
matter of debate. From January, 1987, through June, 1996, 43 patients with acute
type B dissection were treated exclusively by medical therapy according to our
management guidelines. After discharge, aortography and enhanced computed
tomography were performed every 6 months to evaluate the diameter of the
dissected aorta. All 43 patients survived the acute phase and were discharged
alive from the hospital. There was no death related to aortic dissection. Three
patients underwent surgical treatment in the chronic phase because of aortic
enlargement. Aortic enlargement in 3 additional patients was managed medically.
The values for freedom from aortic enlargement for 43 patients at 1, 3, and 5
years were 100%, 91%, and 86%, respectively. The long-term survival rates of
patients treated medically and discharged from the hospital are acceptable.
PMID- 9559428
TI - Deep hypothermic intermittent circulatory arrest--an adjunct technique for
operations on aneurysms involving the aortic arch.
AB - Aneurysms involving the aortic arch were repaired in 12 patients using a
technique known as deep hypothermic intermittent circulatory arrest (DHICA). This
technique consists of repeated cycles of 20 min of circulatory arrest and 10 min
of cerebral and systemic reperfusion. Aneurysms were of the following types: 2
true atherosclerotic aneurysm, 8 aortic dissections, and 2 traumatic aneurysm.
There were 2 operative deaths caused by coagulopathy as a result of hepatic
failure and difficulty with left ventricular venting. The frequency of
circulatory arrest ranged from 2 to 5 cycles, and total circulatory arrest ranged
from 20 to 71 min (mean 43.6 min). The lowest tympanic temperature ranged from
17.7 to 19.2 degrees C. No permanent cerebral complications occurred in 10
patients. We believe that this adjunct technique offers excellent results in the
surgical treatment of aneurysms involving the aortic arch.
PMID- 9559429
TI - Angiographic study of mutant tissue-type plasminogen activator versus urokinase
for acute myocardial infarction.
AB - The effects and problems of intravenous thrombolytic therapy with a bolus
injection of mutant tissue plasminogen activator (t-PA) were investigated in 34
patients with first acute myocardial infarction (AMI). In contrast, 114 patients
were selected from 1,003 patients with AMI for treatment using intravenous
infusion urokinase (UK). Angiography of these 148 patients revealed a complete
occlusion of infarct-related artery with no clear contraindications to the study
treatment. With the exception of thrombolysis in myocardial infarction (TIMI-3)
recanalization 60 min after a bolus injection of mutant t-PA, the patients were
given intracoronary UK in addition to mutant t-PA. The study comparisons were
assessed using the following criteria: (1) 60-min assessment of recanalization
rates, mutant t-PA vs UK; (2) time interval from initiation of thrombolysis to
recanalization, mutant t-PA vs UK; (3) angiographic reocclusion rates within 1
month, mutant t-PA alone vs UK vs mutant t-PA plus UK; and (4) intracerebral
hemorrhage rates, mutant t-PA alone vs UK vs mutant t-PA plus UK. There were no
significant differences in the recanalization rates between mutant t-PA and UK,
but there was a significant reduction in the time to recanalization with mutant t
PA (31.8 +/- 12.7 min) compared with UK (56.5 +/- 6.3 min). There was a
significant difference in the reocclusion rates among the 3 treatment groups (20%
mutant t-PA alone vs 4% UK vs 0% mutant t-PA plus UK). On the other hand, no
significant differences in intracerebral hemorrhage rates among the 3 treatments
were observed. In conclusion, thrombolytic therapy with a bolus injection of
mutant t-PA achieved more rapid recanalization, but treatment with mutant t-PA
led to a high rate of reocclusion.
PMID- 9559430
TI - Evaluation of an automatic intraluminal edge detection technique for
intravascular ultrasound images.
AB - Intravascular ultrasound (IVUS) imaging enables detailed analysis and precise
measurements of vascular cross-sections. However, to achieve a reduction in the
existing level of observer variability requires the development of quantitative
IVUS. We have developed a fully automatic intraluminal edge detection technique,
based on adaptive active contour models and called ADDER (adaptive damping
dependent on echographic regions) that allows the quantitation of the
intraluminal cross-sectional area (ICSA). Using a 30-MHz mechanically rotated
transducer mounted at the tip of a 3.5-F catheter, 58 normal and pathologic
arterial segments (from coronary, renal, splenic, iliac, and carotid arteries)
were imaged in vitro. These images were analyzed by 2 experts, E1 and E2, who
manually traced the intraluminal contour twice for each image, as well as with
ADDER. Intra-observer variabilities for ICSAs were found to be excellent (-1.454
+/- 3.51% for E1, 0.96 +/- 5.4% for E2). The inter-observer variability was 2.1
+/- 4.3%. The success factor for ADDER was 89%. Its intra-observer variability
was null, as the method always finds a unique contour. The correlation between
the automatically detected ICSA and the manual ICSA was: r = 0.99 (y = 1.03x +
0.89 mm2). Morphometric variations between manually and automatically traced
contours, analyzed by the centerline method, were 100 +/- 140 mm on average. In
conclusion, the ADDER automatic contour detection applied to IVUS images is
robust and characterized by small systematic and random errors; therefore,
quantitative IVUS is a useful tool in clinical research trials.
PMID- 9559431
TI - Comparison of the effects of enoximone and isoproterenol on protamine
cardiotoxicity in anesthetized dogs.
AB - In this study we investigated the effects of isoproterenol and enoximone on
protamine cardiotoxicity because administration of protamine for heparin reversal
during open heart surgery depresses left ventricular function. Eighteen mongrel
dogs were entered into this study. After induction of general anesthesia and a
stabilization period, a thermodilution catheter was inserted via the jugular
vein. Another 2 catheters were inserted into the left ventricle and femoral
artery. Heparin and protamine were used in all animals. Heparin dosage was 300
U/kg, and protamine dosage was 4.5 mg/kg. The animals were divided into 3 groups.
Six animals received enoximone (5 micrograms/kg per min), 6 animals received
isoproterenol (0.05 microgram/kg per min), and 6 animals received no inotropic
agent. Measurements were performed before treatment, 5 min after protamine
administration, and at 15-min intervals for 1 h. Cardiac output (CO), mean
arterial pressure, pulmonary capillary wedge pressure, first derivative of left
ventricular pressure (1 +/-) left ventricular systolic pressure, and heart rate
were measured. CO was 1582 +/- 34 ml/min in the isoproterenol group (I + P), 1684
+/- 61 ml/min in the enoximone group (E + P), and 1471 +/- 37 ml/min in the
protamine group (P) (p < 0.05 E + P vs I + P and P) 60 min after protamine
administration. The first derivative of left ventricular pressure (dP/dt) was
1995 +/- 61 mmHg/sec in the I + P group, 2320 +/- 85 mmHg/sec in the E + P group,
and 1816 +/- 48 mmHg/sec in the P group (p < 0.05 E + P vs I + P and P). In our
experimental study, the isoproterenol and protamine combination did not increase
hemodynamic activity. However, isoproterenol alone significantly increased
hemodynamic activity as determined by dP/dt values. Protamine administration
impairs the effects of beta agonists on the myocardium. In the protamine group,
CO and pressure-dependent values were significantly reduced. Isoproterenol
administration did not reverse this deterioration because of the loss of the beta
receptor activity. Inotropic agents acting through the beta-adrenergic system
have partial effects on myocardium. Enoximone, a phosphodiesterase inhibitor,
reverses deterioration of cardiac function after protamine administration because
it increases myocardial function via the phosphodiesterase system.
PMID- 9559432
TI - Hypertrophic cardiomyopathy with apical left ventricular aneurysm.
AB - We report a case of hypertrophic cardiomyopathy (HCM) with apical left
ventricular aneurysm, which is difficult to review because cases are so rare. A
54-year-old Japanese man was first found to have an electrocardiographic
abnormality (T-wave inversion at rest) 19 years ago, and non-obstructive apical
HCM without identifiable cause was diagnosed by echocardiography, left
ventriculography, and clinical findings. After 19 years, he was admitted because
of repeated episodes of palpitation and chest oppression at rest. Widespread left
ventricular hypertrophy from the anteroseptal wall to the apex with an apical
left ventricular aneurysm was detected by echocardiography, left
ventriculography, and cardiac magnetic resonance imaging. Histologic examination
of the hypertrophic apical myocardium surrounding the aneurysm showed that the
myocardial tissue had been extensively replaced by fibrous tissue containing
hypertrophic myocardial fibers, and uptakes of [123I]-metaiodobenzyl guanidine
(MIBG) and [123I-] beta-methyliodophenyl pentadecanoic acid (BMIPP) in single
photon emission photography images were reduced despite high myocardial
perfusion. On the other hand, histologic examination of the hypertrophic anterior
wall revealed myocardial hypertrophy with disorganization; myocardial perfusion
and the uptakes of MIBG and BMIPP were preserved. Abnormalities of myocardial
fatty acid metabolism and sympathetic neuron activity with preserved perfusion
flow and histologic changes such as fibrosis in the apical wall are indicative of
apical myocardial injury or ischemia (infarction) without coronary artery
stenosis; apical aneurysm may have occurred in severe apical HCM with cavity
obliteration up to the midventricular level.
PMID- 9559433
TI - Eosinophilic myocarditis associated with toxicodermia caused by phenobarbital.
AB - We report on a 37-year-old man with congestive heart failure caused by
eosinophilic myocarditis associated with toxicodermia. He developed many annular
skin eruptions and peripheral eosinophilia due to reactions against
phenobarbital. Right ventricular endomyocardial biopsy revealed extensive
infiltration of eosinophils in the myocardium. A drug lymphocyte-stimulating test
(DLST) for phenobarbital was positive. His symptoms, cardiomegaly, and cardiac
function were improved by discontinuing phenobarbital followed by oral
administration of prednisolone. We conclude that this eosinophilic myocarditis
must have been induced by an allergic reaction to phenobarbital and that long
term eosinophilia contributed to the myocardial injury.
PMID- 9559434
TI - Asymptomatic moyamoya disease associated with coronary and renal artery stenoses-
a case report.
AB - Moyamoya disease is an occlusive intracranial arteriopathy with abnormal cerebral
vascular collateral networks. Although this disease is known to be associated
with stenosis of extracranial arteries, such as the renal artery, a case
associated with stenoses of the coronary and renal arteries has not been
reported. We described here a 23-year-old man who had effort angina, renovascular
hypertension, and asymptomatic moyamoya disease. Arterioangiography revealed
bilateral occlusion of the intracranial carotid arteries and stenoses in the left
coronary artery and the left renal artery.
PMID- 9559435
TI - Purulent pericarditis with tamponade caused by Salmonella enteritidis.
AB - The incidence of purulent pericarditis has declined. However, mortality remains
high. We describe a case of purulent pericarditis with tamponade caused by
Salmonella enteritidis, and emphasize the importance of early recognition, prompt
institution of appropriate antibiotic therapy, and early surgical drainage for
survival.
PMID- 9559436
TI - Ischemic change on electrocardiogram induced by hypoglycemia in a diabetic
patient.
AB - A 34-year-old female patient who presented to our hospital had been treated with
insulin for diabetes since she was 25 year old. For the previous year she had
experienced chest pain on exertion and during hypoglycemia. During both chest
pain and exercise tests, ST depression and flattening of the T wave were
recognized in leads II, III, aVF, and V2-V6 on the electrocardiogram, and thus
ischemic heart disease was suspected. Cardiac catheterization was performed, but
no organic stenosis or spasms were found. Hypoglycemia (41 mg/dl) was induced by
intravenous injection of rapid insulin (total 18 U, 0.4 U/kg). However, no
coronary change was seen, although she felt chest pain and the same ischemic
electrocardiographic changes occurred. We hypothesized the causes of the ischemic
change to be both the effects of insulin on the cardiovascular system and the
physiologic stress induced by the existence of microvascular abnormality. Special
care should therefore be taken with diabetic patients being treated with insulin
or hypoglycemic agents.
PMID- 9559437
TI - Transient left bundle branch block induced by left-sided cardiac catheterization
in patients without pre-existing conduction abnormalities.
AB - A traumatic left bundle branch block (LBBB) is uncommon in a patient with intact
atrioventricular conduction. Three of our patients developed LBBB during a left
sided catheterization. Two patients suffered from angina pectoris and the other
had an abdominal aneurysm. Two of them had a history of hypertension. None of the
patients had ever shown any conduction abnormalities before the catheterization.
The electrocardiogram just before the examination was normal in all 3 patients.
LBBB was observed when a catheter was introduced into the left ventricle, and
lasted 2--4 min without significant change in heart rates. Examination revealed
no significant stenosis proximal to the first septal perforator and normal left
ventricular contraction in all patients. One patient developed permanent LBBB 14
months later. Catheter-induced LBBB may occur easily with certain anatomical
characteristics of the left bundle branch or the distal His bundle, with or
without some concealed damage to the conduction system. It is important to keep
this complication in mind and to pay adequate attention to patients'
electrocardiograms as well as their angiographical findings, especially in those
with pre-existing right bundle branch block.
PMID- 9559438
TI - A case of dobutamine-induced coronary arterial spasm with ST-segment elevation.
AB - A 55-year-old Japanese woman demonstrated ST-segment elevation in leads I, aVL,
and V3-V6 with chest pain both in an ergometer exercise test and on dobutamine
stress echocardiography. Although the baseline coronary arteriogram revealed no
organic stenosis, total occlusion of the distal portion of the posterolateral
branch of the left circumflex artery was observed during dobutamine infusion with
ST-segment elevation and chest pain. This is a rare case of documented dobutamine
induced coronary arterial spasm.
PMID- 9559439
TI - Effects of thymosin alpha-1 on erythrocyte lipid levels and erythrocyte membrane
(Na(+)-K+)-ATPase activity in experimental hypercholesterolemia.
AB - Thymosin alpha-1 is an active polypeptide isolated from thymus. This polypeptide
is widely used in the diagnosis and treatment of many diseases, especially immune
diseases. In this present study, we examined the effects of thymosin alpha-1 on
plasma and erythrocyte lipid levels and the changes in erythrocyte membrane (Na+,
K+)ATPase activity in hypercholesterolemic rabbits. The erythrocyte lipid levels
decreased, whereas the erythrocyte membrane (Na+, K+)ATPase activity increased
significantly in these rabbits after thymosin alpha-1 injection. These findings
suggest that thymosin alpha-1 is effective on both the lipid level and
erythrocyte membrane (Na+, K+)ATPase activity.
PMID- 9559440
TI - Evaluation of culture, histological examination, serology and the rapid urease
test for diagnosis of Helicobacter pylori in patients with dyspepsia in
Bangladesh.
AB - Helicobacter pylori, a gram-negative, microaerophilic bacterium, has been
established to have a causal association with chronic gastritis, peptic ulcer,
gastric adenocarcinoma, and low-grade lymphoma. The present study was undertaken
to evaluate the efficacy of culture, histological examination, the rapid urease
test, and serology for the diagnosis of H. pylori infection. A total of 45
consecutive subjects with various upper gastrointestinal symptoms were included
in this study. The rates of diagnosis of H. pylori infection were 51.1%, 55.6%,
82.2%, and 93.3%, by culture, rapid urease test (RUT), histological examination,
and serology, respectively. The sensitivity, specificity, and positive and
negative predictive values were 95.5%, 82.6%, 84.0%, and 95.0%, respectively for
RUT; 95.5%, 30.4%, 56.8%, and 87.5% for histological examination; 100%, 13.6%,
54.8% and 100% for serology.
PMID- 9559441
TI - Discrimination of Listeria monocytogenes strains of serotype 4b by restriction
enzyme analysis of chromosomal DNA.
AB - Epidemiologically related cheese and environmental strains and epidemiologically
unrelated strains of Listeria monocytogenes serotype 4b were examined by
restriction enzyme analysis of chromosomal DNA with a total of 10 restriction
enzymes. The DNA fingerprint patterns generated from each restriction enzyme
digest of total DNA of all strains were classified. The restriction enzyme
patterns of seven strains recovered from cheese and environmental samples in the
same plant were identical to each other, but differed from those of seven
epidemiologically unrelated strains. Two, originating from sporadic human
patients, of eight epidemiologically unrelated strains exhibited the identical
restriction enzyme patterns. Excepting these two strains, restriction enzyme
analysis of the chromosomal DNA of L. monocytogenes serotype 4b can discriminate
serologically indistinguishable strains.
PMID- 9559442
TI - Distribution of Rift Valley fever among cattle in Zambia.
AB - In the present study, 1,421 cattle in 32 herds within nine districts, which are
important cattle-producing centers in the nine provinces of Zambia, were tested
for Rift Valley fever by the indirect immunofluorescence assay. One hundred and
forty-seven cattle (10.5%) in 28 herds (88.9%) in the nine districts tested were
positive for Rift Valley fever implying a country-wide distribution. In districts
associated with flood plains and/or "dambos" (low lying areas of perpetual
flooding), high herd and individual positive rates (100% and > 10%, respectively)
were found, suggesting a significance of these features in the distribution of
the disease.
PMID- 9559443
TI - The effects of cyclosporin A on the polykaryocyte formation induced by measles
virus in a monkey kidney cell line.
AB - The effects of cyclosporin A (CsA) on the polykaryocyte formation induced by
measles virus (MV) in a monkey kidney cell line (BSC-1) were studied. CsA
inhibited virus-induced polykaryocyte formation as well as the production of
infectious MV. The development of polykaryocyte formation in the presence of the
CsA varied with virus strains, while pretreatment of the cells with 5 microM CsA
for 24 hr before the virus infection enhanced polykaryocyte formation. These data
demonstrated that CsA not only inhibits but also enhances virus-induced
polykaryocyte formation depending on the conditions of its use.
PMID- 9559444
TI - A comparison of young and aged populations for the diphtheria and tetanus
antitoxin titers in Japan.
AB - The antitoxin levels for diphtheria and tetanus were measured with samples of a
young group immunized with diphtheria-tetanus-acellular pertussis combined
vaccine and those of an aged group, members of which had not received vaccination
in their youth. In the young group members of which had already received basic
immunization with diphtheria-tetanus-acellular pertussis combined vaccine, the
levels of both antitoxins rose well after injection at 11 to 12 years old with
diphtheria-tetanus combined toxoids and remained high until 20 years of age. In
the aged group, more than 80% showed antitoxin levels above 0.01 u/ml for
diphtheria, while all had levels below that for tetanus, except three persons
with confirmed tetanus immunization history. Maintenance of the protective
antitoxin levels in the population by vaccination is necessary to prevent
outbreaks of infection among unvaccinated or only partially immunized persons.
PMID- 9559445
TI - Pulmonary manifestations of chronic heart failure.
AB - These findings underscore the importance of understanding the complex
interactions of multiple-organ systems in a chronic systemic disease state like
congestive heart failure. The exaggerated ventilatory response in patients with
heart failure is clearly multifactorial and it remains difficult to decipher
whether this response results from or contributes to the sensation of dyspnea.
Pulmonary dysfunction including ventilation-perfusion mismatching, decreased lung
compliance, restriction, airway obstruction, decreased diffusion capacity, and
decreases in respiratory muscle strength and endurance contribute to an
inefficient breathing pattern and increased work of breathing. This is further
compounded by the limited ability of the failing heart to meet the metabolic
demands of the respiratory muscles, leading to under-perfusion and ischemia. This
imbalance contributes to perceived dyspnea and exercise limitations.
Understanding these physiologic cardiopulmonary interactions may lead to
therapeutic modalities, such as respiratory muscle training, aimed at disrupting
this intertwined cycle of events and improving functional capacity in patients
with heart failure.
PMID- 9559446
TI - Predictors of health-related quality of life with cardiac rehabilitation after
acute myocardial infarction.
AB - BACKGROUND: Health-related quality of life (HRQL) instruments provide valid and
responsive outcome measures to assess the impact of disease and the response to
interventions. However, they have not been applied widely to studies of
rehabilitation after myocardial infarction. PURPOSE: To examine the extent to
which baseline sociodemographic and clinical characteristics predict baseline and
change in generic and specific HRQL. METHODS: A randomized controlled trial of an
8-week cardiac rehabilitation intervention or usual care, with follow-up for 12
months, in 201 patients with acute myocardial infarction (MI). Multiple
regression analysis was used to identify predictors of HRQL. RESULTS: Specific
HRQL scores and exercise tolerance improved significantly more in rehabilitation
patients than usual care patients by the end of the 8-week intervention. All HRQL
measures and exercise tolerance in both groups improved significantly during the
12 month follow-up period but the differences between the groups were trivial. A
poor baseline HRQL was the predominant predictor of improved generic and specific
HRQL. Furthermore, greater improvement in HRQL consistently was associated with
lower levels of cardiovascular risks such as absence of a previous MI or coronary
artery bypass surgery, absence of angina, less smoking, and higher exercise
tolerance. CONCLUSIONS: Improved generic and specific HRQL was associated with
poorer baseline HRQL and less baseline cardiovascular risk. This reinforces the
importance of addressing health behavior changes as soon as possible after MI and
the usefulness of assessing both generic and specific HRQL in evaluating
treatment effectiveness.
PMID- 9559447
TI - The development and psychometric evaluation of the Pulmonary Functional Status
Scale: an instrument to assess functional status in pulmonary disease.
AB - BACKGROUND: This article describes the development and psychometric evaluation of
the Pulmonary Functional Status Scale (PFSS). The PFSS was developed to address
the need for a self-administered, disease-specific, functional status outcome
measure that was conceptually based, relatively short, and comprehensively
assessed the psychosocial domains affected by chronic pulmonary disease. METHODS:
Content validity of the PFSS was established by a panel of experts. Construct
validity was determined by principal components factor analysis using data from
365 subjects derived from several studies that used the PFSS. The sample was
predominantly white (80%), married (36%), and male (56%) with a mean age of 68.1
years, mean forced expiratory volume in one second of 1.18 L and mean forced
vital capacity of 2.31 L. Test-retest reliability was evaluated in 17 outpatients
with chronic obstructive pulmonary disease. Concurrent validity was assessed by
correlating responses on the total PFSS with the Sickness Impact Profile (SIP)
score (n = 39), and the 12-minute walk test (n = 104). RESULTS: The factor
structure solution used 35 of the 50 submitted items, explained 48.7% of the
variance, and yielded three factors: Daily Activities/Social Functioning,
Psychological Functioning, and Sexual Functioning. Cronbach's alpha coefficients
for the total PFSS was 0.93 and the test-retest correlation coefficient was rho =
0.75 (P = 0.001). The correlation between the total PFSS score and the SIP and 12
minute walk test were r = -0.54 (P < 0.001) and r = 0.62 (P < 0.001),
respectively. CONCLUSION: The PFSS has solid psychometric properties that make it
acceptable for use in clinical practice as well as research.
PMID- 9559448
TI - A new model for risk stratification and delivery of cardiovascular rehabilitation
services in the long-term clinical management of patients with coronary artery
disease.
AB - This model for risk stratification includes variables that classify patients for
Risk of Event similar to current models of risk stratification, as well as
variables that stratify patients for Risk of Progression of Atherosclerosis by
established risk factors. Categories of risk are established using accepted data
from the literature for each risk factor that targets regression or plaque
stabilization as the goal for Low Risk. A case-rate charging system and the
proposed removal of time restrictions for length of cardiovascular rehabilitation
fit neatly into the present climate for health care. Health maintenance
organizations will be seeking programs that use similar models to address cost
issues inherent in cardiovascular rehabilitation programs under current fee-for
service models. Improved outcomes will also be targets for these programs and
case-management lends itself to disease management, thus, improved outcomes.
Tracking outcomes becomes even more important to both the provider and the
insurer because results drive referrals. Likewise, removal of the time
restriction for cardiovascular rehabilitation allows programs to individualize
care and to target risk factors that are not only most deleterious, but also
where patients show readiness for change. The changing environment of health care
virtually mandates change in cardiovascular rehabilitation. It is imperative that
programs manage the disease process, are effective in achieving outcomes that
affect both patient function and the disease process, and are cost effective.
This model for risk stratification and delivery of services addresses these
requirements and provides a beginning for implementing these changes in
cardiovascular rehabilitation.
PMID- 9559449
TI - Helping older patients to cope with cardiac and pulmonary disease.
AB - Family challenges, depression, and age-related developmental and psychological
issues must be considered when structuring interventions for elder
cardiopulmonary patients. Elderly patients tend to have difficulty coping when
they face novel, unpredictable circumstances and are left to flounder in
suspenseful anticipation. Furthermore, if support is not forthcoming during such
times--or if they are treated in ways that strip them of control rather than in
ways that bolster their sense of control--elderly patients are at great risk of
quickly developing a passive, learned helplessness that can significantly
complicate their rehabilitation. The overall well-being of elderly
cardiopulmonary patients is affected by more than the actions of health-care
providers. Poverty, pension and health-care plans, institutionalization,
concomitant diseases, family issues, and other factors have a profound and,
frequently, an overriding effect on the functional status of the elderly
population. However, it is also true that the provision of spirit-enhancing care
can make a tremendous difference in quality of life for elderly patients,
independent of factors such as residential circumstance or health status. The
most valued and valuable sources of social support for elderly patients come from
family, church, and health-care providers. Our interventions either enhance or
diminish an elderly patient's sense of autonomy and control. Our task-driven
health-care system, replete with its growing emphasis on brevity of treatments
and cost-effectiveness, can create a style and pace of delivering care that
demoralizes an elderly patient. The results can be devastating: "When the spirit
is broken, one has no will to marshall coping skills". But health-care providers
who are attuned to the psychosocial issues relevant to the later life stages can
make a profound difference in enhancing both rehabilitation and quality of life
for elderly cardiopulmonary patients and their loved ones.
PMID- 9559450
TI - Impact of steady-state and exercise modality on estimating oxygen consumption in
men with and without coronary artery disease.
AB - PURPOSE: This study examined the effect of steady-state on the ability of 15 men
with coronary artery disease (CAD) and 13 men without CAD disease (non-CAD) to
reach a rate of oxygen consumption (VO2) relative to population norms during
treadmill and cycle ergometry exercise testing. METHODS: Subjects completed a
maximal graded exercise test on the treadmill and cycle ergometry involving 3
minute stages and a submaximal exercise test involving 6-minute stages to 80% of
maximal effort. Estimates of VO2 were derived from commonly cited clinical
estimation equations. RESULTS: Only the Foster equation accurately estimated
maximal VO2 during a treadmill graded exercise test in patients with CAD.
However, each of cited clinical equations accurately estimated maximal VO2 during
a treadmill graded exercise test in the non-CAD group. No equation accurately
estimated VO2 at submaximal efforts during treadmill exercise for either group.
Cycle ergometry estimation equations accurately estimated VO2 in both groups at
maximal effort, but were inconsistent at submaximal efforts. Both the CAD and the
non-CAD group reached steady-state VO2 within 3 minutes, at submaximal workloads.
CONCLUSIONS: The inability to attain an expected VO2 during exercise did not seem
related to steady-state VO2 because both CAD and non-CAD groups readily reached
steady-state VO2, though the estimation of VO2 remained inaccurate for most
treadmill estimation equations. Because VO2 was accurately estimated for cycle
ergometry exercise, estimation accuracy seems to be influenced by exercise
modality.
PMID- 9559451
TI - The assessment of recovery in patients after myocardial infarction using three
generic quality-of-life measures.
AB - BACKGROUND: To evaluate the sensitivity to change of three generic quality-of
life measures in patients after myocardial infarction (MI). METHODS: Patients
admitted to the Coronary Care Unit of Royal Devon and Exeter Healthcare Trust
over a 9-month period were selected on the basis of a first MI and under 80 years
of age. Quality of life was assessed 6 weeks and 6 months after MI using the
Sickness Impact Profile (SIP), Nottingham Health Profile (NHP), and McMaster
Health Inventory Questionnaire (MHIQ). An index of whether these measures are
sensitive to change over time was determined by dividing the mean change from 6
weeks to 6 months of each instrument subscale by the baseline standard deviation
of that subscale. Values of 0.2, 0.5, and 0.8 and above represent modest,
moderate, and good sensitivity, respectively. RESULTS: Eighty-eight patients
completed and returned the quality-of-life measures at both 6 weeks and 6 months.
Four SIP subscales achieved a sensitivity to change index of 0.20 to 0.50: body
care and movement, emotional behavior, work, and eating. Other SIP, NHP, and MHIQ
subscales showed sensitivity index values of less than 0.20. No sensitivity index
values of 0.50 or more were observed. CONCLUSIONS: During the period of this
study, all three generic quality-of-life measures displayed only modest levels of
sensitivity to change. Other quality-of-life measures need to be developed for
the assessment of cardiac patients. This is particularly important when choosing
suitable quality-of-life measures to assess cardiac rehabilitation.
PMID- 9559453
TI - Format for reporting refractive surgical data.
PMID- 9559452
TI - Circuit weight training in cardiac patients: determining optimal workloads for
safety and energy expenditure.
AB - BACKGROUND: While most studies suggest circuit weight training (CWT) to be safe
in cardiac rehabilitation populations, few investigators have controlled
variables known to impact CWT intensity. Therefore, the purposes of this study
were to determine the energy cost and evaluate safety of cardiac patients while
varying rest interval duration and lifting load in a CWT format. METHODS: Nine
male subjects with documented coronary artery disease had maximal oxygen uptake
(VO2max), one-repetition maximum (1-RM), and body composition tested. In random
order and on separate days, 4 CWT sessions using either 40% or 60% of the 1-RM,
and either 30 or 60 seconds of rest between stations were completed. Energy cost,
heart rate (HR), blood pressure (BP), and rate-pressure product (RPP) were
measured. Data were analyzed with a repeated measures analysis of variance, and
Tukey's post-hoc test was performed when significant results were found. The
alpha level was set at < .05. RESULTS: Subjects exercised at 25% to 32% of VO2max
(58%-67% of HRmax) during CWT. The HR and RPP responses were lower during all CWT
protocols than at 85% of the treadmill VO2max. No subject displayed any ST
segment depression or angina during CWT. The 40%-60-second protocol had an energy
cost (2.98 kcal/min) that was lower (P < .05) than the other protocols (3.48-3.81
kcal/min). Increasing the lifting load resulted in increases (P < .05) in energy
cost, and decreasing the rest interval increased energy cost only during the 40%
1-RM protocols. CONCLUSIONS: Results indicate that CWT protocols of varied
intensity are safe for cardiac patients when compared to treadmill exercise, and
changes in rest interval duration and load can impact the energy cost.
PMID- 9559454
TI - Ophthalmologic biocompatibility: anachronism or oxymoron?
PMID- 9559455
TI - Screening for pupil size in prospective refractive surgery patients.
PMID- 9559456
TI - Screening for pupil size in prospective refractive surgery patients.
PMID- 9559457
TI - Screening for pupil size in prospective refractive surgery patients.
PMID- 9559458
TI - Screening for pupil size in prospective refractive surgery patients.
PMID- 9559459
TI - Screening for pupil size in prospective refractive surgery patients.
PMID- 9559460
TI - Screening for pupil size in prospective refractive surgery patients.
PMID- 9559461
TI - Consultation section. Refractive surgical problem.
PMID- 9559462
TI - Managing inferior zonule tears during manual extracapsular cataract extraction.
AB - We describe a new technique for safely concluding manual extracapsular cataract
extraction in the presence of a rupture of the interior zonules. A lens glide is
inserted in the anterior chamber. The tip of the glide is placed in the inferior
part of the capsular bag, pushing it toward the ciliary sulcus at 6 o'clock. The
extraocular part of the glide is sutured to the sclera to prevent its
displacement during manipulation of the eye. The glide spreads the rolled
inferior capsule, allowing aspiration of retained cortical material and in-the
bag intraocular lens implantation. The glide is then removed. This technique was
used in 12 eyes with pseudoexfoliation in which the complication occurred. No
vitreous loss, lens displacement, or other intraoperative or postoperative
complications were observed.
PMID- 9559463
TI - Photorefractive keratectomy for residual myopia after radial keratotomy. PRK
After RK Study Group.
AB - PURPOSE: To evaluate the visual outcomes in patients having photorefractive
keratectomy (PRK) to correct residual myopia after radial keratotomy (RK).
SETTING: Nine refractive surgery centers in the United States and one in South
Korea. METHODS: This retrospective analysis comprised 38 eyes of 32 patients
treated with PRK after RK and followed for 12 months. Analysis was based on pre
RK and pre-PRK refraction as well as response to RK (pre-RK minus pre-PRK
refractions). RESULTS: Mean pre-RK and pre-PRK refractions were -8.11 diopters
(D) +/- 2.92 (SD) and -4.28 +/- 2.08 D, respectively. One month after PRK, mean
refraction was +0.42 +/- 1.56 D and regressed to -0.95 +/- 1.24 D at 12 months.
At 12 months, 65% of eyes had an uncorrected visual acuity of 20/40 or worse, and
11.1% lost 2 or more lines of best corrected acuity. Of eyes with an original
erro of -6.00 or less, 81.8% were within +/- 1.00 D of intended correction at 12
months and of those with an original error of -9.12 to -20.00 D 50.0% (P = .004).
All eyes with residual (pre-PRK) errors of -3.00 D or less and 42.9% with a
residual error of -6.12 to -9.00 D were within +/- 1.00 D of intended correction
(P = .07). There were no statistically significant differences in the response to
PRK between eyes that had an RK response of 0 to 3.00, 3.12 to 6.00, or 6.12 to
12.00 D. CONCLUSION: Patients with lower original and residual myopia achieved
better visual outcomes after PRK than those with higher myopia. The amount of
myopic correction achieved using RK was not predictive of the amount of myopic
correction using PRK.
PMID- 9559464
TI - Predictability of radial keratotomy after excimer laser photorefractive
keratectomy.
AB - PURPOSE: To evaluate the results of radial keratotomy (RK) after photorefractive
keratectomy (PRK). SETTING: London Centre for Refractive Surgery. METHODS: This
study comprised six eyes having RK enhancement after PRK. Outcome measures were
the effect of the incisions on post-PRK haze and best corrected visual acuity
(BCVA), predictability of the result on already flattened corneas, and the
validity of standard radial keratotomy (RK) nomograms. All PRKs were done when
refraction was stable with one of two VISX lasers: the Twenty-Twenty or Star.
Mean follow-up was 14 months. RESULTS: All eyes had further corneal flattening.
The standard RK nomograms were deemed appropriate. There was no loss of BCVA
because of aggravated haze of irregular astigmatism. CONCLUSION: Radial
keratotomy after PRK proved safe, economical, and effective after PRK in six
eyes.
PMID- 9559465
TI - Radial keratotomy for residual myopia after photorefractive keratectomy.
AB - PURPOSE: To evaluate the safety, efficacy, and complications of radial keratotomy
(RK) after photorefractive keratectomy (PRK) for myopia. SETTING: Laser
Ultravision Institute. Montreal, Canada. METHODS: Surgically induced refractive
and visual acuity changes were retrospectively evaluated in 14 eyes of 10
patients treated with RK after PRK. All patients had simple myopia or compound
myopic astigmatism. Minimum follow-up was 6 months. RESULTS: Three eyes (21%) had
one PRK, 7 (50%) had two treatments, and 4 (29%) had three. Eleven eyes (79%)
required four-incision RK and 3 (21%), eight-incision RK. All patients had
improved uncorrected visual acuity. Six months after the RK retreatment, there
was a significant reduction in spherical equivalent of 2.93 diopters +/- 1.53
(SD) (P < .05). No intraoperative or postoperative complications occurred except
overcorrection (two cases). CONCLUSION: Radial keratotomy is an effective, safe
method for treating undercorrected myopia after PRK. Further study and analysis
of this series of patients are planned.
PMID- 9559466
TI - Prompt re-treatment after photorefractive keratectomy.
AB - PURPOSE: To study eyes that received a photorefractive keratectomy (PRK)
retreatment 1 to 4 months after the first treatment and describe refractive
stability and complications. SETTING: Michael Pop CLinics, Montreal, Canada.
METHODS: Twenty-six eyes of 20 patients were re-treated for undercorrection and,
regression with or without haze. Postoperative refractions were performed at 1,
2, 3, and 6 months. Haze was evaluated on a scale of 0 to 4. RESULTS: Ninety
percent of the 21 eyes followed for 6 months after re-treatment achieved an
uncorrected visual acuity of 20/40. At 6 months, 67 and 95% of eyes were within
+/- 0.50 diopter (D) and +/- 1.00 D, respectively. Regression between 1 and 6
months after re-treatment was 0.71 D, which represented less than one half that
observed after the initial treatment. Six months after re-treatment, haze
decreased by half, and no eye had haze above 1. Best corrected visual acuity
(BCVA) before treatment was well correlated with values 6 months after re
treatment (P < .001). At 6 months, 1 eye lost two lines of BCVA but had an acuity
of 20/30 and 2 eyes lost one line of BCVA. CONCLUSION: Prompt re-treatment after
PRK for myopia allowed management of undercorrections and regressions with low
morbidity and high refractive stability. By re-treating promptly, no additional
complications were created and patients avoided long periods of unsatisfactory
vision.
PMID- 9559467
TI - Photorefractive keratectomy for pediatric myopic anisometropia.
AB - PURPOSE: To evaluate the visual results of excimer laser photorefractive
keratectomy (PRK) to treat pediatric patients with amblyopic myopic anisometropia
in whom conventional amblyopia treatments have failed. SETTING: Instituto
Oftalmologico de Alicante, University of Alicante, Spain. METHODS: Six patients
aged 5 to 7 years with amblyopic myopic anisometropia were treated by PRK in the
more myopic eye using a VISX Twenty-Twenty excimer laser. Minimum preoperative
refraction in the amblyopic eyes ranged from -4.00 to -13.00 diopters and best
corrected visual acuity (BCVA), from 20/40 to 20/400. All cases completed a
minimum of 2 years follow-up of antiamblyopic treatment. RESULTS: After PRK,
preoperative BCVA was maintained without optical correction and complementary
refraction resulted in increased BCVA in every case. One patient with high myopia
developed severe haze. There were no other significant complications. CONCLUSION:
Our results indicate that PRK may be an alternative for the correction of
pediatric myopic anisometropia and an important aid in treating amblyopia. When
other therapies have failed, using PRK in children of the ages in this study must
be carefully evaluated; however, our results suggest a beneficial effect.
PMID- 9559468
TI - Corneal infection after radial keratotomy.
AB - PURPOSE: To evaluate nine eyes that developed corneal infection after radial
keratotomy (RK) and their subsequent management. SETTING: Dr. Rajendra Prasad
Centre for Ophthalmic Sciences, New Delhi, India. METHOD: The parameters
evaluated were interval between RK and development of the ulcer, number of
keratotomy incisions, nature of surgery (primary or secondary), status at
presentation, and best corrected visual acuity (BCVA). Corneal scrapings were
taken from all eyes for microbiological evaluation. Initial therapy was based on
clinical impression and subsequent therapy, on the microbiological report.
RESULTS: Staphylococcus species were the most frequently isolated bacteria
followed by Pseudomonas aeruginosa. Two eyes had fungal growth, and no organisms
were isolated from one. All but one eye responded to medical therapy; healing
took 23 to 26 days. Therapeutic penetrating keratoplasty (PKP) was done in one
eye. Presenting BCVA of hand movement to 6/36 improved to hand movement to 6/18
after the ulcer healed. Final BCVA was 6/36 to 6/9 after lamellar keratoplasty or
PKP or with contact lens of spectacle correction. CONCLUSION: Our study shows
that corneal infection is a potential complication of RK. Therefore, persistent
postoperative irritation should be carefully observed to ensure early diagnosis
and prompt therapy.
PMID- 9559469
TI - Factors that influence patient choice of an excimer laser treatment center.
AB - PURPOSE: To identify the factors that most influenced patient choice of an
excimer laser treatment center and those most likely to deter patients from
selecting a particular center. SETTING: A National Health Service (NHS) excimer
laser unit in the northeast of England. METHODS: An anonymous 24-item
questionnaire was constructed. Each question had a visual analogue scale,
anchored at each end with an adjectival description. Patients were asked to mark
their response to the related question on the scale. Using the database of over
300 patients treated by excimer laser photorefractive keratectomy (PRK) at
Sunderland Eye infirmary between May 1993 and December 1995, the first 140
consecutive patients were identified. Questionnaires were sent to them and
returned between August 1 and October 31, 1995. RESULTS: A 64.3% reply rate (90
patients) was achieved. Overall, the results suggest that patients considered
many factors to be important in their selection of a treatment center for PRK
correction of myopia. Over 95% said that treatment and review by a consultant
ophthalmologist, comprehensive follow-up appointments, professional attitude by
staff, and reputation of the hospital were important factors in their selection
of the center. Ninety to 95% said confidence in the clinical reputation and
skills of the ophthalmic surgeons performing the treatment was important, as was
having follow-up by only one or two staff members. Slightly more than 50% said
that being treated in an NHS hospital setting (51.7%) or that expense of the
treatment (50.5%) were important factors in their decision. CONCLUSION: Patients
who chose to have excimer laser PRK based their choice of a unit on reputation of
the staff and hospital but also on having care and follow-up by a consultant
ophthalmic surgeon, high standards of equipment, continuity of care, and a
comprehensive review system backed up by ready accessibility to staff members.
Although proximity of a unit was important, cost appeared less important than the
other factors.
PMID- 9559470
TI - Contact-angle analysis of intraocular lenses.
AB - PURPOSE: To present contact-angle measurements of commercially available
intraocular lenses (IOLs) in air and in water to facilitate the understanding of
how various IOLs might interact in different environments. SETTING: Laboratory.
METHODS: Five commercially available IOLs were studied: AMO DuraLens PS-59NB. AMO
PhacoFlex SI-26NB, AMO PhacoFlex II SI-30NB, Chiron ChiroFlex C10UB, and Alcon
AcrySof MA60BM. The AMO soft acrylic model AR40, currently under clinical study,
was also evaluated. Contact-angle measurements were made in air and in water
using sessile drop and captive bubble methods. RESULTS: The sessile drop method
indicated that all materials were hydrophobic in air. The captive bubble method
differentiated materials based on their polar and dispersive forces. CONCLUSION:
Contact-angle measurements differed depending on the test conditions. Proper
choice of contact-angle measurement method can generate useful information about
a material surface and its potential biomaterial interactions.
PMID- 9559471
TI - Relationship between intraocular lens biomaterials and posterior capsule
opacification.
AB - PURPOSE: To determine whether posterior capsule opacification (PCO) is influenced
by intraocular lens (IOL) material. SETTING: A British teaching hospital eye
department. METHODS: Ninety eyes were prospectively randomized to receive a
poly(methyl methacrylate) (PMMA), silicone, or AcrySof IOL. All lenses had 6.0 mm
optics and PMMA haptics. A standardized surgical protocol was performed by a
single surgeon using an extracapsular technique with capsulorhexis. Patients
having surgical complications were excluded and all patients had standardized
medication and follow-up. Posterior capsule opacification was assessed by a
digital retroillumination camera using a dedicated software program based on the
analysis of texture in the image and calculated as the percentage area of
opacified capsule. Data were analyzed 2 years postoperatively. RESULTS: There was
a significant difference in percentage of PCO at 2 years among the three lens
types (P < .0001). The AcrySof lenses were associated with less PCO (median
11.75%) than PMMA (43.65%) and silicone (33.50%) lenses (P < .001 and P = .025,
respectively). The difference between PMMA and silicone lenses was not
statistically significant. CONCLUSION: Intraocular lenses made from AcrySof were
associated with a significantly reduced degree of PCO.
PMID- 9559473
TI - Adhesiveness of AcrySof to a collagen film.
AB - PURPOSE: To measure the adhesiveness of the AcrySof intraocular lens (IOL) to a
collagen film to ascertain its capacity to adhere to the lens capsule. SETTING:
Haibara General Hospital, Haibara, and Hamamatsu University School of Medicine,
Hamamatsu, Shizuoka, Japan. METHODS: Each of five AcrySof IOLs was attached to a
collagen film, slightly pressed in intraocular irrigating solution, and then
pulled up and off the film with a DuNouy's surface balance. The force recorded by
the surface balance at the moment it detached from the film was defined as the
lens' adhesiveness. A control experiment was performed using five conventional
poly(methyl methacrylate) (PMMA) IOLs. RESULTS: Mean adhesiveness was 2.76 gram
weight (gw) +/- 0.55 (SD) for AcrySof and 0.81 +/- 0.20 gw for PMMA. The
difference was statistically significant (P < .0001, t-test). CONCLUSION: AcrySof
may have a strong tendency to adhere to the lens capsule, contributing to
posterior and anterior capsule clarity and preventing lens decentration in vivo.
PMID- 9559472
TI - Biocompatibility of poly(methyl methacrylate), silicone, and AcrySof intraocular
lenses: randomized comparison of the cellular reaction on the anterior lens
surface.
AB - PURPOSE: To determine the foreign-body response to three intraocular lens (IOL)
biomaterials (poly[methyl methacrylate] [PMMA], silicone, and AcrySof) and use
this as an indicator of their comparative biocompatibility postoperatively within
the eye. SETTING: A British teaching hospital eye department. METHODS: Ninety
eyes were prospectively randomized to receive a PMMA, silicone, or AcrySof IOL.
All lenses had 6.0 mm optics with PMMA haptics. A standardized surgical protocol
was performed by a single surgeon using an extracapsular technique with
capsulorhexis; eyes that experienced a surgical complication were excluded. All
patients had standardized postoperative medication and follow-up. Specular
microscopy of the anterior IOL surface was carried out after pupil dilation on
days 1, 7, 30, 90, 180, 360, and 720 to assess small cell and giant cell
reactions. RESULTS: All three IOL types produced a mild degree of nonspecific
foreign-body response, which resolved over the study period without detrimental
effect. The silicone group had significantly higher small cell counts than the
PMMA and AcrySof groups (P = .02); the AcrySof group had significantly lower
giant cell counts than the other two groups (P = .003). CONCLUSION: The three IOL
types were sufficiently biocompatible to function in normal eyes with age-related
cataracts. However, AcrySof IOLs were associated with lower giant cell counts
than PMMA and silicone IOLs and might produce better results in eyes with pre
existing blood-aqueous barrier damage.
PMID- 9559474
TI - In vivo study of a fluorocarbon polymer-coated intraocular lens in a rabbit
model.
AB - PURPOSE: To evaluate the biocompatibility in rabbit eyes of poly(methyl
methacrylate) (PMMA) intraocular lenses (IOLs) that were surface modified using
Teflon AF. SETTING: Hotel-Dieu Hospital, Paris Cedex, France. METHODS: The IOLs
were coated with Teflon AF, an amorphous, transparent, and highly hydrophobic
fluorocarbon polymer, by immersing them in Teflon AF 5% and evaporating the
solvent (C8F18). The surface quality of the Teflon-coated IOLs was evaluated by
scanning electron microscopy (SEM). Teflon-coated (n = 20) and control PMMA (n =
10) IOLs were implanted in rabbit eyes. The presence of iris-IOL synechias and
the number of deposits on the IOL surfaces were clinically evaluated in both
groups to assess the antiadhesive effect of Teflon AF. The Teflon-coated IOLs
were removed, their surfaces were evaluated by SEM, and their elemental
composition was checked by EDXA and Raman spectrometry. RESULTS: The PMMA IOLs
were completely coated with Teflon AF. The Teflon group had no iris-IOL synechias
and the control group, two extensive synechias. There were significantly fewer
deposits on the surfaces of Teflon-coated IOLs than on the control IOLs 30 and 60
days postoperatively (P < .0001). Scanning electron microscopy showed lens
epithelium proliferation and spindle-shaped cells on the surfaces of the PMMA
IOLs and cell deposits on the irregular regions of the Teflon-coated IOLs. White
yellow spots were present on the surfaces of both IOL types. The elemental
composition of Teflon-coated IOLs was stable. CONCLUSION: Teflon AF had an
antiadhesive effect that increased the biocompatibility of PMMA IOLs in vivo.
PMID- 9559475
TI - Biocompatibility and blood-aqueous barrier impairment in at-risk eyes with
heparin-surface-modified or unmodified lenses.
AB - PURPOSE: To evaluated the influence of heparin-surface-modified (HSM) versus
unmodified poly(methyl methacrylate) (PMMA) intraocular lenses (IOLs) on the
blood-aqueous barrier (BAB) in at-risk eyes. SETTING: Department of
Ophthalmology, Bundesknappschaft's Hospital, Sulzbach Germany. METHODS: This
study comprised 100 patients with predisposing risk factors for BAB
destabilization (e.g., diabetes mellitus with or without retinopathy, glaucoma,
pseudoexfoliation, uveitis). One eye in each patient received an HSM IOL and the
fellow eye, a conventional unmodified PMMA IOL after phacoemulsification by the
same surgeon. Anterior chamber flare was measured with the Kowa 500 laser flare
meter 1 day before and 1 day, 1 and 6 weeks, and 3 months after surgery. RESULTS:
For most risk factors, mean flare was lower in the HSM group than in the PMMA
group at most follow-ups. Significantly lower flare values (difference between
postoperative and preoperative mean values) were seen in eyes with the HSM IOL at
6 weeks (P < .004) and 3 months (P < .003; Student's t-test). In the group with
preoperative elevated flare values, the eyes with the HSM IOL had significantly
better results 6 weeks (P < .0006) and 3 months (P < .01) postoperatively. The
values in the HSM IOL eyes were also significantly higher in the diabetic with
retinopathy group at 3 months (P < .003). CONCLUSION: The results confirm the
efficacy of IOL surface modification in reducing postoperative intraocular
reaction in at-risk eyes.
PMID- 9559476
TI - Low-vacuum, low-voltage scanning electron microscopy of poly(methyl methacrylate)
intraocular lenses.
AB - PURPOSE: To evaluate the usefulness of low-vacuum, low-voltage scanning electron
microscopy (LVSEM) in examining the surfaces of intraocular lenses (IOLs) without
preparation. SETTING: In vitro laboratory experiment. METHODS: Six commercially
available IOLs made of poly(methyl methacrylate) (PMMA) and one explanted PMMA
IOL were evaluated with LVSEM without sputter coating. Sham surgical maneuvers
were performed on some IOLs and the surface changes observed. RESULTS: Smooth
surfaces of IOL optics and haptics, relatively sharp edges of optic holes, and
irregularities at the optic/haptic junction were clearly observed. Crystalline
deposits were seen on the surfaces after the IOLs were dipped and dried in saline
solution. Scratches and marks were observed after they were grasped with a
forceps. CONCLUSIONS: Low-vacuum, low-voltage scanning electron microscopy is a
time-saving procedure that can be used by inexperienced investigators. The
resolution under relatively low magnification appeared to be satisfactory for
evaluating the IOL surface.
PMID- 9559477
TI - Analysis of zonular-free zone and lens size in relation to axial length of eye
with age.
AB - PURPOSE: To evaluate the anatomical relationships of the zonular-free zone (ZFZ)
of the anterior capsule and crystalline lens diameter in relation to the axial
length of the eye with age. SETTING: Department of Ophthalmology, Yonsei
University College of Medicine, Seoul, Korea, and Storm Eye Institute, Medical
University of South Carolina, Charleston, South Carolina, USA. METHOD: Various
ocular structures in 122 eyes obtained post-mortem were measured without prior
preparation. The correlation between age, anterior-posterior (A-P) length and
globe size, and diameters of the cornea, crystalline lens, and ZFZ were analyzed.
RESULTS: The average A-P globe length, and corneal, lens, and ZFZ diameters were
24.48, 11.67, 9.65, and 6.93 mm, respectively. There was no significant
relationship between A-P length and globe size and corneal diameter in different
age groups. The ZFZ size varied negligibly among age groups. There was a
statistically significant correlation between lens diameter and age (correlation
coefficient = 0.2647; P < .01) and lens diameter and A-P globe length
(correlation coefficient = 0.3183; P < .001). CONCLUSIONS: When choosing an
intraocular lens, one should consider the patient's age and the A-P globe length.
Six eyes (5%) showed unusual anterior insertion of zonular attachment, which
reminds us to be prudent with a large paracentral capsulorhexis.
PMID- 9559478
TI - Ideal size of an intraocular lens for capsular bag fixation.
AB - PURPOSE: To determine the ideal size of an intraocular lens (IOL) for proper
capsular bag fixation in different sizes of evacuated capsular bags. SETTING:
Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea,
and Storm Eye Institute Medical University of South Carolina, Charleston, South
Carolina, USA. METHODS: Fifteen eyes obtained post-mortem were divided by
crystalline lens size into three groups. Intraocular lenses of five different
sizes were implanted in each capsular bag. The arc of contact between the haptics
and capsular equator and the capsular bag distortion with each IOL were measured
and compared using posterior-view analysis. RESULTS: The arc of contact was
directly proportional to the IOL size and inversely related to the lens size. The
smallest arc of contact was 2.0 mm with the smallest IOL implanted in the largest
lens group. The maximum capsular bag distortion was 2.6 mm in the case of the
largest IOL implantation in the smallest lens group. CONCLUSION: Implanting an
IOL smaller than 12.5 mm in a large capsular bag can result in unstable fixation,
while implanting an IOL larger than 12.5 mm in a small capsular bag can result in
excessive stretching and distortion of the capsular bag and surrounding zonules.
PMID- 9559479
TI - Topical versus peribulbar anesthesia, without sedation, for clear corneal
phacoemulsification.
AB - PURPOSE: To investigate patient and surgeon acceptance of topical anesthesia as
an alternative to peribulbar anesthesia for clear corneal phacoemulsification.
SETTING: Department of Ophthalmology, Whipps Cross Hospital, London, England.
METHODS: All cataract surgery was performed using a temporal clear corneal
approach, bimanual phacoemulsification, and in-the-bag intraocular lens
implantation. The results of 51 patients having surgery under topical anesthesia
(amethocaine) were compared with those of 30 patients having peribulbar
anesthesia (50:50 mixture of lignocaine 2% and bupivacaine 0.5% with
hyaluronidase). No sedation was used in either group. Pain perception on
administration of the anesthetic, perioperatively (period immediately surrounding
and during surgery), and postoperatively was assessed using a visual analog scale
from 0 to 10 (0 = no pain: 10 = worst pain imaginable). A questionnaire was used
to assess the degree of patient and surgeon satisfaction. RESULTS: Administration
of topical amethocaine was significantly less painful than peribulbar bupivacaine
(P = .03). Perioperative pain showed a trend toward being worse in the topical
anesthesia group but did not reach statistical significance. There was no
difference in the postoperative pain scores of the two groups. The surgical
experience was rated very satisfactory by 67% in the topical group and 73% in the
peribulbar group. The surgeons reported no difficulties or complications.
CONCLUSION: Topical anesthesia was safe and effective for clear corneal
phacoemulsification and was well tolerated by patients. The slightly greater
awareness of ocular discomfort in the topical group perioperatively did not alter
patient satisfaction with the surgical experience when compared with the
peribulbar group.
PMID- 9559480
TI - Validation of a handheld automated keratometer in adults.
AB - PURPOSE: To evaluate the Nidek handheld automated keratometer and compare it with
the manual Zeiss keratometer. SETTING: St. Paul's Eye Unit, Royal Liverpool
University Hospital, Liverpool, United Kingdom. METHODS: Forty-five normal adult
volunteers were included in the study. Three sets of randomized keratometry
measurements were taken from both eyes of each adult, with both instruments by
two independent observers. Readings included powers of the steep and flat
meridians and axis of the flat meridian. The mean difference between the two
instruments was calculated. The variance of each instrument was calculated for
the axis, the steep and flat meridians, and the mean of the two meridians.
RESULTS: There was no significant difference between the mean Nidek and Zeiss
keratometry readings for the steep (0.015 mm; P = .167) or flat (0.054 mm; P =
.069) meridian or axis measurements (P = .172). On repeated measurements, the
within-subject and within-group variabilities, calculated separately for each
instrument, were significantly less for the Nidek automated keratometer than the
Zeiss keratometer (P < .01) when measuring the steep and flat meridians. There
was however, a significant increase in axis variability using the Nidek
keratometer (range 20 degrees; P < .01). CONCLUSION: The Nidek automated
keratometer was accurate, reliable, and easy to use and compared favorably with
the manual Zeiss keratometer when measuring corneal curvature. In the handheld
mode, the Nidek is not suitable for axis measurements. It has the additional
advantage of portability.
PMID- 9559481
TI - Compression forces of haptics of freely rotating posterior chamber intraocular
lenses.
AB - PURPOSE: To measure the compressive forces of the haptics of 28 intraocular lens
(IOL) models for different modes of compression and compare the results of two
types of measurements. SETTING: Department of Ophthalmology, Central Hospital of
Central Finland, Jyvaskyla, Finland. METHODS: The haptics of 28 types of IOLs
were compressed to a diameter of 9.0 mm between curved anvils. The compression
forces in the plane of compression (i.e., in the plane of the optics) were
measured at 0.5 mm intervals. During compression, the optics and the haptics were
free to rotate with respect to the anvils. The results were compared with those
of earlier measurements in which the optics were held fixed during compression.
Perpendicular forces were measured at 0.4 mm intervals. RESULTS: The measured
forces in the plane of the optics varied between 114 and 659 mg at a diameter of
10.0 mm and 192 and 1047 mg at a diameter of 9.0 mm. When compressed to 10.0 mm
in diameter, the forces were 1 to 75% lower than when lens rotation was not
possible. The forces perpendicular to the optic varied between 0 and 96 mg at a
10.0 mm diameter and correlated with the forces in the plane of the optic.
CONCLUSION: The compression forces of the lens haptics were generally lower when
the lenses were allowed to rotate during compression. The orders of stiffness of
the haptics in these two measurements were similar. The perpendicular forces were
generally small and correlated significantly with the forces measured in the
plane of the optic.
PMID- 9559482
TI - Effects of a large supper on glucose levels the following morning in patients
with type 2 diabetes.
AB - Seventeen patients were studied to test the hypothesis that a large evening meal
influences the fasting glucose level and glucose tolerance the following morning
in patients with type 2 diabetes. Oral hypoglycemic agents were discontinued for
2 weeks. The baseline fasting plasma glucose levels were 12.3 +/- 0.9 mmol/L.
Fasting and postprandial (post-Sustacal) glucose, insulin, and C-peptide
measurements were performed the morning after the patients received three
separate meal protocols spaced 1 week apart. The caloric distribution of the meal
protocols was (1) 7 kcal/kg of ideal body weight breakfast and lunch and 14
kcal/kg supper (small supper); (2) 7 kcal/kg breakfast and lunch and 28 kcal/kg
for supper (large supper); and (3) 14 kcal/kg breakfast and lunch (no supper).
Fasting glucose level were higher the morning after the large supper compared to
no supper (13.6 +/- 0.7 versus 12.3 +/- 0.5 mmol/L, p < 0.05) and also to the
small supper (13.6 +/- 0.7 versus 12.5 +/- 0.6 mmol/L, p = 0.05). No difference
was observed in the fasting glucose levels between the small supper and no supper
(p > 0.2). The fasting insulin and C-peptide levels, and the post-Sustacal areas
under the curve of glucose, insulin, and C-peptide did not differ among the
meals. In patients with type 2 diabetes, a large evening meal is associated with
a modest elevation in fasting glucose the following morning.
PMID- 9559483
TI - Cilazapril and dietary gamma-linolenic acid prevent the deficit in sciatic nerve
conduction velocity in the streptozotocin diabetic rat.
AB - Young adult male Hooded Wistar rats were rendered diabetic by administration of
streptozotocin and maintained for 5 weeks on a diet containing either 6% olive
oil as the total source of fat (OO diet), or purified gamma-linolenic acid (GLA)
at a concentration of 0.5% with the remaining 5.5% provided by olive oil (GLA
diet). Rats were treated with the angiotensin converting inhibitor, cilazapril,
administered in the drinking water at a dose of 20 mg kg-1 body weight day-1. For
the OO diet groups, sciatic nerve conduction velocity (NCV) in diabetic rats was
reduced by 32% (p < 0.01) in comparison with nondiabetic (vehicle-treated) rats
and 27.5% (p < 0.05) in comparison with diabetic rats treated with cilazapril.
Diabetic, cilazapril-treated rats showed no reduction in NCV. For the
nondiabetic, diabetic, and diabetic plus cilazapril groups fed GLA, the NCV was
not significantly different, indicating that dietary GLA also prevented the
deficit in the NCV induced by the diabetic state. Analysis of the sciatic nerve
endoneurial phospholipid fatty acids revealed a significant reduction in the
proportion of GLA and an elevation in the proportion of linoleic acid in the
diabetic groups compared with the nondiabetic groups and this was independent of
the cilazapril treatment or the dietary lipid supplement. Sciatic nerve myo
inositol content was unaltered while mannose, fructose, glucose, and sorbitol
levels were elevated in the diabetic groups and these changes were independent of
the cilazapril treatment or the dietary lipid supplement. These results indicate
that in the rat, cilazapril treatment or dietary GLA, at the doses tested, are
effective in preventing the deficit in the NCV induced by diabetes.
PMID- 9559485
TI - Calcaneal fractures in diabetic patients.
AB - We would like to present 23 calcaneal fractures in 22 patients of whom 21 had
type I diabetes mellitus. There appear to be three basic fracture types: (1) a
superiorly displaced extra-articular avulsion fracture of the posterior calcaneus
(or Iowa fracture), which occurred in 12 patients (five men, seven women); (2) a
mid-calcaneal compression fracture in six patients (four men, two women), and (3)
a cleavage or "wedge" type fracture in four patients extending from the calcaneal
tubercle (one man, 3 women). All four of this last group of patients had a
history of a chronic penetrating ulcer, and this is noteworthy since only one
other patient out of the remaining 18 in groups 1 and 2 had a similar history.
Most patients had decreased bone mineralization: 15 patients were on long-term,
high-dose steroids, and 18 patients had either poor renal function or complete
renal failure (11 of 12). Fourteen patients had received either renal or pancreas
transplants. Eight patients were on restricted weight bearing prior to their
fractures. We believe that diabetic patients are more prone to calcaneal
fractures than the general population, and early diagnosis is imperative,
followed by early treatment to prevent significant bony deformity.
PMID- 9559484
TI - Pregnancy does not induce or worsen retinal and peripheral nerve dysfunction in
insulin-dependent diabetic women.
AB - In order to verify whether pregnancy induces or worsens diabetic retinopathy or
somatic and autonomic neuropathy, 16 insulin-dependent diabetic (IDDM) pregnant
women, 14 age-matched nondiabetic pregnant women, and 12 IDDM nonpregnant women
matched for age and disease duration were studied. Plasma glucose, HbA1c, and
fructosamine were repeatedly assayed during pregnancy. Retinopathic and
neuropathic endpoints were evaluated through ophthalmoscopy, electrophysiology of
left peroneal and sural nerves (motor and sensory conduction velocities), and
cardiovascular autonomic tests (deep breathing, cough test, lying-to-standing).
In the IDDM pregnant women, evaluations were performed three times during
pregnancy and 6 months after delivery. Good metabolic control was achieved during
pregnancy. At baseline, nine IDDM pregnant women did not show signs of
retinopathy, and seven had nonproliferative retinopathy. Only one patient showed
worsening during pregnancy, but she improved after delivery. Motor conduction
velocity, significantly lower in IDDM pregnant women, progressively improved,
and, in the third trimester, was not significantly different from that of
nondiabetic pregnant women. At baseline, none of the IDDM pregnant women had
abnormal responses to cardiovascular autonomic tests. During pregnancy, the
response to deep breathing appeared temporarily reduced in all pregnant women,
possibly due to lowered ventilatory excursion at the end of pregnancy. In IDDM
women with minimal or no retinopathy, and subclinical or no peripheral
neuropathy, pregnancy does not appear to induce or worsen these complications.
PMID- 9559486
TI - Low prevalence of long-term complications in non-insulin-dependent diabetes
mellitus in France: a multicenter study. CODIAB-INSERM-ZENECA Pharma Study Group.
AB - The aim of this study was to assess the prevalence of long-term complications in
a large sample of French NIDDM patients. Therefore, 427 NIDDM patients 35-74
years old were recruited in ten centers. Standardized clinical criteria and
central reading for retinal and electrocardiographic changes were used to assess
the presence of complications. The prevalence rates of complications were 29.7%
and 3.3% for background and proliferative retinopathy; 21.8%, 6.1%, and 2.8% for
microalbuminuria, proteinuria, and renal insufficiency; 19.9 and 11.7% for
asymptomatic and symptomatic pheripheral neuropathy; 8.2% for orthostatic
hypotension; 10.1% and 8.4% for angina pectoris and myocardial infarction; and
13.1% and 6.3% for mild and moderate to severe peripheral vascular disease,
respectively. In conclusion, prevalence rates in this study were lower than in
most studies from other countries.
PMID- 9559487
TI - Change in major amputation rate in a center dedicated to diabetic foot care
during the 1980s: prognostic determinants for major amputation.
AB - From 1990 to 1993, 115 diabetic patients were consecutively hospitalized in our
diabetologic unit for foot ulcer and 27 (23.5%) major amputations were carried
out. The major amputation rate of this series of cases was compared with that
occurring in diabetic subjects taken into our hospital for foot ulcer in two
previous periods: 1979-1981 (17 major amputations in 42 inpatients or 40.5%) and
1986-1989 (26 major amputations in 78 inpatients or 33.3%). The comparison shows
a progressive reduction in major amputation rate [Odds ratio 0.66, 95% confidence
interval (CI) 0.46-0.96]. Univariate and multivariate analysis, carried out in
the population of the 1990-1993 period, in order to detect the independent
factors associated with major amputation show the following prognostic
determinants of major amputation: Wagner grade (odds ratio 7.69, CI 1.58-37.53),
prior stroke (odds ratio 35.05, CI 3.14-390.53), prior major amputation (odds
ratio 3.49, CI 1.26-9.38), transcutaneous oxygen level (odds ratio 1.06, CI 1.01
1.12), and ankle-brachial blood pressure index (odds ratio 4.35, CI 1.58-12.05),
while an independent protective role was attributed to hyperbaric oxygen
treatment (odds ratio 0.15, CI 0.03-0.64). In accordance with other studies, we,
therefore, conclude that a comprehensive protocol as well as a multidisciplinary
approach in a dedicated center can assure a decrease in major amputation rate.
The parameters of limb perfusion were the modifiable prognostic determinants most
strongly predictive for amputation.
PMID- 9559488
TI - Morbidity in 565 type 2 diabetic patients according to stage of nephropathy.
AB - Between 1988 and 1992, 565 type 2 diabetic patients were examined for nephropathy
and diabetes-associated diseases during hospital treatment. Stages of nephropathy
were defined as no clinical sign of nephropathy (N = 280), microalbuminuria (N =
38), overt proteinuria (N = 105), impaired renal function (N = 55), and chronic
dialysis therapy (N = 87). In dialyzed patients, HbA1c averaged 6.8%, and, in the
other groups, HbA1c was between 7.6% and 8.3% (normal range, 3.8%-6.1%). Cataract
was not associated with the severity of nephropathy. Stroke was most common in
the stage of renal insufficiency (34%). The following complications, as found in
medical history or as current event, showed a significant association with the
stage of nephropathy and occurred most frequently in dialysis patients
(percentage is displayed for patients with nephropathy in comparison to diabetic
dialysis patients): hypertension (53%-89%), left ventricular hypertrophy (39%
81%), myocardial infarction (14%-36%), peripheral vascular disease (27%-77%),
foot lesions (7%-75%), minor or major amputations (3%-23%), proliferative
retinopathy (6%-46%), blindness (2.9%-16.1%), and internal carotid artery
stenosis (15%-36%). In this preselected cohort of diabetic patients, a high
morbidity was found already without nephropathy that increased several-fold in
the course of the development of nephropathy. Our data identify patients with
diabetic nephropathy as a high-risk group for excess morbidity.
PMID- 9559490
TI - Bolstering Sisyphus.
PMID- 9559489
TI - Metformin: effects on cardiovascular risk factors in patients with non-insulin
dependent diabetes mellitus.
AB - Non-insulin-dependent diabetes mellitus (NIDDM) affects approximately 12 million
people in the United States. NIDDM is frequently found to coexist with other
conditions, such as obesity, dyslipidemia, atherosclerotic vascular disease, and
hypertension, which contribute to morbidity and mortality. Although the major
clinical objective in the management of NIDDM is to control hyperglycemia, the
long-term objective is to prevent microvascular and macrovascular complications.
Cardiovascular disease is the major cause of death in NIDDM patients. Although
hyperglycemia may be adequately controlled, risk factors for coronary heart
disease may remain unchanged. Treatment with metformin controls hyperglycemia and
may have positive effects on cardiovascular risk factors. When used alone or in
combination with sulfonylureas, metformin tends to stabilize or decrease weight,
maintains or reduces insulin levels, has beneficial effects on plasma lipid
profiles, and may also have beneficial effects on blood pressure and the
fibrinolytic system.
PMID- 9559491
TI - Late removal of releasable sutures after trabeculectomy or combined
trabeculectomy with cataract extraction supplemented with antifibrotics.
AB - PURPOSE: Releasable scleral flap sutures have been effectively used in
trabeculectomy. The suggested time for suture removal is within the first two
postoperative weeks. The authors wished to determine whether the use of
intraoperative antifibrotics alters the time of suture removal and the results of
surgery. METHODS: The charts of 324 patients (388 eyes) undergoing trabeculectomy
and 141 patients (174 eyes) undergoing combined trabeculectomy with cataract
extraction with a minimum follow-up of 12 months were retrospectively reviewed.
All eyes received intraoperative antifibrotics; mitomycin C in 534 eyes and 5
fluorouracil in 29 eyes. Two releasable scleral flap sutures were used in all of
the eyes. RESULTS: The removal time of at least one of the two releasable sutures
was later than 21 days postoperatively in 89 eyes of 83 patients with
trabeculectomy (22.9%) and in 58 eyes of 55 patients with combined surgery
(33.3%). The suture removal was deferred in 39 eyes because of an early
complication such as hypotony (intraocular pressure (IOP) < or = 5 mm Hg), bleb
leak, or shallow or flat anterior chamber. There was no complication in the other
108 eyes, but suture removal was delayed until the IOP was more than 10 mm Hg.
Immediate IOP reduction was (mean +/- standard deviation) 6.3 +/- 2.8 mm Hg when
suture removal was performed beyond 3 weeks. There was a decreased response as
the postoperative time until suture removal increases (r = -0.57). No serious
complication associated with late suture removal was noted during the follow-up
period (mean +/- standard deviation, 19.8 +/- 10.1 months). CONCLUSION:
Intraoperative pharmacologic modulation of wound healing in trabeculectomy and
combined trabeculectomy with cataract extraction extends the period that
releasable suture removal is clinically effective. However the response decreases
with a longer interval to releasable suture removal.
PMID- 9559492
TI - Risk of hypotony after primary trabeculectomy with antifibrotic agents in a black
west African population.
AB - PURPOSE: To evaluate the risk of hypotony and hypotony maculopathy following
trabeculectomy with 5-fluorouracil (5-FU) and mitomycin C (MMC) in a black West
African population. METHODS: One hundred and one eyes of black Ghanaian patients
with advanced primary open-angle glaucoma received intraoperative antifibrotic
therapy with trabeculectomy as part of two randomized clinical trials. Overall,
57 patients received 5-FU (50.0 mg/ml for 5 minutes) and 44 received MMC (0.5
mg/ml for 3.5 minutes). All cases were performed by one of five surgeons at a
single outpatient surgery center. RESULTS: Two of 101 eyes had a final
intraocular pressure (IOP) of less than 5 mm Hg and were thus classified as
having hypotony. No patient in either group was noted to develop hypotony-related
maculopathy. Overall mean pre- and postoperative IOPs were 30.1 and 15.9 mm Hg,
respectively. The patients receiving intraoperative MMC had a lower mean
postoperative IOP (14.7 mm Hg) than those receiving 5-FU (first study, 17.1 mm
Hg; second study, 16.7 mm Hg; p = 0.05). Mean overall follow-up was 17.7 months
and did not differ significantly between the MMC and combined 5-FU groups.
CONCLUSION: Hypotony following trabeculectomy supplemented with antifibrotic
agents is a rare complication in this population. No eyes in either clinical
trial developed hypotony maculopathy, suggesting that the prevalence of this
condition is substantially lower in black West Africans than in whites.
PMID- 9559493
TI - Molteno implant with mitomycin C: intermediate-term results.
AB - PURPOSE: The authors examine the intermediate-term effects of adjunctive
intraoperative mitomycin C (MMC) in a cohort of patients who received double
plate Molteno implants for complicated glaucomas. METHODS: A consecutive series
of 21 patients who received MMC 0.5 mg/ml for 5 minutes as an adjunct to a double
plate Molteno implant was compared by life-table analysis to a historical control
group of 18 patients who received either no adjunct or 5-fluorouracil (5-FU) but
no MMC. RESULTS: At three years follow-up, 35% (95% confidence interval (CI), 15
57%) of patients who received MMC avoided failure criteria of intraocular
pressure (IOP) less than 6 mm Hg or more than 21 mm Hg, addition of glaucoma
medication, reoperation for glaucoma, or tube removal. Seventeen percent (95% CI,
4-37%) of patients in the control group at three years follow-up met similar
criteria (p = 0.039). No late complications of tube erosion were seen in the MMC
group. CONCLUSION: Intraoperative MMC offers an increased likelihood of a two- to
three-year period of medication-free IOP control in patients undergoing double
plate Molteno implants, compared to similar patients receiving 5-FU or no
adjunctive antimetabolite therapy.
PMID- 9559494
TI - The use of the consensual light reflex as an aid to performing laser peripheral
iridectomy in patients with pigment dispersion syndrome and pigmentary glaucoma.
AB - PURPOSE: The authors explore an alternative method of performing laser peripheral
iridectomy (LPI) in patients with pigment dispersion syndrome and pigmentary
glaucoma (PDS/PG) who are high myopes and therefore at increased risk of
developing retinal detachment. METHODS: Four myopic patients with PDS/PG had LPI
performed in one eye. A transilluminator was held up to the opposite eye to
provide pupillary constriction via the consensual light reflex. No miotics were
used. RESULTS: All LPIs were easily performed without complications. CONCLUSION:
The authors present an alternative method to the standard use of pilocarpine for
LPI theoretically to decrease further the incidence of retinal detachment in
populations predisposed to it.
PMID- 9559495
TI - Costs of treating primary open-angle glaucoma and ocular hypertension: a
retrospective, observational two-year chart review of newly diagnosed patients in
Sweden and the United States.
AB - PURPOSE: The objective of this study was to investigate what treatment strategies
prevail in different countries for patients newly diagnosed with primary open
angle glaucoma (POAG) or ocular hypertension (OH) only and initiated on treatment
with beta-blockers, and to estimate the total direct cost of treatment for two
years. In addition, differences in costs between and within the countries and the
determinants of variations in costs across patients were examined. MATERIALS AND
METHODS: The authors performed a retrospective medical record analysis in several
academic and office-based study centers in Sweden and the United States. Standard
costs for each resource item were determined and applied to all centers within
the country. Differences in treatment costs within the countries are thus the
effect of differences in treatment strategies, not of differences in prices.
RESULTS: There was considerable variation between the centers of each country.
Sweden had a higher number of surgical interventions, which may be explained by
the fact that the Swedish cohort had a higher mean intraocular pressure (IOP) at
baseline and a higher proportion of patients with definite POAG and exfoliation
glaucoma. However, in both countries the mean IOP at study end was approximately
18 mm Hg. Total direct costs for two years were 15,119 SEK (US$2,160; $1US = 7
SEK) and $2,109, respectively. In a multiple regression analysis, the estimated
effects of baseline IOP and of IOP change after treatment initiation on treatment
costs were positively and negatively significant, respectively, in both
countries. CONCLUSION: Despite differences in baseline diagnosis and in treatment
strategies, mean IOP was decreased to 18 mm Hg in both countries. Baseline IOP
was positively correlated with treatment costs, while the initial IOP-lowering
effect of treatment was negatively correlated with two-year costs.
PMID- 9559496
TI - Cold pressor test and plasma endothelin-1 concentration in primary open-angle and
capsular glaucoma.
AB - PURPOSE: The authors investigate cutaneous capillary blood flow using the cold
pressor test and plasma endothelin-1 (ET-1) concentration in primary open-angle
glaucoma (POAG) and capsular glaucoma (CG), and evaluate the connection between
the two factors, which reflect vasoconstrictive mechanisms with a potential role
in the pathogenesis of glaucoma. METHODS: The ET-1 concentration of venous blood
plasma samples from 20 patients with POAG, 22 patients with CG, and 44 healthy
volunteers was measured using a radioimmunoassay kit. On a separate occasion, the
right hand was subjected to the cold pressor test (hand immersed in 4 degrees C
water for 30 seconds, then in 30 degrees C water for 2 minutes), during which
cutaneous capillary blood flow of the left middle finger was measured using a
Periflux 4001 Master Laser Doppler Flowmeter (Perimed AB, Jarfalla, Sweden).
RESULTS: In the CG group, baseline cutaneous capillary blood flow was
significantly lower than either that of POAG (p = 0.001) or that of the healthy
group (p = 0.046). In the CG group, time to maximal cold-induced flow reduction
was significantly longer than in the POAG group (p = 0.028) or in the healthy
group (p = 0.025). Also, recovery time was significantly longer in CG than in the
healthy group (p = 0.008) and tended to be longer than in the POAG group. No
statistically significant difference between the groups was found either in the
frequency of increased vasospastic response (cold-induced flow reduction higher
than 70% of the baseline value) or in ET-1 concentration. No correlation was seen
between ET-1 concentration and the findings of the cold pressor test. CONCLUSION:
The results suggest that in CG, which is a systemic disease with vascular
abnormalities, baseline cutaneous capillary perfusion and its response to cold
and warmth are altered, without any alteration of plasma ET-1 level. The authors
found that both plasma ET-1 level and the response to the cold pressor test are
normal in patients with POAG. These findings suggest that regulation of cutaneous
capillary perfusion and the concentration of plasma ET-1 are not related to each
other in patients with glaucoma.
PMID- 9559497
TI - Comparison between high-pass resolution perimetry and differential light
sensitivity perimetry in patients with glaucoma.
AB - PURPOSE: High-pass resolution perimeters such as the Ophthimus (High Tech Vision,
Malmo, Sweden) may provide an easier, faster assessment of the visual field than
conventional perimeters such as the Humphrey (Humphrey Instruments Inc., San
Leandro, CA, U.S.A.), which is based on differential light sensitivity. The
Ophthimus provides global indices and statistical analyses conceptually similar
to those produced by the Humphrey. In addition, the Ophthimus provides, as a
unique parameter, the estimated neural capacity. PATIENTS AND METHODS: Twenty-one
patients with chronic open-angle glaucoma and reliable fields on both Humphrey
and Ophthimus testing were evaluated. The results from the two different
techniques were compared. RESULTS: The estimated neural capacity was correlated
to global deviation and mean deviation at a statistically significant level.
There were also correlations between mean deviation and global deviation and
between pattern standard deviation and local deviation, but not between retest
standard deviation and short-term fluctuation. CONCLUSION: It is not clear at
this point if the neural capacity of the Ophthimus provides any clinically useful
information over and above global deviation. Mean test time was shorter with the
Ophthimus system than the Humphrey. Performance on the reliability indices was
better for the Ophthimus. The Ophthimus may prove useful in following patients
with glaucoma.
PMID- 9559498
TI - Incidence of elevation of intraocular pressure over time and associated factors
in normal-tension glaucoma.
AB - PURPOSE: The authors determine whether intraocular pressure (IOP) increases to
levels that challenge the diagnosis of normal-tension glaucoma (NTG) and
determine clinical factors associated with the IOP elevation. METHODS: Forty
patients with NTG who met the following enrollment criteria were selected: IOPs
less than 21 mm Hg during initial 24-hour pressure curve and throughout the
subsequent 12 months; examined every 1 to 4 months for at least 4 years; and no
ocular hypotensive treatment. The eye with the higher mean IOP during the initial
24-hour pressure curve was selected from each patient. The observation period
ranged from 4.0 years to 7.8 years (mean, 5.2 years). Significant IOP elevation
was defined as a significant increase (p < 0.05) of IOP over time, determined by
Spearman rank correlation coefficient method. The IOP elevation was correlated to
clinical factors by means of a logistic multiple regression analysis (LOGIST
procedure using PC-SAS, SAS Institute, Inc. Cary, NC, U.S.A.). RESULTS: Eleven
eyes were rated positive for IOP elevation. The regression model demonstrated
that maximum IOP during the initial 24-hour pressure curve and the development of
disc hemorrhage (DH) were significantly correlated with IOP elevation (p = 0.006
and p = 0.049, respectively). The odds ratios calculated were 1.98 per 1 mm Hg
rise of maximum IOP during the initial 24-hour pressure curve and 6.54 for
positive DH. CONCLUSIONS: Intraocular pressure might increase in NTG eyes
following the initial diagnosis. A higher maximum IOP during initial 24-hour
pressure curve and the development of DH during follow-up was significantly
associated with subsequent IOP elevation in NTG patients.
PMID- 9559500
TI - Diurnal intraocular pressure curves in healthy rhesus macaques (Macaca mulatta)
and rhesus macaques with normotensive and hypertensive primary open-angle
glaucoma.
AB - PURPOSE: The authors identify any diurnal intraocular pressure (IOP) variation in
healthy Cayo Santiago macaques, as well as Cayo Santiago macaques with
normotensive and hypertensive primary open-angle glaucoma (POAG), to further
evaluate their potential value as a model for human POAG. METHODS: Twenty-four
monkeys (eight animals each of the healthy control, normotensive glaucoma, and
hypertensive glaucoma groups) were sedated with ketamine hydrochloride and the
IOP measured hourly from 8:00 AM until 3:00 PM with a Tonopen XL applanation
tonometer (Mentor, Norwell, MA, U.S.A.). Mean IOP time profiles, mean IOPs at
each observation time, and linear trends in mean IOP over time were compared
among groups. Intraocular pressure rate-of-change over time and residual
variation about the regression line for each individual eye were analyzed.
Cup/disc ratio (C/D) was compared with baseline IOP, IOP profile mean and slope,
and IOP residual variation. RESULTS: A significant group and time effect on mean
IOP (p = 0.0001 and 0.011, respectively), with highest values at 2:00 PM or 3:00
PM, and a significant increasing linear trend in mean IOP over time in the
hypertensive group were observed (p = 0.012). Intermediate readings between
control and hypertensive mean IOPs were identified for the normotensive glaucoma
group. The biggest range of IOP variation was found in the hypertensive glaucoma
monkeys. Higher variations in IOP did not lead to an increase in C/D.
CONCLUSIONS: This study provides evidence that the Cayo Santiago macaques are a
valuable model for human normotensive and hypertensive POAG.
PMID- 9559499
TI - Detection of early glaucomatous structural damage with confocal scanning laser
tomography.
AB - PURPOSE: The authors determine which optic disc topographic parameters obtained
by the Heidelberg Retina Tomograph (HRT, Heidelberg Engineering, Heidelberg,
Germany) are most useful in detecting individuals with early glaucomatous visual
field loss. METHODS: Ninety-nine eyes of 49 healthy individuals and 50 age
matched individuals with early glaucomatous visual field loss were included.
Three images were obtained and the mean topography image was created and used in
the analyses. The HRT discriminant analysis function (software version 2.01) was
applied and compared to the Fisher linear discriminant function developed in this
population. Analysis was repeated after stratifying by disc area (< 2 mm2 or 2-3
mm2). RESULTS: There were statistically significant differences between the
healthy and glaucomatous groups for all optic disc topographic parameters (p <
0.05) measured. These differences remained after the analysis was repeated
controlling for disc size, except for height variation contour. Applying the HRT
discriminant function to this study population resulted in sensitivity and
specificity of 62% and 94%, respectively. The sensitivity was 83% while
specificity remained high (91%) for larger disc sizes. Using this data,
additional discriminant functions that differentiated similarly between the two
groups were found. The best formula used cup-shape measure (third moment), rim
area, height variation contour, and retinal nerve fiber layer thickness and had a
sensitivity and specificity of 78% and 88%, respectively. CONCLUSIONS: Several
different discriminant analysis formulas are capable of detecting early
glaucomatous visual field loss in a comparable manner. The characteristics of the
study population are likely to influence the discriminating power of these
various formulas.
PMID- 9559501
TI - Bleb-related ocular infection.
PMID- 9559502
TI - Initial treatment of exfoliative glaucoma.
PMID- 9559503
TI - Circadian rhythm of intraocular pressure.
AB - Although it is well known that intraocular pressure (IOP) in humans varies
throughout day and night, no consistent circadian pattern has been established.
In laboratory rabbits, however, a consistent circadian rhythm of IOP has been
confirmed and further characterized in recent years. The current knowledge about
the nocturnal IOP elevation in rabbits is reviewed and the implications for the
study of human circadian IOP pattern is discussed.
PMID- 9559504
TI - Managing orbital cellulitis.
PMID- 9559505
TI - Clinical practice guidelines for the management of orbital cellulitis.
AB - PURPOSE: A retrospective study was performed to review the management of
periorbital and orbital cellulitis at Miami Children's Hospital, between January
1, 1993 and February 15, 1996. RESULTS: One hundred and one patients were
included in this study. The variables analyzed in this study included age, sex,
length of hospital stay, imaging studies, laboratory tests, and microbiology
specimens collected. Patients were classified according to the modified Chandler
classification. Average length of stay for our patient population was 4.5 days.
Data regarding the radiologic studies, laboratory tests, and microbiology yield
of specimens were analyzed. CONCLUSIONS: The incidence of orbital infection,
manifested by lid swelling alone is much more common (stages I and II) than
orbital infection involving postseptal findings (stages III, IV, and V); 84.16%
compared with 15.84%, respectively. An updated approach and a general guideline
for the management of periorbital and orbital cellulitis according to the
clinical staging of the process is presented.
PMID- 9559506
TI - Can congenital nasolacrimal-duct obstruction interfere with visual development? A
cohort case control study.
AB - PURPOSE: To ascertain if tear film disturbance in congenital nasolacrimal-duct
obstruction (CNLDO) interferes with visual maturation. METHODS: Review of a
cohort of children in which the occurrence and duration of CNLDO had been
previously documented. Information obtained included acuity, refractive data, and
presence or absence of strabismus. The incidence of abnormality in the CNLDO
group was compared with that in controls, which were fellow eyes in those
children with unilateral obstruction, and all children with no history of CNLDO.
RESULTS: Of 4792 children, visual acuity data were obtained on 2249. There was no
difference in the incidence of amblyopia in CNLDO children compared with controls
(p < 0.89) nor in the watering eye compared with the fellow eye (p < 0.58). No
correlation between refractive error or astigmatism and CNLDO (p < 0.26 and p <
0.32 respectively) was found. Strabismus was no more common in CNLDO than in
controls (p < 0.89). CONCLUSIONS: This study found no evidence to suggest that
visual maturation is adversely affected by allowing spontaneous resolution of
CNLDO.
PMID- 9559507
TI - The accommodative convergence/accommodation (AC/A) and near convergence/distance
(NC/D) ratios in esotropia.
AB - INTRODUCTION: In esotropias, measurement of AC/A and NC/D ratios are important
for exact classification and adequate therapy. We devised a table for the
calculation of AC/A and NC/D ratios to facilitate their estimation. METHOD: For
the assessment of AC/A ratio, we used the gradient method range 6 Dsph and for
the NC/D ratio we used the heterophoria method. For the calculation of both
ratios, we used our own table. A series of 102 children were examined. RESULTS:
The mean value of AC/A ratio for esotropias was 4.86 +/- 2.05. The mean value of
AC/A ratio for the control group was 3.9 +/- 1.92. The difference was 0.96 and
was statistically significant at the level of 5% (Student's t test). The AC/A
ratio is high in esotropia ranging from 1 to 10. At 58% of esotropias, the AC/A
ratio is higher than the mean value of AC/A ratio of the control group. The mean
value of the NC/D ratio for esotropia was 5.9 +/- 1.51. The mean value of the
NC/D ratio for the control group was 5.1 +/- 1.5. The difference of 0.8 was
statistically significant at a level of 5%. Thus, in esotropia the NC/D ratio is
high. The NC/D ratio in esotropia ranges from 1 to 10. The NC/D ratio is low in
16% of esotropias. CONCLUSION: Our own table for calculating the AC/A and NC/D
ratios was useful because it facilitates their determination. The mean values of
AC/A and NC/D ratios in esotropia are high and range from 1 to 10. In 58% of
cases the AC/A ratio is high and in 84% of cases the NC/D ratio is high and can
be responsible for the oculomotor imbalance.
PMID- 9559508
TI - Lenz syndrome in two sisters: clinicopathologic correlations of the ocular
anomalies.
AB - BACKGROUND: The Lenz syndrome (Mendelian inheritance in Man catalog number
309,800) is a presumed X-linked recessive disorder. Major diagnostic criteria
include ocular, skeletal, and urogenital manifestations. We describe two sisters
and the two sons of one of them with Lenz syndrome. The eye from one boy was
removed because of pain and total loss of vision, allowing histopathologic
documentation of the ocular malformations. METHODS: Clinicopathologic case
report. RESULTS: Two sisters in this family displayed several of the major
diagnostic criteria of the Lenz syndrome. The stunted growth of the eye, and the
ocular and non-ocular anomalies defines the microphthalmos as monogenic, complex,
and colobomatous. CONCLUSION: The pattern of inheritance of Lenz syndrome is best
explained by X-linked dominant transmission. Future reports of familial cases
with an excess of affected females are needed to confirm this hypothesis.
PMID- 9559509
TI - CHARGE association: histopathological report of two cases and a review.
AB - BACKGROUND: The CHARGE association (C = coloboma, H = heart disease, A = atresia
or stenosis of the choanae, R = retarded growth and development or CNS anomalies,
G = genital hypoplasia, and E = ear anomalies or deafness) is a rare, recently
well-recognized clinical study. The ophthalmic abnormalities have been described
in numerous reports, but the ocular histopathologic findings have not been
presented in detail. METHODS: We conducted gross and microscopic studies of eyes
of two patients with the CHARGE association obtained postmortem. RESULTS: The
eyes in one case had a small, symmetrical, inferior nasal coloboma of the
choroid. In the other case, extensive inferior nasal colobomas of the iris,
ciliary body, and choroid with retinal dysplasia, ectopic retinal/glial tissue in
the sclera and hypoplasia of the optic nerve head were present. CONCLUSION: We
document the histopathological features of eyes of two subjects with the CHARGE
association. The abnormalities of these eyes were typical ocular colobomas
presumably resulting from the failure of complete closure of the optic fissure.
PMID- 9559510
TI - Evaluation of a hand-held autorefractor in children younger than 6.
AB - PURPOSE: To evaluate a hand-held portable autorefractor in a pediatric population
and compare results with those found on retinoscopy by experienced pediatric
retinoscopists. METHODS: One-hundred and two children aged 5 to 72 months were
examined with and without cycloplegia using an autorefractor, and the results
compared with those found on standard retinoscopy by two ophthalmologists masked
as to the autorefractor findings. Results were converted from conventional
notation using plus cylinder to the h-space notation and compared in three
dimensional h-space. RESULTS: There was remarkable agreement between the results
found by autorefraction and manual retinoscopy using loose lenses or a phoropter.
The findings were similar both for sphere and cylinder across the age ranges
studied. CONCLUSIONS: The Nikon Retinomax is an accurate instrument to estimate
refractive error in children younger than 6 and could prove useful in the office,
the operating room, or as a screening device.
PMID- 9559511
TI - Bilateral Peter's anomaly in an infant with 49,XXXXY syndrome.
PMID- 9559512
TI - Prominent ocular findings as an early manifestation of systemic lupus
erythematosus.
PMID- 9559513
TI - Acquired combined hamartoma of the retina and pigment epithelium following
parainfectious meningoencephalitis with optic neuritis.
PMID- 9559514
TI - Panuveitis associated with rifabutin prophylaxis in a pediatric HIV-positive
patient.
PMID- 9559515
TI - An XX male with microphthalmos and sclerocornea.
PMID- 9559516
TI - Congenital microcoria: case report and histological study.
PMID- 9559517
TI - [Epidemiologic markers of Salmonella].
AB - Salmonellae are enterobacteria responsible for outbreaks of human and animal
clinical diseases, with important hygienic and economic consequences. Accurate
epidemiological studies require the use of efficient markers, which make it
possible to trace the establishment and diffusion of different bacterial strains
and also to evaluate the similarities between different isolates. Numerous
phenotypic and genotypic markers applicable to Salmonella are available for these
epidemiological studies. Nevertheless, the relative interest of those markers
depends on the serotypes, and a different hierarchy can be achieved for the
Typhimurium and Enteritidis serotypes.
PMID- 9559518
TI - Comparative efficacy of different insecticides in the treatment of cattle
hypodermosis in north-eastern Algeria.
AB - The efficacy of different drugs (microdose of ivermectin, doramectin and
moxidectin at the recommended doses and topically applied rotenone) against the
first, second and third instar larvae of Hypoderma bovis and H. lineatum was
studied in cattle in the El Tarf area (northeastern Algeria). Before performing
the efficacy trials, the life cycle of the warble fly was studied at the
slaughterhouse between July 1993 and June 1994. This survey revealed that both
species of warble fly were present in this area: L1 larvae of H. lineatum were
found around the oesophagus between August and January, whereas L1 larvae of H.
bovis were observed around the spine from November until March. Warbles were
present under the skin from the end of October until May. The nymphal phase took
place between February and May. As a result of this study the authors recommend
applying chemoprophylaxis (treatment against L1) in September. This work also
confirmed the excellent efficacy of avermectins and milbemycins against the three
instar larvae of Hypoderma sp. under the field conditions prevailing in Algeria.
Rotenone has a lower efficacy (95%) which is limited to the second and third
instar larvae. However, this drug appears useful in dairy cattle.
PMID- 9559519
TI - Relationship between individual-cow udder health status in early lactation and
dairy cow characteristics in Brittany, France.
AB - Data from a 4-year ecopathological survey involving 47 dairy farms in Brittany
(France) were used to determine the individual animal characteristics associated
with the udder health profiles of clinical and subclinical mastitis, and the
presence of minor or major pathogens in milk during early lactation. Herd effect
was taken into account and a within-herd analysis using factorial correspondence
analysis and a decomposition of chi-square distance was performed. In primiparous
cows, the main association observed was between milk production and intramammary
infections with major pathogens. The dirtiness score showed contradictory
relationships with udder health profiles. The indoor/outdoor transition period
was unfavourable for udder health status; since the frequency rate of subclinical
and clinical mastitis increased during this period. In multiparous cows,
intramammary infections by minor or major pathogens were closely associated with
non-infectious udder diseases, but the main effect was due to parity. Old cows
were generally affected by higher somatic cell counts than younger cows
regardless of whether the SCC were associated with clinical mastitis or not.
PMID- 9559520
TI - In vivo studies on lysosubtilin. 2. Efficacy for treatment of post-partum
endometritis in cows.
AB - Lysosubtilin is a broad-spectrum preparation of lytic enzymes from Bacillus
subtilis designed for veterinary medicine. This study demonstrates its efficacy
for the treatment of post-partum endometritis in cows. Prior to the determination
of optimal therapeutic doses, samples taken from the uterus of sick animals were
examined microbiologically. The examinations revealed a high incidence of
polymicrobial infections (65.0%) caused by various mixtures of bacteria (both
Gram-positive and Gram-negative) and fungi/yeasts. Dose-determination studies
involved 160 cows with clinical signs of post-partum endometritis. For treatment
both aqueous and oil-based formulations were tested and the optimal dose was
found to be 2 x 10(6) U lysosubtilin dissolved in 100 mL of distilled water. When
administered intrauterinarily twice a week until recovery this dose resulted in a
100% clinical recovery rate (versus 90%) and a statistically significant decrease
(73 +/- 5 d), when compared with cows treated with neofur (92 +/- 9 d, P < 0.05)
in the calving-to-conception interval. These findings were confirmed by results
of field trials performed in four Former Soviet Union republics (Byelarus,
Estonia, Lithuania, Russia) on 932 cows. Increases in clinical recovery (93.7
versus 80.2%, P < 0.05) and conception rates (64.4 versus 45.8%, P < 0.01) were
found to be statistically significant when compared with cows treated with neofur
or uterosan. We therefore conclude that lytic enzyme preparations are prospective
antimicrobial drugs and when used to combat animal diseases they may serve as a
possible alternative to common antibiotics.
PMID- 9559521
TI - Small intestinal motility disorders in preruminant calves chronically fed a diet
based on antigenic soya: characterization and possible mediators.
AB - Intestinal motility disorders and some mediators implicated in these disorders
were studied in preruminant calves that had been chronically fed a diet
containing an antigenic heated soyabean flour (HSF) for 3 months. The calves in
the present study had previously been shown to present strong immune reactions
against soyabean proteins, as assessed through plasma antibody titres, direct
skin tests and in vitro lymphoproliferation. Four of these calves sensitive to
soya were fitted with an abomasal catheter and wire electrodes on the jejunum.
Myoelectric activity was recorded over 7 h following test meals containing skim
milk powder (SMP), HSF or a non-antigenic hydrolysed soya protein isolate (HSPI).
The pattern of myoelectric complexes migrating to the jejunum was regular with
SMP (mean durations of phases I, II and III: 26, 38 and 5.28 min, respectively).
With HSF, diarrhoea appeared, and the total duration of phase I decreased from
149 to 68 min (P < 0.01) while that of phase II increased from 239 to 328 min (P
< 0.01). The mean duration of phase III decreased from 5.3 to 3.9 min (P < 0.01).
These changes, including diarrhoea, were substantially reversed by feeding HSPI.
When promethazine, a H-1 histamine receptor antagonist, was administered i.v.
prior to feeding HSF the number of phases I tended to decrease and diarrhoea
virtually disappeared. In contrast, indomethacin, a cyclooxygenase inhibitor, had
limited effects on motility patterns and diarrhoea. These disorders were
partially reproduced by i.p. administration of platelet-activating factor (PAF)
prior to feeding with SMP. These findings suggest that calves chronically fed
antigenic soya suffer from immune-mediated motility disorders which are linked to
histamine action via H-1 receptors, and possibly with PAF. The role of
arachidonic acid catabolites of the cyclooxygenase pathway is probably minor.
PMID- 9559522
TI - Quantification of C5a/C5a(desArg) in bovine plasma, serum and milk.
AB - Complement activation generates two potent inflammatory mediators from C5, C5a
and its derivative C5a(desArg), which results from the removal of the C-terminal
arginine by ubiquitous carboxypeptidases. In this paper we describe the
purification of milligram amounts of bovine C5a(desArg) by a simplified
procedure, and the preparation of mouse monoclonal antibodies (MAbs) to
C5a/C5a(desArg) which do not recognize native C5. A MAb was used to develop a
sandwich ELISA which made it possible to quantify levels of C5a/C5adesArg in
bovine biological fluids. Small amounts (means +/- SEM) of C5a/C5a(desArg) were
found in EDTA-plasma (0.58 +/- 0.06 ng.mL-1). The anticoagulant EDTA was more
efficient than citrate or heparin in inhibiting in vitro activation of the
complement system. Complement activation occurred during coagulation since the
baseline concentration of C5a/C5a(desArg) (15.4 +/- 4.1 ng.mL-1) was higher than
in plasma. Zymosan, a potent activator of the complement cascade, was used to
generate C5a/C5a(desArg). The time-course of the reaction and the dose-effect of
zymosan were investigated. Optimal conditions were incubation at 39 degrees C for
1 or 2 h with 2 mg of zymosan per mL of serum. The maximal concentration of
C5a/C5a desArg attained in zymosan-activated serum was 4.28 +/- 0.14
micrograms.mL-1. Normal milk (from healthy, uninflamed mammary glands) contained
on average 0.12 ng of C5a/C5a(desArg).mL-1 (range 0.02-0.19 ng.mL-1). The maximal
amount of C5a/C5a(desArg) which was generated in milk with zymosan was 1.1 ng.mL
1 (range 0.68-2.17 ng.mL-1). In milk from quarters with subclinical infections by
coagulase-negative staphylococci, values were 0.18 ng.mL-1 and 2.37 ng.mL-1 for
spontaneous and zymosan-generated C5a/C5a(desArg) concentrations, respectively.
In milk from Escherichia coli endotoxin-induced mastitis, C5a/C5a(desArg)
concentrations (means of four cows) before and after zymosan activation reached
6.5 ng.mL-1 and 55 ng.mL-1, respectively. These results indicate that a C5
convertase can operate in normal milk, that only minute amounts of
C5a/C5a(desArg) can be generated (less than 1/1,000 of plasma potential), but
that much higher concentrations are reached in milk during endotoxin-induced
inflammation. The ELISA made it possible to determine normal ranges of
C5a/C5a(desArg) in bovine blood plasma and in milk, and is a valuable tool to
define the variations of its concentrations in exudates during inflammatory
reactions.
PMID- 9559523
TI - Combined effect of ampicillin, colistin and dexamethasone administered
intramuscularly to dairy cows on the clinico-pathological course of E. coli
endotoxin mastitis.
AB - The effects of a single intramuscular injection of a drug product containing
ampicillin, colistin and dexamethasone, as a suspension in a diester of propylene
glycol of medium-chain fatty acids, on the clinico-pathological course of
experimental Escherichia coli-endotoxin mastitis was examined in 30 dairy cows.
Cows were divided into five groups, six cows per group, and 24 of them were
infused with E. coli endotoxin into two quarters of their udders. The drug
product was injected at 25,000 IU colistin sulphate, 10.0 mg ampicillin anhydrate
and 0.025 mg dexamethasone acetate.kg-1 body weight as follows: Group 2 cows,
immediately post-endotoxin infusion (PEI); Group 3 cows, 2 h PEI and, Group 4
cows, 4 h PEI. Group 1 cows were not treated with the product and served as a
positive (endotoxin only) control while Group 5 cows were not challenged with
endotoxin and were not treated with the product. A clinical mastitis score (CMS)
was developed to quantitatively assess the degree of inflammation. Blood
biochemistry and hematological parameters were used to monitor the immediate
effects of treatment on several conventional inflammatory markers. Milk somatic
cell counts (MSCC), milk electrical conductivity and daily milk production were
among the parameters used to monitor systemic and local inflammatory reactions.
Administration of the drug product immediately PEI and 2 h PEI clearly nullified
some of the most severe early systemic reactions to inflammation but the effect
of therapy on the local inflammatory markers was not as obvious. Notewhorthy,
however, were the effects of the treatment on reducing the duration of elevated
quarter MSCC and the increase in the speed of return to pre-endotoxin challenge
daily milk production levels.
PMID- 9559524
TI - Micropuncture study on urea movements in the kidney cortical tubules of low
protein fed sheep.
AB - Micropuncture studies of late proximal, early and late distal cortical tubules
were carried out on kidneys of normal (NP) and low (LP) protein fed sheep in
order to investigate the participation of these segments in the urea sparing
induced by protein restriction in the diet. A low protein diet induced
significant reductions in the fractional (-54%) and total (-84%) urea excretion,
revealing an enhanced capacity for urea conservation. Micropuncture data did not
show any difference in the proximal tubule functions between both groups of
sheep. In distal cortical tubules the fractional delivery of urea (early distal,
0.61 +/- 0.06 for NP and 0.77 +/- 0.06 for LP sheep, not significant (NS); late
distal, 0.45 +/- 0.07 for NP and 0.71 +/- 0.09 for LP sheep, P < 0.05) showed a
relatively larger amount of urea present in the late distal tubule of protein
restricted sheep. The tubular fluid-to-plasma inulin ratio in the late distal
tubule was found to be lower in LP sheep (4.33 +/- 0.23 versus 8.58 +/- 0.9 in NP
sheep, P < 0.01). The tubular flow rate, reduced in the early distal tubules of
LP sheep (10.87 +/- 0.99 versus 18.92 +/- 2.58 nL.min-1 in NP sheep, P < 0.05),
was not different in the late distal tubules from values in normally fed animals
(6.65 +/- 0.90 versus 7.73 +/- 0.94 nL.min-1 in NP sheep, NS). These findings
suggest a decreased distal water reabsorption coincident with the relatively
larger amounts of intraluminal urea in LP sheep. This relatively larger urea
delivery to the initial collecting duct could increase the subsequent urea
reabsorption in protein restricted sheep.
PMID- 9559526
TI - [Viral hepatitis G (HGV)].
PMID- 9559525
TI - Purification of a leucine aminopeptidase from Eimeria falciformis.
AB - A leucine aminopeptidase was purified from the oocysts of Eimeria falciformis
using affinity chromatography and gel filtration techniques. It had a molecular
weight of 45-50 kDa. Its maximal activity against leucyl-p-nitro anilide was at
pH 8.6. It is a metallo-enzyme highly inhibited by bestatin.
PMID- 9559527
TI - [Immunoadjuvant and antiviral properties of saponins].
PMID- 9559528
TI - [Circulation of viruses of the California serocomplex (Bunyaviridae, Bunyavirus)
in the central and southern parts of the Russian plain].
AB - Seventy strains of California group viruses were isolated in the Central and
Southern territories of the Russian plain situated in the Southern taiga, mixed
forest, broad-leaved forest, forest-steppe, steppe, and semiarid zones. Sixty
three of these were isolated from 873,300 mosquitoes, 4 from patients, and 3 from
rodents. 57.1% of strains were isolated from Aedes communis and the associated
species, 28.5% from Aedes excrucians and associated species, and rarely from
other mosquito species. The mosquito infection rate was the highest in the
Southern taiga zone: 0.0103%, this value decreasing towards the Southern areas.
Out of 70 isolated strains 42.3% were identified as the Inkoo virus, 47.2% wer
ejust referred to the California group, and only 2.8% were Tahyna and snowshoe
hare viruses. The findings of serological screening of the population correlate
with the results of virological studies of mosquitoes. Population morbidity is
mainly caused by the Inkoo virus in the Southern taiga and mixed and broad-leaved
forest, by Inkoo and Tahyna viruses in the steppe and forest-steppe zones, and by
Tahyna virus in semiarid zone.
PMID- 9559529
TI - [Diseases associated with viruses of the California encephalitis serogroup, in
Russia].
AB - Studies of 1986-1995 revealed diseases etiologically connected with California
serogroup viruses (Bunyaviridae, Bunyavirus) all over the country. Highly endemic
zones are the tundra, taiga, and leafy forest. The disease occurs mainly in
summer, the patients are mostly young: under 30 years of age. Analysis of 183
cases confirmed by laboratory findings enabled us to distinguish the following
forms: influenza-like (70.9%) with the predominant involvement of the
bronchopulmonary system (bronchitis and pneumonia) and neuroinfection (20.2%)
(serous meningitis and meningoencephalitis).
PMID- 9559530
TI - [A mechanism for limiting reproduction influenza A virus reassortants with
incomplete functional compatibility of hemagglutinin and neuraminidase gene
products].
AB - The mechanism of decrease in the level of virus accumulation in reassortants with
hemagglutinin (HA) and neuraminidase (NA) genes from different parents is
studied. The reassortant viruses and their passage variants do not differ by the
rate of virus protein production or their stability in infected cells. Electron
microscopy and titration of infectious virus in culture fluid and cell-associated
virus showed that the variants selected by serial passages accumulated mainly in
the culture fluid, whereas the initial reassortant virions were predominantly
cell-associated. These data suggest that incomplete removal of sialic acid
residues by viral neuraminidase N1 in some reassortants results in re-attachment
of virions to the infected cells and thus impairs the virus dissemination, which
may be regarded as a reassortant-limiting factor probably significant for virus
evolution.
PMID- 9559531
TI - [Formation of humoral and secretory immunity in elderly persons with different
schemes of immunization with flu vaccines].
AB - The immunological efficacy of 5 protocols of immunization with two influenza
vaccines are compared in 168 elderly subjects aged 64 to 87 years. Russian live
cold-adapted reassortant trivalent (LCIV) and American inactivated cleaved
trivalent (ICIV) influenza vaccines were used. The protocols of vaccination were
as follows: 1) simultaneous vaccination with LCIV and ICIV and revaccination with
LCIV after 1 months; 2) simultaneous vaccination with LCIV and ICIV and
revaccination with placebo after 1 month; 3) vaccination and revaccination with
LCIV; 4) vaccination with ICIV and revaccination with placebo; 5) vaccination and
revaccination with placebo preparation (control); 6) vaccination with ICIV and
revaccination with LCIV after 1 month. The incidence of significant increments
and intensity of accumulation of serum (assessed by the hemagglutination
inhibition test) and secretory (IgA) antibodies (assessed by enzyme immunoassay)
was evaluated. For elderly subjects, simultancous vaccination with LCIV and ICIV
followed by revaccination with LCIV is the most effective. After such
vaccinations both secretory and humoral immune responses are characterized by the
highest production of secretory IgA and serum antibodies. The quantitative
parameters of both types of immune response in elderly subjects thus immunized
are much higher than in young subjects vaccinated traditionally, that is, by LCIV
or ICIV alone.
PMID- 9559532
TI - [Role of certain factors in intracellular oligomerization of influenza virus
nucleoproteins].
AB - Oligomerization of influenza virus nucleoprotein (NP) depends on the virus
strain. NP monomers of viruses A/Duck/Ukraine/63 (H3N8) and
A/Seal/Massachusets/1/80/ (H7N7) are oligomerized completely. The A/USSR/90/77
virus (H1N1) NP is characterized by just partial oligomerization, similarly as a
reassortant containing surface protein genes of virus A/Duck/Ukraine and internal
protein genes of A/USSR/90 virus. Hence, it is probable that NP gene controls the
type of NP oligomerization. NP oligomerization is shown to depend on the
temperature, the optimal t = 37 degrees C, but not on the type of cells or
intracellular concentration of total NP. NP oligomers forming in vivo are
believed to differ from NP oligomers formed in vitro described previously.
PMID- 9559533
TI - [Comparative analysis of distribution of mutant alleles of the gene coding for
the CCR-5 chemokine receptor, among people in Russia, infected and not infected
with HIV-1].
AB - Comparative analysis of the distribution of deletion mutations of CC-chemokine
receptor 5 (CCR-5) gene among HIV-1 infected and not infected subjects in Russia
showed the incidence of the heterozygous genotype to be 17.8% among both HIV
infected and seronegative subjects. The incidence of the homozygous genotype for
the deletion among seronegative individuals was 0.6%, but no homozygotes were
found among HIV-1 infected patients. Study of the incidence of the mutant CCR-5
allele among patients infected with different HIV-1 subtypes showed that the
susceptibility of heterozygotes to HIV-1 infection was not associated with any
special genetic subtype.
PMID- 9559534
TI - [Characteristics of the LTR of endogenous retrovirus in the human T-lymphocyte
CD4 receptor gene].
AB - The nucleotide sequence of the long terminal repeat (LTR) of human endogenous
retrovirus element (HERV), localized in the first introne of the CD4 gene in the
antisense direction, is determined. This new retrotransposon is highly homologous
with different LTR HERV and belongs to HERV-K family. A peculiar feature of this
element is an insertion of the Alu repeated sequence inside LTR. This Alu repeat
has the same orientation as LTR HERV and contains two short open frames with a
high level of homology with DAF (decay accelerating factor) proteins and the
fifth complement component. In addition, this Alu repeat of LTR HERV contains
regulatory elements: enhancer, TATAA box, poly A site, etc. Preservation of
putative regulatory elements in the LTR suggests that they can render distinct
regulatory properties to CD4 receptor gene.
PMID- 9559535
TI - [Isolation of a complex of tick-borne encephalitis viral proteins by affinity
chromatography using monoclonal antibodies to proteins NS5 and NS3].
AB - Affinity chromatography of lysates of continuous porcine embryo cells infected
with tick-borne encephalitis (TBE) virus on sepharose with immobilized monoclonal
antibodies to TBE virus proteins NS5 and NS3 results in isolation of a stable
protein complex. This complex contains viral proteins NS5, NS3, p49, and,
probably, two more cell proteins. This complex is not detected at the early stage
of infection, and 24 h after infection its structure does not depend on the
specificity of immobilized monoclonal antibodies used in affinity chromatography
and on the time elapsed after the infection. Immunoprecipitates of infected cells
phosphorylated TBE virus protein NS5 in vitro, but possessed no RNA-polymerase
activity. Elution of the complex with buffers with pH 3.5 or 11.1 or with 2M urea
failed to purify the active replicase. The complex of viral and cellular proteins
isolated by affinity chromatography on different immunoadsorbents did not possess
RNA-polymerase activity because of inactivation or absence of additional
subunit(s).
PMID- 9559537
TI - [Influenza pandemic: can we fight it?].
PMID- 9559536
TI - [Some mechanisms of the action of oligonucleotides: stimulation of the immune
system and decreased infection of the brain in tickborne encephalitis].
AB - Morphological changes in the thymus, spleen, and brain are analyzed in white mice
injected 16-component oligonucleotide (ON) pE16 complementary to the NS3 protein
gene sequences of tickborne encephalitis (TBE) virus in doses of 1 to 0.001 nM.
ON stimulated thymic and splenic cells. Besides the stimulating effect, injection
of ON to mice infected with TBE enhanced the destruction of lymphocytes and
boosted the macrophagal activity, which was paralleled by a decrease in the
intensity of virus-specific injuries in the brain. Thus, the antiviral activity
of ON may be due to not only the fact that it is complementary to the TBE virus
genome, but to stimulation of the immune system, specifically, the thymus and T
related elements, as well.
PMID- 9559538
TI - [Epizootic situation with regard to rabies in the Moscow area and a way to
improve it].
PMID- 9559539
TI - Mam33p, an oligomeric, acidic protein in the mitochondrial matrix of
Saccharomyces cerevisiae is related to the human complement receptor gC1q-R.
AB - Mam33p (mitochondrial acidic matrix protein) is a soluble protein, located in
mitochondria of Saccharomyces cerevisiae. It is synthesized as a precursor with
an N-terminal mitochondrial targeting sequence that is processed on import.
Mam33p assembles to a homo-oligomeric complex in the mitochondrial matrix. It can
bind to the sorting signal of cytochrome b2 that directs this protein into the
intermembrane space. Mam33p is encoded by an 801 bp open reading frame. Gene
disruption did not result in a significant growth defect. Mam33p exhibits
sequence similarity to gC1q-R, a human protein that has been implicated in the
binding of complement factor C1q and kininogen.
PMID- 9559540
TI - Synthesis of monohydroxylated inositolphosphorylceramide (IPC-C) in Saccharomyces
cerevisiae requires Scs7p, a protein with both a cytochrome b5-like domain and a
hydroxylase/desaturase domain.
AB - Saccharomyces cerevisiae mutants lacking Scs7p fail to accumulate the
inositolphosphorylceramide (IPC) species. IPC-C, which is the predominant form
found in wild-type cells. Instead scs7 mutants accumulate an IPC-B species
believed to be unhydroxylated on the amide-linked C26-fatty acid. Elimination of
the SCS7 gene suppresses the Ca(2+)-sensitive phenotype of csg1 and csg2 mutants.
The CSG1 and CSG2 genes are required for mannosylation of IPC-C and accumulation
of IPC-C by the csg mutants renders them Ca(2+)-sensitive. The SCS7 gene encodes
a protein that contains both a cytochrome b5-like domain and a domain that
resembles the family of cytochrome b5-dependent enzymes that use iron and oxygen
to catalyse desaturation or hydroxylation of fatty acids and sterols. Scs7p is
therefore likely to be the enzyme that hydroxylates the C26-fatty acid of IPC-C.
PMID- 9559541
TI - Assembly of phosphofructokinase-1 from Saccharomyces cerevisiae in extracts of
single-deletion mutants.
AB - Phosphofructokinase-1 from Saccharomyces cerevisiae is an octameric enzyme
comprising two non-identical subunits, alpha and beta, which are encoded by the
unlinked genes PFK1 and PFK2. In this paper, assembly and reactivation of the
enzyme have been studied in cell-free extracts of single-deletion mutants. In
contrast to the previously described lack of phosphofructokinase-1 activity in
cell-free extracts of these mutants, we could measure a temporary enzyme activity
immediately after lysis of protoplasts. This result supports the assumption that
each of the subunits forms an enzyme structure which is active in vivo but not
stable after cell disruption. Upon mixing of separately prepared cell-free
extracts of both deletion mutants very low activity could be measured. About 40%
of the wild-type activity was regained when both mutants were mixed prior to
disruption. The reactivation rate could be slightly increased by addition of ATP
and fructose 6-phosphate and was found to be a function of the growth state,
particularly of the beta-subunit-carrying cells. The individual subunits did not
interact with Cibacron Blue F3G-A, a biomimetic ligand of phosphofructokinase-1.
After reassembly of both subunits in vitro a strong affinity of the reconstituted
phosphofructokinase-1 to the dye-ligand was observed. The inability of the
subunits to reconstitute under certain conditions seems to result from
alterations of the intracellular environment following disruption. These changes
give rise to induce an unproductive side reaction like self-aggregation of the
subunits. Because reconstitution of phosphofructokinase-1 from S. cerevisiae
behaves in a similar way to that of hemoglobin and luciferase, we would speculate
a general mechanism for assembly of oligomeric proteins in vivo.
PMID- 9559542
TI - Purified arginine permease of Candida albicans is functionally active in a
reconstituted system.
AB - We have for the first time purified arginine permease from a pathogenic yeast,
Candida albicans, to homogeneity by affinity chromatography using L-arginine
linked agarose matrix as affinity column. The purified protein (PP) was of 66 kDa
with no subunit structure. Two kinetically distinct binding affinities of PP were
evident where high affinity binding (S1) revealed a dependence on acidic pH while
pH did not have dramatic effect on low affinity (S2) binding. The specificity of
L-arginine binding to PP with regard to other amino acids, structural analogues
and inhibitors, was essentially similar to arginine transport observed in the
intact cells of C. albicans (Rao et al., 1986). The purified arginine permease
was reconstituted into proteoliposomes and its functionality was tested by
imposing a valinomycin-induced membrane potential. All the characteristic
features of L-arginine transport displayed by the reconstituted system were
similar to those observed in intact cells. Thus homogeneous purified arginine
permease was also functionally active.
PMID- 9559543
TI - The importance of the glycerol 3-phosphate shuttle during aerobic growth of
Saccharomyces cerevisiae.
AB - Maintenance of a cytoplasmic redox balance is a necessity for sustained cellular
metabolism. Glycerol formation is the only way by which Saccharomyces cerevisiae
can maintain this balance under anaerobic conditions. Aerobically, on the other
hand, several different redox adjustment mechanisms exist, one of these being the
glycerol 3-phosphate (G3P) shuttle. We have studied the importance of this
shuttle under aerobic conditions by comparing growth properties and glycerol
formation of a wild-type strain with that of gut2 delta mutants, lacking the FAD
dependent glycerol 3-phosphate dehydrogenase, assuming that the consequent
blocking of G3P oxidation is forcing the cells to produce glycerol from G3P. To
impose different demands on the redox adjustment capability we used various
carbon sources having different degrees of reduction. The results showed that the
shuttle was used extensively with reduced substrate such as ethanol, whereas the
more oxidized substrates lactate and pyruvate, did not provoke any activity of
the shuttle. However, the absence of a functional G3P shuttle did not affect the
growth rate or growth yield of the cells, not even during growth on ethanol.
Presumably, there must be alternative systems for maintaining a cytoplasmic redox
balance, e.g. the so-called external NADH dehydrogenase, located on the outer
side of the inner mitochondrial membrane. By comparing the performance of the
external NADH dehydrogenase and the G3P shuttle in isolated mitochondria, it was
found that the former resulted in high respiratory rates but a comparably low P/O
ratio of 1.2, whereas the shuttle gave low rates but a high P/O ratio of 1.7. Our
results also demonstrated that of the two isoforms of NAD-dependent glycerol 3
phosphate dehydrogenase, only the enzyme encoded by GPD1 appeared important for
the shuttle, since the enhanced glycerol production that occurs in a gut2 delta
strain proved dependent on GPD1 but not on GPD2.
PMID- 9559544
TI - The SKS1 gene of Saccharomyces cerevisiae is required for long-term adaptation of
snf3 null strains to low glucose.
AB - The SKS1 gene was originally identified as a multicopy suppressor of the growth
defect of snf3 null mutations on low glucose concentrations. Snf3p is required
for the rapid induction of HXT2 during growth on low substrate concentrations.
Loss of Snf3p leads to a dramatic delay in expression of HXT2. Adaptation to low
substrate concentrations does not occur in snf3 sks1 double null mutant strains,
suggesting that SKS1 is required for the glucose-dependent expression of HXT2 in
the absence of Snf3p activity. Over-expression of SKS1 leads to over-expression
of Hxt2p, thus explaining the mechanism of suppression of the snf3 defect. SKS1
defines a novel, Snf3p-independent pathway for the expression of Hxt2p. Under
certain growth conditions, over-expression of SKS1 itself leads to a growth
defect which is diminished in snf3 hxt2 double mutants. This suggests that over
expression of Hxt2p at physiologically inappropriate times is detrimental to the
cells.
PMID- 9559545
TI - Glycosylation of human alpha 1-antitrypsin in Saccharomyces cerevisiae and
methylotrophic yeasts.
AB - Human alpha 1-antitrypsin (alpha 1-AT) is a major serine protease inhibitor in
plasma, secreted as a glycoprotein with a complex type of carbohydrate at three
asparagine residues. To study glycosylation of heterologous proteins in yeast, we
investigated the glycosylation pattern of the human alpha 1-AT secreted in the
baker's yeast Saccharomyces cerevisiae and in the methylotrophic yeasts,
Hansenula polymorpha and Pichia pastoris. The partial digestion of the
recombinant alpha 1-AT with endoglycosidase H and the expression in the mnn9
deletion mutant of S. cerevisiae showed that the recombinant alpha 1-AT secreted
in S. cerevisiae was heterogeneous, consisting of molecules containing core
carbohydrates on either two or all three asparagine residues. Besides the core
carbohydrates, variable numbers of mannose outer chains were also added to some
of the secreted alpha 1-AT. The human alpha 1-AT secreted in both methylotrophic
yeasts was also heterogeneous and hypermannosylated as observed in S. cerevisiae,
although the overall length of mannose outer chains of alpha 1-AT in the
methylotrophic yeasts appeared to be relatively shorter than those of alpha 1-AT
in S. cerevisiae. The alpha 1-AT secreted from both methylotrophic yeasts
retained its biological activity as an elastase inhibitor comparable to that of
alpha 1-AT from S. cerevisiae, suggesting that the different glycosylation
profile does not affect the in vitro activity of the protein.
PMID- 9559546
TI - Purification and properties of polyphosphatase from Saccharomyces cerevisiae
cytosol.
AB - A homogenous polyphosphatase preparation was obtained from Saccharomyces
cerevisiae cytosol with a 3.8% yield and 3540-fold purification. The enzyme
hydrolysed polyphosphate (polyP) with various chain lengths, including polyP3,
and split Pi off the end of the chain. It was inactive with respect to ATP, PPi,
and p-nitrophenylphosphate. Its specific activity with polyP15 was 283 U/mg
protein. The polyphosphatase was a monomeric protein with a molecular mass of 40
kDa. This enzyme was inactive without divalent cations and with Cu2+ and Ca2+.
The ability of other divalent cations to activate the enzyme decreased in the
following order; Co2+ > Mn2+ > Mg2+ > Zn2+. A kinetic model of the hydrolysis of
polyP3 and action of Mg2+ is proposed.
PMID- 9559547
TI - Construction of PCR-ligated long flanking homology cassettes for use in the
functional analysis of six unknown open reading frames from the left and right
arms of Saccharomyces cerevisiae chromosome XV.
AB - Six open reading frames (ORFs) of unknown function from Saccharomyces cerevisiae
chromosome XV, three from the left and three from the right arm, were deleted in
two diploid strains by the short flanking homology method (Wach et al., 1994).
Transformants were selected as Geneticin (G418)-resistant colonies and correct
integration of the kanMX4 cassette was checked by colony PCR. Following
sporulation of the diploids, tetrads were dissected and scored for the
segregation of the G418-resistant marker. We have developed a widely applicable
method for the construction of gap repair plasmids to obtain the cognate clones
for each of the disrupted ORFs. The 5'- and 3'-flanks of the ORF in question are
linked by a unique restriction endonuclease. When the plasmid is cut at this site
it can be used to obtain, by selection for the appropriate antibiotic resistance,
long flanking homology (LFH) cassettes containing the cognate clone or the
disrupted allele. The LFH cassette containing the cognate clone or the disrupted
allele can be released from the gap-repaired plasmid by cutting at the inserted
flanking restriction sites. One of the six ORFs (YOR319w) corresponds to an
essential gene whose product is part of the spliceosome complex. Haploid as well
as homozygous and heterozygous diploid disruptant strains for each of the five
non-essential ORFs were subjected to growth test on different media at 15 degrees
C, 30 degrees C and 37 degrees C. Disruption of YOR322c causes osmotically
sensitive growth on YEPD at 37 degrees C and the product of YOL091w appears to
play a role in sporulation since the homozygous diploid disruptant has lost the
ability to sporulate.
PMID- 9559548
TI - Isolation and characterization of Kluyveromyces marxianus mutants deficient in
malate transport.
AB - In malic acid-grown cells of the strains ATCC 10022 and KMS3 of Kluyveromyces
marxianus the transport of malic acid occurred by a malate-proton symport, which
accepted L-malic, D-malic, succinic and fumaric acids, but not tartaric, malonic
or maleic acids. The system was inducible and subjected to glucose repression.
Mutants of the strain KMS3, unable to grow in a medium with malic acid, were
isolated and checked for their capacity to utilize several carbon sources and to
transport dicarboxylic acids by the malate-proton symport. Two distinct clones
affected on malate transport were obtained. Both were able to grow on a medium
with glycerol or ethanol but not with DL-malic, succinic, oxoglutaric and
oxaloacetic acids as the sole carbon and energy sources. However, while one of
the mutants (Mal7) displayed activity levels for the enzymes malate
dehydrogenase, isocitrate lyase, and phosphoenolpyruvate carboxykinase similar to
those of the wild strain, in the other mutant type (Mal6) the activities for the
same enzymes were significantly reduced. Plasma membranes from derepressed cells
of the wild strain and of the mutants Mal6 and Mal7 were isolated and the protein
analysed by SDS-PAGE. The electrophoretic patterns of these preparations differed
in a polypeptide with an apparent molecular mass of about 28 kDa, which was
absent only in the mutant Mal7. The results indicated that Mal7 can be affected
in a gene that encodes a malate carrier in K. marxianus.
PMID- 9559549
TI - Identification and analysis of homologues of Saccharomyces cerevisiae Spt3
suggest conserved functional domains.
AB - Spt3 of Saccharomyces cerevisiae is a factor required for normal transcription
from particular RNA polymerase II-dependent promoters. As a step towards
analysing Spt3 structure-function relationships, we have identified and studied
Spt3 homologues from three other yeasts: Kluyveromyces lactis, Clavispora
opuntiae and Schizosaccharomyces pombe. Alignment of their predicted amino acid
sequences shows an overall identity of 30% between all four homologues and
suggests that three conserved domains are present in Spt3. When tested for
function in S. cerevisiae, K. lactis SPT3 was shown to fully complement and S.
pombe SPT3 to partially complement an spt3 delta mutation. These data demonstrate
that Spt3 is functionally conserved among distantly related yeasts.
PMID- 9559550
TI - Heat shock transiently enhances the synthesis rate of Sis1p, a ribosome
associated DnaJ protein in the oleagenous yeast Apiotrichum curvatum.
AB - DnaJ proteins have been localized in different intracellular compartments of
eukaryotes. In Apiotrichum curvatum, a fat-storing yeast, we found a DnaJ homolog
associated with ribosomes and large cytosolic complexes as well. Using a plant
DnaJ probe and a cDNA library constructed from poly(A)(+)-RNA of A. curvatum
grown on oleate we isolated a SIS1 cDNA coding for a 39.5 kDa protein. The
putative protein contains neither a zinc finger motif nor a CAAX motif but is
characterized by a J-domain at the N-terminal region and a large G-rich region in
the middle part of the molecule. Heat shock applied for 1 h resulted in a
pronounced but transient increase of the SIS1 mRNA. An antiserum was raised
against the bacterially expressed protein. Cell fractions from A. curvatum were
further separated by sedimentation centrifugation on sucrose gradients. Analysing
the sub-fractions, we detected Sis1p mainly associated with ribosomes, and with
particles sedimenting at approximately 200S. Hsp70 was found to be associated
with the 200S fraction. The respective cytosolic A. curvatum Hsp70 cDNA was
cloned and sequenced. High salt conditions caused the removal of Hsp70 and Sis1p
from the 200S complexes. Mild RNase treatment of the 200S fraction afforded
monosomes and 200S complexes unaffected by RNase. Heat shock led to a pronounced
increase in the rate of de novo synthesis. However, due to the large pools of
Sis1p on ribosomes and large cytosolic complexes, the increase in gene activation
did not lead to a significant change of the total amount of Sis1p.
PMID- 9559551
TI - Application of mRNA differential display to investigate gene expression in
thermotolerant cells of Saccharomyces cerevisiae.
AB - We have described the use of differential display of PCR-amplified reverse
transcribed mRNA (DDRT-PCR) to survey changes in gene expression profiles induced
by heat shock and carbon catabolite derepression in Saccharomyces cerevisiae. It
is well established that either of these states elicits thermotolerant
phenotypes. An initial analysis conducted on cells of an inherently
thermosensitive strain (Ysen) indicated that approximately 10% of the total
number of cDNAs detected were either up or down regulated following heat shock at
37 degrees C (30 min) in comparison to control cells (25 degrees C). In addition,
whereas 7% of all PCR products were preferentially expressed during derepressive
growth, approximately 2% were found to be common to both heat-shocked and
derepressed cells. A repeat analysis, performed on all three cell types of Ysen
as well as cells of a relatively thermoresistant strain (Yres) yielded 30
differentially displayed cDNA fragments common to heat-shocked and derepressed
cells of both strains. Eighteen of these generated signals on Northern blots, of
which three were confirmed as regulated. Five amplicons, including one not
detected by Northern analysis and another from the derepressed state, were cloned
and sequenced. Three of these exhibited homology to S. cerevisiae genes with well
characterized protein products: HSP 90, HXK1 and STA1. The remaining two
applicons showed nucleotide identity to YTIS11, a homolog of the mammalian TIS11
and putative transcriptional activator, and an orphan gene encoding a
hypothetical transmembrane protein belonging to the multi-drug resistance
translocase family. Our novel application of DDRT-PCR has identified new and
known genes that may be further evaluated as factors involved in stress
regulation and has demonstrated the potential of the technique to systematically
analyse gene expression in yeast.
PMID- 9559552
TI - Evolution of gene order and chromosome number in Saccharomyces, Kluyveromyces and
related fungi.
AB - The extent to which the order of genes along chromosomes is conserved between
Saccharomyces cerevisiae and related species was studied by analysing data from
DNA sequence database. As expected, the extent of gene order conservation
decreases with increasing evolutionary distance. About 59% of adjacent gene pairs
in Kluyveromyces lactis or K. marxianus are also adjacent in S. cerevisiae, and a
further 16% of Kluyveromyces neighbours can be explained in terms of the inferred
ancestral gene order in Saccharomyces prior to the occurrence of an ancient whole
genome duplication. Only 13% of Candida albicans linkages, and no
Schizosaccharomyces pombe linkages, are conserved. Analysis of gene order
arrangements, chromosome numbers, and ribosomal RNA sequences suggests that
genome duplication occurred before the divergence of the four species in
Saccharomyces sensu stricto (all of which have 16 chromosomes), but after this
lineage had diverged from Saccharomyces kluyveri and the Kluyveromyces
lactislmarxianus species assemblage.
PMID- 9559553
TI - Regulation of alcoholic fermentation in batch and chemostat cultures of
Kluyveromyces lactis CBS 2359.
AB - Kluyveromyces lactis is an important industrial yeast, as well as a popular
laboratory model. There is currently no consensus in the literature on the
physiology of this yeast, in particular with respect to aerobic alcoholic
fermentation ('Crabtree effect'). This study deals with regulation of alcoholic
fermentation in K. lactis CBS 2359, a proposed reference strain for molecular
studies. In aerobic, glucose-limited chemostate cultures (D = 0.05-0.40 h-1)
growth was entirely respiratory, without significant accumulation of ethanol or
other metabolities. Alcoholic fermentation occurred in glucose-grown shake-flask
cultures, but was absent during batch cultivation on glucose in fermenters under
strictly aerobic conditions. This indicated that ethanol formation in the shake
flask cultures resulted from oxygen limitation. Indeed, when the oxygen feed to
steady-state chemostat cultures (D = 0.10 h-1) was lowered, a mixed
respirofermentative metabolism only occurred at very low dissolved oxygen
concentrations (less than 1% of air saturation). The onset of respirofermentative
metabolism as a result of oxygen limitation was accompanied by an increase of the
levels of pyruvate decarboxylase and alcohol dehydrogenase. When aerobic, glucose
limited chemostat cultures (D = 0.10 h-1) were pulsed with excess glucose,
ethanol production did not occur during the first 40 min after the pulse.
However, a slow aerobic ethanol formation was invariably observed after this
period. Since alcoholic fermentation did not occur in aerobic batch cultures this
is probably a transient response, caused by an imbalanced adjustment of enzyme
levels during the transition from steady-state growth at mu = 0.10 h to growth at
mu max. It is concluded that in K. lactis, as in other Crabtree-negative yeasts,
the primary environmental trigger for occurrence of alcoholic fermentation is
oxygen limitation.
PMID- 9559554
TI - The list of cytoplasmic ribosomal proteins of Saccharomyces cerevisiae.
AB - Screening of the complete genome sequence from the yeast Saccharomyces cerevisiae
has enabled us to compile a complete list of the genes encoding cytoplasmic
ribosomal proteins in this organism. Putative ribosomal protein genes were
selected primarily on the basis of the sequence similarity of their products with
ribosomal proteins from other eukaryotic organisms, in particular the rat. These
genes were subsequently screened for typical yeast rp-gene characteristics, viz.
(1) a high codon adaptation index; (2) their promoter structure and (3) their
responses to changes in growth conditions. The yeast genome appears to carry 78
different genes, of which 59 are duplicated, encoding 32 different small-subunit
and 46 large-subunit proteins. A new nomenclature for these ribosomal proteins is
proposed.
PMID- 9559555
TI - Nucleotide sequence of the Schizosaccharomyces pombe lys1+ gene and similarities
of the lys1+ protein to peptide antibiotic synthetases.
AB - The 4.2 kbp lys1+ gene of Schizosaccharomyces pombe encoding the large subunit of
alpha-aminoadipate reductase (EC1.2.1.31), an enzyme specific to lysine synthesis
in higher fungi, was completely sequenced at the nucleotide level from pLYS1H.
The S. pombe lys1+ gene product consists of 1415 amino acid residues and has a
putative molecular weight of 155.8 kDa. The encoded protein converts alpha
aminoadipic acid to alpha-aminoadipate-delta-semialdehyde by an ATP-mediated
adenylation. Analysis of the sequence showed that the putative protein encoded by
lys1+ shares strong homology with the peptide antibiotic synthetases which also
use in adenylation step.
PMID- 9559556
TI - Characterization of the Prk1 protein kinase from Schizosaccharomyces pombe.
AB - We report the isolation and characterization of a protein kinase from the fission
yeast Schizosaccharomyces pombe. The proposed Prk1 protein contains 352 amino
acids and has significant homology to the Ume5p kinase (also known as Srb10p,
Ssn3p and Are1p) of the budding yeast Saccharomyces cerevisiae, a cyclin
dependent kinase involved in regulating the transcription of a diverse set of
genes. Disruption of the prk1 gene increases flocculation but does not appear to
have any other significant effect on cell behaviour. This defect can be overcome
by expressing the UME5 gene, indicating that Prk1 is the fission yeast homologue
of Ume5p.
PMID- 9559557
TI - Current awareness on yeast.
PMID- 9559558
TI - Cloning and characterization of high-CO2-specific cDNAs from a marine microalga,
Chlorococcum littorale, and effect of CO2 concentration and iron deficiency on
the gene expression.
AB - Two cDNA clones exclusively induced under an extremely high-CO2 concentration
(20%) were isolated from Chlorococcum littorale by differential screening and
named HCR (high-CO2 response) 1 and 2, respectively. The amino acid sequence of
the protein encoded by HCR2 exhibited homology to the gp91-phox protein, a
critical component of a human phagocyte oxidoreductase, and to the yeast ferric
reductases, Saccharomyces cerevisiae FRE1 and FRE2 and Schizosaccharomyces pombe
Frp1. The induction of both HCR mRNAs required extremely high-CO2 conditions and
iron deficiency, being suppressed under air conditions and by iron sufficiency,
suggesting that the expression of these two HCR genes required extremely high-CO2
conditions and iron deficiency in combination. The HCR2 protein was detected in
the membrane fractions of cells grown under conditions which would favor the
induction of HCR2-mRNA and the protein level was lowered when the cells were
transferred from iron deficient to 10 microM FeSO4 conditions (with 20% CO2).
PMID- 9559559
TI - A protein encoded by din1, a dark-inducible and senescence-associated gene of
radish, can be imported by isolated chloroplasts and has sequence similarity to
sulfide dehydrogenase and other small stress proteins.
AB - In an attempt to isolate cDNA clones for dark-inducible chloroplast proteins, we
screened a cDNA library which was prepared from radish cotyledons by a two-step
method. The source plants were grown under continuous light for 14 d and kept in
darkness for 24 h. One of the selected clones, S2D12, corresponded to the din1
gene which we previously reported as a dark-inducible, senescence-associated gene
[Azumi and Watanabe (1991) Plant Physiol. 95:577]. A 22 kDa polypeptide was
produced from the cDNA in an in vitro expression system in the presence of
[35S]methionine. This polypeptide was capable of being imported by isolated
chloroplasts, processed to a smaller mature form and localized in the stromal
fraction. As the amino acid sequence of the putative mature protein has no
homology to any known chloroplast protein, din1 was suggested to be the first
gene for a chloroplast protein which is negatively controlled by light. The
putative mature protein has similarity to sulfide dehydrogenase from Wolinella
succinogenes and other small stress proteins; glpE and pspE from Escherichia coli
and hsp67B2 from Drosophila melanogaster.
PMID- 9559560
TI - Identification of a novel triterpenoid saponin from Pisum sativum as a specific
inhibitor of the diguanylate cyclase of Acetobacter xylinum.
AB - A specific and highly potent inhibitor of diguanylate cyclase, the key regulatory
enzyme of the cellulose synthesizing apparatus in the bacterium Acetobacter
xylinum, was isolated from extracts of etiolated pea shoots (Pisum sativum). The
inhibitor has been purified by a multistep procedure, and sufficient amounts of
highly purified compound (3-8 mg) for spectral analysis were obtained. The
structure of this compound was established as 3-O-alpha-L-rhamnopyranosyl-(1-->2)
beta-D-galactopyranosyl-(1--> 2)-beta-D-glucuronopyranosyl soyasapogenol B 22-O
alpha-D-glucopyranoside. The structure was elucidated on the basis of
susceptibility to various enzymes, chemical and spectral methods, such as GC-MS,
FAB-MS, and the following types of 2D-NMR: COSY, ROESY, TOCSEY, HMQC, HMBC
analyses. An identical or a very similar compound with identical biological
activity was also isolated from A. xylinum, strongly suggesting that at least
certain aspects of cellulose synthesis in the bacteria and in higher plants may
be regulated in a similar manner. The content of this saponin in etiolated plants
was about 0.04 mumol (g fresh tissue)-1.
PMID- 9559561
TI - Cloning of the gene encoding a protochlorophyllide reductase: the physiological
significance of the co-existence of light-dependent and -independent
protochlorophyllide reduction systems in the cyanobacterium Plectonema boryanum.
AB - Cyanobacteria have two protochlorophyllide (Pchlide) reductases catalyzing the
conversion of Pchlide to chlorophyllide, a key step in the biosynthetic pathway
of chlorophylls (Chls); a light-dependent (LPOR) and a light-independent (DPOR)
reductase. We found an open reading frame (ORF322) in a 2,131-bp EcoRI fragment
from the genomic DNA of the cyanobacterium Plectonema boryanum. Because the
deduced amino acid sequence showed a high similarity to those of various plant
LPORs and the LPOR activity was detected in the soluble fraction of Escherichia
coli cells over-expressing the ORF322 protein, ORF322 was defined as the por gene
encoding LPOR in P. boryanum. A por-disrupted mutant, YFP12, was isolated by
targeted mutagenesis to investigate the physiological importance of LPOR. YFP12
grew as well as wild type under low light conditions (10-25 muE m-2 s-1).
However, its growth was significantly retarded as a result of a significant
decrease in its Chl content under higher light conditions (85-130 muE m-2 s-1).
Furthermore, YFP12 stopped growing and suffered from photobleaching under the
highest light intensity (170 muE m-2 s-1). In contrast, a chlL-disrupted (DPOR
less) mutant YFC2 grew as well as wild type irrespective of light intensity. From
these phenotypic characteristics, we concluded that, although both LPOR and DPOR
contribute to Chl synthesis in the cells growing in the light, the extent of the
contribution by LPOR increases with increasing light intensity; without it, the
cells are unable to grow under light intensities of more than 130 muE m-2 s-1.
PMID- 9559562
TI - Glyoxysomal malate dehydrogenase in pumpkin: cloning of a cDNA and functional
analysis of its presequence.
AB - Glyoxysomal malate dehydrogenase (gMDH) is an enzyme of the glyoxylate cycle that
participates in degradation of storage oil. We have cloned a cDNA for gMDH from
etiolated pumpkin cotyledons that encodes a polypeptide consisting of 356 amino
acid residues. The nucleotide and N-terminal amino acid sequences revealed that
gMDH is synthesized as a precursor with an N-terminal extrapeptide. The N
terminal presequence of 36 amino acid residues contains two regions homologous to
those of other microbody proteins, which are also synthesized as large
precursors. To investigate the functions of the N-terminal presequence of gMDH,
we generated transgenic Arabidopsis that expressed a chimeric protein consisting
of beta-glucuronidase and the N-terminal region of gMDH. Immunological and
immunocytochemical studies revealed that the chimeric protein was imported into
microbodies such as glyoxysomes and leaf peroxisomes and was then subsequently
processed. Site-directed mutagenesis studies showed that the conserved amino
acids in the N-terminal presequence, Arg-10 and His-17, function as recognition
sites for the targeting to plant microbodies, and Cys-36 in the presequence is
responsible for its processing. These results correspond to those from the
analyses of glyoxysomal citrate synthase (gCS), which was also synthesized as a
large precursor, suggesting that common mechanisms that can recognize the
targeting or the processing of gMDH and gCS function in higher plant cells.
PMID- 9559563
TI - An mRNA of tobacco cell, which is rapidly inducible by methyl jasmonate in the
presence of cycloheximide, codes for a putative glycosyltransferase.
AB - Two-dimensional gel electrophoretic display of polypeptides labeled in vivo and
those synthesized in vitro from poly(A)(+)-RNA indicated that treatment of
cultured cells of tobacco (Nicotiana tabacum) BY-2 with methyl jasmonate (MeJA)
induces accumulation of a limited number of specific mRNAs within a few hours.
The MeJA-induction of most of these mRNAs was inhibited by cycloheximide (CHX).
Six MeJA-inducible cDNAs identified by differential screening were classified
into three groups based on the sensitivity of their induction to CHX. Induction
of group I mRNAs by MeJA occurred earlier than the induction of other mRNAs and
it was not inhibited by CHX. The induction of group II mRNAs by MeJA was blocked
by CHX, while group III mRNAs were induced by CHX alone. One group I cDNA was
found to encode a putative protein, JIGT, homologous to UDP-sugar
glycosyltransferases previously characterized from several plant species. JIGT
was structurally different from a putative glycosyltransferase that is rapidly
inducible by salycylic acid (SA) in BY-2 cells. JIGT mRNA was not induced by SA.
In addition to MeJA, as little as 10(-9) M coronatine induced JIGT mRNA. A
sequence highly homologous to JIGT is present as a single copy in the genomes of
Nicotiana sylvestris and N. tomentosiformis. The MeJA-inducible production of
JIGT may be involved in sugar-conjugation of an unknown substrate in a defensive
response and expression of the gene for JIGT in BY-2 cells might serve as a good
model system for disecting molecular events occurring in JA-inducible gene
expression.
PMID- 9559564
TI - Distribution of fallover in the carboxylase reaction and fallover-inducible sites
among ribulose 1,5-bisphosphate carboxylase/oxygenases of photosynthetic
organisms.
AB - The biphasic reaction course, fallover, of carboxylation catalysed by ribulose
1,5-bisphosphate carboxylase/oxygenase (RuBisCO) has been known as a
characteristic of the enzyme from higher land plants. Fallover consists of
hysteresis in the reaction seen during the initial several minutes and a very
slow suicide inhibition by inhibitors formed from the substrate ribulose-1,5
bisphosphate (RuBP). This study examined the relationship between occurrence of
fallover and non-catalytic RuBP-binding sites, and the putative hysteresis
inducible sites (Lys-21 and Lys-305 of the large subunit in spinach RuBisCO)
amongst RuBisCOs of a wide variety of photosynthetic organisms. Fallover could be
detected by following the course of the carboxylase reaction at 1 mM RuBP and the
non-catalytic binding sites by alleviation of fallover at 5 mM RuBP. RuBisCO from
Euglena gracilis showed the same linear reaction course at both RuBP
concentrations, indicating an association between an absence of fallover and an
absence of the non-catalytic binding sites. This was supported by the results of
an equilibrium binding assay for this enzyme with a transition state analogue.
Green macroalgae and non-green algae contained the plant-type, fallover enzyme.
RuBisCOs from Conjugatae, Closterium ehrenbergii, Gonatozygon monotaenium and
Netrium digitus, showed a much smaller decrease in activity at 1 mM RuBP than the
spinach enzyme and the reaction courses of these enzymes at 5 mM RuBP were almost
linear. RuBisCO of a primitive type Conjugatae, Mesotaenium caldariorum, showed
the same linear course at both RuBP concentrations. Sequencing of rbcL of these
organisms indicated that Lys-305 was changed into arginine with Lys-21 conserved.
PMID- 9559566
TI - Characterization of delta 9 acyl-lipid desaturase homologues from Arabidopsis
thaliana.
AB - Two cDNAs, ADS1 and ADS2, were isolated from Arabidopsis. These cDNAs encoded
proteins homologous to delta 9 acyl-lipid desaturases of cyanobacteria and acyl
CoA desaturases of yeast and mammals. The expression of ADS1 and ADS2 was organ
dependent. Cold temperature up-regulated the ADS2 expression, whereas it down
regulated the ADS1 expression.
PMID- 9559567
TI - Assessment of particle size distributions of health-relevant aerosol exposures of
primary lead smelter workers.
AB - Experiments were conducted at a primary lead smelter to investigate the particle
size distributions of lead-containing aerosol to which workers were exposed,
using personal inhalable dust spectrometers (PIDS) in specific smelter process
areas. A total of 46 PIDS samples were evaluated, taken from the ore
storage/mill, sinter plant, blast furnace and dross furnace process areas.
Continuous particle size distributions were derived from the raw PIDS data
employing a recently-developed optimisation routine, enabling determination of
the percentages of inhalable, thoracic and respirable aerosol (in terms of lead
content) as fractions of total lead aerosol. In addition, the mass ratios
thoracic/inhalable and respirable/inhalable were also determined. Although the
parameters of the measured particle size distributions ranged widely, some clear
trends emerged. Firstly, the aerosols were coarser than had been expected based
on measurements of previously reported workplace particle size distributions.
This is thought to be due to the fact that the PIDS collects larger particles
more efficiently than other instruments which have been used for such
measurements. Secondly, there were significant differences in particle size
distribution between process areas, in particular that the aerosol in the blast
furnace area was generally finer than in the sinter plant. Such results may be
used to support the results of workplace studies (reported elsewhere) into the
differences between exposures to inhalable and 'total' aerosol as measured using
different sampling instruments, especially when they are used together with
knowledge of the physical processes governing the performances of such
instruments.
PMID- 9559565
TI - Characterization of a cDNA encoding CuZn-superoxide dismutase from the liverwort
Marchantia paleacea var. diptera.
AB - Suspension-cultured cells of the liverwort Marchantia paleacea var. diptera
contain a cytosolic CuZn-superoxide dismutase (SOD) whose N-terminal amino acid
sequence is similar to those of the isozymes found in chloroplasts of higher
plants [Tanaka et al. (1996) Plant Cell Physiol. 37: 523]. A cDNA (MSODCc)
encoding the cytosolic CuZn-SOD was isolated from cDNA library constructed from a
liverwort cell suspension culture. The deduced amino acid sequence showed a
higher degree of homology with the sequences of CuZn-SODs in chloroplasts than
those in the cytosol of higher plants and an unique additional peptide in the C
terminal region, but no plastid transit sequence. Northern blotting using MSODCc
as a probe and immunoblot analysis with antiserum against the enzyme revealed
that the steady state level of transcript was not affected by copper, but both
CuZn-SOD protein and its activity increased.
PMID- 9559568
TI - Historical exposure to inorganic mercury at the smelter works of Abbadia San
Salvatore, Italy.
AB - Metallic mercury production from cinnabar ore may result in high exposures to
inorganic mercury, that are difficult to assess separately from the exposures
originating from underground extraction, and previously have only been scantily
described. We retrieved and analysed the air and biological mercury
determinations on workers involved in the smelting process of the Abbadia San
Salvatore mine (Monte Amiata, Italy). Native mercury was not present in the ore,
and the exposure in the underground extraction was low. The smelter operated from
1897 to 1983. Blood and urine (24/h urine collections and concentration samples)
had been sampled in 1968 to 1982, and analysed for mercury by atomic absorption
spectrophotometry, and relate to all subjects. Exposure to mercury in air had
been determined in a small set of personal samples in 1982. The data relate to
all jobs in the smelter process, and all jobs entailed substantial exposure to
mercury. The overall distribution of breathing zone air, blood and urinary levels
is right-skewed and similar to the log-normal distribution (air, median 48
micrograms/m3, n = 49; blood, arithmetic mean AM 49 micrograms/L; geometric mean
GM 26 micrograms/L, n = 192; urinary excretion, AM 140 micrograms/24 h, GM 78
micrograms/24 h, n = 839; and urinary concentration, AM 160 micrograms/L, GM 83
micrograms/L, n = 632). Air, blood and urinary values show a high ratio of the
between- and within-job variance, indicating differences in exposure by job.
Cinnabar pigment production, of which the exposure has not been characterised
previously, was the job with the highest air (AM 160 micrograms/m3) and urinary
levels (excretion AM 690 micrograms/24 h; concentration AM 1100 micrograms/L).
Other jobs with high urinary levels were soot purification, laboratory work, and
bottling. Cleaning of condensers showed the highest blood level (AM 280
micrograms/L). There is a downwards time trend in mercury concentration in blood
and in urine. The corresponding trend is not seen for urinary excretion levels,
the reason for this being unclear. Roasters, which is the most frequently
monitored group, show however a decreasing trend in all sets of data (e.g. the
mean of urinary excretion decreased from 300 micrograms/24 h in 1968/69 to 50
micrograms/24 h in 1980/81). The mercury exposure experienced by the smelters of
Abbadia San Salvatore is in line with the few available data on workers from
other mercury mines and smelters, and our data confirm the high exposure levels
in this occupational group, in particular at cinnabar pigment production, soot
purification, and condenser cleaning.
PMID- 9559569
TI - Selecting an adequate respiratory protective device: the choice between a
respirator and breathing apparatus.
AB - An adequate respiratory protective device should keep the concentration of the
pollutant inside the facepiece below the appropriate occupational exposure limit.
Filtering respirators will not provide adequate protection if the device fails in
an atmosphere which is immediately dangerous to life or health (IDLH). It has
therefore been suggested that in contaminant concentrations above an IDLH level
it is more appropriate to select breathing apparatus with an emergency breathing
facility. In this paper IDLH levels published by the US National Institute of
Occupational Safety and Health have been compared with UK occupational exposure
limits. For some substances there was a relatively small difference between the
IDLH level and the short-term occupational exposure limit (STEL). The median
ratio of the IDLH level to the STEL was 10 for gases and vapours and 50 for
aerosols. For almost half the substances with UK occupational exposure limits
there is no IDLH value. It is concluded that the published IDLH concentrations
are, on their own, an insufficient basis for selecting breathing apparatus over a
filtering respirator. It is equally important to consider the likelihood that a
filtering device may fail catastrophically since this determines the risk from
wearing a respirator in an IDLH atmosphere. More emphasis should be placed on the
control of potentially high exposure levels by means other than respiratory
protection.
PMID- 9559570
TI - Monitoring of occupational exposure to polycyclic aromatic hydrocarbons in a
carbon-electrode manufacturing plant.
AB - An investigation is presented of occupational exposure to polycyclic aromatic
hydrocarbons (PAH) in a carbon-electrode manufacturing plant, as assessed by
three monitoring methods, viz. environmental monitoring of the external dose by
analysis of personal air samples, biological monitoring of the internal dose by
analysis of urinary 1-hydroxypyrene (1-OHpyrene), and biological effect
monitoring by dosimetry of PAH-DNA adducts in blood lymphocytes. On the basis of
job conditions, workers at the plant were divided into three groups with presumed
low, intermediate and high exposure to air-borne PAH, respectively. All air
samples showed levels of total PAH below the current MAC-value in the
Netherlands, which is 200 micrograms/m3, whereas the benzo[a]pyrene level was
occasionally higher than the recommended concentration of 2 micrograms/m3. The
values of 1-OHpyrene in urine from the intermediate and high exposure groups were
significantly higher than those of the low exposure group, namely 3.6- and 8.2
fold, respectively. Clear external and internal exposure was thus demonstrated
for workers of the high and intermediate exposure groups, but this did not result
in a measurable effect at the DNA level in blood lymphocytes. Tobacco smoking, on
the other hand, caused a significant increase of the levels of PAH-DNA adducts
but did not affect 1-OHpyrene values. These data suggest that smoking is a more
important risk factor for adverse health effects, i.e. cancer, than occupational
exposure to PAH in this plant.
PMID- 9559571
TI - Individual-based and group-based occupational exposure assessment: some equations
to evaluate different strategies.
AB - Basically, two strategies can be considered for the analysis of hazardous
pollutants in the work environment: group-based and individual-based strategies.
This paper provides existing and recently derived equations for both strategies
describing the influence of several factors on attenuation and on the standard
error of an estimated linear regression coefficient relating a continuous
exposure variable and a continuous health outcome via a simple linear regression
model. We applied these equations using exposure variability information from
industry-wide surveys over the past decade in order to gain more insight into the
effects of various sources of exposure variability on choices among different
analysis strategies. In general, for the modeling scenario considered here, there
is not a straightforward criterion for choosing an optimal analysis strategy.
Researchers have to decide between individual-based strategies generating
precise, though biased, estimates or group-based strategies generating less
precise but essentially unbiased estimates. For most exposure variability
scenarios evaluated, an individual-based strategy yielded substantial
attenuation. It is the authors' contention that the choice between individual
based and group-based strategies should be based on validity, rather than on
precision, of the estimated exposure-response coefficient.
PMID- 9559572
TI - Temporary threshold shift of the vibration perception threshold following a short
duration exposure to vibration.
AB - The objective of this study is to analyze the evolution of the vibration
perception threshold (VPT) following a short duration exposure to vibration. The
literature reports experiments with 3 to 10 min exposure to vibration after which
a steady state is not necessarily reached. The temporary threshold shift (TTS) of
the VPT is extrapolated from data recorded during the recovery period. The
assumption of a linear decrease with the logarithm of time gives erroneous
results for the TTS extrapolated at the end of the exposure. 81 experiments were
conducted on 9 young subjects without any neurological problem, exposed to
acceleration amplitudes of 5, 20 and 80 ms-2 at frequencies of 31.5 (conditions 1
to 3), 125 (conditions 4 to 6) and 500 Hz (conditions 7 to 9). The exposure to
vibration lasted 32 min and was interrupted shortly at time 2, 4, 8, 16 to record
the VPT at 31.5 and 125 Hz. The VPT was also recorded before the exposure and
several times during the recovery. The evolution of the VPT appears to follow a
first order model characterized by a maximum amplitude TTS, a time constant (tau)
and a residual value (r, as a fraction of the TTS). The correlation coefficients
between observed and predicted values in the 81 experiments are 0.881 at 31.5 Hz
and 0.885 at 125 Hz. The TTS is influenced by the exposure amplitude and
frequency and is different at the two test frequencies. It varies also
significantly between the subjects and with their initial VPT value. The time
constant is about 3 minutes at both test frequencies, while the residual fraction
is of the order of 0.14 at 31.5 Hz and 0.07 at 125 Hz. Both parameters appear to
be independent of the exposure parameters.
PMID- 9559573
TI - Measurement and analysis of nicotine and other VOCs in indoor air as an indicator
of passive smoking.
AB - In Finland the Tobacco Act was amended in 1994 to include workplaces. The
developed method for estimating passive smoking, or environmental tobacco smoke
utilised the widely used measurement of volatile organic compounds in indoor air
quality surveys. The method is based on active sorbent sampling, thermal
desorption and gas chromatography/mass selective detection (GC/MS) analysis and
it has been tested in a chamber and in field conditions. The method can be used
simultaneously to measure volatile organic compounds and exposure to tobacco
smoke. We recommend nicotine, collected by active sampling, as an indicator for
the evaluation of the exposure to environmental tobacco smoke spreading from
smoking areas.
PMID- 9559574
TI - The effect of dust-protective respirator mask and the relevance of work category
on urinary 1-hydroxypyrene concentration in PAH exposed electrode paste plant
workers.
AB - Large amounts of polycyclic-aromatic hydrocarbons (PAH) are found in the work
environment of electrode paste workers. Inhalation and skin uptake are both
important routes for PAH exposure. We have studied the effect of dust-protective
respirator masks by measuring urinary 1-hydroxypyrene as a biomarker for PAH
exposure. Eighteen workers divided into work categories at the factory were
monitored by personal air sampling and urinary 1-hydroxypyrene every work shift
for two consecutive weeks. In the second week of the study, the workers were
encouraged to wear respirator masks persistently, which resulted in a significant
reduction in urinary 1-hydroxypyrene in end-of-shift samples (paired t-test, P =
0.009). When correcting urinary 1-hydroxypyrene for ambient air pyrene we found
on average 41% reduction in urinary 1-hydroxypyrene concentration in the second
week of the intervention study. There was a work-category dependent variation in
the correlation between end-of-shift urinary 1-hydroxypyrene samples and pyrene
measured in the breathing zone of the workers, most likely due to variable skin
uptake of pyrene; the overall correlation coefficient was 0.26 (P = 0.015). The 1
hydroxypyrene concentration in pre- and post-shift urine samples varied between
0.7 and 69.6 mumol/mol creatinine in the normal work week, and depended on the
work category. The particulate PAH exposure ranged from 0.6 to 21.4
micrograms/m3. The ratio of particulate pyrene to benzo[a]pyrene varied from 1.6
to 8.0 amongst the various work categories within the same plant. Multiple
regression analysis showed that smoking and work day are explanatory variables
for the concentration of 1-hydroxypyrene in urine. Thirty-nine percent of the
variation in the urinary 1-hydroxypyrene level at the end of shift could be
explained by the independent variables pyrene concentration in air, smoking
habits, work day, use of respiratory mask, work category and age.
PMID- 9559575
TI - Parallel dose-response curves in combination experiments.
AB - A possible experimental design for combination experiments is to compare the dose
response curve of a single agent with the corresponding curve of the same agent
using either a fixed amount of a second one or a fixed dose ratio. No interaction
is then often defined by a parallel shift of these curves. We have performed a
systematic study for various types of dose-response relations both for the dose
additivity (Loewe additivity) and for the independence (Bliss independence)
criteria for defining zero interaction. Parallelism between dose-response curves
of a single agent and those of the same agent in the presence of a fixed amount
of another one is found for the Loewe-additivity criterion for linear dose
response relations. For nonlinear relations, one has to differentiate between
effect parallelism (parallel shift on the effect scale) and dose parallelism
(parallel shift on the dose scale). In the case of Loewe additivity, zero
interaction dose parallelism is found for power, Weibull, median-effect and
logistic dose-response relations, given that special parameter relationships are
fulfilled. The mechanistic model of competitive interaction exhibits dose
parallelism but not effect parallelism for Loewe additivity. Bliss independence
and Loewe additivity lead to identical results for exponential dose-response
curves. This is the only case for which dose parallelism was found for Bliss
independence. Parallelism between single-agent dose-response relations and Loewe
additivity mixture relations is found for examples with a fixed dose-ratio
design. However, this is again not a general property of the design adopted but
holds only if special conditions are fulfilled. The comparison of combination
dose-response curves with single-agent relations has to be performed taking into
account both potency and shape parameters. The results of this analysis lead to
the conclusion that parallelism between zero interaction combination and single
agent dose-response relations is found only for special cases and cannot be used
as a general criterion for defining zero-interaction in combined-action
assessment even if the correct potency shift is taken into account.
PMID- 9559576
TI - Extinction times and phase transitions for spatially structured closed epidemics.
AB - This paper considers the time to extinction for a stochastic epidemic model of
SEIR form without replacement of susceptibles. It first shows how previous
rigorous results can be heuristically explained in terms of the more transparent
dynamics of an approximating deterministic system. The model is then extended to
include a host population structured into patches, with weak nearest-neighbour
mixing of infection. It is shown, by considering the approximating deterministic
system, that the expected time to extinction in a population of n + 1 patches
each of size N is of the form a log N + bn, provided that N > Nc where Nc is a
critical patch size below which transits are unlikely to occur. This corresponds
to the simple decomposition of the time of an epidemic into the time it takes to
spread through one patch plus the time it takes to transit to each of n
successive patches. Expressions for this threshold and the coefficients of the
time to extinction are given in terms of the transmission parameters of infection
and the coupling strength between patches. These expressions are compared with
numerical results using parameters relevant to a study of phocine distemper virus
in North Sea seals, and the agreement is found to be good for large and small N.
In the region when N approximately Nc, where transits may or may not occur,
interesting transitional behaviour is seen, leading to a non-monotonicity of the
extinction time as a function of N.
PMID- 9559577
TI - Resonant population cycles in temporally fluctuating habitats.
AB - Experiments with the flour beetle Tribolium have revealed that animal numbers
were larger in cultures grown in a periodically fluctuating volume of medium than
in cultures grown in a constant volume of the same average size. In this paper we
derive and analyze a discrete stage-structured mathematical model that explains
this phenomenon as a kind of resonance effect. Habitat volume is incorporated
into the model by the assumption that all rates of cannibalism (larvae on eggs,
adults on eggs and pupae) are inversely proportional to the volume of the culture
medium. We tested this modeling assumption by conducting and statistically
analyzing laboratory experiments. For parameter estimates derived from
experimental data, our model indeed predicts, under certain circumstances, a
larger (cycle-average) total population abundance when the habitat volume
periodically fluctuates than when the habitat volume is held constant at the
average volume. The model also correctly predicts certain phase relationships and
transient dynamics observed in data. The analyses involve a thorough integration
of mathematics, statistical methods, biological details and experimental data.
PMID- 9559578
TI - Testing a model for the dynamics of actin structures with biological parameter
values.
AB - A simple mathematical model for the dynamics of network-bundle transitions in
actin filaments has been previously proposed and some of its mathematical
properties have been described. Other models in this class have since been
considered and investigated mathematically. In this paper, we have made the first
steps in connecting parameters in the model with biologically measurable
quantities such as published values of rate constants for filament-crosslinker
association. We describe how this connection was made, and give some preliminary
numerical simulation results for the behavior of the model under biologically
realistic parameter regimes. A key result is that filament length influences the
bundle-network transition.
PMID- 9559579
TI - The loss of immunity in directly transmitted infections modeling: effects on the
epidemiological parameters.
AB - When directly transmitted infectious diseases are modeled assuming an everlasting
induced immunity (and constant contact rate), there are well-established formulas
to deal with, which is not true if we include the loss of induced immunity. In
general, the immunity induced by the disease is everlasting. We propose a model
considering the loss of immunity and present methods for the estimation of two
epidemiological parameters: the force of infection and the basic reproduction
ratio. We also analyze the effects of the loss of immunity on these parameters.
Based on these results, we concluded that reinfection can play an important role
in highly vaccinated populations.
PMID- 9559580
TI - Computational experiments support a competitive function in the CA3 region of the
hippocampus.
AB - The comprehension of activities and functions of complex brain structures
requires, among other things, information on simultaneous activities in several
regions. Results reported in the literature using multi(micro/macro)electrode
recordings or imaging techniques provide incomplete information due either to the
small size and/or small number of investigated regions or to the poor
spatiotemporal resolution, respectively. This is particularly true for the
hippocampus and its subfields, and mathematical modeling and computer simulation
have been used with the aim of obtaining information when this is lacking. Global
activities in the CA3 field of the hippocampus, and in particular the genesis of
theta rhythm and sharp waves, have been investigated here by a mathematical model
formulated within the frame of a kinetic theory of neural systems. The model has
taken into account data of experimental results both on different PSPs recorded
in hippocampal neurons and on recurrent pyramidal collateral geometries. The
computational 'experiments' to which the model was subjected suggest that the
sharp waves arise through a selective and short block of the fast inhibitory
neurons of CA3, produced by a medial septum inhibitory input, whereas the theta
activity is produced by a durable, continuous inhibition of the slow inhibitory
neurons. Information obtained also suggests that the recurrent pyramidal
collaterals subserve a competitive, rather than a cooperative, organization.
Based on these results a hypothesis on the possible functional organization of
the CA3 field and of the entire hippocampus has been formulated. According to
this hypothesis, the CA3 imposes a serial order on the flow of activity arriving
at the hippocampus from the entorhinal cortex and from its connected polymodal
cortical regions. This ordering permits cortical activities, arriving at CA3 on
appropriate time intervals, to produce effects in regions of brain to which the
CA3 projects. The competing cortical activities are lost.
PMID- 9559581
TI - Sulfonated chloroaluminum phthalocyanine incorporates into human plasma
lipoproteins: photooxidation of low-density lipoproteins.
AB - The interactions of sulfonated chloroaluminum phthalocyanine (AlPcSn) with human
low-density lipoproteins (LDL) were studied in vitro in human plasma and in an
isolated LDL fraction, in order to understand the potential effects of the
sensitizer against LDL. The AlPcSn added to plasma distributes in all
lipoproteins as observed by the drastic color changes of the separated fractions
by ultracentrifugation. In isolated LDL, incubation with AlPcSn causes
fluorescence quenching of the apoprotein tryptophan residues. Furthermore, AlPcSn
incorporates in liposomes, with a lipid composition similar to the external
monolayer of human LDL, as indicated by absorbance spectroscopy. The
photosensitizing properties of AlPcSn in LDL particles were studied on the basis
of the fluorescence quenching of previously incorporated cis-parinaric acid
(PnA), used as an oxidation probe, and of O2 consumption. The photooxidation of
either PnA or LDL lipids is highly dependent on irradiation time and on the dye
concentration. Moreover, photooxidation of LDL proceeds only during the
illumination period. After stopping the illumination and upon addition of Cu2+ to
the LDL solution, the oxidative rate is resumed, probably due to hydroperoxide
cleavage and formation of species able to propagate the oxidative reaction. Thus,
our data indicate that AlPcSn distributes in human plasma lipoproteins and, in
isolated LDL, it can interact either with the lipid phase or the apoprotein. The
photooxidation of LDL induced by AlPcSn seems to involve singlet oxygen as the
main reactive species in the degradative process.
PMID- 9559582
TI - UV light-induced duplex-to-duplex crosslinking of DNA molecules in aqueous
ethanol solutions.
AB - Ultraviolet light is known to generate crosslinks between the complementary
strands of DNA and between DNA and proteins. Here we demonstrate that the UV
light also crosslinks DNA duplexes to other DNA duplexes. However, the duplex-to
duplex crosslinks only appear in the presence of about 75% (vol/vol) ethanol plus
a millimolar or submillimolar concentration of monovalent or divalent cations,
e.g. 2 mM Na+. Methanol or formamide are ineffective. The present observations
provide a direct means to detect physical contacts of DNA molecules or their
parts, e.g. during recombination. It is remarkable that the solution conditions
leading to the duplex-to-duplex UV light-induced crosslink formation are the same
as those inducing the B-to-A conformational transition of DNA.
PMID- 9559583
TI - Comparison of the time-resolved absorption and phosphorescence from the
tryptophan triplet state in proteins in solution.
AB - Measurement of the room temperature Trp triplet state lifetime in proteins by
time-resolved phosphorescence can provide valuable information on the structure
and dynamics of proteins in solution. Our time-resolved absorption measurements
on the long-lived states resulting from electronic excitation of the chromophore
demonstrate the presence of more complex behavior than revealed by time-resolved
phosphorescence. To provide additional insight into this behavior, a comparative
study of time-resolved transient absorption and time-resolved phosphorescence of
proteins in solution was carried out. The results show that the time evolution of
the long-lived states observed through transient absorption often differs
considerably from that observed in time-resolved phosphorescence. In some
proteins, the presence of competing reactions complicates the interpretation of
the transient absorption measurements (which may affect the phosphorescence
yield). A more complete characterization of these processes will likely prove
useful in the study of protein structure and dynamics in solution.
PMID- 9559584
TI - Fluoroquinolone antimicrobials: singlet oxygen, superoxide and phototoxicity.
AB - The fluoroquinolone antibacterial agents possess photosensitizing properties that
lead to phototoxic responses in both human and animal subjects. The phototoxicity
order reported in humans is: fleroxacin > lomefloxacin, pefloxacin >>
ciprofloxacin > enoxacin, norfloxacin and ofloxacin. Studies both in vivo and in
vitro have related this phototoxicity to the generation of reactive oxygen
species including hydrogen peroxide and the hydroxyl radical. We determined the
quantum yields of singlet oxygen generation (phi delta) by detection of the
singlet oxygen (1O2) luminescence at 1270 nm for several fluoroquinolones,
naphthyridines and other structurally related compounds. All the fluoroquinolones
examined have low phi delta values ranging from 0.06 to 0.09 in phosphate buffer
at pD 7.5. We also determined the 1O2 quenching constants for these compounds and
their values were on the order of 10(6) M-1 s-1, except for lomefloxacin whose
rate constant was 1.8 x 10(7) M-1 s-1. The phi delta values were significantly
decreased in a solvent of lower polarity such as methanol (0.007 < or = phi delta
< or = 0.02). The production of 1O2 by these antibiotics did not correlate with
the order reported for their phototoxicity. We also measured the photogeneration
(lambda > 300 nm) of superoxide by these antibacterials in dimethylsulfoxide
using electron paramagnetic resonance and the spin trap 5,5-dimethyl-1-pyrroline
N-oxide. Although there is not a one-to-one correspondence between the relative
rates of superoxide generation and the phototoxicity ranking of the
fluoroquinolones, the more phototoxic compounds tended to produce superoxide at a
faster rate. Nevertheless, the magnitudes of the observed differences do not
appear sufficient to explain the range of fluoroquinolone phototoxicity potencies
in human and animal subjects in general and the high activity of fleroxacin and
lomefloxacin in particular. For these latter drugs the photoinduced loss of the
F8 atom as fluoride and the concomitant generation of a highly reactive carbene
at C-8 provide a more plausible mechanism for their potent phototoxic and
photocarcinogenic properties.
PMID- 9559585
TI - Triplet photoreactivity of the diaryl ketone tiaprofenic acid and its
decarboxylated photoproduct. Photobiological implications.
AB - The 2-benzoylthiophene chromophore of the photosensitizing drug tiaprofenic acid
and of its decarboxylated derivative is characterized by a unusually high energy
gap between the T1 (pi, pi*) and T2 (n, pi*) excited states, which makes this a
unique system to study the intrinsic photoreactivity of the two states. Weak
fluorescence and phosporescence emission were detected at room temperature.
Tiaprofenic acid undergoes photodecarboxylation from the triplet manifold as the
main reaction. The photoprocess is temperature dependent with activation energy
of 7-10 kcal/mol, close to the energy gap between T1 and T2. The decarboxylated
product abstracts hydrogen in type I reactions. The involvement of T2 in the
above processes is proposed. Moreover the decarboxylated derivative exhibits
reactivity toward phenols, consistent with a participation of the T1 state as
electron acceptor. The observed photoprocesses can account for biological
photosensitization reactions, like membrane damage and protein modification.
PMID- 9559586
TI - The induction and analysis of micronuclei and cell killing by ultraviolet-B
radiation in human peripheral blood lymphocytes.
AB - The DNA-damaging potential of ultraviolet-B (UVB) radiation was investigated by
analyzing the frequency and origin of micronuclei (MN) in cytokinesis-blocked,
binucleated (BN) peripheral blood lymphocytes (PBL) and cloning efficiencies (CE)
of PBL after exposure to different fluences of UVB. In total, PBL obtained from
five normal donors were investigated. The PBL from all donors showed a dose
related, linear-quadratic increase in the frequency of MN per 1000 BN cells and
in the frequency of micronucleated BN cells. In two experiments the origin of UVB
induced MN was studied by analyzing MN for the presence or absence of centromeres
by applying the MN assay in combination with a centromeric probe and fluorescence
in situ hybridization. This revealed, for the first time, that UVB-induced MN
were centromere negative, indicating that UVB acted exclusively as a clastogenic
agent in the tested dose range. The PBL from all donors showed a clear dose
dependent decrease in CE, after UVB exposure. The UVB-exposed PBL from all donors
showed an inverse relationship between the induction of MN and the decrease in
CE, but regression analysis revealed no correlation between the induction of MN
and the decrease in cell survival. It is concluded that UVB has a clastogenic and
cytotoxic effect on PBL.
PMID- 9559587
TI - Ultraviolet B irradiation modulates the immune system of fish (Rutilus rutilus,
Cyprinidae). I. Phagocytes.
AB - Roach (Rutilus rutilus) were irradiated with a single dose of ultraviolet B (UVB)
radiation (0.4 J/cm2) in order to study the effects of UVB on the nonspecific
immune defense mechanisms of fish. Neutrophils and macrophages were isolated from
the head kidney of fish on days 1-14 postirradiation. Both random and directed
migration of neutrophils, studied by migration under agarose assay, were
suppressed on day 1 after UVB irradiation. The respiratory burst of phorbol 12
myristate 13-acetate-stimulated neutrophils and macrophages was also suppressed
at days 1 and 2 after UVB irradiation. The suppression of migration and
respiratory burst were restored or the responses were even enhanced later, but on
the other hand spontaneous cytotoxicity of neutrophils toward 51chromium-labeled
K562 target cells stayed suppressed throughout the 14 day follow-up. This study
indicates that UVB radiation has the potential to suppress the functioning of
phagocytes and to compromise the immune system of fish.
PMID- 9559588
TI - Light regulation of phytochrome content in wild-type and aphototropic mutants of
the moss Ceratodon purpureus.
AB - In filaments of the moss Ceratodon purpureus, phototropism is controlled by the
photoreceptor phytochrome. Thirty-three aphototropic mutants with a proposed
defect in phytochrome-chromophore biosynthesis were isolated and analyzed. The
phototropic response of those mutants was rescued with the precursor of the
phytochrome chromophore, biliverdin. Phytochrome spectral activity was measured
in 19 arbitrarily chosen mutants. All contained low but still measurable
quantities of photoactive phytochrome; the highest level was around 15% of the
wild-type. The level of total phytochrome (apophytochrome and holophytochrome) as
assayed by immunoblotting was indistinguishable from wild-type. The content of
photoactive phytochrome in Ceratodon is light-regulated. Phytochrome of wild-type
kept for 24 h in red light was reduced to 50% as compared to dark controls but
was unaffected by blue. The red-light-induced decrease was partially reversible
by far-red light, indicating that phytochrome itself is the photoreceptor for
this response. This regulation was further analyzed with the mutant ptr114, which
contains 15% photoactive phytochrome as compared to the wild-type. In this
mutant, continuous red light given for 6 days decreased the level of spectrally
active phytochrome down to 25% of dark controls, whereas the amount of
phytochrome found on immunoblots was hardly reduced. This indicates that the loss
of phytochrome affects only the holoprotein and implies that Ceratodon
phytochrome is specifically degraded as a far-red-absorbing phytochrome.
PMID- 9559589
TI - Protection of UV-induced suppression of skin contact hypersensitivity: a common
feature of flavonoids after oral administration?
AB - In this study we investigated the effect of the dietary ingredients fruit and
vegetable, green tea phenol extract (GTP) and the specific flavonoid components
quercetin and chrysin on the UV-induced suppression of the contact
hypersensitivity (CHS) response to picryl chloride (PCl). The SKH-1 mice were fed
with test diet from 2 or 4 weeks before and during the UV irradiation (daily, 95
mJ/cm2) and tested for the CHS ear-swelling response 10 weeks after the onset of
the irradiation. For the CHS, mice were immunized with PCl by epicutaneous
application on nonirradiated sites. Four days after sensitization all mice were
challenged on both sides of each ear by topical application of one drop PCl. In
addition, from mice fed with the fruit and vegetable mixture the number of
Langerhans cells (LC) were scored in the skin and from mice fed with quercetin,
quercetin levels in plasma were measured at week 11 after the start of UV
irradiation. It was found that fruit and vegetable (19% in the diet), GTP (0.1%
and 0.01% in the drinking water), quercetin (1% in the diet) and chrysin (1% and
0.1% in the diet), prevented statistically significantly the UV-induced
suppression of CHS to PCl. In the skin of mice fed with fruit and vegetables
combined with UV irradiation the number of LC were comparable to the control
mice, whereas the number of LC were significantly diminished in mice treated with
UV only. This protective effect on the presence of LC in the epidermis after UV
irradiation, which was also observed in a previous study with quercetin, may play
a role in the prevention of UV-induced immunosuppression by the flavonoids
tested. In conclusion, we found protection of flavonoids against UV-induced
effects on CHS, which may be a common feature of most flavonoids.
PMID- 9559590
TI - The effect of fluence rate on tumor and normal tissue responses to photodynamic
therapy.
AB - Photodynamic therapy (PDT), carried out at low fluence rates, may enhance tumor
response as well as affect treatment selectivity. We have studied the effects of
fluence rate on the response of the murine radiation-induced fibrosarcoma (RIF)
to PDT using Photofrin (5 mg/kg). Tumor response was tested over a large range of
fluence rates (10-200 mW/cm2) and fluences (25-378 J/cm2). Low fluence rates were
more efficient; approximately 60 J/cm2 at 10 mW/cm2 was needed to achieve the
same tumor growth delay as approximately 100 J/cm2 at 150 mW/cm2 and
approximately 150 J/cm2 at 200 mW/cm2. Despite this increased efficiency, lower
fluence rates still required longer treatment times for equivalent anti-tumor
effects: 95 min for 57 J/cm2 at 10 mW/cm2 versus 11 min for 100 J/cm2 at 150
mW/cm2. Effects of fluence rate on the PDT toxicity to normal tissue were
examined through the response of the murine (C3H) foot to Photofrin PDT.
Treatment with conditions that produced equivalent tumor responses, i.e. 57 J/cm2
at 10 mW/cm2 and 100 J/cm2 at 150 mW/cm2, resulted in a more severe foot response
at the higher fluence rate (median peak response: 0.9 at 10 mW/cm2, 1.5 at 150
mW/cm2) with more time required for tissue to return to normal (8 days at 10
mW/cm2, at least 30 days at 150 mW/cm2). However, when feet were treated with an
equal fluence of 100 J/cm2 at various fluence rates, longer healing times
accompanied the lower fluence rate treatments. Overall, this paper demonstrates
that lower PDT fluence rates are associated with increased efficiency of tumor
response. If this increased efficiency is accounted for by lowering treatment
fluence, lower fluence rates also may result in a more favorable normal tissue
response to treatment.
PMID- 9559591
TI - Clinical trial networks: a unique opportunity for critical care.
PMID- 9559592
TI - Corticosteroids in septic shock: resurrection of the last rites?
PMID- 9559593
TI - Glucocorticoid treatment of sepsis and acute respiratory distress syndrome: time
for a critical reappraisal.
PMID- 9559594
TI - Survivors, beware of posttraumatic stress disorder: What shall we tell the Men in
Black?
PMID- 9559595
TI - Prophylactic granulocyte colony-stimulating factor in critically ill patients:
not time yet.
PMID- 9559596
TI - Inhibition of nitric oxide synthesis in sepsis: a promising strategy?
PMID- 9559597
TI - Pneumocystis pneumonia in the intensive care unit: location, location, location?
PMID- 9559598
TI - Unintended consequences.
PMID- 9559599
TI - Tracheobronchography: old is not necessarily outdated--especially for the young.
PMID- 9559600
TI - Reversal of late septic shock with supraphysiologic doses of hydrocortisone.
AB - OBJECTIVES: Preliminary studies have suggested that low doses of corticosteroids
might rapidly improve hemodynamics in late septic shock treated with
catecholamines. We examined the effect of hydrocortisone on shock reversal,
hemodynamics, and survival in this particular setting. DESIGN: Prospective,
randomized, double-blind, placebo-controlled study. SETTING: Two intensive care
units of a University hospital. PATIENTS: Forty-one patients with septic shock
requiring catecholamine for >48 hrs. INTERVENTIONS: Patients were randomly
assigned either hydrocortisone (100 mg i.v. three times daily for 5 days) or
matching placebo. MEASUREMENTS AND MAIN RESULTS: Reversal of shock was defined by
a stable systolic arterial pressure (>90 mm Hg) for > or =24 hrs without
catecholamine or fluid infusion. Of the 22 hydrocortisone-treated patients and 19
placebo-treated patients, 15 (68%) and 4 (21%) achieved 7-day shock reversal,
respectively, a difference of 47% (95% confidence interval 17% to 77%; p = .007).
Serial invasive hemodynamic measurements for 5 days did not show significant
differences between both groups. At 28-day follow-up, reversal of shock was
higher in the hydrocortisone group (p = .005). Crude 28-day mortality was 7 (32%)
of 22 treated patients and 12 (63%) of 19 placebo patients, a difference of 31%
(95% confidence interval 1% to 61%; p = .091). Shock reversal within 7 days after
the onset of corticosteroid therapy was a very strong predictor of survival.
There were no significant differences in outcome in responders and nonresponders
to a short corticotropin test. The respective rates of gastrointestinal bleeding
and secondary infections did not differ between both groups. CONCLUSIONS:
Administration of modest doses of hydrocortisone in the setting of pressor
dependent septic shock for a mean of >96 hrs resulted in a significant
improvement in hemodynamics and a beneficial effect on survival. These beneficial
effects do not appear related to adrenocortical insufficiency.
PMID- 9559601
TI - Health-related quality of life and posttraumatic stress disorder in survivors of
the acute respiratory distress syndrome.
AB - OBJECTIVES: Despite considerable progress in intensive care management of the
acute respiratory distress syndrome (ARDS), little is known about health-related
quality of life in long-term survivors. In addition, intensive care treatment can
be extremely stressful, and many survivors of ARDS report adverse experiences
such as respiratory distress, anxiety, or pain during intensive care unit (ICU)
treatment. This study was performed to assess health-related quality of life in
survivors of ARDS and to test the hypothesis that adverse experiences during ICU
treatment result in posttraumatic stress disorder (PTSD) and negative effects on
health-related quality of life. DESIGN: Retrospective, cohort, case-controlled
analyses. SETTING: A 12-bed multidisciplinary ICU of a tertiary care university
hospital, capable of providing extracorporeal life support for adults with severe
ARDS. PATIENTS: We studied 80 patients who were admitted to our hospital from
1985 to 1995 and who survived an episode of ARDS. ARDS was defined according to
the criteria of the American-European Consensus Conference on ARDS.
INTERVENTIONS: Health-related quality of life was measured using the Health
Status Questionnaire of the self-administered Medical Outcomes Study Short Form
Survey that consists of 36 questions (SF-36) and the German version of the Post
Traumatic Stress Syndrome 10-Questions Inventory (PTSS-10), a self-report scale
for the diagnosis of posttraumatic stress disorder based on the Diagnostic and
Statistical Manual (Third Edition) criteria (American Psychiatric Association).
The number of adverse experiences (anxiety, respiratory distress, pain, and
nightmares) during intensive care was evaluated by means of a structured
questionnaire. For each patient with ARDS, three age- and gender-comparable
controls were randomly selected from databases providing normal values for the SF
36 and PTSS-10 scores in populations at risk for posttraumatic stress disorder.
MEASUREMENTS AND MAIN RESULTS: Survivors of ARDS showed statistically significant
impairments in all eight health dimensions of the SF-36 when compared with normal
controls (median reduction 21.3%, p < .006) with maximal impairments in physical
function (median reduction 28.9%, p = .000) and a 38% higher frequency of chronic
pain (p = .0001). Three of 34 patients reporting none, or one, adverse experience
had evidence of posttraumatic stress disorder vs. 19 of 46 patients remembering
multiple traumatic episodes (p = .007). Patients reporting multiple adverse
experiences described the lowest health-related quality of life, with maximal
impairments in psychosocial functioning (p < .005) and only small limitations in
physical function. CONCLUSIONS: Long-term survivors of ARDS describe a good
overall health-related quality of life. Major impairments in mental health
domains of health-related quality of life are associated with the development of
posttraumatic stress disorder and are a possible result of traumatic experiences
during ICU therapy.
PMID- 9559602
TI - Prolonged inhibition of nitric oxide synthesis in severe septic shock: a clinical
study.
AB - OBJECTIVES: Inhibitors of nitric oxide synthesis have been suggested to be of
value in the treatment of hypotension during sepsis. However, earlier clinical
reports only describe the initial effects of these nitric oxide inhibitors. This
study was designed to examine the effects of the prolonged inhibition of nitric
oxide synthesis with N(omega)-nitro-L-arginine methyl ester (L-NAME) in patients
with severe septic shock. DESIGN: Prospective, nonrandomized, clinical study.
SETTING: Medical-surgical intensive care unit in a university hospital. PATIENTS:
Eleven consecutive patients with ongoing hyperdynamic septic shock that was
unresponsive to fluid resuscitation and vasopressor therapy. INTERVENTIONS:
Measurements of hemodynamic, hematologic, and biochemical variables were made
before, during, and after the start of a continuous intravenous infusion of 1
mg/kg/hr of L-NAME, an inhibitor of nitric oxide synthesis, for a period of 12
hrs. MEASUREMENTS AND MAIN RESULTS: Continuous infusion of L-NAME resulted in a
direct increase in mean arterial pressure from 65 +/- 3 (SEM) to 93 +/- 4 mm Hg
and an increase in systemic vascular resistance from 426 +/- 54 to 700 +/- 75
dyne x sec/cm5, reaching a maximum at 0.5 hr. Pulmonary arterial pressure was
increased from 31 +/- 2 to a maximum of 36 +/- 2 mm Hg at 1 hr, and pulmonary
vascular resistance increased from 146 +/- 13 to a maximum of 210 +/- 23 dyne x
sec/cm5 at 3 hrs. Paralleling these changes, cardiac output decreased from 10.8
+/- 0.8 to 8.7 +/- 0.7 L/min and oxygen delivery decreased from 1600 +/- 160 to
1370 +/- 130 mL/min (for all changes p < .05 as compared with the baseline
value). Heart rate, cardiac filling pressures, oxygen consumption, urine
production, arterial lactate concentration, and other biochemical parameters were
not significantly changed by L-NAME administration (all p > .05). Arterial
oxygenation was improved during L-NAME infusion, and the dosage of catecholamines
could be reduced (both p< .05). Although sustained hemodynamic effects were seen,
L-NAME was most effective during the early stages of administration, and the
effect of L-NAME on blood pressure and vascular resistance tended to diminish
throughout the continuous infusion of L-NAME. Seven of 11 patients ultimately
died, with survival time ranging from 2 to 34 days. CONCLUSIONS: Nitric oxide
appears to play a role in cardiovascular derangements during human sepsis. The
increased blood pressure and vascular resistance values are sustained during
prolonged inhibition of nitric oxide synthesis with L-NAME in patients with
severe septic shock, although the hemodynamic changes are most significant in the
early stages of L-NAME infusion. The high mortality rate in these patients may
suggest that L-NAME has only limited effects on outcome.
PMID- 9559603
TI - Variations in intensive care unit utilization for patients with human
immunodeficiency virus-related Pneumocystis carinii pneumonia: importance of
hospital characteristics and geographic location.
AB - OBJECTIVE: To determine whether intensive care unit (ICU) use and outcomes for
patients with human immunodeficiency virus (HIV)-related Pneumocystis carinii
pneumonia vary by hospital characteristics and geographic location. DESIGN:
Retrospective review of the medical records of 2,174 patients with HIV-related P.
carinii pneumonia. SETTING: Random sample of 73 private, nine public, and 14
Veterans Affairs hospitals in five cities (Chicago, New York, Los Angeles, Miami,
and Durham, NC). PATIENTS: Stratified random sample of patients hospitalized with
HIV-related P. carinii pneumonia from 1987 to 1990. INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: Among the 2,174 patients with P. carinii
pneumonia, 398 (18%) patients received care in an ICU. ICU utilization varied
significantly by patient and hospital characteristics, as well by as geographic
location. Non-Hispanic whites, patients with Medicaid, and patients with a prior
acquired immunodeficiency syndrome-defining illness were the least likely to
receive care in an ICU. Patients in county- or state-owned hospitals and patients
in hospitals with more P. carinii pneumonia-experience were also less likely to
be cared for in an ICU. These differences in ICU utilization persisted when
controlling for severity of illness, as well as other patient characteristics.
Significant geographic variation in ICU utilization persisted after controlling
for patient and hospital characteristics. Survival to hospital discharge after an
ICU stay was significantly higher for patients without a prior acquired
immunodeficiency syndrome-defining illness and for patients in hospitals with
more P. carinii pneumonia experience. CONCLUSIONS: We found significant
variations in ICU utilization by hospital characteristics and geographic location
that remained significant after controlling for severity of illness and patient
sociodemographic characteristics. Hospital and geographic variations in ICU
utilization may make it difficult to generalize ICU outcomes across different
hospitals.
PMID- 9559604
TI - Acute withdrawal syndrome related to the administration of analgesic and sedative
medications in adult intensive care unit patients.
AB - OBJECTIVES: To estimate the frequency of acute withdrawal syndrome related to the
administration of analgesic and sedative medications in mechanically ventilated
adult intensive care unit (ICU) patients; to identify associated clinical
factors. DESIGN: Retrospective review of medical records. SETTING: An adult
trauma/surgical ICU in an urban Level I trauma center. PATIENTS: Twenty-eight
mechanically ventilated adult trauma/ surgical ICU patients requiring >7 days of
ICU care. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Daily doses of all
opioid, sedative, hypnotic, and major tranquilizer drugs administered to each
patient were measured, as was duration of ICU stay, duration of mechanical
ventilation, and duration of the administration of analgesic, sedative, and
neuromuscular blocking agents (NMBAs) for each patient. All opioids and
benzodiazepines were converted to their respective fentanyl and lorazepam
equivalent units based on potency and bioavailability. Calculation of the weaning
rate for each patient during tapering from opioid and benzodiazepine medications
was performed. The presence or absence of acute withdrawal syndrome was
identified for each patient. Nine (32.1%) patients developed acute withdrawal
syndrome potentially related to the administration of analgesic or sedative
medications. Patients in the withdrawal group received significantly higher mean
daily (p = .049) and peak (p = .032) doses of fentanyl equivalents, as well as
higher mean daily lorazepam equivalents (p = .049) compared with patients not
experiencing withdrawal. Patients in the withdrawal group were also significantly
more likely to have received neuromuscular blocking agents (p = .004) or propofol
(p =.026) for >1 day during ICU admission compared with patients not experiencing
withdrawal. Duration of mechanical ventilation (p = .049), benzodiazepine therapy
(p = .048), and propofol therapy (p = .049) was also significantly longer in the
group experiencing withdrawal. Withdrawal patients received a significantly lower
mean daily dose of haloperidol (p = .026). There was a significant association
between the development of withdrawal syndrome and the presence of ARDS (p =
.017). Finally, the slopes of the lines representing opioid and benzodiazepine
drug weaning were more steep for the withdrawal group, although these results did
not achieve statistical significance. CONCLUSIONS: These results suggest that
mechanically ventilated adult patients with extended ICU care (> or =7 days) who
receive large doses of analgesic and sedative medications are at risk for acute
withdrawal syndromes during drug weaning. The association between ARDS and
withdrawal syndrome, combined with the observation that withdrawal syndromes were
also associated with the use of neuromuscular blocking agents and prolonged
mechanical ventilation, suggests that patients with ARDS may be more likely to
receive high doses of analgesic and sedative medications, and are therefore at
increased risk for withdrawal syndrome.
PMID- 9559606
TI - How to use a review article: prophylactic endoscopic sclerotherapy for esophageal
varices. Evidence Based Critical Care Medicine Group.
AB - OBJECTIVE: To assess the validity of a meta-analysis about sclerotherapy for the
primary prevention of bleeding from esophageal varices, to interpret the results,
and discuss whether they apply in practice. DATA SOURCES: Critical appraisal
techniques for systematic reviews. DATA EXTRACTION: Systematic reviews are
distinct from narrative reviews in that they answer specific clinical questions,
and have explicit and reproducible methods for searching, selecting, and
appraising the primary studies, to create the most valid synthesis of the
evidence. DATA SYNTHESIS: Meta-analyses are systematic reviews containing a
critical appraisal and statistical summary of individual study results and their
confidence limits, whereas qualitative systematic reviews provide a narrative
executive summary of study results. CONCLUSIONS: High-quality systematic reviews
are being used increasingly to guide practice, strengthening the link between
research results and improved health outcomes. Understanding their strengths and
limitations helps us to use them appropriately in practice.
PMID- 9559605
TI - The 67gallium-transferrin pulmonary leak index in patients at risk for the acute
respiratory distress syndrome.
AB - OBJECTIVE: To determine the occurrence and clinical importance of increased
pulmonary microvascular permeability in patients at risk for acute respiratory
distress syndrome (ARDS). DESIGN: Prospective, cohort study. SETTING: Medical and
surgical intensive care unit (ICU) and department of nuclear medicine of a
university hospital. PATIENTS: Thirteen consecutive patients at risk for ARDS
with sepsis (n = 4), multiple trauma (n = 3), hemorrhagic pancreatitis (n = 5),
and near-drowning (n = 1), admitted into the ICU. All patients were intubated and
mechanically ventilated in the course of the study. INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: The 67gallium-transferrin pulmonary leak index
(PLI) (upper limit of normal in patients scheduled for major surgery 14.7 x 10(
3)/min) was measured within 24 hrs of admission. In addition, radiographic, gas
exchange, and ventilatory variables allowing calculation of the Lung Injury
Score, were obtained on the day of the PLI (day 0) and from days 1 to 7. Patients
were followed until discharge or death in the ICU. No patient developed ARDS
(Lung Injury Score of >2.5 in the absence of congestive heart failure) and all
but four patients survived. The PLI (median [range]) was 18.5 (7.0 to 81.9) x 10(
3)/min and was supranormal in 8 of 13 patients (p < .001 vs. normal). The PLI
correlated with the Simplified Acute Physiology Score (SAPS) II (r[s] = .79, p <
.01) and was higher in nonsurvivors than in survivors (p < .05), with a tendency
for a higher SAPS II in the nonsurvivors. On day 0, the chest radiographic score
of alveolar abnormalities was 0 (0 to 4), indicating absence of radiographic
abnormalities in most patients. Also, on day 0, the median PaO2/FIO2 ratio was
257 (range 119 to 460). The Lung Injury Score on day 0 was 1.0 (0 to 2.0), which
is consistent with mild acute lung injury in all but one patient. In the course
of time, the oxygenation ratio was lower and the Lung Injury Score was higher in
nonsurvivors than in survivors, particularly for the Lung Injury Score on days 1
and 2. The PLI correlated directly with the Lung Injury Score on days 0 and 1. On
day 0, the PLI correlated inversely with the oxygenation ratio. On the last
evaluable day of the first ICU week, the PLI correlated directly with the Lung
Injury Score and the positive end-expiratory pressure level. The duration of
mechanical ventilation tended to be longer in patients with a supranormal PLI.
CONCLUSIONS: In this small population, 61% of patients at risk for ARDS and with
only mild respiratory changes exhibited increased microvascular permeability in
the lungs at ICU admission. Increased permeability may be an early marker of
acute lung injury and its clinical features, and may be associated with a
relatively complicated respiratory course during the first week after admission,
even in the absence of progression to ARDS. Finally, increased pulmonary
microvascular permeability may be associated with severe underlying disease and
ultimate mortality in the ICU.
PMID- 9559607
TI - Effect of advance directives on the management of elderly critically ill
patients.
AB - OBJECTIVE: To evaluate the effects of advance directives on the management of
elderly, critically ill patients. DESIGN: Retrospective chart review. SETTING:
Teaching hospital medical/surgical, noncardiac intensive care unit (ICU).
PATIENTS: The medical records of 401 patients, > or =65 yrs of age, admitted to
the ICU between 1992 and 1995 were reviewed. INTERVENTIONS: None. MEASUREMENTS
AND MAIN RESULTS: Advance directive statements included refusal of
cardiopulmonary resuscitation (CPR), nutrition, intravenous medications,
antibiotics, mechanical ventilation, and blood products. Nineteen (5%) patients
had advance directives (study group). These patients were compared with 28 case
matched (age, Acute Physiology and Chronic Health Evaluation II score, and
diagnosis) critically ill patients without advance directives (control group). We
compared the following data: cost per day; number of surgical procedures; number
of radiographic studies; number of central venous and pulmonary artery catheter
insertions; number of complete blood counts, electrolytes, and cultures sent for
laboratory testing; number of days in the ICU/hospital; and mortality rates.
Statistical analysis was performed using the Student's t-test for independent
means and the chi-square equation. For all observed parameters, quantitative and
dichotomous differences between study and control groups were not statistically
significant. Two patients received CPR, despite advance directive statements
refusing this treatment. CONCLUSIONS: Few critically ill seniors have advance
directives. As assessed by objectively documented information, the level of care
delivered to elderly ICU patients is not affected by the presence or absence of
advance directive statements. Medical personnel need to be aware of whether or
not patients have advance directive statements, as unauthorized CPR was
administered to 11% of the patients who died with advance directives.
PMID- 9559608
TI - Total plasma antioxidant capacity is not always decreased in sepsis.
AB - OBJECTIVE: To compare total plasma antioxidant capacity and selected individual
antioxidants in patients with varying degrees of severity of sepsis. DESIGN: A
prospective, observational, consecutive case study. SETTING: A 16-bed intensive
care unit (ICU) in a university teaching hospital. INTERVENTIONS: None. PATIENTS:
Forty-six healthy controls, ten ICU patients, nine patients with systemic
inflammatory response syndrome (SIRS), 11 septic patients, and 14 septic shock
patients. Plasma was obtained in healthy patients scheduled for minor surgery
immediately before anesthesia and in ICU patients within 24 hrs of admittance to
the unit or diagnosis of SIRS, sepsis, or septic shock. MEASUREMENTS AND MAIN
RESULTS: Using the total peroxyl radical trapping method, we found plasma
antioxidant capacity to be lower in septic patients but higher in septic shock
patients, as compared with controls. Bilirubin was the greatest contributor to
the increase with shock, followed by uric acid. Neopterin also correlated with
the peroxyl radical trapping antioxidant parameter values. CONCLUSION: Although
total plasma antioxidant capacity is decreased from normal levels in septic
patients, an increase in some oxidants contributes to an increased total
antioxidant capacity in septic shock patients.
PMID- 9559609
TI - Increasing tidal volumes and pulmonary overdistention adversely affect pulmonary
vascular mechanics and cardiac output in a pediatric swine model.
AB - OBJECTIVES: In a pediatric swine model, the effects of increasing tidal volumes
and the subsequent development of pulmonary overdistention on cardiopulmonary
interactions were studied. The objective was to test the hypothesis that
increasing tidal volumes adversely affect pulmonary vascular mechanics and
cardiac output. An additional goal was to determine whether the effects of
pulmonary overdistention are dependent on delivered tidal volume and/or positive
end-expiratory pressure (PEEP, end-expiratory lung volume). DESIGN: Prospective,
randomized, controlled laboratory trial. SETTING: University research laboratory.
SUBJECTS: Eleven 4- to 6-wk-old swine, weighing 8 to 12 kg. INTERVENTIONS:
Piglets with normal lungs were anesthetized, intubated, and paralyzed. After
median sternotomy, pressure transducers were placed in the right ventricle,
pulmonary artery, and left atrium. An ultrasonic flow probe was placed around the
pulmonary artery. MEASUREMENTS AND MAIN RESULTS: The swine were ventilated and
data were collected with delivered tidal volumes of 10, 15, 20, and 25 mL/kg and
PEEP settings of 5 and 10 cm H2O in a random order. Pulmonary overdistention was
defined as a decrease in dynamic compliance of > or =20% when compared with a
compliance measured at a baseline tidal volume of 10 mL/kg. At this baseline
tidal volume, airway pressure-volume curves did not demonstrate pulmonary
overdistention. Tidal volumes and airway pressures were measured by a
pneumotachometer and the Pediatric Pulmonary Function Workstation. Inspiratory
time (0.75 sec), FIO2 (0.3), and minute ventilation were held constant. We
evaluated the pulmonary vascular and cardiac effects of the various tidal volume
and PEEP settings by measuring pulmonary vascular resistance, pulmonary
characteristic impedance, and cardiac output. When compared with a tidal volume
of 10 mL/kg, a tidal volume of 20 mL/kg resulted in a significant decrease in
dynamic compliance from 10.5 +/- 0.9 to 8.4 +/- 0.6 mL/cm H2O (p = .02) at a
constant PEEP of 5 cm H2O. The decrease in dynamic compliance of 20% indicated
the presence of pulmonary overdistention by definition. As the tidal volume was
increased from 10 to 20 mL/kg, pulmonary vascular resistance (1351 +/- 94 vs.
2266 +/- 233 dyne x sec/cm5; p = .004) and characteristic impedance (167 +/- 12
vs. 219 +/- 22 dyne x sec/cm5; p = .02) significantly increased, while cardiac
output significantly decreased (951 +/- 61 vs. 708 +/- 48 mL/min; p = .001). Each
of these effects of pulmonary overdistention were further magnified when the
tidal volume was increased to 25 mL/kg. The tidal volume-induced alterations in
pulmonary vascular mechanics, characteristic impedance, and cardiac output
occurred to a greater degree when the PEEP was increased to 10 cm H2O. Pulmonary
vascular resistance and characteristic impedance were significantly increased and
cardiac output significantly decreased for all tidal volumes studied at a PEEP of
10 cm H2O as compared with 5 cm H2O. CONCLUSIONS: Increasing tidal volumes,
increasing PEEP levels, and the development of pulmonary overdistention had
detrimental effects on the cardiovascular system by increasing pulmonary vascular
resistance and characteristic impedance while significantly decreasing cardiac
output. Delivered tidal volumes of >15 mL/kg should be utilized cautiously.
Careful monitoring of respiratory mechanics and cardiac function, especially in
neonatal and pediatric patients, is warranted.
PMID- 9559610
TI - Changes in the brain monoamine metabolism in acute liver failure produced by
ischemia-reperfusion injury in rats.
AB - OBJECTIVE: To investigate the relationship between behavioral alterations and
changes in monoaminergic systems provoked by ischemia-reperfusion liver injury in
rats. DESIGN: Prospective, randomized, controlled animal study. SETTING:
University animal laboratory. SUBJECTS: Male Wistar rats. INTERVENTIONS: Acute
liver failure was induced by occlusion of the left portal vein and the hepatic
artery for 90 mins. Twenty animals were subjected to the behavioral examination.
The brain water content was measured in 12 animals. Forty-two animals were used
for the evaluation of brain monoamine turnover. Half of animals in each
experiment were subjected to the ischemic operation. MEASUREMENTS AND MAIN
RESULTS: A step-through passive avoidance test was used for the behavioral
evaluation 48 hrs after the ischemic operation. Then, plasma concentrations of
amino acids were determined. The brain water content was measured with the dry
weight method. The brain monoamine turnover was evaluated by the depletion of
norepinephrine and dopamine induced by alpha-methyl-p-tyrosine, or the
accumulation of 5-hydroxyindoleacetic acid induced by probenecid. In the plasma
analysis performed 48 hrs after the operation, marked damage was found in animals
subjected to liver ischemia. Injured rats demonstrated impairment in the passive
avoidance test. The plasma concentrations of branch-chain amino acids were
decreased, and the plasma concentrations of aromatic amino acids were increased.
However, the brain water content was not changed by liver ischemia. The turnover
of both norepinephrine in the cerebral cortex and dopamine in the striatum was
decreased. The turnover of 5-hydroxytryptamine in the cerebral cortex was
increased markedly. CONCLUSION: In liver injury caused by liver ischemia, the
excitatory neurotransmission by norepinephrine and dopamine is depressed and the
inhibitory neurotransmission mediated by 5-hydroxytryptamine is facilitated,
especially in the telencephalon.
PMID- 9559611
TI - Prophylaxis against lipopolysaccharide-induced acute lung injury by alpha
tocopherol liposomes.
AB - OBJECTIVE: To investigate whether intravenously administered liposomal alpha
tocopherol can protect the lung from the injurious action of Escherichia coli
lipopolysaccharide (LPS). DESIGN: Prospective, randomized animal study. SETTING:
Government research laboratory. SUBJECTS: Twenty adult male Sprague-Dawley rats.
INTERVENTIONS: Animals were intravenously pretreated with alpha-tocopherol
liposomes (20 mg alpha-tocopherol/kg body weight), plain liposomes, or saline.
Twenty-four hours later, pretreated animals were challenged with an intravenous
injection of LPS (E. coli 0111:B4, 1 mg/kg body weight), and killed 2 hrs after
LPS challenge. MEASUREMENTS AND MAIN RESULTS: Challenge of saline-pretreated
animals with LPS resulted in lung injuries as evidenced by an increase in wet
lung weight and a reduction in pulmonary angiotensin converting enzyme (25%) and
alkaline phosphatase (28%), injury markers of lung endothelial and epithelial
type II cells, respectively. Also, LPS administration resulted in an increase in
pulmonary myeloperoxidase and protease activities, indicative of a neutrophilic
inflammatory response. Pretreatment of animals with liposomal alpha-tocopherol
significantly attenuated the LPS-induced edematous lung weight response, and
reduced the extent of injuries to the pulmonary endothelial and epithelial cells,
demonstrated by a significantly smaller reduction in the corresponding enzyme
marker activities. CONCLUSION: These results suggest that augmentation of the
pulmonary antioxidant status can ameliorate LPS-induced lung injuries mediated by
oxidative stress mechanisms.
PMID- 9559612
TI - Effects of filter pore size on efficacy of continuous arteriovenous
hemofiltration therapy for Staphylococcus aureus-induced septicemia in immature
swine.
AB - OBJECTIVE: To evaluate the effect of hemofilter pore size on the efficacy of
continuous arteriovenous hemofiltration (CAVH) in improving morbidity and
mortality in an immature swine model of Staphylococcus aureus-induced septicemia.
DESIGN: Prospective, randomized study with age-matched controls. SETTING:
Biomedical research facility. SUBJECTS: Fourteen 4 to 8-wk-old, weaned Poland
China swine, weighing 5 to 10 kg. INTERVENTIONS: Spontaneously breathing,
ketamine-sedated swine (4 to 8 wks of age) were given an intravenous lethal dose
of live S. aureus. Animals were then filtered with either a 50-kilodalton (kD)
pore size filter (control) or a 100-kD pore size filter (experimental). No
animals received antibiotics. MEASUREMENTS AND MAIN RESULTS: Physiologic,
biochemical, and hematologic parameters were measured in all animals every 1 to 3
hrs. Animals were monitored continuously and survival time (hr) was recorded
(permanent survival = 168 hrs/7 days). Animals filtered with the 100-kD filter
survived significantly longer than control animals (103 +/- 18 [SEM] vs. 56 +/- 9
hrs). The 100-kD-filtered group had one permanent survivor (168 hrs). Protein
concentration of the ultrafiltrate obtained from the 100-kD-filtered animals was
eight-fold higher than control ultrafiltrate. The protein removed did not contain
a high percentage of albumin (as determined by autoanalyzer methods). No
significant differences were seen in any of the other measured parameters.
CONCLUSIONS: CAVH significantly improved survival in swine with S. aureus-induced
sepsis. The superior performance of the 100-kD filter vs. the 50-kD filter
suggests that higher molecular weight mediators that are not removed efficiently
by the 50-kD filter may be responsible for the morbidity and mortality seen in
this model of sepsis. These mediators may be removed in greater proportion by our
customized (100-kD pore size) filter.
PMID- 9559613
TI - Right ventricular overload causes the decrease in cardiac output after nitric
oxide synthesis inhibition in endotoxemia.
AB - OBJECTIVE: To determine whether the decrease in cardiac output after nitric oxide
synthase inhibition in endotoxemia is due to increased left ventricular afterload
or right ventricular afterload. DESIGN: Prospective, randomized, unblinded study.
SETTING: Research laboratory at an academic, university medical center. SUBJECTS:
Nonanesthetized, sedated, mechanically ventilated pigs. INTERVENTIONS: Pigs were
infused with 250 microg/kg of endotoxin over 30 mins. Normal saline was infused
to maintain pulmonary artery occlusion pressure (PAOP) at a value not exceeding
1.5 times the baseline value. Left ventricular dimensions and function were
studied using echocardiography. Right ventricular volumes and ejection fraction
were determined via a rapid thermistor pulmonary artery catheter. We also
measured mean arterial pressure (MAP), cardiac output, pulmonary arterial
pressure, and calculated pulmonary and systemic resistances. Gastric tonometry
was used as an index of gastric mucosal oxygenation and peripheral oxygenation.
When MAP had decreased to < or =60 mm Hg or had decreased 30 mm Hg from baseline,
nine animals received NG-nitro-L-arginine methyl ester (L-NAME) at 15 mg/kg to
restore MAP to baseline. A second group of animals (n = 6) continued to receive
normal saline, ensuring that PAOP did not exceed 1.5 times its baseline value. A
third group of pigs (n = 5) did not receive endotoxin and served as the time
control. In this group, a balloon was used to occlude the descending thoracic
aorta and to increase MAP by approximately the same amount as in the L-NAME
group. MEASUREMENTS AND MAIN RESULTS: Endotoxin caused an increase in pulmonary
arterial pressure and right ventricular volumes, and a decrease in gastric
mucosal pH. Cardiac output was maintained in the animals receiving the saline
infusion. By 2 hrs, pulmonary arterial pressure had decreased but was still
notably higher than baseline. However, by this time, MAP had decreased to < or
=60 mm Hg. L-NAME administration restored MAP to its baseline value but resulted
in worsening pulmonary hypertension, increased right ventricular volumes, and
decreased cardiac output, compared with the saline group. Three animals that
received L-NAME died of right ventricular failure. We did not observe any
evidence of left ventricular dysfunction with increased left ventricular
afterload. Moreover, the restoration of MAP with L-NAME infusion did not correct
gastric mucosal acidosis. No changes were noted in the time-control group.
Occlusion of the thoracic aorta increased MAP but did not change cardiac output.
This finding demonstrates that increases in left ventricular afterload of the
magnitude seen with the infusion of L-NAME do not lead to decreases in cardiac
output. CONCLUSION: The decrease in cardiac output after nitric oxide synthase
inhibition in endotoxemia is due to increased right ventricular afterload and not
to left ventricular afterload.
PMID- 9559615
TI - Use of tracheobronchography as a diagnostic tool in ventilator-dependent infants.
AB - OBJECTIVE: Comparison of investigations of the airway in ventilator-dependent
infants. DESIGN: Consecutive infants with suspected upper airway abnormalities
were investigated using rigid bronchoscopy and tracheobronchography. SETTING:
Tertiary pediatric and neonatal intensive care units. PATIENTS: Eight infants
with suspected airway abnormalities. INTERVENTIONS: Rigid bronchoscopy and
tracheobronchography. MEASUREMENTS AND MAIN RESULTS: Structural abnormalities,
segmental narrowing of the airways and the effect of various levels of positive
end expiratory pressures on the narrowings were documented. In six of the eight
cases, additional airway abnormalities were diagnosed with tracheobronchography
compared with rigid bronchoscopy. CONCLUSIONS: In cases of suspected
abnormalities of the upper airway in small infants unable to be weaned from
ventilatory support, tracheobronchography may be a more reliable investigation
method than rigid bronchoscopy. The ability to assess the structural and dynamic
components of the airway accurately and safely allows a correct and long-term
treatment plan to be established in this group of patients.
PMID- 9559614
TI - Effect of prophylactic administration of recombinant human granulocyte colony
stimulating factor (filgrastim) on the frequency of nosocomial infections in
patients with acute traumatic brain injury or cerebral hemorrhage. The Filgrastim
Study Group.
AB - OBJECTIVE: To determine whether the use of prophylactic recombinant human
granulocyte colony-stimulating factor (filgrastim) reduces the frequency of
nosocomial infections in patients with either acute traumatic brain injury or
cerebral hemorrhage. DESIGN: Randomized, placebo-controlled, double-blind,
multicenter phase II study. SETTING: Intensive care units of seven medical
centers. PATIENTS: Patients with either acute traumatic brain injury or cerebral
hemorrhage who were intubated within 6 hrs of admission and who were expected to
be ventilated for >72 hrs. INTERVENTIONS: Patients were randomized to receive
daily subcutaneous injections of placebo (n = 21) or one of two doses of
filgrastim (75 microg [n = 20] or 300 microg [n = 20]) for 10 days or until the
absolute neutrophil count was >75,000 cells/mm3 or until extubation. MEASUREMENTS
AND MAIN RESULTS: End points included increase in absolute neutrophil count,
safety of filgrastim, and frequency of nosocomial infections (pneumonia,
bacteremia, and urinary tract infection). Filgrastim caused a dose-dependent
increase in absolute neutrophil count. There were no differences in the frequency
of pneumonia or urinary tract infection; however, there was a dose-dependent
decrease in the frequency of bacteremias (p < .05). Adverse events were similar
among the three groups. There was one case of acute respiratory distress syndrome
in the placebo group. CONCLUSION: In this patient population, use of filgrastim
was safe and the agent appeared to reduce the risk of primary bacteremias but had
no beneficial effects on mortality, length of stay, or other nosocomial
infections.
PMID- 9559616
TI - Accuracy of physiologic deadspace measurement in intubated pediatric patients
using a metabolic monitor: comparison with the Douglas bag method.
AB - OBJECTIVE: To evaluate the accuracy of physiologic deadspace (VD/VT) measurement,
using a metabolic monitor. DESIGN: Prospective collection of data. SETTING:
University-affiliated children's hospital with a 51-bed critical care area.
PATIENTS: Infants and children who were sedated and paralyzed and were receiving
mechanical ventilation through a cuffed endotracheal tube. INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: Mixed expired carbon dioxide tension (PECO2) was
measured. With the Douglas bag method, mixed expired gas was collected over 15
mins and was analyzed. With the metabolic monitor, FECO2 was measured for 15 mins
and the results were averaged. The PECO2 was calculated by multiplying FECO2 by
the barometric pressure. The PaCO2 was measured simultaneously. The PECO2 was
corrected for the compressible volume in the ventilator circuit. All gas volumes
were corrected for body temperature, pressure, and water vapor pressure. The
physiologic deadspace/tidal volume ratio (VD/VT) was calculated for both
techniques using the Enghoff modification of the Bohr equation. The accuracy of
the VD/VT measured, by using the metabolic monitor, was assessed by comparing
this measurement against the VD/VT measured by the Douglas bag method. This
comparison was done by simple linear regression and correlation and by bias
analysis (Bland and Altman method). The magnitude of compressible volume
expressed as a fraction of the tidal volume delivered by the ventilator was
compared with the error in VD/VT expressed as the difference between the
uncorrected and corrected VD/VT. Sixteen paired measurements were made in 12
children. The VD/VT measured by the metabolic monitor correlated well with the
VD/VT measured by the Douglas bag method (r2 = .99; p < .0001). There was no
correlation between the bias of VD/VT and the average VD/VT. As the magnitude of
compressible volume increased, the error in VD/VT increased (r2 =.61; p < .001).
CONCLUSIONS: The VD/VT can be measured reliably and accurately in intubated
pediatric patients using a metabolic monitor. The metabolic monitor method is a
convenient and simple alternative to the standard Douglas bag method.
PMID- 9559617
TI - Programs, partnerships, and patient care: moving Society of Critical Care
Medicine and critical care forward. The Presidential Address from the 27th
Educational and Scientific Symposium of the Society of Critical Care Medicine.
PMID- 9559618
TI - Prognosis in the intensive care unit: finding accurate and useful estimates for
counseling patients.
AB - OBJECTIVES: Counseling critically ill patients and their families about what the
future is likely to hold requires accurate prognostic information. Our goal is to
teach clinicians how to find and critically appraise prognostic studies that
examine homogeneous populations. CLINICAL EXAMPLE: An article describing the
outcomes of a group of children who are in a prolonged, persistent vegetative
state. RECOMMENDATIONS: The validity of prognostic studies is increased when: a)
the sample of patients is representative; b) patients are homogeneous with
respect to prognostic risk; c) follow-up is sufficient to minimize the
possibility that the missing patients could alter the interpretation of the
results; and d) health outcomes are evaluated, using objective and unbiased
criteria. The likelihood of these outcomes over time and the precision around
these probability estimates should be easily understandable. Before using the
results of these studies to counsel patients and families, practitioners should
ensure that the patients in the study and their management are similar to the
patient in question, and that follow-up of the subjects is sufficiently long.
CONCLUSIONS: The criteria outlined in this article may assist clinicians in
interpreting articles describing the prognosis of patients with similar clinical
conditions.
PMID- 9559619
TI - Understanding articles comparing outcomes among intensive care units to rate
quality of care. Evidence Based Medicine in Critical Care Group.
AB - OBJECTIVES: Comparisons of risk-adjusted outcomes among intensive care units
(ICUs) is a relatively new but rapidly expanding area of ICU health services
research. By investigating those factors that lead ICUs to have patient outcomes
that differ from the average, the overall quality of care across ICUs may be
improved. Our goal is to teach clinicians how to evaluate these types of
articles. CLINICAL EXAMPLE: An article describing the development and application
of an index used to assess the clinical performance and cost-effectiveness of 25
ICUs. RECOMMENDATIONS: Valid comparisons of the outcomes among ICUs are made
when: a) the outcome measures are accurate and comprehensive; b) the ICUs being
compared serve similar patients; c) the sampling of patients is sufficient and
unbiased; d) appropriate risk adjustment is undertaken by applying a valid model
to reliably collected data; and e) the comparisons focus on care delivered in the
ICU. To evaluate the results of the study, clinicians must evaluate how confident
they are that the outcome differences being described are clinically important.
Before changes in ICU policy are made based on these outcome differences, it is
important to clarify which factors might have resulted in these extreme outcomes
and whether these results are applicable in the ICU population that will see the
impact of the changes. CONCLUSION: The potential for misinterpretation of outcome
performance ratings may decrease if articles describing outcome differences are
evaluated, using the criteria outlined in this article.
PMID- 9559620
TI - Inhaled nitric oxide: technical aspects of administration and monitoring.
AB - OBJECTIVES: Clinical applications of inhaled nitric oxide (NO) therapy resulted
in the development of delivery systems and monitoring devices applicable to
routine clinical care. This article presents the various components necessary for
an adequate clinical use of inhaled NO, and discusses the NO gas mixture
cylinders, inhaled NO delivery techniques and specifications, monitoring devices,
and ending with an exhaustive description of the scavengers of nitrogen oxides
(NOx). DATA SOURCES: Computerized search (CURRENT CONTENTS, MEDLINE) of published
original research and review articles (approximately 200), conference abstracts
and compendiums up to May 1997 (approximately 50), personal files, and contact
with expert informants. STUDY SELECTION: Technical, experimental, and clinical
reports were selected from the recent English, French, German, and Spanish
literature, if pertinent to the administration or monitoring of inhaled NO. DATA
EXTRACTION: The authors extracted all applicable data. DATA SYNTHESIS: The
production of NO gas mixture cylinders must be certified with respect to gas
purity, stability, and concentration (limits between 100 and 1000 ppm),
guaranteed calibration, and specific color. An ideal inhaled NO delivery device
requires a synchronized delivery, a minimal production of nitrogen dioxide (NO2),
and should be simple to use (verification, calibration, convenient flushing,
cylinder change possible while in use and a simple alarm setting) with full
information (high and low alarms and available precision monitoring of NO, NO2,
and O2). Emergency and transport systems must be readily available. The choice of
the monitoring device (chemiluminescence or electrochemistry) should be made
based on the knowledge of their strength and weakness for a particular clinical
application. Finally, scavengers of NOx should be used with caution until
specific filters are proven safe and effective. CONCLUSIONS: The great
expectancies generated by inhaled NO action have led researchers to design
personal inhaled NO delivery systems, but only with mitigated results. At
present, medical companies are finding a financial interest in designing a
delivery system which will suit the needs of clinicians and this, along with
official governmental approval, will only then permit the use of inhaled NO
safely and on a larger scale.
PMID- 9559621
TI - Functional and ultrastructural evidence of myocardial stunning after acute carbon
monoxide poisoning.
AB - OBJECTIVE: To study human myocardial ultrastructural changes after carbon
monoxide (CO) poisoning inducing reversible cardiac failure. DESIGN: CASE
REPORT: clinical, functional and morphologic findings. SETTINGS: Public
university-affiliated hospital and electron microscopy laboratory. PATIENT: A 25
yr-old woman with functional evidence of cardiac failure after acute CO
poisoning. INTERVENTIONS: Hyperbaric and intensive care treatment over 10 days.
Scintigraphic and cardiac angiography with endomyocardial biopsy. MEASUREMENTS
AND MAIN RESULTS: Scintigraphy with 99mTc hexakis 2-methoxy-2-isobutyl isonitrile
(sestaMIBI) showed an uptake defect in the left anterior descending artery
territory. The cardiac angiography demonstrated a slight hypokinesis of the
superior two thirds of the anterior wall and of the septal region with completely
normal coronary angiograms. Electron microscopy of left ventricular biopsies
showed slight ultrastructural changes in the myocytes. In addition, large
glycogen deposits were mostly associated with swollen mitochondria. The patient
was discharged in good clinical condition on day 10. CONCLUSIONS: Presence of
glycogen deposits associated with abnormal mitochondria may be signs of the
incapability of myocardial cells in utilizing energy substrata. In the presence
of normal myocardial perfusion, our findings are consistent with the presence of
a stunned myocardium-like syndrome. Early recognition and treatment of this
clinical syndrome allow the prevention of myocardial infarction.
PMID- 9559622
TI - Atrioventricular nodal reentrant tachycardia.
PMID- 9559623
TI - Peripheral nerve stimulation and clinical assessment for dosing of neuromuscular
blocking agents in critically ill patients.
PMID- 9559624
TI - Abdominal incision tumor implantation following pneumoperitoneum laparoscopic
procedure vs. standard open incision in a syngeneic rat model.
AB - INTRODUCTION: A recent hamster model study suggests that the abdominal wall wound
implantation rate increases following laparoscopic colon cancer surgery compared
with the traditional open technique. However, results of that study were
confounded by several factors, including a midline incision in the laparoscopy
group, an unclear definition of wound implantation, significant age variations in
study subjects, and cell line use with low viability. The aim of this study was
to compare the abdominal incision implantation rates following a pneumoperitoneum
laparoscopic-type procedure with a standard open incision using a syngeneic
host/colon cancer rat model. METHODS: Viable DHD/K12 rat colon carcinoma cells (2
x 10(5) cells/rat) were injected intraperitoneally via 18G angiocath into
anesthetized, immunocompetent BD-IX rats (syngeneic host rats). Rats were then
randomly divided into open incision and laparoscopy groups. At three weeks post
operatively, tumor growth at the injection, incision, and port sites was
measured. RESULTS: Following standard midline incision, 50 percent of rats (26/50
rats) developed wound implantations, whereas only 25 percent of rats (14/57 rats)
developed at least one trocar site wound implantation after laparoscopy with
pneumoperitoneum. Fourteen percent of trocar sites (16/114 port sites) developed
wound implantations. No tumor growth was noted on the peritoneal surfaces other
than in the incisional sites. CONCLUSION: Laparoscopic-type procedure with
pneumoperitoneum did not increase wound implantation in a syngeneic host/colon
carcinoma rat model compared with the standard open incision technique.
PMID- 9559625
TI - Incontinence after lateral internal sphincterotomy: anatomic and functional
evaluation.
AB - PURPOSE: This study was designed to evaluate the anatomic and functional
consequences of lateral internal sphincterotomy in patients who developed anal
incontinence and in matched controls. METHODS: The study includes 13 patients
with anal incontinence after lateral internal sphincterotomy and 13 controls who
underwent the same operation and were continent and satisfied with the results of
the procedure. Patients underwent clinical evaluation, anorectal manometry,
pudendal nerve terminal motor latency testing, and endoanal ultrasonography.
RESULTS: Sphincterotomies were longer in incontinent patients (75 vs. 57
percent), but the resting pressure and length of the high-pressure zone were not
different between groups. Surprisingly, maximum voluntary contraction was higher
in incontinent patients than in continent controls (136 vs. 100 mmHg). Rectal
sensation and pudendal nerve terminal motor latency were similar in both groups.
The defect in the internal sphincter was wider in incontinent patients than in
continent controls (17.3 vs. 14.4 mm), but these differences were not
statistically significant. The thickness of the internal sphincter measured by
endoanal ultrasound was identical in both groups, but the external sphincter was
thinner in incontinent patients both at the site of the sphincterotomy (6.8 vs.
8.1 mm) and in the posterior midline (7.1 vs. 8.6 mm). CONCLUSIONS: Anal
incontinence after lateral internal sphincterotomy is directly related to the
length of the sphincterotomy. Whether secondary to preoperative sphincter
abnormality or the result of lateral internal sphincterotomy, the external
sphincter is thinner in incontinent patients than in continent controls.
PMID- 9559627
TI - Germline mutations of hMLH1 and hMSH2 genes in patients with suspected hereditary
nonpolyposis colorectal cancer and sporadic early-onset colorectal cancer.
AB - PURPOSE: The present study was designed to determine the frequency of germline
mutations in the hMLH1 and hMSH2 genes in 31 families suspected of having
hereditary nonpolyposis colorectal cancer who do not fulfill the criteria of the
International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer
but in whom a genetic basis for colon cancer is strongly suspected and 45
patients with sporadic early-onset colorectal cancer who developed colorectal
cancer before the age of 40 years without any family history of colorectal
cancer. METHODS: Genomic DNAs were prepared from peripheral blood samples of
patients who were tested. All coding exons and exon-intron borders of these two
genes were screened, first with the polymerase chain reaction-single-strand
conformation polymorphism method, followed by sequencing of the DNA fragments
displaying an abnormal single-strand conformation polymorphism pattern. RESULTS:
In 31 families with suspected hereditary nonpolyposis colorectal cancer, we found
six different germline mutations in seven unrelated families, including one
missense mutation and three frame-shift mutations in the hMLH1 gene and one
missense mutation and one frame-shift mutation in the hMSH2 gene. Totally,
frequency of mutation was 23 percent, 16 percent and 7 percent in the hMLH1 and
hMSH2, respectively. Only one missense mutation of the hMSH2 gene was identified
in 45 patients (2 percent) with sporadic early-onset colorectal cancer. The
mutation detection rate in families with suspected hereditary nonpolyposis
colorectal cancer was significantly higher than that of patients with sporadic
early-onset colorectal cancer (P < 0.05). CONCLUSION: Our definition of suspected
hereditary nonpolyposis colorectal cancer is useful in the diagnosis of
hereditary nonpolyposis colorectal cancer and for identifying those families who
need genetic presymptomatic diagnosis. Our results indicate that it may be
important to perform DNA testing in families suspected of having hereditary
nonpolyposis colorectal cancer. On the other hand, we only detected a low
mutation rate (2 percent) in 45 patients with sporadic early-onset colorectal
cancer.
PMID- 9559626
TI - Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary
nonpolyposis colorectal cancer kindreds and the general population.
AB - PURPOSE: This clinical case review aimed to identify phenotypic variations in
colorectal and extracolonic cancer expression between hereditary nonpolyposis
colorectal cancer (HNPCC) families with MLH1 and MSH2 germline mutations and the
general population. METHODS: Colorectal cancer onset and site distribution were
compared among 67 members of MLH1 kindreds, 45 members of MSH2 kindreds, and
1,189 patients from the general population. Synchronous and metachronous cancer
rates, tumor stage, extracolonic cancer incidence, and survival were also
compared. RESULTS: Mean ages of colorectal cancer onset were 44, 46, and 69 years
for MLH1, MSH2, and the general population, respectively (P < 0.001). More
proximal and fewer distal colon cancers were noted in HNPCC than the general
population (P < 0.001, P = 0.04). Site distribution showed disparity of rectal
cancers (8 percent MLH1 vs. 28 percent MSH2; P = 0.01) based on genotypes.
Overall, synchronous colorectal cancer rates were 7.4, 6.7, and 2.4 percent for
MLH1, MSH2, and the general population, respectively (P = 0.016). Annual
metachronous colorectal cancer rates were 2.1, 1.7, and 0.33 percent for MLH1,
MSH2, and the general population, respectively (P = 0.041). Colorectal cancer
stage presentation was lower in HNPCC than the general population (P = 0.0028).
Extracolonic cancers were noted in 33 percent of MSH2 patients, compared with 12
percent of MLH1 patients and 7.3 percent of the general population with
colorectal cancers (P < 0.001). Combined MLH1 and MSH2 ten-year survival was 68.7
percent compared with 47.8 percent for the general population (P = 0.009 stage
stratified, hazard ratio 0.57). CONCLUSION: The presence of rectal cancer should
not preclude the diagnosis of HNPCC, because the incidence of rectal cancer in
MSH2 was comparable with that in the general population. Phenotypic variations,
including the preponderance of extracolonic cancers in MSH2 patients, did not
result in survival differences between genotypic subgroups. These phenotypic
features of HNPCC genotypes may have clinical significance in the design of
specific screening, surveillance, and follow-up for affected individuals.
PMID- 9559628
TI - Sphincter preservation with chemoradiation in anal canal carcinoma:
abdominoperineal resection in selected cases?
AB - PURPOSE: This study contained herein assessed long-term results, toxicity, and
prognostic variables following combined modality therapy of patients with
International Union Against (Cancer Classification T1-4, N0-3, M0 squamous-cell
carcinoma of the anal canal. PATIENTS AND METHODS: Between 1985 and 1996, 62
patients completed treatment with combined modality therapy. A median total dose
of 50 Gy was given to the primary, perirectal, presacral, and inguinal nodes
followed by a local boost in selected cases. 5-Fluorouracil was scheduled as a
continuous infusion of 1,000 mg/m2 per 24 hours on days 1 to 5 and 29 to 33 and
mitomycin C as a bolus of 10 mg/m2 on days 1 and 29. Routinely processed paraffin
embedded sections were stained using monoclonal antibodies for detection of
proliferating cell nuclear antigen and MIB1 (Ki-67) antigen to determine the
labeling index. In addition, DNA ploidy was assessed after Feulgen staining.
RESULTS: Actuarial cancer-related survival, no evidence of disease survival, and
colostomy-free survival rates at five years were 81, 76, and 86 percent,
respectively. In univariate analysis, T category (T1/2 vs. T3/4) was predictive
for no evidence of disease survival (87 vs. 59 percent; P = 0.03) and colostomy
free survival (94 vs. 73 percent; P = 0.05). N category (N0 vs. N1-3) influenced
actuarial cancer-related survival (85 vs. 58 percent; P = 0.002) and no evidence
of disease survival (80 vs. 53 percent; P = 0.02). A higher proliferative
potential as measured by the MIB1 labeling index was associated with a better
colostomy-free survival (90 vs. 50 percent; P = 0.04). In multivariate analysis,
actuarial cancer-related survival was only influenced by the N category (P =
0.03) and no evidence of disease survival by N category (P = 0.03) and mitomycin
C dose (P = 0.04). Salvage abdominoperineal resection achieved long-term control
in only four of seven patients with local failures. CONCLUSION: Treatment with a
combination of radiotherapy and chemotherapy is safe and effective for patients
with anal canal carcinoma. Abdominoperineal resection is indicated as a salvage
procedure in nonresponding and recurrent lesions and may be of benefit in a small
subgroup of patients with poor prognostic factors.
PMID- 9559629
TI - Perioperative blood transfusions reduce long-term survival following surgery for
colorectal cancer.
AB - PURPOSE: The aim of the study contained herein was to investigate the association
between blood transfusion and long-term outcome for patients treated for
colorectal cancer, controlling for the effect of other prognostic factors. We
also wanted to study whether blood storage time influenced the prognosis.
METHODS: Cox's proportional hazards regression analysis was used to analyze data
from 336 patients who survived resection with curative intent. Median follow-up
was 5.8 (2-16.8) years or until death. RESULTS: Local recurrences and distant
metastases were significantly more frequent when more than two units of blood had
been transfused. In the multivariate Cox's analysis, with backward elimination of
nonsignificant factors at the 10 percent level, the following risk factors were
significantly related to death by colorectal cancer: tumor stage (T stage and N
stage), perforation of tumor, age, and the need for a blood transfusion.
Transfusions of more than two units of blood were independently and significantly
associated with death from colorectal cancer (relative hazard, 2.7; 95 percent
confidence intervals, 1.4-5.2). Time of blood storage had no effect on the
prognoses. In patients dying from diseases unrelated to colorectal cancer, age
and American Society of Anesthesiologists group were significantly related to
death, whereas blood transfusion was not. CONCLUSION: We found an independent and
significant association between perioperative blood transfusion and poor
prognosis in colorectal cancer patients. Blood storage time was not a prognostic
factor.
PMID- 9559630
TI - Impaired interleukin-12 production is associated with a defective anti-tumor
response in colorectal cancer.
AB - INTRODUCTION: Despite development of many chemotherapeutic regimens, colorectal
cancer continues to have a high mortality. One of the major new potential
therapies is interleukin-12, a heterodimeric cytokine produced by antigen
presenting cells. In vitro and in vivo studies have demonstrated the role of
interleukin-12 in stimulating a cell-mediated anti-tumor response against a
number of colon adenocarcinoma tumor models. However, it is unknown whether
patients with colorectal cancer have impaired interleukin-12 production. A study
was performed to investigate production of interleukin-12 preoperatively and the
relationship between these levels and disease stage at surgery. METHODS:
Preoperative peripheral blood mononuclear cells from colorectal cancer patients
and age-matched controls were stimulated by Staphylococcus aureus Cowan's Strain
1 (0.0075 percent wt/vol) in vitro for 24 hours. Expression of interleukin-12 was
then assessed by enzyme-linked immunosorbent assay. A single pathologist assessed
the tumors for stage according to TNM and Dukes classifications. RESULTS: Twenty
eight patients with colorectal cancer and 14 controls were recruited for the
study. Interleukin-12 production was significantly impaired in patients with
colorectal cancer compared with controls (P = 0.014), especially those with
advanced disease: Dukes C, P = 0.001 and T4, P < 0.05. CONCLUSION: Interleukin-12
production is impaired in patients with colorectal cancer, especially those with
advanced disease, suggesting a defective Thl-mediated anti-tumor response. These
patients may well benefit from exogenous interleukin-12 treatment.
PMID- 9559631
TI - Metronidazole may inhibit intestinal colonization with Clostridium difficile.
AB - PURPOSE: Antibiotics suppress normal gut flora, allowing overgrowth of acquired
or native Clostridium difficile, with release of toxins that cause mucosal
inflammation. Oral metronidazole is used to treat antibiotic-associated colitis
(pseudomembranous colitis). This study was designed to determine whether oral
metronidazole, as part of preoperative bowel preparation, prevents or decreases
incidence of antibiotic-associated colitis after elective colonic and rectal
procedures. METHODS: Eighty-two patients (40 men) were prospectively, randomly
assigned to receive one of two oral antibiotic regimens before colorectal
surgery. All patients underwent mechanical bowel preparation with polyethylene
glycol-electrolyte lavage solution before administration of oral antibiotics.
Group 1 (n = 42) patients received three doses (1 g/dose) of neomycin and
erythromycin. Group 2 (n = 40) patients received three doses (1 g/dose) of
neomycin and metronidazole. Both groups received one preoperative and three
postoperative doses of intravenous cefotetan (2 g/dose). Both groups had stool
samples tested for C. difficile toxin in the preoperative and postoperative
periods by enzyme-linked immunoabsorbent assay or by tissue culture cytotoxicity.
Patients with preoperative stool studies positive for C. difficile were excluded
from the study. RESULTS: Treatment groups were not different for age, gender, or
surgical procedure. Mean age +/- 1 standard deviation was 67.6 +/- 13.6 (range,
34-94) years in Group 1 and 62.1 +/- 13.5 (range, 35-84) years in Group 2 (P =
0.069). Mean length of hospital stay +/- 1 standard deviation was 9.76 +/- 4.9
(range, 4-28) days for Group 1 and 8.05 +/- 2.6 (range, 3-14) days for Group 2 (P
= 0.053). Five patients in Group 1 (neomycin and erythromycin) and one patient in
Group 2 (neomycin and metronidazole) had positive stool studies for C. difficile.
Relative risk of colonization with C. difficile in Group 1 was 4.76 times that in
Group 2 (95 percent confidence interval, 0.581, 39). This difference was not
statistically significant (P = 0.202). There were no significant differences in
C. difficile colonization rates with respect to age, length of stay, or gender.
CONCLUSIONS: This study suggests that there may be a clinical association between
use of metronidazole preoperatively and inhibition of intestinal colonization by
C. difficile in this patient population undergoing colonic and rectal surgery.
PMID- 9559632
TI - Bursting pressure in anastomotic healing in experimentally induced colitis in
rats.
AB - BACKGROUND: Experimental studies on healing of colonic anastomosis have been
thoroughly investigated. However, clinical parameters of the healing process of
anastomosis in the inflamed colon has not yet been reported. METHODS: In the
present study, healing of anastomosis in trinitrobenzene-sulfonic acid-induced
colitis in rats was assessed by measuring the bursting pressure and bursting wall
tension. RESULTS: On postoperative day 4, bursting pressure and bursting wall
tension were significantly lower (P < 0.001) in rats with colitis with or without
anastomosis and normal colon with anastomosis, compared with normal colon without
anastomosis. On postoperative day 7, bursting pressure and bursting wall tension
of normal colon with anastomosis approached that of normal colon without
anastomosis. However, bursting pressure and bursting wall tension of rats with
colitis with or without anastomosis remained significantly lower (P < 0.001) than
the latter. Furthermore, unlike rats without colitis in which perforation
occurred mostly at the anastomotic line, the bursting site in colitic rats was
predominantly away from the anastomotic line. CONCLUSIONS: These results suggest
that in surgery for inflammatory bowel disease, it is the adjoining inflamed
bowel wall that is vulnerable to be perforated in response to increasing
intraluminal pressure rather than the anastomosis that is braced by the sutures.
PMID- 9559633
TI - Rectal wall contractility in response to an evoked urge to defecate in patients
with obstructed defecation.
AB - PURPOSE: The aim of this study was to examine rectal sensory perception and
rectal wall contractility in response to an evoked urge to defecate and to
identify differences between control subjects and patients with obstructed
defecation. METHODS: Twenty control patients (10 men; median age, 47 (range, 17
78) years) and 29 female patients with disabling obstructed defecation (median
age, 48 (range, 18-70) years) entered the study. Under radiologic control, an
infinitely compliant barostat balloon was inserted over a guide wire into the
proximal part of the rectum. Additionally, a latex balloon was introduced into
the distal part of the rectum. This latex balloon was inflated until an urge to
defecate was experienced. Simultaneously, rectal wall contractility was assessed
by measuring the variations in barostat balloon volume. These variations were
expressed as percentage changes from baseline volume. RESULTS: By comparing
controls and patients with obstructed defecation, a significant difference was
found regarding mean distending volume required to elicit an urge to defecate
(135 +/- 38 vs. 214 +/- 87 ml of air; P < 0.001, Mann-Whitney U-test). In all
controls, the evocation of an urge to defecate induced a pronounced increase in
rectal tone, proximal to the distal stimulating balloon. By comparing controls
and patients, the increase in rectal tone was found to be significantly higher in
control subjects (35 +/- 10 vs. 9 +/- 10 percent; P < 0.001). Twenty-five
patients (86 percent) showed no or only minimum (<20 percent) increase in rectal
tone during the perception of an urge to defecate. In 14 of these patients, the
threshold for this perception was increased. Only four patients (14 percent)
showed a relatively normal increase (>20 percent) in rectal tone. However, their
threshold for perception was greatly increased. CONCLUSION: The assembly used in
this study provides a useful tool for investigation of rectal evacuation. In all
of our patients, obstructed defecation was associated with abnormal rectal
sensory perception and/or altered rectal wall contractility.
PMID- 9559634
TI - Patterns of colonic motility as recorded by a sham fecaloma reveal differences
among patients with idiopathic chronic constipation.
AB - BACKGROUND: By using a technique designated sham fecaloma, we were able to
identify two types of segmentary motor phenomenon: displacement motor phenomena
and nondisplacement motor phenomena. The aim of the study contained herein was to
evaluate for identification of patients with different types of slow-transit
constipation. METHODS: Studies were performed in healthy subjects (n = 5; colonic
transit time <30 hours) and in constipated patients (n = 6; colonic transit time
>125 hours; normal rectoanal manometry). A Foley-type recording probe with two
perfused catheters (proximal and distal) was used. A rigid sigmoidoscope was used
to place the probe at the sigmoid colon. Values recorded by the distal catheter
were subtracted (point by point) from the values recorded by the proximal
catheter. Subtraction curves were analyzed to quantify characteristics of
displacement motor phenomena (an anally directed pressure gradient) and
nondisplacement motor phenomena (an orally directed pressure gradient). RESULTS:
All healthy subjects had contractions during the recording session. Displacement
motor phenomena were predominant (displacement motor phenomena/30 minutes = 21.2
+/- 13.2; range, 3-39). Constipated patients yielded two different patterns:
three patients had a very small number of contractions, and three patients had a
prevalence of nondisplacement motor phenomena, with numbers similar to numbers of
displacement motor phenomena in healthy subjects. A comparison of the patterns of
constipated patients revealed a statistically significant difference (P = 0.039).
CONCLUSION: Sham fecaloma is a simple and safe test. Constipated patients in this
study had two different patterns of colonic motility: scarce activity without
haustration and normal activity without displacement motor phenomena. This method
might be useful as a diagnostic tool for clarification of the pathophysiology of
severe colonic motor disorders.
PMID- 9559635
TI - Experimental models of colorectal cancer.
AB - PURPOSE: A review of in vivo and in vitro models of colorectal cancer is
presented. METHODS: A retrospective literature review was performed with
reference to CD-ROM Medline and Index Medicus. RESULTS: A comparison of the
advantages and disadvantages of the models is presented in addition to a summary
of individual model methodology and applications. CONCLUSIONS: Such models are a
useful adjunct for surgical research in colorectal oncology.
PMID- 9559636
TI - Observations on the treatment of painful cancer of the rectum, without
obstruction, by establishing an anus in the left loin: with cases. 1811-1888.
PMID- 9559637
TI - Foley catheter-assisted endoscopic treatment of severe anastomotic stenosis
following anterior resection of the rectum.
AB - Rectal stenosis following low anterior resection is common. Several methods of
treatment have been described. We introduce a simple method for the treatment of
anastomotic stenosis using a conventional proctoscope and an electric knife with
a Foley catheter as an anvil. Under direct vision, this technique can afford
accurate and safe incision of stenosis.
PMID- 9559638
TI - Large aggressive angiomyxoma of the perineum and pelvis: an alternative approach.
Report of a case.
AB - Aggressive angiomyxomas are rare soft tissue tumors found mainly in the female
reproductive mesenchyme and pelvis. They are low-grade sarcomas that have a
propensity to recur locally. These tumors are encapsulated and have the same
consistency as normal connective tissue, thus making wide excision difficult. We
report a case of a large aggressive angiomyxoma in the perirectal tissues treated
with preoperative angiographic embolization, causing ischemia of the tumor and,
thus, improved visualization of the lesion. In addition, preoperative external
beam irradiation and intraoperative electron beam radiotherapy were used to
decrease the chances of local recurrence.
PMID- 9559639
TI - Peutz-Jeghers syndrome manifesting complete intussusception of the appendix and
associated with a focal cancer of the duodenum and a cystadenocarcinoma of the
pancreas: report of a case.
AB - The unusual occurrence of an "inside-out" appendix reported here is a case of
complete intussusception of the appendix of a 45-year-old woman with Peutz
Jeghers syndrome in whom the diagnosis of intussusception was made
preoperatively. At laparotomy, the lead point of intussusceptum was revealed to
be a Peutz-Jeghers syndrome polyp of the appendix. There was also a cystic lesion
in the pancreas, and subsequent distal pancreatectomy revealed a
cystadenocarcinoma of the pancreas. Two jejunal Peutz-Jeghers syndrome polyps and
two duodenal Peutz-Jeghers syndrome polyps were found via intraoperative
endoscopies. The duodenal polyps were endoscopically removed, whereas a jejunal
wedge resection was performed for the adjoining jejunal polyps. One of the two
duodenal polyps possessed an adenocarcinoma focus. To our knowledge, this is the
first report of complete intussusception of the appendix caused by a Peutz
Jeghers syndrome polyp.
PMID- 9559640
TI - Pursestring mucosal closure after diverting stoma creation.
PMID- 9559641
TI - Outcome following transanal endoscopic microsurgery.
PMID- 9559642
TI - Advanced rectal cancer in a young pregnant Bedouin woman.
PMID- 9559643
TI - Self-assessment quiz.
PMID- 9559644
TI - High expression of uncoupling protein 2 in foetal liver.
AB - To assess the putative role of mitochondrial uncoupling protein 2 (UCP2) during
perinatal development, its expression was analysed in mice and rats. Expression
was detected in a large range of foetal tissues. A unique developmental pattern
of UCP2 expression was found in liver, where the level of UCP2 mRNA was about 30
fold higher in foetuses than in adults (mice data), and started to decline
immediately after birth. Neither UCP1 nor UCP3 mRNA was expressed in foetal
liver. As in adult liver, immunohistochemical analysis suggested exclusive
localisation of UCP2 in the monocyte/macrophage cells. Our results indicate a
role of UCP2 in haematopoietic system development.
PMID- 9559645
TI - Female sterility in mice lacking the basigin gene, which encodes a transmembrane
glycoprotein belonging to the immunoglobulin superfamily.
AB - Basigin (Bsg) is a transmembrane glycoprotein belonging to the immunoglobulin
superfamily. Bsg knock-out mice exhibit infertility of both sexes. Based on
limited results, defective implantation has been considered to be the cause of
the female infertility. We demonstrate here that disruption of the Bsg gene
produces the failure of female reproductive processes including not only
implantation but also fertilization. Bsg mRNA expression in cumulus cells and
basolateral localization of the Bsg protein in the endometrial epithelium further
support the importance of Bsg in these processes.
PMID- 9559646
TI - TRAF2 plays a dual role in NF-kappaB-dependent gene activation by mediating the
TNF-induced activation of p38 MAPK and IkappaB kinase pathways.
AB - We previously demonstrated that p38 MAPK is a crucial mediator in the NF-kappaB
dependent gene activation induced by TNF. Here, we have studied the role of
several TNF receptor-associated proteins and caspases in p38 MAPK activation by
TNF. The latter appears to be dependent on TRAF2, but independent of FADD or
caspases. Remarkably, p38 MAPK activation by TNF proceeds independently of the
TRAF2-associated NF-kappaB-inducing kinase NIK, which is known to bind and
activate two recently identified IkappaB kinases. These results demonstrate that
two kinase pathways involved in NF-kappaB regulation, viz. NIK and p38 MAPK
mediated, diverge at the level of TRAF2.
PMID- 9559647
TI - Expression and regulation of phospholipase D in the human keratinocyte cell line
HaCaT.
AB - The generation of lipid second messengers via phosphatidylcholine (PC)-specific
phospholipase D (PLD) has emerged as an important step leading to transduction of
extracellular signals. In the present investigation the expression of human
cytosolic PLD isoenzymes in the immortalized human keratinocyte cell line HaCat
was determined. At the mRNA level we found the expression of hPLD1b and for the
first time in human cells also the expression of hPLD2. For further analysis of
enzyme expression at the protein level, hPLD1 peptide fragments were synthesized
and specific antibodies were generated (rabbit) to be used for detection of hPLD1
in Western blot experiments. Furthermore, small G-proteins were found to be
involved in the regulation of PLD activity in HaCaT cells using the guanine
nucleotide analogue GTPgammaS.
PMID- 9559648
TI - Cloning, sequencing and expression of the genes encoding the sodium translocating
N5-methyltetrahydromethanopterin : coenzyme M methyltransferase of the
methylotrophic archaeon Methanosarcina mazei Go1.
AB - The N5-methyltetrahydromethanopterin:coenzyme M methyltransferase of
Methanosarcina mazei Go1 is a membrane-associated, corrinoid-containing protein
that uses a transmethylation reaction to drive an energy-conserving sodium ion
pump. The eight open reading frames encoding the eight different subunits of the
methyltransferase were identified and sequenced. All of these subunits are shown
to be heterologously expressed in minicells of the Escherichia coli mutant DK6.
Sequence comparisons with the methyltransferases of thermophilic and
hypothermophilic methanogenic archaea are presented. The participation of the
gene product of mtrD in sodium ion translocation as well as a consensus sequence
of a corrinoid binding motif in MtrA are discussed.
PMID- 9559649
TI - Rapid and specific reactive oxygen species generation via NADPH oxidase
activation during Fas-mediated apoptosis.
AB - To determine Fas-induced reactive oxygen species (ROS) generation in cells
sensitive to Fas-mediated apoptosis, chemiluminescence, a strong indicator of ROS
generation, was monitored after stimulation with agonistic anti-Fas. Fas ligation
resulted in a rapid and sustained ROS generation. The generation reached a
maximum within 5 min and was still observed at least 40 min after the
stimulation. No significant ROS generation was observed under conditions where
apoptosis was absent. Furthermore, an NADPH oxidase inhibitor, diphenylene
iodonium, prevented Fas-mediated ROS generation, suggesting that Fas induces ROS
generation via stimulation of the oxidase system.
PMID- 9559650
TI - Activation of the potato plant uncoupling mitochondrial protein inhibits reactive
oxygen species generation by the respiratory chain.
AB - A variety of plant tissues contain an uncoupling mitochondrial protein (PUMP),
recently described and characterized by our group. In this study we show that the
inhibition of PUMP activity in potato tuber mitochondria significantly increases
mitochondrial H2O2 generation, while PUMP substrates, such as linoleic acid,
reduce mitochondrial H2O2 generation. This H2O2 generation occurred mainly by the
dismutation of superoxide radicals formed through monoelectronic reduction of O2
by semiquinone forms of coenzyme Q. The results presented suggest that protection
against mitochondrial oxidative stress may be a physiological role of PUMP.
PMID- 9559651
TI - Atomic force microscopy examination of tobacco mosaic virus and virion RNA.
AB - Atomic force microscopy (AFM) was applied to study uncoated virus particles and
RNA prepared by stripping of tobacco mosaic virions (TMV) with mild alkali or
urea and dimethylsulfoxide. We found that AFM is an appropriate method to study
ribonucleoprotein and free RNA structures. Images of entire tobacco mosaic
virions, partially uncoated TMV particles with protruding RNA molecule from one
or both ends and individual RNA molecules are presented.
PMID- 9559652
TI - Increase of local hydrogen ion gradient near bilayer lipid membrane under the
conditions of catalysis of proton transfer across the interface.
AB - The measurements of pH profiles in the unstirred layers (USLs) near planar
bilayer lipid membranes (BLM) were applied for the evaluation of the hydrogen ion
fluxes which were induced by nigericin in the presence of potassium ion
gradients. It was shown that at high concentrations of KCl the increase in the
concentration of citrate buffer caused an anomalous effect, namely, an increase
in the local pH shifts in the USLs. The hydrogen ion flux rose 50 times upon the
increase in the citrate concentration from 1 mM to 20 mM. Phosphate stimulated
the flux 7 times under these conditions. In agreement with our previous results,
at low KCl concentrations, when the process is limited by the K+-nigericin
interaction, an increase in the buffer concentration led to a reduction of the
local pH shifts, under these conditions the usual concentration dependence was
observed. The data obtained favor the model implying the existence of the kinetic
barrier for proton transfer at the membrane-water interface.
PMID- 9559653
TI - Apolipoprotein E, transthyretin and actin in the CSF of Alzheimer's patients:
relation with the senile plaques and cytoskeleton biochemistry.
AB - We measured the levels of two beta-amyloid (Abeta)-sequestering proteins,
apolipoprotein (Apo) E and transthyretin (TTR), in ventricular human
cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients and controls in
relation to brain histological findings. We also studied actin levels in CSF as a
marker of the biochemical role of these two proteins in the cytoskeleton. We show
that TTR levels in CSF were significantly decreased in AD patients compared to
controls and negatively correlated with the senile plaque (SP) abundance.
Moreover, actin levels were positively linked to TTR levels and increased in CSF
samples of patients homozygous for the ApoE epsilon4-allele. We propose that TTR
and ApoE4 may have competition in the aggregation of Abeta and its deposition in
the SP of AD brain. The relationships between ApoE, TTR and actin could suggest a
metabolic implication of ApoE genetics and TTR levels in cytoskeletal
biochemistry which may be relevant to the pathogenesis of AD.
PMID- 9559654
TI - X-ray and spectrophotometric studies of the binding of proflavin to the S1
specificity pocket of human alpha-thrombin.
AB - Proflavin can be used to study the interactions of inhibitors and substrates with
thrombin by monitoring the changes in the visible absorption spectrum that occur
on dye displacement. We have used microspectrophotometric methods to investigate
the binding of proflavin to crystals of an alpha-thrombin-hirugen complex and
have determined the structure by X-ray crystallography. The proflavin molecule
binds in the S1 pocket of the enzyme with one of the amino groups hydrogen bonded
to the carboxylate of Asp-189 while the protonated ring nitrogen is hydrogen
bonded to the carbonyl of Gly-219. This result indicates that the proflavin
displacement assay can be used to specifically monitor the binding of inhibitors
to the S1 pocket.
PMID- 9559655
TI - Solution conformation of an ET(B) selective agonist, ET
1[Cys(Acm)1,15,Ala3,Leu7,Aib11], in CD3OH/H2O by 1H NMR and molecular modelling.
AB - To understand the basic structural requirements for the biological activity of
endothelin peptides, the solution structure of an ETB selective agonist, ET-1[Cys
(Acm)1,15, Ala3,Leu7,Aib11, was investigated by 1H NMR spectroscopy and molecular
modelling. The structure is characterised by an alpha-helical conformation
between residues Ser5-His16 but is undefined at both the N and C termini. To
date, neither the solution structures of linear modified peptides nor the effects
of a methanol/water solvent system have been examined for endothelin or
endothelin-like peptides. This structure plays an important role towards the
design of endothelin receptor selective agonists and antagonists.
PMID- 9559656
TI - Ectopic expression of Nramp1 in COS-1 cells modulates iron accumulation.
AB - Nramp1 (natural resistance-associated macrophage protein) controls innate
immunity and encodes a transporter of unknown function. Here we describe an
antibody to Nramp1 displaying immunoreactivity towards a mature heavily
glycosylated polypeptide of 90-100 kDa and a precursor form of 45 kDa in
macrophages. Ectopic expression of the Nramp1 cDNA in COS-1 cells demonstrates
that Nramp1 modulates cellular iron levels following loading with low molecular
weight iron chelates. Surprisingly, Nramp1 does not enhance iron uptake, but
expression is associated with reduced cellular iron loads. We propose Nramp1 may
play a role in a salvage pathway of iron recycling.
PMID- 9559657
TI - Contribution of NO synthases to neutrophil infiltration in the gastric mucosal
lesions in rats with water immersion restraint stress.
AB - A decrease in constitutive NO synthase (cNOS) activity and an increase in
inducible NO synthase (iNOS) activity occurred with an increase in
myeloperoxidase (MPO) activity, an index of neutrophil infiltration, in the
gastric mucosa of rats with water immersion restraint (WIR) stress. This increase
in gastric mucosal MPO activity was enhanced by pretreatment with NG-monomethyl L
arginine, a non-selective NOS inhibitor, but was prevented with maintenance of
gastric mucosal cNOS activity by pretreatment with aminoguanidine, a selective
iNOS inhibitor. The MPO activity was negatively correlated with the cNOS activity
in all WIR-stressed rats used (r=-0.723). These results suggest that a decrease
in cNOS activity could contribute to an increase in neutrophil infiltration in
the gastric mucosa of WIR-stressed rats.
PMID- 9559658
TI - Substitution of Asn for Ser543 in the large fragment of Taq DNA polymerase
increases the efficiency of synthesis of long DNA molecules.
AB - Substitution of Asn for Ser543 in the large fragment of Taq DNA polymerase
(Klentaq) increases several times the efficiency of synthesis of long (over 2
kbp) DNA molecules. The difference in the DNA synthesis efficiencies by the
mutant and native enzymes increased with the increase in the DNA fragment length.
PMID- 9559659
TI - Plant profilin induces actin polymerization from actin : beta-thymosin complexes
and competes directly with beta-thymosins and with negative co-operativity with
DNase I for binding to actin.
AB - Recombinant plant (birch) profilin was analyzed for its ability to promote actin
polymerization from the actin:thymosin beta4 and beta9 complex. Depending on the
nature of the divalent cation, recombinant plant (birch) profilin exhibited two
different modes of interaction with actin, like mammalian profilin. In the
presence of magnesium ions birch profilin promoted the polymerization of actin
from A:Tbeta4. In contrast, in the presence of calcium but absence of magnesium
ions birch profilin was unable to initiate the polymerization of actin from the
complex with Tbeta4. However, under these conditions profilin formed a stable
stoichiometric complex with skeletal muscle alpha-actin, as verified by its
ability to increase the critical concentration of actin polymerization. Chemical
cross-linking indicated that birch profilin competes with Tbeta4 for actin
binding. Ternary complex formation of birch profilin with actin:DNase I complex
was suggested by chemical cross-linking. However, the determination of the
critical concentrations of actin polymerization in the simultaneous presence of
birch profilin and DNase I indicated that profilin and DNase I did not form a
ternary complex. These data indicated a negative co-operativity between the
profilin and DNase I binding sites on actin.
PMID- 9559660
TI - Effect of rutin and its copper complex on superoxide formation and lipid
peroxidation in rat liver microsomes.
AB - Two free radical scavengers, bioflavonoid rutin and the copper-rutin complex
Cu(Rut)Cl2, inhibited lucigenin-amplified chemiluminescence and lipid
peroxidation in rat liver microsomes, Cu(Rut)Cl2 being a 5-9 times more efficient
inhibitor than rutin. The enhanced inhibitory activity of Cu(Rut)Cl2 was due to
the presence of the additional superoxide-dismutating center (Cu), as follows
from the comparison of its effects on microsomal chemiluminescence and cytochrome
c reduction by xanthine oxidase. Similar effects of both inhibitors on superoxide
production and lipid peroxidation as well as the elevated activity of Cu(Rut)Cl2
indicate an important role of superoxide ion in the initiation of microsomal
lipid peroxidation.
PMID- 9559661
TI - Two high conductance channels of the mitochondrial inner membrane are independent
of the human mitochondrial genome.
AB - Patch-clamp techniques were used to characterize the channel activity of
mitochondrial inner membranes of two human osteosarcoma cell lines: a
mitochondrial genome-deficient (rho0) line and its corresponding parental (rho+)
line. Previously, two high conductance channels, mitochondrial Centum picoSiemen
(mCS) and multiple conductance channels (MCC), were detected in murine
mitochondria. While MCC was assigned to the protein import in yeast mitochondria,
the role of mCS is unknown. This study demonstrates that mCs and MCC activities
from mouse mitochondria are indistinguishable from those of human mitochondria.
The channel activities and their functional expression levels are not altered in
cells lacking mtDNA. Hence, rho0 cells may provide a model system for elucidating
the role of mitochondrial channels in disease processes and apoptosis.
PMID- 9559662
TI - Molecular diversity of sterol 14alpha-demethylase substrates in plants, fungi and
humans.
AB - Metabolism of lanosterol (LAN), 24-methylene-24,25-dihydrolanosterol (24
methyleneDHL), dihydrolanosterol (DHL) and obtusifoliol (OBT) by purified human,
plant (Sorghum bicolor) and fungal (Candida albicans) sterol 14alpha-demethylase
(CYP51; P450(14DM)) reconstituted with NADPH cytochrome P450 reductases was
studied in order to elucidate the substrate specificity and sterol stereo- and
regio-structural requirements for optimal CYP51 activity. Both human and C.
albicans CYP51 could catalyse 14alpha-demethylation of each substrate with
varying levels of activity, but having slightly higher activity for their
respective endogenous substrates in vivo, dihydrolanosterol for human CYP51 (Vmax
= 0.5 nmol/min/nmol CYP51) and 24-methylene-24,25-dihydrolanosterol for C.
albicans CYP51 (Vmax = 0.3 nmol/min/nmol CYP51). In contrast, S. bicolor CYP51
showed strict substrate specificity and selectivity towards its own endogenous
substrate, obtusifoliol (Vmax = 5.5 nmol/min/nmol CYP51) and was inactive towards
14alpha-demethylation of lanosterol, 24-methylene-24,25-dihydrolanosterol and
dihydrolanosterol. These findings confirm that the presence of the 4beta-methyl
group in the sterol molecule renders the plant CYP51 incapable of 14alpha
demethylation thus revealing the strict active site conservation of plant CYP51
during evolution.
PMID- 9559663
TI - Inhibition of caspase activity induces a switch from apoptosis to necrosis.
AB - The role of caspases in B lymphocyte cell death was investigated by using two
broad spectrum inhibitors of the caspase family, Z-Asp-cmk and Z-VAD-fmk. They
totally prevented spontaneous and drug-induced apoptosis and inhibited the
CPP32/caspase-3-like activity exhibited by apoptotic cells. However, the
suppression of apoptosis was not associated with a long-term increase of cell
survival, but conversely, with a switch from apoptotic death to the necrotic
form. These results strongly suggest that apoptosis and necrosis share common
initiation pathways, the final issue being determined by the presence of an
active caspase.
PMID- 9559664
TI - Induction of the mitogen-activated protein kinase phosphatase MKP3 by nerve
growth factor in differentiating PC12.
AB - In PC12 sympathetic neurons activation and nuclear translocation of ERK family
MAP kinases plays an essential role in processes underlying nerve growth factor
(NGF)-dependent differentiation. We have recently cloned MKP-3 as a novel dual
specificity phosphatase displaying selectivity towards inactivation of the ERK1
and ERK2 MAP kinases. Here we report that in PC12 cells, MKP-3 undergoes powerful
and specific up-regulation by NGF while a number of mitogens and cellular
stresses are ineffective. NGF-stimulated MKP-3 expression appears after 1 h, is
maximal at 3 h, and is sustained for 5 days. This coincides with a critical
period of neurite outgrowth and terminal differentiation. Consistent with a role
mediating inhibition of PC12 cell MAP kinases, NGF-stimulated ERK2 activation was
suppressed considerably following pretreatment with fibroblast growth factor and
9-cis-retinal, two additional differentiation factors found to induce powerfully
MKP-3 expression. Given the clear cytosolic localization of MKP3 in PC12 cells
and sympathetic neurons, these results suggest a critical role for inactivating
ERK MAP kinases in non-nuclear compartments during essential stages of NGF
mediated PC12 differentiation.
PMID- 9559665
TI - Glucagon-like peptide-1 receptor expression in Xenopus oocytes stimulates
inositol trisphosphate-dependent intracellular Ca2+ mobilization.
AB - The signal transduction pathway of the cloned human glucagon-like peptide-1 (GLP
1) receptor was studied in voltage-clamped Xenopus oocytes. Binding of GLP-1(7
36)amide was associated with cAMP production, increased [Ca2+]i and activation of
Ca2+-dependent Cl- current. The effect of GLP-1(7-36)amide reflects intracellular
Ca2+ mobilization and was suppressed by injection of the Ca2+ chelator BAPTA and
the inositol trisphosphate receptor antagonist heparin. The responses were not
mimicked by the adenylate cyclase activator forskolin and unaffected by the
protein kinase A (PKA) inhibitor Rp-cAMPS. We conclude that GLP-1 receptor
expression in Xenopus oocytes evokes inositol trisphosphate-dependent
intracellular Ca2+ mobilization independent of the cAMP/PKA signaling pathway.
PMID- 9559666
TI - Loss of a consensus heparin binding site by alternative splicing of latent
transforming growth factor-beta binding protein-1.
AB - Latent transforming growth factor-beta binding protein-1 (LTBP-1), plays an
important role in controlling localisation and activation of transforming growth
factor-beta (TGF-beta). We show that alternative splicing generates a form of
mRNA which lacks bases 1277-1435 (termed LTBP-1delta53). The 53 amino acids
encoded by these bases include the eighth cysteine of the first cysteine repeat
and a consensus heparin binding sequence. Sequencing of genomic clones showed
that alternative splicing resulted from the use of an intra-exonic 3' splice
acceptor site. The loss of the heparin binding site implies that LTBP-1delta53
will bind to the extracellular matrix less efficiently than LTBP-1.
PMID- 9559667
TI - Amino acid sequence, glycan structure, and proteolytic processing of the lectin
of Vatairea macrocarpa seeds.
AB - VML is a galactose-binding lectin isolated from Vatairea macrocarpa seeds. By SDS
polyacrylamide gel electrophoresis, VML is a glycoprotein composed of a major 32
34 kDa double band (alpha-chain) and minor 22 kDa and 13 kDa bands. N-terminal
sequencing of electroblotted samples showed that the 22 and 13 kDa bands
corresponded to C-(beta) and N-(gamma) terminal fragments of the alpha-chain,
respectively. The primary structure of VML displays similarity with other
leguminous lectins, particularly with Erythrina variegata, Robinia pseudoacacia
and Sophora japonica lectins. VML is N-glycosylated at asparagine residues at
positions 111 and 183 with one major glycan structure. Tandem mass spectrometry
and methylation analysis indicated the presence of Manalpha1-6[(Manalpha1
3)(Xylbeta1-2)]Manbeta1-4 -GlcNAcbeta1-4(Fucalpha1-3)GlcNAc, a typical plant
Nglycan. Equilibrium sedimentation analysis by analytical centrifugation showed
that VML had a mass of 122-130 kDa, which did not change within the pH range 2.5
8.5. These data indicated that VML is a pH-independent homotetrameric protein and
that a small proportion of the alpha-subunits is cleaved into noncovalently
associated N- and C-terminal fragments. Mass spectrometric analysis suggested a
mechanism for the proteolytic processing of VML. V. macrocarpa lectin contains a
mixture of doubly (28,525 Da) and singly (27,354 Da) glycosylated alpha-chains.
Deglycosylation of Asn-111 correlates with proteolytic cleavage of the Asn-114
Lys-115 bond yielding glycosylated gamma (residues 1-114, 12,304 Da) and
nonglycosylated beta-(residues 115-239, 14,957 Da) chains. Some beta-chain
molecules are further deglycosylated and N-terminally processed yielding products
of molecular masses of 13,783 Da and 13,670 Da.
PMID- 9559668
TI - Phenobarbital induces cytochrome P4501A2 hnRNA, mRNA and protein in the liver of
C57BL/6J wild type and aryl hydrocarbon receptor knock-out mice.
AB - The aryl hydrocarbon receptor mediates the transcriptional response to a variety
of hydrocarbons of members of the aryl hydrocarbon gene battery. Phenobarbital
does not bind the aryl hydrocarbon receptor with high affinity but induces, in
liver cells, expression of cytochrome P4501A. Using both wild type and aryl
hydrocarbon receptor knock out C57BL/6J mice, we demonstrate that phenobarbital
induced hnRNA, mRNA and protein for the cytochrome P-4501A2 gene in the presence
or absence of the aryl hydrocarbon receptor. Using the DNA binding site for the
aryl hydrocarbon receptor as a probe, gel retardation analyses showed that
phenobarbital treatment induced protein binding, regardless of the presence of
the aryl hydrocarbon receptor.
PMID- 9559669
TI - Vanadate fully stimulates insulin receptor substrate-1 associated phosphatidyl
inositol 3-kinase activity in adipocytes from young and old rats.
AB - Vanadate stimulates adipocyte 2-deoxyglucose transport and GLUT-4 translocation
to the membrane through an insulin receptor-independent but wortmannin
inhibitable pathway. Vanadate stimulates PI 3-kinase in anti-IRS-1
immunoprecipitates and the binding between IRS-1 and the p85alpha subunit of PI 3
kinase. In insulin-resistant adipocytes from old rats vanadate fully stimulates
IRS-1-associated PI 3-kinase, but partially activates glucose uptake. We conclude
that: (a) vanadate stimulates 2-deoxyglucose uptake using a pathway that
converges with that of insulin at the level of PI 3-kinase; and (b) adipocytes
from old rats are defective in the insulin pathway at steps located both upstream
and downstream of PI 3-kinase.
PMID- 9559670
TI - cDNA cloning and mRNA distribution of a mouse very long-chain acyl-CoA
synthetase.
AB - The interaction of the adrenoleukodystrophy protein (ALDP), mutated in the
peroxisomal disorder X-linked adrenoleukodystrophy, and the very long-chain acyl
CoA synthetase (VLACS), the enzyme whose function is missing in this disease,
remains obscure. As a first step to studying this interaction in wild type versus
ALDP-deficient mice, we have cloned a VLACS cDNA from mouse liver. The 1860 bp
open reading frame encodes a 620 amino acid protein with a predicted molecular
mass of 70.3 kDa. By Northern blot analysis, a 2.6 kbp VLACS mRNA was highly
abundant in liver and kidney and present at low levels in brain and testes. By RT
PCR VLACS mRNA was also detected in heart and lung but remained undetectable in
skeletal muscle and spleen. In contrast to the peroxisomal beta-oxidation marker
acyl-CoA oxidase, whose mRNA level steadily increases during brain development,
the VLACS transcript was found at a constant low level from embryo through
adulthood, suggesting that additional isoforms may exist in brain.
PMID- 9559671
TI - Structure, chromosome localization, and tissue distribution of the mouse twik K+
channel gene.
AB - We have recently discovered a new class of potassium channels with two pore
forming domains and four membrane-spanning domains. When heterologously
expressed, these channels produce time- and voltage-independent currents that
classify them as background or leak channels. TWIK (for tandem of P domains in a
weak inwardly rectifying K+ channel) was the first member of this family to be
cloned. Here, we describe the genomic organization of TWIK in the mouse. The
coding sequence as well as the untranslated sequences are contained in three
exons. The twik gene (or KCNK1) has been mapped to chromosome 8, consistent with
its localization to 1q42-43 in human. The twik gene is expressed in virtually all
mouse tissues. It is most abundantly expressed in brain and moderately in other
organs such as kidney. The level of expression is increased in brain and kidney
from neonate to adult animals, but the TWIK message is also detected during
embryogenesis, as early as day 7 post conception.
PMID- 9559672
TI - The TRP Ca2+ channel assembled in a signaling complex by the PDZ domain protein
INAD is phosphorylated through the interaction with protein kinase C (ePKC).
AB - Photoreceptors which use a phospholipase C-mediated signal transduction cascade
harbor a signaling complex in which the phospholipase Cbeta (PLCbeta), the light
activated Ca2+ channel TRP, and an eye-specific protein kinase C (ePKC) are
clustered by the PDZ domain protein INAD. Here we investigated the function of
ePKC by cloning the Calliphora homolog of Drosophila ePKC, by precipitating the
TRP signaling complex with anti-ePKC antibodies, and by performing
phosphorylation assays in isolated signaling complexes and in intact
photoreceptor cells. The deduced amino acid sequence of Calliphora ePKC comprises
685 amino acids (MW = 78 036) and displays 80.4% sequence identity with
Drosophila ePKC. Immunoprecipitations with anti-ePKC antibodies led to the
coprecipitation of PLCbeta, TRP, INAD and ePKC but not of rhodopsin. Phorbolester
and Ca2+-dependent protein phosphorylation revealed that, apart from the PDZ
domain protein INAD, the Ca2+ channel TRP is a substrate of ePKC. TRP becomes
phosphorylated in isolated signaling complexes. TRP phosphorylation in intact
photoreceptor cells requires the presence of extracellular Ca2+ in micromolar
concentrations. It is proposed that ePKC-mediated phosphorylation of TRP is part
of a negative feedback loop which regulates Ca2+ influx through the TRP channel.
PMID- 9559673
TI - Yeast putative transcription factors involved in salt tolerance.
AB - Four putative yeast transcription factors (Hal6-9p) have been identified which
upon overexpression in multicopy plasmids increase sodium and lithium tolerance.
This effect is mediated, at least in part, by increased expression of the Enalp
Na+/Li+ extrusion pump. Hal6p and Hal7p are bZIP proteins and their gene
disruptions affected neither salt tolerance nor ENA1 expression. Hal8p and Hal9p
are putative zinc fingers and their gene disruptions decreased both salt
tolerance and ENA1 expression. Therefore, Hal8p and Hal9p, but not Hal6p and
Hal7p, qualify as transcriptional activators of ENA1 under physiological
conditions. Hal8p seems to mediate the calcineurin-dependent part of ENA1
expression.
PMID- 9559674
TI - Effective restoration of dystrophin-associated proteins in vivo by adenovirus
mediated transfer of truncated dystrophin cDNAs.
AB - A series of truncated dystrophin cDNAs (3.1-4.2 kbp) containing only three,
three, two or one rod repeats with hinge 1 and 4 (named deltaDysAX2, AX11, AH3,
M3, respectively) or no rod repeat retaining either hinge 1 or 4 (named
deltaDysH1, H4, respectively) were constructed. These cDNAs were introduced into
skeletal muscle of adult mdx mice using the adenovirus vector with a strong CAG
promoter. deltaDysAX2, AX11, AH3 and deltaDysM3 expressed themselves successfully
and recovered dystrophin-associated proteins effectively. Especially 3.7 kbp cDNA
for deltaDysM3 offers the possibility of an approach utilizing newly developed
virus vectors, such as an adeno-associated virus vector, toward gene therapy of
Duchenne muscular dystrophy.
PMID- 9559675
TI - Substitution of 5-methylcytosines for cytosines enhances the stability of
topoisomerase I-DNA complexes and modulates the sequence selectivity of
camptothecin-induced DNA cleavage.
AB - We have investigated the binding and cleavage of DNA by human topoisomerase I
using a 160 bp restriction fragment containing either natural bases or 5
methylcytosine residues in place of cytosines. Experiments were performed in the
presence and absence of the antitumour drug camptothecin which specifically
inhibits topoisomerase I. Replacement of all cytosines with 5-methylcytosine
residues (i) reinforces the enzyme-DNA interaction, (ii) enhances the stability
of topoisomerase I-DNA complexes and (iii) modulates the sequence selectivity of
camptothecin-induced DNA cleavage. The methyl group exposed in the major groove
of the double helix is identified as a critical element for the interaction
between topoisomerase I and DNA.
PMID- 9559676
TI - Lipid membrane binding of NK-lysin.
AB - The membrane-binding properties and pore-forming potential of the tumor-lysing
and antibacterial polypeptide NK-lysin were investigated. Fluorescence quenching
experiments show a drastic change of accessibility to Trp58 in solution and in
association with a lipid membrane. Calcein release from large unilamellar
vesicles and fluctuating conductivity observed across a planar lipid bilayer of
asolectin show that NK-lysin renders lipid bilayers permeable in a transient
fashion, indicating a nonspecific lipid interaction as the mechanism underlying
the biological activity. FTIR experiments show the same amount and type of
regular secondary structure of NK-lysin in the membrane as in aqueous solution
and exclude a structural rearrangement into a set of parallel or antiparallel
alpha-helices as the predominant conformation. The molecular mechanism of the
membrane-destabilizing effect of NK-lysin is discussed.
PMID- 9559677
TI - Further assignment of resonances in 1H NMR spectra of cerebrospinal fluid (CSF).
AB - A number of previously unidentified 1H NMR signals detected in CSF spectra of
patients with various neurological and metabolic diseases are assigned to
metabolites, drugs and drug excipients. Two-dimensional 1H NMR spectroscopy (COSY
and J-resolved) is employed to resolve resonances which are hidden by
superimposed peaks in one-dimensional spectra. Assignments obtained by making use
of 2-D techniques, and of a 1-D 1H NMR data base created for ca. 150 authentic
compounds, enable us to clarify the nature of complex signal patterns found in
crowded spectral regions of CSF such as the aliphatic methyl region at ca. 1.0
ppm.
PMID- 9559678
TI - A scheme for designating enzymes that hydrolyse the polysaccharides in the cell
walls of plants.
AB - A scheme is proposed for designating enzymes that hydrolyse the polysaccharides
in the cell walls of plants. These enzymes are predominantly beta-1,4-glycanases.
The scheme is based on the classification of the catalytic domains of glycoside
hydrolases into families of related amino acid sequences. The new designation for
an enzyme indicates its family and, because all members of a family have these
characteristics in common, its three-dimensional fold and stereospecificity of
hydrolysis. The scheme is intended to simplify comparison of the systems of
enzymes produced by different microorganisms for the hydrolysis of plant cell
walls.
PMID- 9559679
TI - Conversion of Amadori product of Maillard reaction to Nepsilon
(carboxymethyl)lysine in alkaline condition.
AB - Nepsilon-(carboxymethyl)lysine (CML) is known to be formed by oxidative cleavage
of Amadori products between C-2 and C-3 of the carbohydrate chain. We report here
that CML formation from Amadori compounds is highly accelerated under alkaline
conditions. Incubation of glycated human serum albumin (HSA) in 0.1 N NaOH led to
the formation of CML whereas glycated HSA reduced by NaCNBH3 or non-glycated HSA
did not generate CML. Nalpha-t-butyloxycarbonyl-Nepsilon-fructoselysine (Boc-FL),
a model compound of Amadori product, was converted to CML under alkaline
conditions. CML level of human sera (n=224) preincubated with 0.1 N NaOH
correlated well with glycated albumin value (r=0.912) and hemoglobin A1c
(r=0.797).
PMID- 9559680
TI - The X-ray structure of a divergent cyclophilin from the nematode parasite Brugia
malayi.
AB - A structure of residues 1-177 of the cyclophilin domain of a large divergent
cyclophilin from the filarial nematode parasite Brugia malayi has been
crystallised and solved in two different crystal forms. The active site has a
similar structure to that of human cyclophilin A. Two of the 13 residues
important in forming the human cyclophilin A/cyclosporin A complex are altered in
the B. malayi cyclophilin and explain the relatively poor inhibition of peptidyl
prolyl isomerase activity by cyclosporin A.
PMID- 9559681
TI - Human L-ficolin: plasma levels, sugar specificity, and assignment of its lectin
activity to the fibrinogen-like (FBG) domain.
AB - Ficolins are characterised by the presence of collagen-like and fibrinogen-like
(FBG) sequences. Human L-ficolin is synthesised in the liver and secreted into
blood circulation. In previous studies, it was shown to bind to N-acetyl-D
glucosamine (GlcNAc). In the present study, its detailed sugar specificity and
binding site have been investigated. It was found to bind to GlcNAc and GalNAc (N
acetyl-D-galactosamine) while showing no significant affinity for the precursor
sugars. The structure in these molecules which is recognised by L.-ficolin has
been deduced to include an amide (-CO-NH-) or similar group. L-Ficolin was
digested with collagenase and the collagenase resistant FBG domain was shown to
bind to GlcNAc. Its levels in adult and cord blood-derived human plasma were also
determined and showed that adult plasma contains approximately three times more L
ficolin than that of newborn babies.
PMID- 9559682
TI - A possible involvement of endogenous polyamines in the TNF-alpha cellular
sensitivity.
AB - A critical step in the cytotoxic action mechanism of tumor necrosis factor-alpha
(TNF-alpha) involves, among mitochondrial dysfunctions, an early change of the
inner membrane permeability displaying the characteristics of permeability
transition. Cytosolic polyamines, especially spermine, are known to inhibit it.
Our results show that spermine is only detectable in the TNF-alpha resistant C6
cells while N1-acetylspermidine is present in the TNF-alpha sensitive WEHI-164
cells, and putrescine and spermidine are found in both. TNF-alpha treatment does
not change this distribution but only induces a quantitative alteration in TNF
alpha sensitive cells. Omission of glutamine (energetic substrate) from the
culture media alters neither the TNF-alpha responsiveness of both cell lines nor
their polyamine distributions, only their quantitative polyamine contents.
PMID- 9559683
TI - Cable grafting of the spinal accessory nerve after radical neck dissection.
AB - BACKGROUND: From January 1981 through March 1996, 20 patients with head and neck
cancer underwent radical neck dissection with sacrifice of the spinal accessory
nerve and immediate reconstruction of the nerve using a microsurgical technique
and a cable graft of the great auricular nerve. METHODS: Postoperative shoulder
function was assessed via a subjective questionnaire, objective strength testing,
and/or postoperative electromyography. The latter was used to evaluate for the
presence and amplitude of voluntary motor potentials, the presence of
fibrillation potentials, and nerve conduction latency. The group of patients who
underwent cable grafting of the spinal accessory nerve was compared with a group
of patients who underwent modified radical neck dissection with preservation of
the spinal accessory nerve and with another group of patients who underwent a
classic neck dissection with sacrifice of the spinal accessory nerve and no
reconstruction. RESULTS: In terms of shoulder function, the group of patients in
whom the spinal accessory nerve was reconstructed occupied an intermediate
position; ie, their postoperative shoulder function was better than that of the
patients who underwent radical neck dissection without reconstruction but not as
good as that of the patients who underwent modified neck dissection with
preservation of the spinal accessory nerve. CONCLUSION: Cable grafting of the
spinal accessory nerve that has been sacrificed during radical neck dissection
results in improved shoulder function in the postoperative period.
PMID- 9559684
TI - Effect of pulsed electromagnetic stimulation on facial nerve regeneration.
AB - OBJECTIVE: To determine if exposure to electromagnetic fields influences
regeneration of the transected facial nerve in the rat. DESIGN AND METHODS: The
left facial nerve was transected in the tympanic section of the fallopian canal
in 24 rats randomly assigned to 2 groups. The cut ends of the facial nerve were
reapproximated without sutures within the fallopian canal to maximize the
potential for regeneration. Rats in the experimental group (n= 12) were then
exposed to pulsed electromagnetic stimulation (0.4 millitesla at 120 Hz) for 4
hours per day, 5 days per week, for 8 weeks. Rats in the control group (n=12)
were handled in an identical manner without pulsed electromagnetic stimulation.
Four other rats were given sham operations in which all surgical procedures were
carried out except for the actual nerve transection. Two of these rats were
placed in each group. Nerve regeneration was evaluated using electroneurography
(compound action potentials), force of whisker and eyelid movements, and
voluntary facial movements before and at 2-week intervals after transection.
Histological evaluation was performed at 10 weeks after transection. Each
dependent variable was analyzed using a 2-way analysis of variance with 1 between
variable (groups) and 1 within repeated measures variable (days after
transection). RESULTS: Statistical analysis indicated that N1 (the negative
deflection of depolarization phase of the muscle and/or nerve fibers) area, N1
amplitude, and N1 duration, as well as absolute amplitude of the compound action
potentials, were all significantly greater 2 weeks after transection in the
experimental than in the control group of rats. The force of eye and whisker
movements after electrical stimulation was statistically greater in the
experimental group of rats 4 weeks after transection. Voluntary eye movements in
the experimental group were significantly better at 5 and 10 weeks, while whisker
movements were better at 3 and 10 weeks. There was no statistical difference
between the 2 groups for any histological variable. CONCLUSION: Results of this
study indicate that pulsed electromagnetic stimulation enhances early
regeneration of the transected facial nerve in rats.
PMID- 9559685
TI - Laryngeal abductor reinnervation with a phrenic nerve transfer after a 9-month
delay.
AB - BACKGROUND: Successful restoration of laryngeal abductor function, using the
phrenic nerve, has been described in the cat model in the acute phase. However,
in clinical practice there is usually a considerable delay between injury to the
RLN and presentation for treatment. Delayed reinnervation therefore would be more
suitable in clinical practice. OBJECTIVE: To test the feasibility of delayed
selective abductor reinnervation following transection of the recurrent laryngeal
nerve (RLN). MATERIALS AND METHODS: In 12 cats, the right RLN was severed. Nine
months later, the phrenic nerve was anastomosed to the distal RLN stump with all
its branches directed toward the posterior cricoarytenoid muscle. For 10 weeks
after the reconstruction, electromyography and videolaryngoscopy were performed
weekly. Finally, histological analysis of the RLN was performed. RESULTS:
Evaluation was possible in 11 cats. Reinnervation of the right posterior
cricoarytenoid muscle with the phrenic nerve occurred in 10 cats following nerve
anastomosis, but results of videolaryngoscopy showed adequate to good abduction
in only 4 cats. The main limiting factor was reduced mobility of the
cricoarytenoid joint. Evidence of spontaneous subclinical reinnervation after the
delay was observed in 7 cats but apparently did not impede the surgical
reinnervation. CONCLUSIONS: Delayed selective laryngeal abductor reinnervation
was feasible, but function recovery was less successful than if performed
immediately. Future investigations should concentrate on early determinants of
spontaneous restoration of function to allow early selection of patients who are
eligible for reinnervation surgery.
PMID- 9559686
TI - Comparison of surgical complications after organ-preservation therapy in patients
with stage III or IV squamous cell head and neck cancer.
AB - OBJECTIVE: To determine the incidence of minor and major complications in
patients with squamous cell carcinoma of the upper aerodigestive tract who
require surgical salvage or planned neck dissection after an initial treatment
regimen with radiotherapy or concurrent chemoradiotherapy for organ preservation.
DESIGN: The medical records of 100 patients treated in a phase 3 trial comparing
radiotherapy alone with concurrent chemoradiotherapy for stage III and IV head
and neck squamous cell carcinoma were reviewed. Fifty-four patients underwent 59
surgical procedures. Twenty-nine planned neck dissections were performed for
persistent neck disease or initial stage N2 or greater. For persistent or
recurrent disease at the primary site, 30 salvage operations were performed.
SETTING: Academic tertiary care referral center. RESULTS: Complications occurred
in 15 (46%) of the 33 procedures in the radiation-only group and 12 (46%) of the
26 procedures in the chemoradiotherapy group. Major complications occurred in 4
(12%) of the procedures in the radiation-only group and 3 (12%) of the procedures
in the chemoradiotherapy group. The incidence of minor complications was 33% and
35% in the radiation-only and chemoradiotherapy groups, respectively. The major
complication rate for salvage operations did not differ between the radiation
only and chemoradiotherapy groups (16% and 27%, respectively; P=.79 by chi2
test). The incidence of major complications in planned neck dissections was 7% of
the radiation-only group and 0% of the chemoradiotherapy group. CONCLUSIONS:
After radiation or concurrent chemoradiotherapy, surgery can be performed with an
acceptable rate of major complications. Adding chemotherapy did not increase the
incidence of surgical complications. These results differ from other reports in
the literature.
PMID- 9559687
TI - Complications of microvascular head and neck surgery in the elderly.
AB - OBJECTIVES: To evaluate the complications of head and neck reconstruction using
microvascular free tissue transfers (MFTTs) performed in an elderly population
and to determine whether these complications are more common than in a younger
population. SETTING: Tertiary referral center. PATIENTS AND DESIGN:
Retrospective, consecutive chart review of patients older than 70 years who
underwent MFTT in the past 5 years (group 1). The complications in this
population were compared with those in a second group (group 2) of consecutive
patients younger than 70 years who were matched according to the site of the
primary tumor. MAIN OUTCOME MEASURES: Surgical and medical complications.
RESULTS: The median age for group 1 was 74 years and for group 2, 55 years. The
overall complication rate for group 1 was 48%, compared with 57% for group 2. In
group 1, surgical morbidity was less common and medical morbidity was more common
than in group 2. Mortality rate was 6% for group 1 and 0% for group 2. The types
of complications were similar for both groups. There was no difference in
complication rates when complications were classified by site of the defect,
patient status determined by American Society of Anesthesiologists
classification, or use of preoperative radiation. The overall success rate of
MFTT was 100% for group 1 and 94% for group 2. CONCLUSIONS: Microvascular free
tissue transfers for head and neck reconstruction can be safely performed in the
elderly. An age older than 70 years does not increase the rate of surgical
complications following head and neck reconstruction with MFTT. Medical
complications, however, are more common and are equally divided between
bronchopulmonary and cardiovascular effects.
PMID- 9559688
TI - The effects of more conservative neck dissections and radiotherapy on nodal
yields from the neck.
AB - OBJECTIVE: To determine the effects of conservative neck dissections (NDs) and
preoperative radiotherapy on the quantitative recovery of lymph nodes from the
neck. DESIGN: Retrospective review of case series. Data were obtained for age,
preoperative TNM staging, type of ND, preoperative radiotherapy, total nodal
yield (tNY), and positive nodal yield (pNY). The tNY and pNY were analyzed with
factorial analysis of variance (ANOVA) to determine differences among types of ND
and the effect of radiotherapy. SETTING: Tertiary care center for head and neck
cancer. PATIENTS: Consecutive sample of 135 NDs in 110 patients with cancer of
the head and neck. RESULTS: A significant difference in tNY was found among
dissections (P<.001, ANOVA). Supraomohyoid ND had a significantly lower mean tNY
(9.9 nodes) than both radical ND and modified radical ND (21.8 and 26.3 nodes,
respectively; P<.05). Functional ND also had a significantly lower tNY (16.1
nodes) than modified radical ND (P<.05); the differences between radical ND and
both functional ND and modified radical ND were not statistically significant.
Positive nodal yield was not different among the types of dissections (P=.62).
Preoperative radiotherapy significantly decreased mean tNY from 22.0 to 17.1
nodes (P=.02) over all types of dissections. Differences in tNY among dissection
types were independent of the effect of radiotherapy. The presence or absence of
preoperative radiotherapy had no significant effect on pNY (P=.18). CONCLUSIONS:
Conservative modifications of the classic radical ND differ with respect to the
quantity of cervical lymph nodes excised, but survival may not be altered since
the pNY is not significantly different. When compared with the radical ND, the
modified radical ND and functional ND do not compromise the quantity of cervical
nodes excised. Radiotherapy significantly reduces the quantity of cervical nodes,
but a significant number of nodes will still remain.
PMID- 9559689
TI - Relationship between tympanic membrane perforations and retained ventilation
tubes.
AB - OBJECTIVES: To determine the effects of prolonged ventilation tube retention on
tympanic membrane healing and the efficacy of patching procedures used
concomitantly at the time of tube removal. DESIGN: Retrospective chart review.
SETTING: Tertiary referral academic institution. PATIENTS: Seventy-six patients
aged 12 years and younger, with a total of 99 ears identified from January 1989
to December 1994. All patients underwent ventilation tube removal for prolonged
tube retention or infection unresponsive to medical management. A minimum of 6
months of follow-up was required for inclusion. INTERVENTION: Ventilation tube
removal under general anesthesia, with or without concomitant patching. OUTCOME
MEASURES: All medical charts were reviewed for age, sex, indications for tube
removal, tube retention time, type of patch used (if any), type of tube, outcome
after removal, other medical problems, and previous surgical history. RESULTS:
The perforation rate was significantly higher in children with tubes retained
beyond 36 months (P=.02). History of previous adenoidectomy predicted poor
outcome, with a rate of 47% vs 17% in patients with no such history (P=.002).
Patching did not improve healing. No other patient factors significantly
influenced the perforation rate. CONCLUSIONS: Ventilation tube retention longer
than 36 months resulted in an increased perforation rate after surgical removal.
Paper patching at the time of tube removal does not improve healing. Prospective
studies are needed to confirm these findings and to determine the efficacy of
other patching techniques.
PMID- 9559690
TI - Hearing loss due to myringotomy and tube placement and the role of preoperative
audiograms.
AB - BACKGROUND: Postoperative complications of myringotomy and tube placement often
include otorrhea, tympanosclerosis, and tympanic membrane perforation. However,
the incidence of sensorineural or conductive hearing loss has not been
documented. Recent efforts to curb the use of preoperative audiometric testing
requires documentation of this incidence. OBJECTIVE: To define the incidence of
conductive and sensorineural hearing loss associated with myringotomy and tube
placement. MATERIALS AND METHODS: A retrospective chart review of 550 patients
undergoing myringotomy and tube placement was performed. A total of 520 patients
undergoing 602 procedures (1204 ears), including myringotomy and tube placement,
were assessed for preoperative and postoperative sensorineural and conductive
hearing loss. RESULTS: No patient developed a postoperative sensorineural or
conductive hearing loss. All patients resolved their conductive hearing loss
after myringotomy and tube placement. There was a 1.3% incidence of preexisting
sensorineural hearing loss. CONCLUSIONS: The incidence of sensorineural or
conductive hearing loss after myringotomy and tube placement is negligible and
the use of preoperative audiometric evaluation may be unnecessary in selected
patients, but further studies need to be done to corroborate this small data set.
PMID- 9559691
TI - The role of second-look nasal endoscopy after pediatric functional endoscopic
sinus surgery.
AB - OBJECTIVE: To determine if second-look nasal endoscopy (SLE) improves clinical
outcome after pediatric functional endoscopic sinus surgery (FESS). DESIGN: A
retrospective review was performed for all patients who had undergone FESS
between January 1993 and December 1994. The patients were divided into 2 groups:
those who underwent SLE 2 to 3 weeks after FESS (n=94) and those who did not
undergo SLE after FESS (n=53). Patients with a history of cystic fibrosis, bone
marrow transplantation, or isolated sphenoidal sinus disease were excluded from
the study. SETTING: Pediatric tertiary care hospital. PATIENTS: All patients had
a diagnosis of chronic rhinosinusitis, had failed medical therapy, and had
subsequently undergone FESS. MAIN OUTCOME MEASURES: The need for revision sinus
surgery was used as the definition for poor clinical outcome, indicating that
sinus disease recurred or was persistent. The number of patients requiring
revision sinus surgery in each group was compared. RESULTS: Revision surgery was
performed in 20 of the 94 patients who underwent SLE after FESS. Revision surgery
was performed in 10 of the 53 patients who did not undergo SLE after FESS. Six
patients in the "no-second-look group" underwent follow-up nasal endoscopy at
some time after the initial FESS. There was no significant difference in terms of
clinical outcome between the 2 groups. CONCLUSIONS: The rate of revision sinus
surgery was comparable in those patients who underwent SLE after FESS and those
who did not. The usefulness and application of SLE need to be considered
carefully.
PMID- 9559692
TI - Interstitial Nd:YAG photocoagulation for vascular malformations and hemangiomas
in childhood.
AB - BACKGROUND: Vascular malformations and cavernous hemangiomas are common in
childhood. Although cavernous hemangiomas may resolve spontaneously, aggressive
intervention is required when their growth could damage vital adjacent
structures, such as the orbit, nose, or tongue. OBJECTIVE: To evaluate the
efficacy of interstitial Nd:YAG photocoagulation as an adjunct to intralesional
and systemic corticosteroids for treatment of hemangiomas and vascular
malformations that had failed to respond to other therapies. DESIGN: Prospective,
nonrandomized trial. SETTING: Two referral practices of facial plastic and
reconstructive surgery in tertiary care, academic medical centers. PATIENTS: Ten
consecutive pediatric patients with either hemangioma or vascular malformation of
the head and neck. INTERVENTION: Laser photocoagulation with an interstitial
technique. The Nd:YAG fiber was introduced into the lesion via a 14-gauge
angiocatheter needle, and the laser fiber was advanced as coagulation proceeded
within the tissue. MAIN OUTCOME MEASURES: Decrease in the area of the target
lesion, amount of energy applied, and number of treatments required to achieve
reduction in size. RESULTS: Long-term follow-up demonstrated regression of the
lesion in all 10 patients with good cosmetic results. The range of reduction in
size was 20% to 98%. No reexpansion of the lesions was noted after a mean follow
up of 13 months. CONCLUSIONS: Interstitial photocoagulation of hemangiomas and
vascular malformations is an effective treatment for carefully selected patients.
When properly applied, this technique can achieve reduction in the size of these
lesions without compromising cosmesis.
PMID- 9559693
TI - Serum level of placental growth hormone is raised in pregnancy rhinitis.
AB - OBJECTIVE: To describe any relationship between pregnancy rhinitis and weight
gain or serum levels of estradiol, progesterone, placental growth hormone, or
insulinlike growth factor I. PATIENTS: Twenty-seven nonsmoking healthy pregnant
women aged 22 to 38 years (mean age, 28 years) who had no history of respiratory
allergy or chronic nasal or sinus problems volunteered to enter the study. They
had no nasal complaints at entry. METHODS: Nasal patency was registered daily
from early pregnancy until 1 month after delivery. Nasal and oral peak expiratory
flow rates were established, and the subjective blockage was scored from 0 to 4,
with 0 indicating no blockage. Serum samples were collected and weight was
measured on 4 occasions during pregnancy and again at the end of the study.
Pregnancy rhinitis was diagnosed if the subjective nasal obstruction score was 1
or higher every morning for at least 6 weeks immediately preceding delivery, then
returned to 0 within 2 weeks and remained at 0 until the end of the study. If on
any day other signs of respiratory tract infection occurred, that day was
excluded. RESULTS: Pregnancy rhinitis was diagnosed in 5 women. These 5 women
showed significantly higher levels of placental growth hormone than the women
without the diagnosis. No significant difference was found between the 2 groups
regarding body weight or any of the other serum levels studied. CONCLUSIONS:
Serum level of placental growth hormone is raised in pregnancy rhinitis and may
be involved in its pathogeny. Pregnancy rhinitis does not significantly raise
weight gain or serum levels of estradiol, progesterone, or insulinlike growth
factor I.
PMID- 9559694
TI - Effects of rigid plate fixation and subsequent removal on craniofacial growth in
rabbits.
AB - OBJECTIVE: To examine the effects of rigid plate fixation (RPF) and subsequent
removal on craniofacial growth in rabbits. DESIGN: Randomized controlled
experiment. SUBJECTS: Thirty-two 6-week-old male New Zealand white rabbits.
INTERVENTIONS: Group 1 underwent exposure of the left nasofrontal suture and
midzygomatic arch; group 2, RPF of the left nasofrontal suture and midzygomatic
arch areas; group 3, single osteotomy at left nasofrontal suture and double
osteotomies at midzygomatic arch with RPF of osteotomies; and group 4, controls.
At 11 weeks of age, the RPF was removed. Animals were killed at 20 weeks of age.
Linear and 3-dimensional measurements (euclidean distance matrix analysis) were
used to evaluate craniofacial regions. RESULTS: In comparison with control
animals, linear data showed shortening of the left nasal bone in group 3. Groups
1 through 3 also exhibited shortening of the left zygomatic arch, orbital
diameter, and anterior midfacial height. Euclidean distance matrix analysis
showed significant restrictive shape alterations on both the ipsilateral and
contralateral sides in groups 1 through 3. In comparison with animals in which
RPF was left in place, linear data showed significant shortening of the orbital
diameter in groups 1 through 3 and of anterior midface height in groups 2 and 3.
Euclidean distance matrix analysis showed significant restrictive shape
alterations on both contralateral and ipsilateral sides. CONCLUSION: Rather than
preventing restrictive growth disturbances to the growing midface in rabbits, RPF
with subsequent removal produces a greater amount of restrictive shape alteration
than RPF that is left in place.
PMID- 9559695
TI - The tension wire method: a simple, effective means of mandibular fixation.
AB - OBJECTIVE: To investigate the use of a tension wire band secured to monocortical
screws for open reduction and internal fixation of simple, displaced, and/or
unstable mandibular fractures. DESIGN: Retrospective review with follow-up
duration of at least 6 weeks. SETTING: Level I university trauma center.
PATIENTS: Twenty-nine patients (27 males and 2 females), aged 7 to 46 years. Ten
patients had unilateral fractures (1 patient had 3 separate unilateral fractures)
and 19 had bilateral fractures; 34 of 50 fractures were displaced; 19 were open
intraorally. The location of fractures and the number (number repaired) were as
follows: symphysis or parasymphysis, 13 (10); body, 9 (8); angle, 18 (14); ramus,
6 (4); and subcondylar, 4 (0). Two fractures were each comminuted into 3
fragments, and 1 patient had unilateral parasymphysial, body, and ramus
fractures. INTERVENTION: Intermaxillary fixation was done in all patients except
1 child. Intraoral approaches were used exclusively. A pair of monocortical 2.0
mm screws were placed perpendicular to fracture lines, with 24-gauge wire loops
passed around the screws and tightened to bring the fracture into reduction and
provide stable fixation. A percutaneous trocar system was used to insert screws
at the body, angle, and ramus sites. RESULTS: There were no instances of
infection, malunion, or malocclusion in the 33 fractures repaired with this
technique. A typical intermaxillary fixation with open reduction and internal
fixation of a posterior fracture was done in less than 2 hours. CONCLUSION: Open
reduction and internal fixation of simple mandibular fractures with tension wire
bands around monocortical screws is a simple, quick, and effective technique.
PMID- 9559696
TI - Gamma probe-directed biopsy of the sentinel node in oral squamous cell carcinoma.
AB - OBJECTIVE: Management of the N0 neck in head and neck squamous cell carcinoma is
an important issue for the head and neck surgeon. Experience with radionuclide
labeled colloid injection to identify a sentinel node in malignant melanoma
suggests a high level of accuracy for this approach to identify microscopic
metastasis when present. We set out to explore the feasibility of using the
handheld gamma probe to identify radiolabeled sentinel nodes in oral squamous
cell carcinoma. PATIENT POPULATION: Five individuals with N0 necks and accessible
oral or oropharyngeal primary sites from a major tertiary referral center.
METHODS: Radiolabel with unfiltered technetium Tc 99m sulfur colloid was injected
in quadrants around the primary site followed by immediate dynamic
lymphoscintigraphy. Open biopsy of the sentinel node was accomplished within 2
hours of injection after extirpation of the primary site. Regional or complete
neck dissection was performed after sentinel node biopsy. RESULTS: Sentinel node
biopsy accurately identified one or several nodes in 2 cases, including nodes
containing metastatic cancer in 1. In the other 3 cases, the radiolabel failed to
identify the sentinel node despite the presence of metastatic disease in the
nodes at final pathologic study in 2. CONCLUSIONS: Detection and biopsy of the
sentinel node are feasible for selected patients with oral head and neck squamous
cell carcinoma with N0 necks. There is a potential savings of time, cost, and
morbidity with this approach. However, several substantial problems were
encountered with the technique in this limited series of patients. Establishing
the reliability of lymphoscintigraphy in this setting would require testing in a
much larger patient cohort. Our experience suggests that such an investment may
not be warranted.
PMID- 9559697
TI - Pulsatile tinnitus cured by angioplasty and stenting of petrous carotid artery
stenosis.
AB - Pulsatile tinnitus may result from turbulent flow within the ipsilateral internal
carotid artery. Surgical endarterectomy and carotid artery ligation have been
used to treat atherosclerotic stenosis with or without associated pulsatile
tinnitus. To our knowledge, this is the first reported case of pulsatile
tinnitus, attributable to internal carotid artery stenosis, successfully treated
by angioplasty and stenting.
PMID- 9559699
TI - Pathologic quiz case 1. Nevus sebaceus.
PMID- 9559698
TI - Histopathological features of a cochlear implant and otogenic meningitis in
Mondini dysplasia.
AB - The temporal bones of a 6-year-old boy with a cochlear implant for profound
hearing loss associated with Mondini dysplasia were studied histopathologically.
Despite having severe Mondini dysplasia, he was able to detect sound with the
implant. On histological examination of the temporal bone, he had more than 10000
spiral ganglion cells. Histopathological changes in the inner ear associated with
the cochlear implant were minimal. Patients with severe Mondini dysplasia and
profound hearing loss may, therefore, benefit from cochlear implantation. In the
contralateral ear, the patient had suppurative labyrinthitis and meningitis
associated with chronic otitis media. Histopathological evidence of inflammatory
necrosis of the round window membrane was consistent with suppurative
labyrinthitis secondary to otitis media.
PMID- 9559700
TI - Pathologic quiz case 2. Tracheal tuberculosis (TB).
PMID- 9559701
TI - Laryngeal electromyography is a cost-effective clinically useful tool in the
evaluation of vocal fold function.
PMID- 9559702
TI - Clinical value of laryngeal EMG is dependent on experience of the clinician.
PMID- 9559703
TI - Laryngeal EMG in clinical neurolaryngology [.
PMID- 9559704
TI - Methodological difficulties in assessing contributions by community-based
organizations to improving child health.
PMID- 9559705
TI - Supporting child psychiatric services using current managed care approaches: you
can't get there from here.
AB - For-profit behavioral health care companies have transformed the way mental
health services are provided for children. Using marketplace approaches,
companies have "carved out" mental health services for many patients receiving
care from pediatricians. This report details specific approaches used by these
firms to maximize profits, minimize the role of child and adolescent
psychiatrists, and limit clinical services. Understanding for-profit carveouts
will help primary care pediatricians appreciate the likely consequences of such
reimbursement incentives for the care of children and their families.
PMID- 9559706
TI - The impact of interventions by a community-based organization on inner-city
vaccination coverage: Fulton County, Georgia, 1992-1993.
AB - OBJECTIVE: To evaluate the impact of interventions by a community-based
organization on immunization rates. DESIGN: Controlled community intervention
trial. SETTING AND PARTICIPANTS: Children aged 3 to 59 months in Fulton County,
Georgia, who were patients of 1 of 4 public clinics (clinic based), or residents
of 1 of 9 inner-city communities (residence based). INTERVENTIONS: (1) Clinic
based intervention included monthly review of clinic vaccination records to
identify undervaccinated children followed by contact with family (reminder
recall strategy); (2) residence-based intervention included door-to-door
assessment and education campaigns followed by mobile van vaccinations, temporary
on-site vaccination stations, free child care and transportation to providers,
incentives of food and baby products, focus groups, and coalitions with local
organizations (community saturation with vaccination messages and opportunities).
OUTCOME MEASURES: Change in vaccination rates after 1 year based on clinic record
reviews and population surveys. RESULTS: For clinic-based intervention, series
completion rates improved from 43% (87/204) to 58% (99/170) in intervention
clinics (P=.003), while rates in control clinics did not change from the baseline
of 52% (81/157 to 78/150), for a net difference between intervention and control
arms of +15 percentage points (P=.046). For residence-based intervention, age
appropriate vaccination rates improved from 44% (154/347) to 61% (260/429) in
intervention communities (+17 percentage points; P<.001) compared with
improvement of 44% (78/178) to 58% (129/221) for control communities (+14
percentage points; P=.004), but the difference between arms was not significant
(+3 percentage points, P=.78). CONCLUSIONS: Reminder-recall activities by the
community-based organization improved vaccination rates in intervention clinics
compared with control clinics. A statistically significant impact on vaccination
rates could not be detected for residence-based interventions by the community
based organization.
PMID- 9559707
TI - Reported difficulties in access to quality care for children with asthma in the
inner city.
AB - OBJECTIVE: To characterize perceived access and barriers to quality health care
for asthma among the caregivers of children in the inner city. DESIGN:
Multicenter, cross-sectional survey. SETTING: Eight sites in 7 major metropolitan
US inner cities. PARTICIPANTS: A systematic sample of children with asthma, aged
4 to 9 years, and their caregivers who resided in census tracts in which at least
30% of the households were below the 1990 federal poverty guidelines, recruited
from 25 primary care clinics and 13 emergency departments (EDs) from November 1,
1992, through October 31, 1993. RESULTS: Of the 1528 children enrolled, 1376 had
physician-diagnosed asthma and form the basis of this report. This group was
further divided into 284 children (20.6%) who met all recruitment criteria for
severe asthma and 207 (15.0%) with mild asthma who met none. Of parents in the
total sample, 95.6% reported a usual place for short-term asthma care for their
child; 75.4% used the ED. Children with severe asthma were significantly more
likely to use the ED than those with mild asthma (84.3% vs 63.0%; P<.01). A usual
place for follow-up asthma care was reported by 96.7% of subjects. There were no
differences in access or type of facility used by asthma severity. More than half
the study group reported difficulty in accessing care for acute asthma attacks
and for follow-up care with no differences by asthma severity. Among those with
severe asthma, 47.5% used inhaled steroids or cromolyn, 52.8% used a spacer
device if they had been prescribed a metered dose inhaler, and 21.2% of children
older than 6 years were prescribed a peak flowmeter. Patients with mild asthma
were significantly less likely to report use of all 3 items (steroids or
cromolyn, 1.4%; spacer device, 15.4%; and peak flowmeter, 3.1%, respectively;
P<.01). CONCLUSION: Although access to asthma care among children in US inner
cities appears adequate as determined by the traditional measure of reporting a
regular source of care, barriers are frequently reported, as are deficiencies in
the quality of medical care.
PMID- 9559708
TI - Errors in the use of medication dosage equations.
AB - BACKGROUND: Calculation errors in prescribing are a well-recognized problem;
however, no systematic studies of actual errors involving calculation or other
errors in the use of drug dosage equations are available. OBJECTIVE: To
characterize the nature and potential adverse consequences of actual prescribing
errors involving dosage equations. DESIGN: Analysis of the characteristics of 200
consecutive prescribing errors with potentially adverse outcomes involving dosage
equations. SETTING: Tertiary care teaching hospital. MEASUREMENTS: Potential
adverse outcomes, prescribing service, medication class, and the process point at
which the error was made. RESULTS: Errors most commonly involved children (69.5%)
and antibiotics (53.5%). Forty-two percent of errors were considered to put the
patient at risk for a serious or severe preventable adverse outcome. Errors in
decimal point placement, mathematical calculation, or expression of dosage
regimen accounted for 59.5% of dosage errors. The dosage equation was wrong in
29.5% of dosage errors. CONCLUSIONS: The use of equations to determine medication
dosages presents considerable risk to patients for errant dosing and subsequent
adverse events or therapeutic failure. Errors may occur in any component of a
dosage equation. Health care organizations should implement procedures to reduce
the risk for errors resulting from the use of dosage equations.
PMID- 9559709
TI - Is bone marrow aspiration needed in acute childhood idiopathic thrombocytopenic
purpura to rule out leukemia?
AB - OBJECTIVE: To assess the prevalence of leukemia in a series of bone marrow
aspiration (BMA) samples collected to confirm provisional diagnoses of acute
idiopathic thrombocytopenic purpura (ITP) in children. DESIGN: A retrospective
cohort. SETTING: All BMA reports at The Hospital for Sick Children, Toronto,
Ontario (a tertiary care pediatric hospital), from January 1, 1984, to May 31,
1996, were reviewed. PATIENTS: Included were BMAs performed to confirm
provisional diagnoses of ITP in children (6 months to 18 years of age) with
"typical" contemporaneous hematologic features of ITP (platelet count, < or =50 x
10(9)/L; hemoglobin level, > or =100 g/L [6-12 months of age] or > or =110 g/L [>
1 year of age]; white blood cell count, > or =5 x 10(9)/L [6 months to 6 years of
age] or > or =4 x 10(9)/L [> 6 years of age]; and neutrophil count, > or =1.5 x
10(9)/L [6 months to 6 years of age] or > or =2 x 10(9)/L [> 6 years of age]).
Children with chronic ITP, thrombocytopenia-related chronic conditions, or
leukemic blasts on peripheral smears were excluded. MAIN OUTCOME MEASURE: The
finding of leukemia in the BMA report was chosen a priori as the primary outcome
for the yield of BMA. RESULTS: Four hundred eighty-four BMAs were performed to
confirm provisional diagnoses of acute childhood ITP. No diagnoses of leukemia
were revealed in the 332 children with typical hematologic features of ITP. The
risk of missing the diagnosis of leukemia in this setting is less than 1%.
CONCLUSIONS: The yield of BMA for leukemia in this setting is low. Routine BMA is
not necessary for children with typical acute ITP.
PMID- 9559710
TI - Antibiotics for colds in children: who are the high prescribers?
AB - OBJECTIVE: To examine physician characteristics associated with being a high
prescriber of antibiotics for pediatric upper respiratory tract infections
(URIs). DESIGN AND SETTING: Analysis of 34624 episodes of care for URIs in
children (younger than 18 years) in the Kentucky Medicaid program from July 1,
1995, to June 30, 1996. PARTICIPANTS: Primary care physicians with at least 25
episodes of care (n=205). The proportion of patients with URIs receiving
antibiotics stratified the sample into low (< or =25th percentile) and high (> or
=75th percentile) antibiotic prescribers. MAIN OUTCOME MEASURES: Bivariate
analyses were computed comparing the high and low prescribers. A logistic
regression model was computed for likelihood of being a high prescriber by number
of URI episodes, proportion of patients receiving antibiotics that were broad
spectrum, years since medical school graduation, physician gender, rural/urban
practice, and specialty. RESULTS: The high prescriber group (n=52) included data
from 11899 episodes of care, with a mean prescribing rate of 80%. The low
prescriber group (n=55) included data from 5396 episodes, with a mean prescribing
rate of 16%. High prescribers were significantly more years away from medical
school graduation (27 vs 19 years; P<.001) and had managed significantly more URI
episodes than low prescribers (229 vs 98; P=.001). In the logistic regression,
compared with pediatricians, the odds ratios of being a high prescriber were 409
(95% confidence interval [CI], 29-7276) for family practitioners and 318 (95% CI,
17-6125) for other primary care physicians. CONCLUSION: With the rise of
antibiotic-resistant bacteria, more focused training regarding treatment of URIs
is warranted in residency and in continuing medical education forums.
PMID- 9559711
TI - Contribution of long-bone radiographs to the management of congenital syphilis in
the newborn infant.
AB - OBJECTIVE: To determine the contribution of long-bone radiographs to the
diagnosis and management of newborn infants at risk for congenital syphilis.
DESIGN: Historical cohort. SETTING: Three large hospitals in Houston, Tex.
PATIENTS: Eight hundred fifty-three live born infants who were evaluated for the
presence of congenital syphilis. INTERVENTION: Long-bone radiographs done as part
of the diagnostic evaluation for the presence of congenital syphilis. MAIN
OUTCOME MEASURE: Changes in diagnostic classification or management decisions
that were based on radiographic findings in the long bones. RESULTS: For 450
infants, radiographic results did not affect management because clinical or
historical factors were present that dictated treatment: 26 infants had clinical
symptoms of congenital syphilis (65% [17] had abnormalities on radiographs); and
424 infants were born to mothers who were untreated or reinfected (5.9% [25] had
abnormalities on radiographs). All of these infants required a full course of
therapy regardless of radiologic findings. Born to mothers with possibly
inadequate therapy (according to 1993 Centers for Disease Control and Prevention
guidelines), 237 asymptomatic newborn infants were candidates for a single
injection of penicillin G benzathine if the results of their evaluations were
normal; of these, 2 (0.8%) had abnormal radiographic findings. Of the 166 infants
born to adequately treated mothers with appropriately falling serologic titer
levels, 1 (0.6%) had abnormal radiographic findings (P=.99 between groups). The
results of the long-bone radiographs did not alter management for any of the 853
infants who were evaluated for congenital syphilis. CONCLUSIONS: Long-bone
radiographic findings, often abnormal in symptomatic infants, do not
differentiate between active infection and past infection. The use of long-bone
radiographs should be reconsidered in the routine evaluation of infants for
congenital syphilis.
PMID- 9559712
TI - A number-needed-to-treat analysis of the use of respiratory syncytial virus
immune globulin to prevent hospitalization.
AB - OBJECTIVES: To estimate how many infants in selected high-risk subgroups would
require treatment with respiratory syncytial virus immune globulin (RSV-IG) to
avoid 1 hospital admission and to determine whether this is economically
justified. DESIGN: Cost-benefit analysis. Data from 3 randomized controlled
trials of RSV-IG are used to estimate the number needed to treat to prevent 1
hospital admission for respiratory syncytial virus infection. The threshold
number needed to treat is computed according to a formula incorporating costs and
benefits of RSV-IG prophylaxis. Estimates of the willingness to pay were obtained
from a sample of 39 health care providers (35 physicians and 4 nurses). MAIN
OUTCOME MEASURES: The number needed to treat to prevent 1 hospital admission for
respiratory syncytial virus infection. The threshold number needed to treat that
would balance costs with benefits. RESULTS: More than 16 (95% confidence
interval, 12.5-23.8) infants would need to be treated with RSV-IG to avoid 1
hospital admission for respiratory syncytial virus infection, ranging from 63 for
premature infants without chronic lung disease to 12 (confidence interval, 6.3
100.0) for infants with bronchopulmonary dysplasia. A sensitivity analysis of the
costs and values of hospital admission for respiratory syncytial virus infection
and RSV-IG treatment resulted in a weak recommendation against the treatment of
infants with bronchopulmonary dysplasia and strong recommendations that the costs
and risks of RSV-IG treatment outweigh the benefits for the combined sample of
infants and premature infants without lung disease. CONCLUSIONS: The number
needed-to-treat procedures offer a method to assess evidence of treatment effects
and decision rules for whether to accept treatment recommendations. Under
plausible assumptions, treatment with RSV-IG is not recommended for infants
without lung disease. Institutions can examine cost and benefit assumptions that
best fit their own practice setting.
PMID- 9559713
TI - Identification of psychosocial problems in pediatric primary care: do family
attitudes make a difference?
AB - OBJECTIVE: To evaluate the affect of families' attitudes about the
appropriateness of discussing psychosocial concerns on pediatric providers'
identification of psychosocial problems. DESIGN: These data were collected as
part of the Greater New Haven Child Health Study, New Haven, Conn. The study
design was a prospective cohort. SETTING: Families were recruited from a
stratified random sample of all primary care practices in the greater New Haven
area. Nineteen of 23 invited practices agreed to participate including 2 prepaid
practices, 2 neighborhood health centers, and 7 fee-for-service group and 8 fee
for-service solo practices. PARTICIPANTS: All families of children aged 4 to 8
years who attended these practices during 2 separate 3-week periods (1 in fall
1987 and 1 in spring 1988) were invited to participate in the study. Families
were invited to participate only once, on the first contact with any eligible
child, using approved procedures. Of 2006 eligible families, 1886 (94%) chose to
participate. MAIN OUTCOME MEASURE: The outcome variable for these analyses is the
identification of any behavioral, emotional, or developmental problem by the
pediatrician on the 13-category checklist. Overall, pediatric clinicians
identified 27.5% of children with 1 or more psychosocial problems. RESULTS: Our
data suggest that there is a great deal of discrepancy between what parents
report is appropriate to do when their children have psychosocial problems and
what they actually do when they recognize such problems in their children. Most
(81.1%) believed it was appropriate to discuss 4 or more of the 6 hypothetical
situations with their children's physician, while only 40.9% actually did discuss
any of these problems with a physician when a problem occurred. Given the
correlates of parents who intended to discuss such problems (higher education,
older age, Euro-American ethnicity, higher income, married, availability of
medical insurance) the possibility that parents are providing socially acceptable
responses to such questions seems likely. Further, our data indicate that
parents' actual reports of discussions of psychosocial problems is unrelated to
whether physicians identified those problems in children. CONCLUSIONS:
Pediatricians'judgments about the presence of psychosocial problems in their
young patients seem to be based on their own observations rather than on what
parents report. Physician-parent communication about psychosocial problems will
be increasingly important as primary care physicians assume their role as
gatekeepers to more expensive services such as mental health interventions.
PMID- 9559714
TI - Do pediatricians counsel families about sun protection?: a Massachusetts survey.
AB - BACKGROUND: Pediatric visits during summer months may be especially opportune
times for sun protection counseling for children and their parents. Few data
exist on the extent of such counseling. OBJECTIVE: To begin to assess this, we
surveyed practicing Massachusetts pediatricians to examine current attitudes and
practices of sun protection counseling. DESIGN AND SETTING: Surveys mailed to
Massachusetts pediatricians. RESULTS: We received surveys from 756 (60%) of 1263
eligible Massachusetts pediatricians. Almost 70% indicated that they recommended
safe sun practices to more than 50% of their patients and their parents during
the summer months. Counseling regarding seat belt use, bicycle helmet use, and
smoking prevention were ranked higher in priority than sun protection counseling
by pediatricians; nutritional guidelines were noted by pediatricians to be a
parent's most frequent concern. Four variables were independently associated with
a practitioner's providing safe sun recommendations to more than 50% of parents
and children: (1) private setting and health maintenance organization
practitioners as opposed to academic physicians, (2) high ranking of patients'
safe sun knowledge, (3) high priorities of both parents and physicians for sun
protection counseling and parental knowledge of safe sun practices relative to
other recommendations, and (4) pediatrician interest in receiving instructional
materials. CONCLUSIONS: For the most part, summer sun protection counseling among
Massachusetts pediatricians seems well integrated into standard practice. Most
pediatricians rated their confidence level as high for discussing sun protection
and only a few cited inadequate training or poor reimbursement as barriers toward
improved counseling. Small steps, such as providing more instructional materials
to patients and using office-based reminder systems, may improve the quality of
sun protection counseling practices. Incorporating sunburn prevention into the
list of routinely recommended injury prevention guidelines for pediatricians
should be considered.
PMID- 9559716
TI - Effects of pediatrician characteristics on management decisions in simulated
cases involving apparent life-threatening events.
AB - OBJECTIVES: To study variations in the way pediatricians would evaluate and
manage an infant with an apparent life-threatening event. SUBJECTS AND METHODS: A
survey was mailed to the chief residents of all pediatric residency training
programs in the United States in which respondents were presented with a
simulated case and asked how they would manage an infant who had experienced an
apparent life-threatening event that did not require resuscitation. The survey
also explored each physician's tolerance of uncertainty, knowledge of apparent
life-threatening events, experience, fear of litigation, responsiveness to
parental demands, and propensity to order tests. MAIN OUTCOME MEASURES: Presumed
decisions to prescribe antibiotics and/or order home apnea monitoring in a
simulated case of an infant who had experienced an apparent life-threatening
event not requiring resuscitation. RESULTS: Logistic regression analysis revealed
2 characteristics that made significant and independent contributions to
respondents' presumed decision to prescribe antibiotics: (1) experience with an
adverse outcome, and (2) propensity to order diagnostic tests. Presumed decisions
to order a home apnea monitor were notably affected by fear of litigation.
CONCLUSIONS: These findings suggest that differences in pediatricians'
characteristics contribute to variations in care. Efforts to make management more
uniform must consider that decisions are influenced by a host of different
characteristics and experiences.
PMID- 9559715
TI - Environmental stressors and emotional status of adolescents who have been in
special education classes.
AB - OBJECTIVE: To identify environmental and psychosocial factors associated with
receiving special education services. DESIGN: The 1992 Minnesota Student Survey,
an anonymous, self-report survey. SETTING: Minnesota public schools.
PARTICIPANTS: A total of 121848 adolescents in the 6th, 9th, and 12th grades.
MAIN OUTCOME MEASURES: Emotional status and potential environmental risk factors
including family structure, family substance use problems, family violence, and
sexual abuse were compared between adolescents reporting a history of having been
in classes for learning problems and a grade- and race-matched comparison group
of adolescents who had never been in classes for learning problems. Comparisons
were conducted separately for male and female respondents. RESULTS: Compared with
adolescents who had never been in classes for learning problems, a significantly
greater proportion of male and female students who had been in special education
classes lived in single-parent and nontraditional households, indicated that a
family member had an alcohol or other drug problem, had witnessed or experienced
physical abuse, and reported a history of sexual abuse and poor emotional health.
Most of these associations remained significant when simultaneously controlling
for the other factors in logistic regression. Significant factors showed modest
odds ratios in the multivariate analyses (<1.6), except for the emotional status
variable. Students with a history of receiving special education services had
from 6 to 14 times the odds of reporting poor emotional health. This association
was strongest among the youngest adolescents. CONCLUSION: Several environmental
stressors and psychosocial factors, most notably poor emotional health, are
associated with a history of special class placement for learning problems.
PMID- 9559718
TI - Cat-scratch disease in a child with unique magnetic resonance imaging findings.
AB - OBJECTIVE: To report a patient with cat-scratch disease and the associated
radiological findings. PATIENT: A previously health 10-year-old boy presenting
with fever and joint pain. RESULTS: The presence of multiple abnormal foci in the
bone marrow were noted by magnetic resonance imaging. There was no correlation
with either radionuclide or conventional radiographic imaging findings. The
patient's condition was diagnosed as cat-scratch disease by the demonstration of
elevated antibody titers to the causative organism, Bartonella (formerly
Rochalimaea) henselae. CONCLUSION: Magnetic resonance imaging may be more
sensitive to the early bone marrow changes that can occur with cat-scratch
disease than either radionuclide bone scan or computed tomography.
PMID- 9559717
TI - Predictors of smoking cessation in adolescents.
AB - OBJECTIVE: To examine factors associated with cessation of smoking in adolescents
12 to 18 years of age who smoke cigarettes. DESIGN AND SETTING: Prospective
school-based cohort study of 1384 New Hampshire high school students surveyed at
baseline and annually up to 3 subsequent years regarding their substance abuse
behaviors, including adolescents who smoked 1 or more cigarettes within the past
30 days at baseline. OUTCOME MEASURES: Cessation behavior was defined by a
subsequent response indicating nonsmoking status. We examined associations
between smoking cessation and baseline measurements of the level of addiction
(cigarette consumption pattern), experience with quitting, intent to quit now and
in the future, opinion of adults smoking more than 1 pack of cigarettes per day,
social influences to smoke, sex, and psychological attributes. RESULTS: Of 276
adolescents who qualified as cigarette smokers at baseline, 123 (44.6%) were
occasional smokers, 65 (23.6%) were daily smokers of 1 to 9 cigarettes, and 88
(31.9%) were daily smokers of 10 or more cigarettes. While 39 (14.1%) had smoked
for 1 year or less, 62 (22.5%) had smoked for 6 or more years. Seventy-five
(27.2%) reported failed past attempts to quit smoking, 71 (25.7%) reported
wanting to quit now, and 50 (18.1%) reported definitely intending to be a
nonsmoker in the future. Seventy-nine smokers (28.6%) described themselves as
nonsmokers in follow-up surveys. The smoking cessation rate was 46.3% among
occasional smokers, 12.3% among daily smokers of 1 to 9 cigarettes, and 6.8%
among daily smokers of 10 or more cigarettes. Smoking cessation was associated
with occasional smoking status (adjusted odds ratio 6.67 compared with daily
smokers of 10 or more cigarettes [95% confidence intervals, 2.26-19.69]), and
definite intentions to quit in the future (2.67 [95% confidence intervals, 1.2
5.7]). Most of those with definite intentions to quit in the future were
occasional smokers (92.0%). CONCLUSIONS: This study documents cessation of
smoking in nearly one third of the adolescent smokers. The cessation rate among
daily smokers of 10 or more cigarettes per day is comparable with adult cessation
rates. Adolescents who are less addicted, measured by low frequency of cigarette
use, are more likely than daily users to quit. In addition, definite intent to
quit in the future predicts cessation, but only among occasional smokers. In
contrast with adults, experience with quitting was not associated with a higher
likelihood of cessation. Pediatricians should focus on keeping occasional smokers
from moving into daily smoking status, where nicotine addiction begins to play a
prominent role in maintaining the behavior. Further study is needed to guide
enhancement of the recruitment of adolescents into cessation, assessment of
nicotine dependence in daily adolescent smokers, and appropriate use of nicotine
replacement therapy in this group.
PMID- 9559719
TI - A comparison of performance between third-year students completing a pediatric
ambulatory rotation on campus vs in the community.
AB - OBJECTIVE: To compare the performance of third-year medical students who
completed the ambulatory component of their pediatric rotation in a community
setting with the performance of third-year medical students who had their
ambulatory experience on campus. METHODS: As part of a pilot project to implement
a third-year Multidisciplinary Ambulatory Clerkship, 61 third-year medical
students spent 12 weeks rotating through the primary care disciplines of family
medicine, internal medicine, and pediatric practitioners' offices at sites
distant from the university campus while 127 students remained on campus for
their ambulatory experiences in these disciplines. The components of the overall
pediatric grade consisted of a clinical performance evaluation in the ambulatory
setting (4 weeks), a clinical performance evaluation on a 4-week inpatient
rotation, and a grade from a multiple-choice final examination. RESULTS: The
overall mean+/-SD final pediatric grade of students receiving their ambulatory
pediatrics experience in the Multidisciplinary Ambulatory Clerkship was 86.5+/
3.4 compared with 88.0+/-3.4 for students receiving their ambulatory experience
on campus (P<.007). This difference was accounted for by performance on the
written final examination. Multidisciplinary Ambulatory Clerkship students had a
mean+/-SD score of 78.9+/-8.3 and a failure rate of 18% compared with a mean
score of 83.7+/-8.1 and failure rate of 3.9% for students who remained on campus
for their ambulatory experience (P<.001 for both comparisons). No differences
were noted between the 2 groups on their clinical performance evaluations for
their ambulatory or inpatient experiences. CONCLUSIONS: These data suggest a
difference in the learning experience between students receiving their pediatric
ambulatory experience in the community vs on campus. Differences in exposure to
structured learning experiences that occurred more frequently on campus might
account for some of the difference in final examination results. Development of a
standardized, structured learning experience across community sites would seem to
be an appropriate means of enhancing learning in the community setting.
PMID- 9559720
TI - Radiological case of the month. Jejunojejunal intussusception caused by a
trichobezoar with a tail.
PMID- 9559721
TI - Picture of the month. Generalized lipodystrophy.
PMID- 9559722
TI - Pathological case of the month. Recurrent respiratory papillomatosis.
PMID- 9559723
TI - Two unusual pediatric presentations of sarcoidosis.
PMID- 9559724
TI - Postpartum length of stay.
PMID- 9559725
TI - The physics of bicycle falls revisited.
PMID- 9559726
TI - Circumcision and endocarditis prophylaxis.
PMID- 9559727
TI - Liquefied aftercataract: a complication of continuous curvilinear capsulorhexis
and intraocular lens implantation in the lens capsule.
AB - PURPOSE: To describe a new type of aftercataract that contains a liquefied, milky
white substance between the lens optic and the posterior lens capsule. METHOD: We
reviewed the medical records of 41 patients identified as having this type of
aftercataract. RESULTS: All 41 eyes (41 patients) underwent uneventful
phacoemulsification after continuous curvilinear capsulorhexis and implantation
of a posterior chamber intraocular lens made from polymethylmethacrylate. Two
months to 6 years after surgery (average+/-SD, 3.8+/-1.7 years), fibrosis was
noted evenly along the entire circumference and between the anterior surface of
the intraocular lens optic and the edge of the capsular opening created by
continuous curvilinear capsulorhexis. This led to formation of a closed chamber
between the intraocular lens and the posterior lens capsule, which then
accumulated a liquefied, milky white substance. Twenty-three of the 41 eyes
showed liquefied aftercataract in conjunction with other types of aftercataract:
in 12 eyes with fibrosis, in 11 eyes with Elschnig pearls, and in one eye with a
Soemmering ring. None of the eyes had any signs of inflammation; six of the 41
eyes had reduced visual acuity caused exclusively by the liquefied aftercataract.
Before cataract surgery, 14 eyes were diagnosed with diabetic retinopathy, four
with glaucoma, and two with uveitis. CONCLUSION: We report a new type of
aftercataract characterized by a liquefied, milky white substance that
accumulates between the lens optic and the posterior lens capsule when the
anterior capsular opening, originally created by continuous curvilinear
capsulorhexis, becomes occluded with the lens optic.
PMID- 9559728
TI - Mapping structural to functional damage in glaucoma with standard automated
perimetry and confocal scanning laser ophthalmoscopy.
AB - PURPOSE: To develop a quantitative method for analysis of the topographic
relationship between structural and functional damage in patients with glaucoma.
METHODS: We studied 26 patients with primary open-angle glaucoma, focal optic
disk damage, and focal visual field loss. The visual field was evaluated with
automated perimetry, and the optic disk topography was assessed with a confocal
scanning laser ophthalmoscope. Topographic measurements were calculated in 10
degree sectors and compared with a normative database (n=52). The topographic
relationship of structural damage and functional loss was analyzed. RESULTS: Rim
area ratio was defined as the ratio of rim area in each 10-degree sector divided
by the total rim area. This ratio resulted in the identification of one (46%) or
more (54%) clusters of optic disk sectors as outside normal limits in all 26
patients (12 and 14 patients, respectively). Twenty-two patients (84%) with
superior hemifield sensitivity loss tended to have inferior rim defects, and vice
versa. Nasal visual field defects close to the horizontal midline were matched
with damaged rim areas close to the vertical midline. CONCLUSIONS: This mapping
method allows an objective and quantitative evaluation of the optic disk and
visual field in patients with glaucoma and focal damage. Although the topographic
relationship between structure and function is characterized by considerable
interindividual variability, the identification of certain patterns may be useful
to aid in the evaluation of glaucomatous damage.
PMID- 9559729
TI - Confocal tomographic angiography of the optic nerve head in patients with
glaucoma.
AB - PURPOSE: To demonstrate the superficial and deep blood supply of the optic nerve
using a new method, confocal tomographic angiography, which combines two new
techniques, confocal laser scanning ophthalmoscopy and indocyanine green
angiography, into one system. METHODS: In a prospective study using confocal
tomographic angiography, we evaluated the correlation between the vascular supply
of the optic nerve and that of the visual field in 90 eyes of 49 subjects (25
eyes of 20 subjects with normal visual field and 65 glaucomatous eyes of 39
subjects with visual field defects; 10 subjects each had one eye with normal
visual field and one with visual field defects). RESULTS: In 22 of 25 eyes with a
normal visual field, a diffuse microvascular filling pattern of the optic disk
area was apparent with no filling defects. The confocal tomographic angiography
of 49 of 65 glaucomatous eyes had good correlation with their visual field defect
location. In 20 of 27 eyes with superior visual field loss, an inferior vascular
filling defect was detected. In 10 of 13 eyes with inferior visual field loss, a
superior vascular filling defect was detected. In 10 of 15 eyes with superior and
inferior visual field loss, inferior and superior vascular filling defects were
detected. Finally, in nine of 10 eyes with total visual field loss, no
vascularity of the optic disk could be detected. CONCLUSION: Confocal tomographic
angiography is a new imaging technology that may be applied for the evaluation of
the vascular supply of the optic nerve head.
PMID- 9559730
TI - Acquired pit of the optic nerve: a risk factor for progression of glaucoma.
AB - PURPOSE: To examine acquired pit of the optic nerve as a risk factor for
progression of glaucoma. METHODS: In a retrospective longitudinal study, 25 open
angle glaucoma patients with acquired pit of the optic nerve were compared with a
group of 24 open-angle glaucoma patients without acquired pit of the optic nerve.
The patients were matched for age, mean intraocular pressure, baseline ratio of
neuroretinal rim area to disk area, visual field damage, and duration of follow
up. Serial optic disk photographs and visual fields of both groups were evaluated
by three independent observers for glaucomatous progression. RESULTS: Of 46
acquired pits of the optic nerve in 37 eyes of 25 patients, 36 pits were located
inferiorly (76%) and 11 superiorly (24%; P < .001). Progression of optic disk
damage occurred in 16 patients (64%) in the group with acquired pit and in three
patients (12.5%) in the group without acquired pit (P < .001). Progression of
visual field loss occurred in 14 patients (56%) in the group with acquired pit
and in six (25%) in the group without pit (P=.04). Bilateral acquired pit of the
optic nerve was present in 12 patients (48%). Disk hemorrhages were observed more
frequently in the group with acquired pit (10 eyes, 40%) compared with the group
without pit (two eyes, 8%; P=.02). CONCLUSION: Among patients with glaucoma,
patients with acquired pit of the optic nerve represent a subgroup who are at
increased risk for progressive optic disk damage and visual field loss.
PMID- 9559731
TI - Effects of laser in situ keratomileusis (LASIK) on the corneal endothelium.
AB - PURPOSE: To assess the effects of laser in situ keratomileusis (LASIK) on the
corneal endothelium. METHODS: In a prospective study, the corneal endothelium of
98 eyes of 65 consecutive patients (mean age, 41 years; range, 22 to 66 years)
was photographed before, 2 weeks after, and 12 weeks after LASIK for the
correction of 2.75 to 14.5 diopters of myopia. Theoretical ablation depths were
200 to 330 microm below the corneal surface. Cell density, coefficient of
variation, and percent of hexagonal cells were determined using 150 to 200 cells
from each image. Eighty-eight eyes (91%) of 59 patients had a history of contact
lens wear. RESULTS: The mean+/-SD preoperative endothelial cell density was
2,549+/-365 cells per mm2, and the mean coefficient of variation was 0.35+/-0.06.
There was no statistically significant change in the mean endothelial cell
density or mean coefficient of variation of cell size at the 2-week (2,561+/-360
cells per mm2 and 0.35+/-0.06) or 12-week (2,541+/-364 cells per mm2 and 0.35+/
0.05) postoperative examinations. The percent of hexagonal cells was not
significantly changed 2 weeks postoperatively; however, 12 weeks postoperatively
(P=.0413, two-tailed t test), the percent of hexagonal cells was decreased by 1%.
CONCLUSIONS: Corneal endothelial cell density and morphology were unchanged 2 and
12 weeks after LASIK for the correction of up to 14.5 diopters of myopia. In this
LASIK study, the correction of up to 14.5 diopters of myopia appears to cause no
clinically significant effect on corneal endothelial cell density or morphology.
PMID- 9559732
TI - Analgesic efficacy and safety of nonpreserved ketorolac tromethamine ophthalmic
solution following radial keratotomy. Ketorolac Radial Keratotomy Study Group.
AB - PURPOSE: To compare the analgesic efficacy and safety of nonpreserved ketorolac
tromethamine 0.5% with those of its vehicle in the treatment of postsurgical
ocular pain following radial keratotomy. METHODS: This study employed a
multicenter, double-masked, randomized, parallel-group design. Radial keratotomy
patients were treated with either nonpreserved ketorolac tromethamine 0.5% or its
vehicle four times daily for up to 3 days following surgery. Patients were
provided with an escape medication (acetaminophen) for use only as needed for
intolerable pain. RESULTS: Patients treated with ketorolac reported significantly
greater pain relief (P < or =.023), less pain intensity (P < or =.047), less use
of escape medication (P < or =.001), fewer symptoms of ocular discomfort
(P=.024), and fewer sleep disturbances (P < or =.013) than did patients treated
with vehicle. No treatment-related adverse events were reported in the ketorolac
group, and only one treatment-related adverse event was reported in the vehicle
group. Most other safety findings were equivalent in the two treatment groups
except that there were significantly less eyelid erythema (P=.026) and eyelid
edema (P < or =.001) in the ketorolac group. CONCLUSIONS: Nonpreserved ketorolac
tromethamine 0.5% ophthalmic solution was significantly more effective than, and
as safe as, vehicle in the treatment of postoperative pain associated with radial
keratotomy. Therefore, topical ketorolac may be a valuable treatment option for
the maintenance of patient comfort following refractive surgery.
PMID- 9559733
TI - Experimental study of tetrodotoxin, a long-acting topical anesthetic.
AB - PURPOSE: To determine the effectiveness and toxicity of tetrodotoxin for use as a
long-acting topical anesthetic. METHODS: Four groups of six rabbits each received
a 40-microl aliquot of either tetrodotoxin in one of three concentrations (10 mM,
1 mM, or 0.1 mM) or proparacaine 0.5% into the inferior conjunctival cul-de-sac
of one eye, with the fellow eye of each rabbit receiving 40 microl of a 60-mM, pH
4.3 sodium citrate vehicle as a control. Corneal sensation was tested for up to 8
hours after administration of drugs, and response was noted by no blink, partial
blink without full eyelid closure, and full blink. Slit-lamp examination at 12
and 24 hours after administration and pachymetry before and 24 hours after
administration were performed to detect corneal toxicity. RESULTS: Rabbits
receiving all three concentrations of tetrodotoxin did not demonstrate any ocular
irritation, corneal thickening, or signs of systemic toxicity. At a dose of 10
mM, tetrodotoxin produced an anesthetic effect lasting up to 8 hours. At 1 mM,
tetrodotoxin was an effective but shorter-acting anesthetic. At 0.1 mM,
tetrodotoxin had no significant anesthetic effect. Proparacaine-treated rabbits
initially were anesthetic, but this effect was largely gone by 1 hour and
completely gone by 3 hours. CONCLUSIONS: Tetrodotoxin is a long-acting topical
anesthetic in the rabbit cornea. Although additional toxicity studies are
required, tetrodotoxin may provide an effective, long-lasting topical anesthetic
for use in pain control after corneal procedures such as photorefractive
keratectomy.
PMID- 9559734
TI - Efficient reactivation of latent herpes simplex virus type 1 infection by excimer
laser keratectomy in the experimental rabbit ocular model.
AB - PURPOSE: To investigate the role of excimer laser keratectomy as a trigger for
the reactivation of latent HSV type 1 (HSV-1) in the New Zealand rabbit ocular
model. There are conflicting reports in the current literature about reactivation
of HSV-1 after excimer laser photoablation. METHODS: New Zealand rabbits were
inoculated topically with HSV-1 McKrae or W strain in each eye, and culture
positive dendritic keratitis was documented on day 7. After the establishment of
latency (21+ days), animals were divided into three groups: group I animals
underwent excimer laser photoablation in each eye; group II animals received
intrastromal injections of sterile water to act as positive controls (a standard
method); and group III animals received no treatment and represented spontaneous
shedders. All eyes were swabbed daily from days 1 through 10 and plated on A549
cells. Recovery of HSV-1 on days 1 through 10 postinduction was analyzed to
compare the efficiency of the different methods of viral reactivation. RESULTS:
Reactivation of latent HSV-1 after excimer treatment was observed in nine (45%)
of 20 eyes and was equivalent to the rate of reactivation seen in the positive
control animals (eight [44.4%] of 18 eyes) (P=.99). Both of these rates were
significantly greater than those of the untreated animals (one [5.6%] of 18 eyes)
(P=.018). CONCLUSION: Excimer laser keratectomy appears to be an efficient
trigger for the reactivation of latent HSV-1 in the New Zealand rabbit ocular
model.
PMID- 9559735
TI - Long-term tamoxifen citrate use and potential ocular toxicity.
AB - PURPOSE: To estimate the prevalence of abnormalities in visual function and
ocular structures associated with the long-term use of tamoxifen citrate.
METHODS: A single-masked, cross-sectional study involving multiple community and
institutional ophthalmologic departments was conducted with a volunteer sample of
303 women with breast cancer currently taking part in a randomized clinical trial
to determine the efficacy of tamoxifen (20 mg/day) in preventing recurrences.
Participants included women who had never been on drug (n=85); women who had
taken tamoxifen for an average of 4.8 years, then been off the drug for an
average of 2.7 years (n=140); and women who had been on tamoxifen continuously
for an average of 7.8 years (n=78). Women were evaluated by questionnaire,
psychophysical testing, and clinical examination to determine any abnormalities
in visual function and the comparative prevalences of corneal, lens, retinal, and
optic nerve pathology. RESULTS: There were no cases of vision-threatening ocular
toxicity among the tamoxifen-treated participants. Compared with nontreated
participants, the tamoxifen-treated women had no differences in the activities of
daily vision, visual acuity measurements, or other tests of visual function
except for color screening. Intraretinal crystals (odds ratio [OR]=3.58, P=.178)
and posterior subcapsular opacities (OR=4.03, P=.034) were more frequent in the
tamoxifen-treated group. CONCLUSIONS: Women should have a thorough baseline
ophthalmic evaluation within the first year of initiating tamoxifen therapy and
receive appropriate follow-up evaluations.
PMID- 9559736
TI - A North Carolina macular dystrophy phenotype in a Belizean family maps to the
MCDR1 locus.
AB - PURPOSE: To describe the clinical findings of an autosomal dominant macular
dystrophy in a family of Mayan Indian ancestry in Belize, Central America, and to
determine its molecular genetic relationship with the original North Carolinian
family. METHODS: We performed comprehensive ophthalmic examinations on 56 members
of a single family living in Chicago, Illinois, and Belize, Central America.
Fundus photography and fluorescein angiography were performed on 17 affected
subjects and six affected family members were serially examined over a 12-year
period. Blood was collected from 26 individuals, and DNA was extracted for
genotyping. Two-point linkage, multipoint linkage, and haplotype analysis was
performed. RESULTS: In 17 affected individuals, the clinical features were
consistent with the diagnosis of North Carolina macular dystrophy. Multipoint
linkage analysis generated a peak lod score of 5.6 in the MCDR1 region. The
haplotype associated with the disease was, however, different from that of the
original North Carolinian family. CONCLUSIONS: This family has an autosomal
dominant macular dystrophy that is clinically indistinguishable from North
Carolina macular dystrophy (MCDR1). Our findings indicate that the mutated gene
in this Belizean family maps precisely to the same region as that of the North
Carolina macular dystrophy (MCDR1) locus. This study provides evidence that MCDR1
occurs in various ethnic groups and that there is no evidence of genetic
heterogeneity.
PMID- 9559737
TI - Ocular manifestations of giant cell arteritis.
AB - PURPOSE: To report the ocular manifestations of giant cell arteritis using the
strict criterion of a positive temporal artery biopsy for diagnosis of giant cell
arteritis. METHODS: In a prospective study from 1973 to 1995, we investigated 170
patients whose diagnosis of giant cell arteritis was confirmed on temporal artery
biopsy. At the initial visit, all patients were questioned regarding systemic and
ocular signs and symptoms of giant cell arteritis and underwent ophthalmic,
erythrocyte sedimentation rate (Westergren), and C-reactive protein evaluations.
Any patient with a high index of suspicion of giant cell arteritis was
immediately started on systemic corticosteroid therapy and had temporal artery
biopsy performed as soon as possible. RESULTS: Eighty-five (50.0%) of the 170
patients with giant cell arteritis proven by temporal artery biopsy presented
with ocular involvement. Ocular symptoms in patients with ocular involvement were
visual loss of varying severity in 83 (97.7%), amaurosis fugax in 26 (30.6%),
diplopia in five (5.9%), and eye pain in seven (8.2%); ocular ischemic lesions
consisted of arteritic anterior ischemic optic neuropathy in 69 (81.2%), central
retinal artery occlusion in 12 (14.1%), cilioretinal artery occlusion in 12 (of
55 patients with satisfactory fluorescein angiography [21.8%]), posterior
ischemic optic neuropathy in six (7.1%), and ocular ischemia in one (1.2%). In
almost every patient with giant cell arteritis, fluorescein fundus angiography
disclosed occlusive disease of the posterior ciliary arteries. CONCLUSION:
Because giant cell arteritis is a potentially blinding disease and its early
diagnosis is the key to preventing blindness, it is important to recognize its
various ocular manifestations.
PMID- 9559738
TI - Occult giant cell arteritis: ocular manifestations.
AB - PURPOSE: To report the incidence, visual symptoms, and ocular signs of occult
giant cell arteritis in patients who initially presented with visual symptoms and
ocular signs of giant cell arteritis. Occult giant cell arteritis was defined as
ocular involvement by giant cell arteritis without any systemic symptoms and
signs of giant cell arteritis. METHODS: In a prospective study from 1973 to 1995,
we investigated 85 patients who had ocular involvement caused by giant cell
arteritis and whose diagnosis of giant cell arteritis was confirmed on temporal
artery biopsy. At the initial visit, patients were questioned specifically on
systemic and ocular symptoms and signs of giant cell arteritis at or before the
onset of visual disturbance. Erythrocyte sedimentation rate (Westergren) and C
reactive protein level were evaluated before the start of systemic corticosteroid
therapy. RESULTS: Eighteen (21.2%) of 85 patients had occult giant cell
arteritis. There was no significant difference in age and sex distribution
between patients with and without systemic symptoms of giant cell arteritis.
Although both groups of patients had abnormal erythrocyte sedimentation rate and
C-reactive protein level, there was a significant difference in erythrocyte
sedimentation rate (P < .0001) and C-reactive protein level (P=.0133), these
being relatively lower in patients with occult giant cell arteritis. The ocular
symptoms in the 18 patients with occult giant cell arteritis were visual loss of
varying severity in 18 (100%), amaurosis fugax in six (33.3%), diplopia in two
(11.1%), and eye pain in one (5.6%). Ocular ischemic lesions consisted of
anterior ischemic optic neuropathy in 17 (94.4%), central retinal artery
occlusion in two (11.1%), and cilioretinal artery occlusion in two (of 11
patients with satisfactory fluorescein angiography [18.2%]). The ocular symptoms
and ischemic lesions were seen in a variety of combinations. CONCLUSIONS: Because
occult giant cell arteritis is a potential cause of blindness, its early
diagnosis is the key to preventing blindness; it is important to recognize that
21.2% of patients with giant cell arteritis and visual loss do not have any
systemic symptoms of giant cell arteritis. Thus, in persons older than 55 years,
amaurosis fugax or visual loss, development of an acute ocular ischemic lesion
(particularly arteritic anterior ischemic optic neuropathy), and abnormal C
reactive protein level, with or without elevated erythrocyte sedimentation rate
and systemic symptoms, should raise a high index of suspicion for giant cell
arteritis.
PMID- 9559739
TI - The ophthalmology of intracranial vascular abnormalities.
AB - PURPOSE: To provide a practical review of the ophthalmologic manifestations of
intracranial vascular abnormalities. METHODS: We reviewed ocular manifestations
of the most common intracranial vascular abnormalities: intracranial aneurysms,
carotid-cavernous fistulas, arteriovenous malformations, and cavernous
malformations. RESULTS: Unruptured aneurysms can compress the third cranial nerve
and the anterior visual pathways. Ruptured aneurysms and subarachnoid hemorrhage
can result in Terson syndrome and papilledema. Direct and indirect carotid
cavernous fistulas most commonly cause the classic triad of proptosis,
conjunctival chemosis, and cranial bruit but can masquerade as chronic
conjunctivitis. Arteriovenous malformations, with or without hemorrhage, may
compress portions of the retrochiasmal pathways, causing visual field loss.
Cavernous malformations, when in the brainstem, commonly cause abnormalities of
supranuclear, nuclear, and fascicular ocular motility. CONCLUSIONS: The
ophthalmologist may be the first physician to encounter clinical manifestations
of intracranial vascular abnormalities that may herald devastating neurologic
complications. Prompt diagnosis facilitates appropriate management and therapy.
PMID- 9559740
TI - Capsular bag distention syndrome noted 5 years after intraocular lens
implantation.
AB - PURPOSE: To describe a case of capsular bag distention syndrome with opaque
contents noted 5 years after intraocular lens implantation. METHODS: A 66-year
old man underwent phacoemulsification after circular capsulorhexis and
intraocular lens implantation in the left eye. Five years later, the posterior
capsule was vaulted far posteriorly, the capsular opening was apparently sealed
by the lens optic, and the bag contents were slightly opacified. Two years later,
the contents of the hyperdistended capsular bag showed intensified opacity,
causing definite blurred vision. RESULTS: The opacified medium was emptied from
the capsular bag posteriorly into the vitreous after Nd:YAG laser capsulotomy,
and the distended capsule was restored. CONCLUSIONS: Our findings suggest that
the contents were collagens produced by residual lens epithelial cells or
necrotic and/or apoptotic autolyzed lens epithelial cells.
PMID- 9559741
TI - Lattice corneal dystrophy type 1 in a Canadian kindred is associated with the
Arg124 --> Cys mutation in the kerato-epithelin gene. sgupta@ogh.on.ca.
AB - PURPOSE: To identify the mutation responsible for lattice corneal dystrophy type
1 in an extended Canadian kindred. METHODS: A search for a mutation in the
candidate gene, kerato-epithelin, was carried out by single-strand conformation
polymorphism and sequencing analyses. RESULTS: AC --> T mutation at position 417
was detected in exon 4 of the kerato-epithelin gene, which is expected to cause
an Arg124 --> Cys change. This is the same nucleotide change described previously
in two Swiss families with lattice corneal dystrophy type 1. CONCLUSION: Although
the possibility that the three families (two previously described Swiss families
and this Canadian kindred) are related has not been excluded, it appears that the
unique phenotype of lattice corneal dystrophy type 1 is caused by this particular
amino acid change.
PMID- 9559742
TI - The use of processed pericardial tissue in anterior ocular segment
reconstruction.
AB - PURPOSE: To report the use of processed pericardial tissue in reconstructing the
anterior ocular segment. METHOD: Three case reports. RESULT: Processed
pericardial tissue was found to be a helpful adjunct in providing tectonic
support and promoting epithelialization in the cases described. CONCLUSION:
Processed pericardial tissue has potential application to a variety of anterior
ocular segment conditions.
PMID- 9559743
TI - Aerobic and anaerobic microbiology of dacryocystitis.
AB - PURPOSE: To investigate the aerobic and anaerobic microbiology of dacryocystitis.
METHOD: Retrospective review of the 62 clinical and microbiologic records
collected between 1980 and 1990. RESULTS: Aerobic or facultative bacteria were
recovered in 32 cases (52%), anaerobic bacteria only in 20 cases (32%), mixed
aerobic and anaerobic bacteria in seven cases (11%), and fungi in three cases
(5%). A total of 94 organisms (1.5 per specimen), which included 56 aerobic or
facultative anaerobic organisms, 35 anaerobic organisms, and three fungi, were
recovered. The predominant aerobic and facultative bacteria were Staphylococcus
aureus (15 isolates), Staphylococcus epidermidis (13 isolates), and Pseudomonas
species (seven isolates). The most frequently recovered anaerobes were
Peptostreptococcus species (13 isolates), Propionibacterium species (12
isolates), Prevotella species (four isolates), and Fusobacterium species (three
isolates). The predominant fungus was Candida albicans (two isolates).
Polymicrobial infection was present in 28 cases (45%). CONCLUSION: These data
highlight the potential importance of anaerobic bacteria in dacryocystitis.
PMID- 9559744
TI - Unilateral peripapillary myelinated retinal nerve fibers associated with
strabismus, amblyopia, and myopia.
AB - PURPOSE: To describe the association of unilateral peripapillary myelinated
retinal nerve fibers with myopia, strabismus, and amblyopia and to propose a
possible pathologic mechanism. METHODS: Four patients who have the findings
associated with unilateral peripapillary myelinated nerve fibers are described
and reviewed. RESULT: All patients had poor visual outcomes despite treatment
with full cycloplegic refraction and appropriate patching. CONCLUSIONS: Although
the origin of this association is unknown, we believe that peripapillary
myelinated nerve fibers in a unilateral myopic eye may be secondary to an
imbalance between the process of myelination and the formation of the lamina
cribrosa. Good results have been reported with amblyopic therapy; however, it is
our experience that these patients are somewhat refractory to amblyopia therapy.
PMID- 9559745
TI - Acute posterior multifocal placoid pigment epitheliopathy with corneal stromal
infiltrates.
AB - PURPOSE: To report the association of perilimbal corneal stromal infiltrates with
acute posterior multifocal placoid pigment epitheliopathy. METHOD: Case report.
RESULTS: A 29-year-old woman with bilateral fundus lesions typical of acute
posterior multifocal placoid pigment epitheliopathy presented with peripheral
corneal stromal infiltrates that resolved with fundus lesions. CONCLUSION:
Corneal stromal infiltrates may be associated with characteristic fundus lesions
of acute posterior multifocal placoid pigment epitheliopathy.
PMID- 9559746
TI - Osseous metaplasia in proliferative vitreoretinopathy.
AB - PURPOSE: To report the clinicopathologic features of intraocular osseous
production in association with proliferative vitreoretinopathy. METHOD: The
clinical and histopathologic features of two patients with proliferative
vitreoretinopathy and intraocular bone formation are reviewed. RESULTS:
Preretinal osseous tissue incorporated in the proliferative vitreoretinopathy was
surgically removed in one patient, and osseous tissue was present in the
proliferative vitreoretinopathy in the enucleated eye of the other patient.
CONCLUSIONS: Bone formation, presumably from metaplastic retinal pigment
epithelium, may be present in proliferative vitreoretinopathy tissue. The
intraocular bone is present internal rather than external to the neurosensory
retina.
PMID- 9559747
TI - Systemic small noncleaved cell lymphoma presenting as a posterior choroidal mass.
AB - PURPOSE: To describe a patient with intraocular involvement by systemic, small
noncleaved cell lymphoma. METHODS: Case report and review of the literature.
RESULTS: A patient presented with a diffusely elevated choroidal mass. Systemic
evaluation led to the diagnosis of unsuspected disseminated lymphoma. CONCLUSION:
Small noncleaved cell lymphoma should be included in the differential diagnosis
of a choroidal mass.
PMID- 9559748
TI - Recognizing structural damage to the optic nerve head and nerve fiber layer in
glaucoma.
PMID- 9559749
TI - Recognizing structural damage to the optic nerve head and nerve fiber layer in
glaucoma.
PMID- 9559750
TI - A system for classifying mechanical injuries of the eye (globe)
PMID- 9559751
TI - The relationship between progression of visual field defects and retrobulbar
circulation in patients with glaucoma.
PMID- 9559752
TI - Regression of cytomegalovirus retinitis associated with protease-inhibitor
treatment in patients with AIDS.
PMID- 9559753
TI - Can depression be managed appropriately in primary care?
AB - This review considers the necessary conditions for appropriate management of
depression in primary care. While discussion of primary care management has often
focused on the recognition of depression, recognition alone is not sufficient.
Recent research demonstrates that primary care management of depression
frequently fails to meet recommended standards for intensity of treatment and
follow-up. Several recent randomized trials show that effective treatment of
depression in primary care is possible but will require significant changes in
current practice. Prerequisites for more effective management of depression in
primary care include appropriate patient education, systematic monitoring of care
processes and outcomes, and easy access to the full range of psychiatric
consultation services.
PMID- 9559754
TI - Managing behavioral health care: an employer's perspective.
AB - Employee life cycle events and behavioral health disorders impact productivity
and well-being. Employers use wellness initiatives and employee assistance or
work-family programs to help manage those factors that can distract employees
from performing optimally. Employer-sponsored health benefits are designed to
protect employees from the catastrophic costs of illness. However, today's plan
designers struggle with employee and employer affordability that does not
compromise quality or effectiveness. In 1990, Digital Equipment Corporation,
Maynard, Mass., shifted its strategy from an indemnity model to a managed care
model that uses health maintenance organizations. Comprehensive standards are
used to ensure the delivery of quality behavioral health care that is cost
effective, is delivered at the clinically appropriate levels, and uses a broad
continuum of treatment approaches with measurable outcomes.
PMID- 9559755
TI - Economic outcomes with antidepressant pharmacotherapy: a retrospective intent-to
treat analysis.
AB - Herein we describe a retrospective intent-to-treat evaluation designed to compare
the natural course of antidepressant utilization and direct health service
expenditures for the treatment of a single episode of major depression among
patients enrolled in a multistate network-model health maintenance organization
and initially prescribed either a tricyclic antidepressant (amitriptyline or
nortriptyline) or the serotonin selective reuptake inhibitor (SSRI) fluoxetine.
Patient-level paid-claims data for the period July 1, 1988, through December 31,
1991, were abstracted. During the above time frame, fluoxetine was the only SSRI
available in the United States. Patients prescribed amitriptyline were more than
three times as likely to require a change in antidepressant pharmacotherapy (OR =
3.27, 95% CI = 2.31 to 5.49), while patients prescribed nortriptyline were nearly
four times more likely to change medication (OR = 3.82, 95% CI = 2.74 to 6.83)
relative to patients initially prescribed fluoxetine. Consistent with our intent
to-treat design, all accrued health service expenditures were assigned to the
pharmacotherapeutic option initially prescribed. Multivariate analyses revealed
that initiation of antidepressant pharmacotherapy with amitriptyline resulted in
a 25.7% increase in per capita depression-related health service expenditures per
year, while initiation of antidepressant pharmacotherapy with nortriptyline
resulted in a 28.1% increase in per capita depression-related health service
expenditures per year relative to patients initially prescribed fluoxetine. A
financial break-even point was achieved at the conclusion of Month 5, at which
time all three intent-to-treat cohorts had comparable health service expenditures
in total. From a financial perspective, results stemming from this inquiry
suggest that the initiation of antidepressant pharmacotherapy with an SSRI is
warranted.
PMID- 9559756
TI - Psychotropic drug use during pregnancy: weighing the risks.
AB - Although psychotropic drugs have not been tested or approved by the Food and Drug
Administration for use during pregnancy, some women continue to take these
medications while they are pregnant, particularly since mood and anxiety
disorders cluster in women during childbearing years. The relative risks and
benefits of drug therapy for these women must be weighed with each patient and
treatment limited to those situations in which risks to mother and fetus from the
disorder are presumed to exceed the risk of drug treatment. Risks of psychotropic
drug use during pregnancy include teratogenic effects, direct neonatal toxicity,
and the potential for longer term neurobehavioral sequelae. Of growing concern is
the risk of untreated psychiatric disorder as it may potentially affect
fetoplacental integrity and fetal central nervous system development.
Coordination of care with the patient, her husband or partner, and the
obstetrician is essential, as is careful medical record documentation when
treating pregnant patients with psychiatric disorders.
PMID- 9559757
TI - Course of mood and anxiety disorders during pregnancy and the postpartum period.
AB - Because the onset of mood and anxiety disorders often occurs during the
childbearing years, many women may be taking psychotropic medications for these
disorders when they conceive. These medications easily diffuse across the
placenta, and their impact on the fetus is of concern. But discontinuation may
lead to relapse, in which case psychiatric symptoms may affect the fetus.
Thoughtful treatment planning presents a dilemma to the clinician. Limited data
suggest heightened vulnerability to relapse of mood and anxiety disorders in
women during the postpartum period. Pregnancy appears to exacerbate symptoms of
obsessive-compulsive disorder, while panic disorder patients may remain well
after discontinuing medication. Future studies should address the prevalence and
relapse rates of mood and anxiety disorders, particularly after medication
discontinuation, among pregnant women.
PMID- 9559758
TI - Postpartum mood disorders: diagnosis and treatment guidelines.
AB - Mood disturbance occurs commonly during the postpartum period. The symptoms may
be transient and relatively mild (as in postpartum blues) or may be associated
with significant impairment of functioning (as in postpartum depression and
puerperal psychosis). Despite the prevalence of postpartum mood disorders,
depressive symptoms that emerge during the puerperium are often overlooked.
Puerperal affective illness places the mother at risk for the development of
recurrent depression and has also been associated with significant long-term
effects on child development and behavior. Therefore, the prompt recognition and
efficacious treatment of puerperal mood disorders are essential in order to avoid
adverse outcomes for both mother and infant. This article discusses the
evaluation of postpartum mood disturbance and offers guidelines for the treatment
of affective illness during the puerperium.
PMID- 9559759
TI - Psychotropic medications in lactation.
AB - The use of psychotropic medications during lactation has not been investigated in
a controlled and systematic fashion. The literature is laden with case reports
and small case series containing numerous confounds that render the establishment
of definitive treatment guidelines tenuous. The increasing number of women who
plan to breast-feed and the high rate of psychiatric illness during the
postpartum period underscore the need to develop such guidelines. A MEDLINE
search was conducted for key words either in the titles or abstracts of
publications citing the use of psychotropic medications in lactating women and
describing the pharmacokinetics of medication excretion into breast milk. The
publications identified span over three decades. The largest single study by one
group of investigators examined 12 mother-infant pairs. The majority of studies
report their results as a ratio of the breast milk concentration to the maternal
serum concentration (milk/plasma [M/P]) ratio. Estimations that use the M/P ratio
of the infant daily dose range from 0.1% to 6.2% of the maternal dose. Few
studies attempt to account for the complex variations in the maternal, breast
milk, and infant physiologic environments. The major confounds of the studies
reviewed include (1) failure to document portion of breast milk assayed (foremilk
versus hindmilk), (2) limited metabolite assay, (3) limited assay sensitivity (1
25 ng/mL), not of research quality, (4) concomitant maternal and/or infant
medications, and (5) medication exposure during pregnancy. Despite these
confounds, there are remarkably few reports of adverse effects on nursing infants
exposed to psychotropic medications in breast milk. The limited data confirm that
psychotropic medications are excreted into breast milk and that the infant is
exposed to these medications. The ideal breast milk study that accounts for the
confounds identified has not been completed. The complex matrix of breast milk
and the changing infant metabolic capacity will require a more detailed analysis
with assays of improved sensitivity. Despite the limited reports of adverse
effects on nursing infants, the limitations of the available literature and
minimal sample sizes make it premature to recommend specific medications from a
given class. There is inadequate data on nursing infant exposure to multiple
medications to support changing medication to a different agent in an otherwise
stable patient. An individualized risk/benefit assessment with the empirical goal
of minimizing infant exposure while maintaining maternal emotional health is the
ideal approach.
PMID- 9559760
TI - The impact of maternal psychiatric illness on infant development.
AB - Maternal depression and anxiety are associated with compromises in infant and
maternal social and emotional functioning. In this paper, we briefly review the
literature on this topic and present some preliminary findings on a group of
mothers in treatment for major depressive disorder, panic disorder, or obsessive
compulsive disorder. The findings suggest that the symptom reports of treated
mothers with established DSM diagnoses were similar overall to those of control
mothers. However, the mothers' psychiatric illness had a compromising effect on
their interactions with their infants and on their infants' social and emotional
functioning. The implications of these results are discussed.
PMID- 9559761
TI - Managed care versus managed money.
PMID- 9559762
TI - Role of medication in managed care for depression.
PMID- 9559763
TI - Role of psychiatrists in managed care systems.
PMID- 9559764
TI - Cerebral CO2 vasoreactivity evaluation with and without changes in intrathoracic
pressure in comatose patients.
AB - It is well established that cerebral blood flow (CBF) is sensitive to variations
in arterial PCO2 (PaCO2) and can be influenced by changes in jugular venous
return due to elevated intrathoracic pressure. Therefore, we compared cerebral
CO2 vasoreactivity when PaCO2 was altered either by changing inspired PCO2 or
tidal volume. In addition, we sought to determine if noninvasive transcranial
Doppler ultrasonography can be used instead of invasive CBF measurement to
determine cerebral CO2 vasoreactivity. In 36 mechanically ventilated patients in
coma due to acute brain lesion, we evaluated CBF by continuous jugular
thermodilution, middle cerebral artery flow velocity (Vm) by transcranial Doppler
ultrasonography, intracranial pressure (ICP; in only 23 of them) by
intraventricular catheter, systemic and pulmonary hemodynamic variables, and
arterial and jugular bulb blood gases. Measurements were taken at four levels of
PaCO2 (25, 30, 35, and 40 mmHg) by modifying in a random order either tidal
volume or inspired PCO2. Cerebral, pulmonary, and systemic hemodynamic changes
were similar in magnitude during both methods of altering PaCO2. From the highest
to the lowest PaCO2, CBF decreased from 61+/-7 to 36+/-4 ml/min/100 g (p < 0.001,
mean +/- SE), Vm from 89+/-7 to 65+/-5 cm/s (p < 0.001), and ICP from 29+/-2 to
12+/-2 mmHg (p < 0.001), but cerebral perfusion pressure remained constant,
ranging from 65+/-3 to 67+/-4 mmHg (p = NS). Arteriojugular oxygen content
difference increased from 3.2+/-0.2 to 5.7+/-0.4 ml/dl (p < 0.001). Eleven of the
20 patients with a preserved CBF response to CO2 survived to 6 months, whereas
only two of the 16 patients with an altered response were alive at 6 months (p <
0.05). When compared with CBF by jugular thermodilution, the rates of sensitivity
and specificity of transcranial Doppler ultrasonography to detect impaired
cerebral CO2 vasoreactivity were 69% and 65%, respectively. In conclusion, the
reduction of PaCO2 from 40 to 25 mmHg by modifying either tidal volume or
inspired PCO2 resulted in similar effects on cerebral, pulmonary, and systemic
circulations. Cerebral CO2 vasoreactivity is of prognostic value in brain-injured
patients when determined using CBF but may be misleading when evaluated using
velocities measured by transcranial Doppler ultrasonography.
PMID- 9559765
TI - Correlation of transcranial Doppler sonography mean flow velocity with cerebral
blood flow in patients with intracranial pathology.
AB - Several studies suggest that relative changes in cerebral blood flow (CBF) may be
assessed via transcranial Doppler sonography (TCD). The present study
investigates the correlation between changes in TCD-mean flow velocity (Vm) and
changes in CBF in patients with a variety of types of intracranial pathology
undergoing cerebrovascular reactivity tests. After informed consent was obtained,
32 patients presenting with stenoses of brain-supplying arteries (n = 13),
cerebral vascular malformations (n = 6), surgical decompression for subarachnoid
hemorrhage (n = 2), brain edema after closed head injury (n = 8), or hepatic
encephalopathy (n = 3) were studied. The patients were divided into two groups
for different reactivity tests. Patients in group 1 (awake or sedated, n = 18)
received a 1-g dose of acetazolamide intravenously. In group 2 (n = 14),
mechanical ventilation was adjusted to produce a 20% decrease in arterial CO2
tension compared with baseline. Regional CBF was measured using xenon-enhanced
computed tomography (Xe-CT). Xe-CT scans at the levels of the basal ganglia and
the lateral ventricles were performed during a 4.5-min xenon wash-in period.
Bilateral flow velocity was measured in the middle cerebral artery using a 2-MHz
pulsed TCD system. Mean arterial blood pressure, heart rate, and end-tidal CO2
were continuously recorded during the procedure. After baseline measurements and
either alteration of CO2 or application of acetazolamide, the cerebrovascular
reactivity was assessed at 20 min by a second measurement of CBF, TCD, and all
other physiologic variables. The correlation coefficient for relative changes of
MCA territory CBF versus Vm and for the overall population was r = 0.82. In
groups 1 and 2, the r values were 0.39 and 0.5, respectively. Correlation
coefficients did not exceed r = 0.4 in any subgroup-classification based on
diagnosis. The close correlation between changes in CBF and Vm (r = 0.82) in
patients with heterogeneous intracranial pathology seems to show that TCD is a
measure of CBF. However, in groups 1 and 2 and in subgroups formed of patients
classified according to diagnoses, data dispersion suggests that the actual
correlation is weaker. Relation of changes in Vm to those in CBF may depend on
the underlying diagnosis. These data indicate that the correlation between Vm and
CBF may vary with intracranial pathology.
PMID- 9559766
TI - Effect of mild hypothermia and the 21-aminosteroid U-74389G on neurologic and
histopathologic outcome after transient spinal cord ischemia in the rabbit.
AB - Mild hypothermia and the 21-aminosteroids have both been neuroprotective in
several models of cerebral ischemia. In this study we compared the effects of
mild hypothermia and the 21-aminosteroid U-74389G, alone and in combination on
neurologic and histopathologic outcome after temporary spinal cord ischemia.
Forty male anesthetized New Zealand white rabbits were randomized to four groups
(n = 10): (a) normothermia (control); (b) U-74389G (3 mg/kg intravenously [i.v.]
before aortic occlusion, 1.5 mg/kg i.v. and 10 mg/kg intraperitoneally after
occlusion); (c) mild hypothermia (4 degrees C epidural temperature decrease); and
(d) mild hypothermia combined with U-74389G. Spinal cord ischemia was produced by
40 min of infrarenal aortic balloon occlusion. Forty-eight hours after the
procedure, the neurologic status of the animals was assessed (Tarlov score) and
the animals were killed for histologic evaluation. In the normothermic control
group, eight of 10 animals became paraplegic. There was a significant reduction
of the incidence of paraplegia and overall neurologic deficits and a significant
improved Tarlov score in the mild hypothermic group (one animal paraplegic) and
in the group with both mild hypothermia and U-74389G (two animals with a mild
paraparesis). The histopathologic scores showed significantly less damage in both
hypothermic groups. In group 2, U-74389G administration did not improve
neurologic or histopathologic outcomes. The results of the current study
demonstrate that a slight decrease of intraischemic spinal cord temperature
significantly improved neurologic and histopathologic outcomes after experimental
spinal cord ischemia. Protection by the 21-aminosteroid at normothermic
conditions, or additional protection when U-74389G was added to mild hypothermia,
could not be demonstrated.
PMID- 9559767
TI - Effects of closed head trauma and lipopolysaccharide on body temperature, brain
tissue water content, and PGE2 production in rats.
AB - Closed head trauma (CHT) increases brain tissue prostaglandin E2 (PGE2)
concentration, and that increase is associated with cerebral edema formation and
worsening of the neurologic severity score (NSS). Injection of the bacterial
endotoxin lipopolysacharride (LPS) increases cerebral and hypothalamic PGE2, and
the hypothalamic increase is associated with increased body temperature. The
present study determined (a) whether LPS-induced increase of PGE2 causes brain
edema or worsens NSS and (b) whether CHT increases hypothalamic PGE2 and thereby
increases body temperature. Halothane-anesthetized rats were divided into four
groups: group 1 = surgery with no CHT and no LPS (n = 8); group 2 = surgery with
LPS and no CHT (n = 8); group 3 = surgery with CHT and no LPS (n = 8); and group
4 = surgery with CHT plus LPS (n = 8). NSS was determined at 1 and 24 h after
injury, and brain tissue PGE2 and edema were determined when animals were killed
24 h after injury. As compared with group 1, LPS alone, but not CHT or CHT plus
LPS, increased rectal temperature. CHT and CHT plus LPS, but not LPS alone
increased brain water content and worsened NSS. LPS, CHT, and CHT plus LPS all
increased hypothalamic and cerebral PGE2 production. We conclude that although
LPS and CHT increased PGE2 levels, LPS alone did not affect neurologic status or
brain edema, CHT did not increase rectal temperature, and addition of LPS to CHT
did not aggravate the sequelae of CHT.
PMID- 9559768
TI - A case of severe cerebral trauma in a patient under chronic treatment with
cyclosporine A.
AB - A case of severe cerebral head injury in a child, chronically treated with
cyclosporine A after orthotopic liver transplantation, is presented. The initial
Glasgow Coma Scale score after the motor vehicle accident was 3, and computed
tomography showed multiple sites of intracerebral bleeding, an epidural hematoma,
and signs of perifocal edema. Although these lesions are normally associated with
a poor outcome, the child recovered unexpectedly well. In brain injury, a lucid
interval can be followed by secondary neurologic deterioration due to a loss of
high-energy metabolites, a release of neurotransmitters, and an increase in
intracellular Ca2+. These events finally led to cell damage in the penumbra of an
ischemic infarction. Among other drugs, immunosuppressants such as cyclosporine A
have been shown to exhibit neuroprotective properties in experimental models if
given during this time interval of secondary neurologic deterioration. Although
human data on these effects are still lacking, we conclude that neuroprotective
actions of cyclosporine A may have been involved in the favorable outcome in this
14-year-old boy.
PMID- 9559769
TI - The upper limit of cerebral blood flow autoregulation in acute intracranial
hypertension.
AB - The present series of experiments was performed to investigate the influence of
acute intracranial hypertension on the upper limit (UL) of cerebral blood flow
(CBF) autoregulation. Three groups of eight rats each--one with normal
intracranial pressure (ICP) (2 mmHg), one with ICP = 30 mmHg, and one with ICP =
50 mmHg--were investigated. Intracranial hypertension was maintained by
continuous infusion of lactated Ringer's solution into the cisterna magna, where
the pressure was used as ICP. Cerebral perfusion pressure (CPP), calculated as
mean arterial blood pressure (MABP)-ICP, was increased stepwise by continuous
intravenous infusion of norepinephrine. CBF was calculated by the intracarotid
133Xe method. In all three groups the corresponding CBF/CPP curve included a
plateau where CBF was independent of changes in CPP, showing intact
autoregulation. At normal ICP the UL was found at a CPP of 141 +/-2 mmHg, at ICP
= 30 mmHg the UL was 103+/-5 mmHg, and at ICP = 50 mmHg the UL was found at 88+/
7 mmHg. This shift of the UL was more pronounced than the shift of the lower
limit (LL) of the CBF autoregulation found previously. We conclude that
intracranial hypertension is followed by both a shift toward lower CPP values and
a narrowing of the autoregulated interval between the LL and the UL.
PMID- 9559770
TI - A case of shock subsequent to treatment of intracranial hypertension by mannitol
injection combined with hyperventilation.
AB - This report describes a sudden decrease in blood pressure after conservative
treatment of acute intracranial hypertension. A 63-year-old woman with acute
hydrocephalus after undergoing clipping of an aneurysm of the right
supracerebellar artery developed increased intracranial pressure, necessitating
surgical management. On the operating table, the patient developed Cushing's
reflex. Mannitol injection combined with hyperventilation was begun immediately
to reduce her intracranial pressure. Fifteen minutes later, a sudden and
prolonged suppression of circulation was observed (blood pressure 65/35-85/40
mmHg, heart rate 90-100 beats/min). Postoperatively, computed tomography of the
head showed compression of the brain stem. We believe that this patient's blood
pressure decrease was related to a sudden reduction of intracranial pressure and
that mannitol injection was principally responsible for this occurrence.
PMID- 9559771
TI - A multifunctional helmet for noninvasive neuromonitoring.
AB - Simultaneous and continuous recording and processing of different noninvasive
neuromonitoring parameters were carried out, including spontaneous and evoked
bioelectrical brain activities obtained by new "active electrodes," transcranial
Doppler sonographic measurements using robotic probes, a multiscan principle for
three-dimensional transcranial Doppler imaging, and recording of near-infrared
spectroscopic data. The recording and processing were carried out over periods of
some hours with a new recording technique integrated in a helmet construction.
PMID- 9559772
TI - Response to "Statistics and hypothermia".
PMID- 9559773
TI - Cefepime versus ceftriaxone for empiric treatment of hospitalized patients with
community-acquired pneumonia. The Cefepime Study Group.
AB - Effective empiric treatment of pneumonia requires antibiotic coverage against
gram-negative and gram-positive pathogens, including drug-resistant isolates. We
compared the safety and efficacy of intravenous (i.v.) cefepime (2 g administered
every 12 h) to those of i.v. ceftriaxone (1 g administered every 12 h) for the
empiric treatment of hospitalized patients with community-acquired pneumonia. Of
the 115 patients randomized to the study, 86 (cefepime recipients, n = 40;
ceftriaxone recipients, n = 46) were evaluated for clinical efficacy (clinically
evaluated patients). Favorable clinical outcomes (cure or improvement) were
comparable among clinically evaluated patients in the cefepime and ceftriaxone
treatment arms (95.0 versus 97.8%, respectively; 95% confidence interval for
treatment difference [data for ceftriaxone group minus data for cefepime group],
5.1 to +10.8%). The most common bacteria isolated from patients in both treatment
groups were Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus
aureus. In clinically evaluated patients with a microbiologic response, all
(100%) of the 32 pathogens from cefepime-treated patients and 97.4% (38 of 39) of
the pathogens from ceftriaxone-treated patients were eradicated (documented or
presumed eradication). The one persistent infection in the ceftriaxone group was
caused by Pseudomonas fluorescens. Both treatments were well tolerated. Our data
thus suggest that cefepime and ceftriaxone have comparable safety and efficacy
for the treatment of pneumonia in hospitalized patients.
PMID- 9559774
TI - Thirteen-year evolution of azole resistance in yeast isolates and prevalence of
resistant strains carried by cancer patients at a large medical center.
AB - Drug resistance is emerging in many important microbial pathogens, including
Candida albicans. We performed fungal susceptibility tests with archived isolates
obtained from 1984 through 1993 and fresh clinical isolates obtained from 1994
through 1997 by testing their susceptibilities to fluconazole, ketoconazole, and
miconazole and compared the results to the rate of fluconazole use. All isolates
recovered prior to 1993 were susceptible to fluconazole. Within 3 years of
widespread azole use, we detected resistance to all agents in this class. In
order to assess the current prevalence of resistant isolates in our hematologic
malignancy and transplant patients, we obtained rectal swabs from hospitalized,
non-AIDS, immunocompromised patients between June 1995 and January 1996. The
swabs were inoculated onto sheep's blood agar plates containing 10 microg of
vancomycin and 20 microg of gentamicin/ml of agar. One hundred one yeasts were
recovered from 97 patients and were tested for their susceptibilities to
amphotericin B, fluconazole, flucytosine, ketoconazole, and miconazole. The
susceptibility pattern was then compared to those for all clinical isolates
obtained throughout the medical center. The antifungal drug histories for each
patient were also assessed. The yeasts from this surveillance study were at least
as susceptible as the overall hospital strains. There did not appear to be a
direct linkage between prior receipt of antifungal agent therapy and carriage of
a new, drug-resistant isolate. Increased resistance to newer antifungal agents
has occurred at our medical center, but it is not focal to any high-risk patient
population that we studied. Monitoring of susceptibility to antifungal agents
appears to be necessary for optimizing clinical therapeutic decision making.
PMID- 9559775
TI - Antibiotic-induced lipopolysaccharide (LPS) release from Salmonella typhi: delay
between killing by ceftazidime and imipenem and release of LPS.
AB - It has been suggested that the antibiotic-induced release of lipopolysaccharide
(LPS) is an important cause of the development of septic shock in patients
treated for severe infections caused by gram-negative bacteria. Beta-lactam
antibiotics change the integrity of the bacterial cell envelope by binding to
penicillin-binding proteins (PBP) in the membrane and thus may affect the amount
of LPS that is released and the kinetics of that release. In this respect,
ceftazidime at intermediate concentrations binds with a high affinity to PBP 3
and PBP 1a and thus can induce filament formation in addition to killing, whereas
imipenem preferentially binds to PBP 2 and PBP 1b, leading to spheroplast
formation and rapid cell lysis. We investigated the effects of these antibiotics
on the killing and the release of the radioactively labelled LPS of Salmonella
typhi Ty 21A. A mathematical model was developed to calculate the delay between
bacterial killing and LPS release, designated the lag time. At antibiotic
concentrations inducing equal killing, the amount of LPS released was the same
for both antibiotics. Only after 6 h of incubation at antibiotic concentrations
above 0.5 microg/ml, the amount of 3H-LPS released was slightly higher
(approximately 1.2-fold) in incubations with ceftazidime than in those with
imipenem, and the maximum releases of the total label were 33.2% +/- 0.89% and
27.1% +/- 0.45%, respectively. Despite the clear concentration-dependent effect
on the bacterial killing and subsequent LPS release, the lag time was independent
of the antibiotic concentration. For ceftazidime as well as imipenem the lag time
amounted to approximately 60 min. In conclusion, our findings imply that the
mechanism of antibiotic-induced LPS release is independent of the PBP affinities
for these beta-lactam antibiotics. Furthermore, once the organism is killed by
either imipenem or ceftazidime, the rate of LPS release from S. typhi does not
differ according to the antibiotic with which the organism is killed, and there
is little difference in the relative amount of LPS released.
PMID- 9559776
TI - Use of pharmacodynamic parameters to predict efficacy of combination therapy by
using fractional inhibitory concentration kinetics.
AB - Combination therapy with antimicrobial agents can be used against bacteria that
have reduced susceptibilities to single agents. We studied various tobramycin and
ceftazidime dosing regimens against four resistant Pseudomonas aeruginosa strains
in an in vitro pharmacokinetic model to determine the usability of combination
therapy for the treatment of infections due to resistant bacterial strains. For
the selection of an optimal dosing regimen it is necessary to determine which
pharmacodynamic parameter best predicts efficacy during combination therapy and
to find a simple method for susceptibility testing. An easy-to-use, previously
described E-test method was evaluated as a test for susceptibility to combination
therapy. That test resulted in a MICcombi, which is the MIC of, for example,
tobramycin in the presence of ceftazidime. By dividing the tobramycin and
ceftazidime concentration by the MICcombi at each time point during the dosing
interval, fractional inhibitory concentration (FIC) curves were constructed, and
from these curves new pharmacodynamic parameters for combination therapy were
calculated (i.e., AUCcombi, Cmax-combi, T>MIC-combi, and T>FICi, where AUCcombi,
Cmax-combi, T>MIC-combi, and T>FICi are the area under the FICcombi curve, the
peak concentration of FICcombi, the time that the concentration of the
combination is above the MICcombi, and the time above the FIC index,
respectively). By stepwise multilinear regression analysis, the pharmacodynamic
parameter T>FICi proved to be the best predictor of therapeutic efficacy during
combination therapy with tobramycin and ceftazidime (R2 = 0.6821; P < 0.01). We
conclude that for combination therapy with tobramycin and ceftazidime the T>FICi
is the parameter best predictive of efficacy and that the E-test for
susceptibility testing of combination therapy gives promising results. These new
pharmacodynamic parameters for combination therapy promise to provide better
insight into the rationale behind combination therapy.
PMID- 9559777
TI - Duration and clinical relevance of postantibiotic effect in relation to the
dosing interval.
AB - The influence of half-life on the postantibiotic effect (PAE) of tobramycin
against Pseudomonas aeruginosa and Staphylococcus aureus was investigated during
one dosing interval. Tobramycin half-lives of 0.5 to 2.5 h were simulated in an
in vitro model, and the PAE was determined by an enzymatic inactivation method at
different time points, i.e., when the tobramycin concentrations were 20x, 5x, and
1x the MIC. At the time point during therapy when the tobramycin concentrations
had declined to 1x the MIC, at a tobramycin half-life of 0.5 h, the times of the
PAEs were approximately 0.7 and 1.7 h for P. aeruginosa and S. aureus,
respectively, and the PAE disappeared completely at half-lives corresponding to
those found in humans (i.e., 2 to 2.5 h). The PAE itself cannot be fully
explained by the presence of free intrabacterial tobramycin or the emergence of
resistant subpopulations. The explanation for the disappearance of the PAE during
the dosing interval may therefore be explained by the repair of sublethal damage.
Since the standard method of determining the PAE in animal models is somewhat
different from the method used for measurement of the PAE in vitro, the
conditions under which the PAE is measured in vivo were also simulated in the in
vitro model. This resulted in PAEs longer than those found by the standard method
of obtaining in vitro PAE measurements. We conclude that the PAE of tobramycin,
as determined by conventional in vitro methods, has virtually no clinical
importance. PAEs determined in vivo may have some clinical relevance, but they
are probably primarily caused by sub-MIC effects.
PMID- 9559778
TI - Role of ABC transporters in aureobasidin A resistance.
AB - Aureobasidin A (AbA) has strong antifungal effects arising from an unusual
mechanism. We show that AbA interacts with ATP-binding cassette (ABC)
transporters in yeast and mammalian cells. We isolated a gene of Saccharomyces
cerevisiae that conferred resistance to AbA when the gene was present in multiple
copies. The gene was identical to YOR1/YRS1, which confers resistance to
oligomycin, reveromycin, and organic anions, none of which have structures
similar to that of AbA. We also isolated an aur3R recessive mutant of S.
cerevisiae with increased resistance to AbA. Northern hybridization showed that
the aur3R mutant expressed not only YOR1 but also the ABC transporter-encoding
gene PDR5 at high levels. Genetic studies showed that the aur3R mutant had a
mutation in the PDR1 gene, which encodes a transcriptional regulator of PDR5 and
YOR1. Analysis of a yor1 disruptant of the aur3/pdr1 mutant showed that both the
functional YOR1 gene and the mutation in PDR1 were necessary for AbA resistance.
These results suggest that YOR1 is more important than PDR5 for AbA resistance.
We found in Candida albicans a novel gene whose sequence was similar to the
sequence of YOR1 in S. cerevisiae. The amino acid sequence of the C. albicans
YOR1 homolog showed no significant similarity to the sequences of CDR1 and CDR2,
which are ABC transporters of C. albicans. Furthermore, AbA inhibited the efflux
of the anticancer agent vincristine through P glycoproteins in cancer cells with
multidrug resistance.
PMID- 9559779
TI - Amphotericin B in lipid emulsion: stability, compatibility, and in vitro
antifungal activity.
AB - Newer formulations of amphotericin B (AmB) complexed with liposomes or lipid
suspensions have been developed. Preliminary studies have suggested that AmB in
Intralipid (IL) may be as effective as, but less toxic than, conventional
formulations of AmB, but few data are available regarding its stability,
compatibility, or in vitro antifungal activity. A compatibility study was done to
evaluate the effects of AmB concentrations in IL containing either 10 or 20%
soybean oil. The effects of temperature, shaking, and AmB and IL concentrations
on the stability of AmB-IL suspensions were analyzed by visual inspection and
liquid chromatography. The in vitro antifungal activity of AmB-IL, compared to
that of AmB alone against reference strains of Candida species was determined by
using a broth macrodilution method in accordance with National Committee for
Clinical Laboratory Standards guidelines (M27-T). Samples of AmB-IL which were
lightly shaken retained more than 90% of the AmB concentration over 21 days when
stored at either 4 or 23 degrees C. Varying the AmB concentration did not appear
to affect the stability of AmB-IL. However, a precipitate was formed when
mixtures with more than 30% lipid as a proportion of the total volume were
centrifuged. AmB-IL and AmB alone had similar in vitro antifungal activities
against reference strains of yeasts. Further pharmacologic and clinical studies
with AmB-IL are warranted, although AmB should not be combined with IL in
concentrations capable of producing a precipitate.
PMID- 9559780
TI - In vitro and in vivo antifungal activity of amphotericin B lipid complex: are
phospholipases important?
AB - Amphotericin B lipid complex for injection (ABLC) is a suspension of amphotericin
B complexed with the lipids L-alpha-dimyristoylphosphatidylcholine (DMPC) and L
alpha-dimyristoylphosphatidylglycerol. ABLC is less toxic than amphotericin B
deoxycholate (AmB-d), while it maintains the antifungal activity of AmB-d. Active
amphotericin B can be released from ABLC by exogenously added (snake venom,
bacteria, or Candida-derived) phospholipases or by phospholipases derived from
activated mammalian vascular tissue (rat arteries). Such extracellular
phospholipases are capable of hydrolyzing the major lipid in ABLC. Mutants of C.
albicans that were resistant to ABLC but not AmB-d in vitro were deficient in
extracellular phospholipase activity, as measured on egg yolk agar or as measured
by their ability to hydrolyze DMPC in ABLC. ABLC was nevertheless effective in
the treatment of experimental murine infections produced by these mutants.
Isolates of Aspergillus species, apparently resistant to ABLC in vitro (but
susceptible to AmB-d), were also susceptible to ABLC in vivo. We suggest that
routine in vitro susceptibility tests with ABLC itself as the test material may
not accurately predict the in vivo activity of ABLC and that the enhanced
therapeutic index of ABLC relative to that of AmB-d in vivo may be due, in part,
to the selective release of active amphotericin B from the complex at sites of
fungal infection through the action of fungal or host cell-derived
phospholipases.
PMID- 9559782
TI - Antiproliferative and apoptotic activities of ketonucleosides and keto-C
glycosides against non-small-cell lung cancer cells with intrinsic drug
resistance.
AB - We compared the biological activity of a new group of keto-C-glycosides to that
of a narrow spectrum of unsaturated ketonucleosides in a panel of non-small-cell
lung cancer (NSCLC) cells with various levels of intrinsic resistance to standard
chemotherapy drugs. Unlike cisplatin, etoposide, adriamycin, or taxol, for which
a significant difference in the cytotoxic effect was observed between sensitive
cell lines (H460, H125, and MGH4) and drug-resistant cell lines (H661, MGH7, and
FADU), nucleoside analogs were equally cytotoxic in NSCLC cell lines, with
compound 92 being 10-fold more active than compound 43, 44, 81, or 161, while
compound 3 was the least active. Apoptotic measurements with flow cytometric
analysis of terminal uridine deoxynucleotide nick end-labeled cells revealed that
the cytotoxic activity of these nucleosides correlated with their potency to
induce apoptosis. Compound 92 triggered death in cells with wild-type p53,
mutated p53, or p53 gene deletion. Our findings suggest that keto-C-glycosides
may be promising alternative anticancer agents which merit further studies in in
vivo cancer models refractory to standard chemotherapy drugs.
PMID- 9559781
TI - Effect of dirithromycin on Haemophilus influenzae infection of the respiratory
mucosa.
AB - Macrolides have properties other than their antibiotic action which may benefit
patients with airway infections. We have investigated the effect of dirithromycin
(0.125 to 8.0 microg/ml) on the interaction of Haemophilus influenzae with
respiratory mucosa in vitro using human nasal epithelium, adenoid tissue, and
bovine trachea. Dirithromycin did not affect the ciliary beat frequency of the
nasal epithelium or the transport of mucus on bovine trachea, but dirithromycin
(1 microg/ml) did reduce the slowing of the ciliary beat frequency and the damage
to the nasal epithelium caused by H. influenzae broth culture filtrate.
Amoxicillin (2 microg/ml) did not reduce the effects of the H. influenzae broth
culture filtrate. H. influenzae infection of the organ cultures for 24 h caused
mucosal damage and the loss of ciliated cells. Bacteria adhered to damaged
epithelium and to a lesser extent to mucus and unciliated cells. Incubation of H.
influenzae with dirithromycin at sub-MICs (0.125 and 0.5 microg/ml) prior to
infection of the organ cultures did not reduce the mucosal damage caused by
bacterial infection. By contrast, incubation of adenoid tissue with dirithromycin
(0.125 to 1.0 microg/ml) for 4 h prior to assembling the organ culture reduced
the mucosal damage caused by subsequent H. influenzae infection by as much as
50%. The number of bacteria adherent to the mucosa was reduced, although the
tissue that had been incubated with dirithromycin (0.125 and 0.5 microg/ml) did
not inhibit bacterial growth. This was achieved by a reduction in the amount of
damaged epithelium to which H. influenzae adhered and a reduction in the density
of bacteria adhering to mucus. We conclude that dirithromycin at concentrations
achievable in vivo markedly reduces the mucosal damage caused by H. influenzae
infection due to a cytoprotective effect.
PMID- 9559783
TI - In vivo activity of HSR-903, a new fluoroquinolone, against respiratory
pathogens.
AB - The in vivo activity of HSR-903, a new fluoroquinolone, against major bacteria
which cause respiratory tract infections was evaluated. HSR-903 was active
against experimental respiratory tract infections in mice challenged with
penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae and
Haemophilus influenzae strains. Treatment with HSR-903 reduced the bacterial
numbers in infected murine lungs. In accord with the pulmonary clearance results,
the rates of survival for mice treated with HSR-903, sparfloxacin, levofloxacin,
ciprofloxacin, and benzylpenicillin were 50, 30, 10, 0, and 0%, respectively, 14
days after being infected with penicillin-resistant S. pneumoniae. A
pharmacokinetic study with pneumonic mice showed that the levels of HSR-903 in
the lungs were seven to eight times higher than those in the plasma. These
results indicate that clinical studies of HSR-903 against respiratory tract
infections may be warranted.
PMID- 9559784
TI - Imiquimod, a patient-applied immune-response modifier for treatment of external
genital warts.
AB - Genital human papillomavirus infection is one of the most common sexually
transmitted diseases. Imiquimod is a new agent, an immune-response modifier, that
has been demonstrated to have potent in vivo antiviral and antitumor effects in
animal models. The present prospective, multicenter, double-blind, randomized,
vehicle-controlled trial evaluated the efficacy and safety of daily patient
applied imiquimod for up to 16 weeks for the treatment of external genital warts.
Wart recurrence was investigated during a 12-week treatment-free follow-up
period. In the intent-to-treat analysis, baseline warts cleared from 49 of 94
(52%) patients treated with 5% imiquimod cream, 13 of 90 (14%) patients treated
with 1% imiquimod cream, and 3 of 95 (4%) vehicle-treated patients; the
differences between the groups treated with vehicle and imiquimod were
significant (P < 0.0001). For subjects who completed the follow-up period,
recurrence rates after a complete response were 19% (9 of 48 patients) in the 5%
imiquimod cream group, 17% (2 of 12) in the 1% imiquimod cream group, and 0% (0
of 3) in the vehicle-treated group. There were no systemic reactions, although
local skin reactions (generally of mild or moderate severity) were common,
particularly in the 5% imiquimod cream group. Local reactions caused two patients
to discontinue treatment. The most frequently reported local skin reactions were
erythema, excoriation or flaking, and erosion. Patient-applied 5% imiquimod cream
is effective for the treatment of external genital warts and has a favorable
safety profile.
PMID- 9559786
TI - Generation and characterization of a mutant of influenza A virus selected with
the neuraminidase inhibitor BCX-140.
AB - Influenza neuraminidase (NA) plays an important role in viral replication, and
characterization of viruses resistant to NA inhibitors will help elucidate the
role of active-site residues. This information will assist in designing better
inhibitors targeted to essential active-site residues that cannot generate drug
resistant mutations. In the present study we used the benzoic acid-based
inhibitor BCX-140 to select and characterize resistant viruses. BCX-140 binds to
the NA active site in an orientation that is opposite that of a sialic acid-based
compound, 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid (GANA).
Thus, the guanidino group of BCX-140 binds to Glu-276, whereas in GANA the
guanidino group binds to Glu-119. We passaged influenza A/Singapore/1/57 (H2N2)
in Madin-Darby canine kidney cells in the presence of BCX-140, and virus
resistant to this inhibitor was selected after six passages. The NA of this
mutant was still sensitive to inhibition by BCX-140. However, the mutant virus
was resistant to BCX-140 in plaque and 3-(4,5-dimethylthiazol-2-yl)-2,5
diphenyltetrazolium bromide (MTT) assays. Sequence analysis of hemagglutinin (HA)
and NA genes revealed changes in both, although none were in the active site of
the NA. Depending on the method of selection of the resistant virus, two types of
changes associated with the sialic acid binding site were seen in the HA. One is
a change in HA1 of Ala-133 to Thr, a residue close to the binding site, while the
other change was Arg-132 of HA1 to Gln, which in HA1 of serotype H3 is a sialic
acid contact (Asn-137). Binding studies revealed that both types of resistant
viruses had reduced receptor binding affinity compared to that of the wild type.
Thus, resistance to BCX-140 was generated by modifying the HA. NA active-site
residue 276 may be essential for activity, and thus, it cannot be changed to
generate resistance. However, drug-induced changes in the HA can result in a
virus that is less dependent on NA activity for growth in cells and, hence,
resistant to NA inhibitors.
PMID- 9559785
TI - Accumulation of norfloxacin by Mycobacterium aurum and Mycobacterium smegmatis.
AB - The modified fluorescence method was used to determine the accumulation of
norfloxacin by Mycobacterium aurum A+ and Mycobacterium smegmatis mc(2)155. By
using an exogenous norfloxacin concentration of 10 microg/ml, a steady-state
concentration (SSC) of 160 to 180 ng of norfloxacin/mg of cells was obtained for
M. aurum, and an SSC of 120 to 140 ng of norfloxacin/mg of cells obtained for M.
smegmatis. For both species of mycobacteria, the SSC was achieved within 5 min.
The silicon oil method was investigated and gave higher SSCs than the modified
fluorescence method. Further studies on the mechanism of norfloxacin accumulation
by M. aurum were performed. An increase in the pH of the wash buffer from 7.0 to
9.0 did not significantly affect the final SSC obtained. Accumulation was
nonsaturated over a norfloxacin concentration range of 0 to 100 microg/ml, and
the proton motive force inhibitor 2,4-dinitrophenol (1 and 2 mM), whether it was
added before or after norfloxacin was added, had no effect on the final SSC
obtained. 2,4-Dinitrophenol also had no effect on norfloxacin accumulation by M.
smegmatis. Furthermore, norfloxacin accumulation by M. aurum was unaffected by
the presence of either Tween 80 or subinhibitory concentrations of ethambutol in
the growth medium. Therefore, it is proposed that norfloxacin accumulation by
mycobacteria occurs by simple, energy-independent diffusion.
PMID- 9559788
TI - Activity of amoxicillin-clavulanate against penicillin-resistant Streptococcus
pneumoniae in an experimental respiratory infection model in rats.
AB - High doses of amoxicillin, equivalent to those produced by 500- and 750-mg oral
doses in humans (area under the plasma concentration-time curve), were effective
against a penicillin-resistant strain of Streptococcus pneumoniae in an
experimental respiratory tract infection in immunocompromised rats; this superior
activity confirms the results of previous studies. An unexpected enhancement of
amoxicillin's antibacterial activity in vivo against penicillin-resistant and
susceptible S. pneumoniae strains was observed when subtherapeutic doses of
amoxicillin were coadministered with the beta-lactamase inhibitor potassium
clavulanate. The reason for this enhancement was unclear since these organisms do
not produce beta-lactamase. The differential binding of clavulanic acid and
amoxicillin to penicillin-binding proteins may have contributed to the observed
effects.
PMID- 9559787
TI - Zidovudine pharmacokinetics in premature infants exposed to human
immunodeficiency virus.
AB - We used population analysis techniques to determine zidovudine (ZDV)
pharmacokinetic parameters in 15 preterm neonates (mean gestational age, 29.4
weeks; mean birth weight, 1,230 g) at a mean age of 5.5 days. The values of the
pharmacokinetic parameters were as follows: clearance, 2.53 +/- 0.44 ml/min/kg;
volume of distribution, 1.59 +/- 0.51 liters/kg; and half-life, 7.2 +/- 1.5 h.
For seven infants studied a second time, at a mean age of 17.7 days, an increase
in the mean clearance (2.33 versus 4.35 ml/min/kg; P = 0.024) and a decrease in
the half-life (7.3 versus 4.4 h; P = 0.003) were found. The ZDV clearance is low
and the half-life is prolonged in premature neonates, but the clearance increases
and the half-life decreases with postnatal age. Potentially toxic concentrations
may accumulate in serum if the standard dosage for full-term infants is used. We
suggest that initial ZDV dosing should be reduced to 1.5 mg every 12 h for
preterm neonates.
PMID- 9559789
TI - In vitro evaluation of drug susceptibilities of Babesia divergens isolates.
AB - The susceptibilities of three bovine and two human Babesia divergens isolates to
antimicrobial agents were evaluated in vitro by a tritiated hypoxanthine
incorporation assay. The MICs at which 50% of isolates are inhibited (MIC50s) for
mefloquine (chlorhydrate), chloroquine (sulfate), quinine (chlorhydrate),
clindamycin (phosphate), pentamidine (isethionate), phenamidine (isethionate)
plus oxomemazine (chlorhydrate), lincomycin (chlorhydrate monohydrate), and
imidocarb (dipropionate) were determined. Except for imidocarb, the MIC50s
observed for the different isolates were close. Imidocarb and the combination of
phenamidine plus oxomemazine exhibited the highest in vitro activity, while
antimalarial agents such as mefloquine, choroquine, and quinine were inactive.
Other drugs had intermediate activities. The data support further in vitro
evaluation of antimicrobial agents active against B. divergens for the
improvement of therapeutic strategies.
PMID- 9559791
TI - Cefotaxime-resistant Enterobacteriaceae isolates from a hospital in Warsaw,
Poland: identification of a new CTX-M-3 cefotaxime-hydrolyzing beta-lactamase
that is closely related to the CTX-M-1/MEN-1 enzyme.
AB - A group of cefotaxime-resistant Citrobacter freundii and Escherichia coli
isolates were collected by a clinical laboratory in a hospital in Warsaw, Poland,
in July 1996. Detailed analysis has shown that all of these produced a beta
lactamase (pI, 8.4) belonging to the CTX-M family, one of the minor extended
spectrum beta-lactamase families with a strong cefotaxime-hydrolyzing activity.
Sequencing has revealed that C. freundii isolates produced a new CTX-M-3 enzyme
which is very closely related to the CTX-M-1/MEN-1 beta-lactamase, sporadically
identified in Europe over a period of 6 years. Amino acid sequences of these two
beta-lactamases differ at four positions: Val77Ala, Asp114Asn, Ser140Ala, and
Asn288Asp (the first amino acid of each pair refers to CTX-M-1/MEN-1 and second
refers to CTX-M-3). The partial sequence of the E. coli CTX-M gene was identical
to the corresponding region of bla(CTX-M-3), but a transconjugant of the E. coli
isolate expressed higher levels of resistance to beta-lactams than did C.
freundii transconjugants. These resistance differences correlated with
differences in plasmid DNA restriction patterns. Our results suggest that CTX-M
genes have been spread among different species of the family Enterobacteriaceae
in the hospital and that the CTX-M-3-expressing C. freundii strain causing
routine urinary tract infections has been maintained for a relatively long time
in the hospital environment.
PMID- 9559790
TI - Relationship between didanosine exposure and surrogate marker response in human
immunodeficiency virus-infected outpatients.
AB - We used information available from routine clinic visits to characterize the
pharmacokinetics of didanosine in 82 human immunodeficiency virus-infected
patients. A total of 271 blood samples were collected for the measurement of
didanosine concentrations in plasma (mean +/- standard deviation [SD], 3.30 +/-
2.21 samples/patient). Bayesian estimates of didanosine oral clearance (CL[oral])
were obtained for these patients by the POSTHOC option within the NONMEM software
package. Population priors from a previous NONMEM analysis of didanosine
pharmacokinetics were used. The mean +/- SD CL(oral) was 132 +/- 27.7 liters/h,
which agrees reasonably well with estimates obtained from previous
pharmacokinetic studies of didanosine. Estimates of individual didanosine
exposure were then used to consider potential relationships between drug exposure
and surrogate marker response over a 6-month period. No correlations were found
between the didanosine area under the concentration-time curve from 0 to 6 months
and the absolute CD4 cell count (r = 0.305; 0.1 < P < 0.2), weight response (r =
0.0857; P > 0.4), or percentage of CD4 lymphocytes (r = 0.0559; P > 0.4). Future
efforts to characterize didanosine exposure in outpatients by random sampling
methods should involve more directed efforts to limit residual variability in the
data.
PMID- 9559793
TI - Prophylaxis of acute osteomyelitis with absorbable ofloxacin-impregnated beads.
AB - We investigated the use of an ofloxacin-impregnated bioabsorbable composite for
the prevention of acute Staphylococcus aureus osteomyelitis. New Zealand White
rabbits were anesthetized, the femur was exposed, and a cortical hole was
drilled. Animals were randomly given drug-free composites or ofloxacin
impregnated composites; the composites were placed at the site of injury, and the
incision was closed. One hour later, all animals were intravenously inoculated
with 5 x 10(4) CFU of S. aureus and observed for 28 days. Bone culture data
revealed that S. aureus was isolated from 3 of 12 rabbits in the ofloxacin
composite group and 9 of 11 animals in the control group (P = 0.02). Radiographic
evaluation revealed that the drug-free group had a significantly (P = 0.01)
greater degree of radiographic evidence of infection than the group given
ofloxacin composites. Although a limited number of histologic samples were
available, these data also paralleled the radiographic and culture data. This
study demonstrates the effectiveness of the implantable ofloxacin bioabsorbable
composites to prevent the development of acute osteomyelitis.
PMID- 9559792
TI - Unique metabolism of a novel antiviral L-nucleoside analog, 2'-fluoro-5-methyl
beta-L-arabinofuranosyluracil: a substrate for both thymidine kinase and
deoxycytidine kinase.
AB - 2'-Fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU) is the first L
nucleoside analog with low cytotoxicity discovered to have potent antiviral
activities against both hepatitis B virus and Epstein-Barr virus but not human
immunodeficiency virus. This spectrum of activity is different from those of the
other L-nucleoside analogs examined. L-FMAU enters cells through equilibrative
sensitive and -insensitive nucleoside transport as well as through nonfacilitated
passive diffusion. L-FMAU is phosphorylated stepwise in cells to its mono-, di-,
and triphosphate forms. In the present study the enzymes responsible for the
first step of L-FMAU phosphorylation were identified. This is the first thymidine
analog shown to be a substrate not only for cytosolic thymidine kinase and
mitochondrial deoxypyrimidine kinase but also for deoxycytidine kinase. This
finding suggests that the antiviral activity of L-FMAU will not be limited by the
loss or alteration of any of these deoxynucleoside kinases.
PMID- 9559794
TI - Cyclosporin analogs inhibit in vitro growth of Cryptosporidium parvum.
AB - Cyclosporine and nonimmunosuppressive cyclosporin (CS) analogs were demonstrated
to be potent inhibitors of the growth of the intracellular parasite
Cryptosporidium parvum in short-term (48-h) in vitro cultures. Fifty-percent
inhibitory concentrations (IC50s) were 0.4 microM for SDZ 033-243, 1.0 microM for
SDZ PSC-833, and 1.5 microM for cyclosporine. Two other analogs were less
effective than cyclosporine: the IC50 of SDZ 205-549 was 5 microM, and that of
SDZ 209-313 was 7 microM. These were much lower than the IC50 of 85 microM of
paromomycin, a standard positive control for in vitro drug assays for this
parasite. In addition, intracellular growth of excysted sporozoites that had been
incubated for 1 h in cyclosporine was significantly reduced, suggesting that the
drug can inhibit sporozoite invasion. The cellular activities of the CS analogs
used have been characterized for mammalian cells and protozoa. The two analogs
that were most active in inhibiting C. parvum, SDZ PSC-833 and SDZ 033-243, bind
weakly to cyclophilin, a peptidyl proline isomerase which is the primary target
of cyclosporine and CS analogs. However, they are potent modifiers of the
activity of the P glycoproteins/ multidrug resistance (MDR) transporters, members
of the ATP-binding cassette (ABC) superfamily. Hence, both cyclophilin and some
ABC transporters may be targets for this class of drugs, although drugs that
preferentially interact with the latter are more potent. Cyclosporine (0.5
microM) had no significant chemosensitizing activity. That is, it did not
significantly increase sensitivity to paromomycin, suggesting that an ABC
transporter is not critical in the efflux of this drug. Cyclosporine at
concentrations up to 50 microM was not toxic to host Caco-2 cells in the
CellTiter 96 assay. The results of this study complement those of studies of the
inhibitory effect of cyclosporine and CS analogs on other apicomplexan parasites,
Plasmodium falciparum, Plasmodium vivax, and Toxoplasma gondii.
PMID- 9559795
TI - Population pharmacokinetic study of amikacin administered once or twice daily to
febrile, severely neutropenic adults.
AB - Once-daily (o.d.) administration of 20 mg of amikacin per kg of body weight to
neutropenic patients has been validated by clinical studies, but amikacin
pharmacokinetics have been documented only for the 7.5-mg/kg twice-daily (b.i.d.)
regimen in this population. In order to determine in neutropenic patients (i) the
influence of the dosing regimen on the kinetics of amikacin, (ii) the linearity
of kinetics of amikacin in the range of 7.5 to 20 mg/kg, and (iii) the influence
of patient characteristics on the disposition of amikacin and (iv) to provide a
rationale for dosing recommendations, we evaluated the population
pharmacokinetics of amikacin administered to 57 febrile neutropenic adults
(neutrophil count, <500/mm3) being treated for a hematological disorder and
receiving amikacin at 7.5 mg/kg b.i.d. (n = 29) or 20 mg/kg o.d. (n = 28) and
administered intravenously over 0.5 h. A total of 278 blood samples were obtained
(1 to 14 samples per patient) during one or several administration intervals (1
to 47). Serum amikacin levels were measured by the enzyme-multiplied immunoassay
technique. A mixed-effect modeling approach was used to fit a bicompartmental
model to the data (NONMEM software). The influences of the dosing regimen and the
demographic and biological indices on the pharmacokinetic parameters of amikacin
were evaluated by the maximum-likelihood ratio test on the population model. The
dosing regimen had no influence on amikacin pharmacokinetic parameters, i.e., the
kinetics of amikacin were linear over the range of 7.5 to 20 mg/kg. Amikacin
elimination clearance (CL) was only correlated with creatinine clearance or its
covariates, namely, sex, age, body weight, and serum creatinine level. The
interindividual variability of CL was 21%, while those of the central volume of
distribution, the distribution clearance, and the tissue volume of distribution
were 15, 30, and 25%, respectively. On the basis of the expected distribution of
amikacin concentrations in this population, dosing recommendations as a function
of creatinine clearance (CL[CR]) are proposed: for patients with normal renal
function (CL[CR] of 80 to 130 ml/min), 20 mg/kg o.d. is recommended, whereas for
patients with severe renal impairment (CL[CR], 10 to 20 ml/min), a dosage of 17
mg/kg every 48 h is recommended.
PMID- 9559796
TI - Activities and time-kill studies of selected penicillins, beta-lactamase
inhibitor combinations, and glycopeptides against Enterococcus faecalis.
AB - The activities of piperacillin, piperacillin-tazobactam, ticarcillin, ticarcillin
clavulanate, ampicillin, ampicillin-sulbactam, vancomycin, and teicoplanin were
tested against 212 Enterococcus faecalis strains (9 beta-lactamase producers) by
standard agar dilution MIC testing (10[4] CFU/spot). The MICs at which 50 and 90%
of the isolates were inhibited (MIC50s and MIC90s, respectively) were as follows
(microg/ml): piperacillin, 4 and 8; piperacillin-tazobactam, 4 and 8;
ticarcillin, 64 and 128; ticarcillin-clavulanate, 64 and 128; ampicillin, 2 and
2; ampicillin-sulbactam, 1 and 2; vancomycin, 1 and 4; and teicoplanin, 0.5 and
1. Agar dilution MIC testing of the nine beta-lactamase-positive strains with an
inoculum of 10(6) CFU/spot revealed higher beta-lactam MICs (piperacillin, 64 to
>256 microg/ml; ticarcillin, 128 to >256 microg/ml; and ampicillin, 16 to 128
microg/ml); however, MICs with the addition of inhibitors were similar to those
obtained with the lower inoculum. Time-kill studies of 15 strains showed that
piperacillin-tazobactam was bactericidal (99.9% killing) for 14 strains after 24
h at four times the MIC, with 90% killing of all 15 strains at two times the MIC.
After 12 and 6 h, 90% killing of 14 and 13 strains, respectively, was found at
two times the MIC. Ampicillin gave 99.9% killing of 14 beta-lactamase-negative
strains after 24 h at eight times the MIC, with 90% killing of all 15 strains at
two times the MIC. After 12 and 6 h, 90% killing of 14 and 13 strains,
respectively, was found at two times the MIC. Killing by ticarcillin-clavulanate
was slower than that observed for piperacillin-tazobactam, relative to the MIC.
For the one beta-lactamase-producing strain tested by time-kill analysis with a
higher inoculum, addition of the three inhibitors (including sulbactam) to each
of the beta-lactams resulted in bactericidal activity at 24 h at two times the
MIC. For an enzyme-negative strain, addition of inhibitors did not influence
kinetics. Kinetics of vancomycin and teicoplanin were significantly slower than
those of the beta-lactams, with bactericidal activity against 6 strains after 24
h at eight times the MIC, with 90% killing of 12 and 14 strains, respectively, at
four times the MIC. Slower-kill kinetics by both glycopeptides were observed at
earlier periods.
PMID- 9559797
TI - Efficacy of trovafloxacin against penicillin-susceptible and multiresistant
strains of Streptococcus pneumoniae in a mouse pneumonia model.
AB - The increasing emergence of penicillin-resistant and multidrug-resistant strains
of Streptococcus pneumoniae will create a serious therapeutic problem in coming
years. Trovafloxacin is a novel naphthyridone quinolone with promising activity
against S. pneumoniae, including penicillin-resistant strains (MIC for 90% of the
isolates tested, 0.25 microg/ml). We compared its in vivo efficacy with that of
other fluoroquinolones (ciprofloxacin, temafloxacin, and sparfloxacin) and a
reference beta-lactam (amoxicillin) in a model of acute experimental pneumonia.
Immunocompetent Swiss mice were infected by peroral tracheal delivery of a
virulent, penicillin-susceptible strain (MIC, 0.03 microg/ml); leukopenic Swiss
mice were infected with three poorly virulent, penicillin-resistant strains
(MICs, 4 to 8 microg/ml) and a ciprofloxacin-resistant strain (MIC, 32
microg/ml). Treatments were started 6 h (immunocompetent mice) or 3 h (leukopenic
mice) after infection. Doses ranging from 12.5 to 300 mg/kg were given at 12- or
8-h intervals for 3 days. Trovafloxacin (25 mg/kg) was the most effective agent
in vivo against penicillin-susceptible and -resistant strains. Corresponding
survival rates were 2- to 4-fold higher than with 50-mg/kg sparfloxacin or
temafloxacin and 8- to 16-fold higher than with 100-mg/kg ciprofloxacin. The
ratios of the area under the concentration-time curve to the MIC in serum and
lung tissue were more favorable with trovafloxacin than with the other
quinolones. Efficacy in vivo correlated with pharmacokinetic parameters.
Trovafloxacin shows potential for the treatment of infections due to penicillin
susceptible and -resistant S. pneumoniae but appears to be ineffective against a
ciprofloxacin-resistant strain.
PMID- 9559798
TI - Survey of resistance of herpes simplex virus to acyclovir in northwest England.
AB - Acyclovir (ACV) has been used for more than 15 years in the management of herpes
simplex virus (HSV) and varicella-zoster virus (VZV) disease. The present survey
was undertaken to assess the level of ACV resistance in the population. More than
2,000 HSV isolates from both immunocompetent and immunocompromised patients in
northwest England were collected over a 2-year period and tested for sensitivity
to ACV. These studies suggested a prevalence of resistance of approximately 0.1
to 0.6% in immunocompetent individuals, with no apparent difference in prevalence
between treated and untreated groups. In line with previous studies, the
prevalence of resistance in treated immunocompromised individuals was
approximately 6%.
PMID- 9559799
TI - Efficacy of LY303366 against amphotericin B-susceptible and -resistant
Aspergillus fumigatus in a murine model of invasive aspergillosis.
AB - LY303366 is a novel antifungal echinocandin with excellent in vitro activity
against Aspergillus spp. We compared four doses (1, 2.5, 10, and 25 mg/kg of body
weight) of LY303366 with amphotericin B (0.5 to 5 mg/kg) in a temporarily
neutropenic murine model of invasive aspergillosis against an amphotericin B
susceptible (AF210) and an amphotericin B-resistant (AF65) Aspergillus fumigatus
isolate based on in vivo response. Mice were immunosuppressed with
cyclophosphamide (200 mg/kg) and infected 3 days later. Treatment started 18 h
after infection and lasted for 10 days. LY303366 was given once daily
intravenously for 10 days, and amphotericin B (at 0.5, 2, and 5 mg/kg) was given
once daily intraperitoneally for 10 days, or only on days 1, 2, 4, and 7 (at 5
mg/kg). Kidneys and lungs from survivors were cultured on day 11. Control mice in
both experiments had 90 to 100% mortality. Amphotericin B at 0.5 mg/kg and
LY303366 at 1 mg/kg yielded 10 to 20% survival rates for mice infected with
either AF210 or AF65. Amphotericin B at 2 and 5 (both regimens) mg/kg yielded a
70 to 100% survival rate for mice infected with AF210 but a 10 to 30% survival
rate for mice infected with AF65 (P = 0.01 to 0.04 compared with AF210). Against
AF210 and AF65, LY303366 at 2.5, 10, and 25 mg/kg produced a survival rate of 70
to 80%, which was as effective as amphotericin B for AF210, but superior to
amphotericin B for AF65 (P < 0.03 to 0.0006). For AF65, LY303366 at 10 and 25
mg/kg/day was superior to amphotericin B at 2 and 5 mg/kg/day in reducing tissue
colony counts (P = 0.01 to 0.003), and for AF210, amphotericin B at 5 mg/kg/day
and at 5 mg/kg in four doses was more effective than all four regimens of
LY303366 in reducing renal culture counts (P = 0.01 to 0.0001). The present study
shows, for the first time, that in vivo resistance of A. fumigatus to
amphotericin B exists, although this could not be detected by in vitro
susceptibility assays. Furthermore, LY303366 appears to be effective against
amphotericin B-susceptible and -resistant A. fumigatus infection in this model
and should be further evaluated clinically.
PMID- 9559800
TI - Discriminatory detection of inhibitor-resistant beta-lactamases in Escherichia
coli by single-strand conformation polymorphism-PCR.
AB - Plasmid-mediated mechanisms, comprising TEM hyperproduction, TEM derivative
production, and OXA production, lead to amoxicillin-clavulanic acid resistance in
enterobacteria. The ability of the single-strand conformation polymorphism (SSCP)
PCR method to differentiate the genes encoding inhibitor-resistant beta
lactamases was evaluated with three bla(TEM) primer pairs. The bla(TEM) genes,
which were known to be different on the basis of their nucleotide sequences
(bla[TEM-1A], bla[TEM-1B], bla[TEM-2], bla[TEM-30], bla[TEM-32], and bla[TEM
35]), were identified as different by their electrophoretic mobilities. The
bla(TEM-33), bla(TEM-34), bla(TEM-36), bla(TEM-37), bla(TEM-38), and bla(TEM-39)
genes, whose sequence differences have been established by oligotyping, displayed
different SSCP profiles for different fragments, suggesting genetic differences
in addition to those defined by oligotyping. Confirmed by sequencing, these
additional genetic events concerned silent mutations at certain positions and,
notably, a G-->T transversion at position 1 of the -10 consensus sequence in
bla(TEM-34), bla(TEM-36), bla(TEM-37), and bla(TEM-39). Applied to eight clinical
isolates of Escherichia coli resistant to amoxicillin-clavulanic acid, the SSCP
method detected TEM-1 in three strains and TEM-30, TEM-32, and TEM-35 in three
other strains, respectively. A novel TEM derivative (TEM-58) was detected in
another strain, and the deduced amino acid sequence showed two substitutions:
Arg244Ser, which is known to confer amoxicillin-clavulanic acid resistance in TEM
30, and Val261Ile, which has not been described previously. The eighth strain
produced an OXA beta-lactamase. Given the discriminatory power and the
applicability of SSCP-PCR, this method can be proposed as a means of following
the evolution of the frequencies of the different inhibitor-resistant beta
lactamases.
PMID- 9559801
TI - Double-blind evaluation of the safety and pharmacokinetics of multiple oral once
daily 750-milligram and 1-gram doses of levofloxacin in healthy volunteers.
AB - The safety and pharmacokinetics of once-daily oral levofloxacin in 16 healthy
male volunteers were investigated in a randomized, double-blind, placebo
controlled study. Subjects were randomly assigned to the treatment (n = 10) or
placebo group (n = 6). In study period 1, 750 mg of levofloxacin or a placebo was
administered orally as a single dose on day 1, followed by a washout period on
days 2 and 3; dosing resumed for days 4 to 10. Following a 3-day washout period,
1 g of levofloxacin or a placebo was administered in a similar fashion in period
2. Plasma and urine levofloxacin concentrations were measured by high-pressure
liquid chromatography. Pharmacokinetic parameters were estimated by model
independent methods. Levofloxacin was rapidly absorbed after single and multiple
once-daily 750-mg and 1-g doses with an apparently large volume of distribution.
Peak plasma levofloxacin concentration (Cmax) values were generally attained
within 2 h postdose. The mean values of Cmax and area under the concentration
time curve from 0 to 24 h (AUC0-24) following a single 750-mg dose were 7.1
microg/ml and 71.3 microg x h/ml, respectively, compared to 8.6 microg/ml and
90.7 microg x h/ml, respectively, at steady state. Following the single 1-g dose,
mean Cmax and AUC0-24 values were 8.9 microg/ml and 95.4 microg x h/ml,
respectively; corresponding values at steady state were 11.8 microg/ml and 118
microg x h/ml. These Cmax and AUC0-24 values indicate modest and similar degrees
of accumulation upon multiple dosing at the two dose levels. Values of apparent
total body clearance (CL/F), apparent volume of distribution (Vss/F), half-life
(t1/2), and renal clearance (CL[R]) were similar for the two dose levels and did
not vary from single to multiple dosing. Mean steady-state values for CL/F,
Vss/F, t1/2, and CL(R) following 750 mg of levofloxacin were 143 ml/min, 100
liters, 8.8 h, and 116 ml/min, respectively; corresponding values for the 1-g
dose were 146 ml/min, 105 liters, 8.9 h, and 105 ml/min. In general, the
pharmacokinetics of levofloxacin in healthy subjects following 750-mg and 1-g
single and multiple once-daily oral doses appear to be consistent with those
found in previous studies of healthy volunteers given 500-mg doses. Levofloxacin
was well tolerated at either high dose level. The most frequently reported drug
related adverse events were nausea and headache.
PMID- 9559802
TI - Use of a rapid throughput in vivo screen to investigate inhibitors of eukaryotic
topoisomerase II enzymes.
AB - Topoisomerase II catalyzes the passage of one DNA helix through another via a
transient double-stranded break. The essential nature of this enzyme in cell
proliferation and its mechanism of action make it an ideal target for cytotoxic
agents. Saccharomyces cerevisiae topoisomerase II has been frequently used as a
model for testing potential inhibitors of eukaryotic topoisomerase II as
antitumor agents. The standard in vivo method of estimating the sensitivity of S.
cerevisiae to the antitopoisomerase drugs is via inhibition or kill curves which
rely on viable-cell counts and is labor intensive. We present an alternative to
this, a high-throughput in vivo screen. This method makes use of a drug-permeable
S. cerevisiae strain lacking endogenous topoisomerase II, which is modified to
express either human topoisomerase IIalpha or IIbeta or S. cerevisiae
topoisomerase II carried on plasmids. Each modified strain expresses a full
length topoisomerase II enzyme, as opposed to the more commonly used temperature
sensitive S. cerevisiae mutant expressing yeast or yeast/human hybrid enzymes. A
comparison of this new method with a plating-and-counting method gave similar
drug sensitivity results, with increased accuracy and reduced manual input for
the new method. The information generated has highlighted the sensitivities of
different topoisomerase II enzymes and isoenzymes to several different classes of
topoisomerase II inhibitor.
PMID- 9559803
TI - Impact of bacterial biofilm formation on in vitro and in vivo activities of
antibiotics.
AB - The impact of bacterial adherence on antibiotic activity was analyzed with two
isogenic strains of Staphylococcus epidermidis that differ in the features of
their in vitro biofilm formation. The eradication of bacteria adhering to glass
beads by amikacin, levofloxacin, rifampin, or teicoplanin was studied in an
animal model and in a pharmacokinetically matched in vitro model. The features of
S. epidermidis RP62A that allowed it to grow on surfaces in multiple layers
promoted phenotypic resistance to antibiotic treatment, whereas strain M7 failed
to accumulate, despite initial adherence on surfaces and growth in suspension
similar to those for RP62A. Biofilms of S. epidermidis M7 were better eradicated
than those of strain RP62A in vitro (46 versus 31%; P < 0.05) as well as in the
animal model (39 versus 9%; P < 0.01).
PMID- 9559804
TI - Comparison of fungizone, Amphotec, AmBisome, and Abelcet for treatment of
systemic murine cryptococcosis.
AB - Three lipid-based formulations of amphotericin B have been approved for use in
various countries. The aim of this study was to compare Amphotec (ABCD; Sequus),
AmBisome (AmBi; Nexstar), Abelcet (ABLC; The Liposome Co.), and conventional
deoxycholate amphotericin B (Fungizone; Bristol Meyers Squibb) for the treatment
of experimental systemic cryptococcosis. A model was established in 10-week-old
female CD-1 mice by intravenous (i.v.) injection of 6.25 x 10(5) viable
Cryptococcus neoformans yeast cells. Therapy began 4 days later, with i.v.
administration three times per week for 2 weeks. Mice received either no
treatment, 1 mg of Fungizone per kg of body weight, or 1, 5, or 10 mg of ABCD,
AmBi, or ABLC per kg. Ninety percent of control mice died between days 15 and 34.
All treatment regimens except ABLC at 1 mg/kg prolonged survival compared with no
treatment (P < 0.01 to 0.001). All mice receiving 5 or 10 mg of ABCD or AmBi per
kg and 90% of mice given 10 mg of ABLC per kg survived, whereas < or =50% of
those given other treatment regimens survived. Fungizone was the least effective
of the four formulations, with 5 or 10 mg of ABCD, AmBi, or ABLC per kg resulting
in a significantly better outcome than Fungizone (P < 0.001). Among the three
formulations, ABCD and AmBi were equally effective, both being better than ABLC
at equal 5- or 10-mg/kg doses (P < 0.001). Comparison of residual infectious
burdens in various organs showed that each drug had some dose-responsive efficacy
in three or more organs at escalating doses. In the brain, ABCD or AmBi at 5 or
10 mg/kg or ABLC at 10 mg/kg was more effective than Fungizone at 1 mg/kg or no
treatment, while ABCD or AmBi at 1 mg/kg was as effective as ABLC at 10 mg/kg.
Similar results were obtained for the kidneys and lungs. In the spleen, ABCD at
10 mg/kg cured all mice of infection and was superior to all other regimens. In
the liver, AmBi at 5 mg/kg was superior to an equal dose of ABCD or ABLC.
Overall, the efficacies of ABCD and AmBi were equal to that of Fungizone at 1
mg/kg and were about 10-fold better than that of ABLC, particularly in the brain;
a comparative rank order of efficacies was ABCD approximately equal to AmBi >
ABLC >> Fungizone. This is the first study that compared all four amphotericin B
formulations.
PMID- 9559805
TI - Pharmacokinetics of two multiple-dosing regimens of D0870 in human
immunodeficiency virus-positive patients: a phase I study.
AB - D0870 is a triazole with a broad antifungal spectrum, and it has been shown to
have both in vitro and in vivo activities against wild-type and fluconazole
resistant strains of Candida albicans. Twenty-two human immunodeficiency virus
(HIV)-positive male subjects were enrolled in an open, nonrandomized trial
investigating the pharmacokinetics of two different dosing regimens of D0870 and
assessing the safety of multiple oral doses of D0870 in HIV-positive subjects and
their ability to tolerate multiple oral doses. Nine subjects received an initial
loading dose of 50 mg, followed by four once-daily maintenance doses of 10 mg. A
further nine subjects received an initial 200-mg loading dose followed by four
daily maintenance doses of 25 mg. All subjects were fasting. A single loading
dose of 50 mg of D0870 resulted in a mean maximum concentration in serum (Cmax)
of 107 +/- 32 ng/ml. Concentrations in plasma were maintained by the 10-mg once
daily dosing regimen as seen by the similar values of the area under the
concentration-time curve from 0 to 24 h following dosing on days 1 and 5 and a
mean accumulation ratio close to unity (0.90). The terminal plasma half-life of
D0870 in plasma following dosing on day 5 ranged from 23 to 85 h (mean, 49 h). A
single loading dose of 200 mg of D0870 resulted in a Cmax of 431 +/- 186 ng/ml.
Concentrations in plasma were again maintained by the 25-mg daily dosing regimen,
with the mean accumulation ratio being close to unity (1.17). The terminal half
life of D0870 in plasma following dosing on day 5 of phase II of the study ranged
from 34 to 137 h (mean, 71 h). In addition, the concentrations achieved in the
plasma of these HIV-positive subjects were similar to the values predicted from
simulations based on data derived from normal, healthy subjects. D0870 was well
tolerated. No serious adverse events were experienced during the course of the
study, and all volunteers completed the trial. A total of 15 adverse events were
reported, but none were considered to be related to the administration of D0870
and all had resolved by the end of the trial. No changes in the hematology,
clinical chemistry, or urinalysis parameters were considered to be related to
dosing with D0870. No clinically significant changes in the electrocardiogram
parameters were noted during the trial. The data generated in this trial support
further investigation of these regimens with HIV-positive subjects with
fluconazole-susceptible or -resistant oropharyngeal candidosis.
PMID- 9559807
TI - Synthesis and antibacterial evaluation of novel water-soluble organic peroxides.
AB - A set of new water-soluble organic peroxides has been synthesized and evaluated
for in vitro antibacterial activity as part of an effort to develop new
antibacterial agents for the treatment of acne vulgaris. The water solubility of
these new dialkyl peroxides and peroxyesters was achieved by incorporating either
a quaternary ammonium group or a polyethylene glycol moiety. These peroxides are
effective against both gram-positive and gram-negative bacteria and have a
prolonged activity compared to that of benzoyl peroxide and other peroxide-type
antiseptic agents. Among them 4-[[(tert
butylperoxy)carbonyl]benzyl]triethylammonium chloride and [10-(tert
butylperoxy)decyl]trimethylammonium bromide have the broadest antimicrobial
spectrums. We have shown that the oxidizing properties of the dioxy group of
these compounds are responsible for their antibacterial activities.
PMID- 9559806
TI - Activity of voriconazole, a new triazole, combined with neutrophils or monocytes
against Candida albicans: effect of granulocyte colony-stimulating factor and
granulocyte-macrophage colony-stimulating factor.
AB - The antifungal activity of voriconazole (VCZ) was tested against Candida albicans
in the absence or presence of polymorphonuclear neutrophils (PMN) or monocytes.
In some experiments, VCZ was compared to fluconazole (FCZ). On a weight basis,
VCZ was 10-fold more efficacious than FCZ against C. albicans Sh27. Against an
FCZ-resistant isolate, VCZ at 1 microg/ml produced the same fungistasis as FCZ at
20 microg/ml. VCZ at 0.1 microg/ml collaborated with PMN for enhanced killing to
the same extent as FCZ at 1.0 microg/ml. Granulocyte-colony-stimulating factor (G
CSF) enhanced the candidacidal activity of PMN, and it increased the
collaboration of PMN with VCZ for killing. Granulocyte-macrophage (GM)-CSF also
significantly enhanced both the killing by PMN and the collaboration of PMN with
VCZ for killing. VCZ collaborated with GM-CSF-activated monocytes [corrected] for
enhanced killing of C. albicans Sh27, and GM-CSF increased this collaboration.
Taken together, these data show that VCZ is more potent than FCZ against C.
albicans isolates, alone and in collaboration with PMN or monocytes for enhanced
killing. In addition, G-CSF- or GM-CSF-activated PMN and monocytes have enhanced
collaboration with VCZ compared to that of unstimulated phagocytes with VCZ.
PMID- 9559808
TI - Dual inhibition of human rhinovirus 2A and 3C proteases by homophthalimides.
AB - The 2A and 3C proteases encoded by human rhinoviruses (HRVs) are attractive
targets for antiviral drug development due to their important roles in viral
replication. Homophthalimides were originally identified as inhibitors of
rhinovirus 3C protease through our screening effort. Previous studies have
indicated that the antiviral activity of certain homophthalimides exceeded their
in vitro inhibitory activity against the viral 3C protease, suggesting that an
additional mechanism might be involved. Reported here is the identification of
homophthalimides as potent inhibitors for another rhinovirus protease, designated
2A. Several homophthalimides exhibit time-dependent inhibition of the 2A protease
in the low-micromolar range, and enzyme-inhibitor complexes were identified by
mass spectrometry. Compound LY343814, one of the most potent inhibitors against
HRV14 2A protease, had an antiviral 50% inhibitory concentration of 4.2 microM in
the cell-based assay. Our data reveal that homophthalimides are not only 3C but
also 2A protease inhibitors in vitro, implying that the antiviral activity
associated with these compounds might result from inactivation of both 2A and 3C
proteases in vivo. Since the processing of the viral polyprotein is hierarchical,
dual inhibition of the two enzymes may result in cooperative inhibition of viral
replication. On the basis of the current understanding of their enzyme inhibitory
mechanism, homophthalimides, as a group of novel nonpeptidic antirhinovirus
agents, merit further structure-action relationship studies.
PMID- 9559809
TI - Overexpression, purification, and characterization of the cloned metallo-beta
lactamase L1 from Stenotrophomonas maltophilia.
AB - The metallo-beta-lactamase L1 from Stenotrophomonas maltophilia was cloned,
overexpressed, and characterized by spectrometric and biochemical techniques.
Results of metal analyses were consistent with the cloned enzyme having 2 mol of
tightly bound Zn(II) per monomer. Gel filtration chromatography demonstrated that
the cloned enzyme exists as a tightly held tetramer with a molecular mass of ca.
115 kDa, and matrix-assisted laser desorption ionization and time-of-flight mass
spectrometry indicated a monomeric molecular mass of 28.8 kDa. Steady-state
kinetic studies with a number of diverse penicillin and cephalosporin antibiotics
demonstrated that L1 effectively hydrolyzes all tested compounds, with k(cat)/Km
values ranging between 0.002 and 5.5 microM(-1) s(-1). These characteristics of
the recombinant enzyme are contrasted to those previously reported for metallo
beta-lactamases isolated directly from S. maltophilia.
PMID- 9559810
TI - Effect of grapefruit juice on clarithromycin pharmacokinetics.
AB - To investigate whether grapefruit juice inhibits the metabolism of
clarithromycin, 12 healthy subjects were given water or grapefruit juice before
and after a clarithromycin dose of 500 mg in a randomized crossover study.
Administration of grapefruit juice increased the time to peak concentration of
both clarithromycin (82 +/- 35 versus 148 +/- 83 min; P = 0.02) and 14
hydroxyclarithromycin (84 +/- 38 min versus 173 +/- 85; P = 0.01) but did not
affect other pharmacokinetic parameters.
PMID- 9559811
TI - Fluconazole pharmacokinetics in burn patients.
AB - The pharmacokinetics of fluconazole in nine adult patients with severe (30 to 95%
total body surface area) burns were studied. There was no significant difference
in half-life (t1/2), clearance (CL), or volume of distribution (V) over time in
five patients on days 3 and 8 of the study (P > 0.05). Combined parameter
estimates (means +/- standard deviations) for all nine patients for the two study
periods were as follows: t1/2, 24.4 +/- 5.8 h; CL, 0.36 +/- 0.09 ml/min/kg; and
V, 0.72 +/- 0.12 liters/kg. These estimates of t1/2 and CL in burn patients were
approximately 13% shorter and 30% more rapid, respectively, than the most extreme
estimates reported for other populations.
PMID- 9559812
TI - Efficacy of sulfamethoxypyridazine in a murine model of Pneumocystis carinii
pneumonia.
AB - Sulfamethoxazole is the component of co-trimoxazole responsible for its efficacy
against Pneumocystis carinii pneumonia, but this drug is associated with frequent
adverse effects. Sulfamethoxypyridazine is significantly more effective than
sulfamethoxazole against a murine model of P. carinii and might be a candidate
for testing in infected patients.
PMID- 9559813
TI - Increased overall antibiotic susceptibility in Staphylococcus aureus femAB null
mutants.
AB - The staphylococcal pentaglycine side chain of the peptidoglycan is reduced to one
glycine in femAB null mutants. This is associated with increased susceptibility
to methicillin and to a whole range of unrelated antibiotics as well. Genetic
evidence suggests that femAB null mutants are only viable because of a
compensatory mutation in an unlinked site.
PMID- 9559814
TI - Effects of slime produced by clinical isolates of coagulase-negative
staphylococci on activities of various antimicrobial agents.
AB - A novel in vitro semiquantitative method was developed to investigate the
influence of staphylococcal slime on the activities of 22 antimicrobial agents.
Pefloxacin, teicoplanin, and vancomycin demonstrated remarkable decreases in
efficacy: 30, 52, and 63%, respectively. The activity of rifampin was not
significantly reduced (0.99%), whereas all other agents tested were modestly
affected (<15% decrease). These data could be influential in the treatment of
implant-associated infections caused by slime-producing staphylococci.
PMID- 9559815
TI - Comparative in vitro killing activities of meropenem, imipenem, ceftriaxone, and
ceftriaxone plus vancomycin at clinically achievable cerebrospinal fluid
concentrations against penicillin-resistant Streptococcus pneumoniae isolates
from children with meningitis.
AB - The activities of meropenem, imipenem, ceftriaxone, and vancomycin were evaluated
against 80 penicillin-susceptible and -resistant Streptococcus pneumoniae
strains. Meropenem, imipenem, ceftriaxone, and vancomycin MICs at which 90% of
the isolates are inhibited were 0.5, 0.25, 1, and 0.25 microg/ml, respectively.
Against penicillin-resistant strains, the best killing activity at cerebrospinal
fluid concentrations was obtained with imipenem and ceftriaxone-vancomycin.
However, while the killing activity of imipenem was significantly greater than
that of meropenem, no significant difference was observed between the activities
of meropenem and ceftriaxone-vancomycin.
PMID- 9559816
TI - Antipneumococcal activities of a ketolide (HMR 3647), a streptogramin
(quinupristin-dalfopristin), a macrolide (erythromycin), and a lincosamide
(clindamycin).
AB - Four different compounds belonging to the macrolide-lincosamide-streptogramin B
(MLSb) class of antimicrobial agents were tested against 611 Streptococcus
pneumoniae strains. The ketolide (HMR 3647, previously RU66647) and the
streptogramin (quinupristin-dalfopristin) were both active against pneumococci
with high-level MLSb resistance (clindamycin-resistant strains) as well as those
with low-level macrolide resistance (clindamycin-susceptible strains).
PMID- 9559817
TI - Ribosomes from an oxazolidinone-resistant mutant confer resistance to eperezolid
in a Staphylococcus aureus cell-free transcription-translation assay.
AB - Oxazolidinone-resistant mutants of Staphylococcus aureus, isolated with a spiral
plating technique, had a 16-fold higher MIC (2 versus 32 microg/ml) of eperezolid
when compared to the parental sensitive strain. Eperezolid inhibited in vitro
protein translation with 50% inhibitory concentrations of 30 microM for the
oxazolidinone-sensitive S30 extract and 75 microM for the resistant extract.
Experiments mixing various combinations of S100 and crude ribosome preparations
from oxazolidinone-sensitive and -resistant S. aureus strains in a transcription
translation assay demonstrated that the resistant determinant resided within the
ribosomal fraction. Ribosomes from the oxazolidinone-resistant strain bound less
drug than ribosomes from the sensitive strain, indicating that the ribosome is
the site of action for the oxazolidinones. These experiments demonstrate that an
alteration of the ribosome is responsible for some or all of the oxazolidinone
resistance observed in the S. aureus mutant.
PMID- 9559818
TI - In vitro activity of a new 8-methoxyquinolone, BAY 12-8039, against Chlamydia
pneumoniae.
AB - The in vitro susceptibilities of 10 strains of Chlamydia pneumoniae to a new 8
methoxyquinolone, BAY 12-8039, and to ofloxacin, doxycycline, and erythromycin
were determined. The activity of BAY 12-8039 was similar to that of ofloxacin,
with a MIC at which 90% of the isolates had no inclusions and a minimal
chlamydicidal concentration at which 90% of the isolates had no inclusions after
passage of 1.0 microg/ml, but this activity was less than those of doxycycline
and erythromycin.
PMID- 9559819
TI - Determination of activities of levofloxacin, alone and combined with gentamicin,
ceftazidime, cefpirome, and meropenem, against 124 strains of Pseudomonas
aeruginosa by checkerboard and time-kill methodology.
AB - A total of 124 Pseudomonas aeruginosa strains were tested for synergy between
levofloxacin and cefpirome, ceftazidime, gentamicin, and meropenem. Checkerboards
yielded synergistic fractional inhibitory concentration (FIC) indices (< or =0.5)
with 25 of 496 possible combinations. All other FIC indices were >0.5 to 2
(additive or indifferent), with no antagonism. Time-kill studies with 12 strains
showed that levofloxacin (0.06 to 0.5 microg/ml) was synergistic with cefpirome,
ceftazidime, gentamicin, and meropenem in 10, 9, 4, and 11 strains, respectively.
PMID- 9559820
TI - Killing of Staphylococcus aureus by C-8-methoxy fluoroquinolones.
AB - C-8-methoxy fluoroquinolones were more lethal than C-8-bromine, C-8-ethoxy, and C
8-H derivatives for Staphylococcus aureus, especially when topoisomerase IV was
resistant. The methoxy group also increased lethality against wild-type cells
when protein synthesis was inhibited. These properties encourage refinement of C
8-methoxy fluoroquinolones to kill staphylococci.
PMID- 9559822
TI - Transferable, plasmid-mediated vanB-type glycopeptide resistance in Enterococcus
faecium.
AB - An approximately 60-kb transferable, vanB-carrying plasmid has been identified in
a clinical Enterococcus faecium strain. A similar plasmid has been observed in an
unrelated E. faecium strain, suggesting that plasmid transfer of vanB operons
occurs in nature and plays a role in the dissemination of VanB-type resistance
among strains of E. faecium.
PMID- 9559821
TI - Mutations in aarE, the ubiA homolog of Providencia stuartii, result in high-level
aminoglycoside resistance and reduced expression of the chromosomal
aminoglycoside 2'-N-acetyltransferase.
AB - The aarE1 allele was identified on the basis of the resulting phenotype of
increased aminoglycoside resistance. The aarE1 mutation also resulted in a small
colony phenotype and decreased levels of aac(2')-Ia mRNA. The deduced AarE gene
product displayed 61% amino acid identity to the Escherichia coli UbiA protein,
an octaprenyltransferase required for the second step of ubiquinone biosynthesis.
Complementation experiments in both Providencia stuartii and E. coli demonstrated
that aarE and ubiA are functionally equivalent.
PMID- 9559824
TI - In vitro and in vivo antidermatophyte activities of NND-502, a novel optically
active imidazole antimycotic agent.
AB - In vitro and in vivo antidermatophyte activities of NND-502, a new imidazole
antimycotic agent, were compared with those of two existing antifungal agents,
lanoconazole and terbinafine. NND-502 exhibited strong in vitro antifungal
activity against Trichophyton spp.; its MIC was 1 to 4 times lower than that of
lanoconazole or terbinafine. In an in vivo study with a guinea pig model of tinea
pedis, 7-day topical treatment with a 0.5% solution of NND-502 (dissolved in
polyethylene glycol 400) was more effective than that with a 0.5% solution of
either lanoconazole or terbinafine for eradicating fungi from the infected feet.
When the duration of treatment was shortened to 3 days, a topical 1% solution of
NND-502 achieved a complete mycological cure, while topical 1% solutions of
lanoconazole and terbinafine did not.
PMID- 9559823
TI - In vitro susceptibilities of Bordetella pertussis and Bordetella parapertussis to
two ketolides (HMR 3004 and HMR 3647), four macrolides (azithromycin,
clarithromycin, erythromycin A, and roxithromycin), and two ansamycins (rifampin
and rifapentine).
AB - When tested by agar dilution on Mueller-Hinton agar supplemented with 5% horse
blood, the ketolides HMR 3004 and HMR 3647 were slightly more active (MIC at
which 90% of the isolates were inhibited [MIC90], 0.03 microg/ml) against
Bordetella pertussis than azithromycin, clarithromycin, erythromycin A, and
roxithromycin. Azithromycin (MIC90, 0.06 microg/ml) was the most active compound
against B. parapertussis. Rifampin and rifapentine were considerably less active.
PMID- 9559825
TI - Human cytomegalovirus mutant with sequence-dependent resistance to the
phosphorothioate oligonucleotide fomivirsen (ISIS 2922).
AB - A human cytomegalovirus mutant that was isolated for resistance (10-fold) to the
antisense oligonucleotide fomivirsen (ISIS 2922) exhibited cross-resistance to a
modified derivative of fomivirsen with an identical base sequence but little or
no resistance to an oligonucleotide with an unrelated sequence. No changes in the
mutant's DNA corresponding to the fomivirsen target sequence were found.
PMID- 9559826
TI - Alginate lyase promotes diffusion of aminoglycosides through the extracellular
polysaccharide of mucoid Pseudomonas aeruginosa.
AB - We demonstrated that a 2% suspension of Pseudomonas aeruginosa alginate
completely blocked the diffusion of gentamicin and tobramycin, but not that of
carbenicillin, illustrating how alginate production can help protect P.
aeruginosa growing within alginate microcolonies in patients with cystic fibrosis
(CF) from the effects of aminoglycosides. This aminoglycoside diffusion barrier
was degraded with a semipurified preparation of P. aeruginosa alginate lyase,
suggesting that this enzyme deserves consideration as an adjunctive agent for CF
patients colonized by mucoid strains of P. aeruginosa.
PMID- 9559827
TI - Susceptibilities of clinical and laboratory isolates of Blastomyces dermatitidis
to ketoconazole, itraconazole, and fluconazole.
AB - Eighteen isolates of Blastomyces dermatitidis were evaluated for their in vitro
susceptibilities to ketoconazole, itraconazole, and fluconazole. The MIC ranges
were 0.1 to 0.4 microg/ml for ketoconazole, < or =0.018 to 0.07 microg/ml for
itraconazole, and 2.5 to 4.0 microg/ml for fluconazole. The ranges for the
minimal lethal concentrations were 0.2 to 0.8 microg/ml for ketoconazole, < or
=0.018 to 0.07 microg/ml for itraconazole, and 10 to 40 microg/ml for
fluconazole. Itraconazole was the most active agent against B. dermatitidis in
vitro, while fluconazole was the least active. These results correlate with the
clinical efficacies noted to date with doses of these agents used to treat
blastomycosis.
PMID- 9559828
TI - Efficacy of LY333328 against experimental methicillin-resistant Staphylococcus
aureus endocarditis.
AB - The in vivo efficacy of LY333328, a new glycopeptide antibiotic, was compared
with that of vancomycin by using the rabbit model of left-sided methicillin
resistant Staphylococcus aureus endocarditis. Animals received LY333328 or
vancomycin (25 mg/kg of body weight every 24 or 8 h, respectively) for 4 days.
These drugs were equally effective in clearing bacteremia and in reducing
bacterial counts in vegetations and tissues. We conclude that in this model,
LY333328 was microbiologically effective and may be a therapeutic alternative to
vancomycin.
PMID- 9559829
TI - In vitro activity of levofloxacin against a selected group of anaerobic bacteria
isolated from skin and soft tissue infections.
AB - The in vitro activity of levofloxacin was compared to the activities of
ofloxacin, ciprofloxacin, ampicillin-sulbactam (2:1), cefoxitin, and
metronidazole for a selected group of anaerobes (n = 175) isolated from skin and
soft tissue infections by using the National Committee for Clinical Laboratory
Standards-approved Wadsworth method. Ampicillin-sulbactam and cefoxitin inhibited
99% of the strains of this select group, levofloxacin and ofloxacin inhibited 73
and 50%, respectively, at 2 microg/ml, and ciprofloxacin inhibited 51% at 1
microg/ml. The geometric mean MIC of levofloxacin was lower than those of
ofloxacin and ciprofloxacin for every group except Veillonella.
PMID- 9559830
TI - New antimicrobial agents approved by the U.S. Food and Drug Administration in
1997 and new indications for previously approved agents.
PMID- 9559831
TI - Emergence of erythromycin-resistant, clindamycin-susceptible Streptococcus
pyogenes isolates in Madrid, Spain.
PMID- 9559832
TI - Synergistic activity of trovafloxacin and ceftriaxone or vancomycin against
Streptococcus pneumoniae with various penicillin susceptibilities.
PMID- 9559833
TI - Pathophysiology of clinical varicoceles in infertile men.
AB - In infertile men, clinical varicoceles most often occur bilaterally. In our
experience with these patients, both testicles are smaller than normal. We find
more than 25% to 35% immature and tapered sperm in in the ejaculum of these men,
and the motility of the sperm is usually low. We have found serotonin in the
plasma of the varicoceles, and believe this biogenic amine is responsible for the
poor sperm motility. We now agree that a subset of neuroendocrine cells in the
prostate secrete serotonin. Bilateral varicocele surgery can improve the
patient's fertility potential, and we advocate surgical treatment.
PMID- 9559834
TI - Preliminary report of a modified continent appendix stoma in a sigmoid urinary
reservoir pouch.
AB - BACKGROUND: The application of an appendix stoma in a Mainz urinary reservoir
pouch is an established procedure and assures good continence. We modified this
method for use with a sigmoid pouch. METHODS: In each of 3 men with bladder
carcinoma, an appendix with a blood supply was prepared and anastomosed to the
detubularized sigmoid pouch with a 3-cm submucosal tunnel. RESULTS: In all 3
patients, this procedure was performed successfully, and the pouch was completely
continent. Self-catheterization could be performed without difficulty by 2
patients, and with slight resistance in the remaining patient. The patients are
satisfied with their quality of life. CONCLUSIONS: We conclude, based on our
findings and these preliminary observations, that this procedure is a potentially
good alternative for the placement of continent stoma in continent urinary
reservoir surgery.
PMID- 9559835
TI - Evaluation of the prognostic significance of microvessel count and tumor size in
renal cell carcinoma.
AB - BACKGROUND: We analyzed the significance of tumor microvessel count and tumor
size as prognostic factors for renal cell carcinoma (RCC). METHODS: T criteria
(local invasion), M criteria (distant metastasis), macrovenous invasion,
histological grade, cell type, tumor size, and tumor microvessel count were
investigated as prognostic factors in 62 patients with RCC. Microvessel density
was evaluated by immunohistochemical staining of the endothelial cells. RESULTS:
No significant correlation was found between tumor size and the other prognostic
factors. Analysis of the survival rate based on tumor size revealed that patients
with a small tumor tended to show a good prognosis, but no significant difference
was found in the prognosis between medium-sized and large-sized tumor groups.
Analysis of all patients revealed that M criteria, macrovenous invasion, cell
type and microvessel count were significant factors and that in 37 patients with
low-stage tumors, the only significant prognostic factor was microvessel count
(P=0.003). CONCLUSION: Tumor size cannot be readily justified as a determinant of
prognosis in patients with medium- or large-sized tumors. In patients with low
stage tumors, microvessel count served as the only significant determinant for
prognosis. When the patients were considered as a whole, microvessel count, M
criteria, macrovenous invasion and histological grade were significant prognostic
factors.
PMID- 9559836
TI - Clinical study of renal cell carcinoma with brain metastasis.
AB - BACKGROUND: The clinical outcome of patients with renal cell carcinoma with brain
metastasis was analyzed. METHODS: Nine patients (median age, 60 years) with
primary renal cell carcinoma and distant metastasis, including brain metastasis,
were treated. The median time to the development of brain metastasis was 15
months after the initial visit. Patients with poor performance status or
progressive disease were treated with interferon or conservative therapy alone.
Patients with good performance status and other well-controlled metastatic foci
were treated either with radiotherapy, or by tumorectomy of brain metastasis, or
both. The median follow-up was 26 months after the initial visit. RESULTS: The 1
year, cause-specific survival rate was 17%. Of the 5 patients treated with alpha
interferon alone, all died of disease after the treatments, without improvement
of performance status, 1 to 4 months after the diagnosis of brain metastasis. Two
of 4 patients who underwent radiotherapy were treated with a combination of gamma
knife and tumorectomy of brain metastasis. They remained alive 10 and 22 months
after diagnosis of brain metastasis. The 2 patients who underwent the combination
treatment of gamma-knife and tumorectomy showed improvement of their performance
status after these treatments for brain metastasis. CONCLUSION: Brain metastasis
is an unfavorable prognostic factor in renal cell carcinoma. Although a larger
number of patients would be necessary to demonstrate the definitive effects of
gamma-knife treatment, our results suggest that the combination of gamma-knife
and tumorectomy of brain metastases may be recommended for selected patients with
good performance status and other well-controlled metastatic foci.
PMID- 9559837
TI - Combined treatment of staghorn calculi by fiberoptic transurethral
nephrolithotripsy and extracorporeal shock wave lithotripsy.
AB - BACKGROUND: Although various strategies have been proposed, the treatment of
staghorn calculi is still controversial. We report on the treatment of 27
staghorn calculi using fiberoptic transurethral nephrolithotripsy (f-TUL)
combined with extracorporeal shock wave lithotripsy (ESWL). METHODS: Stones were
initially disintegrated by f-TUL as an inpatient procedure. For stone
fragmentation, we originally used an electrohydraulic lithotriptor (EHL) but
changed to a pulsed-dye laser in 1993. After the stones were disintegrated as
much as possible, a double-J ureteral stent was inserted and the patient was
discharged. ESWL for the residual fragments was begun on an outpatient basis at 1
or 2 weeks after f-TUL and repeated until the residual fragments were smaller
than 4 mm. RESULTS: Since 1989, 27 staghorn calculi in 26 patients have been
treated. Among them, 21 were successfully fragmented using this combined
treatment regimen. From 3 to 26 ESWL sessions (mean, 8.4 sessions) were required
to disintegrate the staghorn calculi. Auxiliary percutaneous endourological
procedures were necessary in 2 cases due to ureteral obstruction. The other 4
patients are still receiving ESWL for residual fragments. Urinary tract injury
occurred in 2 patients early in this series when an EHL was used, but was managed
without any surgical procedures. A fever greater than 38 degrees C developed in 9
patients. CONCLUSION: Combining f-TUL with ESWL provides an alternative treatment
option for staghorn calculi. The use of a small caliber fiberscope (2.6 mm in
diameter) and a laser for fragmentation decreased the risk of complications.
PMID- 9559838
TI - Smoking and obesity in relation to the etiology and disease progression of
prostate cancer in Japan.
AB - BACKGROUND: Various risk factors have been investigated concerning the etiology
of prostate carcinoma, but many questions about the significance of the risk
factors remain unanswered. To evaluate the relationship between smoking and
obesity in prostate cancer, a case-control study was performed. METHODS: Between
1986 and 1995, 329 patients with untreated prostate cancer and 188 patients with
benign prostate hyperplasia (control patients) were evaluated according to their
smoking habits and the degree of obesity. Also, the progression of prostate
cancer in relationship to smoking and obesity was examined. RESULTS: Smoking and
obesity were not risk factors for the development of prostate cancer (odds ratio,
0.986, 0.836; 95% confidence interval, 0.69-1.41, 0.57-1.24, respectively). Nor
were smoking or obesity a risk factor for survival in stage D2 patients, however,
in stage B1-D1 patients, obese men had a tendency for disease progression.
CONCLUSION: This study demonstrated that neither smoking nor obesity increase the
risk of developing prostate cancer, or the risk of disease progression in
prostate cancer patients. However, obese men have a tendency for progression of
stage B1-D1 prostate cancer although further studies are necessary to confirm
this finding.
PMID- 9559839
TI - Familial prostate cancer in Japan.
AB - BACKGROUND: Familial prostate cancer has been studied in Europe and the United
States. This study was conducted to clarify the clinical features and incidence
of the human leukocyte antigen (HLA) in familial prostate cancer in patients seen
at hospitals in Japan. METHODS: The age at diagnosis, clinical stage, histologic
differentiation, prognosis, cause of death and family history were compiled from
43 patients from 20 families with familial prostate cancer (group F) and compared
in patients with sporadic prostate cancer (group S). In addition, HLA class II
gene typing was performed in 17 patients from 11 families with familial prostate
cancer (group F') and their healthy family members (15 males and 25 females).
RESULTS: The age at diagnosis was significantly lower in group F patients (P<
0.001), but neither clinical stage nor prognosis differed between group F and
group S, yet the incidence of moderately differentiated adenocarcinoma was
significantly higher in group F (P< 0.01 ). There were no historical factors that
were specific for group F patients. The frequency of HLA-DRB1 *0901 and *1201
alleles was significantly higher in group F' patients than in group J (the
frequency of alleles in 1216 Japanese people attending the 11th Japan HLA
Workshop), but not between group F' and their healthy male family members.
CONCLUSION: There were no significant differences in clinical parameters between
group F and group S, except that the age at diagnosis was lower in group F
patients, and that the frequency of several HLA class 11 alleles was
significantly higher in patients with prostate cancer. In men with a family
history of prostate cancer, examinations for early detection of prostate cancer
should begin at a young age.
PMID- 9559840
TI - Public awareness and knowledge of prostate cancer in Japan: results of a survey
at short-stay examination facilities.
AB - BACKGROUND: This study was undertaken to determine public awareness and knowledge
of prostate cancer, which has not been adequately studied in Japan. METHODS:
Assessment was made of public awareness and perception of prostate cancer in
Japan, based on health examination data for participants in a short-stay physical
examination program ("human dry dock"). A multiple-choice, thirty-point
questionnaire survey was conducted at 3 "human dry dock" medical facilities
situated in urban areas. RESULTS: Many Japanese adults appeared to be
inadequately aware of prostate cancer and of the means available for its early
detection. One third of the participants were unfamiliar with this malignancy.
Logistic regression analysis indicated smoking to be the only covariate
associated with lack of knowledge of prostate cancer (P< 0.05). Seventy-one
percent of the subjects had heard of digital rectal examination, but only 16% and
8%, respectively, were familiar with the terms transrectal ultrasonography and
PSA testing. Japanese people may possibly be less informed about prostate cancer
than African-American males. Both "human dry dock" facilities and subject gender
were significantly associated with knowledge of digital rectal examination (P<
0.05). Knowledge of transrectal ultrasonography was found to depend on
participation in "human dry dock" programs and level of education (P< 0.05).
Smoking, participation in "human dry dock" programs under employer direction, and
health status were all identified as determinants for knowledge of PSA testing
(P< 0.05). CONCLUSION: Educational programs should be established and put into
effect to instill adequate awareness of prostate cancer in Japan. In a better
informed society, more effort would be directed toward prevention and thus early
stage prostate cancer would be detected more often.
PMID- 9559841
TI - Holmium:YAG laser resection of the prostate versus visual laser ablation of the
prostate and transurethral ultrasound-guided laser induced prostatectomy: a
retrospective comparative study.
AB - BACKGROUND: Transurethral resection of the prostate (TUR-P) is the gold standard
for treating symptomatic benign prostatic hyperplasia (BPH) despite some
perioperative morbidity. As a minimally-invasive alternative to TUR-P, a
neodymium:YAG laser, and more recently a holmium:YAG laser, have been used in
transurethral surgery for BPH. In order to assess the safety and efficacy of
various BPH treatments, the outcome in patients treated with transurethral
ultrasound-guided laser induced prostatectomy (TULIP), visual laser ablation of
the prostate (VLAP) and holmium:YAG laser resection of the prostate (HoLRP) were
retrospectively compared. METHODS: From May 1995 to August 1996, 60 patients with
symptomatic BPH underwent TULIP (n=20), VLAP (n=20), and HoLRP (n=20). All
patients were evaluated preoperatively and at 1 and 3 months postoperatively by
the International Prostate Symptom Score (IPSS), the IPSS quality-of-life score
(QOL), maximum flow rate (MFR), prostate volume, and residual urine volume.
RESULTS: The preoperative mean IPSS was 18.5, 19.3, and 19.6 and the mean MFR was
6.3, 6.9, and 6.1 mL/sec in the TULIP, VLAP, and HoLRP groups, respectively. At 1
month after surgery, the mean IPSS was 10.2, 9.5, and 4.7 and the mean MFR was
9.6, 13.4, and 18.7 mL/sec while at 3 months the mean IPSS was 6.2, 6.1, and 3.6
and the mean MFR was 14.1, 16.0, and 21.5 mL/sec in patients treated with TULIP,
VLAP, and HoLRP, respectively. No serious complication occurred in any patient.
CONCLUSION: Although HoLRP requires expertise, it appears to be a promising
treatment modality for BPH.
PMID- 9559842
TI - Transrectal microwave hyperthermia for patients with benign prostatic
hyperplasia.
AB - BACKGROUND: A randomized study evaluated the efficacy of treatment with
transrectal microwave hyperthermia (TMH) treatment in patients with benign
prostatic hyperplasia (BPH). METHODS: Eighty BPH patients received TMH therapy
and 20 patients were given a sham treatment. TMH was achieved using a
prostathermer which includes a microwave transrectal heat generator, a cooling
system and a transurethral sensor probe. Patients that received TMH had 5 to 6
sessions of 1 hour each where the prostate was heated to 42 degrees C to 43.5
degrees C. The sham treatment consisted of a single session where the temperature
was maintained at 37 degrees C. All patients were evaluated at 3 and 12 months
after treatment. RESULTS: There was an improvement of subjective obstructive
symptoms in 54 patients (75%) after TMH. An evaluation of urodynamic parameters
revealed an increase in the maximum flow rate and a decrease of the detrusor
opening pressure as well as the detrusor pressure at maximum flow in patients
treated with TMH. A significant improvement in the amount of residual urine was
seen in all TMH-treated patients (P < 0.0001). CONCLUSION: Although TMH cannot be
considered a superior alternative to open surgical or transurethral excision of
the prostate, it is a valid option for patients who have indwelling urethral
catheters and for those at high surgical risk.
PMID- 9559843
TI - Role of the transition zone for elevating serum prostate-specific antigen in
benign prostatic hyperplasia.
AB - BACKGROUND: Patients with benign prostatic hyperplasia (BPH) have a wide range of
concentrations of PSA. However, it is not known what factors influence the
concentration of serum PSA other than the prostate volume. BPH is composed of an
enlarged transition zone (TZ) and other zones (nonTZ). The TZ is thought to play
a more important role than the nonTZ in determining the concentration of serum
PSA in BPH patients. METHODS: We investigated the individual glandular zone
volume, the amount of PSA produced by each zone and the PSA density in each zone
in 23 patients with histologically-confirmed BPH. The PSA density in the TZ was
calculated by dividing the difference between the serum PSA before and after
surgical resection by the specimen weight. We examined the influence of these
parameters on the concentration of serum PSA in BPH patients. RESULTS: The serum
PSA concentration correlated with the amount of PSA produced by the TZ (r=0.90,
P< 0.0 1), but not the nonTZ (r=0.25, P=0.29). The concentration of serum PSA
also showed a significant correlation with the TZ volume (r=0.67, P< 0.01) and
the PSA density in the TZ (r=0.51, P< 0.05), but not with the PSA density in the
nonTZ (r=-0.06, P=0.81). Also, age was inversely correlated with the PSA density
in the TZ (r=-0.69, P< 0.01). CONCLUSION: The hypertrophic prostate cell volume
(TZ volume) and activity (PSA density in the TZ) significantly correlated with
the concentration of serum PSA in BPH patients, and the TZ cell activity
decreased inversely with age in these BPH patients.
PMID- 9559844
TI - Results of closure of urethrocutaneous fistulas after hypospadias repair.
AB - BACKGROUND: Urethrocutaneous fistulas are one of the major causes of morbidity
after hypospadias repair. METHODS: During the last 2.5 years, 26 patients
underwent repair of 41 urethrocutaneous fistulas. These fistulas were repaired by
a 3-layered closure method, by using meticulous surgical techniques aided by
optical magnification. In large fistulas, a dermal subcutaneous flap was created
and brought over the surgically repaired urethral fistula. RESULTS: Twenty-four
of the 26 patients with urethrocutaneous fistulas after hypospadias repair had
fistula closure, with a 92% success rate. CONCLUSION: A high success rate was
obtained with a multilayered closure using meticulous techniques to repair
urethrocutaneous fistulas.
PMID- 9559845
TI - Nonfunctioning adrenal cortical cancer and analysis of the steroidogenic activity
of the tumor: a case report.
AB - An adrenocortical cancer was detected by a CT scan in a 37-year-old woman, which
did not have an excessive secretion of steroids or catecholamines. The tumor was
enhanced inhomogeneously by the bolus injection of contrast medium, and magnetic
resonance imaging (MRI) showed that the tumor was hypointense compared to the
liver on a T1-weighted image and was diffusely hyperintense on a T2-weighted
image. Histologically, the tumor consisted predominantly of compact cells with
marked cellular and nuclear pleomorphism, but no capsular or vascular invasion
were observed. An analysis of the steroidogenic activity of the tumor revealed
that the activity of mitochondrial P450c11beta was extremely reduced in the
tumor.
PMID- 9559846
TI - Right paranephric abscess as a rare late complication of laparoscopic
cholecystectomy.
AB - A laparoscopic cholecystectomy on a 63-year-old woman was uneventful. Twenty-one
months after the operation she complained of dull right flank pain, loss of
appetite, weight loss, and cough. CT of the abdomen showed an 8.5 cm mass
adjacent to the posterior aspect of the upper pole of the right kidney. CT also
demonstrated a small calcification (5 mm diameter) posterior to the upper pole of
the right kidney. The patient underwent exploratory laparotomy 2 months after the
presentation with flank pain. Examination of the mass showed a thick abscess wall
and 250 mL of pus. The patient's symptoms improved after the abscess was drained.
PMID- 9559847
TI - Renal cell carcinoma of extraordinarily large size: a case report.
AB - One of our patients was a 66-year-old woman with a T2 renal cell carcinoma
weighing 3900 g. Two years after radical nephrectomy the woman was alive and
well. A survey of Japanese medical literature revealed that patients with renal
cell carcinomas weighing more than 2000 g have an unexpectedly favorable
prognosis with a 5-year survival rate of 76.9%.
PMID- 9559848
TI - Successful treatment with polymyxin B immobilized fiber of septic shock
complicated by renal stone.
AB - We describe a patient with septic shock that was spontaneously complicated by
calyceal diverticular calculus. The patient recovered from shock within a few
days with treatment by extracorporeal elimination of endotoxin using a blood
purification cartridge consisting of polymyxin B immobilized fiber. Standard open
nephrolithotomy was performed, and the patient was discharged from the hospital 2
months after admission.
PMID- 9559849
TI - Laparoscopic nephrectomy in children: two case reports.
AB - We successfully performed a laparoscopic nephrectomy on 2 young girls in March
1994 and August 1994. The first patient was a 9-year-old girl with a hypoplastic
kidney associated with an ectopic ureterocele, and the other was a 3-year-old
girl with a nonfunctioning hydronephrotic kidney caused by stricture of the
pyeloureteral junction. The operating times were 153 and 183 minutes,
respectively. No complications occurred intraoperatively or postoperatively in
either patient. The 9-year-old girl resumed normal daily activities by
postoperative day 2, and the 3-year-old girl by postoperative day 3. Both girls
were discharged on day 4.
PMID- 9559850
TI - Nephrogenic adenoma in a patient with transitional cell carcinoma of the bladder
receiving intravesical bacillus Calmette-Guerin.
AB - A 76-year-old-man was admitted to our hospital for a recurrent bladder tumor. He
had received intravesical bacillus Calmette-Guerin (BCG) treatment for a
transitional cell carcinoma of the bladder. A follow-up cystoscopy revealed a
solitary papillary tumor in the left bladder wall. A transurethral cold cup
biopsy revealed a nephrogenic adenoma without any evidence of malignant cells. We
discuss the pathogenesis of nephrogenic adenoma and suggest that prolonged
cystitis caused by intravesical BCG may play an etiological role.
PMID- 9559851
TI - Detrusor areflexia in a patient with myasthenia gravis.
AB - Myasthenia gravis (MG) is a common neuromuscular disorder, however, voiding
dysfunction in conjunction with MG is rare. A review of the literature yielded
only 7 prior reports of such a combination. Most of the reported cases involved
incontinence in males which developed after a transurethral resection of the
prostate. Only 3 cases described de novo voiding dysfunction. We report a fourth
patient. In all 4 cases of de novo dysfunction, the voiding problem either
heralded a new diagnosis of MG or an exacerbation of the disease process. It is
hypothesized that autonomic dysfunction in patients with MG might indicate a
unique subset with a worse prognosis.
PMID- 9559852
TI - Congenital megalourethra: a case report.
AB - We describe a case of a male infant with a scaphoid megalourethra. A physical
examination showed a large, flabby phallus with bilateral undescended testes. The
corpus spongiosum was absent with normal corpora cavernosa. Urethrography showed
a crescent-shaped dilatation of the anterior urethra. Further examination
revealed an association with concomitant urogenital anomalies, right renal
hypoplasia-dysplasia, bilateral vesicoureteral reflux and the prune-belly
syndrome. A urethroplasty with resection of the excess urethral tissue and
reconstruction of the urethra was performed. There was a satisfactory surgical
result and the patient now voids without difficulty.
PMID- 9559853
TI - Minireview: on the structure and gating mechanism of the mitochondrial channel,
VDAC.
AB - There is considerable evidence that the voltage-gated mitochondrial channel VDAC
forms a beta-barrel pore. Inferences about the number and tilt of beta-strands
can be drawn from comparisons with bacterial beta-barrel pores whose structures
have been determined by x-ray crystallography. A structural model for VDAC is
proposed (based on sequence analysis and electron crystallography) in which the
open state is like that of bacterial porins with several important differences.
Because VDAC does not occur as close-packed trimers, there are probably fewer
interpore contacts than in the bacterial porins. VDAC also appears to lack a
large, fixed intraluminal segment and may not have as extensive a region of
uniformly 35 degrees -tilted beta-strands as do the bacterial porins. These
structural differences would be expected to render VDAC's beta-barrel less stable
than its bacterial counterparts, making major conformational changes like those
associated with gating more energetically feasible. A possible gating mechanism
is suggested in which movement of the N-terminal alpha-helix out of the lumen
wall triggers larger-scale structural changes.
PMID- 9559854
TI - The intriguing evolution of the "b" and "G" subunits in F-type and V-type
ATPases: isolation of the vma-10 gene from Neurospora crassa.
AB - We have characterized the vma-10 gene which encodes the G subunit of the vacuolar
ATPase in Neurospora crassa. The gene is somewhat unusual in filamentous fungi
because it contains five introns, comprising 71% of the region between the
translation start and stop codons. The 5' untranslated region of the gene
contains several elements that have been identified in other genes that encode
subunits of the vacuolar ATPase in N. crassa. A comparison of G subunits from N.
crassa, S. cerevisiae, and animal cells showed that the N-terminal half of the
polypeptide shows the highest degree of sequence conservation. Most striking is
the observation that this region could form an alpha helix in which all of the
conserved residues are clustered on one face. Subunit G appears to be homologous
to the b subunit found in F-type ATPases. The major difference between the b and
G subunits is the lack of a membrane-spanning region in the G subunit. We have
also identified homologous subunits in the operons which encode V-type ATPases in
a eubacterium, Enterrococcus hirae, and an archaebacterium, Methanococcus
jannaschii. As in eukaryotic vacuolar ATPases the G subunit homologs lack a
membrane-spanning region. Although the b and G subunits appear to be derived from
a common ancestor, significant changes have evolved. In F-type and V-type ATPases
these subunits can have zero, one, or two membrane-spanning regions and can also
differ significantly in the number of copies per enzyme.
PMID- 9559855
TI - Bacterial overexpression of putative yeast mitochondrial transport proteins.
AB - Thirty-two genes have been identified within the genome of the yeast
Saccharomyces cerevisiae which putatively encode mitochondrial transport
proteins. We have attempted to overexpress a subset of these genes, namely those
which encode mitochondrial transporters of unknown function, and have succeeded
in overexpressing 19 of these genes. The overexpressed proteins were then
isolated and tested for five well-characterized reconstituted transport
activities (i.e., the transport of citrate, dicarboxylates, pyruvate, camitine,
and aspartate). Utilizing this approach, we have clearly identified the yeast
mitochondrial dicarboxylate transport protein, as well as two additional lower
magnitude transport functions (i.e., tricarboxylate and dicarboxylate transport
activities). The implications of these results and the considerations relevant to
this approach are discussed.
PMID- 9559856
TI - Localized firefly luciferase probes ATP at the surface of mitochondria.
AB - The concentration of ATP generated by yeast mitochondria and consumed by yeast
hexokinase was monitored using native firefly luciferase in solution, or
recombinant luciferase localized at the surface of mitochondria. In the absence
of hexokinase, both probes perform similarly in detecting exogenous or
mitochondrially-generated ATP. The steady-state concentrations of ATP can be
reduced in a dose-dependent manner by hexokinase. With hexokinase added in large
excess, the localized probe reports substantial ATP concentrations while none is
detectable by soluble luciferase. Thus, ATP accumulates near the membrane where
it appears, relatively to solution, and vice versa for ADP. The extent of
nucleotide gradients is shown to be correlated with the specific activity of
oxidative phosphorylation and with the viscosity of the medium, but independent
of the concentration of the organelles. A simple model involving diffusional
restrictions is presented to describe this behavior. The metabolic and
evolutionary implications of cellular catalysis limitation by physical processes
are discussed.
PMID- 9559857
TI - Oscillating Ca2+-induced channel activity obtained in BLM with a mitochondrial
membrane component.
AB - Oscillations in ion fluxes and membrane potential may be observed in cells and in
mitochondria as well. We obtained Ca2+-induced oscillations in channel activity
in black-lipid membranes reconstituted with hydrophobic components extracted from
mitochondria. Mitoplasts prepared from purified rat liver mitochondria were
extracted with ethanol followed by Folch extraction and further partial
purification by silicic acid chromatography. Channel activity was measured in
lipid bilayers formed from bovine brain lipids and 10% cardiolipin with addition
of the purified fractions. The conductance with 10 mM Ca2+ was 100 pS or its
multiples. Ca2+ gradients of 4: 1 induced oscillating channel activity for
several hours, with initial open states of 40 s and closed states of 56 s; the
open times gradually decreasing to 8.6 s. No channel activity was seen without
added fractions. The channel activity was associated with a Ca2+-binding lipid,
nonpolar, low-molecular-weight fraction that in gel electrophoresis was not
stained with Coomassie Blue and did not contain carbohydrate-staining material.
1H-Nuclear magnetic resonance spectra of the substance showed the presence of
aliphatic chains and carbonyls, but the detailed structure remains to be
elucidated.
PMID- 9559858
TI - On the protection by inorganic phosphate of calcium-induced membrane permeability
transition.
AB - The role of inorganic phosphate as inhibitor of mitochondrial membrane
permeability transition was studied. It is shown that in mitochondria containing
a high phosphate concentration, i.e., 68 nmo/mg, Ca2+ did not activate the pore
opening. Conversely, at lower levels of matrix phosphate, i.e., 38 nmol/mg, Ca2+
was able to induce subsequent pore opening. The inhibitory effect of phosphate
was apparent in sucrose-based media, but it was not achieved in KCI media. The
matrix free Ca2+ concentration and matrix pH were lowered by phosphate, but they
were always higher in K+-media. In the absence of ADP, phosphate strengthened the
inhibitory effect of cyclosporin A on carboxyatractyloside-induced Ca2+ efflux.
Acetate was unable to replace phosphate in the induction of the aforementioned
effects. It is concluded that phosphate preserves selective membrane permeability
by diminishing the matrix free Ca2+ concentration.
PMID- 9559859
TI - Response of isolated rat liver mitochondria to variation of external osmolarity
in KCl medium: regulation of matrix volume and oxidative phosphorylation.
AB - When isolated rat liver mitochondria are incubated in KCI medium, matrix volume,
flux, and forces in both hypo- and hyperosmolarity are time-dependent. In
hypoosmotic KCl medium, matrix volume is regulated via the K+/H+ exchanger. In
hyperosmotic medium, the volume is regulated in such a manner that at steady
state, which is reached within 4 min, it is maintained whatever the
hyperosmolarity. This regulation is Pi- and deltamuH+-dependent, indicating Pi-K
salt entry into the matrix. Under steady state, hyperosmolarity has no effect on
isolated rat liver mitochondria energetic parameters such as respiratory rate,
proton electrochemical potential difference, and oxidative phosphorylation yield.
Hypoosmolarity decreases the NADH/NAD+ ratio, state 3 respiratory rate, and
deltamuH+, while oxidative phosphorylation yield is not significantly modified.
This indicates kinetic control upstream the respiratory chain. This study points
out the key role of potassium on the regulation of matrix volume, flux, and
forces. Indeed, while matrix volume is regulated in NaCl hyperosmotic medium,
flux and force restoration in hyperosmotic medium occurs only in the presence of
external potassium.
PMID- 9559861
TI - Estimation of membrane potential deltapsi in reconstituted plasma membrane
vesicles using a numerical model of oxonol VI distribution.
AB - A model of membrane potential-dependent distribution of oxonol VI to estimate the
electrical potential difference deltapsi across Schizosaccharomyces pombe plasma
membrane vesicles (PMV) has been developed. deltapsi was generated by the H+
ATPase reconstituted in the PMV. The model treatment was necessary since the
usual calibration of the dye fluorescence changes by diffusion potentials (K+ +
valinomycin) failed. The model allows for fitting of fluorescence changes at
different vesicle and dye concentrations, yielding deltapsi in ATP-energized PMV
of 80 mV. The described model treatment to estimate deltapsi may be applicable
for other reconstituted membrane systems.
PMID- 9559860
TI - Energetics of isolated hepatocyte swelling induced by sodium co-transported amino
acids.
AB - This study was designed to investigate the energetics of isolated rat hepatocyte
swelling due to sodium-cotransported amino acid accumulation in a medium
containing either glucose or octanoate as basal substrate. We show that the size
of the increase in cytosolic volume is directly correlated with the total amino
acid accumulation, which depends on the difference of electrical potential across
the plasma membrane. Such a change in cell volume, with either glucose or
octanoate, does not modify the mitochondrial volume. Addition of sodium
cotransported amino acids for which the metabolism was avoided showed that the
rise in cell volume, per se, did not change the respiratory rate, deltap, or
phosphate potential in either mitochondrial or cytosolic compartments.
Conversely, the large increase in oxidative phosphorylation flux was due to the
metabolism of amino acids as a consequence of a rise in electron supply for the
respiratory chain rather than an increase in cellular ATP demand, as indicated by
the increase in cytosolic phosphate potential. Moreover, although we confirm that
octanoate addition largely increases the respiratory rate by a process different
from uncoupling, we observed that the same overall thermodynamic driving force
through the respiratory chain and the same mitochondrial or cytosolic phosphate
potential were maintained for much higher oxygen consumption when octanoate was
present. We propose that these octanoate effects are due to a decrease in the
actual protons/2 electrons stoichiometry as a consequence of a shift in electron
supply toward a two-coupling site instead of a three-coupling site. The change in
the FADH2/NADH formation flux ratio in either fatty acid or carbohydrate
oxidation explains such results.
PMID- 9559862
TI - Direct measurement of nitrite transport across erythrocyte membrane vesicles
using the fluorescent probe, 6-methoxy-N-(3-sulfopropyl) quinolinium.
AB - Nitrite was shown to quench the fluorescence of 6-methoxy-N-(3-sulfopropyl)
quinolinium (SPQ) almost twofold more than chloride. SPQ loaded inside vesicles
prepared from asolectin and isolated erythrocyte ghosts allowed for the direct
measurement of nitrite movement across these membranes. Movement of nitrite
across asolectin occurred by diffusion as HNO2 in a pH-dependent manner. By
contrast, erythrocyte ghosts had very low diffusion rates for nitrous acid.
Erythrocyte ghosts preloaded with 50 mM nitrite to quench SPQ fluorescence were
utilized to study heteroexchange with externally added anions. SPQ fluorescence
increases (becomes unquenched) with added bicarbonate and nitrate, indicating
that nitrite is moving out of the preloaded vesicles. The pH optimum for this
exchange was approximately 7.6 and exchange was inhibited by N-ethylmaleimide
(NEM) and dihydro-4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS). These
data indicate that nitrite moves across erythrocyte plasma membranes as NO2- by a
heteroexchange mechanism with other monovalent anions.
PMID- 9559863
TI - The critical role of Hepes in SIN-1 cytotoxicity, peroxynitrite versus hydrogen
peroxide.
AB - The cytotoxicity of the superoxide anion radical- and nitric oxide-releasing
compound SIN-1 to L929 cells was studied in Krebs-Henseleit buffer. pH 7.4, in
the presence and absence of Hepes. SIN-1 cytotoxicity was significantly higher in
the presence of Hepes than in the absence of Hepes. The available amount of
peroxynitrite formed from SIN-1, however, was significantly decreased by Hepes as
indicated by decreased oxidation of dihydrorhodamine 123. On the other hand,
Hepes largely increased the formation of H2O2 from SIN-1. Catalase protected the
L929 cells from SIN-1 cytotoxicity in the buffer with Hepes. In the buffer
without Hepes catalase did not have any protective effect. In contrast, tyrosine
and tryptophan provided significant protection against SIN-1 cytotoxicity
independent of the presence of Hepes. These results demonstrate that the
immediate toxic agent formed from SIN-1 decisively depends on the presence of
Hepes. In its absence cytotoxicity is most likely mediated by peroxynitrite while
in the presence of Hepes, cytotoxicity is conveyed by co-operative action of
hydrogen peroxide and reactive nitrogen species.
PMID- 9559864
TI - Antioxidant activity of lazaroid (U-75412E) and its protective effects against
crystalline silica-induced cytotoxicity.
AB - Lazaroids (21-amino steroids) are believed to be powerful scavengers of reactive
oxygen species (ROS) and inhibitors of lipid peroxidation. Crystalline silica, a
potent cytotoxic agent, causes pulmonary fibrosis in experimental animals and
humans. ROS have been previously shown to be involved in crystalline silica
induced pulmonary injury and inflammation. In the present study, the reaction
rate of lazaroid (U-75412E) with hydroxyl radical (.OH) generated by Fenton
reaction (Fe(II) + H2O2 --> Fe(III) + OH- + .OH) was investigated using ESR spin
trapping competition reactions. The reaction rate constant was found to be 1.0 x
10(10) M(-1)s(-1), which was comparable with those of other efficient .OH radical
scavengers. As indicators of crystalline silica-induced cytotoxicity and its
protection by this antioxidant lazaroid (U-75412E) we measured lactate
dehydrogenase, N-acetyl-beta-glucosaminidase, superoxide dismutase, glutathione
peroxidase, and hydrogen peroxide released from rat alveolar macrophages. Lipid
peroxidation, a prominent manifestation of .OH radical-induced cell injury, was
also measured to evaluate the protective value of lazaroid. Alveolar macrophages
treated with lazaroid (U-75412E) before crystalline silica exposure were
protected against cell injury and lipid peroxidation as demonstrated by those
indicators. Lazaroid (U-75412E) scavenges .OH radicals generated by crystalline
silica-mediated reaction from H2O2 and inhibits lipid peroxidation in macrophages
induced by these particles.
PMID- 9559865
TI - One- and two-electron oxidations of luminol by peroxidase systems.
AB - The kinetics of luminol oxidation catalyzed by horseradish peroxidase (HRP),
Arthromyces ramosus peroxidase (ARP) and lactoperoxidase (LPO) at pH 7.0 was
investigated. One-electron oxidation of luminol by peroxidase systems was
inferred from the detection of luminol radicals, luminol-mediated formation of
ascorbate radicals, and the trapping of luminol-mediated GSH radicals. The
catalytic intermediate of peroxidases in the steady state was Compound II and the
rate constants of HRP, ARP, and LPO Compound II with luminol were 3.6 x 10(4),
1.1 x 10(7), and 2.5 x 10(4) M(-1)s(-1), respectively. The intensity of luminol
chemiluminescence (CL) generated by the peroxidases depended on the rate
constants of the rate-determining step. The luminol CL catalyzed by peroxidases
increased with an increase in the concentration of H2O2 and was inhibited in the
presence of catalase. Neither oxygen consumption during the reaction under
aerobic conditions nor a change of light intensity under anaerobic conditions was
observed. The light emission and oxidation of luminol catalyzed by LPO was
increased by trace amounts of iodide. LPO catalyzes two-electron oxidations of
iodide to form iodinating intermediate (Nakamura, M.; et al. J. Biol. Chem.
260:13546-13552, 1985), which subsequently oxidizes luminol. The results lead us
to conclude that CL of luminol was initiated by peroxidase systems irrespective
of one- or two-electron oxidations of luminol.
PMID- 9559866
TI - Enhanced gamma-glutamyl transpeptidase expression and selective loss of CuZn
superoxide dismutase in hepatic iron overload.
AB - Liver injury caused by iron overload is presumed to involve lipid peroxidation
and the formation of products such as 4-hydroxynonenal (4HNE), which has been
implicated in hepatic fibrogenesis. Cellular antioxidants that modulate the
formation and detoxification of compounds such as 4HNE may represent important
protective mechanisms involved in the response to iron overload. This study
examines the relationship between 4HNE, collagen content, and antioxidant
defenses in the livers of rats fed carbonyl iron for 10 weeks. Iron-loading
resulted in significant increases in iron (8.8-fold), 4HNE (1.7-fold), and
hydroxyproline (1.5-fold). Total glutathione content was unchanged by iron, but
gamma-glutamyl transpeptidase activity (GGT) increased sixfold and CuZn
superoxide dismutase (CuZnSOD) activity decreased >9%. GGT colocalized with iron
deposition and was associated with increased GGT mRNA. Decreased CuZnSOD activity
was paralleled by a reduction in CuZnSOD protein on Western blot and
immunohistochemistry, but no decrease in CuZnSOD mRNA. Glutathione S-transferase
(GST) and Mn superoxide dismutase (MnSOD) activities were also significantly
increased by iron loading. These results demonstrate that iron overload
significantly alters the expression of antioxidant enzymes associated with
glutathione (GGT and GST) and superoxide metabolism (CuZnSOD and MnSOD).
Furthermore, the localized induction of GGT may enhance detoxification of lipid
peroxidation-derived aldehydes via glutathione-dependent pathways in iron-loaded
hepatocytes. These alterations in antioxidant defenses may represent an adaptive
response, limiting accumulation 4HNE, and thus, stimulation of collagen
synthesis, accounting for the mild fibrogenic response seen in this model of iron
overload.
PMID- 9559867
TI - Different mechanisms of thioredoxin in its reduced and oxidized forms in defense
against hydrogen peroxide in Escherichia coli.
AB - The present experiments were done to elucidate the roles of thioredoxin and
thioredoxin reductase system in defense against hydrogen peroxide (H2O2) in
Escherichia coli. The thioredoxin-deficient mutant (trxA) was more sensitive to
H2O2 than was the wild-type strain, when challenged in the stationary and
exponentially growing phase. Thioredoxin reductase-deficient mutant (trxB) in the
stationary phase also exhibited increased sensitivity, compared with the wild
type strain. These results indicated that reduced form of thioredoxin is required
for defense against H2O2, possibly by scavenging radicals generated in the cells.
In contrast, the trxB mutant in the growing phase had higher survival after
exposure to H2O2 than the wild-type strain. The acquirement of resistance related
to increased capacity for removing H2O2 in the trxB mutant and was not observed
in a catalase-negative background. Furthermore, enhanced expression of the katG
:: lacZ gene occurred in the mutant. Therefore, it was concluded that oxidized
form of thioredoxin confers H2O2 resistance on E. coli cells by increasing
activity to remove H2O2, which was brought about by enhanced induction of the
katG-coded catalase/hydroperoxidase I at the transcriptional level. In addition,
this resistance to H2O2 correlated well with reduced amount of DNA damage caused
by H2O2, determined by the induction level of the recA :: lacZ fusion gene after
treatment with H2O2.
PMID- 9559868
TI - Hydroxyl radical as a potential intracellular mediator of polymorphonuclear
neutrophil apoptosis.
AB - We investigated reactive oxygen species (ROS) involvement in polymorphonuclear
neutrophilic leukocyte (neutrophil) apoptosis triggering. Neutrophils were
incubated with xanthine oxidase (XO), which produces superoxide anion (O2.-) and
hydrogen peroxide (H2O2) or glucose oxidase (GO), which produces only H2O2. Both
XO and GO accelerated apoptosis when compared to spontaneously aged neutrophils.
Catalase inhibited both spontaneous apoptosis and XO- or GO-accelerated
apoptosis, but superoxide dismutase did not. Hydrogen peroxide can enter the
cell, thus generating intracellular oxidation, which was observed by flow
cytometry. Furthermore, the intracellular reduced glutathione content fell in the
presence of XO or GO; however, apoptosis was not accelerated in the presence of
buthionine sulfoximine (BSO), suggesting that the fall in glutathione in the
presence of XO or GO is a consequence of oxidative stress but not a trigger of
apoptosis. Hydrogen peroxide can react with iron to form hydroxyl radicals (HO.);
we observed that two iron chelators, deferoxamine and hydroxybenzyl
ethylenediamine (HBED), both inhibited spontaneous and accelerated apoptosis,
suggesting that HO. may mediate neutrophil apoptosis.
PMID- 9559869
TI - Demonstration of the production of oxygen-centered free radicals during
electrolysis using E.S.R. spin-trapping techniques: effects on cardiac function
in the isolated rat heart.
AB - The present study was designed to identify the free radicals generated during the
electrolysis of the solution used to perfuse isolated rat heart Langendorff
preparations. The high reactivity and very short half-life of oxygen free
radicals make their detection and identification difficult. A diamagnetic organic
molecule (spin trap) can be used to react with a specific radical to produce a
more stable secondary radical or "spin adduct" detected by electron spin
resonance (ESR). Isovolumic left ventricular systolic pressure (LVSP) and left
ventricular end diastolic pressure (LVEDP) were measured by a fluid-filled latex
balloon inserted into the left ventricle. The coronary flow was measured by
effluent collection. Electrolysis was performed with constant currents of 0.5, 1,
1.5, 3, 5, 7.5, and 10 mA generated by a Grass stimulator and applied to the
perfusion solution for 1 min. A group of experiments was done using a 1.5 mA
current and a Krebs-Henseleit (K-H) solution containing free radical scavengers
(superoxide dismutase (SOD): 100 IU/ml or mannitol: 50 mM). Heart function
rapidly declined in hearts perfused with K-H buffer that had been electrolyzed
for 1 min. The addition of mannitol (50 mM) to the perfusion solution had no
effect on baseline cardiac function before electrolysis while SOD (100 IU/ml)
increased the coronary flow. However, SOD was more effective than the mannitol in
protecting the heart against decreased of cardiac function, 5 min after the end
of electrolysis. Samples of the K-H medium subjected to electrolysis were
collected in cuvettes containing a final concentration of 125 mM 5,5-dimethyl-1
pyrroline-N-oxide (DMPO) and analyzed by spectroscopy. The ESR spectrum consisted
of a quartet signal (hyperfine couplings aN = aH = 14.9 G) originating from the
hydroxyl adduct signal, DMPO-OH. The intensity of the DMPO-OH signal remained
stable during the 60 s of electrolysis and the quantity of free radicals induced
by electrolysis was directly proportional to the intensity of the current. The
addition of mannitol and SOD to the perfusate scavenged the hydroxyl radicals
present in the solution, suggesting that both hydroxyl and superoxide radicals
were formed during electrolysis.
PMID- 9559870
TI - Oxidative damage, plasma antioxidant capacity, and glucemic control in elderly
NIDDM patients.
AB - A study of oxidative damage was made in elderly noninsulin-dependent diabetes
mellitus (NIDDM) patients. A statistically significant increase in glucose and
fructosamine was found in fasting NIDDM patients, as well as an increase in the
oxidation induced by tert-butyl hydroperoxide. The Total Reactive Antioxidant
Potential (TRAP) of the plasma was much reduced (p < .02) and the uricemia was
unchanged. The erythrocytes of diabetic patients show greater basal oxidation
products (p < .05), and the susceptibility of the diabetic erythrocytes to
oxidation injury was also shown to increase in the oxidation induced by t-BOOH (p
< .05). Linear regression studies showed that TRAP was associated directly with
uric acid (p < .05) and inversely with fructosamine and with glucose (p < .03 and
p < .05 respectively) in patients with NIDDM, but not in the controls. The levels
of fructosamine were found to be related to the basal damage of the red blood
cells (direct correlation, p < .001). This study suggest an useful approach to
diabetic oxidative stress for clinical settings.
PMID- 9559871
TI - Role of antioxidant enzymes on ionizing radiation resistance.
AB - Exposure of cells to ionizing radiation leads to formation of reactive oxygen
species (ROS) that are associated with radiation-induced cytotoxicity. The
antioxidant enzymes manganese superoxide dismutase (MnSOD), copper-zinc
superoxide dismutase (CuZnSOD), and glutathione peroxidase (GPx), are key
intracellular antioxidants in the metabolism of ROS. We investigated the
potential role of the three antioxidant enzymes in radioresistance by analyzing
cell morphology, cell viability, and cellular radioresistance in stably
transfected CHO cell lines overexpressing MnSOD, CuZnSOD, and GPx, respectively.
We found that overexpression of human MnSOD substantially protected cells from
ionizing radiation injury. Relative to MnSOD, GPx could slightly reduce the
radiation sensitivity while the radioresistance in CuZnSOD expressing cells did
not change significantly. The results suggested that MnSOD may play a central
role in protecting cells against reactive oxygen species injury during ionizing
radiation exposure among MnSOD, CuZnSOD, and GPx.
PMID- 9559872
TI - Inhibition of peroxynitrite dependent tyrosine nitration by hydroxycinnamates:
nitration or electron donation?
AB - Peroxynitrite is a cytotoxic species generated by the reaction between superoxide
and nitric oxide. In this study the ability of hydroxycinnamate antioxidants to
decrease peroxynitrite-mediated nitration of tyrosine was investigated. The
results obtained show that all compounds were able to inhibit nitration of
tyrosine. The potency of inhibitory activity was in the order; caffeic acid > or
= chlorogenic acid > or = ferulic acid > p-coumaric acid > ocoumaric acid > m
coumaric acid. Trolox, which was included in the study for comparative purposes,
had an activity between that of ferulic acid and p-coumaric acid. The data
obtained suggest that hydroxycinnamates can act by one of two possible
mechanisms: preferential nitration for monophenolates and electron donation by
catecholates.
PMID- 9559873
TI - Copper can promote oxidation of LDL by markedly different mechanisms.
AB - Oxidation of LDL (0.1 microM) in PBS with copper concentrations ranging from 0.03
to 10 microM, equal to 0.3-100 Cu2+/LDL, was investigated by monitoring the
formation of conjugated dienes at 234 nm. With all 8 LDL samples examined, the
kinetics changed strongly at submicromolar Cu2+ concentrations. Based on time
course of the formation of conjugated dienes, cholesteryl linoleate hydroxides
and hydroperoxides as well as the antioxidant consumption, two oxidation types
were distinguished. Type A oxidations, observed at relatively high Cu2+
concentrations of 10-100 Cu2+/ LDL, represented the conventional kinetics of LDL
oxidation with an inhibition period (= lag-time) followed by a propagation phase.
In contrast, type C oxidations proceeded after a negligibly short lag time
followed by a distinct propagation phase. The rate of this propagation increased
rapidly to 0.5 mol diene/mol LDL and then slowed down in the presence of alpha
,gamma-tocopherols and carotenoids, which were consumed faster than tocopherols.
The increase in diene absorption was due to the formation of both hydroxides and
hydroperoxides suggesting a high initial decomposition of hydroperoxides. At
submicromolar concentrations of about 0.1 to 0.5 microM, type C and type A
oxidation can be combined resulting in 4 consecutive oxidation phases, i.e. 1st
inhibition and 1st propagation (belonging to type C), followed by 2nd inhibition
and 2nd propagation (belonging to type A). Increasing copper concentrations
lowered the 1st propagation and shortened the 2nd inhibition periods until they
melted into one apparent kinetic phase. Decreasing [Cu2+] increased the 1st
propagation and 2nd inhibition but lowered the 2nd propagation phase until it
completely disappeared. A threshold copper concentration, denoted as Cu(lim), can
be calculated as a kinetic constant based on the Cu2+-dependence for the rate of
2nd propagation. Below Cu(lim), LDL oxidation proceeds only via type C kinetics.
The Cu2+-dependence of the oxidation kinetics suggests that LDL contains two
different Cu2+ biding sites. Cu2+ at the low-affinity binding sites, with half
saturation at 5-50 Cu2+/LDL, initiates and accelerates the 2nd propagation by
decomposing lipid hydroperoxides. Cu2+ bound to the high-affinity binding sites,
with half-saturation at 0.3-2.0 Cu2+/LDL, is responsible for the 1st propagation.
Arguments in favor and against this propagation being due to tocopherol mediated
peroxidation (TMP) are discussed. If the lag-time concept is extended to the
conjugated diene curves seen for combined oxidation profiles, then a true
inhibition phase does not apply to this time interval, but instead represents the
time elapsed before the onset of the 2nd propagation phase.
PMID- 9559874
TI - Induction of the mitochondrial permeability transition causes release of the
apoptogenic factor cytochrome c.
AB - It was recently reported that the mitochondrial protein cytochrome c is required
for the induction of apoptosis, and that the overexpression of Bcl-2 caused
increased retention of this apoptogenic factor by mitochondria. Several cellular
toxins, including H2O2, tBOOH and Ca++, induce the Mitochondrial Permeability
Transition (MPT); we tested the possibility that MPT is an intracellular sensor
of toxicity that results in the release of cytochrome c. We observe that the
release of cytochrome c from purified mitochondria is stimulated by the classical
inducers of MPT, and is inhibited by the classical inhibitor of MPT, cyclosporin
A (CsA). After induction of MPT, mitochondrial supernatants gained the activity
to induce cleavage of caspase 3 (CPP32) in cytosolic extracts, and this gain of
activity was inhibited by CsA pretreatment of mitochondria, and was cancelled by
immunodepletion of cytochrome c from the supernatants. After induction of MPT,
mitochondrial supernatants mixed with or without cytosolic extract gained the
activity to ladder nuclei, and this gain of activity was inhibited by CsA
pretreatment of mitochondria, and cancelled by immunodepletion of cytochrome c
from the supernatants. These results demonstrate that the induction of MPT causes
release of cytochrome c from mitochondria, which is required for the hallmarks of
cytosolic and nuclear apoptosis, caspase 3 activation and nuclear laddering, and
identify the MPT as a potential intracellular sensor of oxidants and other
toxins, and as a target for the pharmacological inhibition of apoptosis.
PMID- 9559875
TI - GRP78, HSP72/73, and cJun stress protein levels in lung epithelial cells exposed
to asbestos, cadmium, or H2O2.
AB - Occupational exposure to crocidolite asbestos is associated with the development
of nonmalignant and malignant pulmonary disease. Considerable evidence indicates
that the mechanisms of asbestos-induced toxicity involve the production of active
oxygen species (AOS). Production of AOS in excess of cellular defenses creates an
environment of oxidative stress and stimulates the expression of a number of
different genes whose products may be involved in mediating responses from
oxidant injury. To further investigate the mechanisms of asbestos-induced
pathogenicity, we have examined by Western blot analyses the induction of the
stress response proteins GRP78 and HSP72/73 in rat lung epithelial cells (RLE)
exposed to crocidolite asbestos. In comparative studies, we also examined GRP78,
HSP72/73, and cJun expression in RLE cells exposed to equitoxic concentrations of
cadmium chloride (CdCl2) and hydrogen peroxide (H2O2). Our results demonstrate
that asbestos and H2O2 do not alter GRP78 or HSP72/73 protein levels in RLE
cells, but do increase levels of cJun protein. Increases by asbestos and H2O2
were not accompanied by alterations in cellular glutathione levels in this cell
type, but asbestos caused elevations in protein levels of manganese-containing
superoxide dismutase (MnSOD), an indirect indicator of oxidant stress. In
contrast, exposure of cells to CdCl2 led to no changes in MnSOD protein levels,
but increases in GRP78, HSP72/73, and cJun proteins as well as significant
increases in oxidized and reduced thiol pools. Results suggest that environmental
agents causing oxidative injury to lung epithelium elicit different patterns of
stress responses.
PMID- 9559876
TI - Cutaneous tolerance to nitroxide free radicals in human skin.
AB - No data are available on the irritant effect of nitroxide free radicals in human
skin. Nitroxides are important biomedical skin probes used in Electron
Paramagnetic Resonance spectroscopy and imaging. Our purpose was to study the
skin irritation potential of different nitroxide free radical structures in skin
of healthy human subjects. We investigated the following nitroxides: Tempo
(2,2,6,6-tetramethyl-1-piperidinoxy), Doxo (2,2,5,5-tetramethyl-3-oxazolidinoxy),
Proxo (2,2,5,5-tetramethyl- -dihydro-pyrrolinoxy), and Imidazo (2,2,3,4,5,5
hexamethyl-imidazoline-1-yloxyl). Cutaneous irritation was determined in human
skin following a single application and after repetitive applications in
comparison to the standardized irritant sodium lauryl sulfate (SLS). The response
was evaluated clinically as well as by a bioengineering method analyzing
transepidermal water loss (TEWL) and skin hydration (capacitance). The nitroxides
were classified clinically from nonirritant (Imidazo, Proxo), to slightly
irritant (Doxo, 100 mM), or moderately irritant (Tempo 100 mM) after a single
application. The TEWL values were significantly increased by Doxo and Tempo, but
capacitance values were not changed significantly. In the cumulative irritation
test Tempo was scored as a slight irritant (10 mM). TOLH (2,2,6,6-tetramethyl-1
hydroxypiperidin), the hydroxylamine of Tempo, which is the major skin
metabolite, did not cause skin irritation after a single or repetitive
applications. This may indicate that a loss of cellular reducing equivalents may
be involved in the inflammation process caused by Tempo. The order of nitroxide
irritation potency (Tempo > Doxo >> Imidazo = Proxo) is inverse to the order of
nitroxide biostability in human skin (Imidazo = Proxo >> Doxo > Tempo). In
conclusion, nitroxide free radicals are classified as nonirritant to moderately
irritant in human skin. Particularly, the pyrrolidine and imidazoline type
nitroxides have a low potential to cause acute or subacute skin toxicity.
PMID- 9559877
TI - Double (fluorescent and spin) sensors for detection of reactive oxygen species in
the thylakoid membrane.
AB - A series of dansylated sterically hindered amines designed to trapping reactive
oxygen species, were synthesized. Compounds were tested in isolated thylakoid
membranes subjected to photoinhibition by excess photosynthetically active
radiation (400-700 nm). DanePy showed good selectivity for singlet oxygen and the
formation of nitroxide was detected by appearance of ESR signal and quenching
fluorescence.
PMID- 9559878
TI - Determination of optimal conditions for synthesis of peroxynitrite by mixing
acidified hydrogen peroxide with nitrite.
AB - The measured parameters for the formation of peroxynitrous acid via the reaction
of acidified hydrogen peroxide with nitrous acid and its self-decomposition
corroborate with an earlier suggested mechanism in which H2NO2+ nitrosates H2O2.
The activation energies for the formation and decay of peroxynitrous acid have
been determined to be 15 and 19 kcal/mol, respectively. We found that
perchlorate, nitrate, sulfate and phosphate ions have no effect on the formation
and decay rates, whereas chloride ions enhance the rate of the formation of
peroxynitrous acid at low peroxide concentrations, and have no effect at high
peroxide concentrations. This suggests that at relatively low concentration of
H2O2, Cl- competes with H2O2 for H2NO+ to yield NOCl, which may also nitrosate
H2O2. Simulation of the experimentally observed parameters for the decay and
formation rates suggests that it is not possible to obtain 100% yield of
peroxynitrite under any condition. High yields of peroxynitrite were obtained at
room temperature using an efficient double mixer where acidified peroxide was
mixed with nitrite; after an appropriate delay, the reaction was quenched with
strong alkali. An excess of more than 10% of H2O2 over nitrite, or vice versa, is
sufficient to get ca. 85-90% of peroxynitrite, almost free from nitrite or H2O2,
respectively. The results also suggest that conventional use of ice-cold
solutions of the reactants and the alkali solutions is not required if an
efficient mixer and appropriate quenching times are available.
PMID- 9559879
TI - Involvement of hydrogen peroxide in topoisomerase inhibitor beta-lapachone
induced apoptosis and differentiation in human leukemia cells.
AB - Beta-Lapachone a novel topoisomerase inhibitor, has been found to induce
apoptosis in various human cancer cells. In this study we report that a dramatic
elevation of hydrogen peroxide (H2O2) in human leukemia HL-60 cells following 1
microM beta-lapachone treatment and that this increase was effectively inhibited
by treatment with antioxidant N-acetyl-L-cysteine (NAC), ascorbic acid, alpha
tocopherol. NAC strongly prevented beta-lapachone-induced apoptotic
characteristics such as DNA fragmentation and apoptotic morphology. However,
treatment of HL-60 cells with another topoisomerase inhibitor camptothecin (CPT)
did not induce H2O2 production as compared to untreated cells. NAC also failed to
block CPT-induced apoptosis. Correlated with these findings, we found that cancer
cell lines K562, MCF-7, and SW620, contained high level of intracellular
glutathione (GSH), were not elevated in H2O2 and were resistant to apoptosis
after treatment with beta-lapachone. In contrast, cancer cell lines such as, HL
60, U937, and Molt-4 which have lower level of GSH, were readily increased of
H2O2 and were sensitive to this drug. Furthermore, ectopic overexpression of Bcl
2 in HL-60 cells also attenuated beta-lapachone-induced H2O2 and conferred
resistance to beta-lapachone-induced cell death. Beta-Lapachone at the
concentration as low as 0.25 microM effectively induced HL-60 cells to undergo
monocytic differentiation, as evidenced by CD14 antigenicity and alpha-naphthyl
acetate esterase activity. Again, the beta-lapachone-induced monocytic
differentiation was suppressed by NAC. These results suggest that intracellular
H2O2 generation plays a crucial role in beta-lapachone-induced cell death and
differentiation.
PMID- 9559880
TI - Intramolecular electron transfer in the dipeptide, histidyltyrosine: a pulse
radiolysis study.
AB - The technique of pulse radiolysis has been used to investigate the possibility of
intramolecular charge transfer in the dipeptide histidyltyrosine, following one
electron oxidation of one of its amino acid residues. The radical anion, Br2.-
was found to react with the dipeptide at pH 6.0 with a bimolecular rate constant
of 2.3+/-0.2 x 10(7) dm3 mol(-1)s(-1) suggesting that it reacts very selectively
with the histidine moiety. Spectral observations at, or close to the end of this
reaction show only the presence of a tyrosinyl free radical (TyrO.), however,
indicating that fast (>10(6) s(-1) intramolecular charge transfer has taken place
between histidine radicals (His+.) and tyrosine (TyrOH). This finding was
supported by the direct observation of the rate of formation of TyrO. in
experiments with the free amino acids, histidine and tyrosine, under conditions
where Br2.- reacted selectively with histidine. The bimolecular rate constant for
the reaction between His+. and TyrOH was found to be 2.4+/-0.5 x 10(6) dm3 mol(
1)s(-1). Taken together, the results of the study indicate that His+. is a
relatively strong oxidising agent where (E (His+./His) > 770 mV at pH 6.0.
PMID- 9559881
TI - Does acute exercise affect the susceptibility of low density lipoprotein to
oxidation?
AB - This study describes the effect of an acute exercise bout on the susceptibility
of isolated low density lipoprotein (LDL) to in vitro oxidation. LDL was isolated
from 23 subjects (exercisers, n = 11; sedentary, n = 12) immediately before and
after a single bout of exercise (30 min of treadmill work at 55% & 70% peak
oxygen consumption (VO2 peak) for exercisers and sedentary, respectively). A
statistically significant decrease in lag time for LDL oxidation was observed
following exercise compared to baseline (96.1+/-23.5 min vs. 92.1+/-23.3 minutes;
n = 23, p < or = .03) using a 5 microM copper system. There was a statistically
significant increase in plasma myeloperoxidase (MPO) levels following exercise
compared to baseline values ( 1.58+/-.91 ng/dl versus 2.08+/-1.2 ng/dl; n = 12, p
< or = .03). These results suggest that the 30 min exercise bout at a moderate
intensity and duration was a sufficient oxidative stress to increase the
susceptibility of LDL to in vitro oxidation. Additionally, the exercise bout
appeared to activate neutrophils, subsequently releasing MPO protein.
PMID- 9559882
TI - Interaction of N-benzoyl-D-phenylalanine and related compounds with the
sulphonylurea receptor of beta-cells.
AB - 1. The structure activity relationships for the insulin secretagogues N-benzoyl-D
phenylalanine (NBDP) and related compounds were examined at the sulphonylurea
receptor level by use of cultured HIT-T15 and mouse pancreatic beta-cells. The
affinities of these compounds for the sulphonylurea receptor were compared with
their potencies for K(ATP)-channel inhibition. In addition, the effects of
cytosolic nucleotides on K(ATP)-channel inhibition by NBDP were investigated. 2.
NBDP displayed a dissociation constant for binding to the sulphonylurea receptor
(K(D) value) of 11 microM and half-maximally effective concentrations of K(ATP)
channel inhibition (EC50 values) between 2 and 4 microM (in the absence of
cytosolic nucleotides or presence of 0.1 mM GDP or 1 mM ADP). 3. In the absence
of cytosolic nucleotides or presence of GDP (0.1 mM) maximally effective
concentrations of NBDP (0.1-1 mM) reduced K(ATP)-channel activity to 47% and 44%
of control, respectively. In the presence of ADP (1 mM), K(ATP)-channel activity
was completely suppressed by 0.1 mM NBDP. 4. The L-isomer of N-benzoyl
phenylalanine displayed a 20 fold lower affinity and an 80 fold lower potency
than the D-isomer. 5. Introduction of a p-nitro substituent in the D
phenylalanine moiety of NBDP did not decrease lipophilicity but lowered affinity
and potency by more than 30 fold. 6. Introduction of a p-amino substituent in the
D-phenylalanine moiety of NBDP (N-benzoyl-p-amino-D-phenylalanine, NBADP) reduced
lipophilicity and lowered affinity and potency by about 10 fold. This loss of
affinity and potency was compensated for by formation of the phenylpropionic acid
derivative of NBADP. A similar difference in affinity was observed for the
sulphonylurea carbutamide and its phenylpropionic acid derivative. 7. Replacing
the benzene ring in the D-phenylalanine moiety of NBDP by a cyclohexyl ring
increased lipophilicity, and the K(D) and EC50 values were slightly lower than
for NBDP. Exchange of both benzene rings in NBDP by cyclohexyl rings further
increased lipophilicity without altering affinity and potency. 8. This study
shows that N-acylphenylalanines interact with the sulphonylurea receptor of
pancreatic beta-cells in a stereospecific manner. Their potency depends on
lipophilic but not aromatic properties of their benzene rings. As observed for
sulphonylureas, interaction of N-acylphenylalanines with the sulphonylurea
receptor does not induce complete inhibition of K(ATP)-channel activity in the
absence of inhibitory cytosolic nucleotides.
PMID- 9559883
TI - Phosphodiesterase profile of human B lymphocytes from normal and atopic donors
and the effects of PDE inhibition on B cell proliferation.
AB - 1. CD19+ B lymphocytes were purified from the peripheral blood of normal and
atopic subjects to analyse and compare the phosphodiesterase (PDE) activity
profile, PDE mRNA expression and the importance of PDE activity for the
regulation of B cell function. 2. The majority of cyclic AMP hydrolyzing activity
of human B cells was cytosolic PDE4, followed by cytosolic PDE7-like activity;
marginal PDE3 activity was found only in the particulate B cell fraction. PDE1,
PDE2 and PDE5 activities were not detected. 3. By cDNA-PCR analysis mRNA of the
PDE4 subtypes A, B (splice variant PDE4B2) and D were detected. In addition, a
weak signal for PDE3A was found. 4. No differences in PDE activities or mRNA
expression of PDE subtypes were found in B cells from either normal or atopic
subjects. 5. Stimulation of B lymphocytes with the polyclonal stimulus
lipopolysaccharide (LPS) induced a proliferative response in a time- and
concentration-dependent manner, which was increased in the presence of
interleukin-4 (IL-4). PDE4 inhibitors (rolipram, piclamilast) led to an increase
in the cellular cyclic AMP concentration and to an augmentation of proliferation,
whereas a PDE3 inhibitor (motapizone) was ineffective, which is in accordance
with the PDE profile found. The proliferation enhancing effect of the PDE4
inhibitors was partly mimicked by the cyclic AMP analogues dibutyryl (db) cyclic
AMP and 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole-3',5'-cyclic
monophosphorothioate, Sp-isomer (dcl-cBIMPS), respectively. However, at
concentrations exceeding 100 microM db-cyclic AMP suppressed B lymphocyte
proliferation, probably as a result of cytotoxicity. Prostaglandin E2 (PGE2, 1
microM) and forskolin (10 microM) did not affect B cell proliferation, even when
given in combination with rolipram. 6. Inhibition of protein kinase A (PKA) by
differentially acting selective inhibitors (KT 5720, Rp-8-Br-cyclic AMPS)
decreased the proliferative response of control cells and reversed the
proliferation enhancing effects of rolipram. 7. Importantly, PDE4 activity in
LPS/IL-4-activated B lymphocytes decreased by about 50% compared to unstimulated
control values. 8. We conclude that an increase in cyclic AMP, mediated by down
regulation of PDE4 activity, is involved in the stimulation of B cell
proliferation in response to LPS/IL-4. B cell proliferation in response to a
mitogenic stimulus can be further enhanced by pharmacological elevation of cyclic
AMP.
PMID- 9559884
TI - S-nitrosothiols and the nitrergic neurotransmitter in the rat gastric fundus:
effect of antioxidants and metal chelation.
AB - 1. The effects of the antioxidants ascorbic acid and alpha-tocopherol and of the
metal chelator ethylenediaminetetraacetic acid (EDTA) were studied on relaxations
in response to S-nitrosothiols, authentic nitric oxide (NO) and nitrergic non
adrenergic non-cholinergic stimulation of the rat gastric fundus. 2. The S
nitrosothiols S-nitrosocysteine (1-100 nM), S-nitrosoglutathione (0.01-3 microM)
and S-nitroso-N-acetylpenicillamine (0.01-3 microM) induced concentration
dependent relaxations of the rat gastric fundus muscle strips, which were
precontracted with prostaglandin F2alpha. The relaxations to all S-nitrosothiols
were concentration-dependently enhanced by the antioxidants ascorbic acid (0.1-3
microM) and alpha-tocopherol (3-30 microM) and inhibited by the metal chelator
EDTA (26 microM). 3. Ascorbic acid and alpha-tocopherol alone did not induce a
relaxation of the precontracted rat gastric fundus muscle strip. However, when
ascorbic acid (1 microM) or alpha-tocopherol (1 microM) were injected in the
organ bath 1 minute after S-nitrosoglutathione (0.1 microM) or after S-nitroso-N
acetylpenicillamine (0.1 microM), they induced an immediate, sharp and transient
relaxation. This relaxation was inhibited by the superoxide generator pyrogallol
(2 microM). Such a relaxation to ascorbic acid or alpha-tocopherol was not
observed in the presence of S-nitrosocysteine (10 nM). 4. Electrical field
stimulation (0.5-4 Hz) of the precontracted rat gastric fundus strips induced
frequency-dependent nitrergic relaxations which were mimicked by authentic NO (3
300 nM) and by acidified sodium nitrite NaNO2 (0.3-10 microM). Ascorbic acid
(0.33-3 microM), alpha-tocopherol (3-30 microM) or EDTA (26 microM) did not
affect the relaxations to nitrergic stimulation, NO or NaNO2. 5. In summary,
relaxations to S-nitrosothiols in the rat gastric fundus are enhanced by the
antioxidants ascorbic acid and alpha-tocopherol and inhibited by the metal
chelator EDTA. However, relaxations to nitrergic stimulation of the rat gastric
fundus or those to authentic NO were not affected by the antioxidants or by the
metal chelator. These results indicate that antioxidants and metal chelators have
a different effect on the biological activity of S-nitrosothiols and on that of
the nitrergic neurotransmitter. Therefore, our results suggest that S
nitrosothiols do not act as intermediate compounds in nitrergic neurotransmission
in the rat gastric fundus.
PMID- 9559885
TI - Functional and biochemical evidence for diazepam as a cyclic nucleotide
phosphodiesterase type 4 inhibitor.
AB - 1. The responses of the electrically-driven right ventricle strip of the guinea
pig heart to diazepam were recorded in the absence and in the presence of
different selective cyclic nucleotide phosphodiesterase (PDE) inhibitors. 2.
Diazepam, at concentrations ranging from 1 microM to 100 microM, was devoid of
effect on the contractile force in this preparation. 3. Conversely, diazepam (5
microM-100 microM) produced a consistent positive inotropic response in the
presence of a concentration (1 microM), that was without effect in the absence of
diazepam, of either of the selective PDE 3 inhibitors milrinone or SK&F 94120,
but not in the presence of the selective PDE 4 inhibitor rolipram. 4. This effect
of diazepam was not gamma-aminobutyric acid (GABA)-dependent, since it was
neither mimicked nor potentiated by GABA, and was not affected by either a high
concentration (5 microM) of the antagonists of the benzodiazepine/GABA/channel
chloride receptor complex, picrotoxin, flumazenil and beta-carboline-3-carboxylic
acid methyl ester (betaCCMe), or by the inverse agonists, beta-carboline-3
carboxylic acid N-methylamide (betaCCMa) and methyl 6,7-dimethoxy-4-ethyl-beta
carboline-3-carboxylate (DMCM, 0.1 microM). Furthermore, a specific antagonist of
the peripheral benzodiazepine receptors, PK 11195 (5 microM), did not influence
the effect of diazepam. 5. Biochemical studies with isolated PDEs, confirmed that
diazepam selectively inhibits type 4 PDE from guinea-pig right ventricle rather
than the other PDEs present in that tissue. The compound inhibited this enzyme in
a non-competitive manner. Diazepam was also able to inhibit PDE 5, the cyclic GMP
specific PDE absent from cardiac muscle, with a potency close to that shown for
PDE 4. 6. Diazepam displaced the selective type 4 PDE inhibitor, rolipram from
its high affinity binding site in rat brain cortex membranes, and also
potentiated the rise in cyclic AMP levels induced by isoprenaline in guinea-pig
eosinophils, where only type 4 PDE is present. 7. The PDE inhibitory properties
of diazepam were shared, although with lower potency, by other structurally
related benzodiazepines, that also displaced [3H]-rolipram from its high affinity
binding site. The order of potency found for these compounds in these assays was
not related to their potencies as modulators of the GABA receptor through its
benzodiazepine binding site. 8. The pharmacological and biochemical data
presented in this study indicate that diazepam behaves as a selective type 4 PDE
inhibitor in cardiac tissue and this effect seems neither to be mediated by the
benzodiazepine/GABA/channel chloride receptor complex nor by peripheral type
benzodiazepine receptors.
PMID- 9559886
TI - Myogenic nitric oxide synthase activity in canine lower oesophageal sphincter:
morphological and functional evidence.
AB - 1. Studies on canine lower oesophageal sphincter (LOS) evaluated the existence
and function of a myogenic, nitric oxide synthase (NOS) by use of
immunocytochemistry for NOS isozymes, NADPH-d histochemistry, [3H]-L-arginine to
[3H]-L-citrulline transformation. In addition, functional studies in the muscle
bath were performed. 2. Smooth muscle bundles or freshly isolated smooth muscle
cells of LOS were NADPH-d reactive but did not recognize some antibodies against
neural, endothelial or inducible NOS. NADPH-d reactivity and immunoreactivity to
a neural NOS antibody were colocalized in LOS enteric nerves. Muscle plasma
membrane-enriched fractions from fresh and cultured LOS cells converted [3H]-L
arginine to [3H]-L-citrulline; activity was mostly Ca2+/calmodulin-dependent. 3.
N-Nitro-L-arginine (L-NOARG) persistently increased tone (blocked by L-arginine)
in muscle strips despite blockade of nerve function. Nifedipine prevented or
abolished L-NOARG-induced, but not carbachol-induced, contraction showing that
tone increase by L-NOARG required functional L-Ca channels. 4. Membrane-bound,
myogenic NOS in canine LOS may release NO continuously when Ca2+ entry through L
Ca channels occurs under physiological conditions and thereby modulate tone in
LOS.
PMID- 9559887
TI - Elevated plasma endothelin-1 level in streptozotocin-induced diabetic rats and
responsiveness of the mesenteric arterial bed to endothelin-1.
AB - 1. Both the plasma endothelin-1 (ET-1) levels and the plasma glucose levels were
markedly elevated in streptozotocin (STZ)-induced diabetic rats. 2. The maximum
contractile response of the mesenteric arterial bed to ET-1 was significantly
reduced, and the vasodilatation induced by the ET(B)-receptor agonist IRL-1620 in
the mesenteric arterial bed was significantly reduced in STZ-induced diabetic
rats. 3. ET-1 (10(-8) M) caused a transient vasodilatation followed by a marked
vasoconstriction in methoxamine-preconstricted mesenteric arterial beds. The ET-1
induced vasodilatation was significantly larger in beds from diabetic rats than
in those from age-matched controls. By contrast, the ET-1-induced
vasoconstriction was significantly smaller in STZ-induced diabetic rats than in
the controls. 4. Both removal of the endothelium with Triton X-100 and
preincubation with BQ-788 (10(-6) M) (ET(B)-receptor antagonist) abolished the ET
1-induced vasodilatation. Preincubation with BQ-485 (10(-6) M) or BQ-123 (3 x 10(
6)) (ET(A)-receptor antagonist) significantly augmented the ET-1-induced
vasodilatation in control mesenteric arterial beds, but not that in beds from
diabetic rats. 5. These results demonstrate that marked increases not only in
plasma glucose, but also in plasma ET-1 occur in STZ-induced diabetic rats. We
suggest that the decreased contractile response and the increased vasodilator
response of the mesenteric arterial bed to ET-1 may both be due to
desensitization of ET(A) receptors, though ET(B) receptors may also be
desensitized. This desensitization may result from the elevation of the plasma ET
1 levels seen in STZ-induced diabetic rats.
PMID- 9559889
TI - Influence of potassium channel modulators on cognitive processes in mice.
AB - 1. The effect of i.c.v. administration of different potassium channel openers
(minoxidil, pinacidil, cromakalim) and potassium channel blockers
(tetraethylammonium, apamin, charybdotoxin, gliquidone, glibenclamide) on memory
processes was evaluated in the mouse passive avoidance test. 2. The
administration of minoxidil (10 microg per mouse i.c.v.), pinacidil (5-25 microg
per mouse i.c.v.) and cromakalim (10-25 microg per mouse i.c.v.) immediately
after the training session produced an amnesic effect. 3. Tetraethylammonium
(TEA; 1-5 microg per mouse i.c.v.), apamin (10 ng per mouse i.c.v.),
charybdotoxin (1 microg per mouse i.c.v.), gliquidone (3 microg per mouse i.c.v.)
and glibenclamide (1 microg per mouse i.c.v.), administered 20 min before the
training session, prevented the potassium channel opener-induced amnesia. 4. At
the highest effective doses, none of the drugs impaired motor coordination, as
revealed by the rota rod test, or modified spontaneous motility and inspection
activity, as revealed by the hole board test. 5. These results suggest that the
modulation of potassium channels plays an important role in the regulation of
memory processes. On this basis, the potassium channel blockers could be useful
in the treatment of cognitive deficits.
PMID- 9559888
TI - Induction of nitric oxide synthase in vivo and cell injury in rat duodenal
epithelium by a water soluble extract of Helicobacter pylori.
AB - 1. Helicobacter pylori (Hp) infection, which involves the gastric antrum and
duodenal mucosa, may be involved in peptic ulceration by stimulating the local
release of cytoxic or pro-inflammatory factors. 2. Nitric oxide (NO) is known to
be cytotoxic at high concentration. The aim of the present study was therefore to
investigate the ability of a water soluble extract of Hp to induce NO synthase in
duodenal mucosa and epithelial cells following its administration in vivo in rats
and determine its association with cell damage. 3. Administration of Hp water
extract (4 ml kg(-1)) led to the expression of the calcium-independent inducible
nitric oxide synthase (iNOS) after 4 h in the duodenum, determined as [14C]
arginine conversion to citrulline. 4. This iNOS activity was not reduced by
pretreatment with anti-neutrophil serum (0.4 ml kg(-1), i.p., 3 h before
challenge). However, dexamethasone pretreatment (1 mg kg(-1), i.v., 2 h before
the extract), or administration of the NO synthase inhibitor N(G)-nitro-L
arginine methyl ester (L-NAME, 5 mg kg(-1), i.v., 2.5 h after the extract)
reduced this activity. 5. Furthermore, iNOS was expressed in duodenal isolated
epithelial cells 4 h after the i.v. challenge with the extract, at a time when
the cellular viability was also reduced, as assessed by trypan blue exclusion. 6.
Dexamethasone pretreatment, administration of L-NAME, or pretreatment with
polymyxin B (1 mg kg(-1), i.v.) which binds endotoxin, reduced both the iNOS
activity and epithelial cell damage. 7. The induction of NO synthase by the Hp
extract thus results in duodenal epithelial cell injury and such actions could
play a role in pathogenesis of peptic ulcer disease.
PMID- 9559890
TI - Resistance to myocardial infarction induced by heat stress and the effect of ATP
sensitive potassium channel blockade in the rat isolated heart.
AB - 1. Heat stress (HS) is known to protect against myocardial ischaemia-reperfusion
injury by improving mechanical dysfunction and decreasing necrosis. However, the
mechanisms responsible for this form of cardioprotection remain to be elucidated.
ATP-sensitive potassium (K(ATP)) channels have been shown to be involved in the
delayed phase of protection following ischaemic preconditioning, a phenomenon
closely resembling the HS-induced cardioprotection. The aim of this study was
thus to investigate the role of K(ATP) channels in HS-induced protection of the
isolated rat heart. 2. Twenty four hours after whole body heat stress (at 42
degrees C for 15 min) or sham anaesthesia, isolated perfused hearts were
subjected to a 15 min stabilization period followed by a 15 min infusion of
either 10 microM glibenclamide (Glib), 100 microM sodium 5-hydroxydecanoate (5HD)
or vehicle (0.04% DMSO). Regional ischaemia (35 min) and reperfusion (120 min)
were then performed. 3. Prior heat stress significantly reduced infarct-to-risk
ratio (from 42.4+/-2.4% to 19.4+/-2.9, P<0.001). This resistance to myocardial
infarction was abolished in both Glib-treated (40.1+/-1.8% vs 42.3+/-1.8%) and
5HD-treated (41.2+/-1.8% vs 41.8+/-1.2%) groups. 4. The results of this study
suggest that K(ATP) channel activation contributes to the cytoprotective response
induced by heat stress.
PMID- 9559891
TI - Effect of 17beta-oestradiol on cytokine-induced nitric oxide production in rat
isolated aorta.
AB - 1. Studies were performed on isolated aortic rings without endothelium to
investigate the effect of 17beta-oestradiol on cytokine-induced nitric oxide
production by the inducible nitric oxide synthase (iNOS). 2. Treatment of the
isolated aortic rings with interleukin-1beta (IL-1beta, 20 micro ml(-1)) led to
the expression of iNOS mRNA and protein, as well as significant nitrite
accumulation in the incubation media and suppression of phenylephrine (1 nM-10
microM)-evoked contraction. 3. Cycloheximide (1 microM), a protein synthesis
inhibitor, prevented iNOS protein expression, nitrite accumulation and the
suppression of contractility by IL-1beta on the isolated aortic rings. 17Beta
oestradiol (1 nM-10 microM) and the partial oestrogen receptor agonist 4-OH
tamoxifen (1 nM-10 microM) produced concentration-dependent inhibition of IL
1beta-induced nitrite accumulation and restored vasoconstrictor responsiveness to
phenylephrine, similar to the iNOS inhibitor aminoguanidine (100 microM). 4.
Semiquantitative PCR demonstrated decreased iNOS mRNA in the IL-1beta-induced and
17beta-oestradiol-treated rings. Western blot analysis of rat aorta homogenates
revealed that 17beta-oestradiol treatment resulted in a reduction in IL-1beta
induced iNOS protein level. 5. Incubation with tumour necrosis factor alpha (TNF
alpha, 1 ng ml(-1)) resulted in significant nitrite accumulation in the
incubation media and suppression of the smooth muscle contractile response to
phenylephrine, similar to IL-1beta. The effects of TNF alpha were also inhibited
by co-incubation of the rings with 17beta-oestradiol and 4-OH-tamoxifen (1
microM). 6. The anti-transforming growth factor-beta1 (TGF-beta1) antibody, which
inhibited TGF-beta1-induced suppression of nitrite production from IL-1beta
treated vascular rings, did not affect the inhibitory action of 17beta
oestradiol, suggesting that the effect of oestrogen on iNOS inhibition was not
mediated by TGF-beta1. 7. These results show that the ovarian sex steroid, 17beta
oestradiol is a modulator of cytokine-induced iNOS activity in rat vascular
smooth muscle and its mechanism of action involves decrease of iNOS mRNA and
protein.
PMID- 9559892
TI - The possible mechanisms of the antiproliferative effect of fullerenol,
polyhydroxylated C60, on vascular smooth muscle cells.
AB - 1. The possible mechanisms of the antiproliferative effect of polyhydroxylated
fullerene (fullerenol), a novel free radical trapper, were studied in rat
vascular smooth muscle cells (A7r5 cells) and compared with the effect of
ascorbic acid. 2. Fullerenol-1 and ascorbic acid inhibited the proliferative
responses in a number of cells, including rat aortic smooth muscle cells (A7r5
cells), human coronary artery smooth muscle cells, and human CEM lymphocytes (CEM
cells) in a concentration dependent manner. 3. At the concentration range of 10(
6) to 10(-2) M, fullerenol-1 and ascorbic acid concentration-dependently
inhibited the proliferative responses stimulated by serum in A7r5 cells.
Fullerenol-1 was more potent than ascorbic acid. 4. The production of O2- induced
by alloxan, a diabetogenic compound, was reduced by fullerenol-1 (10(-4) M) in
the presence of A7r5 cells. 5. The cytosolic protein kinase C activity of A7r5
cells stimulated by phorbol ester was reduced by 10(-3) M fullerenol-1, but not
ascorbic acid (10(-4)-10(-2) M) and fullerenol-1 at lower concentrations (10(-6)
10(-4) M). 6. In contrast, the membraneous protein tyrosine kinase activity of
A7r5 cells stimulated by foetal calf serum was significantly reduced by
fullerenol-1 (10(-6)-10(-3) M) and ascorbic acid (10(-4)-10(-2) M). Again, the
inhibitory activity of fullerenol-1 was greater than that of ascorbic acid. 7.
Our results demonstrate that fullerenol-1 and ascorbic acid exhibit inhibitory
effects on transduction signals in addition to their antioxidative property. It
is suggested that the antiproliferative effect of fullerenol-1 on vascular smooth
muscle cells may partly be mediated through the inhibition of protein tyrosine
kinase.
PMID- 9559893
TI - Characterization of K(ATP) channels in intact mammalian skeletal muscle fibres.
AB - 1. The aim of this study was to characterize the K(ATP) channel of intact rat
skeletal muscle (rat flexor digitorum brevis muscle). Changes in membrane
currents were recorded with two-electrode voltage-clamp of whole fibres. 2. The
K(ATP) channel openers, levcromakalim and pinacidil (10-400 microM), caused a
concentration-dependent increase in whole-cell chord conductance (up to
approximately 1.5 mScm(-2)). The activated current had a weak inwardly rectifying
current-voltage relation, a reversal potential near E(K) and nanomolar
sensitivity to glibenclamide--characteristic of a K(ATP) channel current.
Concentration-effect analysis revealed that levcromakalim and pinacidil were not
particularly potent (EC50 approximately 186 microM, approximately 30 microM,
respectively), but diazoxide was completely inactive. 3. The ability of both
classical K(ATP) channel inhibitors (glibenclamide, tolbutamide, glipizide and 5
hydroxydecanoic acid) and a number of structurally related glibenclamide
analogues to antagonize the levcromakalim-induced current was determined.
Glibenclamide was the most potent compound with an IC50 of approximately 5 nM.
However, the non-sulphonylurea (but cardioactive) compound 5-hydroxydecanoic acid
was inactive in this preparation. 4. Regression analysis showed that the
glibenclamide analogues used have a similar rank order of potency to that
observed previously in vascular smooth muscle and cerebral tissue. However, two
compounds (glipizide and DK13) were found to have unexpectedly low potency in
skeletal muscle. 5. These experiments revealed K(ATP) channels of skeletal muscle
to be at least 10x more sensitive to glibenclamide than previously found; this
may be because of the requirement for an intact intracellular environment for the
full effect of sulphonylureas to be realised. Pharmacologically, K(ATP) channels
of mammalian skeletal muscle appear to resemble most closely K(ATP) channels of
cardiac myocytes.
PMID- 9559894
TI - Desensitization and resensitization of delta-opioid receptor-mediated Ca2+
channel inhibition in NG108-15 cells.
AB - 1. To approach the mechanisms underlying desensitization of the opioid receptor
mediated Ca2+ channel inhibition, the effects of prolonged application of [D
Ala2, D-Leu5]enkephalin (DADLE) on Ba2+ currents (I(Ba)) through Ca2+ channels
were analysed in NG108-15 neuroblastoma x glioma hybrid cells. 2. Inhibition of
I(Ba) by 100 nM DADLE desensitized by 57% with a time constant of 4.4 min. 3.
Maximal desensitization of the delta-opioid receptor-Ca2+ channel coupling was
attained by 1 microM DADLE. The EC50 value for desensitization was estimated to
be 78 nM. 4. RNA blot hybridization analysis and immunoblot analysis revealed the
expression of beta-adrenoceptor kinase-1 (betaARK1) in NG108-15 cells. 5.
Heparin, an inhibitor of betaARK, significantly reduced the magnitude and rate of
desensitization, whereas Rp-cyclic AMPS and PKI (14-24)amide, inhibitors of
cyclic AMP-dependent protein kinase (PKA), or long-term treatment with phorbol 12
myristate 13-acetate to induce down-regulation of protein kinase C (PKC) had no
significant effect. 6. Recovery from desensitization (resensitization) proceeded
with a time constant of 6.7 min. Okadaic acid, an inhibitor of serine/threonine
phosphatases 1 and 2A, significantly attenuated the degree of resensitization. 7.
In summary, we have characterized the time course and concentration-dependence of
the desensitization of DADLE-induced I(Ba) inhibition in NG108-15 cells. This
desensitization was reversible after removal of DADLE. It is suggested that
betaARK, but neither PKA nor PKC, is involved in desensitization, while
serine/threonine phosphatases mediate resensitization.
PMID- 9559895
TI - A comparison of the effects of L-NAME, 7-NI and L-NIL on carrageenan-induced
hindpaw oedema and NOS activity.
AB - 1. Intraplantar injection of carrageenan (150 microl, 1-3% w/v) in the rat
resulted in a dose-related increase in hindpaw weight (oedema) characterized by a
rapid 'early' phase (up to 2.5 h) response followed by a more sustained 'late'
phase (2-6 h) response. No change in weight of either the contralateral (i.e.
noninjected) hindpaw or hindpaws injected with saline was observed. 2. Six hours
after intraplantar injection of carrageenan (1-3% w/v) hindpaw constitutive (i.e.
calcium-dependent) nitric oxide synthase (cNOS) activity (determined ex vivo as
the conversion of radiolabelled L-arginine to radiolabelled citrulline) was
increased (e.g. 2% w/v; 0.64+/-0.08 pmol citrulline mg(-1) protein 15 min(-1)
c.f. 0.08+/-0.04 pmol citrulline mg(-1) protein 15 min(-1) in saline-injected,
control animals, n=4, P<0.05). Carrageenan injection also resulted in the
appearance in hindpaw homogenates of inducible (i.e. calcium-independent) nitric
oxide synthase (iNOS, e.g. 2% w/v; 0.67+/-0.14 pmol citrulline mg(-1) protein 15
min(-1), n=4). Hindpaw cyclic GMP concentration was also significantly increased
6 h after intraplantar injection of carrageenan (e.g. 2% w/v; 379.6+/-26.8 fmol
mg(-1) protein c.f. 261.8+/-42.2 fmol mg(-1) protein, in saline-injected, control
animals, n=4, P<0.05). 3. Pretreatment (5-25 mg kg(-1), i.p., 30 min before
carrageenan, 2% w/v) of animals with L-N(G) nitro arginine methyl ester (L-NAME;
isoform nonselective inhibitor of NOS) or 7-nitro indazole (7-NI; inhibitor of
neuronal NOS, nNOS) caused dose-related inhibition of both the early (2 h) and
late (6 h) phase hindpaw oedema, associated with reduced hindpaw iNOS and cNOS
activity and cyclic GMP concentration in animals killed at 6 h. Administration of
7-NI (5-25 mg kg(-1), i.p.) to animals 2.5 h after intraplantar carrageenan (2%
w/v) injection (i.e. at the end of the early phase oedema response) produced dose
related inhibition of the late phase response. 4. Pretreatment (5-25 mg kg(-1),
i.p., 30 min before carrageenan, 2% w/v) of animals with L-N6-iminoethyllysine (L
NIL, selective inhibitor of iNOS) (5-25 mg kg(-1)) failed to affect the early
phase hindpaw oedema response but did produce a dose-related inhibition of the
late phase oedema. L-NIL pretreatment also inhibited the carrageenan-induced
increase in both hindpaw iNOS and cNOS activity as well as the rise in hindpaw
cyclic GMP concentration. 5. The present experiments demonstrate an anti
inflammatory effect of 7-NI as evidenced by inhibition of carrageenan-induced
hindpaw oedema in the rat. Inhibition of nNOS (early phase) and iNOS (late phase)
at the site of inflammation most probably accounts for the anti-inflammatory
activity observed. These data suggest a role for nitric oxide synthesized by the
nNOS isoform (most probably within sensory nerves) in this model of inflammation.
PMID- 9559896
TI - Effects of bradykinin on signal transduction, cell proliferation, and cytokine,
prostaglandin E2 and collagenase-1 release from human corneal epithelial cells.
AB - 1. We recently demonstrated the presence of phospholipase C-coupled bradykinin
(BK) B2-receptors in human primary and SV40 virus-immortalized corneal epithelial
(CEPI) cells. 2. The aims of the present studies were to demonstrate the specific
binding of [3H]-BK to CEPI cell membranes and to study its pharmacological
characteristics. In addition, we wished to study the functional coupling of the
BK receptors to various physiological and pathological mechanisms in the CEPI
cells, including phosphoinositide (PI) turnover, intracellular Ca2+-mobilization
([Ca2+]i), cell proliferation (via [3H]-thymidine incorporation), and the release
of various cytokines, collagenase-1 (matrix metalloproteinase-1) and
prostaglandin E2 (PGE2). 3. Specific [3H]-BK binding comprised 83 +/- 2% of the
total binding, and was of high affinity (Kd = 1.66 +/- 0.52 nM, n = 5), saturable
(Bmax = 640 +/- 154 fmol g(-1) wet weight) and reversible. Competition studies
yielded the following affinity values for BK and a number of BK-related peptides:
Hoe-140 (D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]BK; icatibant): Ki = 0.17 +/- 0.07 nM; BK:
Ki = 1.0 +/- 0.11 nM; [Tyr8]-BK: Ki = 12.9 +/- 2.3 nM; [des-Arg9]-BK: Ki > 9,200
nM (all n = 3-5)). 4. BK potently stimulated PI turnover (EC50 = 2.3 +/- 0.3 nM;
n = 7) and [Ca2+]i mobilization (EC50 = 8-20 nM) in CEPI cells and both responses
were inhibited in a concentration-dependent manner by 100 nM-10 microM Hoe-140, a
selective B2-receptor antagonist, and also inhibited by the selective
phospholipase C (PLC) inhibitor, U73122 (1-(6-((17beta-3-methoxyestra-1,3,5(10)
trien-17-yl)amino)hexyl)-1 H-pyrrole-2,5-dione) (IC50 = 3.0 +/- 1.6 microM). BK
induced [Ca2+]i mobilization was reduced by about 30% in the presence of 4 mM
EGTA, but was not significantly affected by 100 nM nifedipine. 5. BK (0.1 nM-10
microM) significantly (P<0.05-0.001) stimulated [3H]-thymidine incorporation into
CEPI cellular DNA. However, while interleukin-1alpha (IL-1alpha; 10 ng ml(-1))
potently stimulated the release of IL-6, IL-8 and granulocyte macrophage colony
stimulating factor from CEPI cells, BK (0.1 nM-10 microM) was without effect. 6.
Whilst phorbol-12-myristate-13-acetate (PMA; 3 microg ml(-1)) and 10% foetal
bovine serum (positive control agents) significantly stimulated the release of
both MMP-1 and PGE2 from CEPI cells, BK (0.1 nM-10 microM) was without any
significant effect under these conditions. 7. In conclusion, these data indicate
that the CEPI cells express high-affinity [3H]-BK binding sites representing B2
subtype BK receptors coupled to PI turnover and [Ca2+]i mobilization which appear
to stimulate [3H]-thymidine incorporation into cellular DNA. In contrast, BK
failed to elicit the release of PGE2, various cytokines and MMP-1 from CEPI
cells. These results suggest that BK may have a potential role in corneal
epithelium wound healing by stimulating cell proliferation.
PMID- 9559897
TI - Effect of RX 821002 at 5-HT1A-receptors in rabbit spinal cord in vivo.
AB - 1. The activity of RX 821002 (2-methoxy idazoxan) at 5-HT1A-receptors in the
spinal cord has been investigated in decerebrated, spinalized rabbits. Reflexes
evoked in medial gastrocnemius motoneurones by electrical stimulation of the
sural nerve were unaffected by intrathecal (i.th.) administration of RX 821002
(111 and 664 nmol cumulative, n = 7), although the highest dose of this drug did
produce a significant increase in heart rate of 28 +/- 7 beats min(-1).
Subsequent administration of the 5-HT1A-receptor agonist (+/-)-8-hydroxy-2-(di-n
propylamino)tetralin (8-OH-DPAT) at 300 nmol, i.th., facilitated reflexes to a
median of 144% of pre-drug controls, an effect that was partially reversed (to a
median value of 120% of pre-drug values) by subsequent administration of the 5
HT1A-receptor antagonist WAY-100635, at 185 nmol i.th. 2. In a separate set of
experiments, 8-OH-DPAT was given at 30 nmol i.th. and potentiated reflexes to a
median of 170% of pre-drug levels (n = 8). Subsequent administration of RX 821002
(at a cumulative dose of 1.11 micromol, i.th., n = 5) significantly reduced
gastrocnemius responses to a median of 154% of control values. 3. After a 3 h
recovery period, 8-OH-DPAT was re-administered at 30 nmol, i.th., and increased
reflexes to a median value of 151% of pre-drug levels, an effect not
significantly different from when it was given alone. WAY-100635 dose-dependently
antagonized this effect, causing significant reductions in reflexes at a
cumulative dose of 0.55 nmol, i.th., and complete reversal of the effects of 8-OH
DPAT at a cumulative dose of 5.5 nmol. 4. These data show that, at intrathecal
doses up to 664 nmol, RX 821002 is devoid of agonist activity at 5-HT1A
receptors. It appears to be a very weak antagonist at these sites in vivo, being
some 2000 times less potent than WAY-100635. The inability of WAY-100635 to block
completely the effects of high doses of 8-OH-DPAT has been noted previously and
can be explained by non-selective actions of the agonist. However, it would
appear that a 30 nmol i.th. dose of 8-OH-DPAT is selective for 5-HT1A receptors
in this preparation.
PMID- 9559898
TI - Stretch-evoked inhibition of spontaneous migrating contractions in a whole mount
preparation of the guinea-pig upper urinary tract.
AB - 1. The effects of circumferentially-applied stretch on the spontaneous
contractility of a whole mount preparation of the guinea-pig upper urinary tract
(UUT) (renal pelvis and ureter) were investigated by use of standard isometric
tension recording techniques. 2. Simultaneous tension recordings of the proximal
and distal portions of the renal pelvis (RP) and ureter revealed that spontaneous
contractions, in 79% (n = 66) of preparations, originated in the proximal RP (at
a frequency of 4.5 min(-1)) and propagated to the distal RP and ureter at a
velocity of 1-3 cm s(-1). Pretreatment with tetrodotoxin (TTX) (3-10 microM) or
N(G)-nitro-L-arginine (100 microM) had little effect on the spontaneous
contractility of the UUT, motility indexes (MIs) (contraction amplitude x
contraction frequency) calculated after 20 min exposure were little affected by
TTX or N(G)-nitro-L-arginine (L-NOARG). Omega-conotoxin GVIA (100 nM)
significantly reduced MI values in both the proximal RP and ureter. 3. Exposure
of the spontaneously-active UUT to capsaicin (10 microM for 15 min) induced a
transient increase in UUT contractility, followed by a prolonged negative
inotropic effect. The MI values, calculated 60 min after the washout of
capsaicin, for the proximal and distal RP and ureter were reduced to 56%, 53% (n
= 18) and 61% (n = 16), respectively, of their control values. This capsaicin
pretreatment blocked the positive inotropic effects of transmural electrical
nerve stimulation on UUT contractility to reveal a small inhibitory effect which
was readily blocked by tetrodotoxin (3 microM) (n = 3). The excitatory and
inhibitory actions of nerve stimulation were both blocked by TTX (3 microM). 4. A
second exposure to capsaicin (10 microM for 15 min), further reduced the MI
values (calculated 60 min after washout) in the proximal and distal RP to 41% and
31%, respectively (n = 6; P<0.05), of the initial control values. 5. In 61% (n =
99) of preparations, the application of stretch to the proximal RP (0.5 to 2 mm)
evoked a decrease in the amplitude of the contractions recorded in the distal RP,
but not in the ureter. Stretch applied to the distal RP or ureter had no effect
on the contractions recorded in the other regions of the UUT. 6. In 5 out of 6
preparations, a single application of capsaicin (10 microM for 15 min) had little
effect on the change in contractile force of the distal RP evoked upon stretch of
the proximal RP. 7. The inhibition of the distal RP upon stretch of the proximal
RP was partially reduced (P<0.05) when the UUT was pretreated with the calcitonin
gene-related peptide (CGRP) receptor antagonist, hCGRP (8-37) (1 microM). 8. The
application of the CGRP receptor agonist, hCGRP (100 nM) inhibited contractility
in the UUT in a region dependent manner. The MI of the proximal RP was decreased
32% after 6 min; while the MIs of the distal RP and ureter were reduced 83% and
63%, respectively, within 5 min of the application of hCGRP. 9. Glibenclamide (1
microM) had little effect on the spontaneous contractility of the UUT, but
significantly reduced the inhibition of the distal RP evoked upon stretch (0.5 to
2 mm) of the proximal RP. TTX (3-10 microM), L-NOARG (100 microM) or omega
conotoxin GVIA (100 nM) had little effect on the stretch-evoked inhibition of the
distal RP. 10. It was concluded that circumferential stretch of the proximal RP
inhibits the contractility of the distal RP and that a component of this
inhibition involves the activation of a glibenclamide-sensitive mechanism via the
release of endogenous CGRP, possibly from the varicosities of intramural sensory
nerves.
PMID- 9559900
TI - Effect of nitrovasodilators and inhibitors of nitric oxide synthase on ischaemic
and reperfusion function of rat isolated hearts.
AB - 1. The functional role of the nitric oxide (NO)/guanosine 3':5'-cyclic
monophosphate (cyclic GMP) pathway in experimental myocardial ischaemia and
reperfusion was studied in rat isolated hearts. 2. Rat isolated hearts were
perfused at constant pressure with Krebs-Henseleit buffer for 25 min (baseline),
then made ischaemic by reducing coronary flow to 0.2 ml min(-1) for 25 or 40 min,
and reperfused at constant pressure for 25 min. Drugs inhibiting or stimulating
the NO/cyclic GMP pathway were infused during the ischaemic phase only. Ischaemic
contracture, myocardial cyclic GMP and cyclic AMP levels during ischaemia, and
recovery of reperfusion mechanical function were monitored. 3. At baseline, heart
rate was 287+/-12 beats min(-1), coronary flow was 12.8+/-0.6 ml min(-1), left
ventricular developed pressure (LVDevP) was 105+/-4 mmHg and left ventricular end
diastolic pressure 4.6+/-0.2 mmHg in vehicle-treated hearts (control; n=12).
Baseline values were similar in all treatment groups (P>0.05). 4. In normoxic
perfused hearts, 1 microM N(G)-nitro-L-arginine (L-NOARG) significantly reduced
coronary flow from 13.5+/-0.2 to 12.1+/-0.1 ml min(-1) (10%) and LVDevP from 97+/
1 to 92+/-1 mmHg (5%; P<0.05, n=5). 5. Ischaemic contracture was 46+/-2 mmHg,
i.e. 44% of LVDevP in control hearts (n=12), unaffected by low concentrations of
nitroprusside (1 and 10 microM) but reduced to approximately 30 mmHg
(approximately 25%) at higher concentrations (100 or 1000 microM; P<0.05 vs
control, n=6). Conversely, the NO synthase inhibitor L-NOARG reduced contracture
at 1 microM to 26+/-3 mmHg (23%), but increased it to 63+/-4 mmHg (59%) at 1000
microM (n=6). Dobutamine (10 microM) exacerbated ischaemic contracture (81+/-3
mmHg; n = 7) and the cyclic GMP analogue Sp-8-(4-p-chlorophenylthio)-3',5'
monophosphorothioate (Sp-8-pCPT-cGMPS; 10 microM) blocked this effect (63+/-11
mmHg; P<0.05 vs dobutamine alone, n=5). 6. At the end of reperfusion, LVDevP was
58+/-5 mmHg, i.e. 55% of pre-ischaemic value in control hearts, significantly
increased to approximately 80% by high concentrations of nitroprusside (100 or
1000 microM) or L-NOARG at 1 microM, while a high concentration of L-NOARG (1000
microM) reduced LVDevP to approximately 35% (P<0.05 vs control; n=6). 7.
Ischaemia increased tissue cyclic GMP levels 1.8 fold in control hearts (P<0.05;
n=12); nitroprusside at 1 microM had no sustained effect, but increased cyclic
GMP approximately 6 fold at 1000 microM; L-NOARG (1 or 1000 microM) was without
effect (n=6). Nitroprusside (1 or 1000 microM) marginally increased cyclic AMP
levels whereas NO synthase inhibitors had no effect (n=6). 8. In conclusion, the
cardioprotective effect of NO donors, but not of low concentrations of NO
synthase inhibitors may be due to their ability to elevate cyclic GMP levels.
Because myocardial cyclic GMP levels were not affected by low concentrations of
NO synthase inhibitors, their beneficial effect on ischaemic and reperfusion
function is probably not accompanied by reduced formation of NO and peroxynitrite
in this model.
PMID- 9559899
TI - Effect of the triaminopyridine flupirtine on calcium uptake, membrane potential
and ATP synthesis in rat heart mitochondria.
AB - 1. Flupirtine is an analgesic agent which exhibits neuronal cytoprotective
activity and may have value in the treatment of conditions involving cell injury
and apoptosis. Since flupirtine has no action on known receptor sites we have
investigated the effect of this drug on mitochondrial membrane potential, and the
changes in intramitochondrial calcium concentration in particular. 2. The
findings show that flupirtine increases Ca2+ uptake in mitochondria in vitro. At
clinically relevant flupirtine concentrations, corresponding to flupirtine levels
in vitro of 0.2 to 10 nmol mg(-1) mitochondrial protein, there was a 2 to 3 fold
increase in mitochondrial calcium levels (P<0.01). At supra-physiological
flupirtine concentrations of 20 nmol mg(-1) mitochondrial protein and above, the
mitochondrial calcium concentrations were indistinguishable from those in
untreated mitochondria. 3. Mitochondrial membrane potential closely paralleled
the changes in mitochondrial calcium levels showing a 20% (P<0.01) increase when
the flupirtine concentration was raised from 0.2 nmol to 10 nmol mg(-1)
mitochondrial protein and a return to control values at 20 nmol mg(-1) protein.
4. The increase in mitochondrial calcium uptake and membrane potential were
accompanied by an increase in mitochondrial ATP synthesis (30%; P<0.05) and a
similar percentage reduction in mitochondrial volume. 5. Calcium at 80 and 160
nmol mg(-1) mitochondrial protein decreased ATP synthesis by 20-25% (P<0.001).
This decrease was prevented or diminished if flupirtine at 10 nmol mg(-1) protein
was added before the addition of calcium. 6. Since intracellular levels of
flupirtine in intact cells never exceeded 10 nmol mg(-1) mitochondrial protein,
these findings are supportive evidence for an in vivo cytoprotective action of
flupirtine at the mitochondrial level.
PMID- 9559901
TI - Early effects of acute gamma-radiation on vascular arterial tone.
AB - 1. To determine the acute effects of irradiation on the functionality of vessel,
rat aortic rings were mounted in an organ bath for isometric tension measurements
and irradiated (60Co, 1 Gy min(-1), 15 min). 2. Irradiation, which is without
effect on non-contracted or endothelium-denuded vessels, led to an immediate and
reversible increase in vascular tone on (-)-phenylephrine (1 microM)
precontracted aortic rings. The tension reached a plateau about 5 min after the
beginning of irradiation. 3. The maximal radiation-induced contraction occurred
on aortic rings relaxed by acetylcholine (ACh) (1 microM). In this condition, the
addition of catalase (1000 u ml(-1)), which reduces hydrogen peroxide, and DMSO
(0.1% v/v), which scavenges hydroxyl radical, had no influence on tension level
while superoxide dismutase (SOD) (100 u ml(-1)), a superoxide anion scavenger,
reduced the observed contraction. A similar result was obtained in the presence
of indomethacin (10 microM), a cyclo-oxygenase blocker. 4. Pretreatment of rings
with the nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine methyl ester
(L-NAME) (10-100 microM) inhibited the radiation-induced contraction. 5. This
effect was dose rate-dependent and even occurred for a very low dose rate (0.06
Gy min(-1)). 6. The present results indicate that gamma-radiation induces an
instantaneous vascular tone increase that is endothelium and dose rate-dependent.
This effect is (i) maximal when nitric oxide (NO) is produced, (ii) greatly
reduced by SOD and (iii) inhibited by L-NAME, suggesting a major involvement of
complexes between NO and superoxide anion.
PMID- 9559902
TI - Pharmacological comparison of UTP- and thapsigargin-induced arachidonic acid
release in mouse RAW 264.7 macrophages.
AB - 1. Although stimulation of mouse RAW 264.7 macrophages by UTP elicits a rapid
increase in intracellular free Ca2+ ([Ca2+]i), phosphoinositide (PI) turnover,
and arachidonic acid (AA) release, the causal relationship between these
signalling pathways is still unclear. In the present study, we investigated the
involvement of phosphoinositide-dependent phospholipase C (PI-PLC) activation,
Ca2+ increase and protein kinase activation in UTP-induced AA release. The
effects of stimulating RAW 264.7 cells with thapsigargin, which cannot activate
the inositol phosphate (IP) cascade, but results in the release of sequestered
Ca2+ and an influx of extracellular Ca2+, was compared with the effects of UTP
stimulation to elucidate the multiple regulatory pathways for cPLA2 activation.
2. In RAW 264.7 cells UTP (100 microM) and thapsigargin (1 microM) caused 2 and
1.2 fold increases, respectively, in [3H]-AA release. The release of [3H]-AA
following treatment with UTP and thapsigargin were non-additive, totally
abolished in the Ca2+-free buffer, BAPTA (30 microM)-containing buffer or in the
presence of the cPLA2 inhibitor MAFP (50 microM), and inhibited by pretreatment
of cells with pertussis toxin (100 ng ml(-1)) or 4-bromophenacyl bromide (100
microM). By contrast, aristolochic acid (an inhibitor of sPLA2) had no effect on
UTP and thapsigargin responses. 3. U73122 (10 microM) and neomycin (3 mM),
inhibitors of PI-PLC, inhibited UTP-induced IP formation (88% and 83% inhibition,
respectively) and AA release (76% and 58%, respectively), accompanied by a
decrease in the [Ca2+]i rise. 4. Wortmannin attenuated the IP response of UTP in
a concentration-dependent manner (over the range 10 nM-3 microM), and reduced the
UTP-induced AA release in parallel. RHC 80267 (30 microM), a specific
diacylglycerol lipase inhibitor, had no effect on UTP-induced AA release. 5.
Short-term treatment with PMA (1 microM) inhibited the UTP-stimulated
accumulation of IP and increase in [Ca2+]i, but had no effect on the release of
AA. In contrast, the AA release caused by thapsigargin was increased by PMA. 6.
The role of PKC in UTP- and thapsigargin-mediated AA release was shown by the
blockade of these effects by staurosporine (1 microM), Ro 31-8220 (10 microM), Go
6976 (1 microM) and the down-regulation of PKC. 7. Following treatment of cells
with SK&F 96365 (30 microM), thapsigargin-, but not UTP-, induced Ca2+ influx,
and the accompanying AA release, were down-regulated. 8. Neither PD 98059 (100
microM), MEK a inhibitor, nor genistein (100 microM), a tyrosine kinase
inhibitor, had any effect on the AA responses induced by UTP and thapsigargin. 9.
We conclude that UTP-induced cPLA2 activity depends on the activation of PI-PLC
and the sustained elevation of intracellular Ca2+, which is essential for the
activation of cPLA2 by UTP and thapsigargin. The [Ca2+]i-dependent AA release
that follows treatment with both stimuli was potentiated by the activity of
protein kinase C (PKC). A pertussis toxin-sensitive pathway downstream of the
increase in [Ca2+]i was also shown to be involved in AA release.
PMID- 9559903
TI - Receptor mechanisms involved in the 5-HT-induced inotropic action in the rat
isolated atrium.
AB - 1. The effects of 5-hydroxytryptamine (5-HT) in rat cardiac preparations were
studied. 5-HT up to 10 microM failed to affect contractility in papillary
muscles. However, in electrically driven (1 Hz) left atria 5-HT exerted a
positive inotropic effect that started at 1 microM and attained its maximum at 10
microM (312+/-50% of predrug value, n=8). 2. 5-HT 10 microM stimulated the
content of inositol-1,4,5-trisphosphate but not of cyclic AMP in rat left atria.
3. Plasma and serum levels of 5-HT amounted to about 0.3 microM and 15 microM,
respectively. 4. The selective 5-HT4 receptor antagonists GR 125487 (10 nM and 1
microM) and SB 203186 (1 microM) did not attenuate the positive inotropic effect
of 5-HT in rat left atria. In contrast, the 5-HT2 receptor antagonist ketanserin
(5 nM, 50 nM, 1 microM) resulted in a concentration-dependent diminution of the
positive inotropic effect of 5-HT in rat left atria. 5. Reverse transcriptase
polymerase chain reaction with specific primers detected mRNA of the 5-HT2A
receptor in rat atria and ventricles, while expression of the 5-HT4 receptor was
confined to atria. 6. It is suggested that the positive inotropic effect of 5-HT
in electrically driven rat left atria is mediated by ketanserin-sensitive 5-HT2A
receptors and not through 5-HT4 receptors.
PMID- 9559904
TI - Protein kinase C-mediated inhibition of transmembrane signalling through CCK(A)
and CCK(B) receptors.
AB - 1. The rat CCK(A) and CCK(B) receptors were stably expressed in Chinese hamster
ovary (CHO-09) cells in order to compare modes of signal transduction and effects
of protein kinase C (PKC) thereupon. 2. Spectrofluorophotometry of Fura-2-loaded
cells revealed that both receptors retained their pharmacological characteristics
following expression in CHO cells. Sulphated cholecystokinin-(26-33)-peptide
amide (CCK-8-S) increased the cytosolic Ca2+ concentration ([Ca2+]i) in CCK(A)
cells, measured as an increase in Fura-2 fluorescence emission ratio, 1000 fold
more potently than its non-sulphated form (CCK-8-NS) (EC50 values of 0.19 nM and
0.18 microM, respectively). By contrast, CCK-8-S and CCK-8-NS were equally potent
in CCK(B) cells (EC50 values of 0.86 nM and 1.18 nM, respectively). The CCK(A)
receptor agonist JMV-180 increased [Ca2+]i only in CCK(A) cells. Likewise,
pentagastrin increased [Ca2+]i only in CCK(B) cells. Finally, CCK-8-S-induced
Ca2+ signalling through the CCK(A) receptor was most potently inhibited by the
CCK(A) receptor antagonist L364,718, whereas the CCK(B) receptor antagonist
L365,260 was more potent in CCK(B) cells. 3. Receptor-mediated activation of
adenylyl cyclase was measured in the presence of the inhibitor of cyclic
nucleotide phosphodiesterase activity, 3-isobutyl-1-methylxanthine. CCK-8-S and,
to a lesser extent, CCK-8-NS, but not JMV-180 or pentagastrin, stimulated the
accumulation of cyclicAMP in CCK(A) cells. By contrast, none of these agonists
increased cyclicAMP in CCK(B) cells. 4. Short-term (3 min) pretreatment with the
PKC activator 12-O-tetradecanoylphorbol 13-acetate (TPA) evoked a rightward shift
of the dose-response curve for the Ca2+ mobilizing effect of CCK-8-S in both cell
lines. In addition, short-term TPA pretreatment markedly reduced CCK-8-S-induced
cyclicAMP accumulation in CCK(A) cells. In both cases, the inhibitory effect of
TPA was abolished by the PKC inhibitors, GF-109203X and staurosporine, whereas no
inhibition was observed with the inactive phorbol ester, 4-alpha-phorbol 12
myristate 13-acetate. 5. During prolonged TPA treatment, the cells gradually
recovered from phorbol ester inhibition and in the case of CCK-8-S-induced Ca2+
mobilization complete recovery was achieved after 24 h of TPA treatment. Western
blot analysis revealed that this recovery was paralleled by down-regulation of
PKC-alpha, suggesting the involvement of this PKC isotype in the inhibitory
action of TPA. 6. This study demonstrates that following expression in CHO cells
(i) both CCK(A) and CCK(B) receptors are coupled to Ca2+ mobilization, (ii) only
CCK(A) receptors are coupled to cyclicAMP formation and (iii) with both receptors
signalling is inhibited by PKC.
PMID- 9559905
TI - Differential effects of cyclosporine A after acute antigen challenge in
sensitized cats in vivo and ex vivo.
AB - 1. We determined the effect of cyclosporine A (CsA) treatment on mast cell
degranulation and lung resistance (R(L)) in vivo, and tracheal smooth muscle
(TSM) contraction ex vivo after antigen challenge in sensitized cats. We also
determined the direct effects of addition of CsA to the tissue bath on antigen
induced responses of TSM in vitro. 2. Cats (n=10) were sensitized by i.m.
injection of Ascaris suum antigen (AA); 5 cats (CsA+) received CsA twice daily
for 2 weeks before acute antigen challenge in doses sufficient to suppress
interleukin-2 secretion from feline peripheral blood mononuclear cells ex vivo.
3. Lung resistance increased comparably within 10 min of exposure to AA (P<0.03).
Histamine content in bronchoalveolar lavage fluid from both groups increased
comparably within 30 min of antigen challenge, from undetectable levels to 542+/
74 pg ml(-1) post AA for CsA+ and from 74+/-19 pg ml(-1) at baseline, to 970+/
180 pg ml(-1) post AA CsA- (P<0.05; P=NS vs CsA+). 4. In excised TSM, active
tension elicited by exposure to AA in vitro was 107+/-38% KCl in the CsA+ group
vs 144+/-56% KCl in the CsA- group (P=NS). However, contraction of TSM (n=4)
harvested from both groups was abolished or greatly diminished after AA challenge
when tissues were pre-incubated with 1 microM CsA in vitro (8+/-8% KCl, P<0.05 vs
CsA+ and CsA-). This was associated with inhibited release of 5-hydroxytryptamine
into the organ bath fluid of tissues treated with CsA in vitro only. 5. We
demonstrated that CsA treatment in vivo does not inhibit the early phase
asthmatic response or mast cell degranulation following antigen challenge in
sensitized cats. Additionally, the effects of CsA on mast cell function ex vivo
do not reflect lack of effects of CsA on mast cell function in vivo in this
animal model of atopic asthma.
PMID- 9559907
TI - Zn2+ modulation of ATP-responses at recombinant P2X2 receptors and its dependence
on extracellular pH.
AB - 1. Using recombinant P2X2 receptors expressed in Xenopus oocytes, the modulatory
effects of zinc (Zn2+) on ATP-responses were studied under voltage-clamp
conditions and at different levels of extracellular pH. 2. Zn2+ (0.3-300 microM)
added to the bathing medium potentiated ATP-activated membrane currents,
increasing ATP-responses by up to 20 fold. This potentiating effect was reversed
on washout. Zn2+-potentiation was reduced in an exponential manner (decaying 1/e
in 42 s) as the interval was lengthened between adding Zn2+ then ATP to the
superfusate. 3. The potentiating effect of Zn2+ was progressively diminished by
acidic shifts in extracellular pH (pHe) which, of itself, also potentiated ATP
responses at P2X2 receptors. The maximal potentiating effects of Zn2+ and H+ were
not additive. 4. Neither Zn2+ nor H+ potentiation of ATP-responses was abolished
by diethylpyrocarbonate (DEPC, 0.3-3 mM), which irreversibly denatures histidyl
residues. Nine histidyl residues are present in the extracellular loop of P2X2
receptors. 5. Zn2+ also enhanced the blocking activity of the P2 receptor
antagonist suramin at P2X2 receptors. Therefore, Zn2+ also mimics H+ in
increasing suramin-activity at P2X2 receptors. 6. In summary, Zn2+ and H+
potentiate agonist and antagonist activity at P2X2 receptors but their effects
are not wholly alike for receptor agonism. There, the potentiating effects of
Zn2+ are time-dependent and gradually convert to inhibition while those of H+ are
time-independent, persistent and more potent, suggesting that either these
modulators interact in a different way with a single allosteric site or with
different allosteric sites.
PMID- 9559906
TI - Characterization of prejunctional 5-HT1 receptors that mediate the inhibition of
pressor effects elicited by sympathetic stimulation in the pithed rat.
AB - 1. A study was made of the effects of 5-carboxamidotryptamine (5-CT) on pressor
responses induced in vivo by electrical stimulation of the sympathetic outflow
from the spinal cord of pithed rats. All animals had been pretreated with
atropine. Sympathetic stimulation (0.1, 0.5, 1 and 5 Hz) resulted in frequency
dependent increases in blood pressure. Intravenous infusion of 5-CT at doses of
0.01, 0.1 and 1 mg kg(-1) min(-1) reduced the pressor effects obtained by
electrical stimulation. The inhibitory effect of 5-CT was significantly more
pronounced at lower frequencies of stimulation. In the present study we
characterized the pharmacological profile of the receptors mediating the above
inhibitory effect of 5-CT. 2. The inhibition induced by 0.01 microg kg(-1) min(
1) of 5-CT on sympathetically-induced pressor responses was partially blocked
after i.v. treatment with methiothepin (10 microg kg(-1)), WAY-100,635 (100
microg kg(-1)) or GR127935T (250 microg kg(-1)), but was not affected by
cyanopindolol (100 microg kg(-1)). 3. The selective 5-HT1A receptor agonist 8-OH
DPAT and the selective 5-HT(1B/1D) receptor agonists sumatriptan and L-694,247
inhibited the pressor response, whereas the 5-HT1B receptor agonists CGS-12066B
and CP-93,129 and the 5-HT2C receptor agonist m-CPP did not modify the pressor
sympathetic responses. 4. The selective 5-HT1A receptor antagonist WAY-100,635
(100 microg kg(-1)) blocked the inhibition induced by 8-OH-DPAT and the selective
5-HT(1B/1D) receptor antagonist GR127935T (250 microg kg(-1)) abolished the
inhibition induced either by L-694,247 or sumatriptan. 5. None of the 5-HT
receptor agonists used in our experiments modified the pressor responses induced
by exogenous noradrenaline (NA). 6. These results suggest that the presynaptic
inhibitory action of 5-CT on the electrically-induced pressor response is
mediated by both r-5-HT1D and 5-HT1A receptors.
PMID- 9559908
TI - Nitric oxide-related cyclic GMP-independent relaxing effect of N-acetylcysteine
in lipopolysaccharide-treated rat aorta.
AB - 1. We have recently demonstrated the formation of protein-bound dinitrosyl-iron
complexes (DNIC) in rat aortic rings exposed to lipopolysaccharide (LPS) and
shown that N-acetylcysteine (NAC) can promote vasorelaxation in these arteries,
possibly via the release of nitric oxide (NO) as low molecular weight DNIC from
these storage sites. The aim of the present study was to investigate further the
mechanism of the relaxation induced by NAC in LPS-treated vessels. 2. In rings
incubated with LPS (10 microg ml(-1) for 18 h) and precontracted with
noradrenaline (NA, 3 microM) plus N(omega)-nitro-L-arginine methylester (L-NAME,
3 mM), the relaxation evoked by NAC (0.1 to 10 mM) was abolished by 1H
[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 1 microM, a selective inhibitor of
soluble guanylyl cyclase) but not affected by Rp-8-bromoguanosine 3'5'-cyclic
monophosphorothioate (Rp-8BrcGMPS, 60 microM a selective inhibitor of cyclic GMP
dependent protein kinase). Tetrabutylammonium (TBA, 3 mM, as a non selective K+
channels blocker) or elevated concentration of external KCl (25 or 50 mM)
significantly attenuated the NAC-induced relaxation. Selective K+ channels
blockers (10 microM glibenclamide, 0.1 microM charybdotoxin, 0.5 microM apamin or
3 mM 4-aminopyridine) did not affect the NAC-induced relaxation. The relaxing
effect of NAC (10 mM) was not associated with an elevation of guanosine 3':5'
cyclic monophosphate (cyclic GMP) in LPS-treated rings. 3. In aortic rings
precontracted with NA (0.1 microM), low molecular weight DNIC (with thiosulphate
as ligand, 1 nM to 10 microM) evoked a concentration-dependent relaxation which
was antagonized by ODQ (1 microM) and Rp-8BrcGMPS (150 microM) but not
significantly affected by TBA (3 mM) or by the use of KCl (50 mM) as
preconstricting agent. The relaxation produced by DNIC (0.1 microM) was
associated with an 11 fold increase in aortic cyclic GMP content, which was
completely abolished by ODQ (1 microM). 4. Taken together with our previous data,
the main finding of the present study is that the vascular relaxation induced by
NAC in LPS-treated aorta, although probably related to NO through an interaction
via preformed NO stores, was not mediated by activation of the cyclic GMP
pathway. It may involve the activation of TBA-sensitive K+ channels. The
differences in the mechanism of relaxation induced by NAC and by exogenous DNIC
suggest that the generation of low molecular weight DNIC from protein-bound
species does not play a major role in the NAC-induced relaxation observed in LPS
treated rat aorta. In addition, it is suggested that ODQ may display other
properties than the inhibition of soluble guanylyl cyclase.
PMID- 9559909
TI - Cholecystokinin-8 regulation of NGF concentrations in adult mouse brain through a
mechanism involving CCK(A) and CCK(B) receptors.
AB - 1. Nerve growth factor (NGF), a powerful agent for the growth, differentiation
and regeneration of lesioned cells of the central and peripheral nervous systems,
has in recent years been indicated as a potential therapeutic agent capable of
reversing the processes of cell damage in neurodegenerative events in man. Since
NGF does not cross the blood-brain barrier and central NGF administration
requires invasive surgical procedures, the discovery of substances modulating in
vivo NGF synthesis in the brain will be extremely useful for a possible clinical
use of NGF. 2. The aim of the present study to analyse if the content of NGF in
the brain of adult mice can be affected by peripheral administration of
cholecystokinin-8 (CCK-8), a well known neuropeptide which has stimulant actions
on neurons in the brain and promotes a variety of neurobehavioural effects both
in man and rodents. 3. The dose-response and time course effects of an i.p.
injection of CCK-8 on the NGF concentrations in the hippocampus, cortex,
hypothalamus and pituitary of adult male mice were analysed by use of a sensitive
immunoenzymatic assay for NGF. The effects of pretreatment with selective CCK(A)
and CCK(B) receptor antagonists and atropine on the NGF response to CCK injection
were also studied. 4. The effects of CCK-8 were dose- and time-dependent and the
injection of 8 nmol kg(-1) resulted in a 3 fold increase of NGF levels in the
hypothalamus and pituitary, and about a 60% increase in the hippocampus. No
effects were observed in the cortex. Pretreatment with a selective CCK(A)
receptor antagonist blocked the CCK-induced NGF increase in the hypothalamus and
pituitary. In the hippocampus the same effect was obtained with a CCK(B) receptor
antagonist. Pretreatment with atropine suppressed the CCK-induced effects on NGF
levels in all the brain regions examined. 5. Our results showing that i.p.
injection with CCK-8 can modulate NGF levels in the brain through a mechanism
which seems, in part, to be mediated via the vagal afferents, indicate that this
neuropeptide may represent a useful pharmacological approach to enhance
endogenous NGF levels in neuropathologies associated with a neurotrophin deficit.
PMID- 9559911
TI - Prostaglandin E2 suppression of acetylcholine release from parasympathetic nerves
innervating guinea-pig trachea by interacting with prostanoid receptors of the
EP3-subtype.
AB - 1. We have demonstrated recently that exogenous prostaglandin E2 (PGE2) inhibits
electrical field stimulation (EFS)-induced acetylcholine (ACh) release from
parasympathetic nerve terminals innervating guinea-pig trachea. In the present
study, we have attempted to characterize the pre-junctional prostanoid
receptor(s) responsible for the inhibitory action of PGE2 and to assess whether
other prostanoids modulate, at a prejunctional level, cholinergic
neurotransmission in guinea-pig trachea. To this end, we have investigated the
effect of a range of both natural and synthetic prostanoid agonists and
antagonists on EFS-evoked [3H]-ACh release. 2. In epithelium-denuded tracheal
strips pretreated with indomethacin (10 microM), PGE2 (0.1 nM-1 microM) inhibited
EFS-evoked [3H]-ACh release in a concentration-dependent manner with an EC50 and
maximal effect of 7.62 nM and 74% inhibition, respectively. Cicaprost, an IP
receptor agonist, PGF2alpha and the stable thromboxane mimetic, U46619 (each at 1
microM), also inhibited [3H]-ACh release by 48%, 41% and 35%, respectively. PGD2
(1 microM) had no significant effect on [3H]-ACh release. 3. The selective TP
receptor antagonist, ICI 192,605 (0.1 microM), completely reversed the inhibition
of cholinergic neurotransmission induced by U-46619, but had no significant
effect on similar responses effected by PGE2 and PGF2alpha. 4. A number of EP
receptor agonists mimicked the ability of PGE2 to inhibit [3H]-ACh release with a
rank order of potency: GR63799X (EP3-selective) > PGE2 > M&B 28,767 (EP3
selective) > 17-phenyl-omega-trinor PGE2 (EP1-selective). The EP2-selective
agonist, AH 13205 (1 microM), did not affect EFS-induced [3H]-ACh release. 5.
AH6809 (10 microM), at a concentration 10 to 100 times greater than its pA2 at DP
, EP1- and EP2-receptors, failed to reverse the inhibitory effect of PGE2 or 17
phenyl-omega-trinor PGE2 on [3H]-ACh release. 6. These results suggest that PGE2
inhibits [3H]-ACh release from parasympathetic nerves supplying guinea-pig
trachea via an interaction with prejunctional prostanoid receptors of the EP3
receptor subtype. Evidence for inhibitory prejunctional TP- and, possibly, IP
receptors was also obtained although these receptors may play only a minor role
in suppressing [3H]-ACh release when compared to receptors of the EP3-subtype.
However, the relative importance of the different receptors will depend not only
on the sensitivity of guinea-pig trachea to prostanoids but on the nature of the
endogenous ligands released locally that have activity on parasympathetic nerves.
PMID- 9559910
TI - The expression of functional postsynaptic alpha2-adrenoceptors in the corpus
cavernosum smooth muscle.
AB - 1. The purpose of this study was to determine if corpus cavernosum smooth muscle
expresses functional postsynaptic alpha2-adrenoceptors (AR). 2. The alpha2
adrenoceptor agonist UK 14,304 elicited concentration-dependent contractions in
rabbit corpus cavernosum smooth muscle (CCSM). The half-maximal response occurred
at 0.32+/-0.03 microM and the maximum contraction at 10 microM UK 14,304. 3.
Pretreatment of CCSM strips with selective alpha2-adrenoceptor antagonists,
rauwolscine and RS-15385, produced rightward shifts in the dose-response curves
to UK 14,304 (pA2 values 7.1 and 8.5, respectively). In contrast, these
antagonists did not alter contraction induced by the alpha1-adrenoceptor agonist
phenylephrine (PE) or oxymetazoline. UK 14,304-induced contractions were also
inhibited by prazosin (pA2 = 9.08). 4. UK 14,304-induced contractions, unlike
those to PE, were highly dependent on the presence of extracellular Ca2+. 5. [3H]
rauwolscine bound to CCSM membranes with high affinity (Kd = 1.5 nM). [3H]
rauwolscine binding was displaced by unlabelled rauwolscine, RS-15385, UK 14,304
and prazosin, but not by PE. 6. UK 14,304 inhibited forskolin and prostaglandin
E1 (PGE1)-induced increases in intracellular cyclic AMP concentration in primary
cultures of rabbit CCSM cells. 7. These results demonstrate that CCSM expresses
Gi-coupled postsynaptic alpha2-adrenoceptors, and activation of these receptors
causes contraction of trabecular smooth muscle.
PMID- 9559912
TI - SB-205384: a GABA(A) receptor modulator with novel mechanism of action that shows
subunit selectivity.
AB - 1. SB-205384, and its (+) enantiomer (+)-SB-205384 were tested for their
modulatory effects on human GABA(A) receptor subunit combinations expressed in
Xenopus oocytes by electrophysiological methods. 2. The slowing of the decay rate
induced by SB-205384 on native GABA-activated currents in rat neurones was also
seen on GABA(A) currents in oocytes expressing human GABA(A) subunits. This
temporal effect was observed for the alpha3beta2gamma2 subunit combination with
little effect in subunit combinations containing either alpha1 or alpha2. 3.
Potentiation of the peak amplitude of the GABA-activated currents by SB-205384 or
(+)-SB-205384 was less specific for a particular subunit combination, although
the greatest effect at 10 microM drug was seen on the alpha3beta2gamma2 subunit
combination. 4. In contrast, zolpidem, a benzodiazepine site modulator, did not
significantly slow decay rates of GABA(A) currents in oocytes expressing the
alpha3beta2gamma2 subunit combination. Zolpidem, as expected, did selectively
potentiate GABA-activated currents on oocytes expressing the gamma2 subunit
compared to those containing the gamma1. 5. The results show that the novel
kinetic modulatory profile of SB-205384 is selective for the alpha3beta2gamma2
subunit combination. This suggests that the compound is binding to a novel
regulatory site on the subunit complex.
PMID- 9559914
TI - Role of serine esterases in mast cell activation.
AB - 1. A variety of chymotryptic substrates and inhibitors prevented the release of
histamine and prostaglandin D2 from rat peritoneal mast cells stimulated with
anti-IgE but not the calcium ionophore A23187 or a variety of polyamines. 2. The
activity of the compounds was strikingly increased in cells reversibly
permeabilized with ATP, indicating the importance of their effective
incorporation into the cytosol. 3. The compounds produced a comparable inhibition
of immunological, but not pharmacological, histamine release from human mast
cells and basophils. 4. Treatment of rat mast cells with anti-IgE led to a marked
increase in the total chymotryptic activity expressed by the cells. 5.
Immunological, but not pharmacological, stimulation of permeabilized rat mast
cells loaded with a fluorescent chymotryptic substrate led to a pronounced and
rapid increase in fluorescence, indicating activation of the enzyme and
hydrolysis of the substrate. These changes were attenuated by chymotryptic
inhibitors. 6. In total, these data provide compelling evidence for the direct
involvement of a serine protease in IgE-mediated histamine release from mast
cells.
PMID- 9559913
TI - Effect of PDE4 inhibitors on zymosan-induced IL-8 release from human neutrophils:
synergism with prostanoids and salbutamol.
AB - 1. The activation of neutrophils with particulate stimuli such as zymosan induces
the generation of the C-X-C chemokine interleukin (IL)-8. There is evidence that
neutrophil derived IL-8 plays an important role in human diseases such as the
adult respiratory distress syndrome. In the present study, we examined the
effects of cyclic AMP elevating agents on the ability of human neutrophils to
generate IL-8 in response to zymosan particles. 2. The PDE4 inhibitor rolipram
had limited effect on zymosan-induced IL-8 generation. In contrast, the PDE4
inhibitors RP 73401 and SB 207499 concentration-dependently suppressed IL-8
generation. The potency of these inhibitors was RP 73401 > SB 207499 > rolipram
which is correlated with their rank order of potency at inhibiting the catalytic
site of purified neutrophil PDE4. Pretreatment of neutrophils with the PDE3
inhibitor ORG 9935 or the PDE5 inhibitor zaprinast had no effect on IL-8
generation. 3. The prostanoids prostaglandin E1 (PGE1) and PGE2 inhibited zymosan
induced IL-8 release from neutrophils in a dose-dependent manner, in response to
10(-5) M PGE1 and PGE2 inhibiting IL-8 generation by 89% and 75%, respectively.
Similarly, the beta2-adrenoceptor agonist salbutamol also inhibited IL-8
generation, but it was less effective than the prostanoids. 4. Significant
synergism between prostanoids or salbutamol and the PDE4 inhibitors to inhibit IL
8 generation was observed. In contrast, there was no significant synergism
between PGE2 and the PDE3 inhibitor ORG 9935 or the PDE5 inhibitor zaprinast. 5.
In order to evaluate the potential role of protein kinase A in mediating the
inhibitory effects of cyclic AMP-elevating agents, we used the protein kinase A
inhibitors, H 89 and KT 5720. Pretreatment of neutrophils with these drugs
completely reversed the inhibitory effects of a combination treatment with
rolipram and PGE2 on zymosan-induced IL-8 release. 6. Microscopic examination
revealed that most neutrophils contained one or more zymosan particles and that
combination treatment with rolipram and PGE2 noticeably reduced the number of
ingested particles. Moreover, there was a significant reduction in the percentage
of neutrophils which ingested three or more zymosan particles. 7. Thus, our
results demonstrate that cyclic AMP-elevating agents modulate the ability of
neutrophils to generate IL-8 in response to a particulate stimulus. However,
these agents also modulate the ability of neutrophils to phagocytose zymosan
particles. Whether this effect will translate into inhibition of the ability of
neutrophils to deal with infectious agents needs to be investigated further.
PMID- 9559915
TI - Comparison of anaesthetic and non-anaesthetic effects on depolarization-evoked
glutamate and GABA release from mouse cerebrocortical slices.
AB - 1. Investigation with substances that are similar in structure, but different in
anaesthetic properties, may lead to further understanding of the mechanisms of
general anaesthesia. 2. We have studied the effects of two cyclobutane
derivatives, the anaesthetic, 1-chloro-1,2,2-trifluorocyclobutane (F3), and the
non-anaesthetic, 1,2-dichlorohexafluorocyclobutane (F6), on K+-evoked glutamate
and gamma-aminobutyric acid (GABA) release from isolated, superfused,
cerebrocortical slices from mice, by use of h.p.l.c. with fluorescence detection
for quantitative analysis. 3. At clinically relevant concentrations, the
anaesthetic, F3, inhibited 40 mM K+-evoked glutamate and GABA release by 72% and
47%, respectively, whereas the structurally similar non-anaesthetic, F6,
suppressed evoked glutamate release by 70% but had no significant effects on
evoked GABA release. A second exposure to 40 mM KCl after a approximately 30 min
washout of F3 or F6 showed recovery of K+-evoked release, suggesting that F3 and
F6 did not cause any non-specific or irreversible changes in the brain slices. 4.
Our findings suggest that suppression of excitatory neurotransmitter release may
not be directly relevant to the primary action of general anaesthetics. A
mechanism involving inhibitory postsynaptic action is implicated, in which a
moderate suppression of depolarization-evoked GABA release by the anaesthetic may
be consistent with the enhancement of postsynaptic GABAergic activities.
PMID- 9559916
TI - Neurogenic and non-neurogenic responses in the urinary bladder of hibernating
hamster.
AB - 1. Purinergic and cholinergic components of parasympathetic neurotransmission and
contractile responses to exogenous alpha,beta-methylene ATP, acetylcholine,
substance K, substance P, calcitonin gene-related peptide, vasoactive intestinal
polypeptide and capsaicin have been investigated in the urinary bladder of
hibernating hamsters (4 weeks), cold exposed (4 weeks) and age-matched controls.
2. Electrical field stimulation (EFS) evoked increased frequency-dependent
contractions in the detrusor strips from hibernating hamsters compared with those
obtained from cold-exposed and age-matched animals. Tetrodotoxin (10(-6) M)
completely blocked the frequency-dependent contractions in all groups. 3. The
purinergic component of the parasympathetic neurotransmission was not affected in
hibernating and cold-exposed animals while the cholinergic component was
increased with respect to age-matched animals. The neurogenic response to EFS,
still present after incubation with atropine (10(-6) M) and suramin (10(-4) M),
was attenuated by indomethacin (10(-6) M) and blocked by tetrodotoxin (10(-6) M).
4. Exogenous administration of alpha,beta-methylene ATP elicited a significantly
reduced contraction in strips from hibernating and cold-exposed hamsters relative
to age-matched animals. The contractile response to exogenous acetylcholine was
greater in the detrusors from hibernating hamsters than in cold-exposed and age
matched animals. Substance K elicited reduced contractions in preparations from
hibernating animals compared with cold-exposed and control animals. Calcitonin
gene-related peptide, vasoactive intestinal polypeptide, substance P and
capsaicin did not elicit any relaxant or contractile response either at resting
tone or in carbachol (5 x 10(-7) M)-precontracted tissues. 5. In summary, our
findings indicate that 4 weeks of hibernation can significantly increase
neurogenic responses in the hamster urinary bladder. This appears to be due to an
increase in postjunctional responses to acetylcholine. In contrast, there was a
decrease of the postjunctional responses to the parasympathetic cotransmitter ATP
and also to the sensory-motor neurotransmitter substance K.
PMID- 9559917
TI - Active sleep-related depolarization of feline trigemino-thalamic afferent
terminals.
AB - Presynaptic depolarization of trigemino-thalamic (TGT) terminals may contribute
to modulation of ascending oro-facial somatosensory information during active (or
rapid eye movement) sleep. The relative excitability of TGT terminals was
inferred from changes in the current required to maintain an antidromic firing
probability of 50% (EC50) during quiet wakefulness as compared to active sleep.
Depolarization or hyperpolarization of TGT terminals was defined as a decrease or
increase, respectively, in the EC50. Overall, the EC50 of 8 TGT terminals was
reduced by a mean 8.8+/-3.6 microA during active sleep relative to quiet
wakefulness. This result suggests that depolarization of TGT terminals, which may
act to suppress the transfer of sensory information from the trigeminal nucleus
to the thalamus, occurs during active sleep.
PMID- 9559918
TI - Nitric oxide synthase activity in the dorsal periaqueductal gray of rats
expressing innate fear responses.
AB - Immunohistochemical studies have shown nitric oxide synthase (NOS)-positive
neurons in the dorsolateral sector of periaqueductal gray (PAG), a neural site
known to be critical for the expression of defensive responses. In the present
study, we first characterized the dorsal PAG (dPAG) NOS, and then examined NOS
activity and cyclic GMP (cGMP) accumulation in the dPAG of rats exposed to a
predator (cat) for 15 min. NOS activity evaluated by enzymatic conversion of
[3H]arginine to [3H]citrulline in dPAG of exposed rats increased 14.6% and the
cGMP radioimmunoassay showed an increase of 30.6% in relation to non-exposed
rats. These results suggest an involvement of the NO/cGMP pathway in the dPAG
during defensive responses.
PMID- 9559919
TI - Does glutamate mediate brain damage in acute encephalitis?
AB - Cerebrospinal fluid (CSF) amino acid neurotransmitter concentrations in 23
patients with acute encephalitis were compared with those in patients with acute
brain infarction, multiple sclerosis and controls. The concentration of glutamate
was significantly higher in encephalitis (5.2+/-6.7 micromol/l) and stroke
patients (9.6+/-14.2 micromol/l) than in MS patients (1.6+/-0.9 micromol/l) and
controls (1.7+/-0.8 micromol/l; p < 0.001). The concentration of glycine was
significantly higher in encephalitis (11.0+/-4.7 micromol/l) than in stroke
(7.6+/-3.2 micromol/l) and MS patients (6.3+/-2.1 micromol/l) or controls (5.6+/
1.8 micromol/l; p < 0.002). Taurine levels were significantly lower in
encephalitis patients than in the other groups (p = 0.04). The correlation of
high glutamate levels with poor outcome was almost significant (Kendall tau 0.63,
p = 0.06). Our observations suggest that exicitotoxic neurotransmission may play
an important role in the series of events that lead to neuronal damage in
encephalitis.
PMID- 9559920
TI - Activation of inwardly rectifying K+ channels by GABA-B receptors expressed in
Xenopus oocytes.
AB - In Xenopus oocytes coinjected with poly(A)+ RNA derived from the rat cerebellum
and cRNAs for the cloned G protein-gated inwardly rectifying K+ channel (GIRK),
GIRK1 and GIRK2, the GABA-B agonist baclofen elicited inwardly rectifying K+
currents. The inward K+ currents elicited by baclofen were inhibited by the
selective GABA-B antagonists 2-OH saclofen and CGP 35348, and by the GIRK
inhibitor Ba2+. In contrast, baclofen caused no currents in oocytes injected with
the cerebellar poly(A)+ RNA alone, the poly(A)+ RNA and cRNA for GIRK1 or GIRK2,
or only cRNAs for GIRK1 and GIRK2. These findings indicate that GABA-B receptors
in the rat cerebellum were functionally expressed in Xenopus oocytes and
activated the cloned GIRKs composed of GIRK1 and GIRK2 as heteromultimers.
PMID- 9559921
TI - Nitric oxide contributes to central sensitization following intradermal injection
of capsaicin.
AB - This study provides direct evidence from measurements of its metabolites, NO2-
and NO3-, that NO is released in the spinal cord during central sensitization. A
microdialysis fiber was implanted in the dorsal horn at L5 for collecting
dialysate and administering drugs. Dialysate was pumped through a cadminum
reducing column, a post-column derivatizing unit, and then a u.v. detector. After
injection of capsaicin into one hind foot, NO2-increased in the dialysate.
Pretreatment with NG-nitro-L-arginine methyl ester (L-NAME) significantly reduced
NO release induced by a second injection of capsaicin into the opposite foot.
This supports the ideas that NO is involved in central sensitization in the
spinal cord and contributes to hyperalgesia and allodynia following capsaicin
injection.
PMID- 9559922
TI - Estradiol upregulates Bcl-2 expression in adult brain neurons.
AB - Bcl-2, a protein which negatively modulates apoptosis, is up-regulated by
estrogen in several tissues. To determine the effect of estradiol on Bcl-2 in the
adult brain, its immunoreactive distribution was examined in the hypothalamic
arcuate nucleus of female rats under different endocrine conditions. The number
of Bcl-2-immunoreactive neurons was significantly increased (p < 0.001) on the
day of estrus compared with proestrus, diestrus and metestrus, was decreased by
ovariectomy and showed a dose-response increase after estradiol administration to
ovariectomized rats. Progesterone, when injected simultaneously with estradiol,
reduced the effect of estradiol. These findings indicate that ovarian hormones
regulate Bcl-2 in hypothalamic neurons and suggest that this protein may be
involved in the neuroprotective effects of estrogen.
PMID- 9559923
TI - Direct detection of uncaged glutamate and the laser photostimulation of cultured
rat cortex.
AB - The photostimulation of nerve cells using a caged compound is very useful because
it is non-invasive and non-destructive compared with standard
electrophysiological techniques. There are no methods, however, for continuously
measuring the photo-uncaged 'free' compound concentration at high temporal and
spatial resolutions which can detect how much uncaged compound has been applied
to cells. Here, we used an electrochemical detection method for the real-time
measurement of photo-uncaged glutamate. In this way, we were able to determine
the amount of uncaged glutamate and investigate neural activities by tracing
[Ca]i while simultaneously employing photostimulation and on-line glutamate
measurement. The combination of an on-line sensor and laser-photostimulation with
[Ca]i measurement could be a powerful tool with which to investigate synaptic
connections and activities.
PMID- 9559924
TI - Somatotopy of the human arm using fMRI.
AB - We describe a technique for mapping out human somatosensory cortex using
functional magnetic resonance imaging (fMRI). To produce cortical activation, a
pneumatic apparatus presented subjects with a periodic series of air puffs in
which a sliding window of five locations moved along the ventral surface of the
left arm in a proximal-to-distal or distal-to-proximal direction. This approach,
in which the phase-delay of the stimulus can be used to produce somatotopic maps
of somatosensory cortex, is based on a method used to generate retinotopic maps
of visual cortex. Functional images were acquired using an echoplanar 1.5T
scanner and a T2*-weighted spiral acquisition pulse sequence. The periodic series
of air puffs created phase-related activation in two cortical regions of the
contralateral parietal lobe, the posterior bank of the central sulcus and a more
posterior and lateral region.
PMID- 9559925
TI - Selective activation of human cortical area V5A by a rotating visual stimulus in
fMRI; implication of attentional mechanisms.
AB - The human homologue of area V5A of rotation-selective cells in the monkey medial
superior temporal area (MST) was identified using functional magnetic resonance
imaging (fMRI). It was located within the border region of occipito-temporo
parietal cortex, in four of 10 subjects on both sides, and on the right or left
side in three subjects each. The stimulus was a black-and-white sine-modulated
windmill presented either stationary or in rotation phases of 1 s duration. Areas
V1-V3 did not show up with this paradigm. Focusing attention by mentally counting
the number of rotation phases ensured high signal intensity in V5A, whereas
moving attention away by counting electric stimuli to the wrist diminished it
despite persistent fixation of gaze to the centre of the windmill.
PMID- 9559926
TI - Endogenous apolipoprotein E suppresses LPS-stimulated microglial nitric oxide
production.
AB - The human apolipoprotein (apo) E4 isoform is associated with an increased risk
for Alzheimer's disease (AD) and poor prognosis after acute CNS injury. Addition
of human apoE inhibits murine microglial activation in culture, suggesting that
microglia might be an important physiological target of apoE. In the present
study, we examined the role of endogenous murine apoE in modulating microglial
nitric oxide (NO) production following lipopolysaccharide (LPS) stimulation.
Brain cultures from apoE-deficient mouse pups showed enhanced NO production
relative to cultures from wild-type mice and from transgenic mice expressing the
human apoE3 isoform, demonstrating that endogenous apoE produced by glial
cultures is capable of inhibiting microglial function. ApoE produced within the
brain may suppress microglial reactivity and thus alter the CNS response to acute
and chronic injury.
PMID- 9559927
TI - The uterine environment enhances cognitive competence.
AB - Genetically identical mouse embryos were transferred into same-strain uteri
(transfer controls) or into hybrid uteri. A third group was not transferred. When
adult, the mice were given a series of behavioral tests. In-strain transfer
controls differed from non-transfer mice only on two activity measures, and did
not differ on any cognitive variable. In contrast, mice reared in hybrid uteri
were found to be superior to in-strain transfer mice on discrimination learning,
Lashley maze learning and Morris maze learning; they also showed better
adaptation in an avoidance learning shuttlebox. To our knowledge this is the
first study showing that the uterine environment can have a general enhancing
effect upon cognitive competence across a broad range of behaviors.
PMID- 9559928
TI - [K+]out accelerates inactivation of Shal-channels responsible for A-current in
rat CA1 neurons.
AB - Somato-dendritic subthreshold transient potassium current [I(SA)] was measured in
acutely isolated rat hippocampal CA1 pyramidal neurons. The inactivation of this
current was insensitive to externally applied H2O2 (20 mM) which causes cysteine
oxidation. This result suggests that Shal-channels not Shaker Kv1.4 channels
underlie the somato-dendritic I(SA) in rat CA1 pyramidal neurons. The kinetics of
the I(SA) inactivation was measured at various [K+]out. Increase in [K+]out leads
to acceleration of Shal-channel inactivation. Thus, the shift in [K+]out from 1
to 50 mM results in decreased inactivation time constant from 37 to 19 ms. This
effect of [K+]out on the I(SA) is opposite to the previously described action of
[K+]out on the inactivation of Shaker K+ channels.
PMID- 9559929
TI - Attenuation of nociceptin/orphanin FQ-induced signaling by N-methyl-D-aspartate
in neuronal cells.
AB - Acute incubation of NMDA with neuroblastoma x glioma hybrid (NG108-15) cells or
neuroblastoma SK-N-SH cells produced significant attenuation of
nociceptin/orphanin FQ (N/OFQ)-induced activation of G protein and inhibition of
adenylyl cyclase. The attenuation of N/OFQ signaling by NMDA was dose-dependent,
blockable by NMDA antagonists, and not observed in cells lacking NMDA receptors,
indicating that the effect of NMDA is mediated by the NMDA receptor. Furthermore,
NMDA antagonist pretreatment greatly attenuated N/OFQ-induced acute homologous
desensitization of ORL1. Interestingly, the signaling induced by etorphine, an
opioid agonist of wide spectrum, was sensitive to NMDA treatment in NG108-15 but
insensitive in SK-N-SH cells, suggesting differential modulation of opioid
signaling by NMDA. The attenuation effects of NMDA on mu opioid receptor-mediated
signaling were also observed.
PMID- 9559930
TI - MK-801 reinstates drug-seeking behaviour in cocaine-trained rats.
AB - We evaluated the incentive motivational properties of MK-801 by determining its
priming effect on drug-seeking behaviour following extinction of cocaine self
administration, an animal model for drug craving. Rats were allowed to self
administrate cocaine (0.5 mg/kg) or saline during 10 daily sessions. MK-801 (0.1
0.25 mg/kg, i.p.) dose-dependently reinstated responding for cocaine following an
extinction period of 3 weeks. Responding was selectively enhanced in the
previously drug-paired hole and was completely absent in rats with a history of
saline self-administration. These data provide evidence for a possible role of
NMDA receptors in the incentive motivation underlying cocaine-seeking behaviour.
In addition, the ability of MK-801 to elicit drug-seeking behaviour may prove to
be a serious drawback for the proposed use of NMDA antagonists in the treatment
of drug addiction.
PMID- 9559931
TI - 5HT1B and 5HT1D receptor mRNA differential co-localization with peptide mRNA in
the guinea pig trigeminal ganglion.
AB - To investigate the possible role of 5HT1B and/or 5HT1D receptors in controlling
neurogenic inflammation, we performed a co-localization study of the mRNA for
5HT1B and 5HT1D receptors and of substance P or calcitonin gene-related peptide
(CGRP) mRNA in the guinea pig trigeminal ganglion using double labelling in situ
hybridization techniques. The 5HT1D receptor mRNA is abundant whereas 5HT1B
receptor mRNA is scarce. The vast majority of cells containing substance P mRNA
also contained 5HT1B receptor mRNA, but very few cells expressed substance P mRNA
and 5HT1D receptor mRNA. Both receptor mRNAs were co-localized with CGRP mRNA.
Hence, 5HT1D receptors may control the release of CGRP only, whereas 5HT1B
receptors may control the release of both substance P and CGRP. The question
remains whether selective 5HT1D agonists will have migraine abortive properties.
PMID- 9559932
TI - Central antinociceptive effects of meloxicam on rat spinal cord in vitro.
AB - Non-steroidal anti-inflammatory drugs inhibit constitutive (COX-1) and induced
cyclooxygenase (COX-2), blocking prostaglandin production. We have compared the
effects on nociceptive reflexes of meloxicam, which is COX-2 selective, with
indomethacin, which is non-selective, using an in vitro spinal cord preparation.
Cords were taken from naive rats, and from rats with carrageenan-induced
hyperalgesia of one hindpaw. Reflex thresholds were lower in carrageenan
preparations. Superfusion with meloxicam (10-100 microM) dose-dependently
inhibited baseline reflexes and wind-up in normal and carrageenan preparations,
whereas indomethacin (100-300 microM) had no effect. Thus meloxicam inhibits
spinal reflexes, whereas indomethacin does not, despite its high affinity for
both COX isoforms. We conclude that meloxicam has spinal antinociceptive actions
which cannot be explained by the current concept of COX inhibition.
PMID- 9559933
TI - Enhanced visual responses in cat dLGN--potentiation by priming with excitatory
amino acids.
AB - Sustained iontophoresis of NMDA potentiated visual responses for minutes after
the application in 16 of 38 cells (42%), peaking 3 min after the end of the
application and declining to control levels within 12 min. Potentiation was also
seen after application of ACPD (36%, n = 14) and AMPA (29%, n = 14), but not
after application of ACh (n = 20). ACh also excites dLGN cells, but does not
interact with amino acid receptors, and ACh receptors are not directly involved
in the transmission of visual information. We suggest that this modulation is a
form of visually induced potentiation which permits dynamic modification of the
strength of visual information to be relayed to the cortex depending upon the
history of previous activity levels.
PMID- 9559934
TI - Abeta-fiber mediated activation of cingulate cortex as correlate of central post
stroke pain.
AB - A patient is presented who suffered a lateral brainstem infarction which
selectively abolished pain and temperature sensitivity in the lower right limb.
One year later central post-stroke pain had developed in the affected limb with
touch and cold allodynia. P40m dipoles calculated from magnetoencephalographic
fields after electrical stimulation of both tibial nerves were localized in SI as
is seen in normal subjects. However, stimulation of the affected side caused deep
pain sensations and elicited a large N80m component, best explained by an
additionally active dipole in cingulate cortex. This early co-activation in a
limbic structure suggests peripheral Abeta-fiber mediation and lemniscal
projection. Abnormal link to the pain system may be due to sensitization and
reorganization above the level of nociceptive deafferentation.
PMID- 9559935
TI - Actin cytoskeleton regulates ion channel activity in retinal neurons.
AB - The actin cytoskeleton is an important contributor to the integrity of cellular
shape and responses in neurons. However, the molecular mechanisms associated with
functional interactions between the actin cytoskeleton and neuronal ion channels
are largely unknown. Whole-cell and single channel recording techniques were thus
applied to identified retinal bipolar neurons of the tiger salamander (Ambystoma
tigrinum) to assess the role of acute changes in actin-based cytoskeleton
dynamics in the regulation of voltage-gated ion channels. Disruption of
endogenous actin filaments after brief treatment (20-30 min) with cytochalasin D
(CD) activated voltage-gated K+ currents in bipolar cells, which were largely
prevented by intracellular perfusion with the actin filament-stabilizer agent,
phalloidin. Either CD treatment under cell-attached conditions or direct addition
of actin to excised, inside-out patches of bipolar cells activated and/or
increased single K+ channels. Thus, acute changes in actin-based cytoskeleton
dynamics regulate voltage-gated ion channel activity in bipolar cells.
PMID- 9559936
TI - Presynaptic inhibition of GABAergic inputs to rat substantia nigra pars
reticulata neurones by a cannabinoid agonist.
AB - Whole-cell patch-clamp recordings were made from substantia nigra pars reticulata
(SNR) neurones in rat midbrain slices to investigate the electrophysiological
effects of cannabinoids. The cannabinoid receptor agonist WIN 55212-2 (10 microM)
significantly reduced intranigrally evoked and spontaneous inhibitory post
synaptic currents (IPSCs) which were mediated by GABA(A) receptors. The
postsynaptic current induced by bath application of GABA was not affected by the
presence of WIN 55212-2. The actions of WIN 55212-2 were not mimicked by the
inactive enantiomer WIN 55212-3. WIN 55212-2 also hyperpolarized the membrane of
SNR neurones in a tetrodotoxin/0-Ca2+-insensitive manner. These data suggest that
cannabinoids modulate the activity of SNR neurones by presynaptic inhibition of
GABA inputs. They may also exert a direct post-synaptic inhibition on these
neurones.
PMID- 9559937
TI - Anticonvulsant effects of intra-hippocampal injection of TRH in amygdala kindled
rats.
AB - The anticonvulsant effects of intra-hippocampal thyrotropin-release hormone (TRH)
were examined in amygdala kindled rats. Subjects were implanted unilaterally with
an electrode in the amygdala and bilaterally with guide cannulae in the
hippocampus, aimed at the dorsal and ventral dentate gyri. Rats were kindled
daily with suprathreshold electrical stimulation (800 microA, 1 ms pulse width,
100 Hz, duration 0.5 s) until seizures were reliably elicited. The afterdischarge
(AD) duration, seizure duration, and seizure stage were recorded daily, and AD
thresholds were determined after kindling was completed. TRH was infused into
each of the four cannulae of freely moving rats at doses of 0 (vehicle), 1.25,
2.5 and 5 microg/site. Five minutes after the last infusion, the rats received
electrical stimulation at their AD threshold (mean = 135 microA) + 50 microA. TRH
reduced the AD and seizure duration in a dose-dependent manner. At the dose of
2.5 microg/site, TRH also reduced AD and seizure duration in rats stimulated with
suprathreshold current (800 microA). However, TRH had minimal effects on seizure
stage irrespective of the stimulation intensity. These results suggest that the
seizure-induced elevations of TRH in the hippocampus, as demonstrated in previous
studies, may be part of an endogenous anticonvulsant compensatory mechanism and
that further elevations of TRH in the hippocampus can produce anticonvulsant
effects mainly by reducing the AD and seizure duration.
PMID- 9559938
TI - Human chromosomal localization of a gene for inositol monophosphatase by
fluorescence in situ hybridization.
AB - Inhibition of the enzyme inositol monophosphatase (IMPase) (E.C. 3.1.3.25) has
been linked to the therapeutic action of lithium in the treatment of manic
depression (bipolar) disorder. Because of the link between bipolar and IMPase, we
felt it would be of considerable importance to determine the human chromosomal
localization of the IMPase gene. Fluorescence in situ hybridization analysis
using a human cDNA clone, which included the 5'-UTR and the complete coding
region, mapped the human IMPase gene to chromosome 8q21.2-21.3. No gene locus for
manic-depressive disorder has yet been identified. Further studies on this IMPase
gene, and other potential gene variants and mutations, should help to determine
if specific subgroups of patients with manic-depressive disorder can be
determined on a molecular basis, with regard to the IMPase gene.
PMID- 9559939
TI - Nerve growth factor potentiates the oxidative necrosis of striatal cholinergic
neurons.
AB - We examined the effects of nerve growth factor (NGF) on free radical
neurotoxicity in striatal cell cultures. Following exposure to 30 microM Fe2+ or
1 mM L-buthionine-[S,R]-sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine
synthetase, striatal neurons underwent cell body swelling and then widespread
death over the next 24 h. The degeneration was prevented by addition of 100
microM trolox, an antioxidant. Addition of 100 ng/ml BDNF beginning 12 h before
Fe2+ or BSO potentiated necrosis of most striatal neurons after exposure to 10
microM Fe2+ or 1 mM BSO. In contrast, treatment with 100 ng/ml NGF selectively
potentiated the oxidative degeneration of striatal cholinergic neurons. The
present findings provide additional evidence that NGF, like other neurotrophins,
can potentiate oxidative neuronal cell necrosis.
PMID- 9559940
TI - Computer model of antiepileptic effects mediated by alterations in GABA(A)
mediated inhibition.
AB - Results from a computer model of a thalamic network predict that agents
augmenting GABA(A)-mediated inhibition in the reticular thalamic (RE) nucleus
will be antiepileptic or desynchronizing. This provides support for the
hypothesis that antiepileptics like benzodiazepines may exert their effects
through an isolated increase of inhibition in the RE nucleus. When
desynchronized, the model thalamocortical neurons showed a decreased probability
of firing a low threshold spike, a decreased secondary inhibitory postsynaptic
potential and a higher frequency of oscillations. The transition to desynchrony
was also accompanied by an increased frequency in the firing of the model RE
neurons.
PMID- 9559941
TI - Dp116, talin, vinculin and vimentin immunoreactivities following nerve
transection.
AB - The time course of the expression of Dp116, talin, vinculin and vimentin in rat
sciatic nerve was investigated after experimental transection. Dp116 was still
found at 5 days after experiment in some degenerating myelinated fibers of both
proximal and distal stumps. The findings are consistent with the known
preservation of electrical excitability of the distal nerve in the first days
after injury. Some regenerating nerve fibers into the neuroma also expressed
Dp116 at 25 and 40 days after nerve transection. Talin and vinculin markedly and
diffusely immunostained the neuroma. Talin in the distal stump and vimentin in
both proximal and distal stumps were found decreased during the time course of
the experiment. Vinculin binding increased in the distal stump, due to a real
overexpression or simply to a cross-reaction to degeneration products.
PMID- 9559942
TI - Increased survival of dopaminergic neurons by rasagiline, a monoamine oxidase B
inhibitor.
AB - Both deprenyl and rasagiline (R(+)-N-propargyl-1-aminoindane mesylate), at a
concentration of 1-10 microM, increased survival in vitro of rat E14
mesencephalic dopaminergic neurons that had been primed with 10% serum for 12 h
(p < 0.05). Rasagiline, but not deprenyl, also increased total neuronal (MAP2
positive) survival (p < 0.05) Under serum-free conditions, rasagiline, but not
deprenyl, retained its neuroprotective action on dopaminergic neurones. GABAergic
neurons were not affected by either deprenyl or rasagiline. Clorgyline, an MAO-A
inhibitor, did not exert any of these effects. The protective action of
rasagiline on dopaminergic neurons, even under stringent serum-free conditions,
is striking, and warrants further investigation for a role in the treatment of
Parkinson's disease.
PMID- 9559943
TI - Functional thrombin receptor PAR1 in primary cultures of human glioblastoma
cells.
AB - In this study we investigated primary cultures obtained from two glioblastomas
surgically removed from a 64-year-old man and a 50-year-old woman, respectively.
The presence of the tethered ligand thrombin receptor PAR1 (protease-activated
receptor 1) in these cells was demonstrated at the level of receptor binding by
using immunofluorescence studies with the monoclonal anti-PAR1 antibody Mab 31-2.
Stimulation of human glioblastoma cells both with alpha-thrombin and the thrombin
receptor activating peptide TRAP-6 resulted in a series of [Ca+]i spikes as shown
by confocal laser fluorescence microscopy with fluo-3 as calcium sensitive
fluorescence indicator. This effect was completely blocked with the thrombin
receptor antagonist peptide T1. Our results demonstrate functional thrombin
receptors (PAR1) in primary cultures of human glioblastomas for the first time.
PMID- 9559944
TI - Functional imaging of mirror and inverse reading reveals separate coactivated
networks for oculomotion and spatial transformations.
AB - Echoplanar functional magnetic resonance imaging (fMRI) was used to localize the
cortical areas involved in the analysis of spatially transformed letter strings.
Significant increases of the blood oxygen level-dependent (BOLD) signal for
transformed vs normal reading were observed in the superior parietal lobule
(SPL), along the intraparietal sulcus (IPS), in the frontal eye fields (FEF), and
in the latero-occipital area LO. The respective contributions of oculomotor and
spatial transformation areas to this activation pattern were separated by means
of a control condition involving the execution and suppression of eye movements.
Areas activated in association with the control of eye movements included the
superior parietal lobule and the frontal eye fields. The cooperation of different
brain areas was analysed by correlating the time course of task-dependent BOLD
signal changes in these areas. This correlation analysis revealed coactivation of
occipitotemporal object recognition areas and a spatial transformation area in
the intraparietal sulcus during the reading of transformed letter strings. We
suggest that cortical systems that are coactivated during complex cognitive tasks
can be differentiated by the correlation analysis of BOLD signal time courses in
spatially separate brain areas.
PMID- 9559945
TI - Spectral components of cytosolic [Ca2+] spiking in neurons.
AB - We show here, by means of evolutionary spectral analysis and synthesis of
cytosolic Ca2+ ([Ca2+]c) spiking observed at the single cell level using digital
imaging fluorescence microscopy of fura-2-loaded mouse cerebellar granule cells
in culture, that [Ca2+]c spiking can be resolved into evolutionary spectra of a
characteristic set of frequencies. Non-delayed small spikes on top of sustained
[Ca2+]c were synthesized by a main component frequency, 0.132+/-0.012 Hz, showing
its maximal amplitude in phase with the start of depolarization (25 mM KCI)
combined with caffeine (10 mM) application. Delayed complex responses of large
[Ca2+]c spiking observed in cells from a different set of cultures were
synthesized by a set of frequencies within the range 0.018-0.117 Hz. Differential
frequency patterns are suggested as characteristics of the [Ca2+]c spiking
responses of neurons under different conditions.
PMID- 9559946
TI - Cytosolic hippocampal PKC and aging: correlation with discrimination performance.
AB - Adult and aged mice were submitted to a discrimination task in a radial maze
(regular trials), and then to probe trials requiring them to form relational
representations. Three weeks later, animals were again tested for regular and
probe trials. Following another interval of 3 weeks, individual hippocampal
cytosolic calcium-dependent and -independent PKC activities were measured.
Performance of aged animals was impaired on probe but not regular trials and aged
mice had lower hippocampal cytosolic calcium-dependent and -independent PKC
activities than adults. Performance on probe trials was specifically correlated
with calcium-dependent PKC activity. This suggests a specific relationship
between the ability to form relational representations and hippocampal cytosolic
calcium-dependent PKC activity.
PMID- 9559947
TI - In vivo antinociceptive activity of anti-rat mGluR1 and mGluR5 antibodies in
rats.
AB - To examine the specific roles of group I metabotropic glutamate receptors
(mGluRs) in nociceptive processing, we examined the effects of intrathecal (i.t.)
treatment with antibodies raised against the C-terminals of mGluR1 and mGluR5 in
various rat pain models. The effects of anti-mGluR1 IgG and anti-mGluR5 IgG were
assessed in a model of persistent pain induced by intrathecal administration of
the mGluR1/5 agonist DHPG, as well as in models of heat pain (plantar test),
chemical pain (formalin test) and neuropathic pain. DHPG-induced spontaneous
nociceptive behaviours (SNB) were significantly attenuated by i.t. treatment with
either anti-mGluR1 IgG (30 microg) or anti-mGluR5 IgG (10 and 30 microg). Neither
anti-mGluR1 IgG (30 microg) nor anti-mGluR5 IgG (30 microg) significantly
increased response latencies to noxious heat in the plantar test, compared with
anti-rat IgG (control IgG). Moreover, neither antibody (30 microg) significantly
reduced formalin pain scores as compared to control IgG. However, i.t. treatment
with anti-mGluR1 IgG (30 microg) or anti-mGluR5 IgG (30 microg) significantly
reduced cold hypersensitivity exhibited 8 days after constriction injury of the
sciatic nerve, supporting the contention that group I mGluRs play a role in the
development of neuropathic pain. Because these antibodies were effective against
neuropathic pain, and not acute heat or chemical noxious stimuli, these results
suggest that mGluRs are involved in nociceptive processing in chronic pain states
rather than signaling acute noxious stimuli, and that DHPG-induced pain may be
mediated by similar mechanisms as neuropathic pain.
PMID- 9559948
TI - Down-regulated NPY receptor subtype-5 mRNA expression in genetically obese mouse
brain.
AB - Brain neuropeptide Y (NPY) subtype-5 (Y5 receptor) mRNA expression in lean (+/+)
and obese (ob/ob) C57Bl/6 mice was examined using a non-radioactive in situ
hybridization detection method. Significant decreases in Y5 receptor mRNA
expression were found in the ventromedial, dorsomedial and arcuate hypothalamic
nuclei, midline thalamic nuclei, piriform, cingulate and retrosplenial granular
cortices of the obese mouse brain. There were minor changes in the amount of Y5
receptor mRNA expression in the hippocampal formation and medial habenular
nucleus. Results indicated that Y5 receptor mRNA expression is downregulated in
hereditary obese (ob/ob) mice. This is possibly due to over-expression of
hypothalamic NPY which occurs in this phenotype.
PMID- 9559949
TI - Possible synaptic connections of expiratory neurons in the medulla of newborn rat
in vitro.
AB - To elucidate synaptic interactions between expiratory (Exp) and other respiratory
neurons in the ventrolateral medulla of brain stem-spinal cord preparations from
newborn rats, we analyzed postsynaptic potentials in Exp and a subclass of
inspiratory (Insp) neurons using whole-cell recordings. About 72% of the Exp
neurons (Exp-p-i) showed Cl--dependent synaptic inhibition during the Insp and
pre/post-Insp phases, corresponding to the active phase of the Insp and pre
inspiratory (Pre-I) neurons, respectively. The other 28% neurons (Exp-i) received
Cl--dependent inhibition during the Insp phase only. Some Insp neurons showed
reversed IPSPs during the active phase of Exp-p-i after Cl-loading. We suggest
the existence of inhibitory connections from Pre-I and Insp to Exp and from Exp
to Insp neurons. Basic synaptic connections among respiratory neurons similar to
those in intact adult mammals may already exist in newborn rats.
PMID- 9559950
TI - Non-frontal P3b-like activity evoked by the Wisconsin Card Sorting Test.
AB - Event related potentials (ERP) were recorded from 29 electrode positions in 10
normal subjects while they performed a simplified version of the Wisconsin Card
Sorting Test (WCST). The design focused on ERP differences between early and late
trials within each WCST series. Topographic and dipole analyses confirmed the
reliability of two ERP signs: one conspicuous mid-parietal P3b wave and one
asymmetrical frontal-temporal component. A three-dipole model accounted for these
ERP signs with > 90% accuracy even in individual subjects, and suggests a sub
second activation of temporal-parietal and medial temporal association areas
during card sorting. The WCST-related P3b wave is proposed to reflect working
memory operations such as template matching and template formation during card
sorting.
PMID- 9559951
TI - Neuroanatomical correlates of the assessment of facial attractiveness.
AB - Frontal cortical damage can lead to changes in affective aspects of personality.
However, the difficulty of dissociating such abnormalities from cognitive
disorders has overshadowed most previous findings. Regional cerebral blood flow
(rCBF) was measured with positron emission tomography (PET) while normal subjects
were assessing facial attractiveness. Two left frontal regions showed a
significant increase in rCBF while assessing facial attractiveness. The increased
rCBF in the left anterior frontal cortex correlated with the overall percentage
of assessments of a face as unattractive, while that in the left fronto-temporal
junction correlated with the percentage of assessments of a face as attractive.
These findings provide direct evidence that the left frontal regions are engaged
in the assessment of facial attractiveness.
PMID- 9559952
TI - Neuroprotection by dehydroepiandrosterone-sulfate: role of an NFkappaB-like
factor.
AB - Levels of dehydroepiandrosterone (DHEA) and its sulfated derivative (DHEA-S)
decline during aging and reach even lower levels in Alzheimer's disease (AD).
Previously published effects of DHEA and DHEA-S on unchallenged neuronal survival
led us to test them in an excitotoxicity paradigm. While DHEA-S protected
hippocampal neurons against glutamate, little protection was observed with
equivalent doses of DHEA itself. This differential neuroprotection was consistent
with the ability of DHEA-S (but not DHEA) to elevate a kappaB-dependent
transcription factor activity, a phenomenon we previously have connected with
neuroprotection. Furthermore, suppression of kappaB DNA-binding by 'decoy'
oligonucleotides blocked the neuroprotective activity of DHEA-S. These findings
imply that age-related declines in the availability of DHEA-S could exacerbate
neurotoxicity, and the data suggest that therapeutic gains may be obtained with
pharmacological manipulation of kappaB-dependent transcription in neurons.
PMID- 9559953
TI - The time course of brain activations during response inhibition: evidence from
event-related potentials in a go/no go task.
AB - The cortical organization of executive control was investigated using event
related potentials (ERPs). ERPs were collected while subjects performed a go/no
go task that required response inhibition. First, around 260 ms after stimulus
onset, an effect of response inhibition on ERPs was observed over inferior
prefrontal areas. Generators in these regions were confirmed by source analysis.
Later, between 300-600 ms after stimulus onset, a left lateralized fronto-central
ERP effect was found which differed in topography from a non-specific effect of
task difficulty. Source analysis indicated that generators in anterior cingulate
and left premotor areas also contributed to this effect. Orchestrated activation
of prefrontal areas and the anterior cingulate subserves executive function
whereas relatively late activity of the left premotor cortex is involved in motor
control.
PMID- 9559954
TI - Does the cortical representation of body parts follow both injury to the related
sensory peripheral nerve and its regeneration?
AB - A study was made of the borderline between the physiological representations of
the digits (D2, D3 and D4) and sinus whiskers in the rat primary somatosensory
cortex after a contralateral infraorbital nerve crush. Following the injury, the
physiological representation of the digits of the contralateral forepaw extended
posterolaterally, occupying the anterolateral part of the whisker region
(posteromedial barrel subfield). The extended physiological representation of the
digits, though somewhat shrunken, remained after the reappearance of whisker
evoked responses, forming an overlapping area between the obligate digit and
whisker representations. The findings emphasize the importance of afferent inputs
in modulating cortical organization, but show that a reversible change in a
sensory input (nerve damage) does not result in a perfectly reversible change in
cortical representation.
PMID- 9559955
TI - Calculating internal dose by convolution from SPECT/MR fusion images.
AB - A new computer program was developed to calculate the absorbed dose. The program
is based on the use of the convolution method and abdominal SPECT/MR fusion
images. The applicability of the method was demonstrated by using data from
(111)In-labeled thrombocyte and 99mTc-labeled colloid studies of three healthy
volunteers. Dose distributions in the volunteers and the average absorbed doses
in liver and spleen were calculated. The average doses for 99mTc-labeled colloid
study were 0.07 +/- 0.02 (liver) and 0.046 +/- 0.005 mGy/MBq (spleen). The
results are in good agreement with a Monte Carlo (MC) based method (0.074 for
liver and 0.077 mGy/MBq for spleen) used by the International Commission on
Radiological Protection (ICRP). For (111)In-labeled thrombocyte study the doses
were 0.33 +/- 0.05 (liver) and 8.9 +/- 1.2 mGy/MBq (spleen) versus 0.730 and
7.50, respectively. The differences in dose estimates in the (111)In-labeled
thrombocyte study are mainly due to the approximation used in activity
quantitation. Convolution of the activity distribution with a point dose kernel
is an effective method for calculating absorbed dose distribution in a
homogeneous media. Activity distribution must be aligned to anatomical data in
order to utilize the calculated dose distribution. The program developed is
applicable to and practical for clinical use provided that the input data needed
are available.
PMID- 9559957
TI - Relationship between skeletal uptake of 99mTc-HMDP and bone mineral density in
elderly women.
AB - The relationship between bone mineral density in elderly women and the pattern of
skeletal uptake of 99mTc-HMDP, especially in regard to skull uptake, was
investigated. The whole-body skeletal uptake (WBSU) and whole-body skeletal
tracer distribution patterns were studied in 86 disease-free women on bone
scintigraphy with 99mTc-hydroxy-methylene-diphosphonate (HMDP). Bone scans were
quantified by setting regions of interest (ROI) and bone mineral density (BMD)
was assessed by dual-energy X-ray absorptiometry in all patients. WBSU and the
skeletal distribution pattern were compared with bone mineral densities of the
entire skeleton as well as selected regions. WBSU was high in the elderly and
negatively correlated with regional bone mineral densities (r = -0.403 to
0.534). Among the regions, uptake by the skull increased with age more than in
other regions in women and had the highest negative correlation with the bone
mineral density. The skull uptake correlated negatively with total body BMD (r =
0.583) and with lumbar BMD (r = -0.561, p < 0.0001). Our results show that
increased radionuclide uptake in bone scintigraphy, especially skull uptake was
associated with decreased bone mineral density in elderly women, so that,
increased skull uptake in elderly women would be a scintigraphic sign of post
menopausal or senile osteopenia.
PMID- 9559956
TI - Application of a beta microprobe for quantification of regional cerebral blood
flow with (15)O-water and PET in rhesus monkeys.
AB - A beta microprobe was successfully applied to monitor arterial input function for
quantification of regional cerebral blood flow (rCBF) in the monkey brain with
(15)O-water and positron emission tomography (PET). The sensitivity of the probe
was approximately 0.83 to 1.67 cps/kBq/ml depending on the studies. A preliminary
study was performed to find a suitable use and to evaluate the performance of the
system and data analysis procedure. The results showed that dispersion correction
of measured input function was unnecessary if microprobes were connected directly
to the arterial catheter. Then multiple CBF measurements were done in three
monkeys under anesthesia. Identical regions of interest were placed with the aid
of magnetic resonance imaging (MRI) of each monkey and rCBF values were
estimated. Estimated rCBFs were reproducible for several measurements. The mean
CBF value for a pentobarbital anesthetized monkey was 46.0 ml/min/100 g (PaCO2 =
46.3 mmHg). This shows that the use of the beta microprobe for quantification of
rCBF with PET was validated. The lack of a need for dispersion correction of
observed input function is an advantage with the beta microprobe system because
the probes are small enough to be placed near the arterial sampling site.
PMID- 9559958
TI - Acetazolamide induced myocardial ischemia in patients with severe coronary artery
disease.
AB - Acetazolamide (ACZ)-augmented brain SPECT is commonly used for evaluating
cerebral vascular reserve in patients with cerebrovascular disease. ACZ may cause
myocardial ischemia in patients with coronary artery disease. To evaluate the
risk of induction of myocardial ischemia with ACZ-augmented myocardial SPECT, we
performed combined ACZ-augmented Tl-201 myocardial SPECT (ACZ-myo SPECT) with Tc
99m HMPAO brain SPECT in patients with severe coronary artery disease. METHODS:
Nine patients underwent combined ACZ-myo SPECT with Tc-99m HMPAO brain SPECT. (1)
For qualitative analysis, SPECT images were divided into 13 segments to calculate
the total defect scores. (2) Six ROIs were placed on the slices in the myocardial
SPECT short-axis images and the regional uptake ratio was obtained as the ratio
of the mean counts in the myocardium to the maximal count in the slice. The total
defect score and regional uptake ratio of ACZ-myo SPECT were compared with those
of early and delayed dipyridamole Tl-201 myocardial SPECT (DP-Tl SPECT) images.
RESULTS: (1) In the 21 coronary artery territories with coronary stenosis > or =
75%, the total defect score in ACZ-myo SPECT, early and delayed DP-Tl SPECT
images were 3.52 +/- 4.14*, 4.19 +/- 4.65* and 2.25 +/- 3.34, respectively (*: p
< 0.05 vs. delayed DP-Tl SPECT images). (2) In 44 of 54 ROIs with coronary
stenosis > or = 75%, the regional uptake ratio of ACZ-myo SPECT, early and
delayed DP-Tl SPECT images were 0.670 +/- 0.166**, 0.677 +/- 0.194**, 0.721 +/-
0.178, respectively (**: p < 0.01 vs. delayed DP-Tl SPECT images). Systolic blood
pressure fell at 11 min after ACZ infusion without electrocardiographic ST-T
changes or chest pain. CONCLUSION: As ACZ has the potential to cause myocardial
ischemia, ACZ-augmented brain SPECT should be performed with caution in patients
with severe coronary artery disease associated with cerebrovascular disease.
PMID- 9559959
TI - Cerebral blood flow changes in the primary motor and premotor cortices during
hyperventilation.
AB - The aim of this study was to clarify the regional differences in cerebral blood
flow (CBF) change during hyperventilation by using H2(15)O and positron emission
tomography (PET). Eight healthy volunteers (age: 63.0 +/- 8.9 yr.) were studied.
Regional CBF was measured by the H2(15)O autoradiographic method and PET.
Statistical parametric maps (SPM) and conventional regions of interest (ROI)
analysis were used for estimating regional CBF differences in the normocapnic
state with normal breathing and the hypocapnic state induced by hyperventilation.
Total CBF decreased during the hypocapnic state. The SPM revealed that primary
motor and premotor cortices were significantly activated by hyperventilation. In
these areas absolute CBF values were significantly higher than those in the
temporal, occipital and parietal lobes in the hypocapnic state, but there were no
significant regional differences in the normocapnic state. In the hypocapnic
state induced by hyperventilation, the primary motor and premotor CBF shows
combined changes with vasoreaction to hypocapnia and increase in activation due
to hyperventilation.
PMID- 9559960
TI - Cerebral muscarinic acetylcholinergic receptor measurement in Alzheimer's disease
patients on 11C-N-methyl-4-piperidyl benzilate--comparison with cerebral blood
flow and cerebral glucose metabolism.
AB - We studied the cerebral muscarinic acetylcholinergic receptor (mACh-R) by means
of 11C-N-methyl-4-piperidyl benzilate (11C-NMPB) and positron emission tomography
(PET) in Alzheimer's disease (AD) cases, and the findings were compared with the
cerebral blood flow (CBF) and the glucose metabolism (CMRGlc) to evaluate the
relationship between the mACh-R and the CBF or the CMRGlc. The subjects consisted
of 18 patients with AD and 18 age and sex matched normal volunteers. The patients
were clinically diagnosed according to the criteria of the NINDS-ADRDA as having
"probable AD" and were thus classified into two groups (mild and moderate AD)
according to the severity of dementia determined by DSM-III-R. The CBF was
measured by 99mTc-HMPAO SPECT, and the CMRGlc was measured by 18FDG PET. The 11C
NMPB uptake was evaluated by the graphical method and the ratio method
(ROIs/Cerebellum). A significant mACh-R decrease and more severe CMRGlc decrease
in the cortical region was seen in mild and moderate AD. The decrease in the CBF
was not as obvious as that in the mACh-R and the CMRGlc. Our study thus suggested
that the mACh-R decreased in patients with AD, and that the 18FDG PET was the
most sensitive method for detecting the degenerative regions in patients with AD.
PMID- 9559961
TI - Absent myocardial accumulation of two different radioiodinated pentadecanoic
acids.
AB - This article presents two cases with preserved myocardial 201Tl uptake and absent
uptake of two kinds of radioiodinated fatty acids: iodine-123-labeled 15-(p
iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) and iodine-123-labeled 15-(p
iodophenyl)-9-(R,S)-methylpentadecanoic acid (9MPA). Although coronary
angiography showed no stenotic lesion and left ventriculography revealed no wall
motion abnormality, no myocardial uptake of BMIPP and 9MPA was observed in the
first case. In the second case, no myocardial accumulation was recognized even in
the initial phase of dynamic SPECT acquired soon after the injection of 9MPA. The
results suggest that the non-visualized myocardium was not specific for BMIPP
imaging and that rather than the early back diffusion of the tracers from the
myocardium, abnormality of the myocardial cell membrane was a possible mechanism
accounting for the phenomenon.
PMID- 9559962
TI - Four cases of Warthin's tumor of the parotid gland detected with FDG PET.
AB - In the cancer screening with FDG PET for 1,872 medical health club members, high
FDG accumulation in the parotid gland was found in four males (age, 57-70 years).
Warthin's tumor was confirmed by surgical pathology. The exact mechanism of high
FDG accumulation in Warthin's tumor is not yet known. This tumor may be found
incidentally during FDG PET studies. When high FDG accumulation is found in the
parotid gland, integrated consideration of the results of the physical
examination, medical history and 99mTc-pertechnetate scintigraphy makes it
possible to differentiate Warthin's tumor from other lesions.
PMID- 9559963
TI - Gallium-67-citrate scintigraphy of primary renal lymphoma.
AB - We present a case of primary renal lymphoma, which is a rare entity and poses
diagnostic challenge. Ultrasound and CT scan demonstrated a nonspecific solid
tumor in the left kidney. 67Ga-citrate scintigraphy demonstrated an intense
uptake in the tumor, which led to a correct diagnosis, so that we could spare
unnecessary laparotomy and possible nephrectomy.
PMID- 9559964
TI - Metabolite analysis of [11C]flumazenil in human plasma: assessment as the
standardized value for quantitative PET studies.
AB - Analysis of carbon-11 labeled metabolites in plasma was carried out during
positron emission tomography (PET) studies with a central benzodiazepine receptor
ligand [11C]flumazenil ([11C]FMZ) in 24 human subjects (14-76 y.o.) including
five normal volunteers and 19 patients with neurological disorders. Arterial
plasma samples were obtained at 3, 5, 10, 15, 20, 30 and 60 min after i.v.
injection of the tracer, and were analyzed by high-performance liquid
chromatography. The rate of plasma [11C]FMZ degradation was associated with a
large individual variation, but no significant difference was found in the
degradation of [11C]FMZ either between male and female, young and old, or between
normal subjects and patient groups. When the mean fraction of unchanged [11C]FMZ
at each time point was used instead of individually measured metabolite data for
the arterial input function, as much as a 30% error occurred in the distribution
volume of the [11C]FMZ binding in the brain. These results indicate that the mean
percentage of unchanged [11C]FMZ fraction in subjects cannot be used as the
standardized value, and that the analysis of metabolites in plasma is necessary
to determine the exact arterial input function for quantitative PET measurement.
PMID- 9559965
TI - Acute cellular damage in medial smooth muscle cells following experimental
coronary angioplasty in dog. Damage of cytoskeleton and apoptosis.
AB - The purpose of the present study was to investigate the responses of the
cytoskeleton and the presence of apoptosis following acute damage of medial
smooth muscle cells after percutaneous transluminal coronary angioplasty (PTCA).
We killed 20 dogs, 4h and 4 days after PTCA (n=10 in each group). Ten dogs
without PTCA were used as controls. PTCA was achieved by inflating balloon
catheters two times, for 60s each time, to 150 PSI, followed by a 60-s deflation.
The coronary artery obtained from each dog was fixed in 10% formalin neutral
buffer solution. The response of the cytoskeleton was studied
immunohistochemically. using monoclonal antibodies against alpha-smooth muscle
actin, vimentin, and beta-tubulin. Proliferation was determined by proliferating
cell nuclear antigen (PCNA), and DNA fragmentation indicating apoptosis was
determined by in situ nick end labeling. Four h after PTCA, endothelial
denudation, microscopic mural thrombi, rupture of the internal elastic membrane,
medial tear, and stretched smooth muscle cells with nuclei were found at the PTCA
site. An immunohistochemical study revealed diffuse reduction or defective
immunoreactivity in each cytoskeleton of medial smooth muscle cells, 4h after
PTCA. The extent of positive immunoreactivity in the media decreased to 45+/-11%
in alpha-smooth muscle actin (control value, 80+/-10%), 9+/-8% in vimentin
(control value, 83+/-9%), and 10+/-7% in beta-tubulin (control value, 75+/-8%).
The decrease was more significant in vimentin and beta-tubulin than in alpha
smooth muscle actin. Four days after PTCA, the features were diffuse cell death
and the focal proliferation of medial cells, as well as macroscopic intramural
thrombi. The extent of positive immunoreactivity in the media was 15+/-9% in
alpha-smooth muscle actin, 13+/-7% in vimentin, and 14+/-11% in beta-tubulin.
There were no smooth muscle cells with positive PCNA (0%) in the control and 4-h
groups, but 4 days after PTCA the percentage was 19+/-4%. In situ nick end
labeling showed DNA fragmentation in the nuclei of medial smooth muscle cells at
a rate of 15+/-5% 4h after PTCA and at 8+/-6% 4 days after PTCA, compared with 0%
in the control. We concluded that severe damage of the cytoskeleton and medial
smooth muscle cell death were induced immediately after PTCA, followed by
proliferation of smooth muscle cells. Apoptosis may be partially involved in the
death of smooth muscle cells, in addition to necrosis. Damage to the cytoskeleton
and apoptosis may play an important role in the pathogenesis of acute lesions and
the proliferation of smooth muscle cells after PTCA.
PMID- 9559966
TI - Feasibility of diagnosing chronic myocarditis by endomyocardial biopsy.
AB - In studies of all the layers of autopsied hearts from patients with chronic
myocarditis, local clusters of lymphocytes are frequently noted, in contrast with
hearts obtained from patients with acute myocarditis. Myocardial biopsy
specimens, however are no larger than about 2mm x 3mm. With this in mind, the
present study was undertaken to determine whether chronic myocarditis can be
diagnosed by endomyocardial biopsy. Specimens were obtained from seven patients
in whom chronic myocarditis was confirmed by the clinical course and by autopsy
findings. In H&E stained specimens, sites corresponding to the biopsy sites in
both ventricles (right ventricular free wall, right ventricular side of the
ventricular septum, left ventricular lateral wall) were selected at random (five
sites each from the right and left ventricles in each patient) and examined under
a light microscope. A mean of 5 or more lymphocytes per visual field (by light
microscopy at 400-fold magnification), a proposed quantitative diagnostic
criterion of myocarditis, was noted in the right ventricle in three patients (5
lymphocytes in two patients and 6 in one patient) and in the left ventricle in
one patient (5 lymphocytes). Also, when the presence of lymphocyte clusters,
considered to be a characteristic feature of chronic myocarditis, was determined,
clusters of 20 or more lymphocytes per visual field were found in the same
patients as those mentioned above, namely, in three patients (42.8%) in the right
ventricle, as mentioned above, and in one patient (14.3%) in the left ventricle.
At the sites of these lymphocyte clusters. findings such as degenerative changes
of the myocardial cells and interstitial fibrosis were also associated, making
possible a diagnosis of myocarditis. Therefore, in chronic myocarditis, even if
five specimens are obtained by right ventricular biopsy, in approximately one
half of patients the diagnosis of chronic myocarditis will be missed because of
sampling errors.
PMID- 9559967
TI - Altered distribution of collagen type I and hyaluronic acid in the cardiac
outflow tract of mouse embryos destined to develop transposition of the great
arteries.
AB - Complete transposition of the great arteries (TGA) is inducible by treatment with
all-trans retinoic acid in the ICR mouse. In this model, hypoplasia and dysplasia
of the proximal outflow tract cushion tissue lead to non-spiral septation. In
order to evaluate the effect of retinoic acid on the extracellular matrix of the
cardiac outflow tract, we examined the distribution of collagen type I and
hyaluronic acid, immunohistochemically, on days 8-9 of gestation. In controls,
collagen type I fibrils ran mainly in a radial direction, extending towards the
endocardium in the cardiac jelly of the proximal outflow tract. Also, a pair of
longitudinal fiber bundles were formed stretching to the distal outflow tract. As
for hyaluronic acid, intense staining was observed in the submyocardial and
intermyocardial space of the outer curvature of the heart. On the other hand, in
retinoic acid-treated embryos, the submyocardial radial fibrils or longitudinal
fiber bundles of collagen type I were diminished, and irregular and dense
deposits of collagen type I were observed along the endocardium. Furthermore,
hyaluronic acid showed a loss of differential localization between the outer and
inner curvature. Instead, irregular and intense staining was observed uniformly
along the outflow myocardium. Thus, retinoic acid appeared to have perturbed the
differentiation in the proximal outflow tract causing an altered organization of
multiple extracellular matrix molecules, including collagen type I and hyaluronic
acid, which led to an abnormal molecular network of the cardiac jelly in the
cardiac outflow tract, abnormal septation and, further, to TGA or TGA-type
anomalies.
PMID- 9559968
TI - Acetylcholine-induced vasoconstrictor response of coronary vessels in rats: a
possible contribution of M2 muscarinic receptor activation.
AB - A mechanism by which acetylcholine (ACh) may elicit vasoconstrictor response in
coronary vessels was studied in rat hearts perfused at a constant flow rate. In
spontaneously beating hearts, bolus injections of ACh and carbachol (CCh)
produced biphasic changes in coronary perfusion pressure (CPP): a transient
increase at the initial period followed by a sustained decrease. In KCl-arrested
hearts, ACh and CCh produced a monophasic increase in CPP, which was attenuated
by either removal of endothelial cells by saponin or cyclooxygenase inhibition by
diclofenac sodium. In the spontaneously beating heart, ACh-induced
vasoconstriction was almost abolished by atropine (0.1 microM) and was markedly
attenuated by an M2 antagonist, methoctramine (0.1 microM), but not by an M1
antagonist, pirenzepine (1 microM). Arecaidine propargyl ester (APE), an M2
agonist, produced coronary artery constriction which was attenuated by
methoctramine (0.1 microM) but not by pirenzepine (0.1 microM) in both
spontaneously beating and KCl-arrested hearts. McN-A-343, an M1 agonist,
increased CPP in both beating and KCl-arrested hearts, but to a lesser degree
than APE. These results suggest that the release of vasoconstrictor
prostaglandins from endothelial cells contributes to the vasoconstrictor response
to ACh in perfused rat coronary vessels, and the response to ACh appears to be
mediated, in part, via the M2 subtype of muscarinic receptors.
PMID- 9559969
TI - Effect of regional myocardial perfusion abnormalities on regional myocardial
early diastolic function in patients with hypertrophic cardiomyopathy.
AB - Nonuniform hypertrophy of the left ventricle is an important factor in regional
diastolic dysfunction in patients with hypertrophic cardiomyopathy (HCM).
However, the effect of myocardial perfusion abnormalities on regional diastolic
dysfunction has not been established in patients with HCM. We investigated the
relationship between regional myocardial perfusion abnormalities and regional
early diastolic function in 31 patients with HCM and 8 control patients. Short
axis images of the left ventricle recorded by cine magnetic resonance imaging
were divided into ten blocks. The time-to-peak-wall-thickness-thinning rate
(TPWR) and the wall thickness were measured in each block. Of the 310 blocks from
the patients with HCM, 242 (78%) showed normal thallium-201 uptake (group 1), 40
(13%) showed slightly decreased uptake (group 2), and 28 (9%) showed markedly
decreased uptake (group 3). There was no difference in the regional wall
thickness among the three groups. The TPWR was longer in patients with HCM than
in control patients. It was significantly longer in group 3 (190+/-45ms) than in
group 1 (167+/-36 ms) and group 2 (160+/-31 ms). (P < 0.01). The linear
regression slope of the relationship between the TPWR and the regional wall
thickness was significantly steeper in group 3 than in groups 1 and 2 (P < 0.05).
In conclusion, abnormalities in regional myocardial perfusion, in addition to
regional hypertrophy, contributed to the regional early diastolic dysfunction in
patients with HCM.
PMID- 9559970
TI - Successful treatment of intraoperative pulmonary tumor embolism from renal cell
carcinoma.
AB - During left nephrectomy in a 35-year-old woman with a left renal cell carcinoma
extending into the inferior vena cava (IVC) and right atrium, cardiac arrest
occurred. Immediate transesophageal echocardiography demonstrated that the event
was caused by a pulmonary tumor embolism. Emergent cardiopulmonary bypass (CPB)
was established and the tumors in the pulmonary arteries were successfully
removed. The left nephrectomy was completed. The patient recovered in the
intensive care unit without any neurological deficit. A postoperative pulmonary
perfusion scintigram showed no defect in the pulmonary circulation.
Transesophageal echocardiography was useful for making a rapid diagnosis of an
intraoperative pulmonary embolism originating from a tumor of the IVC or right
atrium.
PMID- 9559971
TI - Syncope at sleep onset in a patient with nasopharyngeal carcinoma.
AB - A patient with nasopharyngeal carcinoma developed atypical parapharyngeal-lesion
syncope syndrome associated with stereotypical cycles of heart rate variation,
which occurred only when he was drowsy before falling asleep. Vagal tone
fluctuation is implicated.
PMID- 9559972
TI - Immune responses to stress proteins: applications to infectious disease and
cancer.
AB - Heat shock proteins, or stress proteins have been identified as part of a highly
conserved cellular defence mechanism mediated by multiple, distinct gene families
and corresponding gene products. As intracellular chaperones, stress proteins
participate in many essential biochemical pathways of protein maturation and
function active during times of stress and during normal cellular homeostasis. In
addition to their well-characterized role as protein chaperones, stress proteins
are now realized to possess another important biological property:
immunogenicity. Stress proteins are now understood to play a fundamental role in
immune surveillance of infection and malignancy and this body of basic research
has provided a framework for their clinical application. As key targets of both
humoral and cellular immunity during infection, stress proteins have accordingly
received considerable research interest as prophylactic vaccines for infectious
disease applications. The unique and potent immunostimulatory properties of
stress proteins have similarly been applied to the development of new approaches
to cancer therapy, including both protein and gene-based modalities.
PMID- 9559973
TI - HLA-DR/DQ transgenic, class II deficient mice as a novel model to select for HSP
T cell epitopes with immunotherapeutic or preventative vaccine potential.
AB - Protective immunity against mycobacteria is dependent on antigen/MHC class II
specific, CD4+ Th1 cells. HLA-DR3-restricted Th1 cells respond to a subset of
mycobacterial antigens, including the immunodominant hsp65, and recognize a
single epitope in hsp65, notably p1-20. Altered peptide ligands (APL) of p1-20
can inhibit p1-20/hsp65-induced proliferation of DR3-restricted T cells in an
allele specific manner in vitro. In order to develop a preclinical model in which
p1-20 APL can be tested in vivo in the context of HLA, we have used murine class
II deficient, HLA transgenic (Ab0) mice, in which all CD4+ T cells are restricted
by the tg HLA molecule. BCG-immunized DR3.Ab0 and DQ8.Ab0 mice both responded
well to hsp65. Furthermore, DR3.Ab0 mice recognized precisely the same p1-20
epitope as DR3-restricted human T cells, whereas DQ8.Ab0 mice responded to a
different set of hsp65 peptides. This shows that (i) the same immunodominant
protein and peptide epitope are recognized by T cells from DR3.Ab0 mice and DR3+
humans and (ii) indicates the major role of HLA-polymorphism in controlling the
human T cell response to mycobacterial antigens. Thus, HLA-transgenic, Ab0 mice
provide a novel, preclinical model system to analyze APL and vaccines in the
context of HLA polymorphism.
PMID- 9559974
TI - Heat shock proteins as potential targets in the therapy of inflammatory
arthritis.
AB - Whether heat shock proteins (hsp) will be therapeutic targets in arthritis
depends on their role in pathogenesis. In this article, three possibilities are
considered. Firstly, an excessive immune response to bacterial hsp could be
arthritogenic - as may occur in reactive arthritis. In these circumstances
therapy would be directed to down-regulating this immune response, or altering
the nature of the immune response e.g. by changing cytokine production from
interferon-g to IL-4. However this approach depends on the immune response to
bacterial hsp not being critical for control of the bacterial infection.
Secondly, an immune response to bacterial hsp may induce autoimmunity by cross
reactivity, e.g. with the homologous human. This could also be modulated in the
same way with a lower likelihood of interfering with control of the infectious
agent, since only a component of the immune response against the bacterial hsp
will be cross-reactive with self. Thirdly, recent experiments raise the
possibility that joint inflammation might be controlled by T cells which
recognizes self hsp, particularly hsp60. Therapies might enhance this response;
protection from experimental arthritis by prior immunization with hsp60 is well
established. Whether similar approaches will be viable after arthritis is
established remains to be seen.
PMID- 9559975
TI - Nasal administration of arthritis-related T cell epitopes of heat shock protein
60 as a promising way for immunotherapy in chronic arthritis.
AB - Adjuvant Arthritis (AA) can be induced in Lewis rats by immunisation with
mycobacterial antigens. The disease can be passively transferred with T cell
clone A2b, which recognises the 180-188 amino acid sequence in mycobacterial heat
shock protein 60 (hsp60) and which crossreacts with crude cartilage
proteoglycans. We succeeded to induce peripheral tolerance to this AA-associated
T cell epitope following nasal administration of a peptide containing this
epitope (mycobacterial hsp60 176-190). In rats treated nasally with 176-190 and
immunised with mycobacterial hsp60, proliferative responses to 176-190 were
reduced. AA was inhibited nasally with 176-190 treated rats and not in rats
nasally treated with a control mycobacterial hsp60 peptide (211-225). Moreover,
nasal 176-190 led to similar arthritis protective effects in a non-microbially
induced experimental arthritis (avridine induced arthritis). In a subsequent
study we tried to prevent and to treat AA through nasal administration of
mycobacterial hsp60 peptide 180-188 and a peptide analogue of 180-188, 180
188(L183->A) (Alanine 183), which has been shown to have an increased MHC-binding
affinity for rat RT1 Bl and an increased capacity to inhibit the proliferative
A2b response in vitro. We found that nasal administration of 180-188 had a
moderate arthritis suppressive effect in AA, whereas its analogue peptide Alanine
183, had a strong suppressive effect. This strong arthritis suppressive effect
was only partly due to the higher MHC-binding affinity for rat RT1 Bl.
Furthermore, it was possible to passively transfer nasal Alanine 183 induced
disease protection. The present findings may in our view offer novel prospects
for immunotherapy through nasal administration of (analogue) peptides, with a
mimicry relationship with joint specific cartilage proteoglycan epitopes.
PMID- 9559976
TI - Mucosal modulation of immune responses to heat shock proteins in autoimmune
arthritis.
AB - Induction of oral tolerance to antigens that are targets of self-reactive immune
responses is an attractive approach to antigen-specific immune therapy of
autoimmune diseases. Oral tolerization has indeed proven to be safe and effective
in amelioration of autoimmune diseases in animal models. In humans, results have
been somewhat controversial. The emphasis given to clinical outcome rather than
to immunomodulation, and the difficulty in identifying appropriate candidate
antigens contribute to the controversy. Heat shock proteins are promising targets
for immune intervention. Immune reactivity to heat shock proteins has indeed been
correlated with autoimmune arthritis in animal models, and abnormal immune
responses to heat shock proteins have been described in human arthritis as well.
Despite significant recent progress, little is known at a molecular level
regarding the mechanisms which are responsible for a switch from autoimmunity to
tolerance in humans. This is particularly true with respect to sequential
analysis of several molecular and immunologic markers during both the course and
treatment of disease. Novel approaches are currently under way to fill the gaps.
We will briefly detail here the experience gained to date, and identify some of
the avenues which future research will explore.
PMID- 9559978
TI - Heat shock proteins and the antitumor T cell response.
AB - Heat shock proteins (HSP) have been shown to participate in the antitumor T cell
response. First, HSP play a crucial role in the intracellular pathway for antigen
processing where HSP can make complexes with a broad spectrum of cellular
proteins and peptides through their chaperone functions. In this pathway,
macrophages are required for processing the chaperoned peptides to make stable
molecules with the major histocompatibility complex (MHC) class I molecules, even
when HSP-peptide complexes are exogenously administered. Through this pathway,
vaccination with HSP-peptide complexes is thus able to elicit the response of
CD8+ T cells specific for the chaperoned peptides. These findings suggest an
essential role of HSP in 'cross-priming' and their usefulness for antitumor
vaccination with tumor peptides. Second, HSP have been suggested to be expressed
on the cell surface by transformation and, in addition, to function as antigen
presenting molecules for double negative T cells. Third, HSP derived from tumor
cells have reportedly been recognized by T cells with either T cell receptor
(TCR)-alphabeta or TCR-gammadelta. These lines of evidence therefore indicate
that HSP may be potentially promising target molecules for antitumor T cell
immunotherapy.
PMID- 9559977
TI - Oral administration of HSP-containing E. coli extract OM-89 has suppressive
effects in autoimmunity. Regulation of autoimmune processes by modulating
peripheral immunity towards hsp's?
AB - OM-89 (Subreum) is an E. coli extract used for oral administration in the
treatment of rheumatoid arthritis. It contains bacterial heat shock proteins,
namely hsp60 and hsp70, which were shown to be major immunogenic constituents of
the drug. Immunity to bacterial heat-shock antigens was shown to be a means of
immunomodulation of (experimental) autoimmune disease and possibly inflammation
in general. This was demonstrated for mycobacterial hsp60 respectively hsp70 in
autoimmune disease models for arthritis, diabetes and encephalitis. Parallel to
the effects displayed by immunisation with hsp, oral administration of hsp
containing OM-89 was found to modify autoimmune disease in a number of animal
models, such as for arthritis, diabetes and SLE. In rats immunisation with OM-89
was found to lead to proliferative T cell responses to hsp60 and hsp70 of both E.
coli and mycobacterial origin. Conversely, immunisation with hsp antigens could
induce T cell reactivity specific for OM-89. Given this and the autoimmune
disease modulating properties of both hsp and OM-89 it is argued that OM-89 acts
via the same mechanism as proposed for hsp: that peripheral tolerance is induced
at the level of regulatory T cells with specificity for heat-shock proteins. This
may constitute one mode of action for OM-89 as an arthritis suppressive oral drug
in man.
PMID- 9559979
TI - Antigen-specific therapies in multiple sclerosis.
AB - Multiple sclerosis is the major neurological disease of young adults in the
western world, affecting about 1 per 1,000. It is characterised by chronic or
recurrent lesions of inflammatory damage in the white matter of the central
nervous system. Within such lesions, the protective myelin sheath is stripped off
axons by infiltrated macrophages which leads to impaired conductivity. The
inflammatory process most likely starts by activation of helper T cells directed
against local myelin antigens. Currently, efforts are directed at specifically
blocking such myelin-reactive helper T cells in order to control the disease. In
this chapter, immunological features of multiple sclerosis and the experimental
animal model for the disease, experimental allergic encephalomyelitis, are
discussed. Next, an overview is presented on myelin antigens that have been
suggested to play a role as target antigens in MS. Finally, strategies are
discussed that are currently employed to selectively block the activation of T
cells reactive against myelin antigens.
PMID- 9559980
TI - Muscle fiber type compartmentalization and expression of an immature myosin
isoform in the sternocleidomastoid muscle of rabbits and primates.
AB - The sternocleidomastoid muscle is located in the neck and is both a neck rotator
and flexor. Cervical dystonia, a focal dystonia disorder, is characterized by
forceful involuntary contraction of a group of neck muscles, usually including
the sternocleidomastoid. Little is known about the fiber type composition, fiber
type compartmentalization and innervation patterns in this muscle in rabbit and
primates. Sternocleidomastoid muscles from rabbit and monkey were analyzed for
muscle fiber type composition and number, muscle fiber cross-sectional area and
patterns of innervation. The sternocleidomastoid muscle was composed of two
distinct regions, or compartments, with different fiber type compositions: an
outer or superficial region composed of mostly type 2 myofibers and an inner deep
region composed of both type 2 and type 1 myofibers. Neonatal myosin heavy chain
isoform was detected in approximately 25% of the myofibers in both regions of the
muscle. Neuromuscular junctions were located in seven endplate bands
approximately 1-3 cm apart throughout the length of the muscle. There is clear
evidence of anatomical subdivisions within this muscle. Not only is there
variation in fiber type composition between superficial and deep regions of the
muscle, but unlike most other mature skeletal muscles, it continues to express
neonatal myosin heavy chain isoform in the adult. The motor program for neck
movements is extremely complex, and the histological complexity plays a role in
allowing for a continuum of movements of the head and neck, from maintenance of
posture to rapid head movements.
PMID- 9559981
TI - Selective involvement of large motor neurons in the spinal cord of rats treated
with methylmercury.
AB - Mercury is thought to be a possible epidemiological factor for the pathogenesis
of motor neuron disease, since it has been reported that metallic, inorganic and
organic mercury causes a syndrome clinically resembling amyotrophic lateral
sclerosis. We administered 10 mg/kg/day methylmercury chloride to adult rats for
10 consecutive days. The hind-limbs became flaccid and atrophic, and 14 out of
the 34 rats had died by the 18th day after methylmercury treatment began. Light
microscopical examination of the large motor neurons in the spinal anterior horn
revealed cytoplasmic vacuolation and loss of Nissl substance on the 14th day, and
neuronophagia appeared on the 16th day. On the 18th day, the loss of large motor
neurons was almost complete, whereas small to medium-sized neurons were
preserved. Silver acetate autometallography to detect mercury revealed the
selective accumulation of mercury in the large motor neurons. These findings
suggest that although a high dose is required, organic mercury can cause the
definite loss of large spinal motor neurons in rats.
PMID- 9559982
TI - Polyneuropathy due to cobalamin deficiency in the rat.
AB - In the present study, we investigated the peripheral nervous system (PNS) (both
in terms of its ultrastructure and in terms of its function) of rats made
cobalamin (Cbl)-deficient either through total gastrectomy or through prolonged
feeding on a Cbl-deficient diet. In both these types of Cbl-deficient
neuropathies we found: (a) ultrastructurally, intramyelin and endoneural edema,
with no or minimal axonal damage in the PNS, in dorsal root ganglia, and the
ventral and dorsal rootlets of the spinal cord; (b) electrophysiologically, a
significant reduction in the nerve conduction velocity, consistent with that
reported in (a); (c) morphometrically, a significant reduction in the density of
myelinated fibers both in the sciatic nerve and in the peroneal nerve. All these
pathological changes were reversed by chronic postoperative administration of Cbl
into totally gastrectomized (TGX)-rats, hinting at the specificity of the damage
itself in relation to the permanent Cbl-deficient status of the TGX-rats. No
signs of segmental demyelination or remyelination were found. We also observed a
turning of type I fibers into type II fibers in the soleus muscle of all our Cbl
deficient rats, however the Cbl deficiency had been induced. This muscular change
was still present in TGX- and Cbl-treated rats, and it cannot be related to a
malnutrition status, since it has been observed also in rats fed a Cbl-deficient
diet. All these results demonstrate that Cbl deficiency strongly affects rat PNS
within different parameters.
PMID- 9559983
TI - A novel splicing mutation in the ceruloplasmin gene responsible for hereditary
ceruloplasmin deficiency with hemosiderosis.
AB - Hereditary ceruloplasmin deficiency with hemosiderosis (aceruloplasminemia) is a
newly recognized autosomal recessive disorder of copper-iron metabolism due to
mutations in the ceruloplasmin (Cp) gene. We report here a novel mutation in the
Cp gene in a 54-year-old Japanese woman with this disease. She showed clinical
triad; diabetes mellitus, retinal degeneration and neurological disorder in her
middle age. Laboratory findings were characteristic for no detectable serum
ceruloplasmin and increased serum ferritin. Liver biopsy revealed excessive
storage of iron in hepatocytes and magnetic resonance imaging of the brain was
indicative of increased iron content in the basal ganglia, thalamus and dentate
nucleus. The a-->g substitution at the splice acceptor site of the intron 6 (1209
2) caused a 8-bp deletion in Cp mRNA by defective splicing, resulting in a
premature termination codon at the amino acid position 388. Truncation of Cp,
even if effectively translated, may cause loss of its normal function because of
drastic change in its triangular structure.
PMID- 9559984
TI - Intravenous immunoglobulin preparation increases myoplasmic calcium concentration
by activating the dihydropyridine-ryanodine receptor complex.
AB - A human intravenous immunoglobulin preparation (IVIg) released Ca2+ from the
sarcoplasmic reticulum of cultured human skeletal muscle cells in a dose
dependent manner. Blocking the dihydropyridine-ryanodine receptor complex
abrogated the IVIg-mediated Ca2+ response, whereas inhibition of the voltage
operated Na+-channels or acetylcholine receptors did not. This effect of IVIg was
not mediated by its main component, the IgG molecules, and differed between
preparations from different manufacturers. Heating destroyed the activity. Data
shows that an unidentified serum protein present in IVIg can influence human
muscle cells by an effect on the dihydropyridine receptor. This phenomenon may be
important in interpreting the (side) effects of IVIg in neuromuscular diseases.
PMID- 9559985
TI - A case of mitochondrial encephalomyopathy associated with a muscle coenzyme Q10
deficiency.
AB - We report severe coenzyme Q10 deficiency of muscle in a 4-year-old boy presenting
with progressive muscle weakness, seizures, cerebellar syndrome, and a raised
cerebro-spinal fluid lactate concentration. State-3 respiratory rates of muscle
mitochondria with glutamate, pyruvate, palmitoylcarnitine, and succinate as
respiratory substrates were markedly reduced, whereas ascorbate/N,N,N',N'
tetramethyl-p-phenylenediamine were oxidized normally. The activities of
complexes I, II, III and IV of the electron transport chain were normal, but the
activities of complexes I+III and II+III, both systems requiring coenzyme Q10 as
an electron carrier, were dramatically decreased. These results suggested a
defect in the mitochondrial coenzyme Q10 content. This was confirmed by the
direct assessment of coenzyme Q10 level by high-performance liquid chromatography
in patient's muscle homogenate and isolated mitochondria, revealing levels of 16%
and 6% of the control values, respectively. We did not find any impairment of the
respiratory chain either in a lymphoblastoid cell line or in skin cultured
fibroblasts from the patient, suggesting that the coenzyme Q10 depletion was
tissue-specific. This is a new case of a muscle deficiency of mitochondrial
coenzyme Q in a patient suffering from an encephalomyopathy.
PMID- 9559986
TI - Evolution of brain tuberculomas under standard antituberculous treatment.
AB - The treatment of brain tuberculomas is primarily medical. Surgery, excision or
biopsy, is generally performed when the diagnosis is in doubt or there is no
response to medical therapy. The aim of this study was to determine the
radiological evolution of intracranial tuberculomas under standard anti
tuberculous drug therapy and to establish guidelines for better management of
these patients. Eighteen patients were studied retrospectively. None of them had
surgical intervention and all were treated by standard antituberculous drugs and
had serial computed tomography (CT) scans until disappearance or stabilization of
brain lesions. The regression of lesions' size and number was slow in the first
month (mean -7.3%) then became rapid after this (-15% to -20% per month). A
paradoxical increase in size was noted in three patients in the first month. All
three had associated meningitis. All tuberculomas disappeared on CT scan after 12
months of therapy. Most of the edema images disappeared by 6 months. This study
would suggest that a long treatment regimen of 15-18 months may not be necessary
in most intracranial tuberculomas occurring in non-immunocompromised patients. It
also demonstrates that medical trial in well tolerated suspected cases should
last for at least 2 months before considering other etiologies or surgical
exploration.
PMID- 9559987
TI - Elevated cerebrospinal fluid and serum nitrate and nitrite levels in patients
with central nervous system complications of HIV-1 infection: a correlation with
blood-brain-barrier dysfunction.
AB - As nitric oxide (.NO) is hypothesised to play a role in the immunopathogenesis of
neurological complications associated with inflammation, we compared levels of
cerebrospinal fluid (CSF) and serum .NO metabolites in 24 patients with HIV-1
infection, to those in 58 non-HIV infected patients with neurological disorders.
Levels of .NO metabolites were correlated with blood-brain-barrier dysfunction.
CSF and serum nitrate and nitrite levels were measured by the nitrate reductase
and Griess reaction methods. The .NO metabolites, nitrate and nitrite, were
raised in the CSF and serum of patients with AIDS and central nervous system
complications, when compared to non-HIV infected patients with inflammatory and
non-inflammatory neurological disorders (median nitrate and nitrite: CSF=18.3
microM vs. 11.1 microM vs. 7.0 microM, P<0.001, and serum=53.8 microM vs. 50.3
microM vs. 41.4 microM, P=0.04, respectively). CSF nitrate and nitrite levels
correlated with the albumin quotient. This study supports the evidence that .NO
is a potential mediator of blood-brain-barrier breakdown in inflammatory diseases
of the central nervous system.
PMID- 9559988
TI - Alzheimer's disease: patterns of cognitive impairment at different levels of
disease severity.
AB - The aim of this study was to establish the presence and the consistency of
different cognitive profiles in AD patients taking into consideration the
severity of mental impairment. Therefore we stratified 679 neuropsychological
observations on 119 probable AD patients followed longitudinally on the basis of
overall degree of cognitive impairment. To compare performance on tests with
different score ranges we transformed raw test scores into coefficients; to
summarize our results in terms of language versus visuo-spatial performance we
computed indices of prevalent impairment of performance (IPIP) by subtracting the
coefficients for constructional praxis from coefficients for language-related
tests. Finally, we converted these indices into z-scores for each level of mental
decline to identify patients with generalized, language (L) or visuo-spatial (V)
prevalent impairment. The latter, 30% of the sample, can be detected at all
stages of dementia. There was a higher percentage of males among language
impaired patients (P<0.05). Approximately half of patients with L/V prevalent
impairment continued to show such a focality when followed longitudinally. The
groups did not differ in the annual rate of cognitive decline.
PMID- 9559989
TI - Impairment of mitochondrial function in skeletal muscle of patients with
amyotrophic lateral sclerosis.
AB - In skeletal muscle homogenates of 14 patients with sporadic amyotrophic lateral
sclerosis, an approximately twofold lower specific activity of NADH:CoQ
oxidoreductase in comparison to an age matched control group (n=28) was detected.
This finding was confirmed by a detailed analysis of mitochondrial oxidative
phosphorylation in skeletal muscle using saponin-permeabilized muscle fibers. (i)
A significantly lowered maximal glutamate+malate and pyruvate+malate supported
respiration of saponin-permeabilized fibers was detected in the patients group.
(ii) Titrations with the specific inhibitor of NADH:CoQ oxidoreductase amytal
revealed a higher sensitivity of respiration to this inhibitor indicating an
elevated flux control coefficient of this enzyme. (iii) Applying functional
imaging of mitochondria using ratios of NAD(P)H and flavoprotein autofluorescence
images of saponin-permeabilized fibers we detected the presence of partially
respiratory chain inhibited mitochondria on the single fiber level. A secondary
defect of mitochondrial function due to the neurogenic changes in muscle seems to
be unlikely since no mitochondrial abnormalities were detectable in biopsies of
patients with spinal muscular atrophy. These results support the viewpoint that
an impairment of mitochondria may be of pathophysiological significance in the
etiology of amyotrophic lateral sclerosis.
PMID- 9559990
TI - Crossed cerebellar diaschisis and brain tumor biochemistry studied with positron
emission tomography, [18F]fluorodeoxyglucose and [11C]methionine.
AB - Cerebral gliomas may cause a reduction of glucose metabolism in the cerebellum
contralateral to the tumor side (crossed cerebellar diaschisis, CCD). We
investigated whether CCD is related to tumor localization, histological grade,
size and tumor biochemistry. Cerebellar glucose metabolism was measured in 44
glioma patients and 15 healthy subjects using positron emission tomography and
[18F]fluorodeoxyglucose (FDG). CCD was determined by calculating an asymmetry
index of cerebellar glucose metabolism. Further, the tumor uptake of FDG and
[11C]methionine (MET) was also assessed, and was expressed as ratio of normalized
tracer uptake in tumor over contralateral cortex (T/C). Frontal lobe tumors were
associated with highest CCD values. For these tumors, CCD was higher in malignant
(-11.8+/-9.9%) than in low-grade (-4.3+/-4.1%) gliomas (P=0.010). In addition,
frontal lobe tumors showed increasing CCD values with increasing size. In tumors
of the parietal or temporal lobe, CCD was less marked or absent. T/C ratios of
tumor tracer uptake were higher in malignant than in low-grade gliomas, but were
not correlated with CCD. Our data indicate that the magnitude of CCD is mainly
determined by tumor localization and size, the latter being associated with tumor
grade. These findings raise the question whether CCD provides a measure of
expansion or progression particularly in low-grade tumors of the frontal lobe.
PMID- 9559991
TI - Proton magnetic resonance spectroscopy during transient global amnesia.
AB - There is uncertainty about the etiology of transient global amnesia and none of
the pathogenetic hypotheses proposed so far, i.e. transient ischemia, epileptic
discharge and spreading depression of cortical electrical activity, is completely
satisfactory. Using water suppressed proton magnetic resonance spectroscopy we
studied one patient during a typical episode of transient global amnesia and 2
weeks thereafter in order to investigate the metabolic changes in the hippocampal
region. In both hippocampi, spectra of N-acetyl-aspartate, creatine
phosphocreatine, compounds containing choline and lactate failed to show changes
consistent with cerebral ischemia, both in the acute phase and in the follow-up.
Spreading depression in response to emotional stress seems a likely explanation
in this patient, who suffered from migraine in the past.
PMID- 9559992
TI - Auditory and visual event-related potentials and flash visual evoked potentials
in Alzheimer's disease: correlations with Mini-Mental State Examination and
Raven's Coloured Progressive Matrices.
AB - We investigated possible correlations among neurophysiological examinations
[auditory and visual event-related potentials (A-ERPs, V-ERPs), and flash visual
evoked potentials (F-VEPs)] and neuropsychological tests [Mini-Mental State
Examination (MMSE) and Raven's Coloured Progressive Matrices (RCPM)] in 15
subjects with probable or possible Alzheimer's disease (AD) according to the
National Institute of Neurological and Communicative Disorders and Stroke and the
Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria.
The P300 latency of A-ERPs was correlated with the scores of MMSE but not with
those of RCPM. The P300 latency of V-ERPs was more significantly correlated with
the scores of RCPM than with those of MMSE. The P2 latency of F-VEPs was more
significantly correlated with the scores of RCPM than with those of MMSE. The P2
latency of F-VEPs was not correlated with the P300 latency of A-ERPs but was
correlated with the P300 latency of V-ERPs. The close relationship among V-ERPs,
F-VEPs and RCPM suggests that these examinations at least partly reflect the
functions of visual association areas in AD. Furthermore, discrepancy between
P300 latency by A-ERPs and V-ERPs suggests that the mechanism responsible for
P300 generation is not identical between these two stimulus modalities.
PMID- 9559993
TI - SCA6 mutation analysis in a large cohort of the Japanese patients with late-onset
pure cerebellar ataxia.
AB - Spinocerebellar ataxia type 6 (SCA6) is caused by small CAG repeat expansion in
the gene encoding the alpha1A-voltage-dependent-calcium channel subunit
(CACNLIA4) on chromosome 19p13, and is a subgroup of the late-onset pure
cerebellar ataxia (ADCA III). To investigate the prevalence of SCA6 in the
Japanese, we analyzed this mutation in 23 families and 12 probands with ADCA III.
The specificity and stability of the CAG repeat were examined in additional
individuals and families with other miscellaneous dominant SCAs. The CAG
expansion of SCA6 gene was exclusively observed in 12 of 23 families (52%) and 12
proband cases with ADCA III, but not in others. The CAG repeat was 21-33 in the
disease-associated alleles (n=56), and 4-18 in normal alleles (n=1148). Expanded
alleles were stable during transmission, and a significant inverse correlation
for CAG repeat number with age at onset was noted. Our results indicate that SCA6
shares approximately half of the ADCA III in the Japanese, and that gene
mutations causing the remaining, have yet to be identified.
PMID- 9559994
TI - Transient tonic pupils in botulism type B.
AB - We report a 29-year-old woman who developed unilateral unreactive mydriasis and
cycloplegia after 5 days of persistent constipation. During the next hours the
patient complained of dry mouth and difficulties in swallowing food; iris and
ciliary muscle palsies spread over the second eye. Ocular motility was normal and
there were no clinical signs of neuromuscular involvement. Conventional
electromyography and evoked muscle action potentials following repetitive nerve
stimulation were normal; single-fiber electromyography showed normal jitter and
absence of blocking. The diagnosis of botulism was considered as most likely, and
the patient was given botulinum antitoxin. The post-treatment course was
characterized by bilateral tonic pupillary reaction to near, sectoral iris
contractions to light and pupillary constriction to 2 mm in 40 min following
topical instillation of 0.1% pilocarpine. Ocular manifestations completely
disappeared within 5 weeks. Botulism type B toxin was demonstrated in the
pretreatment stool of the patient but not the serum.
PMID- 9559995
TI - Guillain-Barre syndrome associated with IgG anti-GM1b antibody subsequent to
Mycoplasma pneumoniae infection.
AB - Sera from patients with Guillain-Barre syndrome (GBS) frequently have antibodies
to various gangliosides. We report a girl with GBS after Mycoplasma pneumoniae
infection who had serum IgG antibody to GM1b ganglioside as well as the cold
agglutinins. The cold agglutinins are polyclonal IgM autoantibodies to 'I'
antigen on erythrocytes. Ganglioside GM1b contains the terminal moiety shared
with sialylated I antigen, a main receptor for M. pneumoniae. In this patient,
the anti-GM1b antibody may be elicited in a similar mechanism producing anti-I
antibody, and functioned in the development of GBS.
PMID- 9559996
TI - Plasma levels of neuroexcitatory amino acids in patients with migraine or tension
headache.
AB - Plasma amino acids were analysed in patients with migraine with (9) and without
(80) aura, in patients with tension headache (14) and in controls (62). The
neuroexcitatory amino acids glutamic acid, glutamine, glycine, cysteic acid and
homocysteic acid were elevated in migraine patients while total thiols
(cysteine/cystine) were reduced. Patients with tension headache had values which
were similar to those of controls. Tryptophan was elevated in migraine patients
without aura only. Studies on two patients showed that the raised resting
excitatory amino acid levels became still further elevated during a migraine
attack. These results show that high concentrations of neurotransmitter amino
acids occur normally in migraine patients and suggest that this profile may be a
contributory factor in migraine attacks. Tension headache, however, has different
biochemical parameters.
PMID- 9559997
TI - Exacerbation of myasthenia gravis during the menstrual period.
AB - BACKGROUND: Myasthenia gravis (MG) is an autoimmune disorder mediated by
antiacetylcholine receptor antibodies. It has long been suspected to exacerbate
during the menstrual period but this has never been adequately documented.
SUBJECTS AND METHODS: We questioned 120 female myasthenic patients of different
ages, about their myasthenic symptoms before and during the menstrual period. We
also evaluated the effect of medications, pain and stress during or before the
menstrual period on the exacerbation rate. Exclusion criteria were postmenopausal
age and incomplete information available in the questionnaire. RESULTS: Forty two
premenopausal women with generalized disease were included in the study. Twenty
eight (67%) of the patients reported exacerbation of their myasthenic symptoms 2
to 3 days prior to the menstrual period. This exacerbation persisted in 22 of
them to the third day of the menstrual period. In nine of the women this clinical
worsening necessitated an increased intake of medications during the days prior
to menstruation. No correlation could be found between the presence of
antiacetylcholine receptor antibodies, pain, stress, use of oral contraceptives
or the type of antimyasthenic therapy and the rate of exacerbation before and
during the menstrual period. CONCLUSIONS: (1) MG frequently exacerbates before
and during the menstrual period in 67% of MG patients. (2) The rate of
exacerbation is unrelated to the presence of stress or pain prior to or during
the menstrual period. (3) Different therapies directed against MG, as well as
oral contraceptives do not influence the clinical course. (4) Menstrual
exacerbations occur in both seronegative and seropositive patients. (5) These
exacerbations may frequently necessitate therapeutic changes.
PMID- 9559998
TI - Multiple sclerosis presenting with a Brown-Sequard syndrome.
AB - The Brown-Sequard syndrome as spinal hemiplegia with contralateral sensory
deficits has been related to a variety of underlying diseases. We describe the
case of a 35-year-old right-handed white female presenting with a Brown-Sequard
syndrome as the first and sole symptom of multiple sclerosis, underscoring the
importance of multiple sclerosis as a rare condition for the Brown-Sequard
syndrome.
PMID- 9559999
TI - Multiple system atrophy with severe involvement of the motor cortical areas and
cerebral white matter.
AB - We report multiple system atrophy (MSA) of 14 years' duration in a 75-year-old
woman. Postmortem examination revealed pathological changes typical of MSA.
Furthermore, neuronal loss with astrocytosis in the primary motor and premotor
cortices, especially in the fifth and sixth layers, and extensive myelin and
axonal loss in the frontal and parietal white matter were evident. There were
numerous ubiquitin-positive oligodendroglial inclusions, which are characteristic
of MSA, in these cortical and white matter lesions. These findings suggest that
the motor cortical areas and cerebral white matter are sites of significant
involvement in the MSA disease process and that inclusion-bearing
oligodendroglial alterations contribute to the white matter degeneration.
PMID- 9560000
TI - Comparative conformational studies on cyclic hexapeptides corresponding to
message sequence His-Phe-Arg-Trp of alpha-melanotropin by NMR.
AB - Solution conformation of cyclo(Gly1-His2-Phe3-Arg4-Trp5-Gly6) and its D-Phe
analog corresponding to the message sequence [Gly-alpha-MSH5-10] of alpha-MSH has
been studied by 1D and 2D proton magnetic resonance spectroscopy in dimethyl
sulfoxide (DMSO)-d6 solution and in a DMSO-d6/H2O cryoprotective mixture. The NMR
data for both the analogs in solution at 300 K cannot be interpreted based on a
single ordered conformation, as evidenced by the broadening of only -NH
resonances as well as the temperature coefficients of the amide protons. An
analysis of the nuclear Overhauser effect (NOE) cross-peaks in conjunction with
temperature coefficient data indicates an equilibrium of multiple conformers with
a substantial population of particular conformational states at least in the D
analog. The molecular dynamics simulations without and with NOE constraints also
reveal numerous low-energy conformers with two gamma-turns, a gamma-turn and a
beta-turn, two beta-turns, etc. for both the analogs. The observed NMR spectra
can be rationalized by a dynamic equilibrium of conformers characterized by a
gamma-bend at Gly6, two gamma-bends at Phe3 and Gly6 and a conformer with a
single beta-turn and a gamma-bend for the L-Phe analog. On the other hand, a
conformation with two fused beta-turns around the two tetrads His2-D-Phe3-Arg4
Trp5 and Trp5-Gly6-Gly1-His2 dominates the equilibrium mixture for the D-Phe
analog. For the D-Phe analog, the experimentally observed average conformation is
corroborated by molecular dynamics simulations as well as by studies in
cryoprotective solvent.
PMID- 9560001
TI - Crystal and molecular structure of L-histidyl-L-serine trihydrate: occurrence of
C(alpha)-H...O=C hydrogen bond motif similar to the motif in collagen triple
helix and beta-sheets.
AB - L-Histidyl-L-serine (HSN) trihydrate, C9H14N4O4-H2O, crystallizes in the
orthorhombic space group P2(1)2(1)2(1) with a = 4.865(4), b = 15.604(4), c =
18.918(5) and Z = 4. The crystal structure was solved by direct methods and
refined to R1 = 0.070 by a full-matrix least-squares method. The peptide exists
in a zwitterionic form, with the N-terminus in a protonated form and the C
terminus in an ionized form. The imidazole ring of histidine in its neutral
His(epsilon) tautomeric state has conformational angles chi(1)2 of -53.5(7)
degrees and chi(21)1 of -55.4(8) degrees and the serine hydroxyl group has
chi(1)2 of 68.2(7) degrees. The conformational angles deviate significantly from
those of the dipeptide complexed with glycyl-L-glutamic acid in which the
histidine is protonated. A noteworthy feature of the crystal packing is the
occurrence of a C(alpha)-H O=C hydrogen bond motif similar to that observed in
collagen triple helix and beta-sheets.
PMID- 9560002
TI - The design, synthesis and activity of pentapeptide pp60c-src inhibitors
containing L-phosphotyrosine mimics.
AB - Efficient syntheses of 4-(R,S-hydroxyphosphonomethyl)-L-phenylalanine and 4
carboxy-L-phenylalanine within the context of the pentapeptide Ac-Ile-X-Gly-Glu
Phe-NH2 (wherein X = the unnatural amino acid) illustrate the use of a divergent
synthetic strategy from an advanced common peptide intermediate to more readily
access peptide-based tyrosine kinase inhibitors. The key intermediate, Ac-Ile
Phe(4-formyl)-Gly-Glu(O-tBu)-Phe-NH2, was synthesized by a facile palladium
catalyzed carbonylation of Ac-Ile-Phe(4-iodo)-Gly-Glu(O-tBu)-Phe-NH2. Oxidation
of Ac-Ile-Phe(4-formyl)-Gly-Glu(O-tBu)-Phe-NH2 with tetrabutylammonium
permanganate or addition of di-t-butylphosphite, both followed by trifluoroacetic
acid deprotection, gave the target pentapeptide inhibitors wherein X = 4-carboxy
L-phenylalanine or 4-(R,S-hydroxyphosphonomethyl)-L-phenylalanine, respectively.
These two peptides gave somewhat more potent inhibition of the tyrosine kinase
pp60c-src than the corresponding pentapeptide wherein X = L-phenylalanine,
demonstrating that appended functionalities at the 4-position are accepted and
can enhance binding through added interactions within the catalytic region of the
active site.
PMID- 9560003
TI - Peptides derived from human C-reactive protein inhibit the enzymatic activities
of human leukocyte elastase and cathepsin G: use of overlapping peptide sequences
to identify a unique inhibitor.
AB - Ten overlapping 15-mer peptides, spanning the entire inner disulfide loop of
human C-reactive protein (residues 36-97), were used to isolate a potent
inhibitor of the enzymes human leukocyte elastase and human leukocyte cathepsin
G, which are associated with chronic inflammatory tissue damage. In contrast to
the inability of intact C-reactive protein to inhibit both enzymes, the synthetic
peptide E62ILIFWSKDIGYSFT76 inhibited leukocyte elastase (Ki = 0.18 microM) and
cathepsin G (Ki = 0.25 microM) at concentrations far lower than the acute-phase
concentration of C-reactive protein. Several peptide-enzyme binding motifs were
elucidated by structure-function studies, with the Glu62 residue being crucial in
establishing long-range subsite interactions. Peptides derived from C-reactive
protein, which may be generated in vivo by neutrophil-mediated proteolysis as
part of a complex regulatory homeostatic mechanism, may play an important role in
regulating the activity of matrix-degrading enzymes, specifically at sites of
inflammation. The present results thus may shed additional insight on the
physiological functions of the major acute-phase reactant C-reactive protein, and
perhaps be used as a basis for the design of novel therapeutic substances.
PMID- 9560004
TI - Preparations of Boc-Cys(S-Pyr)-OH and Z-Cys(S-Pyr)-OH and their applications in
orthogonal coupling of unprotected peptide segments.
AB - Boc-Cys(S-Pyr)-OH and Z-Cys(S-Pyr)-OH were prepared by addition of their cysteine
derivatives to 3 equiv of 2,2'-dipyridyldisulfide in one portion. 2
Mercaptopyridine was removed by addition of 0.1 M Cu(NO3)2 to the solution. Both
derivatives are white solids and can be used to facilitate the formations of
heterodisulfide bonds. Two methods of synthesizing peptides with N-terminal Cys(S
Pyr) were also provided. Two peptide thiocarboxylic acids H-Tyr-Ser-Ala-Glu-Leu
Val-SH and H-Tyr-Ser-Ala-Glu-Leu-Gly-SH were prepared on the thioester benzhydryl
resin with the cleavage condition of 1.0 M TFMSA/TFA instead of HF. From the
orthogonal couplings of these peptides with H-Cys(S-Pyr)-Tyr-Ser-Glu-Leu-Ala-NH2,
both intramolecular acyl transfers finished at pH 7 at about 15 to 20 min. The
intermediate acyl disulfide peptide was collected by high-performance liquid
chromatography and identified by liquid chromatography-mass spectrometry.
PMID- 9560005
TI - Self-assembling bis-dendritic peptides: design, synthesis and characterization of
oxalyl-linked bis-glutamyl peptides [Glu(n)(CO2Me)n + 1-CO-]2; n = 1,3,7.
AB - Three generations of glutamic acid dendrons [Glu(n),(CO2Me)n + 1; n = 1, 3, 7]
have been joined together head-to-head by an oxalyl unit to form highly
sterically congested bis-Glu-dendritic peptides with gelling properties. The
single crystal X-ray structure of the first generation bis-dendritic peptide
showed an extended hydrogen-bonded chiral tape with modest nonlinear optical
activity.
PMID- 9560006
TI - Chemical ligation of unprotected peptides directly from a solid support.
AB - In this article we describe a new, convenient procedure to carry out
intramolecular (cyclization) and intermolecular native chemical ligations of
unprotected peptides directly from a solid support. Our solid-phase ligation
approach eliminates the need to manipulate peptide (alpha)thioacid and peptide
(alpha)thioester intermediates in aqueous solution before the ligation step,
thereby leading to a reduction in handling losses and significantly increasing
the overall efficiency of the chemical ligation strategy. A key step in our
ligation scheme is the ability to generate fully unprotected peptides tethered to
a solid support through an (alpha)thioester linkage. This can be achieved
efficiently using optimized Boc-solid-phase peptide synthesis on a 3
mercaptopropionamide-polyethylene glycol-poly-(N,N-dimethylacrylamide) copolymer
support (HS-PEGA). Once the synthesis is complete, the fully protected peptide
(alpha)thioester resin is treated with HF to give the corresponding fully
unprotected peptide (alpha)thioester resin. Using this procedure several
polypeptides ranging from 15 to 47 residues were synthesized successfully. These
peptide-resins were then used to perform both intramolecular (head-to-tail
cyclizations) and intermolecular solid-phase ligations. The intramolecular solid
phase ligations proceeded much faster than their intermolecular counterparts, but
in both cases the reactions were observed to be remarkably clean. The presence of
aromatic thiol cofactors significantly accelerated the relatively slow
intermolecular ligations. This novel methodology was then extended to provide a
general method for performing sequential intermolecular ligations, allowing easy
access to much larger polypeptide and protein systems.
PMID- 9560007
TI - Three-dimensional structure of the Y1 receptor agonist [Leu31, Pro34]NPY as
determined by NMR and molecular modeling.
AB - The solution structure of the Y1 receptor agonist, porcine [Leu31, Pro34]NPY, has
been investigated by two-dimensional NMR and molecular modeling. A complete
assignment of the NMR resonances was achieved and 201 inter-residue nuclear
Overhauser enhancement spectroscopy (NOESY) connectivities could be identified,
comprising several connectivities between the N- and C-terminal segments. A
molecular model was calculated by distance geometry, simulated annealing and
conjugate gradients energy minimization using the NOE constraints. The results
indicate that, like NPY and other peptides of the family, [Leu31, Pro34]NPY
adopts a folded hairpin structure with the terminal segments in close proximity.
Analysis of the secondary chemical shifts for the CH(alpha)'s and of the
temperature dependence of the NH chemical shifts combined with the NOE
constraints indicates a tendency toward helix structure for the segment 18-30 and
the presence of turn structure for the C-terminal segment (residues 31-36).
Native NPY and [Leu31, Pro34]NPY have most of their structures in common but
differ slightly in their C-terminal portion. Based on the structures of NPY and
of its specific agonists, [Leu31, Pro34]NPY and NPY 13-36, conclusions can be
drawn about the structural requirements for binding to the Y1 and Y2 receptor
subtypes.
PMID- 9560008
TI - Neurotrophins and neuronal versus glial differentiation in medulloblastomas and
other pediatric brain tumors.
AB - Medulloblastomas are highly malignant and poorly understood childhood neoplasms.
To determine if neurotrophins might influence the phenotypic properties of
medulloblastoma in a paracrine or autocrine manner, 51 pediatric brain tumors
including 20 biopsy specimens of these primitive neuroectodermal tumors (PNETs)
and 31 other pediatric brain tumors were studied. Immunohistochemistry was used
with antibodies to nerve growth factor (NGF), brain-derived neurotrophic factor
(BDNF), and NT-3, their cognate high affinity receptors as well as to neuronal
and glial markers. TrkA, TrkB, and TrkC were observed in 5 (25%), 8 (40%), and 17
(85%), respectively, of these medulloblastomas while NGF, BDNF, and NT-3 were
observed in 6 (30%), 8 (40%), and 3 (15%), respectively, and antibodies to
neurofilament (NF) and glial fibrillary acidic proteins (GFAP) stained 16 (80%)
and 11 (55%), respectively. TrkA and NGF were not observed in the same biopsy
samples, while TrkB and BDNF were co-distributed in 6 of the cases, all of which
expressed NF proteins. TrkC and NT-3 were co-distributed in 3 of the
medulloblastomas, and these areas overlapped with NF protein-positive tumor cells
in all 3 cases. In contrast to medulloblastomas, TrkA and NGF co-distributed in
other pediatric brain tumors, and both Trk receptors and their neurotrophins co
distributed with GFAP-positive tumor cells in 13 (42%) of the non-PNET pediatric
brain tumors. The absence of medulloblastomas that contain NGF and TrkA is
consistent with in vitro data demonstrating that NGF-mediated TrkA signaling
induces apoptosis. Finally, this study also suggests that BDNF and NT-3 may act
in a paracrine or autocrine manner through TrkB and TrkC receptors, respectively,
to induce neuronal differentiation in medulloblastomas.
PMID- 9560009
TI - Autosomal dominant cerebellar ataxia (SCA6): clinical, genetic and
neuropathological study in a family.
AB - We describe a family with dominantly inherited ataxia of late adult onset.
Expansion of a CAG repeat in the gene encoding the alpha1A voltage-dependent
calcium channel was identified at autopsy in one patient, a 65-year-old woman
with a disease duration of 11 years. In this patient, pathological changes were
confined to the cerebellar cortex and inferior olivary complex. The cerebellar
cortex showed severe loss of Purkinje cells with proliferation of Bergmann's
glia, being more pronounced in the superior parts of the vermis and hemispheres.
In the inferior olivary complex, a reduced neuronal cell population, which could
be interpreted as a change secondary to the cerebellar cortical lesion, was
evident. We conclude that the pathological phenotype of this newly classified
autosomal dominant cerebellar ataxia, SCA6, is cerebello-olivary atrophy, or more
strictly cerebellar cortical atrophy.
PMID- 9560010
TI - Inducible nitric oxide synthase (iNOS)-like immunoreactivity in argyrophilic, tau
positive astrocytes in progressive supranuclear palsy.
AB - The immunoreactivity to the free radical-related enzymes, nitric oxide synthase
(NOS) and superoxide dismutase (SOD), was examined in brain tissue in progressive
supranuclear palsy (PSP). To determine the relationship between the
immunoexpression of these enzymes and tau-positive, argyrophilic cytoplasmic
inclusions, which are constantly present in PSP brains, double-label
immunohistochemistry was applied. We demonstrated for the first time that strong
inducible NOS-like immunoreactivity (iNOS-ir) was detected in tau-positive
astrocytes that bore tufts of abnormal fibers (TAF), but not in oligodendrocytes
containing argyrophilic/tau-positive coiled bodies nor in microglia. No brain NOS
ir was detected in neurons with neurofibrillary tangles. MnSOD-ir was also
detected in tau-positive astrocytes and oligodendrocytes. Nitrotyrosine-ir of
variable intensity was observed in astrocytes, oligodendrocytes and neurons. Our
results indicate: (1) that TAF-bearing astrocytes may be a major source of
excessive NO in PSP brains; (2) that after the induction of iNOS by unknown
stimulating factors, TAF-bearing astrocytes produce an excessive amount of NO
that exceeds the detoxification capability of SOD; and (3) that peroxynitrite and
excessive NO, both cytotoxic, may be present in astrocytes, oligodendrocytes and
neurons. Although the precise relationship between NO production and neuronal
cell death in PSP remained uncertain, based on the specificity of TAF for PSP
brains, our results indicated a possible mechanism of NO-mediated cytotoxicity
that may contribute to the neuronal and glial cell damage followed by abnormal
tau accumulation in this disease.
PMID- 9560011
TI - Immunohistochemical examination of c-Met protein expression in astrocytic tumors.
AB - Hepatocyte growth factor/scatter factor (HGF/SF), which has various physiological
functions, and its receptor c-Met, the human c-met proto-oncogene product, are
thought to be determinant in the pathological processes of various malignancies.
To investigate the possible role of HGF/SF in the progression of development of
astrocytic tumors, we examined the expression of c-Met in these tumors.
Immunohistochemistry using the streptavidin-biotin peroxidase complex method and
immunofluorescence double staining with anti-c-Met polyclonal and anti-glial
fibrillary acidic protein monoclonal antibodies were performed. Positive c-Met
expression was detected in 31 of the 42 astrocytic tumors and some of the control
cases analyzed. c-Met-positive cells showed morphological characteristics of
astrocytes. Especially in the cases of high-grade tumors, c-Met positivity was
abundant in cells in both vascular-rich and peripheral regions of the tumors but
not in the cells with distinctly malignant features. Immunofluorescence double
staining revealed that the c-Met-positive cells were in part of astrocytic
origin. We suggest that c-Met-positive cells are affected by some factors in the
lesions where the pathological processes are in a state of development. Our
studies indicated that c-Met expression might take part in glioma invasion but
not in the development of malignancy.
PMID- 9560012
TI - Structural changes in male trapezius muscle with work-related myalgia.
AB - Muscular changes in male forest machine operators with work-related neck and
shoulder myalgia were studied. Enzyme cyto- and immunohistochemical analysis was
carried on muscle biopsies obtained from ten myalgic subjects (M), nine non
myalgic selected in the same work place (NM) and six healthy young men (C). The M
group displayed a significant increase in type IIA fibres in comparison to the C
group. This hypertrophy was accompanied by a parallel increase in the capillary
bed. Both the M and NM groups exhibited an increase in fibres with a disorganised
mitochondrial pattern. Interestingly, fibres lacking cytochrome c oxidase
occurred in the M group (0.9%) but also in the NM group (0.5%), suggesting a
mitochondrial defect. Central nuclei (5.2%) and developmental myosin (3%) were
also more frequent in the M group. These changes are probably related to injury
regeneration cycles. These data support the association between the work
conditions and muscle changes in work-related trapezius myalgia.
PMID- 9560013
TI - Tick-borne encephalitis in dogs: neuropathological findings and distribution of
antigen.
AB - Eight dogs originating from different regions of Austria [all of them known as
tick-borne encephalitis (TBE) areas] with severe neurological signs were either
euthanatized or died spontaneously. Tick-borne encephalitis virus (TBEV) antigen
was detected in the brains of five of these dogs by immunohistology, but not in
the others. All of the dogs, however, had identical neuropathological changes.
There were moderate lymphohistiocytic meningitis, widespread neuronal necroses,
karyorrhexis of glial cells, numerous neuronophagic nodules, and extensive
microgliosis. In the cerebellum, loss of Purkinje cells and proliferation of
microglial cells in the molecular layer were found. All brain regions showed
numerous perivascular cuffs consisting of lymphocytes, macrophages, plasma cells
and, occasionally, red blood cells. The blood-derived cells were not restricted
to the perivascular spaces but diffusely infiltrated the neuropil. The most
severe changes were localized in the neuroparenchyma surrounding the fourth
ventricle. Lesions were less severe in basal ganglia, thalamus, mesencephalon,
nuclei of pons and medulla oblongata. Moderate lesions were found in the gray
matter of neocortex and allocortex, hippocampus and molecular and Purkinje cell
layers of the cerebellum. White matter was slightly to moderately affected. The
choroid plexus was free of inflammation. Due to rapid virus clearance mechanisms
in this disease, antigen was not detectable in all cases. Neuropathological
changes identical with those of immunohistologically proven cases justified the
diagnosis TBE in these cases. In addition, the neuropathological diagnosis was
supported by the origin of the affected dogs from endemic areas, the seasonal
occurrence of the disease and a clinical history of a highly febrile neurological
disease with short duration.
PMID- 9560014
TI - Characterizations of heterotopic neurons in the spinal cord of amyotrophic
lateral sclerosis patients.
AB - This report concerns a comparative immunocytochemical, ultrastructural and
morphometric investigation on heterotopic neurons in the white matter of the
spinal cords of 19 patients with amyotrophic lateral sclerosis (ALS) and 18 age
matched neurologically normal individuals. The study revealed that the
heterotopic neurons were scattered in the white matter, often adjacent to gray
matter, that they immunoreacted with the antibody to synaptophysin, and that
there were synaptic apparatuses on the surface of their somata and their neuronal
processes. Bunina bodies and ubiquitin-positive inclusions such as Lewy body-like
inclusions and skein-like inclusions, characteristic of anterior horn neurons of
ALS, were present in the cytoplasm of the patients' heterotopic neurons in the
anterior or lateral column of the white matter. These findings suggest that
heterotopic neurons in the anterior or lateral column have the characteristics of
alpha motor neurons. The average number of heterotopic neurons observed in ALS
patients was generally less than in normal subjects. This reduction was
correlated with the severity of neuronal loss. The heterotopic neurons in ALS
were less susceptible to the degenerative process as compared with spinal cord
anterior horn cells. We assume that in this disease the heterotopic neurons may
be degenerated and their number diminished after or concomitantly with the
depletion of anterior horn neurons.
PMID- 9560015
TI - Identification of macrophage populations expressing tumor necrosis factor-alpha
mRNA in acute multiple sclerosis.
AB - Macrophages are involved in central nervous system (CNS) demyelination in
multiple sclerosis (MS) and other demyelinating diseases. Macrophages seen in MS
lesions form a heterogeneous population with respect to their stage of activation
and differentiation. We have analyzed macrophages from active demyelinating
lesions of a patient who died from fulminant MS of Marburg's type to define the
functional heterogeneity of different macrophage populations in acute
demyelination. We examined tumor necrosis factor-alpha (TNF-alpha) mRNA
expression in macrophages defined by different activation markers. The majority
of TNF-alpha mRNA-positive cells were macrophages positive for the pan-macrophage
marker KiM1P. A subgroup of TNF-alpha mRNA-positive macrophages was stained by
the early activation marker MRP14. In contrast, macrophages positive for the
acute activation marker 27E10 were entirely negative for TNF-alpha mRNA. In
conclusion, macrophages in acute demyelinating CNS lesions are heterogeneous as
shown by staining for different activation markers. This heterogeneity is also of
functional relevance as certain subpopulations are involved in TNF-alpha mRNA
expression, while others are not. This may be important for directing therapeutic
strategies against well-defined pathogenic macrophage populations.
PMID- 9560016
TI - Distribution of B-50(GAP-43) mRNA and protein in the normal adult human spinal
cord.
AB - B-50(GAP-43) is a phosphoprotein mainly found in the nervous system which plays a
major role in neurite growth during development and regeneration as well as in
synaptic remodelling. In the mature intact central nervous system, intense B-50
immunoreactivity (B-50-IR) can still be detected in regions which maintain
residual capacity for structural re-organization. B-50 expression has been
studied extensively in laboratory animals; however, its distribution and
regulation in the human spinal cord is largely unknown. As a first step to
analyze lesion-induced structural alterations, we investigated the distribution
of B-50 protein and mRNA in the normal adult human spinal cord and dorsal root
ganglia. Intense B-50-IR was localized to the superficial laminae of the dorsal
horn at all segmental levels, the intermediolateral nucleus at thoracic levels
and Onuf's nucleus at sacral levels. Scattered neurons, particularly in the
ventral horn of lumbar and sacral segmental levels (and occasionally also in
Clarke's nucleus) displayed intense B-50-IR in close apposition to the perikaryal
and proximal dendritic surfaces. Nonradioactive in situ hybridization indicated
that B-50 mRNA could also be detected in neurons of the ventral horn and also in
the intermediolateral nucleus. The distribution of B-50 mRNA and protein in the
normal human spinal cord shows a marked similarity to that reported in
experimental animals, including the selective labelling of Onuf's nucleus.
However, the strong B-50-IR on the surface of some large anterior horn motor
neurons has not been observed in other mammals. This finding might reflect a
particular state of readiness for synaptic plasticity.
PMID- 9560017
TI - Possible neuroprotective role of clusterin in Alzheimer's disease: a quantitative
immunocytochemical study.
AB - Clusterin is a secreted glycoprotein that is expressed in response to tissue
injury both in peripheral organs and in the brain. Recent studies have shown a
substantial increase in clusterin mRNA in pyramidal neurons of the hippocampus
and the entorhinal cortex in Alzheimer's disease (AD), with clusterin
immunoreactivity occurring in neuropil threads, neurofibrillary tangles (NFT),
and senile plaques. To elucidate further the role of this protein in the
degenerative process, a quantitative study of its distribution in the cerebral
cortex of non-demented and AD patients, all older than 85 years of age, was
performed using immunocytochemistry. Using a stereological approach, we found
that in cortical areas affected in AD, such as the entorhinal, inferior temporal
and superior frontal cortices, the percentage of NFT-free neurons displaying
clusterin immunoreactivity was significantly higher than that in non-demented
cases. No such increase in the density of clusterin-immunoreactive neurons was
seen in cortical areas that were less affected in the disease process.
Furthermore, clusterin immunoreactivity was rarely observed in NFT-containing
neurons. In conjunction with previous observations in peripheral tissues, these
data suggest that clusterin may have a neuroprotective role, and that in AD, low
cellular expression of this protein may be associated with neuronal degeneration
and death.
PMID- 9560018
TI - Cytoarchitectonic alterations in the supramarginal gyrus of late onset
Alzheimer's disease.
AB - The intellectual status of 28 women of over 75 years of age had been
prospectively assessed by the Blessed test score. It ranged from nearly normal to
deeply altered by dementia. After autopsy, the supramarginal gyrus was marked at
the surface of the brain. Sections, 1 cm thick, were cut with a specially devised
macrotome. The volume of the parietal lobe was measured by a point counting
method, using Cavalieri principle. A sample from the supramarginal gyrus was
taken from the previously marked area and the shrinkage due to the histological
procedures was measured (it averaged 12%). More than 500 nucleolated neuronal
profiles per case were mapped with a semi-automatic system. Density maps of the
neuronal profiles were drawn and mean density was calculated using Dirichlet
tessellation. The thickness of the cortical ribbon was standardized on the maps.
The density of the neurons per unit volume was calculated, taking into account
the section thickness measured for each sample with a length gauge fastened to
the Z axis of the microscope. Statistical correlations were sought between the
mean and laminar densities of the neurons on one hand, and Blessed test score,
the densities of neurofibrillary tangles (NFT) and of senile plaques profiles, on
the other hand. Finally, the total number of neurons present in the parietal lobe
was estimated in each case. Neuronal loss appeared to be linked with the density
of the NFT (r = -0.52; P < 0.004). The correlation was mainly due to a severe
drop in neuronal number observed in the cases with more than 5 NFT/mm2. An
average difference of 98 x 10(6) neurons per parietal lobe was found between the
cases with less than 5 NFT/mm2 and those with more. The neuronal loss
predominated in layers II and III (upper part). A multivariate analysis showed
that the intellectual status was better correlated with the density of the
tangles than with the neuronal loss.
PMID- 9560020
TI - Laminar spongiosis of the dentate gyrus: a sign of disconnection, present in
cases of severe Alzheimer's disease.
AB - An extensive laminar spongiosis was found in the outer part of the dentate gyrus
in an 84-year-old patient. An old cavitary infarct in the parahippocampal gyrus
disconnected the dentate gyrus from the entorhinal area. This finding prompted us
to seek laminar spongiosis in Alzheimer's disease, where the neuronal loss in the
entorhinal cortex might be severe. The dentate gyrus was systematically examined
in a series of prospectively assessed cases either intellectually normal or
affected by mental impairment of graded severity. Laminar spongiosis was present
in the most severely affected patients. The neuritic crown of the senile plaques
seen in the laminar band of spongiosis contained only a few tau- and Bodian
positive fibers, a sign that was taken as evidence of "plaque denervation". By
contrast, deposits of Abeta peptide remained abundant but lacked a dense core.
These data suggest that dendritic and axonal processes are intermingled in the
senile plaque and that the amyloid core is at least partially dependent on the
presence of the axonal component.
PMID- 9560019
TI - Bcl-2 and Bax protein expression in Alzheimer's disease.
AB - Beta-amyloid deposition and neurofibrillary degeneration are important
pathological findings in the brains of patients with Alzheimer's disease (AD). In
the present study, we have examined Bcl-2 and Bax immunoreactivity in the
hippocampus of AD cases, with special attention to the possible relationship
between Bcl-2 and Bax immunoreactivity, and neurofibrillary degeneration and
senile plaques. Different antibodies were used, including Bcl-2 (N-19), Bcl-2
(BioGenex), Bax (P-19) and Bax (N-20), and their specificity was tested on
Western blots of brain homogenates. No differences between Bcl-2 and Bax
immunoreactivity in tangle-bearing and non-tangle-bearing neurons were observed,
thus suggesting that Bcl-2 and Bax do not participate in tangle formation.
Overexpression of Bcl-2 protein in reactive glial cells surrounding senile
plaques suggests that Bcl-2 may play a role in the survival of reactive glia. On
the other hand, overexpression of Bax immunoreactivity in dystrophic neurites of
senile plaques suggests that Bax is associated with neurite degeneration in
senile plaques. Finally, Bax (P-19), but not Bax (N-20), immunoreactivity was
localized in amyloid fibrils of senile plaques. Since Western blots to Bax (P-19)
recognize multiple bands in addition to the expected band of about 21 kDa, it is
suggested that Bax (P-19) immunoreactivity of amyloid fibrils is not specific.
PMID- 9560021
TI - Lipidized (foamy) tumor cells in a spinal cord ependymoma with collagenous
metaplasia.
AB - We report a 49-year-old woman with a spinal cord ependymoma located in the
thoracolumbar region. At surgery, a soft dark-grayish tumor, which contained a
hard whitish area, was removed. The specimen was a moderately cellular tumor with
a central core made up of collagen nodules poor in cellular elements. Many of the
tumor cells possessed ground glass-like eosinophilic cytoplasm, and frequently
foamy tumor cells were evident. Perivascular pseudorosettes, ependymal rosettes
and canals were present, the latter being rare. Many tumor cells, including those
with foamy cytoplasm, were positive for glial fibrillary acidic protein. Similar
tumor cells were also seen among, and even within, the collagen nodules. The MIB
1 labeling index was 0.66%. Ultrastructurally, the frequent lipidized tumor cells
were ependymal in nature; cytoplasmic 10-nm-wide filaments, and intracytoplasmic
lumina and intercellular microrosettes lined by microvilli were evident. Cilia
were very rare. We considered the present case to be an unusual, lipidized
variant of ependymoma. The collagen nodules appeared to be produced by the tumor
cells themselves.
PMID- 9560022
TI - Sporadic motor neuron disease with severe sensory neuronopathy.
AB - We report a 62-year-old man with sporadic motor neuron disease (MND) of 52
months' duration with progressive sensory disturbance and high cerebrospinal
fluid protein content. Neuropathologically, both the upper and lower motor neuron
systems were severely affected, and light and electron microscopy revealed Bunina
bodies and skein-like inclusions, which are characteristic of amyotrophic lateral
sclerosis, in the remaining anterior horn cells. Moreover, there was severe
degeneration without inflammatory infiltrates in the spinal posterior columns,
spinal ganglia, and peripheral sensory nerves. These findings suggest that this
case may be an unusual variant of sporadic MND with severe somatic sensory system
involvement.
PMID- 9560023
TI - Megalencephaly, hydrocephalus and cortical dysplasia in severe dwarfism mimicking
leprechaunism.
AB - This report concerns an autopsy case of megalencephaly exhibiting a unique
combination of physical and brain malformations. A 4-year-old boy had a peculiar
face, a severe reduction of subcutaneous adipose tissue, severe growth failure
and frequent hypoglycemic episodes. These clinical features were compatible with
leprechaunism; however, the absence of hyperinsulinemia and insulin resistance
prevented the diagnosis of leprechaunism. The autopsy disclosed complex cardiac
and brain malformations. Although hydrocephalus coexisted, the brain weight after
complete removal of the cerebrospinal fluid was 2260 g, which was greater than
the average brain weight of normal Japanese children of the same age. The
neuronal density in the cerebral cortex was decreased, while the surface area of
the cerebral cortex and white matter were greater than those in an age-matched
control. There was cortical dysplasia in the frontal and parietal lobes.
Endocrine tests and immunohistochemical analysis of the brain did not demonstrate
any abnormalities in the hypothalamus-pituitary system. Megalencephaly can be
associated with dwarfism, and this case is important for consideration of the
interrelationship between neuronal proliferation and physical growth.
PMID- 9560024
TI - Sarcoid neuromyopathy with selective involvement of the intramuscular nerves.
AB - A 35-year-old man affected with pulmonary sarcoidosis had a 12-year history of
fatigue and pain in the limbs, with normal neurological examination, except for
diffusely absent deep tendon reflexes. Muscle biopsy samples showed multiple
noncaseating granulomas, most prominent around the intramuscular nerves, with
predominance of CD4+ cells. Intramuscular nerve bundles surrounded by granulomas
were immunolabelled with laminin alpha1, alpha2, beta1 and gamma1 chain, and
collagen IV. Sural nerve biopsy samples were normal. This patient showed a unique
histopathological pattern of sarcoid neuromyopathy characterized by distribution
of granulomas or infiltrating cells around intramuscular nerve fibers. The
clinical picture, restricted to nonspecific symptoms of fatigue and myalgia, and
loss of deep tendon reflexes, correlated well with the selective localization of
sarcoid lesions in contiguity with the intramuscular nerves. To our knowledge,
this peculiar clinico-pathological correlation has not been reported previously.
PMID- 9560025
TI - Quality of general movements in preterm infants with transient periventricular
echodensities: a commentary.
PMID- 9560026
TI - Adrenomedullin: its role in perinatal adaptation.
PMID- 9560027
TI - Risk factors for impaired length growth in early life viewed in terms of the
infancy-childhood-puberty (ICP) growth model.
AB - A difference in length or height growth is observed between populations in
developing and developed countries and, within a country, between well-off and
poor subpopulations. The aim of this community-based study was to identify
possible risk factors for growth stunting in early life using the infancy
childhood-puberty (ICP) growth model. A periurban slum, a village and an urban
slum, plus a local control group in Lahore, Pakistan, were investigated. In
total, there were 425 infants born from September 1984 to March 1987 in the
study. Children were followed from birth to 24 months and anthropometric data
were recorded at each examination. A well-designed questionnaire was used to
collect background information to identify risk factors for growth faltering over
this period. The age at onset of the childhood component was determined
individually using the ICP growth model. A late onset was defined as onset after
12 months. Univariate odds ratio analysis identified 20 significant risk factors
for a delayed childhood onset in the total sample. Backward logistical analysis
showed that only six variables were significant, i.e. small number of rooms in a
household, episode(s) of diarrhoeal diseases, poor house structure, low body mass
index, early end of breastfeeding and birth in warm season. Stratified analysis
showed that episode(s) of diarrhoeal diseases and birth in warm season were the
only significant risk factors in the two poor areas. This study also found that
the impact of diarrhoeal diseases on length growth persisted after allowing for
birth season. Seasonal variation in length growth was seen in the age at onset of
the childhood component. General socioeconomic status was found to be a risk
factor for growth faltering in early life. Diarrhoeal diseases and being born in
a warm season are particular risk factors for growth faltering in early life.
PMID- 9560028
TI - Measured and predicted bone mineral content in healthy boys and girls aged 6-18
years: adjustment for body size and puberty.
AB - Dual-energy X-ray absorptiometry (DEXA) is a rapid and precise technique for the
assessment of bone mineralization in children. Interpretation of the results in
growing children is complex as results are influenced by age, body size (height
and weight) and puberty. Conventionally, bone mineral data derived from DEXA have
been presented as an areal density [BMD; bone mineral content (BMC, g)/projected
bone area (BA, cm2)], yet this fails to account for changes in BMC that result
from changes in age, body size or pubertal development. Measurement of BMC and BA
of the whole body, lumbar spine and left hip were made in 58 healthy boys and
girls using DEXA. The relationship between BMC and BA was curvilinear, with the
best fit being that of a power model (BMD = BMC/BAlambda, where lambda is the
exponent to which BA is raised in order to remove its influence on BMC). The
value of lambda changed when measures of body size and puberty were taken into
account (e.g. for lumbar spine from 1.66 to 1.49). Predictive formulae for BMC
were produced using regression analysis and based on the variables of age, body
size and pubertal development. This provides a method for interpreting the
measured BMC which is independent of such variables and a constant reference
range for children aged 6-18 y.
PMID- 9560029
TI - Early childhood feeding practices in southern Italy: is the Mediterranean diet
becoming obsolete? Study of 450 children aged 6-32 months in Campania, Italy.
Cultural Paediatric Association.
AB - With increasing affluence, the traditional food choices of Mediterranean
populations are changing. The changes appear to begin in early infancy, with
increased consumption of processed foods. To determine current consumption
patterns of the diets of 450 toddlers, 6-32 months old, enrolled from 17
paediatric practices in the Campania region of Italy, quantitative data were
collected for 7 d, using calibrated feeding bottles, cups and dishes. Automated
food analysis was employed and quality control was performed on a sub-sample. The
average daily intake was 373 kJ/kg. Forty-three percent of energy was provided by
carbohydrates, while fats supplied 39%, 45% of fats were saturated and 46.7% were
monosaturated (primarily olive oil). Proteins provided 18% of daily energy; most
(81.4%) were of animal origin. Fibre was virtually absent from the study
children's diet. Total daily cholesterol reached an average value of 191 mg/d,
corresponding to 201 mg/4.2 mJ. The intake per kg of cholesterol increased with
age in the first year, while proteins and fats decreased. Dairy products were the
main source of energy, fats and cholesterol. Vegetables and legumes were a minor
source of energy at all ages: the consumption of fruit decreased with age.
Although the overall pattern of feeding of this cohort remains favourable
compared with other children groups in developed countries, consumption of whole
milk and full fat dairy products may be reduced to equilibrate the diet.
PMID- 9560030
TI - Growth hormone treatment of short children born small-for-gestational-age: the
Nordic Multicentre Trial.
AB - The aims of this study were to evaluate the efficacy and safety of different
doses of growth hormone (GH) treatment in prepubertal short children born small
for-gestational-age (SGA). Forty-eight children born SGA from Sweden, Finland,
Denmark and Norway were randomly allocated to three groups: a control group of 12
children received no treatment for 2 y, one group was treated with GH at 0.1
IU/kg/d (n=16), and one group was treated with GH at 0.2 IU/kg/d (n=20). In total
42 children completed 2 y of follow-up, and 24 children from the treated groups
completed 3 y of treatment. Their mean (SD) age at the start of the study was
4.69 (1.61) y and their mean (SD) height was -3.16 (0.70) standard deviation
scores (SDS). The children remained prepubertal during the course of the study.
No catch-up growth was observed in the untreated group, but a clear dose
dependent growth response was found in the treated children. After the third year
of treatment, the group receiving the higher dose of GH, achieved their target
height. The major determinants of the growth response were the dose of GH used,
the age at the start of treatment (the younger the child, the better the growth
response) and the family-corrected individual height deficit (the higher the
deficit, the better the growth response). Concentration of insulin-like growth
factor-I (IGF-I) and IGF-binding protein-3 increased during treatment. An
increase in insulin levels was found without negative effects on fasting glucose
levels or glycosylated haemoglobin levels. GH treatment was well tolerated. In
conclusion, short prepubertal children born SGA show a dose-dependent growth
response to GH therapy, and their target height SDS can be achieved within 3 y of
treatment given GH at 0.2 IU/kg/d. However, the long-term benefit of different
regimens of GH treatment in children born SGA remains to be established.
PMID- 9560032
TI - Chronic non-specific diarrhoea in childhood: how often is it iatrogenic?
AB - Epidemiological data, the appropriateness of the medical approach, the
effectiveness of unrestricted diet and the subsequent course of chronic non
specific diarrhoea (CNSD) were evaluated in 20 children, mean age at diagnosis
4.7 y, and mean duration of diarrhoea 24 months. A mean of 2.4 previous hospital
admissions and a mean of 2.5 diagnoses other than CNSD were recorded per child
before admission. On admission, 14/20 were following an elimination diet and 8/20
had an inadequate caloric intake; 16/20 had a weight/height ratio below the 50th
percentile. In all cases a normal diet prescribed during hospitalization improved
the diarrhoea and increased weight. A telephone interview performed 5.6 y after
discharge revealed that in 10/20 of the cases, the parents were disappointed with
the unrestricted diet prescribed during hospitalization. Nevertheless they
reported that CNSD stopped spontaneously in a mean time of 1.7 y.
PMID- 9560031
TI - Rotaviral antibodies in the treatment of acute rotaviral gastroenteritis.
AB - The efficacy of hyperimmune bovine colostrum received from cows immunized with
simian rotavirus SA11 in the treatment of rotavirus gastroenteritis was compared
in a randomized double-blind trial to colostrum and ordinary milk preparations.
One hundred and thirty-five children aged 6-30 months with rotaviral
gastroenteritis received either hyperimmune bovine colostrum (n=42), ordinary
colostrum (n=42) or milk (n=41) as a 100 ml solution four times/d for 4 d. Even
though the differences were in favour of hyperimmune bovine colostrum in all the
variables evaluated [greater weight gain (403 vs 343 g), shorter duration of
diarrhoea (3.1 vs 3.6 d), fewer stools during 6 d (11.5 vs 13.6) and fewer stools
during the first 3 d (9.3 vs 11.3)], all the differences were statistically
insignificant. Differences of this size are clinically unimportant in well
nourished immunocompetent children, but we suggest that the hyperimmune bovine
colostrum tested in our trial had some effects in the treatment of acute
rotaviral gastroenteritis and should be evaluated further.
PMID- 9560033
TI - Precipitants and aetiology of cyclic vomiting syndrome.
AB - Thirty-two patients aged 2-22 y with cyclic vomiting syndrome (CVS), and 64 age-
and gender-matched controls were assessed to determine the nature, severity,
precipitants and associated features of attacks and the incidence of potential
aetiological factors. The mean age of onset was 3.5 y. Patients experienced a
mean of nine attacks per year, of average duration 2.4 d, and two-thirds missed
more than 10 d of school per year. Patients were more likely to have migraine and
co-ordination difficulties, a past history of forceps delivery and
gastroesophageal reflux than controls. Compared with controls, subjects had a
higher incidence of psychological symptoms (38% compared with 19%) and migraine
(37% compared with 9%). CVS is a chronic, disabling condition and is a migraine
variant, with attacks usually precipitated by stress and intercurrent infections.
PMID- 9560034
TI - Essential fatty acid metabolism in infants with cholestasis.
AB - Long-chain polyunsaturated fatty acids are important for the growth and early
development of the central nervous system. Cholestatic infants suffer from fat
malabsorption and disturbed lipid metabolism and therefore may be at risk of
developing polyunsaturated fatty acid depletion. The aims of this study were to
determine essential fatty acid status in cholestatic infants and to study the
relationship to disease severity, degree of undernutrition, antioxidant status
and mode of feeding. Twenty-four-hour dietary records were obtained in 34
cholestatic infants, and measurements were taken of skin fold thicknesses,
bilirubin levels, activities of serum alanine aminotransferase, alkaline
phosphatase, gamma-glutamyl transpeptidase, prothrombin time, serum
concentrations of albumin, bile acids, total lipids, phospholipids, cholesterol,
vitamins A and E, the fatty acid composition of plasma phospholipids and plasma
lipid peroxides expressed as thiobarbiturate reactive substance (TBARS). Plasma
phospholipid fatty acids and TBARS were also determined in 12 age-matched healthy
control infants. The cholestatic patients had very low percentage values of
phospholipid essential fatty acids, particularly linoleic acid ( 18:2omega-6,
median 14.74% vs 20.76% in controls, p < 0.001) and its major metabolite
arachidonic acid (20:4omega-6, 6.80 vs 7.87%, p=0.04). The patients' essential
fatty acid depletion was reflected by increased levels of the non-essential fatty
acids, Mead acid (20:3omega-9, 0.74 vs 0.21%, p < 0.001) and palmitoleic acid
(16:1omega-7, 2.20 vs 0.43%, p < 0.001). Polyunsaturated fatty acid profiles did
not differ between infants with biliary atresia (n=13) and those with
intrahepatic cholestasis (n=21), or between 17 infants with severe malnutrition
(all skin folds < 10th percentile) and mild malnutrition (at least two skin folds
> 10th percentile). TBARS were significantly higher in cholestatic patients than
in controls (2.74 vs 0.85 nmol ml(-1), p < 0.001) and correlated with direct
(r=0.41, p=0.02) and total bilirubin. The daily dietary intake of linoleic acid
(per 100 kcal) correlated with plasma phospholipid linoleic acid (r=0.38,p=0.037)
and total omega-6 fatty acids (r=0.38,p=0.036). Breastfed cholestatic infants
(n=6) had higher values of the omega-3 long-chain polyunsaturated fatty acids
docosapentanoic acid (22:5omega-3, 0.47 vs 0.28%, p=0.0006) and docosahexanoic
acid (22:6omega-3, 2.39 vs 1.73%, p=0.01) than formula-fed infants, while disease
severity was similar in the two groups. In conclusion, cholestatic infants are at
high risk of essential fatty acid depletion, which appears to be related to fat
malabsorption, hepatic essential fatty metabolism, enhanced lipid peroxidation
and dietary intake.
PMID- 9560035
TI - Sociodemographic risk factors for sudden infant death syndrome: associations with
other risk factors. The Nordic Epidemiological SIDS Study.
AB - The aim of this study was to investigate associations between sudden infant death
syndrome (SIDS) and social factors in the Nordic countries. A case-control study
was conducted in Denmark, Norway and Sweden: The Nordic Epidemiological SIDS
Study. Parents of 244 SIDS infants and 869 control infants matched on gender, age
at death and place of birth filled in questionnaires. The dataset was analysed by
conditional logistic regression. In univariate analysis, the following
sociodemographic factors were associated with an increased risk of SIDS: low
maternal age [odds ratio (OR) 7.8; 2.8-21.5], high birth order (OR 4.4; 2.5-7.5),
single motherhood (OR 2.9; 1.7-5.0), low maternal education (OR 4.5; 2.8-7.1),
low paternal education (OR 3.0; 1.9-4.7), maternal unemployment (OR 2.4; 1.8-3.4)
and paternal unemployment (OR 4.0; 2.7-5.9). In a multivariate analysis where
maternal smoking was also included, only paternal unemployment, young maternal
age and high birth order remained significantly associated with SIDS. Housing
conditions were not associated with SIDS. However, the risk of SIDS was high if
the family had lived in their present home for only a few years (OR 2.3; 1.3
4.1). Sociodemographic differences remain a major concern in SIDS in a low
incidence situation and even in an affluent population with adequate health
services.
PMID- 9560036
TI - Mental retardation in Norway: prevalence and sub-classification in a cohort of
30037 children born between 1980 and 1985.
AB - OBJECTIVES: We wanted to determine the prevalence and subcategories of mental
retardation (MR) defined as IQ < or = 70 in Akershus county, which rated by
average yearly income, had the second highest socioeconomic status (SES) in
Norway. METHODS: The study population consisted of 30 037 children born between
1980 and 1985. Cases were ascertained from multiple sources and psychometrically
assessed, predominantly with the Wechsler tests, which were standardized in
Norway in 1978. The cases were divided into four groups: profound (IQ < 20),
severe (IQ 20-34), moderate (IQ 35-49), and mild (IQ 50-70) MR, according to the
Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). The
median age was 10.8 y. The frequency and degree of parental consanguinity were
registered, and the average inbreeding coefficient was calculated. RESULTS:
Altogether, 185 had IQ < or = 70, giving a prevalence of MR of 6.2/1000.
Prevalences for profound, severe, moderate, and mild MR were 0.8, 0.4, 1.5 and
3.5/1000, respectively. In two, possibly three, cases the parents were second
cousins, giving an average inbreeding coefficient of 20-30 x 10(-5). CONCLUSIONS:
The low prevalence of MR, particularly mild MR, could partly be explained by high
SES, old standardization of IQ-test, and low inbreeding coefficient. The
proportion of profound MR was considerably higher than estimated by DSM-IV.
PMID- 9560038
TI - Risk factors for low birthweight in Japanese infants.
AB - The purpose of our study was to identify risk factors for low birthweight (LBW;
birthweight < 2500 g) in Japanese infants. The data was collected from
questionnaires completed by the parents of 23132 infants who underwent a
standardized well baby check-up for 1-month-old infants, conducted by the Fukuoka
City Medical Association from 1987 to 1995. The following eight factors and their
second-order interaction terms were examined as potential risk factors for LBW:
maternal age at delivery, history of live-born LBW infant, history of abortion in
previous pregnancies, maternal smoking, coffee and alcohol consumption during
pregnancy, prenatal training and live birth order. The results of multiple
logistic regression analysis showed that the following three factors and one
interaction term significantly contributed to LBW: history of live born LBW
infant, maternal smoking, live birth order and the interaction between maternal
smoking and live birth order. The smoker-related risk for LBW was quite different
in each of the three groups stratified by live birth order. Efforts should be
made, for example, to increase the accessibility of early, high-quality prenatal
care for the high-risk groups with previous LBW babies and to implement smoking
intervention, ranging from specific medical procedures to broad-scale public
health and health-related educational programs in schools.
PMID- 9560037
TI - Acute effects on systemic circulation after intratracheal instillation of
Curosurf or Survanta in surfactant-depleted newborn piglets.
AB - Systemic vasodilatation in surfactant-depleted newborn piglets is induced by 200
mg/kg of modified porcine lung surfactant (Curosurf). The aim of this
investigation was to study whether this effect is dependent on dose and could
further be induced by instillation of a bovine surfactant preparation (Survanta).
Twenty-two 3-5-d old piglets were subjected to repeated saline lung lavage and
then randomized to one of three groups. Instillation of either Curosurf l00 mg/kg
(n=8), Survanta l00 mg/kg (n=7) or Curosurf 200 mg/kg (n=7) was performed through
the endotracheal tube. Systemic vascular resistance decreased 7 (+/-4)%, 15 (+/
12)% and 18 (+/-6)% in the three groups, respectively (p < 0.05 in all three
groups). A significant difference between the high and low dose Curosurf groups
was found (p < 0.05), whereas no significant difference was seen between the
Curosurf 100 mg group and the Survanta group. The decrease in vascular resistance
was compensated by an increase in cardiac output, resulting in a stable mean
arterial blood pressure. In conclusion, both Curosurf and Survanta induce a
significant decrease in systemic vascular resistance in surfactant-depleted
newborn piglets. A more pronounced effect was observed after 200 mg/kg than after
100mg/kg of Curosurf.
PMID- 9560039
TI - Capillary refilling time in newborns--optimal pressing time, sites of testing and
normal values.
AB - Aspects of capillary refilling time (CRT) in newborns, such as pressing time,
sites of testing, normal values and difference between observers were assessed.
CRT was measured in 280 term newborns, divided into 7 groups of 40 each, varying
pressing time (from 1 to 7 s) was applied. CRT was measured in midpoints of
forehead and sternum and plantar surface of heel (defined as head, chest and
heel). No statistically significant difference was found between 3 and 7 s
pressing time groups. The data points of the CRT of the head and chest approached
normality, whilst those of the heel were widely scattered. Normal CRT in newborns
is <3 s. No significant difference between two observers in head and chest CRT
values was found.
PMID- 9560040
TI - The hypothalamic-pituitary-adrenal axis in preterm infants weighing < or = 1250
g: association with perinatal data and chronic lung disease.
AB - The hypothalamic-pituitary-adrenal axis (HPA) was examined in 34 ventilated
preterm infants weighing < or = 1250 g during the first week of life to evaluate
the association between adrenal suppression and subsequent chronic lung disease.
The second aim of the study was to detect perinatal and clinical differences
between the infants with and without persistent suppression of the HPA after
completion of dexamethasone treatment for chronic lung disease. To evaluate the
HPA, the corticotropin-releasing hormone stimulation test was performed, and the
cortisol and adrenocorticotropic hormone (ACTH) levels were measured by
radioimmunoassay. No association could be found between the synthesis of cortisol
and ACTH at the end of the first week of life and the development of chronic lung
disease. After treatment with dexamethasone, baseline cortisol levels < 138 nmol
l(-1) were found in 12 infants (46.2%), 8 of whom (30.8%) had cortisol values
below 83 nmol l(-1). The perinatal data of these patients did not differ from
infants without HPA suppression. However, the infants with cortisol levels < 83
nmol l(-1) after dexamethasone showed a significantly shorter need for mechanical
ventilation and supplemental oxygen (p < 0.01) and a lower incidence of chronic
lung disease (p < 0.05).
PMID- 9560041
TI - Fatty acid balance studies in preterm infants fed formula milk containing long
chain polyunsaturated fatty acids (LCP) II.
AB - A milk formula (Prematil-LCP) containing long-chain polyunsaturated fatty acids
(LCP) and with a fatty acid profile closely resembling breast milk has recently
been introduced for preterm infants. A double-blind randomized controlled trial
was performed comparing fatty acid absorption from Prematil-LCP (n=10) and
standard Prematil (n=10). Formula-fed preterm infants underwent 3 d fat balances
(once full enteral feeds were established) along with a parallel human milk fed
group (n=11). Plasma samples were taken on the last day. Median total fat
excretion (absorption, %) was 2.34g kg(-1) (82.0), 2.64g kg(-1) (82.9) and 1.65g
kg(-1) (87.8) with Prematil, Prematil-LCP and human milk feeding, respectively.
This reflected differences in the excretion and absorption of long-chain
saturated fatty acids. All groups excreted detectable LCP. LCP disappearance was
higher in infants fed human milk than in those fed Prematil-LCP, particularly for
n-6 LCP (p < 0.01). Nevertheless, excreted LCP equated to < 30% dietary intake,
with Prematil-LCP feeding. Plasma lipid fatty acid composition reflected
differences in dietary LCP intake.
PMID- 9560042
TI - Infant Flow Driver or single prong nasal continuous positive airway pressure:
short-term physiological effects.
AB - The effectiveness of single prong nasal continuous positive airway pressure
(CPAP) was compared with the Infant Flow Driver (IFD) in a crossover study in 20
neonates treated with > or = 30% oxygen by nasal CPAP. They were randomized to
the device used at the start of the study. Each infant was studied for four
consecutive 2-h periods alternating between single prong nasal CPAP and the IFD.
The FiO2 from the IFD read 0.02 higher than the same setting on the ventilators
used for single prong nasal CPAP. The IFD improved the mean (95% CI) of the FiO2
by 0.05 (0.02-0.08), p = 0.008. Taking into account the systematic error in the
FiO2 between the devices the real mean improvement in FiO2 produced by the IFD
was 0.03 (-0.005 to 0.06), p=0.09. There were no significant differences in
respiratory rate, heart rate, blood pressure or comfort score of infants during
periods of single nasal prong CPAP compared with periods on the IFD.
PMID- 9560043
TI - Quality of general movements in preterm infants with transient periventricular
echodensities.
AB - By means of sequential videotape recordings, the relevance of the quality of
general movements for neurological outcome was determined in a group of 21
appropriate-for-gestational-age preterm infants with transient periventricular
echodensities of variable localization and duration and in 6 infants without
echodensities. Echodensities, especially in the parieto-occipital area, affected
the quality of general movements. Echodensities persisting beyond 14d were
associated with abnormal general movements; infants with echodensities up to 14 d
had either normal or abnormal general movements. The developmental course of
movement quality was correlated to neurological outcome (p < 0.005): normal
outcomes were found in 11/12 infants with normal general movements throughout and
in 9/11 infants with transient abnormal general movements; all 4 infants with
persistent abnormal general movements had impaired outcomes. In infants with
transient echodensities, longitudinal assessment of the quality of general
movements helps to determine if there is brain dysfunction, either transient or
persistent, and identifies infants at risk for impaired neurological outcomes.
PMID- 9560044
TI - Immunogenicity of hepatitis B vaccine in term and preterm infants.
AB - Some studies have suggested that decreased seroconversion rates might be found in
premature infants with low birthweight (< 2000g) following administration of
hepatitis B vaccine at birth. The aim of the present investigation was to
evaluate possible differences in seropositive rates between full-term and preterm
infants after primary vaccination, in particular when gestational age or
birthweight is very low. Two-thousand and nine neonates born to HBsAg-negative
mothers were vaccinated with 10 microg of recombinant hepatitis B virus (HBV)
vaccine, from May 1991 to October 1994. Children with infections, congenital
malformations or serious illnesses were excluded. HBV vaccine was administered
intramuscularly, on the fourth day of life and again at 1 and 6 months of age. A
1-ml blood sample was drawn from each infant 1 month after the third vaccine dose
for determination of the level of anti-HBs antibody. The response to HBV
vaccination was evaluated in 241 preterm (gestational age <38 weeks) infants and
1727 term neonates. No statistical difference was observed in the distribution of
anti-HBs antibody level, either between preterm infants (<38 weeks) and newborns
of normal gestational age, or between low birthweight (<2500 g) and normal weight
infants. The results suggest that preterm and low birthweight infants (<2500g)
respond to HBV vaccine in the same measure as normal-term infants.
PMID- 9560045
TI - Usefulness of short-term urine collection in the nutritional monitoring of low
birthweight infants.
AB - To establish adequacy of urine collection times shorter than 24h in the metabolic
monitoring of low birthweight infants, we collected urine for 24 h in 39 LBW
infants during the third and fourth week of life. All urine voidings over the 24
h period were separately collected, the volume of each sampling and the time of
voiding were recorded, and 20% of the volume was removed for pooling. All
individual and pooled samples were analysed for total nitrogen, urea and ammonia,
alpha-amino nitrogen, creatinine, sodium, potassium, calcium and phosphorus, and
for each compound the ratio to 1 mol creatinine was established. Individual
sample results were "pooled" to obtain 3-, 6- and 12-h period excretion and than
related to the 24-h excretion as measured in the pooled 24-h sample. As the
volume of urine obtained in any 6-h collecting period depended on the time of
sampling (06:00-12:00 h, 17.5+/-3.1% of total; 12:00-18:00 h, 31.6+/-5.1% of
total; 18:00-24:00 h, 25.6+/-3.1% of total; and 0:00-06:00h, 25.3+/-2.9% of
total), calculations were based on samples obtained from 18:00 to 06:00 h. The
correlation between results of 3- and 24 h-collection periods was weakest, while
results of the 6-h collection correlated highly with the total daily excretion (r
= between 0.82 and 0.93 for the different compounds) and the correlation was only
slightly better when the 12-h collection period was considered. The correlation
between the mean molar substrate/creatinine ratio of all individual samples of a
24-h collecting period and the and total daily excretion of the respective
substrate was weaker (r = between 0.46 and 0.76 for the different compounds) than
the correlation between the results of a 6-h collecting period and the daily
excretion is not as stable than in later life. The data indicate that 6-h urine
sampling may be sufficient for metabolic monitoring of LBW infants. By contrast,
urinary substrate/creatinine ratios are not good markers of the daily excretions
of the respective substrate during the first weeks of life.
PMID- 9560046
TI - Early detection of necrotizing enterocolitis by gastrointestinal tonometry.
AB - The diagnosis of necrotizing enterocolitis (NEC) in neonates has traditionally
depended on a combination of clinical signs, biochemical parameters and
radiological changes. The measurement of intramucosal pH by gastrointestinal
tonometry provides a simple means of long-term monitoring which may detect the
development of NEC before conventional techniques. We present our experience of
tonometry in two 'at risk' term neonates with Hypoplastic Left Heart Syndrome.
PMID- 9560047
TI - Tension pneumopericardium in a preterm infant without mechanical ventilation: a
rare cause of cardiac arrest.
AB - A preterm infant with a gestational age of 32 weeks developed a tension
pneumopericardium during the second day of life. The infant was treated with
nasal continuous positive airway pressure and was not mechanically ventilated
before pneumopericardium occurred. After emergency pericardiocentesis, two
recurrences of pneumopericardium without clinical deterioration were diagnosed by
X-ray during a 2-d observation period. A continuous pericardial drainage was
positioned and was successfully removed on the seventh day of life after weaning
from the ventilator. Tension pneumopericardium may occur even in non-ventilated
newborns and should be considered as a rare but important differential diagnosis
of cardiac arrest.
PMID- 9560048
TI - Coexistence of acquired protein S and protein C deficiency and the Arg506Gln
mutation in factor Va in a child with severe thromboembolic disease.
AB - An 11-y-old girl who presented with cellulitis and clinical signs of deep vein
thrombosis (DVT) is reported here. She developed staphylococcal sepsis, recurrent
septic emboli and a large vegetation on the tricuspid valve. The patient was
found to be heterozygous for the Arg506Gln mutation in factor Va and had low
levels of protein C and protein S during the sepsis. The coexistence of the two
thrombophilic states may explain the severe thromboembolic manifestations.
PMID- 9560049
TI - Cutaneous polyarteritis nodosa in a child and a review of the literature.
AB - The cutaneous form of polyarteritis nodosa in children is extremely rare.
Findings are usually limited to the skin, muscles and joints. It has a benign but
often chronic course. We describe an 8-y-old girl with cutaneous PAN, with
extensive livedo reticularis on lower and upper extremities, tender subcutaneous
nodules, arthralgia and right ankle swelling. Skin biopsy revealed vasculitis of
small and medium-sized blood vessels characterized by fibrinoid necrosis. The use
of prednisolone resulted in clinical improvement initially, but recurrence
occurred during tapering. She showed marked improvement with additional high dose
methyl prednisolone monthly.
PMID- 9560050
TI - Breastfeeding and catch-up growth in SGA infants.
PMID- 9560051
TI - Breastfeeding and catch-up growth in SGA infants: further comments.
PMID- 9560052
TI - Current trends in chemotherapy for metastatic nonseminomatous testicular germ
cell tumors.
AB - With the introduction of cisplatin-based chemotherapy, metastatic testicular
cancer represents a model for a highly curable malignant disease. Approximately
70-80% of patients achieve a durable remission following chemotherapy +/-
secondary surgery of residual tumors. With the development of prognostic
classifications based on clinically available parameters, the aims of
chemotherapy have been twofold: on the one hand, the reduction of toxicity in
patients with 'low-risk' metastatic disease without a concomitant reduction in
treatment efficacy and, on the other hand, the improvement of treatment results
in patients with 'poor-prognosis' criteria who achieve a long-term cure rate of
less than 50% with standard chemotherapy regimens. Despite a number of large
randomized studies attempting either to avoid the toxicity of bleomycin or to
reduce cisplatin-associated side-effects through the substitution with
carboplatin, the combination of cisplatin, etoposide and bleomycin (PEB) given at
3-week intervals still remains the standard treatment for metastatic disease. The
role of high-dose chemotherapy with autologous stem cell support is currently
being investigated in order to improve the outcome of patients with relapse after
previous chemotherapy and of patients initially exhibiting advanced metastatic
disease. For patients with relapsed disease receiving high-dose chemotherapy, a
prognostic score has recently been developed: cisplatin-refractory disease, beta
human gonadotropin values > 1,000 U/l or primary mediastinal germ cell tumors are
factors characterizing patients which will profit less from high-dose
chemotherapy treatment than patients with chemosensitive disease at relapse.
Standard dose salvage regimens only result in a 20% long-term survival rate. In
contrast, high-dose salvage chemotherapy may yield a cure rate of approximately
40%. However, the only randomized study comparing high-dose versus conventional
dose therapy in patients with relapsed disease is still ongoing. The
investigation of dose-intensive approaches as first-line treatment is currently
being studied by several institutions. Despite preliminary favorable results,
this approach still cannot be considered standard treatment. A randomized study
comparing high-dose chemotherapy with 4 cycles of standard PEB was initiated in
the USA in 1996. The evaluation of new drugs in testicular cancer patients with
absolute cisplatin-refractory disease has demonstrated that paclitaxel is one of
the few agents with antitumor activity in these patients. Paclitaxel has
therefore been included in combination regimens--such as cisplatin, ifosfamide
and paclitaxel--for the treatment of patients with first and second relapse of
testicular cancer. These combinations are used as induction therapy prior to high
dose salvage treatment. Due to the large group of patients with metastatic
disease being cured nowadays, the long-term side effects of treatment have become
even more important. One of the major risk factors for the development of late
toxicities such as oto-, neuro-, nephro-, gonadal and cardiovascular toxicity is
the cumulative dose of cisplatin applied during therapy. The development of new
treatment strategies, such as the use of adjuvant chemotherapy for stage I
disease, the widespread application of high-dose chemotherapy with peripheral
stem cell rescue and the use of new cytotoxic agents, makes the evaluation of the
late effects of treatment for testicular cancer within controlled clinical trials
mandatory.
PMID- 9560053
TI - Prognosis and management strategies of lymphatic neoplasias in the elderly. I.
Aggressive non-Hodgkin's lymphomas.
AB - Lymphomas belong to the class of malignant diseases with the fastest increasing
incidence. High-grade non-Hodgkin's lymphomas (NHL) display a peak of incidence
in the age group above 65. In the last few years, age has been recognized as a
major risk factor for overall survival of high-grade NHL patients, and numerous
attempts have been made to analyze the contribution of factors to the age-related
worsening of prognosis in this disease, e.g. the biology of the disease on the
one hand, and age-specific comorbidity or degree of cytotoxicity, reluctance in
diagnosis and treatment and socioeconomic factors on the other. Furthermore, age
adapted treatment protocols have been designed and tested for their
practicability and efficacy in the elderly. Very recently, large randomized
prospective clinical trials have been carried out which support the idea that
treatment with a curative intent is warranted even in the very elderly and that a
successful attempt to cure requires the use of full-dose anthracycline-containing
regimens closely similar to CHOP (cyclophosphamide, doxorubicin, vincristine,
prednisone). In addition, progress has been made in systematically defining
maximally tolerated doses of the cytotoxic drugs and in specifically testing
anthracyclines with reduced cardiotoxicity with an efficacy similar to that of
doxorubicin, and further in investigating the advantage of applying hematopoietic
growth factors and/or cardioprotective drugs in this older population. In limited
stages of disease, three cycles of CHOP chemotherapy followed by involved field
irradiation may be superior to radiotherapy and prolonged chemotherapy and may
produce highly satisfying cure rates.
PMID- 9560054
TI - Management of stage III breast cancer.
AB - Stage III breast cancer encompasses a heterogeneous group of patients. According
to the American Joint Committee on Cancer (AJCC) these tumors include stage IIIA
and stage IIIB disease, the first generally being operable but the second
inoperable. Patients with inflammatory breast cancer are also included in stage
IIIB disease, and these patients have the worst prognosis. Multidisciplinary
therapy has become the treatment of choice for these patients. Primary or
neoadjuvant chemotherapy, followed by locoregional therapy, either surgery,
radiotherapy or both, is now an accepted strategy. Most patients achieve a
response to chemotherapy, resulting in downstaging of the tumor, and 5-year
survival rates have improved from 10-20% with local therapy alone to 30-60% with
the multidisciplinary approach. Although many prospective, mainly phase II trials
have been performed in stage III breast cancer, the optimal treatment scheme
still has to be established. The role of new therapeutic strategies such as high
dose chemotherapy with hematopoietic stem cell rescue and higher dose intensity
regimens with hematopoietic growth factors is currently under investigation. This
article will review the literature and discuss our own research in this area.
PMID- 9560055
TI - Paclitaxel in cisplatin or carboplatin-pretreated ovarian cancer. Phase II study.
AB - A phase II trial was conducted in order to assess the efficacy and toxicity of
paclitaxel given at a dose of 175 mg/m2 in a 3-hour infusion every 3 weeks in
patients with recurrent or cisplatin (CDDP) carboplatin-refractory ovarian
cancer. Forty-two patients with a median age of 61 years (range 34-76 years)
entered the study. Most patients had bulky disease. Thirty-three patients (78.5
%) presented with stage III and IV diseases. Twenty-two patients (52.3%) had
previously been treated with only 1 regimen and 20 patients (47.7%) with > or = 2
regimens. The median treatment interval from the last previous therapy was 4.5
months (range 2-26 months). From 41 patients evaluable for response, 3 (7.3%)
achieved a complete and 4 (9.8%) a partial response. All 3 complete and 2 out of
the 4 partial responders had previously received > or = 2 chemotherapeutic
regimens. Grade 3-4 toxicities included granulocytopenia (35%), which was of
short duration, neurotoxicity (9.75%) and alopecia (60.9%). Two patients with
grade 4 neutropenia were hospitalized due to pneumonia, which was successfully
treated by broad-spectrum antibiotics and administration of G-CSF. A severe
hypersensitivity reaction occurred in 1 patient early during the first cycle,
resulting in discontinuation of treatment. Median relapse-free survival was 6.9
months, median time to progression 6.2 months and median survival 13.2 months. In
conclusion, paclitaxel given at a dose of 175 mg/m2 as a 3-hour infusion every 3
weeks appears to be an efficacious and well-tolerated treatment in patients with
recurrent or CDDP/carboplatin-refractory ovarian cancer.
PMID- 9560056
TI - Mucosal squamous cell carcinoma of the esophagus: a clinicopathologic study of 30
cases.
AB - A clinicopathologic study was carried out on 30 patients with mucosal esophageal
cancer (MEC). The depth of cancer invasion was subdivided histologically into
three categories: m1 = carcinoma in situ (intraepithelial carcinoma) or carcinoma
with questionable invasion beyond the basal membrane; m2 = cancer invasion
confined to the lamina propria, and m3 = cancer reaching to or infiltrating into
the muscularis mucosae. Lymph node metastases and lymphatic invasion were found
only in the tumors reaching or infiltrating the muscularis mucosae (m3). The
maximum histologic vertical extent of the tumors was more than 1 mm in 4 of 5
patients with lymph node metastasis or lymphatic invasion. None of the patients
died of recurrent esophageal disease, and 3 of the 6 patients who had a second
primary tumor died of this other malignancy. It is critical to distinguish
between m1, m2 and m3 tumors to plan a treatment strategy, including an
endoscopic mucosal resection.
PMID- 9560057
TI - Expression of insulin-like growth factor-2 can predict the prognosis of human
colorectal cancer patients: correlation with tumor progression, proliferative
activity and survival.
AB - Expression of insulin-like growth factor-2 (IGF-2) has been reported in tissue
specimens and cell lines of human colorectal cancers. However, the effects of IGF
2 in colorectal cancer patients are not well known. In this study, IGF-2 staining
was performed on tissue samples from 92 patients with colorectal cancer, and the
relationship of IGF-2 staining to clinicopathological variables, proliferating
cell nuclear antigen (PCNA) staining and patient survival was analyzed. IGF-2
staining was correlated with tumor progression, PCNA staining and patient
survival. Our results suggest that IGF-2 plays an important role in tumor
progression and that IGF-2 staining is useful as a prognostic factor in
colorectal cancer patients.
PMID- 9560059
TI - Correlation between telomerase activity and DNA ploidy in gastric cancer.
AB - Telomerase has been reported to be activated in most immortal cells and human
cancers. In the present study, we assessed the correlation between telomerase
activity and cellular DNA ploidy level in gastric cancer. Telomerase activity was
determined semiquantitatively using the telomeric repeat amplification protocol
assay, a polymerase-chain-reaction-based assay, in surgical specimens of primary
tumors obtained from 36 patients with gastric cancer. No correlation was observed
between telomerase activity and the proliferating cell nuclear antigen labeling
index. In contrast, a positive linear correlation was observed between telomerase
activity and the DNA index (r = 0.59; p < 0.01). Tumor cells with aneuploid
patterns showed higher telomerase activity than those with diploid patterns
(27.6+/-5.8 vs. 5.8+/-1.1%; p < 0.01). Telomerase activity of tumors with liver
metastases was significantly higher than activity of those without metastases
(34.5+/-16.6 vs. 11.8+/-2.4; p < 0.05). There was a trend toward a lower survival
rate in 9 patients with a telomerase activity of 20% or higher compared to 27
patients with telomerase activity lower than 20%. These results suggest that the
telomerase activity of gastric cancer tissue may reflect the malignant potential
of the tumor.
PMID- 9560058
TI - Comparative survival analysis of p53 gene mutations and protein accumulation in
colorectal cancer.
AB - Immunohistochemical reactivity for p53 protein is common in various human
malignancies. Increased intracellular concentration of p53, which is frequently,
but not systematically, related to p53 mutation, has been proposed to be
associated with poor prognosis in some tumor types. In colorectal cancer, this
significance is still a matter of debate. To directly investigate the
relationship between prognosis and p53 alterations, we screened a series of 72
colorectal carcinomas for overexpression and mutation of the p53 gene. Mutations
in exons 5-9 of the p53 gene were assayed by single-strand conformation
polymorphism and direct DNA sequencing, whereas p53 protein accumulation was
detected in 10-microm frozen tissue by immunostaining using 2 different
monoclonal antibodies (PAb 1801 and DO7). Thirty-six tumors (50%) showed p53
overexpression. Nineteen of the 36 tumors which contained high levels of p53
protein were found to have missense point mutations. Using a multivariate
survival analysis, stage, differentiation, p53 immunoreactivity and p53 mutation
emerged as risk factors, but only the stage was significant. In univariate
analysis, stage, differentiation and p53 immunoreactivity were significant
prognostic indicators, while p53 mutation was at the borderline of significance.
PMID- 9560060
TI - Undertreatment of hypertension in older Mexican Americans.
AB - OBJECTIVE: To identify the prevalence of hypertension and factors associated with
nontreatment and poor control of hypertension in Mexican Americans aged 65 years
and older. DESIGN: A population-based survey of older Mexican Americans conducted
in 1993-1994. SETTING: Subjects residing in five Southwestern states: Texas, New
Mexico, Colorado, Arizona, and California. PARTICIPANTS: An area probability
sample of 3050 noninstitutionalized Mexican American men and women aged 65 and
older took part in a 90-minute in-home interview, which included review of all
medications taken and two sitting blood pressure measurements. OUTCOME MEASURES:
Measured were previous diagnoses of hypertension, current medication for
hypertension, and current blood pressure RESULTS: Sixty-one percent of older
Mexican-Americans were hypertensive, and 51% of those with hypertension were
taking antihypertensive medications. Only 25% of hypertensive subjects (18% of
males and 30% of females) were in good blood pressure control (i.e., systolic
blood pressure < 140 mm Hg and diastolic blood pressure < 90 mm Hg). In
multivariate analyses, factors associated with increased likelihood of treatment
included female gender (OR = 1.9), history of heart disease (OR = 2.4),
possessing a regular source of health care (OR = 2.7), and having seen a
physician two or more times in the previous year (OR = 3.8). These were also
independent predictors of good blood pressure control. CONCLUSION: Nontreatment
of hypertension is still a major public health concern in older Mexican
Americans. We estimate that adequate blood pressure control in this population
would prevent approximately 30,000 adverse cardiovascular events over 10 years,
affecting approximately 6% of the entire Mexican American older population.
PMID- 9560061
TI - Lower-extremity functioning in older Mexican Americans and its association with
medical problems.
AB - OBJECTIVE: To describe lower-extremity functioning in community-dwelling older
Mexican Americans and to examine its relationship with medical problems. DESIGN:
Cross-sectional analyses of survey and performance-based data obtained in a
population-based study employing area probability sampling. SETTING: Households
within selected census tracts of five Southwestern states: Arizona, California,
Colorado, New Mexico, and Texas. PARTICIPANTS: A total of 2873 Mexican Americans
aged 65 years and older. MEASUREMENTS: A multidimensional questionnaire assessing
demographic, sociocultural, and health variables. Standardized tests of lower
extremity physical functioning included measures of standing balance, repeated
chair stands, walking, and an overall summary measure. RESULTS: Regression
analyses revealed that being more than age 75 and female, having arthritis
diabetes, visual impairments, or being obese or underweight were all
significantly associated with performance on both individual and summary tests of
lower-extremity functioning. In separate regression analyses, the total number of
medical conditions was also associated with performance. CONCLUSIONS: The
likelihood of predicting performance or inability to complete tests of lower
extremity functioning was greatest for those aged 80 and older, those with
arthritis or diabetes, and those with three or more medical conditions. Because
of the high prevalence of diabetes in Mexican Americans, documentation of the
association of diabetes with performance-based tests of lower-extremity
functioning may help guide early interventions targeted to prevent progression to
more severe limitations or disability.
PMID- 9560062
TI - Predicting hospitalization and functional decline in older health plan enrollees:
are administrative data as accurate as self-report?
AB - OBJECTIVE: To compare the predictive accuracy of two validated indices, one that
uses self-reported variables and a second that uses variables derived from
administrative data sources, to predict future hospitalization. To compare the
predictive accuracy of these same two indices for predicting future functional
decline. DESIGN: A longitudinal cohort study with 4 years of follow-up. SETTING:
A large staff model HMO in western Washington State. PARTICIPANTS: HMO Enrollees
65 years and older (n = 2174) selected at random to participate in a health
promotion trial and who completed a baseline questionnaire. MEASUREMENT:
Predicted probabilities from the two indices were determined for study
participants for each of two outcomes: hospitalization two or more times in 4
years and functional decline in 4 years, measured by Restricted Activity Days.
The two indices included similar demographic characteristics, diagnoses, and
utilization predictors. The probabilities from each index were entered into a
Receiver Operating Characteristic (ROC) curve program to obtain the Area Under
the Curve (AUC) for comparison of predictive accuracy. RESULTS: For
hospitalization, the AUC of the self-report and administrative indices were .696
and .694, respectively (difference between curves, P = .828). For functional
decline, the AUC of the two indices were .714 and .691, respectively (difference
between curves, P = .144). CONCLUSIONS: Compared with a self-report index, the
administrative index affords wider population coverage, freedom from nonresponse
bias, lower cost, and similar predictive accuracy. A screening strategy utilizing
administrative data sources may thus prove more valuable for identifying high
risk older health plan enrollees for population-based interventions designed to
improve their health status.
PMID- 9560063
TI - Detecting balance deficits in frequent fallers using clinical and quantitative
evaluation tools.
AB - OBJECTIVE: This investigation sought to determine whether older idiopathic
frequent fallers could be distinguished from healthy older adults on the basis of
balance and movement coordination tests. A secondary objective was to determine
the relationships among clinical balance test scores, balance performance data
obtained by accelerometry, and quantitative motor coordination tests. DESIGN: Two
group comparison designs. SETTING: A motor control research laboratory in a
university setting. PARTICIPANTS: The 16 subjects recruited for this study
included eight healthy older subjects and eight age-matched idiopathic fallers.
MEASUREMENTS: Each participant's balance performance was assessed by
accelerometry, as well as by coordination and clinical tests. Accelerometry
scores, obtained by 1g accelerometers placed at the hip and on the head, were
made with eyes open or closed, either standing on the floor or on a wedge of
compliant foam. Clinical balance scores were obtained using variants of Romberg's
test and the functional reach test. Motor coordination tests obtained included
the heel-to-toe transition and rapid stepping tests. MAIN RESULTS: Statistically
significant differences were obtained between groups for all accelerometry
variables except root mean square. All accelerometry variables were successful in
discriminating between head and hip sites. Moreover, the amplitude of sway
obtained from accelerometry data identified significant differences among the
four test conditions. The Romberg test, using right leg alone with eyes open,
showed a significant difference between fallers and healthy older subjects.
Walking velocity was significantly faster for normal older subjects than for
fallers (1.10 m/sec vs 0.80 m/sec). No significant between-group differences were
obtained using the functional reach test. Coordination skills yielded significant
between-group differences using the rapid stepping test but no significant
differences between groups with the heel-toe transition test. CONCLUSION:
Accelerometry is an inexpensive and clinically useful technique that can
distinguish between healthy older people and idiopathic frequent fallers. In
conjunction with clinical procedures and commercially available tests to assess
motor coordination, these techniques can identify older individuals susceptible
to frequent falls.
PMID- 9560064
TI - Thioridazine dose-related effects on biomechanical force platform measures of
sway in young and old men.
AB - OBJECTIVE: Thioridazine (TDZ) is associated with an increased risk of falls. The
purpose of this study was to determine whether (1) thioridazine increases
Biomechanics Force Platform (BFP) measures of sway in a dose-related manner, (2)
there is a difference in sway between young and old men, (3) there is a
correlation between sway and orthostatic changes in BP and HR. DESIGN: Seven
younger (aged 20-42) and five older (aged 70-76) healthy male volunteers
received, in a randomized order double-blind design, a single oral dose of 0, 25,
and 50 mg of TDZ on three separate days at least 7 days apart and 75 mg on the
fourth day of the study. Sway and blood pressure were measured for 24 hours.
SETTING: A general clinical research center. MEASUREMENTS: Biomechanics force
platform measures of postural sway were measured as the movement of the center of
pressure. The elliptical area (EA) and average velocity (AV) were calculated with
eyes open and eyes closed. Blood pressure and heart rate were measured for 5
minutes supine and 5 minutes standing. RESULTS: Thioridazine increases BFP sway
in a dose-dependent manner. EA increased from 0.56 (SD = .51) cm2 for placebo to
0.88 (SD = 1.09) cm2 for 75 mg TDZ. AV increased from 1.07 (SD = .27) cm/sec,
placebo, to 1.43 (SD = .55) cm/sec, 75 mg TDZ. Older men swayed more than younger
men. Changes followed the expected time course for TDZ. EA and AV were associated
with HR and BP, e.g., SBP versus ln(EA) and ln(AV) (r = -0.21 and r = -0.22,
respectively; P < .0001). CONCLUSIONS: Thioridazine increases validated measures
of fall risk dose dependently in young and old men. This may explain the effects
of neuroleptic drugs on fall risk in older people.
PMID- 9560065
TI - A prospective study of posturography in normal older people.
AB - OBJECTIVE: To follow posturographic measurements over time in a group of normal
older subjects to see if sway increases with aging and if sway is greater in
those with deteriorating balance and falls. SUBJECTS: Seventy-two community
dwelling older people (age range 79-91 years), who initially had normal
neurological evaluations, were followed with three yearly follow-up examinations.
MEASUREMENTS: Amplitude and velocity of sway on static and dynamic posturography,
Tinetti gait and balance score, reports of falls. RESULTS: Velocity of sway on
dynamic tests increased significantly during the 3 years of follow-up. The
percentage increase in sway was about the same in the anterior-posterior and
medial-lateral directions and with eyes open and eyes closed. Subjects with low
Tinetti scores had higher sway amplitude and velocity, particularly on dynamic
tests, but no measure of sway was significantly different in those who reported
falls compared with those who did not report falls. CONCLUSIONS: Sway increases
in normal subjects over time, and sway is greater in older subjects with
deteriorating balance compared with those with normal balance. Sway was not
greater in those who fell compared with those who did not fall, probably because
falls are highly dependent on individual behavior.
PMID- 9560066
TI - Prognostic factors in very old demented adults: a seven-year follow-up from a
population-based survey in Stockholm.
AB - OBJECTIVE: To detect prognostic factors in very old demented subjects with
Alzheimer's disease (AD), vascular dementia (VaD), and other types of dementia
(OD). DESIGN: Follow-up clinical examinations of dementia patients from a
population-based study after 3- and 7-year intervals. SETTING AND PARTICIPANTS:
In an established population aged 75 years and older in Stockholm, Sweden, there
were 133 cases of AD, 52 of VaD, and 38 of OD. MAIN OUTCOME MEASURES: Predictors
of survival at 3- and 7-year follow-up examinations were evaluated by Cox
proportional hazard models. Progression was measured as the annual rate of change
in Mini-Mental State Examination (MMSE) scores. Linear models were used to
evaluate predictors of progression. RESULTS: Older age, male gender, low
education, comorbidity, and functional disability predicted shorter 7-year
survival in the 223 prevalent dementia cases. Other factors, including type of
dementia, dementia severity, and duration of the disease were not significant.
The average rate of cognitive decline in the 81 mild to moderate demented
subjects who survived 3 years was 2.4 MMSE points per year. Type of dementia (AD
vs OD), higher baseline cognitive function, and greater functional disability
predicted faster decline. Despite similar survival probability, predictors of
death varied as a function of dementia type: Older age (for AD and VaD),
comorbidity (for AD and OD), and functional dependency (for VaD). In AD,
prognostic factors were similar to those described for the combined dementia
groups, with the exception of an accelerated cognitive decline among women.
CONCLUSIONS: Although methodological difficulties exist, it is possible to
identify demented subjects with worse prognoses (shorter survival and faster
cognitive decline) by using clinical and demographic data. Clinicians and
healthcare planners should be aware of the potential usefulness of functional
dependence as a prognostic indicator. Finally, the need for careful clinical
examinations of demented subjects is stressed by the increased mortality found
among those demented who are also affected by other chronic conditions.
PMID- 9560067
TI - Atrial natriuretic peptide level contributes to a model of future mortality in
the oldest old.
AB - OBJECTIVES: To determine if atrial natriuretic peptide (ANP) level is associated
with mortality in the oldest old and to develop a comprehensive model of
mortality in the oldest old using clinical and laboratory parameters. DESIGN:
Prospective cohort study with 7 years of follow-up. SETTING: A 725-bed life care
facility. PARTICIPANTS: 282 frail older individuals (mean age 88, range 70-102).
MEASUREMENTS: Variables measured included age, gender, Charlson Comorbidity
Index, functional measurements, weight, blood pressure, and multiple laboratory
variables, including ANP. Main outcome measurement was death. RESULTS: Eighty
four percent (237/282) of subjects died during the 7-year follow-up period. On
univariate analysis, the risk ratio (RR) for ANP tertile was 1.28. On bivariate
analysis, adjusting for the development of congestive heart failure, the RR was
1.22. On multivariate analysis, the following variables were associated with
mortality: ANP tertile (RR 1.24), age (RR 1.04), female gender (RR 0.43),
Charlson Comorbidity Index score (RR 1.13), mentation score (RR 1.27), BUN/Cr
ratio (RR 1.04), albumin level (RR 0.63), and hemoglobin level (RR 0.84).
CONCLUSIONS: ANP level and other variables are independent risk factors for
mortality in frail individuals. ANP level may indicate homeostatic failure to
adapt to fluid volume changes or may reflect subclinical heart disease. ANP level
contributes to a multivariate model of mortality in frail older individuals.
PMID- 9560068
TI - Relationships between sleep and body temperature in middle-aged and older
subjects.
AB - OBJECTIVES: Although changes in the circadian timing system are thought to be a
major factor in the decline of sleep quality that often accompanies aging, few
reports have actually examined this relationship in detail. Because some
treatments for age-related insomnia are based on putative circadian changes, it
is important to expand the limited database that specifically addresses this
issue. This study examined age-related changes in sleep, and relationships
between those sleep changes and alterations in the circadian timing system, in a
group of middle-aged and older subjects. DESIGN: Sixty healthy men and women
between the ages of 40 and 84 were studied. A subset of older subjects (< 65
years) had reported sleep disturbance for at least 1 year before participation.
Polysomnography was obtained, and body core temperature was recorded continuously
for 24 hours. All recordings took place in the Laboratory of Human Chronobiology,
Department of Psychiatry, Cornell University Medical College. RESULTS: There were
no differences in sleep quality between middle-aged and non-sleep-disturbed older
subjects. However, timing of the minimum body temperature was earlier in the
older non-sleep-disturbed subjects than in the middle-aged group. In contrast,
sleep-disturbed older people had shorter total sleep times, reduced sleep
efficiency, more waking time after sleep onset, and a reduced proportion of REM
sleep compared with non-sleep-disturbed older subjects. Yet, there were no
differences between the two older groups in the rhythm of body temperature. For
the entire group, age was correlated negatively with total sleep time, sleep
efficiency, percentage of stage 2 sleep, and the timing of the temperature
minimum. CONCLUSION: The results support the widely held notion that sleep and
circadian rhythm changes occur with aging. However, the hypothesis that age
related changes in sleep may be associated with aging of the circadian system was
supported only to a limited degree, suggesting that age-related sleep disturbance
is likely to have multiple causes. Thus, treatment strategies that incorporate a
combination of interventions may be the most effective.
PMID- 9560069
TI - Nighttime urinary incontinence and sleep disruption among nursing home residents.
AB - OBJECTIVE: To examine the relationship of urinary incontinence episodes to sleep
disruption in a sample of nursing home residents. DESIGN: Descriptive, case
series. SETTING: Three community nursing homes. PARTICIPANTS: Seventy-three
incontinent residents of three nursing homes participating in a trial of a
behavioral intervention for nighttime urinary incontinence. MEASUREMENTS: Data
were collected during a baseline and repeat baseline period about 2 months later
in nursing homes serving as controls for the intervention homes. Incontinence
episodes were identified by incontinence pads, which were wired to detect wetness
of 10 mL or more. Sleep was monitored by wireless wrist actigraphs. Noise and
light changes were monitored by bedside recording devices. MAIN RESULTS:
Recordings covered 403 nights, during which 1715 awakenings from 10 consecutive
minutes of sleep were detected as were 1168 incontinent episodes. Only 4% of the
awakenings were associated with an incontinence episode, and only 23% of the
incontinence episodes occurred during periods of at least 10 consecutive minutes
of sleep. Of the latter episodes, only 12% appeared to awaken the resident.
CONCLUSIONS: Our data raise questions about the relevance of incontinence
episodes to sleep disruption among chronically incontinent nursing home
residents. Our findings must be interpreted cautiously because of limitations in
the technologies and definitions we used to identify sleep, awakenings, and
incontinence episodes. Although logistically and technically difficult to
perform, studies using polysomnographic recordings of sleep are needed to examine
further these important associations.
PMID- 9560070
TI - Urinary incontinence in a community-based cohort: prevalence and healthcare
seeking.
AB - OBJECTIVE: To estimate the prevalence of urinary incontinence and to assess care
seeking behavior for urinary symptoms among community-dwelling people. DESIGN: A
community-based cross-sectional study. SETTING: Randomly selected men and women
from Olmsted County, Minnesota. PARTICIPANTS: Two cohorts, one comprised of both
men (n = 778) and women (n = 762) 50 years of age or older and a second comprised
of men aged 40 years or older (n = 2150). MEASUREMENTS: Participants completed
questionnaires assessing urinary incontinence in the previous 12 months, the
number of days leaked, the amount leaked, and healthcare-seeking measures for
urinary symptoms. RESULTS: In the first cohort, the prevalence of incontinence
was 24% in men and 49% in women; 29% of men and 13% of women with incontinence
had sought care for urinary symptoms. Urinary incontinence was more strongly
associated with care-seeking measures for urinary symptoms in men (Odds Ratio
(OR) = 4.3, 95% Confidence Interval (CI) = 2.4, 8.0) than in women (OR = 2.1, 95%
CI = 1.2, 3.9). Moderate or severe urinary incontinence was associated
significantly with care-seeking for urinary symptoms (OR = 10.5, 95% CI = 5.6,
19.8). In the second cohort, the prevalence of urinary incontinence was 17.3%;
8.5% of men with incontinence had sought care for urinary symptoms. Men with
incontinence were 1.2 times (95% CI = .8, 1.9) as likely to seek care for urinary
symptoms as men without incontinence. CONCLUSION: Our findings indicate that
although urinary incontinence is relatively common in the community, care-seeking
for urinary symptoms among persons with urinary incontinence is low, particularly
among women, for whom the prevalence exceeds 40% between the ages of 50 and 70
years. These findings suggest that strategies to promote care-seeking for
incontinence need to be investigated and employed in the community.
PMID- 9560071
TI - Variation in estimates of urinary incontinence prevalence in the community:
effects of differences in definition, population characteristics, and study type.
AB - OBJECTIVES: Prevalence estimates for urinary incontinence among community
dwelling adults vary from 2 to 55%. A review of the literature was undertaken to
investigate the degree to which differences in definitions of incontinence, age,
and gender of the populations studied, response rates, measurement techniques, or
location could explain differences in reported prevalences. DESIGN: A literature
search was conducted to locate all studies published in English reporting the
prevalence of urinary incontinence in a population-based sample of adults.
MEASUREMENT: Information was abstracted for study size, response rate, type of
survey, definition of urinary incontinence, and prevalence of incontinence by age
group and gender. Prevalence by type of incontinence was also abstracted where
available. Stratification was used to obtain prevalence estimates specific for
age, gender, and frequency of incontinence. Data were examined for associations
between prevalence and survey type, response rate, year, and location of survey.
RESULTS: A total of 21 studies met inclusion criteria. Stratification of reported
prevalence by frequency, gender, and age substantially reduced the variation in
prevalence estimates. For older women, the estimated prevalence of urinary
incontinence ranged from 17 to 55% (median = 35%, pooled mean = 34%), and for
daily incontinence it ranged from 3 to 17% (median = 14%, pooled mean = 12%). For
older men, incontinence prevalence was estimated to be 11 to 34% (median = 17%,
pooled mean = 22%), and 2 to 11% reported daily incontinence (median = 4%, pooled
mean = 5%). Within studies, the prevalence of any incontinence was 1.3 to 2.0
times greater for older women than for older men. Among middle-aged and younger
adults, prevalence of incontinence ranged from 12 to 42% (median = 28%, pooled
mean = 25%) for women and from 3 to 5% (median = 4%, pooled mean = 5%) for men.
The ratio of prevalence of any incontinence for women to men in this age group
ranged from 4.1 to 4.5. Stress incontinence predominated in younger women,
whereas urge and mixed incontinence predominated in older women. There was a
tendency for studies using in-person interviews to report higher prevalences.
CONCLUSIONS: An accurate estimate of the prevalence of urinary incontinence
depends on specifying the definition of incontinence and the age and gender
groups of interest.
PMID- 9560072
TI - Prevalence of coronary artery disease, atherothrombotic brain infarction, and
peripheral arterial disease: associated risk factors in older Hispanics in an
academic hospital-based geriatrics practice.
AB - OBJECTIVE: To investigate the prevalence of coronary artery disease (CAD),
atherothrombotic brain infarction (ABI), and peripheral arterial disease (PAD) in
older Hispanics and the association with risk factors in this population. DESIGN:
A retrospective analysis of charts from all Hispanics seen during January 1996
through July 1997 at an academic hospital-based geriatrics practice. SETTING: An
academic, hospital-based, primary care geriatrics practice staffed by fellows in
a geriatrics training program and by full-time faculty geriatricians. PATIENTS:
One hundred sixty women and 53 men, mean age 80 +/- 8 years (range 64 to 100),
were included in the study. MEASUREMENTS AND MAIN RESULTS: Of 213 Hispanics in
the study, 59 (28%) had documented CAD, 43 (20%) had ABI, 34 (16%) had PAD, and
90 (42%) had either CAD, ABI, or PAD. Serum total cholesterol and triglycerides
were measured in 202 of 213 subjects (95%). Serum high-density lipoprotein
cholesterol was measured in 137 of 213 patients (64%). Other risk factor data
were documented in all patients. Multiple logistic regression analysis performed
in 202 patients using the variables age, gender, cigarette smoking, hypertension,
diabetes mellitus, obesity, serum total cholesterol, and serum triglycerides
showed statistically significant associations between prevalent CAD, ABI, or PAD
and age (P = .002, odds ratio (OR) = 1.083), cigarette smoking (P = .002, (OR) =
3.865), hypertension (P = .007, (OR) = 2.749), diabetes mellitus (P = .028, (OR)
= 2.386), obesity (P = .014, (OR) = 2.608), serum total cholesterol (P < 0.001,
(OR) = 1.025), and serum triglycerides (P = .017, (OR) = .993). CONCLUSIONS:
Either CAD, ABI, or PAD was present in 42% of 213 older Hispanics. There were
statistically significant associations between prevalent CAD, ABI, or PAD in
older Hispanics and risk factors, including age, cigarette smoking, hypertension,
diabetes mellitus, obesity, and serum total cholesterol.
PMID- 9560073
TI - Age dependence of choroidal blood flow.
AB - OBJECTIVE: To investigate the age dependence of choroidal blood flow. DESIGN: A
cross-sectional study. SETTING: Department of Clinical Pharmacology, Vienna
University. PARTICIPANTS: A total of 130 healthy volunteers between the ages of
19 and 83 years. MEASUREMENTS: Fundus pulsation amplitude (FPA) with a recently
developed laser interferometric method, mean arterial pressure (MAP) with an
automated oscillometric device, intraocular pressure (IOP) with an applanation
tonometer, and ocular perfusion pressure (OPP) as calculated from MAP and IOP.
RESULTS: There was a significant correlation of FPA with age r = -0.242 (P =
.005). MAP, IOP, and OPP showed a significant positive correlation with age.
Multiple regression analysis showed that FPA is associated with age but not with
MAP, IOP, or OPP. CONCLUSION: Choroidal blood flow is reduced in older subjects,
which argues in favor of an increase in ocular vascular resistance with age. This
may be a risk factor in the development of common ocular diseases such as age
related macular degeneration or glaucoma.
PMID- 9560074
TI - A census-based comparison of centenarians in New Zealand with those in the United
States.
AB - OBJECTIVE: To describe the characteristics of New Zealand's centenarians, as
given in the 1991 census, and to compare these characteristics with those of
centenarians from the United States. DESIGN: A census-based descriptive study.
SETTING: The complete national population as defined by the 1991 New Zealand
census. RESULTS: In 1991, there were 246 female and 51 male centenarians in New
Zealand. Fifty-one percent of the men and 29% of the women lived at home; 16%
lived at home with someone else (55% with children). People who were widowed were
more likely to be living in a residential institution (69%) than people who were
married (40%). Forty-three percent of men and 39% of women earned less than
NZ$10,000 per year. Most had no formal educational qualification. Fourteen
percent of men and 35% of women living at home did housework in the previous
week. Compared with the United States, there are fewer New Zealand centenarians
per number of population. People of European race were overrepresented in the New
Zealand centenarian population, whereas African Americans were overrepresented in
the United States centenarian population. CONCLUSIONS: Our data have shown the
heterogeneity associated with extreme ageing and can be used as a basis for
comparison with other countries.
PMID- 9560075
TI - Cross-cultural adaptation of the hearing handicap inventory for the Elderly
Screening Version (HHIE-S) for use with Spanish-speaking Mexican Americans.
AB - OBJECTIVE: To cross-culturally adapt the Hearing Handicap Inventory for the
Elderly-Screening Version (HHIE-S) for use with older Spanish-speaking Mexican
Americans. SUBJECTS AND SETTING: Two different samples were used. First, a
convenience sample of 100 older community-dwelling Mexican American men and women
in San Antonio, Texas, was used to test technical equivalence of the Spanish and
English language versions of the HHIE-S. Second, a neighborhood-based sample of
older Mexican Americans was used to establish conceptual (n = 433) and criterion
equivalence (n = 381) of the two HHIE-S language versions. METHODS: Independent
forward and back translations were done to create a Spanish language version of
the HHIE-S. In the convenience sample, subjects were administered the English and
Spanish HHIE-S in random order on separate days. In the neighborhood sample, the
HHIE-S was given on one occasion in the language of the subject's preference.
Depressive symptoms were assessed using the Geriatric Depression scale to see if
the two language versions of the HHIE-S were similarly associated with depression
(conceptual equivalence). Hearing impairment was assessed using the Welch-Allyn
Audioscope to see if the two language versions were similarly associated with an
audiometric measure for hearing loss (criterion equivalence). RESULTS: In the
convenience sample, the overall mean (SD) Spanish and English HHIE-S scores were
6.2 (8.7) and 6.2 (9.3), respectively (P = 1.00). Total scores of the English and
Spanish versions were highly correlated (r = .89), and regression analysis
indicated that the two language versions gave nearly identical results. In the
neighborhood-based sample, men had higher HHIE-S scores than women (OR 2.0, 95%
CI = 1.3-3.5). Having depressive symptoms (OR 3.2, 95% CI = 1.9-5.5) or hearing
impairment (OR 6.1, 95% CI = 3.5-10.5) was associated with higher HHIE-S scores.
After adjustment for gender, depressive symptoms, and/or hearing impairment, the
language of interview was not associated with HHIE-S score. CONCLUSION: We have
developed and tested a Spanish translation of the HHIE-S that yields equivalent
results to those obtained with the English version in bilingual Mexican
Americans. The Spanish HHIE-S presented here is suitable for clinical use and
research studies involving older Mexican Americans.
PMID- 9560076
TI - Systems of care for older populations of the future.
PMID- 9560077
TI - Geriatric nurse practitioners in long-term care: demonstration of effectiveness
in managed care.
AB - OBJECTIVE: This study was undertaken to review the impact of utilizing geriatric
nurse practitioner/physician (GNP/ MD) teams on cost and utilization for a cohort
of Medicare HMO enrollees residing in long-term care facilities. The results
would be used by the organization for further development of the GNP Program.
DESIGN: A 1-year retrospective data analysis on revenues and cost for 1077 HMO
enrollees residing in 45 long term-care facilities. SETTING: Proprietary and not
for-profit, licensed long term care facilities in the HMO's service area of
central Massachusetts. Facilities in the study had both skilled (Medicare
certified) and custodial beds. MEASUREMENTS: Data were collected retrospectively
on overall cost, revenues, emergency department (ED) transfers, hospital, and
subacute days. RESULTS: Of 1077 residents, 414 were cared for by GNP/MD teams
compared with 663 by physicians alone. Acute care and ED costs were significantly
lower for the GNP/MD-covered patients. There was a gain of $72 per resident per
month (PRPM) with the GNP/MD-covered patients compared with a loss of $197 PRPM
for physicians alone. There were no significant differences in ancillary services
or prescriptions. CONCLUSION: The use of GNPs in collaboration with physicians
reduced ED and acute care utilization costs as well as overall costs for a cohort
of HMO enrollees in long-term care. This encouraged the HMO to support the
concept that all long-term care HMO residents should be covered by GNP/MD teams.
PMID- 9560078
TI - Preparing Canadian physicians for health care of older adults.
PMID- 9560079
TI - Getting meaningful informed consent from older adults: a structured literature
review of empirical research.
AB - OBJECTIVES: To perform a structured literature review of the published empirical
research on informed consent with older adults in order to make recommendations
to improve the informed consent process and to highlight areas needing further
examination. DESIGN: Relevant literature was identified by searching electronic
databases (AGELINE, BIOETHICSLINE, CancerLit, Ethics Index, Health, LegalTrac,
MEDLINE, PAIS International, PsycInfo, and Sociofile). Studies were included if
they were reports of primary research data about informed consent and, if
patients or other subjects were used, older subjects were included in the sample.
Data related to the aspect of informed consent under study (recruitment, decision
making capacity, voluntariness, disclosure of information, understanding of
information, consent forms, authorization, and policies and procedures) were
abstracted and entered into a specially designed database. MEASUREMENTS:
Characterization of the population, age of subjects, setting, whether informed
consent was being studied in the context of research or treatment, study design,
the nature of outcome or dependent variables, independent variables (e.g.,
experimental conditions in a randomized controlled trial or patient/subject
characteristics in a nonrandomized comparison), and results according to the
aspect of informed consent under study. RESULTS: A total of 99 articles met all
the inclusion criteria and posed 289 unique research questions covering a wide
range of aspects of informed consent: recruitment (60); decision making capacity
(21); voluntariness (6); disclosure (30); understanding (139); consent forms (7);
authorization (11); policies (13); and other (2). In the secondary analyses of
numerous studies, diminished understanding of informed consent information was
associated with older age and fewer years of education. Older age was also
sometimes associated with decreased participation in research. Studies of
disclosure of informed consent information suggest strategies to improve
understanding and include a variety of novel formats (e.g., simplified,
storybook, video) and procedures (e.g., use of health educators, quizzing
subjects, multiple disclosure sessions). CONCLUSIONS: A systematic review of the
published literature on informed consent reveals evidence for impaired
understanding of informed consent information in older subjects and those with
less formal education. Effective strategies to improve the understanding of
informed consent information should be considered when designing materials,
forms, policies, and procedures for obtaining informed consent. Other than
empirical research that has investigated disclosure and understanding of informed
consent information, little systematic research has examined other aspects of the
informed consent process. This deficit should be rectified to ensure that the
rights and interests of patients and of human subjects who participate in
research are adequately protected.
PMID- 9560080
TI - Heart failure: evaluation and treatment of patient's with left ventricular
systolic dysfunction. Agency for Health Care Policy and Research (AHCPR).
PMID- 9560081
TI - The Balanced Budget Act of 1997: implications for the practice of geriatric
medicine.
PMID- 9560082
TI - Outcomes-based quality improvement: reducing the data collection burden.
PMID- 9560083
TI - On clinical diagnosis of congestive heart failure in older patients.
PMID- 9560084
TI - Prescribing less than recommended doses may be acceptable for geriatric patients.
PMID- 9560085
TI - Urinary incontinence in nursing home residents.
PMID- 9560086
TI - After a major earthquake, stroke death occurs more frequently than coronary heart
disease death in very old subjects.
PMID- 9560087
TI - Risk factors determining mortality in older diabetics: a pilot study in Japanese
patients.
PMID- 9560088
TI - Weight loss precedes Alzheimer's disease symptoms: a case study.
PMID- 9560089
TI - Patent ductus arteriosus in older people.
PMID- 9560090
TI - Rescuing the doctor: swimming lessons for physician-educators.
PMID- 9560091
TI - Intracranial tumors mimicking benign paroxysmal positional vertigo.
AB - Benign paroxysmal positional vertigo is a common type of vertigo seen by the
otolaryngologist; however, intracranial tumors can mimic benign paroxysmal
positional vertigo in their presentation. A review of patients seen in the
Department of Otolaryngology at The Ohio State University between July 1992 and
August 1996 identified five patients with intracranial pathologic conditions
mimicking benign paroxysmal positional vertigo. These patients were first seen
with episodic vertigo associated with positional change. Failure of the symptoms
to respond to the particle repositioning maneuver or the finding of associated
auditory or neurologic symptoms prompted further evaluation by magnetic resonance
imaging of the brain, which revealed intracranial pathologic conditions including
two meningiomas, a vestibular schwannoma, a glioma, and a lipoma. These findings
suggest that patients seen with symptoms like those of benign paroxysmal
positional vertigo who do not show improvement after undergoing the particle
repositioning maneuver or those who describe associated auditory or neurologic
symptoms should have magnetic resonance imaging done to rule out intracranial
pathologic conditions. Additionally, benign paroxysmal positional vertigo and
intracranial tumors may coexist.
PMID- 9560092
TI - Management of otitis media using Agency for Health Care Policy and Research
guidelines. The Agency for Health Care Policy and Research.
AB - Increased costs of managing otitis media and its complications may result from
delays in diagnosis and treatment. The Agency for Health Care Policy and Research
developed guidelines to assist in the management of chronic otitis media with
effusion. We examined the medical care adherence to Agency for Health Care Policy
and Research guidelines in 59 consecutive patients referred because of chronic
otitis media with effusion and recurrent acute otitis media. Patient history and
examination data were collected prospectively. In the group with chronic otitis
media with effusion, the rate of adherence to Agency for Health Care Policy and
Research guidelines was 0%; in those with recurrent acute otitis media, adherence
was 5%. Delayed referral occurred in 34% of patients; 25% of patients were
referred early. The average duration of effusion in patients with chronic otitis
media with effusion was 5.2 months; the duration of recurrent acute otitis media
immediately before referral was 9.3 months. Eighteen patients (47%) in the
chronic otitis media with effusion group had a history of recurrent chronic
otitis media with effusion spanning an average of 22.7 months. On referral,
hearing loss was discovered in 92% of all patients, and in 69% the tympanogram
was flat. The complication and sequelae rate was 49.1%, and speech delay was the
most frequent at 16.9%. We conclude that in our study patients there is a
significant referral delay, long history of chronic otitis media with effusion in
patients before referral, high rate of hearing loss, and high complication rate.
Continued efforts should be directed toward improving education of all clinicians
so that diagnostic tools and timely otolaryngologic referral are better used.
PMID- 9560093
TI - Resistance to biofilm formation on otologic implant materials.
AB - New materials and coatings are now being developed to resist permanent bacterial
contamination of implanted medical devices. This study exposed several styles of
middle ear ventilation tube materials and coatings to high concentrations of
Pseudomonas and Staphylococcus. Electron microscopy was then used to evaluate
these tubes' resistance to bacterial biofilm formations. Ionized, processed
silicone tubes were the only tubes resistant to Pseudomonas adhesion. Tubes that
were made of fluoroplastic or that were ionized processed were very resistant to
Staphylococcus contamination when compared with untreated silicone or silver
oxide-treated silicone. This study suggests that ionized, coated fluoroplastic
would be a highly effective tube material in preventing bacterial biofilm
contamination of implanted ventilation tubes.
PMID- 9560094
TI - Botulinum toxin decreases salivation from canine submandibular glands.
AB - The objective of this study was to determine whether botulinum toxin types A and
D reduced the production of saliva from the submandibular glands of 18 dogs. The
left submandibular glands of 8 dogs were injected with increasing doses of
botulinum type A toxin (range 10 to 70 units), and the left glands of 10 dogs
were injected with botulinum type D toxin (50 or 100 units). The right gland of
each dog was injected with equivalent volumes of saline solution to serve as
control. Six days after the injection, the lingual nerve was electrically
stimulated for 10 minutes (3 mAmp, 20 Hz). The resulting volume of saliva was
collected and weighed. Overall, the glands injected with types A or D toxin
produced significantly less saliva than comparable glands injected with saline
solution. Six of 8 dogs injected with type A toxin showed a significant decrease
in saliva production (range 10.1% to 19.2%, one-sided p value = 0.0375) when
compared with the controls. Nine of 10 dogs injected with type D toxin
demonstrated a highly significant reduction in saliva production (total average
decrease = 60%, two-sided pvalue = 0.001) when compared with the controls. We
concluded that intraglandular injections of botulinum toxin types A and D
significantly reduced the production of saliva from canine submandibular glands.
The potential applications of intraglandular injections of botulinum toxin are
discussed.
PMID- 9560095
TI - Current trends in laryngectomy rehabilitation: a survey of speech-language
pathologists.
AB - This study determined the perceptions of experienced speech-language pathologists
regarding current practices in the speech rehabilitation of laryngectomy patients
since the introduction of the tracheoesophageal puncture-voice prosthesis
technique in 1980. The sample population consisted of 151 experienced speech
language pathologists, or 43% of those who were sent questionnaires. The speech
language pathologists ranked tracheoesophageal puncture-voice prosthesis as their
most preferred speech rehabilitation method and the electrolarynx as their least
preferred, even though the electrolarynx continues to be the most frequently used
method. Variable use of the tracheoesophageal puncture procedure by
otolaryngologists was reported, with only a small portion perceived as using it
routinely. About 65% of the speech-language pathologists reported that more than
half of the laryngectomy patients were being given choices among speech
rehabilitation methods. Nearly 50% of the speech-language pathologists reported
that fewer than six speech therapy sessions were necessary with tracheoesophageal
puncture patients, whereas more than 20% reported the need for 10 sessions or
more. Use of manual closure of the tracheostoma by tracheoesophageal puncture
patients far outweighed their use of automatic speaking valves. Most speech
language pathologists reported that they were involved in teams with
otolaryngologists to determine patient suitability for tracheoesophageal puncture
and to troubleshoot problems. Eighteen different categories of medical and speech
production problems were reported.
PMID- 9560096
TI - Fenretinide-induced apoptosis of human head and neck squamous carcinoma cell
lines.
AB - BACKGROUND: Squamous cell carcinoma of the head and neck (HNSCC) has a high
incidence of recurrence and associated second primary malignancy. The retinoid 13
cis-retinoic acid has been shown to be effective as both a chemopreventive and
chemotherapeutic agent for HNSCC, but often with treatment-limiting toxicity. The
synthetic retinoid fenretinide (N-(4-hydroxyphenyl)retinamide) (HPR) has
significant antiproliferative activity against a number of animal and human
malignancies and has been used in clinical trials as a chemopreventive agent in
patients with breast and prostate cancer and oral leukoplakia. HPR has been shown
to have a toxicity profile lower than that for other retinoids used in clinical
trials. PURPOSE: The aim of this study was to investigate the effect of HPR on
the growth of HNSCC cell lines in vitro. METHODS: Four HNSCC cell lines (JHU-011
SCC, JHU-020-SCC, JHU-022-SCC, and FaDu) were treated with a range of
concentrations of HPR for various times. After HPR exposure, cell viability was
determined by tetrazolium dye (MTT) colorimetric assay, comparing cell survival
with that of untreated control cells. HPR-induced apoptosis was determined by
flow-cytometric deoxyribonucleic acid cell-cycle analysis, ultrastructural
analysis with electron microscopy, and deoxyribonucleic acid fragmentation
detected by gel electrophoresis. RESULTS: HPR caused significant growth
inhibition in three of the four HNSCC cell lines in a dose- and time-dependent
fashion. In two cell lines (JHU-011-SCC, JHU-020-SCC) a significant
antiproliferative effect was achieved between 1 and 2.5 micromol/L HPR after 72
hours of treatment. By deoxyribonucleic acid cell-cycle analysis, electron
microscopy, and gel electrophoresis, HPR was shown to induce apoptosis in the JHU
011-SCC and JHU-020-SCC cell lines, but not in the FaDu cell line, which was
insensitive to the growth inhibitory effect of HPR. CONCLUSIONS: This study has
demonstrated that HPR reduces cell viability in HNSCC cells in vitro at
clinically relevant doses, with the growth inhibition occurring through the
induction of apoptosis.
PMID- 9560097
TI - Leukotrienes C4 and D4 increase the ciliary beat frequency in human upper airway
mucosa in vitro.
AB - It has been suggested that leukotrienes C4 (LTC4) and D4 (LTD4) released from
upper respiratory mucosa influence mucociliary transport during allergic
reactions. We studied the in vitro effects of leukotrienes C4 and D4 on the
ciliary beat frequency (CBF) of human adenoid explants over a 5-hour period.
Tissue explants were cultured at 35 degrees C in Minimum Essential Medium Eagle
(MEM). The CBF was measured using phase contrast microscopy and microphotometry.
Measurements of CBF were recorded in medium alone and in medium containing LTC4
or LTD4 at concentrations of 10(-8) and 10(-6) M. LTC4 and LTD4 increased CBF at
concentrations of 10(-8) and 10(-6) M with increases of 20.51% +/- 2.69% and
29.84% +/- 4.06%, respectively. To determine the specificity of the LTC4 and LTD4
effects, the ciliated epithelium was treated with the specific leukotriene
receptor antagonist LY-171,883 before administration of LTC4 and LTD4. LY-171,883
(10(-6) M) significantly inhibited the ciliostimulatory effects of both
leukotrienes. Our findings indicate that LTC4 and LTD4 increase CBF in vitro by
activation of the LTD4 receptor.
PMID- 9560098
TI - Analysis of short-term outcome after office-based laser-assisted
uvulopalatoplasty.
AB - To determine the short-term effectiveness and outcome of office-based laser
assisted uvulopalatoplasty, a prospective statistically controlled study was done
at the Department of Otolaryngology, Cleveland Clinic Florida. Thirty-eight
consecutive snoring patients underwent a total of 98 laser-assisted
uvulopalatoplasties, and data were gathered through examination, interview, and
analog scales of snoring, pain, and other morbidity. In addition, a failure
analysis was performed. Data were analyzed by descriptive statistics, confidence
intervals, and adjusted analysis of variance (p < 0.008). Our results suggest
that snoring decreased significantly around each laser-assisted uvulopalatoplasty
treatment performed (4 to 8 weeks apart). Postoperative pain diminished after the
first two laser-assisted uvulopalatoplasty treatments. The only morbidity in the
series was the result of significant pain, causing 77% of laser-assisted
uvulopalatoplasty failures.
PMID- 9560099
TI - Cause of hoarseness in elderly patients.
AB - Hoarseness is a common symptom in older individuals and may reflect a wide
variety of pathologic, medical, physiologic, and/or functional causes. Although
vocal fold atrophy is one of the more common reported findings in the elderly,
inconclusive information is known about the differential diagnosis and cause of
dysphonia in older individuals. The purpose of this investigation was to review
the cause of hoarseness in all patients older than 65 years and to determine any
correlation with advancing age and other demographic factors. Additionally, we
wanted to determine the effect vocal pathology has on objective voice measures
with advancing age. The two most common causes of hoarseness found in 393
patients older than 65 years were vocal fold bowing and unilateral vocal fold
paralysis, followed by benign vocal fold lesions, voice tremor, and spasmodic
dysphonia. Although objective measures of vocal function were abnormal compared
with reported normative data, they did not increase in severity with advancing
age. Apparently, the compounding effect of age on underlying vocal pathology does
not increase the severity of the vocal disturbance, at least as represented by
objective voice measures. The high incidence of medical illnesses seen in this
population also needs to be kept in mind because it may further affect the
underlying voice disturbance. It might be interesting to compare data on the
patients' perceptions of their vocal disturbance for each disorder as a function
of age. It would also be helpful to know whether patients responded to treatment
differentially based on age.
PMID- 9560100
TI - Carbon dioxide laser surgery for snoring: results in 192 patients.
AB - Laser-assisted uvulopalatoplasty has been introduced as an alternative to
uvulopalatopharyngoplasty for treatment of snoring and potentially of obstructive
sleep apnea syndrome. Between July 1994 and June 1996, 192 patients underwent 227
laser-assisted uvulopalatoplasty procedures. Loud habitual snoring was evaluated
in 42 women (21.8%) and 150 men (78.2%), who were then treated with laser
assisted uvulopalatoplasty. Among the 192 patients (227 procedures), with ages
from 18 to 81 years (mean 42.6 years), 15.6% (30 patients) had more than one
laser-assisted uvulopalatoplasty treatment. In our series, 80 patients (42.1%)
had a history of obstructive sleep apnea syndrome in addition to snoring. Laser
assisted uvulopalatoplasty treatment in patients with loud snoring resulted in
elimination of snoring in 61%, partial improvement of snoring in 26%, and no
improvement in 13%. The overall success rate was 87%. The mean body mass index
was significantly higher in the patients with no response after the operation
(27.9 kg/m2) compared with that in the patients with a good response (25.9
kg/m2). Obese (body mass index >30 kg/m2) patients were more likely to have no
response to laser-assisted uvulopalatoplasty treatment of snoring than patients
with an ideal body weight (body mass index <25 kg/m2) (p < 0.01). We conclude
that the body mass index may be of significant value in the postoperative success
rate of laser-assisted uvulopalatoplasty for the treatment of snoring.
PMID- 9560101
TI - Interleukin-4, interleukin-5, and granulocyte-macrophage colony-stimulating
factor receptor expression in chronic sinusitis and response to topical steroids.
AB - Chronic sinusitis and its associated eosinophilic infiltrate are believed to be
mediated, at least in part, by the upregulation of Th-2 cytokines, including
interleukin-4, interleukin-5, and granulocyte-macrophage colony-stimulating
factor (GM-CSF). Interleukin-4 is involved in IgE production and in eosinophil
recruitment through upregulation of vascular cell adhesion molecule-1.
Interleukin-5 and GM-CSF are involved in eosinophil growth and survival. The aim
of this study was to investigate the expression of receptors for these cytokines
in the sinus mucosa of subjects with chronic sinusitis. Using the technique of in
situ hybridization to detect specific cytokine receptor messenger RNA, we studied
the sinus mucosa of subjects with nonallergic chronic sinusitis, subjects with
allergic chronic sinusitis, subjects with allergic chronic sinusitis treated with
topical steroids, and normal controls. Our data demonstrate higher expression of
interleukin-4 receptor in subjects with allergic chronic sinusitis than in
controls (p < 0.001) and higher expression of interleukin-5 receptor in both
subjects with nonallergic chronic sinusitis and subjects with allergic chronic
sinusitis than in controls (p < 0.001, p < 0.001). The expression of interleukin
4 receptor and interleukin-5 receptor was higher in subjects with allergic
chronic sinusitis than in subjects with nonallergic chronic sinusitis (p <
0.001). GM-CSF receptor expression was also found to be higher in subjects with
allergic chronic sinusitis and subjects with nonallergic chronic sinusitis than
in controls (p < 0.001, p < 0.001). In contrast to interleukin-4 receptor and
interleukin-5 receptor, however, expression of GM-CSF receptor was higher in
subjects with nonallergic chronic sinusitis than in subjects with allergic
chronic sinusitis (p < 0.001). In subjects with allergic chronic sinusitis
treated with topical corticosteroids, the expression of interleukin-4 receptor
and interleukin-5 receptor messenger RNA levels was significantly lower than
levels in patients with allergic chronic sinusitis who were not taking topical
steroids (p < 0.001, p < 0.001). Steroid treatment had no effect on GM-CSF
receptor messenger RNA expression. In conclusion, our data support a role for Th
2 cytokine receptors in the pathophysiology of chronic sinusitis. Further, our
data lend support to the theory that differential activation of distinct cytokine
pathways mediates inflammation in chronic sinusitis depending on whether there is
associated allergy. Finally, treatment with topical corticosteroids has been
demonstrated in chronic sinusitis to downregulate receptors for interleukin-4 and
interleukin-5.
PMID- 9560102
TI - Intratumoral cisplatin/epinephrine-injectable gel as a palliative treatment for
accessible solid tumors: a multicenter pilot study.
AB - Intratumoral injections of cisplatin/epinephrine-injectable gel were administered
weekly for 4 weeks in 45 patients with malignant tumors of various histologic
types. Tumors were located on the skin and subcutaneous tissue primarily of the
head, neck, and trunk, and on the tongue, oral pharynx, and esophagus. Patients
were not candidates for surgery, radiation, or systemic chemotherapy. Each of the
treated tumors (n = 82) was evaluated 2, 4, 8, and 12 weeks after the final
injection. The initial dose of cisplatin was 1 mg/cm3 tumor volume, with
escalation to 6 mg/cm3 allowed, depending on observed toxicities. The mean
cumulative dose per patient for the four treatments ranged from 0.56 to 380 mg
cisplatin. No dose-limiting cisplatin-related toxicities, such as nephrotoxicity,
neurotoxicity, or ototoxicity, were observed. The overall objective tumor
response rate was 50% (41 of 82), with 40% (33 of 82) complete responses and a
median response duration of 160 days. Complete responses for adenocarcinoma and
squamous cell carcinoma were 58% (21 of 36) and 38% (12 of 32), respectively.
These results justified further clinical trials to evaluate the role of local
chemotherapy with intratumoral cisplatin/epinephrine-injectable gel in the
palliative treatment of patients with selected accessible solid tumors.
PMID- 9560103
TI - Interleukin-6 expression in chronic sinusitis: colocalization of gene transcripts
to eosinophils, macrophages, T lymphocytes, and mast cells.
AB - Chronic sinusitis in allergic (ACS) and nonallergic (NCS) patients is
characterized by persistent inflammation and subepithelial fibrosis of the sinus
mucosa. The inflammatory infiltrate is rich in T lymphocytes,
monocyte/macrophages, plasma cells, and eosinophils. Th2-type cytokines are
thought to regulate inflammatory cell recruitment, activation, survival, and the
release of tissue-damaging mediators. Interleukin-6 is a proinflammatory Th2-type
cytokine that stimulates fibroblast proliferation and collagen synthesis.
Expression of interleukin-6 has been reported in pulmonary fibrosis and a number
of other conditions associated with fibrotic tissue changes. In vitro studies
have indicated that interleukin-6 is produced by macrophages, T cells,
eosinophils, mast cells, and other cell types. Here we examined interleukin-6
messenger RNA and immunoreactivity in the sinus epithelium and subepithelium of
subjects with ACS and NCS by in situ hybridization and immunocytochemistry,
performed on sinus biopsy and polyp sections obtained from patients. Nasal
turbinate biopsy specimens from normal volunteers were used as controls.
Interleukin-6 messenger RNA and immunoreactivity were expressed by a
significantly greater proportion of epithelial and subepithelial cells in ACS and
NCS subjects than in normal controls. There was no difference in epithelial or
subepithelial interleukin-6 expression between ACS and NCS patients.
Colocalization studies revealed that macrophages, T cells, eosinophils, and mast
cells are sources of interleukin-6 messenger RNA in ACS and NCS. The numbers of
interleukin-6 messenger RNA-positive cells coexpressing immunoreactivity for the
mast-cell marker were significantly greater in ACS than in NCS subjects. The
results of this study suggest a role for interleukin-6 in the inflammatory
response of chronic sinusitis.
PMID- 9560104
TI - Long-term model of induced canine phonation.
AB - Experimental induced phonation in the dog has been used in short-term studies by
several investigators and has proved quite useful in laryngeal research. In this
study a long-term canine phonation model is described that uses permanently
implanted electrodes on the superior and recurrent laryngeal nerves. A serial
induced phonation model has not been previously reported and is needed for
laryngeal research in which voice results are a primary end point. Inexpensive,
reliable, nontoxic electrodes were designed and fabricated. The laryngeal nerves
were found to be quite susceptible to injury, necessitating a series of changes
in electrode design. Electrode durability and laryngeal nerve viability improved
with each design modification; the final design gave a recurrent laryngeal nerve
viability rate of 100% at 6 weeks, 83% at 9 weeks, and 73% at 12 weeks. Induced
phonation was successfully produced on a repeated basis by stimulating the
recurrent laryngeal nerves while passing air through the larynx, in 22 (95.6%) of
23 animals. Stimulation of the superior laryngeal nerves increased vocal fold
length and tension but was not required for phonation. Technical aspects of
chronic implantation and stimulation of the laryngeal nerves are discussed. The
development and successful long-term implantation of electrodes on the laryngeal
nerves and their use in repeated induced phonation have not been reported
previously.
PMID- 9560105
TI - Squamous cell carcinoma of the supraglottic larynx in a patient with Fanconi's
anemia.
PMID- 9560106
TI - Giant cell reparative granuloma of the temporal bone: case report and review of
the literature.
PMID- 9560107
TI - Radiation-induced malignant fibrous histiocytoma of the head and neck.
PMID- 9560108
TI - The cochlear aqueduct: an important landmark in lateral skull base surgery.
AB - The cochlear aqueduct (CA) is used as a landmark in lateral skull base surgery.
In this study anatomic relationships between the CA and adjacent neurovascular
structures were examined by dissecting 32 temporal bones. Observations of the
relationship of the external opening (EO) of the CA with the ninth, tenth, and
eleventh cranial nerves, inferior petrosal sinus (IPS), and intrapetrous carotid
artery (ICA) were noted. In addition to the distance of the EO of the CA to the
vertical portion of the ICA, the entire length of the CA and the width of the EO
were also measured. The ninth nerve was the only structure lodged at the EO of
the CA in 34.4% of bones. However, in 40.6% of bones only the IPS crossed the EO
of the CA, although the ninth nerve was situated just anteroinferiorly in the
vicinity of the EO. In 15.6% of bones it was possible to observe both the ninth
nerve and the IPS crossing the EO. In 9.4% of bones the EO of the CA was found to
be occupied by the tenth and eleventh nerves. It was also observed that the ICA
was located anteriorly on the same sagittal plane with the EO in 15.6% of bones.
It was concluded that although in 90% of cases the EO of the CA was in close
relation with the ninth nerve, other structures such as the IPS, the tenth and
eleventh cranial nerves, and the ICA were also at risk during drilling in this
area because of their intimate relationships with the EO of the CA.
PMID- 9560109
TI - Changes in laryngeal muscle activities during hypercapnia in the cat.
AB - The larynx has three functions: phonation, airway protection, and respiration.
Few studies have dealt with laryngeal respiratory function. To elucidate
respiratory regulation by the larynx, we studied the changes in the activity of
the intrinsic laryngeal muscles during hypercapnia in decerebrated cats. The
electromyographic activities of the posterior cricoarytenoid (PCA) and
thyroarytenoid (TA) muscles were recorded simultaneously with an electromyogram
of the diaphragm, endotracheal pressure, and concentrations of O2 and CO2. The
activity of the intrinsic laryngeal muscles during hypercapnia (end-tidal CO2, 8%
to 10%) was analyzed in comparison with that during eucapnia. In hypercapnia,
both the PCA and TA muscles increased their activities, and the endotracheal
pressure during expiration was elevated to a higher level than that in eucapnia.
TA muscle activities returned to the level during eucapnia after ligation of the
common carotid arteries. These findings suggest that hypercapnia causes a further
widening of the glottis during inspiration to decrease inspiratory resistance and
a further narrowing of the glottis during expiration to prevent alveolar
collapse. Thus it may be concluded that the larynx actively participates in
respiratory regulation under the control of the brain stem through a process of
peripheral inputs from the carotid receptors.
PMID- 9560110
TI - Objective scaling of facial nerve function based on area analysis (OSCAR).
AB - An objective scaling of facial nerve function based on area analysis (OSCAR) was
developed using the variations of luminance produced by changes of facial
expression. The presented method of scaling facial motions has the advantage of
being continuous, objective, and reproducible. It is fast and simple to use.
PMID- 9560111
TI - Vancomycin administration in continuous ambulatory peritoneal dialysis: the risk
of ototoxicity.
AB - A prospective study was undertaken in 16 patients with chronic renal failure on
continuous ambulatory peritoneal dialysis, with 22 episodes of peritonitis
treated with vancomycin, a known ototoxic agent. Twelve patients had one episode
each, and four had recurrent peritonitis. Each treatment course consisted of two
infusions of vancomycin (30 mg/kg body weight) in 2 L of peritoneal dialysate
administered at 6-day intervals. Serum vancomycin analyzed by enzyme immunoassay
showed a mean trough level of 11.00 microg/ml on day 6 and mean serum levels of
33.8 and 38.6 microg/ml about 12 hours after administration on days 1 and 7,
respectively. Similar levels, well within the therapeutic range, were encountered
with repeated vancomycin therapy for recurrent episodes of peritonitis,
suggesting that no changes occurred in the pharmacokinetic profile of the drug.
Pure-tone audiometry, electronystagmography, and clinical assessment performed
during each course of treatment showed no evidence of ototoxicity even on
repeated courses of vancomycin therapy. The results suggest that vancomycin
therapy when given in appropriate concentrations as a single therapeutic agent is
both effective and safe. We believe, however, that vancomycin administered in
combination with an aminoglycoside may produce ototoxic effects that may be
greatly aggravated, possibly because of synergism.
PMID- 9560112
TI - Tension pneumocephalus after frontal sinus gunshot wound.
PMID- 9560113
TI - Dermoid cyst of the floor of the mouth.
PMID- 9560114
TI - Healing of complex tracheostomy wounds.
PMID- 9560115
TI - The inflammatory response to open tension-free inguinal hernioplasty versus
conventional repairs.
AB - BACKGROUND: The tension-free inguinal hernioplasty is now a popular method
because of less postoperative disability and low recurrence rate. The laboratory
evaluation of the inflammatory response to the injury is an objective approach to
determine the stress status of a surgical procedure. The aim of this study is to
evaluate and to compare inflammatory responses to open tension-free and
conventional repairs of inguinal hernias. METHODS: Forty-eight male patients with
primary indirect inguinal hernias were treated with elective operations, and
separated into three groups according to surgical procedure: 12 pediatric
patients treated with dissection of hernia sac in group 1, 16 adult patients with
open tension-free hernioplasty in group 2, and 20 adult patients with
conventional repairs in group 3. Ten healthy adult volunteers formed group 4 as
control. The repair was performed with polypropylene mesh and suture as the
Lichtenstein technique in group 2, and with polypropylene suture as one of
Bassini, McVay, or Shouldice techniques in group 3. The inflammatory response was
evaluated with serum interleukin-6 (IL-6) levels at 12 hours and serum C-reactive
protein (CRP) levels at 48 hours postoperatively. Serum levels of IL-6 and CRP
were measured in group 4 as control. Patient characteristics, operating time, and
IL-6 and CRP levels were compared among the four groups. RESULTS: There were no
significant differences in mean age and operating time between the two groups of
adult patients with hernia repair. Mean serum IL-6 levels of 12.1 +/- 5.2 and 8.2
+/- 2.7 pg/mL, and CRP levels of 34.3 +/- 13.8 and 7.5 +/- 4 mg/L in pediatric
and control groups, respectively, were significantly lower than in the other two
hernia groups. Mean serum IL-6 levels were 58.9 +/- 25.4 pg/mL in group 2
(tension-free repair) and 44.3 +/- 18.1 pg/mL in group 3 (conventional repair) (P
> 0.05). Mean serum CRP levels were 111.3 +/- 41.3 and 83 +/- 43.2 mg/L in groups
2 and 3, respectively (P > 0.05). The differences not being statistically
significant, a similar and considerable inflammatory response was noted in
patients with either prosthetic mesh repair or with conventional repairs of
indirect inguinal hernias. CONCLUSIONS: The reinforcement of the posterior wall
of the inguinal canal induces significant cytokine response regardless of tension
free or conventional repair. Open tension-free hernioplasty offered no advantages
over conventional repairs from the standpoint of the inflammatory and acute phase
response.
PMID- 9560116
TI - A comparison of adrenalectomy with other resections for metastatic cancers.
AB - BACKGROUND: Although adrenal metastases were once considered incurable, recent
anecdotal reports recommend adrenalectomy for isolated metastases. METHODS:
Computerized files of all US Department of Veterans Affairs (DVA) hospital
admissions and deaths from 1988 to 1994 identified patients undergoing isolated
adrenal resections, and hospitalization records were obtained. Patients without a
death record were assumed to be alive. RESULTS: In 47 patients with adrenalectomy
for metastases, only 5 patients did not die within 3 years: 2 each had
metachronous renal or colorectal metastases, and 1 had a pulmonary primary.
Thirteen patients with other primary sites all expired within 3 years. Operative
mortality was 4% in these 47 patients and also in 706 other adrenalectomies
without metastases. CONCLUSIONS: Adrenalectomy for metastatic carcinoma in the
DVA was safe, with a projected 5-year survival rate (13%) that is significantly
inferior (P < or = 0.05) to resections for colorectal metastases to lung (36%) or
liver (26%), but superior to brain (none).
PMID- 9560117
TI - Restoration of anal sphincter function by single-stage dynamic graciloplasty with
a modified (split sling) technique.
AB - BACKGROUND: Controlled muscle fiber conversion by electrostimulation makes
transformation of fast twitching type II muscle fibers to slow twitching type I
fibers possible, which gives skeletal muscles the capacity for tetanic
contraction. This phenomenon has been recently applied in the so-called "dynamic
graciloplasty" to restore function of an insufficient or excised anal sphincter.
This paper describes our results with this method in patients with fecal
incontinence or following an abdomino-perineal resection (APR) of the anorectum.
METHODS: From April 1992 through April 1997, 28 patients (12 women and 16 men)
were treated by dynamic graciloplasty. The median age was 53.5 years (range 16 to
79). Indications were as follows: APR + synchronous restoration of the excised
sphincter by graciloplasty (n = 12); total anorectal reconstruction (TAR)
following APR in the past (n = 6); Patients with acquired fecal incontinence (n =
4); and Congenital atresia (n = 6). Muscle transposition, implantation of
stimulation electrodes and pulse generator were done as a single-stage procedure,
the "neosphincter" was wrapped in a modified technique (split-sling technique).
Muscle transformation was performed by controlled neuromuscular stimulation
during 8 weeks (from 1992 to 1995) and 4 weeks (since 1996), respectively.
RESULTS: No postoperative mortality (90 days) was observed in either group. In
our early experience, rectal injury occurred in 4 patients as the most prominent
complication. Evaluation of the functional outcome showed the best results in
patients operated either for congenital of acquired incontinence who achieved a
continence for solids and liquids or solids alone, respectively (1 or 2 according
to Williams' score) in 90%, while patients following APR showed a satisfying
outcome (continence for solids and liquids, solids alone or with occasional
episodes for liquids) in only 55.5%. In patients following APR, defecation
disorders turned out to be the most prominent functional problem and had to be
treated by enemas. CONCLUSION: In this series, we have been able to perform
dynamic graciloplasty as a one-stage procedure using a modified muscle wrap
(split-sling-technique) thus reducing the time period until continence could be
achieved to 7 weeks. We found the appropriate tension of the muscle wrap
essential to prevent direct injury to the rectum as it was seen in our early
experience. For this reason, we have introduced a modified device to perform
intraoperative anal manometry and to measure pressures created by the
neosphincter objectively.
PMID- 9560118
TI - Initial clinical experience with colonic stent placement.
AB - BACKGROUND: The purpose of this study is to review initial experience with a
colonic stent as an alternative to colostomy in patients with colonic
obstruction. METHODS: Ten patients diagnosed with acute colonic obstructions from
both benign and malignant causes underwent stent placement. Self-expandable
metallic stents were deployed using fluoroscopic guidance. Patients were followed
up clinically until removal of the stent or death. RESULTS: Nine of the 10
patients who underwent colonic stent placement achieved clinical decompression
within 6 hours. Six patients underwent standard mechanical bowel preparation and
elective resection of obstructing lesions. The other 4 patients received stent
placement for palliative purposes. Complications included 4 cases of migration
and 1 death. Migrated stents in the rectum were easily retrieved and replaced
using fluoroscopic techniques. There were no perforations. CONCLUSION: Placement
of self-expandable metallic stents for acute colonic obstructions may allow
patients to undergo elective surgical resection avoiding possible colostomy.
PMID- 9560119
TI - The type of K-ras mutation determines prognosis in colorectal cancer.
AB - BACKGROUND: Mutations involving the oncogene K-ras in colorectal cancer may be
related to tumor aggressiveness. However, the value of K-ras gene determination
as a prognostic marker has not been clearly established. PATIENTS AND METHODS:
The results from 98 patients recruited in a prospective study analyzing the
effect of a K-ras mutation as a prognostic factor in colorectal cancer are
reported. RESULTS: Disease-free (P = 0.02) and overall survival (P = 0.03) were
significantly reduced for patients harboring a K-ras mutation. Two specific
mutations demonstrated a significantly increased risk of disease recurrence,
namely, 12-TGT (P = 0.04) and 13-GAC substitutions (P = 0.002). Patients with
either of these substitutions had a 2-year disease-free survival rate of 37%
compared with that of 67% for the group of patients harboring any other mutation
type or a wild-type status (P = 0.01). CONCLUSIONS: The results herein presented
suggest that K-ras acts as a prognostic factor in colorectal cancer and that this
effect is probably related to a limited number of defined mutations.
PMID- 9560120
TI - Comparison of endoscopic retrograde and magnetic resonance
cholangiopancreatography in the surgical diagnosis of pancreatic diseases.
AB - BACKGROUND: Magnetic resonance cholangiopancreatography (MRCP) is a newly
developing noninvasive examination of the biliopancreatic trees. Roles of MRCP in
the diagnosis of pancreatic diseases have not been scrutinized. METHODS:
Endoscopic retrograde cholangiopancreatography (ERCP) and MRCP were reviewed in
52 Japanese patients with various pancreatic diseases and 6 patients with normal
pancreas to compare their diagnostic usefulness and limitation. RESULTS: In those
with normal pancreas, only the main pancreatic duct was visualized by MRCP, while
both the main pancreatic and branch ducts were clearly delineated by ERCP. In 3
patients with serous cystadenoma, the tumor was not visualized by ERCP, whereas
it was visible as a high-intensity mass on MRCP. Of 18 patients with a "mucin
hypersecreting" tumor of the branch type, MRCP demonstrated cystically dilated
branch ducts in all, while ERCP failed to visualize the dilated ducts in 6
patients. However, the details of the cystic lesions (mural nodule, communication
with the main pancreatic duct) were more exactly demonstrated by ERCP than MRCP.
In 5 patients with a mucin hypersecreting tumor of the main pancreatic duct type,
the dilated main pancreatic duct and the presence of mural nodules were similarly
demonstrated both by ERCP and MRCP. In 12 patients with pancreatic
adenocarcinoma, indirect findings were similarly demonstrated both by ERCP and
MRCP, ie, stenosis (4 patients) and obstruction (8) together with dilation of the
main pancreatic duct (9). In 3 patients, the center of the mass showed high
intensity on MRCP, suggesting the secondary change of pancreatic carcinoma. In 8
patients with obstruction of the main pancreatic duct due to carcinoma, the
distal pancreatic duct was visualized by MRCP but not by ERCP. In 9 patients who
had undergone pylorus-preserving or standard pancreatoduodenectomy, follow-up
MRCP was obtainable in all examined and displayed the main pancreatic duct.
CONCLUSIONS: MRCP plays a complementary role in the surgical diagnosis of
pancreatic disorders and is especially useful to examine the pancreatic duct
after pancreatoduodenectomy.
PMID- 9560122
TI - Limb salvage for streptococcal gangrene of the extremity.
AB - BACKGROUND: Extremity soft tissue infections from group A, beta-hemolytic
streptococcus frequently culminate in amputation. This study compares our
protocol for limb salvage with expected results. METHODS: Patients with extremity
streptococcal gangrene treated from 1989 to 1995 were reviewed. The management
protocol mandated immediate, radical excision of involved skin and subcutaneous
tissue, with preservation of fascia. Patients were managed in the burn unit, and
wounds were covered with split-thickness skin grafts. Amputation rate and
mortality were measured. RESULTS: Fourteen cases of extremity streptococcal
gangrene were identified. Delay to surgical referral was 5 days. Eleven (79%)
patients were septic. Ten (71%) were managed with a single debridement before
grafting. Limb salvage was 93% (13 of 14). One patient (7%) died on day 150 from
acute myelogenous leukemia. CONCLUSIONS: Delay in referral of extremity
streptococcal gangrene is common, contributing to a high incidence of sepsis. Our
management protocol of a single, radical debridement with preservation of fascia
maximizes limb salvage and survival.
PMID- 9560121
TI - Effects of aging on the functional outcome of coloanal anastomosis with colonic J
pouch.
AB - BACKGROUND: Many low rectal cancers can be treated radically by proctectomy with
total mesorectal excision followed by colonic J-pouch anal anastomosis (CPAA). In
elderly patients, the fear of poor function might reduce indications for CPAA in
favor of abdomino-perineal excision with end stoma. METHODS: Among 198 patients
with CPAA operated on for low rectal cancer between 1984 and 1992, 20 patients
over 75 years old were alive without recurrence at the time of telephone
interview (July 1995). Minimal follow-up was 3 years (mean 8) for all patients.
Their functional results were compared with those of 37 younger patients operated
consecutively during the last 5 years of the study period. RESULTS: The two
groups were well matched for gender, tumor distance from the anal verge,
histologic staging, and use of adjuvant radiotherapy. Follow-up was longer in the
elderly group than in the young group (96 versus 63 months, respectively). The
elderly group had a median of 1 bowel movement per day and the young group a
median of 1.5 (P = 0.13). The presence of irregular intestinal transit was
reported in 48% of the aged and in 35% of the young group (P = 0.6), but
fragmented defecation was less frequent (25% versus 47%, respectively; P = 0.15).
Urgency was noted, respectively, in 15% and 22% of elderly and young patients (P
= 0.7) and constipation in 40% and 22% (P = 0.2). Incontinence for feces (15%)
and for flatus (40%) in elderly were not significantly different from the younger
group (14% and 46%, P = 1.0 and P = 0.8, respectively). Laxatives were used in
32% of elderly and 17% of young patients (P = 0.3). CONCLUSION: Functional
outcome may be good to excellent in elderly patients after CPAA and compares well
with that obtained in younger patients. Constipation, however, may be more
frequent in the elderly. Age is not a contraindication for CPAA if the sphincter
tone is clinically normal.
PMID- 9560123
TI - Biliary tract cancer accompanied by anomalous junction of pancreaticobiliary
ductal system in adults.
AB - BACKGROUND: Anomalous junction of the pancreaticobiliary ductal system (AJPBDS)
is a congenital anomaly in which the junction is located outside the duodenal
wall. Recently, attention has been focused on the high incidence of malignancy in
this anomaly. The purpose of this study was to clarify the clinicopathological
features of this anomaly and to determine the appropriate surgical approach for
biliary tract cancer associated with AJPBDS. METHODS: The data for 38 patients
with AJPBDS, including 14 who had been treated for biliary tract cancer (2 with
bile duct cancer and 12 with gallbladder cancer), were retrospectively reviewed.
We assessed the clinical features, characteristics of the tumor, operative
procedure, and outcome for each patient. RESULTS: The incidence of malignancy in
AJPBDS was 17.8% (2 patients with bile duct cancer and 3 with gallbladder cancer)
in the bile duct dilatation group (n = 28) and 90% (9 patients with gallbladder
cancer) in the no-dilatation group (n = 10) . The mean length of the common
channel was 24.7 mm (range 20 to 35 mm) . Resection with lymphadenectomy was
performed in 9 (64.3%) of 14 patients, and curative resection in 5 of these 9
patients. Ten (71%) of the 14 patients had lymph node involvement noted either at
the time of initial diagnosis or at surgery. The incidence of lymph node
metastasis was closely related to the depth of tumor involvement. Ten patients
died of recurrence or primary cancer, from 3 to 30 months after operation. Four
patients are still alive without recurrent disease from 2.5 to 13 years after
operation. CONCLUSION: For patients with AJPBDS without bile duct dilatation,
prophylactic cholecystectomy is recommended even if no malignant lesion is found
in the gallbladder because of the high incidence of gallbladder cancer and the
poor prognosis. Both early detection and curative resection of the tumor are
essential for successful treatment of biliary tract cancer.
PMID- 9560124
TI - Regulation of albumin mRNA and its promoter-binding nuclear factors under
different perioperative nutritional methods in hepatectomized rats.
AB - BACKGROUND: Regulation of perioperative albumin synthesis under parenteral (PN)
and enteral (EN) nutrition was investigated. METHODS: Rats were divided into PN
and EN groups. Both groups received the same regimen of artificial nutrition for
7 days and then underwent 70% hepatectomy. Serum albumin and mRNA levels of
albumin and its promoter-binding nuclear factors (C/EBPalpha, beta, and DBP) were
measured. RESULTS: Serum albumin and albumin mRNA in the PN group were
significantly lower than those in the EN group at 72 hours after hepatectomy.
Preoperative and postoperative DBP and C/EBPalpha mRNA levels in the EN group
were significantly higher than those in the PN group. CONCLUSION: Serum albumin
was well maintained by EN after hepatectomy owing to an early recovery of albumin
mRNA level and its nuclear factor mRNA levels (C/EBPalpha and DBP). Compared with
PN, EN is a more advantageous from of perioperative nutrition as pertains to
albumin synthesis.
PMID- 9560125
TI - Litmus paper helps detect potential pancreatoenterostomy leakage.
AB - BACKGROUND: Leakage of pancreatoenterostomy remains as a serious and fatal
complication after pancreatectomy. Several risk factors have been reported, ie,
normal pancreatic parenchyma, small pancreatic duct, a large amount of
intraoperative blood loss, management of the cut surface of the pancreas, and the
presence of preoperative jaundice. Transected pancreatic ductules on the cut
surface of the pancreas that are not drained into the main pancreatic duct after
pancreatectomy are one of the risks. The pancreatic juice is alkaline and turns
red litmus to blue. METHODS: In order to detect the transected pancreatic
ductules on the cut surface of the pancreas, red litmus paper is applied to the
cutting surface of the pancreas after stimulation of secretin. RESULTS:
Nondrained, transected pancreatic ductules on the cut surface of the pancreas can
be detected as blue spots on the red litmus paper. The corresponding areas to the
blue spots can be transfixed with sutures to close the nondrained and transected
pancreatic ductules. CONCLUSION: Litmus paper can be expected to detect
pancreatoenterostomy leakage after pancreatectomy.
PMID- 9560126
TI - Segments I and IV resection as a new approach for hepatic hilar
cholangiocarcinoma.
AB - Major hepatic resection for biliary tract carcinoma with obstructive jaundice has
been reported on as bringing about high surgical morbidity and mortality rates.
It has been also revealed that the extent of hepatic resection is closely
associated with the occurrence of postoperative complications. Therefore, hepatic
resection, limited as much as possible to what is necessary for curative
resection, should be performed according to cancer extent. We performed a new
surgical approach in 3 patients with hepatic hilar cholangiocarcinoma that
included total resection of hepatic segments I and IV (by Couinaud's
classification) and bile duct resection with hepaticojejunostomy of 4 to 6
intrahepatic bile duct stumps. All patients underwent curative surgical
resections and were discharged within 6 weeks after surgery, without any serious
complications. This limited resection of hepatic segments I and IV could be an
effective radical surgical procedure for hepatic hilar cholangiocarcinoma, to
avoid the occurrence of postoperative liver failure.
PMID- 9560127
TI - Laparoscopic appendectomy does not change the incidence of postoperative
infectious complications.
AB - BACKGROUND: It is not clear whether the laparoscopic approach does decrease the
incidence of postoperative infectious complications after appendectomy. METHODS:
One hundred sixty-nine patients were randomized, 87 with laparoscopic (LA) and 82
with open appendectomy (OA). Patients in the OA group had a McBurney incision; LA
was performed in the lithotomy position. RESULTS: Acute appendicitis was
confirmed in 75% of patients. The appendix was perforated in 5 patients of the LA
versus 2 patients of the OA group. No conversion to the open procedure was
necessary. The median operating time was 35 minutes in the LA group and 31
minutes in the open group (P = 0.58). The median postoperative hospital stay was
shorter after laparoscopic than after open surgery (3 days versus 4 days, P =
0.026), whereas the time required for return to work was not significantly
different (14 versus 15 days). There were 5 (6%) patients with superficial wound
infection following LA and 6 (7%) after OA (P = 0.67). Intra-abdominal fluid
collections were found in 2 (2%) patients following LA and 3 (4%) patients
following OA (P = 0.60). In the LA group, 3 patients presented with intra
abdominal hemorrhage and another 3 developed a paralytic ileus that was treated
conservatively. CONCLUSIONS: Laparoscopic appendectomy is as safe and as
effective as the open procedure; however, it does not decrease the rate of
postoperative infectious complications.
PMID- 9560128
TI - The nature and fate of categorical surgical residents who "drop out".
AB - BACKGROUND: Little is known about the fate of categorical surgical residents who
leave a program or if they differ from those who successfully complete a program.
METHODS: Matching into separate categorical and preliminary categories with
elimination of the pyramid began in 1982. The files of all categorical residents
matched between 1982 and 1995 were reviewed for demographic and scholastic data.
Drop-outs were compared with the residents who completed the program and with the
current house staff. All residents have been followed up to the present. RESULTS:
Between 1982 and 1996, 19 of 88 (22%) categorical residents who matched into the
program left voluntarily. Eleven of 63 (17%) were male and 8 of 25 (32%) female
(P = 0.12; test of proportions-Z = -1.55). They entered both surgical and
nonsurgical fields. The major reasons for leaving were related to life-style
issues. Their academic credentials are very similar to those who remained.
CONCLUSIONS: The drop-out rate of categorical surgical residents is significant,
and replacing them is not easy. We have not identified any characteristics that
might predict attrition.
PMID- 9560129
TI - Cytotoxicity of electro-surgical smoke produced in an anoxic environment.
AB - BACKGROUND: The effect on cell viability of smoke produced during high-frequency
electro-surgery has not been previously reported. The aim of this study was to
produce smoke in vitro, in a closed environment similar to that encountered in
minimal access surgery, and to test its cytotoxic effects on cultured cells.
METHODS: Pig liver was cut repeatedly with an electro-surgical hook knife, and
the smoke generated was collected and equilibrated with cell culture medium. MCF
7 human breast carcinoma cells were exposed briefly to various dilutions of this
medium and tested for clonogenicity. RESULTS: Electro-surgical smoke produced in
a helium environment reduced the clonogenicity of the MCF-7 human breast
carcinoma cells in a dose-dependent manner, falling to 30% when the cells were
exposed to undiluted medium for 15 minutes. CONCLUSIONS: We conclude that electro
surgical smoke is cytotoxic. The sublethal effects at lower dilutions are
currently being investigated.
PMID- 9560130
TI - Clinicopathological analysis of local spread of carcinoma of the tongue.
AB - BACKGROUND: The aims of the study are three-dimensional analysis of mode and
distance of local spread of oral tongue carcinoma. METHODS: The glossectomy
specimens were examined in the coronal plane in 3 mm thickness section. RESULTS:
There were 50 glossectomy specimens. The maximum spread was 1.8 cm. Ninety-six
percent of specimens had local spread within 1.2 cm. The distance of spread was
not correlated with tumor size, including the diameter, depth, and volume. The
incidence of local recurrence was 27% with positive histological margin.
Perineural infiltration was the most important prognostic factor for local
recurrence and survival. CONCLUSIONS: A minimum of 1.5-cm surgical resection
margin is recommended. A smaller margin is not recommended as it has significant
risk of local recurrence. A maximum of 2-cm surgical resection margin is
recommended; larger margins will increase the surgical morbidity without a
significant advantage of local control.
PMID- 9560131
TI - Menstrual timing of breast cancer surgery.
AB - PURPOSE AND DESIGN: This is a critical review of the growing body of data, 32
retrospective studies of the outcomes of 9,665 women published since 1989,
relevant to the possibility that the timing of primary breast cancer resection
within the menstrual cycle impacts breast cancer recurrence and/or spread and
patient survival. This article evaluates and contrasts the adequacy of
information and data analysis presented in each publication. The overall purpose
of this exercise is to rigorously determine the relative strength of the
hypothesis that the menstrual cycle timing of operation impacts outcome and,
thereby, to determine whether or not a specific change in the practice of breast
surgical oncology can be recommended. RESULTS: The single most completely
reported and thoroughly analyzed series, involving 1,175 young women, indicates
that surgical resection timing is likely to be relevant to outcome. Seven
additional high-quality studies involving 2,864 women have been most completely
reported. While two of these eight find no impact, six (75%) of these studies
find that breast cancer outcome is affected by operative timing. Nine of the
remaining 24 less-complete studies report a statistically significant effect of
operative timing. Among these 15 studies of the fates of more than 5,000 women,
the opportune menstrual cycle phase almost invariably includes the putative
luteal phase. A large number of retrospective studies of widely varying quality
find no outcome difference as a function of resection timing. The adequacy of
design of each of four ongoing prospective studies is found lacking. CONCLUSIONS:
Although it is likely that the menstrual cycle phase of operation is relevant to
outcome, the nature of the available data cannot allow a clear recommendation of
precisely when to operate. It is, therefore, concluded that current retrospective
data are inadequate to recommend an immediate change in practice. Prospective
studies of this potentially important question are essential. The prospective
trials initiated to date will not be able to definitively answer this question
because of inadequate chronobiological design. The minimal requirements for
adequate prospective study are delineated.
PMID- 9560132
TI - The complex realities of sharing genetic assets.
PMID- 9560133
TI - Ex-UN AIDS chief is blasted for remarks on vaccine strategy.
PMID- 9560134
TI - South African drugs agency to be replaced.
PMID- 9560135
TI - Peer review cuts power of Italy's 'barons'.
PMID- 9560136
TI - British BSE reckoning tells a dismal tale.
PMID- 9560137
TI - When rhetoric hits reality in debate on bioprospecting.
PMID- 9560138
TI - India seeks tighter controls on germplasm.
PMID- 9560139
TI - Social equity versus private property: striking the right balance.
PMID- 9560140
TI - Brazil's scientists warn against 'nationalistic' restrictions.
PMID- 9560141
TI - A formula for indigenous involvement.
PMID- 9560142
TI - Old scores surface as African states face new opportunities.
PMID- 9560143
TI - Numbers of lab animals questioned.
PMID- 9560144
TI - The centenarian Golgi apparatus.
PMID- 9560145
TI - Putting the parkin into Parkinson's.
PMID- 9560146
TI - Worlds in common through NF-kappaB.
PMID- 9560147
TI - Computing. Parallel thinking.
PMID- 9560148
TI - Signal transduction. Taking the Rap.
PMID- 9560149
TI - Hesse-Honegger's hand-work.
PMID- 9560150
TI - Vitamin C exhibits pro-oxidant properties.
PMID- 9560151
TI - Regulatory factor linked to late-onset diabetes?
PMID- 9560152
TI - Chemokines and leukocyte traffic.
AB - Over the past ten years, numerous chemokines have been identified as attractants
of different types of blood leukocytes to sites of infection and inflammation.
They are produced locally in the tissues and act on leukocytes through selective
receptors. Chemokines are now known to also function as regulatory molecules in
leukocyte maturation, traffic and homing of lymphocytes, and the development of
lymphoid tissues.
PMID- 9560153
TI - Essential role of mouse telomerase in highly proliferative organs.
AB - We have investigated the role of the enzyme telomerase in highly proliferative
organs in successive generations of mice lacking telomerase RNA. Late-generation
animals exhibited defective spermatogenesis, with increased programmed cell death
(apoptosis) and decreased proliferation in the testis. The proliferative capacity
of haematopoietic cells in the bone marrow and spleen was also compromised. These
progressively adverse effects coincided with substantial erosion of telomeres
(the termini of eukaryotic chromosomes) and fusion and loss of chromosomes. These
findings indicate an essential role for telomerase, and hence telomeres, in the
maintenance of genomic integrity and in the long-term viability of high-renewal
organ systems.
PMID- 9560154
TI - Dissociation of the neural correlates of implicit and explicit memory.
AB - One presentation of a word to a subject is enough to change the way in which the
word is processed subsequently, even when there is no conscious (explicit) memory
of the original presentation. This phenomenon is known as implicit memory. The
neural correlates of implicit memory have been studied previously, but they have
never been compared with the correlates of explicit memory while holding task
conditions constant or while using a procedure that ensured that the neural
correlates were not 'contaminated' by explicit memory. Here we use scalp-recorded
event-related brain potentials to identify neural activity associated with
implicit and explicit memory during the performance of a recognition memory task.
Relative to new words, recently studied words produced activity in three
neuroanatomically and functionally dissociable neural populations. One of these
populations was activated whether or not the word was consciously recognized, and
its activity therefore represents a neural correlate of implicit memory. Thus,
when task and memory contamination effects are eliminated, the neural correlates
of explicit and implicit memory differ qualitatively.
PMID- 9560155
TI - A cortical representation of the local visual environment.
AB - Medial temporal brain regions such as the hippocampal formation and
parahippocampal cortex have been generally implicated in navigation and visual
memory. However, the specific function of each of these regions is not yet clear.
Here we present evidence that a particular area within human parahippocampal
cortex is involved in a critical component of navigation: perceiving the local
visual environment. This region, which we name the 'parahippocampal place area'
(PPA), responds selectively and automatically in functional magnetic resonance
imaging (fMRI) to passively viewed scenes, but only weakly to single objects and
not at all to faces. The critical factor for this activation appears to be the
presence in the stimulus of information about the layout of local space. The
response in the PPA to scenes with spatial layout but no discrete objects (empty
rooms) is as strong as the response to complex meaningful scenes containing
multiple objects (the same rooms furnished) and over twice as strong as the
response to arrays of multiple objects without three-dimensional spatial context
(the furniture from these rooms on a blank background). This response is reduced
if the surfaces in the scene are rearranged so that they no longer define a
coherent space. We propose that the PPA represents places by encoding the
geometry of the local environment.
PMID- 9560156
TI - Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.
AB - Parkinson's disease is a common neurodegenerative disease with complex clinical
features. Autosomal recessive juvenile parkinsonism (AR-JP) maps to the long arm
of chromosome 6 (6q25.2-q27) and is linked strongly to the markers D6S305 and
D6S253; the former is deleted in one Japanese AR-JP patient. By positional
cloning within this microdeletion, we have now isolated a complementary DNA done
of 2,960 base pairs with a 1,395-base-pair open reading frame, encoding a protein
of 465 amino acids with moderate similarity to ubiquitin at the amino terminus
and a RING-finger motif at the carboxy terminus. The gene spans more than 500
kilobases and has 12 exons, five of which (exons 3-7) are deleted in the patient.
Four other AR-JP patients from three unrelated families have a deletion affecting
exon 4 alone. A 4.5-kilobase transcript that is expressed in many human tissues
but is abundant in the brain, including the substantia nigra, is shorter in brain
tissue from one of the groups of exon-4-deleted patients. Mutations in the newly
identified gene appear to be responsible for the pathogenesis of AR-JP, and we
have therefore named the protein product 'Parkin'.
PMID- 9560157
TI - Disruption and sequence identification of 2,000 genes in mouse embryonic stem
cells.
AB - The dramatic increase in sequence information in the form of expressed sequence
tags (ESTs) and genomic sequence has created a 'gene function gap' with the
identification of new genes far outpacing the rate at which their function can be
identified. The ability to create mutations in embryonic stem (ES) cells on a
large scale by tagged random mutagenesis provides a powerful approach for
determining gene function in a mammalian system; this approach is well
established in lower organisms. Here we describe a high-throughput mutagenesis
method based on gene trapping that allows the automated identification of
sequence tags from the mutated genes. This method traps and mutates genes
regardless of their expression status in ES cells. To facilitate the study of
gene function on a large scale, we are using these techniques to create a library
of ES cells called Omnibank, from which sequence-tagged mutations in 2,000 genes
are described.
PMID- 9560158
TI - Role of Rel/NF-kappaB transcription factors during the outgrowth of the
vertebrate limb.
AB - The development of the vertebrate limb serves as an amenable system for studying
signaling pathways that lead to tissue patterning and proliferation. Limbs
originate as a consequence of a differential growth of cells from the lateral
plate mesoderm at specific axial levels. At the tip of the limb primordia the
progress zone, a proliferating group of mesenchymal cells, induces the overlying
ectoderm to differentiate into a specialized structure termed the apical
ectodermal ridge. Subsequent limb outgrowth requires reciprocal signalling
between the ridge and the progress zone. The Rel/NF-kappaB family of
transcription factors is induced in response to several signals that lead to cell
growth, differentiation, inflammatory responses, apoptosis and neoplastic
transformation. In unstimulated cells, NF-kappaB is associated in the cytoplasm
with an inhibitory protein, I-kappaB. In response to an external signal, I-kappaB
is phosphorylated, ubiquitinated and degraded, releasing NF-kappaB to enter the
nucleus and activate transcription. Here we show that Rel/NF-kappaB genes are
expressed in the progress zone of the developing chick limb bud. When the
activity of Rel/NF-kappaB proteins is blocked by infection with viral vectors
that produce transdominant-negative I-kappaBalpha proteins, limb outgrowth is
arrested. Our results indicate that Rel/NF-kappaB transcription factors play a
role in vertebrate limb development.
PMID- 9560159
TI - Inhibition of NF-kappaB activity results in disruption of the apical ectodermal
ridge and aberrant limb morphogenesis.
AB - In Drosophila, the Dorsal protein establishes the embryonic dorso-ventral axis
during development. Here we show that the vertebrate homologue of Dorsal, nuclear
factor-kappa B (NF-kappaB), is vital for the formation of the proximo-distal
organizer of the developing limb bud, the apical ectodermal ridge (AER).
Transcription of the NF-kappaB proto-oncogene c-rel is regulated, in part, during
morphogenesis of the limb bud by AER-derived signals such as fibroblast growth
factors. Interruption of NF-kappaB activity using viral-mediated delivery of an
inhibitor results in a highly dysmorphic AER, reduction in overall limb size,
loss of distal elements and reversal in the direction of limb outgrowth.
Furthermore, inhibition of NF-kappaB activity in limb mesenchyme leads to a
reduction in expression of Sonic hedgehog and Twist but derepresses expression of
the bone morphogenetic protein-4 gene. These results are the first evidence that
vertebrate NF-kappaB proteins act to transmit growth factor signals between the
ectoderm and the underlying mesenchyme during embryonic limb formation.
PMID- 9560160
TI - A proteolytic system that compensates for loss of proteasome function.
AB - Proteolysis is essential for the execution of many cellular functions. These
include removal of incorrectly folded or damaged proteins, the activation of
transcription factors, the ordered degradation of proteins involved in cell cycle
control, and the generation of peptides destined for presentation by class I
molecules of the major histocompatibility complex. A multisubunit protease
complex, the proteasome, accomplishes these tasks. Here we show that in mammalian
cells inactivation of the proteasome by covalent inhibitors allows the outgrowth
of inhibitor-resistant cells. The growth of such adapted cells is apparently
maintained by the induction of other proteolytic systems that compensate for the
loss of proteasomal activity.
PMID- 9560161
TI - Rap1 mediates sustained MAP kinase activation induced by nerve growth factor.
AB - Activation of mitogen-activated protein (MAP) kinase (also known as extracellular
signal-regulated kinase, or ERK) by growth factors can trigger either cell growth
or differentiation. The intracellular signals that couple growth factors to MAP
kinase may determine the different effects of growth factors: for example,
transient activation of MAP kinase by epidermal growth factor stimulates
proliferation of PC12 cells, whereas they differentiate in response to nerve
growth factor, which acts partly by inducing a sustained activation of MAP
kinase. Here we show that activation of MAP kinase by nerve growth factor
involves two distinct pathways: the initial activation of MAP kinase requires the
small G protein Ras, but its activation is sustained by the small G protein Rap1.
Rap1 is activated by CRK adaptor proteins and the guanine-nucleotide-exchange
factor C3G, and forms a stable complex with B-Raf, an activator of MAP kinase.
Rap1 is required for at least two indices of neuronal differentiation by nerve
growth factor: electrical excitability and the induction of neuron-specific
genes. We propose that the activation of Rap1 by C3G represents a common
mechanism to induce sustained activation of the MAP kinase cascade in cells that
express B-Raf.
PMID- 9560162
TI - The beta2-adrenergic receptor interacts with the Na+/H+-exchanger regulatory
factor to control Na+/H+ exchange.
AB - Stimulation of beta2-adrenergic receptors on the cell surface by adrenaline or
noradrenaline leads to alterations in the metabolism, excitability,
differentiation and growth of many cell types. These effects have traditionally
been thought to be mediated exclusively by receptor activation of intracellular G
proteins. However, certain physiological effects of beta2-adrenergic receptor
stimulation, notably the regulation of cellular pH by modulation of Na+/H+
exchanger (NHE) function, do not seem to be entirely dependent on G-protein
activation. We report here a direct agonist-promoted association of the beta2
adrenergic receptor with the Na+/H+ exchanger regulatory factor (NHERF), a
protein that regulates the activity of the Na+/H+ exchanger type 3 (NHE3). NHERF
binds to the beta2-adrenergic receptor by means of a PDZ-domain-mediated
interaction with the last few residues of the carboxy-terminal cytoplasmic domain
of the receptor. Mutation of the final residue of the beta2-adrenergic receptor
from leucine to alanine abolishes the receptor's interaction with NHERF and also
markedly alters beta2-adrenergic receptor regulation of NHE3 in cells without
altering receptor-mediated activation of adenylyl cyclase. Our findings indicate
that agonist-dependent beta2-adrenergic receptor binding of NHERF plays a role in
beta2-adrenergic receptor-mediated regulation of Na+/H+ exchange.
PMID- 9560163
TI - The gender paradox in suicide.
AB - In most Western countries females have higher rates of suicidal ideation and
behavior than males, yet mortality from suicide is typically lower for females
than for males. This article explores the gender paradox of suicidal behavior,
examines its validity, and critically examines some of the explanations,
concluding that the gender paradox of suicidal behavior is a real phenomenon and
not a mere artifact of data collection. At the same time, the gender paradox in
suicide is a more culture-bound phenomenon than has been traditionally assumed;
cultural expectations about gender and suicidal behavior strongly determine its
existence. Evidence from the United States and Canada suggests that the gender
gap may be more prominent in communities where different suicidal behaviors are
expected of females and males. These divergent expectations may affect the
scenarios chosen by females and males, once suicide becomes a possibility, as
well as the interpretations of those who are charged with determining whether a
particular behavior is suicidal (e.g., coroners). The realization that cultural
influences play an important role in the gender paradox of suicidal behaviors
holds important implications for research and for public policy.
PMID- 9560164
TI - Gender, culture, and suicidal behavior: a feminist critique of theories and
research.
AB - Suicide research has developed historically from philosophical roots in logical
positivism and structural determinism. Thus, much suicide research has been based
on assumptions of cause-and-effect relationships, reductionistic analysis, and
the individual as the primary unit of analysis. In counterpoint, six guiding
themes define feminist research (Worell & Etaugh, 1994). The present manuscript
traces these six themes, illustrating them with suicide research projects. By
challenging scientific tradition, focusing on women, considering power,
recognizing gender constructs, maintaining awareness of the power of language,
and promoting active, practical applications, researchers can combine traditional
and alternative methodologies to make suicide research more robust.
PMID- 9560165
TI - Gender and the cultural construction of good and bad suicides.
AB - Some cultures distinguish two or more types of suicide which are evaluated
differently. The more acceptable or esteemed ones are often not equally
accessible to everyone within the same society. This article focuses on gender
differences in the cultural construction of suicide options, and on the exclusion
of women from superior options. The analysis is based on ethnographic and
historical data from Native Americans of the Great Plains, Muslim societies in
Southeast Asia, and tribal societies in the Amazon area of South America.
PMID- 9560166
TI - Gender and suicide in India: a multiperspective approach.
AB - The gap between male and female suicide rates in India is relatively small.
However, society's views on female and male motives are quite different. In order
to investigate the perceptions of male and female suicide, we interviewed a focus
group of university professors as well as police inspectors, crime reporters, and
hospital nurses in Bangalore. We also obtained four narratives of suicide. Women
tended to be blamed for their own or their husband's suicide, although they were
also viewed more often as victims of life adversities than men. A historical
review illustrates that both men and women have been associated with culturally
sanctioned suicides. One known form is sati, and we discuss the recent case of
sati-murder of Roop Kanwar in 1987. The social sciences and the media also pay a
lot of attention to the typical female suicides, symbolizing their role as
martyrs of society, which seems to compensate for attribution of blame.
PMID- 9560167
TI - Gender differences in nonfatal suicidal behavior in Pakistan: significance of
sociocultural factors.
AB - Suicidal behavior is an understudied subject in Pakistan. A variety of social,
legal, and religious factors make reporting and data collection on suicide and
nonfatal suicidal behavior difficult. To study the problem, a retrospective case
note analysis was carried out in which the sociodemographic and clinical
characteristics of 262 female and 185 male suicidal individuals admitted to a
university hospital in Karachi, Pakistan, are compared. Three quarters of the
suicidal persons were under the age of 30 years. Compared to men, women were
younger and more often married. Both women and men tended to use self-poisoning
with benzodiazepines, but more women used organophosphate insecticides. In
Pakistani society, legal, social, and economic discrimination predisposes women
to psychological distress and subsequent suicidal behavior. The study highlights
the need for culture-specific research on suicidal behavior in Pakistan.
PMID- 9560168
TI - Culture, gender, and suicidal behavior in Sri Lanka.
AB - In less than 50 years, the rate of suicide among Sri Lankans has risen from a
modest level to one of the highest in the world. This article describes the
current pattern of suicides, including sex differences and similarities, and
reviews some of the institutional practices, material conditions, and social
norms that may figure in the increases. A study is reported, which asked how
ordinary Sri Lankans account for suicidal behavior and what practices they
recommend for assisting suicidal individuals. Gender inflected these accounts,
with essentialist accounts associated with women's suicides and contextual
accounts associated with men's suicides.
PMID- 9560169
TI - Women in cultural transition: suicidal behavior in South African Indian women.
AB - Young South African Indian women are a population with relatively high rates of
suicidal behavior. This article presents three illustrative case studies of
nonfatal suicidal behavior by South African Indian women. The cases are discussed
in relation to a review of epidemiological, historical, and sociocultural
perspectives on South African Indian women. It is argued that suicidal behaviors
in this group can be understood in the context of sociocultural transition.
Transitional tensions between traditional Indian culture and Westernization have
an impact on traditional gendered power relations and generate conflicts that
have intrapsychic and interpersonal consequences for women and for men. These in
turn may have adverse effects on marital functioning, quality of life, and
specific aspects of emotional functioning, which have been identified as
precursors of suicidal behavior. The case studies are discussed with reference to
gender narratives. Implications for prevention, intervention, and future research
are discussed.
PMID- 9560171
TI - Effects of sexual victimization on suicidal ideation and behavior in U.S. college
women.
AB - This study examines the relationship between suicidal ideation and behavior and
five types of sexual victimization in a sample of 393 female undergraduate
students. Participants completed self-report measures of sexual victimization,
hopelessness, suicidal ideation, and suicidal behavior. Adult sexual
victimization, but not childhood sexual abuse, predicted current hopelessness and
suicidal ideation. Both childhood sexual abuse and adult sexual victimization
predicted suicidal behavior. One in four rape victims, in contrast to
approximately 1 in 20 nonvictimized women, had engaged in a suicidal act. Vaginal
penetration following the threat or use of physical force was a stronger
predictor of suicidal behavior than penetration without the use of force and/or
force without penetration. The findings point to the importance of inquiring
about experiences of sexual victimization when conducting research or treatment
with suicidal women as well as the need for suicide risk assessment in programs
for victims of sexual violence.
PMID- 9560170
TI - Suicidal behavior in a bicultural society: a review of gender and cultural
differences in adolescents and young persons of Aotearoa/New Zealand.
AB - During the 1990s, Aotearoa/New Zealand has experienced an alarming increase in
youth suicide in the Maori and non-Maori populations. Among 23 Organization for
Economic Cooperation and Development countries surveyed by the World Health
Organization's (1995) World Health Statistics Annual, New Zealand ranks first for
fatal suicidal behavior, in males 15-24 years of age, and third for fatal
suicidal behavior in females. A United Nations Children's Fund (UNICEF, 1996)
survey of 32 countries places New Zealand males as third highest for fatal
suicidal behavior, and females as eighth highest in the age group 15-24 years.
New Zealand has recently undergone a number of social and economic changes that
have created dramatic social and cultural shifts. Given the rapidity of these
changes, the shock on such a small country has been difficult to absorb. These
shifts have placed tremendous pressures on families and service support systems,
such as health and mental health services, to develop programs that are relevant
and acceptable for a bicultural society. This article focuses on these changes
and the effect they have had on cultural narratives of gender and suicidal
behavior, the different cultural etiologies that underlie these statistics, and
recommendations for intervention and prevention program development.
PMID- 9560172
TI - Gender and history of suicidality: are these factors related to U.S. college
students' current suicidal thoughts, feelings, and actions?
AB - Gender and history of suicidality (HS vs. NoHS) were related to current symptoms
of depression, reasons for living, and reports of self-destructive and life
threatening behavior in a college student sample. Overall, college men reported
engaging in more life-threatening and potentially suicidal behavior than college
women on the Life Attitudes Schedule (LAS). No gender effects were obtained on
the symptoms of depression and reasons for living measures. Results suggest that
the LAS may be a particularly effective way to identify college students at risk
for self-destructive and suicidal behavior. As expected, HS individuals were more
depressed, had fewer reasons for living, and reported engaging in more current
suicidal and life-threatening behavior than NoHS participants. However, gender
and history of suicidality were found to interact. NoHS women reported avoiding a
variety of injury-producing and health-diminishing behaviors that were common for
all other groups of college students. Meanwhile, HS women endorsed fewer current
reasons for living than did NoHS women, NoHS men, and NoHS men. These findings
were interpreted both with regard to cultural and gender-specific expectations
for the expression of self-destructive, suicidal, and life-threatening behavior.
Implications for the prevention of college women's and men's suicidal behavior
were also noted.
PMID- 9560173
TI - A critical review of pharmacotherapy for youth with anxiety disorders: things are
not as they seem.
AB - Given the increasing trend in clinical child psychology and psychiatry toward
cost-effective and pharmacological treatment, a review of key factors that
influence treatment outcomes in this area seems warranted. This is especially
important for the rapidly changing area of childhood anxiety disorders. In this
article, we look at different change producing procedures to illustrate the claim
that pharmacological studies are not necessarily what they seem. Specifically,
pharmacological outcome studies are classified and reviewed on the basis of
varying "secondary" treatments described in method sections. Three groups and
efficacy rates were determined: (a) pharmacotherapy only (42.83%), (b)
pharmacotherapy plus general/supportive psychotherapy (27.74%), and (c)
pharmacotherapy plus a behavior therapy component (65.28%). We also discuss the
implications of these findings for research as well as other methodological and
theoretical concerns regarding the reviewed articles. These concerns include (a)
methods used to diagnose participants, (b) methods used to assess improvement,
(c) emphasis on diagnostic categories, (d) exclusionary criteria and comorbidity,
(e) participant attrition and follow-up, and (f) key developmental and social
contextual variables.
PMID- 9560174
TI - Anxiety sensitivity and response to hyperventilation challenge: physiologic
arousal, interoceptive acuity, and subjective distress.
AB - Twenty-four female undergraduates, 12 high on anxiety sensitivity and 12 low on
anxiety sensitivity, were subjected to a hyperventilation challenge task.
Physiologic and subjective measures of arousal and distress were obtained before,
during, and after the hyperventilation challenge. Alternating between the eight
15-second intervals of hyperventilation, participants engaged in a heartbeat
tracking task for eight 10-second intervals to assess interoceptive acuity.
Although the hyperventilation challenge produced phase main effects for
physiologic arousal, and group and time main effects for subjective distress,
there were no significant interaction effects. Results revealed no significant
interoceptive acuity differences across the low and high anxiety sensitivity
groups. However, subjective ratings of physiological sensations during
hyperventilation were significantly greater for the high anxiety sensitivity
group. Hierarchical multiple regression analyses revealed that anxiety
sensitivity accounted for additional variance beyond trait anxiety in explaining
subjective ratings of arousal and distress in this nonclinical sample in response
to a hyperventilation challenge.
PMID- 9560175
TI - The role of self-directed in vivo exposure in combination with cognitive therapy,
relaxation training, or therapist-assisted exposure in the treatment of panic
disorder with agoraphobia.
AB - The effects of self-directed in vivo exposure in the treatment of panic disorder
with agoraphobia were examined. Seventy-four chronic and severe agoraphobic
subjects were randomly assigned to Cognitive Therapy plus graded exposure.
Relaxation Training plus graded exposure, or therapist-assisted graded exposure
alone. Treatment consisted of 16 weekly 2.5-hour sessions. All subjects received
programmed practice instructions for engaging in self-directed exposure as a
concomitant strategy to their primary treatment. All subjects were instructed to
keep systematic behavioral diary recordings of all self-directed exposure
practice. The diary data were analyzed across and within treatments and
assessment phases. Statistically significant findings were obtained across all
diary measure domains with powerful repeated measures effects observed across all
treatments. Significant between group effects and treatment x repeated measures
interactions were obtained across the diary measure domains. Multiple linear
regressions of in vivo anxiety levels and, to a lesser extent, frequency of self
directed exposure practice were found to be significantly associated with global
assessment of severity at posttreatment and 3-month follow-up assessments.
Furthermore, depression and marital satisfaction were significantly associated
with in vivo anxiety. These and other findings are discussed with regard to their
conceptual and clinical implications.
PMID- 9560176
TI - Problem solving and problem orientation in generalized anxiety disorder.
AB - The present study's main objective is to examine whether problem orientation and
problem-solving skills differ according to generalized anxiety disorder (GAD)
symptom level or clinical status (seeking help for GAD). Its secondary goal is to
examine whether two cognitive variables (intolerance of uncertainty and beliefs
about worry) vary according to GAD symptom level or clinical status. Three groups
of subjects participated in the study: (a) nonclinical moderate worriers (N =
15), (b) nonclinical subjects meeting GAD criteria by questionnaire (N = 14), and
(c) GAD patients (N = 14). Problem orientation and problem-solving skills were
measured with the Social Problem-Solving Inventory (D'Zurilla & Nezu, 1990) and
the Problem-Solving Inventory (Heppner & Petersen, 1982), whereas the cognitive
variables were assessed with the Intolerance of Uncertainty questionnaire
(Freeston, Rheaume, Letarte, Dugas, & Ladouceur, 1994) and the Why Worry?
questionnaire (Freeston, Rheaume et al., 1994). The results show that problem
orientation, intolerance of uncertainty, and beliefs about worry were similar in
subjects meeting GAD criteria by questionnaire and GAD patients, whereas moderate
worriers had different scores on these variables. Thus, these variables are more
highly affected by GAD symptom level than by clinical status. The results also
show that problem-solving skills were unaffected by symptom level and clinical
status, thereby indicating that knowledge of problem-solving skills is unrelated
to both GAD symptom level and GAD clinical status. The findings are discussed in
terms of their theoretical and clinical implications.
PMID- 9560177
TI - Children's self-talk under conditions of mild anxiety.
AB - Two studies are described which used think-aloud (Study 1) and verbal thought
listing (Studies 1 and 2) procedures to assess preadolescent children's self-talk
under conditions of mild anxiety. The self-talk reported was coded into six
theoretically meaningful categories and the relationship between self-talk type
and anxiety (state and trait) examined. Increased levels of anxiety were
associated with higher rates of negative self-talk, but not clearly associated
with other types of self-talk. These results suggest negative self-talk plays a
role in the generation or maintenance of anxiety in normal children. From the
data, it is unclear to what extent perceived task difficulty contributes to the
relationship between trait anxiety and negative self-talk. Assessment of self
regulation (Study 1) identified higher levels of anxiety in children reporting
awareness of strategies for managing their anxiety.
PMID- 9560178
TI - Plant parasitic nematodes: digesting a page from the microbe book.
PMID- 9560181
TI - Line spectral analysis for harmonizable processes.
AB - Harmonizable processes with spectral mass concentrated on a number of straight
lines are considered. The asymptotic behavior of the bias and covariance of a
number of spectral estimates is described. The results generalize those obtained
for periodic and almost periodic processes.
PMID- 9560180
TI - Dynamics and function of proteins: the search for general concepts.
PMID- 9560179
TI - HLA class I specificity for natural killer cell receptor CD94/NKG2A: two for one
in more ways than one.
PMID- 9560182
TI - Cosmological implications of a large complete quasar sample.
AB - Objective and reproducible determinations of the probabilistic significance
levels of the deviations between theoretical cosmological prediction and direct
model-independent observation are made for the Large Bright Quasar Sample [Foltz,
C., Chaffee, F. H., Hewett, P. C., MacAlpine, G. M., Turnshek, D. A., et al.
(1987) Astron. J. 94, 1423-1460]. The Expanding Universe model as represented by
the Friedman-Lemaitre cosmology with parameters qo = 0, Lambda = 0 denoted as C1
and chronometric cosmology (no relevant adjustable parameters) denoted as C2 are
the cosmologies considered. The mean and the dispersion of the apparent
magnitudes and the slope of the apparent magnitude-redshift relation are the
directly observed statistics predicted. The C1 predictions of these cosmology
independent quantities are deviant by as much as 11sigma from direct observation;
none of the C2 predictions deviate by >2sigma. The C1 deviations may be
reconciled with theory by the hypothesis of quasar "evolution," which, however,
appears incapable of being substantiated through direct observation. The
excellent quantitative agreement of the C1 deviations with those predicted by C2
without adjustable parameters for the results of analysis predicated on C1
indicates that the evolution hypothesis may well be a theoretical artifact.
PMID- 9560183
TI - Second-order correction to the Bigeleisen-Mayer equation due to the nuclear field
shift.
AB - The nuclear field shift affects the electronic, rotational, and vibrational
energies of polyatomic molecules. The theory of the shifts in molecular spectra
has been studied by Schlembach and Tiemann [Schlembach, J. & Tiemann, E. (1982)
Chem. Phys. 68, 21]; measurements of the electronic and rotational shifts of the
diatomic halides of Pb and Tl have been made by Tiemann et al. [Tiemann, E.,
Knockel, H. & Schlembach, J. (1982) Ber. Bunsenges. Phys. Chem. 86, 821]. These
authors have estimated the relative shifts in the harmonic frequencies of these
compounds due to the nuclear field shift to be of the order of 10(-6). I have
used this estimate of the relative shift in vibrational frequency to calculate
the correction to the harmonic oscillator approximation to the isotopic reduced
partition-function ratio (208)Pb(32)S/(207)Pb(32)S. The correction is 0.3% of the
harmonic oscillator value at 300 K. In the absence of compelling evidence to the
contrary, it suffices to calculate the nuclear field effect on the total isotopic
partition-function ratio from its shift of the electronic zero point energy and
the unperturbed molecular vibration.
PMID- 9560184
TI - Chemical requirements for inhibition of gap junction communication by the
biologically active lipid oleamide.
AB - Oleamide is an endogenous fatty acid primary amide that possesses sleep-inducing
properties in animals and has been shown to effect serotonergic systems and block
gap junction communication in a structurally specific manner. Herein, the
structural features of oleamide required for inhibition of the gap junction
mediated chemical and electrical transmission in rat glial cells are defined. The
effective inhibitors fall into two classes of fatty acid primary amides of which
oleamide and arachidonamide are the prototypical members. Of these two, oleamide
constitutes the most effective, and its structural requirements for inhibition of
the gap junction are well defined. It requires a chain length of 16-24 carbons of
which 16-18 carbons appears optimal, a polarized terminal carbonyl group capable
of accepting but not necessarily donating a hydrogen bond, a Delta9 cis double
bond, and a hydrophobic methyl terminus. Within these constraints, a range of
modifications are possible, many of which may be expected to improve in vivo
properties. A select set of agents has been identified that serves both as
oleamide agonists and as inhibitors of fatty acid amide hydrolase, which is
responsible for the rapid inactivation of oleamide.
PMID- 9560185
TI - Engineering analysis of biological variables: an example of blood pressure over 1
day.
AB - Almost all variables in biology are nonstationarily stochastic. For these
variables, the conventional tools leave us a feeling that some valuable
information is thrown away and that a complex phenomenon is presented
imprecisely. Here, we apply recent advances initially made in the study of ocean
waves to study the blood pressure waves in the lung. We note first that, in a
long wave train, the handling of the local mean is of predominant importance. It
is shown that a signal can be described by a sum of a series of intrinsic mode
functions, each of which has zero local mean at all times. The process of
deriving this series is called the "empirical mode decomposition method."
Conventionally, Fourier analysis represents the data by sine and cosine
functions, but no instantaneous frequency can be defined. In the new way, the
data are represented by intrinsic mode functions, to which Hilbert transform can
be used. Titchmarsh [Titchmarsh, E. C. (1948) Introduction to the Theory of
Fourier Integrals (Oxford Univ. Press, Oxford)] has shown that a signal and i
times its Hilbert transform together define a complex variable. From that complex
variable, the instantaneous frequency, instantaneous amplitude, Hilbert spectrum,
and marginal Hilbert spectrum have been defined. In addition, the Gumbel extreme
value statistics are applied. We present all of these features of the blood
pressure records here for the reader to see how they look. In the future, we have
to learn how these features change with disease or interventions.
PMID- 9560186
TI - The helium paradoxes.
AB - The ratio 3He/4He (R) plays a central role in models of mantle evolution that
propose an undegassed lower mantle, rich in the primordial isotope 3He. A large
primordial volatile-rich reservoir, a feature of recent models, is inconsistent
with high-temperature accretion and with estimates of crustal and bulk Earth
chemistry. High R can alternatively reflect high integrated 3He/(U+Th) ratios or
low 4He abundances, as expected in refractory portions of the upper mantle. I
show that high R materials are gas-poor and are deficient in radiogenic 4He
compared with midocean ridge basalts. The seemingly primitive (i.e., high R)
signatures in "hotspot" magmas may be secondary, derived from CO2-rich gases, or
residual peridotite, a result of differential partitioning of U and He into
magmas. A shallow and low 3He source explains the spatial variability and the
temporal trends of R in ocean islands and is consistent with a volatile-poor
planet. A shallow origin for the "primitive" He signature in ocean island
basalts, such as at Loihi, reconciles the paradoxical juxtaposition of crustal,
seawater, and atmospheric signatures with inferred "primitive" characteristics.
High 238U/204Pb components in ocean island basalts are generally attributed to
recycled altered oceanic crust. The low 238U/3He component may be in the
associated depleted refractory mantle. High 3He/4He ratios are due to low 4He,
not excess 3He, and do not imply or require a deep or primordial or undegassed
reservoir. 40Ar in the atmosphere also argues against such models.
PMID- 9560187
TI - On Calderon's conjecture for the bilinear Hilbert transform.
AB - We show that the bilinear Hilbert transform defined by maps Lp x Lq into Lr for 1
< p, q = infinity, 1/p + 1/q = 1/r, and 2/3 < r < infinity.
PMID- 9560189
TI - Highly resolved chemical imaging of living cells by using synchrotron infrared
microspectrometry.
AB - Using synchrotron radiation as an ultra-bright infrared source, we have been able
to map the distributions of functional groups such as proteins, lipids, and
nucleic acids inside a single living cell with a spatial resolution of a few
microns. In particular, we have mapped the changes in the lipid and protein
distributions in both the final stages of cell division and also during necrosis.
PMID- 9560188
TI - Structure of the catalytic domain of avian sarcoma virus integrase with a bound
HIV-1 integrase-targeted inhibitor.
AB - The x-ray structures of an inhibitor complex of the catalytic core domain of
avian sarcoma virus integrase (ASV IN) were solved at 1.9- to 2.0-A resolution at
two pH values, with and without Mn2+ cations. This inhibitor (Y-3), originally
identified in a screen for inhibitors of the catalytic activity of HIV type 1
integrase (HIV-1 IN), was found in the present study to be active against ASV IN
as well as HIV-1 IN. The Y-3 molecule is located in close proximity to the enzyme
active site, interacts with the flexible loop, alters loop conformation, and
affects the conformations of active site residues. As crystallized, a Y-3
molecule stacks against its symmetry-related mate. Preincubation of IN with metal
cations does not prevent inhibition, and Y-3 binding does not prevent binding of
divalent cations to IN. Three compounds chemically related to Y-3 also were
investigated, but no binding was observed in the crystals. Our results identify
the structural elements of the inhibitor that likely determine its binding
properties.
PMID- 9560190
TI - Regulation of the zinc transporter ZnT-1 by dietary zinc.
AB - The understanding of mechanisms controlling zinc absorption and metabolism at the
molecular level has advanced recently. Kinetics of zinc transport have been
investigated for many years, but only recently have genes coding for proteins
thought to be involved in the transport process been cloned. Four putative zinc
transporters, known as ZnT-1 through ZnT-4, have now been described. Among these
transporters, only ZnT-1 is ubiquitously expressed. In this report, we examine
the pattern of ZnT-1 expression in the intestine and analyze the regulation of
ZnT-1 by dietary zinc in both the intestine and liver. Immunofluorescence
demonstrated that intestinal ZnT-1 was most abundant at the basolateral surface
of enterocytes lining the villi of the duodenum and jejunum. By Western blot
analysis, intestinal and liver ZnT-1 protein migrated as a 42- and 36-kDa
protein, respectively. Dietary zinc supplementation elevated the level of
intestinal ZnT-1 mRNA and protein approximately 50% and 10%, respectively, but
had no effect in the liver. In response to an acute oral zinc dose, the level of
intestinal ZnT-1 mRNA was up-regulated 8-fold, without a corresponding increase
in ZnT-1 protein. Conversely, the acute oral dose did not affect liver ZnT-1
mRNA, but resulted in a 5-fold increase in liver ZnT-1 protein. These results
represent studies on the expression of intestinal and hepatic ZnT-1 in an intact
animal model. The data suggest that ZnT-1 is at least part of the mechanism by
which dietary zinc is absorbed and that, despite the zinc responsiveness of the
ZnT-1 gene, additional factors may be regulating the steady-state level of ZnT-1
transporter protein.
PMID- 9560191
TI - Crystal structure of troponin C in complex with troponin I fragment at 2.3-A
resolution.
AB - Troponin (Tn), the complex of three subunits (TnC, TnI, and TnT), plays a key
role in Ca2+-dependent regulation of muscle contraction. To elucidate the
interactions between the Tn subunits and the conformation of TnC in the Tn
complex, we have determined the crystal structure of TnC (two Ca2+ bound state)
in complex with the N-terminal fragment of TnI (TnI1-47). The structure was
solved by the single isomorphous replacement method in combination with multiple
wavelength anomalous dispersion data. The refinement converged to a
crystallographic R factor of 22.2% (Rfree = 32.6%). The central, connecting alpha
helix observed in the structure of uncomplexed TnC (TnCfree) is unwound at the
center (residues Ala-87, Lys-88, Gly-89, Lys-90, and Ser-91) and bent by 90
degrees. As a result, TnC in the complex has a compact globular shape with direct
interactions between the N- and C-terminal lobes, in contrast to the elongated
dumb-bell shaped molecule of uncomplexed TnC. The 31-residue long TnI1-47 alpha
helix stretches on the surface of TnC and stabilizes its compact conformation by
multiple contacts with both TnC lobes. The amphiphilic C-end of the TnI1-47 alpha
helix is bound in the hydrophobic pocket of the TnC C-lobe through 38 van der
Waals interactions. The results indicate the major difference between Ca2+
receptors integrated with the other proteins (TnC in Tn) and isolated in the
cytosol (calmodulin). The TnC/TnI1-47 structure implies a mechanism of how Tn
regulates the muscle contraction and suggests a unique alpha-helical regulatory
TnI segment, which binds to the N-lobe of TnC in its Ca2+ bound conformation.
PMID- 9560192
TI - A primitive pathway of porphyrin biosynthesis and enzymology in Desulfovibrio
vulgaris.
AB - Culture of Desulfovibrio vulgaris in a medium supplemented with 5-aminolevulinic
acid and L-methionine-methyl-d3 resulted in the formation of porphyrins
(sirohydrochlorin, coproporphyrin III, and protoporphyrin IX) in which the methyl
groups at the C-2 and C-7 positions were deuterated. A previously unknown
hexacarboxylic acid was also isolated, and its structure was determined to be 12,
18-didecarboxysirohydrochlorin by mass spectrometry and 1H NMR. These results
indicate a primitive pathway of heme biosynthesis in D. vulgaris consisting of
the following enzymatic steps: (i) methylation of the C-2 and C-7 positions of
uroporphyrinogen III to form precorrin-2 (dihydrosirohydrochlorin); (ii)
decarboxylation of acetate groups at the C-12 and C-18 positions of precorrin-2
to form 12,18-didecarboxyprecorrin-2; (iii) elimination of acetate groups of the
C-2 and C-7 positions of 12,18-didecarboxyprecorrin-2 to form coproporphyrinogen
III; and (iv) conversion of coproporphyrinogen III to protoporphyrin IX via
protoporphyrinogen IX. We isolated the following three enzymatic activities
involved in steps i-iii from the soluble fraction of the cells by anion-exchange
chromatography: S-adenosyl-L-methionine:uroporphyrinogen III methyltransferase,
precorrin-2 12,18-acetate decarboxylase, and 12, 18-didecarboxyprecorrin-2 2,7
decarboxymethylase; all enzymic products were converted into autooxidized methyl
esters and analyzed by thin-layer chromatography, UV-visible (UV-VIS) absorption,
and mass spectrometry. The enzymatic reactions in D. vulgaris shed new light on
porphyrin biosynthesis at an early stage in the evolution of prokaryotes.
PMID- 9560193
TI - Leukotriene D4 and cystinyl-bis-glycine metabolism in membrane-bound dipeptidase
deficient mice.
AB - We have developed mice deficient in membrane-bound dipeptidase (MBD, EC
3.4.13.19), the enzyme believed to be responsible for the conversion of
leukotriene D4 (LTD4) to leukotriene E4 (LTE4). The MBD mutation generated by us
was demonstrated to be a null mutation by Northern blot analysis and the absence
of beta-lactamase activity in lung, kidney, small intestine, and heart. MBD gene
deletion had no effect on viability or fertility. The mutant mice retain partial
ability to convert LTD4 to LTE4, ranging from 80-90% of the wild-type values in
small intestine and liver to 16% in kidney and 40% in lung, heart, and pancreas.
MBD is also believed to function consecutively after gamma-glutamyl
transpeptidase to cleave cystinyl-bis-glycine (cys-bis-gly) generated from
glutathione cleavage. Our data indicate that kidney homogenates from MBD
deficient mice retain approximately 40% of their ability to cleave cys-bis-gly,
consistent with only modest elevations (3-5-fold) of cys-bis-gly in urine from
MBD-deficient mice. These observations demonstrate that the conversion of LTD4 to
LTE4 and the degradation of cys-bis-gly are catalyzed by at least two alternative
pathways (one of which is MBD) that complement each other to varying extents in
different tissues.
PMID- 9560194
TI - Regulation of a nuclear export signal by an adjacent inhibitory sequence: the
effector domain of the influenza virus NS1 protein.
AB - In the cell nucleus the NS1 protein of influenza A virus inhibits both pre-mRNA
splicing and the nuclear export of mRNAs. Both the RNA-binding and effector
domains of the protein are required for these nuclear functions. Here we
demonstrate that the NS1 protein has a latent nuclear export signal (NES) that is
located at the amino end of the effector domain. In uninfected, transfected cells
the NS1 protein is localized in the nucleus because the NES is specifically
inhibited by the adjacent amino acid sequence in the effector domain.
Substitution of alanine residues for specific amino acids in the adjacent
sequence abrogates its inhibitory activity, thereby unmasking the NES and causing
the full-length NS1 protein to be localized to the cytoplasm. In contrast to
uninfected cells, a substantial amount of the NS1 protein in influenza virus
infected cells is located in the cytoplasm. Consequently, the NES of these NS1
protein molecules is unmasked in infected cells, indicating that the NS1 protein
most likely carries out functions in the cytoplasm as well as the nucleus. A
dramatically different localization of the NS1 protein occurs in cells that are
infected by a virus encoding an NS1 protein lacking the NES: the shortened NS1
protein molecules are almost totally in the nucleus. Because the NES of the full
length NS1 protein is unmasked in infected but not uninfected cells, it is likely
that this unmasking results from a specific interaction of another virus-specific
protein with the NS1 protein.
PMID- 9560195
TI - Experimental support for a beta-propeller domain in integrin alpha-subunits and a
calcium binding site on its lower surface.
AB - Integrins are large, heterodimeric surface molecules of wide importance in cell
adhesion. The N-terminal half of all integrin alpha-subunits contains seven weak
sequence repeats of approximately 60 amino acids that are important in ligand
binding and have been predicted to fold cooperatively into a single beta
propeller domain with seven beta-sheets. We provide evidence supporting this
model with a mouse mAb to human Mac-1 (alphaM beta2, CD11b/CD18). This antibody,
CBRM1/20, binds to amino acid residues that are in different repeats and are 94
residues apart in the primary structure in the loop between strands 1 and 2 of
beta-sheet 5 and in the loop between strands 3 and 4 of beta-sheet 6. The 1-2
loops of beta-sheets 5-7 in integrins have EF hand-like Ca2+-binding motifs.
CBRM1/20 binds to Mac-1 in the presence of Ca2+ or Sr2+ with an EC50 of 0.2 mM.
Mg2+ or Mn2+ cannot substitute. Antibodies to other epitopes on the Mac-1 beta
propeller domain bind in the absence of calcium. mAb CBRM1/20 does not block
ligand binding. Thus, the region on the lower surface of the beta-propeller
domain to which mAb CBRM1/20 binds does not bind ligand and, furthermore, cannot
bind other integrin domains, such as those of the beta-subunit.
PMID- 9560196
TI - Crystal structures of two tropinone reductases: different reaction
stereospecificities in the same protein fold.
AB - A pair of tropinone reductases (TRs) share 64% of the same amino acid residues
and belong to the short-chain dehydrogenase/reductase family. In the synthesis of
tropane alkaloids in several medicinal plants, the TRs reduce a carbonyl group of
an alkaloid intermediate, tropinone, to hydroxy groups with different
diastereomeric configurations. To clarify the structural basis for their
different reaction stereospecificities, we determined the crystal structures of
the two enzymes at 2.4- and 2.3-A resolutions. The overall folding of the two
enzymes was almost identical. The conservation was not confined within the core
domains that are conserved within the protein family but extended outside the
core domain where each family member has its characteristic structure. The
binding sites for the cofactor and the positions of the active site residues were
well conserved between the two TRs. The substrate binding site was composed
mostly of hydrophobic amino acids in both TRs, but the presence of different
charged residues conferred different electrostatic environments on the two
enzymes. A modeling study indicated that these charged residues play a major role
in controlling the binding orientation of tropinone within the substrate binding
site, thereby determining the stereospecificity of the reaction product. The
results obtained herein raise the possibility that in certain cases different
stereospecificities can be acquired in enzymes by changing a few amino acid
residues within substrate binding sites.
PMID- 9560197
TI - Protein-bound acrolein: potential markers for oxidative stress.
AB - Acrolein (CH2==CH---CHO) is known as a ubiquitous pollutant in the environment.
Here we show that this notorious aldehyde is not just a pollutant, but also a
lipid peroxidation product that could be ubiquitously generated in biological
systems. Upon incubation with BSA, acrolein was rapidly incorporated into the
protein and generated the protein-linked carbonyl derivative, a putative marker
of oxidatively modified proteins under oxidative stress. To verify the presence
of protein-bound acrolein in vivo, the mAb (mAb5F6) against the acrolein-modified
keyhole limpet hemocyanin was raised. It was found that the acrolein-lysine
adduct, Nepsilon-(3-formyl-3, 4-dehydropiperidino)lysine, constitutes an epitope
of the antibody. Immunohistochemical analysis of atherosclerotic lesions from a
human aorta demonstrated that antigenic materials recognized by mAb5F6 indeed
constituted the lesions, in which intense positivity was associated primarily
with macrophage-derived foam cells and the thickening neointima of arterial
walls. The observations that (i) oxidative modification of low-density
lipoprotein with Cu2+ generated the acrolein-low-density lipoprotein adducts and
(ii) the iron-catalyzed oxidation of arachidonate in the presence of protein
resulted in the formation of antigenic materials suggested that polyunsaturated
fatty acids are sources of acrolein that cause the production of protein-bound
acrolein. These data suggest that the protein-bound acrolein represents potential
markers of oxidative stress and long-term damage to protein in aging,
atherosclerosis, and diabetes.
PMID- 9560198
TI - Mechanism of platelet inhibition by nitric oxide: in vivo phosphorylation of
thromboxane receptor by cyclic GMP-dependent protein kinase.
AB - Nitric oxide (NO) is a potent vasodilator and inhibitor of platelet activation.
NO stimulates production of cGMP and activates cGMP-dependent protein kinase (G
kinase), which by an unknown mechanism leads to inhibition of Galphaq
phospholipase C-inositol 1, 4,5-triphosphate signaling and intracellular calcium
mobilization for several important agonists, including thromboxane A2 (TXA2). To
explore the mechanism of platelet inhibition by NO, activation of platelet TXA2
receptors in the presence of cGMP was studied. The nonhydrolyzable analog 8-bromo
cyclic GMP (8-Br-cGMP) potently inhibited activation of the TXA2-specific GTPase
in platelet membranes in a concentration-dependent fashion, suggesting that G
kinase catalyzes the phosphorylation of some proximal component of the receptor-G
protein signaling pathway. Nanomolar concentrations of G kinase were found to
catalyze the phosphorylation of platelet TXA2 receptors in vitro, but not Galphaq
copurifying with the TXA2 receptors in these experiments. Using immunoaffinity
methods, in vivo phosphorylation of TXA2 receptors by cyclic GMP was demonstrated
from 32P-labeled cells treated with 8-Br-cGMP. Peptide mapping studies of in vivo
phosphorylated TXA2 receptors demonstrated cGMP mediates phosphorylation of the
carboxyl terminus of the TXA2 receptor. G kinase also catalyzed the
phosphorylation of peptides corresponding to the cytoplasmic tails of both alpha
and beta forms of the receptor but not control peptide or a peptide corresponding
to the third intracytoplasmic loop of the TXA2 receptor. These data identify TXA2
receptors as cGMP-dependent protein kinase substrates and support a novel
mechanism for the inhibition of cell function by NO in which activation of G
kinase inhibits signaling by G protein-coupled receptors by catalyzing their
phosphorylation.
PMID- 9560199
TI - Epstein-Barr virus growth-transformed cells are converted to malignancy following
transfection of a 1.3-kb CATR1 antisense construct independent of a change in the
level of c-myc expression followed by a 8;14 chromosomal translocation.
AB - The AGLCL Epstein-Barr virus (EBV) growth-transformed cell line is incapable of
inducing tumors in nude mice. When the cells were transfected with a 1.3-kb CATR1
antisense cDNA construct, progressively growing lymphomas could be induced in
nude mice. Chromosome analysis of the parental, transfected, and tumor cells
revealed that a chromosomal translocation t(8;14)(q24.1;q32) had occurred in the
transfected cells and was retained in cells derived from tumors. Moreover,
enhanced c-myc expression, usually associated with this translocation, was either
unchanged or under-expressed. These data suggest that the malignant
transformation of the EBV growth-transformed cells was independent of c-myc
expression and suggest that the CATR1 gene may act synergistically with the
chromosomal translocation facilitating the conversion of AGLCL cells from a
growth-transformed state to a malignant phenotype.
PMID- 9560201
TI - Endogenous cellulases in animals: isolation of beta-1, 4-endoglucanase genes from
two species of plant-parasitic cyst nematodes.
AB - beta-1,4-Endoglucanases (EGases, EC 3.2.1.4) degrade polysaccharides possessing
beta-1,4-glucan backbones such as cellulose and xyloglucan and have been found
among extremely variegated taxonomic groups. Although many animal species depend
on cellulose as their main energy source, most omnivores and herbivores are
unable to produce EGases endogenously. So far, all previously identified EGase
genes involved in the digestive system of animals originate from symbiotic
microorganisms. Here we report on the synthesis of EGases in the esophageal
glands of the cyst nematodes Globodera rostochiensis and Heterodera glycines.
From each of the nematode species, two cDNAs were characterized and hydrophobic
cluster analysis revealed that the four catalytic domains belong to family 5 of
the glycosyl hydrolases (EC 3.2.1, 3.2.2, and 3.2.3). These domains show 37-44%
overall amino acid identity with EGases from the bacteria Erwinia chrysanthemi,
Clostridium acetobutylicum, and Bacillus subtilis. One EGase with a bacterial
type of cellulose-binding domain was identified for each nematode species. The
leucine-rich hydrophobic core of the signal peptide and the presence of a
polyadenylated 3' end precluded the EGases from being of bacterial origin. Cyst
nematodes are obligatory plant parasites and the identified EGases presumably
facilitate the intracellular migration through plant roots by partial cell wall
degradation.
PMID- 9560200
TI - Escherichia coli rho factor induces release of yeast RNA polymerase II but not
polymerase I or III.
AB - Purified RNA polymerase II (pol II) from the yeast Saccharomyces cerevisiae
pauses without releasing at many locations during in vitro transcription. Pausing
can be induced by intrinsic DNA sequence as well as by specific DNA bound
proteins such as the RNA pol I termination factor, Reb1p, or lac repressor.
Addition of rho termination factor from E. coli induces RNA pol II to release at
all of these pause sites. Rho-induced release of pol II requires both a rho
binding site in the transcript upstream of the pause sites as well as hydrolysis
of ATP. In contrast, rho factor has no effect on either pausing or release by RNA
pol I or III. When combined with previous observations, these results suggest
that RNA pol II may terminate by a mechanism closely related to the rho-dependent
mechanism of prokaryotes. In contrast, pol I and III appear to utilize a
mechanism more related to the rho-independent terminators of prokaryotes.
PMID- 9560202
TI - The Rhizobium meliloti ExoK and ExsH glycanases specifically depolymerize nascent
succinoglycan chains.
AB - The Rhizobium meliloti ExoK and ExsH glycanases have been proposed to contribute
to production of low molecular weight (LMW) succinoglycan by depolymerizing high
molecular weight succinoglycan chains in R. meliloti cultures. We expressed and
purified ExoK and ExsH and determined that neither enzyme can extensively cleave
succinoglycan prepared from R. meliloti cultures, although neutral/heat treatment
and acid/heat treatment convert succinoglycan to forms that can be cleaved
efficiently by both enzymes. These results were somewhat surprising, given that
the exoK+ and exsH+ genes play a crucial role in production of LMW succinoglycan
in R. meliloti cultures. We demonstrated by Western blot analyses that R.
meliloti expresses ExoK and ExsH, that both proteins can be detected
extracellularly, and that ExsH secretion depends on the prsD+/prsE+ genes,
consistent with previous predictions based on mutant analyses. Furthermore, we
determined that the depolymerization activities associated with purified ExoK and
ExsH are comparable with exoK+ and exsH+-dependent depolymerization activities
expressed in R. meliloti cultures. We resolved the apparent contradiction between
the results of our previous genetic analyses and depolymerization assays by
determining that ExoK and ExsH can cleave high molecular weight succinoglycan
that is being produced actively by R. meliloti, but not succinoglycan that has
accumulated in cultures, to yield LMW succinoglycan. We propose that ExoK and
ExsH dynamically regulate the molecular weight distribution of succinoglycan by
cleaving nascent succinoglycan only during a limited period after its synthesis,
perhaps before it undergoes a time-dependent change in its conformation or
aggregation state.
PMID- 9560203
TI - Acetylation at Lys-92 enhances signaling by the chemotaxis response regulator
protein CheY.
AB - When Escherichia coli cells lacking all chemotaxis proteins except the response
regulator CheY are exposed to acetate, clockwise flagellar rotation results,
indicating the acetate stimulus has activated signaling by CheY. Acetate can be
converted to acetyl-CoA by either of two different metabolic pathways, which
proceed through acetyl phosphate or acetyl-AMP intermediates. In turn, CheY can
be covalently modified by either intermediate in vitro, leading to
phosphorylation or acetylation, respectively. Either pathway is sufficient to
support the CheY-mediated response to acetate in vivo. Whereas phosphorylation of
Asp-57 is a recognized mechanism for activation of CheY to stimulate clockwise
flagellar rotation, acetylation of CheY is less well characterized. We found
evidence for multiple CheY acetylation sites by mass spectrometry and directly
identified Lys-92 and Lys-109 as acetylation sites by Edman degradation of
peptides from [14C]acetate-labeled CheY. Replacement of CheY Lys-92, the
preferred acetylation site, with Arg has little effect on chemotaxis but
completely prevents the response to acetate via the acetyl-AMP pathway. Thus
acetylation of Lys-92 activates clockwise signaling by CheY in vivo. The
mechanism by which acetylation activates CheY apparently is not simple charge
neutralization, nor does it involve enhanced binding to the FliM flagellar switch
protein. Thus acetylation probably affects signal generation by CheY at a step
after switch binding.
PMID- 9560204
TI - Iron-dependent oxidation, ubiquitination, and degradation of iron regulatory
protein 2: implications for degradation of oxidized proteins.
AB - The ability of iron to catalyze formation of reactive oxygen species
significantly contributes to its toxicity in cells and animals. Iron uptake and
distribution is regulated tightly in mammalian cells, in part by iron regulatory
protein 2 (IRP2), a protein that is degraded efficiently by the proteasome in
iron-replete cells. Here, we demonstrate that IRP2 is oxidized and ubiquitinated
in cells before degradation. Moreover, iron-dependent oxidation converts IRP2
into a substrate for ubiquitination in vitro. A regulatory pathway is described
in which excess iron is sensed by its ability to catalyze site-specific
oxidations in IRP2, oxidized IRP2 is ubiquitinated, and ubiquitinated IRP2
subsequently is degraded by the proteasome. Selective targeting and removal of
oxidatively modified proteins may contribute to the turnover of many proteins
that are degraded by the proteasome.
PMID- 9560205
TI - Stable alteration of pre-mRNA splicing patterns by modified U7 small nuclear
RNAs.
AB - In several forms of beta-thalassemia, mutations in the second intron of the beta
globin gene create aberrant 5' splice sites and activate a common cryptic 3'
splice site upstream. As a result, the thalassemic beta-globin pre-mRNAs are
spliced almost exclusively via the aberrant splice sites leading to a deficiency
of correctly spliced beta-globin mRNA and, consequently, beta-globin. We have
designed a series of vectors that express modified U7 snRNAs containing sequences
antisense to either the aberrant 5' or 3' splice sites in the IVS2-705
thalassemic pre-mRNA. Transient expression of modified U7 snRNAs in a HeLa cell
line stably expressing the IVS2-705 beta-globin gene restored up to 65% of
correct splicing in a sequence-specific and dose-dependent manner. Cell lines
that stably coexpressed IVS2-705 pre-mRNA and appropriately modified U7 snRNA
exhibited up to 55% of permanent restoration of correct splicing and expression
of full-length beta-globin protein. This novel approach provides a potential
alternative to gene replacement therapies.
PMID- 9560206
TI - Specificity in cholesterol regulation of gene expression by coevolution of sterol
regulatory DNA element and its binding protein.
AB - When demand for cholesterol rises in mammalian cells, the sterol regulatory
element (SRE) binding proteins (SREBPs) are released from their membrane anchor
through proteolysis. Then, the N-terminal region enters the nucleus and activates
genes of cholesterol uptake and biosynthesis. Basic helix-loop-helix (bHLH)
proteins such as SREBPs bind to a palindromic DNA sequence called the E-box (5'
CANNTG-3'). However, SREBPs are special because they also bind direct repeat
elements called SREs. Importantly, sterol regulation of all promoters studied
thus far is mediated by SREBP binding only to SREs. To study the reason for this
we converted the direct repeat SRE from the sterol-regulated low-density
lipoprotein receptor promoter into an E-box. In this report we show that SREBPs
are still able to bind and activate this promoter however, sterol regulation is
lost. The results are consistent with the mutant promoter being a target for
promiscuous activation by constitutively expressed E-box binding bHLH proteins
that are not regulated by cholesterol. Kim and coworkers [Kim, J. B., Spotts, G.
D., Halvorsen, Y.-D., Shih, H.-M., Ellenberger, T., Towle, H. C. & Spiegelman, B.
M. (1995) Mol. Cell. Biol. 15, 2582-2588] demonstrated that the dual DNA binding
specificity of SREBPs is caused by a specific tyrosine in the conserved basic
region of the DNA binding domain that corresponds to an arginine in all other
bHLH proteins that recognize only E-boxes. Taken together the data suggest an
evolutionary mechanism where a DNA binding protein along with its recognition
site have coevolved to ensure maximal specificity and sensitivity in a crucial
nutritional regulatory response.
PMID- 9560207
TI - Mapping of the ligand-selective domain of the Xenopus laevis corticotropin
releasing factor receptor 1: implications for the ligand-binding site.
AB - The nonselective human corticotropin-releasing factor receptor 1 (hCRF-R1) and
the ligand-selective Xenopus CRF-R1 (xCRF-R1) were compared. To understand the
interactions of sauvagine and ovine CRF, both high-affinity ligands for hCRF-R1
but surprisingly weak ligands for xCRF-R1, chimeric receptors of hCRF-R1 and xCRF
R1 followed by double or multiple point mutations were constructed. Binding
studies and cAMP assays demonstrated that the N-terminal domain exhibited the
complete ligand selectivity of xCRF-R1. The important region was mapped between
amino acids 70 and 89; replacement of amino acids Arg76, Asn81, Gly83, Leu88, and
Ala89 in hCRF-R1 with the corresponding amino acids of xCRF-R1 (Gln76, Gly81,
Val83, His88, and Leu89) resulted in a receptor that had approximately 30-fold
higher affinity for human/rat CRF than for sauvagine. Mutagenesis of these amino
acids in xCRF-R1 to the human sequence completely abolished the ligand
selectivity of xCRF-R1. Mutagenesis of amino acids 88 and 89 in hCRF-R1 or xCRF
R1 had only a minor (approximately 2.5-fold) effect on the ligand selectivity of
the mutant receptor. Substitution of Arg76, Asn81, and Gly83 in hCRF-R1 with the
corresponding sequence of xCRF-R1 (Gln76, Gly81, and Val83) resulted in a
receptor with approximately 11-fold higher affinity for human/rat CRF compared
with ovine CRF or sauvagine. When only two of these three amino acids were
mutated, no effect on the ligand selectivity was observed. On the basis of these
data, it is suggested that amino acids 70-89 of CRF-R1 are important for the
ligand binding site.
PMID- 9560208
TI - Perturbation of nucleosome core structure by the SWI/SNF complex persists after
its detachment, enhancing subsequent transcription factor binding.
AB - To investigate the mechanism of SWI/SNF action, we have analyzed the pathway by
which SWI/SNF stimulates formation of transcription factor-bound nucleosome core
complexes. We report here that the SWI/SNF complex binds directly to nucleosome
cores and uses the energy of ATP hydrolysis to disrupt histone/DNA interactions,
altering the preferred path of DNA bending around the histone octamer. This
disruption occurs without dissociating the DNA from the surface of the histone
octamer. ATP-dependent disruption of nucleosomal DNA by SWI/SNF generates an
altered nucleosome core conformation that can persist for an extended period
after detachment of the SWI/SNF complex. This disrupted conformation retains an
enhanced affinity for the transcription factor GAL4-AH. Thus, ATP-dependent
nucleosome core disruption and enhanced binding of the transcription factor can
be temporally separated. These results indicate that SWI/SNF can act transiently
in the remodeling of chromatin structure, even before interactions of
transcription factors.
PMID- 9560210
TI - Evidence that HetR protein is an unusual serine-type protease.
AB - The hetR gene plays a very important role in cell differentiation of
heterocystous cyanobacteria. To understand the mechanism of the hetR gene product
in regulation of heterocyst differentiation, the recombinant HetR protein (rHetR)
was overproduced in Escherichia coli. Purified rHetR was unstable and degraded
easily in solution. Phenylmethanesulfonyl fluoride, a serine-type protease
inhibitor, prevented the degradation and was shown to modify covalently rHetR.
Dansyl fluoride (DnsF), another serine-type protease inhibitor, also covalently
modifies rHetR as shown by electrophoresis and electroblotting of the labeled
rHetR and by MS. The labeling of rHetR with phenylmethanesulfonyl fluoride and
DnsF was at the same site of rHetR and required Ca2+. S179N-rHetR, a mutant
protein from strain 216 of Anabaena PCC 7120, which cannot differentiate
heterocysts because of the mutation, was also overproduced and characterized.
Although S170N-rHetR still can be labeled with DnsF, no proteolysis was observed,
suggesting that Ser179 is involved in proteolytic activity. DnsF-labeled rHetR
was digested with trypsin, and the labeled peptide was isolated and sequenced.
The labeled peptide matches a sequence from HetR. These results show that HetR is
a protease.
PMID- 9560209
TI - A stationary phase protein in Escherichia coli with binding activity to the major
sigma subunit of RNA polymerase.
AB - Switching of the transcription pattern in Escherichia coli during the growth
transition from exponential to stationary phase is accompanied by the replacement
of the RNA polymerase-associated sigma70 subunit (sigmaD) with sigma38 (sigmaS).
A fraction of the sigma70 subunit in stationary phase cell extracts was found to
exist as a complex with a novel protein, designated Rsd (Regulator of sigma D).
The intracellular level of Rsd starts to increase during the transition from
growing to stationary phase. The rsd gene was identified at 90 min on the E. coli
chromosome. Overexpressed and purified Rsd protein formed complexes in vitro with
sigma70 but not with other sigma subunits, sigmaN, sigmaS, sigmaH, sigmaF, and
sigmaE. Analysis of proteolytic fragments of sigma70 indicated that Rsd binds at
or downstream of region 4, the promoter -35 recognition domain. The isolated Rsd
inhibited transcription in vitro to various extents depending on the promoters
used. We propose that Rsd is a stationary phase E. coli protein with regulatory
activity of the sigma70 function.
PMID- 9560211
TI - Phospholipid composition of the mammalian red cell membrane can be rationalized
by a superlattice model.
AB - Although the phospholipid composition of the erythrocyte membrane has been
studied extensively, it remains an enigma as to how the observed composition
arises and is maintained. We show here that the phospholipid composition of the
human erythrocyte membrane as a whole, as well as the composition of its
individual leaflets, is closely predicted by a model proposing that phospholipid
head groups tend to adopt regular, superlattice-like lateral distributions. The
phospholipid composition of the erythrocyte membrane from most other mammalian
species, as well as of the platelet plasma membrane, also agrees closely with the
predictions of the superlattice model. Statistical analyses indicate that the
agreement between the observed and predicted compositions is highly significant,
thus suggesting that head group superlattices may indeed play a central role in
the maintenance of the phospholipid composition of the erythrocyte membrane.
PMID- 9560213
TI - How evolution makes proteins fold quickly.
AB - Sequences of fast-folding model proteins (48 residues long on a cubic lattice)
were generated by an evolution-like selection toward fast folding. We find that
fast-folding proteins exhibit a specific folding mechanism in which all
transition state conformations share a smaller subset of common contacts (folding
nucleus). Acceleration of folding was accompanied by dramatic strengthening of
interactions in the folding nucleus whereas average energy of nonnucleus
interactions remained largely unchanged. Furthermore, the residues involved in
the nucleus are the most conserved ones within families of evolved sequences. Our
results imply that for each protein structure there is a small number of
conserved positions that are key determinants of fast folding into that
structure. This conjecture was tested on two protein superfamilies: the first
having the classical monophosphate binding fold (CMBF; 98 families) and the
second having type-III repeat fold (47 families). For each superfamily, we
discovered a few positions that exhibit very strong and statistically significant
"conservatism of conservatism"-amino acids in those positions are conserved
within every family whereas the actual types of amino acids varied from family to
family. Those amino acids are in spatial contact with each other. The
experimental data of Serrano and coworkers [Lopez-Hernandez, E. & Serrano, L.
(1996) Fold. Des. (London) 1, 43-55]. for one of the proteins of the CMBF
superfamily (CheY) show that residues identified this way indeed belong to the
folding nucleus. Further analysis revealed deep connections between nucleation in
CMBF proteins and their function.
PMID- 9560212
TI - Dynamics of different functional parts of bacteriorhodopsin: H-2H labeling and
neutron scattering.
AB - We show that dynamics of specific amino acids within a protein can be
characterized by neutron spectroscopy and hydrogen-deuterium labeling, and we
present data on the motions of a selected set of groups within bacteriorhodopsin
(BR), the retinal-based proton pump in the purple membrane of halophilic Archaea.
Elastic incoherent neutron scattering experiments allow the definition of motions
in the nano- to picosecond time scale and have revealed a dynamical transition
from a harmonic to a softer, anharmonic atomic fluctuation regime in the global
behavior of proteins. Biological activity in proteins is correlated with this
transition, suggesting that flexibility is required for function. Elastic
incoherent neutron scattering is dominated by H atom scattering, and to study the
dynamics of a selected part of BR, fully deuterated purple membrane with BR
containing H-retinal, H-tryptophan, and H-methionine was prepared
biosynthetically in Halobacterium salinarum. These amino acids cluster in the
functional center of the protein. In contrast to the protein globally, the
thermal motions of the labeled atoms were found to be shielded from solvent
melting effects at 260 K. Above this temperature, the labeled groups appear as
more rigid than the rest of the protein, with a significantly smaller mean square
amplitude of motion. These experimental results quantify the dynamical
heterogeneity of BR (which meets the functional requirements of global
flexibility), on the one hand, to allow large conformational changes in the
molecule and of a more rigid region in the protein, on the other, to control
stereo-specific selection of retinal conformations.
PMID- 9560214
TI - The sequences of small proteins are not extensively optimized for rapid folding
by natural selection.
AB - The thermodynamic stabilities of small protein domains are clearly subject to
natural selection, but it is less clear whether the rapid folding rates typically
observed for such proteins are consequences of direct evolutionary optimization
or reflect intrinsic physical properties of the polypeptide chain. This issue can
be investigated by comparing the folding rates of laboratory-generated protein
sequences to those of naturally occurring sequences provided that the method by
which the sequences are generated has no kinetic bias. Herein we report the
folding thermodynamics and kinetics of 12 heavily mutated variants of the small
IgG binding domain of protein L retrieved from high-complexity combinatorial
libraries by using a phage-display selection for proper folding that does not
discriminate between rapidly and slowly folding proteins. Although the
stabilities of all variants were decreased, many of the variants fold faster than
wild type. Taken together with similar results for the src homology 3 domain,
this observation suggests that the sequences of small proteins have not been
extensively optimized for rapid folding; instead, rapid folding appears to be a
consequence of selection for stability.
PMID- 9560215
TI - Are protein folds atypical?
AB - Protein structures are a very special class among all possible structures. It has
been suggested that a "designability principle" plays a crucial role in nature's
selection of protein sequences and structures. Here, we provide a theoretical
base for such a selection principle, using a simple model of protein folding
based on hydrophobic interactions. A structure is reduced to a string of 0s and
1s, which represent the surface and core sites, respectively, as the backbone is
traced. Each structure is therefore associated with one point in a high
dimensional space. Sequences are represented by strings of their hydrophobicities
and thus can be mapped into the same space. A sequence that lies closer to a
particular structure in this space than to any other structures will have that
structure as its ground state. Atypical structures, namely those far away from
other structures in the high dimensional space, have more sequences that fold
into them and are thermodynamically more stable. We argue that the most common
folds of proteins are the most atypical in the space of possible structures.
PMID- 9560216
TI - Localization of nascent RNA and CREB binding protein with the PML-containing
nuclear body.
AB - The cellular role of the PML-containing nuclear bodies also known as ND10 or PODs
remains elusive despite links to oncogenesis and viral replication. Although a
potential role in transcription has been considered, direct evidence has been
lacking. By developing a novel in vivo nucleic acid labeling approach, we
demonstrate the existence of nascent RNA polymerase II transcripts within this
nuclear body. In addition, PML and the transactivation cofactor, CREB binding
protein (CBP), colocalize within the nucleus. Furthermore, we show that CBP in
contrast to PML is distributed throughout the internal core of the structure.
Collectively, these findings support a role for this nuclear body in
transcriptional regulation.
PMID- 9560217
TI - Bax directly induces release of cytochrome c from isolated mitochondria.
AB - Bax is a pro-apoptotic member of the Bcl-2 protein family that resides in the
outer mitochondrial membrane. It is controversial whether Bax promotes cell death
directly through its putative function as a channel protein versus indirectly by
inhibiting cellular regulators of the cell death proteases (caspases). We show
here that addition of submicromolar amounts of recombinant Bax protein to
isolated mitochondria can induce cytochrome c (Cyt c) release, whereas a peptide
representing the Bax BH3 domain was inactive. When placed into purified cytosol,
neither mitochondria nor Bax individually induced proteolytic processing and
activation of caspases. In contrast, the combination of Bax and mitochondria
triggered release of Cyt c from mitochondria and induced caspase activation in
cytosols. Supernatants from Bax-treated mitochondria also induced caspase
processing and activation. Recombinant Bcl-XL protein abrogated Bax-induced
release of Cyt c from isolated mitochondria and prevented caspase activation. In
contrast, the broad-specificity caspase inhibitor benzyloxycarbonyl-valinyl
alaninyl-aspartyl-(0-methyl)- fluoromethylketone (zVAD-fmk) and the caspase
inhibiting protein X-IAP had no effect on Bax-induced release of Cyt c from
mitochondria in vitro but prevented the subsequent activation of caspases in
cytosolic extracts. Unlike Ca2+, a classical inducer of mitochondrial
permeability transition, Bax did not induce swelling of mitochondria in vitro.
Because the organellar swelling caused by permeability transition causes outer
membrane rupture, the findings, therefore, dissociate these two events, implying
that Bax uses an alternative mechanism for triggering release of Cyt c from
mitochondria.
PMID- 9560218
TI - Transmembrane heme delivery systems.
AB - Heme proteins play pivotal roles in a wealth of biological processes. Despite
this, the molecular mechanisms by which heme traverses bilayer membranes for use
in biosynthetic reactions are unknown. The biosynthesis of c-type cytochromes
requires that heme is transported to the bacterial periplasm or mitochondrial
intermembrane space where it is covalently ligated to two reduced cysteinyl
residues of the apocytochrome. Results herein suggest that a family of integral
membrane proteins in prokaryotes, protozoans, and plants act as transmembrane
heme delivery systems for the biogenesis of c-type cytochromes. The complete
topology of a representative from each of the three subfamilies was
experimentally determined. Key histidinyl residues and a conserved tryptophan
rich region (designated the WWD domain) are positioned at the site of cytochrome
c assembly for all three subfamilies. These histidinyl residues were shown to be
essential for function in one of the subfamilies, an ABC transporter encoded by
helABCD. We believe that a directed heme delivery pathway is vital for the
synthesis of cytochromes c, whereby heme iron is protected from oxidation via
ligation to histidinyl residues within the delivery proteins.
PMID- 9560219
TI - Endothelial Ca2+ waves preferentially originate at specific loci in caveolin-rich
cell edges.
AB - Stimulation of endothelial cells (ECs) with ATP evoked an increase in
intracellular Ca2+ concentration ([Ca2+]i). In a single bovine aortic EC, the
[Ca2+]i rise started at a specific peripheral locus and propagated throughout the
entire cell as a Ca2+ wave. The initiation locus was constant upon repeated
stimulation with ATP or other agonists (bradykinin and thrombin). The Ca2+ wave
was unaffected by the removal of extracellular Ca2+, demonstrating its dependence
on intracellular Ca2+ release. Microinjection of heparin into the cell inhibited
the ATP-induced Ca2+ responses, indicating that the Ca2+ wave is at least partly
mediated by the inositol 1,4, 5-trisphosphate receptor. Immunofluorescence
staining revealed that caveolin, a marker protein for caveolae, is distributed
heterogeneously in the cell and that Ca2+ waves preferentially originate at
caveolin-rich cell edges. In contrast to caveolin, internalized transferrin and
subunits of the clathrin-associated adaptor complexes such as adaptor protein-1
and -2 were diffusely distributed. Disruption of microtubules by Colcemid led to
redistribution of caveolin away from the edges into the perinuclear center of the
cell, and the ATP-induced [Ca2+]i increase was initiated on the rim of the
centralized caveolin. Thus, caveolae may be involved in the initiation of ATP
induced Ca2+ waves in ECs.
PMID- 9560220
TI - Association of calcium channel alpha1S and beta1a subunits is required for the
targeting of beta1a but not of alpha1S into skeletal muscle triads.
AB - The skeletal muscle L-type Ca2+ channel is a complex of five subunits that is
specifically localized in the triad. Its primary function is the rapid activation
of Ca2+ release from cytoplasmic stores in a process called excitation
contraction coupling. To study the role of alpha1S-beta1a interactions in the
incorporation of the functional channel complex into the triad, alpha1S and
beta1a [or a beta1a-green fluorescent protein (GFP) fusion protein] were
expressed alone and in combination in myotubes of the dysgenic cell line GLT.
betaGFP expressed in dysgenic myotubes that lack the skeletal muscle alpha1S
subunit was diffusely distributed in the cytoplasm. On coexpression with the
alpha1S subunit betaGFP distribution became clustered and colocalized with
alpha1S immunofluorescence. Based on the colocalization of betaGFP and alpha1S
with the ryanodine receptor the clusters were identified as T-tubule/sarcoplasmic
reticulum junctions. Expression of alpha1S with and without beta1a restored Ca2+
currents and depolarization-induced Ca2+ release. The translocation of betaGFP
from the cytoplasm into the junctions failed when betaGFP was coexpressed with
alpha1S mutants in which the beta interaction domain had been altered (alpha1S
Y366S) or deleted (alpha1S-Delta351-380). Although alpha1S-Y366S did not
associate with betaGFP it was incorporated into the junctions, and it restored
Ca2+ currents and depolarization-induced Ca2+ release. Thus, beta1a requires the
association with the beta interaction domain in the I-II cytoplasmic loop of
alpha1S for its own incorporation into triad junctions, but stable alpha1S-beta1a
association is not necessary for the targeting of alpha1S into the triads or for
its normal function in Ca2+ conductance and excitation-contraction coupling.
PMID- 9560221
TI - A distinct cyclin-dependent kinase-activating kinase of Arabidopsis thaliana.
AB - The activation of cyclin-dependent kinases (CDKs) requires phosphorylation of a
threonine residue within the T-loop catalyzed by CDK-activating kinases (CAKs).
Thus far no functional CAK homologue has been reported in plants. We screened an
Arabidopsis cDNA expression library for complementation of a budding yeast CAK
mutant. A cDNA, cak1At, was isolated that suppressed the CAK mutation in budding
yeast, and it also complemented a fission yeast CAK mutant. cak1At encodes a
protein related to animal CAKs. The CAK similarity was restricted to the
conserved kinase domains, leading to classification of Cak1At as a distinct CDK
in the phylogenetic tree. Immunoprecipitates with the anti-Cak1At antibody
phosphorylated human CDK2 at the threonine residue (T160) within the T-loop and
activated its activity to phosphorylate histone H1. Whereas CAKs in animals and
fission yeast are involved in regulation of the cell cycle and basal
transcription by phosphorylating the carboxyl-terminal domain (CTD) of the
largest subunit of RNA polymerase II, Cak1At did not phosphorylate the CTD. An
Arabidopsis CTD-kinase isolated separately from Cak1At was shown to interact with
the yeast protein p13(suc1), but it had no CDK2-kinase activity. Therefore, the
CTD of RNA polymerase II is probably phosphorylated by a Cdc2-related kinase
distinct from Cak1At. cak1At is a single-copy gene in Arabidopsis and is highly
expressed in proliferating cells of suspension cultures.
PMID- 9560222
TI - A cytoplasmic protein, bystin, interacts with trophinin, tastin, and cytokeratin
and may be involved in trophinin-mediated cell adhesion between trophoblast and
endometrial epithelial cells.
AB - Trophinin and tastin form a cell adhesion molecule complex that potentially
mediates an initial attachment of the blastocyst to uterine epithelial cells at
the time of implantation. Trophinin and tastin, however, do not directly bind to
each other, suggesting the presence of an intermediary protein. The present study
identifies a cytoplasmic protein, named bystin, that directly binds trophinin and
tastin. Bystin consists of 306 amino acid residues and is predicted to contain
tyrosine, serine, and threonine residues in contexts conforming to motifs for
phosphorylation by protein kinases. Database searches revealed a 53% identity of
the predicted peptide sequence with the Drosophila bys (mrr) gene. Direct protein
protein interactions of trophinin, tastin, and bystin analyzed by yeast two
hybrid assays and by in vitro protein binding assays indicated that binding
between bystin and trophinin and between bystin and tastin is enhanced when
cytokeratin 8 and 18 are present as the third molecule. Immunocytochemistry of
bystin showed that bystin colocalizes with trophinin, tastin, and cytokeratins in
a human trophoblastic teratocarcinoma cell, HT-H. It is therefore possible that
these molecules form a complex and thus are involved in the process of embryo
implantation.
PMID- 9560223
TI - Targeted disruption of p70(s6k) defines its role in protein synthesis and
rapamycin sensitivity.
AB - Here, we disrupted the p70 S6 kinase (p70(s6k)) gene in murine embryonic stem
cells to determine the role of this kinase in cell growth, protein synthesis, and
rapamycin sensitivity. p70(s6k-/-) cells proliferated at a slower rate than
parental cells, suggesting that p70(s6k) has a positive influence on cell
proliferation but is not essential. In addition, rapamycin inhibited
proliferation of p70(s6k-/-) cells, indicating that other events inhibited by the
drug, independent of p70(s6k), also are important for both cell proliferation and
the action of rapamycin. In p70(s6k-/-) cells, which exhibited no ribosomal S6
phosphorylation, translation of mRNA encoding ribosomal proteins was not
increased by serum nor specifically inhibited by rapamycin. In contrast,
rapamycin inhibited phosphorylation of initiation factor 4E-binding protein 1 (4E
BP1), general mRNA translation, and overall protein synthesis in p70(s6k-/-)
cells, indicating that these events proceed independently of p70(s6k) activity.
This study localizes the function of p70(s6k) to ribosomal biogenesis by
regulating ribosomal protein synthesis at the level of mRNA translation.
PMID- 9560224
TI - Cellular memory: neutrophil orientation reverses during temporally decreasing
chemoattractant concentrations.
AB - Cell directional orientation or shape polarization is the first cellular step in
neutrophil locomotion. To better understand how chemoattractants interact with
cells, we studied neutrophil polarization (or shape changes) during exposure to a
temporally decreasing chemoattractant signal of N-formyl-methionyl-leucyl
phenylalanine (FMLP) in the absence of a spatial concentration gradient. To
accomplish this objective, we used a manifold of differing FMLP concentrations
attached to a stopped-flow microscope chamber. Spatial gradients of a fluorescent
chemotactic peptide could not be detected in the chamber by using
microfluorometry. When FMLP was injected at continually increasing concentrations
at 10-s intervals, the shape and relative direction of the neutrophil persisted.
However, when temporally decreasing FMLP concentrations were injected,
approximately 80% of the cells changed their direction with 44% of the total
cells swinging about to 180 degrees +/- 15 degrees. Most of these directional
changes involved dissolution of both the lamellipodium and uropod and reformation
of these structures 180 degrees from their original positions. This research
suggests that neutrophils reverse their morphological polarity when exposed to
temporally decreasing ligand concentrations by "remembering" their ligand
exposure history and relative direction.
PMID- 9560225
TI - Macrophages resistant to endogenously generated nitric oxide-mediated apoptosis
are hypersensitive to exogenously added nitric oxide donors: dichotomous
apoptotic response independent of caspase 3 and reversal by the mitogen-activated
protein kinase kinase (MEK) inhibitor PD 098059.
AB - Nitric oxide (NO) induction through the inducible NO synthase has been
demonstrated to cause cell death in macrophages. We demonstrate that, in
macrophages that have been rendered resistant to apoptosis induced by inducible
NO synthase (RES cells), exposure to exogenous NO donors results in a
hypersensitive apoptosis reaction when compared with the parental RAW 264.7
cells. The apoptosis induced via exogenous NO donors was found to be caspase 3
independent. Although caspase 3 activity was stimulated in the apoptotic
macrophages, inhibition of caspase 3 by the inhibitor DEVD-CHO (N-acetyl-Asp-Glu
Val-Asp-aldehyde) did not reverse the apoptosis induced by the NO donor S
nitrosoglutathione (GSNO). This suggests that although caspase 3 activity is
stimulated during apoptosis in macrophages, this signal is not sufficient to
induce apoptosis. Cleavage of the enzyme poly(ADP ribose) polymerase mirrors our
results of the caspase activity. Interestingly, we show that exogenous NO
donation results in an accumulation of cells at the G2/M-phase border. Here, we
demonstrate that the mitogen activated protein kinase kinase (MEK) inhibitor PD
098059 can be used to reverse the G2/M-phase block and show that this treatment
also inhibits the observed apoptosis in RES macrophages. Treatment with the MEK
inhibitor also reversed both the caspase 3 activity and poly(ADP ribose)
polymerase cleavage in cells treated with GSNO. This result indicates that the
mitogen-activated protein kinase pathway may be involved in regulation of the
caspase cascade. Alternatively, it may suggest an activity for the MEK inhibitor
heretofore not observed, that of a cyclin kinase inhibitor. Our results suggest
that selection of macrophages by resistance to endogenously generated NO may
cause hypersensitivity to exogenous NO donors. These findings have relevant
implications for the treatment of apoptotic-resistant cell populations that may
occur in both cancer and atheroma.
PMID- 9560226
TI - Activation of protein tyrosine kinase PYK2 by the m1 muscarinic acetylcholine
receptor.
AB - Several G protein-coupled receptors are known to direct the tyrosine
phosphorylation, and in some cases the activation, of diverse tyrosine kinases.
Using a stable cell line approach, we characterize the activation of PYK2, a
tyrosine kinase structurally related to focal adhesion kinase, by the G protein
coupled m1 muscarinic acetylcholine receptor. We find that PYK2 tyrosine kinase
activity is critical for the m1 receptor-stimulated tyrosine phosphorylation of
PYK2. Furthermore, we identify two tyrosine residues that are subject to
phosphorylation in response to muscarinic signaling and show that this
phosphorylation induces two cytosolic proteins, c-Src and Grb2, to bind to PYK2.
This is the first demonstration of the significance played by distinct PYK2
tyrosine residues in G protein-coupled signaling to this kinase. By comparison,
though m1 receptors induce the tyrosine phosphorylation of the cytoskeletal
protein paxillin, the association of paxillin with PYK2 is unaffected by
muscarinic signaling. We also provide evidence that PYK2 specifically
phosphorylates the carboxyl-terminal cytosolic portion of the potassium channel
Kv1.2 in a manner regulated by the m1 receptor. These results delineate molecular
events attending the m1 muscarinic receptor stimulation of this tyrosine kinase
and establish PYK2 as an effector of the m1 muscarinic receptor in the regulation
of multiple cell functions.
PMID- 9560227
TI - Sequestration of the G protein beta gamma subunit complex inhibits receptor
mediated endocytosis.
AB - Cell surface receptors that mediate endocytosis cluster into clathrin-coated
pits, which pinch off to form vesicles that transport the receptors and their
ligands. This multi-step process requires the coordinated action of many factors,
including GTP-hydrolyzing proteins such as dynamin and regulators of actin
cytoskeleton assembly. We note herein that sequestration of heterotrimeric G
protein beta gamma subunits in intact cells strongly inhibits clathrin-coated pit
mediated endocytosis and causes rearrangement of the actin cytoskeleton. Our
results suggest that cells contain a pool of free beta gamma and that it
functions constitutively to permit endocytosis.
PMID- 9560229
TI - Solution structure of SpoIIAA, a phosphorylatable component of the system that
regulates transcription factor sigmaF of Bacillus subtilis.
AB - The establishment of differential gene expression in sporulating Bacillus
subtilis involves four protein components, one of which, SpoIIAA, undergoes
phosphorylation and dephosphorylation. We have used NMR spectroscopy to determine
the solution structure of the nonphosphorylated form of SpoIIAA. The structure
shows a fold consisting of a four-stranded beta-sheet and four alpha-helices.
Knowledge of the structure helps to account for the phenotype of several strains
of B. subtilis that carry known spoIIAA mutations and should facilitate
investigations of the conformational consequences of phosphorylation.
PMID- 9560228
TI - Activation of apurinic/apyrimidinic endonuclease in human cells by reactive
oxygen species and its correlation with their adaptive response to genotoxicity
of free radicals.
AB - Apurinic/apyrimidinic (AP) endonuclease (APE; EC 4.2.99.18) plays a central role
in repair of DNA damage due to reactive oxygen species (ROS) because its DNA 3'
phosphoesterase activity removes 3' blocking groups in DNA that are generated by
DNA glycosylase/AP-lyases during removal of oxidized bases and by direct ROS
reaction with DNA. The major human APE (APE-1) gene is activated selectively by
sublethal levels of a variety of ROS and ROS generators, including ionizing
radiation, but not by other genotoxicants-e.g., UV light and alkylating agents.
Increased expression of APE mRNA and protein was observed both in the HeLa S3
tumor line and in WI 38 primary fibroblasts, and it was accompanied by
translocation of the endonuclease to the nucleus. ROS-treated cells showed a
significant increase in resistance to the cytotoxicity of such ROS generators as
H2O2 and bleomycin, but not to UV light. This "adaptive response" appears to
result from enhanced repair of cytotoxic DNA lesions due to an increased activity
of APE-1, which may be limiting in the base excision repair process for ROS
induced toxic lesions.
PMID- 9560230
TI - Rescue of Caenorhabditis elegans pharyngeal development by a vertebrate heart
specification gene.
AB - Development of pharyngeal muscle in nematodes and cardiac muscle in vertebrates
and insects involves the related homeobox genes ceh-22, nkx2.5, and tinman,
respectively. To determine whether the nematode and vertebrate genes perform
similar functions, we examined activity of the zebrafish nkx2.5 gene in
transgenic Caenorhabditis elegans. Here, we report that ectopic expression of
nkx2.5 in C. elegans body wall muscle can directly activate expression of both
the endogenous myo-2 gene, a ceh-22 target normally expressed only in pharyngeal
muscle, and a synthetic reporter construct controlled by a multimerized CEH-22
binding site. nkx2.5 also efficiently rescues a ceh-22 mutant when expressed in
pharyngeal muscle. Together, these results indicate that nkx2.5 and ceh-22
provide a single conserved molecular function. Further, they suggest that an
evolutionarily conserved mechanism underlies heart development in vertebrates and
insects and pharyngeal development in nematodes.
PMID- 9560231
TI - A paracrine role for the epithelial progesterone receptor in mammary gland
development.
AB - Recently generated progesterone receptor (PR)-negative (PR-/-) mice provide an
excellent model for dissecting the role of progesterone in the development of the
mammary gland during puberty and pregnancy. However, the full extent of the
mammary gland defect in these mice caused by the absence of the PR cannot be
assessed, because PR-/- mice do not exhibit estrous cycles and fail to become
pregnant. To circumvent this difficulty, we have transplanted PR-/- breasts into
wild-type mice, and we have demonstrated that the development of the mammary
gland in the absence of the PR is arrested at the stage of the simple ductal
system found in the young virgin mouse. Mammary transplants lacking the PR in the
stromal compartment give rise to normal alveolar growth, whereas transplants
containing PR-/- epithelium conserve the abnormal phenotype. Chimeric epithelia
in which PR-/- cells are in close vicinity to PR wild-type cells go through
complete alveolar development to which the PR-/- cells contribute. Together,
these results indicate that progesterone acts by a paracrine mechanism on a
subset of mammary epithelial cells to allow for alveolar growth and that
expression of the PR is not required in all the cells of the mammary epithelium
in order for alveolar development to proceed normally.
PMID- 9560232
TI - Targeted disruption of fibroblast growth factor (FGF) receptor 2 suggests a role
for FGF signaling in pregastrulation mammalian development.
AB - We disrupted the fibroblast growth factor (FGF) receptor 2 (FGFR2) gene by
introducing a neo cassette into the IIIc ligand binding exon and by deleting a
genomic DNA fragment encoding its transmembrane domain and part of its kinase I
domain. A recessive embryonic lethal mutation was obtained. Preimplantation
development was normal until the blastocyst stage. Homozygous mutant embryos died
a few hours after implantation at a random position in the uterine crypt, with
collapsed yolk cavity. Mutant blastocysts hatched, adhered, and formed a layer of
trophoblast giant cells in vitro, but after prolonged culture, the growth of the
inner cell mass stopped, no visceral endoderm formed, and finally the egg
cylinder disintegrated. It follows that FGFR2 is required for early
postimplantation development between implantation and the formation of the egg
cylinder. We suggest that FGFR2 contributes to the outgrowth, differentiation,
and maintenance of the inner cell mass and raise the possibility that this
activity is mediated by FGF4 signals transmitted by FGFR2. The role of early FGF
signaling in pregastrulation development as a possible adaptation to mammalian
(amniote) embryogenesis is discussed.
PMID- 9560233
TI - The role of robustness and changeability on the origin and evolution of genetic
codes.
AB - We propose that an essential factor on the origin of genetic codes is a balanced
accomplishment of robustness and changeability, two antithetical, but
fundamental, properties for the survival and evolution of organisms. These
measures are defined as the intrinsic properties of genetic codes. An evaluation
of these properties explains the structural regularity of genetic codes,
estimates the order of codon reassignment in deviant codes, and predicts the most
probable deviant codes that exist. The enumeration of genetic codes that could
have evolved from the standard genetic code under the selection pressure on
robustness and changeability strongly limits the freedom of codon reassignments.
The codon reassignments of all currently known deviant genetic codes belong to
this predicted evolutionary path, and they generally give the highest
improvements on robustness and changeability.
PMID- 9560234
TI - Toward a resolution of the introns early/late debate: only phase zero introns are
correlated with the structure of ancient proteins.
AB - We present evidence that a well defined subset of intron positions shows a non
random distribution in ancient genes. We analyze a database of ancient conserved
regions drawn from GenBank 101 to retest two predictions of the theory that the
first genes were constructed by exon shuffling. These predictions are that there
should be an excess of symmetric exons (and sets of exons) flanked by introns of
the same phase (positions within the codon) and that intron positions in ancient
proteins should correlate with the boundaries of compact protein modules. Both
these predictions are supported by the data, with considerable statistical force
(P values < 0.0001). Intron positions correlate to modules of diameters around
21, 27, and 33 A, and this correlation is due to phase zero introns. We suggest
that 30-40% of present day intron positions in ancient genes correspond to phase
zero introns originally present in the progenote, while almost all of the
remaining intron positions correspond to introns added, or moved, appearing
equally in all three intron phases. This proposal provides a resolution for many
of the arguments of the introns-early/introns-late debate.
PMID- 9560235
TI - Signaling among relatives. III. Talk is cheap.
AB - The Sir Philip Sidney game has been used by numerous authors to show how signal
cost can facilitate honest signaling among relatives. Here, we demonstrate that,
in this game, honest cost-free signals are possible as well, under very general
conditions. Moreover, these cost-free signals are better for all participants
than the previously explored alternatives. Recent empirical evidence suggests
that begging is energetically inexpensive for nestling birds; this finding led
some researchers to question the applicability of the costly signaling framework
to nestling begging. Our results show that cost-free or inexpensive signals, as
observed empirically, fall within the framework of signaling theory.
PMID- 9560236
TI - Runaway ornament diversity caused by Fisherian sexual selection.
AB - Fisher's runaway process of sexual selection is potentially an important force
generating character divergence between closely related populations. We
investigated the evolution of multiple female preferences by Fisher's runaway
process. There are two outcomes of runaway. The first is the evolution of mate
preference to a stable equilibrium. This evolution occurs if the benefits of mate
choice are sufficiently large relative to the cost of choice. Alternatively, mate
preferences evolve cyclically. The rate and pattern of cyclic evolution depends
primarily on the individual cost of choice and epistasis in the joint cost of
choice. If there are small differences in natural selection (e.g., predation
risk) between populations, cyclic evolution quickly leads to divergence in mate
preferences and sexual ornaments and so to sexual isolation.
PMID- 9560237
TI - Diploid hybrid speciation in Penstemon (Scrophulariaceae).
AB - Hybrid speciation has played a significant role in the evolution of angiosperms
at the polyploid level. However, relatively little is known about the importance
of hybrid speciation at the diploid level. Two species of Penstemon have been
proposed as diploid hybrid derivatives based on morphological data, artificial
crossing studies, and pollinator behavior observations: Penstemon spectabilis
(derived from hybridization between Penstemon centranthifolius and Penstemon
grinnellii) and Penstemon clevelandii (derived from hybridization between P.
centranthifolius and P. spectabilis). Previous studies were inconclusive
regarding the purported hybrid nature of these species because of a lack of
molecular markers sufficient to differentiate the parental taxa in the hybrid
complex. We developed hypervariable nuclear markers using inter-simple sequence
repeat banding patterns to test these classic hypotheses of diploid hybrid
speciation in Penstemon. Each species in the hybrid complex was genetically
distinct, separated by 10-42 species-specific inter-simple sequence repeat
markers. Our data do not support the hybrid origin of P. spectabilis but clearly
support the diploid hybrid origin of P. clevelandii. Our results further suggest
that the primary reason diploid hybrid speciation is so difficult to detect is
the lack of molecular markers able to differentiate parental taxa from one
another, particularly with recently diverged species.
PMID- 9560238
TI - Separation of killing and tumorigenic effects of an alkylating agent in mice
defective in two of the DNA repair genes.
AB - Alkylation of DNA at the O6-position of guanine is one of the most critical
events leading to mutation, cancer, and cell death. The enzyme O6-methylguanine
DNA methyltransferase repairs O6-methylguanine as well as a minor methylated
base, O4-methylthymine, in DNA. Mouse lines deficient in the methyltransferase
(MGMT) gene are hypersensitive to both the killing and to the tumorigenic effects
of alkylating agents. We now show that these dual effects of an alkylating agent
can be dissociated by introduction of an additional defect in mismatch repair.
Mice with mutations in both alleles of the MGMT gene and one of the mismatch
repair genes, MLH1, are as resistant to methylnitrosourea (MNU) as are wild-type
mice, in terms of survival, but do have numerous tumors after receiving MNU. In
contrast to MGMT-/- MLH1(+/+) mice with decrease in size of the thymus and
hypocellular bone marrow after MNU administration, no conspicuous change was
found in MGMT-/- MLH1(-/-) mice treated in the same manner. Thus, killing and
tumorigenic effects of an alkylating agent can be dissociated by preventing
mismatch repair pathways.
PMID- 9560239
TI - Modification of bacterial artificial chromosomes through chi-stimulated
homologous recombination and its application in zebrafish transgenesis.
AB - The modification of yeast artificial chromosomes through homologous recombination
has become a useful genetic tool for studying gene function and enhancer/promoter
activity. However, it is difficult to purify intact yeast artificial chromosome
DNA at a concentration sufficient for many applications. Bacterial artificial
chromosomes (BACs) are vectors that can accommodate large DNA fragments and can
easily be purified as plasmid DNA. We report herein a simple procedure for
modifying BACs through homologous recombination using a targeting construct
containing properly situated Chi sites. To demonstrate a usage for this
technique, we modified BAC clones containing the zebrafish GATA-2 genomic locus
by replacing the first coding exon with the green fluorescent protein (GFP)
reporter gene. Molecular analyses confirmed that the modification occurred
without additional deletions or rearrangements of the BACs. Microinjection
demonstrated that GATA-2 expression patterns can be recapitulated in living
zebrafish embryos by using these GFP-modified GATA-2 BACs. Embryos microinjected
with the modified BAC clones were less mosaic and had improved GFP expression in
hematopoietic progenitor cells compared with smaller plasmid constructs. The
precise modification of BACs through Chi-stimulated homologous recombination
should be useful for studying gene function and regulation in cultured cells or
organisms where gene transfer is applicable.
PMID- 9560240
TI - Tight clustering and hemizygosity of apomixis-linked molecular markers in
Pennisetum squamulatum implies genetic control of apospory by a divergent locus
that may have no allelic form in sexual genotypes.
AB - Apomixis is a naturally occurring mode of reproduction that results in embryo
formation without the involvement of meiosis or fertilization of the egg. Seed
derived progeny of an apomictic plant are genetically identical to the maternal
parent. We are studying a form of apomixis called apospory that occurs in the
genus Pennisetum, a taxon in the grass family. A cultivated member of this genus,
pearl millet (Pennisetum glaucum), reproduces sexually. A wild relative of pearl
millet, Pennisetum squamulatum, that is an obligate aposporous species, is cross
compatible with pearl millet when used as a pollen donor in the interspecific
cross. We present herein the genetic mapping of 13 molecular markers in an
interspecific hybrid population of 397 individuals that segregates for apomixis
and sexuality. Surprisingly, 12 of the 13 markers strictly cosegregated with
aposporous embryo sac development, clearly defining a contiguous apospory
specific genomic region in which no genetic recombination was detected. Lack of
or suppression of recombination may be coincidentally associated with the
chromosomal context of the apomixis locus or it may be a consequence of its
evolution that is essential for preservation of gene function as has been
previously shown in studies of complex loci in both plant and animal species.
PMID- 9560241
TI - Reactivation of XIST in normal fibroblasts and a somatic cell hybrid: abnormal
localization of XIST RNA in hybrid cells.
AB - The XIST gene, expressed only from the inactive X chromosome, is a critical
component of X inactivation. Although apparently unnecessary for maintenance of
inactivation, XIST expression is thought to be sufficient for inactivation of
genes in cis even when XIST is located abnormally on another chromosome. This
repression appears to involve the association of XIST RNA with the chromosome
from which it is expressed. Reactivated genes on the inactive X chromosome,
however, maintain expression in several somatic cell hybrid lines with stable
expression of XIST. We describe here another example of an XIST-expressing human
hamster hybrid that lacks X-linked gene repression in which the human XIST gene
present on an active X chromosome was reactivated by treatment with 5-aza-2'
deoxycytidine. These data raise the possibility that human XIST RNA does not
function properly in human-rodent somatic cell hybrids. As part of our approach
to address this question, we reactivated the XIST gene in normal male fibroblasts
and then compared their patterns of XIST RNA localization by subcellular
fractionation and in situ hybridization with those of hybrid cells. Although XIST
RNA is nuclear in all cell types, we found that the in situ signals are much more
diffuse in hybrids than in human cells. These data suggest that hybrids lack
components needed for XIST localization and, presumably, XIST-mediated gene
repression.
PMID- 9560242
TI - A role for Pak protein kinases in Schwann cell transformation.
AB - Neurofibromatosis type 1 (NF1), a common autosomal dominant disorder caused by
loss of the NF1 gene, is characterized clinically by neurofibromas and more
rarely by neurofibrosarcomas. Neurofibromin, the protein encoded by NF1,
possesses an intrinsic GTPase accelerating activity for the Ras proto-oncogene.
Through this activity, it is a negative regulator of Ras. The Pak protein kinase
is a candidate for a downstream signaling protein that may mediate Ras signals
because it is activated by Rac and Cdc42, two small G proteins required for Ras
signaling. Here, we use Pak mutants to explore the role of Pak in Ras signaling
in Schwann cells, the cells affected in NF1. Whereas an activated Pak mutant does
not transform cells, dominant negative Pak mutants are potent inhibitors of Ras
transformation of rat Schwann cells and of a neurofibrosarcoma cell line from an
NF1 patient. Although activated Pak stimulated jun-N-terminal kinase, inhibition
of Ras transformation by dominant negative Pak did not require inhibition of jun
N-terminal kinase. Instead, the Pak mutants appeared to inhibit transformation by
preventing Ras activation of the ERK/mitogen-activated protein kinase cascade.
These results have implications for our understanding of NF1 because a
neurofibrosarcoma cell line derived from a patient with NF1 was reverted by
stable expression of the Pak dominant negative mutants.
PMID- 9560243
TI - Evolution of rhizobia by acquisition of a 500-kb symbiosis island that integrates
into a phe-tRNA gene.
AB - Nodulation and nitrogen fixation genes of Mesorhizobium loti are encoded on the
chromosome of the bacterium. Nevertheless, there is strong evidence that these
genes can be transferred from an inoculant strain to nonsymbiotic mesorhizobia in
the field environment. Here we report that the chromosomal symbiotic element of
M. loti strain ICMP3153 is transmissible in laboratory matings to at least three
genomic species of nonsymbiotic mesorhizobia. The element is 500 kb in size,
integrates into a phe-tRNA gene, and encodes an integrase of the phage P4 family
just within its left end. The entire phe-tRNA gene is reconstructed at the left
end of the element upon integration, whereas the 3' 17 nucleotides of the tRNA
gene are present as a direct repeat at the right end. We termed the element a
symbiosis island on the basis of its many similarities to pathogenicity islands.
It may represent a class of genetic element that contributes to microbial
evolution by acquisition.
PMID- 9560244
TI - Monosomy of a specific chromosome determines L-sorbose utilization: a novel
regulatory mechanism in Candida albicans.
AB - We report the identification of the gene, SOU1, required for L-sorbose
assimilation in Candida albicans. The level of the expression of SOU1 is
determined by the copy number of chromosome III (also denoted chromosome 5), such
that monosomic strains assimilate L-sorbose, whereas disomic strains do not, in
spite of the fact that SOU1 is not on this chromosome. We suggest that C.
albicans contains a resource of potentially beneficial genes that are activated
by changes in chromosome number, and that this elaborate mechanism regulates the
utilization of food supplies and possibly other important functions, thus
representing a novel general means for regulating gene expression in microbes.
PMID- 9560245
TI - ARC, an inhibitor of apoptosis expressed in skeletal muscle and heart that
interacts selectively with caspases.
AB - We have identified and characterized ARC, apoptosis repressor with caspase
recruitment domain (CARD). Sequence analysis revealed that ARC contains an N
terminal CARD fused to a C-terminal region rich in proline/glutamic acid
residues. The CARD domain of ARC exhibited significant homology to the prodomains
of apical caspases and the CARDs present in the cell death regulators Apaf-1 and
RAIDD. Immunoprecipitation analysis revealed that ARC interacts with caspase-2,
8, and Caenorhabditis elegans CED-3, but not with caspase-1, -3, or -9. ARC
inhibited apoptosis induced by caspase-8 and CED-3 but not that mediated by
caspase-9. Further analysis showed that the enzymatic activity of caspase-8 was
inhibited by ARC in 293T cells. Consistent with the inhibition of caspase-8, ARC
attenuated apoptosis induced by FADD and TRADD and that triggered by stimulation
of death receptors coupled to caspase-8, including CD95/Fas, tumor necrosis
factor-R1, and TRAMP/DR3. Remarkably, the expression of human ARC was primarily
restricted to skeletal muscle and cardiac tissue. Thus, ARC represents an
inhibitor of apoptosis expressed in muscle that appears to selectively target
caspases. Delivery of ARC by gene transfer or enhancement of its endogenous
activity may provide a strategy for the treatment of diseases that are
characterized by inappropriately increased cell death in muscle tissue.
PMID- 9560246
TI - Mutation of the Sry-related Sox10 gene in Dominant megacolon, a mouse model for
human Hirschsprung disease.
AB - The spontaneous mouse mutant Dominant megacolon (Dom) is a valuable model for the
study of human congenital megacolon (Hirschsprung disease). Here we report that
the defect in the Dom mouse is caused by mutation of the gene encoding the Sry
related transcription factor Sox10. This assignment is based on (i)
colocalization of the Sox10 gene with the Dom mutation on chromosome 15; (ii)
altered Sox10 expression in the gut and in neural-crest derived structures of
cranial ganglia of Dom mice; (iii) presence of a frameshift in the Sox10 coding
region, and (iv) functional inactivation of the resulting truncated protein.
These results identify the transcriptional regulator Sox10 as an essential factor
in mouse neural crest development and as a further candidate gene for human
Hirschsprung disease, especially in cases where it is associated with features of
Waardenburg syndrome.
PMID- 9560247
TI - An oncogenic form of p53 confers a dominant, gain-of-function phenotype that
disrupts spindle checkpoint control.
AB - Although it is well-established that p53 functions as a tumor suppressor gene,
certain mutations exhibit gain-of-function activities that increase oncogenic
transformation. We have found a common class of p53 missense mutation that
exhibits a dominant, gain-of-function activity that generates genomic
instability. Fibroblasts from Li-Fraumeni syndrome heterozygotes with such
mutations generate polyploid cells when exposed to spindle depolymerizing agents.
Expression of such mutant alleles in normal fibroblasts yields the same
phenotype. This class of dominant, gain-of-function p53 mutation (p53(RSC),
relaxed spindle checkpoint allele) does not require the transcriptional
activation function of p53 for this behavior. Thus p53 mutations can contribute
to progression of a cancer cell not only by absence of p53 tumor suppressor
activity but also by the presence of an activity that promotes genetic
instability.
PMID- 9560248
TI - Homology-directed repair is a major double-strand break repair pathway in
mammalian cells.
AB - Mammalian cells have been presumed to repair potentially lethal chromosomal
double-strand breaks (DSBs) in large part by processes that do not require
homology to the break site. This contrasts with Saccharomyces cerevisiae where
the major DSB repair pathway is homologous recombination. Recently, it has been
determined that DSBs in genomic DNA in mammalian cells can stimulate homologous
recombination as much as 3 or 4 orders of magnitude, suggesting that homology
directed repair may play an important role in the repair of chromosomal breaks.
To determine whether mammalian cells use recombinational repair at a significant
level, we have analyzed the spectrum of repair events at a defined chromosomal
break by using direct physical analysis of repair products. When an endonuclease
generated DSB is introduced into one of two direct repeats, homologous repair is
found to account for 30-50% of observed repair events. Both noncrossover and
deletional homologous repair products are detected, at approximately a 1:3 ratio.
These results demonstrate the importance of homologous recombination in the
repair of DSBs in mammalian cells. In the remaining observed repair events, DSBs
are repaired by nonhomologous processes. The nonhomologous repair events
generally result in small deletions or insertions at the break site, although a
small fraction of events result in larger chromosomal rearrangements.
Interestingly, in two insertions, GT repeats were integrated at one of the broken
chromosome ends, suggesting that DSB repair can contribute to the spread of
microsatellite sequences in mammalian genomes.
PMID- 9560249
TI - Putative pheromone receptors related to the Ca2+-sensing receptor in Fugu.
AB - By a combination of PCR with degenerate primers and low stringency probing, we
have isolated a large family of genes related to the Ca2+-sensing receptor from
the genome of Fugu rubripes. One of the genes (type I) is the Fugu homologue of
the Ca2+-sensing receptor. The remaining genes can be divided into five classes
(type II-VI) on the bases of gene structure. In several types, the genes occur in
clusters as tandem arrays. These genes appear to be the homologues of the
vomeronasal pheromone receptors recently described in rodents. The Fugu genes are
expressed in the tissues of the nose, suggesting that they may have a similar
physiological role.
PMID- 9560250
TI - Transposition of the mariner element from Drosophila mauritiana in zebrafish.
AB - With the increased popularity of zebrafish (Danio rerio) for mutagenesis studies,
efficient methods for manipulation of its genome are needed. One approach is the
use of a transposable element as a vector for gene transfer in this species. We
report here the transformation of zebrafish and germ-line transmission of the
mariner element from Drosophila mauritiana. The mariner element was selected
because its transposition is independent of host-specific factors. One- to two
cell-stage zebrafish embryos were coinjected with a supercoiled plasmid carrying
the nonautonomous mariner element peach and mRNA encoding the transposase.
Surviving larvae were reared to adulthood, and the transmission of peach to the
F1 generation was tested by PCR. Four of the 12 founders, following plasmid
injections on 2 different days, transmitted the element to their progeny.
Inheritance of the transgene from the F1 to the F2 generation showed a Mendelian
pattern. No plasmid sequences were detected by PCR or Southern blot analysis,
indicating transposition of peach rather than random integration of the plasmid
DNA. These data provide evidence of transformation of a vertebrate with a
transposable element and support the host-independent mechanism for transposition
of the mariner element. We suggest this system could be used for insertional
mutagenesis or for identifying active regions of the genome in the zebrafish.
PMID- 9560251
TI - A genetic system based on split-ubiquitin for the analysis of interactions
between membrane proteins in vivo.
AB - A detection system for interactions between membrane proteins in vivo is
described. The system is based on split-ubiquitin [Johnsson, N. & Varshavsky, A.
(1994) Proc. Natl. Acad. Sci. USA 91, 10340-10344]. Interaction between two
membrane proteins is detected by proteolytic cleavage of a protein fusion. The
cleavage releases a transcription factor, which activates reporter genes in the
nucleus. As a result, interaction between membrane proteins can be analyzed by
the means of a colorimetric assay. We use membrane proteins of the endoplasmic
reticulum as a model system. Wbp1p and Ost1p are both subunits of the
oligosaccharyl transferase membrane protein complex. The Alg5 protein also
localizes to the membrane of the endoplasmic reticulum, but does not interact
with the oligosaccharyltransferase. Specific interactions are detected between
Wbp1p and Ost1p, but not between Wbp1p and Alg5p. The new system might be useful
as a genetic and biochemical tool for the analysis of interactions between
membrane proteins in vivo.
PMID- 9560252
TI - Predicting amino acid sequences of the antibody human VH chains from its first
several residues.
AB - A new method for classification of Ig sequences is suggested. The defining
characteristic of a class is presence of particular residues at several class
determining positions. Sequences within a class follow the same amino acid
pattern, i.e., residues at identical positions are, in an overwhelming majority
of sequences of that class, identical or chemically related. Thus, once the class
of a sequence is determined, one can predict the residue(s) at almost any
position in the sequence. In this paper, results of analysis of 1,172 human heavy
chains are presented. It was shown that a sequence can be assigned to one of six
classes depending on which residues are found at its positions 1, 3, 5, 6, 7, 9,
10, 12, and 13. It is important to note that it is possible to achieve same six
class classification of the human heavy chains on the basis of a different set of
positions found not at the beginning but near the end of the sequence (around
position 80). For every class, an amino acid pattern of an entire sequence
(complementarity determining regions excepting) has been determined. Our approach
allowed us to reconstruct the incomplete human heavy chains in which residues at
certain positions at the beginning or end of the chain are known. We developed a
software tool for analysis, classification, and prediction of residues in
sequences of the Ig family.
PMID- 9560253
TI - HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A.
AB - We previously showed that the availability of a nonamer peptide derived from
certain HLA class I signal sequences is a necessary requirement for the
stabilization of endogenous HLA-E expression on the surface of 721.221 cells.
This led us to examine the ability of HLA-E to protect HLA class I transfectants
from natural killer (NK) cell-mediated lysis. It was possible to implicate the
CD94/NKG2A complex as an inhibitory receptor recognizing this class Ib molecule
by using as target a .221 transfectant selectively expressing surface HLA-E. HLA
E had no apparent inhibitory effect mediated through the identified Ig
superfamily (Ig-SF) human killer cell inhibitory receptors or ILT2/LIR1. Further
studies of CD94/NKG2+ NK cell-mediated recognition of .221 cells transfected with
different HLA class I allotypes (i.e., -Cw4, -Cw3, -B7) confirmed that the
inhibitory interaction was mediated by CD94/NKG2A recognizing the surface HLA-E
molecule, because only antibodies directed against either HLA-E, CD94, or
CD94/NKG2A specifically restored lysis. Surface stabilization of HLA-E in cold
treated .221 cells loaded with appropriate peptides was sufficient to confer
protection, resulting from recognition of the HLA class Ib molecule by the
CD94/NKG2A inhibitory receptor. Consistent with the prediction that the ligand
for CD94/NKG2A is expressed ubiquitously, our examination of HLA-E antigen
distribution indicated that it is detectable on the surface of a wide variety of
cell types.
PMID- 9560254
TI - CD40 ligand (CD154) stimulation of macrophages to produce HIV-1-suppressive beta
chemokines.
AB - beta-chemokines play an important role in the development of immunologic
reactions. Macrophages are major beta-chemokine-producing cells during T-cell
directed, delayed-type hypersensitivity reactions in tissues, and have been
reported to be important producers of beta-chemokines in the lymph nodes of HIV-1
infected individuals. However, the physiological signals responsible for inducing
macrophages to produce beta-chemokines have not been established. Two soluble T
cell products, interferon-gamma and granulocyte-macrophage colony stimulating
factor, were added to cultured macrophages, but failed to stimulate the
production of macrophage inflammatory protein-1alpha and -1beta; regulated upon
activation, normal T cell expressed and secreted (RANTES); or monocyte
chemoattractant protein-1. Instead, direct cell-cell contact between macrophages
and cells engineered to express CD40L (also known as CD154) resulted in the
production of large amounts of macrophage inflammatory protein-1alpha and -1beta,
and RANTES (all ligands for CCR5), and monocyte chemoattractant protein-1 (a
ligand for CCR2). Supernatants from CD40L-stimulated macrophages protected CD4(+)
T cells from infection by a nonsyncytium-inducing strain of HIV-1 (which uses
CCR5 as a coreceptor). These results have implications for granulomatous
diseases, and conditions such as atherosclerosis and multiple sclerosis, where
CD40L-bearing cells have been found in the macrophage-rich lesions where beta
chemokines are being produced. Overall, these findings define a pathway linking
the specific recognition of antigen by T cells to the production of beta
chemokines by macrophages. This pathway may play a role in anti-HIV-1 immunity
and the development of immunologic reactions or lesions.
PMID- 9560255
TI - Identification of a meiosis-specific protein as a member of the class of
cancer/testis antigens.
AB - Little is known about the function of human cancer/testis antigens (CTAs), such
as MAGE, BAGE, GAGE, HOM-MEL-40, and NY-ESO-1, the expression of which is
restricted to human malignancies and testis. When screening a cDNA expression
library enriched for testis-specific representative long transcripts for
reactivity with high-titered IgG antibodies from the serum of a patient with
renal cell carcinoma, one repeatedly detected antigen, designated HOM-TES-14,
turned out to be encoded by the synaptonemal complex protein 1 (SCP-1) gene. SCP
1 is known to be selectively expressed during the meiotic prophase of
spermatocytes and is involved in the pairing of homologous chromosomes, an
essential step for the generation of haploid cells in meiosis I. Investigation of
a broad spectrum of normal and malignant tissues revealed expression of SCP-1
transcripts and antigen selectively in a variety of neoplastic tissues and tumor
cell lines. Immunofluorescence microscopy analysis with specific antiserum showed
a cell cycle phase-independent nuclear expression of SCP-1 protein in cancer
cells. SCP-1 differs from other members of the class of CTA by its localization
on chromosome 1 and its frequent expression in malignant gliomas, breast, renal
cell, and ovarian cancer. The aberrant expression of SCP-1 in tumors might
contribute to their genomic instability and suggests that the functional role of
other CTA might also relate to meiosis.
PMID- 9560256
TI - On defining the rules for interactions between the T cell receptor and its
ligand: a critical role for a specific amino acid residue of the T cell receptor
beta chain.
AB - The specificity of T cell-mediated immune responses is primarily determined by
the interaction between the T cell receptor (TCR) and the antigenic peptide
presented by the major histocompatibility complex (MHC) molecules. To refine our
understanding of interactions between the TCR and the antigenic peptide of
vesicular stomatitis virus (VSV) presented by the class I MHC molecule H-2Kb, we
constructed a TCR alpha chain transgenic mouse in a TCR alpha-deficient
background to define specific structural features in the TCR beta chain that are
important for the recognition of the VSV/H-2Kb complex. We found that for a given
peptide, a peptide-specific, highly conserved amino acid could always be
identified at position 98 of the complementarity-determining region 3 (CDR3) loop
of TCR beta chains. Further, we demonstrated that substitutions at position 6,
but not position 1, of the VSV peptide induced compensatory changes in the TCR in
both the amino acid residue at position 98 and the length of the CDR3beta loop.
We conclude that the amino acid residue at position 98 of the CDR3beta loop is a
key residue that plays a critical role in determining the specificity of TCR
VSV/H-2Kb interactions and that a specific length of the CDR3beta loop is
required to facilitate such interactions. Further, these findings suggest that
the alpha and beta chains of TCRs interact with amino acid residue(s) toward the
N and C termini of the VSV peptide, respectively, providing functional evidence
for the orientation of a TCR with its peptide/MHC ligand as observed in the
crystal structures of TCR/peptide/MHC complexes.
PMID- 9560257
TI - Generation of CD8 suppressor factor and beta chemokines, induced by xenogeneic
immunization, in the prevention of simian immunodeficiency virus infection in
macaques.
AB - Previous xenogeneic immunization experiments in rhesus macaques with simian
immunodeficiency virus (SIV) grown in human CD4(+) T cells consistently elicited
protection from challenge with live SIV. However, the mechanism of protection has
not been established. We present evidence that xenogeneic immunization induced
significant CD8 suppressor factor, RANTES (regulated upon activation, normal T
cell expressed and secreted), macrophage inflammatory protein (MIP) 1alpha, and
MIP-1beta (P < 0.001 - P < 0.02). The concentrations of these increased
significantly in protected as compared with infected macaques (P < 0.001).
Xenogeneic stimulation in vitro also up-regulated CD8 suppressor factors (SF; P <
0.001) and the beta chemokines which were neutralized by antibodies to the 3 beta
chemokines. Recombinant human RANTES, MIP-1alpha and MIP-1beta which bind to
simian CCR5, suppressed SIV replication in a dose-dependent manner, with RANTES
being more effective than the other two chemokines. The results suggest that
immunization with SIV grown in human CD4(+) T cells induces CD8-suppressor
factor, RANTES, MIP-1alpha and MIP-1beta which may block CCR5 receptors and
prevent the virus from binding and fusion to CD4(+) cells.
PMID- 9560258
TI - Bacteria-induced neo-biosynthesis, stabilization, and surface expression of
functional class I molecules in mouse dendritic cells.
AB - Here, we show that bacteria induce de novo synthesis of both major
histocompatability complex (MHC) class I and II molecules in a mouse dendritic
cell culture system. The neo-biosynthesis of MHC class I molecules is delayed as
compared with that of MHC class II. Furthermore, bacteria stabilize MHC class I
molecules by a 3-fold increase of their half-life. This has important
consequences for the capacity of dendritic cells to present bacterial antigens in
the draining lymph nodes. In addition, a model antigen, ovalbumin, expressed on
the surface of recombinant Streptococcus gordonii is processed and presented on
MHC class I molecules. This presentation is 10(6) times more efficient than that
of soluble OVA protein. This exogenous pathway of MHC class I presentation is
transporter associated with antigen processing (TAP)-dependent, indicating that
there is a transport from phagolysosome to cytosol in dendritic cells. Thus,
bacteria are shown to be a potentially useful mean for the correct delivery of
exogenous antigens to be presented efficiently on MHC class I molecules.
PMID- 9560260
TI - The CCR5 receptor acts as an alloantigen in CCR5Delta32 homozygous individuals:
identification of chemokineand HIV-1-blocking human antibodies.
AB - The chemokine receptor CCR5 is the major coreceptor for infection by macrophage
tropic R5 HIV-1. A 32-bp deletion in the gene coding for CCR5 (CCR5Delta32)
occurs with a frequency of 10% in the Caucasian population and results in a
receptor protein that is truncated and not expressed at the cell surface.
CCR5Delta32 homozygous individuals are apparently normal but resistant to
infection with R5 HIV-1. In two individuals homozygous for CCR5Delta32, who had
been repeatedly exposed to CCR5-expressing blood cells through sexual activity,
we have identified antibodies to CCR5 that bound specifically to the surface of
CCR5-expressing cell lines. Serum from these individuals, in contrast to serum
from CCR5(+/+) individuals, competed with radiolabeled RANTES for binding to the
CCR5 receptor and inhibited infection of peripheral blood mononuclear cells with
R5, but not X4, primary isolates of HIV-1. The identified human antibodies to
CCR5 define an alloantigen that may cause allograft rejection in a mismatch
situation even in individuals with no history of blood transfusions or i.v. drug
abuse.
PMID- 9560259
TI - Differences in the level of expression of class I major histocompatibility
complex proteins on thymic epithelial and dendritic cells influence the decision
of immature thymocytes between positive and negative selection.
AB - Both positive and negative selection of immature T cells rely on engagement of
their antigen-specific receptors (TCR) by peptide in association with proteins
encoded in the major histocompatibility complex (MHC) protein. The decision made
between these two outcomes seems to be determined by the number of TCR engaged by
peptide-MHC complexes. It has been unclear how such a mechanism can be reconciled
with evidence that positive and negative selection occur in different thymic
compartments and are mediated by different antigen-presenting cells (APCs). In
this study we demonstrate that the level of class I MHC protein is 10-fold higher
on thymic dendritic cells, which mediate the negative selection of immature T
cells, than on thymic epithelial cells, which mediate for positive selection. We
also demonstrate that as little as a 3-fold increase in the level of a particular
cognate peptide-MHC ligand is sufficient to result in negative rather than
positive selection. The results suggest that quantitative differences in the
level of expression of class I MHC proteins on thymic epithelial and dendritic
cells contribute to the opposing roles these cells play in forming the repertoire
of mature class I MHC restricted (CD8+) T cells.
PMID- 9560261
TI - Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer
through loss of expression.
AB - The recently identified PTEN/MMAC1 gene is a candidate tumor suppressor
implicated in multiple tumor types based on mutations or homozygous deletions of
the gene in certain human cancers. No studies of PTEN/MMAC1 mRNA or protein
expression in cancer cells have been reported, primarily because of significant
numbers of normal cells contaminating most tumor samples and because of the lack
of antibody reagents. We examined PTEN/MMAC1 in advanced prostate cancer for gene
mutations or abnormalities in expression by using a series of recently derived
xenografts free of normal human cells and a PTEN/MMAC1-specific antibody. Only 1
of 10 tumors contained a homozygous deletion of PTEN/MMAC1, and no mutations were
detected in the entire coding region of the remaining nine xenografts. However,
five of these showed reduced or absent PTEN/MMAC1 expression by Northern analysis
and reverse transcription-PCR of mRNA. PTEN/MMAC1 mRNA expression was restored in
nonexpressing prostate cancer cells by in vitro treatment with the demethylating
agent 5-azadeoxycytidine. Alterations in PTEN/MMAC1 expression were confirmed at
the protein level by immunoblot analysis, and immunohistochemical studies show
that the endogenous wild-type PTEN/MMAC1 protein is localized exclusively in the
cytoplasm. These results demonstrate that loss of PTEN/MMAC1 expression occurs
frequently in advanced prostate cancer.
PMID- 9560262
TI - Modulation of ventricular function through gene transfer in vivo.
AB - We used a catheter-based technique to achieve generalized cardiac gene transfer
in vivo and to alter cardiac function by overexpressing phospholamban (PL) which
regulates the activity of the sarcoplasmic reticulum Ca2+ ATPase (SERCA2a). By
using this approach, rat hearts were transduced in vivo with 5 x 10(9) pfu of
recombinant adenoviral vectors carrying cDNA for either PL, beta-galactosidase
(beta-gal), or modified green fluorescent protein (EGFP). Western blot analysis
of ventricles obtained from rats transduced by Ad.PL showed a 2.8-fold increase
in PL compared with hearts transduced by Ad.betagal. Two days after infection,
rat hearts transduced with Ad.PL had lower peak left ventricular pressure (58.3
+/- 12.9 mmHg, n = 8) compared with uninfected hearts (92.5 +/- 3.5 mmHg, n = 6)
or hearts infected with Ad.betagal (92.6 +/- 5.9 mmHg, n = 6). Both peak rate of
pressure rise and pressure fall (+3, 210 +/- 298 mmHg/s, -2, 117 +/- 178 mmHg/s,
n = 8) were decreased in hearts overexpressing PL compared with uninfected hearts
(+5, 225 +/- 136 mmHg/s, -3, 805 +/- 97 mmHg/s, n = 6) or hearts infected with
Ad.betagal (+5, 108 +/- 167 mmHg/s, -3, 765 +/- 121 mmHg/s, n = 6). The time
constant of left ventricular relaxation increased significantly in hearts
overexpressing PL (33.4 +/- 3.2 ms, n = 8) compared with uninfected hearts (18.5
+/- 1.0 ms, n = 6) or hearts infected with Ad.betagal (20.8 +/- 2.1 ms, n = 6).
These differences in ventricular function were maintained 7 days after infection.
These studies open the prospect of using somatic gene transfer to modulate
overall cardiac function in vivo for either experimental or therapeutic
applications.
PMID- 9560263
TI - Autologously up-regulated Fc receptor expression and action in airway smooth
muscle mediates its altered responsiveness in the atopic asthmatic sensitized
state.
AB - To elucidate the role of IgE-dependent mechanisms in inducing altered airway
responsiveness in the atopic asthmatic state, the expression and actions of Fc
receptor activation were examined in isolated rabbit tracheal smooth muscle (TSM)
tissue and cultured cells passively sensitized with sera from atopic asthmatic
patients or nonatopic/nonasthmatic (control) subjects. Relative to control
tissues, the atopic asthmatic-sensitized TSM exhibited significantly increased
maximal isometric contractility to acetylcholine (P < 0. 01) and attenuated
maximal relaxation responses and sensitivity (i.e.,-log ED50) to isoproterenol (P
< 0.005). These changes in agonist responsiveness in atopic sensitized TSM were
ablated by pretreating the tissues with a blocking mAb to the low affinity
receptor for IgE, FcepsilonRII (i.e., CD23) or by depleting the sensitizing serum
of its immune complexes. Moreover, in complimentary experiments, exogenous
administration of IgE immune complexes to naive TSM produced changes in agonist
responsiveness that were qualitatively similar to those obtained in the atopic
asthmatic-sensitized state. Extended studies further demonstrated that, in
contrast to their respective controls, atopic asthmatic serum-sensitized human
and rabbit TSM tissue and cultured cells exhibited markedly induced mRNA and cell
surface expression of FcepsilonRII, whereas constitutive expression of the IgG
receptor subtype, FcgammaRIII, was unaltered. Finally, the up-regulated mRNA
expression of FcepsilonRII observed following exposure of TSM to atopic asthmatic
serum or to exogenously administered IgE immune complexes was significantly
inhibited by pretreating the tissues or cells with anti-CD23 mAb. Collectively,
these observations provide evidence demonstrating that the altered agonist
responsiveness in atopic asthmatic sensitized airway smooth muscle is largely
attributed to IgE-mediated induction of the autologous expression and activation
of FcepsilonRII receptors in the airway smooth muscle itself.
PMID- 9560264
TI - Lipophilic siderophores of Mycobacterium tuberculosis prevent cardiac reperfusion
injury.
AB - Reperfusion injury, which occurs upon the reintroduction of blood flow to an
ischemic organ, is responsible for considerable damage in heart attacks and
strokes. However, no treatment for reperfusion injury is currently available. A
major cause of reperfusion injury is the iron-mediated generation of hydroxyl
radical (.OH). In this study we have explored the capacity of novel iron
chelators called "exochelins" to prevent reperfusion injury. Exochelins,
siderophores of Mycobacterium tuberculosis, are unique iron chelators because
they are lipid soluble, and hence able to enter cells rapidly. In the iron-free
state, exochelins prevented .OH formation. Desferri-exochelins prevented
oxidative injury to cultured cardiac myocytes, and did so more rapidly and
effectively than the nonlipid soluble iron chelator deferoxamine. The capacity of
various desferri-exochelins to protect myocytes from oxidative injury varied
directly with their solubility in lipid. Infused into isolated rabbit hearts
during reperfusion after a period of ischemia, desferri-exochelins dramatically
improved systolic and diastolic left ventricular function, preserved coronary
flow, reduced release of the cardiac enzyme lactic dehydrogenase, and reduced
myocardial concentrations of .OH metabolites. Thus, highly diffusible desferri
exochelins block injury caused by .OH production and have potential for the
treatment of reperfusion injury.
PMID- 9560265
TI - Targeted expression of a multifunctional chimeric neurotrophin in the lesioned
sciatic nerve accelerates regeneration of sensory and motor axons.
AB - Peripheral nerve injury markedly regulates expression of neurotrophins and their
receptors in the lesioned nerve. However, the role of endogenously produced
neurotrophins in the process of nerve regeneration is unclear. Expression of a
multifunctional neurotrophin, pan-neurotrophin-1 (PNT-1), was targeted to the
peripheral nerves of transgenic mice by using a gene promoter that is
specifically activated after nerve lesion but that is otherwise silent in all
other tissues and during development. PNT-1 is a chimeric neurotrophin that
combines the active sites of the neurotrophins nerve growth factor, brain-derived
neurotrophic factor, and neurotrophin-3 and binds and activates all known
neurotrophin receptors. In adult transgenic mice, PNT-1 was highly expressed in
transected but not in intact sciatic nerve. Morphometric analyses at the electron
microscopy level showed increased and accelerated recovery of axon diameter of
myelinated fibers in crushed peripheral nerves of transgenic mice compared with
wild type. Examination of nerve bundles in target tissues indicated accelerated
reinnervation of foot pad dermis and flexor plantaris muscle in transgenic mice.
Moreover, transected sensory and motor axons of transgenic mice showed faster and
increased return of neurophysiological responses, suggesting an accelerated rate
of axonal elongation. Importantly, transgenic mice also showed a markedly
ameliorated loss of skeletal muscle weight, indicating functional regeneration of
motor axons. Together, these data provide evidence, at both the anatomical and
functional levels, that neurotrophins endogenously produced by the lesioned nerve
are capable of significantly accelerating the regeneration of both sensory and
motor axons after peripheral nerve damage. In addition, our results indicate that
exogenous PNT-1 administration may be an effective therapeutic treatment of
peripheral nerve injuries.
PMID- 9560266
TI - Increased skin tumorigenesis in mice lacking pi class glutathione S-transferases.
AB - The activity of chemical carcinogens is a complex balance between metabolic
activation by cytochrome P450 monooxygenases and detoxification by enzymes such
as glutathione S-transferase (GST). Regulation of these proteins may have
profound effects on carcinogenic activity, although it has proved impossible to
ascribe the observed effects to the activity of a single protein. GstP appears to
play a very important role in carcinogenesis, although the precise nature of its
involvement is unclear. We have deleted the murine GstP gene cluster and
established the effects on skin tumorigenesis induced by the polycyclic aromatic
hydrocarbon 7, 12-dimethylbenz anthracene and the tumor promoting agent 12-O
tetradecanoylphorbol-13-acetate. After 20 weeks, a highly significant increase in
the number of papillomas was found in the GstP1/P2 null mice [GstP1/P2(-/-) mice,
179 papillomas, mean 9.94 per animal vs. GstP1/P2(+/+) mice, 55 papillomas, mean
2.89 per animal, (P < 0.001)]. This difference in tumor incidence provides direct
evidence that a single gene involved in drug metabolism can have a profound
effect on tumorigenicity, and demonstrates that GstP may be an important
determinant in cancer susceptibility, particularly in diseases where exposure to
polycyclic aromatic hydrocarbons is involved, for instance in cigarette smoke
induced lung cancer.
PMID- 9560267
TI - HIV transcriptional activation by the accessory protein, VPR, is mediated by the
p300 co-activator.
AB - The accessory protein, Vpr, is a virion-associated protein that is required for
HIV-1 replication in macrophages and regulates viral gene expression in T cells.
Vpr causes arrest of cell cycle progression at G2/M, presumably through its
effect on cyclin B1.Cdc2 activity. Here, we show that the ability of Vpr to
activate HIV transcription correlates with its ability to induce G2/M growth
arrest, and this effect is mediated by the p300 transcriptional co-activator,
which promotes cooperative interactions between the Rel A subunit of NF-kappaB
and cyclin B1.Cdc2. Vpr cooperates with p300, which regulates NF-kappaB and the
basal transcriptional machinery, to increase HIV gene expression. Similar effects
are seen in the absence of Vpr with a kinase-deficient Cdc2, and overexpression
of p300 increases levels of HIV Vpr+ replication. Taken together, these data
suggest that p300, through its interactions with NF-kappaB, basal transcriptional
components, and Cdks, is modulated by Vpr and regulates HIV replication. The
regulation of p300 by Vpr provides a mechanism to enhance viral replication in
proliferating cells after growth arrest by increasing viral transcription.
PMID- 9560268
TI - The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl
methanesulfonate treatment.
AB - The BRCA2 gene was identified based on its involvement in familial breast cancer.
The analysis of its sequence predicts that the gene encodes a protein with 3,418
amino acids but provides very few clues pointing to its biological function. In
an attempt to address this question, specific antibodies were prepared that
identified the gene product of BRCA2 as a 390-kDa nuclear protein. Furthermore,
direct binding of human RAD51 to each of the four single 30-amino acid BRC
repeats located at the 5' portion of exon 11 of BRCA2 was demonstrated. Such an
interaction is significant, as BRCA2 and RAD51 can be reciprocally
coimmunoprecipitated by each of the individual, specific antibodies and form
complexes in vivo. Inferring from the function of RAD51 in DNA repair, human
pancreatic cancer cells, Capan-1, expressing truncated BRCA2 were shown to be
hypersensitive to methyl methanesulfonate (MMS) treatment. Exogenous expression
of wild-type BRCA2, but not BRC-deleted mutants, in Capan-1 cells confers
resistance to MMS treatment. These results suggest that the interaction between
the BRC repeats of BRCA2 and RAD51 is critical for cellular response to DNA
damage caused by MMS.
PMID- 9560269
TI - Agrobacterium transcriptional regulator Ros is a prokaryotic zinc finger protein
that regulates the plant oncogene ipt.
AB - Virulence genes of Agrobacterium tumefaciens are under the control of positive
and negative transcriptional regulators. We found that the transcriptional
regulator Ros controls expression of the plant oncogene ipt, which encodes
isopentenyl transferase, in A. tumefaciens. This enzyme is involved in
biosynthesis of the plant growth hormone cytokinin in the host plant. An ipt
promoter::cat reporter gene fusion showed a 10-fold increase in ipt promoter
activity in A. tumefaciens ros mutant strains when compared with wild type. Also,
increased levels (10- to 20-fold) of isopentenyl adenosine, the product of the
reaction catalyzed by isopentenyl transferase, were detected in ros mutant
strains. In vitro studies using purified Ros showed it binds directly to the ipt
promoter. Analysis of the deduced Ros amino acid sequence identified a novel type
of C2H2 zinc finger. In Ros the peptide loop spacing of the zinc finger is 9
amino acids as opposed to the invariant 12 amino acids in the classical C2H2
motif. Site-directed mutagenesis of Cys-82 and His-92 in this motif showed that
these residues are essential for Zn2+ and DNA binding activities of Ros. The
existence of such a regulator in Agrobacterium may be due to horizontal
interkingdom retrotransfer of the ros gene from plant to bacteria.
PMID- 9560270
TI - Mycobacterium bovis Bacille Calmette-Guerin strains secreting listeriolysin of
Listeria monocytogenes.
AB - Recombinant (r) Mycobacterium bovis strains were constructed that secrete
biologically active listeriolysin (Hly) fusion protein of Listeria monocytogenes.
The r-BCG strains pAT261:Hly or pMV306:Hly expressed plasmid multicopies or
chromosomal single copies of the hly gene, respectively. Human and murine
macrophage-like cell lines were infected with r-BCG pAT261:Hly and pMV306:Hly
strains. Interestingly, intracellular persistence of both r-BCG strains was
reduced in macrophages as compared with the parental BCG strain. By immunogold
labeling Hly was detected in membrane structures and within the phagosomal space
of macrophages. In addition, Hly was localized within cytoplasmic vacuoles
outside the mycobacteria-containing phagosome of host cells infected with r-BCG
pAT261:Hly or r-BCG pMV306:Hly. Hly fusions consistently colocalized with a
lysosome-associated membrane glycoprotein, suggesting that membrane-attack
conformation of Hly was not altered. Although r-BCG pAT261:Hly and r-BCG
pMV306:Hly microorganims apparently did not egress into the cytoplasmic
compartment of host cells, they both improved major histocompatibility complex
class I presentation of cophagocytosed soluble protein as compared with wild-type
BCG microbes. These data suggest that Hly secretion endows BCG with an improved
capacity to stimulate CD8 T cells. Because CD8 T cells play a major role in
protection against tuberculosis such Hly secreting r-BCG constructs are
antituberculosis vaccine candidates.
PMID- 9560272
TI - Down-regulation of Leishmania donovani trypanothione reductase by heterologous
expression of a trans-dominant mutant homologue: effect on parasite intracellular
survival.
AB - A trans-dominant mutational strategy was used to down-regulate trypanothione
reductase (TR) activity levels in Leishmania donovani, the causative agent of
visceral leishmaniasis in humans. TR, regarded as an ideal drug target against
trypanosomatid infections, is a homodimeric flavoprotein oxidoreductase unique to
these organisms that plays a central role in the enzymatic regeneration of the
thiol pool. Extrachromosomal, heterologous expression of a trans-dominant mutant
version of the Trypanosoma cruzi enzyme in L. donovani resulted in the formation
of inactive cross-species heterodimers and in a dramatic decrease of endogenous
TR activity levels. Recombinant cells depleted of up to 85% of TR activity were
significantly impaired in their ability to regenerate dihydrotrypanothione from
trypanothione disulfide following oxidation with diamide. Nonetheless trans
dominant mutant recombinants were still capable of maintaining a reduced
intracellular environment during cell growth in culture and were able to
metabolize hydrogen peroxide at wild-type rates in vitro. Importantly, however,
cells expressing the trans-dominant mutant enzyme displayed a decreased ability
to survive inside activated macrophages in a murine model of Leishmania
infection. The apparent inability of Leishmania to modulate the expression of
active TR homodimers in response to the expression of trans-dominant mutant
protein suggests that specific inhibitors of this enzyme should be useful anti
leishmanial agents.
PMID- 9560271
TI - DNA strand separation during activation of a developmental promoter by the
Bacillus subtilis response regulator Spo0A.
AB - Spo0A is the central regulator of commitment to sporulation in Bacillus subtilis.
Spo0A is a member of the response regulator family of proteins and both represses
and stimulates transcription from promoters when activated. In vivo Spo0A
activation takes place by phosphorylation and in vitro activation can be
accomplished by phosphorylation or removal of the N-terminal domain of the
protein. We have examined the mechanism of Spo0A stimulation of transcription
from the promoter of the spoIIG operon. This operon encodes one of the first
compartment specific sigma factors whose appearance regulates sporulation
development. When activated Spo0A was incubated with RNA polymerase and a DNA
fragment containing the spoIIG promoter, bases between -13 and -3, relative to
the start site of transcription, were denatured. Addition of activated Spo0A or
RNA polymerase alone did not induce denaturation. Heteroduplex templates that
contained the nontemplate sequence of the wild-type promoter on both strands
between positions -3 and -13 were efficiently transcribed without activated
Spo0A. These data suggest that DNA strand separation is a two-step process and
that the activation of Spo0A creates a form that interacts with the polymerase to
induce the first of the two steps.
PMID- 9560273
TI - Antibacterial agents that inhibit two-component signal transduction systems.
AB - A class of antibacterials has been discovered that inhibits the growth of Gram
positive pathogenic bacteria. RWJ-49815, a representative of a family of
hydrophobic tyramines, in addition to being a potent bactericidal Gram-positive
antibacterial, inhibits the autophosphorylation of kinase A of the KinA::Spo0F
two-component signal transduction system in vitro. Analogs of RWJ-49815 vary
greatly in their ability to inhibit growth of bacteria and this ability
correlates directly with their activity as kinase A inhibitors. Compared with the
potent quinolone, ciprofloxacin, RWJ-49815 exhibits reduced resistance emergence
in a laboratory passage experiment. Inhibition of the histidine protein
kinase::response regulator two-component signal transduction pathways may present
an opportunity to depress chromosomal resistance emergence by targeting multiple
proteins with a single inhibitor in a single bacterium. Such inhibitors may
represent a class of antibacterials that potentially may represent a breakthrough
in antibacterial therapy.
PMID- 9560274
TI - Differential signaling via the same axon of neocortical pyramidal neurons.
AB - The nature of information stemming from a single neuron and conveyed
simultaneously to several hundred target neurons is not known. Triple and
quadruple neuron recordings revealed that each synaptic connection established by
neocortical pyramidal neurons is potentially unique. Specifically, synaptic
connections onto the same morphological class differed in the numbers and
dendritic locations of synaptic contacts, their absolute synaptic strengths, as
well as their rates of synaptic depression and recovery from depression. The same
axon of a pyramidal neuron innervating another pyramidal neuron and an
interneuron mediated frequency-dependent depression and facilitation,
respectively, during high frequency discharges of presynaptic action potentials,
suggesting that the different natures of the target neurons underlie qualitative
differences in synaptic properties. Facilitating-type synaptic connections
established by three pyramidal neurons of the same class onto a single
interneuron, were all qualitatively similar with a combination of facilitation
and depression mechanisms. The time courses of facilitation and depression,
however, differed for these convergent connections, suggesting that different pre
postsynaptic interactions underlie quantitative differences in synaptic
properties. Mathematical analysis of the transfer functions of frequency
dependent synapses revealed supra-linear, linear, and sub-linear signaling
regimes in which mixtures of presynaptic rates, integrals of rates, and
derivatives of rates are transferred to targets depending on the precise values
of the synaptic parameters and the history of presynaptic action potential
activity. Heterogeneity of synaptic transfer functions therefore allows multiple
synaptic representations of the same presynaptic action potential train and
suggests that these synaptic representations are regulated in a complex manner.
It is therefore proposed that differential signaling is a key mechanism in
neocortical information processing, which can be regulated by selective synaptic
modifications.
PMID- 9560275
TI - Regulation of thalamic neurite outgrowth by the Eph ligand ephrin-A5:
implications in the development of thalamocortical projections.
AB - The cerebral cortex is parcellated into different functional domains that receive
distinct inputs from other cortical and subcortical regions. The molecular
mechanisms underlying the specificity of connections of cortical afferents remain
unclear. We report here that the Eph family tyrosine kinase receptor EphA5 and
the ligand ephrin-A5 may play a key role in the exclusion of the limbic thalamic
afferents from the sensorimotor cortex by mediating repulsive interactions. In
situ hybridization shows that the EphA5 transcript is expressed at high levels in
both cortical and subcortical limbic regions, including the frontal cortex, the
subiculum, and the medial thalamic nuclei. In contrast, ephrin-A5 is transcribed
abundantly in the sensorimotor cortex. Consistent with the complementary
expression, the ligand inhibited dramatically the growth of neurites from neurons
isolated from the medial thalamus but was permissive for the growth of neurites
from lateral thalamic neurons, which is primarily nonlimbic. Similarly, the
growth of neurites from Eph-A5-expressing neurons isolated from the subiculum was
inhibited by ephrin-A5. Our studies suggest that the Eph family ligand ephrin-A5
serves as a general inhibitor of axonal growth from limbic neurons, which may
serve to prevent innervation of inappropriate primary sensorimotor regions, thus
contributing to the generation of specificity of thalamic cortical afferents.
PMID- 9560276
TI - Maternal care during infancy regulates the development of neural systems
mediating the expression of fearfulness in the rat.
AB - The mothers of infant rats show individual differences in the frequency of
licking/grooming and arched-back nursing (LG-ABN) of pups that contribute to the
development of individual differences in behavioral responses to stress. As
adults, the offspring of mothers that exhibited high levels of LG-ABN showed
substantially reduced behavioral fearfulness in response to novelty compared with
the offspring of low LG-ABN mothers. In addition, the adult offspring of the high
LG-ABN mothers showed significantly (i) increased central benzodiazepine receptor
density in the central, lateral, and basolateral nuclei of the amygdala as well
as in the locus ceruleus, (ii) increased alpha2 adrenoreceptor density in the
locus ceruleus, and (iii) decreased corticotropin-releasing hormone (CRH)
receptor density in the locus ceruleus. The expression of fear and anxiety is
regulated by a neural circuitry that includes the activation of ascending
noradrenergic projections from the locus ceruleus to the forebrain structures.
Considering the importance of the amygdala, notably the anxiogenic influence of
CRH projections from the amygdala to the locus ceruleus, as well as the
anxiolytic actions of benzodiazepines, for the expression of behavioral responses
to stress, these findings suggest that maternal care during infancy serves to
"program" behavioral responses to stress in the offspring by altering the
development of the neural systems that mediate fearfulness.
PMID- 9560278
TI - Reinnervation of cross-regenerated gustatory nerve fibers into amiloride
sensitive and amiloride-insensitive taste receptor cells.
AB - Single nerve fiber responses to NaCl and their inhibition by amiloride were
compared among the chorda tympani (CT) and glossopharyngeal (IXth), and their
cross-regenerated nerves in the C57BL/KsJ mice. The CT nerve innervating the
anterior part of the tongue contained approximately equal numbers of two types of
NaCl-responsive neurons; one type showed strong suppression of NaCl responses by
amiloride [amiloride-sensitive (AS) type], and the other type showed only weak or
no suppression of NaCl responses by amiloride [amiloride-insensitive (AI) type].
In contrast, the IXth nerve innervating the posterior part of the tongue has
almost exclusively the AI type. This relative abundance of the AS and AI types of
fibers was not altered by cross-regeneration of the two gustatory nerves into the
reverse tongue regions. This suggests that regenerated taste axons selectively
recouple with the appropriate type of receptor cell whether they innervate the
front or the back of the tongue. Such selective synapse reformation may help
explain the stability of response profiles of taste neurons during continual
receptor cell turnover.
PMID- 9560277
TI - A subclass of prefrontal gamma-aminobutyric acid axon terminals are selectively
altered in schizophrenia.
AB - In the primate cerebral cortex, morphologically and functionally diverse classes
of local circuit neurons containing the inhibitory neurotransmitter gamma
aminobutyric acid (GABA) differentially regulate the activity of pyramidal cells,
the principal type of excitatory output neurons. In schizophrenia, GABA
neurotransmission in the prefrontal cortex (PFC) appears to be disturbed but
whether specific populations of GABA neurons are affected is not known. The
chandelier class of GABA neurons are of particular interest because their axon
terminals, which form distinctive arrays termed "cartridges," provide inhibitory
input exclusively to the axon initial segment of pyramidal cells. Thus,
chandelier cells are positioned to powerfully regulate the excitatory output of
pyramidal neurons and, consequently, to substantially affect the patterns of
neuronal activity within the PFC. In this study, an antibody directed against the
GABA membrane transporter GAT-1 was used to label GABA axon terminals in
postmortem human brains. The relative density of GAT-1-immunoreactive axon
cartridges furnished by chandelier neurons was decreased by 40% in the PFC of
schizophrenic subjects compared with matched groups of normal control and
nonschizophrenic psychiatric subjects. In contrast, markers of the axon terminals
of other populations of GABA neurons were not altered in the schizophrenic
subjects. Furthermore, the density of GAT-1-immunoreactive axon cartridges was
not altered in psychiatric subjects who had been treated with antipsychotic
medications. The changes in GAT-1-immunoreactive axon cartridges of chandelier
neurons in schizophrenia are likely to reflect altered information processing
within the PFC and in its output connections to other brain regions and could
contribute to the cognitive impairments seen in this disorder.
PMID- 9560279
TI - High expression levels in cones of RGS9, the predominant GTPase accelerating
protein of rods.
AB - RGS9 is a member of the RGS family of GTPase accelerating proteins (GAPs) for
heterotrimeric G proteins. We have explored its contribution to GTPase
acceleration in mammalian rod and cone photoreceptors. When RGS9 was specifically
removed from detergent extracts of rod outer segments by immunodepletion, the
extracts lost nearly all of their GAP activity stimulatable by the inhibitory
subunit of cGMP phosphodiesterase. Immunolocalization using monoclonal antibodies
and confocal microscopy revealed that RGS9 is present in cones at significantly
higher levels than in rods. Thus, RGS9 is the predominant source of GAP activity
in rod outer segments, and RGS9 concentration emerges as a potentially important
determinant of the faster response kinetics and lower sensitivity of mammalian
cones, as compared with rods.
PMID- 9560280
TI - Effect of intravenous infusions of 12-O-tetradecanoylphorbol-13-acetate (TPA) in
patients with myelocytic leukemia: preliminary studies on therapeutic efficacy
and toxicity.
AB - Studies by several investigators have shown that 12-0-tetradecanoylphorbol-13
acetate (TPA) is an extraordinarily potent stimulator of differentiation of
cultured human promyelocytic leukemia cells in vitro. In the present study, TPA
was administered to humans by i.v. infusion without irreversible toxicity, and it
was shown to have pharmacological activity for the treatment of myelocytic
leukemia in patients refractory to cytosine arabinoside (Ara C), retinoic acid,
and other antileukemic drugs. Marked decreases in bone marrow myeloblasts as well
as temporary remission of disease symptoms were observed when TPA was
administered alone or in combination with vitamin D3 and Ara C. Additional
studies with TPA after the determination of optimum dosing regimens are needed to
determine whether long-lasting or permanent remissions of myelocytic leukemia can
be achieved. Transient and reversible side effects were observed after a 1-mg
i.v. dose of TPA, but these adverse effects became less intense or disappeared
when a lower dose of TPA was used. The results of this study indicate a
therapeutic effect of TPA in patients with myelocytic leukemia.
PMID- 9560281
TI - 12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced increase in depressed white
blood cell counts in patients treated with cytotoxic cancer chemotherapeutic
drugs.
AB - Fifty-two patients with solid tumors had depressed white blood cell and
neutrophil counts because of prior treatment with cytotoxic cancer
chemotherapeutic drugs. These patients were given one or more i.v. infusions of
0.125-0.25 mg of 12-O-tetradecanoylphorbol-13-acetate (TPA), and this treatment
increased the low white blood cell and neutrophil counts toward the normal range.
The average white blood cell and neutrophil counts were 2.55 x 10(9)/liter and
1.76 x 10(9)/liter, respectively, before treatment with TPA. After one or more
i.v. infusions of TPA, the white blood cell and neutrophil counts increased to
peak values of 5. 92 x 10(9)/liter and 4.76 x 10(9)/liter, respectively, within a
few days. Most patients had increased levels of white blood cells and neutrophils
by 24 hr after a single i.v. infusion of 0.25 mg TPA. Elevated levels were
observed for at least 3 days. This study demonstrates that treatment with
parenteral TPA is feasible with useful biological activity. Only mild and
reversible side effects were observed.
PMID- 9560282
TI - Nerve growth factor abrogates the tumorigenicity of human small cell lung cancer
cell lines.
AB - Nerve growth factor (NGF) has antiproliferative and differentiating effects on
adenomas of neuroendocrine origin. Cell lines derived from small-cell lung
carcinoma (SCLC), a very aggressive neuroendocrine tumor, express NGF receptors.
The role of NGF in the control of proliferation and progression of this
carcinoma, however, has never been investigated. Chronic exposure of NCI-N-592
and GLC8 SCLC cell lines to NGF remarkably inhibited their proliferation rate
both in vitro and in vivo, prevented their anchorage-independent clonal growth in
soft agar, impaired their invasive capacity in vitro, and abolished their
tumorigenic potential in nude mice. The proliferative response of SCLC cell lines
to nicotine was also remarkably impaired by in vitro NGF treatment. Furthermore,
NGF treatment activates in SCLC cell lines the expression and secretion of NGF.
NGF thus reverts SCLC cell lines to a noninvasive, nontumorigenic phenotype that
does not respond to nicotine and produces NGF.
PMID- 9560284
TI - Migrating transformed MDCK cells are able to structurally polarize a voltage
activated K+ channel.
AB - Cell migration of transformed renal epithelial cells (MDCK-F) depends-in addition
to cytoskeletal mechanisms-on the polarized activity of a Ca2+-sensitive K+
channel in the rear part of the cells. However, because of the lack of specific
markers for this channel we are not able to determine whether a polarized
distribution of the channel protein underlies its functional polarization. To
determine whether the migrating MDCK-F cells have retained the ability to target
K+ channels to distinct membrane areas we stably transfected the cells with the
voltage-dependent K+ channel Kv1.4. Stable expression and insertion into the
plasma membrane could be shown by reverse transcription-PCR, genomic PCR, Western
blot, and patch-clamp techniques, respectively. The distribution of Kv1.4 was
assessed with indirect immunofluorescence by using conventional and confocal
microscopy. These experiments revealed that Kv1.4 is expressed only in
transfected cells where it elicits the typical voltage-dependent, rapidly
inactivating K+ current. The Kv1.4 protein is clustered at the leading edge of
protruding lamellipodia of migrating MDCK-F cells. This characteristic
distribution of Kv1.4 provides strong evidence that migrating MDCK-F cells are
able to insert ion channels into the plasma membrane in an asymmetric way, which
reflects the polarization of migrating cells in the plane of movement. These
findings suggest that not only epithelial cells and nerve cells, but also
migrating cells, can create functionally distinct plasma membrane areas.
PMID- 9560283
TI - Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting,
hypercalciuria, and skeletal abnormalities.
AB - Npt2 encodes a renal-specific, brush-border membrane Na+-phosphate (Pi)
cotransporter that is expressed in the proximal tubule where the bulk of filtered
Pi is reabsorbed. Mice deficient in the Npt2 gene were generated by targeted
mutagenesis to define the role of Npt2 in the overall maintenance of Pi
homeostasis, determine its impact on skeletal development, and clarify its
relationship to autosomal disorders of renal Pi reabsorption in humans.
Homozygous mutants (Npt2(-/-)) exhibit increased urinary Pi excretion,
hypophosphatemia, an appropriate elevation in the serum concentration of 1,25
dihydroxyvitamin D with attendant hypercalcemia, hypercalciuria and decreased
serum parathyroid hormone levels, and increased serum alkaline phosphatase
activity. These biochemical features are typical of patients with hereditary
hypophosphatemic rickets with hypercalciuria (HHRH), a Mendelian disorder of
renal Pi reabsorption. However, unlike HHRH patients, Npt2(-/-) mice do not have
rickets or osteomalacia. At weaning, Npt2(-/-) mice have poorly developed
trabecular bone and retarded secondary ossification, but, with increasing age,
there is a dramatic reversal and eventual overcompensation of the skeletal
phenotype. Our findings demonstrate that Npt2 is a major regulator of Pi
homeostasis and necessary for normal skeletal development.
PMID- 9560285
TI - Phosphorylation of a twitchin-related protein controls catch and calcium
sensitivity of force production in invertebrate smooth muscle.
AB - "Catch" is a condition of prolonged, high-force maintenance at resting
intracellular Ca2+ concentration ([Ca2+]) and very low energy usage, occurring in
invertebrate smooth muscles, including the anterior byssus retractor muscle
(ABRM) of Mytilus edulis. Relaxation from catch is rapid on serotonergic nerve
stimulation in intact muscles and application of cAMP in permeabilized muscles.
This release of catch occurs by protein kinase A-mediated phosphorylation of a
high (approximately 600 kDa) molecular mass protein, the regulator of catch.
Here, we identify the catch-regulating protein as a homologue of the mini-titin,
twitchin, based on (i) a partial cDNA of the purified isolated protein showing
77% amino acid sequence identity to the kinase domain of Aplysia californica
twitchin; (ii) a polyclonal antibody to a synthetic peptide in this sequence
reacting with the phosphorylated catch-regulating protein band from permeabilized
ABRM; and (iii) the similarity of the amino acid composition and molecular weight
of the protein to twitchin. In permeabilized ABRM, at all but maximum [Ca2+],
phosphorylation of twitchin results in a decreased calcium sensitivity of force
production (half-maximum at 2.5 vs. 1.3 microM calcium). At a given submaximal
force, with equal numbers of force generators, twitchin phosphorylation increased
unloaded shortening velocity approximately 2-fold. These data suggest that
aspects of the catch state exist not only at resting [Ca2+], but also at higher
submaximal [Ca2+]. The mechanism that gives rise to force maintenance in catch
probably operates together, to some extent, with that of cycling myosin
crossbridges.
PMID- 9560286
TI - Expression of the Na+/Ca2+ exchanger emerges in hepatic stellate cells after
activation in association with liver fibrosis.
AB - Activation of hepatic stellate (Ito) cells is a final common pathway of liver
fibrosis. The findings presented in this paper indicate that expression of
Na+/Ca2+ exchanger (NCX) emerges in rat hepatic stellate cells after activation
in vitro during primary culture or in vivo in response to intoxication with CCl4.
NCX mRNA became detectable by Northern blot analysis in cultured stellate cells
on day 3, as was alpha-smooth muscle actin, an indicator not only of smooth
muscle differentiation but also of stellate cell activation. Western blot
analysis showed expression of the exchanger protein in the activated stellate
cells. Functional expression of the exchanger, monitored by Ni2+-sensitive,
verapamil-insensitive intracellular free Ca2+ increases in response to reduction
of extracellular Na+ concentration, became sizable by using Fura-2 in stellate
cells by 7 days in culture. Furthermore, increased expression of the exchanger
mRNA was found predominantly in stellate cells freshly isolated from the CCl4
model rat of hepatic fibrosis. Thus, it is concluded that NCX expression is
closely associated with activation of hepatic stellate cells in vitro and in
vivo. Because, even at the whole liver level, increased expression of NCX mRNA
became observable after induction of liver fibrosis, it is suggested that NCX
expression serves a useful diagnostic marker of liver fibrosis or cirrhosis.
PMID- 9560287
TI - Cloning and characterization of a potassium-coupled amino acid transporter.
AB - Active solute uptake in bacteria, fungi, plants, and animals is known to be
mediated by cotransporters that are driven by Na+ or H+ gradients. The present
work extends the Na+ and H+ dogma by including the H+ and K+ paradigm.
Lepidopteran insect larvae have a high K+ and a low Na+ content, and their midgut
cells lack Na+/K+ ATPase. Instead, an H+ translocating, vacuolar-type ATPase
generates a voltage of approximately -240 mV across the apical plasma membrane of
so-called goblet cells, which drives H+ back into the cells in exchange for K+,
resulting in net K+ secretion into the lumen. The resulting inwardly directed K+
electrochemical gradient serves as a driving force for active amino acid uptake
into adjacent columnar cells. By using expression cloning with Xenopus laevis
oocytes, we have isolated a cDNA that encodes a K+-coupled amino acid transporter
(KAAT1). We have cloned this protein from a larval lepidopteran midgut (Manduca
sexta) cDNA library. KAAT1 is expressed in absorptive columnar cells of the
midgut and in labial glands. When expressed in Xenopus oocytes, KAAT1 induced
electrogenic transport of neutral amino acids but excludes alpha
(methylamino)isobutyric acid and charged amino acids resembling the mammalian
system B. K+, Na+, and to a lesser extent Li+ were accepted as cotransported
ions, but K+ is the principal cation, by far, in living caterpillars. Moreover,
uptake was Cl(-)-dependent, and the K+/Na+ selectivity increased with
hyperpolarization of oocytes, reflecting the increased K+/Na+ selectivity with
hyperpolarization observed in midgut tissue. KAAT1 has 634 amino acid residues
with 12 putative membrane spanning domains and shows a low level of identity with
members of the Na+ and Cl(-)-coupled neurotransmitter transporter family.
PMID- 9560289
TI - Compartmentalized expression of two structurally and functionally distinct 4
coumarate:CoA ligase genes in aspen (Populus tremuloides).
AB - 4-Coumarate:CoA ligases (4CLs, EC 6.2.1.12) are a group of enzymes necessary for
maintaining a continuous metabolic flux for the biosynthesis of plant
phenylpropanoids, such as lignin and flavonoids, that are essential to the
survival of plants. So far, various biochemical and molecular studies of plant
4CLs seem to suggest that 4CL isoforms in plants are functionally
indistinguishable in mediating the biosynthesis of these phenolics. However, we
have discovered two functionally and structurally distinct 4CL genes, Pt4CL1 and
Pt4CL2 (63% protein sequence identity), that are differentially expressed in
aspen (Populus tremuloides). The Escherichia coli-expressed and purified Pt4CL1
and Pt4CL2 proteins exhibited highly divergent substrate preference as well as
specificity that reveal the association of Pt4CL1 with the biosynthesis of
guaiacyl-syringyl lignin and the involvement of Pt4CL2 with other phenylpropanoid
formation. Northern hybridization analysis demonstrated that Pt4CL1 mRNA is
specifically expressed in lignifying xylem tissues and Pt4CL2 mRNA is
specifically expressed in epidermal layers in the stem and the leaf, consistent
with the promoter activities of Pt4CL1 and Pt4CL2 genes based on the heterologous
promoter-beta-glucouronidase fusion analysis. Thus, the expression of Pt4CL1 and
Pt4CL2 genes is compartmentalized to regulate the differential formation of
phenylpropanoids that confer different physiological functions in aspen; Pt4CL1
is devoted to lignin biosynthesis in developing xylem tissues, whereas Pt4CL2 is
involved in the biosynthesis of other phenolics, such as flavonoids, in epidermal
cells.
PMID- 9560288
TI - Association of the Arabidopsis CTR1 Raf-like kinase with the ETR1 and ERS
ethylene receptors.
AB - In Arabidopsis thaliana, signal transduction of the hormone ethylene involves at
least two receptors, ETR1 and ERS, both of which are members of the two-component
histidine protein kinase family that is prevalent in prokaryotes. The pathway
also contains a negative regulator of ethylene responses, CTR1, which closely
resembles members of the Raf protein kinase family. CTR1 is thought to act at or
downstream of ETR1 and ERS based on double mutant analysis; however, the
signaling mechanisms leading from ethylene perception to the regulation of CTR1
are unknown. By using the yeast two-hybrid assay, we detected a specific
interaction between the CTR1 amino-terminal domain and the predicted histidine
kinase domain of ETR1 and ERS. We subsequently verified these interactions by
using an in vitro protein association assay(s). In addition, we determined that
the amino-terminal domain of CTR1 can associate with the predicted receiver
domain of ETR1 in vitro. Based on deletion analysis, the portion of CTR1 that
interacts with ETR1 roughly aligns with the regulatory region of Raf kinases.
These physical associations support the genetic evidence that CTR1 acts in the
pathway of ETR1 and ERS and suggest that these interactions could be involved in
the regulation of CTR1 activity.
PMID- 9560290
TI - Visual memory-deficit amnesia: a distinct amnesic presentation and etiology.
AB - We describe a form of amnesia, which we have called visual memory-deficit
amnesia, that is caused by damage to areas of the visual system that store visual
information. Because it is caused by a deficit in access to stored visual
material and not by an impaired ability to encode or retrieve new material, it
has the otherwise infrequent properties of a more severe retrograde than
anterograde amnesia with no temporal gradient in the retrograde amnesia. Of the
11 cases of long-term visual memory loss found in the literature, all had amnesia
extending beyond a loss of visual memory, often including a near total loss of
pretraumatic episodic memory. Of the 6 cases in which both the severity of
retrograde and anterograde amnesia and the temporal gradient of the retrograde
amnesia were noted, 4 had a more severe retrograde amnesia with no temporal
gradient and 2 had a less severe retrograde amnesia with a temporal gradient.
PMID- 9560291
TI - The hypoglossal canal and the origin of human vocal behavior.
AB - The mammalian hypoglossal canal transmits the nerve that supplies the muscles of
the tongue. This canal is absolutely and relatively larger in modern humans than
it is in the African apes (Pan and Gorilla). We hypothesize that the human tongue
is supplied more richly with motor nerves than are those of living apes and
propose that canal size in fossil hominids may provide an indication about the
motor coordination of the tongue and reflect the evolution of speech and
language. Canals of gracile Australopithecus, and possibly Homo habilis, fall
within the range of extant Pan and are significantly smaller than those of modern
Homo. The canals of Neanderthals and an early "modern" Homo sapiens (Skhul 5), as
well as of African and European middle Pleistocene Homo (Kabwe and Swanscombe),
fall within the range of extant Homo and are significantly larger than those of
Pan troglodytes. These anatomical findings suggest that the vocal capabilities of
Neanderthals were the same as those of humans today. Furthermore, the vocal
abilities of Australopithecus were not advanced significantly over those of
chimpanzees whereas those of Homo may have been essentially modern by at least
400,000 years ago. Thus, human vocal abilities may have appeared much earlier in
time than the first archaeological evidence for symbolic behavior.
PMID- 9560292
TI - The periodontopathogen Porphyromonas gingivalis binds iron protoporphyrin IX in
the mu-oxo dimeric form: an oxidative buffer and possible pathogenic mechanism.
AB - Mossbauer spectroscopy was used to re-evaluate iron protoporphyrin IX, FePPIX,
binding and the chemical nature of the black iron porphyrin pigment of
Porphyromonas gingivalis. We demonstrate that FePPIX is bound to the cell in the
mu-oxo dimeric form, [Fe(III)PPIX]2O, and that the iron porphyrin pigment is also
composed of this material. P. gingivalis also assimilated monomeric Fe(II)- and
Fe(III)PPIX into mu-oxo dimers in vitro. Scatchard analysis revealed a greater
binding maximum of cells for mu-oxo dimers than for monomeric Fe(III)-or
Fe(II)PPIX, although the relative affinity constant for the dimers was lower.
Formation of [Fe(III)PPIX]2O via reactions of Fe(II)PPIX with oxygen, and its
toxic derivatives, would serve as an oxidative buffer and permit P. gingivalis
and other black-pigmenting anaerobes to engender and maintain a local anaerobic
environment. Tying up of free oxygen species with iron protoporphyrin IX would
also reduce and limit Fe(II)PPIX-mediated oxygen-radical cell damage. More
importantly, formation of a cell-surface mu-oxo dimer layer may function as a
protective barrier against assault by reactive oxidants generated by neutrophils.
Selective interference with these mechanisms would offer the possibility of
attenuating the pathogenicity of P. gingivalis and other iron protoporphyrin IX
binding pathogens whose virulence is regulated by this reactive molecule.
PMID- 9560293
TI - Mucus glycoproteins from pig gastric mucosa: different mucins are produced by the
surface epithelium and the glands.
AB - An antibody (PGM2B) recognizing a pig gastric-mucin apoprotein reacts with the
surface epithelium of pig gastric mucosa. Virtually no reactivity was observed
over the mucin-producing cells in the glands, which were recognized by the GlcNAc
selective Griffonia simplicifolia II (GSA-II) lectin. Mucins from the glandular
tissue of the cardiac region, corpus and antrum were purified using isopycnic
density-gradient centrifugation in CsCl/guanidinium chloride. In the cardiac
region, two major mucin populations at 1.5 and 1.4 g/ml were identified. The high
density population reacted preferentially with the PGM2B antibody and resembled
mucins from the surface epithelium of this region, whereas the low-density
population reacted strongly with the GSA-II lectin and appeared to originate from
the glands. In the glandular tissue of corpus, a component with strong GSA-II
lectin reactivity, which was distinctly different from the surface mucins from
this region, was found at 1.4 g/ml, thus resembling the gland component from the
cardiac region. Mucins from antrum glandular tissue contained at least two GSA-II
lectin-reactive populations banding at 1.5 and 1.4 g/ml, respectively. Gland
mucins from all regions were large oligomeric glycoproteins and heterogeneous
with respect to charge properties, as shown by using rate-zonal centrifugation
and ion-exchange HPLC, respectively. Gel chromatography of mucin glycopeptides
showed that gland mucins from antrum and corpus contained significantly longer
glycosylated domains than those from the surface mucosa. Thus, mucins from pig
gastric glandular tissue comprise a number of large and oligomeric glycoproteins
that differ from those from the surface epithelium in buoyant density, apoprotein
structure and carbohydrate substitution.
PMID- 9560295
TI - The mechanism of catalysis and the inhibition of the Bacillus cereus zinc
dependent beta-lactamase.
AB - The plot of kcat/Km against pH for the Bacillus cereus 569/H beta-lactamase class
B catalysed hydrolysis of benzylpenicillin and cephalosporin indicates that there
are three catalytically important groups, two of pKa 5.6+/-0.2 and one of pKa
9.5+/-0.2. Below pH 5 there is an inverse second-order dependence of reactivity
upon hydrogen ion concentration, indicative of the requirement of two basic
residues for catalysis. These are assigned to zinc(II)-bound water and Asp-90,
both with a pKa of 5.6+/-0.2. A thiol, N-(2'-mercaptoethyl)-2-phenylacetamide, is
an inhibitor of the class B enzyme with a Ki of 70 microM. The pH-dependence of
Ki shows similar pH inflections to those observed in the catalysed hydrolysis of
substrates. The pH-independence of Ki between pH 6 and 9 indicates that the pKa
of zinc(II)-bound water must be 5.6 and not the higher pKa of 9.5. The kinetic
solvent isotope effect on kcat/Km is 1.3+/-0.5 and that on kcat is 1.5. There is
no effect on reactivity by either added zinc(II) or methanol. The possible
mechanisms of action for the class B beta-lactamase are discussed, and it is
concluded that zinc(II) acts as a Lewis acid to stabilize the dianionic form of
the tetrahedral intermediate and to provide a hydroxide-ion bound nucleophile,
whereas the carboxylate anion of Asp-90 acts as a general base to form the
dianion and also, presumably, as a general acid catalyst facilitating C-N bond
fission.
PMID- 9560294
TI - Activation of the signal transducer gp130 by interleukin-11 and interleukin-6 is
mediated by similar molecular interactions.
AB - The transmembrane glycoprotein gp130 is involved in many cytokine-mediated
cellular responses and acts therein as the signal transducing receptor subunit.
Interleukin-6 (IL-6) and interleukin-11 (IL-11), in complex with their specific
alpha-receptors, homodimerize gp130 and, as a consequence, activate the Janus
kinase (Jak)/signal transducer and activator of transcription (STAT) signalling
pathway in their target cells. So far, it is not clear whether gp130 is bound to
these cytokines and their specific alpha-receptor subunits through identical or
different epitopes. In order to study the interaction of IL-11 and IL-11R with
human gp130 the soluble form of the recently cloned human IL-11R was expressed in
baculovirus-infected insect cells. By a coprecipitation binding-assay it is
demonstrated that IL-11 and IL-6 compete for binding to gp130. Using deletion and
point mutants of gp130 it is shown that IL-11-IL-11R and IL-6-IL-6R recognize
overlapping binding motifs on gp130. Moreover, using well-established Jak
deficient cell lines we demonstrate that STAT activation by IL-11 requires Jak1.
Taken together, our data support the concept that IL-6 and IL-11 activate gp130
by very similar molecular mechanisms.
PMID- 9560296
TI - Control of growth and differentiation of normal human epithelial cells through
the manipulation of reactive nitrogen species.
AB - In this work, we addressed the issue of whether exogenous NO and ONOO-
(peroxynitrite) are able to alter growth, viability and/or differentiation of
normal epithelial cells using cultured normal human keratinocytes as a model. 3
Morpholino-sydnonimine (SIN-1), a donor of both NO and O2(-)., leading to the
production of ONOO-, dose-dependently inhibited growth of human keratinocytes
without loss of viability. This inhibitory effect was lowered when SIN-1 was
transformed into a pure NO donor by scavenging O2(-). with superoxide
dismutase/catalase. Finally, scavenging NO release from SIN-1 with carboxy-1H
imidazol-1-yloxy,2-(4-carboxyp henyl)-4,5-dihydro-4,4,5,5 -tetramethyl-3-oxide
(PTIO) resulted in a loss of the inhibitory effect of SIN-1. Together these
findings suggest that both ONOO- and NO exert a growth inhibitory effect on human
keratinocytes without cytotoxicity. Further support for this conclusion came from
the treatment of human keratinocytes with the NO. donor propanamine 3-(2-hydroxy
2-nitroso-1-propyl hydrazino) or with authentic peroxynitrite. Moreover, only SIN
1 or peroxynitrite, and not NO, was able to trigger the expression of markers of
terminal differentiation in human keratinocytes. From a physiological
perspective, the ability of peroxynitrite, a known genotoxic and potentially
carcinogenic agent, to direct proliferating keratinocytes towards terminal
differentiation may be crucial to protect the genomic stability of this barrier
epithelium.
PMID- 9560298
TI - Human cathepsin K cleaves native type I and II collagens at the N-terminal end of
the triple helix.
AB - Cathepsin K (EC 3.4.22.38) is a recently described enzyme that has been shown to
cleave type I collagen in its triple helix. The aim of this study was to
determine if it also cleaves type II collagen in the triple helix and to identify
the helical cleavage site(s) in types I and II collagens. Soluble human and
bovine type II collagen, and rat type I collagen, were incubated with cathepsin K
before the reaction was stopped with trans-epoxysuccinyl-l-leucylamido-(4
guanidino)butane (E-64). Analysis by SDS/PAGE of the collagen digests showed that
optimal activity of cathepsin K against native type II collagen was between pH
5.0 and 5.5 and against denatured collagen between pH 4.0 and 7.0. The enzyme
cleaved telopeptides as well as the alpha1(II) chains, generating multiple
fragments in the range 90-120 kDa. The collagenolytic activity was not due to a
contaminating metalloenzyme or serine proteinase as it was not inhibited by 1,10
phenanthroline, EDTA or 3,4-dichloroisocoumarin. Western blotting with anti
peptide antibodies to different regions of the alpha1(II) chain suggested that
cathepsin K cleaved native alpha1(II) chains in the N-terminal region of the
helical domain rather than at the well-defined collagenase cleavage site. This
was confirmed by N-terminal sequencing of one of the fragments, revealing
cleavage at a Gly-Lys bond, 58 residues from the N-terminus of the helical
domain. By using a similar approach, cathepsin K was found to cleave native type
I collagen close to the N-terminus of its triple helix. These results indicate
that cathepsin K could have a role in the turnover of type II collagen, as well
as type I collagen.
PMID- 9560297
TI - Iron loading of isolated rat hepatocytes inhibits asialoglycoprotein receptor
dynamics and induces formation of rat hepatic lectin-1 [correction of leptin-1]
(RHL-1) oligomers.
AB - The major subunit [rat hepatic lectin-1 (RHL-1)] of the asialoglycoprotein (ASGP)
receptor mediates endocytosis of the iron-binding protein lactoferrin (Lf) by
isolated rat hepatocytes, yet iron loading of cultured adult rat hepatocytes
increases the binding and endocytosis of Lf while greatly inhibiting the uptake
of desialylated ligand. In the present study, we determined whether the iron
induced Lf-binding site is RHL-1 and examined the nature of the iron-induced
block in ASGP receptor endocytic function. Isolated rat hepatocytes increased
their non-haem iron content from 70 to 470 p.p. b. following incubation with
ferric ammonium citrate (<=100 microgram/ml). These conditions blocked
internalization of 125I-asialo-orosomucoid (ASOR) by approximately 90% but
increased 125I-Lf endocytosis by 40%. ASOR and anti-RHL-1 sera blocked the
binding and endocytosis of 125I-Lf on control cells but not on iron-loaded cells,
indicating that the iron-induced Lf-binding site on hepatocytes is not RHL-1.
Iron-loading of hepatocytes in the presence or absence of excess ASOR did not
significantly alter the number of active ASGP receptors on the cell surface. In
contrast, iron-loading decreased the number of active intracellular receptors by
40% and blocked the uptake of 125I-ASOR prebound to the cells by approximately
80%. Under these conditions, we found an iron-dependent evolution of 88 and 140
kDa RHL-1-containing, beta-mercaptoethanol-sensitive multimers that constituted
up to 34 and 23%, respectively, of total immunodetectable RHL-1. We propose that
iron-induced formation of cystinyl-linked RHL-1-containing multimers inhibits
ASGP receptor movement between cell surface and interior and disrupts acylation
of intracellular receptors.
PMID- 9560299
TI - Bisecting GlcNAc structure is implicated in suppression of stroma-dependent
haemopoiesis in transgenic mice expressing N-acetylglucosaminyltransferase III.
AB - Several sugar structures have been reported to be necessary for haemopoiesis. We
analysed the haematological phenotypes of transgenic mice expressing beta-1,4 N
acetylglucosaminyltransferase III (GnT-III), which forms bisecting N
acetylglucosamine on asparagine-linked oligosaccharides. In the transgenic mice,
the GnT-III activity was elevated in bone marrow, spleen and peripheral blood and
in isolated mononuclear cells from these tissues, whereas no activity was found
in these tissues of wild-type mice. Stromal cells after long-term cultures of
transgenic-derived bone marrow and spleen cells also showed elevated GnT-III
activity, compared with an undetectable activity in wild-type stromal cells. As
judged by HPLC analysis, lectin blotting and lectin cytotoxicity assay, bisecting
GlcNAc residues were increased on both blood cells and stromal cells from bone
marrow and spleen in transgenic mice. The transgenic mice displayed spleen
atrophy, hypocellular bone marrow and pancytopenia. Bone marrow cells and spleen
cells from transgenic mice produced fewer haemopoietic colonies. After lethal
irradiation followed by bone marrow transplantation, transgenic recipient mice
showed pancytopenia compared with wild-type recipient mice. Bone marrow cells
from transgenic donors gave haematological reconstitution at the same level as
wild-type donor cells. In addition, non-adherent cell production was decreased in
long-term bone marrow cell cultures of transgenic mice. Collectively these
results indicate that the stroma-supported haemopoiesis is compromised in
transgenic mice expressing GnT-III, providing the first demonstration that the N
glycans have some significant roles in stroma-dependent haemopoiesis.
PMID- 9560301
TI - Overexpression of prothymosin alpha accelerates proliferation and retards
differentiation in HL-60 cells.
AB - Prothymosin alpha (ProTalpha) is an acidic nuclear protein the expression of
which is related to the proliferation and differentiation processes in mammalian
cells. In the present study we have stably transfected HL-60 cells, a biological
system that allows the study of both proliferation and differentiation, with
recombinant vectors encoding sense and antisense ProTalpha mRNA. In the HL-60
cell clones overexpressing ProTalpha we observed an acceleration in the growth
rate, whereas expression of the antisense orientation showed the opposite effect.
Moreover, cell-cycle analysis demonstrated that the G1-phase was shortened in the
cells expressing the sense construct. Before studying how ProTalpha affects
differentiation, we showed that the down-regulation of ProTalpha gene during
differentiation occurs in all mammalian cell lines (HL-60, K562, U937, MEL C88,
N2A and PC12) analysed. The biological effect evoked by the induction of the
ProTalpha sense vector was the retardation of cell differentiation, although
expression of the antisense construct showed no effect on differentiation. In
conclusion, our findings provide evidence that ProTalpha is directly implicated
in cellular proliferation and that the maintenance of high levels of ProTalpha
inside HL-60 cells is incompatible with their ability to differentiate.
PMID- 9560302
TI - Functional consequences of relocating the C-terminal calmodulin-binding
autoinhibitory domains of the plasma membrane Ca2+ pump near the N-terminus.
AB - A mutant of the plasma membrane Ca2+ pump (PMCA) called (nCI)hPMCA4b(ct120), in
which the C-terminal regulatory segment including the calmodulin-binding
autoinhibitory domains C and I had been relocated near the N-terminus, has been
expressed in COS-1 cells. The measurements of Ca2+ transport in microsomal
preparations showed that the rearranged enzyme was functional. The activity of
the (nCI)hPMCA4b(ct120) mutant was compared with those of the wild-type hPMCA4b
and the fully active calmodulin-insensitive mutant hPMCA4b(ct120). In the absence
of calmodulin the activity of (nCI)hPMCA4b(ct120) was higher than that of hPMCA4b
but only 45% of that of hPMCA4b(ct120). Mutant (nCI)hPMCA4b(ct120) exhibited an
apparent affinity for Ca2+ similar to that of hPMCA4b, typical of the inhibited
state of the enzyme. Calmodulin at concentrations that fully activated hPMCA4b
increased the activity of (nCI)hPMCA4b(ct120) to 68% of that of hPMCA4b(ct120).
The lower maximal activity of (nCI)hPMCA4b(ct120) was not due to a lower affinity
for calmodulin because the concentration of calmodulin required for half-maximal
activation of (nCI)hPMCA4b(ct120) was equal to that of the wild-type hPMCA4b.
These results indicate that (1) the disturbance of the N-terminal region of the
PMCA by the insertion of the C-terminal segment decreased the ability of the pump
to transport Ca2+, and (2) the calmodulin-binding autoinhibitory domain was still
able to access its acceptor site from the N-terminal end of the molecule.
However, although the calmodulin-binding and inhibitory functions of the C-domain
were fully preserved, the I domain at its new position seemed less effective at
inhibiting the pump.
PMID- 9560300
TI - Proteoglycans in macrophages: characterization and possible role in the cellular
uptake of lipoproteins.
AB - The murine macrophage cell line J774 was incubated with [35S]sulphate. The cell
associated 35S-labelled macromolecules were shown to be proteoglycans and
glycosaminoglycans in similar amounts. The possible presence of cell-surface
proteoglycans was investigated by incubating [35S]sulphate-labelled cells with
trypsin for 15 min. The released material contained approx. 70% free
glycosaminoglycan chains and 30% proteoglycans. The latter component was
demonstrated by HNO2 treatment to contain heparan sulphate. In the total cell
fraction not treated with trypsin a small but significant portion was shown to be
chondroitin sulphate proteoglycan. The cell-associated glycosaminoglycans
contained both chondroitin sulphate and heparan sulphate. To investigate possible
biological functions of cell-surface proteoglycans in macrophages, cells were
incubated with NaClO3 to inhibit sulphation of proteoglycans and beta-d-xyloside
to abrogate proteoglycan expression. The uptake of oxidized 125I
tyraminylcellobiose-labelled low-density lipoprotein (125I-TC-LDL) was typically
two to three times higher than that of native 125I-TC-LDL in untreated J774
cells. The cellular uptake at 37 degreesC of native 125I-TC-LDL was decreased 25%
after both NaClO3 and xyloside treatment, whereas the uptake of oxidized 125I-TC
LDL was decreased 35% after both types of treatment. The mRNA levels for the
scavenger receptor A-II and the LDL receptor were not affected by NaClO3 or
xyloside treatment. Furthermore, fluid-phase endocytosis, measured as uptake of
horseradish peroxidase, and receptor-mediated endocytosis, measured as uptake of
125I-TC-ovalbumin, were not affected by NaClO3 treatment of J774 cells. Removal
of cell-surface chondroitin sulphate with chondroitinase ABC decreased only the
binding of native 125I-TC-LDL, whereas removal of heparan sulphate with
heparitinase decreased the binding of both oxidized and native 125I-TC-LDL.
Addition of lipoprotein lipase increased the uptake of oxidized 125I-TC-LDL 1.7
times and the uptake of native 125I-TC-LDL 2.1 times. The binding of the former
was more sensitive to NaClO3 treatment than the latter. The results presented
support the notion that some of the uptake pathways for lipoproteins in the foam
cell-forming macrophages depend on the presence of cell-surface heparan sulphate
and chondroitin sulphate.
PMID- 9560303
TI - Inhibition of activation-induced apoptosis of thymocytes by all-trans- and 9-cis
retinoic acid is mediated via retinoic acid receptor alpha.
AB - Thymocytes can be induced to undergo apoptotic cell death by activation through
the T-cell receptor (TCR). This process requires macromolecular synthesis and has
been shown to be inhibited by retinoic acids (RAs). Two groups of nuclear
receptors for RAs have been identified: retinoic acid receptors (RARs) and
retinoid X receptors (RXRs). All-trans-RA is the high-affinity ligand for RARs,
and 9-cis-RA additionally binds to RXRs with high affinity. Because 9-cis-RA is
much more potent in inhibiting TCR-mediated death than all-trans-RA, it was
suggested that RXRs participate in the process. In the present study various
synthetic retinoid analogues were used to address this question further. The
results presented suggest that the inhibitory effect of RAs on activation-induced
death of thymocytes is mediated via RARalpha, because (1) it can be reproduced by
various RARalpha analogues both in vitro and in vivo, (2) the effect of RAs can
be inhibited by the addition of an RARalpha antagonist, (3) CD4+CD8+thymocytes,
which die on TCR stimulation, express RARalpha. Stimulation of RARgamma, in
contrast, enhances the activation-induced death of thymocytes and inhibits its
prevention by RARalpha stimulation. RXR co-stimulation suspends this inhibitory
effect of RARgamma and permits the preventive function of RARalpha on activation
induced death. Our results suggest a complex interaction between the various
isoforms of retinoid receptors and demonstrate that low (physiological)
concentrations of all-trans-RA do not affect the activation-induced death of
thymocytes because the RARalpha-mediated inhibitory and the RARgamma-mediated
enhancing pathways are in balance, whereas if 9-cis-RA is formed, additional
stimulation of RXRs permits the inhibitory action of RARalpha.
PMID- 9560304
TI - Pseudomonas cellulose-binding domains mediate their effects by increasing enzyme
substrate proximity.
AB - To investigate the mode of action of cellulose-binding domains (CBDs), the Type
II CBD from Pseudomonas fluorescens subsp. cellulosa xylanase A (XYLACBD) and
cellulase E (CELECBD) were expressed as individual entities or fused to the
catalytic domain of a Clostridium thermocellum endoglucanase (EGE). The two CBDs
exhibited similar Ka values for bacterial microcrystalline cellulose (CELECBD,
1.62x10(6) M-1; XYLACBD, 1.83x10(6) M-1) and acid-swollen cellulose (CELECBD,
1.66x10(6) M-1; XYLACBD, 1.73x10(6) M-1). NMR spectra of XYLACBD titrated with
cello-oligosaccharides showed that the environment of three tryptophan residues
was affected when the CBD bound cellohexaose, cellopentaose or cellotetraose. The
Ka values of the XYLACBD for C6, C5 and C4 cello-oligosaccharides were estimated
to be 3.3x10(2), 1.4x10(2) and 4.0x10(1) M-1 respectively, suggesting that the
CBD can accommodate at least six glucose molecules and has a much higher affinity
for insoluble cellulose than soluble oligosaccharides. Fusion of either the
CELECBD or XYLACBD to the catalytic domain of EGE potentiated the activity of the
enzyme against insoluble forms of cellulose but not against
carboxymethylcellulose. The increase in cellulase activity was not observed when
the CBDs were incubated with the catalytic domain of either EGE or XYLA, with
insoluble cellulose and a cellulose/hemicellulose complex respectively as the
substrates. Pseudomonas CBDs did not induce the extension of isolated plant cell
walls nor weaken cellulose paper strips in the same way as a class of plant cell
wall proteins called expansins. The XYLACBD and CELECBD did not release small
particles from the surface of cotton. The significance of these results in
relation to the mode of action of Type II CBDs is discussed.
PMID- 9560306
TI - Thiol-independent interaction of protein disulphide isomerase with type X
collagen during intra-cellular folding and assembly.
AB - Protein disulphide isomerase (PDI) has been shown to be a multifunctional protein
capable of catalysing disulphide-bond formation and isomerization, and of
participating as a non-catalytic subunit of prolyl 4-hydroxylase (P4-H) and
microsomal triacylglycerol transfer protein. It has also been proposed to
function as a molecular chaperone during the refolding of denatured proteins in
vitro. To investigate its potential role as a molecular chaperone within a
cellular context, we studied the folding, modification and assembly of type X
collagen in semi-permeabilized cells. Using this approach, we demonstrate that
depletion of ATP has no effect on the rate or extent of helix formation,
indicating that the individual triple helical regions do not interact with the
molecular chaperone immunoglobulin heavy-chain binding protein (BiP). However,
PDI was shown to interact transiently with type X during helix formation in a
role related to its function as the beta subunit of P4-H. Once the collagen
triple helix was formed, PDI re-associated, indicating a role in preventing the
premature assembly of this molecule into higher-order structures. This
interaction was not thiol dependent, as a type X polypeptide that did not contain
any cysteine residues was able to fold correctly and interact with PDI. Both PDI
and the collagen-binding protein hsp47 showed a similar pH-dependent interaction
with folded collagen, dissociating when the pH was lowered to pH 6.0. These
results suggest a role for PDI in chaperoning type X collagen during its
transport through the cell.
PMID- 9560307
TI - Effects of pH on the structure and function of neuronal nitric oxide synthase.
AB - We investigated how pH affects rat brain neuronal nitric oxide synthase (nNOS)
with regard to spin-state equilibrium and the thiolate ligand bond of the haem
group, catalytic activity, and monomerleft and right arrow dimer equilibrium. At
neutral pH, nNOS containing 1 equiv. of (6R)-5,6,7,8-tetrahydro-l-biopterin (BH4)
per dimer was mostly high-spin (lambdamax at 398 nm), whereas the BH4-free enzyme
consisted of a mixture of the high-spin and two low-spin forms (lambdamax at 418
nm, and at 376 and 456 nm respectively). With BH4-free nNOS, an appreciable high
spin fraction was only observed between pH 7 and 8; at pH 6 and 9, the 418 and
376/456 nm low-spin forms predominated respectively. With nNOS containing 1
equiv. of BH4 per dimer, similar observations were made, but these involved only
half of the enzyme; the other half, presumably the BH4-containing subunits,
remained high-spin. Since the spin state in the BH4-free subunit appeared little
affected by the state of the other subunit, we conclude that, in dimeric nNOS,
the two haem groups function independently. Low pH destabilized thiolate binding
and the interaction between NOS subunits, as indicated by CO-binding studies and
gel electrophoresis respectively. Formation of l-citrulline was optimal between
pH 7.0 and 7.5; the decrease in NOS activity at lower pH proved to be due to
uncoupling of NADPH oxidation, resulting in increased formation of H2O2. At high
pH strict coupling of l-arginine and NADPH oxidation was maintained, even in the
absence of exogenous BH4. The possible pathophysiological implications of the
uncoupling at low pH are discussed.
PMID- 9560305
TI - Determinants of the substrate specificity of human cytochrome P-450 CYP2D6:
design and construction of a mutant with testosterone hydroxylase activity.
AB - Cytochrome P-450 CYP2D6, human debrisoquine hydroxylase, metabolizes more than 30
prescribed drugs, the vast majority of which are small molecules containing a
basic nitrogen atom. In contrast, the similar mouse protein Cyp2d-9 was first
characterized as a testosterone 16alpha-hydroxylase. No common substrates have
been reported for the two enzymes. Here we investigate the structural basis of
this difference in substrate specificity. We have earlier used a combination of
NMR data and homology modelling to generate a three-dimensional model of CYP2D6
[Modi, Paine, Sutcliffe, Lian, Primrose, Wolf, C.R. and Roberts (1996)
Biochemistry 35, 4541-4550]. We have now generated a homology model of Cyp2d-9
and compared the two models to identify specific amino acid residues that we
believe form the substrate-binding site in each protein and therefore influence
catalytic selectivity. Although there are many similarities in active site
structure, the most notable difference is a phenylalanine residue (Phe-483) in
CYP2D6, which in the model is located such that the bulky phenyl ring is
positioned across the channel mouth, thus limiting the size of substrate that can
access the active site. In Cyp2d-9, the corresponding position is occupied by an
isoleucine residue, which imposes fewer steric restraints on the size of
substrate that can access the active site. To investigate whether the amino acid
residue at this position does indeed influence the catalytic selectivity of these
enzymes, site-directed mutagenesis was used to change Phe-483 in CYP2D6 to
isoleucine and also to tryptophan. CYP2D6, Cyp2d-9 and both mutant CYP2D6
proteins were co-expressed with NADPH cytochrome P-450 reductase as a functional
mono-oxygenase system in Escherichia coli and their relative catalytic activities
towards bufuralol and testosterone were determined. All four proteins exhibited
catalytic activity towards bufuralol but only Cyp2d-9 catalysed the formation of
16alpha-hydroxytesterone. Uniquely, the CYP2D6F483I mutant acquired the ability
to metabolize testosterone to a novel product, which was identified by MS and
proton NMR spectroscopy as 15alpha-hydroxytestosterone. NMR spin relaxation
experiments were used to measure distances between the haem iron and protons of
testosterone bound to the CYP2D6F483I mutant. These experiments demonstrate that
very minor modifications to the active site structure of CYP2D6 can have a
profound influence on the substrate specificity of the enzyme.
PMID- 9560309
TI - Somatotropin-dependent decrease in fatty acid synthase mRNA abundance in 3T3
F442A adipocytes is the result of a decrease in both gene transcription and mRNA
stability.
AB - Somatotropin (ST) markedly decreases lipogenesis, fatty acid synthase (FAS)
enzyme activity and mRNA abundance in pig adipocytes. The present study was
conducted to determine whether the decrease in FAS mRNA in 3T3-F442A adipocytes
was the result of a decrease in transcription of the FAS gene and/or a change in
FAS mRNA stability. Insulin increased the abundance of FAS mRNA 2-13-fold and
fatty acid synthesis 3-7-fold. Somatotropin decreased the stimulatory effect of
insulin on the abundance of FAS mRNA and lipogenesis by 40-70% and 20-60%
respectively. Subsequent run-on analyses demonstrated that the decrease observed
in FAS mRNA in response to ST was associated with an 82% decrease in
transcription; ST significantly shortened the half-life of FAS mRNA from 35 to 11
h. To corroborate the run-on analyses, cells were stably transfected with a pFAS
CAT5 (in which CAT stands for chloramphenicol acetyltransferase) reporter
construct that contained 2195 bp of the 5' flanking region of the rat FAS gene.
Insulin treatment increased FAS-CAT activity 4.7-fold. When ST was added to the
insulin-containing medium there was an approx. 60% reduction in FAS-CAT activity.
In summary, our results indicate that ST decreases FAS mRNA levels and that this
is the result of a marked decrease in both transcription of the FAS gene and
stability of the FAS mRNA.
PMID- 9560308
TI - A novel assay in vitro of human islet amyloid polypeptide amyloidogenesis and
effects of insulin secretory vesicle peptides on amyloid formation.
AB - Human islet amyloid polypeptide (IAPP) is a 37-residue peptide that is co
secreted with insulin by the beta-cell and might be involved in the pathogenesis
of non-insulin-dependent diabetes mellitus. We developed an improved assay in
vitro based on the fluorescence of bound thioflavin T to study factors affecting
amyloidogenesis. Monomeric IAPP formed amyloid fibrils, as detected by increased
fluorescence and by electron microscopy. Fluorimetric analysis revealed that the
initial rate of amyloid formation was: (1) proportional to the peptide monomer
concentration, (2) maximal at pH 9.5, (3) maximal at 200 mMKCl, and (4)
proportional to temperature from 4 to 37 degreesC. We found that 5-fold and 10
fold molar excesses of proinsulin inhibited fibril formation by 39% and 59%
respectively. Insulin was somewhat more potent with 5-fold and 10-fold molar
excesses inhibiting fibril formation by 69% and 73% respectively, whereas C
peptide had no effect at these concentrations. Thus at physiological ratios of
IAPP to insulin, insulin and proinsulin, but not C-peptide, can retard
amyloidogenesis. Because insulin resistance or hyperglycaemia increase the IAPP
to-insulin ratio, increased intracellular IAPP compared with insulin expression
in genetically predisposed individuals might contribute to intracellular amyloid
formation, beta-cell death and the genesis of non-insulin-dependent diabetes
mellitus.
PMID- 9560310
TI - Regulation of integrin function: evidence that bivalent-cation-induced
conformational changes lead to the unmasking of ligand-binding sites within
integrin alpha5 beta1.
AB - The molecular mechanisms that regulate integrin-ligand binding are unknown;
however, bivalent cations are essential for integrin activity. According to
recent models of integrin tertiary structure, sites involved in ligand
recognition are located on the upper face of the seven-bladed beta-propeller
formed by the N-terminal repeats of the alpha subunit and on the von Willebrand
factor A-domain-like region of the beta subunit. The epitopes of function
altering monoclonal antibodies (mAbs) cluster in these regions of the alpha and
beta subunits; hence these mAbs can be used as probes to detect changes in the
exposure or shape of the ligand-binding sites. Bivalent cations were found to
alter the apparent affinity of binding of the inhibitory anti-alpha5 mAbs JBS5
and 16, the inhibitory anti-beta1 mAb 13, and the stimulatory anti-beta1 mAb
12G10 to alpha5 beta1. Analysis of the binding of these mAbs to alpha5beta1 over
a range of Mn2+, Mg2+ or Ca2+ concentrations demonstrated that there was a
concordance between the ability of cations to elicit conformational changes and
the ligand-binding potential of alpha5 beta1. Competitive ELISA experiments
provided evidence that the domains of the alpha5 and beta1 subunits recognized by
mAbs JBS5/16 and 13/12G10 are spatially close, and that the distance between
these two domains is increased when alpha5 beta1 is occupied by bivalent cations.
Taken together, our findings suggest that bivalent cations induce a
conformational relaxation in the integrin that results in exposure of ligand
binding sites, and that these sites lie near an interface between the alpha
subunit beta-propeller and the beta subunit putative A-domain.
PMID- 9560312
TI - Differential regulation of nicotinic acid-adenine dinucleotide phosphate and cADP
ribose production by cAMP and cGMP.
AB - The sea urchin egg has been used as a system to study calcium-release mechanisms
induced by inositol 1,4,5-trisphosphate (IP3), cADP-ribose (cADPR), and more
recently, nicotinic acid-adenine dinucleotide phosphate (NAADP). In order that
cADPR and NAADP may be established as endogenous messengers for calcium release,
the existence of intracellular enzymes capable of metabolizing these molecules
must be demonstrated. In addition, intracellular levels of cADPR and NAADP should
be under the control of extracellular stimuli. It has been shown that cGMP
stimulates the synthesis of cADPR in the sea urchin egg. The present study shows
that the sea urchin egg is capable of synthesizing and degrading NAADP. cADPR and
NAADP synthetic activities appear to be separate, with different cellular
localizations, pH and temperature optima. We suggest that in the sea urchin egg,
cADPR and NAADP production may be differentially regulated by receptor-coupled
second messengers, with cADPR production being regulated by cGMP and NAADP
production modulated by cAMP.
PMID- 9560313
TI - Organization and alternative splicing of the murine phospholipase D2 gene.
AB - Phospholipase D (PLD) catalyses the hydrolysis of phosphatidylcholine, generating
phosphatidic acid and choline. Mammalian PLD activity derives from a family of
membrane-associated enzymes that are activated by a wide variety of signal
transduction events. cDNA species encoding human, mouse and rat PLD1 and PLD2
have recently been reported. In this study we undertook to determine the
organization of the mouse PLD2 gene. We report that the gene spans 17.1 kb and
contains 25 exons. Mouse PLD2 is notable for a relatively GC-rich and large 5'
untranslated region. Proximal promoter sequences upstream of the first exon
contain several consensus SP1 sequences (GGGCGG) but lack TATA and CAAT boxes.
Finally, alternatively spliced cDNA species identified for PLD1 and PLD2 are
discussed in the context of the PLD2 genomic organization.
PMID- 9560311
TI - Multiple endosomal recycling pathways in rat adipose cells.
AB - Adipose and skeletal-muscle cells can translocate several membrane proteins from
intracellular compartment(s) to the cell surface in an insulin-dependent fashion.
Among these proteins is Glut4, a physiologically important glucose transporter
which mediates insulin's effect on blood glucose clearance. Under basal
conditions, Glut4 is localized in uniform, intracellular membrane vesicles with
an average diameter of 50-70 nm and a sedimentation coefficient of 100-120 S. The
nature of this compartment and its trafficking pathway to the plasma membrane is
still unresolved. We show here that, in addition to Glut4, the aminopeptidase
gp160 or insulin-responsive aminopeptidase ('IRAP'), sortilin, and an acutely
recycling population of the insulin-like growth factor-II/mannose 6-phosphate
receptor, this compartment includes 60% of the intracellular population of the
transferrin receptor. We used subcellular fractionation, cell-surface
biotinylation, and radioactive-ligand (125I-transferrin) uptake to demonstrate
that the transferrin receptor recycles between this compartment and the plasma
membrane in response to insulin along with Glut4 and other protein components of
these vesicles. The co-localization of Glut4 and several endosomal markers in the
terminally differentiated fat-cells during several stages of their cycling
pathways suggests that the 'Glut4 pathway' may derive from the hormone
insensitive endosomes of undifferentiated preadipocytes. The insulin receptor is
excluded from Glut4-containing vesicles in both insulin-stimulated and
unstimulated adipocytes, and thus it is likely to traffic independently from
Glut4 through different intracellular compartments. Our data show that, in
adipose cells, the ligand-dependent recycling pathway of the insulin receptor is
structurally separated from the ligand-independent pathway of the transferrin
receptor, and that Glut4 is specifically targetted to the latter.
PMID- 9560314
TI - Ambient but not incremental oxidant generation effects intercellular adhesion
molecule 1 induction by tumour necrosis factor alpha in endothelium.
AB - Proinflammatory cytokines upregulate endothelial adhesion molecule expression,
thereby initiating the microvascular inflammatory response. We re-evaluated the
reported role of reactive oxygen metabolites (ROMs) in signalling upregulation of
intercellular adhesion molecule 1 (ICAM-1) on endothelial cells by tumour
necrosis factor alpha (TNF-alpha) in vitro. TNF-alpha upregulation of endothelial
cell ICAM-1 expression was inhibited by the cell-permeable antioxidants, or by
the adenovirus-mediated intracellular overexpression of Cu,Zn-superoxide
dismutase, but not by the exogenous (extracellular) administration of the cell
impermeable antioxidants, superoxide dismutase and/or catalase. This ICAM-1
upregulation was also inhibited by inhibitors of NADH dehydrogenase, cytochrome
bc1 complex and NADPH oxidase. However, a measurable increase in net cellular ROM
generation in response to TNF-alpha was not seen using four disparate sensitive
ROM assays. Moreover, the stimulation of exogenous or endogenous ROM generation
did not upregulate ICAM-1, nor enhance ICAM-1 upregulation by TNF-alpha. These
findings suggest that an ambient background flux of ROMs, generated
intracellularly, but not their net incremental generation, is necessary for TNF
alpha to induce ICAM-1 expression in endothelium in vitro.
PMID- 9560315
TI - Osmotic swelling-induced activation of the extracellular-signal-regulated protein
kinases Erk-1 and Erk-2 in intestine 407 cells involves the Ras/Raf-signalling
pathway.
AB - Human Intestine 407 cells respond to hypo-osmotic stress with a rapid stimulation
of compensatory ionic conductances accompanied by a transient increase in the
activity of the extracellular-signal-regulated protein kinases Erk-1 and Erk-2.
In this study, we examined the upstream regulators of hypotonicity-induced Erk
1/Erk-2 activation and their possible role in cell-volume regulation. The
hypotonicity-provoked Erk-1/Erk-2 activation was greatly reduced in cells
pretreated with the specific mitogen-activated/Erk-activating kinase inhibitor
PD098059 and was preceded by a transient stimulation of Raf-1. Pretreatment of
the cells with PMA, GF109203X, wortmannin or Clostridium botulinum C3 exoenzyme
did not appreciably affect the hypotonicity-provoked Erk-1/Erk-2 stimulation,
suggesting the osmosensitive signalling pathway to be largely independent of
protein kinase C and p21(rho). In contrast, expression of dominant negative
RasN17 completely abolished the hypotonicity-induced Erk-1/Erk-2 activation.
Stimulation of the swelling-induced ion efflux was independent of activation of
these mitogen-activated protein kinases, as revealed by hypotonicity-provoked
isotope efflux from 125I-- and 86Rb+-loaded cells after pretreatment with
PD098059 and after expression of RasN17. In addition, the epidermal-growth-factor
induced potentiation of the hypotonicity-provoked anionic response did not depend
on the increase in Erk-1/Erk-2 activity but, instead, was found to depend on Ca2+
influx. Taken together, these results indicate that hypotonic stress induces Erk
1/Erk-2 activation through the Ras/Raf-signalling pathway, and argue against a
direct role for this pathway in cell-volume control.
PMID- 9560316
TI - Cloning and expression of a cDNA encoding a new neurocalcin isoform (neurocalcin
alpha) from bovine brain.
AB - Neurocalcin (NC), a neuron-specific EF-hand Ca2+-binding protein, purified from
bovine brain [Terasawa, Nakano, Kobayashi and Hidaka (1992) J. Biol. Chem. 267,
19596-19599] contains multiple isoforms. We previously cloned NCdelta from bovine
brain and showed high expression in neuronal tissues [Okazaki, Watanabe, Ando,
Hagiwara, Terasawa and Hidaka (1992) Biochem. Biophys. Res. Commun. 185, 147
153]. We report here the molecular cloning and expression of a cDNA encoding
bovine brain NCalpha. The translated bovine protein is 191 amino acids long and
shares 69.1% of its amino acid sequence with NCdelta. Recombinant NCalpha
migrates as a single 23 kDa band and exhibits a Ca2+-dependent mobility shift on
SDS/PAGE. Analysis of fluorescence emission spectra showed the Ca2+-induced peak
at 337 nm. Interestingly, the mobility shift and the fluorescence intensity at
337 nm were larger for NCalpha than for NCdelta. In Ca2+-overlay experiments,
however, the apparent affinity of NCalpha for 45Ca2+ was similar to that of
NCdelta. Immunohistochemical analysis revealed NCalpha expression in the granular
layer of the rat cerebellar cortex whereas NCdelta was found in the Purkinje cell
layer. In the rat olfactory bulb, NCalpha was located in external tufted cells,
and NCdelta was found in the periglomerular cells. These data demonstrate that NC
isoforms differ in their tissue distribution and conformational changes induced
by Ca2+ binding. Thus differential regulation of the two NC isoforms may be
involved in control of neuron function.
PMID- 9560317
TI - Metabolic control analysis of the bc1 complex of Saccharomyces cerevisiae: effect
on cytochrome c oxidase, respiration and growth rate.
AB - A number of strains varying in steady-state level of assembled bc1 complex were
used to test the conclusions from inhibitor titration experiments with isolated
mitochondria that, in cells of Saccharomyces cerevisiae grown on non-fermentable
carbon sources, the control coefficient of the bc1 complex on the mitochondrial
respiratory capacity equals 1 and the respiratory chain consists of
supermolecular respiratory units [Boumans, Grivell and Berden (1998) J. Biol.
Chem. 273, 4872-4877]. In addition, the control coefficient of mitochondrial
respiration on the growth rate was determined. It was found that a reduced level
of bc1 complex is accompanied by an almost parallel decrease in steady-state
level of cytochrome c oxidase. Since the linear relationship between level of
active bc1 complex and respiratory capacity still holds, it is concluded that
cytochrome c oxidase has disappeared from respiratory units that are already
deficient in the bc1 complex and that the cytochrome c oxidase in a respiratory
unit is destabilized when the bc1 complex is deficient. The control coefficient
of the bc1 complex, and thus of mitochondrial electron-transfer capacity, on
respiration of intact cells (without uncoupler added) is 0.20. Addition of
uncoupler results in an increase in the coefficient to 0.36. Thus changing the
respiratory state changes the distribution of control, increasing the control
coefficient of electron-transfer activity as the respiratory state goes towards
State 3u. Rates of growth of the strains on different carbon sources were
determined and subsequently fitted to calculate control coefficients of the bc1
complex (and therefore of the respiratory capacity) on growth. Little variation
was found between lactate-, ethanol- and glycerol-containing media, control
coefficients being around 0.18 at pH 5. At pH 7 the control coefficient increased
to 0.57, indicative of a higher dependence of the cell on ATP derived from
oxidative phosphorylation. During growth on glucose-containing medium, the bc1
complex has no control on the growth rate, as indicated by the fact that all
strains, including a respiratory-deficient strain, grow as fast as the wild-type.
However, the presence of respiratory capacity in the wild-type does result in a
higher growth yield compared with the respiratory-deficient strain, indicating
that, in contrast with what is generally assumed, in S. cerevisiae the 'Pasteur
effect' is not restricted to special experimental conditions.
PMID- 9560318
TI - LIM domains of cysteine-rich protein 1 (CRP1) are essential for its zyxin-binding
function.
AB - Previous studies have demonstrated that the adhesion-plaque protein, zyxin,
interacts specifically with a 23 kDa protein, called the cysteine-rich protein 1
(CRP1), which has been implicated in myogenesis. Primary sequence analyses have
revealed that both zyxin and CRP1 exhibit multiple copies of a structural motif
called the LIM domain. LIM domains, which are defined by the consensus CX2CX16
23HX2CX2CX2CX16-23CX2-3(C,H,D), are found in a variety of proteins that are
involved in cell growth and differentiation. Recent studies have established that
LIM domains are zinc-binding structures that mediate specific protein-protein
interactions. For example, in the case of the zyxin-CRP1 interaction, one of
zyxin's three LIM domains is necessary and sufficient for binding to CRP1.
Because the CRP1 molecule is comprised primarily of two LIM domains, we were
interested in the possibility that the binding site for zyxin on CRP1 might also
be contained within a single LIM domain. Consistent with the hypothesis that the
LIM domains of CRP1 are critical for the protein's zyxin-binding function, zinc
depleted CRP1 displays a reduced zyxin-binding activity. However, domain mapping
analyses have revealed that neither of the two individual LIM domains of CRP1 can
support a wild-type interaction with zyxin. Collectively, our results suggest
that the binding site for zyxin on CRP1 is not contained within a single
contiguous sequence of amino acids. Instead, the interaction appears to rely on
the co-ordinate action of a number of residues that are displayed in both of
CRP1's LIM domains.
PMID- 9560319
TI - Alanine-261 in intracellular loop III of the human gonadotropin-releasing hormone
receptor is crucial for G-protein coupling and receptor internalization.
AB - Gonadotropin-releasing hormone (GnRH) is a decapeptide that regulates
reproductive function via binding to the GnRH receptor, which is a G-protein
coupled receptor (GPCR). For several members of this family, the C-terminal
domain of intracellular loop III is important in ligand-mediated coupling to G
proteins; mutations in that region can lead to constitutive activity. A specific
alanine residue is involved in certain GPCRs, the equivalent of which is Ala-261
in the GnRH receptor. Mutation of this residue to Leu, Ile, Lys, Glu or Phe in
the human GnRH receptor did not result in constitutive activity and instead led
to complete uncoupling of the receptor (failure to support GnRH-stimulated
inositol phosphate production). When this residue was mutated to Gly, Pro, Ser or
Val, inositol phosphate production was still supported. All the mutants retained
the ability to bind ligand, and the affinity for ligand, where measured, was
unchanged. These results show that Ala-261 cannot be involved in ligand binding
but is critical for coupling of the receptor to its cognate G-protein. Coupling
is also dependent on the size of the residue in position 261. When the amino acid
side chain has a molecular mass of less than 40 Da efficient coupling is still
possible, but when its molecular mass exceeds 50 Da the receptor is uncoupled.
Internalization studies on the Ala261-->Lys mutant showed a marked decrease in
receptor internalization compared with the wild type, indicating that coupling is
necessary for effective receptor internalization in the GnRH receptor system.
Activation of protein kinase C (with PMA), but not protein kinase A (with
forskolin) markedly increased the internalization of the mutant receptor while
having a small effect on the wild-type receptor.
PMID- 9560320
TI - Periplasmic nitrate-reducing system of the phototrophic bacterium Rhodobacter
sphaeroides DSM 158: transcriptional and mutational analysis of the napKEFDABC
gene cluster.
AB - The phototrophic bacterium Rhodobacter sphaeroides DSM 158 is able to reduce
nitrate to nitrite by means of a periplasmic nitrate reductase which is induced
by nitrate and is not repressed by ammonium or oxygen. Recently, a 6.8 kb PstI
DNA fragment carrying the napABC genes coding for this periplasmic nitrate
reducing system was cloned [Reyes, Roldan, Klipp, Castillo and Moreno-Vivian
(1996) Mol. Microbiol. 19, 1307-1318]. Further sequence and genetic analyses of
the DNA region upstream from the napABC genes reveal the presence of four
additional nap genes. All these R. sphaeroides genes seem to be organized into a
napKEFDABC transcriptional unit. In addition, a partial open reading frame
similar to the Azorhizobium caulinodans yntC gene and the Escherichia coli yjcC
and yhjK genes is present upstream from this nap gene cluster. The R. sphaeroides
napK gene codes for a putative 6.3 kDa transmembrane protein which is not similar
to known proteins and the napE gene codes for a 6.7 kDa transmembrane protein
similar to the Thiosphaera pantotropha NapE. The R. sphaeroides napF gene product
is a 16.4 kDa protein with four cysteine clusters that probably bind four [4Fe
4S] centres. This iron-sulphur protein shows similarity to the NapF and NapG
proteins of E. coli and Haemophilus influenzae. Finally, the napD gene product is
a 9.4 kDa soluble protein which is also found in E. coli and T. pantotropha. The
5' end of the nap transcript has been determined by primer extension, and a
sigma70-like promoter has been identified upstream from the napK gene. The same
transcriptional start site is found for cells growing aerobically or
anaerobically with nitrate. Different mutant strains carrying defined polar and
non-polar insertions in each nap gene were constructed. Characterization of these
mutant strains demonstrates the participation of the nap gene products in the
periplasmic nitrate reduction in R. sphaeroides.
PMID- 9560321
TI - Interaction of macrophage-migration-inhibitory factor with haematin.
AB - Macrophage-migration-inhibitory factor (MIF) is retained by S-hexylglutathione
agarose but is not specifically eluted in high yield. Human liver MIF was
purified in high yield using retention by phenyl-agarose at low ionic strength
and cation-exchange FPLC as described for bovine lens MIF [Rosengren, Bucala,
Aman, Jacobsson, Odh, Metz and Rorsman (1996) Mol. Med. 2, 143-149]. The l
dopachrome methyl ester tautomerase activity of human liver MIF was not inhibited
by a variety of glutathione S-conjugates, eicosanoids or glucocorticoids but was
very sensitive to inhibition by haematin (IC50 100-200 nM). The inhibition was
non-competitive and showed positive co-operativity (h=5.8). Similar sensitivity
to haematin was obtained with purified recombinant human MIF. The sensitivity of
MIF to haematin is approx. 1000-fold greater than for any previously described
ligands, and is within its physiological range. Therefore the interaction is
likely to be important in modulating the function of MIF in the initiation of
immune responses.
PMID- 9560322
TI - Synergistic transcriptional activation of the mouse urokinase plasminogen
activator (uPA) gene and of its enhancer activator protein 1 (AP1) site by cAMP
and retinoic acid.
AB - We have investigated the mechanism whereby all-trans retinoic acid (tRA)
potentiates the 8-bromo-cAMP (8-BrcAMP)-dependent transcription of the urokinase
plasminogen activator (uPA) gene in SC115 mouse mammary carcinoma cells.
Photoaffinity labelling experiments showed that tRA did not alter the cellular
content of cAMP-dependent protein kinase regulatory subunits I and II. In
agreement with this, nuclear run-on analysis in the presence of the translational
inhibitor puromycin demonstrated that the effect of 8-BrcAMP and its potentiation
by tRA were independent of protein synthesis. A transiently transfected 6.6 kb
uPA 5'-flanking region-chloramphenicol acetyltransferase (CAT) fusion gene
mimicked the response of the endogenous uPA gene. Thus 1 mM 8-BrcAMP induced a
100-200% increase in CAT content, 100 nM tRA had no effect and 100 nM tRA+1 mM 8
BrcAMP induced a 300-500% increase in cells co-transfected with tRA receptor
and/or 9-cis-RA receptor. Analysis of 5'-deleted constructs showed that the tRA
effect required at least two cis regions: -2657 to -2186, encompassing the 100 bp
uPA enhancer, and -709 to -324, which exhibited silencing activity. Neither
region contained a tRA-response element-like motif. Because tRA receptor and 9
cis-RA receptor interact with activator protein 1 (AP1), we tested whether tRA
regulated the uPA enhancer AP1 site in the presence of 8-BrcAMP. We found that a
dimer of this site fused to a minimal uPA-CAT fusion gene was responsive to 1 mM
8-BrcAMP (100% CAT increase), not responsive to 100 nM tRA, and synergistically
responsive to 100 nM tRA+1 mM 8-BrcAMP (240% CAT increase) in cells co
transfected with Fos and Jun. Synergistic activation of the same construct and of
the 6.6 kb uPA-CAT fusion gene was also obtained using tRA and 100 nM PMA. We
conclude that multiple cis elements, probably including the uPA enhancer AP1
site, mediate the tRA potentiation of uPA transcription.
PMID- 9560324
TI - Protein heterogeneity of spinach pullulanase results from the coexistence of
interconvertible isomeric forms of the monomeric enzyme.
AB - Purified pullulanase (starch-debranching enzyme, R-enzyme, EC 3.2.1. 41) from
spinach (Spinacia oleracea L.) chloroplasts separated into at least seven
individual enzymically active proteins (isomers, numbered 1-7) on isoelectric
focusing or column chromatofocusing. At their isoelectric points (between pH 4.7
and 5.2) these forms were rather stable. At slightly alkaline pH, each converted
into the whole set of isomers. PAGE of the purified enzyme under denaturing or
non-denaturing conditions resulted in one protein band. When substrate
(amylopectin or pullulan) was included in the gel, the native enzyme as well as
any of the individual isomers separated into two (sometimes three) bands
('substrate-induced forms', numbered I-III) with different specific activities,
dissociation constants of the enzyme-substrate complexes and activation energies.
Each substrate-induced form produced the whole set of seven isomers on
isoelectric focusing. The specific activity of the total enzyme reflected the
relative proportions of the substrate-induced forms. To some extent the relative
proportions, as determined by crossed immunoelectrophoresis, could be shifted in
favour of the more or the less active forms by reduction with dithiothreitol, and
gentle oxidation respectively. Activation by dithiothreitol did not alter the
mode of action of the enzyme but only increased the velocity of substrate
degradation and extended its activity into the pH range of the chloroplast. As a
consequence of isomer interconversion, microheterogeneity could serve to regulate
pullulanase activity in a biochemical manner that shares some features with
allosteric regulation.
PMID- 9560325
TI - cDNA sequence and heterologous expression of monomeric spinach pullulanase:
multiple isomeric forms arise from the same polypeptide.
AB - The spinach pullulanase gene was cloned and sequenced using peptide sequences of
the purified enzyme as a starting point and employing PCR techniques and cDNA
library screening. Its open reading frame codes for a protein of 964 amino acids
which represents a precursor of the pullulanase. The N-terminal transit peptide
consists of 65 amino acids, and the mature protein, comprising 899 amino acids,
has a calculated molecular mass of 99kDa. Pullulanase is a member of the alpha
amylase family. In addition to a characteristic catalytic (beta/alpha)8-barrel
domain, it contains a domain, F, that is specific for branching and debranching
enzymes. Pullulanase cDNA was expressed in Escherichia coli, and the purified
protein was compared with the enzyme from spinach leaves. Identity of the two
proteins was confirmed in terms of catalytic properties, N-terminal amino acid
sequences and molecular masses. The pullulanase produced by E. coli showed the
same microheterogeneity as the spinach leaf enzyme: it could be resolved into two
substrate-induced forms by electrophoresis in amylopectin-containing
polyacrylamide gels, and, in the absence of substrate, into several free forms
(charge isomers) by isoelectric focusing or chromatofocusing. Rechromatofocusing
of single free forms resulted in the originally observed pattern of molecular
forms. However, heterogeneity of the protein disappeared on isoelectric focusing
under completely denaturing conditions when only one protein band was observed.
Post-translational modifications such as glycosylation and phosphorylation could
be excluded as potential explanations for the protein heterogeneity. Therefore
the microheterogeneity of spinach leaf pullulanase results from neither genetic
variation nor post-translational modifications, but is a property of the single
unmodified gene product. The different interconvertible forms of the pullulanase
represent protein populations of different tertiary structure of the same
polypeptide.
PMID- 9560323
TI - Actin filaments participate in the relocalization of phosphatidylinositol3-kinase
to glucose transporter-containing compartments and in the stimulation of glucose
uptake in 3T3-L1 adipocytes.
AB - Insulin stimulates the rate of glucose uptake into muscle and adipose cells by
translocation of glucose transporters from an intracellular storage pool to the
plasma membrane. This event requires the prior activation of phosphatidylinositol
3-kinase (PI 3-kinase). Here we report that insulin causes an increase in
wortmannin-sensitive PI 3-kinase activity and a gain in the enzyme's regulatory
and catalytic subunits p85alpha and p110beta (but not p110alpha) in the
intracellular compartments containing glucose transporters. The hormone also
caused a marked reorganization of actin filaments, which was prevented by
cytochalasin D. Cytochalasin D also decreased significantly the insulin-dependent
association of PI 3-kinase activity and the levels of insulin receptor substrate
(IRS)-1, p85alpha and p110beta with immunopurified GLUT4-containing compartments.
In contrast, the drug did not alter the insulin-induced tyrosine phosphorylation
of IRS-1, the association of PI 3-kinase with IRS-1, or the stimulation of PI 3
kinase by insulin in anti-(IRS-1) or anti-p85 immunoprecipitates from whole cell
lysates. Cytochalasin D, and the chemically unrelated latrunculin B, which also
inhibits actin filament reassembly, prevented the insulin stimulation of glucose
transport by approx. 50%. Cytochalasin D decreased by about one-half the insulin
dependent translocation to the plasma membrane of the GLUT1 and GLUT4 glucose
transporters. The results suggest that the existence of intact actin filament is
correlated with the full recruitment of glucose transporters by insulin. The
underlying function of the actin filaments might be to facilitate the insulin
mediated association of the p85-p110 PI 3-kinase with glucose-transporter
containing compartments.
PMID- 9560327
TI - Molecular cloning and expression of a cDNA encoding an olfactory-specific mouse
phenol sulphotransferase.
AB - Previously we demonstrated the presence of phenol sulphotransferase (P-ST) in
mouse nasal cytosols and identified its zonal location in mouse nasal cavity by
staining with an antiserum raised against a rat liver P-ST isoenzyme, PSTg. In
the present study a cDNA was isolated from a mouse olfactory cDNA library by
immunological screening with the antiserum. The isolated cDNA consisted of 1347
bp with a 912 bp open reading frame encoding a 304-residue polypeptide. Both the
nucleotide and deduced amino acid sequences of the cDNA were 94% identical with
those of a rat liver P-ST isoenzyme, ST1C1. The expressed enzyme in Escherichia
coli displayed high P-ST activity towards phenolic odorants such as eugenol and
guaiacol, and it showed a high N-hydroxy-2-acetylaminofluorene sulphation
activity in comparison with the rat ST1C1 enzyme. These results indicate that the
olfactory P-ST encoded by the cDNA is a mouse orthologue of rat ST1C1; however,
expression of the olfactory P-ST mRNA is specific for nasal tissues as revealed
by reverse transcriptase-mediated PCR (RT-PCR).
PMID- 9560326
TI - Modulation of Ins(2,4,5)P3-stimulated Ca2+ mobilization by ins(1,3,4, 5)P4:
enhancement by activated G-proteins, and evidence for the involvement of a GAP1
protein, a putative Ins(1,3,4,5)P4 receptor.
AB - We have previously shown that addition of Ins(1,3,4,5)P4 to permeabilized L1210
cells increases the amount of Ca2+ mobilized by a submaximal concentration of
Ins(2,4,5)P3, and we suggested that, in doing this, Ins(1,3,4,5)P4 is not working
via an InsP3 receptor but indirectly via an InsP4 receptor [Loomis-Husselbee,
Cullen, Dreikhausen, Irvine and Dawson (1996) Biochem. J. 314, 811-816]. Here we
have investigated whether this effect might be mediated by GAP1(IP4BP), recently
identified as a putative receptor for Ins(1,3, 4,5)P4. GAP1(IP4BP) is a protein
that interacts with one or more monomeric G-proteins, so we sought evidence for
involvement of monomeric G-proteins in the effects of Ins(1,3,4,5)P4 in
permeabilized L1210 cells. Guanosine 5'-[gamma-thio]triphosphate (GTP[S])
enhanced the effect of Ins(1,3,4,5)P4 on Ins(2,4, 5)P3-stimulated Ca2+
mobilization, but had no effect on the action of Ins(2,4,5)P3 alone. A specific
enhancement of only the action of Ins(1,3,4,5)P4 was also seen with GTP[S]-loaded
R-Ras or Rap1a (two G-proteins known to interact with GAP1(IP4BP)), whereas H-Ras
was inactive at similar concentrations. Guanosine 5'-[beta-thio]diphosphate
(GDP[S]) did not alter the action of either Ins(2,4,5)P3 or Ins(1,3,4,5)P4.
Finally, the addition of exogenous GAP1(IP4BP), purified from platelets, markedly
enhanced the effect of Ins(1,3,4,5)P4, and again, the amount of Ca2+ mobilized by
Ins(2,4,5)P3 alone was unaltered. We conclude that the increase in Ins(2,4,5)P3
stimulated Ca2+ mobilization by Ins(1,3,4, 5)P4 may be mediated by GAP1(IP4BP) or
a closely related protein (such as GAP1(m)), and if so, the action of the GAP1 is
not solely to regulate GTP loading of a G-protein, but rather it acts with a G
protein to cause its effect.
PMID- 9560328
TI - The gene structure and organization of mouse PG-Lb, a small chondroitin/dermatan
sulphate proteoglycan.
AB - PG-Lb was originally characterized as a small chondroitin/dermatan sulphate
proteoglycan expressed preferentially in the zones of flattened chondrocytes in
developing chick limb cartilage. The occurrence of this proteoglycan in mammalian
cartilage has been shown by the isolation of a cDNA clone from mouse cartilage
cDNA library [Kurita, Shinomura,Ujita, Zako, Kida, Iwata and Kimata (1996)
Biochem. J. 318, 909-914]. To understand the regulation mechanisms for such a
unique expression, we have investigated a genomic DNA structure of the PG-Lb
gene. The gene is composed of seven exons and six introns spanning more than 50
kb. The leucine-rich repeats are encoded from exon V to exon VII. The
transcription initiation site has been determined by rapid amplification of the
cDNA ends ('5'-RACE'). The possible TATA box was detected about 90 bp upstream of
the adenosine residue that was numbered as position +1. Further analyses of 1.5
kb of the 5' flanking region and 2.2 kb of the first intron have revealed several
potential binding motifs for transcription factors such as Sox 5 and 9. The
presence of those sequences in the PG-Lb gene was discussed in relation to the
unique expression of this proteoglycan. The chromosomal localization of the
murine PG-Lb gene was determined to be on the mouse chromosome 10 by the
fluorescence-in-situ-hybridization ('FISH') method.
PMID- 9560330
TI - Visual memory: what do you know about what you saw?
AB - Recent studies of visual perception are bringing us closer to an understanding of
what we remember - and what we forget - when we recall a scene.
PMID- 9560331
TI - Face processing: getting by with a little help from its friends.
AB - Functional imaging identified a putative face-specific area within the fusiform
gyrus of human visual cortex; the precise role of this area is still in question,
however, and recent imaging studies have implicated other cortical areas in face
processing. These studies show the dangers of considering a single cortical area
in isolation.
PMID- 9560329
TI - Activation of gelatinase-tissue-inhibitors-of-metalloproteinase complexes by
matrilysin.
AB - Matrilysin, gelatinase A and gelatinase B are matrix metalloproteinases (MMPs)
implicated in normal and pathological processes that require remodelling of the
extracellular matrix. In human prostate tissue, matrilysin is synthesized in
ducts surrounded by inflammatory cells, and focally in prostate carcinoma, but
not in normal glands. Gelatinase B expression is restricted to inflammatory
cells. Gelatinase A can be found in both benign and malignant prostate tissue.
MMP activities are regulated by their transition from latent to activated forms,
as well as by the presence of tissue inhibitors of metalloproteinases (TIMPs). We
investigated whether matrilysin can activate progelatinases A and B in the
presence of their bound inhibitors TIMP2 and TIMP1 respectively. Incubation of
progelatinase B-TIMP1 complex with active matrilysin resulted in 78 and 68 kDa
active forms, as measured by SDS-PAGE and enzyme activity assays. TIMP-free
gelatinase B was also activated by matrilysin. In addition, activation of
progelatinase B by matrilysin was demonstrated in the conditioned medium of
phorbol ester-treated HT1080 cells, confirming the results obtained in the in
vitro experiments. In contrast, matrilysin did not proteolytically cleave
gelatinase A-TIMP2 complex, but led to a transient increase in gelatinolytic
activity of the proenzyme. Matrilysin did not enhance the autocatalytic
conversion of its own proform. The data presented here suggest that matrilysin
participates in a proteolytic cascade and can activate gelatinases in the
presence of TIMPs.
PMID- 9560332
TI - Cell nucleus: chromosome dynamics in nuclei of living cells.
AB - Unraveling chromosome movements in vivo is indispensable for understanding the
functional architecture of the nucleus and its relationship to the functional
state of the cell. New experimental approaches have now made it possible to
monitor chromosome dynamics within the nuclei of living cells.
PMID- 9560333
TI - Neuronal regeneration: extending axons from bench to brain.
AB - Many studies have shown that myelin in the central nervous system strongly
inhibits the regeneration of axons, so it comes as a surprise to discover that
adult neurons transplanted into the brain rapidly extend their axons through
myelinated pathways.
PMID- 9560334
TI - G-protein signaling: fine-tuning signaling kinetics.
AB - Mammalian 'regulators of G protein signaling' (RGS proteins) help shut off G
protein-mediated signaling by GTPase activation. But new evidence shows that RGS
proteins can also speed up the activation of signaling. The combined effect is a
change in signaling kinetics without a decrease in signaling intensity.
PMID- 9560335
TI - Peroxisome biogenesis: back to the endoplasmic reticulum?
AB - Proteins are targeted to the membrane and matrix of peroxisomes by distinct
pathways. Recent observations suggest a further route: a subset of peroxisomal
membrane proteins might be targeted first to the endoplasmic reticulum, and from
there to peroxisomes by vesicle-mediated transport.
PMID- 9560336
TI - Protein folding: think globally, (inter)act locally.
AB - Protein folding appears to be almost too complex for a complete description or
for accurate structure prediction from sequence data. A simple way of analysing
local interactions, however, bears promise of linking theory with experiment and
cutting through some of the complexities.
PMID- 9560337
TI - Auxin signalling: protein stability as a versatile control target.
AB - Two components of an auxin signalling pathway in Arabidopsis have been found to
be homologous to budding yeast enzymes that are known to be involved in
regulating the stability of key cell-cycle regulatory proteins, such as the
cyclin-dependent kinase inhibitor Sic1p.
PMID- 9560338
TI - The malignant capacity of skin tumours induced by expression of a mutant H-ras
transgene depends on the cell type targeted.
AB - BACKGROUND: . Pinpointing the cells from which tumours arise is a major challenge
n tumour biology. Previous work has shown that the targeted expression of a
mutant ras gene within the interfollicular cell compartment of mouse skin induces
the formation of benign papillomas, but these do not spontaneously progress to
malignancy. We have investigated the carcinogenic effects of expressing the same
oncogene in a different population of epidermal cells. RESULTS: Expression of
mutant ras from a truncated keratin 5 gene promoter, which directs expression to
the follicular and interfollicular cells of newborn mice and the hair follicle
cells of adults, stimulated the development of acanthotic areas in newborn mice.
Within one week of birth, the acanthotic skin developed areas of carcinoma in
situ and adult mice developed papillomas and keratoacanthomas, the latter having
a high frequency of spontaneous malignant transformation to squamous and
occasionally spindle carcinomas. The benign tumours that arose had several
hallmarks of tumours at a high risk of malignant progression, including
suprabasal cell proliferation and heterogeneous expression of keratin 13. In
contrast to tumours induced by expressing mutant ras under the control of the
keratin 10 or keratin 1 gene promoters, the formation of these lesions was not
dependent on wounding or a tumour promoter. CONCLUSIONS: Benign tumours that are
at a risk of malignant conversion are primarily derived from cells located within
the hair follicle, and the nature of the cell in which tumour initiation occurs
is a major determinant of malignant potential.
PMID- 9560339
TI - Helios, a novel dimerization partner of Ikaros expressed in the earliest
hematopoietic progenitors.
AB - BACKGROUND: Normal hematopoietic development depends on the activity of the
Ikaros transcription factor, which contains distinct zinc-finger domains that
mediate DNA binding and protein dimerization. Mice homozygous for a transgene
encoding a dominant-negative version of Ikaros that lacks the DNA-binding domain
but not the dimerization domain have a more severe phenotype than Ikaros null
mice. This observation suggests the presence of factor(s) that can dimerize with
Ikaros and partially complement its function. One previously identified factor,
Aiolos, probably serves this role in the lymphoid system; a related factor
involved in hematopoietic progenitors remains unknown, however. RESULTS: Here, we
describe the cloning of an Ikaros-related gene, Helios. Analysis of the primary
sequences of Helios, Ikaros and Aiolos revealed that the DNA-binding,
transcriptional activation and dimerization domains are functionally conserved.
Helios activated transcription from Ikaros DNA-binding sites and could dimerize
with itself, Ikaros or Aiolos. Expression of Helios was detected in the earliest
hematopoietic sites of the embryo, in hematopoietic stem cells in the adult and
was subsequently restricted to a subset of cells in the T cell lineage. Helios co
localized with Ikaros and Aiolos proteins in macromolecular nuclear structures
and formed stable complexes in vivo with the dominant-negative version of Ikaros.
CONCLUSIONS: Distinct but overlapping expression patterns of members of the
Ikaros gene family during hematopoiesis might result in the formation of
different multimeric complexes that have specific roles in lineage progression.
The preferential expression of Helios in the earliest stages of hematopoiesis
suggests that this gene functions predominantly in early progenitors.
PMID- 9560340
TI - The interaction of the cell-contact proteins VASP and vinculin is regulated by
phosphatidylinositol-4,5-bisphosphate.
AB - BACKGROUND: Focal adhesion sites are cell-matrix contacts that are regulated by
phosphatidylinositol-4,5-bisphosphate (PIP2)-dependent pathways. Vinculin is a
major structural component of these sites and is thought to be engaged in
multiple ligand interactions at the cytoplasmic face of these contacts.
Cytoplasmic vinculin is considered to be inactive due to its closed conformation
involving intramolecular head-tail interactions. Recently, the vasodilator
stimulated phosphoprotein (VASP), a substrate of cyclic AMP-dependent or cyclic
GMP-dependent kinases and a component of focal adhesion sites, was shown to bind
to vinculin. RESULTS: VASP-vinculin complexes could be immunoprecipitated from
cell lysates and, using immunofluorescence, both proteins were found to
colocalize in nascent focal adhesions. Consistent with the view that vinculin
must be activated at these sites, we found that PIP2, levels of which are
elevated during the early stages of adhesion, bound to two discrete regions in
the vinculin tail, disrupting the intramolecular head-tail interaction and
inducing vinculin oligomerization. Vinculin-VASP complex formation was greatly
enhanced by PIP2 and both the EVH1 and EVH2 domains of VASP participated in
vinculin binding. CONCLUSIONS: Focal contact assembly involves interaction
between VASP and vinculin, which is enhanced by PIP2-induced vinculin activation
and oligomerization. Given that vinculin and VASP both bind to F-actin, vinculin
VASP complexes might bundle the distal ends of actin filaments in focal contacts.
We propose that PIP2-dependent signalling modulates microfilament organization at
cellular adhesion sites by regulating vinculin-VASP complexes.
PMID- 9560341
TI - A highly conserved RNA-binding protein for cytoplasmic mRNA localization in
vertebrates.
AB - BACKGROUND: Cytoplasmic mRNA localization is a widespread mechanism for
restricting the translation of specific mRNAs to distinct regions of eucaryotic
cells. This process involves specific interactions between cellular factors and
localization signals in the 3' untranslated regions of the localized mRNA.
Because only a few of these cellular factors have been identified, it is not
known whether common factors are utilized for the localization of different
mRNAs. We recently discovered Vera, a protein that binds specifically to the Vg1
localization element and is involved in the localization of Vg1 mRNA in Xenopus
oocytes. RESULTS: To characterize further the role of Vera in the localization of
Vg1 mRNA, we have purified the Vera protein and cloned its gene. Vera is
homologous to chicken zip-code-binding protein (ZBP), which binds to a short RNA
sequence required for localization of beta-actin mRNA in chick embryo
fibroblasts. The predicted amino-acid sequences of Vera and ZBP contain five RNA
binding domains and putative signals for nuclear localization and export. Like
the binding of ZBP to beta-actin mRNA, Vera specifically binds to a repeated
sequence motif in the Vg1 localization element that is required for Vg1 mRNA
localization in Xenopus oocytes. CONCLUSIONS: Vera, a highly conserved component
of the mRNA localization machinery, participates in localizing different mRNAs in
different cell types. Thus, Vera appears to be a general factor for mRNA
localization, and additional factors may be required to specify diverse patterns
of RNA localization.
PMID- 9560342
TI - The Polo-related kinase Cdc5 activates and is destroyed by the mitotic cyclin
destruction machinery in S. cerevisiae.
AB - BACKGROUND: Following chromosome segregation in anaphase, ubiquitin-dependent
degradation of mitotic cyclins contributes to the exit from mitosis. A key step
in this process is catalyzed by a ubiquitin-protein ligase known as the anaphase
promoting complex (APC), the regulation of which is poorly understood. The Polo
related protein kinase Cdc5 in Saccharomyces cerevisiae might encode a regulator
of the APC, because cdc5 mutant cells arrest with a late mitotic phenotype
similar to that observed in cells with defective cyclin destruction. RESULTS: We
investigated the role of Cdc5 in the regulation of mitotic cyclin degradation. In
cdc5-1 mutant cells, we observed a defect in the destruction of cyclins and a
reduction in the cyclin-ubiquitin ligase activity of the APC. Overexpression of
CDC5 resulted in increased APC activity and mitotic cyclin destruction in
asynchronous cells or in cells arrested in metaphase. CDC5 mutation or
overexpression did not affect the degradation of the APC substrate Pds 1, which
is normally degraded at the metaphase-to-anaphase transition. Cyclin-specific APC
activity in cells overexpressing CDC5 was reduced in the absence of the APC
regulatory proteins Hct 1 and Cdc20. In G1, Cdc5 itself was degraded by an APC
dependent and Hct1-dependent mechanism. CONCLUSIONS: We conclude that Cdc5 is a
positive regulator of cyclin-specific APC activity in late mitosis. Degradation
of Cdc5 in G1 might provide a feedback mechanism by which the APC destroys its
activator at the onset of the next cell cycle.
PMID- 9560343
TI - Identification of a ligand for the death-domain-containing receptor Apo3.
AB - The tumor necrosis factor (TNF) cytokine family regulates development and
function of the immune system [1]. TNF is expressed primarily by activated
lymphocytes and macrophages and induces gene transcription or apoptosis in target
cells [2,3]. We have identified a novel relative of TNF that binds to the
recently discovered, death-domain-containing receptor called Apo3 [4] (also known
as DR3, WSL-1, TRAMP or LARD [5-9]). The Apo3 ligand (Apo3L) is a 249 amino-acid,
type II transmembrane protein. The extracellular sequence of Apo3L shows highest
identity to that of TNF. We detected Apo3L mRNA in many human tissues and mapped
its encoding gene to chromosome 17p13, near the p53 tumor-suppressor gene.
Soluble Apo3L induced apoptosis and nuclear factor kappaB (NF-kappaB) activation
in human cell lines. Caspase inhibitors blocked apoptosis induction by Apo3L, as
did a dominant-negative mutant of the cell death adaptor protein Fas-associated
death domain protein (FADD/MORT1), which is critical for apoptosis induction by
TNF [3]. Dominant-negative mutants of several factors that play a key role in NF
kappaB induction by TNF [10] inhibited NF-kappaB activation by Apo3L. Thus, Apo3L
has overlapping signaling functions with TNF, but displays a much wider tissue
distribution.
PMID- 9560344
TI - Angiopoietin-1 induces sprouting angiogenesis in vitro.
AB - Sprouting of new capillaries from pre-existing blood vessels is a hallmark of
angiogenesis during embryonic development and solid tumor growth [1]. In addition
to the vascular endothelial growth factor (VEGF) and its receptors, the Tie
receptors and their newly identified ligands, the angiopoietins, have been
implicated in the control of blood vessel formation [2,3]. Although 'knockouts'
of the gene encoding the Tie2 receptor, or its activating ligand angiopoietin-1
(Ang1), result in embryonic lethality in mice due to an absence of remodeling and
sprouting of blood vessels [4,5], biological activity in vitro has not yet been
described for this receptor-ligand system. In an assay in which a monolayer of
endothelial cells were cultured on microcarrier beads and embedded in three
dimensional fibrin gels, recombinant Ang1 (0.5-10 nM) induced the formation of
capillary sprouts in a dose-dependent manner that was completely inhibited by
soluble Tie2 receptor extracellular domains. In contrast with VEGF, which also
induced sprouting of capillaries, Ang1 was only very weakly mitogenic for
endothelial cells. Suboptimal concentrations of VEGF and Ang1 acted
synergistically to induce sprout formation. Thus, the biological activity of Ang1
in vitro is consistent with the specific phenotype of mice deficient in Tie2 or
Ang1. The data suggest that, like in other developmental systems, blood vessel
formation requires a hierarchy of master-control genes in which VEGF and
angiopoietins, along with their receptors, are amongst the most important
regulators.
PMID- 9560345
TI - The globular domain of histone H1 is sufficient to direct specific gene
repression in early Xenopus embryos.
AB - One molecule of a linker histone such as histone H1 is incorporated into every
metazoan nucleosome [1]. Histone H1 has three distinct structural domains: the
positively charged amino-terminal and carboxy-terminal tails are separated by a
globular domain that is similar to the winged-helix motif found in sequence
specific DNA-binding proteins [2]. The globular domain interacts with DNA
immediately contiguous to that wrapped around the core histones [3,4], whereas
the tail domains are important for the compaction of nucleosomal arrays [5].
Experiments in vivo indicate that histone H1 does not function as a global
transcriptional repressor, but instead has more specific regulatory roles [6-9].
In Xenopus, maternal stores of the B4 linker histone that are assembled into
chromatin during the early cleavage divisions are replaced by somatic histone H1
during gastrulation [10]. This transition in chromatin composition causes the
repression of genes encoding oocyte-type 5S rRNAs, and restricts the competence
of ectodermal cells to differentiate into mesoderm [6,9-11]. Here, we demonstrate
that the globular domain of histone H1 is sufficient for directing gene-specific
transcriptional repression and for restricting the mesodermal competence of
embryonic ectoderm. We discuss our results in the context of specific structural
roles for this domain in the nucleosome.
PMID- 9560346
TI - CPAN, a human nuclease regulated by the caspase-sensitive inhibitor DFF45.
AB - Induction of apoptosis by death receptors such as Fas or tumour necrosis factor
(TNF) R1 leads to distinct changes in cell morphology, activation of the caspase
protease cascade, and the degradation of nuclear chromatin by activated
nucleases. Here, we describe the purification and cDNA cloning of a novel 40 kDa
endonuclease from Jurkat cells that is activated by caspases. This protein,
designated caspase-activated nuclease (CPAN), is sufficient to degrade naked DNA
and to induce apoptotic morphology and DNA fragmentation in naive nuclei. CPAN is
highly homologous to a recently described mouse nuclease, CAD [1], and may
represent the human homologue. Our data on the human cDNA as well as additional
data on the mouse homologue suggest that a 30 amino-acid portion of the recently
published mouse sequence [1] is incorrect. We show that the activity of human
CPAN is regulated by DFF45 [2], an inhibitor necessary for CPAN expression and
stabilization in an inactive state in living cells. Proteolytic cleavage of DFF45
by caspases in vitro leads to dissociation of DFF45 fragments from CPAN and
activation of CPAN as an endonuclease. CPAN is a tightly regulated endonuclease
with unique characteristics that might represent a distinctive family of
endonucleases.
PMID- 9560347
TI - Dynein and dynactin are localized to astral microtubules and at cortical sites in
mitotic epithelial cells.
AB - The mitotic spindle is often positioned in a characteristic location during
development, for example to enable the proper segregation of developmental
determinants [1,2]. When epithelial cells divide, the mitotic spindle is often
positioned parallel to the plane of the epithelium, so that both daughter cells
contribute to the epithelium [3]. The mechanisms by which mitotic spindles are
positioned have not been characterized in great detail, but evidence is
accumulating that in some systems the dynein-dynactin microtubule motor complex
plays a role [4-6]. Dynein has yet not been localized to cortical sites where it
could bind to microtubules and exert a force that might orient the mitotic
spindle, however [7,8]. Here, we report that in mitotic polarized epithelial
cells, the dynein-dynactin complex accumulates, from prometaphase onwards, along
astral microtubules and at cortical spots, into which many of the astral
microtubules dock. The spots are assembled at the lateral plasma membrane, in the
region below the tight junctions. Their formation is inhibited by cytochalasin D,
and under these conditions the spindles do not orient properly. This novel
localization of the dynein-dynactin complex is consistent with a role for the
complex in the positioning of the mitotic spindle. We also show that, during
prophase, the motor complex colocalizes with the nuclear envelope, consistent
with it having a role in separating the centrosomes that are associated with the
nuclear envelope.
PMID- 9560348
TI - Following comets
PMID- 9560349
TI - Sperm and scrambled eggs
PMID- 9560350
TI - Web sequence gazing
PMID- 9560351
TI - For yew and me
PMID- 9560352
TI - Tap water tempest
PMID- 9560353
TI - Of human bandage
PMID- 9560354
TI - Profiles of Great Lakes critical pollutants: a sentinel analysis of human blood
and urine. The Great Lakes Consortium.
AB - To determine the contaminants that should be studied further in the subsequent
population-based study, a profile of Great Lakes (GL) sport fish contaminant
residues were studied in human blood and urine specimens from 32 sport fish
consumers from three Great Lakes: Lake Michigan (n = 10), Lake Huron (n = 11),
and Lake Erie (n = 11). Serum was analyzed for 8 polychlorinated dioxin
congeners, 10 polychlorinated furan congeners, 4 coplanar and 32 other
polychlorinated biphenyl (PCB) congeners, and 11 persistent chlorinated
pesticides. Whole blood was analyzed for mercury and lead. Urine samples were
analyzed for 10 nonpersistent pesticides (or their metabolites) and 5 metals. One
individual was excluded from statistical analysis because of an unusual exposure
to selected analytes. Overall, the sample (n = 31) consumed, on average, 49 GL
sport fish meals per year for a mean of 33 years. On average, the general
population in the GL basin consume 6 meals of GL sport fish per year. The mean
tissue levels of most persistent, bioaccumulative compounds also found in GL
sport fish ranged from less than a twofold increase to that of PCB 126, which was
eight times the selected background levels found in the general population. The
overall mean total toxic equivalent for dioxins, furans, and coplanar PCBs were
greater than selected background levels in the general population (dioxins, 1.8
times; furans, 2.4 times; and coplanar PCBs, 9.6 times). The nonpersistent
pesticides and most metals were not identified in unusual concentrations. A
contaminant pattern among lake subgroups was evident. Lake Erie sport fish
consumers had consistently lower contaminant concentrations than consumers of
sport fish from Lake Michigan and Huron. These interlake differences are
consistent with contaminant patterns seen in sport fish tissue from the
respective lakes; GL sport fish consumption was the most likely explanation for
observed contaminant levels among this sample. Frequent consumers of sport fish
proved to be effective sentinels for identifying sport fish contaminants of
concern. In the larger study to follow, serum samples will be tested for PCBs
(congener specific and coplanar), DDE, dioxin, and furans.
PMID- 9560355
TI - Indoor air quality and acute lower respiratory infection in Indian urban slums.
AB - The present prospective study was conducted at two urban slums of Delhi, Kusumpur
Pahari and Kathputly Colony, in the peak winter season from November 1994 through
February 1995. We studied 642 infants to determine the incidence of acute lower
respiratory infection (ALRI) and its relationship to indoor air pollution due to
fuel used for cooking (wood or kerosene). In Kusumpur Pahari, there were 317
children (142 wood and 175 kerosene), including 64 controls and 78 cases of ALRI
in the wood fuel group and 81 controls and 94 ALRI cases in the kerosene group (p
> 0.05). Out of 316 children in Kathputly Colony (174 wood and 142 kerosene),
there were 33 and 45 ALRI cases in the wood and kerosene groups, respectively (p
< 0.05). Controls were children without ALRI and were used as controls in
different groups. The demographic data and risk factors, namely, nutritional and
immunization status, were comparable in ALRI cases and controls in both study
areas. Pneumonia was the most common ailment in all the groups. Bronchiolitis was
reported in 22.5% of the wood group and 27.1% of the kerosene group in Kathputly
Colony versus 13.7% in the wood group and 12.1% in the kerosene group in Kusumpur
Colony. Only one case of croup was reported from Kusumpur Pahari among wood
users. The duration of illness was longer in the Kusumpur Pahari due to poor
compliance, feeding, and child rearing habits. In conclusion, a higher incidence
of ALRI was reported in kerosene users in Kathputly Colony, a high pollution
area; however, the reasons for the differences observed need further elucidation.
PMID- 9560356
TI - No safe harbor.
PMID- 9560357
TI - Tackling the big three.
PMID- 9560359
TI - Testis-specific proteins and their role in contraceptive vaccine development.
AB - Development of a vaccine(s) based on sperm antigens represents a promising
approach for contraception. The utility of an antigen in immunocontraception is
contingent upon its testis/sperm specificity and involvement in spermatogenesis
and/or fertilization. The aim of the present article is to review the information
regarding the proteins that have been reported to be testis/sperm-specific and
may have an important function in spermatogenesis and/or fertilization. The
potential role of these proteins in the development an antisperm contraceptive
vaccine(s) is discussed.
PMID- 9560358
TI - Cellular activation mechanisms in septic shock.
AB - Septic shock is an increasingly important clinical condition, characterized by
systemic hypotension, ischemia, and ultimately organ failure. In Gram negative
infection, the bacterial cell wall component, lipopolysaccharide (endotoxin,
LPS), has been strongly linked to the pathophysiological responses that result in
septic shock. LPS is bound in plasma to a protein called LPS-binding protein
(LBP), which facilitates the binding of LPS to a cell surface receptor, CD14.
Binding to CD14 stimulates cell signaling mechanisms that result in the
production of inflammatory cytokines. However, the events which follow LPS
binding to CD14 and which lead to the production of cytokines remain unclear. It
has recently become evident that a number of phosphorylation cascades including
MAP kinase pathways and NF-kappaB activation pathway are initiated by exposure of
cells to LPS. These cascades act at both the transcriptional and translational
levels to regulate cytokine production. This review will focus on the signaling
pathways that are initiated by LPS and the cellular effects of the signaling
pathways.
PMID- 9560360
TI - The Mom and Pop Editorial Shop.
PMID- 9560361
TI - Young Jan.
PMID- 9560362
TI - Some recollections and reflections on mutation rates.
PMID- 9560363
TI - Mutation and cancer: the antecedents to our studies of adaptive mutation.
PMID- 9560364
TI - The lacI gene as a target for mutation in transgenic rodents and Escherichia
coli.
AB - The lacI gene has been used extensively for the recovery and analysis of
mutations in bacteria with various DNA repair backgrounds and after exposure to a
wide variety of mutagens. This has resulted in a large database of information on
mutational mechanisms and specificity of many mutagens, as well as the effect of
DNA repair background on mutagenicity. Most importantly, knowledge about the
mutational sensitivity of the lacI gene is now available, yielding information
about mutable nucleotides. This popularity and available knowledge resulted in
the use of the lacI gene in transgenic rodents for the study of mutagenesis in
mammals, where it resides in approximately 40 repeated copies. As the number of
sequenced mutations recovered from these animals increases, we are able to
analyze the sites at which mutations have been recovered in great detail and to
compare the recovered sites between bacteria and transgenic animals. The
nucleotides that code for the DNA-binding domain are nearly saturated with base
substitutions. Even after determining the sequences of approximately 10,000
mutations recovered from the animals, however, new sites and new changes are
still being recovered. In addition, we compare the nature of deletion mutations
between bacteria and animals. Based on the nature of deletions in the animals, we
conclude that each deletion occurs in a single copy of the gene.
PMID- 9560365
TI - Adaptive mutation: has the unicorn landed?
AB - Reversion of an episomal Lac- allele during lactose selection has been studied as
a model for adaptive mutation. Although recent results show that the mutations
that arise during selection are not "adaptive" in the original sense, the
mutagenic mechanism that produces these mutations may nonetheless be of
evolutionary significance. In addition, a transient mutational state induced in a
subpopulation of starving cells could provide a species with a mechanism for
adaptive evolution.
PMID- 9560366
TI - A species barrier between bacteriophages T2 and T4: exclusion, join-copy and join
cut-copy recombination and mutagenesis in the dCTPase genes.
AB - Bacteriophage T2 alleles are excluded in crosses between T2 and T4 because of
genetic isolation between these two virus species. The severity of exclusion
varies in different genes, with gene 56, encoding an essential
dCT(D)Pase/dUT(D)Pase of these phages, being most strongly affected. To
investigate reasons for such strong exclusion, we have (1) sequenced the T2 gene
56 and an adjacent region, (2) compared the sequence with the corresponding T4
DNA, (3) constructed chimeric phages in which T2 and T4 sequences of this region
are recombined, and (4) tested complementation, recombination, and exclusion with
gene 56 cloned in a plasmid and in the chimeric phages in Escherichia coli CR63,
in which growth of wild-type T2 is not restricted by T4. Our results argue
against a role of the dCTPase protein in this exclusion and implicate instead DNA
sequence differences as major contributors to the apparent species barrier. This
sequence divergence exhibits a remarkable pattern: a major heterologous sequence
counter-clockwise from gene 56 (and downstream of the gene 56 transcripts)
replaces in T2 DNA the T4 gene 69. Gene 56 base sequences bordering this
substituted region are significantly different, whereas sequences of the dam
genes, adjacent in the clockwise direction, are similar in T2 and in T4. The gene
56 sequence differences can best be explained by multiple compensating
frameshifts and base substitutions, which result in T2 and T4 dCTPases whose
amino acid sequences and functions remain similar. Based on these findings we
propose a model for the evolution of multiple sequence differences concomitant
with the substitution of an adjacent gene by foreign DNA: invasion by the single
stranded segments of foreign DNA, nucleated from a short DNA sequence that was
complementary by chance, has triggered recombination-dependent replication by
"join-copy" and "join-cut-copy" pathways that are known to operate in the T-even
phages and are implicated in other organisms as well. This invasion, accompanied
by heteroduplex formation between partially similar sequences, and perhaps
subsequent partial heteroduplex repair, simultaneously substituted T4 gene 69 for
foreign sequences and scrambled the sequence of the dCTPase gene 56. We suggest
that similar mechanisms can mobilize DNA segments for horizontal transfer without
necessarily requiring transposase or site-specific recombination functions.
PMID- 9560367
TI - DNA polymerase fidelity: from genetics toward a biochemical understanding.
AB - This review summarizes mutagenesis studies, emphasizing the use of bacteriophage
T4 mutator and antimutator strains. Early genetic studies on T4 identified
mutator and antimutator variants of DNA polymerase that, in turn, stimulated the
development of model systems for the study of DNA polymerase fidelity in vitro.
Later enzymatic studies using purified T4 mutator and antimutator polymerases
were essential in elucidating mechanisms of base selection and exonuclease
proofreading. In both cases, the base analogue 2-aminopurine (2AP) proved
tremendously useful-first as a mutagen in vivo and then as a probe of DNA
polymerase fidelity in vitro. Investigations into mechanisms of DNA polymerase
fidelity inspired theoretical models that, in turn, called for kinetic and
thermodynamic analyses. Thus, the field of DNA synthesis fidelity has grown from
many directions: genetics, enzymology, kinetics, physical biochemistry, and
thermodynamics, and today the interplay continues. The relative contributions of
hydrogen bonding and base stacking to the accuracy of DNA synthesis are beginning
to be deciphered. For the future, the main challenges lie in understanding the
origins of mutational hot and cold spots.
PMID- 9560368
TI - The mutation rate and cancer.
AB - The stability of the human genome requires that mutations in the germ line be
exceptionally rare events. While most mutations are neutral or have deleterious
effects, a limited number of mutations are required for adaptation to
environmental changes. Drake has provided evidence that DNA-based microbes have
evolved a mechanism to yield a common spontaneous mutation rate of approximately
0.003 mutations per genome per replication (Drake 1991). In contrast, mutation
rates of RNA viruses are much larger (Holland et al. 1982) and can approach the
maximum tolerable deleterious mutation rate of one per genome (Eigen and Schuster
1977; Eigen 1993). Drake calculates that lytic RNA viruses display spontaneous
mutation rates of approximately one per genome while most have mutation rates
that are approximately 0.1 per genome (Drake 1993). This constancy of germline
mutation rates among microbial species need not necessarily mean constancy of the
somatic mutation rates. Furthermore, there need not be a constant rate for
somatic mutations during development. In this review, we consider mutations in
cancer, a pathology in which there appears to be an increase in the rate of
somatic mutations throughout the genome. Moreover, within the eukaryotic genome,
as in microbes, there are "hot-spots" that exhibit unusually high mutation
frequencies. It seems conceivable to us that many tumors contain thousands of
changes in DNA sequence. The major question is: how do these mutations arise, and
how many are rate-limiting for tumor progression?
PMID- 9560369
TI - DNA sequence analysis of spontaneous mutagenesis in Saccharomyces cerevisiae.
AB - To help elucidate the mechanisms involved in spontaneous mutagenesis, DNA
sequencing has been applied to characterize the types of mutation whose rates are
increased or decreased in mutator or antimutator strains, respectively. Increased
spontaneous mutation rates point to malfunctions in genes that normally act to
reduce spontaneous mutation, whereas decreased rates are associated with defects
in genes whose products are necessary for spontaneous mutagenesis. In this
article, we survey and discuss the mutational specificities conferred by mutator
and antimutator genes in the budding yeast Saccharomyces cerevisiae. The
implications of selected aspects of the data are considered with respect to the
mechanisms of spontaneous mutagenesis.
PMID- 9560370
TI - Factors affecting inverted repeat stimulation of recombination and deletion in
Saccharomyces cerevisiae.
AB - Inverted DNA repeats are an at-risk motif for genetic instability that can induce
both deletions and recombination in yeast. We investigated the role of the length
of inverted repeats and size of the DNA separating the repeats for deletion and
recombination. Stimulation of both deletion and recombination was directly
related to the size of inverted repeats and inversely related to the size of
intervening spacers. A perfect palindrome, formed by two 1.0-kb URA3-inverted
repeats, increased intra- and interchromosomal recombination in the adjacent
region 2,400-fold and 17,000-fold, respectively. The presence of a strong origin
of replication in the spacer reduced both rates of deletion and recombination.
These results support a model in which the stimulation of deletion and
recombination by inverted repeats is initiated by a secondary structure formed
between single-stranded DNA of inverted repeats during replication.
PMID- 9560372
TI - A new look at old mutants of T4 DNA polymerase.
PMID- 9560371
TI - The chromosome bias of misincorporations during double-strand break repair is not
altered in mismatch repair-defective strains of Saccharomyces cerevisiae.
AB - Recombinational repair of a site-specific, double-strand DNA break (DSB) results
in increased reversion frequency for nearby mutations. Although some models for
DSB repair predict that newly synthesized DNA will be inherited equally by both
the originally broken chromosome and the chromosome that served as a template,
the DNA synthesis errors are almost exclusively found on the chromosome that had
the original DSB (introduced by the HO endonuclease). To determine whether
mismatch repair acts on the template chromosome in a directed fashion to restore
mismatches to the initial sequence, these experiments were repeated in mismatch
repair-defective (pms1, mlh1, and msh2) backgrounds. The results suggest that
mismatch repair is not responsible for the observed bias.
PMID- 9560373
TI - The roles of the bacteriophage T4 r genes in lysis inhibition and fine-structure
genetics: a new perspective.
AB - Seldom has the study of a set of genes contributed more to our understanding of
molecular genetics than has the characterization of the rapid-lysis genes of
bacteriophage T4. For example, T4 rII mutants were used to define gene structure
and mutagen effects at the molecular level and to help unravel the genetic code.
The large-plaque morphology of these mutants reflects a block in expressing lysis
inhibition (LIN), the ability to delay lysis for several hours in response to
sensing external related phages attacking the cell, which is a unique and highly
adaptive attribute of the T4 family of phages. However, surprisingly little is
known about the mechanism of LIN, or how the various r genes affect its
expression. Here, we review the extensive old literature about the r genes and
the lysis process and try to sort out the major players affecting lysis
inhibition. We confirm that superinfection can induce lysis inhibition even while
infected cells are lysing, suggesting that the signal response is virtually
instantaneous and thus probably the result of post-translational regulation. We
identify the rI gene as ORF tk.-2, based on sequence analysis of canonical rI
mutants. The rI gene encodes a peptide of 97 amino acids (Mr = 11.1 kD; pI = 4.8)
that probably is secreted into the periplasmic space. This gene is widely
conserved among T-even phage. We then present a model for LIN, postulating that
rI is largely responsible for regulating the gpt holin protein in response to
superinfection. The evidence suggests that the rIIA and B genes are not directly
involved in lysis inhibition; rather, when they are absent, an alternate pathway
for lysis develops which depends on the presence of genes from any of several
possible prophages and is not sensitive to lysis inhibition.
PMID- 9560374
TI - Regulation of DNA polymerase exonucleolytic proofreading activity: studies of
bacteriophage T4 "antimutator" DNA polymerases.
PMID- 9560376
TI - Differential response of mouse male germ-cell stages to radiation-induced
specific-locus and dominant mutations.
AB - In an attempt to provide a systematic assessment of the frequency and nature of
mutations induced in successive stages of spermato- and spermiogenesis, X
irradiated male mice were re-mated at weekly intervals, and large samples of
progeny, observed from birth onward, were scored and genetically tested for
recessive mutations at seven specific loci and for externally recognizable
dominant mutations. Productivity findings provided a rough measure of induced
dominant-lethal frequencies. A qualitative assessment of specific-locus mutations
(which include deletions and other rearrangements) was made on the basis of
homozygosity test results, as well as from information derived from more recent
complementation studies and molecular analyses. Both recessive and dominant
visibles revealed clear distinctions between spermatogonia and postspermatogonial
stages. In addition, differences for both of these endpoints, as well as for
presumed dominant lethals, were found among various postspermatogonial stages. It
may be concluded that radiation produces its maximum rates of genetic damage in
germ-cell stages ranging from midpachytene spermatocytes through early
spermatids, a pattern unlike any of those that have been defined for chemicals;
further, the frequency peaks for radiation are lower and broader. The difference
between post-stem-cell stages overall and stem-cell spermatogonia was smaller
than is generally found with chemicals, not only with respect to the frequency
but also the nature of mutations.
PMID- 9560375
TI - Transient and heritable mutators in adaptive evolution in the lab and in nature.
AB - Major advances in understanding the molecular mechanism of recombination
dependent stationary-phase mutation in Escherichia coli occurred this past year.
These advances are reviewed here, and we also present new evidence that the
mutagenic state responsible is transient. We find that most stationary-phase
mutants do not possess a heritable stationary-phase mutator phenotype, although a
small proportion of heritable mutators was found previously. We outline
similarities between this well-studied system and several recent examples of
adaptive evolution associated with heritable mutator phenotype in a similarly
small proportion of survivors of selection in nature and in the lab. We suggest
the following: (1) Transient mutator states may also be a predominant source of
adaptive mutations in these latter systems, the heritable mutators being a
minority (Rosenberg 1997); (2) heritable mutators may sometimes be a product of,
rather than the cause of, hypermutation that gives rise to adaptive mutations.
PMID- 9560377
TI - Antimutator mutants in bacteriophage T4 and Escherichia coli.
AB - Antimutators are mutant strains that have reduced mutation rates compared to the
corresponding wild-type strain. Their existence, along with mutator mutants that
have higher mutation rates compared to the wild-type strain, are powerful
evidence that mutation rates are genetically controlled. Compared to mutator
mutants, antimutators have a very distinguishing property. Because they prevent
normally occurring mutations, they, uniquely, are capable of providing insight
into the mechanisms of spontaneous mutations. In this review, antimutator mutants
are discussed in bacteriophage T4 and the bacterium Escherichia coli, with regard
to their properties, possible mechanisms, and implications for the sources of
spontaneous mutations in these two organisms.
PMID- 9560378
TI - Damage control: the pleiotropy of DNA repair genes in Drosophila melanogaster.
PMID- 9560380
TI - Aspects of the ultraviolet photobiology of some T-even bacteriophages.
AB - Bacteriophage T4 DNA metabolism is largely insulated from that of its host,
although some host functions assist in the repair of T4 DNA damage. Environmental
factors sometimes affect survival and mutagenesis after ultraviolet (UV)
irradiation of T4, and can affect mutagenesis in many organisms. We therefore
tested the effect of certain environmental factors and host genetic defects upon
spontaneous and UV-induced mutagenesis and survival in T4 and some related T-even
phages. Plating at pH 9 enhances UV resistance in T4 by about 14% compared to pH
7. The host cAMP regulatory system affects host survival after UV irradiation but
does not affect T4 survival. Thermal rescue, the increasing survival of
irradiated T4 with increasing plating temperature, occurs also in phage T6, but
only weakly in phages T2 and RB69; this temperature effect is not altered by
supplementing infected cells with additional Holliday resolvase (gp49) early in
infection. Phage RB69 turns out to have almost 50% greater UV resistance than T4,
but has a genome of about the same size; RB69 is UV-mutable but does not produce
r mutants, which are easily seen in T2, T4, and T6. Spontaneous mutagenesis in T4
shows no dependence on medium and little dependence on temperature overall, but
mutation rates can increase and probably decrease with temperature at specific
sites. UV mutagenesis is not affected by incubating irradiated particles under
various conditions before plating, in contrast to phage S13.
PMID- 9560379
TI - Mutagenesis and more: umuDC and the Escherichia coli SOS response.
AB - The cellular response to DNA damage that has been most extensively studied is the
SOS response of Escherichia coli. Analyses of the SOS response have led to new
insights into the transcriptional and post-translational regulation of processes
that increase cell survival after DNA damage as well as insights into DNA-damage
induced mutagenesis, i.e., SOS mutagenesis. SOS mutagenesis requires the recA and
umuDC gene products and has as its mechanistic basis the alteration of DNA
polymerase III such that it becomes capable of replicating DNA containing
miscoding and noncoding lesions. Ongoing investigations of the mechanisms
underlying SOS mutagenesis, as well as recent observations suggesting that the
umuDC operon may have a role in the regulation of the E. coli cell cycle after
DNA damage has occurred, are discussed.
PMID- 9560382
TI - Reversion of the tyrosine ochre strain Escherichia coli WU3610 under starvation
conditions depends on a new gene tas.
AB - When 3 x 10(8) bacteria of the Escherichia coli tyrA14(oc) leu308(am) strain
WU3610 are plated on glucose salts agar supplemented with leucine only, colonies
of slow-growing Tyr+ suppressor mutants begin to appear after about a week and
increase in numbers roughly linearly with time thereafter (stationary phase or
starvation-associated mutation). From a library constructed from two of these
mutants, a clone was obtained that suppressed the tyrosine requirement of WU3610
when present on a multicopy plasmid. The activity was identified to an open
reading frame we call tas, the sequence for which has homology with a variety of
known genes with aldo-keto reductase activity. The activity of tas complements
the prephenate dehydrogenase dysfunction of tyrA14 (the chorismate mutase
activity of tyrA possibly being still functional). A strain deleted for tas
showed no spontaneous mutation under starvation conditions. Whereas neither tas+
nor tas bacteria showed any increase in viable or total count when plated under
conditions of tyrosine starvation at 3 x 10(8) cells per plate, at lower density
(approximately 10(7) per plate) tas+ but not tas bacteria showed considerable
residual growth. We suggest that the single copy of tas present in WU3610 allows
cryptic cell or DNA turnover under conditions of tyrosine starvation and that
this is an essential prerequisite for starvation-associated mutation in this
system. The target gene for mutation is not tas, although an increase in the
expression of this gene, for example, resulting from a suppressor mutation
affecting supercoiling, could be responsible for the slow-growing Tyr+ phenotype.
PMID- 9560381
TI - Hypermutability in carcinogenesis.
AB - The presence of numerous chromosomal changes and point mutations in tumors is
well established. At least some of these changes play a role in the development
of the tumors. It has been suggested that the number of these genetic changes
requires that tumorigenesis involves an increase in mutation rate. However, the
presence of numerous changes can also be accounted for by efficient selection.
What is required to settle the issue is some measure of nonselected mutations in
tumors. In order to determine whether the tumor suppressor TP53 (coding for the
protein p53) is hypermutable at some stage of carcinogenesis, the frequency of
silent and multiple mutations in this gene has been examined. Silent mutations
make up approximately 3% of the total recorded but constitute 9.5% of the
mutations found in tumors with multiple mutations. Multiple closely linked
mutations are also observed. Such multiple mutations suggest the operation of an
error-prone replication process in a subclass of cells. The published data
indicate that TP53 is hypermutable at some stage of tumor development. It is not
yet clear whether TP53 is unique or whether other genes display a similar pattern
of silent and multiple mutations.
PMID- 9560383
TI - Functional overlap in mismatch repair by human MSH3 and MSH6.
AB - Three human genes, hMSH2, hMSH3, and hMSH6, are homologues of the bacterial MutS
gene whose products bind DNA mismatches to initiate strand-specific repair of DNA
replication errors. Several studies suggest that a complex of hMSH2 x hMSH6
(hMutSalpha) functions primarily in repair of base x base mismatches or single
extra bases, whereas a hMSH2 x hMSH3 complex (hMutSbeta) functions chiefly in
repair of heteroduplexes containing two to four extra bases. In the present
study, we compare results with a tumor cell line (HHUA) that is mutant in both
hMSH3 and hMSH6 to results with derivative clones containing either wild-type
hMSH3 or wild-type hMSH6, introduced by microcell-mediated transfer of chromosome
5 or 2, respectively. HHUA cells exhibit marked instability at 12 different
microsatellite loci composed of repeat units of 1 to 4 base pairs. Compared to
normal cells, HHUA cells have mutation rates at the HPRT locus that are elevated
500-fold for base substitutions and 2400-fold for single-base frameshifts.
Extracts of HHUA cells are defective in strand-specific repair of substrates
containing base x base mismatches or 1-4 extra bases. Transfer of either
chromosome 5 (hMSH3) or 2 (hMSH6) into HHUA cells partially corrects instability
at the microsatellite loci and also the substitution and frameshift mutator
phenotypes at the HPRT locus. Extracts of these lines can repair some, but not
all, heteroduplexes. The combined mutation rate and mismatch repair specificity
data suggest that both hMSH3 and hMSH6 can independently participate in repair of
replication errors containing base x base mismatches or 1-4 extra bases. Thus,
these two gene products share redundant roles in controlling mutation rates in
human cells.
PMID- 9560384
TI - Topical reversion at the HIS1 locus of Saccharomyces cerevisiae. A tale of three
mutants.
AB - Mutants of the HIS1 locus of the yeast Saccharomyces cerevisiae are suitable
reporters for spontaneous reversion events because most reversions are topical,
that is, within the locus itself. Thirteen mutations of his1-1 now have been
identified with respect to base sequence. Revertants of three mutants and their
spontaneous reversion rates are presented: (1) a chain termination mutation (his1
208, nee his1-1) that does not revert by mutations of tRNA loci and reverts only
by intracodonic suppression; (2) a missense mutation (his1-798, nee his1-7) that
can revert by intragenic suppression by base substitutions of any sort, including
a back mutation as well as one three-base deletion; and (3) a -1 frameshift
mutation (his1-434, nee his1-19) that only reverts topically by +1 back mutation,
+1 intragenic suppression, or a -2 deletion. Often the +1 insertion is
accompanied by base substitution events at one or both ends of a run of A's.
Missense suppressors of his1-798 are either feeders or nonfeeders, and at four
different locations within the locus, a single base substitution encoding an
amino acid alteration will suffice to turn the nonfeeder phenotype into a feeder
phenotype. Late-appearing revertants of his1-798 were found to be slowly growing
leaky mutants rather than a manifestation of adaptive mutagenesis. Spontaneous
revertants of his1-208 and his1-434 produced no late-arising colonies.
PMID- 9560385
TI - The spectrum of acridine resistant mutants of bacteriophage T4 reveals cryptic
effects of the tsL141 DNA polymerase allele on spontaneous mutagenesis.
AB - Mutations in the ac gene of bacteriophage T4 confer resistance to acridine
inhibition of phage development. Previous studies had localized the ac gene
region; we show that inactivation of T4 Open Reading Frame 52.2 confers the Acr
phenotype. Thus, 52.2 is ac. The resistance mechanism is unknown. The ac gene
provides a convenient forward mutagenesis assay. Its compact size (156 bp)
simplifies mutant sequencing and diverse mutant types are found: base
substitutions leading to missense or nonsense codons, in-frame deletions or
duplications within the coding sequence, deletion or duplication frameshifts,
insertions, complex mutations, and large deletions extending into neighboring
sequences. Comparisons of spontaneous mutagenesis between phages bearing the wild
type or tsL141 alleles of DNA polymerase demonstrate that the impact of the
mutant polymerase is cryptic when total spontaneous mutant frequencies are
compared, but the DNA sequences of the ac mutants reveal a substantial alteration
of fidelity by the mutant polymerase. The patterns of base substitution
mutagenesis suggest that some site-specific mutation rate effects may reflect
hotspots for mutagenesis arising by different mechanisms. A new class of
spontaneous duplication mutations, having sequences inconsistent with misaligned
pairing models, but consistent with nick-processing errors, has been identified
at a hotspot in ac.
PMID- 9560386
TI - Rates of spontaneous mutation.
AB - Rates of spontaneous mutation per genome as measured in the laboratory are
remarkably similar within broad groups of organisms but differ strikingly among
groups. Mutation rates in RNA viruses, whose genomes contain ca. 10(4) bases, are
roughly 1 per genome per replication for lytic viruses and roughly 0.1 per genome
per replication for retroviruses and a retrotransposon. Mutation rates in
microbes with DNA-based chromosomes are close to 1/300 per genome per
replication; in this group, therefore, rates per base pair vary inversely and
hugely as genome sizes vary from 6 x 10(3) to 4 x 10(7) bases or base pairs.
Mutation rates in higher eukaryotes are roughly 0.1-100 per genome per sexual
generation but are currently indistinguishable from 1/300 per cell division per
effective genome (which excludes the fraction of the genome in which most
mutations are neutral). It is now possible to specify some of the evolutionary
forces that shape these diverse mutation rates.
PMID- 9560387
TI - Regulation of phosphate assimilation in Rhizobium (Sinorhizobium) meliloti.
AB - We report the isolation of phoB and phoU mutants of the bacterium Rhizobium
(Sinorhizobium) meliloti. These mutants form N2-fixing nodules on the roots of
alfalfa plants. R. meliloti mutants defective in the phoCDET (ndvF) encoded
phosphate transport system grow slowly in media containing 2 mM Pi, and form
nodules which fail to fix nitrogen (Fix-). We show that the transfer of phoB or
phoU insertion mutations into phoC mutant strains restores the ability of these
mutants to: (i) form normal N2-fixing root-nodules, and (ii) grow like the wild
type in media containing 2 mM Pi. We also show that expression of the alternate
orfA pit encoded Pi transport system is negatively regulated by the phoB gene
product, whereas phoB is required for phoCDET expression. We suggest that in R.
meliloti cells growing under Pi limiting conditions, PhoB protein activates
phoCDET transcription and represses orfA pit transcription. Our results suggest
that there are major differences between the Escherichia coli and R. meliloti
phosphate regulatory systems.
PMID- 9560388
TI - Cell cycle arrest in cdc20 mutants of Saccharomyces cerevisiae is independent of
Ndc10p and kinetochore function but requires a subset of spindle checkpoint
genes.
AB - The spindle checkpoint ensures accurate chromosome segregation by inhibiting
anaphase onset in response to altered microtubule function and impaired
kinetochore function. In this study, we report that the ability of the anti
microtubule drug nocodazole to inhibit cell cycle progression in Saccharomyces
cerevisiae depends on the function of the kinetochore protein encoded by NDC10.
We examined the role of the spindle checkpoint in the arrest in cdc20 mutants
that arrest prior to anaphase with an aberrant spindle. The arrest in cdc20
defective cells is dependent on the BUB2 checkpoint and independent of the BUB1,
BUB3, and MAD spindle checkpoint genes. We show that the lesion recognized by
Bub2p is not excess microtubules, and the cdc20 arrest is independent of
kinetochore function. We show that Cdc20p is not required for cyclin proteolysis
at two points in the cell cycle, suggesting that CDC20 is distinct from genes
encoding integral proteins of the anaphase promoting complex.
PMID- 9560389
TI - Identification and characterization of an essential family of inositol
polyphosphate 5-phosphatases (INP51, INP52 and INP53 gene products) in the yeast
Saccharomyces cerevisiae.
AB - We recently demonstrated that the S. cerevisiae INP51 locus (YIL002c) encodes an
inositol polyphosphate 5-phosphatase. Here we describe two related yeast loci,
INP52 (YNL106c) and INP53 (YOR109w). Like Inp51p, the primary structures of
Inp52p and Inp53p resemble the mammalian synaptic vesicle-associated protein,
synaptojanin, and contain a carboxy-terminal catalytic domain and an amino
terminal SAC1-like segment. Inp51p (108 kD), Inp52p (136 kD) and Inp53p (124 kD)
are membrane-associated. Single null mutants (inp51, inp52, or inp53) are viable.
Both inp51 inp52 and inp52 inp53 double mutants display compromised cell growth,
whereas an inp51 inp53 double mutant does not. An inp51 inp52 inp53 triple mutant
is inviable on standard medium, but can grow weakly on media supplemented with an
osmotic stabilizer (1 M sorbitol). An inp51 mutation, and to a lesser degree an
inp52 mutation, confers cold-resistant growth in a strain background that cannot
grow at temperatures below 15 degrees. Analysis of inositol metabolites in vivo
showed measurable accumulation of phosphatidylinositol 4,5-bisphosphate in the
inp51 mutant. Electron microscopy revealed plasma membrane invaginations and cell
wall thickening in double mutants and the triple mutant grown in sorbitol
containing medium. A fluorescent dye that detects endocytic and vacuolar
membranes suggests that the vacuole is highly fragmented in inp51 inp52 double
mutants. Our observations indicate that Inp51p, Inp52p, and Inp53p have distinct
functions and that substrates and/or products of inositol polyphosphate 5
phosphatases may have roles in vesicle trafficking, membrane structure, and/or
cell wall formation.
PMID- 9560390
TI - Sum1, a highly conserved WD-repeat protein, suppresses S-M checkpoint mutants and
inhibits the osmotic stress cell cycle response in fission yeast.
AB - The S-M checkpoint ensures that entry into mitosis is dependent on completion of
DNA replication. In the fission yeast Schizosaccharomyces pombe, the SM
checkpoint mutant cdc2-3w is thought to be defective in receiving the checkpoint
signal. To isolate genes that function in the checkpoint pathway, we screened an
S. pombe cDNA library for genes that, when overexpressed, could suppress the
checkpoint defect of cdc2-3w. Using this approach, we have identified a novel
gene, sum1+ (suppressor of uncontrolled mitosis). sum1+ encodes a highly
conserved WD-transducin repeat protein with striking sequence similarity to the
human transforming growth factor (TGF)-beta-receptor interacting protein TRIP-1
and to the translation initiation factor 3 subunit eIF3-p39, encoded by the TIF34
gene in Saccharomyces cerevisiae. S. pombe sum1+ is an essential gene, required
for normal cell growth and division. In addition to restoring checkpoint control,
overexpression of sum1+ inhibits the normal cell cycle response to osmotic
stress. Furthermore, we demonstrate that inactivation of the stress-activated MAP
kinase pathway, required for cell cycle stress response, restores the S-M
checkpoint in cdc2-3w cells. These results suggest that Suml interacts with the
stress-activated MAP kinase pathway and raise the possibility that environmental
conditions may influence the checkpoint response in fission yeast.
PMID- 9560392
TI - Cdc1 is required for growth and Mn2+ regulation in Saccharomyces cerevisiae.
AB - Cdc1 function was initially implicated in bud formation and nuclear division
because cdc1(Ts) cells arrested with a small bud, duplicated DNA, and undivided
nucleus. Our studies show that Cdc1 is necessary for cell growth at several
stages of the cell cycle, as well as in pheromone-treated cells. Thus, Cdc1
depletion might affect bud formation and nuclear division, as well as other
cellular processes, by blocking a process involved in general cell growth. Cells
depleted of intracellular Mn2+ also exhibit a cdc1-like phenotype and recent
results suggested Cdc1 might be a Mn2+-dependent protein. We show that all of the
conditional Cdc1(Ts) alleles tested cause cells to become sensitive to Mn2+
depletion. In addition, Cdc1 overproduction alleviates the chelator sensitivity
of several Mn2+ homeostasis mutants. These findings are compatible with a model
in which Cdc1 regulates intracellular, and in particular cytosolic, Mn2+ levels
which, in turn, are necessary for cell growth.
PMID- 9560391
TI - Posttranslational inhibition of Ty1 retrotransposition by nucleotide excision
repair/transcription factor TFIIH subunits Ssl2p and Rad3p.
AB - rtt4-1 (regulator of Ty transposition) is a cellular mutation that permits a high
level of spontaneous Ty1 retrotransposition in Saccharomyces cerevisiae. The RTT4
gene is allelic with SSL2 (RAD25), which encodes a DNA helicase present in basal
transcription (TFIIH) and nucleotide excision repair (NER) complexes. The ssl2
rtt (rtt4-1) mutation stimulates Ty1 retrotransposition, but does not alter Ty1
target site preferences, or increase cDNA or mitotic recombination. In addition
to ssl2-rtt, the ssl2-dead and SSL2-1 mutations stimulate Ty1 transposition
without altering the level of Ty1 RNA or proteins. However, the level of Ty1 cDNA
markedly increases in the ssl2 mutants. Like SSL2, certain mutations in another
NER/TFIIH DNA helicase encoded by RAD3 stimulate Ty1 transposition. Although
Ssl2p and Rad3p are required for NER, inhibition of Ty1 transposition is
independent of Ssl2p and Rad3p NER functions. Our work suggests that NER/TFIIH
subunits antagonize Ty1 transposition posttranslationally by inhibiting reverse
transcription or destabilizing Ty1 cDNA.
PMID- 9560393
TI - Cdc1 and the vacuole coordinately regulate Mn2+ homeostasis in the yeast
Saccharomyces cerevisiae.
AB - The yeast CDC1 gene encodes an essential protein that has been implicated in the
regulation of cytosolic [Mn2+]. To identify factors that impinge upon Cdc1 or the
Cdc1-dependent process, we isolated second-site suppressors of the conditional
cdc1-1(Ts) growth defect. Recessive suppressors define 15 COS (CdcOne Suppressor)
genes. Seven of the fifteen COS genes are required for biogenesis of the vacuole,
an organelle known to sequester intracellular Mn2+. An eighth gene, COS16,
encodes a vacuolar membrane protein that seems to be involved in Mn2+
homeostasis. These results suggest mutations that block vacuolar Mn2+
sequestration compensate for defects in Cdc1 function. Interestingly, Cdc1 is
dispensable in a cos16delta deletion strain, and a cdc1delta cos16delta double
mutant exhibits robust growth on medium supplemented with Mn2+. Thus, the single,
essential function of Cdc1 is to regulate intracellular, probably cytosolic,
Mn2+.
PMID- 9560394
TI - Isolation and characterization of fission yeast sns mutants defective at the
mitosis-to-interphase transition.
AB - pim1-d1ts was previously identified in a visual screen for fission yeast mutants
unable to complete the mitosis-to-interphase transition. pim1+ encodes the
guanine nucleotide exchange factor (GEF) for the spi1 GTPase. Perturbations of
this GTPase system by either mutation or overproduction of its regulatory
proteins cause cells to arrest with postmitotic condensed chromosomes, an
unreplicated genome, and a wide medial septum. The septation phenotype of pim1
d1ts was used as the basis for a more extensive screen for this novel class of
sns (septated, not in S-phase) mutants. Seventeen mutants representing 14
complementation groups were isolated. Three strains, sns-A3, sns-A5, and sns-A6,
representing two different alleles, are mutated in the pim1+ gene. Of the 13 non
pim1ts sns complementation groups, 11 showed genetic interactions with the spi1
GTPase system. The genes mutated in 10 sns strains were synthetically lethal with
pim1-d1, and six sns strains were hypersensitive to overexpression of one or more
of the known components of the spil GTPase system. Epistasis analysis places the
action of the genes mutated in nine of these strains downstream of pim1+ and the
action of one gene upstream of pim1+. Three strains, sns-A2, sns-B1, and sns-B9,
showed genetic interaction with the spil GTPase system in every test performed.
sns-B1 and sns-B9 are likely to identify downstream targets, whereas sns-A2 is
likely to identify upstream regulators of the spi1 GTPase system that are
required for the mitosis-to-interphase transition.
PMID- 9560395
TI - The fluffy gene of Neurospora crassa encodes a Gal4p-type C6 zinc cluster protein
required for conidial development.
AB - Neurospora crassa fluffy (fl) mutants are unable to produce macroconidia. We
cloned the fl gene to determine its role in regulating conidiation. A cosmid
clone containing fl was identified by complementation. The sequence of fl
revealed that it encodes a Gal4p-type C6 zinc cluster protein with greatest
similarity to the N. crassa NIT4 protein that regulates genes required for
nitrate utilization. Analysis of several fl mutant alleles demonstrated that null
mutants are blocked in the budding phase of development required to produce
conidiophores. fl mRNA is transiently induced just prior to the developmental
commitment to budding growth. This timing of fl expression is consistent with a
role for FL protein in activation of the previously characterized conidiation
specific (con) genes, con-6 and con-10. These data suggest that FL acts as a
developmentally regulated transcription factor required for conidiophore
morphogenesis.
PMID- 9560396
TI - High-efficiency transformation of Chlamydomonas reinhardtii by electroporation.
AB - We have established a high-efficiency method for transforming the unicellular,
green alga Chlamydomonas reinhardtii by electroporation. Electroporation of
strains CC3395 and CC425, cell wall-less mutants devoid of argininosuccinate
lyase (encoded by ARG7), in the presence of the plasmid pJD67 (which contains
ARG7) was used to optimize conditions for the introduction of exogenous DNA. The
conditions that were varied included osmolarity, temperature, concentration of
exogenous DNA, voltage and capacitance. Following optimization, the maximum
transformation frequency obtained was 2 x 10(5) transformants per microg of DNA;
this frequency is two orders of magnitude higher than obtained with the current
standard method using glass beads to introduce exogenous DNA. The electroporation
procedure described in this article is of general utility, and makes it feasible
to isolate genes by direct complementation of Chlamydomonas reinhardtii mutants.
PMID- 9560397
TI - High frequency recombination during the sexual cycle of Dictyostelium discoideum.
AB - Analysis of Dictyostelium development and cell biology has suffered from the lack
of an ordinary genetic system whereby genes can be arranged in new combinations.
Genetic exchange between two long ignored strains, A2Cycr and WS205 is here
reexamined. Alleles which differ in size or restriction sites between these two
strains were found for seven genes. Six of these are in two clusters on
chromosome 2. Frequencies of recombinant progeny indicate that the genetic map of
the two mating strains is colinear with the physical map recently worked out for
the standard nonsexual strain, NC4. The rate of recombination is high, about 0.1%
per kilobase in three different regions of chromosome 2. This value is comparable
to rates found in yeast, and will permit fine dissection of the genome.
PMID- 9560398
TI - Effects of A and B Wolbachia and host genotype on interspecies cytoplasmic
incompatibility in Nasonia.
AB - Wolbachia endosymbionts cause postmating reproductive isolation between the
sibling species Nasonia vitripennis and N. giraulti. Most Nasonia are doubly
infected with a representative from each of the two major Wolbachia groups (A and
B). This study investigates the role of single (A or B) and double (A and B)
Wolbachia infections in interspecies cytoplasmic incompatibility (CI) and host
genomic influences on the incompatibility phenotype. Results show that the single
A Wolbachia harbored in N. vitripennis (wAv) is bidirectionally incompatible with
the single A Wolbachia harbored in N. giraulti (wAg). Results also indirectly
show that the N. vitripennis wBv is bidirectionally incompatible with the N.
giraulti wBg. The findings support current phylogenetic evidence that suggests
these single infections have independent origins and were acquired via horizontal
transfer. The wAv Wolbachia expresses partial CI in the N. vitripennis nuclear
background. However, following genomic replacement by introgression, wAv
expresses complete CI in the N. giraulti background and remains bidirectionally
incompatible with wAg. Results show that double infections can reinforce
interspecies reproductive isolation through the addition of incompatibility types
and indicate that the host genome can influence incompatibility levels. This
study has implications for host-symbiont coevolution and the role of Wolbachia in
speciation.
PMID- 9560399
TI - Second-site noncomplementation identifies genomic regions required for Drosophila
nonmuscle myosin function during morphogenesis.
AB - Drosophila is an ideal metazoan model system for analyzing the role of nonmuscle
myosin-II (henceforth, myosin) during development. In Drosophila, myosin function
is required for cytokinesis and morphogenesis driven by cell migration and/or
cell shape changes during oogenesis, embryogenesis, larval development and pupal
metamorphosis. The mechanisms that regulate myosin function and the
supramolecular structures into which myosin incorporates have not been
systematically characterized. The genetic screens described here identify genomic
regions that uncover loci that facilitate myosin function. The nonmuscle myosin
heavy chain is encoded by a single locus, zipper. Contiguous chromosomal
deficiencies that represent approximately 70% of the euchromatic genome were
screened for genetic interactions with two recessive lethal alleles of zipper in
a second-site noncomplementation assay for the malformed phenotype. Malformation
in the adult leg reflects aberrations in cell shape changes driven by myosin
based contraction during leg morphogenesis. Of the 158 deficiencies tested, 47
behaved as second-site noncomplementors of zipper. Two of the deficiencies are
strong interactors, 17 are intermediate and 28 are weak. Finer genetic mapping
reveals that mutations in cytoplasmic tropomyosin and viking (collagen IV) behave
as second-site noncomplementors of zipper during leg morphogenesis and that
zipper function requires a previously uncharacterized locus, E3.10/J3.8, for leg
morphogenesis and viability.
PMID- 9560400
TI - A proline-rich region in the Zeste protein essential for transvection and white
repression by Zeste.
AB - The DNA-binding protein encoded by the zeste gene of Drosophila activates
transcription and mediates interchromosomal interactions such as transvection.
The mutant protein encoded by the zeste1 (z1) allele retains the ability to
support transvection, but represses white. Similar to transvection, repression
requires Zeste-Zeste protein interactions and a second copy of white, either on
the homologous chromosome or adjacent on the same chromosome. We characterized
two pseudorevertants of z1 (z1-35 and z1-42) and another zeste mutation (z78c)
that represses white. The z1 lesion alters a lysine residue located between the N
terminal DNA-binding domain and the C-terminal hydrophobic repeats involved in
Zeste self-interactions. The z78c mutation alters a histidine near the site of
the z1 lesion. Both z1 pseudorevertants retain the z1 lesion and alter different
prolines in a proline-rich region located between the z1 lesion and the self
interaction domain. The pseudorevertants retain the ability to self-interact, but
fail to repress white or support transvection at Ultrabithorax. To account for
these observations and evidence indicating that Zeste affects gene expression
through Polycomb group (Pc-G) protein complexes that epigenetically maintain
chromatin states, we suggest that the regions affected by the z1, z78c, and
pseudorevertant lesions mediate interactions between Zeste and the maintenance
complexes.
PMID- 9560401
TI - Evidence for a multistep control in transposition of I factor in Drosophila
melanogaster.
AB - Drosophila melanogaster strains belong to one of two interactive categories,
inducer (I) or reactive (R), with respect to the I-R system of hybrid dysgenesis.
The dysgenic interaction results from the presence of several transposition
competent copies of a LINE-like element, the I factor, only in the genome of I
strains. When a cross is performed between I males and R females, I factor
transposes at high frequency in the germ line of F1 daughters, known as SF
females. This transposition burst results in the sterility of SF females. I
factor transposes by reverse transcription of a full-length transcript. Specific
RT-PCR experiments were done to compare the amount of I factor transcript in
samples corresponding to various transposition frequencies. The sensitivity of
the method allowed the ready detection of the I factor RNA in every tissue and
genetic background examined. Comparison of amplification signals suggests that I
factor activity in ovaries is regulated at different levels. First, the amount of
I factor RNA subjected to negative and positive regulation. Whereas the negative
control, which limits transposition in nonpermissive contexts, may be exerted by
an I factor encoded repressor function, the positive control is linked to
reactivity level, a cellular state maternally inherited from R mothers.
Additionally, negative regulation is also exerted downstream of I factor RNA.
This differs notably from previous conclusions in which transcription was
envisaged as the main level of regulation of the I factor transposition.
PMID- 9560402
TI - Epistatic interactions between smell-impaired loci in Drosophila melanogaster.
AB - Odor-guided behavior is a polygenic trait determined by the concerted expression
of multiple loci. Previously, P-element mutagenesis was used to identify single
P[lArB] insertions, in a common isogenic background, with homozygous effects on
olfactory behavior. Here, we have crossed 12 lines with these smell impaired
(smi) mutations in a half-diallel design (excluding homozygous parental genotypes
and reciprocal crosses) to produce all possible 66 doubly heterozygous hybrids
with P[lArB] insertions at two distinct locations. The olfactory behavior of the
transheterozygous progeny was measured using an assay that quantified the
avoidance response to the repellent odorant benzaldehyde. There was significant
variation in general combining abilities of avoidance scores among the smi
mutants, indicating variation in heterozygous effects. Further, there was
significant variation among specific combining abilities of each cross,
indicating dependencies of heterozygous effects on the smi locus genotypes, i.e.,
epistasis. Significant epistatic interactions were identified for nine
transheterozygote genotypes, involving 10 of the 12 smi loci. Eight of these loci
form an interacting ensemble of genes that modulate expression of the behavioral
phenotype. These observations illustrate the power of quantitative genetic
analyses to detect subtle phenotypic effects and point to an extensive network of
epistatic interactions among genes in the olfactory subgenome.
PMID- 9560403
TI - Early effect of inbreeding as revealed by microsatellite analyses on Ostrea
edulis larvae.
AB - This paper reports new experimental evidence on the effect of inbreeding on
growth and survival in the early developmental phase of a marine bivalve, the
flat oyster Ostrea edulis. Two crosses between full sibs were analyzed using four
microsatellite markers. Samples of 96 individuals were taken just after spawning
(day 1), at the end of the larval stage before metamorphosis (day 10) and at the
postlarval stage (day 70). Significant departure from Mendelian expectation was
observed at two loci in the first cross and two loci in the second. Departure
from 1:1 segregation occurred in one parent of the first cross at three loci and
genotypic selection, which resulted in highly significant heterozygote excesses,
was recorded at three out of four loci in cross C1 and at two out of three loci
in cross C2. Across the four markers, there were similar significant excesses of
multilocus heterozygosity, and significant multilocus heterozygosity-growth
correlations were recorded for both crosses at all stages. These results suggest
that microsatellite markers, often assumed to be neutral, cosegregated with
fitness-associated genes, the number of which is estimated to be between 15 and
38 in the whole genome, and that there is a potentially high genetic load in
Ostrea edulis genome. This load provides a genetic basis for heterosis in marine
bivalves.
PMID- 9560404
TI - Heteroplasmy, length and sequence variation in the mtDNA control regions of three
percid fish species (Perca fluviatilis, Acerina cernua, Stizostedion lucioperca).
AB - The nucleotide sequence of the control region and flanking tRNA genes of perch
(Perca fluviatilis) mtDNA was determined. The organization of this region is
similar to that of other vertebrates. A tandem array of 10-bp repeats, associated
with length variation and heteroplasmy was observed in the 5' end. While the
location of the array corresponds to that reported in other species, the length
of the repeated unit is shorter than previously observed for tandem repeats in
this region. The repeated sequence was highly similar to the Mt5 element which
has been shown to specifically bind a putative D-loop DNA termination protein. Of
149 perch analyzed, 74% showed length variation heteroplasmy. Single-cell PCR on
oocytes suggested that the high level of heteroplasmy is passively maintained by
maternal transmission. The array was also observed in the two other percid
species, ruffe (Acerina cernua) and zander (Stizostedion lucioperca). The array
and the associated length variation heteroplasmy are therefore likely to be
general features of percid mtDNAs. Among the perch repeats, the mutation pattern
is consistent with unidirectional slippage, and statistical analyses supported
the notion that the various haplotypes are associated with different levels of
heteroplasmy. The variation in array length among and within species is ascribed
to differences in predicted stability of secondary structures made between repeat
units.
PMID- 9560405
TI - Signatures of population expansion in microsatellite repeat data.
AB - To examine the signature of population expansion on genetic variability at
microsatellite loci, we consider a population that evolves according to the time
continuous Moran model, with growing population size and mutations that follow a
general asymmetric stepwise mutation model. We present calculations of expected
allele-size variance and homozygosity at a locus in such a model for several
variants of growth, including stepwise, exponential, and logistic growth. These
calculations in particular prove that population bottleneck followed by growth in
size causes an imbalance between allele size variance and heterozygosity,
characterized by the variance being transiently higher than expected under
equilibrium conditions. This effect is, in a sense, analogous to that
demonstrated before for the infinite allele model, where the number of alleles
transiently increases after a stepwise growth of population. We analyze a set of
data on tetranucleotide repeats that reveals the imbalance expected under the
assumption of bottleneck followed by population growth in two out of three major
racial groups. The imbalance is strongest in Asians, intermediate in Europeans,
and absent in Africans. This finding is consistent with previous findings by
others concerning the population expansion of modern humans, with the bottleneck
event being most ancient in Africans, most recent in Asians, and intermediate in
Europeans. Nevertheless, the imbalance index alone cannot reliably estimate the
time of initiation of population expansion.
PMID- 9560406
TI - Genetic basis of response to 50 generations of selection on body weight in inbred
mice.
AB - A long-established inbred strain of mice was divergently selected for body weight
for 50 generations. Selection of new mutations affecting the trait eventually led
to a divergence of approximately three phenotypic standard deviations between the
high and low lines. Heritability for body weight increased at a rate between
0.23% and 0.57% per generation from new mutations, depending on the genetic model
assumed. About two-thirds of the selection response was in the upward direction.
The response was episodic, suggesting a substantial contribution from the
selection of mutations with large effects on the trait. A maximum likelihood
procedure was used to estimate the number of factors contributing to the response
using data from line crosses, with models of n equivalent gene effects (i.e., to
estimate the Wright-Castle index), or n genes with variable effects. The results
of the analysis of data from a cross between the selected high line and an
unselected control line indicated that two major factors were involved, with the
suggestion of an additional minor factor.
PMID- 9560407
TI - Chromosome 14 contains determinants that regulate susceptibility to Theiler's
virus-induced demyelination in the mouse.
AB - Theiler's murine encephalomyelitis virus causes a chronic demyelinating disease
in susceptible strains of mice that is similar to human multiple sclerosis.
Several nonmajor histocompatibility complex-linked genes have been implicated as
determinants of susceptibility or resistance to either demyelination or virus
persistence. In this study, we used linkage analysis of major histocompatibility
complex identical H-2d (DBA/2J x B10.D2) F2 intercross mice to identify loci
associated with susceptibility to virus-induced demyelinating disease. In a 20-cM
region on chromosome 14, we identified four markers, D14Mit54, D14Mit60,
D14Mit61, and D14Mit90 that are significantly associated with demyelination.
Because two peaks were identified, one near D14Mit54 and one near D14Mit90, it is
possible that two loci in this region are involved in controlling demyelination.
PMID- 9560408
TI - Molecular genetic dissection of mouse unconventional myosin-VA: head region
mutations.
AB - The mouse dilute (d) locus encodes unconventional myosin-VA (MyoVA). Mice
carrying null alleles of dilute have a lightened coat color and die from a
neurological disorder resembling ataxia and opisthotonus within three weeks of
birth. Immunological and ultrastructural studies suggest that MyoVA is involved
in the transport of melanosomes in melanocytes and smooth endoplasmic reticulum
in cerebellar Purkinje cells. In studies described here, we have used an RT-PCR
based sequencing approach to identify the mutations responsible for 17 viable
dilute alleles that vary in their effects on coat color and the nervous system.
Seven of these mutations mapped to the MyoVA motor domain and are reported here.
Crystallographic modeling and mutant expression studies were used to predict how
these mutations might affect motor domain function and to attempt to correlate
these effects with the mutant phenotype.
PMID- 9560409
TI - Molecular genetic dissection of mouse unconventional myosin-VA: tail region
mutations.
AB - We used an RT-PCR-based sequencing approach to identify the mutations responsible
for 17 viable dilute alleles, a mouse-coat-color locus encoding unconventional
myosin-VA. Ten of the mutations mapped to the MyoVA tail and are reported here.
These mutations represent the first extensive collection of tail mutations
reported for any unconventional mammalian myosin. They identify sequences
important for tail function and identify domains potentially involved in cargo
binding and/or proper folding of the MyoVA tail. Our results also provide support
for the notion that different myosin tail isoforms produced by alternative
splicing encode important cell-type-specific functions.
PMID- 9560410
TI - Paramutation of the r1 locus of maize is associated with increased cytosine
methylation.
AB - In paramutation two alleles of a gene interact so that one of the alleles is
epigenetically silenced. The silenced state is then genetically transmissible for
many generations. The large (220 kbp) multigenic complex R-r is paramutable: its
level of expression is changed during paramutation. R-r was found to exhibit
increases in its level of cytosine methylation (C-methylation) following
paramutation. These C-methylation changes are localized to the 5' portions of the
two genes in the complex that are most sensitive to paramutation. These
methylation changes flank a small region called sigma that is thought to have
been derived from a transposon named doppia. A mutant derivative of R-r that has
a deletion of the sigma region fails to become methylated under conditions in
which R-r is heavily methylated. This suggests that the presence of sigma
sequences at the locus is required for the methylation changes that are observed
following paramutation.
PMID- 9560411
TI - Physical mapping of the liguleless linkage group in Sorghum bicolor using rice
RFLP-selected sorghum BACs.
AB - Physical mapping of BACs by fluorescent in situ hybridization (FISH) was used to
analyze the liguleless (lg-1) linkage group in sorghum and compare it to the
conserved region in rice and maize. Six liguleless-associated rice restriction
fragment length polymorphism (RFLP) markers were used to select 16 homeologous
sorghum BACs, which were in turn used to physically map the liguleless linkage
group in sorghum. Results show a basic conservation of the liguleless region in
sorghum relative to the linkage map of rice. One marker which is distal in rice
is more medial in sorghum, and another marker which is found within the linkage
group in rice is on a different chromosome in sorghum. BACs associated with
linkage group I hybridize to chromosome It, which was identified by using FISH in
a sorghum cytogenetic stock trisomic for chromosome I (denoted It), and a BAC
associated with linkage group E hybridized to an unidentified chromosome.
Selected BACs, representing RFLP loci, were end-cloned for RFLP mapping, and the
relative linkage order of these clones was in full agreement with the physical
data. Similarities in locus order and the association of RFLP-selected BAC
markers with two different chromosomes were found to exist between the linkage
map of the liguleless region in maize and the physical map of the liguleless
region in sorghum.
PMID- 9560412
TI - High apparent rate of simultaneous compensatory base-pair substitutions in
ribosomal RNA.
AB - We present a model for the evolution of paired bases in RNA sequences. The new
model allows for the instantaneous rate of substitution of both members of a base
pair in a compensatory substitution (e.g., A-U-->G-C) and expands our previous
work by allowing for unpaired bases or noncanonical pairs. We implemented the
model with distance and maximum likelihood methods to estimate the rates of
simultaneous substitution of both bases, alphad, vs. rates of substitution of
individual bases, alphas in rRNA. In the rapidly evolving D2 expansion segments
of Drosophila large subunit rRNA, we estimate a low ratio of alphad/alphas,
indicating that most compensatory substitutions involve a G-U intermediate. In
contrast, we find a surprisingly high ratio of alphad/alphas in the core small
subunit rRNA, indicating that the evolution of the slowly evolving rRNA sequences
is modeled much more accurately if simultaneous substitution of both members of a
base pair is allowed to occur approximately as often as substitution of
individual bases. Using simulations, we have ruled out several potential sources
of error in the estimation of alphad/alphas. We conclude that in the core rRNA
sequences compensatory substitutions can be fixed so rapidly as to appear to be
instantaneous.
PMID- 9560413
TI - Estimating within-locus nonadditive coefficient and discriminating dominance
versus overdominance as the genetic cause of heterosis.
AB - Testing (over)dominance as the genetic cause of heterosis and estimating the
(over)dominance coefficient (h) are related. Using simulations, we investigate
the statistical properties of Mukai's approach, which is intended to estimate the
average (h) of hi across loci by regression of outcrossed progeny on the sum of
the two corresponding homozygous parents. A new approach for estimating h is also
developed, utilizing data on families formed by multiple selfed genotypes from
each outcrossed parent, thus not requiring constructing homozygotes. Assuming
constant mutation effects, h can be estimated accurately by both approaches under
dominance. When rare alleles have low frequencies at any polymorphic locus,
Mukai's approach can estimate h accurately under over(under)dominance. Therefore,
the (over)dominance hypothesis for heterosis can be tested by estimating h, under
either dominance or overdominance at all genomic loci. However, this is invalid
with more plausible mixed dominance and overdominance at different loci.
Estimating the variance of hi across loci is also investigated. In self
compatible outcrossing populations with mutations of variable effects and
lethals, our new approach is better than Mukai's, not only because of not
requiring homozygotes but also because of the better statistical performance
reflected by the smaller mean square errors of the estimates.
PMID- 9560414
TI - Approximate analysis of QTL-environment interaction with no limits on the number
of environments.
AB - An approach is presented here for quantitative trait loci (QTL) mapping analysis
that allows for QTL x environment (E) interaction across multiple environments,
without necessarily increasing the number of parameters. The main distinction of
the proposed model is in the chosen way of approximation of the dependence of
putative QTL effects on environmental states. We hypothesize that environmental
dependence of a putative QTL effect can be represented as a function of
environmental mean value of the trait. Such a description can be applied to take
into account the effects of any cosegregating QTLs from other genomic regions
that also may vary across environments. The conducted Monte-Carlo simulations and
the example of barley multiple environments experiment demonstrate a high
potential of the proposed approach for analyzing QTL x E interaction, although
the results are only approximated by definition. However, this drawback is
compensated by the possibility to utilize information from a potentially
unlimited number of environments with a remarkable reduction in the number of
parameters, as compared to previously proposed mapping models with QTL x E
interactions.
PMID- 9560415
TI - Genetic diversity at a single locus under viability selection and facultative
apomixis: equilibrium structure and deviations from Hardy-Weinberg frequencies.
AB - We extensively analyze the maintenance of genetic variation and deviations from
Hardy-Weinberg frequencies at a diallelic locus under mixed mating with apomixis
and constant viability selection. Analytical proofs show that: (1) at most one
polymorphic equilibrium exists, (2) polymorphism requires overdominant or
underdominant selection, and (3) a simple, modified overdominance condition is
sufficient to maintain genetic variation. In numerical analyses, only
overdominant polymorphic equilibria are stable, and these are stable whenever
they exist, which happens for approximately 78% of random fitness and mating
parameters. The potential for maintaining both alleles increases with increasing
apomixis or outcrossing and decreasing selfing. Simulations also indicate that
equilibrium levels of heterozygosity will often be statistically
indistinguishable from Hardy-Weinberg frequencies and that adults, not seeds,
should usually be censused to maximize detecting deviations. Furthermore,
although both censuses more often have an excess rather than a deficit of
heterozygotes, analytical sign analyses of the fixation indices prove that,
overall, adults are more likely to have an excess and seeds a deficit at
equilibrium.
PMID- 9560416
TI - The oxygen-responsive NIFL-NIFA complex: a novel two-component regulatory system
controlling nitrogenase synthesis in gamma-proteobacteria.
AB - The high energetic requirements for nitrogen fixation and the extreme oxygen
sensitivity of the nitrogenase enzyme impose physiological constraints on
diazotrophy that necessitate stringent control of nitrogen fixation (nif) gene
expression at the transcriptional level. In the gamma-subdivision of the
Proteobacteria, this control is maintained by a regulatory complex comprising an
enhancer-binding protein (NIFA), which activates transcription at sigmaN
dependent nif (nitrogen fixation) promoters, and a sensor protein (NIFL), which
inhibits NIFA activity in response to fixed nitrogen and external concentrations
of molecular oxygen. Inhibition of NIFA activity by NIFL apparently requires
stoichiometric amounts of the two proteins, implying direct protein-protein
interaction rather than catalytic modulation of NIFA activity. NIFL contains FAD
as a prosthetic group and is a novel type of flavoprotein in which the oxidation
state of the bound flavin acts as a molecular switch to control transcriptional
activation by NIFA. The FAD-binding domain of NIFL contains a motif common to a
large family of redox sensory proteins. In addition to its ability to act as a
redox sensor, the activity of NIFL is also responsive to adenosine nucleotides,
particularly ADP, suggesting that formation of the inhibitory complex might be
regulated by the ATP/ ADP ratio. Proposed mechanisms for the inhibition of NIFA
activity by NIFL are beginning to emerge.
PMID- 9560417
TI - Characterization of a new Agrobacterium tumefaciens strain from alfalfa.
AB - Agrobacterium tumefaciens strain 1D1609 is reported here as the first field
isolate from alfalfa (Medicago sativa L.). Unlike well-characterized A.
tumefaciens strains such as C58 and Ach5, strain 1D1609 is highly virulent on
alfalfa and has a distinctive host range. Interestingly, strain 1D1609 is
naturally resistant to kanamycin and spectinomycin. The Ti plasmid in strain
1D1609 is an octopine-type; thus, tumors formed by strain 1D1609 synthesize
octopine, which is utilized by the bacterium as a sole carbon source. Reciprocal
exchange of Ti plasmids between strains 1D1609 and C58 showed that both
chromosomal and Ti plasmid genes in strain 1D1609 contribute specifically to
tumor formation on alfalfa. In addition, the nondormant CUF101 alfalfa cultivar
from which strain 1D1609 was isolated was significantly more susceptible to all
Agrobacterium strains tested than was the dormant Agate cultivar.
PMID- 9560418
TI - Rapid identification of wine yeast species based on RFLP analysis of the
ribosomal internal transcribed spacer (ITS) region.
AB - In this study, we identified a total of 33 wine yeast species and strains using
the restriction patterns generated from the region spanning the internal
transcribed spacers (ITS 1 and 2) and the 5.8S rRNA gene. Polymerase chain
reaction (PCR) products of this rDNA region showed a high length variation for
the different species. The size of the PCR products and the restriction analyses
with three restriction endonucleases (HinfI, CfoI, and HaeIII) yielded a specific
restriction pattern for each species with the exception of the corresponding
anamorph and teleomorph states, which presented identical patterns. This method
was applied to analyze the diversity of wine yeast species during spontaneous
wine fermentation.
PMID- 9560419
TI - The Helicobacter felis ftsH gene encoding an ATP-dependent metalloprotease can
replace the Escherichia coli homologue for growth and phage lambda
lysogenization.
AB - Cloning and sequencing of an approximately 6.0-kb chromosomal DNA fragment from
Helicobacter felis revealed five complete open reading frames. The deduced amino
acid sequence of one ORF exhibited sequence similarity to the FtsH protein, an
ATP-dependent metalloprotease, from various bacterial species. The encoded
protein consists of 638 amino acid residues with a molecular mass of 70.2 kDa.
The hydropathy profile of the FtsH protein predicted two N-terminal transmembrane
regions that were confirmed experimentally. Insertion of ftsH into a new
versatile expression vector resulted in overexpression of FtsH protein in
Escherichia coli. In addition, the E. coli ftsH gene could be replaced by the H.
felis homologue to allow reduced growth and tenfold increased lysogenization by
temperate phage lambda.
PMID- 9560420
TI - Phylogenetic analysis of Methanobrevibacter isolated from feces of humans and
other animals.
AB - Comparative 16S rRNA gene sequence and genomic DNA reassociation analyses were
used to assess the phylogenetic relationships of Methanobrevibacter fecal
isolates. The 16S rRNA gene sequences of Methanobrevibacter smithii strain PS and
the human fecal isolates B181 and ALI were essentially identical, and their
genomic DNA reassociated at values greater than 94%. The analysis of 16S rRNA
sequences of the horse, pig, cow, rat, and goose fecal isolates confirm that they
are members of the genus Methanobrevibacter. They had a high degree of sequence
similarity (97-98%) with the 16S rRNA gene of M. smithii, indicating that they
share a common line of descent. The 16S rRNA genes of the horse and pig isolates
had 99.3% sequence similarity. Sequence analysis of the 16S rRNA gene of the
sheep fecal isolate showed that it formed a separate line of descent in the genus
Methanobrevibacter. Genomic DNA reassociation studies indicate that the horse,
pig, cow, and goose fecal isolates represent at least three new species. The
horse and pig isolates were the only animal isolates that had > 70% genomic DNA
reassociation and represent strains of a single species. The cow, goose, and
sheep isolates had little or no genomic DNA reassociation with M. smithii or with
each other. The relationship of the rat isolate to the other animal isolates was
not determined. An evaluation of the relationship of 16S rRNA gene sequence
similarity and genomic DNA reassociation of Methanobrevibacter and other
methanogenic archaea indicated that genomic DNA reassociation studies are
necessary to establish that two methanogenic organisms belong to the same
species.
PMID- 9560421
TI - Genetic evidence for a role of thioesterase domains, integrated in or associated
with peptide synthetases, in non-ribosomal peptide biosynthesis in Bacillus
subtilis.
AB - Next to almost all prokaryotic operons encoding peptide synthetases, which are
involved in the nonribosomal synthesis of peptide antibiotics, distinct genes
have been detected that encode proteins with strong sequence similarity to type
II fatty acid thioesterases of vertebrate origin. Furthermore, sequence analysis
of bacterial and fungal peptide synthetases has revealed a region at the C
terminal end of modules that are responsible for adding the last amino acid to
the peptide antibiotics; that region also exhibits significant similarities to
thioesterases. In order to investigate the function of these putative
thioesterases in non-ribosomal peptide synthesis of the lipopeptide antibiotic
surfactin in Bacillus subtilis, srfA fragments encoding the thioesterase domain
of the surfactin synthetase 3 and the thioesterase-like protein SrfA-TE were
deleted. This led to a 97 and 84% reduction of the in vivo surfactin production,
respectively. In the double mutant, however, no surfaction production was
detectable. These findings demonstrate for the first time that the C-terminal
thioesterase domains and the SrfA-TE protein are directly involved in
nonribosomal peptide biosynthesis.
PMID- 9560422
TI - Urea uptake and urease activity in Corynebacterium glutamicum.
AB - When Corynebacterium glutamicum is grown with a sufficient nitrogen supply, urea
crosses the cytoplasmic membrane by passive diffusion. A permeability coefficient
for urea diffusion of 9 x 10(-7) cm s-1 was determined. Under conditions of
nitrogen starvation, an energy-dependent urea uptake system was synthesized.
Carrier-mediated urea transport was catalyzed by a secondary transport system
linked with proton motive force. With a Km for urea of 9 microM, the affinity of
this uptake system was much higher than the affinity of urease towards its
substrate (Km approximately 55 mM urea). The maximum uptake velocity depended on
the expression level and was relatively low [2-3.5 nmol min-1 (mg dry wt.)-1].
PMID- 9560423
TI - Characterization of HetR protein turnover in Anabaena sp. PCC 7120.
AB - The hetR gene plays an important role in heterocyst development and pattern
formation in heterocystous cyanobacteria. The hetR gene from Anabaena sp. PCC
7120 was overexpressed in Escherichia coli. Antibodies raised against the
recombinant HetR protein (rHetR) were used to characterize metabolism of the HetR
of Anabaena sp. PCC 7120 in vivo. HetR was present at a low level when Anabaena
sp. PCC 7120 was grown in the presence of combined nitrogen. Shifting from
nitrogen repletion conditions to nitrogen depletion conditions led to a two fold
increase of HetR in total cell extracts, and most of HetR was located in
heterocysts. The amount of HetR in total cellular extracts increased rapidly
after shifting to nitrogen depletion conditions and reached a maximum level 3 h
after the shift. Isoelectrofocusing electrophoresis revealed that the native HetR
had a more acidic isoelectric point than did rHetR. After combined nitrogen was
added to the nitrogen-depleted cultures, the degradation of HetR depended on
culture conditions: before heterocysts were fully developed, HetR was rapidly
degraded; after heterocysts were fully developed, HetR was degraded much more
slowly. The distribution of HetR in other species of cyanobacteria was also
studied.
PMID- 9560424
TI - A periplasmic flavoprotein in Wolinella succinogenes that resembles the fumarate
reductase of Shewanella putrefaciens.
AB - During growth with fumarate as the terminal electron transport acceptor and
either formate or sulfide as the electron donor, Wolinella succinogenes induced a
peri-plasmic protein (54 kDa) that reacted with an antiserum raised against the
periplasmic fumarate reductase (Fcc) of Shewanella putrefaciens. However, the
periplasmic cell fraction of W. succinogenes did not catalyze fumarate reduction
with viologen radicals. W. succinogenes grown with polysulfide instead of
fumarate contained much less (< 10%) of the 54-kDa antigen, and the antigen was
not detectable in nitrate-grown bacteria. The antigen was most likely encoded by
the fccA gene of W. succinogenes. The antigen was absent from a DeltafccABC
mutant, and its size is close to that of the protein predicted by fccA. The fccA
gene probably encodes a pre-protein carrying an N-terminal signal peptide. The
sequence of the mature FccA (481 residues, 52.4 kDa) is similar (31% identity) to
that of the C-terminal part (450 residues) of S. putrefaciens fumarate reductase.
As indicated by Northern blot analysis, fccA is cotranscribed with fccB and fccC.
The proteins predicted from the fccB and fccC gene sequences represent tetraheme
cytochromes c. FccB is similar to the N-terminal part (150 residues) of S.
putrefaciens fumarate reductase, while FccC resembles the tetraheme cytochromes c
of the NirT/NapC family. The DeltafccABC mutant of W. succinogenes grew with
fumarate and formate or sulfide, suggesting that the deleted proteins were not
required for fumarate respiration with either electron donor.
PMID- 9560427
TI - Two new motile phototrophic consortia: "Chlorochromatium lunatum" and
"Pelochromatium selenoides"
AB - Two new phototrophic consortia, "Chlorochromatium lunatum" and "Pelochromatium
selenoides", were observed and collected in the hypolimnion of several dimictic
lakes in Wisconsin and Michigan (USA). The two consortia had the same morphology
but different pigment composition. The cells of the photosynthetic components of
the consortia were half-moon-shaped. This morphology was used to differentiate
them from the previously described motile phototrophic consortia
"Chlorochromatium aggregatum" and "Pelochromatium roseum". These phototrophic
cells did not resemble any described unicellular green sulfur bacteria. The
predominant pigments detected were bacteriochlorophyll d and chlorobactene for
the green-colored "Clc. lunatum", and bacteriochlorophyll e and isorenieratene
for the brown-colored "Plc. selenoides". Their pigment compositions and the
presence of chlorosomes attached to the inner face of the cytoplasmic membrane in
both kinds of photosynthetic cells confirmed this new half-moon-shaped morphotype
as a green sulfur bacterium. Both consortia were found thriving in lakes with low
concentrations of sulfide (< 60 &mgr;M), below the layers of "Clc. aggregatum"
and "Plc. roseum". The green consortia were observed in lakes where the oxic
anoxic interface was located at shallow depths (2-7 m), while the brown consortia
were found at greater depths (8-16 m). The two newly described consortia were
never detected together at the same depth in any lake.
PMID- 9560426
TI - Isocitrate dehydrogenase and glyoxylate cycle enzyme activities in Bradyrhizobium
japonicum under various growth conditions.
AB - Bradyrhizobium japonicum, the nitrogen-fixing symbiotic partner of soybean, was
grown on various carbon substrates and assayed for the presence of the glyoxylate
cycle enzymes, isocitrate lyase and malate synthase. The highest levels of
isocitrate lyase [165-170 nmol min-1 (mg protein)-1] were found in cells grown on
acetate or beta-hydroxybutyrate, intermediate activity was found after growth on
pyruvate or galactose, and very little activity was found in cells grown on
arabinose, malate, or glycerol. Malate synthase activity was present in arabinose
and malate-grown cultures and increased by only 50-80% when cells were grown on
acetate. B. japonicum bacteroids, harvested at four different nodule ages, showed
very little isocitrate lyase activity, implying that a complete glyoxylate cycle
is not functional during symbiosis. The apparent Km of isocitrate lyase for D,L
isocitrate was fourfold higher than that of isocitrate dehydrogenase (61.5 and
15.5 microM, respectively) in desalted crude extracts from acetate-grown B.
japonicum. When isocitrate lyase was induced, neither the Vmax nor the D,L
isocitrate Km of isocitrate dehydrogenase changed, implying that isocitrate
dehydrogenase is not inhibited by covalent modification to facilitate operation
of the glyoxylate cycle in B. japonicum.
PMID- 9560425
TI - Molecular genetic evidence for extracytoplasmic localization of sulfur globules
in Chromatium vinosum.
AB - Purple sulfur bacteria store sulfur as intracellular globules enclosed by a
protein envelope. We cloned the genes sgpA, sgpB, and sgpC, which encode the
three different proteins that constitute the sulfur globule envelope of
Chromatium vinosum D (DSMZ 180(T)). Southern hybridization analyses and
nucleotide sequencing showed that these three genes are not clustered in the same
operon. All three genes are preceded by sequences resembling sigma70-dependent
promoters, and hairpin structures typical for rho-independent terminators are
found immediately downstream of the translational stop codons of sgpA, sgpB, and
sgpC. Insertional inactivation of sgpA in Chr. vinosum showed that the presence
of only one of the homologous proteins SgpA and SgpB suffices for formation of
intact sulfur globules. All three sgp genes encode translation products which -
when compared to the isolated proteins - carry amino-terminal extensions. These
extensions meet all requirements for typical signal peptides indicating an
extracytoplasmic localization of the sulfur globule proteins. A fusion of the
phoA gene to the sequence encoding the proposed signal peptide of sgpA led to
high specific alkaline phosphatase activities in Escherichia coli, further
supporting the envisaged targeting process. Together with electron microscopic
evidence these results provide strong indication for an extracytoplasmic
localization of the sulfur globules in Chr. vinosum and probably in other
Chromatiaceae. Extracytoplasmic formation of stored sulfur could contribute to
the transmembranous Deltap that drives ATP synthesis and reverse electron flow in
Chr. vinosum.
PMID- 9560428
TI - Fractionation of sulfur isotopes during thiosulfate reduction by desulfovibrio
desulfuricans
AB - Sulfur isotope fractionation during reduction of thiosulfate was investigated
with growing batch cultures of Desulfovibrio desulfuricans CSN (DSM 9104) at 30
degreesC. The sulfide produced was depleted in 34S by 10 per thousand as compared
to total thiosulfate sulfur. The depletion was equal to that during sulfate
reduction under similar conditions. The two sulfur atoms of the thiosulfate
molecule were affected differently by fractionation. Sulfide produced from
sulfonate sulfur was depleted by 15.4 per thousand, sulfide produced from sulfane
sulfur by 5.0 per thousand.
PMID- 9560429
TI - The rnf gene products in rhodobacter capsulatus play an essential role in
nitrogen fixation during anaerobic DMSO-dependent growth in the dark
AB - The rnf genes in Rhodobacter capsulatus are essential for nitrogen fixation in
the light. Because R. capsulatus grows readily on N2 in the dark by anaerobic
respiration with dimethylsulfoxide, the diazotrophic capacities of various
strains in the dark were examined. No rnf mutants tested grew diazotrophically,
and a nonpolar fdxN-null mutant showed decreased diazotrophic growth in the dark,
suggesting that the Rnf and FdxN proteins form the primary electron donor pathway
to nitrogenase in the dark as well as in the light. Nonphotosynthetic mutants
lacking the component of cyclic electron transport grew diazotrophically and the
levels of Rnf proteins were similar to those of the wild-type. These results
indicate that rnf gene products play an essential role in nitrogen fixation
without any functional link to the cyclic electron transport system.
PMID- 9560430
TI - The Tup1-Ssn6 general repressor is involved in repression of IME1 encoding a
transcriptional activator of meiosis in Saccharomyces cerevisiae.
AB - Ime1 plays a pivotal role in the initiation of meiosis in a/alpha diploid cells
of Saccharomyces cerevisiae. In the absence of glucose and nitrogen, IME1
expression is greater in a/alpha cells than in either a or alpha cells and
therefore only a/alpha, but not a/a or alpha/alpha, cells are committed to
sporulation. It is known that IME1 expression is positively regulated by Mck1,
Rim1, Ime4 and the Swi-Snf complex but other factors may also be involved. In
addition, Rme1 is assumed to repress IME1 expression. To provide more details of
the repression of expression of IME1, we have isolated mutants in which the IME1p
PHO5 fusion gene integrated at the ura3 locus is expressed in alpha cells under
nutritionally rich conditions. We found that mutations occurred in TUP1, SSN6,
SIN4 and RGR1, among which TUP1 and SSN6 were identified for the first time as
negative regulators of IME1 expression. Deletion of the Rme1-binding site from
the IME1 promoter did not result in activation of the expression of IME1 under
nutritionally rich conditions, suggesting that Rme1 does not function as a DNA
binding protein with the Tup1-Ssn6 repression complex. We also demonstrated that
the 294-bp fragment from nucleotide position -914 to -621 and the 301-bp fragment
from nucleotide position -1215 to -915 of the IME1 promoter region contain
elements acting as URS and UAS in TUP1+ and tup1 mutant cells, respectively.
These findings indicate that IME1 is negatively regulated by the Tup1-Ssn6
repressor complex through two distinct upstream regions in conjunction with
unidentified DNA-binding proteins.
PMID- 9560431
TI - S. pombe sck2+, a second homologue of S. cerevisiae SCH9 in fission yeast,
encodes a putative protein kinase closely related to PKA in function.
AB - The Schizosaccharomyces pombe sck2 gene, originally identified as SPAC22E12.14c
in the genome-sequencing project, encodes a putative protein kinase highly
similar to Saccharomyces cerevisiae Sch9p and S. pombe Sck1p, both of which can
suppress loss of cAMP-dependent protein kinase (PKA) if over-produced. Over
expression of sck2 suppressed typical phenotypes of PKA-defective cells,
including ectopic mating, slow growth and short cell morphology. Wild-type cells
over-expressing sck2 behaved like the PKA-hyperactive mutant. Disruption of sck2
caused no obvious phenotype, but it intensified de-repression for sexual
development when combined with the disruption of sck1. The pka1 sck1 sck2 triple
disruptant could grow but only very slowly. Whereas disruption of sck1 enhanced
the inefficiency of Deltapka1 spores in germination, disruption of sck2 did not.
These results suggest that the molecular function of Sck2p largely overlaps with
that of Sck1p, but also that they differ somewhat either quantitatively or
qualitatively.
PMID- 9560432
TI - Exogenous inositol and genes responsible for inositol transport are required for
mating and sporulation in Shizosaccharomyces pombe.
AB - Fission yeast, Schizosaccharomyces pombe, is a natural inositol auxotroph. We
show here that the amount of exogenous inositol added to the medium is critical
for the control of its life cycle. Above growth-limiting concentrations inositol
stimulates mating and sporulation in minimal medium. The effect of inositol is
also observed on yeast-extract-medium plates. We selected a mutant, IM49, which
mates and sporulates only poorly and show that it is defective in inositol
transport. Its defect is in a gene (itr2) coding for a putative 12 membrane
spanning protein. The polypeptide contains the two sugar-transport motifs typical
for hexose transporters and shows good homology to the two Saccharomyces
cerevisiae inositol transporters. The itr2 gene is essential for cell growth and
its mRNA level is repressed by glucose. Mutant IM49 is also complemented by a
multicopy suppressor gene (itr1) which codes for a putative hexose transporter
with unknown substrate specifity.
PMID- 9560433
TI - The Kluyveromyces lactis gene KLGSK-3 combines functions which in Saccharomyces
cerevisiae are performed by MCK1 and MSD1.
AB - The sequence and characterization of the KlGSK-3 gene in chromosome VI
[corrected] from Kluyveromyces lactis is presented. The deduced amino-acid
sequence predicts a protein of 415 amino acids and an Mr of 47 kDa. A computer
search reveals significant homology to serine/threonine protein kinases closely
related to members of the GSK-3 subfamily. The Klgsk-3::URA3 disrupted strain is
unable to grow in glucose at 37 C but KlGSK-3 is not essential for vegetative
growth at 30 C or 14 C. The KlGSK-3 gene presents the highest homology with the
Saccharomyces cerevisiae MDS1 gene. Expression studies show an increase of mRNA
levels caused both by carbon starvation and when diploids are shifted from rich
to sporulation media. The data reported show that KlGSK-3, like MCK1 from S.
cerevisiae, is related to glycogen storage.
PMID- 9560434
TI - Molecular analysis of the LYS2 gene of Candida albicans: homology to peptide
antibiotic synthetases and the regulation of the alpha-aminoadipate reductase.
AB - The unique alpha-aminoadipate pathway for lysine biosynthesis is present only in
fungi and involves eight enzyme steps. alpha-Aminoadipate semialdehyde
dehydrogenase, commonly called alpha-aminoadipate reductase (AAR), catalyzes the
conversion of alpha-aminoadipic acid to alpha-aminoadipic semialdehyde by a novel
mechanism. Two genes, LYS2 and LYS5, encode the heterodimeric enzyme in
Saccharomyces cerevisiae. The LYS2 gene of Candida albicans was shown to be
contained in the 4.8-kb insert of the plasmid pCaLYS2. This plasmid complemented
lys2 mutants of both S. cerevisiae and C. albicans. The S. cerevisiae and C.
albicans Lys2(+) transformants exhibited 138% and 160% of wild-type AAR activity,
respectively. The DNA-sequence analysis of the 4.8-kb region in plasmid pCaLYS2
and a PCR product from genomic DNA which overlapped with the 4.8-kb insert
revealed a continuous ORF of 4173 nucleotides encoding 1391 amino-acid residues.
The C. albicans LYS2 ORF exhibited 63.0% identity at the nucleotide level and
56.2% identity at the amino-acid level to the LYS2 gene of S. cerevisiae. The ORF
is preceded by consensus sequences for the TATA-, CAAT- and GCN4-box elements. An
S. cerevesiae-type transcription termination signal is seen in the 3' flanking
region. The deduced amino-acid sequence revealed a motif for an AMP-binding site
and also the highly conserved core sequences common to peptide antibiotic
synthetases. The LYS2 mRNA and alpha-aminoadipate reductase activity were
repressed to a higher level in YEPD-grown cells than in cells grown in the
presence of lysine or minimal medium. Additionally, AAR was shown to be feedback
inhibited by lysine and the lysine analog, thialysine. The results of the present
report reveal the molecular characteristics of the LYS2 gene of C. albicans, its
homology to peptide antibiotic synthetases, its divergence from the LYS2 gene of
S. cerevisiae, and the regulation of AAR in C. albicans.
PMID- 9560435
TI - Cloning and characterization of the yeast RAD1 homolog gene (mus-38) from
Neurospora crassa: evidence for involvement in nucleotide excision repair.
AB - A Neurospora crassa gene encoding a product with homology to the Saccharomyces
cerevisiae Rad1 nucleotide excision repair (NER) protein was isolated by
degenerate PCR. The predicted protein consists of 892 amino acids with a
molecular weight of 100.4 kDa, and 32-37% identity to the XPF/ERCC4 protein
family. The homolog was mapped to the left arm of linkage group I, the location
of the mus-38 gene. Subsequently, gene inactivation and complementation studies
identified the RAD1 homolog as mus-38. Immunological assays showed that the mus
18 (UV-specific endonuclease) and mus-38 strains have partial and normal UV
damage excision activities, respectively, but removal of thymine dimers and TC (6
4) photoproducts is abolished in the mus-18 mus-38 double mutant. The double
mutant also was synergistically more sensitive to UV than either single mutant.
The data suggest that mus-38 may participate in a different NER pathway from that
involving the mus-18 gene.
PMID- 9560437
TI - Variation in genome organization of the plant pathogenic fungus Colletotrichum
lindemuthianum.
AB - The genome structure of Colletotrichum lindemuthianum in a set of diverse
isolates was investigated using a combination of physical and molecular
approaches. Flow cytometric measurement of genome size revealed significant
variation between strains, with the smallest genome representing 59% of the
largest. Southern-blot profiles of a cloned fungal telomere revealed a total
chromosome number varying from 9 to 12. Chromosome separations using pulsed-field
gel electrophoresis (PFGE) showed that these chromosomes belong to two distinct
size classes: a variable number of small (< 2.5 Mb) polymorphic chromosomes and a
set of unresolved chromosomes larger than 7 Mb. Two dispersed repeat elements
were shown to cluster on distinct polymorphic minichromosomes. Single-copy
flanking sequences from these repeat-containing clones specifically marked
distinct small chromosomes. These markers were absent in some strains, indicating
that part of the observed variability in genome organization may be explained by
the presence or absence, in a given strain, of dispensable genomic regions and/or
chromosomes.
PMID- 9560436
TI - Trichoderma reesei prs12 encodes a stress- and unfolded-protein-response
inducible regulatory subunit of the fungal 26S proteasome.
AB - We have cloned a gene, prs12, from the filamentous fungus Trichoderma reesei
which encodes a fungal homologue of the mouse and Drosophila regulatory subunit
12 of the 26S proteasome (mov34). Sequencing of both a genomic and a cDNA-clone
predicts a 342-aa protein with high overall identity (56-68 %) to the homologous
counterparts from human, mammals, Drosophila and Saccharomyces cerevisiae. The
predicted protein contains several consensus sequences for phosphorylation, three
of which are conserved in all published Prs12p homologues. Its C-terminus is rich
in alternating K and E/D, and resembles a potential KEKE-motif. Prs12 exhibits a
basal level of transcription during normal growth, but its expression is
significantly increased over 60-120 min under conditions of stress evoked by the
addition of cadmium ions and hygromycin B. It is also stimulated by the addition
of tunicamycin and 2-mercaptoethanol, suggesting its regulation by the presence
of unfolded proteins in the endoplasmic reticulum and by hygromycin B. Consistent
with this behaviour, motifs in the prs12 5'-upstream sequences show sequence
homology with the consensus sequences for general stress response, and for an ER
traffic-response element.
PMID- 9560438
TI - Inducing the loss of conditionally dispensable chromosomes in Nectria
haematococca during vegetative growth.
AB - A procedure for inducing and detecting the loss of conditionally dispensable (CD)
chromosomes in filamentous fungi during vegetative growth was developed using
Nectria haematococca mating population VI as a model. CD chromosomes in two
different isolates of N. haematococca were tagged via integrative transformation
with a gene conferring resistance to hygromycin B. In each case the
transformation vector included chromosome-specific DNA in order to direct its
homologous recombination with the desired chromosome. Chromosome loss was induced
by exposing tagged isolates to inhibitory concentrations of benomyl either for
protracted periods of time on solid medium or for short periods of time in liquid
medium. After exposure to benomyl, isolates that lost the tagged chromosome were
identified by their loss of resistance to hygromycin B. Electrophoretic
karyotyping was used to verify that isolates which failed to grow on hygromycin B
lacked an intact CD chromosome. Ten other chemicals known to interfere with
mitotic events or cell development in other organisms did not induce CD
chromosome loss in N. haematococca.
PMID- 9560439
TI - A ribosomal protein gene cluster is encoded in the mitochondrial DNA of
Dictyostelium discoideum: UGA termination codons and similarity of gene order to
Acanthamoeba castellanii.
AB - We sequenced a region of about 14.5 kb downstream from the ribosomal protein L11
gene (rpl11) in the mitochondrial DNA (54+/-2 kb) of the cellular slime mold
Dictyostelium discoideum. Sequence analysis revealed that eleven ribosomal
protein genes and six open reading frames (ORFs) formed a cluster arranged in the
order: rpl11-orf189-rps12-rps7-rpl2-rps19-+ ++orf425-orf1740-rpl16-rpl14-orf188-
rps14-rps8-rpl6-rps13-orf127-orf796. This order was very similar to that of
homologous genes in Acanthamoeba castellanii mitochondrial DNA. The N-terminal
region of ORF425 and the C-terminal region of ORF1740 had partial similarities to
the S3 ribosomal protein of other organisms. The termination codons of rpl16 and
orf188 were UGA, which has not hitherto been found in genes encoded in D.
discoideum mitochondrial DNA.
PMID- 9560440
TI - Protein kinase C mediates the desensitization of CCh-activated nonselective
cationic current in guinea-pig gastric myocytes.
AB - The possibility of the protein kinase C (PKC) pathway being a mechanism
underlying the desensitization of carbachol- (CCh-)activated nonselective
cationic current (ICCh) was investigated in a study of guinea-pig gastric
myocytes. Using the conventional whole-cell patch-clamp technique with
symmetrical CsCl-rich solution in pipette and bath, ICCh was induced by bath
application of 50 microM CCh. With 0.5 mM EGTA [ethyleneglycol-bis(beta
aminoethyl ether)-N,N,N',N'-tetraacetic acid] in the pipette solution (0.5 mM
[EGTA]i), ICCh decayed spontaneously (desensitization of ICCh) to around 20%
within 10 min. Desensitization of ICCh was significantly attenuated with 2 mM
[EGTA]i. At a concentration of 20 microM OAG (1-oleoyl-2-acetyl-sn-glycerol), a
PKC activator, inhibited ICCh at 0.5 mM [EGTA]i but far less at 2 mM [EGTA]i (18%
and 81% of control, respectively). The same cationic current induced by
intracellular guanosine-5'-O-(3-thiotriphosphate) (GTP[gamma-S]) was not
inhibited by OAG with 0.5 mM [EGTA]i. The pretreatment of gastric myocytes with
PKC inhibitors, either 1 microM chelerythrine or 1 microM peptide inhibitor,
attenuated the desensitization of ICCh. [Ca2+]i was also measured by single cell
microfluorometry using fura-2. Under CCh stimulation with 2 mM [EGTA]i, [Ca2+]i
did not increase above 100 nM while it increased to around 260 nM with 0.5 mM
[EGTA]i. These results suggest that the desensitization of ICCh is partly due to
the Ca2+-dependent PKC pathway in guinea-pig gastric myocytes.
PMID- 9560441
TI - Axial and transverse stiffness measures of cochlear outer hair cells suggest a
common mechanical basis.
AB - The function of the hearing organ is based on mechanical processes occurring at
the cellular level. The mechanical properties of guinea-pig isolated sensory
cells were investigated using two different techniques. The stiffness of the
outer hair cells along the longitudinal axis was measured by compressing the cell
body using stiffness-calibrated quartz fibres. For cells with a mean length of 69
micron, the mean axial compression stiffness was 1. 1+/-0.8 mN/m (+/-SD). There
was an inverse relation between stiffness and cell length. The stiffness of the
cell membrane perpendicular to the longitudinal axis of the sensory cell was
measured by indenting the cell membrane with a known force. The mean lateral
indentation stiffness was 3.3+/-1.5 mN/m (+/-SD) for cells with a mean length of
64 microm. Longer cells were less stiff than short cells. Modelling the hair cell
as a shell with bending resistance, finite element calculations demonstrated that
the axial compression stiffness correlated well with the lateral indentation
stiffness, and that a simple isotropic model is sufficient to explain the
experimental observations despite the different stress strain states produced by
the two techniques. The results imply that the two different stiffness properties
may originate from the same cytoskeletal structures. It is suggested that the
mechanical properties of the outer hair cells are designed to influence the sound
induced motion of the reticular lamina. In such a system, stiffness changes of
the outer hair cell bodies could actively control the efficiency of the
mechanical coupling between the basilar membrane and the important
mechanoelectrical transduction sites at the surface of the hearing organ.
PMID- 9560442
TI - Internalization of urinary trypsin inhibitor in human uterine fibroblasts.
AB - We have characterized the molecular species and internalization of urinary
trypsin inhibitor (UTI) in human uterine fibroblasts. Link protein (LP) has
previously been identified as one of the cell-associated UTI binding proteins.
The truncated forms of UTI were readily detectable in the cells after incubating
the cells with purified UTI. Immunoblotting analysis with a panel of domain
specific antibodies revealed that the UTI species lacked the amino-terminal
domain of UTI, but contained the carboxyl-terminal domain. We have examined
whether LP is involved in the UTI internalization in the cells. Internalization
of 125I-labelled UTI was blocked by the intact UTI, but not by the carboxyl
terminal domain of UTI. Treatment with a polyclonal antibody to the UTI binding
domain of LP partially inhibited UTI binding to the cells, but did not
significantly prevent UTI internalization. In addition, preincubation of the
cells with hyaluronidase reduced the UTI binding to the cells, but had no effect
on the rate with which UTI was internalized. These data allow us to conclude that
there are at least two different mechanisms for internalization of UTI. The major
one is via unknown UTI receptors in a Ca2+, Mg2+-sensitive manner and another is
via LP.
PMID- 9560443
TI - alpha1-adrenoceptor agonists and IGF-1, myocardial hypertrophic factors, regulate
the Kv1.5 K+ channel expression differentially in cultured newborn rat
ventricular cells.
AB - Interest has arisen concerning the importance of alpha-adrenergic function and
insulin-like growth factor-1 (IGF-1) in cardiac remodelling. The hypothesis that
these two factors may underlie the regulation of voltage-gated K+ channel
expression in hypertrophied cardiomyocytes was tested by performing Western blot
analysis of the Kv1.5 K+ channel alpha-subunit in cultured newborn rat
ventricular cells. Myocyte size was quantified by surface area and total cell
protein concentration. Cell exposure to the alpha1-adrenoceptor agonist
phenylephrine (PE, 20 microM) and IGF-1 (60 ng/ml) for 72 h both induced a
significant increase of cell size indicating myocyte hypertrophy, which could be
separately blocked by the protein kinase C inhibitor staurosporine (20 nM) and
the tyrosine kinase inhibitor genistein (15 microM). Western blots of cell
proteins prepared from myocyte cultures showed a single protein band at 75 kD
recognized by the anti-Kv1.5 antibody, and demonstrated a 56% reduction in the
Kv1. 5 immunoreactive protein level in the PE-treated cell preparations. This
suppression was not affected by staurosporine, but was remarkably attenuated by
W7 (20 microM), a selective calmodulin antagonist. In contrast to PE, a 48%
enhancement of the protein expression of Kv1.5 channel was induced by IGF-1 and
this stimulation was specifically blocked by genistein. Our findings suggest that
the differential regulation of cardiac Kv1.5 K+ channel expression can be
produced by alpha1-adrenoceptor activation and IGF-1 via distinctive signalling
pathways. Calmodulin-dependent kinase and tyrosine kinase contribute importantly
to the alpha1-adrenoceptor-mediated decrease and the IGF-1-mediated increase in
cardiac Kv1.5 K+ channel expression, respectively.
PMID- 9560444
TI - Different purinergic receptors lead to intracellular calcium increases in
pancreatic ducts.
AB - Extracellular adenosine 5'-triphosphate (ATP) has been described to act as a
regulator in many cells and tissues, including epithelia, and in the
gastrointestinal tract ATP is one of the substances involved in non-cholinergic
non-adrenergic control. However, very little is known about the effect of ATP on
pancreatic ducts, which normally secrete bicarbonate-rich fluid in response to
secretin. Hence, the aim of our present study was to test the effect of ATP and
other nucleotides on intracellular Ca2+ activity ([Ca2+]i) of pancreatic ducts,
and thereby get information about purinergic receptors that might play a role in
the regulation of pancreatic bicarbonate transport. Native intralobular ducts
were obtained from rat pancreas and [Ca2+]i in 10-20 cells was measured using the
fura-2 method. ATP (10(-4) mol/l) evoked a characteristic biphasic Ca2+ transient
in duct cells. Nucleotides, used to classify the P2 receptors, acted with the
following potency on the peak Ca2+ in many ducts: uridine 5'-triphosphate (UTP)
>/= ATP >inosine 5'-triphosphate >/= 2-methylthio-ATP > beta,gamma-methyl-ATP >
adenosine. However, although the peak [Ca2+]i responses to ATP and UTP were
similar, the plateau [Ca2+]i was nearly doubled with UTP. Moreover, in about one
third of the ducts studied, UTP had no effect on cell Ca2+, while the response to
ATP was normal. In further experiments we found that removal of extracellular
Mg2+ increased the peak [Ca2+]i evoked in response to ATP. 2'&3'-O-(4
benzoylbenzoyl) ATP (BzATP) evoked a monophasic and slower increase in [Ca2+]i,
which was inhibited by removal of extracellular Ca2+, or by addition of 4,4'
diisothiocyanatostilbene-2, 2'-disulphonic acid (DIDS). Taken together, our data
indicate that there are two types of purinergic receptors on pancreatic ducts
through which ATP can act. These are pharmacologically known as P2U and P2Z
receptors and may correspond to P2Y2 and P2X7 receptors.
PMID- 9560446
TI - Characterization of ion currents elicited by a stream of fluid during spontaneous
and ligand-induced chloride current oscillation in Xenopus laevis oocytes.
AB - During Ca2+-activated C- current oscillations a mechanical deformation of the
Xenopus laevis oocyte by a fluid stream evokes transient inward currents of high
amplitude (stream evoked inward current, Ii,st). This current can be observed
either in native or RNA-injected oocytes expressing ligand-controlled ion
channels from rat brain. Ii,st reversed at the equilibrium potential of chloride
and was blocked by 9-anthracene carboxylic acid (2 mM). Power spectral analysis
of the oscillations did not reveal a correlation between the features of the
oscillations and the amplitude of Ii,st. Antagonists of stretch-activated cation
channels [gadolinium (100 microM) and lanthanum (1mM)] did not block Ii,st.
Calcium channel blockers [cobalt and manganese (10 mM)] did not inhibited Ii,st
and Ii,st could also be elicited in calcium-free medium. Preloading oocytes with
pertussis toxin (PTX) for 17 h prevented current oscillations and Ii,st caffeine
(10 mM), an antagonist of the liberation of calcium from intracellular stores,
inhibited Ii,st. Our results proride evidence for modulation of the
mechanosensitivity of chloride currents by activation of intracellular second
messenger cascades.
PMID- 9560445
TI - ATP-induced Ca2+ signals in bronchial epithelial cells.
AB - Ca2+-dependent Cl- secretion in the respiratory tract occurs physiologically or
under pathophysiological conditions when inflammatory mediators are released. The
mechanism of intracellular Ca2+ release was investigated in the immortalized
bronchial epithelial cell line 16HBE14o-. Experiments on both intact and
permeabilized cells revealed that only inositol 1,4,5-trisphosphate (InsP3)
receptors and not ryanodine receptors are involved in intracellular Ca2+ release.
The expression pattern of the three InsP3 receptor isoforms was assessed both at
the mRNA and at the protein level. The level of expression at the mRNA level was
type 3 (92.5%) >> type 2 (5.4%) > type 1 (2.1%) and this rank order was also
observed at the protein level. The ATP-induced Ca2+ signals in the intact cell,
consisting of abortive Ca2+ spikes or fully developed [Ca2+] rises and
intracellular Ca2+ waves, were indicative of positive feedback of Ca2+ on the
InsP3 receptors. Low Ca2+ concentrations stimulated and high Ca2+ concentrations
inhibited InsP3-induced Ca2+ release in permeabilized 16HBE14o- cells. We
localized a cytosolic Ca2+-binding site between amino acid residues 2077 and 2101
in the type-2 InsP3 receptor and between amino acids 2030 and 2050 in the type-3
InsP3 receptor by expressing the respective parts of these receptors as
glutathione S-transferase fusion proteins in bacteria. We conclude that the InsP3
receptor isoforms expressed in 16HBE14o- cells (mainly type-3 and type-2) are
stimulated by Ca2+ and that this phenomenon contributes to the ATP-induced Ca2+
signals in intact 16HBE14o- cells.
PMID- 9560447
TI - Agonist-independent inactivation and agonist-induced desensitization of the G
protein-activated K+ channel (GIRK) in Xenopus oocytes.
AB - The G-protein-activated K+ channels of the GIRK (Kir 3) family are activated by
Gbetagamma subunits of heterotrimeric Gi/Go proteins. Atrial GIRK currents evoked
by acetylcholine (ACh)1 via muscarinic m2 receptors (m2R) display prominent
desensitization. We studied desensitization of basal and ACh-evoked whole-cell
GIRK currents in Xenopus oocytes. In the absence of receptor and/or agonist, the
basal GIRK activity showed inactivation which was prominent when the preparation
was bathed in a low-Na+, high-K+ extracellular solution (96 mM [K+]out and 2 mM
[Na+]out) but did not occur in a normal physiological solution. Ion substitution
experiments showed that this basal, agonist-independent inactivation was caused
by the decrease in [Na+]out rather than by the increased [K+]out. We hypothesize
that it reflects a depletion of intracellular Na+. ACh-evoked GIRK currents
desensitized faster than the basal ones. The agonist-induced desensitization was
present when the preparation was bathed in all solutions tested, independently of
[Na+]out. A protein kinase C (PKC) activator inhibited the GIRK currents both in
high and low [Na+]out, apparently mimicking agonist-induced desensitization;
however, a potent serine/threonine protein kinase blocker, staurosporine, blocked
only a minor part of desensitization. We conclude that basal inactivation and
agonist-induced desensitization are separate processes, the former caused by
changes in Na+ concentrations, and the latter by unknown factor(s) with only a
minor contribution of PKC.
PMID- 9560448
TI - Store depletion triggers the calcium release-activated calcium current (ICRAC) in
macrovascular endothelial cells: a comparison with Jurkat and embryonic kidney
cell lines.
AB - In endothelial cells, different types of Ca2+ conductances have been described,
but none of them has been clearly identified as ICRAC, the Ca2+ release-activated
Ca2+ current originally described in mast and lymphoma cells. Here we show that
in bovine pulmonary artery endothelial cells (CPAE) depletion of intracellular
Ca2+ stores by inositol 1,4,5-trisphosphate (InsP3), Ca2+ ionophores and Ca2+
pump inhibitors activates a Ca2+-selective conductance in the presence of the
Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N', N'-tetraacetic acid (BAPTA).
The current shows inward rectification, a highly positive reversal potential and
is blocked by micromolar concentrations of La3+. The conditions used in studies
of endothelial cells were also employed in those of HEK-293, an embryonic kidney
cell line commonly used to express putative store-operated channels, and Jurkat
cells, the reference cell model. Similar to CPAE, HEK cells also have an ICRAC
like current. At 0 mV holding potential the estimated current density is -0.1 and
-0.2 pA/pF in CPAE and HEK cells respectively, i.e. 15 and 30% of that measured
in Jurkat cells. As shown in studies of Jurkat cells, larger Na+ currents are
detectable in CPAE and HEK cells following store depletion in Ca2+- and Mg2+-free
medium. The current carried by Na+ ions is similarly blocked by micromolar La3+,
is inwardly rectifying and has a positive reversal potential.
PMID- 9560449
TI - Separation of calcium channel current components in mouse chromaffin cells
superfused with low- and high-barium solutions.
AB - This study was carried out to characterize the set of voltage-dependent Ca2+
channel subtypes expressed by mouse adrenal chromaffin cells superfused with
solutions containing low (2 mM) or high (10 mM) Ba2+ concentrations. Using 50-ms
test pulses at 0 mV from a holding potential of -80 mV, averaged peak current in
10 mM Ba2+ was around 1 nA, and in 2 mM Ba2+ 0.36 nA. When using 2 mM Ba2+ as the
charge carrier, nifedipine (3 microM) blocked IBa by 40-45%. omega-Conotoxin GVIA
(1 microM) caused 26% inhibition, while omega-conotoxin MVIIC (3 microM) produced
a 48% blockade. At low concentrations (20 nM), omega-agatoxin IVA caused 5-15% of
current inhibition, while 2 microM gave rise to a 35-40% blockade. In 10 mM Ba2+,
the blocking effects of nifedipine (40%) and omega-conotoxin GVIA (25%) were
similar to those seen in 2 mM Ba2+. In contrast, blockade by omega-conotoxin
MVIIC was markedly reduced in 10 mM Ba2+ (20-25%) as compared to 10 mM Ba2+
(48%). The blocking actions of omega-agatoxin IVA (2 microM) were also slowed
down in 10 mM Ba2+, though the final blockade was unaffected. In 2 mM Ba2+, IBa
was quickly inhibited by over 94% with combined nifedipine + omega-conotoxin
MVIIC + omega-conotoxin GVIA; in 10 mM Ba2+, IBa was blocked by 70% with this
combination. The data suggest that mouse chromaffin cells express L-type (40%) as
well as non-L-type (60%) high-threshold voltage-dependent Ca2+ channels. The
current carried by non-L-type Ca2+ channels consists of about 25% N-type and 35%
P/Q-type; P-type channels, if anything, are poorly expressed. The data also
indicate that the fraction of current blocked by omega-conotoxin MVIIC and omega
agatoxin IVA might considerably change as a function of the Ba2+ concentration of
the extracellular solution; taking this fact into consideration, it seems that a
residual R-type current is not expressed in mouse chromaffin cells.
PMID- 9560450
TI - No evidence for cell-to-cell coupling in rat colonic crypts: studies with Lucifer
Yellow and with photobleaching.
AB - Epithelial cells of exocrine glands (pancreas, lacrimal glands, salivary glands,
sweat glands and gastric glands) are intimately linked together by gap junctions.
Due to this close junctional coupling exocrine secretion occurs as the well
concerted effort of a cell population. Colonic crypts have, on the one hand,
anatomical and functional properties resembling those of exocrine glands (mostly
crypt base cells) and, on the other hand, properties of absorbing cells (mostly
surface cells). In the mid-crypt, depending on the functional status, absorption
and secretion can occur. The present study was aimed at examining whether rat
distal colonic crypt cells co-ordinate their functional status by cell-to-cell
coupling. Two types of measurements were performed: as an independent assessment
of cell viability the membrane voltage (Vm) was measured with the fast whole-cell
patch-clamp technique; to investigate cellular coupling simultaneously Lucifer
Yellow (LY) (mol. wt. 443) distribution was visualized using digital video
imaging. LY (500 micromol/l) was included into the patch pipette filling
solution. The recorded Vm was -73.4+/-2.3 mV in crypt base cells (n=15), -63.7+/
2.1 mV in mid-crypt cells (n=17) and -52.3+/-2. 9 mV in crypt surface cells. All
cells tested reversibly responded to carbachol (100 micromol/l) with a persistent
hyperpolarization, as previously shown. Activation of Cl- secretion by elevation
of the cAMP concentration with forskolin (5 micromol/l) led to a reversible
depolarization. Throughout the duration of each individual experiment [mean
experimental time in basal cells: 18.3+/-2.5 min (n=15), in mid-crypt cells:
19.6+/-3.4 min (n=17) and in crypt surface cells: 11.7+/-3.4 min (n=13)] LY dye
distribution was solely confined to the patched cell. In addition bleaching of
calcein fluorescence in laser scan microscopy was not followed by dye back
diffusion, whereas this was clearly the case in pancreatic acini (n=5). These
data indicate that colonic crypt cells are not coupled by gap junctions under
resting conditions or in the presence of secretagogues.
PMID- 9560451
TI - Acetylcholine-activated chloride current in the T-84 colonic cell line.
AB - The stimulation of epithelial chloride secretion by hormones and
neurotransmitters involves the activation of apical membrane chloride channels.
The regulation of chloride current by acetylcholine in the T-84 colonic cell line
was investigated using single-channel patch-clamp techniques. Treatment with
carbachol resulted in the stimulation of transient chloride currents in 18 of 32
previously quiescent patches. Lack of resolvable single-channel openings suggests
that single-channel conductance is less than 5-pS. Of 18 responsive patches, 4
showed multiple current oscillations. Treatment of the cells with AlF4- activated
sustained chloride currents, suggesting that G proteins are involved. In excised
patches, chloride current was markedly sensitive to free Ca2+ concentrations
between 500 and 1000 nM. Time-dependent activation and inactivation of chloride
current occurred at +60 and -60 mV. These results indicate that the chloride
channels responsible for cholinergic activation of chloride conductance in the T
84 colonic cell line are members of the very low conductance family of chloride
channels.
PMID- 9560452
TI - Single-channel analysis of fast transient outward K+ currents in frog skeletal
muscle.
AB - The patch-clamp method was employed to examine the voltage-dependent gating
mechanism of A-type K+ channels, which generate the transient outward K+ currents
described previously in a study of vesicles derived from the sarcolemma of frog
skeletal muscle. Channels were activated by depolarizing pulses. There is
evidence for non-random grouping of records with channel openings and blank
records when depolarizations were repeated at brief intervals, suggesting a slow
process similar to slow inactivation. Binomial analysis was consistent with
independent behaviour of the channels. Ensemble average currents obtained from
multichannel patches had kinetics similar to those of the macroscopic A-type K+
current, IA. The rate of activation, fitted to n4 kinetics, was fast and voltage
dependent. The rate of inactivation had an exponential time course with a voltage
independent time constant. The mean open time and the probability of a channel
being open increased with depolarization. The histograms of latency to first
opening revealed the presence of more than two voltage-dependent closed states.
Channel openings occurred in bursts and the closed-time histograms could be
fitted by the sum of two or three exponentials. These results suggest a gating
scheme with at least three closed states, probably two open states, and two
inactivated states.
PMID- 9560453
TI - Effects of cyclopiazonic acid on Ca2+ regulation by the sarcoplasmic reticulum in
saponin-permeabilized skeletal muscle fibres.
AB - The effects of the sarcoplasmic reticulum (SR) Ca2+ pump inhibitor cyclopiazonic
acid (CPA) were studied in saponin-permeabilized frog skeletal muscle fibres.
Release of Ca2+ from the SR was triggered by brief (2 s) applications of 40 mM
caffeine at 2-min intervals. Changes in [Ca2+] within the fibre were monitored
continuously using Fura-2 fluorescence. At a bathing [Ca2+] of 100 nM,
introduction of 20 microM CPA induced a slow release of Ca2+ from the SR. The
following one to two caffeine-induced Ca2+ transients were markedly increased in
amplitude and duration. Thereafter, the caffeine-induced Ca2+ transients
decreased progressively and were barely detectable 6-7 min after introduction of
CPA. However, increasing the bathing [Ca2+] or increasing the Ca2+ loading period
resulted in a partial recovery of the caffeine-induced Ca2+ transients,
suggesting that pump inhibition is incomplete, even in the presence of 100 microM
CPA. The slow Ca2+ efflux induced by CPA was insensitive to ryanodine, but absent
following abolition of SR Ca2+ pump activity by ATP withdrawal. These results
suggest that the caffeine-induced Ca2+ transient reflects a balance between
efflux via the SR Ca2+ channel and reuptake by the Ca pump. Ca2+ release upon
addition of CPA may result from inhibition of SR Ca2+ uptake, which reveals a
tonic Ca2+ efflux that is independent of the Ca2+ release channels.
PMID- 9560454
TI - Effect of dehydration on apical Na+-H+ exchange activity and Na+-dependent sugar
transport in brush-border membrane vesicles isolated from chick intestine.
AB - The current work examines the effect of 4 days of water deprivation on Na+-H+
exchange and Na+-sugar cotransport systems in brush-border membrane vesicles
isolated from either the jejunum, ileum or the colon of the chick. Apical Na+-H+
exchange activity was evaluated by measuring the pH-gradient-dependent Na+
uptake. The contribution of the Na+-H+ exchangers NHE2 and NHE3 to total Na+-H+
exchange activity was evaluated from their sensitivity to the amiloride-related
drug HOE694. Dehydration increased plasma aldosterone levels from 12 to 70 pg/ml
and also the activities of both Na+-H+ exchange and Na+-dependent sugar transport
in the three intestinal regions tested. Na+-independent sugar transport was not
modified by 4 days of water deprivation. In the ileum and colon the increase in
Na+-H+ exchange activity was due to an increase in NHE2 activity, whereas in the
jejunum it was due to an increase in both NHE2 and NHE3. Since we have previously
reported that chronic Na+ depletion increases plasma aldosterone levels and NHE2
activity in ileum and colon, decreased small and large intestine Na+-sugar
cotransport activity and had no effect on jejunal apical Na+-H+ exchange
activity, it can be concluded that: (1) aldosterone does not regulate intestinal
Na+-dependent sugar transport, and (2) the regulation of jejunal Na+-H+ exchange
activity differs from that of either the ileum or the colon.
PMID- 9560455
TI - Characterisation of the effects of robustoxin, the lethal neurotoxin from the
Sydney funnel-web spider Atrax robustus, on sodium channel activation and
inactivation.
AB - The present study investigates the actions of robustoxin (atracotoxin-Ar1)
purified from the venom of the male Sydney funnel-web spider Atrax robustus on
sodium channel gating. Using whole-cell patch-clamp techniques the study assessed
the actions of robustoxin on tetrodotoxin-resistant (TTX-R) and tetrodotoxin
sensitive (TTX-S) sodium currents in rat dorsal root ganglion cells. Similar to
the closely related funnel-web spider toxin versutoxin (delta-atracotoxin-Hv1)
from Hadronyche versuta, robustoxin had no effect on TTX-R sodium currents but
exerted potent effects on TTX-S sodium currents. The main action of robustoxin
was a concentration-dependent slowing or removal of TTX-S sodium current
inactivation. This steady-state current was maintained during long-lasting
depolarisations at all test potentials. Robustoxin (30 nM) also caused a 13-mV
hyperpolarising shift in the voltage midpoint of steady-state sodium channel
inactivation (h infinity) leading to a reduced peak current at a holding
potential of -80 mV. Moreover there was a steady-state or non-inactivating
component present (18% of maximal sodium current) at prepulse potentials that
normally inactivate all TTX-S sodium channels (more depolarised than -40 mV). In
addition robustoxin produced a significant increase in the repriming kinetics of
the sodium channel when channels returned to the resting state following
activation. This increase in the rate of recovery of sodium current appears to
explain the use-dependent effects on peak sodium current amplitude at high
stimulation frequencies. Finally 30 nM robustoxin caused an 11-mV hyperpolarising
shift in the voltage dependence of the channel but did not markedly modify tail
current kinetics. These actions suggest that robustoxin inhibits conversion of
the open state to the inactivated state of TTX-S sodium channels, thus allowing a
fraction of the sodium current to remain at membrane potentials at which
inactivation is normally complete. Given the recent reclassification of funnel
web spider toxins as atracotoxins, robustoxin should henceforth be known as delta
atracotoxin-Ar1 to reflect this main action on sodium channel inactivation. These
present results further support the hypothesis that funnel-web spider toxins
interact with neurotoxin receptor site 3 to slow channel inactivation in a manner
similar to that of alpha-scorpion and sea anemone toxins.
PMID- 9560457
TI - The role of cytosolic Ca2+ in the secretion of NaCl in isolated in vitro perfused
rectal gland tubules of Squalus acanthias.
AB - In many exocrine glands cytosolic Ca2+ ([Ca2+]i) plays a pivotal role in
stimulation-secretion coupling. In the rectal gland of the dogfish Squalus
acanthias this appears not to be the case and it is believed that secretion is
mainly controlled by the Cl- conductance of the luminal membrane. We have
examined this question in a study of isolated in vitro perfused rectal gland
tubules (RGT). Three types of measurements were performed: (1) measurements of
[Ca2+]i by the fura-2 technique; (2) measurements of transepithelial electrical
parameters, i.e. transepithelial voltage (Vte), transepithelial resistance (Rte),
the equivalent short-circuit current (Isc) and the voltage across the basolateral
membrane (Vbl), and (3) whole-cell patch-clamp measurements of cellular voltage
(Vm), conductance (Gm) and membrane capacitance (Cm). The data indicates that
carbachol (CCH) increases [Ca2+]i by increasing store release and Ca2+ influx.
Other agonists, producing cytosolic cAMP, also increased [Ca2+] by enhancing Ca2+
influx. CCH hyperpolarized these cells and enhanced Gm significantly. The effect
of CCH on Vte and Isc was most marked under control conditions and disappeared in
RGT otherwise stimulated by agonists that lead to cAMP production. It is
concluded that [Ca2+]i plays a major role in the stimulation of NaCl secretion in
RGT by enhancing the basolateral K+ conductance. cAMP-producing agonists enhance
[Ca2+]i by increased Ca2+ influx. CCH releases Ca2+ from respective stores. CCH,
unlike the cAMP-producing agonists, only increases basolateral K+ conductance. It
modulates secretion especially under conditions in which the cAMP pathway is not
fully activated.
PMID- 9560456
TI - Tyrosine kinase inhibitors suppress N-type and T-type Ca2+ channel currents in
NG108-15 cells.
AB - Modulation of Ca2+ channel activity by protein kinases constitutes one of the
major mechanisms regulating neuronal functions. Here, we explored the possible
modulation of neuronal Ca2+ channels by protein tyrosine kinases (PTKs). To this
end, the effects of PTK inhibitors on whole-cell Ba2+ currents (IBa) through
voltage-gated Ca2+ channels were analysed in differentiated NG108-15
neuroblastoma x glioma hybrid cells. Genistein suppressed IBa in a concentration
dependent fashion (IC50 = 22 microM). Although daidzein, an analogue of genistein
that is devoid of PTK inhibitory activity, also suppressed IBa, we estimated that
specific PTK inhibition by genistein reduced IBa amplitude by 30%. In addition,
lavendustin A (20 microM) and herbimycin A (20 microM), two other distinct PTK
inhibitors, depressed IBa by 22% and 20%, respectively. Genistein suppressed N
type and T-type currents, sparing L-type current, and its effect was independent
of G protein activation. The results suggest that the activity of neuronal Ca2+
channels can be modulated by PTKs, opening the possibility that some of the
functions of PTKs in the nervous system are mediated by Ca2+ channel modulation.
PMID- 9560458
TI - Quantitative analysis of dual whole-cell voltage-clamp determination of gap
junctional conductance.
AB - The dual whole-cell voltage-clamp technique is used widely for determination of
kinetics and conductance of gap junctions. The use of this technique may,
however, occasion to considerable errors. We have analysed the errors in steady
state junctional conductance measurements under different experimental
conditions. The errors in measured junctional conductance induced by series
resistance alone, and by series resistance in combination with membrane
resistance, were quantified both theoretically and experimentally, on equivalent
resistive circuits with known resistance values in a dual voltage-clamp setup. We
present and analyse a method that accounts for series resistance and membrane
resistance in the determination of true junctional conductance. This method
requires that series resistance is determined during the experiment, and involves
some calculations to determine membrane resistance. We demonstrate that
correction for both membrane and series resistance reduces the error in measured
junctional conductance to near zero, even when membrane resistances on both sides
of the gap junction are as low as 20 MOmega and the (true) junctional conductance
is as high as 100 nS.
PMID- 9560460
TI - Investigating the relaxation, following diazo-2 laser flash photolysis, of a
skinned trabecular preparation from SHR hypertrophied left ventricle.
AB - Rat models of cardiac hypertrophy are characterised by a shift in left
ventricular myosin isoform from V1 (adult) to V3 (foetal), the latter being
associated with a slowing of the acto-myosin ATPase rate. The aim of this study
was to examine hypertrophy effects on relaxation by investigating a chemically
skinned cardiac preparation from the SHR, where all the cellular membranes are
rendered non-functional allowing the myofibrils to be studied in isolation. On
comparison, following photolysis of the photolabile caged Ca2+ chelator diazo-2,
it can be seen that the SHR fibres relax at a slower rate than their age-matched
WKY counterparts. We suggest that, since the thin filament regulatory proteins
seem not to be affected by cardiac hypertrophy in the rat, this result can be
attributed to the shift in left ventricular myosin isoforms. The reduced
relaxation rate in the SHR could be the result of a slowing of the dissociation
of actin and myosin during the cross-bridge cycle. These results have previously
been published in abstract form [1].
PMID- 9560459
TI - Modulation by extracellular and intracellular iodide of volume-activated Cl-
current in HeLa cells.
AB - The patch-clamp technique was used to study the effect of extracellular and
intracellular iodide on the properties of the volume-activated anion current in
HeLa cells. Upon hypotonic challenge, HeLa cells responded by activating an
outwardly rectifying Cl- current. Replacement of extracellular Cl- by I-, a more
permeable anion, increased the peak outward and inward current, reduced the
magnitude of deactivation observed at depolarized potentials and shifted the half
maximal (V0.5) deactivation voltage towards more positive values. On the other
hand, when internal Cl- was replaced by I- the volume-activated current was not
observed in normal, Cl--rich hypotonic extracellular solution. However, switching
to a hypotonic extracellular solution containing a mixture of Cl- and I- resulted
in the activation of the volume-sensitive current. Furthermore, once the current
was activated, I- could be excluded from the external solution without
significantly affecting the current properties. These results suggest that the
permeant anion plays a crucial role in the gating mechanism of the volume
activated Cl- current, influencing the swelling-dependent activation and the
voltage-dependent deactivation processes.
PMID- 9560461
TI - Cytoskeletal mechanisms of axon outgrowth and pathfinding.
AB - The use of modern techniques involving gene transfer and functional knock-out
strategies has lead to new concepts of the way in which cytoskeletal elements
interact to produce the unique morphologies of neurons. This review presents
these concepts and discusses their implications for neuronal development,
especially with respect to the role of microtubules, microfilaments, and
neurofilaments.
PMID- 9560462
TI - The significance of the isoforms of plasma membrane calcium ATPase.
AB - The plasma membrane calcium ATPase (PMCA) or Ca2+ pump transports Ca2+ ions out
of the cells, by using the energy stored in ATP. It is essential in the control
of Ca2+ concentration in the cytosol. The plasma membrane Ca2+ pump has been
found in all mammalian cells and is encoded by four independent genes. The number
of possible isoforms is further increased by alternative splicing at two
independent sites; transcripts for more than 20 isoforms have been detected. The
PMCA isoforms, in particular some of their alternatively spliced isoforms, have
been shown to bind calmodulin with different affinity. The activity of these
alternatively spliced pumps is possibly differently regulated by kinase-mediated
phosphorylation. A short summary of recent work on the properties of the PMCA
isoforms is presented here.
PMID- 9560463
TI - Galactosphingolipids and axono-glial interaction in myelin of the central nervous
system.
AB - The myelin of central and peripheral nervous system of UDP-galactose-ceramide
galactosyltransferase deficient mice (cgt-/-) is completely depleted of its major
lipid constituents, galactocerebrosides and sulfatides. The deficiency of these
glycolipids affects the biophysical properties of the myelin sheath and causes
the loss of the rapid saltatory conduction velocity of myelinated axons. With the
onset of myelination, null mutant cgt-/- mice develop fatal neurological defects.
CNS and PNS analysis of cgt-/- mice revealed (1) hypomyelination of axons of the
spinal cord and optic nerves, but no apoptosis of oligodendrocytes, (2) redundant
myelin in younger mice leading to vacuolated nerve fibers in cgt-/- mice, (3) the
occurrence of multiple myelinated CNS axons, and (4) severely distorted lateral
loops in CNS paranodes. The loss of saltatory conduction is not associated with a
randomization of voltage-gated sodium channels in the axolemma of PNS fibers. We
conclude that cerebrosides (GalC) and sulfatides (sGalC) play a major role in CNS
axono-glial interaction. A close axono-glial contact is not a prerequisite for
the spiraling and compaction process of myelin. Axonal sodium channels remain
clustered at the nodes of Ranvier independent of the change in the physical
properties of myelin membrane devoid of galactosphingolipids. Increased
intracellular concentrations of free ceramides do not trigger apoptosis of
oligodendrocytes.
PMID- 9560464
TI - Calcium-binding proteins in the retina of a calbindin-null mutant mouse.
AB - Calcium-binding proteins are abundantly expressed in many neurons of mammalian
retinae. Their physiological roles are, however, largely unknown. This is
particularly true for calcium-modulating proteins ("calcium buffers") such as
calbindin D28k. Here, we have studied retinae of wildtype (+/+) and calbindin
null mutant (-/-) mice by using immunocytochemical methods. Although calbindin
immunoreactivity was completely absent in the calbindin (-/-) retinae, those
cells that express the protein in wildtype retinae, such as horizontal cells,
were still present and appeared normal. This was verified by immunostaining
horizontal cells for various neurofilament proteins. In order to assess whether
other calcium-binding proteins are upregulated in the mutant mouse and may thus
compensate for the loss of calbindin, mouse retinae were also immunolabeled for
parvalbumin, calretinin, and a calmodulin-like protein (CALP). In no instance
could a change in the expression pattern of these proteins be detected by
immunocytochemical methods. Thus, our results show that calbindin is not required
for the maintenance of the light-microscopic structure of the differentiated
retina and suggest roles for this protein in retinal function.
PMID- 9560465
TI - Immunolocalization of a putative unconventional myosin on the surface of motile
mitochondria in locust photoreceptors.
AB - Light stimulation of locust (Schistocerca gregaria) photoreceptors results in an
actin-dependent translocation of mitochondria towards the photoreceptive
microvilli and an antagonistic movement of endoplasmic reticulum towards the cell
body. Using immunocytochemical techniques, we have tried to identify myosin-like
motors that may drive the light-induced organelle motility. A monoclonal antibody
against the motor domain of Acanthamoeba myosin identifies a prominent 110-kDa
protein on Western blots of locust retina. Cross-reactivity with two polyclonal
anti-myosin antibodies and a monoclonal anti-myosin-I-antibody, together with ATP
dependent binding to actin filaments, provides evidence that the 110-kDa protein
is an unconventional myosin. By indirect immunofluorescence, the 110-kDa protein
has been localized to both photoreceptors and pigment cells within the retina. In
the photoreceptor cells, the 110-kDa protein is bound to the surface of
mitochondria. This putative unconventional myosin may thus be a motor protein
involved in the light-induced translocation of mitochondria in photoreceptors.
PMID- 9560466
TI - Neuronal differentiation is accompanied by NSP-C expression.
AB - Neuroendocrine-specific protein (NSP) reticulons are expressed in neural and
neuroendocrine tissues and cell cultures derived therefrom, while most other cell
types lack NSP-reticulons. Three major subtypes have been identified so far,
designated NSP-A, NSP-B, and NSP-C. We have investigated the correlation between
the degree of neuronal differentiation, determined by morphological and
biochemical criteria, and NSP-reticulon subtype expression. For this purpose,
several human neuroblastoma cell lines, exhibiting different degrees of neuronal
differentiation, were examined immuno(cyto)chemically. It became obvious that the
expression of NSP-C, as detected by immunofluorescence microscopy and Western
blotting, is most prominent in cell lines with a high degree of neuronal
differentiation, such as LA-N-5. Such highly differentiated cells also express
other neural and neuroendocrine markers, such as neural cell adhesion molecule
(NCAM), neurofilament proteins, synaptophysin, and chromogranin. NSP-A was
observed in all cell lines to a different extent. However, no clear correlation
was observed with the degree of neuronal differentiation as defined by other
neuronal and neuroendocrine markers or morphology. NSP-B could not be detected.
The induction of neuronal differentiation with nerve growth factor, dbcAMP, and
retinoic acid in the rat pheochromocytoma cell line PC12 and the human
teratocarcinoma cell line hNT2, respectively, induced the expression of NSP-A and
NSP-C in these cell lines parallel to the induction of neurofilament protein
expression. It is concluded that NSP-C expression, in particular, is strongly
correlated with neuronal differentiation.
PMID- 9560467
TI - Partial sequencing of Reissner's fiber glycoprotein I (RF-Gly I).
AB - The bulk of the secretion of the subcommissural organ is formed by glycoproteins
that appear to be derived from two precursor forms of 540 and 320 kDa. Upon
release into the ventricle, these glycoproteins aggregate to form Reissner's
fiber. We report the isolation of three cDNA clones from a cDNA library prepared
from bovine subcommissural organ RNA, by using an anti-Reissner's fiber serum for
immunoscreening. Inserts of 0.7, 1.2, and 2.5 kb were amplified by the polymerase
chain reaction, subcloned into pUC18 vector, and sequenced. Although restriction
mapping of the three inserts initially suggested that all of them were derived
from the same mRNA, sequence analysis showed that a short non-homologous region
was present in the 0.7-kb insert when compared with the 1. 2-kb and 2.5-kb
inserts, suggesting that they corresponded to two different, although highly
homologous, mRNAs. Northern analyses showed a single mRNA species of
approximately 9.5 kb present in the subcommissural organ and missing in the
choroid plexus, brain cortex, and liver. In situ hybridization confirmed that the
expression of the RNA was restricted to cells of the bovine subcommissural organ.
Polyclonal antibodies raised against a synthetic peptide, whose amino-acid
sequence was deduced from the 2.5-kb cDNA, reacted specifically with the bovine
and rat subcommissural organ-Reissner's fiber complex. In immunoblots of bovine
subcommissural organ, this antibody revealed the precursor 540-kDa form and its
putative processed form of 450 kDa. It is concluded that the cloned cDNA encodes
for the major constitutive glycoprotein of Reissner's fiber, here designated as
RF-Gly I. The sequenced region of RF-Gly I displays a high degree of homology
with some regions of the von Willebrand factor and certain mucins; it also
displays two motifs homologous with repeats present in proteins of the spondin
family and other proteins. A core sequence of the RF-Gly I repeats suggests that
this molecule displays protein-binding properties.
PMID- 9560468
TI - Distribution of pro-opiomelanocortin and its peptide end products in the brain
and hypophysis of the aquatic toad, Xenopus laevis.
AB - Using in situ hybridization with a pro-opiomelanocortin (POMC)-mRNA probe and
immunocytochemistry with antisera to POMC and to various POMC-derived peptides,
it is shown that melanotrope cells in the pars intermedia of the hypophysis of
the South African aquatic toad Xenopus laevis contain POMC, alpha-melanophore
stimulating hormone (alpha-MSH), gamma-MSH, acetylated and non-acetylated
endorphins and adrenocorticotropic hormone (ACTH). With the exception of gamma
MSH, these peptides are also found in the corticotrope cells in the rostral pars
distalis. In the Xenopus brain, neuronal cell bodies in the ventral hypothalamic
nucleus express POMC, alpha-MSH, gamma-MSH, non-acetylated endorphins and ACTH,
neurones in the anterior preoptic area reveal POMC, alpha-MSH, gamma-MSH and non
acetylated endorphin, neurones in the suprachiasmatic nucleus contain alpha-MSH,
non-acetylated endorphin and ACTH and neurones in the posterior tubercle show
alpha-MSH, non-acetylated endorphin and ACTH immunoreactivities. In the locus
coeruleus POMC and ACTH coexist, whereas alpha-MSH and non-acetylated endorphin
occur together in the nucleus accumbens, the striatum and the nucleus of the
paraventricular organ. Finally, alpha-MSH alone is present in the olfactory bulb,
the medial septum, the medial and lateral parts of the amygdala, the ventromedial
and posterior thalamic nuclei, the optic tectum and the anteroventral tegmental
nucleus, and non-acetylated endorphin alone appears in the epiphysis. It is
suggested that neurones that form POMC-derived peptides may play a direct or
indirect role in the control of POMC-producing hypophyseal cells and/or in the
physiological processes these endocrine cells regulate. This idea is supported by
the fact that the suprachiasmatic nucleus and the locus coeruleus, both involved
in melanotrope cell control, show POMC and POMC-peptide expression. A possible
involvement in melanotrope and/or corticotrope control of the anterior preoptic
and ventral hypothalamic nuclei, which both express POMC and various POMC-derived
peptides, deserves future attention.
PMID- 9560470
TI - Visualization of interstitial cells of Cajal in the mouse colon by vital
staining.
AB - Interstitial cells of Cajal (ICCs) are believed to be a major element in
generating the spontaneous rhythm of the gastrointestinal tract. A prominent
problem in the study of these cells has been the difficulty in observing them in
intact tissues. We used the lipophilic dye DiI to stain ICCs in the submucosal
circular muscle border of freshly dissected mouse colon. The placement of small
DiI crystals in this area resulted in the labeling of ICC-like cells. Two main
morphological cell types, viz., bipolar and multipolar, were noted. Bipolar cells
had two primary processes emerging from the poles of an elongated soma. The mean
length of these processes was 78.7 microm. These cells constituted 42.3% of the
sample (n=105). Multipolar cells (54.3% of total) had a less elongated soma and
extended 3-6 main processes whose mean length was 56.3 microm. These processes
showed no preferred direction. The length of the primary processes of bipolar
cells was 40% greater than that of multipolar cells (P<0.02). Three cells (2.9%)
had only one primary process. The DiI stain could be converted into a stable
electron-opaque product. Electron-microscopic observations showed that these
cells had the typical appearance of ICCs reported in previous studies. This
staining method should be useful for physiological investigations of ICCs in
gastrointestinal tissues.
PMID- 9560469
TI - Two differing salmon GnRH precursor mRNAs are co-expressed in the brain of
sockeye salmon.
AB - The localization of two salmon-type gonadotropin-releasing hormone (sGnRH)
precursors, pro-sGnRH-I (short type) and pro-sGnRH-II (long type), was
investigated by using in situ hybridization techniques in the brain of the
landlocked sockeye salmon, Oncorhynchus nerka. We used 30-mer oligonucleotide
probes complementary to pro-sGnRH-I and pro-sGnRH-II cDNA. No significant
differences were observed in the localization of sGnRH neurons expressing pro
sGnRH-I and pro-sGnRH-II mRNAs; both were expressed in the olfactory nerve, the
olfactory bulbs, the regions between the olfactory bulb and telencephalon, the
ventral telencephalon, the preoptic area, and the hypothalamus. Almost all sGnRH
neurons examined co-expressed both precursors. The expression of two sGnRH
precursors in the same neuron and the wide distribution of such neurons in the
brain suggest that there are no functional differences between the two
precursors.
PMID- 9560471
TI - Some neurohistochemical properties of nerve elements in myenteric plexus of
rabbit ileum: similarities and dissimilarities to the rodent pattern.
AB - Enteric neurons have distinct neurochemical codings in each species. The basal
tone of the gastrointestinal tract of the rabbit is low and produces neurally
evoked pendular movements. Therefore, it might have an innervation pattern
different from that of other laboratory animals. We have characterised myenteric
neuron populations in rabbit ileum with neurochemical markers that are known to
be associated with distinct cell types and/or fibre systems in the myenteric
plexus. The density of nerve cells estimated with the NADH-diaphorase technique
was about 2500 cells/cm2 and most, if not all, neurons contained microtubule
associated protein 2. NADPH-diaphorase-positive cells were numerous. One cell
type was large and emitted long straight processes, whereas small cells bore thin
filamentous dendrites. Neurons immunoreactive for 28-kDa calcium-binding protein
were rare. Over 70% of them had very strongly labelled lamellar dendrites. Their
axons were beaded and formed pericellular baskets around unstained somata. We
found very few small tyrosine-hydroxylase-positive cells. The fibre network in
the plexus was very strong; the axons formed many pericellular baskets. In double
labelling studies, no co-localisation was revealed between the 28-kDa calcium
binding protein and NADPH-diaphorase. Some fibres containing 28-kDa calcium
binding protein formed only a few contacts on somata of NADPH-diaphorase-positive
cells. None of the NADPH-diaphorase-labelled cells were found to be stained for
tyrosine hydroxylase. Tyrosine-hydroxylase-positive fibres rarely made
pericellular baskets on the surface of NADPH-diaphorase-positive somata. Strongly
immunolabelled pericellular baskets were never observed around NADPH-diaphorase
positive cell somata. The results suggest that myenteric neurons in rabbit
comprise distinct and characteristic neurochemical properties that are different
from the rodent pattern. Therefore, the explanation of the motility pattern of
rabbit intestine can be approached on a chemical neuroanatomical basis.
PMID- 9560472
TI - Nitric oxide synthase (NOS) in mouse skeletal muscle development and
differentiated myoblasts.
AB - The neuronal isoform of nitric oxide synthase (nNOS, termed also NOS-I) is
expressed in normal adult skeletal muscle, suggesting important functions for NO
in muscle biology. However, the expression and subcellular localization of NOS in
muscle development and myoblast differentiation are largely unknown. In the
present study, NOS was immunolocalized with isoform-specific antibodies in
developing muscle and in differentiated myoblast cultures (mouse C2C12) together
with histochemical NADPH-dependent diaphorase activity that is blocked by
specific NOS inhibitors and therefore designated as NOS-associated diaphorase
activity (NOSaD). Western blot analysis revealed immunoreactive bands for NOS-I
III in lysates from perinatal and adult muscle tissue and C2C12-myotubes that
comigrated with prototypical proteins. In embryonic skeletal muscle, but not in
adult myofibers, diffuse cytosolic staining and lack of sarcolemmal NOSaD
activity and NOS-I immunoreaction were evident. In both myoblasts and fusioned
myotubes, NOSaD and NOS isoforms I-III colocalize in the cytosol. Additionally,
members of the sarcolemmal dystrophin-glycoprotein complex (i.e., dystrophin,
adhalin, beta1-dystroglycan) immunolocalize in the cytosol of differentiating
myoblasts, whereas anti-dystrophin and anti-beta1-dystroglycan clearly delineate
the sarcolemma in myotubes. Thus, expression of NOS isoforms I-III and NOSaD is
cytosolic in fusion-competent myoblasts during myotube formation in vitro.
Interaction of NOSaD/NOS-I with the sarcolemmal dystrophin-complex known from
mature myofibers is apparently lacking in prenatal muscle development and
differentiating myoblasts. Localization of NOS isoforms thus characterized in
myogenic cultures may help further to investigate regulated NO formation in
muscle cells in vitro.
PMID- 9560473
TI - Human and hamster procathepsin D, although equally tagged with mannose-6
phosphate, are differentially targeted to lysosomes in transfected BHK cells.
AB - BHK cells transfected with human cathepsin D (CD) cDNA normally segregate the
autologous hamster cathepsin D while secreting a large proportion of the human
proenzyme. In the present work, we have utilized these transfectants to examine
to what extent the mannose-6-phosphate-dependent pathway for lysosomal enzyme
segregation contributes to the differential sorting of human and hamster CD. We
report that, in recipient control BHK cells, the rate of mannose-6-phosphate
dependent endocytosis of human procathepsin D secreted by transfected BHK cells
is lower than that of hamster procathepsin D and much lower than that of human
arylsulphatase A. The missorted human enzyme bears phosphorylated
oligosaccharides and most of its phosphate residues are "uncovered", like the
autologous enzyme. Thus, despite both the Golgi-associated modifications of
oligosaccharides, i.e. the phosphorylation of mannose and the uncovering of
mannose-6-phosphate residues, which proceed on human and hamster procathepsin D
with comparable efficiency, only the latter is accurately packaged into
lysosomes. Ammonium chloride partially affects the lysosomal targeting of
cathepsin D in control BHK cells, whereas in transfected cells, this drug
strongly inhibits the maturation of human procathepsin D and slightly enhances
its secretion. These data indicate that: (1) over-expression of a lysosomal
protein does not saturate the Golgi-associated reactions leading to the synthesis
of mannose-6-phosphate; (2) a portion of cathepsin D is targeted independently of
mannose-6-phosphate receptors in the transfected BHK cells; and (3) whichever
mechanism for lysosomal delivery of autologous procathepsin D is involved, this
is not saturated by the high rate of expression of human cathepsin D.
PMID- 9560475
TI - Differential in situ expression of alpha2(XI) collagen mRNA isoforms in the
developing mouse.
AB - Type XI collagen is an essential structural component of the extracellular matrix
of cartilage and plays a role in collagen fibril formation and skeletal
morphogenesis. The expression of all three type XI collagen genes is not
restricted to cartilage. In addition, alternative exon usage seems to increase
the structural diversity and functional potential of type XI collagen during
development. In order to investigate type XI collagen expression during
development, we have examined alpha2(XI) and alpha1(XI) collagen genes by in situ
hybridization in mice. Transcripts of the alpha2(XI) collagen gene were first
detected in the notochord of mouse embryos after 11.5 days of gestation.
Subsequently, alpha2(XI) mRNA was mainly found in the cartilaginous tissues of
the developing limbs and axial skeleton together with transcripts of the
alpha1(XI) gene. The alpha2(XI) transcripts seemed to be alternatively spliced
isoforms lacking exons 6-8, which code for an acidic domain. Expression of
alpha2(XI) outside the cartilage was relatively restricted, whereas expression of
the alpha1(XI) gene was widespread. However, expression of alpha2(XI) transcripts
containing exons 6-8 was found in non-chondrogenic tissues, including the
calvarium and periosteum where intramembranous ossification occurs. These results
indicate that alpha2(XI) mRNA isoforms are differentially expressed in various
tissues during development. In addition, alpha2(XI) mRNA isoforms containing
alternative exons are present in osteogenic cells, and their expression may be
closely related to the formation of bone or cartilage.
PMID- 9560474
TI - Distribution of murine mannose receptor expression from early embryogenesis
through to adulthood.
AB - The mannose receptor is a 175-kDa transmembrane glycoprotein that appears to be
expressed on the surface of terminally differentiated macrophages and Langerhans
cells. The ectodomain of the mannose receptor has eight carbohydrate recognition
domains. The receptor recognizes the patterns of sugars that adorn a wide array
of bacteria, parasites, yeast, fungi, and mannosylated ligands. Clearance studies
in whole animals have localized radiolabeled ligands, such as mannosylated bovine
serum albumen, not only to macrophages, but also to liver sinusoidal endothelial
cells. Hitherto, there has been no comprehensive analysis of expression of the
mannose receptor in embryonic and adult mouse tissues. In this study, we have
undertaken a systematic survey of the expression of the mannose receptor from
early embryogenesis through to adulthood. The mannose receptor is expressed on
tissue macrophages throughout the adult mouse as expected. However, the mannose
receptor is first observed on embryonic day 9 on cells that line blood island
vessel walls in the yolk sac. The mannose receptor is localized on sinusoidal
endothelial cells in embryonic liver by embryonic day 11 and in bone marrow at
embryonic day 17. This pattern persists in these organs throughout embryogenesis
into adulthood when sinusoidal endothelial cells of lymph nodes also express the
mannose receptor. The receptor is also found on lymphatic endothelial cells of
small intestine. In contrast, sinusoids of spleen and thymus do not express
mannose receptor antigen. This study demonstrates that the mannose receptor is
expressed on tissue macrophages and on subsets of vascular and lymphatic
endothelial cells. Thus, the mannose receptor maybe a marker of the so-called
reticuloendothelial system.
PMID- 9560477
TI - Chymotrypsin gene expression in rat peripheral organs.
AB - Prior studies have revealed the presence of chymotrypsinlike protease in
peripheral organs, although no definitive evidence for the synthesis of this
enzyme in tissue other than the pancreas is available. In an attempt to detect
chymotrypsinogen mRNA in peripheral organs, a fragment of the pancreatic
chymotrypsin mRNA from rat was amplified using PCR. The sequence was identified
as a portion of the rat chymotrypsin B gene overlapping exon 5 through exon 7. It
was subcloned into the pGEM-4Z vector and used as a template for the vitro
transcription of an antisense riboprobe. Using ribonuclease protection and
Northern blot analyses, chymotrypsin mRNA was detected in the rat pancreas,
stomach, duodenum, ovary, and spleen. Monoclonal and polyclonal antisera against
chymotrypsin detected chymotrypsinlike immunoreactivity in rat and human
pancreas, rat stomach, duodenum and jejunum. Electrophoresis and immunoblotting
revealed chymotrypsin-chymotrypsinogen bands (25-29 kDa) in the stomach and
duodenum. Synthesis of a potent protease such as chymotrypsin in tissue other
than pancreas is significant, suggesting a potential physiological and/or
pathological role in these tissues.
PMID- 9560476
TI - Distribution of endoglin in early human development reveals high levels on
endocardial cushion tissue mesenchyme during valve formation.
AB - Endoglin is a component of the receptor complex for transforming growth factor
(TGF)-beta1 and TGF-beta3. We analysed its expression by immunohistochemistry in
human embryos at 4-8 weeks of gestation and in hearts ranging from 4-13 weeks
old. We compared endoglin distribution with that of TGF-beta receptors type I
(TbetaR-I), type II (TbetaR-II) and betaglycan. Endoglin was found on endothelial
cells in all tissues examined, consistent with its expression in adult blood
vessels. TbetaR-I, TbetaR-II and betaglycan were observed on most cell types and
had an overall similar pattern of distribution. Endoglin was detected on the
endocardium as early as 4 weeks, but was absent from myocardium. It was present
at high levels on the endocardial cushion tissue mesenchyme from 5-8 weeks'
gestation, during heart septation and valve formation, and subsequently decreased
as the valves matured. Endoglin expression in heart extracts was confirmed by
Western blot analysis. TbetaR-I, TbetaR-II and betaglycan were mostly found on
cardiac myocytes, but were detectable at low levels on endocardium. They were
expressed transiently on cushion mesenchyme, albeit at much lower levels than
endoglin. All four components of the TGF-beta receptor complex were detected by
RT-PCR in embryonic heart. Thus transient up-regulation of the components of the
TGF-beta receptor complex, and particulartly of endoglin, is associated with
heart septation and valve formation during early human development.
PMID- 9560478
TI - Establishment of oral mucosa phenotype in vitro in correlation to epithelial
anchorage.
AB - Cell-matrix interactions and the ordered deposition of basement membrane (BM)
components are of major importance for the maintenance of tissue homeostasis in
complex epithelia. This aspect was studied in vitro in a coculture system
designed as an oral mucosa model. As crucial epithelial features the kinetics of
proliferation, expression of site-specific keratins as well as integrin patterns
in correlation to synthesis of BM components were assessed by
immunohistochemistry and in situ hybridization. Comparison with non-cornified
gingiva as tissue of origin revealed different stages of epithelial development,
eventually leading to complete reconstruction within a time frame of 1-3 weeks.
First, the initial activated stage up to 1 week was characterized by (a) high
keratinocyte proliferation, (b) extended expression of the basal cell-specific
keratin K5 and (c) a patchy pattern of the differentiation-specific keratins K4
and K13. Second, after 2 weeks the improvement of histoarchitecture correlated to
(a) predominant K5 expression in the basal and (b) extension of K4 and K13 within
the suprabasal cell compartment, (c) high expression of integrins alpha3 beta1
and alpha6 beta4 including their ligand laminin-5 and (d) accumulating deposition
of basement membrane components. Third, virtually complete tissue normalization
at 3 weeks was indicated by (a) restriction of K5 to the basal cell area, (b)
regular suprabasal localization of K4 and K13, (c) polarization of integrins to
basal and parabasal cells and (d) linear codistribution of collagen IV,
"classical" laminin (-1 or -10) and laminin-5 underneath the basal cells. Thus,
these organotypic cocultures represent relevant equivalents for non-keratinized
oral mucosa with typical gingival differentiation features and in addition
suitable models for preclinical trials such as prospective dental material
testing.
PMID- 9560479
TI - Edema formation in the rat larynx.
AB - In the rat larynx, plasma exudation and edema formation were studied by light and
electron microscopy after i.v. injections of the mast cell activator compound
48/80, substance P, and capsaicin. The morphological effects of substance P and
capsaicin on connective tissue mast cells in vivo were also examined. Of the
drugs tested, only compound 48/80 degranulated the connective tissue mast cells.
All drugs induced a subepithelial plasma exudation in the subglottic region, with
edema in the lamina propria and widened intraepithelial intercellular spaces,
though the tight junction regions seemed intact. In the epiglottis, 10 min after
compound 48/80 injection, there was edema in the lamina propria on the lingual
side, with an intact and tight epithelial lining. No morphological sign of edema
was found in the epiglottis after injection of substance P or capsaicin. The
pronounced effect found in the epiglottic region after compound 48/80 injection
was due to the release of mediators such as histamine and 5-hydroxytryptamine
from the connective tissue mast cells. This study supports the belief that
substance P in vivo mediates an increased vascular permeability by a direct
effect on the blood vessels - a mechanism distinct from mast cell degranulation.
PMID- 9560480
TI - Cutaneous glands of male and female impalas (Aepyceros melampus): seasonal
activity changes and secretory mechanisms.
AB - The cutaneous glands of the forehead and the metatarsus were studied by
histological and histochemical methods and electron microscopy in adult male and
female impalas in various seasons of the year. All glandular areas consist of
apocrine and holocrine glands, which, however, occur in different proportions.
Our findings in the apocrine gland cells suggest (1) the synthesis and exocytosis
of a glycoproteinaceous secretory product stored in secretory granules, (2)
typical apocrine secretion of the transformed apical cytoplasm, and (3)
transepithelial fluid transport. The Golgi apparatus and apical membrane have
binding sites for several lectins (PNA, HPA, RCA I, WGA). Cytokeratins 7, 14 and
19 are expressed at various intracellular localizations, suggesting an active
role in the secretory mechanisms. The glands of the male forehead show marked
seasonal changes in activity that are correlated with the main phases of the
reproductive cycle, with the highest cellular activity occurring during the rut
in April/May. The female forehead glands are only moderately developed and do not
undergo seasonal changes. The metatarsal glands are of equal size in males and
females and show no seasonal changes in activity. This study supports the
hypothesis that (1) forehead glands in the male have a signaling role in the rut
and (2) the metatarsal glands have a more general, probably social role
maintaining and restoring contact between herd members.
PMID- 9560481
TI - Uptake of lithium carmine by sinusoidal endothelial and Kupffer cells of the rat
liver: new insights into the classical vital staining and the reticulo
endothelial system.
AB - Sinusoidal cells in the rat liver were studied in vivo and in vitro using the
original vital staining with lithium carmine, which has contributed much to the
development of the concept of the reticulo-endothelial system.
Immunohistochemical and electron-microscopic studies revealed that the dye
incorporating cells were sinusoidal endothelial cells, Kupffer cells, and
monocytes. The endothelial cells took up much more dye than did the Kupffer cells
and bulged largely into the sinusoidal lumen. Electron microscopy revealed that
small particles of lithium carmine were associated with coated vesicles of
endothelial cells and ruffled membranes of Kupffer cells. In the endothelial
cells, these particles were present in various concentrations within vacuolated
structures and condensed in the lysosomes forming large aggregates of lithium
carmine lumps. These lumps showed crystalline structures, within which the size
of the individual particle was up to 30 nm in width and 50 nm in length. A few
endothelial cells containing abundant dye underwent degeneration, and some were
taken up by Kupffer cells. Liver endothelial cells isolated from lithium carmine
administered rats endocytosed fluorescence-labeled collagen. Isolated endothelial
cells from normal rat liver, when cultured with lithium carmine, did not take up
any dye, and their endocytosis of formaldehyde-treated albumin was inhibited dose
dependently. We conclude that in the liver, endothelial cells, but not Kupffer
cells, predominantly take up lithium carmine. Furthermore, we propose the
existence of a generalized cell system based on its vital staining capacity.
PMID- 9560482
TI - Increased functional load on mouse kidney proximal tubule epithelial cells causes
changes in nucleolar 3-D architecture.
AB - Ultrastructural 3-D analysis of nucleolar architecture and Ag-NOR protein
distribution in mouse kidney-cortex proximal-tubule epithelium has been
performed. A principal scheme of structural changes of the nucleolus and
organization of its components during the intensification of pre-rRNA synthesis
(dynamic model of a nucleolus) based on computer spatial modelling has been
advanced. According to the nucleolar composition, three groups of cells, which
differ from each other by rRNA synthesis, are defined in normal kidney. Most
nephron proximal-section cells (about 52%) are characterized by lower activity of
RNA synthesis. Such kind of cells are defined as group I (nucleolar diameter 0.7
1.5 microm) and always contain resting, ring-shaped or close to ring-shaped dense
nucleoli, which have 2 or 3 fibrillar centers. Nucleoli of group II cells (about
37%, nucleolar diameter 1.5-2.5 microm) have a higher level of activity, contain
4-7 fibrillar centers, and their structural organization is close to reticulated
forms due to the first indications of vacuolar network (identified as
prereticulated nucleoli). The most active cells of group III (about 11%,
nucleolar diameter 2.5-3.5 microm) include cells with typical reticulated
nucleoli with a well expressed vacuolar network and numerous fibrillar centers
(18-22). Increased functional load of the epithelium caused by unilateral
nephrectomy and diuretic (4-chlor-H [2-furylmethyl] 5-sulphamyl-antranic acid)
injection changed the proportion of the different cell groups: group I decreased
(about 25%), whereas groups II and III increased (about 8% and 17%,
respectively). The increase of nucleolar activity first causes a deformation of
the individual fibrillar centers as well as complication and growth of their
surface. Further, a progressive fragmentation of the fibrillar centers and the
growth of their total volume is observed. The complication and growth of the
total volume of Ag-positive zones is another indication of the nucleolar
activation. The vacuolar system develops by a gradual fusion of small isolated
cavities into a united vacuolar network. Nucleoli with 2-7 fibrillar centers are
considered to be intermediate forms reflecting successive stages of its
activation or inactivation: from the resting ring-shaped nucleolus via transient
stages of increasing functional activity to the active reticulated nucleoli and
vice versa. The observed differences in the nucleolar ultrastructure are regarded
as evidence of the functional heterogeneity of cell populations within one
functional segment of nephron.
PMID- 9560484
TI - MR angiography: basic principles and theory.
AB - The most commonly used MR angiography techniques are categorized as time-of
flight, phase-contrast, or contrast-enhanced methods. When the basic principles
of the various MR angiographic methods are understood, the techniques can be used
to achieve high-quality angiograms. This article describes the physical
principles and theory of some of the most widely used MR angiographic methods.
PMID- 9560483
TI - Immunocytochemical alterations in the intra-acrosomal antigen MN7 during
epididymal maturation of guinea pig spermatozoa.
AB - We have previously shown that a 90-kDa intra-acrosomal antigen, MN7, is
restricted to the anterior acrosomal region of mouse, rat, and hamster
spermatozoa. The present study has examined the localization and the behavior of
MN7 during sperm maturation in the epididymis of the guinea pig by immunoelectron
microscopy. MN7 showed not only a specific localization in the apical segment of
the guinea pig sperm acrosome, but also a distinct alteration during maturation,
as follows. MN7 was exclusively found both at the dorsal matrix and on the outer
acrosome membrane (OAM)/matrix-associated materials in the apical segment. MN7
was initially distributed throughout the electron-lucent dorsal matrix in
immature sperm but, during maturation, became more restricted to the spherical
bodies within the electron-lucent area. MN7 on OAM/matrix-associated materials
was first distributed along the ventral margin and the small area posterior to
the dorsal matrix but, during maturation, disappeared from the ventral margin and
became restricted to the dorsal region. These results indicate that MN7 is a good
tool for studying the stepwise maturation of epididymal spermatozoa.
PMID- 9560485
TI - Contrast-enhanced MR angiography: theory and optimization.
AB - It is now possible to perform contrast arteriography safely and rapidly by taking
advantage of gadolinium contrast agents and three-dimensional MR imaging.
Although the development of this approach to arteriography is in its infancy, the
image quality already rivals conventional arteriography. As we continue to
develop this technique by taking advantage of more pulse sequence tricks,
improving hardware, and improving contrast agents, the field of vascular imaging
will undoubtedly be transformed. This article discusses the fundamental concepts
underlying this approach to angiography.
PMID- 9560486
TI - MR angiography of the aortic arch vessels and upper extremities.
AB - MR angiography of the aortic arch vessels and upper extremities is a noninvasive
alternative to conventional catheter angiography without the risks of stroke or
the potential toxicity of iodinated contrast. The use of optimized, breath hold
gadolinium-enhanced three-dimensional MR angiography provides excellent image
quality with the capability of display options not available with conventional
angiography. This article demonstrates the utility of this new technique in the
diagnosis of congenital and acquired conditions of the supraaortic vascular
system.
PMID- 9560487
TI - MR angiography of the thoracic aorta.
AB - MR angiography is a powerful tool in evaluating the complete spectrum of
congenital and acquired diseases of the thoracic aorta. The use of gadolinium
chelates in conjunction with rapid three-dimensional sequences performed with
breath holding provides robust image quality with multiple display options. As a
result of technological advances in hardware, software, and pulse sequence
implementation combined with innovative use of contrast agents, MR angiography is
poised to replace conventional catheter angiography of the thoracic aorta for
many indications.
PMID- 9560488
TI - MR angiography of the abdominal aorta.
AB - MR angiography has become a powerful tool for the examination of abdominal aortic
pathology, including aortic aneurysm, dissection, and occlusion. This article
reviews the techniques, indications, and imaging findings obtained from MR
angiography of the abdominal aorta. In addition, the role of MR angiography
relative to existing modalities is discussed.
PMID- 9560489
TI - Mesenteric occlusive disease.
AB - Using contrast-enhanced MR angiography, cine phase contrast MR imaging, and flow
independent T2 measurements, MR imaging can provide both morphologic information
about the degree of stenosis of the mesenteric vessels and quantitative
functional information about blood flow and blood oxygen saturation in these
vessels. The combination of these techniques can potentially revolutionize the
diagnosis and post-treatment assessments of both acute and chronic mesenteric
occlusive disease.
PMID- 9560490
TI - Renal MR angiography.
AB - Three-dimensional gadolinium MR angiography (3D-Gd-MRA) accurately visualizes the
renal arteries with almost no degradation from inplane saturation or motion
artifacts. The diagnostic accuracy for detecting and grading of renal artery
stenosis, as well as the assessment of other vascular pathology, approaches that
of conventional x-ray angiography. For the renovascular system, this technique
requires precise contrast media bolus timing since multiple successively
enhancing structures are present. Details on performing renal MR angiography,
strategies for image analysis, and examples of common renal vascular pathology
are reviewed. The 3D-Gd-MRA protocol can be easily combined with other MR imaging
techniques to provide a comprehensive assessment of the hemodynamic and
functional significance of renal artery stenosis.
PMID- 9560491
TI - MR angiography of the aortoiliac and femoropopliteal vessels.
AB - The variety of MR angiography strategies can be applied to the evaluation of
vascular disease in the aortoiliac and femoropopliteal vessels. When used
appropriately, a combination of these strategies can be offered to patients with
peripheral vascular disease as a safe and effective alternative to conventional
angiography for planning treatment options. This article presents the clinical
issues, MR techniques, and the results of relevant studies in a detailed manner
pertinent to accomplishing diagnostic MR angiography in the aortoiliac and
femoropopliteal segments.
PMID- 9560492
TI - MR angiography of the peripheral vessels.
AB - MR angiography of the inflow vessels has undergone dramatic change in the past
few years; the advent of ultra fast gradient echo pulse sequences combined with
the gadolinium chelate bolus technique has supplanted earlier methods. However,
owing to the highly variable flow velocities and inconsistent rate of vessel
opacification encountered in the outflow vessels, two-dimensional time-of-flight
MR angiography remains the workhorse of the distal vasculature.
PMID- 9560493
TI - Body MR angiography: a surgeon's perspective.
AB - This article addresses the indications for surgical procedures and the anatomic
relationships that must be imaged to effectively plan surgical intervention.
Treatment and imaging of aortic aneurysm, aortic dissection, splanchnic artery
aneurysms, renal artery disease, and arterial disease of the lower extremities
are reviewed.
PMID- 9560494
TI - MR angiography of the thoracic, abdominal, and extremity venous system.
AB - MR angiography is a useful clinical tool for noninvasive evaluation of the
abdominal, thoracic, and peripheral venous system. A variety of MR techniques are
available, although two-dimensional time-of-flight is used most commonly. MR
imaging of the venous system is less hindered by technical limitations and
artifacts commonly encountered with imaging of the arterial system. This article
reviews the most commonly used techniques and their clinical application.
PMID- 9560495
TI - Branchiogenic carcinomas: do they exist?
AB - The existence of branchiogenic carcinomas is questioned in this review, which
also discusses the different possibilities in an adult patient who presents with
a cystic swelling in the upper lateral aspect of the neck. Most cases of
branchiogenic carcinomas reported in the literature may actually have been
secondary metastatic lesions from an occult tonsillar carcinoma. We will also
discuss the different features of cystic metastasis that distinguish them from
solid metastasis, and explain why oropharyngeal carcinomas with cystic neck
metastasis should be in a separate category from other head and neck cancers.
PMID- 9560496
TI - Minimizing the risk of penetrating injury to surgical staff in the operating
theatre: towards sharp-free surgery.
AB - Conventional surgery carries a significant risk of inadvertent injury to members
of the scrub team. Although minor injury is common and usually no more than
unpleasant, serious consequences may occur. Modifications in technique together
with the application of modern instrumentation may reduce the risks of sharp
injury substantially. The techniques and technology available in the conventional
open surgery setting are reviewed.
PMID- 9560497
TI - A randomized controlled trial of double-versus single-gloving in vascular
surgery.
AB - With the increasing incidence of hepatitis B and HIV, and the increasing
awareness of the risk and prevalence of hepatitis C, it is becoming even more
necessary to adopt stricter policies to safeguard personnel and to reduce the
risk of transmission. Previous studies have shown a need for eye protection,
protective clothing and the use of double-gloving during operative or
interventional procedures. The risk of infection is much less with unbroken skin
and conversely more likely when hollow needles are used. Arguments against the
routine use of double-gloving include the loss of dexterity and the discomfort
incurred, and the potential loss of dexterity that might theoretically result in
more rather than fewer needle-stick injuries.
PMID- 9560498
TI - Screening for diabetes on a vascular ward: lessons from an audit.
AB - Owing to the high prevalence of diabetes mellitus in patients with peripheral
arterial disease, screening for this disorder is necessary on a vascular ward.
Our current practice of random plasma glucose (RPG) testing on every admission
was reviewed. This test, although crude, excludes diabetes if the cutoff level is
set as low as 6.0 mmol/L. A total of 36% of our patients had an abnormal result,
but this was not further acted upon. A further 19% had no test result recorded at
all. This practice is inadequate and has resulted in the following
implementations: (1) every patient with clinical evidence of arterial disease
should have their RPG level measured; (2) patients with a level > 6.0 mmol/L
should have a fasting plasma glucose level estimated; and (3) patients with an
abnormal fasting plasma glucose level should be referred to the diabetic clinic.
PMID- 9560499
TI - Prospective audit of 200 patients undergoing laparoscopic inguinal hernia repair
with follow-up from 1 to 4 years.
AB - The results of 215 laparoscopic transabdominal pre-peritoneal inguinal hernia
repairs are reported with a follow-up of 1-4 years (median 2.5 years). The
patients" age range was 17-85 (median 59 years). Three recurrences occurred in
the first 75 repairs, where a 12 x 7 cm mesh was used. There has been no
recurrence in the subsequent 140 repairs where a larger 15 x 10 cm mesh was used
for the repair. A total of 5% of patients developed urinary retention after the
operation and a further 13% developed minor complications. The procedure was
remarkably pain-free, with 25% requiring no analgesia after the operation and 67%
requiring no analgesia after discharge from hospital. There was a rapid return to
normal activity, with 55% driving within 1 week of the operation and 85% within 2
weeks. Sixty per cent returned to work within 2 weeks of the operation and 69%
within 3 weeks. Forty-two of the patients had undergone a previous open hernia
repair and 93% of these preferred the laparoscopic repair as there was less post
operative pain and a quicker recovery. The results show that laparoscopic hernia
repair is remarkably pain-free, allows a rapid return to normal activity and has
a low recurrence rate when a 15 x 10 cm mesh is used.
PMID- 9560500
TI - The effect of a dedicated emergency theatre facility on emergency operating
patterns.
AB - Following the introduction of a dedicated 24-hour emergency theatre facility in a
500-bed district general hospital, the total amount of emergency general surgery
performed after 22.00 hours has been reduced from 37.2 to 13.1%, with a
concomitant increase in emergency day-time operating from 22.1 to 51.2%. The
majority of the workload was previously performed by the junior grades, and this
has remained unchanged. Operative experience has not been diminished with the
reduction in night-time surgery, and senior supervision has been enhanced. There
has been no significant difference in mortality or morbidity with the changes in
operating patterns. Utilization of the theatre staff and time during the night
has been improved.
PMID- 9560501
TI - Variants of papillary carcinoma of the thyroid: experience at Asir Central
Hospital.
AB - Papillary carcinoma of the thyroid is now further subclassifiable into its
different variants. We report incidence, clinical behaviour and outcome of rare
variants of papillary thyroid cancers at Asir Central Hospital, Saudi Arabia.
These variants differ from each other not only on a morphometric basis, but also
in clinical behaviour. Accordingly, we report our experience of different
variants in a series of 35 papillary carcinomas. These cases were received in the
surgical pathology laboratory of Asir Central Hospital from January 1987 to
December 1994. We have reviewed clinical charts, microscopic slides and
pathological reports of these carcinomas. The following results have been
obtained: 20 cases were classical (usual) papillary thyroid carcinomas: seven
were follicular variants; three were tall cell/ columnar variants; two were
oxyphilic variants; and one was a diffuse sclerosing variant. There were two de
differentiated papillary carcinomas (anaplastic carcinomas with foci of well
differentiated papillary carcinomas). These variants were also correlated with
clinical parameters such as age, sex and nationality of the patients,
aggressiveness of the tumours, types of surgery required, and follow-up when
available.
PMID- 9560502
TI - Effect of mangan-desferrioxamin in the prevention of peritoneal adhesions.
AB - An experimental study was carried out using mangan-desferrioxamin chelate, an
effective iron-chelating and free oxygen radical scavenging agent, to prevent
post-operative peritoneal adhesions in 40 Wistar albino rats. The density of
adhesions was evaluated and group scores obtained. The means score (2.5 +/- 0.87)
for the group of rats treated with mangan-desferrioxamin was significantly
different (P < 0.001) (95% confidence interval 0.6 to 1.6) from that of the
control group(mean score 3.9 +/- 0.3). This favourable effect of mangan
desferrioxamin in the prevention of post-operative adhesions should encourage
further research to determine the mechanisms of action.
PMID- 9560503
TI - Combined fascia and mesh closure of large incisional hernias.
AB - Large incisional hernias of the abdominal wall represent substantial defects of
supportive tissues. The repair of these requires the mobilization of fascia or
the use of a prosthetic mesh. A method for closing large midline incisional
hernias using both the fascia and a mesh was described in 1979. This repair was
used for six midline hernias and four large incisional hernias in the right
subcostal region. No wound complications and no recurrences (median follow-up 1
year 5 months) were seen. The combined fascia and mesh repair can be successfully
used for large incisional hernias of the anterior abdominal wall in areas other
than the midline.
PMID- 9560504
TI - Stapler failure in pharyngeal diverticulectomy: a suggested modification in
surgical technique.
AB - The use of a mechanical stapling device during excision of a pharyngeal pouch is
now becoming more common, and has many advantages including less contamination of
the wound by pharyngeal contents and a shorter operating time. The manufacturers
recommend dividing the neck of the pouch flush with the stapler before removing
the stapler. We report a case where the stapler failed, leaving a larger defect
in the pharyngeal wall necessitating a hand sutured closure. We recommend a
change in practice: an artery forcep is applied across the pouch distal to the
stapler, the stapler is then removed and the staple line inspected before
dividing the pouch.
PMID- 9560505
TI - Obturator hernia: a new technique for repair.
AB - An obturator hernia is exceedingly rare and the diagnosis is usually made at
laparotomy for small bowel obstruction. Several methods of dealing with the
hernial defect have been described. Two cases of obturator hernias in
nonagenarians are reported and a new, simple and effective method of repairing
the hernia by suturing a polypropylene (Prolene) mesh to Cooper's ligament is
proposed.
PMID- 9560506
TI - Tarsal tunnel syndrome: a study of the clinical and neurophysiological results of
decompression.
AB - The neurophysiological and clinical outcomes of surgical decompression of 22
cases of tarsal tunnel syndrome are analysed. Recent work by Pfeiffer &
Cracchiolo has suggested a successful outcome in only 44% of cases. We have
reviewed the outcome of surgery both clinically and with the use of nerve
conduction studies. Pre- and post-operative motor conduction delays in the
plantar nerves are compared with clinical results found both in the clinic and
later by a postal questionnaire. Despite careful clinical and neurophysiological
assessment prior to a full surgical release, only 42% of patients had a
satisfactory outcome. A larger reduction in plantar nerve conduction delay post
operatively corresponded well to an improvement in symptoms. However, we were
unable to predict which cases would respond to decompression using clinical or
electrophysiological methods. We question the use of nerve conduction studies in
the diagnosis of tarsal tunnel syndrome, and also the role of surgery in the
management of this condition.
PMID- 9560507
TI - Further uses of polymethylmethacrylate in orthopaedic surgery.
AB - For over 30 years polymethylmethacrylate (PMMA) has been used in orthopaedic
surgery to fix prosthetic components. Two additional uses, relying on the
moulding properties previously utilized in dentistry, are described here: the use
of PMMA as a bone graft template and as a femoral window plug in total hip
replacement.
PMID- 9560508
TI - Quadriceps pull test: an outcome predictor for lateral retinacular release in
recurrent patellar dislocation.
AB - Recurrent dislocation of the patella is a disorder with a complex aetiology.
Several surgical procedures have been recommended for its correction, but there
are few clinical or radiological guidelines to facilitate the selection of a
particular procedure. The results of treating a series of 29 knees are presented
with a follow-up of at least 2 years. A significant correlation has been found
between the horizontal movement of the centre of the patella on quadriceps
contraction (quadriceps pull test) and surgical outcome when lateral release
alone is selected for the correction of recurrent patellar dislocation.
PMID- 9560509
TI - Does early wound infection after elective orthopaedic surgery lead on to chronic
sepsis?
AB - Infection is an uncommon, but occasionally devastating, complication of
orthopaedic surgery. The definition of post-operative infection remains
problematic. A high rate of early post-operative sepsis has previously been
reported using a clinical definition of wound infection as recommended by the
Surgical Infection Study Group. The purposes of this study is to determine the
rate of ongoing wound problems and deep sepsis 1 year after these early wound
infections. Of 1131 consecutive orthopaedic procedures, there were 70 wound
infections occurring within 30 days of surgery. Adequate follow-up data were
obtained in 67 (97%) of the 69 patients alive at 1 year. Of these 67, three had
definite evidence and two possible evidence of ongoing wound problems and/or deep
sepsis. It is concluded that early post-operative wound infection as defined by
the Surgical Infection Study Group is a poor predictor (4-10%) of ongoing wound
problems and deep sepsis at 1 year. All of the confirmed cases of late sepsis
were found to be associated with revision arthroplasty and/or pin tract sepsis.
PMID- 9560510
TI - Profile of the first four years of the Regional Burn Unit based at St. John's
Hospital, West Lothian (1992-1996).
AB - In March 1992, the Regional Adult Burn Unit for the South East of Scotland in
Bangour was transferred to the new District General Hospital in West Lothian.
With the change in site and with changes in NHS policies and staff, it was
expected that some difficulties would occur. An analysis of the initial situation
was considered to be educational as well as of practical value. Parameters of
mortality and infection were looked at in particular. The number of admissions of
patients with burns (and notably those of 15% total body surface area or more)
appears to be reducing annually; the mortality of 4.7% is comparable with
Bangour, but the 42% mortality of patients with burns of 15% or more of the total
body surface area is a cause for concern. Although the most common infectious
organism in the Burn Unit remains Staphylococcus aureus, the advent of MRSA is
worrying. The new unit has been closed twice because of bacterial infection. It
is concluded that it is essential that patients with burns are managed in a
separate Burn Unit within the District General Hospital and not amalgamated with
other areas such as Intensive Care.
PMID- 9560511
TI - A preliminary report: the changes in the neuropeptide containing epidermal
innervation in response to inflammatory reactions elicited in human breast skin.
AB - A pilot study was performed to demonstrate the involvement of the epidermal
innervation in cutaneous neurogenic inflammation following injury or skin
incision. Scratching human skin is known to evoke an inflammatory reaction
dependent in part on sensory nerves (neurogenic inflammation) in the dermis.
Human breast skin from four patients was scratched using a blunt metal ruler to
elicit an inflammatory reaction. Samples of skin along the scratch line were then
removed before and up to 5 min after scratching. Tissue samples were then stained
using immunocytochemical techniques for the neuropeptides PGP 9.5, SP, CGRP and
VIP. Quantitative assessment using image analysis demonstrated a marked variation
between patients in the levels of epidermal PGP 9.5 innervation prior to
scratching of the skin. In addition both increases and decreases in the epidermal
innervation of PGP 9.5 were observed in different patients immediately after
scratching. It is considered that epidermal innervation may have an important
role in the inflammatory reaction to trauma and surgical operations and that a
more extensive study is merited.
PMID- 9560512
TI - Spontaneous retroperitoneal haemorrhage associated with renal disease.
AB - Spontaneous retroperitoneal haemorrhage is an uncommon entity. It is even rarer
when the underlying cause is associated with renal disease. In most cases the non
traumatic rupture of a kidney requires an emergency surgical intervention as the
underlying disease only becomes clear intra-operatively. Most patients with a
spontaneous kidney rupture have a renal tumour. Of these renal tumours,
angiomyolipomas show a particular tendency to rupture. The cases are reported of
five patients who presented with an acute onset of spontaneous retroperitoneal
haemorrhage from different kidney disorders. The importance of considering the
possibility of spontaneous kidney rupture in the evaluation of patients
presenting with spontaneous retroperitoneal haemorrhage is stressed.
PMID- 9560513
TI - Conservative management of splenic rupture in a haemophiliac adult.
AB - The recognition of the grave risk of overwhelming sepsis in splenectomized
individuals has led to the search for alternatives to splenectomy. Conservative
management, first tried successfully in children and later extended to adult
patients, has become the accepted form of treatment and has also been tried with
success in haemophiliac children. The case presented here is important because
this is the first report of a successful outcome of non-operative treatment of a
ruptured spleen in a haemophiliac adult.
PMID- 9560514
TI - A lump in the groin: an unusual presentation of loose hip prosthesis.
AB - We describe the loose hip prosthesis presenting as a mass in the groin, with a
collection of titanium and polyethylene debris within the ileopsoas bursa.
Titanium tissue staining has been noted, at the time of revision of titanium
prostheses, but frank ileopsoas bursitis presenting as a groin mass, after hip
replacement has not previously been described.
PMID- 9560515
TI - Selective arterial embolization in the treatment of arterial priapism.
AB - Arterial or 'high-flow' priapism is a rare complication of penile or perineal
trauma. The case is reported of a patient with a more than 2-week history of
priapism who was successfully treated by selective arterial embolization, with
maintenance of potency.
PMID- 9560516
TI - Non-iatrogenic perforation of the stomach by a chest tube in a patient with
traumatic diaphragmatic hernia.
AB - A 40-year-old Libyan male was admitted to the intensive therapy unit of Zliten
Central Hospital, Libya after a road traffic accident in which he had been the
driver. On physical examination he was irritable, dyspnoeic, cyanotic, had
contusions and abrasions on his chest and abdomen (mainly on the left side), a
lacerated wound on the forehead, a large haematoma over the left thigh and
tenderness over the left side of the chest and abdomen.
PMID- 9560517
TI - Endoscopic sigmoidopexy: a safer way to treat sigmoid volvulus?
AB - Sigmoid volvulus may be treated by sigmoidoscopic reduction and elective
sigmoidopexy or resection at a later stage, provided there is no evidence of
peritonitis, perforation or rectal bleeding. However, operative treatment,
whether urgent or elective, is associated with a relatively high morbidity and
mortality. An endoscopic technique of sigmoidopexy is reported which is
relatively quick and straightforward to perform, and is likely to have a lower
rate of morbidity and mortality than conventional techniques for the treatment of
sigmoid volvulus.
PMID- 9560518
TI - Pancreatic tuberculosis: case reports and review of the literature.
AB - Tuberculosis affecting the pancreas is rare. Its occurrence may pose a diagnostic
problem in differentiating it from carcinoma of the pancreas. Two cases of
tuberculosis affecting the pancreas are reported, illustrating the value of fine
needle aspiration in such a situation. The response of the disease to
antituberculous drugs was slow, but sure.
PMID- 9560519
TI - Anatomy training for surgeons--a personal viewpoint.
PMID- 9560520
TI - Anatomy training for surgeons--a personal viewpoint.
PMID- 9560521
TI - Anatomy training for surgeons--a personal viewpoint.
PMID- 9560522
TI - Anatomy training for surgeons--a personal viewpoint.
PMID- 9560523
TI - Anatomy training for surgeons--a personal viewpoint.
PMID- 9560525
TI - Anatomy training for surgeons--a personal viewpoint.
PMID- 9560524
TI - Anatomy training for surgeons--a personal viewpoint.
PMID- 9560526
TI - The response of liver macrophages to inflammatory stimulation.
AB - The gut is the major source of inflammatory agents that affect the liver. Of
these compounds, the endotoxins are the most frequent and best studied intruders.
The resident macrophages of the liver, the Kupffer cells, are among the first to
respond to this complex. Following contact with the cluster of differentiation
(CD) 14 protein, the complex triggers a signal cascade involving the nuclear
factor kappa B. This factor enhances the expression of inflammation-related
genes, e.g. those encoding cytokines. Tumor necrosis factor-alpha is responsible
for nearly all of the effects ascribed to endotoxins (lipopolysaccharides).
Interleukin (IL)-6, also a product of lipopolysaccharide-activated Kupffer cells,
may be instrumental in eliciting the acute-phase response of hepatocytes, while
transforming growth factor-beta promotes conversion of quiescent hepatic stellate
cells into a collagen-producing myofibroblast-like form. A different signal
pathway triggered by bound endotoxin involves a mitogen-activated protein kinase
and leads to the activation of phospholipase A2 and the synthesis of the
eicosanoids. Endotoxin also induces a nitric oxide synthase in Kupffer cells.
This inorganic mediator may participate in the relaxation of the hepatic
sinusoid, but may also, together with macrophage-derived superoxide, produce
strong oxidants. Tumor necrosis factor-alpha and nitric oxide play a significant
role during liver regeneration after partial hepatectomy. Of the various effects
of eicosanoids, their regulatory role in cytokine production by Kupffer cells may
be the most important. The regulation of Kupffer cell functions by cell volume
change has very recently become apparent.
PMID- 9560527
TI - Mucin glycoproteins in colonic neoplasia.
AB - Mucins are high molecular weight glycoproteins which are heavily glycosylated
with many carbohydrate side chains. In epithelial cancers such as colorectal
cancer, both qualitative and quantitative alterations in carbohydrate and
polypeptide moieties of mucin glycoproteins occur. These changes in mucin
glycoproteins are one of the most common phenotypic markers of colorectal
carcinogenesis and may play an important pathobiological role. The expression of
some of the sialylated carbohydrate antigens appears to correlate with a poor
prognosis and increased metastatic potential in colorectal cancer. The increased
exposure of peptide epitopes of mucin glycoproteins in colorectal cancer appears
to be due to either abnormal glycosylation and/or altered levels of mucin gene
transcription. In addition, dysregulation of tissue specific mucin genes occurs
in colorectal cancers. This information is currently being exploited for further
elucidation of the molecular mechanisms involved in carcinogenesis, tumor
progression and metastasis, and the development of novel methods of colorectal
cancer diagnosis and therapy.
PMID- 9560528
TI - Evaluation of systemic inflammatory response syndrome criteria as a predictor of
mortality in emergency patients transported by ambulance.
AB - Based on the concept of the systemic inflammatory response syndrome (SIRS), a one
year retrospective study was carried out to examine SIRS criteria as a simple and
rapid predictor of outcome for emergency patients. Among a total of 2,180
patients transported to the emergency room by ambulance, 318 (14.8%) had primary
SIRS and 389 (17.8%) met SIRS criteria at some point during the entire treatment
period. The admission rate for primary SIRS increased sequentially as more SIRS
criteria were met, rising from 15.4% in non-SIRS to 100% when all four criteria
were met. The mortality of primary SIRS also increased sequentially as more SIRS
criteria were met, rising from 1.4% in non-SIRS to 35.3% when all four criteria
were met. Furthermore, heart rate, C-reactive protein and platelet count were
considered to be potentially useful new criteria for a group of SIRS patients
with a high risk of mortality (high-risk SIRS), based on a comparison of
variables between SIRS patients who died and SIRS patients who survived. The
mortality associated with primary SIRS increased sequentially as more high-risk
SIRS criteria were met, rising from 7.6% when none were met to 50.0% when two
criteria were met. Considering the high specificity of primary SIRS for admission
(89.5%) and mortality (86.8%), SIRS criteria have clinical and prognostic
importance in the management of emergency patients. Given the high mortality
(29.9%), the new high-risk SIRS criteria may also be useful as entry criteria for
clinical trials of innovative therapies for patients with SIRS.
PMID- 9560529
TI - Vector autoregressive modeling analysis of frequently sampled oral glucose
tolerance test results. 1. A new method for quantifying insulin resistance and
secretion.
AB - To elucidate abnormalities in the feedback relationships between plasma glucose
and plasma insulin levels in diabetic patients, we have introduced the vector
autoregressive modeling method as a new for tool feedback analysis. This
technique was applied to plasma glucose and insulin level data from a series of
977 frequently-sampled oral glucose tolerance tests (FS-OGTT). Neither special
instruments nor medications were used in FS-OGTT. We were able to predict the
degree of the plasma glucose response occurring after an impulse-like increase in
plasma insulin at 1 mU/mL, as well as the plasma insulin response triggered by an
impulse-like increase in plasma glucose at 1 mg/dL, in the form of "impulse
response curves". The predicted impulse response curve of glucose to insulin
gradually changed from negative to positive with incremental changes in the
fasting plasma glucose level, reflecting increased insulin resistance.
Furthermore, the response of insulin to glucose decreased in a stepwise fashion
with the incremental changes in the fasting plasma glucose level. Our findings
confirm the usefulness of impulse response curves as clinical indicators. In
addition, analytical data point to a possible contribution of excessive hepatic
glucose production to the pathogenesis of the insulin resistance in non-insulin
dependent diabetes mellitus.
PMID- 9560530
TI - Fluorometric measurement of intracellular pH in vivo in feline cerebral cortex
during ischemia and reperfusion.
AB - Intracellular acidosis has been considered to play an pivotal role in the
progression of neuronal damage after cerebral ischemia. However, continuous
measurement of the intracellular potential of hydrogen (pH) has not been done
during and after ischemia. We measured temporal changes in intracellular pH in
the feline cerebral cortex in vivo during and after ischemia using a novel
fluorescent pH probe, 2',7'-biscarboxyethyl carboxyfluorescein (BCECF). A closed
cranial window was installed in the left temporal skull. BCECF acetoxymethyl
ester was superfused over the cortex, hydrolyzed and trapped in cortical cells.
Intracellular pH was measured utilizing excitation light at 507 nm and
fluorescent light at 550.5 nm. Focal cerebral ischemia for 60 minutes was induced
by means of middle cerebral artery occlusion. Intracellular pH in the severely
ischemic group became significantly acidic (p < 0.01) during ischemia and the
acidosis persisted for at least 30 minutes after recirculation. The pH change was
not significant in the mildly ischemic group. The severity of ischemia was
determined based on the mean transit time, which was calculated from the
hemodilution curve obtained by bolus injection of saline. The extent of ischemia
was further confirmed pathologically (p < 0.01). The above results suggest that
intracellular acidosis resulting from severe ischemia persists even after
recirculation.
PMID- 9560531
TI - Molecular approaches to the treatment of Fanconi anemia: recent advances.
AB - Fanconi anemia (FA) is an autosomal recessive disorder that leads to aplastic
anemia. Cells from FA patients are abnormally sensitive to DNA cross-linking
agents such as mitomycin C. FA consists of at least five subgroups (FA-A through
E). The genes defective in the FA-C and FA-A groups have recently been cloned.
Transfection of the normal FA gene into mutant cells corrects the
hypersensitivity to DNA cross-linking agents and improves cell viability in
vitro. The function of the FA gene products is still unclear, however. For
patients lacking a compatible bone marrow transplantation donor, an experimental
trial of gene therapy for group C FA is ongoing at the National Institutes of
Health.
PMID- 9560532
TI - A case of rapidly progressing small cell lung cancer incidentally found during
the course of renal failure.
AB - A 65-year-old man with rapidly progressing small cell lung cancer found in the
course of renal failure is reported. The patient had a medical history of
hypertension, diabetes mellitus, and cardiovascular disease. Hemodialysis was
introduced following renal failure, but pneumonia resulted in a transient
exacerbation and his complaint of general fatigue did not improve. Examination
for the fatigue revealed no apparent abnormalities. Three months later, he died
of small cell lung cancer.
PMID- 9560535
TI - [Assessment of the practicability of coronary risk index as a screening method
for ischemic heart disease in preoperative evaluation].
AB - Coronary risk index (CRI) is our newly developed screening method for ischemic
heart disease in preoperative evaluation. In this study, we assessed the
practicability of CRI examining coronary angiograms (CAG) obtained in 106
patients scheduled for operations. CAG was rated with CAG score, then CRI and CAG
score were statistically analyzed. These two parameters showed a significant
positive relationship; the higher CRI, the higher CAG score (P < 0.0001). When
the patients were divided into five groups by their CRI (0-9, 10-14, 15-19, 20
24, and more than 25), the group with higher CRI contained significantly more
patients with severe multivessel coronary lesion (P < 0.0001). Similar results
were obtained even in the patient with minimal change in ECG or exercise ECG, or
those with minimal chest symptoms (P < 0.001). These results suggests that CRI
works effectively as a screening method for ischemic heart disease regardless of
abnormalities in ECG or the chest symptoms. More cautious perioperative
management should be carried out in patients with higher CRI.
PMID- 9560534
TI - [Analysis of postoperative shivering following the deliberate mild hypothermia
during neurosurgery].
AB - We induced deliberate mild hypothermia in 96 patients who underwent intracranial
operations using a water blanket and a convective device blanket. The lowest
temperature measured at the tympanic membrane during mild hypothermia was
adjusted to 34.5 degrees C. The patients were divided into two groups in respect
to the occurrence of postoperative shivering, and the relationship between the
perioperative parameters and the occurrence of postoperative shivering was
evaluated. Shivering was observed postoperatively in 29 to 96 patients (30.2%).
In the group with shivering (SV), age was significantly lower and body weight and
body surface area were significantly larger than the group without shivering
(NSV). Urinary output was significantly larger in SV than in NSV. Tympanic
membrane, nasopharyngeal, and rectal temperatures at the end of surgery and
nasopharyngeal, rectal, and peripheral temperatures just after the extubation
were significantly lower in SV than in NSV. These results suggest that sufficient
rewarming of both the core and peripheral temperatures is important to prevent
the postoperative shivering following the mild hypothermic therapy in
neurosurgical patients, especially in young patients.
PMID- 9560537
TI - [Effect of temperature on Ca induced Ca release (CICR) rate].
AB - The aim of this study is to assess the effect of temperature on CICR rate. The
extensor digitorum longus muscles of male Hartley guinea pigs of about 450 g,
were prepared for this study. According to Endo's method, CICR rates were
measured using chemically skinned fibers. Two plates were prepared: one at 20
degrees C and the other at 30, 35, 37, 40 degrees C controlled by circulating
water at an appropriate temperature placed underneath each plate. The whole
procedure was carried out at 20 degrees C except the step of CICR using a plate
at a given temperature. An increase in temperature (20 to 40 degrees C)
accelerated CICR rate in a logarithmic manner. These experimental findings
suggest that cooling of the patient's body is important not only to control
metabolism but also to reduce an accelerated CICR rate.
PMID- 9560536
TI - [Pharmacokinetics of propofol and ketamine during and after total intravenous
anesthesia with propofol, fentanyl and ketamine for pediatric patients].
AB - Pharmacokinetics of propofol and ketamine during propofol-fentanyl-ketamine (PFK)
anesthesia for pediatric surgery was studied. Plasma levels of propofol (Pp) were
maintained approximately at 2.5 micrograms.ml-1 during surgery. Fifteen minutes
after the cessation of propofol infusion, Pp decreased to 1.5 micrograms.ml-1.
Plasma levels of ketamine (Pk) were maintained at 150-200 ng.ml-1 during the
surgery. After the cessation of ketamine infusion, Pk decreased as quickly as Pp.
Pk values at 15 minutes and 120 minutes after the cessation of the infusion were
93 ng.ml-1, 24 ng.ml-1, respectively. On the other hand, plasma norketamine (Pn)
levels increased gradually during surgery and stayed at 100-150 ng.ml-1 after the
end of ketamine infusion to play an important role in post-operative sedation and
pain relief. In conclusion, pharmacokinetics of propofol and ketamine in
pediatric patients was similar to that in adult patients. PFK anesthesia can be
used safely for pediatric as well as for adult patients.
PMID- 9560538
TI - [A comparison of the incidence of postoperative nausea and vomiting after
propofol-fentanyl anesthesia and that after nitrous oxide-isoflurane anesthesia].
AB - We compared the incidence of postoperative nausea and vomiting after total
intravenous propofol-fentanyl anesthesia (TIVA group) and that after thiamylal
nitrous oxide-isoflurane anesthesia (GOI group) in 60 ASA physical I and II
patients for elective abdominal simple total hysterectomy. When the patients
returned to the ward, the incidence of nausea was lower in TIVA group than in GOI
group (P < 0.05), but no difference was found in the incidence of vomiting
between the two groups. There were no differences in the incidence of nausea and
vomiting 6 hours after the operation and on the next morning between the two
groups. Postoperative pain scores were similar between the two groups, while
total postoperative evaluation scores (nausea, vomiting, pain, fever, and sleep
disturbance) were lower in TIVA group (P < 0.05). We conclude that TIVA with
propofol-fentanyl reduced the incidence of nausea and improved total evaluation
scores in the immediate postoperative period.
PMID- 9560539
TI - [A study of post-operative delirium in elderly patients].
AB - We investigated the post-operative delirium in elderly patients of over 65 years
of age. This investigation consisted of two studies, a prospective study and a
retrospective study. In the prospective study, we evaluated the incidence of post
operative delirium and the incidence of post-operative delirium was estimated pre
operatively using State-Trait Anxiety Inventory (STAI) and Mini Mental State
Examination (MMSE) in 24 patients scheduled for elective surgery under general
anesthesia in the period from Nov. 1995 to Oct. 1996. In the retrospective study,
we selected patients with post-operative delirium from 1600 patients who had
undergone scheduled and emergency operation under general anesthesia in the same
period as in the prospective study and analyzed the incidence of post-operative
delirium and background of these patients. Twenty four patients in the
prospective study were excluded from the retrospective study. In the prospective
study, although post-operative delirium was observed in 2 cases (8.3%), no
specific changes were observed in anxiety state and the ability of recognition.
In the retrospective study, post-operative delirium was observed in 22 cases
(1.37%). In these patients, several factors such as blood transfusion, emergency
operation, dehydration, thrombosis of the superior mesenteric artery, history of
ischemic heart disease, brain infarction and atrial fibrillation were thought to
be major risk factors triggering post-operative delirium. In this study we could
not conclude that STAI or MMSE are useful to estimate the incidence of post
operative delirium preoperatively. However, our result suggests that we should be
careful about the incidence of post-operative delirium in elderly patients with
pre-operative risk factors as mentioned above.
PMID- 9560540
TI - [A case report: inhaled nitric oxide improves respiratory function in an infant
with pulmonary hypertension].
AB - Nitric oxide (NO) was administered to an infant in a near fatal crisis of
pulmonary hypertension after total correction of double outlet right ventricle.
Inhaled NO of 4 parts per million reduced pulmonary arterial pressure (PAP) and
increased tidal volume during pressure limit ventilation. Both respiratory system
compliance and resistance were improved with NO inhalation. There was a
significant negative correlation between mean PAP and respiratory system
compliance. We speculated that a reduction in PAP with NO inhalation resulted in
the improvement of respiratory function. He was successfully weaned from
mechanical ventilation.
PMID- 9560541
TI - [Anesthetic management of parturients with intracranial hemorrhage accompanied by
seizure].
AB - Two preeclamptic parturients, who presented with generalized seizure, underwent
emergency cesarean section without confirmed diagnosis. They developed focal
neurological signs postoperatively, and were subsequently diagnosed as
subarachnoid hemorrhage due to rupture of an intracranial aneurysm and possibly
of arteriovenous malformation. Diagnosis should be made at the earliest possible
time for the optimal anesthetic as well as postoperative management of the
mother.
PMID- 9560542
TI - [Anesthetic management for microlaryngeal surgery with high frequency jet
ventilation and intravenous application of pentazocine and propofol].
AB - Microlaryngeal surgery was performed with total intravenous anesthesia using
pentazocine and propofol in 20 patients. The patients were paralyzed by
suxamethonium infusion and ventilated by high frequency jet ventilation via the
laryngoscope. In place of the opioid analgesics commonly used in TIVA for
microlaryngeal surgery, pentazocine was given. All but one of the patients
received pentazocine 15 m.g. intramuscularly as a premedication and then another
15 m.g. intravenously for induction of anesthesia. Average time of surgeries was
33.6 minutes. Average doses of pentazocine and suxamethonium given during
surgeries were 369 m.g. and 286 m.g., respectively. This technique allowed stable
anesthesia to be achieved with rapid postoperative recovery, without serious
complications like intraoperative return of awareness.
PMID- 9560543
TI - [Clinical indication of propofol for pediatric patients--pharmacokinetics of
propofol and ketamine during and after total intravenous anesthesia with
propofol, fentanyl and ketamine (PFK) in a neonate].
AB - A 60-day-old neonate boy received hepatic portojejunostomy for biliary atresia
under PFK. Pharmacokinetics of propofol and ketamine during and after PFK was
also studied. Plasma levels of propofol (Cp) and ketamine (Ck) were maintained at
2 to 3 micrograms ml-1 and at 200 to 300 ng ml-1 during surgery, respectively.
Both Cp and Ck decreased quickly after the end of infusions. From the
pharmacokinetic point of view, PFK may be safely applied even for neonates.
PMID- 9560544
TI - [The effect of scalp infiltration with bupivacaine on blood coagulability and
fibrinolysis in neurovascular surgery].
AB - We investigated the effect of scalp infiltration with bupivacaine on blood
coagulability and fibrinolysis in neurovascular surgery. Patients were randomly
divided into two groups: scalp infiltration group (who received scalp
infiltration with 0.5% bupivacaine prior to surgical incision, n = 7) and control
group (n = 6). The blood coagulability and fibrinolysis were measured before and
after surgical incision using a thromboelastogram (Thromboelastograph C-3000,
Haemoscope). In the control group, the reaction and coagulation times were
significantly shortened (30% and 23%, respectively, P < 0.05) and the maximum
amplitude, which reflects coagulability, increased significantly (21%, P < 0.01)
compared to each presurgical value. The scalp infiltration prior to the surgical
incision prevented these reactions (P < 0.05). The fibrinolytic rate did not
change in either group. We conclude that scalp infiltration prior to surgical
incision is beneficial for attenuating an increase in blood coagulability, which
could induce perioperative complications due to associated systemic diseases
(i.e. hypertension, diabetes, ischemic heart disease, etc.).
PMID- 9560545
TI - [Activation of bradykinin formation cascade on receiving autologous blood
transfusion through a white cell-reduction filter in a patient treated with an
ACE inhibitor].
AB - We have experienced a case of anaphylactoid reaction on receiving autologous
blood transfusion through a WBC filter for packed red blood cell (PRBC). The
patient was a 71-year-old man with a history of hypertension treated with oral
antihypertensive drug; enalapril, an angiotensin converting enzyme (ACE)
inhibitor, who received anesthesia for Y-graft replacement. Autologous blood was
obtained after the induction of general anesthesia in the operating room. Upon
starting to return the stored blood with an unintentional use of a WBC filter,
arterial blood pressure (ABP) fell within the first minute of the transfusion. We
obtained three blood samples; pre-filtered blood (PRE), postfiltered blood (POST)
and arterial blood (CIRC) after the event, and analyzed concentrations of
bradykinin (BK), high molecular weight kininogen (HMWK) and high molecular weight
kininogen-light chain (HMWK-LC). BK was higher in POST than in PRE. HMWK was
lower in POST than in PRE, while HMWK-LC was higher in POST than in PRE. HMWK in
CIRC was lower than in PRE, and HMWK-LC was higher in CIRC than in PRE. HMWK and
HMWK-LC changes after the event suggest that BK formation cascade in the patient
was activated on receiving the transfusion. ACE inhibitors were reported to
augment such activation. The WBC filter has the negatively charged surface on
filteration material and may activate the cascade. While WBC filters can avoid
transfusion related reactions, hemodynamic responses should be watched closely in
patients treated with ACE inhibitors.
PMID- 9560546
TI - [Anaphylactoid shock caused by chlorhexidine gluconate].
AB - We report two cases of anaphylactoid shock caused by chlorhexidine gluconate.
Both patients had skin flare, severe hypotension and increased airway pressure
during cannulation of an antibacterial IVH catheter containing chlorhexidine
gluconate after skin sterilization with chlorhexidine gluconate. In case 1, we
did not identify the mechanism and causative drugs. In case 2, an intradermal
test to chlorhexidine gluconate was positive 2 months later. Then we confirmed
that the anaphylactoid shock was caused by chlorhexidine gluconate. We should
bear in mind the risk of anaphylactoid shock when we use chlorhexidine gluconate
or the IVH catheter containing the bactericide.
PMID- 9560548
TI - [A successful perioperative anticoagulation therapy and monitoring of a patient
with hereditary plasminogen abnormality undergoing aortic valve replacement].
AB - During perioperative period, plasminogen abnormality can result in unusual or
unexplained clotting that occurs spontaneously or after minor trauma. However,
there has been no report on perioperative anticoagulation therapy and monitoring
in patients with hereditary plasminogen abnormality undergoing cardiac surgery.
We performed a successful perioperative anticoagulation therapy and monitoring of
a patient with hereditary plasminogen abnormality undergoing cardiac surgery. A
48-year-old male patient with severe aortic valve stenosis, who had had no
episode of thrombosis, was scheduled for aortic valve replacement Preoperative
laboratory screenings detected his abnormal plasminogen activity (7.6% normal),
and he was diagnosed as hereditary plasminogen abnormality. Anesthetic course was
uneventful until the initiation of cardiopulmonary bypass (CPB). During CPB,
heparin level was monitored every 30 minutes by Hepcon/HMS (Medtronic Hemotec,
Parker, CO). No thrombus was observed in the CPB circuit. Plasminogen activity,
fibrin degradation products (FDP) and D-dimer were not elevated during
perioperative period. Protamine dosage was determined by protamine titration
method, and protamine was administrated after the termination of CPB. No major
bleeding was observed after protamine administration. When the patient was
admitted to ICU, anticoagulation therapy was started immediately. During
perioperative period, no episode suggesting thrombosis was observed. In
conclusion, we consider that this successful anticoagulation therapy and
monitoring during CPB has been achieved by use of Hepcon/HMS.
PMID- 9560547
TI - [Regional cerebral oxygen saturation as a monitor of cerebral oxygenation and
perfusion during deep hypothermic circulatory arrest and selective cerebral
perfusion].
AB - In order to evaluate cerebral oxygenation and perfusion during deep hypothermic
circulatory arrest (DHCA) and selective cerebral perfusion (SCP), continuous
measurement of regional cerebral oxygen saturation (rSO2) by near-infrared
spectroscopy (NIRS) was performed. Two patients undergoing aortic arch surgery
performed under DHCA and SCP were studied. 1) Circulatory arrest produced a
continuous decrease in rSO2. Introduction of SCP increased rSO2 to even above the
pre-circulatory arrest level (reperfusion hyperoxia). 2) During SCP, changes in
rSO2 correlated well with the naso-pharyngeal temperature, SCP flow rate, and
level of carbon-dioxide insufflation to SCP. 3) These changes in rSO2 paralleled
with those of jugular venous hemoglobin saturation (SjO2) measured
simultaneously, although SjO2 frequently exhibited artifacts. We conclude that
rSO2 measurement may be a non-invasive and continuous measure in the evaluation
of cerebral oxygenation and perfusion during DHCA and SCP.
PMID- 9560549
TI - [Two elderly patients with thoracic herpetic pain and post herpetic neuralgia
treated with continuous thoracic sympathetic ganglion block through a placed
catheter].
AB - Epidural block is very useful in the treatment of herpetic pain and post herpetic
neuralgia. However, in the elderly patients with cardiac disease or diabetes
mellitus, severe cardiovascular changes may occur by epidural block. Epidural
block caused severe hypotension in two elderly patients with herpetic pain and
post herpetic neuralgia who had diabetes mellitus or hypertension. Continuous
thoracic sympathetic ganglion block with local anesthetics through a placed
catheter reduced their pain and caused almost no changes in cardiovascular
system.
PMID- 9560550
TI - [Recurrent nerve palsy after endotracheal intubation].
AB - We encountered left recurrent nerve palsy in four patients who had undergone
surgery unrelated to the course of the vagus nerve or recurrent nerve, during
which they had received endotracheal anesthesia. They were intubated without
difficulty and underwent surgery without trouble, but postoperatively they all
complained of hoarseness. We used a disposable ENTRASOFT endotracheal tube with
high volume, low-pressure cuff in three patients and a disposable PORTEX
endotracheal tube with low volume, standard cuff in one patient. In three
patients recurrent nerve palsy healed completely within two months after the
operation, and one patient was recovering from the palsy on the twentieth day
after the operation. We believe that the most plausible explanation of recurrent
nerve palsy is the excessive pressure from the inflated endotracheal tube cuff on
the intralaryngeal course of the anterior branch of the recurrent nerve.
Monitoring cuff pressure is most important to prevent recurrent nerve palsy after
endotracheal intubation.
PMID- 9560551
TI - [Anesthesia for a child with congenital sensory neuropathy with anhydrosis].
AB - We gave anesthesia twice to a 4-year-old boy with congenital sensory neuropathy
with anhydrosis. At the first surgery, anesthesia was induced with midazolam and
maintained with nitrous oxide, oxygen and sevoflurane 0.5-0.8% under mask
breathing. Surgery was performed without any trouble but the patient vomited
postoperatively for three days. Next time, anesthesia was induced and maintained
with propofol under mask. The patient often moved during surgery, and therefore,
we changed from propofol to oxygen and sevoflurane 1.0-1.5% anesthesia. Nitrous
oxide was not used. After the surgery, no vomiting occurred.
PMID- 9560552
TI - [Cerebral oxygen saturation and hemoglobin index under separate brain perfusion].
AB - We monitored bilateral cerebral oxygen saturation and hemoglobin index while the
brain received separate perfusion for major vascular surgery. Before surgery,
left cerebral oxygen saturation and hemoglobin index were within normal limits
but right cerebral oxygen saturation and right hemoglobin index were low. At the
end of surgery, right cerebral oxygen saturation was elevated and almost equal to
left cerebral oxygen saturation, and right hemoglobin index was elevated too but
slightly lower than left hemoglobin index. We found that oxygen delivery to the
right cerebral hemisphere improved in comparison with presurgical period. No
paralysis or any other neurological complications occurred postoperatively. We
conclude that such monitoring is useful during and after anesthesia under
separate brain perfusion.
PMID- 9560553
TI - Opportunities and dangers in the changing health care system.
PMID- 9560554
TI - Speculations on the etiology of malaria.
PMID- 9560555
TI - A pediatric perspective on the RIte Care Program.
PMID- 9560556
TI - RIte Care.
PMID- 9560557
TI - Implementing a computer-based mammography education project in a managed care
setting.
PMID- 9560558
TI - Geriatric assessment in an HMO.
PMID- 9560559
TI - The impact of managed care on chronic care agency providers.
PMID- 9560560
TI - The emergence of Medicare managed care: Implications for the post-acute sector.
PMID- 9560561
TI - Rhode Island Health Plan Program summary.
PMID- 9560562
TI - Health care quality improvement in Rhode Island.
PMID- 9560563
TI - Enrollment in HMOs in Rhode Island.
PMID- 9560564
TI - The Diagnosis and management of osteoporosis: current considerations.
PMID- 9560565
TI - Physician unions: The wave of the future?
PMID- 9560566
TI - A philatelist's history of smallpox variolation.
PMID- 9560568
TI - Biomimetics: the next great revolution in dentistry. Interview by Phillip Bonner.
PMID- 9560567
TI - Using laser technology on hard tissue.
PMID- 9560569
TI - Dental implants and coronal bone loss: an evaluation of 350 implants.
PMID- 9560570
TI - Integrating implants into the GP practice: innovative technology and simplified
techniques.
PMID- 9560571
TI - Metal-free full-posterior coverage.
PMID- 9560572
TI - Nightguard vital bleaching.
PMID- 9560573
TI - Microscope revolution.
PMID- 9560574
TI - Electrosurgery for crown and bridge.
PMID- 9560575
TI - Intentional composite lip on subgingival Class V restorations.
PMID- 9560576
TI - Understanding networks.
PMID- 9560577
TI - Proposed bill would treat HIV as infectious disease.
PMID- 9560578
TI - Direct composite technique for a smile makeover.
PMID- 9560579
TI - A team approach to a brighter smile.
PMID- 9560580
TI - Indirect composite veneers.
PMID- 9560582
TI - Polyethylene fiber reinforcement for interim restorations and postendodontic
rehabilitation.
PMID- 9560581
TI - Class III composite restorations.
PMID- 9560583
TI - A look at the past and future. Interview with Gordon Christensen, DDS, PhD.
Interview by Phillip Bonner.
PMID- 9560584
TI - Dentistry 2000: meeting the global challenge of change. Interview by Cheryl Farr.
PMID- 9560585
TI - Periodontal microsurgery.
PMID- 9560586
TI - Current concepts in periapical surgery.
PMID- 9560587
TI - Scheduling the new patient exam and prophy.
PMID- 9560588
TI - Eliminating opportunistic infection is essential for AIDS patients.
PMID- 9560589
TI - Enhancing precision through magnification.
PMID- 9560590
TI - Simplifying single anterior crown aesthetics.
PMID- 9560591
TI - Using noncasting technology as an alternative to traditional C&B techniques.
PMID- 9560592
TI - Reconstructive endodontics.
PMID- 9560593
TI - Dental lasers: have recent advances renewed interest?. Interview by Dan Marino.
PMID- 9560594
TI - Aesthetic screw access openings for abutment retained fixed prostheses: one-stage
implants.
PMID- 9560595
TI - Dental unit waterlines: is this one of dentistry's compelling problems?
PMID- 9560596
TI - Strategies for treating the dental phobic.
PMID- 9560597
TI - First looks for '98: a guide to the newest clinical techniques and technology.
PMID- 9560598
TI - Equipping the general practice: evaluating new technologies. Interview by Phillip
Bonner.
PMID- 9560599
TI - Stroke, Alzheimer's patients may benefit from AIDS dementia drug.
PMID- 9560600
TI - Teledental network: dental education in a new millennium.
PMID- 9560601
TI - Combining a philosophy with a plan for success. Interview by Phillip Bonner.
PMID- 9560602
TI - A glance at gingiva.
PMID- 9560603
TI - Micro-endodontic nonsurgical retreatment: silver point removal.
PMID- 9560604
TI - Obturation with preheated multiphase gutta percha.
PMID- 9560605
TI - Effective use of mixed media to correct aesthetic deficiencies.
PMID- 9560606
TI - Nerve injuries following procedures in general practice.
PMID- 9560608
TI - Dysfunction of the human mastication system.
PMID- 9560607
TI - Stabilizing dentures on a severely resorbed mandible.
PMID- 9560609
TI - Reducing stress in the operatory.
AB - Dentists can minimize the levels of physical and mental stress in dental offices
by selecting suitable equipment and maintaining proper posture. The specific
positions and allowable movements require a vigilant attitude on the part of
dentists until these habits become established and are practiced routinely.
PMID- 9560610
TI - What the general practice will look like in 2001.
PMID- 9560611
TI - The top 10 technologies.
PMID- 9560612
TI - Porcelain laminate veneers to restore worn lower teeth.
PMID- 9560613
TI - New applications for new materials.
PMID- 9560614
TI - Midface collapse: an overlooked disease.
AB - Midface collapse is a disease caused by occlusal interferences leading to
excessive tooth attrition and loss of vertical dimension. Although it can cause
premature aging, it can be prevented or treated.
PMID- 9560615
TI - Air abrasion: the new "drill-less" dentistry. Interview by Phillip Bonner.
PMID- 9560616
TI - Dentin and pulp simulation in ceramic restorations.
PMID- 9560617
TI - The design of the clasped removable partial denture.
PMID- 9560618
TI - The files of greater taper: report from the trenches.
PMID- 9560619
TI - Orthopedics, oral surgery, and orthodontia: the past is always with us.
PMID- 9560620
TI - Sealing caries out ... or in?
PMID- 9560621
TI - Increase efficiency and decrease stress.
AB - We have covered the benefits of using three key communication systems, including
the lighting (or digital) system, placing patient's charts in a holding area at
the front desk, and the importance of using and discarding your telephone slip.
The more a practice can systematically organize operations, the more quality time
is left for patient communication and service.
PMID- 9560622
TI - It's live and it's through the Internet.
PMID- 9560623
TI - Alternative approach to AIDS defense shows promise.
PMID- 9560624
TI - Possible HIV vaccine stirs hope.
PMID- 9560625
TI - Local anesthesia for pediatric patients.
PMID- 9560626
TI - The art of endodontics: selected case histories, Part 2.
PMID- 9560627
TI - Microendodontic analysis of failure: identifying missed canals.
PMID- 9560628
TI - A new approach to implant-supported overdentures.
PMID- 9560630
TI - Taking responsibility for occlusion: the perfect occlusion.
AB - Patients free from occlusal dysfunction rarely have their teeth together. But,
when occlusion does occur (i.e., swallowing), the contacts should be simultaneous
and in such a manner as to direct the vector of force down the long axis of the
tooth or implant. The incline planes should not touch.
PMID- 9560629
TI - Xerostomia: managing a complex condition. Interview by Phillip Bonner.
PMID- 9560631
TI - Immediate gratification with laser perio/prosthetic teamwork.
PMID- 9560632
TI - A surgeon's diary: the wounded and ill children of Vietnam.
PMID- 9560633
TI - Building a high-tech practice from the ground up.
PMID- 9560634
TI - Office design: the treatment area.
PMID- 9560635
TI - Ergo space-positioning.
PMID- 9560636
TI - The bottom line: the business of dental hygiene.
PMID- 9560637
TI - Update on dentin bonding. Interview by Phillip Bonner.
PMID- 9560638
TI - Current dental chemotherapeutics, Part 2.
AB - Periodontal diseases are the result of bacterial infections. Antimicrobial and
other chemotherapeutic agents are effective adjuncts to mechanical therapy in
helping practitioners limit the progression of disease. Topical antimicrobials
used as mouthrinses can control supragingival plaque. Studies demonstrate that
irrigation devices enhance the effectiveness of antimicrobials. Antibiotics have
been shown to be of value in treating juvenile periodontitis, and rapidly
advancing and refractory periodontitis. The use of tetracyclines to promote
healing by stabilizing collagen and the use of nonsteroidal anti-inflammatory
drugs and prostaglandin inhibitors offer promise for controlling periodontal
disease.
PMID- 9560639
TI - Periodontal disease monitoring.
PMID- 9560640
TI - Fundamentally changing soft tissue grafting.
PMID- 9560641
TI - A method for maximum clinical control of contacts, aesthetics, and longevity.
PMID- 9560642
TI - The effects of a CO2 laser on the healing of a bone defect.
AB - This case report illustrates a potentially valuable application of the CO2 laser
in periodontal surgery. An intrabony defect was treated with a bone allograft.
During the 28-day postsurgical period, epithelialization of the wound was delayed
by lasing the soft tissue over the bony defect at weekly intervals for 4 weeks.
This procedure resulted in complete regeneration of the bone defect in this case.
Controlled studies need to be carried out to determine if the use of the laser to
retard epithelial downgrowth has a clinically significant effect on bone
regeneration.
PMID- 9560643
TI - Practicing implant dentistry profitably.
AB - The success of dental implants has opened up countless treatment possibilities
for restorative dentists to offer to their patients. Just as our clinical
paradigms have had to change because of this new technology, so too must our
paradigms concerning the way we communicate with our patients change if we are to
get them to say "yes" to treatment that we know that they need. Success in
clinical treatment using implants requires a systematic approach. A systematic
approach to communicating with your patients will allow you to have the same high
degree of success with treatment acceptance that is possible with dental
implants. The key to the systems we have discussed is Relationship Centered Care.
A relationship is fostered and enhanced through a Comprehensive Examination
Process, a structured Consultation Process utilizing the influencing process and
Financial Arrangements that allow the patient to receive what they want while the
office maintains the profitability that it needs. A system for calculating
rational fees can be utilized that allows the practice to have control over an
area that traditionally was controlled by anecdotal factors. The Pride Institute
has developed this material and is presenting it to the profession so that
restorative dentists can truly practice implant dentistry profitably.
PMID- 9560644
TI - An alternative provisional implant for immediate functional loading.
PMID- 9560645
TI - Using copy milling technology in restorative dentistry.
AB - A technique for the fabrication of copy milled ceramic restorations has been
presented. Both direct and indirect fabrication techniques of inlays, onlays,
veneers, and crowns are possible. A copy milling machine can mill accurately
fitting restorations with a marginal gap of 50 microns. The machine uses
premanufactured porcelain blanks, which have improved physical properties over
conventional porcelains used in standard techniques. Recently, the ability to
mill In-Ceram crowns from presintered alumina blocks and Spinell crowns from
alumina/magnesia blocks has been added to the system. The copings are veneered
with aluminous porcelain as in the conventional In-Ceram technique.
PMID- 9560646
TI - Preparation of porcelain veneers: a new approach.
PMID- 9560647
TI - Controversy in TMD: putting the issues in perspective.
PMID- 9560648
TI - Hygiene partnering, Part 1.
PMID- 9560649
TI - Rightsizing right now.
PMID- 9560650
TI - Who is responsible for the schedule?
AB - The focus of this has been to increase communication between the team. We have
covered ways to stay true to the ideal day concept, to effectively capture
details about patients who come in on short notice, and to prepare and update the
day's list in a timely manner.
PMID- 9560651
TI - Researchers develop AIDS-destroying viruses.
PMID- 9560652
TI - Clinton sets goal for AIDS vaccine.
PMID- 9560653
TI - Successful management of the gingival tissues for aesthetic restorative
procedures.
AB - A sage advisor once said, "Why is it that we (dentists) never seem to have the
time to do all steps the first time around, but then find the time when something
goes amiss?" Many of us are caught up in a prison called time that directly
dictates our every move. We must be released from this mindset and rediscover the
importance of patience and devotion to technique. That same wise man added, "The
definition of a short cut is the longest distance between two points." The moral
is time spent to gain tissue health will be returned a thousand fold. Cases will
be completed with greater patient comfort and doctor satisfaction.
PMID- 9560654
TI - Placing porcelain laminate veneers for function and aesthetics.
PMID- 9560655
TI - Advances in restorative dentistry. Interview by Phillip Bonner.
PMID- 9560657
TI - Is patient confirmation an adequate indicator of occlusal adjustment completion?
PMID- 9560656
TI - Resin-bonded margins in direct posterior composites.
PMID- 9560659
TI - Simple, cost-effective, cosmetic periodontal stabilization.
PMID- 9560658
TI - Specialty endodontics: diagnostic challenges, Part 2.
AB - Endodontic diagnosis and treatment can range from simple to extremely complex.
But no matter how simple a case may seem, a thorough examination by the treating
endodontist is imperative before any treatment is done. Taking the time to
perform an examination in a consistent and methodical approach can rescue the
patient from unnecessary treatment, and the treating dentist from potential
liability. The patient may be frustrated from repeating many of the same tests
performed by the referring dentist, but this situation can be resolved with clear
communication from the general dentist and the endodontist as to the benefits of
the endodontist's exam. With proper communication, patients will recognize that
their general dentist and endodontist are concerned that they receive the best of
care.
PMID- 9560660
TI - Biotech in periodontics: molecular engineering yields new therapies.
PMID- 9560661
TI - Power scalers: the new boom in contemporary periodontics.
AB - The choice of which type of instrumentation to use remains the decision of the
practitioner. It all depends on what goal the clinician hopes to achieve, the
resources, and the physical set up within which they work. While speed in
debridement, coupled with ease of use and comfort to the patient and practitioner
are all important, the primary goal must always remain the optimal healing and
success of the dental procedure. With improved tip designs and efficiency, power
scaling has the ability to improve dental hygiene and periodontal care in the
future.
PMID- 9560663
TI - Ensuring dental practice success, Part 1.
PMID- 9560662
TI - Practice building with halitosis treatment.
PMID- 9560664
TI - Nonconfrontational case presentation: the seven laws of patient communication
response.
PMID- 9560665
TI - In search of the fountain of youth.
PMID- 9560666
TI - Instant gratification for patients from laminate veneers.
PMID- 9560667
TI - Bioesthetic guided tips: a new method for creating a youthful smile.
PMID- 9560668
TI - Into the fourth dimension: news from the front as the millennium approaches.
PMID- 9560669
TI - Nonsurgical endodontic retreatment.
PMID- 9560670
TI - Oral rehabilitation: restoring the triad of health, function, beauty.
PMID- 9560671
TI - Conservative technique for replacement of existing posterior bridges.
PMID- 9560672
TI - The integration of dentistry and medicine: is it on the horizon?. Interview by
Phillip Bonner.
PMID- 9560673
TI - Genetic susceptibility to periodontal disease.
PMID- 9560674
TI - Anterior space maintenance: aesthetics and function.
PMID- 9560675
TI - The key to success: maintaining the long-term health of implants.
AB - During the infancy years of dental implantology, the emphasis for long-term
success of osseointegrated implants was the surgical phase of dental
implantology. In the years that followed, the emphasis for success had switched
from a purely surgical influence to focusing more on the proper fixture placement
which would be dictated by the prosthetic and aesthetic needs of each particular
case. In more recent years, the dental profession has recognized professional
implant maintenance and diligent patient home care as two critical factors for
the long-term success of dental implants. The microbiota and clinical
presentation of peri-implantitis is the same as periodontitis around a natural
tooth.
PMID- 9560676
TI - A new condensable composite for the restoration of posterior teeth.
AB - Undoubtedly the greatest resistance of clinicians to use composite resins in
posterior teeth relates to technique sensitivity, time consumption, and
complexity. Placing conventional posterior composite resins does not take into
account that composites differ considerably from amalgam. This is particularly
true with respect to its physical characteristics, especially insertion and
packing properties. The development of a posterior composite resin that can be
placed by an amalgam carrier and subsequently packed or condensed as an amalgam,
should assist clinicians greatly in their ability to successfully restore class
II cavity preparations. Acknowledgment is expressed to Bruce Small, DMD, for the
clinical dentistry and slides.
PMID- 9560677
TI - Scheduling the new patient exam and prophy, Part 2.
PMID- 9560678
TI - Gingival bleeding: why it's critical and how to stop it.
PMID- 9560679
TI - The consolidation of dentistry. Interview by Phillip Bonner.
PMID- 9560680
TI - Restorative endodontics: anatomy of a failure.
PMID- 9560681
TI - Endodontic overfills: good? Bad? Ugly?
PMID- 9560682
TI - The art of endodontics: selected case histories, Part 3.
PMID- 9560683
TI - Porcelain laminate veneers to improve aesthetics.
PMID- 9560684
TI - Making the blues go away.
PMID- 9560685
TI - A combination technique for nonvital bleaching.
PMID- 9560686
TI - A new dimension in temporization.
PMID- 9560687
TI - The growth of nonsurgical treatment of periodontitis. Interview by Randall L.
Valentine.
PMID- 9560688
TI - Smarter and cheaper X-rays. Pushing the limits in digital radiography.
PMID- 9560689
TI - Laser bleaching: a clinical survey.
PMID- 9560690
TI - Occlusion and implants.
PMID- 9560692
TI - Understanding the Internet.
PMID- 9560691
TI - Current trends in dental benefits plans: 1997.
PMID- 9560693
TI - Creating the ideal patient and chart flow structure.
PMID- 9560694
TI - Math versus myth: dispelling legendary management precepts.
PMID- 9560695
TI - Genetic defect wards off AIDS infection, say researchers.
PMID- 9560696
TI - Thalidomide heals AIDS-related mouth ulcers.
PMID- 9560697
TI - Fiber-reinforced restorative materials bring new treatment options. Interview by
Phillip Bonner.
PMID- 9560699
TI - Porcelain laminates: new insights from hindsight.
PMID- 9560698
TI - Crown torquing severely worn incisors to gain clearance for crowns.
PMID- 9560700
TI - To prep or not to prep.
PMID- 9560701
TI - A no-metal, no-mercury, full-mouth smile recovery.
PMID- 9560702
TI - Using flowable composites in direct posterior restorations.
PMID- 9560703
TI - Clinical, radiographic indicators of a pending difficult extraction.
PMID- 9560704
TI - A long-span, acid-etched, fixed partial denture.
PMID- 9560705
TI - Salvaging of adjacent fixed partial dentures using an overcasting technique.
AB - Occasionally, clinicians are faced with a situation in which a solitary tooth
between two bridges requires extraction. When this type of situation occurs, we
must ponder the dilemma of how to replace the missing tooth. Options include
placing an implant where the tooth was extracted or remaking one large multiunit
bridge. Implants are not always possible or practical, and remaking a multiunit
bridge that involves the abutments of the two existing bridges can be challenging
and becomes much more expensive to the patients. The overcasting technique is a
treatment modality that offers a solution in these particular situations.
PMID- 9560706
TI - Maximizing the practice potential of hygiene.
PMID- 9560707
TI - The best marketing tool ever invented....
PMID- 9560708
TI - Scheduling stress-free emergencies.
PMID- 9560709
TI - 31 financial check-off points.
PMID- 9560710
TI - Know your market and present the case.
PMID- 9560711
TI - AIDS deaths decline in the US for first time.
PMID- 9560712
TI - New developments in composite resins. Interview by Phillip Bonner.
PMID- 9560713
TI - The art of tooth preparation and recontouring.
PMID- 9560714
TI - Intraoral porcelain repairs with composite.
PMID- 9560715
TI - Heated bleaching: a safe and rewarding method.
PMID- 9560716
TI - Facial rehabilitation: maximizing aesthetics through a coordinated team approach.
PMID- 9560717
TI - Cosmetic rehabilitation after dental trauma. A conservative approach.
PMID- 9560718
TI - Benefit-driven treatment planning. Fiber-enhanced periodontal therapy.
PMID- 9560719
TI - Calculus and coronary artery disease.
PMID- 9560720
TI - TMJ disorders and their relationship to occlusion and dental compression
syndrome.
PMID- 9560721
TI - An alternative approach to bonding and pulpal protection.
PMID- 9560722
TI - Conservative anterior reconstruction: a combined technique approach.
PMID- 9560723
TI - Predicting bleaching results with computer imaging.
AB - Vital bleaching can be a relatively unpredictable treatment. Photographs of
previous cases and cosmetic imaging, although useful, may lead to unrealistic
expectations on the part of the patient. The high-tech mystique of computer
imaging and viewing one's own teeth has a significant impact on the dental
patient. Whether imaged by the dentist or an auxiliary, patients must be aware of
alternatives that may exist both before and during treatment. Cosmetic imaging
should be used as an adjunct to, not as the prime motivator for, treatment
planning in bleaching cases. Excellent communication between the practitioner and
patient is the most important factor in assuring positive bleaching results and
patient satisfaction.
PMID- 9560724
TI - Intraoral cameras: dentistry's pursuit of wow.
PMID- 9560725
TI - Revitalizing PFM restorations with porcelain veneers.
PMID- 9560726
TI - Integrating computers: a front line perspective.
PMID- 9560727
TI - Hygiene partnering, Part 2.
AB - Today's technology is full of magic and delight in the hygiene arena. Throughout
the years, dental hygiene has shifted into a thriving career, and hygienists have
welcomed the new role with open arms. Innovation, technology, and partnering have
also taken the concept of codiagnosis and comprehensive care to a higher level in
the hygiene department. These benefits, combined with more sophisticated patient
centered communication skills and team-centered management philosophies will,
without doubt, secure the future of dental hygiene departments in practices
worldwide. Moreover, smart practices remaining committed to attracting, training,
and retaining only high-caliber staff with interdependent, overlapping talent
will find the most reward in helping their patients achieve and maintain optimum
oral health for a lifetime.
PMID- 9560728
TI - Doctors plan to inject themselves with live AIDS vaccine.
PMID- 9560729
TI - The bonded tooth-colored onlay.
PMID- 9560730
TI - Enamel microabrasion: is it still a viable procedure?
PMID- 9560731
TI - Two front teeth: a common cosmetic dilemma.
PMID- 9560732
TI - Fiber-reinforced composite bridge. Inlay-to-inlay technique.
PMID- 9560733
TI - Anhydrous glass technique.
PMID- 9560734
TI - Update on pain management. Interview by Phillip Bonner.
PMID- 9560735
TI - An analysis of dental pain for better oral health.
PMID- 9560736
TI - Macrolide antibiotics.
AB - The macrolides remain excellent antibiotics for many infections particularly
those involving intracellular and/or respiratory pathogens. Erythromycin is still
an effective drug for many acute orofacial infections. The newer macrolides,
azithromycin and clarithromycin, should also prove efficacious although there is
very little current data on their use in orofacial infections. They have the
advantages over erythromycin of less GI toxicity, higher tissue concentrations,
greater gram-negative spectrum, and once or twice daily dosing for better patient
compliance. Macrolide concentration in inflammatory cells and transport to the
site of infection is a distinct advantage over other antibiotics. Both
erythromycin and clarithromycin are associated with significant drug interactions
but azithromycin is devoid of such potential toxicity. Azithromycin is less
effective against gram-negative cocci than erythromycin and clarithromycin and
attains very high tissue concentrations for a very long time, but whether either
of these characteristics is clinically significant for orofacial infections is
presently unknown.
PMID- 9560737
TI - Periodontal laser surgery.
AB - A gingivectomy performed with a laser is a short, easy procedure that produces an
immediately dramatic effect. Compared to a scalpel gingivectomy, there is
excellent hemostasis, which improves visualization, requires less need for
periodontal packing, and results in minimal postoperative discomfort. Tissue
rebound also is minimal. Use of lasers requires specific training. The only
approved function in periodontics at this time according to the American Academy
of Periodontology is soft tissue surgery. Some periodontal applications include
frenectomy, soft tissue crown lengthening, distal wedge procedures, soft tissue
tuberosity reductions, gingivectomy, gingivoplasty, stage II of implants,
operculectomies, biopsies, coagulation of graft donor sites, hemorrhage disorder
patients, and stripping procedures for various leukoplakias.
PMID- 9560738
TI - Endodontic re-treatment perspective: cone fit is key to unlocking the power of
hydraulics.
PMID- 9560739
TI - A surgeon's diary: Washington, DC of the '60s.
PMID- 9560740
TI - Using cross-sectional tomography to perform exploratory radiography in lieu of
exploratory surgery.
AB - Preoperative treatment planning for dental implants is crucial to their
integration and especially prosthetic rehabilitation. Exploratory radiography is
an essential component of treatment planning. Radiographic examination using
cross-sectional tomography as an adjunct to panoramic radiographs can
significantly decrease the incidence of exploratory surgery that could result in
unplanned bone augmentation procedures due to insufficiency in alveolar bone
height, width, quantity, quality, and will not allow proper aesthetic prosthetic
rehabilitation subsequent to improper implant placement.
PMID- 9560741
TI - A week in the life of a type-A high-tech practice.
PMID- 9560742
TI - Ten ways to ensure dental practice success, Part 2.
PMID- 9560743
TI - Statistical monitoring of the dental practice.
PMID- 9560744
TI - Effective use of tungsten carbides for restorative dentistry.
PMID- 9560745
TI - Clinical application of power Doppler imaging to visualize coronary arteries in
human beings.
AB - Supplementation of angiographic information during bypass procedures is an
attractive goal for the echocardiographic researcher. Compared with color flow
mapping, power Doppler imaging is superior in terms of identifying small vessels
and noise suppression because of the use of Doppler signal strength for imaging.
Although power Doppler imaging does not provide information about flow velocity
or its direction, it does show detailed vessel flow in a static organ. Our study
was designed to obtain angiographic images of the coronary artery by the use of
power Doppler imaging in 31 patients during open heart surgery. During cold
cardioplegic infusion, the epicardial coronary artery and the coronary artery
within myocardium, such as the septal perforator, could be well visualized by
power Doppler imaging. There was good correlation between the diameters of
coronary arteries measured from power Doppler imaging and those from quantitative
coronary angiography (r = 0.964, p < 0.0001). We obtained clear and accurate
images of the coronary artery by using power Doppler imaging during cardiac
standstill. These images might provide meaningful supplemental information to the
operator, such as confirming the target coronary artery during the cardioplegia
and choosing the appropriate arterial portion for a bypass operation.
PMID- 9560746
TI - Detection of myocardial perfusion defects by contrast echocardiography in the
setting of acute myocardial ischemia with residual antegrade flow.
AB - Although myocardial contrast echocardiography accurately demarcates area at risk
during total coronary occlusion, the ability of MCE to delineate area at risk in
the presence of residual antegrade flow is unknown. We hypothesized that
perfusion defects in myocardial segments supplied by severe coronary stenoses
with residual antegrade flow could be detected by MCE using intravenous FS069. We
studied 13 open-chest dogs using an intravenous injection of FS069 during
intermittent harmonic imaging. Images were collected at baseline, during acute
ischemia with residual antegrade flow, physiologic hyperemia (release of
stenosis), and total coronary occlusion. Regional myocardial blood flow was
assessed using colored microspheres. MCE risk area during acute ischemia with
residual antegrade flow and total occlusion was planimetered and compared with
pathologic risk area (area unstained by monastral blue). Background-subtracted
peak videointensity in the risk area was assessed for all flow states. Regional
myocardial blood flow confirmed expected flow states, being significantly greater
during physiologic hyperemia (4.16 +/- 1.22 ml/min/g) than at baseline (0.71 +/-
0.19 ml/min/g) and significantly diminished during coronary stenosis with
residual antegrade flow (0.20 +/- 0.16 ml/min/g) and total occlusion (0.09 +/-
0.06 ml/min/g; p < 0.0001). Myocardial risk area by MCE during coronary stenosis
with residual antegrade flow correlated well with pathologic risk area determined
by monastral blue staining (r = 0.86). Peak videointensity during coronary
stenosis (111 +/- 27) was significantly less than at baseline (157 +/- 50) but
greater than during total occlusion (81 +/- 34; p < 0.0001). In conclusion,
intravenous FS069 in conjunction with intermittent harmonic imaging delineates
area at risk in ischemic myocardium supplied by a coronary stenoses with residual
antegrade flow. The presence of a perfusion defect on MCE does not necessarily
imply that the coronary artery is totally occluded.
PMID- 9560747
TI - Reduced test time by early identification of patients requiring atropine during
dobutamine stress echocardiography.
AB - In a randomized, controlled clinical trial, we evaluated the ability of an
algorithm to identify, before peak stress, patients who will ultimately require
atropine during dobutamine stress echocardiography. The effects of early atropine
administration on test duration, atropine dose, dobutamine dose, and heart rate
response also were studied. Compared with conventional atropine administration at
peak dobutamine infusion, early atropine administration reduced test duration 8%
(1.1 minutes, p = 0.02) and total dobutamine use 11% (0.41 mg/kg, p = 0.02) but
required 90% more atropine (0.36 mg, p < 0.001). Conventional atropine
administration resulted in a late, rapid rise in both heart rate and rate
pressure product. However, the heart rate and rate-pressure product curves for
patients receiving early atropine paralleled those seen in patients not requiring
atropine during dobutamine stress echocardiography. In conclusion, early atropine
administration provides a more balanced stress and reduces test duration, thus
decreasing total exposure to dobutamine and potentially increasing test
efficiency.
PMID- 9560748
TI - Three-dimensional imaging in aortic disease by lighthouse transesophageal
echocardiography using intravascular ultrasound catheters. Comparison to three
dimensional transesophageal echocardiography and three-dimensional intra-aortic
ultrasound imaging.
AB - Two-dimensional (2D) transesophageal echocardiography (TEE) and 2D intravascular
ultrasound (IVUS) imaging face their greatest limitation in visualizing aortic
disease in patients. With the aid of three-dimensional (3D) image reconstruction,
TEE and IVUS can potentially overcome this limitation but still provide only
limited spatial appreciation in aortic disease because 3D imaging of the thoracic
aorta requires a broader spatial visualization of the mediastinum than provided
by both techniques. Moreover, for timely decision making about aortic disease TEE
is limited by a large probe, which requires sedation. Therefore, we developed an
approach called 3D lighthouse transesophageal echocardiography (LTEE) using a
thin intravascular ultrasound catheter, which provides a full circumferential
(360 degree) image and requires no sedation. The purpose of this study was to
compare the feasibility and accuracy of 3D TEE, 3D IVUS, and 3D LTEE for
obtaining spatial visualization of the thoracic aorta to detect aortic diseases
in patients. 3D image datasets were obtained for 3D LTEE by a manual pullback of
a 3.3 mm thick, 10 MHz intravascular ultrasound catheter positioned in the
esophagus; for 3D TEE using a conventional 15 mm thick probe; and for 3D IVUS
using a 2.6 mm thick, 20 MHz intravascular ultrasound catheter. In 12 consecutive
patients, three with aortic dissection (two with type III, one with type I) and
11 with suspected artherosclerosis, we analyzed and compared spatial
visualization of the thoracic aorta, 3D image quality, patient discomfort, and
study time. Providing a 3D dataset of 360-degree tomographic images of the
mediastinum, 3D LTEE was the only approach that allowed broad spatial
visualization of the aortic arch (9 of 12 patients) with the detection of aortic
dissection or atherosclerotic plaques. Spatial visualization of the aortic arch
by 3D TEE was incomplete because of the relatively narrow 90-degree image sector.
However, in other segments 3D image quality by 3D TEE was superior to 3D LTEE and
3D IVUS. Because of the thin catheter, patient discomfort (p < 0.0001) and
examination time (p = 0.015) were significantly less for 3D LTEE compared with 3D
TEE. 3D LTEE is a promising new technique for 3D imaging of the thoracic aorta
and detection of aortic disease with improved spatial visualization and reduced
patient discomfort compared with 3D TEE and 3D IVUS.
PMID- 9560749
TI - Progressive enlargement of the regurgitant orifice in patients with chronic
aortic regurgitation.
AB - The severity of aortic regurgitation is dependent on the size of the regurgitant
orifice, the left ventricular response to volume overload, and the diastolic
pressure difference across the aortic valve. The purpose of this study was to
test the hypothesis that the aortic regurgitant orifice increases over time in
patients with audible chronic aortic regurgitation. To assess serial changes in
aortic regurgitant severity by the use of two-dimensional and Doppler
echocardiography, 59 patients (29 men and 30 women) with audible chronic aortic
regurgitation were prospectively identified and evaluated annually with two
dimensional and Doppler echocardiograms. Patients were followed for a median of
38 months. We measured two separate indicators of the size of the regurgitant
orifice: the color Doppler regurgitant jet width and the Doppler-derived
regurgitant orifice area. Jet width increased with time (0.5 +/- 0.4 cm at
baseline, 0.04 +/- 0.01 cm/year slope, p < 0.001). The regurgitant orifice area
also increased (0.12 +/- 0.14 cm2 at baseline, 0.01 +/- 0.01 cm2/year, p = 0.05).
Changes in regurgitant orifice area were related to changes in left ventricular
end-diastolic dimension (p < 0.001). There were no significant changes in left
ventricular chamber dimensions, volumes, and regurgitant volume over time in this
cohort. Increases in jet width and orifice area occurred in patients with all
degrees of baseline disease severity, with bicuspid or tricuspid leaflet
morphology, and with male or female sex. In this prospective study of chronic
aortic regurgitation, both jet width and Doppler-derived regurgitant orifice area
increased over time. These findings suggest that one factor in the progression of
chronic aortic regurgitation is enlargement of the orifice.
PMID- 9560750
TI - In vitro analysis of regurgitant fraction using Doppler power-weighted sum of
velocities.
AB - The power-weighted sum of velocities (PWS) is the sum of each velocity component
of the Doppler signal multiplied by its power. The purpose of this study was to
determine (1) whether PWS is linearly related to volume flow and (2) whether PWS
can predict the regurgitant fraction in an in vitro pulsatile flow system
simulating aortic regurgitation. Doppler analysis of aortic flow was performed
with an intact valve and two regurgitant valves. For each valve a linear relation
between the forward flow PWS and forward flow volume was demonstrated, with
excellent correlation (r = 0.99). For the valves with regurgitant orifices, the
values for the PWS-derived regurgitant fraction were compared with measured
regurgitant fraction. A fair correlation was demonstrated (r = 0.59), with low
accuracy in prediction (error 44% +/- 24%). The PWS was inaccurate in predicting
flow ratios in our in vitro system despite the strong relation with forward flow
volume. The error incurred may be due to effects of filters that remove low
velocity and low amplitude information.
PMID- 9560751
TI - Reversible left atrial dysfunction possibly due to afterload mismatch in patients
with left ventricular dysfunction.
AB - Limited data are available concerning the influence of altered loading conditions
on left atrial (LA) function. In addition, the underlying mechanism of the
augmentation of atrial filling (A) velocity (assessed by transmitral Doppler
measurement) after treatment of heart failure has been less studied. Therefore,
we examined various indexes of LA function during the depression of left
ventricular (LV) filling pressure resulting from treatment of heart failure.
Twelve patients with LV dysfunction (ejection fraction < 50%) underwent right
heart catheterization and transthoracic echocardiography before and after optimal
treatment of heart failure. LV/LA volume and ejection fraction and mitral and
pulmonary venous flow velocities were measured. LV stiffness (substitute for LA
afterload) was assessed by the ratio of LV filling pressure to LV end-diastolic
volume. After treatment of heart failure, the mitral A velocity significantly
increased (38 +/- 9 to 58 +/- 16 cm/sec, p < 0.005) and there was a distinct
attenuation of the difference of the pulmonary venous and mitral A-wave duration
(43 +/- 29 to -8 +/- 31 msec, p < 0.005). These findings were associated with a
marked decrease in LV stiffness (0.12 +/- 0.04 to 0.05 +/- 0.02 mm Hg/ml, p =
0.0001) and an increase in LA ejection fraction (27% +/- 7% to 38% +/- 8%, p <
0.005). There was a significant curvilinear relation between LA ejection fraction
and LV stiffness (r = 0.63, p < 0.01). The mitral A velocity correlated
positively with LA ejection fraction (r = 0.77, p < 0.0001) and inversely with LV
stiffness (r = -0.52, p < 0.01). The reversible LA dysfunction suggests that the
initial LA dysfunction is due to LA afterload mismatch rather than intrinsic LA
disease, which also contributes to the augmentation of the mitral A velocity
after heart failure treatment.
PMID- 9560752
TI - Effect of sample volume location on Doppler-derived transmitral inflow velocity
values in 288 normal subjects 20 to 80 years old: an echocardiographic, two
dimensional color Doppler cooperative study.
AB - The aims of the study were to evaluate in a population of 288 normal subjects 20
to 80 years old (1) the normal values of the indexes of the mitral flow velocity
pattern measured either at the tips of the mitral leaflets or at the annulus; (2)
whether there was a significant difference between the values obtained at the
tips compared with those measured at the mitral annulus; (3) the correlation with
aging between the indexes measured in the two different positions; and (4)
whether certain physiological variables have different effects on diastolic
function measured in the two different positions. The highest values were always
measured at the tips of the mitral leaflets (p < 0.05); only atrial filling
fraction, E acceleration time, and E deceleration velocity had higher values when
measured at the level of the annulus (p < 0.05). The A-wave peak velocity had the
same mean value when measured at both the tips and at the annulus. A significant
difference in the correlation between parameters measured at the tips of the
mitral leaflets with age and at the annulus (with age) was observed for the
following parameters: (1) peak E velocity, E integral, total integral and E
acceleration showed better correlation with age when measured at the annulus (p <
0.02); (2) peak A velocity and A integral showed better correlation with age when
measured at the tips of the mitral leaflets (p < 0.001). Multivariate analysis
showed that age was the variable that had the most influence on diastolic
function parameters; heart rate had less influence on the diastolic function
indexes.
PMID- 9560753
TI - Echocardiographic spectrum of supracardiac total anomalous pulmonary venous
connection.
AB - Although infracardiac total anomalous pulmonary venous connection (TAPVC) is
almost always associated with venous obstruction, the incidence and location of
obstruction in supracardiac TAPVC has not been completely delineated. This report
summarizes our experience with 20 cases of supracardiac TAPVC diagnosed by
transthoracic echocardiography from Jan. 1989 to Mar. 1997. Fifty percent were
obstructed, and five different sites of narrowing were found. The most common
sites of obstruction were at the level of the left pulmonary artery (left
vertical vein) and at the insertion into the superior vena cava (right vertical
vein). Because nonobstructed Doppler flow patterns are present proximal to the
actual site of obstruction in the anomalous pathway, a thorough interrogation of
the entire venous channel with two-dimensional and Doppler echocardiography is
essential to provide complete preoperative anatomic and hemodynamic details to
determine the nature and timing of surgery in this condition.
PMID- 9560754
TI - Echocardiography in the diagnostic evaluation of syncope.
AB - To assess the role of echocardiography in patients with syncope, we studied 439
consecutive adults who were referred over a 7-year period. Of all patients, 251
(57.2%) were women, who were generally younger than male referrals. All 439
patients had interpretable echocardiographic studies. Results showed that of
patients younger than 40 years of age, 72.8% had scans that were normal and 18.5%
had mitral valve prolapse (MVP). All (other) patients in this age group with
abnormal echocardiographic findings (8.7%) had either abnormal physical findings
over the heart, an abnormal electrocardiogram, or an abnormal chest radiograph.
In patients 60 years old and older, 29.6% had scans interpreted as normal and
4.6% had MVP (approximately half of these patients had at least moderate mitral
regurgitation). The study demonstrates that patients younger than 40 years of age
with syncope are likely to have a normal Doppler echocardiography or MVP without
significant mitral regurgitation. Thus additional abnormal findings (e.g., heart
murmur, abnormal electrocardiogram, or abnormal chest radiograph) may be needed
before the patient is referred to the echocardiography laboratory.
PMID- 9560755
TI - Cerebrovascular emboli related to pulmonary venous thrombosis after lung
transplantation.
AB - We describe a case of cerebral emboli related to pulmonary venous thrombosis
after bilateral lung transplantation in a young man with cystic fibrosis. The
diagnosis was made by transesophageal echocardiography, leading to aggressive
anticoagulation within 24 hours of surgery. Hemodynamic deterioration in the
following hours was of concern for the development of obstructive thrombus but
was found to be due to pericardial tamponade, which, remarkably, resolved during
a repeat transesophageal echocardiography.
PMID- 9560756
TI - Pseudoaneurysm of the ascending aorta after aortic valve replacement.
AB - A 58-year-old man with fever and chest wall tenderness was seen 8 weeks after
aortic valve replacement. His initial postoperative course had been complicated
by mediastinitis, requiring antibiotics and surgical debridement. A transthoracic
echocardiogram did not reveal the culprit lesion. Pseudoaneurysm of the ascending
aorta was suspected, based on computerized tomographic and magnetic resonance
images of the chest. Intraoperative transesophageal echocardiography confirmed
the diagnosis of pseudoaneurysm and was a key component in the patient's
operative management.
PMID- 9560757
TI - Echocardiography allows early detection and long-term survival after infarct free
wall rupture.
AB - Approximately one third of free wall infarct ruptures are subacute and
theoretically accessible for surgery. Two-dimensional echocardiography is an
important tool in the early diagnosis of cardiac rupture. We report the
successful treatment of a 74-year-old woman with subacute free wall rupture, who
is still alive 3 years after surgery.
PMID- 9560758
TI - Unusual structural abnormality in a biplane transesophageal transducer with
normal imaging function.
AB - We encountered a case of an unusual structural abnormality in a biplane
transesophageal echocardiography transducer. One of the steel wires making up the
flexion cable responsible for anterior flexion was ruptured with one end piercing
through the sheath, and this defect did not affect the imaging function of the
transducer. Measures to detect this defect should be incorporated into the
routine care of the transesophageal transducer.
PMID- 9560759
TI - Veterinary randomized clinical trial reporting: a review of the small animal
literature.
AB - The randomized clinical trial (RCT) is a valuable research method for the
evaluation of new treatment and prevention regimens in veterinary medicine.
Reporting of clinical trials in other disciplines has not been complete. Without
complete information on the conduct and results of a clinical trial, readers
cannot optimize their use of the information presented. This report represents an
objective review of randomized clinical trials in the veterinary small animal
literature from 1986 to 1990. Results indicate that RCT reports in the small
animal veterinary literature are incomplete. The importance of reporting on
particular aspects of RCT research is described.
PMID- 9560760
TI - Granulocytic ehrlichiosis in dogs from North Carolina and Virginia.
AB - Medical records of 3 dogs from North Carolina and 3 dogs from Virginia with
ehrlichial morulae in circulating neutrophils were studied retrospectively. Two
clinically distinct disease syndromes, including chronic, moderate to severe
anemia (n = 3) and polyarthritis (n = 2) were associated with canine granulocytic
ehrlichiosis (CGE) in these dogs. One dog was clinically healthy, and
abnormalities were not detected during physical examination. Clinical signs were
nonspecific and included fever, lethargy, anorexia, vomiting, and diarrhea. The
most frequent laboratory abnormalities were normocytic normochromic
nonregenerative anemia, moderate thrombocytopenia with large platelets,
lymphopenia, and eosinopenia. Considerable variability was found in the serologic
responses to Ehrlichia equi, Ehrlichia canis, and Ehrlichia chaffeensis antigens
among the 5 dogs for which stored sera were available for indirect fluorescent
antibody testing. Polymerase chain reaction amplification and sequencing of
portions of the 16S rRNA gene from blood (collected in ethylenediaminetetraacetic
acid) of 1 severely anemic dog (dog 3) and 1 polyarthritic dog (dog 4) resulted
in DNA sequences nearly identical to the GenBank accessions for Ehrlichia
ewingii. The DNA sequence from a 3rd dog (dog 5) was most similar to that of E.
canis. Serologic or molecular results support the possibility of E. ewingii, E.
equi, and E. canis coinfection or serologic cross-reactivity among canine
granulocytic and monocytic Ehrlichia species in dogs from North Carolina and
Virginia. Variability in response to tetracycline or doxycycline treatment was
noted in these dogs, with more rapid resolution of signs in dogs with
polyarthritis. We report the 1st cases of CGE in dogs from North Carolina and
Virginia, including recognition of CGE in a healthy dog.
PMID- 9560761
TI - Coagulation abnormalities in 22 cats with naturally occurring liver disease.
AB - Twenty-two cats with liver disease were evaluated for coagulation abnormalities
including alterations in prothrombin time, activated partial thromboplastin time,
thrombin time, factor VII activity, and platelet count. The purpose of the study
was to determine the prevalence of coagulation abnormalities in this population
of cats, classify abnormalities according to underlying pathogenesis, and
determine if serum biochemical parameters typically used as indicators of liver
disease showed any correlation with the coagulation abnormalities present. Study
results indicated that at least 1 coagulation abnormality was present in 82% of
the cats. Prolongation of prothrombin time was most common (16/22 cats) and
factor VII activity was below reference range (< 60%) in 15 cats. When classified
according to underlying pathogenesis, vitamin K deficiency was the most common
abnormality found (11/22). Other abnormalities were less common and included
hepatic synthetic failure (3/22), indeterminate (3/22), and disseminated
intravascular coagulation (1/22). Increase in alkaline phosphatase (ALP) activity
was the only biochemical abnormality that showed statistically significant
correlation with coagulation abnormalities (P = .023). Cats with marked increases
in ALP activity were more likely to have coagulation abnormalities than those
with only mild increases in ALP activity.
PMID- 9560762
TI - Results of quantitative cultures of urine by free catch and catheterization from
healthy adult horses.
AB - Quantitative urine cultures were performed on 11 male and 11 female healthy adult
horses. Urine was collected by free catch and catheterization using standard
methods. Results showed that all samples collected by free catch contained less
than 20,000 colony-forming units (CFU)/mL. All samples collected by
catheterization contained 500 CFU/mL or less. A significant difference was found
between collection methods (P < .005), with catheterization having less
contamination. In samples collected by free catch, females had significantly
greater contamination than did males (P < .03). Predominant bacterial species
isolated included Streptococcus spp., Escherichia coli, Enterobacter sp.,
Bacillus sp., Staphylococcus spp., Diptheroids sp., Proteus spp., and
Enterococcus sp. Many samples contained multiple bacterial species. Bacterial
isolates were representative of the normal bacterial flora of the equine
urogenital tract. This paper establishes reference values for quantitative urine
culture results in healthy adult horses to aid in the diagnosis of urinary tract
infections.
PMID- 9560763
TI - Use of serum protein concentration to predict mortality in mixed-source dairy
replacement heifers.
AB - The relationship between serum protein concentration in the 1st week of life and
survival to 16 weeks of age was examined in 3,479 Holstein replacement heifers
over a period of 10 years on a farm with endemic salmonellosis. Thirty-four
percent of calves studied had serum protein concentrations < 5.0 g/dL and 60.5%
of calves had serum protein concentrations < 5.5 g/dL. Cumulative mortality was
7.9%, indicating that calves with marginal passive transfer status can be reared
successfully under conditions of endemic salmonellosis. Optimal survival was
observed in calves with serum protein concentrations > 5.5 g/dL. Calves with
serum protein concentrations of 5.0-5.4 g/dL had only a slightly increased
relative risk (RR) of mortality (RR = 1.3) compared to calves with serum protein
concentrations > 5.5 g/dL. The highest RR was experienced by calves with serum
protein concentrations < 4 g/dL (RR = 4.6) and 4.0-4.4 g/dL (RR = 3.1). Calves
with inadequate passive transfer (serum protein concentration < 5.0 g/dL),
experienced increased mortality until at least 10 weeks of age, indicating that
failure of passive transfer has an effect on calf health that extends into the
juvenile period. Models in which serum protein concentration was treated with as
a continuous variable or as a categorical variable failed to demonstrate any
significant interaction between baseline mortality and the RR of mortality. This
finding suggests that the RR derived in the present study should be applicable to
farms with dramatically different baseline mortality rates.
PMID- 9560764
TI - Efficacy of fresh-frozen plasma and cryoprecipitate in dogs with von Willebrand's
disease or hemophilia A.
AB - Here we report the comparative efficacy of fresh-frozen plasma (FFP) and
cryoprecipitate in the treatment of 2 inherited bleeding disorders in dogs. The
dogs were divided into 3 groups, consisting of 4 Doberman Pinschers with type I
von Willebrand's disease (vWD) (group 1), 1 Scottish Terrier with type III vWD
(group 2), and 4 German Shepherd Dogs with hemophilia A (group 3). In vWD,
therapeutic efficacy was determined by the ability of the products to increase
von Willebrand factor antigen (vWf:Ag) concentrations above 35 canine units
(CU)/dL and to correct the prolonged buccal mucosal bleeding time. Therapeutic
efficacy in hemophilia A was assessed by the ability of the products to increase
the factor VIII coagulant (FVIII:C) activity above 30 CU/dL. In both groups 1 and
2, higher increases in vWf:Ag were achieved with cryoprecipitate than with FFP,
despite a significantly smaller total amount of vWf:Ag (in CU) being infused with
cryoprecipitate. The maximum vWf:Ag attained after infusion in group 1 was
dependent on both the baseline vWf:Ag concentration and on the type of infusion
product. The dogs with vWD in both groups also displayed a delayed increase in
FVIII:C activity after infusion of both plasma products, which is characteristic
of the disease. In group 3, cryoprecipitate achieved similar increases in FVIII:C
activity compared to FFP, although a significantly lesser amount of FVIII:C (in
CU) was delivered with cryoprecipitate. Six of the 9 dogs treated with FFP
experienced adverse effects ranging from mild pruritus to pallor and weakness,
whereas none of the 9 dogs treated with cryoprecipitate had any observable
adverse reactions (P = .009). Based on its efficacy and safety, we recommend
cryoprecipitate over FFP for treatment or prophylaxis of hemorrhagic episodes in
dogs with vWD or hemophilia A.
PMID- 9560765
TI - Comparison of some pharmacokinetic parameters of 5 angiotensin-converting enzyme
inhibitors in normal beagles.
AB - This study was designed to determine the degree of inhibition of the angiotensin
converting enzyme (ACE) in 5 normal dogs given single doses of conventionally
used ACE inhibitors (ACEis). In addition the time required for that inhibition to
return to 50% of the difference between maximum and zero (control values) was
measured as an estimate of duration of action. The 5 ACEis (with dosages given in
parentheses) were benazapril (0.5 mg/kg), captopril (2.0 mg/kg), enalapril (0.5
mg/kg), lisinopril (0.5 mg/kg), and ramipril (0.25 mg/kg). Blood samples for ACE
activities were obtained before dosing and at 1.5, 3.0, 6.0, 12.0, and 24.0 hours
after dosing. All ACEis except captopril decreased ACE activities to
approximately 25% of control by the 1.5- to 3.0-hour sample, and ACE activities
returned to 50% of the difference by the 12-hour sample. The value of AVE
activity returned to normal by 24 hours for benazapril, whereas values for ACE
activity remained below normal for enalapril, lisinopril, and ramipril at 24
hours. For captopril, however, ACE levels decreased to approximately 80% of
control by the 1.5-hour recording, and returned to levels not different from
control by the 3-hour recording. Based upon this study performed on normal dogs
given a single dose, no pharmacokinetic advantage or disadvantage is apparent for
any ACEi except captopril, which, at the dosage used, decreased ACE levels to a
much lesser degree and shorter time.
PMID- 9560766
TI - Possible late potentials in 4 dogs with sustained ventricular tachycardia.
AB - Signal-averaged electrocardiograms (SAEKGs) were performed on 4 dogs with
sustained ventricular tachycardia. Quantitative and qualitative analyses of
SAEKGs were consistent with the presence of late potentials. Two of the 4 dogs
subsequently died suddenly, and ventricular tachycardia and ventricular
fibrillation were observed in 1 dog. High-frequency QRS durations (75-90
milliseconds), duration of low amplitude (less than 40 microV) signals during the
terminal QRS complex (LAS40) (28-40 milliseconds), root mean square voltages of
the terminal 40 milliseconds of the QRS complex (RMS40) (124-6.5 microV), and
root mean square voltages of the terminal 30 milliseconds of the QRS complex
(RMS30) (13-2.1 microV) differed from results obtained in 68 of 70 control dogs.
Echocardiographic data suggested dilated cardiomyopathy in 2 dogs and the cause
of the arrhythmia in 2 dogs was not determined. The SAEKG may be a useful adjunct
in identifying a subset of dogs with ventricular tachyarrhythmias that are at
high risk for sustained ventricular tachycardia and sudden death. The
sensitivity, specificity, and predictive accuracies of the technique remain to be
determined.
PMID- 9560767
TI - Juvenile-onset distal myopathy in Rottweiler dogs.
AB - Two juvenile Rottweiler siblings were presented with the complaint of decreased
activity and various postural abnormalities, including plantigrade and palmigrade
stance and splayed forepaw digits. The neurologic examinations were otherwise
normal. Electromyography revealed rare fibrillation potentials and positive sharp
waves. Motor nerve conduction velocities were normal, whereas compound muscle
action potentials from the interosseous muscles were decreased. These findings
were consistent with a primary myopathy. A 3rd pup from a different litter and a
4th pup from a litter with 3 of 8 affected dogs had similar clinical
presentations. Histopathologic changes in fresh-frozen muscle biopsy samples were
similar in all pups and consisted of myofiber atrophy with mild myonecrosis,
endomysial fibrosis and replacement of muscle with fatty tissue. These changes
were more severe in distal muscles than in proximal muscles. Plasma carnitine
concentrations (total and free) were decreased in all pups. Muscle carnitine
concentrations (total and free) were decreased in 3 of 4 pups and the least
affected pup had a borderline low free muscle carnitine concentration.
Abnormalities involving major metabolic pathways were not found on quantification
of organic and amino acids. Dystrophin immunocytochemistry was normal in 2 dogs
tested. Distal myopathies in humans are classified under the dystrophic group of
muscle disorders. These 4 cases represent a form of muscular dystrophy apparently
not previously reported in dogs.
PMID- 9560768
TI - Left atrial paraganglioma in a dog: echocardiography, surgery, and scintigraphy.
PMID- 9560769
TI - Congenital myotonia in 2 domestic cats.
PMID- 9560770
TI - Possible adult onset myotonic dystrophy in a boxer.
PMID- 9560771
TI - Diazepam used to control cluster seizures in dogs.
PMID- 9560772
TI - Effects of thyroidectomy or thiouracil treatment on copulatory behavior in adult
male rats.
AB - Male copulatory behavior and the function of the hypothalamo-hypophysial-gonadal
axis in hypothyroid male rats were investigated in the present study.
Hypothyroidism was induced by thyroidectomy or thiouracil. In male copulatory
behavior test, intromission latencies in hypothyroid rats were significantly
longer than those in euthyroid rats and ejaculation frequencies were reduced in
hypothyroid male rats compared to control rats without reduction of plasma
concentrations of testosterone. These changes in copulatory behavior in
hypothyroid male rats were restored to control levels by administration of T4 (5
micrograms/rat). Hypothyroidism decreased adrenal weights, and basal and peak
concentrations of corticosterone during diurnal variation, whereas it increased
peak concentrations of ACTH in adult male rats. These results indicate that
hypothyroidism causes adrenal dysfunction directly and results in hypersecretion
of ACTH. The adrenal disturbance observed in hypothyroid rats may affect male
copulatory behavior.
PMID- 9560773
TI - Distribution of uropathogenic virulence factors among Escherichia coli strains
isolated from dogs and cats.
AB - A variety of virulence factors (VFs) such as type 1 fimbriae, pilus associated
with pyelonephritis, S fimbriae, afimbrial adhesin, alpha-hemolysin, aerobactin
and cytotoxic necrotizing factor 1 are associated with uropathogenic Escherichia
coli. In this study, 80 uropathogenic E. coli strains in 50 dogs and 30 cats
suffering from UTI. In addition, 60 E. coli strains were isolated from fecal
samples from 30 each of healthy dogs and cats. The distribution of VFs of
uropathogenic E. coli strains isolated from dogs and cats suffering from urinary
tract infections (UTI) were examined by the colony hybridization test with seven
DNA probes specific for VFs, and the results were compared with those obtained in
the studies on strains from humans with UTI. In uropathogenic E. coli strains
isolated from dogs and cats suffering from UTI, VFs were detected as frequently
as in the strains isolated from humans with UTI. Although less frequently, genes
encoding these VFs especially pap, sfa, hly, and cnf 1 genes were also associated
with E. coli strains isolated from feces of healthy cats, in contrast to the
distribution pattern of uropathogenic E. coli observed in humans. Furthermore,
all VFs except pil were significantly more frequently detected in strains
isolated from urine of animals with cystitis than in those isolated from feces of
healthy humans. These results indicate that VFs of E. coli contribute to the
pathogenesis of UTI in dogs and cats.
PMID- 9560774
TI - A monoclonal antibody against dolphin lymphocytes (6E9) which recognizes bovine
MHC class II antigens.
AB - A monoclonal antibody, 6E9 established from mice injected with dolphin peripheral
blood lymphocytes (PBLs) was characterized. In addition to its reactivity against
89.4% of dolphin PBLs, 6E9 reacted with 33.1% of bovine PBLs of which 22% were
CD5+, 11.1% were CD5-. 6E9 recognized a 34 kD protein on the surface of dolphin
and bovine PBLs. Analysis of the protein's N-terminal amino acid sequence
indicated that 6E9 recognizes bovine major histocompatibility complex (MHC) class
II antigens. These results suggested that 6E9 recognized MHC class II antigens on
bovine PBLs. As we have already produced an anti-dolphin MHC class I monoclonal
antibody, analysis of immune system using these monoclonal antibodies will
advance our understanding of the evolution of the mammalian immune system.
PMID- 9560775
TI - Experimental dual infection of cesarean-derived, colostrum-deprived pigs with
Mycoplasma hyopneumoniae and pseudorabies virus.
AB - To determine whether pseudorabies virus (PRV) infection increases the severity of
pneumonia by Mycoplasma hyopneumoniae, 18, 10-week-old Cesarean-derived,
colostrum-deprived pigs were randomly assigned to 3 groups of 6 pigs each. Pigs
in groups A and C were inoculated intranasally with M. hyopneumoniae at 10-week
old. At 11-week-old, pigs in groups B and C were inoculated intranasally with
PRV. All pigs were initially seronegative for M. hyopneumoniae and PRV. Three
pigs of each group were euthanized at 12-week-old, and remaining pigs at 14-week
old. At necropsy, gross lesions in the lung were observed in the pigs of groups A
and C. On post-inoculation-week (PIW) 2 with M. hyopneumoniae (at 12-week-old),
lung lesions were recognized in one of the 3 pigs in group A and all the pigs in
group C. The mean percentage of the lung lesions were 0.1% in group A and 9.8% in
group C. M. hyopneumoniae was isolated from broncho-alveolar lavage fluids (BALF)
of pigs in group A with titer of 10(2) to 10(3) CCU/0.2 ml and in group C with
titer of 10(5) to 10(6) CCU/0.2 ml. On PIW 4 (at 14-week-old), lung lesions were
observed in all the pigs in groups A and C, and the mean percentage of the lung
lesions were 8.3% in group A and 17.2% in group C. M. hyopneumoniae was isolated
from BALF in group A with titer of 10(4) to 10(7) CCU/0.2 ml and in group C with
titer of 10(6) to 10(7) CCU/0.2 ml. PRVs were isolated from nasal swab and tissue
samples in groups B and C. After inoculation, antibody against M. hyopneumoniae
was detected in groups A and C, and against PRV in groups B and C. Under the
present experimental conditions, PRV infection appear to have effect on the
severity of experimentally induced acute mycoplasmal pneumonia in young pigs.
PMID- 9560777
TI - Sarcocystis suihominis detected for the first time from pigs in Japan.
AB - Sarcoystis suihominis was detected for the first time in Japan from the heart and
diaphragm of 5 out 600 older culled breeding pigs slaughtered in Saitama
Prefecture, Japan. Fresh cysts were 1,080-2,040 x 106-170 microns in size.
Bradysoites measured 15 x 4 microns on average. The cyst wall was usually
observed thick, 4-6 microns, and striated, but occasionally thin and smooth
according to the difference in sectioning angle and in portion of cysts. Scanning
electron microscopy showed that many palisade-like villar protrusions, 6-6 x 0.3
0.5 microns in size, were closely folded onto the surface of cyst. A small number
of microtubules were seen in the core of protrusion. No dogs nor domestic cats
fed with 20 fresh cysts each excreted oocysts or sporocysts in the feces
throughout the experimental period of 30 days.
PMID- 9560776
TI - Pasteurella multocida toxin and Bordetella bronchiseptica dermonecrotizing toxin
elicit similar effects on cultured cells by different mechanisms.
AB - We compared the effects of Pasteurella multocida toxin (PMT) with Bordetella
bronchiseptica dermonecrotizing toxin (DNT) at a cellular level under same
conditions. Both PMT and DNT cause actin stress fiber formation in MC3T3-E1 cells
which is known to be regulated by the small GTP-binding protein Rho. DNT induced
mobility shifts of Rho on SDS-polyacrylamide gel electrophoresis, indicating
direct modification as reported elsewhere. In contrast, no alternations in the
electrophoretic mobility of Rho were found in lysates from PMT-treated cells. PMT
but not DNT increased the intracellular level of inositol phosphates, indicating
the elevation of phospholipase C (PLC) activity in the PMT-treated cells. These
results indicate that PMT does not have Rho as a target but activates PLC. The
formation of actin stress fiber by PMT seems to be stimulated through the
indirect activation of Rho, which resides downstream of PLC, PMT and DNT seem to
elicit similar toxic effects, at least in part, through the activation of Rho.
PMID- 9560778
TI - Prevalence of Listeria species in raw milk from farm bulk tanks in Nagano
prefecture.
AB - Raw milk samples from bulk tanks of a total of 943 farms, which corresponded to
approximately 60% of all dairy farms in Nagano Prefecture were examined for
Listeria species between December 1990 and April 1991. Listeria spp. were
isolated from 29 (3.1%) of 943 milk specimens. In the southern, central, eastern
and northern areas of the prefecture, Listeria spp. were isolated from 6.1%
(22/362), 1.5% (4/272), 1.4% (2/143) and 0.6% (1/166) of samples, respectively.
Listeria monocytogenes was isolated from three (0.3%) bulk tanks in the southern
area: two of the strains isolated from two different farm bulk tanks were serovar
4b, and the other one was 1/2a. Besides, between February 1991 and January 1992,
504 samples of raw milk from farm bulk tanks were collected nine times from 56
farms in the southern area, where the prevalence of Listeria spp. was the
highest, and examined for the seasonal variation in the presence of Listeria spp.
The prevalence of Listeria spp. was higher in spring (14.3%) than in autumn
(4.8%). The 56 farms were divided into three groups according to the prevalence
of Listeria spp., namely, three farms in Group 1 gave a high contamination rate
(50% < or =), 14 farms in Group 2 a low contamination rate and the remaining 39
farms in Group 3 no recovering of Listeria spp. Sixteen strains of L.
monocytogenes serovar 4b were isolated from four farms.
PMID- 9560779
TI - Eight-year observation and comparative study of specific pathogen-free cats
experimentally infected with feline immunodeficiency virus (FIV) subtypes A and
B: terminal acquired immunodeficiency syndrome in a cat infected with FIV
petaluma strain.
AB - Three specific pathogen-free cats experimentally infected with feline
immunodeficiency virus (FIV) strains Petaluma, TM1 and TM2, respectively were
observed for over 8 years. Without showing any significant clinical signs of
immunodeficiency syndrome (AIDS) for 8 years and 4 months of asymptomatic phase,
the Petaluma-infected cat exhibited severe stomatitis/gingivitis, anorexia,
emaciation, hematological and immunological disorders such as severe anemia,
lymphopenia, thrombocytopenia, and decrease of CD4/CD8 ratio to 0.075, and
finally died with hemoperitoneum at 8 years and 8 months post-infection.
Histopathological studies revealed that the cat had systemic lymphoid atrophy and
bone marrow disorders indicating acute myelocytic leukemia (aleukemic type).
Plasma viral titer of the cat at AIDS phase was considerably high and anti-FIV
antibody titer was slightly low as compared with the other FIV-infected cats. In
addition, immunoblotting analysis using serially collected serum/plasma samples
of these cats revealed that antibodies against FIV proteins were induced in all
the infected cats, however in the Petaluma-infected cat anti-Gag antibodies
disappeared during the asymptomatic period. These results suggested that plasma
viral load and anti-FIV Gag antibody response correlated with disease
progression, and supported FIV-infected cats as a suitable animal model of human
AIDS.
PMID- 9560780
TI - A histometrical study on the long bones of raccoon dogs, Nyctereutes procyonoides
and badgers, Meles meles.
AB - To obtain the data required for identification of skeletal remains excavated from
archaeological sites, histometrical observations were made in the cross sections
of the mid-shaft of humerus, radius, femur and tibia of raccoon dogs (Nyctereutes
procyonoides) and badgers (Meles meles) captured in Kagoshima Prefecture. There
were interspecific differences between both animals in the breadth, the depth and
the area of medullary cavity at the mid-shaft of the bones, all measurements were
greater in male than in female bones. The thickness and the area of compact bones
in male raccoon dogs were larger than those of female. No differences in
histological structure could be detected among the bones, but an interspecific
difference was found in the shape of osteons; round and constant-sized osteons
consisting of 3 to 5 lamellae in raccoon dogs, while round or elliptic osteons
varying in size from 3 to 8 lamellae in badgers. The ratios, the osteon areas per
unit compact bone areas, were higher in all the bones of raccoon dogs. The short
diameters of osteons and the ratios were greater in males in both animals. In
females, the short diameter of osteons was smaller, and the number of osteons was
larger. The results revealed interspecific differences between both animals and
sexual dimorphism in each species.
PMID- 9560781
TI - Evaluation of single-injection method of inulin and creatinine as a renal
function test in normal cats.
AB - A single injection method for estimating glomerular filtration rate (GFR) by
measuring plasma inulin and creatinine clearances was evaluated in 10 healthy
cats. GFRs were estimated from the plasma clearance (PC) by dividing the injected
dose of an indicator by the area under the plasma disappearance curve (AUC). AUC
was determined by 2 common pharmacokinetic analyses, the two-compartment model
and the trapezoidal rule. AUCs determined by these two methods were significantly
correlated both in inulin (r = 0.993) and creatinine (r = 0.959). To minimize
errors, GFR was estimated by PC only if AUC/10 was greater than the area under
the curve from the final sampling time to infinitive (A2). GFRs determined by PC
of inulin at final sampling time of 180 and 240 min were 3.61 +/- 0.64 and 3.63
+/- 0.67 ml/min/kg of body weight (mean +/- SD), respectively. These values
corresponded to the reference range reported for normal cats. In contrast, when
creatinine was used as a maker, A2 was always greater than AUC/10 at any final
sampling time and GFRs estimated using these AUCs of creatinine were
significantly greater than those of inulin, suggesting creatinine may not be
suitable indicator for the single injection method.
PMID- 9560782
TI - Pulmonary venous flow in normal dogs recorded by transthoracic echocardiography:
techniques, anatomic validations and flow characteristics.
AB - To observe pulmonary venous flow in dogs, the echocardiographic imaging planes
and the techniques for examination, and the validations of anatomic location were
investigated. Then, the velocity pattern of pulmonary venous flow was recorded in
normal conscious dogs. Six imaging planes were available for observing the right
or left caudal lobe pulmonary venous flow with two-dimensional or pulsed Doppler
echocardiography. Of these, the left lateral apical 4-chamber view can be applied
as standard view, because the pulmonary venous flow and transmitral flow could be
recorded in this view simultaneously with small sampling angle. The velocity
pattern of pulmonary venous flow demonstrated two forward waves in 19 of 20 dogs
examined, with one peak occurring during ventricular systole and another during
ventricular diastole. A reversed flow during atrial contraction was also seen in
11 dogs. In the two forward waves, the mean peak velocity and velocity-time
integral of ventricular diastolic forward flow were significantly higher than
those of systolic forward flow (46.49 +/- 6.79 vs. 31.13 +/- 4.92 cm/s, p <
0.0001 and 8.18 +/- 1.84 vs. 5.14 +/- 0.82 cm, p < 0.0001, respectively). The
deceleration time of diastolic forward flow shortened with the increase of heart
rate (r = -0.87, p < 0.0001). Pulmonary venous flow in dogs can be observed under
transthoracic two-dimensional or pulsed Doppler echocardiography.
PMID- 9560783
TI - Distribution of attenuated goose parvoviruses in Muscovy ducklings.
AB - With a polymerase chain reaction (PCR) method, goose parvovirus (GPV) DNA was
detected in Muscovy ducklings inoculated with attenuated GPV strains, IH and IHC.
Strain IH that had been passed 20 times in Muscovy duck embryos could be detected
in ducklings at 2- to 28-days after oral inoculation by PCR, however, a cell
culture adapted strain IHC that had been passed 15 times in Muscovy duck embryos
and then successively 50 times in Muscovy duck embryo fibroblasts could not be
detected by 6 days postinoculation by the oral route, but via intramuscular
inoculation the virus was detected from 6 dpi. With both strains Muscovy
ducklings produced neutralizing antibodies against GPV, but GPV could be
recovered from heart muscles even in birds that had high titer of neutralizing
antibody. This means that GPV remains in birds for a long period under the
presence of high titer of neutralizing antibody in the serum. Recovery of the
virus was consistent with PCR results with one exception in which the bird had a
neutralizing antibody titer of more than 100,000. After inoculation of these
strains, no clinical signs were detected in ducklings. These results suggest that
strains IH and IHC can be candidates for live attenuated vaccine for GPV
infection.
PMID- 9560784
TI - Monoclonal antibody TSd-1 is specific to elongating and matured spermatids in
testis of common tree shrew (Tupaia glis).
AB - The monoclonal antibody (MAb), named TSd-1, specific to spermatogenic cells of
the common tree shrew (Tupaia glis) was established and characterized using
immunohistochemistry and immunoblotting. MAb TSd-1 reacted with elongating and
matured spermatids in a stage-dependent manner. TSd-1 recognized a 94 kilodalton
(kDa) peptide in the plasma membrane and cytosol. Additionally, an extremely weak
107 kDa band was detected only in the cytosol. The reactions were not detected in
round spermatids. In elongating Stage VI spermatids, the plasma membrane and the
granular structure within the cytoplasm were intensely positive, and most intense
after the appearance of new round spermatids in the lower layer (Stage I). The
reactions were observed neither in the other organs of the common tree shrew nor
in the testes of other animals, indicating that TSd-1 antigen is specific to the
spermatogenic cells of the common tree shrew, and may act on elongating or
matured spermatids.
PMID- 9560785
TI - Localization of metallothionein-I and -II in hypertrophic astrocytes in brain
lesions of dogs.
AB - To study the neurophysiological functions of metallothioneins (MTs), localization
of MT-I and -II was examined immunohistochemically in a variety of brain lesions
in dogs, including infarct, laminar cortical necrosis, hemorrhage, invasive
growth of tumour, inflammatory lesions in granulomatous meningoencephalitis and
distemper encephalitis. MT-I and -II were demonstrated in both nucleus and
cytoplasm of hypertrophic astrocytes in most brain lesions examined regardless of
the type, size, localization and duration of the lesions. In addition, MT
expression was stronger in a population of hypertrophic astrocytes localizing
inside of the surviving brain tissue rather than those localizing at the boundary
between the surviving brain tissue and necrotic area, where severe inflammatory
changes were developing. These results suggest that MT-I and -II may play roles
not only in protection of neurons from metals and free radicals ubiquitous in the
inflammatory lesions but also in repair of injured neural tissues.
PMID- 9560786
TI - Effects of the deleted form of hepatocyte growth factor on serum hyaluronate
levels in rats with liver cirrhosis.
AB - Effects of the deleted form of hepatocyte growth factor (dHGF) on serum
hyaluronate levels, an index for liver cirrhosis, were studied in rats. The
levels of serum hyaluronate increased in rats with dimethylnitrosamine- or
carbontetrachloride-induced cirrhotic liver with prolongation of prothrombin
time, which indicates disorder of liver function. Daily intravenous injection of
dHGF reduced the elevated serum hyaluronate levels with improvement of the
prolonged prothrombin time. These results suggest that the amelioration of
hepatic function disorder by dHGF leads to a reduction of the increased serum
hyaluronate levels.
PMID- 9560787
TI - Rapid and progressive CD4+ decline in a monkey infected with an SIV+HIV-1
chimeric virus.
AB - We previously constructed a simian immunodeficiency virus+human immunodeficiency
virus type 1 (HIV-1) chimeric virus, NM-3rN to generate a pathogenic HIV-1 in
macaque monkeys. During the in vivo passage of this virus in several monkeys, a
viral strain, R43-56 was obtained which acquired a better replication ability in
vivo. MM121, one of the three monkeys inoculated with the R43-56, showed weight
loss, diarrhea and a rapid and continuous decrease in CD4+ lymphocytes at the
moribund stage. An autopsy revealed generalized lymphadenopathy, dehydration, and
ileocecal intussusception. In situ hybridization showed that the virus infection
was in systemic lymphoid organs. We are presently monitoring the survivors to
obtain candidates for a more virulent virus. R43-56 may be a better challenge
virus and useful tool for human acquired immunodeficiency syndrome research.
PMID- 9560788
TI - Effect of oxygen concentration in the gas atmosphere during in vitro insemination
of bovine oocytes on the subsequent embryonic development in vitro.
AB - In vitro matured bovine oocytes were co-incubated with sperm for 18 hr in a
droplet of fertilization medium under a gas atmosphere of 5% CO2 with 5 or 20%
O2. After removing the cumulus cells, they were fixed to examine their
fertilization rate, or cultured for another 154 hr in a chemically defined medium
under 5% O2 to determine their development to the blastocyst stage. There was no
difference between the 5 and 20% O2 groups in the fertilization rate. However,
the percentage of inseminated oocytes which developed to the blastocyst stage was
higher when in vitro insemination was conducted under 5% O2 compared with that
under 20% O2 (34.4 vs. 24.7%, P < 0.05).
PMID- 9560789
TI - Growth inhibitory effect of bovine lactoferrin to Toxoplasma gondii tachyzoites
in murine macrophages: tyrosine phosphorylation in murine macrophages induced by
bovine lactoferrin.
AB - Previous studies have shown that lactoferrin induces growth inhibitory effects in
mouse macrophages against intracellular Toxoplasma gondii, and these effects were
not mediated by the oxygen-dependent and inorganic nitrogen-dependent pathway. To
clarify the mechanism of anti-Toxoplasma gondii activity induced by lactoferrin,
we examined whether lactoferrin promoted the phosphorylation of tyrosine residues
in macrophage proteins. In immunoblotting assays using anti-[phosphorylated
tyrosine] monoclonal antibody, phosphorylation of tyrosine residues was detected
in protein(s) of approximately 30 kDa in macrophages incubated with lactoferrin.
Inhibition of the lactoferrin-induced tyrosine-phosphorylation by genistein led
to loss of the lactoferrin-induced growth inhibitory effect against the
parasites. These findings suggest that lactoferrin induces tyrosine
phosphorylation in macrophages, and the tyrosine-phosphorylation seems to be
associated with the induction of the growth inhibitory activity exerted against
intracellular Toxoplasma gondii.
PMID- 9560790
TI - X-linked locus is responsible for non-insulin-dependent diabetes mellitus in the
OLETF rat.
AB - The Otsuka Long-Evans Tokushima Fatty (OLETF) rat has been recently established
as the best model of non-insulin-dependent diabetes mellitus (NIDDM) with mild
obesity. In this study, we found that the F1 progeny produced from the crosses of
OLETF and F344 rats exhibit a reciprocal cross effect on NIDDM-relevant
phenotypes, fasting and postprandial glucose levels and body weight, suggesting
the existence of X-linked locus affecting susceptibility to NIDDM. We thus
examined the linkage between 7 X-linked microsatellite markers and NIDDM-relevant
phenotypes, using 160 (OLETF x F344)F2 progeny. Suggestive evidence for a X
linked locus affecting glucose levels at 120 min after glucose administration was
found in a region near X-linked marker, DXMgh4. The identified locus also showed
significant effects on fasting glucose levels and body weight.
PMID- 9560791
TI - Increased ductal responsiveness to PGE2 after maternal treatment with aspirin and
ibuprofen.
AB - This work was conducted to determine whether aspirin and ibuprofen, when
administered prenatally may potentiate a reopening of the neonatal ductus
arteriosus (DA) induced by PGE2 after postnatal closure. In the first experiment,
a subcutaneous injection of PGE2 (4 microgram(s)) was administered to newborn
rats 3 hr after a Cesarean delivery from pregnant females which had been orally
given 100 or 300 mg/kg/day of aspirin and 10 or 30 mg/kg/day of ibuprofen on days
18, 19 and 20 of gestation. The ratio of the DA to the pulmonary artery (PA) was
determined at intervals after the injection. The DA/PA ratio was significantly
higher in newborn rats from mothers who were transplacentally administered these
agents than the control. We also examined the hypothesis that maternal treatment
with nonsteroidal anti-inflammatory drugs (NSAID), such as aspirin and ibuprofen,
inhibits the catabolism of PGE2 and that the increased reopening of the DA was
partly due to this inhibition. 15-hydroxy prostaglandin dehydrogenase (15-PGDH)
in neonatal lungs, the key enzyme involved in catalyzing PGE2 to convert it to
its inactive metabolite 15-keto-PGE2, was not affected by maternal treatment with
aspirin and ibuprofen. These results suggest that the increased ductal
responsiveness to PGE2 in newborn rats was a common response after maternal NSAID
treatment, but the catabolism of PGE2 in the lungs did not always contribute to
this response.
PMID- 9560792
TI - The nucleotide and predicted amino acid sequence of the fusion protein of recent
isolates of canine distemper virus in Japan.
AB - Analysis of the molecular properties of fusion (F) proteins of field isolates of
canine distemper virus (CDV) by immunoprecipitation analysis revealed an
identical molecular mass of F protein of 3 field isolates as well as the
Onderstepoort laboratory strain. Sequencing showed that the F gene of a field
isolate (the Yanaka strain) shared 90.1% and 95.7% identities with the
Onderstepoort strain at nucleotide and amino acid levels, respectively. All of
the 13 cysteine residues and 4 potential asparagine-linked glycosylation sites
were completely conserved amongst these strains. These results indicate that the
F proteins is much less heterogeneous than that observed in the hemagglutinin
proteins of CDV.
PMID- 9560793
TI - C-cell adenoma containing variously sized thyroid follicles in a horse.
AB - A thyroid gland tumor, showing unusual histology, was identified in a 13-year-old
male Andalusian horse. Microscopically, the tumor consisted of neoplastic
proliferation of C-cell (parafollicular cell) with cytoplasmic fine granules,
containing diffusely distributed, variously sized colloid-containing follicles.
Immunohistochemically, the neoplastic C-cell were positive for calcitonin and
follicleforming epithelial cells showed a positive reaction for thyroglobulin.
Ultrastructurally, membrane-bound secretory granules up to 250 nm in diameter
were found in the cytoplasm of the parafollicular cells, whereas the follicular
epithelial cells had microvilli, junctional complex, and well-developed
endoplasmic reticulum.
PMID- 9560794
TI - Histological changes in the endometrial arterioles during postpartum offthe
Chinese hamster (Cricetulus griceus).
AB - The morphology of the uterine wall in the postpartum Chinese hamster (Cricetulus
griceus) was studied with particular reference to the changes in the arterioles
in the mesometrial endometrium. At day 0 postpartum, the endometrial arterioles
were characterized by the appearance of trophoblastic giant cells plugging
ruptured arterioles. On days 1 to 3 postpartum, the giant cells were replaced by
epitheloid cells. On days 4 to 5 postpartum, the epitheloid cell mass was invaded
by fibroblasts to occlude the arterial lumens. On days 6 to 7 postpartum,
endometrial regeneration was completed. The giant cell might play a role in
hemostasis immediately after parturition.
PMID- 9560795
TI - Rearrangement of c-myc gene in rapidly induced avian lymphoid leukosis tumors.
AB - Southern blot hybridization of DNA samples from 9 primary tumors of avian
lymphoid leukosis (LL) rapidly induced by ALV infection 27-74 days post
inoculation was carried out to search for rearrangement of the c-myc gene with
human c-myc gene exon III as a probe. Rearrangement of the c-myc gene was
detected by appearance of new EcoRI fragments in 7 out of 9 tumors examined. The
size of the fragments ranged from 3.1 to 4.0 kilobases (kb). In addition to these
fragments, two fragments (9.0 kb and 13 kb) were observed in one tumor, and a
faint fragment (3.5 kb) was observed in another tumor. Rearrangement of the c-myc
gene was not detected in the remaining two tumors kept in unsuitable condition.
These results suggest that rearrangement of c-myc gene was induced even in
rapidly induced LL as well as that induced after long incubation period. This is
the first report of involvement of c-myc gene in rapidly induced B-cell lymphoma
(LL).
PMID- 9560796
TI - Prevalence of antibodies of field pseudorabies virus in pigs of herd vaccinated
with live vaccine.
AB - This trial was performed in a 350-sow farrow-to-finish pig farm in which animals
had been vaccinated against Aujeszky's disease with glycoprotein gC deletion (gC(
)) vaccine. The prevalence of antibodies against field pseudorabies virus (PRV)
in serum samples collected from sows and fattening pigs during the period March
1995 to May 1997 was determined by using a commercial assay kit. The frequencies
with which PRV-positive sows were found were 28.9% and 25.0% in March and October
of 1995, 12.5% and 2.5% in April and October of 1996, and 0% in May of 1997. The
fattening pigs tested at these times had no antibody to field PRV. These results
thus indicate the probability that the PRV infection at the farm was eliminated
by the gC(-) vaccine.
PMID- 9560797
TI - Dietary methionine level affects linoleic acid metabolism through
phosphatidylethanolamine N-methylation in rats.
AB - The effects of dietary methionine level on the profiles of fatty acids and
phospholipids and on the plasma cholesterol concentration were investigated to
confirm whether the methionine content of dietary proteins is one of the major
factors that cause differential effects on lipid metabolism. The effect of
dietary supplementation with eritadenine, which is shown to be a potent inhibitor
of phosphatidylethanolamine (PE) N-methylation, was also investigated. Rats were
fed six diets containing casein (100 g/kg) and amino acid mixture (86.4 g/kg)
differing in methionine content (2.5, 4.5, and 7.5 g/kg) and without or with
eritadenine supplementation (30 mg/kg) for 14 d. The ratio of arachidonic to
linoleic acid of liver microsomal and plasma phosphatidylcholine (PC) was
significantly increased as the methionine level of diet was elevated, indicating
that dietary methionine stimulates the metabolism of linoleic acid. The PC/PE
ratio of liver microsomes and the plasma cholesterol concentration were also
increased by dietary methionine. These effects of methionine were completely
abolished by eritadenine supplementation The S-adenosylmethionine concentration
in the liver reflected the methionine level of diet. These results support the
idea that the differential effects of dietary proteins on lipid metabolism might
be ascribed, at least in part, to their different methionine contents, and that
methionine might exert its effects through alteration of PE N-methylation.
PMID- 9560798
TI - Interaction of n-3 long-chain polyunsaturated fatty acids with n-6 fatty acids in
suckled rat pups.
AB - The addition of long-chain polyunsaturated fatty acids (LCP: C20, and C22) to
infant formula may permit fatty acid accretion rates similar to breast-fed
infants, and may have long-term outcome benefits, such as improved visual acuity
and cognitive development. Although fish oil may provide a source of n-3 LCP,
sources of n-6 LCP have been more difficult to identify. The present study
evaluates the effects of n-3 and n-6 LCP derived from single-cell oils on liver,
plasma, and brain fatty acid levels in a neonatal animal model. Newborn rat pups
were suckled for 14 d by dams receiving diets containing n-3 LCP alone or
combinations of n-3 LCP and increasing doses of linoleic acid (18:2n-6) or
arachidonic acid (20:4n-6). Dietary groups received 2% n-3 LCP and 1, 2, or 5% of
either 18:2n-6 or 20:4n-6. The 20:4n-6 source also contained modest levels of
18:2n-6. At the termination of the study, liver, plasma, and brain were obtained
from the rat pups and the phospholipid fatty acid profiles determined. The
results indicate complex interactions of n-3 and n-6 fatty acids. Groups
receiving dietary 20:4n-6 incorporated higher levels of n-6 LCP into tissues than
did the groups receiving 18:2n-6. The brain was relatively resistant to changes
in fatty acid composition compared with the liver and plasma. As expected, tissue
n-3 LCP levels were reciprocally related to n-6 levels. The present results
document that single-cell LCP oils are bioavailable in a neonatal animal model.
The use of 20:4n-6 is a more effective means of supporting n-6 status than the
use of 18:2n-6. These results may have implications for the addition of LCP to
infant formula.
PMID- 9560799
TI - Diabetes-induced and age-related changes in fatty acid proportions of plasma
lipids in rats.
AB - Diabetes-induced and age-related proportional changes in plasma fatty acids of
triglycerides (TG), phospholipids (PL), and cholesteryl esters (CE) were
investigated using streptozotocin-induced diabetic and control rats. Among n-6
fatty acids from diabetic rat plasma, increased proportions of 18:2n-6 and 20:3n
6 in all three lipid classes and of 18:3n-6 in PL at 1-3 months old and in TG at
3-5 months old were observed. The proportions of 20:4n-6 decreased in both PL and
CE, but were unchanged in diabetic TG. Among the n-3 fatty acids, in the early
stage, diabetes caused increases in the proportions of 18:3n-3 in PL and CE and
of 20:5n-3 and 22:6n-3 in TG, while 22:5n-3 was decreased later in the disease
course. These results suggest reduced delta 5-desaturase activities on 20:3n-6
but not on 20:4n-3, while delta 6-desaturase activity on 18:2n-6 was essentially
unaffected. Furthermore, the reduction in delta 9-desaturase activity in diabetic
rats may well explain the decreases in the proportions of 16:1n-7 and 18:1n-7.
However, the proportion of 18:1n-9, another product of delta 9-desaturase, was
significantly increased in CE and PL as compared to the controls. Thus, there was
a discrepancy between our results and those of earlier studies with respect to
the n-9, n-6, and n-3 fatty acid proportions of plasma lipids in diabetic rats.
We also investigated age-related changes in the proportions of plasma fatty
acids. Although rather small, age-related changes were evident in both diabetic
and control rats.
PMID- 9560800
TI - Effect of continuous enteral medium-chain fatty acid infusion on lipid metabolism
in rats.
AB - This study compared (i) the relative effects of long-chain triglycerides (LCT)
and medium-chain triglycerides (MCT), (ii) the influence of amount of MCT, and
(iii) the impact of medium-chain fatty acid position, on plasma and lymphatic
triglycerides and portal vein free fatty acids. The animals were fed
approximately at 250 kcal/kg.day for 20 h. The lymph from lymphatic duct and
blood from portal vein and systemic circulation were collected. The results
showed that feeding 100% MCT for 20 h was sufficiently long to reduce
significantly the level of linoleic acid in portal vein fatty acids and plasma
and lymph triglycerides. However, this alteration induced by MCT feeding was
partially prevented by adding LCT to the diet. The level of arachidonic acid was
significantly reduced in plasma triglycerides by any of the diets containing
medium-chain fatty acids compared to 100% LCT. When feeding MCT only, palmitoleic
acid, presumably reflecting de novo lipogenesis, was increased in lymphatic
triglycerides and portal vein fatty acids. Total saturated fatty acids as a total
percentage of total fatty acids were also significantly increased in plasma and
lymphatic triglycerides and portal vein fatty acids. Thus, when linoleic acid is
limiting, the conversion of MCT into long-chain fatty acids by de novo
lipogenesis is likely to be an important metabolic route. Providing LCT with MCT
or 2-monodecanoin appears to limit this pathway.
PMID- 9560801
TI - Absorption, excretion, and distribution of plant sterols after proximal gut
resection and autotransplantation of porcine ileum.
AB - Contribution of different gut segments to plant sterol absorption, adaptation of
plant sterol absorption after partial small bowel resection, and effects of gut
transplantation (necessitates extrinsic autonomic denervation and lymphatic
disruption) on plant sterol biodynamics are unclear. We studied the consequences
of massive proximal small bowel resection and autotransplantation of the
remaining ileum on the adaptive absorption and biodynamics of plant sterols.
Dietary, fecal, biliary, hepatic and plasma plant sterols, fecal elimination and
absorption of cholesterol, small bowel morphology, and intestinal transit were
determined before (n = 5) and at 4, 8, and 14 wk after resection of the proximal
75% of the jejunoileum (n = 15) and autotransplantation of the remaining ileum (n
= 15) or transection (n = 5). Proximal gut resection significantly reduced
cholesterol absorption efficiency; percentage absorption and biliary secretion of
plant sterols; plasma, biliary and hepatic campesterol-to-cholesterol
proportions; and sitosterol proportions in plasma and bile. Autotransplantation
of the remaining ileum further significantly decreased cholesterol absorption
efficiency; percentage absorption and biliary secretion of campesterol;
campesterol proportions in plasma, bile and liver; and plasma proportions of
sitosterol while increasing fecal excretion of neutral and acidic steroids.
Plasma proportions of the two plant sterols, but absorption of just campesterol,
were gradually improved with increasing cholesterol absorption and villus height
after proximal gut resection; the same result was observed to a lesser degree
after ileal autotransplantation. In addition, significant positive correlations
were found between percentage cholesterol and campesterol absorption and the
plasma plant sterol proportions in both proximal resection groups, between
campesterol absorption and ileal villus height in the resection group, and
between campesterol absorption and intestinal transit time in the
autotransplantation group. In conclusion, plasma campesterol and sitosterol
closely reflect absorption of cholesterol and plant sterols from intact and
autotransplanted ileum during adaptation to proximal gut resection. A loss of
proximal gut absorptive surface impairs cholesterol and campesterol absorption
more than sitosterol absorption, the latter being apparently less dependent on
available jejunal villus surface area.
PMID- 9560802
TI - The effect of dietary vitamin E supply and a moderately oxidized oil on
activities of hepatic lipogenic enzymes in rats.
AB - Diets rich in polyunsaturated fatty acids (PUFA) are well known to suppress
hepatic lipogenic enzymes compared to fat-free diets or diets rich in saturated
fatty acids. However, the mechanism underlying suppression of lipogenic enzymes
is not quite clear. The present study was undertaken to investigate whether lipid
peroxidation products are involved in suppression of lipogenic enzymes.
Therefore, an experiment with growing male rats assigned to six groups over a
period of 40 d was carried out. Rats received semisynthetic diets containing 9.5%
coconut oil and 0.5% fresh soybean oil (coconut oil diet, peroxide value 5.1 meq
O2/kg oil), 10% fresh soybean oil (fresh soybean oil diet, peroxide value 9.5 meq
O2/kg oil), or 10% thermally treated soybean oil (oxidized soybean oil diet,
peroxide value 74 meq O2/kg oil). To modify the antioxidant state of the rats, we
varied the vitamin E supply (11 and 511 mg alpha-tocopherol equivalents per kg of
diet) according to a bi-factorial design. Food intake and body weight gain were
not influenced by dietary fat and vitamin E supply. Activities of hepatic
lipogenic enzymes were markedly influenced by the dietary fat. Feeding either
fresh or oxidized soybean oil diets markedly reduced activities of fatty acid
synthase, (FAS), acetyl CoA-carboxylase, (AcCX), glucose-6-phosphate
dehydrogenase, (G6PDH), 6-phosphogluconate dehydrogenase, and ATP citrate lyase
(ACL) relative to feeding the coconut oil diet. Moreover, feeding oxidized
soybean oil slightly, but significantly, lowered activities of FAS, AcCX, and ACL
compared to feeding fresh soybean oil. Activities of hepatic lipogenic enzymes
were reflected by concentrations of triglycerides in liver and plasma. Rats fed
the coconut oil diet had markedly higher triglyceride concentrations in liver and
plasma than rats consuming fresh or oxidized soybean oil diets, and rats fed
oxidized soybean oil had lower concentrations than rats fed fresh soybean oil.
The vitamin E supply of the rats markedly influenced concentrations of
thiobarbituric acid-reactive substances in liver, but it did not influence
activities of hepatic lipogenic enzymes. Because the vitamin E supply had no
effect, and ingestion of an oxidized oil had only a minor effect, on activities
of hepatic lipogenic enzymes, it is strongly suggested that neither exogenous nor
endogenous lipid peroxidation products play a significant role in the suppression
of hepatic lipogenic enzymes by diets rich in PUFA. Therefore, we assumed that
dietary PUFA themselves are involved in regulation of hepatic lipogenic enzymes.
Nevertheless, the study shows that ingestion of oxidized oils, regardless of the
vitamin E supply, also affects hepatic lipogenesis, and hence influences
triglyceride levels in liver and plasma.
PMID- 9560803
TI - Effects of polyunsaturated fatty acids and their n-6 hydroperoxides on growth of
five malignant cell lines and the significance of culture media.
AB - We examined effects of polyunsaturated fatty acids (PUFA), their corresponding
hydroperoxy fatty acids (hp-PUFA), as well as various pro- and antioxidants on
the growth of tumor cells in culture. When cultured in RPMI 1640 medium, A-427
and WEHI clone 13 cells were both highly sensitive to hydroperoxy docosahexaenoic
acid (hp-DHA), but they were far less sensitive in minimum essential medium
(MEM). In contrast, A-427 cells were also sensitive to DHA in both culture media,
while WEHI clone 13 cells, as well as other cell lines, tested in their
respective media, were resistant. The lower sensitivity of the cell lines to hp
DHA in MEM-medium was apparently due to a more rapid reduction of hp-DHA to the
corresponding hydroxy-DHA in MEM-medium. Addition of glutathione (GSH) to the
culture medium abolished the effects of hp-DHA, but not the effects of DHA, while
depletion of intracellular GSH levels by L-buthionine-S,R-sulfoximine strongly
enhanced the cytotoxic effect of hp-DHA, but not the cytotoxic effect of DHA.
alpha-Tocopherol protected A-427 cells against the toxic effect of DHA and
abolished the induced lipid peroxidation, while it did not protect against the
toxic effects of hp-DHA in A-427 or WEHI clone 13 cells. Ascorbic acid reduced
the cytotoxic effect of DHA, but potentiated the toxic effect of hp-DHA while
selenite essentially abolished the toxicity of both DHA and hp-DHA. These results
indicate that sensitivity of tumor cell lines to PUFA and their oxidation
products depends on their antioxidant defense mechanisms, as well as culture
conditions, and establishes hp-DHA as a major, but probably not the sole,
metabolite responsible for cytotoxicity of DHA.
PMID- 9560804
TI - Cytotoxicity of tocopherols and their quinones in drug-sensitive and multidrug
resistant leukemia cells.
AB - Cytotoxicities of tocopherols (alpha-T, gamma-T, delta-t), their para (alpha-TQ,
gamma-TQ, delta-TQ)- and ortho (Tocored)-quinone oxidation products, the
synthetic quinone analog of gamma-TQ containing a methyl group substituted for
the phytyl side-chain (TMCQ) and the synthetic quinone analog of Tocored
containing a methyl group substituted for the phytyl side-chain (PR) were
measured in acute lymphoblastic leukemia cell lines that are drug-sensitive (CEM)
and multidrug-resistant (CEM/VLB100). Among tocopherols, only delta-T exhibited
cytotoxicity. Among para quinones, alpha-TQ showed no cytotoxicity, while gamma
TQ and delta-TQ were highly cytotoxic in both CEM and CEM/VLB100 cell lines (LD50
< 10 muM). delta-TQ and gamma-TQ were more cytotoxic than the widely studied
chemotherapeutic agent doxorubicin, which also showed selective cytotoxicity to
CEM cells. The orthoquinone Tocored was less cytotoxic than doxorubicin in drug
sensitive cells but more cytotoxic than doxorubicin in multidrug-resistant cells.
Cytotoxicity was not a function of the phytyl side-chain since both TMCQ and PR
were cytotoxic in leukemia cells. Cytotoxic para and ortho quinones were
electrophiles that formed adducts with nucleophilic thiol groups in glutathione
and 2-mercaptoethanol. Cytotoxicity was enhanced when the glutathione pool was
depleted by preincubation with buthionine-[S,R]-sulfoximine, but cytotoxicity was
diminished by the addition of N-acetylcysteine to cultures. alpha-T also
diminished the cytotoxicity of para- and orthoquinones. Buthionine-[S,R]
sulfoximine did not block the inhibitory effect of either N-acetylcysteine or
alpha-T, showing that these agents did not act solely by maintaining the
glutathione pool as an essential antioxidant system. In conclusion,
tocopherylquinones represent a new class of alkylating electrophilic quinones
that function as highly cytotoxic agents and escape multidrug resistance in acute
lymphoblastic leukemia cell lines.
PMID- 9560805
TI - Conversion of palmitate to unsaturated fatty acids differs in a Neurospora crassa
mutant with impaired fatty acid synthase activity.
AB - The Neurospora crassa cel (fatty acid chain elongation) mutant has impaired fatty
acid synthase activity. The cel mutant requires exogenous 16:0 for growth and
converts 16:0 to other fatty acids. In contrast to wild-type N. crassa, which
converted only 42% of the exogenous [7,7,8,8-(2)H4]16:0 that was incorporated
into cell lipids to unsaturated fatty acids, cel converted 72%. In addition, cel
contains higher levels of 18:3(delta 9,12,15) than wild-type, and synthesizes two
fatty acids, 20:2(delta 11,14 and 20:3(delta 11,14,17, found at only trace levels
in wild-type. Thus, the delta 15-desaturase activity and elongation activity on
18-carbon polyunsaturated fatty acids are higher for cel than wild-type. This
altered metabolism of exogenous 16:0 may be directly due to impaired flux through
the endogenous fatty acid biosynthetic pathway, or may result from altered
regulation of the synthesis of unsaturated fatty acids in the mutant.
PMID- 9560806
TI - Identification of ceramide-phosphorylethanolamine in oomycete plant pathogens:
Pythium ultimum, Phytophthora infestans, and Phytophthora capsici.
AB - Cellular lipids were extracted from three species of Oomycete plant pathogens
(Pythium ultimum, Phytophthora infestans, and Ph. capsici) and analyzed via
normal-phase high-performance liquid chromatography with flame-ionization
detection. The most abundant polar lipids in each of the three species were the
polar membrane lipids, phosphatidylethanolamine (PE), phosphatidylcholine, and a
phosphosphingolipid that eluted soon after PE. Structural analysis via mass
spectrometry and nuclear magnetic resonance spectrometry revealed that the
phosphosphingolipid was ceramide phosphorylethanolamine (Cer-PE). The most
abundant molecular species of Cer-PE in P. ultimum had a molecular weight of
670.5, contained an unusual 19-carbon branched triunsaturated sphingoid (C19
delta 4, 8, 10, 9-methyl long-chain base) and palmitic acid as the amide-linked
fatty acid. The most abundant molecular species of Cer-PE in Ph. infestans had a
molecular weight of 714.5, contained a common 16-carbon 1,3 di-OH sphingoid, and
erucic (cis 13-docosenoic, C22-delta 13) acid as the amide-linked fatty acid. The
Cer-PE in Ph. capsici comprised a mixture of each of the two molecular species
found in P. ultimum and Ph. infestans.
PMID- 9560807
TI - Lipids of Thermococcus hydrothermalis, an archaea isolated from a deep-sea
hydrothermal vent.
AB - The membrane lipids of a deep-sea hydrothermal vent archaea, Thermococcus
hydrothermalis, were isolated, purified, and structurally characterized. On the
basis of acid methanolysis and spectroscopic studies, the polar lipids, amounting
to 4.5% (w/w) of the dry cells, comprised diphytanyl glycerol diethers and
dibiphytanyldiglycerol tetraethers, in a 45:55 ratio. No cyclopentane ring was
present in the tetraethers. From the neutral lipids, accounting for 0.4% (w/w) of
the dry cells, besides low amounts of di- and tetraethers occurring in a free
form, four acyclic tetraterpenoid hydrocarbons, di- and tri-unsaturated were
identified. All were structurally related to lycopane. The presence of these
hydrocarbons provides some evidence that lycopane, widely distributed in oceans,
could be derived, at least partially, from the hydrocarbons synthesized by some
thermophilic Archaea. Finally, analysis of the uninoculated culture medium
indicates that fatty acid derivatives and some steroid and triterpenoid compounds
identified in the lipidic extract of the archaea originated from the culture
medium.
PMID- 9560808
TI - Fatty acid composition of the cellular slime mold Polysphondylium pallidum.
AB - The cellular slime mold Polysphondylium pallidum was grown upon Escherichia coli
B/r, and the fatty acid compositions of total lipids obtained from vegetative
amebae and aggregation-competent cells were compared. Fatty acids isolated from
vegetative cells included C-17 and C-19 cyclopropane fatty acids and also
straight-chain, saturated fatty acids. The cyclopropane fatty acids were derived
from the ingested bacteria. Development of amebae to aggregation-competent cells
was accompanied by a substantial decrease in saturated cyclopropane fatty acids
and a concomitant increase in unsaturated fatty acids and unsaturated
cyclopropane fatty acids, mostly as 18:3 (5,9,12). We report here the fatty acid
composition and identify the occurrence of delta 5 desaturation of cyclopropane
fatty acids, namely, 9,10-methylene 5-hexadecenoic acid and 11,12-methylene 5
octadecenoic acid. These fatty acids have not been reported previously in the
related species Dictyostelium discoideum, which also feeds on E. coli B/r and has
delta 5-desaturation activity.
PMID- 9560810
TI - [Choice of electron equipment for x-ray diagnostic digital scanning system].
AB - The paper deals with the choice of electron equipment for X-ray diagnostic
devices with digital image processing which are intended for population-based
mass prophylactic examinations of lung. Guidelines for the optimization of the
package of electron devices for processing and storing of data and for obtaining
hard copies of X-ray films.
PMID- 9560811
TI - [Methodology of obtaining and digital processing of adhesive cells].
AB - The paper deals with the methodological features of investigations of the
interaction of cells and foreign material surfaces by scanning electron
microscopy. The proposed technique for obtaining electron microscopic images
results in their easy binarization and further treatment using computer software.
The specificity of obtaining electron microphotographs permits detailed
quantitative image analysis. This approach enables one to study both quantity of
objects and their individual morphologies, as well as to define distributions of
objects by their diameter, area, etc. Human platelet adhesion to glass and metal
is considered as an example.
PMID- 9560809
TI - Rapid hydrolysis of bile acid conjugates using microwaves: retention of absolute
stereochemistry in the hydrolysis of (25R) 3 alpha,7 alpha,12 alpha-trihydroxy-5
beta-cholestan-26-oyltaurine.
AB - In recent years, defects of bile acid synthesis caused by disorders of peroxisome
biogenesis have led to increased interest in C27 bile acids. In humans, while the
majority of bile acids are C24 carboxylic acids, the presence of increased
concentrations of C27 bile acids and their metabolites in hereditary diseases
associated with peroxisomal dysfunction can serve as a useful marker for the
intensity of the metabolic disorder. Our present studies describe an efficient
method for the rapid hydrolysis of C27 and C24 bile acid conjugates using a
commercial microwave oven. The advantages of this method include freedom from
racemization, minimal activation, mild reaction conditions, and the highly
stereocontrolled nature of the reaction, thus allowing for free bile acid
recovery in high yield. For example, when (25R) 3 alpha,7 alpha,12 alpha
trihydroxy-5 beta-cholestan-26-oyl taurine, a major compound present in the bile
of Alligator mississippiensis, was deconjugated with 4% NaOH/diethylene glycol or
1 M LiOH/propylene glycol in the microwave oven for 4-6 min, 3 alpha,7 alpha,12
alpha-trihydroxy-5 beta-cholestan-26-oic acid (THCA) was obtained in 81% yield
with retention of configuration at C-25. It is suggested that present studies
will be helpful in delineating the absolute stereochemistry of 3 alpha,7 alpha,12
alpha-trihydroxy-5 beta-cholestanoyl-CoA oxidase, the peroxisomal enzyme that
catalyzes the first step in the oxidation of THCA.
PMID- 9560812
TI - [Study of hydrodynamic characteristics of artificial heart valves by photochromic
imaging].
AB - The paper deals with the hydrodynamics of artificial heart valves (AHVs) used in
clinical practice. It reviews and analyzes the studies of AHV hydrodynamics, as
well as the hydrodynamic beds which stimulate physiological flow through the
valve. Photochronic imaging (PCI) is proposed for examination of AHV hydrodynamic
characteristics under model physiological flow. The hydrodynamics of different
AHVs was tested on the beds simulating blood flow through AHVs by employing PCI.
PCI involved preparation of model photochronic solution that simulates blood,
colour labels by using laser radiation. In the model photochronic solution, 10(
6)-10(-9)-sec laser radiation gave rise to linear colour labels whose movement
was recorded by a speed camera in the flow behind the valve. The profiles of
speed behind the valves, the dimensions of congestive areas, the positions of
flow detachment and regurgitation flow were calculated by a speed shooting in
different periods of valvular performance. PCI defined congestive areas behind
the valves, the areas of closed circulations, the sizes of reversing flow areas
and examined the time course of flow behind the valves as a whole. The paper is
of interest for AHV designers and cardiac surgeons who apply various AHVs.
PMID- 9560813
TI - [Medical technological equipment for correction of impaired homeostasis in
humans].
AB - The paper considers how to correct impaired human homeostasis and to maintain it
at an adequate level, describes some correction methods, such as an original
method of intracorporeal detoxification and technical means for the use of these
methods, including a perfusion roller pump that has better operating
characteristics.
PMID- 9560814
TI - [Experimental evaluation of materials for electrodes in transcutaneous recording
of bioelectric signals].
AB - The authors examined electrodes made of stainless steel, graphitic and metalized
polymeric materials for transcutaneous recording of biopotentials from the human
services by the following parameters: electrode potential difference, noise
voltage, phase difference-signal frequency relationships. If the phase is
adequately corrected, the electrode made of graphitic cloth is effective in
recording biopotentials at an amplitude of more than 20 microV over a wide
frequency range.
PMID- 9560816
TI - [Cane for the blind with a device for detecting and recognizing pedestrian
obstacles].
AB - The paper deals with the development of methods and a device for the blind to
walk by orientating himself through remotely contacting study of what has
happened and is happening on the road. An optoelectron method for detection of
vertical obstacles and ground gaps has been proposed. The authors have drawn up
the structural and functional diagrams of a device which is combined with a
walking-stick and which makes it possible to detect 3 types of pedestrian
obstacles with appropriate sound signalling.
PMID- 9560815
TI - [Theoretical substantiation and experience in vibromechanical dilatation of
hollow organs].
AB - The paper analyzes the principle of operation of a dilatation catheter, a device
designed for expanding hollow organs. The organs (blood vessels, esophagus,
cervix uteri through the cervical canal, uterine tubes) were the subject of
investigation. The effective energy of action on the hollow organ wall in
different catheter operations and the safety index for dilatation of hollow
organs were defined. The aim of the study was to theoretically substantiate the
clinical potentialities of the vibromechanical hollow organ dilatation.
PMID- 9560817
TI - [Assessment of tolerance doses in multifractionated irradiation of the lung using
Ellis and LQ models].
AB - Ellis and LQ models were used to examine the tolerance dose dependences in
different schemes of multifractionated radiation of the lung. For
characterization of multifractionated radiation, a tolerance dose increment
coefficient (TDIC) was introduced, which showed how the tolerance dose increased
during multifractionated radiation as compared to the conventional scheme of dose
fractionation with radiation given once a day. The Ellis models were shown to
yield the TDIC values which were associated with the number of daily radiations
rather than with the number of active days of radiation while the LQ models
provides the TDIC values which depend not only on the number of daily radiations,
but also on the number of active days of radiation. As the number of active
radiation days increased, TDIC reduced. The studies were made according to a
package of specially elaborated programmes which calculated tolerance doses in
relation to the volume of radiation and to the scheme of dose fractionation in
time, by using the TDF and LQ models.
PMID- 9560818
TI - [Diagnostic unit EKS-K1200].
AB - The paper presents the block diagram of the unit, describes some assemblies and
its operation as a whole, gives information on the software and technical data.
The computer-based EKS-K 1200 unit integrates a pacemaker, a 12-channel
electrocardiograph with a monitor, and a database.
PMID- 9560819
TI - [Results of spectral determination of metals in human tissues adjacent to K.M.
Sivash's endoprosthesis].
AB - The paper presents the data of semiquantitative determination of metals in the
tissues surrounding the total titanium-comochromium endoprosthesis of the Sivash
system. The prostheses of this design which have a point of metal-metal friction
have been used in the past 30 years. It has been shown that chromium and cobalt
accumulate constantly and in great quantities, molybdenum and tin do less
frequently and in lower quantities. Seventy tissue specimens were obtained from
20 patients followed up for 3 weeks to 15-19 years. The fine, highly sensitive
method, emission spectral analysis, used by procedure developed by the Moscow
Forensic Bureau of Experts was chosen. The study was undertaken to determine the
association of the severity of metallosis with the aseptic instability of
prostheses. However, there was no strong evidence for this: commensurable
quantities of metals were found when permanent and temporary prostheses had been
used. The author considers that the patients have not survived yet to have
metallic instability that could have developed in some of them in the later
periods of endoprosthesis use. Based on this and early studies, it is concluded
that instability in the given periods is a result of mechanical action of some
parts of the prostheses on bony formations. The findings show that the severity
of metallosis depends on the number of cycles of prosthesis loading, which can be
calculated by the duration of prosthesis use and the number of kilometers covered
by the patient every day. The ascertained number of cycles may be correlated with
the severity of metallosis expressed in arbitrary units.
PMID- 9560820
TI - [Development of technical bases of radiodiagnosis].
PMID- 9560821
TI - [Screening for thyroid diseases by using ultrasound scanners].
PMID- 9560822
TI - Prefrontal glucose deficits in murderers lacking psychosocial deprivation.
AB - Previous research has suggested that links between autonomic nervous system
functioning and violence are strongest in those who come from benign home
backgrounds, but there appears to be no similar research using brain-imaging
measures of central nervous system functioning. It was hypothesized that
murderers who had no early psychosocial deprivation (e.g., no childhood abuse,
family neglect) would demonstrate lower prefrontal glucose metabolism than
murderers with early psychosocial deprivation and a group of normal controls.
Murderers from a previous study, which showed prefrontal deficits in murderers,
were assessed for psychosocial deprivation and divided into those with and
without deprivation. Murderers without any clear psychosocial deficits were
significantly lower on prefrontal glucose metabolism than murderers with
psychosocial deficits and controls. These results suggest that murderers lacking
psychosocial deficits are characterized by prefrontal deficits. It is argued that
among violent offenders without deprived home backgrounds, the "social push" to
violence is minimized, and consequently, brain abnormalities provide a relatively
stronger predisposition to violence in this group.
PMID- 9560823
TI - Interhemispheric memory transfer in the intracarotid amobarbital procedure.
AB - The authors examined interhemispheric memory transfer in 32 patients with
lateralized temporal lobe complex partial epilepsy (15 right onsets, 17 left
onsets). Visually presented verbal, nonverbal, and two types of dually encodable
stimuli were displayed during amobarbital anesthesia, and recognition memory was
tested with verbal and nonverbal (pointing) response modalities. No relationship
was found between the material specificity of stimuli and response modality. The
only significant findings were for poorer recognition memory after injection of
the hemisphere contralateral to the seizure focus. Visual information presented
predominantly to one hemisphere during anesthesia is available to the other
hemisphere for recognition memory on clearing.
PMID- 9560824
TI - Hippocampal cell loss and gliosis: relationship to preoperative and postoperative
memory function.
AB - The authors examined the relationship between neuronal densities, glial cell
densities, and the glial cell/neuron ratio in the CA1 and CA4 hippocampal
subfields and preoperative and postoperative memory function in 47 patients who
had undergone a temporal lobectomy (23 right, RTL; 24 left, LTL) for the relief
of medically intractable epilepsy. The LTL group performed more poorly than the
RTL group on a list learning and story recall task, preoperatively and
postoperatively. Both the RTL and LTL groups performed more poorly on the story
recall task postoperatively. In the LTL group, neuronal densities in the CA1
subfield were significantly correlated with the preoperative scores on the
immediate (r = 0.53, p < 0.01) and delayed (r = 0.53, p < 0.01) recall of the
story. There were no significant correlations in the LTL group between the CA1
and CA4 cell counts and Verbal IQ or scores on a measure of naming ability. None
of the cell density measures in the CA1 and CA4 subfields were significantly
correlated with the preoperative neuropsychological test scores in the RTL group.
Postoperative decline in verbal recall was associated with the excision of a
relatively intact left hippocampus, with high neuronal and low glial cell
densities in the CA1 subfield. The excision of a relatively intact right
hippocampus was also associated with a postoperative deterioration in verbal
recall.
PMID- 9560825
TI - Psychologic adjustment in patients after subarachnoid hemorrhage.
AB - A series of 45 patients after subarachnoid hemorrhage (SAH) with no or only
marginal neurologic impairment and 36 patients with chronic obstructive pulmonary
disease (COPD) were examined with the German Freiburger Personality Inventory
Revised. Both groups showed a comparable frequency of psychologic impairments,
except that the patients with COPD had significantly higher scores in the FPI-R
bodily complaints and bodily concern subscales (p < 0.05). In the patients after
SAH, loss of motivation (42%), abnormal introversion (40%), increased emotional
lability (38%), and strain (31%) were found predominantly. The patients after SAH
of unknown origin exhibited psychologic disturbances comparable with patients
after aneurysmal SAH. A ruptured aneurysm of the anterior communicating artery
did not lead to more psychologic disorders than aneurysms at other locations.
Right frontal and right parietal infarctions were associated with significantly
less emotional sensitivity (p = 0.013) and bodily concern (p < 0.001). The
results demonstrate a substantial discrepancy between the prevalence of
psychologic maladjustment and the moderate degree of functional impairment in
patients after SAH, which remains to be explained by future research.
PMID- 9560826
TI - Autosomal dominant cerebral arteriopathy: neuropsychiatric syndrome in a family.
AB - Though familial vascular leukoencephalopathy was described two decades ago,
recent studies focus on a disorder termed Cerebral Autosomal Dominant
Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a
dominantly inherited disorder causing recurrent strokes and eventual dementia.
The phenotypic boundaries of CADASIL remain indistinct and novel clinical
features continue to arise in the literature. However, the associated
histopathology is fairly consistent, typically demonstrating granular thickening
of cerebral arterioles. The authors evaluated a 38-year-old man who suffered from
progressive change in personality and intellect. His father, paternal aunt, and
older sister had succumbed to a similar disorder. The authors examined relatives
from three generations, including another sister with transient focal symptoms
followed by persisting psychiatric disorder, and reviewed the radiographic
studies from the propositus and his siblings. All the siblings showed diffuse
white matter signal change on magnetic resonance imaging. Brain biopsy from the
propositus revealed normal cortex and white matter but granular sclerosis of
leptomeningeal arterioles. While the family's illness likely represents another
instance of CADASIL, their presentation is unique because neuropsychiatric
disorders predominate over focal ischemic symptoms.
PMID- 9560827
TI - Persistent recurrence of hypomania and prosopoaffective agnosia in a patient with
right thalamic infarct.
AB - The authors report a 63-year-old man with a history of brief isolated manic
episodes who became persistently hypomanic after a small right thalamic infarct.
Detailed behavioral and neuropsychologic assessment were performed 18 months
after the stroke and revealed a prosopoaffective agnosia as the foremost
cognitive disorder, i.e., an impairment in the identification of emotional facial
expressions with preserved discrimination of facial identity. Difficulties in
reasoning on humorous material and other signs of mild right hemisphere
dysfunction were present, but other perceptual, frontal and abstract-reasoning
cognitive functions were unimpaired. Prosopoaffective agnosia has not been
reported previously in thalamic lesions or in primary or secondary mania. The
authors discuss the hypothetical relationships between a right hemisphere deficit
in processing emotions and relapsing of the patient's hypomanic behavior.
PMID- 9560829
TI - Managing patients with vulvovaginal candidiasis.
AB - Epidemiologic studies have demonstrated a continuing increase in the prevalence
of vulvovaginal candidiasis. Although in the past most of these infections were
caused by Candida albicans, an increasing percentage are caused by non-albicans
Candida species that are less sensitive to the most frequently used antifungal
agents. An accurate diagnosis of these infections and the subsequent choice of
the most appropriate therapy can only be made after a thorough evaluation of the
patient. Successful treatment of vulvovaginal candidiasis is dependent on
compliance with therapy; thus, the treatment regimen chosen should fit the
patient's daily lifestyle. Newer single-dose regimens offer the option of
completing therapy with a single treatment for most patients with uncomplicated
vaginal candidiasis. Use of topical agents avoids the potential systemic adverse
effects and drug interactions that have been noted with oral antifungals. Patient
education and support can also enhance satisfaction with the treatment plan and
promote compliance.
PMID- 9560828
TI - Screening, diagnosis, and management of prostate cancer: improving primary care
outcomes.
AB - Prostate cancer (PC) resulted in more than 41,000 related deaths in 1996.
However, much confusion exists about when and whom to screen and treat for PC.
Guidelines opposing the early detection and treatment of PC are based on outcomes
from diagnoses and treatments made prior to recent improvements in screening and
treatment methods. More recently, prostate specific antigen has been shown to be
both specific and sensitive in detecting PC at an early, curable stage. Several
options for treating early PC now exist: anatomic radical prostatectomy, external
beam radiation, implanted radiation seeds, and cryotherapy. Informed primary care
providers have an opportunity to make individualized, rational decisions that
will promote better outcomes for men with PC.
PMID- 9560830
TI - A comprehensive approach to bereavement.
AB - Bereavement is associated with significant mental and physical health
consequences, and risk factors for illness associated with bereavement have been
demonstrated. Although bereavement cannot be eliminated as a health risk, primary
care providers can screen for it, facilitate the normal grief process, and
mitigate risks for bereavement complications and health deterioration.
Considering the time constraints in today's fast-paced health care environment,
this article offers a clear and comprehensive framework for primary care of
grieving people. The framework presented here includes (1) empirically shown risk
factors for health deterioration in bereavement; (2) an assessment and screening
patient history format suitable for primary bereavement care; (3) primary care
guidelines for differential diagnosis of bereavement; and (4) principles of
primary care for the bereaved. This article also addresses primary care for
bereaved children, parents, and other specific bereaved populations, and
discusses pharmacotherapy and multicultural considerations in bereavement.
PMID- 9560831
TI - Diagnosing pediatric epilepsy: an update for the primary care clinician.
AB - Epilepsy is a chronic disorder that first appears in childhood. Seizure types and
presentation vary from dramatic and obvious to subtle and discrete. Accurate
identification of the seizure type is imperative to ensure proper disease
management. The International league Against Epilepsy has developed two
classification systems--the classification of Epileptic Seizures and the
classification of Epilepsies and Epileptic Syndromes--to assist in the provision
of an International language of epilepsy, to improve the diagnosis and management
of seizures, and to establish prognostic criteria. Knowledge of the
classification systems of seizures, seizure types, and management of seizures is
essential in the delivery of health promotion, disease prevention, and
anticipatory guidance for the child with epilepsy. The primary care practitioner
is often the first person consulted when medical questions or problems arise, and
therefore is in a key position to detect seizures, monitor treatment, and educate
the family. A comprehensive knowledge of pediatric epilepsy will allow the
practitioner to provide the additional resources needed to coordinate the care of
this special population.
PMID- 9560832
TI - Low molecular weight heparins: the future of thromboembolic therapy.
PMID- 9560833
TI - Pathogenesis of preeclampsia: a comprehensive model.
AB - The objective of this review was to provide a comprehensive and practical concept
on the pathogenesis of preeclampsia on the basis of the currently available
scientific evidence. A MEDLINE search was performed of English-language articles
published between 1966 and 1997, supplemented with references cited in relevant
research articles. Using our data sources, we developed a scheme describing the
sequence of events between implantation and the time of manifest clinical disease
characterized by generalized endothelial cell dysfunction. A yet unidentified
toxic circulating factor released by the ischemic placenta, is held responsible
for the impaired endothelial cell function. Particularly, epidemiological studies
point to a concept in which immune maladaptation to the fetal allograft plays a
key role in causing defective placentation leading to placental ischaemia. The
incidence of preeclampsia in sisters and daughters of women who had had
preeclampsia is raised. Disease states with vascular involvement, like chronic
hypertension and diabetes mellites, are associated with an increased risk for
preeclampsia. Recently subclinical abnormalities in hemostasis, metabolism and
volume homeostasis have been described in patients with a history of
preeclampsia. Placental ischemia secondary to defective placentation, a
prerequisite for the development of preeclampsia, has a multifactorial origin
consisting of three major components: immune maladaptation, genetic
predisposition, and vascular mediated factors. Probably, a summation of these
factors will determine whether a pregnant woman is to develop the syndrome. The
recently described subclinical abnormalities in hemostasis, metabolism, and
vascular function in patients with a history of preeclampsia might give the
clinician the opportunity to reduce the recurrence risk by pharmacotherapeutic
intervention.
PMID- 9560834
TI - Granulosa and theca cell tumors in children: a report of 17 cases and literature
review.
AB - The files of the Emil Novak Ovarian Tumor Registry (ENOTR) were searched for
granulosa and theca cell tumors in children aged 12 years and less. In addition,
an extensive literature search was done for English publications on children with
these tumors aged 10 years or less. Of the 17 children from the ENOTR, 5 had
adult-type granulosa cell tumors, 6 had juvenile granulosa cell tumors, and 1 had
a luteinized granulosa cell tumor. In addition, there were three cases with
gonadal stomal tumors, one theca cell tumor, and one granulosa-theca cell tumor.
Precocious pseudopuberty was present in 70 percent of the children, abdominal
pain in 24 percent, and ascites in 18 percent. The literature review revealed a
tumor-related mortality rate of 9 percent (based on 163 cases with granulosa cell
tumors, including the juvenile type). Some of these tumors are large with acute
pain, but nevertheless, the prognosis is good, particularly in cases with
precocious puberty. Treatment can be conservative.
PMID- 9560835
TI - The genetics of ovarian cancer: molecular biology and clinical application.
AB - Ovarian cancer is the fifth most common malignancy among American women and the
fourth leading cause of cancer death. The rapid advances in molecular genetic
analysis, presymptomatic detection, and treatment of ovarian cancer are
staggering. In this review, both the genetic component and the molecular biology
of ovarian cancer are discussed, as well as current recommendations for genetic
counseling. It is important for the practicing obstetrician and gynecologist to
become familiar with these concepts, for it is he or she who will likely serve as
a primary resource of information for these patients.
PMID- 9560836
TI - New insights into steroid resistant asthma.
AB - The term "steroid resistant (SR) asthma" refers to a group of asthmatics who have
persistent airway obstruction and immune activation despite treatment with high
doses of systemic glucocorticoids. There are at least two forms of SR asthma,
i.e. primary and acquired types. Type I SR asthma is acquired and is associated
with abnormally reduced glucocorticoid receptor (GCR) ligand and DNA binding
affinity. Type II SR asthma appears to be due to a constitutive defect and is
associated with low numbers of GCRs. An important distinction between these two
types of SR asthma is that the GCR defect in Type I, but not Type II, SR asthma
is reversible in culture and is sustained by incubation with combination IL-2 and
IL-4. Recent studies suggest that the abnormal GCR binding in Type I SR asthma
may be due to cytokine-driven alternative splicing of the GCR pre-mRNA to a novel
isoform called GCRbeta which does not bind glucocorticoids but antagonizes the
transactivating activity of the classic GCR. These GCR changes along with recent
evidence for increased transcription factor activation in SR asthma which may
inhibit GCR/DNA interactions as well as the selective recruitment of neutrophils
into the airways of certain patients with severe asthma contribute to the
heterogeneity of mechanisms underlying steroid resistance.
PMID- 9560837
TI - Randomised controlled trial of advice on an egg exclusion diet in young children
with atopic eczema and sensitivity to eggs.
AB - BACKGROUND: The role of exclusion diets in the management of atopic eczema in
young children is uncertain. This randomised controlled trial evaluates the
effect of excluding egg from the diet in young children with atopic eczema and
sensitivity to eggs. Fifty-five such children were randomised either to a 4-week
regimen, in which mothers were given general advice on care of eczema and
additional specific advice from a dietician about an egg exclusion diet (diet
group), or to a control group in which general advice only was given. Both groups
continued conventional topical treatment. Disease activity was assessed by
estimates of the surface area affected by eczema and by an arbitrary severity
score. Possible egg sensitivity was identified by RAST before randomisation and
after the trial by double-blind placebo-controlled egg challenge. RESULTS: The
mean reduction in surface area affected by eczema was significantly greater (p =
0.02) in the group receiving dietary advice (from 19.6% to 10.9% area affected)
than in the control group (from 21.9% to 18.9%). A significant improvement also
occurred in severity score (p = 0.04): from 33.9 to 24.0 units for the diet group
compared with a decrease from 36.7 to 33.5 in the control group. The study
suggests that advice on the dietary exclusion of eggs is useful as part of the
overall management of young children with atopic eczema and sensitivity to eggs.
PMID- 9560839
TI - Concentrations of cat (Fel d1), dog (Can f1) and mite (Der f1 and Der p1)
allergens in the clothing and school environment of Swedish schoolchildren with
and without pets at home.
AB - To investigate whether our hypothesis that cat and dog owners bring allergens to
public areas in their clothes was true or not, we studied the levels of Fel d1,
Can f1, Der p1 and Der f1 in dust from the clothes and classrooms of children in
a Swedish school. We also investigated the levels of allergen in different areas
in the four classrooms used by the children. Thirty-one children were selected in
four classes, forming three groups: cat owners, dog owners and children without a
cat or dog at home. Furthermore, a group of children with asthma was included.
Cat and dog allergens were detected in all 57 samples from clothes and
classrooms. Mite allergen Der f1 was detected in low concentrations in 6 out of
48 and Der p1 in 5 out of 46 samples investigated. The concentrations of Can f1
were higher than those of Fel d1 in samples from clothes (geometric mean: 2676
ng/g fine dust and 444 ng/g) and classrooms (Can f1: 1092 ng/g, Fel d1: 240
ng/g). The dog owners had significantly higher concentrations of Can f1 (8434
ng/g fine dust) in their clothes than cat owners (1629 ng/g, p < 0.01), children
without cat or dog (2742 ng/g, p < 0.05) and children with asthma (1518 ng/g, p <
0001). The cat owners did not have significantly higher levels of Fel d1 (1105
ng/g) in their clothes compared to the other three groups. (D: 247 ng/g, nCnD:
418 ng/g) but the levels were significantly higher than for all children without
a cat at home (345 ng/g, p < 0.05). No concentrations of mite allergen and low
concentrations of Fel d1 and Can f1 were found in the children's hair. There were
significantly higher concentrations of Fel d1 and Can f1 in dust from curtains
than in samples from floors and bookshelves (p < 0.05). There was no significant
difference between the allergen concentrations in samples from curtains and from
desks and chairs, including the teachers' chairs, the only upholstered furniture
in the rooms. Our results support the hypothesis that cat and dog owners bring
allergens to public areas in their clothes and support other studies showing that
textiles and upholstered furniture function as reservoirs of cat and dog
allergens. Thus, children with asthma and other allergic diseases will be exposed
to cat and dog allergens at school and by contact with pet owners, even if they
avoid animal allergens at home.
PMID- 9560838
TI - Time course of changes in the intestinal permeability of food-sensitized rats
after oral allergen challenge.
AB - Rats were sensitized with ovalbumin (OVA) with a molecular weight of 45 kd,
challenged with OVA orally, followed by orally administered beta-lactoglobulin
(BLG) as an intestinal permeability marker. BLG is a macro-molecular protein with
a molecular weight of 18 kd. Blood BLG concentrations were measured (by ELISA)
serially over 4 hours following BLG administration, which in turn was given 1
hour after OVA challenges. The maximum BLG concentration was at 2 hours. BLG was
then administered orally 1, 3, 6, 12 and 24 hours after oral OVA challenge, and
the serum BLG concentration at 2 hours after BLG administration was compared
among the five groups. BLG appeared in the circulation of the animals 1, 6 and 24
hours after allergen challenge, but not after 3 and 12 hours. The serum BLG
concentration was not significantly different at 1, 6 and 24 hours.
Histopathological examinations of the intestines showed mast cell infiltration of
the intestinal mucosa at 1 hour, remarkable edema of villi at 3 hours, eosinophil
infiltration at 6 hours, an increase of goblet cells at 12 hours and villous
atrophy and lymphocyte infiltration at 24 hours. The appearance in the serum of
three BLG peaks of comparable heights suggested that the intestinal absorption of
BLG may be related to a late and delayed phase as well as the immediate IgE
dependent phase response.
PMID- 9560840
TI - Cat and dog allergen in mattresses and textile covered floors of homes which do
or do not have pets, either in the past or currently.
AB - The aim of this study was to measure the levels of cat and dog allergen in homes
of families that had either never kept pets or kept or had kept cats or dogs.
From a small residential area outside Stockholm consisting of 250 houses with
similar exteriors 70 homes were included. Dust samples were collected from
mattresses and textile-covered floors. The levels of cat and dog allergen were
analysed by ELISA. Fel d1 was found in mattress dust in all 70 homes, median 0.5
micrograms/g [0.24-8.89 micrograms/g (quartiles)] and textile-covered floors 0.7
micrograms/g (0.20-2.52 micrograms/g). Can f1, was found in 98% of the collected
samples, mattress dust 1.89 micrograms/g (0.70-9.20 micrograms/g) and textile
covered floor dust 2.5 micrograms/g (1.04-2.72 micrograms/g). There was a
positive correlation (p < 0.001) between allergen levels in dust from mattresses
and textile-covered floors for both Fel d1 (r = 0.68) and Can f1 (r = 0.78). The
highest levels of cat and dog allergen were found in homes with furred pets (p <
0.001). A significant (p < 0.001) difference was seen in the levels of Fel d1 and
Can f1 between the homes of former pet-owners and homes without pets. In summary;
cat and dog allergens are present in homes regardless of whether such animals
live in the house or not. Mattresses seem to be an underestimated reservoir for
pet allergens even in homes without pets. It is important to note that the homes
of former pet owners have much lower levels of allergen than current pet owners.
PMID- 9560841
TI - Development of latex allergy in children up to 5 years of age--a retrospective
analysis of risk factors.
AB - The aim of the study was to investigate possible associations between the time
course of early sensitization to latex and various life style factors. Of the 398
children from a prospective birth cohort study, 20 (5%) showed specific serum IgE
to latex at the age of 5 years. Sensitization started beyond the first year of
life and 19 out of 20 sensitized children showed increasing specific IgE-values
over time. All 20 sensitized children were atopic (p < 0.00000). Total IgE was
significantly higher in the sensitized group (median 394.5 kU/I) than in the non
sensitized group (median 39.2 kU/l) (p < 0.00001). Comparing the latex-sensitized
group with the non-sensitized children, there were significantly more operations
in the latex group (p < 0.05) during the first 5 years of life. Medical history,
certain foods, the use of pacifiers, mattress composition and socio-economic data
proved not to be significant risk factors. From our study we conclude that
besides the number of operations and an atopic predisposition--no other definite
risk factor for developing sensitization or allergy to latex (such as everyday
household objects) can be identified in children up to 5 years of age.
PMID- 9560842
TI - Longitudinal study on latex sensitization in children with spina bifida.
AB - The course of latex sensitization is rarely documented, and only a few reports
about the influence of prophylaxis in the occupational environment have been
published concerning health care workers. Therefore we did a follow-up study in
the high risk group of patients with spina bifida and evaluated the efficacy of
latex prophylaxis. For this purpose we measured IgE antibodies (FEIA) against
latex and inhalative allergens in the sera of 67 patients with spina bifida and
reevaluated them 0.6 to 4.1 years later, having instructed the patients about
prophylactic measures and established a latex-free environment for surgery of all
spina bifida patients in our hospital. 37% of the patients did not develop latex
antibodies during the follow-up period, 27% showed decreasing levels of
antibodies (12% to non-detectable levels), 19% had an increase in latex
sensitization (6% newly sensitized), and 9% showed no change in levels of latex
antibodies. From our data it may be concluded that surgery without strict latex
prophylaxis is the main cause of new sensitization and worsening of preexisting
latex antibody levels. Mild sensitization can be reduced by prophylactic
measurements to non-detectable antibody levels. With consistent prophylaxis, even
symptomatic patients can be operated without risk of allergic complications or
increasing antibodies.
PMID- 9560843
TI - Lymphocyte subset reference ranges in healthy Saudi Arabian children.
AB - In an attempt to establish the reference ranges for lymphocyte subsets in
children, the distribution of lymphocyte population-bearing surface markers such
as CD3 (T cells), CD19 (B cells), CD4 (T helper/inducer cells), CD8 (T
suppressor/cytotoxic cells), and CD16 and/or CD56 on CD3- cells (NK cells) has
been studied among healthy Saudi Arabian infants and children. Normal adult blood
donors were used for comparison. Anticoagulated peripheral blood was stained with
monoclonal antibodies and the lymphocytes were analyzed by flow cytometry for the
expression of the above markers. Absolute and percentage values for most
lymphocyte populations differed substantially not only between children and
adults but also among children from different age groups. Absolute numbers of all
the lymphocyte subsets decreased with age from 1 month to 13 years; the median
value declined from 4.1 to 1.9 (T cells), 1.6 to 0.6 (B cells), 0.5 to 0.3 (NK
cells), 2.7 to 1.0 (CD4+ T cells) and 1.5 to 0.8 x 10(3) cells/mm3 (CD8+ T
cells). HLA-DR+ T cell counts changed significantly from 0.3 to 0.2 x 10 (3)
cells/mm3 during the same age period. In contrast, the lymphocyte percentage
increased in all the subsets except B cells and CD4+ T cells with time. The
percentage values increased from 66 to 74 (T cells), 8 to 11 (NK cells), 23 to 39
(CD8+ T cells) and 4 to 9 (HLA-DR+ T cells). The values changed from 24 to 12 and
46 to 39 for B cells and CD4+ T cells, respectively, with age from 1 month to 13
years. The variations in CD4+ and CD8+ T cells resulted in a decrease in
CD4+/CD8+ ratio from 2.0 to 1.1 with age. These data should be useful as
reference values for lymphocyte subsets in various diseases of infants and
children.
PMID- 9560844
TI - Thymoma and cellular immune deficiency in an adolescent.
AB - Thymoma has been associated with both humoral immunodeficiency and cellular
immunodeficiency, but the latter association has never been described in the
pediatric age group. We report a 15-year-old female with thymoma, recalcitrant
oropharyngeal candidiasis, recurrent generalized cutaneous herpes simplex virus
type 2 infection, recurrent pneumonia and myasthenia gravis. Pathology of the
thymic lesion showed a 10x5x6 cm extensively hyalinized mass with residual
regions of spindle cell predominant and lymphocyte-rich thymoma. There was no
evidence of humoral immunodeficiency but there was clinical and laboratory
evidence of cellular immunodeficiency with cutaneous anergy and absence of T cell
proliferation to Candida antigen. Six weeks after the thymoma was resected, she
was no longer anergic and Candida proliferation was normal, although she
continued to experience infections. This is the first reported pediatric patient
with an association of cellular immunodeficiency with thymoma.
PMID- 9560845
TI - Pathology of idiopathic dystonia: findings from genetic animal models.
AB - Dystonia is a common movement disorder which is thought to represent a disease of
the basal ganglia. However, the pathogenesis of the idiopathic dystonias, i.e.
the neuroanatomic and neurochemical basis, is still a mystery. Research in
dystonia is complicated by the existence of various phenotypic and genotypic
subtypes of idiopathic dystonia, probably related to heterogeneous dysfunctions.
In neurological diseases in which no obvious neuronal degeneration can be found,
such as in idiopathic dystonia, the identification of a primary defect is
difficult, because of the large number of chemically distinct, but functionally
interrelated, neurotransmitter systems in the brain. The variable response to
pharmacological agents in patients with idiopathic dystonia supports the notion
that the underlying biochemical dysfunctions vary in the subtypes of idiopathic
dystonia. Hence, in basic research it is important to clearly define the involved
type of dystonia. Animal models of dystonias were described as limited. However,
over the last years, there has been considerable progress in the evaluation of
animal models for different types of dystonia. Apart from animal models of
symptomatic dystonia, genetic animal models with inherited dystonia which occurs
in the absence of pathomorphological alterations in brain and spinal cord are
describe. This review will focus mainly on genetic animal models of different
idiopathic dystonias and pathophysiological findings. In particular, in the case
of the mutant dystonic (dt) rat, a model of generalized dystonia, and in the case
of the genetically dystonic hamster (dt(sz)), a model of paroxysmal dystonic
choreoathetosis has been used, as these show great promise in contributing to the
identification of underlying mechanisms in idiopathic dystonias, although even a
proper animal model will probably never be equivalent to a human disease. Several
pathophysiological findings from animal models are in line with clinical
observations in dystonic patients, indicating abnormalities not only in the basal
ganglia and thalamic nuclei, but also in the cerebellum and brainstem. Through
clinical studies and neurochemical data several similarities were found in the
genetic animal models, although the current data indicates different defects in
dystonic animals which is consistent with the notion that dystonia is a
heterogenous disorder. Different supraspinal dysfunctions appear to lead to
manifestation of dystonic movements and postures. In addition to increasing our
understanding of the pathophysiology of idiopathic dystonia, animal models may
help to improve therapeutic strategies for this movement disorder.
PMID- 9560846
TI - The role of excitatory amino acids in behavioral sensitization to psychomotor
stimulants.
AB - Behavioral sensitization refers to the progressive augmentation of behavioral
responses to psychomotor stimulants that develops during their repeated
administration and persists even after long periods of withdrawal. It provides an
animal model for the intensification of drug craving believed to underlie
addiction in humans. Mechanistic similarities between sensitization and other
forms of neuronal plasticity were first suggested on the basis of the ability of
N-methyl-D-aspartate (NMDA) receptor antagonists to prevent the development of
sensitization [Karler, R., Calder, L. D., Chaudhry, I. A. and Turkanis, S. A.
(1989) Blockade of "reverse tolerance" to cocaine and amphetamine by MK-801. Life
Sci., 45, 599-606]. This article will review the large number of subsequent
studies addressing: (1) the roles of NMDA, alpha-amino-3-hydroxy-5-methyl-4
isoxazole propionate (AMPA) and metabotropic glutamate receptors in the
development and expression of behavioral sensitization, (2) excitatory amino
acids (EAAs) and the role of conditioning in sensitization, (3) controversies
regarding EAA involvement in behavioral sensitization based on studies with MK
801, (4) the effects of acute and repeated stimulant administration on EAA
neurochemistry and EAA receptor expression, and (5) the neuroanatomy of EAA
involvement in sensitization. To summarize, NMDA, AMPA metabotropic glutamate
receptors all participate in the development of sensitization, while maintenance
of the sensitized state involves alterations in neurochemical measures of EAA
transmission as well as in the expression and sensitivity of AMPA and NMDA
receptors. While behavioral sensitization likely involves complex neuronal
circuits, with EAAs participating at several points within this circuitry, EAA
projections originating in prefrontal cortex may play a particularly important
role in the development of sensitization, perhaps via their regulatory effects on
midbrain dopamine neurons. The review concludes by critically evaluating various
hypotheses to account for EAA involvement in the development of behavioral
sensitization, and considering the question of whether EAA receptors are involved
in mediating the rewarding effects of psychomotor stimulants and sensitization of
such rewarding effects.
PMID- 9560847
TI - Pharmacology of glutamate receptor antagonists in the kindling model of epilepsy.
AB - It is widely accepted that excitatory amino acid transmitters such as glutamate
are involved in the initiation of seizures and their propagation. Most attention
has been directed to synapses using NMDA receptors, but more recent evidence
indicates potential roles for ionotropic non-NMDA (AMPA/kainate) and metabotropic
glutamate receptors as well. Based on the role of glutamate in the development
and expression of seizures, antagonism of glutamate receptors has long been
thought to provide a rational strategy in the search for new, effective
anticonvulsant drugs. Furthermore, because glutamate receptor antagonists,
particularly those acting on NMDA receptors, protect effectively in the induction
of kindling, it was suggested that they may have utility in epilepsy prophylaxis,
for example, after head trauma. However, first clinical trials with competitive
and uncompetitive NMDA receptor antagonists in patients with partial (focal)
seizures, showed that these drugs lack convincing anticonvulsant activity but
induce severe neurotoxic adverse effects in doses which were well tolerated in
healthy volunteers. Interestingly, the only animal model which predicted the
unfavorable clinical activity of competitive NMDA antagonists in patients with
chronic epilepsy was the kindling model of temporal lobe epilepsy, indicating
that this model should be used in the search for more effective and less toxic
glutamate receptor antagonists. In this review, results from a large series of
experiments on different categories of glutamate receptor antagonists in fully
kindled rats are summarized and discussed. NMDA antagonists, irrespective whether
they are competitive, high- or low-affinity uncompetitive, glycine site or
polyamine site antagonists, do not counteract focal seizure activity and only
weakly, if at all, attenuate propagation to secondarily generalized seizures in
this model, indicating that once kindling is established, NMDA receptors are not
critical for the expression of fully kindled seizures. In contrast, ionotropic
non-NMDA receptor antagonists exert potent anticonvulsant effects on both
initiation and propagation of kindled seizures. This effect can be markedly
potentiated by combination with low doses of NMDA antagonists, suggesting that an
optimal treatment of focal and secondarily generalized seizures may require
combined use of both non-NMDA and NMDA antagonists. Given the promising results
obtained with novel AMPA/kainate antagonists and glycine/NMDA partial agonists in
the kindling model, the hope for soon having potentially useful glutamate
antagonists for use in epileptic patients is increasing.
PMID- 9560848
TI - An international look at adolescent health promotion.
PMID- 9560849
TI - [The measure of the quality of life of adolescents: a new evaluation tool of
their health needs for a new educational approach?].
AB - Hundreds of studies carried out in the past 20 years have worked on youth and
adolescent health indicators linked to general morbidity and mortality and to
specific pathologies. The majority of research has focused on evaluating the
impact of risk behaviours such as tobacco, alcohol and drug use, non-protected
sexual intercourse, and unbalanced nutrition on the health of youth. The
usefulness of medical care and health education programmes has thus traditionally
been evaluated on the basis of their impact on mortality and morbidity. However,
these measures have proven insufficient and the necessity to pay more attention
to quality, and not only length of life is now apparent. This article focuses on
the question of whether the tool for measuring quality of life linked to health,
adapted from what now exists for "sick" adolescents, can constitute a new
indicator allowing for evaluation of the unknown realm of adolescent health
needs. The authors address the concept of measuring the quality of life by
providing several of its definitions, noting the difficulties and insufficiencies
of their measurement. The authors also wonder why the multiple professionals
preoccupied with adolescent health have not yet imagined using a participative
approach to developing these measures, i.e. an approach including the adolescents
themselves, has not been used. The authors propose that to include adolescents in
the development of evaluation tools would ensure that the adolescent's needs for
expression and to be heard are fulfilled. The authors also maintain that
education, both health and general, should enable individuals to understand what
is positive within themselves, and thus develop these aspects to their fullest.
It should not force models of behaviour onto individuals or groups. If this
approach is taken in developing quality of life indicators for young people, a
positive health promotion approach to enabling adolescents can be developed.
PMID- 9560850
TI - Indicators of adolescent health: expanding the framework for assessing health
status among young people.
PMID- 9560851
TI - Community perceptions regarding critical adolescent sexual and reproductive
health: needs and solutions.
PMID- 9560852
TI - An investigation of adolescent health in Vietnam: sexual behaviour and attitudes
of adolescents.
PMID- 9560853
TI - Using the Internet to engage youth in health promotion.
PMID- 9560854
TI - [Promotion of orodental health in adolescents in Africa].
AB - Bad dental hygiene in adults is usually the result of bad care during childhood.
Within the framework of Health for All, WHO and the International Dental
Federation defined global objectives for dental health which allow for monitoring
progress in different countries. The most common dental problems, such as dental
cavities, can be prevented by simple and inexpensive methods. Dental health is
based on dental hygiene, nutrition, fluoride intake and dental service
utilisation. Dental health promotion aims to create an environment favourable to
the adoption of these healthy behaviours. The principle recommended dental health
measures are through fluoridation of water, salt, and milk, a low consumption of
sweets, and modification of the amount of sugar in the diet; implementation of
monitored dental hygiene activities in schools; the organisation of regular
dental services in schools/workplaces; and adopting legislative texts or laws
requiring certain measures of prevention. In the past several years, certain
African countries have set up national dental health programmes (there were 12 in
1993), However, the implementation of dental health promotion generally doesn't
result from a national initiative, but from a regional or local scale. This is
largely due to the lack of integration of dental health in activities of
education and health promotion in general. Programmes planned at a national level
and then implemented at a local level on a multisectoral base have had more
success. This article presents examples of dental health promotion activities in
several African countries, mainly focusing on programmes aimed at 12-13 year olds
in primary school. Programmes from Morocco, Kenya, Madagascar, Cote d'Ivoire,
Benin, and Tanzania are briefly presented and show that in Africa, dental health
promotion has mostly consisted of the implementation of health education actions
and that there are no consistent policies, unlike in other developing countries,
for fluoridation of water, salt, and milk. In terms of dental health promotion,
WHO recommends the promotion of traditional methods of dental hygiene (such as
plants or sticks for cleaning), especially among adolescents living in rural and
low income communities. In turn, the identification and promotion of the positive
aspects of hygiene and traditional care will allow for the implementation of more
culturally acceptable approaches.
PMID- 9560855
TI - [Health promotion in adolescents in Latin America].
AB - The First International Conference on Health Promotion (Ottawa 1996) consolidated
and developed the interest of Latin American countries in the amelioration of the
health of their populations. Initiatives such as the International Conference for
Health Promotion in Columbia in 1992 and the adoption in 1993 of the Caribbean
Charter for Health Promotion show the efforts that have been carried out by
different American countries to work toward the principles of the Ottawa Charter
and to adapt them to their realities. This article focuses on the state of health
of adolescents in Latin America as well as different actions that have been, and
continue to be, carried out. The authors first discuss the peer approach to
health education, which has been used in many health promotion actions throughout
Latin America because of its effectiveness. Often in developing countries, the
oldest children care for the younger ones. This approach therefore provides a way
to reach not only peers of the adolescent involved, but also other youth in
his/her entourage. Also, the participation of youth in health education allows
them to develop relations with adults outside of their families, to improve their
self-perceptions and to acquire a sense of responsibility and belonging within a
social group. Examples from several countries are provided by the authors. What
the authors call "classic" approaches to health promotion and education are also
still used in many countries of Latin America and many of these programmes are
concerned with sexual education and managing adolescent parenthood. Also,
programmes using in approach specific to problems such as alcoholism, drug abuse,
and violence have been developed in many countries. Finally, training programmes
for health personnel focusing on the specific health needs of adolescents have
been developed in Brazil, Peru, Costa Rica, and Uruguay for a large range of
health professionals (psychologists, social workers, etc.). In conclusion, the
authors state that although there is an increasing number of health promotion
actions for adolescents in Latin America, there is still much work to be done.
One of the elements that is priority for managing the health of adolescents is
the integral approach of the adolescent, considering the psychological, social,
and environmental factors that influence his/her well-being. Multi-disciplinary
and intersectoral approaches are also considered as important, as is the
participation of adolescents in the development and implementation of actions
concerning them.
PMID- 9560856
TI - Frameworks to inform the development of U.S. adolescent health indicators for the
21st century.
PMID- 9560857
TI - Adolescent health today: contributions and limitations of epidemiology, facts,
doubts and uncertainties.
PMID- 9560858
TI - Improving the health of youth through a coordinated school health programme.
PMID- 9560859
TI - Lessons derived from evaluating Gulf War syndrome: suggested guidelines for
investigating possible outbreaks of new diseases.
PMID- 9560860
TI - Reducing the need and demand for medical services.
PMID- 9560862
TI - Gender differences in the reporting of physical and somatoform symptoms.
AB - OBJECTIVE: Women have consistently been shown to report greater numbers of
physical symptoms. Our aim in this study was to assess gender differences for
specific symptoms and to assess how much of these differences were attributable
to psychiatric comorbidity. METHOD: Data from the PRIME-MD 1000 study (1000
patients from four primary case sites evaluated with the Primary Care Evaluation
of Mental Disorders interview) were analyzed to determine gender differences in
the reporting of 13 common physical symptoms. The effect of gender on symptom
reporting was assessed by multivariate analysis, adjusting for depressive and
anxiety disorders as well as age, race, education, and medical comorbidity.
RESULTS: All symptoms except one were reported more commonly by women, with the
adjusted odds ratios (typically in the 1.5-2.5 range) showing statistically
significant differences for 10 of 13 symptoms. Somatoform (ie, physically
unexplained) symptoms were also more frequent in women. Although depressive and
anxiety disorders were the strongest correlate of symptom reporting, gender had
an independent effect that persisted even after adjusting for psychiatric
comorbidity. Gender was the most important demographic factor associated with
symptom reporting, followed by education. CONCLUSIONS: Most physical symptoms are
typically reported at least 50% more often by women than by men. Although mental
disorders are also more prevalent in women, gender influences symptom reporting
in patients whether or not there is psychiatric comorbidity.
PMID- 9560861
TI - Treatment costs, cost offset, and cost-effectiveness of collaborative management
of depression.
AB - OBJECTIVE: The report estimates the treatment costs, cost-offset effects, and
cost-effectiveness of Collaborative Care of depressive illness in primary care.
STUDY DESIGN: Treatment costs, cost-offset effects, and cost-effectiveness were
assessed in two randomized, controlled trials. In the first randomized trail (N =
217), consulting psychiatrists provide enhanced management of pharmacotherapy and
brief psychoeducational interventions to enhance adherence. In the second
randomized trial (N = 153). Collaborative Care was implemented through brief
cognitive-behavioral therapy and enhanced patient education. Consulting
psychologist provided brief psychotherapy supplemented by educational materials
and enhanced pharmacotherapy management. RESULTS: Collaborative Care increased
the costs of treating depression largely because of the extra visits required to
provide the interventions. There was a modest cost offset due to reduced use of
specialty mental health services among Collaborative Care patients, but costs of
ambulatory medical care services did not differ significantly between the
intervention and control groups. Among patients with major depression there was a
modest increase in cost-effectiveness. The cost per patient successfully treated
was lower for Collaborative Care than for Usual Care patients. For patients with
minor depression. Collaborative Care was more costly and not more cost-effective
than Usual Care. CONCLUSIONS: Collaborative Care increased depression treatment
costs and improved the cost-effectiveness of treatment for patients with major
depression. A cost offset in specialty mental health costs, but not medical care
costs, was observed. Collaborative Care may provide a means of increasing the
value of treatment services for major depression.
PMID- 9560863
TI - The stability of family decisions to consent or refuse organ donation: would you
do it again?
AB - OBJECTIVE: Past organ donation research has studied attitudes toward donation,
predictors of signing donor cards, and distinguishing characteristics of donors
vs. nondonors. The current study is the first to examine predictors of family
members' satisfaction with the decision to consent or refuse donation of a dying
loved one's organs or tissue. METHOD: This study surveyed 225 family members who
had been approached to donate the organs or tissue of a dying loved one.
Participants were surveyed about demographic characteristics, medical/hospital
factors, previous knowledge of transplantation, the request process, religion,
and characteristics of the deceased and of the recipient. Discriminant analyses
were conducted to characterise four specific groups: a) donors who would donate
again; b) donors who would not donate again; c) nondonors who would now donate;
and d) nondonors who still would not donate. RESULTS: Three significant
discriminant functions emerged discriminating donors from nondonors, those who
were satisfied with their decision from those who were not, and people who would
now donate from those who would not. Donation was predicated by formal education,
being married, volunteerism, signing donor cards, and having personal
conversations about donation. Subsequent satisfaction was predicted by comfort
and confidence during the decision-making process, familiarity with medical
center, and understanding of brain death. A willingness to now donate was
predicted by personal discussions about donation. CONCLUSIONS: People should be
encouraged not only to sign donor cards, but to have discussions with family
about wishes. Individuals should be encouraged to seek the help of family and
friends during the decision, and be aware of the need of social support from
family and friends during and after the decision.
PMID- 9560864
TI - A comparison of related and unrelated marrow donors.
AB - OBJECTIVE: The purpose of this investigation is to test whether related bone
marrow donors experience more distress from marrow donation than volunteer
unrelated donors. METHOD: Participants in the study were 77 related and unrelated
marrow donors who agreed to complete 11 pre- and 8 postdonation self report
questionnaires. Related and unrelated donors were recruited from the Bone Marrow
Transplant Programs at the Brigham and Women's Hospital and the Massachusetts
General Hospital in Boston, MA. Additional unrelated donors were recruited from
the American Red Cross-Carolinas and the Heart of America Bone Marrow Donor
Registry in Kansas City, MO. RESULTS: The 41 unrelated and 36 related marrow
donors who participated in this prospective study had similar demographic
backgrounds and predonation questionnaire results, although related donors
endorsed more items on the Beck Depression Inventory, both before and after
narrow harvesting. After narrow donation, related donors reported significantly
more pain than unrelated donors (p = .0001). CONCLUSIONS: It is unlikely that
intraoperative events alone could account for the increased pain experienced by
related donors. Related donors were more likely to experience moderate to severe
physical pain after marrow donation than unrelated donors, on the basis of
logistic regression analysis (odds ratio = 7.63; 95% confidence interval 2.74,
23.01).
PMID- 9560865
TI - Concern about aspects of body image and adjustment to early stage breast cancer.
AB - OBJECTIVE: Several authors have suggested that patients adjust more poorly to
breast cancer if they are heavily invested in body image as a source of their
sense of self-worth. This prospective study examined this possibility, looking at
two aspects of concern about body image as predictors of several indices of
adjustment over the first postoperative year. METHODS: At diagnosis (and again a
year later) 66 women with early stage breast cancer reported how much they valued
a) a sense of body integrity (or intactness) and b) a good physical appearance.
The day before surgery, a week afterward, and at 3-month, 6-month, and 12-month
follow ups, they reported on their mood. At presurgery and at follow ups they
also rated their attractiveness and sexual desirability and reported on frequency
of sexual interaction. At follow-ups they also indicated how much their illness
and treatment were interfering with social and recreational activities. RESULTS:
Initial investment in appearance was related to distress across the postsurgical
year. In contrast, investment in appearance made women more resilient against
deterioration in their perceptions of attractiveness. Concern about body
integrity did not strongly predict emotional distress, but it related to adverse
impact on social and recreational activities in the follow-up period, to
deterioration in feelings of sexual desirability, and to feelings of alienation
from the self (feeling "not like yourself anymore"). CONCLUSIONS: Body image is
often thought of in terms of physical appearance, but there is also a body image
pertaining to integrity, wholeness, and normal functioning. People who are
greatly concerned about either aspect of their body image are vulnerable to
poorer psychosocial adjustment when confronting treatment for breast cancer. The
poorer adjustment takes a different form, however, depending on the nature of the
patient's body-image concern.
PMID- 9560866
TI - How multiple types of stressors impact on health.
AB - OBJECTIVE: Although many studies have focused on the relationship between stress
and health, few have examined the impact of multiple types of stressors. The
current study investigated the health impact of four stressors: sexual and
physical abuse history, lifetime losses and traumas, turmoil in childhood family,
and recent stressful life events. METHOD: The sample included 239 female patients
from a referral-based gastroenterology clinic. RESULTS: We found that the four
stressors (abuse history, lifetime traumas, turmoil in childhood family, and
recent stressful life events) were related to poor health status (eg, more pain,
symptoms, bed disability days, physician visits, functional disability, and
psychological distress); together, these stressors accounted for 32% of the
variance in overall current health. Furthermore, women who scored high on one
type of stressor also tended to have experienced other types. Unlike many
previous studies, we did not find that social support buffered the effects of
stress. CONCLUSIONS: This study provides evidence that many different types of
stressors independently contribute to poor health outcome. Such findings suggest
that health practitioners and researchers should question patients about
histories of traumatic events, in addition to the examination of the biological
aspects of illness, inasmuch as both may have notable effects on health status.
PMID- 9560867
TI - Stressful life events and smoking were associated with Graves' disease in women,
but not in men.
AB - OBJECTIVE: Although psychological stress and smoking have been proposed as
contributing factors to Graves' disease, their independent roles in the
pathogenesis of this disease have not been determined. We assessed the
association between Graves' disease and psychological stress and smoking by using
multivariate analysis. METHODS: By a matched case-control method, we investigated
the association between Graves' disease and stressful life events, daily hassles,
smoking, drinking habits, coping skills, and social support in 228 patients (182
women and 46 men) with newly diagnosed Graves' disease; we used the conditional
maximum likelihood method. RESULTS: After data were adjusted for daily hassles,
smoking, drinking habits, social support, and coping skills, we found that
stressful life events were significantly associated with the risk of Graves'
disease in women. The relative risk was 7.7 for women with the highest stress
score compared with women with the lowest stress score (95% confidence interval,
2.2 to 27, p for trend < .001). Smoking was also independently associated with
the risk of Graves' disease in women. The relative risk for women with the
highest number group compared with women with the lowest number group for smoking
cigarettes was 5.1 (95% confidence interval, 1.0 to 27; p for trend < .001).
These factors were not significantly associated with Graves' disease in men.
CONCLUSIONS: Psychological stress and smoking were associated with Graves'
disease in women, but not in men.
PMID- 9560869
TI - Obsessionality in anorexia nervosa: the moderating influence of exercise.
AB - OBJECTIVE: Research has confirmed substantial links between OCD and AN. Not only
are there psychopathological similarities between the two syndromes, but a marked
neurochemical correspondence. Extensive exercising is a common feature of AN and
also has relevance in its links with OCD. There is evidence from the exercise
induced weight-loss syndrome in animals that exercise and caloric restriction, in
combination, tend to increase serotonergic activity in a synergistic manner. This
syndrome has been proposed as a valid model of OCD as well as for AN. To date,
little research has directly tested this theory in the human condition. METHOD:
Fifty-three AN patients were categorized as high-level exercisers (N = 22) or
moderate/nonexercisers (N = 31) based on the frequency of their physical activity
over the year before assessment. RESULTS: Exercisers scored significantly higher
on a measure of OC personality characteristics, OC symptomatology, and
perfectionism--a personality factor associated with the development of Obsessive
Compulsive Personality Disorder. On the other hand, there were no group
differences on other salient eating disorder characteristics such as body esteem,
self-esteem, or weight preoccupation. There were also no differences in degree of
emaciation as indicated by Body Mass Index. CONCLUSIONS: Findings suggest that
among AN patients obsessional personality characteristics are linked to high
level exercising, and that exercising is associated with a greater degree of OC
symptomatology. Results are discussed in the context of current theories of AN,
OCD, and some biological mechanisms.
PMID- 9560868
TI - Cardiovascular reactivity to video game predicts subsequent blood pressure
increases in young men: The CARDIA study.
AB - OBJECTIVE: This study was undertaken to determine the relationship between
heightened reactivity of blood pressure (BP) during stress and 5-year changes in
blood pressure and hypertensive status, using the CARDIA study. METHOD: A total
of 3364 participants (910 white men, 909 white women, 678 black men, and 867
black women), initially 20 to 32 years old and normotensive, were included.
Cardiovascular reactivity to psychological stressors (video game and star-tracing
tasks for 3 minutes, cold pressor test for 1 minute) was measured in 1987-1988.
We then examined reactivity as a predictor of significant BP change (> or = 8 mm
Hg, thought to represent a clinically significant increase) over the next 5
years. Logistic regression models were used to control for potential covariates.
Significant BP change and the development of hypertension (BP greater than 140/90
or taking medication for hypertension) over the 5-year follow-up were examined in
separate analyses. RESULTS: Increased systolic blood pressure (SBP) reactivity to
the video game was associated with a significant 5-year SBP increase among the
entire cohort, independent of resting SBP (p < .0001). Subsequent analyses showed
that this relationship held for men but not for women. Reactivity to the star
tracing task or the cold pressor test did not predict significant BP change.
Among black men only, new hypertensives (N = 36) had greater diastolic blood
pressure (DBP) reactivity to the video game (p = .01). CONCLUSIONS: Although BP
reactivity to all physical and mental stressors used in this study did not
consistently predict 5-year change in BP in this young cohort, the results
indicate that reactivity to a video game stressor predicts 5-year change in BP
and early hypertension among young adult men. These findings are consistent with
other studies showing the usefulness of stressors producing a primarily beta
adrenergic response in predicting BP change and hypertension. The results may be
limited by the shortened initial rest and recovery periods used in the CARDIA
protocol.
PMID- 9560871
TI - Changes in cognitive coping skills and social support during cognitive behavioral
stress management intervention and distress outcomes in symptomatic human
immunodeficiency virus (HIV)-seropositive gay men.
AB - OBJECTIVE: We have previously reported decreases in dysphoria, anxiety, and total
mood disturbance in symptomatic HIV seropositive gay men after a 10-week
cognitive behavioral stress management (CBSM) group intervention. This structured
intervention was designed a) to increase cognitive and behavioral coping skills
related to managing the distress of symptomatic HIV, and b) to increase social
support among group members. Here we examine the relative contribution of changes
in coping skills and social support during the intervention period to reductions
in dysphoria, anxiety, and distress-related symptoms in this sample. METHODS:
Participants were randomized to a 10-week CBSM group intervention or to a wait
list control condition. Coping, social supports, and mood were measured before
and after the intervention period. RESULTS: Members of the CBSM group (N = 22)
showed significant improvement in cognitive coping strategies involving positive
reframing and acceptance, and in social supports involving attachment, alliances,
and guidance at the end of the 10-week CBSM program compared with controls (N =
18) who showed decrements in these coping abilities and no changes in social
support. Improved cognitive coping, specifically acceptance of the HIV infection,
was strongly related to lower dysphoria, anxiety, and total mood disturbance in
both conditions. Changes in social support and in cognitive coping skills seem to
mediate the effects of the experimental condition on the changes in distress
noted during the intervention. CONCLUSIONS: These results suggest that cognitive
coping and social support factors can be modified by psychosocial interventions
and may be important determinants of the changes in psychological well-being and
quality of life during symptomatic HIV infection that can be achieved through
this form of intervention.
PMID- 9560870
TI - Elevated levels of psychophysiological arousal and cortisol in patients with
somatization syndrome.
AB - OBJECTIVE: This study investigates psychological and psychobiological processes
in patients with somatization syndrome. METHOD: We compared physiological
measures (heart rate, finger pulse volume, electrodermal activity,
electromyography), cortisol levels, and subjective well-being during rest and
during a mental stress task as well as selective attention and memory for illness
related words in 58 patients with somatization syndrome and 21 healthy controls.
RESULTS: The somatization group had higher morning salivary cortisol
concentrations, higher heart rates, and lower levels of finger pulse volume.
During the mental stress task, patients with somatization syndrome felt more
distressed and had higher heart rates, whereas controls showed habituation to the
experimental situation. We were unable to demonstrate an attention or memory bias
specific for somatization. CONCLUSIONS: The results point to several
psychological, psychophysiological, and psychobiological mechanisms that might be
involved in the maintenance of somatization syndrome. These results are discussed
from a cognitive-psychobiological perspective.
PMID- 9560872
TI - Depressive symptoms as an underlying factor of the sensation of dry mouth.
AB - OBJECTIVE: The purpose of this survey was to study the sensation of oral dryness
and its underlying factors in the 55-year-old population of Oulu (a medium-sized
Finnish town), 780 of whom (77%) participated. METHOD: In addition to the
examination of oral health status and salivary flow rate measurements, depressive
symptoms were determined on the basis of the Zung Self-Rating Depression Scale
(ZSDS). The participants were also interviewed about their health, medication,
physical health, physical activity, smoking habits, alcohol consumption, and
factors related to their work. RESULTS: The prevalence of subjective sensations
of dry mouth was 25.8% among men and 33.3% among women (p = 0.025). A
statistically significant association was found between a subjective sensation of
dry mouth and a low unstimulated flow rate, regular smoking, xerogenic
medication, and the presence of at least one illness connected with dry mouth.
Those who had a sensation of dry mouth also thought their physical condition and
their health to be poorer and more often had a high rate of depressive symptoms.
After the confounding factors had been added stepwise into the logistic
regression model, depressive symptoms were still significantly associated with
the sensation of oral dryness. CONCLUSIONS: When evaluating the causes of the
sensation of dry mouth, the possibility of depression as an underlying factor
should be considered.
PMID- 9560873
TI - Cardiovascular, endocrine, and receptor measures as related to sex and menstrual
cycle phase.
AB - OBJECTIVE: The present study was undertaken to elucidate possible mechanisms
underlying sex differences in cardiovascular measures or reactivity to challenge.
Because there is vastly diverging literature on the issue, we tried to control
for endocrine and psychological factors, which might contribute to some of the
apparent discrepancies. METHODS: Blood pressure, heart rate, adrenaline, and
noradrenaline in women (N = 24) and men (N = 14) were examined during baseline
and challenge (Stroop Test and Cold Face Test). Adrenoceptor density on
lymphocytes (beta 2) and platelets (alpha 2) were determined to examine possible
sex differences in underlying cardiovascular mechanisms. Gender effects were
controlled by assessing gender role orientation and task appraisal. Women were
tested during either the follicular (N = 12) or the luteal (N = 12) phase of the
menstrual cycle (verified by estradiol, progesterone, and luteinizing hormone).
RESULTS: Follicular and luteal phase women did not differ in any parameter except
progesterone. We observed sex-related differences in absolute levels of
physiological parameters, the male group having higher systolic blood pressure
levels, higher adrenaline plasma concentrations, and significantly more alpha 2
adrenergic receptors. Both challenges elicited pronounced cardiovascular and
endocrine responses. Men and women did not differ in response magnitude, in task
appraisal, or gender role orientation. CONCLUSIONS: The assumption that female
sex hormones reduce reactivity to challenge is not supported by our data. The
frequently reported male/female differences in reactivity may be caused by an
interaction of gender and task characteristics.
PMID- 9560874
TI - Endogenous opioids inhibit ambulatory blood pressure during naturally occurring
stress.
AB - OBJECTIVE: Laboratory experiments suggest that endogenous opioids inhibit blood
pressure responses during psychological stress. Moreover, there seem to be
considerable individual differences in the efficacy of opioid blood pressure
inhibition, and these differences may be involved in the expression of risk for
cardiovascular disease. To further evaluate the possible role of opioid
mechanisms in cardiovascular control, the present study sought to document the
effects of the long-lasting oral opioid antagonist naltrexone (ReVia, DuPont,
Wilmington, DE) on ambulatory blood pressure responses during naturally occurring
stress. METHOD: Thirty male volunteers participated in a laboratory stress study
using naltrexone followed by ambulatory blood pressure under placebo and during
the subsequent 24-hour period. Within-subject analyses were performed on
ambulatory blood pressures under placebo and naltrexone conditions. RESULTS:
Laboratory results indicate no significant group effects of naltrexone on blood
pressure levels or reactivity. Ambulatory results indicate that during periods of
low self-reported stress, no effect of opioid blockade was apparent. In contrast,
during periods of high stress, opioid blockade increased ambulatory blood
pressure. CONCLUSIONS: These findings suggest that naltrexone-sensitive opioid
mechanisms inhibit ambulatory blood pressure responses during naturally occurring
stress.
PMID- 9560875
TI - Laterality in somatization.
PMID- 9560876
TI - Evolution of pathology practice in the United States: current status and future
trends.
AB - This article traces the development of pathology practice from its origins in
autopsy pathology to its current practice in the United States. The American
model of practice differs markedly from that in continental European countries
because of the extensive incorporation of "Clinical Pathology" with the
traditional disciplines of anatomic pathology under the auspices of the Pathology
Department. "Clinical Pathology" as it is now defined includes the laboratory
testing disciplines of Chemistry, Hematology, Immunology, Medical Microbiology,
and Transfusion Medicine. The increasing importance of computers and information
management, DNA diagnostic techniques, and the multiple roles of the pathologist
as a researcher and consultant in pathology practice in the United States is
discussed.
PMID- 9560877
TI - [Fetal pathology in Fabry's disease and mucopolysaccharidosis type I].
AB - Fetal Fabry disease (defect of alfa galactosidase) and mucopolysaccharidosis I
(defect of alfa iduronidase, family with IH phenotype) were diagnosed by
biochemistry in two risk gravidities subsequently interrupted according to
mother's demand. Fetus with Fabry disease (gestation age 19 weeks) had
rudimentary storage in kidney and myenteric plexuses cells, cardiocytes were
normal. Biopsy of chorionic villi showed a bit more conspicuous storage in single
trophoblastic elements. Much more striking storage was observed in MPS I
(gestational age 14-15 weeks) especially in liver (hepatocytes and sinus cells),
spleen (sinus endothelial cells and pulp macrophages) and fibroblasts of skin and
placenta. Skin peripheral nerves and cerebral cortical gangliocytes did not show
any lysosomal storage. Different manifestation of storage in fetal age may reflex
the speed of lysosomal storage development in both lysosomal enzymopathies.
PMID- 9560878
TI - [The effect of two beta-2 sympathomimetic bronchospasmolytics on the ratio of
sialylated and sulfated glycoconjugates in goblet cell secretions of the tracheal
epithelium].
AB - Rabbits were made to inhale two different beta 2 sympathomimetic
bronchospasmolytics-salbutamol in Ventolin and phenoterolhydrobromid in Berotec.
Changes of secretion contents in tracheal goblet cells were evaluated by
classical and lectin histochemistry 30 minutes after administration of drugs.
When comparing with control rabbits Ventolin completely suppressed the secretion
of neutral glycoconjugates for the benefit of acidic glycoconjugates and
completely suppressed sialylation. The administration of Berotec suppressed
neutral glycoconjugates, either, but the suppression of sialylation was
uncomplete. Berotec was found a less damaging agent.
PMID- 9560879
TI - [Desmoplastic fibroblastoma].
AB - We report a light microscopic and ultrastructural appearance, and
immunohistochemical profile of two benign tumours of soft tissue recently
designated as desmoplastic fibroblastoma (collagenous fibroma). The tumours were
located in the foot and well demarcated. Microscopically, they were composed of
stellate--or spindle--shaped cells embedded in a hypovascular fibrous of
fibromyxoid stroma. Immunohistochemical examination showed that tumours were
diffusely positive for vimentin and focaly positive for smooth muscle actin and
muscle specific actin. Ultrastructurally, the neoplastic cells had features of
fibroblasts and myofibroblasts.
PMID- 9560880
TI - [Synovial metaplasia around breast implants].
AB - Three cases of the periprosthetic breast capsules showing typical features of
synovial metaplasia are presented. The histological picture is characterized by
the presence of cellular layer mimicking synovial membrane. These elements are
devoid of basement membrane, otherwise, nevertheless, they strongly resemble
single- or multilayered epithelium. Focally, the differentiation towards giant
multinucleated cells is noted. Immunohistochemical profile, as well as the
ultrastructure of the cells, confirms their histiocytic origin with advanced
differentiation towards elements of the synovial membrane. These histological
features are referred to as synovial or synovial-like metaplasia. They are found
in considerable fraction of textured breast implant capsules. The pathogenesis
remains uncertain; however, similar picture was observed in other locations in
association with prolonged or repeated action of mechanical forces. Thus,
movement of the implant in situ is the most probable trigger of synovial
metaplasia.
PMID- 9560881
TI - [DNA image cytometry in urothelial carcinomas. A pilot study of a new application
module of the Lucia G DNA analysis system].
AB - OBJECTIVE: To introduce and test a standardized measurement protocol for DNA
image cytometry into a newly developed LUCIA G system application program.
Contribution to a discussion concerning the possibility of using the histology
sections for DNA image cytometry. STUDY DESIGN: Routine biopsy material from 18
urinary bladder cancer cases was analyzed (Grade 1: n = 6, Grade 2: n = 6, Grade
3: n = 6), both in histological and in cytoseparated preparations. More than one
hundred diagnostic and more than 30 reference cells were measured. DNA features
(mean DNA value, 2cDI, Bocking's grade of malignancy) and histogram types in
Auer's classification (AI-IV) were compared. RESULTS: Most carcinomas measured
were aneuploid (two thirds G1, all G2, G3). The most common histogram type was A
IV. Malignancy grade was mostly slightly higher in cytoseparated material, the
shape of the histogram was analogous. Two carcinomas looking euploid in histology
sections were proven aneuploid in cytoseparation. CONCLUSION: More convenient
tissue section measurement provided useful DNA profile information in most cases.
Those without proven aneuploidy should be additionally measured in
cytoseparations. An experienced pathologist meeting strictly measurement protocol
demands is an important part of the measurement system.
PMID- 9560882
TI - [Detection of point mutations on the Ki-ras gene using the PCR technique].
AB - Present study was undertaken to detect Ki-ras point mutation at codon 12 in
pancreatic adenocarcinomas (CaP) using the polymerase chain reaction-restriction
fragment lengths polymorphism (PCR-RFLP). Three modifications of PCR-RFLP were
performed with a mismatched primers creating a recognition site with only one
allelic from (wild or mutated). Using two-step PCR-RFLP and two modifications of
one-step PCR-RFLP we examined 5 resected adenocarcinomas of pancreas, 6
pancreatic juices and one DNA sample from peripheral blood of patient with
generalized stadium of CaP. We compare all techniques and conclude, that the very
sensitive two step PCR-RFLP is a suitable method for detection point mutations
and eliminates the need for either oligonucleotide hybridization or DNA
sequencing.
PMID- 9560883
TI - [Detection of lorazepam and lormetazepam metabolites in urine using thin-layer
chromatography].
AB - The determination of benzodiazepine derivatives lorazepam and lormetazepam in
urine is based on detection of their metabolites 2-amino-2',5
dichlorobenzophenone and 2-methylamino-2'5-dichlorbenzophenone in hydrolyzed
urine. Both substances are structurally very similar to the metabolites of
diazepam 2-amino-5-chlorbenzophenone and 2-methylamino-5-chlorbenzophenone and
their mobility on thin layer chromatograms is similar as well. This could cause
their confusion and misinterpretation of the results. Therefore suitable
combination of mobile phases and thin layer plates was sought in this study for
the unambiguous identification of respective benzophenones by thin layer
chromatography.
PMID- 9560884
TI - [The concept of forensic medicine].
PMID- 9560886
TI - [Present knowledge of human spleen function].
AB - The human spleen is an important lymphoid organ participating in immune reactions
against all types of circulating antigens. It also removes particles of
nonantigenic nature from blood circulation. The structure of the spleen,
containing specialized cells types, provides a microenvironment where various
intercellular interactions occur and determines the course of development of
immune and nonimmune reactions. Though the spleen significantly participates in
host defense reactions it is not inevitable for life. However, removing of the
spleen increases the risk of overwhelming infections by bacteria with
polysaccharide capsules.
PMID- 9560887
TI - [The spleen in hereditary spherocytosis].
AB - Hereditary spherocytosis is the most common inherent, autosomal dominant
hemolytic anemia. Mild splenomegaly, venostasis and common decrease of while pulp
is characteristic for hereditary spherocytosis. Cords are filled with
spherocytes, sinuses can be empty or squeezed. Both sinuses and veins include
ghost erythrocytes that lost haemoglobin. They are seen light-microscopically in
differential interferent contrast. Macrophages are numerous, sinus lining cells
are hypertrophic. Erythrophagocytosis is hardly seen by electron microscope. Not
all red blood cells are spherocytes. Spherocytes are seen well in
electronmicroscopy. We did not observed transition of erythrocytes through sinus
walls. In certain circumstances lots of ferritin is seen both intra and
extracytoplasmically. Iron accumulation in cords can result in their fibrosis.
PMID- 9560888
TI - [Chronic autoimmune thrombocytopenia in the spleen and microparticles as seen in
scanning electron microscopy].
AB - In chronic autoimmune thrombocytopenia numerous round formations in the sinus
lining cells are observed by scanning electron microscopy. They occur sometimes
on the surface of erythrocytes passing through the sinus wall. It is possible
that they are not cytoplasmic processes but platelet microparticles sticking on
the surfaces of various cells. These particles are too small in routine counting
of blood platelets in the light microscopy and probably too fragile in examining
in transmission electron microscopy.
PMID- 9560889
TI - [Fibronectin and the human spleen].
AB - Fibronectins are glycoproteins with a function of molecular glue. The aim of the
study is to encourage interest in processes in extracellular matrix of the
spleen. Undigested cryostat or formol-paraffin sections and commercially
available antibodies were used. We were mostly successful in extracellular
localization of fibronectin in trabeculae, vessel walls and lamellae of
circumferent reticulum of periarterial lymphatic sheaths and in the ring fibres
of the sinuses. Changes in the amount of fibronectin occurred, for example, in
circulation disturbances. In hereditary spherocytosis the ring fibres were
reduced. Increase of fibronectin can suggest the development of fibrosis.
PMID- 9560890
TI - [Reactivity of antibodies to collagen types I to IV and antibodies to chondroitin
sulfate in the spleen].
AB - Antibodies to collagen type I and III reacted negatively, antibodies to collagen
type IV positively with reticulin, trabeculae and circumferent reticulum of
lymphatic sheaths, poorly positively with capsula, strongly positively with
subcapsular zone. Antibodies to collagen type II reacted positively with capsula,
poorly with subcapsular zone, strongly with sinus wall and poorly with
trabeculae. They did not react with circumferent reticulum of periarterial
lymphoid sheaths. Antibodies to collagen type II and IV reacted positively with
central arteries. Antibodies to chondroitinsulphate C reacted poorly and
antibodies to chondroitinsulphate B strongly positively with sinus walls and oval
cells spread in the white and red pulpa. Antibodies to chondroitin sulphate A
reacted similarly as antibodies to chondroitinsulphate B.
PMID- 9560891
TI - [Morphometric analysis of the spleen].
AB - Present possibilities of morphometric analysis of the spleen have been studied.
We have compared possibilities provided by stereological calculation and by
computer image analysators a) Telemet II (Tesla, Piestany) and b) CUE-2 GALAI
(Israel). In both latter cases equidensitometric evaluation and image processing
methods were used. Stereological calculations are not technically demanding but
time consuming. Computer image processing on the base of equidensitometric
measurements is more effective that stereological calculations. The difference
between used equipments is based on access to appropriate microscopic and
computer technique and software equipment.
PMID- 9560892
TI - [Traumatic rupture of the spleen. Histopathologic findings].
AB - The most common causes of splenic rupture are blunt injury and surgical
intervention in abdominal cavity. Morphological investigation of the spleen often
shows but a small capsular laceration as well as haemorrhage and granulocytic
infiltration in microscopy of its margins. The laceration may be sometimes
difficult to find. There are two types of microscopical haemorrhage. One in sinus
lacking subcapsular tissue zone, the other in deeper layers. In this case the
tissue haemorrhage is diffuse, sometimes within or around the marginal zone. The
sinuses are neither collapsed nor obturated by any material even close to margins
of the wound.
PMID- 9560893
TI - [Dermoid cyst of the spleen].
AB - The case report of a 14-year old girl is given. In her spleen of the weight of
1580 g an irregular cyst of glossy inner surface and with striking trabeculation
developed. It was filled with clear greenish liquid. The wall was formed by
hyalinised collagen tissue which was covered by epidermoid and cuboidal
epithelium on the inner surface. Vessel conglomerates were frequent, some
bleeding or mononuclear infiltrates, foci of giant cell granulation tissue,
lymphoid or fatty tissue were present.
PMID- 9560894
TI - [Technical problems in the preparation of biopsy samples of the spleen].
AB - Spleen tissue sampling for bioptical examination should be performed after mutual
consultation of clinician and pathologist. Clinician should know what is expected
from the pathologist. This can influence preparation and sampling method
considerably. In a great amount of cases the whole organ is removed. A lab
technician is sampling on her own and her contribution to a good result can be
either positive or negative. Imprint preparations from the tissue sections can be
useful. Specialized examination should be performed in the presence of a
pathologist or his co-workers. The active approach of a lab technician can
significantly contribute to the value of examined sample of the spleen, of the
organ until recently considered to be not important or full of mysteries.
PMID- 9560895
TI - Brown adipose tissue. I. Morphology. (Review).
AB - Brown adipose tissue appeared in mammals with the development of homeothermy. In
consequence of this, their organism became able to maintain constant body
temperature independent on the thermal conditions of the surroundings. This
tissue-contrary to the white adipose tissue-is distributed only in certain
restricted portions of the body. The paper deals with actual literary data of
morphology and function of brown adipose tissue.
PMID- 9560896
TI - Brown adipose tissue. II. Effect of pathologic and environmental conditions
(Review).
AB - Brown adipose tissue is an important source of non-shivering thermogenesis. Its
metabolic activity and development are regulated by adrenalin secretion. The
greatest amount of brown adipose tissue in humans was observed during the first
decade of life. Later it disappears from many sites, but is preserved in the neck
and around the kidneys and the adrenal glands. Increased amounts of brown adipose
tissue have been reported to occur in association with certain situations and
diseases. A review of these literary data is presented.
PMID- 9560898
TI - [Homicide and mutilation of the body--review of the literature].
AB - In two hitherto not elucidated murders of two young women the bodies were
devastated in a peculiar way and some organs were removed. The author presents a
review of literature focused on manipulation with the human body and also with
regard to the ability to commit such operations.
PMID- 9560899
TI - [Drowning--characteristic signs and calculation of their diagnostic value].
AB - In a group of 387 drowned subject and 50 controls typical signs of drowning were
investigated. Paltaufs spots, aqueous emphysema of the lungs, liquid in the
stomach, significant drop of chlorides, creatinine and urea in the left heart and
presence of liquid in the paranasal sinuses. The author investigated the
frequency of these signs and by comparison of data of these signs in the two
groups the diagnostic importance of different diagnostic signs was calculated.
PMID- 9560901
TI - [Sinus histiocytosis with massive lymphadenopathy--a disseminated form of the
Rosai-Dorfman syndrome].
AB - A 20 year-old black male presented with a generalized lymphadenopathy, skin
papules with maximum involvement of the head and trunk region, and elevated
temperature. Ultrasound, CT and bone scans revealed infiltration of the kidneys
and bones. Surgical specimens of the cervical lymph nodes showed massive
infiltration of sinuses by histiocytes with engulfed lymphocytes and granulocytes
in their cytoplasm. A similar finding was found in the excised dermis and
nasopharyngeal mucosa. Immunohistochemical investigations showed a strong
positive reaction of sinusoidal macrophages with anti S100 protein, anti alpha-1
antitrypsin and alpha-1 antichymotrypsin antibodies, negative CD1a. The engulfed
granulocytes were positive with lysozyme and MAC387 antibodies; lymphocytes
reacted with antilymphocytic antibodies L26, HLADR, UCHL-1 and OPD4 only rarely,
possibly due to alterations of their cell membranes in the cytoplasmic
environment of histiocytes. Occasional plasma cells were also entrapped in the
macrophages. The best results were obtained with CD3 antibody which showed focal
predominance of phagocytosed T cells. These findings confirm a nonselective
nature of the emperipolesis. In situ hybridization with probes EBER and BHLF
against Epstein-Barr virus sequences was negative. The pacient was treated by
multidrug chemotherapy with a moderate regression of the infiltrates. The
symptoms of the disease persisted for 10 months from the treatment start but
further course of the disease is uncertain. The patients is lost to follow up.
PMID- 9560902
TI - [Typing of malignant mantle zone lymphomas].
AB - Principles derived from a group of 46 ML of the mantle zone are presented: Mantle
pattern of a ML and its cytological structure are mostly sufficient for positive
basic diagnosis. Diffuse mantle zone ML need detection of BCL-1 and CD5
hyperexpression which are characteristic for small-cell and centrocytoid forms
when compared with BCL-2 positive centrofollicular lymphomas. B monocytoid
lymphomas from the parafollicular subgroup as well as plasmacytoid ML from the
marginal subgroup retain faint BCL-1 positivity but lose CD5 positivity. That may
results in attempt of problematic narrowing of mantle zone definition because of
existence of the mixed cellularity forms of mantle zone ML. Nodular mantle zone
ML are clinically recognized late and are unsensitive to treatment which is
opposite to the original idea of their relative benignity. M-coding of mantle
zone ML is very defective because the codes do not separate nodular
(perifollicular) and diffuse variants.
PMID- 9560903
TI - [PCR analysis of DNA in paraffin sections of malignant lymphomas].
AB - The polymerase chain reaction was used to detect the clonal rearrangement of
immunoglobulin heavy chain gene in paraffin embedded samples of human lymph
nodes. We developed a sensitive and reliable method of the DNA isolation from 4-5
tissue sections, which enabled us to perform 50-100 PCR reactions. We compared
the reactive lymph nodes and non-Hodgkin's malignant lymphomas using framework 3
and J region primers. PCR products were examined by agarose gel electrophoresis.
The dominant 80-120 bp amplification product was found in all lymphoma samples.
The samples of reactive nodes were negative.
PMID- 9560904
TI - [Visceral and cutaneous leishmaniasis].
AB - Two cases of kala azar and 5 cases of cutaneous leishmaniasis were found in
bioptic files from previous 50 years in Hlava Institute of Pathology in Prague, 4
of them were cumulated in 1994 and 1995. All cases followed short stays in
Mediterranean or Caribbean area. The latest kala azar was identified from bone
marrow trephine biopsy and subsequently, leishmanias were also found in an
inapparent hepatopathy. In cutaneous cases, a fibrinoid vasculitis was observed
in addition to accumulation of leishmanias laden macrophages and tuberculoid
granulomas.
PMID- 9560905
TI - Medulloepithelioma in a cat.
AB - Castrated male of European cat, bastard, 16 month-old suffered from a grayish
pink tumour in the anterior chamber of the right eyeball in the course of last
six months. After enucleation, the eye was examined by histology,
immunohistochemistry (NSE, NPF, S-100 protein) and electronmicroscopy. The tumour
was classified as malignant medulloepithelioma. Existence of neuroblastoma in
animals and frequency of neuroblastoma and medulloepithelioma in humans and
animals is discussed.
PMID- 9560906
TI - [Tumors in wildlife].
AB - Wild animal tumours have not been much studied yet. Authors found six mostly
benign cases in Czech Republic in checking hunts between the years 1988 and 1993:
Mature differentiated ovarian teratoma and apocrine skin adenoma in field hare,
intraductal mammary papillomatosis in a roe, complex odontoma and pleomorphic
mammary carcinoma (single malignancy in the group) in fox. A soft tissue tumour
in a fallow-buck's neck could not be histogenetically classified. A high
structural equivalence of animal and human tumours allows using ICD-O
classification as a whole.
PMID- 9560907
TI - [Anniversary of the International Academy of Pathology].
PMID- 9560908
TI - [Complications in catheterization of the subclavian vein].
AB - The authors of the article inform about the complications of the infraclavicular
subclavian vein catheterization, enclosing some practical cases. They suggest the
applicable steps that should be taken in case of the death due to the
catheterization not only for pathologists but also for the regular clinical
staff.
PMID- 9560909
TI - [Evaluation of the vital reaction in injuries].
AB - Evidence of an early vital reaction after a skin injury is sometimes of decisive
importance in forensic practice. Attention is devoted increasingly to
immunohistochemical evidence of substances, the presence of which in the borders
of the wounds signalizes an intravital origin of the injury. In this context
evidence was focused on detection of glycophorine at sites of haematomas of the
skin and subcutaneous layer and to fibronection in the borders of injuries and in
haematomas. To visualize the two substances in paraffin tissue sections, the
immunohistochemical method of indirect immunoperoxidase reaction was selected
where in the first layer specific sera were used wither against glycophorine A, B
or against fibronectin. Glycophorine is a sialoglycoprotein which is part of the
red cell membrane. It can be detected at the site of haematomas and after the
disintegration of erythrocytes during post-mortem autolysis. Conversely it is
lacking where membrane structures were not present. This makes it possible even
during advanced stages of post-mortem changes to differentiate actual haematomas
from mere post-mortem inhibition of tissue by blood pigment (e.g. in hypostasis)
where glycophorine cannot be detected. Fibronectin, another glycoprotein
substance can, already in the early stage of injury, form the basis for a netlike
structure in the shape of fine "strings". Detection of fibronectin suggests the
intravital development of injury and in the authors cases it could be detected
already within several minutes after the development of the injury.
PMID- 9560910
TI - Brown adipose tissue. III. Effect of ethanol, nicotine and caffeine exposure.
AB - Brown adipose tissue is known to be the most important organ for generating heat
in non-shivering thermogenesis. Process of thermogenesis and thermoregulation may
be affected by many drugs. The paper deals with actual literary data of effect of
ethanol, nicotine and caffeine on brown adipose tissue, heat production and its
regulation in experimental animals and in human.
PMID- 9560912
TI - [Antiphospholipid syndrome and spontaneous abortions].
PMID- 9560913
TI - [Drug interaction and oral contraception].
PMID- 9560914
TI - [How to prescribe and interprete obstetric ultrasonography].
PMID- 9560915
TI - [Preimplantation genetic diagnosis].
PMID- 9560916
TI - [Chlamydia trachomatis: should it be systematically be screened or treated?
Literature review and cost/benefit estimation in France].
AB - Chlamydia trachomatis is a primary cause of acute or silent salpingitis leading
to infertility and ectopic pregnancy. The C. trachomatis epidemic, undiscovered
in most cases, spreads, mostly in adolescents, during the years following the
onset of sexual activity. As opposed to gonococcal infection which has greatly
decreased, C. trachomatis cervical and urethral infection is commun in young
occidentals. More then 30 different studies covering 200-12000 subjects screened
in family planning centers, college women and men, students and military recruits
in different parts of the USA, in Scandinavian countries and France, indicate a
prevalence of 5-20% (mean 10%) in apparently healthy young females < 25 years and
5-10% in males. Female prevalence is strongly related to age, being highest (5
20%) in women < 20 years old. Several cost-benefit analysis show that the total
cost of the general screening in young populations, which can easily be carried
out for women in family planning centers, could save twice the cost of treatment
for pelvic inflammatory disease caused by C. trachomatis and six times the total
cost of C. trachomatis epidemics if late sequelae are taken into account (tubal
infertility treatment, ectopic pregnancy). In France, screening should save 12 to
48 millions French francs each year, depending of the cost of detection. The
final benefit of detection should be the eradication of the epidemic as obtained
to date in Scandinavian countries.
PMID- 9560917
TI - [Mixed endoscopic colposuspension (retroperitoneal and vaginal) for the treatment
of female stress urinary incontinence: technique and preliminary results].
AB - Preliminary results of a mixed technique of cervical bladder suspension by
retroperitoneal laparoscopy and vaginal route. 35 patients, average age 55 years
with stress incontinence. Every patients had positive Bonney test. Associated
lesions were prolapse (72%). In this retrospective study, we give technique in
details. Average operative time: 65 minutes. Average hospital stay: 5.4 days.
Success rate: 89%. Retzius hematoma were treated by laparoscopy. Average lapse of
time: 10.5 months. Interesting technique in associated prolapse.
PMID- 9560918
TI - [Emergency obstetrical hysterectomy].
AB - Hysterectomy on pregnant uterus is a mutilating procedure used by obstetrician
only when he haven't choice in case of major complications of pregnancy or
delivery. This retrospective study worked on 35 cases of obstetrical hysterectomy
performed on 22 months period (January 94-October 95). The frequency of the
procedure among all the in hospital deliveries was 0.45%. The mean age of the
patients was 31 years, and the mean parity was 7. 77.5% of the women were
referred from over surrounding hospitals where natural deliveries had failed. We
performed the hysterectomy because of uncontrolled haemorrhage in 71.7%, and
infection in 25.8%. Sub-total hysterectomy was performed in 82.8%. Maternal
mortality was 20%. Hysterectomy is very mutilating, but is a life rescueing
procedure behind a lifethreatening complication of pregnancy or delivery. The
best strategy to prevent the necessity of hysterectomy, is to develop the early
obstetrical reference program that unfortunately is not yet in practice in our
health care system.
PMID- 9560919
TI - [Ureteral endometriosis: three cases. Diagnostic and therapeutic management.
Literature review].
AB - Ureteral endometriosis is a rare but serious entity because of its insidious
evolution which can lead to the loss of kidney function. Three cases are
reported: two patients have received a medical and endoscopic management and the
third one has undergone a surgical procedure. According to the literature, the
authors suggest a diagnostic and therapeutic tree.
PMID- 9560920
TI - [Screening high-risk pregnancies].
PMID- 9560921
TI - [Birth control practices in Morocco. 200 laparoscopic Yoon ring tubal ligations].
PMID- 9560922
TI - [Treatment of sexually transmitted diseases and pelvic infections in gynecology].
PMID- 9560923
TI - [Fusarium toxins in grain: results of monitoring].
PMID- 9560924
TI - [Hygienic certification of registering of biologically active food additives].
PMID- 9560925
TI - [Occupational hygiene and physiology of miners extracting multimetal ore in the
Far North].
PMID- 9560926
TI - [Problems of occupational diseases in workers of nickel-cobalt industry].
PMID- 9560927
TI - [Evaluation of preclinical signs due to exposure of workers to static magnetic
fields].
PMID- 9560928
TI - [Clinico-immunological characteristics of the state of upper airways in workers
engaged in plasma technology].
PMID- 9560929
TI - [Hygienic problems in the use of industrial waste in various branches of national
economy].
PMID- 9560930
TI - [Sanitary legislation: history, ways of improvement].
PMID- 9560932
TI - [Problems of sanitary-epidemiological services in the Stavropol territory under
present conditions].
PMID- 9560931
TI - [Organizational, legal, methodical provisions and planning of the state sanitary
epidemiological services in emergency situations].
PMID- 9560933
TI - [Improvement of the state sanitary and epidemiological surveillance: experience
and goals].
PMID- 9560934
TI - [Experience in inspecting low-output food production industries].
PMID- 9560935
TI - [Problems in assessing carcinogenic risk of exposure to chemical pollution of the
environment].
AB - The main stages of and principles of methodology of assessment of a carcinogenic
risk from exposure to environmental factors are considered. The carcinogenic
risks of exposure to MAC of in the ambient air of the populated areas, in the
reservoir water, and in the air of a working zone were calculated by using the
carcinogenic potential. Analyzing the data obtained has indicated that a great
variety of potential carcinogens presents a high risk even if the hygienic
standards approved now are followed. The methodological and organization aspects
of the use of the procedure for assessing carcinogenic risks in Russia are
discussed.
PMID- 9560936
TI - [Health status of residents of ecologically unsound urban areas].
PMID- 9560937
TI - [Hygienic assessment of alkaline coagulants and zeolites in obtaining drinking
water].
PMID- 9560938
TI - [Health status of workers engaged in metallurgy industry].
PMID- 9560939
TI - [Quality of agricultural crops from lands irrigated with purified sewage].
AB - Anionic surfactants (AS) not only can move from the soil to cereals, but can
increase the translocation of some toxic agents (lead, copper, zinc). The
tolerable anionic AS in the irrigation of soddy podzolic soils is 12 kg/ha.
PMID- 9560940
TI - [Features of physical and sexual development of school children at different-type
schools].
AB - The results of examination of 932 schoolchildren who study at school of different
types are presented. They show that the physical and sexual developments of
children depend on the type of school. Harmonious development is observed in
Lyceum schoolchildren while dysharmonious one is more common in children from
general educational schools. Physical development is associated with
socioeconomic and ethnic factors.
PMID- 9560941
TI - [Characteristics of the radio-ecologic situation in the area of Totsk nuclear
explosion and the immune status of schoolchildren residing in the vicinity].
AB - Environmental pollution caused by radioactive and non-radioactive chemicals, and
the immunity of schoolchildren who reside in the area exposed to the Totsk
nuclear explosion (1954) are comparatively analyzed. The results indicate that
the area under study has higher levels of 137Cs than that of a control area.
There were immunological changes in children, which are obviously associated with
the nuclear explosion.
PMID- 9560942
TI - [Use of ultraviolet irradiation in the prevention of ecologically-induced immune
diseases].
PMID- 9560943
TI - [Characteristics of modifying effects of formaldehyde on carcinogenesis].
PMID- 9560944
TI - [Evaluation of the quality of activities of state sanitary and epidemiological
surveillance subdivisions under present-day conditions].
PMID- 9560945
TI - [Comparative characteristics of research methods in congenital disorders of color
vision].
PMID- 9560946
TI - ["Information ecology" snd human health under present-day conditions].
PMID- 9560947
TI - Mitochondrial disorders.
AB - In this minireview, we attempt to survey the three main group of mitochondrial
disorders, defects of nuclear DNA, defects of mitochondrial DNA, and defects of
intergenomic signaling, with emphasis on recent contributions and pathogenetic
mechanisms. In so doing, we have tried to point out some of the numerous unsolved
problems in genotype/phenotype correlation and to indicate future directions of
research.
PMID- 9560948
TI - PCR-based genotyping of MNSs blood group: subtyping of M allele to MG and MT.
AB - PCR-based genotyping of MNSs blood group system was investigated in combination
with restriction fragment length polymorphism (RFLP), single-stand conformation
polymorphism (SSCP) and allele-specific PCR amplification (ASPA) techniques. M
and N alleles are based on three nucleotide substitutions in exon 2 and one base
change (G or T) in an intron of glycophorin A locus. The latter single base
change was also found among M alleles analyzed in this study, so that M allele
appeared to be subdivided into MG and MT. All three alleles, MG, MT and N were
identified clearly by RFLP or SSCP analysis following a single amplification. S
and s alleles are based on one nucleotide substitution in exon 3 of glycophorin B
gene. Genotyping of Ss blood group system was also explored by PCR-SSCP or ASPA
analysis, and problems in the methods were discussed.
PMID- 9560949
TI - DNA-based prenatal diagnosis of a Korean family with tyrosinase-related
oculocutaneous albinism (OCA1).
AB - Tyrosinase-related oculocutaneous albinism (OCA1), an autosomal recessive inborn
error of pigmentation, is caused by the deficiency of tyrosinase. We had
previously identified two different mutations of the TYR gene in a four year old
Korean male with mild OCA; a P310insC frameshift in exon 2 and an IVS2-7t-->a,-10
11deltt splice junction mutation in exon 3. Here we report a prenatal diagnostic
study of a subsequent fetus of the above family that was at 25% risk of OCA1.
SSCP/heteroduplex screening, restriction enzyme digestion, and allele-specific
oligonucleotide hybridization analyses of DNA obtained by chorionic villus
sampling indicated that the fetus was a compound heterozygote for the paternal
P310insC and the maternal IVS2-7t-->a,-10-11deltt mutations. The diagnosis was
later confirmed by observation of poorly pigmented irides of the abortus
terminated at the 18th week of gestation. This approach provides a fast and
reliable method for DNA-based prenatal diagnosis when specific mutations are
known in families at high risk of OCA1.
PMID- 9560950
TI - DNA typing of HLA in the patients with moyamoya disease.
AB - Moyamoya disease is a clinical entity demonstrating a chronic occlusion of the
cerebrovascular system. Although some possible etiological factors have been
postulated, the etiology of this disease is still unknown. So far, some
investigations have suggested the association between moyamoya disease and HLA in
the serological typing. However, DNA typing of HLA have not been performed yet.
Thus, we performed DNA-typing of HLA in the unrelated Japanese patients with
definite moyamoya disease, using the polymerase chain reaction-sequence specific
oligonucleotide probe (PCR-SSOP) technique. In the total patients, DQB1*0502 had
a positive association with the disease. On the other hand, DRB1*0405 and
DQB1*0401 showed a negative association. In comparing the early-onset and late
onset groups, two groups did not share the same disease associated alleles at
all. Thus, the etiology of moyamoya disease seem to have a genetic background.
Furthermore, different genetic factors might also be involved in the difference
between the early-onset and late-onset groups.
PMID- 9560951
TI - Dual-color fish analysis of breakpoints on Robertsonian translocations.
AB - We investigated six Robertsonian translocations, including two cases of
rob(13q14q); one of rob(14q21q), one of rob (13q22q), and two of rob(21q21q), by
means of fluorescence in situ hybridization (FISH) using five repetitive DNA
probes: two alpha-satellite DNAs (D21Z1/D13Z1 and D14Z1/D22Z1), satellite III
DNA, beta-satellite DNA, and ribosomal DNA. Single color FISH successfully
defined the breakpoints in four cases of the six. Since the remaining two cases,
rob(13q22q) and rob(21q21q), revealed to retain rDNA, we tried to define the
breakpoints in detail by dual color FISH in these rare types. In the rob(13q22q)
the chromosomal breakage on chromosome 22 was likely to have occurred within the
rDNA region and that the chromosome 13 breakpoint was within the alpha-satellite
region. In one rob(21q21q) case we defined the breakpoint on one chromosome
distal to, or within, the beta-satellite region distal to the rDNA, and the other
chromosome breakage had occurred within alpha-satellite DNA. Our results
underscored the power of dual-color FISH for defining the precise locations of
breakpoints in Robertsonian translocations.
PMID- 9560952
TI - Fish mapping of a translocation breakpoint at 6q21 (or q22) in a patient with
heterotaxia.
AB - Heterotaxia is a congenital lateralization defect of visceral organs. As several
single-genes that act on the formation of left-right asymmetry during
embryogenesis have been identified in animals, a defect in the similar system may
play a role in heterotaxia in man. We previously reported a Japanese girl with
heterotaxia associated with a de novo balanced translocation (6;18)(q21 or
q22;q21.3 or q22). In the present study, based on a hypothesis that one of the
putative situs-determining genes is disrupted at a breakpoint of the
translocation, we first isolated a yeast artificial chromosome (YAC) clone
covering a breakpoint, 6q21 (or q22) of the translocation. Then, using STSs
mapped on the YAC, we isolated bacterial artificial chromosome (BAC) clones
spanning the breakpoint. FISH analysis using the BAC clones as probes revealed
that the breakpoint is confined to a segment between two STS loci, WI-4066 and
the CHLC.GATA6B06.192, within a genetic distance of 1.4 cM. The human connexin43
gene was not disrupted in our patient, although mutations of this gene have been
reported in patients with complex heart disease and heterotaxia. The molecular
localization of the translocation breakpoint in our patient may contribute to the
positional cloning of a putative heterotaxia gene.
PMID- 9560953
TI - Allelic frequencies of twelve dinucleotide repeat marker loci on chromosome 13 in
the normal Japanese population.
AB - To establish a genotypic database for dinucleotide repeat marker loci in the
Japanese population, we determined allelic frequencies of 12 such markers on
chromosome 13 and compared them with data from Caucasians in the GDB archive. The
average heterozygosity (79%) for the 12 loci was the same for the two
populations. However, allelic distributions at two of the marker loci were quite
different. These data will be useful for disease studies in the Japanese
population that involve linkage or sibship-pair analyses, or association studies.
PMID- 9560954
TI - Agenesis of corpus callosum in three sibs.
PMID- 9560955
TI - Characterization of marker chromosomes by fish using microdissected probes from
old Carnoy-fixed cells: report of two cases.
AB - We reported on two patients with a de novo marker chromosome of which the origins
were successfully identified by FISH using microdissected probes. These probes
were established by microdissections of extra chromosomal segments from Carnoy
fixed cells stored at -20 degrees C for several years. Using these probes, we
could verify partial 1q32 trisomy in a patient with 17p+ as well as partial 16q2
trisomy in another patient with 4p+.
PMID- 9560956
TI - Direct insertion of euchromatic material from chromosome Y in the X-chromosome in
hypogonadotropic hypogonadisms with Crohn's disease.
AB - The relationship between chromosomal abnormalities and Crohn's disease has not
been established. Crohn's disease is associated with inflammation of the bowel,
severe abdominal pain and chronic diarrhea. Its etiology is not known at present.
A recessive gene with incomplete penetrance is thought to be a factor which does
not follow simple mendelian inheritance. We report a case, where the euchromatin
material of Y chromosome (p11.1 p11.2) has been directly inserted into the long
arm of the X chromosome (q21.2), and is assumed to be the most likely cause of
hypogonadotropic hypogonadism in this patients. It could also be that the
function of the testis-determining factor (SRY) has been disrupted due to the
insertion, causing loss of testicular development.
PMID- 9560957
TI - Met 235 Thr polymorphism of angiotensinogen in Indonesians.
PMID- 9560958
TI - [Cancer in children does not have to be painful. Efficient analgesia provided by
skilled personnel is a the children's right].
PMID- 9560960
TI - [Increased patient participation requires new fees].
PMID- 9560959
TI - [Fetal monitoring does not prevent growth retardation. Preparedness for
unexpected complications is the most significant benefit].
PMID- 9560961
TI - [Why does the time go faster?].
PMID- 9560962
TI - [Must I prescribe over-the-counter drugs?].
PMID- 9560963
TI - [Omega-3 fatty acids against schizophrenia?!].
PMID- 9560964
TI - [Are famciclovir and valaciclovir truly effective in the treatment of shingles?].
PMID- 9560965
TI - [Disability evaluation: "Society takes advantage of physicians--and physicians
let it go"].
PMID- 9560966
TI - [Pain in children with cancer is mostly caused by treatment and interventions.
Personnel would like to have more time for analgesic care and more training].
PMID- 9560967
TI - [Vaccination against cancer soon a therapeutic possibility. B-cell tumors,
colonic cancer and melanoma may be suitable for this treatment].
AB - The theoretical basis of cancer vaccination having been well established during
the past two decades, the translation of this knowledge into clinically
applicable immunisation procedures is now an urgent need. Numerous antigenic
preparations are available that are capable of inducing specific anti-tumour
immunity which can be augmented by appropriate cytokines. Promising tumour
vaccination results have been obtained in B-cell malignancies, colorectal
carcinoma, and melanoma; tumour regression has been noted in myeloma, non-Hodgkin
lymphoma, colorectal carcinoma, and melanoma patients, and significantly
prolonged disease-freed survival in non-Hodgkin lymphoma and colorectal carcinoma
patients. The presence of only minimal residual disease would seem to be a
clinical prerequisite for tumour vaccination.
PMID- 9560968
TI - [Fetal growth retardation is difficult to detect. Quality criteria for obstetric
care are not functioning in the clinical practice].
AB - In a study of the practical efficacy of quality criteria for obstetric care, it
was found that fetal growth disorders are difficult to detect, even when growth
retardation is suspected. Examination of the quality indicator, unrecognised SGA
(small for gestational age), showed barely half the cases of subnormal
gestational age-related birthweight.
PMID- 9560969
TI - [Traumatic stress in adult refugees: when ill-health is silent or speaks broken
Swedish].
AB - It is well established that a significant proportion of refugees in Sweden have
had traumatic experiences prior to immigration, causing mental and psychosomatic
disorders. The actual frequency is difficult to assess because of methodological
problems. Of refugees resettled in Stockholm county in 1996, 13 per cent were
immediately referred to specialised trauma centres, thus comprising half of all
referrals. Moreover, it has to be borne in mind that underdiagnosis is common in
clinical practice. In the article, the relevance of accessible data, the clinical
picture and epidemiological issues are discussed with regard to the refugee
population.
PMID- 9560970
TI - [Now who was Asklepios?].
PMID- 9560971
TI - [Drunken driver examinations. CD-transferrin is a valuable marker of alcohol
consumption].
AB - The article reports findings in a study of 198 subjects attending a psychiatric
out-patient clinic, with known or suspected high alcohol consumption during a 12
month period, about half of whom had had their driving licences revoked. The
level of carbohydrate-deficient transferrin (CDT) was found to be a valuable
marker of alcohol consumption, and a useful adjunct to the measurement of liver
enzymes. Both GGT (gamma-glutamyltransferase) and CDT levels were significantly
higher in high alcohol consumers than in low consumers. Alcohol the two markers
did not differ from each other in statistical significance, CDT was associated
with greater sensitivity and specificity; the sensitivity of CDT was 69% for men
and 79% for women, as compared with 62% and 40%, respectively, for GGT; the
specificity of CDT was 81% for men and 100% for women, as compared with 82% and
72%, respectively, for GGT. Together, GGT and CDT detected 91% of the male and
93% of the female high consumers. Among younger men, CDT values were higher in
the subgroup with a history of traffic offences than in the subgroup without such
a history, thus suggesting that CDT levels may be increased by heavy weekend beer
consumption. A few cases of false-positive CDT results were found to be
attributable to genetic anomalies of the transferrin molecule. Cases
characterised by disparity between the CDT level and the clinical picture require
further, more specific, analysis. Used in combination with GGT, CDT is thus a
feasible marker for use in monitoring alcohol consumption in drivers needing to
qualify for the restoration of their licences.
PMID- 9560972
TI - [Time to break up "psychosomatic families"! The model is not empirically
supported].
PMID- 9560973
TI - [To compare clinics, a considerate handling].
PMID- 9560974
TI - [Topic problems of gerontology in otorhinolaryngology].
AB - The paper characterizes age-specific involution of the ENT tissues, acoustic and
vestibular analyzers, hearing and equilibrium defects. Original investigations of
the authors give wider possibilities of early detection of age-related failure of
the internal ear functions. Relevant tests are proposed.
PMID- 9560975
TI - [Problem of cochlear implantation: brief introduction].
AB - The only method of hearing rehabilitation for patients with severe hypoacusis and
peripheral deafness is cochlear implantation consisting of insertion of
electrodes into the scala tympani and direct electric impulse stimulation of the
auditory nerve adjusted to the input acoustic signal. Only few such operations
have been performed in this country. Much effort should be devoted to training of
specialists and advocating this method among practitioners.
PMID- 9560976
TI - [Acoustic evoked potentials in patients with vocal problems in relation to their
hearing in wide frequency range].
AB - The function of different compartments of the acoustic analyser was assessed by
the findings at tonal audiometry in standard and extended range of frequencies
(10, 12, 14 and 16 kHz) as well as by characteristics of acoustic evoked
potentials. A total of 62 patients with chronic vocal dysfunction (CVD) and 20
subjects with normal hearing and voice were examined. CVD patients were found to
have: normal hearing both in standard and extended range of frequencies (25.8%);
normal hearing in standard but defective one in extended range of frequencies
(51.6%); defective hearing sensitivity to tones both in standard (4, 6 and 8 kHz)
and extended frequency range (22.58%). CVD patients with abnormal hearing in the
extended frequency range exhibited affection of the brain stem and cortical
compartments of the acoustic analyser. Acoustic evoked potentials were especially
abnormal in patients with high hearing thresholds (17.4 +/- 1.6; 25.8 +/- 1.9,
29.7 +/- 2.1 dB) in standard frequency range (4, 6 and 8 kHz), respectively. In
such patients the disease ran a protracted course with frequent relapses. These
findings can help in making decision on the treatment policy, occupational
fitness expertise and selection of patients with vocal professions.
PMID- 9560977
TI - [Transplantation of fetal tissues in otorhinolaryngology: current status and
prospects for the future].
AB - Insufficient efficacy of treatment of neurosensory hypoacusis makes investigators
search for new methods. Transplantation of fetal tissue taken from healthy
embryos of gestation stage II tried in various fields of medicine, such as
neurology, endocrinology, surgery, etc., was also tested in management of various
forms of neurosensory hypoacusis. Endonasal, endaural, endolumbal and
intracochlear methods of the transplantation are detailed. Results of combined
dynamic audiological control of these patients including tonal threshold
audiometry in extended frequency range are presented. A 1-year follow-up provided
evidence in favour of endolumbal and intracochlear transplantation. Further
investigations are needed.
PMID- 9560978
TI - [Validation of therapeutical policy choice in exudative otitis media].
AB - 132 patients with diagnosis acute or subacute exudative otitis media were treated
conservatively (n = 79) or surgically (n = 53). Conservative treatment was
effective in 41% of the cases, surgical treatment produced positive results in
62.3%. The operative treatment combined elements of endoscopic nasal surgery and
methods used in tympanoplasty, plastic treatment of the auditory tube, surgery of
the internal ear.
PMID- 9560979
TI - [Plastic reconstruction of mastoid cavity in patients with chronic suppurative
otitis media].
AB - The authors describe a mastoidoplasty modification--repair of the retrotympanal
cavity with a large osteomusculoperiosteal graft on the lower feeding pedicle.
This intervention was conducted in 25 patients with otitis media purulenta
chronica with cholesteatoma and in 6 patients with incomplete epidermization of
the cavity after radical operation on the ear. Prior to and following the
operation turundas containing mixed salts of acid ethers of cellulose, bound
calcium ions and antibiotics were inserted into the external acoustic meatus and
postoperative cavity. The treatment duration was shorter. The effect was achieved
in 27 patients.
PMID- 9560980
TI - [Congenital malformations of nose and paranasal sinuses].
AB - 410 patients with malformations of the external ear or nasal cavity were
examined. Basing on this evidence, clinical and diagnostic aspects of agenesias,
hypogenesias, hypergenesia, dysgenesia, persistence and dystopias of the nose and
intranasal structures are analyzed. Both severe and "minor" anomalies are
considered. Endoscopic diagnosis of the malformations is described.
PMID- 9560981
TI - [Current problems of temporary expert evaluation of disability due to ENT
diseases].
AB - The paper is concerned with problems of expert evaluation of disability due to
ENT diseases including temporary disability, differentiation of temporary and
persistent disability, indications for expert examination. Recommendations for
experts making the decisions on temporary ENT disability are given. Medical and
social factors of ENT disability, especially occupational risks, are analysed.
PMID- 9560982
TI - [Application of polymeric endoprostheses in surgery of external ear].
AB - Biocompatible polymeric endoprostheses EFOS are offered for endoprosthetic
reconstruction of the external acoustic meatus in atresia. Such endoprostheses
are safe for the adjacent tissues. Moreover, such prostheses contain
antibacterial drugs (quinoxidine, dioxidin) and substances promoting tissue
regeneration (orotic acid derivatives). This provides good epithelization of the
walls of the newly established external acoustic meatus and sufficient lumen of
the organ. The removal of the endoprosthesis is recommended on the postoperative
day 90-120 in the outpatient setting.
PMID- 9560983
TI - Postoperative use of gelecel sorbent in patients with chronic suppurative otitis
media.
AB - Local sorption therapy of postoperative wounds in patients with exacerbation of
otitis media purulenta chronica with gelecel stimulates cleansing of the wounds
from pyonecrotic substances on postoperative day 2-3. Regeneration in the
trepanation or radical cavity starts on day 2-3. Intoxication ceased 2 days
earlier compared to the procedure with the use of medical gauze. To prevent
dehydration of the soft tissue gelecel should be applied on postoperative day 5
6.
PMID- 9560984
TI - [Congenital parotid fistula].
AB - 21 cases of congenital parotid fistula are reported. The patients' age ranged
from 7 to 50 years. Dissection of the fistula under local anesthesia was made in
9 patients. A 7-year-old patient was operated under intravenous calipsol
anesthesia. Four kinds of the fistula depending on its shape and size are
described. Two of them cause no trouble, the other two manifest from early
childhood with inflammation, recurrences with abscesses. In such cases the
fistula should be radically removed.
PMID- 9560985
TI - [An unusual complication of chronic suppurative otitis media].
PMID- 9560986
TI - [A rare case of cyst from the skull base simulating recurrence of peritonsillar
abscess].
PMID- 9560987
TI - [Esthesioneuroepithelioma combination with choanal polyp].
PMID- 9560988
TI - [Polypous rhinosinusitis].
PMID- 9560989
TI - [Removal of palatine tonsils].
PMID- 9560990
TI - [The use of human skin reflectance spectra for the quantitative assessment of
individual sensitivity to ultraviolet radiation].
AB - Reflection spectra of human skin of various ethnic types in the range of 370-790
nm were measured and analyzed. Correlation between reflection coefficients and
minimal erythemal doses was estimated. The formula has been devised which is
suitable for defining minimal erythemal doses both for open and closed parts of
the body irrespective of pre-exposition to sun radiation.
PMID- 9560991
TI - [An analysis of the clinical effects of ion-parametric magnetotherapy].
PMID- 9560992
TI - [The laser therapy of hypertension patients in the initial stages].
AB - The effect of low-energy laser irradiation used as monotherapy was studied in 42
patients with early essential hypertension. Hypotensive and antioxidant effects
of laser therapy, its ability to decrease total peripheral resistance were more
pronounced in patients with stage I hypertension.
PMID- 9560993
TI - [The seasonal nature of the course of ischemic heart disease and the prophylactic
correction of the lipid structure of the erythrocyte membrane using laser
radiation].
PMID- 9560994
TI - [The magnetic-laser therapy of patients with complicated forms of varicose
veins].
PMID- 9560995
TI - [A comparative evaluation of the effect of an extremely high-frequency
electromagnetic field on cerebral hemodynamics in hypertension patients exposed
in different reflexogenic areas].
AB - A single session and multiple sinocarotid and temporal exposures to EHF
electromagnetic field in patients with stage I and II hypertension had different
effects on cerebral circulation Variants of the above treatment are proposed.
PMID- 9560996
TI - [A unit setup and experience in using pulsed barotherapeutic conditioning in a
regimen of atmospheric pressure fluctuations every other day in correcting the
meteoropathic reactions of patients with diseases of the circulatory organs].
PMID- 9560997
TI - [The mathematical aspects of constructing a system for choosing the treatment
method at a health resort in chronic nonspecific lung diseases].
AB - The paper presents the analysis of present-day approaches to solution of the
problem of spa-treatment method choice. Principal mathematical means and
methodological approaches consist of; formalization of the subject field;
accumulation of sufficient clinical material; classification of the patients'
condition, functional changes and methods of treatment, multivariate (cluster,
factor), inductive formation of concepts, models of thinking, etc.
PMID- 9560999
TI - [The combined use of dry-air carbon dioxide baths and applications of peloids at
low temperatures in the rehabilitation of patients with psoriatic arthritis].
AB - Low-temperature peloids and dry effervescent baths were tried in the treatment of
106 patients with psoriatic arthritis. The response was achieved in 70% of
patients. The articular index, psoriatic lesions of the skin, inflammation
diminished for 6-9 months.
PMID- 9560998
TI - [An SHF electromagnetic field (460 MHz) combined with the preparation Tribimol in
treating duodenal peptic ulcer associated with Helicobacter pylori].
AB - Epigastric exposure to EHF (460 MHz) electromagnetic field and administration of
Tribimol were combined in the treatment of 103 patients with uncomplicated
duodenal ulcer. As shown by clinical, endoscopic and morphological examinations,
biochemical and imprint tests for Helicobacter pylori, intragastric pH-metry, the
method is pathogenetically sound and can be recommended for combined treatment
and rehabilitation of patients with duodenal ulcer associated with Helicobacter
pylori.
PMID- 9561000
TI - [An experimental rationale for the use of sulfide sludge in adjuvant arthritis].
AB - The experiments on 176 Wistar rats were performed for the first time to clarify
mechanisms underlying anti-inflammatory action of the Deshembinskoe Lake mud in
experimental arthritis. The new data obtained gave evidence supporting
application of Deshembinskoe Lake mud in inflammatory diseases of the joints.
PMID- 9561001
TI - [The use of millimeter waves in neurosurgery under electrophysiological control].
AB - Patients with organic CNS lesions including epileptic syndrome can be treated
using indirect influence of millimetric waves upon major brain regulatory systems
via specific peripheral receptor fields under control of adequate bioelectric
criteria. 42 brain-affected patients were studied. The above method used as a
part of combined surgical treatment resulted in stable functional restoration and
normalization of bioelectric brain activity.
PMID- 9561002
TI - [Microzonal physiotherapy of the neck and face area].
PMID- 9561003
TI - [The effect of a single inhalation of mineral water on the blood hormonal status
in healthy volunteers].
AB - Concentrations of ACTH, TTH, STH, LH, PSH, hydrocortisone, insulin, glucagone,
triiodthyronine, thyroxine, aldosterone, glucose and unesterified fatty acids
(NEFA) were measured in the blood of 23 healthy male volunteers aged 18 to 35
years 15, 30 and 60 min after a single nose inhalation and oral intake of mineral
water Essentuki No. 17. Inhalation of Essentuki No. 17 stimulated secretion of
the hormones and some parameters of metabolic reactions: the levels of glucose,
NEFA, hydrocortisone, aldosterone, TTH, PSH and LH rose while those of insulin
and growth hormone decreased. Oral intake of this water brought about the same
changes in the hormone status except blood insulin the levels of which went up.
PMID- 9561004
TI - [Magneto- and cryotherapy of diseases of the locomotor system].
PMID- 9561005
TI - [The therapeutic use of Chokrak mud].
PMID- 9561006
TI - [The catalytic activity of medicinal mineral waters].
PMID- 9561007
TI - [The basic climate categories of western Siberia from the viewpoint of health
resort and recreational development].
PMID- 9561008
TI - [Traction of the extremities in patients with osteoarthritis (a review of the
literature)].
PMID- 9561009
TI - Radiologic versus surgical placement of vena cava filters: a comparative study of
cost, time and complications.
AB - OBJECTIVE: To compare the cost- and time-effectiveness of 2 methods of placement
of vena cava filters for the prevention of pulmonary embolism: the radiologic
percutaneous placement of the Vena Tech LGM filter and the surgical cutdown
placement of the 24 Fr Greenfield filter. METHODS: Retrospective review of
radiologic and clinical records for 15 consecutive patients who had the Vena Tech
LGM filter placed radiologically and 15 consecutive patients who had the
Greenfield filter placed surgically. Factors studied were cost, procedure time,
waiting time and rates of immediate and delayed complications. The follow-up
period ranged from 1 to 26 months (mean 7 months). RESULTS: The procedure cost
for the radiologic method was $702 less than for the surgical method. The
procedure time for the radiologic method was 30 minutes shorter, and the waiting
time for placement was also shorter. There was no difference in the complication
rates following each procedure. The higher cost of the Greenfield filter
accounted for 80% of the total cost difference. CONCLUSION: The radiologic
percutaneous method of filter placement is preferred over the surgical cutdown
method because of its benefits in terms of cost and time with no increase in
risk. However, when the difference in cost between filters is taken into account,
there is little difference in overall costs for the 2 methods. Therefore,
radiology and surgery departments can place a filter percutaneously at a similar
cost. Other factors such as waiting times, complication rates, venography
capabilities and physician interest in performing the procedure will dictate
which department places the filter.
PMID- 9561010
TI - Complications of radiologically placed central venous ports and Hickman catheters
in patients with AIDS.
AB - OBJECTIVE: To determine any differences in the complications following radiologic
placement of 2 devices--Hickman catheters and central venous ports--to permit
long-term central venous access in patients with AIDS. PATIENTS AND METHODS:
Thirty-eight patients with AIDS received 52 long-term central venous access
catheters. Seventeen received 23 Hickman catheters and 27 received 29 central
venous ports (hence, 6 patients received both). Complications rates were
determined retrospectively from clinical records and radiologic studies. RESULTS:
The only acute complications were pneumothoraces--3 in the patients receiving
Hickman catheters and 2 in the patients receiving central venous ports.
Infections developed in 12 of the patients receiving Hickman catheters a median
of 53 and a mean of 96 days after placement. Infection developed in 8 of the
patients receiving central venous ports a median of 125 days and a mean of 184
days after placement. This difference was statistically significant (p < 0.001).
The most common organism in these infections was Staphylococcus aureus. The only
other nonacute complication was 1 nonocclusive thrombosis of the superior vena
cava, which occurred in a patient with a Hickman catheter 240 days after
placement and resolved once the catheter was removed. CONCLUSION: Central venous
ports are preferred over Hickman catheters for long-term central venous access in
patients with AIDS.
PMID- 9561011
TI - Osseous tumours of the foot: a pictorial essay.
PMID- 9561012
TI - Focal osteolysis as a complication of therapy for Paget's disease: case report.
PMID- 9561013
TI - Bone dysplasias: an introduction.
AB - Although individual bone dysplasias are rare, as a group they are relatively
common and have a significant effect on morbidity and mortality at all ages. In
this brief introduction, radiologic classification, diagnosis and differential
diagnosis are given. The radiologic diagnosis is emphasized, since distinction
among the various bone dysplasias is based largely on radiographic findings.
Prenatal diagnosis relies heavily on high-resolution real-time ultrasonography of
the fetus. Precise antenatal ultrasonographic diagnosis of a bone dysplasia may
be very difficult; however, accurate differentiation of a lethal versus a
nonlethal anomaly is relatively easy. There has been a recent explosion of
knowledge about the genetic basis of skeletal dysplasias. Collagen gene mutations
have been found to be responsible for osteogenesis imperfecta and many other bone
dysplasias. The locations of the genes implicated in achondroplasia and some
other chondrodysplasias are now known. Histologic analysis of the growth plate
may also provide specific diagnostic features in achondroplasia and other bone
dysplasias. A team approach is mandatory for the diagnosis and management of this
fascinating and challenging group of diseases.
PMID- 9561014
TI - Osteogenesis imperfecta: a review.
AB - The wide spectra of the clinical features, classification, genetics and imaging
features of osteogenesis imperfecta (OI) are discussed, especially in the context
of distinguishing the condition from child abuse. A broad general knowledge of
the clinical and genetic aspects of the disease, as well as the imaging features
of OI, is required for radiologists to knowledgeably provide the proper diagnosis
and to participate responsibly in a team approach with geneticists, clinicians,
lawyers and child protection services. There are 4 major types of OI, ranging
from mild to severe. The diagnosis is made from clinical, genetic and
radiographic features. The complications of OI and the use of bone mineral
density measurements, collagen analysis and prenatal ultrasonography are
presented. Their clinical relevance to the diagnosis of OI are discussed. Skin
biopsy for collagen analysis may be needed to aid in the diagnosis in confusing
or mild cases. It is important to distinguish OI from child abuse in order to
protect an abused child or to avoid an improper accusation of child abuse in a
child with obvious OI.
PMID- 9561015
TI - Malignant suprasellar gliomas: 4 case reports.
PMID- 9561016
TI - Residents' corner. Answer to case of the month #53. Beta-thalassemia intermedia
with extramedullary hematopoiesis.
PMID- 9561017
TI - Residents' corner. Answer to case of the month #54. Cecal lipoma with colocolic
intussusception.
PMID- 9561018
TI - [Circadian rhythm of melatonin in liver cirrhosis].
AB - The liver plays an important role in the intermediate metabolism of numerous
substances involved in hormonal action. Starting from the presupposition that the
pineal has an inhibitory effect on the reproduction system through melatonin
(aMT) and that hepatic cirrhosis can be included among the pathologies
characterised by sexual disorders, the authors felt that it was interesting to
evaluate the light/darkness rhythm of aMT in some patients suffering from hepatic
cirrhosis in order to highlight the possible pathogenetic role of aMT in causing
the altered sexual activity observed in this pathology. A total of 4 subjects (3
males and 1 female), with a mean age of 60.5 years, suffering from hepatic
cirrhosis and a matched group of healthy controls were included in the study.
Circadian changes in aMT plasma levels and plasma levels before and after TRH
stimulus (200 micrograms) of aMT and PRL were studied in all subjects. The
results revealed the presence of a circadian rhythm of aMT with a nocturnal peak
secretion in both groups; in patients with cirrhosis, however, the rhythm
appeared to be "out of phase" and presented a late and prolonged increase in aMT
compared to controls. Responses to TRH did not show any differences in aMT
between the two groups, but the response to PRL was higher and longer than in
hepatopathic patients. These findings showed an alteration in the secretory
pattern of aMT in cirrhotic patients which can be attributed to reduced hormone
metabolism at an hepatic level. The altered response to PRL is attributable to an
altered neurotransmitter function at the central level.
PMID- 9561019
TI - Prognostic significance of the estrogen-regulated proteins, cathepsin-D and pS2,
in breast cancer.
AB - The evaluation of prognostic factors for breast cancers is important for
therapeutic decisions both at the time of surgery and during postoperative
surveillance. Cathepsin-D (cath-D) is an estrogen inducible aspartyl protease.
Studies have demonstrated two biological activities, at an acidic PH, of the
protein: a mitogenic and a proteolytic activity; both the growth promoting
activity and the extracellular proteolytic activity suggest that cathepsin D
(cath-D) may have prognostic significance in breast cancer. Measurement of cath-D
in breast tissue, in fact, is highly significant in predicting recurrence as well
as disease free interval and overall survival. The pS2 is a small cysteine-rich
protein specifically expressed under estrogen transcriptional control. Expression
of the pS2 protein in breast carcinoma is a useful guide to prognosis and
response to tamoxifen: appropriate adjuvant therapy can be selected on the pS2
status of the tumor; patients with pS2 expression had better overall survival and
a longer survival time after the first recurrence than those without pS2
expression. For these reasons, these two new prognostic markers could be
suggested as habit factors in breast cancer.
PMID- 9561020
TI - [Differential diagnosis of fever of unknown origin. A case of adult onset Still
disease].
AB - BACKGROUND: A case of Still's disease in the adult, an uncommon seronegative
rheumatoid arthritis-like disease with prominent systemic features is reported.
This case did not show the typical clinical features and appeared like a fever of
unknown origin. CASE REPORT: A 60 year-old female was admitted to the hospital
for high fever occurred two months before without other important clinical
symptoms and signs. Laboratory tests and morphologic images were negative for
infectious diseases, tumours and immunological disorders. The course of the
disease worsened and an hepatic failure threatened the patient life. The onset of
many other typical clinical features, i.e. joints pain, characteristic skin rash,
splenomegaly, throat pain, serositis and weight loss, led us to make a sure
diagnosis and to save the patient with steroid therapy.
PMID- 9561021
TI - [Correlation between pulmonary pharmacokinetics and pharmacodynamics support the
hypothesis of the usefulness of ceftazidime at a single 1g daily dose in the
treatment of bacterial exacerbation of chronic obstructive bronchopneumonia with
moderate functional damage].
AB - INTRODUCTION AND BACKGROUND: Experimental studies have shown that cephalosporins
have an antibacterial effect in vivo even when their levels are above MIC for
only 40-50% of dosing intervals, whereas maximum killing is obtained when
concentrations are above MIC for 60-70% of the time. Since most patients treated
with antibiotics have neutrophils and other natural defence mechanisms, it is
likely that a bacteriostatic effect should be sufficient to induce an effective
therapeutic response. METHODS: Given that in the potential sites of lung
infection ceftazidime reaches significantly higher levels than the MIC of the
most commonplace respiratory pathogens, even 8-12 hours after the administration
of 1 g i.m., the authors evaluated the efficacy of treatment of renewed acute
episodes of COPD using this antibiotic at a dose of 1 g once a day. In order to
do this, 20 outpatients were enrolled in the study, half of whom presented
moderate bronchial obstruction (FEV1 = 50-70% of theoretical) whereas the
remainder presented marked bronchial obstruction (FEV1 = < 50% of theoretical).
RESULTS: The 10 patients with moderate obstruction at the time of enrollment, who
presented Haemophilus influenzae, Streptococcus pneumoniae or Moraxella
catarrhalis as causal agents in the sputum (Escherichia coli was only isolated in
one patient), showed a marked improvement following treatment with 1 g
ceftazidime one a day. A real or presumed eradication of the causal microorganism
was observed in all subjects. Treatment with ceftazidime at the dose of 1 g/die
once a day was much less effective in patients with marked bronchial obstruction.
Treatment was successful in 7 out of 10 subjects, but 2 of them relapsed within 2
weeks. In this second group, Pseudomonas aeruginosa was found in the sputum of 3
patients; one of the patients showed a persistence of the bacterium after
ceftazidime treatment, and another presented reinfection 12 days after the end of
treatment. The two patients in whom Staphylococcus aureus was isolated did not
benefit from ceftazidime treatment at this dosage. One subject who initially
presented Streptococcus pneumoniae in his sputum and was then thought to have
recovered, underwent a new acute episode caused by Moraxella catarrhalis 2 weeks
after the suspension of ceftazidime treatment. CONCLUSIONS: The therapeutic
responses observed during this study suggest the possibility of using ceftazidime
in a single daily dose of 1 g i.m. to treat those patients with exacerbations of
COPD who only present moderately impaired functional symptoms. On the contrary,
this type of therapeutic approach must be used with extreme caution in subjects
with marked functional damage, although a satisfactory clinical response may be
obtained in some cases. However, the small number of patients included in this
study does not allow firm conclusions to be drawn. Only a study involving a
larger group of patients could provide the necessary information to confirm the
hypothesis for treatment put forward by the authors.
PMID- 9561023
TI - [The new financing system in the Italian National Health Service. Implications
for internal medicine].
AB - Since 1995, the Italian National Health Service has begun to fund its hospitals
on a DRG basis. This paper presents the main features of the DRG system as well
as its likely implications for general internal medicine. The first part
describes the introduction of DRGs in the US. The first paragraphs summarize the
features of the US health-care system and particularly its private nature with
two major exceptions: Medicare and Medicaid. The development of the DRG system
and its adoption by Medicare are then described. Finally, the main effects of
Medicare's DRG system are underlined: shorter hospital stays, fewer hospital
admissions, several diagnostic and surgical procedures shifted from the inpatient
to the outpatient setting, and apparently no negative quality implications. The
second part focuses on Italy, in general and with specific reference to general
internal medicine. For general internal medicine, the new funding system has two
major implications. First, it may lead to the creation of larger medical
departments including both the current general internal medicine divisions and
the various specialties. Second, even under the current organisational structure,
divisions will be increasingly required to produce positive financial margins. In
this respect, general internal medicine divisions seem to be in a favourable
position, especially in terms of costs (both per-diem and per-admission).
PMID- 9561022
TI - [Laboratory diagnosis of intestinal micro-parasitosis in AIDS patients: state of
the art].
AB - BACKGROUND: The diarrhea, often associated with growing thin and weight loss, is
important for nutritional state and quality of life in AIDS patients. It was
demonstrated that patients with AIDS who present diarrhea have a greater degree
of immunosuppression than those without diarrhea, predisposing the
gastrointestinal tract to the action of protozoa, bacterial, viral, fungal
pathogens which may cause morbidity and death. HIV-patients are particularly
susceptible to protozoa infections. Cryptosporidium infection is among the most
common causes of enteric disease but Microsporidium (Enterocytozon bieneusi) and
Cyclospora are emerging as potentially important enteric pathogens in AIDS
patients. In spite of frequent interest of gastrointestinal tract the knowledge
of diarrhea syndromes AIDS-related are often greatly limited by diagnostic
difficulties. OBJECTIVE: A review is made of the different laboratory methods
employed in intestinal microparasitosis in the light of considerable
dangerousness and aggressiveness of some protozoa on HIV-patients. METHODS: The
methods for the diagnosis of intestinal microparasitosis are based particularly
on direct diagnosis (macroscopic or microscopic examination at fresh or after
concentration) or an immunological diagnosis. RESULTS: The laboratory methods
available at present permit to evidence different protozoa not evidenced in the
past and without invasive techniques. CONCLUSIONS: The etiological diagnosis of
diarrhea in AIDS-patients is often difficult and/or disappointing.
Epidemiological knowledge on protozoa pathology has been limited by diagnostic
difficulties but their identification is important particularly because an
increasing therapeutic regimens are now available to treat these infections.
PMID- 9561024
TI - Differential responsiveness of murine T lymphomas to local growth and invasion
factors may determine metastasis formation in the ovaries.
AB - The murine T cell hybridomas BW-14 and BW-19, both derived from a fusion between
the nonmetastatic BW 5147 lymphoma and a cytotoxic T cell line, differ in their
capacity to metastasize to the ovaries. While ovary colonization by BW-19 cells
is marginal and limited to the ovary follicles, BW-14 cells extensively colonize
the complete ovary. The present study shows that the two T cell hybridomas
respond differentially to ovary-derived migration and growth-modulating factors,
in a way that correlates with their differential capacity to metastasize to the
ovaries. More specifically, we observed that conditioned medium from cultured
ovary fragments or from the ovary-derived granulosa cell line GRMO1V inhibited
the migration of BW-19 cells in vitro, but stimulated the migration of BW-14
cells. Likewise, the local hormone prostaglandin E2 (PGE2) and the steroid
hormone progesterone, both known to be secreted by GRMO1V cells, stimulated the
migration of BW-14 cells, indicating that the stimulatory effect of the
conditioned medium can be at least partially ascribed to the action of these two
hormones. In contrast, the migration of BW-19 cells was inhibited by PGE2. In
addition to the modulatory effect on hybridoma cell migration, conditioned medium
from the granulosa cell line GRMO1V inhibited the proliferation of BW-19 cells in
vitro, an effect that is likely to be mediated at least partially by PGE2. The
proliferation of BW-14 cells, on the other hand was, depending on the dilution
used, stimulated or inhibited by GRMO1V-conditioned medium. Our findings indicate
that the differential capacity of the T cell hybridomas BW-14 and BW-19 to
metastasize to the ovaries is mediated by the differential action of granulosa
cell-derived factors, in particular the sex hormone progesterone and the local
hormone PGE2, on both the migration and proliferation of the T cell hybridomas.
PMID- 9561025
TI - IL-10 inhibition of human prostate PC-3 ML cell metastases in SCID mice: IL-10
stimulation of TIMP-1 and inhibition of MMP-2/MMP-9 expression.
AB - The molecular mechanism by which IL-10 inhibits metastases was examined using a
SCID mouse model. Human PC-3 ML subclones normally metastasize to the lumbar
vertebrae (approximately 70% mice injected, n = 14/20) following intravenous
injection in severe combined immunodeficient (SCID) mice. IL-10 treatment of the
PC-3 ML cells (15 ng/ml for 36 h) and the SCID mice (0.03 mg/kg/day for 30 days)
reduced the number of metastases to 5% of the mice (n = 1/20). More importantly,
following discontinuation of IL-10 treatment on day 30, the mice remained tumor
free and mouse survival rates increased dramatically (from < 30% in untreated
mice) to about 85% in IL-10-treated mice. IL-10 did not appear to alter the
growth rates or colony-forming ability of the PC-3 ML cells in vitro. Likewise,
the growth of subcutaneous tumors and established bone marrow metastases was not
inhibited by IL-10 treatment of the SCID mice. However IL-10 may inhibit the
production of matrix metalloproteases (MMP) and prevent the establishment of
metastasis. We therefore examined the influence of IL-10 on PC-3 ML production of
MMP-2/MMP-9 and the tissue inhibitors of metalloproteinases (TIMP-1/2). Enzyme
linked immunosandwich assays (ELISAs) revealed that IL-10 (15 ng/ml for 36 h)
treatment of the PC-3 ML cells down-regulated MMP-2 and MMP-9 while up-regulating
TIMP-1 (not TIMP-2) expression. Likewise, IL-10-treated mice exhibited similar
changes in TIMP-1 and MMP-2/MMP-9 expression. The IL-10 effects were blocked by
IL-10 receptor antibodies. In comparison to IL-10, IL-4 failed to influence
metastasis or the expression of TIMP-1, TIMP-2, MMP-2 and MMP-9 by PC-3 ML cells.
We suggest that IL-10-regulated increases in the molar ratio of TIMP-1/MMP-9 and
TIMP-2/MMP-2 might inhibit processes critical to the establishment of bone marrow
metastasis.
PMID- 9561026
TI - Immunophenotype of human HT29 colon cancer cell metastases in the lungs of scid
mice: spontaneous versus artificial metastases.
AB - The aim of this study was to compare the immunophenotype of the human colon
cancer cell line HT29 tumour deposits in the lung which occurred spontaneously
after subcutaneous implantation with those which arose after intravenous
injection into severe combined immunodeficient (scid) mice. Irrespective of the
route of implantation the colon cancer cells were readily observed in the lungs
of the scid mice. Similar patterns of immunoreactivity for the proliferative
markers (MiB-1, PCNA), and for the tumour suppressor gene (p53) were detected in
both groups, and for carcinoembryonic antigen, with only minor quantitative
differences in levels of marker expression. Whereas the marker CD44 variant 6
gave very little reaction after either route, cytokeratin expression varied
amongst the different cytokeratins (CK 7, 18 or 20), and with the route of
implantation. CA125 and E-cadherin were weakly expressed after intravenous
injection, but generally not after subcutaneous implantation. Vimentin was not
demonstrated in any of the specimens examined. In general, the expression of
proliferative markers, and of oncogenes, appears to be independent of the
implantation route, whilst expression of cell adhesion molecules can be dependent
on the route of implantation.
PMID- 9561027
TI - Alpha-melanocyte-stimulating hormone blocks invasion of reconstituted basement
membrane (Matrigel) by murine B16 melanoma cells.
AB - We have examined the effect of alpha-melanocyte-stimulating hormone (alpha-MSH)
on invasive ability of murine melanoma cell lines with different metastatic
potential in a Matrigel invasion assay. alpha-MSH potently blocked the invasion
of B16-BL6 cells with highly metastatic potential in a concentration-dependent
manner, whereas it was less effective in inhibiting the invasion of weakly
metastatic B16-F1 cells. Pretreatment of B16-BL6 cells with alpha-MSH resulted in
a decrease of the adhesiveness to fibronectin and laminin substrates in a time
dependent fashion. As assessed by zymographic analysis, alpha-MSH partially
inhibited the production of matrix metalloproteinase (MMP)-2 and -9 from both
cell lines to a similar degree without affecting the degradative activity of
these MMPs. alpha-MSH was more potent in inhibiting the migration of B16-BL6
cells towards both fibronectin- and laminin-coated substrates than that of B16-F1
cells. The growth and morphology of B16-BL6 cells were not changed after a 7-day
incubation with alpha-MSH. The number of lung tumor colonies markedly decreased
when B16-BL6 cells were coinjected intravenously with 10(-6) M alpha-MSH.
However, alpha-MSH had no effect on the experimental lung metastases by B16-F1
cells. These results suggest that alpha-MSH suppressed the invasive and
metastatic properties of B16 melanoma cells, and the degree of inhibition was
associated with metastatic potential of B16 melanoma cells.
PMID- 9561028
TI - Relationship of epidermal growth factor binding capacity to histopathologic
features and prognosis in human renal cell carcinoma.
AB - We studied the association between epidermal growth factor (EGF) binding capacity
and histopathologic features or prognosis in human renal cell carcinoma (RCC) by
Scatchard analysis in 67 patients. EGF binding capacity was significantly greater
in metastatic than in nonmetastatic tumors, and in nuclear grade 3 than nuclear
grade 1 tumors. Multivariate analysis revealed that tumor stage, nuclear grade,
EGF binding capacity, and tumor size significantly correlated with overall
survival. These results suggest that EGF binding may be an important determinant
of prognosis in patients with RCC.
PMID- 9561030
TI - Macromolecular contrast media-enhanced MRI estimates of microvascular
permeability correlate with histopathologic tumor grade.
PMID- 9561029
TI - Adhesion of human breast carcinoma to extracellular matrix proteins is modulated
by galectin-3.
AB - In this report, we have analyzed the adhesive interactions of a breast carcinoma
cell line, BT-549, and its galectin-3-transfected subclone 11-9-1-4 with laminin,
collagen IV and fibronectin. We determined that 11-9-1-4 cells adhered much more
rapidly (within 1 h of plating) to laminin- and collagen IV-coated wells than the
galectin-3 null expressing BT-549 cells. However, after 24 h, both cell lines
fully adhered to laminin and collagen IV. Both cell lines also achieved maximum
adhesion to fibronectin within 30 min. Not only did 11-9-1-4 express galectin-3
in the usual punctate pattern on its cell surface, it demonstrated a higher
surface expression of alpha 6 beta 1 integrin compared to BT-549. The 11-9-1-4
cells were able to invade through matrigel-coated polycarbonate filters at
approximately 3 times the rate of BT-549 parental cells. Our data suggest that
galectin-3 is essential for adhesion to laminin and collagen IV but not
fibronectin by breast carcinoma cells. In addition, galectin-3 expression may
modulate the surface expression of some of the integrins specific for laminin and
collagen IV adhesion and invasion of basement membrane by breast carcinoma cells.
PMID- 9561031
TI - New liposomal liver-specific contrast agent for CT: first human phase I clinical
trial assessing efficacy and safety.
PMID- 9561032
TI - Contrast enhancement of the liver in healthy male volunteers following
intravenous administration of FP 736-04.
PMID- 9561033
TI - Efficacy of the hepatocyte-specific contrast medium FP 736-04 for CT in two
models of experimental diffuse liver disease.
PMID- 9561034
TI - Lipid-based blood-pool CT imaging of the liver.
AB - RATIONALE AND OBJECTIVES: We have recently developed an iodinated lipid-based
contrast agent capable of residing in the blood pool for extended periods of time
relative to conventional water-soluble contrast agents. The purpose of this study
was to examine the effects of combining this new blood-pool agent (ITG-PEG) with
a hepatocyte-selective agent (ITG-LE; Molecular Biosystems) for accurate CT
detection of small (< 10 mm) VX2 tumors in rabbit liver. MATERIALS AND METHODS:
Preliminary pharmacokinetic analyses were conducted in SD rats (12) by injection
of either I-125-labeled ITG-PEG or I-125-labeled ITG-LE followed by subsequent
blood collection and quantification of radioactivity. Preliminary CT studies were
conducted in both normal (3) and tumor-bearing NZW rabbits (2). Tumor-bearing
rabbits were laparotomized and VX2 cells injected directly into the hepatic
parenchyma to produce a total of eight focal lesions (2-10 mm diameter). Animals
underwent CT scanning 10 days later with multiple techniques including
noncontrast and helical i.v. enhanced (600 mg I/kg iohexol), and then 24 hours
later using both ITG-PEG and ITG-LE (200 mg I/kg). Tissue density measurements
(HU) of liver, tumor, and blood (descending aorta) were acquired in each case for
comparison. Tumor morphology was verified by gross pathologic inspection.
RESULTS: Pharmacokinetic analysis in rats as well as CT studies in normal rabbits
revealed that ITG-PEG remains in the blood-pool phase for more than 2 hours
following i.v. administration. In fact, blood density in normal rabbit obtained
with ITG-PEG was 95.1 HU +/- 5.8 at 120 minutes compared to 90.7 HU +/- 6.1
immediately after injection. Although liver enhancement was greater with iohexol
(67 HU within 1 minute of injection), than for ITG-PEG/ITG-LE (32 HU, 60 minutes
postinjection), liver to lesion ratios favored ITG-PEG/ITG-LE due to significant
enhancement of tumor itself with iohexol (+40 HU). Tumor enhancement was minimal
with ITG-PEG/ITG-LE. Lesions were subjectively much better defined with ITG
PEG/ITG-LE with sharper edge definition. CONCLUSION: In these animal models, a
new iodinated lipid-based contrast agent composed of both blood pool and
hepatocyte-selective components afforded favorable CT imaging results compared to
a conventional urographic agent, albeit at one-third the total iodine dose.
PMID- 9561035
TI - Safety and pharmacokinetics of BR21, a liver-specific CT agent, in healthy
volunteers.
PMID- 9561036
TI - Evaluation of N,N'-bis-dimethyldiatrizoic acid analogs as liver imaging agents.
PMID- 9561037
TI - Assessment of acute and reperfused myocardial ischemia using GdDTPA, GdDTPA
cascade-24-polymer and albumin-GdDTPA.
PMID- 9561038
TI - Investigation of MR contrast media utility with the VX-2 tumor model.
PMID- 9561039
TI - Validation of intracoronary delivery of metalloporphyrin as an in vivo
"histochemical staining" for myocardial infarction with MR imaging.
PMID- 9561040
TI - Toward necrotic cell fraction measurement by contrast-enhanced MRI of reperfused
ischemically injured myocardium.
PMID- 9561042
TI - Selection of contrast medium for CT: what percentage of patients receiving CT
needs nonionic contrast media (low-osmolarity contrast media)?
PMID- 9561041
TI - Human pharmacokinetics and modeling of the concentration-attenuation relationship
of a new liposomal liver-specific contrast agent for CT.
PMID- 9561043
TI - Safety of carbon dioxide as a contrast medium in cerebral angiography.
PMID- 9561044
TI - Clinical usefulness of iomeprol 400 mgl/ml in cardioangiography evaluation of
patient discomfort and hemodynamic and ECG effects.
PMID- 9561045
TI - Prospective randomized crossover pilot study of the safety and efficacy of carbon
dioxide versus iodinated contrast for peripheral angiography.
PMID- 9561046
TI - High-resolution harmonic gray-scale imaging of normal and abnormal vessels and
tissues in animals.
PMID- 9561047
TI - Phase II, placebo-controlled trial of MRX115 (Aerosomes) for left heart and
myocardial perfusion imaging.
PMID- 9561048
TI - Clinical experience with AF0150 (Imagent US), a new ultrasound contrast agent.
PMID- 9561049
TI - Contrast-enhanced MRI of focal liver lesions: differentiation and detection of
primary and secondary liver lesions using Resovist-enhanced versus gadolinium
enhanced MRI in the same patient.
PMID- 9561050
TI - Experimental hepatic dysfunction: evaluation by MR imaging with Gd-EOB-DTPA.
PMID- 9561051
TI - Efficacy and safety of liver-specific MRI contrast agents in rats with hepatitis
and cirrhosis.
PMID- 9561052
TI - Multihance clinical pharmacology: biodistribution and MR enhancement of the
liver.
PMID- 9561053
TI - Dysprosium EOB DTPA: a new liver-specific contrast agent for computed tomography.
PMID- 9561054
TI - Can contrast media Act as "pseudoantigens"?
PMID- 9561055
TI - Effect of steroid pretreatment on contrast media-induced potassium release.
PMID- 9561056
TI - Involvement of the lung in the histamine-releasing effects of iodinated contrast
media.
PMID- 9561057
TI - Contrast-enhanced magnetic resonance angiography in the coronary and peripheral
arteries.
PMID- 9561058
TI - Application of superparamagnetic iron oxide (AMI-227) for 3D phase-contrast MR
angiography.
PMID- 9561059
TI - Good resolution of contrast-enhanced MRA using USPIO on coronal plane
acquisition: experimental evaluation of time-of-flight effect using flow phantom
and animal study.
PMID- 9561060
TI - Receptor-mediated mechanisms in contrast medium-induced renal vasoconstriction.
PMID- 9561061
TI - Influence of iotrolan on renal cortical and outer medullary blood flow in the
rat.
PMID- 9561063
TI - Optimizing imaging techniques to reduce errors in microvascular quantitation with
macromolecular MR contrast agents.
PMID- 9561062
TI - Visualizing renal anatomy and function with 1-10,000-nm radiocontrast agents.
PMID- 9561064
TI - T1 and T2 relaxometry of monocrystalline iron oxide nanoparticles (MION-46L):
theory and experiment.
PMID- 9561065
TI - Simultaneous use of Gd-DTPA and spin-lock imaging: a Phantom Study.
PMID- 9561066
TI - Multisite study of the safety and efficacy of LumenHance, a new gastrointestinal
contrast agent for MRI of the abdomen and pelvis.
PMID- 9561067
TI - Pharmacokinetic and hemodynamic safety of two superparamagnetic agents, Endorem
and Sinerem, in cirrhotic rats.
PMID- 9561068
TI - Multicenter evaluation of the safety, tolerance, and efficacy of OptiMARK in
magnetic resonance imaging of the brain and spine.
PMID- 9561069
TI - Delayed adverse reaction of monomeric contrast media: comparison of plain CT and
enhanced CT.
PMID- 9561070
TI - Drug eruption caused by nonionic iodinated X-ray contrast media.
PMID- 9561071
TI - Delayed hypersensitivity to X-ray CM: possible mechanisms and models.
PMID- 9561072
TI - MR imaging of lymph nodes in patients with primary abdominal and pelvic
malignancies using ultrasmall superparamagnetic iron oxide (Combidex).
PMID- 9561073
TI - MR lymphography: evidence of extravasation of superparamagnetic nanoparticles
into the lymph.
PMID- 9561074
TI - Enhanced detection of thrombi with a novel fibrin-targeted magnetic resonance
imaging agent.
PMID- 9561075
TI - X-ray phototherapy for solid tumors.
PMID- 9561076
TI - Contrast-enhancement properties of irradiated normal lymph nodes: initial
experience with interstitially delivered iodinated nanoparticles.
PMID- 9561077
TI - Diagnostic improvement of renal ultrasonography in humans after i.v. injection of
perflenapent emulsion.
PMID- 9561078
TI - Liver-tumor detection with ultrasound contrast: a blinded prospective study in
rabbits.
PMID- 9561079
TI - Safety of levovist injection in patients undergoing exercise stress
echocardiography: a placebo-controlled study.
PMID- 9561080
TI - Enhancement of power Doppler signals from breast lesions with the ultrasound
contrast agent EchoGen emulsion: subjective and quantitative assessment.
PMID- 9561081
TI - Blood-pool contrast agents for MRI: a critical evaluation.
PMID- 9561082
TI - Kinetics of a novel blood pool agent (MP-2269) with persistent high relaxivity
for MR angiography.
PMID- 9561083
TI - Development of a novel nonaromatic small-molecule MR contrast agent for the blood
pool.
PMID- 9561084
TI - Evaluation of Gd-DOTA-labeled dextran polymer as an intravascular MR contrast
agent for myocardial perfusion.
PMID- 9561085
TI - Contrast-enhanced MR angiography and first-pass renal perfusion imaging using MS
325, an intravascular contrast agent.
PMID- 9561086
TI - Use of intravascular contrast agents in MRI.
PMID- 9561087
TI - Factors determining tumor contrast enhancement-time curves.
PMID- 9561088
TI - Dynamic susceptibility contrast MR imaging for the evaluation of probable
Alzheimer disease: a cost-effectiveness analysis.
PMID- 9561089
TI - Stimulated acoustic emission imaging ("sono-scintigraphy") with the ultrasound
contrast agent Levovist: a reproducible Doppler ultrasound effect with potential
clinical utility.
PMID- 9561090
TI - Evaluation of new thrombus-specific ultrasound contrast agent.
PMID- 9561091
TI - Targeting of ultrasound contrast material: selective imaging of microbubbles in
vitro.
PMID- 9561092
TI - MRX 501: a novel ultrasound contrast agent with therapeutic properties.
PMID- 9561093
TI - Use of intravenous Optison contrast echocardiography reduces downstream resource
use and enhances cost savings.
PMID- 9561094
TI - Some recent advances in leukotriene research.
PMID- 9561095
TI - Practical aspects of prostaglandin E1 before and after solid organ
transplantation.
PMID- 9561096
TI - Prostaglandins in liver transplantation.
AB - This review summarizes experimental studies and clinical experiences with
prostaglandins in liver transplantation emphasizing two randomized, double
blinded placebo controlled clinical trials of prostaglandin E1 (PGE1) involving
nearly 300 liver transplant recipients. Resource utilization and pharmacoeconomic
aspects are also discussed. In the randomized trials, PGE1 did not affect patient
and graft survival. Acute cellular rejection and primary allograft non-function
were not reduced by PGE1. Postoperative renal failure was significantly less
frequent among PGE1 patients in both trials and in one study perioperative blood
product utilization was significantly lower. PGE1 treated patients had reduced
intensive care unit length of stay, shorter hospitalization, and significantly
lower total health care charges. Despite its failure to show improvements in
patient and graft survival, rejection, or primary non-function, PGE1 use in
hepatic allograft recipients reduces morbidity and results in notable reduction
in the cost of liver transplantation.
PMID- 9561097
TI - Prostaglandins in heart transplantation.
PMID- 9561098
TI - Eicosanoids in periodontal diseases: potential for systemic involvement.
AB - The potential application of gingival crevicular fluid (GCF) levels of
prostaglandin E2 (PGE2) for predicting periodontal disease severity and
reflecting disease activity has been described by several investigators. The
potential application of GCF levels of PGE2 for predicting amniotic fluid levels
of PGE2, and thereby estimating risk of preterm low birth weight, has not been
explored until recently. The fact that intraamniotic levels of many inflammatory
mediators, such as prostaglandin E2, increase during pregnancy and peak at
delivery suggests that these mechanisms play an important role in normal
physiologic parturition. There is increasing evidence to suggest that the
presence of a subclinical endogenous Gram-negative infection of periodontal
disease may present a systemic challenge sufficient to initiate the onset of
premature labor, either as a source of lipopolysaccharide (LPS, endotoxin) and/or
through stimulation of secondary inflammatory mediators such as PGE2 and
interleukin 1 beta (IL-1 beta). This pilot investigation determines associations
among the levels of PGE2 in gingival crevicular fluid, within serum, and within
amniotic fluid of 18 women who were undergoing routine amniocentesis during early
midtrimester, in an attempt to reveal new baseline data regarding the
relationship between periodontal inflammatory mediators and intraamniotic
mediators during normal parturition. Full-mouth periodontal examinations were
performed and samples of GCF, serum and amniotic fluid were collected from each
subject for the quantitative assessment of PGE2 by radioimmunoassay (RIA).
Results of a pairwise regression analysis model reveal that PGE2 levels within
the GCF are positively associated with intraamniotic PGE2 levels at the P = 0.018
level of significance. Thus, gingival crevicular levels of PGE2 may be used to
provide an indirect estimate of the amniotic fluid levels of PGE2.
PMID- 9561099
TI - Mitogen-activated protein kinases and endothelial prostacyclin secretion.
PMID- 9561100
TI - Crosstalk between elevation of [Ca2+]i, reactive oxygen species generation and
phospholipase A2 stimulation in a human keratinocyte cell line.
AB - The aim of the study was to explore the possible interrelationship between
reactive oxygen species (ROS) formation and cPLA2 activation and the mediator
role that [Ca2+]i may play in these processes in the human keratinocyte cell
line, HaCaT. HaCaT cells can be invoked to transiently produce ROS by epidermal
growth factor (EGF), thapsigargin (TPG) and the Ca(2+)-ionophore, A23187. These 3
agonists transiently increase [Ca2+]i with characteristic kinetics and magnitude.
TPG and A23187 each activates on its own [3H]AA release from prelabeled cells,
whereas EGF on its own has no effect on [3H]AA release. However, EGF augments
[3H]AA release invoked by TPG or A23187 several fold. EGF activates MAP kinase
cascades in HaCaT cells, leads to ROS formation and induces relatively small (1.6
fold) elevation in [Ca2+]i, whereas A23187 and TPG lead to a substantial
elevation in [Ca2+]i (2.5 to 5 fold) and to ROS formation. Both have a minor
effect on MAP kinase activation. The synergism in PLA2 activation by EGF and TPG
or A23187, and the sensitivity of [3H]AA release to N-acetylcysteine (NAC) and
dithiothreitol (DTT) (potent reducing agents) or to DPI (an inhibitor of FAD
dependent oxidases) lead to the suggestion that ROS formation, elevation of
[Ca2+]i and PLA2 activation are causally related. Since we show that elevation of
[Ca2+]i is a prerequisite for both ROS and PLA2 activation, it is possible that
these processes contribute to the toxicity (apoptosis) exerted by chronic
elevation of [Ca2+]i.
PMID- 9561101
TI - Cloning, tissue-specific expression and regulation of the bovine thromboxane A2
receptor.
PMID- 9561102
TI - Weak inhibitors of cyclooxygenases may exert their antinociceptive effect by
modulation of transcription factors.
PMID- 9561104
TI - Biosynthesis of novel divinyl ether oxylipins by enzyme from garlic (Allium
sativum L.) bulbs.
PMID- 9561103
TI - New group of lipid mediators containing omega-hydroxyarachadonic acid (20-HETE).
PMID- 9561105
TI - Catalytic and spectroscopic properties of linoleate diol synthase of the fungus
Gaumannomyces graminis.
PMID- 9561106
TI - Avenoleic acid: a new oxylipin from oat seeds.
PMID- 9561107
TI - Discovery of novel cannabinoid receptor ligands from diverse marine organisms.
PMID- 9561108
TI - Accumulation of platelets as a key mechanism of human erection. A scintigraphic
study in patients with erectile dysfunction receiving intracavernous injection of
PGE1, papaverine/phentolamine.
PMID- 9561109
TI - Can self-injection therapy cure impotence?
PMID- 9561110
TI - Cytokine levels in five different fluid compartments during amniotic fluid
infection and labour.
PMID- 9561111
TI - Characterization of A-93178, an iminoxy-quinoline inhibitor of leukotriene
biosynthesis.
PMID- 9561112
TI - Transcellular synthesis of Cys-LT: from isolated cells to complex organ system.
PMID- 9561113
TI - Leukotriene D4-induced signalling events in human epithelial cells: G alpha i3
activation and translocation.
AB - Our model of LTD4-induced signal transduction in epithelial cells is summarised
in Figure 2. Extending what is already known about LTD4 signalling in epithelial
cells, we identified the Gi3-protein as the crucial PTX sensitive G-protein and
found that it is translocated to what might be a cytoskeletal fraction. This
finding suggests a subtle response to LTD4, mediated via the bifurcation at the
alpha/beta gamma junction. Although little is known about the role of epithelial
cells in inflammation, it has been shown that such cells produce the potent
chemoattractant LTB4 and the proinflammatory 5-HETE in response to intracellular
accumulation of Ca2+ 24. The target protein(s) and the effect(s) of the
translocation of the activated G alpha i3-proteins, as well as the possible role
of the beta/gamma-subunits of Gi3, remain to be elucidated.
PMID- 9561114
TI - Interactions of renal cytochrome P450 (CYP), angiotensin (AII) and tumor necrosis
factor-alpha (TNF): implications for ion transport.
PMID- 9561115
TI - Modulation of leukocyte-endothelial cell interaction and leukotriene dependent
vasoconstriction by prostacyclin mimetics in the isolated rabbit heart.
PMID- 9561116
TI - Improvement of renal function with selective thromboxane A2 synthetase inhibitor,
DP-1904 in lupus nephritis.
PMID- 9561117
TI - Characterization of the prostaglandin EP3-receptor from porcine heart.
PMID- 9561118
TI - Bisallylic hydroxylation of linoleic and arachidonic acids by adult and fetal
human liver microsomes and a comparison with human recombinant cytochromes P450.
PMID- 9561119
TI - Organization of the human prostacyclin synthase gene and association analysis of
a novel CA repeat in essential hypertension.
PMID- 9561120
TI - Mechanism of action of anti-inflammatory drugs.
PMID- 9561122
TI - In vivo measurement of interstitial TxB2-concentrations in skeletal muscle during
ischemia and reperfusion.
PMID- 9561121
TI - Differential effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the expression of
prostaglandin-H synthase isoenzymes in mouse tissues.
PMID- 9561123
TI - Mutation of Tyr-383 in leukotriene A4 hydrolase: effects on enzyme activities.
PMID- 9561124
TI - Prostaglandin receptors of the EP2 and EP4 subtypes regulate B lymphocyte
activation and differentiation to IgE-secreting cells.
PMID- 9561125
TI - Urinary 9 alpha, 11 beta-PGF2 as a marker of mast cell activation in allergic and
aspirin-intolerant asthma.
PMID- 9561126
TI - Induction of nitric oxide synthase (NOS) and vascular endothelial growth factor
(VEGF) in experimental model of angioplasty and heart ischemia.
PMID- 9561127
TI - CGP57698: a structurally simple, highly potent peptido-leukotriene (pLT)
antagonist of the quinoline type.
PMID- 9561128
TI - S 18886, a new thromboxane (TP)-receptor antagonist is the active isomer of S
18204 in all species, except in the guinea-pig.
PMID- 9561130
TI - Prostaglandin E2 downregulates inducible nitric oxide synthase expression in
microglia by increasing cAMP levels.
PMID- 9561129
TI - Glial and neuronal expression of cyclooxygenase-2: relevance to Alzheimer's
disease.
PMID- 9561131
TI - Formation of a novel class of F3-isoprostanes during peroxidation of
eicosapentaenoic acid (EPA).
PMID- 9561132
TI - Plasma 8-epi PGF2 alpha levels in health and disease.
PMID- 9561133
TI - Regulation of MAP-kinase activation by 8-iso-prostaglandin F2a in cultured rat
aortic smooth muscle cells.
PMID- 9561134
TI - The effect of non-prostanoid prostacyclin mimetics on cyclic AMP production by
neuronal SK-N-SH cells.
PMID- 9561135
TI - Biosynthesis of 2-arachidonoyl-glycerol, a novel cannabimimetic eicosanoid, in
mouse neuroblastoma cells.
PMID- 9561136
TI - Hyperalgesia-associated spinal synthesis and release of prostaglandins.
PMID- 9561137
TI - Functional consequences of the identification and localisation of cyclooxygenase
isoforms in dorsal horn of rat spinal cord.
PMID- 9561138
TI - Cyclooxygenase-2 in the spinal cord: localization and regulation after a
peripheral inflammatory stimulus.
AB - Prostaglandins are known as mediators in spinal nociceptive processing after
peripheral inflammation. Cyclooxygenase isozymes Cox-1 and Cox-2 as enzymes
essential for prostaglandin biosynthesis were therefore investigated in rat
spinal cord. mRNA and protein of both enzymes was detected in cervical and lumbar
sections of the spinal cord of normal animals. Enzyme activity of Cox-1 and Cox-2
could be determined by the use of specific inhibitors. Cox-2-immunoreactivity
(IR) was found in the spinal cord of untreated rats in neurons of laminae II-III,
motoneurons of lamina IX and in glial cells. Most prominent staining was observed
in the nuclear envelope. Under an acute peripheral inflammatory stimulus a
transient 2-fold increase in Cox-2 mRNA was noticed bilaterally in the lumbar
spinal cord by reverse transcription-polymerase chain reaction. This increase was
reflected on a smaller scale at protein levels in Western blot analysis of spinal
membrane preparations. In the chronic state of adjuvant-induced arthritis, Cox-2
levels were raised again significantly. Cox-2 might therefore be regarded as the
Cox isozyme responsible for increased spinal prostanoid release in nociceptive
processing under peripheral stimulation.
PMID- 9561139
TI - The production of biologically active eicosanoids by yeasts.
PMID- 9561140
TI - Is lipoxygenation of pathogen-derived arachidonic acid involved in plant
protection?
PMID- 9561141
TI - The production of eicosanoid precursors by mucoralean fungi.
PMID- 9561142
TI - Biotransformation of arachidonic acid and other eicosanoids by the yeast
Dipodascopsis uninucleata, the oomycete fungi Saprolegnia diclina and Leptomitus
lacteus and the zygomycete fungus Mortierella isabellina.
PMID- 9561143
TI - Human prostacyclin receptor: cloning and co-expression with EP3 prostaglandin
receptor.
PMID- 9561144
TI - Three isoforms of the prostaglandin E receptor EP3 subtype different in agonist
independent constitutive Gi activity and agonist-dependent Gs activity.
PMID- 9561145
TI - Neurogenic inhibitory action through platelets of platelet activating factor
(PAF) on vasoconstrictive responsiveness to pressor agents.
PMID- 9561146
TI - High and low affinity mutants of platelet-activating factor receptor.
PMID- 9561147
TI - Differential effect of corticotropin releasing factor on interleukin-1 alpha and
interleukin-1 beta-induced prostaglandin synthesis in endothelial cells and
fibroblasts.
PMID- 9561148
TI - Brain and peripheral anandamide amidohydrolase and its inhibition by synthetic
arachidonate analogues.
PMID- 9561149
TI - Effects of 13-HODE and other momohydroxides on integrin/ligand binding:
implications for cell cell interactions.
PMID- 9561150
TI - Effect of linoleic acid supplements on vessel wall hyperplasia in rabbits.
PMID- 9561151
TI - Effects of linoleic acid and/or marine fish oil supplements on vessel wall
thromboresistance in patients undergoing cardiac surgery.
PMID- 9561152
TI - 13-Hydroxyoctadecadienoic acid reverses epidermal hyperproliferation via
selective inhibition of membrane protein kinase C-beta activity.
PMID- 9561154
TI - The importance of linoleic acid metabolites in cancer metastasis and in the
synthesis and actions of 13-HODE.
AB - Large scale human epidemiological studies indicate that high intakes of linoleic
acid protect against the development of cancer. One mechanism may be the
generation of 13-HODE from linoleic acid. 13-HODE prevents cell adhesion to
endothelial cells and can inhibit cancer metastasis. 13-HODE synthesis is
enhanced by cyclic AMP. Gamma-linolenic acid, a desaturated metabolite of
linoleic acid, causes substantial stimulation of 13-HODE synthesis. A fall in
gamma-linolenic acid synthesis with age may be related to the age-related fall in
13-HODE formation.
PMID- 9561153
TI - Effects of linoleic acid supplements on atopic dermatitis.
PMID- 9561156
TI - Mice lacking 5-lipoxygenase have increased cortical bone thickness.
PMID- 9561155
TI - The role of prostaglandins and nitric oxide in the response of bone to mechanical
stimulation.
PMID- 9561157
TI - Parathyroid hormone induction of cyclooxygenase-2 expression in human osteoblasts
depends on both cyclic AMP and calcium-dependent pathways.
PMID- 9561159
TI - Mechanotransduction in bone cells: induction of nitric oxide and prostaglandin
synthesis by fluid shear stress, but not by mechanical strain.
PMID- 9561158
TI - Involvement of prostaglandin endoperoxide H synthase-2 in osteoclast formation
induced by parathyroid hormone.
AB - Prostaglandin (PG)E2 is one of the most important endogenous bone resorbing
factors. In the previous study, we demonstrated that osteoclast formation induced
by IL-1 beta was mediated by PGE2 produced by induced prostaglandin endoperoxide
H synthase-2 (PGHS-2) in osteoclastic cells. In the same bone marrow culture
system, indomethacin also suppressed the osteoclast formation induced by PTH. The
inhibition was abolished by exogenously added PGE2 at dose as low as 3 x 10(-9)
M, which was too low to elevate the intracellular cAMP and calcium levels and
also it was too low to cause osteoclast formation by itself. In order to estimate
what kind of cell produced such small amount of PGE2 in the PTH treatment, we
carried out antibody staining of PGHS-1&PGHS-2 and PGHS activity in the intact
bone marrow cells. PTH was found to induce PGHS activity in tartrate-resistant
acid phosphatase (TRACP) positive mononuclear cells and the PGHS activity was
inhibited by NS-398, a specific inhibitor of PGHS-2. Immunocytochemical staining
supported the expression of PGHS-2 in TRACP-positive mononuclear cells. These
findings suggest that PGHS-2 induced by PTH may regulate osteoclast formation by
different mechanism from that induced by IL-1 beta.
PMID- 9561160
TI - Histamine potentiates leukotriene B4-induced leukocyte adhesion: a potential role
of histamine1-receptor antagonism in allergic leukocyte recruitment.
PMID- 9561161
TI - Gastric prostacyclin (PGI2) prevents stress-induced gastric mucosal injury in
rats by inhibiting leukocyte activation.
PMID- 9561162
TI - Anti-P-selectin antibody exacerbated inflammatory responses in acetic acid
induced colitis.
PMID- 9561163
TI - Heterogeneous distribution of COX-2 over-expression in human colon carcinoma
cells.
PMID- 9561164
TI - Hsp70: a subunit of the cytosolic 12(S)-HETE binding complex.
PMID- 9561165
TI - Apoptosis induction and inhibition of colon-26 tumour growth and angiogenesis:
findings on COX-1 and COX-2 inhibitors in vitro & in vivo and topical diclofenac
in hyaluronan.
PMID- 9561167
TI - Prostaglandin D synthase, beta-trace and sleep.
PMID- 9561166
TI - Phospholipase A2 inhibitory activity in lung cancer cell lines.
PMID- 9561168
TI - Human beta-trace in normal and pathological CNS tissues, genital organs and body
fluids.
AB - The function of BTP is still unknown. In CNS, the high amount of BTP in the white
CNS matter and the glial cells as well as in genital organs of the stroma of
epididymis suggest that BTP has a supportive function. Slight evidence of a
synthesis in patients with MS and slightly increased CSF values in stroke
patients may suggest that BTP is involved in repair mechanism of damaged brain
tissue, or may be related from destroyed brain tissue. In samples of CSF,
determination of BTP could be of value as differentiating glial cell tumors from
tumors of other kinds, as well as the recently suggested diagnostic value of the
Creutzfeldt-Jakob disease (20). However, also other functions of BTP has been
suggested. (21, 22).
PMID- 9561169
TI - Effect of immunization with beta-trace protein on testosterone levels in animals.
PMID- 9561170
TI - Eicosanoids mediate insect cellular immune reactions to bacterial infections.
PMID- 9561171
TI - Arachidonic acid and eicosanoids in Hydra: possible endogenous signals involved
in chemoreception and modulation of the feeding behaviour.
PMID- 9561172
TI - Synthesis and action of eicosanoids in warm and cold-acclimated amphibians.
PMID- 9561173
TI - Molecular and catalytic properties of mammalian lipoxygenases compared with
soybean lipoxygenase-1.
PMID- 9561174
TI - Leukotriene A4 hydrolase activity in Xenopus laevis.
PMID- 9561175
TI - Monocyte binding to endothelial cells induced by oxidized phospholipids present
in minimally oxidized low density lipoprotein is inhibited by a platelet
activating factor receptor antagonist.
AB - Our group has previously demonstrated that oxidized phospholipids derived from
mildly oxidized low density lipoprotein (MM-LDL) or oxidized 1-palmitoyl-2
arachidonoyl-sn-glycero-3-phosphorylcholine (oxPAPC) increase monocyte
endothelial interactions. There are indications that the effects of these
phospholipids are receptor mediated. Oxidized phospholipids have previously been
shown to activate cells via the platelet activating factor (PAF) receptor,
therefore, we pretreated human aortic endothelial cells (HAECs) with a PAF
receptor antagonist (WEB 2086) prior to treatment with oxPAPC. WEB 2086 inhibited
monocyte binding to endothelial cells induced by oxPAPC (200 micrograms/ml) at
concentrations from 1 nM to 10 microM, but had no effect on the induction of
monocyte binding induced by lipopolysaccharide (LPS). We were able to isolate and
identify several active oxidized phospholipids by combined normal phase high
performance liquid chromatography (HPLC) and electrospray mass spectrometry
(LC/MS). The induction of monocyte binding to HAECs by two of these partially
purified phospholipids was totally abolished by the pretreatment of HAECs with
WEB 2086 (100 nM). PAF itself, however, when tested at concentrations from 10 nM
to 10 microM had no effect on monocyte binding. These results suggest that
several of the oxidized phospholipids present in MM-LDL and oxPAPC induce
monocyte binding through a receptor which is perhaps distinct from the PAF
receptor, but can be blocked by the PAF-receptor antagonist WEB 2086.
PMID- 9561176
TI - Regulation of 5-lipoxygenase activity by selenium-dependent peroxidases-effects
of transforming growth factor-beta and 1,25-dihydroxyvitamin D3.
PMID- 9561177
TI - Thromboxane A2 potentiates thrombin-induced proliferation of coronary artery
smooth muscle cells.
AB - The activation of thrombin is the key event in clot formation after vascular
injury. Thrombin itself, but also other clot-derived factors, such as thromboxane
A2 (TXA2), are mitogenic for vascular smooth muscle cells. We have studied the
possible interactions between thrombin and TXA2 in stimulation of coronary artery
smooth muscle cell (SMC) proliferation. Thrombin (1 U/ml) caused a significant
proliferatory response in SMC. U 46619, a stable TXA2 mimetic, had only a minor
stimulating effect by its own but markedly potentiated the thrombin-induced
mitogenesis. A possible mechanism for these potentiating effects is provided by
the demonstration of a marked (6 fold) but transient (maximum after 20 min)
increase in the expression of TXA2 receptor (TP receptor) mRNA in SMC by
thrombin. Since a significant clot-related TXA2 generation was detected for at
least 2 hours, the up-regulation of TP receptors by thrombin may represent a
mechanism that is relevant for the in vivo situation of SMC proliferation after
vessel injury.
PMID- 9561178
TI - Isoforms of type-I 15-hydroxyprostaglandin dehydrogenase mRNA.
PMID- 9561179
TI - Keratinocyte growth factor increases LTC4 synthesis and expression of flap in
cultured rat alveolar type II cells.
PMID- 9561180
TI - Type-I 15-hydroxyprostaglandin dehydrogenase: role in macrophage/osteoclast
differentiation.
PMID- 9561181
TI - PGE2 and TXA2 production by isolated macrophages from human placenta.
PMID- 9561182
TI - Intrauterine eicosanoid production in uncomplicated and hypertensive pregnancies:
alterations of placental 12-hydroxyeicosatetraenoic acid.
PMID- 9561183
TI - Formation of cytochrome P450 metabolites of arachidonic acid by human placenta.
PMID- 9561184
TI - Prostaglandin endoperoxide H synthase-2 expression in human amnion cells:
involvement of tyrosine kinases in the regulation.
PMID- 9561186
TI - The development of a highly specific, sensitive enzyme immunoassay for
prostaglandin E1.
PMID- 9561185
TI - Prostaglandin E2 production by endogenous secretion of interleukin-1 in decidual
cells from term fetal membrane.
PMID- 9561187
TI - The use of chemiluminescence to detect eicosanoids with greater speed and
sensitivity.
PMID- 9561188
TI - Vascular wall-rather than platelet PGE1-pretreatment in-vivo (but not in-vitro)
decreases thrombogenicity.
PMID- 9561189
TI - A model of arachidonic acid binding for 15-lipoxygenase.
PMID- 9561190
TI - Changes in kinetic properties of cytosolic phospholipase A2 in activated rat
neutrophils.
PMID- 9561191
TI - Stimulation of PG I2-synthesis in the periodontal tissue by interleukin-1 alpha
and -1 beta.
PMID- 9561192
TI - Activation of cardiac EP3 receptors by PGE1 reduces beta-adrenergic inotropic
effects.
PMID- 9561193
TI - The aspartic proteinases. An historical overview.
PMID- 9561194
TI - The regulation of sequential processing of HIV-1 Gag by the viral protease.
PMID- 9561195
TI - A cellular anti-apoptosis protein is cleaved by the HIV-1 protease.
AB - Cleavage of non-viral proteins is rarely observed with the HIV-1 protease (HIV
pr). One such cleavage event occurs with bcl-2, an important cytoprotective
protein. The loss of bcl-2 has biological consequences, leading to enhanced HIV
replication and programmed death of the host cell. A strategy is proposed to
suppress HIV with non-cleavable mutants of bcl-2.
PMID- 9561196
TI - Engineering catalytically defective forms of HIV protease to modulate its
activity.
PMID- 9561197
TI - The aspartic proteinase from equine infectious anaemia virus.
PMID- 9561198
TI - The effect of substrates on the kinetics and the in vivo threshold activity of
mutant HIV-1 proteases.
PMID- 9561199
TI - A comparison of gag-pol precursor cleavage in naturally arising HIV variants.
PMID- 9561200
TI - X-ray crystallographic studies of the structure-function relationships of HIV-1
protease.
PMID- 9561201
TI - Optimization of a macromolecular inhibitor of HIV-1 protease.
PMID- 9561202
TI - In vitro selection and characterization of VX-478 resistant HIV-1 variants.
AB - VX-478 (141W94), a potent inhibitor of HIV protease, is in late stage clinical
trials for the treatment of HIV infection and AIDS. Resistant viruses were raised
in vitro by passage of HIV-1IIIB in the presence of increasing concentrations of
VX-478 and the related hydroxyethylamino sulfonamide inhibitor VB-11,328. By
direct PCR analysis of selected viruses, a number of mutations were identified
(L10F, M46I, I47V, I50V and I84V) in the protease gene. These mutations were
introduced into recombinant HIV-1 protease and the mutant enzymes assayed against
a panel of inhibitors of diverse chemical structure. For VX-478, significant
increases in IC90 and Ki were observed for virus or protease, respectively,
containing I50V single mutation or an M46I/I47V/I50V triple mutation. The mutant
proteases were also characterized for their kinetic competence to process
substrates representing cleavage sites of gag-pol viral polypeptide. The kinetic
data were interpreted with the aid of molecular modeling to understand the effect
of mutations on inhibitor binding and processing of the gag-pol polypeptide to
generate infective virions.
PMID- 9561203
TI - Sensitivity to inhibition and catalytic efficiency of HIV proteinase mutants.
PMID- 9561205
TI - Investigation of an allosteric site of HIV-1 proteinase involved in inhibition by
Cu2+.
PMID- 9561204
TI - Computer assisted evaluation of inhibitor sensitivity to HIV-1 PR mutants.
PMID- 9561206
TI - Analysis of autoprocessing of Mason-Pfizer monkey virus proteinase in vitro.
Three active forms of proteinase.
PMID- 9561207
TI - Subsequent selfprocessing of bovine leukemia virus proteinase in vitro.
PMID- 9561208
TI - Mechanism of action of aspartic proteases.
PMID- 9561209
TI - Theory and method of a priori computation of catalytic acts of aspartic and
serine proteinases.
PMID- 9561210
TI - Comparison of the specificity of the aspartic proteinases towards internally
consistent sets of oligopeptide substrates.
PMID- 9561211
TI - Expression of chimeric human aspartic proteinases.
PMID- 9561212
TI - Cathepsin E. The best laid plans of mice and men.
PMID- 9561214
TI - An aspartic proteinase expressed in the equine placenta.
AB - This manuscript describes the cloning of a novel aspartic proteinase expressed in
the placenta of the horse (order Perrisodactyla). Evidence for similar genes in
the cat (Carnivora) and ruminants (Artiodactyla), indicates that these molecules
have been conserved within widely divergent species with distinct types of
placentation. Since ePAG is produced by the outer cell layer (trophoblast) of the
placenta, it can tentatively be grouped with the pregnancy-associated
glycoproteins (PAG) of cattle, sheep, and pig. The high sequence identity that
ePAG shares with pepsinogens as well as the PAG, indicates that ePAG may be the
evolutionary bridge that links these two groups of aspartic proteinases.
PMID- 9561213
TI - Biosynthesis and intracellular targeting of the lysosomal aspartic proteinase
cathepsin D.
PMID- 9561215
TI - Protein engineering aspartic proteinases. Site-directed mutagenesis, biochemical
characterisation, and X-ray analysis of chymosins with substituted single amino
acid substitutions and loop replacements.
PMID- 9561216
TI - Post X-ray crystallographic studies of chymosin specificity. The role of
histidine-proline cluster of kappa-casein in catalytic reactions.
PMID- 9561217
TI - Epitope mapping of recombinant human procathepsin D.
PMID- 9561218
TI - Construction of chimeric enzymes to probe subsite contributions to catalytic
specificity.
PMID- 9561219
TI - Expression of multiple genes for pregnancy-associated glycoproteins in the sheep
placenta.
AB - Together these experiments have showed that there are many PAG genes in the ovine
genome and many of these are expressed in the placenta. These PAG genes vary as
much as 40% in nucleotide sequence identity. Thus, a wide range of ovPAG
molecules are secreted at the placental-uterine surface during pregnancy.
PMID- 9561220
TI - Mass spectrometry as a tool for studying the action of human aspartic proteases
on peptides and proteins.
PMID- 9561221
TI - Skin surface proteolytic activity. Partial characterization and identification.
AB - Skin surface proteolytic activity in the living animal was determined by a
sensitive, non-invasive methodology developed in our laboratory. A non-leaky well
was constructed on the shaved back of an anesthetized guinea pig. The well
contained the reaction mixture including the substrate 125I-S-carboxymethylated
insulin B-chain (ICMI). The proteolytic activity was shown to be time-dependent.
The activity was strongly inhibited by pepstatin A, indicating the involvement of
aspartic proteinase(s) such as cathepsin D and/or E. Pretreatment of the skin
with propylene glycol blocked the proteolytic activity. The present study
demonstrates the presence of proteolytic activity located on skin surface using a
unique, non-invasive method for in situ proteinase determination in the living
animal.
PMID- 9561222
TI - Cathepsin E in the central nervous system.
PMID- 9561223
TI - Detailed analysis of human cathepsin E prime region specificity.
PMID- 9561224
TI - Proteolytic and non-proteolytic activation of prorenin.
PMID- 9561225
TI - The roles of the basic residues in the prosegment of aspergillopepsinogen I.
PMID- 9561226
TI - Activation mechanism of pepsinogen as compared to the processing of HIV protease
gag-pol precursor protein.
PMID- 9561227
TI - Cardosinogen A. The precursor form of the major aspartic proteinase from cardoon.
PMID- 9561228
TI - Crystal structure of human pepsinogen A.
PMID- 9561229
TI - Crystallographic studies of an activation intermediate of human gastricsin.
PMID- 9561230
TI - Aspergillus niger acid proteinase A. Structure and function.
PMID- 9561231
TI - Crystal structure of the Rhizomucor miehei aspartic proteinase.
PMID- 9561232
TI - Rhizomucor miehei aspartic proteinases having improved properties.
PMID- 9561233
TI - Structure of secreted aspartic proteinases from Candida. Implications for the
design of antifungal agents.
AB - Pathogens of the genus Candida can cause life threatening infections in immuno
compromised patients. The three-dimensional structures of two closely related
secreted aspartic proteinases from C. albicans complexed with a potent (Ki = 0.17
nM) inhibitor, and an analogous enzyme from C. tropicalis reveal variations on
the classical aspartic proteinase theme that dramatically alter the specificity
of this class of enzymes. The novel fungal proteases present: i) an 8 residue
insertion near the first disulfide (Cys45-Cys50, pepsin numbering) that results
in a broad flap extending towards the active site; ii) a seven residue deletion
replacing helix hN2 (Ser110-Tyr114), which enlarges the S3 pocket; iii) a short
polar connection between the two rigid body domains that alters their relative
orientation and provides certain specificity; and i.v.) an ordered 12 residue
addition at the carboxy terminus. The same inhibitor (A-70450) binds in an
extended conformation in the two variants of C. albicans protease, and presents a
branched structure at the P3 position. However, the conformation of the terminal
methylpiperazine ring is different in the two crystals structures. The
implications of these findings for the design of potent antifungal agents are
discussed.
PMID- 9561235
TI - Bacterial aspartic proteinases as novel antibiotic targets.
PMID- 9561234
TI - Yapsin1. Structure, biosynthesis, and specificity.
PMID- 9561236
TI - Structural thermodynamic study of the binding of renin inhibitors to
endothiapepsin.
PMID- 9561237
TI - Development and testing of inhibitors of Candida aspartic proteinases.
PMID- 9561238
TI - Primary substrate specificities of secreted aspartic proteases of Candida
albicans.
PMID- 9561239
TI - Functional aspects of secreted Candida proteinases.
PMID- 9561240
TI - Substrate specificity of non-pepsin-type acid proteinase, Aspergillus niger
proteinase A.
PMID- 9561241
TI - Pepstatin-insensitive carboxyl proteinases from prokaryotes. Catalytic residues
and substrate specificities.
PMID- 9561242
TI - Overcoming the unfavourable entropic contribution of ligand binding with a
macrocyclic inhibitor bound to penicillopepsin.
PMID- 9561243
TI - Structural analysis of plasmepsin II. A comparison with human aspartic proteases.
PMID- 9561244
TI - Screening aspartyl proteases with combinatorial libraries.
AB - Large numbers of pharmaceutically relevant low-molecular weight compounds can now
be synthesized using combinatorial methods. Screening these large libraries of
compounds requires high throughput assays. These methods are utilized to search
for inhibitors of the aspartyl proteases, plasmepsin II and cathepsin D.
Plasmepsin II, a protease found in the malaria parasite, hydrolyzes human
hemoglobin, the nutrient source for the parasite and is a new target for anti
malaria therapy. Cathepsin D may be involved in many biological processes and
inhibitors would help to clarify the role of cathepsin D in these processes.
Plasmepsin II and cathepsin D are approximately 35% identical in amino acid
sequence. Therefore, a comparison of the screening results of these two enzymes
will be very useful in determining each enzyme's specificity and demonstrating
the power of utilizing encoded combinatorial libraries.
PMID- 9561245
TI - Thermodynamics and proton uptake for pepstatin binding to retroviral and
eukaryotic aspartic proteases.
PMID- 9561246
TI - Expression, purification, and characterization of the recombinant pepsin
inhibitor from Ascaris suum.
PMID- 9561247
TI - X-ray crystallographic studies of the complex between porcine pepsin and the
aspartic proteinase inhibitor PI-3 from the nematode Ascaris suum.
PMID- 9561248
TI - Studies on plasmepsins I and II from the malarial parasite Plasmodium falciparum
and their exploitation as drug targets.
PMID- 9561249
TI - Plasmepsins I and II from the malarial parasite Plasmodium falciparum.
PMID- 9561250
TI - Molecular cloning of aspartic proteinases from flowers of Cynara cardunculus
SUBSP. flavescens CV. cardoon and Centaurea calcitrapa.
PMID- 9561251
TI - Aspartic proteinases and inhibitors in plant pathogenesis.
PMID- 9561252
TI - Acid proteinase from Nepenthes distillatoria (Badura).
PMID- 9561253
TI - A comparative study on the aspartic proteinases from different species of Cynara.
PMID- 9561254
TI - An aspartic proteinase from flowers of Centaurea calcitrapa. Purification,
characterization, molecular cloning, and modelling of its three-dimensional
structure.
PMID- 9561255
TI - Substrate specificity and molecular modelling of aspartic proteinases (cyprosins)
from flowers of Cynara cardunculus subsp. flavescens cv. cardoon.
PMID- 9561256
TI - Improved diagnosis of breast implant rupture with sonographic findings and
artificial neural networks.
AB - RATIONALE AND OBJECTIVES: The authors evaluated the use of sonographic findings
combined with artificial neural networks as an aid to the diagnosis of breast
implant rupture. MATERIALS AND METHODS: From a database of 78 breast implants
that were evaluated prospectively with sonography and then surgically removed,
sonographic findings and surgical results were used to train and test
backpropagation and radial basis function artificial neural networks by using the
leave-one-out method. Receiver operating characteristic (ROC) curve analysis was
used to compare the performance of the different neural networks with that of the
radiologists involved. RESULTS: By using the ROC area index as a measure of
performance, the artificial neural network (Az = 0.8744) outperformed the
radiologists (Az = 0.8057), although not by a statistically significant
difference (P = .09). The best-performing network used, in addition to the
sonographic findings, the diagnosis of the radiologist as an input. This network
(Az = 0.9245) outperformed both the radiologists and the "unaided" networks by a
statistically significant margin (P = .02 for radiologists, P = .04 for the
unaided network). The network performed remarkably well in those cases in which
the radiologists classified the implant as indeterminate, predicting the correct
diagnosis in 23 of 25 cases (92%). CONCLUSION: The results suggest that
artificial neural networks in tandem with the unaided radiologic diagnosis can
improve the accuracy rate in the detection of implant rupture based on
sonographic findings. This "team" approach provided the best results.
PMID- 9561257
TI - Automated lung segmentation in digitized posteroanterior chest radiographs.
AB - RATIONALE AND OBJECTIVES: The authors developed and tested a gray-level
thresholding-based approach to automated lung segmentation in digitized
posteroanterior chest radiographs. MATERIALS AND METHODS: Gray-level histogram
analysis was initially performed to establish a range of thresholds for use
during an iterative global gray-level thresholding technique. Local gray-level
threshold analysis was then performed on the output of global thresholding. The
resulting contours were subjected to several smoothing processes, including a
rolling-ball technique. The final contours closely approximated the boundaries of
the aerated lung regions. The method was applied to a database of 600
posteroanterior chest images. Radiologists rated the accuracy and completeness of
the contours with a five-point scale. RESULTS: Results of the subjective rating
evaluation indicated that this method was accurate, with 79% of the assigned
ratings reflecting moderately or highly accurate segmentation and only 8% of the
ratings indicating moderately or highly inaccurate segmentation. CONCLUSION: This
gray-level thresholding-based approach provides accurate automated lung
segmentation in digital posteroanterior chest radiographs.
PMID- 9561258
TI - Fine needle aspiration biopsy of the breast: importance of benign, nonspecific
results.
AB - RATIONALE AND OBJECTIVES: The authors attempted to determine the importance of
benign but nonspecific findings from an adequate sample obtained with image
guided, fine-needle aspiration biopsy (FNAB) of the breast. MATERIALS AND
METHODS: Four hundred thirty-seven image-guided FNAB specimens obtained over a 4
year period were reviewed. Pathologic results, mammograms, sonograms, and
radiology reports were correlated for all cases described as benign but
nonspecific on the basis of cytologic results. Lesion characterization, type of
imaging, and targeting accuracy were assessed. Follow-up method (imaging and/or
clinical follow-up, core biopsy, open biopsy) was determined. RESULTS: Of the 427
lesions, 99 (23%) were designated benign but nonspecific. In 75 of the cases,
biopsy (core or open) had been performed or there had been at least 2 years of
follow-up at the time of this study. Of these, 32 lesions were benign on the
basis of follow-up, 27 (36%) were benign at secondary biopsy, seven (9%) were
malignant at final biopsy, and nine (12%) were lost to follow-up. Five of the
seven cancers occurred in the 1st year of the study; these lesions were sampled
for biopsy based on their mammographic appearance. The lesions in an additional
24 patients were benign after at least 1 year of follow-up. CONCLUSIONS: Benign,
nonspecific imaged-guided FNAB results are reliable if targeting is accurate and
if the mammographic findings support a benign process.
PMID- 9561259
TI - Pulsatile cycle-specific data acquisition in carotid MR angiography with
segmented FLASH sequence: experimental and clinical investigation.
AB - RATIONALE AND OBJECTIVES: The authors evaluated the usefulness of diastolic data
acquisition in magnetic resonance (MR) angiography of the carotid artery.
MATERIALS AND METHODS: MR angiographic images of phantom models of 30%, 40%, and
50% stenosis were obtained at different pulsatile cycles by using variable delay
times from the electrocardiogram triggering with segmented fast low-angle shot
sequences (14/7.3 [repetition time msec/echo time msec]) with k-space
segmentation. The degree of stenosis was measured on the MR angiographic images
by three observers. Poststenotic signal intensity loss was analyzed by measuring
the signal intensity on the axial image acquired 10 mm distal to the stenotic
portion of the 50% stenosis phantom at variable delay time from triggering. Six
patients with stenosis of the internal carotid artery also underwent conventional
and MR angiography. The degree of stenosis depicted on diastolic- and systolic
phase MR angiographic images was measured by three observers and compared with
that shown on the conventional angiographic images. RESULTS: The diastolic-phase
images more accurately depicted the degree of stenosis than did the systolic
phase images in the phantom and all six patients, although the degree of stenosis
tended to be overestimated on both images. The degree of stenosis was most
overestimated with triggering that occurred at the time of peak flow velocity. In
the phantom with 50% stenosis, the signal intensity 10 mm distal to the stenotic
portion was decreased in the systolic phase. CONCLUSION: Diastolic data
acquisition is a useful method of reducing intra- and poststenotic signal
intensity loss in the carotid artery.
PMID- 9561260
TI - Fast spectroscopic imaging of water and fat resonances to improve the quality of
MR images.
AB - RATIONALE AND OBJECTIVES: The authors evaluated whether fast spectroscopic
imaging of water and fat resonances can produce high-quality anatomic magnetic
resonance (MR) images of rodent tumors and human breast. MATERIALS AND METHODS:
Fast MR spectroscopic images of eight rats with mammary tumors were acquired by
using a 4.7-T MR unit equipped with self-shielded gradient coils. MR
spectroscopic images of four human breasts were acquired with a 1.5-T MR unit.
RESULTS: Artifacts due to eddy currents were minimal. Images synthesized from MR
spectroscopic data, in which intensity was proportional to water signal peak
height, were similar to T2-weighted MR images. Boundaries of rodent mammary
tumors are similar but not identical on peak height-weighted and T2-weighted
images. MR spectroscopic images of human breast showed improved detail compared
to gradient-echo MR images. CONCLUSION: Preliminary results suggest that
incorporation of fast MR spectroscopic imaging methods into many standard
clinical MR imaging procedures may substantially improve image quality.
PMID- 9561261
TI - Tips for getting a position with an independent private practice radiology group.
PMID- 9561262
TI - Virtual colonoscopy: current status and future implications.
PMID- 9561263
TI - Magnetic resonance angiography: a review.
PMID- 9561264
TI - Fragmentary window filtering for multiscale lung nodule detection: preliminary
study.
AB - RATIONALE AND OBJECTIVES: The authors evaluated computer-assisted diagnostic
(CAD) methods used to detect suspicious areas on lung radiographs. MATERIALS AND
METHODS: The authors designed a fragmentary window filtering (FWF) algorithm for
detecting lung nodule patterns, which generally appear as circular areas of high
opacity on the chest radiograph. The FWF algorithm helps differentiate circular
patterns from overlapping radiographic background. A multiscale analysis was
performed to locate multiscale nodules. Receiver operating characteristic
analysis was performed by using a lung nodule that was extracted from a chest
radiograph. The nodule underwent scalings and subsequent superimposition onto 140
normal regions of interest from six chest radiographs. RESULTS: The FWF method
was superior to the matched filtering method in the detection of suspicious
areas. CONCLUSION: The proposed FWF-based method should provide improved
detection of lung nodules on chest radiographs.
PMID- 9561265
TI - Key effectors of signal transduction and G1 progression.
PMID- 9561266
TI - p53 in tumor progression: life, death, and everything.
PMID- 9561267
TI - Signal transduction through MAP kinase cascades.
PMID- 9561268
TI - FHIT in human cancer.
PMID- 9561269
TI - Phosphoinositide 4- and 5-kinases and the cellular roles of phosphatidylinositol
4,5-bisphosphate.
PMID- 9561270
TI - A diet with the right ingredients.
PMID- 9561271
TI - Adhesion reduction as a new treatment innovation.
AB - A new treatment option, an antiadhesion device, has proved effective in the
reduction of postoperative adhesion formation and is now approved for use in the
United States. The device is a thin, filmy membrane composed of two organic
substances that are resorbed by the body. The device is inserted intraoperatively
between apposing tissue surfaces that are potentially adhesiogenic. It proved
effective in reducing the incidence of adhesions after both abdominal and pelvic
surgery.
PMID- 9561273
TI - Should do-not-resuscitate orders be suspended during surgical procedures?
AB - One of the most controversial ethical dilemmas faced by perioperative nurses,
surgeons, and anesthesia care providers is the do-not-resuscitate (DNR) order for
a surgical patient. This article discusses informed consent, decision makers,
laws and policy, DNR orders, and ethical considerations.
PMID- 9561272
TI - The continuing ethical dilemma of the do-not-resuscitate order.
AB - The continued use of the do-not-resuscitate (DNR) order remains very confusing to
health care workers, especially when surgical intervention is undertaken either
by choice or necessity. Although ethics committees can aid in clarification, and
the use of advance directives can further define patient wishes, patient and
family member education is necessary to ascertain what a surgical patient really
desires. As technology advances, perioperative nurses will continue to be
bombarded with ethical issues surrounding the DNR order. This article addresses
how nurses can be proactive in obtaining answers to these difficult questions and
learn how to deal with this dilemma.
PMID- 9561274
TI - Cardiac anatomy and physiology: a review.
AB - This article reviews the normal anatomy and physiology of the heart.
Understanding the normal anatomic and physiologic relationships described in this
article will help perioperative nurses care for patients who are undergoing
cardiac procedures. Such knowledge also assists nurses in educating patients
about cardiac procedures and about activities that can prevent, reverse, or
improve cardiac illness.
PMID- 9561275
TI - Perioperative nursing care when sudden patient death occurs in the OR.
AB - This article explores how nurses cope with sudden death in the OR. It reviews the
literature on this topic and explores grief and bereavement models, as well as
provides a discussion of clinical coping methods identified through nursing
experience. An education model presents information about implementing nursing
care for the patient and family members. Critical care nursing research has been
used to develop the model with adaptation to the perioperative setting. The model
discusses the value of support for perioperative nurses and peers experiencing
sudden patient death.
PMID- 9561276
TI - Ultraclean laminar airflow ORs.
AB - To minimize postoperative infections, ultraclean laminar airflow (LAF) units
equipped with high-efficiency particulate air filters developed for electronic
and aerospace technology have been adapted for ORs. Traditionally, the airflow
was either vertical or horizontal and, to function properly, encompassed extra
side walls inside the OR. Recently, new airstream technology has provided zoned
down-flow units that provide an exponential airflow (i.e., resembling an upside
down trumpet mouth). The exponential airflow allows for omission of extra side
walls, making them more versatile in clinical use. Each different type of LAF
requires knowledge of airstream patterns and how OR team members need to dress
and work to prevent contamination of the sterile air and the aseptic areas. This
article discusses different LAF systems and related demands on OR clothing and
behavior.
PMID- 9561277
TI - Can providing paging devices relieve waiting room anxiety?
AB - The purpose of this study was to evaluate the effect of providing individuals who
are waiting for surgical patients with digital pagers. Twenty-eight subjects
received routine waiting room procedures, and 29 subjects were given digital
pagers during surgical procedures. Subjects completed questionnaires concerning
activity, state anxiety, and their perceived threat while patients were
undergoing surgical procedures. The group that received the paging devices
reported significantly greater state anxiety (i.e., P < .03) and a greater
percentage of time spent outside surgical waiting rooms (i.e., P < .00) than the
group that did not receive paging devices.
PMID- 9561278
TI - Improving patient positioning for laparoscopic procedures.
PMID- 9561279
TI - An abrupt zero-preoxygenation altitude threshold for decompression sickness
symptoms.
AB - INTRODUCTION: The altitude threshold for decompression sickness (DCS) symptoms
has been variously described as being 18,000 ft (5,487 m) to above 25,000 ft
(7,620 m). Safety and efficiency of aerospace operations require more precise
determination of the DCS threshold. METHODS: Subjects were 124 males who were
exposed to simulated altitudes (11 at 11,500 ft; 10 at 15,000 ft; 8 at 16,500 ft;
10 at 18,100 ft; 10 at 19,800 ft; 20 at 21,200 ft; 20 at 22,500 ft; 10 at 23,800
ft, and 25 at 25,000 ft) for 4 to 8 h. All breathed 100% oxygen beginning with
ascent. Subjects were monitored for precordial venous gas emboli (VGE) and DCS
symptoms. Probit curves representing altitude vs. incidence of DCS symptoms and
VGE allowed estimation of respective risk. RESULTS: VGE were first observed at
15,000 ft with increasing incidence at higher altitudes; over 50% at 21,200 ft
and 70% or higher at 22,500 ft and above. The lowest altitude occurrence of DCS
was a 5% incidence at 21,200 ft. At 22,500 ft, the DCS incidence abruptly climbed
to 55%. CONCLUSION: A 5% threshold for DCS symptoms was concluded to be 20,500 ft
under the conditions of this study. The abrupt increase in DCS symptoms, with
zero-preoxygenation exposure above 21,200 ft implies a need for reconsideration
of current USAF and FAA altitude exposure guidance.
PMID- 9561280
TI - Alterations in muscular performance and orthostatic tolerance during Ramadan.
AB - BACKGROUND: During Ramadan, physiological changes are expected to result from
both long-term dietary restriction and partial sleep loss. HYPOTHESIS: We
speculated that Ramadan fasting has deleterious effects on muscle performances
and on orthostatic tolerance. METHODS: There were 11 senior fighter pilots tested
on three occasions during the first week of Ramadan (Beg-R), during the fourth
week (End-R) and during a control period, 2 mo after Ramadan (C). Each test
session consisted of an assessment of the strength and endurance performances of
the knee extensors and elbow flexors and of an analysis of the HR and BP
responses to the orthostatic stress imposed by a 80 degrees head-up tilt.
RESULTS: Body weight decreased by 2.7% at End-R in comparison with C period (p <
0.01). Maximum isometric strength (MVC) of elbow flexor muscles decreased
immediately (by 10-12%; p < 0.05). Muscular endurance at both 35 and 70% MVC were
lower at End-R in comparison with C period (-28%, -22%, respectively; p < 0.05).
The head-up tilt test at End-R was accompanied by a higher increase in heart
response than during orthostasis during C and Beg-R periods, and by a decrease in
pulse pressures (p < 0.001). These alterations in responses to the head-up tilt
were associated with a fall by about 7% in plasma volume. CONCLUSIONS: These data
demonstrate that Ramadan fasting leads to an impairment in muscular performances
and to a decrease in orthostatic tolerance. Further studies are needed to verify
the impact of these changes on +Gz tolerance.
PMID- 9561281
TI - Red cell volume and [erythropoietin] responses during exposure to simulated
microgravity.
AB - In order to test the hypothesis that normal gravity is an important influence on
human serum [Erythropoietin] ([Epo]), the hematologic response to 16 d of 6
degrees head-down tilt (HDT, n = 6 men) was compared with 16 d of normal gravity
exposure (CON, n = 7 men). Prior to bed rest, CON and HDT subjects, respectively,
were similar in the following characteristics (mean +/- SD): age = 40 +/- 3, 39
+/- 6 yr; height = 181 +/- 5, 182 +/- 6 cm; weight = 88.5 +/- 11.3, 81.7 +/- 12.0
kg; maximal oxygen consumption in supine 6 degrees head-down tilt position
(VO2max) = 2.63 +/- 0.38, 2.67 +/- 0.52 L.min-1; hematocrit = (Hct) 41.6 +/- 2.4,
43.0 +/- 3.4%; hemoglobin ([Hb]) = 15.1 +/- 1.0, 14.5 +/- 1.0 g.100 ml-1; plasma
volume (PV) = 3829 +/- 857, 3768 +/- 512 ml; and [Epo] = 11.6 +/- 2.9, 10.0 +/-
6.2 mU.ml-1. Calculated red cell volume (RCV) was greater in HDT than CON (2845
+/- 410 vs. 2139 +/- 253 ml, p < 0.05) at baseline. Decreases in PV (-15%, 580
ml, p < 0.05) and an insignificant decrease in RCV (-12%, 354 ml, p = 0.07) were
observed in the HDT group, with a concurrent 6% increase in [Hb] (p < 0.05). PV,
RCV and [Hb] remained unchanged in the CON group. [Epo] remained unchanged during
HDT (12.2 +/- 3.2; 10.8 +/- 3.8; 11.2 +/- 3.1; 11.2 +/- 2.6 mU.ml-1 for HDT days
1, 2, 8 and 16, respectively). There was no difference between CON and HDT groups
in [Epo] before or during HDT. It was concluded that the insignificant change (
12%) in RCV observed during HDT was insufficient to stimulate an increase in
[Epo], probably because the content of oxygen in arterial blood remained
unaffected. The observation that [Epo] remained unchanged despite this loss of
RCV during HDT also suggests a possible decrease in the responsiveness of the
erythropoietic system to [Epo].
PMID- 9561282
TI - Evolved gas, pain, the power law, and probability of hypobaric decompression
sickness.
AB - The intensity of a pain-only decompression sickness (DCS) symptom with respect to
time at altitude increases, peaks, and then declines in some cases. A similar
pattern is also seen in a graph of the probability density function [f(t)] for
DCS. The f(t) is the proportion of DCS per unit time with respect to time at
altitude. The integration of f(t) with respect to time provides the cumulative
probability of DCS [P(DCS)]. We suspect that the perceived intensity of pain with
a given stimulus intensity is related to the P(DCS); it may be related to the
intensity of the stimulus to a power (alpha). Our stimuli are defined as pressure
ratio [PR = (phi P1N2/ P2)-11] or pressure difference [delta P = phi P1N2-P2],
where phi P1N2 is the N2 partial pressure calculated in the 360 min half-time
(t1/2) compartment or t1/2 is estimated with other parameters and P2 is ambient
pressure after the ascent. Both stimuli represent a potential released volume of
gas. We tested the null hypothesis that alpha > 1 was no better than alpha = 1 in
PR alpha and delta P alpha in a log logistic survival analysis of 1085 exposures
in hypobaric chambers. The log likelihood number increased from -1198 for alpha =
0 for the null model to -724 for PR alpha when alpha = 3.52 with a 42 min t1/2
and -714 for delta P alpha when alpha = 8.44 with a 91 min t1/2. We conclude that
the improvement in our expressions for decompression dose with alpha > 1 is not
by random chance and that alpha may link the physics of gas evolution to the
biology of pain perception. Because of our empirical approach, we do not exclude
other possible interpretations.
PMID- 9561283
TI - A comparison of heart rate, eye activity, EEG and subjective measures of pilot
mental workload during flight.
AB - BACKGROUND: Mental workload is a major consideration in the design and operation
of modern aircraft systems. Objective measures of mental workload that are
sensitive and diagnostic are required to meet the needs of both pilots and
designers. Due to the multifaceted nature of these complex mental demands
multiple measures are required. HYPOTHESIS: Psychophysiological and subjective
measures provide unique information about mental workload during flight. METHODS:
Cardiac, eye, brain and subjective data were collected during an actual flight
scenario designed to provide tasks which required different piloting skills at
several levels of mental workload. RESULTS: Heart rate was sensitive to the
demands of flight but not diagnostic with regard to determining the cause of the
workload. Heart rates increased during take offs and landings and to an
intermediate level during instrument flight rules (IFR) segments. By showing
sensitivity to only the visual demands of the various segments of flight eye
activity was more diagnostic. The theta band of the EEG demonstrated increased
power during those flight segments which required inflight mental calculations.
The subjective measures showed trends suggesting different levels of mental
demand but demonstrated few statistically significant differences. CONCLUSIONS:
Multiple measures, especially psychophysiological measures, provide a
comprehensive picture of the mental demands of flight. The measures used in this
study were shown to provide unique, non-overlapping information. Because of the
continuous nature of the psychophysiological data it may be possible to develop
systems which provide on-line monitoring of mental workload that can provide
feedback to the pilot and aircraft systems.
PMID- 9561284
TI - The effects of low levels of CO2 on ventilation during rest and exercise.
AB - BACKGROUND: Measurements of pulmonary gas exchange are especially sensitive to
low levels of CO2 in the environment; this is an important consideration in
measurements in enclosed spaces. METHODS: In order to determine the responses to
these low levels, subjects were exposed in five studies to partial pressures of
inspired CO2 (PICO2) of 5.7 and 7.5 mmHg for 30 min during basal conditions at
rest and to 5.4, 9.4 and 15 mmHg during a progressive exercise to VO2max on a
cycle ergometer. RESULTS: In the two resting studies, total pulmonary ventilation
and alveolar ventilation were increased by 19% at 7.5 mmHg (1.1% sea level
equivalent) and 10% at 5.4 mmHg (0.8% equivalent), with clear evidence of CO2
retention in both studies. During exercise at 15 mmHg the VO2max was reduced
significantly by 13%, compared with air at about the same maximal ventilation,
but VO2max was not reduced at 9.4 mmHg. A 6% decrease in VO2max at a PICO2 of 5.4
mmHg may have resulted from these subjects being less fit. The maximal CO2 output
and respiratory exchange ratio in the three exercise studies was always lower
with CO2 than corresponding air measurements, indicating CO2 storage. Evaluation
of submaximal measurements provided an equation for predicting ventilation as a
function of PICO2 and VO2/VO2max and demonstrated that ventilation during
submaximal exercise is increased significantly by the lowest CO2 level. BP and
heart rate responses during submaximal and maximal work were not predictably
altered by CO2 at these levels. CONCLUSION: These studies demonstrate that
minimal CO2 levels have significant influences on pulmonary ventilation during
rest and exercise and must be considered in acute studies in confined spaces such
as space cabins. The inspired CO2 should be stated when ventilation measurements
are reported under these conditions.
PMID- 9561285
TI - Hypervolemia in men from fluid ingestion at rest and during exercise.
AB - BACKGROUND: Plasma osmolality (Osm) is important for controlling and maintaining
plasma volume (PV) and body water. The effect of oral rehydration fluids for
ameliorating dehydration is well-established; but optimal composition and Osm of
fluids for hyperhydrating normally hydrated subjects is less clear. METHODS: Six
treatments were used without and with oral fluids of varying ionic and
constituent concentrations for hyperhydrating six previously euhydrated men (30
+/- SD 8 yr, 76.84 +/- 16.19 kg, 73 +/- 12 ml.kg-1 PV, 40 +/- 10 ml.min-1.kg-1
peak VO2) sitting at rest for 90 min (VO2 = 0.39 +/- SE 0.02 L.min-1) and during
subsequent 70 min of submaximal exercise (VO2 = 2.08 +/- SE 0.33 L.min-1, 70 +/-
7% peak VO2). The hypothesis was that the fluid composition is more important
than plasma Osm for increasing PV in euhydrated subjects at rest and maintaining
it during exercise. Drink formulation compositions, given at 10 ml.kg-1 body wt,
(mean = 768 ml), for the sitting period were: Performance 1 (P1; 55 mEq Na+, 365
mOsm.kg H2O-1), P2 (97 mEq Na+, 791 mOsm.kg-1), P2G (113 mEq Na+, 4% glycerol,
1382 mOsm.kg-1), AstroAde (AA; 164 mEq Na+, 253 mOsm.kg-1), and 01 and 02 (no
drinking). The exercise drink (10 ml.kg-1, 768 ml) was P1 for all treatments
except 02 (no drinking); thus, drink designations were: P1/P1, P2/P1, P2G/P1,
AA/P1, 0/P1, and 0/0. RESULTS: PV at rest increased (p < 0.05) by 4.7% with P1
and by 7.9% with AA. Percent change in PV during exercise was +1% to +3% (NS)
with AA/P1; -6% to 0% (NS) with P1/P1, P2/P1, P2G/P1, and 0/P1; and -8% to -5% (p
< 0.05) with 0/0. AA, with the lowest Osm of 253 mOsm.kg-1, increased PV at rest
(as did P1) and maintained it during exercise, whereas the other drinks with
lower Na+ and higher Osm of 365-1382 mOsm.kg-1 did not. CONCLUSION: Drink
composition appears to be more important than its Osm for increasing PV at rest
and for maintaining it during exercise in previously euhydrated subjects.
PMID- 9561286
TI - Low level CO2 effects on pulmonary function in humans.
AB - The purpose of the study was to determine whether chamber exposure to low levels
of CO2 results in functional alterations in gas mixing and closing volume in
humans. Four healthy volunteer subjects were exposed to 0.7% CO2 and to 1.2% CO2.
Spirometry, lung volumes, single breath nitrogen washout, diffusing capacity for
carbon monoxide (DLCO) by two methods, and cardiac output were measured in
triplicate. Values were obtained over two non-consecutive days during the
training period (control) and on days 2 or 3, 4, 6, 10, 13, and 23 of exposure to
each CO2 level. Measurements were made during the same time of day. There was one
day of testing after exposure, while still in the chamber but off carbon dioxide.
The order of testing, up until measurements of DLCO and cardiac output, were
randomized to avoid presentation effects. The consistent findings were a
reduction in diffusing capacity for carbon monoxide and a fall in cardiac output,
occurring to a similar degree with both exposures. For the group as a whole,
there was no indication of major effects on spirometry, lung volumes, gas mixing
or dead space. We conclude that small changes may occur in the function of distal
gas exchanging units; however, these effects were not associated with any adverse
health effects. The likelihood of pathophysiologic changes in lung function or
structure with 0.7 or 1.2% CO2 exposure for this period of time, is therefore,
low.
PMID- 9561287
TI - Hypercapnic ventilatory response in humans before, during, and after 23 days of
low level CO2 exposure.
AB - Alterations in ventilation and the chemoreceptor response to CO2 during 23 d of
1.2% inspired CO2 were studied in four male subjects. Resting ventilation (VE),
tidal volume (VT), respiratory frequency (fR), inspired and end tidal O2 and CO2
and the hypercapnic ventilatory response (HCVR) measured by CO2 rebreathing were
measured once before entering the chamber, on days 2, 5, 11, and 22 of CO2
exposure, and one day after. Resting VE slightly increased (5%) on day 2 of
exposure and significantly increased (22%) by day 5 followed by a progressive
decrease to pre-chamber levels by day 22 and on the first day of recovery. Tidal
volume and fR were not statistically different. During the exposure PetCO2 was
significantly elevated with day 2 having the largest increase (19.6%). PetCO2
returned to normal within 24 h post exposure. The HCVR was characterized by the
slope (SHCVR), intercept at zero ventilation (B), and the ventilation at a PCO2 =
60 mmHg (VE60). The SHCVR decreased (14%) on day 2, but was not significant; the
SHCVR on the other exposure days were also not different. The SHCVR on the first
recovery day significantly increased (37%). The HCVR B was shifted to the right
on day 2 by 5.2 mmHg, then progressively returned to the pre-exposure position.
On recovery the B significantly shifted 6.9 mmHg to the right of pre-exposure B.
The VE60 decreased by approximately 32% and 16% on day 2 and 5, respectively,
then returned within pre-exposure range for the remainder of the exposure and
during recovery. During the early phase and one day after the exposure the HCVR
was right shifted. One day after exposure chemoreceptor sensitivity to elevated
CO2 was increased but, the B was right shifted resulting in a reduced HCVR below
PCO2 of 60 mmHg and a greater HCVR above 60 mmHg.
PMID- 9561288
TI - Effects of chronically increased ambient CO2 concentrations on aerobic capacity.
AB - As part of a joint NASA-ESA-DARA study on the effects of chronically increased
CO2 concentrations in ambient air, changes in parameters indicating aerobic
capacity were investigated by cycle ergometry. Two potential sources for
reductions of aerobic capacities were hypothesized: 1) the adaptations to CO2
such as reduction in H(+)-buffer capacities which may influence muscle
metabolism; 2) the reduced physical activities which may lead to a detraining
effect. Four subjects were exposed to 0.7% and 1.2% CO2 concentration in a
confined compartment for 23 d each with 3 mo in between the two campaigns. A
combined exercise test was applied before, during (on days 5, 11, and 22) and
after CO2 exposure. Comparing steady-states at 30 W and 80 W power, elevated
ventilation was found increased during CO2 exposure with significant differences
between the two campaigns. Peak oxygen uptake decreased over the period of CO2
exposure, but was found not significantly different on day 5 compared to pre
exposure measurements. This decrease was not dependent on the CO2 concentration.
The lactate concentration at low exercise intensities was found elevated during
CO2 exposure. A shift in reverse direction was observed after the CO2 exposure.
Since peak oxygen uptake did not differ on day 5 and the lactate concentration
was found increased, it was concluded that the potential changes in muscle
metabolism by adaptation to elevated CO2 concentrations did not influence the
aerobic capacities. Therefore, it was concluded that the changes in aerobic
capacities are the result of the reduced physical activities of the subjects
while living in the confined compartment.
PMID- 9561289
TI - Towards new paradigms for the treatment of hypobaric decompression sickness.
AB - Altitude induced (hypobaric) decompression sickness (DCS) has long been treated
with ground level oxygen and U.S. Navy Treatment Tables 5 and 6. These treatment
tables originate from surface excursion diving and, when implemented, require
significant resource allocation. Although they are effective treatment regimens,
these tables were not developed for treating hypobaric DCS which has an etiology
similar to saturation diving DCS. In this review, different treatment options for
hypobaric DCS are presented. These options include more aggressive use of ground
level oxygen and treatment tables using a maximum pressure of 2 atmospheres
(ATA). Specific attention is given to USAF Table VIII, an experimental hypobaric
DCS treatment-table, and space suit overpressurization treatment. This paradigm
shift for DCS treatment is based on a projected increase in hypobaric DCS
treatment from exposure to low pressure during several operational conditions:
cruise flight in the next generation aircraft (e.g., F-22); high altitude,
unpressurized flight by special operations forces; and the extraordinary amount
of extravehicular activity (EVA) required to construct the international space
station. Anticipating the need to treat DCS encountered during these and other
activities, it is proposed that 2 ATA or less hyperbaric oxygen (HBO) treatment
conjoined with new collapsible chamber technology can be used to address these
issues in a safe and cost effective fashion.
PMID- 9561290
TI - An objective measure of seat comfort.
AB - Uncomfortable aircrew seating is more than just a nuisance, it has the potential
to produce a cumulative trauma which can significantly affect attention,
information processing, and task performance to the extent of interfering with
mission completion or contributing to mishaps. Yet, for decades uncomfortable
seating has endured as an aircrew complaint with little progress made toward
resolving it. Aircraft design techniques have steadily progressed, but the method
for ascertaining seating pressure issues has remained, unfortunately, the same:
simply ask aircrew where it hurts and hope some cushion changes work. Currently,
there exist sensor technologies which potentially can economically and
effectively address this problem by reducing the comfort analysis to the
examination of an objective, quantitative pressure map. This technical note
discusses the brief history of seat pressure measurement research, enumerates
some of the technologies that are available that can be applied to the problem,
and finally, describes a seated pressure measurement demonstration which shows
the power of the approach for maximizing comfort.
PMID- 9561291
TI - The 17th Andre Allard Memorial Lecture: to smoke or not to smoke in civil
aviation.
PMID- 9561292
TI - Protocol for the evaluation of coronary artery disease.
PMID- 9561293
TI - Defence evaluation and research agency centre for human sciences.
PMID- 9561294
TI - Report of the inflight emergency medical kit task force. Emergency Medical Kit Ad
Hoc Task Force. Aerospace Medical Association.
PMID- 9561295
TI - Mitochondria revisited. Alternative functions of mitochondria.
AB - This review explores the alternative functions of mitochondria inside the cell.
In a general picture of mitochondrial functioning, the importance and uniqueness
of these intrinsic functions make them irreplaceable by other intracellular
compartments. Among these are, participation in apoptosis and cellular
proliferation, regulation of the cellular redox state and level of second
messengers, heme and steroid syntheses, production and transmission of a
transmembrane potential, detoxication and heat production. In most of the listed
functions, reactive oxygen species modulate a number of non-destructive cellular
activities. Some of the mitochondrial functions are reviewed in detail.
PMID- 9561296
TI - An uncoupling of the processes of oxidation and phosphorylation in glycolysis.
AB - Data on alterations of the properties of glyceraldehyde-3-phosphate dehydrogenase
upon oxidation of its functional groups are reviewed; a mechanism of uncoupling
of oxidation and phosphorylation in glycolysis is considered. Possible ways of
regulating uncoupling, and the physiological importance of this process, are
discussed.
PMID- 9561297
TI - Mitochondrial dehydrogenases in different taxa of tetrahymena: effect of insulin.
AB - Mitochondrial dehydrogenase activity was measured in seven taxa of Tetrahymena
(T. pyriformis G1. T. hegewishi, T. malaccensis, T. pigmentosa, T. shapiro, T.
thermophila CU-399, T. thermophila MS-1). Enzyme activity was different in the
taxa investigated. Insulin reduced enzyme activity in six of the seven taxa
studied. The duration of activity reduction was relatively long (5-10 min.) in
most of the cases, and in T. hegewishi this lasted up to the end of the
measurements (30 min.). There was no interrelation between the basic
dehydrogenase activity of the taxon and the effect of insulin. There was also no
correlation between the degree of relationship (of the taxa) and the
dehydrogenase profile after insulin treatment.
PMID- 9561298
TI - Imprinting effects of proline containing dipeptides (proline-glycine, proline
leucine, proline-valine and their retro variants) in tetrahymena. Evolutionary
conclusions.
AB - Proline-glycine, proline-leucine and proline-valine dipeptides and their retro
variants were used in the experiments to study the effects of pretreatment
(imprinting) in Tetrahymena, by investigating fluorescein isothiocyanate (FITC)
conjugated peptide binding. The protozoan organism could differentiate between
the proline-dipeptides containing different partner amino-acids and between the
dipeptides having the amino acids in reversed positions. The effect of imprinting
was positive or negative and this was dependent on the type of the partner amino
acid and on its position. Pro-Gly and Pro-Leu induced positive imprinting
(elevated FITC-dipeptide binding) and Pro-Val induced negative imprinting
(decrease of FITC-peptide binding). There was positive imprinting induction in
two cases for the retro FITC-peptide and in one case for the FITC-conjugate of
the imprinter peptide itself. The highest positive imprinting (almost 60%
increase) was induced by Pro-Gly for FITC-Gly-Pro. Considering earlier-
chemotaxis--experiments, the results of the present--binding--studies run
parallel with the physiological effects. The experiments call attention to the
sharp differentiating ability of small peptides at a unicellular level, that
could have some role in the selection of molecules for hormone formation, during
evolution.
PMID- 9561299
TI - Sodium nitrite alone protects the brain microsomal Ca(2+)-ATPase against
potassium cyanide-induced neurotoxicity in rats.
AB - The effect of a short-term oral administration of potassium cyanide (KCN) (200
ppm in diet) with or without sodium nitrite (NaNO2) pretreatment on rat brain
microsomal Ca2 +/- ATPase was investigated. The specific activity value of the
enzyme significantly decreased (p < 0.05) by 50% compared with control and by 63%
for KCN-treated rats compared with KCN-treated rats pretreated with NaNO2. There
was no significant difference at the h = 0.05 level between the values obtained
for the control and KCN-treated rats pretreated with NaNO2. These results show
both that feeding lowers brain microsomal Ca(2+)-ATPase activity and that NaNO2
has a protective role (antidote function) in that respect.
PMID- 9561300
TI - Apoptosis dependent decrease of the intramembrane ion traffic in cultured mouse
fibroblasts shown by conductivity dispersion.
AB - We have investigated the intramembranal ion traffic in apoptotic 3T6 cells in
culture. Apoptosis was induced by various treatments, such as serum deprivation,
high density growth and hydrogen peroxide at subnecrotic doses. Cell death was
assessed by nucleosomal DNA fragmentation, single cell electrophoresis,
immunofluorescence and histological staining. To study the modifications of
membrane structure and function, we adopted a well established biophysical
strategy based on the measurement of the electrical conductivity of cell
suspensions, as a function of the frequency of the electrical field applied to
the sample. A comparison between the conductivity of normal and apoptotic cell
suspensions shows that programmed cell death causes a decrease of membrane
conductivity which indicates a diminished intramembranal ion traffic. Our results
strongly suggest that one of the early events in the triggering of apoptosis is
represented by an overall reduction of plasma membrane function. Finally, our
results are in agreement with the idea that the nucleus is not the sole target of
the apoptotic process.
PMID- 9561301
TI - Sensitivity of Ca2+ transport of mitochondria to reactive oxygen species.
AB - The relationship between Ca2+ transport and energy transduction of myocardial
mitochondria in the presence of reactive oxygen species was investigated.
Following treatment with oxygen free radicals [superoxide(O2.-) or hydroxyl
radical (.OH)], lipid free radicals in myocardial mitochondrial membrane could be
detected by using the method of EPR spin trap. Simultaneously there were obvious
alterations in the free Ca2+ ([Ca2+]m) in the mitochondrial matrix; the physical
state of membrane lipid; the efficiency of oxidative phosphorylation (ADP/O); the
value of the respiratory control ratio (RCR); and the membrane potential of the
inner membrane of myocardial mitochondria. If the concentrations of reactive
oxygen species were reduced by about 30%, the alterations in the physical state
of the membrane lipid and energy transduction of myocardial mitochondria were not
observed, but the changes in Ca2+ homeostasis remained. We conclude that Ca2+
transport by myocardial mitochondria is more sensitive to agents such as O2.- or
OH, etc. than are oxidation phosphorylation and the respiratory chain.
PMID- 9561302
TI - Psychoanalytic psychotherapy with men with intellectual disabilities: a
preliminary outcome study.
AB - Psychotherapy has been demonstrated to be an effective form of treatment for
people with psychological problems. However, there is considerable resistance to
attempts to generalize these findings to people with intellectual disabilities.
Such therapeutic disdain has a long history without any empirical foundation.
Recently it has been argued on philosophical grounds that people with
intellectual disabilities should have access to the same services as everyone
else. Furthermore, that people with intellectual disabilities should be actively
targeted as they are more likely to have psychological difficulties than non
handicapped people. The therapeutic literature concerning people with
intellectual disabilities is overwhelmingly behavioural. More recently various
psychotherapeutic approaches have been explored as alternatives to behavioural
interventions. Publication of several case studies in the late 1980s and early
1990s has provided some evidence for the benefit of various psychotherapeutic
approaches with people with intellectual disabilities. However, there are no
outcome studies. This paper reports an outcome study of individual psychoanalytic
psychotherapy provided in normal clinical practice for 25 men with intellectual
disabilities who were referred for behaviour problems. Of the 25 participants in
the study, 20 completed treatment. In most cases the problem behaviour was
eliminated and this was maintained at six months follow-up.
PMID- 9561303
TI - The role of personal therapy for therapists: a review.
AB - This paper reviews the research literature on personal therapy and makes some
recommendations for how future work in this area may be improved. Despite the
general acceptance of the importance of personal therapy amongst therapists,
there has been relatively little research to evaluate its effectiveness. The vast
majority of studies have consisted of surveys of therapists' opinions and
experiences of therapy or naturalistic comparisons across therapists who have or
have not had therapy. The interpretation of most findings is compromised because
of small sample sizes and confounding variables, nevertheless some conclusions
can be made. Whilst the majority of therapists feel that they have benefited
professionally from personal therapy there is very little empirical evidence that
it has any measurable effect on client outcome. However, there is some evidence
that personal therapy has a positive effect on those therapist qualities often
cited as constructive to client change (e.g. empathy, warmth, genuineness). What
is evident is that there is a need for more methodologically sound research as
well as a more theoretical understanding of how personal therapy affects clinical
practice, before any firm conclusions can be drawn about its usefulness. It is
suggested that it may be more useful for future research in this area to focus on
therapy process rather than client outcome.
PMID- 9561304
TI - A current psychodynamic understanding of panic disorder.
AB - While there has been burgeoning interest in the psychiatric literature about the
phenomenology and biology of panic disorder, there is little new information
about the psychodynamics of this condition. The reintroduction of a psychodynamic
perspective could be useful in guiding research strategies to identify traits
which predispose to panic and in designing treatments to address such traits. A
psychodynamic model hypothesizes a relationship between current psychological
functioning, early experiences, and ongoing psychological traits. Recent
published reports about the nature of underlying psychodynamics and psychological
characteristics of panic disorder are discussed.
PMID- 9561305
TI - Asthma and menstruation: the relationship between psychological and bronchial
hyperreactivity.
AB - The aim of this study was to investigate a possible interrelation between
bronchial hyperreactivity and psychological hyperreactivity. In order to record
changes in both bronchial and psychological reactions throughout the menstrual
cycle, 10 women out-patients with moderate asthma were followed up for six
months, and their physical and psychological status as well as their reactions to
life-events and environmental influences were assessed through self-reporting
measures and weekly psychotherapeutic sessions. Psychotherapy was used both as a
supplement to the medical treatment and as a method of data collection. A
relationship between lowered resistance to stress, lowered resistance to
infections and increased bronchial hyperreactivity is suggested as background
aetiological factors for the exacerbation of asthma around menstruation.
PMID- 9561306
TI - Attachment representations and representations of the self in relation to others:
a study of preschool children in inner-city London.
AB - The study examined the relationship between attachment representations and
representations of the self in relation to others in a sample of 42 children aged
between 4 and 5.9 years. The relationship between children's attachment
representations and parents' style of regulating negative affect was also
explored. The families were using local authority day-care facilities in a
deprived inner-city area of London. The quality of attachment representations was
assessed using a modified version of the Separation Anxiety Test. Assessments of
the representation of the self in relation to others consisted of (a) assessment
of the child's view of self within the relationship with the attachment figure,
using an incomplete doll story procedure; and (b) assessment of the child's
perceptions of the way others view them using a puppet interview. Significant
connections between attachment representations, representations of self in
relation to others, and parents' negative affect regulation were found. Children
with secure attachment representations had a significantly more positive view of
the self in the relationship with the attachment figure than children with
disorganized attachment representations, and a significantly more positive
perception of the way others view them than children with avoidant attachment
representations. Children with secure attachment representations had parents with
more adaptive ways of regulating their own negative affect than children with
ambivalent or disorganized attachment representations.
PMID- 9561307
TI - A group for the adult daughters of mentally ill mothers: looking backwards and
forwards.
AB - A closed time-limited therapy group was conducted for four women who had all been
raised by mentally ill mothers. Themes recurring frequently included hatred of
self and mother, current lack of extended family support, current parenting
difficulties, ongoing stigma and isolation. All group members perceived
themselves as troubled despite others' perceptions of them as resilient. The
results for the individuals treated are outlined using clinical material, as
statistical analysis was not undertaken. All were able to cease individual
therapy. Conclusions focus on the benefits of such a group process of recognition
and affirmation of the profound consequences of a mother's mental illness on her
daughters and thence to grandchildren. The possibility of primary prevention
using techniques from infant-parent and child-group therapy is discussed.
PMID- 9561308
TI - The contribution of depression and denial towards understanding the unawareness
of symptoms in schizophrenic out-patients.
AB - OBJECTIVES: Unawareness of schizophrenic symptoms was postulated to be partially
attributable to patients denying symptoms in order to avoid depression. METHOD:
The 24-item version of the Brief Psychiatric Rating Scale (BPRS) was administered
to 41 schizophrenic patients (chart diagnoses were validated by a DSM-III-R
checklist). The first 14 of these items were then used to gather information
about patients' symptomatology from 55 relatives of patients. Unawareness of
symptoms was calculated by subtracting patients' total for these 14 items from
parents' totals. Two measures of depression were obtained. Subjective depression
was the score on the depression item based on patients responses to interview
questions, objective depression was the score based on interviews with relatives
about their ill family member. Family functioning was also assessed by
administering patients' relatives the Camberwell Family Interview and the FACES
III. RESULTS: Hierarchical regression analyses revealed that both subjective and
objective measures of depression were significantly related to unawareness;
subjective depression was negatively related, and objective depression was
positively related. The employed measures of family functioning were unrelated to
unawareness of symptomatology. CONCLUSION: This opposing pattern of subjective
and objective depression was interpreted as evidence of the self-deception which
characterizes all defence mechanisms including denial.
PMID- 9561309
TI - Psychological functioning in primary progressive versus secondary progressive
multiple sclerosis.
AB - Psychological functioning in two types of multiple sclerosis (MS) patients is
assessed: primary progressive (PP) and secondary progressive (SP) patients. On
the basis of differences in clinical course and underlying pathology we
hypothesized that primary progressive patients and secondary progressive patients
might have different psychological functioning. Seventy patients treated in an MS
centre were examined cross-sectionally. Forty had an SP course of MS and 30 a PP
course. The 33 male and 37 female patients had a mean age of 48.4 years (SD 11.2)
and mean age of onset of MS of 30.7 years (SD 11.1). Patients completed
questionnaires measuring among others the following aspects of psychological
functioning: depression (BDI, SCL-90), anxiety (STAI, SCL-90), agoraphobia (SCL
90), somatic complaints (SCL-90), hostility (SCL-90) and attitude towards
handicap (GHAS). Patients with a PP-MS scored significantly better on 5 out of 14
subscales than patients with SP-MS (p < .05). On the basis of our
operationalizations of psychological functioning, the findings support the
conclusion that on average 18 years after diagnosis of MS, amongst patients
attending an MS unit, primary progressive patients were found to have better
psychological functioning.
PMID- 9561310
TI - On facing facts: what kinds of information do pre-assessment psychotherapy
questionnaires provide?
AB - More than two-thirds of NHS psychotherapy departments now use questionnaires in
assessment of new patients. Their content is described for the first time. Most
are primarily designed to gather biographical information but salient questions
are frequently omitted. These questionnaires have suffered from being designed
and used in isolation. Psychotherapy service providers need to consider how
collaboration will enable questionnaires to be more effective during their
assessments and to assist research into which historical factors are of greatest
prognostic significance among newly referred patients.
PMID- 9561311
TI - Managing patients with personality disorders.
PMID- 9561312
TI - Treatment outcome of personality disorders.
AB - OBJECTIVE: To review the treatment outcome of personality disorders. METHOD: A
literature search of studies pertaining to personality disorder and outcome was
conducted, and studies that focused primarily on Axis II were retained. Of these,
naturalistic outcome studies were distinguished from those that addressed
treatment outcome specifically. The treatment outcome studies were examined in
terms of type of treatment intervention, dependent variables, and outcome.
RESULTS: Contrary to contemporary assumptions about Axis II, a substantial number
of treatment outcome studies were identified. Trends in the assumptions
underlying psychosocial and pharmacologic approaches were identified on the basis
of dependent variables. CONCLUSION: There is evidence that effective treatments
exist to alleviate symptoms and reduce symptomatic behaviours that accompany
personality disorders. What these results hold for the idea of remission from
personality disorder is considered.
PMID- 9561313
TI - Developing effective services for patients with personality disorders.
AB - OBJECTIVE: This review focused on empirical research that addressed the
effectiveness of service models for the care of patients with personality
disorders. METHOD: Services discussed included those delivering acute care, such
as crisis and emergency services and acute psychiatric hospitalization;
continuing care, such as outpatient services, day hospital treatment, and
assertive community treatment programs; and other community programming, such as
integrated treatment for comorbid substance abuse and psychoeducational
interventions for families of patients with personality disorders. The review
focused on studies that included patients with personality disorders, and it
measured outcomes relevant to patients with personality disorders. Evidence from
randomized controlled trials was highlighted. RESULTS: Few systematic studies of
acute services were available. Community programming can decrease the risk of
suicide attempts and reliance on inpatient admissions. Services must develop
methods of ensuring compliance with treatment. Assertive community treatment for
Axis II patients should be developed, implemented, and tested. Comprehensive
programming for patients with personality disorders must include integrated
treatment for substance abuse and family psychoeducational programs. CONCLUSION:
Promising new models of care for patients with personality disorders are ready
for testing and wider application.
PMID- 9561314
TI - The first asylums in Canada: a response to neglectful community care and current
trends.
AB - OBJECTIVE: Humane treatment and care of mentally ill people can be viewed from a
historical perspective. Intramural (the institution) and extramural (the
community) initiatives are not mutually exclusive. METHOD: The evolution of the
psychiatric institution in Canada as the primary method of care is presented from
an historical perspective. A province-by-province review of provisions for
mentally ill people prior to asylum construction reveals that humanitarian
motives and a growing sensitivity to social and medical problems gave rise to
institutional psychiatry. The influence of Great Britain, France, and, to a
lesser extent, the United States in the construction of asylums in Canada is
highlighted. The contemporary redirection of the Canadian mental health system
toward "dehospitalization" is discussed and delineated. RESULTS: Early promoters
of asylums were genuinely concerned with alleviating human suffering, which led
to the separation of mental health services from the community and from those
proffered to the criminal and indigent populations. While the results of the past
institutional era were mixed, it is hoped that the "care" cycle will not repeat
itself in the form of undesirable community alternatives. CONCLUSION: Severely
psychiatrically disabled individuals can be cared for in the community if
appropriate services exist.
PMID- 9561315
TI - Prospective follow-up study of borderline personality disorder: prognosis,
prediction of outcome, and Axis II comorbidity.
AB - OBJECTIVE: To examine the rate of persistence of borderline personality disorder
(BPD), the existence of concomitant personality disorders on follow-up, and the
predictors of outcome in patients who met criteria for BPD compared with patients
with borderline features who failed to meet all of the criteria. METHOD: This
prospective cohort study reassessed subjects for BPD diagnosis and cooccurring
personality pathology at 7 years follow-up. Initial measures of borderline and
comorbid personality psychopathology were used to predict levels of borderline or
other personality disorder psychopathology at follow-up. RESULTS: Of the 57
subjects who initially met the criteria for BPD, 30 (52.6%) were found to have
remitted BPD, and 27 (47.4%) were characterized as having persistent BPD. The
remitted group met significantly fewer comorbid personality disorder diagnoses
than the persistent group (mean = 0.8, mean = 3.5 respectively; P < 0.05).
Results also indicated that the initial level of borderline psychopathology was
predictive of borderline psychopathology at follow-up, which explained 17% of the
variance. CONCLUSIONS: This prospective follow-up study found that almost 50% of
former inpatients with BPD continue to test positive for BPD at 7 years follow
up, and these persistent BPD patients also had significantly more comorbid
personality psychopathology. Borderline psychopathology at follow-up was
primarily predicted by the level of borderline psychopathology recorded at the
initial assessment.
PMID- 9561316
TI - Impairment of semantic categorization processes among thought-disordered
schizophrenic patients.
AB - OBJECTIVE: To explore semantic categorization strategies in patients with
schizophrenia. METHOD: A short-term memory-recognition task that reveals the
effects associated with categorization was created and applied to 2 groups of
patients with schizophrenia and depression. RESULTS: Only the schizophrenic
subgroup with formal thought disorder (measured using Andreasen's Thought,
Language, and Communication [TLC] scale) exhibited a deficiency in semantic
categorization strategies during the task. CONCLUSION: These results support the
hypothesis of the impairment of the processes involved in the processing of
contextual information in patients with schizophrenia who suffer from formal
thought disorder.
PMID- 9561317
TI - Neuroendocrine responses to inhibitors of steroid biosynthesis in patients with
major depression resistant to antidepressant therapy.
AB - OBJECTIVE: Patients with major depression frequently have high cortisol levels
and resistance to dexamethasone. We sought to determine to what extent major
depression might be influenced by inhibitors of steroid biosynthesis and to study
the endocrine changes produced. METHOD: After drug washout, 20 treatment
resistant patients with major depression were given aminoglutethimide,
metyrapone, and/or ketoconazole, along with a small dose of cortisol for 8 weeks.
Hamilton Depression Rating Scale (HDRS) ratings, 8:00 AM cortisol
dehydroepiandrosterone sulfate (DHAS), adrenocorticotropin (ACTH), and
testosterone levels were followed weekly or oftener. A dexamethasone suppression
test (DST) was conducted before and after treatment. RESULTS: Seventeen patients
(85%) completed the course of treatment, and a significant mean drop (P < or =
0.0001) of 50% in the HDRS score occurred by 7 weeks of treatment. Cortisol
levels fluctuated widely and were often still high after the patient had improved
clinically. Dehydroepiandrosterone sulfate levels fell more uniformly and were
found to be a useful indicator of compliance and, to some extent, efficacy with
aminoglutethimide and ketoconazole therapy. The correlation between DHAS and HDRS
(r = 0.94) was significant (P = 0.02). Testosterone levels in men fell with
ketoconazole but returned promptly to normal at the end of treatment.
Adrenocorticotropin levels were normal or elevated, depending on the assay used,
and rose (P = 0.07; n = 13) in most subject during therapy. Of the 6 responders
who had nonsuppressor DSTs before starting therapy, 5 had reverted to normal 1 to
2 weeks following cessation of therapy (P = 0.0006). CONCLUSIONS: Abnormal
metabolism of adrenocortical steroids may perpetuate depression, and alterations
of synthesis or metabolism of these steroids may lead to a remission.
PMID- 9561318
TI - Fitness to stand trial: characteristics of remands since the 1992 Criminal Code
amendments.
AB - OBJECTIVE: To examine the characteristics of a sample of remands after the
introduction of the 1992 Criminal Code amendments, to compare those deemed fit
with those deemed unfit as the result of an institution-based evaluation of
fitness, and to determine the impact of the Code changes on one's detention
period by investigating the length of time that individuals were held on remand.
METHOD: File information was collected and analyzed for 180 males who were
remanded for inpatient evaluations of their fitness to stand trial between
October 1994 and July 1995. RESULTS: The results indicated that remanded
defendants are more likely to be single, unemployed, and living alone and that
unfit defendants are significantly more likely to have never been married. As
well, individuals who were found to be unfit to stand trial were significantly
less likely to have been diagnosed with a drug- or alcohol-use disorder and were
4 times more likely to have been diagnosed with a psychotic disorder. The results
also indicated that while the 1992 Criminal Code revisions called for a 5-day
evaluation period, it appears that this is rarely accomplished, and, in fact, the
average length of time for an assessment of fitness is 23 days. Finally, the
majority of remanded individuals are certified and treated with psychotropic
medications while on remand. CONCLUSION: The results of this study suggest that
the fitness remand period is being used for purposes other than assessing
fitness.
PMID- 9561319
TI - Anxious attachment and self-reported depressive symptomatology in women.
AB - OBJECTIVE: Lack of intimacy has been identified as an important provoking agent
that increases the risk of depressive symptoms in women. This study precisely
characterized lack of intimacy by assessing a woman's attachment style and
investigated the specificity of association between depressive symptoms and an
anxious attachment pattern. METHOD: Four hundred and twenty women participated in
this cross-sectional study of depressive symptomatology and anxious attachment.
All participants completed the following measures: a sociodemographic
questionnaire, the Centre for Epidemiological Studies Depression Scale (CES-D),
the Reciprocal Attachment Questionnaire, the Social Support Questionnaire, the
Rosenberg Self-Esteem Scale, and the Global Assessment of Recent Stress Scale.
RESULTS: A score of 16 or above on the CES-D, which indicates the presence of
depressive symptoms, was used to divide the sample into 2 groups: a depressed
group (N = 129) and a nondepressed group (N = 291). We found that women in the
depressive symptomatology group were more likely than women in the nondepressive
symptomatology group to exhibit anxious attachment and adverse social and
cognitive characteristics. Lower levels of self-esteem and higher levels of
recent stress were also predictive of depressive symptomatology. Feared loss of
the attachment figure and a lack of use of the attachment figure were independent
predictors of depressive symptomatology in the same model. CONCLUSION: The feared
loss of security associated with an attachment figure seems to be related to an
increased likelihood of depressive symptoms.
PMID- 9561320
TI - Gabapentin: long-term antianxiety and hypnotic effects in psychiatric patients
with comorbid anxiety-related disorders.
PMID- 9561321
TI - ECT continuation and maintenance in a patient with psychosis and mental
disability.
PMID- 9561322
TI - All that seizes is not clozapine.
PMID- 9561323
TI - Extrapyramidal reactions from concurrent SSRI and atypical antipsychotic use.
PMID- 9561324
TI - Delusional physical misidentification in the syndrome of subjective doubles.
PMID- 9561326
TI - Progressive cerebral degeneration of childhood with liver disease (Alpers
Huttenlocher disease) with cytochrome oxidase deficiency presenting with
epilepsia partialis continua as the first clinical manifestation.
AB - A previously healthy and normally developed 17-year-old young female presented
with a sudden onset of focal motor seizure status that proved to be refractory to
anticonvulsive treatment. Severe encephalopathy with visual impairment leading to
blindness, mental deterioration, and predominantly left spastic tetraparesis
developed progressively. Hepatic disease evolved 4 months after onset of the
first symptoms and led to death in hepatic failure 1 month later. Diagnostic
studies revealed an elevated protein and lactate in the cerebrospinal fluid, slow
wave and intermittently continuous spike-wave activity in the EEG, and a complex
i.v. (cytochrome-C oxidase) deficiency in the muscle biopsy. MRI scans revealed
signal abnormalities in the occipital lobe, thalamus, and basal ganglia only
after 3 months. Histopathological findings in liver biopsy and in postmortem
brain examination displaying widespread predominantly right cortical spongiosis,
neuronal loss and astrocytosis were consistent with the clinically suspected
diagnosis of progressive neuronal degeneration of childhood with liver disease
(PNDC) or Alpers Huttenlocher disease. This rare disorder of unknown origin is
usually seen in infants and young children and is rarely reported in adolescence.
PMID- 9561327
TI - Association of oligodendroglioma-like cell proliferation and angiomatous
vasculature--coincidence or pathogenetically related lesions?
AB - We report a case of an oligodendroglioma associated with a cavernous angioma. The
patient, a 20-year-old man with an 8-year history of epileptic seizures,
presented an acute onset of headache, nausea, and vomiting. Computerized
tomographic scan and angiogram revealed multiple vascular malformations in both
hemispheres including a cystic hemorraghic lesion with a perifocal edema
attributing to a mass effect. Repeated puncture of the cyst failed to give
improvement of elevated intracranial pressure. At surgery, the cyst and the
underlying lesion were excised and found to be oligodendrocyte-rich tissue with
malformed vascular tissue. Final histological examination revealed an
oligodendroglioma associated with a cavernous angioma. As concurrence of
oligodendroglioma and vascular malformation is rare, this case raises a broad
range of differential diagnoses such as reactive oligodendroglial gliosis due to
a vascular malformation, unusual vascularity of an oligodendroglioma as well as
other kinds of cerebral tumors or malformations. The diagnostic difficulties as
well as the pathogenetic and pathological significance of the concurrence of an
oligodendroglioma and cavernous angioma are discussed.
PMID- 9561329
TI - Factor XIIIa-immunoreactivity in tumors of the central nervous system.
AB - The clotting factor XIIIa (FXIIIa) has been shown to be present both in tumor
cells and in tumor-associated macrophages of different neoplasms such as
Hodgkin's disease, giant cell tumor of bone, malignant fibrous histiocytoma,
meningeal tumors, and hemangiopericytoma. The biological significance of these
findings, however, are still unclear. This study investigates the
immunohistochemical distribution of FXIIIa in 186 tumors of the central nervous
system (CNS) in order to evaluate its possible diagnostic or prognostic
significance in neuro-oncology. High-grade gliomas such as glioblastoma,
gliosarcoma, astrocytoma (grade III WHO), and ependymoma (III) as well as
meningiomas and meningeal hemangiopericytomas consistently contained factor XIIIa
positive cells, whereas low-grade glial tumors did not do so. One desmoplastic
medulloblastoma and one anaplastic schwannoma also showed FXIIIa-positive cells.
With the exception of hemangiopericytomas, however, the major source of FXIIIa
expression in all these tumors consisted of a subpopulation of tumor-associated
macrophages, the exact role of which still remains unclear. Because of its non
discriminatory staining in a wide variety of CNS tumors, the differential
diagnostic contribution of FXIIIa in neuro-oncology seems to be limited.
PMID- 9561328
TI - Solitary fibrous tumor of the meninges.
AB - The clinical, radiologic, and pathologic features of a case of solitary fibrous
tumor of the meninges at the base of the brain are reported. The tumor caused
clinical symptoms in a 42-year-old Caucasian male which were indicative of
compression of hypothalamus, basal ganglia, and third ventricle. Radiologically
it was a large extra-axial mass isointense to brain parenchyma on precontrast T1
weighted images that filled the suprasellar cistern and deformed the left
cerebral peduncle. At surgery, the tumor was firm to hard and attached to dura.
Histologically the tumor was composed of spindle-cell proliferation in a collagen
rich background but exhibited regional variations. CD34 immunoreactivity was a
prominent histologic finding. Ultrastructural features of meningioma, such as
complex interdigitation of cell processes and intercellular specialized junctions
were absent. The cells showed the typical appearances of fibroblasts with
proximity of banded collagen and precollagen and cytoplasmic rough-surfaced
endoplasmic reticulum. DNA ploidy analysis showed diploid DNA content. Awareness
of this neoplasm may lead to increasingly frequent recognition and the current
WHO classification of brain neoplasms should be modified to include this new
entity.
PMID- 9561330
TI - Disseminated neocortical and subcortical encephalopathy (DNSE) with widespread
activation of brain macrophages: a new dementia disorder? Autopsy reports of two
postmenopausal women from families with mitochondrial DNA mutations.
AB - In this study we present 2 postmenopausal women who showed clinical symptoms that
resembled those of a rather well-defined group of vascular dementia disorders,
termed subcortical dementia (Binswanger disease, CADASIL). Patient 1 exhibited
mitochondrial DNA (mtDNA) variants in the ND5 gene at position 13,708 and the
Cytb gene at position 15,257. These DNA variants have been described in a number
of neurologic disorders, but their pathogenetic potential is unclear. Patient 2
showed the same DNA alterations and an additional mtDNA variant at position
15,812 in the Cytb gene. The principal neurohistologic features of the 2 atrophic
brains presented here include: subtotal selective neuronal cell loss in the
cortex and, to a lesser degree, in the basal ganglia (claustrum, putamen, globus
pallidus), sparing palaeocortex and periarchaeocortex, and a very characteristic
and diagnostic feature was detachment of astrocytic processes from capillary
walls resulting in pericapillary space formation. These pericapillary spaces were
partially filled with macrophages. The spaces were not associated with total
breakdown of the blood vessel walls as demonstrated by the absence of
erythrocytes, lymphocytes, or polymorphonuclear leukocytes outside the vascular
bed of the brain; progressive subcortical encephalopathy, as it is seen in
subcortical dementia (Binswanger), but lacking arterial lipohyalinosis. The
cerebral grey and white matter revealed cuffing of arteries and arterioles by
adventitial macrophages. The neocortical and subcortical changes were accompanied
by myriads of activated macrophages filled with lipids. The pathology of our 2
cases differs from that of other neurodegenerative disorders and we suggest the
term of "disseminated neocortical and subcortical encephalopathy (DNSE) with
widespread activation of brain macrophages".
PMID- 9561331
TI - Brain HIV burden and length of survival after AIDS diagnosis.
AB - Patients with AIDS in the late stages of disease can develop dementia. Previous
studies have suggested HIV encephalitis is the pathological substrate of HIV
associated dementia. We hypothesized that patients who survive longer after the
initial diagnosis of AIDS would have a higher brain HIV burden and consequently
manifest dementia. We examined the relationship between length of survival after
AIDS diagnosis and the presence of HIV encephalitis or HIV-associated dementia.
We studied retrospectively the following parameters in 74 consecutive AIDS
autopsies: length of survival after AIDS diagnosis, clinical diagnosis of
dementia, and neuropathologic findings (including HIV burden assessment).
Multinucleated giant cells (MNGC) were identified in 20% of the brains studied.
HIV gp41 was detected by immunocytochemistry in 54%, approximately half of which
had abundant HIV burden. Brains from all 4 patients who were clinically diagnosed
with dementia and had no opportunistic neuropathologic changes contained MNGC and
abundant HIV burden. Survival after AIDS diagnosis was significantly longer in
patients with MNGC (p = 0.03) or abundant HIV burden (p = 0.02). A trend toward
longer survival after AIDS diagnosis was apparent in patients with dementia, but
did not reach statistical significance. These findings suggest that prolonged
survival with immunosuppression may be a prerequisite for the development of HIV
encephalitis.
PMID- 9561332
TI - Abnormal cytoarchitecture of cortical dysplasia verified by immunohistochemistry.
AB - Cortical dysplasia is a broad category for an abnormal structure of the cerebrum
due to a disorder of the normal developmental process for neocortex. We
investigated the cortical dysplastic lesions which were surgically resected from
4 patients with intractable epilepsy. All cases showed a derangement of the
cortical laminar structure and dysplastic changes in the neurons. In addition, 3
of them showed large round cells (balloon cells) in the deep cortex and
subcortical white matter. Since each lesion showed slightly different features,
we further examined the lesions immunohistochemically by using a panel of
antibodies against cytoskeletal proteins to recognize and classify the cortical
dysplastic lesions. An immunohistochemical study revealed marked abnormalities of
the cytoskeletal structures of dysplastic neurons, bizarre glial cells and
balloon cells. These cells showed an accumulation of either phosphorylated NF,
MAP2 or GFAP in a distinct fashion. Ubiquitin immunoreactivity highlighted the
extent of cortical dysplastic lesions. In a young patient, we also found the
neuronal cytoplasmic lipofuscin deposition. It is thus considered that these
diverse immunohistochemical appearances of cortical dysplasia may thus imply a
different pathogenesis and they should therefore be classified based on the
extent of histological abnormalities.
PMID- 9561333
TI - Primary epithelioid hemangioendothelioma of the clivus.
AB - We describe the clinical, radiologic, and pathologic features of a primary
intracranial hemangioendothelioma arising in the clivus in a 38-year-old female,
emphasizing the importance of including this rare entity in the differential
diagnosis of tumors arising at the base of the skull. To our knowledge, this is
the first reported case of a clival hemangioendothelioma. Aside from its unusual
location, this case is also notable for its apparent rapid growth and mixed
epithelioid-spindle cell morphology. Appropriate neuroimaging studies may offer
crucial information, ensuring that this uncommon entity is included in the
differential diagnosis of a clival mass.
PMID- 9561334
TI - Malignant peripheral nerve sheath tumors developing multifocally in the central
nervous system in a patient with neurofibromatosis type 2.
AB - We describe autopsy findings of multifocal malignant peripheral nerve sheath
tumors (MPNSTs) appearing in the central nervous system in a 45-year-old Japanese
female with neurofibromatosis type 2. Multiple MPNSTs were detected in both III
and VIII, left IV, and V cranial nerves, and a number of nerve roots of the
spinal cord. Neurofibromata were on the other hand evident on some nerve roots of
the spinal cord and femoral and sciatic nerves. Our results suggest that a
mutation of p53 gene may have played a role in the malignant transformation of
nerve tumors in this patient since p53 protein was immunohistochemically detected
in MPNST cells but not in tumor cells of the neurofibromata.
PMID- 9561336
TI - Physiology of the nose and paranasal sinuses.
PMID- 9561335
TI - Immunity, infection, and nasal disease.
PMID- 9561337
TI - The role of allergy in sinus disease. Children and adults.
PMID- 9561339
TI - Lipid mediators in inflammatory disorders.
AB - During the past few decades, intensive collaborative research in the fields of
chronic and acute inflammatory disorders has resulted in a better understanding
of the pathophysiology and diagnosis of these diseases. Modern therapeutic
approaches are still not satisfactory and shock, sepsis and multiple organ
failure remain the great challenge in intensive care medicine. However, the
treatment of inflammatory diseases like rheumatoid arthritis, ulcerative colitis
or psoriasis also represents an unresolved problem. Many factors contribute to
the complex course of inflammatory reactions. Microbiological, immunological and
toxic agents can initiate the inflammatory response by activating a variety of
humoral and cellular mediators. In the early phase of inflammation, excessive
amounts of interleukins and lipid-mediators are released and play a crucial role
in the pathogenesis of organ dysfunction. Arachidonic acid (AA), the mother
substance of the pro-inflammatory eicosanoids, is released from membrane
phospholipids in the course of inflammatory activation and is metabolised to
prostaglandins and leukotrienes. Various strategies have been evaluated to
control the excessive production of lipid mediators on different levels of
biochemical pathways, such as inhibition of phospholipase A2, the trigger enzyme
for release of AA, blockade of cyclooxygenase and lipoxygenase pathways and the
development of receptor antagonists against platelet activating factor and
leukotrienes. Some of these agents exert protective effects in different
inflammatory disorders such as septic organ failure, rheumatoid arthritis or
asthma, whereas others fail to do so. Encouraging results have been obtained by
dietary supplementation with long chain omega-3 fatty acids like eicosapentaenoic
acid (EPA). In states of inflammation, EPA is released to compete with AA for
enzymatic metabolism inducing the production of less inflammatory and chemotactic
derivatives.
PMID- 9561338
TI - Diagnosis and treatment of acute and subacute sinusitis in children and adults.
PMID- 9561340
TI - Antiendotoxin strategies for the prevention and treatment of septic shock. New
approaches and future directions.
AB - Therapy for Gram-negative sepsis remains unsatisfactory despite a concerted
effort to develop new treatments for this common, life-threatening syndrome.
Current research continues on several fronts to improve the treatment options
available to clinicians in the management of these critically ill patients.
Recently, a greater understanding of the complex molecular basis of endotoxin
mediated pathophysiological effects in humans has generated a number of novel
therapeutic agents for sepsis. Several of these treatment strategies have already
entered clinical trials and it is hoped that some of these therapies will become
widely available in the near future. In this review, the current status of the
most promising new antiendotoxin agents is summarised, and the major obstacles to
the successful clinical development of these therapies are described. New
antiendotoxin therapies include those which interrupt the synthesis of endotoxin,
bind and neutralise its activity, prevent endotoxin interactions with host
effector cells and interfere with endotoxin-mediated signal transduction
pathways. Potential therapeutic strategies involving these agents consist of
endotoxin analogues, antibodies, subunit vaccines, binding columns, recombinant
human proteins and small molecule inhibitors of endotoxin synthesis and
intracellular signalling. The pitfalls of previous antiendotoxin clinical
investigations and the perils of future clinical trial designs are discussed in
the context of unmet needs and realistic expectations for success. While
considerable progress has been made, effective and new treatments for Gram
negative bacterial sepsis continues to elude us at the present time. This has
been to the detriment of patients, investigators and pharmaceutical companies
alike. It will require focused efforts by basic scientists, continued support by
industry and enlightened study designs by clinical investigators to successfully
develop antiendotoxin in therapies for use in septic patients in the future.
PMID- 9561341
TI - The classification of calcium antagonists and their selection in the treatment of
hypertension. A reappraisal.
AB - Calcium antagonists have become one of the most important advances in the
treatment of hypertension since their introduction over 20 years ago. The
increase in the number of available calcium antagonists (as new formulations of
pre-existing drugs or new chemical entities) over recent years has contributed to
an ever-changing scenario regarding their appropriate use compared with other
antihypertensive agents. As a consequence of this evolving situation, several
authors have proposed a 3-generation classification of calcium antagonists
currently, or soon to be, marketed in several counties. The classification system
is based among other variables, on chemical structure, tissue selectivity,
administration frequency and duration of action. In this article, this
classification is reviewed and updated on the basis of new information that is
available. In addition, factors which influence the selection of calcium
antagonists in the treatment of hypertension in specific patient populations are
discussed. As well as pharmacodynamic and pharmacokinetic considerations, these
factors also include previous experience with particular drugs in specific
patient populations, cost of treatment and drug interactions. Among the
dihydropyridine calcium antagonists, the first generation compounds have been
clearly superseded and are not recommended for use in hypertensive patients.
Whilst the second generation agents represent an adequate treatment, third
generation calcium antagonists possess distinct advantages. Definitive
confirmation of the role of calcium antagonists in hypertension lies in several
ongoing large multicentre trials.
PMID- 9561343
TI - Hyperthyroidism. Current treatment guidelines.
AB - Hyperthyroidism is common and affects approximately 2% of women and 0.2% of men.
The most common cause of hyperthyroidism is Graves' disease, an autoimmune
disorder associated with circulating immunoglobulins that bind to and stimulate
the thyrotropin (TSH) receptor, resulting in sustained thyroid overactivity.
Toxic nodular goitres cause hyperthyroidism due to autonomous hyperfunctioning of
localised areas of the thyroid. There are 3 recognised modalities of treatment
for hyperthyroidism: antithyroid drugs, surgery and radioiodine. All are
effective but no single method offers an absolute cure. Patients with Graves'
disease may be prescribed antithyroid drugs over a period of 12 to 18 months with
a view to inducing a long term remission. These drugs are also often given for a
short period to render the patient euthyroid before definitive therapy with
radioiodine or thyroidectomy. However, antithyroid drugs will not 'cure'
hyperthyroidism associated with a toxic nodular goitre. The use of radioiodine as
a first-line therapy for hyperthyroidism is growing. It is well tolerated, with
the only long term sequelae being the risk of developing radioiodine-induced
hypothyroidism. Radioiodine can be used in all age groups other than children,
although it should also be avoided in pregnancy and during lactation. Pregnancy
should be avoided for 4 months following its administration. Radioiodine may
cause a deterioration in Graves' ophthalmopathy and corticosteroid cover may
reduce the risk of this complication. The treatment of choice for toxic nodular
goitre hyperthyroidism is radioiodine. Surgery, either subtotal or near-total
thyroidectomy, has limited but specific roles to play in the treatment of
hyperthyroidism: this approach is rarely used in patients with Graves' disease
unless radioiodine has been refused or there is a large goitre causing symptoms
of compression in the neck. The goal of surgery is to cure the underlying
pathology while leaving residual thyroid tissue to maintain postoperative
euthyroidism.
PMID- 9561342
TI - A practical guide to the management of distal ulcerative colitis.
AB - This article reviews the role of corticosteroids, sulfasalazine and mesalazine (5
aminosalicylic acid, mesalamine), immunosuppressive agents and alternative novel
drugs for the treatment of distal ulcerative colitis. Short cycles of
traditional, rectally administered corticosteroids (methylprednisolone,
betamethasone, hydrocortisone) are effective for the treatment of mild to
moderately active distal ulcerative colitis. In this context, their systemic
administration is limited to patients who are refractory to either oral 5-amino
salicylates, topical mesalazine or topical corticosteroids. Of no value in
maintaining remission, the long term use of either or topical corticosteroids may
be hazardous. A new class of topically acting corticosteroids [budesonide,
fluticasone, beclomethasone dipropionate, prednisolone-21-methasulphobenzoate,
tixocortol (tixocortol pivalate)] represents a valid alternative for the
treatment of active ulcerative colitis, and may be useful in the treatment of
refractory distal ulcerative colitis. Although there is controversy concerning
dosage or duration of therapy, oral and topical mesalazine is effective in the
treatment of mild to moderately active distal ulcerative colitis. Sulfasalazine
and mesalazine remain the first-choice drugs for the maintenance therapy of
distal ulcerative colitis. Evidence exists showing a trend to a higher remission
rate with higher doses of oral mesalazine. Topical mesalazine (suppositories or
enemas) also is effective in maintenance treatment. For patients with chronically
active or corticosteroid-dependent disease, azathioprine and mercaptopurine are
effective in reducing either the need for corticosteroids or clinical relapses.
Moreover, they are effective for long term maintenance remission. Cyclosporin may
be useful in inducing remission in patients with acutely severe disease who do
not achieve remission with an intensive intravenous regimen. Existing data
suggest that azathioprine and mercaptopurine may be effective in prolonging
remission in these patients. The role of alternative drugs for the treatment of
distal ulcerative colitis and its different forms is reviewed. In particular data
are reported concerning the effectiveness of 5-lipoxygenase inhibitors, topical
use of short chain fatty acids, nicotine, local anaesthetics, bismuth
subsalicylate enema, sucralfate, clonidine, free radical scavengers, heparin and
hydroxychloroquine.
PMID- 9561344
TI - Recognition and treatment of idiopathic pulmonary fibrosis.
AB - The diagnosis of idiopathic pulmonary fibrosis can be made only after exclusion
of other entities such as neoplasm, toxic treatments, collagen vascular diseases,
occupational exposure or granulomatous diseases, such as sarcoidosis. The
repercussions on gas exchanges are the most reliable indications of the severity
of the disease, the measure of lung volume or chest x-rays alone often being
misleading. Biopsies obtained during transbronchial procedures by thoracoscopies
or thoracotomy are of great help, but mainly to rule out other diseases. In many
cases, only a high resolution computerised tomography (CT) scan and
bronchoalveolar lavage are performed to rule out infection or tumour and to
assess the inflammatory state of the disease. Due to the fact that barely a
quarter of patients respond to corticosteroids alone, cytostatics (in particular
azathioprine) are often prescribed simultaneously with low dose corticosteroids,
either initially or after an unsuccessful trial of corticosteroids. Cyclosporin
has been useful for only a limited number of patients. Colchicine has been shown
useful in an open trial but its role still needs to be assessed. Anticytokine
therapy and the role of substances such as relaxin are still at the experimental
stage. Lung transplantation is now a therapeutic option for selected patients.
PMID- 9561345
TI - Glimepiride. A review of its use in the management of type 2 diabetes mellitus.
AB - Glimepiride is a sulphonylurea agent that stimulates insulin release from
pancreatic beta-cells and may act via extrapancreatic mechanisms. It is
administered once daily to patients with type 2 (non-insulin-dependent) diabetes
mellitus in whom glycaemia is not controlled by diet and exercise alone, and may
be combined with insulin in patients with secondary sulphonylurea failure. The
greatest blood glucose lowering effects of glimepiride occur in the first 4 hours
after the dose. Glimepiride has fewer and less severe effects on cardiovascular
variables than glibenclamide (glyburide). Pharmacokinetics are mainly unaltered
in elderly patients or those with renal or liver disease. Few drug interactions
with glimepiride have been documented. In patients with type 2 diabetes,
glimepiride has an effective dosage range of 0.5 to 8 mg/day, although there is
little difference in efficacy between dosages of 4 and 8 mg/day. Glimepiride was
similar in efficacy to glibenclamide and glipizide in 1-year studies. However,
glimepiride appears to reduce blood glucose more rapidly than glipizide over the
first few weeks of treatment. Glimepiride and gliclazide were compared in
patients with good glycaemic control at baseline in a 14-week study that noted no
differences between their effects. Glimepiride plus insulin was as effective as
insulin plus placebo in helping patients with secondary sulphonylurea failure to
reach a fasting blood glucose target level of < or = 7.8 mmol/L, although lower
insulin dosages and more rapid effects on glycaemia were seen with glimepiride.
Although glimepiride monotherapy was generally well tolerated, hypoglycaemia
occurred in 10 to 20% of patients treated for < or = 1 year and > or = 50% of
patients receiving concomitant insulin for 6 months. Pooled clinical trial data
suggest that glimepiride may have a lower incidence of hypoglycaemia than
glibenclamide, particularly in the first month of treatment. Dosage is usually
started at 1 mg/day, titrated to glycaemic control at 1- to 2-week intervals to a
usual dosage range of 1 to 4 mg/day (maximum 6 mg/day in the UK or 8 mg/day in
the US). CONCLUSIONS: Glimepiride is a conveniently administered alternative to
other sulphonylureas in patients with type 2 diabetes mellitus not well
controlled by diet alone. Its possible tolerability advantages and use in
combination with other oral antidiabetic drugs require further study. Glimepiride
is also reported to reduce exogenous insulin requirements in patients with
secondary sulphonylurea failure when administered in combination with insulin.
PMID- 9561347
TI - Adolescent psychiatry: its potential to reduce the burden of mental disorder.
PMID- 9561348
TI - Stability and change in externalising behaviours.
AB - This paper provides an overview of a series of issues relating to continuity and
discontinuity in externalising disorders including conduct disorder, attention
deficit disorder and substance use disorders in childhood and adolescence. These
issues include: (a) the assessment of stability and change; (b) the origins of
behavioural stability; (c) the origins of behavioural change; and (d) the
preventive and clinical implications of research into behavioural stability and
change. It is concluded that future research into this area should involve: (a)
further research into the genetic factors underlying externalising disorders; (b)
continued research into the developmental progressions; (c) refinement and
revision of measurement methodologies; and (d) greater use of designed
experimentation to examine the extent to which externalising behaviours are
amenable to change through both public health and clinical interventions.
PMID- 9561346
TI - Liposomal amphotericin B. Therapeutic use in the management of fungal infections
and visceral leishmaniasis.
AB - Incorporation of amphotericin B into small unilamellar liposomes (AmBisome)
alters the pharmacokinetic properties of the drug, but allows it to retain
significant in vitro and in vivo activity against fungal species, including
Candida, Aspergillus and Cryptococcus, and parasites of the genus Leishmania.
Used as prophylaxis against fungal infections in immunocompromised patients,
liposomal amphotericin B appeared to reduce the incidence of both fungal
colonisation and proven fungal infections, but did not affect overall survival.
Empirical therapy with liposomal amphotericin B in immunocompromised adults or
children with suspected fungal infections was at least as effective as therapy
with conventional amphotericin B. In the largest noncomparative studies,
liposomal amphotericin B produced mycological eradication in 40 and 83% of
patients with proven Candida infections and 41 and 60% with proven Aspergillus
infections; however, these studies included relatively few patients. Mycological
eradication rates of 67 to 85% in patients with cryptococcal meningitis have been
reported. Liposomal amphotericin B is an effective treatment for visceral
leishmaniasis in immunocompetent adults and children, including those with severe
or drug-resistant disease. The drug also produces good response rates in
immunocompromised patients; however, relapse rates in these patients are high.
Liposomal amphotericin B is generally well tolerated. Few patients require
discontinuation or dose reduction of the drug because of adverse events. The most
frequently reported adverse events are hypokalaemia, nephrotoxicity and infusion
related reactions; however, these occur significantly less often after liposomal
amphotericin B than after the conventional formulation of the drug. The
acquisition cost of liposomal amphotericin B is higher than that of conventional
amphotericin B. Cost-effectiveness analysis did not clearly show an economic
benefit for empirical liposomal amphotericin B antifungal therapy in adults;
however, one model suggested that initial empirical therapy with the liposomal
formulation in children may cost less per cure than initial therapy with the
conventional formulation. Liposomal amphotericin B appears to be an effective
alternative to conventional amphotericin B in the management of immunocompromised
patients with proven or suspected fungal infections. Use of the drug is
facilitated by its greatly improved tolerability profile compared with
conventional amphotericin B. Because of this, liposomal amphotericin should be
preferred to conventional amphotericin B in the management of suspected or proven
fungal infections in immunocompromised patients with pre-existing renal
dysfunction, amphotericin B-induced toxicity or failure to respond to
conventional amphotericin B. Liposomal amphotericin B may also be considered for
first- or second-line treatment of immunocompetent patients with visceral
leishmaniasis.
PMID- 9561349
TI - Increased rates of psychosocial disorders in youth.
AB - The evidence for an increased incidence of rates of psychosocial disorders
including depression, suicide, delinquency, eating disorders, and drug and
alcohol abuse is summarized. Findings from prospective studies, family genetic
studies, community surveys, repeated cross-sectional surveys, and data from
mortality and police statistics suggest that the increase over time of several of
these disorders is supported by epidemiological evidence, particularly for
suicide, delinquency, addictive behaviors, and depression. Several studies also
indicate that an earlier age of onset for these disorders is seen in the most
recent birth cohorts, with most of these disorders having their onset in
adolescent years. The implications of these findings for child psychiatric
treatment and services are discussed.
PMID- 9561350
TI - "A stitch in time" ... the scope for preventive strategies in early psychosis.
AB - Preventive endeavours in psychotic disorders have been hampered by many obstacles
over the past century. One important barrier has been the corrosive pessimism
which has attached to the treatment prospects for schizophrenia in particular
since the time of Kraepelin, and the isolation of this disorder from progressive
models of preventive intervention which operate in general health care. This
paper outlines a rationale, logic and model for realistic preventive efforts in
early psychosis, focusing on indicated prevention in the pre-psychotic phase and
early intervention from the onset of frank psychotic symptoms through the early
years of illness. The latter is discussed through a series of clinical challenges
which will be familiar to clinicians during this phase of illness. The existing
evidence is introduced and the gaps indicated. It is argued that the case for a
preventive approach possesses more than face validity alone, and that momentum is
building for a significant paradigm shift. If this to be securely based and
durable, it will need to become increasingly evidence based and demonstrate cost
effectiveness. The nature of the evidence and the strategy for its assembly are
also considered.
PMID- 9561351
TI - Prevention and early intervention for depression in adolescence and early adult
life.
AB - Over the past decade there has been increasing interest in the possibility that
early intervention might prevent mental disorders later in life. Indeed, in the
United Kingdom the Department of Health recommends that health promotion should
be one of the main functions of child mental health services, a suggestion that
has been endorsed by professional bodies. It is easy to see why both purchasers
and providers of mental health services would be interested in prevention, but
will preventive interventions work in practice? This paper discusses the
possibility of preventing depressive disorder in late adolescence and early adult
life by intervening in childhood and early adolescence. The paper begins with a
description of the phenomenology of depression and its risk factors. It then goes
on to describe a framework of prevention and within this framework explores
whether there is an adequate knowledge base. The general perspective that is
presented is one of cautious scepticism. It is argued that difficulties in
defining depression and identifying risk factors that can easily be remedied make
it unlikely that within the foreseeable future primary prevention programmes will
prove to be more effective than treatment and rehabilitation of affected
individuals. The possibility that preventive programmes could do harm will also
be discussed. The paper concludes with some proposals about appropriate targets
for prevention. It is suggested that apart from a few policy areas where there
are some relatively harmless measures that could protect from later depression, a
balanced preventive programme will give higher priority to treatment services
than to those concerned with early intervention.
PMID- 9561352
TI - Differentiation of autonomic nervous activity in different stages of coma
displayed by power spectrum analysis of heart rate variability.
AB - The analysis of heart rate (HR) variability offers a noninvasive method to
investigate autonomic nervous system activity in comatose patients. We analyzed
three components of the HR variability in a group of comatose patients: the low
frequency band (LF), representing mainly sympathetic influence, the mid-frequency
band (MF), representing sympathetic and parasympathetic influence, and the high
frequency band (HF), representing the parasympathetic influence. A value for
sympathovagal balance was defined as LF/HF and MF/HF ratio. Moreover, the skin
conductance level (SCL) and the skin conductance resistance (SCR) variability
were recorded. The patient group consisted of 22 patients with traumatic brain
injuries. Coma depth was assessed by the Glacow Coma Scale and artifact-free HR,
SCL, and SCR were measured 75 times in the patient group. The results documented
a significant gain in sympathetic nervous system activity corresponding with the
state of emerging from coma. This gain was most pronounced in the HF component of
the HR and in the sympathovagal balance between LF/HF. The findings in SCL and
SCR variability endorsed this result. It is concluded that emerging from coma is
accompanied by an increasing influence of the sympathetic nervous system on HR
control. This leads to a change in the sympathovagal balance, i.e., a
reintegration of parasympathetic and sympathetic activity.
PMID- 9561353
TI - Quantitative proton magnetic resonance spectroscopy of the basal ganglia in
patients with affective disorders.
AB - Proton magnetic resonance spectra were recorded from a subcortical region
containing the basal ganglia in 40 patients with affective disorders (18 with
bipolar disorder and 22 with major depression) and in 20 normal controls. The
absolute concentration of the choline-containing compounds (Cho) in the patients
with bipolar disorder in the depressive state was significantly higher than that
in the normal controls. The patients with bipolar disorder had significantly
higher levels of the Cho/creatine + phosphocreatine (Cr) and Cho/N-acetly-1
aspartate (NAA) peak ratio compared with the normal controls in both the
depressive and euthymic states, with a tendency to higher levels in the
depressive state. The Cho/NAA peak ratio was also significantly higher in the
patients with major depression compared with the normal controls. These results
suggest that the membrane phospholipid metabolism in the basal ganglia is altered
in affective disorders.
PMID- 9561354
TI - Visual fields after removal of subretinal hemorrhages and neovascular membranes
in age-related macular degeneration.
AB - BACKGROUND: Surgical removal of subretinal hemorrhaging and membranes in eyes
with age-related macular degeneration is feasible from a technical point of view,
but no advantage over the spontaneous course of the disease has been proven.
Visual acuity usually does not improve much. A realistic aim of surgical
intervention may be diminution of the central scotoma size, which has not been
studied. METHOD: In a prospective study visual fields were measured
preoperatively and 6 weeks and 6 months postoperatively in eyes operated on for
subretinal hemorrhages and membranes in exudative age-related macular
degeneration. The OCTOPUS 1-2-3 program glx, which tests the visual field of 60
degrees diameter at 59 points, was used. Changes in the total size of areas with
sensitivity loss of 10-20 dB (= relative scotoma) and > 20 dB (= absolute
scotoma) were interpreted as surgical effect. Patients with postoperative retinal
detachment or neovascular recurrence were excluded. 30 eyes of 29 patients were
enrolled (mean age 75.3 years, 11 male, 18 female) and divided into 3 groups: 14
eyes with massive subretinal hemorrhage of diameters > 30 degrees; 12 eyes with
hemorrhages of 10 degrees-30 degrees; 4 eyes with mere neovascular membranes < 10
degrees. RESULTS: (1) The visible area of damage is diminished by surgery (P <
0.01). The reduction for lesions > 30 degrees is 80%; for lesions between 10
degrees and 30 degrees the improvement is 43%. For lesions < 10 degrees there is
no significant change. (2) The absolute scotoma size diminishes in all three
groups (P = 0.05). The reductions are 63%, 57% and 21%, respectively. (3) Areas
of absolute scotoma do not regain full function but are converted to relative
scotoma depth, at best. Therefore, in the > 30 degrees group an overall increase
(P < 0.01) of the relative scotoma size is observed. (4) The mean sensitivity in
the 60 degrees field enhances by 1.6 dB (average over 30 eyes, P = 0.04). (5)
Mean preoperative visual acuities were 0.03, 0.12 and 0.17, respectively, with no
significant change after surgery. The power of testing is sufficient (0.93) to
reject an increase of acuity from 0.12 to 0.2 in group 2. CONCLUSIONS: For
hemorrhagic subretinal lesions of diameter > 10 degrees a relevant reduction of
central scotoma size is achieved by surgery. The final benefit for the patients
depends on the frequency of surgical complications and neovascular recurrence.
PMID- 9561355
TI - Ultrastructure of epiretinal membranes associated with macular holes.
AB - BACKGROUND: The role of tangential traction exerted by epiretinal membranes in
the pathogenesis of macular holes is not fully understood. Furthermore, the role
of glial cells in the formation and/or closure of macular holes remains to be
elucidated. METHODS: To better understand the pathogenesis of macular hole
formation and to compare the ultrastructural features of epiretinal membranes
associated with macular holes of primary and secondary etiology, we harvested 23
translucent epiretinal membranes associated with macular holes stages III-IV at
the time of pars plana vitrectomy and examined them electron microscopically.
Eighteen membranes were obtained from patients with idiopathic macular holes. 3
membranes from patients with myopic macular holes and 2 epiretinal membranes were
associated with macular holes which had developed after retinal detachment
surgery. RESULTS: Eighteen membranes contained a continuous undulating piece of
inner limiting lamina (ILL). Sixteen of 18 epiretinal membranes at the margins of
idiopathic macular holes, 2 of 3 membranes in myopic macular holes and both
membranes associated with a macular hole after retinal detachment surgery
demonstrated mono- or multilayers of fibrous astrocytes with single macrophage-
or fibrocyte-like cells. Vitreous and newly formed collagen occupied the space
between the ILL and the glial cells. Three macular holes were surrounded by
rather firmly attached acellular ILL. CONCLUSIONS: Glial cells and newly formed
collagen may play an important role in macular hole formation by exerting
tangential traction regardless of the underlying disease process. Glial cells,
however, may also be involved in healing of the retinal defect and pars plana
vitrectomy with peeling of an epiretinal membrane, and/or the ILL may induce
directed glial cell proliferation and migration. The similar ultrastructure of
epiretinal membranes associated with macular holes and "simple epiretinal
membranes" as described by Foos [8] suggests a common pathogenesis for macular
holes and macular pucker.
PMID- 9561356
TI - Results of penetrating keratoplasty in bullous silicone oil keratopathy.
AB - BACKGROUND: To evaluate the results of penetrating keratoplasty (PK) in bullous
silicone oil keratopathy (BSK). MATERIAL AND METHODS: PK for BSK was performed in
13 patients, aged from 31 to 82 years. In all patients, pars plana vitrectomy
(PPV) with silicone oil implantation (SOI) had been previously performed as the
definitive surgery: for complicated retinal detachment with advanced
proliferative vitreoretinopathy in 12 eyes and for diabetic traction detachment
in one eye. Seven patients were monocular. All 13 eyes were aphakic and there was
a long-lasting contact of silicone oil with the corneal endothelium. Before
keratoplasty, each eye underwent between two and five operations, on average
three, for retinal detachment or late complications of SOI. The interval between
SOI and PK was from 11 to 79 months. The patients were followed up for 12-52
months. RESULTS: At the last follow-up examination, a clear graft was found in 6
out of 13 eyes (46%). The six clear grafts were found in the ten eyes where
silicone oil had been removed before keratoplasty. The graft became opaque in all
three eyes in which silicone oil had not been removed. Six out of seven eyes with
failed grafts atrophied. Visual acuity improved in all six eyes with the clear
graft from had movement preoperatively to 0.05-0.25. The decreased visual acuity
was caused by irreparable damage to the macula, which resulted from high myopia,
proliferative vitreoretinopathy or long-lasting detachment of the macula.
CONCLUSIONS: PK in BSK was successful only in those eyes in which the attached
retina enabled the removal of the silicone oil before the PK. The reattached
retina and useful visual acuity before the development of BSK were the
preconditions for functional success of the PK.
PMID- 9561357
TI - Prognostic value of the pattern electroretinogram in cases of tumors affecting
the optic pathway.
AB - BACKGROUND: Tumors compressing the optic pathway may lead to irreversible loss of
vision which may be detected by the pattern electroretinogram (PERG) because of
its relation to ganglion cell function. METHODS: Eyes of 19 patients were tested
shortly before and 5-10 days after tumor surgery. Visual acuity, the 30-deg
visual field and the transient and steady-state pattern reversal ERG were
measured. RESULTS: Using patterns of 1.5 x 1.2 deg there was a good correlation
between the change of pre- and post-surgical visual performance and most of the
pattern ERG amplitudes. For all variables tested--P50, N95- and steady-state
amplitude--there was a critical value beyond which the visual outcome could be
bad or favorable, whereas patients showing higher amplitudes always remained
stable or improved after surgery. CONCLUSION: The positive correlation between
pattern ERG amplitudes and the post-surgical outcome in the case of tumors
affecting the optic pathway may be helpful in predicting the outcome for these
patients.
PMID- 9561358
TI - Progression of retinopathy and alteration of the blood-retinal barrier in
patients with type 2 diabetes: a 7-year prospective follow-up study.
AB - BACKGROUND: The study was carried out to evaluate the correlation between blood
retinal barrier (BRB) permeability and the progression of diabetic retinopathy
(DR), defined by development of "need for photocoagulation", over a 7-year period
by means of vitreous fluorometry (VF). METHODS: Forty type 2 diabetic patients
with minimal or no retinopathy, aged 40-65 years (mean 53.9 + 7.3 years), were
followed up prospectively for 7 years. Investigations including standard
ophthalmological examination, fundus photography, fluorescein angiography and VF
were performed at entry and 1, 4, 5 and 7 years later. Only one eye per patient
was included in the study. Need for photocoagulation was based on Early Treatment
Diabetic Retinopathy Study protocols and decided by the attending
ophthalmologist. RESULTS: After 7 years of follow-up a total of 22 of the 40 eyes
had received photocoagulation. The eyes that needed photocoagulation were those
that had higher VF values at the entry of the study and showed higher rates of
deterioration (initial values 5.1 + 1.9 vs 2.8 + 1.5 x 10(-6) min-1, P < 0.001;
annual increase in leakage for the first year, 1.5 + 0.8 vs 0.5 + 1.0 x 10(-6)
min-1, P < 0.001,). The eyes that did not need photocoagulation during the 7
years of follow-up showed stable VF readings (-0.1 + 1.2 x 10(-6) min-1,
difference between initial values and 7 years later). CONCLUSIONS: Abnormally
high VF values and their rapid increase over time are good indicators of
progression and worsening of the retinopathy in diabetes type 2.
PMID- 9561359
TI - Age-related deterioration of motion perception and detection.
AB - PURPOSE: The purpose of this study was to evaluate the effect of aging on motion
detection and perception. METHODS: Forty-six subjects, ages 19-92 years, were
asked to view a motion stimulus. Infrared oculography was used to objectively
evaluate motion detection by documenting the presence of optokinetic nystagmus as
the subjects viewed the stimulus. Subjective responses to motion perception were
recorded using a computer joystick. RESULTS: Optokinetic nystagmus was clearly
detectable in all 46 subjects. Motion detection and perception thresholds showed
age-related deterioration. No relationship was found to gender or age-gender
interaction. CONCLUSION: The results indicate motion detection and perception
thresholds deteriorate with age. This may reflect a susceptibility to age-related
degeneration in specific cortical areas responsible for motion perception as well
as neurodegeneration in the retinogeniculate pathway.
PMID- 9561360
TI - Reproducibility of measurements with a new slit lamp-mounted ocular blood flow
tonograph.
AB - PURPOSE: To assess the reliability of measurements of intraocular pressure
(i.o.p.), pulse amplitude (PA), and pulsatile ocular blood flow (POBF) and the
validity of measurements of IOP with a new ocular blood flow tonograph. METHODS:
Intraocular pressure pulse was assessed with pneumatic tonometry. In this study,
we used the OBF Labs ocular blood flow tonograph with two different pneumatic
probes, a modified Langham probe and a newly developed probe. One ophthalmologist
compared two machines, first with the modified Langham probe and secondly with
the newly developed probe (40 volunteers). Additionally, two ophthalmologists
performed measurements on different days and in different sequence (34
volunteers). Furthermore, results of IOP measurements performed with this
tonograph were compared to those of Goldmann applanation tonometry (213
volunteers). RESULTS: Using the modified Langham probe, POBF and PA were
associated with the machine used for the test. However, using the newly developed
pobe, no relevant or statistically significant differences were found for any
variables, and reliability coefficients were between 0.70 and 0.90. Linear
regression analysis of the Goldmann applanation tonometer on the measurements of
IOP with the tonograph showed a regression coefficient of 0.765. CONCLUSIONS:
Results of measurements performed with this ocular blood flow tonograph and the
newly developed probe are expected to be reliable and comparable.
PMID- 9561362
TI - Retinal sensitivity measurement over drusen using scanning laser ophthalmoscope
microperimetry.
AB - BACKGROUND: Retinal sensitivity over drusen was examined using a scanning laser
ophthalmoscope to confirm a previous report of no change in sensitivity over
drusen. METHODS: Microperimetry was performed using a scanning laser
ophthalmoscope in 23 eyes of 19 subjects. Subject age ranged from 42 to 86 years
(mean 68.5 years). Fifty-four drusen bigger than the diameter of a major retinal
vein at the optic disc rim were examined, and drusen were classified as soft
drusen and other large drusen. RESULTS: Nine eyes of eight subjects showed a
decrease in retinal sensitivity over drusen. The decrease in retinal sensitivity
was more than 5 dB less than the sensitivity at a peripheral non-drusen area
peripheral to the measurement point. The sensitivity decrease was noted over 15
of 29 large drusen and the decrease was statistically significant (P < 0.02).
However, no relationship between the size of the drusen and the amount by which
sensitivity decreased was found. Nevertheless, a decrease in retinal sensitivity
was not seen over any of 25 soft drusen. CONCLUSION: Large drusen may influence
retinal sensitivity and function.
PMID- 9561361
TI - Seroprevalence of anti-Borrelia antibodies among patients with confirmed
sarcoidosis in a region of Japan where Lyme borreliosis is endemic.
AB - BACKGROUND: Sarcoidosis is a multisystemic granulomatous disease of unknown
etiology, while Lyme borreliosis is a multisystemic disorder caused by Borrelia
burgdorferi. The purpose of this study is to evaluate the relationship between
sarcoidosis and Lyme borreliosis in a region of Japan where Lyme borreliosis is
endemic. METHODS: We determined the seroprevalence of anti-Borrelia burgdorferi
antibodies as well as antibodies three Japanese Borrelia strains by enzyme-linked
immunosorbent assay and dotblot assay using purified Borrelia-specific proteins
in 46 patients with confirmed sarcoidosis and 150 controls (50 disease controls
and 100 healthy controls) in Hokkaido, the affected region. RESULTS: Fifteen
patients with sarcoidosis (32.6%) tested positive for Borrelia spirochete in both
assays, compared with two disease controls (4.0%) and two healthy controls
(2.0%). The seroprevalence of anti-Borrelia antibodies in patients with
sarcoidosis was much higher in the affected region than in the region in our
previous study were Lyme borreliosis is non-endemic. CONCLUSION: In a region
where Lyme borreliosis is endemic, Borrelia infection may be partially associated
with sarcoidosis.
PMID- 9561363
TI - Granular corneal dystrophy: treatment with soft contact lenses.
AB - Perforating keratoplasty was performed in both eyes of two siblings (sister and
brother) with typical granular corneal dystrophy. Three of the operated eyes
showed a recurrence of the underlying disease. In one eye, a recurrence could not
be detected 14 years after the operation. This eye had been fitted with a contact
lens 16 months after keratoplasty because of aphakia. Thus a contact lens may
have a therapeutic effect in this primary epithelial disease.
PMID- 9561364
TI - Expression of basic fibroblast growth factor and its receptor mRNA in retinal
tissue following ischemic injury in the rat.
AB - BACKGROUND: Our purpose was to determine the time-dependent changes of expression
of basic fibroblast growth factor (bFGF) and its receptor in pressure-induced
retinal ischemia in rats. METHODS: Retinal ischemia was induced in Wistar rats by
increasing the intraocular pressure to 110 mmHg for 45 min by cannulation into
the eyes. At the end of the ischemic period, reperfusion of the retinal
vasculature was confirmed. Localization of bFGF and FGF receptor-1 (FGF-R) mRNAs
were evaluated by in situ hybridization at various times after reperfusion. The
reverse-transcription polymerase chain reaction (RT-PCR) method was used to
detect the expression of bFGF and FGF-R mRNA in the sensory retina. RESULTS: In
normal sensory retina, bFGF and FGF-R mRNAs were observed in the ganglion cell
layer and inner nuclear layer. bFGF gene expression in the sensory retina
increased within 24 h, particularly at 6-12 h. FGF-R gene expression increased
earlier than that of bFGF. By RT-PCR, expression of bFGF gene reached a peak at 6
24 h, and FGF-R reached a peak at 3-12 h. These RT-PCR results are comparable to
those of in situ hybridization. CONCLUSIONS: These results demonstrate that
transient retinal ischemia leads to the induction of bFGF mRNA synthesis, and
suggest that bFGF has a protective role, e.g., a defense mechanism for the
sensory retina.
PMID- 9561365
TI - The effect of intraocular pressure on the absorption of air from the vitreous
cavity.
AB - BACKGROUND: The duration of an intraocular gas bubble used in vitreoretinal
surgery is an important determinant of the safety and effectiveness of
intraocular gas use. Considerable variability impedes the clinical determination
of this parameter. The aim of the study was to study experimentally the
relationship between intraocular pressure (i.o.p.) and the absorption of an
intravitreal air bubble. METHODS: We compared the rate of absorption of an
intravitreal air bubble in rabbit eyes that had been treated with
cyclocryotherapy (n = 17) to the absorption of air bubbles in untreated fellow
eyes (n = 17). RESULTS: Intravitreal air bubble persisted longer in the
cyclocryotherapy-treated rabbit eye (mean +/- SD 78 +/- 16 h) than in the control
fellow eyes (43 +/- 15 h). This difference was statistically significant (P <
0.001). The length of time an air bubble persisted could be predicted from the
IOP. CONCLUSIONS: The reason for the increased length of time an air bubble
remained in cyclocryotherapy-treated eyes is probably the result of several
factors, including primarily reduced aqueous flow and reduced IOP. Our results
show that the duration of air injected into the vitreous cavity correlated to
IOP. In addition to other known factors, the IOP should be considered in
predicting intravitreal gas persistence.
PMID- 9561366
TI - The lens influences aqueous humor levels of transforming growth factor-beta 2.
AB - BACKGROUND: Transforming growth factor-beta 2 (TGF-beta 2) is a pluripotent
cytokine which has been suggested to play a number of roles in ocular physiologic
and pathologic states. Intraocular fluid (i.o.f.) levels of TGF-beta 2 are quite
high. Although the sources of ocular TGF-beta are not completely defined, the
retinal pigment epithelium, the epithelium of the ciliary body and trabecular
meshwork cells all secrete it. In this study we utilized canine lens and rabbit
ciliary pigmented epithelial cell cultures to quantitate the in vitro secretion
of TGF-beta 2. In addition, the effects of aphakia or the presence of cataractous
lenses on IOF TGF-beta 2 levels were determined. METHODS: Lens and ciliary body
epithelial cell culture supernatants and aqueous humors were assayed for total
TGF-beta 2 levels by ELISA and bioassay. RESULTS: TGF-beta 2 accumulated in the
media bathing lens epithelial cell cultures (0.7 +/- 0.03 ng/ml at day 2) and
ciliary pigmented epithelial cell cultures (0.8 +/- 0.06 ng/ml at day 2) in a
time-dependent manner. Surprisingly, aqueous humor from aphakic rabbit eyes
contained significantly higher levels of TGF-beta 2 than their contralateral
phakic controls. Furthermore, aqueous humor from canine eyes with cataracts also
contained significantly higher levels of TGF-beta 2 than normal eyes.
CONCLUSIONS: These results suggest that the lens secretes TGF-beta 2 and that the
presence and status of the lens may influence IOF TGF-beta 2 levels.
PMID- 9561367
TI - A sensitive method for testing the quality of organ culture media and of
individual medium components in a cornea bank.
AB - BACKGROUND: It has been suggested that variations in the quality of organ culture
preservation media are responsible for variations in early postoperative graft
morphology. Spates of such variations have been observed repeatedly for short
periods. This paper reports the results of a series of grafts with low
postoperative clearing observed during a period of 6 weeks. Simultaneously,
preoperative phase-contrast microscopy evaluation of the corneal endothelium
revealed that an unusually large proportion of donor corneae were unsuitable for
transplantation. METHODS: The corneal storage media were therefore rigorously
screened, paying particular attention to specific components and properties of
the medium, including L-glutamine, amphotericin B, water quality, pH, and the
glassware used. Possible toxic effects were identified by means of a sensitive
growth assay performed using isolated human corneal endothelial cells. RESULTS:
The evaluation demonstrated that both the water quality and the L-glutamine which
had been used for preparation of the medium were substandard during the period in
which poor clinical results were obtained. CONCLUSION: It is recommended that
cornea banks undertaking long-term organ culture use standardized protocols and
carefully monitored equipment. The quality of the basal media and supplements
should be routinely checked.
PMID- 9561368
TI - Mature dendritic cells respond to SDF-1, but not to several beta-chemokines.
AB - Immature dendritic cells (DCs) are highly motile, but after differentiation they
stop migration. Chemokines are chemotactic cytokines that direct leukocyte
trafficking, therefore we looked for the expression and function of chemokine
receptors in immature and mature DCs. As a model, we used the human DCs that
develop from CD14+ peripheral blood monocytes cultured with GM-CSF and IL-4.
After 6-7 days in culture, these cells have the characteristics of immature DCs,
but can be induced to mature further by inflammatory stimuli or by monocyte
conditioned medium (MCM). Immature DCs express mRNA for CXCR4, CCR3 and CCR5. The
receptors are expressed on the cell surface, as assessed with monoclonal
antibodies, and are functional (with the exception of CCR3) as assessed by CA++
mobilization in response to specific chemokines. Further differentiation and
maturation of DC in MCM causes a downregulation of expression and function of the
beta-chemokine receptors, while CXCR4 still remains, and signals a calcium flux
on mature DCs. We argue that the downregulation of beta-chemokine receptors
during maturation helps to stop DC movement after T cells have been identified in
lymphoid organs or at sites of delayed-type hypersensitivity.
PMID- 9561369
TI - Comparative analysis of dendritic cells derived from blood monocytes or CD34+
hematopoietic progenitor cells.
AB - In human tissues different populations of dendritic cells (DC) emerge from
hematopoietic progenitor cells (HPC) in the bone marrow, with the intermediate
steps of differentiation not being completely understood. In vitro, DC can be
directly obtained from HPC or from blood monocytes (MO) cultured in the presence
of GM-CSF and additional cytokines. We compared the antigenic profile of DC
derived from either MO or HPC and studied their capacity to stimulate naive
lymphocytes (LY) in the allogeneic mixed lymphocyte reaction. Both types of DC
expressed high levels of CD1a, MHC class II, CD80, CD86 and CD40 and were potent
stimulators of LY proliferation. DC of HPC origin, though, induced a stronger
mixed lymphocyte reaction than MO-derived DC and showed a slightly higher average
expression of costimulatory antigens. Low-level expression of CD14 did not
negatively correlate with DC function on DC stimulated with lipopolysaccharide
and was even slightly higher expressed on DC differentiating from HPC than on DC
from CD14+ MO.
PMID- 9561370
TI - Human dendritic cells express functional interleukin-7.
AB - Interleukin-7 (IL-7) supports the proliferation of mature T lymphocytes, however,
the cellular source of IL-7 for T lymphocyte activation has not been well
established. We therefore investigated whether human peripheral blood dendritic
cells (DC) produce IL-7 as a contribution towards T lymphocyte activation. Human
CMRF-44+/CD14-/CD19- low density DC, purified after overnight tissue culture,
contained IL-7 transcripts, detected by direct cell reverse transcription
polymerase chain reaction. Intracytoplasmic staining confirmed IL-7 protein in at
least a subpopulation of cultured low density DC. In contrast, resting/immature
DC, isolated directly by immunodepletion of lineage marker positive cells,
contained no IL-7 mRNA. Thus, the expression of IL-7 by DC follows the pattern
described previously for CD80, CD86 and CD40. However, tissue culture of purified
resting/immature DC, in contrast to CD80, CD86 and CD40, failed to induce IL-7
transcripts. The functional importance of DC IL-7 expression was demonstrated in
an allogeneic mixed leukocyte reaction (MLR). Neutralising mAb to IL-7
significantly inhibited T lymphocyte proliferation when low DC numbers were used,
but at higher stimulator numbers, anti-IL-7 mAb failed to inhibit an allogeneic
MLR. This suggests, that when DC are in excess, other co-stimulatory pathways can
compensate for the lack of IL-7. Addition of IL-7 to a MLR caused a significant
increase in the proliferative response stimulated by monocytes and B lymphocytes
but not by DC. These data support the concept of an initial phase of antigen
uptake by DC followed by the optimisation of DC co-stimulatory potential. The co
stimulatory repertoire expressed, including IL-7, may be regulated by exogenous
stimuli, thereby ensuring DC flexibility in mounting a response appropriate to
the environmental changes.
PMID- 9561371
TI - Specific autologous anti-melanoma T cell response in vitro using monocyte-derived
dendritic cells.
AB - Dendritic cells (DC) are antigen-presenting cells initiating primary and
secondary immune responses. Since malignant tumors are able to escape immunologic
control, DC might be prime candidates to activate the immune system against tumor
cells. In an autologous system, a dynamic interaction among monocyte-derived DC
(MoDC), T lymphocytes, and tumor cells obtained from melanoma patients could be
noted. MoDC were generated from blood monocytes in the presence of GM-CSF, IL-4,
and IFN-gamma. T cells were isolated either from peripheral blood or from lymph
nodes. Melanoma cells were harvested from surgically removed tumor metastases.
They were then gamma-irradiated and co-cultured with autologous MoDC and T
lymphocytes. After 5 days, the lymphocytes showed a high proliferative activity
and the majority of them were CD8-positive. In five cases tested, they revealed a
high cytotoxic activity resulting in apoptosis of tumor cells. These findings
suggest that MoDC are capable of initiating an effective specific anti-tumor
response in a strictly autologous mixed lymphocyte tumor culture (MLTC), even
though tumor-specific antigens had not been individually defined. Therefore (I)
whole melanoma cells can serve as a source of antigen, (II) monocyte-derived
dendritic cells may process and present melanoma-specific antigens resulting in a
strong lymphocyte proliferation, (III) the majority of responding T lymphocytes
are CD8-positive, and (IV) an acquired cytotoxic response eventually leads to
apoptosis of the melanoma cells. The reaction demonstrated here permits to in
vitro and quantitatively monitoring the effect of T cell directed immunotherapies
such as the adoptive immunotherapy of tumors.
PMID- 9561372
TI - Focussing human B cell specificity by immunoselection via antigen-presenting
cells in vitro.
AB - We present a protocol for in vitro immunization of B cells using monocyte-derived
accessory cells (MoAC). MoAC are developed from human peripheral blood monocytes
in culture and represent functionally competent inducers of antigen-specific
immune responses. Using MoAC, we attempted to immunoselect TT-specific
lymphocytes by rosetting. Adherent human MoAC were pulsed with tetanus toxoid
(TT) and allowed to form clusters with autologous lymphocytes, followed by
removal of non-adherent cells. After one week of culture, a specific anti-TT
antibody response emerged on a low background of unspecific Ig. In comparison,
cultures which had not been selected for adherent cells produced a high
polyclonal background. Our results demonstrate that from peripheral blood cells,
previously not a favourable source for in vitro immunization, in a majority of
tests antigen-specific B cells could efficiently be immunoselected via adherence
to autologous antigen-presenting cells, leading to a high-titre in vitro
immunization.
PMID- 9561373
TI - The distinctive features of influenza virus infection of dendritic cells.
AB - CD8+ cytolytic T lymphocytes (CTLs) are considered to be critical mediators for
resistance to influenza virus infection. We have previously demonstrated that
dendritic cells are potent antigen presenting cells in the development of anti
influenza CTLs. Here we identify distinctive features of the interaction of
influenza virus with dendritic cells. Exposure of dendritic cells to influenza
virus at MOIs of 2-4:1 leads to > 90% infection, as manifested by the expression
of the viral proteins HA and NS1. The infection is non-toxic as viral protein
expression is sustained for > 2 days with retention of viability, but little
infectious virus is produced. Substantial induction of the anti-viral cytokine
IFN-alpha also occurs. Influenza infection of macrophages also results in viral
protein expression in a majority of cells, and synthesis of IFN-alpha. In
contrast to dendritic cells, macrophages display evidence of apoptosis within 10
12 hours, and the majority of cells die within 24-36 hours. During this interval
macrophages synthesize > 10-fold higher levels of virus than dendritic cells.
Infected dendritic cells but not macrophages, can induce substantial CTL
responses from purified blood CD8+ T cells in the absence of exogenous cytokines
such as IL-2. Low levels of infection (MOIs of 0.02) are sufficient to generate
potent CTL responses. Influenza virus expressing non-cleaved HA does not elicit
CTLs indicating that virus must access the cytoplasm of dendritic cells to
utilize traditional class I processing pathways. These observations indicate that
DCs are distinct in their handling of influenza virus and for the induction of
anti-viral immunity.
PMID- 9561375
TI - Epidermal Langerhans cell development and differentiation.
AB - Epidermal Langerhans cells (LC) play a critical role in host defense. Still we
know rather little about the development and functional specialization of these
bone marrow-derived dendritic cells (DC) located in the most peripheral
ectodermal tissue of the mammalian organism. How LC develop from their primitive
progenitors in bone marrow and to what extent LC are related in their development
to other lineages of the hemopoietic system is still under debate. There are
currently 3 major areas of debate: 1) which are the signals required for LC
development and differentiation to occur, 2) what are the (molecular)
characteristics of the intermediate stages of LC differentiation, and 3) how are
LC related in their development and/or function to other cells of the hemopoietic
system? A better understanding of LC development and answers to these questions
can be expected from recently developed technologies which allow the in vitro
generation of DC with the typical molecular, morphological and functional
features of LC from purified CD34+ progenitor cells under defined serum-free
culture conditions. TGF-beta 1 was found to be an absolute requirement for in
vitro LC development under serum-free conditions upon stimulation with the
classical DC growth and differentiation factors GM-CSF, TNF-alpha and SCF. The
recently identified cytokine FLT3 ligand further dramatically enhanced in vitro
LC development and even allowed efficient in vitro generation of LC colonies from
serum-free single cell cultures of CD34+ hemopoietic progenitor cells.
PMID- 9561374
TI - Expression of maturation-/migration-related molecules on human dendritic cells
from blood and skin.
AB - Progress in dendritic cell research has been overwhelming in the past few years.
This was made possible by the recent development of simple methods to generate
large numbers of dendritic cells. These methods use as starting populations for
culture either CD34+ progenitor cells from cord blood or bone marrow, or
monocytes from peripheral blood. The latter approach is critically dependent on
the combination of GM-CSF and interleukin 4. Such "priming cultures" yield
populations of immature dendritic cells (CD83-/CD86 +/- /CD115+/antigen uptake
high/antigen processing high/T cell sensitization low). In order to generate
mature dendritic cells a subsequent "differentiation culture" has to be added
whereby monocyte-conditioned medium appears to be the optimal stimulus for
maturation. This results in terminally mature dendritic cells (CD83+/CD86++/CD115
/antigen uptake low/antigen processing low/T cell sensitization high). We
investigated the expression of some molecules involved in maturation and
migration on human monocyte-derived dendritic cells from blood in comparison with
dermal dendritic cells and epidermal Langerhans cells. We present a method to
highly enrich epidermal Langerhans cells. Survival of purified Langerhans cells
in culture is dependent on the presence of GM-CSF and TNF-alpha. During
maturation a substantial part of the Langerhans cells loses expression of the
cutaneous lymphocyte antigen (CLA); mature dendritic cells from the dermis are
completely devoid of CLA. Similarly, CLA as well as CD15s (Sialyl Lewis x) and
CD31 (PECAM-1) that can be readily detected on immature monocyte-derived
dendritic cells are down-regulated upon maturation. CD68 expression is very low
in cutaneous dendritic cells; in monocyte-derived dendritic cells this molecule
is abundantly present. Subsets of monocyte-derived dendritic cells express E
cadherin; CD87 (urokinase plasminogen activator receptor) is weakly expressed on
both immature and mature monocyte-derived dendritic cells. Taken together, these
data suggest that the phenotype of monocyte-derived dendritic cells (E-cadherin
low to negative, CD68++) is not indicative for a cutaneous destiny. Furthermore,
the downregulation upon maturation of molecules involved in migration through
vessel walls (CD31, CLA, CD15s) indicates that the entry of mature dendritic
cells into lymphatic vessels may not be as rigidly regulated by adhesion
molecules as the process of extravasation from blood vessels.
PMID- 9561377
TI - Positive blood cultures for coagulase-negative staphylococci in neonates: does
highly selective vancomycin usage affect outcome?
AB - The implication of highly-selective vancomycin usage on the outcome for infants
with positive blood cultures for coagulase-negative staphylococci (CONS) was
assessed retrospectively. The analysis was performed on partly prospective
collected data from infants under 3 months of age with a least one CONS-positive
blood culture in the neonatal intensive care unit at the Soroka University
Medical Center between 1990 and 1996. During the study period, 239 episodes of
CONS-positive blood cultures were identified from among 64,226 live births (3.7
per 1,000). Vancomycin was administered in 22 (9%) episodes, in all cases only
after identification of the bacteria. The remaining 217 episodes were managed
either without antibiotics or with continuation or initiation of empiric
antibiotic therapy (usually ceftazidime +/- ampicillin) for suspected sepsis.
Severity of the initial illness, subsequent morbidity and mortality were low
regardless of the treatment administered. Only a single case of a blood-borne
vancomycin resistant gram-positive organism was observed during the study period.
The approach to CONS-positive blood cultures in neonates used here was associated
with low morbidity and mortality. These findings support a policy of highly
selective vancomycin usage in an era of emerging vancomycin resistance.
PMID- 9561376
TI - The significance of endotoxin release in experimental and clinical sepsis in
surgical patients--evidence for antibiotic-induced endotoxin release?
AB - Sepsis and peritonitis remain a serious challenge for surgical patients, despite
improvement in surgical therapy and intensive care and the introduction of new
powerful antibiotics. Recent in vitro studies revealed the potential of certain
antibiotics, e.g. penicillin-binding protein (PBP) 3-specific antibiotics, to
cause antibiotic-induced endotoxin release. Other types of antibiotics, e.g., PBP
2-specific antibiotics, were associated with no or less endotoxin release.
Further in vitro experiments and investigations in animals support the hypothesis
of antibiotic-induced endotoxin release, but there is little clinical evidence.
The clinical significance of endotoxin is subject of open dispute with many pro's
and contra's. Endotoxin, although an important trigger, may not be the only
factor to induce cytokine release, e.g., peptidoglycans were able to stimulate
cells to release cytokines. Gram-positive pathogens have gained more importance
in clinical sepsis and may not be sufficiently reflected in current clinical
studies. The hypothesis that neutralization of endotoxin and pro-inflammatory
cytokines is beneficial in sepsis was seriously challenged by the results of
recent clinical and experimental studies. The better understanding of mechanisms
in endotoxin-induced cell activation and cell, cell-receptor and soluble receptor
interactions led to new treatment options. Recent reports on the complex
pathogenesis of peritonitis and the detection of pathogen-related factors with
intraperitoneal immune response may have implications on clinical studies
investigating the potential of new compounds and the effect of antibiotics on
endotoxin release. However, only few reports are available on the clinical
significance of antibiotic-induced endotoxin release, and association of
endotoxin release with pathogens, mortality or alteration of physiological
parameters were not observed. With regard to the particulars of these studies,
e.g., a small study population or low mortality rate, mortality may not be an
ideal outcome parameter for these studies. There is clinical evidence for
antibiotic-induced endotoxin release. However, the need for well-designed and
performed studies using newly developed monitoring devices in intensive care
therapy is obvious.
PMID- 9561378
TI - Mediterranean leishmaniasis in HIV-infected patients: epidemiological, clinical,
and diagnostic features of 22 cases.
AB - Twenty-two Italian HIV-infected patients developed leishmaniasis, clinically
manifested as visceral (13 cases), cutaneous (2 cases) and disseminated disease
(7 cases). Twenty were males and two females (mean age: 32.8 years) with a mean
CD4+ cell count of 46.8/microliter at diagnosis; risk factors were intravenous
drug use (17 patients) and sexual behaviour (two bisexual, two homosexual, one
heterosexual). All but one patient lived or travelled in hypoendemic Italian
regions and other Mediterranean countries. Apart from the two patients with
cutaneous leishmaniasis, the clinico-pathological and biological spectrum of the
infection was often atypical, especially in patients with disseminated disease.
The diagnosis was routinely made by direct recovery of parasites in biological
specimens, mainly in bone marrow aspirate, whereas serology was negative or
borderline in most of the patients. Among 17 in vitro isolates, Leishmania
infantum was the only species involved with previously undescribed isoenzyme
patterns in two cases. Treatment with antimonials and other drugs showed only
temporary clinical improvement in some patients. Relapses were the rule.
Leishmaniasis confirms itself as an opportunistic infection in HIV-positive
persons. Secondary chemoprophylaxis should be considered in cases of relapsing
disease.
PMID- 9561379
TI - Correlation between plasma levels of cytokines and HIV-1 RNA copy number in HIV
infected patients.
AB - The plasma levels of HIV-1 RNA, tumor necrosis factor alpha (TNF-alpha), soluble
receptors type II of TNF-alpha (sTNF-alpha RII), soluble receptors of interleukin
4 (sR IL-4), interleukin-6 (IL-6), soluble receptors of interleukin-6 (sR IL-6),
granulocyte macrophage colony stimulating factor (GM-CSF), soluble receptors of
GM-CSF (sR GM-CSF), RANTES, MIP-1 alpha and MIP-1 beta were measured in 80 HIV
infected patients. All patients had not been treated previously with
antiretroviral drugs and did not present a recent history of opportunistic
infection. A statistically significant correlation was found between HIV-1 RNA
and TNF-alpha (p = 0.005) or sTNF-alpha RII levels (p < 0.001). RANTES and MIP-1
alpha levels did not correlate with HIV-1 RNA. MIP-1 beta levels were correlated
with plasma RNA titers in patients with CD4+ T cells < 200 x 10(6)/l (p = 0.03).
MIP-1 alpha and sR IL-4 levels were significantly different according to the CD4+
T cell range (p = 0.003 and p = 0.0002, respectively). GM-CSF and sR GM-CSF were
undetectable in each case. These data confirm that HIV-1 replication in the
plasma is correlated with TNF-alpha levels, but do not show a clear correlation
with levels of the chemokines studied.
PMID- 9561380
TI - Immune status against diphtheria among immigrants from the former USSR who
arrived in Israel during 1990-1991.
AB - Large outbreaks of diphtheria occurred recently in the former USSR. Between 1989
and 1994, a total of about 600,000 Soviet immigrants arrived in Israel. The
immune status against diphtheria in a sample of 992 men aged 17-49 and 195 women
aged 17-19, who arrived in Israel during 1990-91, was studied in order to
evaluate the need for vaccination. Participants completed a self-administered
questionnaire and diphtheria antitoxin antibody levels were measured by means of
ELISA. At age 17-19, the prevalence of antitoxin antibody levels below the
protective level of 0.01 IU/ml was 4.8% in the men and 2.1% in the women. Among
the men, the percentage lacking protection declined from 4.8% at age 17-19 years
to 1.6% at age 20-24, and increased to 18.2% at age 35-49. In the oldest group,
the prevalence of those lacking protection was considerably higher than for the
general Israeli population. In the multivariate analysis, age, mother's education
and republic of origin were significantly associated with the absence of
protection. Immigrants from the former USSR appear to be more susceptible to
diphtheria, thus increasing the possibility of clinical disease, and it is
recommended that they receive booster doses of diphtheria toxoid.
PMID- 9561381
TI - Imbalance in cytokine production by whole blood related to presence of
cytopathogenic HIV-1 strains in HIV-1-infected patients.
AB - The possible association between the emergence of cytopathogenic HIV-1 variants
and disturbance of the cytokine production in the course of HIV-1 infection was
studied in 18 infected patients. The cytopathogenicity of the isolates was
studied in a microassay based on the use of HIV-1-infectible Hela-CD4 cells
carrying the bacterial LacZ gene under the control of the HIV-LTR (P4 cells). In
addition, the production of cytokines by heparinized whole blood (HWB) obtained
the same day from HIV-1(+) patients was measured. TNF-alpha was determined in a
one-step procedure combining HWB culture in the presence of LPS+PHA for 24 h and
detection of cytokines in the same wells. In separate experiments HWB was
cultured in the presence of LPS+PHA for 48 h, then the supernatants were
collected and stored until assayed by ELISa for IFN-gamma and IL-4. Higher TNF
alpha levels were found in activated HWB of patients with cytopathic strains (n =
9) than in patients with non-cytopathic strains (n = 9, p = 0.02) assessed with
P4 cells. A defective production of type 1 cytokine (IFN-gamma) and no increased
secretion of type 2 cytokines (IL-4) was observed in patients with cytopathic
strains. IFN-gamma/IL-4 ratios were significantly lower in patients with
cytopathic strains (n = 9) than in other patients (n = 9, p = 0.009). The results
show that the disarray of cytokine production, as assessed with whole blood
culture, is associated with the cytopathogenicity of HIV-1 isolates in HIV-1
infected individuals.
PMID- 9561382
TI - Hepatitis G virus coinfection in chronic hepatitis B and C patients in Poland.
AB - This study evaluated the epidemiology and impact of hepatitis G virus (HGV)
infection in patients with chronic hepatitis B and C. Serum samples were obtained
from 128 consecutive untreated patients with chronic hepatitis B (72 cases) or C
(56 cases). The presence of HGV RNA was determined by PCR amplification of the
5'untranslated region; the sensitivity of the assays was ten template copy
equivalents. The prevalence of HGV RNA in hepatitis B and C was found to be 25%
and 34%, respectively. HGV-positive and HGV-negative patients did not differ with
respect to risk factors for infection, age, sex, or alanine aminotransferase
activity. Similarly, there was no difference in the severity of liver disease, as
assessed with HAI score. In conclusion, we found a very high prevalence of HGV
infection in chronic hepatitis B and C patients in Poland. Nevertheless, no
evidence was found that HGV coinfection has any impact on the severity of the
underlying disease.
PMID- 9561383
TI - IgA1 protease production by bacteria colonizing the upper respiratory tract.
AB - Thirty-eight clinical isolates of Haemophilus influenzae and ten clinical
isolates of Streptococcus pneumoniae were examined for IgA1 protease production.
A suspension of surface material of each individual strain was incubated with
human secretory IgA; IgA1 cleavage products were detected by SDS-PAGE and
immunoblotting. The high incidence of IgA1 protease-positive strains (68.4% of
the examined H. influenzae and 100% of the examined S. pneumoniae strains)
confirms that IgA1 protease activity is a frequent characteristic of these two
species. Yet the presence of this enzyme is, if at all, only a minor decisive
factor for the induction of symptomatic infections of the upper respiratory tract
by IgA1 protease-positive bacteria.
PMID- 9561385
TI - Experimental genital tract infection with Chlamydia psittaci (GPIC agent) in male
rats.
AB - The course of experimental chlamydial infection of the male genital tract was
studied. Inoculation of the Chlamydia psittaci agent of guinea pig inclusion
conjunctivitis (GPIC agent) into the vas deferens of rats resulted in chlamydial
infection of the epididymis, testis and the prostate gland. The inflammatory
response was most prominent at 14 days after infection. Chlamydiae were recovered
from the epididymides and the prostate glands for up to 90 and 60 days post
inoculation, respectively. Histopathological changes associated with chlamydial
infection of the epididymis or prostate gland were characterized by intratubular
and interstitial purulent inflammation. Chlamydia-specific IgM- and IgG
antibodies were found in sera of nearly all infected animals. Results of this
study indicate that this animal model may be useful to study the pathogenesis,
immune responses and sequelae of chlamydial infections of the male genital tract.
PMID- 9561386
TI - Brucella-infected ovarian dermoid cyst causing initial treatment failure in a
patient with acute brucellosis.
AB - A 37-year-old woman was diagnosed with acute brucellosis. Despite appropriate
antimicrobial therapy, high fever persisted. A contrast enhanced CT scan of the
abdomen and pelvis revealed a left ovarian dermoid cyst. On the first
postoperative day after left ovariectomy and right ovarian cystectomy were
performed, the patient defervesced abruptly and continued to be completely
afebrile. Cultures from bone marrow and dermoid cyst grew Brucella melitensis.
The observation of a Brucella-infected ovarian dermoid cyst, which has not been
previously reported, illustrates the importance of localized brucellosis as a
cause of persistent infection despite appropriate antimicrobial therapy.
PMID- 9561387
TI - Hepatitis A and B in persons with learning disabilities living in institutions:
the need for vaccination.
PMID- 9561384
TI - In vitro effect of cefodizime, imipenem/cilastatin and co-trimoxazole on
dexamethasone and cyclosporin A depressed phagocytosis.
AB - Phagocytosis is an important part of the host defense against infection.
Antibiotics can influence phagocytic function. In the present study, leukocyte
metabolic response to phagocytic challenge by latex was assessed in relation to
in vitro addition of cotrimoxazole, imipenem/cilastatin, cefodizime,
dexamethasone (DXM), and/or cyclosporin A (CsA). Using latex particles as
phagocytic challenge, glucose-1-14C utilization and 14CO2 production were
measured by liquid scintillation counting. The phagocytic response was impaired
by in vitro addition of DXM or CsA and this setup was used as an experimental
model of immunodepression. The addition of co-trimoxazole to control samples
(without DXM or CsA) depressed the response to latex challenge, whereas imipenem
and cefodizime had a neutral effect. In the presence of DXM, co-trimoxazole
induced a further decrease. The depressive effect of DXM was partially
neutralized in the presence of cefodizime. With CsA depression, co-trimoxazole
also induced a further decrease, imipenem had a neutral effect, while cefodizime
partially restored the CsA suppressed reaction. Co-trimoxazole depressed the
phagocytic response, imipenem had a neutral effect, whereas cefodizime restored
the experimentally induced immunosuppression.
PMID- 9561388
TI - Prophylaxis of Pneumocystis carinii pneumonia in HIV-infected children one to
five years old: a multicenter surveillance study in paediatric hospitals in
Germany.
PMID- 9561389
TI - Single-dose cefodizime as infection prophylaxis in abdominal surgery: a
prospective multicenter study.
AB - This prospective pilot study was performed to evaluate the efficacy, safety and
tolerability of a single dose of cefodizime as infection prophylaxis in patients
undergoing major abdominal surgery. One hundred forty-nine patients received 2g
cefodizime, a third-generation cephalosporin, 30 min before abdominal surgery.
The mean operation time was 116 +/- 66 min. Eighteen patients received
metronidazole additionally. In 8/149 patients (5.4%) the final outcome was
considered to be a treatment failure. 94.6% of the patients had no signs of
infection. The long half-life of cefodizime allows a single-dose perioperative
prophylaxis even in abdominal surgery lasting 3 to 4 h. Cefodizime can be
regarded as a safe antibiotic prophylaxis with few side effects.
PMID- 9561390
TI - Volatile organic compounds from the indoor mould Trichoderma viride cause
histamine release from human bronchoalveolar cells.
PMID- 9561391
TI - A regulatory role for carbon monoxide in mast cell function.
PMID- 9561392
TI - Sick building syndrome: association of symptoms with serum IgE specific to fungi.
PMID- 9561393
TI - Effects of permethrin on human basophils and lymphocytes in vitro.
PMID- 9561394
TI - Current-voltage relationship in isolated mast cells during histamine liberation
and membrane fluidisation.
PMID- 9561395
TI - Ambroxol inhibits histamine release from human adenoidal mast cells.
PMID- 9561396
TI - Effects of atrial natriuretic peptide, brain natriuretic peptide and urodilatin
on histamine induced bronchoconstriction in the conscious guinea pig.
PMID- 9561397
TI - Effects of prostanoid receptor agonists on immunologically-activated rat
peritoneal mast cells.
PMID- 9561398
TI - Effects of non-steroidal anti-inflammatory drugs and cyclooxygenase-2 specific
inhibitors on mediator release from rat peritoneal mast cells.
PMID- 9561399
TI - Role of phospholipase A2 and split lipid products in histamine release from mast
cells.
PMID- 9561400
TI - Tricyclic antidepressants change plasma histamine kinetics after its secretion
induced by compound 48/80 in the rat.
PMID- 9561401
TI - Imipramine inhibits histamine and serotonin secretion induced by various
secretagogues.
PMID- 9561402
TI - Motor behavioural function for histamine-dopamine interaction in brain.
PMID- 9561404
TI - Histamine-induced synthesis and secretion of nerve growth factor from astrocytes.
PMID- 9561403
TI - Increase of acetylcholine release from cortex of freely moving rats by
administration of histamine into the nucleus basalis magnocellularis.
PMID- 9561405
TI - Towards the optimal antihistamine: studies with ebastine.
PMID- 9561406
TI - Mechanistic hypothesis concerning the unexpected suitable and undesirable effects
of H1-antihistamines.
PMID- 9561408
TI - Tiotidine, a classical H2-antagonist, presents characteristics of an inverse
agonist in U937 cell line.
PMID- 9561407
TI - Histamine receptors in human epithelial cells--characterization of the receptor G
protein-effector system.
PMID- 9561409
TI - Histamine synthesis by liver macrophages and its role in regeneration of the
injured liver.
PMID- 9561410
TI - Benzamidine-sensitive proteinase in activated cleavage of recombinant 74 kDa
histidine decarboxylase into its 53 kDa form in mastocytoma cells.
PMID- 9561411
TI - Induction of histidine decarboxylase in type 2 T helper lymphocytes treated with
anti-CD3 antibody.
PMID- 9561412
TI - Histamine receptors signalling in epidermal tumor cell lines with H-ras gene
alterations.
PMID- 9561413
TI - Day-to-day variation in urinary excretion of the histamine metabolite
methylimidazoleacetic acid.
PMID- 9561414
TI - The different effects of Helicobacter pylori strains on basal and histamine
stimulated acid and pepsin production: an in vitro study.
PMID- 9561415
TI - The relationship between mucosal histamine and fibrinolytic activity in duodenal
ulcer disease.
PMID- 9561416
TI - Identity of the diamine oxidase proteins in porcine kidney and intestine.
PMID- 9561417
TI - Analysis of tissue and subcellular localization of mammalian diamine oxidase by
confocal laser scanning fluorescence microscopy.
PMID- 9561418
TI - Expression and cellular localisation of diamine oxidase in the gastrointestinal
tract of pigs.
PMID- 9561419
TI - Evidence for mast cell activation in collagenous colitis.
PMID- 9561420
TI - Clinic modelling randomised trials (CMRT's) in animals as a new intermediate
between biological experiments and randomised clinical trials: application to
antihistamine prophylaxis in anaesthesia and surgery.
PMID- 9561421
TI - Histamine release during rapid vancomycin administration.
PMID- 9561422
TI - Causality-based diagnosis of histamine-related cardiorespiratory disturbances in
surgical patients.
PMID- 9561424
TI - Secular trends in the incidence of anorexia nervosa: integrative review of
population-based studies.
AB - OBJECTIVE AND METHOD: Aggregating across retrospective cohort samples, this
integrative review synthesizes the findings of 12 cumulative incidence studies
(45 hypotheses) on anorexia nervosa secular trends. RESULTS: (1) The female/male
anorexia incidence rate ratio was estimated to be 8.20, 18.46 versus 2.25 cases
per 100,000 per year, p < .05; (2) female teenagers experienced anorexia at a
rate fivefold greater than other women, 50.82 versus 10.37 incident cases per
100,000 per year, p < .001; (3) no secular trend or change in the incidence of
anorexia was observed among teenagers, while a near threefold increase was
observed over the past 40 years among women in their 20s and 30s, 6.28 (1950
1964) versus 17.70 (1980-1992) cases per 100,000 per year, p < .05; and (4) the
two cohort characteristics of age, and the age by year interaction accounted for
nearly two thirds of the variability among anorexia incidence estimates, R2 =
.614, F(2,27) = 21.49, p < .001. After the two factors of age and the Age x Year
interaction were accounted for, none of the other study characteristics,
including study year(s), were found to be significantly associated with anorexia
incidence, that is, a main effect of time was not observed. DISCUSSION: The
integrative evidence across the population-based epidemiologic studies covering
40 years in this field suggests strongly that, overall, the incidence of anorexia
nervosa, particularly among those very young women at greatest risk of
experiencing it, has not increased significantly. However, the risk does seem to
have increased significantly among women in their 20s and 30s.
PMID- 9561423
TI - Can clinically relevant histamine release be accurately diagnosed in
anaesthetised patients without plasma histamine measurements? Randomised study
with nested sampling aimed to change paradigms.
PMID- 9561425
TI - Food cravers: characteristics of those w